PMID- 26000459 TI - Performance assessment of two whole-lake acoustic positional telemetry systems- is reality mining of free-ranging aquatic animals technologically possible? AB - Acoustic positional telemetry systems (APTs) represent a novel approach to study the behaviour of free ranging aquatic animals in the wild at unprecedented detail. System manufactures promise remarkably high temporal and spatial resolution. However, the performance of APTs has rarely been rigorously tested at the level of entire ecosystems. Moreover, the effect of habitat structure on system performance has only been poorly documented. Two APTs were deployed to cover two small lakes and a series of standardized stationary tests were conducted to assess system performance. Furthermore, a number of tow tests were conducted to simulate moving fish. Based on these data, we quantified system performance in terms of data yield, accuracy and precision as a function of structural complexity in relation to vegetation. Mean data yield of the two systems was 40% (Lake1) and 60% (Lake2). Average system accuracy (acc) and precision (prec) were Lake1: acc = 3.1 m, prec = 1.1 m; Lake2: acc = 1.0 m, prec = 0.2 m. System performance was negatively affected by structural complexity, i.e., open water habitats yielded far better performance than structurally complex vegetated habitats. Post-processing greatly improved data quality, and sub-meter accuracy and precision were, on average, regularly achieved in Lake2 but remained the exception in the larger and structurally more complex Lake1. Moving transmitters were tracked well by both systems. Whereas overestimation of moved distance is inevitable for stationary transmitters due to accumulation of small tracking errors, moving transmitters can result in both over- and underestimation of distances depending on circumstances. Both deployed APTs were capable of providing high resolution positional data at the scale of entire lakes and are suitable systems to mine the reality of free ranging fish in their natural environment. This opens important opportunities to advance several fields of study such as movement ecology and animal social networks in the wild. It is recommended that thorough performance tests are conducted in any study utilizing APTs. The APTs tested here appear best suited for studies in structurally simple ecosystems or for studying pelagic species. In such situations, the data quality provided by the APTs is exceptionally high. PMID- 26000460 TI - Estimating physical activity energy expenditure with the Kinect Sensor in an exergaming environment. AB - Active video games that require physical exertion during game play have been shown to confer health benefits. Typically, energy expended during game play is measured using devices attached to players, such as accelerometers, or portable gas analyzers. Since 2010, active video gaming technology incorporates marker less motion capture devices to simulate human movement into game play. Using the Kinect Sensor and Microsoft SDK this research aimed to estimate the mechanical work performed by the human body and estimate subsequent metabolic energy using predictive algorithmic models. Nineteen University students participated in a repeated measures experiment performing four fundamental movements (arm swings, standing jumps, body-weight squats, and jumping jacks). Metabolic energy was captured using a Cortex Metamax 3B automated gas analysis system with mechanical movement captured by the combined motion data from two Kinect cameras. Estimations of the body segment properties, such as segment mass, length, centre of mass position, and radius of gyration, were calculated from the Zatsiorsky Seluyanov's equations of de Leva, with adjustment made for posture cost. GPML toolbox implementation of the Gaussian Process Regression, a locally weighted k Nearest Neighbour Regression, and a linear regression technique were evaluated for their performance on predicting the metabolic cost from new feature vectors. The experimental results show that Gaussian Process Regression outperformed the other two techniques by a small margin. This study demonstrated that physical activity energy expenditure during exercise, using the Kinect camera as a motion capture system, can be estimated from segmental mechanical work. Estimates for high-energy activities, such as standing jumps and jumping jacks, can be made accurately, but for low-energy activities, such as squatting, the posture of static poses should be considered as a contributing factor. When translated into the active video gaming environment, the results could be incorporated into game play to more accurately control the energy expenditure requirements. PMID- 26000461 TI - Fabrication of PMMA nanofluidic electrochemical chips with integrated microelectrodes. AB - A novel method based on plasma etching was proposed for monolithically integrating planar nanochannels and microelectrodes on a poly (methyl methacrylate) (PMMA) plate, and complete PMMA nanofluidic electrochemical chips with integrated microelectrodes were constructed by bonding with another PMMA plate containing microchannels. The fabrication sequences of nanochannels and microelectrodes were optimized. The oxygen plasma etching rate of PMMA nanochannels was studied, and the average rate was 15 nm/min under optimal conditions. An UV-ozone assisted thermal bonding method was developed to realize a low-temperature chip bonding, and the variations in width and depth of nanochannels before and after bonding were 2% and 5%, respectively. As a demonstration, a nanoparticle crystal (NPC)-based nanofluidic biosensor with integrated Ag microelectrodes was designed and fabricated. Sub-microchannel arrays with a depth of 400 nm and a width of 30 MUm on the biosensor functioned as filters, and trapped 540 nm silica nanoparticles modified with streptavidin inside the connected microchannel to assemble the NPC. The interspaces in the NPC formed a three-dimensional nanochannel network with an equivalent diameter of 81 nm. By measuring the conductance across the NPC, a high quality nanofluidic sensing of biotin was achieved. The limit of detection was 1 aM, and the detection range was from 1 aM to 0.1 nM. PMID- 26000462 TI - Ultrasensitive detection of uranyl by graphene oxide-based background reduction and RCDzyme-based enzyme strand recycling signal amplification. AB - We proposed a novel strategy which combines graphene oxide-based background reduction with RCDzyme-based enzyme strand recycling amplification for ultrahigh sensitive detection of uranyl. The RCDzyme is designed to contain a guanine (G) rich sequence that replaces the partial sequence in an uranyl-specific DNAzyme. This multifunctional probe can act as the target recognition element, DNAzyme and the primer of signal amplification. The presence of UO2(2+) can induce the cleavage of the substrate strands in RCDzyme. Then, each released enzyme strand can hybridize with another substrate strands to trigger many cycles of the cleavage by binding uranyl, leading to the formation of more G-quadruplexes by split guanine-rich oligonucleotide fragments. The resulting G-quadruplexes could bind to N-methyl-mesoporphyrin IX (NMM), causing an amplified detection signal for the target uranyl. Next, graphene oxide-based background reduction strategy was further employed for adsorbing free ssDNA and NMM, thereby providing a proximalis zero-background signal. The combination of RCDzyme signal amplification and proximalis zero-background signal remarkably improves the sensitivity of this method, achieving a dynamic range of two orders of magnitude and giving a detection limit down to 86 pM, which is much lower than those of related literature reports. These achievements might be helpful in the design of highly sensitive analytical platform for wide applications in environmental and biomedical fields. PMID- 26000463 TI - Portable optical aptasensor for rapid detection of mycotoxin with a reversible ligand-grafted biosensing surface. AB - As food safety is gaining prominence as a global issue, the demand for developing rapid, simple, on-site, accurate and low-cost biosensor technologies will continue to grow. This study demonstrates an evanescent wave optical aptasensor with a reversible ligand-grafted biosensing surface for rapid, sensitive and highly selective detection of ochratoxin A (OTA) in food. In this system, the OTA molecules were covalently immobilized onto the surface of an optical fiber using glutaraldehyde and ethylenediamine as space linkers. An integrated evanescent wave all-fiber (EWA) biosensing platform was developed for investigating the binding kinetics between the tethered ligand and free OTA-aptamer, the performance of the aptamer-based bioassay and the reversibility of biosensing surface. The affinity constant (Ka) of aptamer with tethered OTA was measured to be 2.2 * 10(8)M(-1) based on the EWA biosensing platform. With a competitive detection mode, the quantification of OTA over concentration ranges from 0.73 MUg L(-1) to 12.50 MUg L(-1) with a detection limit of 0.39 MUg L(-1). The performance of the aptasensor with other interfering mycotoxins and spiked real wheat samples shows high specificity and selectivity, good recovery, precision, and accuracy, indicating that it can be applied for on-site, inexpensive and easy to-use monitoring of OTA in real samples. Moreover, since the organic ligands are grafted onto the fiber surface, this strategy may avoid the potential disadvantages caused by immobilizing the nucleic acid biomolecules, such as weak restoration to the original DNA conformation after repeated uses. PMID- 26000465 TI - Successful percutaneous coronary intervention for multivessel stenosis complicated by a huge coronary artery fistula with the combined physiology and intracoronary anatomy techniques. PMID- 26000464 TI - Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. AB - BACKGROUND/OBJECTIVES: Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. METHODS: Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. RESULTS: We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (-14 to 15 mV at 23 degrees C vs -24 mV at 37 degrees C). The uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P < 0.05, n = 6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardial injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1alpha regulated miR-210, to H9C2 cardiomyocytes in vitro. CONCLUSIONS: Exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represents novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an "off the-shelf" therapy to rescue ischemic cardiomyocytes in conditions such as MIR. PMID- 26000466 TI - Topological surface states in nodal superconductors. AB - Topological superconductors have become a subject of intense research due to their potential use for technical applications in device fabrication and quantum information. Besides fully gapped superconductors, unconventional superconductors with point or line nodes in their order parameter can also exhibit nontrivial topological characteristics. This article reviews recent progress in the theoretical understanding of nodal topological superconductors, with a focus on Weyl and noncentrosymmetric superconductors and their protected surface states. Using selected examples, we review the bulk topological properties of these systems, study different types of topological surface states, and examine their unusual properties. Furthermore, we survey some candidate materials for topological superconductivity and discuss different experimental signatures of topological surface states. PMID- 26000467 TI - Pyrabactin regulates root hydraulic properties in maize seedlings by affecting PIP aquaporins in a phosphorylation-dependent manner. AB - Pyrabactin, an agonist of abscisic acid (ABA), has led to the isolation and characterization of pyrabactin resistance 1/pyrabactin resistance 1-like (PYR1/PYLs) ABA receptors in Arabidopsis, which has well explained ABA-mediated stomatal movement and stress-related gene expression. In addition to inducing stomatal closure and inhibiting transpiration, ABA can also enhance root hydraulic conductivity (Lpr), thus maintaining water balance under water deficiency-related stress, but its molecular mechanism remains unclear. In the present study, the root hydraulic properties of maize seedlings in response to pyrabactin were compared to those caused by ABA. Similar to ABA, lower concentration of pyrabactin induced a remarkable increase in Lpr as well as in the gene expression of the plasma membrane intrinsic protein (ZmPIP) aquaporin and in the ZmPIP2; 1/2; 2 protein abundance. The pyrabactin-induced enhancement of Lpr was abolished by H2O2 application, indicating that pyrabactin regulates Lpr by modulating ZmPIP at transcriptional, translational and post-translational (activity) level. Pyrabactin-mediated water transport and ZmPIP gene expression were phosphorylation-dependent, suggesting that ABA-PYR1-(PP2C)-protein kinase AQP signaling pathway may be involved in this process. As we know this is the first established ABA signaling transduction pathway that mediated water transport in roots. This observation further addressed the importance of PYR1/PYLs ABA receptor in regulating plant water use efficiency from the under ground level. Except inhibiting transpiration in leaves, our result introduces the exciting possibility of application ABA agonists for regulating roots water uptake in field, with a species- and dose dependent manner. PMID- 26000468 TI - Privileged Structures Meet Human T-Cell Leukemia Virus-1 (HTLV-1): C2-Symmetric 3,4-Disubstituted Pyrrolidines as Nonpeptidic HTLV-1 Protease Inhibitors. AB - 3,4-disubstituted pyrrolidines originally designed to inhibit the closely related HIV-1 protease were evaluated as privileged structures against HTLV-1 protease (HTLV-1 PR). The most potent inhibitor of this series exhibits two-digit nanomolar affinity and represents, to the best of our knowledge, the most potent nonpeptidic inhibitor of HTLV-1 PR described so far. The X-ray structures of two representatives bound to HTLV-1 PR were determined, and the structural basis of their affinity is discussed. PMID- 26000469 TI - MARTINI Coarse-Grained Models of Polyethylene and Polypropylene. AB - The understanding of the interaction of nanoplastics with living organisms is crucial both to assess the health hazards of degraded plastics and to design functional polymer nanoparticles with biomedical applications. In this paper, we develop two coarse-grained models of everyday use polymers, polyethylene (PE) and polypropylene (PP), aimed at the study of the interaction of hydrophobic plastics with lipid membranes. The models are compatible with the popular MARTINI force field for lipids, and they are developed using both structural and thermodynamic properties as targets in the parametrization. The models are then validated by showing their reliability at reproducing structural properties of the polymers, both linear and branched, in dilute conditions, in the melt, and in a PE-PP blend. PE and PP radius of gyration is correctly reproduced in all conditions, while PE-PP interactions in the blend are slightly overestimated. Partitioning of PP and PE oligomers in phosphatidylcholine membranes as obtained at CG level reproduces well atomistic data. PMID- 26000470 TI - Enantioselective Synthesis of beta-Arylamines via Chiral Phosphoric Acid Catalyzed Asymmetric Reductive Amination. AB - A new method for the synthesis of chiral beta-aryl amines via chiral phosphoric acid-catalyzed enantioselective reductive amination of benzyl methyl ketone derivatives with Hantzsch ester was developed. Various chiral beta-aryl amines were obtained in high yields and with good to high enantioselectivities. This transformation is applicable to gram-scale reactions, and the catalyst loading can be reduced to 1 mol % without sacrificing any catalytic efficacy. Furthermore, the resulting beta-aryl amine was successfully converted into a tetrahydroisoquinoline compound without any loss of enantioselectivity. PMID- 26000471 TI - A Li-Mg-N-H composite as H2 storage material: a case study with Mg(NH2)2-4LiH LiNH2. AB - A reversible hydrogen storage capacity of ~7 wt% at ~150 degrees C without releasing ammonia can be achieved using a mechanically activated three-component composite of Mg(NH2)2-4LiH-LiNH2. PMID- 26000472 TI - A CRISPR Connection between Chromatin Topology and Genetic Disorders. AB - Structural variations are common in the human genome, but their contributions to human diseases have been hard to define. Lupianez et al. demonstrate that some structural variants can interrupt chromatin topology, resulting in ectopic enhancer-promoter interactions, altered spatiotemporal gene expression patterns, and developmental disorders. PMID- 26000473 TI - Treasure your exceptions: unusual domains in immune receptors reveal host virulence targets. AB - A mechanistic understanding of how plant pathogens modulate their hosts is critical for rationally engineered disease resistance in agricultural systems. Two new studies show that genomically paired plant immune receptors have incorporated decoy domains that structurally mimic pathogen virulence targets to monitor attempted host immunosuppression. PMID- 26000474 TI - Deciphering the tubulin code. AB - Enzymes of the tubulin tyrosine ligase-like (TTLL) family posttranslationally modify and thereby mark microtubules by glutamylation, generating specific recognition sites for microtubule-interacting proteins. Garnham et al. report the first structure of a TTLL protein alone and in complex with microtubules, elucidating their mechanism of action. PMID- 26000475 TI - Turning up the heat on membrane fluidity. AB - How do cells maintain the fluidity of cellular membrane in response to temperature fluctuation? In this issue of Cell, Ma et al. identify a regulatory circuit involving a heat-induced acyl-CoA dehydrogenase that controls the lipid saturation level and the fluidity of cellular membranes by transcriptionally regulating a lipid desaturase. PMID- 26000476 TI - A CRISPR View of Cleavage. AB - Seminal studies showed that CRISPR-Cas systems provide adaptive immunity in prokaryotes and promising gene-editing tools from bacteria to humans. Yet, reports diverged on whether some CRISPR systems naturally target DNA or RNA. Here, Samai and colleagues unify the studies, showing that a single type III CRISPR-Cas system cleaves both DNA and RNA targets, independently. PMID- 26000477 TI - Alike but Different: RAF Paralogs and Their Signaling Outputs. AB - RAF links RAS, one of the most potent human oncogenes, to its effector ERK and to proliferation. This role is evolutionarily conserved, but while simpler multicellular organisms express one RAF, mammals have three. This Minireview highlights common and divergent features of RAF paralogs, their signaling outputs, and roles in tumorigenesis. PMID- 26000478 TI - Using Genome-scale Models to Predict Biological Capabilities. AB - Constraint-based reconstruction and analysis (COBRA) methods at the genome scale have been under development since the first whole-genome sequences appeared in the mid-1990s. A few years ago, this approach began to demonstrate the ability to predict a range of cellular functions, including cellular growth capabilities on various substrates and the effect of gene knockouts at the genome scale. Thus, much interest has developed in understanding and applying these methods to areas such as metabolic engineering, antibiotic design, and organismal and enzyme evolution. This Primer will get you started. PMID- 26000479 TI - The mechanical world of bacteria. AB - In the wild, bacteria are predominantly associated with surfaces as opposed to existing as free-swimming, isolated organisms. They are thus subject to surface specific mechanics, including hydrodynamic forces, adhesive forces, the rheology of their surroundings, and transport rules that define their encounters with nutrients and signaling molecules. Here, we highlight the effects of mechanics on bacterial behaviors on surfaces at multiple length scales, from single bacteria to the development of multicellular bacterial communities such as biofilms. PMID- 26000480 TI - Treatment of obesity with celastrol. AB - Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity. PMID- 26000481 TI - In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. AB - Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV uptake can lead to transfer of functional mRNA and altered cellular behavior. However, similar in vivo experiments remain challenging because cells that take up EVs cannot be discriminated from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly identify tumor cells that take up EVs in vivo. We show that EVs released by malignant tumor cells are taken up by less malignant tumor cells located within the same and within distant tumors and that these EVs carry mRNAs involved in migration and metastasis. By intravital imaging, we show that the less malignant tumor cells that take up EVs display enhanced migratory behavior and metastatic capacity. We postulate that tumor cells locally and systemically share molecules carried by EVs in vivo and that this affects cellular behavior. PMID- 26000482 TI - Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. AB - Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation. PMID- 26000483 TI - A receptor pair with an integrated decoy converts pathogen disabling of transcription factors to immunity. AB - Microbial pathogens infect host cells by delivering virulence factors (effectors) that interfere with defenses. In plants, intracellular nucleotide-binding/leucine rich repeat receptors (NLRs) detect specific effector interference and trigger immunity by an unknown mechanism. The Arabidopsis-interacting NLR pair, RRS1-R with RPS4, confers resistance to different pathogens, including Ralstonia solanacearum bacteria expressing the acetyltransferase effector PopP2. We show that PopP2 directly acetylates a key lysine within an additional C-terminal WRKY transcription factor domain of RRS1-R that binds DNA. This disrupts RRS1-R DNA association and activates RPS4-dependent immunity. PopP2 uses the same lysine acetylation strategy to target multiple defense-promoting WRKY transcription factors, causing loss of WRKY-DNA binding and transactivating functions needed for defense gene expression and disease resistance. Thus, RRS1-R integrates an effector target with an NLR complex at the DNA to switch a potent bacterial virulence activity into defense gene activation. PMID- 26000484 TI - A Plant Immune Receptor Detects Pathogen Effectors that Target WRKY Transcription Factors. AB - Defense against pathogens in multicellular eukaryotes depends on intracellular immune receptors, yet surveillance by these receptors is poorly understood. Several plant nucleotide-binding, leucine-rich repeat (NB-LRR) immune receptors carry fusions with other protein domains. The Arabidopsis RRS1-R NB-LRR protein carries a C-terminal WRKY DNA binding domain and forms a receptor complex with RPS4, another NB-LRR protein. This complex detects the bacterial effectors AvrRps4 or PopP2 and then activates defense. Both bacterial proteins interact with the RRS1 WRKY domain, and PopP2 acetylates lysines to block DNA binding. PopP2 and AvrRps4 interact with other WRKY domain-containing proteins, suggesting these effectors interfere with WRKY transcription factor-dependent defense, and RPS4/RRS1 has integrated a "decoy" domain that enables detection of effectors that target WRKY proteins. We propose that NB-LRR receptor pairs, one member of which carries an additional protein domain, enable perception of pathogen effectors whose function is to target that domain. PMID- 26000485 TI - Chromosomes Progress to Metaphase in Multiple Discrete Steps via Global Compaction/Expansion Cycles. AB - Mammalian mitotic chromosome morphogenesis was analyzed by 4D live-cell and snapshot deconvolution fluorescence imaging. Prophase chromosomes, whose organization was previously unknown, are revealed to comprise co-oriented sister linear loop arrays displayed along a single, peripheral, regularly kinked topoisomerase II/cohesin/condensin II axis. Thereafter, rather than smooth, progressive compaction as generally envisioned, progression to metaphase is a discontinuous process involving chromosome expansion as well as compaction. At late prophase, dependent on topoisomerase II and with concomitant cohesin release, chromosomes expand, axes split and straighten, and chromatin loops transit to a radial disposition around now-central axes. Finally, chromosomes globally compact, giving the metaphase state. These patterns are consistent with the hypothesis that the molecular events of chromosome morphogenesis are governed by accumulation and release of chromosome stress, created by chromatin compaction and expansion. Chromosome state could evolve analogously throughout the cell cycle. PMID- 26000486 TI - Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. AB - The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co expression network analysis (WGCNA), we uncovered molecular properties of CD133(+)/GFAP(-) ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133(+)/GFAP(-) quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133(+) ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation. PMID- 26000487 TI - Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. AB - It has long been the dream of biologists to map gene expression at the single cell level. With such data one might track heterogeneous cell sub-populations, and infer regulatory relationships between genes and pathways. Recently, RNA sequencing has achieved single-cell resolution. What is limiting is an effective way to routinely isolate and process large numbers of individual cells for quantitative in-depth sequencing. We have developed a high-throughput droplet microfluidic approach for barcoding the RNA from thousands of individual cells for subsequent analysis by next-generation sequencing. The method shows a surprisingly low noise profile and is readily adaptable to other sequencing-based assays. We analyzed mouse embryonic stem cells, revealing in detail the population structure and the heterogeneous onset of differentiation after leukemia inhibitory factor (LIF) withdrawal. The reproducibility of these high throughput single-cell data allowed us to deconstruct cell populations and infer gene expression relationships. VIDEO ABSTRACT. PMID- 26000488 TI - Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. AB - Cells, the basic units of biological structure and function, vary broadly in type and state. Single-cell genomics can characterize cell identity and function, but limitations of ease and scale have prevented its broad application. Here we describe Drop-seq, a strategy for quickly profiling thousands of individual cells by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell's RNAs, and sequencing them all together. Drop-seq analyzes mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts' cell of origin. We analyzed transcriptomes from 44,808 mouse retinal cells and identified 39 transcriptionally distinct cell populations, creating a molecular atlas of gene expression for known retinal cell classes and novel candidate cell subtypes. Drop-seq will accelerate biological discovery by enabling routine transcriptional profiling at single-cell resolution. VIDEO ABSTRACT. PMID- 26000490 TI - SnapShot: Intrinsic Structural Disorder. AB - Many proteins (intrinsically disordered proteins, IDPs) or regions of proteins (intrinsically disordered regions, IDRs) lack a well-defined 3D structure under physiological conditions. Albeit unfolded and highly dynamic, these proteins are not denatured; rather, intrinsic structural disorder is their native, functional state. PMID- 26000491 TI - Synthetic indole Mannich bases: Their ability to modulate in vitro cellular immunity. AB - The synthetic indole Mannich bases 1-13 have been investigated for their ability to modulate immune responses measured in vitro. These activities were based on monitoring their affects on T-lymphocyte proliferation, reactive oxygen species (ROS), IL (interleukin)-2, IL-4, and nitric oxide production. Compound 5 was found to be the most potent immunomodulator in this context. Four of the synthesized compounds, 5, 11, 12, and 13, have significant potent inhibitory effects on T-cell proliferation, IL-4, and nitric oxide production. However, none of the thirteen indole compounds exerted any activity against ROS production. PMID- 26000492 TI - 13,14-Dihydroxy groups are critical for the anti-cancer effects of garcinol. AB - In the presence of K2CO3/Cs2CO3 (molar ratio 10:1), garcinol was subjected to methylation by reaction with iodomethane at room temperature to afford 13,14 dimethoxy garcinol. The methylated garcinol derivative was screened against oral cancer cell line SCC15 for cell proliferation and apoptosis. 13,14-Dimethoxy garcinol showed weaker inhibitory activity on SCC15 cell growth than garcinol, and had little effect on cell cycle and apoptosis of SCC15, whereas garcinol effectively induced cell cycle arrest and cell apoptosis. Meanwhile, the ELISA data showed that the inhibitory effect of garcinol on 5-Lox pathway was more potent than 13,14-dimethoxy garcinol (P<0.05). All these results have confirmed the important role of 13,14-dihydroxy groups for anti-cancer effects of garcinol. PMID- 26000489 TI - Integrative clinical genomics of advanced prostate cancer. AB - Toward development of a precision medicine framework for metastatic, castration resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R spondin, BRAF/RAF1, APC, beta-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals. PMID- 26000495 TI - Taking charge of health care. PMID- 26000496 TI - The American College of Obstetricians and Gynecologists Supports Access to Women's Health Care. PMID- 26000497 TI - Perspective on the american college of obstetricians and gynecologists' support of access to elective abortion. PMID- 26000498 TI - Recognition by Women's Health Care Providers of Long-Term Cardiovascular Disease Risk After Preeclampsia. AB - OBJECTIVE: To assess health care providers' knowledge regarding pregnancy outcome as a risk factor for cardiovascular disease and evaluate the variables associated with their responses to questions about routine surveillance for cardiovascular disease. METHODS: A voluntary, anonymous survey of internal medicine and obstetric and gynecologic health care providers at an academic institution. Responses to a case-based and direct inquiry questionnaire were evaluated. RESULTS: The overall response rate was 65% (173/265). When assessing cardiovascular risk, gynecologists compared with internists significantly more often requested a pregnancy history (44/49 [90%] compared with 56/75 [75%], P=.039) and more often attached importance to a history of preeclampsia (35/48 [73%] compared with 41/75 [55%], P=.028). When a history of preeclampsia was obtained, internists more often obtained a fasting glucose test (25/52 [48%] compared with 9/43 [20.9%], P=.009). A minority of health care providers recognized the importance of fetal growth restriction. Both health care provider groups demonstrated similar knowledge of general cardiovascular risk factors, screening tools, and interventions. Higher general cardiovascular knowledge was significantly associated with identification of pregnancy complications as cardiovascular risk factors (P=.001). CONCLUSION: When assessing cardiovascular risk, internists were less likely than gynecologists to include a pregnancy history. However, once identified as at risk for cardiovascular disease, gynecologists were less likely than internists to obtain appropriate testing. Education concerning the link between certain pregnancy complications and future cardiovascular disease is needed. Areas of opportunity for education in both medical specialties are identified. PMID- 26000499 TI - Ebola virus disease and Marburg disease in pregnancy: a review and management considerations for filovirus infection. AB - The largest-ever recorded outbreak of viral hemorrhagic fever is ongoing. As a result of the epidemic and rural nature of outbreaks, little is published about the Filovirus infections Ebola virus disease and Marburg disease in pregnancy. This review of viral hemorrhagic fever focusing on Marburg and Ebola uses knowledge of disease in nonpregnant individuals and pregnancy-specific data to inform management for pregnant women. Filovirus infection presentation is similar between pregnant and nonpregnant patients, although infections may be more severe in pregnancy. Although labeled as hemorrhagic fevers, Marburg and Ebola do not commonly cause gross bleeding and should be conceptualized as diseases of high gastrointestinal losses. Early, aggressive supportive care is the mainstay of Filovirus infection management with massive fluid resuscitation as the key management principle. Patients often require 5-10 L or more per day of intravenous or oral fluid to maintain circulating blood volume in the setting of ongoing gastrointestinal loss. Fluid shifts warrant aggressive monitoring and correction of potassium levels and acid-base disturbances to prevent life threatening arrhythmias and metabolic complications. Regardless of maternal survival, fetal loss rates are nearly 100% in Filovirus infection, likely resulting from unchecked transplacental and hematogenous viral spread. High fetal loss rates support the placenta as a difficult-to-eradicate Filovirus infection reservoir. In conclusion, the management of Filovirus infection in pregnancy should focus on stabilizing the mother with intensive monitoring and aggressive fluid and electrolyte repletion as well as maintaining strict infection control to minimize transmission to others. PMID- 26000500 TI - Look before you leap: genomic screening in obstetrics and gynecology. AB - There are a number of new genetic tests and a variety of recommendations for obstetrician-gynecologists. In recent years, screening of low-risk pregnant women with noninvasive prenatal testing has been proposed as well as universal BRCA1 and BRCA2 screening of all women regardless of risk status. Both proposed genetic screening tests raise complicated issues relating to predictive value, cost, and consequences after screening to both the health care system as a whole as well as serious potential adverse consequences for the patient. In addition, there are significant barriers relating to clinician education in proper use of these genetic tests as well as logistic issues of performing adequate genetic counseling in a busy general practice. We recommend that pregnant women offered noninvasive prenatal testing be informed of its advantages and disadvantages compared with standard screening with the caveat that positive noninvasive prenatal tests must be confirmed with further, invasive testing. We recommend against population genetic screening of all women for BRCA1 and BRCA2 mutations until there are comprehensive data regarding harms and benefits as well as cost effectiveness. Finally, we recommend that new educational models for genetics be developed for obstetrics and gynecology residency training so that future health care providers will be prepared for the opportunities and challenges that genetic testing creates. PMID- 26000501 TI - Variation in Women's Understanding of Prenatal Testing. AB - OBJECTIVE: To investigate women's understanding of prenatal testing options and of their own experience with screening, diagnostic genetic testing, or both. METHODS: This was a secondary analysis of data from a randomized controlled trial of enhanced information and values clarification regarding prenatal genetic testing in the absence of financial barriers to testing. Women in the third trimester of pregnancy were asked whether they had discussed prenatal genetic testing with their health care providers, whether they understood this testing was optional, and whether they had undergone testing during their pregnancy. Multivariable logistic regression models were fit to determine independent predictors of these outcomes. RESULTS: Data were available from 710 study participants. Discussions about screening tests were reported by 654 participants (92%); only 412 (58%) reported discussing diagnostic testing. That screening and diagnostic testing were optional was evident to approximately two thirds of women (n=470 and 455, respectively). Recall of actual tests undergone was correct for 626 (88%) for screening and for 700 (99%) for diagnostic testing. Racial, ethnic and socioeconomic variation existed in the understanding of whether screening and diagnostic tests were optional and in the correct recall of whether screening had been undertaken in the current pregnancy. In the usual care group, women receiving care in low-income settings were less likely to recall being offered diagnostic testing (adjusted odds ratio 0.23 [0.14-0.39]). CONCLUSION: Disparities exist in women's recall of prenatal genetic testing discussions and their understanding of their own experience. Interventions that explain testing options to women and help clarify their preferences may help to eliminate these differences. PMID- 26000503 TI - Use of cell-free DNA in the investigation of intrauterine fetal demise and miscarriage. AB - OBJECTIVE: To estimate whether cell-free DNA is present in nonviable pregnancies and thus can be used in diagnostic evaluation in this setting. METHODS: We conducted a prospective cohort study of 50 participants at MedStar Washington Hospital Center, Washington, DC, between June 2013 and January 2014. Included were women with pregnancies complicated by missed abortion or fetal demise. All gestational ages were considered for study participation. Participants with fetal demise were offered the standard workup for fetal death per the American College of Obstetricians and Gynecologists. Maternal blood samples were processed to determine the presence of cell-free DNA, the corresponding fetal fractions, and genetic abnormalities. RESULTS: Fifty samples from nonviable pregnancies were analyzed. The average clinical gestational age was 16.9 weeks (standard deviation 9.2). The mean maternal body mass index was 30.3 (standard deviation 9.1). Seventy-six percent (38/50) of samples yielded cell-free DNA results, that is, had fetal fractions within the detectable range of 3.7-65%. Among the 38, 76% (29) were classified as euploid, 21% (8) as trisomies, and 3% (1) as microdeletion. A cell-free DNA result was obtained more frequently at ultrasonographic gestational ages of 8 weeks or greater compared with less than 8 weeks (87.9% [n=29/33, 95% confidence interval (CI) 72.7-95.2; and 52.9%, n=9/17, 95% CI 31.0-73.8] of the time, respectively, P=.012). Time from demise was not associated with obtaining a result. CONCLUSION: Among nonviable pregnancies, cell free DNA is present in the maternal plasma with fetal fractions greater than 3.7% in more than three fourths of cases after an ultrasonographic gestational age of 8 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01916928. LEVEL OF EVIDENCE: III. PMID- 26000502 TI - A national survey on public perceptions of miscarriage. AB - OBJECTIVE: To assess attitudes and perceptions of U.S. survey respondents regarding prevalence, causes, and emotional effects of miscarriage. METHODS: We used a questionnaire consisting of 33 questions administered in January of 2013 to men and women aged 18-69 years across the United States. RESULTS: Participants from 49 states completed the questionnaire: 45% male and 55% female (N=1,084). Fifteen percent reported they or their partner experienced at least one miscarriage. Fifty-five percent of respondents believed that miscarriage occurred in 5% or less of all pregnancies. Commonly believed causes of miscarriage included a stressful event (76%), lifting a heavy object (64%), previous use of an intrauterine device (28%), or oral contraceptives (22%). Of those who had a miscarriage, 37% felt they had lost a child, 47% felt guilty, 41% reported feeling that they had done something wrong, 41% felt alone, and 28% felt ashamed. Nineteen percent fewer people felt they had done something wrong when a cause for the miscarriage was found. Seventy-eight percent of all participants reported wanting to know the cause of their miscarriage, even if no intervention could have prevented it from occurring. Disclosures of miscarriages by public figures assuaged feelings of isolation for 28% of respondents. Level of education and gender had a significant effect on perceptions and understanding of miscarriage. CONCLUSION: Respondents to our survey erroneously believed that miscarriage is a rare complication of pregnancy, with the majority believing that it occurred in 5% or less of all pregnancies. There were also widespread misconceptions about causes of miscarriage. Those who had experienced a miscarriage frequently felt guilty, isolated, and alone. Identifying a potential cause of the miscarriage may have an effect on patients' psychological and emotional responses. LEVEL OF EVIDENCE: II. PMID- 26000504 TI - Cell-free DNA analysis in maternal plasma in cases of fetal abnormalities detected on ultrasound examination. AB - OBJECTIVE: To evaluate the utility of noninvasive prenatal testing using cell free circulating fetal DNA for detection of the three main autosomal fetal trisomies in the setting of ultrasonographically identified fetal anomalies. METHODS: Nine hundred patients at risk for fetal aneuploidy with or without ultrasonography anomalies and who underwent invasive procedures were included in the study. Cell-free DNA analysis was performed by massive parallel sequencing during a multicenter, noninterventional, prospective study and the results were compared with a fetal karyotype. RESULTS: Among all 900 pregnancies, cell-free DNA identified 76 of 76 (100%) fetal Down syndrome, 22 of 25 (88%) trisomy 18, and 12 of 12 (100%) trisomy 13. In those with a normal ultrasonogram and normal cell-free DNA analysis, karyotype identified 2 of 483 (0.4%) additional aneuploidies other than trisomies 13, 18, and 21. In those with an abnormal ultrasonogram and a normal cell-free DNA analysis, there were 23 of 290 (7.9%) additional pathogenic karyotypes. These additional aneuploidies included sex chromosome abnormalities and triploidy. The rates of additional aneuploidies not identifiable by standard cell-free DNA screening in the two groups is significantly different at P<.01. CONCLUSION: In women with fetal abnormalities by ultrasonography, the rate of pathogenic chromosome abnormalities missed by cell-free DNA was 8%. Noninvasive prenatal testing should not be offered to women with fetal abnormalities because a negative result is falsely reassuring. LEVEL OF EVIDENCE: III. PMID- 26000505 TI - Trends in relative survival for ovarian cancer from 1975 to 2011. AB - OBJECTIVE: To examine relative survival (a metric that incorporates changes in survival within a population) in women with ovarian cancer from 1975 to 2011. METHODS: Women diagnosed with ovarian cancer from 1975 to 2011 and recorded in the National Cancer Institute's Surveillance, Epidemiology, and End Results database were examined. Relative survival, estimated as the ratio of the observed survival of cancer patients (all-cause mortality) to the expected survival of a comparable group from the general population, was matched to the patients with the main factors that are considered to affect patient survival such as age, calendar time, and race. Hazard ratios were adjusted for age, race, year of diagnosis, time since diagnosis, and the interaction of age and years since diagnosis (except for stage II). RESULTS: A total of 49,932 women were identified. For stage I ovarian cancer, the adjusted excess hazard ratio for death in 2006 was 0.51 (95% confidence interval [CI] 0.41-0.63) compared with those diagnosed in 1975. The reduction in excess mortality remained significant when compared with 1980 and 1985. For women with stage III-IV tumors, the excess hazard of mortality was lower in 2006 compared with all other years of study ranging from 0.49 (95% CI 0.44-0.55) compared with 1975 to 0.93 (95% CI 0.87 0.99) relative to 2000. For women aged 50-59 years, 10-year relative survival was 0.85 (99% CI 0.61-0.95) for stage I disease and 0.18 (99% CI 0.10-0.27) for stage III-IV tumors. For women aged 60-69 years, the corresponding 10-year relative survival estimates were 0.89 (99% CI 0.58-0.98) and 0.15 (99% CI 0.09-0.21). CONCLUSION: Relative survival has improved for all stages of ovarian cancer from 1975 to 2011. LEVEL OF EVIDENCE: II. PMID- 26000506 TI - Comparing mortality of vaginal sarcoma, squamous cell carcinoma, and adenocarcinoma in the surveillance, epidemiology, and end results database. AB - OBJECTIVE: To evaluate the mortality outcomes of vaginal sarcomas in a large cohort compared with vaginal squamous cell and adenocarcinomas. METHODS: Women with primary invasive vaginal sarcomas, squamous cell carcinomas, and adenocarcinomas diagnosed between 1988 and 2010 were identified within the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Parametric and nonparametric methods were used to compare the demographic and clinical characteristics of women among the three tumor types as well as between sarcoma histologic subtypes. Overall and cancer-specific mortality outcomes were examined using Kaplan-Meier and multivariable Cox proportional hazards models. RESULTS: The final cohort consisted of 3,121 patients with vaginal squamous cell carcinoma, 720 patients with adenocarcinoma, and 221 patients with sarcoma. Compared with women with squamous cell carcinoma and adenocarcinoma, patients diagnosed with vaginal sarcomas tended to be younger, have larger tumors with less regional extension and lymph node positivity, and be treated primarily with surgery without radiation. In unadjusted analysis, 5-year mortality rates border 30% for all three histologies. After adjusting for other prognostic factors including use of radiation and surgery, patients with vaginal sarcomas had a 69% greater risk of cancer-related mortality compared with patients with squamous cell carcinoma (hazard ratio 1.69, 95% confidence interval 1.26-2.26). Although sarcoma histology failed to associate with mortality risk, age, tumor extension and metastasis, and surgery were poor prognostic factors. CONCLUSION: Primary vaginal sarcomas are aggressive neoplasms with different presenting characteristics and increased adjusted risk of mortality compared with squamous cell and adenocarcinoma subtypes. LEVEL OF EVIDENCE: III. PMID- 26000507 TI - Incidence and effects on mortality of venous thromboembolism in elderly women with endometrial cancer. AB - OBJECTIVE: To describe the incidence of thromboembolic events (venous thromboembolism) before and after the diagnosis of epithelial endometrial cancer and to evaluate the effects of these events on survival. METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claim files to identify patients with epithelial endometrial cancer diagnosed between 1992 and 2009. To identify venous thromboembolism events 3 months before diagnosis and up to 24 months after diagnosis, we used International Classification of Diseases, 9th Revision, and Healthcare Common Procedure Coding System codes. RESULTS: A total of 23,122 patients were included; of them 1,873 (8.1%) developed a venous thromboembolism. Patients with low-grade (grades 1 and 2) endometrioid adenocarcinoma had a significantly lower rate of venous thromboembolism 3 months before and 6 months after the diagnosis of cancer (3.6%; 95% confidence interval [CI] 3.3-3.9%) compared with carcinosarcoma (9.2%; 95% CI 7.8-10.8%), clear cell (6.9%; 95% CI 4.8-9.7%), uterine serous cancer (8.1%; 95% CI 7.01-9.3%), and grade 3 endometrioid adenocarcinoma (6.1%; 95% CI 5.4-6.9%) (P<.001). On multivariate analysis during the same time period, most recent time periods of diagnosis, carcinosarcoma histology compared with lower grade endometrial cancer, higher stage, African American race, marital status, chemotherapy delivery, and lymph node dissection were associated with increased risk of venous thromboembolism. The median overall survival for women who experienced a venous thromboembolism 3 months before the diagnosis of endometrial cancer was 31 months (95% CI 20-48 months); in women diagnosed with venous thromboembolism 6 months after the cancer diagnosis was 37 months (95% CI 31-44), and in women who did not experienced a venous thromboembolism was 111 months (95% CI 109-114). After adjusting for prognostic factors, there was an association between venous thromboembolism diagnosed 3 months before endometrial cancer (hazard ratio 1.69, 95% CI 1.34 2.13) or 6 months after the diagnosis (hazard ratio 1.57, 95% CI 1.44-1.71) and lower survival. CONCLUSION: Patients with uterine serous cancer, carcinosarcoma, clear cell carcinoma, and grade 3 endometrioid adenocarcinoma had a higher rate of venous thromboembolism than patients with low-grade endometrioid adenocarcinoma. A diagnosis of venous thromboembolism was associated with decreased survival in elderly patients with endometrial cancer. LEVEL OF EVIDENCE: II. PMID- 26000508 TI - Enoxaparin dosing after cesarean delivery in morbidly obese women. AB - OBJECTIVE: To compare the adequacy of venous thromboembolism prophylaxis based on anti-Xa concentrations between weight-based enoxaparin dosing and body mass index (BMI)-stratified dosing in morbidly obese women after cesarean delivery. METHODS: A prospective sequential cohort study of women with BMIs of 40 or greater who underwent cesarean delivery was conducted. Participants received either weight based or BMI-stratified enoxaparin dosing to prevent venous thromboembolism formation. The weight-based regimen was 0.5 mg/kg of enoxaparin every 12 hours. In the BMI-stratified regimen, women with BMIs of 40-59.9 received 40 mg enoxaparin every 12 hours and women with BMIs of 60 or greater received 60 mg every 12 hours. The primary outcome was an anti-Xa concentration in the adequate thromboprophylaxis range (0.2-0.6 international units/mL). Secondary outcomes included enoxaparin dosage, timing of dosing and anti-Xa concentration, estimated surgical blood loss, postoperative changes in hemoglobin and platelets, wound hematoma, and adverse reactions to enoxaparin. Univariate analysis was used to compare dosing regimens. RESULTS: Forty-two morbidly obese women received weight based enoxaparin, and 43 received BMI-stratified dosing. Anti-Xa concentrations were significantly higher in the weight-based group compared with the BMI stratified group (0.29+/-0.08 international units/mL compared with 0.17+/-0.07 international units/mL, P<.001). Thirty-six participants (86%) on weight-based dosing had anti-Xa concentrations within the prophylactic range compared with 11 (26%) on BMI-stratified dosing (P<.001). No participant had an anti-Xa concentration of 0.6 international units/mL or greater, the therapeutic threshold for venous thromboembolism prophylaxis. CONCLUSION: In morbidly obese women after cesarean delivery, weight-based dosing of enoxaparin for venous thromboembolism prophylaxis is significantly more effective than BMI-stratified dosing in achieving adequate anti-Xa concentrations. LEVEL OF EVIDENCE: II. PMID- 26000509 TI - Association Between Antenatal Corticosteroid Administration-to-Birth Interval and Outcomes of Preterm Neonates. AB - OBJECTIVE: To assess the association between antenatal corticosteroid administration-to-birth interval and outcomes. METHODS: In this retrospective cohort study, data on singleton neonates born between 24 0/7 and 33 6/7 weeks of gestation and admitted to tertiary neonatal units in Canada during 2010-2012 were obtained from the Canadian Neonatal Network. Neonatal outcomes were compared among four groups based on the interval between antenatal corticosteroid administration and birth: no antenatal corticosteroids, partial antenatal corticosteroids (less than 24 hours before birth), antenatal corticosteroids 1-7 days before birth, and antenatal corticosteroids greater than 7 days before birth. Composite outcome was defined as any of neonatal mortality, bronchopulmonary dysplasia, grade 3-4 intraventricular hemorrhage, periventricular leukomalacia, or stage 3 or higher retinopathy. RESULTS: Of 6,870 eligible neonates, 1,378 (20%) received no antenatal corticosteroids; 1,473 (21%) received partial antenatal corticosteroids; 2,721 (40%) received antenatal corticosteroids 1-7 days before birth; and 1,298 (19%) received antenatal corticosteroids greater than 7 days before birth. The odds of the composite adverse outcome were significantly higher in all groups compared with neonates who received antenatal corticosteroids 1-7 days before birth (no antenatal corticosteroids: adjusted odds ratio [OR] 2.12, 95% confidence interval [CI] 1.69 2.65; partial antenatal corticosteroids: adjusted OR 1.48, 95% CI 1.22-1.80; and antenatal corticosteroids at greater than 7 days: adjusted OR 1.46, 95% CI 1.20 1.77). Similar findings were observed with respect to neonatal mortality (no antenatal corticosteroids: adjusted OR 2.56, 95% CI 1.83-3.59; partial antenatal corticosteroids: adjusted OR 1.59, 95% CI 1.16-2.18; and antenatal corticosteroids at greater than 7 days: adjusted OR 1.40, 95% CI 1.00-1.97). CONCLUSION: Antenatal corticosteroids had maximum benefit when given between 1 and 7 days before birth. LEVEL OF EVIDENCE: II. PMID- 26000510 TI - Neurodevelopmental Outcome After a Single Course of Antenatal Steroids in Children Born Preterm: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To systematically review and integrate data on the neurodevelopmental outcome of children after administration of a single course of antenatal corticosteroids for threatened preterm labor. DATA SOURCES: MEDLINE, Scopus, CENTRAL, and www.clinicaltrials.gov (inception to August 2014) using combinations of the terms "prenatal," "antenatal," "cortico*," "*steroid*," "betamethasone," "dexamethasone," "neurodevelopment*," "*development*," and "follow-up." We perused the references of the retrieved articles. METHODS OF STUDY SELECTION: We included randomized and nonrandomized trials reporting on the neurodevelopmental outcomes of children whose mothers were administered a single course of betamethasone or dexamethasone antenatally for threatened preterm birth as opposed to placebo or no treatment. TABULATION, INTEGRATION, AND RESULTS: Summary risk ratio (RR) was calculated for dichotomous data; standardized mean difference was calculated for trials that measured the same outcome but used different methods. Heterogeneity was assessed using the I statistic. Sensitivity and subgroup analyses were planned according to study design, specific steroid, and mean gestational age at birth. A single course of antenatal corticosteroids was associated with reduced risk for cerebral palsy (seven studies; treated: 390 of 5,199, untreated: 146 of 1,379; RR 0.678, 95% confidence interval [CI] 0.564 0.815), psychomotor development index less than 70 (two studies; treated: 783 of 3,049, untreated: 258 of 969; RR 0.829, 95% CI 0.737-0.933), and severe disability (five studies; treated: 1,567 of 4,840, untreated: 475 of 1,211; RR 0.787, 95% CI 0.729-0.850). Steroid treatment increased the rates of intact survival (six studies; treated: 1,082 of 2,013, untreated: 273 of 561; RR 1.186, 95% CI 1.056-1.332). Betamethasone was found to significantly decrease the risk for severe disability and increase the rate of intact survival. Dexamethasone increased the rate of intact survival; however, data for dexametasone and the other planned subgroup analyses were limited (fewer than 1,000 children at most). The major limitations involved inclusion of nonrandomized studies and scarcity of data on finer neurodevelopmental outcomes. CONCLUSION: A single course of antenatal corticosteroids in women at high risk for preterm birth appears to improve most neurodevelopmental outcomes in offspring born before 34 weeks of gestation. PMID- 26000511 TI - Implications of polycystic ovary syndrome for pregnancy and for the health of offspring. AB - OBJECTIVE: To study the influence of polycystic ovary syndrome (PCOS) on obstetric and perinatal outcomes and on offspring in childhood. METHODS: Using statewide data linkage systems within Western Australia, 2,566 hospitalized women with a PCOS diagnosis and at least one pregnancy at 20 weeks of gestation or greater, between 1997 and 2011, were compared with 25,660 randomly selected age matched women not hospitalized with a PCOS diagnosis with regard to perinatal outcomes, congenital anomalies, and general health of offspring. Hospitalizations were categorized by International Classification of Diseases, 10th Revision diagnoses and rates by 10 years by Kaplan-Meier estimates. Polycystic ovary syndrome effects were summarized using adjusted odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) after controlling for maternal and perinatal characteristics, including maternal diabetes and obesity. RESULTS: Of women with PCOS (n=1,789), 69.7% and 62.9% (n=16,139) of women without PCOS had one or more births. Hospitalizations up to 31 years were examined for 38,361 offspring. Offspring of women with PCOS were at higher risk of preterm birth (15.5% compared with 7.6% OR 1.74, 95% CI 1.53-1.98), perinatal mortality (2.3% compared with 0.7%, OR 1.49, 95% CI 1.02-2.18), more postnatal hospitalizations (14.1% compared with 7.9%, OR 1.21, 95% CI 1.05-1.40), more congenital anomalies (6.3% compared with 4.9%, OR 1.20, 95% CI 1.03-1.40), cardiovascular (1.5% compared with 1.0%, OR 1.37, 95% CI 1.01-1.87), and urogenital defects (2.0% compared with 1.4% OR 1.36, 95% CI 1.03-1.81). Maternal PCOS was associated with increased hospitalizations for their offspring, including metabolic disorder (7.9% compared with 5.3%, HR 1.43, 95% CI 1.26-1.65), disease of the nervous system (9.4% compared with 6.9%, HR 1.17, 95% CI 1.03-1.33), and asthma (6.9% compared with 4.9%, HR 1.32, 95% CI 1.13-1.54). CONCLUSION: Controlling for increased perinatal risk, maternal PCOS was associated with a predisposition to adverse health outcomes for their offspring. LEVEL OF EVIDENCE: II. PMID- 26000512 TI - Bowel injury in gynecologic laparoscopy: a systematic review. AB - OBJECTIVE: To evaluate the incidence of bowel injury in gynecologic laparoscopy and determine the presentation, mortality, cause, and location of injury within the gastrointestinal tract. DATA SOURCES: The PubMed, EMBASE, ClinicalTrials.gov, and Cochrane Library databases were searched. Additional studies were obtained from references of retrieved papers. METHODS OF STUDY SELECTION: Included retrospective studies and randomized controlled trials reported the incidence of bowel injury in gynecologic laparoscopy. Studies were excluded if they were not in English or duplicated data. TABULATION, INTEGRATION, AND RESULTS: Two reviewers extracted data in duplicate from each study regarding incidence, cause, and location of bowel injury. Ninety studies published between 1972 and 2014 met eligibility criteria, representing 474,063 gynecologic laparoscopies. Six hundred four bowel injuries were reported for an incidence of 1 in 769 (0.13%, 95% confidence interval [CI] 0.12-0.14%). The rate of bowel injury varied by procedure, ranging from 1 in 3,333 (0.03%, 95% CI 0.01-0.03%) for sterilization to 1 in 256 (0.39%, 95% CI 0.34-0.45%) for hysterectomy. The small intestine was the most frequently damaged region of the gastrointestinal tract, representing 166 of 354 (47%) injuries. The majority of bowel injuries occurred during abdominal access and insufflation obtained using a Veress needle or trocar placement (201/366, 55% of injuries). Although most bowel injuries were recognized intraoperatively, diagnosis was delayed by more than 1 day in 154 of 375 cases (41%, 95% CI 36-46%). Bowel injuries were managed primarily by laparotomy (80%). Mortality occurred after bowel injury in 5 of 604, or 1 of 125 (0.8%, 95% CI 0.36-1.9%) cases. All deaths occurred as a result of delayed recognition of bowel injury (n=154), making the mortality rate for unrecognized bowel injury 5 in 154 or 1 in 31 (3.2%, 95% CI 1-7%). There were no deaths associated with intraoperatively diagnosed bowel injury. CONCLUSION: The overall incidence of bowel injury in gynecologic laparoscopy is 1 in 769 but increases with surgical complexity. Delayed diagnosis is associated with a mortality rate of 1 in 31. PMID- 26000513 TI - The significant morbidity of removing pelvic mesh from multiple vaginal compartments. AB - OBJECTIVE: To investigate perioperative complications of mesh removal performed in the operating room from a single-site, tertiary care center with a large volume of referrals for mesh removal and to compare the morbidity associated with single-compartment mesh removal compared with removal from multiple vaginal compartments. METHODS: A retrospective review was performed on all patients who underwent mesh removal from January 2008 to April 2014. Patients were identified based on Current Procedural Terminology codes for removal of vaginal mesh or sling. Summary statistics were calculated for the patient population. Complications were compared between single-compartment mesh removal surgery and multicompartment mesh removal surgery. A P value of <.05 was considered significant for all analyses. RESULTS: During a 75-month period, a total of 398 procedures were performed for the removal of vaginally placed mesh. A total of 326 (82%) patients underwent single-compartment surgery, 48 (12%) underwent multicompartment surgery, and in 26 (6%), the type of surgery was unclear. The indications for mesh removal included: pain (63%), dyspareunia (57%), mesh exposure (54%), and voiding dysfunction (39%). The mean length of mesh removed was 4 cm (standard deviation+/-2.8). Those with multicompartment surgery had approximately three times higher estimated blood loss compared with single compartment surgery (P<.001). The odds of blood transfusion after multicompartment surgery were more than nine times higher than the odds of transfusion after a single-compartment surgery (odds ratio 9.7, 95% confidence interval 2.1-44.6; P<.01). CONCLUSION: Bleeding complications are higher with concomitant removal of mesh from multiple vaginal compartments. LEVEL OF EVIDENCE: III. PMID- 26000514 TI - Comparative Effectiveness of Anticholinergic Therapy for Overactive Bladder in Women: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To summarize evidence about reduction in voiding and resolution of urine loss in overactive bladder comparing data from the active drug arms with the placebo arms of randomized trials. DATA SOURCES: We searched MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, and ClinicalTrials.gov in March 2014. METHODS OF STUDY SELECTION: Multiple reviewers screened original research published in English on community-dwelling women with nonneurogenic overactive bladder undergoing pharmacotherapy with medications available in the United States. Studies in which women comprised less than 75% of the population or those with a sample size less than 50 were excluded. Study designs included randomized controlled trials for meta-analysis and cohorts, case-control, and case series for harms data. Our search identified 50 randomized controlled trials from among 144 candidate publications (one was of good quality, 38 fair, and 11 poor). TABULATION, INTEGRATION, AND RESULTS: Multiple team members performed data extraction independently with secondary review of data entry to ensure quality and validity. Studies were assessed for risk of bias. Meta-analysis was performed using fixed-effects regression models. The primary outcomes and measurements were the numbers of daily voids and urge incontinence episodes. Medications delivered as a daily dose reduced urge incontinence by 1.73 episodes per day (95% confidence interval [CI] 1.37-2.09) and voids by 2.06 per day (95% CI 1.66-2.46) from 2.79 (95% CI 0.70-4.88) and 11.28 (95% CI 7.77-14.80) at baseline, respectively. Placebo reduced urge incontinence episodes by 1.06 (95% CI 0.7 1.42) and voids by 1.2 (95% CI 0.72-1.67) per day. No individual agent demonstrated superiority over another. The majority (98%) of studies reporting funding were sponsored by industry. CONCLUSION: Evidence from more than 27,000 women participating in randomized controlled trials suggests that improvement in symptoms with anticholinergic management of overactive bladder is modest and rarely fully resolves symptoms. PMID- 26000515 TI - Pregnancy outcomes after antepartum tetanus, diphtheria, and acellular pertussis vaccination. AB - OBJECTIVE: To evaluate pregnancy outcomes of women who received tetanus, diphtheria, and acellular pertussis (Tdap) vaccination at or after 32 weeks of gestation. Outcomes from consecutive pregnancies during which the mother received Tdap were also analyzed. METHODS: In a retrospective cohort study at a single institution, we compared pregnancy outcomes between those who accepted or declined Tdap at 32 weeks of gestation. Additionally, women who received Tdap vaccination in this and a prior pregnancy in the past 5 years were compared with multiparous women who only received Tdap in this pregnancy. RESULTS: Since 2013, 7,378 women who were offered the Tdap vaccine antenatally delivered at our institution: 7,152 accepted (97%). There was no difference in stillbirths, major malformations, chorioamnionitis, 5-minute Apgar score, or cord blood pH. Neonatal complications including ventilation requirement, sepsis, intraventricular hemorrhage, and neonatal death were also similar. However, preterm birth rates at 36 weeks of gestation or less (6% compared with 12%, P<.001), incidence of small for gestational age (10% compared with 15%, P=.03), and length of neonatal hospitalization (3.9 compared with 4.7 days, P<.001) were all significantly increased in the unvaccinated cohort. No difference in neonatal outcomes was noted between women who were administered at least two Tdap vaccines in the past 5 years (n=1,229) and those who received only a single dose (n=4,159). CONCLUSION: No adverse pregnancy outcomes were identified in association with antepartum Tdap vaccination. This remained true in women receiving more than one Tdap vaccine in a 5-year timeframe. This may be the result of a type II error. LEVEL OF EVIDENCE: II. PMID- 26000517 TI - Association of reported trimester-specific smoking cessation with fetal growth restriction. AB - OBJECTIVE: To assess the association of reported smoking cessation at various time points during pregnancy with fetal growth restriction. METHODS: This was a population-based retrospective cohort study of singleton nonanomalous live births using Ohio birth certificates, 2006-2012. Outcomes of women who reported smoking only in the 3 months before conception and women who reported smoking through the first, second, or third trimester were compared with a referent group of nonsmokers. Multivariate logistic regression assessed the association between smoking cessation at various times in pregnancy and fetal growth restriction less than the 10th and 5th percentiles. RESULTS: Of 927,424 births analyzed, 75% of mothers did not smoke. Of smokers, 24% smoked preconception only, 10% quit after the first trimester, 4% quit after the second trimester, and 59% smoked throughout pregnancy. The rate of fetal growth restriction less than the 10th and 5th percentiles among nonsmokers was 8.1% and 3.6%, respectively. Although smoking only in the preconception period did not significantly increase fetal growth restriction risk, smoking in any trimester did. The adjusted odds ratio (95% confidence interval) for fetal growth restriction less than the 10th and 5th percentiles, respectively, of cessation after the first trimester was 1.19 (1.13 1.24) and 1.25 (1.17-1.33) and 1.67 (1.57-1.78) and 1.83 (1.68, 1.99) for cessation after the second trimester. Women who reported smoking throughout pregnancy had the highest risks of fetal growth restriction, 2.26 (2.22-2.31) and 2.44 (2.37-2.51), after accounting for the influence of race, low socioeconomic status, and medical comorbidities. CONCLUSION: Smoking of any duration during pregnancy is associated with an increased risk of fetal growth restriction with decreasing risk the earlier that cessation occurs. Smoking cessation programs should focus on the benefit of quitting as early in pregnancy as possible. LEVEL OF EVIDENCE: II. PMID- 26000516 TI - Risks Associated With Smallpox Vaccination in Pregnancy: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To estimate the maternal and fetal risks of smallpox vaccination during pregnancy. DATA SOURCES: MEDLINE, Web of Science, EMBASE, Global Health, ClinicalTrials.gov, and CINHAL from inception to September 2014. METHODS OF STUDY SELECTION: We included published articles containing primary data regarding smallpox vaccination during pregnancy that reported maternal or fetal outcomes (spontaneous abortion, congenital defect, stillbirth, preterm birth, or fetal vaccinia). TABULATIONS, INTEGRATION, AND RESULTS: The primary search yielded 887 articles. After hand-searching, 37 articles were included: 18 articles with fetal outcome data and 19 case reports of fetal vaccinia. Outcomes of smallpox vaccination in 12,201 pregnant women were included. Smallpox vaccination was not associated with an increased risk of spontaneous abortion (pooled relative risk [RR] 1.03, confidence interval [CI] 0.76-1.41), stillbirth (pooled RR 1.03, CI 0.75-1.40), or preterm birth (pooled RR 0.84, CI 0.62-1.15). When vaccination in any trimester was considered, smallpox vaccination was not associated with an increased risk of congenital defects (pooled RR 1.25, CI 0.99-1.56); however, first-trimester exposure was associated with an increased risk of congenital defects (2.4% compared with 1.5%, pooled RR 1.34, CI 1.02-1.77). No cases of fetal vaccinia were reported in the studies examining fetal outcomes; 21 cases of fetal vaccinia were identified in the literature, of which three neonates survived. CONCLUSION: The overall risk associated with maternal smallpox vaccination appears low. No association between smallpox vaccination and spontaneous abortion, preterm birth, or stillbirth was identified. First trimester vaccination was associated with a small increase in congenital defects, but the effect size was small and based on limited data. Fetal vaccinia appears to be a rare consequence of maternal smallpox vaccination but is associated with a high rate of fetal loss. PMID- 26000518 TI - Racial and ethnic disparities in maternal morbidity and obstetric care. AB - OBJECTIVE: To evaluate whether racial and ethnic disparities exist in obstetric care and adverse outcomes. METHODS: We analyzed data from a cohort of women who delivered at 25 hospitals across the United States over a 3-year period. Race and ethnicity was categorized as non-Hispanic white, non-Hispanic black, Hispanic, or Asian. Associations between race and ethnicity and severe postpartum hemorrhage, peripartum infection, and severe perineal laceration at spontaneous vaginal delivery as well as between race and ethnicity and obstetric care (eg, episiotomy) relevant to the adverse outcomes were estimated by univariable analysis and multivariable logistic regression. RESULTS: Of 115,502 studied women, 95% were classified by one of the race and ethnicity categories. Non Hispanic white women were significantly less likely to experience severe postpartum hemorrhage (1.6% non-Hispanic white compared with 3.0% non-Hispanic black compared with 3.1% Hispanic compared with 2.2% Asian) and peripartum infection (4.1% non-Hispanic white compared with 4.9% non-Hispanic black compared with 6.4% Hispanic compared with 6.2% Asian) than others (P<.001 for both). Severe perineal laceration at spontaneous vaginal delivery was significantly more likely in Asian women (2.5% non-Hispanic white compared with 1.2% non-Hispanic black compared with 1.5% Hispanic compared with 5.5% Asian; P<.001). These disparities persisted in multivariable analysis. Many types of obstetric care examined also were significantly different according to race and ethnicity in both univariable and multivariable analysis. There were no significant interactions between race and ethnicity and hospital of delivery. CONCLUSION: Racial and ethnic disparities exist for multiple adverse obstetric outcomes and types of obstetric care and do not appear to be explained by differences in patient characteristics or by delivery hospital. LEVEL OF EVIDENCE: II. PMID- 26000519 TI - Contraception after delivery and short interpregnancy intervals among women in the United States. AB - OBJECTIVE: To investigate women's patterns of contraceptive use after delivery and the association between method use and risk of pregnancy within 18 months. METHODS: We used the 2006-2010 National Survey of Family Growth to examine women's contraceptive use after delivery and at 3, 6, 12, and 18 months after giving birth. The sample included 3,005 births that occurred within 3 years of the survey date and for which information on contraceptive use was available. We estimated multivariable-adjusted Cox regression models to assess the association between women's method use and risk of pregnancy within 18 months after delivery. We also examined the percentage of pregnancies occurring 18 months or less after the index birth that were unintended. RESULTS: Between delivery and 3 months postpartum, contraceptive use increased from 21% to 72%. At 3 months, 13% of women used permanent contraception, 6% used long-acting reversible contraceptives, 28% used other hormonal methods, and 25% relied on less-effective methods; the distribution of method use was similar in subsequent months. Among women using hormonal methods, 12.6% became pregnant within 18 months of delivery or less compared with 0.5% using permanent and long-acting contraception (adjusted hazard ratio [HR] 21.2, 95% confidence interval [CI] 6.17-72.8). Additionally, 17.8% of women using less-effective methods (HR 34.8, 95% CI 9.26 131) and 23% using no method (HR 43.2, 95% CI 12.3-152) became pregnant 18 months or less. At least 70% of pregnancies within 1 year after delivery were unintended. CONCLUSION: Few women use long-acting reversible contraceptives after delivery, and those using less-effective methods have an increased risk of unintended pregnancy. LEVEL OF EVIDENCE: II. PMID- 26000520 TI - Rating Pregnancy Wheel Applications Using the APPLICATIONS Scoring System. AB - OBJECTIVE: To identify the top-rated pregnancy wheel applications (apps) using a newly developed APPLICATIONS scoring system. METHODS: A list of pregnancy wheel apps was identified. Consumer-based and inaccurate apps were excluded. The APPLICATIONS scoring system was developed to rate the remaining apps. Application comprehensiveness was evaluated. Objective rating components included price, paid subscription, literature used, in-app purchases, connectivity to the Internet, advertisements, text search field, interdevice compatibility, and other components such as images or figures, videos, and special features. Subjective rating components were ease of navigation and subjective presentation. RESULTS: A complete list of 55 pregnancy wheel apps was created from three sources. Thirty nine (71%) were consumer-based, inaccurate, or both, leaving 16 (29%) for analysis using the APPLICATIONS scoring system. CONCLUSION: More than two thirds of pregnancy wheel apps were excluded from our study secondary to being consumer based, inaccurate, or both. This highlights the importance of identifying systematically, reviewing critically, and rating the thousands of available apps to health care providers to ensure accuracy and applicability. We propose that our APPLICATIONS scoring system be used to rate apps in all specialties with the goal of improving health care provider performance and thereby patient outcomes. LEVEL OF EVIDENCE: III. PMID- 26000521 TI - What is new in recurrent pregnancy loss?: best articles from the past year. AB - This month we focus on current research in recurrent pregnancy loss. Dr. Fox discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 26000522 TI - Intimate partner violence and maternal cigarette smoking before and during pregnancy. PMID- 26000523 TI - In reply. PMID- 26000524 TI - What is New in Labor Management? Best Articles From the Past Year. PMID- 26000525 TI - Appropriate use of antenatal corticosteroid prophylaxis. PMID- 26000526 TI - In reply. PMID- 26000527 TI - Female sexual dysfunction: focus on low desire. PMID- 26000528 TI - In reply. PMID- 26000529 TI - Female sexual dysfunction: focus on low desire. PMID- 26000530 TI - Time interval between endometrial biopsy and surgical staging for type I endometrial cancer: association between tumor characteristics and survival outcome. PMID- 26000531 TI - In reply. PMID- 26000532 TI - Influence of Endometriosis on Assisted Reproductive Technology Outcomes: A Systematic Review and Meta-analysis. PMID- 26000533 TI - In reply. PMID- 26000534 TI - Sodium fluorescein use during intraoperative cystoscopy. PMID- 26000535 TI - In reply. PMID- 26000536 TI - Underrepresentation of women in clinical trials: why gynecologic oncologists are worried. PMID- 26000539 TI - Practice bulletin no. 151: Cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy. PMID- 26000540 TI - Committee opinion no 632: Expedited partner therapy in the management of gonorrhea and chlamydial infection. AB - Sexually transmitted infections (STIs) disproportionately affect women and create a preventable threat to their fertility. One factor that contributes to young women's high rates of STIs is reinfection from an untreated sexual partner. One way to address this problem is through expedited partner therapy, the practice of treating the sexual partners of patients in whom STIs are diagnosed. Expedited partner therapy enables the obstetrician-gynecologist or other provider to give prescriptions or medications to patients to take to their partners without first examining these partners. Despite the effectiveness of expedited partner therapy, numerous legal, medical, practical, and administrative barriers hinder its routine use by obstetrician-gynecologists. The American College of Obstetricians and Gynecologists supports the use of expedited partner therapy as a method of preventing gonorrhea and chlamydial reinfection when a patient's partners are unable or unwilling to seek medical care. Expedited partner therapy should be accompanied by patient counseling and written treatment instructions for the patient's partner(s). Partners receiving expedited partner therapy should be encouraged to seek additional medical evaluation as soon as possible to discuss screening for other STIs, including human immunodeficiency virus (HIV) infection. PMID- 26000541 TI - Committee opinion no. 633: Alcohol abuse and other substance use disorders: ethical issues in obstetric and gynecologic practice. AB - Alcohol abuse and other substance use disorders are major, often underdiagnosed health problems for women, regardless of age, race, ethnicity, and socioeconomic status, and have resulting high costs for individuals and society. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, defines substance use disorder as a pathologic pattern of behaviors related to the use of any of 10 separate classes of substances, including alcohol and licit and illicit substances. In order to optimize care of patients with substance use disorder, obstetrician-gynecologists are encouraged to learn and appropriately use routine screening techniques, clinical laboratory tests, brief interventions, and treatment referrals. The purpose of this Committee Opinion is to propose an ethical framework for incorporating such care into obstetric and gynecologic practice and for resolving common ethical dilemmas related to substance use disorder. PMID- 26000542 TI - Committee opinion no. 634: Hereditary cancer syndromes and risk assessment. AB - A hereditary cancer syndrome is a genetic predisposition to certain types of cancer, often with onset at an early age, caused by inherited mutations in one or more genes. Cases of cancer commonly encountered by obstetrician-gynecologists or other obstetric-gynecologic providers--such as breast cancer, ovarian cancer, and endometrial cancer--are features of specific hereditary cancer syndromes. The most common hereditary cancer syndromes related to gynecologic cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and Peutz-Jeghers syndrome. A hereditary cancer risk assessment is the key to identifying patients and families who may be at increased risk of developing certain types of cancer. Screening should include, at minimum, a personal cancer history and a first- and second-degree relative cancer history that includes a description of the type of primary cancer, the age of onset, and the lineage (paternal versus maternal) of the family member. In addition, a patient's ethnic background can influence her genetic risk. If a hereditary cancer risk assessment suggests an increased risk of a hereditary cancer syndrome, referral to a specialist in cancer genetics or a health care provider with expertise in genetics is recommended for expanded gathering of family history information, risk assessment, education, and counseling, which may lead to genetic testing. PMID- 26000543 TI - Committee opinion no: 635: Prenatal and perinatal human immunodeficiency virus testing: expanded recommendations. AB - Given the enormous advances in the prevention of perinatal transmission of human immunodeficiency virus (HIV), it is clear that early identification and treatment of all pregnant women with HIV is the best way to prevent neonatal infection and also improve women's health. Furthermore, new evidence suggests that early initiation of antiretroviral therapy in the course of infection is beneficial for individuals infected with HIV and reduces the rate of sexual transmission to partners who are not infected. Screening should be performed after women have been notified that HIV screening is recommended for all pregnant patients and that they will receive an HIV test as part of the routine panel of prenatal tests unless they decline (opt-out screening). Obstetrician-gynecologists or other obstetric providers should follow opt-out prenatal HIV screening where legally possible. Repeat HIV testing in the third trimester is recommended for women in areas with high HIV incidence or prevalence and women known to be at risk of acquiring HIV infection. Women who were not tested earlier in pregnancy or whose HIV status is otherwise undocumented should be offered rapid screening on labor and delivery using the opt-out approach where allowed. If a rapid HIV test result in labor is reactive, antiretroviral prophylaxis should be immediately initiated while waiting for supplemental test results. If the diagnosis of HIV infection is established, the woman should be linked into ongoing care with a specialist in HIV care for comanagement. PMID- 26000544 TI - Committee opinion no: 636: Management of women with phenylketonuria. AB - Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism characterized by deficient activity of the hepatic enzyme, phenylalanine hydroxylase. Increased blood Phe levels are toxic to a variety of tissues, particularly the developing fetal brain. The mainstay of treatment for PKU is the dietary restriction of Phe, which results in decreased blood Phe levels. Lifelong dietary restriction and therapy improves quality of life in patients with PKU and should be encouraged. Genetic counseling is recommended for all reproductive-aged women with PKU, and should include information on reproductive choices and family planning as well as management of maternal PKU. If possible, pregnant women with PKU or hyperphenylalaninemia should be monitored in consultation with practitioners from experienced PKU centers. Optimally, treatment of neonates diagnosed with PKU should be initiated within the first week of life. All unaffected children of women with PKU are carriers and should receive genetic counseling when they are able to understand the consequences. Consultation with a genetics professional to discuss reproductive options is recommended. PMID- 26000545 TI - Development of and Recovery from Secondary Hypogonadism in Aging Men: Prospective Results from the EMAS. AB - CONTEXT: Secondary hypogonadism is common in aging men; its natural history and predisposing factors are unclear. OBJECTIVES: The objectives were 1) to identify factors that predispose eugonadal men (T >= 10.5 nmol/L) to develop biochemical secondary hypogonadism (T < 10.5 nmol/L; LH <= 9.4 U/L) and secondary hypogonadal men to recover to eugonadism; and 2) to characterize clinical features associated with these transitions. DESIGN: The study was designed as a prospective observational general population cohort survey. SETTING: The setting was clinical research centers. PARTICIPANTS: The participants were 3369 community-dwelling men aged 40-79 years in eight European centers. INTERVENTION: Interventions included observational follow-up of 4.3 years. MAIN OUTCOME MEASURE: Subjects were categorized according to change/no change in biochemical gonadal status during follow-up as follows: persistent eugonadal (n = 1909), incident secondary hypogonadal (n = 140), persistent secondary hypogonadal (n = 123), and recovered from secondary hypogonadism to eugonadism (n = 96). Baseline predictors and changes in clinical features associated with incident secondary hypogonadism and recovery from secondary hypogonadism were analyzed by regression models. RESULTS: The incidence of secondary hypogonadism was 155.9/10 000/year, whereas 42.9% of men with secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by obesity (body mass index >= 30 kg/m(2); odds ratio [OR] = 2.86 [95% confidence interval, 1.67; 4.90]; P < .0001), weight gain (OR = 1.79 [1.15; 2.80]; P = .011), and increased waist circumference (OR = 1.73 [1.07; 2.81], P = .026; and OR = 2.64 [1.66; 4.21], P < .0001, for waist circumference 94-102 and >=102 cm, respectively). Incident secondary hypogonadal men experienced new/worsening sexual symptoms (low libido, erectile dysfunction, and infrequent spontaneous erections). Recovery from secondary hypogonadism was predicted by nonobesity (OR = 2.28 [1.21; 4.31]; P = .011), weight loss (OR = 2.24 [1.04; 4.85]; P = .042), normal waist circumference (OR = 1.93 [1.01; 3.70]; P = .048), younger age (< 60 y; OR = 2.32 [1.12; 4.82]; P = .024), and higher education (OR = 2.11 [1.05; 4.26]; P = .037), but symptoms did not show significant concurrent improvement. CONCLUSION: Obesity-related metabolic and lifestyle factors predispose older men to the development of secondary hypogonadism, which is frequently reversible with weight loss. PMID- 26000546 TI - The Role of Alcohol Consumption in Regulating Circulating Levels of Adiponectin: A Prospective Cohort Study. AB - CONTEXT: The role of alcohol intake in influencing longitudinal trajectories of adiponectin is unclear. OBJECTIVE: The objective of the study was to examine the association between alcohol intake and changes in the circulating levels of adiponectin over repeat measures. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 2855 men and women (74% men with a mean age of 50 y at baseline) drawn from the Whitehall II study. Data from study phases 3 (1991 1993), 5 (1997-1999), and 7 (2002-2004) were used. MAIN OUTCOME MEASURE: Adiponectin serum concentrations (nanograms per milliliter) were measured, and alcohol intake was defined in terms of number of UK units (1 U = 8 g ethanol) consumed in the previous 7 days on three occasions. Cross-sectional associations between alcohol and adiponectin levels were calculated using linear regression. A bivariate dual-change score model was used to estimate the effect of alcohol intake on upcoming change in adiponectin. Models were adjusted for age, sex, ethnicity, and smoking status. RESULTS: Alcohol consumption was cross-sectionally associated with (log transformed) adiponectin levels (beta ranging from .001 to .004, depending on phase and level of adjustment) but was not associated with changes in adiponectin levels over time [gamma = -0.002 (SE 0.002), P = 0.246]. CONCLUSION: Alcohol intake is not associated with changes in circulating adiponectin levels in this cohort. This finding provides evidence that adiponectin levels are unlikely to mediate the relationship between moderate alcohol consumption and reduced risk of type 2 diabetes. It is important to consider dynamic longitudinal relationships rather than cross-sectional associations. PMID- 26000547 TI - The impacts of maternal mortality and cause of death on children's risk of dying in rural South Africa: evidence from a population based surveillance study (1992 2013). AB - BACKGROUND: Maternal mortality, the HIV/AIDS pandemic, and child survival are closely linked. This study contributes evidence on the impact of maternal death on children's risk of dying in an HIV-endemic population in rural South Africa. METHODS: We used data for children younger than 10 years from the Agincourt health and socio-demographic surveillance system (1992 - 2013). We used discrete time event history analysis to estimate children's risk of dying when they experienced a maternal death compared to children whose mother survived (N=3,740,992 child months). We also examined variation in risk due to cause of maternal death. We defined mother's survival status as early maternal death (during pregnancy, childbirth, or within 42 days of most recent childbirth or identified cause of death), late maternal death (within 43-365 days of most recent childbirth), any other death, and mothers who survived. RESULTS: Children who experienced an early maternal death were at 15 times the risk of dying (RRR 15.2; 95% CI 8.3-27.9) compared to children whose mother survived. Children under 1 month whose mother died an early (p=0.002) maternal death were at increased risk of dying compared to older children. Children whose mothers died of an HIV/AIDS or TB-related early maternal death were at 29 times the risk of dying compared to children with surviving mothers (RRR 29.2; 95% CI 11.7-73.1). The risk of these children dying was significantly higher than those children whose mother died of a HIV/AIDS or TB-related non-maternal death (p=0.017). CONCLUSIONS: This study contributes further evidence on the impact of a mother's death on child survival in a poor, rural setting with high HIV prevalence. The intersecting epidemics of maternal mortality and HIV/AIDS - especially in sub Saharan Africa - have profound implications for maternal and child health and well-being. Such evidence can help guide public and primary health care practice and interventions. PMID- 26000548 TI - Relative index of inequality and slope index of inequality: a structured regression framework for estimation. AB - BACKGROUND: The relative index of inequality and the slope index of inequality are the two major indices used in epidemiologic studies for the measurement of socioeconomic inequalities in health. Yet the current definitions of these indices are not adapted to their main purpose, which is to provide summary measures of the linear association between socioeconomic status and health in a way that enables valid between-population comparisons. The lack of appropriate definitions has dissuaded the application of suitable regression methods for estimating the slope index of inequality. METHODS: We suggest formally defining the relative and slope indices of inequality as so-called least false parameters, or more precisely, as the parameters that provide the best approximation of the relation between socioeconomic status and the health outcome by log-linear and linear models, respectively. From this standpoint, we establish a structured regression framework for inference on these indices. Guidelines for implementation of the methods, including R and SAS codes, are provided. RESULTS: The new definitions yield appropriate summary measures of the linear association across the entire socioeconomic scale, suitable for comparative studies in epidemiology. Our regression-based approach for estimation of the slope index of inequality contributes to an advancement of the current methodology, which mainly consists of a heuristic formula relying on restrictive assumptions. A study of the educational inequalities in all-cause and cause-specific mortality in France is used for illustration. CONCLUSION: The proposed definitions and methods should guide the use and estimation of these indices in future studies. PMID- 26000549 TI - Aflatoxin M1 in raw milk in Qazvin Province, Iran: a seasonal study. AB - Occurrence of aflatoxin M1 (AFM1) was determined in 254 samples of raw milk obtained from dairy cow farms of Qazvin Province, Iran. Aflatoxin M1 analysis was carried out by using the competitive enzyme-linked immunosorbent assay technique for screening and high-performance liquid chromatography with fluorescence detection for confirmatory purposes. The limit of detection and quantification of the confirmatory method were 0.003 and 0.01 ug/l, respectively. Aflatoxin M1 was detected in 204 analysed samples (80.3%), ranging from 0.011 to 0.321 MUg/l, and 144 samples (56.7%) had levels above the Iranian national standard limit of 0.050 MUg/l. Considering the seasonal variability, the occurrence and levels of AFM1 in samples obtained in winter were significantly higher (P < 0.05) than those obtained in summer. The results of this survey indicate the usefulness of a monitoring programme to supervise food safety for consumers. PMID- 26000550 TI - Does delayed facial involvement implicate a pattern of "descending reversible paralysis" in Fisher syndrome? AB - OBJECTIVE: Delayed facial palsy (DFP) has often been described during the recovery stage of Fisher syndrome (FS), but the implications of DFP in FS pathophysiology have not been reported previously. The aim of this study was to identify the incidence and clinical course of DFP in FS, and to determine its clinical/pathophysiological implications in FS. METHODS: About 71 FS patients were enrolled from seven university-based hospitals in Korea. DFP was defined with respect to new development of unilateral or bilateral facial palsies with delayed onset after either the nadir or improvement of initial neurological signs of FS. RESULTS: Eleven of the 71 patients (16%) satisfied the definition of DFP. No other cranial palsies developed as a delayed pattern. With the exception of two patients with bulbar involvement, DFP developed after a latent period of upper-cranial neuropathies. Comparison of FS patients without and with DFP revealed no significant clinical, serological, or electrophysiological differences. All except one patient with DFP exhibited a good outcome within 1 month of follow-up. CONCLUSION: DFP was identified as a common and specific phenomenon in FS. Nearly all cases of DFP were developed in a descending manner and were associated with a good outcome, while other cranial neuropathies developed or followed as a sequential pattern. These findings suggest the involvement of so-called "descending reversible paralysis" in the pathophysiology of FS. PMID- 26000551 TI - Black cohosh improves objective sleep in postmenopausal women with sleep disturbance. AB - OBJECTIVE: Sleep problems are prominent after menopause. The aim of our study was to look into the effect of black cohosh on both objective and subjective sleep in early postmenopausal women with sleep complaints. METHODS: We performed a randomized, double-blind and placebo-controlled research during a 6-month period. Forty-eight postmenopausal women aged 45-60 years with sleep disturbance were enrolled and received daily administration of either black cohosh or placebo. Polysomnography and the Pittsburg Sleep Quality Index (PSQI) were performed at the initiation and termination of the study, as well as the Menopause-specific Quality of Life questionnaire and estradiol and follicle stimulating hormone tests. Liver and renal functions and breast and pelvic ultrasound were set as safety measures, carried out every 3 months. RESULTS: Seventy-six women were interviewed, of whom 42 women completed the whole trial. Compared with placebo, black cohosh treatment led to significant polysomnographic changes, including increased sleep efficiency and decreased wake after sleep onset (WASO) duration, and tended to improve PSQI with a medium effect size. On average, 15.8% of WASO duration was reduced in the black cohosh group. Vasomotor and physical domains of life quality were improved compared with placebo. Safety measures did not yield any adverse event assigned to black cohosh. CONCLUSIONS: In early postmenopausal women with a major sleep complaint, black cohosh effectively improved sleep and might be a safe measure in managing menopausal sleep disturbance. PMID- 26000552 TI - Synthesis, Characterization, and Some Properties of Cp*W(NO)(H)(eta(3)-allyl) Complexes. AB - Sequential treatment at low temperatures of Cp*W(NO)Cl2 in THF with 1 equiv of a binary magnesium allyl reagent, followed by an excess of LiBH4, affords three new Cp*W(NO)(H)(eta(3)-allyl) complexes, namely, Cp*W(NO)(H)(eta(3)-CH2CHCMe2) (1), Cp*W(NO)(H)(eta(3)-CH2CHCHPh) (2), and Cp*W(NO)(H)(eta(3)-CH2CHCHMe) (3). Complexes 1-3 are isolable as air-stable, analytically pure yellow solids in good to moderate yields by chromatography or fractional crystallization. In solutions, complex 1 exists as two coordination isomers in an 83:17 ratio differing with respect to the endo/exo orientation of the allyl ligand. In contrast, complexes 2 and 3 each exist as four coordination isomers, all differing by the orientation of their allyl ligands which can have either an endo or an exo orientation with the phenyl or methyl groups being either proximal or distal to the nitrosyl ligand. A DFT computational analysis using the major isomer of Cp*W(NO)(H)(eta(3) CH2CHCHMe) (3a) as the model complex has revealed that its lowest-energy thermal decomposition pathway involves the intramolecular isomerization of 3a to the 16e eta(2)-alkene complex, Cp*W(NO)(eta(2)-CH2?CHCH2Me). Such eta(2)-alkene complexes are isolable as their 18e PMe3 adducts when compounds 1-3 are thermolyzed in neat PMe3, the other organometallic products formed during these thermolyses being Cp*W(NO)(PMe3)2 (5) and, occasionally, Cp*W(NO)(H)(eta(1)-allyl)(PMe3). All new complexes have been characterized by conventional spectroscopic and analytical methods, and the solid-state molecular structures of most of them have been established by single-crystal X-ray crystallographic analyses. PMID- 26000553 TI - Metabolic potential of fatty acid oxidation and anaerobic respiration by abundant members of Thaumarchaeota and Thermoplasmata in deep anoxic peat. AB - To probe the metabolic potential of abundant Archaea in boreal peats, we reconstructed two near-complete archaeal genomes, affiliated with Thaumarchaeota group 1.1c (bin Fn1, 8% abundance), which was a genomically unrepresented group, and Thermoplasmata (bin Bg1, 26% abundance), from metagenomic data acquired from deep anoxic peat layers. Each of the near-complete genomes encodes the potential to degrade long-chain fatty acids (LCFA) via beta-oxidation. Fn1 has the potential to oxidize LCFA either by syntrophic interaction with methanogens or by coupling oxidation with anaerobic respiration using fumarate as a terminal electron acceptor (TEA). Fn1 is the first Thaumarchaeota genome without an identifiable carbon fixation pathway, indicating that this mesophilic phylum encompasses more diverse metabolisms than previously thought. Furthermore, we report genetic evidence suggestive of sulfite and/or organosulfonate reduction by Thermoplasmata Bg1. In deep peat, inorganic TEAs are often depleted to extremely low levels, yet the anaerobic respiration predicted for two abundant archaeal members suggests organic electron acceptors such as fumarate and organosulfonate (enriched in humic substances) may be important for respiration and C mineralization in peatlands. PMID- 26000554 TI - Passive microfluidic chamber for long-term imaging of axon guidance in response to soluble gradients. AB - Understanding how axons are guided to target locations within the brain is of fundamental importance for neuroscience, and is a widely studied area of research. Biologists have an unmet need for reliable and easily accessible methods that generate stable, soluble molecular gradients for the investigation of axon guidance. Here we developed a microfluidic device with contiguous media filled compartments that uses gravity-driven flow to generate a stable and highly reproducible gradient within a viewing compartment only accessible to axons. This device uses high-resistance microgrooves to both direct the growth of axons into an isolated region and to generate a stable gradient within the fluidically isolated axon viewing compartment for over 22 h. Establishing a stable gradient relies on a simple and quick pipetting procedure with no external pump or tubing. Since the axons extend into the axonal compartment through aligned microgrooves, the analysis of turning is simplified. Further, the multiple microgrooves in parallel alignment serve to increase sample sizes, improving statistical analyses. We used this method to examine growth cone turning in response to the secreted axon guidance cue netrin-1. We report the novel finding that growth cones of embryonic mouse cortical axons exhibited attractive turning in the lower concentrations of netrin-1, but were repulsed when exposed to higher concentrations. We also performed immunocytochemistry in growth cones exposed to a netrin-1 gradient within the axon viewing compartment and show that netrin receptors associated with both attraction and repulsion, DCC and UNC5H, localized to these growth cones. Together, we developed an accessible gradient chamber for higher throughput axon guidance studies and demonstrated its capabilities. PMID- 26000555 TI - Covariation bias in women with a negative body evaluation: How is it expressed and can it be diminished? AB - BACKGROUND AND OBJECTIVES: Women with a negative body evaluation display covariation bias: They overestimate the relation between their own body and negative social feedback. This study aimed to develop a more fine-grained understanding of this covariation bias and to determine whether it could be diminished. METHODS: Seventy women completed a computer task wherein three categories of stimuli--pictures of their own body, a control woman's body, and a neutral object--were followed by (nonverbal) negative social feedback or nothing. Participants' estimates of the relation between each stimulus category and negative social feedback were assessed throughout the task. RESULTS: Before starting the task, women with a more negative state body evaluation expected their body to be followed by more negative social feedback (demonstrating a priori covariation bias). During the task, when the relation between stimulus category and negative social feedback was random, women with a more negative trait and state body evaluation perceived at the present moment (online covariation bias) and retrospectively (a posteriori covariation bias) that their body was followed by more negative social feedback. When contingencies were manipulated so that women's own body was rarely followed by negative social feedback, covariation bias was temporarily diminished; this coincided with improvements in state body evaluation. LIMITATIONS: The task did not incorporate neutral or positive social feedback and focused only on undergraduate women. CONCLUSIONS: Covariation bias exists preexperimentally and occurs when situational information is ambiguous. It is possible to (temporarily) diminish covariation bias. This might be a technique for improving body evaluation. PMID- 26000556 TI - Electric Dipole Transition Moments and Solvent-Dependent Interactions of Fluorescent Boron-Nitrogen Substituted Indole Derivatives. AB - Fluorescent analogues of the indole side chain of tryptophan can be useful spectroscopic probes of protein-protein and protein-DNA interactions. Here we present linear dichroism and solvent-dependent spectroscopic studies of two fluorescent analogues of indole, in which the organic C?C unit is substituted with the isosteric inorganic B-N unit. We studied the so-called "external" BN indole, which has C2v symmetry, and the "fused" BN indole with Cs symmetry. We performed a combination of absorption and fluorescence spectroscopy, ultraviolet linear dichroism (UV-LD) in stretched poly(ethylene) (PE) films, and quantum chemical calculations on both BN indole compounds. Our measurements allowed us to characterize the degree of alignment for both molecules in stretched PE films. We thus determined the orientations and magnitudes of the two lowest energy electric dipole transition moments (EDTMs) for external BN indole, and the two lowest energy EDTMs for fused BN indole within the 30 000-45 000 cm(-1) spectral range. We compared our experimental results to those of quantum chemical calculations using standard density functional theory (DFT). Our theoretical predictions for the low-energy EDTMs are in good agreement with our experimental data. The absorption and fluorescence spectra of the external and the fused BN indoles are sensitive to solvent polarity. Our results indicate that the fused BN indole experiences much greater solvation interactions with polar solvents than does the external BN indole. PMID- 26000558 TI - Rosmarinus officinalis L. extract and some of its active ingredients as potential emulsion stabilizers: a new approach to the formation of multiple (W/O/W) emulsion. AB - Nowadays, novel topical formulations loaded with natural functional actives are under intense investigations. Therefore, the aim of our study was to evaluate how the rosemary extract and some of its active ingredients [rosmarinic acid (RA), ursolic acid (UA) and oleanolic acid (OA)] affect technological characteristics of multiple emulsion. Formulation has been prepared by adding investigated solutions (10%) in water/oil/water (W/O/W) multiple emulsion consisting of different lipophilic phases: olive oil and liquid paraffin, with 0.5% emulsifying agent (complex of sodium polyacrylate and polysorbate 20) under constant stirring with mechanical stirrer at room temperature. The emulsion parameters were evaluated using centrifugation test, freeze-thaw cycle test, microscopical and texture analyses. Rosemary's triterpenic saponins UA and OA showed the highest emulsion stabilizing properties: they decreased CI from 3.26% to 10.23% (p < 0.05). According to obtained interfacial tension data, the effect of rosemary active ingredients is not surfactant-like. Even though emulsifier itself at low concentration intends to form directly the multiple emulsion, the obtained results indicate that rosemary extract containing active ingredients does not only serve as functional cosmetic agent due to a number of biological activities, but also offer potential advantages as a stabilizer and an enhancer of W/O/W emulsions formation for dermopharmaceutical and cosmetic preparations. PMID- 26000557 TI - Hearing the light: neural and perceptual encoding of optogenetic stimulation in the central auditory pathway. AB - Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior. PMID- 26000559 TI - Sitagliptin for Type 2 diabetes: a 2015 update. AB - Sitagliptin, a dipeptidyl peptidase 4 inhibitor, was the first in its class to receive approval from the US FDA in 2006 for the treatment of Type 2 diabetes mellitus. It has been evaluated in numerous clinical trials and has several attractive features as an antidiabetic agent, including a low risk for hypoglycemia, a neutral effect on weight, and an ability to be used in chronic kidney disease and more. This article provides an up-to-date discussion of the pharmacokinetics/pharmacodynamics, clinical efficacy, safety and tolerability of sitagliptin. PMID- 26000560 TI - Once-weekly exenatide as a treatment for Type 2 diabetes. AB - Type 2 diabetes mellitus is a progressive disease that requires pharmacologic treatment to prevent microvascular and macrovascular complications. As the disease progresses, most patients require combination therapy to achieve glucose control targets. Exenatide once weekly (EQW) is a glucagon-like peptide-1 receptor agonist approved in the United States in 2012 for use as a second-line agent to treat Type 2 diabetes mellitus. EQW has shown reductions in HbA1c and weight without causing an increased risk of hypoglycemia. This review will summarize the current clinical trial, observational study, and pharmacoeconomic analyses evaluating EQW and its impact on HbA1c and weight. PMID- 26000561 TI - Rebirth of left radial artery access: could this be the 'right' radial artery? AB - Cardiac catheterization has several risks, notably which include bleeding, stroke and death. The transradial (TR) approach to catheterization is associated with a lower bleeding risk. The right radial approach is the default method in most laboratories and the left radial artery (LRA) serves as the bail-out approach. This article discusses the advantages and disadvantages of transfemoral and TR access routes. The authors envisage an increased adoption of the LRA approach, due to the anatomical superiority and ease of catheter engagement afforded by this approach. The authors discuss ways to increase operator ease for LRA in the laboratory and propose a novel way to improve LRA work-flow. PMID- 26000562 TI - Management and prognosis of atrial fibrillation in the diabetic patient. AB - The global burden of atrial fibrillation and diabetes mellitus (diabetes) is considerable, and prevalence rates are increasing. Diabetes is associated with an increased risk of developing atrial fibrillation; however, diabetes also influences the management and prognosis of atrial fibrillation. In the following article, the authors describe the association between diabetes and atrial fibrillation; specifically, the significance of diabetes on the risk of atrial fibrillation, ischemic stroke and bleeding complications associated with anticoagulation. In addition, the authors evaluate the risks and outcomes of heart failure and the success rates of both ablation and cardioversion in atrial fibrillation patients with diabetes. Finally, this article describes the association of HbA1c levels with the management and prognosis of atrial fibrillation patients. PMID- 26000563 TI - Managing aortic aneurysms and dissections during pregnancy. AB - Cardiovascular diseases during pregnancy account for significant morbidity and mortality, with aortic aneurysms, complicated by aortic dissection or rupture, being high on the list of underlying causes in this category. Correct knowledge of the diagnosis, risks and treatment is mandatory to improve the outcome and save lives. In this article, the authors aim to provide an overview of the underlying causes and risk factors for aortic aneurysms and dissections during pregnancy, while presenting the ways of preventing and treating these conditions. Although an important focus lies on the proximal part of the aorta due to it bearing the greatest risk for complications and being more frequently implicated in aortic disease in younger subjects, many aspects on the etiology and underlying diseases also apply to the other parts of the vessel. PMID- 26000564 TI - Cu/Pd-Catalyzed, Three-Component Click Reaction of Azide, Alkyne, and Aryl Halide: One-Pot Strategy toward Trisubstituted Triazoles. AB - A Cu/Pd-catalyzed, three-component click reaction of azide, alkyne, and aryl halide has been developed. By using this Cu/Pd transmetalation relay catalysis, a variety of 1,4,5-trisubstituted 1,2,3-triazoles were quickly assembled in one step in high yields with complete regioselectivity, just like assembling Lego bricks. Notably, different from the well-established CuAAC click reactions only working on terminal alkynes, this reaction offers an alternative solution for the problem of the click reaction of internal alkynes. PMID- 26000565 TI - Monoterpenes from the leaves of Hydrangea paniculata and their hepatoprotective activities. AB - Three new monoterpenes, hydrangines A-C (1-3), together with four known compounds, were isolated from the ethanol extract of the leaves of Hydrangea paniculata. The structures of new isolates were elucidated on the basis of extensive 1D and 2D NMR analyses, and their absolute configurations were determined by comparison of experimental and calculated electronic circular dichroism spectra. In in vitro bioassays at 10 MUM, compounds 1-6 showed hepatoprotective activities against dl-galactosamine-induced toxicity in HL-7702 cells. PMID- 26000567 TI - Geometric pumping in autophoretic channels. AB - Many microfluidic devices use macroscopic pressure differentials to overcome viscous friction and generate flows in microchannels. In this work, we investigate how the chemical and geometric properties of the channel walls can drive a net flow by exploiting the autophoretic slip flows induced along active walls by local concentration gradients of a solute species. We show that chemical patterning of the wall is not required to generate and control a net flux within the channel, rather channel geometry alone is sufficient. Using numerical simulations, we determine how geometric characteristics of the wall influence channel flow rate, and confirm our results analytically in the asymptotic limit of lubrication theory. PMID- 26000566 TI - Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. AB - Minocycline is a broad-spectrum tetracycline antibiotic. A number of preclinical studies have shown that minocycline exhibits neuroprotective effects in various animal models of neurological diseases. However, it remained unknown whether minocycline is effective to prevent neuron loss. To systematically evaluate its effects, minocycline was used to treat Dicer conditional knockout (cKO) mice which display age-related neuron loss. The drug was given to mutant mice prior to the occurrence of neuroinflammation and neurodegeneration, and the treatment had lasted 2 months. Levels of inflammation markers, including glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule1 (Iba1) and interleukin6 (IL6), were significantly reduced in minocycline-treated Dicer cKO mice. In contrast, levels of neuronal markers and the total number of apoptotic cells in Dicer cKO mice were not affected by the drug. In summary, inhibition of neuroinflammation by minocycline is insufficient to prevent neuron loss and apoptosis. PMID- 26000569 TI - The role of the molecular structure of carboxylate-alumoxanes in the enhanced nucleation of polypropylene. AB - We have reported the use of carboxylate-alumoxanes as efficient nucleating agents for isotactic polypropylene (iPP) with a possible structural correlation to the nucleation efficiency. The unique, butterfly-like structure of carboxylate alumoxanes correlates well with the nucleation characteristics of iPP and, for the first time, the impact of a thermally induced, crystalline transition of carboxylate-alumoxanes, which alters neither the structural conformation nor the nucleation efficiency of the transformed material, is demonstrated. PMID- 26000568 TI - The Prevalence of Angiostrongylus cantonensis/mackerrasae Complex in Molluscs from the Sydney Region. AB - Angiostrongylus cantonensis and Angiostrongylus mackerrasae are metastrongyloid nematodes that infect various rat species. Terrestrial and aquatic molluscs are intermediate hosts of these worms while humans and dogs are accidental hosts. Angiostrongylus cantonensis is the major cause of angiostrongyliasis, a disease characterised by eosinophilic meningitis. Although both A. cantonensis and A. mackerrasae are found in Australia, A. cantonensis appears to account for most infections in humans and animals. Due to the occurrence of several severe clinical cases in Sydney and Brisbane, the need for epidemiological studies on angiostrongyliasis in this region has become apparent. In the present study, a conventional PCR and a TaqMan assay were compared for their ability to amplify Angiostrongylus DNA from DNA extracted from molluscs. The TaqMan assay was more sensitive, capable of detecting the DNA equivalent to one hundredth of a nematode larva. Therefore, the TaqMan assay was used to screen molluscs (n=500) of 14 species collected from the Sydney region. Angiostrongylus DNA was detected in 2 of the 14 mollusc species; Cornu aspersum [14/312 (4.5%)], and Bradybaenia similaris [1/10 (10%)], which are non-native terrestrial snails commonly found in urban habitats. The prevalence of Angiostrongylus spp. was 3.0% +/- 0.8% (CI 95%). Additionally, experimentally infected Austropeplea lessoni snails shed A. cantonensis larvae in their mucus, implicating mucus as a source of infection. This is the first Australian study to survey molluscs using real-time PCR and confirms that the garden snail, C. aspersum, is a common intermediate host for Angiostrongylus spp. in Sydney. PMID- 26000570 TI - Co-solvent enhanced zinc oxysulfide buffer layers in Kesterite copper zinc tin selenide solar cells. AB - A co-solvent, dimethylsulfoxide (DMSO), is added to the aqueous chemical "bath" deposition (CBD) process used to grow ZnOS buffer layers for thin film Cu2ZnSnSe4 (CZTSe) solar cells. Device performance improves markedly as fill factors increase from 0.17 to 0.51 upon the co-solvent addition. X-ray photoelectron spectroscopy (XPS) analyses are presented for quasi-in situ CZTSe/CBD-ZnOS interfaces prepared under an inert atmosphere and yield valence band offsets equal to -1.0 eV for both ZnOS preparations. When combined with optical band gap data, conduction band offsets exceed 1 eV for the water and the water/DMSO solutions. XPS measurements show increased downward band bending in the CZTSe absorber layer when the ZnOS buffer layer is deposited from water only. Admittance spectroscopy data shows that the ZnOS deposited from water increases the built-in potential (Vbi) yet these solar cells perform poorly compared to those made with DMSO added. The band energy offsets imply an alternate form of transport through this junction. Possible mechanisms are discussed, which circumvent the otherwise large conduction band spike between CZTSe and ZnOS, and improve functionality with the low-band gap absorber, CZTSe (Eg = 0.96 eV). PMID- 26000571 TI - Are We Doing Enough to Address the Cancer Care Needs ?of the LGBT Community? AB - The 2011 film titled Gen Silent (http://gensilent.com) focuses on the needs and issues of six aging lesbian, gay, bisexual, and transgender (LGBT) people, at least two of whom had cancer. One of the issues made apparent in the film was the lack of trust in the healthcare system and the discrimination these individuals faced at a time when their needs were growing and they were increasingly vulnerable. It was sad and caused us to reflect on what we, as oncology nurses, are doing to meet the needs of LGBT individuals faced with a cancer diagnosis.?. PMID- 26000572 TI - Response to "biologic, demographic, and social factors affecting triple negative breast cancer outcomes"?. PMID- 26000573 TI - A workshop for educating nurses to address sexual health in patients with breast cancer. AB - Breast cancer is associated with significant sexual side effects. However, nurses and other healthcare providers are often reluctant to initiate a discussion about sexual health with their patients because of numerous barriers, including knowledge, time, and confidence. This article describes the development and implementation of a sexual health workshop for oncology nurses intended to increase their knowledge about common sexual side effects in patients with breast cancer, strengthen their confidence in addressing sexual health, and provide them with tools and resources to educate their patients. PMID- 26000574 TI - Peripherally inserted central catheter cushioning: ?a pilot study comparing gauze with silicone foam. AB - A pilot study was conducted to compare gauze with silicone foam that may be left in place for as long as seven days. Adult patients who were receiving treatment via peripherally inserted central catheters were recruited and alternately assigned to either the gauze or silicone foam group. Patient-reported itch and discomfort, nurse-reported ease of removal, and skin status were recorded for four weeks at each weekly dressing change. PMID- 26000575 TI - Stimulating a Culture of Improvement: Introducing ?an Integrated Quality Tool for Organizational Self-Assessment. AB - As leaders and systems-level agents of change, oncology nurses are challenged by opportunities to guide organizational transformation from the front line to the board room. Across all care settings, reform and change initiatives are constants in the quest to optimize quality and healthcare outcomes for individuals, teams, populations, and organizations. This article describes a practical, evidence based, integrated quality tool for initiating organizational self-assessment to prioritize issues and stimulate a culture of continuous improvement. PMID- 26000576 TI - Use of robotics in oncology surgery. AB - Robotic surgery is an exciting technology that allows the surgeon to sit at a computer console near the operating table, using mechanical arms with surgical instruments attached to them. This type of surgery is minimally invasive, and the procedure is performed through tiny incisions. This technology is widely used in the United States and is expected to evolve over time with an increase in the number and types of procedures. PMID- 26000577 TI - Implementation and Evaluation ?of a High-Dose Cytarabine Neurologic Assessment Tool. AB - Patients receiving high-dose cytarabine as part of their chemotherapy regimen have a chance of experiencing neurotoxicities. Prompt identification of signs and symptoms can greatly reduce the chance of patients sustaining permanent neurologic damage. This article describes the development and successful implementation of an evidence-based, standardized neurologic assessment and documentation tool that was evaluated using a clinical utility questionnaire and an adherence audit. PMID- 26000578 TI - A pilot study comparing the neutropenic diet to a non-neutropenic diet in the allogeneic hematopoietic stem cell transplantation population. AB - BACKGROUND: Historically, dietary restrictions imposed on patients undergoing hematopoietic stem cell transplantation (HSCT) were severe and limited to prevent exposure to foodborne organisms. With improvements in supportive care and anti infective agents, the necessity of the neutropenic diet for this population has been in question. OBJECTIVES: This study aimed to determine whether the incidence of infection differs and to analyze the nutritional status in patients undergoing myeloablative allogeneic HSCT with a neutropenic diet as compared to those with a diet without restrictions. METHODS: This study was a randomized, controlled prospective pilot study beginning within the first 24 hours of the start of the conditioning regimen. Patients were randomized to receive a neutropenic diet or a diet without restrictions. All patients received care in a high-efficiency particulate air-filtered room on the inpatient adult blood and marrow transplantation unit (ABMTU). All patients received antibacterial and antifungal prophylaxis. Patients were followed until the end of neutropenia (defined as absolute neutrophil count of greater than 500 for three days) or until discharge from the inpatient ABMTU. FINDINGS: In 46 evaluable patients, no significant difference was found between infection rates or nutritional status. The neutropenic diet did not offer a protective effect against infection in patients undergoing myeloablative allogeneic HSCT. No differences were found in nutritional status between the two groups. PMID- 26000579 TI - Nurse perspectives regarding the meaningfulness of oncology nursing practice. AB - BACKGROUND: Recruiting, retaining, and training oncology nurses is challenging given the stress levels associated with a field with constantly evolving treatments and a need for expertise in death and dying. OBJECTIVES: This research was conducted to assess what is unique about oncology nursing, to identify what motivates oncology nurses to continue working in the specialty, and to determine what sustains them in daily practice. METHODS: A phenomenologic approach was used to analyze data. FINDINGS: Nurses identified three main themes: the importance of vulnerability and thankfulness in patients, the feeling of spirituality associated with oncology practice, and the value of being in the moment and recognizing priorities as meaningful aspects of oncology nursing. PMID- 26000580 TI - Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution. AB - BACKGROUND: Sipuleucel-T, an autologous cellular immunotherapy, is approved for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first personalized treatment for prostate cancer to be manufactured using the immune system of each individual patient. Patient preparation and compliance are critical because patients undergo serial leukapheresis and reinfusion procedures within a relatively short time period, which may result in transient reactions. OBJECTIVES: The study aims to identify patients best suited for sipuleucel-T treatment, provide an overview of treatment, and encourage infusion sites to consider a primary contact model for the efficient coordination of care. METHODS: Treatment experiences were evaluated from 124 patients with mCRPC who received sipuleucel-T from January 2010 to August 2013 according to current best practices. Feedback was collected from reflective interdisciplinary discussion within the sipuleucel-T delivery team (nurses, advanced practice providers, urologists, and medical oncologists). FINDINGS: Early patient identification and education on treatment rationale, delivery, and expectations help ensure a successful sipuleucel-T treatment experience. A multidisciplinary coordinated-care process can facilitate proficient sipuleucel-T delivery, and the selection of a primary contact for care coordination offers benefits, such as clear and efficient education. PMID- 26000581 TI - Systematic review of oncology nurse practitioner navigation metrics. AB - BACKGROUND: Nurse practitioners should become more active in patient navigation and its subcomponent, care coordination, because research has shown that these roles are influential in improving patient care at all levels of an organization. Well-defined process and outcome measures, as well as educational initiatives, are critical to these programs because they serve as the structure for program evaluation. OBJECTIVES: This article aims to assess and define metrics that nurse practitioners in the oncology setting can use to evaluate navigation programs, which is essential for the evolution of research pertaining to the navigation field. METHODS: The current article is a systematic review that describes oncology nurse practitioner navigation metrics using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) format for the systematic literature review process. These metrics are then compared to current standards of care. FINDINGS: Seven studies met the criteria for this review. Research is emerging that shows benefit in using an oncology nurse practitioner navigator for ensuring timely care and patient and staff satisfaction. These metrics are in line with expert consensus recommendations. The need for more research identifying sound research tools that have been rigorously tested has been identified. PMID- 26000582 TI - Hepatic artery infusion pump in the treatment of liver metastases. AB - BACKGROUND: Hepatic artery infusion pump (HAIP) use in chemotherapy started in the 1960s as a way to treat liver metastases that were not amendable to locoregional therapy or surgical resection. Because of complications and limited survival benefit, the use of HAIPs fell out of favor. A resurgence has occurred in the use of these pumps, but limited information is available in the literature guiding nursing care of these patients. OBJECTIVES: The purpose of this study was to review the literature regarding the use, procedures, and nursing care of patients with HAIPs. METHODS: A systematic literature review was conducted to obtain a comprehensive range of publications. FINDINGS: Database searching resulted in 511 titles and abstracts. After eliminating duplicates and nonrelevant titles, 65 remained and were read in full. Of these, 20 were excluded because they did not fit the inclusion criteria. PMID- 26000583 TI - From evidence to practice: developing an outpatient acuity-based staffing model. AB - BACKGROUND: Reliable and valid outpatient oncology acuity-based staffing systems are lacking. The existing staffing model in a midwestern cancer center demonstrated inefficiencies related to unpredictable patient flow, treatment regimen complexity, and physician practice variation. OBJECTIVES: A project was initiated to implement an evidence-based oncology outpatient staffing system maximizing patient satisfaction, employee engagement, and equity in workload distribution. The strength of evidence for 34 articles and 12 additional documents was moderate to strong, supporting development of an acuity-based staffing system. Evidence indicates that nursing assignments directly contribute to patient flow efficiency. An acuity point system was established. METHODS: A six-month pilot was completed comparing a control group to a pilot group, with defined maximum acuity points per nurse. Inter-group comparison included acuity scores, patient satisfaction, wait time, employee engagement, nurse overtime, and turnover. FINDINGS: Resultant changes included scheduled nurse time (preparation, charting, lunch breaks), revised acuity-based patient scheduling, and a revised nursing care delivery model. Implementation of the acuity-based system provided consistent staffing, improved efficiency, reduced overtime, and improved patient and staff satisfaction. Recommendations include adaptation of the acuity-based system to other outpatient settings and development of staffing level benchmarks. PMID- 26000584 TI - Symptom alleviation and self-care among breast cancer survivors after treatment completion. AB - BACKGROUND: This article elucidates the symptom experiences of breast cancer survivors after completion of their treatment. It also provides self reports of the types, frequency of use, and effectiveness of self-care measures to treat the symptoms they are experiencing. OBJECTIVES: The purpose of this article is to describe the self-care strategies used to alleviate symptoms reported by breast cancer survivors recruited from a secure state coalition database. METHODS: The Therapy-Related Symptom Checklist (TRSC) was used to identify the occurrence and severity of ongoing symptoms in breast cancer survivors who were six months or more post-treatment. Two groups were identified for further exploration of self care. FINDINGS: The self-care method category most commonly reported was diet/nutrition/lifestyle and the least common category was herbs/vitamins/complementary therapy. With few exceptions, the reported methods were perceived as effective. PMID- 26000585 TI - Effectiveness of standard of care protocol on patient satisfaction and perceived staff caring. AB - BACKGROUND: Nurse caring has been linked to many clinical outcomes, including patient satisfaction, well-being, and healing. In addition, it is valued by nursing staff and viewed as being essential to clinical practice. OBJECTIVES: The purpose of this program evaluation study was to determine the difference in patient satisfaction with overall nursing care and perceived nurse caring when a nursing staff standard of care protocol, which included caring activities, was implemented within a nursing department at a National Cancer Institute-designated comprehensive cancer center. METHODS: A pre-experimental pre-/post-test design with comparison group and a post-test-only design were used to test the effect of the caring protocol on patient satisfaction with nursing care and perceived nurse caring. The study was conducted on seven inpatient units. FINDINGS: Patient satisfaction with nursing care increased for some items, and perceived nurse caring was ranked highly immediately before discharge. Additional program evaluation studies involving a modified caring protocol may improve satisfaction with nursing care in other settings. PMID- 26000586 TI - Clinical nursing care for transgender patients with cancer. AB - Transgender people often face barriers in their pursuit of receiving sensitive and informed health care, and many avoid preventive care and care for life threatening conditions because of those obstacles. This article focuses on cancer care of the transgender patient, as well as ways that nurses and other providers can help to create a transgender-sensitive healthcare environment. PMID- 26000587 TI - The evolution of a malignant hematology ?nurse practitioner service. AB - Nurse practitioners (NPs) have been suggested as one possible solution to the predicted oncologist shortage. Although NPs are in a unique position to positively affect the care of patients with hematologic malignancies who are hospitalized, little information exists regarding the inpatient role of the NP in hematology and oncology. The purpose of this article is to describe the successful implementation and evolution of a highly functioning inpatient malignant hematology NP service. PMID- 26000588 TI - Workplace fatigue among oncology nursing personnel. AB - Workplace fatigue is common among occupations that have prolonged work hours, rotating shifts, night-time work hours, inadequate time for rest during work, and insufficient time for recovery between shifts. Available evidence suggests that workplace fatigue poses a substantial threat to patient safety and contributes to worker injury and decreased vigilance. However, little is known about workplace fatigue among nursing personnel working in institutions dedicated solely to the care of patients with cancer. This study describes the scope and severity of workplace fatigue among nursing personnel working in the inpatient and ambulatory care divisions of a comprehensive cancer center.? PMID- 26000589 TI - Palliative pharmacologic sedation for terminally ill adults. PMID- 26000590 TI - Ibrutinib: a new targeted therapy for hematologic cancers. AB - BACKGROUND: Hematologic cancers can occur from the overactivity of Bruton's tyrosine kinase, a proto-oncogene in blood cell maturation. Ibrutinib, a new oral targeted therapy drug, is the first agent that binds to the Bruton's tyrosine kinases and inhibits overgrowth of B cells. In blocking this overgrowth, ibrutinib has been shown to achieve lengthy remissions for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Remissions are highly valued in these cancers; cure is rare in MCL, and CLL is incurable. OBJECTIVES: This article reviews ibrutinib, its risks and benefits, and the role that oncology nurses play in educating patients and promoting drug adherence. METHODS: A comprehensive review of the literature was conducted using key words such as ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, tyrosine kinase inhibitor, and oral chemotherapy. FINDINGS: Ibrutinib has been shown to be well tolerated, with manageable, low-grade toxicities compared to traditional cytotoxic agents. For all patients with a hematologic cancer, but particularly for the large proportion of older adults affected by hematologic malignancies, ibrutinib provides a new treatment option with a low toxicity profile. PMID- 26000591 TI - Mammography: review of the controversy, health disparities, and impact on young african american women. AB - BACKGROUND: Ongoing debate about mammography screening for women in their 40s has brought awareness to the opportunities and challenges for achieving optimal breast health in young African American women and in battling health inequities that place them at greater risk for mortality from breast cancer. Despite the screening controversy, a need exists to understand the complex issues related to mammography knowledge, attitudes, and behaviors of young minority women, while empowering them to take an active role in their breast health care. OBJECTIVES: The purpose of this article is to describe the complicated issues related to screening in young African American women within the context of the uncertainty about the evidence surrounding screening practices. METHODS: Literature was reviewed to garner a comprehensive update of the mammography screening controversy and its impact on mammography practices. FINDINGS: Nurses should be aware of the mammography screening controversy and breast cancer risk assessment and how they affect young women's participation in mammography screening. Mammography screening should be a shared decision between the patient and healthcare provider. A better understanding of breast health and its effect on young minority women is needed. Nurses have a prominent role to advocate for, empower, and educate patients as they face the task of deciding whether to begin or continue mammography in their 40s. PMID- 26000592 TI - Nursing considerations for patients with sarcoma on pazopanib therapy. AB - BACKGROUND: Pazopanib was approved by the U.S. Food and Drug Administration for use in patients with soft tissue sarcoma (STS) in 2012. Because of the scarcity of effective treatments for advanced STS, pazopanib has become commonly prescribed. OBJECTIVES: The purpose of this study was to assess the knowledge level of nurses regarding the safe administration of pazopanib, as well as management of its side effects. The study was also intended to examine the consistency of patient education about pazopanib. METHODS: A 12-question online survey was completed by six nurses working in the outpatient sarcoma department of a National Cancer Institute-designated comprehensive cancer center. The survey included questions about patient education, including side-effect management and medication safety. FINDINGS: The survey revealed that most nurses were consistent with best practices surrounding pazopanib teaching and side-effect management. However, many differences were observed, and patient education regarding drug interactions and the safe administration of pazopanib is lacking. Further standardization of nursing practice in this regard would greatly benefit patients taking pazopanib. PMID- 26000593 TI - Community interventions for survivors and their families: a literature synthesis. AB - BACKGROUND: Advancements in technology and treatment have increased the survival rate for many cancers. Because many people in the United States who are living with cancer reside in communities, a need exists for community-based interventions for survivors and their families. OBJECTIVES: The goal of this article is to inform nurses and researchers about current evidence-based community intervention outcomes and make recommendations to support care of community survivors of cancer. METHODS: A literature search was conducted for community interventions with a survivor component. Fifteen articles were selected for analysis in two categories of community intervention research, women with breast cancer and people with all types of cancer. FINDINGS: The literature synthesis indicated that community-based interventions are beneficial to enhancing quality of life and decreasing symptoms in survivors. Exercise, support, and family-centered interventions for children and spouses demonstrated promising results. These findings have implications for nursing practice in communities, where oncology nurses and other professionals can begin concentrating intervention efforts. Additional studies are needed on high quality, cost-effective, and collaborative community-based interventions for survivors of cancer, including underrepresented populations. PMID- 26000595 TI - Comparison of the effects of glycerol, dimethyl sulfoxide, and hydroxyethyl starch solutions for cryopreservation of avian red blood cells. AB - OBJECTIVE: To compare effectiveness of glycerol, dimethyl sulfoxide (DMSO), and hydroxyethyl starch (HES) solutions for cryopreservation of avian RBCs. SAMPLE: RBCs from 12 healthy Ameraucana hens (Gallus gallus domesticus). PROCEDURES: RBCs were stored in 20% (wt/vol) glycerol, 10% (wt/vol) DMSO freezing medium, or various concentrations of HES solution (7.5%, 11.5%, and 20% [wt/vol]) and frozen for 2 months in liquid nitrogen. Cells were then thawed and evaluated by use of cell recovery and saline stability tests, cell staining (7-aminoactinomycin D and annexin V) and flow cytometry, and scanning electron microscopy. RESULTS: Percentage of RBCs recovered was highest for 20% glycerol solution (mean +/- SE, 99.71 +/- 0.04%) and did not differ significantly from the value for 7.5% HES solution (99.57 +/- 0.04%). Mean saline stability of RBCs was highest for 10% DMSO (96.11 +/- 0.25%) and did not differ significantly from the value for 20% HES solution (95.74 +/- 0.25%). Percentages of cells with 7-aminoactinomycin D staining but without annexin V staining (indicating necrosis or late apoptosis) were lowest for 10% DMSO freezing medium (3%) and 20% glycerol solution (1%) and highest for all HES concentrations (60% to 80%). Scanning electron microscopy revealed severe membrane changes in RBCs cryopreserved in 20% HES solution, compared with membrane appearance in freshly harvested RBCs and RBCs cryopreserved in 10% DMSO freezing medium. CONCLUSIONS AND CLINICAL RELEVANCE: Cryopreservation of avian RBCs with HES solution, regardless of HES concentration, resulted in greater degrees of apoptosis and cell death than did cryopreservation with other media. Transfusion with RBCs cryopreserved in HES solution may result in posttransfusion hemolysis in birds. PMID- 26000596 TI - Measurement of intraocular pressure in healthy unanesthetized inland bearded dragons (Pogona vitticeps). AB - OBJECTIVE: To evaluate the use of rebound and applanation tonometry for the measurement of intraocular pressure (IOP) and to assess diurnal variations in and the effect of topical anesthesia on the IOP of healthy inland bearded dragons (Pogona vitticeps). ANIMALS: 56 bearded dragons from 4 months to 11 years old. PROCEDURES: For each animal following an initial ophthalmic examination, 3 IOP measurements were obtained on each eye between 9 AM and 10 AM, 1 PM and 2 PM, and 5 PM and 7 PM by use of rebound and applanation tonometry. An additional measurement was obtained by rebound tonometry for each eye in the evening following the application of a topical anesthetic to evaluate changes in the tolerance of the animals to the tonometer. Descriptive data were generated, and the effects of sex, time of day, and topical anesthesia on IOP were evaluated. RESULTS: Bearded dragons did not tolerate applanation tonometry even following topical anesthesia. Median daily IOP as determined by rebound tonometry was 6.16 mm Hg (95% confidence interval, 5.61 to 6.44 mm Hg). The IOP did not differ significantly between the right and left eyes. The IOP was highest in the morning, which indicated that the IOP in this species undergoes diurnal variations. Topical anesthesia did not significantly affect IOP, but it did improve the compliance for all subjects. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that rebound tonometry, but not applanation tonometry, was appropriate for measurement of IOP in bearded dragons. These findings provided preliminary guidelines for IOP measurement and ophthalmic evaluation in bearded dragons. PMID- 26000597 TI - Optimal cutoff points of entropy indices for use in predicting responses elicited during determination of minimum alveolar concentration of sevoflurane in dogs. AB - OBJECTIVE: To investigate values of spectral indices for use in predicting responses in dogs during determination of minimum alveolar concentration (MAC) of sevoflurane. ANIMALS: 15 healthy German Shepherd Dogs. PROCEDURES :Sevoflurane MAC was determined by use of tail clamping. Entropy indices consisting of response entropy and state entropy were recorded during MAC determination. Optimal cutoff points of response entropy and state entropy for use in predicting responses to tail clamping were analyzed with multiple logistic regression. RESULTS: Sevoflurane MAC ranged from 1.8% to 2.6% (mean +/- SD, 2.2 +/- 0.3%). Response entropy and state entropy were significantly higher during positive responses to tail clamping (88 +/- 2 and 76 +/- 2, respectively) than during negative responses to tail clamping (63 +/- 3 and 52 +/- 3, respectively). The difference between the 2 entropy indices did not differ between positive (11 +/- 1) and negative (13 +/- 1) responses to tail clamping. Response entropy and state entropy served as independent predictors of a positive response, with areas under the curve for receiver operating characteristic curves 0.810 (95% confidence interval, 0.716 to 0.903) and 0.828 (95% confidence interval, 0.741 to 0.916), respectively. Optimal cutoff points to predict a positive response were 75 for response entropy and 65 for state entropy, which corresponded to mean +/- SD ORs of 25.2 +/- 15.6 and 14.9 +/- 7.9, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Response entropy and state entropy were good predictors of responses to tail clamping elicited during determination of sevoflurane MAC in healthy dogs. PMID- 26000598 TI - Immunomodulatory effects of tulathromycin on apoptosis, efferocytosis, and proinflammatory leukotriene B4 production in leukocytes from Actinobacillus pleuropneumoniae-or zymosan-challenged pigs. AB - OBJECTIVE: To investigate the anti-inflammatory and immunomodulatory properties of tulathromycin in vitro and in experimental models of Actinobacillus pleuropneumoniae-induced pleuropneumonia and zymosan-induced pulmonary inflammation in pigs. ANIMALS: Blood samples from six 8- to 30-week-old healthy male pigs for the in vitro experiment and sixty-five 3-week-old specific pathogen free pigs. PROCEDURES: Neutrophils and monocyte-derived macrophages were isolated from blood samples. Isolated cells were exposed to tulathromycin (0.02 to 2.0 mg/mL) for various durations and assessed for markers of apoptosis and efferocytosis. For in vivo experiments, pigs were inoculated intratracheally with A pleuropneumoniae, zymosan, or PBS solution (control group) with or without tulathromycin pretreatment (2.5 mg/kg, IM). Bronchoalveolar lavage fluid was collected 3 and 24 hours after inoculation and analyzed for proinflammatory mediators, leukocyte apoptosis, and efferocytosis. RESULTS: In vitro, tulathromycin induced time- and concentration-dependent apoptosis in neutrophils, which enhanced their subsequent clearance by macrophages. In the lungs of both A pleuropneumoniae- and zymosan-challenged pigs, tulathromycin promoted leukocyte apoptosis and efferocytosis and inhibited proinflammatory leukotriene B4 production, with a concurrent reduction in leukocyte necrosis relative to that of control pigs. Tulathromycin also attenuated the degree of lung damage and lesion progression in A pleuropneumoniae-inoculated pigs. CONCLUSIONS AND CLINICAL RELEVANCE: Tulathromycin had immunomodulatory effects in leukocytes in vitro and anti-inflammatory effects in pigs in experimental models of A pleuropneumoniae infection and nonmicrobial-induced pulmonary inflammation. These data suggested that in addition to its antimicrobial properties, tulathromycin may dampen severe proinflammatory responses and drive resolution of inflammation in pigs with microbial pulmonary infections. PMID- 26000599 TI - Plasma and serum serotonin concentrations and surface-bound platelet serotonin expression in Cavalier King Charles Spaniels with myxomatous mitral valve disease. AB - OBJECTIVE: To investigate serum and plasma serotonin concentrations, percentage of serotonin-positive platelets, level of surface-bound platelet serotonin expression (mean fluorescence intensity [MFI]), and platelet activation (CD62 expression) in platelet-rich plasma from Cavalier King Charles Spaniels with myxomatous mitral valve disease (MMVD). ANIMALS: Healthy dogs (n = 15) and dogs with mild MMVD (18), moderate-severe MMVD (19), or severe MMVD with congestive heart failure (CHF; 10). PROCEDURES: Blood samples were collected from each dog. Serum and plasma serotonin concentrations were measured with an ELISA, and surface-bound platelet serotonin expression and platelet activation were determined by flow cytometry. RESULTS: Dogs with mild MMVD had higher median serum (746 ng/mL) and plasma (33.3 ng/mL) serotonin concentrations, compared with MMVD-affected dogs with CHF (388 ng/mL and 9.9 ng/mL, respectively), but no other group differences were found. Among disease groups, no differences in surface bound serotonin expression or platelet activation were found. Thrombocytopenic dogs had lower serum serotonin concentration (482 ng/mL) than nonthrombocytopenic dogs (731 ng/mL). In 26 dogs, a flow cytometry scatterplot subpopulation (FSSP) of platelets was identified; dogs with an FSSP had a higher percentage of serotonin-positive platelets (11.0%), higher level of surface-bound serotonin expression (MFI, 32,068), and higher platelet activation (MFI, 2,363) than did dogs without an FSSP (5.7%, 1,230, and 1,165, respectively). An FSSP was present in 93.8% of thrombocytopenic dogs and in 29.5% of nonthrombocytopenic dogs. CONCLUSIONS AND CLINICAL RELEVANCE: A substantive influence of circulating serotonin on MMVD stages prior to CHF development in Cavalier King Charles Spaniels was not supported by the study findings. An FSSP of highly activated platelets with pronounced serotonin binding was strongly associated with thrombocytopenia but not MMVD. PMID- 26000600 TI - Evaluation of three point-of-care meters and a portable veterinary chemistry analyzer for measurement of blood glucose concentrations in black-tailed prairie dogs (Cynomys ludovicianus). AB - OBJECTIVE: To compare blood glucose concentrations of black-tailed prairie dogs (Cynomys ludovicianus) measured by use of a variety of portable analyzers with results from a laboratory biochemistry analyzer. SAMPLE: Venous blood samples (3 mL) obtained from each of 16 healthy black-tailed prairie dogs. PROCEDURES: A portion of each blood sample was used to measure glucose concentrations by use of an amperometric human point-of-care glucometer and a colorimetric species specific portable blood glucose meter designed for veterinary use with both canine (code 5) and feline (code 7) settings. The remainder of each blood sample was placed into 2 tubes (one contained lithium heparin and the other contained no anticoagulant). A portable veterinary chemistry analyzer (PVCA) and a handheld analyzer were used to measure glucose concentration in heparinized blood. Serum glucose concentration was measured in the remaining portion by use of a biochemistry analyzer. A general linear mixed models approach was used to compare glucose concentrations and measurement bias obtained with the various measurement methods. RESULTS: Measurement bias and differences in mean glucose concentrations were apparent with all measurement methods. In particular, the veterinary glucometer, whether used on the canine or feline setting, overestimated mean glucose concentrations, whereas the human glucometer, PVCA, and handheld analyzer underestimated mean glucose concentrations relative to the concentration obtained with the biochemistry analyzer. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that none of the measurement methods provided consistently accurate blood glucose concentrations of black-tailed prairie dogs, compared with values determined with a biochemistry analyzer. PMID- 26000601 TI - Comparison of ultrasound biomicroscopy and standard ocular ultrasonography for detection of canine uveal cysts. AB - OBJECTIVE: To compare ultrasound biomicroscopy (UBM) with standard ocular ultrasonography for detection of canine uveal cysts and to determine the sensitivity, specificity, and interobserver agreement for detection of uveal cysts with UBM. SAMPLE: 202 enucleated eyes from 101 dogs. PROCEDURES: 2 examiners examined 202 eyes by means of UBM (50 MHz) to identify uveal cysts. A board-certified radiologist then examined 98 of the 202 eyes by means of standard ocular ultrasonography (7- to 12-MHz linear transducer). Subsequently, 1 examiner dissected all 202 eyes under magnification from an operating microscope to definitively identify uveal cysts. Each examiner was masked to other examiners' findings. Sensitivity, specificity, and interobserver agreement were calculated for detection of cysts by UBM. RESULTS: Cysts were detected by use of UBM in 55 of 202 (27%) eyes by one examiner and 29 of 202 (14%) eyes by the other. No cysts were detected in the 98 eyes examined with standard ocular ultrasonography. Dissection results revealed that cysts were present in 64 of 202 (32%) eyes, including 29 of 98 (30%) eyes examined by standard ocular ultrasonography. Mean sensitivity of UBM for cyst detection was 47%; mean specificity was 92%. Uveal cysts not identified with UBM were often small (mean diameter, 490 um). Interobserver agreement was high (kappaP = 0.81). CONCLUSIONS AND CLINICAL RELEVANCE: UBM was more effective than standard ocular ultrasonography for detection of uveal cysts in enucleated eyes. Small-diameter cysts were difficult to visualize even with UBM. PMID- 26000602 TI - Indirect prediction of total body water content in healthy adult Beagles by single-frequency bioelectrical impedance analysis. AB - OBJECTIVE: To develop equations for prediction of total body water (TBW) content in unsedated dogs by combining impedance (resistance and reactance) and morphological variables and to compare the results of those equations with TBW content determined by deuterium dilution (TBW(d)). ANIMALS: 26 healthy adult Beagles. PROCEDURES: TBW content was determined directly by deuterium dilution and indirectly with equations developed from measurements obtained by use of a portable bioelectric impedance device and morphological variables including body length, height, weight, and thoracic and abdominal circumferences. RESULTS: Impedance and morphological data from 16 of the 26 dogs were used to determine coefficients for the following 2 equations: TBW(1) = -0.019 (BL(2)/R) + -0.199 (RC + AC) + 0.996 W + 0.081 H + 12.31; and TBW(2) = 0.048 (BL(2)/R) + -0.144 (RC + AC) + 0.777 W + 0.066 H + 0.031 X + 7.47, where AC is abdominal circumference, H is height, BL is body length, R is resistance, RC is rib cage circumference, W is body weight, and * is reactance. Results for TBW(1) (R(2)(1) = 0.843) and TBW(2) (R(2)(2) = 0.816) were highly correlated with the TBW(d). When the equations were validated with data from the remaining 10 dogs, the respective mean differences between TBW(d) and TBW(1) and TBW(2) were 0.17 and 0.11 L, which equated to a nonsignificant underestimation of TBW content by 2.4% and 1.6%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that impedance and morphological data can be used to accurately estimate TBW content in adult Beagles. This method of estimating TBW content is less expensive and easier to perform than is measurement of TBW(d), making it appealing for daily use in veterinary practice. PMID- 26000603 TI - Induction of thioredoxin-1 in response to oxidative stress in dogs. AB - OBJECTIVE: To determine whether thioredoxin (TRX)-1 can be used as a valid biomarker for oxidative stress in dogs. ANIMALS AND SAMPLES: 10 Beagles and Madin Darby canine kidney cells. PROCEDURES: Madin-Darby canine kidney cells were used to verify antigen cross-reactivity between human and canine anti-TRX-antibodies. Dogs were assigned to receive 21% or 100% O2 (5 dogs/group) via an artificial respirator during a 3-hour period of isoflurane anesthesia (starting at 0 hours). Blood and urine samples were collected before (baseline) and at 6, 12, 24, and 48 hours after commencement of inhalation anesthesia. Concentrations of TRX-1 and 8 hydroxy-2'-deoxyguanosine (8-OHdG) in plasma and urine samples were analyzed; urine concentrations were reported as ratios against urine creatinine concentration. RESULTS: Canine TRX-1 was recognized by monoclonal human anti-TRX 1 antibodies (clones of adult T-cell leukemia-derived factor [ADF]-11 and ADF21) by western blot analysis. Results of an ELISA indicated that plasma TRX-1 concentration and urine TRX-1-to-creatinine concentration ratio increased rapidly after the 3-hour period of hyperoxia with maximal peaks at 12 and 6 hours, respectively. Urine 8-OHdG-to-creatinine concentration ratio also increased significantly after hyperoxia induction. However, unlike the rapid increase in urine TRX-1-to-creatinine concentration ratio, maximal urine 8-OHdG-to-creatinine concentration ratio was attained at 48 hours after hyperoxia induction. These variables remained unchanged from baseline in the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that human anti-TRX monoclonal antibodies cross-reacted with canine TRX, and plasma TRX-1 concentrations were rapidly increased in dogs following an oxidative stress challenge. Thus, TRX may be a valuable clinical biomarker for detecting oxidative stress more rapidly than 8 OHdG in dogs. PMID- 26000604 TI - Evaluation of the ability of a gravitational filtration system to enhance recovery of equine bone marrow elements. AB - OBJECTIVE: To assess efficiency of gravity filtration to enhance recovery of equine bone marrow elements including stem and progenitor cells. ANIMALS: 12 healthy adult horses. PROCEDURES: Bone marrow aspirates were collected from the fifth sternebral body and filtered by gravitational flow to obtain bone marrow elements. Raw and harvested bone marrow and marrow effluent were evaluated for WBC and platelet counts, automated and cytomorphologic cell differential counts, mesenchymal stem cell CFUs, cell viability, and differentiation capacity. Isolated cells were analyzed for CD90 and major histocompatibility complex (MHC) class I and II antigens. RESULTS: Mean cell viability of harvested bone marrow was 95.9%. Total WBCs and platelets were efficiently captured on the filter (> 95%), and mean recovery in harvested bone marrow was 30%. Cytologic cell differential counts indicated that the percentage of neutrophils was significantly less and the progenitor cell population was significantly higher and concentrated 1.56-fold in harvested bone marrow, compared with results for raw bone marrow. Flow cytometry and cell culture were used to characterize harvested bone marrow cells as positive for expression of CD90 and negative for MHCI and MHCII, which indicated stem cells with a multipotent phenotype that differentiated into chondrocytes, osteocytes, adipocytes, and tenocytes. CONCLUSIONS AND CLINICAL RELEVANCE: Gravitational filtration of bone marrow efficiently yielded platelets and cells and produced a progenitor-enriched, leukocyte-reduced product, compared with raw bone marrow. PMID- 26000605 TI - Biodegradation: Updating the concepts of control for microbial cleanup in contaminated aquifers. AB - Biodegradation is one of the most favored and sustainable means of removing organic pollutants from contaminated aquifers but the major steering factors are still surprisingly poorly understood. Growing evidence questions some of the established concepts for control of biodegradation. Here, we critically discuss classical concepts such as the thermodynamic redox zonation, or the use of steady state transport scenarios for assessing biodegradation rates. Furthermore, we discuss if the absence of specific degrader populations can explain poor biodegradation. We propose updated perspectives on the controls of biodegradation in contaminant plumes. These include the plume fringe concept, transport limitations, and transient conditions as currently underestimated processes affecting biodegradation. PMID- 26000606 TI - Adverse outcomes after major surgery in patients with pressure ulcer: a nationwide population-based retrospective cohort study. AB - BACKGROUND: Postoperative adverse outcomes in patients with pressure ulcer are not completely understood. This study evaluated the association between preoperative pressure ulcer and adverse events after major surgeries. METHODS: Using reimbursement claims from Taiwan's National Health Insurance Research Database, we conducted a nationwide retrospective cohort study of 17391 patients with preoperative pressure ulcer receiving major surgery in 2008-2010. With a propensity score matching procedure, 17391 surgical patients without pressure ulcer were selected for comparison. Eight major surgical postoperative complications and 30-day postoperative mortality were evaluated among patients with pressure ulcer of varying severity. RESULTS: Patients with preoperative pressure ulcer had significantly higher risk than controls for postoperative adverse outcomes, including septicemia, pneumonia, stroke, urinary tract infection, and acute renal failure. Surgical patients with pressure ulcer had approximately 1.83-fold risk (95% confidence interval 1.54-2.18) of 30-day postoperative mortality compared with control group. The most significant postoperative mortality was found in those with serious pressure ulcer, such as pressure ulcer with local infection, cellulitis, wound or treatment by change dressing, hospitalized care, debridement or antibiotics. Prolonged hospital or intensive care unit stay and increased medical expenditures were also associated with preoperative pressure ulcer. CONCLUSION: This nationwide propensity score matched retrospective cohort study showed increased postoperative complications and mortality in patients with preoperative pressure ulcer. Our findings suggest the urgency of preventing and managing preoperative pressure ulcer by a multidisciplinary medical team for this specific population. PMID- 26000607 TI - The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells. AB - Death signaling provided by tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce death in cancer cells with little cytotoxicity to normal cells; this cell death has been thought to involve caspase-dependent apoptosis. Reactive oxygen species (ROS) are also mediators that induce cell death, but their roles in TRAIL-induced apoptosis have not been elucidated fully. In the current study, we investigated ROS and caspases in human pancreatic cancer cells undergoing two different types of TRAIL-induced cell death, apoptosis and necroptosis. TRAIL treatment increased ROS in two TRAIL-sensitive pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, but ROS were involved in TRAIL-induced apoptosis only in MiaPaCa-2 cells. Unexpectedly, inhibition of ROS by either N acetyl-L-cysteine (NAC), a peroxide inhibitor, or Tempol, a superoxide inhibitor, increased the annexin V-/propidium iodide (PI)+ early necrotic population in TRAIL-treated cells. Additionally, both necrostatin-1, an inhibitor of receptor interacting protein kinase 1 (RIP1), and siRNA-mediated knockdown of RIP3 decreased the annexin V-/PI+ early necrotic population after TRAIL treatment. Furthermore, an increase in early apoptosis was induced in TRAIL-treated cancer cells under inhibition of either caspase-2 or -9. Caspase-2 worked upstream of caspase-9, and no crosstalk was observed between ROS and caspase-2/-9 in TRAIL treated cells. Together, these results indicate that ROS contribute to TRAIL induced apoptosis in MiaPaCa-2 cells, and that ROS play an inhibitory role in TRAIL-induced necroptosis of MiaPaCa-2 and BxPC-3 cells, with caspase-2 and -9 playing regulatory roles in this process. PMID- 26000608 TI - CD36 Mediated Fatty Acid-Induced Podocyte Apoptosis via Oxidative Stress. AB - BACKGROUND: Hyperlipidemia-induced apoptosis mediated by fatty acid translocase CD36 is associated with increased uptake of ox-LDL or fatty acid in macrophages, hepatocytes and proximal tubular epithelial cells, leading to atherosclerosis, liver damage and fibrosis in obese patients, and diabetic nephropathy (DN), respectively. However, the specific role of CD36 in podocyte apoptosis in DN with hyperlipidemia remains poorly investigated. METHODS: The expression of CD36 was measured in paraffin-embedded kidney tissue samples (Ctr = 18, DN = 20) by immunohistochemistry and immunofluorescence staining. We cultured conditionally immortalized mouse podocytes (MPC5) and treated cells with palmitic acid, and measured CD36 expression by real-time PCR, Western blot analysis and immunofluorescence; lipid uptake by Oil red O staining and BODIPY staining; apoptosis by flow cytometry assay, TUNEL assay and Western blot analysis; and ROS production by DCFH-DA fluorescence staining. All statistical analyses were performed using SPSS 21.0 statistical software. RESULTS: CD36 expression was increased in kidney tissue from DN patients with hyperlipidemia. Palmitic acid upregulated CD36 expression and promoted its translocation from cytoplasm to plasma membrane in podocytes. Furthermore, palmitic acid increased lipid uptake, ROS production and apoptosis in podocytes, Sulfo-N-succinimidyloleate (SSO), the specific inhibitor of the fatty acid binding site on CD36, decreased palmitic acid-induced fatty acid accumulation, ROS production, and apoptosis in podocytes. Antioxidant 4-hydroxy-2,2,6,6- tetramethylpiperidine -1-oxyl (tempol) inhibited the overproduction of ROS and apoptosis in podocytes induced by palmitic acid. CONCLUSIONS: CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress might participate in the process of DN. PMID- 26000609 TI - Health Behaviors of Korean Gastric Cancer Survivors with Hypertension: A Propensity Analysis of KNHANES III-V (2005-2012). AB - OBJECTIVE: This study provides a comparison of health behaviors between gastric cancer survivors with hypertension and non-cancer subjects in Korea. METHODS: Data from the Korean National Health and Nutrition Examination Survey (KNHANES) for the period of 2005-2012 were used in this study. A propensity score matching method was used to compare health behaviors. Before the matching of propensity scores, the number of participants was 11034 (102 gastric cancer survivors and 10932 non-cancer participants). A 1:5 propensity score matching procedure yielded a total of 480 participants (80 gastric cancer survivors and 400 non-cancer participants) for the final analysis. Drinking, smoking, physical activity, antihypertensive medication adherence, self-reported diet control, and sodium intake accordance in the two groups were compared. A complex samples logistic regression analysis was conducted to assess any differences between the two groups. RESULTS: The group of hypertensive gastric cancer survivors had lower alcohol consumption (OR = 0.30; 95% CI: 0.14-0.66; p-value = 0.003). They were more likely to be on dietary control than the control group (OR = 3.12; 95% CI: 1.60-6.10; p-value = 0.001). However, there was no significant (p > 0.05) difference in sodium intake accordance or other health behaviors (including medication adherence, smoking, and physical activity) between the two groups. CONCLUSIONS: Our results revealed that gastric cancer survivors with hypertension were more likely to be on dietary control with lower alcohol consumption than the control group. However, there was no significant difference in sodium intake accordance or other health behaviors between the two groups. Therefore, primary care physicians should inform cancer survivors about the appropriate health behaviors to reduce their risk of cardiovascular disease and improve their overall survival rate, even though they say they have been doing health behaviors. PMID- 26000610 TI - A customized light sheet microscope to measure spatio-temporal protein dynamics in small model organisms. AB - We describe a customizable and cost-effective light sheet microscopy (LSM) platform for rapid three-dimensional imaging of protein dynamics in small model organisms. The system is designed for high acquisition speeds and enables extended time-lapse in vivo experiments when using fluorescently labeled specimens. We demonstrate the capability of the setup to monitor gene expression and protein localization during ageing and upon starvation stress in longitudinal studies in individual or small groups of adult Caenorhabditis elegans nematodes. The system is equipped to readily perform fluorescence recovery after photobleaching (FRAP), which allows monitoring protein recovery and distribution under low photobleaching conditions. Our imaging platform is designed to easily switch between light sheet microscopy and optical projection tomography (OPT) modalities. The setup permits monitoring of spatio-temporal expression and localization of ageing biomarkers of subcellular size and can be conveniently adapted to image a wide range of small model organisms and tissue samples. PMID- 26000611 TI - High efficiency adsorption and removal of selenate and selenite from water using metal-organic frameworks. AB - A series of zirconium-based, metal-organic frameworks (MOFs) were tested for their ability to adsorb and remove selenate and selenite anions from aqueous solutions. MOFs were tested for adsorption capacity and uptake time at different concentrations. NU-1000 was shown to have the highest adsorption capacity, and fastest uptake rates for both selenate and selenite, of all zirconium-based MOFs studied here. Herein, the mechanism of selenate and selenite adsorption on NU 1000 is explored to determine the important features that make NU-1000 a superior adsorbent for this application. PMID- 26000612 TI - Phthalocyanine-Based Organic Thin-Film Transistors: A Review of Recent Advances. AB - Metal phthalocyanines (MPcs) are versatile conjugated macrocycles that have attracted a great deal of interest as active components in modern organic electronic devices. In particular, the charge transport properties of MPcs, their chemical stability, and their synthetic versatility make them ideal candidate materials for use in organic thin-film transistors (OTFTs). This article reviews recent progress in both the material design and device engineering of MPc-based OTFTs, including the introduction of solubilizing groups on the MPcs and the surface modification of substrates to induce favorable MPc self-assembly. Finally, a discussion on emerging niche applications based on MPc OTFTs will be explored, in addition to a perspective and outlook on these promising materials in OTFTs. The scope of this review is focused primarily on the advances made in the field of MPc-based OTFTs since 2008. PMID- 26000613 TI - Structure and properties of electronic and hole centers in CsBr from theoretical calculations. AB - The electronic structure, geometry, diffusion barriers and optical properties of fundamental defects of CsBr are calculated using hybrid functional DFT and TD-DFT methods. The B3LYP functional with a modified exchange contribution has been used in an embedded cluster scheme to model the structure and spectroscopic properties of the self-trapped triplet exciton, interstitial Br atoms and ions, self-trapped holes and Br vacancies. The calculated migration barriers and positions of maxima of optical absorption bands are in good agreement with experiment, justifying the obtained defect geometries. The off-center triplet exciton luminescence energy is also accurately calculated. PMID- 26000614 TI - Preparation and Characterization of Polyhedral Oligomeric Silsesquioxane Containing, Titania-Thiol-Ene Composite Photocatalytic Coatings, Emphasizing the Hydrophobic-Hydrophilic Transition. AB - Coatings prepared from titania-thiol-ene compositions were found to be both self cleaning, as measured by changes in water contact angle, and photocatalytic toward the degradation of an organic dye. Stable titania-thiol-ene dispersions at approximately 2 wt % solids were prepared using a combination of high-shear mixing and sonication in acetone solvent from photocatalytic titania, trisilanol isobutyl polyhedral oligomeric silsesquioxane (POSS) dispersant, and select thiol ene monomers, i.e., trimethylolpropane tris(3-mercaptopropionate) (TMPMP), pentaerythritol allyl ether (APE), and 1,3,5-triallyl-1,3,5-triazine 2,4,6(1H,3H,5H)-trione (TTT). The dispersed particle compositions were characterized by DLS and TEM. The synthetic methods employed yield a strongly bound particle/POSS complex, supported by IR, 29Si NMR, and TGA. The factors of spray techniques, carrier solvent volatility, and particle size and size distributions, in combination, likely all contribute to the highly textured but uniform surfaces observed via SEM and AFM. Polymer composites possessed thermal transitions (e.g., Tg) consistent with composition. In general, the presence of polymer matrix provided mechanical integrity, without significantly compromising or prohibiting other critical performance characteristics, such as film processing, photocatalytic degradation of adsorbed contaminants, and the hydrophobic-hydrophilic transition. In all cases, coatings containing photocatalytic titania were converted from superhydrophobic to superhydrophilic, as defined by changes in the water contact angle. The superhydrophilic state of samples was considered persistent, since long time durations in complete darkness were required to observe any significant hydrophobic return. In a preliminary demonstration, the photocatalytic activity of prepared coatings was confirmed through the degradation of crystal violet dye. This work demonstrates that a scalable process can be found to prepare titania-thiol-ene coatings having improved coating properties which also exhibit photocatalytic and self-cleaning attributes. PMID- 26000615 TI - Selective Secondary Face Modification of Cyclodextrins by Mechanosynthesis. AB - alpha-, beta-, and gamma-cyclodextrins (CDs) were modified on their secondary face by mechanosynthesis at room temperature using a laboratory-scale ball-mill. Mono-2-tosylated alpha-, beta-, and gamma-CDs were obtained in good yield from mixtures of native alpha-, beta-, and gamma-CDs, respectively, N-tosylimidazole, and an inorganic base, with each of them being in the solid state. The yields appeared to be dependent upon the nature of the base and the reaction time. A kinetic monitoring by (1)H NMR spectroscopy demonstrated that the highest yields in mono-2-tosyl-CDs were measured using KOH as a base in very short reaction times (up to 65% in 80 s). Mono-(2,3-manno-epoxide) alpha-, beta-, and gamma-CDs were subsequently synthesized by ball-milling a mixture of monotosylated alpha-, beta-, and gamma-CDs, respectively, and KOH. The characterization of the modified CDs was carried out by X-ray diffraction, mass spectrometry, solid-state NMR, and diffuse reflectance UV-vis (DR UV-vis) spectroscopies. Clues to the supramolecular arrangement of the molecules in the solid state provide information on the reaction mechanism. PMID- 26000616 TI - Increased gastrointestinal blood flow: An essential circulatory modification for euryhaline rainbow trout (Oncorhynchus mykiss) migrating to sea. AB - The large-scale migrations of anadromous fish species from freshwater to seawater have long been considered particularly enigmatic, as this life history necessitates potentially energetically costly changes in behaviour and physiology. A significant knowledge gap concerns the integral role of cardiovascular responses, which directly link many of the well-documented adaptations (i.e. through oxygen delivery, water and ion transport) allowing fish to maintain osmotic homeostasis in the sea. Using long-term recordings of cardiorespiratory variables and a novel method for examining drinking dynamics, we show that euryhaline rainbow trout (Oncorhynchus mykiss) initiate drinking long before the surrounding environment reaches full seawater salinity (30-33 ppt), suggesting the presence of an external osmo-sensing mechanism. Onset of drinking was followed by a delayed, yet substantial increase in gastrointestinal blood flow through increased pulse volume exclusively, as heart rate remained unchanged. While seawater entry did not affect whole animal energy expenditure, enhanced gastrointestinal perfusion represents a mechanism crucial for ion and water absorption, as well as possibly increasing local gastrointestinal oxygen supply. Collectively, these modifications are essential for anadromous fish to maintain homeostasis at sea, whilst conserving cardiac and metabolic scope for activities directly contributing to fitness and reproductive success. PMID- 26000617 TI - The cerebellum ages slowly according to the epigenetic clock. AB - Studies that elucidate why some human tissues age faster than others may shed light on how we age, and ultimately suggest what interventions may be possible. Here we utilize a recent biomarker of aging (referred to as epigenetic clock) to assess the epigenetic ages of up to 30 anatomic sites from supercentenarians (subjects who reached an age of 110 or older) and younger subjects. Using three novel and three published human DNA methylation data sets, we demonstrate that the cerebellum ages more slowly than other parts of the human body. We used both transcriptional data and genetic data to elucidate molecular mechanisms which may explain this finding. The two largest superfamilies of helicases (SF1 and SF2) are significantly over-represented (p=9.2x10-9) among gene transcripts that are over-expressed in the cerebellum compared to other brain regions from the same subject. Furthermore, SNPs that are associated with epigenetic age acceleration in the cerebellum tend to be located near genes from helicase superfamilies SF1 and SF2 (enrichment p=5.8x10-3). Our genetic and transcriptional studies of epigenetic age acceleration support the hypothesis that the slow aging rate of the cerebellum is due to processes that involve RNA helicases. PMID- 26000618 TI - N-Substituted Derivatives of the Azadithiolate Cofactor from the [FeFe] Hydrogenases: Stability and Complexation. AB - Experiments are described that probe the stability of N-substituted derivatives of the azadithiolate cofactor recently confirmed in the [FeFe] hydrogenases (Berggren, G., et al. Nature 2013, 499, 66). Acid-catalyzed hydrolysis of bis(thioester) BnN(CH2SAc)2 gives [BnNCH2SCH2]2 rather than azadithiol BnN(CH2SH)2. Treatment of BnN(CH2SAc)2 with NaO(t)Bu generates BnN(CH2SNa)2, which was trapped with NiCl2(diphos) (diphos = 1,2-C2H4(PR2)2; R = Ph (dppe) and Cy (dcpe)) to give fully characterized complexes Ni[(SCH2)2NBn](diphos). The related N-aryl derivative Ni[(SCH2)2NC6H4Cl](diphos) was prepared analogously from 4-ClC6H4N(CH2SAc)2, NaO(t)Bu, and NiCl2(dppe). Crystallographic analysis confirmed that these rare nonbridging [adt(R)](2-) complexes feature distorted square planar Ni centers. The analogue Pd[(SCH2)2NBn](dppe) was also prepared. (31)P NMR analysis indicates that Ni[(SCH2)2NBn](dppe) has basicity comparable to typical amines. As shown by cyclic voltammetry, the couple [M[(SCH2)2NBn](dppe)](+/0) is reversible near -2.0 V versus Fc(+/0). The wave shifts to -1.78 V upon N-protonation. In the presence of CF3CO2H, Ni[(SCH2)2NBn](dppe) catalyzes hydrogen evolution at rate of 22 s(-1) in the acid independent regime, at room temperature in CH2Cl2 solution. In contrast to the instability of RN(CH2SH)2 (R = alkyl, aryl), the dithiol of tosylamide TsN(CH2SH)2 proved sufficiently stable to allow full characterization. This dithiol reacts with Fe3(CO)12 and, in the presence of base, NiCl2(dppe) to give Fe2[(SCH2)2NTs](CO)6 and Ni[(SCH2)2NTs](dppe), respectively. PMID- 26000621 TI - Erratum to: Assessment of a combination screening assay for celiac disease. AB - [This corrects the article DOI: 10.1007/s13317-011-0020-1.]. PMID- 26000619 TI - GORAB Missense Mutations Disrupt RAB6 and ARF5 Binding and Golgi Targeting. AB - Gerodermia osteodysplastica is a hereditary segmental progeroid disorder affecting skin, connective tissues, and bone that is caused by loss-of-function mutations in GORAB. The golgin, RAB6-interacting (GORAB) protein localizes to the Golgi apparatus and interacts with the small GTPase RAB6. In this study, we used different approaches to shed more light on the recruitment of GORAB to this compartment. We show that GORAB best colocalizes with trans-Golgi markers and is rapidly displaced upon Brefeldin A exposition, indicating a loose association with Golgi membranes. A yeast two-hybrid screening revealed a specific interaction with the small GTPase ADP-ribosylation factor (ARF5) in its active, GTP-bound form. ARF5 and RAB6 bind to GORAB via the same internal Golgi-targeting RAB6 and ARF5 binding (IGRAB) domain. Two GORAB missense mutations identified in gerodermia osteodysplastica patients fall within this IGRAB domain. GORAB carrying the mutation p.Ala220Pro had a cytoplasmic distribution and failed to interact with both RAB6 and ARF5. In contrast, the p.Ser175Phe mutation displaced GORAB from the Golgi compartment to vesicular structures and selectively impaired ARF5 binding. Our findings indicate that the IGRAB domain is crucial for the Golgi localization of GORAB and that loss of this localization impairs its physiological function. PMID- 26000622 TI - Improvement of spontaneous language in stroke patients with chronic aphasia treated with music therapy: a randomized controlled trial. AB - AIM OF THE STUDY: The aim of this research is to evaluate the effects of active music therapy (MT) based on free-improvisation (relational approach) in addition to speech language therapy (SLT) compared with SLT alone (communicative-pragmatic approach: Promoting Aphasic's Communicative Effectiveness) in stroke patients with chronic aphasia. MATERIALS AND METHODS: The experimental group (n = 10) was randomized to 30 MT individual sessions over 15 weeks in addition to 30 SLT individual sessions while the control group (n = 10) was randomized to only 30 SLT sessions during the same period. Psychological and speech language assessment were made before (T0) and after (T1) the treatments. RESULTS: The study shows a significant improvement in spontaneous speech in the experimental group (Aachener Aphasie subtest: p = 0.020; Cohen's d = 0.35); the 50% of the experimental group showed also an improvement in vitality scores of Short Form Health Survey (chi square test = 4.114; p = 0.043). CONCLUSIONS: The current trial highlights the possibility that the combined use of MT and SLT can lead to a better result in the rehabilitation of patients with aphasia than SLT alone. PMID- 26000623 TI - Functional assessment of antibody oxidation by native mass spectrometry. AB - Oxidation of methionine (Met) residues is one of several chemical degradation pathways for recombinant IgG1 antibodies. Studies using several methodologies have indicated that Met oxidation in the constant IgG1 domains affects in vitro interaction with human neonatal Fc (huFcRn) receptor, which is important for antibody half-life. Here, a completely new approach to investigating the effect of oxidative stress conditions has been applied. Quantitative ultra-performance liquid chromatography mass spectrometry (MS) peptide mapping, classical surface plasmon resonance and the recently developed FcRn column chromatography were combined with the new fast-growing approach of native MS as a near native state protein complex analysis in solution. Optimized mass spectrometric voltage and pressure conditions were applied to stabilize antibody/huFcRn receptor complexes in the gas phase for subsequent native MS experiments with oxidized IgG1 material. This approach demonstrated a linear correlation between quantitative native MS and IgG-FcRn functional analysis. In our study, oxidation of the heavy chain Met-265 resulted in a stepwise reduction of mAb3/huFcRn receptor complex formation. Remarkably, a quantitative effect of the heavy chain Met-265 oxidation on relative binding capacity was only detected for doubly oxidized IgG1, whereas IgG1 with only one oxidized heavy chain Met-265 was not found to significantly affect IgG1 binding to huFcRn. Thus, mono-oxidized IgG1 heavy chain Met-265 most likely does not represent a critical quality attribute for pharmacokinetics. PMID- 26000624 TI - Toxic potential of copper-doped ZnO nanoparticles in Drosophila melanogaster (Oregon R). AB - AIMS: In the present study, copper-doped ZnO nanoparticles (doped ZnO NPs Cu) were synthesized, characterized and evaluated for their possible toxic effects in Drosophila melanogaster (Oregon R). METHODS AND RESULTS: X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy and energy dispersive X-ray spectrometry confirm the formation of doped ZnO NPs Cu. Doped ZnO NPs Cu (3%) were mixed in the diet at final concentrations of 1, 2, 4 and 8 ug/ul. The starved male flies were allowed to feed on it for 4 days. After completion of the desired duration, climbing ability, activity pattern, activity of acetylcholinesterase (AChE), glutathione (GSH), glutathione-S-transferase (GST), lipid peroxidation (LPO), total protein content and caspases were studied. SDS-PAGE was also performed for whole fly homogenate of control as well as treated flies. No loss in the climbing and activity pattern was observed at the selected doses of doped ZnO NPs Cu. No significant change in the levels of AChE, GSH, GST, LPO, caspase 9/3 and total protein content was observed. The brain sections showed no gross changes in the structure and SDS-PAGE patterns also revealed no change in the protein expression. CONCLUSIONS: The results suggest that doped ZnO NPs Cu are non-toxic at 1, 2, 4 and 8 ug/ul of concentration in D. melanogaster. PMID- 26000625 TI - A clinical opinion on how to manage the risk of preterm birth in twins based on literature review. AB - Twin pregnancies are prone to preterm birth and consequent morbidity. There is an increasing evidence base concerning the prediction and prevention of preterm birth in singletons, including the reduction of morbidity with therapies such as magnesium sulphate and antenatal corticosteroids. However, the research in twins is less clear, partly due to fewer numbers being investigated, but also evidence is largely based on twins without a previous history. Prophylactic interventions such as cerclage, progesterone and vaginal pessaries are increasingly showing benefit in singleton pregnancies with a prior history and when the cervix is short. Cerclage in twins has not been adequately researched in women with previous preterm birth, and as with singletons should not be used on the basis of a short cervix alone. Vaginal progesterone does not work in twins, but its value in high-risk twins, with a prior history and short cervix is uncertain. The vaginal pessary may be valuable in the twin with a short cervix. Currently, it is reasonable to extrapolate some of the evidence from singletons to twins, e.g. with antenatal corticosteroids and magnesium sulphate. Cerclage, vaginal pessaries and progesterone should not be routinely used in twin pregnancies without an additional high-risk factor such as prior history of preterm birth or short cervix, until further evidence is obtained. PMID- 26000626 TI - Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis. AB - OBJECTIVE: To estimate the cost-effectiveness of fetal aneuploidy screening in the general pregnancy population using non-invasive prenatal testing (NIPT) as compared to first trimester combined screening (FTS) with serum markers and NT ultrasound. METHODS: Using a decision-analytic model, we estimated the number of fetal T21, T18, and T13 cases identified prenatally, the number of invasive procedures performed, corresponding normal fetus losses, and costs of screening using FTS or NIPT with cell-free DNA (cfDNA). Modeling was based on a 4 million pregnant women cohort, which represents annual births in the U.S. RESULTS: For the general pregnancy population, NIPT identified 15% more trisomy cases, reduced invasive procedures by 88%, and reduced iatrogenic fetal loss by 94% as compared to FTS. The cost per trisomy case identified with FTS was $497,909. At a NIPT unit, cost of $453 and below, there were cost savings as compared to FTS. Accounting for additional trisomy cases identified by NIPT, a NIPT unit cost of $665 provided the same per trisomy cost as that of FTS. CONCLUSIONS: NIPT in the general pregnancy population leads to more prenatal identification of fetal trisomy cases as compared to FTS and is more economical at a NIPT unit cost of $453. PMID- 26000627 TI - 0.5 vs. 1.0 mg estradiol in combination with drospirenone for the treatment of hot flushes. AB - OBJECTIVE: To compare the efficacy of 0.5 and 1.0 mg estradiol in combination with different doses of drospirenone for the treatment of menopausal hot flushes. METHODS: This retrospective analysis included data from two prospective, randomized, double-blind, multicenter, placebo-controlled studies. Inclusion criteria were seven to eight moderate to severe hot flushes per day during the 1 week screening period. The focus was the rate of responders. A responder was defined as a subject that had at least a perceptible improvement of 19.1 hot flushes per week at 4 weeks and a substantial improvement of 40.3 hot flushes per week at 12 weeks compared to baseline. Secondary focus was the absolute change of moderate to severe hot flushes per week over 12 weeks. RESULTS: A total of 832 subjects were included. At baseline, the median weekly number of moderate to severe hot flushes was between 62 and 67. After 12 weeks of treatment, combinations of 0.5 and 1 mg estradiol achieved a median reduction of 54-55 and 57-64 moderate to severe hot flushes, respectively. In the 0.5-mg estradiol group, the responder rates for combinations with drospirenone 0.25 and 0.5 mg were 62.7% and 75.8%, respectively. In the 1-mg estradiol group, the responder rates for combinations with drospirenone 1, 2 and 3 mg were 86.7%, 100% and 89.7%, respectively. CONCLUSION: Effective relief from hot flushes can be reached within 12 weeks with estradiol doses of 0.5 and 1 mg in combination with different drospirenone doses. PMID- 26000628 TI - High-Throughput Single-Cell Labeling (Hi-SCL) for RNA-Seq Using Drop-Based Microfluidics. AB - The importance of single-cell level data is increasingly appreciated, and significant advances in this direction have been made in recent years. Common to these technologies is the need to physically segregate individual cells into containers, such as wells or chambers of a micro-fluidics chip. High-throughput Single-Cell Labeling (Hi-SCL) in drops is a novel method that uses drop-based libraries of oligonucleotide barcodes to index individual cells in a population. The use of drops as containers, and a microfluidics platform to manipulate them en-masse, yields a highly scalable methodological framework. Once tagged, labeled molecules from different cells may be mixed without losing the cell-of-origin information. Here we demonstrate an application of the method for generating RNA sequencing data for multiple individual cells within a population. Barcoded oligonucleotides are used to prime cDNA synthesis within drops. Barcoded cDNAs are then combined and subjected to second generation sequencing. The data are deconvoluted based on the barcodes, yielding single-cell mRNA expression data. In a proof-of-concept set of experiments we show that this method yields data comparable to other existing methods, but with unique potential for assaying very large numbers of cells. PMID- 26000629 TI - Trait Anxiety Has Effect on Decision Making under Ambiguity but Not Decision Making under Risk. AB - Previous studies have reported that trait anxiety (TA) affects decision making. However, results remain largely inconsistent across studies. The aim of the current study was to further address the interaction between TA and decision making. 304 subjects without depression from a sample consisting of 642 participants were grouped into high TA (HTA), medium TA (MTA) and low TA (LTA) groups based on their TA scores from State Trait Anxiety Inventory. All subjects were assessed with the Iowa Gambling Task (IGT) that measures decision making under ambiguity and the Game of Dice Task (GDT) that measures decision making under risk. While the HTA and LTA groups performed worse on the IGT compared to the MTA group, performances on the GDT between the three groups did not differ. Furthermore, the LTA and HTA groups showed different individual deck level preferences in the IGT: the former showed a preference for deck B indicating that these subjects focused more on the magnitude of rewards, and the latter showed a preference for deck A indicating significant decision making impairment. Our findings suggest that trait anxiety has effect on decision making under ambiguity but not decision making under risk and different levels of trait anxiety related differently to individual deck level preferences in the IGT. PMID- 26000630 TI - Cancer Incidence among Patients with Anorexia Nervosa from Sweden, Denmark and Finland. AB - A diet with restricted energy content reduces the occurrence of cancer in animal experiments. It is not known if the underlying mechanism also exists in human beings. To determine whether cancer incidence is reduced among patients with anorexia nervosa who tend to have a low intake of energy, we carried out a retrospective cohort study of 22 654 women and 1678 men diagnosed with anorexia nervosa at ages 10-50 years during 1968-2010 according to National Hospital Registers in Sweden, Denmark and Finland. The comparison group consisted of randomly selected persons from population registers who were similar to the anorexia nervosa patients in respect to sex, year of birth and place of residence. Patients and population comparisons were followed for cancer by linkage to Cancer Registries. Incidence rate ratios (IRR) were estimated using Poisson models. In total, 366 cases of cancer (excluding non-melanoma skin cancer) were seen among women with anorexia nervosa, and the IRR for all cancer sites was 0.97 (95% CI = 0.87-1.08) adjusted for age, parity and age at first child. There were 76 breast cancers corresponding to an adjusted IRR of 0.61 (95% CI = 0.49-0.77). Significantly increased IRRs were observed for esophageal, lung, and liver cancer. Among men with anorexia nervosa, there were 23 cases of cancer (age-adjusted IRR = 1.08; 95% CI = 0.71-1.66). There seems to be no general reduction in cancer occurrence among patients with anorexia nervosa, giving little support to the energy restriction hypothesis. PMID- 26000631 TI - Mitochondrial Fragmentation Due to Inhibition of Fusion Increases Cyclin B through Mitochondrial Superoxide Radicals. AB - During the cell cycle, mitochondria undergo regulated changes in morphology. Two particularly interesting events are first, mitochondrial hyperfusion during the G(1)-S transition and second, fragmentation during entry into mitosis. The mitochondria remain fragmented between late G(2)- and mitotic exit. This mitotic mitochondrial fragmentation constitutes a checkpoint in some cell types, of which little is known. We bypass the 'mitotic mitochondrial fragmentation' checkpoint by inducing fragmented mitochondrial morphology and then measure the effect on cell cycle progression. Using Drosophila larval hemocytes, Drosophila S2R(+) cell and cells in the pouch region of wing imaginal disc of Drosophila larvae we show that inhibiting mitochondrial fusion, thereby increasing fragmentation, causes cellular hyperproliferation and an increase in mitotic index. However, mitochondrial fragmentation due to over-expression of the mitochondrial fission machinery does not cause these changes. Our experiments suggest that the inhibition of mitochondrial fusion increases superoxide radical content and leads to the upregulation of cyclin B that culminates in the observed changes in the cell cycle. We provide evidence for the importance of mitochondrial superoxide in this process. Our results provide an insight into the need for mitofusin degradation during mitosis and also help in understanding the mechanism by which mitofusins may function as tumor suppressors. PMID- 26000632 TI - Automated axial right ventricle to left ventricle diameter ratio computation in computed tomography pulmonary angiography. AB - BACKGROUND AND PURPOSE: Right Ventricular to Left Ventricular (RV/LV) diameter ratio has been shown to be a prognostic biomarker for patients suffering from acute Pulmonary Embolism (PE). While Computed Tomography Pulmonary Angiography (CTPA) images used to confirm a clinical suspicion of PE do include information of the heart, a numerical RV/LV diameter ratio is not universally reported, likely because of lack in training, inter-reader variability in the measurements, and additional effort by the radiologist. This study designs and validates a completely automated Computer Aided Detection (CAD) system to compute the axial RV/LV diameter ratio from CTPA images so that the RV/LV diameter ratio can be a more objective metric that is consistently reported in patients for whom CTPA diagnoses PE. MATERIALS AND METHODS: The CAD system was designed specifically for RV/LV measurements. The system was tested in 198 consecutive CTPA patients with acute PE. Its accuracy was evaluated using reference standard RV/LV radiologist measurements and its prognostic value was established for 30-day PE-specific mortality and a composite outcome of 30-day PE-specific mortality or the need for intensive therapies. The study was Institutional Review Board (IRB) approved and HIPAA compliant. RESULTS: The CAD system analyzed correctly 92.4% (183/198) of CTPA studies. The mean difference between automated and manually computed axial RV/LV ratios was 0.03+/-0.22. The correlation between the RV/LV diameter ratio obtained by the CAD system and that obtained by the radiologist was high (r=0.81). Compared to the radiologist, the CAD system equally achieved high accuracy for the composite outcome, with areas under the receiver operating characteristic curves of 0.75 vs. 0.78. Similar results were found for 30-days PE specific mortality, with areas under the curve of 0.72 vs. 0.75. CONCLUSIONS: An automated CAD system for determining the CT derived RV/LV diameter ratio in patients with acute PE has high accuracy when compared to manual measurements and similar prognostic significance for two clinical outcomes. PMID- 26000633 TI - Improving 3D Genome Reconstructions Using Orthologous and Functional Constraints. AB - The study of the 3D architecture of chromosomes has been advancing rapidly in recent years. While a number of methods for 3D reconstruction of genomic models based on Hi-C data were proposed, most of the analyses in the field have been performed on different 3D representation forms (such as graphs). Here, we reproduce most of the previous results on the 3D genomic organization of the eukaryote Saccharomyces cerevisiae using analysis of 3D reconstructions. We show that many of these results can be reproduced in sparse reconstructions, generated from a small fraction of the experimental data (5% of the data), and study the properties of such models. Finally, we propose for the first time a novel approach for improving the accuracy of 3D reconstructions by introducing additional predicted physical interactions to the model, based on orthologous interactions in an evolutionary-related organism and based on predicted functional interactions between genes. We demonstrate that this approach indeed leads to the reconstruction of improved models. PMID- 26000635 TI - Aspect-object alignment with Integer Linear Programming in opinion mining. AB - Target extraction is an important task in opinion mining. In this task, a complete target consists of an aspect and its corresponding object. However, previous work has always simply regarded the aspect as the target itself and has ignored the important "object" element. Thus, these studies have addressed incomplete targets, which are of limited use for practical applications. This paper proposes a novel and important sentiment analysis task, termed aspect object alignment, to solve the "object neglect" problem. The objective of this task is to obtain the correct corresponding object for each aspect. We design a two-step framework for this task. We first provide an aspect-object alignment classifier that incorporates three sets of features, namely, the basic, relational, and special target features. However, the objects that are assigned to aspects in a sentence often contradict each other and possess many complicated features that are difficult to incorporate into a classifier. To resolve these conflicts, we impose two types of constraints in the second step: intra-sentence constraints and inter-sentence constraints. These constraints are encoded as linear formulations, and Integer Linear Programming (ILP) is used as an inference procedure to obtain a final global decision that is consistent with the constraints. Experiments on a corpus in the camera domain demonstrate that the three feature sets used in the aspect-object alignment classifier are effective in improving its performance. Moreover, the classifier with ILP inference performs better than the classifier without it, thereby illustrating that the two types of constraints that we impose are beneficial. PMID- 26000634 TI - The Patient- And Nutrition-Derived Outcome Risk Assessment Score (PANDORA): Development of a Simple Predictive Risk Score for 30-Day In-Hospital Mortality Based on Demographics, Clinical Observation, and Nutrition. AB - OBJECTIVE: To develop a simple scoring system to predict 30 day in-hospital mortality of in-patients excluding those from intensive care units based on easily obtainable demographic, disease and nutrition related patient data. METHODS: Score development with general estimation equation methodology and model selection by P-value thresholding based on a cross-sectional sample of 52 risk indicators with 123 item classes collected with questionnaires and stored in an multilingual online database. SETTING: Worldwide prospective cross-sectional cohort with 30 day in-hospital mortality from the nutritionDay 2006-2009 and an external validation sample from 2012. RESULTS: We included 43894 patients from 2480 units in 32 countries. 1631(3.72%) patients died within 30 days in hospital. The Patient- And Nutrition-Derived Outcome Risk Assessment (PANDORA) score predicts 30-day hospital mortality based on 7 indicators with 31 item classes on a scale from 0 to 75 points. The indicators are age (0 to 17 points), nutrient intake on nutritionDay (0 to 12 points), mobility (0 to 11 points), fluid status (0 to 10 points), BMI (0 to 9 points), cancer (9 points) and main patient group (0 to 7 points). An appropriate model fit has been achieved. The area under the receiver operating characteristic curve for mortality prediction was 0.82 in the development sample and 0.79 in the external validation sample. CONCLUSIONS: The PANDORA score is a simple, robust scoring system for a general population of hospitalised patients to be used for risk stratification and benchmarking. PMID- 26000636 TI - Use of the analytic hierarchy process for medication decision-making in type 2 diabetes. AB - AIM: To investigate the feasibility and utility of the Analytic Hierarchy Process (AHP) for medication decision-making in type 2 diabetes. METHODS: We conducted an AHP with nine diabetes experts using structured interviews to rank add-on therapies (to metformin) for type 2 diabetes. During the AHP, participants compared treatment alternatives relative to eight outcomes (hemoglobin A1c lowering and seven potential harms) and the relative importance of the different outcomes. The AHP model and instrument were pre-tested and pilot-tested prior to use. Results were discussed and an evaluation of the AHP was conducted during a group session. We conducted the quantitative analysis using Expert Choice software with the ideal mode to determine the priority of treatment alternatives. RESULTS: Participants judged exenatide to be the best add-on therapy followed by sitagliptin, sulfonylureas, and then pioglitazone. Maximizing benefit was judged 21% more important than minimizing harm. Minimizing severe hypoglycemia was judged to be the most important harm to avoid. Exenatide was the best overall alternative if the importance of minimizing harms was prioritized completely over maximizing benefits. Participants reported that the AHP improved transparency, consistency, and an understanding of others' perspectives and agreed that the results reflected the views of the group. CONCLUSIONS: The AHP is feasible and useful to make decisions about diabetes medications. Future studies which incorporate stakeholder preferences should evaluate other decision contexts, objectives, and treatments. PMID- 26000637 TI - Beyond two-stage models for lung carcinogenesis in the Mayak workers: implications for plutonium risk. AB - Mechanistic multi-stage models are used to analyze lung-cancer mortality after Plutonium exposure in the Mayak-workers cohort, with follow-up until 2008. Besides the established two-stage model with clonal expansion, models with three mutation stages as well as a model with two distinct pathways to cancer are studied. The results suggest that three-stage models offer an improved description of the data. The best-fitting models point to a mechanism where radiation increases the rate of clonal expansion. This is interpreted in terms of changes in cell-cycle control mediated by bystander signaling or repopulation following cell killing. No statistical evidence for a two-pathway model is found. To elucidate the implications of the different models for radiation risk, several exposure scenarios are studied. Models with a radiation effect at an early stage show a delayed response and a pronounced drop-off with older ages at exposure. Moreover, the dose-response relationship is strongly nonlinear for all three stage models, revealing a marked increase above a critical dose. PMID- 26000638 TI - Transcriptome Profiling and Genetic Study Reveal Amplified Carboxylesterase Genes Implicated in Temephos Resistance, in the Asian Tiger Mosquito Aedes albopictus. AB - BACKGROUND: The control of Aedes albopictus, a major vector for viral diseases, such as dengue fever and chikungunya, has been largely reliant on the use of the larvicide temephos for many decades. This insecticide remains a primary control tool for several countries and it is a potential reliable reserve, for emergency epidemics or new invasion cases, in regions such as Europe which have banned its use. Resistance to temephos has been detected in some regions, but the mechanism responsible for the trait has not been investigated. PRINCIPAL FINDINGS: Temephos resistance was identified in an Aedes albopictus population isolated from Greece, and subsequently selected in the laboratory for a few generations. Biochemical assays suggested the association of elevated carboxylesterases (CCE), but not target site resistance (altered AChE), with this phenotype. Illumina transcriptomic analysis revealed the up-regulation of three transcripts encoding CCE genes in the temephos resistant strain. CCEae3a and CCEae6a showed the most striking up-regulation (27- and 12-folds respectively, compared to the reference susceptible strain); these genes have been previously shown to be involved in temephos resistance also in Ae. aegypti. Gene amplification was associated with elevated transcription levels of both CCEae6a and CCEae3a genes. Genetic crosses confirmed the genetic link between CCEae6a and CCEae3a amplification and temephos resistance, by demonstrating a strong association between survival to temephos exposure and gene copy numbers in the F2 generation. Other transcripts, encoding cytochrome P450s, UDP-glycosyltransferases (UGTs), cuticle and lipid biosynthesis proteins, were upregulated in resistant mosquitoes, indicating that the co evolution of multiple mechanisms might contribute to resistance. SIGNIFICANCE: The identification of specific genes associated with insecticide resistance in Ae. albopictus for the first time is an important pre-requirement for insecticide resistance management. The genomic resources that were produced will be useful to the community, to study relevant aspects of Ae. albopictus biology. PMID- 26000639 TI - N-terminal region of the catalytic domain of human N-myristoyltransferase 1 acts as an inhibitory module. AB - N-myristoyltransferase (NMT) plays critical roles in the modulation of various signaling molecules, however, the regulation of this enzyme in diverse cellular states remains poorly understood. We provide experimental evidence to show for the first time that for the isoform 1 of human NMT (hNMT1), the regulatory roles extend into the catalytic core. In our present study, we expressed, purified, and characterized a truncation mutant devoid of 28 N-terminal amino acids from the catalytic module (Delta28-hNMT1s) and compared its properties to the full-length catalytic domain of hNMT1. The deletion of the N-terminal peptide had no effect on the enzyme stability. Our findings suggest that the N-terminal region in the catalytic module of hNMT1 functions serves as a regulatory control element. The observations of an ~3 fold increase in enzymatic efficiency following removal of the N-terminal peptide of hNMT1s indicates that N-terminal amino acids acts as an inhibitory segment and negatively regulate the enzyme activity. Our findings that the N-terminal region confers control over activity, taken together with the earlier observations that the N-terminal of hNMT1 is differentially processed in diverse cellular states, suggests that the proteolytic processing of the peptide segment containing the inhibitory region provides a molecular mechanism for physiological up-regulation of myristoyltransferase activity. PMID- 26000640 TI - Ultrafast Energy Transfer from Solvent to Solute Induced by Subpicosecond Highly Intense THz Pulses. AB - The ultrafast energy transfer from an intense, subpicosecond THz pulse to bulk water at 300 K and density 1 g/cm(3) is simulated by ab initio molecular dynamics with explicit inclusion of the laser pulse. A 200 fs subcycle pulse of intensity 5 * 10(12) W/cm(2) corresponding to a peak field amplitude of 0.6 V/A and achievable nowadays using optical rectification techniques results in a temperature jump from 300 K up to ~1000 K within the first picosecond after the pulse. We discuss in detail the time-dependent structural changes caused by the THz pulse in the water medium and suggest possible ways to measure those changes by pump-probe experimental techniques. The ultrafast energy transfer from the energized water molecules to a solute molecule is studied on a test system, phenol. We find that phenol is, in the gas phase, insensitive to the THz pulse and only gains energy in solution via collisional energy transfer with the water molecules in its environment. The reason for this is found in the mode of interaction of the THz pulse with the aqueous medium. In short, water molecules respond mainly through their permanent dipole moments trying to orient themselves in the strong electric field of the pulse and disrupting their hydrogen-bonding structure. As compared with the water molecule, phenol has a smaller but still substantial permanent dipole moment. The moments of inertia of phenol are, however, too large for it to rotate in the short duration of the THz pulse. Therefore, the direct heating-up mechanism is mostly selective to the solvent molecules, whereas the solute heats up indirectly via collisions with its hot environment in about 1 to 2 ps. PMID- 26000641 TI - Antennae hold a key to Varroa-sensitive hygiene behaviour in honey bees. AB - In honey bees, Varroa sensitive hygiene (VSH) behaviour, which involves the detection and removal of brood parasitised by the mite Varroa destructor, can actively participate in the survival of colonies facing Varroa outbreaks. This study investigated the mechanisms of VSH behaviour, by comparing the antennal transcriptomes of bees that do and do not perform VSH behaviour. Results indicate that antennae likely play a key role in the expression of VSH behaviour. Comparisons with the antennal transcriptome of nurse and forager bees suggest that VSH profile is more similar to that of nurse bees than foragers. Enhanced detection of certain odorants in VSH bees may be predicted from transcriptional patterns, as well as a higher metabolism and antennal motor activity. Interestingly, Deformed wing virus/Varroa destructor virus infections were detected in the antennae, with higher level in non-VSH bees; a putative negative impact of viral infection on bees' ability to display VSH behaviour is proposed. These results bring new perspectives to the understanding of VSH behaviour and the evolution of collective defence by focusing attention on the importance of the peripheral nervous system. In addition, such data might be useful for promoting marker-assisted selection of honey bees that can survive Varroa infestations. PMID- 26000642 TI - Feasibility of a Modified Cone-Beam CT Rotation Trajectory to Improve Liver Periphery Visualization during Transarterial Chemoembolization. AB - PURPOSE: To compare liver coverage and tumor detectability by using preprocedural magnetic resonance (MR) images as a reference, as well as radiation exposure of cone-beam computed tomography (CT) with different rotational trajectories. MATERIALS AND METHODS: Fifteen patients (nine men and six women; mean age +/- standard deviation, 65 years +/- 5) with primary or secondary liver cancer were retrospectively included in this institutional review board-approved study. A modified cone-beam CT protocol was used in which the C-arm rotates from +55 degrees to -185 degrees (open arc cone-beam CT) instead of -120 degrees to +120 degrees (closed arc cone-beam CT). Each patient underwent two sessions of transarterial chemoembolization between February 2013 and March 2014 with closed arc and open arc cone-beam CT (during the first and second transarterial chemoembolization sessions, respectively, as part of the institutional transarterial chemoembolization protocol). For each cone-beam CT examination, liver volume and tumor detectability were assessed by using MR images as the reference. Radiation exposure was compared by means of a phantom study. For statistical analysis, paired t tests and a Wilcoxon signed rank test were performed. RESULTS: Mean liver volume imaged was 1695 cm(3) +/- 542 and 1857 cm(3) +/- 571 at closed arc and open arc cone-beam CT, respectively. The coverage of open arc cone-beam CT was significantly higher compared with closed arc cone beam CT (97% vs 86% of the MR imaging liver volume, P = .002). In eight patients (53%), tumors were partially or completely outside the closed arc cone-beam CT field of view. All tumors were within the open arc cone-beam CT field of view. The open arc cone-beam CT radiation exposure by means of weighted CT index was slightly lower compared with that of closed arc cone-beam CT (-5.1%). CONCLUSION: Open arc cone-beam CT allowed for a significantly improved intraprocedural depiction of peripheral hepatic tumors while achieving a slight radiation exposure reduction. PMID- 26000643 TI - Stereoselective Rearrangement of (Trifluoromethyl)prolinols to Enantioenriched 3 Substituted 2-(Trifluoromethyl)piperidines. AB - 3-Substituted 2-(trifluoromethyl)piperidines B were synthesized by ring expansion of (trifluoromethyl)prolinols A, which were obtained from L-proline via an aziridinium intermediate C. The ring opening of the (trifluoromethyl)aziridinium intermediate by different nucleophiles is regio- and diastereoselective. PMID- 26000644 TI - Re-establishing a place for phage therapy in western medicine. PMID- 26000645 TI - 1995-2015: it is time to celebrate 20 years of (intensive) genotyping of Toxoplasma gondii strains. PMID- 26000646 TI - Isavuconazole: a new extended spectrum triazole for invasive mold diseases. AB - Isavuconazole is the first broad spectrum prodrug triazole with efficacy against invasive fungal diseases including aspergillosis and mucormycosis. Characteristics include linear dose-proportional pharmacokinetics, intravenous and oral formulations allowing therapeutic streamlining, once daily dosing, absence of nephrotoxic solubilizing agents and excellent oral bioavailability independent of prandial status and gastric acidity. An open label noncomparator study demonstrated encouraging results for isavuconazole as primary or salvage therapy for a range of fungi including mucormycosis. Isavuconazole had fewer premature drug discontinuations and adverse events in the eye, hepatobiliary and psychiatry systems than the comparator agent, voriconazole in a randomized double blind clinical trial. Cross-resistance of isavuconazole best correlates with voriconazole. In vitro resistance is not invariably predictive of clinical failure. Isavuconazole signals progress in pharmacokinetics, bioavailability and toxicity/tolerability supported by clinical efficacy from Phase III trials. PMID- 26000647 TI - Amphiphilic cationic Zn-porphyrins with high photodynamic antimicrobial activity. AB - AIM: Photodynamic inactivation of microbes can efficiently eradicate antibiotic resistant strains. Systematic structural modification was used to investigate how porphyrin-based photosensitizers (PSs) could be designed for improved antibacterial activity. MATERIALS & METHODS: Zinc(II)5,10,15,20-tetrakis(N alkylpyridinium-2(3,4)-yl)porphyrins presenting systematic modifications at the periphery of the porphyrin ring were evaluated for toxicity and antimicrobial photodynamic activity by measuring metabolic activity, cell membrane integrity and viability using antibiotic-sensitive and resistant Escherichia coli strains as model Gram-negative targets. RESULTS: Maximal sensitizer uptake, and, upon illumination, decrease of viable bacteria by >6 log10 were achieved by positively charged amphiphilic PSs with longer (six to eight carbon) alkyl substituents. CONCLUSION: Antibacterial photoefficiency (throughout the text photoefficiency has been used as equivalent of photocytotoxic efficacy) can be increased by orders of magnitude by increasing the lipophilicity of cationic alkylmetalloporphyrin PSs. PMID- 26000648 TI - Optimization of sporicidal activity and environmental Bacillus endospores decontamination by biogenic silver nanoparticle. AB - AIM: The intent of this study is to decontaminate Bacillus endospores and to determine the D-values using silver nanoparticles (AgNPs) synthesized from Streptomyces sp. cell filtrate. MATERIALS & METHODS: AgNPs synthesis was performed extracellularly followed by characterization using spectrophotometer, High Resolution Transmission Electron Microscope and x-ray diffraction pattern analysis. Subsequently, the optimized conditions for the decontamination and D value estimation of Bacillus endospores were determined using the response surface methodology. The environmental spore decontamination study was performed in mice model. RESULTS: AgNPs were visibly and spectroscopically identified which were spherical with the size range of less than 20 nm. The synthesized AgNPs destroyed 1log10 CFU Bacillus endospores at around 20 min. The adherence of AgNPs to the surface of spore coat, pit formation and its complete structural loss was detected under field emission scanning electron microscopy. All the mice exposed to AgNP-treated spores showed no sign of pathological lesions. CONCLUSION: The results of our study strongly suggest that the application of AgNPs as a sporicidal agent could be a new approach in consistently eliminating the hazardous Bacillus spores. PMID- 26000649 TI - Carbapenem resistance confers to Klebsiella pneumoniae strains an enhanced ability to induce infection and cell death in epithelial tissue-specific in vitro models. AB - BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae strains (KPC-Kp) are emerging worldwide causing different nosocomial infections including those of the urinary tract, lung or skin wounds. For these strains, the antibiotic treatment is limited to only few choices including colistin, whose continuous use led to the emergence of carbapenem-resistant KPC-Kp strains resistant also to this treatment (KPC-Kp Col-R). AIM: Very little is known about the capacity of the different strains of KPC-Kp to invade the epithelial cells in vitro. To verify if the acquisition of carbapenem-resistant and the colistin-resistant phenotypes are correlated with a different ability to infect a series of epithelial cell lines of various tissutal origin and with a different capacity to induce cellular death. MATERIALS & METHODS: We used Klebsiella pneumoniae (KP), KPC-Kp and KPC-Kp Col-R strains, isolated from different patients carrying various tissue-specific infections, to infect a series of epithelial cell lines of different tissutal origin. The invasive capacity of the strains and the extent and characteristics of the cell damage and death induced by the bacteria were evaluated and compared. CONCLUSION: Our results show that both KPC-Kp and KPC-Kp Col-R display a greater ability to infect the epithelial cells, with respect to KP, and that the bacterial cell invasion results in a nonprogrammed cell death. PMID- 26000650 TI - A novel triterpene from Astraeus hygrometricus induces reactive oxygen species leading to death in Leishmania donovani. AB - AIM: The effect of astrakurkurone, a novel triterpene, isolated from Indian mushroom Astraeus hygrometricus has been investigated to elucidate the mechanisms involved in selective cell death of Leishmania donovani. MATERIALS & METHODS: The hypotheses were investigated using flow-cytometry, scanning electron microscopy and confocal microscopy. RESULTS: The time dependent elevation of astrakurkurone induced reactive oxygen species (ROS) was found intimately associated with apoptosis. The involvement of ROS in promastigote death was found confirmed as NAC and GSH could decrease the ROS level and restored the mitochondrial membrane potential (DeltaPsi(m)). It also inhibited the intracellular amastigotes. CONCLUSION: We claim the present invention as substantial in depth evidences that mushroom derived active molecules can be exploited as target specific, comparatively nontoxic leads for antileishmanial therapy. PMID- 26000651 TI - How a multidisciplinary 'One Health' approach can combat the tick-borne pathogen threat in Europe. AB - In Europe, ticks are the major arthropod vectors of disease agents to humans and domestic animals. They are capable of transmitting many pathogens most of which have been discovered or identified as tick-borne pathogens in the last 20 years. In recent years, unexplained syndromes occurring after a tick bite have become an increasingly important issue in public and animal health. Ticks and wildlife (the main reservoir of tick-borne pathogens) are highly susceptible to global environmental and socio-economic changes, which in turn may lead to an increased burden of tick-borne diseases. In this review, we explain the importance of a 'One Health' approach to better combat tick-borne diseases. PMID- 26000652 TI - The complex epidemiology of extended-spectrum beta-lactamase-producing Enterobacteriaceae. AB - Antimicrobial resistance is a growing worldwide iatrogenic complication of modern medical care. Extended-spectrum beta-lactamases have emerged as one of the most successful resistance mechanisms, limiting our therapeutic options to treat various human infections. The dissemination of these enzymes to the community probably signifies an irreversible step. This paper will review the evolution of human infections associated with extended-spectrum beta-lactamase-producing organisms in the past 20 years, and will present and discuss the current challenges, controversies, debates and knowledge gaps in this research field. PMID- 26000654 TI - Macrophage takeover and the host-bacilli interplay during tuberculosis. AB - Macrophages are key type of antigen-presenting cells that arbitrate the first line of defense against various intracellular pathogens. Tuberculosis, both pulmonary and extrapulmonary, is an infectious disease of global concern caused by Mycobacterium tuberculosis. The bacillus is a highly successful pathogen and has acquired various strategies to downregulate critical innate-effector immune responses of macrophages, such as phagosome-lysosome fusion, autophagy, induction of cytokines, generation of reactive oxygen and nitrogen species and antigen presentation. In addition, the bacilli also subvert acquired immunity. In this review, we aim to provide an overview of different antimycobacterial immune functions of macrophage and the strategies adopted by the bacilli to manipulate these functions to favor its survival and replication inside the host. PMID- 26000655 TI - Acquired metallo-beta-lactamases and their genetic association with class 1 integrons and ISCR elements in Gram-negative bacteria. AB - Metallo-beta-lactamases (MBLs) can hydrolyze almost all beta-lactam antibiotics and are resistant to clinically available beta-lactamase inhibitors. Numerous types of acquired MBLs have been identified, including IMP, VIM, NDM, SPM, GIM, SIM, DIM, KHM, TMB, FIM and AIM. IMPs and VIMs are the most frequent MBLs and disseminate in members of the family Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. Acquired MBL genes are often embedded in integrons, and some are associated with insertion sequence (IS) elements. The class 1 integrons and IS common region (ISCR) elements are usually harbored in transposons and/or plasmids, forming so-called mobile vesicles for horizontal transfer of captured genes between bacteria. Here, we review the MBL superfamily identified in Gram negative bacteria, with an emphasis on the phylogeny of acquired MBLs and their genetic association with class 1 integrons and IS common region elements. PMID- 26000653 TI - An update on iron acquisition by Legionella pneumophila: new pathways for siderophore uptake and ferric iron reduction. AB - Iron acquisition is critical for the growth and pathogenesis of Legionella pneumophila, the causative agent of Legionnaires' disease. L. pneumophila utilizes two main modes of iron assimilation, namely ferrous iron uptake via the FeoB system and ferric iron acquisition through the action of the siderophore legiobactin. This review highlights recent studies concerning the mechanism of legiobactin assimilation, the impact of c-type cytochromes on siderophore production, the importance of legiobactin in lung infection and a newfound role for a bacterial pyomelanin in iron acquisition. These data demonstrate that key aspects of L. pneumophila iron acquisition are significantly distinct from those of long-studied, 'model' organisms. Indeed, L. pneumophila may represent a new paradigm for a variety of other intracellular parasites, pathogens and under studied bacteria. PMID- 26000656 TI - Systematic review on intervention with prebiotics/probiotics in patients with obesity-related nonalcoholic fatty liver disease. AB - BACKGROUND: The gut microbiota is modulated by metabolic derangements, such as nutrition overload and obesity. AIM: The aim of this systematic review is to summarize the role of these gut modifiers in nonalcoholic fatty liver disease (NAFLD) and obesity. METHODS: A systematic search of MEDLINE (from 1946), PubMed (from 1946) and EMBASE (from 1949) databases through May 2014 was carried out to identify relevant articles. The search terms were 'probiotic' AND 'NAFLD', 'prebiotic' AND 'NAFLD', 'antibiotic' AND 'NAFLD', 'probiotics' AND 'obesity', 'prebiotic' AND 'obesity' or 'antibiotic' AND 'obesity'; these terms were searched as text word in 'clinical trials' and as exploded medical subject headings where possible. RESULTS: The evidence in the literature is scant, due to the scarcity of appropriately powered, randomized, controlled clinical trials, involving various centers and population of different origin. CONCLUSION: Although probiotics and prebiotics have been proposed in the treatment and prevention of patients with obesity-related NAFLD, their therapeutic use is not supported by high-quality clinical studies. PMID- 26000657 TI - Acute stress disorder among civilians during a war and post-traumatic growth six years later: the impact of personal and social resources. AB - BACKGROUND AND OBJECTIVES: Various studies suggest a link between stress response to a traumatic event and post-traumatic growth (PTG), but little is known about their long-term relationship. In this study, the relationship between acute stress disorder (ASD) among civilians during a war on the home front and PTG six years later was examined for the first time. Based on the conservation of resources (COR) theory, the role of personal and social resource loss and gain as moderating factors was investigated. DESIGN AND METHODS: At Time 1 of the research (the Second Lebanon War in 2006), a structured questionnaire was administered to 370 civilians living within rocket range. At Time 2, 6 years later, 301 participants from Time 1 were again examined. The data analysis refers to the 301 respondents who participated at Time 2. RESULTS: The findings indicate a significant relationship between ASD and PTG. Examination of the interaction revealed that resource gain (but not resource loss) moderates (strengthens) the relationship between the two. CONCLUSIONS: These findings are not consistent with the COR view that resource loss has a greater effect on stress responses than resource gain. PMID- 26000658 TI - Spin-dependent Seebeck Effect, Thermal Colossal Magnetoresistance and Negative Differential Thermoelectric Resistance in Zigzag Silicene Nanoribbon Heterojunciton. AB - Spin-dependent Seebeck effect (SDSE) is one of hot topics in spin caloritronics, which examine the relationships between spin and heat transport in materials. Meanwhile, it is still a huge challenge to obtain thermally induced spin current nearly without thermal electron current. Here, we construct a hydrogen-terminated zigzag silicene nanoribbon heterojunction, and find that by applying a temperature difference between the source and the drain, spin-up and spin-down currents are generated and flow in opposite directions with nearly equal magnitudes, indicating that the thermal spin current dominates the carrier transport while the thermal electron current is much suppressed. By modulating the temperature, a pure thermal spin current can be achieved. Moreover, a thermoelectric rectifier and a negative differential thermoelectric resistance can be obtained in the thermal electron current. Through the analysis of the spin dependent transport characteristics, a phase diagram containing various spin caloritronic phenomena is provided. In addition, a thermal magnetoresistance, which can reach infinity, is also obtained. Our results put forward an effective route to obtain a spin caloritronic material which can be applied in future low power-consumption technology. PMID- 26000659 TI - Long-decay near-infrared-emitting doped quantum dots for lifetime-based in vivo pH imaging. AB - pH-responsive doped quantum dots with an ultrasmall size (~3.5 nm), near-infrared emission (~720 nm) and long lifetime (~1 MUs), which exhibit a linear response range from pH 5.5 to 7.0 with the maximum change in the fluorescence lifetime up to ~600 nm, were synthesized as lifetime-based pH nanosensors for in vivo imaging. PMID- 26000660 TI - On-line coupling of continuous-flow gel electrophoresis with inductively coupled plasma-mass spectrometry to quantitatively evaluate intracellular metal binding properties of metallochaperones HpHypA and HpHspA in E. coli cells. AB - On-line coupling of gel electrophoresis with inductively coupled plasma-mass spectrometry (GE-ICP-MS) offers a strategy to monitor intracellular metals and their associated proteins simultaneously. Herein, we examine the feasibility of the GE-ICP-MS system in the quantitative analysis of intracellular metal binding properties using two Helicobacter pylori metallochaperones HypA and HspA overexpressed in E. coli cells as showcases. We show that parallel detection of metal and sulfur signals allows accurate quantification of intracellular metal protein stoichiometries, even for metalloproteins that bind metal ions with micromolar affinities. Using this approach, we demonstrate that only a trace amount of Ni(2+) is associated with HpHypA in cells, distinct from the in vitro observation of stoichiometric binding, while HpHypA exhibits high fidelity towards its structural metal Zn(2+) with stoichiometric Zn(2+) binding. In contrast, HpHspA associates with Zn(2+), Ni(2+), Cu(2+) and Co(2+) from an essential metal pool with ca. 0.5 molar equivalents of total metals bound per HpHspA monomer. The metal binding properties of both HpHypA and HpHspA were altered by Bi(3+). The binding of both Zn(2+) and Ni(2+) to HpHypA was suppressed under the stress of Bi(3+) in cells, different from in vitro studies that showed that Bi(3+) interfered with Zn(2+) but not Ni(2+) binding. This study provides an analytical approach to investigate the intracellular metal selectivity of overexpressed metalloproteins. PMID- 26000661 TI - Ideological Anachronism Involving Needle and Syringe Exchange Programs: Lessons From the Indiana HIV Outbreak. PMID- 26000662 TI - Tuning the thermodynamic onset potential of electrocatalytic O2 reduction reaction by synthetic iron-porphyrin complexes. AB - A porphyrin ligand with two beta-pyrrolic electron withdrawing ester groups is synthesized and its Co complex is crystallographically characterized. The iron complex of this porphyrin ligand shows an ~200 mV positive shift in its Fe(III/II) potential in organic as well as aqueous solvents and in the onset potential of ORR relative to that of an unsubstituted porphyrin. PMID- 26000663 TI - Traumatic axonal injury and persistent emotional lability in an adolescent following moderate traumatic brain injury: A case study. AB - A 15-year-old male was treated secondary to sustaining a moderate traumatic brain injury (moderate TBI). Symptom self-report, and computerized and paper-and-pencil based neurocognitive, vestibular/ocular motor, and imaging data were used throughout to document impairment and recovery. The patient demonstrated persistent emotional lability concurrent with vestibular impairment. In addition to clinical evaluation and management, the patient also underwent susceptibility weighted imaging, which revealed axonal shearing across the corpus callosum and areas innervating the prefrontal cortex. Paper-and-pencil neurocognitive measures revealed persisting deficits, despite normal-appearing computerized test results. Implications of this case underline the importance of an integrative evaluation process including clinical interview, neurocognitive and vestibular/ocular physical therapy, and advanced neuroimaging, especially in cases with atypical presentation. PMID- 26000664 TI - Structure and segregation of dopant-defect complexes at grain boundaries in nanocrystalline doped ceria. AB - Grain boundaries (GBs) dictate vital properties of nanocrystalline doped ceria. Thus, to understand and predict its properties, knowledge of the interaction between dopant-defect complexes and GBs is crucial. Here, we report atomistic simulations, corroborated with first principles calculations, elucidating the fundamental dopant-defect interactions at model GBs in gadolinium-doped and manganese-doped ceria. Gadolinium and manganese are aliovalent dopants, accommodated in ceria via a dopant-defect complex. While the behavior of isolated dopants and vacancies is expected to depend on the local atomic structure at GBs, the added structural complexity associated with dopant-defect complexes is found to have key implications on GB segregation. Compared to the grain interior, energies of different dopant-defect arrangements vary significantly at the GBs. As opposed to bulk, the stability of oxygen vacancy is found to be sensitive to the dopant arrangement at GBs. Manganese exhibits a stronger propensity for segregation to GBs than gadolinium, revealing that accommodation of dopant-defect clusters depends on the nature of dopants. Segregation strength is found to depend on the GB character, a result qualitatively supported by our experimental observations based on scanning transmission electron microscopy. The present results indicate that segregation energies, availability of favorable sites, and overall stronger binding of dopant-defect complexes would influence ionic conductivity across GBs in nanocrystalline doped ceria. Our comprehensive investigation emphasizes the critical role of dopant-defect interactions at GBs in governing functional properties in fluorite-structured ionic conductors. PMID- 26000665 TI - Comparison of Percutaneous Vertebroplasty and Balloon Kyphoplasty for the Treatment of Single Level Vertebral Compression Fractures: A Meta-analysis of the Literature. AB - BACKGROUND: Percutaneous vertebroplasty (PVP) and percutaneous balloon kyphoplasty (PKP) can increase bone strength as well as alleviate the pain caused by vertebral compression fractures (VCFs), and both procedures rely on polymethyl methacrylate (PMMA) cement injected into the fractured vertebra for mechanical stabilization of the VCFs. However, there is debate over which of these 2 surgical procedures can give better short-term and long-term outcomes. A lot of studies and meta-analysis were designed to assess the advantages and drawbacks of PKP and PVP in the treatment of VCFs, but most of them didn't consider the effect of VCF levels on the treatment outcome, which can influence the results. OBJECTIVE: To assess the safety and efficacy of PKP compared to PVP in the treatment of single level osteoporotic vertebral compression fractures (OVCF). STUDY DESIGN: Studies with the following criteria were included: patients with VCFs due to osteoporosis; PKP comparing PVP; study design, RCT or prospective or retrospective comparative studies. Furthermore, the studies which reported at least one of the following outcomes: subjective pain perception, quality of life evaluation, incidence of new adjacent vertebral fracture, bone cement leakage, and post-operative kyphotic angle. Articles were excluded in our meta-analysis if they had a neoplastic etiology (i.e., metastasis or myeloma), infection, neural compression, traumatic fracture, neurological deficit, spinal stenosis, severe degenerative diseases of the spine, previous surgery at the involved vertebral body, and PKP or PVP with other invasive or semi-invasive intervention treatment. SETTING: University hospital. METHODS: A systematic search of all articles published through May 2014 was performed by Medline, EMASE, OVID, and other databases. All the articles that compared PKP with PVP on single level OVCF were identified. The evidence quality levels of the selected articles were evaluated by Grade system. Data about the clinical outcomes and complications were extracted and analyzed. RESULTS: Eight studies, encompassing 845 patients, met the inclusion criteria. Overall, the results indicated that there were significant differences between the 2 groups in the short-term visual analog scale (VAS) scores, the long-term Oswestry Disability Index (ODI), short- and long-term kyphosis angle, the kyphosis angle improvement, the injected cement, and the cement leakage rates. However, there were no significant differences in the long-term VAS scores, the short-term ODI scores, the short- and long-term SF 36 scores, or the adjacent-level fracture rates. LIMITATIONS: Statistical efficacy can be improved by more studies, low evidence based non-RCT articles are likely to induce various types of bias, no accurate definition of short-term and long-term outcome time points. CONCLUSION: PKP and PVP are both safe and effective surgical procedures in treating OVCF. PKP has a similar long-term pain relief, function outcome (short-term ODI scores, short-and long-term SF-36 scores), and new adjacent VCFs in comparison to PVP. PKP is superior to PVP for the injected cement volume, the short-term pain relief, the improvement of short- and long-term kyphotic angle, and lower cement leakage rate. However, PKP has a longer operation time and higher material cost than PVP. To confirm this evaluation, a large multi-center randomized controlled trial (RCT) should be conducted. PMID- 26000666 TI - Lack of evidence for central sensitization in idiopathic, non-traumatic neck pain: a systematic review. AB - BACKGROUND: Chronic neck pain is a common problem with a poorly understood pathophysiology. Often no underlying structural pathology can be found and radiological imaging findings are more related to age than to a patient's symptoms. Besides its common occurrence, chronic idiopathic neck pain is also very disabling with almost 50% of all neck pain patients showing moderate disability at long-term follow-up. Central sensitization (CS) is defined as "an amplification of neural signaling within the central nervous system that elicits pain hypersensitivity," "increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input," or "an augmentation of responsiveness of central neurons to input from unimodal and polymodal receptors." There is increasing evidence for involvement of CS in many chronic pain conditions. Within the area of chronic idiopathic neck pain, there is consistent evidence for the presence and clinical importance of CS in patients with traumatic neck pain, or whiplash-associated disorders. However, the majority of chronic idiopathic neck pain patients are unrelated to a traumatic injury, and hence are termed chronic idiopathic non-traumatic neck pain. When comparing whiplash with idiopathic non-traumatic neck pain, indications for different underlying mechanisms are found. OBJECTIVE: The goal of this article was to review the existing scientific literature on the role of CS in patients with chronic idiopathic non-traumatic neck pain. STUDY DESIGN: Systematic review. SETTING: All selected studies were case control studies. METHODS: A systematic search of existing, relevant literature was performed via the electronic databases Medline, Embase, Web of Science, Cinahl, PubMed, and Google Scholar. All titles and abstracts were checked to identify relevant articles. An article was considered eligible if it met following inclusion criteria: (1) participants had to be human adults (> 18 years) diagnosed with idiopathic non-traumatic chronic (present for at least 3 months) neck pain; (2) papers had to report outcomes related to CS; and (3) articles had to be full-text reports or original research (no abstracts, case-reports, reviews, meta-analysis, letters, or editorials). RESULTS: Six articles were found eligible after screening the title, abstract and - when necessary - the full text for in- and exclusion criteria. All selected studies were case-control studies. Overall, results regarding the presence of CS were divergent. While the majority of patients with chronic traumatic neck pain (i.e. whiplash) are characterized by CS, this is not the case for patients with chronic idiopathic neck pain. The available evidence suggests that CS is not a major feature of chronic idiopathic neck pain. Individual cases might have CS pain, but further work should reveal how they can be characterized. LIMITATIONS: Very few studies available. CONCLUSIONS: Literature about CS in patients with chronic idiopathic non-traumatic neck pain is rare and results from the available studies provide an inconclusive message. CS is not a characteristic feature of chronic idiopathic and non-traumatic neck pain, but can be present in some individuals of the population. In the future a subgroup with CS might be defined, but based on current knowledge it is not possible to characterize this subgroup. Such information is important in order to provide targeted treatment. PMID- 26000667 TI - Effectiveness of Parasagittal Interlaminar Epidural Local Anesthetic with or without Steroid in Chronic Lumbosacral Pain: A Randomized, Double-Blind Clinical Trial. AB - BACKGROUND: Epidural injections (EI) are the most commonly performed minimally invasive intervention to manage chronic low back pain (CLBP) with lumbosacral radicular pain (LRP). Local anesthetic (LA) and/or steroids are frequently used injectates for EI and are reported with variable effectiveness. The majority of earlier studies have used either caudal, transforaminal (TF), or undefined interlaminar approaches for EI. The parasaggital interlaminar (PIL) approach route is reported to have good ventral epidural spread and comparable effectiveness to the TF route. However, there is a lack of head-to-head comparative effectiveness research of LA with or without steroid for managing CLBP with LRP using a PIL approach. OBJECTIVE: To compare the effectiveness of EI of LA alone and LA with steroid using a PIL approach for managing CLBP with LRP. STUDY DESIGN: Randomized, double blind, active control one year follow-up study. SETTING: Interventional pain management clinic in a tertiary care center in India. METHODS: Sixty-nine patients were randomized to receive fluoroscopic guided EI of either 8 mL of 0.5% lidocaine (group L, n = 34) or 6 mL of 0.5% lidocaine mixed with 80 mg (2 mL) of methylprednisolone acetate (group LS, n = 35). Patients were evaluated for pain intensity using 0 - 10 numerical rating scale (NRS) and functional disability using Modified Oswestry Disability Questionnaire (MODQ) at baseline; and 2 weeks, one, 2, 3, 6, 9, and 12 months after injection. Patients with inefficacy with the initial injection or response deterioration received an additional injection of the same injectate and dose. Patients were evaluated for achieving effective pain relief (EPR, i.e., >= 50% from baseline), overall NRS and MODQ, number of injections, and presence of ventral and perineural spread over one year follow-up. Primary outcome was proportion of patients achieving EPR at 3 months. RESULTS: A significantly higher proportion of patients achieved EPR at 3 months in group LS [30 (86%, 90% CI 73% 93%)] as compared to group L [17 (50%, 90% CI 36% - 64%)] (P = 0.02). Similar results were obtained at 6, 9, and 12 months, respectively. The probability of achieving EPR was significantly higher in group LS at various time-points during the one year follow-up as compared to group L (P = 0.01) A significant reduction in NRS and improvement in MODQ were observed at all time-points post-intervention compared to baseline (P < 0.001) in both groups. NRS and MODQ scores were significantly lower in group LS as compared to group L at all time intervals post baseline. On average patients in group L received 2.0 (0.85) and group LS received 1.7 (0.71) injections annually (P = 0.07). Ventral epidural spread was comparable in both groups (97%). No major complications were encountered in either group; however, intravascular spread of contrast was noted during 2 injections (one in each group) requiring relocation. LIMITATIONS: A single center study, lack of documentation of adjuvant therapies like individual analgesic medication, and lack of placebo group. CONCLUSIONS: Using a PIL approach and the addition of steroid to LA for EI may provide superior effectiveness in terms of extent and duration of pain relief for managing CLBP with unilateral LRP, even though, local anesthetic alone also was effective. TRIAL REGISTRATION: CTRI/2014/04/004572 PMID- 26000668 TI - A New Transmucous-Buccal Formulation of Acetaminophen for Acute Traumatic Pain: A Non-inferiority, Randomized, Double-Blind, Clinical Trial. AB - BACKGROUND: Acetaminophen (APAP) consumption is large and sometimes excessive, and guidelines suggest to diminish the dosage prescription. In emergency situations of mild/moderate pain intravenous (iv) APAP is recommended, but the route of administration is invasive. OBJECTIVE: To determine the efficacy of a new transmucous-buccal (B) pharmaceutical form of 125mg-APAP in patients. To confirm the findings obtained in 2 previous clinical trials in healthy volunteers. STUDY DESIGN: A randomized, double-blind, non-inferiority, clinical trial (NCT01586143) was carried out from 03/05/2012 to 13/05/2013. SETTING: The study took place in the Emergency Department of the University Hospital, Clermont Fd, France. METHODS: Forty-three patients were included and 40 analyzed. Patients were eligible if they had leg or arm traumatic pain of moderate intensity. Pain intensity was measured using a numerical scale (0 - 10) at regular times for 120 minutes and the main endpoint was at 30 minutes. The hypothesis of non inferiority was formulated from previous works with healthy volunteers. After pain assessment, patients received at baseline 1 g-iv-APAP or saline and concomitantly, 125 mg APAP in 1 mL hydroalcoholic solution (HAS) or placebo (HAS only) was applied in the left mucogingival sulcus. Non-inferiority of the primary outcome was assessed by one-sided 2 group t-test of equivalence in means with equal variances with a non-inferiority limit difference of 1. Other tests were two-sided, with a type I error set at alpha = 0.05. RESULTS: Intention-to-treat analysis shows that pain intensity of B-APAP and iv-APAP groups were not significantly different at t30 minutes (3 +/- 1.3 vs 2.7 +/- 1.2, P = 0.23, one sided Student t-test), and at any other times for 120 minutes. The difference of pain intensity between groups was 0.30 with 2-sided IC90% = [-0.38 - 0.98], not including the non-inferiority margin ( ? = 1). Time to exhibit a statistical significance in pain relief from baseline was reached at t10 for B-APAP (P = 0.03) and iv-APAP (P < 0.001). Patients preferred the buccal rather than the iv route of administration. LIMITATIONS: Small population study with limited doses. CONCLUSIONS: For acute traumatic pain of moderate intensity, B-APAP has a non inferior analgesic effect compared to iv-APAP for 2 hours. Such a pharmaceutical form would be useful in emergency situations and breakthrough moderate pain episodes. It would diminish APAP consumption per dosage unit, limit the risk of adverse events and toxicity, and adhere to actual guidelines of APAP prescription. It must be now studied in a larger population and with repeated doses. PMID- 26000669 TI - Do the gaps in the ligamentum flavum in the cervical spine translate into dural punctures? An analysis of 4,396 fluoroscopic interlaminar epidural injections. AB - BACKGROUND: Cervical interlaminar epidural injections are performed frequently in managing chronic neck and upper extremity pain, although less commonly than lumbar interlaminar epidural injections. Recently, the US Food and Drug Administration warnings and safeguards to prevent neurologic complications. These were developed by the Multi-Society Pain Workgroup have taken center stage for all types of epidural injections, including cervical interlaminar epidural injections. The recommendations of safeguards to prevent neurologic complications after epidural steroid injections include that cervical interlaminar epidural injections must be performed utilizing fluoroscopy with anteroposterior, lateral, or oblique views with injection of contrast medium and that entry be limited to the C7-T1 epidural space or occasionally the C6-C7 with requirements for magnetic resonance imaging assessment of the epidural space. OBJECTIVES: To assess the incidence of dural puncture associated with fluoroscopically directed cervical interlaminar epidural injections. STUDY DESIGN: A retrospective assessment of patients undergoing cervical interlaminar epidural injections from January 2013 through February 2015. SETTING: A private interventional pain management practice; a specialty referral center in the United States. METHODS: The data were collected for 4,396 consecutive cervical interlaminar epidural injections performed from January 2013 through February 2015. The procedures were all performed under fluoroscopic visualization under posteroanterior view with contrast medium injection with lateral view confirmation when indicated. The procedures were performed by one of 2 physicians; the dural puncture and subsequent postoperative complications with level of epidural entry were determined. OUTCOMES ASSESSMENT: The outcome was assessment of dural puncture. RESULTS: A review of multiple manuscripts showed that defects in the ligamentum flavum may extend to as much as 100% of the population. However, it also has been shown that among the levels with a gap, the location of a gap in the caudal third of the ligamentum flavum was more frequent than in the middle or cephalic portion of the ligamentum flavum. Among the 4,396 epidural injections performed at C7-T1, C6-C7, and C5-C6, 1,227 were performed at C7-T1; 1,835 were performed at C6-C7; and 1,334 were performed at C5-C6. Dural punctures were observed in 1.8% (24 procedures) at the C5-C6 level entry; 0.87% (16 procedures) at the C6-C7 level entry; and 1.71% (21 procedures) at the C7-T1 level. There was no significant difference among the entry levels. No complications or spinal cord damage or postdural puncture headache were observed. LIMITATIONS: The limitations of this report include that it is an assessment by only 2 well experienced physicians, even though it included a relatively large number of patients. CONCLUSION: This study illustrates that dural puncture is equally prevalent, though very rare, irrespective of the needle entry level into the epidural space, with an overall dural puncture rate of 1.4%, with 1.8% at the C5-C6 level, 0.87% at the C6-C7 level, and 1.71% at the C7-T1 level. Based on the present literature, it appears that performing the procedure by inserting the needle into the cephalic portion of the intervertebral space rather than the caudal portion may be safer. PMID- 26000670 TI - Intravenous parecoxib and continuous femoral block for postoperative analgesia after total knee arthroplasty. A randomized, double-blind, prospective trial. AB - BACKGROUND: Up until now, the optimal strategy for postoperative pain management after total knee arthroplasty (TKA) remains to be elucidated. OBJECTIVE: The current investigation aimed to examine the analgesic efficacy and the opioid sparing effects of intravenous parecoxib in combination with continuous femoral blockade. STUDY DESIGN: Randomized, double-blind, prospective trial. SETTING: University hospital in the United Kingdom. METHODS: In total, 90 patients underwent TKA under subarachnoid anesthesia and received continuous femoral block initially as a bolus with 20 mL of ropivacaine 0.75%. Infusion of 0.2% on 10 mL/h followed. Patients were randomized into 2 groups. Group D and Group P received parecoxib and placebo, respectively at 12 hour time intervals. Visual analog scale (VAS) pain scores were obtained at different time intervals including 4, 8, 12, 24 and 36 hours. The pain scores were measured with patients in a resting position. Morphine could also be administered with a patient controlled analgesia (PCA) pump if the specified analgesia was deemed inadequate (VAS > 5). RESULTS: None of the patients were withdrawn from the study. Parecoxib provided greater relief than placebo following TKA. The VAS pain scores measured at rest were statistically significantly lower in parecoxib-treated patients compared to the placebo group (P = 0.007) at 4 (P = 0.044), 12 (P = 0.001), and 24 hours (P = 0.012), postoperatively. Patients receiving parecoxib consumed less morphine at all time intervals than patients receiving placebo, with borderline statistical significance (P = 0.054). In each time period, all patients receiving continuous femoral block irrespectively of the treatment group, required low morphine doses. LIMITATIONS: Current protocol did not answer question as to functional recovery. CONCLUSION: According to our findings intravenous parecoxib in combination with continuous femoral block provided superior analgesic efficacy and opioid sparing effects in patients undergoing TKA. PMID- 26000671 TI - Immediate and acute adverse effects following transforaminal epidural steroid injections with dexamethasone. AB - BACKGROUND: Transforaminal epidural steroid injections (TFESI) are widely used for the conservative treatment of radicular pain. The use of dexamethasone in TFESIs is relatively new; therefore, immediate and acute adverse effects that it may cause are not fully updated. OBJECTIVE: To evaluate immediate and acute adverse effects following TFESI with dexamethasone. STUDY DESIGN: Prospective, observational study. SETTING: A spine center affiliated with a rehabilitation hospital. METHODS: One hundred fifty consecutive patients receiving TFESI for the management of radicular and axial spinal pain at the cervical, lumbar, and sacral levels with dexamethasone using fluoroscopic guidance with digital subtraction technology were enrolled. The occurrence of adverse effects in patients in the 2 week time period following interventions was monitored through a set of questionnaires followed up by phone calls scheduled for 1 day, day 3, and day 14. Intensity and duration of side effects were recorded. RESULTS: Of the 150 patients enrolled, 31 patients (19.5%) experienced adverse effects within the first 30 minutes following the intervention. The most common adverse effects were numbness and tingling in the limb, which developed in 19 patients (11.95%) followed by perineal pruritus that occurred in 7 cases (4.4%). Patients also reported experiencing adverse effects within the 3 days following intervention; most complained of headaches, insomnia, hiccups, flushing, and increased radicular pain. No major complications were noted. LIMITATIONS: The sample size enrolled might be too small to perceive possible rare side effects related to the procedure. The 2-week follow-up period is a limitation for evaluating late side effects. CONCLUSIONS: This study offers provision to interventionalists that TFESI with dexamethasone when performed by experienced hands and with proper technique has minor self-limited transient adverse effects that can be easily managed. Patients should be made aware of these adverse effects and their management. Further larger studies are needed to validate the safe use of dexamethasone and the safety of transforaminal epidural injections. PMID- 26000672 TI - Treatment outcomes after combination interventional and cognitive motivational counseling on analgesic medication use in patients with chronic spine pain. AB - BACKGROUND: Pain interventionists can interrupt pain through anesthetic blockade of neural transmission to virtually any part of the body. Temporary pain relief can be achieved by the direct application of targeted anesthetic. Diagnostically, nerve blocks help identify specific pain generators, refine differential diagnosis, and disrupt the neural transmission mechanisms to stop pain generation peripherally. OBJECTIVE: This study of patients with chronic spine pain was conducted to test the hypothesis that decreasing pain through interventional techniques coupled with cognitive motivational counseling can be highly effective in reducing chronic pain interference, reliance on prescription opioids, and enhancing overall function and quality of life. STUDY DESIGN: Retrospective case series. SETTING: Rehabilitation center. METHODS: PATIENTS: This study involved a retrospective cohort of 78 consecutive patients with spine pain that underwent interventional procedures and cognitive motivational counseling, as well as a comparison group of 77 consecutive patients that underwent interventional procedures only. OUTCOME MEASURES: Pain intensity (DoD VAS), Functional capacity (DoD SS), Global Appraisal (PGIC), Pain site measurement (Drawing), and prescription medication use questionnaires were administered at initial evaluation and after treatment. Pre- and post-treatment changes were compared using paired t-tests. Chi-squared analysis was performed pre- and post-treatment for medication use. RESULTS: The pre- and post-treatment scores for pain intensity, function, and global appraisal demonstrated significant response to treatment (P < 0.001) for the combined interventional and cognitive motivational group (P < 0.001) and the interventional only group (P < 0.05). Compared to initial intake, opioid (P < 0.01), benzodiazepine (P < 0.01), muscle relaxant (P < 0.05), and antidepressant/antianxiolytic (P < 0.05) use only decreased for the combined interventional and cognitive motivational group. LIMITATIONS: This is a retrospective study using medical records and patient self-reported symptoms with possible missed coding and no true random selection, assignment, or genuine control group comparison. CONCLUSION: This study's results support the hypothesis that a combined interventional and cognitive motivational counseling treatment program can be effective in decreasing spine pain, reducing prescription pain medication use, and improving overall quality of life in chronic spine pain patients. PMID- 26000673 TI - Referred pain patterns of the third and fourth dorsal interosseous muscles. AB - BACKGROUND: Myofascial pain (MP) is a common disorder that can involve any skeletal muscle in the human body. There are no published reports of the referred pain patterns of the third and fourth dorsal interosseous muscles. OBJECTIVE: To investigate the referred pain patterns of the third and fourth dorsal interosseous muscles. STUDY DESIGN: Prospective evaluation. SETTING: Academic medical center. METHODS: Twenty healthy adults participated in the study. Needle placement and injection of 0.2 mL 6% hypertonic saline solution into the midpoint of the interosseous muscles were performed under ultrasonographic (US) guidance. After the injections, the participants were instructed to wait until they felt the most pain and then draw a pain diagram. This drawing was transferred to the computer for analysis. RESULTS: The referred pain distributions for the third dorsal interosseous muscle were as follows: the interdigital space of the third and fourth fingers, 80%; the distal phalanx of the third and fourth fingers, 45%; and the ulnar side of the palm, 55%. Three and 6 participants reported pain on the volar side of the wrist and in the fifth finger, respectively. The referred pain distributions for the fourth dorsal interosseous muscle were as follows: the interdigital space of the fourth and fifth fingers, 80%; the hypothenar area, 65%; and the distal phalanx of the fourth and fifth fingers, 60%. Seven and 3 participants also reported pain on the ulnar side of the wrist and the ulnar side of the forearm, respectively. LIMITATION: This study is limited by its small sample size. CONCLUSION: Referred pain patterns of the third and fourth interosseous muscles resemble the pain experienced in C7 or C8 radiculopathies or the ulnar neuropathy. Thus, identification of the third and fourth interosseous muscle trigger point should be considered when patients experience pain on the ulnar aspect of the hand and wrist. PMID- 26000674 TI - In errata. PMID- 26000675 TI - Analysis of the carrot and stick policy of repeal of the sustainable growth rate formula: the good, the bad, and the ugly. AB - The Balanced Budget Act which became law in 1997 was designed to help stem the increasing in costs of healthcare. The Sustainable Growth Rate (SGR) formula was incorporated into that law as a method of helping balance the budget through a complex formula tying reimbursement to the growth in the economy. Soon after its inception, the flawed nature of the formula, linking the balancing of the federal budget to physician professional fees was realized. Congress has provided multiple short-term fixes known as SGR patches over the years so as to avoid generally progressively larger negative corrections to professional reimbursement. The near annual SGR correction requirement has been compared to Groundhog Day in the legislative arena. Over the years, physician and other providers faced numerous looming, large cuts. Most recently, on April 1, 2015 physicians faced a 21.2% cut in provider payments. To the surprise of many, in April 2015 a bipartisan bicameral effort permanently repealed the Medicare SGR formula for controlling provider payment. The repeal of SGR means the temporary measures to override the growth rate formula will no longer dominate Medicare policy discussions and now the focus turns to continue payment reforms. The MACRA provides physicians and other health care professionals with stable fee update for 5 years and it follows with a new incentive program, termed the Merit-based Incentive Payment System (MIPS) replacing and consolidating pre-existing incentive payment programs: meaningful use of electronic health records (EHR), physician quality reporting system, and the value-based payment modified. Thus, payments to clinicians will be subjected to adjustments based on participation in MIPS or other approved alternative payment mechanisms. This legislation also creates numerous other regulations. The MACRA has been criticized for providing insufficient statutory updates, enacting a flawed quality and performance improvement program associated with MIPS and inappropriate use of utilization and payment data. Thus, the MACRA offers physicians a predictable schedule for Medicare rates - a carrot, and controls the physician behaviors with payment reforms analogous to a stick. Thus, it could be said that this legislation embodies some good, bad, and ugly aspects. PMID- 26000676 TI - A case for restraint of explosive growth of health information technology: first, do no harm. AB - Information technology has brought significant advances to modern life. We, like many others, believe that IT properly utilized in the delivery of health care ultimately bodes well for the care of our patients. The challenge is that the current technology does not live up to that promised state of multiple elements of improved care through IT. Despite that, legislative mandates have required large-scale adoption of present day health care IT solutions. These regulations have been particularly challenging for independent practitioners.Our efforts at making these points are now supported by a growing body of research including a very important analysis by the ECRI. PMID- 26000677 TI - Economic Analysis of Kiva VCF Treatment System Compared to Balloon Kyphoplasty Using Randomized Kiva Safety and Effectiveness Trial (KAST) Data. AB - BACKGROUND: Vertebral compression fractures (VCFs) are the most common osteoporotic fractures and cause persistent pain, kyphotic deformity, weight loss, depression, reduced quality of life, and even death. Current surgical approaches for the treatment of VCF include vertebroplasty (VP) and balloon kyphoplasty (BK). The Kiva(r) VCF Treatment System (Kiva System) is a next generation alternative surgical intervention in which a percutaneously introduced nitinol Osteo Coil guidewire is advanced through a deployment cannula and subsequently a PEEK Implant is implanted incrementally and fully coiled in the vertebral body. The Kiva System's effectiveness for the treatment of VCF has been evaluated in a large randomized controlled trial, the Kiva Safety and Effectiveness Trial (KAST). The Kiva System was non-inferior to BK with respect to pain reduction (70.8% vs. 71.8% in Visual Analogue Scale) and physical function restoration (38.1 % vs. 42.2% reduction in Oswestry Disability Index) while using less bone cement. The economic impact of the Kiva system has yet to be analyzed. OBJECTIVE: To analyze hospital resource use and costs of the Kiva System over 2 years for the treatment of VCF compared to BK. SETTING: A representative US hospital. STUDY DESIGN: Economic analysis of the KAST randomized trial, focusing on hospital resource use and costs. METHODS: The analysis was conducted from a hospital perspective and utilized clinical data from KAST as well as unit-cost data from the published literature. The cost of initial VCF surgery, reoperation cost, device market cost, and other medical costs were compared between the Kiva System and BK. The relative risk reduction rate in adjacent-level fracture with Kiva [31.6% (95% CI: -22.5%, 61.9%)] demonstrated in KAST was used in this analysis. RESULTS: With 304 vertebral augmentation procedures performed in a representative U.S. hospital over 2 years, the Kiva System will produce a direct medical cost savings of $1,118 per patient and $280,876 per hospital. This cost saving with the Kiva System was attributable to 19 reduced adjacent-level fractures with the Kiva System. LIMITATIONS: This study does not compare the Kiva System with VP or any other non-surgical procedures for the treatment of VCF. CONCLUSION: This first-ever economic analysis of the KAST data showed that the Kiva System for vertebral augmentation is hospital resource and cost saving over BK in a hospital setting over 2 years. These savings are attributable to reduced risk of developing adjacent-level fractures with the Kiva System compared to BK. PMID- 26000678 TI - Reducing opioid analgesic deaths in America: what health providers can do. AB - BACKGROUND: Available data have shown steady increases of drug overdose deaths between 1992 and 2011. We review evidenced-based recommendations provided by a few prominent North American pain societies and suggest ways on how health providers might help reduce opioid analgesic deaths by implementing these practices. OBJECTIVE: To identify health care providers' roles in reducing opioid analgesic deaths. STUDY DESIGN: A comprehensive review of current literature. METHODS: The review included relevant literature identified through searches of MEDLINE, Cochran reviews, and Google Scholar, PubMed and EMBASE from January 1998 to January 2014. The level of evidence was classified as I (good), II (fair), and III (limited) based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). RESULTS: Several practices such as too high doses overall, giving too high doses to opioid naive patients, too fast opioid titration, insufficient use and knowledge of urine drug testing, not updating knowledge of drug metabolism/interactions, and inadequate patient monitoring are associated with higher risks of opioid analgesic deaths. Suboptimal risk stratification of patients, rotation practices, and use of opioids analgesics in chronic noncancer pain are also associated factors. LIMITATIONS: There were a paucity of good evidence studies which show recommendations reduce death. CONCLUSION: Providers should be aware of all associated factors with opiate analgesic deaths and apply the available evidence in reducing opioid analgesic deaths. PMID- 26000679 TI - Opioid therapy in the treatment of chronic pain conditions in Germany. AB - BACKGROUND: Primarily used for treating malignant pain, opioids are recently applied for chronic non-tumor pain. For the lack of evidence based strategies from long-term studies, opioids are discussed controversially, esp. considering cost-benefit. OBJECTIVES: The purpose of this study is to evaluate characteristics in prescribing opioids for tumor and non-tumor pain conditions. STUDY DESIGN: Cost effectiveness study/observational study SETTING/METHODS: Health insurance data of a German statutory health insurance company (N = 6.800.000, data acquisition from 2006 to 2010) was evaluated by assigning opioid prescriptions to certain pain related diagnoses using CART (Classification And Regression Tree) segmentation analysis. Age- and gender-specific characteristics of prescriptions were calculated. RESULTS: The number of prescriptions of opioid prescriptions increased linearly. Prescriptions of mild opioids were decreasing for non-tumor pain, but increasing for tumor pain, while the number of prescriptions of strong opioids was increasing both for tumor and nontumor pain. Differences occurred in terms of duration and kind of the preferred substances, including the considerations of common contraindications (e.g. somatoform disorders). The majority of strong opioids being prescribed for non-tumor pain were fentanyl pain patches for 40 to 45 year old males with average annual costs of 1833 Euros per patient. Out of 21000 patients with somatoform pain disorder, 44.4% were treated with opioids (20.7% with mild, 23.7% with strong opioids). LIMITATIONS: The results did not consider if the opioid medication was actually taken by the patients. Another difference in terms of representativeness might occur since the gender distribution varies between the official statistical data and data collected by the health insurance company. Because of the acquisition of the data, no conclusions about possible correlation of pain syndromes and educational and social classes are possible. Tumor patients who received an opioid prescription for non-tumor pain could not be excluded. CONCLUSIONS: While the overall expenditure of the health insurance companies increased, it remains unknown which patient is receiving a particular opioid medication. Prescribing behavior was often not consistent with common indications and contraindications. PMID- 26000680 TI - Low back pain: guidelines for the clinical classification of predominant neuropathic, nociceptive, or central sensitization pain. AB - BACKGROUND: Low back pain (LBP) is a heterogeneous disorder including patients with dominant nociceptive (e.g., myofascial low back pain), neuropathic (e.g., lumbar radiculopathy), and central sensitization pain. In order to select an effective and preferably also efficient treatment in daily clinical practice, LBP patients should be classified clinically as either predominantly nociceptive, neuropathic, or central sensitization pain. OBJECTIVE: To explain how clinicians can differentiate between nociceptive, neuropathic, and central sensitization pain in patients with LBP. STUDY DESIGN: Narrative review and expert opinion SETTING: Universities, university hospitals and private practices METHODS: Recently, a clinical method for the classification of central sensitization pain versus neuropathic and nociceptive pain was developed. It is based on a body of evidence of original research papers and expert opinion of 18 pain experts from 7 different countries. Here we apply this classification algorithm to the LBP population. RESULTS: The first step implies examining the presence of neuropathic low back pain. Next, the differential diagnosis between predominant nociceptive and central sensitization pain is done using a clinical algorithm. LIMITATIONS: The classification criteria are substantiated by several original research findings including a Delphi survey, a study of a large group of LBP patients, and validation studies of the Central Sensitization Inventory. Nevertheless, these criteria require validation in clinical settings. CONCLUSION: The pain classification system for LBP should be an addition to available classification systems and diagnostic procedures for LBP, as it is focussed on pain mechanisms solely. PMID- 26000681 TI - Percutaneous vertebroplasty combined with percutaneous pediculoplasty for lytic vertebral body and pedicle lesions of metastatic tumors. AB - BACKGROUND: Percutaneous pediculoplasty (PP) consists of the injection of Poly(methyl methacrylate) (PMMA) into the fractured pedicle or lytic vertebral pedicle lesions, as a technique derived from vertebroplasty. OBJECTIVES: To evaluate the short-term analgesic effect of percutaneous vertebroplasty (PV) and percutaneous pediculoplasty (PP) in patients with lytic vertebral body and pedicle lesions of metastatic tumors. STUDY DESIGN: Single-center retrospective observational study. SETTING: An interventional pain management practice, a medical center, major metropolitan city, China. METHODS: Single-center retrospective observational study of all patients managed with PV and PP for painful vertebral body and pedicle metastatic tumors between 2007 and 2013. For each patient, symptom duration and pain intensity were recorded. PP was performed under local analgesia, in the prone position, with C-arm fluoroscopy guidance. The mixture of PMMA and Doxorubicin was delivered into the vertebral body with a non-beveled needle for the initial treatment followed by the mixture delivery into the lytic pedicle during needle withdrawal. RESULTS: Nine patients (5 women, 4 men) were enrolled in the study with a mean age of 65.9 years (range 57 - 75). Technical success was defined as the ability to access the lesion using the approach. A positive clinical response for pain relief was achieved in these patients in whom vertebroplasty and pediculoplasty had been performed. Pain level was not significantly reduced in 3 patients in whom just vertebroplasty has been performed because the medial wall of the pedicle was destroyed by the metastatic lesion. LIMITATIONS: This study is limited by its sample size. CONCLUSIONS: PV and PP via the transpedicular approach for infiltrated vertebral bodies and infiltrated pedicles of metastatic tumors may be considered a valid therapeutic option. PMID- 26000682 TI - Increased dose of betamethasone for transforaminal epidural steroid injections is not associated with superior pain outcomes at 4 weeks. AB - BACKGROUND: Fluoroscopically guided transforaminal epidural steroid injections (FG-TFESIs) have been shown to provide both immediate and long-term improvement in patient's self-reported pain. Administration of the lowest possible dose of epidural betamethasone is desired to minimize side effects while maintaining efficacy. We hypothesize that a 3 mg or a 6 mg dose of betamethasone will demonstrate equivalent analgesic properties. OBJECTIVES: To compare the analgesic efficacy of 3 mg and a 6 mg dose of betamethasone for use in FG-TFESI. STUDY DESIGN: Retrospective evaluation. SETTING: Academic outpatient pain center. METHODS: One hundred fifty-eight patients underwent FG-TFESI for lumbar back pain between 2012 and 2013. Depending on the date of service, a dose of 3 mg or a dose of 6 mg betamethasone was used in the single level unilateral TFESI. Opioid consumption and NRS pain score were analyzed pre-procedurally and at a clinic visit 4 weeks post-procedurally. RESULTS: Changes in numerical rating scale (NRS) pain score (-1.21 +' 2.61 vs. -0.81 +' 2.40 respectively, P = 0.17) and changes in opioid consumption as measured in oral morphine equivalents (-2.94 +' 16.4 mg vs. -2.93 +' 14.8 mg, P = 0.17) were statistically equivalent between both groups. Intergroup sub-analysis of those with > 50% reduction in baseline VRS {sp} pain score was not different (15.2% vs. 34%, P = 0.56), and the proportion with a VRS pain score < 3 were similar (24.5% vs. 23.8%, P = 0.92). LIMITATIONS: Potential selection bias inherent with study design. CONCLUSIONS: Reduction in NRS pain scores and narcotic usage at 4 weeks after FG-TFESI were statistically equivalent between patients who received 3 mg or 6 mg of betamethasone, suggesting that a lower steroid dose has similar analgesic efficacy. IRB Number: Cedars Sinai Medical Center Institutional Review Board Pro00031594 PMID- 26000683 TI - Cryoablation for the treatment of occipital neuralgia. AB - BACKGROUND: Treatment of occipital neuralgia (ON) can be complex, though many treatment options exist. Cryoablation (CA) is an interventional modality that has been used successfully in chronic neuropathic conditions and is one such option. OBJECTIVE: To study and evaluate the efficacy and safety of cryoablation for treatment of ON. STUDY DESIGN: Retrospective evaluation. SETTING: Academic university-based pain management center. METHODS: All patients received local anesthetic injections for ON. Patients with greater than or equal to 50% relief and less than 2 week duration of relief were treated with CA. RESULTS: Thirty eight patients with an average age of 49.6 years were included. Of the 38 patients, 20 were treated for unilateral greater ON, 10 for unilateral greater and lesser ON, and 8 for bilateral greater ON. There were 10 men and 28 women, with an average age of 45.2 years and 51.1 years, respectively. The average relief for all local anesthetic injections was 71.2%, 58.3% for patients who reported 50 - 74% relief (Group 1) and 82.75% for patients who reported greater than 75% relief (Group 2). The average improvement of pain relief with CA was 57.9% with an average duration of 6.1 months overall. Group 1 reported an average of 45.2% relief for an average of 4.1 months with CA. In comparison, Group 2 reported an average of 70.5% relief for 8.1 months. The percentage of relief (P = 0.007) and duration of relief (P = 0.0006) was significantly improved in those reporting at least 75% relief of pain with local anesthetic injections (Group 2 vs Group 1). Though no significance in improvement from CA was found in men, significance was seen in women with at least 75% benefit with local anesthetic injections in terms of duration (P = 0.03) and percentage (P = 0.001) of pain relief with CA. The average pain score prior to CA was 8 (0 - 10 visual analog scale, VAS), this improved to 4.2, improvement of 3.8 following CA at 6 months (P = 0.03). Of the 38 patients, 3 (7.8%) adverse effects were seen. Two patients reported post procedure neuritis and one was monitored for procedure-related hematoma. LIMITATIONS: Study limitations include the retrospective nature of the study. Additionally, only the percentage of relief, pain score, and duration of relief were collected. CONCLUSIONS: CA is safe, and should be considered in patients with ON. KEY WORDS: Cryoablation, cryoanalgesia, occipital neuralgia, treatment, adverse effects. PMID- 26000684 TI - Analysis of psychological characteristics impacting spinal cord stimulation treatment outcomes: a prospective assessment. AB - BACKGROUND: Psychological factors are recognised as influencing the outcome of spinal cord stimulation (SCS) although there is currently no consensus as to which factors impact upon SCS efficacy. OBJECTIVE: To identify psychological characteristics that may impact the efficacy of SCS. STUDY DESIGN: Prospective evaluation. SETTING: Single secondary care center in Dudley, United Kingdom. METHODS: PATIENTS: Seventy-five patients were initially recruited and 56 patients (31 women and 25 men) were followed-up for 12-months. INTERVENTION: SCS for the management of chronic non-cancer pain. MAIN OUTCOME MEASURES: Outcome measures assessed at baseline, 6 months, and 12 months following SCS implantation included the visual analogue scale (VAS), Oswestry disability index (ODI), hospital anxiety and depression (HAD) scale, and the pain coping strategies questionnaire (PCSQ). RESULTS: Statistically significant improvements were observed for the VAS (P < 0.001), ODI (P = 0.011), anxiety (P = 0.042), and depression (P = 0.010) in the HAD scale and for the subscales reinterpreting pain sensation (P = 0.018), control over pain (P = 0.001), and ability to decrease pain (P < 0.001) of the PCSQ. We observed that depression and autonomous coping (control over pain, ability to reduce pain, and catastrophizing) may impact sensory aspects such as pain intensity and disability scores affecting the outcome of SCS treatment. Age at time of implant and duration of pain prior to implant were also found to impact SCS efficacy. LIMITATIONS: It has been reported that loss of analgesia may be experienced within 12 to 24 months following SCS implantation and therefore, it would be of interest to follow patients over a longer period. CONCLUSIONS: This study demonstrates that psychological aspects such as depression and autonomous coping may impact SCS treatment. Addressing these issues prior to SCS implantation may improve SCS long-term outcome. PMID- 26000685 TI - Effects of ultrasound-guided stellate ganglion block on acute pain after arthroscopic shoulder surgery. AB - BACKGROUND AND OBJECTIVES: Apart from a few case reports, the effectiveness of stellate ganglion block (SGB) as a monotherapy in acute nociceptive pain has not been determined. We aimed to assess the effects of SGB on postoperative pain after arthroscopic shoulder surgery. STUDY DESIGN: Randomized, blind, controlled, clinical trial SETTING: University Hospital outpatient METHODS: Forty-six patients undergoing arthroscopic shoulder surgery were assigned randomly to 2 groups: group S included patients who underwent SGB prior to surgery and group C did not. In group S, subfascial ultrasound-guided SGB was conducted with 4 mL of 0.375% levobupivacaine. For the first postoperative 48 hours, postoperative visual analog scale (VAS) and analgesic requirements were compared. RESULTS: The results of 40 patients were included in the study. There was no difference between groups with regards to analgesics requirement for the first postoperative 48 hours and no difference in VAS score (P > 0.05). LIMITATIONS: Small number of patients in study. CONCLUSION: Preoperative ultrasound-guided SGB did not reduce postoperative acute pain in arthroscopic shoulder surgery. PMID- 26000686 TI - Cognitive Performance Is Related to Central Sensitization and Health-related Quality of Life in Patients with Chronic Whiplash-Associated Disorders and Fibromyalgia. AB - BACKGROUND: A growing body of research has demonstrated that impaired central pain modulation or central sensitization (CS) is a crucial mechanism for the development of persistent pain in chronic whiplash-associated disorders (WAD) and fibromyalgia (FM) patients. Furthermore, there is increasing evidence for cognitive dysfunctions among these patients. In addition, chronic WAD and FM patients often report problems with health-related quality of life (QoL). Yet, there is limited research concerning the interrelations between cognitive performance, indices of CS, and health-related QoL in these patients. OBJECTIVES: (1) Examining the presence of cognitive impairment, CS, and limitations on health related QoL in patients with chronic WAD and FM compared to healthy controls. (2) Examining interrelations between performance-based cognitive functioning, CS, and self-reported health-related QoL in these 3 study groups. STUDY DESIGN: A case control study was conducted. SETTING: The present study took place at the University Hospital Brussels, the University of Brussels, and the University of Antwerp. METHODS: Fifty-nine patients (16 chronic WAD patients, 21 FM patients, and 22 pain-free volunteers) filled out the Short Form 36 item Health Survey (SF 36), a self-reported psychosocial questionnaire, to assess health-related QoL. Next, they were subjected to various pain measurements (pressure hyperalgesia, deep-tissue hyperalgesia, temporal summation [TS], and conditioned pain modulation [CPM]). Finally, participants completed a battery of performance-based cognitive tests (Stroop task, psychomotor vigilance task [PVT], and operation span task [OSPAN]). RESULTS: Significant cognitive impairment, bottom-up sensitization, and decreased health-related QoL were demonstrated in patients with chronic WAD and FM compared to healthy controls (P < 0.017). CPM was comparable between the 3 groups. Cognitive performance was significantly related to central pain modulation (deep-tissue hyperalgesia, TS, CPM) as well as to self reported health-related QoL (P < 0.05). Decreased cognitive performance was related to deficient central pain modulation in healthy controls. Further, significant correlations between decreased cognitive performance and reduced health-related QoL were revealed among all study groups. Additionally, FM patients showed correlations between cognitive impairment and increased health related QoL. Remarkably, impaired selective attention and working memory were related to less TS, whereas impaired sustained attention was correlated with dysfunctional CPM in FM patients. LIMITATIONS: Based on the current cross sectional study no firm conclusions can be drawn on the causality of the relations. CONCLUSION: In conclusion, this paper has demonstrated significant cognitive deficits, signs of CS, and reduced health-related QoL in chronic WAD and FM patients compared to healthy individuals. Significant relations between cognitive performance and CS as well as health-related QoL were demonstrated. These results provide preliminary evidence for the clinical importance of objectively measured cognitive deficits in patients with chronic WAD and FM. KEY WORDS: Chronic pain, fibromyalgia, whiplash, central sensitization, conditioned pain modulation, temporal summation, cognition, quality of life. PMID- 26000687 TI - Sphenopalatine ganglion electrical nerve stimulation implant for intractable facial pain. AB - Persistent idiopathic facial pain can be extremely difficult and significantly challenging to manage for the patient and the clinician. Pharmacological treatment of these painful conditions is not always successful. It has been suggested that the autonomic reflex plays an important role in the pathophysiology of headaches and facial neuralgia. The key structure in the expression of cranial autonomic symptoms is the sphenopalatine ganglion (SPG), also known as the pterygopalatine ganglion. The role of the SPG in the pathophysiology of headaches and facial pain has become clearer in the past decade. In this case report, we describe a 30 year-old woman with insidious onset of right facial pain. She was suffering from daily pain for more than 9 years prior to her visit at the pain clinic. Her pain was constant with episodic aggravation without a predisposing trigger factor. The patient was evaluated by multiple different specialties and tried multimodal therapy, which included antiepileptic medications, with minimal pain relief. A SPG block using short acting local anesthetic provided significant temporary pain relief. The second and third attempt of SPG block using different local anesthetic medications demonstrated the same responses. After a thorough psychological assessment and ruling out the presence of a correctable cause for the pain, we decided to proceed with SPG electrical neuromodulation. The patient reported significant pain relief during the electrical nerve stimulation trial. The patient underwent a permanent implant of the neurostimulation electrode in the SPG region. The patient was successfully taken off opioid medication and her pain was dramatically responsive during a 6 month follow-up visit. In this article we describe the SPG nerve stimulation and the technical aspect of pterygopalatine fossa electrode placement. The pterygoplatine fossa is an easily accessible location. This case report will be encouraging for physicians treating intractable facial pain by demonstrating a novel therapeutic option. This report shows a minimally invasive approach to the SPG. PMID- 26000688 TI - Ultrasound-Guided Pulsed Radiofrequency Application via the Pterygopalatine Fossa: A Practical Approach to Treat Refractory Trigeminal Neuralgia. AB - Although pharmacological therapy is the primary treatment modality for trigeminal neuralgia associated pain, ineffective analgesia and dose limiting side effects often prompt patients to seek alternative pharmacological solutions such as interventional nerve blockade. Blockade of the Gasserian ganglion or its branches is an effective analgesic procedure for trigeminal neuralgia, traditionally performed using fluoroscopy or CT imaging. Ultrasonography allows point of care and real time visualization of needle placement within the surrounding anatomical structures. The use of ultrasonography with pulsed radiofrequency therapy for trigeminal neuralgia has not been reported. Our case is a 66-year-old male suffering from trigeminal neuralgia for 4 years that was refractory to pharmacologic therapy. Neurological examination was normal with no sensory deficit. Imaging showed no vascular compression or mass involving the trigeminal nerve. A diagnostic ultrasound-guided trigeminal nerve block via the pterygopalatine fossa with 4 mL of bupivacaine 0.25% and 4 mg dexamethasone provided immediate pain relief (100%) with sustained analgesia >50% at 2 weeks. Pain relief was not sustained at one month, with return to pretreatment symptoms. A series of injections were performed with similar intermittent analgesic effectiveness. The decision was made that the patient was a suitable candidate for pulsed radiofrequency application in the pterygopalatine fossa. We successfully used an alternative approach through the pterygopalatine fossa to treat trigeminal neuralgia using ultrasound guidance in an office setting. Our case demonstrates the utility of ultrasound-guidance pulsed radiofrequency treatment in the pterygopalatine fossa as a potential alternative to other percutaneous techniques for patients with medical refractory trigeminal neuralgia. PMID- 26000689 TI - The Successful Treatment of Opioid Withdrawal-Induced Refractory Muscle Spasms with 5-HTP in a Patient Intolerant to Clonidine. AB - Instituting drug holidays for chronic opioid using patients is becoming commonplace for pain practitioners initiating procedures such as intrathecal pump or spinal cord stimulator trials. As such, pain practitioners need to be adept in their management of acute opioid withdrawal. Successfully weaning an opioid dependent patient off of chronic opioids requires a thorough knowledge of the available adjuvants to assist in this process. However, that selection can become exhausted by adjuvant side effects or by ineffective attenuation of opioid withdrawal symptoms. In that case, novel drugs, or novel application of currently available medications must be sought after to assist in the drug holiday. We present a case in which refractory muscle spasms secondary to opioid withdrawal were successfully treated with an over-the-counter supplement that is not typically used for the attenuation of opioid withdrawal symptoms. In a patient intolerant to the side effects of clonidine, we were able to successfully wean chronic opiates by treating refractory muscle spasms with the serotonin precursor, 5-hydroxytryptophan (5-HTP). We hypothesize that our success with this medication gives further credence to the role of serotonin in opioid withdrawal somatic symptomatology, and supports the need for future research to clarify the role of serotonin precursors or serotonin modulating drugs as potential alternatives in those unable to follow standard treatment protocols. PMID- 26000690 TI - Serratus anterior plane block: a new analgesic technique for post-thoracotomy pain. AB - Pain following thoracotomy is of moderate to severe nature. Management of thoracotomy pain is a challenging task. Post thoracotomy pain has acute effects in the post operative period by affecting respiratory mechanics, which increases the morbidity. Poorly controlled thoracotomy pain in the acute phase may also lead to the development of a chronic pain syndrome. A young male patient underwent esophagectomy and esophago-gastric anastomosis for corrosive stricture of the esophagus. Epidural analgesia is standard of care for patients undergoing thoracotomy. Due to hypotension and fluid losses following surgery, he was maintained on intravenous sedato-analgesia during postoperative mechanical ventilation. The thoracic epidural catheter which was placed pre-operatively, had developed blockage during the hospital stay. However, during weaning from ventilation and sedation, he indicated severe pain in the thoracotomy incision. The pain was severe enough to impair tidal breathing. We wanted to evaluate the efficacy of the serratus anterior plane block in the management of thoracotomy pain. The usefulness of this block has been discussed in the management of pain of rib fractures and breast surgeries. Despite the hypothesis of its usefulness in causing anaesthesia of the hemithorax, there are no available reports of clinical use for pain relief following thoracotomy. We performed the serratus anterior place block under ultrasound guidance and placed a catheter for continuous infusion of local anaesthetic and opioid. The patient had significant pain relief following a single bolus of the drug. The infusion was started thereafter, which provided excellent analgesia and facilitated an uneventful recovery. Here, we describe the successful management of thoracotomy pain using the serratus anterior plane block. PMID- 26000691 TI - Initial Experience with IV Ketamine Infusion for Treatment of Post Sternotomy Pain in a Patient with a Total Artificial Heart. AB - The implantation of total artificial hearts (TAH) via midline sternotomy for the treatment of severe biventricular cardiac dysfunction is associated with complex postoperative pain management. Ketamaine increases blood pressure by raising sympathetic outflow and cardiac output; however, ketamine is a direct vasodilator on isolated arterial tissues. In the setting of a TAH with a mechanically fixed cardiac output, a ketamine infusion for postoperative pain control has the potential to decrease blood pressure due to direct arterial vasodilation. We present the initial experience with a ketamine infusion in a patient with a TAH with minimal observed decreases in blood pressure and significantly improved postoperative pain. PMID- 26000692 TI - A Costly Lesson: Fatal Respiratory Depression Induced by Clindamycin during Postoperative Patient Controlled Analgesia. AB - Many drugs can cause neuromuscular blockade. Clindamycin-related neuromuscular blockade is commonly reported, but fatal clindamycin-induced neuromuscular blockade is rarely reported. We describe a 47-year-old woman who initially presented with endometrial carcinoma. She underwent a laparoscopic-assisted vaginal hysterectomy (LAVH) and bilateral adnexectomy under general anesthesia, secondary to antibiotic treatment with clindamycin 1.2g in 250 mL for about 30 minutes through the peripheral intravenous route during postoperative patient controlled analgesia (PCA). She became unconscious near the end of the infusion, then, despite resuscitation attempts, she died. Clindamycin appeared to have triggered delayed respiratory depression during PCA. A combination of clindamycin and fentanyl led to her respiratory depression in the fatal case. PMID- 26000693 TI - Management of refractory trigeminal neuralgia using extended duration pulsed radiofrequency application. AB - Trigeminal neuralgia (TN) produces incapacitating facial pain that reduces quality of life in patients. Thermal radiofrequency (RF) ablation of gasserian ganglion (GG) is associated with masseter weakness and unpleasant sensations along the distribution of the ablated nerve. Pulsed radiofrequency (PRF) of GG has minimal side effects but literature is inconclusive regarding its benefit in refractory TN. Increasing the duration of PRF application to 6 minutes in TN produced encouraging results. PRF application to the saphenous nerve for 8 minutes reported improved pain relief and patient satisfaction. We report successful management of two patients of classic TN, which were refractory to medical management and interventional nerve blocks. The lesion site were confirmed with motor and sensory stimulation through a 22 G, 10 cm RF needle with 5 mm active tip. Both the patients received four cycles of PRF at 42 degrees C with each cycle of 120 seconds (8 minutes). The visual analogue scale (VAS) in case 1 reduced from pre-block score of 80 to score 10 post-block, while in case 2 the VAS reduced from pre-block score of 85 to score 15 post-block. During follow up both the patients are now pain free with minimal dose of carbamazepine at 12 and 6 months respectively. We used PRF for longer duration (8 minutes) in these patients, which resulted in improved VAS and WHOQOL-BREF score in these patients. PRF of mandibular division of GG for extended duration provided long-term effective pain relief and quality of life in patients of refractory classic TN. PMID- 26000694 TI - Ulnar tunnel syndrome with ultrasonographic nerve imaging. AB - A 32-year-old man presented to our clinic complaining of numbness of the little finger and the ulnar aspect of the ring finger of his right hand. He complained about the weakness of grip strength and ulnar-sided pain. At the first glance, wasting of the first interossei muscle could be recognized. In his detailed examination, the medial half of the palmar aspect of the hand, including the hypothenar eminence, along with the palmar side of the fourth and fifth digits showed decreased sensation to light touch. Severe weakness of the abductor digiti minimi (ADM) was noted. No sensory loss was found in the dorsum of the hand, excluding the diagnosis of ulnar neuropathy at the elbow. PMID- 26000695 TI - Integrating Clinical Pharmacokinetics, Pharmacogenetics, and Quantitative Cytochrome P450 Polymorphic Gene Drug-Drug Interactions (DDIs). PMID- 26000696 TI - In response. PMID- 26000697 TI - Perioperative use of systemic lidocaine. PMID- 26000698 TI - In response to perioperative use of systemic lidocaine. PMID- 26000699 TI - The effect of abuse-deterrent extended-release oxycodone leads to inappropriate conclusions with over estimation of safety of abuse-deterrent formulations. PMID- 26000701 TI - Effect of clear aligner therapy on the buccolingual inclination of mandibular canines and the intercanine distance. AB - OBJECTIVE: To compare the changes in buccolinugal inclination of mandibular canines and intercanine distance in patients treated with clear aligners to those treated with preadjusted edgewise appliances. MATERIALS AND METHODS: The buccolingual inclination of mandibular canines and the intercanine distance were measured on pre- and posttreatment cone-beam computed tomograms of 30 patients who had been treated with clear aligners and 30 patients who had been treated with fixed preadjusted edgewise appliances. Differences between the aligner and fixed appliance groups and between pre- and posttreatment measurements were tested for statistical significance. RESULTS: In both groups, most of the mandibular canines had positive buccolingual inclinations (ie, their crowns were positioned lateral to their roots) both before and after treatment. While there was no difference between the groups pretreatment, the posttreatment buccolingual inclination was significantly greater in the aligner group. In the fixed appliance group, the canines became more upright with treatment, while the buccolingual inclination did not change significantly in the clear aligner group. The intercanine distance did not differ between the groups either before or after treatment. However, it increased significantly over the course of treatment in the aligner group, whereas it did not change significantly in the fixed appliance group. CONCLUSIONS: Orthodontic treatment with clear aligners tends to increase the mandibular intercanine distance with little change in inclination in contrast to treatment with fixed appliances, which leaves the intercanine distance unchanged but leads to more upright mandibular canines. PMID- 26000702 TI - The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma. AB - BACKGROUND: c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance. METHODS: We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses. RESULTS: We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF alpha as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone. CONCLUSION: c-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC. PMID- 26000703 TI - Partitioning behavior of heavy metals and persistent organic pollutants among feto-maternal bloods and tissues. AB - Heavy metals and persistent organic pollutants (POPs), including Pb, Cd, T-Hg, MeHg, PCDD/Fs, PCBs, PBDEs, PCNs, and PBDD/Fs, were analyzed in 20 paired samples of cord blood, maternal blood, maternal urine, and placenta. The samples were collected from pregnant mothers and neonates from South Korea in 2010. The distribution of heavy metals among the samples varied with their physicochemical characteristics. The concentrations of Pb and Hg in the maternal and the cord blood samples were significantly correlated each other, implying efficient transplacental transport (TPT). Cd and Hg were accumulated in the placenta, forming protein conjugates, and T-Hg was higher in the cord blood samples than the maternal blood samples due to the binding affinity of Hg with fetal proteins. POPs generally showed the highest concentrations in the maternal serum samples, and the POPs levels in the cord serum and the placenta samples were dependent on the degree of halogenation. The TPT of POPs was seemingly related to lipoprotein transportation. Some PBDE congeners, however, showed their highest concentrations in the cord serum samples, suggesting an additional TPT mechanism. This is the first study to detect PCNs and PBDD/Fs in the cord serum samples, showing that the PCN levels were comparable to other POPs. According to the principal component analysis (PCA) results of the contaminant levels, POPs and heavy metals showed significantly different characteristics, whereas PBDEs had an intermediate attribute. Despite the limited number of participants, the comprehensive analysis of trace contaminants in the paired sample sets enabled us to infer the distribution and TPT mechanism of various contaminants. PMID- 26000704 TI - Three Homology Models of PAR2 Derived from Different Templates: Application to Antagonist Discovery. AB - Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The only compounds reported to date to inhibit PAR2 activation are of moderate potency. Three structural models for PAR2 have been constructed based on sequence homology with known crystal structures for bovine rhodopsin, human ORL-1 (also called nociceptin/orphanin FQ receptor), and human PAR1. The three PAR2 model structures were compared and used to predict potential interactions with ligands. Virtual screening for ligands using the Chembridge database, and either ORL-1 or PAR1 derived PAR2 models led to identification of eight new small molecule PAR2 antagonists (IC50 10-100 MUM). Notably, the most potent compound 1 (IC50 11 MUM) was derived from the less homologous template protein, human ORL-1. The results suggest that virtual screening against multiple homology models of the same GPCR can produce structurally diverse antagonists and that this may be desirable even when some models have less sequence homology with the target protein. PMID- 26000706 TI - Increased pulse wave velocity in pulmonary sarcoidosis: a preliminary study. PMID- 26000705 TI - Meaning-Centered Psychotherapy for Cancer Caregivers (MCP-C): Rationale and Overview. AB - OBJECTIVE: The multidimensional burden that results from providing care to a patient with cancer is well documented and a growing number of psychosocial interventions have been developed to address this burden. None, however, target existential distress, a critical, common element - and potentially driving mechanism - of caregiver burden. Meaning-Centered Psychotherapy (MCP) is a structured psychotherapeutic intervention originally developed by our group to target existential distress and spiritual well-being among patients with advanced cancer. We are currently developing Meaning-Centered Psychotherapy for Cancer Caregivers (MCP-C). The objective of this qualitative study is to describe the application of MCP to the unique experience of caregivers of patients with advanced cancer. METHODS: A case study of a participant from an initial MCP-C group is presented, with a focus on the application of sources of meaning to the cancer caregiving experience. RESULTS: The exploration of critical sources of meaning in the participant's life generally, and related to caregiving specifically, highlighted significant areas of growth, including an increased understanding of the historical context shaping her experience of providing care, the recognition of the need for improved self-care and reconnecting with meaningful activities, and the possibility for continued connectedness to others and the world, despite the limitations resulting from her husband's terminal illness. SIGNIFICANCE OF RESULTS: Existential distress is a critical and often overlooked element of burden among cancer caregivers. MCP-C is intended to target this component of burden and address this critical gap in the palliative care literature. Clinical trials are underway to evaluate the efficacy of MCP-C delivered over the Internet. Future studies are needed to evaluate the benefits of MCP-C for particularly burdened groups of caregivers, such as caregivers of patients with brain tumors and those undergoing hematopoietic stem cell transplantations, and to identify target points of delivery that will optimize the intervention's benefits. PMID- 26000707 TI - Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa. AB - Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa. The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8alpha-hydroxy-Delta(9) tetrahydrocannabinol (1), 8beta-hydroxy-Delta(9)-tetrahydrocannabinol (2), 10alpha-hydroxy-Delta(8)-tetrahydrocannabinol (3), 10beta-hydroxy-Delta(8) tetrahydrocannabinol (4), 10alpha-hydroxy-Delta(9,11)-hexahydrocannabinol (5), 9beta,10beta-epoxyhexahydrocannabinol (6), and 11-acetoxy-Delta(9) tetrahydrocannabinolic acid A (7). The binding affinity of isolated compounds 1 8, Delta(9)-tetrahydrocannabinol, and Delta(8)-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied. The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only. PMID- 26000708 TI - Validity and reliability of the Chinese version of the care transition measure. AB - BACKGROUND: The 15-item care transition measure (CTM-15) is a reliable and valid instrument assessing the quality of care transition from patients' perspectives. The aim of this study was to evaluate the psychometric properties of the CTM-15 and the CTM-3 (a 3-item short version of the CTM-15) in Mainland China. METHODOLOGY/FINDINGS: This was a cross-sectional study with a convenience sample of 646 patients in a general tertiary-level hospital in Chengdu, China. The results indicated that the Cronbach's alpha values of the Chinese version of the two measures were 0.90 and 0.56, and the test-retest reliability values were 0.91 and 0.87, respectively. Three factors were extracted for the CTM-15 in Chinese populations. The CTM-15 and the CTM-3 scores discriminated well between patients with and without re-hospitalization for their index condition. The CTM-15 and the CTM-3 had significant positive relationships with self-rated health status. The CTM-3 score was significantly related to the CTM-15 score, and the CTM-3 score accounted for 64.23% of the variance of the CTM-15 score. CONCLUSIONS/SIGNIFICANCE: This study has demonstrated the psychometric properties of the CTM-15 and the CTM-3 in Mainland China. Although the Cronbach's alpha value of the CTM-3 is suboptimal, it has exhibited high test-retest reliability, convergent validity and criterion validity. Therefore, the CTM-3 can substitute the CTM-15 as a performance measurement tool when the sample size is large enough to compensate its suboptimal reliability or the reduced response burden is a concern. PMID- 26000709 TI - Magnetic Droplet Microfluidics as a Platform for the Concentration of [18F]Fluoride and Radiosynthesis of Sulfonyl [18F]Fluoride. AB - The radioisotope 18F is often considered the best choice for positron emission tomography (PET) owing to its desirable chemical and radiochemical properties. However, nucleophilic 18F-fluorination of large, water-soluble biomolecules, based on C-F bond formation, has traditionally been difficult. Thus, several aqueous fluorination approaches that offer significant versatility in radiopharmaceutical synthesis with sensitive targeting vectors have been developed. Furthermore, because 18F decays rapidly, production of these 18F labeled compounds requires an automated process to reduce production time, reduce radiation exposure, and minimize losses due to the transfer of reagents during tracer synthesis. Herein, we report the use of magnetic droplet microfluidics (MDM) as a means to concentrate [18F]fluoride from the cyclotron target solution, followed by the synthesis of an 18F-labeled compound on a microfluidic platform. Using this method, we have demonstrated 18F preconcentration in a small-volume droplet through the use of anion exchanging magnetic particles. By using MDM, the preconcentration step took approximately 5 min, and the [18F]fluoride solution was preconcentrated by 15-fold. After the preconcentration step, an 18F-labeling reaction was performed on the MDM platform using the S-F bond formation in aqueous conditions to produce an arylsulfonyl [18F]fluoride compound which can be used as a prosthetic group to label PET targeting ligands. The high radiochemical purity of 95+/-1% was comparable to the 96% previously reported using a conventional method. In addition, when MDM was used, the total synthesis time was improved to 15 min with lower reagent volumes (50-60 MUL) used. PMID- 26000710 TI - Direct Observation of Xe and Kr Adsorption in a Xe-Selective Microporous Metal Organic Framework. AB - The cryogenic separation of noble gases is energy-intensive and expensive, especially when low concentrations are involved. Metal-organic frameworks (MOFs) containing polarizing groups within their pore spaces are predicted to be efficient Xe/Kr solid-state adsorbents, but no experimental insights into the nature of the Xe-network interaction are available to date. Here we report a new microporous MOF (designated SBMOF-2) that is selective toward Xe over Kr under ambient conditions, with a Xe/Kr selectivity of about 10 and a Xe capacity of 27.07 wt % at 298 K. Single-crystal diffraction results show that the Xe selectivity may be attributed to the specific geometry of the pores, forming cages built with phenyl rings and enriched with polar -OH groups, both of which serve as strong adsorption sites for polarizable Xe gas. The Xe/Kr separation in SBMOF-2 was investigated with experimental and computational breakthrough methods. These experiments showed that Kr broke through the column first, followed by Xe, which confirmed that SBMOF-2 has a real practical potential for separating Xe from Kr. Calculations showed that the capacity and adsorption selectivity of SBMOF-2 are comparable to those of the best-performing unmodified MOFs such as NiMOF-74 or Co formate. PMID- 26000711 TI - Magnetic field driven interminiband charge transfer in InGaAs/InP superlattices. AB - The characteristic energies, occupancies and polarizations of the minibands formed by the Gamma-Gamma and Gamma-Xz interlayer electon tunnelings in the InGaAs/InP superlattices are studied in the regime of the integer quantum Hall effect by polarization resolved photoluminescence. Accordingly, the magnetic field induced shrinkage of the interminiband gap, predicted by the theory, and as a consequence, the redistribution of charge over the superlattice minibands and the depolarization of the quantum Hall electron states are observed at odd filling factors. The response of the electrons residing in the InGaAs/InP superlattice minibands to the magnetic field is found very similar to the corresponding response of the electrons confined in the symmetric and anti symmetric two-dimensional minibands of GaAs/AlGaAs double quantum wells. The presented results are evidence of the formation of the correlated states in multi component electron systems formed in semiconductor multiple layers at odd filling factors. PMID- 26000712 TI - The impact of attention on judgments of frequency and duration. AB - Previous studies that examined human judgments of frequency and duration found an asymmetrical relationship: While frequency judgments were quite accurate and independent of stimulus duration, duration judgments were highly dependent upon stimulus frequency. A potential explanation for these findings is that the asymmetry is moderated by the amount of attention directed to the stimuli. In the current experiment, participants' attention was manipulated in two ways: (a) intrinsically, by varying the type and arousal potential of the stimuli (names, low-arousal and high-arousal pictures), and (b) extrinsically, by varying the physical effort participants expended during the stimulus presentation (by lifting a dumbbell vs. relaxing the arm). Participants processed stimuli with varying presentation frequencies and durations and were subsequently asked to estimate the frequency and duration of each stimulus. Sensitivity to duration increased for pictures in general, especially when processed under physical effort. A large effect of stimulus frequency on duration judgments was obtained for all experimental conditions, but a similar large effect of presentation duration on frequency judgments emerged only in the conditions that could be expected to draw high amounts of attention to the stimuli: when pictures were judged under high physical effort. Almost no difference in the mutual impact of frequency and duration was obtained for low-arousal or high-arousal pictures. The mechanisms underlying the simultaneous processing of frequency and duration are discussed with respect to existing models derived from animal research. Options for the extension of such models to human processing of frequency and duration are suggested. PMID- 26000713 TI - Are gender differences in upper-body power generated by elite cross-country skiers augmented by increasing the intensity of exercise? AB - In the current study, we evaluated the impact of exercise intensity on gender differences in upper-body poling among cross-country skiers, as well as the associated differences in aerobic capacity, maximal strength, body composition, technique and extent of training. Eight male and eight female elite skiers, gender-matched for level of performance by FIS points, carried out a 4-min submaximal, and a 3-min and 30-sec maximal all-out test of isolated upper-body double poling on a Concept2 ski ergometer. Maximal upper-body power and strength (1RM) were determined with a pull-down exercise. In addition, body composition was assessed with a DXA scan and training during the previous six months quantified from diaries. Relative to the corresponding female values (defined as 100%), the power output produced by the men was 88%, 95% and 108% higher during the submaximal, 3-min and 30-sec tests, respectively, and peak power in the pull down strength exercise was 118% higher (all P<0.001). During the ergometer tests the work performed per cycle by the men was 97%, 102% and 91% greater, respectively, and the men elevated their cycle rate to a greater extent at higher intensities (both P<0.01). Furthermore, men had a 61% higher VO2peak, 58% higher 1RM, relatively larger upper-body mass (61% vs 56%) and reported considerably more upper-body strength and endurance training (all P<0.05). In conclusion, gender differences in upper-body power among cross-country skiers augmented as the intensity of exercise increased. The gender differences observed here are greater than those reported previously for both lower- and whole-body sports and coincided with greater peak aerobic capacity and maximal upper-body strength, relatively more muscle mass in the upper-body, and more extensive training of upper-body strength and endurance among the male skiers. PMID- 26000714 TI - Repeated nipple fluid aspiration: compliance and feasibility results from a prospective multicenter study. AB - BACKGROUND: Despite intensive surveillance, a high rate of interval malignancies is still seen in women at increased breast cancer risk. Therefore, novel screening modalities aiming at early detection remain needed. The intraductal approach offers the possibility to directly sample fluid containing cells, DNA and proteins from the mammary ductal system where, in the majority of cases, breast cancer originates. Fluid from the breast can non-invasively be obtained by oxytocin-assisted vacuum aspiration, called nipple fluid aspiration (NFA). The goal of this feasibility study was to evaluate the potential of repeated NFA, which is a critical and essential step to evaluate its possible value as a breast cancer screening method. METHODS: In this multicenter, prospective study, we annually collected nipple fluid for up to 5 consecutive years from women at increased breast cancer risk, and performed a questionnaire-based survey regarding discomfort of the aspiration. Endpoints of the current interim analyses were the feasibility and results of 994 NFA procedures in 451 women with total follow-up of 560 person years of observation. RESULTS: In this large group of women at increased risk of breast cancer, repetitive NFA appeared to be feasible and safe. In 66.4% of aspirated breasts, nipple fluid was successfully obtained. Independent predictive factors for successful NFA were premenopausal status, spontaneous nipple discharge, smaller breast size, bilateral oophorectomy and previous use of hormone replacement therapy or anti-hormonal treatment. The procedure was well tolerated with low discomfort. Drop-out rate was 20%, which was mainly due to repeated unsuccessful aspiration attempts. Only 1.6% of women prematurely declined further participation because of side effects. CONCLUSIONS: Repeated NFA in women at increased breast cancer risk is feasible and safe. Therefore, NFA is a promising method to non-invasively obtain a valuable source of potential breast cancer specific biomarkers. PMID- 26000715 TI - Noninvasive analysis of thin turbid layers using microscale spatially offset Raman spectroscopy. AB - Here, we demonstrate, for the first time, the extension of applicability of recently developed microscale spatially offset Raman spectroscopy (SORS), micro SORS, from the area of cultural heritage to a wider range of analytical problems involving thin, tens of micrometers thick diffusely scattering turbid layers. The method can be applied in situations where a high turbidity of layers prevents the deployment of conventional confocal Raman microscopy with its depth resolving capability. The method was applied successfully to detect noninvasively the presence of thin, highly turbid layers within polymers, wheat seeds, and paper. An invasive, cross sectional analysis confirmed the micro-SORS findings. Micro SORS represents a new Raman imaging modality expanding the portfolio of noninvasive, chemically specific analytical tools. PMID- 26000716 TI - Maternal plasma and amniotic fluid sphingolipids profiling in fetal Down syndrome. AB - INTRODUCTION: Sphingolipids can be potentially involved in the formation of the central and peripheral nervous systems, which are particularly connected with the pathogenesis of Down syndrome. The aim of the study was to determine the concentration of selected sphingolipids in the plasma and amniotic fluid of pregnant patients with fetal Down syndrome. MATERIAL AND METHODS: Out of 190 amniocentesis we had 10 patients with confirmed Down syndrome. For the purpose of our control we chose 14 women without confirmed chromosomal aberration. To assess the concentration of 11 sphingolipids in the blood plasma and amniotic fluid we used an ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC/MS/MS). RESULTS: We showed a significant increase in the concentration of 2 ceramides, C22-Cer and C24:1-Cer, in the plasma of women with fetal Down syndrome. Furthermore we showed a decrease in the concentration of 7 ceramides--C16-Cer, C18-Cer, C18:1-Cer, C20-Cer, C22-Cer, C24:1-Cer, and C24-Cer--in the amniotic fluid of women with fetal Down syndrome. We created ROC curves for all significant sphingolipids in maternal plasma, which set the threshold values and allowed for predicting the likelihood of Down syndrome in the fetus with specific sensitivity and specificity. We demonstrated a significantly higher risk of Down syndrome when the plasma concentration of C22 Cer > 12.66 ng/100 ul (sens. 0.9, sp. 0.79, P value = 0.0007) and C24:1-Cer > 33,19 ng/100 ul (sens. 0.6, sp. 0.86, P value = 0.0194). CONCLUSION: On the basis of our findings, it seems that the sphingolipids may play a role in the pathogenesis of Down syndrome. Defining their potential as biochemical markers of Down syndrome requires further investigation on a larger group of patients. PMID- 26000718 TI - Tuning Morphologies of Langmuir Polymer Films Through Controlled Relaxations of Non-Equilibrium States. AB - Langmuir polymers films (LPFs) frequently form nonequilibrium states which are manifested in a decay of the surface pressure with time when the system is allowed to relax. Monitoring and manipulating the temporal evolution of these relaxations experimentally helps to shed light on the associated molecular reorganization processes. We present a systematic study based on different compression protocols and show how these reorganization processes impact the morphology of LPFs of poly(gamma-benzyl-L-glutamate)(PBLG), visualized by means of atomic force microscopy. Upon continuous compression, a fibrillar morphology was formed with a surface decorated by squeezed-out islands. By contrast, stepwise compression promoted the formation of a fibrillar network with a bimodal distribution of fibril diameters, caused by merging of fibrils. Finally, isobaric compression induced in-plane compaction of the monolayer. We correlate these morphological observations with the kinetics of the corresponding relaxations, described best by a sum of two exponential functions with different time scales representing two molecular processes. We discuss the observed kinetics and the resulting morphologies in the context of nucleation and growth, characteristic for first-order phase transitions. Our results demonstrate that the preparation conditions of LPFs have tremendous impact on ordering of the molecules and hence various macroscopic properties of such films. PMID- 26000717 TI - Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age associated mitochondrial respiration defects. AB - Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. We carried out reprogramming of human fibroblast lines derived from elderly subjects by generating their induced pluripotent stem cells (iPSCs), and examined another possibility, namely that these aging phenotypes are controlled not by mutations but by epigenetic regulation. Here, we show that reprogramming of elderly fibroblasts restores age associated mitochondrial respiration defects, indicating that these aging phenotypes are reversible and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either the nuclear or the mitochondrial genome. Microarray screening revealed that epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in glycine production in mitochondria, is partly responsible for these aging phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented the expression of these aging phenotypes. PMID- 26000719 TI - Requirement of ATR for maintenance of intestinal stem cells in aging Drosophila. AB - The stem cell genomic stability forms the basis for robust tissue homeostasis, particularly in high-turnover tissues. For the genomic stability, DNA damage response (DDR) is essential. This study was focused on the role of two major DDR related factors, ataxia telangiectasia-mutated (ATM) and ATM- and RAD3-related (ATR) kinases, in the maintenance of intestinal stem cells (ISCs) in the adultDrosophila midgut. We explored the role of ATM and ATR, utilizing immunostaining with an anti-pS/TQ antibody as an indicator of ATM/ATR activation, gamma-irradiation as a DNA damage inducer, and the UAS/GAL4 system for cell type specific knockdown of ATM, ATR, or both during adulthood. The results showed that the pS/TQ signals got stronger with age and after oxidative stress. The pS/TQ signals were found to be more dependent on ATR rather than on ATM in ISCs/enteroblasts (EBs). Furthermore, an ISC/EB-specific knockdown of ATR, ATM, or both decreased the number of ISCs and oxidative stress-induced ISC proliferation. The phenotypic changes that were caused by the ATR knockdown were more pronounced than those caused by the ATM knockdown; however, our data indicate that ATR and ATM are both needed for ISC maintenance and proliferation; ATR seems to play a bigger role than does ATM. PMID- 26000720 TI - Tailoring Nanoscale Friction in MX2 Transition Metal Dichalcogenides. AB - Lattice dynamics of MX2 transition metal dichalcogenides (M = Mo, W; X = S, Se, Te) have been studied with density functional theory techniques to control the macroscopic tribological behavior. Long-range van der Waals forces have been modeled with Grimme correction to capture the interlayer interactions. A new lattice dynamic metric, named cophonicity, is proposed and used in combination with electronic and geometric descriptors to relate the stability of the lattice distortions with the electro-structural features of the system. The cophonicity analysis shows that the distortion modes relevant to the microscopic friction can be controlled by tuning the relative M/X atomic contributions to the phonon density of states. Guidelines on how to engineer macroscopic friction at nanoscale are formulated, and finally applied to design a new Ti-doped MoS2 phase with enhanced tribologic properties. PMID- 26000721 TI - Malaria medicines: a glass half full? AB - Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compound or product profiles, to assess progress and gaps, and to recommend priorities. PMID- 26000722 TI - Regulatory watch: Why do oncology drugs fail to gain US regulatory approval? PMID- 26000724 TI - Panning for gold: sourcing pharmaceutical innovation. PMID- 26000723 TI - Prospects for the development of epigenetic drugs for CNS conditions. AB - Advances in our understanding of the epigenetic mechanisms that control gene expression in the central nervous system (CNS) and their role in neuropsychiatric disorders are paving the way for a potential new therapeutic approach that is focused on reversing the epigenetic underpinnings of neuropsychiatric conditions. In this article, the complexity of epigenetic processes and the current level of proof for their involvement in CNS disorders are discussed. The preclinical evidence for efficacy of pharmacological approaches that target epigenetics in the CNS and the particular challenges of this approach are also examined. Finally, strategies to address these challenges through the development of improved evidence-based epigenetic therapeutics and through combining pharmacological and behavioural approaches are presented. PMID- 26000726 TI - Drug development for airway diseases: looking forward. AB - Advancing drug development for airway diseases beyond the established mechanisms and symptomatic therapies requires redefining the classifications of airway diseases, considering systemic manifestations, developing new tools and encouraging collaborations. PMID- 26000725 TI - Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. AB - Scientific insights into the human immune system have recently led to unprecedented breakthroughs in immunotherapy. In the twenty-first century, drugs and cell-based therapies developed to bolster humoral and T cell immunity represent an established and growing component of cancer therapeutics. Although natural killer (NK) cells have long been known to have advantages over T cells in terms of their capacity to induce antigen-independent host immune responses against malignancies, their therapeutic potential in the clinic has been largely unexplored. A growing number of scientific discoveries into pathways that both activate and suppress NK cell function, as well as methods to sensitize tumours to NK cell cytotoxicity, have led to the development of numerous pharmacological and genetic methods to enhance NK cell antitumour immunity. These findings, as well as advances in our ability to expand NK cells ex vivo and manipulate their capacity to home to the tumour, have now provided investigators with a variety of new methods and strategies to harness the full potential of NK cell-based cancer immunotherapy in the clinic. PMID- 26000727 TI - Temporal pattern of Toll-like receptor 9 upregulation in neurons and glial cells following cerebral ischemia reperfusion in mice. AB - PURPOSE: The family of Toll-like receptors (TLRs) has recently been reported to play a role in ischemic injury, but the time course and cell types of the post stroke TLR9 upregulation remain unclear. In this study, we investigated the dynamic changes of TLR9 expression and the expression of TLR9 in neurons and glial cells after cerebral ischemia reperfusion in mice. METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for 90 min in male C57BL/6 mice. The TLR9 expression levels in the tissue surrounding the infarct were detected by Western Blot at 6 h, 3 d, 7 d, 14 d, 21 d, and 28 d after reperfusion. The expression of TLR9 in neurons and glial cells was observed by immunofluorescence staining. RESULTS: The expression of TLR9 protein first increased and then decreased, with the peak observed at 14 d-21 d. Only small punctate intracellular TLR9 was occasionally observed in the neurons at each time point, and the TLR9-positive rate showed no difference at different time points. By contrast, the activated microglia gathered at the margin of the infarct, and the intracellular TLR9 changed from scattered small punctate to coarse and lumpy. The TLR9-positive rate of microglia was first increased and then decreased with time, with the peak observed at 3 d. No positive TLR9 staining was found in the astrocytes and oligodendrocytes. CONCLUSIONS: TLR9 expression showed dynamic changes for a long period of time and microglias were the main brain cells to express TLR9 after cerebral ischemia and reperfusion. PMID- 26000729 TI - Chaos-chaos transition of left hemisphere EEGs during standard tasks of Waterloo Stanford Group Scale of hypnotic susceptibility. AB - A recent study, recurrence quantification analysis of EEG signals during standard tasks of Waterloo-Stanford Group Scale of hypnotic susceptibility investigated recurrence quantifiers (RQs) of hypnotic electroencephalograph (EEG) signals recorded after hypnotic induction while subjects were doing standard tasks of Waterloo-Stanford Group Scale (WSGS) of hypnotic susceptibility to distinguish subjects of different hypnotizability levels. Following the same analysis, the current study determines the capability of different RQs to distinguish subjects of low, medium and high hypnotizability level and studies the influence of hypnotizability level on underlying dynamic of tasks. Besides, EEG channels were sorted according to the number of their RQs, which differed significantly among subjects of different hypnotizability levels. Another valuable result was determination of major brain regions in observing significant differences in various task types (ideomotors, hallucination, challenge and memory). PMID- 26000730 TI - Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: The patient perspective. AB - A series of clinical practice guidelines were recently developed by the Canadian Association of Gastroenterology (CAG) to provide clinicians with recommendations for the medical management of nonhospitalized ulcerative colitis (UC) patients. These guidelines were developed, reviewed and agreed on by expert clinicians and methodologists. Following the finalization of the guidelines, a group of patients with UC as well as several inflammatory bowel disease clinicians, were brought together for a half-day workshop to provide feedback from the patient perspective. At the workshop, the guideline development process was described and the guidelines were reviewed to ensure comprehension. Patients then had the opportunity to provide their insight to the relevance of the guideline development process and the content of the guidelines as it related to their personal experiences with UC. The patient group believed that, although the new guidelines will be a tremendous resource for the health care provider community, a more 'lay-friendly' version would better facilitate dialogue between patients and their health care practitioners. The importance of the patient/physician relationship is paramount when making decisions regarding treatment plans, in which patient preferences play a key role in determining the most appropriate therapy and dosing regimen, which, in turn, impact the likelihood of adherence to the treatment plan. It was also believed that quality of life issues were not fully addressed in the guidelines. Much could be learned from shared experiences and coping strategies that would empower patients to take charge of their health and become equal partners with their care providers. PMID- 26000728 TI - General hallmarks of microRNAs in brain evolution and development. AB - MicroRNAs (miRNAs) are endogenous, small non-coding RNA molecules that mediate post-transcriptional gene suppression by incomplete matches with their host mRNAs. In the central nervous system, miRNAs that functionally interact with their target genes constitute a flexible, robust and buffered regulatory network, exerting diverse roles in brain evolution and development. However, distinct variation either in hub miRNA expression levels or patterns may initiate and/or progress various adult-onset nerve-related diseases. In this review, we will summarize the current knowledge about the general hallmarks of brain miRNAs that act as vital determinants in increasingly complicated neural activities. We endeavor to provide a constructive insight into the neuroscience research in the quest to comprehend molecular underpinnings of physiological functions and pathological disorders in central nervous system. PMID- 26000731 TI - Growth inhibition of bacterial fish pathogens and quorum-sensing blocking by bacteria recovered from chilean salmonid farms. AB - The main goal of this study was to find bacterial isolates with the ability to inhibit the growth of the fish pathogens Aeromonas hydrophila, Vibrio anguillarum, and Flavobacterium psychrophilum and to inhibit the blockage of the quorum-sensing (QS) system. A total of 80 gram-negative strains isolated from various freshwater Chilean salmonid farms were studied. We determined that 10 strains belonging to the genus Pseudomonas inhibited at least one of the assayed fish pathogens. Of these, nine strains were able to produce siderophores and two strains were able to inhibit the growth of all assayed pathogenic species. When the 80 strains were examined for QS-blocking activity, only the strains Pseudomonas sp. FF16 and Raoultella planticola R5B1 were identified as QS blockers. When the QS-blocker strains were analyzed for their ability to produce homoserine lactone (HSL) molecules, thin-layer chromatography analysis showed that both strains were able to produce C6-HSL- and C8-HSL-type molecules. Strain R5B1 did not show growth inhibition properties, but strain FF16 also led to inhibition of growth in A. hydrophila and F. psychrophilum as well as to siderophore production. Pseudomonas sp. FF16 exhibited potentially useful antagonistic properties and could be a probiotic candidate for the salmon farming industry. PMID- 26000732 TI - Mesoporous Mn- and La-doped cerium oxide/cobalt oxide mixed metal catalysts for methane oxidation. AB - New precious-metal-free mesoporous materials were investigated as catalysts for the complete oxidation of methane to carbon dioxide. Mesoporous cobalt oxide was first synthesized using KIT-6 mesoporous silica as a hard template. After removal of the silica, the cobalt oxide was itself used as a hard template to construct cerium oxide/cobalt oxide composite materials. Furthermore, cerium oxide/cobalt oxide composite materials doped with manganese and lanthanum were also prepared. All of the new composite materials retained the hierarchical long-range order of the original KIT-6 template. Temperature-programmed oxidation measurements showed that these cerium oxide/cobalt oxide and doped cerium oxide/cobalt oxide materials are effective catalysts for the total oxidation of methane, with a light-off temperature (T50%) of ~400 degrees C observed for all of the nanostructured materials. PMID- 26000733 TI - Intergenerational impacts of maternal mortality: Qualitative findings from rural Malawi. AB - BACKGROUND: Maternal mortality, although largely preventable, remains unacceptably high in developing countries such as Malawi and creates a number of intergenerational impacts. Few studies have investigated the far-reaching impacts of maternal death beyond infant survival. This study demonstrates the short- and long-term impacts of maternal death on children, families, and the community in order to raise awareness of the true costs of maternal mortality and poor maternal health care in Neno, a rural and remote district in Malawi. METHODS: Qualitative in-depth interviews were conducted to assess the impact of maternal mortality on child, family, and community well-being. We conducted 20 key informant interviews, 20 stakeholder interviews, and six sex-stratified focus group discussions in the seven health centers that cover the district. Transcripts were translated, coded, and analyzed in NVivo 10. RESULTS: Participants noted a number of far-reaching impacts on orphaned children, their new caretakers, and extended families following a maternal death. Female relatives typically took on caregiving responsibilities for orphaned children, regardless of the accompanying financial hardship and frequent lack of familial or governmental support. Maternal death exacerbated children's vulnerabilities to long-term health and social impacts related to nutrition, education, employment, early partnership, pregnancy, and caretaking. Impacts were particularly salient for female children who were often forced to take on the majority of the household responsibilities. Participants cited a number of barriers to accessing quality child health care or support services, and many were unaware of programming available to assist them in raising orphaned children or how to access these services. CONCLUSIONS: In order to both reduce preventable maternal mortality and diminish the impacts on children, extended families, and communities, our findings highlight the importance of financing and implementing universal access to emergency obstetric and neonatal care, and contraception, as well as social protection programs, including among remote populations. PMID- 26000734 TI - Mapping the space of genomic signatures. AB - We propose a computational method to measure and visualize interrelationships among any number of DNA sequences allowing, for example, the examination of hundreds or thousands of complete mitochondrial genomes. An "image distance" is computed for each pair of graphical representations of DNA sequences, and the distances are visualized as a Molecular Distance Map: Each point on the map represents a DNA sequence, and the spatial proximity between any two points reflects the degree of structural similarity between the corresponding sequences. The graphical representation of DNA sequences utilized, Chaos Game Representation (CGR), is genome- and species-specific and can thus act as a genomic signature. Consequently, Molecular Distance Maps could inform species identification, taxonomic classifications and, to a certain extent, evolutionary history. The image distance employed, Structural Dissimilarity Index (DSSIM), implicitly compares the occurrences of oligomers of length up to k (herein k = 9) in DNA sequences. We computed DSSIM distances for more than 5 million pairs of complete mitochondrial genomes, and used Multi-Dimensional Scaling (MDS) to obtain Molecular Distance Maps that visually display the sequence relatedness in various subsets, at different taxonomic levels. This general-purpose method does not require DNA sequence alignment and can thus be used to compare similar or vastly different DNA sequences, genomic or computer-generated, of the same or different lengths. We illustrate potential uses of this approach by applying it to several taxonomic subsets: phylum Vertebrata, (super)kingdom Protista, classes Amphibia Insecta-Mammalia, class Amphibia, and order Primates. This analysis of an extensive dataset confirms that the oligomer composition of full mtDNA sequences can be a source of taxonomic information. This method also correctly finds the mtDNA sequences most closely related to that of the anatomically modern human (the Neanderthal, the Denisovan, and the chimp), and that the sequence most different from it in this dataset belongs to a cucumber. PMID- 26000735 TI - Neural Correlates of Attentional Flexibility during Approach and Avoidance Motivation. AB - Dynamic, momentary approach or avoidance motivational states have downstream effects on eventual goal success and overall well being, but there is still uncertainty about how those states affect the proximal neurocognitive processes (e.g., attention) that mediate the longer-term effects. Attentional flexibility, or the ability to switch between different attentional foci, is one such neurocognitive process that influences outcomes in the long run. The present study examined how approach and avoidance motivational states affect the neural processes involved in attentional flexibility using fMRI with the aim of determining whether flexibility operates via different neural mechanisms under these different states. Attentional flexibility was operationalized as subjects' ability to switch between global and local stimulus features. In addition to subjects' motivational state, the task context was manipulated by varying the ratio of global to local trials in a block in light of recent findings about the moderating role of context on motivation-related differences in attentional flexibility. The neural processes involved in attentional flexibility differ under approach versus avoidance states. First, differences in the preparatory activity in key brain regions suggested that subjects' preparedness to switch was influenced by motivational state (anterior insula) and the interaction between motivation and context (superior temporal gyrus, inferior parietal lobule). Additionally, we observed motivation-related differences the anterior cingulate cortex during switching. These results provide initial evidence that motivation induced behavioral changes may arise via different mechanisms in approach versus avoidance motivational states. PMID- 26000736 TI - Quantifying the tendency of therapeutic target proteins to bind promiscuous or selective compounds. AB - The ability of target proteins to bind structurally diverse compounds and compounds with different degrees of promiscuity (multi-target activity) was systematically assessed on the basis of currently available activity data and target annotations. Intuitive first- and second-order target promiscuity indices were introduced to quantify these binding characteristics and relate them to each other. For compounds and targets, opposite promiscuity trends were observed. Furthermore, the analysis detected many targets that interacted with compounds representing a similar degree of structural diversity but displayed strong tendencies to recognize either promiscuous or selective compounds. Moreover, target families were identified that preferentially interacted with promiscuous compounds. Taken together, these findings further extend our understanding of the molecular basis of polypharmacology. PMID- 26000737 TI - Inexpensive multiplexed library preparation for megabase-sized genomes. AB - Whole-genome sequencing has become an indispensible tool of modern biology. However, the cost of sample preparation relative to the cost of sequencing remains high, especially for small genomes where the former is dominant. Here we present a protocol for rapid and inexpensive preparation of hundreds of multiplexed genomic libraries for Illumina sequencing. By carrying out the Nextera tagmentation reaction in small volumes, replacing costly reagents with cheaper equivalents, and omitting unnecessary steps, we achieve a cost of library preparation of $8 per sample, approximately 6 times cheaper than the standard Nextera XT protocol. Furthermore, our procedure takes less than 5 hours for 96 samples. Several hundred samples can then be pooled on the same HiSeq lane via custom barcodes. Our method will be useful for re-sequencing of microbial or viral genomes, including those from evolution experiments, genetic screens, and environmental samples, as well as for other sequencing applications including large amplicon, open chromosome, artificial chromosomes, and RNA sequencing. PMID- 26000738 TI - Monoallelic loss of the imprinted gene Grb10 promotes tumor formation in irradiated Nf1+/- mice. AB - Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis. PMID- 26000739 TI - Genome-Wide Characterization of Simple Sequence Repeat (SSR) Loci in Chinese Jujube and Jujube SSR Primer Transferability. AB - Chinese jujube (Ziziphus jujuba), an economically important species in the Rhamnaceae family, is a popular fruit tree in Asia. Here, we surveyed and characterized simple sequence repeats (SSRs) in the jujube genome. A total of 436,676 SSR loci were identified, with an average distance of 0.93 Kb between the loci. A large proportion of the SSRs included mononucleotide, dinucleotide and trinucleotide repeat motifs, which accounted for 64.87%, 24.40%, and 8.74% of all repeats, respectively. Among the mononucleotide repeats, A/T was the most common, whereas AT/TA was the most common dinucleotide repeat. A total of 30,565 primer pairs were successfully designed and screened using a series of criteria. Moreover, 725 of 1,000 randomly selected primer pairs were effective among 6 cultivars, and 511 of these primer pairs were polymorphic. Sequencing the amplicons of two SSRs across three jujube cultivars revealed variations in the repeats. The transferability of jujube SSR primers proved that 35/64 SSRs could be transferred across family boundary. Using jujube SSR primers, clustering analysis results from 15 species were highly consistent with the Angiosperm Phylogeny Group (APGIII) System. The genome-wide characterization of SSRs in Chinese jujube is very valuable for whole-genome characterization and marker assisted selection in jujube breeding. In addition, the transferability of jujube SSR primers could provide a solid foundation for their further utilization. PMID- 26000740 TI - Probing the Hydrogen-Bonded Water Network at the Active Site of a Water Oxidation Catalyst: [Ru(bpy)(tpy)(H2O)](2+).(H2O)(0-4). AB - The infrared spectra of gas-phase mass-selected [Ru(bpy)(tpy)(H2O)](2+).(H2O)(0 4) clusters (bpy = 2,2'-bipyridine; tpy = 2,2':6,2"-terpyridine) in the OH stretching region are reported. These species are formed by bringing the homogeneous water oxidation catalyst [Ru(bpy)(tpy)(H2O](2+) from solution into the gas phase via electrospray ionization (ESI) and reconstructing the water network at the active site by condensing additional water onto the complex in a cryogenic ion trap. Infrared predissociation spectroscopy is used to probe the structure of these clusters via their distinctive OH stretch frequencies, which are sensitive to the shape and strength of the local hydrogen-bonding network. The analysis of the spectra, aided by electronic structure calculations, highlights the formation of strong hydrogen bonds between the aqua ligand and the solvating water molecules in the first solvation shell. These interactions are found to propagate through the subsequent solvation shells and lead to the stabilization of asymmetric solvation motifs. Electronic structure calculations show that these strong hydrogen bonds are promoted by charge transfer from the H atom of the aqua ligand to the Ru-OH2 bond. PMID- 26000741 TI - Synthesis, spectral characterization and DNA bindings of tridentate N2O donor Schiff base metal(II) complexes. AB - To evaluate the biological preference of synthetic small drugs towards DNA target, new metal based chemotherapeutic agents of Cu(II), Co(II), Ni(II) and Zn(II), 2,4-diiodo-6-((pyridin-2-ylmethylimino)methyl)phenol (L) Schiff base complexes (1, 2, 3 &4) having N,N,O donor system respectively were synthesized and thoroughly characterized. The IR results confirmed the tridentate binding of the ligand with metal centre during complexation and reflects the proposed structure. The density function theory calculations were also used to further investigate the electronic structure and properties of ligand and complexes. The preliminary investigation of herring Sperm (HS-DNA) interaction propensity of complexes 1-4 were carried out in Tris-HCl buffer at pH 7.1 to demonstrate their mode of interactions. The obtained results reveal that these complexes significantly interact with DNA on the grooves, further, this observed mode of interactions was also confirmed by molecular docking evaluations. The complexes 1 4 were also screened for antimicrobial evaluations which demonstrated that their significant activity against various human pathogens. The cleavage studies with pBR322 plasmid DNA revealed higher nuclease activity of 1 as compared to other complexes. PMID- 26000742 TI - Fluorescence in neurosurgery: Its diagnostic and therapeutic use. Review of the literature. AB - Fluorescent agents, e.g. 5-aminolevulinic acid (5-ALA), fluorescein and indocyanine green (ICG) are in common use in neurosurgery for tumor resection and neurovascular surgery. Protoporphyrine IX (PPIX) as major metabolite of 5-ALA is a strong fluorescent substance accumulated within malignant glioma tissue and a very sensitive and specific tool for visualizing high grade glioma tissue during surgery. Furthermore, 5-ALA or rather PPIX also offers an intratumoral therapeutic option stimulated by laser light in specific wavelength. Fluorescein was demonstrated to show similar fluorescent reactions in neurosurgery, but is controversial in its use, especially in high grade tumor surgery. Intraoperative angiography during resection of arterio-venous malformations, extracranial intracranial-bypass or aneurysm surgery is supported by ICG fluorescence. Generally ICG will provide beneficial information for both, exposure of the pathology and illustration of healthy structures. This manuscript shows an overview of the literature focussing fluorescence in neurosurgery. PMID- 26000743 TI - Bouncing off the Walls: Excited Protein Complexes Tell Their Story. AB - "Native" mass spectrometry has become a valuable tool for structural biology. In this issue of Chemistry & Biology, Quintyn et al. (2015) show that modified instruments capable of surface-induced dissociation allow dissection of protein complexes in a way that is reminiscent of their native topology and architecture. PMID- 26000744 TI - A dive into membrane dynamics with sponge peptides. AB - In this issue of Chemistry & Biology, Arita et al. (2015) report that theonellamides can specifically recognize cholesterol in liquid-disordered environment, modulate membrane order, and change cell morphology and thus may serve as probes to unveil the enigmatic nature of cell membranes. PMID- 26000745 TI - Simplifying complexity in metabolomics. AB - Metabolomics analysis to unravel secondary metabolite dynamics in microorganisms faces the challenge of immense data sets and complex experimental setups. In this issue, Goodwin et al. present a multiple stimuli approach combined with self organizing map-based analysis to elucidate variations in the metabolome of Streptomyces coelicolor caused by biotic and environmental perturbations. PMID- 26000746 TI - Light moves mountains in the cell. AB - In this issue of Chemistry & Biology, Duan et al. (2015) report the use of a light-inducible protein-protein interaction system to dynamically control the movement of intracellular organelles with spatial and temporal precision in living cells. PMID- 26000747 TI - The Effect of Detergent, Temperature, and Lipid on the Oligomeric State of MscL Constructs: Insights from Mass Spectrometry. AB - The mechanosensitive channel of large conductance (MscL) acts as an emergency release valve for osmotic shock of bacteria preventing cell lysis. The large pore size, essential for function, requires the formation of oligomers with tetramers, pentamers, or hexamers observed depending on the species and experimental approach. We applied non-denaturing (native) mass spectrometry to five different homologs of MscL to determine the oligomeric state under more than 50 different experimental conditions elucidating lipid binding and subunit stoichiometry. We found equilibrium between pentameric and tetrameric species, which can be altered by detergent, disrupted by binding specific lipids, and perturbed by increasing temperature (37 degrees C). We also established the presence of lipopolysaccharide bound to MscL and other membrane proteins expressed in Escherichia coli, revealing a potential source of heterogeneity. More generally, we highlight the use of mass spectrometry in probing membrane proteins under a variety of detergent-lipid environments relevant to structural biology. PMID- 26000748 TI - Peroxide-Dependent MGL Sulfenylation Regulates 2-AG-Mediated Endocannabinoid Signaling in Brain Neurons. AB - The second messenger hydrogen peroxide transduces changes in the cellular redox state by reversibly oxidizing protein cysteine residues to sulfenic acid. This signaling event regulates many cellular processes but has never been shown to occur in the brain. Here, we report that hydrogen peroxide heightens endocannabinoid signaling in brain neurons through sulfenylation of cysteines C201 and C208 in monoacylglycerol lipase (MGL), a serine hydrolase that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in nerve terminals. The results suggest that MGL sulfenylation may provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling. PMID- 26000750 TI - A subdomain swap strategy for reengineering nonribosomal peptides. AB - Nonribosomal peptide synthetases (NRPSs) protect microorganisms from environmental threats by producing diverse siderophores, antibiotics, and other peptide natural products. Their modular molecular structure is also attractive from the standpoint of biosynthetic engineering. Here we evaluate a methodology for swapping module specificities of these mega-enzymes that takes advantage of flavodoxin-like subdomains involved in substrate recognition. Nine subdomains encoding diverse specificities were transplanted into the Phe-specific GrsA initiation module of gramicidin S synthetase. All chimeras could be purified as soluble protein. One construct based on a Val-specific subdomain showed sizable adenylation activity and functioned as a Val-Pro diketopiperazine synthetase upon addition of the proline-specific GrsB1 module. These results suggest that subdomain swapping could be a viable alternative to previous NRPS design approaches targeting binding pockets, domains, or entire modules. The short length of the swapped sequence stretch may facilitate straightforward exploitation of the wealth of existing NRPS modules for combinatorial biosynthesis. PMID- 26000749 TI - Depletion of T cell epitopes in lysostaphin mitigates anti-drug antibody response and enhances antibacterial efficacy in vivo. AB - The enzyme lysostaphin possesses potent anti-staphylococcal activity and represents a promising antibacterial drug candidate; however, its immunogenicity poses a barrier to clinical translation. Here, structure-based biomolecular design enabled widespread depletion of lysostaphin DRB1(*)0401 restricted T cell epitopes, and resulting deimmunized variants exhibited striking reductions in anti-drug antibody responses upon administration to humanized HLA-transgenic mice. This reduced immunogenicity translated into improved efficacy in the form of protection against repeated challenges with methicillin-resistant Staphylococcus aureus (MRSA). In contrast, while wild-type lysostaphin was efficacious against the initial MRSA infection, it failed to clear subsequent bacterial challenges that were coincident with escalating anti-drug antibody titers. These results extend the existing deimmunization literature, in which reduced immunogenicity and retained efficacy are assessed independently of each other. By correlating in vivo efficacy with longitudinal measures of anti-drug antibody development, we provide the first direct evidence that T cell epitope depletion manifests enhanced biotherapeutic efficacy. PMID- 26000751 TI - In-gel imaging of RNA processing using broccoli reveals optimal aptamer expression strategies. AB - RNA aptamers can be expressed in cells to influence and image cellular processes. Aptamer folding is maintained by inserting the aptamers into highly structured RNA scaffolds. Here, we show that commonly used RNA scaffolds exhibit unexpected instability and cleavage in bacterial and mammalian cells. Using an in-gel staining approach for rapid and simple detection of Spinach- or Broccoli-tagged RNAs in cells, we monitored the processing of RNAs tagged with scaffolded aptamers, revealing endonucleolytic cleavage, RNA instability, and poor expression. We reengineered a natural three-way junction structure to generate an alternative scaffold that enables stable aptamer expression in cells. This scaffold was used to create cassettes containing up to four Broccoli units, markedly enhancing the brightness of mammalian cells expressing cassette-tagged RNAs. These experiments describe methods for screening RNA cleavage events in cells and identify cell-compatible scaffolds that enable efficient tagging of RNAs with aptamers for cellular expression. PMID- 26000752 TI - Association between Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Prognosis of Kidney Transplantation: A Meta-Analysis. AB - PURPOSE: Angiotensin I-converting enzyme (ACE) is crucial in the renin angiotensin-aldosterone system. ACE insertion/deletion (I/D) polymorphism is a common genetic variation of this gene and is associated with several disease phenotypes. However, the results of published studies on the influence of this polymorphism on renal transplantation are inconsistent. Therefore, a meta analysis was performed to evaluate the association between ACE I/D polymorphism and prognosis of kidney transplantation. METHODS: A meta-analysis was performed based on 21 case-control studies from 12 publications (1497 cases and 2029 controls) and 10 studies with quantitative values from 5 publications (814 patients). Pooled odds ratios (ORs) and weighted mean differences (WMDs) with their corresponding 95% confidence intervals (CIs) were used to estimate associations. RESULTS: ACE I/D polymorphism was found to be associated with acute rejection (AR) in genotypes DD+ID versus II (OR = 1.62, 95% CI = 1.14-2.29) and with serum creatinine concentration after renal transplantation in genotypes DD versus ID (WMD = 13.12, 95% CI = 8.09-18.16). Stratified analysis revealed that recipients transplanted within a year had higher serum creatinine concentrations in the DD versus ID model. No significant association was found between hypertension and ACE I/D polymorphism. CONCLUSION: ACE I/D polymorphism is associated with AR and allograft function after kidney transplantation. PMID- 26000753 TI - The BDNF Val66Met polymorphism, resting-state hippocampal functional connectivity and cognitive deficits in acute late-onset depression. AB - OBJECTIVE: To investigate the relationship between hippocampal functional connectivity (HFC), cognitive deficits, and the influence of BDNF Val66Met polymorphism on the HFC in acute late-onset depression (LOD). METHODS: 26 LOD patients and 33 and normal controls (NCs) completed clinical assessments, neuropsychological testing, blood samples collecting for genotyping, and resting state functional MRI (R-fMRI) scans. The LOD and NCs groups were further divided into four groups according to BDNF Met allele carrier or not (LOD Met-(n=8); LOD Met+(n=18); NCs Met-(n=9); NCs Met+(n=24)). Then, seed-based correlation analyses and two-way analysis of covariance (ANCOVA) were performed to explore the main effects and interactive effects of LOD and BDNF Val66Met polymorphism on the HFC. Spearman correlation was applied to examine the cognitive and emotional significance of these altered HFC networks. RESULTS: Compared with NCs, bilateral positive HFC with the right insula, left positive HFC with bilateral orbit frontal cortex (OFC) and left precuneus, right positive HFC with right dorsolateral prefrontal cortex (dlPFC) were decreased, and bilateral negative HFC with right postcentral gyrus were reversed in LOD patients. BDNF Met allele mainly decreased bilateral positive HFC with the cerebellum. The interaction of LOD and BDNF Met allele primarily influenced the bilateral HFC with the temporal cortex and dorsal nexus. The changed HFC with the OFC, postcentral gyrus, cerebellum and temporal cortex significantly correlated to the cognitive deterioration. There was no significant association between the depressive severity and any altered HFC networks. CONCLUSION: The cognitive deterioration in LOD patients, BDNF Met allele carriers, and LOD patients carring Met allele were associated with the changed HFC networks in the OFC/postcentral gyrus, cerebellum and temporal cortex respectively. PMID- 26000754 TI - Spectroscopic markers of memory impairment, symptom severity and age of onset in older people with lifetime depression: Discrete roles of N-acetyl aspartate and glutamate. AB - BACKGROUND: Glutamate (Glu) and N-acetyl aspartate (NAA) are markers of excitatory processes and neuronal compromise respectively. Increased Glu and decreased NAA concentrations have been implicated in the pathophysiology of depression and cognitive impairment respectively. OBJECTIVE: To determine the relationship between NAA, Glu, memory and key clinical features in older people with lifetime depression compared to comparison subjects. METHOD: Thirty-five health-seeking older adults (mean age=63.57 years), with a lifetime depression diagnosis, and 21 age-matched healthy comparison subjects (mean age=65.48 years) underwent neuropsychological testing, psychiatric assessment and proton magnetic resonance spectroscopy from which Glu and NAA were measured (reported as a ratio to creatine). RESULTS: Compared to comparison subjects, the depressed subjects showed poorer verbal learning and memory retention. Hippocampal NAA and Glu did not differ significantly between groups. However, in comparison subjects, lower levels of hippocampal Glu were associated with poorer memory retention (r=0.55, p=0.018). In the depressed subjects, lower levels of hippocampal NAA were related to poorer verbal learning (r=0.44, p=0.008) and memory retention (r=0.41, p=0.018). Greater hippocampal Glu was associated with more severe depressive symptoms (r=0.35, p=0.039) and an earlier age of illness onset (r=-0.37, p=0.031). LIMITATIONS: This is a cross sectional study with a heterogeneous group of depressed subjects. CONCLUSION: Our findings highlight that hippocampal neurometabolites are entwined with both clinical and cognitive features associated with depression in older adults and further suggest that differential mechanisms may underpin these features. PMID- 26000755 TI - The relative importance of diet-related and waterborne effects of copper for a leaf-shredding invertebrate. AB - Copper (Cu) exposure can increase leaf-associated fungal biomass, an important food component for leaf-shredding macroinvertebrates. To test if this positive nutritional effect supports the physiological fitness of these animals and to assess its importance compared to waterborne toxicity, we performed a 24-day bioassay in combination with a 2*2 factorial design using the amphipod shredder Gammarus fossarum and a field-relevant Cu concentration of 25 MUg/L (n = 65). Waterborne toxicity was negligible, while gammarids fed leaves exposed to Cu during microbial colonization exhibited a near-significant impairment in growth (~30%) and a significantly reduced lipid content (~20%). These effects appear to be governed by dietary uptake of Cu, which accumulated in leaves as well as gammarids and likely overrode the positive nutritional effect of the increased fungal biomass. Our results suggest that for adsorptive freshwater contaminants dietary uptake should be evaluated already during the registration process to safeguard the integrity of detritus-based ecosystems. PMID- 26000756 TI - Source identification of perylene in surface sediments and waterbird eggs in the Anzali Wetland, Iran. AB - Following the marked increase of perylene concentration in southern coast of Caspian Sea, waterbird eggs were used as biomonitoring agents. Surface sediments and eggs of five bird species were collected from colonies in Anzali Wetland in the above coast for perylene analysis. The perylene concentrations in sediment and egg samples ranged within 70.6-204.4 and 25.5-43.2 ng/g dw, respectively. Diagnostic perylene ratios showed that the perylene found in all samples was of biogenic origin, possibly developing from terrestrial materials. The combination pattern of perylene was found to be similar in all samples. Conclusively, perylene observed in the area was transmitted from sediments in breeding areas into the eggs, so the eggs are biomonitoring agents and the prevalence of oxic conditions in surface sediments limits formation of perylene, reflecting perylene formation in the catchment area. We found that perylene distribution in surface sediments follows irregular patterns, representing significant effects from local inputs. PMID- 26000758 TI - A tribute to Philip Marcus and the development of the clonogenic assay. AB - Philip Marcus (1927-2013), a prominent and celebrated virus and interferon researcher, was also influential to the field of radiobiology. His work as a graduate student led to the development of the first mammalian cell clonogenic assay. This tribute to Philip Marcus is written to memorialize this inventive scientist and share the stimulating story of how he and his mentors developed the clonogenic assay. PMID- 26000757 TI - A transdiagnostic comparison of enhanced cognitive behaviour therapy (CBT-E) and interpersonal psychotherapy in the treatment of eating disorders. AB - Eating disorders may be viewed from a transdiagnostic perspective and there is evidence supporting a transdiagnostic form of cognitive behaviour therapy (CBT E). The aim of the present study was to compare CBT-E with interpersonal psychotherapy (IPT), a leading alternative treatment for adults with an eating disorder. One hundred and thirty patients with any form of eating disorder (body mass index >17.5 to <40.0) were randomized to either CBT-E or IPT. Both treatments involved 20 sessions over 20 weeks followed by a 60-week closed follow up period. Outcome was measured by independent blinded assessors. Twenty-nine participants (22.3%) did not complete treatment or were withdrawn. At post treatment 65.5% of the CBT-E participants met criteria for remission compared with 33.3% of the IPT participants (p < 0.001). Over follow-up the proportion of participants meeting criteria for remission increased, particularly in the IPT condition, but the CBT-E remission rate remained higher (CBT-E 69.4%, IPT 49.0%; p = 0.028). The response to CBT-E was very similar to that observed in an earlier study. The findings indicate that CBT-E is potent treatment for the majority of outpatients with an eating disorder. IPT remains an alternative to CBT-E, but the response is less pronounced and slower to be expressed. CURRENT CONTROLLED TRIALS: ISRCTN 15562271. PMID- 26000759 TI - In memoriam: Warren K. Sinclair (March 9, 1924-May 14, 2014). PMID- 26000760 TI - In memoriam: H. Rodney Withers (21 September 1932-25 February 2015). PMID- 26000762 TI - Oxidation Dynamics of Methionine with Singlet Oxygen: Effects of Methionine Ionization and Microsolvation. AB - We report an in-depth study on the gas-phase reactions of singlet O2[a(1)Deltag] with methionine (Met) at different ionization and hydration states (including deprotonated [Met - H](-), hydrated deprotonated [Met - H](-)(H2O)1,2, and hydrated protonated MetH(+)(H2O)1,2), using guided-ion-beam scattering mass spectrometry. The measurements include the effects of collision energy (Ecol) on reaction cross sections over a center-of-mass Ecol range from 0.05 to 1.0 eV. The aim of this study is to probe the influences of Met ionization and hydration on its oxidation mechanism and dynamics. Density functional theory calculations, Rice-Ramsperger-Kassel-Marcus modeling, and quasi-classical, direct dynamics trajectory simulations were performed to examine the properties of various complexes and transition states that might be important along reaction coordinates, probe reaction potential energy surfaces, and to establish the atomic-level mechanism for the Met oxidation process. No oxidation products were observed for the reaction of [Met - H](-) with (1)O2 due to the high-energy barriers located in the product channels for this system. However, this nonreactive property was altered by the microsolvation of [Met - H](-); as a result, hydroperoxides were captured as the oxidation products for [Met - H]( )(H2O)1,2 + (1)O2. For the reaction of MetH(+)(H2O)1,2 + (1)O2, besides formation of hydroperoxides, an H2O2 elimination channel was observed. The latter channel is similar to what was found in the reaction of dehydrated MetH(+) with (1)O2 (J. Phys. Chem. B 2011, 115, 2671). The reactions of hydrated protonated and deprotonated Met are all inhibited by Ecol, becoming negligible at Ecol >= 0.5 eV. The kinetic and dynamical consequences of microsolvation on Met oxidation and their biological implications are discussed. PMID- 26000761 TI - Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues. AB - Hepatitis B virus (HBV) is a hepatotropic virus causing hepatitis, cirrhosis and hepatocellular carcinoma (HCC). The methylation status of the HBV DNA in its different forms can potentially provide insight into the pathogenesis of HBV related liver diseases, including HCC, however this is unclear. The goal of this study is to obtain comprehensive DNA methylation profiles of the three putative CpG islands in the HBV DNA in infected livers, with respect to liver disease progression. The extent of methylation in these CpG islands was first assessed using bisulfite PCR sequencing with a small set of tissue samples, followed by analysis using both quantitative bisulfite-specific PCR and quantitative methylation-specific PCR assays in a larger sample size (n = 116). The level of HBV CpG island 3 methylation significantly correlated with hepatocarcinogenesis. We also obtained, for the first time, evidence of rare, non-CpG methylation in CpG island 2 of the HBV genome in infected liver. Comparing methylation of the HBV genome to three known HCC-associated host genes, APC, GSTP1, and RASSF1A, we did not identify a significant correlation between these two groups. PMID- 26000763 TI - One-pot tandem catalysis over Pd@MIL-101: boosting the efficiency of nitro compound hydrogenation by coupling with ammonia borane dehydrogenation. AB - The hydrogenation efficiency of nitro compounds was found to be greatly boosted by coupling with dehydrogenation of ammonia borane. The Pd@MIL-101 with tiny Pd NPs is exceptionally efficient and recyclable in the tandem reactions and diverse nitro compounds can be selectively reduced to the corresponding amines in 1.5-5 min with quantitative yields. PMID- 26000764 TI - Ru(II)-Pheox-Catalyzed Asymmetric Intramolecular Cyclopropanation of Electron Deficient Olefins. AB - The first highly enantioselective intramolecular cyclopropanation of electron deficient olefins, in the presence of Ru(II)--Pheox catalyst, is reported. The corresponding cyclopropane-fused gamma-lactones were obtained in high yields (up to 99%) with excellent enantioselectivities (ee up to 99%). Moreover, this method enables efficient access to enantioenriched dicarbonyl cyclopropane derivatives, which are important intermediates for the synthesis of various bioactive compounds. PMID- 26000765 TI - Common AZFc structure may possess the optimal spermatogenesis efficiency relative to the rearranged structures mediated by non-allele homologous recombination. AB - The azoopsermia factor c (AZFc) region of human Y-chromosome is an essential genomic segment for spermatogenesis with frequent non-allele homologous recombination (NAHR). Recent case-control studies on the association of the NAHR based AZFc structural mutations with spermatogenic failure produced inconsistent results. To more precisely evaluate their spermatogenesis effects, we investigated the correlation between the subdivided AZFc mutations and sperm production in 3,439 Han Chinese males. Our results showed that both partial AZFc deletion-only and primary duplication mutation presented a significant risk for decreased sperm production. Restoration of the reduced dosage of the AZFc content to the normal level had a milder effect, whereas an overdose of the AZFc content arising from multiple duplications of a partial AZFc-deleted structure produced a more serious consequence compared to the partial deletion-only mutation. Additionally, the AZFc-mutated structures with excessive NAHR-substrate showed a notably negative effect on spermatogenesis. These results suggest that the recurrent NAHR-based AZFc mutations may be associated with decreased spermatogenesis efficiency in present population. More significantly, our finding implies that the overdose of AZFc NAHR-substrate may produce an additional risk for the massive AZFbc deletions during the multi-stage division process of germ cells and thus impair the global spermatogenesis efficiency in the carriers. PMID- 26000766 TI - Isolation and metagenomic characterization of bacteria associated with calcium carbonate and struvite precipitation in a pure moving bed biofilm reactor membrane bioreactor. AB - A bench-scale pure moving bed bioreactor-membrane bioreactor (MBBR-MBR) used for the treatment of urban wastewater was analyzed for the identification of bacterial strains with the potential capacity for calcium carbonate and struvite biomineral formation. Isolation of mineral-forming strains on calcium carbonate and struvite media revealed six major colonies with a carbonate or struvite precipitation capacity in the biofouling on the membrane surface and showed that heterotrophic bacteria with the ability to precipitate calcium carbonate and struvite constituted ~7.5% of the total platable bacteria. These belonged to the genera Lysinibacillus, Trichococcus, Comamomas and Bacillus. Pyrosequencing analysis of the microbial communities in the suspended cells and membrane biofouling showed a high degree of similarity in all the samples collected with respect to bacterial assemblage. The study of operational taxonomic units (OTUs) identified through pyrosequencing suggested that ~21% of the total bacterial community identified in the biofouling could potentially form calcium carbonate or struvite crystals in the pure MBBR-MBR system used for the treatment of urban wastewater. PMID- 26000767 TI - Exploring residents' communication learning process in the workplace: a five phase model. AB - CONTEXT: Competency-based education is a resurgent paradigm in professional medical education. However, more specific knowledge is needed about the learning process of such competencies, since they consist of complex skills. We chose to focus on the competency of skilled communication and want to further explore its learning process, since it is regarded as a main competency in medical education. OBJECTIVE: This study aims to explore in more detail the learning process that residents in general practice go through during workplace-based learning in order to become skilled communicators. METHODS: A qualitative study was conducted in which twelve GP residents were observed during their regular consultations, and were interviewed in-depth afterwards. RESULTS: Analysis of the data resulted in the construction of five phases and two overall conditions to describe the development towards becoming a skilled communicator: Confrontation with (un)desired behaviour or clinical outcomes was the first phase. Becoming conscious of one's own behaviour and changing the underlying frame of reference formed the second phase. The third phase consisted of the search for alternative behaviour. In the fourth phase, personalization of the alternative behaviour had to occur, this was perceived as difficult and required much time. Finally, the fifth phase concerned full internalization of the new behaviour, which by then had become an integrated part of the residents' clinical repertoire. Safety and cognitive & emotional space were labelled as overall conditions influencing this learning process. CONCLUSIONS: Knowledge and awareness of these five phases can be used to adjust medical working and learning environments in such a way that development of skilled medical communication can come to full fruition and its benefits are more fully reaped. PMID- 26000768 TI - Detection of microRNA SNPs with ultrahigh specificity by using reduced graphene oxide-assisted rolling circle amplification. AB - Here we report a reduced graphene oxide-assisted rolling circle amplification for the detection of miRNA SNPs. The difference of the signal of a miRNA SNP reaches 100 fold, a value over 10 times larger than some current methodologies, which allows the discrimination of a SNP even with the naked eye. PMID- 26000769 TI - The non-proliferative nature of ascidian folliculogenesis as a model of highly ordered cellular topology distinct from proliferative epithelia. AB - Previous studies have addressed why and how mono-stratified epithelia adopt a polygonal topology. One major additional, and yet unanswered question is how the frequency of different cell shapes is achieved and whether the same distribution applies between non-proliferative and proliferative epithelia. We compared different proliferative and non-proliferative epithelia from a range of organisms as well as Drosophila melanogaster mutants, deficient for apoptosis or hyperproliferative. We show that the distribution of cell shapes in non proliferative epithelia (follicular cells of five species of tunicates) is distinctly, and more stringently organized than proliferative ones (cultured epithelial cells and Drosophila melanogaster imaginal discs). The discrepancy is not supported by geometrical constraints (spherical versus flat monolayers), number of cells, or apoptosis events. We have developed a theoretical model of epithelial morphogenesis, based on the physics of divided media, that takes into account biological parameters such as cell-cell contact adhesions and tensions, cell and tissue growth, and which reproduces the effects of proliferation by increasing the topological heterogeneity observed experimentally. We therefore present a model for the morphogenesis of epithelia where, in a proliferative context, an extended distribution of cell shapes (range of 4 to 10 neighbors per cell) contrasts with the narrower range of 5-7 neighbors per cell that characterizes non proliferative epithelia. PMID- 26000770 TI - Prevalence and Transmission of Trypanosoma cruzi in People of Rural Communities of the High Jungle of Northern Peru. AB - BACKGROUND: Vector-borne transmission of Trypanosoma cruzi is seen exclusively in the Americas where an estimated 8 million people are infected with the parasite. Significant research in southern Peru has been conducted to understand T. cruzi infection and vector control, however, much less is known about the burden of infection and epidemiology in northern Peru. METHODOLOGY: A cross-sectional study was conducted to estimate the seroprevalence of T. cruzi infection in humans (n=611) and domestic animals [dogs (n=106) and guinea pigs (n=206)] in communities of Cutervo Province, Peru. Sampling and diagnostic strategies differed according to species. An entomological household study (n=208) was conducted to identify the triatomine burden and species composition, as well as the prevalence of T. cruzi in vectors. Electrocardiograms (EKG) were performed on a subset of participants (n=90 T. cruzi infected participants and 170 age and sex matched controls). The seroprevalence of T. cruzi among humans, dogs, and guinea pigs was 14.9% (95% CI: 12.2-18.0%), 19.8% (95% CI: 12.7-28.7%) and 3.3% (95% CI: 1.4-6.9%) respectively. In one community, the prevalence of T. cruzi infection was 17.2% (95% CI: 9.6-24.7%) among participants < 15 years, suggesting recent transmission. Increasing age, positive triatomines in a participant's house, and ownership of a T. cruzi positive guinea pig were independent correlates of T. cruzi infection. Only one species of triatomine was found, Panstrongylus lignarius, formerly P. herreri. Approximately forty percent (39.9%, 95% CI: 33.2 46.9%) of surveyed households were infested with this vector and 14.9% (95% CI: 10.4-20.5%) had at least one triatomine positive for T. cruzi. The cardiac abnormality of right bundle branch block was rare, but only identified in seropositive individuals. CONCLUSIONS: Our research documents a substantial prevalence of T. cruzi infection in Cutervo and highlights a need for greater attention and vector control efforts in northern Peru. PMID- 26000771 TI - Genome-wide analysis of positively selected genes in seasonal and non-seasonal breeding species. AB - Some mammals breed throughout the year, while others breed only at certain times of year. These differences in reproductive behavior can be explained by evolution. We identified positively-selected genes in two sets of species with different degrees of relatedness including seasonal and non-seasonal breeding species, using branch-site models. After stringent filtering by sum of pairs scoring, we revealed that more genes underwent positive selection in seasonal compared with non-seasonal breeding species. Positively-selected genes were verified by cDNA mapping of the positive sites with the corresponding cDNA sequences. The design of the evolutionary analysis can effectively lower the false-positive rate and thus identify valid positive genes. Validated, positively selected genes, including CGA, DNAH1, INVS, and CD151, were related to reproductive behaviors such as spermatogenesis and cell proliferation in non seasonal breeding species. Genes in seasonal breeding species, including THRAP3, TH1L, and CMTM6, may be related to the evolution of sperm and the circadian rhythm system. Identification of these positively-selected genes might help to identify the molecular mechanisms underlying seasonal and non-seasonal reproductive behaviors. PMID- 26000772 TI - Risk and outcome after ablation of isthmus-dependent atrial flutter in elderly patients. AB - PURPOSE OF THE RESEARCH: To study the influence of age on the clinical presentation and long-term outcome of patients referred for atrial flutter (AFL) ablation. Age-related differences have been reported regarding the prognosis of arrhythmias. METHODS: A total of 1187 patients with a mean age 65+/-12 years consecutively referred for AFL ablation were retrospectively analyzed in the study. RESULTS: 445 (37.5%) patients were aged >=70 (range 70 to 93) among which 345 were aged 70 to 79 years (29.1%) and 100 were aged >=80 (8.4%). In multivariable analysis, AFL-related rhythmic cardiomyopathy and presentation with 1/1 AFL were less frequent (respectively adjusted OR = 0.44, 0.27-0.74, p = 0.002 and adjusted OR = 0.29, 0.16-0.52, p<0.0001). AFL ablation-related major complications were more frequent in patients >=70 although remained lower than 10% (7.4% in >=70 vs. 4.2% in <70, adjusted OR = 1.74, 1.04-2.89, p = 0.03). After 2.1+/-2.7 years, AFL recurrence was less frequent in patients >=70 (adjusted OR = 0.54, 0.37-0.80, p = 0.002) whereas atrial fibrillation (AF) occurrence was as frequent in the 70-79 and >=80 age subsets. As expected, cardiac mortality was higher in older patients. Patients aged >=80 also had a low probability of AFL recurrence (5.0%) and AF onset (19.0%). CONCLUSIONS: Older patients represent 37.5% of patients referred for AFL ablation and displayed a <10% risk of ablation-related complications. Importantly, AFL recurrences were less frequent in patients >=70 while AF occurrence was as frequent as in patients <70. Similar observations were made in patients >=80 years. AFL ablation appears to be safe and efficient and should not be ruled out in elderly patients. PMID- 26000773 TI - Bone marrow suppression and associated consequences in patients after heart transplantation: A 6-year retrospective review. AB - AIMS: To evaluate the incidence of bone marrow suppression and consequences of MMF dose adjustment in patients within the first year after heart transplantation. METHODS: Group I (n=47) was treated with a regimen currently used in patients after heart transplantation (mycophenolatemofetil - MMF, valganciclovir - VGC and trimethoprim/sulfamethoxazole - TMP-SMX). Group II (n=47) received only MMF of potentially myelotoxic medications. The myelotoxic effect and need for dose modification were assessed. The incidence of rejections and infectious episodes associated with MMF adjustment were analyzed during the first 12 months in Group I. RESULTS: There was a significantly greater proportion of patients with leukopenia (leukocyte count < 4 x 10^9/L) at 3 months after orthotopic heart transplantation in Group I compared with Group II (19.1% vs 2.1%; P = 0.02). The difference in lymphopenia (lymphocyte count < 0.8 x 10^9/L) at 3 months follow-up was highly significant (38.3 % vs 6.4 %; P = 0.0002). MMF was modified due to bone marrow suppression or severe infection in 63.8% patients in Group I and in only 8.5% of patients in Group II (P < 0.001). Reducing or stopping MMF was not associated with increased rejections. In Group I, at least 1 episode of higher degree cellular or humoral rejection occurred in 35% of patients with the standard MMF dosage compared with only 26% in patients with modified MMF (P = 0.0534). CONCLUSIONS: Addition of VGC+TMP-SMX to current immunosuppressive medication regimen in patients after heart transplantation is associated with significant lymphocytopenia and leukopenia. Importantly, modification of immunosuppressive prophylaxis (reducing or stopping MMF) leads to normalization of blood count without increased incidence of rejections. PMID- 26000774 TI - Aquaporin-4 gene variant independently associated with oedema after intracerebral haemorrhage. AB - INTRODUCTION: Aquaporin-4 (AQP4) is the prominent water-channel protein in the brain playing a critical role in controlling cell water content. After intracerebral haemorrhage (ICH), perihematomal oedema (PHE) formation leads to a rapid increase in intracranial pressure (ICP) after the initial bleed. We sought to investigate the effect of a common genomic variant in the AQP4 gene on PHE formation after ICH. METHODS: We reviewed the literature and identified a candidate polymorphism in AQP4 genes previously reported in Genome Wide Association Studies (GWAS). Between February 2009 and March 2011, 128 patients consented to genetic testing and were genotyped for single nucleotide polymorphism (SNP) on the AQP4 gene. Genomic DNA was extracted from buccal swabs using MasterAmp extraction kits (Epicentre, Madison, WI, USA). DNA extracted from buffy coats of whole blood samples was amplified via PCR. Linear regression with log-transformed ICH + PHE volume as the response variable was used to determine the association of SNP controlled for admission variables age, GCS, infratentorial location, hypertension, systolic blood pressure (SBP), blood urea nitrogen (BUN), glucose and alkaline phosphatase. RESULTS: Nine of 128 patients had the minor allele for SNP rs1058427. Presence of the minor allele was significant in the model (P = 0.021), and associated with an increase of 88% in ICH + PHE volume (beta = 0.632, exp(beta) = 1.88) after controlling for admission variables. The only other significant variables included in the model was GCS (P < 0.001). CONCLUSION: The establishment of an independent association between rs1054827 and ICH + PHE volume provides evidence implicating the AQP4 gene in haematoma and oedema formation after ICH. Further investigation is needed to characterise this link. PMID- 26000775 TI - Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation. AB - Bioconjugation methodologies have proven to play a central enabling role in the recent development of biotherapeutics and chemical biology approaches. Recent endeavours in these fields shed light on unprecedented chemical challenges to attain bioselectivity, biocompatibility, and biostability required by modern applications. In this review the current developments in various techniques of selective bond forming reactions of proteins and peptides were highlighted. The utility of each endogenous amino acid-selective conjugation methodology in the fields of biology and protein science has been surveyed with emphasis on the most relevant among reported transformations; selectivity and practical use have been discussed. PMID- 26000776 TI - Analysis of connectivity in NeuCube spiking neural network models trained on EEG data for the understanding of functional changes in the brain: A case study on opiate dependence treatment. AB - The paper presents a methodology for the analysis of functional changes in brain activity across different conditions and different groups of subjects. This analysis is based on the recently proposed NeuCube spiking neural network (SNN) framework and more specifically on the analysis of the connectivity of a NeuCube model trained with electroencephalography (EEG) data. The case study data used to illustrate this method is EEG data collected from three groups-subjects with opiate addiction, patients undertaking methadone maintenance treatment, and non drug users/healthy control group. The proposed method classifies more accurately the EEG data than traditional statistical and artificial intelligence (AI) methods and can be used to predict response to treatment and dose-related drug effect. But more importantly, the method can be used to compare functional brain activities of different subjects and the changes of these activities as a result of treatment, which is a step towards a better understanding of both the EEG data and the brain processes that generated it. The method can also be used for a wide range of applications, such as a better understanding of disease progression or aging. PMID- 26000777 TI - Corrigendum. PMID- 26000778 TI - Prolactin serum concentrations after electroconvulsive therapy in a depressed patient with cabergoline-treated prolactinoma: implications for treatment. PMID- 26000779 TI - Ubiquitous occurrence of chlorinated byproducts of bisphenol A and nonylphenol in bleached food contacting papers and their implications for human exposure. AB - The occurrence of bisphenol A (BPA), nonylphenol (NP), and their six chlorinated byproducts were investigated in 74 food contacting papers (FCPs) from China, the U.S.A., Japan, and Europe using a sensitive dansylation LC-MS/MS method. BPA ( 0.05) was observed between the two humidity levels for magnetite. There was no correlation between iron solubility and exposure to SO2 in any mineral for any size fraction. X-ray absorption near edge structure (XANES) measurements showed no change in iron speciation [Fe(II) and Fe(III)] in any minerals following SO2 exposure. SEM EDS measurements of SO2-exposed goethite revealed small amounts of sulfur uptake on the samples; however, the incorporated sulfur did not affect iron solubility. Our results show that although sulfur is incorporated into particles via gas phase processes, changes in iron solubility also depend on other species in the aerosol. PMID- 26000787 TI - Zinc Protoporphyrin Suppresses beta-Catenin Protein Expression in Human Cancer Cells: The Potential Involvement of Lysosome-Mediated Degradation. AB - Zinc protoporphyrin (ZnPP) has been found to have anticancer activity both in vitro and in vivo. We have recently demonstrated that ZnPP diminishes beta catenin protein expression in cancer cells. The present study examined the cellular mechanisms that mediate ZnPP's suppression of beta-catenin expression. We demonstrate that ZnPP induces a rapid degradation of the beta-catenin protein in cancer cells, which is accompanied by a significant inhibition of proteasome activity, suggesting that proteasome degradation does not directly account for the suppression. The possibility that ZnPP induces beta-catenin exportation was rejected by the observation that there was no detectable beta-catenin protein in the conditioned medium after ZnPP treatment of cancer cells. Further experimentation demonstrated that ZnPP induces lysosome membrane permeabilization, which was reversed by pretreatment with a protein transportation inhibitor cocktail containing Brefeldin A (BFA) and Monensin. More significantly, pretreatment of cancer cells with BFA and Monensin attenuated the ZnPP-induced suppression of beta-catenin expression in a concentration- and time dependent manner, indicating that the lysosome protein degradation pathway is likely involved in the ZnPP-induced suppression of beta-catenin expression. Whether there is cross-talk between the ubiquitin-proteasome system and the lysosome pathway that may account for ZnPP-induced beta-catenin protein degradation is currently unknown. These findings provide a novel mechanism of ZnPP's anticancer action and reveal a potential new strategy for targeting the beta-catenin Wnt signaling pathway for cancer therapy. PMID- 26000789 TI - Molecular Epidemiology of Clostridium difficile Infection in a Large Teaching Hospital in Thailand. AB - Clostridium difficile infection (CDI) is a leading cause of healthcare-associated morbidity and mortality worldwide. In Thailand, CDI exhibits low recurrence and mortality and its molecular epidemiology is unknown. CDI surveillance was conducted in a tertiary facility (Siriraj Hospital, Bangkok). A total of 53 toxigenic C. difficile strains from Thai patients were analyzed by multi-locus sequence typing (MLST), PCR ribotyping, and pulse-field gel electrophoresis (PFGE). The mean age of the cohort was 64 years and 62.3% were female; 37.7% of patients were exposed to > two antibiotics prior to a diagnosis of CDI, with beta lactams the most commonly used drug (56.3%). Metronidazole was used most commonly (77.5%; success rate 83.9%), and non-responders were treated with vancomycin (success rate 100%). None of the isolates carried binary toxin genes. Most isolates (98.2-100%) were susceptible to metronidazole, vancomycin, tigecycline and daptomycin. There were 11 sequence types (STs), 13 ribotypes (RTs) and four PFGE types. Six previously identified STs (ST12, ST13, ST14, ST33, ST41 and ST45) and five novel STs unique to Thailand (ST66, ST67, ST68, ST69 and ST70) were identified. PCR RTs UK 017 (ST45) (45.3%) and UK 014/020 (ST33) (24.5%) were the most common. High concordance was observed between the MLST and ribotyping results (p<0.001). C. difficile isolates from Thai patients were highly susceptible to standard antimicrobial agents. In conclusion, the five STs indicate the high genetic diversity and unique polymorphisms in Thailand. Moreover, the emergence of antimicrobial resistance to vancomycin warranted continuous surveillance to prevent further spread of the toxigenic C. difficile isolates. PMID- 26000790 TI - Impact of hot events at different developmental stages of a moth: the closer to adult stage, the less reproductive output. AB - Hot days in summer (involving a few hours at particularly high temperatures) are expected to become more common under climate change. How such events at different life stages affect survival and reproduction remains unclear in most organisms. Here, we investigated how an exposure to 40 degrees C at different life stages in the global insect pest, Plutella xylostella, affects immediate survival, subsequent survival and reproductive output. First-instar larvae showed the lowest survival under heat stress, whereas 3rd-instar larvae were relatively heat resistant. Heat exposure at the 1(st)-instar or egg stage did not influence subsequent maturation success, while exposure at the 3rd-instar larval stage did have an effect. We found that heat stress at developmental stages closer to adult stage caused greater detrimental effects on reproduction than heat stress experienced at earlier life stages. The effects of hot events on insect populations can therefore depend critically on the timing of the event relative to an organism's life-cycle. PMID- 26000791 TI - Within-range translocations and their consequences in European larch. AB - In contrast to biological invasions, translocations of individuals within a species range are understudied, due to difficulties in systematically detecting them. This results in limited knowledge about the corresponding processes and uncertainties regarding the status of extant populations. European larch, a forest tree whose fragmented native distribution is restricted to the Alps and to other Central European mountains, has been massively planted for at least 300 years. Here we focus on the genetic characterization of translocations having taken place within its native range. Microsatellite variation at 13 nuclear loci and sequence data of two mitochondrial DNA fragments were analyzed on the basis of a comprehensive range-wide population sample. Two complementary methods (Geneclass and Structure) were used to infer translocation events based on nuclear data whereas mitochondrial data were used for validation of these inferences. Using Geneclass, we found translocation events in a majority of populations. Additional cases of translocation and many instances of admixture were identified using Structure, thanks to the clear-cut ancestral genetic structure detected in this species. In particular, a strong divide between Alpine and Central European populations, also apparent at mitochondrial markers, helped uncover details on translocation events and related processes. Translocations and associated admixture events were found to be heterogeneously distributed across the species range, with a particularly high frequency in Central Europe. Furthermore, translocations frequently involved multiple geographic sources, some of which were over-represented. Our study illustrates the importance of range wide investigations for tracing translocations back to their origins and for revealing some of their consequences. It provides some first clues for developing suitable conservation and management strategies. PMID- 26000793 TI - Rare-earth-doped nanophosphors for multicolor cathodoluminescence nanobioimaging using scanning transmission electron microscopy. AB - We describe rare-earth-doped nanophosphors (RE-NPs) for biological imaging using cathodoluminescence(CL) microscopy based on scanning transmission electron microscopy (STEM). We report the first demonstration of multicolor CL nanobioimaging using STEM with nanophosphors. The CL spectra of the synthesized nanophosphors (Y2O3?Eu, Y2O3?Tb) were sufficiently narrow to be distinguished. From CL images of RE-NPs on an elastic carbon-coated copper grid, the spatial resolution was beyond the diffraction limit of light.Y2O3?Tb and Y2O3?Eu RE-NPs showed a remarkable resistance against electron beam exposure even at high acceleration voltage (80 kV) and retained a CL intensity of more than 97% compared with the initial intensity for 1 min. In biological CL imaging with STEM, heavy-metal-stained cell sections containing the RE-NPs were prepared,and both the CL images of RE-NPs and cellular structures, such as mitochondria, were clearly observed from STEM images with high contrast. The cellular CL imaging using RE-NPs also had high spatial resolution even though heavy-metal-stained cells are normally regarded as highly scattering media. Moreover, since theRE-NPs exhibit photoluminescence (PL) excited by UV light, they are useful for multimodal correlative imaging using CL and PL. PMID- 26000792 TI - Suitability of UK Biobank Retinal Images for Automatic Analysis of Morphometric Properties of the Vasculature. AB - PURPOSE: To assess the suitability of retinal images held in the UK Biobank--the largest retinal data repository in a prospective population-based cohort--for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease. METHODS: Non-mydriatic fundus images from both eyes of 2,690 participants--people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345)- were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry. RESULTS: Total operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001). CONCLUSIONS: A proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group. PMID- 26000794 TI - Optical coherence tomography system requirements for clinical diagnostic middle ear imaging. AB - Noninvasive middle ear imaging using optical coherence tomography (OCT) presents some unique challenges for real-time, clinical use in humans. We present results from a two-dimensional/three-dimensional OCT system built to assess the imaging requirements of clinical middle ear imaging, and the technical challenges associated with them. These include the need to work at a low numerical aperture, the deleterious effects of transtympanic imaging on image quality at the ossicles, sensitivity requirements for clinical fidelity of images at real-time rates, and the high dynamic-range requirements of the ear. We validated the system by imaging cadaveric specimens with simulated disorders to show the clinical applicability of the images. We also provide additional insight into the likely role of OCT in clinical otology. PMID- 26000795 TI - Optimization of image reconstruction for magnetic resonance imaging-guided near infrared diffuse optical spectroscopy in breast. AB - An optimized approach to nonlinear iterative reconstruction of magnetic resonance imaging (MRI)-guided near-infrared spectral tomography (NIRST) images was developed using an L-curve-based algorithm for the choice of regularization parameter. This approach was applied to clinical exam data to maximize the reconstructed values differentiating malignant and benign lesions. MRI/NIRST data from 25 patients with abnormal breast readings (BI-RADS category 4-5) were analyzed using this optimal regularization methodology, and the results showed enhanced p values and area under the curve (AUC) for the task of differentiating malignant from benign lesions. Of the four absorption parameters and two scatter parameters, the most significant differences for benign versus malignant were total hemoglobin (HbT) and tissue optical index (TOI) with p values = 0.01 and 0.001, and AUC values = 0.79 and 0.94, respectively, in terms of HbT and TOI. This dramatically improved the values relative to fixed regularization (p value = 0.02 and 0.003; AUC = 0.75 and 0.83) showing that more differentiation was possible with the optimal method. Through a combination of both biomarkers, HbT and TOI, the AUC increased from 82.9% (fixed regulation = 0.1) to 94.3% (optimal method). PMID- 26000796 TI - Surface modification of alignment layer by ultraviolet irradiation to dramatically improve the detection limit of liquid-crystal-based immunoassay for the cancer biomarker CA125. AB - Liquid crystal (LC)-based biosensing has attracted much attention in recent years. We focus on improving the detection limit of LC-based immunoassay techniques by surface modification of the surfactant alignment layer consisting of dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride (DMOAP). The cancer biomarker CA125 was detected with an array of anti-CA125 antibodies immobilized on the ultraviolet (UV)-modified DMOAP monolayer. Compared with a pristine counterpart, UV irradiation enhanced the binding affinity of the CA125 antibody and reproducibility of immunodetection in which a detection limit of 0.01 ng/ml for the cancer biomarker CA125 was achieved. Additionally, the optical texture observed under a crossed polarized microscope was correlated with the analyte concentration. In a proof-of-concept experiment using CA125-spiked human serum as the analyte, specific binding between the CA125 antigen and the anti CA125 antibody resulted in a distinct and concentration-dependent optical response despite the high background caused by nonspecific binding of other biomolecules in the human serum. Results from this study indicate that UVmodification of the alignment layer, as well as detection with LCs of large birefringence, contributes to the enhanced performance of the label-free LC-based immunodetection, which may be considered a promising alternative to conventional label-based methods. PMID- 26000797 TI - Comparison of three light doses in the photodynamic treatment of actinic keratosis using mathematical modeling. AB - Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for cancer therapy. Although high efficacy is demonstrated for PDT using standardized protocols in nonhyperkeratotic actinic keratoses, alternative light doses expected to increase efficiency, to reduce adverse effects or to expand the use of PDT, are still being evaluated and refined. We propose a comparison of the three most common light doses in the treatment of actinic keratosis with 5-aminolevulinic acid PDT through mathematical modeling. The proposed model is based on an iterative procedure that involves determination of the local fluence rate, updating of the local optical properties, and estimation of the local damage induced by the therapy. This model was applied on a simplified skin sample model including an actinic keratosis lesion, with three different light doses (red light dose, 37 J/cm2, 75 mW/cm2, 500 s; blue light dose, 10 J/cm2, 10 mW/cm2, 1000 s; and daylight dose, 9000 s). Results analysis shows that the three studied light doses, although all efficient, lead to variable local damage. Defining reference damage enables the nonoptimal parameters for the current light doses to be refined and the treatment to be more suitable. PMID- 26000798 TI - Self-driven filter-based blood plasma separator microfluidic chip for point-of care testing. AB - There is currently a growing need for lab-on-a-chip devices for use in clinical analysis and diagnostics, especially in the area of patient care. The first step in most blood assays is plasma extraction from whole blood. This paper presents a novel, self-driven blood plasma separation microfluidic chip, which can extract more than 0.1 MUl plasma from a single droplet of undiluted fresh human blood (~5 MUl). This volume of blood plasma is extracted from whole blood with high purity (more than 98%) in a reasonable time frame (3 to 5 min), and without the need for any external force. This would be the first step towards the realization of a single-use, self-blood test that does not require any external force or power source to deliver and analyze a fresh whole-blood sample, in contrast to the existing time-consuming conventional blood analysis. The prototypes are manufactured in polydimethylsiloxane that has been modified with a strong nonionic surfactant (Silwet L-77) to achieve hydrophilic behavior. The main advantage of this microfluidic chip design is the clogging delay in the filtration area, which results in an increased amount of extracted plasma (0.1 MUl). Moreover, the plasma can be collected in one or more 10 MUm-deep channels to facilitate the detection and readout of multiple blood assays. This high volume of extracted plasma is achieved thanks to a novel design that combines maximum pumping efficiency without disturbing the red blood cells' trajectory through the use of different hydrodynamic principles, such as a constriction effect and a symmetrical filtration mode. To demonstrate the microfluidic chip's functionality, we designed and fabricated a novel hybrid microdevice that exhibits the benefits of both microfluidics and lateral flow immunochromatographic tests. The performance of the presented hybrid microdevice is validated using rapid detection of thyroid stimulating hormone within a single droplet of whole blood. PMID- 26000800 TI - Bifunctional organocatalysts for the enantioselective synthesis of axially chiral isoquinoline N-oxides. AB - Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is the first example of highly enantioselective synthesis of axially chiral biaryls by bifunctional organocatalysts. Good-to-excellent enantioselectivities were obtained with a range of substrates. PMID- 26000799 TI - Re-examination of 30-day survival and relapse rates in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. AB - BACKGROUND AND OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are characterized by microangiopathic hemolytic anemia and thrombocytopenia. Interestingly, markedly different survival rates have been reported despite increases in survivability. We studied TTP-HUS 30-day mortality and relapse rates of patients who received TPE at our institution and compared them to published data. PATIENTS AND METHODS: Retrospective study analyzed 30-day mortality and relapse rates attributed to TTP-HUS from 01/01/2008 to 12/31/2012 and compared them to comparable literature reporting mortality and survival. Studies describing other etiologies for TPE and different mortality time interval were excluded. RESULTS: Fifty-nine patients were analyzed and all were initially treated with TPE and corticosteroids. Eleven patients were classified as not having TTP-HUS due to testing or clinical reassessment which ruled in other etiologies, and 18/59 patients had ADAMTS13 activity <10%. Of remaining patients, 36/48 (75%) were diagnosed as idiopathic and 12/48 (25%) as secondary TTP-HUS. Patients received a mean of 12 TPEs (range 1-42); 42/48 (87.5%) patients had ADAMTS13 activity measured; complete response obtained in 39/48 (81.2%) patients (platelet count >100 x 10(9)/L); partial response in 4/48 (8%); and 5/48 (10.4%) did not have increases in platelet counts (2/5 of these patients died within the study period). Forty percent of patients obtained platelet counts >150 x 10(9)/L. Overall 30-day mortality for our patient cohort was 6.7% (4/59). Comparison of our mortality rate to combined data of five published studies of 16% (92/571) showed a significant difference, p = 0.04. Our relapse rate was 18.6% (11/59) similar to previous reports. CONCLUSIONS: Wide differences in mortality may be due to grouping of two distinct pathologic entities under TTP-HUS; and presence of confounding factors in the patient populations under study such as co-morbidities, promptness of TPE initiation, delay in diagnosis and therapeutic practice. PMID- 26000801 TI - Spreading of an Oil-in-Water Emulsion on a Glass Plate: Phase Inversion and Pattern Formation. AB - Rigid blade coating of glass plates by oil-in-water emulsions stabilized by surfactants is studied. Complete surface coverage is obtained only for speeds exceeding a threshold velocity dependent on the height between the blade end and the surface. Below this threshold, the emulsion can be inverted in the vicinity of the blade. The inversion dynamics of the oil-in-water emulsion and the deposition patterns induced by this phase inversion are studied using a microscope mounted set up. We show that these dynamics are universal for different volume fractions and deposition velocities. This inversion as well as the destabilization of the emulsion film deposited at high speeds gives rise to different patterns on the glass surface. These patterns are discussed in terms of the emulsion characteristics as well as the deposition velocity. PMID- 26000802 TI - Role of Spin States in Nitric Oxide Binding to Cobalt(II) and Manganese(II) Porphyrins. Is Tighter Binding Always Stronger? AB - Binding of nitric oxide (NO) to metalloporphyrins and heme groups is important in biochemistry while challenging to describe accurately by density functional theory (DFT) calculations. Here, the structural and thermochemical aspect of NO binding to Co(II) and Mn(II) porphyrins is investigated by DFT and DFT-D (dispersion-corrected) calculations, supported by reliable coupled-cluster methodology (CCSD(T)), and critically correlated with the experimental data. It is argued that whereas the bonding of NO to Co(II) porphyrin is a simple radical recombination, the bonding of NO to Mn(II) porphyrin is accompanied by a crossing of spin states. For this reason, the spin-state conversion energy contributes to the Mn-NO bond energy, and the paradigmatic correlation between bond length and bond energy is violated for the considered nitrosyl complexes: the Mn-NO bond is (structurally) shorter by ~0.2 A, albeit (energetically) weaker by a few kcal/mol, compared with the Co-NO bond. Moreover, none of the many tested DFT methods can reproduce the Co-NO and Mn-NO bond energies simultaneously, except for calculations with B3LYP*-D3, TPSSh-D3, and M06-D3 methods supplemented with the proposed spin-state energy correction (to compensate for an error on the calculated spin-state conversion energy). The results of this study are important to appreciate the role of spin-state changes in ligand binding properties of heme related models. They also highlight the need for accurate calculations for correct interpretation of experimental data, including the qualitative structure energy relationship. PMID- 26000803 TI - Expedited CO2 respiration in people with Miltenberger erythrocyte phenotype GP.Mur. AB - In Southeast Asia, Miltenberger antigen subtype III (Mi.III; GP.Mur) is considered one of the most important red blood cell antigens in the field of transfusion medicine. Mi.III functions to promote erythrocyte band 3 expression and band 3-related HCO3(-) transport, with implications in blood CO2 metabolism. Could Mi.III affect physiologic CO2 respiration in its carriers? Here, we conducted a human trial to study the impacts of Mi.III expression in respiration. We recruited 188 healthy, adult subjects for blood typing, band 3 measurements, and respiratory tests before and after exercise. The 3-minute step exercise test forced the demand for CO2 dissipation to rise. We found that immediately following exercise, Mi.III + subjects exhaled CO2 at greater rates than Miltenberger-negative subjects. Respiration rates were also higher for Mi.III + subjects immediately after exercise. Blood gas tests further revealed distinct blood CO2 responses post-exercise between Mi.III and non-Mi.III. In contrast, from measurements of heart rates, blood O2 saturation and lactate, Mi.III phenotype was found to be independent of one's aerobic and anaerobic capacities. Thus, Mi.III expression supported physiologic CO2 respiration. Conceivably, Mi.III + people may have advantages in performing physically enduring activities. PMID- 26000804 TI - The use of MMSE and MoCA in patients with acute ischemic stroke in clinical. AB - BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are brief cognitive screening tools that have been developed for the screening of patients with Mild Cognitive Impairment. METHODS: A total of 105 patients were included in this study, aged 53-89 years, with acute ischemic stroke admitted to hospital and fell into two groups: stroke patients with cognitive impairment (SCI) and controls with no cognitive impairment (n-SCI). The patient's characteristics are collected and regression analyses were performed to predict cognitive impairments. We use MMSE and MoCA assessment as prognostic indices for cognitive impairments of patient's with stroke. OBJECTIVES: Our aim was to examine the effectiveness of the MMSE and MoCA in screening cognitive impairments. MAIN RESULTS: There were significant difference among the two groups in the prevalence of diabetes mellitus (p < 0.05) and intracranial atherosclerosis (p < 0.05). A linear regression determined that the age, diabetes, intracranial atherosclerosis predicted the cognitive impairments. The ROC results for MoCA with an AUC of 0.882 and the corresponding results for MMSE show a similar AUC of 0.839. CONCLUSION: Neuropsychological performance of stroke patients was influenced by biological and demographic variables: age, diabetes and intracranial atherosclerosis. The MoCA and MMSE are both reliable assessments for the diagnosis of cognitive impairment after stroke. PMID- 26000805 TI - Difference of injury of the corticospinal tract according to surgical or conservative treatment in patients with putaminal hemorrhage. AB - OBJECTIVE: We investigated difference of injury of the corticospinal tract (CST) according to surgical or conservative treatment in patients with putaminal hemorrhage (PH), using diffusion tensor tractography (DTT). METHODS: Forty-six patients with PH (hematoma volume on the brain CT: 20-40 ml) were recruited. Patients were classified as the surgical treatment group and the conservative treatment group. The hematoma volume on the initial brain CT (median 2 hours after onset; range 1-14 hours) and volumes of the hematoma, the total lesion and the peri-hematomal edema volume on the follow-up brain magnetic resonance imaging (MRI) (median 23.5 days after onset; range 12-46 days) were estimated. Diffusion tensor imaging was performed and we defined the injury of the CST in terms of the configuration or abnormal DTT parameters. RESULTS: In the conservative treatment group, the total lesion volume on the brain MRI was increased compared with the hematoma volume on the initial brain CT (p < 0.05). On brain MRI, the hematoma volume, peri-hematomal edema volume, and total lesion volume were larger in the conservative treatment group than in the surgical treatment group (p < 0.05). Twelve patients (60%) in the surgical treatment group and 24 patients (92%) in the conservative treatment group had injury of the CST. CONCLUSION: Injury of the CST was less prevalent in the surgical treatment group than in the conservative treatment group in patients with PH. Therefore, it appears that surgical treatment could be helpful in prevention of injury of the CST in patients with PH. PMID- 26000806 TI - Combining restricted diet with forced or voluntary exercises improves hippocampal BDNF and cognitive function in rats. AB - Dietary restriction (RDt) and exercise (Ex) enhances cognitive function due, at least in part, levels of neurotrophins such as brain-derived neurotrophic factor (BDNF). This study examined changes in BDNF levels and data acquisition and retention following every-other-day RDt alone, and combined with either voluntary wheel (VxRDt) or forced swimming Exs (FxRDt) in rats. Hippocampal BDNF was measured using ELISA while learning and memory formation were assessed with the radial arm water maze (RAWM) paradigm. After 6 weeks, VxRDt and FxRDt enhanced BDNF levels, and short- and long-term memories (p < 0.05). The magnitude of the increase in BDNF was significantly higher in VxRDt group than in other groups (p < 0.05). However, no differences were found in learning and memory formation between the Ex regiments (VxRDt versus FxRDt). Additionally, RDt alone neither modulated BDNF level nor enhanced learning and memory formation (p > 0.05). These results suggest more important role of Ex, as opposed to RDt, in enhancing learning and memory formation. In addition, VxRDt appears to be more potent in enhancing brain BDNF levels than FxRDt, when combined with RDt in rats. PMID- 26000807 TI - Role of BDNF Val66Met functional polymorphism in temporal lobe epilepsy. AB - Various studies suggested that brain-derived neurotrophic factor (BDNF) gene polymorphisms contributed to the development of many neurological disorders. However, whether BDNF Val66Met polymorphism is associated with epilepsy remains controversial. In our study, we tried to investigate the effects of this functional polymorphism on the occurrence of temporal lobe epilepsy (TLE) and its clinical phenotypes. Case-control studies were employed to study the association between BDNF Val66Met polymorphism and TLE, as well as its clinical phenotypes, and magnetic resonance imaging examinations and voxel-based morphometry analyses were carried out for further study. Our results showed that the frequency of Met allele was found to be lower in the TLE patients compared with the control subjects (43.9% vs. 48.6%, P = 0.012, OR = 1.21, 95% CI = 1.04-1.41), and the frequency of Met66 allele carriers in the TLE with hippocampal sclerosis was significantly lower than those non-carriers (20.5% vs. 29.1%, P = 0.040). However, we failed to find the difference between different genotypes and hippocampal asymmetry. Our findings suggested that BDNF Val66Met polymorphism might be correlated with epileptogenesis, and Met66 allele might play a protective role against the occurrence of TLE. PMID- 26000808 TI - Aldehyde dehydrogenase 2 polymorphism as a protective factor for intracranial vascular stenosis in ischemic stroke in Han Chinese. AB - AIM: Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that metabolizes acetaldehyde to acetic acid. ALDH2 gene polymorphism modifies its activity and the mutation of ALDH2 gene has been reported to be associated with the protection against ischemic stroke. However, the potential association of allelic variation of ALDH2 with intracranial vascular stenosis and the clinical characteristics of ischemic stroke without coronary artery disease remains unclear. METHODS: In this study, ischemic stroke patients were recruited, National Institutes of Health Stroke Scale scores were analyzed, intracranial arterial stenosis were evaluated by magnetic resonance angiography and gene typing of ALDH2 was determined by polymerase chain reaction and sequencing. RESULTS: We found that the rate of heavy drinking was significantly lower in the ALDH2 mutation group ((*)1/(*)2 and (*)2/(*)2) than in wild-type group ((*)1/(*)1) (18.6% vs. 38.0%, p = 0.01). Plasma homocysteine (Hcy) levels were significantly different in the two groups (15.45 +/- 6.39 vs. 13.14 +/- 4.45, p = 0.015). The ALDH2 mutation genotype was negatively correlated with severe intracranial vascular stenosis (OR, 0.34; p = 0.002), even after adjustment for high-density lipoprotein cholesterol, Hcy, and heavy drinking (adjusted OR, 0.44; p = 0.03). CONCLUSION: ALDH2(*)2 could be a protective factor and negative predictor for severe intracranial vascular stenosis in ischemic stroke in Han Chinese. PMID- 26000809 TI - Injury of the corticobulbar tract in patients with dysarthria following cerebral infarct: diffusion tensor tractography study. AB - OBJECTIVES: Little is known about injury of the corticobulbar tract (CBT) in stroke patients. We attempted to investigate injury of the CBT in patients with dysarthria following cerebral infarct, using diffusion tensor tractography (DTT). METHODS: Eight patients with dysarthria following a corona radiata infarct and 12 control subjects were recruited for this study. Diffusion tensor imaging was performed at 14.3 days after onset and reconstruction of the CBT was performed using the probabilistic tractography method. Fractional anisotropy, mean diffusivity, and tract volume of the CBT were measured. RESULTS: Reconstructed CBTs in the affected hemisphere of the patient group were thinner than those of the unaffected hemisphere of the patient group and the control group. Regarding the DTT parameters of the CBTs, fractional anisotropy and tract volume were significantly lower in the affected hemisphere of the patient group than in the unaffected hemisphere of the patient group and the control group (p < 0.05). However, we did not observe any difference in the mean diffusivity value (p > 0.05). CONCLUSIONS: We demonstrated injury of the CBT in patients with dysarthria following cerebral infarct in the corona radiata using DTT. This result indicates the importance of CBT evaluation for dysarthria in patients with cerebral infarct. Therefore, we suggest that evaluations of the CBT using DTT would be useful for patients with dysarthria following cerebral infarct. PMID- 26000810 TI - Botulinum toxin A in the treatment of trigeminal neuralgia. AB - AIMS: The aims of this study were to investigate the clinical effects and safety of botulinum toxin A (BTX-A) in treating trigeminal neuralgia and its influences on accompanied depression, anxiety, sleep disorders, and quality of life. METHODS AND MATERIAL: Eighty-seven patients with one-branch classical trigeminal neuralgia were injected with BTX-A in the pain area. The visual analogic scale score, sleep interference score, Hamilton Anxiety Scale score, Hamilton Depression Scale score, and side effects were assessed at 1 week prior to and 8 weeks after treatment, respectively. RESULTS: The effective rates after 1, 2, 4, and 8 weeks of treatment were 48.28%, 66.67%, 78.16%, and 80.46%, respectively. The effective rates of anxiety and depression were 90.32% and 96.77%, respectively. When compared to that before treatment, the quality of life was significantly better in terms of role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health (all P < 0.01), while physical function was not significantly improved (P = 0.317). CONCLUSION: BTX-A treatment can significantly relieve the pain in trigeminal neuralgia patients; improve anxiety, depression, and sleep; and increase the quality of life. BTX-A treatment is a safe and effective method to treat classical trigeminal neuralgia. PMID- 26000811 TI - Multimodal imaging evaluation of excessive daytime sleepiness in Parkinson's disease. AB - PURPOSE OF THE STUDY: The multimodal imaging investigation of excessive daytime sleepiness (EDS) in Parkinson's disease (PD). The role of dopaminergic treatment and other clinical parameters was also evaluated. MATERIALS AND METHODS: Seventeen non-demented PD patients with EDS (PD-EDS) and 17 PD patients without EDS were enrolled. Clinical, treatment and MRI data were acquired. Gray matter (GM) volume was examined with voxel-based morphometry, while white matter (WM) integrity was assessed with diffusion tensor imaging by means of fractional anisotropy, mean diffusivity, axial diffusivity (AD) and radial diffusivity measures. RESULTS: Increased regional GM volume was found in the PD-EDS group bilaterally in the hippocampus and parahippocampal gyri. Increased AD values were also shown in the PD-EDS group, in the left anterior thalamic radiation and the corticospinal tract and bilaterally in the superior corona radiata and the superior longitudinal fasciculus. Levodopa equivalent dose differed significantly between the groups and was the only predictor of EDS, while the only predictor of the Epworth sleepiness scale score in the PD-EDS group was the dopamine-agonist dose. Increased frequency of gamblers was also observed in the PD-EDS group. CONCLUSIONS: Regional GM increases and increased AD values in certain WM tracts were found in the PD-EDS group. The changes could result from disinhibited signaling pathways or represent compensatory changes in response to anatomical or functional deficits elsewhere. The study findings support also the contribution of the total dopaminergic load in the development of EDS, while the dose of dopamine agonists was found to predict the severity of the disorder. PMID- 26000812 TI - Long-term metabolic alterations in a febrile seizure model. AB - OBJECTIVE: Febrile seizures (FS) are the most common neurological disease in infancy and early childhood, it can lead to metabolic changes and have long-term health implications. Aim of this study was to investigate the long-term effects of FS on metabolism. METHODS: We measured certain metabolic parameters in hyperthermia-prone (HP) rats, which were developed using a selective breeding process and showed a lower seizure threshold than wild-type (WT) rats. Body weight, body length, abdominal circumference and the levels of fasting blood glucose, serum triglyceride, and total cholesterol concentrations were analyzed. The mRNA expression of genes involved in glucose and lipid metabolism was determined by qPCR and the histone methylation level in the liver was determined by western blot. RESULTS: We found that the body weight of the HP rats was significantly lower than that of the WT rats. Similarly, the fasting blood glucose and serum triglyceride levels were lower in the HP group compared with the WT group. These changes were accompanied by increased mRNA expression of genes such as phosphoenolpyruvate carboxykinase (PEPCK) and carnitine palmitoyl transferase-1 (CPT-1), but not peroxisome proliferator-activated receptor alpha (PPARalpha). We also found tri-methylation of histone 3 at Lys9 and Lys27 was decreased in the HP group. CONCLUSIONS: These data may suggest an underlying mechanism by which FS have a long-term effect on energy metabolism via histone methylation. PMID- 26000813 TI - Effects of simvastatin on the expression of inducible nitric oxide synthase and brain-derived neurotrophic factor in a lipopolysaccharide-induced rat model of Parkinson disease. AB - OBJECTIVE: To investigate the effects of simvastatin on the expression of inducible nitric oxide synthase (iNOS) and brain-derived neurotrophic factor (BDNF) in the substantia nigra in a lipopolysaccharide (LPS)-induced rat model of Parkinson disease (PD), and to study the mechanisms underlying the neuroprotective effects of simvastatin in PD. METHODS: The LPS-PD model was established by injection of LPS (5 mg/mL, 2.0 MUL) into the right substantia nigra compacta (SNC). Rats in the sham-operated group received saline. The simvastatin treatment group was intraperitoneally administered simvastatin (5 mg/kg, 2.0 MUL) at 1 h before, and daily for 14 days after surgery, while the sham-operated and LPS-model groups received saline. Iba-1-positive cells and tyrosine hydroxylase (TH), as well as iNOS and BDNF in the SNC were detected by immunohistochemistry and Western blotting, respectively. The effect of simvastatin in the PD model was also examined in behavioral tests. RESULTS: The LPS-model group exhibited typical animal PD behaviors. Compared with the control group, the LPS-model group exhibited a decreased number of DA neurons (p < 0.01) in the SNC, as well as increases in the Iba-1-positive cell number and iNOS expression (p < 0.05), while BDNF expression was downregulated (p < 0.01). These effects were inhibited by simvastatin treatment (p < 0.05). CONCLUSION: Simvastatin mediates a protective effect on dopaminergic neurons in the SNC in the LPS-PD model, possibly by promoting neuronal repair and regeneration, and by inhibiting oxidative stress, thus improving substantia nigra function. PMID- 26000814 TI - Mutations in the glucocerebrosidase gene are common in patients with Parkinson's disease from Eastern Canada. AB - BACKGROUND: Mutations in the beta-glucocerebrosidase gene (GBA) have been implicated as a risk factor for Parkinson's disease (PD). However, GBA mutations in PD patients of different ethnic origins were reported to be inconsistent. METHODS: We sequenced all exons of the GBA gene in 225 PD patients and 110 control individuals from Eastern Canada. RESULT: Two novel GBA variants of c.-119 A/G and S(-35)N, five known GBA mutations of R120W, N370S, L444P, RecNciI and RecTL mutation (del55/D409H/RecNciI) as well as two non-pathological variants of E326K and T369M were identified from PD patients while only one mutation of S13L and two non-pathological variants of E326K and T369M were found in the control individuals. The frequency of GBA mutations within PD patients (4.4%) is 4.8 times higher than the 0.91% observed in control individuals (X(2) = 2.91, p = 0.088; odds ratio = 4.835; 95% confidence interval = 2.524-9.123). The most common mutations of N370S and L444P accounted for 36.0% (9/25) of all the GBA mutations in this Eastern Canadian PD cohort. The frequency (6.67%) of E326K and T369M in PD patients is comparable to 7.27% in control individuals (X(2) = 0.042, p = 0.8376), further supporting that these two variants have no pathological effects on PD. Phenotype analysis showed that no significant difference in family history, age at onset and cognitive impairment was identified between the GBA mutation carriers and non-GBA mutation carriers. CONCLUSION: GBA mutations were found to be a common genetic risk factor for PD in Eastern Canadian patients. PMID- 26000815 TI - Neural overexpression of multidrug resistance-associated protein 1 and refractory epilepsy: a meta-analysis of nine studies. AB - OBJECTIVE: Overexpression of adenosine triphosphate-binding cassette (ATP-binding cassette (ABC)) transporters may contribute to intractable epilepsy (IE) by reducing brain accumulation of antiepileptic drugs (AEDs). We conducted a meta analysis of studies on expression and cellular distribution of multidrug resistance-associated protein 1 (MRP1) in IE patients to evaluate the contribution of this protein to AED resistance. In addition, we summarize experiments examining MRP1 expression and substrates in animal models of IE. METHODS: The literature search based on pre-established inclusion and exclusion criteria, as well as quality assessment, data extraction and statistical analyses were conducted concurrently by two independent researchers. We identified nine high-quality studies (Jadad score >=3) published between 2000 and 2014 on the expression and cellular distribution of MRP1 in IE patients. A fixed effect model was used to calculate pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). Forest and funnel plots were constructed to assess study heterogeneity and publication bias, respectively. RESULTS: MRP1 expression was significantly higher in both astrocytes (OR = 17.04, 95% CI: 7.69-37.76, P < 0.00001) and neurons (OR = 22.13, 95% CI: 8.52-57.46, P < 0.00001) of IE patients compared to controls, while there was no significant difference in endothelial cell MRP1 expression (OR: 1.47, 95% CI: 0.09-1.79, P = 0.48). Funnel plot symmetry indicated no substantial publication bias. Most relevant preclinical studies from 2000 to 2014 found higher MRP1 expression in IE model rodents. Furthermore, MRP1 overexpression reduced the extracellular concentration of AEDs in brain, while MRP1 inhibitors enhanced brain AED concentrations. CONCLUSION: Pooled results strongly suggest that MRP1 is overexpressed in both neurons and astrocytes of IE patients. Inhibition of MRP1 may enhance AED efficacy by increasing local drug availability. PMID- 26000816 TI - MicroRNAs and cell cycle of malignant glioma. AB - The control of malignant glioma cell cycle by microRNAs (miRNAs) is well established. The deregulation of miRNAs in glioma may contribute to tumor proliferation by directly targeting the critical cell-cycle regulators. Tumor suppressive miRNAs inhibit cell cycle through repressing the expression of positive cell-cycle regulators. However, oncogenic miRNAs promote the cell-cycle progression by targeting cell-cycle negative regulators. Recent studies have identified that transcription factors had involved in the expression of miRNAs. Transcription factors and miRNAs are implicated in regulatory network of glioma cell cycle, the deregulation of these transcription factors might be a cause of the deregulation of miRNAs. Abnormal versions of miRNAs have been implicated in the cell cycle of glioma. Based on those, miRNAs are excellent biomarker candidates and potential targets for therapeutic intervention in glioma. PMID- 26000817 TI - Association between angiotensin-converting enzyme insertion/deletion polymorphism and migraine: a meta-analysis. AB - BACKGROUND: Many studies investigated the association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and migraine, with controversial results. Thus, we performed a meta-analysis to better evaluate the correlation of this polymorphism and migraine. METHODS: We retrieved studies published up to September 2014 about the ACE gene polymorphism and migraine from electronic database. Pooled odds ratios (ORs) with 95% confidence interval (CI) were calculated to examine the strength of association between the ACE I/D polymorphism and migraine, using random-effects models. RESULTS: We identified 14 separate studies, in which 7334 migraineurs and 22 990 healthy controls were eligible for the meta-analysis. The results showed no relationship between the ACE I/D polymorphism and any migraine. Stratification revealed a protective effect in the Turkish population against migraine with aura for the II genotype model (II vs. DD: pooled OR = 0.366, 95% CI = 0.137-0.980; II vs. DI + DD: pooled OR = 0.370, 95% CI = 0.145-0.945). Similar results were obtained for Turkish people with migraine without aura (II vs. DD: pooled OR = 0.386; 95% CI = 0.166 0.900; II vs. DI + DD: pooled OR = 0.347; 95% CI = 0.156-0.773). CONCLUSIONS: The data suggest that the ACE II genotype could exert a protective effect against migraine with aura and without aura at least in the Turkish population. PMID- 26000818 TI - Oligodendrocytes and Alzheimer's disease. AB - Extensive evidence has indicated that the breakdown of myelin is associated with Alzheimer's disease (AD) since the vulnerability of oligodendrocytes under Alzheimer's pathology easily induces the myelin breakdown and the loss of the myelin sheath which might be the initiating step in the changes of the earliest stage of AD prior to appearance of amyloid and tau pathology. Considerable research implicated that beta-amyloid (Abeta)-mediated oligodendrocyte dysfunction and myelin breakdown may be via neuroinflammation, oxidative stress and/or apoptosis. It also seems that the oligodendrocyte dysfunction is triggered by the formation of neurofibrillary tangles (NFTs) through inflammation and oxidative stress as the common pathophysiological base. Impaired repair of oligodendrocyte precursor cells (OPCs) might possibly enhance the disease progress under decreased self-healing ability from aging process and pathological factors including Abeta pathology and/or NFTs. Thus, these results have suggested that targeting oligodendrocytes may be a novel therapeutic intervention for the prevention and treatment of AD. PMID- 26000819 TI - A meta-analysis on relationship of MAOB intron 13 polymorphisms, interactions with smoking/COMT H158L polymorphisms with the risk of PD. AB - BACKGROUND: To date, many studies have examined the correlation between Monoamine oxidase B (MAOB) intron 13 A/G polymorphisms and the susceptibility to Parkinson's disease (PD). However, the results of these studies are inconclusive. METHODS: In order to confirm this correlation, a meta-analysis of 15 studies was performed and the dichotomous data are presented as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Carriers of the MAOB intron 13 A allele were more likely to have PD than carriers of the G allele in the Asian population (OR = 1.182, 95% CI = 1.012-1.380, p < 0.05). When combined with the COMT LL genotype, the MAOB intron 13 AA/(A) genotype increased the risk of PD susceptibility more than with the GA genotype or GG + GA/(G) genotype (AA/(A) vs. GG + GA/(G): OR = 1.610, 95% CI = 1.094-2.369; AA/(A) vs. GA: OR = 1.621, 95% CI = 1.004-2.619). Irrespective of whether individuals were in the AA/(A) genotype or GG + GA/(G) genotype subgroup, this meta-analysis indicated that smoking was a PD-preventive factor (AA/(A): OR = 1.823, 95% CI = 1.150-2.891; GG + GA/(G): OR = 2.245, 95% CI = 1.277-3.948). CONCLUSION: The results of this meta-analysis suggest that people with the MAOB intron 13 A allele have an increased risk of PD in the Asian population, especially when combined with the COMT LL genotype. PMID- 26000820 TI - Ulinastatin decreases permeability of blood--brain barrier by inhibiting expression of MMP-9 and t-PA in postoperative aged rats. AB - Tissue-type plasminogen activator (t-PA) and matrix metalloproteinase-9 (MMP-9) have been reported to play important roles in increased permeability of blood brain barrier (BBB) under many pathological circumstances. We have showed that Ulinastatin, a broad-spectrum serine protease inhibitor, could alleviate inflammation in the hippocampus of aged rats following partial hepatectomy. In this study, we investigate the expression and potential roles of t-PA and MMP-9 in the protective effect of Ulinastatin. We found that partial hepatectomy increased Evans blue leakage in hippocampus at day 1 and 3 postoperatively. Furthermore, surgery decreased the protein levels of claudin-5, ZO-1, and NF-kB p65 while upregulating the mRNA and protein levels of t-PA and MMP-9 in brain capillaries. All these effects caused by surgery were partially reversed by administering Ulinastatin. Our study sheds light on the roles of t-PA and MMP-9 of BBB in post-surgical neuroinflammation and postoperative cognitive dysfunction. Besides, it could also help to understand the mechanism of Ulinastatin alleviating neuroinflammation. PMID- 26000821 TI - Neural injury by frontal approach of external ventricular drainage in stroke patients. AB - OBJECTIVES: No study on the characteristics of injury of neural tracts following external ventricular drainage (EVD) in a large number of consecutive patients following EVD has been reported. In this study, using diffusion tensor tractography (DTT), we attempted to investigate the characteristics of injury of neural tracts associated with EVD using a frontal approach in stroke patients. METHODS: We recruited 43 consecutive hemorrhagic stroke patients with a history of EVD using a frontal approach. Five neural tracts were reconstructed [corticospinal-tract (CST), corticoreticular-pathway (CRP), arcuate-fasciculus (AF), cingulum, and superior-longitudinal-fasciculus (SLF)]. RESULTS: Among five neural tracts, neural injury by EVD was observed on only two neural tracts (the CRP and the cingulum): CRP-seven (16.3%, five patients-partial tearing and two patients-complete discontinuation) of 43 patients and cingulum-eight (18.6%, eight patients-complete discontinuation of the anterior portion of the cingulum) of 43 patients. CONCLUSIONS: It appears that neural injury occurred in a considerable number of patients who underwent EVD; therefore, conduct of further studies on measures to prevent or minimize neural injury by EVD should be encouraged. PMID- 26000822 TI - Association between sex, systemic iron variation and probability of Parkinson's disease. AB - OBJECTIVE: Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD. MATERIALS AND METHODS: In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins. RESULTS: The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation. CONCLUSIONS: This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex. PMID- 26000823 TI - Therapeutic effects of lipo-prostaglandin E1 on angiogenesis and neurogenesis after ischemic stroke in rats. AB - Previous studies have demonstrated that prostaglandin E1 (PGE1) has a neuroprotective effect on cerebral ischemia. However, it remains unknown whether PGE1 promotes angiogenesis and neurogenesis after ischemic stroke. In this study, adult male Sprague-Dawley rats were subjected to permanently distal middle cerebral artery occlusion (MCAO). Rats were treated with lipo-prostaglandin E1(lipo-PGE1, 10 MUg/kg/d) or the same volume of 0.9% saline starting 24 hours after MCAO daily for 6 consecutive days. All rats were injected 5'-bromo-2' deoxyuridine (BrdU, 50 mg/kg) intraperitoneally every 12 hours for 3 consecutive days before being sacrificed. At 7 and 14 days after MCAO or sham-operation, rats were sacrificed. Post-stroke neurological outcome, infarction volume, angiogenesis and neurogenesis were evaluated. Treatment with lipo-PGE1 significantly increased the vascular density in the peri-infarct areas at 7 and 14 days after MCAO. The lipo-PGE1 treatment significantly enhanced the proliferation and migration of endogenous neural stem cells in the ipsilateral subventricular zone. The neural stem cells associated with blood vessels closely within a neurovascular niche in lipo-PGE1-treated rats after stroke. The lipo PGE1 treatment also significantly improved the neurological recovery after MCAO. These results indicate that treatment with lipo-PGE1 promotes post-stroke angiogenesis, neurogenesis and their interaction, which would contribute to neurological recovery after cerebral infarction. Our study provides novel experimental evidences for the neuroprotective roles of PGE1 in ischemic stroke. PMID- 26000824 TI - The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. AB - WDR45/WIPI4, encoding a WD40 repeat-containing PtdIns(3)P binding protein, is essential for the basal autophagy pathway. Mutations in WDR45 cause the neurodegenerative disease beta-propeller protein-associated neurodegeneration (BPAN), a subtype of NBIA. We generated CNS-specific Wdr45 knockout mice, which exhibit poor motor coordination, greatly impaired learning and memory, and extensive axon swelling with numerous axon spheroids. Autophagic flux is defective and SQSTM1 (sequestosome-1)/p62 and ubiquitin-positive protein aggregates accumulate in neurons and swollen axons. Nes-Wdr45(fl/Y) mice recapitulate some hallmarks of BPAN, including cognitive impairment and defective axonal homeostasis, providing a model for revealing the disease pathogenesis of BPAN and also for investigating the possible role of autophagy in axon maintenance. PMID- 26000825 TI - Antitumor and antimetastatic effects of pemetrexed-loaded targeted nanoparticles in B16 bearing mice. AB - Using nanoparticle delivery for anticancer therapy is a potential new drug modality. We developed a novel gelatinase-stimuli nanoparticle. In this study, we studied the antitumor and antimetastasis effect of pemetrexed-loaded targeted nanoparticles and evaluated the correlation between E-cadherin expression and lung metastasis in subcutaneous xenograft model. Compared with free pemetrexed, pemetrexed-loaded targeted nanoparticles exhibited the best antitumor and antimetastasis efficacy among the four therapeutic groups. The study also indicated that there was an inverse correlation between lung metastasis and E cadherin expression. These results showed pemetrexed-loaded targeted nanoparticles may be a potent drug for tumor therapy and our preclinical data could provide new direction for clinical therapy of malignant melanoma. PMID- 26000826 TI - Thermal Stabilization of Proteins by Mono- and Oligosaccharides: Measurement and Analysis in the Context of an Excluded Volume Model. AB - The reversible thermal denaturation of apo alpha-lactalbumin and lysozyme was monitored via measurement of changes in absorbance and ellipticity in the presence of varying concentrations of seven mono- and oligosaccharides: glucose, galactose, fructose, sucrose, trehalose, raffinose, and stachyose. The temperature dependence of the unfolding curves was quantitatively accounted for by a two-state model, according to which the free energy of unfolding is increased by an amount that is independent of temperature and depends linearly upon the concentration of added saccharide. The increment of added unfolding free energy per mole of added saccharide was found to depend approximately linearly upon the extent of oligomerization of the saccharide. The relative strength of stabilization of different saccharide oligomers could be accounted for by a simplified statistical-thermodynamic model attributing the stabilization effect to volume exclusion deriving from steric repulsion between protein and saccharide molecules. PMID- 26000827 TI - Continuing with "...a heavy heart" - consequences of maternal death in rural Kenya. AB - BACKGROUND: This study analyzes the consequences of maternal death to households in Western Kenya, specifically, neonatal and infant survival, childcare and schooling, disruption of daily household activities, the emotional burden on household members, and coping mechanisms. METHODS: The study is a combination of qualitative analysis with matched and unmatched quantitative analysis using surveillance and survey data. Between September 2011 and March 2013 all households in the study area with a maternal death were surveyed. Data were collected on the demographic characteristics of the deceased woman; household socio-economic status; a history of the pregnancy that led to the death; schooling experiences of surviving school-age children; and disruption to household functioning due to the maternal death. These data were supplemented by in-depth and focus group discussions. Quantitative data on neonatal and infant survival from a demographic surveillance system in the study area were also used. Descriptive and bivariate analyses were conducted with the quantitative data, and qualitative data were analyzed through text analysis using NVivo. RESULTS: More than three-quarters of deceased women performed most household tasks when healthy. After the maternal death, the responsibility for these tasks fell primarily on the deceased's husbands, mothers, and mothers-in-law. Two-thirds of the individuals from households that suffered a maternal death had to shift into another household. Most children had to move away, mostly to their grandmother's home. About 37% of live births to women who died of maternal causes survived till age 1 year, compared to 65% of live births to a matched sample of women who died of non-maternal causes and 93% of live births to surviving women. Older, surviving children missed school or did not have enough time for schoolwork, because of increased housework or because the loss of household income due to the maternal death meant school fees could not be paid. Respondents expressed grief, frustration, anger and a sense of loss. Generous family and community support during the funeral and mourning periods was followed by little support thereafter. CONCLUSION: The detrimental consequences of a maternal death ripple out from the woman's spouse and children to the entire household, and across generations. PMID- 26000828 TI - Epidemiology and genetic characterization of measles strains in Senegal, 2004 2013. AB - BACKGROUND: In Senegal, with the variable routine vaccination coverage, the risk for illness and death from measles still exists as evidenced by the measles epidemic episode in 2009. Since 2002 a laboratory-based surveillance system of measles was established by the Ministry of Health and the Institut Pasteur de Dakar. The present study analysed the data collected over the 10 years inclusive between 2004-2013 in order to define a measles epidemiological profile in Senegal, and we carried out a phylogenetic analysis of measles virus circulating in Senegal over the period 2009-2012. METHODOLOGY AND RESULTS: A total number of 4580 samples were collected from suspected cases, with the most cases between 2008 and 2010 (2219/4580; 48.4%). The majority of suspected cases are found in children from 4-6 years old (29%). 981 (21.4%) were measles laboratory-confirmed by IgM ELISA. The measles confirmation rate per year is very high during 2009 2010 periods (48.5% for each year). Regarding age groups, the highest measles IgM positivity rate occurred among persons aged over 15 years with 39.4% (115/292) followed by 2-3 years old age group with 30.4% (323/1062) and 30% (148/494) in children under one year old group. The majority of suspected cases were collected between February and June and paradoxically confirmed cases rates increased from July (77/270; 28.6%) and reached a peak in November with 60% (93/155). Phylogenetic analysis showed that all the 29 sequences from strains that circulated in Senegal between 2009 and 2012 belong to the B3 genotype and they are clustered in B3.1 (2011-2012) and B3.3 (2009-2011) sub-genotypes according to a temporal parameter. CONCLUSION: Improvements in the measles surveillance in Senegal are required and the introduction of oral fluid and FTA cards as an alternative to transportation of sera should be investigated to improve surveillance. The introduction of a national vaccine database including number of doses of measles-containing vaccine will greatly improve efforts to interrupt and ultimately eliminate measles virus transmission in Senegal. PMID- 26000829 TI - Adding content to contacts: measurement of high quality contacts for maternal and newborn health in Ethiopia, north east Nigeria, and Uttar Pradesh, India. AB - BACKGROUND: Families in high mortality settings need regular contact with high quality services, but existing population-based measurements of contacts do not reflect quality. To address this, in 2012, we designed linked household and frontline worker surveys for Gombe State, Nigeria, Ethiopia, and Uttar Pradesh, India. Using reported frequency and content of contacts, we present a method for estimating the population level coverage of high quality contacts. METHODS AND FINDINGS: Linked cluster-based household and frontline health worker surveys were performed. Interviews were conducted in 40, 80 and 80 clusters in Gombe, Ethiopia, and Uttar Pradesh, respectively, including 348, 533, and 604 eligible women and 20, 76, and 55 skilled birth attendants. High quality contacts were defined as contacts during which recommended set of processes for routine health care were met. In Gombe, 61% (95% confidence interval 50-72) of women had at least one antenatal contact, 22% (14-29) delivered with a skilled birth attendant, 7% (4-9) had a post-partum check and 4% (2-8) of newborns had a post natal check. Coverage of high quality contacts was reduced to 11% (6-16), 8% (5 11), 0%, and 0% respectively. In Ethiopia, 56% (49-63) had at least one antenatal contact, 15% (11-22) delivered with a skilled birth attendant, 3% (2-6) had a post-partum check and 4% (2-6) of newborns had a post-natal check. Coverage of high quality contacts was 4% (2-6), 4% (2-6), 0%, and 0%, respectively. In Uttar Pradesh 74% (69-79) had at least one antenatal contact, 76% (71-80) delivered with a skilled birth attendant, 54% (48-59) had a post-partum check and 19% (15 23) of newborns had a post-natal check. Coverage of high quality contacts was 6% (4-8), 4% (2-6), 0%, and 0% respectively. CONCLUSIONS: Measuring content of care to reflect the quality of contacts can reveal missed opportunities to deliver best possible health care. PMID- 26000830 TI - Efficacy of deferoxamine in animal models of intracerebral hemorrhage: a systematic review and stratified meta-analysis. AB - Intracerebral hemorrhage (ICH) is a subtype of stroke associated with high morbidity and mortality rates. No proven treatments are available for this condition. Iron-mediated free radical injury is associated with secondary damage following ICH. Deferoxamine (DFX), a ferric-iron chelator, is a candidate drug for the treatment of ICH. We performed a systematic review of studies involving the administration of DFX following ICH. In total, 20 studies were identified that described the efficacy of DFX in animal models of ICH and assessed changes in the brain water content, neurobehavioral score, or both. DFX reduced the brain water content by 85.7% in animal models of ICH (-0.86, 95% CI: -.48- -0.23; P < 0.01; 23 comparisons), and improved the neurobehavioral score by -1.08 (95% CI: 1.23- -0.92; P < 0.01; 62 comparisons). DFX was most efficacious when administered 2-4 h after ICH at a dose of 10-50 mg/kg depending on species, and this beneficial effect remained for up to 24 h postinjury. The efficacy was higher with phenobarbital anesthesia, intramuscular injection, and lysed erythrocyte infusion, and in Fischer 344 rats or aged animals. Overall, although DFX was found to be effective in experimental ICH, additional confirmation is needed due to possible publication bias, poor study quality, and the limited number of studies conducting clinical trials. PMID- 26000831 TI - ProteINSIDE to Easily Investigate Proteomics Data from Ruminants: Application to Mine Proteome of Adipose and Muscle Tissues in Bovine Foetuses. AB - Genomics experiments are widely acknowledged to produce a huge amount of data to be analysed. The challenge is to extract meaningful biological context for proteins or genes which is currently difficult because of the lack of an integrative workflow that hinders the efficiency and the robustness of data mining performed by biologists working on ruminants. Thus, we designed ProteINSIDE, a free web service (www.proteinside.org) that (I) provides an overview of the biological information stored in public databases or provided by annotations according to the Gene Ontology, (II) predicts proteins that are secreted to search for proteins that mediate signalisation between cells or tissues, and (III) analyses protein-protein interactions to identify proteins contributing to a process or to visualize functional pathways. Using lists of proteins or genes as a unique input, ProteINSIDE is an original all-in-one tool that merges data from these searches to present a fast overview and integrative analysis of genomic and proteomic data from Bovine, Ovine, Caprine, Human, Rat, and Murine species. ProteINSIDE was bench tested with 1000 proteins identifiers from each species by comparison with DAVID, BioMyn, AgBase, PrediSi, and Phobius. Compared to DAVID or BioMyn, identifications and annotations provided by ProteINSIDE were similar from monogastric proteins but more numerous and relevant for ruminants proteins. ProteINSIDE, thanks to SignalP, listed less proteins potentially secreted with a signal peptide than PrediSi and Phobius, in agreement with the low false positive rate of SignalP. In addition ProteINSIDE is the only resource that predicts proteins secreted by cellular processes that do not involve a signal peptide. Lastly, we reported the usefulness of ProteINSIDE to bring new biological hypotheses of research from proteomics data: the biological meaning of the uptake of adiponectin by the foetal muscle and a role for autophagy during ontogenesis of adipose and muscle tissues. PMID- 26000832 TI - Toward the Prediction of Water Exchange Rates in Magnetic Resonance Imaging Contrast Agents: A Density Functional Theory Study. AB - We present a theoretical investigation of Gd-Owater bonds in different complexes relevant as contrast agents in magnetic resonance imaging (MRI). The analysis of the Ln-Owater distances, electron density (rhoBCP), and electron localization function (ELF) at the bond critical points of [Ln(DOTA)(H2O)](-) and [Ln(DTPA BMA)(H2O)] indicates that the strength of the Ln-Owater bonds follows the order DTPA-BMA > DOTA (M isomer) > DOTA (m isomer). The ELF values decrease along the 4f period as the Ln-Owater bonds get shorter, in line with the labile capping bond phenomenon. Extension of these calculations to other Gd(3+) complexes allowed us to correlate the experimentally observed water exchange rates and the calculated rhoBCP and ELF values. The water exchange reaction becomes faster as the Gd-Owater bonds are weakened, which is reflected in longer bond distances and lower values of rhoBCP and ELF. DKH2 calculations show that the two coordinated water molecules may also have significantly different (17)O hyperfine coupling constants (HFCCs). PMID- 26000833 TI - Determining methane emissions from biogas plants--Operational and meteorological aspects. AB - A micrometeorological method, combining an inverse dispersion technique with path integrated concentration measurements, was applied on an Austrian biogas plant over the period of more than one year to determine emissions of the whole plant. Measurement campaigns were conducted to characterize the emission response to operational activities (e.g. digestate management) and meteorological changes. When digestate storage tanks were filled, an average emission rate of 7.2 kg CH4/h (approx. 4% of the calculated CH4 production) was determined, while 5.4 kg CH4/h of emissions (approx. 3% of the calculated CH4 production) were quantified after the tanks had been emptied. It could be observed that besides the operation mode (e.g. filling level or agitation of the openly stored digestate, maintenance), the meteorological conditions such as wind speed and solar radiation (e.g. heat flux) can also affect the emission rate. PMID- 26000834 TI - Hydrolysis of bamboo biomass by subcritical water treatment. AB - The aim of present study was to obtain total reducing sugars (TRS) from bamboo under subcritical water (SCW) treatment in a batch reactor at the temperature ranging from 170 degrees C to 220 degrees C and 40 min hydrolysis time. Experiments were performed to investigate the effects of temperature and time on TRS yield. The maximum TRS yield (42.21%) was obtained at lower temperature (180 degrees C), however longer reaction time (25 min). X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM) analysis were used to characterise treated and untreated bamboo samples. The XRD profile revealed that crystallinity of bamboo increased to 71.90% with increase in temperature up to 210 degrees C and decreased thereafter to 70.92%. The first-order reaction kinetic model was used to fit the experimental data to obtain rate constants. From the Arrhenius plot, activation energy and pre exponential factor at 25 min time were found to be 17.97 kJ mol(-1) and 0.154 min(-1), respectively. PMID- 26000835 TI - Catalytic pyrolysis of Alcea pallida stems in a fixed-bed reactor for production of liquid bio-fuels. AB - Pyrolysis of Alcea pallida stems was performed in a fixed-bed tubular reactor with and without catalyst at three different temperatures. The effects of pyrolysis parameters including temperature and catalyst on the product yields were investigated. It was found that higher temperature resulted in lower liquid (bio-oil) and solid (bio-char) yields and higher gas yields. Catalysts had different effects on product yields and composition of bio-oils. Liquid yields were increased in the presence of zinc chloride and alumina but decreased with calcium hydroxide, tincal and ulexite. The highest bio-oil yield (39.35%) by weight including aqueous phase was produced with alumina catalyst at 500 degrees C. The yields of bio-char, bio-oil and gas produced, as well as the compositions of the resulting bio-oils were determined by elemental analysis, TGA, FT-IR and GC-MS. 160 different compounds were identified by GC-MS in the bio-oils obtained at 500 degrees C. PMID- 26000836 TI - Agricultural residue valorization using a hydrothermal process for second generation bioethanol and oligosaccharides production. AB - In the present work, the hydrothermal valorization of an abundant agricultural residue has been studied in order to look for high added value applications by means of hydrothermal pretreatment followed by fed-batch simultaneous saccharification and fermentation, to obtain oligomers and sugars from autohydrolysis liquors and bioethanol from the solid phase. Non-isothermal autohydrolysis was applied to barley straw, leading to a solid phase with about a 90% of glucan and lignin and a liquid phase with up to 168 g kg(-1) raw material valuable hemicellulose-derived compounds. The solid phase showed a high enzymatic susceptibility (up to 95%). It was employed in the optimization study of the fed batch simultaneous saccharification and fermentation, carried out at high solids loading, led up to 52 g ethanol/L (6.5% v/v). PMID- 26000837 TI - Performance and enhanced mechanism of a novel bio-diatomite biofilm pretreatment process treating polluted raw water. AB - A lab-scale novel bio-diatomite biofilm process (BDBP) was established for the polluted raw water pretreatment in this study. Results showed that a shorter startup period of BDBP system was achieved under the completely circulated operation mode, and the removal efficiencies of nitrogen and disinfection by product precursor were effective at low hydraulic retention time of 2-4 h due to high biomass attached to the carrier and diatomite. A maximum NH4(+)-N oxidation potential predicted by modified Stover-Kincannon model was 333.3 mg L(-1) d(-1) in the BDBP system, which was 4.7 times of that in the control reactor. Results demonstrated that the present of bio-diatomite favors the accumulation of functional microbes in the oligotrophic niche, and the pollutants removal performance of this novel process was enhanced for polluted raw water pretreatment. PMID- 26000838 TI - Technology: fast forward. PMID- 26000839 TI - Toward Whole-Transcriptome Editing with CRISPR-Cas9. AB - Targeted regulation of gene expression holds huge promise for biomedical research. In a series of recent publications (Gilbert et al., 2014; Konermann et al., 2015; Zalatan et al., 2015), sophisticated, multiplex-compatible transcriptional activator systems based on the CRISPR-Cas9 technology and genome scale libraries advance the field toward whole-transcriptome control. PMID- 26000840 TI - Single-cell transcriptomics enters the age of mass production. AB - Two publications in the current issue of Cell introduce novel methods for high throughput single-cell transcriptomics by using droplet microfluidics and sophisticated barcoding schemes for transcriptional profiling of thousands of individual cells. PMID- 26000841 TI - Collateral DNA damage produced by genome-editing drones: exception or rule? AB - In the recent issue of Nature Biotechnology, Frock et al. (2015) developed an elegant technique to capture translocation partners that can be utilized to determine off-target regions of genome-editing endonucleases as well as endogenous mutators at nucleotide resolution. PMID- 26000842 TI - Expanding the Biologist's Toolkit with CRISPR-Cas9. AB - Few discoveries transform a discipline overnight, but biologists today can manipulate cells in ways never possible before, thanks to a peculiar form of prokaryotic adaptive immunity mediated by clustered regularly interspaced short palindromic repeats (CRISPR). From elegant studies that deciphered how these immune systems function in bacteria, researchers quickly uncovered the technological potential of Cas9, an RNA-guided DNA cleaving enzyme, for genome engineering. Here we highlight the recent explosion in visionary applications of CRISPR-Cas9 that promises to usher in a new era of biological understanding and control. PMID- 26000843 TI - Choosing the Right Tool for the Job: RNAi, TALEN, or CRISPR. AB - The most widely used approach for defining gene function is to reduce or completely disrupt its normal expression. For over a decade, RNAi has ruled the lab, offering a magic bullet to disrupt gene expression in many organisms. However, new biotechnological tools--specifically CRISPR-based technologies--have become available and are squeezing out RNAi dominance in mammalian cell studies. These seemingly competing technologies leave research investigators with the question: "Which technology should I use in my experiment?" This review offers a practical resource to compare and contrast these technologies, guiding the investigator when and where to use this fantastic array of powerful tools. PMID- 26000844 TI - High-throughput sequencing technologies. AB - The human genome sequence has profoundly altered our understanding of biology, human diversity, and disease. The path from the first draft sequence to our nascent era of personal genomes and genomic medicine has been made possible only because of the extraordinary advancements in DNA sequencing technologies over the past 10 years. Here, we discuss commonly used high-throughput sequencing platforms, the growing array of sequencing assays developed around them, as well as the challenges facing current sequencing platforms and their clinical application. PMID- 26000846 TI - The technology and biology of single-cell RNA sequencing. AB - The differences between individual cells can have profound functional consequences, in both unicellular and multicellular organisms. Recently developed single-cell mRNA-sequencing methods enable unbiased, high-throughput, and high resolution transcriptomic analysis of individual cells. This provides an additional dimension to transcriptomic information relative to traditional methods that profile bulk populations of cells. Already, single-cell RNA sequencing methods have revealed new biology in terms of the composition of tissues, the dynamics of transcription, and the regulatory relationships between genes. Rapid technological developments at the level of cell capture, phenotyping, molecular biology, and bioinformatics promise an exciting future with numerous biological and medical applications. PMID- 26000845 TI - Advances and applications of single-cell sequencing technologies. AB - Single-cell sequencing (SCS) has emerged as a powerful new set of technologies for studying rare cells and delineating complex populations. Over the past 5 years, SCS methods for DNA and RNA have had a broad impact on many diverse fields of biology, including microbiology, neurobiology, development, tissue mosaicism, immunology, and cancer research. In this review, we will discuss SCS technologies and applications, as well as translational applications in the clinic. PMID- 26000847 TI - Designing Cell-Type-Specific Genome-wide Experiments. AB - Multicellular organisms depend on cell-type-specific division of labor for survival. Specific cell types have their unique developmental program and respond differently to environmental challenges, yet are orchestrated by the same genetic blueprint. A key challenge in biology is thus to understand how genes are expressed in the right place, at the right time, and to the right level. Further, this exquisite control of gene expression is perturbed in many diseases. As a consequence, coordinated physiological responses to the environment are compromised. Recently, innovative tools have been developed that are able to capture genome-wide gene expression using cell-type-specific approaches. These novel techniques allow us to understand gene regulation in vivo with unprecedented resolution and give us mechanistic insights into how multicellular organisms adapt to changing environments. In this article, we discuss the considerations needed when designing your own cell-type-specific experiment from the isolation of your starting material through selecting the appropriate controls and validating the data. PMID- 26000848 TI - Molecular spies for bioimaging--fluorescent protein-based probes. AB - Convergent advances in optical imaging and genetic engineering have fueled the development of new technologies for biological visualization. Those technologies include genetically encoded indicators based on fluorescent proteins (FPs) for imaging ions, molecules, and enzymatic activities "to spy on cells," as phrased by Roger Tsien, by sneaking into specific tissues, cell types, or subcellular compartments, and reporting on specific intracellular activities. Here we review the current range of unimolecular indicators whose working principle is the conversion of a protein conformational change into a fluorescence signal. Many of the indicators have been developed from fluorescence resonance energy transfer- and single-FP-based approaches. PMID- 26000849 TI - Imaging live-cell dynamics and structure at the single-molecule level. AB - Observation of molecular processes inside living cells is fundamental to a quantitative understanding of how biological systems function. Specifically, decoding the complex behavior of single molecules enables us to measure kinetics, transport, and self-assembly at this fundamental level that is often veiled in ensemble experiments. In the past decade, rapid developments in fluorescence microscopy, fluorescence correlation spectroscopy, and fluorescent labeling techniques have enabled new experiments to investigate the robustness and stochasticity of diverse molecular mechanisms with high spatiotemporal resolution. This review discusses the concepts and strategies of structural and functional imaging in living cells at the single-molecule level with minimal perturbations to the specimen. PMID- 26000850 TI - Quantifying ubiquitin signaling. AB - Ubiquitin (UB)-driven signaling systems permeate biology, and are often integrated with other types of post-translational modifications (PTMs), including phosphorylation. Flux through such pathways is dictated by the fractional stoichiometry of distinct modifications and protein assemblies as well as the spatial organization of pathway components. Yet, we rarely understand the dynamics and stoichiometry of rate-limiting intermediates along a reaction trajectory. Here, we review how quantitative proteomic tools and enrichment strategies are being used to quantify UB-dependent signaling systems, and to integrate UB signaling with regulatory phosphorylation events, illustrated with the PINK1/PARKIN pathway. A key feature of ubiquitylation is that the identity of UB chain linkage types can control downstream processes. We also describe how proteomic and enzymological tools can be used to identify and quantify UB chain synthesis and linkage preferences. The emergence of sophisticated quantitative proteomic approaches will set a new standard for elucidating biochemical mechanisms of UB-driven signaling systems. PMID- 26000851 TI - Cryo-EM: A Unique Tool for the Visualization of Macromolecular Complexity. AB - 3D cryo-electron microscopy (cryo-EM) is an expanding structural biology technique that has recently undergone a quantum leap progression in its achievable resolution and its applicability to the study of challenging biological systems. Because crystallization is not required, only small amounts of sample are needed, and because images can be classified in a computer, the technique has the potential to deal with compositional and conformational mixtures. Therefore, cryo-EM can be used to investigate complete and fully functional macromolecular complexes in different functional states, providing a richness of biological insight. In this review, we underlie some of the principles behind the cryo-EM methodology of single particle analysis and discuss some recent results of its application to challenging systems of paramount biological importance. We place special emphasis on new methodological developments that are leading to an explosion of new studies, many of which are reaching resolutions that could only be dreamed of just a couple of years ago. PMID- 26000854 TI - SnapShot: Kinase Inhibitors I. AB - Selective small-molecule inhibitors of protein kinases can serve as powerful tools to elucidate biological function. Efforts to develop potential drug candidates have yielded a wealth of kinase inhibitors. However, selecting the optimal kinase inhibitor for a particular application can be challenging. While the optimal inhibitor will be application specific, we have attempted to summarize some of the best reported inhibitors for various kinases. PMID- 26000853 TI - Defining the metabolome: size, flux, and regulation. AB - Renewed interest in metabolic research over the last two decades has inspired an explosion of technological developments for studying metabolism. At the forefront of methodological innovation is an approach referred to as "untargeted" or "discovery" metabolomics. The experimental objective of this technique is to comprehensively measure the entire metabolome, which constitutes a largely undefined set of molecules. Given its potential comprehensive coverage, untargeted metabolomics is often the first choice of experiments for investigators pursuing a metabolic research question. It is important to recognize, however, that untargeted metabolomics may not always be the optimal experimental approach. Conventionally, untargeted metabolomics only provides information about relative differences in metabolite pool sizes. Therefore, depending on the specific scientific question at hand, a complementary approach involving stable isotopes (such as metabolic flux analysis) may be better suited to provide biological insights. Unlike untargeted metabolomics, stable-isotope methods can provide information about differences in reaction rates. PMID- 26000852 TI - The cancer cell map initiative: defining the hallmark networks of cancer. AB - Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these cancer cell maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. PMID- 26000855 TI - SnapShot: Kinase Inhibitors II. AB - Selective small-molecule inhibitors of protein kinases can serve as powerful tools to elucidate biological function. Efforts to develop potential drug candidates have yielded a wealth of kinase inhibitors. However, selecting the optimal kinase inhibitor for a particular application can be challenging. While the optimal inhibitor will be application specific, we have attempted to summarize some of the best reported inhibitors for various kinases. PMID- 26000856 TI - Effective coverage and systems effectiveness for malaria case management in sub Saharan African countries. AB - Scale-up of malaria preventive and control interventions over the last decade resulted in substantial declines in mortality and morbidity from the disease in sub-Saharan Africa and many other parts of the world. Sustaining these gains will depend on the health system performance. Treatment provides individual benefits by curing infection and preventing progression to severe disease as well as community-level benefits by reducing the infectious reservoir and averting emergence and spread of drug resistance. However many patients with malaria do not access care, providers do not comply with treatment guidelines, and hence, patients do not necessarily receive the correct regimen. Even when the correct regimen is administered some patients will not adhere and others will be treated with counterfeit or substandard medication leading to treatment failures and spread of drug resistance. We apply systems effectiveness concepts that explicitly consider implications of health system factors such as treatment seeking, provider compliance, adherence, and quality of medication to estimate treatment outcomes for malaria case management. We compile data for these indicators to derive estimates of effective coverage for 43 high-burden Sub Saharan African countries. Parameters are populated from the Demographic and Health Surveys and other published sources. We assess the relative importance of these factors on the level of effective coverage and consider variation in these health systems indicators across countries. Our findings suggest that effective coverage for malaria case management ranges from 8% to 72% in the region. Different factors account for health system inefficiencies in different countries. Significant losses in effectiveness of treatment are estimated in all countries. The patterns of inter-country variation suggest that these are system failures that are amenable to change. Identifying the reasons for the poor health system performance and intervening to tackle them become key priority areas for malaria control and elimination policies in the region. PMID- 26000858 TI - Analysis of HR-STEM theory for thin specimen. AB - A compact mathematical model of the STEM imaging process including bright field (BF) and dark field (DF) is derived. This description is valid for thin samples, does not rely on the weak phase approximation and does not require time-consuming simulation of the scanning process. It is well-known that STEM imaging is a nonlinear technique and therefore cannot be described in terms of a sample independent linear contrast transfer function (CTF). In this work we derive a nonlinear description showing that a STEM image can in fact be described with two terms. Both terms are cross-correlations between a function that is independent of the sample and a function that depends only on the sample. The latter two can be seen as two different objects. These objects directly correspond to two specific cases: the weak phase approximation (WPA) and annular dark field (ADF) imaging, which are known from the literature. We clarify the need for recognizing and understanding what the object is of any particular STEM technique. The model was validated using simulated STEM images and an excellent agreement as well as a reduction in computation time of 3 orders of magnitude was found. PMID- 26000857 TI - Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model. AB - In vitro disease modeling based on induced pluripotent stem cells (iPSCs) provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID), a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK) activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(D)J recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications. PMID- 26000859 TI - Sovereigns under Siege. How the medical profession is changing in Italy. AB - In this article, the concept of medical dominance is "unfolded" into four different components: 1) professional autonomy; 2) superiority over other healthcare professions; 3) influence on policy makers; 4) authority with respect to patients. These four components will serve to bring to surface the transformations which the medical profession in Italy is currently undergoing. Special emphasis is placed on the challenges that Italian physicians are facing and the strategies they are adopting to try to maintain their dominant position. Coming to conclusions, Italian physicians seem to retain their supremacy over other healthcare professions, and are particularly adept at controlling the legislative process on healthcare issues. Conversely, Italian physicians are losing their influence on patients (as evidenced by the growing number of allegations of malpractice) and complain that their professional autonomy is diminishing and their work has become far too bureaucratized. PMID- 26000860 TI - Simultaneous determination of icariin, naringin and osthole in rat plasma by UPLC MS/MS and its application for pharmacokinetic study after oral administration of Gushudan capsules. AB - A rapid, sensitive and selective ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of icariin, naringin and osthole in rat plasma. Plasma samples pretreatment involved a one-step liquid-liquid extraction with a mixture of ethyl acetate-methyl tert-butyl ether (3:1, nu/nu). The separation was performed on an ACQUITY UPLCTM BEH C18 column with a gradient mobile phase system of methanol and water. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) by multiple reactions monitoring (MRM), with the transitions at m/z 513.3->366.8 (icariin), m/z 579.3->150.9 (naringin), m/z 245.1->189.0 (osthole) and m/z 237.1->194.1 (IS), respectively. A good linear response was observed over the concentration ranges of 1.06-424ng/ml, 2.10-525ng/ml and 1.05-1.05*10(3)ng/ml with lower limit of quantification (LLOQ) of 1.06, 2.10 and 1.05ng/ml for icariin, naringin and osthole, respectively. The intra- and inter-day precisions (R.S.D.) were within 14.3%, and the accuracy (R.E.) ranged from -4.1% to 4.6% at three quality control levels. The sensitive and selective method was applied to a pharmacokinetic study of icarrin, naringin and osthole in rats after oral administration of Gushudan capsule. PMID- 26000861 TI - Prediction of fetal lung maturity using the lecithin/sphingomyelin (L/S) ratio analysis with a simplified sample preparation, using a commercial microtip-column combined with mass spectrometric analysis. AB - Fetal lung maturity is estimated using the lecithin/sphingomyelin ratio (L/S ratio) in amniotic fluid and it is commonly measured with thin-layer chromatography (TLC). The TLC method is time consuming and technically difficult; however, it is widely used because there is no alternative. We evaluated a novel method for measuring the L/S ratio, which involves a tip-column with a cation exchange resin and mass spectrometry. Phospholipids in the amniotic fluid were extracted using methanol and chloroform. Choline-containing phospholipids such as lecithin and sphingomyelin were purified by passing them through the tip-column. LC-MS/MS and MALDI-TOF were used to directly analyze the purified samples. The L/S ratio by mass spectrometry was calculated from the sum peak intensity of the six lecithin, and that of sphingomyelin 34:1. In 20 samples, the L/S ratio determined with TLC was significantly correlated with that obtained by LC-MS/MS and MALDI-TOF. There was a 100% concordance between the L/S ratio by TLC and that by LC-MS/MS (kappa value=1.0). The concordance between the L/S ratio by TLC and that by MALDI-TOF was also 100% (kappa value=1.0). Our method provides a faster, simpler, and more reliable assessment of fetal lung maturity. The L/S ratio measured by LC-MS/MS and MALDI-TOF offers a compelling alternative method to traditional TLC. PMID- 26000862 TI - Control of relative timing and stoichiometry by a master regulator. AB - Developmental processes in cells require a series of complex steps. Often only a single master regulator activates genes in these different steps. This poses several challenges: some targets need to be ordered temporally, while co functional targets may need to be synchronized in both time and expression level. Here we study in single cells the dynamic activation patterns of early meiosis genes in budding yeast, targets of the meiosis master regulator Ime1. We quantify the individual roles of the promoter and protein levels in expression pattern control, as well as the roles of individual promoter elements. We find a consistent expression pattern difference between a non-cofunctional pair of genes, and a highly synchronized activation of a co-functional pair. We show that dynamic control leading to these patterns is distributed between promoter, gene and external regions. Through specific reciprocal changes to the promoters of pairs of genes, we show that different genes can use different promoter elements to reach near identical activation patterns. PMID- 26000863 TI - Alkyl-imidazolium glycosides: non-ionic-cationic hybrid surfactants from renewable resources. AB - A series of surfactants combining carbohydrate and imidazolium head groups were prepared and investigated on their assembly behavior. The presence of the imidazolium group dominated the interactions of the surfactants, leading to high CMCs and large molecular surface areas, reflected in curved rather than lamellar surfactant assemblies. The carbohydrate, on the other hand, stabilized molecular assemblies slightly and reduced the surface tension of surfactant solutions considerably. A comparative emulsion study discourages the use of pure alkyl imidazolium glycosides owing to reduced assembly stabilities compared with APGs. However, the surfactants are believed to have potential as component in carbohydrate based surfactant mixtures. PMID- 26000864 TI - Sugar transport across the plant vacuolar membrane: nature and regulation of carrier proteins. AB - The ability of higher plants to store sugars is of crucial importance for plant development, adaption to endogenous or environmental cues and for the economic value of crop species. Sugar storage and accumulation, and its homeostasis in plant cells are managed by the vacuole. Although transport of sugars across the vacuolar membrane has been monitored for about four decades, the molecular entities of the transporters involved have been identified in the last 10 years only. Thus, it is just recently that our pictures of the transporters that channel the sugar load across the tonoplast have gained real shape. Here we describe the molecular nature and regulation of an important group of tonoplast sugar transporter (TST) allowing accumulation of sugars against large concentration gradients. In addition, we report on proton-driven tonoplast sugar exporters and on facilitators, which are also involved in balancing cytosolic and vacuolar sugar levels. PMID- 26000865 TI - Synergistic Effect of S224P and N383D Substitutions in the PA of H5N1 Avian Influenza Virus Contributes to Mammalian Adaptation. AB - The adaptation of H5N1 avian influenza viruses to human poses a great threat to public health. Previous studies indicate the adaptive mutations in viral polymerase of avian influenza viruses are major contributors in overcoming the host species barrier, with the majority of mammalian adaptive mutations occurring in the PB2 protein. However, the adaptive mutations in the PA protein of the H5N1 avian influenza virus are less defined and poorly understood. In this study, we identified the synergistic effect of the PA/224P + 383D of H5N1 avian influenza viruses and its ability to enhance the pathogenicity and viral replication in a mammalian mouse model. Interestingly, the signature of PA/224P + 383D mainly exists in mammalian isolates of the H5N1 influenza virus and pdmH1N1 influenza virus, providing a potential pathway for the natural adaptation to mammals which imply the effects of natural adaptation to mammals. Notably, the mutation of PA/383D, which is highly conserved in avian influenza viruses, increases the polymerase activity in both avian and human cells, and may have roles in maintaining the avian influenza virus in their avian reservoirs, and jumping species to infect humans. PMID- 26000866 TI - Bladder function in obstructed men - does age matter? AB - AIM: The high prevalence of diseases and disabilities in the elderly will therefore impose major future challenges for governments, particularly in social security, health system and social care. METHODS: Nine hundred and seventy-one men, 40 years or older referred for low urinary tract symptoms (LUTS) evaluation who underwent full urodynamic investigation, were reviewed. Urodynamic parameters were obtained, such as Uroflowmetry, those of Filling Cystometry and those of pressure flow study (PFS). RESULTS: Mean age was of 66.1 years old. Most the patients included in the analysis were categorized as Schafer score 2-4. Correlation analysis of uroflowmetry parameters revealed statistically significant decrease in voided volume (p = 0.013), Qmax (p = 0.023) with aging. Cystometric parameters revealed significant age-related decrease in bladder capacity (p < 0.001) and bladder compliance (p = 0.004). PFS revealed significant decrease in voiding efficiency (p = 0.029), voided volume (p < 0.001), Qave (p = 0.008) and Qmax (p = 0.048) with progressing age. Age subgroup analyses showed significant differences in voiding efficiency (KW, p = 0.032), voided volume (KW, p < 0.001) and Qave (KW, p = 0.036). CONCLUSIONS: Age-related changes in voiding function might not be a result of impaired detrusor contractility or increased outflow obstruction, intrinsic causes must be suspected. Changes in the storage function of the bladder represent specific pathophysiological mechanisms influenced by aging. PMID- 26000867 TI - A pi-electronic covalent organic framework catalyst: pi-walls as catalytic beds for Diels-Alder reactions under ambient conditions. AB - We report a strategy for developing pi-electronic covalent organic frameworks as heterogeneous catalysts that enable the use of columnar pi-walls as catalytic beds to facilitate organic transformations in their one-dimensional open channels. The pi-frameworks exhibit outstanding catalytic activity, promote Diels Alder reactions under ambient conditions and are robust for cycle use. PMID- 26000868 TI - Comparison of PELDOR and RIDME for Distance Measurements between Nitroxides and Low-Spin Fe(III) Ions. AB - EPR-based nanometre distance measurements are becoming ever more important in structural biology. Usually the distance constraints are measured between two nitroxide spin labels. Yet, distance measurements between a metal center and spin labels enable, e.g., the localization of metal ions within the tertiary fold of biomolecules. Therefore, it is important to find methods that provide such distance information quickly, with high precision and reliability. In the present study, two methods, pulsed electron-electron double resonance (PELDOR) and relaxation-induced dipolar modulation enhancement (RIDME), are compared on the heme-containing and spin-labeled cytochrome P450cam. Special emphasis is put on the optimization of the dead-time free RIDME experiment and several ways of data analysis. It turned out that RIDME appears to be better suited for distance measurements involving metal ions like low-spin Fe(3+) than PELDOR. PMID- 26000869 TI - Oxalyl chloride as a practical carbon monoxide source for carbonylation reactions. AB - A method for generation of high-quality carbon monoxide by decomposition of oxalyl chloride in an aqueous hydroxide solution is described. The usefulness of the method is demonstrated in the synthesis of heterocycles and for hydroxy-, alkoxy-, amino-, and reductive carbonylation reactions, in several cases under milder conditions than previously reported. PMID- 26000870 TI - Genome evolution of intermediate wheatgrass as revealed by EST-SSR markers developed from its three progenitor diploid species. AB - Intermediate wheatgrass (Thinopyrum intermedium (Host) Barkworth & D.R. Dewey), a segmental autoallohexaploid (2n = 6x = 42), is not only an important forage crop but also a valuable gene reservoir for wheat (Triticum aestivum L.) improvement. Throughout the scientific literature, there continues to be disagreement as to the origin of the different genomes in intermediate wheatgrass. Genotypic data obtained from newly developed EST-SSR primers derived from the putative progenitor diploid species Pseudoroegneria spicata (Pursh) A. Love (St genome), Thinopyrum bessarabicum (Savul. & Rayss) A. Love (J = J(b) = E(b)), and Thinopyrum elongatum (Host) D. Dewey (E = J(e) = E(e)) indicate that the V genome of Dasypyrum (Coss. & Durieu) T. Durand is not one of the three genomes in intermediate wheatgrass. Based on all available information in the literature and findings in this study, the genomic designation of intermediate wheatgrass should be changed to J(vs)J(r)St, where J(vs) and J(r) represent ancestral genomes of present-day J(b) of Th. bessarabicum and J(e) of Th. elongatum, with J(vs) being more ancient. Furthermore, the information suggests that the St genome in intermediate wheatgrass is most similar to the present-day St found in diploid species of Pseudoroegneria from Eurasia. PMID- 26000872 TI - Natural products in soil microbe interactions and evolution. AB - In recent years, bacterial interspecies interactions mediated by small molecule natural products have been found to give rise to a surprising array of phenotypes in soil-dwelling bacteria, especially among Streptomyces and Bacillus species. This review examines these interspecies interactions, and the natural products involved, as they have been presented in literature stemming from four disciplines: soil science, interspecies microbiology, ecology, and evolutionary biology. We also consider how these interactions fit into accepted paradigms of signaling, cueing, and coercion. PMID- 26000871 TI - Influence of immigration on prematurity in the context of a free healthcare system with universal coverage. AB - We assessed the risk of preterm birth according to the mother's place of origin in the context of a free and universal healthcare system. We analysed 75,292 newborn infants born between 2008-2011 in Alicante (Spain). The outcomes were: 1) very preterm (gestational age <= 32 weeks) and 2) moderate-to-late preterm (gestational age 33-37 weeks). Other variables: infant's gender, maternal age and origin. We estimated adjusted odds ratios to analyse the relationship between the outcomes and the other variables. The distribution of the gestational age groups in our sample was: very preterm, 812; moderate-to-late preterm, 5,295; full-term, 69,997. There were no statistically significant differences between the mother's place of origin and the outcomes in this free universal healthcare system, which is experiencing the recent phenomenon of immigration. This equality should be maintained throughout the time the immigrants remain in the country. PMID- 26000873 TI - Reactions of the methylsulfinyl radical [CH3(O)S] with oxygen ((3)O2) in solid argon. AB - The atmospherically highly relevant methylsulfinyl radical (CH3(O)S) readily reacts with molecular triplet oxygen in cryogenic argon matrices containing small amounts of (3)O2. Comparison of experimental and computed IR- and UV/Vis spectra, including isotope exchange, show that the initially formed (3)O2 adduct has the structure of a peroxyl radical (CH3(O)SOO), which upon irradiation with UV light isomerizes to the methylsulfonoxyl radical (CH3SO3). The latter transforms into the methansulfonic acid radical (CH2SO3H) by irradiation with visible light. During the matrix photolysis small amounts of SO3 and the methyl radical were detected indicating competitive direct photodissociation. PMID- 26000874 TI - Lung cancer, pulmonary emphysema and pleural effusion: An autopsy study. AB - OBJECTIVES: To determine the exact incidence of lung cancer, pulmonary emphysema and pleural effusion we decided to carry out an autopsy study. METHODS: In this autopsy study carried out over two years, we compared the results of autopsy findings with the clinical data in accompanying records of the deceased. RESULTS: Among the 708 deceased subjects, there were 398 males and 310 females with a median age of 71 years. At autopsy, 55 cases of lung carcinoma (BCA) were found, of which 24 have not been identified during life (44%). Among the deceased with BCA, emphysema was also observed at autopsy in 40% of the cases. Pulmonary emphysema was described macroscopically in 28% of the full set of 708 deceased, whereas the accompanying records of the deceased described this condition in only 12% of the cases. Microscopic changes compatible with emphysema were identified in 54% of the examined lungs. Pleural effusions were described in the accompanying records of 13% of the deceased, while the autopsies showed this condition in 33% of the deceased. BCA was accompanied by effusion in 25% of the cases. CONCLUSIONS: The obtained results show that the studied conditions are present in more cases than are reported by clinicians. The study confirms the commonly accepted association between lung cancer and emphysema. PMID- 26000875 TI - A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot-Marie-Tooth type 2D in a Chinese family. AB - OBJECTIVE: To explore the clinical features of a novel glycyl-tRNA synthetase (GARS) gene mutation in a family with Charcot-Marie-Tooth disease type 2D (CMT2D). METHODS: Exome capture with the next-generation sequencing technique was used to detect gene mutations. The mutations were verified by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique combined with DNA sequencing. RESULTS: In this pedigree, eight members were affected; seven males and one female. The affected members initially manifested with the onset of hand muscle weakness and atrophy in adolescence followed by gradual development of distal lower limb involvement and minor sensory involvement. Electrophysiological studies revealed that this disease mainly involves axonal damage. Genetic detection showed that all affected family members had a heterozygous missense mutation, c.999G>T (p.E333D), of the GARS gene. CONCLUSIONS: The c.999G>T mutation is a novel mutation of the GARS gene that has not been previously reported. The phenotype of this family is CMT2D, which is first reported in Chinese population. PMID- 26000876 TI - Mechanism of Photochemical O-Atom Exchange in Nitrosamines with Molecular Oxygen. AB - The detection of an oxygen-atom photoexchange process of N-nitrosamines is reported. The photolysis of four nitrosamines (N-nitrosodiphenylamine 1, N nitroso-N-methylaniline 2, N-butyl-N-(4-hydroxybutyl)nitrosamine 3, and N nitrosodiethylamine 4) with ultraviolet light was examined in an (18)O2-enriched atmosphere in solution. HPLC/MS and HPLC-MS/MS data show that (18)O-labeled nitrosamines were generated for 1 and 2. In contrast, nitrosamines 3 and 4 do not exchange the (18)O label and instead decomposed to amines and/or imines under the conditions. For 1 and 2, the (18)O atom was found not to be introduced by moisture or by singlet oxygen [(18)((1)O2 (1)Deltag)] produced thermally by (18)O (18)O labeled endoperoxide of N,N'-di(2,3-hydroxypropyl)-1,4-naphthalene dipropanamide (DHPN(18)O2) or by visible-light sensitization. A density functional theory study of the structures and energetics of peroxy intermediates arising from reaction of nitrosamines with O2 is also presented. A reversible head-to-tail dimerization of the O-nitrooxide to the 1,2,3,5,6,7-hexaoxadiazocane (30 kcal/mol barrier) with extrusion of O?(18)O accounts for exchange of the oxygen atom label. The unimolecular cyclization of O-nitrooxide to 1,2,3,4 trioxazetidine (46 kcal/mol barrier) followed by a retro [2 + 2] reaction is an alternative, but higher energy process. Both pathways would require the photoexcitation of the nitrooxide. PMID- 26000877 TI - A comparison study of aliphatic and aromatic structure directing agents influencing the crystal and electronic structures, and properties of iodoplumbate hybrids: water induced structure conversion and visible light photocatalytic properties. AB - The introduction of the aliphatic amines en (ethylenediamine), aep (N-(2 aminoethyl)piperazine) and tepa (tetraethylenepentamine), and the aromatic species 2,2'-bipy (2,2'-bipyridine) and dpe (1,2-di(4-pyridyl)ethylene) as structure directing agents (SDAs) into inorganic iodoplumbates affords six hybrids, namely [(Hen)4(H2.5O)2I](PbI6) (1), Cs2n[Pb3I8(en)2]n (2), (H3tepa)n(PbI5)n (3), (H2aep)n(PbI4)n (4), (Et22,2'-bipy)n(Pb2I6)n (5) and (Et2dpe)n(Pb2I6)n (6). 1 contains a discrete octahedral (PbI6)(4-) anion generated under the direction of a novel co-template, [(Hen)4(H2.5O)2I](4+). 2 contains inorganic Cs(+) ions and a novel hybrid anionic layer [Pb3I8(en)2]n(2n-) that has never been encountered in iodoplumbate hybrids. 3 features a zigzag (PbI5)(3-) chain with the charge being compensated by a triprotonated tepa cation. 4 is composed of perovskite sheets of lead(ii) octahedra and aep cations that are generated from tepa via an unprecedented in situ ligand reaction. Both 5 and 6 have (Pb2I6)n(2n-) chains and represent the first example of introducing a 2,2'-bipy or dpe derivative cation in iodoplumbate hybrids, respectively. The comparative study reveals that aliphatic amines and aromatic species contribute differently to the crystal and electronic structures, and the properties of the hybrids. Importantly, 1-4 exhibit interesting water induced structure conversions, while 5 and 6 can be used as heterogeneous photocatalysts for dye wastewater treatment under visible light irradiation. PMID- 26000878 TI - Fractionated Ionizing Radiation Promotes Epithelial-Mesenchymal Transition in Human Esophageal Cancer Cells through PTEN Deficiency-Mediated Akt Activation. AB - In some esophageal cancer patients, radiotherapy may not prevent distant metastasis thus resulting in poor survival. The underlying mechanism of metastasis in these patients is not well established. In this study, we have demonstrated that ionizing radiation may induce epithelial-mesenchymal transition (EMT) accompanied with increased cell migration and invasion, through downregulation of phosphatase and tensin homolog (PTEN), and activation of Akt/GSK-3beta/Snail signaling. We developed a radioresistant (RR) esophageal squamous cancer cell line, KYSE-150/RR, by fractionated ionizing radiation (IR) treatment, and confirmed its radioresistance using a clonogenic survival assay. We found that the KYSE-150/RR cell line displayed typical morphological and molecular characteristics of EMT. In comparison to the parental cells, KYSE 150/RR cells showed an increase in post-IR colony survival, migration, and invasiveness. Furthermore, a decrease in PTEN in KYSE-150/RR cells was observed. We postulated that over-expression of PTEN may induce mesenchymal-epithelial transition in KYSE-150/RR cells and restore IR-induced increase of cell migration. Mechanistically, fractionated IR inhibits expression of PTEN, which leads to activation of Akt/GSK-3beta signaling and is associated with the elevated levels of Snail protein, a transcription factor involved in EMT. Correspondingly, treatment with LY294002, a phosphatidylinositol-3-kinase inhibitor, mimicked PTEN overexpression effect in KYSE-150/RR cells, further suggesting a role for the Akt/GSK-3beta/Snail signaling in effects mediated through PTEN. Together, these results strongly suggest that fractionated IR mediated EMT in KYSE-150/RR cells is through PTEN-dependent pathways, highlighting a direct proinvasive effect of radiation treatment on tumor cells. PMID- 26000880 TI - Two new illudin type sesquiterpenoids from cultures of Phellinus tuberculosus and Laetiporus sulphureus. AB - Chemical investigation on the cultures of Phellinus tuberculosus and Laetiporus sulphureus lead to the isolation of two new illudin-type sesquiterpenoids (phellinuin J and sulphureuine A). Their structures were elucidated by 1D, 2D NMR and MS spectroscopic data. These compounds were purposely evaluated for their cytotoxicity against HL-60, SMMC-7721, A549, MCF-7, and SW480 cell lines. PMID- 26000879 TI - Female adolescents with severe substance and conduct problems have substantially less brain gray matter volume. AB - OBJECTIVE: Structural neuroimaging studies have demonstrated lower regional gray matter volume in adolescents with severe substance and conduct problems. These research studies, including ours, have generally focused on male-only or mixed sex samples of adolescents with conduct and/or substance problems. Here we compare gray matter volume between female adolescents with severe substance and conduct problems and female healthy controls of similar ages. HYPOTHESES: Female adolescents with severe substance and conduct problems will show significantly less gray matter volume in frontal regions critical to inhibition (i.e. dorsolateral prefrontal cortex and ventrolateral prefrontal cortex), conflict processing (i.e., anterior cingulate), valuation of expected outcomes (i.e., medial orbitofrontal cortex) and the dopamine reward system (i.e. striatum). METHODS: We conducted whole-brain voxel-based morphometric comparison of structural MR images of 22 patients (14-18 years) with severe substance and conduct problems and 21 controls of similar age using statistical parametric mapping (SPM) and voxel-based morphometric (VBM8) toolbox. We tested group differences in regional gray matter volume with analyses of covariance, adjusting for age and IQ at p<0.05, corrected for multiple comparisons at whole-brain cluster-level threshold. RESULTS: Female adolescents with severe substance and conduct problems compared to controls showed significantly less gray matter volume in right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, bilateral somatosensory cortex, left supramarginal gyrus, and bilateral angular gyrus. Considering the entire brain, patients had 9.5% less overall gray matter volume compared to controls. CONCLUSIONS: Female adolescents with severe substance and conduct problems in comparison to similarly aged female healthy controls showed substantially lower gray matter volume in brain regions involved in inhibition, conflict processing, valuation of outcomes, decision-making, reward, risk-taking, and rule-breaking antisocial behavior. PMID- 26000882 TI - World-Wide Indoor Exposure to Polyfluoroalkyl Phosphate Esters (PAPs) and other PFASs in Household Dust. AB - Human exposure to perfluorooctanoic acid (PFOA) and other per- and polyfluoroalkyl substances (PFASs) is ongoing and in some cases increasing, despite efforts made to reduce emissions. The role of precursor compounds such as polyfluorinated phosphate esters (PAPs) has received increasing attention, but there are knowledge gaps regarding their occurrence and impact on human exposure. In this study, mono-, di-, and triPAPs, perfluorinated alkyl acids (PFAAs), saturated, and unsaturated fluorotelomer carboxylic acids (FTCA/FTUCAs), perfluoroalkane sulfonamides, and sulfonamidethanols (FOSA/FOSEs), and one fluorotelomer sulfonic acid (FTSA)) were compared in household dust samples from Canada, the Faroe Islands, Sweden, Greece, Spain, Nepal, Japan, and Australia. Mono-, di-, and triPAPs, including several diPAP homologues, were frequently detected in dust from all countries, revealing an ubiquitous spread in private households from diverse geographic areas, with significant differences between countries. The median levels of monoPAPs and diPAPs ranged from 3.7 ng/g to 1 023 ng/g and 3.6 ng/g to 692 ng/g, respectively, with the lowest levels found in Nepal and the highest in Japan. The levels of PAPs exceeded those of the other PFAS classes. These findings reveal the importance of PAPs as a source of PFAS exposure worldwide. PMID- 26000881 TI - Pan-phylum Comparison of Nematode Metabolic Potential. AB - Nematodes are among the most important causative pathogens of neglected tropical diseases. The increased availability of genomic and transcriptomic data for many understudied nematode species provides a great opportunity to investigate different aspects of their biology. Increasingly, metabolic potential of pathogens is recognized as a critical determinant governing their development, growth and pathogenicity. Comparing metabolic potential among species with distinct trophic ecologies can provide insights on overall biology or molecular adaptations. Furthermore, ascertaining gene expression at pathway level can help in understanding metabolic dynamics over development. Comparison of biochemical pathways (or subpathways, i.e. pathway modules) among related species can also retrospectively indicate potential mistakes in gene-calling and functional annotation. We show with numerous illustrative case studies that comparisons at the level of pathway modules have the potential to uncover biological insights while remaining computationally tractable. Here, we reconstruct and compare metabolic modules found in the deduced proteomes of 13 nematodes and 10 non nematode species (including hosts of the parasitic nematode species). We observed that the metabolic potential is, in general, concomitant with phylogenetic and/or ecological similarity. Varied metabolic strategies are required among the nematodes, with only 8 out of 51 pathway modules being completely conserved. Enzyme comparison based on topology of metabolic modules uncovered diversification between parasite and host that can potentially guide therapeutic intervention. Gene expression data from 4 nematode species were used to study metabolic dynamics over their life cycles. We report unexpected differential metabolism between immature and mature microfilariae of the human filarial parasite Brugia malayi. A set of genes potentially important for parasitism is also reported, based on an analysis of gene expression in C. elegans and the human hookworm Necator americanus. We illustrate how analyzing and comparing metabolism at the level of pathway modules can improve existing knowledge of nematode metabolic potential and can provide parasitism related insights. Our reconstruction and comparison of nematode metabolic pathways at a pan-phylum and inter-phylum level enabled determination of phylogenetic restrictions and differential expression of pathways. A visualization of our results is available at http://nematode.net and the program for identification of module completeness (modDFS) is freely available at SourceForge. The methods reported will help biologists to predict biochemical potential of any organism with available deduced proteome, to direct experiments and test hypotheses. PMID- 26000884 TI - Annexin A1 Preferentially Predicts Poor Prognosis of Basal-Like Breast Cancer Patients by Activating mTOR-S6 Signaling. AB - INTRODUCTION: Annexin A1 (ANXA1) is an anti-inflammatory protein reported to play a role in cell proliferation and apoptosis, and to be deregulated in breast cancer. The exact role of annexin A1 in the biology of breast cancer remains unclear. We hypothesized that the annexin A1 plays an oncogenic role in basal subtype of breast cancer by modulating key growth pathway(s). METHODS: By mining the Cancer Genome Atlas (TCGA)-Breast Cancer dataset and manipulating annexin A1 levels in breast cancer cell lines, we studied the role of annexin A1 in breast cancer and underlying signaling pathways. RESULTS: Our in-silico analysis of TCGA breast cancer dataset demonstrated that annexin A1 mRNA expression is higher in basal subtype compared to luminal and HER2 subtypes. Within the basal subtype, patients show significantly poorer overall survival associated with higher expression of annexin A1. In both TCGA patient samples and cell lines, annexin A1 levels were significantly higher in basal-like breast cancer than luminal and Her2/neu-positive breast cancer. Stable annexin A1 knockdown in TNBC cell lines suppressed the mTOR-S6 pathway likely through activation of AMPK but had no impact on the MAPK, c-Met, and EGFR pathways. In a cell migration assay, annexin A1-depleted TNBC cells showed delayed migration as compared to wild-type cells, which could be responsible for poor patient prognosis in basal like breast cancers that are known to express higher annexin A1. CONCLUSIONS: Our data suggest that annexin A1 is prognostic only in patients with basal like breast cancer. This appears to be in part due to the role of annexin A1 in activating mTOR-pS6 pathway. PMID- 26000885 TI - Sequence Variations in the Flagellar Antigen Genes fliCH25 and fliCH28 of Escherichia coli and Their Use in Identification and Characterization of Enterohemorrhagic E. coli (EHEC) O145:H25 and O145:H28. AB - Enterohemorrhagic E. coli (EHEC) serogroup O145 is regarded as one of the major EHEC serogroups involved in severe infections in humans. EHEC O145 encompasses motile and non-motile strains of serotypes O145:H25 and O145:H28. Sequencing the fliC-genes associated with the flagellar antigens H25 and H28 revealed the genetic diversity of the fliCH25 and fliCH28 gene sequences in E. coli. Based on allele discrimination of these fliC-genes real-time PCR tests were designed for identification of EHEC O145:H25 and O145:H28. The fliCH25 genes present in O145:H25 were found to be very similar to those present in E. coli serogroups O2, O100, O165, O172 and O177 pointing to their common evolution but were different from fliCH25 genes of a multiple number of other E. coli serotypes. In a similar way, EHEC O145:H28 harbor a characteristic fliCH28 allele which, apart from EHEC O145:H28, was only found in enteropathogenic (EPEC) O28:H28 strains that shared some common traits with EHEC O145:H28. The real time PCR-assays targeting these fliCH25[O145] and fliCH28[O145] alleles allow better characterization of EHEC O145:H25 and EHEC O145:H28. Evaluation of these PCR assays in spiked ready-to eat salad samples resulted in specific detection of both types of EHEC O145 strains even when low spiking levels of 1-10 cfu/g were used. Furthermore these PCR assays allowed identification of non-motile E. coli strains which are serologically not typable for their H-antigens. The combined use of O-antigen genotyping (O145wzy) and detection of the respective fliCH25[O145] and fliCH28[O145] allele types contributes to improve identification and molecular serotyping of E. coli O145 isolates. PMID- 26000886 TI - Should infants cry over spilled milk? Fecal glycomics as an indicator of a healthy infant gut microbiome. PMID- 26000887 TI - Efficacy and safety of adalimumab after infliximab failure in pediatric Crohn disease. AB - OBJECTIVES: The objective of the present study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with Crohn disease (CD) who experienced infliximab (IFX) failure at the population level. METHODS: The present retrospective study included all of the children with CD from a pediatric onset population-based cohort who received ADA before 18 years because of IFX failure or intolerance. Efficacy of ADA was evaluated using the physician's global assessment score, C-reactive protein and orosomucoid, and nutritional and growth indicators. RESULTS: A total of 27 children with CD received ADA. Median age at CD diagnosis and at ADA initiation was 11 years (Q1 = 9; Q3 = 12) and 15 years (12; 15), respectively. After a median follow-up of 16 (8; 26) months after ADA initiation, ADA had clinical benefit as measured by the physical global assessment score in 19 patients (70%). Cumulative probability of failure to ADA treatment was 38% at 6 months and 55% at 1 year. Eight patients had a primary failure (30%) and 5 of 19 (26%) a secondary failure to ADA. Furthermore, 11 patients (40%) experienced a total of 19 adverse effects. No serious adverse effects were observed and none resulted in ADA discontinuation. There was no significant change in growth and nutritional patterns during the study period, but we found a significant decrease in median C-reactive protein (15 mg/L [4; 44] vs 9 mg/L [3; 19]; P = 0.05) and orosomucoid (1.6 g/L [1.5; 2.6] vs 1.1 g/L [0.8; 1.9]; P = 0.001) from ADA initiation to maximal follow-up in patients responding to ADA. CONCLUSIONS: In the present population-based cohort of pediatric-onset CD with IFX failure, treatment with ADA was safe and effective in two-thirds of patients. PMID- 26000888 TI - Epidemiology of irritable bowel syndrome in children and adolescents in Asia. AB - OBJECTIVES: Several cross-sectional surveys have been conducted to study the prevalence of irritable bowel syndrome (IBS) in children. The aim of the present study was to conduct a systematic review and a meta-analysis of published literature to estimate the prevalence of IBS among Asian children. METHOD: A computer-assisted search of MEDLINE, EMBASE, PsycINFO, and regional databases of Asia was carried out. Selected articles were reviewed in depth and data were extracted. Pooled prevalence, sex differences, and 95% confidence intervals were calculated. Heterogeneity of the studies was assessed using the I(2) test. RESULTS: A total of 16 cross-sectional studies that reported prevalence of IBS (in children and adolescents) and qualified to be included were taken into the final analysis containing 38,076 patients. Selected studies are from China, Korea, Japan, Iran, Sri Lanka, and Saudi Arabia. Studies showed a marked heterogeneity with I(2) of 98.59 (P < 0.0001). Prevalence of IBS ranges from 2.8% to 25.7%, with a pooled prevalence of 12.41% (95% confidence interval 9.87 14.95). Prevalence risk ratio of girl:boy is 1.39. Prevalence of subtypes is diverse and varies between studies. CONCLUSIONS: The published data indicate that IBS is a significant problem among Asian children and adolescents. Female sex predisposes children and adolescents to develop IBS. PMID- 26000889 TI - Potentiality of yeast Candida sp. SMN04 for degradation of cefdinir, a cephalosporin antibiotic: kinetics, enzyme analysis and biodegradation pathway. AB - A new yeast strain isolated from the pharmaceutical wastewater was capable of utilizing cefdinir as a sole carbon source for their growth in mineral medium. The yeast was identified and named as Candida sp. SMN04 based on morphology and 18S-ITS-D1/D2/D3 rRNA sequence analysis. The interaction between factors pH (3.0 9.0), inoculum dosage (1-7%), time (1-11 day) and cefdinir concentration (50-450 mg/L) was studied using a Box-Behnken design. The factors were studied as a result of their effect on cell dry weight (R1; g/L), extended spectrum beta lactamase (ESBL) assay (R2; mm), P450 activity (R3; U/mL) and degradation (R4; %). Maximum values of R1, R2, R3 and R4 were obtained at central values of all the parameters. The isolated yeast strain efficiently degraded 84% of 250 mg L-1 of cefdinir within 6 days with a half-life of 2.97 days and degradation rate constant of 0.2335 per day. Pseudo-first-order model efficiently described the process. Among the various enzymes tested, the order of activity at the end of Day 4 was noted to be: cytochrome P450 (1.76 +/- 0.03) > NADPH reductase (1.51 +/ 0.20) > manganese peroxidase and amylase (0.66 +/- 0.15; 0.66 +/- 0.70). Intermediates were successfully characterized by liquid chromatography-mass spectrometry. The opening of the beta-lactam ring involving ESBL activity was considered as one of the major steps in the cefdinir degradation process. Fourier transform-infrared spectroscopy analysis showed the absence of spectral vibrations between 1766 and 1519 cm-1 confirming the complete removal of lactam ring during cefdinir degradation. The results of the present study are promising for the use of isolated yeast Candida sp. SMN04 as a potential bioremediation agent. PMID- 26000890 TI - Kinetics of Several Oxygen-Containing Carbon-Centered Free Radical Reactions with Nitric Oxide. AB - Kinetics of four carbon-centered, oxygen-containing free radical reactions with nitric oxide (NO) were investigated as a function of temperature at a few Torr pressure of helium, employing flow tube reactors coupled to a laser photolysis/resonance-gas-discharge-lamp photoionization mass spectrometer (LP RPIMS). Rate coefficients were directly determined from radical (R) decay signals under pseudo-first-order conditions ([R]0 ? [NO]). The obtained rate coefficients showed negative temperature dependences, typical for a radical-radical association process, and can be represented by the following parametrizations (all in units of cm(3) molecule(-1) s(-1)): k(CH2OH + NO) = (4.76 * 10(-21)) * (T/300 K)(15.92) * exp[50700/(RT)] (T = 266-363 K, p = 0.79-3.44 Torr); k(CH3CHOH + NO) = (1.27 * 10(-16)) * (T/300 K)(6.81) * exp[28700/(RT)] (T = 241-363 K, p = 0.52-3.43 Torr); k(CH3OCH2 + NO) = (3.58 +/- 0.12) * 10(-12) * (T/300 K)(-3.17+/ 0.14) (T = 221-363 K, p = 0.50-0.80 Torr); k(T)3 = 9.62 * 10(-11) * (T/300 K)( 5.99) * exp[-7100/(RT)] (T = 221-473 K, p = 1.41-2.95 Torr), with the uncertainties given as standard errors of the fits and the overall uncertainties estimated as +/-20%. The rate of CH3OCH2 + NO reaction was measured in two density ranges due to its observed considerable pressure dependence, which was not found in the studied hydroxyalkyl reactions. In addition, the CH3CO + NO rate coefficient was determined at two temperatures resulting in k298K(CH3CO + NO) = (5.6 +/- 2.8) * 10(-13) cm(3) molecule(-1) s(-1). No products were found during these experiments, reasons for which are briefly discussed. PMID- 26000891 TI - Low-Cost Copper Nanostructures Impart High Efficiencies to Quantum Dot Solar Cells. AB - Quantum dot solar cells (QDSCs) were fabricated using low-cost Cu nanostructures and a carbon fabric as a counter electrode for the first time. Cu nanoparticles (NPs) and nanoneedles (NNs) with a face-centered cubic structure were synthesized by a hydrothermal method and electrophoretically deposited over a CdS QD sensitized titania (TiO2) electrode. Compared to Cu NPs, which increase the light absorption of a TiO2/CdS photoanode via scattering effects only in the visible region, Cu NNs are more effective for efficient far-field light scattering; they enhance the light absorption of the TiO2/CdS assembly beyond the visible to near infrared (NIR) regions as well. The highest fluorescence quenching, lowest excited electron lifetime, and a large surface potential (deduced from Kelvin probe force microscopy (KPFM)) observed for the TiO2/CdS/Cu NN electrode compared to TiO2/CdS and TiO2/CdS/Cu NP electrodes confirm that Cu NNs also facilitate charge transport. KPFM studies also revealed a larger shift of the apparent Fermi level to more negative potentials in the TiO2/CdS/Cu NN electrode, compared to the other two electrodes (versus NHE), which results in a higher open-circuit voltage for the Cu NN based electrode. The best performing QDSC based on the TiO2/CdS/Cu NN electrode delivers a stellar power conversion efficiency (PCE) of 4.36%, greater by 56.8% and 32.1% than the PCEs produced by the cells based on TiO2/CdS and TiO2/CdS/Cu NPs, respectively. A maximum external quantum efficiency (EQE) of 58% obtained for the cell with the TiO2/CdS/Cu NN electrode and a finite EQE in the NIR region which the other two cells do not deliver are clear indicators of the enormous promise this cheap, earth-abundant Cu nanostructure holds for amplifying the solar cell response in both the visible and near infrared regions through scattering enhancements. PMID- 26000892 TI - Piezoelectric coefficients and spontaneous polarization of ScAlN. AB - We present a computational study of spontaneous polarization and piezoelectricity in Sc(x)Al(1-x)N alloys in the compositional range from x = 0 to x = 0.5, obtained in the context of density functional theory and the Berry-phase theory of electric polarization using large periodic supercells. We report composition dependent values of piezoelectric coefficients e(ij), piezoelectric moduli d(ij) and elastic constants C(ij). The theoretical findings are complemented with experimental measurement of e33 for a series of sputtered ScAlN films carried out with a piezoelectric resonator. The rapid increase with Sc content of the piezoelectric response reported in previous studies is confirmed for the available data. A detailed description of the full methodology required to calculate the piezoelectric properties of ScAlN, with application to other complex alloys, is presented. In particular, we find that the large amount of internal strain present in ScAlN and its intricate relation with electric polarization make configurational sampling and the use of large supercells at different compositions necessary in order to accurately derive the piezoelectric response of the material. PMID- 26000893 TI - Development of a Paper Spray Mass Spectrometry Cartridge with Integrated Solid Phase Extraction for Bioanalysis. AB - A novel paper spray cartridge with an integrated solid phase extraction (SPE) column is described. The cartridge performs extraction and pre-concentration, as well as sample ionization by paper spray, from complex samples such as plasma. The cartridge allows for selective enrichment of target molecules from larger sample volumes and removal of the matrix, which significantly improved the signal intensity of target compounds in plasma samples by paper spray ionization. Detection limits, quantitative performance, recovery, ionization suppression, and the effects of sample volume were evaluated for five drugs: carbamazepine, atenolol, sulfamethazine, diazepam, and alprazolam. Compared with direct paper spray analysis of dried plasma spots, paper spray analysis using the integrated solid phase extraction improved the detection limits significantly by a factor of 14-70, depending on the drug. The improvement in detection limits was, in large part, due to the capability of analyzing larger sample volumes. In addition, ionization suppression was found to be lower and recovery was higher for paper spray with integrated SPE, as compared to direct paper spray analysis. By spiking an isotopically labeled internal standard into the plasma sample, a linear calibration curve for the drugs was obtained from the limit of detection (LOD) to 1 MUg/mL, indicating that this method can be used for quantitative analysis. The paper spray cartridge with integrated SPE could prove valuable for analytes that ionize poorly, in applications where lower detection limits are required, or on portable mass spectrometers. The improved performance comes at the cost of requiring a more complex paper spray cartridge and requiring larger sample volumes than those used in typical direct paper spray ionization. PMID- 26000894 TI - Correction: Population Genetic History of Aristeus antennatus (Crustacea: Decapoda) in the Western and Central Mediterranean Sea. PMID- 26000896 TI - Indoor and Outdoor Levels and Sources of Submicron Particles (PM1) at Homes in Edmonton, Canada. AB - Exposure to submicron particles (PM1) is of interest due to their possible chronic and acute health effects. Seven consecutive 24-h PM1 samples were collected during winter and summer 2010 in a total of 74 nonsmoking homes in Edmonton, Canada. Median winter concentrations of PM1 were 2.2 MUg/m(3) (interquartile range, IQR = 0.8-6.1 MUg/m(3)) and 3.3 MUg/m(3) (IQR = 1.5-6.9 MUg/m(3)) for indoors and outdoors, respectively. In the summer, indoor (median 4.4 MUg/m(3), IQR = 2.4-8.6 MUg/m(3)) and outdoor (median 4.3 MUg/m(3), IQR = 2.6 7.4 MUg/m(3)) levels were similar. Positive matrix factorization (PMF) was applied to identify and apportion indoor and outdoor sources of elements in PM1 mass. Nine sources contributing to both indoor and outdoor PM1 concentrations were identified including secondary sulfate, soil, biomass smoke and environmental tobacco smoke (ETS), traffic, settled and mixed dust, coal combustion, road salt/road dust, and urban mixture. Three additional indoor sources were identified i.e., carpet dust, copper-rich, and silver-rich. Secondary sulfate, soil, biomass smoke and ETS contributed more than 70% (indoors: 0.29 MUg/m(3), outdoors: 0.39 MUg/m(3)) of measured elemental mass in PM1. These findings can aid understanding of relationships between submicron particles and health outcomes for indoor/outdoor sources. PMID- 26000895 TI - Use of otolith for detecting strontium-90 in fish from the harbor of Fukushima Dai-ichi Nuclear Power Plant. AB - To clarify the level of contamination with radioactive cesium (radiocesium) discharged from Fukushima Dai-ichi Nuclear Power Plant (FDNPP), three fish species caught in the main harbor of FDNPP were subjected to gamma-ray analysis. The concentration of radiocesium in muscle differed among individual fish, even those of similar size of the same species, and showed little relation to the standard length of fish. The maximum concentration of radiocesium (202 kBq/kg wet) was detected from fat greenling samples. A comparison to data from outside the port indicated that the level of radiocesium contamination inside the port was higher than that outside. We found that beta-rays were emitted from otoliths of fishes caught in the port of FDNPP. beta-ray intensities were correlated with the concentrations of radiocesium in muscles of the three fish species. In Japanese rockfish, the beta-ray count rates from otoliths were significantly correlated with the concentration of radiocesium and (90)Sr in the whole body without internal organs of Japanese rockfish. However, no beta-rays were detected from brown hakeling samples collected around FDNPP, suggesting that the detection of beta-rays from otoliths may indicate living in the main harbor of FDNPP. PMID- 26000897 TI - What is the best anticoagulant therapy during primary percutaneous coronary intervention for acute myocardial infarction? AB - Both ST-segment elevation myocardial infarction and percutaneous coronary intervention (PCI) are associated with a highly prothrombotic state, and thrombin plays a critical role during occlusive clot generation and subsequent occurrence of an ischemic event. Therefore, a strategy of anticoagulation plus dual antiplatelet therapy has been regarded as de facto standard therapy during primary PCI (pPCI). Recently, there has been great controversy surrounding the role of bivalirudin versus unfractionated heparin in pPCI. Earlier, the results of the HORIZONS-AMI trial, particularly those regarding the long-lasting mortality benefit, provided a strong rationale for recommending bivalirudin therapy in pPCI. However, the mortality benefit of bivalirudin observed in HORIZONS-AMI has not been repeated in more contemporary studies or demonstrated in recent meta-analyses. The current report will provide a concise review of the controversy surrounding the optimal anticoagulant therapy for pPCI. Recent evidence suggests that unfractionated heparin deserves strong reconsideration despite the reports of pharmacologic weaknesses, particularly when used with a strategy of selective glycoprotein IIb/IIIa therapy, and it appears that a strategy of bivalirudin therapy in pPCI should be reserved for patients at high bleeding risk. PMID- 26000898 TI - Comprehensive analysis of individual pulp fiber bonds quantifies the mechanisms of fiber bonding in paper. AB - The process of papermaking requires substantial amounts of energy and wood consumption, which contributes to larger environmental costs. In order to optimize the production of papermaking to suit its many applications in material science and engineering, a quantitative understanding of bonding forces between the individual pulp fibers is of importance. Here we show the first approach to quantify the bonding energies contributed by the individual bonding mechanisms. We calculated the impact of the following mechanisms necessary for paper formation: mechanical interlocking, interdiffusion, capillary bridges, hydrogen bonding, Van der Waals forces, and Coulomb forces on the bonding energy. Experimental results quantify the area in molecular contact necessary for bonding. Atomic force microscopy experiments derive the impact of mechanical interlocking. Capillary bridges also contribute to the bond. A model based on the crystal structure of cellulose leads to values for the chemical bonds. In contrast to general believe which favors hydrogen bonding Van der Waals bonds play the most important role according to our model. Comparison with experimentally derived bond energies support the presented model. This study characterizes bond formation between pulp fibers leading to insight that could be potentially used to optimize the papermaking process, while reducing energy and wood consumption. PMID- 26000899 TI - Chemical Vapor Deposition Growth of Monolayer WSe2 with Tunable Device Characteristics and Growth Mechanism Study. AB - Semiconducting transition metal dichalcogenides (TMDCs) have attracted a lot of attention recently, because of their interesting electronic, optical, and mechanical properties. Among large numbers of TMDCs, monolayer of tungsten diselenides (WSe2) is of particular interest since it possesses a direct band gap and tunable charge transport behaviors, which make it suitable for a variety of electronic and optoelectronic applications. Direct synthesis of large domains of monolayer WSe2 and their growth mechanism studies are important steps toward applications of WSe2. Here, we report systematical studies on ambient pressure chemical vapor deposition (CVD) growth of monolayer and few layer WSe2 flakes directly on silica substrates. The WSe2 flakes were characterized using optical microscopy, atomic force microscopy, Raman spectroscopy, and photoluminescence spectroscopy. We investigated how growth parameters, with emphases on growth temperatures and durations, affect the sizes, layer numbers, and shapes of as grown WSe2 flakes. We also demonstrated that transport properties of CVD-grown monolayer WSe2, similar to mechanically exfoliated samples, can be tuned into either p-type or ambipolar electrical behavior, depending on the types of metal contacts. These results deepen our understandings on the vapor phase growth mechanism of WSe2, and may benefit the uses of these CVD-grown monolayer materials in electronic and optoelectronics. PMID- 26000901 TI - Assessment of Strain-Generated Oxygen Vacancies Using SrTiO3 Bicrystals. AB - Atomic-scale defects strongly influence the electrical and optical properties of materials, and their impact can be more pronounced in localized dimensions. Here, we directly demonstrate that strain triggers the formation of oxygen vacancies in complex oxides by examining the tilt boundary of SrTiO3 bicrystals. Through transmission electron microscopy and electron energy loss spectroscopy, we identify strains along the tilt boundary and oxygen vacancies in the strain imposed regions between dislocation cores. First-principles calculations support that strains, irrespective of their type or sign, lower the formation energy of oxygen vacancies, thereby enhancing vacancy formation. Finally, current-voltage measurements confirm that such oxygen vacancies at the strained boundary result in a decrease of the nonlinearity of the I-V curve as well as the resistivity. Our results strongly indicate that oxygen vacancies are preferentially formed and are segregated at the regions where strains accumulate, such as heterogeneous interfaces and grain boundaries. PMID- 26000903 TI - Pneumococcal vaccination-promoting health. PMID- 26000902 TI - fMRI Study of Social Anxiety during Social Ostracism with and without Emotional Support. AB - Social anxiety is characterized by an excessive fear of being embarrassed in social interactions or social performance situations. Emotional support can help to decrease or diminish social distress. Such support may play an important role at different points of social interaction. However, it is unclear how the beneficial effects of social support are represented in the brains of socially anxious individuals. To explore this, we used the same paradigm previously used to examine the effects of emotional support on social pain caused by exclusion. Undergraduates (n = 46) showing a wide range of social anxiety scores underwent functional magnetic resonance imaging (fMRI) while participating in a Cyberball game. Participants were initially included and later excluded from the game. In the latter half of the session in which participants were excluded, they were provided with supportive messages. In line with our previous work, we found that social exclusion led to increased anterior cingulate cortex (ACC) activity, whereas emotional support led to increased left dorsolateral prefrontal cortex (DLPFC) activity. Despite validation of the paradigm, social anxiety was not associated with increased ACC activity during social exclusion, or during perceived emotional support. Instead, fear of negative evaluation as assessed by the Brief Fear of Negative Evaluation (BFNE) scale showed positive associations with left DLPFC activation while receiving emotional support, compared to while being socially excluded. The more socially anxious an individual was, the greater was the left DLPFC activity increased during receipt of messages. This suggests that highly socially anxious people still have the ability to perceive social support, but that they are nevertheless susceptible to negative evaluation by others. PMID- 26000904 TI - Call to action on pneumococcal disease: review of vaccination evidence and outcomes of webcast programs. AB - In 2015, the Advisory Committee on Immunization Practices issued updated recommendations for the use of 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) to immunize adults aged 19 to 64 years with risk factors and all adults aged 65 years or older. Despite these recommendations, rates of vaccination among adults remain low. Federal and state initiatives have been launched to encourage health care providers to incorporate vaccination screening and recommendations in practice. Several resources are available to improve vaccination rates, including implementing electronic medical records; engaging non-physician staff in assessing vaccination history and administering immunizations; adopting standing order protocols; and implementing strong recommendations to patients regarding needed immunizations. However, even in the face of compelling evidence-based research, implementing changes in practice is challenging. The American Osteopathic Association implemented a 2-part Web program called the Call to Action on Pneumococcal Disease. Although some changes in attitudes and intent to change were demonstrated by this initiative, there were no statistically significant increases in self-reported actual adoption of standing order protocols or increases in adult pneumococcal immunization. Nonetheless, some lessons were learned, and these results support the need for ongoing efforts in this area of medicine. PMID- 26000905 TI - Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training. AB - This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (p<0.05) in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05) of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR) showed that TS rats had higher mRNA levels (P < 0.05) of glucose-regulated protein 78 (GRP78) and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage. PMID- 26000906 TI - Negative feedbacks on bark beetle outbreaks: widespread and severe spruce beetle infestation restricts subsequent infestation. AB - Understanding disturbance interactions and their ecological consequences remains a major challenge for research on the response of forests to a changing climate. When, where, and how one disturbance may alter the severity, extent, or occurrence probability of a subsequent disturbance is encapsulated by the concept of linked disturbances. Here, we evaluated 1) how climate and forest habitat variables, including disturbance history, interact to drive 2000s spruce beetle (Dendroctonus rufipennis) infestation of Engelmann spruce (Picea engelmannii) across the Southern Rocky Mountains; and 2) how previous spruce beetle infestation affects subsequent infestation across the Flat Tops Wilderness in northwestern Colorado, which experienced a severe landscape-scale spruce beetle infestation in the 1940s. We hypothesized that drought and warm temperatures would promote infestation, whereas small diameter and non-host trees, which may reflect past disturbance by spruce beetles, would inhibit infestation. Across the Southern Rocky Mountains, we found that climate and forest structure interacted to drive the 2000s infestation. Within the Flat Tops study area we found that stands infested in the 1940s were composed of higher proportions of small diameter and non-host trees ca. 60 years later. In this area, the 2000s infestation was constrained by a paucity of large diameter host trees (> 23 cm at diameter breast height), not climate. This suggests that there has not been sufficient time for trees to grow large enough to become susceptible to infestation. Concordantly, we found no overlap between areas affected by the 1940s infestation and the current infestation. These results show a severe spruce beetle infestation, which results in the depletion of susceptible hosts, can create a landscape template reducing the potential for future infestations. PMID- 26000907 TI - 3D-printed silicate porous bioceramics using a non-sacrificial preceramic polymer binder. AB - Silicate bioceramics possess an excellent bioactivity; however, shaping them into complex geometries is still challenging. Therefore, this paper aims to present a new strategy for the shaping of a bioglass-ceramic with controlled geometry and properties starting from a glass powder combined with a preceramic polymer, i.e. a silicon resin, and reactive fillers. The powder-based three-dimensional (3D) printing of wollastonite (CaSiO3)-based silicate bioceramic parts was demonstrated in this work. The resin plays a dual role, as it not only acts as a non-sacrificial binder for the filler powders in the printing process but it also reacts with the fillers to generate the desired bioceramic phases. The mechanical and physical properties, i.e. ball-on-three-balls test, density, porosity and morphology, were evaluated in 3D-printed discs. These samples possessed a total porosity around 64 vol% and a biaxial flexural strength around 6 MPa. The raw materials used in this work also enabled the 3D-printing of scaffolds possessing a designed multi-scale porosity, suitable bioceramic phase assemblage and a compressive strength of 1 MPa (for cylindrical scaffolds with total porosity ~80 vol%). Solubility in TRIS/HCl and in vitro assays, i.e. viability, cytotoxicity and apoptosis assays, were also performed. In vitro tests indicated good cell viability and no cytotoxicity effect on the cells. PMID- 26000909 TI - Particle Segregation at Contact Lines of Evaporating Colloidal Drops: Influence of the Substrate Wettability and Particle Charge-Mass Ratio. AB - Segregation of particles during capillary/convective self-assembly is interesting for self-stratification in colloidal deposits. In evaporating drops containing colloidal particles, the wettability properties of substrate and the sedimentation of particles can affect their accumulation at contact lines. In this work we studied the size segregation and discrimination of charged particles with different densities. We performed in-plane particle counting at evaporating triple lines by using fluorescence confocal microscopy. We studied separately substrates with very different wettability properties and particles with different charge-mass ratios at low ionic strength. We used binary colloidal suspensions to compare simultaneously the deposition of two different particles. The particle deposition rate strongly depends on the receding contact angle of the substrate. We further observed a singular behavior of charged polystyrene particles in binary mixtures under "salt-free" conditions explained by the "colloidal Brazil nut" effect. PMID- 26000908 TI - TSC1 Promotes B Cell Maturation but Is Dispensable for Germinal Center Formation. AB - Accumulating evidence indicates that the tuberous sclerosis complex 1 (TSC1), a tumor suppressor that acts by inhibiting mTOR signaling, plays an important role in the immune system. We report here that TSC1 differentially regulates mTOR complex 1 (mTORC1) and mTORC2/Akt signaling in B cells. TSC1 deficiency results in the accumulation of transitional-1 (T1) B cells and progressive losses of B cells as they mature beyond the T1 stage. Moreover, TSC1KO mice exhibit a mild defect in the serum antibody responses or rate of Ig class-switch recombination after immunization with a T-cell-dependent antigen. In contrast to a previous report, we demonstrate that both constitutive Peyer's patch germinal centers (GCs) and immunization-induced splenic GCs are unimpaired in TSC1-deficient (TSC1KO) mice and that the ratio of GC B cells to total B cells is comparable in WT and TSC1KO mice. Together, our data demonstrate that TSC1 plays important roles for B cell development, but it is dispensable for GC formation and serum antibody responses. PMID- 26000910 TI - Robust population inversion by polarization selective pulsed excitation. AB - The coherent state preparation and control of single quantum systems is an important prerequisite for the implementation of functional quantum devices. Prominent examples for such systems are semiconductor quantum dots, which exhibit a fine structure split single exciton state and a V-type three level structure, given by a common ground state and two distinguishable and separately excitable transitions. In this work we introduce a novel concept for the preparation of a robust inversion by the sequential excitation in a V-type system via distinguishable paths. PMID- 26000911 TI - Polymorphisms in protein disulfide isomerase are associated with sporadic amyotrophic lateral sclerosis in the Chinese Han population. AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that targets the motor system; it is caused by the loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. However, the etiology of ALS remains unknown, although genetic factors may play an important role in its development. The purpose of this study was to investigate the association between common polymorphisms in protein disulfide isomerase (PDI) with sporadic amyotrophic lateral sclerosis (SALS) in a Chinese Han population. Two single nucleotide polymorphisms (SNPs) in P4HB (rs876016 and rs2070872) were genotyped in 322 patients with SALS and 265 control subjects using polymerase chain reaction-restriction fragment length polymorphism. Our results showed that SNPs rs876016 and rs2070872 were significantly associated with ALS. The minor allele frequencies of rs876016 (C) and rs2070872 (G) were significantly higher in patients with sporadic ALS than in control subjects (P = 0.035 and 0.003, respectively). The genotype frequencies of rs876016 and rs2070872 were significantly different between SALS patients and control subjects (genotypic P < 0.001). Individuals carrying rs876016/ rs2070872 C/G genotypes were associated with a significantly increased risk of SALS. These results suggest that common variants in PDI might contribute to the development of SALS in the Chinese Han population. PMID- 26000912 TI - Serum protein biomarkers screening in patients with ischemic stroke by LC-MS/MS. AB - BACKGROUND: The purpose of this study was to investigate the serum proteins biomarkers by label-free liquid chromatography coupled to tandem mass spectrometry quantification methods in the Chinese patients with acute ischemic stroke (AIS). METHOD: In the study period, sera from 40 AIS patients and 40 normal cases were selected for screening study. The selected protein associations with disease risk were further evaluated by enzyme-linked immunosorbent assay (ELISA) testing of the remaining stroke cases and controls. Its value for biomarkers diagnosis was appreciated through receiver operating characteristic (ROC) curve. RESULTS: Patients versus control levels differences were suggested for 19 proteins (nominal P < 0.05) for stroke, with three proteins having a false discovery rate <0.05. The association of mannose-binding lectin (MBL) with stroke (P < 0.001) was confirmed using ELISA in replication studies. Based on the ROC curve, the optimal serum concentration of MBL as a surrogate marker to support the diagnosis of ischemic cerebral injury was found to be 1050 ug/L, which yielded a sensitivity of 81.8% and a specificity of 80.2%, the area under the curve was 0.812 (95% CI: 0.724-0.876). In multivariate analysis, there was an increased risk of AIS associated with MBL levels >=1050 ug/L (OR: 4.76, 95% CI: 1.59-10.12) after adjusting for possible confounders. CONCLUSION: The discovery and replication studies presented here show MBL to be a risk marker for AIS in the Chinese population, which appears to be a novel finding. PMID- 26000913 TI - MRI imaging and clinical features of sciatic nerve injection injury. PMID- 26000914 TI - Genome-wide gene expression analysis of peripheral leukocytes in relation to the male predominance of Guillain-Barre syndrome: differential gene expression between male and female patients. AB - BACKGROUND: Guillain-Barre syndrome (GBS) fulfils most of the clinical features of an autoimmune disease except for its male predominance. No previous studies have evaluated the differential genome-wide expression between male and female GBS patients. OBJECTIVE: This study sought to identify differences between male and female GBS patients in the gene expression profiles of peripheral leukocytes. METHODS: We downloaded gene chip data-sets pertaining to peripheral leukocyte samples from GBS patients using the gene expression omnibus (submitted by Chang et al.) and applied hierarchical cluster analysis to detect whether there was a gender difference in genome-wide gene expression levels. Then, we identified the sexually differentially expressed genes using a bioinformatic approach and applied enrichment analysis to the gene ontology and Kyoto Encyclopaedia of Genes and Genomes terms to identify significant pathways related to these genes. RESULTS: We observed gender stratification among GBS patients. Twenty genes were expressed more highly in male patients and were enriched for functions, such as macrophage differentiation, leukocyte migration, bladder cancer, pathogenic Escherichia coli infection. In female patients, 62 genes were more highly expressed and were enriched for responses to viral infection and defence, retinoic acid-inducible gene I (RIG-I)-like receptors, cytoplasmic DNA sensing. Matrix metalloproteinase 9 (MMP9) seem to play an important role in the male predominance of GBS. CONCLUSIONS: This study demonstrated gender differences in the genome-wide gene expression of patients with GBS. Bioinformatic approaches offer new means for identifying candidate genes and pathways relevant to the pathophysiology of GBS. PMID- 26000915 TI - Can neurotrophic cytokines help to regenerate the mammalian central nervous system? PMID- 26000916 TI - Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1 and NQO-1 in mice. AB - Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention, which has been discovered to reduce ischemia/reperfusion (I/R) injury in heart, kidney, brain and skeletal muscle experimentally. However, its potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the protective effect of RIPostC in cerebral I/R injury and explore the new putative mechanisms of neuroprotection elicited by it. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in male CD1 mice. RIPostC was generated by three cycles of 5-min reperfusion/5-min occlusion of the bilateral femoral artery on the bilateral limbs at the onset of middle cerebral artery reperfusion. RIPostC significantly improved neurological outcome, lessened infarct volume and brain edema, upregulated the expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1) and activity of superoxide dismutase (SOD), and downregulaed the formation of malondialdehyde (MDA) (p < 0.05). Taken together, these findings demonstrated that RIPostC protected the brain from I/R injury after focal cerebral ischemia by reducing oxidative stress and activating the Nrf2-ARE (antioxidant response element) pathway. PMID- 26000917 TI - Angiotensin converting enzyme (I/D) gene polymorphism contributes to ischemic stroke risk in Caucasian individuals: a meta-analysis based on 22 case-control studies. AB - BACKGROUND: Stroke is a multifactorial disease in which genetic factors play an important role. Previous studies associated angiotensin converting enzyme (ACE) (insertion/deletion, I/D) gene polymorphism with ischemic stroke risk in Caucasian individuals reported conflicting results. The purpose of this study was to evaluate the association between ACE (I/D) gene polymorphism and ischemic stroke risk by a meta-analysis. METHODS: The related studies were searched in MEDLINE, EMBASE and HuGEnet databases. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for ischemic stroke risk associated with this polymorphism were estimated using fixed-effect or random-effects model. Twenty two studies (5528/5081 cases/controls) were eligible in our meta-analysis. RESULTS: Overall, statistical associations of the ACE (I/D) polymorphism with ischemic stroke risk were found in dominant model (DD + ID versus II) : OR = 1.21, 95% CI = (1.06,1.38), P = 0.006, recessive model (DD versus ID + II): OR = 1.28, 95% CI = (1.05,1.55), P = 0.01, and homozygote comparison (DD versus II): OR = 1.37, 95% CI = (1.14,1.65), P = 0.001 for Caucasians. When stratifying according to stroke subtypes, there were similarly significant differences for small vessel disease in dominant model (DD + ID versus II) : OR = 1.44, 95% CI = (1.01,2.05), P = 0.04, recessive model (DD versus ID + II): OR = 1.30,95% CI = (1.09,1.55), P = 0.004, and homozygote comparison (DD versus II): OR = 1.44, 95% CI = (1.15,1.80), P = 0.001. CONCLUSION: This analysis suggests that the ACE (I/D) polymorphism may be a risk factor for ischemic stroke, genotype DD of ACE could increase the risk of ischemic stroke in Caucasians. Subgroup analyses indicate that stroke subtypes may be a genetic risk factor of ischemic stroke, and there might be a greater genetic liability with small vessel disease. PMID- 26000918 TI - Molecular characterization of genes modifying the age at onset in Huntington's disease in Uruguayan patients. AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder. The genetic cause is an expansion of CAG repeats located in the IT15 gene. Though the number of CAG repeats ((CAG)n) can largely explain the age at onset (AAO) of symptoms, a percentage of its variation could be attributed to modifier genes and to environmental factors. The study aimed to evaluate the influence of genetic modifiers of the AAO of HD including: (CAG)n and del2642 in the IT15 gene, ADORA2A rs5751876, HAP1 rs4523977, PGC1-alpha rs7665116 and UCH-L1 rs5030732. Eighteen patients with positive family history and HD-suggestive symptoms were recruited. The (CAG)n and gene polymorphisms were determined by different molecular biology techniques. We observed that the (CAG)n influenced in a 64.5% of the variability in the AAO. We also showed that the rs5751876 variant significantly affected this variability. However, the influence of UCH-L1, del2642, HAP1 and PGC1-alpha gene polymorphisms could not be replicated, perhaps due to small sample size. Genetic studies including the molecular determination of (CAG)n, in addition to other genetic modifiers involved in the variability of the AAO, were first performed in Uruguay. We could replicate in our cohort the anticipation effect on the AAO by the ADORA2A rs5751876. Our results confirm the usefulness of an expanded molecular characterization in HD patients. PMID- 26000919 TI - Intractable epilepsy and the P-glycoprotein hypothesis. AB - Epilepsy is a serious neurological disorder that affects more than 60 million people worldwide. Intractable epilepsy (IE) refers to approximately 20%-30% of epileptic patients who fail to achieve seizure control with antiepileptic drug (AED) treatment. Although the mechanisms underlying IE are not well understood, it has been hypothesized that multidrug transporters such as P-glycoprotein (P gp) play a major role in drug efflux at the blood-brain barrier, and may be the underlying factor in the variable responses of patients to AEDs. The main goal of the present review is to show evidence from different areas that support the idea that the overexpression of P-gp is associated with IE. We discuss here evidence from animal studies, pharmacology, clinical cases and genetic studies. PMID- 26000920 TI - Association of TLR9 polymorphisms with sporadic Parkinson's disease in Chinese Han population. AB - Previous studies have acknowledged that inflammatory reaction has implicated in Parkinson's disease (PD) pathogenesis nowadays. Toll-like receptors (TLRs), as key players in the inflammatory reaction, play a pivotal role in the PD pathogenesis and accumulating evidences have shown that TLRs are increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD. Therefore, the present study aimed to identify the role of the polymorphisms of rs187084 and rs352140 in TLR9 gene with PD. The genotypes were detected by polymerase chain reaction and restriction fragment length polymorphism analysis in 380 PD patients and 380 healthy matched individuals in Chinese Han population. For rs352140, our data revealed a significant difference in allele distribution in female PD group and its healthy matched control (P = 0.040). Moreover, rs352140 T allele carriers of female group were associated with a reduced risk of PD (TT + TC vs. CC, P = 0.018). However, no significant differences in genotype and allele distribution were found between the age and gender subgroups for rs187084. Therefore, our studies indicate that the rs352140 gene polymorphism may be associated with the susceptibility of female PD in Chinese Han population. PMID- 26000921 TI - Up-regulated cytoplasmic FMRP-interacting protein 1 in intractable temporal lobe epilepsy patients and a rat model. AB - Cytoplasmic FMRP-interacting protein 1 (CYFIP1) is a multifunctional protein which expresses highly at excitatory synapses and can locally regulate actin cytoskeletal dynamics, spine morphology and synaptic alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid receptor lateral diffusion. Altered synaptic actin plays a role in the pathogenesis of epilepsy. The aim of this study was to investigate the expression pattern of CYFIP1 in temporal lobe epilepsy (TLE). Protein and mRNA expression levels were compared in temporal lobe tissue from patients with TLE versus trauma patients without TLE using quantitative real-time polymerase chain reaction (qRT-PCR), double-label immunofluorescence and Western blot analysis. We have further determined the expression pattern of Cyfip1 mRNA and protein in the hippocampus and adjacent cortex of a common rat model of TLE, lithium-pilocarpine treatment, compared to control rats. CYFIP1 expression was significantly up-regulated in the temporal neocortex of patients with intractable TLE and pilocarpine-treated rats compared to control groups. CYFIP1 localizes to the cytoplasm of neurons, and is not expressed in the astrocytes. Furthermore, CYFIP1 expression levels increased significantly in the two months after pilocarpine treatment, which corresponds to the period of epileptogenesis. Thus, our results indicate that CYFIP1 may be involved in the pathogenesis of TLE. PMID- 26000922 TI - Quality of life in 188 patients with myasthenia gravis in China. AB - Myasthenia gravis (MG) is a kind of chronic autoimmune disease which can weaken patients' motor function and, furthermore, produce negative impact on the health related quality of life (HRQoL). The primary purpose of this research was to evaluate factors that might affect the HRQoL of MG patients. A cross-sectional clinical research was carried out including 188 successive patients with MG. Myasthenia Gravis Foundation of America (MGFA) classification and Quantitative Myasthenia Gravis (QMG) score were applied to assess the severity of the disease. The Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36) was used to estimate the HRQoL. Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were utilized to measure the depression and anxiety symptom. Factors may influence the HRQoL of MG patients include age, educational level, occupation, the situation of the thymus, the type of MG and generalized myasthenia gravis (GMG), the severity of the disease and the psychological disorder. Higher QMG and HARS scores were two significant factors that can prognosticate lower Physical Composite Score (PCS) and Mental Composite Score (MCS), while older age was just a significant factor which has prognostic value for lower PCS. The results of this research may have a potential guiding significance for the clinical treatment strategy and improve the quality of life in patients with MG consequently. In addition to the treatment of physical symptoms, the psychological symptoms such as anxiety and depression should be concerned as well. PMID- 26000923 TI - Dysferlinopathy: mitochondrial abnormalities in human skeletal muscle. AB - PURPOSE: Mitochondrial defects have been associated with a series of muscular diseases. Dysferlinopathy, however, has been rarely reported with mitochondrial dysfunction. Here we report a cohort of dysferlinopathy patients with mitochondrial abnormalities found in muscle. METHODS: Clinical data and muscle pathologies of nine cases with dysferlinopathy were retrospectively studied. mtDNA copy number, protein levels and activities of mitochondrial enzyme complexes were assayed. RESULTS: Nine patients were diagnosed as having dysferlinopathy by DYSF sequencing and quantification of dysferlin levels in muscle homogenates. Muscle biopsies exhibited dystrophic changes (n = 9), ragged red fibers (n = 9) and cytochrome c oxidase-deficient fibers (n = 9). mtDNA copy number increased significantly in 56% (15/27) of fibers with mitochondrial histology. Protein levels of complex IV subunits II (n = 5), complex III subunit core 2 (n = 2) and complex I NDUFB1 (n = 1) decreased. Impaired activities of complexes I, III and IV were observed in 56%, 33% and 78% of subjects and the activities were reduced by 21%, 18% and 40%, respectively. Besides, loss activities of complexes I/IV and decreased ATP level were also found in fibroblasts from dysferlinopathy. CONCLUSION: Prominent mitochondrial abnormalities are common pathological findings in muscle from dysferlinopathy. Our data indicated that mitochondria may play a significant role in the progression of dysferlinopathy and also highlighted the potential of mitochondrial protective drugs in rescuing the symptoms of dysferlinopathy. PMID- 26000924 TI - Lack of association between the ATP13A2 A746T variant and Parkinson's disease susceptibility in Han Chinese: a meta-analysis. AB - PURPOSE: To perform a meta-analysis to help resolve the controversy of whether the ATP13A2 A746T variant is associated with Parkinson's disease (PD) susceptibility in Han Chinese. METHODS: Six literature databases were searched for case-control studies published up to October 2014: Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang and SinoMed. RESULTS: Five eligible articles were identified, which reported six case-control studies and a total of 1703 cases and 2050 controls. The overall results suggested low frequencies of the A746T variant in Han Chinese patients (9/1703, 0.55%) and controls (6/2050, 0.29%). We failed to find evidence of significant differences in variant frequencies among Han Chinese, Uyghur and Japanese patients (p = 0.263). Analysis of pooled odds ratios (ORs) and 95% confidence interval (CIs) revealed no association between the A746T variant and overall PD risk (GA vs. GG: OR 1.78, 95%CI 0.71-4.46, p = 0.216; allele A vs. G: OR 1.90, 95%CI 0.77-4.69, p = 0.167). CONCLUSION: The ATP13A2 A746T variant is rare in Han Chinese patients and controls and is not associated with PD susceptibility in this ethnic group. Variant frequencies do not differ significantly among Han Chinese, Uyghur and Japanese patients. Further well-designed studies with larger samples are needed to validate these results. PMID- 26000925 TI - Prolongation of F-wave minimal latency: a sensitive predictor of polyneuropathy. AB - INTRODUCTION: To evaluate the sensitivity of F-wave minimal latencies, we compared F-waves with motor and sensory nerve conduction studies (MNCS and SNCS) in patients with peripheral neuropathy. METHODS: A retrospective chart review conducted in 484 patients confirmed the clinical evidence of a polyneuropathy, and studies of F-wave minimal latencies as well as MNCS and SNCS in each patient. RESULTS: Overall rate of abnormality reached 469/484 (96.9%) for F-wave minimal latencies as compared to 374/484 (77%) for nerve conduction studies ( p < 0.0001). Nerve-specific abnormalities of F-waves showed 290/354 (82%), 140/171 (82%), 367/398 (92%) and 357/376 (95%) for median, ulnar, peroneal and tibial nerves, respectively. Corresponding values for MNCS consisted of 108/354 (31%), 29/171 (17%), 258/398 (65%) and 189/376 (50%) (all p < 0.0001). In contrast, SNCS revealed abnormalities in 120/333 (36%), 60/159 (38%) and 266/474 (56%) of median, ulnar and sural nerves. CONCLUSION: F-wave minimal latencies serve as the best predictor of polyneuropathy followed by SNCS and then MNCS. PMID- 26000926 TI - Association of the p22phox polymorphism C242T with the risk of late-onset Alzheimer's disease in a northern Han Chinese population. AB - The C242T polymorphism of the CYBA gene that encodes p22phox, a component of nicotinamide adenine dinucleotide phosphate oxidase, has been found to modulate reactive oxygen species (ROS) production. Oxidative stress is thought to play a pivotal role in the pathophysiology of Alzheimer's disease (AD), which is manifested as increased availability of ROS because of an imbalanced redox state. Therefore, the aim of this study was to investigate potential associations of the p22phox C242T polymorphism with the risk of late-onset AD (LOAD) in a northern Han Chinese population. Patients with LOAD (n = 276) and 320 control subjects were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes. No significant differences were found between LOAD and p22phox C242T polymorphism, but a significant association was obtained in the genotype and allele distributions of p22phox C242T between LOAD patients and controls in apolipoprotein E (ApoE) epsilon4 carriers. These results suggested that p22phox C242T polymorphism has a possible role in changing the genetic susceptibility to LOAD in ApoE epsilon4 carriers of this northern Han Chinese population. PMID- 26000927 TI - Neuro-urological manifestations of Parkinson's disease. AB - This article highlights the urological manifestations of Parkinson's disease, the neurological pathways shared by Parkinson's and its urological diseases. PMID- 26000928 TI - Nerve defect repair by differentiated adipose-derived stem cells and chondroitinase ABC-treated acellular nerves. AB - OBJECTIVE: To evaluate the effects of differentiated adipose-derived stem cells (dADSC) and chondroitinase ABC (ChABC)-treated acellular nerves (ACN) in building artificial nerves and repairing nerve defects. METHODS: ADSC were isolated from the adipose tissue of Wistar rats, induced to differentiate into Schwann-like cells, and implanted into ChABC-treated ACN to repair a 15-mm sciatic nerve defect in Sprague-Dawley rats (the experimental group, group D). The control groups were an autologous nerve transplantation group (group E); ACN (group A), ChABC-treated ACN graft group (group B), and dADSC + ACN (group C). Twelve weeks after surgery, electromyography recordings, tricep surae muscle wet weight recovery rate, and axon counts were measured to evaluate the repair of peripheral nerve defects. RESULTS: The nerve conduction velocity, compound muscle action potentials, tricep surae muscle wet weight recovery rate, and myelinated axon counts in the ChABC-ACN/dADSC group were significantly higher than in the other groups (P < 0.05), which were all lower than the autologous group (P < 0.05). CONCLUSIONS: The combination of ChABC-treated ACN and dADSC exhibited a synergistic effect in promoting nerve regeneration, and could be an alternative for effective tissue-engineered nerves. PMID- 26000929 TI - Diagnostic approaches to predict persistent post-traumatic symptoms after mild traumatic brain injury - a literature review. AB - Mild traumatic brain injury (mTBI) is one of the most frequently diagnosed neurological disorders in emergency departments. Although there are established recommendations for the diagnosis and treatment in the acute stage, there is an on-going debate in which diagnostic methods and risk factors predict unfavourable long-term outcome after mTBI. This literature review addresses the question, which diagnostic approaches may best predict persistent post-traumatic symptoms (pPTS). A literature search for experimental studies from January 2000 to September 2014 evaluating the following diagnostic approaches (1) susceptibility weighted imaging (SWI), (2) diffusion tensor imaging (DTI), (3) magnetic resonance spectroscopy (MRS), (4) functional magnetic resonance imaging (fMRI), as predictive factors of pPTS or unfavourable cognitive outcome in adult populations with mTBI was performed. DTI has been proved to be a valuable tool to identify diffuse axonal injury (DAI) after mTBI. Additionally, some studies showed associations between DAI and unfavourable cognitive outcome. SWI has shown to be a highly sensitive imaging method to identify microbleeds. The presence and quantity of microbleeds in this imaging technique can further provide aetiological evidence for pPTS. MRS provides information about local neurons metabolism and preliminary data show that creatine-phosphocreatine levels measured after mTBI are predictive of cognitive outcome and emotional distress. The results of one study have shown fMRI as a useful tool to differentiate mTBI patients with pPTS from controls and mTBI patients without pPTS in a resting state condition. From the evaluated diagnostic approaches to predict pPTS after mTBI, DTI, SWI, MRS, and fMRI seem to have adequate sensitivity and specificity as predictive diagnostic tools for pPTS. Large longitudinal clinical trials are warranted to validate the prognostic applicability and practicability in daily clinical practice. PMID- 26000930 TI - Guillain-Barre syndrome following chickenpox: a case series. AB - Guillain-Barre syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy, usually triggered by an infectious episode, mostly of viral origin. Varicella zoster virus (VZV) is a rare cause of GBS, mainly in the case of latent infection reactivation. We report on three adult patients who developed GBS following chickenpox, after a short period of latency. They were promptly treated with intravenous immunoglobulin, and the first one with plasma exchange additionally. All the patients experienced almost complete clinical recovery. Our experience suggests that primary VZV infection constitutes a GBS triggering event. PMID- 26000931 TI - Electrodiagnosis and muscle biopsy in asymptomatic hyperckemia. AB - : Purpose/aim of the study: An increased serum level of creatine kinase (CK) in asymptomatic individuals is a diagnostic challenge, as it may be associated with either physiological conditions, such as exercise or even signal an ominous neuromuscular disease at a presymptomatic stage. The electromyogram (EMG) and the muscle biopsy play a key role in the evaluation of asymptomatic hyperckemia. The objective of this study was to investigate asymptomatic individuals with increased CK levels. MATERIALS AND METHODS: We comparatively studied EMG, quantitative EMG and muscle biopsy in asymptomatic clinically normal individuals with repeatedly increased CK levels. RESULTS: Conventional EMG was abnormal in 76% of patients, while quantitative EMG showed abnormal results in 88.9%. Muscle biopsy was diagnostic in 28%, one patient had neurogenic findings, 40% showed non specific changes and 28% had normal results. CONCLUSIONS: EMG and especially quantitative EMG are highly sensitive in detecting subclinical neuromuscular diseases, whereas muscle biopsy may better contribute in the final diagnosis. No strong correlations were found between histological abnormalities and electrophysiological data, but further research is needed. PMID- 26000932 TI - A functional 5HT2A receptor polymorphism (His452Tyr) and memory performances in Alzheimer's disease. AB - The functional His452Tyr polymorphism in the 5HT2A receptor has been described to be associated with verbal memory in healthy adults, with worse episodic memory performances in Tyr452 (T) carriers. The aim of our study was to investigate a possible effect of this polymorphism on memory performances in Alzheimer disease (AD). We enrolled 169 patients affected by probable AD. 5HT2A genotype was determined as previously described. According to their genotype, patients were divided in T carriers ( n = 111) and non-carriers ( n = 69). We evaluated the possible effect of 5HT2A polymorphism on verbal memory tasks. A one-way MANOVA analysis did not show a positive interaction between the two groups ( p > 0.05) at the baseline and at the follow-up. Nevertheless, the analyses of the single task effect showed lower performances for non-T carriers only in Rey's recognition task. Recent data reported poorer memory performances in healthy subjects carrying the T variant, in age-dependent manner (no differences between T vs. nT carriers were observed for age >50 years). In our AD sample, we did not find significant differences in verbal memory scores in T vs. nT carriers while a significant difference was found only in attentional task. At variance with that in healthy subjects, no correlation has been found between memory profiles of AD patients and His452Tyr polymorphism. PMID- 26000933 TI - Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis. AB - Calcineurin plays an important role in the development of neuronal excitability, modulation of receptor's function and induction of apoptosis in neurons. It has been established in kindling models that status epilepticus induces brain focal edema and astrocyte activation. However, the role of calcineurin in brain focal edema and astrocyte activation in status epilepticus has not been fully understood. In this study, we employed a model of lithium-pilocarpine-induced status epilepticus and detected calcineurin expression in hippocampus by immunoblotting, brain focal edema by non-invasive magnetic resonance imaging (MRI 7T) and astrocyte expression by immunohistochemistry. We found that the brain focal edema was seen at 24 h after status epilepticus, and astrocyte expression was obviously seen at 7 d after status epilepticus. Meanwhile, calcineurin expression was seen at24 h and retained to 7 d after status epilepticus. A FK506, a calcineurin inhibitor, remarkably suppressed the status epilepticus-induced brain focal edema and astrocyte expression. Our data suggested that calcineurin overexpression plays a very important role in brain focal edema and astrocyte expression. Therefore, calcineurin may be a novel candidate for brain focal edema occurring and intracellular trigger of astrogliosis in status epilepticus. PMID- 26000934 TI - The clinical significance of the neutrophil-to-lymphocyte ratio in multiple sclerosis. AB - Multiple sclerosis (MS) is one of the main chronic inflammatory diseases of the central nervous system that causes functional disability in young people. The aim of this study was to investigate the neutrophil-to-lymphocyte ratio (NLR) in patients with MS and the relationship between the NLR and the severity of the disease. One hundred and two MS patients (31 patients were in relapse; 71 patients were in remission) and 56 healthy controls were included. Complete blood counts as well as demographic and clinical data from MS patients were evaluated retrospectively. The NLRs were calculated for all participants and were compared; the cut-off value was also determined for the NLR and Expanded Disability Status Scale (EDSS). MS patients had a significantly higher NLR (p < 0.001) than the control group. The NLR levels were significantly higher in patients who were in relapse than patients in remission (p = 0.039). The cut-off value for the NLR to predict an MS diagnosis and activity were determined to be 2.04 and 3.90, respectively. The NLRs were directly correlated with erythrocyte sedimentation rate levels (r = 0.795, p < 0.001). Logistic regression analysis with dichotomous EDSS score showed that a high NLR was an independent predictor of the progression of disability. The NLR may be a biomarker that has simple, quick, inexpensive and reproducible properties in MS to predict patient's prognosis. PMID- 26000935 TI - Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3. AB - AIM: Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy. METHODS: A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis. RESULTS: All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected. CONCLUSION: We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56. PMID- 26000936 TI - The complete mitochondrial genome of Nyctalus noctula (Chiroptera: Vespertilionidae). AB - The mitochondrial genome of Nyctalus noctula is a circular molecule of 17,478 bp in length, containing 22 transfer RNA genes, 13 protein-coding genes, 2 ribosomal RNAs and a D-loop region. The overall A + T content of the H-strand is 61.4% (A 32.0%, T 29.4%, C 24.1% and G 14.5%). Among the 13 protein-coding genes, most of them begin with ATG as the start codon except for ND5 with ATA and ND2 and ND3 with ATT. ND1 and ND2 genes terminate with TAG as the stop codon, Cyt b ends with AGA, COIII, ND3 and ND4 genes end with an incomplete stop codon (T- -) and the other protein-coding genes end with TAA. In Bayesian inference (BI) and Maximum likelihood (ML) trees, we found that N. noctula is a sister clade to Pipistrellus abramus, and (Nyctalus + Pipistrellus) is a sister clade to (Chalinolobus + (Eptesicus + Vespertilio)) (1.00 in BI and 100% in ML). PMID- 26000937 TI - The complete F-type mitochondrial genome of Chinese freshwater mussel Anodonta euscaphys. AB - Anodonta euscaphys is the endemic species of freshwater mussel in China. The complete F-type mitochondrial genome of the A. euscaphys is amplified and analyzed in this study. It is 15,741 bp in length. The base composition of the genome with A + T bias is 64.78%. There are 24 noncoding regions found throughout the mitogenome of A. euscaphys, ranging in size from 3 to 302 bp, the largest of which was between ND2 and tRNA(Glu). The phylogenetic tree based on 22 mitogenome, including 16 F-type freshwater mussels, 2 M-type freshwater mussels and 4 marine mussels were analyzed in our study, the results showed that the F type and the M-type of the freshwater mussels were clustered respectively, the A. euscaphys was clustered with Anodonta family species firstly, and it was the closest to the Anodonta arcaeformis in our analysis. PMID- 26000938 TI - Corrigendum. PMID- 26000939 TI - Complete mitochondrial genome of Lutzomyia (Nyssomyia) umbratilis (Diptera: Psychodidae), the main vector of Leishmania guyanensis. AB - The nearly complete mitochondrial genome of Lutzomyia umbratilis Ward & Fraiha, 1977 (Psychodidae: Phlebotominae), considered as the main vector of Leishmania guyanensis, is presented. The sequencing has been performed on an Illumina Hiseq 2500 platform, with a genome skimming strategy. The full nuclear ribosomal RNA segment was also assembled. The mitogenome of L. umbratilis was determined to be at least 15,717 bp-long and presents an architecture found in many mitogenomes of insect (13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs, and one non-coding region also referred as the control region). The control region contains a large repeated element of c. 370 bp and a poly-AT region of unknown length. This is the first mitogenome of Psychodidae to be described. PMID- 26000940 TI - Phylogeography and spatial structure of the lowland tapir (Tapirus terrestris, Perissodactyla: Tapiridae) in South America. AB - We sequenced the mitochondrial cytochrome b gene of 141 lowland tapirs (Tapirus terrestris) - representing the largest geographical distribution sample of this species studied across of South America to date. We compare our new data regard to two previous works on population structure and molecular systematics of T. terrestris. Our data agree with the Thoisy et al.'s work in (1) the Northern Western Amazon basin was the area with the highest gene diversity levels in T. terrestris, being probably the area of initial diversification; (2) there was no clear association between haplogroups and specific geographical areas; (3) there were clear population decreases during the last glacial maximum for the different haplogroups detected, followed by population expansions during the Holocene; and (4) our temporal splits among different T. terrestris haplogroups coincided with the first molecular clock approach carried out by these authors (fossil calibration). Nevertheless, our study disagreed regard to other aspects of the Thoisy et al.'s claims: (1) meanwhile, they detected four relevant clades in their data, we put forward six different relevant clades; (2) the Amazon River was not a strong barrier for haplotype dispersion in T. terrestris; and (3) we found reciprocal monophyly between T. terrestris and T. pinchaque. Additionally, we sequenced 42 individuals (T. terrestris, T. pinchaque, T. bairdii, and the alleged "new species", T. kabomani) for three concatenated mitochondrial genes (Cyt-b, COI, and COII) agreeing quite well with the view of Voss et al., and against of the claims of Cozzuol et al. Tapirus kabomani should be not considered as a full species with the results obtained throughout the mitochondrial sequences. PMID- 26000941 TI - The complete mitochondrial genome of Southern pig-tailed macaque, Macaca nemestrina, and comparative mitochondrial genomics of Macaca species. AB - In this study, we report the complete mitochondrial genome sequence of Southern pig-tailed, Macaca nemestrina for the first time. The genome is found to be 16,560 bp in length and has a base composition of A (32.25%), G (12.31%), C (30.51%), and T (24.93%), indicating that the percentage of A + T (57.18%) was higher than G + C (42.82%). Similar to other monkeys, it contains a typically conserved structure including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 control region (D-loop). Most of the genes were located on the H-strand except for the ND6 gene and 8 tRNA genes. To obtain a more complete understanding of the evolutionary history of Macaca genus, 11 mitochondrial genomes were used for phylogenetic analysis. This mitochondrial sequence reported here would be useful to uncover the monkey's evolution and add a new genetic resource for the genus Macaca. PMID- 26000942 TI - Next generation sequencing yields the complete mitochondrial genome of the Zebra moray, Gymnomuraena zebra (Anguilliformes: Muraenidae). AB - In this study, the complete mitogenome sequence of the Zebra moray, Gymnomuraena zebra (Anguilliformes: Muraenidae) has been sequenced by the next-generation sequencing method. The assembled mitogenome consisting of 16,576 bp includes 13 protein coding genes, 22 transfer RNAs, and two ribosomal RNAs genes. The overall base composition of Zebra moray is 30.2% for A, 26.8% for C, 17.2% for G, and 25.8% for T and show 80% identities to Kidako moray, Gymnothorax kidako. The complete mitogenome of the Zebra moray provides an essential and important DNA molecular data for further phylogeography and evolutionary analysis for moray eel phylogeny. PMID- 26000943 TI - The complete mitochondrial genome of Chaenogobius gulosus (Gobiidae, Perciformes) from the South Sea, Korea. AB - The morphology-based taxonomy of Chaenogobius is so complex that some species have been transferred to other genera. To obtain basic information on the phylogenetic relationships among gobies, the complete mitochondrial DNA sequence of C. gulosus was determined using next-generation sequencing. The complete mitochondrial genome is 16,477 bp in length and consists of 22 tRNAs, two ribosomal RNAs, 13 protein-coding genes, and two non-coding regions (the light strand replication origin and the control region). The gene order and locations are similar to those in most other vertebrates. The nucleotide composition of the mitogenome contains 29.1% A, 29.6% T, 15.9% G, and 25.4% C, with a slight AT bias (58.7%). The genus most related to Chaenogobius was Luciogobius, as revealed by phylogenetic relationships derived using a maximum likelihood tree. This mitogenome will help to elucidate the morphological systematic complexity and phylogenetic structure of Chaenogobius and related species. PMID- 26000944 TI - Complete mitochondrial genome of Gekko chinensis (Squamata, Gekkonidae). AB - We sequenced the complete mitochondrial genome of Gekko chinensis, which is an endemic species to China. The complete mitogenome is 17,906 bp in size, containing 37 genes coding for 13 proteins, two ribosomal RNAs, 22 transfer RNAs, and a control region. The A + T content of the overall base composition of H strand is 61.1% (T: 27.6%, C: 25.5%, A: 33.5%, and G: 13.4%). The major non coding region (control region) is 2530 bp in length and the A + T content is 67.9%. Besides, four tandem repeats were found within the control region. In Bayesian inference (BI), maximum likelihood (ML) and maximum parsimony (MP) trees, we found G. chinensis is a sister clade to Gekko swinhonis. PMID- 26000945 TI - PCR-free shotgun sequencing of the stone loach mitochondrial genome (Barbatula barbatula). AB - The complete mitochondrial genome of the stone loach Barbatula barbatula (Linnaeus, 1758) (Actinopterygii: Cypriniformes: Nemacheilidae) has been sequenced using a genome-skimming approach on an Illumina Hiseq 2500 platform. The mitochondrial genome of B. barbatula was determined to be 16,630 bp long and presents an organization typical of vertebrate mitogenomes. The mean coverage was 82* with a minimum coverage of 33* for the control region and 52* for the remaining part of the genome. A phylogenetic analysis of the Nemacheilidae family shows the monophyly of the Barbatula genus with strong support. PMID- 26000946 TI - Mitochondrial tRNA(Thr) A15951G mutation may not be associated with Leber's Hereditary Optic Neuropathy. AB - Mutation in mitochondrial DNA (mtDNA) has been found to play an important role in the pathogenesis of Leber's Hereditary Optic Neuropathy (LHON). Three primary mutations, the ND4 G11778A, ND6 T14484C, and ND1 G3460A, have been found to account more than 90% of LHON patients in many families worldwide. In addition to the mutations in genes encoding the respiratory chain complex I, reports concerning the mt-tRNA gene mutations associated with LHON have increased, some pathogenic mutations caused the failure in mt-tRNA metabolism, thereby worsened the mitochondrial dysfunction that is responsible for LHON. Recently, the A15951G mutation in mt-tRNA(Thr) gene has been reported to be a "modified" factor in increasing the penetrance and expressivity of LHON-associated ND4 G11778A mutation in three Chinese families. However, evolutionary conservation analysis of this mutation suggested a poor conservation index and the pathogenicity scoring system showed that this mutation was a neutral polymorphism. PMID- 26000947 TI - Next generation sequencing yields the complete mitochondrial genome of the largescale mullet, Liza macrolepis (Teleostei: Mugilidae). AB - In this study, the complete mitogenome sequence of largescale mullet (Teleostei: Mugilidae) has been sequenced by the next-generation sequencing method. The assembled mitogenome, consisting of 16,832 bp, had the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a non-coding control region of D-loop. D-loop which has a length of 1094 bp is located between tRNA-Pro and tRNA-Phe. The overall base composition of largescale mullet is 27.8% for A, 30.1% for C, 16.2% for G, and 25.9% for T. The complete mitogenome may provide essential and important DNA molecular data for further phylogenetic and evolutionary analysis for Mugilidae. PMID- 26000948 TI - Complete mitochondrial genome of Pterophyllum scalare (Perciformes, Cichlidae). AB - The complete mitochondrial genome of Pterophyllum scalare was determined in order to characterize and compare their mitochondrial genomes (GenBank accession number KP231206). The total length of the mitochondrial genome was 16,581 bp which contained 37 genes (13 protein-coding genes, two ribosomal RNA, and 22 transfer RNAs) and a major non-coding control region which was similar to those reported mitochondrial genomes. Phylogenetic analyses identified P. scalare shared 80-86% sequence identity with other assayed fishes. The relationship was more close to the cichlid family in the perciformes. Most genes were encoded on the H-strand, except for the ND6 and eight tRNA genes, encoding on the L-strand. The nucleotide skewness for the coding strands of P. scalare (AT-skew = 0.02, GC-skew = -0.32) was biased toward A and C. The complete mitogenome may add new information to existing mitogenome data for cichlids, providing further information that may contribute for their taxonomy, evolution, and phylogeny. PMID- 26000949 TI - Taxonomic status of the three color variants in sea cucumber (Apostichopus japonicus): evidence from mitochondrial phylogenomic analyses. AB - Color variation in sea cucumber is one of the most crucial traits affecting price and taste in East Asian countries. However, the relationship and taxonomic status of the three color variants are still unclear. We used 14 samples that covered all three color variants and their geographic distributions, to construct the first phylogeny for the color variants based on the complete mitochondrial genome sequence and a number of tree-building methods (maximum parsimony (MP), maximum likelihood (ML), and Bayesian inference (BI)). The divergence times within color variants were estimated by the Bayesian molecular clock approach using the BEAST program. Our results showed that the color variants were not monophyletic in the well-resolved phylogenetic tree, which strongly refuted their separate species status. The molecular dating estimate revealed that the sea cucumber was a young group, which originated in the early Miocene period (22.03 mya) and rapidly diverged after the late Miocene period. It is interesting that individuals within each variant or geographic distribution were not always closely related and thus did not share a common origin. We propose that although they differ in body color, the three color morphs all belong to a single species of Apostichopus japonicus and the historical marine climate and the hydrographic complexity of the ocean currents could be responsible for their present distribution patterns. PMID- 26000950 TI - Lysosomal calcium regulates autophagy. AB - Recent evidence has indicated that the lysosome is able to act as a signaling organelle that senses nutrient availability and generates an adaptive response that is important for cellular homeostasis. We recently discovered another example of lysosomal signaling where lysosomal calcium release activates the master autophagy regulator TFEB via the phosphatase calcineurin. PMID- 26000951 TI - Variable gene dispersal conditions and spatial deforestation patterns can interact to affect tropical tree conservation outcomes. AB - Tropical lowland rain forest (TLRF) biodiversity is under threat from anthropogenic factors including deforestation which creates forest fragments of different sizes that can further undergo various internal patterns of logging. Such interventions can modify previous equilibrium abundance and spatial distribution patterns of offspring recruitment and/or pollen dispersal. Little is known about how these aspects of deforestation and fragmentation might synergistically affect TLRF tree recovery demographics and population genetics in newly formed forest fragments. To investigate these TLRF anthropogenic disturbance processes we used the computer program NEWGARDEN (NG), which models spatially-explicit, individual-based plant populations, to simulate 10% deforestation in six different spatial logging patterns for the plant functional type of a long-lived TLRF canopy tree species. Further, each logging pattern was analyzed under nine varying patterns of offspring versus pollen dispersal distances that could have arisen post-fragmentation. Results indicated that gene dispersal condition (especially via offspring) had a greater effect on population growth and genetic diversity retention (explaining 98.5% and 88.8% of the variance respectively) than spatial logging pattern (0.2% and 4.7% respectively), with 'Near' distance dispersal maximizing population growth and genetic diversity relative to distant dispersal. Within logged regions of the fragment, deforestation patterns closer to fragment borders more often exhibited lower population recovery rates and founding genetic diversity retention relative to more centrally located logging. These results suggest newly isolated fragments have populations that are more sensitive to the way in which their offspring and pollen dispersers are affected than the spatial pattern in which subsequent logging occurs, and that large variation in the recovery rates of different TLRF tree species attributable to altered gene dispersal regimens will be a likely outcome of fragmentation. Conservation implications include possible manual interventions (manual manipulations of offspring dispersers and/or pollinators) in forest fragments to increase population recovery and genetic diversity retention. PMID- 26000952 TI - Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation. AB - 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (Pe), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (Pe = 0.32 +/- 0.01 * 10(-6 )cm/s). Using the Caco-2 cell system, the Papp AP-BL in absorptive direction (3.36 +/- 0.02 * 10(-5 )cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 +/- 0.07 * 10(-5 )cm/s), suggesting a polarized transport. The efflux ratio (Papp AP-BL/Papp BL-AP = 0.52 +/- 0.02) indicated a low affinity of DA-PHEN to efflux carriers. The forced swim test highlighted a reduction of immobility time in both pre-test and test sessions (p < 0.0001), with an exacerbation in the number of headshakes and divings in the pretest (p < 0.0001). Morris water maze strengthened the hypothesis that DA-PHEN induces adaptive responses to environmental challenges which are involved on cognitive functions (DA-PHEN versus CTR: escape latency; p < 0.001; distance swum p < 0.001, time spent on target quadrant p < 0.001), without any change in locomotor activity for the administered dose. The molecular docking revealed the interaction of DA-PHEN with the identified D1 site mapping human brain receptor. PMID- 26000953 TI - The economic burden of maternal mortality on households: evidence from three sub counties in rural western Kenya. AB - BACKGROUND: This study explores the consequences of a maternal death to households in rural Western Kenya focusing particularly on the immediate financial and economic impacts. METHODS: Between September 2011 and March 2013 all households in the study area with a maternal death were surveyed. Data were collected on the demographic characteristics of the deceased woman; household socio-economic status; a history of the pregnancy and health care access and utilization; and disruption to household functioning due to the maternal death. These data were supplemented by in-depth and focus group discussions. RESULTS: The health service utilization costs associated with maternal deaths were significantly higher, due to more frequent service utilization as well as due to the higher cost of each visit suggesting more involved treatments and interventions were sought with these women. The already high costs incurred by cases during pregnancy were further increased during delivery and postpartum mainly a result of higher facility-based fees and expenses. Households who experienced a maternal death spent about one-third of their annual per capita consumption expenditure on healthcare access and use as opposed to at most 12% among households who had a health pregnancy and delivery. Funeral costs were often higher than the healthcare costs and altogether forced households to dis save, liquidate assets and borrow money. What is more, the surviving members of the households had significant redistribution of labor and responsibilities to make up for the lost contributions of the deceased women. CONCLUSION: Kenya is in the process of instituting free maternity services in all public facilities. Effectively implemented, this policy can lift a major economic burden experienced by a very large number of household who seek maternal health services which can be catastrophic in complicated cases that result in maternal death. There needs to be further emphasis on insurance schemes that can support households through catastrophic health spending. PMID- 26000954 TI - Pseudopotential-Based Correlation Consistent Composite Approach (rp-ccCA) for First- and Second-Row Transition Metal Thermochemistry. AB - The relativistic-pseudopotential correlation consistent composite approach (rp ccCA) was used to determine the enthalpy of formation (DeltaHf) of 24 first row (3d) transition metal compounds. The rp-ccCA-derived DeltaHf's were compared to DeltaHf's previously obtained with an all-electron composite method for transition metals (ccCA-TM). For the 3d metal systems, rp-ccCA achieves transition metal accuracy, within 3 kcal/mol of reliable experimental data, overall. By utilizing pseudopotentials within the rp-ccCA methodology, we observed a significant computational time savings (53%) in comparison to the all electron basis sets employed within ccCA-TM. With the proven reliability and accuracy of rp-ccCA, the methodology was employed to construct a calibration set of 210 second-row (4d) transition metal compounds and their DeltaHf's. The 4d calibration set is referred to as 4dHf-210. Within the 4dHf-210 set, there were 61 molecules with available experimental data. The average experimental uncertainty was 4.05 kcal/mol and the mean absolute deviation of rp-ccCA was 3.64 kcal/mol, excluding outliers (10 total). This study provides a large set of energetics that can be used to gauge existing and future computational methodologies and to aid experimentalists in reaction design. PMID- 26000955 TI - Vertebrae length and ultra-structure measurements of collagen fibrils and mineral content in the vertebrae of lordotic gilthead seabreams (Sparus aurata). AB - Skeletal deformities of gilthead seabream (Sparus aurata) are a major factor affecting the production cost, the external morphology and survival and growth of the fish. Adult individuals of S. aurata were collected from a commercial fish farm in Greece and were divided into two groups: one with the presence of lordosis, a skeletal deformity, and one without any skeletal deformity. Fishes were X-rayed, and cervical, abdominal and caudal vertebrae lengths were measured. Vertebrae were taken from the site of the vertebral column where lordosis occurred. One part was decalcified and prepared for collagen examination with transmission electron microscopy, and the rest were incinerated, and the Ca and P contents were measured. The stoichiometries of the samples were obtained by EDS (Energy Dispersive Spectroscopy). The same procedure was followed for fish without skeletal deformities (vertebrae were taken from the middle region of the vertebral column). The decalcified vertebrae parts were examined with TEM, collagen micrographs were taken and the fibrils' periods and diameters were measured. There were no significant differences for both Ca and P or the collagen fibrils' periods between the two fish groups. The mean lengths of the cervical, abdominal and caudal vertebrae where lordosis occurred were similar to the lengths of the respective regions of the individuals without the skeletal deformity. The TEM examination showed a significantly smaller mean vertebrae collagen fibril diameter from the fishes with lordosis compared with those from the controls, revealing the significance of collagen to bone structure. PMID- 26000956 TI - You are that smiling guy I met at the party! Socially positive signals foster memory for identities and contexts. AB - The emotional influence of facial expressions on memory is well-known whereas the influence of emotional contextual information on memory for emotional faces is yet to be extensively explored. This study investigated the interplay between facial expression and the emotional surrounding context in affecting both memory for identities (item memory) and memory for associative backgrounds (source memory). At the encoding fearful and happy faces were presented embedded in fear or happy scenes (i.e.: fearful faces in fear-scenes, happy faces in happy-scenes, fearful faces in happy-scenes and happy faces in fear-scenes) and participants were asked to judge the emotional congruency of the face-scene compounds (i.e. fearful faces in fear-scenes and happy faces in happy-scenes were congruent compounds). In the recognition phase, the old faces were intermixed with the new ones: all the faces were presented isolated with a neutral expression. Participants were requested to indicate whether each face had been previously presented (item memory). Then, for each old face the memory for the scene originally compounded with the face was tested by a three alternative forced choice recognition task (source memory). The results evidenced that face identity memory is differently modulated by the valence in congruent face-context compounds with better identity recognition (item memory) for happy faces encoded in happy-scenarios. Moreover, also the memory for the surrounding context (source memory) benefits from the association with a smiling face. Our findings highlight that socially positive signals conveyed by smiling faces may prompt memory for identity and context. PMID- 26000957 TI - Correlation between Either Cupriavidus or Porphyromonas and Primary Pulmonary Tuberculosis Found by Analysing the Microbiota in Patients' Bronchoalveolar Lavage Fluid. AB - Pulmonary tuberculosis (TB) has gained attention in recent decades because of its rising incidence trend; simultaneously, increasing numbers of studies have identified the relationship between microbiota and chronic infectious diseases. In our work, we enrolled 32 patients with primary TB characterised by unilateral TB lesion formation diagnosed by chest radiographic exam. Bronchoalveolar lavage fluid was taken from both lungs. Twenty-four healthy people were chosen as controls. Pyrosequencing was performed on the V3 hypervariable region of 16S rDNA in all bacterial samples and used as a culture-independent method to describe the phylogenetic composition of the microbiota. Through pyrosequencing, 271,764 amplicons were detected in samples and analysed using tools in the Ribosomal Database Project (RDP) and bioinformatics. These analyses revealed significant differences in the microbiota in the lower respiratory tract (LRT) of TB patients compared with healthy controls; in contrast, the microbiota of intra/extra-TB lesions were similar. These results showed that the dominant bacterial genus in the LRT of TB patients was Cupriavidus and not Streptococcus, which resulted in a significant change in the microbiota in TB patients. The abundance of Mycobacteria and Porphyromonas significantly increased inside TB lesions when compared with non-lesion-containing contralateral lungs. From these data, it can be concluded that Cupriavidus plays an important role in TB's secondary infection and that in addition to Mycobacteria, Porphyromonas may also be a co-factor in lesion formation. The mechanisms underlying this connection warrant further research. PMID- 26000958 TI - If It's Not One Thing, It's Another: An Inverse Relationship of Malignancy and Atherosclerotic Disease. AB - Atherosclerosis and malignancy are pervasive pathological conditions that account for the bulk of morbidity and mortality in developed countries. Our current understanding of the patholobiology of these fundamental disorders suggests that inflammatory processes may differentially affect them; thus, atherosclerosis can be largely driven by inflammation, where as cancer often flourishes as inflammatory responses are modulated. A corollary of this hypothesis is that cancer (or its treatment may significantly attenuate atherosclerotic disease by diminishing host inflammatory response, suggesting potential therapeutic approaches. To evaluate the relationship between cancer and cardiovascular atherosclerotic disease, we assessed 1,024 autopsy reports from Brigham and Women's Hospital and performed correlative analyses on atherosclerotic severity and cancer prevalence. In gender- and age-matched populations, there is a statistically significant inverse correlation between history of malignancy and autopsy-proven atherosclerotic disease. In a second analysis, we evaluated 147,779 patients through analysis of the Harvard Catalyst SHRINE database and demonstrated a reduced non-coronary atherosclerotic disease rate: control (27.40%), leukemia/lymphoma (12.57%), lung (17.63%), colorectal (18.17%), breast (9.79%), uterus/cervix (11.47%), and prostate (18.40%). We herein report that, based on two separate medical records analysis, an inverse correlation between cancer and atherosclerosis. Furthermore, this correlation is not uniformly associated with anti-neoplastic treatment, suggesting that the inverse relationship may be in part attributable to an individual's intrinsic inflammatory propensity, and/or to inflammation-modulatory properties of neoplasms. PMID- 26000959 TI - Characterization of microbial dysbiosis and metabolomic changes in dogs with acute diarrhea. AB - Limited information is available regarding the metabolic consequences of intestinal dysbiosis in dogs with acute onset of diarrhea. The aim of this study was to evaluate the fecal microbiome, fecal concentrations of short-chain fatty acids (SCFAs), as well as serum and urine metabolites in healthy dogs (n=13) and dogs with acute diarrhea (n=13). The fecal microbiome, SCFAs, and serum/urine metabolite profiles were characterized by 454-pyrosequencing of the 16S rRNA genes, GC/MS, and untargeted and targeted metabolomics approach using UPLC/MS and HPLC/MS, respectively. Significantly lower bacterial diversity was observed in dogs with acute diarrhea in regards to species richness, chao1, and Shannon index (p=0.0218, 0.0176, and 0.0033; respectively). Dogs with acute diarrhea had significantly different microbial communities compared to healthy dogs (unweighted Unifrac distances, ANOSIM p=0.0040). While Bacteroidetes, Faecalibacterium, and an unclassified genus within Ruminococcaceae were underrepresented, the genus Clostridium was overrepresented in dogs with acute diarrhea. Concentrations of fecal propionic acid were significantly decreased in acute diarrhea (p=0.0033), and were correlated to a decrease in Faecalibacterium (rho=0.6725, p=0.0332). The predicted functional gene content of the microbiome (PICRUSt) revealed overrepresentations of genes for transposase enzymes as well as methyl accepting chemotaxis proteins in acute diarrhea. Serum concentrations of kynurenic acid and urine concentrations of 2-methyl-1H-indole and 5-Methoxy-1H indole-3-carbaldehyde were significantly decreased in acute diarrhea (p=0.0048, 0.0185, and 0.0330, respectively). These results demonstrate that the fecal dysbiosis present in acute diarrhea is associated with altered systemic metabolic states. PMID- 26000960 TI - Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR. AB - Lung fibrosis is a poor prognostic factor for pulmonary adenocarcinoma, and the effect of a rigid microenvironment on cancer behavior is unclear. We cultured A549 cells on matrices of 0.2, 2, and 25 kPa to mimic the rigidities of normal lung parenchyma, progressive fibrotic change, and lung fibrosis, respectively. Lung tissue from patients with pulmonary adenocarcinoma was used to confirm the in vitro findings. Increased matrix rigidity promoted cell proliferation and upregulated the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-Met), and Snail expression in A549 cells. A549 cells became more resistant to the EGFR inhibitor (Erlotinib) and c-Met inhibitor (PHA-665752) when matrix rigidity increased; however, a high concentration of PHA-665752 reversed the rigidity-induced morphological pleomorphism. In human lung tissue, expression of type I collagen was more consistent with clinical fibrosis than the expression of alpha-smooth muscle antibody was. c-Met- and Snail-expressing tumor cells, rather than EGFR-experssing cells, were localized with lung parenchyma rich in type I collagen. Our findings suggest that c-Met causes the rigidity-induced biophysical reaction in pulmonary adenocarcinoma. Treatment targeting both EGFR and c-Met should be considered for patients with lung fibrosis and who are abundant type I collagen expression in the tumor mass. PMID- 26000961 TI - Arginine-rich polyplexes for gene delivery to neuronal cells. AB - Neuronal gene therapy potentially offers an effective therapeutic intervention to cure or slow the progression of neurological diseases. However, neuronal cells are difficult to transfect with nonviral vectors, and in vivo their transport across the blood-brain barrier (BBB) is inefficient. We synthesized a series of arginine-rich oligopeptides, grafted with polyethyleneimine (PEI) and modified with a short-chain polyethylene glycol (PEG). We hypothesized that the arginine would enhance cellular uptake and transport of these polyplexes across the BBB, with PEG imparting biocompatibility and "stealth" properties and PEI facilitating DNA condensation and gene transfection. The optimized composition of the polyplexes demonstrated hemocompatibility with red blood cells, causing no lysis or aggregation, and showed significantly better cytocompatibility than PEI in vitro. Polyplexes formulated with luciferase-expressing plasmid DNA could transfect rat primary astrocytes and neurons in vitro. Confocal imaging data showed efficient cellular uptake of DNA and its sustained intracellular retention and nuclear localization with polyplexes. Intravenous administration of the optimized polyplexes in mice led to gene expression in the brain, which upon further immunohistochemical analysis demonstrated gene expression in neurons. In conclusion, we have successfully designed a nonviral vector for in vitro and in vivo neuronal gene delivery. PMID- 26000962 TI - The Impacts of Migraine among Outpatients with Major Depressive Disorder at a Two Year Follow-Up. AB - BACKGROUND: No study has investigated the impacts of migraine on depression, anxiety, and somatic symptoms and remission at the two-year follow-up point among patients with major depressive disorder (MDD). This study aimed to investigate the above issues. METHODS: Psychiatric outpatients with MDD recruited at baseline were investigated at a two-year follow-up (N = 106). The Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale, and Depression and Somatic Symptoms Scale were used. Migraine was diagnosed according to the International Classification of Headache Disorders, 2nd edition. The patients were divided into no migraine, inactive migraine, and active migraine subgroups. Multiple logistic regressions were used to investigate the significant factors related to full remission of depression. RESULTS: Among patients without pharmacotherapy at the follow-up, patients with active migraine had significantly greater severities of anxiety and somatic symptoms as compared with patients without migraine; moreover, patients with active migraine had the lowest improvement percentage and full remission rate. There were no significant differences in depression, anxiety, and somatic symptoms between patients with inactive migraine and those without migraine. Active headache at follow-up was a significant factor related to a lower full remission rate. CONCLUSIONS: Active headache at follow-up was associated with a lower rate of full remission and more residual anxiety and somatic symptoms at follow-up among patients with migraine. Physicians should integrate a treatment plan for depression and migraine for the treatment of patients with MDD. PMID- 26000963 TI - Quantitative chemical-structure evaluation using atom probe tomography: Short range order analysis of Fe-Al. AB - Short-range-order (SRO) has been quantitatively evaluated in an Fe-18Al (at%) alloy using atom probe tomography (APT) data and by calculation of the generalised multicomponent short-range order (GM-SRO) parameters, which have been determined by shell-based analysis of the three-dimensional atomic positions. The accuracy of this method with respect to limited detector efficiency and spatial resolution is tested against simulated D03 ordered data. Whilst there is minimal adverse effect from limited atom probe instrument detector efficiency, the combination of this with imperfect spatial resolution has the effect of making the data appear more randomised. The value of lattice rectification of the experimental APT data prior to GM-SRO analysis is demonstrated through improved information sensitivity. PMID- 26000964 TI - Assessing coverage, equity and quality gaps in maternal and neonatal care in sub saharan Africa: an integrated approach. AB - BACKGROUND: Gaps in coverage, equity and quality of health services hinder the achievement of the Millennium Development Goals 4 and 5 in most countries of sub Saharan Africa as well as in other high-burden countries, yet few studies attempt to assess all these dimensions as part of the situation analysis. We present the base-line data of a project aimed at simultaneously addressing coverage, equity and quality issues in maternal and neonatal health care in five districts belonging to three African countries. METHODS: Data were collected in cross sectional studies with three types of tools. Coverage was assessed in three hospitals and 19 health centres (HCs) utilising emergency obstetric and newborn care needs assessment tools developed by the Averting Maternal Death and Disability program. Emergency obstetrics care (EmOC) indicators were calculated. Equity was assessed in three hospitals and 13 HCs by means of proxy wealth indices and women delivering in health facilities were compared with those in the general population to identify inequities. Quality was assessed in three hospitals using the World Health Organization's maternal and neonatal quality of hospital care assessment tool which evaluates the whole range of aspects of obstetric and neonatal care and produces an average score for each main area of care. RESULTS: All the three hospitals qualified as comprehensive EmOC facilities but none of the HCs qualified for basic EmOC. None of the districts met the minimum requisites for EmOC indicators. In two out of three hospitals, there were major quality gaps which were generally greater in neonatal care, management of emergency and complicated cases and monitoring. Higher access to care was coupled by low quality and good quality by very low access. Stark inequities in utilisation of institutional delivery care were present in all districts and across all health facilities, especially at hospital level. CONCLUSION: Our findings confirm the existence of serious issues regarding coverage, equity and quality of health care for mothers and newborns in all study districts. Gaps in one dimension hinder the potential gains in health outcomes deriving from good performances in other dimensions, thus confirm the need for a three-dimensional profiling of health care provision as a basis for data-driven planning. PMID- 26000965 TI - Parp3 negatively regulates immunoglobulin class switch recombination. AB - To generate highly specific and adapted immune responses, B cells diversify their antibody repertoire through mechanisms involving the generation of programmed DNA damage. Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by the recruitment of activation-induced cytidine deaminase (AID) to immunoglobulin loci and by the subsequent generation of DNA lesions, which are differentially processed to mutations during SHM or to double-stranded DNA break intermediates during CSR. The latter activate the DNA damage response and mobilize multiple DNA repair factors, including Parp1 and Parp2, to promote DNA repair and long-range recombination. We examined the contribution of Parp3 in CSR and SHM. We find that deficiency in Parp3 results in enhanced CSR, while SHM remains unaffected. Mechanistically, this is due to increased occupancy of AID at the donor (SMU) switch region. We also find evidence of increased levels of DNA damage at switch region junctions and a bias towards alternative end joining in the absence of Parp3. We propose that Parp3 plays a CSR-specific role by controlling AID levels at switch regions during CSR. PMID- 26000966 TI - Vaccinia virus Transmission through Experimentally Contaminated Milk Using a Murine Model. AB - Bovine vaccinia (BV) is a zoonosis caused by Vaccinia virus (VACV), which affects dairy cattle and humans. Previous studies have detected the presence of viable virus particles in bovine milk samples naturally and experimentally contaminated with VACV. However, it is not known whether milk contaminated with VACV could be a route of viral transmission. However, anti-Orthopoxvirus antibodies were detected in humans from BV endemic areas, whom had no contact with affected cows, which suggest that other VACV transmission routes are possible, such as consumption of contaminated milk and dairy products. Therefore, it is important to study the possibility of VACV transmission by contaminated milk. This study aimed to examine VACV transmission, pathogenesis and shedding in mice orally inoculated with experimentally contaminated milk. Thirty mice were orally inoculated with milk containing 107 PFU/ml of VACV, and ten mice were orally inoculated with uncontaminated milk. Clinical examinations were performed for 30 consecutive days, and fecal samples and oral swabs (OSs) were collected every other day. Mice were euthanized on predetermined days, and tissue and blood samples were collected. Nested-PCR, plaque reduction neutralization test (PRNT), viral isolation, histopathology, and immunohistochemistry (IHC) methods were performed on the collected samples. No clinical changes were observed in the animals. Viral DNA was detected in feces, blood, OSs and tissues, at least in one of the times tested. The lungs displayed moderate to severe interstitial lymphohistiocytic infiltrates, and only the heart, tonsils, tongue, and stomach did not show immunostaining at the IHC analysis. Neutralizing antibodies were detected at the 20th and 30th days post infection in 50% of infected mice. The results revealed that VACV contaminated milk could be a route of viral transmission in mice experimentally infected, showing systemic distribution and shedding through feces and oral mucosa, albeit without exhibiting any clinical signs. PMID- 26000967 TI - Evaluation of changes in equine care and limb-related abnormalities in working horses in Jaipur, India, as part of a two year participatory intervention study. AB - BACKGROUND: Previous studies have found the prevalence of lameness in working horses to be 90-100%. Risk factors for lameness in this important equine population, together with risk-reduction strategies adopted by their owners, are poorly understood. The objective was to uncover risk factors for lameness and limb abnormalities in working horses, by associating clinical lameness examination findings on three occasions over two years with owner reported changes in equine management and work practices over this period. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-one communities of horse owners in Jaipur, India, took part in a participatory intervention (PI) project aiming to reduce risk factors for poor welfare, particularly lameness and limb problems. Associations between quantitative measures of equine lameness/limb abnormalities and reported changes in management and work practices were compared with 21 control (C) communities of owners where no intervention had taken place. Key findings from 'complete cases', where the same horse stayed with the same owner for the whole study period (PI group = 73 owners of 83 horses, C group = 58 owners of 66 horses), were that more positive statements of change in equine management and work practices were made by PI group owners than C group owners. A mixed picture of potential risk factors emerged: some reported management improvements, for example reducing the weight of the load for cart animals, were associated with improved limbs and lameness, and others, such as making improvements in shoeing and increasing the age at which their animals started work, with negative outcomes. CONCLUSIONS/SIGNIFICANCE: This study illustrates the complexity and interacting nature of risk factors for lameness in working horses, and highlights the importance of longitudinal investigations that recognise and address this. PI group owners found the project useful and requested similar inputs in future. Our findings demonstrate the value of exploratory and participatory research methodology in the field of working horse welfare. PMID- 26000968 TI - Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model. AB - Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8 week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131 hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, beta-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3. PMID- 26000969 TI - Revising the Role of a Dioxirane as an Intermediate in the Uncatalyzed Hydroperoxidation of Cyclohexanone in Water. AB - The mechanism of the oxidation of cyclohexanone with an aqueous solution of hydrogen peroxide has been investigated. Experiments revealed the preliminary formation of an intermediate, identified as cyclohexylidene dioxirane, in equilibrium with the ketone, followed by formation of 1-hydroperoxycyclohexanol (Criegee adduct). Computational analysis with explicit inclusion of up to two water molecules rationalized the formation of the dioxirane intermediate via addition of the hydroperoxide anion to the ketone and revealed that this species is not involved in the formation of the Criegee adduct. The direct addition of hydrogen peroxide to the ketone is predicted to be favored over hydrolysis of the dioxirane, the latter in competition with ring opening to carbonyl oxide followed by hydration. However, dioxirane may account for the formation of the bis hydroperoxide derivative. PMID- 26000970 TI - Tumor Necrosis Factor-alpha-Induced Ototoxicity in Mouse Cochlear Organotypic Culture. AB - Tumor necrosis factor (TNF)-alpha is a cytokine involved in acute inflammatory phase reactions, and is the primary upstream mediator in the cochlear inflammatory response. Treatment of the organ of Corti with TNF-alpha can induce hair cell damage. However, the resulting morphological changes have not been systematically examined. In the present study, cochlear organotypic cultures from neonatal mice were treated with various concentrations and durations of TNF-alpha to induce inflammatory responses. Confocal microscopy was used to evaluate the condition of hair cells and supporting cells following immunohistochemical staining. In addition, the ultrastructure of the stereocilia bundle, hair cells, and supporting cells were examined by scanning and transmission electron microscopy. TNF-alpha treatment resulted in a fusion and loss of stereocilia bundles in hair cells, swelling of mitochondria, and vacuolation and degranulation of the endoplasmic reticulum. Disruption of tight junctions between hair cells and supporting cells was also observed at high concentrations. Hair cell loss was preceded by apoptosis of Deiters' and pillar cells. Taken together, these findings detail the morphological changes in the organ of Corti after TNF alpha treatment, and provide an in vitro model of inflammatory-induced ototoxicity. PMID- 26000971 TI - Acetic acid enhances endurance capacity of exercise-trained mice by increasing skeletal muscle oxidative properties. AB - Acetic acid has been shown to promote glycogen replenishment in skeletal muscle during exercise training. In this study, we investigated the effects of acetic acid on endurance capacity and muscle oxidative metabolism in the exercise training using in vivo mice model. In exercised mice, acetic acid induced a significant increase in endurance capacity accompanying a reduction in visceral adipose depots. Serum levels of non-esterified fatty acid and urea nitrogen were significantly lower in acetic acid-fed mice in the exercised mice. Importantly, in the mice, acetic acid significantly increased the muscle expression of key enzymes involved in fatty acid oxidation and glycolytic-to-oxidative fiber-type transformation. Taken together, these findings suggest that acetic acid improves endurance exercise capacity by promoting muscle oxidative properties, in part through the AMPK-mediated fatty acid oxidation and provide an important basis for the application of acetic acid as a major component of novel ergogenic aids. PMID- 26000972 TI - Cell death, perfusion and electrical parameters are critical in models of hepatic radiofrequency ablation. AB - PURPOSE: A sensitivity analysis has been performed on a mathematical model of radiofrequency ablation (RFA) in the liver. The purpose of this is to identify the most important parameters in the model, defined as those that produce the largest changes in the prediction. This is important in understanding the role of uncertainty and when comparing the model predictions to experimental data. MATERIALS AND METHODS: The Morris method was chosen to perform the sensitivity analysis because it is ideal for models with many parameters or that take a significant length of time to obtain solutions. A comprehensive literature review was performed to obtain ranges over which the model parameters are expected to vary, crucial input information. RESULTS: The most important parameters in predicting the ablation zone size in our model of RFA are those representing the blood perfusion, electrical conductivity and the cell death model. The size of the 50 degrees C isotherm is sensitive to the electrical properties of tissue while the heat source is active, and to the thermal parameters during cooling. CONCLUSIONS: The parameter ranges chosen for the sensitivity analysis are believed to represent all that is currently known about their values in combination. The Morris method is able to compute global parameter sensitivities taking into account the interaction of all parameters, something that has not been done before. Research is needed to better understand the uncertainties in the cell death, electrical conductivity and perfusion models, but the other parameters are only of second order, providing a significant simplification. PMID- 26000973 TI - Photothermal stress triggered by near-infrared-irradiated carbon nanotubes up regulates osteogenesis and mineral deposition in tooth-extracted sockets. AB - PURPOSE: The bone regenerative healing process is often prolonged, with a high risk of infection particularly in elderly and diseased patients. A reduction in healing process time usually requires mechanical stress devices, chemical cues, or laser/thermal therapies. Although these approaches have been used extensively for the reduction of bone healing time, the exact mechanisms involved in thermal stress-induced bone regeneration remain unclear. METHODS: Photothermal stress (PTS) stimulation was carried out using a novel photothermal device, composed of an alginate gel (AG) including carbon nanotubes (CNT-AGs) and their irradiator with near-infrared (NIR) light. We investigated the effects of optimal hyperthermia on osteogenesis, its signalling pathway in vitro and mineral deposition in tooth-extracted sockets in vivo. RESULTS: The PTS (10 min at 42 degrees C, every day), triggered by NIR-induced CNT, increased the activity of alkaline phosphatase (ALP) in mouse osteoblast MC3T3-E1 cells in a time-dependent manner compared with the non-thermal stress control. PTS significantly induced the expression of osteogenic-related molecules such as ALP, RUNX2 and Osterix in a time-dependent manner with phosphorylated mitogen-activated protein kinases (MAPK). PTS increased the expression of heat shock factor (HSF) 2, but not HSF1, resulting in activation of heat shock protein 27. PTS significantly up-regulated mineral deposition in tooth-extracted sockets in normal and ovariectomised osteoporotic model mice in vivo. CONCLUSIONS: Our novel CNT-based PTS up regulated osteogenesis via activation of heat shock-related molecules, resulting in promotion of mineral deposition in enhanced tooth-extracted sockets. PMID- 26000975 TI - Rapid degradation of methylene blue in a novel heterogeneous Fe3O4 @rGO@TiO2 catalyzed photo-Fenton system. AB - Herein, a ternary nanocomposite with TiO2 nanoparticles anchored on reduced graphene oxide (rGO)-encapsulated Fe3O4 spheres (Fe3O4@rGO@TiO2) is presented as a high efficient heterogeneous catalyst for photo-Fenton degradation of recalcitrant pollutants under neutral pH. Fe3O4@rGO@TiO2 was synthesized by depositing TiO2 nanoparticles on the surface of the Fe3O4 spheres wrapped by graphene oxide (GO) which was obtained by an electrostatic layer-by-layer method. This as-prepared catalyst reflected good ferromagnetism and superior stability which makes it convenient to be separated and recycled. Due to the synergic effects between the different components composed the catalyst, swift reduction of Fe(3+) can be achieved to regenerate Fe(2+). Fe3O4@rGO@TiO2 exhibited enhancing catalytic activity for the degradation of azo-dyes compared with Fe3O4, Fe3O4@SiO2@TiO2 or SiO2@rGO@TiO2, further conforming the rapid redox reaction between Fe(2+) and Fe(3+). All these merits indicate that the composite catalyst possesses great potential for visible-light driven destruction of organic compounds. PMID- 26000974 TI - Competence of Cimex lectularius Bed Bugs for the Transmission of Bartonella quintana, the Agent of Trench Fever. AB - BACKGROUND: Bartonella quintana, the etiologic agent of trench fever and other human diseases, is transmitted by the feces of body lice. Recently, this bacterium has been detected in other arthropod families such as bed bugs, which begs the question of their involvement in B. quintana transmission. Although several infectious pathogens have been reported and are suggested to be transmitted by bed bugs, the evidence regarding their competence as vectors is unclear. METHODOLOGY/PRINCIPAL FINDINGS: Bed bugs at the adult and instar developmental stages were fed three successive human blood meals inoculated with B. quintana bacterium from day one (D1) to D5; subsequently they were fed with pathogen-free human blood until the end of the experiment. Bed bugs and feces were collected in time series, to evaluate their capacities to acquire, multiply and expel viable B. quintana using molecular biology, immunohistochemistry and cultures assays. B. quintana was detected molecularly in 100% of randomly selected experimentally infected bed bug specimens (D3). The monitoring of B. quintana in bed bug feces showed that the bacterium was detectable starting on the 3rd day post-infection (pi) and persisted until day 18+/-1 pi. Although immunohistochemistry assays localized the bacteria to the gastrointestinal bed bug gut, the detection of B. quintana in the first and second instar larva stages suggested a vertical non-transovarial transmission of the bacterium. CONCLUSION: The present work demonstrated for the first time that bed bugs can acquire, maintain for more than 2 weeks and release viable B. quintana organisms following a stercorarial shedding. We also observed the vertical transmission of the bacterium to their progeny. Although the biological role of bed bugs in the transmission of B. quintana under natural conditions has yet to be confirmed, the present work highlights the need to reconsider monitoring of these arthropods for the transmission of human pathogens. PMID- 26000977 TI - Symmetry breaking polymerization: one-pot synthesis of plasmonic hybrid Janus nanoparticles. AB - Asymmetric hybrid nanoparticles have many important applications in catalysis, nanomotion, sensing, and diagnosis, however ways to generate the asymmetric hybrid nanoparticles are quite limited and inefficient. Most current methods rely on interfacial adhesion and modification of already formed particles. In this article we report a one-pot, facile and scalable synthesis of anisotropic Au polymer hybrid nanoparticles via interfacial oxidative dispersion polymerization. The interfacial nucleation and polymerization lead to spontaneous symmetry breaking and formation of the Janus particles. The reaction is initiated by monomer radicals generated by the strong oxidant HAuCl4, which is itself later reduced by the electron-rich monomers to self-nucleate and form Au nanoparticles (NPs). The competition between divinylbenzene adsorption and the PVP capping agent results in effective partial surface wetting, forming asymmetric Au-PDVB hybrid nanoparticles, by confining growth of each material to its own phase. Such spontaneous symmetry breaking, important in morphogenesis, with control over the subsequent growth processes should lead to significant advances in the synthesis of asymmetric nanostructures. PMID- 26000976 TI - Whitefly genome expression reveals host-symbiont interaction in amino acid biosynthesis. AB - BACKGROUND: Whitefly (Bemisia tabaci) complex is a serious insect pest of several crop plants worldwide. It comprises several morphologically indistinguishable species, however very little is known about their genetic divergence and biosynthetic pathways. In the present study, we performed transcriptome sequencing of Asia 1 species of B. tabaci complex and analyzed the interaction of host-symbiont genes in amino acid biosynthetic pathways. METHODOLOGY/PRINCIPAL FINDINGS: We obtained about 83 million reads using Illumina sequencing that assembled into 72716 unitigs. A total of 21129 unitigs were annotated at stringent parameters. Annotated unitigs were mapped to 52847 gene ontology (GO) terms and 131 Kyoto encyclopedia of genes and genomes (KEGG) pathways. Expression analysis of the genes involved in amino acid biosynthesis pathways revealed the complementation between whitefly and its symbiont partner Candidatus Portiera aleyrodidarum. Most of the non-essential amino acids and intermediates of essential amino acid pathways were supplied by the host insect to its symbiont. The symbiont expressed the pathways for the essential amino acids arginine, threonine and tryptophan and the immediate precursors of valine, leucine, isoleucine and phenyl-alanine. High level expression of the amino acid transporters in the whitefly suggested the molecular mechanisms for the exchange of amino acids between the host and the symbiont. CONCLUSIONS/SIGNIFICANCE: Our study provides a comprehensive transcriptome data for Asia 1 species of B. tabaci complex that focusses light on integration of host and symbiont genes in amino acid biosynthesis pathways. PMID- 26000978 TI - Antitumour activity of AMG 900 alone or in combination with histone deacetylase inhibitor SaHa on medulloblastoma cell lines. AB - OBJECTIVES: Medulloblastoma (MB) is the most common malignant childhood brain tumour. Aurora kinases are essential for cell division and are primarily active during mitosis. Recently, the combination of aurora kinases inhibitors (iAURK) and histone deacetylase inhibitors (iHDAC) has shown potential antitumour effects and had significant biological effects in preclinical cancer models. In this study, we analysed the effects of the pan-aurora kinases inhibitor AMG 900 alone or in combination with the iHDAC SaHa (Vorinostat) on paediatric MB cell lines (UW402, UW473 and ONS-76). METHODS: Cell proliferation was measured by XTT assay, apoptosis was determined by flow cytometry and clonogenic capacity was studied. qRT-PCR assays were used to determine the mRNA expression in MB cell lines after treatment. Drug combination analyses were made based on Chou-Talalay method. RESULTS: AMG 900 caused the inhibition of cell proliferation, diminution of clonogenic capacity and increased the apoptosis rate in cell lines (P < 0.05). A synergistic effect in the AMG900-SaHa combination was evidenced on the inhibition of cell proliferation in all cell lines, especially in sequential drug treatment. Moreover, the combination of these drugs reached 100% of the inhibition in colony formation (synergistic effect). The treatment with AMG 900 increased the p21 and GDF15 expression, but did not alter the TP53 in one of the cell lines. CONCLUSIONS: These results indicate that AMG 900 may be a promising drug for the adjuvant treatment of MB, mainly when combined with iHDAC. PMID- 26000980 TI - Correction: In Silico Screening for Novel Inhibitors of DNA Polymerase III Alpha Subunit of Mycobacterium tuberculosis (MtbDnaE2, H37Rv). PMID- 26000979 TI - The amount of keratins matters for stress protection of the colonic epithelium. AB - Keratins (K) are important for epithelial stress protection as evidenced by keratin mutations predisposing to human liver diseases and possibly inflammatory bowel diseases. A role for K8 in the colon is supported by the ulcerative colitis phenotype with epithelial hyperproliferation and abnormal ion transport in K8 knockout (K8-/-) mice. The heterozygote knockout (K8+/-) colon appears normal but displays a partial ion transport-defect. Characterizing the colonic phenotype we show that K8+/- colon expresses ~50% less keratins compared to K8 wild type (K8+/+) but de novo K7 expression is observed in the top-most cells of the K8+/- and K8-/- crypts. The K8+/- colonic crypts are significantly longer due to increased epithelial hyperproliferation, but display no defects in apoptosis or inflammation in contrast to K8-/-. When exposed to colitis using the dextran sulphate sodium-model, K8+/- mice showed higher disease sensitivity and delayed recovery compared to K8+/+ littermates. Therefore, the K8+/- mild colonic phenotype correlates with decreased keratin levels and increased sensitivity to experimental colitis, suggesting that a sufficient amount of keratin is needed for efficient stress protection in the colonic epithelia. PMID- 26000981 TI - A Combination of Divergence and Conservatism in the Niche Evolution of the Moorish Gecko, Tarentola mauritanica (Gekkota: Phyllodactylidae). AB - The quantification of realized niche overlap and the integration of species distribution models (SDMs) with calibrated phylogenies to study niche evolution are becoming not only powerful tools to understand speciation events, but can also be used as proxies regarding the delimitation of cryptic species. We applied these techniques in order to unravel how the fundamental niche evolved during cladogenesis within the Tarentola mauritanica species-complex. Our results suggest that diversification within this complex, during the Miocene and Pleistocene, is associated with both niche divergence and niche conservatism, with a pattern that varies depending on whether the variables involved are related to the mean or seasonality of temperature and humidity. Moreover, climatic variables related to humidity and temperature seasonality were involved in the niche shift and genetic diversification of the European/North African clade during the Pleistocene and in its maintenance in a fundamental niche distinct from that of the remaining members of the group. This study further highlights the need for a taxonomic revision of the T. mauritanica species complex. PMID- 26000983 TI - Metal-Ion-Dependent Motion of Self-Propelled Droplets Due to the Marangoni Effect. AB - Chemically driven self-propulsion of soft matter is useful for various applications because it can move toward a desired location, without external power fields, in response to chemical signals in environmental media. We have developed a suitable steering mechanism to maintain the orientation of self propelled droplets loaded with surfactant in fluidic environments. A spatial gradient of alkaline-earth metal ions induces directional sensing. These metal ions can be arranged in descending order of directional sensing as Ba(2+) ~ Sr(2+) > Ca(2+) > Mg(2+). On the other hand, the affinity between metal ions and di-(2-ethylhexyl)phosphoric acid (DEHPA) decreases in the order as Ca(2+) > Ba(2+) > Sr(2+) > Mg(2+). To clarify the difference between the order of directional sensing and that of affinity, we investigated the effect of metal ions on the driving force to create asymmetric convection. We found that changes in the interfacial tension under nonequilibrium conditions play an important role in directional sensing. PMID- 26000982 TI - SEPTIN2 and STATHMIN Regulate CD99-Mediated Cellular Differentiation in Hodgkin's Lymphoma. AB - Hodgkin's lymphoma (HL) is a lymphoid neoplasm characterized by Hodgkin's and Reed-Sternberg (H/RS) cells, which is regulated by CD99. We previously reported that CD99 downregulation led to the transformation of murine B lymphoma cells (A20) into cells with an H/RS phenotype, while CD99 upregulation induced differentiation of classical Hodgkin's lymphoma (cHL) cells (L428) into terminal B-cells. However, the molecular mechanism remains unclear. In this study, using fluorescence two-dimensional differential in-gel electrophoresis and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), we have analyzed the alteration of protein expression following CD99 upregulation in L428 cells as well as downregulation of mouse CD99 antigen-like 2 (mCD99L2) in A20 cells. Bioinformatics analysis showed that SEPTIN2 and STATHMIN, which are cytoskeleton proteins, were significantly differentially expressed, and chosen for further validation and functional analysis. Differential expression of SEPTIN2 was found in both models and was inversely correlated with CD99 expression. STATHMIN was identified in the A20 cell line model and its expression was positively correlated with that of CD99. Importantly, silencing of SEPTIN2 with siRNA substantially altered the cellular cytoskeleton in L428 cells. The downregulation of STATHMIN by siRNA promoted the differentiation of H/RS cells toward terminal B-cells. These results suggest that SEPTIN2-mediated cytoskeletal rearrangement and STATHMIN-mediated differentiation may contribute to changes in cell morphology and differentiation of H/RS cells with CD99 upregulation in HL. PMID- 26000984 TI - Serious adverse events are uncommon with combination neonatal antiretroviral prophylaxis: a retrospective case review. AB - Six weeks of zidovudine (ZDV) is recommended for postnatal prophylaxis of HIV exposed infants, but combination antiretrovirals are indicated if HIV transmission risk is increased. We investigated the frequency and severity of adverse events (AE) in infants receiving multiple drug prophylaxis compared to ZDV alone. In this retrospective review of 148 HIV-exposed uninfected infants born between 1997-2009, we determined clinical and laboratory AE that occurred between days of life 8-42. Thirty-six infants received combination prophylaxis; among those, a three-drug regimen containing ZDV, lamivudine, and nevirapine was most common (53%). Rates of laboratory AE grade >=1 were as follows for the combination prophylaxis and ZDV alone groups, respectively: neutropenia 55% and 39%; anemia 50% and 39%; thrombocytopenia 0 and 3%; elevated aspartate aminotransferase 3% and 3%; elevated alanine aminotransferase 0 and 1%; hyperbilirubinemia 19% and 42%. Anemia occurred more frequently in infants who received three-drug prophylaxis compared to infants who received ZDV alone (63% vs. 39%, p = 0.04); all anemia AE were grade 1 or 2 in the three-drug prophylaxis group. Overall, 75% of infants on combination prophylaxis and 66% of infants on ZDV alone developed grade >=1 AE (p = 0.32), and 17% of infants in either group developed grade >=3 AE. Stavudine was substituted for ZDV in 23 infants due to anemia or neutropenia. After this antiretroviral change, 50% of evaluable infants demonstrated improvement in AE grade, and 25% had no change. In conclusion, low grade anemia, neutropenia, and hyperbilirubinemia occurred frequently regardless of the prophylactic regimen, but serious AE were uncommon. Although most AE were typical of ZDV toxicity, the combination of ZDV with lamivudine and nevirapine resulted in an increased frequency of low-grade anemia. Further studies are needed to identify prophylactic regimens with less toxicity for infants born to HIV-infected mothers. PMID- 26000986 TI - A cascade approach to hetero-pentanuclear manganese-oxide clusters in polyoxometalates and their single-molecule magnet properties. AB - Structurally well-defined hetero-pentanuclear manganese-oxide clusters {MMn4} were successfully synthesized in TBA7Hn[MMn4(OH)2(A-alpha-SiW9O34)2].2H2O.C2H4Cl2 (, M = Fe(iii), Co(ii), Ni(ii), Cu(ii), Ga(iii)) by sequential introduction of metal cations into the trivacant lacunary polyoxometalates (POMs). The pentanuclear manganese-oxide cluster {Mn5} showed a small spin ground state and a low energy barrier for magnetization relaxation. In contrast, the magnetic interactions in the hetero-pentanuclear clusters could be controlled by the arrangements of metals, and the clusters showed large magnetic anisotropy and single-molecule magnet behavior. In particular, the cluster {FeMn4} in (S = 11/2) showed the slowest relaxation and the highest energy barrier among the previously reported transition metal-containing POMs. PMID- 26000987 TI - Towards multifunctional MOFs--transforming a side reaction into a post-synthetic protection/deprotection method. AB - The contaminant commonly found in the important amino-substituted metal-organic framework UiO-66-NH2 has been shown to arise from partial formylation during the synthesis in DMF. Mild conditions have now been developed for both post-synthetic deformylation and near-complete formylation, offering a new post-synthetic protection-deprotection method for the synthesis of multifunctional MOFs. PMID- 26000985 TI - Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn's disease patients. AB - Previous studies have highlighted the role of genetic predispositions in disease, and several genes had been identified as important in Crohn's disease (CD). However, many of these genes are likely rare and not associated with susceptibility in Chinese CD patients. We found 294 shared identical variants in the CD patients of which 26 were validated by Sanger sequencing. Two heterozygous IFN variants (IFNA10 c.60 T > A; IFNA4 c.60 A > T) were identified as significantly associated with CD susceptibility. The single-nucleotide changes alter a cysteine situated before the signal peptide cleavage site to a stop code (TGA) in IFNA10 result in the serum levels of IFNA10 were significantly decreased in the CD patients compared to the controls. Furthermore, the IFNA10 and IFNA4 mutants resulted in an impairment of the suppression of HCV RNA replication in HuH7 cells, and the administration of the recombinant IFN subtypes restored DSS induced colonic inflammation through the upregulation of CD4(+) Treg cells. We identified heterozygous IFNA10 and IFNA4 variants as a cause of impaired function and CD susceptibility genes in Chinese patients from multiple center based study. These findings might provide clues in the understanding of the genetic heterogeneity of CD and lead to better screening and improved treatment. PMID- 26000988 TI - Response to comments on "Unexpected occurrence of volatile dimethylsiloxanes in Antarctic soils, vegetation, phytoplankton and krill". PMID- 26000989 TI - Carbon- and Nitrogen-Based Organic Frameworks. AB - This Account provides an overview of organic, covalent, porous frameworks and solid-state materials mainly composed of the elements carbon and nitrogen. The structures under consideration are rather diverse and cover a wide spectrum. This Account will summarize current works on the synthetic concepts leading toward those systems and cover the application side where emphasis is set on the exploration of those systems as candidates for unusual high-performance catalysis, electrocatalysis, electrochemical energy storage, and artificial photosynthesis. These issues are motivated by the new global energy cycles and the fact that sustainable technologies should not be based on rare and expensive resources. We therefore present the strategic design of functionality in cost effective, affordable artificial materials starting from a spectrum of simple synthetic options to end up with carbon- and nitrogen-based porous frameworks. Following the synthetic strategies, we demonstrate how the electronic structure of polymeric frameworks can be tuned and how this can modify property profiles in a very unexpected fashion. Covalent triazine-based frameworks (CTFs), for instance, showed both enormously high energy and high power density in lithium and sodium battery systems. Other C,N-based organic frameworks, such as triazine based graphitic carbon nitride, are suggested to show promising band gaps for many (photo)electrochemical reactions. Nitrogen-rich carbonaceous frameworks, which are developed from C,N-based organic framework strategies, are highlighted in order to address their promising electrocatalytic properties, such as in the hydrogen evolution reaction, oxygen reduction reaction (ORR), and oxygen evolution reaction (OER). With careful design, those materials can be multifunctional catalysts, such as a bifunctional ORR/OER electrocatalyst. Although the majority of new C,N-based materials are still not competitive with the best (usually nonsustainable candidates) for each application, the framework/N approach as such is still in its infancy and has already moved organic materials to regions where otherwise only traditional noble metals or special inorganic semiconductors are found. As one potential way to enhance the properties of polymeric frameworks, the idea of catalysts having unique active surfaces based on Mott-Schottky heterojunctions and related concepts are addressed. In order to integrate all of the above versatile subjects from synthesis to applications on C,N-based organic frameworks, we begin the discussion with synthetic concepts and strategies for these frameworks to distinguish these systems from typical covalent organic frameworks based on boron oxide rings. Next we focus on the semiconducting properties of C,N-based organic frameworks in order to show a continuous transition between CTFs and other systems, such as graphitic carbon nitrides. At the end, applications of these materials are shown by highlighting their properties in electrochemical energy storage and photo- and electrocatalysis. PMID- 26000990 TI - Genuine Multipartite Entanglement without Multipartite Correlations. AB - Nonclassical correlations between measurement results make entanglement the essence of quantum physics and the main resource for quantum information applications. Surprisingly, there are n-particle states which do not exhibit n partite correlations at all but still are genuinely n-partite entangled. We introduce a general construction principle for such states, implement them in a multiphoton experiment and analyze their properties in detail. Remarkably, even without multipartite correlations, these states do violate Bell inequalities showing that there is no classical, i.e., local realistic model describing their properties. PMID- 26000991 TI - Experimental passive round-robin differential phase-shift quantum key distribution. AB - In quantum key distribution (QKD), the bit error rate is used to estimate the information leakage and hence determines the amount of privacy amplification making the final key private by shortening the key. In general, there exists a threshold of the error rate for each scheme, above which no secure key can be generated. This threshold puts a restriction on the environment noises. For example, a widely used QKD protocol, the Bennett-Brassard protocol, cannot tolerate error rates beyond 25%. A new protocol, round-robin differential phase shifted (RRDPS) QKD, essentially removes this restriction and can in principle tolerate more environment disturbance. Here, we propose and experimentally demonstrate a passive RRDPS QKD scheme. In particular, our 500 MHz passive RRDPS QKD system is able to generate a secure key over 50 km with a bit error rate as high as 29%. This scheme should find its applications in noisy environment conditions. PMID- 26000992 TI - Demonstration of a memory for tightly guided light in an optical nanofiber. AB - We report the experimental observation of slow-light and coherent storage in a setting where light is tightly confined in the transverse directions. By interfacing a tapered optical nanofiber with a cold atomic ensemble, electromagnetically induced transparency is observed and light pulses at the single-photon level are stored in and retrieved from the atomic medium. The decay of efficiency with storage time is also measured and related to concurrent decoherence mechanisms. Collapses and revivals can be additionally controlled by an applied magnetic field. Our results based on subdiffraction-limited optical mode interacting with atoms via the strong evanescent field demonstrate an alternative to free-space focusing and a novel capability for information storage in an all-fibered quantum network. PMID- 26000993 TI - Geometrically induced magnetic catalysis and critical dimensions. AB - We discuss the combined effect of magnetic fields and geometry in interacting fermionic systems. At leading order in the heat-kernel expansion, the infrared singularity (that in flat space leads to the magnetic catalysis) is regulated by the chiral gap effect, and the catalysis is deactivated by the effect of the scalar curvature. We discover that an infrared singularity is found in higher order terms that mix the magnetic field with curvature, and these lead to a novel form of geometrically induced magnetic catalysis. The dynamical mass squared is then modified not only due to the chiral gap effect by an amount proportional to the curvature, but also by a magnetic shift ?(4-D)eB, where D represents the number of space-time dimensions. We argue that D=4 is a critical dimension across which the behavior of the magnetic shift changes qualitatively. PMID- 26000994 TI - Imaginary parts and discontinuities of Wilson line correlators. AB - We introduce a notion of position-space cuts of eikonal diagrams, the set of diagrams appearing in the perturbative expansion of the correlator of a set of straight semi-infinite Wilson lines. The cuts are applied directly to the position-space representation of any such diagram and compute its imaginary part to the leading order in the dimensional regulator. Our cutting prescription thus defines a position-space analog of the standard momentum-space Cutkosky rules. Unlike momentum-space cuts which put internal lines on shell, position-space cuts constrain a number of the gauge bosons exchanged between the energetic partons to be lightlike, leading to a vanishing and a non-vanishing imaginary part for space and timelike kinematics, respectively. PMID- 26000995 TI - Yang-Mills as massive Chern-Simons theory: a third way to three-dimensional gauge theories. AB - The Yang-Mills (YM) equation in three spacetime dimensions (3D) can be modified to include a novel parity-preserving interaction term, with an inverse mass parameter, in addition to a possible topological mass term. The novelty is that the modified YM equation is not the Euler-Lagrange equation of any gauge invariant local action for the YM gauge potential alone. Instead, consistency is achieved in the "third way" exploited by 3D minimal massive gravity. We relate our results to the "novel Higgs mechanism" for Chern-Simons gauge theories. PMID- 26000996 TI - Thermalization of gluons with Bose-Einstein condensation. AB - We study the thermalization of gluons far from thermal equilibrium in relativistic kinetic theory. The initial distribution of gluons is assumed to resemble that in the early stage of ultrarelativistic heavy ion collisions. Only elastic scatterings in static, nonexpanding gluonic matter are considered. At first we show that the occurrence of condensation in the limit of vanishing particle mass requires a general constraint for the scattering matrix element. Then the thermalization of gluons with Bose-Einstein condensation is demonstrated in a transport calculation. We see a continuously increasing overpopulation of low energy gluons, followed by a decrease to the equilibrium distribution, when the condensation occurs. The times of the completion of the gluon condensation and of the entropy production are calculated. These times scale inversely with the energy density. PMID- 26000997 TI - Mercury monohalides: suitability for electron electric dipole moment searches. AB - Heavy polar diatomic molecules are the primary tools for searching for the T violating permanent electric dipole moment of the electron (eEDM). Valence electrons in some molecules experience extremely large effective electric fields due to relativistic interactions. These large effective electric fields are crucial to the success of polar-molecule-based eEDM search experiments. Here we report on the results of relativistic ab initio calculations of the effective electric fields in a series of molecules that are highly sensitive to an eEDM, the mercury monohalides (HgF, HgCl, HgBr, and HgI). We study the influence of the halide anions on E_{eff}, and identify HgBr and HgI as attractive candidates for future electric dipole moment search experiments. PMID- 26000998 TI - Time-resolved spectroscopy in time-dependent density functional theory: an exact condition. AB - A fundamental property of a quantum system driven by an external field is that when the field is turned off the positions of its response frequencies are independent of the time at which the field is turned off. We show that this leads to an exact condition for the exchange-correlation potential of time-dependent density functional theory. The Kohn-Sham potential typically continues to evolve after the field is turned off, which leads to time dependence in the response frequencies of the Kohn-Sham response function. The exchange-correlation kernel must cancel out this time dependence. The condition is typically violated by approximations currently in use, as we demonstrate by several examples, which has severe consequences for their predictions of time-resolved spectroscopy. PMID- 26000999 TI - Antihydrogen Formation via Antiproton Scattering with Excited Positronium. AB - Utilizing the two-center convergent close-coupling method, we find a several order of magnitude enhancement in the formation of antihydrogen via antiproton scattering with positronium in an excited state over the ground state. The effect is greatest at the lowest energies considered, which encompass those achievable in experiment. This suggests a practical approach to creating neutral antimatter for testing its interaction with gravity and for spectroscopic measurements. PMID- 26001000 TI - Ancillary qubit spectroscopy of vacua in cavity and circuit quantum electrodynamics. AB - We investigate theoretically how the spectroscopy of an ancillary qubit can probe cavity (circuit) QED ground states containing photons. We consider three classes of systems (Dicke, Tavis-Cummings, and Hopfield-like models), where nontrivial vacua are the result of ultrastrong coupling between N two-level systems and a single-mode bosonic field. An ancillary qubit detuned with respect to the boson frequency is shown to reveal distinct spectral signatures depending on the type of vacua. In particular, the Lamb shift of the ancilla is sensitive to both ground state photon population and correlations. Backaction of the ancilla on the cavity ground state is investigated, taking into account the dissipation via a consistent master equation for the ultrastrong coupling regime. The conditions for high-fidelity measurements are determined. PMID- 26001001 TI - All-optical nanomechanical heat engine. AB - We propose and theoretically investigate a nanomechanical heat engine. We show how a levitated nanoparticle in an optical trap inside a cavity can be used to realize a Stirling cycle in the underdamped regime. The all-optical approach enables fast and flexible control of all thermodynamical parameters and the efficient optimization of the performance of the engine. We develop a systematic optimization procedure to determine optimal driving protocols. Further, we perform numerical simulations with realistic parameters and evaluate the maximum power and the corresponding efficiency. PMID- 26001002 TI - Boosting terahertz generation in laser-field ionized gases using a sawtooth wave shape. AB - Broadband ultrashort terahertz (THz) pulses can be produced using plasma generation in a noble gas ionized by femtosecond two-color pulses. Here we demonstrate that, by using multiple-frequency laser pulses, one can obtain a waveform which optimizes the free electron trajectories in such a way that they acquire the largest drift velocity. This allows us to increase the THz conversion efficiency to 2%, an unprecedented performance for THz generation in gases. In addition to the analytical study of THz generation using a local current model, we perform comprehensive 3D simulations accounting for propagation effects which confirm this prediction. Our results show that THz conversion via tunnel ionization can be greatly improved with well-designed multicolor pulses. PMID- 26001003 TI - Enhancement of second-order nonlinear-optical signals by optical stimulation. AB - Second-order nonlinear optical interactions such as sum- and difference-frequency generation are widely used for bioimaging and as selective probes of interfacial environments. However, inefficient nonlinear optical conversion often leads to poor signal-to-noise ratio and long signal acquisition times. Here, we demonstrate the dramatic enhancement of weak second-order nonlinear optical signals via stimulated sum- and difference-frequency generation. We present a conceptual framework to quantitatively describe the interaction and show that the process is highly sensitive to the relative optical phase of the stimulating field. To emphasize the utility of the technique, we demonstrate stimulated enhancement of second harmonic generation (SHG) from bovine collagen-I fibrils. Using a stimulating pulse fluence of only 3 nJ/cm2, we obtain an SHG enhancement >10(4) relative to the spontaneous signal. The stimulation enhancement is greatest in situations where spontaneous signals are the weakest--such as low laser power, small sample volume, and weak nonlinear susceptibility--emphasizing the potential for this technique to improve signal-to-noise ratios in biological imaging and interfacial spectroscopy. PMID- 26001004 TI - Exponentially tempered Levy sums in random lasers. AB - Levy fluctuations have associated infinities due to diverging moments, a problem that is circumvented by putting restrictions on the magnitude of the fluctuations, realizing a process called the truncated Levy flight. We show that a perfect manifestation of this exotic process occurs in coherent random lasers, and it turns out to be the single underlying explanation for the complete statistical behavior of nonresonant random lasers. A rigorous parameter estimation of the number of summand variables, the truncation parameter, and the power-law exponent is carried out over a wide range of randomness, inversion, and system size. Random laser intensity is modeled on a unique platform of exponentially tempered Levy sums. The computed behavior exhibits an excellent agreement with the experimentally observed fluctuation behavior. PMID- 26001005 TI - Synergistic laser-wakefield and direct-laser acceleration in the plasma-bubble regime. AB - The concept of a hybrid laser plasma accelerator is proposed. Relativistic electrons undergoing resonant betatron oscillations inside the plasma bubble created by a laser pulse are accelerated by gaining energy directly from the laser pulse and from its plasma wake. The resulting phase space of self-injected plasma electrons is split into two, containing a subpopulation that experiences wakefield acceleration beyond the standard dephasing limit because of the multidimensional nature of its motion that reduces the phase slippage between the electrons and the wake. PMID- 26001006 TI - Sixth-order resonance of high-intensity linear accelerators. AB - It is shown that the sixth-order 6sigma=720 degrees (or 6?2) resonance is manifested for high-intensity beams of linear accelerators through the space charge potential when the depressed phase advance per cell sigma is close to and below 120 degrees but no resonance effect is observed for sigma above 120 degrees . Simulation studies show a clear emittance growth by this resonance and a characteristic sixfold resonance structure in phase space. To verify that this is a resonance, a frequency analysis was conducted and a study was performed of crossing the resonance from above and from below the resonance. Canonical perturbation is carried out to show that this resonance arises through perturbation of strong 2sigma=360 degrees (2?1) and 4sigma=360 degrees (4?1) space charge resonances. Simulations also show that the space charge 6sigma=360 degrees (or 6?1) resonance is very weak. PMID- 26001007 TI - Modulated electron cyclotron drift instability in a high-power pulsed magnetron discharge. AB - The electron cyclotron drift instability, implicated in electron heating and anomalous transport, is detected in the plasma of a planar magnetron. Electron density fluctuations associated with the mode are identified via an adapted coherent Thomson scattering diagnostic, under direct current and high-power pulsed magnetron operation. Time-resolved analysis of the mode amplitude reveals that the instability, found at MHz frequencies and millimeter scales, also exhibits a kHz-scale modulation consistent with the observation of larger-scale plasma density nonuniformities, such as the rotating spoke. Sharply collimated axial fluctuations observed at the magnetron axis are consistent with the presence of escaping electrons in a region where the magnetic and electric fields are antiparallel. These results distinguish aspects of magnetron physics from other plasma sources of similar geometry, such as the Hall thruster, and broaden the scope of instabilities which may be considered to dictate magnetron plasma features. PMID- 26001008 TI - Compton-like polariton scattering in hyperbolic metamaterials. AB - We study the scattering of polaritons by free electrons in hyperbolic photonic media and demonstrate that the unconventional dispersion and high local density of states of electromagnetic modes in composite media with hyperbolic dispersion can lead to a giant Compton-like shift and dramatic enhancement of the scattering cross section. We develop a universal approach to study multiphoton processes in nanostructured media and derive the intensity spectrum of the scattered radiation for realistic metamaterial structures. PMID- 26001009 TI - Reentrant Origami-Based Metamaterials with Negative Poisson's Ratio and Bistability. AB - We investigate the unique mechanical properties of reentrant 3D origami structures based on the Tachi-Miura polyhedron (TMP). We explore the potential usage as mechanical metamaterials that exhibit tunable negative Poisson's ratio and structural bistability simultaneously. We show analytically and experimentally that the Poisson's ratio changes from positive to negative and vice versa during its folding motion. In addition, we verify the bistable mechanism of the reentrant 3D TMP under rigid origami configurations without relying on the buckling motions of planar origami surfaces. This study forms a foundation in designing and constructing TMP-based metamaterials in the form of bellowslike structures for engineering applications. PMID- 26001010 TI - First-order character and observable signatures of topological quantum phase transitions. AB - Topological quantum phase transitions are characterized by changes in global topological invariants. These invariants classify many-body systems beyond the conventional paradigm of local order parameters describing spontaneous symmetry breaking. For noninteracting electrons, it is well understood that such transitions are continuous and always accompanied by a gap closing in the energy spectrum, given that the symmetries protecting the topological phase are maintained. Here, we demonstrate that a sufficiently strong electron-electron interaction can fundamentally change the situation: we discover a topological quantum phase transition of first-order character in the genuine thermodynamic sense that occurs without a gap closing. Our theoretical study reveals the existence of a quantum critical endpoint associated with an orbital instability on the transition line between a 2D topological insulator and a trivial band insulator. Remarkably, this phenomenon entails unambiguous signatures related to the orbital occupations that can be detected experimentally. PMID- 26001011 TI - Magneto-optics of massive dirac fermions in bulk Bi2Se3. AB - We report on magneto-optical studies of Bi2Se3, a representative member of the 3D topological insulator family. Its electronic states in bulk are shown to be well described by a simple Dirac-type Hamiltonian for massive particles with only two parameters: the fundamental band gap and the band velocity. In a magnetic field, this model implies a unique property-spin splitting equal to twice the cyclotron energy: Es=2Ec. This explains the extensive magnetotransport studies concluding a fortuitous degeneracy of the spin and orbital split Landau levels in this material. The Es=2Ec match differentiates the massive Dirac electrons in bulk Bi2Se3 from those in quantum electrodynamics, for which Es=Ec always holds. PMID- 26001012 TI - Exciton-polariton gas as a nonequilibrium coolant. AB - Using angle-resolved Raman spectroscopy, we show that a resonantly excited ground state exciton-polariton fluid behaves like a nonequilibrium coolant for its host solid-state semiconductor microcavity. With this optical technique, we obtain a detailed measurement of the thermal fluxes generated by the pumped polaritons. We thus find a maximum cooling power for a cryostat temperature of 50 K and below where optical cooling is usually suppressed, and we identify the participation of an ultrafast cooling mechanism. We also show that the nonequilibrium character of polaritons constitutes an unexpected resource: each scattering event can remove more heat from the solid than would be normally allowed using a thermal fluid with normal internal equilibration. PMID- 26001013 TI - Fluctuation theorem for a small engine and magnetization switching by spin torque. AB - We consider a reversal of the magnetic moment of a nanomagnet by a fluctuating spin torque induced by a nonequilibrium current of electron spins. This is an example of the problem of the escape of a particle from a metastable state subjected to a fluctuating nonconservative force. Spin torque is a nonconservative force, and its fluctuations are beyond the description of the fluctuation-dissipation theorem. We estimate the joint probability distribution of work done by the spin torque and the Joule heat generated by the current, which satisfies the fluctuation theorem for a small engine. We predict a threshold voltage above which the spin-torque shot noise induces probabilistic switching events and below which such events are blocked. We adopt the theory of full-counting statistics under the adiabatic pumping of spin angular momentum. This enables us to account for the backaction effect, which is crucial to maintain consistency with the fluctuation theorem. PMID- 26001014 TI - Paramagnetic spin seebeck effect. AB - We report the observation of the longitudinal spin Seebeck effect in paramagnetic insulators. By using a microscale on-chip local heater, we generate a large thermal gradient confined to the chip surface without a large increase in the total sample temperature. Using this technique at low temperatures (<20 K), we resolve the paramagnetic spin Seebeck effect in the insulating paramagnets Gd3Ga5O12 (gadolinium gallium garnet) and DyScO3 (DSO), using either W or Pt as the spin detector layer. By taking advantage of the strong magnetocrystalline anisotropy of DSO, we eliminate contributions from the Nernst effect in W or Pt, which produces a phenomenologically similar signal. PMID- 26001015 TI - Correlation lengths and topological entanglement entropies of unitary and nonunitary fractional quantum Hall wave functions. AB - Using the newly developed matrix product state formalism for non-Abelian fractional quantum Hall (FQH) states, we address the question of whether a FQH trial wave function written as a correlation function in a nonunitary conformal field theory (CFT) can describe the bulk of a gapped FQH phase. We show that the nonunitary Gaffnian state exhibits clear signatures of a pathological behavior. As a benchmark we compute the correlation length of a Moore-Read state and find it to be finite in the thermodynamic limit. By contrast, the Gaffnian state has an infinite correlation length in (at least) the non-Abelian sector, and is therefore gapless. We also compute the topological entanglement entropy of several non-Abelian states with and without quasiholes. For the first time in the FQH effect the results are in excellent agreement in all topological sectors with the CFT prediction for unitary states. For the nonunitary Gaffnian state in finite size systems, the topological entanglement entropy seems to behave like that of the composite fermion Jain state at equal filling. PMID- 26001016 TI - Precise Quantization of the Anomalous Hall Effect near Zero Magnetic Field. AB - We report a nearly ideal quantum anomalous Hall effect in a three-dimensional topological insulator thin film with ferromagnetic doping. Near zero applied magnetic field we measure exact quantization in the Hall resistance to within a part per 10 000 and a longitudinal resistivity under 1 Omega per square, with chiral edge transport explicitly confirmed by nonlocal measurements. Deviations from this behavior are found to be caused by thermally activated carriers, as indicated by an Arrhenius law temperature dependence. Using the deviations as a thermometer, we demonstrate an unexpected magnetocaloric effect and use it to reach near-perfect quantization by cooling the sample below the dilution refrigerator base temperature in a process approximating adiabatic demagnetization refrigeration. PMID- 26001017 TI - Collective ion dynamics in liquid zinc: evidence for complex dynamics in a non free-electron liquid metal. AB - A detailed inelastic neutron scattering investigation of the THz dynamics of liquid zinc is presented. The observed Q dependence clearly reveals the existence of a complex dynamics made up of two distinct excitations. The highest energy mode is the prolongation of the longitudinal acoustic density fluctuations whereas the comparison with the phonon dynamics of crystalline hcp zinc suggests a transverse acousticlike nature for the second one. This mode seems related to peculiar anisotropic interactions, possibly connected to the behavior of the crystalline phase. PMID- 26001018 TI - Curvature dependence of hydrophobic hydration dynamics. AB - We investigate the solute curvature dependence of water dynamics in the vicinity of hydrophobic spherical solutes using molecular dynamics simulations. For both the lateral and perpendicular diffusivity, as well as for H-bond kinetics of water in the first hydration shell, we find a nonmonotonic solute-size dependence, exhibiting extrema close to the well-known structural crossover length scale for hydrophobic hydration. Additionally, we find an apparent anomalous diffusion for water moving parallel to the surface of small solutes, which, however, can be explained by topology effects. Our findings regarding the intimate connection between solute curvature and water dynamics has implications for our understanding of hydration dynamics at heterogeneous biomolecular surfaces. PMID- 26001019 TI - Margination regimes and drainage transition in confined multicomponent suspensions. AB - A mechanistic theory is developed to describe segregation in confined multicomponent suspensions such as blood. It incorporates the two key phenomena arising in these systems at low Reynolds number: hydrodynamic pair collisions and wall-induced migration. In simple shear flow, several regimes of segregation arise, depending on the value of a "margination parameter" M. Most importantly, there is a critical value of M below which a sharp "drainage transition" occurs: one component is completely depleted from the bulk flow to the vicinity of the walls. Direct simulations also exhibit this transition as the size or flexibility ratio of the components changes. PMID- 26001020 TI - Collective dynamics in a binary mixture of hydrodynamically coupled microrotors. AB - We study, numerically, the collective dynamics of self-rotating nonaligning particles by considering a monolayer of spheres driven by constant clockwise or counterclockwise torques. We show that hydrodynamic interactions alter the emergence of large-scale dynamical patterns compared to those observed in dry systems. In dilute suspensions, the flow stirred by the rotors induces clustering of opposite-spin rotors, while at higher densities same-spin rotors phase separate. Above a critical rotor density, dynamic hexagonal crystals form. Our findings underscore the importance of inclusion of the many-body, long-range hydrodynamic interactions in predicting the phase behavior of active particles. PMID- 26001021 TI - Droplet clusters: exploring the phase space of soft mesoscale atoms. AB - We report three-dimensional structures--mesoscale "atoms"--comprising up to N=8 aqueous droplets compressed in a liquid shell. In contrast to hard colloids that self-assemble into structures unique for a given N, we observe multiple metastable states. We attribute this unexpected richness of metastable structures to the deformability of the cores that introduces irreducible many-body interactions between the droplets. These exotic, often highly anisotropic, structures are locally stable. The structures displaying highly nonoptimum packing-and hence interfacial energy much higher than that of the lowest-energy state-exhibit finite energy barriers that prevent restructuring and relaxation of energy. PMID- 26001022 TI - Evaluating molecular cobalt complexes for the conversion of N2 to NH3. AB - Well-defined molecular catalysts for the reduction of N2 to NH3 with protons and electrons remain very rare despite decades of interest and are currently limited to systems featuring molybdenum or iron. This report details the synthesis of a molecular cobalt complex that generates superstoichiometric yields of NH3 (>200% NH3 per Co-N2 precursor) via the direct reduction of N2 with protons and electrons. While the NH3 yields reported herein are modest by comparison to those of previously described iron and molybdenum systems, they intimate that other metals are likely to be viable as molecular N2 reduction catalysts. Additionally, a comparison of the featured tris(phosphine)borane Co-N2 complex with structurally related Co-N2 and Fe-N2 species shows how remarkably sensitive the N2 reduction performance of potential precatalysts is. These studies enable consideration of the structural and electronic effects that are likely relevant to N2 conversion activity, including the pi basicity, charge state, and geometric flexibility. PMID- 26001023 TI - Green synthesis of peptide-templated gold nanoclusters as novel fluorescence probes for detecting protein kinase activity. AB - A green method was employed for synthesizing peptide-templated nanoclusters without requiring strong reducing agents. Using synthetic peptide-gold nanoclusters as fluorescence probes, a novel assay for detecting protein kinase is developed based on phosphorylation against carboxypeptidase Y digestion. PMID- 26001024 TI - Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1. AB - BACKGROUND: The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. RESULTS: Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF 1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. CONCLUSIONS: The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development. PMID- 26001025 TI - In good company? Perception of movement synchrony of a non-anthropomorphic robot. AB - Recent technological developments like cheap sensors and the decreasing costs of computational power have brought the possibility of robotic home companions within reach. In order to be accepted it is vital for these robots to be able to participate meaningfully in social interactions with their users and to make them feel comfortable during these interactions. In this study we investigated how people respond to a situation where a companion robot is watching its user. Specifically, we tested the effect of robotic behaviours that are synchronised with the actions of a human. We evaluated the effects of these behaviours on the robot's likeability and perceived intelligence using an online video survey. The robot used was Care-O-bot3, a non-anthropomorphic robot with a limited range of expressive motions. We found that even minimal, positively synchronised movements during an object-oriented task were interpreted by participants as engagement and created a positive disposition towards the robot. However, even negatively synchronised movements of the robot led to more positive perceptions of the robot, as compared to a robot that does not move at all. The results emphasise a) the powerful role that robot movements in general can have on participants' perception of the robot, and b) that synchronisation of body movements can be a powerful means to enhance the positive attitude towards a non-anthropomorphic robot. PMID- 26001026 TI - Acceptability of drug detection monitoring among participants in an open-label pre-exposure prophylaxis study. AB - In the world of HIV pre-exposure prophylaxis (PrEP) research, there is emerging interest in providing study participants with pharmacokinetic results from drug level testing to guide adherence counseling. The iPrEx randomized control trial was the first study to produce meaningful results of PrEP in humans. In the iPrEx open-label extension (OLE) study, blood plasma samples collected in the first 12 weeks of study participation were tested for the presence of tenofovir/emtricitabine--the drugs which compromise PrEP. Study clinicians shared results (detectable/undetectable) with participants at their 24-week visit. We evaluated the acceptability of receiving these results among a subset of iPrEx OLE participants. We conducted in-depth interviews (n = 59) with participants (those with and those without drug detected) enrolled in Boston, Chicago, and San Francisco to assess their experiences with receiving drug detection feedback. Incorporating drug detection results into the clinical study visit was well received and no negative reactions were expressed. For about half of participants, receiving their drug detection lab result was useful while for others it was not important. In a few cases, no drug detected results led to increased efforts to take PrEP consistently and in most cases enhanced open discussion of missed doses. Participants reported a desire for greater specificity, particularly quantitative drug levels needed for protection. We recommend exploring strategies to increase the salience of drug level results, including using feedback to target adherence counseling, and reducing the time between specimen collection, testing, and receipt of results. Future studies should evaluate the feasibility and impact of providing more specific quantitative drug levels using biomarkers of longer term PrEP exposure, i.e., hair/dried blood spots. PMID- 26001027 TI - Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets. AB - The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 +/- 8.7) * 10(-6) cm/s in the apical to-basolateral (AP-BL) direction and (41.4 +/- 1.6) * 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 +/- 0.9) * 10( 6) cm/s and BL-AP Papp of (34.6 +/- 4.6) * 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk. PMID- 26001029 TI - Learning: Behavior Grounded in Experiences. PMID- 26001028 TI - Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes. AB - BACKGROUND: Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia study compares neurodevelopmental outcomes after awake RA or GA in otherwise healthy infants. The aim of the study is to describe success and failure rates of RA and report factors associated with failure. METHODS: This was a nested cohort study within a prospective, randomized, controlled, observer-blind, equivalence trial. Seven hundred twenty two infants 60 weeks or less postmenstrual age scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural, or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, were analyzed. Possible predictors of failure were assessed including patient factors, technique, experience of site and anesthetist, and type of local anesthetic. RESULTS: RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty-four patients required conversion to GA, and an additional 23 patients (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (odds ratio = 2.46). CONCLUSIONS: The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone. PMID- 26001030 TI - Prehabilitation for Prevention of Postoperative Cognitive Dysfunction? PMID- 26001031 TI - Behavioral Modification of Intraoperative Hyperglycemia Management with a Novel Real-time Audiovisual Monitor. AB - BACKGROUND: Hyperglycemia, defined as blood glucose (BG) levels above 200 mg/dl (11.1 mM), is associated with increased postoperative morbidity. Yet, the treatment standard for intraoperative glycemic control is poorly defined for noncardiac surgery. Little is known of the interindividual treatment variability or methods to modify intraoperative glycemic management behaviors. AlertWatch (AlertWatch, USA) is a novel audiovisual alert system that serves as a secondary patient monitor for use in operating rooms. The authors evaluated the influence of use of AlertWatch on intraoperative glycemic management behavior. METHODS: AlertWatch displays historical patient data (risk factors and laboratory results) from multiple networked information systems, combined with the patient's live physiologic data. The authors extracted intraoperative data for 19 months to evaluate the relationship between AlertWatch usage and initiation of insulin treatment for hyperglycemia. Outcome associations were adjusted for physical status, case duration, procedural complexity, emergent procedure, fasting BG value, home insulin therapy, patient age, and primary anesthetist. RESULTS: Overall, 2,341 patients had documented intraoperative hyperglycemia. Use of AlertWatch (791 of 2,341; 33.5%) was associated with 55% increase in insulin treatment (496 of 791 [62.7%] with and 817 of 1,550 [52.7%] without AlertWatch; adjusted odds ratio [95% CI], 1.55 [1.23 to 1.95]; P < 0.001) and 44% increase in BG recheck after insulin administration (407 of 791 [51.5%] with AlertWatch and 655 of 1,550 [42.3%] in controls; adjusted odds ratio [95% CI], 1.44 [1.14 to 1.81]; P = 0.002). CONCLUSION: AlertWatch is associated with a significant increase in desirable intraoperative glycemic management behavior and may help achieve tighter intraoperative glycemic control. PMID- 26001032 TI - Impact of Preoperative Environmental Enrichment on Prevention of Development of Cognitive Impairment following Abdominal Surgery in a Rat Model. AB - BACKGROUND: Sustained neuroinflammation may contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Here, the authors evaluated the preventive effect of preoperative environmental enrichment (PEE) on the development of neuroinflammation and concomitant POCD in a rat abdominal surgery model. METHODS: Young and aged rats were assigned to one of four groups using a 2 * 2 experimental design: PEE versus sedentary condition for 14 days, by abdominal surgery versus anesthesia alone (n = 8 in each group). After a 7-day postsurgical recovery period, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of proinflammatory cytokines. Under identical conditions, microglia were isolated from the hippocampus for assessment of cytokine response to lipopolysaccharide. RESULTS: In the sedentary group, aged, but not young, rats receiving surgery showed memory deficits (novel object preference during testing phase of 54.6 +/- 7.8% vs. 76.9 +/- 11.3% in nonsurgery group, P < 0.05) and increased hippocampal levels of cytokines compared with nonsurgical rats. PEE had no effects on novel object preference in nonsurgery animals (78.6 +/- 10.7%), whereas it attenuated surgery-induced impairment of novel object preference (70.9 +/- 15.0%, P < 0.05 vs. sedentary/surgery group) as well as increase of cytokine levels in hippocampus. Furthermore, upon ex vivo stimulation with lipopolysaccharide, cytokines release from hippocampal microglia isolated from aged rats before intervention was significantly higher in comparison with young rats. PEE resulted in reduction of these age-related microglial phenotypic changes. CONCLUSIONS: PEE could prevent the development of neuroinflammation and related POCD in aged rats by reversion of a proinflammatory phenotype of hippocampal microglia. PMID- 26001034 TI - Postoperative Apnea in Former Preterm Infants: General Anesthesia or Spinal Anesthesia--Do We Have an Answer? PMID- 26001035 TI - Micro/Nano gas sensors: a new strategy towards in-situ wafer-level fabrication of high-performance gas sensing chips. AB - Nano-structured gas sensing materials, in particular nanoparticles, nanotubes, and nanowires, enable high sensitivity at a ppb level for gas sensors. For practical applications, it is highly desirable to be able to manufacture such gas sensors in batch and at low cost. We present here a strategy of in-situ wafer level fabrication of the high-performance micro/nano gas sensing chips by naturally integrating microhotplatform (MHP) with nanopore array (NPA). By introducing colloidal crystal template, a wafer-level ordered homogenous SnO2 NPA is synthesized in-situ on a 4-inch MHP wafer, able to produce thousands of gas sensing units in one batch. The integration of micromachining process and nanofabrication process endues micro/nano gas sensing chips at low cost, high throughput, and with high sensitivity (down to ~20 ppb), fast response time (down to ~1 s), and low power consumption (down to ~30 mW). The proposed strategy of integrating MHP with NPA represents a versatile approach for in-situ wafer-level fabrication of high-performance micro/nano gas sensors for real industrial applications. PMID- 26001033 TI - Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial. AB - BACKGROUND: Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. METHODS: Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded. RESULTS: Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio [OR], 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature. CONCLUSIONS: RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants. PMID- 26001036 TI - A mass in the junction of the body and tail of the pancreas with negative IgG4 serology: IgG4-related disease with negative serology. AB - BACKGROUND: Autoimmune pancreatitis is an IgG4-related fibroinflammatory condition often associated with obstructive jaundice, as most lesions are located at the head of the pancreas. IgG4 level can help in the diagnosis, but it is normal in nearly 30% of affected patients. CASE REPORT: A 55-year-old woman presented with a 5-month history of 20-pound unintentional weight loss and intermittent abdominal pain. She had an unremarkable abdominal exam and significant findings included a small, non-mobile rubbery left axillary lymph node. Complete blood count, complete metabolic panel, amylase, anti-smooth muscle antibody, antimitochondrial antibody, carcinoembryonic antigen, Ca 19-9, complement C3 and C4, antinuclear antibody, anti-Smith double-strand antibody, and IgG4 were all within normal limits. CT of the abdomen showed a mass in the junction of the body and tail of the pancreas and endoscopic ultrasound showed it as encasing the splenic artery. Fine-needle aspiration cytology demonstrated follicular hyperplasia, obliterative phlebitis, storiform fibrosis, and negative staining for IgG4 and malignancy. Left axillary lymph node biopsy demonstrated follicular hyperplasia. PET scan revealed hypermetabolic uptake of the pancreas tail, bone marrow, and spleen, as well as diffuse lymphadenopathy. Bone marrow biopsy showed follicular hyperplasia and was negative for malignancy. The patient was started on 40 mg of oral prednisone for possible autoimmune disease. During follow-up, she reported progressive improvement and a repeat PET scan 6 months later showed marked improvement. CONCLUSIONS: A normal IgG4 value should not decrease the clinical suspicion of IgG4-related disease. If clinical, histological, and radiological findings coincide, glucocorticoids should be initiated with subsequent follow-up to evaluate for a response. PMID- 26001037 TI - Copper, lead and zinc removal from metal-contaminated wastewater by adsorption onto agricultural wastes. AB - The use of agricultural wastes (groundnut shell, orange and banana peel, rice husk, coconut husk and Wawa tree saw dust) as potential cost-effective adsorbent for heavy metal removal from wastewater was evaluated. The effect of pH (2.0 6.0), adsorbent dosage (0.6-2.2 g), contact time (10-130 min) and initial concentration (Pb: 5-105 mg/L, Cu and Zn: 2.5-52.7 mg/L) on the metal removal efficiency and uptake capacity were investigated using response surface methodology to optimize the process conditions. Groundnut shell showed a high potential to remove Cu, Pb and Zn from synthetic wastewater. The highest removal efficiencies with groundnut as the adsorbent were 85% at pH 5.0 for Cu and 98% at pH 3.0 for Pb and Zn. The optimum conditions obtained were 2.5 g adsorbent with 40.7 mg/L Cu at pH 4.4 and 64 min contact time, 2.5 g adsorbent with 196.1 mg/L Pb at pH 5.6 and 60 min contact time and 3.1 g adsorbent with 70.2 mg/L Zn at pH 4.3 and 50 min contact time, for Cu, Pb and Zn, respectively. The regeneration of the groundnut shell was possible for a maximum of three cycles using 0.2 M HCl as the desorbing solution without any significant change in the adsorbing efficiency. PMID- 26001038 TI - Corrigendum: Fault-tolerant quantum computation with a soft-decision decoder for error correction and detection by teleportation. PMID- 26001039 TI - Epitaxial Growth of GaN Nanowires with High Structural Perfection on a Metallic TiN Film. AB - Vertical GaN nanowires are grown in a self-induced way on a sputtered Ti film by plasma-assisted molecular beam epitaxy. Both in situ electron diffraction and ex situ ellipsometry show that Ti is converted to TiN upon exposure of the surface to the N plasma. In addition, the ellipsometric data demonstrate this TiN film to be metallic. The diffraction data evidence that the GaN nanowires have a strict epitaxial relationship to this film. Photoluminescence spectroscopy of the GaN nanowires shows excitonic transitions virtually identical in spectral position, line width, and decay time to those of state-of-the-art GaN nanowires grown on Si. Therefore, the crystalline quality of the GaN nanowires grown on metallic TiN and on Si is equivalent. The freedom to employ metallic substrates for the epitaxial growth of semiconductor nanowires in high structural quality may enable novel applications that benefit from the associated high thermal and electrical conductivity as well as optical reflectivity. PMID- 26001040 TI - Identifying/Quantifying Environmental Trade-offs Inherent in GHG Reduction Strategies for Coal-Fired Power. AB - Improvements to coal power plant technology and the cofired combustion of biomass promise direct greenhouse gas (GHG) reductions for existing coal-fired power plants. Questions remain as to what the reduction potentials are from a life cycle perspective and if it will result in unintended increases in impacts to air and water quality and human health. This study provides a unique analysis of the potential environmental impact reductions from upgrading existing subcritical pulverized coal power plants to increase their efficiency, improving environmental controls, cofiring biomass, and exporting steam for industrial use. The climate impacts are examined in both a traditional-100 year GWP-method and a time series analysis that accounts for emission and uptake timing over the life of the power plant. Compared to fleet average pulverized bed boilers (33% efficiency), we find that circulating fluidized bed boilers (39% efficiency) may provide GHG reductions of about 13% when using 100% coal and reductions of about 20-37% when cofiring with 30% biomass. Additional greenhouse gas reductions from combined heat and power are minimal if the steam coproduct displaces steam from an efficient natural gas boiler. These upgrades and cofiring biomass can also reduce other life cycle impacts, although there may be increased impacts to water quality (eutrophication) when using biomass from an intensely cultivated source. Climate change impacts are sensitive to the timing of emissions and carbon sequestration as well as the time horizon over which impacts are considered, particularly for long growth woody biomass. PMID- 26001041 TI - Surface Modification of Multiwalled Carbon Nanotubes with Cationic Conjugated Polyelectrolytes: Fundamental Interactions and Intercalation into Conductive Poly(methyl methacrylate) Composites. AB - This research investigates the modification and dispersion and of pristine multiwalled carbon nanotubes (MWCNTs) through a simple solution mixing technique based on noncovalent interactions between poly(phenylene ethynylene)-based conjugated polyelectrolytes functionalized with cationic imidazolium solubilizing groups (PIM-2 and PIM-4) and MWCNTs. Spectroscopic studies demonstrated the ability of PIMs to strongly interact with and efficiently disperse MWCNTs in different solvents, mainly due to pi interactions between the PIMs and the MWCNTs. Transmission electron microscopy and atomic force microscopy revealed the coating of the polyelectrolytes on the walls of the nanotubes. Scanning electron microscopy (SEM) studies confirm the homogeneous dispersion of PIM-modified MWCNTs in the poly(methyl methacrylate) (PMMA) matrix. The addition of 1 wt % PIM modified MWCNTs to the matrix has led to a significant decrease in DC resistivity of the composite (13 orders of magnitude). The increase in electrical conductivity and the improvement in the thermal and mechanical properties of the membranes containing the PIM-modified MWCNTs is ascribed to the formation of MWCNT networks and cross-linking sites that provided channels for the electrons to move in throughout the matrix and reinforced the interface between MWCNTs and PMMA. PMID- 26001042 TI - Measuring Subvisible Particles in Protein Formulations Using a Modified Light Obscuration Sensor with Improved Detection Capabilities. AB - Although light obscuration is the "gold standard" for subvisible particle measurements in biopharmaceutical products, the current technology has limitations with respect to the detection of translucent proteinaceous particles and particles of sizes smaller and around 2 MUm. Here, we describe the evaluation of a modified light obscuration sensor utilizing a novel measuring mode. Whereas standard light obscuration methodology monitors the height (amplitude) of the signal, the new approach monitors its length (width). Experimental evaluation demonstrated that this new detection mode leads to improved detection of subvisible particles of sizes smaller than 2 MUm, reduction of artifacts during measurements especially of low concentrations of translucent protein particles, and higher counting accuracy as compared to flow imaging microscopy and standard light obscuration measurements. PMID- 26001043 TI - Five new bioactive compounds from Chenopodium ambrosioides. AB - Five new bioactive compounds, chenopodiumamines A-D (1-4) and chenopodiumoside A (5), were isolated from the ethanol extract of Chenopodium ambrosioides. The structures of these compounds were elucidated by various spectroscopic means (UV, IR, HR-ESI-MS, 1D and 2D NMR). Compounds 1-3 had moderate antioxidant and anti inflammatory activities. PMID- 26001044 TI - Finger Prick Dried Blood Spots for HIV Viral Load Measurement in Field Conditions in Zimbabwe. AB - BACKGROUND: In the context of a community-randomized trial of antiretrovirals for HIV prevention and treatment among sex workers in Zimbabwe (the SAPPH-IRe trial), we will measure the proportion of women with HIV viral load (VL) above 1000 copies/mL ("VL>1000") as our primary endpoint. We sought to characterize VL assay performance by comparing results from finger prick dried blood spots (DBS) collected in the field with plasma samples, to determine whether finger prick DBS is an acceptable sample for VL quantification in the setting. METHODS: We collected whole blood from a finger prick onto filter paper and plasma samples using venipuncture from women in two communities. VL quantification was run on samples in parallel using NucliSENS EasyQ HIV-1 v2.0. Our trial outcome is the proportion of women with VL>1000, consistent with WHO guidelines relating to regimen switching. We therefore focused on this cut-off level for assessing sensitivity and specificity. Results were log transformed and the mean difference and standard deviation calculated, and correlation between VL quantification across sample types was evaluated. RESULTS: A total of 149 HIV-positive women provided DBS and plasma samples; 56 (63%) reported being on antiretroviral therapy. VL ranged from undetectable-6.08 log10 using DBS and undetectable-6.40 log10 using plasma. The mean difference in VL (plasma-DBS) was 0.077 log10 (95%CI = 0.025-0.18 log10; standard deviation = 0.63 log10,). 78 (52%) DBS and 87 (58%) plasma samples had a VL>1000. Based on plasma 'gold-standard', DBS sensitivity for detection of VL>1000 was 87.4%, and specificity was 96.8%. CONCLUSION: There was generally good agreement between DBS and plasma VL for detection of VL>1000. Overall, finger prick DBS appeared to be an acceptable sample for classifying VL as above or below 1000 copies/mL using the NucliSENS assay. PMID- 26001045 TI - The effect of graft strength on knee laxity and graft in-situ forces after posterior cruciate ligament reconstruction. AB - Surgical reconstruction is generally recommended for posterior cruciate ligament (PCL) injuries; however, the use of grafts is still a controversial problem. In this study, a three-dimensional finite element model of the human tibiofemoral joint with articular cartilage layers, menisci, and four main ligaments was constructed to investigate the effects of graft strengths on knee kinematics and in-situ forces of PCL grafts. Nine different graft strengths with stiffness ranging from 0% (PCL rupture) to 200%, in increments of 25%, of an intact PCL's strength were used to simulate the PCL reconstruction. A 100 N posterior tibial drawer load was applied to the knee joint at full extension. Results revealed that the maximum posterior translation of the PCL rupture model (0% stiffness) was 6.77 mm in the medial compartment, which resulted in tibial internal rotation of about 3.01 degrees . After PCL reconstruction with any graft strength, the laxity of the medial tibial compartment was noticeably improved. Tibial translation and rotation were similar to the intact knee after PCL reconstruction with graft strengths ranging from 75% to 125% of an intact PCL. When the graft's strength surpassed 150%, the medial tibia moved forward and external tibial rotation greatly increased. The in-situ forces generated in the PCL grafts ranged from 13.15 N to 75.82 N, depending on the stiffness. In conclusion, the strength of PCL grafts have has a noticeable effect on anterior-posterior translation of the medial tibial compartment and its in-situ force. Similar kinematic response may happen in the models when the PCL graft's strength lies between 75% and 125% of an intact PCL. PMID- 26001046 TI - Intra-rater and inter-rater reliability of a medical record abstraction study on transition of care after childhood cancer. AB - BACKGROUND: The abstraction of data from medical records is a widespread practice in epidemiological research. However, studies using this means of data collection rarely report reliability. Within the Transition after Childhood Cancer Study (TaCC) which is based on a medical record abstraction, we conducted a second independent abstraction of data with the aim to assess a) intra-rater reliability of one rater at two time points; b) the possible learning effects between these two time points compared to a gold-standard; and c) inter-rater reliability. METHOD: Within the TaCC study we conducted a systematic medical record abstraction in the 9 Swiss clinics with pediatric oncology wards. In a second phase we selected a subsample of medical records in 3 clinics to conduct a second independent abstraction. We then assessed intra-rater reliability at two time points, the learning effect over time (comparing each rater at two time-points with a gold-standard) and the inter-rater reliability of a selected number of variables. We calculated percentage agreement and Cohen's kappa. FINDINGS: For the assessment of the intra-rater reliability we included 154 records (80 for rater 1; 74 for rater 2). For the inter-rater reliability we could include 70 records. Intra-rater reliability was substantial to excellent (Cohen's kappa 0-6 0.8) with an observed percentage agreement of 75%-95%. In all variables learning effects were observed. Inter-rater reliability was substantial to excellent (Cohen's kappa 0.70-0.83) with high agreement ranging from 86% to 100%. CONCLUSIONS: Our study showed that data abstracted from medical records are reliable. Investigating intra-rater and inter-rater reliability can give confidence to draw conclusions from the abstracted data and increase data quality by minimizing systematic errors. PMID- 26001047 TI - CD229 is expressed on the surface of plasma cells carrying an aberrant phenotype and chemotherapy-resistant precursor cells in multiple myeloma. AB - Multiple Myeloma (MM) is a plasma cell (PC) malignancy, which despite significant therapeutic advances, is still considered incurable. This is due to the persistence of chemotherapy-resistant minimal residual disease in the patients' bone marrow (BM) after an effective induction therapy. Immunotherapies targeting surface molecules expressed on the bulk of tumor cells and the chemotherapy resistant, myeloma-propagating cells could play a central role in this clinical setting. We recently described surface molecule CD229 as a potential therapeutic target for MM. In our current study we assessed the expression of CD229 on different PC subtypes and on cells with a myeloma-propagating phenotype in a total of 77 patients with PC dyscrasias independently at 2 different cancer centers. We found that CD229 was strongly and homogeneously overexpressed on the PC of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, MM, and PC leukemia. CD229 was particularly overexpressed on those PC showing an abnormal phenotype such as expression of CD56. Most importantly, CD229 was also highly expressed on those cells in the patients' BM displaying the phenotype of chemotherapy-resistant and myeloma-propagating cells. In conclusion, our combined findings suggest that immunotherapies targeting CD229 will not only be effective for the bulk of tumor cells but will also help to eradicate chemotherapy-resistant cells remaining in the patients' BM after induction treatment. Hopefully, the design of CD229-specific monoclonal antibodies or chimeric antigen receptor-transduced T cells will help to achieve prolonged remissions or even cures in MM patients. PMID- 26001048 TI - The Bass Parasites of Oneida Lake, 80 Years Later. AB - A survey of largemouth (Micropterus salmoides) and smallmouth bass (Micropterus dolomieu) parasite communities in Oneida Lake, New York, was conducted in the summer of 2012 and compared to an earlier survey conducted by Van Cleave and Mueller during the summers of 1929 to 1931. The component helminth communities between surveys were 31% similar in composition for largemouth and 28% similar for smallmouth bass. Between species, the component helminth communities were considerably more similar in the present survey (71%) than in the survey conducted by Van Cleave and Mueller (47%). Seven species reported by Van Cleave and Mueller were present in this survey and 21 species are new records for the bass of Oneida Lake. Van Cleave and Mueller did not report prevalence values for several taxa (Monogenea, Copepoda, Myxozoa, and a Trichodina sp.) that were important for separation of parasite infracommunities in species space for both bass species. These parasites represented 28% of all species found in the current survey and may be ecologically important. Several species of parasites exhibited differences in prevalence between surveys. Two species (Rhipidocotyle papillosa and Crepidostomum cornutum) were absent from this survey but were reported as common in the 1929-1931 survey and almost certainly represent extirpations that coincide with the loss of their native bivalve hosts from Oneida Lake. Other differences in the parasite communities may also be explained by the ecological disturbances in Oneida Lake over the past 81 yr. The changes in bass parasite communities between surveys emphasize the importance of recognizing the historical nature of parasite communities, especially in ecosystems with a history of large-scale changes. Most importantly our findings suggest that, similar to trends observed in free-living freshwater biotic communities, anthropogenic ecosystem disturbances may homogenize fish parasite communities. PMID- 26001049 TI - Extended-Spectrum beta-Lactamase- and Carbapenemase-Producing Enterobacteriaceae Isolated from Egyptian Patients with Suspected Blood Stream Infection. AB - OBJECTIVES: The aim of the study was to investigate the prevalence of extended spectrum beta-lactamase and carbapenemase production among Enterobacteriaceae isolated from Egyptian patients with suspected blood stream infection. METHODS: Ninety-four Enterobacteriaceae blood culture isolates from Egyptian patients with suspected blood stream infection were collected, one isolate per patient. Identification of bacterial isolates was performed with MALDI-TOF (MS-based Vitek MS system, bioMerieux). Screening for ESBLs and carbapenemases production was done with the Vitek 2 system (bioMerieux). ESBL production was confirmed using the combined disk diffusion method for cefotaxime, ceftazidime, and cefepime, all with and without clavulanic acid (Rosco). Real-time PCR and sequencing were used to characterize the resistance genes. The phylogenetic groups of E. coli were identified by a PCR-based method. RESULTS: Of the 94 Enterobacteriaceae isolates 46 (48.93%) showed an ESBL phenotype. One Enterobacter spp isolate was ESBL producer and meropenem-resistant. The genetic analysis showed that CTX-M was present in 89.13% (41/46) of the ESBL-producing Enterobacteriaceae, whereas TEM and SHV were detected in 56.52% (26/46) and 21.74% (10/46) respectively (47.83%) of the ESBL-producing isolates were multidrug resistant (MDR). Eleven out of 30 ESBL-producing E-coli isolates were assigned to phylogroup B2, followed by groups B1 (8 isolates), A (6 isolates) and D (5 isolates). CONCLUSIONS: The high ESBL-E rates (48.93%) found in this study together with the identification of one carbapenem-resistant Enterobacter spp isolate is worrisome. Our results indicate that systems for monitoring and detection of ESBL-producing bacteria in Egyptian hospitals have to be established. Also strict hospital infection control policies with the restriction of the consumption of extended-spectrum cephalosporins are necessary. PMID- 26001050 TI - Isotopic and Elemental Composition of Roasted Coffee as a Guide to Authenticity and Origin. AB - This study presents the stable isotopic and elemental compositions of single origin, roasted coffees available to retail consumers. The delta(13)C, delta(15)N, and delta(18)O compositions were in agreement with those previously reported for green coffee beans. The delta(15)N composition was seen to be related to organic cultivation, reflected in both delta(2)H and delta(18)O compositions. The delta(13)C composition of extracted caffeine differed little from that of the bulk coffee. Stepwise discriminant analysis with jackknife tests, using isotopic and elemental data, provided up to 77% correct classification of regions of production. Samples from Africa and India were readily classified. The wide range in both isotopic and elemental compositions of samples from other regions, specifically Central/South America, resulted in poor discrimination between or within these regions. Simpler X-Y and geo-spatial plots of the isotopic data provided effective visual means to distinguish between coffees from different regions. PMID- 26001052 TI - Emerging therapies: angiogenesis inhibitors for ovarian cancer. AB - INTRODUCTION: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ~ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC. AREAS COVERED: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib. EXPERT OPINION: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date. PMID- 26001051 TI - Naturally occurring marine brominated indoles are aryl hydrocarbon receptor ligands/agonists. AB - The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the toxic and biological effects of structurally diverse chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of a larger effort to identify the full spectrum of chemicals that can bind to and activate the AhR, we have examined the ability of several naturally occurring marine-derived brominated indoles and brominated (methylthio)indoles (collectively referred to as brominated indoles) to bind to the AhR and stimulate AhR-dependent gene expression. Incubation of mouse, rat, and guinea pig recombinant cell lines containing a stably transfected AhR responsive luciferase reporter gene with eight brominated indoles revealed that all compounds stimulated luciferase reporter gene activity, although some species specific differences were observed. All compounds induced significantly more luciferase activity when incubated with cells for 4 h as compared to 24 h, demonstrating that these compounds are transient activators of the AhR signaling pathway. Three of the brominated indoles induced CYP1A1 mRNA in human HepG2 cells in vitro and Cyp1a mRNA in zebrafish embryos in vivo. The identification of the brominated indoles as direct ligands and activators/agonists of the AhR was confirmed by their ability to compete with [(3)H]TCDD for binding to the AhR and to stimulate AhR transformation and DNA binding in vitro. Taken together, these results indicate that marine-derived brominated indoles are members of a new class of naturally occurring AhR agonists. PMID- 26001054 TI - The PTIP-Associated Histone Methyltransferase Complex Prevents Stress-Induced Maladaptive Cardiac Remodeling. AB - Pressure overload induces stress-induced signaling pathways and a coordinated transcriptional response that begets concentric cardiac hypertrophy. Although concentric hypertrophy initially attenuates wall stress and maintains cardiac function, continued stress can result in maladaptive cardiac remodeling. Cardiac remodeling is orchestrated by transcription factors that act within the context of an epigenetic landscape. Since the epigenetic landscape serves as a molecular link between environmental factors (stress) and cellular phenotype (disease), defining the role of the epigenome in the development and progression of cardiac remodeling could lead to new therapeutic approaches. In this study, we hypothesized that the epigenetic landscape is important in the development of cardiac hypertrophy and the progression to maladaptive remodeling. To demonstrate the importance of the epigenome in HF, we targeted the PTIP-associated histone methyltransferase complex in adult cardiac myocytes. This complex imparts histone H3 lysine 4 (H3K4) methylation marks at actively expressed genes. We subjected PTIP null (PTIP-) mice to 2 weeks of transverse aortic constriction, a stress that induces concentric hypertrophy in control mice (PTIP+). PTIP- mice have a maladaptive response to 2wk of transverse aortic constriction (TAC)-induced pressure overload characterized by cardiac dilatation, decreased LV function, cardiac fibrosis, and increased cell death. PTIP deletion resulted in altered stress-induced gene expression profiles including blunted expression of ADRA1A, ADRA1B, JUN, ATP2A2, ATP1A2, SCN4B, and CACNA1G. These results suggest that H3K4 methylation patterns and the complexes that regulate them, specifically the PTIP associated HMT, are necessary for the adaptive response to TAC. PMID- 26001055 TI - RNA-seq based whole transcriptome analysis of the cyclopoid copepod Paracyclopina nana focusing on xenobiotics metabolism. AB - Copepods are among the most abundant taxa in marine invertebrates, and cyclopoid copepods include more than 1500 species and subspecies. In marine ecosystems, planktonic copepods play a significant role as food resources in the food web and sensitively respond to environmental changes. The copepod Paracylopina nana is one of the planktonic brackish water copepods and considered as a promising model species in ecotoxicology. We sequenced the whole transcriptome of P. nana using RNA-seq technology. De novo sequence assembly by Trinity integrated with TransDecoder produced 67,179 contigs including putative alternative spliced variants. A total of 12,474 genes were identified based on BLAST analysis, and gene sequences were most similar to the sequences of the branchiopod Daphnia. Gene Ontology and KEGG pathway analysis showed that most transcripts annotated were involved in pathways of various metabolisms, immune system, signal transduction, and translation. Considering numbers of sequences and enzymes involved in the pathways, particularly attention was paid to genes potentially involved in xenobiotics biodegradation and metabolism. With regard to xenobiotics metabolism, various xenobiotic metabolizing enzymes such as oxidases, dehydrogenases, and transferases were obtained from the annotated transcripts. The whole transcriptome analysis of P. nana provides valuable resources for future studies of xenobiotics-related metabolism in this marine copepod species. PMID- 26001056 TI - The centrosomal linker and microtubules provide dual levels of spatial coordination of centrosomes. AB - The centrosome is the principal microtubule organizing center in most animal cells. It consists of a pair of centrioles surrounded by pericentriolar material. The centrosome, like DNA, duplicates exactly once per cell cycle. During interphase duplicated centrosomes remain closely linked by a proteinaceous linker. This centrosomal linker is composed of rootletin filaments that are anchored to the centrioles via the protein C-Nap1. At the onset of mitosis the linker is dissolved by Nek2A kinase to support the formation of the bipolar mitotic spindle. The importance of the centrosomal linker for cell function during interphase awaits characterization. Here we assessed the phenotype of human RPE1 C-Nap1 knockout (KO) cells. The absence of the linker led to a modest increase in the average centrosome separation from 1 to 2.5 MUm. This small impact on the degree of separation is indicative of a second level of spatial organization of centrosomes. Microtubule depolymerisation or stabilization in C Nap1 KO cells dramatically increased the inter-centrosomal separation (> 8 MUm). Thus, microtubules position centrosomes relatively close to one another in the absence of linker function. C-Nap1 KO cells had a Golgi organization defect with a two-fold expansion of the area occupied by the Golgi. When the centrosomes of C Nap1 KO cells showed considerable separation, two spatially distinct Golgi stacks could be observed. Furthermore, migration of C-Nap1 KO cells was slower than their wild type RPE1 counterparts. These data show that the spatial organization of centrosomes is modulated by a combination of centrosomal cohesion and microtubule forces. Furthermore a modest increase in centrosome separation has major impact on Golgi organization and cell migration. PMID- 26001057 TI - High resolution structural characterization of Abeta42 amyloid fibrils by magic angle spinning NMR. AB - The presence of amyloid plaques composed of amyloid beta (Abeta) fibrils is a hallmark of Alzheimer's disease (AD). The Abeta peptide is present as several length variants with two common alloforms consisting of 40 and 42 amino acids, denoted Abeta1-40 and Abeta1-42, respectively. While there have been numerous reports that structurally characterize fibrils of Abeta1-40, very little is known about the structure of amyloid fibrils of Abeta1-42, which are considered the more toxic alloform involved in AD. We have prepared isotopically (13)C/(15)N labeled AbetaM01-42 fibrils in vitro from recombinant protein and examined their (13)C-(13)C and (13)C-(15)N magic angle spinning (MAS) NMR spectra. In contrast to several other studies of Abeta fibrils, we observe spectra with excellent resolution and a single set of chemical shifts, suggesting the presence of a single fibril morphology. We report the initial structural characterization of AbetaM01-42 fibrils utilizing (13)C and (15)N shift assignments of 38 of the 43 residues, including the backbone and side chains, obtained through a series of cross-polarization based 2D and 3D (13)C-(13)C, (13)C-(15)N MAS NMR experiments for rigid residues along with J-based 2D TOBSY experiments for dynamic residues. We find that the first ~5 residues are dynamic and most efficiently detected in a J-based TOBSY spectrum. In contrast, residues 16-42 are easily observed in cross polarization experiments and most likely form the amyloid core. Calculation of psi and phi dihedral angles from the chemical shift assignments indicate that 4 beta-strands are present in the fibril's secondary structure. PMID- 26001059 TI - Consequences of maternal mortality on infant and child survival: a 25-year longitudinal analysis in Butajira Ethiopia (1987-2011). AB - BACKGROUND: Maternal mortality remains the leading cause of death and disability for reproductive-age women in resource-poor countries. The impact of a mother's death on child outcomes is likely severe but has not been well quantified. This analysis examines survival outcomes for children whose mothers die during or shortly after childbirth in Butajira, Ethiopia. METHODS: This study uses data from the Butajira Health and Demographic Surveillance System (HDSS) site. Child outcomes were assessed using statistical tests to compare survival trajectories and age-specific mortality rates for children who did and did not experience a maternal death. The analyses leveraged the advantages of a large, long-term longitudinal dataset with a high frequency of data collection; but used a strict date-based method to code maternal deaths (as occurring within 42 or 365 days of childbirth), which may be subject to misclassification or recall bias. RESULTS: Between 1987 and 2011, there were 18189 live births to 5119 mothers; and 73 mothers of 78 children died within the first year of their child's life, with 45% of these (n=30) classified as maternal deaths due to women dying within 42 days of childbirth. Among the maternal deaths, 81% of these infants also died. Children who experienced a maternal death within 42 days of their birth faced 46 times greater risk of dying within one month when compared to babies whose mothers survived (95% confidence interval 25.84-81.92; or adjusted ratio, 57.24 with confidence interval 25.31-129.49). CONCLUSIONS: When a woman in this study population experienced a maternal death, her infant was much more likely to die than to survive--and the survival trajectory of these children is far worse than those of mothers who do not die postpartum. This highlights the importance of investigating how clinical care and socio-economic support programs can better address the needs of orphans, both throughout the intra- and post-partum periods as well as over the life course. PMID- 26001060 TI - Microbial analyses of traditional Italian salami reveal microorganisms transfer from the natural casing to the meat matrix. AB - In this study the bacterial biodiversity, during the maturation process of traditional sausages (Salame Mantovano), produced with two different kinds of casing (hog middle or "Crespone" and hog bung or "Gentile"), was investigated by means of culture-dependent and -independent methods. In order to assess the natural variability linked to the type of casing used in production, the ingredients, as well as ripening conditions, were identical in both productions. The aim of the study was to understand the contribution of casing microflora during sausage ripening by identifying the dominant species and strains. The bacterial ecology of casings and salami at different ripening stages, as determined by plating, revealed higher staphylococci and enterococci counts for Gentile casing and for the entire ripening period of the salami studied. After molecular identification of 219 Lactobacilli and 225 cocci gram positive catalase positive (GPCP) isolates, the species most frequently isolated were Lactobacillus sakei, Lactobacillus curvatus, Staphylococcus xylosus, and Staphylococcus saprophyticus. Some L. sakei and S. saprophyticus strains, coming from casing, were also found in the salami at different times of ripening. A richer biodiversity was only detected at the beginning of maturation. We also report the first detection, by PCR-DGGE method, of Arcobacter marinus and Brochothrix thermosphacta species in casings and Kokuria salsicia in fresh sausage. Results suggesting that casing can be an important source of bacteria during natural fermentation when starter cultures are not used. PMID- 26001061 TI - Fungi in Ontario maple syrup & some factors that determine the presence of mold damage. AB - Maple syrup is a high value artisanal product produced mainly in Canada and a number of States primarily in the northeast USA. Mold growth (Wallemia sebi) on commercial product was first reported in syrup in 1908. Since then, few data have been published. We conducted a systematic examination for fungi in maple syrup from 68 producers from all of the syrup-producing areas of Ontario, Canada. The mean pH of the samples was pH 6.82, sugar content averaged 68.0+/-0.89 degrees Brix and aw averaged 0.841+/-0.011. Some 23 species of fungi were isolated based on morphology and molecular techniques. The most common fungus in the maple syrup samples was Eurotium herbariorum, followed by Penicillium chrysogenum, Aspergillus penicillioides, Aspergillus restrictus, Aspergillus versicolor and two species of Wallemia. Cladosporium cladosporioides was also common but only recovered when fungi known from high sugar substrates were also present in the mold damaged sample. The rarely reported yeast Citeromyces matrinsis was found in samples from three producers. There appear to be three potential causes for mold damage observed. High aw was associated with about one third of the mold damage. Independently, cold packing (bottling at ~25 degrees C) was a risk factor. However, syrup of good quality and quite low aw values was contaminated. We hypothesize that sanitation in the bottling line and other aspects of the bottling process may be partial explanations. Clarifying this requires further study. PMID- 26001062 TI - Effectiveness of levulinic acid and sodium dodecyl sulfate employed as a sanitizer during harvest or packing of cantaloupes contaminated with Salmonella Poona. AB - Freshly harvested Eastern variety cantaloupes (Cucumis melo L. var. reticulatus cv. Athena) were subjected to three different harvest and wash treatments to examine conditions under which the efficacy of the sanitizer, levulinic acid (LV) plus sodium dodecyl sulfate (SDS), could be enhanced to reduce Salmonella contamination. In treatment set one, cantaloupes were spot inoculated with Salmonella enterica serovar Poona (prepared from solid or liquid media cultures) before or after a 1-min dip treatment in LV (2.5, 5.0, 7.5, or 10%) and 2.5% SDS. S. Poona initial populations on rind tissue (4.26-5.04 log CFU/sample) were reduced to detection by enrichment culture when cantaloupes were subsequently exposed to any of the LV/SDS solutions. When S. Poona was introduced after cantaloupes had been dip-treated, greater decreases in pathogen populations at the stem scar were observed when cantaloupes were treated with increasing concentrations of LV. In treatment set two, the response of S. Poona dip-treated with 5% LV/2.5% SDS was compared to a simulated commercial dump tank treatment incorporating 200 ppm chlorine as well as a two-stage treatment employing both the chlorine tank and LV/SDS dip treatments. S. Poona levels (log CFU/sample or # positive by enrichment culture/# analyzed) after treatments were 5.25, 3.07, 7/10, 5/10 (stem scar) and 3.90, 25/40, 28/40, 20/40 (rind) for non-treated, chlorine tank, LV/SDS dip, and tank plus dip treatments, respectively. In treatment set three, freshly harvested cantaloupes were first treated in the field using a needle-free stem scar injection (200 MUl, 7.5% LV/1.0% SDS, 60 psi) and a cantaloupe spray (30 ml, 7.5% LV/0.5% SDS). Cantaloupe stem scar and rind tissue were then spot-inoculated with S. Poona using either a liquid or soil based medium followed by a simulated dump tank treatment incorporating either 200 ppm chlorine or 5% LV/2% SDS. S. Poona inoculated on field-treated cantaloupe rind decreased by 4.7 and 5.31 (liquid) and 3.27 and 3.36 (soil) log CFU/sample after simulated chlorine and LV/SDS tank treatments, respectively. In the case of stem scar tissue, S. Poona populations exhibited a 1.0 log greater reduction when cantaloupes were treated with LV/SDS compared to chlorine in the dump tank (P<0.05). Based on this study, application of multiple hurdles is warranted, as additional decreases in S. Poona populations were obtained when cantaloupes were subjected to a chlorine dump tank followed by a LV/SDS dip treatment. PMID- 26001058 TI - Minireview: Emerging Concepts in Islet Macrophage Biology in Type 2 Diabetes. AB - Chronic systemic inflammation is a hallmark feature of obesity and type 2 diabetes. Both resident and recruited islet macrophages contribute to the proinflammatory milieu of the diabetic islet. However, macrophages also appear to be critical for beta-cell formation during development and support beta-cell replication in experimental models of pancreas regeneration. In light of these findings, perhaps macrophages in the islet need to be viewed more as a fulcrum where deleterious inflammatory activation is balanced with beneficial tissue repair processes. Undoubtedly, defining the factors that contribute to the ontogeny, heterogeneity, and functionality of macrophages in normal, diseased, and regenerating islets will be necessary to determine whether that fulcrum can be moved to preserve functional beta-cell mass in persons with diabetes. The intent of this review is to introduce the reader to emerging concepts of islet macrophage biology that may challenge the perception that macrophage accumulation in islets is merely a pathological feature of type 2 diabetes. PMID- 26001063 TI - Incorporation of nisin Z and lauric arginate into pullulan films to inhibit foodborne pathogens associated with fresh and ready-to-eat muscle foods. AB - A combination of food grade compounds with edible films, used to inhibit foodborne pathogens associated with fresh or further processed muscle foods, is receiving considerable attention. In this study, pullulan films containing lauric arginate (LAE) and nisin Z (produced by Lactococcus lactis subsp. lactis I8-7-3 and isolated from catfish gut), alone or in combination, were investigated for controlling foodborne pathogens on fresh and further processed muscle foods after long-term refrigerated storage. Salmonella Typhimurium and Salmonella Enteritidis on raw turkey breast slices wrapped with a film containing LAE or the combination of LAE with nisin Z were reduced throughout the experiment, 2.5 to 4.5 log10 CFU/cm(2) and 3.5 to 5.1 log10 CFU/cm(2), respectively. Film containing a combination of LAE with nisin Z reduced Staphylococcus aureus and Listeria monocytogenes Scott A inoculated onto ham surfaces by approximately 5.53 and 5.62 log10 CFU/cm(2), respectively during refrigerated storage. Escherichia coli O157:H7, O111, and O26 also were reduced by >4 log 10CFU/cm(2) on raw beef slices after treatment with the combination film and refrigerated storage. The results obtained from this study indicate the LAE- and LAE-nisin Z-containing pullulan films displayed excellent inhibition against foodborne pathogens on fresh and further processed muscle foods. PMID- 26001064 TI - Prevalence and characterization of extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in ready-to-eat vegetables. AB - The objective of this investigation was to determine the prevalence and characteristics of extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae in ready-to-eat (RTE) vegetables. A total of 189 RTE vegetable samples (91 sprouts and 98 mixed salads) were collected in a retail market in South Korea from October 2012 to February 2013. The prevalence of ESBL producing E. coli and K. pneumoniae was 10.1%. Of these, 94.7% were from the sprout samples. All isolates were resistant to cefotaxime, and many of the ESBL producers were also resistant to non-beta-lactam antibiotics, including gentamicin, trimethoprim/sulfamethoxazole, and ciprofloxacin (73.7%, 63.2%, and 26.3% respectively). TEM-1, SHV-1, -2, -11, -12, -27, -28 and -61, and CTX-M-14, 15 and -55 beta-lactamases were detected alone or in combination. The genetic platforms of all CTX-M producing isolates were ISEcp1-blaCTX-M-orf477 and ISEcp1 blaCTX-M-IS903 in CTX-M groups 1 and 9, respectively. To our knowledge, this is the first report of the prevalence and characterization of ESBL-producing E. coli and K. pneumoniae isolated from RTE vegetables. The results of this study indicate that RTE vegetables, sprouts, in particular, may play a role in spreading antimicrobial resistant bacteria and ESBL genes to humans. PMID- 26001065 TI - Unveiling Singlet Fission Mediating States in TIPS-pentacene and its Aza Derivatives. AB - Femtosecond pump-depletion-probe experiments were carried out in order to shed light on the ultrafast excited-state dynamics of triisopropylsilylethynyl (TIPS) pentacene and two nitrogen-containing derivatives, namely, diaza-TIPS-pentacene and tetraaza-TIPS-pentacene. Measurements performed in the visible and near infrared spectral range in combination with rate model simulations reveal that singlet fission proceeds via the extremely short-lived intermediate (1)TT state, which absorbs in the near-infrared spectral region only. The T1 -> T3 transition probed in the visible region shows a rise time that comprises two components according to a consecutive reaction (S1 -> (1)TT -> T1). The incorporation of nitrogen atoms into the acene structure leads to shorter dynamics, but the overall triplet formation follows the same kinetic model. This is of particular importance, since experiments on tetraaza-TIPS-pentacene allow for investigation of the triplet state in the visible range without an overlapping singlet contribution. In addition, the pump-depletion-probe experiments show that the triplet absorption in the visible (T1 -> T3) and near-infrared (T1 -> T2) regions occurs from the same initial state, which was questioned in previous studies. Furthermore, an additional ultrafast transfer between the excited triplet states (T3 -> T2) is identified, which is also in agreement with the rate model simulation. By applying depletion pulses, which are resonant with higher vibrational levels, we gain insight into internal vibrational energy redistribution processes within the triplet manifold. This additional information is of great relevance regarding the study of loss channels within these materials. PMID- 26001066 TI - Metasynthesis of youth suicidal behaviours: perspectives of youth, parents, and health care professionals. AB - BACKGROUND: Youth suicide is a major public health issue throughout the world. Numerous theoretical models have been proposed to improve our understanding of suicidal behaviours, but medical science has struggled to integrate all the complex aspects of this question. The aim of this review is to synthesise the views of suicidal adolescents and young adults, their parents, and their healthcare professionals on the topics of suicidal behaviour and management of those who have attempted suicide, in order to propose new pathways of care, closer to the issues and expectations of each group. METHODS AND FINDINGS: This systematic review of qualitative studies--Medline, PsycInfo, Embase, CINAHL, and SSCI from 1990 to 2014--concerning suicide attempts by young people used thematic synthesis to develop categories inductively from the themes identified in the studies. The synthesis included 44 studies from 16 countries: 31 interviewed the youth, 7 their parents, and 6 the healthcare professionals. The results are organised around three superordinate themes: the individual experience, that is, the individual burden and suffering related to suicide attempts in all three groups; the relational experience, which describes the importance of relationships with others at all stages of the process of suicidal behaviour; and the social and cultural experience, or how the group and society accept or reject young people in distress and their families and how that affects the suicidal process and its management. CONCLUSION: The violence of the message of a suicidal act and the fears associated with death lead to incomprehension and interfere with the capacity for empathy of both family members and professionals. The issue in treatment is to be able to witness this violence so that the patient feels understood and heard, and thus to limit recurrences. PMID- 26001067 TI - Molecular dynamics of Kv1.3 ion channel and structural basis of its inhibition by scorpion toxin-OSK1 derivatives. AB - Kv1.3 is one of the widely distributed Shaker type voltage gated potassium channel which performs the outward flow of K(+) ions in excitable cells. In immunological synapse, Kv1.3 plays a pivotal role in antigen dependent activation and proliferation of lymphocytes along with the KCa3.1. The up-regulation of Kv1.3 leads to several T-cell-mediated autoimmune diseases, hence considered as an attractive pharmacological drug target. Here, we have employed molecular modeling, docking and simulation techniques to examine the dynamical properties of Kv1.3 in both open and closed state conformation embedded in DPPC membrane as well as its modes of inhibition against the popularly known scorpion venom OSK1 and its three mutant analogues. The Kv1.3 in open conformation took comparatively more time to get stabilized than the closed state. Both conformations ascertain their stability and the transition between closed to active states is more consistent with the paddle model of channel gating. The binding modes of channel toxin complexes are well established by identifying strongly interacting amino acids lining at their polar surfaces. Our findings suggest that, two mutant derivatives OSK1-K16,D20 & OSK1-P12,K16,D20 have increased inhibitory potency against Kv1.3. We also pointed out some particular residues responsible for binding of OSK1 with Kv1.3 over other Shaker-type ion channels. We believe that the insights came from Kv1.3-OSK1 interaction will be valuable in pharmacological studies for strategic development of both potent and selective therapeutic drugs against T-cell-mediated autoimmune diseases. PMID- 26001068 TI - Impact of molecular weight and degree of conjugation on the thermodynamics of DNA complexation and stability of polyethylenimine-graft-poly(ethylene glycol) copolymers. AB - Poly(ethylene glycol) (PEG) is often conjugated to polyethylenimine (PEI) to provide colloidal stability to PEI-DNA polyplexes and shield charge leading to toxicity. Here, a library of nine cationic copolymers was synthesized by grafting three molecular weights (750, 2000, 5000Da) of PEG to linear PEI at three conjugation ratios. Using isothermal titration calorimetry, we have quantified the thermodynamics of the associations between the copolymers and DNA and determined the extent to which binding is hindered as a function of PEG molecular weight and conjugation ratio. Low conjugation ratios of 750Da PEG to PEI resulted in little decrease in DNA affinity, but a significant decrease-up to two orders of magnitude-was found for the other copolymers. We identified limitations in determination of affinity using indirect assays (electrophoretic mobility shift and ethidium bromide exclusion) commonly used in the field. Dynamic light scattering of the DNA complexes at physiological ionic strength showed that PEI modifications that did not reduce DNA affinity also did not confer significant colloidal stability, a finding that was supported by calorimetric data on the aggregation process. These results quantify the DNA interaction thermodynamics of PEGylated polycations for the first time and indicate that there is an optimum PEG chain length and degree of substitution in the design of agents that have desirable properties for effective in vivo gene delivery. PMID- 26001069 TI - The Ovary of Tubifex tubifex (Clitellata, Naididae, Tubificinae) Is Composed of One, Huge Germ-Line Cyst that Is Enriched with Cytoskeletal Components. AB - Recent studies on the ovary organization and oogenesis in Tubificinae have revealed that their ovaries are small polarized structures that are composed of germ cells in subsequent stages of oogenesis that are associated with somatic cells. In syncytial cysts, as a rule, each germ cell is connected to the central cytoplasmic mass, the cytophore, via only one stable intercellular bridge (ring canal). In this paper we present detailed data about the composition of germ-line cysts in Tubifex tubifex with special emphasis on the occurrence and distribution of the cytoskeletal elements. Using fixed material and live cell imaging techniques, we found that the entire ovary of T. tubifex is composed of only one, huge multicellular germ-line cyst, which may contain up to 2,600 cells. Its architecture is broadly similar to the cysts that are found in other clitellate annelids, i.e. a common, anuclear cytoplasmic mass in the center of the cyst and germ cells that are connected to it via intercellular bridges. The cytophore in the T. tubifex cyst extends along the long axis of the ovary in the form of elongated and branched cytoplasmic strands. Rhodamine-coupled phalloidin staining revealed that the prominent strands of actin filaments occur inside the cytophore. Similar to the cytophore, F-actin strands are branched and they are especially well developed in the middle and outermost parts of the ovary. Microfilaments are also present in the ring canals that connect the germ cells with the cytophore in the narrow end of the ovary. Using TubulinTracker, we found that the microtubules form a prominent network of loosely and evenly distributed tubules inside the cytophore as well as in every germ cell. The well-developed cytoskeletal elements in T. tubifex ovary seem to ensure the integrity of such a huge germ-line cyst of complex (germ cells-ring canals-cytophore) organization. A comparison between the cysts that are described here and other well-known female germ-line cysts is also made. PMID- 26001070 TI - Diversification and Distribution of Ruminant Chlamydia abortus Clones Assessed by MLST and MLVA. AB - Chlamydia abortus, an obligate intracellular bacterium, is the most common infectious cause of abortion in small ruminants worldwide and has zoonotic potential. We applied multilocus sequence typing (MLST) together with multiple locus variable-number tandem repeat analysis (MLVA) to genotype 94 ruminant C. abortus strains, field isolates and samples collected from 1950 to 2011 in diverse geographic locations, with the aim of delineating C. abortus lineages and clones. MLST revealed the previously identified sequence types (STs) ST19, ST25, ST29 and ST30, plus ST86, a recently-assigned type on the Chlamydiales MLST website and ST87, a novel type harbouring the hemN_21 allele, whereas MLVA recognized seven types (MT1 to MT7). Minimum-spanning-tree analysis suggested that all STs but one (ST30) belonged to a single clonal complex, possibly reflecting the short evolutionary timescale over which the predicted ancestor (ST19) has diversified into three single-locus variants (ST86, ST87 and ST29) and further, through ST86 diversification, into one double-locus variant (ST25). ST descendants have probably arisen through a point mutation evolution mode. Interestingly, MLVA showed that in the ST19 population there was a greater genetic diversity than in other STs, most of which exhibited the same MT over time and geographical distribution. However, the evolutionary pathways of C. abortus STs seem to be diverse across geographic distances with individual STs restricted to particular geographic locations. The ST30 singleton clone displaying geographic specificity and represented by the Greek strains LLG and POS was effectively distinguished from the clonal complex lineage, supporting the notion that possibly two separate host adaptations and hence independent bottlenecks of C. abortus have occurred through time. The combination of MLST and MLVA assays provides an additional level of C. abortus discrimination and may prove useful for the investigation and surveillance of emergent C. abortus clonal populations. PMID- 26001071 TI - MAGE-A Cancer/Testis Antigens Inhibit MDM2 Ubiquitylation Function and Promote Increased Levels of MDM4. AB - Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically. PMID- 26001072 TI - Orthogonally oriented scaffolds with aligned fibers for engineering intestinal smooth muscle. AB - Controlling cellular alignment is critical in engineering intestines with desired structure and function. Although previous studies have examined the directional alignment of cells on the surface (x-y plane) of parallel fibers, quantitative analysis of the cellular alignment inside implanted scaffolds with oriented fibers has not been reported. This study examined the cellular alignment in the x z and y-z planes of scaffolds made with two layers of orthogonally oriented fibers. The cellular orientation inside implanted scaffolds was evaluated with immunofluorescence. Quantitative analysis of coherency between cell orientation and fiber direction confirmed that cells aligned along the fibers not only on the surface (x-y plane) but also inside the scaffolds (x-z & y-z planes). Our study demonstrated that two layers of orthogonally aligned scaffolds can generate the histological organization of cells similar to that of intestinal circular and longitudinal smooth muscle. PMID- 26001073 TI - Circumferentially aligned fibers guided functional neoartery regeneration in vivo. AB - An ideal vascular graft should have the ability to guide the regeneration of neovessels with structure and function similar to those of the native blood vessels. Regeneration of vascular smooth muscle cells (VSMCs) with circumferential orientation within the grafts is crucial for functional vascular reconstruction in vivo. To date, designing and fabricating a vascular graft with well-defined geometric cues to facilitate simultaneously VSMCs infiltration and their circumferential alignment remains a great challenge and scarcely reported in vivo. Thus, we have designed a bi-layered vascular graft, of which the internal layer is composed of circumferentially aligned microfibers prepared by wet-spinning and an external layer composed of random nanofibers prepared by electrospinning. While the internal circumferentially aligned microfibers provide topographic guidance for in vivo regeneration of circumferentially aligned VSMCs, the external random nanofibers can offer enhanced mechanical property and prevent bleeding during and after graft implantation. VSMCs infiltration and alignment within the scaffold was then evaluated in vitro and in vivo. Our results demonstrated that the circumferentially oriented VSMCs and longitudinally aligned ECs were successfully regenerated in vivo after the bi-layered vascular grafts were implanted in rat abdominal aorta. No formation of thrombosis or intimal hyperplasia was observed up to 3 month post implantation. Further, the regenerated neoartery exhibited contraction and relaxation property in response to vasoactive agents. This new strategy may bring cell-free small diameter vascular grafts closer to clinical application. PMID- 26001074 TI - Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo photothermal treatment of rheumatoid arthritis. AB - We have developed methotrexate (MTX)-loaded poly(lactic-co-glycolic acid, PLGA) gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with arginine glycine-aspartic acid (RGD), which can be applied for magnetic targeted chemo photothermal treatment, and in vivo multimodal imaging of rheumatoid arthritis (RA). Upon near-infrared (NIR) irradiation, local heat is generated at the inflammation region due to the NIR resonance of Au half-shells and MTX release from PLGA nanoparticles is accelerated. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T2-magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in collagen-induced arthritic (CIA) mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA. PMID- 26001075 TI - Tissue engineered humanized bone supports human hematopoiesis in vivo. AB - Advances in tissue-engineering have resulted in a versatile tool-box to specifically design a tailored microenvironment for hematopoietic stem cells (HSCs) in order to study diseases that develop within this setting. However, most current in vivo models fail to recapitulate the biological processes seen in humans. Here we describe a highly reproducible method to engineer humanized bone constructs that are able to recapitulate the morphological features and biological functions of the HSC niches. Ectopic implantation of biodegradable composite scaffolds cultured for 4 weeks with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone organ including a large number of human mesenchymal cells which were shown to be metabolically active and capable of establishing a humanized microenvironment supportive of the homing and maintenance of human HSCs. A syngeneic mouse-to mouse transplantation assay was used to prove the functionality of the tissue engineered ossicles. We predict that the ability to tissue engineer a morphologically intact and functional large-volume bone organ with a humanized bone marrow compartment will help to further elucidate physiological or pathological interactions between human HSCs and their native niches. PMID- 26001076 TI - Enhancing neurogenesis and angiogenesis with target delivery of stromal cell derived factor-1alpha using a dual ionic pH-sensitive copolymer. AB - In this study, we hypothesized that the delivery of molecules that regulate the microenvironment after a cerebral infarction can influence regeneration potential after a stroke. Stromal cell-derived factor-1alpha (SDF-1alpha) is a chemoattractant molecule that plays a pivotal role in recruiting endothelial progenitor cells (EPCs) to the infarct region after stroke. Increased SDF-1alpha expression leads to increased EPCs homing at the infarct region and induces neurogenesis, angiogenesis, neuroprotection, and stem cell homing. Thus, we evaluated the effects of targeted delivery of SDF-1alpha using a pH-sensitive polymer poly (urethane amino sulfamethazine) (PUASM), a synthetic macromolecule with potential for targeted drug delivery in acidic conditions, to enhance therapeutic neurogenesis and angiogenesis in a rat model of permanent middle cerebral artery occlusion. A dual ionic pH-sensitive copolymer PUASM-based random copolymer was designed and synthesized for the controlled release of SDF-1alpha in stroke. Owing to the unique characteristics of PUASM, it exhibited a dual ionic pH-sensitive property in an aqueous solution. At pH 8.5, the copolymer exhibited a negative charge and was water soluble. Interestingly, when the pH decreased to 7.4, PUASM could form a micelle and encapsulate protein effectively via the ionic interaction between a negatively charged polymer and a positively charged protein. At pH 5.5, the ionization of tertiary amines led to the disassembly of the micellar structure and released the protein rapidly. Then, we investigated the effect of systemic administration of SDF-1alpha-loaded pH sensitive polymeric micelles in a stroke induced rat model. An enzyme-linked immunosorbent assay showed increased expression of SDF-1alpha in the ischemic region, indicating that the pH-sensitive micelles effectively delivered SDF 1alpha into the ischemic region. In order to observe the biodistribution of SDF 1alpha in the ischemic region, it was labeled with the near-infrared dye, Cy5.5. Optical imaging showed that the Cy5.5 signal increased in the infarct region 24 h after administration. Immunohistochemistry data showed that targeted delivery of SDF-1alpha enhanced neurogenesis and angiogenesis, but did not influence cell survival or inflammation. These observations suggest that SDF-1alpha-loaded pH sensitive polymeric micelles can be used as pH-triggered targeting agents and can effectively modify the microenvironment to increase innate neurorestorative processes. PMID- 26001077 TI - The effect of osteoimmunomodulation on the osteogenic effects of cobalt incorporated beta-tricalcium phosphate. AB - Osteoblast lineage cells are direct effectors of osteogenesis and are, therefore, commonly used to evaluate the in vitro osteogenic capacity of bone substitute materials. This method has served its purposes when testing novel bone biomaterials; however, inconsistent results between in vitro and in vivo studies suggest the mechanisms that govern a material's capacity to mediate osteogenesis are not well understood. The emerging field of osteoimmunology and immunomodulation has informed a paradigm shift in our view of bone biomaterials from one of an inert to an osteoimmunomodulatory material-highlighting the importance of immune cells in materials-mediated osteogenesis. Neglecting the importance of the immune response during this process is a major shortcoming of the current evaluation protocol. In this study we evaluated a potential angiogenic bone substitute material cobalt incorporated with beta-tricalcium phosphate (CCP), comparing the traditional "one cell type" approach with a "multiple cell types" approach to assess osteogenesis, the latter including the use of immune cells. We found that CCP extract by itself was sufficient to enhance osteogenic differentiation of bone marrow stem cells (BMSCs), whereas this effect was cancelled out when macrophages were involved. In response to CCP, the macrophage phenotype switched to the M1 extreme, releasing pro-inflammatory cytokines and bone catabolic factors. When the CCP materials were implanted into a rat femur condyle defect model, there was a significant increase of inflammatory markers and bone destruction, coupled with fibrous encapsulation rather than new bone formation. These findings demonstrated that the inclusion of immune cells (macrophages) in the in vitro assessment matched the in vivo tissue response, and that this method provides a more accurate indication of the essential role of immune cells when assessing materials-stimulated osteogenesis in vitro. PMID- 26001078 TI - Drivers of bushmeat hunting and perceptions of zoonoses in Nigerian hunting communities. AB - Bushmeat hunting threatens biodiversity and increases the risk of zoonotic pathogen transmission. Nevertheless, limited information exists on patterns of contact with wildlife in communities that practice bushmeat hunting, especially with respect to social drivers of hunting behavior. We used interview responses from hunters and non-hunters in rural hunting communities in Nigeria to: 1) quantify contact rates with wildlife, 2) identify specific hunting behaviors that increase frequency of contact, 3) identify socioeconomic factors that predispose individuals to hunt, and 4) measure perceptions of risk. Participants engaged in a variety of behaviors that increased contact with wild animals, including: butchering to sell (37%), being injured (14%), using body parts for traditional medicine (19%), collecting carcasses found in forests and/or farms (18%), and keeping as pets (16%). Hunters came into contact with wildlife significantly more than non-hunters, even through non-hunting exposure pathways. Participants reported hunting rodents (95%), ungulates (93%), carnivores (93%), primates (87%), and bats (42%), among other prey. Reported hunting frequencies within taxonomic groups of prey were different for different hunting behaviors. Young age, lower education level, larger household size, having a father who hunts, and cultural group were all associated with becoming a hunter. Fifty-five percent of respondents were aware that they could contract diseases from wild animals, but only 26% of these individuals reported taking protective measures. Overall, hunters in this setting frequently contact a diversity of prey in risky ways, and the decision to become a hunter stems from family tradition, modified by economic necessity. Conservation and public health interventions in such settings may be most efficient when they capitalize on local knowledge and target root socio economic and cultural drivers that lead to hunting behavior. Importantly, interventions that target consumption alone will not be sufficient; other drivers and modes of interaction with wildlife must also be considered. PMID- 26001079 TI - A systematic review and meta-analysis of the effect of short birth interval on infant mortality in Ethiopia. AB - INTRODUCTION: Even though Ethiopia has been celebrating the achievements of MDG 4, still one in every 17 Ethiopian children dies before their first birthday. This is the biggest of the African regional average. Short birth interval is inconsistently reported as a risk factor by limited and independent studies in Ethiopia. Therefore, the purpose of this meta-analysis was to determine the pooled effect size of the preceding birth interval length on infant mortality. METHODS: Studies were accessed through the electronic web-based search mechanism from PUBMED, Advanced Google Scholar, WHO databases and journals: PLOS ONE, and BMC, using independent and combinations of key terms. Comprehensive meta-analysis version 2 was used to analyze the data. An I2 test was used to assess heterogeneity. Funnel plot and statistical significance by Egger's test of the intercept was used to check publication bias. The final estimate was determined in the form of odds ratio by applying Duval and Tweedie's trim and fill analysis in the Random-effects model. RESULTS: 872 studies were identified on the reviewed topic. During screening, forty-five studies were found to be relevant for data abstraction. However, only five studies fulfilled the inclusion criteria and were included in the analysis. In all of the studies included in the analysis, the preceding birth interval had a significant association with under-one mortality. The final pooled estimate in the form of the odds ratio for infant mortality with a preceding birth interval of less than 24 months was found to be 2.03 (95% CI: 1.52, 2.70, random effect (five studies, n=43,909), I2=70%, P<0.05). CONCLUSION: In Ethiopia, promoting the length of birth interval to at least two years lowered under-one mortality by 50% (95% CI: 35%, 63%). PMID- 26001080 TI - Central Role of Core Binding Factor beta2 in Mucosa-Associated Lymphoid Tissue Organogenesis in Mouse. AB - Mucosa-associated lymphoid tissue (MALT) is a group of secondary and organized lymphoid tissue that develops at different mucosal surfaces. Peyer's patches (PPs), nasopharynx-associated lymphoid tissue (NALT), and tear duct-associated lymphoid tissue (TALT) are representative MALT in the small intestine, nasal cavity, and lacrimal sac, respectively. A recent study has shown that transcriptional regulators of core binding factor (Cbf) beta2 and promotor-1 transcribed Runt-related transcription factor 1 (P1-Runx1) are required for the differentiation of CD3-CD4+CD45+ lymphoid tissue inducer (LTi) cells, which initiate and trigger the developmental program of PPs, but the involvement of this pathway in NALT and TALT development remains to be elucidated. Here we report that Cbfbeta2 plays an essential role in NALT and TALT development by regulating LTi cell trafficking to the NALT and TALT anlagens. Cbfbeta2 was expressed in LTi cells in all three types of MALT examined. Indeed, similar to the previous finding for PPs, we found that Cbfbeta2-/- mice lacked NALT and TALT lymphoid structures. However, in contrast to PPs, NALT and TALT developed normally in the absence of P1-Runx1 or other Runx family members such as Runx2 and Runx3. LTi cells for NALT and TALT differentiated normally but did not accumulate in the respective lymphoid tissue anlagens in Cbfbeta2-/- mice. These findings demonstrate that Cbfbeta2 is a central regulator of the MALT developmental program, but the dependency of Runx proteins on the lymphoid tissue development would differ among PPs, NALT, and TALT. PMID- 26001081 TI - Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model. AB - Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin alpha4beta7 pre-challenge, followed by a significant down-regulation post challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases. PMID- 26001083 TI - Nowcasting unemployment rates with Google searches: evidence from the Visegrad Group countries. AB - The online activity of Internet users has repeatedly been shown to provide a rich information set for various research fields. We focus on job-related searches on Google and their possible usefulness in the region of the Visegrad Group--the Czech Republic, Hungary, Poland and Slovakia. Even for rather small economies, the online searches of inhabitants can be successfully utilized for macroeconomic predictions. Specifically, we study unemployment rates and their interconnection with job-related searches. We show that Google searches enhance nowcasting models of unemployment rates for the Czech Republic and Hungary whereas for Poland and Slovakia, the results are mixed. PMID- 26001082 TI - Ribonucleotide reductase subunit M2 predicts survival in subgroups of patients with non-small cell lung carcinoma: effects of gender and smoking status. AB - BACKGROUND: Ribonucleotide reductase catalyzes the conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates. The functional enzyme consists of two subunits - one large (RRM1) and one small (RRM2 or RRM2b) subunit. Expression levels of each subunit have been implicated in prognostic outcomes in several different types of cancers. EXPERIMENTAL DESIGN: Immunohistochemistry for RRM1 and RRM2 was performed on a lung cancer tissue microarray (TMA) and analyzed. 326 patients from the microarray were included in this study. RESULTS: In non-small cell lung cancer (NSCLC), RRM2 expression was strongly predictive of disease-specific survival in women, non-smokers and former smokers who had quit at least 10 years prior to being diagnosed with lung cancer. Higher expression was associated with worse survival. This was not the case for men, current smokers and those who had stopped smoking for shorter periods of time. RRM1 was not predictive of survival outcomes in any subset of the patient group. CONCLUSION: RRM2, but not RRM1, is a useful predictor of survival outcome in certain subsets of NSCLC patients. PMID- 26001084 TI - Short-term complete submergence of rice at the tillering stage increases yield. AB - Flooding is a major threat to agricultural production. Most studies have focused on the lower water storage limit in rice fields, whereas few studies have examined the upper water storage limit. This study aimed to explore the effect of waterlogging at the rice tillering stage on rice growth and yield. The early ripening late japonica variety Yangjing 4227 was selected for this study. The treatments included different submergence depths (submergence depth/plant height: 1/2 (waist submergence), 2/3 (neck submergence), and 1/1 (complete submergence)) and durations (1, 3, and 5 d). The control group was treated with the conventional alternation of drying and wetting. The effects of waterlogging at the tillering stage on root characteristics, dry matter production, nitrogen and phosphorus accumulation, yield, yield components, and 1-aminocyclopropane-1 carboxylic acid synthase (ACS) gene expression were explored. Compared with the control group, the 1/1 group showed significant increases in yield, seed-setting rate, photosynthetically efficient leaf area, and OS-ACS3 gene expression after 1 d of submergence. The grain number per panicle, dry weight of the aboveground and belowground parts, and number of adventitious roots also increased. Correlation analysis revealed a significant positive correlation between the panicle number and nitrogen content; however, no significant correlation was found for phosphorus content. If a decrease in rice yield of less than 10% is acceptable, half, 2/3, and complete submergence of the plants can be performed at the tillering stage for 1-3 d; this treatment will increase the space available for rice field water management/control and will improve rainfall resource utilization. PMID- 26001085 TI - In vivo effects of UV radiation on multiple endpoints and expression profiles of DNA repair and heat shock protein (Hsp) genes in the cycloid copepod Paracyclopina nana. AB - To evaluate the effects of ultraviolet (UV) radiation on energy acquisition and consumption, the copepod Paracyclopina nana was irradiated with several doses (0 3kJ/m(2)) of UV. After UV radiation, we measured the re-brooding success, growth pattern of newly hatched nauplii, ingestion rate, and assimilation of diet. In addition, we checked the modulated patterns of DNA repair and heat shock protein (hsp) chaperoning genes of P. nana. UV-B radiation induced a significant reduction (7-87%) of the re-brooding rate of ovigerous females, indicating that UV-induced egg sac damage is closely correlated with a reduction in the hatching rate of UV-irradiated ovigerous female offspring. Using chlorophyll a and stable carbon isotope incubation experiments, we found a dose-dependent decrease (P<0.05) in food ingestion and the rate of assimilation to the body in response to UV radiation, implying that P. nana has an underlying ability to shift its balanced-energy status from growth and reproduction to DNA repair and adaptation. Also, expression of P. nana base excision repair (BER)-associated genes and hsp chaperoning genes was significantly increased in response to UV radiation in P. nana. These findings indicate that even 1kJ/m(2) of UV radiation induces a reduction in reproduction and growth patterns, alters the physiological balance and inhibits the ability to cope with UV-induced damage in P. nana. PMID- 26001086 TI - Metabolic Needs and Capabilities of Toxoplasma gondii through Combined Computational and Experimental Analysis. AB - Toxoplasma gondii is a human pathogen prevalent worldwide that poses a challenging and unmet need for novel treatment of toxoplasmosis. Using a semi automated reconstruction algorithm, we reconstructed a genome-scale metabolic model, ToxoNet1. The reconstruction process and flux-balance analysis of the model offer a systematic overview of the metabolic capabilities of this parasite. Using ToxoNet1 we have identified significant gaps in the current knowledge of Toxoplasma metabolic pathways and have clarified its minimal nutritional requirements for replication. By probing the model via metabolic tasks, we have further defined sets of alternative precursors necessary for parasite growth. Within a human host cell environment, ToxoNet1 predicts a minimal set of 53 enzyme-coding genes and 76 reactions to be essential for parasite replication. Double-gene-essentiality analysis identified 20 pairs of genes for which simultaneous deletion is deleterious. To validate several predictions of ToxoNet1 we have performed experimental analyses of cytosolic acetyl-CoA biosynthesis. ATP citrate lyase and acetyl-CoA synthase were localised and their corresponding genes disrupted, establishing that each of these enzymes is dispensable for the growth of T. gondii, however together they make a synthetic lethal pair. PMID- 26001087 TI - Emerging nanotechnology for detection of mycotoxins in food and feed. AB - The term mycotoxin was coined for toxic metabolites secreted by some fungi in food, food products and feed. The most prominent mycotoxins include aflatoxins (AFs), deoxynivalenol, zearalenone, ochratoxin, fumonisin and patulin. Among these some are proved to be strong carcinogenic agents such as AFs B1 while others are under suspicion to have carcinogenic effects. Ingestion of such mycotoxin-contaminated food and feed pose to a threat, mycotoxicoses. Various conventional techniques are available for the detection of mycotoxins, but unfortunately as a consequence of their constraint, the development of new and rapid techniques is the need of the hour. The use of nanotechnology for the development of nanobiosensors would be the alternative sensitive methods for the rapid detection of mycotoxins. Implementation of nanomaterials in the fabrication of nanobiosensors and their use for the detection of the mycotoxins in food and feed is the centre of interest of this review. We have inventoried nanomaterials applied for weaving nanobiosensors, which includes carbon nanotubes, nanowires, nanoparticles, quantum dots, nanorods and nanofibers. In addition, we have extensively reviewed available nanobiosensors specific for different mycotoxins, their advantages and challenges. PMID- 26001088 TI - Use of viscous fibres in beverages for appetite control: a review of studies. AB - Dietary fibres, particularly viscous fibres appear to be more effective for appetite control (reduce subjective appetite, energy intake and/or body weight). Three types of viscous fibres, pectin, alginate and cereal beta-glucan, were identified as potential satiety-enhancing ingredients. The aim of this review was to collect evidence from human intervention studies evaluating pectins, alginates and beta-glucans in beverages, liquid preloads and liquid test meals for their satiety effects. Our focused, narrative review of several satiety studies shows an overall consistent result on the effectiveness of pectin, alginate and beta glucan for appetite control. Beverages or liquid test meals are probably the better delivery mode for these fibres, as their effect on satiety is affected by their physico-chemical properties. Most, if not all, of these reviewed studies gave little or no consideration to the potential effects of common food processing (e.g. pasteurisation, ultra-high temperature process) on the physico chemical properties of these fibre-containing beverages. This is one of the research gaps we have identified warranting further work, which is likely to be of significance from the industry and consumer perspective. PMID- 26001089 TI - Olive oil enriched in lycopene from tomato by-product through a co-milling process. AB - The aim of this investigation was to produce an olive oil (OO) naturally enriched with antioxidants, recovering carotenoids, in particular lycopene, using an industrial by-product of tomato seeds and skin. For this purpose, a technological process in a low-scale industrial plant to co-mill olives and tomato by-product in de-frosted or freeze-dried forms was applied and studied with respect to control samples. Preliminary results obtained from two different experiments were carried out by 40 kg of cultivar Correggiolo olives and 60 kg of olive blends from different cultivars. In both the experiments, the co-milling showed significant enrichment in carotenoids, especially in lycopene (mean values of 5.4 and 7.2 mg/kg oil from defrosted and freeze-dried by-products, respectively). The experimental results demonstrated the possibility to obtain a new functional food naturally enriched in antioxidant compounds, which might be marketed as "OO dressing enriched in lycopene" or "condiment produced using olives and tomato by product". PMID- 26001090 TI - A systematic review and meta-analysis of beta-glucan consumption on glycemic control in hypercholesterolemic individuals. AB - Evidence from animal and observational studies has supported the beneficial effects of beta-glucan intake on glycemic control, but intervention studies in hypercholesterolemic crowd have generated mixed results and have not been systematically examined. In the present study, we aimed to quantitatively evaluate the relation between beta-glucan consumption from oats or barley on glycemic control in hypercholesterolemic individuals. A systematic literature review was conducted for relevant published randomized controlled trials studies (RCTs) in electronic databases through July 2014. Twelve trials with a total of 603 subjects were included in the meta-analysis. Beta-glucan consumption did not significantly affect measures of glycemic control. Summary estimates of weighted mean differences (WMD) and 95% confidence interval was 0.05 mmol/L (-0.11, 0.02) for fasting glucose concentration and 0.75 pmol/L (-1.82, 3.32) for fasting insulin concentrations. In conclusion, there was not a significant overall effect of beta-glucan intake on improvements of fasting glucose and insulin concentrations in hypercholesterolemic subjects. PMID- 26001091 TI - An oat bran-based beverage reduce postprandial glycaemia equivalent to yoghurt in healthy overweight subjects. AB - An acute meal study was performed to determine postprandial glucose and insulin responses after consumption of two fermented oat bran-based beverages (with and without exopolysaccharides) and yoghurt. This randomized, single-blind, within subject study included 18 healthy, overweight participants. Four breakfast meals, including a reference meal, were tested; all meals contained 50 g of available carbohydrates, but differed in energy and macronutrient composition. All experimental meals reduced the postprandial glucose response compared with the reference meal. The oat drinks as well as the yoghurt elicited higher early (0-15 min) insulin responses, but the overall insulinaemia were similar to the reference meal. A new food product containing fermented liquid oat bran and milk reduced the postprandial blood glucose response as efficiently as yoghurt after a high-glycaemic index white wheat bread meal, but the presence of microbial exopolysaccharides did not affect the outcome. PMID- 26001092 TI - Simultaneous real-time visible and infrared video with single-pixel detectors. AB - Conventional cameras rely upon a pixelated sensor to provide spatial resolution. An alternative approach replaces the sensor with a pixelated transmission mask encoded with a series of binary patterns. Combining knowledge of the series of patterns and the associated filtered intensities, measured by single-pixel detectors, allows an image to be deduced through data inversion. In this work we extend the concept of a 'single-pixel camera' to provide continuous real-time video at 10 Hz , simultaneously in the visible and short-wave infrared, using an efficient computer algorithm. We demonstrate our camera for imaging through smoke, through a tinted screen, whilst performing compressive sampling and recovering high-resolution detail by arbitrarily controlling the pixel-binning of the masks. We anticipate real-time single-pixel video cameras to have considerable importance where pixelated sensors are limited, allowing for low cost, non-visible imaging systems in applications such as night-vision, gas sensing and medical diagnostics. PMID- 26001093 TI - Prevalence of restless legs syndrome in Trabzon in the northeast Black Sea Region of Turkey: co-morbidities, socioeconomic factors and biochemical parameters. AB - OBJECTIVES: Factors including heritability, climate features, co-morbid diseases and methodological differences between studies may underlie variation in the prevalence of restless legs syndrome (RLS). The purpose of this study was to assess the prevalence of RLS in Trabzon and to evaluate associated factors by including biochemical investigations. METHODS: This community-based study was conducted among a random sample of 3789 adults. The criteria suggested by the International RLS Study Group were used in the assessment of RLS. Individuals responding affirmatively to at least one question were interviewed and examined by neurologists for definitive diagnosis of RLS. Age- and gender-matched RLS negative individuals were enrolled in the control group. Blood samples from RLS patients and control subjects were collected after 12-hour fasting to evaluate fasting blood glucose, ferritin, vitamin B12, folic acid and creatinine. RESULTS: The prevalence of RLS was 4.5%. Age, female gender and educational level were identified as independent risk factors for RLS. Peak prevalence rates were observed in the fourth decade in women and in the sixth decade in man. A familial history of RLS, low ferritin and vitamin B12 levels and multiparity were more common in women with RLS. Fasting blood glucose, folic acid and creatinine levels were not significantly different between the patients and controls. DISCUSSION: The prevalence of RLS is relatively consistent in different regions of Turkey. Women with RLS may have different risk factors from men with RLS that may lead to increased prevalence at earlier ages. Low socioeconomic status may also affect the prevalence of RLS. PMID- 26001094 TI - Association between dietary phytoestrogen intake and bone mineral density varied with estrogen receptor alpha gene polymorphisms in southern Chinese postmenopausal women. AB - INTRODUCTION: several studies have investigated the relationship between the estrogen receptor (ER) gene polymorphisms and the efficacy of estrogen replacement therapy in postmenopausal osteoporosis. However, the association of ER polymorphisms with the effects of dietary phytoestrogens on bone metabolism has not yet been reported. This study explores the possibility that ER alpha subtype (ERalpha) gene polymorphisms are involved in the effects of dietary phytoestrogens on bone mineral density (BMD) in postmenopausal women. METHODS: a total of 301 postmenopausal southern Chinese women were enrolled. Dietary phytoestrogen intake was evaluated using a food frequency questionnaire. ERalpha polymorphisms were examined with restriction fragment length polymorphism at the polymorphic PvuII and XbaI sites within intron 1. Dual-energy X-ray absorptiometry scans were performed to determine the BMD of the lumbar spine and hip. RESULTS: the positive association of the lumbar spine BMD with dietary phytoestrogen intake was maintained only in groups with pp or xx genotypes (p < 0.05) and disappeared in groups with other genotypes. A positive association of the hip BMD with dietary phytoestrogen intake was observed only in the xx genotype group (p < 0.05). CONCLUSIONS: the association of the dietary phytoestrogen intake and BMD in southern Chinese postmenopausal women varied with ERalpha gene polymorphisms. PMID- 26001095 TI - Pd(II) catalyzed ortho C-H iodination of phenylcarbamates at room temperature using cyclic hypervalent iodine reagents. AB - A novel approach to access ortho iodinated phenols using cyclic hypervalent iodine reagents through palladium(II) catalyzed C-H activation has been developed through weak coordination. The reaction showed excellent regioselectivity, reactivity and good functional group tolerance. A unique mechanism was proposed. PMID- 26001096 TI - Band edge engineering of TiO2@DNA nanohybrids and implications for capacitive energy storage devices. AB - Novel mesoporous TiO2@DNA nanohybrid electrodes, combining covalently encoded DNA with mesoporous TiO2 microbeads using dopamine as a linker, were prepared and characterised for application in supercapacitors. Detailed information about donor density, charge transfer resistance and chemical capacitance, which have an important role in the performance of an electrochemical device, were studied by electrochemical methods. The results indicated the improvement of electrochemical performance of the TiO2 nanohybrid electrode by DNA surface functionalisation. A supercapacitor was constructed from TiO2@DNA nanohybrids with PBS as the electrolyte. From the supercapacitor experiment, it was found that the addition of DNA played an important role in improving the specific capacitance (Cs) of the TiO2 supercapacitor. The highest Cs value of 8 F g(-1) was observed for TiO2@DNA nanohybrids. The nanohybrid electrodes were shown to be stable over long-term cycling, retaining 95% of their initial specific capacitance after 1500 cycles. PMID- 26001097 TI - High-resolution mapping of sources contributing to urban air pollution using adjoint sensitivity analysis: benzene and diesel black carbon. AB - The adjoint of the Community Multiscale Air Quality (CMAQ) model at 1 km horizontal resolution is used to map emissions that contribute to ambient concentrations of benzene and diesel black carbon (BC) in the San Francisco Bay area. Model responses of interest include population-weighted average concentrations for three highly polluted receptor areas and the entire air basin. We consider both summer (July) and winter (December) conditions. We introduce a novel approach to evaluate adjoint sensitivity calculations that complements existing methods. Adjoint sensitivities to emissions are found to be accurate to within a few percent, except at some locations associated with large sensitivities to emissions. Sensitivity of model responses to emissions is larger in winter, reflecting weaker atmospheric transport and mixing. The contribution of sources located within each receptor area to the same receptor's air pollution burden increases from 38-74% in summer to 56-85% in winter. The contribution of local sources is higher for diesel BC (62-85%) than for benzene (38-71%), reflecting the difference in these pollutants' atmospheric lifetimes. Morning (6 9am) and afternoon (4-7 pm) commuting-related emissions dominate region-wide benzene levels in winter (14 and 25% of the total response, respectively). In contrast, afternoon rush hour emissions do not contribute significantly in summer. Similar morning and afternoon peaks in sensitivity to emissions are observed for the BC response; these peaks are shifted toward midday because most diesel truck traffic occurs during off-peak hours. PMID- 26001098 TI - Congeners of Pyrromethene-567 Dye: Perspectives from Synthesis, Photophysics, Photostability, Laser, and TD-DFT Theory. AB - In an attempt to develop photostable and efficient BODIPY (PM) dyes for use in liquid dye lasers, three new congeners of widely used laser dye, PM567, were synthesized and their photophysical properties in various organic solvents, laser performances, and photostabilities in a selected solvent, 1,4-dioxane, have been investigated using a frequency doubled Q-switched (10 Hz) Nd:YAG laser at 532 nm. The results of photostability study in nonpolar 1,4-dioxane revealed the remarkable enhancement in stability of the novel dyes compared to that of PM567 as well as improved laser performances. Cyclic voltammetry study strongly supports the observed enhancement in photostability of the novel dyes compared to that of PM567. The observed properties of the novel dyes in relation to those of PM567 have been rationalized by extensive use of DFT and TD-DFT using the B3LYP/6 31G(d) method of theory. PMID- 26001100 TI - Just said no. PMID- 26001099 TI - Asymmetric Mating Interference between Two Related Mosquito Species: Aedes (Stegomyia) albopictus and Aedes (Stegomyia) cretinus. AB - Aedes (Stegomyia) albopictus (Skuse) and Aedes (Stegomyia) cretinus Edwards are closely related mosquito species with common morphological features and bio ecological similarities. Recent mosquito surveillance in Athens, Greece, showed that they are sympatric mosquito species, with Ae. albopictus [corrected] developing quite higher population densities than Ae. cretinus [corrected] . The potential of mating interference between these species was investigated by reciprocal and homologous mating experiments in cages under laboratory conditions. In non-choice interspecific crosses (groups of males and females) females of both species produced sterile eggs. Insemination rate was 58% for Ae. cretinus females and only 1% for Ae. albopictus [corrected] females. Aedes albopictus males were sexually aggressive and inseminated Ae. cretinus females (31%) in choice experiments, where males of one species had access to mate with females of both species. Whereas, interspecific mating of Ae. albopictus [corrected] females with Ae. cretinus males in the co-occurrence of Ae. cretinus females was weaker (4%). Aedes cretinus females from non-choice crossing with Ae. albopictus [corrected] or Ae. cretinus males were paired individually with conspecific males. The percentage of fertile Ae. cretinus females was 17.5% when had encaged before with Ae. albopictus [corrected] males, compared to 100% when Ae. cretinus [corrected] females were encaged with conspecific males only. Probable ecological consequences of asymmetric mating between these ecologically homologous species in nature are discussed. PMID- 26001101 TI - Exploration of binding of C.I. Food Red 9 with pepsin by optical spectroscopic and molecular docking methods. AB - A comprehensive study of the effects of C.I. Food Red 9 on the conformation and activity of pepsin was performed using multi-spectral methods and molecular docking technique. Fluorescence and circular dichroism spectral analyzes showed that C.I. Food Red 9 binding induced the changes of secondary and tertiary structure of pepsin. The activity experimental results indicated that the activity of pepsin decreased remarkably with the increasing concentration of C.I. Food Red 9. Multi non-covalent interactions including hydrogen bonds, hydrophobic, and electrostatic forces played important roles in the complex formation between C.I. Food Red 9 and pepsin. The binding constants of pepsin with C.I. Food Red 9 were (1.21+/-0.036)*10(4) L mol(-1) (298 K) and (1.05+/ 0.043)*10(4) L mol(-1) (310 K). Moreover, the putative binding site of C.I. Food Red 9 on pepsin was near to activity pocket. This study demonstrates that C.I. Food Red 9 could cause some negative effects on pepsin. PMID- 26001102 TI - Interaction evaluation of silver and dithizone complexes using DFT calculations and NMR analysis. AB - Silver has distinct antibacterial properties and has been used as a component of commercial products with many applications. An increasing number of commercial products cause risks of silver effects for human and environment such as the symptoms of Argyria and the release of silver to the environment. Therefore, the detection of silver in the aquatic environment is important. The colorimetric chemosensor is designed by the basic of ligand interactions with metal ion, leading to the change of signals for the naked-eyes which is very useful method to this application. Dithizone ligand is considered as one of the effective chelating reagents for metal ions due to its high selectivity and sensitivity of a photochromic reaction for silver as well as the linear backbone of dithizone affords the rotation of various isomeric forms. The present study is focused on the conformation and interaction of dithizone with silver using density functional theory (DFT). The interaction parameters were determined in term of binding energy of complexes and the geometry optimization, frequency of the structures and calculation of binding energies using density functional approaches B3LYP and the 6-31G(d,p) basis set. Moreover, the interaction of silver-dithizone complexes was supported by UV-Vis spectroscopy, FT-IR spectrum that were simulated by using B3LYP/6-31G(d,p) and (1)H NMR spectra calculation using B3LYP/6-311+G(2d,p) method compared with the experimental data. The results showed the ion exchange interaction between hydrogen of dithizone and silver atom with minimized binding energies of silver-dithizone interaction. Therefore, the results can be the useful information for determination of complex interaction using the analysis of computer simulations. PMID- 26001103 TI - Room-Temperature Electron Spin Relaxation of Triarylmethyl Radicals at the X- and Q-Bands. AB - Triarylmethyl radicals (trityls, TAMs) represent a relatively new class of spin labels. The long relaxation of trityls at room temperature in liquid solutions makes them a promising alternative for traditional nitroxides. In this work we have synthesized a series of TAMs including perdeuterated Finland trityl (D36 form), mono-, di-, and triester derivatives of Finland-D36 trityl, the deuterated form of OX63, the dodeca-n-butyl homologue of Finland trityl, and triamide derivatives of Finland trityl with primary and secondary amines attached. We have studied room-temperature relaxation properties of these TAMs in liquids using pulsed electron paramagnetic resonance (EPR) at two microwave frequency bands. We have found the clear dependence of phase memory time (Tm ~ T2) on the magnetic field: room-temperature Tm values are ~1.5-2.5 times smaller at the Q-band (34 GHz, 1.2 T) than at the X-band (9 GHz, 0.3 T). This trend is ascribed to the contribution from g-anisotropy that is negligible at lower magnetic fields but comes into play at the Q-band. In agreement with this, the difference between T1 and Tm becomes more pronounced at the Q-band than at the X-band due to increased contributions from incomplete motional averaging of g-anisotropy. Linear dependence of (1/Tm - 1/T1) on viscosity implies that g-anisotropy is modulated by rotational motion of the trityl radical. On the basis of the analysis of previous data and results of the present work, we conclude that, in the general situation where the spin label is at least partly mobile, the X-band is most suitable for application of trityls for room-temperature pulsed EPR distance measurements. PMID- 26001106 TI - Kinetics of Iodine-Free Redox Shuttles in Dye-Sensitized Solar Cells: Interfacial Recombination and Dye Regeneration. AB - Dye-sensitized solar cells (DSCs) have gained widespread attentions owing to their low production cost, tunable optical response, and high light-to electricity conversion. In DSCs, the performance of redox mediators with iodide/triiodide or iodine-free redox couples is vital to internal quantum efficiency. For a long time, iodide/triiodide based electrolytes are the most widely used mediators because of their desirable kinetics. Recently, exciting progress has been made with respect to iodine-free metallorganic and pure organic redox shuttles. Their tunable redox potential and diverse electron transfer behaviors enable the rational screening of electrolyte composition for enhancing the light-to-electricity conversion efficiency of DSCs toward the Shockley Queisser limit. In this Account, we emphasize on current knowledge of two distinct but interrelated interfacial processes (electron recombination and dye regeneration), particularly for DSCs with iodine-free redox couples. We show that a deeper understanding of electron transfer kinetics of the alternative redox couples is fundamental to develop rational strategies for cell optimization. Compared with iodine electrolyte, iodine-free metallorganic redox couples such as iron, cobalt, and nickel complexes display much faster electron transfer kinetics in dye regeneration and interfacial recombination. Evidently, rapid regeneration enables the employment of more positive metal complex for attaining a higher photovoltage. However, severe recombination reactions have to be well controlled by using several effective surface treatments such as the addition of Bronsted bases and atomic layer deposition. Although these methods offer different pathways in surface passivation, a trade-off between charge injection efficiency and electron diffusion length is always observed. It follows that an appropriate LUMO level of sensitizer is essential to ensure efficient electron injection at the passivated TiO2 surface. Apart from fast recombination behavior, bulky metal complexes suffer from inefficient charge transport. Thus, the combination of thinner TiO2 film and sensitizers with high mole extinction coefficient has been employed for both enhancing diffusion-limited current and maintaining light harvesting efficiency. Unlike metal complexes, most of organic sulfur redox couples in DSCs exhibit slow recombination kinetics. This allows the use of thicker TiO2 film to achieve an optimized light harvesting. However, the concomitant sluggish behavior of dye regeneration requires the use of sensitizers with more positive HOMO level, which is beneficial to efficient regeneration. Moreover, lower level of TiO2 band edge in DSCs based on organic sulfur mediators hinders the achievement of desirable photovoltage, spurring future explorations on this class of redox mediator. Based on the comparison of electron transfer behavior between iodine-free metallorganic complexes and pure organic redox couples, we aim to provide a comprehensive Account of the intriguing interfacial processes in iodine-free DSCs as the key scientific point is linked with the kinetics of interfacial reactions. This demonstrates the advantages as well as disadvantages of each class of iodine-free electrolyte and should shed light on to judicious selection of the energy levels for redox mediators, sensitizers, and the conduction band of TiO2 for DSCs. The knowledge of the reaction kinetics in DSCs should be also beneficial to the interface engineering on recent developed perovskite cells. PMID- 26001105 TI - Distance Dependence of Electron Spin Polarization during Photophysical Quenching of Excited Naphthalene by TEMPO Radical. AB - Quenching of excited states by a free radical is generally studied in systems where these two are separate entities freely moving in a liquid solution. Random diffusive encounters bring them together to cause the quenching and leave the spins of the radical polarized. In the dynamics of the radical-triplet pair mechanism of the generation of electron spin polarization (ESP), the distance dependent exchange interaction plays a crucial role. To investigate how the distance between the excited molecule and the radical influences the ESP, we have covalently linked a naphthalene moiety to a TEMPO free radical through a spacer group of three different lengths. We compared the ESP process of these linked compounds with that of the usual "unlinked system" of naphthalene and TEMPO through time-resolved EPR experiments at low temperature in n-hexane solution. The time evolution of both the linked and the "unlinked system" was treated on a similar footing. The time-dependent EPR signal was analyzed by combining photophysical kinetics and time-dependent Bloch equations incorporating spin dynamics. Sequential quenching of the singlet state and the triplet state of naphthalene was seen in all the systems, as revealed through the spin-polarized TREPR spectra of opposite phase. The magnitudes of the ESP in the linked molecules were higher than those of the "unlinked system," showing that when the two moieties are held together greater mixing of quartet-doublet states takes place. The magnitudes of ESP steadily decrease with increasing the length of the spacer group. The polarization magnitudes due to triplet quenching and singlet quenching are very similar, differing by a factor of only ~2. These characteristics show that for all the linked molecules the quenching takes place in the "weak exchange" regime and at almost the same distance of separation between the two moieties. Our results also showed that observation of small absorptive TREPR signals does not necessarily imply that its magnitude of polarization is small. PMID- 26001107 TI - Variations in the spatial distribution of the amplitude of surface electromyograms are unlikely explained by changes in the length of medial gastrocnemius fibres with knee joint angle. AB - This study investigates whether knee position affects the amplitude distribution of surface electromyogram (EMG) in the medial gastrocnemius (MG) muscle. Of further concern is understanding whether knee-induced changes in EMG amplitude distribution are associated with regional changes in MG fibre length. Fifteen surface EMGs were acquired proximo-distally from the MG muscle while 22 (13 male) healthy participants (age range: 23-47 years) exerted isometric plantar flexion at 60% of their maximal effort, with knee fully extended and at 90 degrees flexion. The number of channels providing EMGs with greatest amplitude, their relative proximo-distal position and the EMG amplitude averaged over channels were considered to characterise changes in myoelectric activity with knee position. From ultrasound images, collected at rest, fibre length, pennation angle and fat thickness were computed for MG proximo-distal regions. Surface EMGs detected with knee flexed were on average five times smaller than those collected during knee extended. However, during knee flexed, relatively larger EMGs were detected by a dramatically greater number of channels, centred at the MG more proximal regions. Variation in knee position at rest did not affect the proximo distal values obtained for MG fibre length, pennation angle and fat thickness. Our main findings revealed that, with knee flexion: i) there is a redistribution of activity within the whole MG muscle; ii) EMGs detected locally unlikely suffice to characterise the changes in the neural drive to MG during isometric contractions at knee fully extended and 90 degrees flexed positions; iii) sources other than fibre length may substantially contribute to determining the net, MG activation. PMID- 26001108 TI - Interdisciplinarity and impact: distinct effects of variety, balance, and disparity. AB - Interdisciplinary research is increasingly recognized as the solution to today's challenging scientific and societal problems, but the relationship between interdisciplinary research and scientific impact is still unclear. This paper studies the association between the degree of interdisciplinarity and the number of citations at the paper level. Different from previous studies compositing various aspects of interdisciplinarity into a single indicator, we use factor analysis to uncover distinct dimensions of interdisciplinarity corresponding to variety, balance, and disparity. We estimate Poisson models with journal fixed effects and robust standard errors to analyze the divergent relationships between these three factors and citations. We find that long-term (13-year) citations (1) increase at an increasing rate with variety, (2) decrease with balance, and (3) increase at a decreasing rate with disparity. Furthermore, interdisciplinarity also affects the process of citation accumulation: (1) although variety and disparity have positive effects on long-term citations, they have negative effects on short-term (3-year) citations, and (2) although balance has a negative effect on long-term citations, its negative effect is insignificant in the short run. These findings have important implications for interdisciplinary research and science policy. PMID- 26001109 TI - The Italian START-Register on Anticoagulation with Focus on Atrial Fibrillation. AB - START-Register--Survey on anTicoagulated pAtients RegisTer--is an independent, inception-cohort, observational, collaborative database aimed at recording prospectively the clinical history of adult patients starting anticoagulant treatment for any reason and using whatever drug. In this article we present the START-Register and give cross section baseline data focusing on non valvular atrial fibrillation (NVAF). Participants are asked to insert prospectively consecutive patients recorded as electronic file on the web-site of the registry. Required data are: demographic and clinical characteristics of patients, associated risk factors for stroke and bleeding, laboratory routine data, clinical indication for treatment, expected therapeutic range (in cases of treatment with vitamin K antagonists -VKAs). The follow-up is carried out to record: quality of treatment (for patients on VKAs), bleeding complications, thrombotic events, and the onset of any type of associated disease. To date 5252 patients have been enrolled; 97.6% were on VKAs because direct oral anticoagulants (DOAC) have been available in Italy only recently. The median age was 74 years [interquartile range (IQR) 64-80]; males 53.7%. This analysis is focused on the 3209 (61.1%) NVAF patients. Mean CHADS2 score was 2.1 +/- 1.1, CHADSVASc score was 3.1 +/- 1.3;median age was 76 years (IQR 70-81); 168 patients (5.3%) had severe renal failure [Creatinine clearance (CrCl) <30 ml/min]. Moderate renal failure (CrCl 30-59 ml/min) was found in 1265 patients (39.5%). The analysis of the START-Register data shows that two-third of patients who started chronic anticoagulant treatment had NVAF, one-third of them was > 80 years with high prevalence of renal failure. PMID- 26001111 TI - Correction to Structural Properties and Singular Phase Transitions of Metallic Pr0.50Sr0.50CoO3 Cobaltite. PMID- 26001110 TI - Enhanced segregation of concurrent sounds with similar spectral uncertainties in individuals with autism spectrum disorder. AB - When acoustic signals from different sound sources are mixed upon arrival at the ears, the auditory system organizes these acoustic elements by their features. This study shows that individuals with autism spectrum disorder (ASD) performed better in terms of hearing a target sequence among distractors that had similar spectral uncertainties. Their superior performance in this task indicates an enhanced discrimination between auditory streams with the same spectral uncertainties but different spectro-temporal details. The enhanced discrimination of acoustic components may be related to the absence of the automatic grouping of acoustic components with the same features, which results in difficulties in speech perception in a noisy environment. On the other hand, the ASD group and the control group had similar performance in hearing a target sequence among distractors that had different spatial cues defined by interaural intensity differences. PMID- 26001112 TI - Detection of cerebral hemorrhage in rabbits by time-difference magnetic inductive phase shift spectroscopy. AB - Cerebral hemorrhage, a difficult issue in clinical practice, is often detected and studied with computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). However, these expensive devices are not readily available in economically underdeveloped regions, and hence are unable to provide bedside and emergency on-site monitoring. The magnetic inductive phase shift (MIPS) is an emerging technology that may become a new tool to detect cerebral hemorrhage and to serve as an inexpensive partial substitute to medical imaging. In order to study a wider band of cerebral hemorrhage MIPS and to provide more useful information for measuring cerebral hemorrhage, we established a cerebral hemorrhage magnetic induction phase shift spectroscopy (MIPSS) detection system. Thirteen rabbits with five cerebral hemorrhage states were studied using a single coil-coil within a 1 MHz-200 MHz frequency range in linear sweep. A feature band (FB) with the highest detection sensitivity and the greatest stability was selected for further analysis and processing. In addition, a maximum conductivity cerebrospinal fluid (CSF) MRI was performed to verify and interpret the MIPSS result. The average phase shift change induced by a 3 ml injection of autologous blood under FB was -7.7503 degrees +/- 1.4204 degrees , which was considerably larger than our previous work. Data analysis with a non parametric statistical Friedman M test showed that in the FB, MIPSS could distinguish the five states of cerebral hemorrhage in rabbits, with a statistical significance of p<0.05. A B-F distribution profile was designed according to the MIPSS under FB that can provide instantaneous diagnostic information about the cerebral hemorrhage severity from a single set of measurements. The results illustrate that the MIPSS detection method is able to provide a new possibility for real-time monitoring and diagnosis of the severity of cerebral hemorrhage. PMID- 26001113 TI - ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26. PMID- 26001116 TI - Impact of Surface-Bound Small Molecules on the Thermoelectric Property of Self Assembled Ag2Te Nanocrystal Thin Films. AB - Small molecules with functional groups can show different electron affinity and binding behavior on nanocrystal surface, which in principle could be used to alternate the electrical transport in self-assembled nanocrystal thin films. These small molecules can also serve for scattering the phonons to reduce the thermal conductivity. Here, we present our research on the thermoelectric characteristic of self-assembled silver telluride (Ag2Te) nanocrystal thin films that are fabricated by a layer-by-layer (LBL) dip-coating process. We perform investigations on the electrical conductivity and Seebeck coefficient on the Ag2Te nanocrystal thin films containing hydrazine, 1,2-ethanedithiol, and ethylenediamine between 300 and 400 K. We also use photothermal (PT) technique to obtain the thermal conductivity of the films at room temperature and estimate the thermoelectric figure of merit (ZT). The experimental results suggest that the surface-bound small molecules could serve as a beneficial component to build nanocrystal-based thermoelectric devices operating at low temperature. PMID- 26001114 TI - Evaluation of DNA variants associated with androgenetic alopecia and their potential to predict male pattern baldness. AB - Androgenetic alopecia, known in men as male pattern baldness (MPB), is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes and polymorphisms to be associated with susceptibility to MPB. In this study, 50 candidate SNPs for androgenetic alopecia were analyzed in order to verify their potential to predict MPB. Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20. A simple 5-SNP prediction model and an extended 20-SNP model were developed based on a discovery panel of 305 males from various European populations fitting one of two distinct phenotype categories. The first category consisted of men below 50 years of age with significant baldness and the second; men aged 50 years or older lacking baldness. The simple model comprised the five best predictors: rs5919324 near AR, rs1998076 in the 20p11 region, rs929626 in EBF1, rs12565727 in TARDBP and rs756853 in HDAC9. The extended prediction model added 15 SNPs from five genomic regions that improved overall prevalence-adjusted predictive accuracy measured by area under the receiver characteristic operating curve (AUC). Both models were evaluated for predictive accuracy using a test set of 300 males reflecting the general European population. Applying a 65% probability threshold, high prediction sensitivity of 87.1% but low specificity of 42.4% was obtained in men aged <50 years. In men aged >=50, prediction sensitivity was slightly lower at 67.7% while specificity reached 90%. Overall, the AUC=0.761 calculated for men at or above 50 years of age indicates these SNPs offer considerable potential for the application of genetic tests to predict MPB patterns, adding a highly informative predictive system to the emerging field of forensic analysis of externally visible characteristics. PMID- 26001117 TI - Pediatric Emergency CT Scans at a Children's Hospital and at Community Hospitals: Radiation Technical Factors Are an Important Source of Radiation Exposure. AB - OBJECTIVE: This article compares the technical factors-in particular, tube current and voltage-and the resultant exposure to radiation associated with CT examinations performed at a children's hospital and at more general community hospital emergency departments (EDs). MATERIALS AND METHODS: CT scans obtained at community hospital EDs were retrospectively reviewed and compared with CT scans obtained at a children's hospital, to assess differences in kilovoltage, tube current, and volume CT dose index (CTDIvol) used. The number of scans obtained during the contrast-enhanced phase was also assessed. Parametric and nonparametric statistical analyses were used to test differences. RESULTS: A total of 233 body CT examinations were performed at community hospitals, and 287 were performed at a children's hospital. At both types of hospital, the median patient age was 12 years (p = 0.66). Of the body CT scans obtained at community hospitals that focused on the care of adult patients, 194 of 233 (83%) used a tube voltage of 120 kVp, 29 of 233 (12%) used 100 kVp, and two of 233 (< 1%) used 80 kVp. Of the body CT scans obtained at the children's hospital, 121 of 287 (42%) used a tube voltage of 120 kVp, 129 of 287 (45%) used 100 kVp, and 36 of 287 (13%) used 80 kVp. The median tube current was also lower at the children's hospital (110 vs 125 mA) (p < 0.001). At the community hospitals, 11 of 233 studies were multiphasic, whereas at the children's hospital, there were no multiphasic studies. For all CT types, the median CTDIvol was 4.9 mGy (range, 2.5 8.2 mGy) at the children's hospital and 8.6 mGy (range, 6.0-14.4 mGy) at the community hospitals (p < 0.001). CONCLUSION: The results of this study suggest that a large proportion of children who undergo CT at community hospitals receive relatively higher radiation doses than children who undergo CT at children's hospitals. This finding is related to the higher tube settings (in particular, kilovoltage) used at community hospitals. PMID- 26001118 TI - Spectrum of Physiologic and Pathologic Skeletal Muscle (18)F-FDG Uptake on PET/CT. AB - OBJECTIVE: Skeletal muscle (18)F-FDG uptake on PET/CT can be either physiologic or related to a variety of different pathologic conditions. FDG PET/CT can be used for assessment of primary and metastatic tumors and infective or inflammatory conditions affecting the musculature. CONCLUSION: In this article, we describe the various causes and patterns of skeletal muscle FDG uptake. Familiarity with these patterns is essential for proper interpretation of clinical FDG PET/CT images. PMID- 26001115 TI - The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition. AB - Intrinsic immunity describes the set of recently discovered but poorly understood cellular mechanisms that specifically target viral pathogens. Their discovery derives in large part from intensive studies of HIV and SIV that revealed restriction factors acting at various stages of the retroviral life cycle. Recent studies indicate that some factors restrict both retroviruses and retrotransposons but surprisingly in ways that may differ. We screened known interferon-stimulated antiviral proteins previously untested for their effects on cell culture retrotransposition. Several factors, including BST2, ISG20, MAVS, MX2, and ZAP, showed strong L1 inhibition. We focused on ZAP (PARP13/ZC3HAV1), a zinc-finger protein that targets viruses of several families, including Retroviridae, Tiloviridae, and Togaviridae, and show that ZAP expression also strongly restricts retrotransposition in cell culture through loss of L1 RNA and ribonucleoprotein particle integrity. Association of ZAP with the L1 ribonucleoprotein particle is supported by co-immunoprecipitation and co localization with ORF1p in cytoplasmic stress granules. We also used mass spectrometry to determine the protein components of the ZAP interactome, and identified many proteins that directly interact and colocalize with ZAP, including MOV10, an RNA helicase previously shown to suppress retrotransposons. The detection of a chaperonin complex, RNA degradation proteins, helicases, post translational modifiers, and components of chromatin modifying complexes suggest mechanisms of ZAP anti-retroelement activity that function in the cytoplasm and perhaps also in the nucleus. The association of the ZAP ribonucleoprotein particle with many interferon-stimulated gene products indicates it may be a key player in the interferon response. PMID- 26001119 TI - FDG PET/CT for Management and Assessing Outcomes of Squamous Cell Cancer of the Oral Cavity. AB - OBJECTIVE: FDG PET/CT has excellent diagnostic accuracy for detecting locoregional nodal and distant metastases, can be used to assess therapeutic response, and provides valuable information about prognosis in patients with oral cavity cancer. The aim of this article is to summarize the value of FDG PET/CT in the treatment of patients with squamous cell cancer of the oral cavity. CONCLUSION: FDG PET/CT is a valuable imaging study in the management of oral squamous cell cancer and in predicting patient outcome. PMID- 26001120 TI - New approaches in vaccine-based immunotherapy for human papillomavirus-induced cancer. AB - The identification of human papillomavirus as the etiological factor for cervical cancer provides an opportunity to treat these malignancies by vaccination. Although therapeutic vaccination against viral oncogenes regularly induces a specific T cell response, clinical effectivity remains low. Three factors are particularly important for clinical outcome: the balance between cytotoxic T cells and regulatory immune subsets, the balance between cytotoxic T cells and tumor cells and finally the killing efficiency of cytotoxic T cells within the tumor. To improve these three factors, therapeutic vaccination is combined with other treatments. Here, we review those studies that are based on understanding the inhibitory mechanisms that prevent unleashing the full power of therapeutic vaccine-induced T cells and utilize combinatorial interventions based on these insights. PMID- 26001121 TI - Toxic metal content in 52 frequently prescribed herbal medicines on the Korean market. AB - This study was conducted to investigate the toxic metal content (Pb, As, Cd and Hg) of 52 frequently prescribed herbal medicines and to identify herbal medicines that exceed the Korea Food and Drug Administration (KFDA) maximum limits. A total of 3534 samples, including 1966 domestic samples and 1568 imported samples, were analysed using an Inductively Coupled Plasma-Mass Spectrometer (ICP-MS). Total amounts of Pb, As, Cd and Hg were significantly different between domestic (0.63 mg kg(-1)) and imported (0.81 mg kg(-1)) medicines (p < 0.05). Among the 52 kinds of samples, 4 kinds of herbs required quality control for Pb and 12 kinds of herbs required quality control for Cd. No sample contained As and Hg above the limits. PMID- 26001122 TI - Asterosaponins and glycosylated polyhydroxysteroids from the starfish Culcita novaeguineae and their cytotoxic activities. AB - Using combined chromatographic methods, two asterosaponins (compounds 1 and 2), including a new compound novaeguinoside E (compound 1), and six glycosylated polyhydroxysteroids (compounds 3-8) were isolated from a methanol extract of the starfish Culcita novaeguineae. Their structures were determined on the basis of spectroscopic data ((1)H and (13)C NMR, HSQC, HMBC, (1)H-(1)H COSY, ROESY, and HRESI-MS) and by comparison with the literature values. The new compound 1 represents the third example of asterosaponins containing the 5alpha-cholesta 9(1l)-en-3beta,6alpha,20,22-tetraol aglycone. Among isolated compounds, 4-7 exhibited moderate to weak cytotoxic activities against five human cancer cell lines such as Hep-G2 (hepatoma), KB (epidermoid carcinoma), LNCaP (prostate cancer), MCF7 (breast cancer), and SK-Mel2 (melanoma). PMID- 26001123 TI - Neuregulin 1 Type II-ErbB Signaling Promotes Cell Divisions Generating Neurons from Neural Progenitor Cells in the Developing Zebrafish Brain. AB - Post-mitotic neurons are generated from neural progenitor cells (NPCs) at the expense of their proliferation. Molecular and cellular mechanisms that regulate neuron production temporally and spatially should impact on the size and shape of the brain. While transcription factors such as neurogenin1 (neurog1) and neurod govern progression of neurogenesis as cell-intrinsic mechanisms, recent studies show regulatory roles of several cell-extrinsic or intercellular signaling molecules including Notch, FGF and Wnt in production of neurons/neural progenitor cells from neural stem cells/radial glial cells (NSCs/RGCs) in the ventricular zone (VZ). However, it remains elusive how production of post-mitotic neurons from neural progenitor cells is regulated in the sub-ventricular zone (SVZ). Here we show that newborn neurons accumulate in the basal-to-apical direction in the optic tectum (OT) of zebrafish embryos. While neural progenitor cells are amplified by mitoses in the apical ventricular zone, neurons are exclusively produced through mitoses of neural progenitor cells in the sub-basal zone, later in the sub-ventricular zone, and accumulate apically onto older neurons. This neurogenesis depends on Neuregulin 1 type II (NRG1-II)-ErbB signaling. Treatment with an ErbB inhibitor, AG1478 impairs mitoses in the sub-ventricular zone of the optic tectum. Removal of AG1478 resumes sub-ventricular mitoses without precedent mitoses in the apical ventricular zone prior to basal-to-apical accumulation of neurons, suggesting critical roles of ErbB signaling in mitoses for post-mitotic neuron production. Knockdown of NRG1-II impairs both mitoses in the sub-basal/sub ventricular zone and the ventricular zone. Injection of soluble human NRG1 into the developing brain ameliorates neurogenesis of NRG1-II-knockdown embryos, suggesting a conserved role of NRG1 as a cell-extrinsic signal. From these results, we propose that NRG1-ErbB signaling stimulates cell divisions generating neurons from neural progenitor cells in the developing vertebrate brain. PMID- 26001124 TI - Differential Gene Expression Reflects Morphological Characteristics and Physiological Processes in Rice Immunity against Blast Pathogen Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae is a serious pathogen that jeopardises the world's most important food-security crop. Ten common Malaysian rice varieties were examined for their morphological, physiological and genomic responses to this rice blast pathogen. qPCR quantification was used to assess the growth of the pathogen population in resistant and susceptible rice varieties. The chlorophyll content and photosynthesis were also measured to further understand the disruptive effects that M. oryzae has on infected plants of these varieties. Real-time PCR was used to explore the differential expression of eight blast resistance genes among the ten local varieties. Blast disease has destructive effects on the growth of rice, and the findings of our study provide evidence that the Pikh, Pi9, Pi21, and Osw45 genes are involved in defence responses in the leaves of Malaysian rice at 31 h after inoculation with M. oryzae pathotype P7.2. Both the chlorophyll content and photosynthesis were reduced, but the levels of Pikh gene expression remained constant in susceptible varieties, with a developed pathogen population and mild or severe symptoms. The Pi9, Pi21, and Osw45 genes, however, were simultaneously upregulated in infected rice plants. Therefore, the presence of the Pikh, Pi9, Pi21, and Osw45 genes in the germplasm is useful for improving the resistance of rice varieties. PMID- 26001125 TI - Gated electron transfer reactions of truncated hemoglobin from Bacillus subtilis differently orientated on SAM-modified electrodes. AB - Electron transfer (ET) reactions of truncated hemoglobin from Bacillus subtilis (trHb-Bs) are suggested to be implicated in biological redox signalling and actuating processes that may be used in artificial environment-sensing bioelectronic devices. Here, kinetics of ET in trHb-Bs covalently attached via its surface amino acid residues either to COOH- or NH2-terminated (CH2)2-16 alkanethiol SAM assembled on gold are shown to depend on the alkanethiol length and functionalization, not being limited by electron tunnelling through the SAMs but gated by ET preceding reactions due to conformational changes in the heme active site/at the interface. ET gating was sensitive to the properties of SAMs that trHb-Bs interacted with. The ET rate constant ks for a 1e(-)/H(+) reaction between the SAM-modified electrode and heme of trHb-Bs was 789 and 110 s(-1) after extrapolation to a zero length SAM, while the formal redox potential shifted 142 and 31 mV, for NH2- and COOH-terminated SAMs, respectively. Such domain-specific sensitivity and responsivity of redox reactions in trHb-Bs may be of immediate biological relevance and suggest the existence of bioelectronic regulative mechanisms of ET proceeding in vivo at the protein-protein charged interfaces that modulate the protein reactivity in biological redox signalling and actuating events. PMID- 26001126 TI - Long-term in situ oxidation of biogenic uraninite in an alluvial aquifer: impact of dissolved oxygen and calcium. AB - Oxidative dissolution controls uranium release to (sub)oxic pore waters from biogenic uraninite produced by natural or engineered processes, such as bioremediation. Laboratory studies show that uraninite dissolution is profoundly influenced by dissolved oxygen (DO), carbonate, and solutes such as Ca(2+). In complex and heterogeneous subsurface environments, the concentrations of these solutes vary in time and space. Knowledge of dissolution processes and kinetics occurring over the long-term under such conditions is needed to predict subsurface uranium behavior and optimize the selection and performance of uraninite-based remediation technologies over multiyear periods. We have assessed dissolution of biogenic uraninite deployed in wells at the Rifle, CO, DOE research site over a 22 month period. Uraninite loss rates were highly sensitive to DO, with near-complete loss at >0.6 mg/L over this period but no measurable loss at lower DO. We conclude that uraninite can be stable over decadal time scales in aquifers under low DO conditions. U(VI) solid products were absent over a wide range of DO values, suggesting that dissolution proceeded through complexation and removal of oxidized surface uranium atoms by carbonate. Moreover, under the groundwater conditions present, Ca(2+) binds strongly to uraninite surfaces at structural uranium sites, impacting uranium fate. PMID- 26001127 TI - Male circumcision for HIV prevention in India: emerging viewpoints and practices of health care providers. AB - A compelling case for promoting male circumcision (MC) as an intervention for reducing the risk of heterosexually acquired HIV infection was made by dissemination of the results of three studies in Africa. The WHO/UNAIDS recommendation for MC for countries like India, where the epidemic in concentrated in high-risk groups, advocates MC for specific population groups such as men at higher risk for HIV acquisition. A multicentre qualitative study was conducted in four geographically distinct districts (Belgaum, Kolkata, Meerut and Mumbai) in India during June 2009 to June 2011. Two categories of health care providers: Registered Healthcare Providers (RHCPs) and traditional circumcisers were interviewed by trained research staff who had received master's level education using interview guides with probes and open-ended questions. Respondents were selected using purposive sampling. A comparative analysis of the perspectives of the RHCP vs. traditional circumcisers is presented. Representatives of both categories of providers expressed the need for Indian data on MC. Providers feared that promoting circumcision might jeopardize/undermine the progress already made in the field of condom promotion. Reservation was expressed regarding its adoption by Hindus. Behavioural disinhibition was perceived as an important limitation. A contrast in the practice of circumcision was apparent between the traditional and the trained providers. MC should be mentioned as a part of comprehensive HIV prevention services in India that includes HIV counselling and testing, condom distribution and diagnosis and treatment of sexually transmitted infections. It should become an issue of informed personal choice rather than ethnic identity. PMID- 26001128 TI - Arrangement of Maghemite Nanoparticles via Wet Chemical Self-Assembly in PS-b PNIPAM Diblock Copolymer Films. AB - The structure and magnetic behavior of hybrid films composed of maghemite (gamma Fe2O3) nanoparticles (NPs) and an asymmetric diblock copolymer (DBC) polystyrene61-block-polyN-isopropylacrylamide115 are investigated. The NPs are coated with PS chains, which allow for a selective incorporation inside the PS domains at different NP concentrations. Upon incorporation of low amounts of NPs into the DBC thin films, the initial parallel (to film surface) cylinder morphology changes to a well ordered, perpendicularly oriented one. The characteristic domain distance of the DBC is increased due to the swelling of the PS domains with NPs. At higher NP concentrations, the excess NPs which can no longer be embedded in the PS domains, are accumulated at the film surface, and NP aggregates form. Irrespective of NP concentration, a superparamagnetic behavior of the metal oxide-DBC hybrid films is found. Such superparamagnetic properties make the established hybrid films interesting for high density magnetic storage media and thermoresponsive magnetic sensors. PMID- 26001130 TI - Two fixed ratio dilutions for soil salinity monitoring in hypersaline wetlands. AB - Highly soluble salts are undesirable in agriculture because they reduce yields or the quality of most cash crops and can leak to surface or sub-surface waters. In some cases salinity can be associated with unique history, rarity, or special habitats protected by environmental laws. Yet in considering the measurement of soil salinity for long-term monitoring purposes, adequate methods are required. Both saturated paste extracts, intended for agriculture, and direct surface and/or porewater salinity measurement, used in inundated wetlands, are unsuited for hypersaline wetlands that often are only occasionally inundated. For these cases, we propose the use of 1:5 soil/water (weight/weight) extracts as the standard for expressing the electrical conductivity (EC) of such soils and for further salt determinations. We also propose checking for ion-pairing with a 1:10 or more diluted extract in hypersaline soils. As an illustration, we apply the two-dilutions approach to a set of 359 soil samples from saline wetlands ranging in ECe from 2.3 dS m(-1) to 183.0 dS m(-1). This easy procedure will be useful in survey campaigns and in the monitoring of soil salt content. PMID- 26001129 TI - C-reactive protein and risk of breast cancer: A systematic review and meta analysis. AB - Associations between elevated C-reactive protein (CRP) and breast cancer risk have been reported for many years, but the results remain controversial. To address this issue, a meta-analysis was therefore conducted. Eligible studies were identified by searching the PubMed and EMBASE up to December 2014. Study specific risk estimates were combined using a random-effects model. Altogether fifteen cohort and case-control studies were included in this meta-analysis, involving a total of 5,286 breast cancer cases. The combined OR per natural log unit change in CRP for breast cancer was 1.16 (95% CI: 1.06-1.27). There was moderate heterogeneity among studies (I(2) = 45.9%). The association was stronger in Asian population (OR = 1.57, 95% CI: 1.25-1.96) compared to European (OR = 1.12, 95% CI: 1.02-1.23) and American (OR = 1.08, 95% CI: 1.01-1.16). Prediagnostic high-sensitivity CRP concentrations (OR = 1.22, 95% CI: 1.10-1.35) was superior to common CRP (OR = 1.08, 95% CI: 1.01-1.15) in predicting breast cancer risk. The meta-analysis indicated that elevated CRP levels was associated with increased risk of breast cancer. Further research effort should be performed to identify whether CRP, as a marker of inflammation, plays a direct role in breast carcinogenesis. PMID- 26001131 TI - Influence of interlayer cations on organic intercalation of montmorillonite. AB - The influence of the types of interlayer cations on organic intercalation of montmorillonite (Mt) was studied in this paper. The distribution of Na(+), K(+), Mg(2+), Ca(2+) and Fe(3+) in montmorillonite interlayer, their interaction with structure layers and the effect of interlayer cations on the basal spacing of Mt, the amount of binding water for different interlayer cations and the binding force between them were investigated systematically. 1-Hexadecy1-3 methylimidazolium chloride monohydrate (C16mimCl) was intercalated into montmorillonites with different interlayer cations. The influence of interlayer cations on organic intercalation was investigated. Molecular dynamics (MD) modeling was used to speculate the interlayer microstructures of the organically intercalated Mt with different interlayer cations. These simulations help to predict the microstructure of organo-Mt and guide their relevant engineering applications. PMID- 26001132 TI - Determination of melamine in powdered milk by molecularly imprinted stir bar sorptive extraction coupled with HPLC. AB - A novel molecularly imprinted stir bar (MIP-SB) was developed with melamine (MA) as the template molecule in this study. The sorptive capacity of MIP-SB was nearly three times over that of non-imprinted stir bar (NIP-SB). The MIP-SB presented much better selectivity than NIP-SB when used to absorb MA and its analogues. An analytical method to determine MA in powdered milk was established by combining MIP-SB sorptive extraction with HPLC. The liner range was 0.0631 12.6ng/mL with good correlation coefficient of 0.9983, and the limit of detection was 0.0127ng/mL based on three times ratio of signal to noise. This method was successfully applied to the determination of MA in powdered milk with satisfactory results. The method built is simple and suitable for the determination of MA in milk products which is of great significance for quality control of milk products. PMID- 26001133 TI - Jellyfish mesoglea as a matrix for the synthesis of extremely high content silver dendrites. AB - HYPOTHESIS: Using macroporous jellyfish mesoglea which consists of nano-sized layers and fibers as a matrix, metal nanoparticles with different morphologies might be formed in it. EXPERIMENT: Hierarchical silver dendrites are prepared by in situ reduction of silver nitrate (AgNO3) in the jellyfish mesoglea. FINDINGS: The formation of silver dendrites is affected by the concentration of AgNO3. The biogel-metal nanoparticles hybrid materials with silver dendrites show an extremely high solid content of silver dendrites and good catalytic activity as well as excellent recyclability for the reduction of 4-nitrophenol (4-NP) to 4 aminophenol (4-AP). PMID- 26001134 TI - The role of metal ion-ligand interactions during divalent metal ion adsorption. AB - A suite of seven different divalent metal ions (Ca(II), Cd(II), Cu(II), Mg(II), Ni(II), Pb(II), Zn(II)) was adsorbed from solution onto two Fe2O3 samples, quartz SiO2 and three different amphoteric polystyrene latices (containing amine and carboxyl functional groups). For the metal oxides, a high correlation was observed between the pH at which 50% of the metal was removed from solution (pH50) and the first hydrolysis constant for the metal ion (pK1). For the polystyrene latices, a much higher correlation was observed between the pH50 and pKc (equilibrium constant describing metal-carboxyl affinity) as opposed to pK1. These observations provide evidence of a strong relationship that exists between a metal's affinity for a particular ligand in solution and for that metal ion's affinity for the same ligand present as part of an adsorbing surface. The isoelectric point of the amphoteric latex surface can be increased by decreasing the carboxyl content of the latex surface. For all 7 metal ions, this resulted in a substantial decrease, for any given pH, in adsorption. We suggest that this may be partly due to the decreased carboxyl content, but is dominantly attributable to the presence of less favorable electrostatic conditions. This, in turn, demonstrates that electrostatics play a controlling role in metal ion adsorption onto amphoteric latex surfaces and, in addition to the nature of the metal ion, also controls the pH at which adsorption takes place. PMID- 26001135 TI - Colloidal methods for the fabrication of carbon nanotube-manganese dioxide and carbon nanotube-polypyrrole composites using bile acids. AB - Nature inspired strategies have been developed for the colloidal processing of advanced composites for supercapacitor applications. New approach was based on the use of commercially available bile acid salts, such as sodium cholate (ChNa) and taurocholic acid sodium salt (TChNa). It was demonstrated that cholic acid (ChH) films can be obtained by electrophoretic deposition (EPD) from ChNa solutions. The analysis of deposition yield, quartz crystal microbalance and cyclic voltammetry data provided an insight into the anodic deposition mechanism. The outstanding suspension stability of multiwalled carbon nanotubes (MWCNT), achieved using bile acids as anionic dispersants, allowed the fabrication of MWCNT films by EPD. The use of ChNa for EPD offered advantages of binding and film forming properties of this material. Composite MnO2-MWCNT films, prepared using ChNa as a dispersant and film forming agent for EPD, showed promising capacitive behavior. In another colloidal strategy, TChNa was used as a dispersant for MWCNT for the fabrication of polypyrrole (PPy) coated MWCNT. The use of PPy coated MWCNT allowed the fabrication of electrodes with high active mass loading, high capacitance and excellent capacitance retention at high charge discharge rates. PMID- 26001137 TI - Diagonal free homonuclear correlation using heteronuclei at natural abundance. AB - Homonuclear correlated spectroscopy such as COSY and TOCSY provides crucial structural information. In all homonuclear correlation, the most intense peaks are represented by the diagonal. As a result, the useful cross peaks close to the diagonal get obscured by the huge tails of diagonal peaks. Herein, we show that by editing the proton magnetization by a 13C nucleus in natural abundance, it is possible to eliminate the inphase coherence or untransferred magnetization that leads to the diagonal peak while retaining the antiphase coherence or transferred magnetization required for creation of cross peak. After the coherence transfer step, the untransferred magnetization directly attached to 13C evolves under one bond heteronuclear coupling while the transferred transverse magnetization directly attached to remote 12C does not. As a result, the untransferred magnetization directly attached to 13C can be converted to an unobservable heteronuclear multiple quantum coherence leading to a diagonal free correlated spectrum with a sensitivity penalty of two orders of magnitude but comparable to HSQC kind of experiments at natural abundance. The method demonstrated for COSY and TOCSY allows all proton-proton correlations to be observed except the geminal proton-proton correlations. Further, protons directly attached to heteronuclei other than 13C must be scalar coupled to protons directly attached to 13C to have a detectable cross peak. PMID- 26001136 TI - miR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling. AB - Obesity results from numerous, interacting genetic, behavioral, and physiological factors. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this study, we examined the roles of adipocyte-selective miRNAs in the differentiation of hMSCs-Ad to adipocytes. Results showed that the levels of miR 148a, miR-26b, miR-30, and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a exhibited significant effects on increasing PPRE luciferase activity (it represents PPAR-dependent transcription, a major factor in adipogenesis) than others. Furthermore, miR-148a expression levels increased in adipose tissues from obese people and mice fed high-fat diet. miR-148a acted by suppressing its target gene, Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a accelerated differentiation and partially rescued Wnt1-mediated inhibition of adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt1, thereby promoting adipocyte differentiation. PMID- 26001138 TI - Ultrasensitive Detection of Ricin Toxin in Multiple Sample Matrixes Using Single Domain Antibodies. AB - Ricin is an extremely potent ribosomal inactivating protein listed as a Category B select agent. Although ricin intoxication is not transmittable from person to person, even a single ricin molecule can lead to cell necrosis because it inactivates 1500 ribosomes/min. Since there is currently no vaccine or therapeutic treatment for ricin intoxication, ultrasensitive analytical assays capable of detecting ricin in a variety of matrixes are urgently needed to limit exposure to individuals as well as communities. In this paper, we present the development and application of a single-molecule array (Simoa) for the detection of ricin toxin in human urine and serum. Single-domain antibodies (sdAbs), among the smallest engineered binding fragments, were chemically coupled to the surface of paramagnetic beads for the sensitive detection of ricin toxin. The Simoa was able to detect ricin at levels of 10 fg/mL, 100 fg/mL, and 1 pg/mL in buffer, urine and serum, respectively, in a fraction of the assay time need using immuno polymerase chain reaction (IPCR). Using a fully automated state-of-the-art platform, the Simoa HD-1 analyzer, the assay time was reduced to 64 min. PMID- 26001140 TI - Stereotactic Ablative Radiation Therapy for the Treatment of Early-stage Non Small-Cell Lung Cancer: CEPO Review and Recommendations. AB - BACKGROUND: Lung cancer is the second most diagnosed cancer and the leading cause of cancer-related mortality in Canada. Surgical resection is the treatment of choice for patients with stage I non-small-cell lung cancer (NSCLC). However, 20% to 30% of them are deemed medically inoperable and may be offered radiation therapy. Standard external-beam radiation therapy (EBRT) is associated with high rates of local recurrence and poor long-term survival. Stereotactic ablative radiation therapy (SABR) is increasingly being proposed for inoperable patients, and the use of this treatment modality for operable patients is also being contemplated. The objective of this guideline is to review the efficacy and safety of SABR in these two clinical situations and to develop evidence-based recommendations. METHOD: A review of the scientific literature published up to December 2013 was performed. A total of 44 publications were included. RECOMMENDATIONS: Considering the evidence available to date, the Comite de l'evolution des pratiques en oncologie recommends the following: (1) for medically operable patients with stage T1-2N0M0 NSCLC, surgery remains the standard treatment because comparative data regarding the efficacy of SABR and surgery are currently insufficient for SABR to be considered an equivalent alternative to surgery for these patients; (2) for medically inoperable patients with stage T1-2N0M0 NSCLC or medically operable patients who refuse surgery, SABR should be preferred to standard EBRT (grade B recommendation); (3) the biological equivalent dose (BED(10)) used for SABR treatment should be at least 100 Gy (grade B recommendation); (4) for patients with a central tumor, a large-volume tumor (large planning target volume) or severe pulmonary comorbidity, a risk adaptive schedule should be used (dose reduction or increase in the number of fractions; grade B recommendation); (5) the choice of using SABR to treat NSCLC should be discussed within tumor boards; treatment with SABR (or with standard EBRT) should not be considered for patients whose life expectancy is very limited because of comorbidities (grade D recommendation). PMID- 26001141 TI - The BIM Deletion Polymorphism and its Clinical Implication in Patients with EGFR Mutant Non-Small-Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors. AB - INTRODUCTION: A germline BIM deletion polymorphism has been proposed to predict poor treatment response to certain kinase inhibitors. The purpose of this study was to explore whether the BIM deletion polymorphism predicts treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in Korean patients with EGFR-mutant non-small-cell lung cancer (NSCLC). METHODS: Peripheral blood samples from a total of 205 patients with EGFR-mutant NSCLC who were treated with EGFR TKIs between July 2008 and April 2013 were included. The incidence of BIM deletions in these samples was detected by polymerase chain reaction. We compared the clinical outcomes in patients with and without the polymorphism after treatment with EGFR TKIs (gefitinib or erlotinib). RESULTS: The BIM deletion polymorphism was present in 15.6% (32 of 205) of patients. One patient was homozygous for the deletion, and the remaining 31 had heterozygous deletions. The majority of patients were younger than 65 years (74%), female (68%), never smokers (76%), and had stage IV NSCLC (67%). There were no associations between the BIM deletion polymorphism and clinicopathological features including gender, age, smoking status, histology, stage, and number of metastasis sites. Patients with and without the BIM deletion polymorphism had similar objective response rates (91 vs. 84%, p = 0.585). Progression-free survival and overall survival did not differ significantly between patients with and without the BIM deletion polymorphism (median progression-free survival 12 vs. 11 months, p = 0.160; median overall survival 31 vs. 30 months, p = 0.452). Multivariate analysis identified significantly predictive markers for clinical outcomes of EGFR TKIs including Eastern Cooperative Oncology Group performance status 0-1, adenocarcinoma histology, recurrent disease, and EGFR mutation type. The results were validated in an independent cohort of 69 NSCLC patients. CONCLUSIONS: It remains to be determined whether the BIM deletion polymorphism provides intrinsic resistance or decreased sensitivity to EGFR TKIs in EGFR mutant NSCLC patients. PMID- 26001142 TI - The role of extended pulmonary metastasectomy. AB - BACKGROUND: The role of extended pulmonary resection for lung metastases is still unclear, and little information is available in the literature. This study was performed to analyze the outcomes and prognostic factors of patients who underwent extended resections for pulmonary metastases. METHODS: From 1998 to 2013, 1027 patients underwent lung metastasectomy procedures. Twenty-nine patients had extended pulmonary resections: three resections of the chest wall, one azygos, one diaphragm, four vascular resections/reconstructions, six sleeve resections, and 14 pneumonectomies. RESULTS: Extended resection was performed for metastatic disease mainly from epithelial (62.1%) and sarcomatous (20.7%) tumors. Complete resection was obtained in all patients. Thirty-day operative morbidity and mortality rates were 38% (11 of 29) and 0%, respectively. Only one patient had a major complication due to a bronchopleural fistula. Mean hospital stay was 6.3 days. After a median follow-up of 27 months, 16 patients (55%) had died. At univariate analysis, survival was determined by primary tumor histology (p = 0.03); the number of metastases, nodal status, disease-free interval or extension of surgery (pneumonectomy vs. lobar resection) were not related to survival probably due to the low number of patients. Overall survival after a complete extended metastasectomy was 66% at 2 years, 42% at 5 years, and 36% at 10 years. CONCLUSIONS: Extended resections performed during pulmonary metastasectomies are associated with low mortality and morbidity rates and an acceptable long-term survival when performed in selected patients susceptible to complete resection. PMID- 26001143 TI - Mediastinal nodal involvement in patients with clinical stage I non-small-cell lung cancer: possibility of rational lymph node dissection. AB - BACKGROUND: The aim of this study is to elucidate the optimal candidate of selective lymph node dissection (LND) that reduces the extent of mediastinal LND according to clinical information including radiological evaluation in primary non-small-cell lung cancer (NSCLC) patients. METHODS: Eight hundred and seventy six patients with clinical(c)-stage I NSCLC (adenocarcinoma and squamous cell carcinoma), who underwent complete surgical resection between January 2003 and December 2009 were included in this study. We elucidated the lymph node metastatic incidence and distribution according to the primary tumor lobe location and extracted the associated clinicopathological factors, especially thin-section computed tomographic findings, with mediastinal lymph node involvement. RESULTS: The total incidence of mediastinal lymph node metastasis was 9.1%. There were no cases with hilar and mediastinal lymph node metastasis in ground glass opacity-predominant tumors. There was no significant association of clinical factors with subcarinal lymph node metastasis in right upper-lobe and left upper-division adenocarcinoma. An elevated preoperative serum carcinoembryonic antigen level (p < 0.001) showed significant associations with upper mediastinal lymph node metastasis in the patients with bilateral lower-lobe primary lung adenocarcinoma. CONCLUSIONS: It would be acceptable to perform selective LND in patients with c-stage I NSCLC with ground glass opacity- predominant tumor. Elevated serum carcinoembryonic antigen was associated with upper mediastinal lymph node involvement in lower-lobe primary lung adenocarcinoma with radiologically solid-predominant tumor. We should be careful when applying selective LND to patients with solid-predominant tumor, especially located in the lower lobe. PMID- 26001144 TI - Primary Pulmonary NUT Midline Carcinoma: Clinical, Radiographic, and Pathologic Characterizations. AB - NUT midline carcinoma (NMC) is a poorly differentiated tumor typically driven by a t(15;19) rearrangement leading to a NUT fusion event. This rare and uniformly fatal tumor arises in multiple organ sites; however the clinical, radiographic, and pathologic characteristics of primary pulmonary NMC are poorly defined. We identified eight cases of primary pulmonary NMC in our consult practice over 4 years and, using a NUT immunohistochemistry screen, retrospectively identified one additional case from 166 (0.6%) consecutive in-house biopsies of lung carcinomas lacking glandular differentiation. Eight cases had available clinical and radiographic data and shared a remarkable degree of similarity. The median age at presentation was 30 (range 21-68). Six patients had little or no smoking history. All complained of 1 to 3 months of cough at presentation. Computed tomography scans showed a large, centrally located primary mass with confluent involvement of mediastinal lymph nodes, pleural disease, and sparing of the contralateral lung. Lytic bone metastases were common but brain metastases were absent in all cases. Pathologically, all cases showed primitive-appearing round to epitheloid cells growing in nests and sheets. All tumors expressed keratin, p63 or p40, and NUT protein. Eight cases had a fluorescence in situ hybridization proven BRD4-NUT or BRD3-NUT rearrangement; one case was presumed to have a NUT variant fusion event. Median overall survival was 2.2 months. Despite the rarity of primary pulmonary NMC, it is important to recognize this entity to counsel patients regarding outcome and to identify candidates for targeted BRD inhibitors currently in clinical trials. PMID- 26001145 TI - Stereotactic body radiotherapy using a radiobiology-based regimen for stage I non small-cell lung cancer: five-year mature results. AB - INTRODUCTION: Although the protocol of 48 Gy in four fractions over 4 days has been most often employed in stereotactic body radiotherapy (SBRT) for stage I non small-cell lung cancer in Japan, higher doses are necessary to control larger tumors, and interfraction intervals should be longer than 24 hours to take advantage of reoxygenation. We report the final results of our study testing the following regimen: for tumors less than 1.5, 1.5-3, and greater than 3 cm in diameter, 44, 48, and 52 Gy, respectively, were given in four fractions with interfraction intervals of greater than or equal to 3 days. METHODS: Among 180 histologically proven patients entered, 120 were medically inoperable and 60 were operable. The median patient age was 77 years (range, 29-89). SBRT was performed with 6-MV photons using four noncoplanar and three coplanar beams. Isocenter doses of 44, 48, and 52 Gy were given to four, 124, and 52 patients, respectively. RESULTS: The 5-year overall survival rate was 52.2% for all 180 patients and 66% for 60 operable patients. The 5-year local control rate was 86% for tumors less than or equal to 3 cm (44/48 Gy) and 73% for tumors greater than 3 cm (52 Gy; p = 0.076). Grade greater than or equal to 2 radiation pneumonitis developed in 13% (10% for the 44/48-Gy group and 21% for the 52-Gy group; p = 0.056). Other grade 2 toxicities were all less than 4%. CONCLUSIONS: Our first prospective SBRT study yielded reasonable local control and overall survival rates and acceptable toxicity. Refinement of the protocol including dose escalation may lead to better outcome. PMID- 26001146 TI - Diffuse Hemorrhagic Brain Metastases in an ALK Fusion Positive Patient on Crizotinib. PMID- 26001148 TI - Spatial Tumor Heterogeneity in Lung Cancer with Acquired Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance: Targeting High-Level MET Amplification and EGFR T790M Mutation Occurring at Different Sites in the Same Patient. PMID- 26001147 TI - BIRC6-ALK, a Novel Fusion Gene in ALK Break-Apart FISH-Negative Lung Adenocarcinoma, Responds to Crizotinib. PMID- 26001149 TI - A Long-Term Spinal Intramedullary Response to Ceritinib in ALK Rearranged Non Small-Cell Lung Cancer. AB - PATIENTS: With advanced non-small-cell lung cancer (NSCLC) harboring, the anaplastic lymphoma kinase (ALK) gene rearrangement often responds impressively to ALK inhibitors, such as crizotinib. Acquired tumor resistance to ALK inhibition develops after a median progression-free survival of 7.7 to 10.9 months, with several mechanisms of resistance already described. Second generation ALK inhibitors, such as ceritinib, may overcome some of these mechanisms and have known efficacy in brain metastases. Their effect on intramedullary spinal cord metastases, a rare form of central nervous system metastases, is unknown. PMID- 26001150 TI - Metabolomics a novel biomarker in lung cancer. PMID- 26001151 TI - Beware of the "Bronchocele," Particularly in Patients with a History or Risk Factors for a Mucinous Carcinoma: A Response to the Article "Resection of a Solitary Pulmonary Metastasis from Prostatic Adenocarcinoma Misdiagnosed as a Bronchocele: Usefulness of 18F-Choline and 18F-FDG PET/CT" by Calais et al. PMID- 26001152 TI - Reply to "18F-Choline PET-CT in the Management of Lung Cancer and Mucinous Tumors?". PMID- 26001153 TI - Uncommon EGFR Exon 19 Mutations Confer Gefitinib Resistance in Advanced Lung Adenocarcinoma. PMID- 26001154 TI - MicroRNA Assays for Diagnosis Lung Cancer Biopsy. PMID- 26001155 TI - Reply to "MiR-205 and miR-375 microRNA Assays to Distinguish Squamous Cell Carcinoma From Adenocarcinoma in Lung Cancer Biopsies". PMID- 26001156 TI - Reply to "better prognostic models may result in improved patient selection for adjuvant therapies after complete resection of solitary fibrous tumors of the pleura". PMID- 26001157 TI - The neural antecedents to voluntary action: Response to commentaries. AB - Cognitive neuroscience must attend to the conceptual coherence of its hypotheses as well as to their empirical support. Examining the most influential studies of the neural antecedents to voluntary action, our Discussion Paper sought to identify the real-world consequences of neglecting the former in what we argued has been too narrow a pursuit of the latter. Though conceptual in form, our analysis is sharply empirical in its conclusions, revealing what have long been thought to be momentous experimental observations--such as the readiness potential--as the outcome of previously unidentified confounds that rob them of significance. Conversely, we suggested that experimental studies of two-way control, amongst other defining features of the voluntary, have been given less emphasis than the subject demands. Here, we ramify our analysis down the paths identified by others in the commentaries we received. PMID- 26001158 TI - Unbiased Clustering of Molecular Dynamics for Spatially Resolved Analysis of Chemically Heterogeneous Surfaces. AB - A technique is described for resolving and interpreting molecular interactions with a chemically heterogeneous surface. Using total internal reflection fluorescence microscopy, dynamic single molecule trajectories were accumulated simultaneously for fluorescently labeled fatty acid (interacting primarily via hydrophobic interactions) and dextran (interacting via hydrogen-bonding interactions) probe molecules at the interface between an aqueous solvent and a photopatterned solid surface with distinct regions of amine-terminated and poly(ethylene glycol) self-assembled monolayers. Using dynamic properties of the probe molecules (adsorption rate, surface diffusion coefficient, residence time), an unsupervised Gaussian mixture model algorithm was used to identify areas of the surface that were chemically related to each other, and the dynamic behaviors of the probe molecules were studied statistically on these distinct regions. The dynamic data were compared to data from homogeneous surfaces of known chemistry to provide a chemical identification of each location on the surface. Spatial maps were also constructed, allowing for spatial visualization of surface chemistry on a hydrophilic substrate. This work enables the direct study of interactions between single-molecule probes and distinct surface chemistries, even in the presence of spatial heterogeneity, without human bias, assumptions about surface structure, or model-dependent analysis. PMID- 26001159 TI - Effect of pressure on superconductivity in the indium-doped topological crystalline insulator SnTe. AB - We report on the impact of hydrostatic pressure on the superconductivity of optimally (indium)-doped SnTe which is established to be derived from a topological crystalline insulating phase. Single crystals of Sn(1-x)In(x)Te were synthesized by a modified Bridgman method that exhibited maximum superconducting Tc of 4.4 K for x = 0.5. Hydrostatic pressure up to 2.5 GPa was applied on the crystals of Sn0.5In0.5Te, and electrical resistivity as a function of temperature and pressure was measured. We observed a decrease in the onset superconducting transition temperature from 4.4 K to 2.8 K on increasing pressure from ambient to 2.5 GPa. The normal state resistivity also decreased abruptly by an order of magnitude at 0.5 GPa but for higher pressures, it decreased marginally. From onset, offset and zero resistivity values, dTc/dP of ~ -0.6 K GPa(-1) was confirmed. The low temperature normal state resistivity followed T(2) dependence suggesting Fermi liquid behaviour both for ambient and high pressure data. This increase in metallic characteristics accompanied by normal state Fermi liquid behaviour is in accordance with a 'dome structure' for Tc variation with varying carrier concentration. PMID- 26001104 TI - Nonelective surgery at night and in-hospital mortality: Prospective observational data from the European Surgical Outcomes Study. AB - BACKGROUND: Evidence suggests that sleep deprivation associated with night-time working may adversely affect performance resulting in a reduction in the safety of surgery and anaesthesia. OBJECTIVE: Our primary objective was to evaluate an association between nonelective night-time surgery and in-hospital mortality. We hypothesised that urgent surgery performed during the night was associated with higher in-hospital mortality and also an increase in the duration of hospital stay and the number of admissions to critical care. DESIGN: A prospective cohort study. This is a secondary analysis of a large database related to perioperative care and outcome (European Surgical Outcome Study). SETTING: Four hundred and ninety-eight hospitals in 28 European countries. PATIENTS: Men and women older than 16 years who underwent nonelective, noncardiac surgery were included according to time of the procedure. INTERVENTION: None. MAIN OUTCOME MEASURES: Primary outcome was in-hospital mortality; the secondary outcome was the duration of hospital stay and critical care admission. RESULTS: Eleven thousand two hundred and ninety patients undergoing urgent surgery were included in the analysis with 636 in-hospital deaths (5.6%). Crude mortality odds ratios (ORs) increased sequentially from daytime [426 deaths (5.3%)] to evening [150 deaths (6.0%), OR 1.14; 95% confidence interval 0.94 to 1.38] to night-time [60 deaths (8.3%), OR 1.62; 95% confidence interval 1.22 to 2.14]. Following adjustment for confounding factors, surgery during the evening (OR 1.09; 95% confidence interval 0.91 to 1.31) and night (OR 1.20; 95% confidence interval 0.9 to 1.6) was not associated with an increased risk of postoperative death. Admittance rate to an ICU increased sequentially from daytime [891 (11.1%)], to evening [347 (13.8%)] to night time [149 (20.6%)]. CONCLUSION: In patients undergoing nonelective urgent noncardiac surgery, in-hospital mortality was associated with well known risk factors related to patients and surgery, but we did not identify any relationship with the time of day at which the procedure was performed. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01203605. PMID- 26001160 TI - "Without a mother": caregivers and community members' views about the impacts of maternal mortality on families in KwaZulu-Natal, South Africa. AB - BACKGROUND: Maternal mortality in South Africa is high and a cause for concern especially because the bulk of deaths from maternal causes are preventable. One of the proposed reasons for persistently high maternal mortality is HIV which causes death both indirectly and directly. While there is some evidence for the impact of maternal death on children and families in South Africa, few studies have explored the impacts of maternal mortality on the well-being of the surviving infants, older children and family. This study provides qualitative insight into the consequences of maternal mortality for child and family well being throughout the life-course. METHODS: This qualitative study was conducted in rural and peri-urban communities in Vulindlela, KwaZulu-Natal. The sample included 22 families directly affected by maternal mortality, 15 community stakeholders and 7 community focus group discussions. These provided unique and diverse perspectives about the causes, experiences and impacts of maternal mortality. RESULTS AND DISCUSSION: Children left behind were primarily cared for by female family members, even where a father was alive and involved. The financial burden for care and children's basic needs were largely met through government grants (direct and indirectly targeted at children) and/or through an obligation for the father or his family to assist. The repercussions of losing a mother were felt more by older children for whom it was harder for caregivers to provide educational supervision and emotional or psychological support. Respondents expressed concerns about adolescent's educational attainment, general behaviour and particularly girl's sexual risk. CONCLUSION: These results illuminate the high costs to surviving children and their families of failing to reduce maternal mortality in South Africa. Ensuring social protection and community support is important for remaining children and families. Additional qualitative evidence is needed to explore differential effects for children by gender and to guide future research and inform policies and programs aimed at supporting maternal orphans and other vulnerable children throughout their development. PMID- 26001161 TI - Identification and quantification of acidosis inducing metabolites in cases of alcohols intoxication by GC-MS for emergency toxicology. AB - A simple, cost effective, and fast gas chromatography method with mass spectrometry detection (GC-MS) for simultaneous measurement of formic acid, glycolic acid, methoxyacetic acid, ethoxyacetic acid and 2-hydroxyethoxyacetic acid in serum and urine was developed and validated. This multi-analyte method is highly suitable for clinical and emergency toxicology laboratory diagnostic, allowing identification and quantification of five most common acidosis inducing organic acids present in cases of alcohol intoxication. Furthermore, when patients are admitted to emergency unit at late stage of toxic alcohol intoxication, the concentration of parent compound may be already low or not detectable. This new method employs a relatively less used class of derivatization agents - alkyl chloroformates, allowing the efficient and rapid derivatization of carboxylic acids within seconds. The entire sample preparation procedure is completed within 5 min. The optimal conditions of derivatization procedure have been found using chemometric approach (design of experiment). The calibration dependence of the method was proved to be quadratic in the range of 25-3000 mg L(-1), with adequate accuracy (97.3-108.0%) and precision (<12.8%). The method was successfully applied for identification and quantification of the selected compounds in serum of patients from emergency units. PMID- 26001162 TI - HPTLC and RP-HPLC methods for simultaneous determination of Paracetamol and Pamabrom in presence of their potential impurities. AB - Two chromatgraphic methods were developed for determination of Paracetamol (PCM) and Pamabrom (PAM) in presence of P-aminophenol (PAP) and Theophylline (THEO) as potential impurities of both drugs respectively. First method is HPTLC which depends on separation and quantitation of the studied drugs on aluminum plates pre-coated with silica gel 60 F254 as a stationary phase using chloroform:methanol:ethyl acetate:glacial acetic acid (8:0.8:0.6:0.2, v/v/v/v) as mobile phase followed by densitometric measurement of the bands at 254 nm. Second method is RP-HPLC which comprises separation of the studied drugs on a Phenomenex C8 column by gradient elution using mobile phase consisting of sodium dihydrogen phosphate buffer (0.05 M): methanol:acetonitrile (85:10:5, v/v/v) at a flow rate of 1 mL/min for first 7.5 min and (70:20:10, v/v/v) at a flow rate of 1.5 mL/min for the next 5 min. The proposed methods were successfully applied for determination of the potential impurities of PCM and PAM after resolving them from the pure drugs. The developed methods have been validated and proved to meet the requirements delineated by ICH guidelines with respect to linearity, accuracy, precision, specificity and robustness. The validated methods were successfully applied for determination of the studied drugs in their pharmaceutical formulation. The results were statistically compared to those obtained by the reported RP-HPLC method where no significant difference was found; indicating the ability of proposed methods to be used for routine quality control analysis of these drugs. PMID- 26001164 TI - Ab Initio Screening Approach for the Discovery of Lignin Polymer Breaking Pathways. AB - The directed depolymerization of lignin biopolymers is of utmost relevance for the valorization or commercialization of biomass fuels. We present a computational and theoretical screening approach to identify potential cleavage pathways and resulting fragments that are formed during depolymerization of lignin oligomers containing two to six monomers. We have developed a chemical discovery technique to identify the chemically relevant putative fragments in eight known polymeric linkage types of lignin. Obtaining these structures is a crucial precursor to the development of any further kinetic modeling. We have developed this approach by adapting steered molecular dynamics calculations under constant force and varying the points of applied force in the molecule to diversify the screening approach. Key observations include relationships between abundance and breaking frequency, the relative diversity of potential pathways for a given linkage, and the observation that readily cleaved bonds can destabilize adjacent bonds, causing subsequent automatic cleavage. PMID- 26001163 TI - Inhibition of cadmium- induced genotoxicity and histopathological changes in Nile tilapia fish by Egyptian and Tunisian montmorillonite clay. AB - Cadmium (Cd) is an important inorganic toxicant widely distributed in the environment because of its various industrial uses. The aims of the current study were to investigate the efficacy of purified Egyptian and Tunisian montmorillonite clays (EMC and TMC) to inhibit genotoxicity and histological alterations induced by cadmium chloride (CdCl2) utilizing the Nile tilapia fish as an in vivo model. Chromosomal aberrations (CAs), micronucleus (MN) frequencies and DNA fingerprinting profile were genotoxic end points and histopathological changes that were used in this investigation. Six groups of fish were treated for 2 weeks and included control group, CdCl2-treated group and groups treated with EMC or TMC alone or in combination with CdCl2. The present results revealed that, treatment of fish with CdCl2 exhibited significant increased in the number of micronucleated erythrocytes (MnRBCs), frequency of CAs and instability of genomic DNA. Treatment of EMC and TMC in combination with CdCl2 significantly reduced the frequency of MnRBCs by the percentage of 53.28% and 60.77% and the frequency of CAs by 43.91% and 52.17% respectively. As well as, normalized DNA fingerprinting profile and significantly improved histopathological picture induced by Cadmium treatment. It is worth mention that both clays have the ability to tightly bind CdCl2 and decreased its cytotoxicity and genotoxicity; however, Tunisian clay was more efficient in binding with the CdCl2 than Egyptian clay. PMID- 26001165 TI - Aromatic monomers by in situ conversion of reactive intermediates in the acid catalyzed depolymerization of lignin. AB - Conversion of lignin into well-defined aromatic chemicals is a highly attractive goal but is often hampered by recondensation of the formed fragments, especially in acidolysis. Here, we describe new strategies that markedly suppress such undesired pathways to result in diverse aromatic compounds previously not systematically targeted from lignin. Model studies established that a catalytic amount of triflic acid is very effective in cleaving the beta-O-4 linkage, most abundant in lignin. An aldehyde product was identified as the main cause of side reactions under cleavage conditions. Capturing this unstable compound by reaction with diols and by in situ catalytic hydrogenation or decarbonylation lead to three distinct groups of aromatic compounds in high yields acetals, ethanol and ethyl aromatics, and methyl aromatics. Notably, the same product groups were obtained when these approaches were successfully extended to lignin. In addition, the formation of higher molecular weight side products was markedly suppressed, indicating that the aldehyde intermediates play a significant role in these processes. The described strategy has the potential to be generally applicable for the production of interesting aromatic compounds from lignin. PMID- 26001166 TI - Psychometric evaluation of a standardized set of alcohol cue photographs to assess craving. AB - INTRODUCTION: Research using alcohol-related visual stimuli has been limited due to a lack of published studies examining the psychometric properties of alcohol cues. The primary aim of the current study was to examine the factor structure, validity, and reliability of craving ratings following exposure to alcohol cues (including beer, wine, hard liquor, and mixed drinks) in an alcohol cue reactivity paradigm. METHODS: U.S. adults ages 21-69 [N = 195; Mage = 32.19, SD = 10.63; 74.4% male; 56.4% Asian/Pacific Islander, 34.9% White (non-Hispanic), 4.6% Other, 2.0% Hispanic/Latino, 1.5% Native American/Alaskan Native, and 0.5% African-American] completed questionnaires and provided craving, arousal, and valence ratings following alcohol, positive, negative and neutral cues in a web based study. RESULTS: The alcohol craving ratings following alcohol cues formed one internally consistent factor. Convergent and incremental validity was supported as alcohol cue craving ratings were positively correlated with general craving, past-year hazardous alcohol use, and behavioral activation facets, even while controlling for neutral cue craving ratings and other related variables. Alcohol craving was significantly higher following alcohol cues compared to neutral cues and unrelated to behavioral inhibition, supporting discriminant validity. CONCLUSIONS: These findings provide support that the alcohol cues we developed are reliable and valid stimuli for the use in alcohol cue reactivity paradigms. Future research assessing alcohol cue reactivity using this validated photographic cue set may facilitate a greater understanding of the affective processes associated with alcohol use and allow for more targeted behavioral change interventions for alcohol-related problems. PMID- 26001167 TI - When abuse primes addiction - automatic activation of alcohol concepts by child maltreatment related cues in emotionally abused alcoholics. AB - INTRODUCTION: Recent research indicates that there is a link between emotional maltreatment and alcohol dependence (AD), but the underlying mechanisms still need to be clarified. There is reason to assume that maltreatment related cues automatically activate an associative memory network comprising cues eliciting craving as well as alcohol-related responses. The current study aimed to examine this network in AD patients who experienced emotional abuse using a priming paradigm. METHODS: A specific priming effect in emotionally abused AD subjects was hypothesized for maltreatment related words that preceded alcohol related words. 49 AD subjects (n=14 with emotional abuse vs. n=35 without emotional abuse) and 34 control subjects performed a priming task with maltreatment related and neutral prime words combined with alcohol related and neutral target words. Maltreatment related words consisted of socially and physically threatening words. RESULTS: As hypothesized, a specific priming effect for socially threatening and physically threatening cues was found only in AD subjects with emotional abuse. CONCLUSIONS: The present data are the first to provide evidence that child maltreatment related cues automatically activate an associative memory network in alcoholics with emotional abuse experiences. PMID- 26001168 TI - Impact of preconditioning with retinoic acid during early development on morphological and functional characteristics of human induced pluripotent stem cell-derived neurons. AB - Human induced pluripotent stem cells (hiPSCs) are a suitable tool to study basic molecular and cellular mechanisms of neurodevelopment. The directed differentiation of hiPSCs via the generation of a self-renewable neuronal precursor cell line allows the standardization of defined differentiation protocols. Here, we have investigated whether preconditioning with retinoic acid during early neural induction impacts on morphological and functional characteristics of the neuronal culture after terminal differentiation. For this purpose we have analyzed neuronal and glial cell markers, neuronal outgrowth, soma size, depolarization-induced distal shifts of the axon initial segment as well as glutamate-evoked calcium influx. Retinoic acid preconditioning led to a higher yield of neurons vs. glia cells and longer axons than unconditioned controls. In contrast, glutamatergic activation and depolarization induced structural plasticity were unchanged. Our results show that the treatment of neuroectodermal cells with retinoic acid during early development, i.e. during the neurulation phase, increases the yield of neuronal phenotypes, but does not impact on the functionality of terminally differentiated neuronal cells. PMID- 26001170 TI - Protein delivery options: how well have we succeeded? PMID- 26001169 TI - Impaired function of bone marrow stromal cells in systemic mastocytosis. AB - Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit) in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Finally, we performed an expression analysis and found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. We suggest that some of the symptoms associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow of the patients. PMID- 26001171 TI - Vesicle-based artificial cells: recent developments and prospects for drug delivery. PMID- 26001172 TI - Optically modulated cancer therapeutic delivery: past, present and future. AB - Chemotherapeutic regimens are often restricted by dose-limiting toxicities that arise from drug exposure to off-site tissues. Nanoparticle drug carriers that specifically deliver therapeutics to the site of malignant tissue are being actively researched today. One strategy is to utilize materials that are light responsive, such that the carrier can be triggered to release its drug payload at the distinct time and location of light exposure. This review discusses recent advances in the development of such light-responsive drug carriers. With continued optimization and in vivo validation, these approaches may offer novel treatment options for cancer management. PMID- 26001173 TI - The therapeutic potential of vaginal drug delivery in the treatment of cervical cancer. AB - Cervical cancer is usually treated by surgery, with the more advanced cancers requiring adjuvant chemo or radiotherapy. Its location makes it easily accessible through the vagina for the localized delivery of chemotherapeutic drugs. Localized delivery has the advantage of direct delivery to the site of action resulting in a lower dose being required and a reduction in systemic side effects. This approach would be advantageous in fertility-sparing surgery, where by localized delivery could be used to reduce tumor size allowing for a much smaller tumor to be removed, reducing the risk of preterm birth. Furthermore, localized delivery could be used after surgery to reduce the risk of recurrence, which is significantly higher in fertility-sparing surgery compared with standard surgery. PMID- 26001174 TI - Advances in the bioanalytical study of drug delivery across the skin. AB - The study of a drug's dermal penetration profile provides important pharmaceutical data for the rational development of topical and transdermal delivery systems because the skin is a broadly used delivery route for local and systemic drugs and a potential route for gene therapy and vaccines. Monitoring drug penetration across the skin and quantifying its levels in different skin layers have been constant challenges due to the detection limitations of the available techniques, as well as the inherent interference in this tissue. This review explores and discusses several bionalytical methods that are indispensable tools to study drugs across the skin. In addressing the main topic, we structure the review highlighting the skin as an important route of drug administration and its structure, skin membrane models most used and its properties, in vitro and in vivo assays most used in the study of drug delivery to the skin, the techniques for processing the skin for subsequent analysis by bioanalytical methods that have a theoretical and practical approach showing its applicability, limitations and also including examples of its use. This review has a comprehensive approach in order to help researchers design their experiments and update the applicability and advances in this area of expertise. PMID- 26001175 TI - Advanced drug delivery systems for local treatment of the oral cavity. AB - Good oral health is of major importance for general health and well-being. Several innovative drug delivery systems have been developed for the local treatment and prevention of various diseases in the oral cavity. However, there are currently few optimal systems and many therapeutic challenges still remain, including low drug efficacy and retention at targeted site of action. The present review provides an insight into the latest drug delivery strategies for the local treatment and prevention of the four most common oral pathologies, namely, dental caries, periodontitis, oral mucosal infections and oral cancer. The potential of bioadhesive formulations, nanoparticulate platforms, multifunctional systems and photodynamic methodologies to improve therapy and prophylaxis in future local applications for the oral cavity will be discussed. PMID- 26001176 TI - An artificial pancreas for automated blood glucose control in patients with Type 1 diabetes. AB - Automated glucose control in patients with Type 1 diabetes is much-coveted by patients, relatives and healthcare professionals. It is the expectation that a system for automated control, also know as an artificial pancreas, will improve glucose control, reduce the risk of diabetes complications and markedly improve patient quality of life. An artificial pancreas consists of portable devices for glucose sensing and insulin delivery which are controlled by an algorithm residing on a computer. The technology is still under development and currently no artificial pancreas is commercially available. This review gives an introduction to recent progress, challenges and future prospects within the field of artificial pancreas research. PMID- 26001177 TI - Generation of tailored aerosols for inhalative drug delivery employing recent vibrating-mesh nebulizer systems. AB - Direct drug delivery to the lungs is considered the gold standard for the treatment of a variety of respiratory diseases, owing to the increased therapeutic selectivity of the inhalative approach. Airborne formulations with defined size characteristics are required to improve the deposition pattern within the airways. In this respect, different nebulizer systems have been conceived, which has enabled the generation of respirable medicament mists. Here, vibrating-mesh technology revealed significant potential to overcome the main shortcomings associated with 'traditional' devices. Tailored orifice dimensions and defined formulation characteristics are of special interest for the generation of suitable aerosol droplets for inhalative purposes. Ongoing developments in device and formulation design will optimize the clinical outcome of inhalative drug delivery under application of vibrating-mesh technology. PMID- 26001178 TI - Should patients in need be given access to experimental drugs? AB - Patient access to experimental drugs outside of clinical trials is called compassionate use or expanded access. Compassionate use/expanded access presents a powerful ethical dilemma in that it involves competing claims that both have moral weight: specifically, an individual patient's very understandable desire to try to extend his or her life versus the orderly and efficient functioning of a drug development and clinical trial system that benefits much larger numbers of patients. Patient advocates, the FDA, pharmaceutical trade groups, and state and national legislators in the US are all currently weighing in on patient access to experimental drugs, and new guidelines and rules are being introduced. In this editorial, we discuss the impulse to rescue individual patients facing dire diseases and underscore the ethical questions that such rescue efforts raise. PMID- 26001179 TI - How can we improve prognostic models in renal cell carcinoma? AB - The therapeutic improvements in renal cell carcinoma brought about by the transition from the 'cytokine era' to the 'targeted agents era', have not affected the peculiar prognostic heterogeneity of the disease, nor have they diminished the importance of risk group classification based on easily assessable and commonly available laboratory and clinical variables. In the landmark study conducted by Motzer et al. before biological agents were available, the median survival of patients in the good prognosis group was 20 months, while the patients in the poor-risk group had a median survival time of only 4 months. With the introduction of anti-VEGF agents, overall survival has approximately doubled in all risk classes. In a population-based analysis of 670 patients treated with anti-VEGF agents, either in the first-line setting or in the second-line setting after cytokines, stratification according to the Database Consortium model showed that patients in the favorable risk group had a median overall survival of 43.2 months, while patients in the poor-risk group had a median overall survival of 7.8 months. PMID- 26001180 TI - BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. AB - INTRODUCTION: BRAF inhibition alone has achieved unprecedented efficacy results in patients affected by BRAF-mutated advanced melanoma. Since these findings, it was postulated that dual inhibition of BRAF and other components of the RAS/RAF/MEK/ERK MAPK pathway (such as MEK) would be superior to BRAF inhibition as monotherapy. A series of recent clinical trials have confirmed this hypothesis. AREAS COVERED: In this article, the biological rationale for both single and concomitant inhibitions of the MAPK pathway in BRAF mutant melanoma is provided. Moreover, available clinical data on the efficacy and toxicity of BRAF and MEK inhibition as single agents and in combination are extensively reviewed. EXPERT OPINION: Dual BRAF and MEK inhibition in advanced BRAF-mutated melanoma is superior to single inhibition in terms of efficacy without significant increase in toxicity. Therefore, BRAF plus MEK inhibition is expected to supersede single agent BRAF inhibition in these patients in the near future. PMID- 26001181 TI - HIV integrase inhibitors: a new era in the treatment of HIV. AB - INTRODUCTION: Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming 'standard' drugs in the treatment of both naive as well as heavily pretreated individuals with HIV. AREAS COVERED: Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings. EXPERT OPINION: Due to their outstanding data of efficacy, tolerability, safety--shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals--INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice. PMID- 26001182 TI - Antipsychotic use in pregnancy. AB - INTRODUCTION: Antipsychotic medications are being prescribed for a growing number of women with mental illnesses. However, evidence regarding their safety in pregnancy is still insufficient to provide adequate support for clinical practice, creating increasing concern among pregnant women and clinicians. AREAS COVERED: The aim of this article is to review published data regarding the safety of antipsychotic medications in pregnancy with a focus on the most commonly used atypical antipsychotics. EXPERT OPINION: Given the potential harm of not treating severe psychiatric illnesses during pregnancy, careful administration of antipsychotics is recommended for pregnant women who suffer from severe mental disorders. The most frequently used antipsychotics in pregnancy are olanzapine, risperidone and quetiapine, and do not appear to cause consistent, congenital harm to the fetus. No specific patterns of fetal limb or organ malformation related to these drugs have been reported. There is some evidence suggesting an association between antipsychotic use in pregnancy and the development of gestational diabetes. Also there appears to be an association between antipsychotic medication use in pregnancy and increased neonatal respiratory distress and withdrawal symptoms. Further studies are needed for clinicians to balance good maternal mental health, healthy pregnancies and good infant health outcomes. PMID- 26001183 TI - An update on pharmacotherapy for the treatment of fibromyalgia. AB - INTRODUCTION: Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness, cognitive impairment, and psychological distress. Multidisciplinary treatment combining pharmacological and nonpharmacological therapies is advised. AREAS COVERED: Publications describing randomized controlled trials and long-term extension studies evaluating drug treatment for fibromyalgia were searched in PubMed and Scopus and included in this review. EXPERT OPINION: Different drugs are recommended for the treatment of fibromyalgia by different published guidelines, although only three of them have been approved for this indication by the US FDA, and none have been approved by the European Medicines Agency. According to the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs with at least one positive clinical trial include some selective serotonin reuptake inhibitors, moclobemide, pirlindole, gabapentin, tramadol, tropisetron, sodium oxybate and nabilone. None of the currently available drugs are fully effective against the whole spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances and depression, among the most relevant symptoms. Combination therapy is an option that needs to be more thoroughly investigated in clinical trials. PMID- 26001184 TI - Polycystic ovary syndrome: chemical pharmacotherapy. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease among women of childbearing age. The clinical features are heterogeneous and vary in intensity. Hirsutism, menstrual disorders and infertility are the most frequent conditions observed; however, long-term complications (dyslipidemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, endometrial cancer) are also often described. Each disorder may be managed by tailored strategies, employing sequential or combined pharmacological and/or non-pharmacological treatment. AREAS COVERED: The authors review the drugs used for PCOS management and discuss new approaches. A systematic MEDLINE search regarding the randomized controlled trials, retrospective and observational studies about medical treatments of PCOS, the Cochrane library for reviews and also search for registered trials on ClinicalTrials.gov is performed. EXPERT OPINION: A uniform treatment for PCOS patients does not exist. Clinicians should perform an accurate evaluation of patients' characteristics, identifying the phenotypic target and, subsequently, the best-tailored treatment to manage one or more clinical issues. Lifestyle intervention should always be the first recommended approach unless other issues indicate that drug or hormonal interventions are superior. PMID- 26001185 TI - Tiotropium bromide as add-on therapy to inhaled corticosteroids for treating asthma. AB - INTRODUCTION: Bronchial asthma is becoming increasingly prevalent worldwide. Although first-line therapy with inhaled corticosteroids (ICS) with or without long-acting beta2 agonists (LABA) has significantly improved the clinical outcomes of asthma, they cannot provide all asthmatics with good control and thus alternatives or add-on drugs are required. Tiotropium is a long-acting muscarinic antagonist that has been used to treat chronic obstructive pulmonary disease and it has been approved for treating asthma in some countries. This agent has similar bronchodilatory effects to those of LABA and might also have anti inflammatory and anti-remodeling effects. AREAS COVERED: Some pivotal clinical trials have found tiotropium effective as an add-on medication for low-to-medium doses of ICS for treating symptomatic asthma and asthma that remains uncontrolled despite ICS plus LABA therapy. EXPERT OPINION: Whether or not tiotropium has anti inflammatory and anti-remodeling effects in humans with asthma is an important issue. Predictors that would identify patients who would derive the maximal potential benefit from treatment with tiotropium in addition to their current therapy are also needed. Although the cardiovascular toxicity of tiotropium is less remarkable in asthma than in chronic obstructive pulmonary disease, longer and larger studies are still needed to confirm the safety of tiotropium for treating asthma. PMID- 26001187 TI - Cerium dioxide nanoparticles affect in vitro fertilization in mice. AB - Due to their catalytic and oxidative properties, cerium dioxide nanoparticles (CeO2NPs) are widely used as diesel additive or as promising therapy in cancerology; yet, scarce data are available on their toxicity, and none on their reproductive toxicity. We showed a significant decrease of fertilization rate, assessed on 1272 oocytes, during in vitro fertilization (IVF) carried out in culture medium containing CeO2NP at very low concentration (0.01 mg.l(-1)). We also showed significant DNA damage induced in vitro by CeO2NP on mouse spermatozoa and oocytes at 0.01 mg.l(-1) using Comet assay. Transmission Electron Microscopy did not detect any nanoparticles in the IVF samples at 0.01 mg.l(-1), but showed, at high concentration (100 mg.l(-1)), their endocytosis by the cumulus cells surrounding oocytes and their accumulation along spermatozoa plasma membranes and oocytes zona pellucida. We did not observe any nanoparticles in the cytoplasm of spermatozoa, oocytes or embryos. This study demonstrates for the first time the impact of CeO2NP on in vitro fertilization, as well as their genotoxicity on mouse spermatozoa and oocytes, at low nanoparticle concentration exposure. Decreased fertilization rates may result from: (1) CeO2NP's genotoxicity on gametes; (2) a mechanical effect, disrupting gamete interaction and (3) oxidative stress induced by CeO2NP. These results add new and important insights with regard to the reproductive toxicity of nanomaterials requesting urgent evaluation, and support several publications on metal nanoparticles reprotoxicity. Our data highlight the need for in vivo studies after low-dose exposure. PMID- 26001188 TI - Suitability of analytical methods to measure solubility for the purpose of nanoregulation. AB - Solubility is an important physicochemical parameter in nanoregulation. If nanomaterial is completely soluble, then from a risk assessment point of view, its disposal can be treated much in the same way as "ordinary" chemicals, which will simplify testing and characterisation regimes. This review assesses potential techniques for the measurement of nanomaterial solubility and evaluates the performance against a set of analytical criteria (based on satisfying the requirements as governed by the cosmetic regulation as well as the need to quantify the concentration of free (hydrated) ions). Our findings show that no universal method exists. A complementary approach is thus recommended, to comprise an atomic spectrometry-based method in conjunction with an electrochemical (or colorimetric) method. This article shows that although some techniques are more commonly used than others, a huge research gap remains, related with the need to ensure data reliability. PMID- 26001189 TI - Nanotechnological Approaches to Therapeutic Delivery Using Elastin-Like Recombinamers. AB - This Review discusses the use of elastin-like polymers and their recombinant version, elastin-like recombinamers, in drug-delivery systems. These macromolecules exhibit a number of interesting properties that are rarely found together in any other family of materials, especially extremely high biocompatibility, high bioactivity and functionality, complex yet fully controlled composition, and stimuli responsiveness. Appropriate design of these molecules opens up a broad range of different possibilities for their use in new therapeutic platforms. The first of these described herein is the use of ELRs in single-molecule devices as therapeutic entities in their own right. Subsequently, we describe how the self-assembly properties of these materials can be exploited to create nanocarriers and, eventually, microcarriers that are able to temporally and spatially control and direct the release of their drug load. Intracellular drug-delivery devices and nanocarriers for treating cancer are among the uses described in that section. Finally, the use of ELRs as base materials for implantable drug depots, in the form of hydrogels, is discussed. PMID- 26001190 TI - Diagnostic value of symptom screening for pulmonary tuberculosis in China. AB - OBJECTIVE: To evaluate the diagnostic value of symptom screening for tuberculosis (TB) case finding defined in National Tuberculosis Control Program in China (China NTP) among elderly people(>=65 years) and younger people(<65 years). METHODS: We made a secondary analysis in a population-based TB prevalence survey in China in 2010. Questionnaire including information for cough and haemoptysis was completed by face to face interview, and then chest radiography was conducted in all eligible participants. Sputum smear and culture were followed for all TB suspects. We calculated the odds ratios (OR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve (AUC) of using different symptoms for screening to detect bacteriologically positive TB in subpopulations stratified by age 65, to evaluate the performance of symptom screening for TB. FINDINGS: Of 315 newly diagnosed bacteriologically positive TB, 131 patients (41.59%) were elderly, and 48.57% of TB patients were asymptomatic. Nearly 50% patients did not present cough of any duration, and less than half present cough more than 2 weeks, a defined suspected symptom in China NTP. Cough of any duration was reported more in patients aged under 65 than those in elderly, especially for the acute cough (9.78% vs 6.87%). Those symptoms defined by China NTP were reported by less than half participants in two subpopulations. Acute cough (<2 weeks) was an independent predictor of TB in people aged under 65 (adjusted OR: 3.3, 95% CI: 2.0-5.5), but not in those aged 65 and above (adjusted OR: 1.4, 95% CI: 0.7-2.9). The specificity for each symptom was significantly higher in participants aged under 65 (P<0.01), and sensitivities of most symptoms were significantly higher among elderly (P<0.05 or P<0.01). When compared with cough for 2 weeks and more, using cough of any duration for symptom screening increased the sensitivity from 42.9% to 51. % for all participants, and the AUC increased from 0.70 to 0.74 for participants aged under 65 without significant difference. CONCLUSIONS: There is a high percent of asymptomatic TB patients, and those symptoms adopted in China NTP for screening is poorly predictive for TB. The presence of TB symptoms, the sensitivities and specificities of symptoms for TB were distinct between two subpopulations cut by age 65, implying different case finding strategies should be established for them. The current case finding strategy should be improved, and further studies should be done to evaluate the performance and cost effectiveness of different symptom screening strategy. PMID- 26001191 TI - The Heme Transport Capacity of LHR1 Determines the Extent of Virulence in Leishmania amazonensis. AB - Leishmania spp. are trypanosomatid parasites that replicate intracellularly in macrophages, causing serious human morbidity and mortality throughout the world. Trypanosomatid protozoa cannot synthesize heme, so must acquire this essential cofactor from their environment. Earlier studies identified LHR1 as a Leishmania amazonensis transmembrane protein that mediates heme uptake. Null mutants of LHR1 are not viable and single knockout strains have reduced virulence, but very little is known about the properties of LHR1 directly associated with heme transport. Here, we use functional assays in Saccharomyces cerevisiae to show that specific tyrosine residues within the first three predicted transmembrane domains of LHR1 are required for efficient heme uptake. These tyrosines are unique to LHR1, consistent with the low similarity between LHR1 and its corresponding homologs in C. elegans and human. Substitution of these tyrosines in LHR1 resulted in varying degrees of heme transport inhibition, phenotypes that closely mirrored the impaired ability of L. amazonensis to replicate as intracellular amastigotes in macrophages and generate cutaneous lesions in mice. Taken together, our results imply that the mechanism for heme transport by LHR1 is distinctive and may have adapted to secure heme, a limiting cofactor, inside the host. Since LHR1 is significantly divergent from the human heme transporter HRG1, our findings lay the groundwork for selective targeting of LHR1 by small molecule antagonists. PMID- 26001192 TI - TREK-1 Regulates Cytokine Secretion from Cultured Human Alveolar Epithelial Cells Independently of Cytoskeletal Rearrangements. AB - BACKGROUND: TREK-1 deficient alveolar epithelial cells (AECs) secrete less IL-6, more MCP-1, and contain less F-actin. Whether these alterations in cytokine secretion and F-actin content are related remains unknown. We now hypothesized that cytokine secretion from TREK-1-deficient AECs was regulated by cytoskeletal rearrangements. METHODS: We determined F-actin and alpha-tubulin contents of control, TREK-1-deficient and TREK-1-overexpressing human A549 cells by confocal microscopy and western blotting, and measured IL-6 and MCP-1 levels using real time PCR and ELISA. RESULTS: Cytochalasin D decreased the F-actin content of control cells. Jasplakinolide increased the F-actin content of TREK-1 deficient cells, similar to the effect of TREK-1 overexpression in control cells. Treatment of control and TREK-1 deficient cells with TNF-alpha, a strong stimulus for IL-6 and MCP-1 secretion, had no effect on F-actin structures. The combination of TNF alpha+cytochalasin D or TNF-alpha+jasplakinolide had no additional effect on the F-actin content or architecture when compared to cytochalasin D or jasplakinolide alone. Although TREK-1 deficient AECs contained less F-actin at baseline, quantified biochemically, they contained more alpha-tubulin. Exposure to nocodazole disrupted alpha-tubulin filaments in control and TREK-1 deficient cells, but left the overall amount of alpha-tubulin unchanged. Although TNF-alpha had no effect on the F-actin or alpha-tubulin contents, it increased IL-6 and MCP 1 production and secretion from control and TREK-1 deficient cells. IL-6 and MCP 1 secretions from control and TREK-1 deficient cells after TNF alpha+jasplakinolide or TNF-alpha+nocodazole treatment was similar to the effect of TNF-alpha alone. Interestingly, cytochalasin D decreased TNF-alpha-induced IL 6 but not MCP-1 secretion from control but not TREK-1 deficient cells. CONCLUSION: Although cytochalasin D, jasplakinolide and nocodazole altered the F actin and alpha-tubulin structures of control and TREK-1 deficient AEC, the changes in cytokine secretion from TREK-1 deficient cells cannot be explained by cytoskeletal rearrangements in these cells. PMID- 26001193 TI - Associations between Serum Sex Hormone Concentrations and Whole Blood Gene Expression Profiles in the General Population. AB - BACKGROUND: Despite observational evidence from epidemiological and clinical studies associating sex hormones with various cardiometabolic risk factors or diseases, pathophysiological explanations are sparse to date. To reveal putative functional insights, we analyzed associations between sex hormone levels and whole blood gene expression profiles. METHODS: We used data of 991 individuals from the population-based Study of Health in Pomerania (SHIP-TREND) with whole blood gene expression levels determined by array-based transcriptional profiling and serum concentrations of total testosterone (TT), sex hormone-binding globulin (SHBG), free testosterone (free T), dehydroepiandrosterone sulfate (DHEAS), androstenedione (AD), estradiol (E2), and estrone (E1) measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay. Associations between sex hormone concentrations and gene expression profiles were analyzed using sex-specific regression models adjusted for age, body mass index, and technical covariables. RESULTS: In men, positive correlations were detected between AD and DDIT4 mRNA levels, as well as between SHBG and the mRNA levels of RPIA, RIOK3, GYPB, BPGM, and RAB2B. No additional significant associations were observed. CONCLUSIONS: Besides the associations between AD and DDIT4 expression and SHBG and the transcript levels of RPIA, RIOK3, GYPB, BPGM, and RAB2B, the present study did not indicate any association between sex hormone concentrations and whole blood gene expression profiles in men and women from the general population. PMID- 26001195 TI - Development of a squamous cell carcinoma mouse model for immunotoxicity testing. AB - An important component of safety assessment of new pharmaceuticals is evaluation of their potential to increase the risk of developing cancer in humans. The traditional 2-year rodent bioassay often is not feasible or scientifically applicable for evaluation of biotherapeutics. Additionally, it has poor predictive value for non-genotoxic immunosuppressive compounds. Thus, there is a need for alternative testing strategies. A novel 3-stage tumor model in syngeneic C3H/HeN mice was evaluated here to study the effects of immunosuppressive drugs on tumor promotion and progression in vivo. The model employed a skin squamous cell carcinoma cell line (SCC VII) due to the increased prevalence of squamous cell carcinoma (SCC) in humans associated with immunosuppression after transplants. Local invasion, colonization and tumor progression were evaluated. The validation set of immunosuppressive drugs included: Cyclosporin (CSA), cyclophosphamide (CTX), azathioprine, etanercept, abatacept and prednisone. Local invasion was evaluated by histological assessment as well as fluorescence trafficking from Qdot((r))-labeled tumor cells from the site of inoculation to the draining lymph node. Colonization was evaluated by lung colony counts following intravenous inoculation. Tumor progression was assessed by morphometric analysis of lesion area, angiogenesis and growth fraction of established metastatic neoplasia. Immunosuppressive drugs in the validation set yielded mixed results, including decreased progression. The methods and results described herein using an in vivo syngeneic mouse tumor model can provide insight about the assessment of immunosuppressive drugs in carcinogenicity risk assessment. PMID- 26001194 TI - L-Rhamnosylation of Listeria monocytogenes Wall Teichoic Acids Promotes Resistance to Antimicrobial Peptides by Delaying Interaction with the Membrane. AB - Listeria monocytogenes is an opportunistic Gram-positive bacterial pathogen responsible for listeriosis, a human foodborne disease. Its cell wall is densely decorated with wall teichoic acids (WTAs), a class of anionic glycopolymers that play key roles in bacterial physiology, including protection against the activity of antimicrobial peptides (AMPs). In other Gram-positive pathogens, WTA modification by amine-containing groups such as D-alanine was largely correlated with resistance to AMPs. However, in L. monocytogenes, where WTA modification is achieved solely via glycosylation, WTA-associated mechanisms of AMP resistance were unknown. Here, we show that the L-rhamnosylation of L. monocytogenes WTAs relies not only on the rmlACBD locus, which encodes the biosynthetic pathway for L-rhamnose, but also on rmlT encoding a putative rhamnosyltransferase. We demonstrate that this WTA tailoring mechanism promotes resistance to AMPs, unveiling a novel link between WTA glycosylation and bacterial resistance to host defense peptides. Using in vitro binding assays, fluorescence-based techniques and electron microscopy, we show that the presence of L-rhamnosylated WTAs at the surface of L. monocytogenes delays the crossing of the cell wall by AMPs and postpones their contact with the listerial membrane. We propose that WTA L rhamnosylation promotes L. monocytogenes survival by decreasing the cell wall permeability to AMPs, thus hindering their access and detrimental interaction with the plasma membrane. Strikingly, we reveal a key contribution of WTA L rhamnosylation for L. monocytogenes virulence in a mouse model of infection. PMID- 26001196 TI - Relationship between Spinal Cord Volume and Spinal Cord Injury due to Spinal Shortening. AB - Vertebral column resection is associated with a risk of spinal cord injury. In the present study, using a goat model, we aimed to investigate the relationship between changes in spinal cord volume and spinal cord injury due to spinal shortening, and to quantify the spinal cord volume per 1-mm height in order to clarify a safe limit for shortening. Vertebral column resection was performed at T10 in 10 goats. The spinal cord was shortened until the somatosensory-evoked potential was decreased by 50% from the baseline amplitude or delayed by 10% relative to the baseline peak latency. A wake-up test was performed, and the goats were observed for two days postoperatively. Magnetic resonance imaging was used to measure the spinal cord volume, T10 height, disc height, osteotomy segment height, and spinal segment height pre- and postoperatively. Two of the 10 goats were excluded, and hence, only data from eight goats were analyzed. The somatosensory-evoked potential of these eight goats demonstrated meaningful changes. With regard to neurologic function, five and three goats were classified as Tarlov grades 5 and 4 at two days postoperatively. The mean shortening distance was 23.6 +/- 1.51 mm, which correlated with the d-value (post-pre) of the spinal cord volume per 1-mm height of the osteotomy segment (r = 0.95, p < 0.001) and with the height of the T10 body (r = 0.79, p = 0.02). The mean d-value (post-pre) of the spinal cord volume per 1-mm height of the osteotomy segment was 142.87 +/- 0.59 mm3 (range, 142.19-143.67 mm3). The limit for shortening was approximately 106% of the vertebral height. The mean volumes of the osteotomy and spinal segments did not significantly change after surgery (t = 0.310, p = 0.765 and t = 1.241, p = 0.255, respectively). Thus, our results indicate that the safe limit for shortening can be calculated using the change in spinal cord volume per 1-mm height. PMID- 26001198 TI - Simultaneous Improvement of Hole and Electron Injection in Organic Field-effect Transistors by Conjugated Polymer-wrapped Carbon Nanotube Interlayers. AB - Efficient charge injection is critical for flexible organic electronic devices such as organic light-emitting diodes (OLEDs) and field-effect transistors (OFETs). Here, we investigated conjugated polymer-wrapped semiconducting single walled carbon nanotubes (s-SWNTs) as solution-processable charge-injection layers in ambipolar organic field-effect transistors with poly(thienylenevinylene-co phthalimide)s. The interlayers were prepared using poly(9,9-di-n-octylfluorene alt-benzothiadiazole) (F8BT) or poly(9,9-dioctylfluorene) (PFO) to wrap s-SWNTs. In the contact-limited ambipolar OFETs, the interlayer led to significantly lower contact resistance (Rc) and increased mobilities for both holes and electrons. The resulting PTVPhI-Eh OFETs with PFO-wrapped s-SWNT interlayers showed very well-balanced ambipolar transport properties with a hole mobility of 0.5 cm(2)V( 1)S(-1) and an electron mobility of 0.5 cm(2)V(-1)S(-1) in linear regime. In addition, the chirality of s-SWNTs and kind of wrapping of conjugated polymers are not critical to improving charge-injection properties. We found that the improvements caused by the interlayer were due to the better charge injection at the metal/organic semiconductor contact interface and the increase in the charge concentration through a detailed examination of charge transport with low temperature measurements. Finally, we successfully demonstrated complementary ambipolar inverters incorporating the interlayers without excessive patterning. PMID- 26001197 TI - Analysis of Human RSV Immunity at the Molecular Level: Learning from the Past and Present. AB - Human RSV is one of the most prevalent viral pathogens of early childhood for which no vaccine is available. Herein we provide an analysis of RSV epitope data to examine its application to vaccine design and development. Our objective was to provide an overview of antigenic coverage, identify critical antibody and T cell determinants, and then analyze the cumulative RSV epitope data from the standpoint of functional responses using a combinational approach to characterize antigenic structure and epitope location. A review of the cumulative data revealed, not surprisingly, that the vast majority of epitopes have been defined for the two major surface antigens, F and G. Antibody and T cell determinants have been reported from multiple hosts, including those from human subjects following natural infection, however human data represent a minority of the data. A structural analysis of the major surface antigen, F, showed that the majority of epitopes defined for functional antibodies (neutralizing and/or protective) were either shown to bind pre-F or to be accessible in both pre- and post-F forms. This finding may have has implications for on-going vaccine design and development. These interpretations are in agreement with previous work and can be applied in the larger context of functional epitopes on the F protein. It is our hope that this work will provide the basis for further RSV-specific epitope discovery and investigation into the nature of antigen conformation in immunogenicity. PMID- 26001199 TI - Numerical study of acoustophoretic motion of particles in a PDMS microchannel driven by surface acoustic waves. AB - We present a numerical study of the acoustophoretic motion of particles suspended in a liquid-filled PDMS microchannel on a lithium niobate substrate acoustically driven by surface acoustic waves. We employ a perturbation approach where the flow variables are divided into first- and second-order fields. We use impedance boundary conditions to model the PDMS microchannel walls and we model the acoustic actuation by a displacement function from the literature based on a numerical study of piezoelectric actuation. Consistent with the type of actuation, the obtained first-order field is a horizontal standing wave that travels vertically from the actuated wall towards the upper PDMS wall. This is in contrast to what is observed in bulk acoustic wave devices. The first-order fields drive the acoustic streaming, as well as the time-averaged acoustic radiation force acting on suspended particles. We analyze the motion of suspended particles driven by the acoustic streaming drag and the radiation force. We examine a range of particle diameters to demonstrate the transition from streaming-drag-dominated acoustophoresis to radiation-force-dominated acoustophoresis. Finally, as an application of our numerical model, we demonstrate the capability to tune the position of the vertical pressure node along the channel width by tuning the phase difference between two incoming surface acoustic waves. PMID- 26001201 TI - Treatment of unruptured vertebral dissecting aneurysms: internal trapping or stent-assisted coiling. AB - PURPOSE: Endovascular treatment is an attractive approach for the treatment of unruptured vertebral dissecting aneurysms, and includes internal trapping and stent-assisted coil embolization. However, the optimal therapy remains debatable. We reviewed our experience with both endovascular treatment modalities and compared the safety, efficacy, and short-term outcomes for each approach. MATERIALS AND METHODS: We retrospectively reviewed 65 consecutive patients with unruptured vertebral dissecting aneurysms who underwent endovascular treatment between January 2003 and January 2014. 24 patients underwent endovascular internal trapping (group A) while 41 patients underwent stent-assisted coiling (group B). Thirteen patients underwent single stent with coiling while 28 patients underwent double or three stent-assisted coiling. Short-term outcomes were evaluated using the modified Rankin Scale. RESULTS: A favorable clinical outcome was achieved in 58 of 65 patients. Procedure-related complications included ischemic symptoms (n = 6) and recurrence (n = 4). There was no statistical difference in modified Rankin Scale scoring between groups. Group A patients had more ischemia symptoms compared with group B patients (p = 0.043), Group B patients had higher recurrence rates compared with group A patients, but the difference had no statistical significance (p = 1.00). However, recurrence only occurred in patients who underwent stent-assisted coiling alone (p = 0.046). CONCLUSION: Stent-assisted coiling for unruptured vertebral dissecting aneurysms may maintain artery patency. Multilayer disposition of stents with coils may decrease complications and facilitate aneurysm occlusion. Larger, prospective studies are necessary to determine the long-term outcomes of reconstructive therapy. PMID- 26001200 TI - Suppressor of Fused Is Required for Determining Digit Number and Identity via Gli3/Fgfs/Gremlin. AB - The anterior-posterior patterning of the vertebrate limb bud requires closely coordinated signaling interactions, including Sonic Hedgehog (Shh)-mediated counteraction of the Gli3 transcription factor in the distal and posterior mesenchyme of the limb bud. Suppressor of Fused (Sufu), an intracellular negative regulator of Shh signaling via Gli2 and Gli3, is implicated in early development of the mouse limb bud. However, how Sufu is involved in the genetic regulation of limb bud patterning still remains elusive. In this study, we show that the conditional deletion of Sufu in the mesenchyme of the early limb bud results in polydactyly with loss of digit identity and supernumerary bones in the wrist and the ankle. These pattern alterations are associated with anterior expansion of HoxD genes located at the 5' end of the cluster. By focusing on gene expression analysis of Shh/Gremlin1/Fgf signaling critical for the establishment and maintenance of anterior-posterior patterning, we show that early response to loss of Sufu involves anterior prolongation of Fgf4 and Fgf8 expression in the apical ectodermal ridge at E10.5. We also reveal the anterior activation of Shh dependent posterior markers Ptc1, Gli1 and Gremlin in limb buds lacking Sufu. Furthermore, we find that loss of Sufu leads to attenuated levels of repressor Gli2 and repressor Gli3 in the early limb bud. Moreover, expression of Hand2 is activated in the entire limb bud at the early outgrowth stage in the mutant lacking Sufu. Thus, we provide evidence that Sufu is involved in the genetic network that restricts the posterior expression of Gli2/3/Hand2 and Gremlin/Fgf in limb bud patterning. PMID- 26001202 TI - Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease. AB - AIM: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. METHODS: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale - Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale - Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. RESULTS: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. CONCLUSIONS: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired. PMID- 26001203 TI - Reducing the gap in neuroscience research between developed and developing countries. PMID- 26001204 TI - Elevated plasma CaM expression in patients with acute cerebral infarction predicts poor outcomes and is inversely associated with miR-26b expression. AB - BACKGROUND: Calcium overload plays an important role in ischemia/reperfusion injury during ischemic brain damage and is mediated by calmodulin (CaM). However, the understanding of the regulatory mechanisms of CaM expression at the gene level is limited. The expression levels of miR-26b change significantly during ACI, and bioinformatic analyses predict that miR-26b would be a potential regulator of calmodulin (CALM1) mRNA. This study aimed to determine the expression of miR-26b and CaM in the plasma of patients with ACI and investigate the impact of miR-26b on CALM1 expression. METHODS: CaM and miR-26b expression analyses from the plasma of patients with ACI and normal controls were performed using ELISA and qRT-PCR, respectively. Correlations between CaM, miR-26b, and NIHSS scores were analyzed. Then, miR-26b mimics and inhibitors were transfected into HUVE cell lines via lipofectamine. CALM1 mRNA expression in HUVECs was detected by RT-PCR, and the protein levels were detected by Western blot. RESULTS: Plasma CaM expression in patients with ACI was significantly higher when compared with normal controls, and miR-26b expression was significantly lower. The plasma levels of CaM and miR-26b were correlated with the NIHSS scores in ACI patients. miR-26b modulated CALM1 in vitro. The transfected miR-26b mimic and inhibitor significantly altered the expression of CALM1/CAM at the mRNA and protein levels in cultured HUVECs. CONCLUSIONS: CaM might be a potential novel blood marker in patients with ACI. miR-26b targeted CALM1 and affected the expression of CaM at the post-transcriptional level, which likely contributed to the progression of ACI brain injury. PMID- 26001205 TI - Association of uric acid with traditional inflammatory factors in stroke. AB - Uric acid (UA) plays an important role in the oxidant stress that causes inflammation. We assessed the association between UA and neutrophil ratio, white blood cell (WBC) count and blood lipid in 524 patients admitted with stroke. Stroke patients with a neutrophil ratio >70% displayed significantly lower UA levels than those with a neutrophil ratio <=70% (p < 0.05). According to UA quartiles, neutrophil ratio, WBC count, and high-density lipoprotein cholesterol in the UA grade 1 group (<=214.10 MUmol/L) were significantly increased over those in other UA grade groups. The results of stepwise regression analysis found that UA levels were inversely associated with neutrophil ratios (B +/- SE = -1.11 +/- 0.35), high-density lipoprotein cholesterol (B +/- SE = -46.18 +/- 14.17), total cholesterol (B +/- SE = 9.82 +/- 3.66), blood urea nitrogen (B +/- SE = 6.30 +/- 1.73), and creatinine (B +/- SE = 0.63 +/- 0.10). There is a correlationship between lower serum uric acid with neutrophil ratios in inflammation associated with stroke and the reasons need to be investigated further. PMID- 26001206 TI - The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-gamma) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta analysis. We found the effect of PPAR-gamma agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to moderate AD patients have been improved who were treated with PPAR-gamma agonists in our research. However, PPAR-gamma agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm. PMID- 26001207 TI - TNF-a (-238G/A and -308G/A) gene polymorphisms may not contribute to the risk of ischemic stroke. AB - BACKGROUND: The common and major pathological change in ischemic stroke is atherosclerosis in the artery. Tumor necrosis factor-a (TNF-a) is closely related to the pathogenesis of atherosclerosis. The aim of our study was to investigate whether TNF-a gene variants (-238G/A and -308G/A) are associated with ischemic stroke. METHODS: A total of 619 ischemic stroke patients and 612 controls were recruited to estimate the frequencies of two TNF-a (-238G/A and -308G/A) single nucleotide polymorphisms using a Sequenom MassARRAY time-of-flight mass spectrometer. The association between TNF-a gene polymorphisms and ischemic stroke risk was evaluated by computing the odds ratio (OR) and 95% Confidence Interval with multivariate unconditional logistic regression analyses. RESULTS: The OR results indicated that no significant associations were found between TNF a gene (-238G/A and -308G/A) polymorphisms and the risk of ischemic stroke using five genetic models, including the allele model (A vs. G), co-dominant model 1 (GA vs. GG), co-dominant model 2 (AA vs. GG), the dominant model (AA+GA vs. GG), and the recessive model (GG+GA vs. AA). CONCLUSIONS: The TNF-a (-238G/A and 308G/A) gene polymorphisms may not be a susceptible predictor of ischemic stroke in Chinese populations. PMID- 26001208 TI - Nicotine contributes to the neural stem cells fate against toxicity of microglial derived factors induced by Abeta via the Wnt/beta-catenin pathway. AB - Recent studies have demonstrated that the molecules secreted from microglias play important roles in the cell fate determination of neural stem cells (NSCs), and nicotinic acetylcholine receptor agonist treatment could reduce neuroinflammation in some neurodegenerative disease models, such as Alzheimer's disease (AD). However, it is not clear how nicotine plays a neuroprotective role in inflammation-mediated central nervous diseases, and its possible mechanisms in the process remain largely elusive. The aim of this study is to improve the survival microenvironment of NSCs co-cultured with microglias in vitro by weakening inflammation that mediated by accumulation of beta-amyloid peptide (Abeta). The viability, proliferation, differentiation, apoptosis of NSCs and underlying mechanisms associated with Wnt signaling pathway were investigated. The results showed that Abeta could directly damage NSCs. Furthermore, concomitant to elevated levels of TNF-alpha, IL-1beta derived from microglias, the NSCs had been damaged more severely with the upregulation of Axin 2, p-beta catenin and the downregulation of beta-catenin, p-GSK-3beta, microtubule associated protein-2, choline acetyltransferase. However, addition of 10 MUmol/L nicotine before microglias treated with Abeta was beneficial to protect the NSCs against neurotoxicity of microglial-derived factors induced by Abeta, which partially rescued proliferation, differentiation and inhibited apoptosis of NSCs via activation of Wnt/beta-catenin pathway. Taken together, these data imply that low concentration nicotine attenuates NSCs injury induced by microglial-derived factors via Wnt signaling pathway. Thus, treatment with nicotinic acetylcholine receptor agonist provides a promising research field for neural stem cell fate and therapeutic intervention in neuroinflammation diseases. PMID- 26001209 TI - A Multiscale Model Evaluates Screening for Neoplasia in Barrett's Esophagus. AB - Barrett's esophagus (BE) patients are routinely screened for high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) through endoscopic screening, during which multiple esophageal tissue samples are removed for histological analysis. We propose a computational method called the multistage clonal expansion for EAC (MSCE-EAC) screening model that is used for screening BE patients in silico to evaluate the effects of biopsy sampling, diagnostic sensitivity, and treatment on disease burden. Our framework seamlessly integrates relevant cell-level processes during EAC development with a spatial screening process to provide a clinically relevant model for detecting dysplastic and malignant clones within the crypt structured BE tissue. With this computational approach, we retain spatio-temporal information about small, unobserved tissue lesions in BE that may remain undetected during biopsy-based screening but could be detected with high resolution imaging. This allows evaluation of the efficacy and sensitivity of current screening protocols to detect neoplasia (dysplasia and early preclinical EAC) in the esophageal lining. We demonstrate the clinical utility of this model by predicting three important clinical outcomes: (1) the probability that small cancers are missed during biopsy-based screening, (2) the potential gains in neoplasia detection probabilities if screening occurred via high-resolution tomographic imaging, and (3) the efficacy of ablative treatments that result in the curative depletion of metaplastic and neoplastic cell populations in BE in terms of the long-term impact on reducing EAC incidence. PMID- 26001210 TI - Effect of interface shape on advancing and receding fluid-contact angles around spherical particles. AB - The angle of contact between a solid surface and a fluid interface plays a key role in wetting and is therefore a focus in studies of a wide range of natural phenomena and fluidic technologies. The contact angle ranges between two values, a maximum (advancing) angle and a minimum (receding) angle. These limiting angles are thought to be properties of the fluids and of the chemistry or topography of the solid. By contrast, we find that the value of the receding angle can be significantly reduced by altering the interface shape. Using millimeter-sized spheres coated with polydimethylsiloxane and pulled through an air-water interface, we observe that the receding angle decreases from 101 +/- 1 degrees at a planar interface to as low as 80 +/- 1 degrees at saddle- or cylinder shaped interfaces. The angle decreases smoothly with the deviatoric curvature of the interface (a measure of the shape anisotropy) and is linked to a non-circular contact line. PMID- 26001211 TI - Synthesis of Alkenylphosphonates through Palladium-Catalyzed Coupling of alpha Diazo Phosphonates with Benzyl or Allyl Halides. AB - An efficient method for the synthesis of organophosphonates through palladium catalyzed coupling of alpha-diazo phosphonates with benzyl or allyl halides has been developed. Trisubstituted alkenylphosphonates bearing versatile functional groups can be easily accessed in good yields and with excellent stereoselectivity through this method. Moreover, with similar strategy alpha-substituted vinylphosphonates can also be attained by the palladium-catalyzed coupling reaction of N-tosylhydrazones and aryl bromides. Migratory insertion of palladium carbene is proposed as the key step in this reaction. PMID- 26001212 TI - A novel shell-like supramolecular assembly of 4,4'-bipyridyl derivatives and a twisted cucurbit[14]uril molecule. AB - This work showed that the 4,4'-bipyridyl group and alkyl chains of 4,4'-bipyridyl derivatives are completely located in the shell-like cavity of the twisted cucurbit[14]uril molecule and formed novel shell-like 1 : 1 inclusion complexes. As it is enthalpy-driven the complexation benefits from ion-dipole interactions. PMID- 26001213 TI - Gd(3+) Spin Labels Report the Conformation and Solvent Accessibility of Solution and Vesicle-Bound Melittin. AB - Although Gd(3+)-based spin labels have been shown to be an alternative to nitroxides for double electron-electron resonance (DEER) distance measurements at high fields, their ability to provide solvent accessibility information, as nitroxides do, has not been explored. In addition, the effect of the label type on the measured distance distribution has not been sufficiently characterized. In this work, we extended the applicability of Gd(3+) spin labels to solvent accessibility measurements on a peptide in model membranes, namely, large unilamellar vesicles (LUVs) using W-band (2)H Mims electron-nuclear double resonance (ENDOR) and electron spin echo envelope modulation (ESEEM) techniques and Gd(3+)-ADO3A-labeled melittin. In addition, we carried out Gd(3+)-Gd(3+) DEER distance measurements to probe the peptide conformation in solution and when bound to LUVs. A comparison with earlier results reported for the same system with nitroxide labels shows that, although in both cases the peptide binds parallel to the membrane surface, the Gd(3+)-ADO3A label tends to protrude from the membrane into the solvent, whereas the nitroxide does the opposite. This can be explained on the basis of the hydrophilicity of the Gd(3+)-ADO3A labels in contrast with the hydrophobicity of nitroxides. The distance distributions obtained from different labels are accordingly different, with the Gd(3+)-ADO3A yielding consistently broader distributions. These discrepancies are most pronounced when the peptide termini are labeled, which implies that such labeling positions may be inadvisible. PMID- 26001214 TI - Supervised and dynamic neuro-fuzzy systems to classify physiological responses in robot-assisted neurorehabilitation. AB - This paper presents the application of an Adaptive Resonance Theory (ART) based on neural networks combined with Fuzzy Logic systems to classify physiological reactions of subjects performing robot-assisted rehabilitation therapies. First, the theoretical background of a neuro-fuzzy classifier called S-dFasArt is presented. Then, the methodology and experimental protocols to perform a robot assisted neurorehabilitation task are described. Our results show that the combination of the dynamic nature of S-dFasArt classifier with a supervisory module are very robust and suggest that this methodology could be very useful to take into account emotional states in robot-assisted environments and help to enhance and better understand human-robot interactions. PMID- 26001215 TI - Multinuclear Solid-State NMR and DFT Studies on Phosphanido-Bridged Diplatinum Complexes. AB - Multinuclear ((31)P, (195)Pt, (19)F) solid-state NMR experiments on (nBu4N)2[(C6F5)2Pt(MU-PPh2)2Pt(C6F5)2] (1), [(C6F5)2Pt(MU-PPh2)2Pt(C6F5)2](Pt-Pt) (2), and cis-Pt(C6F5)2(PHPh2)2 (3) were carried out under cross polarization/magic-angle-spinning conditions or with the cross-polarization/Carr Purcell Meiboom-Gill pulse sequence. Analysis of the principal components of the (31)P and (195)Pt chemical shift (CS) tensors of 1 and 2 reveals that the variations observed comparing the isotropic chemical shifts of 1 and 2, commonly referred to as "ring effect", are mainly due to changes in the principal components oriented along the direction perpendicular to the Pt2P2 plane. DFT calculations of (31)P and (195)Pt CS tensors confirmed the tensor orientation proposed from experimental data and symmetry arguments and revealed that the different values of the isotropic shieldings stem from differences in the paramagnetic and spin-orbit contributions. PMID- 26001216 TI - High rate and durable, binder free anode based on silicon loaded MoO3 nanoplatelets. AB - In order to make fast-charging batteries a reality for electric vehicles, durable, more energy dense and high-current density resistant anodes need to be developed. With such purpose, a low lithiation potential of 0.2 V vs. Li/Li(+) for MoO3 nanoplatelet arrays is reported here for anodes in a lithium ion battery. The composite material here presented affords elevated charge capacity while at the same time withstands rapid cycling for longer periods of time. Li2MoO4 and Li(1.333)Mo(0.666)O2 were identified as the products of lithiation of pristine MoO3 nanoplatelets and silicon-decorated MoO3, respectively, accounting for lower than previously reported lithiation potentials. MoO3 nanoplatelet arrays were deposited using hot-wire chemical vapor deposition. Due to excellent voltage compatibility, composite lithium ion battery anodes comprising molybdenum oxide nanoplatelets decorated with silicon nanoparticles (0.3% by wt.) were prepared using an ultrasonic spray. Silicon decorated MoO3 nanoplatelets exhibited enhanced capacity of 1037 mAh g(-1) with exceptional cyclability when charged/discharged at high current densities of 10 A g(-1). PMID- 26001217 TI - Chaperone-like protein p32 regulates ULK1 stability and autophagy. AB - Mitophagy mediates clearance of dysfunctional mitochondria, and represents one type of mitochondrial quality control, which is essential for optimal mitochondrial bioenergetics. p32, a chaperone-like protein, is crucial for maintaining mitochondrial membrane potential and oxidative phosphorylation. However, the relationship between p32 and mitochondrial homeostasis has not been addressed. Here, we identified p32 as a key regulator of ULK1 stability by forming complex with ULK1. p32 depletion potentiated K48-linked but impaired K63 linked polyubiquitination of ULK1, leading to proteasome-mediated degradation of ULK1. As a result, silencing p32 profoundly impaired starvation-induced autophagic flux and the clearance of damaged mitochondria caused by mitochondrial uncoupler. Importantly, restoring ULK1 expression in p32-depleted cells rescued autophagy and mitophagy defects. Our findings highlight a cytoprotective role of p32 under starvation conditions by regulating ULK1 stability, and uncover a crucial role of the p32-ULK1-autophagy axis in coordinating stress response, cell survival and mitochondrial homeostasis.Cell Death and Differentiation advance online publication, 24 April 2015; doi:10.1038/cdd.2015.34. PMID- 26001218 TI - Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity. AB - The AMP-activated protein kinase, a key regulator of energy homeostasis, has a critical role in metabolic disorders and cancers. AMPK is mainly regulated by cellular AMP and phosphorylation by upstream kinases. Here, we show that PIKE-A binds to AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. PIKE-A directly interacts with AMPK catalytic alpha subunit and impairs T172 phosphorylation, leading to repression of its kinase activity on the downstream targets. Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK. Cell proliferation and oncogenic assays demonstrate that PIKE-A antagonizes tumor suppressive actions of AMPK. In human glioblastoma samples, PIKE-A expression inversely correlates with the p-AMPK levels, supporting that PIKE-A negatively regulates AMPK activity in cancers. Thus, our findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression. PMID- 26001220 TI - Submission to Publication in AJR: Do We Need a New Approach? PMID- 26001219 TI - Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner. AB - Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD(+)) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD(+) promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD(+)-dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD(+) does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors. PMID- 26001221 TI - Anaphylactoid reactions to the nonvascular administration of water-soluble iodinated contrast media. AB - OBJECTIVE: Anaphylactoidlike reactions occur during the nonvascular administration of iodinated contrast media. Many of these reactions have been severe. These reactions have occurred with many procedures, including gastrointestinal imaging, cystography, sialography, and hysterosalpingography. CONCLUSION: This article reviews reports of these reactions. It also reviews what the literature recommends concerning how to deal with individuals undergoing these procedures who are at a higher risk for anaphylactoidlike reactions. PMID- 26001222 TI - Incidence of CT Contrast Agent-Induced Nephropathy: Toward a More Accurate Estimation. AB - OBJECTIVE: Acute kidney injury is common among hospitalized patients and likely leads to inflated reports of the incidence of CT contrast agent-induced nephropathy as a cause of acute kidney injury. For a more accurate estimation, we compared the incidence of acute kidney injury immediately after contrast agent administration and a few days afterward in the same population. We also controlled for a creatinine level increase starting before and continuing after CT, which may be incorrectly associated with the scan itself. MATERIALS AND METHODS: After excluding patients undergoing dialysis, we included all adults who underwent CT from January 2006 through May 2013 in our health region. The incidence of acute kidney injury (Acute Kidney Injury Network stages) and dialysis after acute kidney injury were assessed in the immediate period (24-48 hours) and in a delayed period (72-96 hours) after the scan. New acute kidney injury in either period occurred if the creatinine level had increased at a greater rate than that in a preceding 24-hour interval. The incidence of acute kidney injury and dialysis after acute kidney injury attributable to CT were calculated by subtracting the delayed incidence from the immediate incidence. RESULTS: Incidences of acute kidney injury and dialysis after acute kidney injury attributable to contrast-enhanced CT were statistically insignificant across glomerular filtration rate (GFR) subgroups. Acute kidney injury incidences (Acute Kidney Injury Network stage I or worse) were 0.5% (95% CI, -0.4% to 1.4%) for GFR greater than 60 mL/min/1.73 m(2), 2.4% (95% CI, -0.7% to 5.6%) for GFR 30-59 mL/min/1.73 m(2), -4.3% (95% CI, -19.8% to 11.3%) for GFR 15-29 mL/min/1.73 m(2), and 0% (95% CI, -24.5% to 24.5%) for GFR less than 15 mL/min/1.73 m(2). CONCLUSION: There appears to be a minimal risk of CT contrast agent-induced nephropathy at mild to moderate levels of renal dysfunction. PMID- 26001223 TI - Metrics for Original Research Articles in the AJR: From First Submission to Final Publication. AB - OBJECTIVE: The objective of our study was to evaluate manuscript metrics pertaining to AJR submissions, assessing the pathway from manuscript submission to publication, including the reviewer allocation time, decisions rendered, timing of decisions rendered, and time to publication. MATERIALS AND METHODS: Six hundred ninety-six unsolicited Original Research manuscripts submitted to the AJR between July 1, 2012, and December 21, 2012, were included in this retrospective analysis. Metrics pertaining to manuscripts' decision status and associated timelines were extracted by journal editorial staff and assessed using standard summary statistics. RESULTS: For new submissions, decisions rendered were as follows: Accept, 0.3%; Minor Revision, 8.5%; Major Revision, 19.7%; Reject, 65.1%; and Reject Without Review, 6.5%. For first and second resubmissions, 40.0 55.2% of manuscripts representing a Major Revision and 91.5-94.7% of manuscripts representing a Minor Revision were accepted; 100% of manuscripts undergoing a third resubmission were accepted; 98.3% and 84.7% of manuscripts receiving at first submission a decision of Minor Revision and Major Revision, respectively, ultimately achieved acceptance. The time (mean +/- SD) to review a new submission was 30.5 +/- 43.1 days (Accept), 42.7 +/- 27.4 days (Minor Revision), 39.4 +/- 17.6 days (Major Revision), and 40.2 +/- 20.3 days (Reject) and decreased with each subsequent resubmission to 6.3 +/- 6.3 days (Accept) for third resubmissions. The mean days for authors to submit a first resubmission was 21.1 +/- 15.3 days (Minor Revision) and 73.7 +/- 65.1 days (Major Revision) and decreased with each subsequent resubmission to 9.8 +/- 11.3 days (Minor Revision) and 27.0 +/- 0.0 days (Major Revision) for third resubmissions. The mean time from acceptance to publication was 242.5 +/- 47.5 days. CONCLUSION: The observed metrics may provide valuable insights for authors and for AJR editorial staff in ongoing efforts to shorten turnaround times from manuscript submission to publication. PMID- 26001224 TI - Extraurinary Incidental Findings on CT for Hematuria: The Radiologist's Role and Downstream Cost Analysis. AB - OBJECTIVE: The purposes of this study of patients who underwent CT for hematuria were to understand how radiologists' recommendations regarding incidental findings affect their management, assess long-term outcomes from important incidental findings, and calculate estimates of downstream costs. MATERIALS AND METHODS: A retrospective analysis was performed of 1295 patients who underwent CT for hematuria from 2004 to 2006 at our institution. Incidental findings outside the urinary tract were recorded and imaging reports categorized on the basis of recommendations, interpretations, and actions of radiologists. Patients with important incidental findings were followed for 6-8 years. Costs related to incidental findings were estimated and tallied. RESULTS: Two hundred fourteen important findings were found in 143 of 1295 patients, with 93 patients undergoing clinical follow-up, including 30 patients who underwent invasive procedures leading to 154 hospital days and 16 operations (group 1). In 63 patients, no invasive procedures were performed (group 2). Costs were higher in group 1 than in group 2, and the average per-patient cost for all 1295 patients was $385. In group 1, 95% of recommendations were followed compared with 80% in group 2. There was probable therapeutic benefit in 25 of 143 (17%) patients. There were serious complications in six of 143 (4.2%) patients, including death in two of 143 (1.4%). CONCLUSION: Radiologists' recommendations were generally followed for important incidental findings. These recommendations can direct the most cost-efficient and effective care for incidental findings. Although some patients with incidental findings had probable benefit, others incurred morbidity or mortality. A small number of invasive procedures resulted in substantial costs in this symptomatic population. Costs averaged over the entire population were higher than have been previously reported. PMID- 26001225 TI - JOURNAL CLUB: Incidence of Urinary Leak and Diagnostic Yield of Excretory Phase CT in the Setting of Renal Trauma. AB - OBJECTIVE: The purpose of this article is to calculate the incidence of urinary leak, at both admission and delayed presentation, in the setting of blunt or penetrating renal trauma, and to determine the diagnostic yield of 5-minute excretory phase images on admission CT. MATERIALS AND METHODS: Renal injuries were retrospectively identified from the trauma registry at an urban level I trauma center over a 6-year period. Follow-up imaging and clinical and surgical notes were reviewed and served as the aggregate reference standard. The total incidence of urinary leak, diagnostic yield of 5-minute-delayed admission CT scan, and the incidence of missed urinary leak not identified on admission 5 minute-delayed scan were calculated. RESULTS: There were a total of 431 renal injuries in 413 patients, of whom 201 patients (48.7%, including 60.8% of patients with grade IV or V injuries) underwent delayed phase imaging at admission, yielding 25 patients with 26 urinary leaks (all grade IV or V injuries). The incidence of urinary leak in grade IV or V injuries was 26.8%. One patient had a delayed diagnosis of urinary leak 36 hours after the initial CT scan, which did not show a urinary leak (0.23% of the total, or 1.0% of all high grade renal injuries). CONCLUSION: The incidence of urinary leak after blunt or penetrating renal trauma was 6.1% and was seen in 26.8% of grade IV and V injuries. Admission excretory phase CT identified urinary leaks in 96% of patients. The incidence of delayed diagnosis of urinary leak is low. PMID- 26001226 TI - Approach to Very Small (< 1.5 cm) Cystic Renal Lesions: Ignore, Observe, or Treat? AB - OBJECTIVE: This article will review the current available literature on the prevalence, behavior, and pathology of very small (< 1.5 cm) cystic renal lesions. A summary of the recommended approach to these very small lesions is provided. CONCLUSION: Limited data exist to guide the management of very small cystic renal lesions. Because most data favor benign or indolent behavior, vigorous workup of the very small cystic renal lesion seems unnecessary. PMID- 26001227 TI - Evolving Early Lung Cancers Detected During Follow-Up of Idiopathic Interstitial Pneumonia: Serial CT Features. AB - OBJECTIVE: The purpose of this study was to evaluate the CT characteristics of newly developed lung cancer on CT studies obtained during follow-up of idiopathic interstitial pneumonia (IIP) before the appearance of identifiable tumors to the time of detectable lung cancer and thereafter. MATERIALS AND METHODS: The study sample included 66 cancers diagnosed in 63 patients with IIP and lung cancer (59 men, four women; median age, 64 years; range, 40-85 years) between October 1998 and July 2012. Two radiologists independently reviewed 193 CT scans, determined the earliest presence of cancer and IIP, and evaluated tumor size, lobar and axial location, shape, and tumor density. Delay in clinical diagnosis and doubling time were measured with first and second follow-up CT examinations. RESULTS: Interobserver agreement was good (kappa > 0.77). The median tumor size was 17 mm (range, 5-30 mm) for the 46 T1a and 20 T1b cancers. Most of the tumors (42 [63.6%]) were located in the lower lobes. Thirty-five tumors (53.0%) were at the interface between fibrotic cyst and normal lung, and 21 (31.8%) were in the midst of fibrotic lung cysts. Most of the tumors had a round or oval shape (52 [78.8%]) and were solid (62 [93.9%]). The median delay in diagnosis was 46 days (range, 8-760 days). The first median doubling time was 77 days (range, 15-525 days), and the second was 53 days (27-248). CONCLUSION: New lung cancers during CT follow-up of IIP usually appear as small solid nodules with a round or oval shape. Most cancers are located at the interface between fibrotic cyst and normal lung or in the midst of fibrotic cysts of the lower lobes of subpleural lung. PMID- 26001229 TI - Pulmonary Toxocariasis: Initial and Follow-Up CT Findings in 63 Patients. AB - OBJECTIVE: The objective of our study was to describe the characteristic radiologic findings of pulmonary toxocariasis on initial and follow-up chest CT. MATERIALS AND METHODS: Between June 2010 and May 2014, 63 patients with serologically proven, clinically diagnosed pulmonary toxocariasis and chest CT examinations performed within 2 months of an enzyme-linked immunosorbent assay for toxocariasis were identified. Two chest radiologists retrospectively analyzed the chest CT examinations in consensus; they focused on the distribution, location, number, and internal characteristics of the pulmonary lesions. RESULTS: The pulmonary lesions tended to involve three or more lobes (49% [31/63]) on the initial CT; predominance of the abnormalities in a subpleural location (81% [51/63]) and in the lower lung zone (98% [62/63]) was noted. The number of pulmonary lesions per patient were from two to five (46% [29/63]), more than five (32% [20/63]), or one (22% [14/63]). The radiologic findings of pulmonary toxocariasis could be categorized into four different patterns: ground-glass opacities (GGOs), solid nodules, consolidations, and linear opacities. The most common pattern was ill-defined GGOs with or without solid portions (84% [53/63]). The solid nodule and patchy consolidation patterns were found in 29% (18/63) and 21% (13/63) of patients, respectively. In addition, linear opacities (1-2 mm thick and 8-25 mm long) were present in 19% of patients (12/63); this finding is a subtle, yet novel, finding. On follow-up CT, the pulmonary lesions had either disappeared or migrated; when they had migrated, they revealed radiologic manifestations similar to the findings on the initial CT. CONCLUSION: Pulmonary toxocariasis manifested as multiple lesions in four radiologic patterns with subpleural and lower lung predominance on initial and follow-up CT. A linear opacity may be one of many clues in the diagnosis of pulmonary toxocariasis on CT. PMID- 26001228 TI - Ultra-Low-Dose CT of the Thorax Using Iterative Reconstruction: Evaluation of Image Quality and Radiation Dose Reduction. AB - OBJECTIVE: The purpose of this study is to assess the image quality and radiation dose reduction of ultra-low-dose CT using sinogram-affirmed iterative reconstruction (SAFIRE). SUBJECTS AND METHODS: This prospective study enrolled 25 patients who underwent three consecutive unenhanced CT scans including low-dose CT (120 kVp and 30 mAs) and two ultra-low-dose CT protocols (protocol A, 100 kVp and 20 mAs; protocol B, 80 kVp and 30 mAs) with image reconstruction using SAFIRE. The image quality and radiation dose reduction were assessed. RESULTS: The mean (+/- SD) effective radiation dose was 1.06 +/- 0.11, 0.44 +/- 0.05, and 0.31 +/- 0.03 mSv for low-dose CT, ultra-low-dose CT protocol A, and ultra-low dose CT protocol B, respectively. Overall image quality was determined as diagnostic in 100% of low-dose CT scans, 96% of ultra-low-dose CT protocol A scans, and 88% of ultra-low-dose CT protocol B scans. All patients with nondiagnostic quality images had a body mass index (weight in kilograms divided by the square of height in meters) greater than 25. There was no statistically significant difference in detection frequencies of 14 lesion types among the three CT protocols, but pulmonary emphysema was detected in fewer patients (3/25) in ultra-low-dose CT protocol B scans compared with ultra-low-dose CT protocol A scans (5/25) or low-dose CT scans (6/25). We measured the longest dimensions of 33 small solid nodules (3.8-12.4 mm in long diameter) and found no statistically significant difference in the values afforded by the three CT protocols (p = 0.135). CONCLUSION: Iterative reconstruction allows ultra-low-dose CT and affords acceptable image quality, allowing size measurements of solid pulmonary nodules to be made. PMID- 26001231 TI - Transient respiratory motion artifact during arterial phase MRI with gadoxetate disodium: risk factor analyses. AB - OBJECTIVE: The purpose of this article is to identify risk factors for arterial phase respiratory motion artifact in gadoxetate disodium-enhanced liver MRI. MATERIALS AND METHODS: We retrospectively identified 220 consecutive patients who underwent 357 MRI examinations, including 68 patients who underwent multiple MRI examinations, with gadoxetate disodium between 2010 and 2013. The arterial phase timing was determined by a fluoroscopic-triggering method. T1-weighted unenhanced and contrast-enhanced images were reviewed to record respiratory motion artifact, which was graded on a 5-point scale. Arterial phase transient severe motion was considered to be present if the motion score was 4 or greater on the arterial phase images and if the motion scores were 2 or less on unenhanced and other contrast-enhanced images. Patient characteristics and risk factors (e.g., age, sex, weight, body mass index, medical and radiologic history, allergy to MRI and iodinated contrast agents, estimated glomerular filtration rate, Child-Pugh class, and findings on current MRI examinations) were recorded. We included a history of transient severe motion on prior MRI as a predictor variable. We performed univariable and multivariable analysis using the generalized estimated equations to adjust for clustering. RESULTS: The incidence of transient severe motion was 12.9% (46/357). On univariable analysis, a history of transient severe motion (odds ratio [OR] = 3.31; p = 0.04) on prior MRI and allergy to iodinated contrast agent (OR = 3.03; p = 0.01) statistically significantly increased the incidence of transient severe motion for a given MRI examination. These associations were not seen on multivariable analysis (adjusted OR = 2.38 and p = 0.23 for a history of transient severe motion; adjusted OR = 1.93 and p = 0.23 for allergy to CT contrast agent). CONCLUSION: The occurrence of transient severe motion during arterial phase MRI with gadoxetate disodium is 12.9% and is poorly predicted on the basis of risk factors. PMID- 26001230 TI - A novel reporting system to improve accuracy in appendicitis imaging. AB - OBJECTIVE: The purpose of this study was to ascertain if standardized radiologic reporting for appendicitis imaging increases diagnostic accuracy. MATERIALS AND METHODS: We developed a standardized appendicitis reporting system that includes objective imaging findings common in appendicitis and a certainty score ranging from 1 (definitely not appendicitis) through 5 (definitely appendicitis). Four radiologists retrospectively reviewed the preoperative CT scans of 96 appendectomy patients using our reporting system. The presence of appendicitis specific imaging findings and certainty scores were compared with final pathology. These comparisons were summarized using odds ratios (ORs) and the AUC. RESULTS: The appendix was visualized on CT in 89 patients, of whom 71 (80%) had pathologically proven appendicitis. Imaging findings associated with appendicitis included appendiceal diameter (odds ratio [OR] = 14 [> 10 vs < 6 mm]; p = 0.002), periappendiceal fat stranding (OR = 8.9; p < 0.001), and appendiceal mucosal hyperenhancement (OR = 8.7; p < 0.001). Of 35 patients whose initial clinical findings were reported as indeterminate, 28 (80%) had appendicitis. In this initially indeterminate group, using the standardized reporting system, radiologists assigned higher certainty scores (4 or 5) in 21 of the 28 patients with appendicitis (75%) and lower scores (1 or 2) in five of the seven patients without appendicitis (71%) (AUC = 0.90; p = 0.001). CONCLUSION: Standardized reporting and grading of objective imaging findings correlated well with postoperative pathology and may decrease the number of CT findings reported as indeterminate for appendicitis. Prospective evaluation of this reporting system on a cohort of patients with clinically suspected appendicitis is currently under way. PMID- 26001232 TI - Projected Effects of Radiation-Induced Cancers on Life Expectancy in Patients Undergoing CT Surveillance for Limited-Stage Hodgkin Lymphoma: A Markov Model. AB - OBJECTIVE: Patients with limited-stage Hodgkin lymphoma (HL) undergo frequent posttreatment surveillance CT examinations, raising concerns about the cumulative magnitude of radiation exposure. The purpose of this study was to project radiation-induced cancer risks relative to competing risks of HL and account for the differential timing of each. MATERIALS AND METHODS: We adapted a previously developed Markov model to project lifetime mortality risks and life expectancy losses due to HL versus radiation-induced cancers in HL patients undergoing surveillance CT. In the base case, we modeled 35-year-old men and women undergoing seven CT examinations of the chest, abdomen, and pelvis over 5 years. Radiation-induced cancer risks and deaths for 17 organ systems were modeled using an organ-specific approach, accounting for specific anatomy exposed at CT. Cohorts of 20-, 50-, and 65-year-old men and women were evaluated in secondary analyses. Markov chain Monte Carlo methods were used to estimate the uncertainty of radiation risk projections. RESULTS: For 35-year-old adults, we projected 3324/100,000 (men) and 3345/100,000 (women) deaths from recurrent lymphoma and 245/100,000 (men, 95% uncertainty interval [UI]: 121-369) and 317/100,000 (women, 95% UI: 202-432) radiation-induced cancer deaths. Discrepancies in life expectancy losses between HL (428 days in men, 482 days in women) and radiation induced cancers (11.6 days in men, [95% UI: 5.7-17.5], 15.6 days in women [95% UI: 9.8-21.4]) were proportionately greater because of the delayed timing of radiation-induced cancers relative to recurrent HL. Deaths and life expectancy losses from radiation-induced cancers were highest in the youngest cohorts. CONCLUSION: Given the low rate of radiation-induced cancer deaths associated with CT surveillance, modest CT benefits would justify its use in patients with limited-stage HL. PMID- 26001233 TI - Performance Evaluation of Material Decomposition With Rapid-Kilovoltage-Switching Dual-Energy CT and Implications for Assessing Bone Mineral Density. AB - OBJECTIVE: The purpose of this article is to quantitatively investigate the accuracy and performance of dual-energy CT (DECT) material density images and to calculate the areal bone mineral density (aBMD) for comparison with dual-energy x ray absorptiometry (DEXA). MATERIALS AND METHODS: A rapid-kilovoltage-switching DECT scanner was used to create material density images of various two-material phantoms of known concentrations under different experimental conditions. They were subsequently also scanned by single-energy CT and DEXA. The total uncertainty and accuracy of the DECT concentration measurements was quantified by the root-mean-square (RMS) error, and linear regression was performed to evaluate measurement changes under varying scanning conditions. Alterations to accuracy with concentric (anthropomorphic) phantom geometry were explored. The sensitivity of DECT and DEXA to changes in material density was evaluated. Correlations between DEXA and DECT-derived aBMD values were assessed. RESULTS: The RMS error of DECT concentration measurements in air ranged from 9% to 244% depending on the materials. Concentration measurements made off-isocenter or with a different DECT protocol were slightly lower (~ 5%), whereas measurement in scattering conditions resulted in a reduction of 8-27%. In concentric phantoms, higher-attenuating material in the outer chamber increased measured values of the inner material for all methods. DECT was more sensitive than DEXA to changes in BMD at 2 mg/mL K2HPO4. Measurements of aBMD using DECT and DEXA were highly correlated (R(2) = 0.98). CONCLUSION: DECT material density images were linear in response but prone to poor accuracy and biases. DECT-based aBMD could be used to monitor relative change in bone density. PMID- 26001234 TI - Pulmonary nodules with ground-glass opacity can be reliably measured with low dose techniques regardless of iterative reconstruction: results of a phantom study. AB - OBJECTIVE: Pulmonary nodules of ground-glass opacity represent one imaging manifestation of a slow-growing variant of lung cancer. The objective of this phantom study was to quantify the effect of the radiation dose used for the examination (volume CT dose index [CTDI(vol)]), type of reconstruction algorithm, and choice of postreconstruction enhancement algorithms on the measurement error when assessing the volume of simulated lung nodules with CT, focusing on two radiodensity levels. MATERIALS AND METHODS: Twelve synthetic nodules of two radiodensities (-630 and -10 HU), three shapes (spherical, lobulated, and spiculated), and two sizes (nominal diameters of 5 and 10 mm) were inserted into an anthropomorphic chest phantom and scanned with techniques varying in CTDI(vol) (from subscreening dose [0.8 mGy] to diagnostic levels [6.5 mGy]), reconstruction algorithms (iterative reconstruction and filtered back projection), and different postreconstruction enhancement algorithms. Nodule volume was measured from the resulting reconstructed CT images with a matched filter estimator. RESULTS: No significant over- or underestimation of nodule volume was observed across individual variables, with low percentage error overall (-1.4%) and for individual variables (range, -3.4% to 0.4%). The magnitude of percentage error was also low (overall average percentage error < 6% and SD values < 4.5%) and for individual variables (absolute percentage error range 3.3-5.6%). No clinically significant differences were observed between different levels of CTDI(vol), use of iterative reconstruction algorithms, or use of different postreconstruction enhancement algorithms. CONCLUSION: These results indicate that, if validated for other measurement tools and scanners, lung nodule volume measurements from scans acquired and reconstructed with significantly different acquisition and reconstruction techniques can be reliably compared. PMID- 26001235 TI - Optimal parameters and location for diffusion-tensor imaging in the diagnosis of carpal tunnel syndrome: a prospective matched case-control study. AB - OBJECTIVE: The purpose of this study was to determine the optimal parameters and location for diffusion-tensor imaging in the diagnosis of carpal tunnel syndrome. SUBJECTS AND METHODS: A single 3-T MRI (single-shot echo-planar imaging pulse sequence; b value, 1000 s/mm(2)) and nerve conduction study were performed prospectively for patients with carpal tunnel syndrome and age- and sex-matched control subjects. Fractional anisotropy, apparent diffusion coefficient, radial diffusivity, and parallel diffusivity of the median nerve were measured at the inlet, middle, and outlet of the carpal tunnel and were compared with the nerve conduction study parameters. RESULTS: A total of 50 patients with carpal tunnel syndrome and 50 control subjects were enrolled. Demographic data were comparable between the groups. For all three locations, mean fractional anisotropy increased significantly, and the mean radial diffusivity and apparent diffusion coefficient decreased significantly in carpal tunnel syndrome (p < 0.05). The carpal tunnel inlet had the largest and most consistent changes in diffusion-tensor imaging parameters. Fractional anisotropy measured at the carpal tunnel inlet had the highest diagnostic accuracy, as measured with ROC curves (AUC, 0.82). For a fractional anisotropy threshold of 0.44 or less at the carpal tunnel inlet, sensitivity was 72%; specificity, 82%; positive predictive value, 80%; and negative predictive value, 75%. CONCLUSION: The use of fractional anisotropy measured at the carpal tunnel inlet is optimal for diagnosing carpal tunnel syndrome. PMID- 26001236 TI - CT of Anatomic Variants of the Paranasal Sinuses and Nasal Cavity: Poor Correlation With Radiologically Significant Rhinosinusitis but Importance in Surgical Planning. AB - OBJECTIVE: The purpose of this study was to determine the incidence of sinonasal anatomic variants and to assess their relation to sinonasal mucosal disease. MATERIALS AND METHODS: A retrospective evaluation of 192 sinus CT examinations of patients with a clinical history of rhinosinusitis was conducted. The CT scans were evaluated for the presence of several anatomic variants of the sinonasal cavities, and the prevalence of each variant was calculated. Prevalences of all sinonasal anatomic variants were compared between patients who had minimal to no apparent imaging evidence of rhinosinusitis and those who had radiologic evidence of clinically significant rhinosinusitis. RESULTS: The most common normal variants were nasal septal deviation, Agger nasi cells, and extension of the sphenoid sinuses into the posterior nasal septum. We found no statistically significant difference in the prevalence of any of the studied anatomic variants between patients with minimal and those with clinically significant paranasal sinus or nasal cavity disease. CONCLUSION: Analysis of every routine CT scan of the paranasal sinuses obtained for sinusitis or rhinitis for the presence of different anatomic variants is of questionable value unless surgery is planned. PMID- 26001237 TI - Value of (18)F-FDG PET for Predicting Response to Neoadjuvant Therapy in Rectal Cancer: Systematic Review and Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to assess the predictive value of (18)F FDG PET/ CT for pathologic response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. MATERIALS AND METHODS: A systematic search was performed (PubMed and Cochrane databases) for potentially relevant studies up to January 2014. Pooled sensitivity and specificity were calculated. The AUCs of the global cohort and for "major response," "complete response," "only PET after chemoradiotherapy," "ad interim PET," "major response excluding ad interim studies," "complete response excluding ad interim studies," "response index (RI)," "posttreatment maximum standardized uptake value (SUV(max) post)," "visual response analysis (VRA)," "percentage reduction of the total lesion glycolysis (DeltaTLG)," and "percentage reduction of the metabolic tumor volume (DeltaMTV)" were analyzed. Heterogeneity was explored for multiple variables. Pooled prevalence and 95% CI were calculated. RESULTS: Thirty-four of 131 (26%) initial articles met the inclusion criteria. Those articles included 1526 patients. PET/CT showed good pooled accuracy both in the global cohort (pooled sensitivity, 73%; pooled specificity, 77%; pooled AUC, 0.83) and for subgroups. Pooled accuracy was similar for early PET restaging and at 1 and 2 weeks after beginning chemoradiotherapy (pooled sensitivity, 84%; pooled specificity, 81%; pooled AUC, 0.89). The major response group showed similar sensitivity to the complete response group (74% and 71%, respectively). RI, SUV(max), and VRA were the most frequent parameters used. Pooled RI and SUV(max) postcutoff values were 63% and 4.4. Pooled time to PET during and after chemoradiotherapy was 1.5 and 6.5 weeks, respectively. CONCLUSION: This meta-analysis supports the use of FDG PET for restaging locally advanced rectal cancer. PMID- 26001239 TI - Pulmonary embolism in children. AB - OBJECTIVE: Pediatric pulmonary thromboembolism (PE) has historically been considered a rare entity with relatively little published in the medical literature. The purpose of this article is to bridge some of the current knowledge gap regarding PE by presenting a comprehensive review of the topic, including discussion of its epidemiology, pathophysiology, clinical manifestations, nonimaging diagnostic examinations, imaging evaluation, treatment and prognosis, and future imaging research directions. CONCLUSION: Imaging plays a key role in the evaluation of pediatric PE, and imaging technology will continue to improve. CT will likely remain a first-line diagnostic modality with newer techniques such as dual-energy CT having the potential to become more widely used while improving sensitivity and specificity for small and distal PE. Alternatively, given its lack of ionizing radiation and high sensitivity and specificity when technically adequate, MRI is appealing and may become a viable first-line substitute to CT. PMID- 26001238 TI - Diffusion-weighted MRI in pediatric inflammatory bowel disease. AB - OBJECTIVE: Pediatric patients with inflammatory bowel disease (IBD) commonly need repetitive imaging to assess disease activity and complications. Recently, MR enterography has become a first-line radiologic study in children with IBD because of improved image quality, excellent soft-tissue contrast resolution, and lack of ionizing radiation. The purpose of this article is to describe the use of diffusion-weighted imaging (DWI) in MR enterography and the evaluation of pediatric IBD. CONCLUSION: Several contemporary publications have shown that DWI can be useful for assessing both pediatric and adult patients with IBD as an important adjunct pulse sequence. Specifically, DWI can be used to identify abnormal bowel segments, assess disease inflammatory activity, and detect and characterize a variety of extraintestinal IBD-related manifestations and complications. PMID- 26001240 TI - Septic arthritis in children: frequency of coexisting unsuspected osteomyelitis and implications on imaging work-up and management. AB - OBJECTIVE: Osteomyelitis and septic arthritis clinically present at any age with overlapping signs and symptoms. The purposes of this study were to evaluate the demographic distribution of septic arthritis and osteomyelitis in children and to explore optimal imaging guidelines for these patients. MATERIALS AND METHODS: We performed a retrospective study of children up to 18 years old who were treated for osteomyelitis or septic arthritis between January 2011 and September 2013. All patients underwent MRI without previous intervention. Studies were reviewed to determine the incidence of septic arthritis or superimposed osteomyelitis. The reference diagnosis was based on the combined review by the orthopedic surgeon and infectious disease notes, discharge summary, operative report, and MRI examination. RESULTS: One hundred sixty-two children who underwent 177 MRI examinations were diagnosed with acute musculoskeletal infection. One hundred three patients were included in the septic arthritis category, of whom 70 (68%) had septic arthritis with osteomyelitis. Seventy-four (42.1%) patients had isolated osteomyelitis without septic arthritis. Children under 2 years old were more likely to have septic arthritis (either isolated or with osteomyelitis) than isolated osteomyelitis compared with older children (p = 0.0003). CONCLUSION: In children who underwent MRI for suspected musculoskeletal infection, septic arthritis was more prevalent in children under the age of 2 years than in older children. However, both septic arthritis and osteomyelitis were found frequently in older children. Musculoskeletal infection imaging workup guidelines for children of all ages should address the frequent association of osteomyelitis and septic arthritis. We recommend that MRI should be used in the evaluation of suspected musculoskeletal infections in children, and the nearest joint should always be included to evaluate the extent of articular disease. PMID- 26001241 TI - Quantification of Bone Marrow Involvement in Treated Gaucher Disease With Proton MR Spectroscopy: Correlation With Bone Marrow MRI Scores and Clinical Status. AB - OBJECTIVE: The objective of our study was to use proton MR spectroscopy (MRS) to quantitatively evaluate bone marrow infiltration by measuring the fat fraction (FF) and to compare the FF with semiquantitative bone marrow MRI scores and clinical status in children treated for type 1 Gaucher disease (GD). SUBJECTS AND METHODS: Over a 2-year period, we prospectively evaluated 10 treated GD patients (six males, four females; median age, 15.1 years) and 10 healthy age-matched control subjects (five males, five females; median age, 15.3 years) using 3-T proton MRS of L5 and the femoral neck. Water and lipid AUCs were measured to calculate the FF. Two blinded pediatric musculoskeletal radiologists performed a semiquantitative analysis of the conventional MR images using the bone marrow burden score and modified Spanish MRI score. We evaluated symptoms, spleen and liver volumes, platelet levels, hemoglobin levels, and bone complications. RESULTS: In the femur, the FF was higher in the control subjects (median, 0.71) than the GD patients (0.54) (p = 0.02). In L5, the difference in FF--higher FF in control subjects (0.37) than in GD patients (0.26)--was not significant (p = 0.16). In both groups and both regions, the FF increased with patient age (p < 0.02). Semiquantitative scores showed no differences between control subjects and treated GD patients (p > 0.11). Eight of 10 GD patients were asymptomatic and two had chronic bone pain. The median age of patients at symptom onset was 4.0 years, the median age of patients at the initiation of enzyme replacement therapy was 4.3 years, and the median treatment duration was 10.2 years. Hemoglobin level, platelet count, and liver volume at MRI were normal. Mean pretreatment spleen volume (15.4-fold above normal) decreased to 2.8-fold above normal at the time of MRI (p = 0.01). CONCLUSION: Proton MRS detected FF differences that were undetectable using conventional MRI; for that reason, proton MRS can be used to optimize treatment of GD patients. PMID- 26001242 TI - Spontaneous soft-tissue hemorrhage in anticoagulated patients: safety and efficacy of embolization. AB - OBJECTIVE: The purpose of this study was to report the effectiveness and safety of selective arterial embolization for the management of anticoagulation-related soft-tissue bleeding. MATERIALS AND METHODS: All consecutive patients from June 1, 2003, to June 1, 2010, with intractable anticoagulation-related soft-tissue bleeding treated by embolization were included. The clinical files, MDCT angiographic examinations, and procedure details were reviewed. The primary goal of this study was to report the safety and efficacy of embolization for the management of anticoagulation-related soft-tissue bleeding. The secondary goal was to evaluate the correlation between the MDCT angiography (MDCTA) findings and conventional catheter angiography. RESULTS: Thirty-six consecutive patients were included. All patients were under anticoagulant therapy. Overdosage of the anticoagulant was found in 12 (33%) patients. MDCT was performed with multiphasic contrast media injection in 30 patients (83%) and showed extravasation in 22 (73.3%) of those 30 patients. Catheter angiography revealed extravasation in 27 of 36 (75%) patients, and no active bleeding was observed in nine patients who were empirically embolized. The sensitivity of MDCTA for depicting ongoing active bleeding was 87%. The transfusion requirement for RBC units decreased from 4.0 (range, 0-12.0) before to 0 (range, 0-4.0) after embolization. Nine patients underwent a second embolization but only one in the same vascular territory. Eleven patients died within 30 days despite the embolization. No complications related to embolization were reported. CONCLUSION: Anticoagulation-related soft tissue bleeding can be efficiently and safely treated by selective arterial embolization. However, this serious pathologic condition may be fatal in many cases, and rebleeding is not rare. MDCTA could help to guide treatment. PMID- 26001243 TI - MR Angiography at 3 T of Peripheral Arterial Disease: A Randomized Prospective Comparison of Gadoterate Meglumine and Gadobutrol. AB - OBJECTIVE: This large-scale randomized study aimed to show the noninferiority in terms of diagnostic performance of gadoterate meglumine-enhanced versus gadobutrol-enhanced 3-T MR angiography (MRA) using digital subtraction angiography (DSA) as the reference standard in patients with peripheral arterial occlusive disease (PAOD). SUBJECTS AND METHODS: In this prospective international randomized double-blind phase IV trial, 189 patients were enrolled. Of them, 156 could be included in the per-protocol population for on-site assessments and 154 for off-site readings. Subjects underwent peripheral MRA, after injection of 0.1 mmol/kg of either gadoterate meglumine or gadobutrol, and DSA within 30 days. The diagnostic accuracy was evaluated and compared using a noninferiority analysis. Secondary endpoints included sensitivity, specificity, diagnostic confidence, contrast-to-noise ratio, and signal-to-noise ratio evaluations. RESULTS: The percentage agreement between MRA and DSA for stenosis detection was similar for on-site readings for both groups (mean +/- SD, 80.6% +/- 16.1% with gadoterate meglumine vs 77.1% +/- 19.6% with gadobutrol; 3.5% difference), and the same was true for off-site readings (73.9% +/- 16.9% with gadoterate meglumine vs 75.1% +/ 13.8% with gadobutrol; 1.1% difference). The noninferiority of gadoterate meglumine to gadobutrol was shown for both on- and off-site readings. Sensitivity in detecting significant stenosis (> 50%) was 72.3% for gadoterate meglumine versus 70.6% for gadobutrol, whereas specificity (92.6% vs 92.3%), diagnostic confidence (87.0% vs 86.0%), signal-to-noise ratio (165.5 vs 161.0), and contrast to-noise ratio (159.5 vs 155.3) did not differ statistically significantly between the two groups. CONCLUSION: Gadoterate meglumine was found to be not inferior to gadobutrol in terms of diagnostic performance in patients with PAOD undergoing 3-T contrast-enhanced MRA. No statistically significant differences were detected between the two MRA groups. PMID- 26001244 TI - Chemoembolization of recurrent hepatoma after curative resection: prognostic factors. AB - OBJECTIVE: The long-term prognosis after hepatic resection for the treatment of hepatocellular carcinoma (HCC) has been disappointing because of the high recurrence rates in the remnant liver, which constitutes the major cause of death. The purpose of this study was to identify the prognostic factors for overall survival after transarterial chemoembolization (TACE) in recurrent HCC after the initial curative surgical resection. MATERIALS AND METHODS: From January 2003 through October 2012, 362 patients who developed recurrent HCC after initial surgical resection and underwent TACE as the first-line therapy were retrospectively studied at a single institution in our hospital. Patients who met our inclusion criteria were followed until December 2012. Prognostic factors for overall survival were analyzed. RESULTS: In total, 287 patients were enrolled. The median overall survival period was 747 days. The 1-, 2-, and 3-year overall survival rates after TACE were 72.9%, 51.8%, and 31.8%, respectively. Multivariate analysis indicated that the number of resected HCCs (>= 2, p < 0.001), the number (>= 2, p < 0.001) and size (> 5 cm, p = 0.022) of the recurrent HCCs, and the number of TACE sessions (<= 3, p < 0.001) are independent risk factors for poor survival after TACE for recurrent HCC after HCC resection. CONCLUSION: TACE appears to be an effective treatment of patients who experienced a recurrence after curative HCC resection. An initial solitary HCC, a solitary recurrence, and recurrent tumor mass 5 cm or smaller are statistically significant independent prognostic factors for survival. PMID- 26001245 TI - Intraductal Cooling via a Nasobiliary Tube During Radiofrequency Ablation of Central Liver Tumors Reduces Biliary Injuries. AB - OBJECTIVE: The objective of our study was to determine the safety and efficacy of intraductal perfusion of chilled 5% dextrose in water (D5W) via an endoscopic nasobiliary tube (NBT) for the prevention of thermal bile duct injury in patients undergoing percutaneous radiofrequency ablation (RFA) of central liver tumors. MATERIALS AND METHODS: We performed a retrospective study comparing outcomes of 32 consecutive patients who underwent percutaneous RFA of central liver tumors without intraductal perfusion of chilled D5W (control cohort) and 14 consecutive patients who underwent temporary intraductal perfusion of chilled D5W at 2 mL/s via endoscopic NBT placement before RFA (endoscopic NBT cohort). The primary and secondary outcomes were the rate of biliary complications and local tumor progression, respectively. RESULTS: All patients tolerated the procedures well. There was a significantly lower rate of biliary complications in the endoscopic NBT cohort (0/14 patients, 0%) than in the control cohort (10/32 patients, 31%) (p < 0.03) with a trend toward improved preservation of liver function in the endoscopic NBT cohort (12/14 patients, 86%) compared with the control cohort (20/32 patients, 62%) (p = 0.05). There was no difference in the rate of local tumor progression between the endoscopic NBT cohort (4/19 tumors, 21%) and the control cohort (9/39 tumors, 23%) (p = 1.0). CONCLUSION: Perfusion of chilled water through an endoscopic NBT helps prevent thermal biliary injury during RFA of central liver tumors without increasing rates of local tumor progression. PMID- 26001246 TI - "Do unto others as you would have them do unto you": breast imagers' perspectives regarding screening mammography for others and for themselves--do they practice what they preach? AB - OBJECTIVE: Our aim was to determine the screening recommendations that breast radiologists promote to average-risk patients and family or friends and do or would follow for themselves. MATERIALS AND METHODS: A survey of breast radiologists in the United States collected data regarding their personal and practice backgrounds, their recommendations to others for mammography and clinical and self-breast examination, and their personal screening habits based on respondent sex. The radiologists were divided into three cohorts: women 40 years old or older (group 1), women younger than 40 years (group 2), and men (group 3). The distribution of responses for each question was summarized, and proportions of total radiologists and cohorts were computed. RESULTS: Four hundred eighty-seven surveys were collected. None of the radiologists recommended biennial mammography for patients ages 50-74 years, 98% (477/487) recommended yearly mammography for patients 40 years old and older, and 99% (470/476) recommended yearly mammography for family and friends 40 years old and older. The most common reasons for variance were institutional policy or provider preferences. In group 1, 96% (191/198) have yearly mammography. In group 2, 100% (83/83) have or will have yearly mammography at age 40 years and beyond. In group 3, 97% (171/176) would have yearly mammography at age 40 years and beyond if they were women. Overall, 97% (445/457) of radiologists have or would have yearly mammography at age 40 years and beyond. CONCLUSION: Nearly all (98%) of the radiologists recommend yearly mammography for average-risk women 40 years old and older and were consistent in that they "practice what they preach." Because radiologists diagnose all stages of breast cancer, their personal convictions should influence providers, patients, and the public when considering the U.S. Preventive Services Task Force screening guidelines. PMID- 26001247 TI - Diagnostic workup and costs of a single supplemental molecular breast imaging screen of mammographically dense breasts. AB - OBJECTIVE: The purpose of this study was to examine additional diagnostic workup and costs generated by addition of a single molecular breast imaging (MBI) examination to screening mammography for women with dense breasts. SUBJECTS AND METHODS: Women with mammographically dense breasts presenting for screening mammography underwent adjunct MBI performed with 300 MBq (99m)Tc-sestamibi and a direct-conversion cadmium-zinc-telluride dual-head gamma camera. All subsequent imaging tests and biopsies were tracked for a minimum of 1 year. The positive predictive value of biopsies performed (PPV3), benign biopsy rate, cost per patient screened, and cost per cancer detected were determined. RESULTS: A total of 1651 women enrolled in the study. Among the 1585 participants with complete reference standard, screening mammography alone prompted diagnostic workup of 175 (11.0%) patients and biopsy of 20 (1.3%) and yielded five malignancies (PPV3, 25%). Results of combined screening mammography plus MBI prompted diagnostic workup of 279 patients (17.6%) and biopsy of 67 (4.2%) and yielded 19 malignancies (PPV3, 28.4%). The benign biopsy rates were 0.9% (15 of 1585) for screening mammography alone and 3.0% (48 of 1585) for the combination (p < 0.001). The addition of MBI increased the cost per patient screened from $176 for mammography alone to $571 for the combination. However, cost per cancer detected was lower for the combination ($47,597) than for mammography alone ($55,851). CONCLUSION: The addition of MBI to screening mammography of women with dense breasts increased the overall costs and benign biopsy rate but also increased the cancer detection rate, which resulted in a lower cost per cancer detected than with screening mammography alone. PMID- 26001249 TI - Corrections. PMID- 26001248 TI - Breast cancer molecular subtype as a predictor of the utility of preoperative MRI. AB - OBJECTIVE: The purpose of this study was to discern whether breast cancer molecular subtype, a known prognostic indicator, can be used to select patients with the highest likelihood of having clinically significant additional findings on breast MRI. MATERIALS AND METHODS: A database review from January 2010 through December 2013 identified 299 patients who underwent preoperative breast MRI with tumors classifiable into molecular subtypes. Subtypes were classified on the basis of immunohistochemical staining surrogates as luminal A (hormone receptor [ER or PR] positive, ERBB2 [formerly HER2 or HER2/neu] negative, luminal B (hormone receptor positive, ERBB2 positive), ERBB2 (hormone receptor negative, ERBB2 positive), or basal (hormone receptor and ERBB2 negative). Univariate and multivariate logistic regression analyses were used to determine the association between subtype and additional breast MRI findings, including multicentric or multifocal disease, contralateral disease, chest wall involvement, skin and nipple involvement, and internal mammary and axillary lymphadenopathy. RESULTS: The subtype distribution was luminal A, 70.6% (211/299); luminal B, 14.1% (42/299); ERBB2, 5.4% (16/299); and basal, 10.0% (30/299). ERBB2 and luminal B sub-types were more often associated with multicentric disease (25.0% and 26.2%), multifocal disease (37.5% and 35.7%), and axillary disease (50.0% and 45.2%) than were luminal A cancers (multicentric disease, 10.9%; multifocal disease 20.4%; axillary disease, 22.7%) (p < 0.001). In multivariate analysis, after control for patient age, tumor size, and nuclear grade, patients with ERBB2-overexpressing tumors were 2.4 times as likely as patients with luminal A tumors to have multicentric disease (p = 0.016), 2.0 times as likely to have multifocal disease (p = 0.024), 1.7 times as likely to have skin and nipple involvement (p = 0.013), and 1.9 times as likely to have axillary disease (p = 0.011). CONCLUSION: Preoperative MRI may most benefit patients with tumors with ERBB2 overexpression because of the increased likelihood of the presence of additional disease. PMID- 26001250 TI - Anatomy and pathology of the facial nerve. PMID- 26001251 TI - Hormonal therapy in oncology: a primer for the radiologist. AB - OBJECTIVE: The purpose of this article is to provide a comprehensive imaging review of the common hormonal therapies used in oncology and the side effects associated with them. CONCLUSION: Commonly used hormones in oncology include corticosteroids, somatostatin analogues, progestins, gonadotropin-releasing hormone agonists and antagonists, antiandrogens, aromatase inhibitors, and selective estrogen receptor modulators. Familiarity with these hormones and their side effects can help radiologists to be vigilant for the side effects and complications of these agents. PMID- 26001252 TI - Imaging of acute and emergent genitourinary conditions: what the radiologist needs to know. AB - OBJECTIVE: Acute and emergent genitourinary conditions require accurate and rapid diagnosis to minimize patient morbidity and mortality. CONCLUSION: Radiologists' familiarity with the various conditions of the urinary system and of the male and female reproductive organs is important given the widespread use of imaging for the diagnosis of common clinical entities presenting to the emergency department. PMID- 26001253 TI - Transcatheter structural cardiac intervention: a radiology perspective. AB - OBJECTIVE: Valvular heart disease continues to remain a significant cardiovascular problem worldwide. Imaging techniques, such as echocardiography, CT, and MRI have enabled development of newer transcatheter approaches for cardiovascular diseases. CONCLUSION: In this article, we discuss the commonly seen valvular diseases and various transcatheter valvular intervention techniques. We highlight the roles of CT and MRI in planning these procedures and discuss critical reporting information that needs to be conveyed to the interventionalists. PMID- 26001254 TI - High Spatiotemporal Resolution Dynamic Contrast-Enhanced MR Enterography in Crohn Disease Terminal Ileitis Using Continuous Golden-Angle Radial Sampling, Compressed Sensing, and Parallel Imaging. AB - OBJECTIVE: The purpose of this article was to assess the feasibility of golden angle radial acquisition with compress sensing reconstruction (Golden-angle RAdial Sparse Parallel [GRASP]) for acquiring high temporal resolution data for pharmacokinetic modeling while maintaining high image quality in patients with Crohn disease terminal ileitis. MATERIALS AND METHODS: Fourteen patients with biopsy-proven Crohn terminal ileitis were scanned using both contrast-enhanced GRASP and Cartesian breath-hold (volume-interpolated breath-hold examination [VIBE]) acquisitions. GRASP data were reconstructed with 2.4-second temporal resolution and fitted to the generalized kinetic model using an individualized arterial input function to derive the volume transfer coefficient (K(trans)) and interstitial volume (v(e)). Reconstructions, including data from the entire GRASP acquisition and Cartesian VIBE acquisitions, were rated for image quality, artifact, and detection of typical Crohn ileitis features. RESULTS: Inflamed loops of ileum had significantly higher K(trans) (3.36 +/- 2.49 vs 0.86 +/- 0.49 min(-1), p < 0.005) and v(e) (0.53 +/- 0.15 vs 0.20 +/- 0.11, p < 0.005) compared with normal bowel loops. There were no significant differences between GRASP and Cartesian VIBE for overall image quality (p = 0.180) or detection of Crohn ileitis features, although streak artifact was worse with the GRASP acquisition (p = 0.001). CONCLUSION: High temporal resolution data for pharmacokinetic modeling and high spatial resolution data for morphologic image analysis can be achieved in the same acquisition using GRASP. PMID- 26001255 TI - Prospective analysis of an interprofessional team training program using high fidelity simulation of contrast reactions. AB - OBJECTIVE: Successful management of a contrast reaction requires prompt recognition and treatment and effective team dynamics among radiologists, technologists, and nurses. A radiology department implemented a simulation program in which teams of nurses, technologists, and physicians managed simulated contrast reactions. The purpose of this study was to evaluate whether simulation improved the participants' abilities to manage a contrast reaction and work in a team during an emergency. SUBJECTS AND METHODS: Physicians, nurses, and technologists worked in inter-professional teams to manage two high-fidelity simulated adverse contrast reactions. Participants completed surveys before and after the simulation that included knowledge-based questions about the appropriate management of contrast reactions. Surveys also included questions for assessing participants' perceptions of their ability to manage adverse contrast reactions, measured with a 6-point Likert scale. Before and after comparisons were made with the McNemar test with a Bonferroni correction requiring p <= 0.003 for significance. For the other analyses, p <= 0.05 was considered significant. RESULTS: After completion of the simulation exercises, participants had significant improvement in knowledge (p < 0.001). After the simulation, participants reported significant improvement in their ability to manage an anaphylactoid reaction and their ability to work in a team (p < 0.00001). Participants requested repeat simulation exercises every 6-12 months. CONCLUSION: Simulation exercises improved the self-reported ability of radiology personnel to manage contrast reactions and work in a team during an emergency. Simulation should be incorporated into future educational initiatives to improve patient safety in radiology practices. PMID- 26001256 TI - CT Dose Reduction for Visceral Adipose Tissue Measurement: Effects of Model-Based and Adaptive Statistical Iterative Reconstructions and Filtered Back Projection. AB - OBJECTIVE: The objective of our study was to evaluate the effects of radiation dose reduction and the reconstruction algorithm used--filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), or model-based iterative reconstruction (MBIR)--on the measurement of abdominal visceral fat using CT. SUBJECTS AND METHODS: Standard-dose and low-dose abdominal CT examinations were performed simultaneously with automatic exposure control in 59 patients; the noise index for a 5-mm slice thickness was 12 for routine-dose CT and 24 for low-dose CT. The routine-dose CT images were reconstructed using FBP (reference standard), and the low-dose CT images were reconstructed using FBP, ASIR (so-called hybrid iterative reconstruction [IR]), and MBIR (so-called pure IR). In the 236 image series obtained, the visceral fat area was measured. Data were analyzed by the Pearson correlation coefficient test and a Bland-Altman difference analysis. RESULTS: The radiation dose of the low-dose abdominal CT examinations was 73.0% (mean) lower than that of routine-dose CT examinations. Excellent correlations were observed between the visceral fat areas measured on the routine-dose FBP images and those measured on the low-dose FBP, low-dose ASIR, and low-dose MBIR images (r = 0.998, 0.998, and 0.998, respectively; p < 0.001). A Bland-Altman difference analysis revealed excellent agreements, with mean biases of -0.47, -0.41, and 0.18 cm(2) for the visceral fat area between the routine-dose FBP images and the low-dose FBP, low-dose ASIR, and low-dose MBIR images, respectively. CONCLUSION: A 73.0% reduction of the radiation dose would be possible in CT for the measurement of the abdominal visceral fat regardless of which reconstruction algorithm is used (i.e., FBP, hybrid IR, or pure IR). PMID- 26001257 TI - MRI-Arthroscopy Correlation for Shoulder Anatomy and Pathology: A Teaching Guide. AB - OBJECTIVE: The objectives of the article are to improve the radiologist's understanding of shoulder arthroscopy and see how it correlates with MRI. We review the basic principles of arthroscopy followed by a comparison of its strengths and weaknesses relative to MRI. This discussion is supplemented by a series of cases that show the relationship between arthroscopy and MRI in terms of the visualization of normal and abnormal anatomy in the diagnosis of common shoulder abnormalities. CONCLUSION: By understanding what our orthopedic colleagues are seeing (and not seeing) during arthroscopic shoulder surgery, we can better understand the strengths and weaknesses of MRI, which provides us the opportunity to improve our imaging interpretations and produce valuable management-guiding diagnostic reports. PMID- 26001258 TI - T2* relaxation time of acetabular and femoral cartilage with and without intraarticular gadopentetate dimeglumine in patients with femoroacetabular impingement. AB - OBJECTIVE: The purpose of this study was to assess whether the presence of intraarticular gadopentetate dimeglumine during clinical MR arthrography significantly alters the T2* relaxation time of hip articular cartilage in patients with femoroacetabular impingement. SUBJECTS AND METHODS: T2* mapping of 10 patient volunteers (seven female patients, three male patients; age range, 14 49 years; mean, 33.0 +/- 12.2 [SD] years) with symptomatic femoroacetabular impingement was performed before and after intraarticular administration of gadopentetate dimeglumine. Overall 323 ROIs were defined in each acetabular and femoral cartilage before and after gadolinium injection. Agreement of the T2* relaxation times before and after gadolinium injection was assessed with the Krippendorff alpha coefficient and linear regression through the origin. RESULTS: T2* relaxation times before and after gadolinium injection in both acetabular and femoral cartilage were found to agree strongly. Specifically, estimated Krippendorff alpha values were greater than 0.8 for both acetabular and femoral cartilage, linear regressions through the origin yielded estimated slopes very close to 1, and R(2) values were greater than 0.98. CONCLUSION: The results indicate that intraarticular injection of gadopentetate dimeglumine according to the protocol described in this study has little effect on the T2* of femoral and acetabular cartilage. The results suggest that T2* mapping can be safely performed as an addition to a standard clinical hip imaging protocol that includes gadopentetate dimeglumine administration. PMID- 26001259 TI - Dose Reduction in Contrast-Enhanced Cervical MR Angiography: Field Strength Dependency of Vascular Signal Intensity, Contrast Administration, and Arteriographic Quality. AB - OBJECTIVE: Cervical contrast-enhanced MR angiography (MRA) has proven accurate and superior to noncontrast alternatives. We proposed the systematic investigation of dose reduction in contrast-enhanced MRA, hypothesizing heightened tolerance at 3 T vs 1.5 T. Quantitative and qualitative features were compared between full-dose and 50%-reduced dose examinations at 1.5 T and 3 T. MATERIALS AND METHODS: One hundred eight cervical contrast-enhanced MRA examinations were reviewed for qualitative and quantitative (signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]) features across four dose-field strength combinations: 1.5 T, 0.05 mmol/kg; 3 T, 0.05 mmol/kg; 1.5 T, 0.1 mmol/kg; and 3 T, 0.1 mmol/kg. Quantitative features were evaluated among the following segments: aortic arch, common carotid arteries, common carotid bifurcations, and cervical internal carotid arteries. A qualitative visual rating scale was applied for the same segments as well as to the vertebral arteries along their proximal (V1), intraforaminal (V2), and distal extraforaminal (V3) courses. Significant between-group differences were reported at p < 0.05. RESULTS: Qualitatively good arteriography was observed in all segments for all protocols. No significant qualitative differences between protocols were noted throughout evaluation of the anterior cervical circulation. Significant qualitative differences were observed only for V2 and V3 segments at half-dose 1.5-T compared with the remaining protocols (p < 0.05). No significant quantitative differences were present between full-dose and dose-reduced 3-T MRA in any segment. At 1.5 T, significant decrement in SNR and CNR at half-dose was present only within the cervical internal carotid artery. CONCLUSION: Dose reduction in cervical contrast-enhanced MRA is feasible at 3 T without significant compromise in arteriographic quality in most segments. Particularly at 3 T, arteriography is quantitatively and qualitatively robust and may be advisable in high-risk patients. PMID- 26001260 TI - Value of Focused Appendicitis Ultrasound and Alvarado Score in Predicting Appendicitis in Children: Can We Reduce the Use of CT? AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of focused appendicitis ultrasound combined with Alvarado score to accurately identify appendicitis in children in whom it is suspected, thereby reducing unnecessary CT examinations and associated radiation exposure. MATERIALS AND METHODS: We retrospectively evaluated the focused appendicitis ultrasound, CT, clinical, and laboratory findings of 522 consecutively registered children (231 boys, 291 girls; mean age, 13.04 [SD, 5.02] years; range, 0.74 months-21 years) who underwent focused appendicitis ultrasound for abdominal pain in a pediatric emergency department from January 2008 through October 2009. All children underwent surgery or clinical follow-up to exclude missed appendicitis. Sonographic findings were characterized as positive, negative, or inconclusive (appendix not visualized). Alternative diagnoses were noted. Alvarado score (0-10 points based on multiple clinical criteria) was determined. Focused appendicitis ultrasound and Alvarado score results were compared with surgical and pathologic reports. RESULTS: Both focused appendicitis ultrasound results and Alvarado score were associated with likelihood of surgery for appendicitis (p = 0.0001). Focused appendicitis ultrasound had conclusive results: 105 positive and 27 negative in 132 of 522 (25.2%) children. In the 390 of 522 (74.7%) children with inconclusive focused appendicitis ultrasound findings, 43 of 390 (11.0%) eventually had a diagnosis of appendicitis with CT (n = 26) or Alvarado score (n = 17). Among children with inconclusive focused appendicitis ultrasound findings and an Alvarado score less than 5 (241/522, 46.1%), only one patient had appendicitis. The negative predictive value (NPV) of inconclusive ultrasound findings and low Alvarado score combined was 99.6%. Among children with inconclusive focused appendicitis ultrasound findings and an Alvarado score of 5-8, the NPV decreased to 89.7%. CONCLUSION: Children with inconclusive focused appendicitis ultrasound findings and a low Alvarado score are extremely unlikely to have appendicitis (NPV, 99.6%). Avoiding unnecessary CT of these patients is a safe approach to diagnosis. PMID- 26001261 TI - Estimates of diagnostic reference levels for pediatric peripheral and abdominal fluoroscopically guided procedures. AB - OBJECTIVE: The objective of our study was to survey radiation dose indexes of pediatric peripheral and abdominal fluoroscopically guided procedures from which estimates of diagnostic reference levels (DRLs) can be proposed for both a standard fluoroscope and a novel fluoroscope with advanced image processing and lower radiation dose rates. MATERIALS AND METHODS: Radiation dose structured reports were retrospectively collected for 408 clinical pediatric cases: Half of the procedures were performed with a standard imaging technology and half with a novel x-ray technology. Dose-area product (DAP), air Kerma (AK), fluoroscopy time, number of digital subtraction angiography images, and patient mass were collected to calculate and normalize radiation dose indexes for procedures completed with the standard and novel fluoroscopes. RESULTS: The study population was composed of 180 and 175 patients who underwent procedures with the standard and novel technology, respectively. The 21 different types of pediatric peripheral and abdominal interventional procedures produced 408 total studies. Median ages, mass and body mass index, fluoroscopy time per procedure, and total number of recorded images for the standard and novel technologies were not statistically different. The area of the x-ray beams was square at the level of the patient with a dimension of 10-13 cm. The dose reduction achieved with the novel fluoroscope ranged from 18% to 51% of the dose required with the standard fluoroscope. The median DAP and AK patient dose indexes were 0.38 Gy . cm(2) and 4.00 mGy, respectively, for the novel fluoroscope. CONCLUSION: Estimates of dose indexes of pediatric peripheral and abdominal fluoroscopically guided, clinical procedures should assist in the development of DRLs to foster management of radiation doses of pediatric patients. PMID- 26001262 TI - A prospective clinical study to evaluate the safety and performance of wireless localization of nonpalpable breast lesions using radiofrequency identification technology. AB - OBJECTIVE: The purpose of this study was to evaluate the safety and performance of localizing nonpalpable breast lesions using radiofrequency identification technology. SUBJECTS AND METHODS: Twenty consecutive women requiring preoperative localization of a breast lesion were recruited. Subjects underwent placement of both a hook wire and a radiofrequency identification tag immediately before surgery. The radiofrequency identification tag was the primary method used by the operating surgeon to localize each lesion during excision, with the hook wire serving as backup in case of tag migration or failed localization. Successful localization with removal of the intended lesion was the primary outcome measured. Tag migration and postoperative infection were also noted to assess safety. RESULTS: Twenty patients underwent placement of a radiofrequency identification tag, 12 under ultrasound guidance and eight with stereotactic guidance. In all cases, the radiofrequency identification tag was successfully localized by the reader at the level of the skin before incision, and the intended lesion was removed along with the radiofrequency identification tag. There were no localization failures and no postoperative infections. Tag migration did not occur before incision, but in three cases, occurred as the lesion was being retracted with fingers to make the final cut along the deep surface of the specimen. CONCLUSION: In this initial clinical study, radiofrequency tags were safe and able to successfully localize nonpalpable breast lesions. Radiofrequency identification technology may represent an alternative method to hook wire localization. PMID- 26001263 TI - MR Spectroscopy for Differentiating Benign From Malignant Solid Adnexal Tumors. AB - OBJECTIVE: The purpose of this article is to investigate the proton MR spectroscopy ((1)H-MRS) features of solid adnexal tumors and to evaluate the efficacy of (1)H-MRS for differentiating benign from malignant solid adnexal tumors. MATERIALS AND METHODS: Sixty-nine patients with surgically and histologically proven solid adnexal tumors (27 benign and 42 malignant) underwent conventional MRI and (1)H-MRS. Single-voxel spectroscopy was performed using the point-resolved spectroscopy localization technique with a voxel size of 2 * 2 * 2 cm(3). Resonance peak integrals of choline, N-acetyl aspartate (NAA), creatine, lactate, and lipid were analyzed, and the choline-tocreatine, NAA-to-creatine, lactate-to-creatine, and lipid-to-creatine ratios were recorded and compared between benign and malignant tumors. RESULTS: A choline peak was detected in all 69 cases (100%), NAA peak in 67 cases (97%, 25 benign and 42 malignant), lipid peak in 47 cases (17 benign and 30 malignant), and lactate peak in eight cases (four benign and four malignant). The mean (+/- SD) choline-tocreatine ratio was 5.13 +/- 0.6 in benign tumors versus 8.90 +/- 0.5 in malignant solid adnexal tumors, a statistically significant difference (p = 0.000). There were no statistically significant differences between benign and malignant tumors in the NAA-to-creatine and lipid-to-creatine ratios (p = 0.263 and 0.120, respectively). When the choline-to-creatine threshold was 7.46 for differentiating between benign and malignant tumors, the sensitivity, specificity, and accuracy were 94.1%, 97.1%, and 91.2%, respectively. CONCLUSION: Our preliminary study shows that the (1)H-MRS patterns of benign and malignant solid adnexal tumors differ. The choline-to-creatine ratio can help clinicians differentiate benign from malignant tumors. PMID- 26001264 TI - Medicolegal--malpractice and ethical issues in radiology. Report A Radiographic Examination Scheduled but Not Performed? PMID- 26001265 TI - Laser ablation for hepatic metastases from neuroendocrine tumors. PMID- 26001266 TI - Reply to "Laser ablation for hepatic metastases from neuroendocrine tumors". PMID- 26001267 TI - Empyema necessitatis: yet another mimic of necrotizing fasciitis in the torso. PMID- 26001268 TI - Aneurysmal intrahepatic portosystemic venous shunt: beware of this masquerader. PMID- 26001269 TI - Extracellular vesicles shuffling intercellular messages: for good or for bad. AB - The release of extracellular vesicles (EVs) is a highly conserved process exploited by diverse organisms as a mode of intercellular communication. Vesicles of sizes ranging from 30 to 1000nm, or even larger, are generated by blebbing of the plasma membrane (microvesicles) or formed in multivesicular endosomes (MVEs) to be secreted by exocytosis as exosomes. Exosomes, microvesicles and other EVs contain membrane and cytosolic components that include proteins, lipids and RNAs, a composition that differs related to their site of biogenesis. Several mechanisms are involved in vesicle formation at the plasma membrane or in endosomes, which is reflected in their heterogeneity, size and composition. EVs have significant promise for therapeutics and diagnostics and for understanding physiological and pathological processes all of which have boosted research to find modulators of their composition, secretion and targeting. PMID- 26001270 TI - Aflatoxin M1 in raw milk from different regions of Sao Paulo state--Brazil. AB - A total of 635 raw milk samples from 45 dairy farms, from three regions of Sao Paulo state - Brazil, were evaluated during 15 months for aflatoxin M1 (AFM1). AFM1 was determined by high performance liquid chromatograph with fluorescence detection. AFM1 was detected (>0.003 ug kg(-1)) in 72.9%, 56.3% and 27.5% of the samples from Bauru, Aracatuba and Vale do Paraiba regions, respectively. The mean AFM1 contamination considering all the samples was 0.021 ug kg(-1). Furthermore, the concentration of AFM1 was quite different among Bauru (0.038 ug kg(-1)), Aracatuba (0.017 ug kg(-1)) and Vale do Paraiba (<0.01 ug kg(-1)) regions. Only three samples (0.5%) had higher contamination than the tolerated limit in Brazil (0.50 ug kg(-1)) and 64 samples (10.1%) had a higher contamination than the maximum limit as set by the European Union (0.050 ug kg(-1)). The estimated AFM1 daily intake was 0.358 and 0.120 ng kg(-1) body weight per day for children and adults, respectively. PMID- 26001271 TI - Two new monoterpenoid alpha-pyrones from a fungus Nectria sp. HLS206 associated with the marine sponge Gelliodes carnosa. AB - Two new monoterpenoid alpha-pyrones, named nectriapyrones C and D (1 and 2), along with a known alpha-pyrone (nectriapyrone, 3) were isolated from a marine derived fungus Nectria sp. HLS206 associated with the marine sponge Gelliodes carnosa collected from the South China Sea. Their structures were determined on the basis of 1D NMR, 2D NMR, HR-ESI-MS methods. PMID- 26001272 TI - Naturalness as an ethical stance: idea(l)s and practices of care in western herbal medicine in the UK. AB - An association of non-biomedical healthcare with appeals to nature and naturalness, and an invocation of a rhetoric of gentleness, goodness, purity and moral power has been noted previously, and some scholars argue that nature has taken on a meaning broadly opposed to the rational scientific order of modernity. Drawing on an ethnographic study of women's practice and use of western herbal medicine (WHM) in the UK, the intertwining of the perceived naturalness of WHM with distinct care practices points to a further avenue for exploration. To examine patients' and herbalists' discourses of the naturalness of WHM and associated idea(l)s and practices of care, understandings of nature and a feminist ethics of care are utilized as analytical frameworks. The analysis presented suggests that, through WHM, patients and herbalists become embedded in a complex spatio-temporal wholeness and web of care that intertwines past, present and future, self and others, and local and global concerns. In the emerging 'ordinary ethics of care', naturalness constitutes a sign of goodness and of a shared humanity within the organic world, while care, underpinned by idea(l)s of natural and holistic care practices, links human and non-human others. Thus, the naturalness of WHM, as perceived by some patients and herbalists, engages and blends with a continually unfolding field of relationships in the lifeworld(s), where care practices, caring relations and collective wellbeing may constitute an ethical stance that raises deeper questions about the significance of relationality, the values of care/caring and the mutual involvement of nature and human being(s). PMID- 26001273 TI - A new family of StART domain proteins at membrane contact sites has a role in ER PM sterol transport. AB - Sterol traffic between the endoplasmic reticulum (ER) and plasma membrane (PM) is a fundamental cellular process that occurs by a poorly understood non-vesicular mechanism. We identified a novel, evolutionarily diverse family of ER membrane proteins with StART-like lipid transfer domains and studied them in yeast. StART like domains from Ysp2p and its paralog Lam4p specifically bind sterols, and Ysp2p, Lam4p and their homologs Ysp1p and Sip3p target punctate ER-PM contact sites distinct from those occupied by known ER-PM tethers. The activity of Ysp2p, reflected in amphotericin-sensitivity assays, requires its second StART-like domain to be positioned so that it can reach across ER-PM contacts. Absence of Ysp2p, Ysp1p or Sip3p reduces the rate at which exogenously supplied sterols traffic from the PM to the ER. Our data suggest that these StART-like proteins act in trans to mediate a step in sterol exchange between the PM and ER. PMID- 26001274 TI - Piezo1 links mechanical forces to red blood cell volume. AB - Red blood cells (RBCs) experience significant mechanical forces while recirculating, but the consequences of these forces are not fully understood. Recent work has shown that gain-of-function mutations in mechanically activated Piezo1 cation channels are associated with the dehydrating RBC disease xerocytosis, implicating a role of mechanotransduction in RBC volume regulation. However, the mechanisms by which these mutations result in RBC dehydration are unknown. In this study, we show that RBCs exhibit robust calcium entry in response to mechanical stretch and that this entry is dependent on Piezo1 expression. Furthermore, RBCs from blood-cell-specific Piezo1 conditional knockout mice are overhydrated and exhibit increased fragility both in vitro and in vivo. Finally, we show that Yoda1, a chemical activator of Piezo1, causes calcium influx and subsequent dehydration of RBCs via downstream activation of the KCa3.1 Gardos channel, directly implicating Piezo1 signaling in RBC volume control. Therefore, mechanically activated Piezo1 plays an essential role in RBC volume homeostasis. PMID- 26001275 TI - Chemical activation of the mechanotransduction channel Piezo1. AB - Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date, mechanical stimuli are the only means to activate Piezo ion channels and whether other modes of activation exist is not known. In this study, we screened ~3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function. PMID- 26001276 TI - Impacts of maternal mortality on living children and families: A qualitative study from Butajira, Ethiopia. AB - BACKGROUND: The consequences of maternal mortality on orphaned children and the family members who support them are dramatic, especially in countries that have high maternal mortality like Ethiopia. As part of a four country, mixed-methods study (Ethiopia, Malawi, South Africa, and Tanzania) qualitative data were collected in Butajira, Ethiopia with the aim of exploring the far reaching consequences of maternal deaths on families and children. METHODS: We conducted interviews with 28 adult family members of women who died from maternal causes, as well as 13 stakeholders (government officials, civil society, and a UN agency); and held 10 focus group discussions with 87 community members. Data were analyzed using NVivo10 software for qualitative analysis. RESULTS: We found that newborns and children whose mothers died from maternal causes face nutrition deficits, and are less likely to access needed health care than children with living mothers. Older children drop out of school to care for younger siblings and contribute to household and farm labor which may be beyond their capacity and age, and often choose migration in search of better opportunities. Family fragmentation is common following maternal death, leading to tenuous relationships within a household with the births and prioritization of additional children further stretching limited financial resources. Currently, there is no formal standardized support system for families caring for vulnerable children in Ethiopia. CONCLUSIONS: Impacts of maternal mortality on children are far-reaching and have the potential to last into adulthood. Coordinated, multi-sectorial efforts towards mitigating the impacts on children and families following a maternal death are lacking. In order to prevent impacts on children and families, efforts targeting maternal mortality must address inequalities in access to care at the community, facility, and policy levels. PMID- 26001277 TI - Changes in springbok (Antidorcas marsupialis) Longissimus thoracis et lumborum muscle during conditioning as assessed by a trained sensory panel. AB - This study aimed to determine the effect of ageing in vacuum bags at 5.4+/-0.60 degrees C on the sensory quality of springbok (Antidorcas marsupialis) Longissimus thoracis et lumborum (LTL) muscle. Four randomly assigned portions of muscle from six male and six female mature springbok were aged for 1, 3, 8 or 28days, after which they were blast frozen. Assessment by a trained sensory panel found a significant increase in gamey, metallic, liver-like, sour/aged and off/manure attributes and a decline in beef-like aroma during ageing. Sensory tenderness and sustained juiciness increased and residue decreased significantly; however there was no significant change in the Warner Bratzler shear force of the cooked meat, which was below 24N for all ageing periods. Significant gender effects were only present for metallic aroma (female>male), residue (male>female) and cooking loss (male>female). It was concluded that springbok LTL should be aged for a maximum of eight days. PMID- 26001278 TI - Influence of antibodies and T cells on dengue disease outcome: insights from interferon receptor-deficient mouse models. AB - Dengue virus (DENV) is a globally important mosquito-borne virus that causes a spectrum of diseases ranging from dengue fever (DF) to dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), affecting 3.6 billion people in 128 countries [1,2(*)]. There is an urgent need for a drug or vaccine against DENV, yet none are presently available. In fact, results from recent Phase IIb and III trials of an attenuated tetrameric vaccine revealed that the vaccine provided limited protection against DENV serotype 2 in DENV-immune people, and no protection against any serotype in naive individuals [3-5], highlighting the difficulties associated with dengue vaccine development. A challenge in the development of a DENV vaccine is that a vaccine must protect against all four DENV serotypes, which co-circulate in endemic areas. Further complicating DENV vaccine development is that the correlates of protection are not fully defined, mechanisms regulating the generation of protective antibody and T cell responses against all four DENV serotypes are as yet to be deciphered, and the adaptive immune response may actually contribute to severe disease. Recent studies using the only available animal model of DHF/DSS in mice lacking one or more components of the interferon (IFN) system have begun to provide crucial insights into the protective versus pathogenic nature of both antibody and T cell responses to DENV. Herein, we highlight key studies using the IFN receptor-deficient mouse models toward understanding the contribution of antibodies and T cells in impacting the outcome of DENV infection. PMID- 26001279 TI - Heteroaggregation of engineered nanoparticles and kaolin clays in aqueous environments. AB - The increasing and wide use of nanoparticles (NPs), including TiO2 and Ag NPs, have raised concerns due to their potential toxicity and environmental impacts. Kaolin is a very common mineral in aquatic systems, and there is a very high probability that nanoparticles (NPs) will interact with these clay minerals. We studied the effect of kaolin particles on the aggregation of NPs under different conditions, including the role of pH, ionic strength (IS), and humic acid (HA). We show that kaolin reduces the energy barrier and the Critical Coagulation Concentration (CCC) at pH 4. At pH 8, even though the energy barrier of the system without kaolin increases, kaolin promotes NP aggregation via heteroaggregation. When IS is equal to or greater than the CCC, on the one hand HA promotes aggregation of TiO2 NPs, but on the other hand HA decreases the rate of Ag NP aggregation because the existence of a surface coating may limit the adsorption of HA on these Ag NPs. In addition, the presence of HA increases the energy barrier and the CCC of the binary system (kaolin + NPs). Thus, the complex interactions of clay, NPs, IS, pH, and HA concentration determine the colloidal stability of the NPs. We find that kaolin is a potential coagulant for removal of NPs that behave like Ag and TiO2. PMID- 26001280 TI - Towards a better understanding on agglomeration mechanisms and thermodynamic properties of TiO2 nanoparticles interacting with natural organic matter. AB - Interaction between engineered nanoparticles and natural organic matter is investigated by measuring the exchanged heat during binding process with isothermal titration calorimetry. TiO2 anatase nanoparticles and alginate are used as engineered nanoparticles and natural organic matter to get an insight into the thermodynamic association properties and mechanisms of adsorption and agglomeration. Changes of enthalpy, entropy and total free energy, reaction stoichiometry and affinity binding constant are determined or calculated at a pH value where the TiO2 nanoparticles surface charge is positive and the alginate exhibits a negative structural charge. Our results indicate that strong TiO2 alginate interactions are essentially entropy driven and enthalpically favorable with exothermic binding reactions. The reaction stoichiometry and entropy gain are also found dependent on the mixing order. Finally correlation is established between the binding enthalpy, the reaction stoichiometry and the zeta potential values determined by electrophoretic mobility measurements. From these results two types of agglomeration mechanisms are proposed depending on the mixing order. Addition of alginate in TiO2 dispersions is found to form agglomerates due to polymer bridging whereas addition of TiO2 in alginate promotes a more individually coating of the nanoparticles. PMID- 26001281 TI - Stable partial nitritation for low-strength wastewater at low temperature in an aerobic granular reactor. AB - Partial nitritation for a low-strength wastewater at low temperature was stably achieved in an aerobic granular reactor. A bench-scale granular sludge bioreactor was operated in continuous mode treating an influent of 70 mg N-NH4(+) L(-1) to mimic pretreated municipal nitrogenous wastewater and the temperature was progressively decreased from 30 to 12.5 degrees C. A suitable effluent nitrite to ammonium concentrations ratio to a subsequent anammox reactor was maintained stable during 300 days at 12.5 degrees C. The average applied nitrogen loading rate at 12.5 degrees C was 0.7 +/- 0.3 g N L(-1) d(-1), with an effluent nitrate concentration of only 2.5 +/- 0.7 mg N-NO3(-) L(-1). The biomass fraction of nitrite-oxidizing bacteria (NOB) in the granular sludge decreased from 19% to only 1% in 6 months of reactor operation at 12.5 degrees C. Nitrobacter spp. where found as the dominant NOB population, whereas Nitrospira spp. were not detected. Simulations indicated that: (i) NOB would only be effectively repressed when their oxygen half-saturation coefficient was higher than that of ammonia oxidizing bacteria; and (ii) a lower specific growth rate of NOB was maintained at any point in the biofilm (even at 12.5 degrees C) due to the bulk ammonium concentration imposed through the control strategy. PMID- 26001282 TI - EDTA functionalized magnetic nanoparticle sorbents for cadmium and lead contaminated water treatment. AB - Cadmium (Cd(2+)) and lead (Pb(2+)) are toxic to human beings and other organisms, and the U.S. Environmental Protection Agency (EPA) has classified both as probable human carcinogens. In this study, a regenerable magnetic ligand particle (Mag-Ligand) which includes a metal-binding organic ligand (EDTA) attached to an iron oxide nanoparticle was developed for rapid removal of Cd(2+) and Pb(2+) as well as other metals from contaminated water. Mag-Ligand showed fast removal ability for both Cd(2+) (<2 h) and Pb(2+) (<15 min) with relatively high sorption capacity (79.4 and 100.2 mg/g for Cd(2+) and Pb(2+), respectively). The removal performance of Mag-Ligand was high across a wide pH range (3-10) as well as in the presence of competitive metal ions (Ca(2+) and Mg(2+)). In addition, Mag Ligands can be easily regenerated (washed by 1% HCl) and reused several cycles with high sorption capacity. This study indicated that Mag-Ligand is a reusable sorbent for rapid, convenient, and efficient removal of Cd(2+) and Pb(2+) from contaminated aquatic systems. PMID- 26001283 TI - Interactions of triazine herbicides with biochar: Steric and electronic effects. AB - We studied the adsorption of triazine herbicides and several reference heteroaromatic amines from water onto a temperature series of hardwood biochars (300-700 degrees C, labeled B300-B700). Adsorption on biochars correlated poorly with pyrolysis temperature, H/C, O/C, mean minimum fused ring size, surface area (N2 or CO2), microporosity, and mesoporosity, but correlated well with a weighted sum of microporosity and mesoporosity. Steric effects were evident by the negative influence of solute molecular volume on adsorption rate. For a given compound, adsorption rate maximized for the biochar with the greatest mesoporosity-to-total-porosity ratio, suggesting that mesopores are important for facilitating diffusion into pore networks. The cationic forms of amines adsorb more slowly than the neutral forms. To further probe steric and electronic effects, adsorption on a biochar (B400) was compared to adsorption on graphite-a nonporous reference material with an unhindered, unfunctionalized graphene surface-and in comparison with reference compounds (benzene, naphthalene, pyridine, quinoline and 1,3-triazine). Relative to benzene, the surface area normalized adsorption of the triazine herbicides was disfavored on B400 (favored on graphite) by 11-19 kJ/mol, depending on concentration. It is estimated that steric suppression of B400 adsorption comprises 6.2 kJ/mol of this difference, the remainder being the difference in polar electronic effects. Based on the behavior of the reference amines, the difference in polar effects is dominated by pi-pi electron donor-acceptor (EDA) interactions with sites on polyaromatic surfaces, which are more electropositive and/or more abundant on graphite. Overall, our results show that mesoporosity is critical, that adsorption rate is a function of solute molecular size and charge, that steric bulk in the solute suppresses equilibrium adsorption, and that pi-pi EDA forces play a role in triazine polar interactions with biochar. PMID- 26001284 TI - Spatially explicit fate modelling of nanomaterials in natural waters. AB - Site specific exposure assessments for engineered nanoparticles (ENPs) require spatially explicit fate models, which however are not yet available. Here we present an ENP fate model (NanoDUFLOW) that links ENP specific process descriptions to a spatially explicit hydrological model. The link enables the realistic modelling of feedbacks between local flow conditions and ENP fate processes, such as homo- and heteroaggregation, resuspension and sedimentation. Spatially explicit simulations using five size classes of ENPs and five size classes of natural solids showed how ENP sediment contamination 'hot spots' and ENP speciation can be predicted as a function of place and time. For the catchment modelled, neglect of spatial heterogeneity caused relatively small differences in ENP retention. However, simplification of the number of size classes to one average class, resulted in up to 3.3 times lower values of retention compared to scenarios that used detailed size distributions. Local concentrations in sediment were underestimated up to 20 fold upon simplification of spatial heterogeneity or particle size distribution. We conclude that spatial heterogeneity should not be neglected when assessing the risks of ENPs. PMID- 26001285 TI - Pharmacological management strategies for stroke prevention following transcatheter aortic valve replacement: A systematic review. AB - BACKGROUND: The most appropriate pharmacological treatment for stroke prevention after transcatheter aortic valve replacement (TAVR) is unclear. We performed a systematic review of randomized controlled trials (RCTs) and observational studies examining the effect of various pharmacological treatment regimens on rates of stroke, bleeding, and death after TAVR. METHODS: We searched Cochrane Library, Embase, and Medline for RCTs and observational studies comparing >=2 antithrombotic regimens in TAVR patients. Included antithrombotic regimens were defined as one or more antiplatelet agents (aspirin, clopidogrel, prasugrel, or ticagrelor) and/or anticoagulants (vitamin K antagonists or novel oral anticoagulants). RESULTS: Eight studies (2 RCTs and 6 observational studies) met our inclusion criteria (n=1598). Rates of major stroke ranged from 0% to 5.6% with no detected differences between treatment arms. All-cause mortality ranged from 5% to 15%, and no differences in mortality were detected between therapies. A consistent pattern of reduction in major or life-threatening bleeding was found with a single antiplatelet therapy (SAPT) compared to dual antiplatelet therapy (DAPT). However, this difference only reached statistical significance in a single cohort study (risk ratio 0.24; 95% confidence interval 0.12, 0.46). No differences between anticoagulant therapies were detected for any endpoint. Overall, studies were underpowered to detect differences between treatment groups. CONCLUSION: Similar rates of stroke, bleeding, and mortality were found among most studies. A trend towards reduced rates of major or life-threatening bleeding when comparing SAPT to DAPT was found. Numbers of events were small, highlighting the need for larger studies on which to base pharmacological recommendations post-TAVR. PMID- 26001286 TI - A novel biological role for nsLTP2 from Oriza sativa: Potential incorporation with anticancer agents, nucleosides and their analogues. AB - Development of a protein-based drug delivery system has major impact on the efficacy and bioavailability of unstable and water insoluble drugs. In the present study, the binding modes of a nonspecific lipid transfer protein (nsLTP2) from Oryza sativa with various nucleosides and analogous molecules were identified. The 3-D structure of the protein was designed and validated using modeler 9.13, Molegro virtual docker and procheck tool, respectively. The binding affinity and strength of interactions, key contributing residues and specificity toward the substrates were accomplished by computational docking and model prediction. The protein presented high affinity to acyclovir and vidarabine as purine-analogous drugs. Binding affinity is influenced by the core template and functional groups of the ligands which are structurally different cause the variation of interaction energies with nsLTP2. Nonetheless, all the evaluated analogous drugs occupy the proximity space at the nsLTP active site with high similarity in their binding modes. Our findings hold great promise for the future applications of nsLTPs in various aspects of pharmaceutical science and molecular biology. PMID- 26001287 TI - An autonomous real-time single-channel detection of absence seizures in WAG/Rij rats. AB - This paper presents a real-time, completely automated and patient independent algorithm for detection of absence seizures in WAG/Rij rats as a valid animal model of human absence epilepsy. Single-channel EEG recordings containing totally 488 seizures from 8 WAG/Rij rats were analyzed using the real-time SWD detection algorithm. The proposed algorithms based on the variation of wavelet power to the background power in two specific frequency bands whose spectral power are highly correlated with SWDs. The wavelet powers of two specific frequency bands are calculated with a pattern-adapted mother wavelet and compared with an adaptive ratio of background power of each frequency band. The results indicate used algorithm is able to detect the whole 488 seizures within less than 1 s with sensitivity of 100%. The average precision for 1200, 1400 and 1600 point of window size was 95.2%, 98.3% and 99.17%, respectively. The present algorithm, with its high sensitivity and specificity, could be used for further studies of absence seizures in humans and rats and could be implemented as real-time system for closed loop deep brain stimulation systems. PMID- 26001288 TI - Biophysical characterization of inwardly rectifying potassium currents (I(K1) I(K,ACh), I(K,Ca)) using sinus rhythm or atrial fibrillation action potential waveforms. AB - Although several physiological, pathophysiological and regulatory properties of classical inward rectifier K+ current I(K1), G-protein coupled inwardly rectifying K+ current I(K,ACh) and the small-conductance Ca2+ activated K+ current I(K,Ca) have been identified, quantitative biophysical details remain unclear. Both I(K1) and I(K,ACh) are implicated in atrial fibrillation (AF), and recently also I(K,Ca) has been speculated to be linked with the genesis and sustainability of AF. All these three currents have been shown to be involved in the electrical remodeling in the atria of patients suffering from AF, and it is therefore important to characterize their biophysical properties and compare their relative current contribution in atrial electrophysiology in both sinus rhythm (SR) and AF. The aim of this study is to investigate the contribution of the three potassium currents when subjected to voltage protocols adapted from atrial action potentials recorded in human tissue at 1 and 3 Hz. The current recordings were performed in the HEK-293 heterologous cell system expressing either I(K1), I(K,ACh) or I(K,Ca) to establish the individual contribution of each of these currents during the voltage changes of atrial action potential waveforms. I(K1) primarily contributes to the atrial electrophysiology at the latter part of repolarization and during the diastolic phase, while both I(K,Ca) under high [Ca2+]i and I(K,ACh) contribute relatively most during repolarization. PMID- 26001289 TI - Lenalidomide treatment induced the normalization of marker protein levels in blood plasma of patients with 5q-myelodysplastic syndrome. AB - A specific type of myelodysplastic syndrome (MDS) is associated with isolated deletion on the long arm of chromosome 5, i.e., 5q-syndrome (del(5q)). The treatment approaches for MDS del(5q) include the immunomodulating drug lenalidomide (LEN). Thirteen MDS del(5q) patients were included in this study. We found elevated activities of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the blood plasma of MDS del(5q) patients as compared with healthy controls. This was stabilized to control values after LEN treatment. Similar behavior we registered also for the thioredoxin and calnexin contents in BP. Peripheral blood mononuclear cells (PBMC) from patients with MDS del(5q) prior to and after treatment with LEN did not exhibit any detectable amount of P-glycoprotein (P-gp) gene transcript. However, we detected a measurable amount of multidrug resistance associated protein 1 (MRP1) mRNA in PBMCs from three patients prior to LEN treatment and in one patient during LEN treatment but it was not present prior to treatment. These data indicated on usefulness of applied protein markers estimation for monitoring of MDS del(5q) patient treatment effectiveness by LEN. Expression of MRP1 seems to be independent on LEN treatment and reflects probably the molecular variability in the ethiopathogenesis of MDS del(5q). PMID- 26001290 TI - Effect of crocin on oxidative stress in recovery from single bout of swimming exercise in rats. AB - Physical exercise could cause muscle and tissue damage due to increase in the formation of free oxygen radicals during exercise. The aim of the present study was to investigate the effect of crocin on parameters associated with oxidative stress in recovery from acute swimming exercise in rats. Rats were divided into eight groups; Normal Control (NC: untreated and did not swim), Crocin Control (CC: received crocin and did not swim), Exercise-1 (Exe-1: untreated and swam), Exercise-24 (Exe-24: untreated and swam), Exercise-48 (Exe-48: untreated and swam), Exercise+Crocin-1 (Exe-Cro-1: received crocin and swam), Exercise+Crocin 24 (Exe-Cro-24: received crocin and swam), Exercise+Crocin-48 (Exe-Cro-48: received crocin and swam). AST, ALP, LDH, CK, XO enzymes levels increased after swimming in untreated and crocin-treated groups, but there was a less increase in crocin-treated groups. The highest MDA levels in serum were determined in Exe-1 compared with all other groups. There was significant difference between control and exercise groups in MDA level (p = 0.033). In contrast, there was significant difference between control and exercise groups in GSH level (p < 0.001). In addition, crocin given to swimming rats significantly increased GSH levels (p < 0.05) and decreased MDA levels when compared with untreated exercise groups. In conclusion, crocin is able to protect liver and skeletal muscle tissue against exercise-induced oxidative damage by preventing reactive oxygen species (ROS) production. PMID- 26001291 TI - Mitochondrial ATP-sensitive K+ channels mediate the antioxidative influence of diosgenin on myocardial reperfusion injury in rat hearts. AB - The contribution of reactive oxygen species and oxidative stress in the pathogenesis of ischemia-reperfusion (I/R) injury has been supported by many studies. The effect of diosgenin on oxidative stress induced by I/R injury was evaluated in this study. Rat hearts were subjected to 30 minutes of global ischemia followed by 90 minutes of reperfusion. 5-hydroxydecanoate (5-HD) was used before administration of diosgenin and before ischemia. The activities of myocardial creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured. Administration of diosgenin before ischemia significantly lowered CK and MDA levels as compared with control group (p < 0.05) and increased GPX (p < 0.05) and SOD (p < 0.01) activities in comparison with control group. Pre-administration of 5-HD significantly attenuated the protective effects of diosgenin. In conclusion, opening of mitochondrial ATP-sensitive K(+) channels and attenuating of oxidative stress can be suggested as underlying mechanisms for cardioprotective effect of diosgenin in I/R injury. PMID- 26001292 TI - ATRX represses alternative lengthening of telomeres. AB - The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here that knockout or knockdown of ATRX in mortal cells or immortal telomerase-positive cells is insufficient to activate ALT. Notably, however, in SV40-transformed mortal fibroblasts ATRX loss results in either a significant increase in the proportion of cell lines activating ALT (instead of telomerase) or in a significant decrease in the time prior to ALT activation. These data indicate that loss of ATRX function cooperates with one or more as-yet unidentified genetic or epigenetic alterations to activate ALT. Moreover, transient ATRX expression in ALT-positive/ATRX-negative cells represses ALT activity. These data provide the first direct, functional evidence that ATRX represses ALT. PMID- 26001293 TI - High CD204+ tumor-infiltrating macrophage density predicts a poor prognosis in patients with urothelial cell carcinoma of the bladder. AB - Macrophages (Mphis) are a major cell type that can infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. This study attempted to investigate the prognostic values of various tumor-infiltrating Mphi phenotypes in patients with urothelial cell carcinoma of the bladder (UCB), with a focus on Mphi tissue microlocalization. Mphis were assessed by immunohistochemistry in tissues from 302 UCB patients using CD68 as a pan-Mphi marker, and CD204 and CD169 as robust pro- and anti-tumoral Mphi phenotype markers, respectively. Our data showed that these Mphi phenotypes were predominately distributed in stromal (ST) rather than in intratumoral (INT) regions (all P < 0.0001). Surprisingly, CD204 and CD169 can be co-expressed by the same CD68+ Mphis. Kaplan-Meier analysis revealed that all INT- and ST infiltrating CD204+ or CD169+ Mphi densities were inversely associated with overall survival (all P < 0.01). By multivariate analysis, ST-infiltrating CD204+ Mphi density emerged as an independent prognostic factor for overall survival (HR, 1.981; P = 0.022). Moreover, the density of ST-infiltrating CD204+ Mphis was positively associated with the tumor size (P = 0.001), tumor stage (P < 0.0001), nodal metastasis (P < 0.0001), and histological grade (P < 0.0001). Our findings suggest that CD204+ Mphis might play detrimental protumoral roles and represent the predominant Mphi phenotype in human bladder cancer. PMID- 26001294 TI - p63 drives invasion in keratinocytes expressing HPV16 E6/E7 genes through regulation of Src-FAK signalling. AB - Using microarray information from oro-pharyngeal data sets and results from primary human foreskin keratinocytes (HFK) expressing Human Papilloma Virus (HPV) 16 E6/E7 proteins, we show that p63 expression regulates signalling molecules which initiate cell migration such as Src and focal adhesion kinase (FAK) and induce invasion in 3D-organotypic rafts; a phenotype that can be reversed by depletion of p63. Knockdown of Src or FAK in the invasive cells restored focal adhesion protein paxillin at cell periphery and impaired the cell migration. In addition, specific inhibition of FAK (PF573228) or Src (dasatinib) activities mitigated invasion and attenuated the expression/activity of matrix metalloproteinase 14 (MMP14), a pivotal MMP in the MMP activation cascade. Expression of constitutively active Src in non-invasive HFK expressing E6/E7 proteins upregulated the activity of c-Jun and MMP14, and induced invasion in rafts. Depletion of Src, FAK or AKT in the invasive cells normalised the expression/activity of c-Jun and MMP14, thus implicating the Src-FAK/AKT/AP-1 signalling in MMP14-mediated extra-cellular matrix remodelling. Up-regulation of Src, AP-1, MMP14 and p63 expression was confirmed in oro-pharyngeal cancer. Since p63 transcriptionally regulated expression of many of the genes in this signalling pathway, it suggests that it has a central role in cancer progression. PMID- 26001295 TI - An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells. AB - Reversing drug resistance with concurrent treatment confers anticancer benefits. In this study, we investigated the potential mechanism of glucosylceramide synthase (GCS)-mediated vinca alkaloid vinorelbine (VNR) resistance in human lung adenocarcinoma cells. Compared with PC14PE6/AS2 (AS2) and CL1-0 cells, apoptotic analysis showed that both A549 and CL1-5 cells were VNR-resistant, while these cells highly expressed GCS at the protein level. VNR treatment significantly converts ceramide to glucosylceramide in VNR-resistant cells; however, pharmacologically inhibiting GCS with (+/-)-threo-1-Phenyl-2-decanoylamino-3 morpholino-1-propanol hydrochloride (PDMP) induced ceramide accumulation, accompanied by a decrease in glucosylceramide. Under concurrent treatment with VNR and PDMP, an increase in cell apoptosis could be identified; furthermore, genetically silencing GCS confirmed these effects. In VNR-resistant cells, Bcl-xL expression was aberrantly increased, while pharmacologically inhibiting Bcl-xL with ABT-737 sensitized cells to VNR-induced apoptosis. Conversely, enforced expression of Bcl-xL strengthened the survival response of the VNR-susceptible cells AS2 and CL1-0. Without changes in mRNA expression, Bcl-xL was overexpressed independent of beta-catenin-mediated transcriptional regulation in VNR-resistant cells. Simultaneous GCS inhibition and VNR treatment caused a decrease in Bcl-xL expression. According to these findings, an increase in GCS caused Bcl-xL augmentation, facilitating VNR resistance in lung adenocarcinoma cells. PMID- 26001297 TI - Charge Transfer Excitons at van der Waals Interfaces. AB - The van der Waals interfaces of molecular donor/acceptor or graphene-like two dimensional (2D) semiconductors are central to concepts and emerging technologies of light-electricity interconversion. Examples include, among others, solar cells, photodetectors, and light emitting diodes. A salient feature in both types of van der Waals interfaces is the poorly screened Coulomb potential that can give rise to bound electron-hole pairs across the interface, i.e., charge transfer (CT) or interlayer excitons. Here we address common features of CT excitons at both types of interfaces. We emphasize the competition between localization and delocalization in ensuring efficient charge separation. At the molecular donor/acceptor interface, electronic delocalization in real space can dictate charge carrier separation. In contrast, at the 2D semiconductor heterojunction, delocalization in momentum space due to strong exciton binding may assist in parallel momentum conservation in CT exciton formation. PMID- 26001296 TI - A six gene expression signature defines aggressive subtypes and predicts outcome in childhood and adult acute lymphoblastic leukemia. AB - Abnormal gene expression in cancer represents an under-explored source of cancer markers and therapeutic targets. In order to identify gene expression signatures associated with survival in acute lymphoblastic leukemia (ALL), a strategy was designed to search for aberrant gene activity, which consists of applying several filters to transcriptomic datasets from two pediatric ALL studies. Six genes whose expression in leukemic blasts was associated with prognosis were identified:three genes predicting poor prognosis (AK022211, FASTKD1 and STARD4) and three genes associated with a favorable outcome (CAMSAP1, PCGF6 and SH3RF3). Combining the expression of these 6 genes could successfully predict prognosis not only in the two discovery pediatric ALL studies, but also in two independent validation cohorts of adult patients, one from a publicly available study and one consisting of 62 newly recruited Chinese patients. Moreover, our data demonstrate that our six gene based test is particularly efficient in stratifying MLL or BCR.ABL negative patients. Finally, common biological traits characterizing aggressive forms of ALL in both children and adults were found, including features of dormant hematopoietic stem cells, suggesting new therapeutic strategies. PMID- 26001298 TI - The European Union Food Distribution programme for the Most Deprived Persons of the community, 1987-2013: From agricultural policy to social inclusion policy? AB - The European Union Food Distribution programme for the Most Deprived Persons (MDP) of the community ran from 1987 until 2013. It was funded from Common Agricultural Policy budgets. The programme initially made use of surplus foods from the food mountains resulting from intervention stocks. This food was then distributed through aid agencies within member states, coordinated at a national government level. Reform of the CAP and global rises in food prices resulted in an increase in budget from ?300 to ?500 million Euros in 2010 with the added power to buy food on the open market. This led to a formal challenge to the scheme on the basis that buying goods on the open market shifted the emphasis from an agricultural/financial basis to a social one. A court ruling found that because the program was no longer used for removing surpluses the link to agriculture policy has become tenuous and therefore had no basis in community law. As a result of this legal challenge a number of policy compromises ensured the MDP would continue until the end of 2013 with a reduced budget. The scheme has been superseded by a new scheme in March 2014 called the Fund for European Aid to the Most Deprived (FEAD). This is seen as a social programme. The way that policy and politics developed and changed the MDP programme are set out. The article tracks its move from being an agricultural policy to a social welfare one. The key policy players and actors in this move are set out as are the changing context and policy frameworks. The replacement of the MDP by FEAD is discussed as is how intensive lobbying in 2012/13 resulted in the development of a new Fund for European Aid to the Most Deprived (FEAD). PMID- 26001299 TI - Corporate governance in Czech hospitals after the transformation. AB - BACKGROUND: This contribution is a response to the current issue of corporate governance in hospitals in the Czech Republic, which draw a significant portion of funds from public health insurance. This not only has a significant impact on the economic efficiency of hospitals, but ultimately affects the whole system of healthcare provision in the Czech Republic. Therefore, the effectiveness of the corporate governance of hospitals might affect the fiscal stability of the health system and, indirectly, health policy for the whole country. OBJECTIVES: The main objective of this paper is to evaluate the success of the transformation in connection with the performance of corporate governance in hospitals in the Czech Republic. Specifically, there was an examination of the management differences in various types of hospitals, which differed in their ownership structure and legal form. METHODOLOGY/APPROACH: A sample of 100 hospitals was investigated in 2009, i.e., immediately after the transformation had been completed, and then three years later in 2012. With regard to the different public support of individual hospitals, the operating subsidies were removed from the economic results of the corporations in the sample. The adjusted economic results were first of all examined in relationship to the type of hospital (according to owner and legal form), and then in relation to its size, the size of the supervisory board and the education level of the senior hospital manager. A multiple median regression was used for the evaluation. FINDINGS: One of the basic findings was the fact that the hospital's legal form had no influence on economic results. Successful management in the form of adjusted economic results is only associated with the private type of facility ownership. From the perspective of our concept of corporate governance other factors were under observation: the size of the hospital, the size of the supervisory board and the medical qualifications of the senior manager had no statistically verifiable influence on the efficiency of the hospital management, though we did record certain developments as a result of the transformation process. The economic results that were reported were significantly distorted by the operating subsidies from the founder. PRACTICAL IMPLICATIONS: The results can be used immediately on several practical levels: on the macro level as part of the state's formulation of health policy, particularly in the optimization of the structure of healthcare providers, as well as for the completion of reforms in legal forms and hospital founders, and on the micro level as part of the effective administration and governance of hospitals through corporate governance regardless of the form of ownership. PMID- 26001304 TI - Introducing Ultrasound to Rural Africa: A Radiology Resident's Recipe for Success. PMID- 26001305 TI - Improving Current Procedural Terminology Coding Accuracy in Imaging-Related Musculoskeletal Interventions. PMID- 26001306 TI - ACR Appropriateness Criteria Evaluation of the Symptomatic Male Breast. AB - Most male breast problems are benign, and men with typical symptoms of gynecomastia or pseudogynecomastia do not usually need imaging. When a differentiation between benign disease and breast cancer cannot be made on the basis of clinical findings or when the clinical findings are suspicious for breast cancer, imaging is indicated. Mammography is useful in both identifying cancer and obviating the need for biopsy in patients for whom a benign mammographic impression confirms the clinical impression. However, because of the relationship of breast cancer to increasing age, age-based protocols that do not include mammography have been developed. For men with an indeterminate palpable mass, begin with ultrasound if the patient is <25 years of age, because breast cancer is highly unlikely. Mammography should be performed if ultrasound is suspicious. For men >=25 years of age or having a highly concerning physical examination, usually begin with mammography; ultrasound is useful if mammography is inconclusive or suspicious. The ACR Appropriateness Criteria are evidence based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals, and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26001307 TI - The Wisdom of Tumor Boards. PMID- 26001309 TI - Assembling the Puzzle: Pathways of Oxytocin Signaling in the Brain. AB - Oxytocin (OT) is a neuropeptide, which can be seen to be one of the molecules of the decade due to its profound prosocial effects in nonvertebrate and vertebrate species, including humans. Although OT can be detected in various physiological fluids (blood, saliva, urine, cerebrospinal fluid) and brain tissue, it is unclear whether peripheral and central OT releases match and synergize. Moreover, the pathways of OT delivery to brain regions involved in specific behaviors are far from clear. Here, we discuss the evolutionarily and ontogenetically determined pathways of OT delivery and OT signaling, which orchestrate activity of the mesolimbic social decision-making network. Furthermore, we speculate that both the alteration in OT delivery and OT receptor expression may cause behavioral abnormalities in patients afflicted with psychosocial diseases. PMID- 26001310 TI - Direct Medical Costs and Utilization of Health Care Services to Treat Pneumonia in the United States: An Analysis of the 2007-2011 Medical Expenditure Panel Survey. AB - PURPOSE: This study aimed to assess how pneumonia incidence, health care resource utilization, costs, and hospital length of stay differ by age category in the United States. METHODS: A retrospective cross-sectional analysis of the Medical Expenditure Panel Survey database was conducted from 2007 to 2011 for patients with pneumonia. Study outcomes were pneumonia incidence, annual health care utilization, and expenditures across 5 age groups. Early trends of outcomes in the period after introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) (2011) were compared with the pre-PCV13 period (2007-2009). FINDINGS: Pneumonia incidence rates for the 1790 patients ranged from 9.2 to 33.0 per 1000 patients. Patients <5 years old had the highest incidence rate at 33.0 per 1000 patients, followed by patients >=65 years old (27.2 per 1000 patients) and patients >=45 to <65 years old (14.4 per 1000 patients). The percentages of patients with pneumonia-related hospitalization were 26%, 7%, 15%, 24%, and 46%, respectively (P < 0.0001). Mean (SD) days in hospital stay were 1.73 (0.08), 0.31 (0.50), 0.58 (0.10), 1.86 (0.29), and 3.05 (0.33), respectively (P < 0.05), for patients <5, >=5 to <18, >=18 to <45, >=45 to <65, and >=65 years old. Mean total pneumonia-related medical costs in patients aged <5 years ($3376; P = 0.009), >=45 to <=65 years ($4726; P < 0.0001), and >65 years ($7206; P < 0.0001) were significantly higher compared with patients >=5 to <18 years old ($1175) after controlling for covariates. Compared with the pre-PCV13 period (2007-2009; n = 1075), a 16% decrease in incidence, a 27% decrease length of stay in hospital, and a 22% decrease in medical costs were observed in the post-PCV13 period (2011; n = 382), although these differences were not statistically significant (P > 0.05). IMPLICATIONS: Pneumonia remains a disease with significant burden in the United States, and clinical and economic outcomes varied widely by age. Hospitalization for pneumonia has a considerable effect on economic burden, particularly for the very young (<5 years old), middle-aged (>=45 to <65 years old), and elderly (>=65 years old) populations. A trend toward reductions in pneumonia incidence and associated medical costs was observed after the PCV13 was introduced, although these findings were not statistically significant. PMID- 26001311 TI - Glycaemic control in people with diabetes influences the beneficial role of physical activity on cardiovascular mortality. Prospective data from the HUNT Study, Norway. AB - AIM: To examine whether glycaemic control in people with diabetes, measured as glycated haemoglobin (HbA1c), influences the role of leisure time physical activity on the increased risk of death from cardiovascular disease. METHODS: We prospectively examined the joint association of diabetes according to glycemic control, measured as glycated haemoglobin (HbA1c), and physical activity with cardiovascular mortality. A total of 53,549 were followed up for 12 years through the Norwegian Cause of Death Registry. Cox proportional adjusted hazard ratios (HRs) with 95% confidence intervals (CI) were estimated. RESULTS: Overall, 1710 people died from cardiovascular disease during the follow-up. Compared to the reference group of inactive people without diabetes, people with diabetes and HbA1c<8.0%, had a hazard ratio (HR) of 1.46 (95% CI: 0.96, 2.21) if they were physically inactive and a HR of 1.33 (95% CI: 0.81, 2.19) if they were physically active. Among people with diabetes and HbA1c >= 8.0%, the corresponding comparison gave HRs 2.69 (95% CI: 2.11, 3.42) and 0.93 (95% CI: 0.64, 1.36), respectively. CONCLUSIONS: The data suggest that physical activity should be more strongly encouraged as a therapeutic measure additional to medical treatment, especially among those with most severe hyperglycemia. PMID- 26001313 TI - Risk Factors for Recurrent Clostridium difficile Infection in Children: A Nested Case-Control Study. AB - OBJECTIVE: To identify risk factors for recurrent Clostridium difficile infection (RCDI) in children. STUDY DESIGN: A nested case-control study was performed to identify RCDI risk factors using a pediatric cohort of inpatients and outpatients diagnosed with Clostridium difficile infection by tcdB polymerase chain reaction (PCR) at an academic children's hospital between December 9, 2012, and June 30, 2014. Strict inclusion criteria were adopted to limit selection bias related to inappropriate inclusion of patients with probable C difficile colonization. RESULTS: Thirty children with RCDI were compared with 94 children with non-RCDI. Statistically significant associations were identified between RCDI and malignancy (OR 2.8, 95% CI 1.0-7.4, P = .044), tracheostomy tube dependence (OR 5.2, 95% CI 1.1-24.7, P = .037), and tcdB PCR cycle threshold (OR 0.87, 95% CI 0.78-0.97, P = .01) using multivariable logistic regression modeling. The receiver operator characteristic curve for PCR cycle threshold as a predictor of RCDI demonstrated area under the curve = 0.67. The highest predictive rate (75%) for RCDI was demonstrated at cycle threshold cutpoint <= 20. The difference between sensitivity (64%) and specificity (68%) was minimized at cycle threshold cutpoint <= 23. Compared with controls with non-RCDI, children excluded because of probable C difficile colonization had a similar cycle threshold value (27.5 vs 27.2, P = .77). CONCLUSIONS: Malignancy and tracheostomy tube dependence were identified as RCDI risk factors. Although RCDI was associated with positivity at a lower tcdB PCR cycle threshold, the clinical utility of cycle threshold as a tool to predict recurrence was limited. Better methods to predict RCDI are needed to prioritize pediatric populations to target for RCDI prevention efforts. PMID- 26001312 TI - The choreography of neuroinflammation in Huntington's disease. AB - Currently, the concept of 'neuroinflammation' includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. The roles of brain-resident and peripheral immune cells in these inflammatory settings are poorly understood, and it is unclear whether neuroinflammation results from immune reaction to neuronal dysfunction/degeneration, and/or represents cell-autonomous phenotypes of dysfunctional immune cells. Here, we review recent studies examining these questions in the context of Huntington's disease (HD), where mutant Huntingtin (HTT) is expressed in both neurons and glia. Insights into the cellular and molecular mechanisms underlying neuroinflammation in HD may provide a better understanding of inflammation in more complex neurodegenerative disorders, and of the contribution of the neuroinflammatory component to neurodegenerative disease pathogenesis. PMID- 26001314 TI - Downregulation of Umbilical Cord Blood Levels of miR-374a in Neonatal Hypoxic Ischemic Encephalopathy. AB - OBJECTIVE: To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction. RESULTS: Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction in expression among infants with HIE compared with those with perinatal asphyxia and healthy controls (mean relative quantification [SD] = 0.52 [0.37] vs 1.10 [1.52] vs 1.76 [1.69], P < .02). CONCLUSIONS: We have shown a significant step-wise downregulation of hsa-miR-374a expression in cord blood of infants with perinatal asphyxia and subsequent HIE. PMID- 26001316 TI - Factors Associated with Pain Severity in Children with Calcaneal Apophysitis (Sever Disease). AB - OBJECTIVE: To identify any association between the pain experienced as a result of calcaneal apophysitis, anthropometric data, and lower limb measurements. STUDY DESIGN: This study was a cross-sectional study, nested within a wider randomized, comparative efficacy trial. One hundred twenty-four children between the ages of 8 and 14 years with a clinical diagnosis of calcaneal apophysitis were recruited for this study. Of the participating children, 72 were male. The measures recorded were height, weight, waist circumference, body mass index, foot posture, and ankle joint range of motion; comparison with normative values was also completed. Univariate and multivariable regression analyses were undertaken to identify factors associated with the severity of pain experienced (visual analog scale). RESULTS: The children within this study had a higher mean body mass index (P < .001), increased weight (P < .001), and were taller (P < .001) compared with normative values. The children also demonstrated differences in foot posture and ankle joint range of motion. Multivariable regression analyses identified that older participants (P = .046) and those who had experienced pain for longer (P = .043) reported higher pain severity. CONCLUSIONS: Children presenting with calcaneal apophysitis were anthropometrically different from their peers and had experienced a lengthy period of pain. Therefore, early management focussing on the anthropometric differences may minimize the intensity and duration of pain experienced. TRIAL REGISTRATION: Registered with Australian New Zealand Clinical Trials Registry: ACTRN12609000696291. PMID- 26001317 TI - Timing of adiposity rebound and prevalence of obesity. PMID- 26001315 TI - Antiretroviral Drugs in Meconium: Detection for Different Gestational Periods of Exposure. AB - OBJECTIVES: To determine whether antiretroviral (ARV) medications can be detected in meconium from second or third trimester, labor and delivery (L&D), or postnatal exposures. STUDY DESIGN: Twenty ARV medications were quantified by liquid chromatography-tandem mass spectrometry in 598 meconium samples from uninfected infants born to pregnant women with HIV enrolled in the Pediatric HIV/AIDS Cohort Study. RESULTS: ARV detection in meconium following third trimester exposure was 85.7%-94.4% for all ARVs except stavudine (0%, n = 2), likely because of low doses and a high limit for quantification. Of 107 samples with some second trimester only ARV exposures, meconium was positive for only lopinavir, tenofovir, or efavirenz in 11.8%-14.3% of exposed neonates; administration of these ARVs occurred between gestational weeks 25-28 in the positive samples. Days without lopinavir or tenofovir before delivery significantly correlated with decreasing concentrations of lopinavir and tenofovir in meconium. Tenofovir and lamivudine concentrations significantly correlated with increasing gestational age among infants with continuous second and third trimester exposure. Zidovudine given during L&D or for neonatal prophylaxis was detected in 95.1% and 94.6% of meconium samples, respectively. CONCLUSIONS: Changes in ARV treatments during pregnancy offered a unique opportunity to investigate ARV detection in meconium. ARVs in meconium primarily reflect third trimester ARV exposures, although 6 of 107 second trimester only exposures were detected. Zidovudine administration during L&D was detected in meconium indicating potential urine contamination or rapid incorporation into meconium. These data will improve interpretation of meconium drug test results. PMID- 26001318 TI - The effect of remifentanil on the minimum alveolar concentration of isoflurane in children. AB - STUDY OBJECTIVE: To evaluate the effect of remifentanil on the isoflurane end tidal concentration required to eliminate movement reaction upon surgical incision in children. DESIGN: Prospective, double blinded, serial study. SETTING: Operating room of a university-affiliated hospital. PATIENTS: Patients of ASA status 1 or 2, aged 4 to 7 years, scheduled for either inguinal hernia repair or orchidopexy surgery with general anesthesia. INTERVENTIONS AND MEASUREMENTS: After endotracheal intubation, 108 children serially received 1 of 6 dose (nil, 0.05, 0.10, 0.15, 0.20, or 0.25 MUg kg(-1) min(-1)) of remifentanil. End-tidal isoflurane concentration was adjusted according to a Dixon's up-and-down approach. Twenty-five minutes after starting the remifentanil infusion, the surgical incision was performed. The response of patients was classified as either "response" or "no response." Response was defined as a purposeful response in response to skin incision. MAIN RESULTS: The MAC of isoflurane were 1.50 +/- 0.16%, 1.33 +/- 0.27%, 0.93 +/- 0.13%, 0.73 +/- 0.27%, 0.63 +/- 0.19%, and 0.60 +/- 0.15% for remifentanil infusion rates of nil, 0.05, 0.10, 0.15, 0.20, and 0.25 MUg kg(-1) min(-1), respectively. CONCLUSION: The MAC of isoflurane decreased with increasing infusion rate of remifentanil, showing an initial step reduction followed by a ceiling effect. PMID- 26001319 TI - Synchronous distance anesthesia education by Internet videoconference between Uganda and the United States. AB - STUDY OBJECTIVE: We evaluated the effectiveness of anesthesia education delivered via Internet videoconferencing between the Massachusetts General Hospital, Boston, MA, and Mbarara Regional Referral Hospital, Uganda. DESIGN: This is a prospective educational study. SETTING: The setting is the education in 2 hospitals in Uganda and the United States. SUBJECTS: The subjects are anesthesia residents. INTERVENTIONS: The interventions are anesthesia education lectures delivered in person and via Internet videoconferencing. MEASUREMENTS: The average pre-lecture and post-lecture scores of the local, remote, and combined audiences were compared. MAIN RESULTS: Post-lecture test scores improved over pre-lecture scores: local audience, 59% +/- 22% to 81% +/- 16%, P = .0002, g = 1.144; remote audience, 51% +/- 19% to 81% +/- 8%, P < .0001, g = 2.058; and combined scores, 56% +/- 14% to 82% +/- 8%, P < .0001, g = 2.069). CONCLUSIONS: Transfer of anesthetic knowledge occurs via small group lectures delivered both in person and remotely via synchronous Internet videoconferencing. This technique may be useful to expand educational capacity and international cooperation between academic institutions, a particular priority in the growing field of global health. PMID- 26001321 TI - Re: 'long-term results of a randomized controlled trial analyzing the role of systematic pre-operative coronary angiography before elective carotid endarterectomy in patients with asymptomatic coronary artery disease'. PMID- 26001320 TI - Editor's Choice - ECAR (Endovasculaire ou Chirurgie dans les Anevrysmes aorto iliaques Rompus): A French Randomized Controlled Trial of Endovascular Versus Open Surgical Repair of Ruptured Aorto-iliac Aneurysms. AB - OBJECTIVES/BACKGROUND: ECAR (Endovasculaire ou Chirurgie dans les Anevrysmes aorto-iliaques Rompus) is a prospective multicentre randomized controlled trial including consecutive patients with ruptured aorto-iliac aneurysms (rAIA) eligible for treatment by either endovascular (EVAR) or open surgical repair (OSR). Inclusion criteria were hemodynamic stability and computed tomography scan demonstrating aorto-iliac rupture. METHODS: Randomization was done by week, synchronously in all centers. The primary end point was 30 day mortality. Secondary end points were post-operative morbidity, length of stay in the intensive care unit (ICU), amount of blood transfused (units) and 6 month mortality. RESULTS: From January 2008 to January 2013, 107 patients (97 men, 10 women; median age 74.4 years) were enrolled in 14 centers: 56 (52.3%) in the EVAR group and 51 (47.7%) in the OSR group. The groups were similar in terms of age, sex, consciousness, systolic blood pressure, Hardman index, IGSII score, type of rupture, use of endoclamping balloon, and levels of troponin, creatinine, and hemoglobin. Delay to treatment was higher in the EVAR group (2.9 vs. 1.3 hours; p < .005). Mortality at 30 days and 1 year were not different between the groups (18% in the EVAR group vs. 24% in the OSR group at 30 days, and 30% vs. 35%, respectively, at 1 year). Total respiratory support time was lower in the EVAR group than in the OSR group (59.3 hours vs. 180.3 hours; p = .007), as were pulmonary complications (15.4% vs. 41.5%, respectively; p = .050), total blood transfusion (6.8 vs. 10.9, respectively; p = .020), and duration of ICU stay (7 days vs. 11.9 days, respectively; p = .010). CONCLUSION: In this study, EVAR was found to be equal to OSR in terms of 30 day and 1 year mortality. However, EVAR was associated with less severe complications and less consumption of hospital resources than OSR. PMID- 26001322 TI - Strategies for free flap transfer and revascularisation with long-term outcome in the treatment of large diabetic foot lesions. AB - OBJECTIVE/BACKGROUND: To analyse the impact of ischaemia and revascularisation strategies on the long-term outcome of patients undergoing free flap transfer (FFT) for large diabetic foot lesions penetrating to the tendon, bone, or joint. METHODS: Foot lesions of 63 patients with diabetes (median age 56 years; 70% male) were covered with a FTT in 1991-2003. Three groups were formed and followed until 2009: patients with a native in line artery to the ulcer area (n = 19; group A), patients with correctable ischaemia requiring vascular bypass (n = 32; group B), and patients with uncorrectable ischaemia lacking a recipient vessel in the ulcer area (n = 12; group C). RESULTS: The respective 1, 5, and 10 year amputation free survival rates were 90%, 79%, and 63% in group A; 66%, 25%, and 18% in group B; and 50%, 42%, and 17%, in group C. The respective 1, 5, and 10 year leg salvage rates were 94%, 94%, and 87% in group A; 71%, 65%, and 65% in group B; and 50%, 50%, and 50% in group C. In 1 year, 43%, 45%, and 18% of the patients in groups A, B, and C, respectively, achieved stable epithelisation for at least 6 months. The overall amputation rate was associated with smoking (relative risk [RR] 3.09, 95% confidence interval [CI] 1.8-5.3), heel ulceration (RR 2.25, 95% CI 1.1-4.7), nephropathy (RR 2.24, 95% CI 1.04-4.82), and an ulcer diameter of >10 cm (RR 2.08, 95% CI 1.03-4.48). CONCLUSION: Despite diabetic comorbidities, complicated foot defects may be covered by means of an FFT with excellent long-term amputation free survival, provided that a patent native artery feeds the ulcer area. Ischaemic limbs may also be salvaged with combined FFT and vascular reconstruction in non-smokers and in the absence of very extensive heel ulcers. Occasionally, amputation is avoidable with FFT, even without the possibility of direct revascularisation. PMID- 26001323 TI - So Many False Dawns. PMID- 26001324 TI - Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP). AB - INTRODUCTION: Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics. METHODS: Jacketed external telemetry with an implanted miniature blood pressure transmitter (JET BP) was used to characterize the tolerability, functionality, and sensitivity of this study design in dogs. Thirty-six male or female beagles (n=6 dogs/sex/group) were administered vehicle control (reverse osmosis water) or etilefrine (1, 10mg/kg), sotalol (3, 30mg/kg), and hydralazine (1, 10mg/kg) on separate days. Telemetry data were evaluated for positive control article-related changes and retrospective power analysis was also completed. Animals were evaluated for instrumentation-related changes in clinical and anatomic pathology endpoints. RESULTS: All three positive controls elicited the expected pharmacologic responses that were statistically different at high and low doses. Retrospective power analysis confirmed this study design was able to statistically differentiate minor (approximately 5 to 15%) changes in electrocardiography and blood pressure values. This study also demonstrated the potential advantages of combining cardiovascular data across sex when the test article exposure and pharmacodynamics were consistent. Data collection using miniature telemetry blood pressure transmitters did not result in anatomic or clinical pathology findings that would prevent their use in general toxicology studies. DISCUSSION: This characterization study indicates that JET-BP in dogs offers a scientifically robust method to evaluate novel therapeutics for potential cardiovascular liabilities. PMID- 26001325 TI - QT interval correction assessment in the anesthetized guinea pig. AB - INTRODUCTION: The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP. METHODS: Atrial pacing (n=10), ivabradine or ephedrine (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship. RESULTS: From 100 to 220bpm, QTcb underestimated the change in QT interval duration (QT/HR slope=0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better (QT/HR slope=-0.02 and 0.07) as compared to QTcf (QT/HR slope=-0.18 to -0.1) and QTcVdW (QT/HR slope=-0.2 to -0.17) (p<0.01). All the correction formulas identified dofetilide- and sotalol-dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220bpm) with ephedrine (n=6). DISCUSSION: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula. PMID- 26001326 TI - HPV16 CpG methyl-haplotypes are associated with cervix precancer and cancer in the Guanacaste natural history study. AB - OBJECTIVE: To evaluate HPV16 CpG methylation and methyl-haplotypes and their association with cervix precancer and cancer utilizing massively parallel single molecule next-generation sequencing (NGS). METHODS: A nested case-control study of HPV16 positive women was performed in a prospective cohort from Guanacaste, Costa Rica designed to study the natural history of HPV and cervical neoplasia. Controls encompassed 31 women with transient infections; there were 44 cases, including 31 women with CIN3 and 13 with cervical cancer. DNA samples from exfoliated cervical cells were treated with bisulfite and four regions (E6, E2, L2 and L1) were amplified with barcoded primers and tested by NGS. CpG methylation was quantified using a bioinformatics pipeline. RESULTS: Median methylation levels were significantly different between the CIN3+ cases versus controls in the E2, L2, and L1 regions. Methyl-haplotypes, specifically in 5 CpG sites included in the targeted L2 region, with the pattern "--+-+" had the highest Area Under the Curve value (AUC=88.40%) observed for CIN3 vs. CONTROLS: The most significant CpG site, L2 4277, determined by bisulfite NGS had an AUC=78.62%. CONCLUSIONS: This study demonstrates that NGS of bisulfite treated HPV DNA is a useful and efficient technique to survey methylation patterns in HPV16. This procedure provides quantitative information on both individual CpG sites and methyl-haplotypes that identify women with elevated present or subsequent risk for HPV16 CIN3 and cancer. PMID- 26001327 TI - The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer. AB - OBJECTIVE: Extra-abdominal metastases in epithelial ovarian cancer (EOC) are relatively rare. Interpreting computed tomography (CT) scans, during initial work up, little attention is focused on enlargement of paracardiac lymph nodes (PCLN) and their significance is not clear. We aimed to examine whether the presence of PCLN during initial diagnosis of EOC influences prognosis. METHODS: A retrospective study comparing patients with stage 3 EOC who were diagnosed with PCLN on CT scan during initial evaluation to stage 3C patients without PCLN. Scans were reviewed by a single radiologist for peritoneal involvement, distal metastases and presence of PCLN. Disease status at diagnosis, results of surgery, chemotherapy and response, disease-free interval (DFI) and overall survival (OS) were recorded. RESULTS: Thirty one patients with stage 3C EOC with PCLN on initial CT scan were included and compared with 41 controls. There was no significant difference between groups in abdominal optimal cytoreduction rate. Lower rates of complete response (CR) to initial treatment were detected in the study group (45.2% vs. 78.0%, p=.004). In survival analysis, the DFI for patients with PCLN was shorter (median 9.0 vs. 24.0 months, p=.0097) and overall survival was shorter (median 31.7 vs. 61.3 months, p=.001). Multivariate analysis showed that PCLN was significantly associated with a lower rate of CR, a shorter DFI and a shorter OS. CONCLUSION: The presence of enlarged PCLN at presentation appears to be associated with poor prognosis in stage 3C EOC. Further attention should be given to detection and follow-up of such findings when considering treatment. PMID- 26001329 TI - A novel clinical trial recruitment strategy for women's cancer. AB - OBJECTIVE: To address a deficiency in clinical trial and research enrollment in gynecologic cancer studies, we launched a paper based patient research registry. To improve registry enrollment, we transitioned to an online registry and trial matching mechanism to aid women in accessing open studies. METHODS: Utilizing a validated verification platform, we designed a web-based registry and trial matching mechanism for women over age 18. Participants completed a questionnaire to provide information for trial matching. A focus group of registry participants was held 9 months after the start of the study to evaluate barriers to participation. RESULTS: A total of 322 women were enrolled in the online registry over a 14 month period which was a 4.3 fold increase over the paper-based registry (p<0.0001). Two hundred and sixty three (82%) women were matched to at least one study. Fifteen percent (39/263) of those eligible for studies went on to enroll. The online enrollment rate to studies was not different from that observed in the paper-based registry (26/172, p=0.934), however, the web-based registry linked participants to subsequent studies 27% more rapidly (68 (+/-98) days vs. 93 (+/-81) days for the paper-based registry, p=0.017). Focus group participants identified areas for improvement. CONCLUSION: Web-based patient driven registry provides dramatic improvement in the number of participants enrolled and the time to trial linkage compared to a paper based registry at a single institution. Further studies of barriers to research participation are necessary to improve on this model. PMID- 26001328 TI - Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-alpha and interleukin-6 in predicting reduced progression free survival in epithelial ovarian cancer. AB - OBJECTIVES: Epithelial ovarian cancer (EOC) typically presents with advanced disease. Even with optimal debulking and response to adjuvant chemotherapy, the majority of patients will have disease relapse. We evaluated cytokine and chemokine profiles in ascites at primary surgery as biomarkers for progression free survival (PFS) and overall survival (OS) in patients with advanced EOC. METHODS: Retrospective analysis of patients (n =70) who underwent surgery at Roswell Park Cancer Institute between 2002 and 2012, followed by platinum-based chemotherapy. RESULTS: The mean age at diagnosis was 61.8 years, 85.3% had serous EOC, and 95.7% had stage IIIB, IIIC, or IV disease. Univariate analysis showed that ascites levels of tumor necrosis factor (TNF)-alpha were associated with reduced PFS after primary surgery. Although the ascites concentration of interleukin (IL)-6 was not by itself predictive of PFS, we found that stratifying patients by high TNF-alpha and high IL-6 levels identified a sub-group of patients at high risk for rapid disease relapse. This effect was largely independent of clinical prognostic variables. CONCLUSIONS: The combination of high TNF-alpha and high IL-6 ascites levels at primary surgery predicts worse PFS in patients with advanced EOC. These results suggest an interaction between ascites TNF-alpha and IL-6 in driving tumor progression and resistance to chemotherapy in advanced EOC, and raise the potential for pre-treatment ascites levels of these cytokines as prognostic biomarkers. This study involved a small sample of patients and was an exploratory analysis; therefore, findings require validation in a larger independent cohort. PMID- 26001330 TI - Strategy for design NIR calibration sets based on process spectrum and model space: An innovative approach for process analytical technology. AB - The pharmaceutical industry is under stringent regulations on quality control of their products because is critical for both, productive process and consumer safety. According to the framework of "process analytical technology" (PAT), a complete understanding of the process and a stepwise monitoring of manufacturing are required. Near infrared spectroscopy (NIRS) combined with chemometrics have lately performed efficient, useful and robust for pharmaceutical analysis. One crucial step in developing effective NIRS-based methodologies is selecting an appropriate calibration set to construct models affording accurate predictions. In this work, we developed calibration models for a pharmaceutical formulation during its three manufacturing stages: blending, compaction and coating. A novel methodology is proposed for selecting the calibration set -"process spectrum"-, into which physical changes in the samples at each stage are algebraically incorporated. Also, we established a "model space" defined by Hotelling's T(2) and Q-residuals statistics for outlier identification - inside/outside the defined space - in order to select objectively the factors to be used in calibration set construction. The results obtained confirm the efficacy of the proposed methodology for stepwise pharmaceutical quality control, and the relevance of the study as a guideline for the implementation of this easy and fast methodology in the pharma industry. PMID- 26001332 TI - Granular cell tumors overexpress TFE3 without corollary gene rearrangement- Reply. PMID- 26001331 TI - Broadening the spectrum of SMARCB1-associated malignant tumors: a case of uterine leiomyosarcoma in a patient with schwannomatosis. AB - Schwannomatosis is a tumor predisposition syndrome characterized by development of multiple intracranial, spinal, and peripheral schwannomas. Constitutional alterations in either SMARCB1 or LZTR1 on 22q are responsible of the phenotype. We describe a 34-year-old woman who developed multiple benign peripheral sheath tumors and a uterine leiomyosarcoma. The patient carried a de novo constitutional alteration in exon 8 of SMARCB1, c.1118G > A, which destroyed the splice donor site of intron 8. Two schwannomas and the leiomyosarcoma of the patient retained the SMARCB1 mutation; in addition, the tumors showed loss of the normal chromosome 22. In conclusion, our findings enlarged the spectrum of SMARCB1 predisposing tumors and demonstrated, for the first time, the association of a malignant smooth muscle tumor to schwannomatosis. Therefore, clinicians should definitely be aware that a constitutional SMARCB1 mutation, which mainly predisposes to benign nerve sheath tumors, may also predispose to aggressive neoplasms throughout life, within an unexpected spectrum. PMID- 26001333 TI - Traditional serrated adenoma: an update. AB - Although recognized 25 years ago, the traditional serrated adenoma (TSA) remains an ongoing source of diagnostic and biologic debate. Recent research has greatly improved our understanding of the morphological and molecular aspects of these polyps. In particular, the recognition of ectopic crypt foci (ECFs) in combination with typical cytology and slitlike serrations improves diagnostic reproducibility. Awareness that many TSAs, particularly BRAF-mutated TSAs, arise in precursor microvesicular hyperplastic polyps and sessile serrated adenomas can aid in making this diagnosis and should not be confused with a sessile serrated adenoma with dysplasia. At a molecular level, TSAs can be divided into 2 groups based on their BRAF or KRAS mutation status. The development of overt cytologic dysplasia is accompanied by TP53 mutation, Wnt pathway activation, and, in some cases, silencing of CDKN2A. Importantly, however, mismatch repair enzyme function is retained. Thus, the TSA is an important precursor of aggressive molecular subtypes of colorectal carcinoma. PMID- 26001334 TI - Bonding between CAD/CAM resin and resin composite cements dependent on bonding agents: three different in vitro test methods. AB - OBJECTIVES: The aim of this study was to assess the bonding properties between CAD/CAM resin and three resin composite cements combined with different bonding agents using three test methods. MATERIALS AND METHODS: Four hundred twenty CAD/CAM resin substrates were fabricated and divided into three test methods (shear bond strength (SBS, n = 180), tensile bond strength (TBS, n = 180) and work of adhesion (WA, n = 60)), further into four pretreatment methods (VP connect (VP), visio.link (VL), Clearfil Ceramic Primer (CP) and no pretreatment (CG)) and three cements (RelyX ARC, Variolink II and Clearfil SA Cement). Each subgroup contained 15 specimens. SBS and TBS were measured after 24 h H2O/37 degrees C + 5000 thermal-cycles (5/55 degrees C) and failure types were assessed. WA was determined for pretreated CAD/CAM resin and non-polymerized resin composite cements. Data were analysed with Mann-Whitney U, Kruskal-Wallis H, Chi(2) and Spearman's Rho tests. RESULTS: Within SBS and TBS tests, CGs and groups pretreated with CP (regardless of resin composite cements), and VP pretreated with Clearfil SA Cement showed no bond. However, CG combined with RelyX ARC showed a TBS of 5.6 +/- 1.3 MPa. In general, highest bond strength was observed for groups treated with VL. CG and groups pretreated using VL showed lower WA than the groups treated with VP or CP. CONCLUSIONS: Measured TBS values were higher than SBS ones. In general, SBS and TBS showed similar trends for the ranges of the values for the groups. WA results were not comparable with SBS/TBS results and admitted, therefore, no conclusions on it. CLINICAL RELEVANCE: For a clinical use of XHIP-CAD/CAM resin, the bond surface should be additionally pretreated with visio.link as bonding agent. PMID- 26001335 TI - A Rare Cause of Melena With an Unusual Finding on Gastroscopy. PMID- 26001336 TI - Prevalence of Antibodies Against JC Virus in Patients With Refractory Crohn's Disease and Effects of Natalizumab Therapy. AB - BACKGROUND & AIMS: Natalizumab, a humanized antibody against the alpha4 integrin subunit, effectively induces and maintains remission in patients with Crohn's disease (CD) refractory to conventional treatments. Progressive multifocal leukoencephalopathy is a rare but fatal brain infection caused by John Cunningham (JC) virus and has been associated with natalizumab use. We assessed the prevalence of and risk factors for antibodies to JC virus in serum of patients with refractory CD who were candidates for, or already were receiving, natalizumab. We also assessed the effects of natalizumab treatment of these patients. METHODS: In a retrospective study, we analyzed clinical charts from 191 patients with CD (74 males; mean age, 38.7 y; mean duration of disease, 14.9 y) tested for serum JC virus antibody from December 2012 through May 2014 at 2 medical centers in the United States. We calculated JC virus antibody prevalence and compared the characteristics of patients who tested negative vs those who tested positive, to identify risk factors. We also assessed the rate of subsequent natalizumab use, surgery, and seroconversion during natalizumab therapy. RESULTS: A total of 129 of the patients (67.5%) tested positive for serum JC virus antibody. Multivariate analysis showed that past use of thiopurine was a risk factor for testing positive for JC virus antibody (odds ratio, 7.8; 95% confidence interval, 2.0-30.4; P = .003). Twenty-two of the patients who tested negative for JC virus antibody (35.5%) and 16 of the 129 patients who tested positive (12.4%) had been treated with natalizumab. Cox regression analysis determined that natalizumab use was the only factor associated with avoiding subsequent surgery (hazard ratio, 0.23; 95% confidence interval, 0.06 0.98). Seroconversion (from testing negative to positive for JC virus antibody) occurred in 1 of the 22 patients (4.5%) who initially tested negative during natalizumab therapy. CONCLUSIONS: The prevalence of CD patients exposed to JC virus is comparable with that of the general population. In this retrospective study, prior thiopurine use was associated with an increased risk for testing positive for JC virus antibody. Natalizumab use reduced the risk of subsequent surgery. PMID- 26001337 TI - Relamorelin Relieves Constipation and Accelerates Colonic Transit in a Phase 2, Placebo-Controlled, Randomized Trial. AB - BACKGROUND & AIMS: Ghrelin receptors are located in the colon. Relamorelin is a pentapeptide selective agonist of ghrelin receptor 1a with gastric effects, but its effects in the colon are not known. We aimed to evaluate the effects of relamorelin on bowel movements (BMs) and gastrointestinal and colonic transit (CT) in patients with chronic constipation. METHODS: We performed a study of 48 female patients with chronic constipation who fulfilled the Rome III criteria and had 4 or fewer spontaneous BMs (SBMs)/wk. In a randomized (1:1), double-blind, parallel-group, placebo-controlled trial, the effects of relamorelin (100 MUg/d, given subcutaneously) were tested during 14 days after a 14-day baseline, single blind phase in which patients were given placebo at 2 Mayo Clinic sites. The participants' mean age was 40.6 +/- 1.5 y, with a mean body mass index of 25.7 +/ 0.6 kg/m(2), with 1.7 +/- 0.1 SBM/wk, and a mean stool consistency of 1.2 +/- 0.1 on the Bristol scale during this baseline period. The effect of treatment on transit was measured in 24 participants with colonic transit of less than 2.4 (geometric center at 24 h) during the baseline period. Gastric emptying, small bowel transit, and CT were measured during the last 2 days that patients received relamorelin or placebo. Bowel function was determined from daily diaries kept by patients from days 1 through 28. Study end points were time to first BM, SBMs/wk, complete SBMs/wk, stool form, and ease of stool passage. Effects of relamorelin were assessed by analysis of covariance. RESULTS: Compared with placebo, relamorelin accelerated gastric emptying half-time (P = .027), small-bowel transit (P = .051), and CT at 32 hours (P = .040) and 48 hours (P = .017). Relamorelin increased the number of SBMs (P < .001) and accelerated the time to first BM after the first dose was given (P = .004) compared with placebo, but did not affect stool form. Adverse events associated with relamorelin included increased appetite, fatigue, and headache. CONCLUSIONS: Relamorelin acts in the colon to significantly reduce symptoms of constipation and accelerate CT in patients with chronic constipation, compared with placebo. ClinicalTrial.Gov registration number: NCT01781104. PMID- 26001338 TI - Detection of Dysplasia or Cancer in 3.5% of Patients With Inflammatory Bowel Disease and Colonic Strictures. AB - BACKGROUND & AIMS: Colonic strictures complicate inflammatory bowel disease (IBD) and often lead to surgical resection to prevent dysplasia or cancer. We assessed the frequency of dysplasia and cancer among IBD patients undergoing resection of a colorectal stricture. METHODS: We analyzed data from the Groupe d'etudes et therapeutiques des affections inflammatoires du tube digestif study. This was a nationwide retrospective study of 12,013 patients with IBD in France who underwent surgery for strictures at 16 centers from August 1992 through January 2014 (293 patients for a colonic stricture, 248 patients with Crohn's disease, 51% male, median age at stricture diagnosis of 38 years). Participants had no preoperative evidence of dysplasia or cancer. We collected clinical, endoscopic, surgical, and pathology data and information on outcomes. RESULTS: When patients were diagnosed with strictures, they had IBD for a median time of 8 years (3-14). The strictures were a median length of 6 cm (4-10) and caused symptoms in 70% of patients. Of patients with Crohn's disease, 3 (1%) were found to have low-grade dysplasia, 1 (0.4%) was found to have high-grade dysplasia, and 2 (0.8%) were found to have cancer. Of patients with ulcerative colitis, 1 (2%) had low-grade dysplasia, 1 (2%) had high-grade dysplasia, and 2 (5%) had cancer. All patients with dysplasia or cancer received curative surgery, except 1 who died of colorectal cancer during the follow-up period. No active disease at time of surgery was the only factor associated with dysplasia or cancer at the stricture site (odds ratio, 4.86; 95% confidence interval, 1.11-21.27; P = .036). CONCLUSIONS: In a retrospective study of patients with IBD undergoing surgery for colonic strictures, 3.5% were found to have dysplasia or cancer. These findings can be used to guide management of patients with IBD and colonic strictures. PMID- 26001339 TI - Effect of once-daily generic ciclesonide on exhaled nitric oxide in atopic children with persistent asthma. AB - BACKGROUND: Ciclesonide (CIC) is an effective inhaled corticosteroid for treating asthmatic children. However, its effect on airway inflammation assessed by the fraction of exhaled nitric oxide (FENO) in children with persistent asthma is virtually unknown. We aimed to assess the effect of once-daily generic CIC, 80 or 160 MUg, on FENO, lung function, asthma control and bronchial hyperresponsiveness, in atopic children with persistent asthma. METHODS: This was a 12-week, randomised, double-blind, parallel-group study. Sixty children with mild-to-moderate persistent asthma were recruited. Changes in FENO, asthma control score, lung function (FEV1) and bronchial hyperresponsiveness to methacholine (BHR) were used to assess the effects of both CIC doses. Non normally distributed variables were log-transformed to approximate normality, and parametric tests were used for comparisons within and between groups at baseline and after 12 weeks of treatment. RESULTS: In the CIC 80 MUg group, FENO decreased from 45.0 ppb (95% CI 37.8-53.7) to 32.7 ppb (95% CI 21.0-47.3) at the end of study (P=0.021), whereas in the CIC 160 MUg group, FENO decreased from 47.3 ppb (95% CI 40.4-55.3) to 30.5 ppb (95% CI 24.1-38.7) (P<0.001). The difference between groups in FENO at the end of study was not significant (P=0.693). There was a significant improvement of asthma control with both CIC doses but there was no significant change in BHR or FEV1 in either group. CONCLUSION: Once-daily generic ciclesonide (80 MUg or 160 MUg), for 12 weeks, is effective to improve airway inflammation and asthma control in atopic children with persistent asthma. PMID- 26001340 TI - Novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone: a new class of beta-glucuronidase inhibitors and in silico studies. AB - A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a-3r) was synthesized and evaluated for their potential as beta-glucuronidase inhibitors. Several compounds such as 3a-3d, 3e-3j, 3l-3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50=48.4+/ 1.25MUM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies. PMID- 26001341 TI - Preparation and biological evaluation of conformationally constrained BACE1 inhibitors. AB - The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described. PMID- 26001342 TI - Trichormamides C and D, antiproliferative cyclic lipopeptides from the cultured freshwater cyanobacterium cf. Oscillatoria sp. UIC 10045. AB - Extract from the cultured freshwater cf. Oscillatoria sp. UIC 10045 showed antiproliferative activity against HT-29 cell line. Bioassay-guided fractionation led to the isolation of two new cyclic lipopeptides, named trichormamides C (1) and D (2). The planar structures were determined by combined analyses of HRESIMS, Q-TOF ESIMS/MS, and 1D and 2D NMR spectra. The absolute configurations of the amino acid residues were assigned by advanced Marfey's analysis after partial and complete acid hydrolysis. Trichormamides C (1) is a cyclic undecapeptide and D (2) is a cyclic dodecapeptide, both containing a lipophilic beta-aminodecanoic acid residue. Trichormamide C (1) displayed antiproliferative activities against HT-29 and MDA-MB-435 cancer cell lines with IC50 values of 1.7 and 1.0MUM, respectively, as well as anti-Mycobacterium tuberculosis activity with MIC value of 23.8MUg/mL (17.3MUM). Trichormamide D (2) was found to be less potent against both HT-29 and MDA-MB-435 cancer cell lines with IC50 values of 11.5 and 11.7MUM, respectively. PMID- 26001343 TI - Synthesis and antimicrobial activity of chloramphenicol-polyamine conjugates. AB - A series of chloramphenicol (CAM) amides with polyamines (PAs), suitable for structure-activity relationship studies, were synthesized either by direct attachment of the PA chain on the 2-aminopropane-1,3-diol backbone of CAM, previously oxidized selectively at its primary hydroxyl group, or from chloramphenicol base (CLB) through acylation with succinic or phthalic anhydride and finally coupling with a PA. Conjugates 4 and 5, in which the CLB moiety was attached on N4 and N1 positions, respectively, of the N(8),N(8)-dibenzylated spermidine through the succinate linker, were the most potent antibacterial agents. Both conjugates were internalized into Escherichia coli cells by using the spermidine-preferential uptake system and caused decrease in protein and polyamine content of the cells. Noteworthy, conjugate 4 displayed comparable activity to CAM in MRSA or wild-type strains of Staphylococcus aureus and Escherichia coli, but superior activity in E. coli strains possessing ribosomal mutations or expressing the CAM acetyltransferase (cat) gene. Lead compounds, and in particular conjugate 4, have been therefore discovered during the course of the present work with clinical potential. PMID- 26001344 TI - Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues. AB - A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3 phosphonates have been synthesized via cycloaddition of N-methyl-C (diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9MUM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45 58MUM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73MUM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19MUM range. PMID- 26001345 TI - Best BETS - The next chapter. PMID- 26001346 TI - [Toothache: At what point has a pontocerebellar angle tumor to be evoked?]. AB - INTRODUCTION: Dental pain may have another origin than teeth. It may be caused by myofascial, neurovascular, cardiac, neurological, sinusal or psychological factors. We will discuss 2 rare cases of patients who presented with a cerebellopontine tumor, who initially manifested with symptoms of dental pain. OBSERVATION: The first patient, male, 44 years of age presented to his dentist with toothache (47), which led to its extraction. Five months later, a second painful episode, more characteristic, revealed the presence of a vestibular schwannoma, which was successfully treated and led to the disappearance of the pain. The second case, a 43-year-old female presented to her dentist with toothache (46), which lead the dentist perform a root filling. Two years later, with a 3rd episode of dental pain, more relevant of a trigeminal neuralgia, a epidermoid cyst of the right cerebellopontine angle was identified and successfully treated leading to the disappearance of the pain. DISCUSSION: Cerebellopontine tumors of this type may lead, in exceptional cases to symptoms of dental pain. Therefore, in face of atypical tooth or facial pain, both a detailed medical history and a detailed examination are necessary, in order to investigate any neurological signs and symptoms, before undertaking any non essential dental treatment, which may be detrimental for the patients. PMID- 26001347 TI - [Surgery of pleomorphic adenoma of the parotid gland]. AB - INTRODUCTION: Pleomorphic adenoma is the most common benign tumor of the parotid gland. It has a tendency of recurrence and malignant transformation. The surgical excision of this lesion continues to be the subject of a major debate. In this study, we discuss optimal surgical options for pleomorphic adenoma. MATERIALS AND METHODS: We reviewed clinical records of 82 patients who underwent surgery. RESULTS: The tumor was localized in the superficial lobe in 81.7% of cases. Tumors of the deep lobe were removed by total parotidectomy. Those of the superficial lobe underwent partial exofacial parotidectomy (7 cases), exofacial parotidectomy (44 cases), or total parotidectomy (16 cases). Transitory facial paralysis was higher after total parotidectomy. Only one patient developed a recurrence, his tumor showed capsule infiltration. DISCUSSION: Conventional or partial superficial parotidectomy may be a good compromise with fewer complications and low incidence of recurrence. PMID- 26001348 TI - PROMIS Physical Function Computer Adaptive Test Compared With Other Upper Extremity Outcome Measures in the Evaluation of Proximal Humerus Fractures in Patients Older Than 60 Years. AB - OBJECTIVES: To compare the PROMIS Physical Function Computer Adaptive Test (PROMIS PF CAT) to commonly used traditional PF measures for the evaluation of patients with proximal humerus fractures. DESIGN: Prospective. SETTING: Two Level I trauma centers. PATIENTS/PARTICIPANTS: Forty-seven patients older than 60 years with displaced proximal humerus fractures treated between 2006 and 2009. INTERVENTION: Evaluation included completion of the PROMIS PF CAT, the Constant Shoulder Score, the Disabilities of the Arm, Shoulder, and Hand (DASH) and the Short Musculoskeletal Functional Assessment (SMFA). MAIN OUTCOME MEASUREMENT: Observed correlations among the administered PF outcome measures. RESULTS: On average, patients responded to 86 outcome-related items for this study: 4 for the PROMIS PF CAT (range: 4-8 items), 6 for the Constant Shoulder Score, 30 for the DASH, and 46 for the SMFA. Time to complete the PROMIS PF CAT (median completion time = 98 seconds) was significantly less than that for the DASH (median completion time = 336 seconds, P < 0.001) and for the SMFA (median completion time = 482 seconds, P < 0.001). PROMIS PF CAT scores correlated statistically significantly and were of moderate-to-high magnitude with all other PF outcome measure scores administered. CONCLUSIONS: This study suggests using the PROMIS PF CAT as a sole PF outcome measure can yield an assessment of upper extremity function similar to those provided by traditional PF measures, while substantially reducing patient assessment time. PMID- 26001349 TI - A microstructurally based continuum model of cartilage viscoelasticity and permeability incorporating measured statistical fiber orientations. AB - The remarkable mechanical properties of cartilage derive from an interplay of isotropically distributed, densely packed and negatively charged proteoglycans; a highly anisotropic and inhomogeneously oriented fiber network of collagens; and an interstitial electrolytic fluid. We propose a new 3D finite strain constitutive model capable of simultaneously addressing both solid (reinforcement) and fluid (permeability) dependence of the tissue's mechanical response on the patient-specific collagen fiber network. To represent fiber reinforcement, we integrate the strain energies of single collagen fibers weighted by an orientation distribution function (ODF) defined over a unit sphere over the distributed fiber orientations in 3D. We define the anisotropic intrinsic permeability of the tissue with a structure tensor based again on the integration of the local ODF over all spatial fiber orientations. By design, our modeling formulation accepts structural data on patient-specific collagen fiber networks as determined via diffusion tensor MRI. We implement our new model in 3D large strain finite elements and study the distributions of interstitial fluid pressure, fluid pressure load support and shear stress within a cartilage sample under indentation. Results show that the fiber network dramatically increases interstitial fluid pressure and focuses it near the surface. Inhomogeneity in the tissue's composition also increases fluid pressure and reduces shear stress in the solid. Finally, a biphasic neo-Hookean material model, as is available in commercial finite element codes, does not capture important features of the intra tissue response, e.g., distributions of interstitial fluid pressure and principal shear stress. PMID- 26001350 TI - [Pathology of the mediastinum. Case 5. Well-differentiated neuroendocrine carcinoma. Atypical carcinoid]. PMID- 26001351 TI - [Pathology of the mediastinum. Case 6. Intimal sarcoma]. PMID- 26001352 TI - [Pathology of the mediastinum. Case 8. Seminoma]. PMID- 26001353 TI - [Pathology of the mediastinum. Case 3. Type AB thymoma]. PMID- 26001354 TI - [Pathology of the mediastinum. Pre-test]. PMID- 26001355 TI - [Pathology of the mediastinum. Case 2. B cell unclassifiable lymphoma with intermediate features between classic Hodgkin lymphoma and primary large B cell lymphoma]. PMID- 26001357 TI - Colistin and neurotoxicity: recommendations for optimal use in cystic fibrosis patients. AB - Case description The use of i.v. colistin reappeared recently for the treatment of multidrug-resistant Gram negative organisms in the intensive care and cystic fibrosis (CF) setting. According to the latest pharmacokinetic data, a loading dose and high antibiotic doses are given. Two cases of adverse events (paraesthesias, bad taste) were observed immediately after the start of infusion of a high dose of i.v. colistin in adult CF patients at the Ghent University Hospital. Conclusion Recommendations for optimal administration of i.v. colistin in adult CF patients are scarce. This article highlights the importance of mode of administration to avoid toxicity and relates it to recent pharmacokinetic/ dynamic literature. PMID- 26001356 TI - Effectiveness of clinical pharmacy services: an overview of systematic reviews (2000-2010). AB - BACKGROUND: Multiple reviews have evaluated the impact of pharmacist-delivered patient care on health-related outcomes. However, it is unclear which of the pharmacist-delivered interventions in these services are the most effective. Aim of the review To gather the evidence of the impact of clinical pharmacy services on the medication use process or on patient outcomes using an overview of systematic reviews. METHODS: PubMed was searched to retrieve systematic reviews published between 2000 and 2010 that assessed the impact of clinical pharmacy services on the medication use process or patient outcomes. Two independent reviewers evaluated the study eligibility and one extracted the description and results of the services. The methodological quality of each review was assessed with the R-AMSTAR tool. RESULTS: Of the 343 potentially relevant records identified, 49 systematic reviews, comprising a total of 269 randomized controlled trials, met the selection criteria. Clinical pharmacy services that focused on specific medical conditions, such as hypertension or diabetes mellitus, revealed a positive impact of pharmacists' interventions on patient outcomes. For other medical conditions, however, the results were inconclusive (e.g., dyslipidemia or thromboprophylaxis). Interventions that targeted medication adherence and assessed the impact of clinical pharmacy services in prescription appropriateness also produced inconclusive results because of the variability of methods used to assess both medication adherence and medication appropriateness. CONCLUSIONS: Systematic reviews that assessed clinical pharmacy services targeting specific conditions were more conclusive given that the intervention was well defined, and the measured outcomes were unequivocal and tangible. Conversely, the results were inconclusive for interventions with a broader target and with monitoring parameters that were unclearly established or inconsistently assessed across studies. These findings emphasize the need to better define clinical pharmacy services and standardize methods that assess the impact of these services on patient health outcomes. PMID- 26001358 TI - [Implantable cardioverter-defibrillator at the end of life]. AB - Brady- and tachyarrhythmias at the end of life are common observations. Implantable cardioverter-defibrillators answer with antibrady and antitachycardia pacing, which will not be associated with any complaints of the dying patient. In contrast, defibrillation and cardioversion shocks are extremely painful. Therefore shocks should be inactivated at the end of life. Family doctors, internists, emergency physicians and paramedics are unable to inactivate shocks. Deactivation of shocks at the end of life is not comparable to euthanasia or assisted suicide, but allow the patient to die at the end of an uncurable endstage disease. Deactivation of shocks should be discussed with the patient before initial implantation of the devices. The precise moment of the inactivation at the end of life should be discussed with patients and relatives. There is no common recommendation for the time schedule of this decision; therefore it should be based on the individual situation of the patient. Emergency health care physicians need magnets and sufficient information to inactivate defibrillators. The wishes of the patient have priority in the decision process and should be written in the patient's advance directive, which must be available in the final situation. However the physician must not necessarily follow every wish of the patient. As long as the laws in the European Union are not uniform, German recommendations are needed. PMID- 26001360 TI - An unexpected late complication of retropubic midurethral sling: vaginal obliteration. PMID- 26001359 TI - [Primary and secondary prophylactic ICD therapy in congenital electrical and structural cardiomyopathies]. AB - Congenital electrical and structural cardiomyopathies are rare and associated with an increased risk for syncope and sudden cardiac death in the young. Due to the young age of the patients and the limited data available, risk stratification and especially ICD therapy are challenging. In this young patient collective, ICD therapy is associated with a high complication rate, which does not justify unreserved primary prophylactic ICD implantation. The aim of this review is to elucidate risk stratification and ICD therapy of various electrical and structural cardiomyopathies. PMID- 26001361 TI - Abdominal strength in voiding cystometry: a risk factor for recurrent urinary tract infections in women. AB - INTRODUCTION AND HYPOTHESIS: Recurrent urinary tract infections are a common condition in women. The aim of this study is the evaluation of lower urinary tract dysfunctions that are risk factors for recurrent urinary tract infections in women. METHODS: We conducted a case-control study in 49 women with recurrent urinary tract infections (rUTIs) and 49 control women without rUTIs, comparing the urinary symptoms and urodynamic data of both groups. RESULTS: The main significant differences between these groups were age (the women were older in the control group) and the value of abdominal pressure during voiding cystometry (this was higher in the group with rUTIs). After controlling age as a confounding factor, it was confirmed that the value of maximum abdominal pressure during voiding was the only factor to facilitate the rUTIs and the ideal cut-off was 28 cm H(2)O. CONCLUSIONS: Abdominal strength in the voiding phase constitutes a risk factor for recurrent urinary tract infections in women. PMID- 26001362 TI - Mest and Sfrp5 are biomarkers for healthy adipose tissue. AB - Obesity depends on a close interplay between genetic and environmental factors. However, it is unknown how these factors interact to cause changes in the obese condition during the progression of obesity from the neonatal to the aged individual. We have utilized Mest and Sfrp5 genes, two genes highly correlated with adipose tissue expansion in diet-induced obesity, to characterize the obese condition during development of 2 genetic models of obesity. A model for the early onset of obesity was presented by leptin-deficient mice (ob/ob), whereas late onset of obesity was induced with high-fat diet (HFD) consumption in C57BL/6J mice with inherent risk of obesity (DIO). We correlated obese and diabetic phenotypes with Mest and Sfrp5 gene expression profiles in subcutaneous fat during pre-weaning, pre-adulthood and adulthood. A rapid development of obesity began in ob/ob mice immediately after weaning at 21 days of age, whereas the obesity of DIO mice was not evident until after 2 months of age. Even after 5 months of HFD treatment, the adiposity index of DIO mice was lower than in ob/ob mice at 2 months of age. In both obesity models, the expression of Mest and Sfrp5 genes increased in parallel with fat mass expansion; however, gene expression proceeded to decrease when the adiposity reached a plateau. The reduction in the expression of genes of caveolae structure and glucose metabolism were also suppressed in the aging adipose tissue. The analysis of fat mass and adipocyte size suggests that reduction in Mest and Sfrp5 is more sensitive to the age of the fat than its morphology. The balance of factors controlling fat deposition can be evaluated in part by the differential expression profiles of Mest and Sfrp5 genes with functions linked to fat deposition as long as there is an active accumulation of fat mass. PMID- 26001363 TI - Thyroid gland rupture after blunt neck trauma: A case report and review of the literature. AB - INTRODUCTION: Soft tissue injuries are relatively common after blunt neck trauma, because of its complex anatomy, many vital structures can be compromised. Isolated trauma to the thyroid is highly uncommon and there are few cases reported in the literature. PRESENTATION OF CASE: A 19 year-old female patient with no known pathologies who sustained direct blunt trauma to the right frontal half of the neck after falling down from a stair case. She arrived at the ER with moderate neck swelling and pain. There were no visible hematomas and no respiratory compromise was noted. Contrast enhanced CT-scan showed rupture and hematoma of the right thyroid lobe; she underwent surgical exploration with hemi thyroidectomy and recovered uneventfully. DISCUSSION: Despite soft tissue injuries are relatively common after blunt neck trauma, isolated thyroid gland injury is extremely rare and is present in about 1-2% of the cases and in most of the cases there is an underlining pathology within the gland. Most patients arrived at the emergency room hemodynamically stable, presenting neck swelling, pain, respiratory distress, dysphagia and hoarseness. Diagnosis strategy should be focused to rule out respiratory or vascular compromise. Surgical exploration remains the most common treatment strategy. CONCLUSIONS: Although the rarity of this condition, physicians should take in mind the possibility of thyroid injury after blunt neck trauma. Early detection and prompt treatment, can reduce life threatening complications. Management should be individualized to patient's characteristics and surgeon's experience. PMID- 26001364 TI - Abdominopelvic actinomycosis in three different locations with invasion of the abdominal wall and ureteric obstruction: An uncommon presentation. AB - INTRODUCTION: Actinomycosis is a rare chronic infectious disease caused by Gram positive anaerobic bacteria that normally colonize the bronchial system and gastrointestinal tract in humans. The most common diseases associated with actinomycosis are orocervicofacial, thoracic and abdominal infections involving Actinomyces israelii. Due to its rarity, its various clinical presentations and often-infiltrative characteristics in radiological imaging, it can easily be mistaken for other clinical conditions, including malignancy. PRESENTATION OF CASE: We present an uncommon case of extended abdominopelvic actinomycosis with infiltrative lesions in multiple locations, including an abscess in the abdominal wall and ureteric obstruction, which underwent successful surgical and subsequent long-term antibiotic therapy. DISCUSSION: To our knowledge, such a combination of different sites of manifestation has not yet been reported for actinomycosis in the presence of an IUD. Possible differential diagnoses included diverticulitis with covered perforation, pelvic inflammatory disease, tuberculosis and inflammatory bowel disease. The possibility of a malignant process required radical resection. As in most cases of actinomycosis, diagnosis could not be established with certainty until postoperative pathology investigation. CONCLUSION: A rare actinomyceal infection should be considered in patients with a non-specific pelvic mass and atypical abdominal presentations, especially if a previous history of IUD usage is known. PMID- 26001365 TI - Brainstem White Matter Predicts Individual Differences in Manual Motor Difficulties and Symptom Severity in Autism. AB - Mounting evidence suggests that poorer motor skills may be related to more severe autism symptoms. This study investigated if atypical white matter microstructure in the brain mediated the relationship between motor skills and ASD symptom severity. Sixty-seven males with ASD and 42 males with typical development (5-33 years old) completed a diffusion tensor imaging scan and measures of grip strength, finger tapping, and autism symptom severity. Within the ASD group, weaker grip strength predicted more severe autism symptoms. Fractional anisotropy of the brainstem's corticospinal tract predicted both grip strength and autism symptom severity and mediated the relationship between the two. These findings suggest that brainstem white matter may contribute to autism symptoms and grip strength in ASD. PMID- 26001366 TI - Intraprocedural 3D Quantification of Lipiodol Deposition on Cone-Beam CT Predicts Tumor Response After Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma. AB - PURPOSE: To evaluate whether intraprocedural 3D quantification of Lipiodol deposition on cone-beam computed tomography (CBCT) can predict tumor response on follow-up contrast-enhanced magnetic resonance imaging (CE-MRI) in patients with hepatocellular carcinoma (HCC) treated with conventional transarterial chemoembolization (cTACE). MATERIALS AND METHODS: This IRB approved, retrospective analysis included 36 patients with 51 HCC target lesions, who underwent cTACE with CBCT. CE-MRI was acquired at baseline and 1 month after cTACE. Overall tumor volumes as well as intratumoral Lipiodol volumes on CBCT were measured and compared with the overall and necrotic (non-enhancing) tumor volumes on CE-MRI using the paired student's t test. Tumor response on CE-MRI was assessed using modified response evaluation criteria in solid tumors (mRECIST). A linear regression model was used to correlate tumor volumes, Lipiodol volumes, and the percentage of Lipiodol deposition on CBCT with the corresponding parameters on CE-MRI. Nonparametric spearman rank-order correlation and trend test were used to correlate the percentage of Lipiodol deposition in the tumor with tumor response. RESULT: A strong correlation between overall tumor volumes on CBCT and CE-MRI was observed (R(2) = 0.986). In addition, a strong correlation was obtained between the volume of Lipiodol deposition on CBCT and tumor necrosis (in cm(3)) on CE-MRI (R(2) = 0.960), and between the percentage of Lipiodol deposition and tumor necrosis (R(2) = 0.979). Importantly, the extent of Lipiodol deposition (in percentage of total tumor volume) correlated strongly with tumor response on CE-MRI (Spearman rho = 0.84, p < 0.001). CONCLUSIONS: Intraprocedural 3D quantification of Lipiodol deposition on CBCT can be used to predict tumor response on follow-up CE-MRI. PMID- 26001367 TI - Laparoscopic Distal Pancreatectomy in Benign or Premalignant Pancreatic Lesions: Is It Really More Cost-Effective than Open Approach? AB - BACKGROUND: Data regarding the quality of life in patients undergoing laparoscopic distal pancreatectomy are lacking and no studies have reported a real cost-effectiveness analysis of this surgical procedure. The aim of this study was to evaluate and compare the quality of life and the cost-effectiveness of a laparoscopic distal pancreatectomy with respect to an open distal pancreatectomy. METHODS: Forty-one patients who underwent a laparoscopic distal pancreatectomy and 40 patients who underwent an open distal pancreatectomy were retrospectively studied as regards postoperative results, quality of life and cost-effectiveness analysis. The Italian neutral version of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C 30, version 3.0, was used to rate the quality of life. RESULTS: Postoperative results were similar in the two groups; the only difference was that the first oral intake took place significantly earlier in the laparoscopic group than in the open group (P < 0.001). Regarding quality of life, the laparoscopic approach was able to ameliorate physical functioning (P = 0.049), role functioning (P = 0.044) and cognitive functioning (P = 0.030) and reduce the sleep disturbance scale (P = 0.050). The cost-effectiveness analysis showed that the acceptability curve for a laparoscopic distal pancreatectomy had a higher probability of being more cost-effective than an open distal pancreatectomy when a willingness to pay above 5400 Euros/quality-adjusted life years (QALY) was accepted. CONCLUSION: Despite the limitations of the study, laparoscopic distal pancreatectomy can be considered not only safe and feasible but also permits a better quality of life and is acceptable in terms of cost-effectiveness to Italian and European health care services. PMID- 26001368 TI - Survival After Resection of Gastrointestinal Stromal Tumor and Sarcoma Liver Metastases in 146 Patients. AB - BACKGROUND: We investigated outcomes by primary tumor type in patients who underwent resection of liver metastases from gastrointestinal stromal tumors (GIST), leiomyosarcomas, and other sarcomas. METHOD: Our institutional liver database was used to identify patients who underwent resection from 1998 through 2013. Histopathological, clinical, and survival data were analyzed. RESULTS: One hundred forty-six patients underwent resection of liver metastases from GIST (n = 49), leiomyosarcomas (n = 47), or other sarcomas (n = 50). The 5-year overall survival (OS) rates in patients with GIST, leiomyosarcomas, and other sarcomas were 55.3, 48.4, and 44.9%, respectively, and the 10-year OS rates were 52.5, 9.2, and 23.0%, respectively. The 5-year recurrence-free survival (RFS) rate was better for GIST (35.7%; p = 0.003) than for leiomyosarcomas (3.4%) and other sarcomas (21.4%). Lung recurrence was more common for leiomyosarcomas (36% of patients; p < 0.0001) than for other sarcomas (12%) and GIST (2%). For GIST, the findings support a benefit of imatinib regarding the 5-year RFS rate compared to resection alone (47.1 vs. 9.5%; p = 0.013). For leiomyosarcoma, primary tumor location did not affect the 5-year RFS rate (intraabdominal 14.5%; other location 0%; p = 0.182). CONCLUSION: Liver metastases from GIST, leiomyosarcomas, and other sarcomas should be assessed separately as their survival and recurrence patterns are different. This is especially important for GIST, for which imatinib is now available. PMID- 26001369 TI - A Multidisciplinary Approach to Medical Weight Loss Prior to Complex Abdominal Wall Reconstruction: Is it Feasible? AB - Obesity is a major risk factor for perioperative morbidity, especially for patients undergoing complex incisional hernia repair. The feasibility and effectiveness of medical weight loss programs prior to complex abdominal wall reconstruction have not been well characterized. Here, we report our experience collaborating with a medical weight loss specialist utilizing a protein sparing modified fast in order to optimize weight loss prior to complex abdominal wall reconstruction. Morbidly obese patients (body mass index (BMI) > 35 kg/m(2)) evaluated by our medical weight loss specialist prior to complex ventral hernia repair were identified within our prospective database. Our primary outcome measure was the amount of weight lost prior to surgical intervention. Our secondary outcome measure was to determine the maintenance of weight loss during long-term follow-up after the surgical intervention. A total of 25 patients with a BMI > 35 kg/m(2) were evaluated by our medical weight loss specialist prior to undergoing a planned incisional hernia repair. The mean weight of the patients preoperatively was 128 kg +/- 25 (range 96-205 kg) (mean +/- standard deviation), and the mean BMI was 49 kg/m(2) +/- 10 (range 36-85). After completion of the preoperative modified protein sparing fast, the mean preoperative weight loss of the group was 24 kg +/- 21 (range 2-80 kg). The overall change in BMI for the group prior to surgery was 9 kg/m(2) +/- 8 (0.6 to 33). The percentage of excess BMI loss and total BMI loss preoperatively was 37 % +/- 23 (2 to 83) and 18 % +/- 12 (1 to 43), respectively. Of the 24 patients that initially lost weight in the program preoperatively, 22 (88 %) successfully maintained their weight loss for the entire study period for an average of 18 months. Collaboration with a medical weight loss specialist and a surgeon with a structured approach using a modified protein sparing fast can successfully result in meaningful weight loss prior to complex abdominal wall reconstruction. The majority of patients in this study were able to maintain their weight loss during long-term follow-up. Utilization of a protein sparing modified fast in collaboration with a medical weight loss specialist is a valuable resource for guiding weight loss in patients with morbid obesity prior to elective complex surgical procedures. PMID- 26001370 TI - Underreporting of Gastrointestinal Stromal Tumors: Is the True Incidence Being Captured? AB - BACKGROUND: Hospital cancer registries are only required to report gastrointestinal stromal tumors (GISTs) if labeled malignant or metastatic, leading to potential loss of cases in national cancer registries. Our objective was to determine whether GISTs are underreported in the US. METHODS: Retrospective review of pathology reports between 2010 and 2013 with diagnosis of GIST was performed at two academic medical centers. Recurrent GISTs were excluded. Pathology reports were cross-referenced to cases reported by each cancer registry. Risk for metastasis/death was determined according to National Comprehensive Cancer Network (NCCN) guidelines. RESULTS: Forty-nine cases of non recurrent GIST were identified. Only 19/49 (38.8%) cases were reported. None of the 30 non-reported cases were labeled malignant/metastatic on final pathology. To illustrate malignant potential, these tumors were risk stratified. Most (60%) of the non-reported cases were low risk, but there were 4 (13.3%) cases each in the intermediate, high, and unknown risk groups. Additionally, 7/30 (23.0%) cases were treated with tyrosine kinase inhibitors, highlighting clinical concern of malignant GIST. CONCLUSIONS: Our results show that nearly two thirds of GIST cases have been underreported, suggesting that current reporting practices underestimate its true incidence. Revision of reporting guidelines may result in a more accurate estimation of the US disease burden of GIST. PMID- 26001371 TI - Solid Pseudopapillary Neoplasms of the Pancreas: a 19-Year Multicenter Experience in China. AB - AIM: The aim of this study was to determine the clinicopathological features, surgical management, and prognosis of solid pseudopapillary neoplasms (SPNs) of the pancreas. METHODS: This study conducted a retrospective analysis of 97 patients who underwent surgery for a pathologically confirmed SPN in five hospitals between January 1996 and December 2014. RESULTS: The 97 cases included 93 female and 4 male patients, and the average age was 31.2 years. The tumor was located in the body or tail (70.1%), the head (20.6%), and the neck (9.3%). All patients underwent surgical exploration, including distal pancreatectomy (63.9%), pancreaticoduodenectomy (20.6%) (partial portal vein or superior mesenteric vein resection and artificial vascular graft reconstruction performed in 4.1% of the patients), central pancreatectomy (10.3%), enucleation (5.2%), and liver resection (1.0%). 16.5% of the patients had malignant tumors. The positive rate of Ki-67 was 66.7% in patients diagnosed with a malignant neoplasm and was comparable to 8.4% of the patients diagnosed to have a benign neoplasm (p < 0.001). After a median follow-up of 70.1 months, three patients had recurrence and one patient died of liver metastasis. CONCLUSIONS: SPN is a rare neoplasm with low malignant potential. Surgical resection is warranted even in the presence of local invasion or metastases as patients demonstrate excellent long term survival. Positive immunoreactivity for Ki-67 may predict the malignant potential and poor outcome of SPNs. PMID- 26001372 TI - Association mapping of soybean seed germination under salt stress. AB - Soil salinity is a serious threat to agriculture sustainability worldwide. Seed germination is a critical phase that ensures the successful establishment and productivity of soybeans in saline soils. However, little information is available regarding soybean salt tolerance at the germination stage. The objective of this study was to identify the genetic mechanisms of soybean seed germination under salt stress. One natural population consisting of 191 soybean landraces was used in this study. Soybean seeds produced in four environments were used to evaluate the salt tolerance at their germination stage. Using 1142 single-nucleotide polymorphisms (SNPs), the molecular markers associated with salt tolerance were detected by genome-wide association analysis. Eight SNP-trait associations and 13 suggestive SNP-trait associations were identified using a mixed linear model and the TASSEL 4.0 software. Eight SNPs or suggestive SNPs were co-associated with two salt tolerance indices, namely (1) the ratio of the germination index under salt conditions to the germination index under no-salt conditions (ST-GI) and (2) the ratio of the germination rate under salt conditions to the germination rate under no-salt conditions (ST-GR). One SNP (BARC-021347-04042) was significantly associated with these two traits (ST-GI and ST-GR). In addition, nine possible candidate genes were located in or near the genetic region where the above markers were mapped. Of these, five genes, Glyma08g12400.1, Glyma08g09730.1, Glyma18g47140.1, Glyma09g00460.1, and Glyma09g00490.3, were verified in response to salt stress at the germination stage. The SNPs detected could facilitate a better understanding of the genetic basis of soybean salt tolerance at the germination stage, and the marker BARC 021347-04042 could contribute to future breeding for soybean salt tolerance by marker-assisted selection. PMID- 26001375 TI - Midazolam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system. AB - Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1alpha and HIF 2alpha proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro. PMID- 26001376 TI - Listeria monocytogenes-carrying consortia in food industry. Composition, subtyping and numerical characterisation of mono-species biofilm dynamics on stainless steel. AB - In order to find out how real Listeria monocytogenes-carrying biofilms are in industrial settings, a total of 270 environmental samples belonging to work surfaces from fish (n = 123), meat (n = 75) and dairy industries (n = 72) were analysed in order to detect L. monocytogenes. 12 samples were positive for L. monocytogenes and a total of 18 different species were identified as accompanying microbiota in fish and meat industry. No L. monocytogenes was found in samples from dairy industry. Molecular characterisation combining results of AscI and ApaI macrorestriction PFGE assays yielded 7 different subtypes of L. monocytogenes sharing in 71.43% of cases the same serogroup (1/2a-3a). Results from dynamic numerical characterisation between L. monocytogenes monospecies biofilms on stainless steel (SS) using MATLAB-based tool BIOFILMDIVER demonstrated that except in isolate A1, in which a significant increase in the percentage of covered area (CA), average diffusion distance (ADD) and maximum diffusion distance (MDD) was observed after 120 h of culture, no significant differences were observed in the dynamics of the rest of the L. monocytogenes isolates. Quantitative dual-species biofilm association experiments performed on SS indicated that L. monocytogenes cell counts presented lower values in mixed species cultures with certain species at 24 and 48 h compared with mono-species culture. However, they remained unaltered after 72 h except when co-cultured with Serratia fonticola which presented differences in all sampling times and was also the dominant species within the dual-species biofilm. When considering frequency of appearance of accompanying species, an ecological distribution was demonstrated as Escherichia coli appeared to be the most abundant in fish industry and Carnobacterium spp. in meat industry. PMID- 26001374 TI - Omega-3 fatty acids, lipid rafts, and T cell signaling. AB - n-3 polyunsaturated fatty acids (PUFA) have been shown in many clinical studies to attenuate inflammatory responses. Although inflammatory responses are orchestrated by a wide spectrum of cells, CD4(+) T cells play an important role in the etiology of many chronic inflammatory diseases such as inflammatory bowel disease and obesity. In light of recent concerns over the safety profiles of non steroidal anti-inflammatory drugs (NSAIDs), alternatives such as bioactive nutraceuticals are becoming more attractive. In order for these agents to be accepted into mainstream medicine, however, the mechanisms by which nutraceuticals such as n-3 PUFA exert their anti-inflammatory effects must be fully elucidated. Lipid rafts are nanoscale, dynamic domains in the plasma membrane that are formed through favorable lipid-lipid (cholesterol, sphingolipids, and saturated fatty acids) and lipid-protein (membrane-actin cytoskeleton) interactions. These domains optimize the clustering of signaling proteins at the membrane to facilitate efficient cell signaling which is required for CD4(+) T cell activation and differentiation. This review summarizes novel emerging data documenting the ability of n-3 PUFA to perturb membrane cytoskeletal structure and function in CD4(+) T cells. An understanding of these underlying mechanisms will provide a rationale for the use of n-3 PUFA in the treatment of chronic inflammation. PMID- 26001373 TI - New targets to treat obesity and the metabolic syndrome. AB - Metabolic syndrome (MetS) is a cluster ofassociated metabolic traits that collectively confer unsurpassed risk for development of cardiovascular disease (CVD) and type 2 diabetes compared to any single CVD risk factor. Truncal obesity plays an exceptionally critical role among all metabolic traits of the MetS. Consequently, the prevalence of the MetS has steadily increased with the growing epidemic of obesity. Pharmacotherapy has been available for obesity for more than one decade, but with little success in improving the metabolic profiles. The serotonergic drugs and inhibitors of pancreatic lipases were among the few drugs that were initially approved to treat obesity. At the present time, only the pancreatic lipase inhibitor orlistat is approved for long-term treatment of obesity. New classes of anti-diabetic drugs, including glucagon-like peptide 1 receptor (GLP-1R) agonists and Dipeptidyl-peptidase IV (DPP-IV) inhibitors, are currently being evaluated for their effects on obesity and metabolic traits. The genetic studies of obesity and metabolic syndrome have identified novel molecules acting on the hunger and satiety peptidergic signaling of the gut-hypothalamus axis or the melanocortin system of the brain and are promising targets for future drug development. The goal is to develop drugs that not only treat obesity, but also favorably impact its associated traits. PMID- 26001377 TI - Reduction and restoration of culturability of beer-stressed and low-temperature stressed Lactobacillus acetotolerans strain 2011-8. AB - Lactic acid bacteria (LAB) are the most common beer-spoilage bacteria, regardless of beer type, and therefore pose significant problems for the brewing industry. The aim of this study was to investigate the viable, but putatively non culturable (VPNC) state of the hard-to-culture beer-spoilage species, Lactobacillus acetotolerans. Upon prolonged contact with degassed beer, L. acetotolerans was found to show decreased culturability. After 17 subcultures in beer, 100-MUL aliquots of the culture were no longer culturable on MRS agar until 14 days of incubation despite the presence of 10(5) viable cells, indicating that a large population of cells entered into a VPNC state. Furthermore, a significant reduction or even putative loss of culturability, but maintenance of viability, of L. acetotolerans could also be induced by storing the strain at 0 degrees C for 105 days. Adding catalase at a concentration of 1000 U/plate enabled the VPNC cells, both induced by beer subculture treatment and cold treatment, to regain culturability with a resuscitation time of 4 days and 3 days, respectively. Scanning electron microscopy results demonstrated that cells decreased in size and gradually changed morphology from short rods to coccoids when they entered the VPNC state. It was concluded that the difficulty in culturing the spoilage bacterium from brewery environments could be partly attributed the hard-to culture or the viable, but non-culturable characteristic of this organism. PMID- 26001378 TI - Effects of carbon, nitrogen and ambient pH on patulin production and related gene expression in Penicillium expansum. AB - Patulin, a potent mycotoxin which can cause serious health concerns, is mainly produced in foods by Penicillium expansum. Environmental factors play important roles in regulating biosynthesis of mycotoxins; however, information about the effects of environmental factors on patulin production and the involved mechanisms in P. expansum is limited. Here, we investigated the effects of different carbon (C) and nitrogen (N) sources, and ambient pH on patulin production in three P. expansum strains T01, M1 and Pe21, and the expression profile of 15 genes involved in patulin biosynthetic pathway. It was found that C and N sources and pH had great influence on patulin production in P. expansum. In general, patulin production of all three P. expansum strains showed similar trends under different C and N sources and pH conditions, though there were some differences in the optimal conditions among these strains. Glucose-containing sugars, complex N sources, and acidic conditions were favorable conditions for patulin production. The results of RT-qPCR showed that the relative expressions of most of the patulin genes were up-regulated under patulin-permissive conditions, indicating that patulin biosynthesis was mainly regulated at transcriptional level by these environmental factors. These findings will provide useful information to better understand the regulation mechanisms of patulin biosynthesis, and be helpful in developing effective means for controlling patulin contamination. PMID- 26001379 TI - Salmonella isolated from ready-to-eat pasteurized liquid egg products: Thermal resistance, biochemical profile, and fatty acid analysis. AB - The Egg Products Inspection Act of 1970 requires that egg products in the U.S. must be pasteurized prior to release into commerce. The USDA Food Safety and Inspection Service (FSIS) is responsible for regulating egg products. Salmonellae are infrequently isolated from pasteurized egg products by food manufacturers or the FSIS and may be present as a result of either pasteurization-resistant bacteria or post-processing contamination. In this study, seventeen strains of Salmonella isolated from pasteurized egg products and three heat-resistant control strains were compared for the following attributes: thermal resistance in liquid whole egg (LWE) at 60 degrees C, enzymatic profiles, and serotyping and phage typing, antibiotic susceptibility, fatty acid analysis and strain morphological variation evaluated by scanning electron microscopy. Isolates were serotyped as Heidelberg (4 isolates), Widemarsh, Mbandaka, Cerro, Thompson, 4,12:i:-, and Enteritidis (8 isolates). All 20 isolates were sensitive to all 14 antibiotics tested for. The D60 values in LWE ranged from 0.34 to 0.58 min. All 20 strains were recovered from LWE inoculated with 8.5 logCFU/mL of Salmonella and pasteurized at 60 degrees C for 3.5 min; however, some isolates were not recovered from pasteurized LWE that had been inoculated with only 4.5 logCFU/mL Salmonella and treated at 60 degrees C for 3.5 min. Although some strains exhibited atypical enzymatic activity (e.g., reduction of adonitol, hydrolysis of proline nitroanilide or p-n-p-beta-glucuronide, and nonreduction of melibiose), differences in biochemical reactions could not be correlated with differences in thermal resistance. Furthermore, fatty acid analysis revealed that differences insaturate/unsaturated profiles may be correlated with differences in heat resistance, in two instances. One heat resistant strain (#13, Enteritidis) had the statistically lowest unsaturated/saturate ratio at 39%. However, one heat sensitive strain (#3, serovar 4,12:i:-) had the highest unsaturated/saturate ratio at 81%, and also the lowest concentration of stearic acid. This data represents the first steps in determining whether Salmonella contamination in pasteurized egg products may be the result of either thermally-resistant isolates or post-processing contamination. Contamination of LWE by Salmonella strains with higher heat resistance, (e.g., isolate #'s 2, 6, 10 and 12) may indicate the ability of Salmonella to survive pasteurization, while contamination of LWE strains with lower heat resistance (e.g., isolate #'s 1, 3, 5, 7, 8, 11, and 15) may indicate post-processing contamination of LWE by this foodborne pathogen. PMID- 26001380 TI - Mitral regurgitation quantification by cardiovascular magnetic resonance: a comparison of indirect quantification methods. AB - Quantification of mitral regurgitation (MR) using cardiovascular magnetic resonance can be achieved by three indirect methods. The aims of the study were to determine their agreement, observer variability and effect on grading MR severity. The study comprised 16 healthy volunteers and 36 MR patients. Quantification was performed using the 'standard' [left ventricular stroke volume (LVSV)-aortic forward flow (AoFF)], 'volumetric' [LVSV-right ventricular stroke volume (RVSV)] and 'flow' method [mitral inflow (MiIF)-AoFF]. In healthy volunteers without MR, LVSV was larger than AoFF (mean difference +/-SD: 12 +/- 6 ml, P < 0.0001). Only small differences were found between LVSV-RVSV (3 +/- 6 ml) and MiIF-AoFF (1 +/- 5 ml). In patients, mitral regurgitant volumes (MRVs)/fractions (MRFs) were larger (P < 0.0001) using the 'standard' method (90 +/- 31 ml/51 +/- 11%) compared with the 'volumetric' (76 +/- 30 ml/42 +/- 11%) and 'flow' method (70 +/- 32 ml/44 +/- 15%). Inter-observer variability was lowest for the 'flow' and highest for the 'volumetric' method, while intra observer variability was similar for all three methods. In 29 operated patients with severe MR, MRVs were above the guideline threshold (>=60 ml) in 100, 86 and 83% of the cases, and MRFs were above the threshold (>=50%) in 76, 32 and 48% of the cases, when using the 'standard', 'volumetric' and 'flow' method respectively. In conclusion, the choice of method can affect the grading of MR severity and thereby eventually the clinical decision-making and timing of surgery. PMID- 26001381 TI - Cross-modal cueing in audiovisual spatial attention. AB - Visual processing is most effective at the location of our attentional focus. It has long been known that various spatial cues can direct visuospatial attention and influence the detection of auditory targets. Cross-modal cueing, however, seems to depend on the type of visual cue: facilitation effects have been reported for endogenous visual cues while exogenous cues seem to be mostly ineffective. In three experiments, we investigated cueing effects on the processing of audiovisual signals. In Experiment 1, we used endogenous cues to investigate their effect on the detection of auditory, visual, and audiovisual targets presented with onset asynchrony. Consistent cueing effects were found in all target conditions. In Experiment 2, we used exogenous cues and found cueing effects only for visual target detection, but not auditory target detection. In Experiment 3, we used predictive exogenous cues to examine the possibility that cue-target contingencies were responsible for the difference between Experiment 1 and 2. In all experiments, we investigated whether a response time model can explain the data and tested whether the observed cueing effects were modality dependent. The results observed with endogenous cues imply that the perception of multisensory signals is modulated by a single, supramodal system operating in a top-down manner (Experiment 1). In contrast, bottom-up control of attention, as observed in the exogenous cueing task of Experiment 2, mainly exerts its influence through modality-specific subsystems. Experiment 3 showed that this striking difference does not depend on contingencies between cue and target. PMID- 26001382 TI - Advancing the science of dissemination and implementation in behavioral medicine: evidence and progress. AB - The enormous time lag between the discovery of new knowledge and its implementation poses a significant challenge to improving public health because of the very slow uptake into policy and practice. The field of dissemination and implementation research in behavioral medicine is receiving increased attention because of the keen interest in accelerating knowledge transfer from relevant research to improve the health and wellbeing of populations in many different settings, contexts, and countries around the world. This is particularly important in high-risk populations, resource-poor and developing regions of the world where the difference in health systems, languages, and cultures very significantly influences the translation of evidence into policy and practice. Moreover, demonstrating the broader societal and economic value of behavioral interventions in settings where they are implemented can further support the sustainability, uptake, and implementation of these findings in other settings and contexts. This special issue presents a series of empirical studies, reviews, and case studies that address dissemination, implementation, and translation issues in both developed and developing countries. Specifically, the learnings from the application of many and varied theories and research methodologies are very relevant for bridging the current division between research findings and their translation and uptake into policy and practice. PMID- 26001383 TI - Development and performance analysis of Si-CaP/fine particulate bone powder combined grafts for bone regeneration. AB - BACKGROUND: Although autogenous bone grafts as well as several bone graft substitute material have been used for some time, there is high demand for more efficient and less costly bone-substitute materials. Silicon-substituted calcium phosphates (Si-CaP) and fine particulate bone powder (FPBP) preparations have been previously shown to individually possess many of the required features of a bone graft substitute scaffold. However, when applied individually, these two materials fall short of an ideal substitute material. We investigated a new concept of combining Si-CaP with FPBP for improved performance in bone-repair. METHODS: We assessed Si-CaP/FPBP combined grafts in vitro, by measuring changes in pH, weight loss, water absorption and compressive strength over time. RESULTS: Si-CaP/FPBP combined grafts was found to produce conditions of alkaline pH levels compared to FPBP, and scaffold surface morphology conducive to bone cell adhesion, proliferation, differentiation, tissue growth and transport of nutrients, while maintaining elasticity and mechanical strength and degradation at a rate closer to osteogenesis. CONCLUSION: Si-CaP/FPBP combined grafts was found to be superior to any of the two components individually. PMID- 26001384 TI - Incidence of lower extremity amputation in the diabetic compared to the non diabetic population: a systematic review protocol. AB - BACKGROUND: Diabetic individuals have a largely increased risk of lower extremity amputation (LEA) compared with non-diabetic patients. Prior systematic reviews of incidence of LEA have some limitations with respect to lack of consensus in the definition of LEA, level of LEA (all, major, minor), and definition of source population (general population or population with diabetes at risk). The purpose of our review is to evaluate the incidence of LEA in the diabetic population and its differences with regard to sex, ethnicity, age, and regions; to compare the incidence rate (IR) in the diabetic and non-diabetic population; and to investigate time trends. METHODS/DESIGN: We will perform a systematic literature search in MEDLINE, Embase, Web of Knowledge, and publisher databases such as Journals@OVID and ScienceDirect. We will develop comprehensive systematic search strategies according to established guidelines for meta-analyses of observational studies in epidemiology (the MOOSE group). Two authors will independently screen abstracts and full text of all references on the basis of inclusion criteria with respect to types of study, types of population, and the main outcome. We will exclude studies if they report solely incidences of LEA among persons with diabetes mellitus when referring to the total population (diabetic and non diabetic) and not exclusively to the diabetic population. Data extraction and assessment of risk of bias will be undertaken by two review authors working independently. We will assess incidence rate (IR) or cumulative incidence (CumI), relative risk of amputations comparing the diabetic to non-diabetic populations, cause of LEA, and type of diabetes. If we find subsets of studies to be homogeneous enough, we will perform meta-analyses for incidence rates by Poisson generalized linear mixed models (GLMM). SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015017809. PMID- 26001385 TI - Comprehensive health literacy in Japan is lower than in Europe: a validated Japanese-language assessment of health literacy. AB - BACKGROUND: Health literacy, or the ability to access, understand, appraise and apply health information, is central to individuals' health and well-being. A comprehensive, concept-based measure of most dimensions of health literacy has been developed for the general population in Europe, which enables comparisons within and between countries. This study seeks to validate this tool for use in Japan, and to use a Japanese translation to compare health literacy levels in Japan and Europe. METHODS: A total of 1054 Japanese adults recruited through an Internet research service company, completed a Japanese-language version of the 47-item European Health Literacy Survey Questionnaire (HLS-EU-Q47). The survey was administered via an online questionnaire, and participant demographics were closely matched to those of the most recent Japanese national census. Survey results were compared with those previously reported in an eight-country European study of health literacy. RESULTS: Internal consistency for the translated questionnaire was valid across multiple metrics. Construct validity was checked using confirmatory factor analyses. The questionnaire correlated well with existing scales measuring health literacy and mental health status. In general, health literacy in the Japanese population was lower than in Europe, with Japanese respondents rating all test items as more difficult than European respondents. The largest difference (51.5 %) was in the number of respondents finding it difficult to know where to get professional help when they are ill. CONCLUSIONS: This study translated a comprehensive health literacy questionnaire into Japanese and confirmed its reliability and validity. Comparative results suggest that Japanese health literacy is lower than that of Europeans. This discrepancy may be partly caused by inefficiency in the Japanese primary health care system. It is also difficult to access reliable and understandable health information in Japan, as there is no comprehensive national online platform. Japanese respondents found it more difficult to judge and apply health information, which suggests that there are difficulties in health decision-making in Japan. Numerous issues may be linked to lower levels health literacy in Japan, and further studies are needed to improve this by developing individual competencies and building supportive environments. PMID- 26001386 TI - Mites of sheep and goats in Oromia Zone of Amhara Region, North Eastern Ethiopia: species, prevalence and farmers awareness. AB - BACKGROUND: Mites are one of the most common and widely distributed ectoparasites of small ruminants in Ethiopia, contributing to major hindrances in livestock productivity in the country. Despite of this fact, specific study was not conducted on mites of small ruminants in Ethiopia. Therefore, the present study was performed from October 2009 to May 2010 to determine the prevalence and species composition of mites in three agroecological zones in north eastern Ethiopia. In addition, a questionnaire survey on mites was conducted to assess the control practices and awareness of farmers in the study areas. RESULTS: Out of a total of 1280 sheep and 1264 goats examined, 97(7.6 %) of sheep and 174(13.8 %) goats were infested with one or more species of mites. In goats an overall prevalence of 10.3 % Sarcoptes, 2.8 % Demodex and 0.6 % Psoroptes were recorded whereas in sheep an overall prevalence of 3.5 % Sarcoptes, 2.1 % Demodex and 1.6 % Psoroptes were observed. Sarcoptes (P = 0.03; OR = 2.1) and Demodex (OR = 3.25; p = 0.004) were significantly more common in young than in adult sheep. Demodectic mange was significantly higher in young (4.1 %) compared to adult (2.3 %) goats (OR = 2.2; P = 0.02). Significantly higher (P < 0.01) overall prevalence of sarcoptic and demodectic mites in both sheep and goats with poor than with good body condition was recorded. Results of the questionnaire survey supported results of our cross-sectional study. CONCLUSIONS: This study demonstrates high prevalence of mange mites in sheep and goats of the study area. The study revealed that Sarcoptes is the predominant mite in both sheep and goats. Animal owners and veterinarians should consider mite control in small ruminants as part of the routine ectoparasite control in Ethiopia. PMID- 26001388 TI - Drinking on special occasions shows huge increase on people's typical drinking estimates. PMID- 26001387 TI - Improving response inhibition systems in frontotemporal dementia with citalopram. AB - Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel-based morphometry confirmed significant atrophy of inferior frontal gyrus, alongside insular, orbitofrontal and temporal cortex in our patient cohort. Together, these data suggest that the dysfunctional prefrontal cortical systems underlying response inhibition deficits in behavioural variant frontotemporal dementia can be partially restored by increasing serotonergic neurotransmission. The results support a translational neuroscience approach to impulsive neurological disorders and indicate the potential for symptomatic treatment of behavioural variant frontotemporal dementia including serotonergic strategies to improve disinhibition.media 1vid110.1093/brain/awv133_video_abstractawv133_video_abstract. PMID- 26001389 TI - Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer. AB - OBJECTIVE: Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) MSI CRC. DESIGN: Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2 directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown. RESULTS: Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR deficient colorectal neoplasms (p=0.008). Characterisation of BRAF(wt) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors. CONCLUSIONS: We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC. PMID- 26001390 TI - Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies. AB - BACKGROUND: As one of its responses to the increasing global burden of breast cancer (BC), China has deployed a national registration and BC screening campaign. The present report describes these programs and the initial results of these national BC control strategies, highlighting the challenges to be considered. MATERIALS AND METHODS: The primary BC incidence and prevalence data were obtained from the Chinese National Central Cancer Registry. MapInfo software was used to map the geographic distribution and variation. The time trends were estimated by the annual percentage of change from 2003 to 2009. The description of the screening plans and preliminary results were provided by the Ministry of Health. RESULTS: Chinese cancer registries were primarily developed and activated in the East and Coastal regions of China, with only 12.5% of the registries located in West China. Geographic variation was noted, with the incidence of BC higher in North China than in South China and in urban areas compared with rural areas. Of great interest, these registries reported that the overall BC incidence has been increasing in China, with an earlier age of onset compared with Western countries and a peak incidence rate at age 50. In response to this increasing incidence and early age of onset, BC screening programs assessed 1.46 million women aged 35-59 years, using clinical breast examinations and ultrasound as primary screening tools between 2009 and 2011. The diagnostic rate for this screening program was only 48.0/10(5) with 440 cases of early stage BC. Early stage BC was detected in nearly 70% of screened patients. Subsequently, a second generation screening program was conducted that included older women aged 35-64 years and an additional 6 million women were screened. CONCLUSION: The cancer registration system in China has been uneven, with a greater focus on East rather than West China. The data from these registries demonstrate regional variation, an increasing BC incidence, and an early age of onset. The 2009 to 2011 BC screening program targeting women aged 35-59 years had a low detection rate that resulted in a second-generation screening program that extended the cohort size and ages screened to 35-64 years. IMPLICATIONS FOR PRACTICE: Cancer registration has been active in China for decades; however, a national survey of registries has not been routinely reported. This study used MapInfo to describe the reported data and found asymmetric registration activities, geographic variations in breast cancer (BC) burdens, and an increasing incidence with a peak at age 50. The initial Chinese BC screening programs focused on a relatively young population of women aged 35-59 years and had a low detection rate, but 69.7% of patients had early stage BC. Older women were included in the second-generation screening programs, and an additional 6 million women were screened. Consideration of regional variations and age is necessary to optimize the efficiency and utility of BC screening in China, with the ultimate goal to reduce BC mortality. PMID- 26001392 TI - Development of a cervical cancer progress prediction tool for human papillomavirus-positive Koreans: A support vector machine-based approach. AB - OBJECTIVES: To develop a Web-based tool to draw attention to patients positive for human papillomavirus (HPV) who have a high risk of progression to cervical cancer, in order to increase compliance with follow-up examinations and facilitate good doctor-patient communication. METHODS: Records were retrospectively analysed from women who were positive for HPV on initial testing (before any treatment). Information concerning age, Papanicolaou (PAP) smear result and presence of 15 high-risk HPV genotypes was used in a support vector machine (SVM) model, to identify the patient features that maximally contributed to progression to high-risk cervical lesions. RESULTS: Data from 731 subjects were analysed. The maximum number of correct cancer predictions was seen when four features (PAP, HPV16, HPV52 and HPV35) were used, giving an accuracy of 74.41%. A web-based high-risk cervical lesion prediction application tool was developed using the SVM model results. CONCLUSIONS: Use of the web-based prediction tool may help to increase patient compliance with physician advice, and may heighten awareness of the significance of regular follow-up HPV examinations for the prevention of cervical cancer, in Korean women predicted to have heightened risk of the disease. PMID- 26001393 TI - High-mobility group box 1 protein activating nuclear factor-kappaB to upregulate vascular endothelial growth factor C is involved in lymphangiogenesis and lymphatic node metastasis in colon cancer. AB - OBJECTIVES: To investigate the roles of high-mobility group box 1 (HMGB1) protein in lymphangiogenesis and lymphatic node metastasis in colon cancer. METHODS: Archival tumour specimens from patients with colon cancer were analysed in this retrospective immunohistochemical study. HMGB1, vascular endothelial growth factor C (VEGF-C) and podoplanin protein levels were analysed immunohistochemically. In vitro studies using the colon cancer cell line HCT116 were also undertaken to investigate the relationship between HMGB1, VEGF-C and nuclear factor (NF)-kappaB. RESULTS: Specimens from 70 patients with colon cancer were reviewed. The presence of positive HMGB1 immunohistochemical staining significantly correlated with lymphatic microvessel density, lymph node metastasis and VEGF-C immunohistochemical staining in colon cancer specimens. The presence of positive VEGF-C immunohistochemical staining significantly correlated with lymph node metastasis. The in vitro studies demonstrated that HMGB1 upregulated VEGF-C mRNA and protein in a dose-dependent manner in HCT116 cells, and that this was mediated via NF-kappaB. CONCLUSIONS: HMGB1 immunohistochemical staining was significantly associated with lymphangiogenesis and lymphatic node metastasis in colon cancer. There was evidence that HMGB1 upregulates VEGF-C by activating NF-kappaB in a colon cancer cell line. PMID- 26001391 TI - Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. AB - Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR-2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti-VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors. IMPLICATIONS FOR PRACTICE: Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF-targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents. PMID- 26001394 TI - Palliative care and other physicians' knowledge, attitudes and practice relating to the law on withholding/withdrawing life-sustaining treatment: Survey results. AB - BACKGROUND: To effectively care for people who are terminally ill, including those without decision-making capacity, palliative care physicians must know and understand the legal standing of Advance Care Planning in their jurisdiction of practice. This includes the use of advance directives/living wills and substitute decision-makers who can legally consent to or refuse treatment if there is no valid advance directive. AIM: This study aimed to investigate the knowledge, attitudes and practices of medical specialists most often involved in end-of-life care in relation to the law on withholding/withdrawing life-sustaining treatment from adults without decision-making capacity. DESIGN/PARTICIPANTS: A pre-piloted survey was posted to specialists in palliative, emergency, geriatric, renal and respiratory medicine; intensive care; and medical oncology in three Australian States. Surveys were analysed using SPSS 20 and SAS 9.3. RESULTS: The overall response rate was 32% (867/2702) - 52% from palliative care specialists. Palliative care specialists and geriatricians had significantly more positive attitudes towards the law (chi42(2) = 94.352; p < 0.001) and higher levels of knowledge about the withholding/withdrawing life-sustaining treatment law (chi7(2) = 30.033; p < 0.001) than did the other specialists, while still having critical gaps in their knowledge. CONCLUSION: A high level of knowledge of the law is essential to ensure that patients' wishes and decisions, expressed through Advance Care Planning, are respected to the maximum extent possible within the law, thereby according with the principles and philosophy of palliative care. It is also essential to protect health professionals from legal action resulting from unauthorised provision or cessation of treatment. PMID- 26001395 TI - Testing pilocarpine drops for dry mouth in advanced cancer using n-of-1 trials: A feasibility study. AB - BACKGROUND: Dry mouth is a common and troublesome symptom in palliative care. Pilocarpine is a cholinergic agent that promotes salivation. AIM: This study aimed to test the feasibility of using n-of-1 trials to test pilocarpine drops compared to placebo, for patients of palliative care units with advanced cancer, who experienced dry mouth. DESIGN: This was an N-of-1 study, in which each participant was offered three cycles of pilocarpine drops 4% (6 mg tds) (3 days) and placebo drops (3 days) in random order. SETTING/PARTICIPANTS: Participants were patients of specialist palliative care services with advanced cancer assessed as having a dry mouth, defined as having a score of ? 3 on an 11-point self-rated xerostomia numerical rating scale, from any cause. Patients self completed a diary using validated symptom and quality-of-life scores. The randomisation order was unmasked at the end of each person's trial by a clinician independent of the trial to allow a treatment decisions for individual patients to be made. RESULTS: Nine patients completed at least 1 cycle; 33 cycles of data were completed in total, comprising 438 doses of pilocarpine. Four patients completed the trial: two responded and two did not. Most withdrawals related to deteriorating condition, unacceptable toxicity, non-compliance with study procedures or withdrawal of consent. Many issues contributed to slow recruitment and high withdrawal rate. CONCLUSION: The formulation of pilocarpine drops proved unacceptable to most participants. More work is required to determine an appropriate formulation, dose and method of delivery and then a retest of pilocarpine drops for this symptom. PMID- 26001397 TI - Reactivity to N-Terminally Truncated GAD65(96-585) Identifies GAD Autoantibodies That Are More Closely Associated With Diabetes Progression in Relatives of Patients With Type 1 Diabetes. AB - GAD autoantibodies (GADAs) identify individuals at increased risk of developing type 1 diabetes, but many people currently found to be GADA positive are unlikely to progress to clinical disease. More specific GADA assays are therefore needed. Recent international workshops have shown that the reactivity of sera from healthy donors varies according to assay type and indicated that the use of N terminally truncated GAD65 radiolabels in GADA radiobinding assays is associated with higher specificity. To determine whether a radiobinding assay using radiolabeled GAD65(96-585) identified individuals who are at higher risk of developing diabetes, samples from recent-onset patients and GADA-positive first degree relatives participating in the Bart's-Oxford type 1 diabetes family study were reassayed with full-length or N-terminally truncated GAD using the National Institute of Diabetes and Digestive and Kidney Diseases harmonized protocol. The sensitivity in patients was the same with both labels, but fewer relatives retested positive with truncated GAD. Among relatives who progressed to diabetes, similar proportions were found to be GADA positive when tested with either label, but because of their higher specificity the cumulative risk of diabetes was higher in those with autoantibodies to GAD65(96-585). Autoantibodies to GAD65(96 585) in relatives are more closely associated with diabetes risk than those to full-length GAD, suggesting that assays using N-terminally truncated GAD should be used to select participants for intervention trials. PMID- 26001396 TI - Improved Insulin Sensitivity 3 Months After RYGB Surgery Is Associated With Increased Subcutaneous Adipose Tissue AMPK Activity and Decreased Oxidative Stress. AB - Morbidly obese individuals are predisposed to a wide range of disorders, including type 2 diabetes, atherosclerotic cardiovascular disease, fatty liver disease, and certain cancers. Remarkably, all of these disorders can be improved or prevented by Roux-en-Y gastric bypass (RYGB) surgery. We have reported that decreased AMPK activity, together with increased oxidative stress and inflammation in adipose tissue, is associated with insulin resistance in morbidly obese bariatric surgery patients. In the current study, we assessed how these parameters are affected by RYGB surgery. Eleven patients (average age of 46 +/- 4 years) were studied immediately prior to surgery and 3 months postoperatively. We measured subcutaneous adipose tissue AMPK phosphorylation (threonine 172, an index of its activation), malonyl-CoA content, protein carbonylation (a marker of oxidative stress), plasma adiponectin, and mRNA expression of several inflammatory cytokines. After surgery, AMPK activity increased 3.5-fold and oxidative stress decreased by 50% in subcutaneous adipose tissue. In addition, malonyl-CoA levels were reduced by 80%. Furthermore, patients had improvements in their BMI and insulin sensitivity (HOMA) and had increased circulating high molecular weight adiponectin and decreased fasting plasma insulin levels. In contrast, the expression of inflammatory markers in subcutaneous adipose tissue was unchanged postoperatively, although plasma CRP was diminished by 50%. PMID- 26001399 TI - Intramural esophageal dissection caused by upper endoscopy. PMID- 26001400 TI - Cookie bite cortical osteolytic lesions: a hint of skeletal metastasis from bronchogenic carcinoma. PMID- 26001398 TI - DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts. AB - The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation-associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and B12 intake (all P for interaction <0.01). The differences in the BMI changes per increment of minor allele were -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.12 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B2 intake and -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity. PMID- 26001401 TI - Cornea bee sting. PMID- 26001406 TI - Ligand-Enabled Stereoselective beta-C(sp(3))-H Fluorination: Synthesis of Unnatural Enantiopure anti-beta-Fluoro-alpha-amino Acids. AB - A quinoline-based ligand was shown to promote palladium-catalyzed beta-C(sp(3))-H fluorination for the first time. A range of unnatural enantiopure fluorinated alpha-amino acids were obtained through sequential beta-C(sp(3))-H arylation and subsequent stereoselective fluorination from readily available L-alanine. PMID- 26001409 TI - PKU-3: An HCl-Inclusive Aluminoborate for Strecker Reaction Solved by Combining RED and PXRD. AB - A novel microporous aluminoborate, denoted as PKU-3, was prepared by the boric acid flux method. The structure of PKU-3 was determined by combining the rotation electron diffraction and synchrotron powder X-ray diffraction data with well resolved ordered Cl(-) ions in the channel. Composition and crystal structure analysis showed that there are both proton and chlorine ions in the channels. Part of these protons and chlorine ions can be washed away by basic solutions to activate the open pores. The washed PKU-3 can be used as an efficient catalyst in the Strecker reaction with yields higher than 90%. PMID- 26001407 TI - A Series of Case Studies of Tinnitus Suppression With Mixed Background Stimuli in a Cochlear Implant. AB - PURPOSE: Background sounds provided by a wearable sound playback device were mixed with the acoustical input picked up by a cochlear implant speech processor in an attempt to suppress tinnitus. METHOD: First, patients were allowed to listen to several sounds and to select up to 4 sounds that they thought might be effective. These stimuli were programmed to loop continuously in the wearable playback device. Second, subjects were instructed to use 1 background sound each day on the wearable device, and they sequenced the selected background sounds during a 28-day trial. Patients were instructed to go to a website at the end of each day and rate the loudness and annoyance of the tinnitus as well as the acceptability of the background sound. Patients completed the Tinnitus Primary Function Questionnaire (Tyler, Stocking, Secor, & Slattery, 2014) at the beginning of the trial. RESULTS: Results indicated that background sounds were very effective at suppressing tinnitus. There was considerable variability in sounds preferred by the subjects. CONCLUSION: The study shows that a background sound mixed with the microphone input can be effective for suppressing tinnitus during daily use of the sound processor in selected cochlear implant users. PMID- 26001410 TI - Culture and adenoviral infection of sinoatrial node myocytes from adult mice. AB - Pacemaker myocytes in the sinoatrial node of the heart initiate each heartbeat by firing spontaneous action potentials. However, the molecular processes that underlie pacemaking are incompletely understood, in part because of our limited ability to manipulate protein expression within the native cellular context of sinoatrial node myocytes (SAMs). Here we describe a new method for the culture of fully differentiated SAMs from adult mice, and we demonstrate that robust expression of introduced proteins can be achieved within 24-48 h in vitro via adenoviral gene transfer. Comparison of morphological and electrophysiological characteristics of 48 h-cultured versus acutely isolated SAMs revealed only minor changes in vitro. Specifically, we found that cells tended to flatten in culture but retained an overall normal morphology, with no significant changes in cellular dimensions or membrane capacitance. Cultured cells beat spontaneously and, in patch-clamp recordings, the spontaneous action potential firing rate did not differ between cultured and acutely isolated cells, despite modest changes in a subset of action potential waveform parameters. The biophysical properties of two membrane currents that are critical for pacemaker activity in SAMs, the "funny current" (If) and voltage-gated Ca(2+) currents (ICa), were also indistinguishable between cultured and acutely isolated cells. This new method for culture and adenoviral infection of fully-differentiated SAMs from the adult mouse heart expands the range of experimental techniques that can be applied to study the molecular physiology of cardiac pacemaking because it will enable studies in which protein expression levels can be modified or genetically encoded reporter molecules expressed within SAMs. PMID- 26001411 TI - Load-dependent extracellular matrix organization in atrioventricular heart valves: differences and similarities. AB - The extracellular matrix of the atrioventricular (AV) valves' leaflets has a key role in the ability of these valves to properly remodel in response to constantly varying physiological loads. While the loading on mitral and tricuspid valves is significantly different, no information is available on how collagen fibers change their orientation in response to these loads. This study delineates the effect of physiological loading on AV valves' leaflets microstructures using Second Harmonic Generation (SHG) microscopy. Fresh natural porcine tricuspid and mitral valves' leaflets (n = 12/valve type) were cut and prepared for the experiments. Histology and immunohistochemistry were performed to compare the microstructural differences between the valves. The specimens were imaged live during the relaxed, loading, and unloading phases using SHG microscopy. The images were analyzed with Fourier decomposition to mathematically seek changes in collagen fiber orientation. Despite the similarities in both AV valves as seen in the histology and immunohistochemistry data, the microstructural arrangement, especially the collagen fiber distribution and orientation in the stress-free condition, were found to be different. Uniaxial loading was dependent on the arrangement of the fibers in their relaxed mode, which led the fibers to reorient in-line with the load throughout the depth of the mitral leaflet but only to reorient in-line with the load in deeper layers of the tricuspid leaflet. Biaxial loading arranged the fibers in between the two principal axes of the stresses independently from their relaxed states. Unlike previous findings, this study concludes that the AV valves' three-dimensional extracellular fiber arrangement is significantly different in their stress-free and uniaxially loaded states; however, fiber rearrangement in response to the biaxial loading remains similar. PMID- 26001412 TI - A high-resolution thermoelectric module-based calorimeter for measuring the energetics of isolated ventricular trabeculae at body temperature. AB - Isolated ventricular trabeculae are the most common experimental preparations used in the study of cardiac energetics. However, the experiments have been conducted at subphysiological temperatures. We have overcome this limitation by designing and constructing a novel calorimeter with sufficiently high thermal resolution for simultaneously measuring the heat output and force production of isolated, contracting, ventricular trabeculae at body temperature. This development was largely motivated by the need to better understand cardiac energetics by performing such measurements at body temperature to relate tissue performance to whole heart behavior in vivo. Our approach uses solid-state thermoelectric modules, tailored for both temperature sensing and temperature control. The thermoelectric modules have high sensitivity and low noise, which, when coupled with a multilevel temperature control system, enable an exceptionally high temperature resolution with a noise-equivalent power an order of magnitude greater than those of other existing muscle calorimeters. Our system allows us to rapidly and easily change the experimental temperature without disturbing the state of the muscle. Our calorimeter is useful in many experiments that explore the energetics of normal physiology as well as pathophysiology of cardiac muscle. PMID- 26001413 TI - Voluntary exercise delays heart failure onset in rats with pulmonary artery hypertension. AB - Increased physical activity is recommended for the general population and for patients with many diseases because of its health benefits but can be contraindicated if it is thought to be a risk for serious cardiovascular events. One such condition is pulmonary artery hypertension (PAH). PAH and right ventricular failure was induced in rats by a single injection of monocrotaline (MCT). MCT rats with voluntary access to a running wheel ran on average 2 km/day. The time for half the animals to develop heart failure signs (median survival time) was 28 days (exercise failure group), significantly longer than sedentary animals (sedentary failure group, 23 days). The contractility of single failing myocytes in response to increasing demand (stimulation frequency) was significantly impaired compared with that in both sedentary control and exercising control myocytes. However, myocytes from exercising MCT rats, tested at 23 days (exercise + MCT group), showed responses intermediate to the control (sedentary control and exercising control) and failing (sedentary failure and exercise failure) groups. We conclude that voluntary exercise is beneficial to rats with heart failure induced by PAH, and this is evidence to support the consideration of appropriate exercise regimes for potentially vulnerable groups. PMID- 26001414 TI - Exercise training attenuates chemoreflex-mediated reductions of renal blood flow in heart failure. AB - In chronic heart failure (CHF), carotid body chemoreceptor (CBC) activity is increased and contributes to increased tonic and hypoxia-evoked elevation in renal sympathetic nerve activity (RSNA). Elevated RSNA and reduced renal perfusion may contribute to development of the cardio-renal syndrome in CHF. Exercise training (EXT) has been shown to abrogate CBC-mediated increases in RSNA in experimental heart failure; however, the effect of EXT on CBC control of renal blood flow (RBF) is undetermined. We hypothesized that CBCs contribute to tonic reductions in RBF in CHF, that stimulation of the CBC with hypoxia would result in exaggerated reductions in RBF, and that these responses would be attenuated with EXT. RBF was measured in CHF-sedentary (SED), CHF-EXT, CHF-carotid body denervation (CBD), and CHF-renal denervation (RDNX) groups. We measured RBF at rest and in response to hypoxia (FiO2 10%). All animals exhibited similar reductions in ejection fraction and fractional shortening as well as increases in ventricular systolic and diastolic volumes. Resting RBF was lower in CHF-SED (29 +/- 2 ml/min) than in CHF-EXT animals (46 +/- 2 ml/min, P < 0.05) or in CHF-CBD animals (42 +/- 6 ml/min, P < 0.05). In CHF-SED, RBF decreased during hypoxia, and this was prevented in CHF-EXT animals. Both CBD and RDNX abolished the RBF response to hypoxia in CHF. Mean arterial pressure increased in response to hypoxia in CHF-SED, but was prevented by EXT, CBD, and RDNX. EXT is effective in attenuating chemoreflex-mediated tonic and hypoxia-evoked reductions in RBF in CHF. PMID- 26001415 TI - Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice. AB - Although exercise mediates beneficial effects in patients after myocardial infarction (MI), the underlying mechanisms as well as the question of whether an early start of exercise after MI is safe or even beneficial are incompletely resolved. The present study analyzed the effects of exercise before and reinitiated early after MI on cardiac remodeling and function. Male C57BL/6N mice were housed sedentary or with the opportunity to voluntarily exercise for 6 wk before MI induction (ligation of the left anterior descending coronary artery) or sham operation. After a 5-day exercise-free phase after MI, mice were allowed to reexercise for another 4 wk. Exercise before MI induced adaptive hypertrophy with moderate increases in heart weight, cardiomyocyte diameter, and left ventricular (LV) end-diastolic volume, but without fibrosis. In sedentary mice, MI induced eccentric LV hypertrophy with massive fibrosis but maintained systolic LV function. While in exercised mice gross LV end-diastolic volumes and systolic function did not differ from sedentary mice after MI, LV collagen content and thinning of the infarcted area were reduced. This was associated with ameliorated activation of inflammation, mediated by TNF-alpha, IL-1beta, and IL-6, as well as reduced activation of matrix metalloproteinase 9. In contrast, no differences in the activation patterns of various MAPKs or adenosine receptor expressions were observed 5 wk after MI in sedentary or exercised mice. In conclusion, continuous exercise training before and with an early reonset after MI ameliorates adverse LV remodeling by attenuating inflammation, fibrosis, and scar thinning. Therefore, an early reonset of exercise after MI can be encouraged. PMID- 26001417 TI - Emissions of 1,3-Dichloropropene and Chloropicrin after Soil Fumigation under Field Conditions. AB - Soil fumigation is an important agronomic practice in the production of many high value vegetable and fruit crops, but the use of chemical fumigants can lead to excessive atmospheric emissions. A large-scale (2.9 ha) field experiment was conducted to obtain volatilization and cumulative emission rates for two commonly used soil fumigants under typical agronomic practices: 1,3-dichloropropene (1,3 D) and chloropicrin. The aerodynamic method and the indirect back-calculation method using ISCST3 and CALPUFF dispersion models were used to estimate flux loss from the treated field. Over the course of the experiment, the daily peak volatilization rates ranged from 12 to 30 MUg m(-2) s(-1) for 1,3-D and from 0.7 to 2.6 MUg m(-2) s(-1) for chloropicrin. Depending on the method used for quantification, total emissions of 1,3-D and chloropicrin, respectively, ranged from 16 to 35% and from 0.3 to 1.3% of the applied fumigant. A soil incubation study showed that the low volatilization rates measured for chloropicrin were due to particularly high soil degradation rates observed at this field site. Understanding and quantifying fumigant emissions from agricultural soil will help in developing best management practices to reduce emission losses, reducing adverse impacts to human and ecosystem health, and providing inputs for conducting risk assessments. PMID- 26001418 TI - Assessing the Performance of the Diffusion Monte Carlo Method As Applied to the Water Monomer, Dimer, and Hexamer. AB - The diffusion Monte Carlo (DMC) method is applied to the water monomer, dimer, and hexamer using q-TIP4P/F, one of the most simple empirical water models with flexible monomers. The bias in the time step (Deltatau) and population size (Nw) is investigated. For the binding energies, the bias in Deltatau cancels nearly completely, whereas a noticeable bias in Nw remains. However, for the isotope shift (e.g, in the dimer binding energies between (H2O)2 and (D2O)2), the systematic errors in Nw do cancel. Consequently, very accurate results for the latter (within ~0.01 kcal/mol) are obtained with moderate numerical effort (Nw ~ 10(3)). For the water hexamer and its (D2O)6 isotopomer, the DMC results as a function of Nw are examined for the cage and prism isomers. For a given isomer, the issue of the walker population leaking out of the corresponding basin of attraction is addressed by using appropriate geometric constraints. The population size bias for the hexamer is more severe, and to maintain accuracy similar to that of the dimer, Nw must be increased by ~2 orders of magnitude. Fortunately, when the energy difference between the cage and prism is taken, the biases cancel, thereby reducing the systematic errors to within ~0.01 kcal/mol when using a population of Nw = 4.8 * 10(5) walkers. Consequently, a very accurate result for the isotope shift is also obtained. Notably, both the quantum and isotope effects for the prism-cage energy difference are small. PMID- 26001420 TI - Building a national electronic medical record exchange system - experiences in Taiwan. AB - There are currently 501 hospitals and about 20,000 clinics in Taiwan. The National Health Insurance (NHI) system, which is operated by the NHI Administration, uses a single-payer system and covers 99.9% of the nation's total population of 23,000,000. Taiwan's NHI provides people with a high degree of freedom in choosing their medical care options. However, there is the potential concern that the available medical resources will be overused. The number of doctor consultations per person per year is about 15. Duplication of laboratory tests and prescriptions are not rare either. Building an electronic medical record exchange system is a good method of solving these problems and of improving continuity in health care. In November 2009, Taiwan's Executive Yuan passed the 'Plan for accelerating the implementation of electronic medical record systems in medical institutions' (2010-2012; a 3-year plan). According to this plan, a patient can, at any hospital in Taiwan, by using his/her health insurance IC card and physician's medical professional IC card, upon signing a written agreement, retrieve all important medical records for the past 6 months from other participating hospitals. The focus of this plan is to establish the National Electronic Medical Record Exchange Centre (EEC). A hospital's information system will be connected to the EEC through an electronic medical record (EMR) gateway. The hospital will convert the medical records for the past 6 months in its EMR system into standardized files and save them on the EMR gateway. The most important functions of the EEC are to generate an index of all the XML files on the EMR gateways of all hospitals, and to provide search and retrieval services for hospitals and clinics. The EEC provides four standard inter-institution EMR retrieval services covering medical imaging reports, laboratory test reports, discharge summaries, and outpatient records. In this system, we adopted the Health Level 7 (HL7) Clinical Document Architecture (CDA) standards to generate clinical documents and Integrating the Healthcare Enterprise (IHE) Cross-enterprise Document Sharing (XDS) profile for the communication infrastructure. By December of 2014, the number of hospitals that provide an inter-institution EMR exchange service had reached 321. Hospitals that had not joined the service were all smaller ones with less than 100 beds. Inter institution EMR exchange can make it much easier for people to access their own medical records, reduce the waste of medical resources, and improve the quality of medical care. The implementation of an inter-institution EMR exchange system faces many challenges. This article provides Taiwan's experiences as a reference. PMID- 26001421 TI - Telemedicine framework using case-based reasoning with evidences. AB - Telemedicine is the medical practice of information exchanged from one location to another through electronic communications to improve the delivery of health care services. This research article describes a telemedicine framework with knowledge engineering using taxonomic reasoning of ontology modeling and semantic similarity. In addition to being a precious support in the procedure of medical decision-making, this framework can be used to strengthen significant collaborations and traceability that are important for the development of official deployment of telemedicine applications. Adequate mechanisms for information management with traceability of the reasoning process are also essential in the fields of epidemiology and public health. In this paper we enrich the case-based reasoning process by taking into account former evidence based knowledge. We use the regular four steps approach and implement an additional (iii) step: (i) establish diagnosis, (ii) retrieve treatment, (iii) apply evidence, (iv) adaptation, (v) retain. Each step is performed using tools from knowledge engineering and information processing (natural language processing, ontology, indexation, algorithm, etc.). The case representation is done by the taxonomy component of a medical ontology model. The proposed approach is illustrated with an example from the oncology domain. Medical ontology allows a good and efficient modeling of the patient and his treatment. We are pointing up the role of evidences and specialist's opinions in effectiveness and safety of care. PMID- 26001424 TI - Online Extra Publication in JAAOS. PMID- 26001423 TI - GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration. AB - Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-beta molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia. PMID- 26001425 TI - Open surgical release for contractures of the elbow. AB - Compared with arthroscopic release, open release is more commonly used for the treatment of stiff elbow. Flexion is recovered by releasing posterior tethering soft-tissue structures and by removing anterior impingement between the coronoid and/or radial head and the distal humerus. Extension is improved by releasing anterior soft-tissue tethers and by removing impingement between the olecranon tip and the olecranon fossa. Open elbow release is most commonly performed via ligament-sparing approaches. Ulnar nerve identification and transposition is recommended in the presence of nerve dysfunction or when correction of significant loss of elbow flexion is anticipated. Long-term improvement in flexion and extension can be expected with proper patient selection. Less predictable results are obtained in adolescent patients and in those with underlying traumatic brain injury. PMID- 26001426 TI - Male and female differences in musculoskeletal disease. AB - Gender differences exist in the presentation of musculoskeletal disease, and recognition of the differences between men and women's burden of disease and response to treatment is key in optimizing care of orthopaedic patients. The role of structural anatomy differences, hormones, and genetics are factors to consider in the analysis of differential injury and arthritic patterns between genders. PMID- 26001427 TI - Medial epicondylitis: evaluation and management. AB - Medial epicondylitis, often referred to as "golfer's elbow," is a common pathology. Flexor-pronator tendon degeneration occurs with repetitive forced wrist extension and forearm supination during activities involving wrist flexion and forearm pronation. A staged process of pathologic change in the tendon can result in structural breakdown and irreparable fibrosis or calcification. Patients typically report persistent medial-sided elbow pain that is exacerbated by daily activities. Athletes may be particularly symptomatic during the late cocking or early acceleration phases of the throwing motion. Nonsurgical supportive care includes activity modification, NSAIDs, and corticosteroid injections. Once the acute symptomology is alleviated, focus is turned to flexor pronator mass rehabilitation and injury prevention. Surgical treatment via open techniques is typically reserved for patients with persistent symptoms. PMID- 26001428 TI - Infection prevention in total knee arthroplasty. AB - Periprosthetic joint infections are devastating complications that are difficult and expensive to treat and have a substantial mortality rate. A major goal of modern joint arthroplasty is to minimize these infections. Preoperative factors associated with increased risk of infection include malnutrition, diabetes mellitus, obesity (body mass index >40 kg/m(2)), and rheumatoid arthritis. Administration of appropriate antibiotics before the surgical incision is made is essential to minimize infection. The use of laminar flow rooms, proper skin preparation, limiting operating room traffic, and the use of various wound closure techniques can help to decrease infection rates. Postoperatively, optimal management of indwelling urinary catheters, blood transfusions, and wound drainage also may decrease infection rates. PMID- 26001429 TI - Replantation of the upper extremity: current concepts. AB - Replantation is the process of reattaching amputated parts. Relative indications for replantation in the upper extremity include amputation of the thumb or multiple digits as well as amputations proximal to zone II and pediatric finger amputations at any level. Preoperatively, the part should be sealed in a bag and placed on ice; maximum ischemia times are approximately 12 hours of warm and 24 hours of cold time for digits, with shorter times tolerated for amputations at more proximal levels. With multiple digit involvement, an assembly line approach is used in the operating room. Postoperatively, close attention must be paid to detect thrombosis because secondary ischemia times are shorter. Success rates vary; survival is predicted in part by the mechanism of injury, with sharp cut injuries having better outcomes. There is no consensus on appropriate postoperative anticoagulation, the number of vessels that must be anastomosed, or whether replantations should be centralized or performed in every hospital. PMID- 26001430 TI - Atlantoaxial rotatory subluxation in children. AB - Atlantoaxial rotatory subluxation is a rare condition in which patients present with the acute onset of torticollis. Atlantoaxial rotatory subluxation represents a spectrum of disease from muscle spasm to a fixed mechanical block to reduction of the atlantoaxial complex. If left untreated, some cases may resolve spontaneously; however, other cases may result in the development of secondary changes in the bony anatomy of the atlantoaxial joint, leading to persistent deformity. Diagnosis of the condition is largely clinical but can be aided by various imaging modalities, including radiographs, dynamic CT scanning, three dimensional CT reconstructions, or MRI. Consideration should always be given to infection or other inflammatory disease as an underlying, precipitating cause. Treatments include observation, the use a cervical collar and analgesics, halter or skeletal traction, and posterior fusion of C1-C2. The most important factor for success of conservative treatment is the time from the onset of symptoms to recognition and the initiation of treatment. PMID- 26001431 TI - Errata. PMID- 26001432 TI - Altered host immune responses to membrane vesicles from Salmonella and Gram negative pathogens. AB - Membrane vesicles (MVs), discrete nano-structures produced from the outer membrane of Gram-negative bacteria such as Salmonella enterica Typhimurium (S. Typhimurium), strongly activate dendritic cells (DCs), contain major antigens (Ags) recognized by Salmonella-specific B-cells and CD4+ T-cells, and provide protection against S. Typhimurium challenge in a mouse model. With this in mind, we hypothesized that alterations to the gene expression profile of bacteria will be reflected in the immunologic response to MVs. To test this, we assessed the ability of MVs from wild-type (WT) S. Typhimurium or a strain with a phenotype mimicking the intracellular-phase of S. Typhimurium (PhoP(c)) to activate dendritic cells and initiate a strong inflammatory response. MVs, isolated from wild-type and PhoP(c)S. Typhimurium (WTMVs and PhoPcMVs, respectively) had pro inflammatory properties consistent with the parental bacterial strains: PhoPcMVs were less stimulatory for DC activation in vitro and were impaired for subsequent inflammatory responses compared to WTMVs. Interestingly, the reduced pro inflammatory properties of PhoPcMVs did not completely rely on signals through TLR4, the receptor for LPS. Nonetheless, both WTMVs and PhoPcMVs contained abundant immunogenic antigens capable of being recognized by memory-immune CD4+ T cells from mice previously infected with S. Typhimurium. Furthermore, we analyzed a suite of pathogenic Gram-negative bacteria and their purified MVs for their ability to activate DCs and stimulate inflammation in a manner consistent with the known inflammatory properties of the parental strains, as shown for S. Typhimurium. Finally, analysis of the potential vaccine utility of S. Typhimurium MVs revealed their capacity to encapsulate an exogenous model antigen and stimulate antigen-specific CD4+ and CD8+ T-cell responses. Taken together, our results demonstrate the dependence of bacterial cell gene expression for MV immunogenicity and subsequent in vitro immunologic response, as well as their potential utility as a vaccine platform. PMID- 26001433 TI - MPG-based nanoparticle: An efficient delivery system for enhancing the potency of DNA vaccine expressing HPV16E7. AB - DNA vaccines against human papillomavirus (HPV) type 16 have not been successful in clinical trials, due to the lack of an appropriate delivery system. In this study, a peptide-based gene delivery system, MPG, which forms stable non-covalent nanoparticles with nucleic acids, was used for in vitro and in vivo delivery of HPV16 E7 DNA as a model antigen. The results demonstrated that at Nitrogen/Phosphate (N/P) ratio over 10:1, this peptide can effectively condense plasmid DNA into stable nanoparticles with an average size of 180-210nm and a positive surface charge. The transfection efficiency of MPG-based nanoparticles was shown to be comparable with Polyethyleneimine (PEI). The efficient protein expression detected by western blotting and flow cytometry supports the potential of MPG-based nanoparticles as a potent delivery system in DNA vaccine formulations. Immunization with MPG/E7DNA nanoparticles at an N/P ratio of 10:1 induced a stronger Th1 cellular immune response with a predominant interferon gamma (IFN-gamma) profile than those induced by E7DNA alone in a murine tumor model. These findings suggest that MPG peptide as a novel gene delivery system could have promising applications in improving HPV therapeutic vaccines. PMID- 26001434 TI - Left ventricular remodeling and fibrosis: Sex differences and relationship with diastolic function in hypertrophic cardiomyopathy. AB - OBJECTIVES: We investigated sex differences in left ventricular (LV) remodeling and fibrosis and their relationship with LV diastolic dysfunction by cardiovascular magnetic resonance (CMR). METHODS: CMR imaging was performed simultaneously in 152 age-matched patients (76 men, 76 women; mean age: 49+/-9 years) without LV systolic dysfunction. LV remodeling index (LVRI) was calculated as the ratio of LV mass and end-diastolic volume. Diastolic function indexes including peak filling rate (PFR) and time to PFR (tPFR) were evaluated. Extent of late gadolinium enhancement (LGE) was measured. RESULTS: LVRI and extent of LGE were greater in women compared with men (1.48+/-0.22 vs. 1.36+/-0.28g/ml; 13.15+/-2.48 vs. 11.35+/-2.34g, respectively, both P<0.001). Women had lower PFR and higher tPFR (both P<0.001) than men. LVRI and the extent of LGE showed significant relationships with parameters of diastolic function in both sex. In a multivariate analysis, LVRI remained a strong independent predictor of PFR and TPFR in women (beta=-0.272, P=0.032; beta=0.348, P=0.016, respectively), and in men (beta=-0.374, P<0.001; beta=0.660, P<0.001, respectively). Furthermore, the extent of LGE also remained an independent predictor of PFR in women (beta= 0.283, P=0.033) and men (beta=-0.492, P<0.001). CONCLUSIONS: There are prominent sex differences in LV remodeling and myocardial fibrosis. We suggest that the effects of LV remodeling and fibrosis may lead to diastolic dysfunction with greater susceptibility to worse clinical outcome in women. PMID- 26001435 TI - Non-invasive prediction of hemodynamically significant coronary artery stenoses by contrast density difference in coronary CT angiography. AB - OBJECTIVES: Coronary computed tomography angiography (CTA) allows the detection of obstructive coronary artery disease. However, its ability to predict the hemodynamic significance of stenoses is limited. We assessed differences in plaque characteristics and contrast density difference between hemodynamically significant and non-significant stenoses, as defined by invasive fractional flow reserve (FFR). METHODS: Lesion characteristics of 59 consecutive patients (72 lesions) in whom invasive FFR was performed in at least one coronary artery with moderate to high-grade stenoses in coronary CTA were evaluated by two experienced readers. Coronary CTA data sets were acquired on a second-generation dual-source CT scanner using retrospectively ECG-gated spiral acquisition or prospectively ECG-triggered axial acquisition mode. Plaque volume and composition (non calcified, calcified), remodeling index as well as contrast density difference (defined as the percentage decline in luminal CT attenuation/cross-sectional area over the lesion) were assessed using a semi-automatic software tool (Autoplaq). Additionally, the transluminal attenuation gradient (defined as the linear regression coefficient between intraluminal CT attenuation and length from the ostium) was determined. Differences in lesion characteristics between hemodynamically significant (invasively measured FFR <=0.80) and non-significant lesions (FFR >0.80) were determined. RESULTS: Mean patient age was 64+/-11 years with 44 males (75%). 21 out of 72 coronary artery lesions (29%) were hemodynamically significant according to invasive FFR. Mean invasive FFR was 0.66+/-0.12 vs. 0.91+/-0.05 for hemodynamically significant versus non significant lesions. Hemodynamically significant lesions showed a significantly greater percentage of non-calcified plaque compared to non-hemodynamically relevant lesions (51.3+/-15.3% vs. 43.6+/-16.5%, p=0.021). Contrast density difference was significantly increased in hemodynamically relevant lesions (26.0+/-20.2% vs. 16.6+/-10.9% for non-significant lesions; p=0.013). At a threshold of >=24%, the contrast density difference predicted hemodynamically significant lesions with a specificity of 75%, sensitivity of 33%, PPV of 35% and NPV of 73%. The transluminal attenuation gradient showed no significant difference between hemodynamically significant and non-significant lesions ( 1.4+/-1.4HU/mm vs. -1.1+/-1.3HU/mm, p=n.s.). CONCLUSIONS: Quantitative contrast density difference across coronary lesions in coronary CTA data sets may be applied as a non-invasive tool to identify hemodynamically significant stenoses. PMID- 26001436 TI - Effect of staff training on radiation dose in pediatric CT. AB - OBJECTIVE: To evaluate the efficacy of staff training on radiation doses applied in pediatric CT scans. METHODS: Pediatric patient doses from five CT scanners before (1426 scans) and after staff training (2566 scans) were compared statistically. Examinations included cranial CT (CCT), thoracic, abdomen-pelvis, and trunk scans. Dose length products (DLPs) per series were extracted from CT dose reports archived in the PACS. RESULTS: A pooled analysis of non-traumatic scans revealed a statistically significant reduction in the dose for cranial, thoracic, and abdomen/pelvis scans (p<0.01). This trend could be demonstrated also for trunk scans, however, significance could not be established due to low patient frequencies (p>0.05). The percentage of scans performed with DLPs exceeding the German DRLs was reduced from 41% to 7% (CCT), 19% to 5% (thorax CT), from 9% to zero (abdominal-pelvis CT), and 26% to zero (trunk; DRL taken as summed DRLs for thorax plus abdomen-pelvis, reduced by 20% accounting for overlap). Comparison with Austrian DRLs - available only for CCT and thorax CT - showed a reduction from 21% to 3% (CCT), and 15 to 2% (thorax CT). CONCLUSIONS: Staff training together with application of DRLs provide an efficient approach for optimizing radiation dose in pediatric CT practice. PMID- 26001438 TI - Communication: Relation of centroid molecular dynamics and ring-polymer molecular dynamics to exact quantum dynamics. AB - We recently obtained a quantum-Boltzmann-conserving classical dynamics by making a single change to the derivation of the "Classical Wigner" approximation. Here, we show that the further approximation of this "Matsubara dynamics" gives rise to two popular heuristic methods for treating quantum Boltzmann time-correlation functions: centroid molecular dynamics (CMD) and ring-polymer molecular dynamics (RPMD). We show that CMD is a mean-field approximation to Matsubara dynamics, obtained by discarding (classical) fluctuations around the centroid, and that RPMD is the result of discarding a term in the Matsubara Liouvillian which shifts the frequencies of these fluctuations. These findings are consistent with previous numerical results and give explicit formulae for the terms that CMD and RPMD leave out. PMID- 26001437 TI - Unenhanced third-generation dual-source chest CT using a tin filter for spectral shaping at 100kVp. AB - OBJECTIVE: To prospectively investigate image quality and radiation dose of 100kVp spectral shaping chest CT using a dedicated tin filter on a 3rd generation dual-source CT (DSCT) in comparison to standard 100kVp chest CT. METHODS: Sixty patients referred for a non-contrast chest on a 3rd generation DSCT were prospectively included and examined at 100kVp with a dedicated tin filter. These patients were retrospectively matched with patients that were examined on a 2nd generation DSCT at 100kVp without tin filter. Objective and subjective image quality was assessed in various anatomic regions and radiation dose was compared. RESULTS: Radiation dose was decreased by 90% using the tin filter (3.0 vs 0.32mSv). Soft tissue attenuation and image noise was not statistically different for both examination techniques (p>0.05), however image noise was found to be significantly higher in the trachea when using the additional tin filter (p=0.002). SNR was found to be statistically similar in pulmonary tissue, significantly lower when measured in air and significantly higher in the aorta for the scans on the 3rd generation DSCT. Subjective image quality with regard to overall quality and image noise and sharpness was not statistically significantly different (p>0.05). CONCLUSION: 100kVp spectral shaping chest CT by means of a tube-based tin-filter on a 3rd generation DSCT allows 90% dose reduction when compared to 100kVp chest CT on a 2nd generation DSCT without spectral shaping. PMID- 26001439 TI - Communication: Ion mobility of the radical cation dimers: (Naphthalene)2(+*) and naphthalene(+*)-benzene: Evidence for stacked sandwich and T-shape structures. AB - Dimer radical cations of aromatic and polycyclic aromatic molecules are good model systems for a fundamental understanding of photoconductivity and ferromagnetism in organic materials which depend on the degree of charge delocalization. The structures of the dimer radical cations are difficult to determine theoretically since the potential energy surface is often very flat with multiple shallow minima representing two major classes of isomers adopting the stacked parallel or the T-shape structure. We present experimental results, based on mass-selected ion mobility measurements, on the gas phase structures of the naphthalene(+?) ? naphthalene homodimer and the naphthalene(+?) ? benzene heterodimer radical cations at different temperatures. Ion mobility studies reveal a persistence of the stacked parallel structure of the naphthalene(+?) ? naphthalene homodimer in the temperature range 230-300 K. On the other hand, the results reveal that the naphthalene(+?) ? benzene heterodimer is able to exhibit both the stacked parallel and T-shape structural isomers depending on the experimental conditions. Exploitation of the unique structural motifs among charged homo- and heteroaromatic-aromatic interactions may lead to new opportunities for molecular design and recognition involving charged aromatic systems. PMID- 26001440 TI - Communication: Saturated CO2 absorption near 1.6 MUm for kilohertz-accuracy transition frequencies. AB - Doppler-free saturated-absorption Lamb dips were measured on weak rovibrational lines of (12)C(16)O2 between 6189 and 6215 cm(-1) at sub-Pa pressures using optical feedback frequency stabilized cavity ring-down spectroscopy. By referencing the laser source to an optical frequency comb, transition frequencies for ten lines of the 30013<-00001 band P-branch and two lines of the 31113<-01101 hot band R-branch were determined with an accuracy of a few parts in 10(11). Involving rotational quantum numbers up to 42, the data were used for improving the upper level spectroscopic constants. These results provide a highly accurate reference frequency grid over the spectral interval from 1599 to 1616 nm. PMID- 26001441 TI - Solving the Schrodinger equation of molecules by relaxing the antisymmetry rule: Inter-exchange theory. AB - The Schrodinger equation (SE) and the antisymmetry principle constitute the governing principle of chemistry. A general method of solving the SE was presented before as the free complement (FC) theory, which gave highly accurate solutions for small atoms and molecules. We assume here to use the FC theory starting from the local valence bond wave function. When this theory is applied to larger molecules, antisymmetrizations of electronic wave functions become time consuming and therefore, an additional breakthrough is necessary concerning the antisymmetry principle. Usually, in molecular calculations, we first construct the wave function to satisfy the antisymmetry rule, "electronic wave functions must be prescribed to be antisymmetric for all exchanges of electrons, otherwise bosonic interference may disturb the basis of the science." Starting from determinantal wave functions is typical. Here, we give an antisymmetrization theory, called inter-exchange (iExg) theory, by dividing molecular antisymmetrizations to those within atoms and between atoms. For the electrons belonging to distant atoms in a molecule, only partial antisymmetrizations or even no antisymmetrizations are necessary, depending on the distance between the atoms. So, the above antisymmetry rule is not necessarily followed strictly to get the results of a desired accuracy. For this and other reasons, the necessary parts of the antisymmetrization operations become very small as molecules become larger, leading finally to the operation counts of lower orders of N, the number of electrons. This theory creates a natural antisymmetrization method that is useful for large molecules. PMID- 26001442 TI - Frequency dispersion of the first hyperpolarizabilities of reference molecules for nonlinear optics. AB - The frequency dispersion of the hyper-Rayleigh scattering first hyperpolarizabilities (betaHRS) of five reference molecules for nonlinear optics, namely, carbon tetrachloride, chloroform, dichloromethane, acetonitrile, and trichloroacetonitrile, is described using the coupled-cluster singles and doubles quadratic response function (CCSD-QRF) as well as approximate schemes. Comparisons to approximate schemes in which the frequency dispersion is evaluated as either a multiplicative or an additive correction to the static hyperpolarizability yield the following observations: (i) errors of the order of 10% or less are usually encountered when using the multiplicative scheme for photon energies far from the lowest dipole-allowed excitation energies, (ii) spurious cases cannot be excluded as evidenced by carbon tetrachloride where the multiplicative scheme predicts a decrease of betaHRS in contradiction to the increase obtained using the CCSD-QRF method, and (iii) the additive scheme is at best as reliable as the multiplicative approximation. The two-state approximation presents the advantage of correcting the wrong behavior of the additive and multiplicative schemes for carbon tetrachloride, but it is not an improved solution for the other compounds, while the question of selecting the appropriate dominant excited state remains unanswered. Finally, a new beta(xyz) value of 18.9 a.u. is proposed for carbon tetrachloride in gas phase at lambda = 1064 nm, to be compared with the measured 16.9 +/- 1.4 a.u. value due to Shelton. PMID- 26001443 TI - An ergodic configurational thermostat using selective control of higher order temperatures. AB - The conventional Nose-Hoover type deterministic thermostat scheme for controlling temperature by configurational variables (Braga-Travis (BT) thermostat) is non ergodic for systems with a few degrees of freedom. While for the original Nose Hoover kinetic thermostat ergodicity has been achieved by controlling the higher order moments of kinetic energy, the issues of nonergodicity of BT thermostat persists. In this paper, we introduce two new measures of configurational temperature (second and third order) based on the generalized temperature curvature relationship and obtain a family of deterministic thermostatting schemes by selectively (and simultaneously) controlling the different orders of temperatures through pseudo-friction terms. The ergodic characteristics of the proposed thermostats are tested using a single harmonic oscillator through statistical (normality of joint distributions at different Poincare sections) as well as dynamical tests (difference of the minimum and maximum largest Lyapunov exponent). Our results indicate that simultaneously controlling the first and the second order configurational temperatures (C(1,2) thermostat) is sufficient to make the dynamics ergodic. A 2000 particle Lennard-Jones system is subjected to (i) equilibrium and (ii) sudden temperature change under BT and C(1,2) thermostatting schemes. The C(1,2) thermostat is found to be more robust than the BT thermostat without increasing computational costs. PMID- 26001444 TI - Electrolytes between dielectric charged surfaces: Simulations and theory. AB - We present a simulation method to study electrolyte solutions in a dielectric slab geometry using a modified 3D Ewald summation. The method is fast and easy to implement, allowing us to rapidly resum an infinite series of image charges. In the weak coupling limit, we also develop a mean-field theory which allows us to predict the ionic distribution between the dielectric charged plates. The agreement between both approaches, theoretical and simulational, is very good, validating both methods. Examples of ionic density profiles in the strong electrostatic coupling limit are also presented. Finally, we explore the confinement of charge asymmetric electrolytes between neutral surfaces. PMID- 26001445 TI - A periodic energy decomposition analysis method for the investigation of chemical bonding in extended systems. AB - The development and first applications of a new periodic energy decomposition analysis (pEDA) scheme for extended systems based on the Kohn-Sham approach to density functional theory are described. The pEDA decomposes the bonding energy between two fragments (e.g., the adsorption energy of a molecule on a surface) into several well-defined terms: preparation, electrostatic, Pauli repulsion, and orbital relaxation energies. This is complemented by consideration of dispersion interactions via a pairwise scheme. One major extension toward a previous implementation [Philipsen and Baerends, J. Phys. Chem. B 110, 12470 (2006)] lies in the separate discussion of electrostatic and Pauli and the addition of a dispersion term. The pEDA presented here for an implementation based on atomic orbitals can handle restricted and unrestricted fragments for 0D to 3D systems considering periodic boundary conditions with and without the determination of fragment occupations. For the latter case, reciprocal space sampling is enabled. The new method gives comparable results to established schemes for molecular systems and shows good convergence with respect to the basis set (TZ2P), the integration accuracy, and k-space sampling. Four typical bonding scenarios for surface-adsorbate complexes were chosen to highlight the performance of the method representing insulating (CO on MgO(001)), metallic (H2 on M(001), M = Pd, Cu), and semiconducting (CO and C2H2 on Si(001)) substrates. These examples cover diverse substrates as well as bonding scenarios ranging from weakly interacting to covalent (shared electron and donor acceptor) bonding. The results presented lend confidence that the pEDA will be a powerful tool for the analysis of surface adsorbate bonding in the future, enabling the transfer of concepts like ionic and covalent bonding, donor-acceptor interaction, steric repulsion, and others to extended systems. PMID- 26001446 TI - Explicitly correlated ring-coupled-cluster-doubles theory. AB - The connection between the random-phase approximation and the ring-coupled cluster-doubles method bridges the gap between density-functional and wave function theories and the importance of the random-phase approximation lies in both its broad applicability and this linking role in electronic-structure theory. In this contribution, we present an explicitly correlated approach to the random-phase approximation, based on the direct ring-coupled-cluster-doubles ansatz, which overcomes the problem of slow basis-set convergence, inherent to the random-phase approximation. Benchmark results for a test set of 106 molecules and a selection of 10 organic complexes from the S22 test set demonstrate that convergence to within 99% of the basis-set limit is reached for triple-zeta basis sets for atomisation energies, while quadruple-zeta basis sets are required for interaction energies. Corrections due to single excitations into the complementary auxiliary space reduce the basis-set incompleteness error by one order of magnitude, while contributions due to the coupling of conventional and geminal amplitudes are in general negligible. We find that a non-iterative explicitly correlated correction to first order in perturbation theory exhibits the best ratio of accuracy to computational cost. PMID- 26001447 TI - Semiclassical modelling of finite-pulse effects on non-adiabatic photodynamics via initial condition filtering: The predissociation of NaI as a test case. AB - Femtosecond-laser pulse driven non-adiabatic spectroscopy and dynamics in molecular and condensed phase systems continue to be a challenge for theoretical modelling. One of the main obstacles is the "curse of dimensionality" encountered in non-adiabatic, exact wavepacket propagation. A possible route towards treating complex molecular systems is via semiclassical surface-hopping schemes, in particular if they account not only for non-adiabatic post-excitation dynamics but also for the initial optical excitation. One such approach, based on initial condition filtering, will be put forward in what follows. As a simple test case which can be compared with exact wavepacket dynamics, we investigate the influence of the different parameters determining the shape of a laser pulse (e.g., its finite width and a possible chirp) on the predissociation dynamics of a NaI molecule, upon photoexcitation of the A(0(+)) state. The finite-pulse effects are mapped into the initial conditions for semiclassical surface-hopping simulations. The simulated surface-hopping diabatic populations are in qualitative agreement with the quantum mechanical results, especially concerning the subpicosend photoinduced dynamics, the main deviations being the relative delay of the non-adiabatic transitions in the semiclassical picture. Likewise, these differences in the time-dependent electronic populations calculated via the semiclassical and the quantum methods are found to have a mild influence on the overall probability density distribution. As a result, the branching ratios between the bound and the dissociative reaction channels and the time-evolution of the molecular wavepacket predicted by the semiclassical method agree with those computed using quantum wavepacket propagation. Implications for more challenging molecular systems are given. PMID- 26001448 TI - Fractional charge and spin errors in self-consistent Green's function theory. AB - We examine fractional charge and spin errors in self-consistent Green's function theory within a second-order approximation (GF2). For GF2, it is known that the summation of diagrams resulting from the self-consistent solution of the Dyson equation removes the divergences pathological to second-order Moller-Plesset (MP2) theory for strong correlations. In the language often used in density functional theory contexts, this means GF2 has a greatly reduced fractional spin error relative to MP2. The natural question then is what effect, if any, does the Dyson summation have on the fractional charge error in GF2? To this end, we generalize our previous implementation of GF2 to open-shell systems and analyze its fractional spin and charge errors. We find that like MP2, GF2 possesses only a very small fractional charge error, and consequently minimal many electron self interaction error. This shows that GF2 improves on the critical failings of MP2, but without altering the positive features that make it desirable. Furthermore, we find that GF2 has both less fractional charge and fractional spin errors than typical hybrid density functionals as well as random phase approximation with exchange. PMID- 26001449 TI - Entropic stochastic resonance without external force in oscillatory confined space. AB - We have studied the dynamics of Brownian particles in a confined geometry of dumbbell-shape with periodically oscillating walls. Entropic stochastic resonance (ESR) behavior, characterizing by a maximum value of the coherent factor Q at some optimal level of noise, is observed even without external periodic force in the horizontal direction, which is necessary for conventional ESR where the wall is static and the particle is subjected to the force. Interestingly, the ESR can be remarkably enhanced by the particle gravity G, in contrast to the conventional case. In addition, Q decreases (increases) with G in the small (large) noise limit, respectively, while it non-monotonically changes with G for moderate noise levels. We have applied an effective 1D coarsening description to illustrate such a nontrivial dependence on G, by investigating the property of the 1D effective potential of entropic nature and paying special attention to the excess part resulting from the boundary oscillation. Dependences of the ESR strength with other related parameters are also discussed. PMID- 26001450 TI - A systematic comparison of different approaches of density functional theory for the study of electrical double layers. AB - Based on the best available knowledge of density functional theory (DFT), the reference-fluid perturbation method is here extended to yield different approaches that well account for the cross correlations between the Columbic interaction and the hard-sphere exclusion in an inhomogeneous ionic hard-sphere fluid. In order to quantitatively evaluate the advantage and disadvantage of different approaches in describing the interfacial properties of electrical double layers, this study makes a systematic comparison against Monte Carlo simulations over a wide range of conditions. The results suggest that the accuracy of the DFT approaches is well correlated to a coupling parameter that describes the coupling strength of electrical double layers by accounting for the steric effect and that can be used to classify the systems into two regimes. In the weak-coupling regime, the approaches based on the bulk-fluid perturbation method are shown to be more accurate than the counterparts based on the reference fluid perturbation method, whereas they exhibit the opposite behavior in the strong-coupling regime. More importantly, the analysis indicates that, with a suitable choice of the reference fluid, the weighted correlation approximation (WCA) to DFT gives the best account of the coupling effect of the electrostatic excluded volume correlations. As a result, a piecewise WCA approach can be developed that is robust enough to describe the structural and thermodynamic properties of electrical double layers over both weak- and strong-coupling regimes. PMID- 26001451 TI - Application of multireference equation of motion coupled-cluster theory to transition metal complexes and an orbital selection scheme for the efficient calculation of excitation energies. AB - This paper presents the first application of the multireference equation of motion coupled-cluster (MR-EOMCC) approach to the calculation and characterization of excitation energies of transition metal complexes. The calculated MR-EOM excitation energies are compared with experimental UV/Vis. band maxima, Brueckner based similarity transformed equation of motion (STEOM) calculations and Brueckner based equation of motion coupled cluster (EOM-CCSD(T)) calculations, as well as results calculated with other methods from the literature. The agreement of the excitation energies with experiment is found to be reasonable, and suitable rationalization is given for the discrepancies. An orbital selection scheme is introduced, which can be employed to extend the applicability of the MR-EOMCC methodology to considerably larger systems. PMID- 26001452 TI - Coagulation kinetics beyond mean field theory using an optimised Poisson representation. AB - Binary particle coagulation can be modelled as the repeated random process of the combination of two particles to form a third. The kinetics may be represented by population rate equations based on a mean field assumption, according to which the rate of aggregation is taken to be proportional to the product of the mean populations of the two participants, but this can be a poor approximation when the mean populations are small. However, using the Poisson representation, it is possible to derive a set of rate equations that go beyond mean field theory, describing pseudo-populations that are continuous, noisy, and complex, but where averaging over the noise and initial conditions gives the mean of the physical population. Such an approach is explored for the simple case of a size independent rate of coagulation between particles. Analytical results are compared with numerical computations and with results derived by other means. In the numerical work, we encounter instabilities that can be eliminated using a suitable "gauge" transformation of the problem [P. D. Drummond, Eur. Phys. J. B 38, 617 (2004)] which we show to be equivalent to the application of the Cameron Martin-Girsanov formula describing a shift in a probability measure. The cost of such a procedure is to introduce additional statistical noise into the numerical results, but we identify an optimised gauge transformation where this difficulty is minimal for the main properties of interest. For more complicated systems, such an approach is likely to be computationally cheaper than Monte Carlo simulation. PMID- 26001453 TI - Exploring the potential energy landscape of the Thomson problem via Newton homotopies. AB - Locating the stationary points of a real-valued multivariate potential energy function is an important problem in many areas of science. This task generally amounts to solving simultaneous nonlinear systems of equations. While there are several numerical methods that can find many or all stationary points, they each exhibit characteristic problems. Moreover, traditional methods tend to perform poorly near degenerate stationary points with additional zero Hessian eigenvalues. We propose an efficient and robust implementation of the Newton homotopy method, which is capable of quickly sampling a large number of stationary points of a wide range of indices, as well as degenerate stationary points. We demonstrate our approach by applying it to the Thomson problem. We also briefly discuss a possible connection between the present work and Smale's 7th problem. PMID- 26001454 TI - On the accuracy of density functional theory and wave function methods for calculating vertical ionization energies. AB - The best practice in computational methods for determining vertical ionization energies (VIEs) is assessed, via reference to experimentally determined VIEs that are corroborated by highly accurate coupled-cluster calculations. These reference values are used to benchmark the performance of density functional theory (DFT) and wave function methods: Hartree-Fock theory, second-order Moller-Plesset perturbation theory, and Electron Propagator Theory (EPT). The core test set consists of 147 small molecules. An extended set of six larger molecules, from benzene to hexacene, is also considered to investigate the dependence of the results on molecule size. The closest agreement with experiment is found for ionization energies obtained from total energy difference calculations. In particular, DFT calculations using exchange-correlation functionals with either a large amount of exact exchange or long-range correction perform best. The results from these functionals are also the least sensitive to an increase in molecule size. In general, ionization energies calculated directly from the orbital energies of the neutral species are less accurate and more sensitive to an increase in molecule size. For the single-calculation approach, the EPT calculations are in closest agreement for both sets of molecules. For the orbital energies from DFT functionals, only those with long-range correction give quantitative agreement with dramatic failing for all other functionals considered. The results offer a practical hierarchy of approximations for the calculation of vertical ionization energies. In addition, the experimental and computational reference values can be used as a standardized set of benchmarks, against which other approximate methods can be compared. PMID- 26001455 TI - Mechanistic insights into the dehalogenation reaction of fluoroacetate/fluoroacetic acid. AB - Fluoroacetate is a toxic compound whose environmental accumulation may represent an important contamination problem, its elimination is therefore a challenging issue. Fluoroacetate dehalogenase catalyzes its degradation through a two step process initiated by an S(N)2 reaction in which the aspartate residue performs a nucleophilic attack on the carbon bonded to the fluorine; the second step is hydrolysis that releases the product as glycolate. In this paper, we present a study based on density functional theory calculations of the S(N)2 initiation reaction modeled through the interaction between the substrate and the propionate anion as the nucleophile. Results are analyzed within the framework of the reaction force and using the reaction electronic flux to identify and characterize the electronic activity that drives the reaction. Our results reveal that the selective protonation of the substrate catalyzes the reaction by decreasing the resistance of the structural and electronic reorganization needed to reach the transition state. Finally, the reaction energy is modulated by the degree of stabilization of the fluoride anion formed after the S(N)2 reaction. In this way, a site-induced partial protonation acts as a chemical switch in a key process that determines the output of the reaction. PMID- 26001456 TI - Intermediate energy electron impact excitation of composite vibrational modes in phenol. AB - We report differential cross section results from an experimental investigation into the electron impact excitation of a number of the low-lying composite (unresolved) vibrational modes in phenol (C6H5OH). The measurements were carried out at incident electron energies in the range 15-40 eV and for scattered electron angles in the range 10-90 degrees . The energy resolution of those measurements was typically ~80 meV. Calculations, using the GAMESS code, were also undertaken with a B3LYP/aug-cc-pVDZ level model chemistry, in order to enable us to assign vibrational modes to the features observed in our energy loss spectra. To the best of our knowledge, the present cross sections are the first to be reported for vibrational excitation of the C6H5OH molecule by electron impact. PMID- 26001457 TI - Gas-phase study on uridine: Conformation and X-ray photofragmentation. AB - Fragmentation of RNA nucleoside uridine, induced by carbon 1s core ionization, has been studied. The measurements by combined electron and ion spectroscopy have been performed in gas phase utilizing synchrotron radiation. As uridine is a combination of d-ribose and uracil, which have been studied earlier with the same method, this study also considers the effect of chemical environment and the relevant functional groups. Furthermore, since in core ionization the initial core hole is always highly localized, charge migration prior to fragmentation has been studied here. This study also demonstrates the destructive nature of core ionization as in most cases the C 1s ionization of uridine leads to concerted explosions producing only small fragments with masses <=43 amu. In addition to fragmentation patterns, we found out that upon evaporation the sugar part of the uridine molecule attains hexagonal form. PMID- 26001458 TI - The Renner-Teller effect in HCCCl(+)(X(2)Pi) studied by zero-kinetic energy photoelectron spectroscopy and ab initio calculations. AB - The spin-vibronic energy levels of the chloroacetylene cation up to 4000 cm(-1) above the ground state have been measured using the one-photon zero-kinetic energy photoelectron spectroscopic method. The spin-vibronic energy levels have also been calculated using a diabatic model, in which the potential energy surfaces are expressed by expansions of internal coordinates, and the Hamiltonian matrix equation is solved using a variational method with harmonic basis functions. The calculated spin-vibronic energy levels are in good agreement with the experimental data. The Renner-Teller (RT) parameters describing the vibronic coupling for the H-C=C bending mode (epsilon4), Cl-C=C bending mode (epsilon5), the cross-mode vibronic coupling (epsilon45) of the two bending vibrations, and their vibrational frequencies (omega4 and omega5) have also been determined using an effective Hamiltonian matrix treatment. In comparison with the spin-orbit interaction, the RT effect in the H-C=C bending (epsilon4) mode is strong, while the RT effect in the Cl-C=C bending mode is weak. There is a strong cross-mode vibronic coupling of the two bending vibrations, which may be due to a vibronic resonance between the two bending vibrations. The spin-orbit energy splitting of the ground state has been determined for the first time and is found to be 209 +/ 2 cm(-1). PMID- 26001459 TI - Integral cross sections for electron impact excitation of vibrational and electronic states in phenol. AB - We report on measurements of integral cross sections (ICSs) for electron impact excitation of a series of composite vibrational modes and electronic-states in phenol, where the energy range of those experiments was 15-250 eV. There are currently no other results against which we can directly compare those measured data. We also report results from our independent atom model with screened additivity rule correction computations, namely, for the inelastic ICS (all discrete electronic states and neutral dissociation) and the total ionisation ICS. In addition, for the relevant dipole-allowed excited electronic states, we also report f-scaled Born-level and energy-corrected and f-scaled Born-level (BEf scaled) ICS. Where possible, our measured and calculated ICSs are compared against one another with the general level of accord between them being satisfactory to within the measurement uncertainties. PMID- 26001460 TI - Femtosecond time-resolved electronic relaxation dynamics in tetrathiafulvalene. AB - In the present paper, the ultrafast electronic relaxation of tetrathiafulvalene (TTF) initiated around 4 eV is studied by femtosecond time-resolved velocity-map imaging. The goal is to investigate the broad double structure observed in the absorption spectrum at this energy. By monitoring the transients of the parent cation and its fragments and by varying the pump and the probe wavelengths, two internal conversions and intramolecular vibrational relaxation are detected both on the order of a few hundred of femtoseconds. Photoelectron images permit the assignment of a dark electronic state involved in the relaxation. In addition, the formation of the dimer of TTF has been observed. PMID- 26001461 TI - Accurate quantum dynamics calculations of vibrational spectrum of dideuteromethane CH2D2. AB - We report a rigorous variational study of the infrared (IR) vibrational spectra of both CH2D2 and (13)CH2D2 isotopomers using an exact molecular Hamiltonian. Calculations are carried out using a recently developed multi-layer Lanczos algorithm based on the accurate refined Wang and Carrington potential energy surface of methane and the low-order truncated ab initio dipole moment surface of Yurchenko et al. [J. Mol. Spectrosc. 291, 69 (2013)]. All well converged 357 vibrational energy levels up to 6100 cm(-1) of CH2D2 are obtained, together with a comparison to previous calculations and 91 experimental bands available. The calculated frequencies are in excellent agreement with the experimental results and give a root-mean-square error of 0.67 cm(-1). In particular, we also compute the transition intensities from the vibrational ground state for both isotopomers. Based on the theoretical results, 20 experimental bands are suggested to be re-assigned. Surprisingly, an anomalous C isotopic effect is discovered in the nnu5 modes of CH2D2. The predicted IR spectra provide useful information for understanding those unknown bands. PMID- 26001462 TI - Continuum model for chiral induced spin selectivity in helical molecules. AB - A minimal model is exactly solved for electron spin transport on a helix. Electron transport is assumed to be supported by well oriented p(z) type orbitals on base molecules forming a staircase of definite chirality. In a tight binding interpretation, the spin-orbit coupling (SOC) opens up an effective pi(z) - pi(z) coupling via interbase p(x,y) - p(z) hopping, introducing spin coupled transport. The resulting continuum model spectrum shows two Kramers doublet transport channels with a gap proportional to the SOC. Each doubly degenerate channel satisfies time reversal symmetry; nevertheless, a bias chooses a transport direction and thus selects for spin orientation. The model predicts (i) which spin orientation is selected depending on chirality and bias, (ii) changes in spin preference as a function of input Fermi level and (iii) back-scattering suppression protected by the SO gap. We compute the spin current with a definite helicity and find it to be proportional to the torsion of the chiral structure and the non-adiabatic Aharonov-Anandan phase. To describe room temperature transport, we assume that the total transmission is the result of a product of coherent steps. PMID- 26001463 TI - Short range order in elemental liquids of column IV. AB - The short range order (SRO) in liquid elements of column IV is analysed within the quasi-crystalline model across a wide range of temperatures. It is found that l-Si, Ge, and Sn are well described with a beta-tin like SRO. In contrast, Pb retains a bcc-like SRO similar to other simple elemental liquids. However, a distinction is found between the SRO in Si and Ge and that in Sn, where the latter has a more rigid structure. This difference persists across the entire temperature range examined but is overcome in Si at pressures above 8 GPa, where the liquid structure evolves towards that of Sn. PMID- 26001464 TI - Quantum calculations of the IR spectrum of liquid water using ab initio and model potential and dipole moment surfaces and comparison with experiment. AB - The calculation and characterization of the IR spectrum of liquid water have remained a challenge for theory. In this paper, we address this challenge using a combination of ab initio approaches, namely, a quantum treatment of IR spectrum using the ab initio WHBB water potential energy surface and a refined ab initio dipole moment surface. The quantum treatment is based on the embedded local monomer method, in which the three intramolecular modes of each embedded H2O monomer are fully coupled and also coupled singly to each of six intermolecular modes. The new dipole moment surface consists of a previous spectroscopically accurate 1-body dipole moment surface and a newly fitted ab initio intrinsic 2 body dipole moment. A detailed analysis of the new dipole moment surface in terms of the coordinate dependence of the effective atomic charges is done along with tests of it for the water dimer and prism hexamer double-harmonic spectra against direct ab initio calculations. The liquid configurations are taken from previous molecular dynamics calculations of Skinner and co-workers, using the TIP4P plus E3B rigid monomer water potential. The IR spectrum of water at 300 K in the range of 0-4000 cm(-1) is calculated and compared with experiment, using the ab initio WHBB potential and new ab initio dipole moment, the q-TIP4P/F potential, which has a fixed-charged description of the dipole moment, and the TTM3-F potential and dipole moment surfaces. The newly calculated ab initio spectrum is in very good agreement with experiment throughout the above spectral range, both in band positions and intensities. This contrasts to results with the other potentials and dipole moments, especially the fixed-charge q-TIP4P/F model, which gives unrealistic intensities. The calculated ab initio spectrum is analyzed by examining the contribution of various transitions to each band. PMID- 26001465 TI - Pressure-induced polymerization of P(CN)3. AB - Motivated to explore the formation of novel extended carbon-nitrogen solids via well-defined molecular precursor pathways, we studied the chemical reactivity of highly pure phosphorous tricyanide, P(CN)3, under conditions of high pressure at room temperature. Raman and infrared (IR) spectroscopic measurements reveal a series of phase transformations below 10 GPa, and several low-frequency vibrational modes are reported for the first time. Synchrotron powder X-ray diffraction measurements taken during compression show that molecular P(CN)3 is highly compressible, with a bulk modulus of 10.0 +/- 0.3 GPa, and polymerizes into an amorphous solid above ~10.0 GPa. Raman and IR spectra, together with first-principles molecular-dynamics simulations, show that the amorphization transition is associated with polymerization of the cyanide groups into CN bonds with predominantly sp(2) character, similar to known carbon nitrides, resulting in a novel phosphorous carbon nitride (PCN) polymeric phase, which is recoverable to ambient pressure. PMID- 26001466 TI - Modeling nanoscale hydrodynamics by smoothed dissipative particle dynamics. AB - Thermal fluctuation and hydrophobicity are two hallmarks of fluid hydrodynamics on the nano-scale. It is a challenge to consistently couple the small length and time scale phenomena associated with molecular interaction with larger scale phenomena. The development of this consistency is the essence of mesoscale science. In this study, we use a nanoscale fluid model based on smoothed dissipative particle dynamics that accounts for the phenomena associated with density fluctuations and hydrophobicity. We show consistency in the fluctuation spectrum across scales. In doing so, it is necessary to account for finite fluid particle size. Furthermore, we demonstrate that the present model can capture the void probability and solvation free energy of nonpolar hard particles of different sizes. The present fluid model is well suited for an understanding of emergent phenomena in nano-scale fluid systems. PMID- 26001467 TI - Rubber friction on road surfaces: Experiment and theory for low sliding speeds. AB - We study rubber friction for tire tread compounds on asphalt road surfaces. The road surface topographies are measured using a stylus instrument and atomic force microscopy, and the surface roughness power spectra are calculated. The rubber viscoelastic modulus mastercurves are obtained from dynamic mechanical analysis measurements and the large-strain effective modulus is obtained from strain sweep data. The rubber friction is measured at different temperatures and sliding velocities, and is compared to the calculated data obtained using the Persson contact mechanics theory. We conclude that in addition to the viscoelastic deformations of the rubber surface by the road asperities, there is an important contribution to the rubber friction from shear processes in the area of contact. The analysis shows that the latter contribution may arise from rubber molecules (or patches of rubber) undergoing bonding-stretching-debonding cycles as discussed in a classic paper by Schallamach. PMID- 26001468 TI - Hysteresis and change of transition temperature in thin films of Fe{[Me2Pyrz]3BH}2, a new sublimable spin-crossover molecule. AB - Thin films of the spin-crossover (SCO) molecule Fe{[Me2Pyrz]3BH}2 (Fe-pyrz) were sublimed on Si/SiO2 and quartz substrates, and their properties investigated by X ray absorption and photoemission spectroscopies, optical absorption, atomic force microscopy, and superconducting quantum interference device. Contrary to the previously studied Fe(phen)2(NCS)2, the films are not smooth but granular. The thin films qualitatively retain the typical SCO properties of the powder sample (SCO, thermal hysteresis, soft X-ray induced excited spin-state trapping, and light induced excited spin-state trapping) but present intriguing variations even in micrometer-thick films: the transition temperature decreases when the thickness is decreased, and the hysteresis is affected. We explain this behavior in the light of recent studies focusing on the role of surface energy in the thermodynamics of the spin transition in nano-structures. In the high-spin state at room temperature, the films have a large optical gap (~5 eV), decreasing at thickness below 50 nm, possibly due to film morphology. PMID- 26001469 TI - Electrode polarization vs. Maxwell-Wagner-Sillars interfacial polarization in dielectric spectra of materials: Characteristic frequencies and scaling laws. AB - The characteristic frequencies of electrode polarization and of interfacial polarization effects in dielectric spectra of ionic liquids and of polymer bi layers are determined and systematically analyzed, based on dielectric measurements by means of broadband dielectric spectroscopy, numerical simulations, and analytical calculations. It is shown that, to a large extent, identical scaling laws can be derived for these two dielectric phenomena taking place at external and internal interfaces. Surprisingly, a fundamentally different behavior concerning the interrelation between the characteristic frequencies is found. This brings direct evidence that different manifestations of the phenomenon of electrical polarization can be discriminated by examining the inter-relation governing their characteristic frequencies, which can be of significant importance in disseminating the nature of different contributions appearing in the dielectric spectra of complex materials. Based on our analysis, we derive a new formula, valid for both electrode polarization and interfacial polarization effects, that allows one to determine the conductivity value from the frequency position of the Maxwell-Wagner-Sillars peak. An excellent agreement between experiment and calculations is obtained. The formula can be used, furthermore, to estimate the thickness of the interfacial layers formed due to electrode polarization effects. Values in the order of several nanometers, increasing with decreasing temperature, are reported. PMID- 26001470 TI - Defect topologies in chiral liquid crystals confined to mesoscopic channels. AB - We present Monte Carlo simulations in the grand canonical and canonical ensembles of a chiral liquid crystal confined to mesochannels of variable sizes and geometries. The mesochannels are taken to be quasi-infinite in one dimension but finite in the two other directions. Under thermodynamic conditions chosen and for a selected value of the chirality coupling constant, the bulk liquid crystal exhibits structural characteristics of a blue phase II. This is established through the tetrahedral symmetry of disclination lines and the characteristic simple-cubic arrangement of double-twist helices formed by the liquid-crystal molecules along all three axes of a Cartesian coordinate system. If the blue phase II is then exposed to confinement, the interplay between its helical structure, various anchoring conditions at the walls of the mesochannels, and the shape of the mesochannels gives rise to a broad variety of novel, qualitative disclination-line structures that are reported here for the first time. PMID- 26001471 TI - The perturbation energy: A missing key to understand the "nobleness" of bulk gold. AB - The nobleness of gold surfaces has been appreciated since long before the beginning of recorded history. Yet, the origin of this phenomenon remains open because the so far existing explanations either incorrectly imply that silver should be the noblest metal or would fail to predict the dissolution of Au in aqua regia. Here, based on our analyses of oxygen adsorption, we advance that bulk gold's unique resistance to oxidation is traced to the large energy cost associated with the perturbation its surfaces undergo upon adsorption of highly electronegative species. This fact is related to the almost totally filled d-band of Au and relativistic effects, but does not imply that the strength of the adsorbate-Au bond is weak. The magnitude of the structural and charge-density perturbation energy upon adsorption of atomic oxygen-which is largest for Au-is assessed from first-principles calculations and confirmed via a multiple regression analysis of the binding energy of oxygen on metal surfaces. PMID- 26001472 TI - Onsager's reciprocal relations for electroacoustic and sedimentation: Application to (concentrated) colloidal suspensions. AB - In this article, the relations for electroacoustic phenomena, such as sedimentation potential, sedimentation intensity, colloid vibration potential, colloid vibration intensity/current, or electric sonic amplitude, are given, on the basis of irreversible thermodynamics. This formalism allows in particular to discuss the different expressions for concentrated suspensions found by various authors, which are of great practical interest. It was found that some existing expressions have to be corrected. Relations between the electrophoretic mobilities assessed by the different experiments are derived. PMID- 26001473 TI - Interaction between random heterogeneously charged surfaces in an electrolyte solution. AB - We study, using Monte Carlo simulations, the interaction between infinite heterogeneously charged surfaces inside an electrolyte solution. The surfaces are overall neutral with quenched charged domains. An average over the quenched disorder is performed to obtain the net force. We find that the interaction between the surfaces is repulsive at short distances and is attractive for larger separations. PMID- 26001474 TI - Two-Yukawa fluid at a hard wall: Field theory treatment. AB - We apply a field-theoretical approach to study the structure and thermodynamics of a two-Yukawa fluid confined by a hard wall. We derive mean field equations allowing for numerical evaluation of the density profile which is compared to analytical estimations. Beyond the mean field approximation, analytical expressions for the free energy, the pressure, and the correlation function are derived. Subsequently, contributions to the density profile and the adsorption coefficient due to Gaussian fluctuations are found. Both the mean field and the fluctuation terms of the density profile are shown to satisfy the contact theorem. We further use the contact theorem to improve the Gaussian approximation for the density profile based on a better approximation for the bulk pressure. The results obtained are compared to computer simulation data. PMID- 26001475 TI - The crystal-fluid interfacial free energy and nucleation rate of NaCl from different simulation methods. AB - In this work, we calculate the crystal-fluid interfacial free energy, gamma(cf), for the Tosi-Fumi model of NaCl using three different simulation techniques: seeding, umbrella sampling, and mold integration. The three techniques give an orientationaly averaged gamma(cf) of about 100 mJ/m(2). Moreover, we observe that the shape of crystalline clusters embedded in the supercooled fluid is spherical. Using the mold integration technique, we compute gamma(cf) for four different crystal orientations. The obtained interfacial free energies range from 100 to 114 mJ/m(2), being (100) and (111) the crystal planes with the lowest and highest gamma(cf), respectively. Within the accuracy of our calculations, the interfacial free energy either does not depend on temperature or changes very smoothly with it. Combining the seeding technique with classical nucleation theory, we also estimate nucleation free energy barriers and nucleation rates for a wide temperature range (800-1040 K). The obtained results compare quite well with brute force calculations and with previous results obtained with umbrella sampling [Valeriani et al., J. Chem. Phys, 122, 194501 (2005)]. PMID- 26001476 TI - Stabilization of Pt monolayer catalysts under harsh conditions of fuel cells. AB - We employed density functional theory to explore the stability of core (M = Cu, Ru, Rh, Pd, Ag, Os, Ir, Au)-shell (Pt) catalysts under harsh conditions, including solutions and reaction intermediates involved in the oxygen reduction reaction (ORR) in fuel cells. A pseudomorphic surface alloy (PSA) with a Pt monolayer (Pt(1ML)) supported on an M surface, Pt(1ML)/M(111) or (001), was considered as a model system. Different sets of candidate M cores were identified to achieve a stable Pt(1ML) shell depending on the conditions. In vacuum conditions, the Pt1ML shell can be stabilized on the most of M cores except Cu, Ag, and Au. The situation varies under various electrochemical conditions. Depending on the solutions and the operating reaction pathways of the ORR, different M should be considered. Pd and Ir are the only core metals studied, being able to keep the Pt(ML) shell intact in perchloric acid, sulfuric acid, phosphoric acid, and alkaline solutions as well as under the ORR conditions via different pathways. Ru and Os cores should also be paid attention, which only fall during the ORR via the *OOH intermediate. Rh core works well as long as the ORR does not undergo the pathway via *O intermediate. Our results show that PSAs can behave differently from the near surface alloy, Pt(1ML)/M(1ML)/Pt(111), highlighting the importance of considering both chemical environments and the atomic structures in rational design of highly stable core-shell nanocatalysts. Finally, the roles that d-band center of a core M played in determining the stability of supported Pt(1ML) shell were also discussed. PMID- 26001477 TI - Reconstruction of steps on the Cu(111) surface induced by sulfur. AB - A rich menagerie of structures is identified at 5 K following adsorption of low coverages (<=0.05 monolayers) of S on Cu(111) at room temperature. This paper emphasizes the reconstructions at the steps. The A-type close-packed step has 1 row of S atoms along its lower edge, where S atoms occupy alternating pseudo fourfold-hollow (p4fh) sites. Additionally, there are 2 rows of S atoms of equal density on the upper edge, bridging a row of extra Cu atoms, together creating an extended chain. The B-type close-packed step exhibits an even more complex reconstruction, in which triangle-shaped groups of Cu atoms shift out of their original sites and form a base for S adsorption at (mostly) 4fh sites. We propose a mechanism by which these triangles could generate Cu-S complexes and short chains like those observed on the terraces. PMID- 26001478 TI - Hydrodynamics and Brownian motions of a spheroid near a rigid wall. AB - In this work, we study in detail the hydrodynamics and the Brownian motions of a spheroidal particle suspended in a Newtonian fluid near a flat rigid wall. We employ 3D Finite Element Method (FEM) simulations to compute how the mobility tensor of the spheroid varies with both the particle-wall separation distance and the particle orientation. We then study the Brownian motion of the spheroid by means of a discretized Langevin equation. We specifically focus on the additional drift terms arising from the position and orientational dependence of the mobility matrix. In this respect, we also propose a numerically convenient approximation of the orientational divergence of the mobility matrix that is required in the solution of the Langevin equation. Our results illustrate that both hydrodynamics and Brownian motions of a spheroidal particle near a confining wall display novel features from those of a sphere in the same type of confinement. PMID- 26001479 TI - Perspective: Single polymer mechanics across the force regimes [corrected]. AB - I review theoretical and experimental results on the force-extension response of single polymers, with a focus on scaling pictures of low-force elastic regimes, and recent measurements of synthetic and biological chains that explore those regimes. The mechanical response of single polymers is an old theoretical problem whose exploration was instigated by the curious thermomechanical behavior of rubber. Up until the 1990s, the main utility of those calculations was to explain bulk material mechanics. However, in that decade, it became possible to directly test the calculations through high-precision single-chain stretching experiments (i.e., force spectroscopy). I present five major single-chain elasticity models, including scaling results based on blob-chain models, along with analytic results based on linear response theory, and those based on freely jointed chain or worm like chain structure. Each model is discussed in terms of the regime of force for which it holds, along with the status of its rigorous assessment with experiment. Finally, I show how the experiments can provide new insight into polymer structure itself, with particular emphasis on polyelectrolytes. PMID- 26001480 TI - Practical thermodynamics of Yukawa systems at strong coupling. AB - Simple practical approach to estimate thermodynamic properties of strongly coupled Yukawa systems, in both fluid and solid phases, is presented. The accuracy of the approach is tested by extensive comparison with direct computer simulation results (for fluids and solids) and the recently proposed shortest graph method (for solids). Possible applications to other systems of softly repulsive particles are briefly discussed. PMID- 26001481 TI - Adaptive resolution simulation of a biomolecule and its hydration shell: Structural and dynamical properties. AB - A fully atomistic modelling of many biophysical and biochemical processes at biologically relevant length- and time scales is beyond our reach with current computational resources, and one approach to overcome this difficulty is the use of multiscale simulation techniques. In such simulations, when system properties necessitate a boundary between resolutions that falls within the solvent region, one can use an approach such as the Adaptive Resolution Scheme (AdResS), in which solvent particles change their resolution on the fly during the simulation. Here, we apply the existing AdResS methodology to biomolecular systems, simulating a fully atomistic protein with an atomistic hydration shell, solvated in a coarse grained particle reservoir and heat bath. Using as a test case an aqueous solution of the regulatory protein ubiquitin, we first confirm the validity of the AdResS approach for such systems, via an examination of protein and solvent structural and dynamical properties. We then demonstrate how, in addition to providing a computational speedup, such a multiscale AdResS approach can yield otherwise inaccessible physical insights into biomolecular function. We use our methodology to show that protein structure and dynamics can still be correctly modelled using only a few shells of atomistic water molecules. We also discuss aspects of the AdResS methodology peculiar to biomolecular simulations. PMID- 26001482 TI - Active migration and passive transport of malaria parasites. AB - Malaria parasites undergo a complex life cycle between their hosts and vectors. During this cycle the parasites invade different types of cells, migrate across barriers, and transfer from one host to another. Recent literature hints at a misunderstanding of the difference between active, parasite-driven migration and passive, circulation-driven movement of the parasite or parasite-infected cells in the various bodily fluids of mosquito and mammalian hosts. Because both active migration and passive transport could be targeted in different ways to interfere with the parasite, a distinction between the two ways the parasite uses to get from one location to another is essential. We discuss the two types of motion needed for parasite dissemination and elaborate on how they could be targeted by future vaccines or drugs. PMID- 26001483 TI - Do women have poorer outcomes following total knee replacement? AB - OBJECTIVE: To investigate whether women have poorer pain and functional outcomes following total knee replacement (TKR) and to investigate factors that may contribute to this poorer outcome. METHODS: In a cohort of 494 people, outcomes were the Pain and Function/Daily Activity subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months post-surgery. Sequential multivariable regression analyses evaluated the following independent variables: (1) sex; (2) sex and age; (3) sex, age and pre-surgery score for respective outcome measures; and, (4) model 3 and body mass index (BMI), education, low back pain (LBP), depression, comorbidities, and symptomatic joint count. RESULTS: The sample included 323 women and 171 men. Women were significantly worse on several factors pre-surgery: pain: 39.0 vs 44.9, P = 0.002; function: 47.7 vs 55.0, P < 0.0001; depression 5.6 vs 4.7, P = 0.006; obesity (BMI >=30): 54.2 vs 36.3%, P = 0.0002; and, symptomatic joint count: >=4: 61.3 vs 44.4%, P = 0.002. Women had worse outcomes for pain (72.2 vs 76.1, P = 0.04) and function (75.2 vs 80.5, P = 0.007) at 6 months. This effect was attenuated by adding pre-surgery pain/function. However, the magnitude of the association of pre-surgery pain/function was reduced when LBP, depression, BMI, education level, joint count and comorbidity count were added suggesting association with pre-surgery pain and function. Twelve month results were similar. CONCLUSION: Women appear to have worse outcomes than men possibly due to a putative pre-operative profile across many factors. Consideration of TKR when impairments in pain and function are less severe along with interventions that address mood and comorbidity may improve outcomes for women having TKR. PMID- 26001484 TI - [Dermatological implications of the PI3K pathway]. PMID- 26001485 TI - Microbiological monitoring of flexible bronchoscopes after high-level disinfection and flushing channels with alcohol: Results and costs. AB - BACKGROUND: Routine microbiological surveillance of flexible bronchoscopes is recommended in different guidelines. The study aims to assess whether bronchoscopes reprocessing methods achieved an appropriate decontamination level and whether manual flushing of 70% ethyl alcohol at the end of the cycle reduces the risk of microbiological contamination. METHODS: 18 different bronchoscopes were cultured on a monthly basis during a four-year period to examine growing of bacteria, fungi and mycobacteria. 9 equipment were usually disinfected using automatic reprocessors, and the other 9 equipments were manually disinfected. Additional manual flushing of bronchoscope's channels with 70% ethyl alcohol at the end of each disinfection cycle, was implemented for automatically reprocessed equipments for a two-year period. RESULTS: A total of 620 samples were obtained. 564 samples (91.0%) tested negative and 56 samples (9%) tested positive for at least one specimen, of whom 3% were pathogenic or potentially pathogenic microorganisms. Only one positive sample was detected among the 167 alcohol treated bronchoscopes (0.6%), whereas before the introduction of this technique the percentage of contamination with risk pathogens was 4.1% (p = 0.04). The mean annual cost of the surveillance program was estimated at 23,035 euros, and the mean cost for bronchoscope was 111.5 euros. CONCLUSIONS: The results of our study support to improve the final reprocessing of bronchoscope channels by means of additional manual flushing with 70% ethyl alcohol after each disinfection cycle. Routine microbiologic monitoring of endoscopes is both time-consuming and expensive but could be saved by implementing a highly efficient decontaminating procedure. PMID- 26001486 TI - Mechanical dissociation of the M-band titin/obscurin complex is directionally dependent. AB - Titin and obscurin, two giant muscle proteins, bind to each other in an antiparallel Ig-Ig fashion at the M-band. This interaction must be able to withstand the mechanical strain that the M-band typically experiences and remain intact. The mechanical force on these domains is likely exerted along one of two axes: a longitudinal axis, resulting in a 'shearing' force, or a lateral axis, resulting in a 'peeling' force. Here we present molecular dynamics data suggesting that these forces result in distinct unraveling pathways of the titin/obscurin complex and that peeling the domains apart requires less work and force. PMID- 26001487 TI - The Impact of Freeze-Thaw Cycles on Epinephrine. AB - OBJECTIVES: Epinephrine is the first-line medical treatment for anaphylaxis, a life-threatening allergic syndrome. To treat anaphylaxis, backcountry recreationalists and guides commonly carry epinephrine autoinjectors. Epinephrine may be exposed to cold temperatures and freezing during expeditions. An epinephrine solution must contain 90% to 115% of the labeled epinephrine amount to meet United States Pharmacopeia standards. The purpose of this study was to determine whether freeze-thaw cycles alter epinephrine concentrations in autoinjectors labeled to contain 1.0 mg/mL epinephrine. A further objective was to determine whether samples continued to meet United States Pharmacopeia concentration standards after freeze-thaw cycles. METHODS: Epinephrine from 6 autoinjectors was extracted and divided into experimental and control samples. The experimental samples underwent 7 consecutive 12-hour freeze cycles followed by 7 12-hour thaw cycles. The control samples remained at an average temperature of 23.1 degrees C for the duration of the study. After the seventh thaw cycle, epinephrine concentrations were measured using a high-performance liquid chromatography assay with mass spectrometry detection. RESULTS: The mean epinephrine concentration of the freeze-thaw samples demonstrated a statistically significant increase compared with the control samples: 1.07 mg/mL (SD +/- 8.78; 95% CI, 1.04 to 1.11) versus 0.96 mg/mL (SD +/- 6.81; 95% CI, 0.94 to 0.99), respectively. The maximal mean epinephrine concentration in the experimental freeze-thaw group was 1.12 mg/mL, which still fell within the range of United States Pharmacopeia standards for injectables (0.90 to 1.15 mg/mL). CONCLUSIONS: Although every attempt should be made to prevent freezing of autoinjectors, this preliminary study demonstrates that epinephrine concentrations remain within 90% to 115% of 1.0 mg/mL after multiple freeze-thaw cycles. PMID- 26001488 TI - In Reply to Drs Weinstein and White. PMID- 26001489 TI - Three-dimensional finite element analysis of endodontically treated teeth with weakened radicular walls restored with different protocols. AB - STATEMENT OF PROBLEM: The restoration of weakened roots with glass fiber posts (GFPs) remains a challenge. PURPOSE: The purpose of this study was to evaluate the stress distribution of endodontically treated teeth with weakened radicular walls restored with different protocols by 3-dimensional finite element analysis (3D-FEA). MATERIAL AND METHODS: The following 4 models of endodontically treated maxillary canines restored with metal ceramic crowns were simulated on the basis of computed microtomographic images to characterize the groups: GNW (control), a nonweakened root restored with a GFP; GW, a weakened root restored with a GFP; GDA, a weakened root restored with a direct anatomic GFP; and GIA, a weakened root restored with an indirect anatomic GFP. Loads of 180 N were applied to the lingual surface on the incisal third of the teeth at 45 degrees. The models were supported by a periodontal ligament and fixed in 3 axes (x=y=z=0). The von Mises stress (VMS) was calculated. RESULTS: All models exhibited VMS concentrations at the loading area and were distributed along the proximal surfaces of the root. The GFP exhibited a homogeneous stress distribution, and similar VMS distributions were observed in all of the reconstructive techniques. CONCLUSIONS: Similar stress distributions were observed in the endodontically treated teeth, regardless of root weakness and the reconstructive technique for the radicular walls. PMID- 26001490 TI - Comparison of interim restorations fabricated by CAD/CAM with those fabricated manually. AB - STATEMENT OF PROBLEM: Interim restorations represent an essential treatment step; however, the optimal resin material for long-term interim restorations requires investigation. PURPOSE: The purpose of this in vitro study was to compare the color stability, water sorption, wear resistance, surface hardness, fracture resistance, and microleakage of computer-aided design/computer-aided manufacturing-(CAD/CAM) fabricated interim restorations with those of manually fabricated interim restorations. MATERIAL AND METHODS: Epoxy replicas were made from a prepared maxillary first premolar. On the replicas, interim crowns were fabricated and divided into the following groups: CAD/CAM poly(methyl methacrylate) (PMMA) blocks (CC), autopolymerizing temporary resin (AP), automix temporary resin (AM), and thermoplastic resin (TP). After cementation, all specimens were subjected to thermocycling and dynamic fatigue. The CIE Laboratory color coordinates were then recorded before and after immersion in coffee, tea, carbonated cola, and red wine. Water sorption was evaluated by using an immersion technique. Wear resistance was measured in a surface abrasion device. Vickers microhardness was measured on polished specimens. Fracture resistance was evaluated by axial loading with a universal testing machine. Marginal dye penetration was evaluated by sectioning the interim restorations after immersion in methylene blue (alpha=.05). RESULTS: Colorimetric analysis revealed a large degree of color alteration (DeltaE) in the manually fabricated interim restorations: AP = DeltaE of 6.7 +/-2); AM = DeltaE of 7.1 +/-1.5), and TP = DeltaE of =5.4 +/-3.1. The CC group demonstrated color stability (DeltaE=2.1 +/ 0.2). CAD/CAM interim restorations demonstrated significantly lower water sorption, higher wear resistance, higher surface hardness, and significantly higher fracture resistance (1289+/-56N) compared with manually fabricated interim restorations (AP=996 +/-45, AM=899 +/-37, and TP=1179 +/-41). The stereomicroscopic examination of sectioned specimens demonstrated the absence of dye penetration in all tested specimens. CONCLUSIONS: CAD/CAM interim crowns presented stable physical and mechanical properties and may be used for long-term interim restorations. PMID- 26001491 TI - Customized occlusal reduction guide made from a thermoplastic sheet. PMID- 26001492 TI - Crown fracture: Failure load, stress distribution, and fractographic analysis. AB - STATEMENT OF PROBLEM: The outcomes from load-to-failure tests may not be applicable to clinical situations. PURPOSE: The purpose of this study was to critically evaluate the efficacy of load-to-failure tests in the investigation of the fracture load and pattern of metal-free crowns. MATERIAL AND METHODS: Four groups were formed from 128 bovine roots restored with metal posts, resin cores, and feldspathic, leucite, or lithium disilicate ceramic systems or polymer crowns. Each group was divided into 4 (n=8) according to the cement: zinc phosphate, self-adhesive resin, autopolymerizing resin, and glass ionomer. Mean fracture loads from compressive tests were submitted to ANOVA and Tukey HSD test. Finite element and fractographic analyses were performed and associated with the fracture load and pattern. RESULTS: Significantly higher fracture load values were obtained for the lithium disilicate ceramic, but finite element and fractographic analyses showed that the cement effect could not be determined. The finite element analysis showed the cement likely affected the fracture pattern, confirmed that stresses in the cements were little affected by the crown materials, and found that the stressed conditions were lowest in the lithium disilicate compared with other crowns for all cement combinations. The stressed conditions in the crowns depended more on the adhesive properties than on the elastic modulus of the cement materials. The level of the stressed condition in the crowns at the occlusal surface was about the same or higher than along their cement interface, consistent with the fractography, which indicated fractures starting at the load point. Higher stress levels in the crowns corresponded with a lower number of catastrophic fractures, and higher stresses in the cements seemed to reduce the number of catastrophic fracture patterns. The highest stressed conditions occurred along the occlusal surface for crown materials with a low elastic modulus or in combination with adhesive cements. CONCLUSIONS: The method used was not appropriate either for investigating the crowns' fracture load and pattern or for stating the role of the cements within the crown-cement tooth interaction. PMID- 26001493 TI - Advances in industrial prospective of cellulosic macromolecules enriched banana biofibre resources: A review. AB - Biological macromolecules enriched resources are rapidly emerging as sustainable, cost effective and environmental friendly materials for several industrial applications. Among different biological macromolecules enriched resources, banana fibres are one of the unexplored high potential bio-resources. Compared to various natural fibres such as jute, coir, palm etc., the banana fibres exhibits a better tensile strength i.e. 458 MPa with 17.14 GPa tensile modulus. Traditionally used petroleum based synthetic fibres have been proven to be toxic, non-biodegradable and energy intensive for manufacturing. Cellulosic banana fibres are potential engineering materials having considerable scope to be used as an environmental friendly reinforcing element for manufacturing of polymer based green materials. This paper summarizes the world scenario of current production of biological macromolecules rich banana residues and fibres; major user's of banana fibres. The quality and quantity of biological macromolecules especially the cellulose, hemicellulose, lignin, wax, engineering and mechanical properties of banana biofibre resources are reported and discussed. Subsequently, the findings of the recent research on bio resource composites, materials performance and opportunities have been discussed which would be a real challenge for the tomorrow world to enhance the livelihood environmental friendly advancement. PMID- 26001494 TI - Synthesis of pH- and ionic strength-responsive microgels and their interactions with lysozyme. AB - Microgels composed of carboxymethyl cellulose (CMC) polymers via chemical crosslinking with sodium trimetaphosphate were synthesized and characterized using thermogravimetric analysis (TGA), swelling, and rheological analysis. The effects of pH, ionic strength, and crosslinking density on lysozyme loading in microgels were also studied. The microgel particle size ranged primarily from 10 to 20 MUm. TGA revealed that the crosslinking increased the thermal stability of CMC. The swelling degree increased as pH increased from 3 to 5, and remained almost constant from pH 5 to 8. However, the swelling degree decreased with increasing ionic strength. The rheological analysis was in good agreement with the results of swelling degree. The protein uptake decreased with increasing ionic strength and crosslinking density. The pH 6 was the optimal pH for lysozyme absorption at ionic strength 0.05 M. The lysozyme-microgel complex was identified by confocal laser scanning microscopy, and the lysozyme distribution in the microgel was observed to be rather homogeneous. PMID- 26001495 TI - Life cycle impact assessment modeling for particulate matter: A new approach based on physico-chemical particle properties. AB - Particulate matter (PM) causes severe damage to human health globally. Airborne PM is a mixture of solid and liquid droplets suspended in air. It consists of organic and inorganic components, and the particles of concern range in size from a few nanometers to approximately 10MUm. The complexity of PM is considered to be the reason for the poor understanding of PM and may also be the reason why PM in environmental impact assessment is poorly defined. Currently, life cycle impact assessment is unable to differentiate highly toxic soot particles from relatively harmless sea salt. The aim of this article is to present a new impact assessment for PM where the impact of PM is modeled based on particle physico-chemical properties. With the new method, 2781 characterization factors that account for particle mass, particle number concentration, particle size, chemical composition and solubility were calculated. Because particle sizes vary over four orders of magnitudes, a sound assessment of PM requires that the exposure model includes deposition of particles in the lungs and that the fate model includes coagulation as a removal mechanism for ultrafine particles. The effects model combines effects from particle size, solubility and chemical composition. The first results from case studies suggest that PM that stems from emissions generally assumed to be highly toxic (e.g. biomass combustion and fossil fuel combustion) might lead to results that are similar compared with an assessment of PM using established methods. However, if harmless PM emissions are emitted, established methods enormously overestimate the damage. The new impact assessment allows a high resolution of the damage allocatable to different size fractions or chemical components. This feature supports a more efficient optimization of processes and products when combating air pollution. PMID- 26001496 TI - Perfluoroalkyl substances (PFAS) including structural PFOS isomers in plasma from elderly men and women from Sweden: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). AB - Per- and polyfluoroalkyl substances (PFASs) are a class of compounds with unique chemical properties that have been shown useful in a wide variety of applications because they provide materials with reduced surface tension and exceptional non stick properties. PFASs are commonly found in impregnation materials, coatings of papers and textiles, fire-fighting foams, pesticides, and cleaning agents. The potential for human exposure to PFASs is high because of their widespread distribution. The aim of this study was to investigate levels of PFASs in men and women from Sweden and to assess the influence of gender and parity among women. Levels of 13 PFASs were determined in plasma samples collected during 2001-2004 from 1016 (507 women) 70year-old participants from the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). The PFASs studied were nine perfluorinated carboxylic acids (PFCAs), four perfluorinated sulfonic acids (PFSAs) and perfluorooctane sulfonamide (PFOSA). In addition, structural isomers of perfluorooctane sulfonic acid (PFOS) were determined in a subset of 398 individuals. The detection rates were high and the majority of the studied compounds were detected in more than 75% of the participants. Levels of the selected analytes were found to be similar to other studies of non occupationally exposed populations. Gender differences were observed in levels of PFHpA which was higher in men, while PFHxS was higher in women. Parity among women was shown to have a minor effect on PFAS concentrations and we found primi- and multiparous women to have slightly lower levels of PFUnDA when compared to nulliparous women. PMID- 26001497 TI - Elevated levels of PFOS and PFHxS in firefighters exposed to aqueous film forming foam (AFFF). AB - Exposure to aqueous film forming foam (AFFF) was evaluated in 149 firefighters working at AFFF training facilities in Australia by analysis of PFOS and related compounds in serum. A questionnaire was designed to capture information about basic demographic factors, lifestyle factors and potential occupational exposure (such as work history and self-reported skin contact with foam). The results showed that a number of factors were associated with PFAA serum concentrations. Blood donation was found to be linked to low PFAA levels, and the concentrations of PFOS and PFHxS were found to be positively associated with years of jobs with AFFF contact. The highest levels of PFOS and PFHxS were one order of magnitude higher compared to the general population in Australia and Canada. Study participants who had worked ten years or less had levels of PFOS that were similar to or only slightly above those of the general population. This coincides with the phase out of 3M AFFF from all training facilities in 2003, and suggests that the exposures to PFOS and PFHxS in AFFF have declined in recent years. Self reporting of skin contact and frequency of contact were used as an index of exposure. Using this index, there was no relationship between PFOS levels and skin exposure. This index of exposure is limited as it relies on self-report and it only considers skin exposure to AFFF, and does not capture other routes of potential exposure. Possible associations between serum PFAA concentrations and five biochemical outcomes were assessed. The outcomes were serum cholesterol, triglycerides, high-density lipoproteins, low density lipoproteins, and uric acid. No statistical associations between any of these endpoints and serum PFAA concentrations were observed. PMID- 26001498 TI - Medical Costs and Productivity Costs Related to Voice Symptoms in Colombian Teachers. AB - OBJECTIVES: To investigate the medical costs and productivity costs of voice symptoms among teachers and to assess the contribution of the characteristics of voice symptoms, sociodemographic characteristics, health conditions, and work related factors to these costs. STUDY DESIGN: This is a cross-sectional study. METHODS: In 2012, we conducted a longitudinal study in 12 public schools in Bogota D.C., Colombia. This study is focused on cross-sectional results obtained in the first stage of the data collection process. Participants filled out a questionnaire on sociodemographics, voice symptoms, work-related conditions, use of health care, productivity loss at work, and sickness absence. Multiple logistic regression analysis was used to explore associations among health care use, voice-related absenteeism and productivity loss with duration and severity of voice symptoms, sociodemographic characteristics, health conditions, and work related factors. RESULTS: In total, 621 Colombian teachers participated in this research, 438 of whom had self-reported voice complaints and who therefore made up the study population. Total medical costs and productivity costs due to presence of voice symptoms among teachers with voice complaints equaled around 37% of their monthly wage. Approximately, 3% of the costs were direct costs for health care use, and 97% were indirect costs for productivity losses. Severity of voice symptoms was significantly associated with health care use and absenteeism. CONCLUSIONS: Voice symptoms among teachers have important economic consequences because of health care use, voice-related absenteeism, and productivity loss at work. PMID- 26001499 TI - Flow Glottogram Characteristics and Perceived Degree of Phonatory Pressedness. AB - OBJECTIVES: Phonatory pressedness is a clinically relevant aspect of voice, which generally is analyzed by auditory perception. The present investigation aimed at identifying voice source and formant characteristics related to experts' ratings of phonatory pressedness. STUDY DESIGN: Experimental study of the relations between visual analog scale ratings of phonatory pressedness and voice source parameters in healthy voices. METHODS: Audio, electroglottogram, and subglottal pressure, estimated from oral pressure during /p/ occlusion, were recorded from five female and six male subjects, each of whom deliberately varied phonation type between neutral, flow, and pressed in the syllable /pae/, produced at three loudness levels and three pitches. Speech-language pathologists rated, along a visual analog scale, the degree of perceived phonatory pressedness in these samples. RESULTS: The samples were analyzed by means of inverse filtering with regard to closed quotient, dominance of the voice source fundamental, normalized amplitude quotient, peak-to-peak flow amplitude, as well as formant frequencies and the alpha ratio of spectrum energy above and below 1000 Hz. The results were compared with the rating data, which showed that the ratings were closely related to voice source parameters. CONCLUSIONS: Approximately, 70% of the variance of the ratings could be explained by the voice source parameters. A multiple linear regression analysis suggested that perceived phonatory pressedness is related most closely to subglottal pressure, closed quotient, and the two lowest formants. PMID- 26001500 TI - Aerodynamic Outcomes of Four Common Voice Disorders: Moving Toward Disorder Specific Assessment. AB - OBJECTIVES: The two goals of the present study were to (1) determine the ability of commonly used aerodynamic voice measures to capture change as a function of known interventions and (2) determine if certain aerodynamic measures demonstrate better responsiveness to change in specific disorder types than others. STUDY DESIGN: This is a retrospective, longitudinal, single-blinded, cross-sectional study. METHODS: Patients (n = 70) with a single voice disorder diagnosis of benign vocal fold lesions (lesions), unilateral vocal fold paralysis (UVFP), primary muscle tension dysphonia (MTD-1), or vocal fold atrophy (atrophy) underwent baseline testing, a single intervention (phonosurgery or voice therapy), and follow-up testing. Common aerodynamic measurements were completed in repeated syllables and an all-voiced sentence. RESULTS: Statistically significant improvements were observed for two outcome measures, average airflow in syllables, and average airflow in the all-voiced sentence. Patients with lesions, UVFP, and MTD-1 improved in average airflow in the all-voiced sentence. Patients with UVFP also improved in airflow in syllables. CONCLUSIONS: Average airflow in the all-voiced sentence changed as a function of treatment for the lesion, MTD-1, and UVFP groups, demonstrating a disorder-specific pattern. Laryngeal airway resistance, and estimates of average subglottal pressure did not show significant change. Average airflow in the all-voiced sentence measurements is recommended as a routine voice measure, and further investigation of other aerodynamic measures' sensitivity to change is warranted. PMID- 26001501 TI - Voice Tremor in Patients with Essential Tremor: Effects of Deep Brain Stimulation of Caudal Zona Incerta. AB - OBJECTIVES: The present study aimed at evaluating the effect of deep brain stimulation (DBS) of the caudal zona incerta (cZi) on voice tremor in patients with essential tremor (ET). STUDY DESIGN: This is a prospective nonrandomized design with consecutive patients. METHODS: Twenty-six patients operated with cZi DBS were evaluated under two conditions: without stimulation (Stim OFF) and with stimulation (Stim ON). Voice tremor was assessed on the basis of recordings of sustained vowel productions using a four-point rating scale in a blinded and randomized procedure. Averaged values of multiple assessments for each stimulus were used in statistical testing. The group of patients with voice tremor in Stim OFF was analyzed separately from the group of patients without voice tremor. RESULTS: Voice tremor was significantly reduced on stimulation compared with off for the subgroup with initial voice tremor. Voice tremor prevalence was found to be 50% (13 patients). Individual differences in voice tremor outcome were noticeable. Six of the patients with voice tremor at baseline improved substantially by cZi DBS treatment. CONCLUSIONS: On the group level, voice tremor in patients with ET was found to reduce when stimulating the cZi. Bilateral stimulation was indicated to be more effective in reducing voice tremor than unilateral stimulation. However, individual voice tremor outcomes suggest that not all patients benefit from cZi DBS. Severity of voice tremor at baseline may not be a good predictor of voice tremor outcome after cZi DBS. Patients should be informed before surgery regarding individual differences in response to DBS treatment. PMID- 26001502 TI - Use Videostrobokymography to Quantitatively Analyze the Vibratory Characteristics Before and After Conservative Medical Treatment of Vocal Fold Leukoplakia. AB - OBJECTIVES: To quantitatively analyze the vibratory characteristics of vocal folds before and after conservative treatments to evaluate the outcomes of conservative treatments for vocal fold leukoplakia using videostrobokymography (VSK). STUDY DESIGN: This is a prospective study. METHODS: Twenty patients and 20 controls were enrolled into the study. All patients received conservative treatments for 3 weeks and received VSK examination before and 3 weeks after the treatments. All controls only received VSK examination once. Vocal fold lengths of 25%, 50%, and 75% were chosen as the line-scan positions to evaluate the vocal fold vibration. Open quotient (OQ) and asymmetry index (AI) were obtained using VSK. RESULTS: Significant improvements in the main symptoms including voice hoarseness were found. Videostroboscopic findings showed that the white lesions on the vocal folds almost completely disappeared in all patients, and the vocal fold flexibility returned to normal. All OQs and AIs at each line-scan position in patients before the treatments were larger than those in controls (P < 0.017), whereas all OQs and AIs at each line-scan position decreased 3 weeks after conservative treatments (P < 0.017). No significant differences in OQs and AIs at each line-scan position were detected between patients after the treatments and controls (P > 0.017). CONCLUSIONS: VSK could quantitatively evaluate the vibratory characteristics of vocal folds before and after the treatments, and conservative treatment could improve VSK measurements to normal control values, suggesting that VSK is a tool to assess the outcomes of the conservative treatments for vocal fold leukoplakia. PMID- 26001503 TI - Sustainable approaches for minimizing biosolids production and maximizing reuse options in sludge management: A review. AB - Sludge generation during wastewater treatment is inevitable even with proper management and treatment. Yet proper handling and disposal of sludge are still challenging in terms of treatment cost, presence of recalcitrant contaminants of concern, sanitary issues, and public acceptance. Conventional disposal methods (i.e. landfilling, incineration) have created concerns in terms of legislative restrictions and community perception, incentivizing consideration of substitute sludge management options. Furthermore, with proper treatment, biosolids from sludge, rich in organic materials and nutrients, could be utilizable as fertilizer. Despite the challenges of dealing with sludge, no review has dealt with integrated source reduction and reuse as the best sustainable management practices for sludge treatment. In this review, we present two main approaches as potentially sustainable controls: (i) pretreatment for minimizing extensive sludge treatment, and (ii) recycling and reuse of residual sludge. Drawing on these approaches, we also suggest strategies for efficient pretreatment mechanisms and residual reuse, presenting ideas for prospective future research. PMID- 26001504 TI - Supraventricular extrasystolic activity and the elusive goal of identifying the imminent triggers of atrial fibrillation. PMID- 26001505 TI - Pulmonary vein isolation using the Rhythmia mapping system: Verification of intracardiac signals using the Orion mini-basket catheter. AB - BACKGROUND: During pulmonary vein isolation (PVI), a circular lasso catheter is positioned at the junction between the left atrium (LA) and the pulmonary vein (PV) to confirm PVI. The Rhythmia mapping system uses the Orion mini-basket catheter with 64 electrodes instead of the lasso catheter. However, its feasibility to determine PVI has not been studied. OBJECTIVE: The purpose of this study was to compare signals between the mini-basket and lasso catheters at the LA-PV junction. METHODS: In 12 patients undergoing PVI using Rhythmia, the mini basket and lasso catheters were placed simultaneously at the LA-PV junction for baseline and post-PVI signal assessment. Pacing from both catheters was performed to examine the presence of exit block. RESULTS: At baseline, recordings of LA and PV potentials were concordant in all PVs. However, after PVI, concordance between the catheters was only 68%. Discordance in all cases resulted from loss of PV potentials on the lasso catheter with persistence of PV potentials on the mini basket catheter. In 9 of 13 PVs (69%), these potentials represented true PV potentials that were exclusively recorded with the smaller and closely spaced mini-basket electrodes. In the other 4 PVs (31%), these potentials originated from neighboring structures and resulted in underestimation of PVI. CONCLUSION: The use of the mini-basket catheter alone is sufficient to determine PVI. While it improves recording of PV potentials after incomplete ablation, it is also associated with frequent recording of "PV-like" potentials originating from neighboring structures. In these cases, pacing maneuvers are helpful to determine PVI and avoid excessive ablation. PMID- 26001506 TI - Paroxysmal atrial fibrillation ablation: Where and what to ablate. PMID- 26001507 TI - New echocardiographic insights in short QT syndrome: More than a channelopathy? AB - BACKGROUND: Short QT syndrome (SQTS) is a congenital ion channel disease characterized by an increased risk of sudden cardiac death. Little is known about the possibility that accelerated repolarization alters mechanical function in SQTS. OBJECTIVES: The study investigated the presence of left ventricular dysfunction and mechanical dispersion, assessed by tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE), and their correlation with QT interval duration and genetics. METHODS: Fifteen SQTS patients (7 with HERG and 3 with KCNQ1 mutation) were studied. Electrocardiographic and echocardiographic parameters were compared with age- and sex-matched healthy controls. RESULTS: When compared to the control group, SQTS patients showed reduced left ventricular contraction (global longitudinal strain: -16.0% +/- 3.4% vs -22.6% +/- 1.7%, P < .001; myocardial performance index 0.59 +/- 0.17 vs 0.34 +/- 0.08, P < .001) and a higher incidence of ejection fraction <55% (odds ratio 11, 95% confidence interval 1.045-374, P = .04). Mechanical dispersion assessed by TDI (P < .01) and STE (P < .001) was higher in the SQTS group than in controls; each parameter showed a significant inverse correlation with QT interval but not with QT dispersion. CONCLUSION: This study showed that in SQTS systolic function may also be affected. SQTS patients presented a significant dispersion of myocardial contraction. TDI and STE could become part of the evaluation of this rare disease. PMID- 26001508 TI - Reduction of radiation exposure during atrial fibrillation ablation using a novel fluoroscopy image integrated 3-dimensional electroanatomic mapping system: A prospective, randomized, single-blind, and controlled study. AB - OBJECTIVE: We explored whether the use of a novel fluoroscopy image integrated 3 dimensional electroanatomic mapping (F-EAM) system could result in a reduction of overall fluoroscopy time and radiation doses during the whole procedure of atrial fibrillation (AF) ablation. METHODS: Eighty patients (44 men (55%); mean age 63 +/- 10 years) who underwent catheter ablation due to paroxysmal AF were recruited consecutively in the present study. Patients were randomized (1:1) into 2 arms for AF ablation: one using a conventional 3-dimensional electroanatomical mapping (EAM) system and the other using the F-EAM system. RESULTS: Fluoroscopy time (10:42 [interquartile range {IQR} 8:45-12:46] minutes:seconds vs 1:45 [IQR 1:05 2:22] minutes:seconds; P < .001) and radiation doses (2440 [IQR 1593-3091] cGy.cm(2) vs 652 [IQR 326-1489] cGy.cm(2); P < .001) in the EAM group were significantly greater than those in the F-EAM group. The majority of reduction of radiation exposure was achieved after transseptal puncture, which was near-zero fluoroscopic exposure. In total, approximately 84% of fluoroscopy time and 73% of radiation doses have been reduced during the AF ablation procedure using the F EAM system compared to using the conventional EAM system. However, procedure time did not differ significantly (1:39 [IQR 1:18-2:10] hours:minutes vs 1:37 [IQR 1:17-1:50] hours:minutes; P = .362). During follow-up (5.9 +/- 1.3 months), 61 patients (76.3%) had no recurrence of atrial arrhythmias. The recurrence rate between the 2 groups did not differ. CONCLUSION: AF catheter ablation using the F EAM system was safe and resulted in a significant reduction of radiation exposure to patients and staff without complicating the workflow of the procedure. A near zero fluoroscopic catheter ablation procedure could be performed without compromising acute/mid-term efficacy and safety. PMID- 26001509 TI - Interlead anatomic and electrical distance predict outcome in CRT patients. AB - BACKGROUND: The implantation strategy appears to play a pivotal role in determining response to cardiac resynchronization therapy (CRT). OBJECTIVE: The aim of our study was to determine the association between anatomic and electrical interlead distance and clinical outcome after CRT implantation. METHODS: We included 216 first-time CRT recipients with left bundle branch block and sinus rhythm. On implantation, the electrical interlead distance (EID), defined as the time interval between spontaneous peak R waves detected at the right ventricular (RV) and left ventricular (LV) pacing sites, was measured. The anatomic distance between the RV and LV lead tips was determined on chest radiographs. RESULTS: The mean EID was 74 +/- 41 ms, and the mean horizontal corrected interlead distance (HCID) was 125 +/- 73 mm. After 12 months, 87 patients (40%) displayed an improvement in their clinical composite score. The cutoff values that best predicted an improved clinical status were as follows: 84 ms for EID (area under the curve 0.59; confidence interval [CI] 0.52-0.66; P = .026) and 90 mm for HCID (area under the curve 0.62; CI 0.55-0.69; P = .004). On multivariate analysis, only EID >84 ms (hazard ratio 0.36; CI 0.14-0.89; P = .028) and HCID >90 mm (hazard ratio 0.45; CI 0.23-0.90; P = .025) were significantly associated with the composite endpoint of death or cardiovascular hospitalization. In particular, the presence of both conditions (EID <84 ms and HCID <90 mm) was associated with the highest rate of events (log-rank test P = .002). CONCLUSIONS: The interlead anatomic and electrical distance are strongly and independently associated with patient outcome after CRT implantation. The 2 measures show an additive predictive value. (CRT MORE: Cardiac Resynchronization Therapy Modular Registry; www.clinicaltrials.gov, unique identifier: NCT01573091.) PMID- 26001510 TI - Characterization and predictors of first and subsequent inappropriate ICD therapy by heart rate ranges: Result of the MADIT-RIT efficacy analysis. AB - BACKGROUND: Data on inappropriate implantable cardioverter-defibrillator (ICD) therapy and effects of programming by heart rate are lacking. OBJECTIVE: We aimed to characterize inappropriate ICD therapy and assess the effects of novel programming by heart rate. METHODS: Incidence and causes of inappropriate therapy by heart rate range (below or above 200 bpm) were assessed. Predictors of inappropriate therapy and effects of programming by heart rate were evaluated with multivariate Cox regression models. Crossovers were excluded. RESULTS: Inappropriate therapy occurred in 9.2% of the total patient population, with 19% of patients randomized to study arm A, 3.6% in arm B, and 4.7% in arm C. Inappropriate therapies <200 bpm were attributable to supraventricular tachycardia (SVT)/sinus tachycardia (78%) or atrial fibrillation/flutter (20%). Inappropriate therapy >=200 bpm occurred because of SVT (47%), atrial fibrillation/flutter (41%), or electromagnetic interference (13%). Conventional ICD programming was associated with more inappropriate therapy <200 bpm than high rate or delayed therapy, as were younger age, history of atrial arrhythmia, advanced New York Heart Association functional class, ICD versus cardiac resynchronization therapy with defibrillator, and absence of diabetes. High-rate and long-delay therapy significantly reduced the risk of inappropriate therapy in the <200 bpm range. Long delay was associated with further reduction of fast (>=200 bpm) inappropriate therapy (P = .032) and a reduction in subsequent inappropriate episodes (P = .006). CONCLUSION: In MADIT-RIT, inappropriate ICD therapy is most frequent at rates below 200 bpm and can be predicted, and effectively prevented, with high-rate cutoff programming. Long-delay therapy effectively reduces fast inappropriate therapy >=200 bpm and subsequent events. [ CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00947310]. PMID- 26001511 TI - Draft genome sequence of cyanobacteria Arthrospira sp. TJSD091 isolated from seaside wetland. AB - The cyanobacteria TJSD091 strain, a member of the genus Arthrospira was isolated from seaside wetland in China, Bohai. The draft genome sequence of Arthrospira sp. TJSD091 with a genome size of approximately 6.3 Mbp and a G+C content of 44.75% is reported. PMID- 26001512 TI - Meiofaunal community analysis by high-throughput sequencing: comparison of extraction, quality filtering, and clustering methods. AB - Using molecular tools to examine community composition of meiofauna, animals 45MUm to 1mm in size living between sediment grains in aquatic environments, is relatively new in comparison to bacterial and archaeal microbial studies. Although high-throughput molecular approaches are starting to be applied to these ccommunities, effectiveness of different approaches for nucleic acid extraction from meiofauna is poorly known and bioinformatic pipelines vary between studies. Given this situation, there is a need for protocols to be developed that promote consistency in sample collection and processing, sequence quality filtering, and Operational Taxonomic Unit (OTU) clustering methods. Herein, we assess different approaches used for DNA extraction (DNA extracted directly from sediment versus elutriated material retained on a 45MUm sieve) as well as how different quality filtering methods of sequences and OTU clustering algorithms impact genetic assessment of meiofauna community composition. DNA extracted directly from sediment resulted in higher presence of non-metazoan eukaryotic taxa; in contrast, an elutriation (resuspension with decanting) approach increased meiofauna abundance and enriched metazoan OTUs. In regards to bioinformatics analyses, the number of overall OTUs varied by clustering algorithm, primarily due to the applied method of sequence quality filtering. However, alpha and beta diversity analyses showed similar trends regardless of bioinformatics pipeline utilized. Based on our results, we recommend studies of meiofauna communities first elutriate samples prior to DNA extraction and include multiple biological replicates to account for variation in community-level composition. The quality filtering method should be carefully considered as this step accounted for large discrepancy in the number of OTUs inferred. PMID- 26001513 TI - Spatio-temporal transcriptome analysis in the marine snail Tegula atra along central-northern Chile (28-31 degrees S). AB - This study describes the results from transcriptomes sequenced by illumina technology from four populations in the marine snail Tegula atra along central northern Chile (28-31 degrees S) during summer and winter 2014. In silico differential expression of transcripts annotated to known proteins revealed several local patterns associated to the environmental thermal variability. Herein, northern populations evidenced lower number of genes highly regulated, while southern populations displayed opposite patterns. This relationship could suggest that northern snail populations are more adapted to high temperature variations, enabling specific genes (e.g. HSPs and antioxidant system) to maintain high transcriptional activity under controlled physiological conditions. This transcriptome response or "frontloading" strategy can significantly increase the speed of response to thermal stress, and also be a relevant molecular underpinning to explain the genomic diversity along the Chilean coast. PMID- 26001514 TI - [Facial cutaneous lesions]. PMID- 26001515 TI - There is nothing new under the sun. PMID- 26001516 TI - Admission neurophysiological abnormalities in Guillain-Barre syndrome: A single center experience. AB - OBJECTIVE: Although patients with Guillain-Barre syndrome (GBS) are often hospitalized few days after symptoms onset, nerve conduction studies (NCS) abnormalities in early phases of the disease are not well characterized. Our aim was to report early neurophysiological abnormalities from a cohort of GBS patients. METHODS: In this single-center study, we retrospectively reviewed the NCS data of 71 consecutive GBS patients in whom neurophysiology was performed within two weeks after disease onset. We further divided our cohort in three subgroups according to the interval between disease onset and NCS (<= 4 days; 5-7 days; 8-14 days). RESULTS: A great proportion of patients (37%) with an early NCS (<= 4 days) showed normal neurophysiological results. The most altered parameters were F waves and their proportion increases in correspondence to number of days after onset. Conduction blocks were observed preferentially in upper limbs, in about a third of cases. CONCLUSION: This study confirms that NCS may be normal in the early phases of GBS syndrome and suggests to perform an extensive neurophysiological evaluation in these patients. SIGNIFICANCE: Our results may help the clinicians in the interpretation of NCS in early-onset GBS. PMID- 26001517 TI - NOAD, a novel nitric oxide donor, induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma Bel-7402 cells. AB - O(2)-(2,4-dinitro-5-{[2-(12-en-28-b-d-galactopyranosyl-oleanolate-3-yl)-oxy-2 oxoethyl]amino}phenyl)1-(N-hydroxyethylmethylamino)diazen-1-ium-1,2-diolate (NOAD), a novel NO-releasing derivative of oleanolic acid (OA), is an active cytotoxic component. In this study, NOAD induced a rise in intracellular NO levels and showed cytotoxic effects which were prevented by hemoglobin (NO scavenger). Meanwhile, NOAD induced G2/M phase cell cycle arrest in a concentration-dependent manner. Analysis of the cell cycle regulatory proteins demonstrated that NOAD did not change the steady-state levels of cyclin A, cyclin B, cyclin E, Cdk2 and Cdk4, but decreased the protein levels of Cdk1 and Cdc25C. Meanwhile, the levels of phosphorylation of Cdc25C and Cdk1 were significantly increased by NOAD in a concentration-dependent manner. Moreover, NOAD modulated the phosphorylation of protein kinases Chk2. During the G2/M arrest, cyclin dependent kinase inhibitors (CDKIs), p21(WAF1/CIP1) and p27(kip1) were increased in a concentration-dependent manner. In addition, NOAD also caused a marked increase in the apoptotic cells, as characterized by fragmented nuclei, sub G1 formation, the level of 8-OHDG increase and poly (ADP-ribose) polymerase (PARP) cleavage, which was associated with activation of caspase-3, caspase-8 and caspase-9. Up-regulation of Bax and down-regulation of Bcl-2 were also observed in Bel-7402 cells treated with NOAD. These data suggest that NOAD produces anti tumor effect via induction of G2/M cell cycle arrest and apoptosis. PMID- 26001518 TI - One swallow does not make a summer. PMID- 26001519 TI - Calcium alginate matrix increases the stability and recycling capability of immobilized endo-beta-1,4-xylanase from Geobacillus stearothermophilus KIBGE IB29. AB - Exploration of microbial pool from extremely diversified ecosystem is significantly important for various industrial applications. Bacterial communities from extreme habitats including volcanic vents, hot springs, and industrial sectors are eagerly explored for the isolation of thermophiles. Geobacillus stearothermophilus KIBGE-IB29, isolated from blast furnace site of a steel processing industry, is capable of producing thermostable endo-beta-1,4 xylanase. In the current study, this enzyme was immobilized within calcium alginate beads using entrapment technique. Amalgamation of sodium alginate (40.0 gL(-1)) and calcium chloride (0.4 M) was used for the formation of immobilized beads. It was observed that temperature (50 degrees C) and pH (7.0) optima of immobilized enzyme remained same, but enzyme-substrate reaction time increased from 5.0 to 30.0 min as compared to free enzyme. Diffusion limit of high molecular weight xylan (corncob) caused a decline in V max of immobilized enzyme from 4773 to 203.7 U min(-1), whereas K m value increased from 0.5074 to 0.5722 mg ml(-1) with reference to free enzyme. Immobilized endo-beta-1,4-xylanase showed its stability even at high temperatures as compared to free enzyme and retained 18 and 9 % residual activity at 70 and 80 degrees C, respectively. Immobilized enzyme also exhibited sufficient recycling efficiency up to five reaction cycles which indicated that this enzyme can be a plausible candidate in paper and pulp industry. PMID- 26001520 TI - Differentiating between apparent and actual rates of H2O2 metabolism by isolated rat muscle mitochondria to test a simple model of mitochondria as regulators of H2O2 concentration. AB - Mitochondria are often regarded as a major source of reactive oxygen species (ROS) in animal cells, with H2O2 being the predominant ROS released from mitochondria; however, it has been recently demonstrated that energized brain mitochondria may act as stabilizers of H2O2 concentration (Starkov et al. [1]) based on the balance between production and the consumption of H2O2, the later of which is a function of [H2O2] and follows first order kinetics. Here we test the hypothesis that isolated skeletal muscle mitochondria, from the rat, are able to modulate [H2O2] based upon the interaction between the production of ROS, as superoxide/H2O2, and the H2O2 decomposition capacity. The compartmentalization of detection systems for H2O2 and the intramitochondrial metabolism of H2O2 leads to spacial separation between these two components of the assay system. This results in an underestimation of rates when relying solely on extramitochondrial H2O2 detection. We find that differentiating between these apparent rates found when using extramitochondrial H2O2 detection and the actual rates of metabolism is important to determining the rate constant for H2O2 consumption by mitochondria in kinetic experiments. Using the high rate of ROS production by mitochondria respiring on succinate, we demonstrate that net H2O2 metabolism by mitochondria can approach a stable steady-state of extramitochondrial [H2O2]. Importantly, the rate constant determined by extrapolation of kinetic experiments is similar to the rate constant determined as the [H2O2] approaches a steady state. PMID- 26001521 TI - DICOM for Clinical Research: PACS-Integrated Electronic Data Capture in Multi Center Trials. AB - Providing surrogate endpoints in clinical trials, medical imaging has become increasingly important in human-centered research. Nowadays, electronic data capture systems (EDCS) are used but binary image data is integrated insufficiently. There exists no structured way, neither to manage digital imaging and communications in medicine (DICOM) data in EDCS nor to interconnect EDCS with picture archiving and communication systems (PACS). Manual detours in the trial workflow yield errors, delays, and costs. In this paper, requirements for a DICOM based system interconnection of EDCS and research PACS are analysed. Several workflow architectures are compared. Optimized for multi-center trials, we propose an entirely web-based solution integrating EDCS, PACS, and DICOM viewer, which has been implemented using the open source projects OpenClinica, DCM4CHEE, and Weasis, respectively. The EDCS forms the primary access point. EDCS to PACS interchange is integrated seamlessly on the data and the context levels. DICOM data is viewed directly from the electronic case report form (eCRF), while PACS based management is hidden from the user. Data privacy is ensured by automatic de identification and re-labelling with study identifiers. Our concept is evaluated on a variety of 13 DICOM modalities and transfer syntaxes. We have implemented the system in an ongoing investigator-initiated trial (IIT), where five centers have recruited 24 patients so far, performing decentralized computed tomography (CT) screening. Using our system, the chief radiologist is reading DICOM data directly from the eCRF. Errors and workflow processing time are reduced. Furthermore, an imaging database is built that may support future research. PMID- 26001522 TI - Increase of fruity aroma during mixed T. delbrueckii/S. cerevisiae wine fermentation is linked to specific esters enhancement. AB - The aim of this work was to study ester formation and the aromatic impact of Torulaspora delbrueckii when used in association with Saccharomyces cerevisiae during the alcoholic fermentation of must. In order to evaluate the influence of the inoculation procedure, sequential and simultaneous mixed cultures were carried out and compared to pure cultures of T. delbrueckii and S. cerevisiae. Our results showed that mixed inoculations allowed the increase, in comparison to S. cerevisiae pure culture, of some esters specifically produced by T. delbrueckii and significantly correlated to the maximal T. delbrueckii population reached in mixed cultures. Thus, ethyl propanoate, ethyl isobutanoate and ethyl dihydrocinnamate were considered as activity markers of T. delbrueckii. On the other hand, isobutyl acetate and isoamyl acetate concentrations were systematically increased during mixed inoculations although not correlated with the development of either species but were rather due to positive interactions between these species. Favoring T. delbrueckii development when performing sequential inoculation enhanced the concentration of esters linked to T. delbrueckii activity. On the contrary, simultaneous inoculation restricted the growth of T. delbrueckii, limiting the production of its activity markers, but involved a very important production of numerous esters due to more important positive interactions between species. These results suggest that the ester concentrations enhancement via interactions during mixed modalities was due to S. cerevisiae production in response to the presence of T. delbrueckii. Finally, sensory analyses showed that mixed inoculations between T. delbrueckii and S. cerevisiae allowed to enhance the complexity and fruity notes of wine in comparison to S. cerevisiae pure culture. Furthermore, the higher levels of ethyl propanoate, ethyl isobutanoate, ethyl dihydrocinnamate and isobutyl acetate in mixed wines were found responsible for the increase of fruitiness and complexity. PMID- 26001523 TI - Potential of lactic acid bacteria in aflatoxin risk mitigation. AB - Aflatoxins (AF) are ubiquitous mycotoxins contaminating food and feed. Consumption of contaminated food and feed can cause a severe health risk to humans and animals. A novel biological method could reduce the health risks of aflatoxins through inhibiting mold growth and binding aflatoxins. Lactic acid bacteria (LAB) are commonly used in fermented food production. LAB are known to inhibit mold growth and, to some extent, to bind aflatoxins in different matrices. Reduced mold growth and aflatoxin production may be caused by competition for nutrients between bacterial cells and fungi. Most likely, binding of aflatoxins depends on environmental conditions and is strain-specific. Killed bacteria cells possess consistently better binding abilities for aflatoxin B1 (AFB1) than viable cells. Lactobacilli especially are relatively well studied and provide noticeable possibilities in binding of aflatoxin B1 and M1 in food. It seems that binding is reversible and that bound aflatoxins are released later on (Haskard et al., 2001; Peltonen et al., 2001). This literature review suggests that novel biological methods, such as lactic acid bacteria, show potential in mitigating toxic effects of aflatoxins in food and feed. PMID- 26001524 TI - Combination treatment of chlorine dioxide gas and aerosolized sanitizer for inactivating foodborne pathogens on spinach leaves and tomatoes. AB - The objective of this study was to evaluate the antimicrobial effect of chlorine dioxide (ClO2) gas and aerosolized sanitizer, when applied alone or in combination, on the survival of Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes inoculated onto spinach leaves and tomato surfaces. Spinach leaves and tomatoes were inoculated with a cocktail of three strains each of the three foodborne pathogens. ClO2 gas (5 or 10 ppmv) and aerosolized peracetic acid (PAA) (80 ppm) were applied alone or in combination for 20 min. Exposure to 10 ppmv of ClO2 gas for 20 min resulted in 3.4, 3.3, and 3.4 log reductions of E. coli O157:H7, S. Typhimurium, and L. monocytogenes on spinach leaves, respectively. Treatment with 80 ppm of aerosolized PAA for 20 min caused 2.3, 1.9, and 0.8 log reductions of E. coli O157:H7, S. Typhimurium, and L. monocytogenes, respectively. Combined treatment of ClO2 gas (10 ppmv) and aerosolized PAA (80 ppm) for 20 min caused 5.4, 5.1, and 4.1 log reductions of E. coli O157:H7, S. Typhimurium, and L. monocytogenes, respectively. E. coli O157:H7, S. Typhimurium, and L. monocytogenes on tomatoes experienced similar reduction patterns to those on spinach leaves. As treatment time increased, most combinations of ClO2 gas and aerosolized PAA showed additive effects in the inactivation of the three pathogens. Combined treatment of ClO2 gas and aerosolized PAA produced injured cells of three pathogens on spinach leaves while generally did not produce injured cells of these pathogens on tomatoes. Combined treatment of ClO2 gas (10 ppmv) and aerosolized PAA (80 ppm) did not significantly (p>0.05) affect the color and texture of samples during 7 days of storage. PMID- 26001525 TI - The impact of fermentation with exopolysaccharide producing lactic acid bacteria on rheological, chemical and sensory properties of pureed carrots (Daucus carota L.). AB - Fermentation with lactic acid bacteria (LAB) offers a natural means to modify technological and nutritional properties of foods and food ingredients. This study explored the impact of fermentation with different exopolysaccharide (EPS) producing LAB on rheological, chemical and sensory properties of pureed carrots in water, as a vegetable model, with the focus on texture formation. The screening of 37 LAB strains for starter selection revealed 16 Lactobacillus, Leuconostoc and Weissella strains capable of EPS (dextran, levan, and/or beta glucan) production in the carrot raw material. Fermentations with five out of six selected EPS producers modified perceived texture of the liquid carrot model (p<0.05). The formation of low-branched dextran correlated with perceived thickness, whereas the production of beta-glucan correlated with perceived elasticity. Low-branched dextran producing Weissella confusa and Leuconostoc lactis strains produced thick texture accompanied by pleasant odour and flavour. The fermentation with the selected EPS-producing LAB strains is a promising clean label approach to replace hydrocolloid additives as texturizers in vegetable containing products, not only carrot. PMID- 26001526 TI - Time-dependent retinal ganglion cell loss, microglial activation and blood-retina barrier tightness in an acute model of ocular hypertension. AB - Glaucoma is a group of neurodegenerative diseases characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, and is the second leading cause of blindness worldwide. Elevated intraocular pressure is a well known risk factor for the development of glaucomatous optic neuropathy and pharmacological or surgical lowering of intraocular pressure represents a standard procedure in glaucoma treatment. However, the treatment options are limited and although lowering of intraocular pressure impedes disease progression, glaucoma cannot be cured by the currently available therapy concepts. In an acute short-term ocular hypertension model in rat, we characterize RGC loss, but also microglial cell activation and vascular alterations of the retina at certain time points. The combination of these three parameters might facilitate a better evaluation of the disease progression, and could further serve as a new model to test novel treatment strategies at certain time points. Acute ocular hypertension (OHT) was induced by the injection of magnetic microbeads into the rat anterior chamber angle (n = 22) with magnetic position control, leading to constant elevation of IOP. At certain time points post injection (4d, 7d, 10d, 14d and 21d), RGC loss, microglial activation, and microvascular pericyte (PC) coverage was analyzed using immunohistochemistry with corresponding specific markers (Brn3a, Iba1, NG2). Additionally, the tightness of the retinal vasculature was determined via injections of Texas Red labeled dextran (10 kDa) and subsequently analyzed for vascular leakage. For documentation, confocal laser-scanning microscopy was used, followed by cell counts, capillary length measurements and morphological and statistical analysis. The injection of magnetic microbeads led to a progressive loss of RGCs at the five time points investigated (20.07%, 29.52%, 41.80%, 61.40% and 76.57%). Microglial cells increased in number and displayed an activated morphology, as revealed by Iba1-positive cell number (150.23%, 175%, 429.25%,486.72% and 544.78%) and particle size analysis (205.49%, 203.37%, 412.84%, 333.37% and 299.77%) compared to contralateral control eyes. Pericyte coverage (NG2-positive PC/mm) displayed a significant reduction after 7d of OHT in central, and after 7d and 10d in peripheral retina. Despite these alterations, the tightness of the retinal vasculature remained unaltered at 14 and 21 days after OHT induction. While vascular tightness was unchanged in the course of OHT, a progressive loss of RGCs and activation of microglial cells was detected. Since a significant loss in RGCs was observed already at day 4 of experimental glaucoma, and since activated microglia peaked at day 10, we determined a time frame of 7-14 days after MB injection as potential optimum to study glaucoma mechanisms in this model. PMID- 26001527 TI - The effect of tibial slope in acute ACL-insufficient patients on concurrent meniscal tears. AB - INTRODUCTION: The aim of this study is to evaluate the effect of the medial and lateral posterior tibial slope (MPTS, LPTS) in patients with acutely ruptured ACL on the menisci. It was hypothesized that medial and lateral meniscus lesions are seen more often with high PTS (posterior tibial slope). We hypothesized that in case of a high tibial slope a possible meniscus lesion is more often located in the posterior horn of the meniscus than in knees with a low tibial slope. MATERIALS AND METHODS: We identified 537 patients with ACL insufficiency between 2012 and 2013. Of these, 71 patients were eligible for the study according to the study's criteria. PTS was measured via MRI and classified into two groups: >10 degrees for high tibial slope and <=10 degrees for low tibial slope. Any meniscal lesion was documented during arthroscopic ACL reconstruction and evaluated regarding meniscal lesion patterns with high and low PTS, taking into account the type and the location of the tear (anterior horn, intermediate part and posterior horn). Statistical analysis for differences in meniscal lesion was performed using Chi-square tests and McNemar tests for dependent variables. The level of significance was set at p <= 0.05. RESULTS: High PTS (MPTS and LPTS) was associated with a higher incidence of meniscal lesions with an odds ratio of 2.11, respectively, 3.44; however, no statistical significance was found. Among the total number of ACL-insufficient knees studied, the meniscal lesion spread more often to the posterior part in the group with a low PTS. In contrast, less damage of the posterior horn of the meniscus could be found in the group with a high PTS. CONCLUSION: High PTS seems to predetermine for meniscal lesion in an acute ACL-insufficient knee. More damage to the posterior part of the menisci could generally be seen but was not associated with a high PTS. There was no statistical significance to support the initial hypothesis. Further research is needed to find out if factors other than tibial slope are risk factors for meniscal lesion in acute ACL injury. LEVEL OF EVIDENCE: IV. PMID- 26001528 TI - Velocity control of servo systems using an integral retarded algorithm. AB - This paper presents a design technique for the delay-based controller called Integral Retarded (IR), and its applications to velocity control of servo systems. Using spectral analysis, the technique yields a tuning strategy for the IR by assigning a triple real dominant root for the closed-loop system. This result ultimately guarantees a desired exponential decay rate sigma(d) while achieving the IR tuning as explicit function of sigma(d) and system parameters. The intentional introduction of delay allows using noisy velocity measurements without additional filtering. The structure of the controller is also able to avoid velocity measurements by using instead position information. The IR is compared to a classical PI, both tested in a laboratory prototype. PMID- 26001531 TI - Gemcitabine plus split-dose cisplatin could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with advanced urothelial carcinoma. AB - PURPOSE: Cisplatin-based chemotherapies are standard treatment regimens of advanced urothelial cell carcinoma. But a significant proportion of patients are unsuitable for cisplatin due to impaired renal function. Carboplatin-based regimens such as gemcitabine and carboplatin regimen (GCb) were applied due to less nephrotoxicity and side effects in these patients. However, it is known that clinical outcome of carboplatin-based regimens was unsatisfactory compared to cisplatin-based regimens. We compared the nephrotoxicity and response to treatment between GCb and gemcitabine plus split-dose cisplatin regimen (GC-S). METHODS: GC-S consists of cisplatin 35 mg/m(2) given on day 1, 2 and gemcitabine 1000 mg/m(2) on day 1, 8 every 3 weeks. GCb consists of carboplatin (AUC 4.5) on day 1 and gemcitabine 1000 mg/m(2) on day 1, 8 every 3 weeks. Patient demographics, serum creatinine and calculated GFR, adverse events, and radiologic response were retrospectively reviewed. RESULTS: Forty-four patients with advanced urothelial carcinoma treated with GCb (n = 22) or GC-S (n = 22) in our institution. There was no difference at deterioration of serum creatinine or GFR between GCb and GC-S (p = 0.442, p = 0.345). For patients who had GFR < 60 mL/min/1.73 m(2) subgroup, similar results were produced (p = 0.292, p = 0.186). In addition, GC-S (68.4 %) showed improved response compared to GCb (31.6 %) (p = 0.023). Both treatments were well tolerated, and there were no unexpected serious adverse events. CONCLUSIONS: Based on preserved renal function, favorable response, and tolerability, GC-S could be a promising alternative to GCb for cisplatin-unfit patients with advanced urothelial carcinoma. PMID- 26001532 TI - The somatic autosomal mutation matrix in cancer genomes. AB - DNA damage in somatic cells originates from both environmental and endogenous sources, giving rise to mutations through multiple mechanisms. When these mutations affect the function of critical genes, cancer may ensue. Although identifying genomic subsets of mutated genes may inform therapeutic options, a systematic survey of tumor mutational spectra is required to improve our understanding of the underlying mechanisms of mutagenesis involved in cancer etiology. Recent studies have presented genome-wide sets of somatic mutations as a 96-element vector, a procedure that only captures the immediate neighbors of the mutated nucleotide. Herein, we present a 32 * 12 mutation matrix that captures the nucleotide pattern two nucleotides upstream and downstream of the mutation. A somatic autosomal mutation matrix (SAMM) was constructed from tumor specific mutations derived from each of 909 individual cancer genomes harboring a total of 10,681,843 single-base substitutions. In addition, mechanistic template mutation matrices (MTMMs) representing oxidative DNA damage, ultraviolet-induced DNA damage, (5m)CpG deamination, and APOBEC-mediated cytosine mutation, are presented. MTMMs were mapped to the individual tumor SAMMs to determine the maximum contribution of each mutational mechanism to the overall mutation pattern. A Manhattan distance across all SAMM elements between any two tumor genomes was used to determine their relative distance. Employing this metric, 89.5% of all tumor genomes were found to have a nearest neighbor from the same tissue of origin. When a distance-dependent 6-nearest neighbor classifier was used, 10.4% of the SAMMs had an Undetermined tissue of origin, and 92.2% of the remaining SAMMs were assigned to the correct tissue of origin. [corrected]. Thus, although tumors from different tissues may have similar mutation patterns, their SAMMs often display signatures that are characteristic of specific tissues. PMID- 26001533 TI - Polymorphisms in ERCC1 and ERCC2/XPD genes and carcinogen DNA adducts in human lung. AB - OBJECTIVES: In this exploratory study, we aimed to investigate whether polymorphisms in excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways associated with DNA adducts in human lung tissue. We also analyzed the association stratified by the major histologic subtypes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). METHODS: The study population consisted of 107 early stage NSCLC patients from the Massachusetts General Hospital (MGH) in Boston who underwent curative surgical resection. Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using a PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (Taqman). DNA adduct levels were measured as relative adduct levels per 10(10) nucleotides by (32)P postlabeling in non-tumor lung tissue. RESULTS: After adjusting for potential confounders, lung DNA adduct levels increased by 103.2% [95% confidence interval (CI), -11.5 to 366.6] for ERCC2/XPD rs1799793AA genotype compared with their corresponding wild type homozygous genotypes in overall NSCLC, but the difference did not reach statistical significance. When we stratified by the subtypes of NSCLC, we found that DNA adducts levels in lung increased by 204.9% (95% CI, 0.8 to 822.2, P=0.059) for ERCC2/XPD rs1799793AA genotype in subjects with SQCC and the trend was statistically significant (P for trend=0.0489). CONCLUSIONS: Polymorphisms in ERCC2/XPD Asp312Asn may be associated with increased DNA adduct levels in the lung, especially among subjects with SQCC. Further large scale studies are needed to confirm our findings. PMID- 26001534 TI - Zeta Potential and Aggregation of Virus-Like Particle of Human Norovirus and Feline Calicivirus Under Different Physicochemical Conditions. AB - Although the spread of human norovirus reportedly depends on its ability to bind to food materials, the mechanism of the phenomenon remains unknown. Since protein size and electrical charge are reportedly important parameters in their adsorption, the current work is focused on determining human noroviruses isoelectric point (IEP), electrical charge and aggregate size at different pH, ionic strength (IS), and temperature. Using the baculovirus expression vector system, we produced and purified virus-like particles (VLPs) of GI.1 and GII.4 noroviruses and feline calicivirus, determined their IEP, and examined their size and electrical charge using a Zetasizer Nano ZS apparatus. Shape and size were also visualized using transmission electron microscopy. IEPs were found close to pH 4. Net charge increased as the pH deviated from the IEP. VLPs were negatively charged at all IS tested and showed a gradual decrease in charge with increasing IS. At low temperature, VLPs were 20-45 nm in diameter at pH far from their IEP and under almost all IS conditions, while aggregates appeared at or near the IEP. At increased temperatures, aggregates appeared at or near the IEP and at high IS. Aggregation at the IEP was also confirmed by microscopy. This suggests that electrostatic interactions would be the predominant factor in VLPs adhesion at pH far from 4 and at low ionic strength. In contrast, non-electrostatic interactions would prevail at around pH 4 and would be reinforced by aggregates, since size generally favors multiple bonding with sorbents. PMID- 26001535 TI - Outbreak of Hepatitis A in Italy Associated with Frozen Redcurrants Imported from Poland: A Case Study. AB - Hepatitis A virus (HAV) was detected in a batch of imported non-packaged frozen redcurrants purchased in a Bari grocery. Sequence and phylogenetic analysis showed the HAV strain clustered tightly with the HAV strain from the 2013 Italian epidemic, providing additional evidence that frozen redcurrants were the main vehicle of the HAV outbreak. PMID- 26001536 TI - Action potential initiation in a multi-compartmental model with cooperatively gating Na channels in the axon initial segment. AB - Somatic action potentials (AP) of cortical pyramidal neurons have characteristically high onset-rapidness. The onset of the AP waveform is an indirect measure for the ability of a neuron to respond to temporally fast changing stimuli. Theoretical studies on the pyramidal neuron response usually involves a canonical Hodgkin-Huxley (HH) type ion channel gating model, which assumes statistically independent gating of each individual channel. However, cooperative activity of ion channels are observed for various cell types, meaning that the activity (e.g. opening) of one channel triggers the activity (e.g. opening) of a certain fraction of its neighbors and hence, these groups of channels behave as a unit. In this study, we describe a multi-compartmental conductance-based model with cooperatively gating voltage-gated Na channels in the axon initial segment. Our model successfully reproduced the somatic sharp AP onsets of cortical pyramidal neurons. The onset latencies from the initiation site to the soma and the conduction velocities were also in agreement with the previous experimental studies. PMID- 26001537 TI - Preoperative localization of adult nesidioblastosis using 68Ga-DOTA-exendin-4 PET/CT. PMID- 26001538 TI - Capacity to consent to sex reframed: IM, TZ (no 2), the need for an evidence based model of sexual decision-making and socio-sexual competence. AB - Recent English cases have set a very low threshold for the capacity to consent to sexual activity, and the Court of Appeal in IM v LM (2014) has held that "the ability to use and weigh information is unlikely to loom large in the evaluation of consent to sexual relations." Such cases significantly affect the legal status of such activities involving persons diagnosed with a learning disability (LD), an autistic spectrum disorder (ASD) or other neurodiverse (ND) conditions. A principal focus on two cases in particular-IM v LM (2014) and A Local Authority v TZ (no 2) (2014)-supports the argument that the current test needs reframing from a relationship-centred perspective, in order to reflect an evidence-based model of sexual decision-making. Relevant training for persons diagnosed as LD, ASD, or ND is essential in order to promote socio-sexual competence. This is critical for resolving existing tensions between (1) sexual rights guaranteed in international agreements; (2) criminal law provisions and local authorities' obligations to protect the vulnerable; and (3) sexual health concerns. PMID- 26001539 TI - Capsule Commentary on Duru et al., Adherence to Metformin, Statins, and ACE/ARBs Within the Diabetes Health Plan (DHP). PMID- 26001540 TI - Capsule Commentary on Goldman et al., Comparative Effectiveness of Multifaceted Outreach to Initiate Colorectal Cancer Screening in Community Health Centers: A Randomized Controlled Trial. PMID- 26001541 TI - Capsule Commentary on Tartaglia et al., Medical Student Perceptions of Cost Conscious Care in an Internal Medicine Clerkship: A Thematic Analysis. PMID- 26001542 TI - Collaboration and Authorship of High-Impact Randomized Clinical Trials. PMID- 26001543 TI - Campylobacter-Associated Hemolytic Uremic Syndrome Associated with Pulmonary Renal Syndrome. AB - Common causes of pulmonary-renal syndrome include anti-glomerular basement membrane (anti-GBM) disease anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis, and systemic lupus erythematosus. We describe a case of life threatening pulmonary hemorrhage associated with Campylobacter hemolytic uremic syndrome (HUS), which we believe is a new disease entity. We hypothesize that the cause of this pulmonary-renal syndrome was an immunological reaction to Campylobacter; and that the initiation of high-dose steroids was responsible for the rapid reversal of the patient's pulmonary and renal impairment. The aim of this article is to raise awareness of this unusual cause of a pulmonary-renal syndrome, guiding physicians to recognize it as a potential complication, and to consider high-dose steroids in managing the condition. PMID- 26001544 TI - Capsule Commentary on Wolff, et al., A Look at Person- and Family-Centered Care Among Older Adults: Results from a National Survey. PMID- 26001546 TI - Ambulatory Computerized Prescribing and Preventable Adverse Drug Events. AB - BACKGROUND: Adverse drug events (ADEs) represent a significant cause of injury in the ambulatory care setting. Computerized physician order entry reduces rates of serious medication errors that can lead to ADEs in the inpatient setting, but few studies have evaluated whether computerized prescribing in the ambulatory setting reduces preventable ADE rates in ambulatory care. OBJECTIVE: To determine the rates of preventable ADEs before and after the implementation of computerized prescribing with basic clinical decision support for ordering medications. DESIGN: Before-after study of ADE rates in practices implementing computer order entry. PARTICIPANTS: Adult patients seeking care in primary care practices at academic medical centers in Boston, Massachusetts (n = 41,819), and Indianapolis, Indiana (n = 9128). MAIN MEASURES: We attempted to standardize the medication related decision support knowledge base provided at the 2 sites, although the electronic records and presentation layers used at the 2 sites differed. The primary outcome was preventable ADEs identified based on structured results or symptoms defined by extracting symptom concepts from provider notes; potential ADEs were a secondary outcome. RESULTS: Computerized prescribing did not significantly change the rate of preventable ADEs at either site. Compared with Boston practices, the rate of potential ADEs was more than seven-fold greater at Indianapolis (6.4/10,000 patient-months vs. 49.5/10,000 patient-months, P < 0.001). Computerized prescribing was associated with a 56% decrease in the potential ADE rate at Indianapolis (49.5 to 21.9/10,000 patient-months, P < 0.001) but a 104% increase at Boston (6.4 to 13.0/10,000 patient-months, P < 0.001). Preventable ADEs that occurred after computerized prescribing was implemented were due to patient education issues, physicians ignoring feedback from CDSS, and incomplete computerized knowledge base was incomplete (34%, 33%, and 33% in Indianapolis and 44%, 28%, and 28% in Boston). CONCLUSIONS: The implementation of computerized prescribing in the ambulatory setting was not associated with any change in preventable ADEs but was associated with a decrease in potential ADEs at Indianapolis but an increase at Boston, although the absolute rate of ADEs was much lower in Boston. PMID- 26001547 TI - Structured Handover in General Surgery: An Audit of Current Practice. AB - INTRODUCTION: Verbal handover alone compromises patient safety, and supporting written documents significantly increases retention of information, with printed handover sheets being the best at avoiding data loss. The Royal College of Surgeons (RCS) has produced guidelines on safe handover practice, in which a minimum dataset is recommended for inclusion when handing over patients to incoming surgical teams, and studies have indicated better adherence to these guidelines when preprinted handover proformas are used. METHODS: All surgical handover sessions were attended for a one-week period, and copies of handover sheets were taken. These were analyzed against RCS guidelines on the essential dataset for safe handover practice. A standardized handover sheet, developed in accordance with these guidelines and designed to encourage impartation of this minimum dataset, was then circulated among members of the surgical department and made readily available on wards. After a 6-week period, a postintervention audit was conducted using the same methods. RESULTS: Striking differences were seen in the quality of information handed over preintervention and postintervention. The documentation of patient location increased significantly (56%-87%, P < 0.0001; 95% CI, 0.460-0.151), as did the documentation of important outstanding clinical tasks (45%-89%, P = 0.004; 95% CI, 0.439-0.089). Documentation of blood results increased (P < 0.0001; 95% CI, 0.523-0.226), and the proportion of patients for whom the occurrence of a senior review was documented increased from 28% (18) to 85% (45) (P < 0.0001; 95% CI, 0.717-0.419) CONCLUSIONS: The use of a structured, computer-generated handover proforma significantly improved compliance with RCS guidelines within the surgical department of our hospital, and we recommend its continued use among on-call surgical teams. PMID- 26001545 TI - Effect of 6-month caloric restriction on Cu bound to ceruloplasmin in adult overweight subjects. AB - In a randomized clinical trial of calorie restriction (CR), we demonstrated that important cardiovascular disease (CVD) biomarkers were favorably influenced by CR alone and in conjunction with physical exercise. The aim of this study was to examine the effects of CR with or without exercise on copper bound to ceruloplasmin (CuCp), a well-known biomarker for CVD, in overweight men and women enrolled in the CALERIE phase 1 study. Forty-six individuals were randomized to one of four groups for 6 months: control, healthy weight maintenance; CR, 25% CR from baseline energy requirements; CR+exercise, 12.5% CR and 12.5% through aerobic exercise; and low-calorie diet, low-calorie diet until 15% reduction in body weight followed by weight maintenance diet. CuCp was determined in fasting blood samples by a high-performance liquid chromatography-inductively coupled plasma mass spectrometry methodology and compared with changes in body composition and markers of CVD. After 6 months, CR combined with exercise induced a decrease in plasma concentration of CuCp. CuCp was inversely correlated with insulin sensitivity at baseline and after 6 months of intervention. A cluster analysis showed that the percent change of weight after 6 months of intervention was the most important variable that could discriminate the intervention groups. The percent change of CuCp was the only other variable selected by the analysis. Decreased CuCp in overweight subjects by CR combined with exercise suggests a positive effect of this intervention on metabolic health. Further studies to explain the relationship between weight loss and CuCp and its relevance for cardiovascular health are needed. PMID- 26001548 TI - Curbing Inappropriate Usage of STAT Imaging at a Large Academic Medical Center. AB - PURPOSE: To evaluate a new system for processing and performing inpatient STAT diagnostic imaging with respect to utilization and time-based performance metrics. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was not required. The radiology information system of a large academic medical center was queried for all inpatient diagnostic imaging exams performed and interpreted from August 1, 2010, to October 31, 2012. Using customized software, data were evaluated based on order priority (non-STAT or STAT) and exam modality with respect to exam volume and time-based performance metrics (time-to-performance and preliminary interpretation time). Data were compared over 3 periods: August 1, 2010, to October 31, 2010 (preimplementation period); November 1, 2010, to October 31, 2011 (year 1 postimplementation); and November 1, 2011, to October 31, 2012 (year 2 postimplementation). RESULTS: In the first year after implementation of the new STAT policy, the percentage of inpatient exams ordered STAT significantly decreased from 22.1% to 5.4% (P < 0.001). This represented a proportional decrease of 26% (CT), 16% (MRI), 20% (US), and 24% (radiographs) relative to pre STAT policy levels. The median time-to-performance and median preliminary interpretation time significantly decreased for all modalities after implementation of the policy (P < 0.05 for all modalities), decreasing by an average of 104 and 162 minutes, respectively. These changes persisted throughout year 2 postimplementation. CONCLUSION: A new institutional system for handling inpatient STAT diagnostic imaging results in a decreased number of STAT exams ordered and improved time-based performance metrics, thereby increasing workflow efficiency. PMID- 26001549 TI - Attitudes Toward Patient Safety and Tendencies to Medical Error Among Turkish Cardiology and Cardiovascular Surgery Nurses. AB - BACKGROUND: Patient safety and medical errors are among the most discussed topics in recent years. Identifying and reporting medical errors is one of the most significant steps toward the adoption of measures to increase patient safety. OBJECTIVES: The goal of this descriptive, cross-sectional study was to evaluate attitudes toward patient safety and the tendencies to medical error among cardiology and cardiovascular surgery nurses in Turkey. METHODS: The study sample consisted of nurses who worked in the cardiology and cardiovascular surgery departments of a University Hospital in Izmir, the third largest city in Turkey. A total of 103 nurses working in the day shift of the mentioned departments volunteered and participated in the study. A "Nurse Information Form," a "Patient Safety Attitude Questionnaire (PSAQ)," and a "Malpractice Tendency Scale in Nursing-(MTSN)" were used as data collection instruments. RESULTS: The mean +/- 1 standard deviation of the nurses' PSAQ scores were 141.86 +/- 18.39, whereas their MTSN scores were 237.20 +/- 18.12. Although no statistically significant difference could be evidenced between cardiology and cardiovascular surgery nurses in their total MTSN scores (t = -0.99, P = 0.32), their PSAQ scores showed a significant difference (t = 2.34, P = 0.02). CONCLUSIONS: This study showed that the tendencies to medical error among cardiology and cardiovascular surgery nurses working in a Turkish facility were low, whereas their attitudes toward patient safety were not at a particularly satisfactory level. The cardiology nurses were found to have a more positive attitude toward patient safety than their colleagues in cardiovascular surgery. PMID- 26001550 TI - Acute Fracture Neck of Femur Among Inpatients: Severe Injuries Which Need to be Taken Seriously. AB - OBJECTIVES: This study assesses fall prevention measures and subsequent incident reporting of falls resulting in an "inpatient fracture neck of femur (FNOF)" within a single NHS Trust, with the aim of identifying potential areas of improvement and changing practice within a Trust. METHODS: Forty patients (mean age, 82.6 years) sustained an injury while being treated in hospital for an unrelated cause between January 2012 and June 2013. Case notes and incident reports were analyzed retrospectively. RESULTS: Thirty-three (82.5%) of 40 patients had at least 1 fall screen on admission, with 27 patients (81.8%) identified as a fall risk. Fifteen patients (37.5%) had at least one fall before sustaining a FNOF. Fifteen falls occurred between midnight-0500 hours and only 4 falls were witnessed. Thirty-nine of 40 falls were reported, but none were rated as "severe" injuries. Twenty-eight (71.8%) of 39 patients had a root cause analysis performed for the injury, but only 10 root cause analyses (25.6%) produced an action plan. Fifty percent of patients died within 1 year of injury. CONCLUSION: Accurate fall risk assessments and adequate patient supervision are essential to minimize risks of falls, as the inpatient FNOF is linked to a higher mortality rate than patients injured in the community. A standardized method of analyzing such incidents and dissemination of the results of investigation are also required to reduce the risk of similar incidents from occurring within the hospital environment. PMID- 26001551 TI - Adverse Events in Korean Traditional Medicine Hospitals: A Retrospective Medical Record Review. AB - OBJECTIVES: Traditional medicine has been used worldwide in recent decades. The aim of this study was to determine the incidence of adverse events (AEs) in traditional medicine hospitals and investigate patient and health-care utilization factors associated with AE occurrence. METHODS: A 2-stage review of 1152 randomly sampled charts in 2 teaching Korean traditional medicine hospitals was conducted. Three physicians and a quality improvement specialist identified AE occurrence, severity, and preventability using the Global Trigger Tool (Appendix 1, Supplemental Digital Content, http://links.lww.com/JPS/A19). Two traditional Korean medicine professors validated the findings. Logistic regression analysis was performed to determine factors associated with AE occurrence. RESULTS: One hundred twenty-two admissions (10.6%) had at least one AE (7.39 events per 1000 patient days and 14.5 events per 100 admissions). Among 167 AEs, 73.7% were mild and 70.7% were judged preventable. Procedure-related AEs were most common. After considering other patient and health-care utilization characteristics, factors associated with AE occurrence were altered mental status on admission (OR, 3.86; 95% confidence interval [CI], 1.20-12.44), use of various traditional medicine therapies (OR, 1.69; 95% CI, 1.32-2.15), length of stay (OR, 1.02; 95% CI, 1.01-1.03), and number of unique triggers (OR, 6.35; 95% CI, 4.54 8.89). CONCLUSIONS: Approximately 11% of inpatients in traditional medicine hospitals experienced AEs. Because patients have a higher risk of AEs, special attention should be paid to those with altered mental status on admission, receiving various traditional medicine therapies, staying for a longer period, and having various positive triggers. PMID- 26001552 TI - An Assessment of Basic Patient Safety Skills in Residents Entering the First Year of Clinical Training. AB - OBJECTIVES: During safety rounds, we observed few residents demonstrating hand hygiene and patient identification as they began their postgraduate clinical training. We assessed baseline performance of these 2 basic safety skills in residents entering the first year of postgraduate clinical training (PGY1). METHODS: PGY1 residents beginning training on July 1, 2013, and July 1, 2014, at our institution were examined using a simulated scenario testing for hand hygiene and patient identification. Nurse volunteers posed as patients and evaluated each resident using a standardized scoring tool. Residents were observed for the following behaviors when interacting: (1) hand hygiene before or upon entry into the patient's room (HHE); (2) resident introducing himself or herself (INTRO); (3) resident identifying patient (IDNB); (4) resident comparing patient's stated name and date of birth to patient's ID band (IDC); (5) resident explaining procedure to patient (EXP); and (6) resident performing hand hygiene upon exiting patient's room (HHL). RESULTS: A total of 114 residents were examined. Compliance results were as follows: HHE at 66% (75); INTRO at 96% (110); IDNB at 52% (59); IDC at 42% (48); EXP at 90% (103); and HHL at 58% (66). CONCLUSIONS: Developing and hardwiring basic patient safety skills is essential for creating an institutional culture of safety. We used a simulated patient scenario to provide a baseline assessment of 2 important safety skills.The results obtained demonstrate poor compliance with hand hygiene and patient identification. Our results suggest that there is a need for additional training and perhaps new methods of training and reinforcement in medical school and beyond, to hardwire these basic patient safety skills. PMID- 26001553 TI - U.S. Compounding Pharmacy-Related Outbreaks, 2001-2013: Public Health and Patient Safety Lessons Learned. AB - OBJECTIVES: Pharmacy-compounded sterile preparations (P-CSPs) are frequently relied upon in U.S. health care but are increasingly being linked to outbreaks of infections. We provide an updated overview of outbreak burden and characteristics, identify drivers of P-CSP demand, and discuss public health and patient safety lessons learned to help inform prevention. METHODS: Outbreaks of infections linked to contaminated P-CSPs that occurred between January 1, 2001, and December 31, 2013, were identified from internal Centers for Disease Control and Prevention reports, Food and Drug Administration drug safety communications, and published literature. RESULTS: We identified 19 outbreaks linked to P-CSPs, resulting in at least 1000 cases, including deaths. Outbreaks were reported across two-thirds of states, with almost one-half (8/19) involving cases in more than 1 state. Almost one-half of outbreaks were linked to injectable steroids (5/19) and intraocular bevacizumab (3/19). Non-patient-specific compounding originating from nonsterile ingredients and repackaging of already sterile products were the most common practices associated with P-CSP contamination. Breaches in aseptic processing and deficiencies in sterilization procedures or in sterility/endotoxin testing were consistent findings. Hospital outsourcing, preference for variations of commercially available products, commercial drug shortages, and lower prices were drivers of P-CSP demand. CONCLUSIONS: Recognized outbreaks linked to P-CSPs have been most commonly associated with non-patient specific repackaging and nonsterile to sterile compounding and linked to lack of adherence to sterile compounding standards. Recently enhanced regulatory oversight of compounding may improve adherence to such standards. Additional measures to limit and control these outbreaks include vigilance when outsourcing P-CSPs, scrutiny of drivers for P-CSP demand, as well as early recognition and notification of possible outbreaks. PMID- 26001554 TI - Improving Reliability in Healthcare. PMID- 26001555 TI - The effect of national hospital accreditation in bariatric surgery on perioperative outcomes and long-term mortality. AB - BACKGROUND: Controversy exists regarding the relevance of Center of Excellence accreditation to bariatric surgery outcomes. The objective of this study was to evaluate the impact of national hospital accreditation on perioperative and long term outcomes following bariatric surgery. METHODS: Retrospective, longitudinal study using 2004-2010 data from the New York Statewide Planning and Research Cooperative longitudinal administrative database (n = 47,342). Multivariable logistic regression analyzed outcomes following laparoscopic bariatric surgery. Accredited hospitals and accreditation year were identified from the Centers for Medicaid and Medicare website. Outcomes were analyzed with and without temporal correlation to accreditation year.>30-day mortality was determined from social security death records. RESULTS: Risk of perioperative morbidity OR 1.4 (range 1.2-1.6, P<.001), mortality OR 2.6 (range 1.3-5.4, P = .01) and all-cause long term mortality OR 1.4 (range 1.2-1.7, P = .0002) were significantly increased in unaccredited versus accredited hospitals on univariate analysis. In accredited hospitals, significant changes in payor and patient mix, operation, perioperative, and long-term outcomes were demonstrated following accreditation. A significant decrease in operations performed on black patients, Hispanic patients, and Medicare patients was also identified. Controlling for patient demographics, co-morbidity, insurance, and operative procedure, multivariable logistic regression demonstrated accreditation as independently associated with fewer major complications versus unaccredited hospitals OR 0.72 (range .63-.83, P<.001) and within the same hospital following accreditation OR .86 (range 0.77 0.96, P = .01). Following multiple cox proportional hazard model analysis, long term mortality differences were not significant. CONCLUSION: In New York State, bariatric hospital accreditation improved patient outcomes as compared to unaccredited hospitals and within the same hospital compared to preaccreditation. Significant changes were identified for some underserved at-risk populations. Measures to ensure equitable health care for at-risk populations following institutional accreditation are imperative. PMID- 26001556 TI - Preoperative glucocorticoid use and risk of postoperative bleeding and infection after gastric bypass surgery for the treatment of obesity. AB - BACKGROUND: Previous research suggests that patients using glucocorticoids may be at increased risk of postoperative bleeding and infection after major surgery. The objective was to investigate the association between preoperative glucocorticoid use and risk of bleeding and infection after Roux-en-Y gastric bypass surgery (RYGB). SETTING: Nationwide cohort study of 13,195 patients, who underwent RYGB 2006-2012 using Danish population-based medical databases. METHODS: Information was obtained on current (redeemed prescription<60 d before surgery), recent (prescription 60-180 d before surgery), or no glucocorticoid use, and postoperative bleeding or infection within 30 days of surgery. We computed risk differences and odds ratios (ORs) as a measure of relative risk with 95% confidence intervals (95% CIs) for the association between glucocorticoid use and bleeding or infection, adjusting for gender, age, and co morbidities by logistic regression. RESULTS: Among RYGB patients, 325 (2.5%) were current glucocorticoid users, and 365 (2.8%) were recent users. The risk of bleeding was increased in current users: 2.8% versus 1.6% among nonusers (risk difference: 1.2%, 95% CI: -.6, 3.0) corresponding to an adjusted OR of 1.5 (95% CI: .8, 3.0). For recent users, the adjusted OR for bleeding was 1.2 (95% CI: .5, 2.5). The risk of infection did not differ materially between current (1.8%), recent (1.0%) and nonusers (1.7%), corresponding to an adjusted OR of .9 (95% CI: .4, 2.1) among current versus nonusers. CONCLUSIONS: Current use of glucocorticoids is associated with a slightly increased risk of postoperative bleeding, but not infection, after RYGB. No increased risks were found for recent users. PMID- 26001557 TI - Fly in/fly out health workers: a barrier to quality in health care. PMID- 26001558 TI - Antibacterial activity of native California medicinal plant extracts isolated from Rhamnus californica and Umbellularia californica. AB - BACKGROUND: Antimicrobial resistance (AMR) is a major threat to global public health. Medicinal plants have long been used as remedies for infectious diseases by native cultures around the world and have the potential for providing effective treatments for antibiotic-resistant infections. Rhamnus californica (Rhamnaceae) and Umbellularia californica (Lauraceae) are two indigenous California plant species historically used by Native Americans to treat skin, respiratory and gastrointestinal infections. This study aimed to assess the in vitro antimicrobial activity of methanolic extracts of leaves and bark of R. and U. californica against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive and Gram-negative bacteria. METHODS: Methanolic extracts of leaves and bark of R. and U. californica were prepared by soxhlet extraction and evaluated for their antimicrobial activity against Bacillus cereus, Streptococcus pyogenes, Mycobacterium smegmatis, Staphylococcus aureus, MRSA, Escherichia coli and Pseudomonas aeruginosa using disc diffusion and minimal inhibitory concentration (MIC) assays. Chemical profiling of the extracts was performed using standard methods. RESULTS: All extracts inhibited the growth of MRSA and other Gram-positive bacteria with MICs of 3.3-6.0 mg/ml. Gram-negative organisms were unaffected by these extracts. U. californica extracts (leaves and bark) had the lowest MIC values. Chemical profiling detected the presence of quinones, alkaloids, flavonoids, cardenolides, tannins and saponins in these extracts. Our study is the first to report the antimicrobial properties of R. and U. californica and illustrates their promising anti-MRSA potential. CONCLUSIONS: Our results give scientific credence to the traditional medicinal uses of these plants by the indigenous peoples of California. Further investigation of the secondary metabolites responsible for the antimicrobial activity of these extracts against MRSA is warranted. PMID- 26001559 TI - Bone strength and muscle properties in postmenopausal women with and without a recent distal radius fracture. AB - Distal radius (wrist) fracture (DRF) in women over age 50 years is an early sign of bone fragility. Women with a recent DRF compared to women without DRF demonstrated lower bone strength, muscle density, and strength, but no difference in dual-energy x-ray absorptiometry (DXA) measures, suggesting DXA alone may not be a sufficient predictor for DRF risk. INTRODUCTION: The objective of this study was to investigate differences in bone and muscle properties between women with and without a recent DRF. METHODS: One hundred sixty-six postmenopausal women (50 78 years) were recruited. Participants were excluded if they had taken bone altering medications in the past 6 months or had medical conditions that severely affected daily living or the upper extremity. Seventy-seven age-matched women with a fracture in the past 6-24 months (Fx, n = 32) and without fracture (NFx, n = 45) were measured for bone and muscle properties using the nondominant (NFx) or non-fractured limb (Fx). Peripheral quantitative computed tomography (pQCT) was used to estimate bone strength in compression (BSIc) at the distal radius and tibia, bone strength in torsion (SSIp) at the shaft sites, muscle density, and area at the forearm and lower leg. Areal bone mineral density at the ultradistal forearm, spine, and femoral neck was measured by DXA. Grip strength and the 30-s chair stand test were used as estimates of upper and lower extremity muscle strength. Limb-specific between-group differences were compared using multivariate analysis of variance (MANOVA). RESULTS: There was a significant group difference (p < 0.05) for the forearm and lower leg, with the Fx group demonstrating 16 and 19% lower BSIc, 3 and 6% lower muscle density, and 20 and 21% lower muscle strength at the upper and lower extremities, respectively. There were no differences between groups for DXA measures. CONCLUSIONS: Women with recent DRF had lower pQCT-derived estimated bone strength at the distal radius and tibia and lower muscle density and strength at both extremities. PMID- 26001560 TI - Biochemical and clinical deficiency is uncommon in African immigrants despite a high prevalence of low vitamin D: the Africans in America study. AB - African ancestry is associated with low vitamin D levels but high bone density. Fifty percent of African immigrants had low vitamin D levels, but <10 % had evidence of deficiency. The value of providing vitamin D supplementation to African immigrants without evidence of deficiency needs to be determined. INTRODUCTION: The Endocrine Society and Institute of Medicine (IOM) have concluded from studies in largely white populations that 25(OH)D is necessary for bone health. However, their definition of vitamin D insufficiency differs. The Endocrine Society recommends a 25(OH)D threshold of <30 ng/mL. The IOM uses a lower threshold of 25(OH)D of <20 ng/mL. As African ancestry is associated with decreased 25(OH)D but increased bone mineral density (BMD), the applicability of these thresholds to Africans is unknown. Therefore, we examined in African immigrants the relationship of 25(OH)D to parathyroid hormone (PTH) and BMD. METHODS: One hundred eighty-six African immigrants(69 % male, age 38 +/- 10 (mean +/- SD), range 20-64 years) living in metropolitan Washington, DC, were enrolled. BMD was determined from whole-body dual-energy X-ray absorptiometry (DXA) scans. Decreased BMD required T-scores <=-1.0. The threshold for low 25(OH)D was the concentration of 25(OH)D at which PTH became suppressed. This is known as the inflection point. Biochemical deficiency required low 25(OH)D and PTH of >65 pg/mL. Clinical deficiency required low 25(OH)D and T-scores <=-1.0. RESULTS: 25(OH)D <30 and <20 ng/mL occurred in 83 and 46 % of African immigrants, respectively. PTH inversely correlated with 25(OH)D (r = -0.31, P = 0.002). The inflection point occurred at a 25(OH)D concentration of 20 ng/mL. Biochemical and clinical deficiency occurred in only 8 and 3 % of immigrants, respectively. CONCLUSION: As PTH became suppressed at 25(OH)D of 20 ng/mL, the 25(OH)D <20 ng/mL threshold for insufficiency may apply to African immigrants. However, ~50 % of African immigrants have 25(OH)D <20 ng/mL, but only <10 % had evidence of deficiency. The value of providing vitamin D supplementation to the large number of African immigrants with 25(OH)D <20 ng/mL and no detectable evidence of deficiency needs to be determined. PMID- 26001562 TI - WHO should be able to impose sanctions on states that ban travel to countries with epidemics, panel says. PMID- 26001561 TI - Clinical efficacy and safety of monthly oral ibandronate 100 mg versus monthly intravenous ibandronate 1 mg in Japanese patients with primary osteoporosis. AB - The MOVEST study evaluated the efficacy and safety of monthly oral ibandronate versus licensed monthly IV ibandronate in Japanese osteoporotic patients. Relative BMD gains after 12 months were 5.22 % oral and 5.34 % IV, showing non inferiority of oral to IV ibandronate (primary endpoint). No new safety concerns were identified. INTRODUCTION: The randomized, phase 3, double-blind MOVEST (Monthly Oral VErsus intravenouS ibandronaTe) study evaluated the efficacy and safety of monthly oral ibandronate versus the licensed monthly intravenous (IV) ibandronate regimen in Japanese patients with osteoporosis. METHODS: Ambulatory patients aged >= 55 years with primary osteoporosis were randomized to receive oral ibandronate 100 mg/month plus monthly IV placebo, or IV ibandronate 1 mg/month plus monthly oral placebo. The primary endpoint was non-inferiority of oral versus IV ibandronate with respect to bone mineral density (BMD) gains at the lumbar spine after 12 months of treatment. RESULTS: Four hundred twenty-two patients were enrolled with 372 patients in the per-protocol set (183 and 189 in the oral and IV ibandronate groups, respectively). The relative change from baseline in lumbar spine BMD values for the oral and IV ibandronate groups, respectively, was 5.22 % (95 % confidence interval [CI] 4.65, 5.80) and 5.34 % (95 % CI 4.78, 5.90). The least squares mean difference between the two groups was -0.23 % (95 % CI -0.97, 0.51), showing non-inferiority of oral ibandronate to IV ibandronate (non-inferiority limit = -1.60). Changes in BMD values at other sites, and bone turnover marker levels in the oral ibandronate group, were comparable with those of the IV group. The safety profile was similar to that previously demonstrated; no new safety concerns were identified. CONCLUSIONS: This study demonstrated the non-inferiority of oral ibandronate 100 mg/month to IV ibandronate 1 mg/month (licensed dose in Japan) in increasing lumbar spine BMD in Japanese patients with primary osteoporosis. PMID- 26001563 TI - Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. AB - INTRODUCTION: In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. METHODS: LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo controlled period of variable duration and pooled across both studies. RESULTS: The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin low patients (all doses: 5% reduction); no dose-response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. CONCLUSIONS: These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of care treatment. TRIAL REGISTRATION NUMBERS: The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov. PMID- 26001564 TI - High-Throughput Silencing Using the CRISPR-Cas9 System: A Review of the Benefits and Challenges. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system has been seized upon with a fervor enjoyed previously by small interfering RNA (siRNA) and short hairpin RNA (shRNA) technologies and has enormous potential for high-throughput functional genomics studies. The decision to use this approach must be balanced with respect to adoption of existing platforms versus awaiting the development of more "mature" next-generation systems. Here, experience from siRNA and shRNA screening plays an important role, as issues such as targeting efficiency, pooling strategies, and off-target effects with those technologies are already framing debates in the CRISPR field. CRISPR/Cas can be exploited not only to knockout genes but also to up- or down-regulate gene transcription-in some cases in a multiplex fashion. This provides a powerful tool for studying the interaction among multiple signaling cascades in the same genetic background. Furthermore, the documented success of CRISPR/Cas-mediated gene correction (or the corollary, introduction of disease-specific mutations) provides proof of concept for the rapid generation of isogenic cell lines for high-throughput screening. In this review, the advantages and limitations of CRISPR/Cas are discussed and current and future applications are highlighted. It is envisaged that complementarities between CRISPR, siRNA, and shRNA will ensure that all three technologies remain critical to the success of future functional genomics projects. PMID- 26001566 TI - Evaluation of the metabolic chiral inversion of d-selenomethionine in rats by stable isotope dilution gas chromatography-mass spectrometry. AB - The stereoselective pharmacokinetics of selenomethionine enantiomers in rats has been studied to evaluate the chiral inversion of D-selenomethionine to the L enantiomer. After bolus intravenous administration of D- or L-selenomethionine to rats, the plasma concentrations of these two enantiomers were determined by stereoselective gas chromatography-mass spectrometry with selected ion monitoring. This method involved derivatization of selenomethionine enantiomers with HCl in methanol to form methyl ester followed by N-acylation with (+)-alpha methoxy-alpha-trifluoromethylphenylacetyl chloride to form the diastereomeric amide, and separation of the diastereomer on GC with an achiral column. Plasma concentrations of administered D- and L-selenomethionine declined with terminal half-lives of 96 +/- 17 min and 91 +/- 6 min, respectively. L-Selenomethionine appeared rapidly in plasma after administration of D-selenomethionine, whereas D selenomethionine was not detected in plasma after administration of L selenomethionine. The fraction of conversion of D-selenomethionine to L selenomethionine was estimated to be 61.3 +/- 14.5%. The present method evaluates the stereoselective pharmacokinetics of selenomethionine enantiomers, including the estimation of the metabolic chiral inversion. PMID- 26001565 TI - Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. AB - INTRODUCTION: Microglia are tissue macrophages of the central nervous system that monitor brain homeostasis and react upon neuronal damage and stress. Aging and neurodegeneration induce a hypersensitive, pro-inflammatory phenotype, referred to as primed microglia. To determine the gene expression signature of priming, the transcriptomes of microglia in aging, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) mouse models were compared using Weighted Gene Co-expression Network Analysis (WGCNA). RESULTS: A highly consistent consensus transcriptional profile of up-regulated genes was identified, which prominently differed from the acute inflammatory gene network induced by lipopolysaccharide (LPS). Where the acute inflammatory network was significantly enriched for NF-kappaB signaling, the primed microglia profile contained key features related to phagosome, lysosome, antigen presentation, and AD signaling. In addition, specific signatures for aging, AD, and ALS were identified. CONCLUSION: Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects. PMID- 26001567 TI - Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers. AB - Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimer's disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders. PMID- 26001569 TI - Global access to surgical care: moving forward. PMID- 26001568 TI - Characterization of single-domain antibodies against Foot and Mouth Disease Virus (FMDV) serotype O from a camelid and imaging of FMDV in baby hamster kidney-21 cells with single-domain antibody-quantum dots probes. AB - BACKGROUND: Foot-and-mouth disease (FMD) is a highly contagious disease that affects cloven-hoofed animals and causes significant economic losses to husbandry worldwide. The variable domain of heavy-chain antibodies (VHHs or single domain antibodies, sdAbs) are single-domain antigen-binding fragments derived from camelid heavy-chain antibodies. RESULTS: In this work, two sdAbs against FMD virus (FMDV) serotype O were selected from a camelid phage display immune library and expressed in Escherichia coli. The serotype specificity and affinity of the sdAbs were identified through enzyme-linked immunosorbent assay and surface plasmon resonance assay. Moreover, the sdAbs were conjugated with quantum dots to constitute probes for imaging FMD virions. Results demonstrated that the two sdAbs were specific for serotype O and shared no cross-reactivity with serotypes A and Asia 1. The equilibrium dissociation constant (KD) values of the two sdAbs ranged from 6.23 nM to 8.24 nM, which indicated high affinity to FMDV antigens. Co-localization with the sdAb-AF488 and sdAb-QD probes indicated the same location of FMDV virions in baby hamster kidney-21 (BHK-21) cells. CONCLUSIONS: sdAb-QD probes are powerful tools to detect and image FMDV in BHK-21 cells. PMID- 26001570 TI - Mapping the geographical distribution of yaws. PMID- 26001571 TI - Achieving gender equality to reduce intimate partner violence against women. PMID- 26001572 TI - Financing universal health coverage by cutting fossil fuel subsidies. PMID- 26001573 TI - State capability and Rwanda's health gains. PMID- 26001574 TI - Intimate partner violence and HIV: embracing complexity. PMID- 26001575 TI - Tackling tobacco smoking in Saudi Arabia. PMID- 26001576 TI - Global epidemiology of yaws: a systematic review. AB - BACKGROUND: To achieve yaws eradication, the use of the new WHO strategy of initial mass treatment with azithromycin and surveillance twice a year needs to be extended everywhere the disease occurs. However, the geographic scope of the disease is unknown. We aimed to synthesise published and unpublished work to update the reported number of people with yaws at national and subnational levels and to estimate at-risk populations. METHODS: We searched PubMed and WHO databases to identify published data for prevalence of active and latent yaws from Jan 1, 1990, to Dec 31, 2014. We also searched for ongoing or recently completed unpublished studies from the WHO yaws surveillance network. We estimated yaws prevalence (and 95% CIs). We collected yaws incidence data from official national surveillance programmes at the first administrative level from Jan 1, 2010, to Dec 31, 2013, and we used total population data at the second administrative level to estimate the size of at-risk populations. FINDINGS: We identified 103 records, of which 23 published articles describing 27 studies and four unpublished studies met the inclusion criteria. Prevalence of active disease ranged from 0.31% to 14.54% in yaws-endemic areas, and prevalence of latent yaws ranged from 2.45% to 31.05%. During 2010-13, 256 343 yaws cases were reported to WHO from 13 endemic countries, all of which are low-income and middle-income countries. 215 308 (84%) of 256 343 cases reported to WHO were from three countries-Papua New Guinea, Solomon Islands, and Ghana. We estimated that, in 2012, over 89 million people were living in yaws-endemic districts. INTERPRETATION: Papua New Guinea, Solomon Islands, and Ghana should be the focus of initial efforts at implementing the WHO yaws eradication strategy. Community based mapping and active surveillance must accompany the implementation of yaws eradication activities. FUNDING: None. PMID- 26001577 TI - Cross-national and multilevel correlates of partner violence: an analysis of data from population-based surveys. AB - BACKGROUND: On average, intimate partner violence affects nearly one in three women worldwide within their lifetime. But the distribution of partner violence is highly uneven, with a prevalence of less than 4% in the past 12 months in many high-income countries compared with at least 40% in some low-income settings. Little is known about the factors that drive the geographical distribution of partner violence or how macro-level factors might combine with individual-level factors to affect individual women's risk of intimate partner violence. We aimed to assess the role that women's status and other gender-related factors might have in defining levels of partner violence among settings. METHODS: We compiled data for the 12 month prevalence of partner violence from 66 surveys (88 survey years) from 44 countries, representing 481 205 women between Jan 1, 2000, and Apr 17, 2013. Only surveys with comparable questions and state-of-the-art methods to ensure safety and encourage violence disclosure were used. With linear and quantile regression, we examined associations between macro-level measures of socioeconomic development, women's status, gender inequality, and gender-related norms and the prevalence of current partner violence at a population level. Multilevel modelling and tests for interaction were used to explore whether and how macro-level factors affect individual-level risk. The outcome for this analysis was the population prevalence of current partner violence, defined as the percentage of ever-partnered women (excluding widows without a current partner), aged from 15 years to 49 years who were victims of at least one act of physical or sexual violence within the past 12 months. FINDINGS: Gender-related factors at the national and subnational level help to predict the population prevalence of physical and sexual partner violence within the past 12 months. Especially predictive of the geographical distribution of partner violence are norms related to male authority over female behaviour (0.102, p<0.0001), norms justifying wife beating (0.263, p<0.0001), and the extent to which law and practice disadvantage women compared with men in access to land, property, and other productive resources (0.271, p<0.0001). The strong negative association between current partner violence and gross domestic product (GDP) per person ( 0.055, p=0.0009) becomes non-significant in the presence of norm-related measures (-0.015, p=0.472), suggesting that GDP per person is a marker for social transformations that accompany economic growth and is unlikely to be causally related to levels of partner violence. We document several cross-level effects, including that a girl's education is more strongly associated with reduced risk of partner violence in countries where wife abuse is normative than where it is not. Likewise, partner violence is less prevalent in countries with a high proportion of women in the formal work force, but working for cash increases a woman's risk in countries where few women work. INTERPRETATION: Our findings suggest that policy makers could reduce violence by eliminating gender bias in ownership rights and addressing norms that justify wife beating and male control of female behaviour. Prevention planners should place greater emphasis on policy reforms at the macro-level and take cross-level effects into account when designing interventions. FUNDING: What Works to Prevent Violence Against Women and Girls-a research and innovation project funded by UK Aid. PMID- 26001579 TI - Objective measurement of sedentary behavior: impact of non-wear time rules on changes in sedentary time. AB - BACKGROUND: Accelerometry non-wear time rules might affect sedentary time, and the associations with health outcomes such as adiposity. However, the exact effect of different non-wear time rules on sedentary time and reported changes in sedentary time is unknown. This study evaluated the effect of different accelerometry non-wear time rules on sedentary time and changes in sedentary time from age 9-12 years. METHODS: Accelerometry data were collected as part of the Gateshead Millennium Birth Cohort study. Participants were 9.3 (+/- 0.4) years at baseline (n = 17) and 12.5 (+/- 0.3) years at follow-up (n = 440). Sedentary time was defined using an accelerometry cut-point of 25 counts per 15 s. Non-wear time was defined using manual data reduction (the reference method) and 10 min, 20 min and 60 min consecutive zeros. Differences between methods were analyzed using repeated measures ANOVA with Bonferroni post-hoc analyses. RESULTS: Mean daily sedentary time at age 9 ranged from 364 min per day to 426 min using the 10 min and 60 min rule, respectively (p < 0.05). At 12 years, mean daily sedentary times ranged from 424 min to 518 min (p < 0.05). Mean changes in daily sedentary time over the three years ranged from 60 min to 93 min using the 10 min and 60 min rule, respectively (p < 0.05). When adjusting for wear time, differences in average sedentary time between methods decreased from 62 min to 27 min (age 9), 95 min to 32 min (age 12) and 33 min to 10 min (changes between 9 to 12 years). CONCLUSIONS: Using different non-wear time rules results in significant differences in daily sedentary time and changes in sedentary time. Correcting for wear time appears to be a reasonable approach to limiting these differences and may improve comparability between future studies. Using the 20 min rule, while correcting for wear time, provided the most accurate estimates of sedentary time and changes in sedentary time, compared to the manual reference in 9-12 year olds. PMID- 26001580 TI - Anticipating and Resisting the Temptation to Behave Unethically. AB - Ethical dilemmas pose a self-control conflict between pursuing immediate benefits through behaving dishonestly and pursuing long-term benefits through acts of honesty. Therefore, factors that facilitate self-control for other types of goals (e.g., health and financial) should also promote ethical behavior. Across four studies, we find support for this possibility. Specifically, we find that only under conditions that facilitate conflict identification--including the consideration of several decisions simultaneously (i.e., a broad decision frame) and perceived high connectedness to the future self--does anticipating a temptation to behave dishonestly in advance promote honesty. We demonstrate these interaction patterns between conflict identification and temptation anticipation in negotiation situations (Study 1), lab tasks (Study 2), and ethical dilemmas in the workplace (Studies 3-4). We conclude that identifying a self-control conflict and anticipating a temptation are two necessary preconditions for ethical decision making. PMID- 26001581 TI - Sequential metalation of benzene: electronic, bonding, magnetotropic and spectroscopic properties of coinage metalated benzenes studied by DFT. AB - A series of coinage metalated benzenes formulated as C6H6-nMn (M = Cu, Ag, Au, n = 1-5) were investigated by means of density functional theory (DFT) calculations. The structural, energetic, magnetotropic and spectroscopic properties of the coinage metalated benzenes were analyzed thoroughly and compared to the respective properties of the archetype aromatic benzene molecule. In contrast to the latter, the C6H6-nMn (M = Cu, Ag, Au, n = 1-5) molecules are predicted to be aromatic even in their excited triplet state. Excellent linear correlations between (I) the zz component of the nucleus independent chemical shift [NICSzz(1)] values and the total negative natural charge acquired by the carbocyclic ring, and (ii) the NICSzz(1) vs wavelength (lambda) of the HOMO -> LUMO transitions in the absorption spectra of the coinage metalated benzenes were established. The emission spectra of the coinage metalated benzenes were characterized by high [Formula: see text] values, particularly for the di substituted - and p-isomers, with the highest [Formula: see text] value of 67 kcal mol(-1) calculated for the m-M6H4Au2 species. The bonding pattern of the coinage metalated benzenes was analyzed thoroughly by means of a multitude of electronic structure calculation methods [natural bond orbital (NBO), atoms-in molecules (AIM), electron localization function (ELF), reduced density gradient (RDG) and Sign(lambda 2(r))rho(r) functions]. Our findings indicate whole classes of new coinage metalated benzenes (mono-, di-, tri-, four- and five-substituted) opening a new chemistry for the coinage metalated benzenes, indicating that their chemistry will be worthwhile studying both experimentally and theoretically in the future. Graphical Abstract The complete series of coinage metalated benzenes were investigated by density functional theory methods. The structural, energetic, bonding, magnetotropic and spectroscopic properties of the coinage metalated benzenes were analyzed thoroughly. In contrast to the archetype aromatic benzene molecule, the coinage metalated benzenes are predicted to be aromatic even in their excited triplet state. PMID- 26001582 TI - Energetic stability, atomic and electronic structures of extended gamma-graphyne: A density functional study. AB - The energetic stability, atomic and electronic structures of gamma-graphyne and its derivatives (gamma-GYs) with extended carbon chains were investigated as a function of chain length by density functional calculations in this work. The studied gamma-GYs consist of hexagon carbon rings connected by linear chains with C atoms n = 0-22. We predict that the even-numbered C chains of gamma-GYs consist of alternating single and triple C-C bonds (polyyne), energetically more stable than the odd-numbered C chains made of continuous C-C double bonds (polycumulene). The calculated electronic structures indicate that gamma-GYs can be either metallic (odd n) or semiconductive (even n) depending on the parity of the number of C chain atoms. The semiconducting gamma-GYs are predicted to have ~1.2 eV direct band gaps and 0.1-0.2 effective electron masses independent of the chain length. Thus introducing sp carbon atoms into sp (2)-based graphene provides a novel way to open up band gaps without doping and defects while maintaining small electron masses critical to good transport properties. Graphical Abstract The typical atomic model of graphyne (middle) as well as their band gaps (left) and electron density (right). PMID- 26001583 TI - Probing long-range interactions by extracting free energies from genome-wide chromosome conformation capture data. AB - BACKGROUND: A variety of DNA binding proteins are involved in regulating and shaping the packing of chromatin. They aid the formation of loops in the DNA that function to isolate different structural domains. A recent experimental technique, Hi-C, provides a method for determining the frequency of such looping between all distant parts of the genome. Given that the binding locations of many chromatin associated proteins have also been measured, it has been possible to make estimates for their influence on the long-range interactions as measured by Hi-C. However, a challenge in this analysis is the predominance of non-specific contacts that mask out the specific interactions of interest. RESULTS: We show that transforming the Hi-C contact frequencies into free energies gives a natural method for separating out the distance dependent non-specific interactions. In particular we apply Principal Component Analysis (PCA) to the transformed free energy matrix to identify the dominant modes of interaction. PCA identifies systematic effects as well as high frequency spatial noise in the Hi-C data which can be filtered out. Thus it can be used as a data driven approach for normalizing Hi-C data. We assess this PCA based normalization approach, along with several other normalization schemes, by fitting the transformed Hi-C data using a pairwise interaction model that takes as input the known locations of bound chromatin factors. The result of fitting is a set of predictions for the coupling energies between the various chromatin factors and their effect on the energetics of looping. We show that the quality of the fit can be used as a means to determine how much PCA filtering should be applied to the Hi-C data. CONCLUSIONS: We find that the different normalizations of the Hi-C data vary in the quality of fit to the pairwise interaction model. PCA filtering can improve the fit, and the predicted coupling energies lead to biologically meaningful insights for how various chromatin bound factors influence the stability of DNA loops in chromatin. PMID- 26001584 TI - Home-based movement therapy in neonatal brachial plexus palsy: A case study. AB - STUDY DESIGN: Case report. INTRODUCTION: The value of movement-based therapy in peripheral nerve injury conditions such as neonatal brachial plexus palsy (NBPP) is unclear. PURPOSE OF THE STUDY: To determine the effectiveness of a home-based movement therapy program in a 17 year old female patient with a right NBPP pan plexopathy. METHODS: Home training consisted of arm reaching and object manipulation tasks using devices which recorded performance. Training occurred for 1 h/day, 5 days/week for 6 weeks with periodic webcam supervision. Pre- and post clinical, functional and kinematic assessments were performed in a laboratory setting. RESULTS: Following training, shoulder flexion and elbow extension active range of motion increased by 13 degrees and 9 degrees , respectively, and functional ability also improved. Reach movement duration decreased significantly with a concomitant improvement in movement coordination. CONCLUSIONS: These results demonstrate that movement therapy has the potential to improve motor function in NBPP years after the initial insult. LEVEL OF EVIDENCE: 4. PMID- 26001585 TI - How therapists specializing in hand therapy evaluate the ability of patients to participate in their daily lives: An exploratory study. AB - STUDY DESIGN: Exploratory, Survey Design. INTRODUCTION: A gap in current knowledge exists regarding how therapists evaluate patient difficulty participating in life situations. PURPOSE: The goal is to explore how therapists measure participation. METHODS: A survey questionnaire was developed, piloted, and tested for reliability and validity. Convenience sample of 249 participants responded, providing information about assessment tools employed, problems and goals identified, indications for patient discharge, and participants' demographics. RESULTS: Participants used tools to measure body structures/functions, and informal discussion about daily activities, daily to weekly. Participation measures were employed monthly or less. Participation was noted more often in goals than problems identified in case study vignettes. Body structures/functions and participation were considered equally when anticipating patient discharge. CONCLUSIONS: Evaluations principally employed tools and identified problems relevant to impairments in body structures/functions. Yet, when looking forward, setting goals and anticipating discharge, patients' participation needs were also attended. LEVEL OF EVIDENCE: 2c. PMID- 26001586 TI - Impact of study design and database parameters on NOAEL distributions used for toxicological concern (TTC) values. AB - TTC values for chemicals with unknown toxicity but known structure are derived from 5th percentiles of NOAEL distributions from compounds with known toxicity. The impact of chemical structures on TTC values was repeatedly investigated but not the impact of parameters such as study numbers per compound and differences in study design. Recently, study design parameters such as application route with related dose-decrements, dose-spacing and number of animals per group but not exposure duration were found to affect NOAEL distributions. Here, the impact of study design parameters on lowest NOAEL distributions and consequently on TTC values was analyzed in a database on 423 Cramer class III pesticides. Using NOAELs related to lowest LOAELs instead of lowest NOAELs, excluding studies with a dose spacing >8, and standardizing NOAELs to the initial dose animals received shifted the 5th percentile of NOAEL distributions from 0.22 to 0.5mg/kg body weight per day. In contrast, weighting of NOAELs for the study numbers per compound shifts 5th percentiles downwards to lower values by 10-20%. The results show that database and study design parameters influence NOAEL distributions to a minor degree and derived TTC values therefore can be considered reliable in that perspective. PMID- 26001588 TI - Advanced glycation end products and schizophrenia: A systematic review. AB - Oxidative stress has become an exciting area of research on schizophrenia, which is a highly prevalent condition that affects approximately 1% of the worldwide population. Advanced glycation end products (AGEs), which are considered metabolic biomarkers of increased oxidative stress, have a pathogenic role in the development and progression of different oxidative stress-based diseases including atherosclerosis, diabetes, neurodegenerative disorders and schizophrenia. AGE formation and accumulation as well as the activation of its receptor (RAGE) can lead to signaling through several inflammatory signaling pathways and further damaging effects. This systematic review is based on a search conducted in July 2014 in which 6 studies were identified that met our criteria. In this work, we describe how recent methodological advances regarding the role of AGEs may contribute to a better understanding of the pathophysiology of schizophrenia and provide a different approach in the comprehension of the relationship between cardiovascular disease and schizophrenia. These latest findings may lead to new directions for future research on novel diagnostic and treatment strategies. PMID- 26001587 TI - Suicidal ideation in depressed postpartum women: Associations with childhood trauma, sleep disturbance and anxiety. AB - BACKGROUND: Suicide is one of the leading causes of death in postpartum women. Identifying modifiable factors related to suicide risk in mothers after delivery is a public health priority. Our study aim was to examine associations between suicidal ideation (SI) and plausible risk factors (experience of abuse in childhood or as an adult, sleep disturbance, and anxiety symptoms) in depressed postpartum women. METHODS: This secondary analysis included 628 depressed mothers at 4-6 weeks postpartum. Diagnosis was confirmed with the Structured Clinical Interview for DSM-IV. We examined SI from responses to the Edinburgh Postnatal Depression Scale-EPDS item 10; depression levels on the Structured Interview Guide for the Hamilton Depression Rating Scale, Atypical Depression Symptoms (SIGH-ADS); plus sleep disturbance and anxiety levels with subscales from the EPDS and SIGH-ADS items on sleep and anxiety symptoms. RESULTS: Of the depressed mothers, 496 (79%) 'never' had thoughts of self-harm; 98 (15.6%) 'hardly ever'; and 34 (5.4%) 'sometimes' or 'quite often'. Logistic regression models indicated that having frequent thoughts of self-harm was related to childhood physical abuse (odds ratio-OR = 1.68, 95% CI = 1.00, 2.81); in mothers without childhood physical abuse, having frequent self-harm thoughts was related to sleep disturbance (OR = 1.15, 95% CI = 1.02, 1.29) and anxiety symptoms (OR = 1.11, 95% CI = 1.01, 1.23). DISCUSSION: Because women with postpartum depression can present with frequent thoughts of self-harm and a high level of clinical complexity, conducting a detailed safety assessment, that includes evaluation of childhood abuse history and current symptoms of sleep disturbance and anxiety, is a key component in the management of depressed mothers. PMID- 26001589 TI - Impaired mitochondrial energy metabolism in Alzheimer's disease: Impact on pathogenesis via disturbed epigenetic regulation of chromatin landscape. AB - The amyloid cascade hypothesis for the pathogenesis of Alzheimer's disease (AD) was proposed over twenty years ago. However, the mechanisms of neurodegeneration and synaptic loss have remained elusive delaying the effective drug discovery. Recent studies have revealed that amyloid-beta peptides as well as phosphorylated and fragmented tau proteins accumulate within mitochondria. This process triggers mitochondrial fission (fragmentation) and disturbs Krebs cycle function e.g. by inhibiting the activity of 2-oxoglutarate dehydrogenase. Oxidative stress, hypoxia and calcium imbalance also disrupt the function of Krebs cycle in AD brains. Recent studies on epigenetic regulation have revealed that Krebs cycle intermediates control DNA and histone methylation as well as histone acetylation and thus they have fundamental roles in gene expression. DNA demethylases (TET1 3) and histone lysine demethylases (KDM2-7) are included in the family of 2 oxoglutarate-dependent oxygenases (2-OGDO). Interestingly, 2-oxoglutarate is the obligatory substrate of 2-OGDO enzymes, whereas succinate and fumarate are the inhibitors of these enzymes. Moreover, citrate can stimulate histone acetylation via acetyl-CoA production. Epigenetic studies have revealed that AD is associated with changes in DNA methylation and histone acetylation patterns. However, the epigenetic results of different studies are inconsistent but one possibility is that they represent both coordinated adaptive responses and uncontrolled stochastic changes, which provoke pathogenesis in affected neurons. Here, we will review the changes observed in mitochondrial dynamics and Krebs cycle function associated with AD, and then clarify the mechanisms through which mitochondrial metabolites can control the epigenetic landscape of chromatin and induce pathological changes in AD. PMID- 26001590 TI - Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM). AB - Type 1 diabetes (T1DM) is an autoimmune disease with aberrant immune responses to specific beta-cell autoantigens, resulting in insulin deficiency. Children and adolescents with T1DM may also develop organ-specific multiple autoimmunity in the context of APS (autoimmune polyendocrine syndrome) type 1, 2 or 3. The most frequently encountered associated autoimmune disorders in T1DM are autoimmune thyroid, followed by celiac, autoimmune gastric disease and other rare autoimmune conditions. There are limited previous studies on the prevalence of associated autoimmunity, especially multiple, in children with T1DM. The present review reports on the classification of autoimmune diabetes, and on the prevalence, pathogenesis, predictive factors and clinical presentation of pancreatic autoimmunity and of all associated autoimmune disorders in children with T1DM. The impact of associated autoimmunity on diabetes control and general health is also discussed, along with suggestions regarding screening strategies and follow up for early detection and management of the autoimmunity. PMID- 26001592 TI - Air pollution in UK: the public health problem that won't go away. PMID- 26001591 TI - Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. AB - INTRODUCTION: Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer's disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions. RESULTS: Here we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD + HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer's Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and CD68 (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD + HS aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB. CONCLUSIONS: We conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes. PMID- 26001593 TI - Identification of E545k mutation in plasma from a PIK3CA wild-type metastatic breast cancer patient by array-based digital polymerase chain reaction: Circulating-free DNA a powerful tool for biomarker testing in advance disease. AB - PIK3CA gene is frequently mutated in patients with breast cancer and it has been the focus of intense research. Inhibitors of PI3K pathway are being evaluated in ongoing clinical trials but the impact of PIKC3A mutation status on tumor response is yet uncertain. In the metastatic setting, several studies are evaluating the predictive value of PIK3CA mutations. However, results could be biased by biopsy localization. Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood and can potentially overcome such situation. As a proof of the concept, we present the case of a metastatic patient with a PIK3CA wild-type primary tumor in which the PIK3CA E545K mutation was identified in both the circulating-free DNA obtained from a peripheral blood sample and in the formalin fixed, paraffin-embedded liver metastasis. PMID- 26001594 TI - Applications and limitations in translating genomics to clinical practice. AB - Recent efforts to broadly apply genetics to clinical practice have been driven by the rapid advancement of genomic technologies and the discovery of genes associated with disease risk, progression, and treatment response. Yet there remain valid concerns about the complexities and limitations that confront the popular notion of clinical utility of genetics in personalized medicine. Research is still very much in the mode of discovery. The excitement of discovery and applications to diagnostics are well described in each of the articles in this issue. Yet, each article appropriately acknowledges the limitations that need to be overcome to apply new knowledge to clinical practice. PMID- 26001596 TI - Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression. AB - Proinflammatory T helper 1 (Th1) and T helper 17 (Th17) cell subsets have been reported to have an immunopathogenic role in metabolic disease. We previously demonstrated that CD4(+) T cells are increased in kidneys in type 2 diabetic patients. However, the role of Th1 and Th17 cells in the development and progression of diabetic nephropathy is unclear. In this study, we examined the hypothesis that mycophenolate mofetil (MMF) attenuates diabetic kidney injury by the suppression of renal T-cell proliferation and related cytokines. Four groups of male C57/BL6 mice (8-weeks-old) were studied: (1) untreated controls, (2) MMF treated controls (30 mg/kg of body weight per day), (3) streptozotocin (STZ) induced diabetes, and (4) MMF-treated STZ-induced diabetes. The interferon gamma (IFN-gamma) and interleukin 17 (IL-17) from renal CD4(+) T cells were analyzed in kidney mononuclear cells by flow cytometry. We found proliferating CD4(+) T cells were significantly increased in the kidney compared with the spleen. There were increases in IFN-gamma(+) CD4(+) and IL-17A(+) CD4(+) T cells from the initiation of albuminuria in the kidneys of diabetic mice. We found MMF suppresses only the intrarenal IL-17A(+) CD4(+) T cells from early diabetic nephropathy and improves albuminuria, tubulointerstitial fibrosis independent of glycemic control. Our study results suggest that Th17 may play an independent role in the progression of diabetic nephropathy and modulation of IL-17 has potential as an immunologic therapeutic target. PMID- 26001595 TI - High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis. AB - Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value <0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis. PMID- 26001597 TI - Progression of activity and structural changes in the anterior cingulate cortex during remote memory formation. AB - The progression of activity and structural changes in the anterior cingulate cortex during remote contextual fear memory formation was measured by imaging c fos expression and dendritic spines following retrieval tests administered at six post-training time points (days 1, 5, 7, 14, 21, 36). Here we report that conditioned mice exhibit robust freezing at each time point. C-fos expression starts to augment on day 5, showing a monotonic increase over the successive time points, and then stabilized in relation to the higher freezing scores. The first significant increase in mean spine density emerges on day 7. By day 14, the net number of spines remained stable, yet the distribution of single neuron spine density becomes progressively more homogeneous. Our findings reveal that activity changes precede structural remodeling of neurons in the neocortex while remodeling coherence develops gradually in cortical neuron ensembles. PMID- 26001598 TI - Effect of primary culture medium type for culture of canine fibroblasts on production of cloned dogs. AB - Fibroblasts are common source of donor cells for SCNT. It is suggested that donor cells' microenvironment, including the primary culture, affects development of reconstructed embryos. To prove this, canine embryos were cloned with fibroblasts that were cultured in two different primary media (RCMEp vs. Dulbecco's modified Eagle's medium [DMEM]) and in vivo developments were compared with relative amount of stemness, reprogramming, apoptosis gene transcripts, and telomerase activity. Donor cells cultured in RCMEp contained a significantly higher amount of SOX2, NANOG, DPPA2, REXO1, HDAC, DNMT1, MECP2 and telomerase activity than those cultured in DMEM (P < 0.05). In vivo developmental potential of cloned embryos with donor cells cultured in RCMEp had a higher birth rate than that of embryos derived from DMEM (P < 0.05). The culture medium can induce changes in gene expression of donor cells and telomerase activity, and these alterations can also affect in vivo developmental competence of the cloned embryos. PMID- 26001599 TI - The use of altrenogest to avoid hyperestrogenism after eCG-hCG ovulation induction in southern tigrina (Leopardus guttulus). AB - The goal of this study was to optimize an ovulation induction protocol for use with artificial insemination in the southern tigrina (Leopardus guttulus). The specific aims were to report the efficacy of using altrenogest, an oral progestin (Regumate, MSD Animal Health, Merck Animal Health), to suppress ovarian activity and prevent follicular hyperstimulation and hyperestrogenism after the administration of exogenous eCG and hCG. To monitor ovarian responses, fecal estrogen and progestogen metabolites were quantified by enzyme immunoassay in females before and after intramuscular administration of 200-IU eCG and 150-IU hCG in two trials, 4 months apart. During the first trial, there was no use of altrenogest, only the eCG-hCG ovulation induction protocol. In the second trial, the ovulation induction protocol was preceded by the administration of oral altrenogest for 14 days (minimum of 0.192 mg per kg per day). Altrenogest administration resulted in a suppression of follicular activity in three out of six females before eCG-hCG administration on the basis of lower mean estrogen concentrations (P < 0.05). It also resulted in four out of six females presenting lower fecal estrogen metabolite concentrations (P < 0.05) after ovulation induction, and two out of six individuals showed a reduction (P < 0.05) in postovulatory fecal progestogen metabolite concentrations, all when compared to the same female's cycles without the progestin. Fecal estrogen metabolite concentrations were closer to baseline in 50% of these individuals after altrenogest and eCG-hCG treatments when compared to basal concentrations before gonadotropins without the use of altrenogest. This study reported that use of altrenogest in southern tigrina can suppress ovarian activity and avoid hyperestrogenism after administration of eCG and hCG treatment. However, not all females responded uniformly, so more studies are needed to increase the efficacy of ovulation induction for use with artificial insemination in this species. PMID- 26001600 TI - Effect of 5-aminoimidazole-4-carboxamide ribonucleoside on the mitochondrial function and developmental ability of bovine oocytes. AB - Oocyte nuclear maturation depends on sufficient energy supply through oxidative phosphorylation and beta-oxidation. AMP-activated protein kinase (AMPK) is an energy sensor controlling the oocyte energy metabolism. The main aim of this study was to examine the effect of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent activator of AMPK, on the ATP content and mitochondrial DNA copy number (Mt-number) of bovine oocytes and on their developmental ability. Oocytes were collected from slaughterhouse-derived bovine ovaries. When these oocytes were cultured in a maturation medium containing 0-, 50-, 250-, and 500 MUM AICAR, higher AICAR concentrations reduced the rate of meiotic maturation and the ATP content in oocytes, whereas lower AICAR increased the ATP content in oocytes without affecting the maturation rate. Supplementation of the maturation medium with a low concentration of AICAR (50 and 250 MUM) increased phospho-AMPK expression level, as determined by immunostaining. In addition, AICAR treatment increased the ATP content in oocytes, which remained elevated for as long as 2 days after fertilization. On culturing the oocytes with AICAR (250 MUM), the fertilization outcome, rate of blastulation, and total cell number of the blastocysts significantly improved. When the proteosomal mitochondrial degradation was inhibited by supplementing the maturation medium with MG132, the Mt-number, as determined by real-time polymerase chain reaction, significantly increased. However, the treatment of oocytes with AICAR did not affect the Mt number in the presence or absence of MG132. From these data, we conclude that low concentrations of AICAR improved the embryonic developmental ability, presumably via the upregulation of the ATP content in oocytes, but the increase in the ATP content was not due to the upregulation of mitochondrial biogeneration. PMID- 26001601 TI - Damage control orthopaedics: Variability of construct design for external fixation of the lower extremity and implications on cost. AB - INTRODUCTION: To evaluate relative cost of external fixator constructs applied for damage control purposes in a cohort of advanced orthopaedic trainees and orthopaedic staff traumatologists. We also sought to evaluate physicians' understanding of component cost. MATERIALS AND METHODS: Participants were asked to apply an external fixator for three separate fracture patterns in damage control fashion. A total of 19 physicians (nine PGY-4 residents, five PGY-5 residents, two orthopaedic trauma fellows and three orthopaedic staff traumatologists) participated. Total construct cost was calculated. Participants provided an estimate of the cost of each component in a fill-in format survey. Main outcome measures included cost of external fixator construct applied and the estimated cost of external fixator components. RESULTS: Average whole sale cost of an external fixator construct was $5252 (+/-$1798). Of the three fracture types examined, the tibial plafond fracture external fixator construct on average cost the most, followed by the tibial plateau fracture and the femur fracture construct. The large ex-fix combination clamp was the major contributor to cost for each construct. The combination clamp may be substituted for a multi-pin clamp, resulting in significant cost savings. The self-drilling Schanz pin and the large ex-fix combination clamp were most highly underestimated (25% and 22% of their actual cost, respectively). CONCLUSION: Innumerous construct designs exist and even small changes can significantly impact cost. Knowledge of component cost is low among staff and trainees. Education of component cost is vital to allow adequate consideration of construct design prior to fixator application. PMID- 26001602 TI - The outcome of early revision of malaligned pediatric supracondylar humerus fractures. AB - BACKGROUND: Supracondylar humerus fractures (SCHF) are the most common elbow fractures requiring surgical treatment in the pediatric age group. Most fractures are reduced and stabilised adequately. Yet, post-surgical malunion may occur. The purpose of this study is to evaluate our results of early revision surgery in 21 surgically treated pediatric SCHF with immediate postoperative loss of alignment and compare them with previous reports of late corrective osteotomies. METHODS: Twenty-one pediatric SCHF patients that underwent revision surgery for malalignment within 3 weeks of the initial reduction and fixation consisted the study group. Indications for revision were unacceptable radiographic alignment diagnosed within the first 3 weeks after the index surgery. Clinical outcome included pain, range of motion (ROM) and appearance of the elbow. Radiographic outcome was defined as fracture healing and final alignment, assessed in both coronal and sagittal planes. RESULTS: The average time interval between index and revision surgery was 7.6 days (range 3-18). In revision surgery, closed reduction was performed in 17 out of 21 patients, and open reduction was required in four. In one patient, an external fixator was added. In the most recent follow up, all patients but three regained full ROM. The remaining three had a deficit of 10 degrees or less. Two patients had cubitus varus of 10 degrees or less. All patients had a marked radiographic improvement after revision, especially in the sagittal plane increasing the humero-capitaller flexion angle by an average of 20 degrees . DISCUSSION: Malunion after reduction and Kirschner wires (KW) fixation of SCHF is an uncommonly reported phenomenon. When malunion is recognised after fracture healing, corrective osteotomies may carry a significant complications rate. We describe our favourable experience with early diagnosis and revision surgery of malaligned SCHF. PMID- 26001603 TI - Concordance and discordance between taxonomic and functional homogenization: responses of soil mite assemblages to forest conversion. AB - The compositional characteristics of ecological assemblages are often simplified; this process is termed "biotic homogenization." This process of biological reorganization occurs not only taxonomically but also functionally. Testing both aspects of homogenization is essential if ecosystem functioning supported by a diverse mosaic of functional traits in the landscape is concerned. Here, we aimed to infer the underlying processes of taxonomic/functional homogenization at the local scale, which is a scale that is meaningful for this research question. We recorded species of litter-dwelling oribatid mites along a gradient of forest conversion from a natural forest to a monoculture larch plantation in Japan (in total 11 stands), and collected data on the functional traits of the recorded species to quantify functional diversity. We calculated the taxonomic and functional beta-diversity, an index of biotic homogenization. We found that both the taxonomic and functional beta-diversity decreased with larch dominance (stand homogenization). After further deconstructing beta-diversity into the components of turnover and nestedness, which reflect different processes of community organization, a significant decrease in the response to larch dominance was observed only for the functional turnover. As a result, there was a steeper decline in the functional beta-diversity than the taxonomic beta-diversity. This discordance between the taxonomic and functional response suggests that species replacement occurs between species that are functionally redundant under environmental homogenization, ultimately leading to the stronger homogenization of functional diversity. The insights gained from community organization of oribatid mites suggest that the functional characteristics of local assemblages, which support the functionality of ecosystems, are of more concern in human dominated forest landscapes. PMID- 26001604 TI - Seasonal change in tropical habitat quality and body condition for a declining migratory songbird. AB - Many migratory songbirds spend their non-breeding season in tropical humid forests, where climate change is predicted to increase the severity and frequency of droughts and decrease rainfall. For conservation of these songbirds, it is critical to understand how resources during the non-breeding season are affected by seasonal patterns of drying, and thereby predict potential long-term effects of climate change. We studied habitat quality for a declining tropical forest dwelling songbird, the wood thrush (Hylocichla mustelina), and tested the hypothesis that habitat moisture and arthropod abundance are drivers of body condition during the overwintering period. We examined habitat moisture, abundance of arthropods and fruit, and condition of individual birds (n = 418) in three habitat types--mature forest, mature forest with increased presence of human activity, and riparian scrub--from October to April. We found a strong pattern of habitat drying from October (wet season) to March (prior to spring migration) in all habitats, with concurrent declines in arthropod and fruit abundance. Body condition of birds also declined (estimated ~5 % decline over the wintering period), with no significant difference by habitat. Relatively poor condition (low body condition index, low fat and pectoral muscles scores) was equally apparent in all habitat types in March. Climate change is predicted to increase the severity of dry seasons in Central America, and our results suggest that this could negatively affect the condition of individual wood thrushes. PMID- 26001605 TI - Spatially structured environmental filtering of collembolan traits in late successional salt marsh vegetation. AB - Both the environment and the spatial configuration of habitat patches are important factors that shape community composition and affect species diversity patterns. Species have traits that allow them to respond to their environment. Our current knowledge on environment to species traits relationships is limited in spite of its potential importance for understanding community assembly and ecosystem function. The aim of our study was to examine the relative roles of environmental and spatial variables for the small-scale variation in Collembola (springtail) communities in a Dutch salt marsh. We used a trait-based approach in combination with spatial statistics and variance partitioning, between environmental and spatial variables, to examine the important ecological factors that drive community composition. Turnover of trait diversity across space was lower than for species diversity. Most of the variation in community composition was explained by small-scale spatial variation in topography, on a scale of 4-6 m, most likely because it determines the effect of inundation, which restricts where habitat generalists can persist. There were only small pure spatial effects on species and trait diversity, indicating that biotic interactions or dispersal limitation probably were less important for structuring the community at this scale. Our results suggest that for springtails, life form (i.e. whether they live in the soil or litter or on the surface/in vegetation) is an important and useful trait to understand community assembly. Hence, using traits in addition to species identity when analysing environment-organism relationships results in a better understanding of the factors affecting community composition. PMID- 26001606 TI - Habitat complexity reduces parasitoid foraging efficiency, but does not prevent orientation towards learned host plant odours. AB - It is well known that many parasitic wasps use herbivore-induced plant odours (HIPVs) to locate their inconspicuous host insects, and are often able to distinguish between slight differences in plant odour composition. However, few studies have examined parasitoid foraging behaviour under (semi-)field conditions. In nature, food plants of parasitoid hosts are often embedded in non host-plant assemblages that confer both structural and chemical complexity. By releasing both naive and experienced Cotesia glomerata females in outdoor tents, we studied how natural vegetation surrounding Pieris brassicae-infested Sinapis arvensis and Barbarea vulgaris plants influences their foraging efficiency as well as their ability to specifically orient towards the HIPVs of the host plant species on which they previously had a positive oviposition experience. Natural background vegetation reduced the host-encounter rate of naive C. glomerata females by 47 %. While associative learning of host plant HIPVs 1 day prior to foraging caused a 28 % increase in the overall foraging efficiency of C. glomerata, it did not reduce the negative influence of natural background vegetation. At the same time, however, females foraging in natural vegetation attacked more host patches on host-plant species on which they previously had a positive oviposition experience. We conclude that, even though the presence of natural vegetation reduces the foraging efficiency of C. glomerata, it does not prevent experienced female wasps from specifically orienting towards the host plant species from which they had learned the HIPVs. PMID- 26001607 TI - Inhibitory effects of soil biota are ameliorated by high plant diversity. AB - The idea that plant communities with high species diversity are more stable, productive, and resistant to invasion at small spatial scales has become an important ecological paradigm. Recently, the role of soil biota has emerged as a major driver of this relationship between plant species diversity and ecosystem function. In greenhouse experiments, we found that soil collected from experimentally constructed species-rich plant assemblages (that originally contained between 10 and 16 species) promoted the growth of 4 native target plant species more than soil from species-poor communities (that originally contained between 2 and 5 species). Sterilization of soils from species-poor communities improved the growth of these target species more than sterilization of soils from species-rich plant communities, indicative that inhibitory soil biota had greater negative impacts on plant growth in low versus high diversity soils. These results suggest that strong soil biota effects in soils do not simply accrue in experimental monocultures, but can occur in low diversity assemblages that are more realistic of what occurs in nature. Our findings suggest a mechanistic explanation for the diversity-productivity relationship, and further support the importance of inhibitory soil biota as significant contributors to spatial and temporal patterns of abundance in natural plant communities through negative plant-soil feedback. PMID- 26001608 TI - A porcine reproductive and respiratory syndrome virus (PRRSV) vaccine candidate based on the fusion protein of PRRSV glycoprotein 5 and the Toll-like Receptor-5 agonist Salmonella Typhimurium FljB. AB - BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is characterized by severe reproductive failure and severe pneumonia in neonatal pigs and is caused by PRRS virus (PRRSV). Glycoprotein 5 (GP5) from PRRSV is a key inducer of neutralizing antibodies. Flagellin, a toll-like receptor 5 (TLR-5) agonist, is an effective inducer of innate immune responses. This study presents a novel PRRSV vaccine candidate based on the adjuvant effect of Salmonella Typhimurium FljB fused with PRRSV GP5. RESULTS: A truncated rGP5 gene lacking the signal peptide and transmembrane sequences was amplified and inserted into prokaryotic expression vectors, pColdI or pGEX-6p-1. Salmonella Typhimurium flagellin fljB was amplified and inserted into the plasmid pCold-rGP5, generating recombinant plasmid pCold-rGP5-fljB. Histidine (His)-tagged rGP5 and fusion protein rGP5-FljB were induced with isopropyl-beta-d-thiogalactoside, verified by SDS-PAGE and western blotting, and purified via Ni-NTA affinity columns. The TLR-5-specific bioactivity of fusion protein rGP5-FljB was determined by detecting the expression levels of the cytokine IL-8 in HEK293-mTLR5 cells by sandwich ELISA. The purified endotoxin-free proteins were administered intraperitoneally in a C3H/HeJ mouse model. The results show that immunization with the fusion protein rGP5-FljB induced a significantly enhanced GP5-specific and PRRSV-specific IgG response that persisted for almost 5 weeks. Co-administration of the rGP5 with R848 or Alum also yielded a higher IgG response than administration of rGP5 alone. The IgG1/IgG2a ratio in the rGP5-FljB immunization group was significantly higher (9-fold) than that in the rGP5 alone group and was equivalent to the response in the rGP5 + Alum immunization group, suggesting a strong Th2 immune response was induced by the fusion protein. CONCLUSIONS: Purified fusion protein rGP5-FljB is capable of activating the innate immune response, as demonstrated by the results of our TLR-5-specific bioactivity assay, and FljB has adjuvant activity, as shown by the results from our administration of rGP5-FljB in a mouse model. Our findings confirm that FljB could serve as an excellent adjuvant for the production of GP5-specific and PRRSV-specific IgG antibodies as part of an induction of a robust humoral immune response. PMID- 26001609 TI - The prostatic urethral lift procedure: enough bang for the buck? PMID- 26001610 TI - Adherence to European Association of Urology Guidelines on Prophylactic Antibiotics: An Important Step in Antimicrobial Stewardship. AB - BACKGROUND: The evolution of resistant pathogens is a worldwide health crisis and adherence to European Association of Urology (EAU) guidelines on antibiotic prophylaxis may be an important way to improve antibiotic stewardship and reduce patient harm and costs. OBJECTIVE: To evaluate the prevalence of antibiotic resistant bacterial strains and health care costs during a period of adherence to EAU guidelines in a tertiary referral urologic institution. DESIGN, SETTING, AND PARTICIPANTS: A protocol for adherence to EAU guidelines for antibiotic prophylaxis for all urologic procedures was introduced in January 2011. Data for 3529 urologic procedures performed between January 2011 and December 2013 after protocol introduction were compared with data for 2619 procedures performed between January 2008 and December 2010 before protocol implementation. The prevalence of bacterial resistance and health care costs were compared between the two periods. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome measures were the proportion of resistant uropathogens and costs related to antibiotic consumption and symptomatic postoperative infection. We used chi2 and Fisher's exact tests to test the significance of differences. RESULTS AND LIMITATIONS: The proportion of patients with symptomatic postoperative infection did not differ (180/3529 [5.1%] vs. 117/2619 [4.5%]; p=0.27). A total of 342 isolates from all patients with symptomatic postoperative infections were analysed. The rate of resistance of Escherichia coli to piperacillin/tazobactam (9.1% vs. 5.4%; p=0.03), gentamicin (18.3% vs. 11.2%; p=0.02), and ciprofloxacin (32.3% vs. 19.1%; p=0.03) decreased significantly after protocol introduction. The defined daily dose (DDD) use of ciprofloxacin fell from 4.2 to 0.2 DDD per 100 patient-days after implementation (p<0.001). Antibiotic drug costs (?76,980 vs. ?36,700) and costs related to postoperative infections (?45,870 vs. ?29,560) decreased following introduction of the protocol (p<0.001). CONCLUSIONS: Adherence to EAU guidelines on antibiotic prophylaxis reduced antibiotic usage without increasing post-operative infection rate and lowered the prevalence of resistant uropathogens. PATIENT SUMMARY: We analysed the impact of adherence to European Association of Urology guidelines on antibiotic prophylaxis for all surgical urologic procedures on the prevalence of infections and resistant bacterial strains and on costs. We found that adherence to the guidelines reduced the rate of bacterial resistance, in particular against piperacillin/tazobactam, gentamicin, and ciprofloxacin, and reduced costs without increasing the risk of postoperative infection after urologic procedures. We recommend adherence to the guidelines as an important part of antibiotic stewardship programmes. PMID- 26001611 TI - Results of the first trial assessing adjuvant tyrosine kinase inhibitors in renal cell carcinoma do not reASSURE. PMID- 26001612 TI - Molecular subtyping of prostate cancer: a partnership model. PMID- 26001613 TI - Acute epididymitis: what you think is not always what you get. PMID- 26001614 TI - TNF compromises lysosome acidification and reduces alpha-synuclein degradation via autophagy in dopaminergic cells. AB - Tumor necrosis factor-alpha (TNF) is increasingly implicated as a critical pro inflammatory cytokine involved in chronic inflammation and neurodegeneration of Parkinson's disease (PD). However, the cellular and molecular events that lead to dopaminergic neuron degeneration are not fully understood. In this study, we demonstrated that microglia-released and recombinant TNF disrupted alpha synuclein (alpha-SYN) degradation and caused its accumulation in PC12 cells and midbrain neurons. At subtoxic doses, recombinant TNF was found to increase the number of LC3 puncta dots and LC3II protein level, associated with the increases of P62 protein level. Inhibition of lysosomal degradation with Bafilomycin A1 pretreatment abrogated the TNF-induced elevation in LC3II protein level whereas autophagy inhibitor 3-methyladenine did not affect it. Moreover, TNF led to a marked increase in the number of yellow LC3 dots with a marginal elevation in red only dots in RFP-GFP-tandem fluorescent LC3 (tf-LC3) transfected PC12 cells, implying the impairment in autophagic flux. Furthermore, TNF treatment reduced lysosomal acidification, as LysoTracker Red fluorescence and LysoSensor fluorescence shift from blue to yellow was markedly decreased in TNF-treated PC12 cells. Co-treatment with mammalian target of rapamycin kinase complex 1 (mTORC1) inhibitor PP242, which activated transcription factor EB (TFEB) signaling and lysosome biogenesis, partially rescued the accumulation of alpha-SYN in PC12 cells and midbrain neurons. Taken together, our results demonstrated that at subtoxic levels, TNF was able to impair autophagic flux and result in alpha-SYN accumulation by compromising lysosomal acidification in dopaminergic cells. This may represent a novel mechanism for TNF-induced dopaminergic neuron degeneration in PD. PMID- 26001615 TI - Intranigral administration of substance P receptor antagonist attenuated levodopa induced dyskinesia in a rat model of Parkinson's disease. AB - Levodopa (L-dopa) remains the most effective drug in the treatment of Parkinson's disease (PD). However, L-dopa-induced dyskinesia (LID) has hindered its use for PD patients. The mechanisms of LID are not fully understood. Substance P (SP) receptor antagonist has been shown to reduce parkinsonism in animal models of PD, and ameliorate LID in PD rats. But the concrete mechanism is not fully understood. To address this issue, we produced a rat model of PD using 6 hydroxydompamine (6-OHDA) injections, and valid PD rats were intranigrally administrated with different doses of SP receptor antagonist LY303870 (5 nmol/day, 10 nmol/day and 20 nmol/day) following L-dopa (6 mg/kg/day, i.p.) plus benserazide (12 mg/kg/day, i.p.) for 23 days. We found that nigral SP levels were increased on days 3, 7 and 14 and decreased on day 21 after 6-hydroxydompamine lesions. But nigral SP levels kept increasing after repeated L-dopa administration in PD rats. Intranigral administration of low and moderate LY303870 reduced abnormal involuntary movements (AIMs) while improving motor deficits in PD rats treated with L-dopa plus benserazide. Microdialysis revealed that LY303870 (10 nmol/day) treatment attenuated the increase of striatal dopamine and the reduction of gamma-aminobutyric acid in ventromedial thalamus of PD rats primed with L-dopa. Additionally, LY303870 (10 nmol/day) treatment prior to L-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa at Thr 34 and extracellular signal-regulated kinases 1/2 as well as the levels of activity regulated cytoskeleton-associated protein and Penk in L-dopa-primed PD rats. Taken together, these data showed that low and moderate SP receptor antagonists LY303870 could ameliorate LID via neurokinin 1 receptor without affecting therapeutic effect of L-dopa. PMID- 26001617 TI - Acute Paget-Schroetter syndrome: does the first rib routinely need to be removed after thrombolysis? AB - BACKGROUND: Most clinicians feel that treatment for patients with acute primary axillosubclavian vein thrombosis ("effort thrombosis") is catheter-directed thrombolysis followed by thoracic outlet decompression. Several investigators feel that first rib resection (FRR) is not indicated in every case. No randomized data exist to answer this question. METHODS: A MEDLINE search was done using the terms "Paget-Schroetter syndrome," "upper extremity DVT," "first rib resection," "effort thrombosis," and "primary upper extremity thrombosis," with thrombolysis used as an "AND" term. We also specifically explored references cited to support either side of this argument in the past. Analysis was limited to patients aged 18 years or older with symptoms of 14-day duration or less undergoing thrombolysis for primary axillosubclavian vein thrombosis. Those studies that did not report follow-up, duplicate series from the same institution, and those in which patients were stented were excluded. Results were analyzed on an intent-to treat basis, with groups assigned according to each authors' prospectively described algorithm. RESULTS: Twelve series were included. Patients were divided into 3 groups according to treatment after thrombolysis: FRR (448 patients), FRR plus endovenous balloon venoplasty (FRR + PLASTY; 68 patients), and those with no further intervention after thrombolysis (rib not removed; 168 patients). Symptom relief at last follow-up was significantly more likely in the FRR (95%) and FRR + PLASTY (93%) groups than in the rib not removed (54%) group (both <0.0001) as was patency (98%, 86%, and 48%, respectively; both <0.0001 vs. rib not removed). More than 40% of patients in the rib not removed group eventually required rib resection for recurrent symptoms. No differences in symptom-free rates were seen when comparing FRR with FRR + PLASTY. CONCLUSIONS: In patients with acute effort thrombosis who undergo thrombolysis, permanent symptom relief and long-term patency are more likely to be achieved in patients who undergo FRR with or without endovenous balloon venoplasty than those whose rib is left intact. PMID- 26001616 TI - Emergence of OXA-204 beta-lactamase in Tunisia. AB - A retrospective epidemiological survey was carried out to determine the prevalence of carbapenemase producers among enterobacterial clinical isolates recovered in the center of maternity and neonatology of Monastir (Tunisia). PCR screening identified 1 OXA-48 and 2 OXA-204 producers, which coexpressed the CTX M-15 or the CMY-4 beta-lactamases. PCR mapping showed that the bla(OXA-48) gene was carried by a Tn1999.2 transposon, whereas the bla(OXA-204) gene was part of the Tn2016 transposon-like structure. The OXA-48- or OXA-204-producing Klebsiella pneumoniae clinical isolates and the OXA-204-expressing Escherichia coli clinical isolate belonged to the widespread sequence types ST11, ST101, and ST617, respectively. The OXA-204 enzyme, which is a point derivative of the OXA-48 carbapenemase, had hitherto been reported in 2013 from K. pneumoniae isolate. Our study shows for the first time the dissemination of this resistance marker in E. coli strain. The coproduction of OXA-204 with CTX-M-15 and CMY-4 enzymes may potentiate the risk of multiresistance and may enhance the risk of dissemination. PMID- 26001618 TI - Treatment of popliteal artery aneurysms by means of cryopreserved homograft. AB - BACKGROUND: Autologous saphenous vein is considered the gold standard conduit in the femoral-popliteal revascularization for popliteal artery aneurysms (PAAs). In several cases, it may be absent or unsuitable for length or diameter and so it may be considered unfit for a conduit. In such patients, a synthetic graft or the endovascular correction can be useful, but results are controversial. In this retrospective case series, we have analyzed the safety and efficacy of the cryopreserved homograft (CHg) as a conduit in the PAA revascularization. METHODS: In the period between January 2005 and December 2013, 54 PAAs have been treated with an arterial CHg. Indications to surgery were asymptomatic aneurysm with >25 mm diameter in 30 cases (55.6%), ischemic symptoms in 20 (37%), and compressive symptoms in 4 (7.4%). An urgent treatment was performed in 8 cases (14.8%) for severe ischemic symptoms. All cases have been operated by the same vascular team: a posterior surgical approach was preferred whenever possible (33 cases, 61.1%). All patients received a clinical and radiologic follow-up, and all data were collected in a specific database. A >10-mm diameter increase of the conduit was considered significant for an aneurysmatic degeneration. RESULTS: The primary outcomes were complications and reoperation rate, limb salvage, and primary and secondary patency. Secondary outcome was the incidence of aneurysmatic degeneration of the CHg. Mean diameter of the homografts was 6.3 mm (range, 4-8 mm). In the 30-day postoperative period, 7 PAAs (13%) developed a complication: 3 wound infections, 3 graft thrombosis, and 1 anastomotic bleeding. Six cases needed a reoperation: 2 surgical revascularizations, 2 wound debridement, and 1 anastomotic hemostasis; 1 major amputation was necessary for graft failure after the revascularization. Mean follow-up was 34.8 months (range, 1-96). Five cases (9.3%) developed a graft complication with 4 reoperations necessary (7.4%): 2 grafts required a percutaneous transluminal angioplasty for a perigraft stenosis and 2 underwent a femorodistal bypass in CHg for severe ischemic symptoms after CHg occlusion. Another one CHg occlusion was treated conservatively because it was clinically asymptomatic. Primary patency was 96.3%, 93.9%, and 88.3% at 12, 36, and 60 months, respectively; secondary patency was 98.1% at 12, 36, and 60 months. Freedom from amputation resulted in 98.1%. No aneurysmatic degeneration was observed. Univariate and multivariate analysis showed urgent surgery to be independent risk factors for complications, reoperations, and CHg occlusion (P < 0.05). CONCLUSIONS: In this retrospective study, the use of CHg showed to be safe and effective in the surgery of PAAs, either in the short or in the long-term follow-up. Urgent surgery can be considered predictive of graft failure. In our experience, CHg can be considered a good alternative conduit to the autologous saphenous vein. PMID- 26001619 TI - Impact of qualitative and quantitative variations in nitrogen supply on catch-up growth in food-deprived-refed young rats. AB - BACKGROUND: Optimization of the refeeding strategy for the management of malnutrition in early life may enable to improve the quality of catch-up growth. While some data suggest better assimilation of peptides rather than whole proteins the evidence are scarce. OBJECTIVE: To compare the nutritional properties of peptides, partially hydrolyzed proteins or whole proteins in food deprived/refed young rats. METHODS: Male SD rats (n = 109, 60-70 g) were food deprived for 48 h and refed for 2-13 days. According to the set of experiments, refeeding was performed at 90% or 100% basal spontaneous intake or ad libitum with either peptide-, partially hydrolyzed protein- or whole protein-containing pediatric enteral nutrition formulas. Body weight, caloric intake and nitrogen balance were measured daily, intestinal trophicity was measured after two-day refeeding, and body composition was determined at the end of the refeeding period. RESULTS: A 2-day food deprivation in young rats led to significant body and organ weight losses, alterations of gut morphology, and decreased plasma citrulline, a marker of gut function. A cautious 2-day renutrition at 90% pre deprivation level did not restore nutritional status whatever the form of nitrogen supply. Ad libitum feeding was shown to be feasible with improved nitrogen efficiency. After 13 days, compared to chow diet, body weight gain was the lowest with peptide- and whole protein-containing diets, and significantly improved with partially hydrolyzed proteins with limited improvement in body lean mass (+8%, NS). Additional experiments indicated that in this model it will be necessary to significantly increase nitrogen supply in order to restore initial body weight and lean body mass. CONCLUSIONS: Our results show benefits of ad libitum refeeding on catch-up growth. Our data suggest that partially hydrolyzed proteins may be beneficial in terms of body weight gain but that probably their effectiveness may be improved with higher nitrogen supply. PMID- 26001620 TI - Role of surfactant derived intermediates in the efficacy and mechanism for radiation chemical degradation of a hydrophobic azo dye, 1-phenylazo-2-naphthol. AB - A combined methodology involving gamma and pulse radiolysis, product analysis and toxicity studies has been adopted to comprehend the degradation process of a model hydrophobic azo dye, 1-phenylazo-2-naphthol, emphasizing the role of the surfactant, which is an integral part of textile waste. Two new and important findings are underlined in this article. The first is the direct attestation of the hydrazyl radical-parent adduct, formed in the reaction of the dye with e(-)aq followed by protonation and subsequent addition to the unreacted dye molecule. This has been confirmed from concentration dependent studies. Secondly, we have clearly shown that in the reaction of hydroxyl radical with the dye in Triton X 100 media, the initially produced TX radicals cause reductive degradation of the dye. Identification and detailed analysis of HPLC and GCMS data reveals that similar products are formed in both the reactions of e(-)aq and OH radicals. Moreover, the cytotoxicity of 10(-4)moldm(-3) dye was found to be reduced significantly after irradiation. Thus, the present study not only depicts new pathways for the degradation of hydrophobic azo dye, but also demonstrates the role of a surfactant in the entire process. PMID- 26001621 TI - Three-dimensional Fe3O4-graphene macroscopic composites for arsenic and arsenate removal. AB - 3D graphene macroscopic gel synthesized via self-assembly of GO nanosheets under basic conditions at low temperature is modified with polydopamine and Fe3O4 nanoparticles. The modification of polydopamine can not only strengthen the 3D graphene-based macroscopic architecture but also enhance the loadage and binding ability of Fe3O4 nanoparticles. The synthesized 3D Fe3O4-graphene macroscopic composites are characterized by SEM, XRD, XPS, BET, Raman and magnetic property and used as a versatile adsorbent for sub-ppm concentration of As(III) and As(V) removal from aqueous solutions. The experimental results suggest that the synthesized 3D Fe3O4-graphene macroscopic composites are promising for treating low concentration of arsenic contaminated water. PMID- 26001622 TI - Nanoparticle formation in a chemical storage room as a new incidental nanoaerosol source at a nanomaterial workplace. AB - Chemical storage rooms located near engineered nanomaterials (ENMs) workplaces can be a significant source of unintentional nanoaerosol generation. A new incidental nanoparticle source was identified and characterized in a chemical storage room located at an ENMs workplace. Stationary and mobile measurements using on-line instruments and chemical analysis of volatile organic compounds (VOCs) were carried out to identify the source. The number of nanoaerosols emitted from the chemical storage room was found to be several orders of magnitude higher than that existing in the ENMs workplace. VOC analysis showed that the accumulated precursors and oxygenated VOCs in the chemical storage room could be attributed to incidental particle formation via gas-to-particle conversion. We stress the importance of identification of the incidental nanoaerosols to allow characterization of the nanoaerosols at ENMs workplaces, and to estimate additional nanoaerosols exposure, which was previously unknown. Hazardous chemical substances in the workplace have been regulated in many countries; however, most of the regulations are focused on gas-phase or liquid phase substances. The present study emphasizes the importance of secondary pollutants in particulate form that can be generated from the gas or liquid phase of hazardous chemical substances. PMID- 26001623 TI - Complexity and insidiousness of cryptic function loss mechanisms. PMID- 26001624 TI - An explanatory model of community pharmacists' support in the secondary prevention of cardiovascular disease. AB - BACKGROUND: Community pharmacists have faced ongoing challenges in the delivery of clinical pharmacy services. Various attitudinal and environmental factors have been found to be associated with the provision of general clinical pharmacy services or services which focus on a specific condition, including cardiovascular disease (CVD). However, the interrelationship and relative influence of explanatory factors has not been investigated. OBJECTIVE: To develop a model illustrating influences on CVD support provision by community pharmacists. METHODS: Mail surveys were sent to a random sample of 1350 Australian community pharmacies to investigate determinants of CVD support provision. A theoretical model modified from the Theory of Planned Behavior (TPB) was used as a framework for the survey instrument. Structural equation modeling was used to determine how pharmacists' attitudes and environmental factors influence CVD support. RESULTS: A response rate of 15.8% (209/1320) was obtained. The model for CVD support provision by community pharmacists demonstrated good fit: chi(2)/df = 1.403, RMSEA = 0.047 (90% CI = 0.031-0.062), CFI = 0.962, TLI = 0.955 and WRMR = 0.838. Factors found to predict CVD support included: two attitudinal latent factors ("subjective norms of pharmacists' role in CVD support" and "pharmacists' perceived responsibilities in CVD support") and environmental factors i.e. pharmacy infrastructure (documentation and a private area), workload, location; government funded pharmacy practice programs; and pharmacists' involvement with Continuing Professional Development and attendance at CVD courses. CONCLUSIONS: Pharmacists' attitudes appeared to be the strongest predictor of CVD support provision. The TPB framework was useful in identifying "subjective norms" and "pharmacists' beliefs" as key constructs of community pharmacists' attitudes. Community pharmacies would be able to provide such an advanced clinical service if they strongly believed that this was an acknowledged part of their scope of practice, had adequate infrastructure and employed sufficient numbers of pharmacists with appropriate and relevant knowledge. PMID- 26001625 TI - New Sources for Comparative Social Science: Historical Population Panel Data From East Asia. AB - Comparison and comparability lie at the heart of any comparative social science. Still, precise comparison is virtually impossible without using similar methods and similar data. In recent decades, social demographers, historians, and economic historians have compiled and made available a large number of micro level data sets of historical populations for North America and Europe. Studies using these data have already made important contributions to many academic disciplines. In a similar spirit, we introduce five new micro-level historical panel data sets from East Asia, including the China Multi-Generational Panel Dataset-Liaoning (CMGPD-LN) 1749-1909, the China Multi-Generational Panel Dataset Shuangcheng (CMGPD-SC) 1866-1913, the Japanese Ninbetsu-Aratame-Cho Population Register Database-Shimomoriya and Niita (NAC-SN) 1716-1870, the Korea Multi Generational Panel Dataset-Tansung (KMGPD-TS) 1678-1888, and the Colonial Taiwan Household Registration Database (CTHRD) 1906-1945. These data sets in total contain more than 3.7 million linked observations of 610,000 individuals and are the first such Asian data to be made available online or by application. We discuss the key features and historical institutions that originally collected these data; the subsequent processes by which the data were reconstructed into individual-level panels; their particular data limitations and strengths; and their potential for comparative social scientific research. PMID- 26001626 TI - Vesicovaginal fistulas: a gynecological experience in 41 cases at a German pelvic floor center. AB - PURPOSE: Etiology, diagnosis and management of vesicovaginal fistulas in women referred to the German pelvic floor center Tuebingen over a 9-year period of time were analyzed. METHODS: Records of 41 consecutive women suffering from vesicovaginal fistulas between February 2006 and February 2015 were reviewed retrospectively. RESULTS: In the German case series presented, the most common etiology of vesicovaginal fistulas was total abdominal hysterectomy. Other causes, in descending order of frequency, were abdominal radical hysterectomy, endometriosis surgery, total laparoscopical hysterectomy, vaginal hysterectomy, surgical treatment for ovarian cancer, radiotherapy, supracervical laparoscopic hysterectomy, surgery for genital malformation, cesarean section and forceps delivery. The transvaginal approach, for surgical fistula treatment, was primarily adopted whenever the primary or recurrent fistula was accessible vaginally because of its minimally invasive nature and low morbidity. The vesicovaginal fistula cure rate was 97.5 %. 36 out of 41 vesicovaginal fistulas were closed transvaginally. In one case, the postradiation vesicovaginal fistula could not be cured and the patient required urinary diversion. CONCLUSION: To avoid repeated surgeries, fistula management in specialized centers is advantageous. PMID- 26001627 TI - The Effect of Exercise on Respiratory Resistance in Athletes With and Without Paradoxical Vocal Fold Motion Disorder. AB - PURPOSE: An investigational, portable instrument was used to assess inspiratory (R(i)) and expiratory (R(e)) resistances during resting tidal breathing (RTB), postexercise breathing (PEB), and recovery breathing (RB) in athletes with and without paradoxical vocal fold motion disorder (PVFMD). METHOD: Prospective, controlled, repeated measures within-subject and between-groups design. Twenty four teenage female athletes, 12 with and 12 without PVFMD, breathed into the Airflow Perturbation Device for baseline measures of respiratory resistance and for two successive 1-min trials after treadmill running for up to 12 min. Exercise duration and dyspnea ratings were collected and compared across groups. RESULTS: Athletes with PVFMD had lower than control R(i) and R(e) values during RTB that significantly increased at PEB and decreased during RB. Control athletes' R(e) decreased significantly from RTB to PEB but not from PEB to RB, whereas R(i) did not change from RTB to PEB but decreased from PEB to RB. Athletes without PVFMD ran longer, providing lower dyspnea ratings. CONCLUSION: Immediately following exercise, athletes with PVFMD experienced increased respiratory resistance that affected their exercise performance. The difference in resting respiratory resistances between groups is intriguing and could point to anatomical differences or neural adaptation in teenagers with PVFMD. The Airflow Perturbation Device appears to be a clinically feasible tool that can provide insight into PVFMD and objective data for tracking treatment progress. PMID- 26001628 TI - "Plant or poison": A netnographic study of recreational use of 1,3 dimethylamylamine (DMAA). PMID- 26001630 TI - Developing and Implementing a Culture of Safety in the Dentoalveolar Surgical Practice. AB - The health care industry and delivery systems are placing greater emphasis on making their organizations safe. They do this by cultivating a culture of safety to help anticipate and prevent injuries and documenting and investigating injuries to develop prevention protocols. Many of the strategies used in the hospital industry can be applied to the dentoalveolar surgery practice of oral maxillofacial surgeons and other dentists. This article discusses the development of a culture of safety in the dentoalveolar practice and gives ideas of how threats of injuries to patients, guests, and the surgical care team can be reduced or eliminated. PMID- 26001629 TI - Improved tolerance of acute severe hypoxic stress in chronic hypoxic diaphragm is nitric oxide-dependent. AB - The effects of chronic hypoxia (CH) on respiratory muscle performance have hardly been investigated, despite clinical relevance. Results from recent studies are indicative of unique adaptive strategies in hypoxic diaphragm. Respiratory muscle tolerance of acute severe hypoxic stress was examined in normoxic and CH diaphragm in the presence and absence of a nitric oxide (NO) synthase inhibitor. We tested the hypothesis that improved tolerance of severe hypoxic stress in CH diaphragm is NO-dependent. Wistar rats were exposed to normoxia (sea-level, n = 6) or CH (ambient pressure = 380 mmHg, n = 6) for 6 weeks. Diaphragm muscle functional properties were determined ex vivo under severe hypoxic conditions (gassed with 95%N2/5% CO2) with and without 1 mM L-N(G)-nitroarginine (L-NNA, nNOS inhibitor). Fatigue tolerance, but not force, was significantly improved in CH diaphragm (p = 0.008). CH exposure did not affect diaphragm muscle fibre oxidative capacity determined from cluster analysis of area-density plots of muscle fibre succinate dehydrogenase activity. Acute NOS inhibition reduced diaphragm peak tetanic force (p = 0.018), irrespective of gas treatment, and completely reversed improved fatigue tolerance of the CH diaphragm. We conclude that CH exposure improves fatigue tolerance during acute severe hypoxic stress in an NO-dependent manner, independent of muscle fibre oxidative capacity. PMID- 26001631 TI - Safety of biologic and nonbiologic disease-modifying antirheumatic drug therapy in veterans with rheumatoid arthritis and hepatitis B virus infection: a retrospective cohort study. AB - INTRODUCTION: We evaluated the safety of current treatment regimens for patients with RA and HBV in a large US cohort. METHODS: We identified biologic and nonbiologic treatment episodes of RA patients using 1997 to 2011 national data from the US Veterans Health Administration. Eligible episodes had evidence of HBV infection (HBV surface antigen, HBV core antibody, HBV e-antibody and/or HBV DNA) and had a baseline alanine aminotransferase (ALT) <1.5 times the upper limit of laboratory normal within 90 days prior to initiation of a new biologic or nonbiologic DMARD. The main outcome of interest was hepatotoxicity, defined as ALT elevation >100 IU/mL. Results were reported as the cumulative incidence of treatment episodes achieving hepatotoxicity at 3, 6 and 12 months post biologic exposure. RESULTS: Five hundred sixty-six unique RA patients with HBV contributed 959 treatment episodes. Mean age was 62.1 +/- 10.3 years; 91.8% were male. Hepatotoxicity was uncommon, with 26 events identified among 959 episodes (2.7%) within 12 months. Hepatotoxicity was comparable between biologic and nonbiologic DMARDs (2.6% vs. 2.8%, P = 0.87). The median time between HBV screening and starting a new RA drug was 504 days (IQR 144, 1,163). Follow-up HBV testing occurred among 14 hepatotoxicity episodes (53.8%) at a median of 202 days (IQR 82, 716) from the date of ALT elevation. A total of 146 (15.2%) treatment episodes received at least one test for HBV DNA at any point in the observation period. CONCLUSIONS: Among US veterans with RA and HBV the risk of hepatotoxicity is low (2.7%), and comparable between biologic and nonbiologic DMARDS (2.8% vs. 2.6%, P = 0.87). HBV testing associated with DMARD initiation or hepatotoxicity was infrequent. PMID- 26001632 TI - Characterizing the effect of Bortezomib on Rift Valley Fever Virus multiplication. AB - Rift Valley Fever Virus (RVFV) belongs to the family Bunyaviridae and is a known cause of epizootics and epidemics in Africa and the Middle East. With no FDA approved therapeutics available to treat RVFV infection, understanding the interactions between the virus and the infected host is crucial to developing novel therapeutic strategies. Here, we investigated the requirement of the ubiquitin-proteasome system (UPS) for the establishment of a productive RVFV infection. It was previously shown that the UPS plays a central role in RVFV multiplication involving degradation of PKR and p62 subunit of TFIIH. Using the FDA-approved proteasome inhibitor Bortezomib, we observed robust inhibition of intracellular and extracellular viral loads. Bortezomib treatment did not affect the nuclear/cytoplasmic distribution of the non-structural S-segment protein (NSs); however, the ability of NSs to form nuclear filaments was abolished as a result of Bortezomib treatment. In silico ubiquitination prediction analysis predicted that known NSs interactors (SAP30, YY1, and mSin3A) have multiple putative ubiquitination sites, while NSs itself was not predicted to be ubiquitinated. Immunoprecipitation studies indicated a decrease in interaction between SAP30 - NSs, and mSin3A - NSs in the context of Bortezomib treatment. This decrease in association between SAP30 - NSs also correlated with a decrease in the ubiquitination status of SAP30 with Bortezomib treatment. Bortezomib treatment, however, resulted in increased ubiquitination of mSin3A, suggesting that Bortezomib dynamically affects the ubiquitination status of host proteins that interact with NSs. Finally, we observed that expression of interferon beta (IFN-beta) was increased in Bortezomib treated cells which indicated that the cellular antiviral mechanism was revived as a result of treatment and may contribute to control of viral multiplication. PMID- 26001633 TI - Health-related quality of life in patients with long-standing rheumatoid arthritis in the era of biologics: data from the German biologics register RABBIT. AB - OBJECTIVE: To compare the 24-month course of health-related quality of life (HRQoL) in patients with long-standing RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care. METHODS: Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment. HRQoL was captured by the SF36 health survey. Within strata of sequential bDMARD therapy, we examined patients' HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores. RESULTS: All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12. In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24. The improvement of HRQoL was not attributable to a particular bDMARD. The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%. CONCLUSION: Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure. Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population. PMID- 26001634 TI - Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience. AB - OBJECTIVES: Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. METHODS: We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. RESULTS: Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose >=30 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. CONCLUSION: TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis. PMID- 26001635 TI - Are patient-reported outcome instruments for ankylosing spondylitis fit for purpose for the axial spondyloarthritis patient? A qualitative and psychometric analysis. AB - OBJECTIVES: Several patient-reported outcome (PRO) instruments have been validated in AS. This study aims to evaluate several measurement properties of such PROs in a broad axial SpA (axSpA) population, including both AS and non radiographic axSpA (nr-axSpA) subpopulations. METHODS: PROs assessed were total and nocturnal back pain, patient global assessment of disease activity, BASDAI, BASFI and the 36-item Short Form Health Survey. A literature review and both clinician and patient qualitative interviews provided information on instrument content validity. Reliability (test-retest and internal consistency), construct validity (PROs, clinical-outcome correlations and known-groups validity) and PRO responsiveness were assessed. Data from the RAPID-axSpA trial (NCT01087762) investigating certolizumab pegol efficacy in axSpA, including relevant subpopulations, were utilized. RESULTS: Concepts identified for the broad axSpA population by both clinician and patient interviews were consistent with those identified through literature review of AS. All PROs demonstrated reliability in the RAPID-axSpA population (n = 325), with test-retest intraclass correlation coefficients and internal consistency Cronbach's alpha >0.8. Validity was supported by agreement between PROs and clinician-rated measures; except for the 36-item Short Form Health Survey Mental Components Summary, correlations between PROs and physician global assessment of disease activity ranged from 0.28 to 0.42 for week 0 and from 0.53 to 0.65 for week 24. PRO measures showed good sensitivity to change (effect size >0.8) at weeks 12 and 24 for responders. No variations in measurement properties were noted between the subpopulations. CONCLUSION: This study indicates that both content validity and measurement properties of PRO instruments utilized in AS are preserved in the broad axSpA population. PMID- 26001636 TI - Evaluation of sperm nuclear integrity in patients with different percentages of decapitated sperm in ejaculates. AB - The decapitated sperm defect is a rare type of teratozoospermia responsible for male infertility. Spermatozoa from patients affected by this syndrome are used for intracytoplasmic sperm injection (ICSI) although little is known about their DNA integrity. This study evaluated sperm nuclear alterations in four patients and ten fertile men (control group). Sperm samples were examined by light, transmission electron and high-magnification contrast microscopy and analysed after terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling, aniline blue staining and fluorescence in-situ hybridization. Spermatozoa from patients presented varying degrees of decapitation, along with morphological and ultrastructural head abnormalities. Whereas the proportion of spermatozoa with fragmented DNA and numerical chromosome abnormalities was similar in patients 1-3 and controls, the percentage of spermatozoa with hypocondensed chromatin was higher in patients 1-3 than in fertile men. Patient 4 presented a distinct phenotype, with an increased proportion of flagellated spermatozoa with DNA strand breaks as well as increased aneuploidy and diploidy rates compared with controls and with patients 1-3. No successful pregnancy resulted from ICSI although embryos were obtained for three patients. The morphological defects and the nuclear alterations observed in spermatozoa of patients with the decapitated sperm syndrome may have contributed to ICSI failures. PMID- 26001637 TI - [Hepatic bruceloma: Therapeutic approach]. PMID- 26001638 TI - The transfer function of neuron spike. AB - The mathematical modeling of neuronal signals is a relevant problem in neuroscience. The complexity of the neuron behavior, however, makes this problem a particularly difficult task. Here, we propose a discrete-time linear time invariant (LTI) model with a rational function in order to represent the neuronal spike detected by an electrode located in the surroundings of the nerve cell. The model is presented as a cascade association of two subsystems: one that generates an action potential from an input stimulus, and one that represents the medium between the cell and the electrode. The suggested approach employs system identification and signal processing concepts, and is dissociated from any considerations about the biophysical processes of the neuronal cell, providing a low-complexity alternative to model the neuronal spike. The model is validated by using in vivo experimental readings of intracellular and extracellular signals. A computational simulation of the model is presented in order to assess its proximity to the neuronal signal and to observe the variability of the estimated parameters. The implications of the results are discussed in the context of spike sorting. PMID- 26001639 TI - Six years beyond pediatric trauma: child and parental ratings of children's health-related quality of life in relation to parental mental health. AB - PURPOSE: To examine the relationship between child self-report and parent proxy report of health-related quality of life (HRQL) and how parents' mental health status relates to the HRQL ratings 6 years after minor to severe injury of the child. MATERIALS AND METHODS: This cross-sectional cohort study was performed at a regional pediatric trauma center in Stockholm, Sweden. The PedsQL 4.0 versions for ages 5-7, 8-12, and 13-18 years were completed by 177 child-parent dyads 6 years after injury to the child. The parents also rated their own mental health through the mental health domain (MH) in the SF-36 Health Survey. RESULTS: The children's median age was 13 years (IQR 10-16 years), 54 % were males, and the median ISS was 5 (IQR 2-9). Most of the parents were female (77 %), born in Sweden (79 %), and half had university degrees. There was no statistically significant difference between child self-report and parent proxy report in any of the PedsQL 4.0 scales or summary scales. The levels of agreement between child self-report and parent proxy reports were excellent (ICC >= 0.80) for all scales with the exception of emotional functioning (ICC 0.53) which also was the scale with the lowest internal consistency in child self-report (alpha 0.60). Multiple regression analyses showed that worse parental mental health status correlated with worse child self-report and parent proxy report of children's HRQL. CONCLUSIONS: Children and their parents' reports on child's HRQL were in agreement. Decreased mental health in parents was associated with lower scores on parent proxy reports and child self-reports of HRQL after injury. The current investigation highlights the possible relationship between parent's mental health status and children's HRQL long after an injury, which should be considered in future investigations and in clinical care. PMID- 26001640 TI - Medication adherence on quality of life among adults with type 2 diabetes mellitus: an exploratory analysis on the EDDMQoL study. AB - PURPOSE: This study examined the association between medication adherence (MA) and health-related quality of life (HRQoL) among the adult type 2 diabetes mellitus at the primary care level. METHODS: In this cross-sectional study, the 8 item Morisky Medication Adherence Scale (MMAS) was the main independent variable and the World Health Organization Quality of Life-Brief the dependent variable. Besides socio-demographic data, diabetes-related distress (DRD) and depression (DS) were included as covariates. Independent association between the MMAS score and HRQoL was done using multiple linear regression. RESULTS: The participants' response rate was 93.1 % (700/752). Majorities were female (52.8 %), Malay (52.9 %) and married (79.1 %). The mean (SD) for age and the MMAS score was 56.9 (10.18) and 5.6 (1.42), respectively. MMAS total score correlated significantly with all HRQoL domains: overall QoL (OQoL) (r = 0.17), physical QoL (r = 0.11), psychological QoL (r = 0.10), social relationship QoL (r = 0.15) and environmental QoL (EQoL) (r = 0.18). After adjustment for covariates (age, gender, ethnicity, religion, education, income, exercise, macrovascular complications, DRD and DS), MA had persistent effects on OQoL (B = 0.53, 95 % CI 0.012-1.048) and EQoL (B = 0.95, 95 % CI 0.235-1.667). CONCLUSION: MA showed prevalent correlation and positive effects on the domains of HRQoL. Despite the small effects of MA on HRQoL, the sheer presence of the independent effects provides healthcare providers good reason for initiative and intervention to improve MA, which would improve quality of life. PMID- 26001643 TI - Wyrm: A Brain-Computer Interface Toolbox in Python. AB - In the last years Python has gained more and more traction in the scientific community. Projects like NumPy, SciPy, and Matplotlib have created a strong foundation for scientific computing in Python and machine learning packages like scikit-learn or packages for data analysis like Pandas are building on top of it. In this paper we present Wyrm ( https://github.com/bbci/wyrm ), an open source BCI toolbox in Python. Wyrm is applicable to a broad range of neuroscientific problems. It can be used as a toolbox for analysis and visualization of neurophysiological data and in real-time settings, like an online BCI application. In order to prevent software defects, Wyrm makes extensive use of unit testing. We will explain the key aspects of Wyrm's software architecture and design decisions for its data structure, and demonstrate and validate the use of our toolbox by presenting our approach to the classification tasks of two different data sets from the BCI Competition III. Furthermore, we will give a brief analysis of the data sets using our toolbox, and demonstrate how we implemented an online experiment using Wyrm. With Wyrm we add the final piece to our ongoing effort to provide a complete, free and open source BCI system in Python. PMID- 26001644 TI - The effects of remodeling with heart failure on mode of initiation of ventricular fibrillation and its spatiotemporal organization. AB - PURPOSE: The effect of the heart failure substrate on the initiation of ventricular fibrillation (VF) and its resulting mechanism is not known. The objective of this study was to determine the effects of substrate on VF initiation and its spatiotemporal organization in the heart failure model. METHODS: Optical action potentials were recorded from LV wedge preparations either from structurally normal hearts (control, n = 11) or from congestive heart failure (CHF; n = 7), at the epicardial surface, endocardial surface which included a papillary muscle, and a transmural cross section. Action potential duration (APD(80)) was determined, and VF was initiated. A fast Fourier transform was calculated, and the dominant frequency (DF) was determined. RESULTS: The CHF group showed increased VF vulnerability (69 vs 26 %, p < 0.03), and every mapped surface showed an APD(80) gradient which included islands of higher APDs on the transmural surface (M cells) which was not observed in controls. VF in the CHF group was characterized by stable, discrete, high-DF areas that correlated to either foci or spiral waves located on the transmural surface at the site of the papillary muscle. Overall, the top 10 % of DFs correlated to an APD of 101 ms while the bottom 10 % of DFs correlated to an APD of 126 ms (p < 0.01). CONCLUSIONS: In the CHF model, APD gradients correlated with an increased vulnerability to VF, and the highest stable DFs were located on the transmural surface which was not seen in controls. This indicates that the CHF substrate creates unique APD and DF characteristics. PMID- 26001648 TI - Periodontal changes after surgically assisted rapid maxillary expansion (SARME). AB - PURPOSE: The objective of the present study was to evaluate the health status of the periodontal tissue after surgically assisted rapid maxillary expansion (SARME). METHODS: Periodontal status was assessed after an average of 25 months (range, 6-66) in 61 patients who underwent SARME by plaque index, gingival index, probing depth, and probing attachment level. In the maxilla, six measurements were made at the central incisor, second premolar, and first molar. Corresponding measurements were made in the mandible as control. The measurements were estimated and expressed with 95 % confidence interval (CI). Additionally, maxillary occlusal radiographs of the maxillary central incisors were evaluated for signs of root resorption. RESULTS: There was no statistically significant difference between experimental and control teeth with respect to plaque index, probing depth, or attachment level. The gingival index of the maxillary central incisor was significantly higher compared to control (CI 0.175 (0.09-0.26), p value p < 0.001). External apical root resorption of the anterior maxillary teeth was observed in 36 % of the patients. CONCLUSIONS: Within the limitations of a retrospective study, the present study seems to demonstrate that SARME does not affect the health status of the periodontal tissues. However, further randomized long-term studies are needed before final conclusions can be provided. PMID- 26001645 TI - Components of Cognitive Behavioral Therapy Related to Outcome in Childhood Anxiety Disorders. AB - The present article uses meta-analysis to examine treatment components related to outcome within 35 randomized controlled trials (RCTs) for childhood anxiety disorders (CADs) and eight RCTs for childhood obsessive compulsive disorder (OCD). Examination of the RCTs of cognitive behavioral therapy (CBT) for CADs suggested that adding relaxation and delaying exposures until after the introduction of other anxiety management strategies does not increase the efficacy of exposure-based treatment. In addition, compared to the large effect size (ES) associated with exposure and response prevention (ERP) for OCD (k = 9, mean ES = 1.93), the effect size associated with CBT for CADs (k = 44, mean ES = 0.89) did not differentiate from attention placebo (k = 11, mean ES = 0.55), although it was more effective than waitlist control (k = 24, mean ES = 0.22). Instructively, ERP for OCD involved more exposure initiated earlier and less relaxation than CBT for CADs. In addition, RCTs of ERP were more likely to use clinician-administered measures as opposed to self-report and to be conducted in clinical versus recruited samples. These results suggest that dismantling studies using a gold-standard clinician-rated outcome measure to compare the value of adding anxiety management strategies to exposure will be necessary to increase the efficacy of CBT for CADs to levels achieved by ERP for OCD. PMID- 26001649 TI - ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection. AB - Gammaherpesviruses are cancer-associated pathogens that establish life-long infection in most adults. Insufficiency of Ataxia-Telangiectasia mutated (ATM) kinase leads to a poor control of chronic gammaherpesvirus infection via an unknown mechanism that likely involves a suboptimal antiviral response. In contrast to the phenotype in the intact host, ATM facilitates gammaherpesvirus reactivation and replication in vitro. We hypothesized that ATM mediates both pro and antiviral activities to regulate chronic gammaherpesvirus infection in an immunocompetent host. To test the proposed proviral activity of ATM in vivo, we generated mice with ATM deficiency limited to myeloid cells. Myeloid-specific ATM deficiency attenuated gammaherpesvirus infection during the establishment of viral latency. The results of our study uncover a proviral role of ATM in the context of gammaherpesvirus infection in vivo and support a model where ATM combines pro- and antiviral functions to facilitate both gammaherpesvirus specific T cell immune response and viral reactivation in vivo. PMID- 26001651 TI - Nutriepigenomics: the role of nutrition in epigenetic control of human diseases. AB - PURPOSE OF REVIEW: Nutrients or even diets affect the epigenome by lifelong remodeling. Nutritional imbalances are associated with noncommunicable diseases. Thus, nutriepigenomics is a promising field in the treatment of complex human diseases. RECENT FINDINGS: The epigenome is susceptible to changes and can be shaped by nutritional states, especially in prenatal period through transgenerational mechanisms and in early postnatal life when critical developmental processes are taking place. Although more stable, the epigenetic marks in adulthood are also dynamic and modifiable by environmental factors including diet. SUMMARY: The present review is focused on the most recent knowledge of epigenetically active nutrients/diets including transgenerational inheritance and prenatal predispositions related to increased risk for cancer, metabolic syndrome, and neurodegenerative diseases. PMID- 26001650 TI - A case of metastatic renal cell carcinoma and bile duct carcinoma treated with a combination of sunitinib and gemcitabine. AB - BACKGROUND: Metastatic renal cell carcinoma (mRCC) had been a chemo-refractory disease, but recent advances in multiple kinase inhibitors such as sunitinib have dramatically changed the clinical course of mRCC. Sunitinib is used for mRCC chemotherapy based on the favorable results of a recent clinical trial, but specific biomarkers predicting efficacy and safety are not yet available. Locally advanced bile duct carcinoma (BDC) has generally been treated with single agent gemcitabine or as doublet therapy with cisplatin. Concomitant occurrence of mRCC and BDC is extremely rare, and a standard therapeutic strategy has not been established. CASE PRESENTATION: A 65-year-old woman was diagnosed as having multiple mRCC and intercurrent, locally advanced BDC. A single course of combination therapy with sunitinib (25 mg/day, day2-15) and gemcitabine (750 mg/m(2), days 1, 8) was administered, and this showed obvious effects, with partial response for mRCC and stable disease for BDC. However, the patient also experienced severe adverse events, including hematological and various non hematological toxicities; the combination therapy was then terminated on day 13 after its initiation. She recovered on day 28 and is alive 3.5 years after the diagnosis. The plasma trough levels of sunitinib and its active metabolite SU12662 on day 13 were 91.5 ng/mL and 19.2 ng/mL, respectively, which were relatively higher than in previous reports. Analysis of her single nucleotide polymorphisms (SNPs) detected TC in ABCB1 3435C/T, TC in 1236C/T and TT in 2677G/T, suggesting a possible TTT haplotype. CONCLUSION: A rare case of double cancer of mRCC and BDC was treated by combination chemotherapy. Although unknown synergistic mechanisms of these agents may be involved, severe toxicities might be possibly associated with high sunitinib exposure. Further exploration of combination therapy with sunitinib and gemcitabine is required. PMID- 26001652 TI - Hepatic glycogen storage disorders: what have we learned in recent years? AB - PURPOSE OF REVIEW: Glycogen storage disorders (GSDs) are inborn errors of metabolism with abnormal storage or utilization of glycogen. The present review focuses on recent advances in hepatic GSD types I, III and VI/IX, with emphasis on clinical aspects and treatment. RECENT FINDINGS: Evidence accumulates that poor metabolic control is a risk factor for the development of long-term complications, such as liver adenomas, low bone density/osteoporosis, and kidney disease in GSD I. However, mechanisms leading to these complications remain poorly understood and are being investigated. Molecular causes underlying neutropenia and neutrophil dysfunction in GSD I have been elucidated. Case series provide new insights into the natural course and outcome of GSD types VI and IX. For GSD III, a high protein/fat diet has been reported to improve (cardio)myopathy, but the beneficial effect of this dietary concept on muscle and liver disease manifestations needs to be further established in prospective studies. SUMMARY: Although further knowledge has been gained regarding pathophysiology, disease course, treatment, and complications of hepatic GSDs, more controlled prospective studies are needed to assess effects of different dietary and medical treatment options on long-term outcome and quality of life. PMID- 26001653 TI - Exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus. AB - PURPOSE OF REVIEW: The primary focus of this review is threefold: first, to summarize available knowledge on exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus (T1DM); second, to elucidate physiological mechanisms predisposing to glycemic variations in patients in T1DM; and third, to describe novel approaches derived from physiological perceptions applicable to stabilize exercise-related glycemia in individuals with T1DM. RECENT FINDINGS: Recent studies corroborate the concept that despite partial differences in counter-regulatory mechanisms individuals with T1DM do not fundamentally differ in their glucose response to exercise when compared with healthy individuals if studies are performed under standardized conditions with insulin and glucose levels held close to physiological ranges. Novel approaches derived from a better understanding of exercise-associated glucose metabolism (e.g., the concept of intermittent high-intensity exercise) may provide alternative ways to master the challenges imposed by exercise to individuals with T1DM. SUMMARY: Exercise still imposes high demands on patients with T1DM and increases risks for hypoglycemia and hyperglycemia. Deeper insight into the associated metabolic pathways has revealed novel options to stabilize exercise associated glucose levels in these patients. PMID- 26001654 TI - Intestinal nutrient sensing and blood glucose control. AB - PURPOSE OF REVIEW: Nutrient-specific sensor systems in enteroendocrine cells detect intestinal contents and cause gut hormone release upon activation. Among these peptide hormones, the incretins glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 are of particular interest by their role in glucose homeostasis, metabolic control and for proper beta-cell function. This review focuses on intestinal nutrient-sensing processes and their role in health and disease. RECENT FINDINGS: All macronutrients, respectively, their digestion products can cause incretin release by targeting specific sensors. Luminal glucose is the strongest stimulant for incretin release with the Na-dependent glucose transporter as the prime sensor. For peptides, the H-dependent peptide transporter together with calcium-sensing-receptor act as a sensing system. That transporters can function as nutrient-sensing 'transceptors' is conceptually new as G-protein coupled receptors so far were thought to be the sensing entities. This still holds true for GPR40 and GPR120 as sensors for medium/long-chain fatty acids and GPR41 and GPR43 for microbiota-derived short-chain fatty acids. Synthetic agonists for these receptors show impressive effects on glucagon-like peptide 1 output and glycemic control. Moreover, the remarkable and immediate antidiabetic effects of bariatric surgery/gastric bypass put intestinal nutrient sensing into focus of new strategies for metabolic control. SUMMARY: Targeting the intestinal nutrient-sensing machinery by dietary and/or pharmacological means holds promises in particular for treatment of type 2 diabetes. This interest may help to better understand the nutrient-sensing processes and the involvement of the intestine in overall endocrine, neuronal and metabolic control. PMID- 26001655 TI - Metabolic and mind shifts: from glucose to glutamine and acetate addictions in cancer. AB - PURPOSE OF REVIEW: Glutamine and acetate were recently identified as alternatives to glucose for fueling the tricarboxylic acid (TCA) cycle in cancer cells, particularly in the context of hypoxia. RECENT FINDINGS: Molecular mechanisms orchestrating glutamine and acetate metabolism were elicited through the combination of C tracer analysis and genetic silencing, or pharmacological modulation of key metabolic enzymes including those converting glutamate into alpha-ketoglutarate (alphaKG) (and beyond) and acetate into acetyl-coenzyme A (CoA). SUMMARY: Oxidative decarboxylation and reductive carboxylation of alphaKG represent two options for the glutamine metabolism. The canonical forward mode of the TCA cycle fuelled by glutamine may benefit from the decarboxylation of malate into pyruvate for fueling pyruvate dehydrogenase and generating acetyl-CoA to offer a self-sustainable TCA cycle. Under hypoxia and mutations in the TCA cycle, the reductive carboxylation of glutamine-derived alphaKG into citrate mainly supports lipogenesis via the ATP citrate lyase that cleaves citrate into oxaloacetate and acetyl-CoA. Still, a largely unsuspected source of acetyl-CoA was shown to derive from the direct ligation of acetate to CoA by acetyl-CoA synthetases. Altogether, these findings identify critical metabolic nodes in the glutamine and acetate metabolism as new determinants of tumor metabolic plasticity that may facilitate the design of synthetic lethal treatments. PMID- 26001656 TI - Galactose metabolism and health. AB - PURPOSE OF REVIEW: Galactose - a key source of energy and a crucial structural element in complex molecules - is particularly important for early human development. However, galactose metabolism might be important not only for fetal and neonatal development but also for adulthood, as evidenced by the inherited disorders of galactose metabolism. The purpose of this review is to summarize the current evidence of galactose metabolism in health and disease. RECENT FINDINGS: The biological importance of galactose goes beyond its importance as a nutrient and a metabolite. Galactose has been selected by evolutionary pressure to exert also a crucial structural role in macromolecules. Additionally, galactose has recently been reported as beneficial in a number of diseases, particularly in those affecting the brain. SUMMARY: Galactose is crucial for human metabolism, with an established role in energy delivery and galactosylation of complex molecules, and evidence for other roles is emerging. PMID- 26001657 TI - The Usefulness of 0.2% Topical Nitroglycerin for Chondrodermatitis Nodularis Helicis. AB - BACKGROUND AND OBJECTIVE: Chondrodermatitis nodularis helicis (CNH) is a painful idiopathic degenerative condition involving the skin and cartilage of the helix or antihelix of the ear. Topical nitroglycerin 2% is a relatively recent treatment option for CNH that has produced good results, although with adverse effects (17% of cases). The use of a lower concentration would probably achieve similar results with fewer adverse effects. The aim of this study was to evaluate the effectiveness and safety of topical nitroglycerin 0.2% in the treatment of CNH. MATERIAL AND METHODS: We performed a retrospective observational study of patients treated in 2 Spanish hospitals between 2012 and 2014. The effectiveness of treatment was determined by clinical photography and assessment of symptoms using a verbal numerical rating scale. RESULTS: Of the 29 patients treated, 93% showed clinical improvement. In the group of responders, mean treatment duration was 1.8 months and mean follow-up was 5.9 months. Overall tolerance was good in all cases. CONCLUSION: Topical nitroglycerin 0.2% is an effective and well tolerated conservative treatment option that improves the appearance of lesions and provides symptomatic relief in the majority of patients with CNH. PMID- 26001658 TI - Adrenal tuberculosis mimicking a malignancy by direct hepatic invasion: emphasis on adrenohepatic fusion as the potential route. AB - A 64-year-old female with primary adrenal insufficiency presented with a right adrenal mass showing quantitative nonadenoma features on dedicated adrenal computed tomography (CT). CT showed direct invasion of the mass to the adjacent hepatic parenchyma, and high uptake was noted on 18F-fluorodeoxyglucose positron emission tomography/CT. Laparoscopy revealed gross invasion of the adrenal lesion into the liver, which led to the en bloc resection including the involved liver. Polymerase chain reaction analysis of the surgical specimen revealed adrenal tuberculosis. PMID- 26001659 TI - Optimal cut-off value of perfusion parameters for diagnosing prostate cancer and for assessing aggressiveness associated with Gleason score. AB - To determine cut-off value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters for differentiation of prostate malignant from benign and cancer with high-grade Gleason score (GS) (GS>7) from low-grade GS (GS<=7), 35 patients (24 malignant and 11 benign) who underwent DCE-MRI were included. Difference between malignant and benign was statistically significant for all magnetic resonance parameters except Ve. The cut-off values were K(trans)=0.184min(-1), Kep=0.695min(-1), iAUC=4.219mmol/l/min, and ADC=1340.5mm(2)/s. A significant difference in mean values of K(trans) and Kep between cancer with high-grade GS and low-grade GS was also observed. K(trans) and Kep showed a significant correlation with GS. PMID- 26001660 TI - Massive superior mesenteric venous aneurysm with portal venous thrombosis. AB - Portal venous aneurysm is a rare and sometimes dangerous vascular pathology, which can result in thrombosis or rupture. We present the computed tomography, magnetic resonance, and sonographic imaging of a 27-year-old man with superior mesenteric venous aneurysm and subsequent thrombosis following acute pancreatitis. This multimodality imaging approach can prove useful in the evaluation of these rare aneurysms. PMID- 26001661 TI - Mortality and secular trend in the incidence of bipolar disorder. AB - BACKGROUND: The world-wide interest in bipolar disorder is illustrated by an exponential increase in publications on the disorder registered in Pubmed since 1990. This inspired an investigation of the epidemiology of bipolar disorder. METHODS: This was a register-based cohort study. All first-ever diagnoses of bipolar disorder (International Classification of Diseases-10: F31) were identified in the nationwide Danish Psychiatric Central Research Register between 1995 and 2012. Causes of death were obtained from The Danish Register of Causes of Death. Age- and gender standardized incidence rates, standardized mortality ratio (SMR) and Kaplan-Meier survival estimates were calculated. RESULTS: We identified 15,334 incident cases of bipolar disorder. The incidence rate increased from 18.5/100,000 person-years (PY) in 1995 to 28.4/100,000 PY in 2012. The mean age at time of diagnosis decreased significantly from 54.5 years in 1995 to 42.4 years in 2012 (p<0.001). The mean time from first affective diagnosis to diagnosis of bipolar disorder was 7.9 years (SD 9.1). The SMR was 1.7 (95%-CI 1.2 2.1). Causes of death were mainly natural; 9% died from suicide. LIMITATIONS: Only patients in psychiatric care were included. The outpatient registry opened in 1995. Patients treated solely in outpatient units are not recorded previously. Systematic studies validating all the clinical diagnoses of the registry do not exist. CONCLUSIONS: The incidence of bipolar disorder has increased in the last 10 years. The SMR was significantly increased. Half of the patients were known to have another affective disorder. This should be considered in future decisions regarding the healthcare organization. PMID- 26001662 TI - Prospective progression from high-prevalence disorders to bipolar disorder: Exploring characteristics of pre-illness stages. AB - BACKGROUND: Identification of risk factors within precursor syndromes, such as depression, anxiety or substance use disorders (SUD), might help to pinpoint high risk stages where preventive interventions for Bipolar Disorder (BD) could be evaluated. METHODS: We examined baseline demographic, clinical, quality of life, and temperament measures along with risk clusters among 52 young people seeking help for depression, anxiety or SUDs without psychosis or BD. The risk clusters included Bipolar At-Risk (BAR) and the Bipolarity Index as measures of bipolarity and the Ultra-High Risk assessment for psychosis. The participants were followed up for 12 months to identify conversion to BD. Those who converted and did not convert to BD were compared using Chi-Square and Mann Whitney U tests. RESULTS: The sample was predominantly female (85%) and a majority had prior treatment (64%). Four participants converted to BD over the 1-year follow up period. Having an alcohol use disorder at baseline (75% vs 8%, chi(2)=14.1, p<0.001) or a family history of SUD (67% vs 12.5%, chi(2)=6.0, p=0.01) were associated with development of BD. The sub-threshold mania subgroup of BAR criteria was also associated with 12-month BD outcomes. The severity of depressive symptoms and cannabis use had high effects sizes of association with BD outcomes, without statistical significance. CONCLUSIONS AND LIMITATIONS: The small number of conversions limited the power of the study to identify associations with risk factors that have previously been reported to predict BD. However, subthreshold affective symptoms and SUDs might predict the onset of BD among help-seeking young people with high-prevalence disorders. PMID- 26001663 TI - Aberrant connectivity within the default mode network in first-episode, treatment naive major depressive disorder. AB - BACKGROUND: Convergent studies have highlighted the dysfunction of default mode network (DMN) in major depressive disorder (MDD). The altered connectivity in posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) was especially found to be of interest in the resting state functional connectivity analysis. Recently, more attention has turned to the internal functional connectivity within the DMN. However, the internal connection patterns within the DMN remain unclear at the initial onset of MDD. METHODS: Resting-state fMRI was performed on 38 first-episode, treatment-naive MDD patients along with 38 matched healthy controls. Seed-based analysis was used to define the DMN and then a region-to-region connectivity analysis was performed to inspect the functional connectivity within the DMN. Spearman's rank correlation analysis was performed between significantly abnormal connectivities in MDD patients and clinical measurements. RESULTS: Decreased region-to-region connectivities within DMN were found between the PCC and dorsal medial prefrontal cortex (dmPFC), between PCC and the right inferior parietal gyrus/angular, as well as between the left thalamus and cerebellar tonsil. No significant increase in connectivity was found. Moreover, functional connectivity between the left thalamus and cerebellar tonsil revealed a marginal significant negative correlation with clinical Hamilton Depression Rating Scale (HDRS) scores. LIMITATIONS: Noteworthiness in morbidity, a high risk of mortality, and a high rate of medical service utilization of MDD make the current results uncertain to apply to the more complicated situations. CONCLUSIONS: Each region within DMN may have a specific, individual functional role. The reason to identify the pathological mechanism of MDD may not lie in the abnormal DMN functional connectivity, but rather in the abnormal functional connectivity within DMN. PMID- 26001664 TI - Comparison of precipitating factors for mania and partial seizures: Indicative of shared pathophysiology? AB - OBJECTIVES: Mania in bipolar disorder (BD) and partial (focal) seizures (PS) arising from the temporal lobes, have a number of similarities. Typically, a chronic course of the disorders is punctuated by acute illness episodes. Common features of episodes may include sensory, perceptual, cognitive and affective changes. Both respond to anticonvulsant treatment. Common mechanisms imputed include neurotransmitters and kindling processes. Further investigation may improve understanding of the occurrence of both mania and PS, casting light on the relevance of temporal lobe mediated processes and pathology. One avenue of investigation is to compare aetiological factors and determine the extent of overlap which may indicate shared brain localization or pathophysiology. Aetiology includes predisposing, precipitating or perpetuating factors. This paper examines the literature on precipitating factors of mania, first or subsequent episode, and of PS in diagnosed epilepsy, which is the second or subsequent seizure, to identify the extent and nature of their overlap. METHOD: Narrative review based on a literature search of PubMed and Google Scholar. RESULTS: Precipitating factors for both mania and PS were stress, sleep deprivation, antidepressant medication and, tentatively, emotion. For mania alone, goal-attainment events, spring and summer season, postpartum, and drugs include steroids and stimulants. For PS alone, winter season, menstruation and specific triggers in complex reflex epilepsies. Those not substantiated include lunar phase and menopause. A wide range of chemicals may provoke isolated seizures but by definition epilepsy requires at least two seizures. CONCLUSIONS: The overlap of precipitating factors in mania and PS imply that common brain processes may contribute to both, consistent with findings from neuroscience research. PMID- 26001665 TI - The interpersonal theory of suicide and adolescent suicidal behavior. AB - BACKGROUND: Joiner's interpersonal theory of suicide (IPTS) proposes that suicide results from the combination of a perception of burdening others, social alienation, and the capability for self-harm. The theory gained some empirical support, however the overall model has yet to be tested. This study aimed to test the main predictions of IPTS in a large community sample of Israeli adolescents. METHOD: 1196 Israeli Jewish and Arab high-school pupils participating in the SEYLE project completed a self-report questionnaire measuring perceived burdensomeness, thwarted belongingness, health risk behaviors, and non-suicidal self-injury (risk variables), and suicidal ideation and suicide attempts (outcome measures). The data were tested in cross-sectional regression models. RESULTS: Consistent with IPTS, perceived burdensomeness was found to interact with thwarted belongingness, predicting suicidal ideation. Depression mediated most of the effect of thwarted belongingness and perceived burdensomeness on suicidal ideation. Acquired capability for self-harm, as measured by health risk behaviors and direct non-suicidal self-injurious behaviors, predicted suicide attempt. However, this mechanism operated independently from ideation rather than in interaction with it, at variance with IPTS-based predictions. LIMITATIONS: The cross-sectional design precludes conclusions about causality and directionality. Proxy measures were used to test the interpersonal theory constructs. CONCLUSION: The findings support some of the IPTS predictions but not all, and imply two separate pathways for suicidal behavior in adolescents: one related to internalizing psychopathology and the other to self-harm behaviors. This conceptualization has clinical implications for the differential identification of adolescents at risk for suicidal behavior and for the development of prevention strategies. PMID- 26001666 TI - The effect of body-mind relaxation meditation induction on major depressive disorder: A resting-state fMRI study. AB - BACKGROUND: Meditation has been increasingly evaluated as an important complementary therapeutic tool for the treatment of depression. The present study employed resting-state functional magnetic resonance imaging (rs-fMRI) to examine the effect of body-mind relaxation meditation induction (BMRMI) on the brain activity of depressed patients and to investigate possible mechanisms of action for this complex intervention. METHOD: 21 major depressive disorder patients (MDDs) and 24 age and gender-matched healthy controls (HCs) received rs-fMRI scans at baseline and after listening to a selection of audio designed to induce body-mind relaxation meditation. The rs-fMRI data were analyzed using Matlab toolbox to obtain the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal for the whole brain. A mixed-design repeated measures analysis of variance (ANOVA) was performed on the whole brain to find which brain regions were affected by the BMRMI. An additional functional connectivity analysis was used to identify any atypical connection patterns after the BMRMI. RESULTS: After the BMRMI experience, both the MDDs and HCs showed decreased ALFF values in the bilateral frontal pole (BA10). Additionally, increased functional connectivity from the right dorsal medial prefrontal cortex (dmPFC) to the left dorsal lateral prefrontal cortex (dlPFC) and the left lateral orbitofrontal cortex (OFC) was identified only in the MDDs after the BMRMI. LIMITATION: In order to exclude the impact of other events on the participants' brain activity, the Hamilton Rating Scales for Depression (HDRS) was not measured after the body-mind relaxation induction. CONCLUSION: Our findings support the hypothesis that body-mind relaxation meditation induction may regulate the activities of the prefrontal cortex and thus may have the potential to help patients construct reappraisal strategies that can modulate the brain activity in multiple emotion-processing systems. PMID- 26001667 TI - Role of depression severity and impulsivity in the relationship between hopelessness and suicidal ideation in patients with major depressive disorder. AB - BACKGROUND: Hopelessness, depression and impulsivity all contribute to the development of suicidal ideation in patients with major depressive disorder, but the pathway of these factors to suicidal ideation is not clear. This study examined the meditating effect of depression severity on the relationship between hopelessness and suicidal ideation and explored how this mediating effect was moderated by impulsivity. METHODS: A total of 162 patients with major depressive disorder (MDD) completed a structured clinical diagnostic interview and a battery of scales assessing depression severity, hopelessness, suicidal ideation, and impulsivity. Regression analyses with bootstrapping methods were used to examine the mediating and moderating effects of various risk factors. RESULTS: Mediation analysis revealed a significant indirect effect of hopelessness on suicidal ideation, and the effect was fully mediated through depression severity. On moderation analysis, the moderating effects of the relationship between depression severity and suicidal ideation were significant in both the medium and high impulsivity groups. LIMITATIONS: The present study was limited by the assessment of trait impulsivity and observer-rated depression severity, which might not fully reflect momentary impulsivity and feeling of depression when suicidal ideation occurs. CONCLUSION: Depression severity plays a mediator role in the relationship between hopelessness and suicidal ideation and this mechanism is contingent on the levels of impulsivity. MDD patients with higher impulsivity appear to be more likely to have suicidal ideations even when they are less depressed. These findings highlight the importance of impulsivity assessment and alleviation of depressive symptoms to prevent suicidality in patients with MDD. PMID- 26001668 TI - Serotonin gene polymorphisms and lifetime mood disorders in predicting interferon induced depression in chronic hepatitis C. AB - BACKGROUND: IFN-induced depression is a suitable model for investigating vulnerability to depression. We aimed at investigating the role of two vulnerability factors, lifetime mood disorder (LMD) and 5-HT-related gene polymorphisms in treated patients with infection by Hepatitis C Virus (HCV). METHODS: Depressive symptoms of 130 consecutive HCV patients with no current psychopathology were measured during treatment with interferon and ribavirin. At baseline, LMD and 3 genotypes (5-HTTLPR, HTR1A, and TPH2) were also assessed. RESULTS: Subgroups of 43 patients with LMD, 96 with HTR1A-G allele, and 12 with both LMD and HTR1A-G homozigosity scored significantly higher to depression compared to the remaining patients during antiviral therapy. At the multiple regression analysis, LMD and HTR1A-G, whether separately or combined together, explained a similar amount of 10-22% of depression score variance, after controlling for the associated variables (age and gender). LIMITATIONS: HCV patients referred to a tertiary care center are not representative of all patients with chronic hepatitis C. Mediating factors, including proinflammatory cytokines and other potentially relevant gene polymorphisms, could not be evaluated. Patients were not stratified by degree of liver inflammation. LMD diagnoses were not cross-checked with medical records and IFN-induced depression was measured with a self-report scale only. CONCLUSIONS: History of mood disorders and HTR1A G allele variation, the C-1019G polymorphism of the transcriptional control region of the 5-HT1A receptor, independently predicted the incidence of IFN-induced depression in HCV patients, whether separately or jointly considered and although not reciprocally associated. PMID- 26001669 TI - Characteristics of people dying by suicide after job loss, financial difficulties and other economic stressors during a period of recession (2010-2011): A review of coroners' records. AB - BACKGROUND: Suicide rates increase during periods of economic recession, but little is known about the characteristics of people whose deaths are related to recession, the timing of risk in relation to job loss, the nature of financial stresses and the sources of help individuals used. METHODS: We extracted information on social and economic circumstances, mental health and help-seeking from the coroners' records of 286 people who died by suicide in 2010 and 2011 in four areas of England. We graded each death on a 5-point scale of 'recession relatedness', measuring the extent to which recession, employment and financial problems contributed to the death. RESULTS: Financial and employment-related issues contributed substantially to 38 (13%) of the deaths and were thought to be the key contributing factor in 11 (4%). Individuals whose deaths were thought to be related to the recession were less likely to have previously self-harmed but were more likely to be employed (61% vs. 43%), have financial difficulties (76% vs. 23%) and financial dependents (55% vs. 23%). Amongst the subset of 11 people where financial/employment issues were the key contributory factor, only two (18%) had ever had contact with psychiatric services. LIMITATIONS: Details on finances and employment were not systematically recorded by coroners. We found richer information was usually available for people who were living with other people. CONCLUSIONS: Financial difficulties, little past psychiatric history, low levels of service contact and having financial dependents were more common in 'recession-related' deaths. This suggests that interventions to prevent recession related rises in suicide should be focused on non-clinical agencies and initiatives. PMID- 26001670 TI - Efficacy of an integrative CBT for prolonged grief disorder: A long-term follow up. AB - BACKGROUND: While some intervention trials have demonstrated efficacy in treating prolonged grief disorder (PGD), data on long-term treatment effects are scarce. METHODS: Fifty-one outpatients with clinically relevant prolonged grief symptoms, who had participated in a randomized controlled trial (RCT), were followed up, on average, 1.5 years after integrative cognitive behavioral therapy for PGD (PG CBT). Initial assessment procedures were repeated, with PGD symptom severity as the main outcome and general mental health symptoms as secondary outcomes. As results in the immediate and delayed treatment groups (former wait list) were similar, the follow-up data were pooled. RESULTS: Overall, 80% of the original ITT sample could be reached, that is 89% of the 37 treated participants, as well as 8 out of 14 participants who had dropped out of the RCT. The considerable short-term treatment success of PG-CBT was stable; pre to follow-up Cohen's d was large, with 1.24 in the ITT analysis and 2.22 for completers. The pre to post improvement in overall mental health was maintained. LIMITATIONS: Since the RCT wait list group had been treated after their waiting period as well, no controlled long-term outcomes are available. CONCLUSIONS: PG-CBT proved to be effective in the longer run. In comparison to other RCTs on prolonged grief this is the largest sample followed up for this long. PMID- 26001671 TI - Increased risk of suicide attempt in bipolar patients with severe tobacco dependence. AB - BACKGROUND: The aim of our study was to investigate, in bipolar patients, the association between tobacco status (use and dependence) and history of suicide attempt, and to assess the possible role of inflammation as a missing link in the association between smoking status and history of suicide attempt. METHODS: A total of 453 adult bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups: 274 patients without past history of suicide attempt (non-SA), and 179 patients with a past history of suicide attempt (SA). Tobacco use and dependence, psychiatric and somatic comorbidities, history of childhood abuse, family history of suicide were assessed. Fasting blood tests yielded samples collected for the measurement of high sensitivity (hs-)CRP. RESULTS: The risk of suicide attempt increased with smoking dependence. Notably, bipolar patients with a history of suicide attempt were three times more likely to have severe tobacco dependence, independently of confounding factors. However, we failed to find arguments promoting the hypothesis of inflammatory markers (through hs-CRP measure) in the link between tobacco dependence and suicidal behavior. CONCLUSIONS: We found a significant association between severe tobacco dependence and history of suicide attempt, but not with level of CRP, independently of confusing factors. Longitudinal studies taken into account all these potential confusing factors are needed to confirm our results. PMID- 26001672 TI - Impact of urinary tract infection definitions on colorectal outcomes. AB - BACKGROUND: Hospital-acquired urinary tract infections (UTIs) significantly impact hospital outcomes. Colorectal surgery is inherently high risk for postoperative infections including UTI, and these patients may have unique outcomes as compared to other medical and surgical hospitalizations. We aim to assess the impact of the differing definitions of UTI captured by our hospital quality measures on hospital charges, length of stay (LOS), and mortality after colorectal resections at our institution. MATERIALS AND METHODS: Existing hospital quality surveillance was used to retrospectively identify postcolorectal resection UTI, as defined by the National Surgical Quality Improvement Program (NSQIP), and the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN)-defined catheter-associated UTIs (CAUTI), from 2006-2012. Both groups were compared to colorectal resections performed during the same period that did not develop a UTI. Groups were compared for differences in 30-d surgical outcomes with multivariate analysis of total hospital charges and LOS. RESULTS: During our study period, we identified 18 CAUTIs and 42 NSQIP-UTI, and 1064 other colorectal resections (UTI rate, 5.3%). Our overall mortality rate was 4.4% and was not associated with CAUTI or NSQIP-UTI on univariate analysis. CAUTI, but not NSQIP-UTI, was associated with a 73% increase in LOS and 70% increase in total hospital charges on multivariate analysis. CONCLUSIONS: By reviewing quality outcomes surveillance modalities at our hospital, we identified postcolorectal resection CAUTI, but not NSQIP-UTI, to be associated with increased total hospital charges and LOS. Neither was associated with mortality. PMID- 26001673 TI - Hextend-perfluorocarbon cocktail inhibits mean arterial pressure response in a rabbit shock model. AB - BACKGROUND: Hextend (HEX) is standard of care resuscitation fluid for combat related traumatic hemorrhage. Because HEX has limited oxygen-carrying capacity, combination therapy with oxygen therapeutics could improve oxygen delivery after hemodynamic shock. We hypothesized that addition of perfluorocarbon (PFC) to HEX would improve hemodynamics and oxygen delivery marker response in a rabbit model of hemorrhagic shock. METHODS: Anesthetized New Zealand rabbits (n = 23) were randomly allocated to resuscitation with fresh whole blood (FWB), HEX, or HEX plus PFC (HEX + PFC) after 60 min of hemorrhagic hypotension. Mean arterial pressure (MAP) was sampled every 2-3 min for 120 min postinfusion; MAP profiles were modeled by a one-compartment pharmacokinetic model to determine peak MAP (Pmax), time to peak MAP (tmax), and postinfusion MAP persistence. Arterial blood was sampled every 15 min to examine pH, blood gases PO2 and pCO2, metabolites lactate and glucose, methemoglobin (metHb), and electrolytes. RESULTS: Compared with FWB and HEX, HEX + PFC administration resulted in delayed peak MAP and less persistent (P < 0.0001) MAP elevation; metHb was significantly elevated (P < 0.0001) compared with FWB and HEX. There were no significant differences in PO2, pCO2, or pH. Glucose, hematocrit, and hemoglobin of both HEX and HEX + PFC were significantly lower relative to FWB. Lactate clearance was modest and transient for all treatments; base deficit was significantly more negative for HEX + PFC. CONCLUSIONS: Addition of PFC to HEX did not improve hemodynamics or acidosis. Further dose- and volume-range studies are required to test efficacy of PFC in combination with HEX for hemorrhagic shock. PMID- 26001674 TI - Development and testing of a silicone in vitro model of descending aortic dissection. AB - BACKGROUND: Stanford type B dissection of the descending aorta is a potentially fatal condition that is poorly understood. Limited scientific understanding of the role of current interventional techniques, as well as heterogeneity in the condition, contributes to lack of consensus as to the most effective treatment strategy. This study introduces an anatomically accurate model for investigating aortic dissection in a laboratory setting. MATERIALS AND METHODS: A silicone model was fabricated and filled with fluid to mimic human blood. Flow was established, and the model was scanned using a four-dimensional flow magnetic resonance imaging protocol. On analysis, luminal flow rates were quantified by multiplying local velocity by included area. RESULTS: The upstream total flow was compared with the sum of the flow in the true and false lumens. The two values were within the margin of error. Furthermore, flow rates matched with the relative areas of each compartment. CONCLUSIONS: These results validate our model as a novel and unique system that mimics a type B aortic dissection and will allow for more sophisticated analysis of dissection physiology in future studies. PMID- 26001675 TI - HTJoinSolver: Human immunoglobulin VDJ partitioning using approximate dynamic programming constrained by conserved motifs. AB - BACKGROUND: Partitioning the human immunoglobulin variable region into variable (V), diversity (D), and joining (J) segments is a common sequence analysis step. We introduce a novel approximate dynamic programming method that uses conserved immunoglobulin gene motifs to improve performance of aligning V-segments of rearranged immunoglobulin (Ig) genes. Our new algorithm enhances the former JOINSOLVER algorithm by processing sequences with insertions and/or deletions (indels) and improves the efficiency for large datasets provided by high throughput sequencing. RESULTS: In our simulations, which include rearrangements with indels, the V-matching success rate improved from 61% for partial alignments of sequences with indels in the original algorithm to over 99% in the approximate algorithm. An improvement in the alignment of human VDJ rearrangements over the initial JOINSOLVER algorithm was also seen when compared to the Stanford.S22 human Ig dataset with an online VDJ partitioning software evaluation tool. CONCLUSIONS: HTJoinSolver can rapidly identify V- and J-segments with indels to high accuracy for mutated sequences when the mutation probability is around 30% and 20% respectively. The D-segment is much harder to fit even at 20% mutation probability. For all segments, the probability of correctly matching V, D, and J increases with our alignment score. PMID- 26001676 TI - A model of dopamine modulated glutamatergic synapse. AB - The dopamine neurotransmitter regulates important neural pathways and its action in the brain is very complex. When dopaminergic neurons make synapses on spiny neurons of the striatum nucleus, they tune the responsiveness of glutamatergic synapses by means of the dopamine D1 and D2 receptors. We studied the effect of dopamine D1 receptors on glutamatergic synapse of GABAergic spiny neurons in striatum nucleus where they are located on the neck of the same spine. The action of dopamine consists essentially in promoting the phosphorylation of AMPA and NMDA receptors thus increasing the Excitatory Post Synaptic Current peak amplitude. The consequence is a cooperative effect of glutamatergic and dopaminergic synapses for the regulation of the GABAergic neuronal code. The mechanisms by which the phosphorylation induces the increase of the EPSC amplitude still remain unclear although the lack of this regulation can be involved in several pathologies as, for example, the Parkinson's disease. We tested, by computational experiments based on our model of glutamatergic synapse, three parameters of the synaptic function that could be involved in dopamine action: (a) time binding of glutamate to receptors; (b) open probability of the receptors; and (c) single receptor conductance. For different reasons, any of the three parameters could be responsible of the increased EPSC-dopamine-dependent. Our computational results were compared and discussed with experimental results found in literature. Although for our model both the open probability and the single receptor conductance can reproduce the phosphorylation effect of dopamine, we argue that the dopamine effect consists essentially in an increase of the single receptor conductance due to a 3D rearrangement of the phosphorylated receptors. PMID- 26001677 TI - Emodin mitigates diesel exhaust particles-induced increase in airway resistance, inflammation and oxidative stress in mice. AB - Clinical and experimental studies have reported that short-term exposure to particulate air pollution is associated with inflammation, oxidative stress and impairment of lung function. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has a strong antioxidant and anti-inflammatory actions. Therefore, in the present study, we evaluated the possible ameliorative effect of emodin on diesel exhaust particles (DEP)-induced impairment of lung function, inflammation and oxidative stress in mice. Mice were intratracheally instilled with DEP (20 MUg/mouse) or saline (control). Emodin was administered intraperitoneally 1h before and 7h after pulmonary exposure to DEP. Twenty-four hours following DEP exposure, we evaluated airway resistance measured by forced oscillation technique, lung inflammation and oxidative stress. Emodin treatment abated the DEP-induced increase in airway resistance, and prevented the influx of neutrophils in bronchoalveolar lavage fluid. Similarly, lung histopathology confirmed the protective effect of emodin on DEP-induced lung inflammation. DEP induced a significant increase of proinflammatory cytokines in the lung including tumor necrosis factor alpha, interleukin 6 and interleukin 1beta. The latter effect was significantly ameliorated by emodin. DEP caused a significant increase in lung lipid peroxidation, reactive oxygen species and a significant decrease of reduced glutathione concentration. These effects were significantly mitigated by emodin. We conclude that emodin significantly mitigated DEP-induced increase of airway resistance, lung inflammation and oxidative stress. Pending further pharmacological and toxicological studies, emodin may be considered a potentially useful pulmonary protective agent against particulate air pollution-induced lung toxicity. PMID- 26001678 TI - Differences in respiratory changes and Fos expression in the ventrolateral medulla of rats exposed to hypoxia, hypercapnia, and hypercapnic hypoxia. AB - Respiratory responses to hypoxia and/or hypercapnia, and their relationship to neural activity in the ventrolateral medulla (VLM), which includes the respiratory center, have not yet been elucidated in detail. We herein examined respiratory responses during exposure of 10% O2 (hypoxia), 10% CO2 (hypercapnia), and 10% O2-10% CO2 (hypercapnic hypoxia) using plethysmography. In addition to recording respiration, Fos expressions were examined in the VLM of the rat exposed to each gas to analyze neural activity. Respiratory frequency was increased in rats exposed to hypoxia, and Fos-positive neurons were observed in the caudal VLM (cVLM) and medial VLM (mVLM). Tidal volume was increased in rats exposed to hypercapnia, and Fos-positive neurons were observed in the rostral VLM (rVLM) includes the retrotrapezoid nucleus (RTN) and mVLM. Tidal volume was enhanced in rats exposed to hypercapnic hypoxia, similar to that in hypercapnia exposed rats, and Fos-positive neurons were observed in the entire region of the VLM. In the mVLM and cVLM, double immunofluorescence showed Fos-immunoreactive nerve cells were also immunoreactive to dopamine beta-hydroxylase, the marker for A1/C1 catecholaminergic neuron. These results suggested that hypoxia and hypercapnia modulated rhythmogenic microcircuits in the mVLM via A1/C1 neurons and the RTN, respectively. PMID- 26001679 TI - Peritoneal tuberculosis presenting as persistent ascites. PMID- 26001680 TI - Becoming expert. PMID- 26001681 TI - Letter to the editor: "the physician as chameleon": the hidden role of the resident physician. PMID- 26001682 TI - Adverse Neonatal Outcomes Among Women Living With HIV: A Population-Based Study. AB - BACKGROUND: There have been few population-based studies describing the risk of adverse neonatal outcomes among women living with HIV in Canada. Accordingly, we compared the risk of preterm birth (PTB), low birth weight (LBW) and small for gestational age births among Ontario women aged 18 to 49 years living with and without HIV infection. METHODS: We conducted a population-based study using Ontario health administrative data. Generalized estimating equations with a logit link function were used to derive adjusted odds ratios (aORs) and 95% confidence intervals for the association of HIV infection with adverse neonatal outcomes. RESULTS: Between 2002-2003 and 2010-2011, a total of 1 113 874 singleton live births were available for analysis, of which 615 (0.06%) were to women living with HIV. The proportion of singleton births that were SGA (14.6% vs. 10.3%; P < 0.001), PTB (14.6% vs. 6.3%; P < 0.001), and LBW (12.5% vs. 4.6%; P < 0.001) were higher among women living with HIV than among women without HIV. Following multivariable adjustment, the risks of PTB (aOR 1.76; 95% CI 1.38 to 2.24), SGA (aOR 1.43; 95% CI 1.12 to 1.81), and LBW (aOR 1.90; 95% CI 1.47 to 2.45) were higher for women living with HIV than for women without HIV. CONCLUSION: Women with HIV are at higher risk of adverse neonatal outcomes than HIV-negative women. Further research is required to develop preconception and prenatal interventions that could reduce the excess burden of poor pregnancy outcomes among women living with HIV. PMID- 26001683 TI - The Use of Intermittent Auscultation in Parturients of Varying BMI Categories: Experience From a Mid-Sized Tertiary Care Obstetrical Unit. AB - OBJECTIVES: The aim of this quality assurance project was to determine how many patients who qualified for intermittent auscultation (IA) in labour were actually monitored by intermittent auscultation. A secondary objective was to assess whether the rate of IA use depended on maternal BMI. METHODS: We performed a retrospective chart review in a sample of women who received obstetrical care at Kingston General Hospital over one year from July 31, 2012. Eligibility was determined using the inclusion and exclusion criteria outlined by the hospital's guideline on intermittent auscultation. RESULTS: Two hundred seven of 244 charts analyzed in this review qualified for IA. The mean age of women in the study was 29.3 (range 17 to 41) years. Their mean gestational age was 39.6 (range 37 to 42) weeks. Fifty-six percent (116/207) of the eligible women actually had IA. Forty seven percent of obese women who were eligible (47/100) had IA, compared with 64.4% of overweight women (58/90). This difference (17.4%) was statistically significant (P = 0.019, Fisher exact test). CONCLUSION: Fifty-six percent (116/207) of women with low risk pregnancies who were deemed eligible to have IA rather than electronic fetal heart rate monitoring actually had IA. Obese women were less likely to have IA than overweight women. More research is required regarding barriers to using IA in eligible women in our institution and elsewhere. PMID- 26001684 TI - Maternal and paternal birthplace and risk of stillbirth. AB - OBJECTIVES: To evaluate the influence of maternal and paternal country of origin on stillbirth risk. METHODS: We conducted a retrospective case-control study of all deliveries in Ontario between 2002 and 2011. We included 1373 stillbirths and 1 166 097 live births that had a documented country of origin for both parents. All newborns were singleton, born at between 20 and 42 weeks' gestation, and weighed 250 g to 7000 g. We computed adjusted odds ratios (aOR) and 95% confidence intervals for the risk of stillbirth associated with parental country of origin. Models were adjusted for infant sex, maternal age, parity, marital status, and residential income quintile. RESULTS: Compared with parent pairs in which both parents were Canadian-born, the aOR of stillbirth was higher whether immigrant parents came from the same country (aOR 1.32, 95% CI 1.16 to 1.51) or from different countries (aOR 1.34, 95% CI 1.08 to 1.65). The risk of stillbirth was highest for immigrant parents coming from the same country if that country had a high domestic stillbirth rate (aOR 1.60, 95% CI 1.30 to 1.97). CONCLUSION: Maternal and paternal country of origin influences stillbirth risk. Foreign-born couples, especially those originating from a country with a high stillbirth rate, are at greater risk. Attention should focus on identifying genetic and environmental risk factors for stillbirth among specific immigrant groups, including developing prevention strategies for high-risk couples. PMID- 26001685 TI - Prolonged second stage of labour and the risk for subsequent preterm birth. AB - OBJECTIVE: To assess whether prolonged second stage of labour influences the gestational age at the subsequent delivery. METHODS: We performed a retrospective cohort study. Clinical information was retrieved from the McGill Obstetrical and Neonatal Database for the period of January 2001 to February 2008. We evaluated primiparous women with term singleton pregnancies who reached the second stage of labour. Women were divided into two groups, according to the duration of the second stage: delivery after more than three hours of full cervical dilatation, or delivery within three hours. The primary outcome measured was the incidence of spontaneous preterm births at the subsequent delivery. RESULTS: Among 1818 women whose records were available for analysis, 416 women (22.9%) had a prolonged second stage of labour in their first delivery. Women with a prolonged second stage in their first delivery did not deliver prematurely more often in the successive delivery than those women whose second stage was not prolonged (rate of preterm birth 4.3% in the prolonged second stage group and 5.5% in the normal second stage group; P = 0.3). CONCLUSION: In our population of primiparous women with a singleton term delivery, a prolonged second stage of labour lasting more than three hours was not associated with preterm birth at their subsequent delivery. PMID- 26001686 TI - Cardiovascular risk reduction and weight management at a hospital-based postpartum preeclampsia clinic. AB - OBJECTIVE: Women who develop preeclampsia during pregnancy are at high risk of developing future chronic diseases, including premature cardiovascular disease. We have established an interdisciplinary clinic that aims to prevent cardiovascular disease through educational counselling focused on lifestyle modifications in the early postpartum period. The objective of this study was to evaluate changes in weight and cardiovascular risk factors in participating women after six months of attendance at the clinic. METHODS: We conducted a retrospective chart review of women who had a pregnancy complicated by preeclampsia, and who subsequently attended the Postpartum Preeclampsia Clinic. Study subjects had baseline assessments of lifestyle, physical, and laboratory parameters. Individualized goals for cardiovascular risk reduction and lifestyle were established, centering on physical activity and dietary modifications. The primary outcome was change in weight. RESULTS: Over the study period, 21 women were seen for a minimum of six months of follow-up. At an average (+/- SD) of 4.4 +/- 1.4 months postpartum, subjects showed a non-significant improvement in weight (mean weight loss of 0.4 +/- 4.5 kg) and BMI (mean decrease in BMI 0.1 +/- 1.7 kg/m2). Physical activity improved significantly, from 14% of subjects participating in physical activity before pregnancy to 76% at a mean of 4.4 months postpartum. CONCLUSION: This study has demonstrated the early benefits of a longitudinal interdisciplinary intervention with counselling about lifestyle modifications for prevention of cardiovascular disease in women with recent preeclampsia. A study with a larger sample size and longer duration of follow-up is planned to confirm these findings. PMID- 26001687 TI - Time to surgery and the risk of cancer progression in patients with gynaecologic cancers of the lower genital tract. AB - OBJECTIVE: There is little current evidence to define an appropriate surgical wait time in patients with cancer. The aim of this study was to examine whether increased time to surgery in patients with early-stage lower genital tract cancers resulted in a risk of cancer progression. METHODS: We conducted a population-based retrospective cohort study of women presenting with stage I squamous cell carcinoma of the cervix, vulva, and vagina and undergoing surgical treatment in Calgary, Alberta between 2000 and 2010. Cancer stage and disease characteristics were compared at two time points: the time of initial presentation to the gynaecologic oncology service and the time of surgery. RESULTS: One hundred fifty-six patients met the inclusion criteria. There was progression of cancer stage in 10 cases (6.4%). In keeping with the current wait time targets, time to surgery was categorized as <= 28 days (59 patients; 38%) and > 28 days (97 patients; 62%). Progression occurred in seven of the 123 cases of cervical cancer (9%). In all seven cases, time to surgery was > 28 days (P = 0.095). None of the three cases of vaginal cancer had disease progression. Progression occurred in three (10%) of the 30 cases of vulvar cancer. In two of these three cases, time to surgery was > 28 days (P = 0.586). The relative risk for disease progression with prolonged time to surgery for all women in the cohort was 5.5 (95% CI 0.7 to 42.1) (P = 0.091). CONCLUSION: In patients with early squamous cell carcinoma of the lower genital tract, increased time to surgery (> 28 days) is not associated with cancer progression. PMID- 26001688 TI - IUD String Perforation Through Anterior Cervix: A Case Report. AB - BACKGROUND: Intrauterine devices are increasingly the preferred method of contraception chosen by Canadian women. IUD strings are commonly not visible at follow-up, but rarely are visible yet not located within the endocervical canal. We report a case of IUD strings perforating the ectocervix. CASE: An asymptomatic, 26-year-old woman presented for removal of her levonorgestrel releasing intrauterine system, over a year following insertion of the device. Upon examination the IUD strings were found to be emerging from within the cervical tissue, 10 mm above the external os. CONCLUSION: We discuss removal techniques, review the literature, and examine possible reasons for this presentation. These techniques may interest a range of practitioners managing contraceptive care for women. PMID- 26001689 TI - Competency-based medical education: the wave of the future. AB - Competency-based medical education (CBME) is a new educational paradigm that will enable the medical education community to meet societal, patient, and learner needs of the 21st century. CBME offers a renewed commitment to both clinical and educational outcomes, a new focus on assessment and developmental milestones, a mechanism to promote a true continuum of medical education, and a method to promote learner-centred curricula in the context of accountability. Accountability is central to CBME, ensuring that graduating practitioners are well-rounded and competent to provide safe and effective patient care. The structure of CBME in obstetrics and gynaecology must be rooted in, and reflect, Canadian practice. Its development and implementation require an understanding of the principles that are the foundation of CBME, along with the involvement of the entire community of obstetricians and gynaecologists and other maternity care providers. We provide here an overview of the basic principles of teaching and learning and the theories underpinning CBME. PMID- 26001690 TI - Learning from experience: development of a cognitive task-list to assess the second stage of labour for operative delivery. AB - OBJECTIVE: Ensuring the availability of operative vaginal delivery is one strategy for reducing the rising Caesarean section rate. However, current training programs appear inadequate. We sought to systematically identify the core steps in assessing women in the second stage of labour for safe operative delivery, and to produce an expert task-list to assist residents and obstetricians in deciding on the safest mode of delivery for their patients. METHODS: Labour and delivery nursing staff of three large university-associated hospitals identified clinicians they considered to be skilled in operative vaginal deliveries. Obstetricians who were identified consistently were invited to participate in the study. Participants were filmed performing their normal assessment of the second stage of labour on a model. Two clinicians reviewed all videos and documented all verbal and non-verbal components of the assessment; these components were grouped into overarching themes and combined into an integrated expert task-list. The task-list was then circulated to all participants for additional comments, checked against SOGC guidelines, and redrafted, allowing production of a final expert task-list. RESULTS: Thirty clinicians were identified by this process and 20 agreed to participate. Themes identified were assessment of suitability, focused history, physical examination including importance of an abdominal examination, strategies to accurately assess fetal position, station, and the likelihood of success, cautionary signs to prompt reassessment in the operating room, and warning signs to abandon operative delivery for Caesarean section. Communication strategies were emphasized. CONCLUSION: Having expert clinicians teach assessment in the second stage of labour is an important step in the education of residents and junior obstetricians to improve confidence in managing the second stage of labour. PMID- 26001691 TI - Endometrial ablation in the management of abnormal uterine bleeding. AB - BACKGROUND: Abnormal uterine bleeding (AUB) is the direct cause of a significant health care burden for women, their families, and society as a whole. Up to 30% of women will seek medical assistance for the problem during their reproductive years. OBJECTIVE: To provide current evidence-based guidelines on the techniques and technologies used in endometrial ablation (EA), a minimally invasive technique for the management of AUB of benign origin. METHODS: Members of the guideline committee were selected on the basis of individual expertise to represent a range of practical and academic experience in terms of both location in Canada and type of practice, as well as subspecialty expertise and general background in gynaecology. The committee reviewed all available evidence in the English medical literature, including published guidelines, and evaluated surgical and patient outcomes for the various EA techniques. Recommendations were established by consensus. EVIDENCE: Published literature was retrieved through searches of MEDLINE and The Cochrane Library in 2013 and 2014 using appropriate controlled vocabulary and key words (endometrial ablation, hysteroscopy, menorrhagia, heavy menstrual bleeding, AUB, hysterectomy). RESULTS were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English from January 2000 to November 2014. Searches were updated on a regular basis and incorporated in the guideline to December 2014. Grey (unpublished) literature was identifies through searching the websites of health technology assessment and health technology related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). RESULTS: This document reviews the evidence regarding the available techniques and technologies for EA, preoperative and postoperative care, operative set-up, anaesthesia, and practical considerations for practice. BENEFITS, HARMS, AND COSTS: Implementation of the guideline recommendations will improve the provision of EA as an effective treatment of AUB. Following these recommendations would allow the surgical procedure to be performed safely and maximize success for patients. CONCLUSIONS: EA is a safe and effective minimally invasive option for the treatment of AUB of benign etiology. Summary Statements 1. Endometrial ablation is a safe and effective minimally invasive surgical procedure that has become a well-established alternative to medical treatment or hysterectomy to treat abnormal uterine bleeding in select cases. (I) 2. Endometrial preparation can be used to facilitate resectoscopic endometrial ablation (EA) and can be considered for some non-resectoscopic techniques. For resectoscopic EA, preoperative endometrial thinning results in higher short-term amenorrhea rates, decreased irrigant fluid absorption, and shorter operative time than no treatment. (I) 3. Non-resectoscopic techniques are technically easier to perform than resectoscopic techniques, have shorter operative times, and allow the use of local rather than general anaesthesia. However, both techniques have comparable patient satisfaction and reduction of heavy menstrual bleeding. (I) 4. Both resectoscopic and non-resectoscopic endometrial ablation (EA) have low complication rates. Uterine perforation, fluid overload, hematometra, and cervical lacerations are more common with resectoscopic EA; perioperative nausea/vomiting, uterine cramping, and pain are more common with non resectoscopic EA. (I) 5. All non-resectoscopic endometrial ablation devices available in Canada have demonstrated effectiveness in decreasing menstrual flow and result in high patient satisfaction. The choice of which device to use depends primarily on surgical judgement and the availability of resources. (I) 6. The use of local anaesthetic and blocks, oral analgesia, and conscious sedation allows for the provision of non-resectoscopic EA in lower resource-intense environments including regulated non-hospital settings. (II-2) 7. Low-risk patients with satisfactory pain tolerance are good candidates to undergo endometrial ablation in settings outside the operating room or in free-standing surgical centres. (II-2) 8. Both resectoscopic and non-resectoscopic endometrial ablation are relatively safe procedures with low complication rates. The complications perforation with potential injury to contiguous structures, hemorrhage, and infection. (II-2) 9. Combined hysteroscopic sterilization and endometrial ablation can be safe and efficacious while favouring a minimally invasive approach. (II-2) Recommendations 1. Preoperative assessment should be comprehensive to rule out any contraindication to endometrial ablation. (II-2A) 2. Patients should be counselled about the need for permanent contraception following endometrial ablation. (II-2B) 3. Recommended evaluations for abnormal uterine bleeding, including but not limited to endometrial sampling and an assessment of the uterine cavity, are necessary components of the preoperative assessment. (II-2B) 4. Clinicians should be vigilant for complications unique to resectoscopic endometrial ablation such as those related to fluid distention media and electrosurgical injuries. (III-A) 5. For resectoscopic endometrial ablation, a strict protocol should be followed for fluid monitoring and management to minimize the risk of complications of distension medium overload. (III-A) 6. If uterine perforation is suspected to have occurred during cervical dilatation or with the resectoscope (without electrosurgery), the procedure should be abandoned and the patient should be closely monitored for signs of intraperitoneal hemorrhage or visceral injury. If the perforation occurs with electrosurgery or if the mechanism of perforation is uncertain, abdominal exploration is warranted to obtain hemostasis and rule out visceral injury. (III B) 7. With resectoscopic endometrial ablation, if uterine perforation has been ruled out acute hemorrhage may be managed by using intrauterine Foley balloon tamponade, injecting intracervical vasopressors, or administering rectal misoprostol. (III-B) 8. If repeat endometrial ablation (EA) is considered following non-resectoscopic or resectoscopic EA, it should be performed by a hysteroscopic surgeon with direct visualization of the cavity. Patients should be counselled about the increased risk of complications with repeat EA. (II-2A) 9. If significant intracavitary pathology is present, resectoscopic endometrial ablation combined with hysteroscopic myomectomy or polypectomy should be considered in a non-fertility sparing setting. (II-3A). PMID- 26001692 TI - Induction of labour: review. PMID- 26001694 TI - How Do Pretransplantation Peripheral Blood Counts Inform Us about Post Transplantation Outcomes in Acute Myeloid Leukemia? PMID- 26001693 TI - Long-term continuous positive airway pressure therapy improves cardiac autonomic tone during sleep in patients with obstructive sleep apnea. AB - BACKGROUND: Cardiac autonomic tone after long-term continuous positive airway pressure therapy in patients with obstructive sleep apnea remains unexplored. METHODS: Thirty patients with obstructive sleep apnea (14 with moderate and 16 with severe obstructive sleep apnea) were studied during a baseline polysomnographic study, after a full night of acute continuous positive airway pressure treatment, and after long-term (~2 years) chronic continuous positive airway pressure therapy. Twenty age- and gender-matched controls with baseline sleep study were selected for comparison purposes. Cross-spectral analysis and the low-frequency (LF) and high-frequency (HF) components of the heart rate variability were computed separately over 10-min ECG epochs during rapid eye movement sleep, non-rapid eye movement sleep, and wakefulness. RESULTS: During the baseline study, obstructive sleep apnea patients exhibited increased LF, decreased HF, and increased LF/HF ratio during sleep when compared to controls. In a multiple regression model, the mean oxygen saturation explained the increased LF during rapid and non-rapid eye movement sleep in obstructive sleep apnea patients. Acute continuous positive airway pressure therapy decreased the LF modulations and the LF/HF ratio and increased the HF modulations during sleep in patients with severe obstructive sleep apnea. Long-term continuous positive airway pressure therapy decreased LF modulations and LF/HF ratio with increased HF modulations during sleep in patients with moderate and severe obstructive sleep apnea. CONCLUSIONS: Long-term continuous positive airway pressure reduces the sympathovagal imbalance in patients with moderate and severe obstructive sleep apnea, both during rapid and non-rapid eye movement sleep. Continuous positive airway pressure seems to exert its changes in cardiac autonomic modulation by decreasing the burden of nocturnal hypoxia. PMID- 26001695 TI - Reduced-Intensity Conditioning Combined with (188)Rhenium Radioimmunotherapy before Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: The Role of In Vivo T Cell Depletion. AB - The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome. PMID- 26001697 TI - Portrayal of tobacco in Mongolian language YouTube videos: policy gaps. AB - OBJECTIVES: This study examined how effectively current policy measures control depictions of tobacco in Mongolian language YouTube videos. METHODS: A search of YouTube videos using the Mongolian term for 'tobacco', and employing 'relevance' and 'view count' criteria, resulted in a total sample of 120 videos, from which 38 unique videos were coded and analysed. RESULTS: Most videos were antismoking public service announcements; however, analyses of viewing patterns showed that pro-smoking videos accounted for about two-thirds of all views. Pro-smoking videos were also perceived more positively and had a like:dislike ratio of 4.6 compared with 3.5 and 1.5, respectively, for the magic trick and antismoking videos. Although Mongolia prohibits tobacco advertising, 3 of the pro-smoking videos were made by a tobacco company; additionally, 1 pro-smoking video promoted electronic cigarettes. CONCLUSIONS: Given the popularity of Mongolian YouTube videos that promote smoking, policy changes are urgently required to control this medium, and more effectively protect youth and young adults from insidious tobacco marketing. PMID- 26001696 TI - Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells. AB - Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced intensity and myeloablative conditioning. We investigated, in a cohort of 40 high risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/MUL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting. PMID- 26001698 TI - Is the illicit cigarette market really growing? The tobacco industry's misleading math trick. PMID- 26001699 TI - The vascular phenotype of children with systemic lupus erythematosus. AB - BACKGROUND: The increased risk of cardiovascular disease (CVD) in adults with systemic lupus erythematosus (SLE) has been known since the 1970s, but studies in juvenile-onset SLE (JSLE) have reported conflicting results and more data are needed. The aim of this cross-sectional study was to establish the baseline risk of CVD in a cohort of UK patients with JSLE. METHODS: Data were collected to establish disease duration, disease activity, medication use and activity levels, as well as demographic data, including family history of CVD. Vascular phenotype was established using well-validated measures of carotid intima media thickness (cIMT) and pulse wave velocity (PWV). RESULTS: In total, 45 children (39 female; mean age 13.5 +/- 2.9 years) with JSLE were recruited to the study. Of these, 24 had a history of biopsy-proven lupus nephritis and five had an estimated glomerular filtration rate of <90 ml/min/1.73 m(2). Comparison of these JSLE patients with healthy controls previously scanned at our hospital revealed that the cIMT value was significantly higher in the former (0.45 vs. 0.37 mm, respectively; p < 0.0001). This difference was associated with the use of antihypertensives (p = 0.04) and higher or lower doses of prednisolone (p < 0.0001). PWV was not significantly different in the patient and control group (5.27 vs. 5.34 m/s, respectively; p = 0.77). In the patient group, the mean body mass index percentile was 65.63 +/- 28.8, and the median physical activity score was 1,773 (676-2,854) metabolic equivalents of task (METs). None of the patients admitted to cigarette smoking, and ten had a positive family history of cardiovascular disease (CVD). CONCLUSION: This study shows that our patients with JSLE had increased cIMT without an increase in PWV, suggesting possible early adaptive changes in JSLE. Follow-up data are needed to determine whether these changes result in clinically significant CVD. PMID- 26001700 TI - Impact of gestational age, sex, and postnatal age on urine biomarkers in premature neonates. AB - BACKGROUND: Urine proteins may help in understanding physiology and diagnosing disease in premature infants. Determining how urine proteins vary by degree of prematurity, sex, and postnatal day is warranted. METHODS: We performed a prospective cohort study to assess the independent correlation of 14 urine biomarkers (measured on postnatal days 1-4) with gestational age (GA), sex, and postnatal age in 81 premature infants (mean, 1017 g) without acute kidney injury using a random-effects mixed model. RESULTS: Neutrophil gelatinase-associated lipocalin (NGAL) and vascular endothelial growth factor (VEGF) showed significant associations for sex, GA, and postnatal age. Cystatin C, osteopontin (OPN), and trefoil factor 3 (TFF3) were associated with postnatal age and GA, but not sex. Epithelial growth factor (EGF) and uromodulin were associated with GA only. Clusterin was associated with postnatal age and sex. Albumin was associated with sex only. Beta-2-microglbulin (B2M), osteoactivin, kidney injury molecule -1 (KIM 1), and alpha glutathione S-transferase (alphaGST) were associated with postnatal age only. CONCLUSIONS: Postnatal age affects B2M, cystatin C, NGAL, OPN, clusterin, Kim-1, osteoactivin, TFF3, VEGF, alphaGST. GA affects cystatin C, EGF, NGAL, OPN, UMOD, TFF3, and VEGF. Sex affects albumin, NGAL, and clusterin. Interpretation of urine biomarkers will need to account for these associations. PMID- 26001701 TI - Analyzing the Usability of the 5-Level Canadian Triage and Acuity Scale By Paramedics in the Prehospital Environment. AB - INTRODUCTION: ED crowding negatively affects throughput, quality of care, and outcomes. Paramedics do not have an evidence-based, feasible triage instrument to guide classification of patients. No studies have compared the Canadian Triage and Acuity Scale (CTAS) used by prehospital paramedics against the Emergency Severity Index (ESI) used by nurses in the emergency department. This study sought to determine if a relationship exists between paramedics' triage scores and emergency nurses' scores in the emergency department using 2 common 5-level triage instruments, as well as to determine whether either instrument correlates with patient admission. METHODS: CTAS scores determined by paramedics on arrival at the emergency department were compared with the initial ESI scores determined by emergency nurses. Both scores were compared with the patient's disposition status. Data analyses included descriptive statistics, chi(2) statistics, and hierarchical regression analysis. RESULTS: The analysis included 2,222 patients. There was a poor relationship between the CTAS and the ESI at the facility (P = .599, kappa = -0.003). The final regression model explained 32.9% of the admission variance (P < .001). The model correctly predicted 61.5% of admissions, with an 82% accuracy rate for all other forms of disposition and an overall model prediction rate of 73.7%. DISCUSSION: Using the CTAS, paramedics can predict admission comparably with nurses using the ESI. However, both instruments showed weakness in over- and under-triage rates. Additional studies are indicated to better understand prehospital paramedic triage and its impact on throughput. PMID- 26001702 TI - Do public health services in Egypt help young married women exercise their reproductive rights? AB - OBJECTIVE: To assess supply and demand of family planning services from a reproductive rights perspective among young married women (YMW) in Egypt. METHODS: Data sources related to family planning included structured interviews with service providers (n=216); an inventory of equipment and supplies (n=40); exit interviews with YMW (n=147); and focus group discussions (n=12) with YMW, husbands, and mothers and/or mothers in law. YMW, husbands and mothers in law were not necessarily related. RESULTS: Although family planning services were readily available and affordable, YMW had limited access to information and services. Shortfalls were noted regarding respect for privacy, choice of family planning method, access to fertility services, and premarital counseling. Few YMW had sufficient autonomy to make informed reproductive decisions. Effective accountability mechanisms and processes for redress were also lacking. CONCLUSION: Implementation of a rights-based approach and structural changes to family planning service delivery are recommended to empower YMW in Egypt to demand and exercise their reproductive rights. PMID- 26001703 TI - Regional trends in the use of short-acting and long-acting contraception accessed through the private and public sectors. AB - OBJECTIVE: To examine trends in the source of modern contraception (public versus private sector); method choice (long-acting or permanent methods versus short acting methods); and method and source combined. METHODS: A retrospective analysis was conducted using data collected by national Demographic and Health Surveys and Reproductive Health Surveys during the period 1992-2012. The dataset included 18 low-income countries in Sub-Saharan Africa, 10 from Latin America and the Caribbean (LAC), and 8 from Asia. RESULTS: A substantial proportion-between 40% and 49%-of modern contraceptive users relied on the private sector in Asia and LAC in the last 20years, yet the proportion has been smaller in Sub-Saharan Africa, between 27% and 30%. Increased use of short-acting methods from both public and private sectors has driven the rise in contraceptive prevalence in Asia and LAC. Similarly, increased contraceptive prevalence in Sub-Saharan Africa reflected the increased use of short-acting methods obtained mainly through the public sector, with only limited use of long-acting or permanent methods through the private sector. CONCLUSION: The private sector has played a key role in the increase of modern CPR and the provision of modern contraceptives around the world, providing almost half of them in low-income countries. Yet, such increase was driven primarily by a more substantial role in the provision of short-acting methods than long acting and permanent methods. PMID- 26001704 TI - Introduction of rapid syphilis testing in antenatal care: A systematic review of the impact on HIV and syphilis testing uptake and coverage. AB - BACKGROUND: Global guidelines recommend universal syphilis and HIV screening for pregnant women. Rapid syphilis testing (RST) may contribute toward achievement of universal screening. OBJECTIVES: To examine the impact of RST on syphilis and HIV screening among pregnant women. SEARCH STRATEGY: We searched MEDLINE for English- and non-English language articles published through November, 2014. SELECTION CRITERIA: We included studies that used a comparative design and reported on syphilis and HIV test uptake among pregnant women in low- and middle-income countries (LMICs) following introduction of RST. DATA COLLECTION AND ANALYSIS: Data were extracted from six eligible articles presenting findings from Asia, Africa, and Latin America. MAIN RESULTS: All studies reported substantial increases in antenatal syphilis testing following introduction of RST; the latter did not appear to adversely impact antenatal HIV screening levels at sites already offering rapid HIV testing and may increase HIV screening among pregnant women in some settings. Qualitative data revealed that women were highly satisfied with RST. Nevertheless, ensuring adequate training for healthcare workers and supplies of commodities were cited as key implementation barriers. CONCLUSIONS: RST may increase antenatal syphilis and HIV screening and contribute to the improvement of antenatal care in LMICs. PMID- 26001705 TI - Use of mental health services by US children and teens rises. PMID- 26001706 TI - Effects of Material Properties on Bacterial Adhesion and Biofilm Formation. AB - Adhesion of microbes, such as bacteria and fungi, to surfaces and the subsequent formation of biofilms cause multidrug-tolerant infections in humans and fouling of medical devices. To address these challenges, it is important to understand how material properties affect microbe-surface interactions and engineer better nonfouling materials. Here we review the recent progresses in this field and discuss the main challenges and opportunities. In particular, we focus on bacterial biofilms and review the effects of surface energy, charge, topography, and stiffness of substratum material on bacterial adhesion. We summarize how these surface properties influence oral biofilm formation, and we discuss the important findings from nondental systems that have potential applications in dental medicine. PMID- 26001707 TI - A Major Fimbrilin Variant of Mfa1 Fimbriae in Porphyromonas gingivalis. AB - The periodontal pathogen Porphyromonas gingivalis is known to express 2 distinct types of fimbriae: FimA and Mfa1 fimbriae. However, we previously reported that fimbria-like structures were found in a P. gingivalis strain in which neither FimA nor Mfa1 fimbriae were detected. In this study, we identified a major protein in the bacterial lysates of the strain, which has been reported as the 53 kDa major outer membrane protein of P. gingivalis (53K protein) and subsequently reported as a major fimbrilin of a novel-type fimbria. Sequencing of the chromosomal DNA of the strain showed that the 53k gene (encoding the 53K protein) was located at a locus corresponding to the mfa1 gene (encoding the Mfa1 protein, which is a major fimbrilin of Mfa1 fimbriae) of the ATCC 33277 type strain. However, the 53K and Mfa1 proteins showed a low amino acid sequence homology and different antigenicity. The 53K protein was detected in 34 of 84 (41%) P. gingivalis strains, while the Mfa1 protein was detected in 44% of the strains. No strain expressed both 53K and Mfa1 proteins. Additionally, fimbriae were normally expressed in mutants in which the 53k and mfa1 genes were interchanged. These results indicate that the 53K protein is another major fimbrilin of Mfa1 fimbriae in P. gingivalis. PMID- 26001708 TI - A Large National Cohort Study of the Association between Bisphosphonates and Osteonecrosis of the Jaw in Patients with Osteoporosis: A Nested Case-control Study. AB - The purpose of this study was to examine the association between bisphosphonate exposure and osteonecrosis of the jaw (ONJ) in Korean patients with osteoporosis. A nested case-control study was performed using the claims database during 2002 to 2010 provided by the National Health Insurance Service. We identified a cohort of individuals with diagnosis of osteoporosis during 2002 to 2010. Cases and controls were identified during 2004 to 2010, and the date of potential cases of ONJ was defined as the index date. Bisphosphonate exposure was evaluated during 2 y prior to the index date. The association between bisphosphonate exposure and ONJ was tested by performing a conditional logistic regression analysis for matched data, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented. Subjects were classified as nonuser, recent user, past user, or continuous user, depending on the prescription of bisphosphonates in 2 periods (1 to 2 y and 0 to 1 y prior to the index date). Continuous users were defined as patients who were exposed to bisphosphonate in both periods. We also examined the impact of bisphosphonate medication compliance by measuring the cumulative duration of exposure (CDE) on the risk of ONJ. A total of 212 cases with ONJ and 2,120 controls matched by sex, age, income level, and insurance type were identified among 109,787 patients with osteoporosis out of 1,025,340 enrollees in the sample cohort. The odds of having ONJ after adjusting for patient comorbidities significantly increased in continuous users of bisphosphonates (OR, 3.9; 95% CI, 2.4 to 6.2) compared to nonusers. Increased odds of ONJ were observed as CDE increased. The adjusted OR in patients with 1.5 y < CDE <= 2 y prior to the index date was 7.8 (95% CI, 4.0 to 15.5) versus nonusers. Our study results support significantly increased occurrences of potential ONJ in patients with osteoporosis who were exposed to bisphosphonates compared to those without exposure. PMID- 26001709 TI - The continuing stigma of mental illness. PMID- 26001710 TI - Re-analysis of troubled dating in adolescents. PMID- 26001711 TI - The relations between violence exposure, posttraumatic stress symptoms, secondary traumatization, vicarious post traumatic growth and illness attribution among psychiatric nurses. AB - This study examined posttraumatic stress disorder symptoms (PTSD), secondary traumatization (ST) and vicarious posttraumatic growth (VG) among Israeli psychiatric nurses (PN) who were compared to community nurses (CN). Furthermore, we examined the contribution of PN perceptions of the etiology of their patients' mental illness to their PTSD, ST and VG. Results show that PN reported higher levels of both PTSD and ST symptoms, but lower levels of VG, as compare to CN. While ST symptoms were positively related to VG among CN, PTSD and ST symptoms were negatively associated among PN. Finally, exposure to patients' violence, PTSD or ST symptoms, and illness attribution dimensions of 'powerful others', predicted nurses' VG. PN are an at-risk population for work-related stress residues. PMID- 26001712 TI - Caring for an adolescent with anorexia nervosa: parent's views and experiences. AB - There is a distinct lack of studies that explore the views and opinions of parents in relation to people diagnosed with an eating disorder. This study specifically investigated the subjective experiences of parents who were caring for an adolescent with anorexia nervosa in Ireland. A qualitative descriptive approach was used to elicit the unique views and experiences of seven mothers and three fathers. The findings showed that parents recognised the significant impact that the illness was having on all facets of family life. Despite the negative impact of the illness, parents remained hopeful that the adolescent would recover. In terms of current mental health nursing practice, this study demonstrates the importance of viewing parents as an integral resource and involving parents in care planning and treatment approaches. PMID- 26001713 TI - Gender-related sexual abuse experiences reported by children who were examined in an emergency department. AB - The purpose of this study was to examine the experiences of sexual abuse by 95 children of two gender groups to determine differences in their reported sexual exploits by perpetrators. Significant differences between female and male children were reported. Male child-victims experienced more anal penetration by penis (54.5%, 10.7% respectively) and finger (27.3%, 2.7% respectively), however; female child-victims experienced more mouth contact to their genitalia (22.7%, 10.0% respectively) and body kisses (47.9%, 9.1% respectively). A more gender specific approach could help to facilitate prevention, and produce better outcomes. PMID- 26001714 TI - College student engaging in cyberbullying victimization: cognitive appraisals, coping strategies, and psychological adjustments. AB - The study's purpose was to explore whether frequency of cyberbullying victimization, cognitive appraisals, and coping strategies were associated with psychological adjustments among college student cyberbullying victims. A convenience sample of 121 students completed questionnaires. Linear regression analyses found frequency of cyberbullying victimization, cognitive appraisals, and coping strategies respectively explained 30%, 30%, and 27% of the variance in depression, anxiety, and self-esteem. Frequency of cyberbullying victimization and approach and avoidance coping strategies were associated with psychological adjustments, with avoidance coping strategies being associated with all three psychological adjustments. Interventions should focus on teaching cyberbullying victims to not use avoidance coping strategies. PMID- 26001715 TI - Quality of life in long-term forensic psychiatric care: comparison of self-report and proxy assessments. AB - OBJECTIVE: To compare quality of life (QoL) ratings of long term forensic psychiatric care patients with the ratings of psychiatric nurses, in which the nurses indicate how they think the patient would answer. METHODS: Agreement on QoL-scores according to the Forensic inpatient Quality of Life Questionnaire (FQL) was investigated for seventy- seven pairs of patients and psychiatric nurses from two forensic psychiatric long-care facilities where QoL is seen as an important treatment goal. This study also examined whether the amount of agreement was related to specific patient characteristics and characteristics of the patient- psychiatric nurse relationship. RESULTS: On group level, only small and mostly non-significant differences were found between patients' and psychiatric nurses' mean QoL scores. However, pairwise comparisons revealed poor agreement between patients' and nurses' QoL scores for half of the domains and moderate agreement on the other half of the domains, except for Leave, which was the only domain on which patients and their nurses had similar scores. Patient characteristics such as type of offence and type of psychopathology were negligibly related to the level of agreement. However, characteristics of the patient-nurse relationship such as age of the nurse and length of the patient nurse relationship did influence the amount of consensus between patients' and proxies' QoL-scores significantly. CONCLUSIONS: Nurses were not sufficiently able to accurately estimate their patients' QoL experience and could probably benefit from a training aimed at assessing QoL of their patients and how to support their patients in optimizing their QoL themselves. PMID- 26001716 TI - Teen experiences following a suicide attempt. AB - Teen suicide is the third leading cause of death for 15-24year olds. A clear understanding of what the experience of being suicidal means to adolescents living the phenomenon has not been clearly addressed in the literature. The aim of this research was to generate a comprehensive interpretation of the experiences of six adolescents who visited the ED following a suicide attempt, using hermeneutic phenomenological methodology. Participants ranged in age from 15 to 19years old, and all had been hospitalized for their attempt. Two patterns emerged: attempting as communicating and attempting as transforming. Underlying themes are described in detail. The findings have implications for nursing practice including how to assess and intervene with adolescent suicide attempters. PMID- 26001717 TI - Effectiveness of individual psychoeducation on recurrence in bipolar disorder; a controlled study. AB - This research was conducted as an controlled experimental study which aimed to determine the effectiveness of individual psychoeducation program on recurrence rate during 1year follow up period. The study included eighty-two patients who had been diagnosed with bipolar disorder. There were no hospitalizations in intervention group, while 7.3% of control patients experienced hospitalizations; recurrence rates were 18.9% in the intervention group patients and 34.1% in the control group patients, but statistical significant difference between the groups was not found. Four sessions of individual psychoeducation may have some positive effects but seem to be ineffective for preventing recurrences in patients with bipolar disorder during one year prospective follow up. PMID- 26001718 TI - Health-related quality of life--from the perspective of mothers and fathers of adult children suffering from long-term mental disorders. AB - There is a lack of studies on mothers' and fathers' experiences of Health-Related Quality of Life (HRQOL) associated with caregiving of adult children suffering from mental disorder. A cross-sectional study was therefore carried out with 108 mothers and 43 fathers. Data were collected by means of the Short Form Health Survey (SF-36), the Hospital Anxiety and Depression Scale (HADS), the Family Involvement and Alienation Questionnaire (FIAQ) and the Burden Assessment Scale (BAS). Mothers' HRQOL was affected more than fathers' and lower compared to Swedish age related norms. HRQOL was predominantly related to ratings on HADS and BAS. PMID- 26001719 TI - A qualitative study of nursing care for hospitalized patients with acute mania. AB - Patients with a bipolar disorder and currently experiencing acute mania often require hospitalization. We explored patient problems, desired patient outcomes, and nursing interventions by individually interviewing 22 nurses. Qualitative content analysis gave a top five of patients problems, desired patient outcomes and nursing interventions, identified as most important in the interviews. We then conducted three focus group meetings to gain greater insight into these results. Intensive nursing care is needed, fine-tuning on the patient as a unique person is essential, taking into account the nature and severity of the manic symptoms of the patient. PMID- 26001720 TI - Mindfulness meditation and aromatherapy to reduce stress and anxiety. PMID- 26001721 TI - Health promoting prisons in the era of mass incarceration in the US. PMID- 26001722 TI - Beneficial effects of exogenous CDP-choline (citicoline) in EAE. PMID- 26001723 TI - Cortical burst dynamics predict clinical outcome early in extremely preterm infants. AB - Intermittent bursts of electrical activity are a ubiquitous signature of very early brain activity. Previous studies have largely focused on assessing the amplitudes of these transient cortical bursts or the intervals between them. Recent advances in basic neuroscience have identified the presence of scale-free 'avalanche' processes in bursting patterns of cortical activity in other clinical contexts. Here, we hypothesize that cortical bursts in human preterm infants also exhibit scale-free properties, providing new insights into the nature, temporal evolution, and prognostic value of spontaneous brain activity in the days immediately following preterm birth. We examined electroencephalographic recordings from 43 extremely preterm infants (gestational age 22-28 weeks) and demonstrated that their cortical bursts exhibit scale-free properties as early as 12 h after birth. The scaling relationships of cortical bursts correlate significantly with later mental development-particularly within the first 12 h of life. These findings show that early preterm brain activity is characterized by scale-free dynamics which carry developmental significance, hence offering novel means for rapid and early clinical prediction of neurodevelopmental outcomes. PMID- 26001725 TI - Reply: Beneficial effects of exogenous CDP-choline (citicoline) in EAE. PMID- 26001724 TI - Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. AB - The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration. PMID- 26001726 TI - Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial-lysosomal axis and alleviates autophagic blockage in Pompe disease. AB - A unifying feature in the pathogenesis of aging, neurodegenerative disease, and lysosomal storage disorders is the progressive deposition of macromolecular debris impervious to enzyme catalysis by cellular waste disposal mechanisms (e.g., lipofuscin). Aerobic exercise training (AET) has pleiotropic effects and stimulates mitochondrial biogenesis, antioxidant defense systems, and autophagic flux in multiple organs and tissues. Our aim was to explore the therapeutic potential of AET as an ancillary therapy to mitigate autophagic buildup and oxidative damage and rejuvenate the mitochondrial-lysosomal axis in Pompe disease (GSD II/PD). Fourteen weeks of combined recombinant acid alpha-glucosidase (rhGAA) and AET polytherapy attenuated mitochondrial swelling, fortified antioxidant defense systems, reduced oxidative damage, and augmented glycogen clearance and removal of autophagic debris/lipofuscin in fast-twitch skeletal muscle of GAA-KO mice. Ancillary AET potently augmented the pool of PI4KA transcripts and exerted a mild restorative effect on Syt VII and VAMP 5/myobrevin, collectively suggesting improved endosomal transport and Ca(2+)- mediated lysosomal exocytosis. Compared with traditional rhGAA monotherapy, AET and rhGAA polytherapy effectively mitigated buildup of protein carbonyls, autophagic debris/lipofuscin, and P62/SQSTM1, while enhancing MnSOD expression, nuclear translocation of Nrf-2, muscle mass, and motor function in GAA-KO mice. Combined AET and rhGAA therapy reactivates cellular clearance pathways, mitigates mitochondrial senescence, and strengthens antioxidant defense systems in GSD II/PD. Aerobic exercise training (or pharmacologic targeting of contractile activity-induced pathways) may have therapeutic potential for mitochondrial lysosomal axis rejuvenation in lysosomal storage disorders and related conditions (e.g., aging and neurodegenerative disease). PMID- 26001727 TI - c-Jun N-terminal kinase attenuates TNFalpha signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells. AB - Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, causes vascular smooth muscle cell (VSMC) proliferation and migration and promotes inflammatory vascular lesions. Nuclear factor-kappa B (NF-kappaB) activation by TNFalpha requires endosomal superoxide production by Nox1. In endothelial cells, TNFalpha stimulates c-Jun N-terminal kinase (JNK), which inhibits NF-kappaB signaling. The mechanism by which JNK negatively regulates TNFalpha-induced NF kappaB activation has not been defined. We hypothesized that JNK modulates NF kappaB activation in VSMC, and does so via a Nox1-dependent mechanism. TNFalpha induced NF-kappaB activation was TNFR1- and endocytosis-dependent. Inhibition of endocytosis with dominant-negative dynamin (DynK44A) potentiated TNFalpha-induced JNK activation, but decreased ERK activation, while p38 kinase phosphorylation was not altered. DynK44A attenuated intracellular, endosomal superoxide production in wild-type (WT) VSMC, but not in NADPH oxidase 1 (Nox1) knockout (KO) cells. siRNA targeting JNK1 or JNK2 potentiated, while a JNK activator (anisomycin) inhibited, TNFalpha-induced NF-kappaB activation in WT, but not in Nox1 KO cells. TNFalpha-stimulated superoxide generation was enhanced by JNK1 inhibition in WT, but not in Nox1 KO VSMC. These data suggest that JNK suppresses the inflammatory response to TNFalpha by reducing Nox1-dependent endosomal ROS production. JNK and endosomal superoxide may represent novel targets for pharmacologic modulation of TNFalpha signaling and vascular inflammation. PMID- 26001728 TI - Thrombin inhibits the anti-myeloperoxidase and ferroxidase functions of ceruloplasmin: relevance in rheumatoid arthritis. AB - Human ceruloplasmin (CP) is a multifunctional copper-binding protein produced in the liver. CP oxidizes Fe(2+) to Fe(3+), decreasing the concentration of Fe(2+) available for generating harmful oxidant species. CP is also a potent inhibitor of leukocyte myeloperoxidase (MPO) (Kd=130nM), a major source of oxidants in vivo. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting flexible joints and characterized by activation of both inflammatory and coagulation processes. Indeed, the levels of CP, MPO, and thrombin are markedly increased in the synovial fluid of RA patients. Here we show that thrombin cleaves CP in vitro at (481)Arg-Ser(482) and (887)Lys-Val(888) bonds, generating a nicked species that retains the native-like fold and the ferroxidase activity of the intact protein, whereas the MPO inhibitory function of CP is abrogated. Analysis of the synovial fluid of 24 RA patients reveals that CP is proteolytically degraded to a variable extent, with a fragmentation pattern similar to that observed with thrombin in vitro, and that proteolysis is blocked by hirudin, a highly potent and specific thrombin inhibitor. Using independent biophysical techniques, we show that thrombin has intrinsic affinity for CP (Kd=60-270nM), independent of proteolysis, and inhibits CP ferroxidase activity (KI=220+/-20nM). Mapping of thrombin binding sites with specific exosite-directed ligands (i.e., hirugen, fibrinogen gamma'-peptide) and thrombin analogues having the exosites variably compromised (i.e., prothrombin, prethrombin-2, betaT thrombin) reveals that the positively charged exosite-II of thrombin binds to the negatively charged upper region of CP, while the protease active site and exosite I remain accessible. These results suggest that thrombin can exacerbate inflammation in RA by impairing the MPO inhibitory function of CP via proteolysis and by competitively inhibiting CP ferroxidase activity. Notably, local administration of hirudin, a highly potent and specifc thrombin inhibitor, reduces the concentration of active MPO in the synovial fluid of RA patients and has a beneficial effect on the clinical symptoms of the disease. PMID- 26001729 TI - Histone acetyltransferase p300 is induced by p38MAPK after photodynamic therapy: the therapeutic response is increased by the p300HAT inhibitor anacardic acid. AB - Oxidative stress mediated by photodynamic therapy (PDT) mediates the tumoricidal effect, but has also been shown to induce the expression of prosurvival molecules, such as cyclooxygenase-2 (COX-2), which is involved in tumor recurrences after PDT. However, the molecular mechanism is still not fully understood. In this study, we found that activated p38MAPK could significantly up regulate the activity and expression of histone acetyltransferase p300 (p300HAT) in A375 and C26 cells treated with ALA-and chlorin e6 (Ce6)-mediated photodynamic treatment. A colony-formation assay showed that PDT-induced cytotoxicity was dramatically elevated in the presence of the p300HAT inhibitor anacardic acid (AA). Further studies showed that increased p300HAT acetylates histone H3 and NF kappaB p65 subunit to up-regulate the COX-2 expression, which was reduced by AA or p300HAT shRNA. Using chromatin immunoprecipitation analysis, we found that the augmented acetylation of histone H3 and NF-kappaB increases their binding to the COX-2 promoter region. These in vitro findings were further verified in mice bearing murine C26 and human A375 tumors treated with liposomal Ce6 mediated PDT. Meanwhile, the combination of PDT and AA resulted in greater tumor regression in BALB/c mice bearing C26 tumors, compared with PDT only or combined with COX-2 inhibitor. Finally, we demonstrated that suppression of the PDT-induced p300HAT activity also resulted in the decreased expression of survivin, restoring caspase 3 activity and sensitizing PDT-treated cells from autophagy to apoptosis due to the Becline-1 cleavage. This study demonstrates for the first time the molecular mechanisms involved in histone modification induced by PDT-mediated oxidative stress, suggesting that HAT inhibitors may provide a novel therapeutic approach for improving PDT response. PMID- 26001730 TI - Studies on the protective efficacy of freeze thawed promastigote antigen of Leishmania donovani along with various adjuvants against visceral leishmaniasis infection in mice. AB - Visceral leishmaniasis (VL) caused by Leishmania donovani persists as a major public health issue in tropical and subtropical areas of the world. Current treatment of this disease relies on use of drugs. It is doubtful that chemotherapy can alone eradicate the disease, so there is a need for an effective vaccine. Killed antigen candidates remain a good prospect considering their ease of formulation, stability, low cost and safety. To enhance the efficacy of killed vaccines suitable adjuvant and delivery system are needed. Therefore, the current study was conducted to determine the protective efficacy of freeze-thawed L. donovani antigen in combination with different adjuvants against experimental infection of VL. For this, BALB/c mice were immunized thrice at an interval of two weeks. Challenge infection was given two weeks after last immunization. Mice were sacrificed after last immunization and on different post challenge/infection days. Immunized mice showed significant reduction in parasite burden, enhanced DTH responses with increased levels of Th1 cytokines and lower levels of Th2 cytokines, thus indicating the development of a protective Th1 response. Maximum protection was achieved with liposome encapsulated freeze thawed promastigote (FTP) antigen of L. donovani and it was followed by group immunized with FTP+MPL A, FTP+saponin, FTP+alum and FTP antigen (alone). The present study highlights greater efficacy of freeze thawed promastigote antigen as a potential vaccine candidate along with effective adjuvant formulations against experimental VL infection. PMID- 26001731 TI - Recognition of Candida albicans by Dectin-1 induces mast cell activation. AB - Mast cells are crucial elements of the innate immune response. They reside in tissues that are commonly exposed to the external environment, such as the skin and mucosae, where they can rapidly detect the presence of pathogens and mount a potent inflammatory response that recruits other cellular effectors of the immune response. The contribution of mast cells to the immune response to viruses, bacteria, protozoa and multicellular parasites is well established, but there is scarce information about the role of these cells in fungal infections. In this study, we analyzed if mast cells are activated by Candida albicans and if the C type lectin receptor Dectin-1 is involved in its recognition. We found that both yeasts and hyphae of C. albicans-induced mast cell degranulation and production of TNF-alpha, IL-6, IL-10, CCL3 and CCL4, while only yeasts were able to induce IL-1beta. Mast cells also produced ROS after stimulation with both dimorphic phases of C. albicans. When mast cells were activated with yeasts and hyphae, they showed decreased expression of IkappaBalpha and increased presence of phosphorylated Syk. Blockade of the receptor Dectin-1, but not Toll-like receptor 2, decreased TNF-alpha production by mast cell in response to C. albicans. These results indicate that mast cells are capable of sensing the two phases of C. albicans, and suggest that mast cells participate as an early inductor of inflammation during the early innate immune response to this fungus. PMID- 26001732 TI - The paradoxical roles of C1q and C3 in autoimmunity. AB - In this review we will focus on the links between complement and autoimmune diseases and will highlight how animal models have provided insights into the manner by which C1q and C3 act to modulate both adaptive and innate immune responses. In particular we will highlight how C1q may not only act as initiator of the classical complement pathway, but can also mediate multiple immune responses in a complement activation independent manner. PMID- 26001733 TI - Neurocognitive Mechanisms of Prejudice Formation: The Role of Time-Dependent Memory Consolidation. AB - Prejudice is generally thought to derive from learned, emotion-laden experiences. The mechanisms underlying the formation of prejudice over time, however, remain unknown. In the present research, we proposed and tested hypotheses regarding prejudice formation derived from research on memory consolidation and social perception. We hypothesized that time-dependent memory consolidation would produce better implicit memory for negative out-group information and positive in group information, compared with negative in-group information and positive out group information. Fifty undergraduates learned positive and negative information about racial in-group (Latino) and out-group (African American) targets. Participants returned after both a short time delay (2-6 hr after the learning session) and a long time delay (48 hr after the learning session) to complete a lexical decision task. Results demonstrated that participants responded to information consistent with an in-group bias faster after a long time delay than after a short time delay. Our findings have important implications for the study of social perception and memory consolidation. PMID- 26001734 TI - Suppressing Unwanted Autobiographical Memories Reduces Their Automatic Influences: Evidence From Electrophysiology and an Implicit Autobiographical Memory Test. AB - The present study investigated the extent to which people can suppress unwanted autobiographical memories in a memory-detection context involving a mock crime. Participants encoded sensorimotor-rich memories by enacting a lab-based crime (stealing a ring) and received instructions to suppress memory of the crime in order to evade guilt detection in a brain-wave-based concealed-information test. Aftereffects of suppression on automatic memory processes were measured in an autobiographical Implicit Association Test. Results showed that suppression attenuated brain-wave activity (the P300) associated with crime-relevant memory retrieval, which rendered waveforms from innocent and guilty participants indistinguishable. However, the two groups could nevertheless be discriminated via the late-posterior-negative slow wave, which may reflect the need to monitor response conflict arising between voluntary suppression and automatic recognition processes. Finally, extending recent findings that suppression can impair implicit memory processes, we provide novel evidence that suppression reduces automatic cognitive biases often associated with actual autobiographical memories. PMID- 26001735 TI - Retrieval-Induced Inhibition in Short-Term Memory. AB - We used a visual illusion called motion repulsion as a model system for investigating competition between two mental representations. Subjects were asked to remember two random-dot-motion displays presented in sequence and then to report the motion directions for each. Remembered motion directions were shifted away from the actual motion directions, an effect similar to the motion repulsion observed during perception. More important, the item retrieved second showed greater repulsion than the item retrieved first. This suggests that earlier retrieval exerted greater inhibition on the other item being held in short-term memory. This retrieval-induced motion repulsion could be explained neither by reduced cognitive resources for maintaining short-term memory nor by continued inhibition between short-term memory representations. These results indicate that retrieval of memory representations inhibits other representations in short-term memory. We discuss mechanisms of retrieval-induced inhibition and their implications for the structure of memory. PMID- 26001736 TI - A different look at the conventional 12-lead electrocardiogram. PMID- 26001737 TI - Performance of an expedited rhythm control method for recent onset atrial fibrillation in a community hospital. AB - BACKGROUND: A standard approach to recent onset atrial fibrillation (AF) in the emergency department (ED) in the United States has not been established. PURPOSE: The purpose of this prospective clinical trial was to determine how an ED protocol emphasizing rhythm control for recent onset AF compared similar patients receiving standard therapy in the same facility. METHODS: We enrolled consecutive patients presenting to our community hospital with recent onset AF into a protocol, which called for rhythm control with procainamide and if unsuccessful electrical cardioversion and discharge home. We compared this prospective cohort with matched historical controls. Primary outcome was admission rate. We also compared ED conversion rates and lengths of stay (LOS). We reported 30-day data on the study group including ED recidivism, recurrent AF, outpatient follow-up, and any important adverse events. RESULTS: Fifty-four patients were enrolled in the study group with 4 being admitted compared with 30 of 50 in the historical control group. Ninety-four percent of the study group converted compared with 28% in the historical control. Both hospital and ED LOS were significantly shorter for the study group. Six patients had recurrent AF, and 4 of those returned to the ED. CONCLUSION: An ED protocol that uses rhythm control decreased hospital admission and LOS, and there were no adverse events at 30 days. PMID- 26001738 TI - The role of charity care and primary care physician assignment on ED use in homeless patients. AB - OBJECTIVE: Homeless patients are a vulnerable population with a higher incidence of using the emergency department (ED) for noncrisis care. Multiple charity programs target their outreach toward improving the health of homeless patients, but few data are available on the effectiveness of reducing ED recidivism. The aim of this study is to determine whether inappropriate ED use for nonemergency care may be reduced by providing charity insurance and assigning homeless patients to a primary care physician (PCP) in an outpatient clinic setting. METHODS: A retrospective medical records review of homeless patients presenting to the ED and receiving treatment between July 2013 and June 2014 was completed. Appropriate vs inappropriate use of the ED was determined using the New York University ED Algorithm. The association between patients with charity care coverage, PCP assignment status, and appropriate vs inappropriate ED use was analyzed and compared. RESULTS: Following New York University ED Algorithm standards, 76% of all ED visits were deemed inappropriate with approximately 77% of homeless patients receiving charity care and 74% of patients with no insurance seeking noncrisis health care in the ED (P=.112). About 50% of inappropriate ED visits and 43.84% of appropriate ED visits occurred in patients with a PCP assignment (P=.019). CONCLUSIONS: Both charity care homeless patients and those without insurance coverage tend to use the ED for noncrisis care resulting in high rates of inappropriate ED use. Simply providing charity care and/or PCP assignment does not seem to sufficiently reduce inappropriate ED use in homeless patients. PMID- 26001739 TI - DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck. AB - Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5 year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q, XRCC1 R399Q, and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. PMID- 26001740 TI - Increased daylight availability reduces length of hospitalisation in depressive patients. AB - In a retrospective study, hospital stay in two hospitals was compared for depressive patients. The mean amount of accumulated light impinging the patient's area was 86,145 lux/light period in Hospital Universitari Son Dureta and 258,909 lux/light period in Hospital Universitari Son Espases (~300 % increase). The median stay was 14 days (1q-3q 8-19, n = 101) and 11 (1q-3q 6-15, n = 106) days, respectively. The reduction was significant only for the entire group, though not for subgroups (p < 0.007). Although the light received was not individually measured, results point to a significant effect of light in the recovery time of depressive patients. Prospective studies are needed. PMID- 26001741 TI - Intra-nodal injection of gentamicin for the treatment of suppurated cat scratch disease's lymphadenitis. AB - PURPOSE: Cat scratch disease (CSD)'s lymphadenitis may have a protracted course with painful suppuration necessitating several needle aspirations or surgical drainage. The objective of this study was to evaluate the benefit of an intra nodal injection of gentamicin add-on oral azithromycin treatment on the outcome of suppurated CSD's lymphadenitis. METHODS: We performed a retrospective monocentric study including 51 consecutive patients diagnosed between Jan 2009 and Mar 2014 with suppurated CSD who had a positive PCR for Bartonella henselae DNA in pus collected from lymph node by needle aspiration, and who were treated with azithromycin. RESULTS: Among them, 26/51 patients (51%) received oral azithromycin only, of whom 8 patients (31%) were cured and 18 patients (69%) had complications, while 25/51 patients (49%) received an intra-nodal injection of gentamicin add-on oral azithromycin, of whom 16 patients (64 %) were cured and 9 patients (36%) had complications. In univariate analysis, the combined treatment was the only variable related to cure without complications (64 versus 31%, p = 0.01), but this difference did not remain statistically significant in multivariate analysis (OR = 3.84, 95% CI: 0.95-15.56, p = 0.06). CONCLUSIONS: Intra-nodal injection of gentamicin add-on oral azithromycin treatment might improve the outcome of patients with suppurated CSD's lymphadenitis, deserving further randomized studies. PMID- 26001743 TI - RNA secondary structures in a polymer-zeta model how foldings should be shaped for sparsification to establish a linear speedup. AB - Various tools used to predict the secondary structure for a given RNA sequence are based on dynamic programming used to compute a conformation of minimum free energy. For structures without pseudoknots, a worst-case runtime proportional to n3, with n being the length of the sequence, results since a table of dimension n2 has to be filled in while a single entry gives rise to a linear computational effort. However, it was recently observed that reformulating the corresponding dynamic programming recursion together with the bookkeeping of potential folding alternatives (a technique called sparsification) may reduce the runtime to n2 on average, assuming that nucleotides of distance d form a hydrogen bond (i..e., are paired) with probability b/d(c) for some constants b > 0, c > 1. The latter is called the polymer-zeta model and plays a crucial role in speeding up the above mentioned algorithm. In this paper we discuss the application of the polymer-zeta property for the analysis of sparsification, showing that it must be applied conditionally on first and last positions to pair. Afterwards, we will investigate the combinatorics of RNA secondary structures assuming that the corresponding conditional probabilities behave according to a polymer-zeta probability model. We show that even if some of the structural parameters exhibit an almost realistic behavior on average, the expected shape of a folding in that model must be assumed to highly differ from those observed in nature. More precisely, we prove our polymer-zeta model to be appropriate for mRNA molecules but to fail in connection with almost every other family of RNA. Those findings explain the huge speedup of the dynamic programming algorithm observed empirically by Wexler et al. when applying sparsification in connection with mRNA data. PMID- 26001742 TI - Modelling of platelet-fibrin clot formation in flow with a DPD-PDE method. AB - The paper is devoted to mathematical modelling of clot growth in blood flow. Great complexity of the hemostatic system dictates the need of usage of the mathematical models to understand its functioning in the normal and especially in pathological situations. In this work we investigate the interaction of blood flow, platelet aggregation and plasma coagulation. We develop a hybrid DPD-PDE model where dissipative particle dynamics (DPD) is used to model plasma flow and platelets, while the regulatory network of plasma coagulation is described by a system of partial differential equations. Modelling results confirm the potency of the scenario of clot growth where at the first stage of clot formation platelets form an aggregate due to weak inter-platelet connections and then due to their activation. This enables the formation of the fibrin net in the centre of the platelet aggregate where the flow velocity is significantly reduced. The fibrin net reinforces the clot and allows its further growth. When the clot becomes sufficiently large, it stops growing due to the narrowed vessel and the increase of flow shear rate at the surface of the clot. Its outer part is detached by the flow revealing the inner part covered by fibrin. This fibrin cap does not allow new platelets to attach at the high shear rate, and the clot stops growing. Dependence of the final clot size on wall shear rate and on other parameters is studied. PMID- 26001744 TI - Stochastic eco-evolutionary model of a prey-predator community. AB - We are interested in the impact of natural selection in a prey-predator community. We introduce an individual-based model of the community that takes into account both prey and predator phenotypes. Our aim is to understand the phenotypic coevolution of prey and predators. The community evolves as a multi type birth and death process with mutations. We first consider the infinite particle approximation of the process without mutation. In this limit, the process can be approximated by a system of differential equations. We prove the existence of a unique globally asymptotically stable equilibrium under specific conditions on the interaction among prey individuals. When mutations are rare, the community evolves on the mutational scale according to a Markovian jump process. This process describes the successive equilibria of the prey-predator community and extends the polymorphic evolutionary sequence to a coevolutionary framework. We then assume that mutations have a small impact on phenotypes and consider the evolution of monomorphic prey and predator populations. The limit of small mutation steps leads to a system of two differential equations which is a version of the canonical equation of adaptive dynamics for the prey-predator coevolution. We illustrate these different limits with an example of prey predator community that takes into account different prey defense mechanisms. We observe through simulations how these various prey strategies impact the community. PMID- 26001745 TI - Surviving evolutionary escape on complex genotype-phenotype networks. AB - We study the problem of evolutionary escape and survival of cell populations with a genotype-phenotype structure. We refer to evolutionary escape as the process where a cell of a given ill-adapted population to reach a well-adapted phenotype. Similarly, survival refers to the dynamics of the population once the escape phenotype has been reached. The aim of this paper is to analyse the influence of topological properties associated to robustness and evolvability on the probability of escape and on the probability of survival. In order to explore these issues, we formulate a population dynamics model, consisting of a multi type time-continuous branching process, where types are associated to genotypes and their birth and death probabilities depend on the associated phenotype (non escape or escape). We exploit the separation of time scales introduced by the the difference in reproductive ratios between the ill-adapted phenotypes and the escape phenotype. Two dynamical regimes emerge: a fast-decaying regime associated to the escape process itself, and a slow regime which corresponds to the survival dynamics of the population once the escape phenotype has been reached. We exploit this separation of time scales to analyse the topological factors which determine escape and survival probabilities. We show that, while the escape probability depends on the degree of escape phenotype, the probability of survival is essentially determined by its robustness, measured in terms of a weighted clustering coefficient. PMID- 26001746 TI - Hypomagnesaemia in kidney transplantation. AB - In the era of calcineurin inhibitors, hypomagnesaemia is a very common finding in kidney transplant recipients. Especially the first weeks after transplantation it is the rule rather than the exception. Hypomagnesaemia or low magnesium intake have been associated with a higher mortality or more cardiovascular events in the general population, but this association has never been explored in kidney transplant recipients, despite their increased cardiovascular risk. Kidney transplant recipients with pre- or post-transplant hypomagnesaemia seem to have an aberrant glucose metabolism and develop diabetes mellitus more frequently. Moreover, observations from alternate study populations, animal experiments or in vitro studies suggest a possible role of magnesium deficiency in graft dysfunction, bone metabolism and transplant immunology. Future observational and especially interventional studies should further define whether and to what extent we should make effort to correct this electrolyte disturbance in transplant recipients. Considering the mechanism of renal magnesium wasting, normalizing the serum magnesium concentration by oral supplementation alone might turn out to be cumbersome in kidney transplant recipients. PMID- 26001747 TI - Outcomes of an International Cooperative Education Experience for Undergraduate Nursing Students. AB - A qualitative study was conducted to identify the outcomes of international cooperative education in nursing. Seventeen alumni who completed 19 cooperative work experiences were interviewed. International cooperative experiences support learning about culture and contribute to personal and professional development. Outcomes included increased maturation, confidence, and flexibility; elevated political and global awareness; and ability to create effective relationships with culturally diverse patients and coworkers. PMID- 26001748 TI - Online Social Media as a Curation Tool for Teaching. AB - This case study shows how students used online social media to disseminate curated knowledge to the public. This is a "redefined" way of having the students show that they have analyzed the existing knowledge on a topic, synthesized/reorganized it in a meaningful way, and created a new presentation of that knowledge in various ways. This case study demonstrates an effective teaching approach to ensure that students develop competencies in teamwork, collaboration, and informatics. PMID- 26001749 TI - Hybrid and Flipped Strategies in a Blended RN-BSN Program: Determining Student and Faculty Perceptions. PMID- 26001750 TI - Substance abuse: a national survey of Canadian residency program directors and site chiefs at university-affiliated anesthesia departments. AB - PURPOSE: The abuse of substances available to anesthesiologists in their workspace is a potentially lethal occupational hazard. Our primary objective was to define the prevalence of substance abuse cases among Canadian anesthesiologists at university-affiliated hospitals. Our secondary aim was to describe the current management of confirmed cases, rehabilitation procedures being offered, and preventative strategies being employed. METHODS: We conducted a cross-sectional electronic survey of all Canadian anesthesia residency program directors and site chiefs at university-affiliated hospitals. Data analysis was performed using descriptive statistics. RESULTS: The survey response rate was 54% (53/98). Substance abuse was reported as 1.6% for residents and 0.3% for clinical fellows over a ten-year period ending in June 2014. Fentanyl was abused in nine of 24 reported cases. At present, one of 22 respondents (4.5%) reported a formal education program on substance abuse for faculty members, and 72% described mandatory education for residents. The majority of participants did not perceive substance abuse as a growing problem. Seventy-one percent of respondents indicated that methods for controlled-drug handling had changed in the previous ten years; however, 66% did not think that the incidence of controlled substance abuse could be decreased further by more stringent measures. Only 21% of respondents supported the introduction of random urine drug testing. CONCLUSION: The prevalence of substance abuse among Canadian anesthesiologists and the substances abused appear comparable with data from the United States, with residents being the group most often affected. Early recognition and treatment of chemically dependent anesthesiologists remain imperfect. PMID- 26001751 TI - Postoperative recovery after anesthesia in morbidly obese patients: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: Obese patients present a challenge to safe general anesthesia because of impaired cardiopulmonary physiology and increased risks of aspiration and acute upper airway obstruction. Since studies are lacking regarding the postoperative effects on recovery from general anesthesia in morbidly obese patients, we conducted a systematic review and meta-analysis of recovery outcomes in morbidly obese patients who had undergone general anesthesia. SOURCE: We systematically searched the PubMed, EMBASETM, Cochrane, and ScopusTM databases for randomized controlled trials that evaluated the outcome of anesthesia with desflurane, sevoflurane, isoflurane, or propofol in morbidly obese patients. Using a random effects model, we conducted meta-analyses to assess recovery times (eye opening, hand squeezing, tracheal extubation, and stating name or birth date), time to discharge from the postanesthesia care unit (PACU), and the incidence and severity of postoperative nausea and vomiting (PONV). PRINCIPAL FINDINGS: We reviewed results for 11 trials and found that patients given desflurane took less time: to respond to commands to open their eyes (weighted mean difference [WMD] 3.10 min; 95% confidence interval (CI): -5.13 to -1.08), to squeeze the investigator's hand (WMD -7.83 min; 95% CI: -8.81 to -6.84), to be prepared for tracheal extubation (WMD -3.88 min; 95% CI: -7.42 to -0.34), and to state their name (WMD -7.15 min; 95% CI: -11.00 to -3.30). We did not find significant differences in PACU discharge times, PONV, or the PACU analgesic requirement. CONCLUSION: Postoperative recovery was significantly faster after desflurane than after sevoflurane, isoflurane, or propofol anesthesia in obese patients. No clinically relevant differences were observed regarding PACU discharge time, incidence of PONV, or postoperative pain scores. The systematic review was registered with PROSPERO (CRD42014009480). PMID- 26001752 TI - DNA repair capacity of cultured human lymphocytes exposed to mutagens measured by the comet assay and array expression analysis. AB - Repair of mutagen-induced DNA lesions during transportation, storage and cultivation of lymphocytes may have a significant impact on results obtained in human biomonitoring after occupational and environmental exposure of human populations to genotoxic chemicals. Using the comet assay in combination with the repair inhibitor aphidicolin and array gene expression analysis of 92 DNA repair genes, we investigated the repair of DNA lesions induced by methyl methanesulfonate (MMS) and benzo[a]pyrenediolepoxide (BPDE) in phytohaemagglutinin (PHA)-stimulated cultured human lymphocytes in the time segment before replication. The comet assay indicated fast repair of MMS-induced damage during the first hours of cultivation. In contrast, removal of BPDE induced lesions was slower and significant amounts of damage seem to persist until S-phase. Gene expression analysis revealed that PHA stimulation had a clear effect on gene regulation in lymphocytes already during the first 18h of cultivation. Under the conditions of this study, genotoxic concentrations of MMS did not induce significant changes in gene expression. In contrast, exposure to BPDE led to altered expression of several genes in a time- and concentration related manner. Of the significantly up-regulated genes, only two genes (XPA and XPC) were directly related to nucleotide excision repair. Our results suggest that PHA stimulation of human lymphocytes influences the expression of DNA repair genes in human lymphocytes. The effect of induced DNA damage on gene expression is comparatively low and depends on the mutagens used. PHA-stimulated lymphocytes repair induced DNA damage before they start to replicate but the repair activity during the first 18h of cultivation is not affected by changes in the expression of DNA repair genes during this period of time. PMID- 26001753 TI - Chronic and acute effects of endurance training on telomere length. AB - Telomere shortening is considered a cellular marker of health status and biological ageing. Exercise may influence the health and lifespan of an individual by affecting telomere length (TL). However, it is unclear whether different endurance exercise levels may have beneficial or detrimental effects on biological aging. The aims of the study were to assess both chronic and acute effects of endurance training on TL after an exceptional and extreme trail race. TL was assessed in 20 endurance athletes (17 males; age = 45.4 +/- 9.2 years) and 42 age- and gender-matched sedentary controls (32 males; age = 45.9 +/- 9.5 years) with quantitative real-time PCR at baseline conditions. Of the 20 runners enrolled in the 'Tor des Geants (r)' ultra-distance trail race, 15 athletes (12 males; age = 47.2 +/- 8.5 years) were re-evaluated at the intermediate point and 14 athletes (11 males; age = 47.1 +/- 8.8 years) completed the competition and were analysed at the final point. Comparison between the two groups (endurance athletes vs. sedentary controls) revealed a significant difference in TL (1.28 +/ 0.4 vs. 1.02 +/- 0.3, P = 0.005). TL was better preserved in elder endurance runners compared with the same age control group (1.3 +/- 0.27 vs. 0.91 +/- 0.21, P = 0.003). TL was significantly reduced at the intermediate (0.88 +/- 0.36 vs. 1.11 +/- 0.34, P = 0.002) and final point compared with baseline measurements (0.86 +/- 0.4 vs. 1.11 +/- 0.34, P = 0.0006) for athletes engaged in the ultra marathon race. Our data suggest that chronic endurance training may provide protective effects on TL attenuating biological aging. Conversely, acute exposure to an ultra-distance endurance trail race implies telomere shortening probably caused by oxidative DNA damage. PMID- 26001754 TI - Quantitative analysis of the relative mutagenicity of five chemical constituents of tobacco smoke in the mouse lymphoma assay. AB - Quantifying health-related biological effects, like genotoxicity, could provide a way of distinguishing between tobacco products. In order to develop tools for using genotoxicty data to quantitatively evaluate the risk of tobacco products, we tested five carcinogens found in cigarette smoke, 4-aminobiphenyl (4-ABP), benzo[a]pyrene (BaP), cadmium (in the form of CdCl2), 2-amino-3,4-dimethyl-3H imidazo[4,5-f]quinoline (MeIQ) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the mouse lymphoma assay (MLA). The resulting mutagenicity dose responses were analyzed by various quantitative approaches and their strengths and weaknesses for distinguishing responses in the MLA were evaluated. L5178Y/Tk (+/-) 3.7.2C mouse lymphoma cells were treated with four to seven concentrations of each chemical for 4h. Only CdCl2 produced a positive response without metabolic activation (S9); all five chemicals produced dose-dependent increases in cytotoxicity and mutagenicity with S9. The lowest dose exceeding the global evaluation factor, the benchmark dose producing a 10%, 50%, 100% or 200% increase in the background frequency (BMD10, BMD50, BMD100 and BMD200), the no observed genotoxic effect level (NOGEL), the lowest observed genotoxic effect level (LOGEL) and the mutagenic potency expressed as a mutant frequency per micromole of chemical, were calculated for all the positive responses. All the quantitative metrics had similar rank orders for the agents' ability to induce mutation, from the most to least potent as CdCl2(-S9) > BaP(+S9) > CdCl2(+S9) > MeIQ(+S9) > 4 ABP(+S9) > NNK(+S9). However, the metric values for the different chemical responses (i.e. the ratio of the greatest value to the least value) for the different chemicals ranged from 16-fold (BMD10) to 572-fold (mutagenic potency). These results suggest that data from the MLA are capable of discriminating the mutagenicity of various constituents of cigarette smoke, and that quantitative analyses are available that can be useful in distinguishing between the exposure responses. PMID- 26001755 TI - Elucidation of changes in molecular signalling leading to increased cellular transformation in oncogenically progressed human bronchial epithelial cells exposed to radiations of increasing LET. AB - The early transcriptional response and subsequent induction of anchorage independent growth after exposure to particles of high Z and energy (HZE) as well as gamma-rays were examined in human bronchial epithelial cells (HBEC3KT) immortalised without viral oncogenes and an isogenic variant cell line whose p53 expression was suppressed but that expressed an active mutant K-RAS(V12) (HBEC3KT P53KRAS). Cell survival following irradiation showed that HBEC3KT-P53KRAS cells were more radioresistant than HBEC3KT cells irrespective of the radiation species. In addition, radiation enhanced the ability of the surviving HBEC3KT P53RAS cells but not the surviving HBEC3KT cells to grow in anchorage-independent fashion (soft agar colony formation). HZE particle irradiation was far more efficient than gamma-rays at rendering HBEC3KT-P53RAS cells permissive for soft agar growth. Gene expression profiles after radiation showed that the molecular response to radiation for HBEC3KT-P53RAS, similar to that for HBEC3KT cells, varies with radiation quality. Several pathways associated with anchorage independent growth, including the HIF-1alpha, mTOR, IGF-1, RhoA and ERK/MAPK pathways, were over-represented in the irradiated HBEC3KT-P53RAS cells compared to parental HBEC3KT cells. These results suggest that oncogenically progressed human lung epithelial cells are at greater risk for cellular transformation and carcinogenic risk after ionising radiation, but particularly so after HZE radiations. These results have implication for: (i) terrestrial radiation and suggests the possibility of enhanced carcinogenic risk from diagnostic CT screens used for early lung cancer detection; (ii) enhanced carcinogenic risk from heavy particles used in radiotherapy; and (iii) for space radiation, raising the possibility that astronauts harbouring epithelial regions of dysplasia or hyperplasia within the lung that contain oncogenic changes, may have a greater risk for lung cancers based upon their exposure to heavy particles present in the deep space environment. PMID- 26001756 TI - Antigenotoxic and antimutagenic effects of diphenyl ditelluride against several known mutagens in Chinese hamster lung fibroblasts. AB - The present study evaluates antigenotoxic and antimutagenic properties of diphenyl ditelluride (DPDT) against several known mutagens in Chinese hamster lung fibroblasts (V79 cells). DPDT was not cytotoxic and genotoxic at concentrations ranging from 0.01 to 0.1 MUM. The pre-treatment for 2h with this organotellurium compound at non-cytotoxic dose range (0.01, 0.05 and 0.1 MUM) increased cell survival after challenge with hydrogen peroxide (H2O2), t-butyl hydroperoxide (t-BOOH), methylmethanesulphonate (MMS) or ultraviolet (UV)C radiation. In addition, the pre-treatment with DPDT decreased the DNA damage and Formamidopyrimidine DNA-glycosylase (Fpg)- and Endonuclease III (Endo III) sensitive sites induction by the studied genotoxic agents, as verified by comet assay and modified comet assay, respectively. The pre-treatment also reduced micronucleus frequency, revealing the protector effect of DPDT against MMS and UVC-induced mutagenesis. Our results demonstrate that DPDT-treated cells at concentration range of 0.01-0.1 MUM do not change thiobarbituric acid reactive species (TBARS) levels and ROS generation. Moreover, DPDT pre-treatment at this concentration range decreases the ROS induction by H2O2 and t-BOOH treatment indicating antioxidant potential. On the other hand, concentrations higher than 0.1 MUM increase TBARS formation and inhibited superoxide dismutase (SOD) activity, suggesting pro-oxidative effect of this compound at high concentrations. Our results suggest that DPDT presents antigenotoxic and antimutagenic properties at concentration range of 0.01-0.1 MUM. The protection effect could be attributed to antioxidant capacity of DPDT at this concentration range in V79 cells. PMID- 26001757 TI - Emtricitabine/rilpivirine/tenofovir disoproxil fumarate for the treatment of HIV 1 infection in adults. AB - This paper reviews the current literature and information on the combination drug Complera(TM) (rilpivirine/emtricitabine/tenofovir disoproxil fumarate) that was approved by the Food and Drug Administration (FDA) in August 2011. PubMed, Cochrane and Embase (2001-2014) were searched for primary and review articles on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate, individually or in combination. Data from drug manufacturer and product label was also used. Clinical trial reports were selected, extracted and analyzed to include relevant and recent ones. Selected English-language trials were limited to those with human subjects and included both safety and efficacy outcomes. Results from two phase 3 randomized double blind trials (ECHO and THRIVE) showed that rilpivirine is non-inferior to efavirenz in suppressing viral load below 50 copies/mL in anti retroviral therapy (ART) naive human immunodeficiency virus (HIV) infected patients. In addition, psychiatric disturbances, rash and increase in lipid levels occurred less frequently with rilpivirine when compared to efavirenz. However, virological failure and drug resistance were higher with rilpivirine in patients with baseline viral load >100,000 copies/mL. Rilpivirine showed cross resistance to efavirenz and etravirine. Efavirenz, on the other hand, did not demonstrate cross resistance to rilpivirine and etravirine, leaving the latter drugs as options for use in case of virological failure with efavirenz. Complera(TM) remains an acceptable alternative treatment to Atripla(TM) in ART naive patients who have a pre-ART plasma HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm(3) with non-inferior efficacy and better safety and tolerability. PMID- 26001760 TI - Teaching Adults With Intellectual Disability Manual Signs Through Their Support Staff: A Key Word Signing Program. AB - PURPOSE: The goal of this study was to evaluate a key word signing (KWS) program in which adults with mild to severe intellectual disability (ID) were taught manual signs through their support staff. Our hypothesis was that spontaneous manual sign production of participants would increase significantly after 12 months of implementation of the KWS program. METHOD: A KWS immersion program was implemented in a facility for adults with ID. First, 8 support workers received 8 hr of training. These KWS ambassadors then taught 2 manual signs per week to their colleagues, who modeled the use of the signs throughout the day in natural interactions with their clients. KWS use in 15 adults with ID and 15 of their support staff was evaluated before the start of the program and at a 12-month follow-up using a narrative task and during spontaneous conversation. RESULTS: Manual sign production of support workers and adults with ID had increased significantly 12 months after the start of the program. The adults with ID were able to express significantly more communicative functions in their narrative language after the intervention and when using KWS. CONCLUSION: The KWS program was successful and can be applied in similar clinical settings. PMID- 26001761 TI - Differentiation of Wharton's Jelly-Derived Mesenchymal Stem Cells into Motor Neuron-Like Cells on Three-Dimensional Collagen-Grafted Nanofibers. AB - Cell transplantation strategies have provided potential therapeutic approaches for treatment of neurodegenerative diseases. Mesenchymal stem cells from Wharton's jelly (WJMSCs) are abundant and available adult stem cells with low immunological incompatibility, which could be considered for cell replacement therapy in the future. However, MSC transplantation without any induction or support material causes poor control of cell viability and differentiation. In this study, we investigated the effect of the nanoscaffolds on WJMSCs differentiation into motor neuronal lineages in the presence of retinoic acid (RA) and sonic hedgehog (Shh). Surface properties of scaffolds have been shown to significantly influence cell behaviors such as adhesion, proliferation, and differentiation. Therefore, polycaprolactone (PCL) nanofibers were constructed via electrospinning, surface modified by plasma treatment, and grafted by collagen. Characterization of the scaffolds by means of ATR-FTIR, contact angel, and Bradford proved grafting of the collagen on the surface of the scaffolds. WJMSCs were seeded on nanofibrous and tissue culture plate (TCP) and viability of WJMSCs were measured by MTT assay and then induced to differentiate into motor neuron-like cells for 15 days. Differentiated cells were evaluated morphologically, and real-time PCR and immunocytochemistry methods were done to evaluate expression of motor neuron-like cell markers in mRNA and protein levels. Our results showed that obtained cells could express motor neuron biomarkers at both RNA and protein levels, but the survival and differentiation of WJMSCs into motor neuron-like cells on the PCL/collagen scaffold were higher than cultured cells in the TCP and PCL groups. Taken together, WJMSCs are an attractive stem cell source for inducing into motor neurons in vitro especially when grown on nanostructural scaffolds and PCL/collagen scaffolds can provide a suitable, three dimensional situation for neuronal survival and differentiation that suggest their potential application towards nerve regeneration. PMID- 26001763 TI - The first record of Gyrodactylus corleonis Paladini, Cable, Fioravanti, Faria & Shinn, 2010 (Monogenea: Gyrodactylidae) from the wild. AB - Specimens of Gyrodactylus corleonis Paladini, Cable, Fioravanti, Faria & Shinn, 2010 (Monogenea: Gyrodactylidae) were collected from the body and fins of Gobius cobitis Pallas in the western Mediterranean Sea off northwestern Sardinia. This is the first finding of this species in the wild and also represents a new host record. A morphological comparison of the new material with the type description of G. corleonis is presented. Since G. corleonis was found in the wild on representatives of the Gobiidae, a comparison with species of Gyrodactylus von Nordmann, 1832 parasitising gobies is included. The occurrence of G. corleonis on different host species and its phylogenetic relationships with gyrodactylids from sand gobies are discussed. PMID- 26001762 TI - Chronic Treatment with a Clinically Relevant Dose of Methylphenidate Increases Glutamate Levels in Cerebrospinal Fluid and Impairs Glutamatergic Homeostasis in Prefrontal Cortex of Juvenile Rats. AB - The understanding of the consequences of chronic treatment with methylphenidate is very important since this psychostimulant is extensively prescribed to preschool age children, and little is known about the mechanisms underlying the persistent changes in behavior and neuronal function related with the use of methylphenidate. In this study, we initially investigate the effect of early chronic treatment with methylphenidate on amino acids profile in cerebrospinal fluid and prefrontal cortex of juvenile rats, as well as on glutamatergic homeostasis, Na(+),K(+)-ATPase function, and balance redox in prefrontal cortex of rats. Wistar rats at early age received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 45th day of age. Twenty-four hours after the last injection, the animals were decapitated and the cerebrospinal fluid and prefrontal cortex were obtained. Results showed that methylphenidate altered amino acid profile in cerebrospinal fluid, increasing the levels of glutamate. Glutamate uptake was decreased by methylphenidate administration, but GLAST and GLT-1 were not altered by this treatment. In addition, the astrocyte marker GFAP was not altered by MPH. The activity and immunocontent of catalytic subunits (alpha1, alpha2, and alpha3) of Na(+),K(+)-ATPase were decreased in prefrontal cortex of rats subjected to methylphenidate treatment, as well as changes in alpha1 and alpha2 gene expression of catalytic alpha subunits of Na(+),K(+)-ATPase were also observed. CAT activity was increased and SOD/CAT ratio and sulfhydryl content were decreased in rat prefrontal cortex. Taken together, our results suggest that chronic treatment with methylphenidate at early age induces excitotoxicity, at least in part, due to inhibition of glutamate uptake probably caused by disturbances in the Na(+),K(+)-ATPase function and/or in protein damage observed in the prefrontal cortex. PMID- 26001765 TI - Outcomes of The BODY Project: A Program to Halt Obesity and Its Medical Consequences in High School Students. AB - Adolescent obesity continues to be a major public health issue with a third of American adolescents being overweight or obese. Excess weight is associated with cardiovascular risk factors and pre-diabetes. High school students identified as carrying excess weight [body mass index (BMI) >=25 kg/m(2), or BMI percentile >=85 %] were invited to participate in The BODY Project, an intervention that included a medical evaluation and a personalized medical report of the results of that evaluation sent to the parent/guardian at home. The medical evaluation and report was repeated 12 months later. The reports also contained advice on how the individual student could modify their lifestyle to improve the specific medical parameters showing abnormalities. Outcomes were change in BMI, blood pressure, high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting glucose, and fasting insulin. Students participating in The BODY Project intervention demonstrated modest, yet significant, reductions in BMI (p < 0.001) 1 year later, and also had significant improvements in systolic blood pressure (p < 0.001) and cholesterol profile (HDL p = 0.002; LDL p < 0.001) at follow-up. The BODY Project, by means of a minimal educational program anchored on the principle of teachable moments around the students' increased perception of their own risk for disease from the medical abnormalities uncovered, demonstrates evidence of potential effectiveness in addressing adolescent obesity. PMID- 26001766 TI - [Acute abdomen due to complicated intramural duodenal haematoma. Report of a case and review of the literature]. AB - BACKGROUND: Intramural duodenal haematoma is a rare entity that usually occurs in the context of patients with coagulation disorders. A minimum percentage is related to processes such as pancreatitis and pancreatic tumours. CLINICAL CASE: The case is presented of a 45 year-old male with a history of chronic pancreatitis secondary to alcoholism. He was seen in the emergency room due to abdominal pain, accompanied by toxic syndrome. The abdominal computed tomography reported increased concentric duodenal wall thickness, in the second and third portion. After oesophageal-gastro-duodenoscopy, he presented with haemorrhagic shock. He had emergency surgery, finding a hemoperitoneum, duodenopancreatic tumour with intense inflammatory component, as well a small bowel perforation of third duodenal portion. A cephalic duodenopancreatectomy was performed with pyloric preservation and reconstruction with Roux-Y. DISCUSSION: Treatment of a duodenal haematoma is nasogastric decompression, blood transfusion and correction of coagulation abnormalities. Surgery is indicated in the cases in which there is no improvement after 2 weeks of treatment, or there is suspicion of malignancy or major complications arise. CONCLUSIONS: Duodenal intramural haematoma secondary to chronic pancreatitis is rare, although the diagnosis should be made with imaging and, if suspected, start conservative treatment and surgery only in complicated cases. PMID- 26001767 TI - [Cutaneous malignant melanoma and the new drugs]. AB - The treatment of cutaneous melanoma has historically been essentially surgical. Much progress has been made in this area, and the resection margins have been established based on tumour depth. Candidates are also identified for lymphadenectomy, avoiding the morbidity of the procedure in patients who do not require it. But little progress has been made in systemic treatment, since the 70's when the use of dacarbazine was introduced for the treatment of patients with tumour progression or distant metastasis, with disappointing results. Despite this, Dacarbazine has been the most used drug to the present. Three years ago, two new drugs were introduced, one of them based on the target therapy and other one in the immunotherapy, offering, with the obtained results, an alternative in the treatment of cutaneous melanoma The objectives of this article are to show the pathways of these drugs, to describe the current role of surgery in cutaneous melanoma, with the arrival of these drugs, as well as to know the therapeutic alternatives that are emerging for the cutaneous melanoma based on scientific evidence. PMID- 26001768 TI - HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase dependent pathway in an in vitro model. AB - Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves F-actin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, a process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c Met signaling during oval cell-mediated mouse liver regeneration. PMID- 26001769 TI - A comparison of outcomes after percutaneous nephrolithotomy in children and adults: a matched cohort study. AB - INTRODUCTION: Percutaneous nephrolithotomy (PCNL) has surpassed open stone surgery as the operation of choice for large and complex stone burdens (figure). Although the procedure was developed in adults, its principles have been extrapolated to children. There is a paucity of literature comparing outcomes of PCNL in adults and children for similar stone burdens. OBJECTIVE: The purpose of this study was to evaluate outcomes following PCNL among children and adults with similar stone burdens. PATIENTS AND METHODS: Data on patient characteristics and outcomes for 2196 consecutive patients undergoing PCNL at a single institution were collected prospectively from January 1992 to July 2013. Thirty-one pediatric patients undergoing 39 PCNLs were identified. Each pediatric PCNL was matched in a ratio of 1:4 to adult PCNLs by year of surgery and stone burden characteristics (staghorn, partial staghorn, number of stones). All PCNLs were performed by two fellowship-trained endourologists who operate on both adult and pediatric patients. Ultrasonic lithotripsy was used primarily. The primary outcome measure was stone-free rate (SFR) at hospital discharge. Secondary outcomes included the need for second-look nephroscopy, length of hospital stay, complication rate, and blood transfusion rate. The Student t test was used for continuous variables and the Fisher exact for categorical variables. RESULTS: The median age for the pediatric group was 13.9 +/- 4.30 years and for the adult group was 55.4 +/- 15.1 years. Pediatric patients tended to present with metabolic stones, with no difference in rates of infection stones. No difference was found in SFR at time of hospital discharge (86.1% vs. 86.4%, p = 0.2). More pediatric patients required a second access tract than adult patients (15.4% vs. 4.52%, p = 0.02). There was no significant difference in the need for second-look nephroscopy, length of stay, or complication rates (overall and by Clavien classification subgroup) between both groups. The rates of blood transfusion were low in both groups (0% vs. 0.6%, p = 0.80). DISCUSSION: There was no difference in primary and secondary outcomes among children compared with adults undergoing PCNL in our study. The outcomes reported in this study were similar to published literature. A limitation of this study is the low number of pediatric patients. However, it is unique to have a single-center study that compares PCNL outcomes in both adult and pediatric patient and accounts for stone burden characteristics. CONCLUSIONS: Although principles of PCNL were developed in adults, this study affirms the safety and efficacy of PCNL in both pediatric and adult patients. PMID- 26001770 TI - Activation of Hippocampal CREB by Rolipram Partially Recovers Balance Between TNF alpha and IL-10 Levels and Improves Cognitive Deficits in Diabetic Rats. AB - Diabetes damages the central nervous system, inducing cognitive dysfunction and structural changes, known as diabetic encephalopathy (DE). Some research suggests that the pathogenesis of DE may involve an inflammatory imbalance in the nervous system, along with beta-amyloid deposition, similar to Alzheimer's disease. Less data have been yet provided to prove that mechanism. The aim of this study was to evaluate the influence of diabetes on the expression of TNF-alpha, IL-10, and cAMP response element-binding protein (CREB)/phosphorylated CREB (pCREB). Moreover, we investigated whether rolipram can improve memory, suppress the inflammatory response, and improve balance of CREB/pCREB in the hippocampus of diabetic rats. We used a 4-week high-fat diet and a low dose of streptozocin (30 mg/kg) to induce diabetes with hyperinsulinemia and hyperglycemia. Cognitive impairment was induced over a period of 4 months, and rolipram treatment was concomitantly given. Cognitive impairment was evaluated with the Morris water maze test. We also assessed expression of the pro-inflammatory cytokine TNF-alpha and the anti-inflammatory cytokine IL-10. We found that memory in rats with long term diabetes was impaired. Treatment with rolipram increased expression of CREB and pCREB, reduced the inflammatory reaction (decreased TNF-alpha levels and increased IL-10 levels), and prevented cognitive impairment in these diabetic animals. This present study suggests that rolipram improves cognitive function by activating the CREB signaling pathway and alleviating neuroinflammation in type 2 diabetic rats. Rolipram may have therapeutic potential in DE. PMID- 26001771 TI - Altered brain rhythms and functional network disruptions involved in patients with generalized fixation-off epilepsy. AB - Generalized Fixation-off Sensitivity (CGE-FoS) patients present abnormal EEG patterns when losing fixation. In the present work, we studied two CGE-FoS epileptic patients with simultaneous EEG-fMRI. We aim to identify brain areas that are specifically related to the pathology by identifying the brain networks that are related to the EEG brain altered rhythms. Three main analyses were performed: EEG standalone, where the voltage fluctuations in delta, alpha, and beta EEG bands were obtained; fMRI standalone, where resting-state fMRI ICA analyses for opened and closed eyes conditions were computed per subject; and, EEG-informed fMRI, where EEG delta, alpha and beta oscillations were used to analyze fMRI. Patient 1 showed EEG abnormalities for lower beta band EEG brain rhythm. Fluctuations of this rhythm were correlated with a brain network mainly composed by temporo-frontal areas only found in the closed eyes condition. Patient 2 presented alterations in all the EEG brain rhythms (delta, alpha, beta) under study when closing eyes. Several biologically relevant brain networks highly correlated (r > 0.7) to each other in the closed eyes condition were found. EEG-informed fMRI results in patient 2 showed hypersynchronized patterns in the fMRI correlation spatial maps. The obtained findings allow a differential diagnosis for each patient and different profiles with respect to healthy volunteers. The results suggest a different disruption in the functional brain networks of these patients that depends on their altered brain rhythms. This knowledge could be used to treat these patients by novel brain stimulation approaches targeting specific altered brain networks in each patient. PMID- 26001772 TI - Application of hydrogels as submucosal fluid cushions for endoscopic mucosal resection and submucosal dissection. AB - Numerous new techniques have recently been reported and described for the endoscopic mucosal resection (EMR) of large superficial lesions of the gastrointestinal tract, using various natural, synthetic, and semi-synthetic materials such as chitin/chitosan and their derivatives. Although saline-assisted EMR is an established minimally invasive therapy, en bloc resection and histopathological analyses are required to determine its curative potential. In addition, complete resection of lesions of >2 cm in diameter remains difficult, despite improved EMR techniques. The development of endoscopic submucosal dissection (ESD) has increased dissection rates for en bloc resection of large lesions, but perforation occurs more frequently during ESD than during EMR. Submucosal injections of those biomaterials which have high viscosity and hydrogelatinization ability as submucosal fluid cushions (SFC) may facilitate ESD as well as EMR for the treatment of superficial tumors of the alimentary tract. In this review, we describe the application of biomaterials such as chitosan derivatives, sodium hyaluronate, and 50% glucose as a SFC for ESD, focusing photocrosslinked chitosan hydrogels (PCH) which we have originally developed. PMID- 26001774 TI - ICAM-1-dependent and ICAM-1-independent neutrophil lung infiltration by porcine reproductive and respiratory syndrome virus infection. AB - Neutrophils are innate immune cells that play a crucial role in the first line of host defense. It is also known that neutrophil lung recruitment and infiltration may cause lung injury. The roles of neutrophils in virus infection-induced lung injury are not clear. We explore the mechanisms of neutrophil lung infiltration and the potential biomarkers for lung injury in a swine model of lung injury caused by natural or experimental porcine reproductive and respiratory syndrome virus (PRRSV) infection. Neutrophil lung infiltration was determined by measurement of myeloperoxidase expression and enzyme activity of lung tissues. Myeloperoxidase expression and enzyme activity were dramatically increased in the naturally and experimentally infected lung tissues. Chemokine analysis by quantitative PCR and ELISA showed that IL-8 expression was increased in both infections, while monocyte chemoattractant protein-1 expression was increased only in experimentally infected lung tissues. Expression of the cell adhesion molecules VCAM-1 and ICAM-1 was measured by quantitative PCR and Western blotting. VCAM-1 expression was increased in experimentally and naturally infected lungs, whereas ICAM-1 expression was increased only in the naturally infected lung samples. Our results suggest that neutrophil lung infiltrations in the infected animals are both ICAM-1- and -independent and that combined expression of VCAM-1 and IL-8 may serve as the biomarker for lung injury induced by virus infection. PMID- 26001773 TI - Automated acquisition and analysis of airway surface liquid height by confocal microscopy. AB - The airway surface liquid (ASL) is a thin-liquid layer that lines the luminal side of airway epithelia. ASL contains many molecules that are involved in primary innate defense in the lung. Measurement of ASL height on primary airway cultures by confocal microscopy is a powerful tool that has enabled researchers to study ASL physiology and pharmacology. Previously, ASL image acquisition and analysis were performed manually. However, this process is time and labor intensive. To increase the throughput, we have developed an automatic ASL measurement technique that combines a fully automated confocal microscope with novel automatic image analysis software that was written with image processing techniques derived from the computer science field. We were able to acquire XZ ASL images at the rate of ~ 1 image/s in a reproducible fashion. Our automatic analysis software was able to analyze images at the rate of ~ 32 ms/image. As proofs of concept, we generated a time course for ASL absorption and a dose response in the presence of SPLUNC1, a known epithelial sodium channel inhibitor, on human bronchial epithelial cultures. Using this approach, we determined the IC50 for SPLUNC1 to be 6.53 MUM. Furthermore, our technique successfully detected a difference in ASL height between normal and cystic fibrosis (CF) human bronchial epithelial cultures and detected changes in ATP-stimulated Cl(-)/ASL secretion. We conclude that our automatic ASL measurement technique can be applied for repeated ASL height measurements with high accuracy and consistency and increased throughput. PMID- 26001775 TI - Time course of cigarette smoke-induced changes of systemic inflammation and muscle structure. AB - It has become more evident that long-term cigarette smoking (LTCS) has an important extrapulmonary toxicity. The aim of the study was to investigate the time-dependent effects of cigarette smoke exposure on exercise capacity, markers of systemic inflammation, and skeletal muscle structure. c57bl/6j-mice were either exposed to mainstream cigarette smoke for 6 h/day, 5 days/wk [smoke exposed (SE) group] or assigned to the control, unexposed group (Con group). SE group mice were exposed for 8, 16, 24, and 32 wk to smoke and unexposed Con mice were used as age-matched controls. Exercise capacity was investigated by spiroergometry. Systemic inflammatory status was analyzed by flow cytometry and multiplexed fluorescent immunoassay. For analysis of muscle tissue, histological techniques and microarray analysis were used. Mice of the SE group exhibited a lower increase of body mass and a decrease of Vo2 max (P < 0.05). An increase of lymphocyte CD62, ICAM, and VCAM expression was found in SE mice (P < 0.05). A biphasic trend of protein up- and downregulation was observed in markers of systemic inflammation, tissue deterioration, and allergic reactions such as C reactive protein (CRP), eotaxin, haptoglobin, macrophage colony-stimulating factor-1 (M-CSF-1), and macrophage inflammatory protein-1gamma (MIP-1gamma). Thereby, the expression of several chemotactic proteins in plasma correlated with their expression in muscle. A time-dependent decrease of muscle mass, oxidative type-I fibers, and muscle cross-sectional area was found (P < 0.05). Microarray analysis revealed a SE-induced upregulation of several pathways of metabolic processes and tissue degradation. Taken together it was found that the loss of exercise capacity and systemic inflammation are early events of SE, which might induce muscular atrophy and loss of oxidative muscle capacity. PMID- 26001776 TI - 14-3-3 isoforms bind directly exon B of the 5'-UTR of human surfactant protein A2 mRNA. AB - Human surfactant protein (SP) A (SP-A), an innate immunity molecule, is encoded by two genes, SFTPA1 and SFTPA2. The 5'-untranslated splice variant of SP-A2 (ABD), but not SP-A1 (AD), contains exon B (eB). eB is an enhancer for transcription and translation and contains cis-regulatory elements. Specific trans-acting factors, including 14-3-3, bind eB. The 14-3-3 protein family contains seven isoforms that have been found by mass spectrometry in eB electromobility shift assays (Noutsios et al. Am J Physiol Lung Cell Mol Physiol 304: L722-L735, 2013). We used four different approaches to investigate whether 14-3-3 isoforms bind directly to eB. 1) eB RNA pulldown assays showed that 14-3-3 isoforms specifically bind eB. 2) RNA electromobility shift assay complexes were formed using purified 14-3-3 isoforms beta, gamma, epsilon, eta, sigma, and tau, but not isoform zeta, with wild-type eB RNA. 3 and 4) RNA affinity chromatography assays and surface plasmon resonance analysis showed that 14-3-3 isoforms beta, gamma, epsilon, eta, sigma, and tau, but not isoform zeta, specifically and directly bind eB. Inhibition of 14-3-3 isoforms gamma, epsilon, eta, and tau/theta with shRNAs in NCI-H441 cells resulted in downregulation of SP-A2 levels but did not affect SP-A1 levels. However, inhibition of 14-3-3 isoform sigma was correlated with lower levels of SP-A1 and SP-A2. Inhibition of 14-3-3 isoform zeta/delta, which does not bind eB, had no effect on expression levels of SP-A1 and SP-A2. In conclusion, the 14-3-3 protein family affects differential regulation of SP-A1 and SP-A2 by binding directly to SP-A2 5'-UTR mRNA. PMID- 26001777 TI - IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle. AB - Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay. IL-6 trans-signaling had no effect on phosphoinositide-3 kinase and Erk MAP kinase pathways in HASM cells. Both classical and IL-6 trans signaling in HASM involves activation of Stat3. However, the kinetics of Stat3 phosphorylation by IL-6 trans-signaling was different than classical IL-6 signaling. This was further reflected in the differential gene expression profile by IL-6 trans-signaling in HASM cells. Under IL-6 trans-signaling conditions 36 genes were upregulated, including PLA2G2A, IL13RA1, MUC1, and SOD2. Four genes, including CCL11, were downregulated at least twofold. The expression of 112 genes was divergent between IL-6 classical and trans-signaling, including the genes HILPDA, NNMT, DAB2, MUC1, WWC1, and VEGFA. Pathway analysis revealed that IL-6 trans-signaling induced expression of genes involved in regulation of airway remodeling, immune response, hypoxia, and glucose metabolism. Treatment of HASM cells with IL-6+sIL6R induced proliferation in a dose-dependent fashion, suggesting a role for IL-6 trans-signaling in asthma pathogenesis. These novel findings demonstrate differential effect of IL-6 trans-signaling on airway cells and identify IL-6 trans-signaling as a potential modifier of airway inflammation and remodeling. PMID- 26001778 TI - Influenza-induced type I interferon enhances susceptibility to gram-negative and gram-positive bacterial pneumonia in mice. AB - Suppression of type 17 immunity by type I interferon (IFN) during influenza A infection has been shown to enhance susceptibility to secondary bacterial pneumonia. Although this mechanism has been described in coinfection with gram positive bacteria, it is unclear whether similar mechanisms may impair lung defense against gram-negative infections. Furthermore, precise delineation of the duration of type I IFN-associated susceptibility to bacterial infection remains underexplored. Therefore, we investigated the effects of preceding influenza A virus infection on subsequent challenge with the gram-negative bacteria Escherichia coli or Pseudomonas aeruginosa and the temporal association between IFN expression with susceptibility to Staphylococcus aureus challenge in a mouse model of influenza and bacterial coinfection. Here we demonstrate that preceding influenza A virus led to increased lung E. coli and P. aeruginosa bacterial burden, which was associated with suppression of type 17 immunity and attenuation of antimicrobial peptide expression. Enhanced susceptibility to S. aureus coinfection ceased at day 14 of influenza infection, when influenza-associated type I IFN levels had returned to baseline levels, further suggesting a key role for type I IFN in coinfection pathogenesis. These findings further implicate type I IFN-associated suppression of type 17 immunity and antimicrobial peptide production as a conserved mechanism for enhanced susceptibility to both gram positive and gram-negative bacterial coinfection during influenza infection. PMID- 26001779 TI - Longitudinal analysis of peripheral blood T cell receptor diversity in patients with systemic lupus erythematosus by next-generation sequencing. AB - INTRODUCTION: T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) beta loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity. METHODS: Total RNA was isolated from the PB of 11 SLE patients. Each subject had three samples, collected at periods of clinical quiescence and at a flare. Twelve age matched healthy controls (HC) were used for reference. NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR beta loci. RESULTS: Relative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P <0.0002), a more uneven distribution of the repertoire (Gini coefficient, HC vs SLE, P = 0.015), and a trend toward increased percentage of expanded clones in the repertoire (clone size >1.0%, HC vs SLE, P = 0.078). No significant correlation between the overall repertoire diversity and clinical disease activity was observed for most SLE patients with only two of eleven SLE patients showing a decreasing trend in repertoire diversity approaching the flare time point. We did not observe any overlap of CDR3 amino acid sequences or a preferential Vbeta or Jbeta gene usage among the top 100 expanded clones from all SLE patients. In both HC and SLE, the majority of the expanded clones were remarkably stable over time (HC = 5.5 +/-0.5 months, SLE = 7.2 +/-2.4 months). CONCLUSIONS: A significant decrease in T cell repertoire diversity was observed in PB of SLE patients compared to HC. However, in most SLE patients, repertoire diversity did not change significantly with increases in disease activity to a flare. Thus, without a priori knowledge of disease-specific clones, monitoring TCR repertoire in PB from SLE patients is not likely to be useful to predict changes in disease activity. PMID- 26001780 TI - Transactional sex and HIV risks - evidence from a cross-sectional national survey among young people in Uganda. AB - BACKGROUND: Transactional sex is associated with the HIV epidemic among young people in Uganda. Few quantitative studies based on nationally representative survey data explored the relationship between sexual behaviors, HIV infection, and transactional sex. OBJECTIVE: This study aimed to determine the associations between risky sexual behaviors, participation in transactional sex, and HIV sero status among men and women aged 15-24 in Uganda. DESIGN: The study uses data from the Uganda AIDS Indicator Survey, a cross-sectional national HIV serological study conducted in 2011. We analyzed data on 1,516 men and 2,824 women aged 15-24 who had been sexually active in the 12 months preceding the survey. Private, face to-face interviews were also conducted to record the sociodemographics, sexual history, and experiences of sexual coercion. Logistic regression analysis was performed to measure associations between sexual behaviors and transactional sex, and associations between HIV sero-status and transactional sex. RESULTS: Among young people who had been sexually active in the 12 months prior to the survey, 5.2% of young men reported paying for sex while 3.7% of young women reported receiving gifts, favors, or money for sex. Lower educational attainment (ORadjusted 3.25, CI 1.10-9.60) and experience of sexual coercion (ORadjusted 2.83, CI 1.07-7.47) were significantly associated with paying for sex among men. Multiple concurrent sexual relationships were significantly associated with paying for sex among young men (ORadjusted 5.60, CI 2.08-14.95) and receiving something for sex among young women (ORadjusted 8.04, CI 2.55-25.37). Paying for sex among young men and having three to five lifetime sexual partners among young women were associated with increased odds of testing positive for HIV. CONCLUSIONS: Transactional sex is associated with sexual coercion and HIV risk behaviors such as multiple concurrent sexual partnerships among young people in Uganda. In addition, transactional sex appears to place young men at increased risk for HIV in Uganda. Both sexes appear equally vulnerable to risks associated with transactional sex, and therefore should be targeted in intervention programs. In addition, strengthening universal education policy and improving school retention programs may be beneficial in reducing risky sexual behaviors and transactional sex. PMID- 26001781 TI - Limited Addition of the 6-Arm beta1,2-linked N-Acetylglucosamine (GlcNAc) Residue Facilitates the Formation of the Largest N-Glycan in Plants. AB - The most abundant N-glycan in plants is the paucimannosidic N-glycan with core beta1,2-xylose and alpha1,3-fucose residues (Man3XylFuc(GlcNAc)2). Here, we report a mechanism in Arabidopsis thaliana that efficiently produces the largest N-glycan in plants. Genetic and biochemical evidence indicates that the addition of the 6-arm beta1,2-GlcNAc residue by N-acetylglucosaminyltransferase II (GnTII) is less effective than additions of the core beta1,2-xylose and alpha1,3-fucose residues by XylT, FucTA, and FucTB in Arabidopsis. Furthermore, analysis of gnt2 mutant and 35S:GnTII transgenic plants shows that the addition of the 6-arm non reducing GlcNAc residue to the common N-glycan acceptor GlcNAcMan3(GlcNAc)2 inhibits additions of the core beta1,2-xylose and alpha1,3-fucose residues. Our findings indicate that plants limit the rate of the addition of the 6-arm GlcNAc residue to the common N-glycan acceptor as a mechanism to facilitate formation of the prevalent N-glycans with Man3XylFuc(GlcNAc)2 and (GlcNAc)2Man3XylFuc(GlcNAc)2 structures. PMID- 26001782 TI - Exploring Multimodularity in Plant Cell Wall Deconstruction: STRUCTURAL AND FUNCTIONAL ANALYSIS OF Xyn10C CONTAINING THE CBM22-1-CBM22-2 TANDEM. AB - Elucidating the molecular mechanisms regulating multimodularity is a challenging task. Paenibacillus barcinonensis Xyn10C is a 120-kDa modular enzyme that presents the CBM22/GH10/CBM9 architecture found in a subset of large xylanases. We report here the three-dimensional structure of the Xyn10C N-terminal region, containing the xylan-binding CBM22-1-CBM22-2 tandem (Xyn10C-XBD), which represents the first solved crystal structure of two contiguous CBM22 modules. Xyn10C-XBD is folded into two separate CBM22 modules linked by a flexible segment that endows the tandem with extraordinary plasticity. Each isolated domain has been expressed and crystallized, and their binding abilities have been investigated. Both domains contain the R(W/Y)YYE motif required for xylan binding. However, crystallographic analysis of CBM22-2 complexes shows Trp-308 as an additional binding determinant. The long loop containing Trp-308 creates a platform that possibly contributes to the recognition of precise decorations at subsite S2. CBM22-2 may thus define a subset of xylan-binding CBM22 modules directed to particular regions of the polysaccharide. Affinity electrophoresis reveals that Xyn10C-XBD binds arabinoxylans more tightly, which is more apparent when CBM22-2 is tested against highly substituted xylan. The crystal structure of the catalytic domain, also reported, shows the capacity of the active site to accommodate xylan substitutions at almost all subsites. The structural differences found at both Xyn10C-XBD domains are consistent with the isothermal titration calorimetry experiments showing two sites with different affinities in the tandem. On the basis of the distinct characteristics of CBM22, a delivery strategy of Xyn10C mediated by Xyn10C-XBD is proposed. PMID- 26001783 TI - UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase. AB - Anserine (beta-alanyl-N(Pi)-methyl-L-histidine), a methylated derivative of carnosine (beta-alanyl-L-histidine), is an abundant constituent of vertebrate skeletal muscles. Although it has been suggested to serve as a proton buffer and radical scavenger, its physiological function remains mysterious. The formation of anserine is catalyzed by carnosine N-methyltransferase, recently identified in chicken as histamine N-methyltransferase-like (HNMT-like) protein. Although the HNMT-like gene is absent in mammalian genomes, the activity of carnosine N methyltransferase was reported in most mammalian species. In the present investigation, we purified carnosine N-methyltransferase from rat muscles about 2600-fold. Three polypeptides of ~ 45, 50, and 70 kDa coeluting with the enzyme activity were identified in the preparation. Mass spectrometry analysis of these polypeptides resulted in the identification of UPF0586 protein C9orf41 homolog as the only meaningful candidate. Rat UPF0586 and its yeast, chicken, and human orthologs were expressed in COS-7 cells and purified to homogeneity. Although all recombinant proteins catalyzed the formation of anserine, as confirmed by chromatographic and mass spectrometry analysis, rat UPF0586 was more active on carnosine than other orthologs. Confocal microscopy of HeLa cells expressing recombinant UPF5086 proteins revealed their presence in both cytosol and nucleus. Carnosine and Gly-His were the best substrates for all UPF0586 orthologs studied, although the enzymes also methylated other l-histidine-containing di- and tripeptides. Finally, cotransfection of COS-7 cells with rat or human UPF0586 and carnosine synthase transformed the cells into efficient anserine producers. We conclude that UPF0586 is mammalian carnosine N-methyltransferase and hypothesize that it may also serve as a peptide or protein methyltransferase in eukaryotes. PMID- 26001784 TI - Severe Extracellular Matrix Abnormalities and Chondrodysplasia in Mice Lacking Collagen Prolyl 4-Hydroxylase Isoenzyme II in Combination with a Reduced Amount of Isoenzyme I. AB - Collagen prolyl 4-hydroxylases (C-P4H-I, C-P4H-II, and C-P4H-III) catalyze formation of 4-hydroxyproline residues required to form triple-helical collagen molecules. Vertebrate C-P4Hs are alpha2beta2 tetramers differing in their catalytic alpha subunits. C-P4H-I is the major isoenzyme in most cells, and inactivation of its catalytic subunit (P4ha1(-/-)) leads to embryonic lethality in mouse, whereas P4ha1(+/-) mice have no abnormalities. To study the role of C P4H-II, which predominates in chondrocytes, we generated P4ha2(-/-) mice. Surprisingly, they had no apparent phenotypic abnormalities. To assess possible functional complementarity, we established P4ha1(+/-);P4ha2(-/-) mice. They were smaller than their littermates, had moderate chondrodysplasia, and developed kyphosis. A transient inner cell death phenotype was detected in their developing growth plates. The columnar arrangement of proliferative chondrocytes was impaired, the amount of 4-hydroxyproline and the Tm of collagen II were reduced, and the extracellular matrix was softer in the growth plates of newborn P4ha1(+/ );P4ha2(-/-) mice. No signs of uncompensated ER stress were detected in the mutant growth plate chondrocytes. Some of these defects were also found in P4ha2( /-) mice, although in a much milder form. Our data show that C-P4H-I can to a large extent compensate for the lack of C-P4H-II in proper endochondral bone development, but their combined partial and complete inactivation, respectively, leads to biomechanically impaired extracellular matrix, moderate chondrodysplasia, and kyphosis. Our mouse data suggest that inactivating mutations in human P4HA2 are not likely to lead to skeletal disorders, and a simultaneous decrease in P4HA1 function would most probably be required to generate such a disease phenotype. PMID- 26001785 TI - Structure Guided Chemical Modifications of Propylthiouracil Reveal Novel Small Molecule Inhibitors of Cytochrome b5 Reductase 3 That Increase Nitric Oxide Bioavailability. AB - NADH cytochrome b5 reductase 3 (CYB5R3) is critical for reductive reactions such as fatty acid elongation, cholesterol biosynthesis, drug metabolism, and methemoglobin reduction. Although the physiological and metabolic importance of CYB5R3 has been established in hepatocytes and erythrocytes, emerging investigations suggest that CYB5R3 is critical for nitric oxide signaling and vascular function. However, advancement toward fully understanding CYB5R3 function has been limited due to a lack of potent small molecule inhibitors. Because of this restriction, we modeled the binding mode of propylthiouracil, a weak inhibitor of CYB5R3 (IC50 = ~275 MUM), and used it as a guide to predict thiouracil-biased inhibitors from the set of commercially available compounds in the ZINC database. Using this approach, we validated two new potent derivatives of propylthiouracil, ZINC05626394 (IC50 = 10.81 MUM) and ZINC39395747 (IC50 = 9.14 MUM), both of which inhibit CYB5R3 activity in cultured cells. Moreover, we found that ZINC39395747 significantly increased NO bioavailability in renal vascular cells, augmented renal blood flow, and decreased systemic blood pressure in response to vasoconstrictors in spontaneously hypertensive rats. These compounds will serve as a new tool to examine the biological functions of CYB5R3 in physiology and disease and also as a platform for new drug development. PMID- 26001787 TI - Biogeographic history and cryptic diversity of saxicolous Tropiduridae lizards endemic to the semiarid Caatinga. AB - BACKGROUND: Phylogeographic research has advanced in South America, with increasing efforts on taxa from the dry diagonal biomes. However, the diversification of endemic fauna from the semiarid Caatinga biome in northeastern Brazil is still poorly known. Here we targeted saxicolous lizards of the Tropidurus semitaeniatus species group to better understand the evolutionary history of these endemic taxa and the Caatinga. We estimated a time-calibrated phylogeny for the species group based on two mitochondrial and two nuclear genes and jointly estimated the species limits and species tree within the group. We also devoted a denser phylogeographic sampling of the T. semitaeniatus complex to explore migration patterns, and the spatiotemporal diffusion history to verify a possible role of the Sao Francisco River as a promoter of differentiation in this saxicolous group of lizards. RESULTS: Phylogenetic analysis detected high cryptic genetic diversity, occurrence of unique microendemic lineages associated with older highlands, and a speciation history that took place during the Pliocene Pleistocene transition. Species delimitation detected five evolutionary entities within the T. semitaeniatus species group, albeit with low support. Thus, additional data are needed for a more accurate definition of species limits and interspecific relationships within this group. Spatiotemporal analyses reconstructed the geographic origin of the T. semitaeniatus species complex to be located north of the present-day course of the Sao Francisco River, followed by dispersal that expanded its distribution towards the northwest and south. Gene flow estimates showed higher migration rates into the lineages located north of the Sao Francisco River. CONCLUSIONS: The phylogenetic and population structures are intrinsically associated with stable rock surfaces and landscape rearrangements, such as the establishment of drainage basins located to the northern and southern distribution ranges. The T. semitaeniatus complex preserved high genetic diversity during range expansion, possibly as a result of frequent long-distance dispersal events. Our results indicate that both the current course of the Sao Francisco River and its paleo-courses had an important role in promoting diversification of the Caatinga endemic T. semitaeniatus species group. PMID- 26001786 TI - Structure and Regulation of the Movement of Human Myosin VIIA. AB - Human myosin VIIA (HM7A) is responsible for human Usher syndrome type 1B, which causes hearing and visual loss in humans. Here we studied the regulation of HM7A. The actin-activated ATPase activity of full-length HM7A (HM7AFull) was lower than that of tail-truncated HM7A (HM7ADeltaTail). Deletion of the C-terminal 40 amino acids and mutation of the basic residues in this region (R2176A or K2179A) abolished the inhibition. Electron microscopy revealed that HM7AFull is a monomer in which the tail domain bends back toward the head-neck domain to form a compact structure. This compact structure is extended at high ionic strength or in the presence of Ca(2+). Although myosin VIIA has five isoleucine-glutamine (IQ) motifs, the neck length seems to be shorter than the expected length of five bound calmodulins. Supporting this observation, the IQ domain bound only three calmodulins in Ca(2+), and the first IQ motif failed to bind calmodulin in EGTA. These results suggest that the unique IQ domain of HM7A is important for the tail neck interaction and, therefore, regulation. Cellular studies revealed that dimer formation of HM7A is critical for its translocation to filopodial tips and that the tail domain (HM7ATail) markedly reduced the filopodial tip localization of the HM7ADeltaTail dimer, suggesting that the tail-inhibition mechanism is operating in vivo. The translocation of the HM7AFull dimer was significantly less than that of the HM7ADeltaTail dimer, and R2176A/R2179A mutation rescued the filopodial tip translocation. These results suggest that HM7A can transport its cargo molecules, such as USH1 proteins, upon release of the tail-dependent inhibition. PMID- 26001788 TI - Primary diffuse large B-cell lymphoma associated with clonally-related monoclonal B lymphocytosis indicates a common precursor cell. PMID- 26001789 TI - Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk-assessment models. AB - Hospital-associated venous thromboembolism, including deep vein thrombosis and pulmonary embolism, is increasing in pediatric centers. The objective of this work was to systematically review literature on pediatric hospital-acquired venous thromboembolism risk factors and risk-assessment models, to inform future prevention research. We conducted a literature search on pediatric venous thromboembolism risk via PubMed (1946-2014) and Embase (1980-2014). Data on risk factors and risk-assessment models were extracted from case-control studies, while prevalence data on clinical characteristics were obtained from registries, large (n>40) retrospective case series, and cohort studies. Meta-analyses were conducted for risk factors or clinical characteristics reported in at least three studies. Heterogeneity among studies was assessed with the Cochran Q test and quantified by the I(2) statistic. From 394 initial articles, 60 met the final inclusion criteria (20 case-control studies and 40 registries/large case series/cohort studies). Significant risk factors among case-control studies were: intensive care unit stay (OR: 2.14, 95% CI: 1.97-2.32); central venous catheter (OR: 2.12, 95% CI: 2.00-2.25); mechanical ventilation (OR: 1.56, 95%CI: 1.42 1.72); and length of stay in hospital (per each additional day, OR: 1.03, 95% CI: 1.03-1.03). Three studies developed/applied risk-assessment models from a combination of these risk factors. Fourteen significant clinical characteristics were identified through non-case-control studies. This meta-analysis confirms central venous catheter, intensive care unit stay, mechanical ventilation, and length of stay as risk factors. A few pediatric hospital-acquired venous thromboembolism risk scores have emerged employing these factors. Prospective validation is necessary to inform risk-stratified prevention trials. PMID- 26001791 TI - Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia. AB - Multiparametric flow cytometry is an alternative approach to the polymerase chain reaction method for evaluating minimal residual disease in treatment protocols for primary acute lymphoblastic leukemia. Given considerable differences between primary and relapsed acute lymphoblastic leukemia treatment regimens, flow cytometric assessment of minimal residual disease in relapsed leukemia requires an independent comprehensive investigation. In the present study we addressed evaluation of minimal residual disease by flow cytometry in the clinical trial for childhood relapsed acute lymphoblastic leukemia using eight-color flow cytometry. The major challenge of the study was to reliably identify low amounts of residual leukemic cells against the complex background of regeneration, characteristic of follow-up samples during relapse treatment. In a prospective study of 263 follow-up bone marrow samples from 122 patients with B-cell precursor acute lymphoblastic leukemia, we tested various B-cell markers, adapted the antibody panel to the treatment protocol, and evaluated its performance by a blinded parallel comparison with the polymerase chain reaction data. The resulting eight-color single-tube panel showed a consistently high overall concordance (P<0.001) and, under optimal conditions, sensitivity similar to that of the reference polymerase chain reaction method. Overall, evaluation of minimal residual disease by flow cytometry can be successfully integrated into the clinical management of relapsed childhood acute lymphoblastic leukemia either as complementary to the polymerase chain reaction or as an independent risk stratification tool. ALL-REZ BFM 2002 clinical trial information: NCT00114348. PMID- 26001790 TI - BRCC3 mutations in myeloid neoplasms. AB - Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. PMID- 26001792 TI - The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention. AB - Standard treatment for Glanzmann thrombasthenia, a severe inherited bleeding disorder, is platelet transfusion. Recombinant factor VIIa is reported to be effective in Glanzmann thrombasthenia with platelet antibodies and/or refractoriness to platelet transfusions. We aimed to evaluate recombinant factor VIIa effectiveness and safety for the treatment and prevention of surgical bleeding in patients, with or without platelet antibodies and/or refractoriness, using data from the Glanzmann Thrombasthenia Registry, an international, multicenter, observational, post-marketing study of rFVIIa. Between 2007 and 2011, 96 patients were treated for 206 surgical procedures (minor 169, major 37). History of platelet antibodies was present in 43 patients, refractoriness in 23, antibodies+refractoriness in 17, while 47 had no confirmed antibodies/refractoriness. Treatments analyzed included antifibrinolytics, recombinant factor VIIa, recombinant factor VIIa+antifibrinolytics, platelets+/ antifibrinolytics and recombinant factor VIIa+platelets+/-antifibrinolytics. The most frequent treatment for minor procedures was recombinant factor VIIa+antifibrinolytics (n=65), and for major procedures, recombinant factor VIIa+platelets+/-antifibrinolytics (n=13). In patients without antibodies/refractoriness, recombinant factor VIIa, either alone or with antifibrinolytics, and platelets+/-antifibrinolytics were rated 100% effective for minor and major procedures. The effectiveness of treatment for minor procedures in patients with antibodies and refractoriness was 88.9% for recombinant factor VIIa, 100% for recombinant factor VIIa+antifibrinolytics, 66.7% for platelets+/-antifibrinolytics and 100% for recombinant factor VIIa+platelets+/-antifibrinolytics. One of four adverse events reported for surgery was considered recombinant factor VIIa-treatment-related (non-fatal thromboembolic event in an adult female receiving recombinant factor VIIa+platelets+antifibrinolytics). For all patients, regardless of platelet antibody or refractoriness status, recombinant factor VIIa, administered with or without platelets (+/-antifibrinolytics), provided effective hemostasis with a low frequency of adverse events in surgical procedures in Glanzmann thrombasthenia patients. This trial was registered at clinicaltrials.gov identifier: 01476423. PMID- 26001793 TI - The international, prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes of non-surgical bleeding episodes in patients with Glanzmann thrombasthenia. AB - Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets+/-antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets+/-antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets+/ antifibrinolytics, 78.8% for platelets+/-antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423. PMID- 26001794 TI - TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice. AB - The homeostasis of neutrophil granulocytes can affect the outcome of several inflammation-associated diseases including cancer. The regulation of this homeostasis is still not completely understood. We previously found that elevated systemic levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) induce an increase of neutrophils in the liver, which in turn strongly promotes liver metastasis. Here, we report that increasing systemic TIMP-1 levels were sufficient to induce neutrophilia in mice. This was not attributed to prolonged survival or direct mobilization of neutrophils. However, TIMP-1 induced enrichment of myeloid progenitors and concomitant upregulation of granulopoiesis associated genes in the bone marrow compartment. BrdU pulse-labeling confirmed that proliferating progenitors accounted for TIMP-1-induced neutrophilia. TIMP-1 variants that dissect its protease-inhibitory from its CD63 binding function relevant for cell signaling revealed that the TIMP-1 signaling domain was necessary and sufficient to augment granulopoiesis. Consequently, ablation of the TIMP-1 receptor CD63 abolished both neutrophilia and TIMP-1-enhanced granulopoiesis in the bone marrow. Our findings reveal that elevated levels of TIMP-1 impact on neutrophil homeostasis via signaling through CD63. This may provide a link to clinical observations, where TIMP-1 correlates with high severity and bad prognosis in inflammation-associated diseases. PMID- 26001795 TI - LARP4B is an AU-rich sequence associated factor that promotes mRNA accumulation and translation. AB - mRNAs are key molecules in gene expression and subject to diverse regulatory events. Regulation is accomplished by distinct sets of trans-acting factors that interact with mRNAs and form defined mRNA-protein complexes (mRNPs). The resulting "mRNP code" determines the fate of any given mRNA and thus controlling gene expression at the post-transcriptional level. The La-related protein 4B (LARP4B) belongs to an evolutionarily conserved family of RNA-binding proteins characterized by the presence of a La-module implicated in direct RNA binding. Biochemical experiments have shown previously direct interactions of LARP4B with factors of the translation machinery. This finding along with the observation of an association with actively translating ribosomes suggested that LARP4B is a factor contributing to the mRNP code. To gain insight into the function of LARP4B in vivo we tested its mRNA association at the transcriptome level and its impact on the proteome. PAR-CLIP analyses allowed us to identify the in vivo RNA targets of LARP4B. We show that LARP4B binds to a distinct set of cellular mRNAs by contacting their 3' UTRs. Biocomputational analysis combined with in vitro binding assays identified the LARP4B-binding motif on mRNA targets. The reduction of cellular LARP4B levels leads to a marked destabilization of its mRNA targets and consequently their reduced translation. Our data identify LARP4B as a component of the mRNP code that influences the expression of its mRNA targets by affecting their stability. PMID- 26001797 TI - In vitro permeability of silver nanoparticles through porcine oromucosal membrane. AB - Silver nanoparticles (AgNPs) can come in contact with human oral mucosa due to their wide use in food industry and hygiene devices. We evaluate transmucosal absorption of 19 nm AgNPs using excised porcine buccal mucosa applied on Franz diffusion cells. Two donor solutions were used: one containing AgNPs (0.5 g/L) and one derived from the ultrafiltration of the former and containing only Ag in its soluble form. Experiments were carried out separately for 4 h. Silver flux permeation was demonstrated through oral mucosa, showing similar values for AgNPs (6.8+/-4.5 ng cm(-2) h(-1)) and Ag ions (5.2+/-4.3 ng cm(-2) h(-1)). Our study demonstrates that silver can permeate the oromucosal barrier and that absorption is substantially due to Ag ions, since no permeation difference was found using the two solutions. Mucosal absorption has to be considered in further risk assessment studies. PMID- 26001796 TI - DcpS is a transcript-specific modulator of RNA in mammalian cells. AB - The scavenger decapping enzyme DcpS is a multifunctional protein initially identified by its property to hydrolyze the resulting cap structure following 3' end mRNA decay. In Saccharomyces cerevisiae, the DcpS homolog Dcs1 is an obligate cofactor for the 5'-3' exoribonuclease Xrn1 while the Caenorhabditis elegans homolog Dcs-1, facilitates Xrn1 mediated microRNA turnover. In both cases, this function is independent of the decapping activity. Whether DcpS and its decapping activity can affect mRNA steady state or stability in mammalian cells remains unknown. We sought to determine DcpS target genes in mammalian cells using a cell permeable DcpS inhibitor compound, RG3039 initially developed for therapeutic treatment of spinal muscular atrophy. Global mRNA levels were examined following DcpS decapping inhibition with RG3039. The steady-state levels of 222 RNAs were altered upon RG3039 treatment. Of a subset selected for validation, two transcripts that appear to be long noncoding RNAs HS370762 and BC011766, were dependent on DcpS and its scavenger decapping catalytic activity and referred to as DcpS-responsive noncoding transcripts (DRNT) 1 and 2, respectively. Interestingly, only the increase in DRNT1 transcript was accompanied with an increase of its RNA stability and this increase was dependent on both DcpS and Xrn1. Importantly, unlike in yeast where the DcpS homolog is an obligate cofactor for Xrn1, stability of additional Xrn1 dependent RNAs were not altered by a reduction in DcpS levels. Collectively, our data demonstrate that DcpS in conjunction with Xrn1 has the potential to regulate RNA stability in a transcript selective manner in mammalian cells. PMID- 26001798 TI - Cancer targeting propensity of folate conjugated surface engineered multi-walled carbon nanotubes. AB - Our main aim in the present investigation was to investigate the cancer targeting potential of docetaxel (DTX) loaded, folic acid (FA) terminated, poly (ethylene glycol) (PEG) conjugated, surface engineered multi walled carbon nanotubes (DTX/FA-PEG-MWCNTs) in tumor bearing Balb/c mice. The percent loading efficiency of DTX/FA-PEG-MWCNTs and DTX loaded MWCNTS (DTX/MWCNTs) was calculated to be 93.40+/-3.82% and 76.30+/-2.62%, respectively. Flow cytometry analysis suggested that the DTX/FA-PEG-MWCNTs arrested MCF-7 cells' cycle in the G2 phase and was more cytotoxic as compared to DTX/MWCNTs as well as free drug solution. The obtained pharmacokinetic parameters clearly describe the biocompatibility of engineered nanotubes to degree of functionalization and ability for prolonged residence inside the body. DTX/FA-PEG-MWCNTs was found to be significantly more efficient in tumor suppression as compared with plain MWCNTs (non-targeted) as well as drug solution owing to the enhanced drug release from endosomes after internalization. The DTX/FA-PEG-MWCNTs showed highly significant prolonged survival span (40 days) as compared to DTX/MWCNTs (24 days), free DTX (19 days) and control group (12 days). Overall, we can conclude that the DTX/FA-PEG-MWCNTs shows higher cancer targeting propensity vis a vis minimal side effects in tumor bearing Balb/c mice. PMID- 26001799 TI - Black hemostatic sponge based on facile prepared cross-linked graphene. AB - In this study, we demonstrate for the first time the remarkable hemostatic performance of a cross-linked graphene sponge (CGS) as a superb hemostat. The CGS can absorb plasma immediately (<40 ms) to form a blood cell layer and promotes subsequent clotting. The interaction between the interface of the CGS and blood cells reveals that the fast blood coagulation is primarily attributed to the enrichment of hemocytes and platelets on the wound surface. An in vitro dynamic whole-blood clotting test further highlights the effectiveness of the CGS. Considering the facile preparation, low cost, nontoxicity, and long shelf life of the portable black sponge, the CGS has great potential for trauma treatment. PMID- 26001800 TI - Stability and softening of a lipid monolayer in the presence of a pain-killer drug. AB - The aim of this study is to investigate the interaction of a drug (Piroxicam, 4 hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1 dioxide) with a lipid (DMPC) monolayer used as a membrane-mime in terms of drug-induced changes in stability and compressibility with variation in temperature, surface pressure, drug-dose and ionic states of the monolayers. Drug-induced fluidization is noticed in the pi-A isotherms through increase in phase-transition pressure at constant temperature. The long-term dynamics of the lipid-monolayer is characterized by algebraic decays in surface-energy E with time t, E~t(-p1,2,3), with an initial decay exponent p1 that changes to p2 after ~1000 s, and, at high surface pressures and/or drug-dose, to a third exponent p3 after ~3500 s, suggesting structural reorganizations in the monolayer. With increasing drug lipid ratio (D/L), p1 shows a decrease ending at an almost constant value after 0.05, p2 shows an almost negligible lowering while p3 shows a monotonic and considerable increase. The reorganization is summarized by proposing two mechanisms: (a) 'charging-discharging' where drug-molecules sitting parallel to the interface increase headgroup separations and (b) 'discharging-charging' where drug-molecules sitting roughly perpendicular to the interface bring headgroups closer. Drug-induced softening of lipid-monolayers is characterized by the compressibilites of pure and mixed lipid monolayers. Compressibility-change (i.e., compressibility difference between drug/lipid and pure lipid monolayer) with pressure is maximum in the LE-LC transition zone and compressibility-change with drug-dose reveals an optimum dose of drug for maximum increase in compressibility. Molecular dynamics simulation shows that the ordering in the different parts of the lipid chains is changed to different extents in the presence of drugs with maximum change near the headgroups and again points to an optimum dose for maximum disorder. PMID- 26001806 TI - Role of vitamin A in type 2 diabetes mellitus biology: effects of intervention therapy in a deficient state. AB - Diabetes has emerged as the biggest pandemic of our times, growing parallel to obesity. Insulin treatment regimens have been unable to completely inhibit protein glycation, which is responsible for the development of increased oxidative stress in diabetic tissues. Coupled with recent evidences that highlight the role of reactive oxygen species in the onset and progression of type 2 diabetes mellitus (T2DM), the antioxidants have taken prime focus as a possible intervention strategy. Studies have established a role of antioxidant vitamins C and E in improving patient condition in the past. Vitamin A, in addition to its role as an antioxidant, boasts a pleiotropic role in cell regulation through its action on gene regulation, maintenance of epithelial cell integrity, and resistance to infection. Studies have also ascribed a role to vitamin A in up-regulating the antioxidant enzyme functions in the body. Additionally, a link has been found between diabetes and deficient vitamin A levels indicating vitamin A supplementation may have a role in T2DM biology. This review therefore focuses on the vitamin A intervention in T2DM patients having deficient in vitamin A. PMID- 26001801 TI - Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy. AB - BACKGROUND: Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated. METHODS: Sixty-four MM patients (50 +/- 15 years, 44% male) and 25 matched controls (52 +/- 14 years, 36% male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: (a) CPEO/KSS (N = 33); (b) MELAS/-like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17). RESULTS: Among the 64 MM patients, 34 (53%) had at least one abnormal CMR finding: 18 (28%) demonstrated an impaired left ventricular ejection-fraction (LV-EF <60%), 14 (22%) had unexplained LV hypertrophy and 21 (33%) were LGE-positive. Compared to controls, MM patients showed significantly higher maximal wall thickness (10 +/- 3 vs. 8 +/- 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 +/- 0.27 vs. 0.67 +/- 0.11, p < 0.0001) with frequent presence of non-ischemic LGE (30% vs. 0%, p = 0.001). CPEO/KSS showed a predominantly intramural pattern of LGE mostly confined to the basal LV inferolateral wall (8/10; 80%) in addition to a tendency toward concentric remodelling. MELAS/-like patients showed the highest frequency of cardiac disease (in 10/11 (91%)), a mostly concentric LV hypertrophy (6/9; 67%) with or without LV systolic dysfunction and a predominantly focal, patchy LGE equally distributed among LV segments (8/11; 73%). Patients with MERRF and non specific MM had no particular findings. Pathological CMR findings indicating cardiac involvement were detected significantly more often than pathological ECG results or elevated cardiac serum biomarkers (34 (53%) vs. 18 (28%) vs. 21 (33%); p = 0.008). CONCLUSION: Cardiac involvement is a frequent finding in MM patients and particularly present in KSS/CPEO as well as MELAS/-like patients. Despite a high variability in clinical presentation, CPEO/KSS patients typically show an intramural pattern of LGE in the basal inferolateral wall whereas MELAS patients are characterized by overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE. PMID- 26001808 TI - Scrap NHS 111, and "strangle at birth" any similar proposals, say GPs. PMID- 26001807 TI - Effect of a 5-mo nutritional intervention on nutritional status and quality of life for patient with 3-hydroxyisobutyryl-coenzyme A hydrolase deficiency: A case report. AB - 3-Hydroxy-isobutyryl-coenzyme A (CoA) hydrolase (HBICH) deficiency is a rare cerebral organic aciduria caused by disturbance of valine catabolism that leads to the accumulation of toxic metabolites, methacrylyl-CoA. The major feature exhibited by a patient with HBICH deficiency includes multiple congenital malformations and abnormal neurologic findings. However, the pathophysiology of this disease remains unknown. The major treatment for HBICH deficiency involves a low-protein diet, especially restricting valine, supplemented with micronutrients and carnitine. To our knowledge, only four patients with HBICH deficiency have been reported. These patients were boys and presented with different clinical, biochemical, and genetic features than our patient. In this report, we described what was to our knowledge the first genetically confirmed girl with HBICH deficiency in China. A 5-mo nutritional intervention was given to the patient by a nutritional support team. On this regimen, the patient's symptoms were alleviated and her quality of life was improved. PMID- 26001809 TI - Ca(2+) concentration-dependent conformational change of FVIII B-domain observed by atomic force microscopy. AB - FVIII is a multi-domain protein organized in a heavy and a light chain, and a B domain whose biological function is still a matter of debate. The 3D structure of a B-domain-deleted FVIII variant has been determined by X-ray crystallography, leaving unexplained the functional nature of the flexible B-domain which could play an important role in the structure-function relationship since it is removed during the activation process. To obtain clues on the function of the B-domain, the morphology of full-length FVIII and its isolated domains was determined in the absence or presence of Ca(2+). Recombinant full-length FVIII, the purified heavy chain, light chain and B-domain as well as B-domain-deleted rFVIII were analysed in buffers of different Ca(2+) concentrations by atomic force microscopy. In the absence of Ca(2+), FVIII appeared as a globular molecule, whereas at high amounts of Ca(2+) up to 50-nm long tail structures emerged. These tails could be identified as unravelled B-domains, as images of isolated B domains showed the same morphology and heavy chains which include the B-domain were also rich of tails, whereas the isolated light chains and B-domain-deleted FVIII lacked any deviation from a globular shape. The images further suggested that the B-domain interacts with the light chain particularly at low Ca(2+) concentrations. Our results show a Ca(2+)-regulated conformational change of the B-domain in the context of full-length rFVIII. As the B-domain tightly associated with the core of the FVIII molecule under low Ca(2+)-concentrations, a stabilizing function on FVIII under non-activating conditions may be proposed. PMID- 26001812 TI - Impairment of cognitive function by chemotherapy: association with the disruption of phase-locking and synchronization in anterior cingulate cortex. AB - BACKGROUND: Patients following prolonged cancer chemotherapy are at high risk of emotional and cognitive deficits. Research indicates that the brain neuronal temporal coding and synaptic long-term potentiation (LTP) are critical in memory and perception. We studied the effects of cisplatin on induction of LTP in the basolateral amygdala (BLA)-anterior cingulate cortex (ACC) pathway, characterized the coordination of spike timing with local theta oscillation, and identified synchrony in the BLA-ACC network integrity. RESULTS: In the study presented, the impacts of cisplatin on emotional and cognitive functions were investigated by elevated plus-maze test, Morris water maze test, and rat Iowa gambling task (RGT). Electrophysiological recordings were conducted to study long-term potentiation. Simultaneous recordings from multi-electrodes were performed to characterize the neural spike firing and ongoing theta oscillation of local field potential (LFP), and to clarify the synchronization of large scale of theta oscillation in the BLA-ACC pathway. Cisplatin-treated rats demonstrated anxiety- like behavior, exhibited impaired spatial reference memory. RGT showed decrease of the percentage of good decision-makers, and increase in the percentage of maladaptive behavior (delay-good decision-makers plus poor decision-makers). Cisplatin suppressed the LTP, and disrupted the phase-locking of ACC single neural firings to the ongoing theta oscillation; further, cisplatin interrupted the synchrony in the BLA-ACC pathway. CONCLUSIONS: We provide the first direct evidence that the cisplatin interrupts theta-frequency phase-locking of ACC neurons. The block of LTP and disruption of synchronized theta oscillations in the BLA-ACC pathway are associated with emotional and cognitive deficits in rats, following cancer chemotherapy. PMID- 26001814 TI - Future Time Perspective and End-of-Life Planning in Older Adults. AB - This study explores the extent to which cognitive processes, specifically perceptions of one's distance to death, are associated with informal and formal advance care planning (ACP) in a sample of older adults. Data come from the New Jersey End-of-Life (EOL) study, a survey of 305 adults aged 55-91. Binary logistic regression models evaluate the odds that someone conducted ACP. Persons who perceive remaining life span to be expansive or limited have significantly lower odds of formally planning for the EOL, relative to those in the middle category. Death anxiety and having a family confidante partially explain these associations. The association between future time perspective (FTP) and discussions is not statistically significant. Practitioners may consider individuals' FTPs when discussing preferences for EOL medical care. PMID- 26001813 TI - Valuing the work of unpaid community health workers and exploring the incentives to volunteering in rural Africa. AB - Community health worker (CHW) programmes are currently being scaled-up in sub Saharan Africa to improve access to healthcare. CHWs are often volunteers; from an economic perspective, this raises considerations whether reliance on an unpaid workforce is sustainable and how to appropriately cost and value the work of CHWs. Both these questions can be informed by an understanding of CHWs' workload, their opportunity costs of time and the perceived benefits of being a CHW. However, to date few studies have fully explored the methodological challenges in valuing CHW time. We examined the costs and benefits of volunteering in a sample of 45 CHWs providing integrated community case management of common childhood illnesses in rural Uganda in February 2012 using different methods. We assessed the value of CHW time using the minimum public sector salary rate and a CHW elicited replacement wage, as well as the opportunity cost of time based on CHW estimated annual income and alternative work opportunities, respectively. Reported monthly CHW workload, a median of 19.3 h (range 2.5-57), was valued at USD 6.9 (range 0.9-20.4) per month from the perspective of the healthcare system (applicable replacement wage) and at a median of USD 4.1 (range 0.4-169) from the perspective of the CHWs (individual opportunity cost of time). In a discrete choice experiment on preferred work characteristics, remuneration and community appreciation dominated. We find that volunteering CHWs value the opportunity to make a social contribution, but the decision to volunteer is also influenced by anticipated future rewards. Care must be taken by those costing and designing CHW programmes to acknowledge the opportunity cost of CHWs at the margin and over the long term. Failure to properly consider these issues may lead to cost estimations below the amount necessary to scale up and sustain programmes. PMID- 26001815 TI - Yellow-Orange Palpebral Spots. PMID- 26001817 TI - A quarter of US adults with health insurance are underinsured, report finds. PMID- 26001816 TI - Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease. AB - PURPOSE: To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). DESIGN: Prospective study. PARTICIPANTS: Eighty-four patients diagnosed with chronic ocular GVHD. METHODS: We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. MAIN OUTCOME MEASURES: We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. RESULTS: The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5+/-17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with the exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P < 0.001), SANDE (R = -0.56, P < 0.001), CFS (R = -0.36, P = 0.001), and BCVA (R = -0.30, P = 0.004). CONCLUSIONS: Patients with ocular GVHD experience measurable impairment of vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition. PMID- 26001818 TI - Enumeration of viable non-culturable Vibrio cholerae using propidium monoazide combined with quantitative PCR. AB - The well-known human pathogenic bacterium, Vibrio cholerae, can enter a physiologically viable but non-culturable (VBNC) state under stress conditions. The differentiation of VBNC cells and nonviable cells is essential for both disease prevention and basic research. Among all the methods for detecting viability, propidium monoazide (PMA) combined with real-time PCR is popular because of its specificity, sensitivity, and speed. However, the effect of PMA treatment is not consistent and varies among different species and conditions. In this study, with an initial cell concentration of 1*10(8) CFU/ml, time and dose effect relationships of different PMA treatments were evaluated via quantitative real-time PCR using live cell suspensions, dead cell suspensions and VBNC cell suspensions of V. cholerae O1 El Tor strain C6706. The results suggested that a PMA treatment of 20 MUM PMA for 20 min was optimal under our conditions. This treatment maximized the suppression of the PCR signal from membrane-compromised dead cells but had little effect on the signal from membrane-intact live cells. In addition to the characteristics of PMA treatment itself, the initial concentration of the targeted bacteria showed a significant negative influence on the stability of PMA-PCR assay in this study. We developed a strategy that mimicked a 1*10(8) CFU/ml cell concentration with dead bacteria of a different bacterial species, the DNA of which cannot be amplified using the real time PCR primers. With this strategy, our optimal approach successfully overcame the impact of low cell density and generated stable and reliable results for counting viable cells of V. cholerae in the VBNC state. PMID- 26001820 TI - Cardiac Arrest in Takotsubo Cardiomyopathy. PMID- 26001819 TI - Comparison of outcomes after percutaneous coronary intervention for chronic total occlusion using everolimus- versus sirolimus- versus paclitaxel-eluting stents (from the Korean National Registry of Chronic Total Occlusion Intervention). AB - For the treatment of chronic total occlusion (CTO), the efficacy and safety of the everolimus-eluting stent (EES) remain less well defined. Also, there are limited data for the predictors of outcome after CTO intervention. The purpose of this study was to compare clinical outcomes of the EES with the first-generation drug-eluting stent (DES) in CTO intervention and to investigate the predictors of clinical outcome. The Korean National Registry of CTO Intervention is a retrospective cohort of 26 centers from the past 5 years. The primary end point was major adverse cardiovascular events (MACE) defined as a composite of cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Of the 1,754 all-comer patients, 1,509 patients (EES 311, sirolimus-eluting stent [SES] 642, paclitaxel-eluting stent 556) were finally analyzed after excluding 245 patients (mixed DESs in 46 and follow-up loss in 199). In the inverse probability weighting-adjusted population, the 1-year MACE rate of the EES was comparable with that of the SES (5.8% vs 3.4%, p = 0.796) and the paclitaxel eluting stent (5.8% vs 6.9%, p = 0.740). Each component of MACE was also comparable among the 3 stents. Importantly, the independent predictors of MACE were diabetes mellitus, previous congestive heart failure, and left circumflex CTO. In conclusion, for the first time in the largest CTO cohort, the EES showed good 1-year clinical outcomes that were comparable with the SES. Independent predictors of MACE after CTO intervention were clinical factors (diabetes and congestive heart failure) and lesion location. PMID- 26001821 TI - Counselor Attitudes Toward Contingency Management for Substance Use Disorder: Effectiveness, Acceptability, and Endorsement of Incentives for Treatment Attendance and Abstinence. AB - Despite research demonstrating its effectiveness, use of contingency management (CM) in substance use disorder treatment has been limited. Given the vital role that counselors play as arbiters in the use of therapies, examination of their attitudes can provide insight into how further use of CM might be effectively promoted. In this paper, we examine 731 counselors' attitudes toward the effectiveness and acceptability of CM in treatment, as well as their specific attitudes toward both unspecified and tangible incentives for treatment attendance and abstinence. Compared to cognitive behavioral therapy, motivational interviewing, and community reinforcement approach, counselors rated CM as the least effective and least acceptable psychosocial intervention. Exposure through the use of CM in a counselor's employing organization was positively associated with perceptions of acceptability, agreement that incentives have a positive effect on the client-counselor relationship, and endorsement of tangible incentives for abstinence. Endorsement of tangible incentives for treatment attendance was significantly greater among counselors with more years in the treatment field, and counselors who held at least a master's degree. Counselors' adaptability or openness to innovations was also positively associated with attitudes toward CM. Further, female counselors and counselors with a greater 12 step philosophy were less likely to endorse the use of incentives. A highlight of our study is that it offers the first specific assessment of the impact of "Promoting Awareness of Motivational Incentives" (PAMI), a Web-based tool based on findings of CM protocols tested within the Clinical Trials Network (CTN), on counselors employed outside the CTN. We found that 10% of counselors had accessed PAMI, and those who had accessed PAMI were more likely to report a higher degree of perceived effectiveness of CM than those who had not. This study lays the groundwork for vital research on the impact of multiple Web-based educational strategies. Given the barriers to CM adoption, identifying predictors of positive attitudes among counselors can help diffuse CM into routine clinical practice. PMID- 26001822 TI - Modeling effects of DO and SRT on activated sludge decay and production. AB - The effect of dissolved oxygen (DO) on the endogenous decay of active heterotrophic biomass and the hydrolysis of cell debris were studied. With the inclusion of a hydrolysis process for the cell debris, mathematical models that are capable of quantifying the effects of DO and sludge retention time (SRT) on concentrations of active biomass and cell debris in activated sludge are presented. By modeling the biomass cultivated with unlimited DO, the values of endogenous decay coefficient for heterotrophic biomass, the hydrolysis constant of cell debris, and the fraction of decayed biomass that became cell debris were determined to be 0.38 d(-1), 0.013 d(-1), and 0.28, respectively. Results from modeling the biomass cultivated under different DO conditions suggested that the experimental low DO (~0.2 mg/L) did not inhibit the endogenous decay of heterotrophic biomass, but significantly inhibited the hydrolysis of cell debris with a half-velocity constant value of 2.1 mg/L. Therefore, the increase in sludge production with low DO was mainly contributed by cell debris rather than the active heterotrophic biomass. Maximizing sludge production during aerobic wastewater treatment could reduce aeration energy consumption and improve biogas energy recovery potential. PMID- 26001823 TI - System evaluation and microbial analysis of a sulfur cycle-based wastewater treatment process for Co-treatment of simple wet flue gas desulfurization wastes with freshwater sewage. AB - A sulfur cycle-based wastewater treatment process, namely the Sulfate reduction, Autotrophic denitrification and Nitrification Integrated process (SANI((r)) process) has been recently developed for organics and nitrogen removal with 90% sludge minimization and 35% energy reduction in the biological treatment of saline sewage from seawater toilet flushing practice in Hong Kong. In this study, sulfate- and sulfite-rich wastes from simple wet flue gas desulfurization (WFGD) were considered as a potential low-cost sulfur source to achieve beneficial co treatment with non-saline (freshwater) sewage in continental areas, through a Mixed Denitrification (MD)-SANI process trialed with synthetic mixture of simple WFGD wastes and freshwater sewage. The system showed 80% COD removal efficiency (specific COD removal rate of 0.26 kg COD/kg VSS/d) at an optimal pH of 7.5 and complete denitrification through MD (specific nitrogen removal rate of 0.33 kg N/kg VSS/d). Among the electron donors in MD, organics and thiosulfate could induce a much higher denitrifying activity than sulfide in terms of both NO3(-) reduction and NO2(-) reduction, suggesting a much higher nitrogen removal rate in organics-, thiosulfate- and sulfide-based MD in MD-SANI compared to sulfide alone based autotrophic denitrification in conventional SANI((r)). Diverse sulfate/sulfite-reducing bacteria (SRB) genera dominated in the bacterial community of sulfate/sulfite-reducing up-flow sludge bed (SRUSB) sludge without methane producing bacteria detected. Desulfomicrobium-like species possibly for sulfite reduction and Desulfobulbus-like species possibly for sulfate reduction are the two dominant groups with respective abundance of 24.03 and 14.91% in the SRB genera. Diverse denitrifying genera were identified in the bacterial community of anoxic up-flow sludge bed (AnUSB) sludge and the Thauera- and Thiobacillus-like species were the major taxa. These results well explained the successful operation of the lab-scale MD-SANI process. PMID- 26001824 TI - Control strategy for maximum anaerobic co-digestion performance. AB - A control strategy for optimising the performance of anaerobic co-digestion in terms of methane productivity, digestate quality and process stability is presented. A linear programming approach is adopted to calculate the feeding of multiple substrates for maximum methane productivity, subjected to restrictions based on experimental and heuristic knowledge. Process stability is quantitatively assessed by an empirical diagnosis function comparing alkalinity ratio measurements against reference values (outputs between (-1,1]). A second empirical diagnosis function is defined to compare methane flow rate measurements against a reference value of maximum capacity (outputs between (0,1]). A variable gain control function (outputs between (-1,1]), derived from the diagnosis functions, is defined to determine the quantitative change applied to the most active constraint of the substrate blend optimisation problem leading to a new set-point of feeding substrates blend. The control strategy works in a closed loop architecture under which the process performance for each blend of substrates is continuously assessed. The system was successfully validated in a 1 m(3) hybrid Upflow Anaerobic Sludge Blanket - Anaerobic Filter (UASB-AF) reactor, treating blends of substrates (gelatine, glycerine and pig manure supernatant) at OLR values between 0.71 and 6.33 gCOD/L d over a period of 210 days at mesophilic conditions. PMID- 26001825 TI - Downstream processing of reverse osmosis brine: Characterisation of potential scaling compounds. AB - Reverse osmosis (RO) brine produced at a full-scale coal seam gas (CSG) water treatment facility was characterized with spectroscopic and other analytical techniques. A number of potential scalants including silica, calcium, magnesium, sulphates and carbonates, all of which were present in dissolved and non dissolved forms, were characterized. The presence of spherical particles with a size range of 10-1000 nm and aggregates of 1-10 microns was confirmed by transmission electron microscopy (TEM). Those particulates contained the following metals in decreasing order: K, Si, Sr, Ca, B, Ba, Mg, P, and S. Characterization showed that nearly one-third of the total silicon in the brine was present in the particulates. Further, analysis of the RO brine suggested supersaturation and precipitation of metal carbonates and sulphates during the RO process should take place and could be responsible for subsequently capturing silica in the solid phase. However, the precipitation of crystalline carbonates and sulphates are complex. X-ray diffraction analysis did not confirm the presence of common calcium carbonates or sulphates but instead showed the presence of a suite of complex minerals, to which amorphous silica and/or silica rich compounds could have adhered. A filtration study showed that majority of the siliceous particles were less than 220 nm in size, but could still be potentially captured using a low molecular weight ultrafiltration membrane. PMID- 26001826 TI - Slanic-Prahova low background calibration facility. AB - The reduced background of 2 nSv h(-1) of the Slanic-Prahova Low Background Radiation Laboratory allowed installing a calibration stand for low-dose-rates dosimetry. The stand is provided with (60)Co, (137)Cs and (241)Am low activity sources. A Physikalisch-Technische Bundesanstalt-calibrated AUTOMESS 6150 AD-6 dose rate meter with a 6150 AD-b/H external probe was used to check to what extent this stand could serve as a low background calibration facility. A detailed analysis of possible uncertainties in measuring dose rates evidenced an extended uncertainty related to the certified calibration as well as instrument readings of about 3 % for a confidence level of 95 %. In these conditions, the experimentally determined dose rates for all three gamma ray sources and for source-to-probe distances varying between 0.3 and 2.0 m confirmed a good correlation between the calculated and measured dose rates. At the same time, dose rates perfectly obey to an inverse squared distances law. PMID- 26001827 TI - Evaluation of diagnostic medical exposure in Republic of Korea. AB - National statistical data for diagnostic radiation exposure in Republic of Korea were collected from four public institutes and government agencies during the period 2006-2013. The data were pooled, reclassified and analysed. A total of 1574 million exposures occurred during the study period. To evaluate the effective diagnostic radiation exposure dose, the dose conversion factors developed by the Korea Food and Drug Administration were applied. The number of diagnostic radiation exposures was 197 million per year. The collective effective dose averaged 64 043 man Sv y(-1), and the annual per caput effective dose averaged 1.27 mSv. The annual per caput effective dose in 2013 was 1.54 mSv compared with 0.89 mSv in 2006, a marked increase of 73.9 % over the study period. These research data, compiled from reliable sources within the public health system of Republic of Korea, demonstrate a trend of increasing diagnostic radiation exposure and provide valuable information for further research. PMID- 26001828 TI - Silencing SOX2 Expression by RNA Interference Inhibits Proliferation, Invasion and Metastasis, and Induces Apoptosis through MAP4K4/JNK Signaling Pathway in Human Laryngeal Cancer TU212 Cells. AB - SRY (sex determining region Y)-box 2 (SOX2) plays an important role in tumor cell metastasis and apoptosis. Laryngeal squamous cell carcinoma (LSCC), responsible for 1.5% of all cancers, is one of the most common head and neck malignancies. Accumulating evidence shows that SOX2 is overexpressed in several human tumors, including lung cancer, esophageal carcinoma, pancreatic carcinoma, breast cancer, ovarian carcinoma and glioma. Our study aimed to investigate the silencing effects of SOX2 expression using RNA interference (RNAi) on various biological processes in laryngeal cancer TU212 cells, including proliferation, apoptosis, invasion and metastasis. We also studied the involvement of the MAPK/JNK signaling pathway in the biological effects of SOX2 siRNA in TU212 cells. We found that silencing SOX2 decreased the proliferation, migration, and invasion of TU212 cells, and induced apoptosis. This effect of silencing SOX2 could be reversed by silencing MAP4K4. Therefore, we consider SOX2 as a key regulator of the upstream MAP4K4/JNK signaling pathways that could be a potential therapeutic target in the treatment of patients with or prevention of laryngeal cancer. PMID- 26001830 TI - A man with an infected finger: a case report. AB - INTRODUCTION: Whitlow is an infection of a finger or around the fingernails, generally caused by bacterium. However, in rare cases, it may also be caused by the herpes simplex virus. As herpetic whitlow is not seen often, it may go under recognised or be mistaken for a different kind of infection of the finger. Delayed recognition and/or treatment puts patients at risk of complications ranging from superinfection to herpetic encephalitis. CASE PRESENTATION: A 23 year-old Caucasian man with no medical history was referred by his primary care physician because of erythema and swelling of the little finger of his left hand. The primary care physician had already treated him with the oral antibiotic Augmentin(r) (amoxicillin-clavulanic acid) and incision of the finger, but this had not resolved his complaints. He had multiple vesicles on the finger, which led to the diagnosis of herpetic whitlow, which we confirmed by polymerase chain reaction testing. All cutaneous abnormalities disappeared after treatment. CONCLUSIONS: Whitlow is rarely caused by the herpes simplex virus, but this disease requires a swift recognition and treatment to prevent complications. This case serves to emphasise that not all whitlow is caused by a bacterial infection, and that it is important to differentiate between herpetic and bacterial whitlow, as these diseases require a different treatment. PMID- 26001829 TI - Decorin in Human Colon Cancer: Localization In Vivo and Effect on Cancer Cell Behavior In Vitro. AB - Decorin is generally recognized as a tumor suppressing molecule. Nevertheless, although decorin has been shown to be differentially expressed in malignant tissues, it has often remained unclear whether, in addition to non-malignant stromal cells, cancer cells also express it. Here, we first used two publicly available databases to analyze the current information about decorin expression and immunoreactivity in normal and malignant human colorectal tissue samples. The analyses demonstrated that decorin expression and immunoreactivity may vary in cancer cells of human colorectal tissues. Therefore, we next examined decorin expression in normal, premalignant and malignant human colorectal tissues in more detail using both in situ hybridization and immunohistochemistry for decorin. Our results invariably demonstrate that malignant cells within human colorectal cancer tissues are devoid of both decorin mRNA and immunoreactivity. Identical results were obtained for cells of neuroendocrine tumors of human colon. Using RT qPCR, we showed that human colon cancer cell lines are also decorin negative, in accordance with the above in vivo results. Finally, we demonstrate that decorin transduction of human colon cancer cell lines causes a significant reduction in their colony forming capability. Thus, strategies to develop decorin-based adjuvant therapies for human colorectal malignancies are highly rational. PMID- 26001831 TI - High throughput profiling of the cotton bollworm Helicoverpa armigera immunotranscriptome during the fungal and bacterial infections. AB - BACKGROUND: Innate immunity is essential in defending against invading pathogens in invertebrates. The cotton bollworm, Helicoverpa armigera (Hubner) is one of the most destructive lepidopteran pests, which causes enormous economic losses in agricultural production worldwide. The components of the immune system are largely unknown in this insect. The application of entomopathogens is considered as an alternative to the chemical insecticides for its control. However, few studies have focused on the molecular mechanisms of host-pathogen interactions between pest insects and their pathogens. Here, we investigated the immunotranscriptome of H. armigera larvae and examined gene expression changes after pathogen infections. This study provided insights into the potential immunity-related genes and pathways in H. armigera larvae. RESULTS: Here, we adopted a high throughput RNA-seq approach to determine the immunotranscriptome of H. armigera larvae injected with buffer, fungal pathogen Beauveria bassiana, or Gram-negative bacterium Enterobacter cloacae. Based on sequence similarity to those homologs known to participate in immune responses in other insects, we identified immunity-related genes encoding pattern recognition receptors, signal modulators, immune effectors, and nearly all members of the Toll, IMD and JAK/STAT pathways. The RNA-seq data indicated that some immunity-related genes were activated in fungus- and bacterium-challenged fat body while others were suppressed in B. bassiana challenged hemocytes, including the putative IMD and JAK-STAT pathway members. Bacterial infection elevated the expression of recognition and modulator genes in the fat body and signal pathway genes in hemocytes. Although fat body and hemocytes both are important organs involved in the immune response, our transcriptome analysis revealed that more immunity related genes were induced in the fat body than that hemocytes. Furthermore, quantitative real-time PCR analysis confirmed that, consistent with the RNA-seq data, the transcript abundances of putative PGRP-SA1, Serpin1, Toll-14, and Spz2 genes were elevated in fat body upon B. bassiana infection, while the mRNA levels of defensin, moricin1, and gloverin1 were up-regulated in hemocytes. CONCLUSIONS: In this study, a global survey of the host defense against fungal and bacterial infection was performed on the non-model lepidopteran pest species. The comprehensive sequence resource and expression profiles of the immunity-related genes in H. armigera are acquired. This study provided valuable information for future functional investigations as well as development of specific and effective agents to control this pest. PMID- 26001832 TI - Heat stress-induced memory impairment is associated with neuroinflammation in mice. AB - BACKGROUND: Heat stress induces many pathophysiological responses and has a profound impact on brain structure. It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans. Although the effects of heat stress have long been studied, the mechanisms by which heat stress affects brain structure and cognition not well understood. METHODS: In our longitudinal study of mice exposed to heat over 7, 14, or 42 days, we found that heat stress time dependently impaired cognitive function as determined by Y-maze, passive avoidance, and novel object recognition tests. To elucidate the histological mechanism by which thermal stress inhibited cognitive abilities, we examined heat stress-induced inflammation in the hippocampus. RESULTS: In mice subjected to heat exposure, we found: 1) an increased number of glial fibrillary acid protein (GFAP)- and macrophage-1 antigen (Mac-1)-positive cells, 2) up-regulated nuclear factor (NF)-kappaB, a master regulator of inflammation, and 3) marked increases in cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cytokine interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in the mouse hippocampus. We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression. Moreover, in heat-exposed mice, we found that the number of cells positive for doublecortin (DCX), a marker of neurogenesis, was significantly decreased compared with control mice. Finally, anti-inflammatory agent minocycline inhibited the heat stress-induced cognitive deficits and astogliosis in mice. CONCLUSIONS: Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis. PMID- 26001833 TI - Bardoxolone methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high-fat diet. AB - High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor (IR), IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the beta-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFalpha mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver. PMID- 26001834 TI - Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes. AB - The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in skin homeostasis. However, whether these transcription factors cooperate in binding genomic regulatory regions in epidermal keratinocytes was not known. Here, we show that in dexamethasone treated keratinocytes GR and Klf4 are recruited to genomic regions containing adjacent GR and KLF binding motifs to control transcription of the anti inflammatory genes Tsc22d3 and Zfp36. GR- and Klf4 loss of function experiments showed total GR but partial Klf4 requirement for full gene induction in response to dexamethasone. In wild type keratinocytes induced to differentiate, GR and Klf4 protein expression increased concomitant with Tsc22d3 and Zfp36 up regulation. In contrast, GR-deficient cells failed to differentiate or fully induce Klf4, Tsc22d3 and Zfp36 correlating with increased expression of the epithelium-specific Trp63, a known transcriptional repressor of Klf4. The identified transcriptional cooperation between GR and Klf4 may determine cell type specific regulation and have implications for developing therapies for skin diseases. PMID- 26001836 TI - Losing concentration: time for a new MAPP? PMID- 26001835 TI - Activin A, B and AB decrease progesterone production by down-regulating StAR in human granulosa cells. AB - Activins are homo- or heterodimers of inhibin beta subunits that play important roles in the reproductive system. Our previous work has shown that activins A (betaAbetaA), B (betaBbetaB) and AB (betaAbetaB) induce aromatase/estradiol, but suppress StAR/progesterone production in human granulosa-lutein cells. However, the underlying molecular determinants of these effects have not been examined. In this continuing study, we used immortalized human granulosa cells (SVOG) to investigate the effects of activins in regulating StAR/progesterone and the potential mechanisms of action. In SVOG cells, activins A, B and AB produced comparable down-regulation of StAR expression and progesterone production. In addition, all three activin isoforms induced equivalent phosphorylation of both SMAD2 and SMAD3. Importantly, the activin-induced down-regulation of StAR, increase in SMAD2/3 phosphorylation, and decrease in progesterone were abolished by the TGF-beta type I receptor inhibitor SB431542. Interestingly, the small interfering RNA-mediated knockdown of ALK4 but not ALK5 reversed the activin induced suppression of StAR. Furthermore, the knockdown of SMAD4 or SMAD2 but not SMAD3 abolished the inhibitory effects of all three activin isoforms on StAR expression. These results provide evidence that activins A, B and AB down regulate StAR expression and decrease progesterone production in human granulosa cells, likely via an ALK4-mediated SMAD2/SMAD4-dependent pathway. Our findings provide important insights into the molecular mechanisms underlying the regulatory effects of activins on human granulosa cell steroidogenesis. PMID- 26001837 TI - Perioperative myocardial injury in patients receiving cardiac output-guided haemodynamic therapy: a substudy of the OPTIMISE Trial. AB - BACKGROUND: Evidence suggests that cardiac output-guided haemodynamic therapy algorithms improve outcomes after high-risk surgery, but there is some concern that this could promote acute myocardial injury. We evaluated the incidence of myocardial injury in a perioperative goal-directed therapy trial. METHODS: Patients undergoing major gastrointestinal surgery (n=723) were randomly assigned to cardiac output-guided haemodynamic therapy (intervention group) or usual care as part of the OPTIMISE trial. At four participating sites, 288 patients were enrolled in a biomarker substudy. Serum high-sensitivity cardiac troponin I (TnI) concentration and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration were measured before and at 24 and 72 h after surgery. RESULTS: Median preoperative TnI and NT-ProBNP concentrations were 4.3 ng litre(-1) and 144 pg ml(-1), respectively. After surgery, 67 (46%) patients in the intervention group and 68 (48%) patients receiving usual care had TnI concentrations above the 99th centile upper reference limit (P=0.82). Peak serum TnI concentration was similar in the intervention and usual care groups (median [interquartile range]: 10.0 [5.3-21.5] vs 7.8 [5.0-21.8] ng litre(-1); P=0.85), and no differences were observed in serum TnI concentrations over 72 h (repeated-measures anova, P=0.51). Likewise, there were no differences in peak NT-proBNP concentration between intervention and usual care groups (645 [362-1169] vs 659 [381-1028] pg ml(-1); P=0.86) or in serial NT-proBNP concentrations over 72 h (P=0.20). CONCLUSIONS: Myocardial injury is common among patients undergoing major gastrointestinal surgery. In this study, the frequency was not affected by cardiac output-guided fluid and low-dose inotropic therapy. PMID- 26001838 TI - Climbing the delirium mountain: is alpine anaesthesia the perioperative cause? PMID- 26001839 TI - Filling in the missing puzzle piece between cardiac MIBG scintigraphy findings and Parkinson's disease pathology. PMID- 26001840 TI - Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease: a systematic review and meta-analysis of cohort studies. AB - OBJECTIVE: We sought to identify the risk factors for predicting the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: We searched 6 electronic databases for cohort studies published from January 1966 to March 2015. Eligible studies were required to be relevant to the subject and provide sufficient data for our needs. RESULTS: 60 cohort studies with 14,821 participants from 16 countries were included in the meta-analysis. The strongest positive associations between risk factors and the progression from MCI to AD were found for abnormal cerebrospinal fluid (CSF), phosphorylated tau (p-tau) (relative risk (RR)=2.43, 95% CI=1.70 to 3.48), abnormal CSF tau/Abeta1-42 (RR=3.77, 95% CI=2.34 to 6.09), hippocampal atrophy (RR=2.59, 95% CI=1.95 to 3.44), medial temporal lobe atrophy (RR=2.11, 95% CI=1.70 to 2.63) and entorhinal atrophy (RR=2.03, 95% CI=1.57 to 2.62). Further positive associations were found for the presence of apolipoprotein E (APOE)epsilon4epsilon4 and at least 1 APOEepsilon4 allele, CSF total-tau (t-tau), white matter hyperintensity volume, depression, diabetes, hypertension, older age, female gender, lower mini-mental state examination (MMSE) score and higher AD assessment scale cognitive subscale (ADAS-cog) score. Negative associations were found for high body mass index (RR=0.85, 95% CI=0.76 to 0.96) and higher auditory verbal learning test delay score (RR=0.86, 95% CI=0.77 to 0.96). CONCLUSIONS: Patients with MCI with APOEepsilon4, abnormal CSF tau level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hypertension, older age, female gender, lower MMSE score and higher ADAS-cog score, had a high risk for the progression to AD. PMID- 26001841 TI - Nurse who drove debate on euthanasia in India dies after 42 years in vegetative state. PMID- 26001842 TI - Work Conditions and Health and Well-Being of Latina Hotel Housekeepers. AB - Hotel housekeepers are exposed to a plethora of disproportionately high work induced hazards that can lead to adverse health consequences. Latina hotel housekeepers are rendered particularly vulnerable to elevated occupational hazards and resultant health strains due to their socioeconomic status, immigration status, language barriers, and lack of access to healthcare services. The findings from the 27 interviews with Latina hotel housekeepers indicated that the interviewees were exposed to physical, chemical, and social hazards in the workplace and suffered musculoskeletal injuries. In terms of psychological wellness, the time pressure of cleaning rooms quickly and work-related stress stemming from workplace mistreatment emerged as major work-related stressors. Recommendations are made for the introduction of multilevel interventions designed to prevent work-related injuries and illnesses and to promote healthier workplaces. PMID- 26001843 TI - HPV Vaccine and Latino Immigrant Parents: If They Offer It, We Will Get It. AB - HPV vaccination rates remain low in the fast growing Latino children population while we continue to observe large HPV-associated cancer disparities in the Latino population. In this study, we sought to elucidate Latino immigrant parents' barriers to obtaining the HPV vaccine for their children. Five focus groups were conducted with Latino immigrant parents of minors (i.e., 9-17 year old) who had not yet initiated the HPV vaccine series. Three major findings were identified from the focus groups: (1) low levels of awareness and knowledge of HPV and the HPV vaccine, (2) high confidence that parent can get the vaccine for their eligible child and (3) lack of provider recommendation as the main barrier to vaccination. Children of Latino immigrant parents could benefit from increased provider recommendation for the HPV vaccine while providing tailored HPV information to parents. PMID- 26001845 TI - Pathophysiological rationale and diagnostic targets for diastolic stress testing. AB - Cardiopulmonary functional reserve measured as peak oxygen uptake is predicted better at rest by measures of cardiac diastolic function than by systolic function. Normal adaptations in the trained heart include resting bradycardia, increased LV end-diastolic volume and augmented early diastolic suction on exercise. In normal populations early diastolic relaxation declines with age and end-diastolic stiffness increases, but in healthy older subjects who have exercised throughout their lives diastolic function can be well preserved. The mechanisms by which LV diastolic filling and pressures can be impaired during exercise include reduced early diastolic recoil and suction (which can be exacerbated by increased late systolic loading), increased preload and reduced compliance. Abnormal ventricular-arterial coupling and enhanced ventricular interaction may contribute in particular circumstances. One common final pathway that causes breathlessness is an increase in LV filling pressure and left atrial pressure. Testing elderly subjects with breathlessness of unknown aetiology in order to detect worsening diastolic function during stress is proposed to diagnose heart failure with preserved EF. In invasive studies, the most prominent abnormality is an early and rapid rise in pulmonary capillary wedge pressure. A systematic non-invasive diagnostic strategy would use validated methods to assess different mechanisms of inducible diastolic dysfunction and not just single parameters that offer imprecise estimates of mean LV filling pressure. Protocols should assess early diastolic relaxation and filling as well as late diastolic filling and compliance, as these may be affected separately. Better refined diagnostic targets may translate to more focused treatment. PMID- 26001844 TI - Protocol for CHANGE: a randomized clinical trial assessing lifestyle coaching plus care coordination versus care coordination alone versus treatment as usual to reduce risks of cardiovascular disease in adults with schizophrenia and abdominal obesity. AB - BACKGROUND: Life expectancy in patients with schizophrenia is reduced by 20 years for males and 15 years for females compared to the general population. About 60% of the excess mortality is due to physical illnesses, with cardiovascular disease being the single largest cause of death. METHODS/DESIGN: The CHANGE trial is an investigator-initiated, independently funded, randomized, parallel-group, superiority, multi-centre trial with blinded outcome assessment. 450 patients aged 18 years or above, diagnosed with schizophrenia spectrum disorders and increased waist circumference, will be recruited and randomized 1:1:1 to 12 months interventions. We will compare the effects of 1) affiliation to the CHANGE team, offering a tailored, manual-based intervention targeting physical inactivity, unhealthy dietary habits, and smoking, and facilitating contact to their general practitioner to secure medical treatment of somatic comorbidity; versus 2) affiliation to a care coordinator who will secure guideline-concordant monitoring and treatment of somatic comorbidity by facilitating contact to their general practitioner; versus 3) treatment as usual to evaluate the potential add on effects of lifestyle coaching plus care coordination or care coordination alone to treatment as usual. The primary outcome is the 10-year risks of cardiovascular disease assessed at 12 months after randomization. DISCUSSION: The premature mortality observed in this vulnerable population has not formerly been addressed specifically by using composite surrogate outcomes for mortality. The CHANGE trial expands the evidence for interventions aiming to reduce the burden of metabolic disturbances with a view to increase life expectancy. Here, we present the trial design, describe the methodological concepts in detail, and discuss the rationale and challenges of the intermediate outcomes. TRIAL REGISTRATION: Clinical Trials.gov NCT01585493 . Date of registration 27(th) of March 2012. PMID- 26001846 TI - Holter ECG for pacemaker/defibrillator carriers: what is its role in the era of remote monitoring? AB - Nowadays several diagnostic tools are available to investigate cardiovascular symptoms like palpitations, dizziness and syncope: ECG Holter (or ambulatory ECG, AECG), external and implantable event/loop recorders. Despite this technological burden, many diagnoses are still missed. In the meantime, we are facing an increasing use of implantable devices for cardiac pacing/defibrillation (CIED), which have rapidly evolved from simple pacing/shock boxes to devices including several diagnostic features. However, these functions are not adequately exploited in current clinical practice and several redundant diagnostic tests, like AECG, are still prescribed to CIED carriers, leading to an increase of costs and a delay in final diagnosis. This review is aimed at identifying the current role of AECG in CIED carriers in view of this technological improvement. First, we will briefly present the indications for AECG according to current guidelines. We will then provide a direct comparison of the different diagnostic features provided by AECG (and event/loop recorders) versus automatic diagnostic CIED to highlight the respective pros and cons. This will serve to carefully discuss these indications in view of the results of recent studies on CIED carriers, highlighting the need for proper implantation and follow-up. Eventually, we will provide useful hints to properly analyse AECG in CIED carriers, considering the different behaviours according to the implemented algorithms. We will conclude by suggesting updated indications for AECG. PMID- 26001847 TI - Prevalence and predictors of sexual violence among commercial sex workers in Northern Ethiopia. AB - BACKGROUND: Gender-based violence is a natural outgrowth of the stigma and discrimination experienced by commercial sex workers (CSWs) across the globe. In light of this, the current study aimed to describe the prevalence and character of sexual violence, as well as any risk factors for violence, experienced by CSWs in Mekelle City, Northern Ethiopia. METHODS: A cross-sectional study was conducted in Mekelle City in April 2013. 250 CSWs were selected for participation using simple random sampling. Data were collected via a questionnaire instrument. Descriptive statistics and multiple logistic regression analyses were performed using SPSS 20 for Windows. RESULTS: The overall prevalence of sexual violence among CSWs was 75.6 %. Basic literacy [(AOR = 5.3, 95 % of CI (1.15-25.20)], completion of only elementary school [AOR = 6.9, 95 % of CI (1.55-31.25)], completion of only high school [AOR = 7.9, 95 % of CI (1.65-38.16)], being married [(AOR = 3.8, 95 % CI (1.34-11.09)], engaging in sex work for 1-4 years [(AOR = 5.3, 95 % CI(1.7-16.2)] and drug use [AOR = 5.3, 95 % of CI (1.78-16.21)] were all significant risk factors for sexual violence. CSWs with lower monthly income were also more likely to experience sexual violence; monthly income of 51.2-101.9 USD yielded AOR = 2.4 (95 % CI 1.12-5.37) and monthly income of 102.2 153.1 USD yielded AOR = 7.9 (95 % CI 2.46-25.58), compared to CSWs earning 153.2 USD or more. CONCLUSION: The prevalence of sexual violence among CSWs is high. Lower educational attainment, being married, lower monthly income, drug use, and shorter duration of sex work are all risk factors for sexual violence. PMID- 26001848 TI - Bleeding "Dieulafoy's-like" lesion resembling the duodenal papilla: a case report. AB - INTRODUCTION: Dieulafoy's lesion is an uncommon but important cause of gastrointestinal bleeding in which hemorrhage occurs from a pinpoint, non ulcerated arterial lesion. DLs are usually located in the stomach, most commonly in people between the ages of 50 and 70 years. In this report, we describe a teenage patient with an unusual presentation of a bleeding duodenal Dieulafoy's like lesion that resembled the duodenal papilla. CASE PRESENTATION: An 18-year old Pakistani woman presented to our emergency department with hematemesis of 6 hours' duration. Her past medical history was unremarkable. A nasogastric aspirate was negative for blood. The patient's hemoglobin was found to be 4 g/dl. She was resuscitated with intravenous fluids and blood transfusion. An esophagogastroduodenoscopy was performed, which revealed swelling in the first part of the duodenum, the initial appearance of which suggested that it was an abnormally placed or accessory papilla. There was a small, <3-mm opening on the lesion that resembled the biliary or pancreatic orifice. On gentle manipulation with a catheter, blood spurted from the swelling area, and a vessel was visible. Adrenaline was used for hemostasis. After hemostasis was achieved, it became clear that the lesion was most consistent with a Dieulafoy's-like lesion and not a papilla. Band ligation was then performed, and the patient did not develop any complications and did not have any further episodes of bleeding. The patient was eventually discharged to home in stable condition. CONCLUSIONS: This case report highlights the importance of considering a DL as a cause of small-bowel hemorrhage and recognizing its potential resemblance to the papilla. Although the endoscopic diagnostic criteria for a Dieulafoy's lesion have been described in great detail, there is a paucity of literature describing a Dieulafoy's lesion or a similar lesion resembling the duodenal papilla. PMID- 26001849 TI - Pollicization of the index finger requiring secondary fusion of the new metacarpophalangeal joint. AB - In children with absent thumbs, some authors have stated that 'relative' contraindications of pollicization include severe fixed flexion contracture and instability of the proximal interphalangeal joint of the index finger. The current author does not consider severe proximal interphalangeal joint deformities of the index finger as a contraindication to pollicization; and hence these children are offered the procedure. A literature review did not reveal any study that specifically documents the outcome of pollicization in these cases. The current series included five children: four with severe (over 80 degrees ) fixed flexion contracture of the proximal interphalangeal joint of the index finger and one with instability of the proximal interphalangeal joint. All children were initially assessed during infancy at their local hospitals and the parents were informed that a pollicization procedure would yield a poor outcome. Presentation to the author was relatively late at a mean of 9.3 years (range 2.5 12). All children underwent two surgical procedures: a pollicization followed by fusion of the new metacarpophalangeal joint. The overall early functional outcome was good and all children/parents were satisfied with the procedure. These encouraging results warrant a prospective long term study on various conditions that are considered as 'relative' contraindications to the pollicization procedure.Level evidence: IV Therapeutic (case series). PMID- 26001850 TI - Age-series based link prediction in evolving disease networks. AB - Recently, several research efforts based on social network analysis and methods have been made for medical care information. One of these efforts is to extract the relationships between diseases by using social network modeling. However, all of previous works used the relationships in a simple way in a network consisting of diseases regardless of time or age factors. In this paper, we predict the onset of future diseases on the basis of the current health status of patients by considering age factor. The problem of predicting the relations between diseases is a really difficult and, at the same time, an important task. For this purpose, this paper first constructs a weighted disease network and then, it proposes a novel link prediction method, to identify the connections between diseases, building the evolving structure of the disease network with respect to patients' ages. To the best of our knowledge, this is the first attempt in predicting the connections between diseases according to patients' ages. Experiments on a real network demonstrate that the proposed approach can reveal disease correlations accurately and perform well at capturing future disease risks. PMID- 26001851 TI - Evaluation of vermillion border descriptors and relevance vector machines discrimination model for making probabilistic predictions of solar cheilosis on digital lip photographs. AB - INTRODUCTION: Solar cheilosis (SC), a common precancer of the lower lip with a high potential to progress to invasive squamous cell carcinoma, presents with characteristic morphological vermillion-skin border alterations, like the border retraction. AIM: To determine robust macro-morphological descriptors of the vermillion border from non-standardized digital photographs and to exploit a probabilistic model for SC recognition in real clinical environments. METHODS: Lip borders of 150 individuals (75 SC patients, 75 non-SC controls) were quantified on the basis of the extent of vermillion retraction and the degree of border irregularity employing fractal features and type-P Fourier descriptors. Eight lip border quantifiers were evaluated in terms of their reliability and reproducibility. The probabilistic 'diagnostic' model was implemented using the relevance vector machine (RVM) algorithm. RESULTS: Picture acquisition contributes substantially to overall variability of lip border images; however, for the different lip descriptors 33% to 65% of border morphological variability is due to differences among individuals. Different camera operators or the use of cameras with different specifications did not affect significantly the extracted lip features. The proposed RVM probabilistic model yielded a high sensitivity and specificity of 94.6% and 96%, respectively. CONCLUSION: We explored the use of digital photography within the clinical routine setting to validate a probabilistic model for the assessment of lip conditions like SC. The proposed method opens new perspectives toward a cost effective, non-invasive monitoring of SC to support large scale epidemiological and interventional studies in different clinical environments. PMID- 26001852 TI - Using Petri nets for experimental design in a multi-organ elimination pathway. AB - Genistein is a soy metabolite with estrogenic activity that may result in (un)favorable effects on human health. Elucidation of the mechanisms through which food additives such as genistein exert their beneficiary effects is a major challenge for the food industry. A better understanding of the genistein elimination pathway could shed light on such mechanisms. We developed a Petri net model that represents this multi-organ elimination pathway and which assists in the design of future experiments. Using this model we show that metabolic profiles solely measured in venous blood are not sufficient to uniquely parameterize the model. Based on simulations we suggest two solutions that provide better results: parameterize the model using gut epithelium profiles or add additional biological constrains in the model. PMID- 26001853 TI - Left atrial dilatation is associated with severe ischemic stroke in men with non valvular atrial fibrillation. AB - BACKGROUND: Increased left atrial volume is an independent predictive factor of first ischemic stroke and other cardiovascular events in patients with non valvular atrial fibrillation (NVAF). However, correlations between left atrial dilatation and ischemic stroke severity or ischemic lesion pattern have not been previously reported. The aim of this study was to evaluate whether left atrial enlargement is associated with worse initial stroke severity and lesion patterns. METHODS: Consecutive patients with acute ischemic stroke and NVAF who were anticoagulation-naive were enrolled, and all patients were stratified into moderate-to-severe and mild neurologic deficit groups using the National Institutes of Health Stroke Scale (NIHSS) at admission. Left atrial diameter (LAD) and left atrial volume index (LAVI), stratified by sex, were compared between the two groups. Ischemic lesion patterns were also investigated in relation to the LAD and LAVI. RESULTS: A total of 98 patients were enrolled. Of these, 37 were classified as having a moderate-to-severe neurologic deficit (NIHSS>=10), and 61 were classified as having a mild neurologic deficit at admission. After adjusting for confounding factors, increases in LAD and LAVI were significantly associated with moderate-to-severe neurologic deficits, especially in men. Men in the upper two tertiles of LAD and LAVI had more severe stroke symptoms when compared with participants in the lowest tertile. In partial correlation coefficient analysis adjusted for CHA2DS2-VASc risk factors, LAD and LAVI in men were positively correlated with NIHSS score (r=0.553; p<0.001 and r=0.393; p=0.004, respectively), and LAVI in all enrolled patients was significantly correlated with NIHSS score (r=0.215; p=0.045). CONCLUSION: Increased LAD and LAVI were associated with worse initial neurologic deficits in anticoagulation-naive patients with acute ischemic stroke and NVAF, especially in men. Recognition of the atrial abnormalities and effective anticoagulation may reduce thrombogenesis in NVAF. PMID- 26001854 TI - A systematic review of the effectiveness of strategies and interventions to improve the transition from student to newly qualified nurse. AB - BACKGROUND: The transition from student to newly qualified nurse can be stressful for many newly qualified nurses who feel inadequately prepared. A variety of support strategies to improve the transition process have been reported across the international literature but the effectiveness of such strategies is unknown. OBJECTIVES/AIM: To determine the effectiveness of the main strategies used to support newly qualified nurses during the transition into the clinical workplace and, where identified, evaluate the impact of these on individual and organisational outcomes. DESIGN: Systematic review. DATA SOURCES: A search of electronic databases to identify published studies (CINAHL, MEDLINE, British Nursing Index, Cochrane Library, EMBASE, PsychLit, PsychINFO, PsychARTICLES, Web Of Science, EBM Reviews, BioMed, TRIP, ERIC, SCOPUS (January 2000-April 2011) was conducted. Relevant journals were hand-searched and reference lists from retrieved studies were reviewed to identify any further studies. The search was restricted to English language papers. The key words used were words that described new graduate nurses and support strategies (e.g. internship, residency, orientation programmes). REVIEW METHODS: The inclusion criteria were quantitative studies that investigated the effectiveness of support strategies for newly qualified graduate nurses. Studies that involved students in their final year of graduate study were excluded (for example extern programmes). Extraction of data was undertaken independently by two reviewers. A further two reviewers assessed the methodological quality against agreed criteria. RESULTS: A total of 8199 studies were identified from the database search and 30 met the inclusion criteria for the review. The evidence suggests that transition interventions/strategies do lead to improvements in confidence and competence, job satisfaction, critical thinking and reductions in stress and anxiety for the newly qualified nurse. CONCLUSIONS: This systematic review demonstrates the beneficial effects of transitional support strategies for newly qualified nurses from the perspective of the new nurse and their employer. The overall impact of support strategies appears positive, irrespective of the type of support provided. This may suggest that it is the organisations' focus on new graduate nurses that is important, rather than simply leaving them to acclimatise to their new role themselves. Future research should involve well designed randomised controlled trials with larger sample sizes, using more objective and reliable outcome measures. PMID- 26001855 TI - Parents' preferences strongly influence their decisions to withhold prescribed opioids when faced with analgesic trade-off dilemmas for children: a prospective observational study. AB - BACKGROUND: Despite parents' stated desire to treat pain in their children, recent studies have critiqued their underuse of prescribed analgesics to treat pain in their children after painful procedures. Parents' analgesic preferences, including their perceived importance of providing pain relief or avoiding adverse drug effects may have important implications for their analgesic decisions, yet no studies have evaluated the influence of preferences on decisions to withhold prescribed opioids for children. OBJECTIVES: We prospectively explored how parents' preferences influenced decisions to withhold prescribed opioids when faced with hypothetical dilemmas and after hospital discharge. DESIGN: Prospective Observational Study Design: Phase 1 included hypothetical analgesic decisions and Phase 2, real analgesic decisions after hospital discharge. SETTING: Large tertiary care pediatric hospital in the Midwest of the United States. PARTICIPANTS: Five-hundred seven parents whose children underwent a painful surgical procedure requiring an opioid prescription were included. METHODS: At baseline, parents completed surveys assessing their pain relief preference (i.e., their rated importance of pain relief relative to adverse drug event avoidance), preferred treatment thresholds (i.e., pain level at which they would give an opioid), adverse drug event understanding, and hypothetical trade off decisions (i.e., scenarios presenting variable pain and adverse drug event symptoms in a child). After discharge, parents recorded all analgesics they gave their child as well as pain scores at the time of administration. RESULTS: Higher preference to provide pain relief (over avoid analgesic risk) lessened the likelihood that parents would withhold the prescribed opioid when adverse drug event symptoms were present together with high pain scores in the hypothetical scenarios. Additionally, higher preferred treatment thresholds increased the likelihood of parents withholding opioids during their hypothetical decision making as well as at home. The strong influence of these preferences weakened the effect of opioid ADE understanding on decisions to withhold opioids when ADEs (i.e., nausea/vomiting or oversedation) were present together with high pain. CONCLUSIONS: Findings from this study suggest that preferences strongly influence and may interfere with parents' effective and safe analgesic decision-making when conflicting symptoms (i.e., high pain and an ADE) are present. To improve effective analgesic use, there is a need to shape parents' preferences and improve their understanding of safe actions that will treat pain when ADE symptoms are present. PMID- 26001856 TI - Effects of In Vitro Osteogenic Induction on In Vivo Tissue Regeneration by Dental Pulp and Periodontal Ligament Stem Cells. AB - INTRODUCTION: The aim of this study was to determine the effects of in vitro odontogenic/cementogenic differentiation on the in vivo tissue regeneration of dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs). METHODS: DPSCs and PDLSCs were predifferentiated for 0, 4, or 8 days with an odontogenic/cementogenic medium and then transplanted into subcutaneous pockets in immunocompromised mice. The transplants were harvested 9 weeks after transplantation, and the characteristics of the newly formed tissues in vivo were analyzed by histologic staining; examining alkaline phosphate activity; immunohistochemical staining for osteocalcin, dentin sialoprotein, and type XII collagen; and quantitative real-time polymerase chain reaction to analyze the expression patterns of the following genes: RUNX2, OC, DMP1, DSPP, POSTN, CP23, and Col XII. RESULTS: In DPSC transplants, the amount of new tissues was similar in all groups, whereas in predifferentiated transplants the OC and DSPP expression were higher than undifferentiated transplants. Predifferentiated PDLSC transplants generated more hard tissue and expressed higher alkaline phosphatase activity than undifferentiated transplants. In particular, 8-day predifferentiated PDLSC transplants formed tissue closer to the cementum/PDL complex in vivo as confirmed by the higher expression levels of POSTN, CP23, and Col XII. CONCLUSIONS: Although there was no significant increase in tissue forming ability among DPSCs after predifferentiation, predifferentiated DPSCs generated hard tissue closer to dentin. Also, predifferentiated PDLSCs appeared to be able to generate higher-quality and greater amounts of tissue for dental regeneration than undifferentiated PDLSCs. PMID- 26001857 TI - Bioactivity of a Calcium Silicate-based Endodontic Cement (BioRoot RCS): Interactions with Human Periodontal Ligament Cells In Vitro. AB - INTRODUCTION: Tricalcium silicate-based materials are recognized as bioactive materials through their capacity to induce hard tissue formation both in the dental pulp and bone. Sealing the apex implies that the root canal filling materials interact with the periapical tissues. This work was designed to study the interactions of newly developed tricalcium silicate cement (BioRoot RCS; Septodont, Saint Maur Des Fosses, France) with apical tissue compared with a standard zinc oxide-eugenol sealer (Pulp Canal Sealer [PCS]; SybronEndo, Orange, CA). METHODS: Cell viability was assessed by direct contact between human periodontal ligament (PDL) cells and BioRoot RCS or PCS. In addition, an in vitro tooth model was used to study the interactions between these materials and PDL cells. For this purpose, human extracted incisors were sectioned at the enamel cementum junction; root canals were prepared, sterilized, and filled with lateral condensation with both materials. The root apices were dipped in the culture medium for 24 hours. These conditioned media were used to investigate their effects on human PDL cells. Cell proliferation was investigated with the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the secretion of angiogenic and osteogenic growth factors was quantified using an enzyme-linked immunosorbent assay. RESULTS: BioRoot RCS has less toxic effects on PDL cells than PCS and induced a higher secretion of angiogenic and osteogenic growth factors than PCS. CONCLUSIONS: Taken together, these preclinical results suggest that the calcium silicate cement (BioRoot RCS) has a higher bioactivity than the zinc oxide-eugenol sealer (PCS) on human PDL cells. PMID- 26001858 TI - Role of ALK5/Smad2/3 and MEK1/ERK Signaling in Transforming Growth Factor Beta 1 modulated Growth, Collagen Turnover, and Differentiation of Stem Cells from Apical Papilla of Human Tooth. AB - INTRODUCTION: Transforming growth factor beta1 (TGF-beta1) plays an important role in cell proliferation, matrix formation, and odontogenesis. This study investigated the effects of TGF-beta1 on stem cells from apical papilla (SCAPs) and its signaling by MEK/ERK and Smad2. METHODS: SCAPs were exposed to TGF-beta1 with/without pretreatment and coincubation by SB431542 (an ALK5/Smad 2/3 inhibitor) or U0126 (a MEK/ERK inhibitor). Cell growth was examined by 3-(4,5 dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay or direct counting of viable cells. Collagen content was determined by using the Sircol collagen assay (Biocolor Ltd, Newtownabbey, Northern Ireland). Cell differentiation was evaluated by measuring alkaline phosphatase (ALP) activity. Smad2 and ERK1/2 phosphorylation was analyzed by Western blotting or PathScan phospho-enzyme linked immunosorbent assay (Cell Signaling Technology Inc, Danvers, MA). RESULTS: TGF-beta1 stimulated the growth and collagen content of cultured SCAPs. TGF-beta1 stimulated ERK1/2 and Smad2 phosphorylation within 60 minutes of exposure. Pretreatment by U0126 and SB431542 effectively prevented the TGF-beta1-induced cell growth and collagen content in SCAPs. TGF-beta1 stimulated ALP activity at lower concentrations (0.1-1 ng/mL) but down-regulated ALP at higher concentrations (>5 ng/mL). U0126 prevented 0.5 ng/mL TGF-beta1-induced ALP activity but showed little effect on 10 ng/mL TGF-beta1-induced decline of ALP in SCAPs. Interestingly, SB431542 attenuated both the stimulatory and inhibitory effects on ALP by TGF-beta1. CONCLUSIONS: TGF-beta1 may affect the proliferation, collagen turnover, and differentiation of SCAPs via differential activation of ALK5/Smad2 and MEK/ERK signaling. These results highlight the future use of TGF beta1 and SCAP for engineering of pulpal regeneration and apexogenesis. PMID- 26001859 TI - Treatment of colchicine-resistant Familial Mediterranean fever in children and adolescents. AB - Familial Mediterranean fever (FMF) is the most common autoinflammatory disease worldwide. Approximately 5-10 % of patients are unresponsive to colchicine. Aim of this study was to determine the short- and long-term efficacy and safety of anti-interleukin 1 (anti-IL1) and anti-tumor necrosis factor agents in colchicine resistant FMF cases in Turkish children and adolescents. This is a single-center retrospective case series of colchicine-resistant FMF patients. The included patients were treated with biologics for either colchicine resistance or because of one of the following: (1) amyloidosis, (2) recurrent prolonged febrile myalgia and frequent need of steroid and (3) persistent arthritis. Colchicine resistance was defined as at least one attack per month for three consecutive months and elevated erythrocyte sedimentation rate or C-reactive protein or serum amyloid A in-between attacks despite taking adequate dose of colchicine. Response to biologicals was evaluated by the Autoinflammatory Diseases Activity Index (AIDAI) score sheet, patients/parents'/physicians' global assessment of disease severity and laboratory parameters every 3-6 months. Fourteen patients were included in the study. Three patients were treated with etanercept for median 7 months (range 3-11 months), and all patients had to be switched to anti-IL1 treatment because of adverse effects and/or partial response. Eleven patients were treated with anakinra with a median duration of 8 months (4-60 months). Nine patients responded to treatment at the third month, but four of them switched to canakinumab because of noncompliance, local side effects and active arthritis. Nine patients were treated with canakinumab, all responded. At follow-up, in two patients the dose had to be increased, and on the other hand, in three patients the interval was increased to every 12-16 weeks. In three patients, anti-IL1 treatment could be stopped and they are fine with colchicine. This case series describes the largest cohort of colchicine-resistant FMF patients in childhood and adolescence. Anti-IL1 treatment is a safe and effective therapy to control inflammation. The treatment should be modified and decided for each patient on an individual basis. PMID- 26001860 TI - Back to Basics: Traditional Nottingham Grade Mitotic Counts Alone are Significant in Predicting Survival in Invasive Breast Carcinoma. AB - BACKGROUND: Newer multigene molecular profiling assays for breast carcinoma rely heavily on the quantification of genes of proliferation, whereas traditional histological grading reports the mitotic count. The mitotic activity of invasive breast carcinomas may be undervalued; therefore, an evaluation of the prognostic significance of mitotic score in predicting prognosis was performed. METHODS: Retrospective analysis of a single institutional cohort of newly diagnosed estrogen receptor positive (ER+), HER2 negative (HER2-) unilateral invasive breast carcinomas was performed. Mitotic scores from the 3-part Nottingham combined histological grade were compared with clinical parameters. Mitoses were counted on Olympus BX50 microscopes and assigned scores of 1-3 based on observed mitoses. RESULTS: A total of 1292 ER+, HER2- invasive breast carcinoma patients were identified, with a median follow-up time of 2.6 years (range 0-14 years). Higher mitotic score was significantly associated with younger age, larger tumor size, angiolymphatic invasion, node-positive disease, higher stage, and the use of hormonal and cytotoxic chemotherapy. Mitotic score was significant in modeling time to local/regional recurrence (p = 0.02), recurrence-free survival/RFS (p < 0.001), and overall survival/OS (p = 0.01) with higher mitotic scores associated with worse outcomes. Higher mitotic score correlated significantly with intermediate/high risk Oncotype Dx recurrence scores (p = 0.009). CONCLUSIONS: First-generation molecular profiling assays for estrogen receptor positive invasive breast carcinomas derive much of their predictive power from quantifying genes of proliferation into a single score. Sometimes overlooked in the profusion of molecular data, the time-tested, mitotic count in the Nottingham combined histological grade is a good single-parameter predictor of survival. PMID- 26001861 TI - Influence of Different Neoadjuvant Chemotherapy Regimens on Response, Prognosis, and Complication Rate in Patients with Esophagogastric Adenocarcinoma. AB - BACKGROUND: Perioperative chemotherapy improves survival in patients with advanced esophagogastric cancer, but the optimal treatment regimen remains unclear. More intensive chemotherapy may improve outcome, but also increase toxicity and complications. METHODS: A total of 843 patients were included in this retrospective study and stratified in 4 groups: doublet therapy with cisplatin or oxaliplatin and 5-fluorouracil (groups A/B) or triplet therapy with additional epirubicin or taxane (groups C/D). The influence of the different neoadjuvant chemotherapy regimens on response, prognosis, and complications was assessed. RESULTS: Clinical and pathological response were associated with longer overall survival (OS; p < 0.001). No significant differences regarding response or OS were found, but there was a trend toward better outcome in group D (taxane containing triplet). In the subgroup of 669 patients with adenocarcinomas of the esophagogastric junction (AEG), patients who had received taxane-containing regimens had a significantly longer OS (p = 0.037), but taxane use was not an independent factor in multivariate analysis. Triple therapy with taxanes did not result in a higher complication rate or postoperative mortality. CONCLUSIONS: Although no superior neoadjuvant chemotherapy regimen was identified for patients with esophagogastric adenocarcinoma, taxane-containing regimens should be further investigated in randomized trials, especially in patients with AEG tumors. PMID- 26001862 TI - The Effect of Contralateral Prophylactic Mastectomy on Perioperative Complications in Women Undergoing Immediate Breast Reconstruction: A NSQIP Analysis. AB - BACKGROUND: Women with breast cancer are increasingly choosing to undergo contralateral prophylactic mastectomy (CPM) despite questionable survival benefit and limited data on added risks. Little is known about differences in perioperative complications between women who undergo bilateral mastectomy (BM) versus unilateral mastectomy (UM) with reconstruction. METHODS: The American College of Surgeons National Surgery Quality Improvement Program Participant Use Files (2005-2013) were used to identify women with unilateral breast cancer who underwent UM or BM with reconstruction. Adjusted 30-day complications were compared between UM and BM groups using logistic regression models. RESULTS: A total of 20,501 patients were identified, of whom 35.3 % underwent BM. Of these, 84.3 % had implant reconstruction and 15.7 % had autologous reconstruction. For all women, BM was associated with longer hospital stays (adjusted odds ratio [aOR] 1.98-2.09, p < 0.001) and a higher transfusion rate than UM (aOR 2.52-3.06, p < 0.001). BM with implant reconstruction was associated with a modestly increased reoperation rate (aOR 1.15, p = 0.029). BM with autologous reconstruction was associated with a higher wound disruption rate (aOR 2.51, p = 0.015). Surgical site infections, prosthesis failure, and medical complications occurred at similar rates in UM and BM groups. CONCLUSIONS: CPM is associated with significant increases in some, but not all, surgical site complications. CPM does not increase the likelihood of medical complications, which are generally infrequent. PMID- 26001863 TI - Caesarean scar pregnancy. PMID- 26001864 TI - Getting accepted. PMID- 26001865 TI - The incidence of maternal artefact during intrapartum fetal heart rate monitoring. PMID- 26001866 TI - The incidence of Maternal Artefact During Intrapartum Fetal Heart Rate Monitoring. PMID- 26001867 TI - Newborn outcomes in british columbia after caesarean section for non-reassuring fetal status. AB - OBJECTIVE: To assess the incidence in British Columbia of severe morbidity in neonates delivered by Caesarean section for non-reassuring fetal status, and to examine the accuracy of Apgar score and umbilical cord gas values in predicting severe neonatal morbidity. METHODS: We assessed rates of hypoxic ischemic encephalopathy, NICU admission, and ventilator days, individually and as a composite outcome with neonatal death, among a total of 8466 term singletons delivered by Caesarean section for non-reassuring fetal status between January 1, 2007, and December 31, 2011. We calculated the predictive accuracy of Apgar scores and umbilical cord blood gas values using the area under the receiver operating characteristic (ROC) curve and the sensitivity and specificity for each outcome. RESULTS: The incidence of Apgar score at one minute < 4 was 8.0%, and for Apgar score at five minutes < 4 it was 0.6%. The incidence of umbilical cord pH < 7.10 was 6.5%, and for base-excess < -12 it was 2.9%. Apgar score at one minute < 7 had the greatest predictive accuracy for the composite outcome (81% for both sensitivity and specificity). The area under the ROC curve for Apgar score at one minute and at five minutes, umbilical cord pH, and base-excess was 0.87, 0.86, 0.76, and 0.78, respectively. CONCLUSION: The incidence of abnormal Apgar score and abnormal umbilical cord gas values is very low among neonates in British Columbia delivered by Caesarean section for non-reassuring fetal status. Apgar score at one minute < 7 is a good predictor of severe neonatal morbidity. Electronic fetal monitoring remains a non-specific method for detection of fetal compromise in the intrapartum period. PMID- 26001868 TI - Maternal and perinatal outcomes of pregnancies delivered at 23 weeks' gestation. AB - OBJECTIVE: To evaluate the maternal and perinatal outcomes of pregnancies delivered at 23+0 to 23+6 weeks' gestation. METHODS: This prospective cohort study included women in the Canadian Perinatal Network who were admitted to one of 16 Canadian tertiary perinatal units between August 1, 2005, and March 31, 2011, and who delivered at 23+0 to 23+6 weeks' gestation. Women were included in the network if they were admitted with spontaneous preterm labour with contractions, a short cervix without contractions, prolapsing membranes with membranes at or beyond the external os or a dilated cervix, preterm premature rupture of membranes, intrauterine growth restriction, gestational hypertension, or antepartum hemorrhage. Maternal outcomes included Caesarean section, placental abruption, and serious complication. Perinatal outcomes were mortality and serious morbidity. RESULTS: A total of 248 women and 287 infants were included in the study. The rate of Caesarean section was 10.5% (26/248) and 40.3% of women (100/248) had a serious complication, the most common being chorioamnionitis (38.6%), followed by blood transfusion (4.5%). Of infants with known outcomes, perinatal mortality was 89.9% (223/248) (stillbirth 23.3% [67/287] and neonatal death 62.9% [156/248]). Of live born neonates with known outcomes (n = 181), 38.1% (69/181) were admitted to NICU. Of those admitted to NICU, neonatal death occurred in 63.8% (44/69). Among survivors at discharge, the rate of severe brain injury was 44.0% (11/25), of retinopathy of prematurity 58.3% (14/24), and of any serious neonatal morbidity 100% (25/25). Two subgroup analyses were performed: in one, antepartum stillbirths were excluded, and in the other only centres that indicated they offered fetal monitoring at 23 weeks' gestation were included and antepartum stillbirths were excluded. In each of these, perinatal outcomes similar to the overall group were found. CONCLUSION: Pregnant women delivering at 23 weeks' gestation are at risk of morbidity. Their infants have high rates of serious morbidity and mortality. Further research is needed to identify strategies and forms of management that not only increase perinatal survival but also reduce morbidities in these extremely low gestational age infants and reduce maternal morbidity. PMID- 26001869 TI - Factors Associated With Women's Plans to Gain Weight Categorized as Above or Below the National Guidelines During Pregnancy. AB - OBJECTIVE: Given that planning to gain gestational weight categorized as above the national guidelines is associated with actually gaining above the guidelines, we sought to identify physical, lifestyle, knowledge, and psychological factors associated with planned weight gain. METHODS: Using a piloted, self-administered questionnaire, a cross-sectional study of women with singleton pregnancies was conducted. Women's plans for weight gain were categorized as above, within, or below the guidelines. Univariate and multivariate analyses were performed. RESULTS: The response rate was 90.7% (n = 330). Compared with women whose plans to gain weight were within the guidelines, women whose plans to gain were above the guidelines were more likely to be older (adjusted odds ratio [aOR] 1.09 per year; 95% CI 1.03 to 1.16), to have a greater pre-pregnancy BMI (aOR 1.17 per unit of BMI; 95% CI 1.10 to 1.25), to drink more than one glass of soft drink or juice per day (aOR 2.73; 95% CI 1.27 to 5.87), and to report receiving a recommendation by their care provider to gain weight above the guidelines (aOR 5.46; 95% CI 1.56 to 19.05). Women whose plans to gain weight were categorized as below the guidelines were more likely to eat lunch in front of a screen (aOR 2.27; 95% CI 1.11 to 4.66) and to aspire to greater social desirability (aOR 2.51; 95% CI 1.01 to 6.22). CONCLUSION: Modifiable factors associated with planned gestational weight gain categorized as above the guidelines included soft drink or juice consumption and having a recommendation from a care provider, while planned weight gain categorized as below the guidelines was associated with eating lunch in front of a screen and social desirability. PMID- 26001870 TI - Medical students' intentions to seek abortion training and to provide abortion services in future practice. AB - OBJECTIVES: Lack of providers is a barrier to accessing abortion in Canada. The factors influencing the number of abortion providers are poorly understood. In this study, we assessed the attitudes and intentions of medical students towards abortion training and provision to gain insight into the future supply of abortion providers. METHODS: We surveyed first, second, and third year medical students at an Ontario university to determine their intentions to train in and provide abortion services during different stages of training and in future practice. We assessed students' attitudes and intentions towards training in and providing abortions, their perceptions of social support, their perceived ability to receive training in and to provide abortion services, and their attitudes towards the legality of abortion. RESULTS: Surveys were completed by 337 of 508 potential respondents (66.7%). The responses indicated that the students in the survey held relatively positive attitudes towards the legality and availability of abortion in Canada. Respondents had significantly more positive attitudes towards first trimester medical abortions (and a greater intention to provide them) than towards second trimester surgical abortions. Thirty-five percent of students planned to enter a specialty in which they could perform abortions, but fewer than 30% of these students planned to provide any type of abortion. Intentions to provide abortions were correlated with positive attitudes toward abortion in general and greater perceived social support for abortion provision. CONCLUSION: A small proportion of students sampled intended both to enter a specialty in which abortion would be within the scope of practice and to provide abortion services. Lack of perceived social support for providing abortions and the perceived inability to obtain abortion training or to logistically provide abortions were identified as two potentially modifiable barriers to abortion provision. We propose increasing education on abortion provision and creating policies to promote medical abortion as a method of improving access to abortion across Canada. PMID- 26001871 TI - Performance measures related to colposcopy for canadian cervical cancer screening programs: identifying areas for improvement. AB - OBJECTIVE: To describe performance measures related to colposcopic examinations in Canadian cervical cancer screening programs; specifically, time to colposcopy, histological investigation rate, and agreement between cytology and histology. METHODS: As part of a national report on the performance of cervical cancer screening, aggregate provincial cervical cancer screening data provided by provinces to the Pan-Canadian Cervical Screening Network were used to evaluate colposcopy program performance measures for women 20 to 69 years of age who had a Pap test in 2009 and 2010. RESULTS: A total of 37 523 women had a high-grade or more severe Pap test result. The proportion of women who had a colposcopy <= 90 days after their Pap test ranged from 30.9% to 51.5%. Fewer women 60 to 69 years of age had a colposcopy than women in younger age groups. The proportion of women who had a high-grade or more severe Pap test result and colposcopy who had a biopsy within 12 months ranged from 82.1% to 96.5%. The proportion of biopsy results that agreed with the Pap test result ranged from 59.5% to 82.1%. CONCLUSION: The time from having a high-grade Pap test result to undergoing colposcopy must be reduced to lower the risk of adverse outcomes and the stress associated with delayed follow-up. The agreement between screening cytology and histology meets the national target of >= 65%. Although six of 13 provinces and territories provided data for colposcopy-related performance measures, more information is needed to assess colposcopy services accurately at the national level. PMID- 26001872 TI - Obstetrical and neonatal outcomes of methadone-maintained pregnant women: a canadian multisite cohort study. AB - OBJECTIVE: To describe obstetrical and neonatal outcomes including neonatal abstinence syndrome (NAS) in a Canadian cohort of methadone-maintained pregnant women. METHODS: We conducted a retrospective chart review at three integrated care programs in Vancouver, Toronto, and Montreal. Pregnant women on methadone maintenance treatment (MMT) who attended for care between 1997 and 2009 were included in this multisite study. Maternal and neonatal outcomes in each of the three contributing centres were compared. RESULTS: A total of 94 pregnant methadone-maintained women were included in the final analysis: 36 from Toronto, 36 from Vancouver, and 22 from Montreal. Maternal demographics showed inter-site differences in ethnicity and marital status. Obstetrical complications were not frequent; the most frequent was antenatal hemorrhage, which occurred in 14% of the total cohort. The incidence of premature labour was significantly higher in Vancouver and Montreal than in Toronto. The mean gestational age at delivery for the entire cohort was 38 weeks; mean birth weight was 2856 grams. The average length of hospital stay for babies with NAS was 19 days, with 27% of neonates requiring pharmacological treatment for NAS. Approximately 60% of neonates were discharged from hospital to the care of their mother. CONCLUSION: Integrated care programs resulted in satisfactory obstetrical and neonatal outcomes for pregnant women on MMT. Policies promoting maternal-newborn contact, rooming-in, and breastfeeding may help to decrease the severity of NAS and the need for pharmacological treatment of NAS. We strongly recommend the development of similar programs across Canada to address gaps in services. PMID- 26001873 TI - An integrated approach to male-factor subfertility: bridging the gap between fertility specialists trained in urology and gynaecology. AB - Subfertile men and women are usually cared for by different clinicians, namely urologists and gynaecologists. While these doctors share each other's goals, they may not always appreciate the content or implications of their opposite number's clinical decisions; to some degree they may practice in "silos." We address this problem by reviewing the effectiveness of medical treatments for male factor subfertility in the context of female factors. The effectiveness of treatments for couples with male factor subfertility, other than IVF with ICSI, appears modest. However, data from randomized controlled trials suggest benefits from some treatments: clomiphene and tamoxifen for the male (common odds ratio for pregnancy [COR] 2.42; 95% CI 1.47 to 3.94), antioxidants (COR 4.18; 95% CI 2.65 to 6.59) and surgical management of a clinical varicocele (COR 2.39; 95% CI 1.56 to 3.66). Nevertheless, close attention to female age and the duration of subfertility help to avoid lost opportunity through delays in treatment when IVF with ICSI is indicated. Making treatment decisions squarely in the context of the couple's overall prognosis is key for optimal outcomes. Future trials of male fertility treatments should focus on pregnancy as the primary outcome, rather than less important surrogates such as sperm quality. PMID- 26001874 TI - Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. AB - OBJECTIVE: To review the evidence and provide recommendations on screening for and management of vulvovaginal candidiasis, trichomoniasis, and bacterial vaginosis. OUTCOMES: OUTCOMES evaluated include the efficacy of antibiotic treatment, cure rates for simple and complicated infections, and the implications of these conditions in pregnancy. EVIDENCE: Published literature was retrieved through searches of MEDLINE, EMBASE, CINAHL, and The Cochrane Library in June 2013 using appropriate controlled vocabulary (e.g., vaginitis, trichomoniasis, vaginal candidiasis) and key words (bacterial vaginosis, yeast, candidiasis, trichomonas vaginalis, trichomoniasis, vaginitis, treatment). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to May 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. Vulvovaginal candidiasis affects 75% of women at least once. Topical and oral antifungal azole medications are equally effective. (I) 2. Recurrent vulvovaginal candidiasis is defined as 4 or more episodes per year. (II 2) 3. Trichomonas vaginalis is a common non-viral sexually transmitted infection that is best detected by antigen testing using vaginal swabs collected and evaluated by immunoassay or nucleic acid amplification test. (II-2) 4. Cure rates are equal at up to 88% for trichomoniasis treated with oral metronidazole 2 g once or 500 mg twice daily for 7 days. Partner treatment, even without screening, enhances cure rates. (I-A) 5. Current evidence of the efficacy of alternative therapies for bacterial vaginosis (probiotics, vitamin C) is limited. (I) Recommendations 1. Following initial therapy, treatment success of recurrent vulvovaginal candidiasis is enhanced by maintenance of weekly oral fluconazole for up to 6 months. (II-2A) 2. Symptomatic vulvovaginal candidiasis treated with topical azoles may require longer courses of therapy to be resolved. (1-A) 3. Test of cure following treatment of trichomoniasis with oral metronidazole is not recommended. (I-D) 4. Higher-dose therapy may be needed for treatment-resistant cases of trichomoniasis. (I-A) 5. In pregnancy, treatment of symptomatic Trichomonas vaginalis with oral metronidazole is warranted for the prevention of preterm birth. (I-A) 6. Bacterial vaginosis should be diagnosed using either clinical (Amsel's) or laboratory (Gram stain with objective scoring system) criteria. (II-2A) 7. Symptomatic bacterial vaginosis should be treated with oral metronidazole 500 mg twice daily for 7 days. Alternatives include vaginal metronidazole gel and oral or vaginal clindamycin cream. (I-A) 8. Longer courses of therapy for bacterial vaginosis are recommended for women with documented multiple recurrences. (I-A). PMID- 26001875 TI - The management of uterine fibroids in women with otherwise unexplained infertility. AB - OBJECTIVE: To provide recommendations regarding the best management of fibroids in couples who present with infertility. Usual and novel treatment options for fibroids will be reviewed with emphasis on their applicability in women who wish to conceive. OPTIONS: Management of fibroids in women wishing to conceive first involves documentation of the presence of the fibroid and determination of likelihood of the fibroid impacting on the ability to conceive. Treatment of fibroids in this instance is primarily surgical, but must be weighed against the evidence of surgical management improving clinical outcomes, and risks specific to surgical management and approach. OUTCOMES: The outcomes of primary concern are the improvement in pregnancy rates and outcomes with management of fibroids in women with infertility. EVIDENCE: Published literature was retrieved through searches of PubMed, MEDLINE, the Cochrane Library in November 2013 using appropriate controlled vocabulary (e.g., leiomyoma, infertility, uterine artery embolization, fertilization in vitro) and key words (e.g., fibroid, myomectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2013. Grey (unpublished literature) was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: These recommendations are expected to allow adequate management of women with fibroids and infertility, maximizing their chances of pregnancy by minimizing risks introduced by unnecessary myomectomies. Reducing complications and eliminating unnecessary interventions are also expected to decrease costs to the health care system. Summary Statements 1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3) 2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of the target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as a stand-alone treatment for fibroids in the infertile population. (III) 3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III) 4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3) 5. In the infertile population, cumulative pregnancy rates by the laparoscopic and the minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2) 6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendations 1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A) 2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III B) 3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B) 4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D) 5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2A) 6. Removal of subserosal fibroids is not recommended. (III-D) 7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C) 8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A) 9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A) 10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E). PMID- 26001880 TI - Impaired vagus-mediated immunosuppression in microsomal prostaglandin E synthase 1 deficient mice. AB - The cholinergic anti-inflammatory pathway controls innate immune responses and inflammation. The prostaglandin (PG) system is involved in several neuro processes and associated with inflammatory activation of cells in vagal nuclei. Here we aimed to investigate the potential role of PG in cholinergic neuro regulation. The effect of vagus nerve stimulation (VNS) has been evaluated in microsomal prostaglandin E synthase-1 (mPGES-1) knockout (-/-) and wild-type (+/+) mice regarding cytokine and PG levels after lipopolysaccharides (LPS) challenge. As expected, VNS decreased the release of pro-inflammatory cytokines both in serum and spleen extracts of mPGES-1 (+/+)animals. However, the immune suppressive effect of VNS was completely abolished in mPGES-1 (-/-) mice. The PG content was not affected by VNS in the spleen of mPGES-1 (+/+) and mPGES-1 (-/-) mice but interestingly, acetylcholine (ACh) release in spleen induced by VNS confirmed an intact cholinergic pathway in mPGES-1 (+/+) whereas no VNS-induced ACh release was found in mPGES-1 (-/-) animals. Our data show that mPGES-1 and consequently PGE2 are crucial in the cholinergic anti-inflammatory pathway. Moreover, the mechanisms involved do not affect PG content in the spleen, but lack of mPGES-1 was found to strongly affect cholinergic mechanisms in the inflamed spleen. These findings illustrate previously unrecognized associations between the cholinergic and prostaglandin systems, and may be of importance for further development of therapeutic strategies directed at modulation of the inflammatory reflex, and immunosuppression in chronic inflammatory diseases. PMID- 26001881 TI - Outcomes in Patients with Helicobacter pylori Undergoing Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: In vertical sleeve gastrectomy (VSG), the majority of the stomach is resected and much of the tissue colonized with Helicobacter pylori and the bulk of acid producing cells are removed. In addition, the effect of H. pylori colonization of the stomach of patients undergoing stapling procedures is unclear. As a result, the need for detection and treatment of H. pylori in patients undergoing VSG is unknown. METHODS: Four hundred and eighty patients undergoing VSG are the subject of this study. Three surgeons at a single institution performed the procedures. The remnant stomach was sent to pathology and tested for the presence of H. pylori using immunohistochemistry. All patients were discharged on proton pump inhibitors. RESULTS: Of the 480 patients who underwent VSG, 52 were found to be H. pylori positive based on pathology. There was no statistically significant difference in age (p = 0.77), sex (p = 0.48), or BMI (p = 0.39) between the groups. There were 17 readmissions post-op. Five of these were in the H. pylori positive cohort. Six of these complications were classified as severe (anastomotic leak, intra-abdominal collection, or abscess), with two in the H. pylori positive cohort (Table 1). There was no statistically significant difference in the severe complication rates between the two groups (p = 0.67). There were no readmissions for gastric or duodenal ulceration or perforation. CONCLUSIONS: Our data suggests that there is no increase in early complications in patients with H. pylori undergoing VSG. If these findings are confirmed in a long-term follow-up, it would mean that preoperative H. pylori screening in patients scheduled for VSG is not necessary. PMID- 26001882 TI - Outcomes of Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass in Patients Older than 60. AB - BACKGROUND: The proportion of population older than 60 years is rapidly increasing. The majority of this older population suffers from multiple comorbid conditions including obesity. Non-surgical means of weight loss do not offer a predictable solution. Surgical interventions seem to be the most promising solution for the obesity problem, but there is a relative lack of data in literature regarding bariatric procedures in older populations. OBJECTIVES: Our study aims to evaluate the safety and efficacy of bariatric surgery in patients older than 60 years of age, to determine the weight loss, rate of operation related complications, and impacts of surgery on comorbid conditions, and to compare the effectiveness of bariatric surgery in older patients to the effectiveness of bariatric surgery for the general population at Montefiore Medical Center. METHODS: A retrospective review of patients' medical records were used to collect data to create databases to identify patients older than 60 years age who underwent bariatric surgery procedures spanning a 4-year period between January 2009 and October 2013. Data reviewed included age, sex, height, pre operative weight, and body mass index (BMI), presence of obesity-related comorbid conditions, procedures performed, mortality, immediate or delayed complications, length of follow-up, excess weight lost, BMI points lost, percent of excess weight loss (%EWL), hemoglobin Alc (HgbA1c), and effects on obesity-related comorbid conditions. The percent of excess weight loss and number of complications within the older patient group were compared to the general population, which consists of patients between the ages of 22 and 59. RESULTS: Ninety-eight patients were identified. Seven patients did not follow up at any time period, and the eight patients who had laparoscopic adjustable gastric band (LAGB) were also excluded due to insufficient data. Overall, 83 patients who were above the age of 60 were examined; 30 patients had laparoscopic sleeve gastrectomy (LSG), and 53 patients underwent laparoscopic Roux-en-Y gastric bypass (LRYGB). The average patient age was 63.4 years, the average pre-operative weight was 122.3 kg, and the average excess body weight was 54.8 kg. The pre existing comorbid conditions included 90.4 % hypertension (HTN), 63.9 % diabetes mellitus (DM), 50.6 % hyperlipidemia (HL), 34.9 % obstructive sleep apnea (OSA), and 30.1 % asthma. The average %EWL at 3 months, 6 months, and 12 months was 37.0, 51.3, and 65.2 %, respectively. A significant proportion of patients reported resolution or improvement in comorbid conditions. When results were compared to the general, population there was no significant difference in the number of complications that occurred within each of the two groups. The difference in %EWL at the 12-month follow-up was not statistically significant between the general population and the older patients, which suggests that both groups lost a similar amount of weight and that bariatric surgery on patients who are above the age of 60 is effective. CONCLUSIONS: Bariatric surgery can be safe and effective for patients older than 60 years of age with a low morbidity and mortality; the weight loss and improvement in comorbidities in older patients were clinically significant. When compared to the general population, there was no statistically significant difference in the average %EWL at 12 months or the number of complications due to surgery. Long-term effects of such interventions will need further studies and investigations. PMID- 26001883 TI - Impact of Bariatric Surgery on the Saliva of Patients with Morbid Obesity. AB - BACKGROUND: The oral condition of obese patients may change following bariatric surgery owing to adverse effects that cause alterations in the oral cavity. The aim of this study was to evaluate the impact of bariatric surgery on the saliva of patients with morbid obesity. METHODS: Whole saliva samples were collected from 27 patients with morbid obesity (BMI >40 kg/m(2)), prior to and 6 months after bariatric surgery. Stimulated salivary flow rate, pH, buffering capacity, and microbial levels of mutans streptococci, Lactobacillus spp., and Candida albicans were analyzed from saliva. RESULTS: Values of all salivary variables before and after bariatric surgery were within the normal range, except for the level of C. albicans, which was elevated at both times. An increase in the level of mutans streptococci was observed after bariatric surgery (p < 0.05). CONCLUSIONS: The results suggest that the salivary levels of mutans streptococci increase following bariatric surgery in morbidly obese patients. PMID- 26001884 TI - Getting there--working toward minimizing blood loss in scoliosis surgery. AB - COMMENTARY ON: Ryan KM, O'Brien K, Reqan I, O'Byrne JM, Moore D, Kelly PM, et al. The prevalence of abnormal preoperative coagulation tests in pediatric patients undergoing spinal surgery for scoliosis. Spine J 2015;15:1217-22 (in this issue). PMID- 26001885 TI - Improving methodology when analyzing shockwave evidence. PMID- 26001886 TI - Screening method for major depressive disorders by questionnaire survey in patients with chronic spinal pain. PMID- 26001887 TI - Reply to the letter to the editor regarding "What is the best screening test for depression in chronic spinal patients?". PMID- 26001888 TI - Engineering the bioelectrochemical interface using functional nanomaterials and microchip technique toward sensitive and portable electrochemical biosensors. AB - Electrochemical biosensors have played active roles at the forefront of bioanalysis because they have the potential to achieve sensitive, specific and low-cost detection of biomolecules and many others. Engineering the electrochemical sensing interface with functional nanomaterials leads to novel electrochemical biosensors with improved performances in terms of sensitivity, selectivity, stability and simplicity. Functional nanomaterials possess good conductivity, catalytic activity, biocompatibility and high surface area. Coupled with bio-recognition elements, these features can amplify signal transduction and biorecognition events, resulting in highly sensitive biosensing. Additionally, microfluidic electrochemical biosensors have attracted considerable attention on account of their miniature, portable and low-cost systems as well as high fabrication throughput and ease of scaleup. For example, electrochemical enzymetic biosensors and aptamer biosensors (aptasensors) based on the integrated microchip can be used for portable point-of-care diagnostics and environmental monitoring. This review is a summary of our recent progress in the field of electrochemical biosensors, including aptasensors, cytosensors, enzymatic biosensors and self-powered biosensors based on biofuel cells. We presented the advantages that functional nanomaterials and microfluidic chip technology bring to the electrochemical biosensors, together with future prospects and possible challenges. PMID- 26001889 TI - A case series in patients with enteropathy and granulomatous diseases. AB - BACKGROUND: Although sarcoidosis and celiac disease are both chronic immunologic disorders involving multiple organ systems, reports about association of diseases in individual patients are sparse. While sarcoidosis is a chronic granulomatous disease presumably reflecting an exaggerated response to an unknown antigen, celiac disease is a T cell-driven disease triggered by ingestion of gluten, a protein composite found in wheat and related grains. CASE PRESENTATION: We present three cases with a longstanding history of sarcoidosis that have been additionally diagnosed with celiac-like enteropathy. In two cases, celiac disease was established applying celiac-specific serology and duodenal histology, while one case was revealed as an AIE-75-positive autoimmune enteropathy. The HLA DR3/DQ2 haplotype was confirmed in both celiac patients, hence confirming previous data of linkage disequilibrium as a cause for disease association. Remarkably, one celiac patient presented with granulomatous nodulae in the ileum, thus reflecting an intestinal sarcoid manifestation. In contrast the patient with an autoimmune enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. CONCLUSIONS: Associations of sarcoidosis and celiac disease are rare but do occur. Determining the HLA status in patients with complex autoimmune associations might help classifying involved disease entities. PMID- 26001890 TI - Spanish cultural adaptation and validation of the shoulder pain and disability index, and the oxford shoulder score after breast cancer surgery. AB - BACKGROUND: The Oxford Shoulder Score (OSS) and the Shoulder Pain and Disability Index (SPADI) are patient-based outcome scores with valid psychometric properties which are widely used for shoulder interventions. OBJECTIVE: The purpose of the study is to adapt both questionnaires cross-culturally to Spanish, and to test their reliability, validity, responsiveness, and feasibility. DESIGN: Cultural adaptation and psychometric validation study. METHODS: Consecutive patients who had undergone breast cancer surgery referred to an outpatient clinic at the University of Alcala de Henares, Spain. One hundred and twenty women who had undergone breast cancer surgery, with pain and shoulder dysfunction. Cross cultural adaptation was performed according to the international guidelines. Reliability was analysed by test-retest reliability and internal consistency. Content and convergent construct validity were measured by the Expert Committee's and Spearman coefficient respectively. Responsiveness, feasibility, floor and ceiling effects were also tested. RESULTS: One hundred and twenty women aged 54.2 (+/-11) years took part in the study. The reliability was excellent; test-retest reliability was 0.974 (p < 0.001) for OSS, and 0.992 (p < 0.001) for SPADI; and Cronbach's alpha value was 0.947 for OSS, and 0.965 for SPADI. High construct validity was found between the OSS and SPADI questionnaires (r = -0.674). The effect size (ES) and standardized response mean (SRM) was moderate in OSS (ES = 0.50 and SRM = 0.70 (p < 0.001)), and moderate to good in SPADI (ES = 0.59 and SRM = 0.82 (p < 0.001)). LIMITATIONS: This study has some limitations, such as the group of participants is composed only of women following breast cancer treatment; the measurement took place in a single centre; and all the questionnaires administered were always provided to the participants in the same order. CONCLUSIONS: The OSS and SPADI Spanish versions are applicable, reliable, valid, and responsive to assess shoulder symptoms and quality of life in Spanish women with shoulder pain and disability after breast cancer treatment. PMID- 26001892 TI - Standby for amazement. PMID- 26001891 TI - Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease. AB - Nasu-Hakola disease (NHD) is a form of presenile dementia associated with sclerosing leukoencephalopathy and polycystic lipomembranous osteodysplasia. This extremely rare inherited disease is caused by mutations in either DAP12 or TREM2. The present study was designed to assess the relationship between DAP12/TREM2 genotype, mRNA and protein expression levels by both Western blotting and immunohistochemistry, and the tissue distribution and pathomorphological phenotype of the microglia. Molecular genetic testing performed in three NHD cases confirmed that two cases had mutations in DAP12 and that one case carried a mutation in TREM2. Protein levels were analyzed in four cases. Interestingly, significant DAP12 expression was found in numerous microglia in one NHD case with a homozygous DAP12 single-base substitution, and both real-time PCR and Western blotting confirmed the finding. In contrast, levels of both DAP12 and TREM2, respectively, were much lower in the other cases. Immunohistochemistry using established microglial markers revealed consistently mild activation of microglia in the cerebral white matter although there was no or only little expression of DAP12 in three of the NHD cases. The highly different expression of DAP12 represents the first description of such variable expressivity in NHD microglia. It raises important questions regarding the mechanisms underlying dementia and white matter damage in NHD. PMID- 26001894 TI - Ocular discomfort responses after short periods of contact lens wear. AB - PURPOSE: To investigate if contact lens-related discomfort is a function of the time of day at which lenses are worn. METHODS: This was a randomized, crossover, open-label clinical trial where subjective responses, with and without contact lenses, were assessed every 2 hours during five stages (A to E). Each stage began at the time when subjects would normally have inserted their contact lenses (T0). During stage A, no lenses were worn, whereas in stage B, lenses were worn continuously for 12 hours. In stages C to E, lenses were worn for only 4 hours. Contact lenses were inserted at T0 for stage C, but for stages D and E, lenses were not inserted until T0 + 4 and T0 + 8 hours, respectively. Mixed linear models were used for statistical analysis. RESULTS: In the absence of contact lenses, ocular comfort and dryness remained reasonably constant throughout the observation period. Ocular comfort and dryness decreased during 12 hours of continuous lens wear and became significantly worse from the 8-hour time onward compared with insertion (p < 0.023). There were no significant differences in terms of ocular comfort and dryness between any of the 4-hour lens wear stages (p < 0.82). During each 4-hour stage, both comfort and dryness behaved in a similar fashion (p > 0.05) to the first 4 hours of continuous contact lens wear. Comparing the scores of each of these stages with the no-lens response at the corresponding time showed no significant differences for comfort (p > 0.23) or dryness (p > 0.37). CONCLUSIONS: Short periods of wear can be experienced at any time of day without significant change in ocular discomfort and dryness. This suggests that subjective responses at the end of the day are determined by the length of time lenses are in contact with the eye, rather than the time of day at which lenses are worn. PMID- 26001895 TI - Clinical pearls. PMID- 26001897 TI - GPs vote to end "disastrous" out of area scheme. PMID- 26001898 TI - Assessing protein kinase target similarity: Comparing sequence, structure, and cheminformatics approaches. AB - In just over two decades, structure based protein kinase inhibitor discovery has grown from trial and error approaches, using individual target structures, to structure and data driven approaches that may aim to optimize inhibition properties across several targets. This is increasingly enabled by the growing availability of potent compounds and kinome-wide binding data. Assessing the prospects for adapting known compounds to new therapeutic uses is thus a key priority for current drug discovery efforts. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties now accompany a transformation of protein kinase inhibitor research, away from single, block-buster drug models, and toward "personalized medicine" with niche applications and highly specialized research groups. Major hurdles for the transformation to data driven drug discovery include mismatches in data types, and disparities of methods and molecules used; at the core remains the problem that ligand binding energies cannot be predicted precisely from individual structures. However, there is a growing body of experimental data for increasingly successful focussing of efforts: focussed chemical libraries, drug repurposing, polypharmacological design, to name a few. Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate proteins. Although structural evaluation offers more information, the flexibility of protein kinases, and differences between the crystal and physiological environments may make the use of crystal structures misleading when structures are considered individually. Cheminformatics may enable the "calibration" of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, "the devil is in the details." Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. PMID- 26001899 TI - Regulatory function of the C-terminal segment of guanylate cyclase-activating protein 2. AB - Neuronal responses to Ca2+-signals are provided by EF-hand-type neuronal Ca2+ sensor (NCS) proteins, which have similar core domains containing Ca2+-binding and target-recognizing sites. NCS proteins vary in functional specificity, probably depending on the structure and conformation of their non-conserved C terminal segments. Here, we investigated the role of the C-terminal segment in guanylate cyclase activating protein-2, GCAP2, an NCS protein controlling the Ca2+-dependent regulation of photoreceptor guanylate cyclases. We obtained two chimeric proteins by exchanging C-terminal segments between GCAP2 and its photoreceptor homolog recoverin, a Ca2+-sensor controlling rhodopsin kinase (RK) activity. The exchange affected neither the structural integrity of GCAP2 and recoverin nor the Ca2+-sensitivity of GCAP2. Intrinsic fluorescence, circular dichroism, biochemical studies and hydrophobic dye probing revealed Ca2+ dependent conformational transition of the C-terminal segment of GCAP2 occurring in the molecular environment of both proteins. In Ca2+-GCAP2, the C-terminal segment was constrained and its replacement provided the protein with approximately two-fold inhibitory activity towards RK, suggesting that the segment contributes to specific target recognition by interfering with RK binding. Upon Ca2+-release, it became less constrained and more available for phosphorylation by cyclic nucleotide-dependent protein kinase. The transition from the Ca2+-bound to the apo-state exposed hydrophobic sites in GCAP2, and was associated with its activating function without affecting its dimerization. The released C-terminal segment participated further in photoreceptor membrane binding making it sensitive to phosphorylation. Thus, the C-terminal segment in GCAP2 confers target selectivity, facilitates membrane binding and provides sensitivity of the membrane localization of the protein to phosphorylation by signaling kinases. PMID- 26001900 TI - Clinical correlates of enlarged cavum septum pellucidum in schizophrenia: A revisit through computed tomography. AB - Like prevalence of abnormal cavum septum pellucidum in patients of schizophrenia remains controversial, its role in clinical outcome, duration of illness and effect on treatment remains less understood as well. Our study examined clinical correlates of enlarged cavum septum pellucidum in schizophrenia. A total of 139 patients diagnosed with schizophrenia during the year 2012 and 2013 were taken for the study. We compared them in respect to the presence and absence of enlarged cavum septum pellucidum. We found 16 patients with enlarged cavum septum pellucidum and were compared with those without enlarged cavum septum pellucidum for socio-demographic and clinical variables. We also correlated these clinical variables with dimension of cavum septum pellucidum. We found statistically significant increased current age and duration of illness in patients with enlarged cavum septum pellucidum. The implications of these findings are discussed with possible confounding effect of current age on neuroimaging. No meaningful correlation was found. No difference in clinical variables was found. Retrospective design and use of computed tomography were limitation of our study. PMID- 26001901 TI - Two sides of a coin: Perpetrators and survivors perspectives on the triad of alcohol, intimate partner violence and mental health in South India. AB - The present study explored the intersection among alcohol consumption, gender roles, intimate partner violence (IPV) and mental health from the perspective of heavy drinking men who also perpetrate IPV (perpetrators) and their spouses (survivors). Interpretive phenomenological approach was used, and in-depth interviews were conducted with adult married heavy drinking men who reported to have perpetrated IPV (N=10) and their spouses (N=10). These interviews were audio recorded, and salient themes were generated using the NVivo software. Findings indicated a deeply embedded association among alcohol consumption, IPV, and mental health, with culturally sanctioned gender norms strongly contributing to this association. There was evidence for anxiety and depression in the survivors and emotional-behavioural and academic difficulties in their children. The study provides valuable insight into the intersecting problems of alcohol and IPV, which independently and together signify an emergent public health problem that can have immense ramifications on mental health of individuals and families. PMID- 26001902 TI - Chemokines and microRNAs in atherosclerosis. AB - The crucial role of chemokines in the initiation and progression of atherosclerosis has been widely recognized. Through essential functions in leukocyte recruitment, chemokines govern the infiltration with mononuclear cells and macrophage accumulation in atherosclerotic lesions. Beyond recruitment, chemokines also provide homeostatic functions supporting cell survival and mediating the mobilization and homing of progenitor cells. As a new regulatory layer, several microRNAs (miRNAs) have been found to modulate the function of endothelial cells (ECs), smooth muscle cells and macrophages by controlling the expression levels of chemokines and thereby affecting different stages in the progression of atherosclerosis. For instance, the expression of CXCL1 can be down regulated by miR-181b, which inhibits nuclear factor-kappaB activation in atherosclerotic endothelium, thus attenuating the adhesive properties of ECs and exerting early atheroprotective effects. Conversely, CXCL12 expression can be induced by miR-126 in ECs through an auto-amplifying feedback loop to facilitate endothelial regeneration, thus limiting atherosclerosis and mediating plaque stabilization. In contrast, miR-155 plays a pro-atherogenic role by promoting the expression of CCL2 in M1-type macrophages, thereby enhancing vascular inflammation. Herein, we will review novel aspects of chemokines and their regulation by miRNAs during atherogenesis. Understanding the complex cross-talk of miRNAs controlling chemokine expression may open novel therapeutic options to treat atherosclerosis. PMID- 26001905 TI - Impact of Sorghum Supplementation on Growth and Micronutrient Status of School Going Children in Southern India - A Randomized Trial. AB - OBJECTIVES: To study the impact of sorghum diet on growth, and micronutrient status of school going children for a period of 8 mo. METHODS: Children (n = 160 boys and n = 160 girls) aged between 9 to 12 y were randomly allocated into two groups (n = 80 in the control and n = 80 in the experimental group) to receive 60% sorghum diet and 40% of rice diet (Exp G) and regular rice diet (100%; CG). Anthropometric indices and biochemical parameters were measured at baseline and at 8 mo using standardized methods. RESULTS: The growth rate was significantly higher (p < 0.01) in the Exp G of girls, whereas in boys it was in the CG. Hemoglobin (Hb), serum ferritin, albumin, retinol binding protein (RBP) and iron levels were significantly improved (p < 0.05) in the Exp G of both the genders and in boys, serum folic acid and calcium levels were also improved with sorghum diet. CONCLUSIONS: Serum micronutrient status, in terms of hemoglobin, serum folic acid, albumin, RBP, ferritin, calcium and iron can be improved with sorghum supplementation in school going children. PMID- 26001903 TI - Cytoplasmic dynein and early endosome transport. AB - Microtubule-based distribution of organelles/vesicles is crucial for the function of many types of eukaryotic cells and the molecular motor cytoplasmic dynein is required for transporting a variety of cellular cargos toward the microtubule minus ends. Early endosomes represent a major cargo of dynein in filamentous fungi, and dynein regulators such as LIS1 and the dynactin complex are both required for early endosome movement. In fungal hyphae, kinesin-3 and dynein drive bi-directional movements of early endosomes. Dynein accumulates at microtubule plus ends; this accumulation depends on kinesin-1 and dynactin, and it is important for early endosome movements towards the microtubule minus ends. The physical interaction between dynein and early endosome requires the dynactin complex, and in particular, its p25 component. The FTS-Hook-FHIP (FHF) complex links dynein-dynactin to early endosomes, and within the FHF complex, Hook interacts with dynein-dynactin, and Hook-early endosome interaction depends on FHIP and FTS. PMID- 26001906 TI - The influence of reduced oxygen availability on gene expression in laboratory (H37Rv) and clinical strains (S7 and S10) of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis has the ability to persist within the host in a dormant stage. One important condition believed to contribute to dormancy is reduced access to oxygen known as hypoxia. However, the response of M. tuberculosis to such hypoxia condition is not fully characterized. Virtually all dormant models against tuberculosis tested in animals used laboratory strain H37Rv or Erdman strain. But major outbreaks of tuberculosis (TB) occur with the strains that have widely different genotypes and phenotypes compared to H37Rv. In this study, we used a custom oligonucleotide microarray to determine the overall transcriptional response of laboratory strain (H37Rv) and most prevalent clinical strains (S7 and S10) of M. tuberculosis from South India to hypoxia. Analysis of microarray results revealed that a total of 1161 genes were differentially regulated (>=1.5 fold change) in H37Rv, among them 659 genes upregulated and 502 genes down regulated. Microarray data of clinical isolates showed that a total of 790 genes were differentially regulated in S7 among which 453 genes were upregulated and 337 down regulated. Interestingly, numerous genes were also differentially regulated in S10 (total 2805 genes) of which 1463 genes upregulated and 1342 genes down regulated during reduced oxygen condition (Wayne's model). One hundred and thirty-four genes were found common and upregulated among all three strains (H37Rv, S7, and S10) and can be targeted for drug/vaccine development against TB. PMID- 26001904 TI - Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance. AB - Toll-like receptors (TLRs) are membrane-bound microbial sensors that mediate important host-to-microbe responses. Cell biology aspects of TLR function have been intensively studied in professional immune cells, in particular the macrophages and dendritic cells, but not well explored in other specialized epithelial cell types. The adult intestinal epithelial cells are in close contact with trillions of enteric microbes and engage in lifelong immune surveillance. Mature intestinal epithelial cells, in contrast to immune cells, are highly polarized. Recent studies suggest that distinct mechanisms may govern TLR traffic and compartmentalization in these specialized epithelial cells to establish and maintain precise signaling of individual TLRs. We, using immune cells as references, discuss here the shared and/or unique molecular machineries used by intestinal epithelial cells to control TLR transport, localization, processing, activation, and signaling. A better understanding of these mechanisms will certainly generate important insights into both the mechanism and potential intervention of leading digestive disorders, in particular inflammatory bowel diseases. PMID- 26001907 TI - Long-term outcomes in high-risk patients with non-ST-segment elevation myocardial infarction. AB - Greater use of evidence-based therapies has improved outcomes for patients with acute coronary syndromes (ACS) in recent decades. Consequently, more ACS patients are surviving beyond 12 months; however, limited data exist to guide treatment in these patients. Long-term outcomes have not improved in non-ST-segment elevation myocardial infarction (NSTEMI) patients at the same rate seen in ST-segment elevation myocardial infarction patients, possibly reflecting NSTEMI patients' more complex clinical phenotype, including older age, greater burden of comorbidities and higher likelihood of a previous myocardial infarction (MI). This complexity impacts clinical decision-making, particularly in high-risk NSTEMI patients, in whom risk-benefit assessments are problematical. This review examines the need for more effective long-term management of NSTEMI patients who survive >=12 months after MI. Ongoing risk assessment using objective measures of risk (for bleeding and ischemia) should be used in all post-MI patients. While 12 months appears to be the optimal duration of dual antiplatelet therapy for most patients, this may not be the case for high-risk patients, and more research is urgently needed in this population. A recent subgroup analysis from the DAPT study in patients with or without MI who had undergone coronary stenting (31 % presented with MI; 53 % had NSTEMI) and the prospective PEGASUS-TIMI 54 trial in patients with a prior MI and at least one other risk factor (40 % had NSTEMI) demonstrated that long-term dual antiplatelet therapy improved cardiovascular outcomes but increased bleeding. Further studies will help clarify the role of dual antiplatelet therapy in stable post-NSTEMI patients. PMID- 26001908 TI - Standardized use of novel oral anticoagulants plasma level thresholds in a new thrombolysis decision making protocol. AB - Acute ischemic stroke (AIS) patients receiving non-vitamin-K antagonist oral anticoagulants (NOAC) are commonly excluded from thrombolytic therapy, as interpretation of coagulation tests remains unclear. We aimed to investigate the applicability of a novel institutional protocol for thrombolysis based on current expert recommendations and NOAC specific coagulation assessment. We included hospitalized AIS patients receiving NOAC for at least 24 h and consecutive AIS patients not receiving NOAC into a prospective study. We performed standard coagulation tests and specific tests for dabigatran, rivaroxaban and apixaban plasma levels. We studied 65 patients: mean age 72 +/- 13 years, 30 (46 %) male, median NIHSS score 3 (IQR 6). Fifteen (23 %) were on NOAC treatment (5 dabigatran, 5 rivaroxaban, and 5 apixaban, respectively) and 50 (77 %) were not. In patients without NOAC, dabigatran was not detectable (0 ng/ml), and plasma levels of rivaroxaban (median: 10.0 ng/ml, IQR 7.0) and apixaban (7.2 ng/ml, IQR 6.7) were below our lower thresholds that allow thrombolysis. In patients with dabigatran pre-treatment, trough levels (58.0 ng/ml, IQR 143.0) were below our upper threshold that would allow thrombolysis in 3/5 patients. In patients receiving rivaroxaban, trough level (68.0 ng/ml, IQR 64.0) was below our predefined upper thresholds that would allow thrombolysis in 4/5 patients. In all patients on apixaban, trough level was above our predefined threshold of 40 ng/ml that precludes thrombolysis (98.2 ng/ml, IQR 84.3). Predefined thresholds of NOAC plasma levels in the decision of thrombolysis in NOAC treated AIS patients might supplement routine coagulation tests and should be validated in a larger study population. PMID- 26001909 TI - Simultaneous determination and pharmacokinetic study of Atractylenolide I, II and III in rat plasma after intragastric administration of Baizhufuling extract and Atractylodis extract by UPLC-MS/MS. AB - A simple and rapid ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of Atractylenolide I, II and III in rat plasma. Plasma samples were processed by liquid-liquid extraction with ethyl acetate, using schisandrin as internal standard (IS). Chromatographic separation was accomplished on a Thermo Hypersil GOLD C18 column (2.1mm*50mm, 1.9MUm) with mobile phase consisting of acetonitrile and 0.1% formic acid-water (50:50, v/v). The detection was carried out by ESI-MS (positive ionization mode) and low-energy collision dissociation tandem mass spectrometric analyses using the multiple-reaction monitoring (MRM) scan mode. The quantification was performed using the transitions of the protonated molecule >product ion at m/z 231.0->185.1 for Atractylenolide I, at m/z 233.1->187.1 for Atractylenolide II and at m/z 249.1->231.1 for Atractylenolide III, respectively. Method validation revealed excellent linearity over investigated range together with satisfactory intra- and inter-day precision, accuracy, matrix effects and extraction recoveries. This method was successfully applied to the comparative pharmacokinetic study of Atractylenolide I, II and III in rat plasma after intragastric administration of Baizhufuling extract and Atractylodis extract. PMID- 26001910 TI - Assessing the utility of intraoperative educational time-outs in the promotion of medical student knowledge. PMID- 26001912 TI - HIV-associated neurocognitive disorders. PMID- 26001911 TI - A rare case of congenital myopathy with excess muscle spindles: expanding the clinical spectrum of HRAS-associated neuromuscular disease. PMID- 26001913 TI - Tailored care for somatoform vertigo/dizziness: study protocol for a randomised controlled trial evaluating integrative group psychotherapy. AB - Vertigo/dizziness (VD) ranks high in lifetime prevalence and clinical relevance. Nearly half of the complex VD disorders presenting at specialised units for vertigo or otoneurological disorders are not fully explained by an identifiable medical illness, but instead are related to anxiety, depressive, or somatoform disorders. Although there is some evidence that psychotherapy may be effective for these patients, therapeutic options remain unsatisfactory. This report describes the objectives, design and methods of a randomised, controlled clinical trial, evaluating the efficacy of manualised, multimodal group psychotherapy, based on integrative psychotherapy (IPT) and tailored to subgroups of mental disorders in medically unexplained VD. This psychotherapeutic approach will be compared to self-help groups (n = 172; n = 86 per study arm). Improvements with regard to handicap due to VD at 12 months follow-up will serve as primary outcome. Additionally, measures of generic quality of life, severity of vertigo, depression, anxiety, somatisation as well as Head Impulse Test and Computerized Static Posturography will be applied. We will also analyse the cost-effectiveness of this trial. The study aims to improve treatment of this therapeutically underserved population who are often severely impaired in their working and daily lives. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02320851. TRIAL STATUS: This is an on-going study; recruitment for the study is about to start. PMID- 26001914 TI - Evaluation of eosinophilia in immigrants in Southern Spain using tailored screening and treatment protocols: A prospective study. AB - OBJECTIVE: To determine the etiology of eosinophilia in immigrant patients in Southern Spain. METHODS: Prospective study of immigrant patients with eosinophilia (> 500 Eo/MUL) attended in a reference Tropical Medicine Unit and evaluated through the implementation of a specific protocol structured in different levels meant to be accomplished depending on the findings of each previous level. RESULTS: Out of the 549 patients included in the study (89.6% from sub-Saharan countries), a diagnosis of helminthiasis was reached in 417 (75.9%), mainly by Strongyloides stercoralis (n = 190), Schistosoma (n = 33) and Hookworms (n = 126). 30 patients (5.5%) had a non-parasitic disorder (asthma, allergic rhinoconjunctivitis, skin conditions and drug-related eosinophilia). Multiple helminthic infections were very common: in 107 patients (19.5%) 2 helminth species were identified, three in 21 patients (3.8%), and four or more in 6 patients (1.1%). Eosinophilia was resolved in 31 of the 33 patients (93.9%) who received empirical treatment with ivermectin, albendazole and praziquantel as an etiological diagnosis was not reached after applying the whole protocol. CONCLUSIONS: Diagnosis of helminthic infections in immigrant patients with eosinophilia can be improved by using tailored protocols based on geographical exposure. The implementation of these protocols may also save costs by systematizing diagnostic explorations. Empirical treatment with ivermectin, albendazol and praziquantel in sub-Saharan population when an etiologic diagnosis of eosinophilia has not been attained is an effective measure. PMID- 26001916 TI - Global patterns of methamphetamine use. AB - PURPOSE OF REVIEW: As the most popular psychostimulant in the world, methamphetamine use has reached epidemic proportions. Its enormous popularity has created subcultures of methamphetamine users all over the globe. The purpose of this review is to describe the geographic availability of different types of methamphetamine, the characteristics of each user population, and the psychosocial impact the two have on society. RECENT FINDINGS: Methamphetamine has diversified immensely from the early days of its use. Different forms of methamphetamine - ICE, powder, and pills - have different pharmacokinetic characteristics that make them popular among certain types of users. New studies have shown that addiction to methamphetamine results in a very characteristic loss of inhibition that augments various risk-taking behaviors in its users. Also, recent seizure data suggest that its production and trafficking is spreading into new areas of the globe. SUMMARY: From recreational use to addiction, methamphetamine use represents a serious risk to health and wellbeing of the community. Recognizing the pattern of abuse in specific populations is the key to assessing the risk, implementing prevention, and harm reduction measures, as well as making public policies. PMID- 26001917 TI - The impact of amphetamine-type stimulants on emergency services. AB - PURPOSE OF REVIEW: Amphetamine-type stimulants now rank second worldwide in the table of most widely used recreational drugs. Many countries report increased availability and increased purity of the drugs.Surprisingly, while many authors in the last decade have described clinical issues and demographic patterns associated with amphetamine use, there is little published research quantifying the specifics of the impact of 'ICE' use on health resources.It is, therefore, timely to review the available literature on the impact of this group of drugs on emergency medical systems. RECENT FINDINGS: Recent research has focused on the increase in production and availability of metamphetamines. Clinical findings at acute presentation and long-term sequelae have been studied and in particular, the impact of the drugs on mental health and development of long-term neurological problems. Work has also been done unsuccessfully to develop therapeutic agents for the acute management of patients who present under the influence of amphetamines. SUMMARY: It is clear that the use of metamphetamine type substances places an increasing burden on acute health services. There is a need for preventive and harm-minimization strategies. PMID- 26001915 TI - The validity of the Patient Health Questionnaire for screening depression in chronic care patients in primary health care in South Africa. AB - BACKGROUND: People with chronic health conditions are known to have a higher prevalence of depressive disorder. The Patient Health Questionnaire (PHQ-9) is a widely-used screening tool for depression which has not yet been validated for use on chronic care patients in South Africa. METHODS: A sample of 676 chronic care patients attending two primary health facilities in North West Province, South Africa were administered the PHQ-9 by field workers and a diagnostic interview (the Structured Clinical Interview for DSM-IV) (SCID) by clinical psychologists. The PHQ-9 and the PHQ-2 were evaluated against the SCID, as well as for sub-samples of patients who were being treated for HIV infection and for hypertension. RESULTS: Using the SCID, 11.4 % of patients had major depressive disorder. The internal consistency estimate for the PHQ-9 was 0.76, with an area under the receiver operator curve (AUROC) of 0.85 (95 % CI 0.82-0.88), which was higher than the AURUC for the PHQ-2 (0.76, 95 % CI 0.73-0.79). Using a cut-point of 9, the PHQ-9 has sensitivity of 51 % and specificity of 94 %. The PHQ-9 AUROC for the sub-samples of patients with HIV and with hypertension were comparable (0.85 and 0.86, respectively). CONCLUSIONS: The PHQ-9 is useful as a screening tool for depression among patients receiving treatment for chronic care in a public health facility. PMID- 26001918 TI - The development and evaluation of stimulant treatment programmes. AB - PURPOSE OF REVIEW: To summarize the recent literature (1st January 2014-1st February 2015) on stimulant treatment programme evaluations, and highlight key areas for future programme development. RECENT FINDINGS: Advances have been made in addressing both sexual risks and stimulant use among gay and bisexual men in the United States, and in adapting evidence-based resource-intense interventions to real-world settings. Programme outcome measures increasingly include changes in substance use as well as health and wellbeing indicators and measures of risk. SUMMARY: Future programme directions include: expansion of the psychosocial repertoire to include narrative and mindfulness-based therapies; web-based programme delivery; sex-sensitive programming to attract and retain women; comprehensive programming to address coexisting mental and physical illness and polysubstance use (including tobacco smoking); and improving accessibility to promote early intervention. Comparability of evaluation data can be improved by developing standardized tools particularly for measuring change in sexual-risk behavior. The use of new statistical techniques can address the lack of comparison populations. PMID- 26001919 TI - Responding to illicit drug use in family practice. AB - PURPOSE OF REVIEW: To examine and analyse recent published research on the impact and management of drug use and related disorders in primary care settings. Emerging trends in drug use and the development of new treatment approaches are making new demands on the primary care sector. RECENT FINDINGS: Most recent publications relate to descriptions of the drugs used and their impact on mental health. The use of cannabis and newer stimulants and 'legal highs' tends to coexist with opiate use, and their physical and mental health sequelae often overlap. Several studies address methadone and buprenorphine prescribing, its efficacy and limitations, and organizational issues in delivery of treatment. Other areas identified in this review are pain control, adverse consequences of drug use including morbidity from infections associated with drug taking and death due to overdose, and longer-term outcomes. Several publications cover management of chronic conditions in an ageing population of drug users with multiple health problems, and others examine the trend toward community instead of specialist care. SUMMARY: A picture is presented of extensive use of psychoactive substances in many communities. This ranges from club drug taking and low level cannabis use to more invasive and self-harming drug taking resulting from the use of opiates and stimulants. Treatment services are challenged with the need to change. PMID- 26001920 TI - Diversion of prescription stimulant drugs among 10-18-year-olds. AB - PURPOSE OF REVIEW: Public health concern regarding the nonmedical use of prescription stimulants among youth has generated the need for increased understanding of diversion, which is the illegal sharing and selling of prescription drugs. Although our understanding of nonmedical use of stimulants has increased, the same cannot be said of diversion behavior among youth. RECENT FINDINGS: The aim of this article is to use data from the National Monitoring of Adolescent Prescription Stimulants Study, which assessed prescription stimulant use among 10-18 years old across 10 US cities to report on prescription stimulant diversion among those who misused those medications. Findings indicate that more than one half (52%) of youth had engaged in one of the three forms of diversion (incoming only, outgoing only and both incoming and outgoing diversion). Engaging in incoming diversion only and both incoming and outgoing diversion increased with age and nonmedical use of prescription stimulants. All forms of diversion increased with marijuana use and among 16-18 years old with a friend's use of prescription stimulant. SUMMARY: Findings provide an understanding of the subtypes of diversion and risk correlates of youth prescription stimulant diverter's that has value in preventing prescription stimulant diversion. PMID- 26001921 TI - The pathways to mental healthcare worldwide: a systematic review. AB - PURPOSE OF REVIEW: Pathways-to-care studies represent a valid and cost-effective tool to provide information on patients' access to psychiatric care. However, no direct comparison of data concerning the pathways to mental healthcare, at the world level, is available yet. RECENT FINDINGS: Data obtained from different countries of the world may offer a global perspective on psychiatric pathways to mental healthcare, highlighting the strengths and weaknesses of different mental health systems and reflecting cultural, economic, social and political differences. We evaluated all studies that used a standardized methodology to describe pathways to mental healthcare of all adult patients, presenting for the first time to psychiatric services. SUMMARY: Our findings highlight that considerable variations of pathways to mental healthcare across different countries still exist. A consensus on the quality standards of psychiatric care should be reached and actions to ensure their implementation in low-middle income countries should be taken in the near future. The role of primary care doctors and social networks still represent an unsolved issue for psychiatric care worldwide. Stigma and discrimination towards patients with mental illnesses may still represent a relevant limiting factor for equal delivery of mental healthcare. PMID- 26001923 TI - Psychosocial interventions for very early and early-onset schizophrenia: a review of treatment efficacy. AB - PURPOSE OF REVIEW: Very early (VEOS) and early-onset schizophrenia (EOS) represent more severe forms of the disorder, with clear differences from adult onset schizophrenia (AOS). However, there is a distinct lack of evidence regarding the efficacy of psychosocial interventions in this group of patients, and to date no systematic review has been conducted on the topic. The aim of this article is to review the current knowledge and evidence on the efficacy of psychosocial interventions in VEOS/EOS. RECENT FINDINGS: A total of eight articles were eligible for inclusion. Four studies evaluated psychoeducational and family interventions for patients with VEOS/EOS, whereas four studies focused on cognitive behavioral therapy or cognitive remediation. Overall, we found some preliminary evidence for the efficacy of psychosocial interventions in the treatment of VEOS/EOS. This evidence was strongest for cognitive remediation. SUMMARY: Heretofore, VEOS/EOS have been treated primarily with psychosocial interventions based on evidence from interventions tailored for and tested on adults. Although more conclusive studies are still needed, thanks to recent clinical trials, we now have greater evidence to support the efficacy of psychosocial interventions in EOS/VEOS. PMID- 26001922 TI - Epidemiology of posttraumatic stress disorder: prevalence, correlates and consequences. AB - PURPOSE OF REVIEW: This review discusses recent findings from epidemiological surveys of traumatic events and posttraumatic stress disorder (PTSD) globally, including their prevalence, risk factors, and consequences in the community. RECENT FINDINGS: A number of studies on the epidemiology of PTSD have recently been published from diverse countries, with new methodological innovations introduced. Such work has not only documented the prevalence of PTSD in different settings, but has also shed new light on the PTSD conditional risk associated with specific traumatic events, and on the morbidity and comorbidities associated with these events. SUMMARY: Recent community studies show that trauma exposure is higher in lower-income countries compared with high-income countries. PTSD prevalence rates are largely similar across countries, however, with the highest rates being found in postconflict settings. Trauma and PTSD-risk factors are distributed differently in lower-income countries compared with high-income countries, with sociodemographic factors contributing more to this risk in high income than low-income countries. Apart from PTSD, trauma exposure is also associated with several chronic physical conditions. These findings indicate a high burden of trauma exposure in low-income countries and postconflict settings, where access to trained mental health professionals is typically low. PMID- 26001924 TI - Service provision to physicians with mental health and addiction problems. AB - PURPOSE OF REVIEW: Physicians are reluctant to ask for help when they suffer from substance use disorders and/or other mental illnesses (i.e. when they become 'sick doctors'). This can result in greater morbidity/mortality and may lead to significant problems in medical practice. This review aims to describe the nature and development of programs that specifically treat sick doctors [Physician Health Programs (PHPs)]. RECENT FINDINGS: PHPs were first developed in the United States in the late 1970s. The purpose was to identify and treat physicians with problems resulting from mental health issues, mainly substance use disorders. Since then, other PHPs have been developed in Canada, Australia, and the United Kingdom, trying to reach sick doctors, offering counseling or other preventive interventions when needed. New models to help sick doctors, such as the Spanish PHP, were also developed. Counseling and support services for sick doctors have been implemented elsewhere in Europe (e.g. Norway and Switzerland). SUMMARY: PHPs provide interventions specifically designed for physicians and other medical professionals with substance use and other mental health problems. The balance between guaranteeing safe practice and yet encouraging all physicians to ask for help when in trouble raises questions regarding how these programs should be designed. PMID- 26001925 TI - Provision of mental healthcare for children and adolescents: a worldwide view. AB - PURPOSE OF REVIEW: There has been increased attention towards the burden imposed by mental disorders on children and adolescents. The present overview explores the current state of child and adolescent mental healthcare provision around the globe. RECENT FINDINGS: Current research indicates a concerning gap in the provision of care for the child and adolescent population. The disparities between need, demand and access to youth mental healthcare are likely to be even greater in low and- middle-income countries (LAMIC), where the proportion of children and adolescents in the population is higher. The scarcity of available resources for youth mental healthcare, especially in LAMIC, represents a major obstacle to decreasing the impact of mental disorders across the lifespan. SUMMARY: Our review highlights the discrepancy between demands and availability of mental healthcare for youth populations throughout the world. We describe some of the potential contributors to the current state of youth mental healthcare, such as problematic access to services, implementation deficiencies and inadequacy of policies. Recent innovative strategies to reduce these barriers are also presented. PMID- 26001926 TI - Is e-health the answer to gaps in adolescent mental health service provision? AB - PURPOSE OF REVIEW: Depression and anxiety are prevalent among adolescents; however, many young people do not seek help from professional services. This is due, in part, to the inadequacies of existing healthcare systems. This article aims to review the current evidence for e-health interventions for depression and anxiety in youth, as a potential solution to the gaps in mental health service provision. RECENT FINDINGS: Five randomized controlled trials reporting on e health interventions for youth depression or anxiety were identified. Of these, two trials focused exclusively on anxiety symptoms, and three trials examined both anxiety and depression. The majority of trials assessed online cognitive behavioral therapy and focused on prevention rather than treatment. In all but one trial, results demonstrated positive effects for the e-health interventions, relative to the control. SUMMARY: There is growing evidence for the effectiveness of online cognitive behaviour therapy interventions for reducing the level of anxiety and depressive symptoms in adolescents aged between 12 and 18 years, when delivered in school and clinical settings, with some level of supervision. However, there are a number of gaps in the literature. More research is needed to strengthen the evidence base for prevention and treatment programs that are delivered via the internet, particularly for depression. PMID- 26001927 TI - Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis. AB - BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients. METHODS: Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling. RESULTS: During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood. CONCLUSIONS: In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis. PMID- 26001929 TI - Surgical clipping of a dissecting aneurysm of the precommunicating segment of the anterior cerebral artery: a case report and review of the literature. AB - INTRODUCTION: Dissecting aneurysms of the cerebral arteries are uncommon vascular malformations. Neurosurgical treatment remains critical in the management of patients with such vascular pathologies. CASE PRESENTATION: A 20-year-old Caucasian woman presented with a sudden onset of severe headache and loss of consciousness. Computed tomography revealed diffuse subarachnoid hemorrhage, while a computed tomography disclosed a dissecting aneurysm of the precommunicating segment of the right anterior cerebral artery. Cerebral carotid angiography confirmed the presence of the dissecting aneurysm. Due to the peculiar anatomic configuration, endovascular treatment was excluded and surgery was selected. As the left circulation perfused both postcommunicating segments of the anterior cerebral artery and the distal right precommunicating segment was hypoplastic, direct clipping of the right precommunicating segment, close to its origin from the internal carotid artery, was carried out. She recovered after surgery and a late angiography showed the correct positioning of the clip, with regular perfusion of both right and left postcommunicating segments. CONCLUSIONS: The management of dissecting aneurysms of the cerebral arteries is still controversial. With this report we highlight a possible neurosurgical option among therapeutic strategies for these uncommon vascular lesions. PMID- 26001930 TI - Salusin-beta contributes to vascular remodeling associated with hypertension via promoting vascular smooth muscle cell proliferation and vascular fibrosis. AB - Vascular smooth muscle cell (VSMC) proliferation and vascular fibrosis are closely linked with hypertension and atherosclerosis. Salusin-beta is a bioactive peptide involved in the pathogenesis of atherosclerosis. However, it is still largely undefined whether salusin-beta is a potential candidate in the VSMC proliferation and vascular fibrosis. Experiments were carried out in human vascular smooth muscle cells (VSMCs) and in rats with intravenous injection of lentivirus expressing salusin-beta. In vitro, salusin-beta promoted VSMCs proliferation, which was attenuated by adenylate cyclase inhibitor SQ22536, PKA inhibitor Rp-cAMP, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, ERK inhibitor U0126 or cAMP response element binding protein (CREB) inhibitor KG501. It promoted the phosphorylation of ERK1/2, CREB and EGFR, which were abolished by SQ22536 or Rp-cAMP. Furthermore, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 diminished the salusin-beta evoked ERK1/2 and CREB phosphorylation. On the other hand, salusin-beta increased collagen-I, collagen-III, fibronectin and connective tissue growth factor (CTGF) mRNA and phosphorylation of Smad2/3, which were prevented by ALK5 inhibitor A83 01. In vivo, salusin-beta overexpression increased the media thickness, media/lumen ratio coupled with ERK1/2, CREB, EGFR and Smad2/3 phosphorylation, as well as the mRNA of collagen-I, collagen-III, fibronectin, transforming growth factor-beta1 (TGF-beta1) and CTGF in arteries. Moreover, salusin-beta overexpression in rats caused severe hypertension. Intravenous injection of salusin-beta dose-relatedly increased blood pressure, but excessive salusin-beta decreased blood pressure and heart rate. These results indicate that salusin-beta promotes VSMC proliferation via cAMP-PKA-EGFR-CREB/ERK pathway and vascular fibrosis via TGF-beta1-Smad pathway. Increased salusin-beta contributes to vascular remodeling and hypertension. PMID- 26001928 TI - Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease. AB - BACKGROUND & AIMS: The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy. METHODS: We collected blood and intestinal biopsy specimens from 268 patients at tertiary medical centers in the United States and Italy from 2004 to 2012. All subjects had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutaminase 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin 15 were measured by immunohistochemistry, and ultrastructural alterations in intestinal epithelial cells (IECs) were assessed by electron microscopy. RESULTS: IECs from subjects with a family history of celiac disease, but not from subjects who already had immunity to gluten, expressed higher levels of HS27, HSP70, and interleukin-15 than controls; their IECs also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to up-regulate activating NK receptors. CONCLUSIONS: A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture had epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease. PMID- 26001931 TI - Neuraminidase-1 mediates skeletal muscle regeneration. AB - Neuraminidase-1 (NEU1) is the sialidase responsible for the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency causes sialidosis, a severe lysosomal storage disease associated with a broad spectrum of clinical manifestations, which also include skeletal deformities, skeletal muscle hypotonia and weakness. Neu1(-/-) mice, a model of sialidosis, develop an atypical form of muscle degeneration caused by progressive expansion of the connective tissue that infiltrates the muscle bed, leading to fiber degeneration and atrophy. Here we investigated the role of Neu1 in the myogenic process that ensues during muscle regeneration after cardiotoxin-induced injury of limb muscles. A comparative analysis of cardiotoxin-treated muscles from Neu1(-/-) mice and Neu1(+/+) mice showed increased inflammatory and proliferative responses in the absence of Neu1 during the early stages of muscle regeneration. This was accompanied by significant and sequential upregulation of Pax7, MyoD, and myogenin mRNAs. The levels of both MyoD and myogenin proteins decreased during the late stages of regeneration, which most likely reflected an increased rate of degradation of the myogenic factors in the Neu1(-/-) muscle. We also observed a delay in muscle cell differentiation, which was characterized by prolonged expression of embryonic myosin heavy chain, as well as reduced myofiber cross sectional area. At the end of the regenerative process, collagen type III deposition was increased compared to wild-type muscles and internal controls, indicating the initiation of fibrosis. Overall, these results point to a role of Neu1 throughout muscle regeneration. PMID- 26001932 TI - Gene expression changes in Porphyromonas gingivalis W83 after inoculation in rat oral cavity. AB - BACKGROUND: The development of chronic periodontitis was due to not only periodontal pathogens, but also the interaction between periodontal pathogens and host. The aim of this study is to investigate the alterations in gene expression in Porphyromonas gingivalis (P.gingivalis) W83 after inoculation in rat oral cavity. RESULTS: P.gingivalis W83 inoculation in rat oral cavity caused inflammatory responses in gingival tissues and destroyed host alveolar bone. Microarray analysis revealed that 42 genes were upregulated, and 22 genes were downregulated in the detected 1786 genes in the inoculated P.gingivalis W83. Real time quantitative PCR detection confirmed the expression alterations in some selected genes. Products of these upregulated and downregulated genes are mainly related to transposon functions, cell transmembrane transportation, protein and nucleic acid metabolism, energy metabolism, cell division and bacterial pathogenicity. CONCLUSIONS: P.gingivalis W83 has a pathogenic effect on host oral cavity. Meanwhile, inflammatory oral environment alters P.gingivalis W83 gene expression profile. These changes in gene expression may limit the proliferation and weaken the pathogenicity of P.gingivalis W83, and favor themselves to adapt local environment for survival. PMID- 26001933 TI - Atypical Antipsychotics and the Risk of Hyperlipidemia: A Sequence Symmetry Analysis. AB - INTRODUCTION: Although hyperlipidemia is a well known adverse event of atypical antipsychotic (AAP) medication, there are few studies that have quantitatively compared the risks of various AAPs. OBJECTIVE: Our aim was to comparatively evaluate the risk of hyperlipidemia associated with the use of AAPs approved in Japan through a consecutive epidemiological study. METHODS: We conducted a sequence symmetry analysis (SSA) using health insurance claims data to analyze the following nine AAPs approved for use in Japan: risperidone, paliperidone, perospirone hydrochloride hydrate, blonanserin, clozapine, olanzapine, quetiapine fumarate, aripiprazole, and zotepine. Exposed cases were identified from drug dispensing records as those who had been administered both AAPs and antihyperlipidemic drugs. The adjusted sequence ratio (ASR) and 95 % confidence interval (CI) for each individual AAP and for all AAPs were calculated while controlling for time trends in dispensing patterns. RESULTS: Olanzapine was significantly associated with increased hyperlipidemia occurrence (ASR 1.56; 95 % CI 1.25-1.95). The ASRs obtained for risperidone (1.01; 95 % CI 0.80-1.27), perospirone hydrochloride hydrate (0.93; 95 % CI 0.63-1.39), blonanserin (0.83; 95 % CI 0.52-1.33), quetiapine fumarate (0.93; 95 % CI 0.73-1.18), and aripiprazole (1.02; 95 % CI 0.82-1.26) were approximately 1.0. Unstable estimates (wide CIs) were obtained for paliperidone and zotepine due to the small sample sizes. CONCLUSIONS: Among the AAPs used in Japan, only olanzapine was found to have an elevated risk of hyperlipidemia. In contrast, risperidone, perospirone hydrochloride hydrate, blonanserin, quetiapine fumarate, and aripiprazole had relatively low risks. PMID- 26001938 TI - A model assessment of the importance of direct photolysis in the photo-fate of cephalosporins in surface waters: Possible formation of toxic intermediates. AB - The direct and indirect photodegradation of six cephalosporins was predicted using a photochemical model, on the basis of literature values of photochemical reactivity. Environmental photodegradation would be important in surface water bodies with depth ? 2-3m, and/or in deeper waters with low values of the dissolved organic carbon (DOC ? 1 mg C L(-1)). The half-life times would range from a few days to a couple of weeks in summertime. In deeper and higher-DOC waters and/or in different seasons, hydrolysis could prevail over photodegradation. The direct photolysis of cephalosporins is environmentally concerning because it is known to produce toxic intermediates. It would be a major pathway for cefazolin, an important one for amoxicillin and cefotaxime and, at pH<6.5, for cefapirin as well. In contrast, direct photolysis would be negligible for cefradine and cefalexin. The DOC values would influence the fraction of photodegradation accounted for by direct photolysis in shallow water, to a different extent depending on the role of sensitisation by the triplet states of chromophoric dissolved organic matter. PMID- 26001937 TI - Transformations of chloro and nitro groups during the peroxymonosulfate-based oxidation of 4-chloro-2-nitrophenol. AB - Dechlorination and denitration are known to occur during the oxidative degradation of chloronitroaromatic compounds, but the possibility of re chlorination and re-nitration of chloro and nitro groups is not assessed despite of its importance in evaluating the applicability of advanced oxidation processes (AOPs). In this study, transformation of chloro and nitro groups in degradation of 4-chloro-2-nitrophenol (4C2NP) by sulfate radical generated via Co-mediated peroxymonosulfate activation was investigated. Both chloride and nitrate ions were found as the main inorganic products of chloro and nitro groups in 4C2NP, but their levels were much lower than that of degraded parent 4C2NP. A typical dual effect of chloride on the 4C2NP degradation kinetics was observed, whereas no measurable influence was found for addition of low level nitrate. Re chlorination took place, but re-nitration was not verified because several polychlorophenols but none of polynitrophenols were detected. The specific degradation mechanism involved in the transformation of nitro group and chloro group was proposed. PMID- 26001939 TI - Surface coal mine land reclamation using a dry flue gas desulfurization product: Short-term and long-term water responses. AB - Abandoned coal-mined lands are a worldwide concern due to their potential negative environmental impacts, including erosion and development of acid mine drainage. A field study investigated the use of a dry flue gas desulfurization product for reclamation of abandoned coal mined land in USA. Treatments included flue gas desulfurization product at a rate of 280 Mg ha(-1) (FGD), FGD at the same rate plus 112 Mg ha(-1) yard waste compost (FGD/C), and conventional reclamation that included 20 cm of re-soil material plus 157 Mg ha(-1) of agricultural limestone (SOIL). A grass-legume sward was planted after treatment applications. Chemical properties of surface runoff and tile water (collected from a depth of 1.2m below the ground surface) were measured over both short-term (1-4 yr) and long-term (14-20 yr) periods following reclamation. The pH of surface runoff water was increased from approximately 3, and then sustained at 7 or higher by all treatments for up to 20 yr, and the pH of tile flow water was also increased and sustained above 5 for 20 yr. Compared with SOIL, concentrations of Ca, S and B in surface runoff and tile flow water were generally increased by the treatments with FGD product in both short- and long term measurements and concentrations of the trace elements were generally not statistically increased in surface runoff and tile flow water over the 20-yr period. However, concentrations of As, Ba, Cr and Hg were occasionally elevated. These results suggest the use of FGD product for remediating acidic surface coal mined sites can provide effective, long-term reclamation. PMID- 26001940 TI - Letter From the Guest Editor: Neonatal Imaging--Part II. PMID- 26001941 TI - Congenital brain malformations in the neonatal and early infancy period. AB - Congenital brain malformations are a major cause of morbidity and mortality in pediatric patients who are younger than 2 years. Optimization of patient care requires accurate diagnosis, which can be challenging as congenital brain malformations include an extensive variety of anomalies. Radiologic imaging helps to identify the malformations and to guide management. Understanding radiologic findings necessitates knowledge of central nervous system embryogenesis. This review discusses the imaging of congenital brain malformations encountered in patients who are younger than 2 years in the context of brain development. PMID- 26001942 TI - Imaging neck masses in the neonate and young infant. AB - Head and neck masses occurring in the neonatal period and early infancy consist of vascular tumors, vascular malformations, benign and malignant soft tissue tumors, and other developmental lesions. Although some lesions can be diagnosed on clinical grounds, others can only be diagnosed by imaging. Beyond diagnosis, imaging plays a significant role in evaluating the location and extent of a lesion for possible intervention. In this article, we review the clinical presentation and imaging appearance of common and rare masses that may be encountered in this age group. We also highlight current treatment strategies for specific lesions. PMID- 26001943 TI - Newborn respiratory distress: airway abnormalities. AB - Respiratory distress is a common symptom in the newborn. Surfactant deficiency in the preterm infant and meconium aspiration and transient tachypnea in the term newborn are among the most common causes of respiratory distress, but primary airway abnormalities can also present with respiratory distress in the newborn. Delay in diagnosis of airway abnormality can be life threatening. Radiologists are among the first to be consulted in the evaluation of a neonate with respiratory distress, and knowledge of the spectrum of airway anomalies is essential for making the correct diagnosis. This article describes airway abnormalities that can present as respiratory distress in a neonate. PMID- 26001944 TI - Computed tomography and magnetic resonance imaging in neonates with congenital cardiovascular disease. AB - Most cardiac diseases in the newborn are caused by structural abnormalities developed in utero. With few exceptions, palliative and definitive treatments require cardiac surgery. The diagnosis and management decisions regarding uncomplicated lesions, such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot, can be accomplished by echocardiography alone. Abnormalities beyond the sonographic window, complex 3 dimensional lesions, and detailed functional information require additional imaging. In the past, this was fulfilled by catheter angiography, but today much of the information can be obtained from noninvasive computed tomography angiography and magnetic resonance imaging. This article discusses the design and application of these imaging techniques to the newborn, with emphasis on safety, efficacy, and image quality. Understanding the capabilities and limitations of these techniques is crucial for making rational choices among imaging options based on sound risk and benefit considerations. Important examples of congenital heart lesions have been illustrated with 3-dimensional reconstruction from computed tomography and magnetic resonance images. PMID- 26001945 TI - Meconium in perinatal imaging: associations and clinical significance. AB - An abnormal location, distribution, volume, or appearance of meconium is associated with a spectrum of bowel abnormalities, including atresia, obstruction, perforation, fistula, aganglionosis, immaturity, and absorptive dysfunction. This review discusses the fetal and perinatal imaging of these entities, their differential diagnoses, clinical significance, and appropriate imaging workup. Understanding the spectrum of normal and abnormal, specific and nonspecific appearances of meconium and its associated abnormalities on imaging will provide a practical, useful framework for performing and interpreting imaging studies and guiding clinical management. PMID- 26001946 TI - Ovary and testicle and everything in between: lesions and imaging in the newborn. AB - Assessment of the neonatal reproductive tract requires an understanding of embryology, awareness of common clinical presentations, and familiarity with normal newborn variation. This review of the neonatal reproductive tract emphasizes the use of sonography in the evaluation of developmental, acquired, and neoplastic conditions in male and female newborns. Anchored in embryologic origins, the discussion also includes descriptions of findings that may be encountered in prenatal imaging. Comments on clinical correlation are included to guide appropriate triaging of these complex cases. Imaging pearls and pitfalls are incorporated into this review, including the recognized effects of maternal hormones in female infants. PMID- 26001947 TI - Vascular lesions--congenital, acquired, and iatrogenic: imaging in the neonate. AB - The imaging of vasculitis, vasculopathies, and other vascular disorders in neonates presents unique challenges compared with the vascular imaging of older children or adults. These challenges include small-caliber vessels, the need for sedation or anesthesia, a high rate of vasospasm, higher respiratory rates, and a greater susceptibility to long-term effects of ionizing radiation. Duplex ultrasound (US) is typically the first-line imaging modality; in most cases, US provides key diagnostic information necessary for guiding initial management. Magnetic resonance or computed tomography angiography may be performed following US to further define vascular anatomy and relationships, to achieve a definitive diagnosis, and to guide endovascular or surgical planning when necessary. This review article presents and illustrates an update on the imaging strategies for congenital, acquired, and iatrogenic vasculopathies and vascular disorders in neonates. PMID- 26001948 TI - The Effects of Re-challenge in Patients with a History of Acute Anterior Uveitis Following Intravenous Zoledronate. AB - To determine the incidence of adverse ocular side effects following re-challenge in patients who previously developed ocular symptoms following intravenous zoledronate. Secondary data analysis of a large, prospective, randomized, double blind, placebo-controlled clinical trial was performed. Participants consisted of postmenopausal females with osteopenia randomized to placebo (N = 1000) or zoledronate 5 mg (N = 1001) intravenous infusion. Recruitment occurred over a 2 year period, with the first infusion being administered at recruitment, and subsequent infusions every 18 months. Eight participants developed acute anterior uveitis (AAU) (diagnosed by an ophthalmologist) following the first infusion of zoledronate. Following appropriate ophthalmic treatment, no patients had visual loss or other ocular sequelae. One further participant reported "sore red eyes" but did not attend for ophthalmology review. Six participants declined further infusions. The remaining three participants were administered two further zoledronate infusions, 18 months apart, and none developed any ocular symptoms following each infusion. As a precaution, two of these participants were examined by an ophthalmologist 3 days after their second infusion and neither had ocular symptoms or signs of AAU and no subsequent ocular side effects. AAU following zoledronate infusion is likely to be part of the acute phase response. If treated promptly under the care of an ophthalmologist, the visual prognosis is excellent. The results of this study suggest that the development of AAU should not be a contraindication to further infusion. However, in such cases, patients should be warned of the symptoms of AAU (ocular pain, redness, photophobia or blurred vision) and should be promptly referred to an ophthalmologist if symptoms develop. PMID- 26001949 TI - The relationship is everything: Women's reasons for choosing a privately practising midwife in Western Australia. AB - OBJECTIVE: the purpose of this study was to describe women's reasons for choosing to birth with a privately practising midwife. DESIGN: a modified grounded theory methodology was used. PARTICIPANTS AND SETTING: the sample comprised 14 Western Australian women who had received maternity care from a privately practising midwife within the previous five years. FINDINGS: data analysis revealed three categories: the first was conceptualised as 'I knew what I wanted from my caregiver', which included sub-categories of: I wanted continuity of care; I wanted a relationship with my care provider; and I wanted a care provider with the same childbirth philosophy as me. The second encapsulated 'I knew what I wanted from my pregnancy and birth experience,' with two sub-categories, I wanted a natural, active, intervention free pregnancy and birth and I wanted my partner and family to be included. The final category was labelled 'I was willing to get the research to get what I wanted' and incorporated two sub-categories, I researched my care options and I researched my care provider options and the evidence around pregnancy and birth to be actively involved. KEY CONCLUSIONS: findings offer insight around women's reasons for choosing this model of midwifery care and highlight that women know exactly what they want from their caregiver. Women valued working with their midwife towards a shared goal of an intervention-free, normal birth, researched their options and found mainstream services restrictive and focused on medical risk status rather than on the individual woman. IMPLICATIONS FOR PRACTICE: findings will be of interest to maternity care practitioners and policy makers, as they highlight why some women prefer a social model of midwifery care that reflects a family centred, individualised and holistic approach. This insight can inform the development of maternity health care practices to recognise and accommodate the needs and values of all childbearing women. PMID- 26001950 TI - Early life factors associated with the exclusivity and duration of breast feeding in an Irish birth cohort study. AB - OBJECTIVE: to investigate the influence of parental and infant characteristics on exclusive breast feeding from birth to six months of age and breast feeding rates at two, six and 12 months of age in Ireland. METHODOLOGY: secondary data analysis from the Cork BASELINE Birth Cohort Study (http://www.baselinestudy.net/). Infants were seen at birth and two, six, and 12 months of age. Maternal and paternal history, neonatal course and feeding data were collected at birth and using parental questionnaires at each time point. PARTICIPANTS: 1094 singleton infants of primiparous women recruited at 20 weeks' gestation who were breastfeeding on discharge from the maternity hospital. FINDINGS: at discharge from the maternity hospital and at two months, neonatal intensive-care unit admission had the strongest influence on exclusive breast feeding status (adjusted OR 0.17, 95% CI 0.07-0.41 at discharge) and at two months (adjusted OR=0.20, 95% CI 0.05-0.83). A shorter duration of breast feeding was significantly associated with younger maternal age, non-tertiary education, Irish nationality and neonatal intensive-care unit admission. There was a significant difference in the duration of any breast feeding between infants who were and were not admitted to the neonatal intensive-care unit, 28(10.50, 32) weeks versus 32(27, 40) weeks. Mothers whose maternity leave was between seven and 12 months (adjusted OR=2.76, 95% CI 1.51-5.05) breast fed for a longer duration compared to mothers who had less than six months of maternity leave. KEY CONCLUSIONS: admission to the neonatal intensive care unit negatively influenced both exclusivity and duration of breast feeding. Length of maternity leave, and not employment status, was significantly associated with duration of breast feeding. IMPLICATIONS FOR PRACTICE: additional support may be required to ensure continued breast feeding in infants admitted to the neonatal intensive-care unit. Length of maternity leave is a modifiable influence on breast feeding and offers the opportunity for intervention to improve our rates of breast feeding. PMID- 26001951 TI - Exploring Theory of Mind Use in Blind Adults During Natural Communication. AB - The aim of this article is to explore whether people who are blind are as successful in recognising other people's mental states in communicative situations as people who are sighted. In the current investigation, a group of blind and sighted individuals were tested on their first and higher-order ToM abilities to recognise the intentions, feelings and beliefs of people engaged in natural conversations. The results revealed significant differences between the groups in the recognition of mental states, but no differences were found in their first-order and higher-order ToM use. The study shows that people who are blind may understand other people's intentions, feelings and beliefs differently than people who are sighted. This is not because of their ToM deficits or linguistic incompetence, but because during communication blind individuals have limited access to the information about others' mental states. PMID- 26001952 TI - Infrared Imaging and Spectroscopy Beyond the Diffraction Limit. AB - Progress in nanotechnology is enabled by and dependent on the availability of measurement methods with spatial resolution commensurate with nanomaterials' length scales. Chemical imaging techniques, such as scattering scanning near field optical microscopy (s-SNOM) and photothermal-induced resonance (PTIR), have provided scientists with means of extracting rich chemical and structural information with nanoscale resolution. This review presents some basics of infrared spectroscopy and microscopy, followed by detailed descriptions of s-SNOM and PTIR working principles. Nanoscale spectra are compared with far-field macroscale spectra, which are widely used for chemical identification. Selected examples illustrate either technical aspects of the measurements or applications in materials science. Central to this review is the ability to record nanoscale infrared spectra because, although chemical maps enable immediate visualization, the spectra provide information to interpret the images and characterize the sample. The growing breadth of nanomaterials and biological applications suggest rapid growth for this field. PMID- 26001953 TI - Functionalizing Microporous Membranes for Protein Purification and Protein Digestion. AB - This review examines advances in the functionalization of microporous membranes for protein purification and the development of protease-containing membranes for controlled protein digestion prior to mass spectrometry analysis. Recent studies confirm that membranes are superior to bead-based columns for rapid protein capture, presumably because convective mass transport in membrane pores rapidly brings proteins to binding sites. Modification of porous membranes with functional polymeric films or TiO2 nanoparticles yields materials that selectively capture species ranging from phosphopeptides to His-tagged proteins, and protein-binding capacities often exceed those of commercial beads. Thin membranes also provide a convenient framework for creating enzyme-containing reactors that afford control over residence times. With millisecond residence times, reactors with immobilized proteases limit protein digestion to increase sequence coverage in mass spectrometry analysis and facilitate elucidation of protein structures. This review emphasizes the advantages of membrane-based techniques and concludes with some challenges for their practical application. PMID- 26001955 TI - [Quality of life in patients wearing scleral lenses]. AB - OBJECTIVE: To evaluate the contribution of scleral lenses in terms of improving the quality of life in the treatment of astigmatism after penetrating keratoplasty or in keratoconus. METHODS: We conducted an observational retrospective study, evaluating quality of life (QOL) of patients who failed to adapt to RPG lenses, fitted with SPOT((r)) scleral lenses between October 2007 and March 2011 in the University Hospital of Besancon Department of Ophthalmology. QOL was assessed before and after scleral lens adaptation with the French version of the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ 25). RESULTS: We included 47 patients (83 eyes) fitted with scleral lenses on one or both eyes: 56 eyes with keratoconus and 27 post-keratoplasty eyes. The average duration of wearing scleral lenses was 18+/-10months and the average wearing time was 14+/-3hours per day. The rate of participation in the survey was 86.5% (41 patients). Visual acuity in the better eye progressed from 0.68+/-0.46 to 0.15+/-0.17 logMAR at the 6th month after scleral lens adaptation (P<0.0001). The average scores on the NEI-VFQ 25 questionnaire of patients fitted with scleral lenses for at least 6 months were significantly higher than those without scleral lenses, with a global score of 80.2/100 with, versus 48.1/100 without, scleral lenses (P<0.0001). The global score increased by an average of 32.1+/-4.6 points (-28, 82) (P<0.0001). Statistical analysis found no significant difference in global score between patients in the keratoconus and keratoplasty groups (P>0.05). Scleral lenses showed a significant improvement in quality of life for patients who had failed or are intolerant to conventional rigid gas permeable contact lenses. In our two main optical indications, keratoconus and keratoplasty, they represent an alternative or a step prior to surgery. PMID- 26001956 TI - TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis. AB - Lung carcinogenesis is a multistep process in which normal lung epithelial cells are converted to cancer cells through the sequential acquisition of multiple genetic or epigenetic events. Despite the utility of current genetically engineered mouse (GEM) models of lung cancer, most do not allow temporal dissociation of the cardinal events involved in lung tumor initiation and cancer progression. Here we describe a novel two-switch GEM model for BRAF(V600E) induced lung carcinogenesis allowing temporal dissociation of these processes. In mice carrying a Flp recombinase-activated allele of Braf (Braf(FA)) in conjunction with Cre-regulated alleles of Trp53, Cdkn2a, or c-MYC, we demonstrate that secondary genetic events can promote bypass of the senescence-like proliferative arrest displayed by BRAF(V600E)-induced lung adenomas, leading to malignant progression. Moreover, restoring or activating TP53 in cultured BRAF(V600E)/TP53(Null) or BRAF(V600E)/INK4A-ARF(Null) lung cancer cells triggered a G1 cell-cycle arrest regardless of p19(ARF) status. Perhaps surprisingly, neither senescence nor apoptosis was observed upon TP53 restoration. Our results establish a central function for the TP53 pathway in restricting lung cancer development, highlighting the mechanisms that limit malignant progression of BRAF(V600E)-initiated tumors. PMID- 26001957 TI - Management of pancreatic, gastrointestinal and liver complications in adult cystic fibrosis. AB - INTRODUCTION: The gastrointestinal tract is a major source of morbidity in adults with cystic fibrosis (CF), with a wide range of complications, some of them being specific to the underlying disease. STATE OF KNOWLEDGE: Abnormal CFTR function, with reduced bicarbonate and other ion transport levels through the apical surface of epithelial cells, affects the intestinal tract including the pancreas and the liver. Similarly to what is observed in the respiratory tract, gastrointestinal CFTR dysfunction leads to mucus accumulation, dysmotility, small bowel bacterial overgrowth and inflammation with alteration of innate immune responses, all of which being likely to be interrelated. In developed countries, almost half of patients with CF are adults followed in multidisciplinary CF care centres by pneumologists who often have to manage gastrointestinal complications. CONCLUSION: It therefore appears essential that adult gastroenterologists develop the expertise needed for managing CF gastrointestinal complications in close collaboration with multidisciplinary CF care centre teams to improve the quality of life of adults with CF. PMID- 26001958 TI - The past, present, and future of pacemaker therapies. AB - Since its introduction into clinical practice, electronic pacing has saved many lives. Despite continuous improvements, electronic pacemakers have important shortcomings, which stimulated the development of biological alternatives. Biological pacemakers generate the cardiac impulse using genes or cells to treat bradycardias. Over the past decade, significant improvements have been made in biological pacemakers, but issues remain in relation to long-term outcomes and safety. Concurrently, efforts to improve electronic pacemakers have also intensified. Whether new generations of electronic pacemakers will erase lingering concerns with regard to electronic pacing or whether biologicals will ultimately supplement or supplant electronics remains to be seen. PMID- 26001959 TI - Diurnal cortisol rhythm: Associated with anxiety and depression, or just an indication of lack of energy? AB - Dysregulation of hypothalamus-pituitary-adrenal-activity has been associated with low back pain (LBP). The underlying mechanisms are not fully explained, but psychological mechanisms are considered important. In this study we examine the association between psychiatric disorders/symptoms measured with different instruments, and cortisol in a population with LBP. Participants (n=305) sick listed 2-10 months due to non-specific LBP were included in the study. The screening instruments were the MINI-interview, HADS and HSCL-25. Saliva cortisol were measured on 2 consecutive days; at awakening, 30min later, at 15:00h and 22:00h. Results showed no associations between any of the main diagnostic categories from the MINI-interview, or anxiety/depression measured with HADS or HSCL-25 and cortisol. However, significant associations were found between low cortisol awakening response, low cortisol slope during the day and the somatization scale from HSCL-25 (dizziness or lack of energy, lack of sexual interest, the feeling that everything requires substantial efforts, difficulties to fall asleep, headache). The results indicate that cortisol, may not be directly associated with psychopathology, such as anxiety and depression, but instead are associated with one dimension of the psychopathology, namely lack of energy. This could help explain the inconsistency in the literature, and it should be explored further. PMID- 26001960 TI - Dealing with feeling: Specific emotion regulation skills predict responses to stress in psychosis. AB - Elevated negative affect is an established link between minor stressors and psychotic symptoms. Less clear is why people with psychosis fail to regulate distressing emotions effectively. This study tests whether subjective, psychophysiological and symptomatic responses to stress can be predicted by specific emotion regulation (ER) difficulties. Participants with psychotic disorders (n=35) and healthy controls (n=28) were assessed for ER-skills at baseline. They were then exposed to a noise versus no stressor on different days, during which self-reported stress responses, state paranoia and skin conductance levels (SCL) were assessed. Participants with psychosis showed a stronger increase in self-reported stress and SCL in response to the stressor than healthy controls. Stronger increases in self-reported stress were predicted by a reduced ability to be aware of and tolerate distressing emotions, whereas increases in SCL were predicted by a reduced ability to be aware of, tolerate, accept and modify them. Although paranoid symptoms were not significantly affected by the stressors, individual variation in paranoid responses was also predicted by a reduced ability to be aware of and tolerate emotions. Differences in stress responses in the samples were no longer significant after controlling for ER skills. Thus, interventions that improve ER-skills could reduce stress sensitivity in psychosis. PMID- 26001961 TI - A Bmp Reporter Transgene Mouse Embryonic Stem Cell Model as a Tool to Identify and Characterize Chemical Teratogens. AB - Embryonic stem cells (ESCs) were first isolated from mouse embryos more than 30 years ago. They have proven invaluable not only in generating genetically modified mice that allow for analysis of gene function in tissue development and homeostasis but also as models for genetic disease. In addition, ESCs in vitro are finding inroads in pharmaceutical and toxicological testing, including the identification of teratogenic compounds. Here, we describe the use of a bone morphogenetic protein (Bmp)-reporter ESC line, isolated from a well-characterized transgenic mouse line, as a new tool for the identification of chemical teratogens. The Bmp-mediated expression of the green fluorescent protein enabled the quantification of dose- and time-dependent effects of valproic acid as well as retinoic acid. Significant effects were detectable at concentrations that were comparable to the ones observed in the classical embryonic stem cell test, despite the fact that the reporter gene is expressed in distinct cell types, including endothelial and endodermal cells. Thus these cells provide a valuable new tool for the identification and characterization of relevant mechanisms of embryonic toxicity. PMID- 26001962 TI - Na+/Taurocholate Cotransporting Polypeptide and Apical Sodium-Dependent Bile Acid Transporter Are Involved in the Disposition of Perfluoroalkyl Sulfonates in Humans and Rats. AB - Among the perfluoroalkyl sulfonates (PFASs), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) have half-lives of several years in humans, mainly due to slow renal clearance and potential hepatic accumulation. Both compounds undergo enterohepatic circulation. To determine whether transporters involved in the enterohepatic circulation of bile acids are also involved in the disposition of PFASs, uptake of perfluorobutane sulfonate (PFBS), PFHxS, and PFOS was measured using freshly isolated human and rat hepatocytes in the absence or presence of sodium. The results demonstrated sodium-dependent uptake for all 3 PFASs. Given that the Na(+)/taurocholate cotransporting polypeptide (NTCP) and the apical sodium-dependent bile salt transporter (ASBT) are essential for the enterohepatic circulation of bile acids, transport of PFASs was investigated in stable CHO Flp-In cells for human NTCP or HEK293 cells transiently expressing rat NTCP, human ASBT, and rat ASBT. The results demonstrated that both human and rat NTCP can transport PFBS, PFHxS, and PFOS. Kinetics with human NTCP revealed Km values of 39.6, 112, and 130 uM for PFBS, PFHxS, and PFOS, respectively. For rat NTCP Km values were 76.2 and 294 uM for PFBS and PFHxS, respectively. Only PFOS was transported by human ASBT whereas rat ASBT did not transport any of the tested PFASs. Human OSTalpha/beta was also able to transport all 3 PFASs. In conclusion, these results suggest that the long half-live and the hepatic accumulation of PFOS in humans are at least, in part, due to transport by NTCP and ASBT. PMID- 26001963 TI - Transcriptomic Changes in Zebrafish Embryos and Larvae Following Benzo[a]pyrene Exposure. AB - Benzo[a]pyrene (BaP) is an environmentally relevant carcinogenic and endocrine disrupting compound that causes immediate, long-term, and multigenerational health deficits in mammals and fish. Previously, we found that BaP alters DNA methylation patterns in developing zebrafish, which may affect gene expression. Herein, we performed a genome-wide transcriptional analysis and discovered differential gene expression and splicing in developing zebrafish. Adult zebrafish were exposed to control or 42.0 +/- 1.9 ug/l BaP for 7 days. Eggs were collected and raised in control conditions or continuously exposed to BaP until 3.3 and 96 h post-fertilization (hpf). RNA sequencing (RNA-Seq) was conducted on zebrafish embryos and larvae. Data were analyzed to identify differentially expressed (DE) genes (changed at the gene or transcript variant level) and genes with differential exon usage (DEU; changed at the exon level). At 3.3 hpf, BaP exposure resulted in 8 DE genes and 51 DEU genes. At 96 hpf, BaP exposure altered expression in 1153 DE genes and 159 DEU genes. Functional ontology analysis by Ingenuity Pathway Analysis revealed that many disease pathways, including organismal death, growth failure, abnormal morphology of embryonic tissue, congenital heart disease, and adverse neuritogenesis, were significantly enriched for the DE and DEU genes, providing novel insights on the mechanisms of action of BaP-induced developmental toxicities. Collectively, we discovered substantial transcriptomic changes at the gene, transcript variant, and exon levels in developing zebrafish after early life BaP waterborne exposure, and these changes may lead to long-term adverse physiological consequences. PMID- 26001964 TI - The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1 Dependent Reduction in Food Intake. AB - The environmental pollutants perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) cause a dramatic reduction in the size of the major adipose tissue depots and a general body weight decrease when they are added to the food of mice. We demonstrate here that this is mainly due to a reduction in food intake; this reduction was not due to food aversion. Remarkably and unexpectedly, a large part of the effect of PFOA/PFOS on food intake was dependent on the presence of the uncoupling protein 1 (UCP1) in the mice. Correspondingly, PFOA/PFOS treatment induced recruitment of brown adipose tissue mitochondria: increased oxidative capacity and increased UCP1-mediated oxygen consumption (thermogenesis). In mice pair-fed to the food intake during PFOA/PFOS treatment in wildtype mice, brown-fat mitochondrial recruitment was also induced. We conclude that we have uncovered the existence of a regulatory component of food intake that is dependent upon brown adipose tissue thermogenic activity. The possible environmental consequences of this novel PFOA/PFOS effect (a possible decreased fitness) are noted, as well as the perspectives of this finding on the general understanding of control of food intake control and its possible extension to combatting obesity. PMID- 26001965 TI - Global analysis of RNA cleavage by 5'-hydroxyl RNA sequencing. AB - RNA cleavage by some endoribonucleases and self-cleaving ribozymes produces RNA fragments with 5'-hydroxyl (5'-OH) and 2',3'-cyclic phosphate termini. To identify 5'-OH RNA fragments produced by these cleavage events, we exploited the unique ligation mechanism of Escherichia coli RtcB RNA ligase to attach an oligonucleotide linker to RNAs with 5'-OH termini, followed by steps for library construction and analysis by massively parallel DNA sequencing. We applied the method to RNA from budding yeast and captured known 5'-OH fragments produced by tRNA Splicing Endonuclease (SEN) during processing of intron-containing pre-tRNAs and by Ire1 cleavage of HAC1 mRNA following induction of the unfolded protein response (UPR). We identified numerous novel 5'-OH fragments derived from mRNAs: some 5'-OH mRNA fragments were derived from single, localized cleavages, while others were likely produced by multiple, distributed cleavages. Many 5'-OH fragments derived from mRNAs were produced upstream of codons for highly electrostatic peptides, suggesting that the fragments may be generated by co translational mRNA decay. Several 5'-OH RNA fragments accumulated during the induction of the UPR, some of which share a common sequence motif that may direct cleavage of these mRNAs. This method enables specific capture of 5'-OH termini and complements existing methods for identifying RNAs with 2',3'-cyclic phosphate termini. PMID- 26001966 TI - Bacillus subtilis RecO and SsbA are crucial for RecA-mediated recombinational DNA repair. AB - Genetic data have revealed that the absence of Bacillus subtilis RecO and one of the end-processing avenues (AddAB or RecJ) renders cells as sensitive to DNA damaging agents as the null recA, suggesting that both end-resection pathways require RecO for recombination. RecA, in the rATP.Mg(2+) bound form (RecA.ATP), is inactive to catalyze DNA recombination between linear double-stranded (ds) DNA and naked complementary circular single-stranded (ss) DNA. We showed that RecA.ATP could not nucleate and/or polymerize on SsbA.ssDNA or SsbB.ssDNA complexes. RecA.ATP nucleates and polymerizes on RecO.ssDNA.SsbA complexes more efficiently than on RecO.ssDNA.SsbB complexes. Limiting SsbA concentrations were sufficient to stimulate RecA.ATP assembly on the RecO.ssDNA.SsbB complexes. RecO and SsbA are necessary and sufficient to 'activate' RecA.ATP to catalyze DNA strand exchange, whereas the AddAB complex, RecO alone or in concert with SsbB was not sufficient. In presence of AddAB, RecO and SsbA are still necessary for efficient RecA.ATP-mediated three-strand exchange recombination. Based on genetic and biochemical data, we proposed that SsbA and RecO (or SsbA, RecO and RecR in vivo) are crucial for RecA activation for both, AddAB and RecJ-RecQ (RecS) recombinational repair pathways. PMID- 26001967 TI - Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes. AB - Global network modeling of distal regulatory interactions is essential in understanding the overall architecture of gene expression programs. Here, we developed a Bayesian probabilistic model and computational method for global causal network construction with breast cancer as a model. Whereas physical regulator binding was well supported by gene expression causality in general, distal elements in intragenic regions or loci distant from the target gene exhibited particularly strong functional effects. Modeling the action of long range enhancers was critical in recovering true biological interactions with increased coverage and specificity overall and unraveling regulatory complexity underlying tumor subclasses and drug responses in particular. Transcriptional cancer drivers and risk genes were discovered based on the network analysis of somatic and genetic cancer-related DNA variants. Notably, we observed that the risk genes were functionally downstream of the cancer drivers and were selectively susceptible to network perturbation by tumorigenic changes in their upstream drivers. Furthermore, cancer risk alleles tended to increase the susceptibility of the transcription of their associated genes. These findings suggest that transcriptional cancer drivers selectively induce a combinatorial misregulation of downstream risk genes, and that genetic risk factors, mostly residing in distal regulatory regions, increase transcriptional susceptibility to upstream cancer-driving somatic changes. PMID- 26001968 TI - Structure-guided sequence specificity engineering of the modification-dependent restriction endonuclease LpnPI. AB - The eukaryotic Set and Ring Associated (SRA) domains and structurally similar DNA recognition domains of prokaryotic cytosine modification-dependent restriction endonucleases recognize methylated, hydroxymethylated or glucosylated cytosine in various sequence contexts. Here, we report the apo-structure of the N-terminal SRA-like domain of the cytosine modification-dependent restriction enzyme LpnPI that recognizes modified cytosine in the 5'-C(mC)DG-3' target sequence (where mC is 5-methylcytosine or 5-hydroxymethylcytosine and D = A/T/G). Structure-guided mutational analysis revealed LpnPI residues involved in base-specific interactions and demonstrated binding site plasticity that allowed limited target sequence degeneracy. Furthermore, modular exchange of the LpnPI specificity loops by structural equivalents of related enzymes AspBHI and SgrTI altered sequence specificity of LpnPI. Taken together, our results pave the way for specificity engineering of the cytosine modification-dependent restriction enzymes. PMID- 26001969 TI - Haploinsufficiency predictions without study bias. AB - Any given human individual carries multiple genetic variants that disrupt protein coding genes, through structural variation, as well as nucleotide variants and indels. Predicting the phenotypic consequences of a gene disruption remains a significant challenge. Current approaches employ information from a range of biological networks to predict which human genes are haploinsufficient (meaning two copies are required for normal function) or essential (meaning at least one copy is required for viability). Using recently available study gene sets, we show that these approaches are strongly biased towards providing accurate predictions for well-studied genes. By contrast, we derive a haploinsufficiency score from a combination of unbiased large-scale high-throughput datasets, including gene co-expression and genetic variation in over 6000 human exomes. Our approach provides a haploinsufficiency prediction for over twice as many genes currently unassociated with papers listed in Pubmed as three commonly-used approaches, and outperforms these approaches for predicting haploinsufficiency for less-studied genes. We also show that fine-tuning the predictor on a set of well-studied 'gold standard' haploinsufficient genes does not improve the prediction for less-studied genes. This new score can readily be used to prioritize gene disruptions resulting from any genetic variant, including copy number variants, indels and single-nucleotide variants. PMID- 26001971 TI - Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma. AB - Chromosomal rearrangements of the NTRK1 gene, which encodes the high affinity nerve growth factor receptor (tropomyosin related kinase, TRKA), have been observed in several epithelial cancers, such as colon cancer, papillary thyroid carcinoma or non small cell lung cancer. The various NTRK1 fusions described so far lead to constitutive activation of TRKA kinase activity and are oncogenic. We further investigated here the existence and the frequency of NTRK1 gene rearrangements in colorectal cancer. Using immunohistochemistry and quantitative reverse transcriptase PCR, we analyzed a series of human colorectal cancers. We identified two TRKA positive cases over 408, with NTRK1 chromosomal rearrangements. One of these rearrangements is a TPM3-NTRK1 fusion already observed in colon cancer, while the second one is a TPR-NTRK1 fusion never described in this type of cancer. These findings further confirm that translocations in the NTRK1 gene are recurring events in colorectal cancer, although occurring at a low frequency (around 0.5%). PMID- 26001970 TI - Reinforcement of Mono- and Bi-layer Poly(Ethylene Glycol) Hydrogels with a Fibrous Collagen Scaffold. AB - Biomaterial-based tissue engineering strategies hold great promise for osteochondral tissue repair. Yet significant challenges remain in joining highly dissimilar materials to achieve a biomimetic, mechanically robust design for repairing interfaces between soft tissue and bone. This study sought to improve interfacial properties and function in a bi-layer hydrogel interpenetrated with a fibrous collagen scaffold. 'Soft' 10% (w/w) and 'stiff' 30% (w/w) PEGDM was formed into mono- or bi-layer hydrogels possessing a sharp diffusional interface. Hydrogels were evaluated as single-(hydrogel only) or multi-phase (hydrogel + fibrous scaffold penetrating throughout the stiff layer and extending >500 MUm into the soft layer). Including a fibrous scaffold into both soft and stiff mono layer hydrogels significantly increased tangent modulus and toughness and decreased lateral expansion under compressive loading. Finite element simulations predicted substantially reduced stress and strain gradients across the soft-stiff hydrogel interface in multi-phase, bilayer hydrogels. When combining two low moduli constituent materials, composites theory poorly predicts the observed, large modulus increases. These results suggest material structure associated with the fibrous scaffold penetrating within the PEG hydrogel as the major contributor to improved properties and function-the hydrogel bore compressive loads and the 3D fibrous scaffold was loaded in tension thus resisting lateral expansion. PMID- 26001972 TI - Survey of chloroquine-resistant mutations in the Plasmodium falciparum pfcrt and pfmdr-1 genes in Hadhramout, Yemen. AB - Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium falciparum. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax. PMID- 26001973 TI - Controlling Taenia solium and soil transmitted helminths in a northern Lao PDR village: Impact of a triple dose albendazole regime. AB - Taenia solium taeniasis-cysticercosis and soil-transmitted helminths (STHs) are parasitic Neglected Tropical Diseases endemic throughout Southeast Asia. Within Lao PDR, a remote northern hill tribe village had previously been identified as a hyper endemic focus for T. solium. To reduce this observed prevalence, a One Health intervention covering both pigs and humans was implemented, which included two Mass drug administrations (MDA1 and MDA2) for village residents using a triple dose albendazole 400mg treatment regime. In addition to the effect on T. solium levels, the dual impact of this anthelmintic regime on STHs within the community was also monitored. Faecal samples were collected pre and post MDA1 and MDA2 and analysed for the presence of Taenia species and the STHs Ascaris lumbricoides, Trichuris trichiura and hookworm species. The McMaster technique was used to measure the changes in both prevalence and intensity of infection. Molecular characterisation of Taenia and hookworm species was conducted to detect zoonotic species. The level of taeniasis within the sampled population decreased by 79.4% after MDA1, remained steady during the five month inter-treatment interval and decreased again by 100% after MDA2. The prevalence of STHs decreased by 65.5% and 62.8% after MDA1 and MDA2 respectively; however an increase to 62.1% of pre MDA1 levels was detected during the inter-treatment interval. Individually, hookworm prevalence decreased by 83.4% (MDA1) and 84.5% (MDA2), A. lumbricoides by 95.6% and 93.5% and T. trichiura by 69.2% and 61%. The intensity of infection within the sampled population also decreased, with egg reduction rates of 94.4% and 97.8% for hookworm, 99.4% and 99.3% for A. lumbricoides and 77.2% and 88.5% for T. trichiura. Molecular characterisation identified a T. solium tapeworm carrier from 21.6% (13/60) of households in the village. T. saginata was identified in 5% (3/60) of households. The zoonotic hookworm A. ceylanicum was detected in the resident dog population. These results suggest that the triple dose albendazole 400mg treatment regime achieved a significant reduction in the level of taeniasis whilst simultaneously reducing the STH burden within the village. The increased STH prevalence detected between MDAs reflects the need for behavioural changes and a sustained chemotherapy programme, which may also need to include the resident dog population. PMID- 26001974 TI - High morphological plasticity and global geographical distribution of the Pacific broad tapeworm Adenocephalus pacificus (syn. Diphyllobothrium pacificum): molecular and morphological survey. AB - The most important causative agent of human diphyllobothriosis in South America, Diphyllobothrium pacificum, is transferred to the original genus Adenocephalus Nybelin, 1931; revised and redescribed on the basis of the evaluation of an extensive material collected mainly from northern fur seal, Callorhinus ursinus, from St. Paul Island, Alaska. Detailed analysis of morphological and morphometrical data shows a high variability in most of the characteristics traditionally used in diagnosis of diphyllobothriid tapeworms. Phylogenetic analyses based on newly characterised sequences of mitochondrial cytochrome c oxidase subunit 1 and nuclear large subunit ribosomal RNA genes consistently reveal Adenocephalus pacificus as a sister lineage to the clade formed of the remaining Diphyllobothrium species and other genera (Digramma, Diplogonoporus, Ligula). Despite the generally similar morphology, A. pacificus can be differentiated from the closely related taxa in the presence of transverse papilla-like tegumental protuberances distributed anteriorly, separated by narrow semicircular grooves on the ventral surface of proglottids between their anterior margin and the anterior edge of the male gonopore, and relatively small eggs. A. pacificus displays a relatively low host specificity (found in 9 of 16 otariids, and in accidental hosts such as man, dog and jackal, the latter representing a new host) and a uniquely wide geographical distribution on both hemispheres. In addition, suitability of morphological criteria used in diagnostics of diphyllobothriid cestodes is discussed. PMID- 26001976 TI - Impact of minimum contrast media volumes during elective percutaneous coronary intervention for prevention of contrast-induced nephropathy in patients with stable coronary artery disease. AB - Contrast-induced nephropathy (CIN) is an important complication following percutaneous coronary intervention (PCI). The clinical importance of a minimum contrast media volume (CMV) for PCI to prevent CIN has not been well evaluated. The purpose of this study was to evaluate the impact of minimum CMV to prevent CIN after PCI. In this study, 2052 consecutive patients who underwent elective PCI in our institute were analyzed. We divided patients into two groups according to CMV: a minimum CMV PCI group [CMV <=50 ml (n = 94)] and a non-minimum CMV PCI group [CMV >50 ml (n = 1958)]. CIN occurred in 160 (7.8 %) patients. The incidence of CIN was significantly lower in the minimum CMV PCI group than in the non-minimum CMV PCI group (2.1 vs. 8.1 %; P = 0.03). According to multivariate analysis, elderly patients and diabetes mellitus patients were at high risk of developing CIN in this study population. When analyzing only high-risk patients, the incidence of CIN was also significantly lower in the minimum CMV group than in the non-minimum CMV group (2.6 vs. 10.3 %; P = 0.03). Minimum CMV PCI could reduce the incidence of CIN, particularly in high-risk patients; as such, defining the minimum CMV clinical cut-off values may be useful for the prevention of CIN. PMID- 26001975 TI - Metabolomic analysis to define and compare the effects of PAHs and oxygenated PAHs in developing zebrafish. AB - Polycyclic aromatic hydrocarbons (PAHs) and their oxygenated derivatives are ubiquitously present in diesel exhaust, atmospheric particulate matter and soils sampled in urban areas. Therefore, inhalation or non-dietary ingestion of both PAHs and oxy-PAHs are major routes of exposure for people; especially young children living in these localities. While there has been extensive research on the parent PAHs, limited studies exist on the biological effects of oxy-PAHs which have been shown to be more soluble and more mobile in the environment. Additionally, investigations comparing the metabolic responses resulting from parent PAHs and oxy-PAHs exposures have not been reported. To address these current gaps, an untargeted metabolomics approach was conducted to examine the in vivo metabolomic profiles of developing zebrafish (Danio rerio) exposed to 4 uM of benz[a]anthracene (BAA) or benz[a]anthracene-7,12-dione (BAQ). By integrating multivariate, univariate and pathway analyses, a total of 63 metabolites were significantly altered after 5 days of exposure. The marked perturbations revealed that both BAA and BAQ affect protein biosynthesis, mitochondrial function, neural development, vascular development and cardiac function. Our previous transcriptomic and genomic data were incorporated in this metabolomics study to provide a more comprehensive view of the relationship between PAH and oxy-PAH exposures on vertebrate development. PMID- 26001977 TI - Editorial Comment. PMID- 26001978 TI - Knowledge, attitudes and practices on HIV/AIDS and prevalence of HIV in the general population of Sucre, Bolivia. AB - BACKGROUND: To analyse knowledge, attitudes and sexual practices on HIV/AIDS, and estimate HIV prevalence among residents of Sucre (Bolivia). METHODOLOGY: Population-based survey of residents aged 15-49 randomly selected during 2008/2009. Blood samples were collected on Whatman-filter paper and tested with enzyme-linked immunosorbent assay. Knowledge on HIV/AIDS, sexual risk practices and discriminatory attitudes against people living with HIV/AIDS (PLWHA) were modelled with multiple logistic regression. RESULTS: Of 1499 subjects, 59% were women. All subjects were HIV-negative. Inadequate knowledge of HIV/AIDS transmission and prevention was observed in 67% and risk factors varied by gender (interaction p-value<0.05). Discriminatory attitudes were displayed by 85% subjects; associated factors were: rural residence, low educational level and low income. Unsafe sex was reported by 10%; risk factors varied by residence area (interaction p-value<0.05). In urban areas, risk factors were male sex, younger age and being in common-law union. CONCLUSIONS: Prevalence of HIV infection is very low and unsafe sex is relatively uncommon. Inadequate knowledge on HIV/AIDS and discriminatory attitudes towards PLWHA are extremely high and are associated to gender, ethnic and economic inequalities. PMID- 26001979 TI - Asthma exacerbation and viral infection in adult patients, Brazil. PMID- 26001980 TI - A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity. AB - The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. Metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy (RR=0.88, 95% CI=0.64-1.21, p=0.43). Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection. PMID- 26001981 TI - Peclet number as affected by molecular diffusion controls transient anomalous transport in alluvial aquifer-aquitard complexes. AB - This study evaluates the role of the Peclet number as affected by molecular diffusion in transient anomalous transport, which is one of the major knowledge gaps in anomalous transport, by combining Monte Carlo simulations and stochastic model analysis. Two alluvial settings containing either short- or long-connected hydrofacies are generated and used as media for flow and transport modeling. Numerical experiments show that 1) the Peclet number affects both the duration of the power-law segment of tracer breakthrough curves (BTCs) and the transition rate from anomalous to Fickian transport by determining the solute residence time for a given low-permeability layer, 2) mechanical dispersion has a limited contribution to the anomalous characteristics of late-time transport as compared to molecular diffusion due to an almost negligible velocity in floodplain deposits, and 3) the initial source dimensions only enhance the power-law tail of the BTCs at short travel distances. A tempered stable stochastic (TSS) model is then applied to analyze the modeled transport. Applications show that the time nonlocal parameters in the TSS model relate to the Peclet number, Pe. In particular, the truncation parameter in the TSS model increases nonlinearly with a decrease in Pe due to the decrease of the mean residence time, and the capacity coefficient increases with an increase in molecular diffusion which is probably due to the increase in the number of immobile particles. The above numerical experiments and stochastic analysis therefore reveal that the Peclet number as affected by molecular diffusion controls transient anomalous transport in alluvial aquifer-aquitard complexes. PMID- 26001982 TI - Healthcare use for acute gastrointestinal illness in two Inuit communities: Rigolet and Iqaluit, Canada. AB - BACKGROUND: The incidence of self-reported acute gastrointestinal illness (AGI) in Rigolet, Nunatsiavut, and Iqaluit, Nunavut, is higher than reported elsewhere in Canada; as such, understanding AGI-related healthcare use is important for healthcare provision, public health practice and surveillance of AGI. OBJECTIVES: This study described symptoms, severity and duration of self-reported AGI in the general population and examined the incidence and factors associated with healthcare utilization for AGI in these 2 Inuit communities. DESIGN: Cross sectional survey data were analysed using multivariable exact logistic regression to examine factors associated with individuals' self-reported healthcare and over the-counter (OTC) medication utilization related to AGI symptoms. RESULTS: In Rigolet, few AGI cases used healthcare services [4.8% (95% CI=1.5-14.4%)]; in Iqaluit, some cases used healthcare services [16.9% (95% CI=11.2-24.7%)]. Missing traditional activities due to AGI (OR=3.8; 95% CI=1.18-12.4) and taking OTC medication for AGI symptoms (OR=3.8; 95% CI=1.2-15.1) were associated with increased odds of using healthcare services in Iqaluit. In both communities, AGI severity and secondary symptoms (extreme tiredness, headache, muscle pains, chills) were significantly associated with increased odds of taking OTC medication. CONCLUSIONS: While rates of self-reported AGI were higher in Inuit communities compared to non-Inuit communities in Canada, there were lower rates of AGI-related healthcare use in Inuit communities compared to other regions in Canada. As such, the rates of healthcare use for a given disease can differ between Inuit and non-Inuit communities, and caution should be exercised in making comparisons between Inuit and non-Inuit health outcomes based solely on clinic records and healthcare use. PMID- 26001983 TI - The Role of eHealth in Optimizing Preventive Care in the Primary Care Setting. AB - Modifiable health risk behaviors such as smoking, overweight and obesity, risky alcohol consumption, physical inactivity, and poor nutrition contribute to a substantial proportion of the world's morbidity and mortality burden. General practitioners (GPs) play a key role in identifying and managing modifiable health risk behaviors. However, these are often underdetected and undermanaged in the primary care setting. We describe the potential of eHealth to help patients and GPs to overcome some of the barriers to managing health risk behaviors. In particular, we discuss (1) the role of eHealth in facilitating routine collection of patient-reported data on lifestyle risk factors, and (2) the role of eHealth in improving clinical management of identified risk factors through provision of tailored feedback, point-of-care reminders, tailored educational materials, and referral to online self-management programs. Strategies to harness the capacity of the eHealth medium, including the use of dynamic features and tailoring to help end users engage with, understand, and apply information need to be considered and maximized. Finally, the potential challenges in implementing eHealth solutions in the primary care setting are discussed. In conclusion, there is significant potential for innovative eHealth solutions to make a contribution to improving preventive care in the primary care setting. However, attention to issues such as data security and designing eHealth interfaces that maximize engagement from end users will be important to moving this field forward. PMID- 26001984 TI - Inhibitory Control in Pediatric Trichotillomania (Hair Pulling Disorder): The Importance of Controlling for Age and Symptoms of Inattention and Hyperactivity. AB - Trichotillomania (hair pulling disorder, HPD) is characterized by significant psychological distress, childhood-onset, and, in adults, certain cognitive deficits such as inhibitory control. A total absence of such literature exists within pediatric HPD samples, including research investigating neurocognitive aspects of disparate pulling-styles. The present study aims to address these gaps in the literature. Youth with HPD and healthy controls (N = 45) were compared on an automated neurocognitive task--stop-signal task (SST)--assessing inhibitory control. Youth with HPD (n = 17), controlling for age and attention issues, were found to perform better on the stop-signal reaction time compared to controls (n = 28). No significant relationships between performance on the SST and HPD severity, distress/impairment, or pulling-styles were noted. Findings from the current study suggest that children with HPD may not exhibit deficits in motor inhibition as compared to controls when the effects of age and attentional problems are controlled. PMID- 26001986 TI - Decreases in Phospholipids Containing Adrenic and Arachidonic Acids Occur in the Human Hippocampus over the Adult Lifespan. AB - One of the biggest risk factors for developing Alzheimer's disease is advanced age. Despite several studies examining changes to phospholipids in the hippocampus during the pathogenesis of Alzheimer's disease, little is known regarding changes to phospholipids in this region during normal adult aging. This study examined the phospholipid composition of the mitochondrial and microsomal membranes of the human hippocampus from post-mortem tissue of neurologically normal subjects aged between 18 and 104 years. Many of the age-related changes found were in low-to-moderately abundant phospholipids in both membrane fractions, with decreases with age being seen in many phospholipids containing either adrenic or arachidonic acid. The most abundant phospholipid of this type was phosphatidylethanolamine 18:0_22:4, which decreased in both the mitochondrial and microsomal membranes by approximately 20% from ages 20 to 100. Subsequent decreases with age were seen in total adrenic and arachidonic acid in the phospholipids of both membrane fractions, but not in either fatty acid specifically within the phosphatidylethanolamine class. Increases with age were seen in the hippocampus for mitochondrial phosphatidylserine 18:0_22:6. This is the first report of changes to molecular phospholipids of the human hippocampus over the adult lifespan, with this study also providing a comprehensive profile of the phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine phospholipids of the human hippocampus. PMID- 26001987 TI - Thrombus rupture via cavitation. AB - Aneurysm growth is accompanied by formation of intraluminal thrombus. The onset of thrombus rupture via unstable void growth is studied in the present note. The experimentally calibrated constitutive model of thrombus developed by Wang et al. (2001) is enhanced with a failure description and used for analysis of cavitation. It is found that unstable cavity growth can start at hydrostatic tension of 0.18 MPa which lies within the physiological range of stresses in the arterial wall. PMID- 26001988 TI - Efficacy of a brief nurse-led pilot psychosocial intervention for newly diagnosed Asian cancer patients. AB - PURPOSE: Cancer patients experience distress and high levels of psychosocial concerns. However, in Asian countries like Singapore, patients are often unwilling to seek support and help from mental healthcare professionals, but, instead, are more willing to confide in nurses. This quasi-experimental study developed and tested the efficacy of a brief nurse-led psychosocial intervention to alleviate these patients' distress, minor psychiatric morbidity, and psychosocial concerns. METHODS: The semi-structured intervention comprised 20- to 30-minute face-to-face sessions with trained oncology nurses, monthly for 2 months and then bimonthly for 4 months. Patients received psycho-education on symptoms of stress, anxiety, and depression and counseling and were taught behavioral techniques such as deep breathing, progressive muscle relaxation, and positive self-talk. RESULTS: The results of this study found that patients who received the intervention had reduced distress, depression, and anxiety levels and improved quality of life (QOL) at 6 months. CONCLUSIONS: Although further research is necessary to explore the efficacy and viability of this intervention, findings support brief nurse-led psycho-educational interventions in Asian settings especially for cancer patients reluctant to seek help from mental health professionals. PMID- 26001989 TI - Two proteins of Cucurbit chlorotic yellows virus, P59 and P9, are self interacting. AB - The yeast two-hybrid (Y2H) assay, a powerful tool for identifying protein-protein interactions, has been widely used to study viral protein interactions and to elucidate the functions of viral proteins. In this study, Cucurbit chlorotic yellows virus-encoded proteins were investigated by Y2H assays in all possible pairwise combinations, and the self-interactions of P59 and P9 were detected. The interacting domains of P59 and P9 were identified using vectors carrying an activation domain fused to a truncated version of P59 or P9. We found that the middle region (amino acids 173-344) of P59 was necessary for this self interaction, while three different truncated versions of P9 showed no interaction with full-length P9. This is the first report of the self-interaction of P59 in the genus Crinivirus. PMID- 26001990 TI - Activity Theories and the Ontology of Psychology: Learning from Danish and Russian Experiences. AB - Psychology has permanent problems of theoretical coherence and practical, analytic and critical efficiency. It is claimed that Activity Theory (AT) with roots in a long European philosophical tradition and continued in Russian AT is a first step to remedy this. A Danish version of AT may have a key to exceed some, mostly implicit, ontological restrictions in traditional AT and free it from an embracement of functionalism and mechanicism, rooted in Renaissance Physics. The analysis goes back to Aristotle's understanding of the freely moving animal in its ecology and introduces some dualities in the encounter between subject and object which replace the dualistic dichotomies traditionally splitting Psychology in Naturwissenschaft vs. Geisteswissenshaft. This also implies a "Copernican turn" of Cartesian dualism. The perspectives are to give place for a phenomenology of meaning without cutting human psyche out of Nature and to open Psychology to its domain. PMID- 26001991 TI - BPA qualtitative and quantitative assessment associated with orthodontic bonding in vivo. AB - OBJECTIVE: To assess the in vivo amount of BPA released from a visible light cured orthodontic adhesive, immediately after bracket bonding. METHODS: 20 orthodontic patients were recruited after obtaining informed consent. All patients received 24 orthodontic brackets in both dental arches. In Group A (11 patients), 25 ml of tap water were used for mouth rinsing, whereas in Group B (9 patients) a simulated mouth rinse formulation was used: a mixture of 20 ml de ionized water plus 5 ml absolute ethanol. Rinsing solutions were collected before, immediately after placing the orthodontic appliances and after washing out the oral cavity and were then stored in glass tubes. Rinsing was performed in a single phase for 60s with the entire volume of each liquid. The BPA analysis was performed by gas chromatography-mass spectrometry. RESULTS: An increase in BPA concentration immediately after the 1st post-bonding rinse was observed, for both rinsing media, which was reduced after the 2nd post-bonding rinse. Water exhibited higher levels of BPA concentration than water/ethanol after 1st and 2nd post-bonding rinses. Two-way mixed Repeated Measures ANOVA showed that the primary null hypothesis declaring mean BPA concentration to be equal across rinsing medium and rinsing status was rejected (p-value <0.001). The main effects of the rinsing medium and status, as well as their interaction were found to be statistically significant (p-values 0.048, <0.001 and 0.011 respectively). SIGNIFICANCE: A significant pattern of increase of BPA concentration, followed by a decrease that reached the initial values was observed. The amount of BPA was relatively low and far below the reference limits of tolerable daily intake. PMID- 26001992 TI - Circumference as an alternative for diameter measurement in endovascular aneurysm repair. AB - Appropriate sizing of endografts for endovascular aneurysm repair has traditionally been performed by one standardized method. By measuring the average of the minor and major axes in the sealing zone, the endograft size is traditionally calculated. However, no adequate scientific evaluation has been performed to validate this method. The guidelines that were published are based on theories and experience, more than scientific evidence. In case the central lumen line artery cross-section is a circular disk, the vessel diameter is a reliable estimation. Yet the aortic neck cross-section may not always be geometrically a perfect circular disk. Application of the standardized method might therefore lead to inaccurate endograft sizing, potentially leading to endoleaks. We hypothesize that in these cases the circumference of the vessel is a mathematically correct reference to deduct the appropriate endograft diameter. The following formula was applied in this study: diameter of the corresponding circle (d) equals circumference (C) divided by pid=Cpi. This study provides a theoretical analysis of the mathematical implications of this method. Only in case of highly irregularly shaped cylinders, the circumference-based method was more accurate than the standardized method. Nonetheless, the circumferential method was a practical reference in case the aortic neck was irregularly shaped. Also, the circumference method was accurate in all cases in deducting the diameter of a matching circle. Therefore, the hypothesis that was raised in this study has a strong theoretical base. We predict that in case this hypothesis holds true in the clinical practice, application of the circumference method might lead to less endoleaks than the standardized method. PMID- 26001993 TI - Adults with flexible pes planus and the approach to the prescription of customised foot orthoses in clinical practice: A clinical records audit. AB - A clinical records audit of the University of South Australia's podiatry clinic clients attending in 2010 was undertaken to determine prevalence of symptomatic flexible pes planus, presenting reasons and treatment options most frequently used. Analysis of rearfoot measures (resting calcaneal stance position, subtalar joint range of motion) between those prescribed a vertical (heel) or inverted (heel) cast pour and a medial heel (Kirby) skive was undertaken. Of 223 clinical records audited, 50% (111/223) of clients were assessed with flexible pes planus, 77% (86/111) of clients with pes planus presented with back or lower limb pain and 58% (64/111) were prescribed customised foot orthoses. Of 42 prescriptions for customised foot orthoses audited; 64% (27/42) were prescribed a vertical (heel) cast pour, 36% (15/42) an inverted (heel) cast pour and 19% (8/42) received a medial heel (Kirby) skive. Those prescribed a medial heel (Kirby) skive had a more everted resting calcaneal stance position than those that were not (mean -8.6+/-2.8 degrees vs. -5.5+/-3.4 degrees , p=0.02). Those prescribed an inverted (heel) cast pour had a greater range of subtalar joint motion than those prescribed a vertical (heel) cast pour (median 36.0+/-10.0 degrees vs. 29.0+/-5.0 degrees , p=0.01). PMID- 26001994 TI - Effect of shoes with rounded soft soles in the anterior-posterior direction on the center of pressure during static standing. AB - Shoes with curved rocker bottom soles may induce an unstable standing posture. This study was aimed to mainly examine the effect of such shoes on the center of pressure (COP) during static standing. Ten healthy young male adults had their COP measured during static standing with four types of shoe conditions (Stretch Walker((r)): SW (shoes with curved rocker bottom soles), Masai Barefoot Technology(r): MBT (similar to SW in form and material), more conventionally soled shoes with a typical toe-spring: MCS, and bare feet: BF) for 60s. The mean path length and mean velocity of Y (front-back) axis were significantly greater when wearing the MBT than when wearing the SW, and when wearing the SW than when BF or when wearing the MCS. In addition, mean velocity of X (left-right) axis, area surrounding root mean square, root mean square, and root mean square of Y axis were significantly greater when wearing the MBT than when wearing the SW, MCS, or when BF. In conclusion, when wearing the MBT or SW with rounded sole, static standing posture becomes unstable because of their characteristics as compared with wearing MCS or when BF, but the MBT has a larger sway in the front back direction than the SW. PMID- 26001995 TI - Lower extremity manifestations of "skin-popping" an illicit drug use technique: A report of two cases. AB - Presented is a rare case of tibial and fibular osteomyelitis and a case of fibular periositis, both a direct consequence of a peculiar drug use technique. The osseous manifestations secondary to presentation of necrotic wounds with indurated rim and serous drainage with associated cellulitis, both resulting from "skin popping." Due to the complex treatment plan required, the importance of a motivated patient, a strong social support system, a controlled environment, and a multidisciplinary team cannot be overstated. Despite comprehensive efforts, devastating consequences may be unavoidable as individuals plunge downward, victimized by their addiction. LEVEL OF CLINICAL EVIDENCE: 4. PMID- 26001996 TI - Onset and duration of anesthesia for local anesthetic combinations commonly used in forefoot surgery; surprise results with sequential blocks. AB - Local anesthetic nerve blocks are frequently used for postoperative analgesia and to the best of our knowledge no studies have evaluated the effects of injecting bupivacaine into an area previously injected with lidocaine. Sensation was tested in three groups of subjects receiving local anesthetic digital blocks. Group A received bupivacaine 0.25% plain. Group B received a 1:1 mixture of lidocaine 1% plain and bupivacaine 0.25%. Group C received an initial block of lidocaine 1% plain sequentially followed by bupivacaine 0.25% 1h later. Bupivacaine exhibited a delayed onset and the longest duration when compared to the other two groups. The group receiving the 1:1 mixture showed a rapid onset that resembled that of lidocaine and a shortened duration that did not resemble bupivacaine. The group receiving the sequential injections showed that even after a 1h interval following the lidocaine infiltration, there was a deleterious effect on duration of action of the bupivacaine. Using bupivacaine as a post-surgical block in the presence of residual lidocaine from a preoperative block is not warranted as once again, the extended duration of bupivacaine is mitigated. Bupivacaine alone as an initial operative block affords clinically acceptable onset of anesthesia while also providing extended duration of action. PMID- 26001997 TI - Fifty years of Medicare. PMID- 26001998 TI - A cotton fiber-preferential promoter, PGbEXPA2, is regulated by GA and ABA in Arabidopsis. AB - KEY MESSAGE: PGbEXPA2 (Promoter of GbEXPA2 ) was preferentially and strongly expressed during cotton fiber development, and the 461-bp PGbEXPA2 fragment was essential for responding to exogenous GA and ABA in Arabidopsis. Cotton fibers are highly elongated single-cell, unbranched and non-glandular seed trichomes. Previous studies have reported that the transcript level of GbEXPA2 is significantly up-regulated during fiber cell elongation, suggesting that GbEXPA2 has an important function in fiber development. In this study, the promoter of GbEXPA2 (839 bp) from the D(T) sub-genome was isolated from Gossypium barbadense 3-79. Consistent with the expression pattern of GbEXPA2, the promoter PGbEXPA2 was able to express GUS to high levels in elongating fibers, but not in the root, stem, or leaf. In Arabidopsis, GUS activity was only found in the rosette leaf trichomes and rosette leaf vascular tissue, indicating that the transcription factors which bind to PGbEXPA2 in the leaf trichomes of transgenic Arabidopsis were similar to those found in cotton fiber. A deletion analysis of PGbEXPA2 revealed that a 461-bp fragment was sufficient to drive GUS expression in cotton fibers and Arabidopsis rosette leaf trichomes. Exogenous phytohormonal treatments on transgenic Arabidopsis with different promoter lengths (P-839, P-705, P-588 and P-461) showed that GUS activity in Arabidopsis trichomes could be strongly up regulated by GA and, in contrast, down-regulated by ABA. PMID- 26001999 TI - Vitis vinifera VvWRKY13 is an ethylene biosynthesis-related transcription factor. AB - KEY MESSAGE: A novel transcription factor VvWRKY13 was cloned from Vitis vinifera and found functioning in ethylene biosynthesis pathway by mediating ACS2 and ACS8 expression. Grapevine is one of the most economically important plants, and ethylene is a plant hormone related with its growth, development, abiotic and biotic resistance. Until now, the regulators and their mechanism of ethylene biosynthesis are still not well understood. We have cloned a novel gene from a grapevine cultivar 'Zuoyouhong' and named it VvWRKY13. By qRT-PCR analysis, VvWRKY13 was found to be ubiquitously expressed in the leaf, stem, flower, fruit, and root tissues, indicating that it is probably involved in numerous processes of grapevine growth and development. Overexpression of VvWRKY13 in Arabidopsis leads to constitutive triple responses and improved ethylene production. Bioinformatics analysis indicated that the promoters of ACC synthase genes ACS2 and ACS8 contain WRKYs specific binding element W-box. As a result, the expression of ACS2 and ACS8 was found to be increased significantly in VvWRKY13 overexpression lines. Together, these data reveal that the novel transcription factor VvWRKY13 is likely involved in ethylene biosynthesis by the regulation of ACS2 and ACS8 expression. PMID- 26002000 TI - [How I do... a cervical cerclage in consulting room without suture or analgesia]. PMID- 26002001 TI - Measuring Infant Visual Acuity with Gaze Tracker Monitored Visual Fixation. AB - PURPOSE: To validate a method of measuring grating acuity with remote gaze tracking (GT) against a current clinical test of visual acuity (VA), the Teller Acuity Cards (TACs), as part of the development of an automated VA test for infants. METHODS: Visual acuity for computer-generated horizontal square-wave gratings was determined from relative fixation time on a grating area compared with the background. In experiment 1, binocular VA was based on eye movements with a GT in 15 uncorrected myopic adults and compared with VA measured with subjective responses with the same stimuli and with the TACs. In experiment 2, binocular VA was determined in 19 typically developing infants aged 3 to 11 months on two visits with both the GT and TACs. RESULTS: In adults, the mean difference between VA measured by the GT and TACs was 0.01 log cycles per degree (cpd) and the 95% limits of agreement were 0.11. One hundred percent of GT VA results were within 0.5 octave of the TACs' VAs. The mean difference between the GT and TACs for infants was 0.17 log cpd on both the first and second visit (95% limits of agreement, 0.42 and 0.47, respectively). The mean difference between test and retest for infant GT VA was 0.06 log cpd, and limits of agreement for repeatability were 0.48 log cpd. In infants, both the TACs and the GT had a reliability of 89% within less than or equal to 1 octave between visits. Gaze tracking VA improved with age and is in agreement with published norms. CONCLUSIONS: The agreement between the TACs and GT in adults and infants validates the method of measuring grating acuity with the remote GT. These results demonstrate its potential for an automated test of infant VA. PMID- 26002002 TI - Biological and Clinical Implications of Lysozyme Deposition on Soft Contact Lenses. AB - Within a few minutes of wear, contact lenses become rapidly coated with a variety of tear film components, including proteins, lipids, and mucins. Tears have a rich and complex composition, allowing a wide range of interactions and competitive processes, with the first event observed at the interface between a contact lens and tear fluid being protein adsorption. Protein adsorption on hydrogel contact lenses is a complex process involving a variety of factors relating to both the protein in question and the lens material. Among tear proteins, lysozyme is a major protein that has both antibacterial and anti inflammatory functions. Contact lens materials that have high ionicity and high water content have an increased affinity to accumulate lysozyme during wear, when compared with other soft lens materials, notably silicone hydrogel lenses. This review provides an overview of tear film proteins, with a specific focus on lysozyme, and examines various factors that influence protein deposition on contact lenses. In addition, the impact of lysozyme deposition on various ocular physiological responses and bacterial adhesion to lenses and the interaction of lysozyme with other tear proteins are reviewed. This comprehensive review suggests that deposition of lysozyme on contact lens materials may provide a number of beneficial effects during contact lens wear. PMID- 26002003 TI - Competitive Effects from an Artificial Tear Solution to Protein Adsorption. AB - PURPOSE: To compare the adsorption of lysozyme, lactoferrin, and albumin to various contact lens materials, between single-protein solutions and a multicomponent artificial tear solution (ATS). Additionally, extra steps were taken to distinguish loosely and tightly bound protein, the latter of which may be fully or partially denatured. METHODS: Using a previously described ATS, we measured the time-dependent adsorption of lys, lac, and alb onto one conventional hydrogel and four silicone hydrogel contact lens materials between the first minute and up to 1 week of protein interaction with the material surface. Proteins were quantified using I radiolabeling of each protein individually in ATS and buffered saline. Extra steps were taken to limit the amount of unbound I and to quantify the amount of reversibly bound protein. RESULTS: Comfilcon A, balafilcon A, and etafilcon A did not show any relevant competitive adsorption between the ATS components and lys, lac, or alb until after 1 week. Competitive adsorption effects for lys, lac, and alb were observed in as little as 1 minute on lotrafilcon B. Lotrafilcon B had no reversibly bound protein at any time points. The ionic materials balafilcon A and etafilcon A deposited significant amounts of reversibly bound lysozyme and lactoferrin in just 10 minutes. Senofilcon A apparent deposition was below our thresholds of confidence for this protein quantification method. CONCLUSIONS: Both the competition between lys, lac, and alb and ATS components and the reversibility of these bound proteins is material specific. Coadsorption of lys, lac, and alb with ATS components can increase the reversibility of their adsorption. PMID- 26002004 TI - Microincision versus Standard Corneal Incision Phacoemulsification: Visual Outcome. AB - PURPOSE: To compare the visual outcome of microincision (2.2 mm) with standard (2.75 mm) corneal incision phacoemulsification. METHODS: In this prospective, randomized comparative study, patients with senile cataract and less than 1 diopter (D) of astigmatism were divided into two groups. Group 1 included patients undergoing phacoemulsification with 2.2 mm clear corneal incision and group 2 included those undergoing phacoemulsification with 2.75 mm incision. The steep axis measured on keratometry was marked preoperatively. Phacoemulsification was performed through clear corneal incision on this steep axis. Assessment of visual acuity (distance and near), keratometry, keratometric cylinder, contrast sensitivity by Functional Acuity Contrast Test, and surgically induced astigmatism (SIA) was performed at 1 day, 1 week, and 1, 3, and 6 months. RESULTS: Fifty eyes of 50 patients were included in the study (29 were male). There were 25 patients in each group. The mean (+/-SD) SIA calculated by vector analysis method (Holladay-Cravy-Koch) using keratometry value, at the end of 6 months, was 0.54 (+/-0.18) D and 0.58 (+/-0.14) D in groups 1 and 2, respectively (p = 0.27). No significant differences were found in the distance and near uncorrected visual acuity, mean keratometry, keratometric cylinder, contrast sensitivity, and SIA at any follow-up visit between two groups. CONCLUSIONS: In patients with less than 1 D astigmatism undergoing phacoemulsification, both 2.2 mm and 2.75-mm clear corneal incisions result in similar postoperative visual outcome in terms of SIA, keratometry, and contrast sensitivity. PMID- 26002005 TI - Is Pupil Diameter Influenced by Refractive Error? AB - PURPOSE: To investigate the relationship between pupil diameter and refractive error and how refractive correction, target luminance, and accommodation modulate this relationship. METHODS: Sixty emmetropic, myopic, and hyperopic subjects (age range, 18 to 35 years) viewed an illuminated target (luminance: 10, 100, 200, 400, 1000, 2000, and 4100 cd/m) within a Badal optical system, at 0 diopters (D) and -3 D vergence, with and without refractive correction. Refractive error was corrected using daily disposable contact lenses. Pupil diameter and accommodation were recorded continuously using a commercially available photorefractor. RESULTS: No significant difference in pupil diameter was found between the refractive groups at 0 D or -3 D target vergence, in the corrected or uncorrected conditions. As expected, pupil diameter decreased with increasing luminance. Target vergence had no significant influence on pupil diameter. In the corrected condition, at 0 D target vergence, the accommodation response was similar in all refractive groups. At -3 D target vergence, the emmetropic and myopic groups accommodated significantly more than the hyperopic group at all luminance levels. There was no correlation between accommodation response and pupil diameter or refractive error in any refractive group. In the uncorrected condition, the accommodation response was significantly greater in the hyperopic group than in the myopic group at all luminance levels, particularly for near viewing. In the hyperopic group, the accommodation response was significantly correlated with refractive error but not pupil diameter. In the myopic group, accommodation response level was not correlated with refractive error or pupil diameter. CONCLUSIONS: Refractive error has no influence on pupil diameter, irrespective of refractive correction or accommodative demand. This suggests that the pupil is controlled by the pupillary light reflex and is not driven by retinal blur. PMID- 26002006 TI - Comparison of Whole Eye versus First-Surface Astigmatism in Down Syndrome. AB - PURPOSE: Subjects with Down syndrome have structural differences in the cornea and lens, as compared with the general population. This study investigates objectively measured refractive and corneal astigmatism, as well as calculated internal astigmatism in subjects with and without Down syndrome. METHODS: Refractive (Grand Seiko autorefraction) and anterior corneal astigmatism (difference between steep and flat keratometry obtained with Zeiss Atlas corneal topography) were measured in 128 subjects with Down syndrome (mean [+/-SD] age, 24.8 [+/-8.7] years) and 137 control subjects without Down syndrome (mean [+/-SD] age, 24.9 [+/-9.9] years), with one eye randomly selected for analysis per subject. Refractive astigmatism and corneal astigmatism were converted to vector notation (J0, J45) to calculate internal astigmatism (Refractive - Corneal) and then converted back to minus cylinder form. RESULTS: Mean [+/-SD] refractive astigmatism was significantly greater in subjects with Down syndrome than in control subjects (-1.94 [+/-1.30] DC vs. -0.66 [+/-0.60] DC, t = -10.16, p < 0.001), as were mean corneal astigmatism (1.70 [+/-1.04] DC vs. 1.02 [+/-0.63] DC, t = 6.38, p < 0.001) and mean internal astigmatism (-1.07 [+/-0.68] DC vs. 0.77 [+/-0.41] DC, t = -4.21, p < 0.001). A positive linear correlation between corneal and refractive astigmatism was observed for both study populations for both the J0 and J45 vectors (p < 0.001 for all comparisons; R(2) range, 0.31 to 0.74). The distributions of astigmatism orientation differed significantly between the two study populations for comparisons of corneal and calculated internal astigmatism (chi(2), p < 0.007), but not refractive astigmatism (p = 0.46). CONCLUSIONS: This study demonstrates that corneal astigmatism is predictive of overall refractive astigmatism in subjects with Down syndrome, as it is in the general population. The greater magnitudes of astigmatism and wider variation of astigmatism orientation in subjects with Down syndrome for refractive, corneal, and calculated internal astigmatism are likely attributable to previously reported differences in the structure of the cornea and internal optical components of the eye from that of the general population. PMID- 26002007 TI - Corneal Bullous Epithelial Detachment in Diabetic Cataract Surgery. AB - PURPOSE: Diabetic keratopathy is an ocular complication secondary to diabetes. Patients receiving ocular surgery have an increased risk for intraoperative and postoperative corneal complications, and the preexisting keratopathy aggravation may impact postoperative visual quality. We observed a rare case of corneal complication during cataract surgery and analyzed the possible pathogenesis and methods to avoid occurrence. CASE REPORT: A 64-year-old male diabetic patient received routine phacoemulsification (phaco) in the right eye. After the phaco handpiece entered the anterior chamber and irrigation was begun, the corneal epithelium detached and a bleb was formed, expanding to the entire cornea, and then wrinkled along the limbus for the remainder of the surgery. On the first day postoperatively, diffuse corneal edema occurred with Descemet membrane striae, and the corneal epithelium detached on a large scale. Within 2 weeks, the cornea was clear with adherent epithelium and smooth Descemet membrane. CONCLUSIONS: To our knowledge, intraoperative epithelial detachment during cataract surgery is rare. Because elevated glucose changes the normal corneal structure, surgery such as phaco might also cause unpredictable corneal lesions. To avoid this possibility, serum glucose control before surgery and careful performance during surgery are essential. PMID- 26002008 TI - YAG Laser Membranotomy for Subinternal Limiting Membrane Hemorrhage. AB - PURPOSE: To report the use of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser internal limiting membranotomy to successfully treat the first reported case of subinternal limiting membrane (sub-ILM) hemorrhage that developed after coil embolization of a cerebral aneurysm. CASE REPORT: A 59-year-old Korean woman visited our clinic complaining of central scotoma in her left eye, which developed shortly after stent-assisted coil embolization of an unruptured internal carotid artery aneurysm. Fundus examination revealed a sub-ILM hemorrhage in her left eye, and after 2 days, a Nd:YAG laser membranotomy was performed with a single 4.5-mJ burst. There was a marked reduction in the sub-ILM hemorrhage 1 day after Nd:YAG laser membranotomy, and after 1 month, her best corrected visual acuity improved to 20/20, with complete resolution of the sub ILM hemorrhage. CONCLUSIONS: Sub-ILM hemorrhage can develop after coil embolization of a cerebral aneurysm, and Nd:YAG laser internal limiting membranotomy can be a useful noninvasive treatment alternative to surgical intervention. PMID- 26002009 TI - Variability of Corneal Deformation Response in Normal and Keratoconic Eyes. AB - PURPOSE: To compare the corneal deformation response, central corneal thickness (CCT), and intraocular pressure (IOP) measurements and their test-retest variability obtained with an ultrahigh-speed Scheimpflug camera between normal and keratoconus eyes. METHODS: Three consecutive measurements were obtained using Corvis ST. The following parameters were analyzed: A1 and A2 length (length of flattened cornea at first and second applanation), A1 and A2 velocity (deformation velocity until first and second applanation), corneal deformation amplitude (deformation amplitude of cornea at the highest concavity), peak distance (distance of two apices of cornea at time of highest concavity), and radius of corneal curvature at the time of maximum deformation. Repeatability coefficient and intraclass correlation coefficient were measured. Linear mix models were used to adjust for the effect of age, CCT, and IOP on corneal deformation response parameters. RESULTS: Twelve normal subjects and 12 keratoconus patients were included. Data from only one eye of each participant were randomly selected for analysis. Significant differences were found in corneal deformation amplitude (p < 0.001) and radius of corneal curvature (p < 0.001) between normal and keratoconus eyes after adjusting for age, CCT, and IOP. Although there was no significant difference of intraclass correlation coefficient between the groups, repeatability coefficient values of A1 and A2 length, A1 velocity, and peak distance were significantly smaller in normal eyes as compared with keratoconus eyes (p <= 0.023). CONCLUSIONS: Corvis ST showed adequate repeatability for measurement of corneal deformation amplitude, CCT, and IOP in normal and keratoconus eyes. It may be used to understand ocular pathologies associated with altered biomechanical properties. PMID- 26002010 TI - The Charles F. Prentice Award Lecture 2014: A 50-Year Research Journey: Giants and Great Collaborators. AB - This article, an edited version of the 2014 Charles F. Prentice Medal presentation, recounts my 50-year journey in research, from graduation in 1965 to PhD to 2015. The most important lessons I have learned are that great people, "Giants" as I call them, are generous of spirit, creative, insightful, sharing, and caring, and second, that collaboration is really the only way to do what I want to get done. I have been very fortunate to have worked with many outstanding people. As someone said to me at the Prentice Medal presentation, "I don't like you very much but the people you work with are wonderful."My journey started with a PhD investigation into seeing if orthokeratology could control myopia at the City University London in 1966. It then moved to Australia where all aspects of contact lenses were researched to try to make contact lenses safer and more effective by understanding the cornea and anterior eye systems. That journey has now turned to making contact lenses the best they can be to slow the progress of myopia. An extremely high proportion of people who are involved with global eye care initiatives and ambitious projects to develop treatments and interventions for the major vision problems impacting the world are a joy to work with. Evidence-based systems for delivering vision to the more than 600 million people globally that are blind or vision impaired because of uncorrected refractive error have involved amazing people and collaborations. This article pays tribute to the generosity and humanity of my family and the Giants in and outside the field, and many more not so well known, and the people I work with, who have punctuated and greatly enriched this journey and made many of the scientific advances documented here possible. PMID- 26002011 TI - Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis. AB - Glioma represents a disparate group of tumors characterized by high invasion ability, and therefore it is of clinical significance to identify molecular markers and therapeutic targets for better clinical management. Previously, metastasis-associated protein family (MTA) is considered to promote tumor cell invasion and metastasis of human malignancies. Recently, the newly identified MTA3 has been shown to play conflicting roles in human malignancies, while the expression pattern and potential clinical significance of MTA3 in human glioma have not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay and analyzed its association with glioma prognosis in 186 cases of patients. Results showed that MTA3 expression was decreased in glioma compared with that in normal brain (P < 0.05). In addition, tumors with high MTA3 expression were more likely to be of low WHO grade (P = 0.005) and reserve of body function (P = 0.014). Survival analysis showed that decreased MTA3 expression was independently associated with unfavorable overall survival of patients (P < 0.001). These results provide the first evidence that MTA3 expression was decreased in human glioma and negatively associated with prognosis of patients, suggesting that MTA3 may play a tumor suppressor role in glioma. PMID- 26002012 TI - Antimicrobial photodynamic therapy: a promise candidate for caries lesions treatment. AB - BACKGROUND: Antibacterial photodynamic therapy (aPDT) is a promising adjunctive therapy to the treatment of caries lesions, mainly in the minimally invasive approach to preserve dental tissue and favor its repair. Here we analyzed both the efficacy of aPDT in reducing the bacterial load in cariogenic biofilms and the indirect effect of noxious components produced by aPDT on the viability of dental pulp cells. METHODS: The aPDT protocol was established using 0.025g/mL methylene blue (MB) and 5min pre-irradiation time. A continuous-wave diode laser (660nm, 0.04cm(2) spot size, 40mW, 60s, 60J/cm(2) and 2.4J) was used in punctual and distance modes to excite the MB. The protocol was first tested against Streptococcus mutans (U159) biofilms produced in 96-well microplates, and then evaluated on caries-like affected human dentin discs of three thicknesses. The number of colony forming units (CFU) was compared between groups. Discs were then assembled in metallic inserts to produce an artificial pulp chamber and allow investigation of the indirect effects of aPDT on dental pulp cells by the 3-(4,5 dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay. Data were analyzed using Student's t test or one-way analysis of variance (ANOVA) followed by the Tukey's test at a significance level of 5%. RESULTS: Bacterial load reduction was observed in biofilms produced both in the microplates (p<0.05) and on the caries like affected dentin discs (81.01% or mean reduction of log21.010+/-0.1548; p=0.0029). The cell viability of aPDT and control group was similar (p>0.05). CONCLUSIONS: aPDT may be considered a promise adjunctive therapy for deep carious lesions. PMID- 26002013 TI - Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database. AB - BACKGROUND: The current study aims to determine cause-specific survival in patients with high-grade osteosarcoma while reporting risk factors for decreased survival out to 10 years. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify all patients diagnosed with high-grade osteosarcoma from 1991 to 2010. Patient, tumor, and county-level socioeconomic measures were analyzed to determine prognostic factors for survival. RESULTS: Cause-specific 10-year survival for patients with local/regional disease at the time of diagnosis was 65.8%, compared to 24.0% for patients with metastatic disease. Multivariate analysis revealed metastatic disease at presentation, age>=60 years, male sex, axial location, and size>=10cm as independent risk factors for decreased cause-specific survival at 10 years. Patients with the lowest socioeconomic status had a disproportionate frequency of metastatic disease and large tumors at presentation as compared to more affluent patients. CONCLUSIONS: Patients with high-grade osteosarcoma have decreased cause specific survival at 10 years when metastatic at diagnosis, patient age>=60 years, male sex, axial tumor location, and tumors measuring>=10cm. Patients living in low socioeconomic counties present more frequently with metastatic disease and large tumors. Public health efforts should focus on identifying patients with osteosarcoma prior to metastasis. PMID- 26002014 TI - Visual determination of aliphatic diamines based on host-guest recognition of calix[4]arene derivatives capped gold nanoparticles. AB - Since amine compounds have been widespread pollutants in nature and they are extensively used in pharmaceutical industries and dye manufacturing, it is highly desirable to develop simple, effective and naked-eye available analytical methods for such aliphatic diamines determination. Calixarenes as macrocycles have drawn intensive interests for fields such as biomedicine, supramolecular chemistry and smart materials. Here, instead of the normal complicated modification strategy, a facile and efficient method for one-pot synthesis of calix[4]arene crown ether (CCE4) capped gold nanoparticles (AuNPs) is proposed. The as-prepared CCE4-AuNPs are not only high water dispersity and stability even after storage for 3 months, but also capable of host-guest recognition of diamines in aqueous systems. Size selective encapsulation of amine group between CCE4 and diamines carry out the aggregation of CCE4-AuNPs. The determination of diamines such as hexamethylenediamine or spermine can be realized by the UV-vis absorbance change and visual color difference. PMID- 26002015 TI - Graphene electrode modified with electrochemically reduced graphene oxide for label-free DNA detection. AB - A novel printed graphene electrode modified with electrochemically reduced graphene oxide was developed for the detection of a specific oligonucleotide sequence. The graphene oxide was immobilized onto the surface of a graphene electrode via pi-pi bonds and electrochemical reduction of graphene oxide was achieved by cyclic voltammetry. A much higher redox current was observed from the reduced graphene oxide-graphene double-layer electrode, a 42% and 36.7% increase, respectively, in comparison with that of a bare printed graphene or reduced graphene oxide electrode. The good electron transfer activity is attributed to a combination of the large number of electroactive sites in reduced graphene oxide and the high conductivity nature of graphene. The probe ssDNA was further immobilized onto the surface of the reduced graphene oxide-graphene double-layer electrode via pi-pi bonds and then hybridized with its target cDNA. The change of peak current due to the hybridized dsDNA could be used for quantitative sensing of DNA concentration. It has been demonstrated that a linear range from 10(-7)M to 10(-12)M is achievable for the detection of human immunodeficiency virus 1 gene with a detection limit of 1.58 * 10(-13)M as determined by three times standard deviation of zero DNA concentration. PMID- 26002016 TI - Multi-color quantum dot-based fluorescence immunoassay array for simultaneous visual detection of multiple antibiotic residues in milk. AB - Antibiotic residues, which are among the most common contaminants in animal-based food products such as milk, have become a significant public health concern. Here, we combine a multicolor quantum dot (QD)-based immunofluorescence assay and an array analysis method to achieve simultaneous, sensitive and visual detection of streptomycin (SM), tetracycline (TC), and penicillin G (PC-G) in milk. Antibodies (Abs) for SM, TC and PC-G were conjugated to QDs with different emission wavelengths (QD 520 nm, QD 565 nm and QD 610 nm) to serve as detection probes (QD-Ab). Then a direct competitive fluorescent immunoassay was performed in antigen-coated microtiter plate wells for simultaneous qualitative and quantitative detection of SM, TC, and PC-G residues, based on fluorescence of the QD-Ab probes. The linear ranges for SM, TC and PC-G were 0.01-25 ng/mL, 0.01-25 ng/mL and 0.01-10 ng/mL, respectively, with detection limit of 5 pg/mL for each of them. Based on fluorescence of the QD-Ab probes, residues of the three antibiotics were determined visually and simultaneously. Compared with a commercial enzyme-linked immunosorbent assay kit, our method could achieve simultaneous analysis of multiple target antibiotics in multiple samples in a single run (high-throughput analysis) and improved accuracy and sensitivity for analysis of residues of the three antibiotics in authentic milk samples. This new analytical tool can play an important role in ameliorating the negative impact of the residual antibiotics on human health and the ecosystem. PMID- 26002017 TI - A label-free fluorescent biosensor for ultratrace detection of terbium (sh) based on structural conversion of G-quadruplex DNA mediated by ThT and terbium (sh). AB - In this paper, a novel label-free fluorescent biosensor for terbium (sh) (Tb(3+)) was proposed based on structural conversion of G-quadruplex DNA mediated by Thioflavin T (ThT) and Tb(3+). In the presence of K(+), ThT could bind to K(+) stabilized parallel G-quadruplex, giving rise to high fluorescence intensity. Upon the addition of Tb(3+), Tb(3+) could competitively bind to parallel G quadruplex leading to the structural change, which resulted in fluorescence decrease. The change of fluorescence intensity (DeltaF=F0-F) showed a good linear response toward the concentration of Tb(3+) over the range from 1.0 pM to 10.0 uM with a limit of detection of 0.55 pM. This proposed biosensor was simple and cost effective in design and in operation with ultrahigh sensitivity and selectivity. Thus, the proposed biosensor could be a promising candidate for monitoring ultratrace Tb(3+) in environment. PMID- 26002018 TI - Nickel oxide and carbon nanotube composite (NiO/CNT) as a novel cathode non precious metal catalyst in microbial fuel cells. AB - Comparing with the precious metal catalysts, non-precious metal catalysts were preferred to use in microbial fuel cells (MFCs) due to the low cost and high oxygen reduction reaction (ORR) efficiency. In this study, the transmission electron microscope and X-ray diffraction as well as Raman investigation revealed that the prepared nanoscale NiO was attached on the surface of CNT. Cyclic voltammogram and rotating ring-disk electrode tests showed that the NiO/CNT composite catalyst had an apparent oxygen reduction peak and 3.5 electron transfer pathway was acquired under oxygen atmosphere. The catalyst performance was highly dependent on the percentage of NiO in the CNT nanocomposites. When 77% NiO/CNT nano-sized composite was applied as cathode catalyst in membrane free single-chamber air cathode MFC, a maximum power density of 670 mW/m(2) and 0.772 V of OCV was obtained. Moreover, the MFC with pure NiO (control) could not achieve more than 0.1 V. All findings suggested that NiO/CNT could be a potential cathode catalyst for ORR in MFCs. PMID- 26002019 TI - Non-enzymatic detection of urea using unmodified gold nanoparticles based aptasensor. AB - Biosensing nitrogenous compounds like urea is required to control the incidents of Economically Motivated Adulteration (EMA). In this study, we report the FluMag Systematic Evolution of Ligands by Exponential Enrichment (FluMag-SELEX) method to isolate a urea specific DNA aptamer with a dissociation constant (Kd) of 232 nM. The interaction of DNA aptamer with urea has been confirmed by affinity assay, CD analysis, melting curve analysis and truncation studies. Unlike other urea sensing methods reported so far, using this urea aptamer, we demonstrate a simple, 'non-enzymatic' easy-to-use, dual readout aptasensor that exploits unmodified gold nanoparticles (AuNPs) to transduce the signals of aptamer binding to urea in terms of intrinsic fluorescence differences and color changes simultaneously. This method is free from complicated sample processing and labeling steps. The urea aptasensor displays high selectivity for urea and is free from interference from common milk adulterants. The developed aptasensor reliably detects urea adulteration in milk. The response signals linearly correlate with the increasing concentrations of urea in milk ranging from 20mM to 150 mM with detection limit of 20mM. We also show that this aptasensor can also be used as a simple fluorescence based "turn-on" sensor. The results obtained in this study are comparable to the commercial urease based detection methods. PMID- 26002020 TI - [Diabetes, prediabetes and cardiovascular risk]. AB - Cardiovascular diseases continue to be the mainstay in morbidity and mortality in modern society with diabetes mellitus being a known risk factor for coronary artery disease, heart failure and vascular events. Most patients present with a combination of hypertension, dyslipoproteinaemia and (pre)diabetic metabolism potentiating the risk. From the perspective of organ damage two of three patients with coronary artery disease present with impaired glucose metabolism. In case of myocardial infarction 25-28% of patients do not present with impaired glucose metabolism. Women are more often affected than men and exhibit a more severe outcome, if diagnoses of vascular events and diabetes occur in parallel. Atrial fibrillation and heart failure are significantly associated with diabetes and significantly confer to the overall prognosis. Epidemiologically, the risk for vascular events is closely associated with the glucose burden of the affected patient. PMID- 26002021 TI - Distinct kinetics and pathways of apoptosis in influenza A and B virus infection. AB - Annual influenza epidemics are associated with high incidence and mortality rates, and are an important cause of work absenteeism and productivity losses. For successful replication, influenza viruses have evolved as to counteract and/or take a part on host defense mechanisms. Manipulation of apoptosis is one of such mechanisms that have been subject of attention, particularly in relation to influenza type A viruses over the past years. However, this knowledge has not been extended to include influenza type B viruses. In this study, MDCK-SIAT1 cells were infected with influenza A and B strains and the kinetics and pathways of apoptosis post infection were studied, through LDH measurements, Hoechst dye staining, caspase activity assays and protein expression analysis. The resulting data points to a difference in induction of apoptosis profiles between influenza A and B strains. While influenza A strain induced apoptosis later in the course of infection and mainly by the intrinsic pathway, influenza B strain induced apoptosis early in infection by both intrinsic and extrinsic pathways. Also, data revealed the IkappaB/NF-kappaB pathway as the major contributor for the observed differences. The study of the virus-host interactions, particularly those that could have an impact on viral replication, are essential in both influenza A and B viruses, as they will allow the identification of viral/host targets common to both influenza types, which could affect viral replication. This information may prove useful for vaccine and antiviral research. PMID- 26002022 TI - The intestinal microbiome in spondyloarthritis. AB - PURPOSE OF REVIEW: Microbial dysbiosis in the gut is emerging as a common component in various inflammatory disorders including spondyloarthritis (SpA). The depth of this influence has begun to be realized with next-generation sequencing of the gut microbiome providing unbiased assessment of previously uncharted bacterial populations. RECENT FINDINGS: Decreased numbers of Firmicutes, a major phyla of gut commensals, especially the species Faecalibacterium prausnitzii and Clostridium leptum have been found in various inflammatory disorders including SpA and inflammatory bowel disease (IBD), and could be an important link between SpA and gut inflammation. Multiple studies in ankylosing spondylitis, psoriatic arthritis, juvenile SpA, and animal models of SpA are revealing common bacterial associations among these diseases as well as IBD. SUMMARY: We are beginning to appreciate the complex relationship between the gut microbiome and host immune regulation and dysregulation in health and disease. Potentially important differences have been revealed in SpA, but cause and effect relationships remain far from established. Many critical questions remain to be answered before we can apply new knowledge to improve therapeutics in SpA. PMID- 26002023 TI - Syndesmophyte growth in ankylosing spondylitis. AB - PURPOSE OF REVIEW: Syndesmophytes are characteristic components of the spine disorder of ankylosing spondylitis. Understanding their growth may reveal insights to pathogenesis and potential treatment. We review recent studies on rates of development of syndesmophytes, patient characteristics associated with more rapid syndesmophyte growth, local vertebral abnormalities that precede syndesmophytes, systemic biomarkers of syndesmophytes, and studies of medications. RECENT FINDINGS: New syndesmophytes develop in one-third of patients over 2 years. Consistent clinical predictors are male sex, elevated serum C reactive protein levels, and preexisting syndesmophytes. Concomitant vertebral inflammation and fat dysplasia on MRI predict future syndesmophytes at the same vertebral location, but most syndesmophytes do not have recognized antecedents. Associations with serum levels of Wingless pathway proteins are inconsistent, as are the results of observational studies of tumor necrosis factor-alpha inhibitors. SUMMARY: Although there is better understanding of the frequency of syndesmophyte development, the pathogenesis of syndesmophytes remains unclear. PMID- 26002024 TI - Novel imaging modalities in spondyloarthritis. AB - PURPOSE OF REVIEW: The role of imaging in the diagnosis, management, and follow up of patients with spondyloarthritis (SpA) has become dramatically more important with the introduction of new therapies such as tumor necrosis factor alpha inhibitors. In the current review, contemporary perspectives on developments and advancements in the field of SpA imaging along with several novel imaging techniques for the diagnosis and follow-up of SpA will be discussed. RECENT FINDINGS: No new imaging modalities have been introduced in the last decade. However, new advances and improvements within the known modalities are constantly being presented and tested. Such advances include the use of contrast material and sonoelastography in the ultrasound evaluation of enthesitis, hybridization of PET imaging with computed tomography and MRI for the evaluation of the axial and peripheral skeleton, as well as advances within MRI such as whole-body MRI and diffusion-weighted sequences. These techniques will be presented and their advantages and disadvantages will be critically discussed. SUMMARY: Promising new techniques in the field of SpA imaging are constantly emerging. The benefits and advantages of the presented techniques over the known ones need further validation. PMID- 26002025 TI - Biomarkers in axial spondyloarthritis. AB - PURPOSE OF REVIEW: To assess the literature for biomarker validation studies that address key unmet needs related to the evaluation and management of patients with axial spondyloarthritis (SpA). This review focused on biomarkers facilitating early diagnosis and reflecting disease activity, structural damage on radiography, and clinical response to major therapies. RECENT FINDINGS: Early diagnosis may be facilitated by measurement of antibodies to the human leukocyte antigen class II-associated invariant chain peptide (anti-CD74) but sensitivity declines with increasing duration of disease. No disease activity biomarkers have demonstrated consistent superiority over standard C-reactive protein (CRP), and future validation should employ multivariate analysis aimed at demonstrating the added value of any associated biomarkers beyond available clinical parameters of disease activity and the use of magnetic resonance imaging inflammation as the primary endpoint. Several biomarkers reflecting inflammation (CRP and calprotectin), angiogenesis (vasoactive endothelial growth factor), and connective tissue turnover (C2 M, C3 M, and citrullinated metalloproteinase degraded fragment of vimentin ) have recently been shown to reflect radiographic progression in multivariate studies adjusted for baseline severity. Future studies should be prospective and demonstrate that predictive capacity adds to the information provided by known predictors such as CRP and baseline modified Stoke AS Spine Score. Calprotectin is a promising predictor of response to major therapies for axial SpA. SUMMARY: Several promising biomarkers addressing major unmet clinical needs require further validation in prospective studies. PMID- 26002026 TI - Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics. AB - PURPOSE OF REVIEW: This article will review the genetic evidence implicating ERAP1, which encodes the endoplasmic reticulum-associated amino-peptidase 1, in susceptibility to rheumatic disease. RECENT FINDINGS: Genetic variants and haplotypes of ERAP1 are associated with AS, psoriasis, and Behcet's disease in people of varying ancestries. In each of these diseases, disease-associated variants of ERAP1 have been shown to interact with disease-associated class I human leukocyte antigen alleles to influence disease risk. Functionally, disease associated missense variants of ERAP1 concertedly alter ERAP1 enzymatic function, both quantitatively and qualitatively, whereas other disease-associated variants influence ERAP1 expression. Therefore, ERAP1 haplotypes (or allotypes) should be examined as functional units. Biologically, this amounts to an examination of the gene regulation and function of the protein encoded by each allotype. Genetically, the relationship between disease risk and ERAP1 allotypes should be examined to determine whether allotypes or individual variants produce the most parsimonious risk models. SUMMARY: Future investigations of ERAP1 should focus on comprehensively characterizing naturally occurring ERAP1 allotypes, examining the enzymatic function and gene expression of each allotype, and identifying specific allotypes that influence disease susceptibility. PMID- 26002027 TI - Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional variation. AB - PURPOSE OF REVIEW: To review the recent developments in our understanding of endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) function in relation to its role in major histocompatibility complex (MHC) class I peptide presentation and human leukocyte antigen (HLA) class I-associated diseases. RECENT FINDINGS: ERAP1 polymorphisms exhibiting loss-of-function have been associated with protection from AS. The aminopeptidase function of ERAP1 optimizes peptides for binding and presentation by MHC class I. Most of the studies have revealed reduced MHC class I expression in situations of reduced ERAP1 function. Under these circumstances, the presented peptides are often N-terminally extended, and cell surface complexes are unstable and fall apart more readily. In contrast, peptides presented by HLA-B*27 : 05 when ERAP1 is silenced are frequently extended on the C-terminus. Recent work has emphasized on the importance of assessing the function of allotypes encoded by ERAP1 haplotypes, rather than effects of single amino acid substitutions. The allotypes found in a series of AS patients were poorer at restoring HLA-B27 expression than allotypes found in unaffected controls, which may seem contrary to the genetic data linking loss-of-function to protection. SUMMARY: More work is needed to understand how ERAP1 variants associated with risk and protection influence the quality and quantity of peptides available for binding to HLA class I molecules in the ER. Moreover, we need to determine allele-specific effects of ERAP1 variants in the context of HLA B*51 and HLA-Cw*6, which are associated with Behcet's disease and psoriasis, respectively. PMID- 26002029 TI - Influence and effect of the human microbiome in allergy and asthma. AB - PURPOSE OF REVIEW: Studies have illustrated that the healthy human microbiome (i.e. the communities of microbes, their genomic content and interaction with the host) plays a role in the maintenance of immune homeostasis. Perturbation of these communities is an emerging characteristic of an increasing number of inflammatory diseases. The goal of this article is to review the current literature on both respiratory and gut microbiomes and their established relationship with allergy and asthma. RECENT FINDINGS: Multiple studies have demonstrated airway microbiota dysbiosis, characterized by Proteobacteria expansion in the lower airways, to be a consistent trait of established adult asthma. Members of this phylum are associated with disease features such as bronchial hyperreactivity or corticosteroid resistance. Emerging evidence implicates the neonatal gut microbiome as playing a significant role in the development of childhood atopy, a common precursor to asthma. Murine studies have demonstrated that specific bacterial species (e.g. Lactobacillus johnsonii, Bacteroides fragilis) and microbial metabolites (e.g. the short-chain fatty acid propionate), when supplemented to animals, confer protection against allergen induced airway disorders. SUMMARY: The emerging view of atopy and asthma is one consistently related to inappropriate microbial community composition and function in both the airway and gastrointestinal tract. This opens up the possibility that strategies to rationally manipulate microbiota at these sites may represent a novel approach to disease prevention or management. PMID- 26002028 TI - Juvenile spondyloarthritis. AB - PURPOSE OF REVIEW: This article provides a comprehensive update of the pathogenesis, diagnostic imaging, treatments, and disease activity measurements of juvenile spondyloarthritis (JSpA). RECENT FINDINGS: Genetic and microbiome studies have provided new information regarding possible pathogenesis of JSpA. Recent work suggests that children with JSpA have decreased thresholds for pain in comparison to healthy children. In addition, pain on physical examination and abnormalities on ultrasound of the entheses are not well correlated. Treatment guidelines for juvenile arthritis, including JSpA, were published by the American College of Rheumatology and are based on active joint count and presence of sacroiliitis. Recent studies have established the efficacy of tumor necrosis factor inhibitors in the symptomatic treatment of axial disease, although their efficacy for halting progression of structural damage is less clear. Newly developed disease activity measures for JSpA include the Juvenile Arthritis Disease Activity Score and the JSpA disease activity index. In comparison to other categories of juvenile arthritis, children with JSpA are less likely to attain and sustain inactive disease. SUMMARY: Further microbiome and genetic research may help elucidate JSpA pathogenesis. More randomized therapeutic trials are needed and the advent of new composite disease activity measurement tools will hopefully allow the design of these greatly needed trials. PMID- 26002031 TI - The gut microbiota and inflammatory bowel disease. AB - PURPOSE OF REVIEW: Inflammatory bowel diseases (IBDs) reflect the cooperative influence of numerous host and environmental factors, including those of elements of the intestinal immune system, the gut microbiota, and dietary habits. This review focuses on features of the gut microbiota and mucosal immune system that are important in the development and control of IBDs. RECENT FINDINGS: Gut innate type immune cells, including dendritic cells, innate lymphoid cells, and mast cells, educate acquired-type immune cells and intestinal epithelial cells to achieve a symbiotic relationship with commensal bacteria. However, perturbation of the number or type of commensal microorganisms and endogenous genetic polymorphisms that affect immune responses and epithelial barrier system can ultimately lead to IBDs. Providing beneficial bacteria or fecal microbiota transplants helps to reestablish the intestinal environment, maintain its homeostasis, and ameliorate IBDs. SUMMARY: The gut immune system participates in a symbiotic milieu that includes cohabiting commensal bacteria. However, dysbiotic conditions and aberrations in the epithelial barrier and gut immune system can disrupt the mutualistic relationship between the host and gut microbiota, leading to IBDs. Progress in our molecular and cellular understanding of this relationship has yielded numerous insights regarding clinical applications for the treatment of IBDs. PMID- 26002030 TI - The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity. AB - PURPOSE OF REVIEW: This review will highlight recent advances functionally linking the gut microbiome with mucosal and systemic immune cell activation underlying autoimmunity. RECENT FINDINGS: Dynamic interactions between the gut microbiome and environmental cues (including diet and medicines) shape the effector potential of the microbial organ. Key bacteria and viruses have emerged that, in defined microenvironments, play a critical role in regulating effector lymphocyte functions. The coordinated interactions between these different microbial kingdoms - including bacteria, helminths, and viruses (termed transkingdom interactions) - play a key role in shaping immunity. Emerging strategies to identify immunologically relevant microbes with the potential to regulate immune cell functions both at mucosal sites and systemically will likely define diagnostic and therapeutic targets. SUMMARY: The microbiome constitutes a critical microbial organ with coordinated interactions that shape host immunity. PMID- 26002032 TI - Evidence for a vascular microbiome and its role in vessel health and disease. AB - PURPOSE OF REVIEW: We have summarized available evidence for and against the presence of a vascular microbiome. Studies that have attempted to detect bacteria and viruses in blood vessels in both health and disease are critiqued in an attempt to explain contrary results that may be due to variations in methodology. RECENT FINDINGS: Many studies have demonstrated the presence of both bacteria and viruses within diseased blood vessels. Evidence is most compelling in atherosclerosis; however, recent reports have raised questions about the potential role of microbes in nonatherosclerotic aortic aneurysms and vasculitis. Preliminary evidence also suggests that apparently normal vessels may harbor microbes. With the exception of certain viral infections (e.g. hepatitis C virus, HIV, Epstein-Barr virus, and cytomegalovirus) and infectious endocarditis, systemic vasculitides have not been convincingly associated with infectious agents. However, emerging data suggest that different communities of microbes may be present in noninflammatory and inflammatory large-vessel diseases. Whether variations in vascular microbial communities are the cause or a secondary result (epiphenomena) of vessel injury remains to be determined. SUMMARY: Blood vessels may not be sterile. Future studies of microbes in vessel health and disease may provide important insights into disease pathogenesis and suggest new therapies for diseases now considered to be idiopathic and refractory. PMID- 26002033 TI - Role of cortical bone in bone fragility. AB - PURPOSE OF REVIEW: Trabecular bone loss and vertebral fractures are historical hallmarks of osteoporosis. During the past 70 years, this view has dominated research aiming to understand the structural basis of bone fragility. We suggest this notion needs to be revised to recognize and include the role of cortical bone deterioration as an important determinant of bone strength throughout life. RECENT FINDINGS: About 80% of the fragility fractures involve the appendicular skeleton, at regions comprising large amounts of cortical bone. Up to 70% of the age-related bone loss at these locations is the result of intracortical remodeling that cavitates cortical bone producing porosity. It is now possible to accurately quantify cortical porosity in vivo and use this information to understand the pathogenesis of bone fragility throughout life, assist in identifying patients at risk for fracture, and use this as a potential marker to monitor the effects of treatment on bone structure and strength. SUMMARY: Cortical bone has an important role in determining bone strength. The loss of strength is the result of intracortical and endocortical remodeling imbalance that produces cortical porosity and thinning. Studies are needed to determine whether porosity is an independent predictor of fracture risk and whether a reduction in porosity serves as a surrogate of antifracture efficacy. PMID- 26002034 TI - Obesity and fractures in postmenopausal women. AB - PURPOSE OF REVIEW: Although obesity was previously believed to be protective against fracture, there is now evidence that a significant proportion of fractures in postmenopausal women occur in those who are obese. RECENT FINDINGS: In this article the epidemiology, pathophysiology and clinical management of fractures in obese postmenopausal women are discussed with particular focus on the site specificity of the effect of BMI on fracture, interactions between fat and bone and risk assessment and prevention of fractures. There is similarity in many respects between risk factors for fracture in obese and nonobese women, although falls may play a particularly important role in the obese. Treatment rates in obese postmenopausal women with fracture are currently low, and further studies are required to establish effective preventive strategies. SUMMARY: Fractures in obese postmenopausal women contribute significantly to the overall fracture burden in this population. Further work is required to establish their pathophysiology and to develop effective preventive strategies. PMID- 26002035 TI - Subchondral bone and osteoarthritis. AB - PURPOSE OF REVIEW: Increasing evidence show that bone is a key factor in the development of osteoarthritis. This article reviews the latest results of basic and clinical research on the role of the subchondral bone in osteoarthritis. RECENT FINDINGS: Early changes in the subchondral bone can predict subsequent symptoms or disease structural progression. New tools may help clinicians to stratify different osteoarthritis phenotypes with regards to bone remodeling status. SUMMARY: The involvement of bone in osteoarthritis has long been thought to be secondary to cartilage damage as an adaptation of the joint. Recent clinical studies with MRI have demonstrated that bone changes could be observed in early stages of the disease, even preceding cartilage lesions. Moreover, there is clear evidence of an association between subchondral bone mineral density and osteoarthritis. The level of bone remodeling plays a critical role under mechanical loading conditions as demonstrated by consistent experimental studies. Yet new clinical biomarkers are being developed to assess the bone phenotype of osteoarthritic patients. This stratification strategy is likely to better identify groups of patients who would benefit from bone-acting drugs to decrease disease progression and improve pain and disability. PMID- 26002036 TI - Molecular characterization, transcriptional activity and nutritional regulation of peroxisome proliferator activated receptor gamma in Nile tilapia (Oreochromis niloticus). AB - Peroxisome proliferator activated receptor gamma (PPARgamma) is a master regulator in lipid metabolism and widely exists in vertebrates. However, the molecular structure and transcriptional activity of PPARgamma in fish are still unclear. This study cloned PPARgamma from Nile tilapia (Oreochromis niloticus) referred as NtPPARgamma and transfected the NtPPARgamma plasmids into HEK-293 cells to explore its mechanism of transcriptional regulation in fish. The expression of NtPPARgamma was compared in fed and fasted fish. Two transcripts of NtPPARgamma varied at the 5'-untranslated region and the DNA binding domain was highly conserved. Thirty-nine amino acid residues in the ligand binding domain in Nile tilapia were different from those in human. Two transcripts showed different expression profiles in 11 tissues, but both were highly expressed in liver, intestine and kidney. The transcriptional activity assay showed that NtPPARgamma collaborates with retinoid X-receptor alpha (NtRXRalpha) to regulate the expression of Nile tilapia fatty acid binding protein 4 (FABP4), the compartment of which have been identified as the target gene of PPARgamma in human. In the fish fasting trial, the mRNA expression of NtPPARgamma1 and NtPPARgamma2 in intestine and liver at 3h post-feeding (HPF) was lower than those at 8 HPF, 24 HPF and in fish fasted for 36h, but was relatively stable in kidney among different feeding treatments. In conclusion, the DNA binding domain in PPARgamma was highly conserved, while the ligand binding domain was moderately conserved. In Nile tilapia, the PPARgamma collaborates with RXRalpha to perform transcriptional regulation of FABP4 at least in vitro. The plasmid system established in this study along with a cell line from Nile tilapia will be useful tools for the further functional study of PPARgamma in fish. PMID- 26002037 TI - Gonadotropins in European sea bass: Endocrine roles and biotechnological applications. AB - Follicle stimulating hormone (Fsh) and luteinizing hormone (Lh) are central endocrine regulators of the gonadal function in vertebrates. They act through specific receptors located in certain cell types found in the gonads. In fish, the differential roles of these hormones are being progressively elucidated due to the development of suitable tools for their study. In European sea bass (Dicentrarchus labrax), isolation of the genes coding for the gonadotropin subunits and receptors allowed in first instance to conduct expression studies. Later, to overcome the limitation of using native hormones, recombinant dimeric gonadotropins, which show different functional characteristics depending on the cell system and DNA construct, were generated. In addition, single gonadotropin beta-subunits have been produced and used as antigens for antibody production. This approach has allowed the development of detection methods for native gonadotropins, with European sea bass being one of the few species where both gonadotropins can be detected in their native form. By administering recombinant gonadotropins to gonad tissues in vitro, we were able to study their effects on steroidogenesis and intracellular pathways. Their administration in vivo has also been tested for use in basic studies and as a biotechnological approach for hormone therapy and assisted reproduction strategies. In addition to the production of recombinant hormones, gene-based therapies using somatic gene transfer have been offered as an alternative. This approach has been tested in sea bass for gonadotropin delivery in vivo. The hormones produced by the genes injected were functional and have allowed studies on the action of gonadotropins in spermatogenesis. PMID- 26002038 TI - Burden of herpes zoster and post-herpetic neuralgia in Sweden. AB - BACKGROUND: The societal economic burden of herpes zoster in Sweden is not well described today. This study is a top-down analysis of Swedish registers with the objective to describe the burden of herpes zoster and post-herpetic neuralgia in Sweden during 2011. METHODS: Data for inpatient care; outpatient primary and specialized cares; the prescriptions of drugs, sick leave and the number or diagnostic tests were collected from Swedish national databases. The incidence of the disease was estimated based on the number of prescriptions of antiviral drugs. RESULTS: The incidence of herpes zoster was estimated to 315 and 577 cases per 100,000 people for patients at all ages and > = 50 years, respectively. Almost 30,000 patients at all ages were diagnosed with herpes zoster and the societal cost to treat these patients, including the cost to treat those patients who later developed post-herpetic neuralgia, added up to nearly 227 MSEK (31.6 M?) which corresponds to 7,600 SEK (?870) per patient. The main contributors to the total cost for the treatment of HZ patients were primary care (43 %); sick leave (28 %); hospitalization (10 %) and specialist care (7 %). Medication was a relatively small contributor with 8.5 MSEK (4 %; 1.0 M?) to the overall costs for patients at all ages. The corresponding total cost including only patients 50 years and older was 168 MSEK (19.2 M?) or 8,200 SEK (?939) per patient. CONCLUSIONS: The current study demonstrates that the burden of herpes zoster is significant in Sweden. The society, the health care payers and the patients potentially have a lot to gain by introducing a vaccination program to patients 50 years and older and as a consequence reduce the economic and clinical burden of herpes zoster and post-herpetic neuralgia. PMID- 26002040 TI - NICE to advise firms on how to speed up NHS adoption of their drugs. PMID- 26002039 TI - Effects of hypoxia inducible factor-1alpha on apoptotic inhibition and glucocorticoid receptor downregulation by dexamethasone in AtT-20 cells. AB - BACKGROUND: Hypoxia inducible factor-1alpha (HIF-1alpha) is the central transcriptional regulator of hypoxic responses during the progression of pituitary adenomas. Although previous immunohistochemical studies revealed that HIF-1alpha is expressed in adreno-cortico-tropic-hormone (ACTH) pituitary adenomas, the role of HIF-1alpha remains unclear. METHODS: AtT-20 cells were incubated under hypoxic conditions (1 % O2) for 12 h. HIF-1alpha mRNA and protein expression levels were measured by real-time PCR and western blotting, respectively. BrdU was used to determine the effects of hypoxia on cell viability. AtT-20 cells were transfected with siRNA targeting HIF-1alpha, followed by hypoxia (1 % O2) for 12 h. Apoptosis was determined by annexin V-FITC flow cytometry and Tdt-mediated dUTP nick end-labelling (TUNEL) assay. In addition, we examined interactions between HIF-1alpha, glucocorticoid receptor (GR), and dexamethasone under both normoxic and hypoxic conditions. RESULTS: Hypoxia triggered the time-dependent proliferation of AtT-20 cells in association with increased HIF-1alpha mRNA and protein levels. However, the viability of AtT 20 cells decreased greatly when they were first transfected with HIF-1alpha-siRNA and then exposed to hypoxia. According to flow cytometry (annexin V-FITC and PI staining) and TUNEL analyses, a greater percentage of cells were apoptotic when transfected with HIF-1alpha siRNA and subsequently cultured under hypoxic conditions compared to those in the normoxia and mock groups. After AtT-20 cells were cultured in 1 % O2 and then treated with dexamethasone, HIF-1alpha levels significantly increased or decreased in normoxic or hypoxic conditions, respectively. Dexamethasone suppressed GR expression to a higher degree in hypoxic than normoxic conditions. Downregulation of GR by dexamethasone was greatly prevented in cells that were transfected with HIF-1alpha siRNA. CONCLUSIONS: These findings strongly suggest that HIF-1alpha exerts an antiapoptotic role and participates in the downregulation of GR by dexamethasone in hypoxic AtT-20 cells. PMID- 26002041 TI - 2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line. AB - Ligands of 18-kDa translocator protein (TSPO) are known for their ability to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells. In this study, we investigated a number of 2-phenyl-imidazo[1,2-a]pyridine acetamide derivatives, analogs of alpidem, for their ability to bind TSPO and to affect steroidogenesis in a mouse Leydig tumor cell line. We observed that not only some compounds behaved as agonists, stimulating steroidogenesis (e.g., 3 and 4) with EC50 values (15.9 and 6.99MUM) close to that determined for FGIN-1-27 used as positive control (7.24MUM), but two compounds, namely 5 and 6, which on the other hand are the most lipophilic ones in the investigated series, behaved as antagonists, by significantly inhibiting steroid production at concentrations at least twenty times lower than the cytotoxic ones. To our surprise, the newly synthesized compound 3, which is a strict analog of alpidem bearing at the para position of the 2-phenyl group a methoxy group instead of chlorine, achieved a ten-fold stimulation of the steroid production (for comparison FGIN-1-27 achieved 1.6-fold stimulation). Within the limits of the examined property space, some unprecedented SARs were unveiled, which can help in understanding the key molecular factors underlying the transition from agonism to antagonism in the steroidogenesis process. Besides the substitution pattern and the physicochemical features (mainly hydrogen bonding potential) of the substituents at the positions C(6) and C(8) of the imidazo[1,2-a]pyridine nucleus, and at the para position of the 2-phenyl group, the structure-activity relationship analysis suggested lipophilicity, whose increase seems to be generally related to steroidogenesis inhibition, and steric hindrance, which appeared as a stimulation-limiting factor, as two main properties to control in the design or optimization of novel imidazo[1,2-a]pyridine-based TSPO ligands endowed with potential in modulating the steroidogenesis process. PMID- 26002042 TI - Selection of resistant acute myeloid leukemia SKM-1 and MOLM-13 cells by vincristine-, mitoxantrone- and lenalidomide-induced upregulation of P glycoprotein activity and downregulation of CD33 cell surface exposure. AB - Bone marrow cells and peripheral blood mononuclear cells obtained from both acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients contain upregulated levels of cell surface antigen CD33 compared with healthy controls. This difference enables the use of humanized anti-CD33 antibody conjugated to cytotoxic agents for CD33 targeted immunotherapy. However, the expression of the membrane-bound drug transporter P-glycoprotein (P-gp) has been shown to be critical for resistance against the cytotoxicity of a humanized anti-CD33 antibody conjugated to maytansine-derivative DM4. The aim of the present study was to examine whether the expression of P-gp in AML cell lines is associated with changes in CD33 expression. For this purpose, we established drug resistant variants of SKM-1 and MOLM-13 AML cell lines via the selection of parental cells for resistance to vincristine, mitoxantrone and lenalidomide. All three substances induced a multidrug resistance (MDR) phenotype in SKM-1 cells associated with strong upregulation of P-gp and downregulation of CD33. However, in MOLM-13 cells, the upregulation of P-gp and downregulation of CD33 were present only in cells selected for resistance to vincristine and mitoxantrone but not lenalidomide. Inverse expression of P-gp and CD33 were observed in all resistant variants of SKM-1 and MOLM-13 cells. The MDR phenotype of resistant variants of SKM-1 and MOLM-13 cells was associated with alterations in apoptotic regulatory proteins and downregulation of the multidrug resistance associated protein 1 and breast cancer resistance protein. PMID- 26002045 TI - The organophosphate insecticide chlorpyrifos confers its genotoxic effects by inducing DNA damage and cell apoptosis. AB - The organophosphate insecticide chlorpyrifos (CPF) is known to induce neurological effects, malformation and micronucleus formation, persistent developmental disorders, and maternal toxicity in rats and mice. The binding of chlorpyrifos with DNA to produce DNA adducts leads to an increasing social concern about the genotoxic risk of CPF in human, but CPF-induced cytotoxicity through DNA damage and cell apoptosis is not well understood. Here, we quantified the cytotoxicity and potential genotoxicity of CPF using the alkaline comet assay, gammaH2AX foci formation, and the DNA laddering assay in order to detect DNA damage and apoptosis in human HeLa and HEK293 cells in vitro. Drosophila S2 cells were used as a positive control. The alkaline comet assay showed that sublethal concentrations of CPF induced significant concentration-dependent increases in single-strand DNA breaks in the treated cells compared with the control. The percentage of gammaH2AX-positive HeLa cells revealed that CPF also causes DNA double-strand breaks in a time-dependent manner. Moreover, DNA fragmentation analysis demonstrated that exposure to CPF induced a significant concentration- and time-dependent increase in cell apoptosis. We conclude that CPF is a strongly genotoxic agent that induces DNA damage and cell apoptosis. PMID- 26002043 TI - The Benefits and Risks of Being a Standardized Patient: A Narrative Review of the Literature. AB - Standardized patients (SPs) are a widely used, valid, and reliable means of teaching and evaluating healthcare providers (HCPs) across all levels of training and across multiple domains of both clinical and communication skills. Most research on SP programs focuses on outcomes pertinent to the learners (i.e., HCPs) rather than how this experience affects the SPs themselves. This review seeks to summarize the current literature on the risks and benefits of being an SP. We reviewed the literature on the effects that simulation has on adults, children/adolescents, and medical professionals who serve as SPs, in addition to real patients (RPs) who are involved in teaching by sharing their medical histories and experiences. To collect the literature, we conducted two separate systematic searches: one for SPs and one for RPs. Following the searches, we applied standardized eligibility criteria to narrow the literature down to articles within the scope of this review. A total of 67 studies were included that focused on the outcomes of SPs or RPs. The benefits for those portraying SP roles include improved health knowledge and attitudes, relationships with their HCPs, and changed health behaviors. Negative effects of being an SP include anxiety, exhaustion/fatigue, and physical discomfort immediately following a simulation, but the literature to date appears to indicate that there are no long lasting effects. These findings are consistent across age groups and the type of role being simulated. They are also supported by studies of RPs who are involved in medical education. Overall, the benefits of being an SP appear to outweigh the known risks. However, there are significant limitations in the current literature, and additional studies are needed to better characterize the SP experience. PMID- 26002046 TI - Aquatic risk assessment of priority and other river basin specific pesticides in surface waters of Mediterranean river basins. AB - To meet good chemical and ecological status, Member States are required to monitor priority substances and chemicals identified as substances of concern at European Union and local/river-basin/national level, respectively, in surface water bodies, and to report exceedances of the environmental quality standards (EQSs). Therefore, standards have to be set at national level for river basin specific pollutants. Pesticides used in dominant crops of several agricultural areas within the catchment of Mediterranean river basins ('Mondego', 'Sado' and 'Tejo', Portugal) were selected for monitoring, in addition to the pesticides included in priority lists defined in Europe. From the 29 pesticides and metabolites selected for the study, 20 were detected in surface waters of the river basins, seven of which were priority substances: alachlor, atrazine, chlorfenvinphos, chlorpyrifos, endosulfan, simazine and terbutryn, all of which exceeded their respective EQS values. QSs for other specific pollutants were calculated using different extrapolation techniques (i.e. deterministic or probabilistic) largely based on the method described in view of the Water Framework Directive. Non-acceptable aquatic risks were revealed for molinate, oxadiazon, pendimethalin, propanil, terbuthylazine, and the metabolite desethylatrazine. Implications of these findings for the classification of the ecological status of surface water bodies in Portugal and at the European level are discussed. PMID- 26002047 TI - Evaluation of the toxic effects of four anti-cancer drugs in plant bioassays and its potency for screening in the context of waste water reuse for irrigation. AB - Anti-cancer drugs are compounds that are of high environmental relevance because of their lack of specific mode of action. They can be extremely harmful to living organisms even at low concentrations. The present study evaluated the toxic effects of four frequently used anti-cancer drugs against plant seedlings, namely Cyclophosphamide (CP), Methotrexate (MTX), 5-Fluorouracil (5-FU) and Imatinib (IM). The phytotoxicity experiments were performed with Lactuca sativa seedlings whereas cytotoxicity, genotoxicity and mutagenicity investigations were performed with the well-established Allium cepa assays. MTX was the most phytotoxic compound, followed by 5-FU, CP and IM. Significant differences in the Mitotic Indexes (MI) were observed in three of the studied compounds (MTX, 5-FU and CP), indicating potential cytotoxic activity of these substances. Chromosome aberrations were registered in cells that were exposed to 5-FU, CP and IM. All the four compounds caused the formation of micronucleated cells indicating mutagenic potential. Besides, the assays performed with MTX samples presented a high number of cell apoptosis (cell death). Although it is unlikely that the pharmaceuticals concentrations measured in the environment could cause lethal effects in plants, the obtained results indicate that these compounds may affect the growth and normal development of these plants. So, both tests can constitute important tools for a fast screening of environmental contamination e.g. in the context of the reuse of treated wastewater and biosolids of agricultural purpose. PMID- 26002048 TI - Preliminary study of blood methylmercury effects on reproductive hormones and relevant factors among infertile and pregnant women in Taiwan. AB - Methylmercury (MeHg) is the most poisonous mercury species and an endocrine disrupting chemical that could cause reproductive and developmental harm effects in animals. In this study, we recruited 310 infertile women and 57 pregnant women and investigated their blood MeHg levels. The distribution of blood reproductive hormone, selenium and zinc levels, and the difference of relevant factors by the reference level of blood MeHg (5.8 MUg/L) of infertile women were further examined. Results showed that greater percentages of sashimi consumption, frequencies of Chinese herbal medicine use, alcohol consumption, and lack of physical activity were observed in infertile women than those for pregnant women. Blood MeHg concentration was significantly greater in infertile than that in pregnant women. Significant concentration differences for FSH and LH by the dichotomized reference level of blood MeHg (5.8 MUg/L) in infertile women were not observed, which may stem from that these reproductive hormones in participated infertile women were mostly in the normal reference range. Consumption of fish and sashimi represented the major source of MeHg exposure in infertile women. MeHg levels were elevated in infertile women, and consistent with fish consumption frequency. Compared to the referent level of blood MeHg levels <5.8 MUg/L, the elevated blood MeHg levels (?5.8 MUg/L) in infertile women were 3.35 and 4.42 folds risk in categorized frequencies of fish consumption 1-2 meals per week and more than 3 meals per week, respectively. The obtained results provide evidences and help updating the advisory of fish consumption and improving women's reproductive health. PMID- 26002049 TI - Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril. AB - PURPOSE: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that affects blood pressure by promoting vasodilation mediated by nitric oxide. Angiotensin-converting enzyme inhibitors (ACEi) up-regulate the VEGF expression; thus, genetic polymorphisms in the VEGFA gene could affect the antihypertensive responses to these drugs. METHODS: Hypertensive patients (n = 102) were prospectively treated only with the ACEi enalapril for 60 days. We compared the effect of VEGFA polymorphisms on changes in blood pressure after enalapril treatment. In addition, multiple linear regression analysis was carried out to assess the effect of covariates on blood pressure. Genotypes for g.-2578C>A (rs699947), g.-1154G>A (rs1570360), and g.-634G>C (rs2010963) VEGFA polymorphisms were determined, and haplotype frequencies were estimated. RESULTS: Individuals carrying the CA and AA genotypes for the g.-2578C>A polymorphism and the AGG haplotype showed more intense decrease in blood pressure in response to enalapril 20 mg/day. A multiple linear regression analysis showed that the AA genotype for the g.-2578C>A polymorphism and the AGG haplotype are associated with more intense decrease in blood pressure in response to enalapril 20 mg/day, while the CC genotype for the g.-2578C>A polymorphism and the CGG haplotype are associated with the opposite effect. CONCLUSIONS: These findings suggest that polymorphisms in VEGFA gene may affect the antihypertensive responses to enalapril. PMID- 26002051 TI - Clock drawing in children with perinatal stroke. AB - BACKGROUND: Children with perinatal stroke may show evidence of contralateral spatial neglect. The goal of this study was to determine whether the Clock Drawing Test commonly used in adults to identify neglect would be effective in detecting neglect in children with perinatal stroke. METHODS: Thirty-eight individuals (age range 6-21 years) with left hemisphere or right hemisphere perinatal onset unilateral lesions and 179 age-matched controls were given a free drawn Clock Drawing Test in a cross-sectional design. An adapted scoring system that evaluated right- and left-sided errors separately was developed as part of the investigation. RESULTS: Children with right hemisphere lesions made a greater number of errors on both the right and left sides of the clock drawings in all age subgroups (6-8 years, 9-14 years, and 15-21 years) compared with controls. Children with right hemisphere lesions showed greater left and right errors in the younger groups compared with controls, with significantly poorer performance on the left at 6-8 years, suggestive of contralateral neglect. However, by ages 15-21 years, the right hemisphere lesion subjects no longer differed from controls. CONCLUSIONS: Clock drawing can identify spatial neglect in children with early hemispheric damage. However, brain development is a dynamic process, and as children age, spatial neglect may no longer be evident. These findings demonstrate the limitations of predicting long-term outcome after perinatal stroke from early neurocognitive data. Children with perinatal stroke may require different neural pathways to accomplish specific skills or to overcome deficits, but ultimately they may have "typical" outcomes. PMID- 26002052 TI - Efficacy of Glutamate Modulators in Tic Suppression: A Double-Blind, Randomized Control Trial of D-serine and Riluzole in Tourette Syndrome. AB - BACKGROUND: It has been hypothesized that glutamatergic transmission may be altered in Tourette syndrome. In this study, we explored the efficacy of a glutamate agonist (D-serine) and antagonist (riluzole) as tic-suppressing agents in children with Tourette syndrome. METHODS: We performed a parallel three-arm, 8 week, double-blind, randomized placebo-controlled treatment study in children with Tourette syndrome. Each child received 6 weeks of treatment with D-serine (maximum dose 30 mg/kg/day), riluzole (maximum dose 200 mg/day), or placebo, followed by a 2-week taper. The primary outcome measure was effective tic suppression as determined by the differences in the Yale Global Tic Severity Scale score; specifically, the total tic score and the combined score (total tic score + global impairment) between treatment arms after 6 weeks of treatment. Mann-Whitney U tests were performed to analyze differences between each group and the placebo group. RESULTS: Twenty-four patients (males = 21, ages 9-18) enrolled in the study; one patient dropped out before completion. Combined Yale Global Tic Severity Scale score and total tic scores improved in all groups. The 6-week mean percent improvement of the riluzole (n = 10), D-serine (n = 9), and placebo (n = 5) groups in the combined Yale Global Tic Severity Scale score were 43.7, 39.5, and 30.2 and for total tic scores were 38.0, 25.0, and 34.0, respectively. There were no significant differences in Yale Global Tic Severity Scale score or total tic score, respectively, between the riluzole and placebo (P = 0.35, 0.85) or D serine and placebo (P = 0.50, 0.69) groups. CONCLUSION: Tics diminished by comparable percentages in the riluzole, D-serine, and placebo groups. These preliminary data suggest that D-serine and riluzole are not effective in tic suppression. PMID- 26002053 TI - Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation. AB - BACKGROUND: Synaptic vesicle protein 2A (SV2a) is the binding site of the antiepileptic drug levetiracetam and the only known synaptic vesicle target of an epilepsy medication. To date, no pathogenic mutation in SV2A, which is the gene encoding synaptic vesicle glycoprotein 2A, has been identified in humans. We report a homozygous mutation in the SV2A gene in a patient with intractable epilepsy. METHODS: We investigated a patient with intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Both parents were multiply consanguineous and an earlier-born brother of the proband had a similar course and died at 7 months of age. Detailed clinical history, imaging, electroencephalograph and metabolic testing were obtained. Full exome sequencing was performed using genomic DNA isolated from the patient and both parents. RESULTS: Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid position 383 (R383Q) in exon 5 of the SV2A gene. Both parents were carriers for the R383Q variant, suggesting that R383Q is a recessive mutation. There were no other candidate alterations in the exome that could explain the phenotype in the proband. The amino acid arginine at position 383 of SV2a gene is evolutionally conserved throughout vertebrates. R383Q change is not observed in known healthy cohorts, exome databases, or the Database of Single Nucleotide Polymorphisms. The R383Q mutation is located in the second adenine binding domain in SV2a protein and may alter adenine nucleotides binding to SV2a. CONCLUSION: Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy in humans. Levetiracetam, which binds to SV2A, was not effective as an antiepileptic medication. The location of the mutation in our patient supports an important role of adenine nucleotides binding in SV2A function. PMID- 26002054 TI - Ruptured Aneurysm and Terson Syndrome in a 1-Month-Old Infant. PMID- 26002055 TI - The myelin proteolipid plasmolipin forms oligomers and induces liquid-ordered membranes in the Golgi complex. AB - Myelin comprises a compactly stacked massive surface area of protein-poor thick membrane that insulates axons to allow fast signal propagation. Increasing levels of the myelin protein plasmolipin (PLLP) were correlated with post-natal myelination; however, its function is unknown. Here, the intracellular localization and dynamics of PLLP were characterized in primary glial and cultured cells using fluorescently labeled PLLP and antibodies against PLLP. PLLP localized to and recycled between the plasma membrane and the Golgi complex. In the Golgi complex, PLLP forms oligomers based on fluorescence resonance energy transfer (FRET) analyses. PLLP oligomers blocked Golgi to plasma membrane transport of the secretory protein vesicular stomatitis virus G protein (VSVG), but not of a VSVG mutant with an elongated transmembrane domain. Laurdan staining analysis showed that this block is associated with PLLP-induced proliferation of liquid-ordered membranes. These findings show the capacity of PLLP to assemble potential myelin membrane precursor domains at the Golgi complex through its oligomerization and ability to attract liquid-ordered lipids. These data support a model in which PLLP functions in myelin biogenesis through organization of myelin liquid-ordered membranes in the Golgi complex. PMID- 26002050 TI - Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models. AB - BACKGROUND: Arterial ischemic stroke occurs more frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared with childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. Our understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many factors remain incompletely understood. METHODS: In this review, we focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment. RESULTS: Studies in neonatal rodent models of cerebral ischemia have suggested a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort is underway to investigate neuroprotective molecules based on our increasing understanding of the pathophysiology. CONCLUSION: In this review, we provide a comprehensive summary of new insights concerning pathophysiology of focal and global perinatal brain injury and their implications for new therapeutic approaches. PMID- 26002056 TI - ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-beta accumulation. AB - Intracellular amyloid-beta (Abeta) accumulation is a key feature of early Alzheimer's disease and precedes the appearance of Abeta in extracellular plaques. Abeta is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Abeta production is unclear. APP has been localized to multivesicular bodies (MVBs) where sorting of APP onto intraluminal vesicles (ILVs) could promote amyloidogenic processing, or reduce Abeta production or accumulation by sorting APP and processing products to lysosomes for degradation. Here, we show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and that it is delivered to lysosomes for degradation. Depletion of the endosomal sorting complexes required for transport (ESCRT) components, Hrs (also known as Hgs) or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes, and led to increased intracellular Abeta accumulation. This was accompanied by dramatically decreased Abeta secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Abeta accumulation through targeting of APP and processing products to the lysosome for degradation, and promoting Abeta secretion. PMID- 26002057 TI - An approach for determining quantitative measures for bone volume and bone mass in the pediatric spina bifida population. AB - BACKGROUND: The pediatric spina bifida population suffers from decreased mobility and recurrent fractures. This study aimed to develop a method for quantifying bone mass along the entire tibia in youth with spina bifida. This will provide information about all potential sites of bone deficiencies. METHODS: Computed tomography images of the tibia for 257 children (n=80 ambulatory spina bifida, n=10 non-ambulatory spina bifida, n=167 typically developing) were analyzed. Bone area was calculated at regular intervals along the entire tibia length and then weighted by calibrated pixel intensity for density weighted bone area. Integrals of density weighted bone area were used to quantify bone mass in the proximal and distal epiphyses and diaphysis. Group differences were evaluated using analysis of variance. FINDINGS: Non-ambulatory children suffer from decreased bone mass in the diaphysis and proximal and distal epiphyses compared to ambulatory and control children (P<=0.001). Ambulatory children with spina bifida showed statistically insignificant differences in bone mass in comparison to typically developing children at these sites (P>0.5). INTERPRETATION: This method provides insight into tibial bone mass distribution in the pediatric spina bifida population by incorporating information along the whole length of the bone, thereby providing more information than dual-energy x-ray absorptiometry and peripheral quantitative computed tomography. This method can be applied to any population to assess bone mass distribution across the length of any long bone. PMID- 26002058 TI - Fatalism, Diabetes Management Outcomes, and the Role of Religiosity. AB - This study aimed to determine whether fatalistic beliefs were associated with elevated levels of glycated hemoglobin (HbA1c) and to establish the role of religiosity in this relationship. A cross-sectional survey was conducted on a sample of 183 Jewish adults with diabetes visiting a large medical center in northern Israel. Self-administered questionnaires assessed level of religiosity, fatalistic beliefs, diabetes management behaviors, and demographic/personal characteristics; laboratory tests were used to measure HbA1c. Multivariate regression indicated that fatalism was significantly associated with HbA1c (beta = 0.51, p = 0.01). The association was no longer statistically significant after including self-reported religiosity in the model (beta = 0.31, p = 0.13). This phenomenon is likely due to a confounding relationship between the religious/spiritual coping component of the fatalism index and self-reported religiosity (r = 0.69). The results indicate that addressing fatalistic attitudes may be a viable strategy for improving diabetes management, but call for a better understanding of the interplay between religiosity and fatalism in this context. PMID- 26002059 TI - The Impact of an Ego Depletion Manipulation on Performance-Based and Self-Report Assessment Measures. AB - We investigated the impact of ego depletion on selected Rorschach cognitive processing variables and self-reported affect states. Research indicates acts of effortful self-regulation transiently deplete a finite pool of cognitive resources, impairing performance on subsequent tasks requiring self-regulation. We predicted that relative to controls, ego-depleted participants' Rorschach protocols would have more spontaneous reactivity to color, less cognitive sophistication, and more frequent logical lapses in visualization, whereas self reports would reflect greater fatigue and less attentiveness. The hypotheses were partially supported; despite a surprising absence of self-reported differences, ego-depleted participants had Rorschach protocols with lower scores on two variables indicative of sophisticated combinatory thinking, as well as higher levels of color receptivity; they also had lower scores on a composite variable computed across all hypothesized markers of complexity. In addition, self reported achievement striving moderated the effect of the experimental manipulation on color receptivity, and in the Depletion condition it was associated with greater attentiveness to the tasks, more color reactivity, and less global synthetic processing. Results are discussed with an emphasis on the response process, methodological limitations and strengths, implications for calculating refined Rorschach scores, and the value of using multiple methods in research and experimental paradigms to validate assessment measures. PMID- 26002060 TI - The Genetics of Soft Connective Tissue Disorders. AB - Over the last few years, the field of hereditary connective tissue disorders has changed tremendously. This review highlights exciting insights into three prototypic disorders affecting the soft connective tissue: Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and cutis laxa. For each of these disorders, the identification and characterization of several novel but related conditions or subtypes have widened the phenotypic spectrum. In parallel, the vast underlying molecular network connecting these phenotypes is progressively being uncovered. Identification and characterization (both clinical and molecular) of new phenotypes within the connective tissue disorder spectrum are often key to further unraveling the pathways involved in connective tissue biology and delineating the clinical spectrum and pathophysiology of the disorders. Although difficult challenges remain, recent findings have expanded our pathophysiological understanding and may lead to targeted therapies in the near future. PMID- 26002061 TI - Addressing the Genetics of Human Mental Health Disorders in Model Organisms. AB - Mental health disorders are notoriously difficult to diagnose and treat for a variety of reasons, including genetic heterogeneity, comorbidities, and qualitative diagnostic criteria. Discovery of the molecular pathology underlying these disorders is crucial to the development of quantitative biomarkers and novel therapeutics. In this review, we discuss contributions to the mental health field of different cellular and whole-animal approaches in characterizing psychiatric genetics and molecular pathology. These approaches include mammalian cell and neuronal culture, cerebral organoids, induced pluripotent stem cells, and the whole-animal models of nematodes, flies, mollusks, frogs, mice, and zebrafish, on the last of which we place extra emphasis. Integrative use of these cellular and animal systems in a complementary and informative fashion maximizes the potential contributions to the mental health field as a whole. PMID- 26002062 TI - Multi-dimensionality and variability in folk classification of stingless bees (Apidae: Meliponini). AB - BACKGROUND: Not long ago Eugene Hunn suggested using a combination of cognitive, linguistic, ecological and evolutionary theories in order to account for the dynamic character of ethnoecology in the study of folk classification systems. In this way he intended to question certain homogeneity in folk classifications models and deepen in the analysis and interpretation of variability in folk classifications. This paper studies how a rural culturally mixed population of the Atlantic Forest of Misiones (Argentina) classified honey-producing stingless bees according to the linguistic, cognitive and ecological dimensions of folk classification. We also analyze the socio-ecological meaning of binomialization in naming and the meaning of general local variability in the appointment of stingless bees. METHODS: We used three different approaches: the classical approach developed by Brent Berlin which relies heavily on linguistic criteria, the approach developed by Eleonor Rosch which relies on psychological (cognitive) principles of categorization and finally we have captured the ecological dimension of folk classification in local narratives. For the second approximation, we developed ways of measuring the degree of prototypicality based on a total of 107 comparisons of the type "X is similar to Y" identified in personal narratives. RESULTS: Various logical and grouping strategies coexist and were identified as: graded of lateral linkage, hierarchical and functional. Similarity judgments among folk taxa resulted in an implicit logic of classification graded according to taxa's prototypicality. While there is a high agreement on naming stingless bees with monomial names, a considerable number of underrepresented binomial names and lack of names were observed. Two possible explanations about reported local naming variability are presented. CONCLUSIONS: We support the multidimensionality of folk classification systems. This confirms the specificity of local classification systems but also reflects the use of grouping strategies and mechanisms commonly observed in other cultural groups, such as the use of similarity judgments between more or less prototypical organisms. Also we support the idea that alternative naming results from a process of fragmentation of knowledge or incomplete transmission of knowledge. These processes lean on the facts that culturally based knowledge, on the one hand, and biologic knowledge of nature on the other, can be acquired through different learning pathways. PMID- 26002064 TI - Long-term Strenuous Endurance Exercise and the Right Ventricle: Is It a Real Matter of Concern? PMID- 26002063 TI - Linkage mapping, molecular cloning and functional analysis of soybean gene Fg3 encoding flavonol 3-O-glucoside/galactoside (1 -> 2) glucosyltransferase. AB - BACKGROUND: Flavonol glycosides (FGs) are major components of soybean leaves and there are substantial differences in FG composition among genotypes. The first objective of this study was to identify genes responsible for FG biosynthesis and to locate them in the soybean genome. The second objective was to clone the candidate genes and to verify their function. Recombinant inbred lines (RILs) were developed from a cross between cultivars Nezumisaya and Harosoy. RESULTS: HPLC comparison with authentic samples suggested that FGs having glucose at the 2"-position of glucose or galactose that is bound to the 3-position of kaempferol were present in Nezumisaya, whereas FGs of Harosoy were devoid of 2"-glucose. Conversely, FGs having glucose at the 6"-position of glucose or galactose that is bound to the 3-position of kaempferol were present in Harosoy, whereas these FGs were absent in Nezumisaya. Genetic analysis suggested that two genes control the pattern of attachment of these sugar moieties in FGs. One of the genes may be responsible for attachment of glucose to the 2"-position, probably encoding for a flavonol 3-O-glucoside/galactoside (1 -> 2) glucosyltransferase. Nezumisaya may have a dominant whereas Harosoy may have a recessive allele of the gene. Based on SSR analysis, linkage mapping and genome database survey, we cloned a candidate gene designated as GmF3G2"Gt in the molecular linkage group C2 (chromosome 6). The open reading frame of GmF3G2"Gt is 1380 bp long encoding 459 amino acids with four amino acid substitutions among the cultivars. The GmF3G2"Gt recombinant protein converted kaempferol 3-O-glucoside to kaempferol 3-O-sophoroside. GmF3G2"Gt of Nezumisaya showed a broad activity for kaempferol/quercetin 3-O glucoside/galactoside derivatives but it did not glucosylate kaempferol 3-O rhamnosyl-(1 -> 4)-[rhamnosyl-(1 -> 6)-glucoside] and 3-O-rhamnosyl-(1 -> 4) [glucosyl-(1 -> 6)-glucoside]. CONCLUSION: GmF3G2"Gt encodes a flavonol 3-O glucoside/galactoside (1 -> 2) glucosyltransferase and corresponds to the Fg3 gene. GmF3G2"Gt was designated as UGT79B30 by the UGT Nomenclature Committee. Based on substrate specificity of GmF3G2"Gt, 2"-glucosylation of flavonol 3-O glycoside may be irreconcilable with 4"-glycosylation in soybean leaves. PMID- 26002065 TI - Young Women With Abdominal Obesity Have Subclinical Myocardial Dysfunction. AB - BACKGROUND: Abdominal obesity is an independent risk factor for cardiovascular disease. The effect of abdominal obesity on myocardial function in young obese women remains unknown. Therefore, we aimed to investigate cardiac morphology and function, myocardial deformation, and mechanical indices, in young women with and without abdominal obesity. METHODS: Cross-sectional analyses of 39 women with abdominal obesity (waist circumference >= 80 cm) and 33 nonobese control subjects (waist circumference < 80 cm) aged 18-30 years underwent conventional echocardiographic measures of cardiac morphology and function together with tissue Doppler, and 2-dimensional speckle tracking measures of myocardial deformation and mechanics. Cardiometabolic risk factors including anthropometric, hypertension, biochemistry, and fitness were also assessed. RESULTS: Standard echocardiography results for cardiac morphology and function were similar between groups, with the exception of larger left atrial dimensions in women with abdominal obesity (P <= 0.05). Compared with control subjects, women with abdominal obesity also demonstrated reduced systolic and diastolic mitral annular plane velocities, increased left atrial pressure surrogates (E/diastolic mitral annular plane velocity), and prolonged timing measures of diastolic function including isovolumic relaxation time and transmitral deceleration time (P <= 0.05). In addition, longitudinal strain and diastolic strain rate were reduced in women with abdominal obesity (P <= 0.05) but circumferential deformation and myocardial mechanics (twist indices and rotation) were preserved. Markers of abdominal obesity retained an independent direct correlation with parameters of cardiac dysfunction, explaining 12%-39% of the overall variability. CONCLUSIONS: A young, otherwise healthy group of women with abdominal obesity displayed subclinical cardiac dysfunction indicated using selected tissue Doppler imaging and speckle tracking echocardiography measures. PMID- 26002066 TI - Patterns of sunscreen use on the face and other exposed skin among US adults. AB - BACKGROUND: Sunscreen is a common form of sun protection, but little is known about patterns of use. OBJECTIVE: We sought to assess patterns of sunscreen use on the face and other exposed skin among US adults. METHODS: Using cross sectional data from the 2013 Summer ConsumerStyles survey (N = 4033), we calculated descriptive statistics and adjusted risk ratios to identify characteristics associated with regular sunscreen use (always/most of the time when outside on a warm sunny day for >=1 hour). RESULTS: Few adults regularly used sunscreen on the face (men: 18.1%, 95% confidence interval [CI] 15.8-20.6; women: 42.6%, 95% CI 39.5-46.7), other exposed skin (men: 19.9%, 95% CI 17.5 22.6; women: 34.4%, 95% CI 31.5-37.5), or both the face and other exposed skin (men: 14.3%, 95% CI 12.3-16.6; women: 29.9%, 95% CI 27.2-32.8). Regular use was associated with sun-sensitive skin, an annual household income >=$60,000, and meeting aerobic activity guidelines (Ps < .05). Nearly 40% of users were unsure if their sunscreen provided broad-spectrum protection. LIMITATIONS: Reliance on self-report and lack of information on sunscreen reapplication or other sun safety practices are limitations. CONCLUSION: Sunscreen use is low, especially among certain demographic groups. These findings can inform sun-safety interventions and the interpretation of surveillance data on sunscreen use. PMID- 26002067 TI - Sharing light between two photosystems: mechanism of state transitions. AB - In the thylakoid membrane, the two photosystems act in series to promote linear electron flow, with the concomitant production of ATP and reducing equivalents such as NADPH. Photosystem I, which is preferentially activated in far-red light, also energizes cyclic electron flow which generates only ATP. Thus, changes in light quality and cellular metabolic demand require a rapid regulation of the activity of the two photosystems. At low light intensities, this is mediated by state transitions. They allow the dynamic allocation of light harvesting antennae to the two photosystems, regulated through protein phosphorylation by a kinase and phosphatase pair that respond to the redox state of the electron transfer chain. Phosphorylation of the antennae leads to remodeling of the photosynthetic complexes. PMID- 26002068 TI - Crop yield: challenges from a metabolic perspective. AB - Considering the dual use of plants, as bio-factories for foods and feedstock for bio-refining, along with a rising world population, the plant biotechnology field is currently facing a dramatic challenge to develop crops with higher yield. Furthermore, convergent studies predict that global changes in climate will influence crop productivity by modifying most yield-associated traits. Here, we review recent advances in the understanding of plant metabolism directly or indirectly impacting on yield and provide an update of the different pathways proposed as targets for metabolic engineering aiming to optimize source-sink relationships. PMID- 26002069 TI - Measurement of plant growth in view of an integrative analysis of regulatory networks. AB - As the regulatory networks of growth at the cellular level are elucidated at a fast pace, their complexity is not reduced; on the contrary, the tissue, organ and even whole-plant level affect cell proliferation and expansion by means of development-induced and environment-induced signaling events in growth regulatory processes. Measurement of growth across different levels aids in gaining a mechanistic understanding of growth, and in defining the spatial and temporal resolution of sampling strategies for molecular analyses in the model Arabidopsis thaliana and increasingly also in crop species. The latter claim their place at the forefront of plant research, since global issues and future needs drive the translation from laboratory model-acquired knowledge of growth processes to improvements in crop productivity in field conditions. PMID- 26002070 TI - Comparisons of Predictive Equations for Resting Energy Expenditure in Patients with Cerebral Infarct during Acute Care. AB - BACKGROUND: Estimation of resting energy expenditure (REE) is essential in planning nutrition support. Several equations are used for this estimation in the clinical setting. The purpose of this study was to compare the predictive accuracy of existing equations for REE in patients with cerebral infarct during acute care. METHODS: We assessed the Harris-Benedict, Mifflin, Owen, Japanese simplified, Wang, and Cunningham equations. The Owen and Japanese simplified equations use sex and weight as explanatory variables, the Harris-Benedict and Mifflin equations include sex, weight, age, and height, and the Wang and Cunningham equations use fat-free mass (FFM) measured using bioelectrical impedance technology. Actual REE values were measured by indirect calorimetry on days 2 and 7 and were then averaged. Applying analysis of variance, predictive accuracy was assessed by comparing the predicted and actual values. RESULTS: A total of 30 patients were analyzed. Actual REE values ranged from 796 to 1637 kcal (mean, 1109). The standard deviation of these values was the smallest with the Harris-Benedict equation (99), followed by the Cunningham (165), and Wang (181) equations. The Mifflin equation underestimated REE in females, whereas the Owen and Japanese simplified equations tended to overestimate it. CONCLUSIONS: Based on our results, the Harris-Benedict equation provides the most accurate prediction of REE. In addition, the Cunningham and Wang equations may be useful in long-term care settings involving patients at risk of malnutrition resulting in uneven loss of FFM relative to weight. PMID- 26002071 TI - Cerebrovascular Events in Lyme Neuroborreliosis. AB - BACKGROUND: Cerebrovascular events in neuroborreliosis are a rare condition described only in isolated or small case series. No specific clinical or radiological features have been identified, and diagnosis is based on very different criteria. METHODS: We retrospectively describe cases diagnosed in the Stroke Unit of Nancy Hospital, located in the endemic area of the northeast of France. We also reviewed other cases found in the literature. RESULTS: We identified 5 cases in our center and 57 other reported cases. Mean age was 39 years (range 5 to 77). Possible previous contact with Borrelia burgdorferi (B burgdorferi) was found in about half of cases. Additional neurologic symptoms (headache, cognitive impairment, and/or gait disturbance) were found in 44% of cases. Cerebral imaging revealed both ischemic (87%) and hemorrhagic lesions (13%) with a multiterritorial aspect in 22% of strokes, and signs of vasculitis in 71%. Analysis of cerebrospinal fluid (CSF) revealed lymphocytic meningitis in 90% of cases and elevated protein level in 86%. CSF/serum anti-B burgdorferi antibody index (AI) was positive in 91% of cases. Outcome was favorable after appropriate antibiotic treatment. Our 5 patients presented a modified Rankin scale score 0-1, without any stroke recurrence, after a median follow-up of 2.8 years. CONCLUSIONS: The diagnosis of Lyme neuroborreliosis should be considered for patients with cerebrovascular events without obvious cause living in an endemic area, in the presence of repeat multiterritorial strokes at short intervals, other neurologic symptoms, a history of B burgdorferi infection, and radiological signs of vasculitis. Diagnosis can be confirmed by CSF analysis with AI but with an incomplete sensitivity. PMID- 26002072 TI - Schizotypy and clinical symptoms, cognitive function, and quality of life in individuals with a psychotic disorder. AB - BACKGROUND: Schizotypy is a range of perceptual experiences and personality features related to risk and familial predisposition to psychosis. Despite evidence that schizotypy is related to psychosis vulnerability, very little is known about the expression of schizotypal traits in individuals with a psychotic disorder, and their relationship to clinical symptoms, cognition, and psychosocial functioning. METHODS: 59 healthy subjects and 68 patients with a psychotic disorder (47 schizophrenia spectrum disorder; 21 bipolar disorder with psychotic features) completed four schizotypy scales, the Perceptual Aberration Scale, the Revised Physical and Social Anhedonia Scales, and the Schizotypal Personality Questionnaire, a brief neuropsychological assessment, and a self report measure of quality of life. Clinical symptoms of psychosis were quantified in patients with the Positive and Negative Syndrome Scale (PANSS). RESULTS: Psychosis patients scored higher than healthy subjects on all schizotypy scales. Correlations between schizotypy and PANSS scores were modest, ranging from r=.06 to r=.43, indicating that less than 20% of the variance in self-reported schizotypy overlapped with clinical symptoms. After controlling for clinical symptoms, patients with schizophrenia spectrum disorders reported higher levels of cognitive-perceptual disturbances and negative traits than patients with bipolar disorder. Elevated schizotypy was associated with lower cognitive functioning and self-reported quality of life. CONCLUSIONS: Schizotypal personality traits are markedly elevated in psychotic disorders, especially schizophrenia spectrum disorders, relatively weakly correlated with positive and negative psychotic symptoms, and associated with greater cognitive impairment and lower quality of life. Assessing schizotypy in patients with psychosis may be useful for predicting functional outcome and differential diagnosis. PMID- 26002073 TI - Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans. AB - Apicomplexan parasites cause some of the most severe human diseases, including malaria (caused by Plasmodium), toxoplasmosis, and cryptosporidiosis. Treatments are limited by the lack of effective drugs and development of resistance to available agents. By exploiting novel features of protein kinases in these parasites, it may be possible to develop new treatments. We summarize here recent advances in identifying small molecule inhibitors against a novel family of plant like, calcium-dependent kinases that are uniquely expanded in apicomplexan parasites. Analysis of the 3D structure, activation mechanism, and sensitivity to small molecules had identified several attractive chemical scaffolds that are potent and selective inhibitors of these parasite kinases. Further optimization of these leads may yield promising new drugs for treatment of these parasitic infections. PMID- 26002074 TI - Computational modeling of cardiac optogenetics: Methodology overview & review of findings from simulations. AB - Cardiac optogenetics is emerging as an exciting new potential avenue to enable spatiotemporally precise control of excitable cells and tissue in the heart with low-energy optical stimuli. This approach involves the expression of exogenous light-sensitive proteins (opsins) in target heart tissue via viral gene or cell delivery. Preliminary experiments in optogenetically-modified cells, tissue, and organisms have made great strides towards demonstrating the feasibility of basic applications, including the use of light stimuli to pace or disrupt reentrant activity. However, it remains unknown whether techniques based on this intriguing technology could be scaled up and used in humans for novel clinical applications, such as pain-free optical defibrillation or dynamic modulation of action potential shape. A key step towards answering such questions is to explore potential optogenetics-based therapies using sophisticated computer simulation tools capable of realistically representing opsin delivery and light stimulation in biophysically detailed, patient-specific models of the human heart. This review provides (1) a detailed overview of the methodological developments necessary to represent optogenetics-based solutions in existing virtual heart platforms and (2) a survey of findings that have been derived from such simulations and a critical assessment of their significance with respect to the progress of the field. PMID- 26002075 TI - Transcriptional analysis of the cell division-related ssg genes in Streptomyces coelicolor reveals direct control of ssgR by AtrA. AB - SsgA-like proteins are a family of actinomycete-specific regulatory proteins that control cell division and spore maturation in streptomycetes. SsgA and SsgB together activate sporulation-specific cell division by controlling the localization of FtsZ. Here we report the identification of novel regulators that control the transcription of the ssgA-like genes. Transcriptional regulators controlling ssg gene expression were identified using a DNA-affinity capture assay. Supporting transcriptional and DNA binding studies showed that the ssgA activator gene ssgR is controlled by the TetR-family regulator AtrA, while the gamma-butyrolactone-responsive AdpA (SCO2792) and SlbR (SCO0608) and the metabolic regulator Rok7B7 (SCO6008) were identified as candidate regulators for the cell division genes ssgA, ssgB and ssgG. Transcription of the cell division gene ssgB depended on the sporulation genes whiA and whiH, while ssgR, ssgA and ssgD were transcribed independently of the whi genes. Our work sheds new light on the mechanisms by which sporulation-specific cell division is controlled in Streptomyces. PMID- 26002076 TI - Ferrovibrio xuzhouensis sp. nov., a cyhalothrin-degrading bacterium isolated from cyhalothrin contaminated wastewater. AB - A novel cyhalothrin-degrading strain, designated as LM-6(T), was isolated from a cyhalothrin contaminated wastewater sample. The bacterium was found to be Gram stain-negative, non-spore-forming, vibrio-shaped, and motile with a single polar flagellum. Strain LM-6(T) was observed to grow optimally at 28-30 degrees C, pH 6.0 and in the absence of NaCl. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain LM-6(T) is a member of the genus Ferrovibrio, and showed the highest sequence similarity with Ferrovibrio denitrificans Sp-1(T) (97.7 %), followed by Taonella mepensis H1(T) (93.3 %). The major fatty acids of strain LM-6(T) (>5 %) were determined to be C18:1 omega7c and/or C18:1 omega6c, C16:0, C18:1 2-OH and C17:1 iso I and/or anteiso B. The major polar lipids were identified to be phosphatidylglycerol, phosphatidylethanolamine and phosphatidylmethylethanolamine. The major respiratory quinone was determined to be ubiquinone-10. The genomic DNA G+C content of strain LM-6(T) is 66.5 mol %. Strain LM-6(T) showed low DNA-DNA relatedness with F. denitrificans Sp-1(T) (53.1 +/- 0.5 %). On the basis of phylogenetic, genomic, phenotypic and chemotaxonomic data, strain LM-6(T) is considered to represent a novel species of the genus Ferrovibrio, for which the name Ferrovibrio xuzhouensis sp. nov. is proposed. The type strain is Ferrovibrio xuzhouensis LM-6(T) (=KCTC 42182(T) = ACCC 19710(T)). PMID- 26002077 TI - Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9 releasing cell type constituting the blood-brain barrier in vitro. AB - In the acute phase of intracerebral hemorrhage (ICH), hemorrhagic transformation and brain edema are associated with blood-brain barrier (BBB) disruption. Elevated levels of thrombin, a coagulation factor, contribute to the development of brain edema during ICH through matrix metalloproteinase (MMP)-9 production. Thrombin directly induces a variety of cellular responses through its specific receptors known as protease-activated receptors (PARs). However, it remains unclear which cell types constituting the BBB mainly produce MMP-9 in response to thrombin. Here, we compared the MMP-9 release induced by thrombin using primary cultures of rat brain microvascular endothelial cells, astrocytes, and pericytes. Brain pericytes exhibited the highest levels of MMP-9 release due to thrombin stimulation among the BBB cells. The pattern of PAR mRNA expression in pericytes was characterized by high expression of PAR1 and moderate expression of PAR4. Heat-inactivated thrombin failed to stimulate pericytes to release MMP-9. A selective PAR1 inhibitor SCH79797 blocked the thrombin-induced MMP-9 release from pericytes. These findings suggest that both PAR1 and PAR4 mediate thrombin induced MMP-9 release from pericytes. The present study raises the possibility that brain pericytes could play a pivotal role as a highly thrombin-sensitive and MMP-9-producing cell type at the BBB in brain damage including ICH. PMID- 26002078 TI - IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging. AB - Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5 hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. PMID- 26002079 TI - Establishment of an experimental system to study the influence of electrical field on cochlear structures. AB - Treatment of partial hearing loss with the combined electrical and acoustical stimulation (EAS) aims at restoring the hearing while preserving the residual hearing. The aim of present study was to establish an in vitro system to study the effects of an electrical field on the auditory hair cells and spiral ganglion cells. Cochlear tissues containing the organ of Corti, spiral limbus and spiral ganglion neurons were dissected from post-natal Wistar rats (p3-p5) and cultured in the micro-channels. Electric current was homogenously applied on the apical, medial and basal parts of explants. Biphasic rectangular pulses were applied continuously over a period of 30 h or 42 h and the explants were fixed and stained to visualize the hair cells and neurites. Application of electrical field for 30 h has not induced significant changes in the number of inner or outer hair cells when compared to the control. However, after 42 h of electric stimulation, the number of hair cells decreased significantly by about 30%. The medial and basal fragments were particularly affected. The number of neurites has not been influenced but significant neuritic beading, consistent with neurodegeneration, was observed after 42 h of electric stimulation. Although performed with immature auditory tissues, our findings hint at the possibility of particular electric current inducing damage or loss of auditory hair cells, which should be considered when designing EAS electrodes. PMID- 26002080 TI - Transcriptional regulation of the alpha-synuclein gene in human brain tissue. AB - The transcriptional regulation of the gene encoding alpha-synuclein (SNCA) is thought to play a critical role in the pathogenesis of Parkinson's disease (PD), as common genetic variability in this gene is associated with an elevated risk of developing PD. However, the relevant mechanisms are still poorly understood. So far, only few proteins have been identified as transcription factors (TFs) of SNCA in cellular models. Here we show that two of these TFs bind to the DNA in human brain tissue: the zinc finger protein ZSCAN21 occupies a region within SNCA intron 1, as described before, while GATA2 occupies a specific region within intron 2, where we have identified a new binding site within the complex structure of the 5'-promoter region of SNCA. Electrophoretic mobility shift assays confirmed these binding sites. Genetic investigations revealed no polymorphisms or mutations within these sites. A better understanding of TF-DNA interactions within SNCA may allow to develop novel therapies designed to reduce alpha-synuclein levels. PMID- 26002082 TI - Strabismus Surgery Reoperation Rates With Adjustable and Conventional Sutures. AB - PURPOSE: To determine the association of strabismus surgery reoperation rates with adjustable or conventional sutures. DESIGN: Retrospective cross-sectional study. METHODS: setting: Review of a large national private insurance database. STUDY POPULATION: Adults aged 18-89 having strabismus surgery between 2007 and 2011. INTERVENTION: Adjustable vs conventional suture strabismus surgery. OUTCOME MEASURE: Reoperation rate in the first postoperative year. RESULTS: Overall, 526 of 6178 surgical patients had a reoperation (8.5%). Reoperations were performed after 8.1% of adjustable suture surgeries and after 8.6% of conventional suture surgeries (P = .57). Of the 4357 horizontal muscle surgeries, reoperations were performed after 5.8% of adjustable suture surgeries, and after 7.8% of conventional suture surgeries (P = .02). Of the 1072 vertical muscle surgeries, reoperations were performed after 15.2% of adjustable suture surgeries and after 10.4% of conventional suture surgeries (P = .05). Younger age (18-39 years) was associated with a lower reoperation rate (P <= .02). The significant multivariable predictors of reoperation for horizontal surgery were adjustable sutures (odds ratio [OR] 0.69, 95% confidence interval 0.52-0.91), monocular deviation (OR 0.64), complex surgery (OR 1.63), and unilateral surgery on 2 horizontal muscles (OR 0.70, all P <= .01). Adjustable sutures were not significantly associated with reoperation rates after vertical muscle surgery (multivariable OR 1.45, P = .07). CONCLUSIONS: Adjustable sutures were associated with significantly fewer reoperations for horizontal muscle surgery. Adjustable sutures tended to be associated with more reoperations for vertical muscle surgery, but this observation was not statistically significant in the primary analysis after controlling for age. PMID- 26002083 TI - Acidic pH and divalent cation sensing by PhoQ are dispensable for systemic salmonellae virulence. AB - Salmonella PhoQ is a histidine kinase with a periplasmic sensor domain (PD) that promotes virulence by detecting the macrophage phagosome. PhoQ activity is repressed by divalent cations and induced in environments of acidic pH, limited divalent cations, and cationic antimicrobial peptides (CAMP). Previously, it was unclear which signals are sensed by salmonellae to promote PhoQ-mediated virulence. We defined conformational changes produced in the PhoQ PD on exposure to acidic pH that indicate structural flexibility is induced in alpha-helices 4 and 5, suggesting this region contributes to pH sensing. Therefore, we engineered a disulfide bond between W104C and A128C in the PhoQ PD that restrains conformational flexibility in alpha-helices 4 and 5. PhoQ(W104C-A128C) is responsive to CAMP, but is inhibited for activation by acidic pH and divalent cation limitation. phoQ(W104C-A128C) Salmonella enterica Typhimurium is virulent in mice, indicating that acidic pH and divalent cation sensing by PhoQ are dispensable for virulence. PMID- 26002085 TI - Hydroxycinnamic acids and UV-B depletion: Profiling and biosynthetic gene expression in flesh and peel of wild-type and hp-1. AB - Hydroxycinnamic acids (HCAs) are phenolic compounds widely found in most plant families. Aim of the present work was to investigate their accumulation and biosynthetic gene expression in presence or absence of UV-B radiation in tomato fruits of wild-type and hp-1, a mutant characterized by exaggerated photoresponsiveness and increased fruit pigmentation. Gene expression and HCAs content were higher in hp-1 than in wild type peel and UV-B depletion determined a decrease in HCAs accumulation in wild-type and an increase in hp-1 fruits, generally in accordance with biosynthetic gene expression. In flesh, despite a similar transcript level of most genes between the two genotypes, HCAs content was generally higher in wild type than in hp-1, although remaining at a lower level with respect to wild type peel. Under UV-B depletion, a general reduction of HCAs content was observed in wild-type flesh, whereas an increase in the content of p-coumaric acid and caffeic acid was observed in hp-1 flesh. PMID- 26002081 TI - Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions. AB - An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-beta, FAK, IGF-1, HIF-1alpha, IL-6, IL-1alpha, CTLA-4 and PD 1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression. PMID- 26002084 TI - The homo-oligomerisation of both Sas-6 and Ana2 is required for efficient centriole assembly in flies. AB - Sas-6 and Ana2/STIL proteins are required for centriole duplication and the homo oligomerisation properties of Sas-6 help establish the ninefold symmetry of the central cartwheel that initiates centriole assembly. Ana2/STIL proteins are poorly conserved, but they all contain a predicted Central Coiled-Coil Domain (CCCD). Here we show that the Drosophila Ana2 CCCD forms a tetramer, and we solve its structure to 0.8 A, revealing that it adopts an unusual parallel-coil topology. We also solve the structure of the Drosophila Sas-6 N-terminal domain to 2.9 A revealing that it forms higher-order oligomers through canonical interactions. Point mutations that perturb Sas-6 or Ana2 homo-oligomerisation in vitro strongly perturb centriole assembly in vivo. Thus, efficient centriole duplication in flies requires the homo-oligomerisation of both Sas-6 and Ana2, and the Ana2 CCCD tetramer structure provides important information on how these proteins might cooperate to form a cartwheel structure. PMID- 26002086 TI - [Meeting "Visceral leishmaniasis in Maghreb", 2-4 April 2015 in Tunis. Recommendations]. PMID- 26002087 TI - Disclosure of HIV Serostatus and Sexual Orientation Among HIV-Positive Men Who Have Sex with Men in China. AB - This study addressed the issue of disclosing HIV status and sexual orientation, and explored the consequences of such disclosures among HIV-positive men who have sex with men (MSM) in China. In-depth individual interviews were conducted with 37 HIV-positive MSM. Of these participants, 3 (8.1%) disclosed neither their HIV status nor their sexual orientation to anyone; 24 (64.9%) voluntarily disclosed both their HIV-positive status and their sexual orientation; 7 (18.9%) voluntarily disclosed their HIV status only, and 3 (8.1%) involuntarily disclosed their HIV status and sexual orientation. Parents, partners, siblings and close friends were the most common disclosure targets. HIV-positive MSM were less likely to disclose their sexual orientation than their HIV status. The positive consequences of disclosure included receiving support, acquiring family care, reducing stress, improving mood and developing more positive values and beliefs. The negative consequences included the participants' perception of rejection and stigma toward themselves and their families. However, the stigma mainly comes from "outsiders" rather than family members and close friends. We did not find any differences with respect to consequences between participants who disclosed their HIV status only and those who disclosed both their HIV status and sexual orientation. In conclusion, partners, siblings and friends were main disclosure targets, and HIV positive MSM preferred to disclose their HIV serostatus than their sexual orientation. Voluntarily disclosing one's HIV status to significant others resulted in more positive consequences than negative consequences. Theses results were informative for developing mental health and coping interventions. PMID- 26002092 TI - Retaining vets in farm animal practice: a cross-sectional study. AB - Concerns have been raised about a potential shortage of farm animal vets in the UK. There is no apparent lack of new graduates willing to work with farm animals, but practices report difficulties in recruiting and retaining experienced farm animal vets. Retention of vets in farm animal practice has been identified as a key issue for the sustainability of veterinary businesses and livestock health. A cross-sectional study design was used to identify factors associated with vets remaining in farm animal practice. Data were collected via an online questionnaire covering employment, education, personal background and future plans. The target population was vets with experience of farm animal work in the UK. 380 responses were included in the analysis. Working in a practice where accommodation was provided and an increasing number of years since graduation were associated with significantly lower odds of remaining in farm animal practice, while working in a practice where staff appraisals were carried out; coming from a family with a commercial farm; spending more time on farm work and being on call with an experienced vet in the first job after graduation increased the odds of remaining in farm work. Gender was not significantly associated with retention. PMID- 26002091 TI - "Everybody brush!": protocol for a parallel-group randomized controlled trial of a family-focused primary prevention program with distribution of oral hygiene products and education to increase frequency of toothbrushing. AB - BACKGROUND: Twice daily toothbrushing with fluoridated toothpaste is the most widely advocated preventive strategy for dental caries (tooth decay) and is recommended by professional dental associations. Not all parents, children, or adolescents follow this recommendation. This protocol describes the methods for the implementation and evaluation of a quality improvement health promotion program. OBJECTIVE: The objective of the study is to show a theory-informed, evidence-based program to improve twice daily toothbrushing and oral health related quality of life that may reduce dental caries, dental treatment need, and costs. METHODS: The design is a parallel-group, pragmatic randomized controlled trial. Families of Medicaid-insured children and adolescents within a large dental care organization in central Oregon will participate in the trial (n=21,743). Families will be assigned to one of three groups: a test intervention, an active control, or a passive control condition. The intervention aims to address barriers and support for twice-daily toothbrushing. Families in the test condition will receive toothpaste and toothbrushes by mail for all family members every three months. In addition, they will receive education and social support to encourage toothbrushing via postcards, recorded telephone messages, and an optional participant-initiated telephone helpline. Families in the active control condition will receive the kit of supplies by mail, but no additional instructional information or telephone support. Families assigned to the passive control will be on a waiting list. The primary outcomes are restorative dental care received and, only for children younger than 36 months old at baseline, the frequency of twice-daily toothbrushing. Data will be collected through dental claims records and, for children younger than 36 months old at baseline, parent interviews and clinical exams. RESULTS: Enrollment of participants and baseline interviews have been completed. Final results are expected in early summer, 2017. CONCLUSIONS: If proven effective, this simple intervention can be sustained by the dental care organization and replicated by other organizations and government. TRIAL REGISTRATION: TRIAL REGISTRATION: ClinicalTrials.gov NCT02327507; http://clinicaltrials.gov/ct2/show/NCT02327507 (Archived by WebCite at http://www.webcitation.org/6YCIxJSor). PMID- 26002093 TI - Responses of benthic foraminifera to the 2011 oil spill in the Bohai Sea, PR China. AB - The 2011 oil spill in the Bohai Sea was the largest spill event in China. Nine sediment cores were taken near the spill site and environmental factors including Polycyclic Aromatic Hydrocarbon (PAHs), oils, sulfides, organic carbon were measured 6 months later. Benthic foraminifera were separated into >150 MUm (large) and 63-150 MUm (small) size fractions for 2-cm depth interval of each sediment core. Statistical analyses suggested that the species composition of living foraminifera was impacted by oils, PAHs and sulfides. Large foraminifera were more sensitive to the oils than the small. Abnormal specimens were positively correlated with oils or PAHs. Small forms, however, tended to have high reproduction and mortality. Pollution-resistant and opportunistic taxa were identified to calculate a Foraminiferal Index of Environmental Impacts (FIEI). The FIEI increased from low to high oil-polluted station and from deep layer to surface sediment reflects the impact of oil pollution in this area. PMID- 26002094 TI - Quantification of the effect of oil layer thickness on entrainment of surface oil. AB - This study quantifies the effect of oil layer thickness on entrainment and dispersion of oil into seawater, using a plunging jet with a camera system. In contrast to what is generally assumed, we revealed that for the low viscosity "surrogate MC252 oil" we used, entrainment rate is directly proportional to layer thickness. Furthermore, the volume of stably suspended small oil droplets increases with energy input (plunge height) and is mostly proportional to layer thickness. Oil pre-treated with dispersants (dispersant-oil ratio ranges from 1:50 to 1:300) is greatly entrained in such large amounts of small droplets that quantification was impossible with the camera system. Very low interfacial tension causes entrainment by even minor secondary surface disturbances. Our results indicate that the effect of oil layer thickness should be included in oil entrainment and dispersion modelling. PMID- 26002095 TI - Baseline nutrient dynamics in shallow well mixed coastal lagoon with seasonal harmful algal blooms and hypoxia formation. AB - Weekly inorganic nutrient and chlorophyll-a concentrations were measured to establish baseline conditions in Corpus Christi Bay, Texas during seasonal hypoxia and harmful algal bloom (HAB) formation. Two fixed stations along the southern shoreline were sampled weekly for a continuous year at the same time each day. Weekly shoreline observations were found to be statistically similar to quarterly observations in the bay center, but with a greater power to detect seasonal trends. Dissolved Oxygen (DO)<4 mg/L was measured in June, 2012 along the southern shoreline of Corpus Christi Bay, which places lower DO conditions west of previous estimates. During a bay-wide HAB event in November of 2011 no changes were observed in any of the nutrient or chlorophyll-a observations. This study documents a baseline of nutrients and chlorophyll-a in Corpus Christi Bay during a dry (average salinity>36 PSU) year. PMID- 26002096 TI - Hydrophobic poly(alkoxysilane) organogels as sorbent material for oil spill cleanup. AB - In this study, reusable poly(alkoxysilane) organogels with high absorption capacities were synthesized by the condensation of a cyclo aliphatic glycol (UNOXOLTM) and altering the chain length of the alkyltriethoxysilanes. The structural and thermal properties of cross-linked poly(alkoxysilane) polymers were determined by FTIR, solid-state (13)C and (29)Si CPMAS NMR and TGA. The oil absorbency of poly(alkoxysilane)s was determined through oil absorption tests, absorption and desorption kinetics. Results showed that the highest oil absorbency capacities were found to be 295% for hexane, 389% for euro diesel, 428% for crude oil, 652% for gasoline, 792% for benzene, 792% for toluene, 868% for tetrahydrofuran, and 1060% for dichloromethane for the poly(alkoxysilane) gels based on UNOXOLTM and dodecyltriethoxysilane. Owing to their hydrophobic structure, the poly(alkoxysilane) organogels can selectively absorb crude oil from water. The reusability of the absorbents was quantitatively investigated, demonstrating that absorbents can be used effectively at least nine times. PMID- 26002097 TI - Modelling the fate of micropollutants in the marine environment using passive sampling. AB - Polydimethylsiloxane sheets were used to determine freely dissolved concentrations (C(diss)) of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in the Belgian coastal zone. Equilibrium models were used to predict the whole water concentrations (C(ww)) of these compounds as well as their concentrations in sediment, suspended particulate matter (SPM) and biota. In general, contaminant concentrations were predicted well for whole water and biota. C(ww) was increasingly underpredicted as K(oc) increased, possibly because of the presence of black carbon. Concentrations in biota were overestimated by the equilibrium approach when logK(ow) exceeded 6.5, suggesting an increasing role of transformation processes. Concentrations of PAHs and PCBs in sediment and SPM were consistently underpredicted although a good correlation between measured and predicted values was observed. This was potentially due to the use of experimental K(oc) values which have been found to underestimate partitioning of hydrophobic substances to sediment in field studies. PMID- 26002098 TI - Preliminary study on brominated dioxins/furans and hydroxylated/methoxylated PBDEs in Baltic cod (Gadus morhua) liver. Comparison to the levels of analogue chlorinated co-occurring pollutants. AB - Low pg levels of PBDD/Fs in 0.8-38.9 pg g(-1) (fat) range (mean 14.2 pg g(-1)) observed in the tested cod liver samples were significantly lower than levels of their chlorinated analogues (25.1-95.9 range, 37.7 mean pg g(-1) fat). Brominated furans dominated the congener profile. Elevated levels of OH-/MeO-BDE were however observed with mean concentrations at 2769+/-1319 and 5441+/-2918 pg g(-1) (fat) respectively. The observed congener profiles with the predominance of 6-OH BDE 47 and the relatively high proportion between the native and hydroxylated compounds indicate on natural origin of those compounds or at least presence of various exposure sources. A large fraction of studied samples did not comply with the currently standing EU regulations concerning PCBs and chlorinated dioxins (11%), especially as regards non-dioxin like PCBs (88%). PMID- 26002099 TI - Distribution and assessment of heavy metals off the Changjiang River mouth and adjacent area during the past century and the relationship of the heavy metals with anthropogenic activity. AB - Forty-three surface sediment samples and one gravity core obtained from the offshore area of the Changjiang River were analyzed for selected heavy metals (Cu, Pb, Zn, Cd, As, Hg) to evaluate the spatial distribution and potential ecological risk during the last century. The results indicated that the sediments are composed of silty sand, sandy silt and silt and were deposited in a relatively stable environment over the last century. The studied marine sediments are fine and easily adsorb heavy metals from aquatic systems. The heavy metal concentrations were found to be enriched in the sediments and were generally closely related to anthropogenic activities. However, the data analysis demonstrated that the levels of heavy metal contamination were below background values during the last century, indicating low ecological risk. Spatially, a higher concentration was found at the entrance to the Changjiang River, while it decreased to the northeast. The vertical distribution of contamination levels and ecological risk can be divided into four periods based on the downcore variation in heavy metals: pre-1940s, 1940s-1970s, 1970s-1990s and the late 1990s to the present. These conclusions form the basis for implementing appropriate policies to protect marine sediment quality. PMID- 26002100 TI - Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD TDP) are two neurodegenerative disorders characterized by the accumulation of TDP 43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FTLD TDP and ALS; however, little is known about its role in disease pathogenesis. We have previously developed transgenic mice overexpressing low levels of TDP-25 (TgTDP-25(+/0)), which at 6 months of age show mild cognitive impairments and no motor deficits. To better understand the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP, we generated TDP-25 homozygous mice (TgTDP-25(+/+)), thereby further increasing TDP-25 expression. We found a gene-dosage effect on cognitive and motor function at 15 months of age, as the TgTDP-25(+/+) showed more severe spatial and working memory deficits as well as worse motor performance than TgTDP 25(+/0) mice. These behavioral deficits were associated with increased soluble levels of TDP-25 in the nucleus and cytosol. Notably, high TDP-25 levels were also linked to reduced autophagy induction and proteasome function, two events that have been associated with both ALS and FTLD-TDP. In summary, we present strong in vivo evidence that high levels of TDP-25 are sufficient to cause behavioral deficits and reduce function of two of the major protein turnover systems: autophagy and proteasome. These mice represent a new tool to study the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP. PMID- 26002101 TI - Model mice for 15q11-13 duplication syndrome exhibit late-onset obesity and altered lipid metabolism. AB - Copy number variations on human chromosome 15q11-q13 have been implicated in several neurodevelopmental disorders. A paternal loss or duplication of the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region confers a risk of obesity, although the mechanism remains a mystery due to a lack of an animal model that accurately recreates the obesity phenotype. We performed detailed analyses of mice with duplication of PWS/AS locus (6 Mb) generated by chromosome engineering and found that animals with a paternal duplication of this region (patDp/+) show late-onset obesity, high sensitivity for high-fat diet, high levels of blood leptin and insulin without an increase in food intake. We show that prior to becoming obese, young patDp/+ mice already had enlarged white adipocytes. Transcriptome analysis of adipose tissue revealed an up-regulation of Secreted frizzled-related protein 5 (Sfrp5), known to promote adipogenesis. We additionally generated a new mouse model of paternal duplication focusing on a 3 Mb region (3 Mb patDp/+) within the PWS/AS locus. These mice recapitulate the obese phenotypes including expansion of visceral adipose tissue. Our results suggest paternally expressed genes in PWS/AS locus play a significant role for the obesity and identify new potential targets for future research and treatment of obesity. PMID- 26002102 TI - X chromosome-linked intellectual disability protein PQBP1 associates with and regulates the translation of specific mRNAs. AB - X chromosome-linked intellectual disability is a common developmental disorder, and mutations of the polyglutamine-binding protein 1 (PQBP1) gene have been linked to this disease. In addition to existing in the nucleus as a splicing factor, PQBP1 is also found in cytoplasmic RNA granules, where it associates with RNA-binding proteins. However, the roles of cytoplasmic PQBP1 are largely unknown. Here, we show that the Drosophila homolog of PQBP1 (dPQBP1) is present in the cytoplasm of photoreceptor cells, and its loss results in defective rhabdomere morphogenesis, which is due to impaired Chaoptin translation. We also show that dPQBP1 regulates mRNA translation by interacting with dFMR1, which binds to specific mRNAs and facilitates their assembly into translating ribosomes, a function that is conserved for human PQBP1 and FMRP. Our findings reveal the conserved function of PQBP1 in mRNA translation and provide molecular insights into the pathogenic mechanisms underlying Renpenning syndrome. PMID- 26002104 TI - A successful attempt to prevent postoperative adhesions between the mediastinum and a lung: a canine model. AB - A bioabsorbable sheet was sutured to cover the right-sided mediastinal pleurectomy defect, whereas not in a control. There was a significant difference in mediastinal adhesions with a lung between the groups. Our findings suggested that the sheet may prevent postoperative adhesions between the mediastinum and a lung. PMID- 26002103 TI - CDK5 phosphorylates DRP1 and drives mitochondrial defects in NMDA-induced neuronal death. AB - Defects in mitochondrial fission and cyclin dependent kinase 5 (CDK5) activation are early events that precede neuronal loss following NMDA-induced neuronal death. Here, we report that the cytoplasmic CDK5 tightly regulates mitochondrial morphology defects associated with NMDA-induced neuronal injury via regulation of the mitochondrial fission protein, dynamin-related protein 1 (DRP1). We show that DRP1 is a direct target of CDK5. CDK5-mediated phosphorylation of DRP1 at a conserved Serine residue, S585, is elevated at the mitochondria and is associated with increased mitochondrial fission. Ectopic expression of a cytoplasmic CDK5 or mutant DRP1-S585D results in increased mitochondrial fragmentation in primary neurons. Conversely, expression of a dominant negative form of cytoplasmic CDK5 or mutant DRP1-S585A results in elongated mitochondria. In addition, pharmacological inhibition of CDK5 by Roscovitine inhibits DRP1 phosphorylation and mitochondrial fission associated with NMDA-induced neuronal loss. Importantly, conditional deletion of CDK5 significantly attenuates DRP1 phosphorylation at S585 and rescues mitochondrial fission defects in neurons exposed to NMDA. Our studies delineate an important mechanism by which CDK5 regulates mitochondrial morphology defects associated with neuronal injury. PMID- 26002105 TI - A closer study of peak distortions in supercritical fluid chromatography as generated by the injection. AB - In SFC the sample cannot be dissolved in the mobile phase, so it is often dissolved in pure modifier, or another liquid, sometimes resulting in serious distortions of the eluted peak profiles already at moderately high injection volumes. It is suspected the reasons for these effects are solvent strength mismatch and/or viscosity mismatch. This study presents a systematic and fundamental investigation of the origin of these peak deformations due to the injection solvent effects in SFC, using both systematic experiments and numerical modeling. The first set of experiments proved that the injection volume and the elution strength of the sample solution had a major impact of the shapes of the eluted peaks. Secondly, the sample band elution profile was numerically modeled on a theoretical basis assuming both un-retained and retained co-solvent injection plugs, respectively. These calculations quantitatively confirmed our first set of experiments but also pointed out that there is also an additional significant effect. Third, viscous fingering experiments were performed using viscosity contrast conditions imitating those encountered in SFC. These experiments clearly proved that viscous fingering effects play a significant role. A new method for determination of adsorption isotherms of solvents was also developed, called the "Retention Time Peak Method" (RTPM). The RTPM was used for fast estimation of the adsorption isotherms of the modifier and required using only two experiments. PMID- 26002106 TI - Comparison of zonal elution and nonlinear chromatography in determination of the interaction between seven drugs and immobilised beta(2)-adrenoceptor. AB - Zonal elution and nonlinear chromatography are two mainstream models for the determination of drug-protein interaction in affinity chromatography. This work intended to compare the results by zonal elution with that by nonlinear chromatography when it comes to the analysis of the interaction between seven drugs and immobilised beta2-adrenoceptor (beta2-AR). The results of the zonal elution showed that clorprenaline, clenbuterol, methoxyphenamine, salbutamol, terbutaline, tulobuterol and bambuterol have only one type of binding site on immobilised beta2-AR, while nonlinear chromatography confirmed the existence of at least two types of binding sites between beta2-AR and clorprenaline, clenbuterol and bambuterol. On these sites, both zonal elution and nonlinear chromatography presented the same rank order for the association constants of the seven drugs. Compared with the data from zonal elution, the association constants calculated using nonlinear chromatography gave a good linear response to the corresponding values by radio-ligand binding assay. The sampling efficiencies of nonlinear chromatography were clearly higher than zonal elution. Nonlinear chromatography will probably become a powerful alternative for the high throughput determination of drug-protein interaction. PMID- 26002107 TI - Achalasia symptom response after Heller myotomy segregated by high-resolution manometry subtypes. AB - BACKGROUND: Achalasia is classified into three HRM subtypes that predict outcomes from diverse management strategies. We assessed if symptomatic response varied when a single management strategy-Heller myotomy (HM)-is employed. METHODS: Treatment-naive subjects with achalasia referred for HM were followed in this observational cohort study. Chicago criteria designated achalasia subtypes (subtype I: no esophageal pressurization; subtype II: panesophageal pressurization in >=20 % swallows; subtype III: premature contractions in >=20 % swallows). Symptom questionnaires assessed symptom burden before and after HM on five-point Likert scales (0 = no symptoms, 4 = severe symptoms) and on 10-cm visual analog scales (global symptom severity, GSS); satisfaction with HM was recorded similarly. Data were analyzed to determine predictors of GSS change across subtypes. RESULTS: Sixty achalasia subjects (56.1 +/- 2.4 years, 55 % female) fulfilled inclusion criteria, 15 % with subtype I, 58 % with subtype II, and 27 % with subtype III achalasia. Baseline symptoms included dysphagia (solids: 85 %, liquids: 73 %), regurgitation (84 %), and chest pain (35 %); mean GSS was 7.1 +/- 0.3. Upon follow-up 2.1 +/- 0.2 years after HM, GSS declined to 1.9 +/- 0.4 (p < 0.001), with surgical satisfaction score of 8.7 +/- 0.3 out of 10; these were similar across achalasia subtypes. On univariate analysis, female gender, Eckardt score, severity of transit symptoms, and maximal IRP predicted linear GSS improvement; female gender (p = 0.003) and dysphagia for liquids (p = 0.043) remained predictive on multivariate analysis. CONCLUSIONS: When a uniform surgical approach is utilized, symptomatic outcome and satisfaction with therapy are similar across achalasia subtypes. Female gender and severity of dysphagia for solids may predict better HM outcome. PMID- 26002108 TI - Assessing Connections Between Behavior Change Theories Using Network Analysis. AB - BACKGROUND: A cross-disciplinary scoping review identified 83 of behavior change theories, with many similarities and overlapping constructs. Investigating the derivation of these theories may provide further understanding of their contribution and intended application. PURPOSE: To develop and apply a method to describe the explicit derivation of theories of behavior change. METHODS: A network analysis of the explicit "contributing to" relations between the 83 theories was conducted. Identification of relations involved textual analysis of primary theory sources. FINDINGS: One hundred and twenty-two connections between the theories were identified amounting to 1.8% of the number possible. On average, theories contributed to one or two theories (mean = 1.47 +/- 3.69 contributions) and were informed by one or two theories (mean = 1.47 +/- 1.61 contributing theories). DISCUSSION: Most behavior change theories appear to be explicitly informed by few prior theories. If confirmed, this suggests a considerable dislocation between generations of theories which would be expected to undermine scientific progress. PMID- 26002109 TI - Purification and biochemical characterization of two detergent-stable serine alkaline proteases from Streptomyces sp. strain AH4. AB - Streptomyces sp. strain AH4 exhibited a high ability to produce two extracellular proteases when cultured on a yeast malt-extract (ISP2)-casein-based medium. Pure proteins were obtained after heat treatment (30 min at 70 degrees C) and ammonium sulphate fractionation (30-60 %), followed by size exclusion HPLC column. Matrix assisted laser desorption ionization-time of flight mass spectrometry analysis revealed that the purified enzymes (named SAPS-P1 and SAPS P2) were monomers with molecular masses of 36,417.13 and 21,099.10 Da, respectively. Their identified N-terminal amino acid displayed high homologies with those of Streptomyces proteases. While SAPS-P1 was optimally active at pH 12.0 and 70 degrees C, SAPS-P2 showed optimum activity at pH 10.0 and 60 degrees C. Both enzymes were completely stable within a wide range of temperature (45-75 degrees C) and pH (8.0-11.5). They were noted to be completely inhibited by phenylmethanesulfonyl fluoride and diisopropyl fluorophosphates, which confirmed their belonging to the serine proteases family. Compared to SAPS-P2, SAPS-P1 showed high thermostability and excellent stability towards bleaching, denaturing, and oxidizing agents. Both enzymes displayed marked stability and compatibility with a wide range of commercial laundry detergents and significant catalytic efficiencies compared to Subtilisin Carlsberg and Protease SG-XIV. Overall, the results indicated that SAPS-P1 and SAPS-P2 can be considered as potential promising candidates for future application as bioadditives in detergent formulations. PMID- 26002110 TI - Neoadjuvant chemotherapy for ovarian cancer: do we have enough evidence? PMID- 26002111 TI - Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. AB - BACKGROUND: The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen. METHODS: In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m(2), or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1.18. This trial is registered, number ISRCTN74802813, and is closed to new participants. FINDINGS: Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22.6 months in the primary-surgery group versus 24.1 months in primary chemotherapy. The HR for death was 0.87 in favour of primary chemotherapy, with the upper bound of the one sided 90% CI 0.98 (95% CI 0.72-1.05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0.0007, and 14 women [6%] vs 1 woman [<1%], p=0.001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0.0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group. INTERPRETATION: In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer. FUNDING: Cancer Research UK and the Royal College of Obstetricians and Gynaecologists. PMID- 26002112 TI - Reducing Accidental Dislodgement of the Percutaneous Endoscopic Gastrostomy: A Prospective Trial of the "SafetyBreak" Device. AB - BACKGROUND: The percutaneous endoscopic gastrostomy (PEG) is a ubiquitous feeding tube with high rates of accidental dislodgement, with significant morbidity and health care costs. We hypothesized use of a decoupling device is a safe and effective mechanism to reduce dislodgements. STUDY DESIGN: We studied a prospective cohort of 100 patients from an academic center. Enrollment included patients requiring PEG tube placement with follow up extending through an individual's lifetime use of their PEG tube. The primary endpoint was accidental dislodgement of the principally placed PEG tube. The secondary endpoint was time to accidental dislodgement of the PEG tube. RESULTS: All 100 patients received the SafetyBreak device and had complete follow-up. Half of the patients had at least a single episode of device decoupling, indicating prevention of dislodgement of the PEG. Eight patients ultimately had dislodgement, resulting in a significantly lower dislodgement rate when compared with a historical cohort (P = .036) and significantly longer survival of the PEG (log rank = 0.005). When compared with a concurrent cohort (without the device) there was also significantly lower dislodgement rate (P = .03) and a trend toward longer survival of the PEG (log rank = 0.08). CONCLUSIONS: When compared with both a historical and concurrent cohort of patients, the SafetyBreak device reduces accidental dislodgement of PEG tubes. As an increasing number of PEGs are being placed, an increasing number of patients are at risk for dislodgement. The SafetyBreak device is an innovative, economical solution to the problem of accidental dislodgement of the PEG tube. PMID- 26002113 TI - Antonin Poncet (1849-1913): The Innovator Who Changed Surgical Operations With His Dogma of "Clear Open Surgery" ("Chirurgie a Ciel Ouvert"). PMID- 26002114 TI - Laparoscopic Mobilization of a Rectus Abdominis Myofascial Flap for the Prevention of Perineal Hernia Post-Abdominoperineal Resection of the Rectum: A Feasibility Study? PMID- 26002115 TI - Leap Motion Gesture Control With Carestream Software in the Operating Room to Control Imaging: Installation Guide and Discussion. AB - Nowadays, routine cross-sectional imaging viewing during a surgical procedure requires physical contact with an interface (mouse or touch-sensitive screen). Such contact risks exposure to aseptic conditions and causes loss of time. Devices such as the recently introduced Leap Motion (Leap Motion Society, San Francisco, CA), which enables interaction with the computer without any physical contact, are of wide interest in the field of surgery, but configuration and ergonomics are key challenges for the practitioner, imaging software, and surgical environment. This article aims to suggest an easy configuration of Leap Motion on a PC for optimized use with Carestream Vue PACS v11.3.4 (Carestream Health, Inc, Rochester, NY) using a plug-in (to download at https://drive.google.com/open?id=0B_F4eBeBQc3yNENvTXlnY09qS00&authuser=0) and a video tutorial (https://www.youtube.com/watch?v=yVPTgxg-SIk). Videos of surgical procedure and discussion about innovative gesture control technology and its various configurations are provided in this article. PMID- 26002117 TI - Recent advances in omic technologies for meat quality management. AB - The knowledge of the molecular organization of living organisms evolved considerably during the last years. The methodologies associated also progressed with the development of the high-throughput sequencing (SNP array, RNAseq, etc.) and of genomic tools allowing the simultaneous analysis of hundreds or thousands of genes, proteins or metabolites. In farm animals, some proteins, mRNAs or metabolites whose abundance has been associated with meat quality traits have been detected in pig, cattle, chicken. They constitute biomarkers for the assessment and prediction of qualities of interest in each species, with potential biomarkers across species. The ongoing development of rapid methods will allow their use for decision-making and management tools in slaughterhouses, to better allocate carcasses or cuts to the appropriate markets. Besides, their application on living animals will help to improve genetic selection and to adapt a breeding system to fulfill expected quality level. The ultimate goal is to propose effective molecular tools for the management of product quality in meat production chains. PMID- 26002116 TI - A purified truncated form of yeast Gal4 expressed in Escherichia coli and used to functionalize poly(lactic acid) nanoparticle surface is transcriptionally active in cellulo. AB - Gal4/UAS system is a powerful tool for the analysis of numerous biological processes. Gal4 is a large yeast transcription factor that activates genes including UAS sequences in their promoter. Here, we have synthesized a minimal form of Gal4 DNA sequence coding for the binding and dimerization regions, but also part of the transcriptional activation domain. This truncated Gal4 protein was expressed as inclusion bodies in Escherichia coli. A structured and active form of this recombinant protein was purified and used to cover poly(lactic acid) (PLA) nanoparticles. In cellulo, these Gal4-vehicles were able to activate the expression of a Green Fluorescent Protein (GFP) gene under the control of UAS sequences, demonstrating that the decorated Gal4 variant can be delivery into cells where it still retains its transcription factor capacities. Thus, we have produced in E. coli and purified a short active form of Gal4 that retains its functions at the surface of PLA-nanoparticles in cellular assay. These decorated Gal4-nanoparticles will be useful to decipher their tissue distribution and their potential after ingestion or injection in UAS-GFP recombinant animal models. PMID- 26002118 TI - Exploring future patterns of meat consumption. AB - The nutrition transition encompasses a set of major shifts in human diet and nutritional status, throughout history and that is influenced by a wide range of factors such as income, technical change, urbanisation and culture. High-income societies are witnessing a shift towards diets with more fat, sugar, processed foods and less fibre, leading to a sharp increase in non-communicable diseases, such as obesity. This trend can also be observed among the middle classes of emerging countries. However, increasing evidence suggests that a final shift is occurring, following behavioural change towards consuming higher-quality fats, more whole grains, fruit and vegetables, and particularly less meat. The purpose of this paper is twofold. First, an assessment is made of where different countries are located in the different phases of the nutrition transition. Second, a qualitative investigation is made into the factors enhancing and hindering the latest phase of the transition-particularly towards less meat consumption-taking into account cultural differences between consumer groups across countries. The analysis of both objectives generates insights into possible future scenarios of meat consumption. PMID- 26002119 TI - A new frontier: oral microbes without borders. PMID- 26002120 TI - Technique for comprehensive head and neck irradiation using 3-dimensional conformal proton therapy. AB - Owing to the technical and logistical complexities of matching photon and proton treatment modalities, we developed and implemented a technique of comprehensive head and neck radiation using 3-dimensional (3D) conformal proton therapy. A monoisocentric technique was used with a 30-cm snout. Cervical lymphatics were treated with 3 fields: a posterior-anterior field with a midline block and a right and a left posterior oblique field. The matchline of the 3 cervical nodal fields with the primary tumor site fields was staggered by 0.5cm. Comparative intensity-modulated photon plans were later developed for 12 previously treated patients to provide equivalent target coverage, while matching or improving on the proton plans' sparing of organs at risk (OARs). Dosimetry to OARs was evaluated and compared by treatment modality. Comprehensive head and neck irradiation using proton therapy yielded treatment plans with significant dose avoidance of the oral cavity and midline neck structures. When compared with the generated intensity-modulated radiation therapy (IMRT) plans, the proton treatment plans yielded statistically significant reductions in the mean and integral radiation dose to the oral cavity, larynx, esophagus, and the maximally spared parotid gland. There was no significant difference in mean dose to the lesser-spared parotid gland by treatment modality or in mean or integral dose to the spared submandibular glands. A technique for cervical nodal irradiation using 3D conformal proton therapy with uniform scanning was developed and clinically implemented. Use of proton therapy for cervical nodal irradiation resulted in large volume of dose avoidance to the oral cavity and low dose exposure to midline structures of the larynx and the esophagus, with lower mean and integral dose to assessed OARs when compared with competing IMRT plans. PMID- 26002121 TI - Effect of intrafractional prostate motion on simultaneous boost intensity modulated radiotherapy to the prostate: a simulation study based on intrafractional motion in the prone position. AB - Although the prostate displacement of patients in the prone position is affected by respiration-induced motion, the effect of intrafractional prostate motion in the prone position during "simultaneous integrated boost intensity-modulated radiotherapy" (SIB-IMRT) is unclear. The purpose of this study was to evaluate the dosimetric effects of intrafractional motion on SIB-IMRT to a dominant intraprostatic lesion (IPL) using measured motion data of patients in a prone position, fixed with a thermoplastic shell. We obtained 2 orthogonal x-ray fluoroscopic images at the same moment every 0.2 seconds for 30 seconds before and after treatment, once weekly, from 7 patients with localized prostate cancer with detectable prostatic calcification. Prostate displacements in the left-right (LR), anteroposterior (AP), and superoinferior (SI) directions were calculated using the prostatic calcification as a fiducial marker. We defined the displacement between pretreatment and posttreatment as baseline drift (BD). An SIB-IMRT plan was generated in which each IPL + 3mm received a dose of 94.5Gy, whereas the remainder of the prostate + 7mm received a dose of 75.6Gy in 9 fields. A simulated plan of dose blurring was generated by the convolution of isocenter-shifted plans using measured motion data in 30 seconds and motion in 30 seconds + distance between pretreatment and posttreatment position (BD) for each of the 7 patients. The motion in 30 seconds mainly reflected respiration-induced motion. The mean displacements of BD were 1.4mm (- 3.1 to 8.2mm), - 2.2mm (- 9.1 to 1.5mm), and - 0.3mm (- 5.0 to 1.8mm) in the AP, SI, and LR directions, respectively. The differences in the target coverage with V90% of the IPL and V100% of the prostate between the simulated plan and original plan were - 3.9% to - 0.3% and - 0.6% to 1.1% for respiration-induced motion and 3.1% to - 67.8% and 3.6% to - 13.3% for BD with respiration-induced motion, respectively. The large motion of BD resulted in an inadequate coverage by the prescribed dose of the SIB IMRT to the IPL. A 7-mm margin is recommended when real-time tracking techniques are not applied. The effect of respiration-induced motion was small, so long as a 3-mm margin was added. PMID- 26002122 TI - Dosimetric benefit of adaptive re-planning in pancreatic cancer stereotactic body radiotherapy. AB - Stereotactic body radiotherapy (SBRT) shows promise in unresectable pancreatic cancer, though this treatment modality has high rates of normal tissue toxicity. This study explores the dosimetric utility of daily adaptive re-planning with pancreas SBRT. We used a previously developed supercomputing online re-planning environment (SCORE) to re-plan 10 patients with pancreas SBRT. Tumor and normal tissue contours were deformed from treatment planning computed tomographies (CTs) and transferred to daily cone-beam CT (CBCT) scans before re-optimizing each daily treatment plan. We compared the intended radiation dose, the actual radiation dose, and the optimized radiation dose for the pancreas tumor planning target volume (PTV) and the duodenum. Treatment re-optimization improved coverage of the PTV and reduced dose to the duodenum. Within the PTV, the actual hot spot (volume receiving 110% of the prescription dose) decreased from 4.5% to 0.5% after daily adaptive re-planning. Within the duodenum, the volume receiving the prescription dose decreased from 0.9% to 0.3% after re-planning. It is noteworthy that variation in the amount of air within a patient's stomach substantially changed dose to the PTV. Adaptive re-planning with pancreas SBRT has the ability to improve dose to the tumor and decrease dose to the nearby duodenum, thereby reducing the risk of toxicity. PMID- 26002123 TI - Comparison of a new noncoplanar intensity-modulated radiation therapy technique for craniospinal irradiation with 3 coplanar techniques. AB - When standard conformal x-ray technique for craniospinal irradiation is used, it is a challenge to achieve satisfactory dose coverage of the target including the area of the cribriform plate, while sparing organs at risk. We present a new intensity-modulated radiation therapy (IMRT), noncoplanar technique, for delivering irradiation to the cranial part and compare it with 3 other techniques and previously published results. A total of 13 patients who had previously received craniospinal irradiation with standard conformal x-ray technique were reviewed. New treatment plans were generated for each patient using the noncoplanar IMRT-based technique, a coplanar IMRT-based technique, and a coplanar volumetric-modulated arch therapy (VMAT) technique. Dosimetry data for all patients were compared with the corresponding data from the conventional treatment plans. The new noncoplanar IMRT technique substantially reduced the mean dose to organs at risk compared with the standard radiation technique. The 2 other coplanar techniques also reduced the mean dose to some of the critical organs. However, this reduction was not as substantial as the reduction obtained by the noncoplanar technique. Furthermore, compared with the standard technique, the IMRT techniques reduced the total calculated radiation dose that was delivered to the normal tissue, whereas the VMAT technique increased this dose. Additionally, the coverage of the target was significantly improved by the noncoplanar IMRT technique. Compared with the standard technique, the coplanar IMRT and the VMAT technique did not improve the coverage of the target significantly. All the new planning techniques increased the number of monitor units (MU) used-the noncoplanar IMRT technique by 99%, the coplanar IMRT technique by 122%, and the VMAT technique by 26%-causing concern for leak radiation. The noncoplanar IMRT technique covered the target better and decreased doses to organs at risk compared with the other techniques. All the new techniques increased the number of MU compared with the standard technique. PMID- 26002124 TI - Multiple procedures and cumulative individual radiation exposure in interventional cardiology: A long-term retrospective study. AB - INTRODUCTION: Various studies address discrepancies between guideline recommendations for coronary angiographies and clinical practice. While the issue of the appropriateness of recurrent angiographies was studied focusing on the role of the cardiologist, little is known about individual patients' histories and the associated radiation exposures. METHODS: We analyzed all patients with coronary artery disease (CAD) in an academic teaching practice who underwent at least one angiography with or without intervention between 2004 and 2009. All performed angiographies in these patients were analyzed and rated by three physicians for appropriateness levels according to cardiology guidelines. Typical exposure data from the medical literature were used to estimate individual radiation exposure. RESULTS: In the cohort of 147 patients, a total of 441 procedures were analyzed: between 1981 and 2009, three procedures were performed per patient (range 1-19) on average. Appropriateness ratings were 'high/intermediate' in 71%, 'low/no' in 27.6% and data were insufficient for ratings in 1.4%. Procedures with 'low/no' ratings were associated with potentially avoidable exposures of up to 186 mSv for single patients. CONCLUSIONS: Using retrospective data, we exemplify the potential benefit of guideline adherence to decrease patients' radiation exposures. KEY POINTS: * A cohort study of 147 patients showed 27.6% low appropriateness procedures. * Potentially avoidable radiation exposure cumulated up to about 186 mSv for single patients. * Predisposing factors were prior bypass surgery and first treatment in a tertiary centre. * 7.5% of the patients received 58% of the potentially avoidable radiation exposure. * The benefits of guideline adherence in decreasing patient radiation exposure are exemplified. PMID- 26002125 TI - Reconciling quality and cost: A case study in interventional radiology. AB - OBJECTIVES: To provide a method to calculate delay cost and examine the relationship between quality and total cost. METHODS: The total cost including capacity, supply and delay cost for running an interventional radiology suite was calculated. The capacity cost, consisting of labour, lease and overhead costs, was derived based on expenses per unit time. The supply cost was calculated according to actual procedural material use. The delay cost and marginal delay cost derived from queueing models was calculated based on waiting times of inpatients for their procedures. RESULTS: Quality improvement increased patient safety and maintained the outcome. The average daily delay costs were reduced from 1275 ? to 294 ?, and marginal delay costs from approximately 2000 ? to 500 ?, respectively. The one-time annual cost saved from the transfer of surgical to radiological procedures was approximately 130,500 ?. The yearly delay cost saved was approximately 150,000 ?. With increased revenue of 10,000 ? in project phase 2, the yearly total cost saved was approximately 290,000 ?. Optimal daily capacity of 4.2 procedures was determined. CONCLUSIONS: An approach for calculating delay cost toward optimal capacity allocation was presented. An overall quality improvement was achieved at reduced costs. KEY POINTS: * Improving quality in terms of safety, outcome, efficiency and timeliness reduces cost. * Mismatch of demand and capacity is detrimental to quality and cost. * Full system utilization with random demand results in long waiting periods and increased cost. PMID- 26002126 TI - Differentiating malignant vertebral tumours from non-malignancies with CT spectral imaging: a preliminary study. AB - OBJECTIVES: To investigate the value of dual-energy spectral computed tomography (DESCT) for differentiating malignant vertebral tumours from non-malignancies during venous phase. METHODS: This study was institutional review board-approved, and written informed consent was obtained from all patients. Thirty-seven patients were examined by DESCT during venous phase. Twenty patients had malignant vertebral tumours, 17 had non-malignant vertebral tumours. The iodine/water densities for the lesion, the lesion-to-muscle ratio, and lesion-to artery ratio for iodine density measurements were calculated and compared between the two groups with the two-tailed Student t test. A p-value < 0.05 was considered statistically significant. Sensitivity and specificity were compared between the qualitative and quantitative studies. RESULTS: The iodine density, lesion-to-muscle ratio, and lesion-to-artery ratio of the iodine density measurement for malignant vertebral tumours were significantly different from the respective values for non-malignancies (all p < 0.05). Using 0.52 as the threshold value for the lesion-to-artery iodine density ratio, one could obtain sensitivity of 85% and specificity of 100% for differentiating malignant vertebral tumours from non-malignancies, significantly higher than the qualitative diagnosis. CONCLUSIONS: DESCT imaging enables analysis of a number of additional quantitative CT parameters to improve the accuracy for differentiating malignant vertebral tumours from non-malignancies during venous phase. KEY POINTS: * Dual-energy CT provides a new quantitative method. * CT spectral imaging improves the accuracy of differential diagnosis. * Lesion-to-artery iodine density ratio for malignant vertebral tumours was higher than for non malignancies. PMID- 26002127 TI - Contrast-enhanced MRI features in the early diagnosis of Juvenile Idiopathic Arthritis. AB - OBJECTIVES: To determine whether clinical, laboratory or Magnetic Resonance Imaging (MRI) measures differentiate Juvenile Idiopathic Arthritis (JIA) from other forms of active childhood arthritis. MATERIALS AND METHODS: We prospectively collected data of 80 treatment-naive patients clinically suspected of JIA with active non-infectious arthritis of (at least) one knee for <12 months duration. Upon presentation patients underwent clinical and laboratory assessments and contrast-enhanced MRI. MRI was not used as a diagnostic criterion. RESULTS: Forty-four (55%) patients were clinically diagnosed with JIA, whereas in 36 (45%) patients the diagnosis of JIA was discarded on clinical or laboratory findings. MRI-based synovitis was present in 27 (61.4%) JIA patients and in 7 (19.4%) non-JIA patients (P < 0.001). Five factors (male gender, physician's global assessment of overall disease activity, joints with limited range of motion, HLA-B27, MRI-based synovitis) were associated with the onset of JIA. In multivariate analysis MRI-based synovitis proved to be independently associated with JIA (OR 6.58, 95% CI 2.36-18.33). In patients with MRI-based synovitis, the RR of having JIA was 3.16 (95% CI 1.6-6.4). CONCLUSIONS: The presence of MRI-based synovitis is associated with the clinical onset of JIA. Physical examination could be supported by MRI, particularly to contribute in the early differentiation of different forms of non-infectious childhood arthritis. KEY POINTS: * Juvenile Idiopathic Arthritis (JIA) is a diagnosis of exclusion. * Differentiating JIA and other forms of childhood arthritis can be difficult. * MRI-techniques have substantially improved evaluation of joint abnormalities in JIA patients. * MRI-based synovitis is significantly associated with the clinical onset of JIA. * MRI could support physical examination in the early differentiation of childhood arthritis. PMID- 26002128 TI - Astrocytic tumour grading: a comparative study of three-dimensional pseudocontinuous arterial spin labelling, dynamic susceptibility contrast enhanced perfusion-weighted imaging, and diffusion-weighted imaging. AB - OBJECTIVES: We hypothesized that three-dimensional pseudocontinuous arterial spin labelling (pCASL) may have similar efficacy in astrocytic tumour grading as dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI), and the grading accuracy may be further improved when combined with apparent diffusion coefficient (ADC) values. METHODS: Forty-three patients with astrocytic tumours were studied using diffusion weighted imaging (DWI), pCASL, and DSC-PWI. Histograms of ADC and normalized tumour cerebral blood flow values (nCBF on pCASL and nrCBF on DSC-PWI) were measured and analyzed. RESULTS: The mean 10 % ADC value was the DWI parameter that provided the best differentiation between low grade astrocytoma (LGA) and high-grade astrocytoma (HGA). The nCBF and nrCBF (1.810 +/- 0.979 and 2.070 +/- 1.048) in LGA were significantly lower than those (4.505 +/- 2.270 and 5.922 +/- 2.630) in HGA. For differentiation between LGA and HGA, the cutoff values of 0.764 * 10(-3) mm(2)/s for mean 10 % ADC, 2.374 for nCBF, and 3.464 for nrCBF provided the optimal accuracy (74.4 %, 86.1 %, and 88.6 %, respectively). Combining the ADC values with nCBF or nrCBF could further improve the grading accuracy to 97.7 % or 95.3 %, respectively. CONCLUSIONS: pCASL is an alternative to DSC-PWI for astrocytic tumour grading. The combination of DWI and contrast-free pCASL offers a valuable choice in patients with risk factors. KEY POINTS: * pCASL shows positive correlation with DSC-PWI in astrocytic tumour grading. * ADC values based on ADC histograms can be an objective method. * Combination of DWI and pCASL or DSC-PWI can improve grading accuracy. PMID- 26002129 TI - High resolution MRI for preoperative work-up of neonates with an anorectal malformation: a direct comparison with distal pressure colostography/fistulography. AB - OBJECTIVE: To compare MRI and colostography/fistulography in neonates with anorectal malformations (ARM), using surgery as reference standard. METHODS: Thirty-three neonates (22 boys) with ARM were included. All patients underwent both preoperative high-resolution MRI (without sedation or contrast instillation) and colostography/fistulography. The Krickenbeck classification was used to classify anorectal malformations, and the level of the rectal ending in relation to the levator muscle was evaluated. RESULTS: Subjects included nine patients with a bulbar recto-urethral fistula, six with a prostatic recto-urethral fistula, five with a vestibular fistula, five with a cloacal malformation, four without fistula, one with a H-type fistula, one with anal stenosis, one with a rectoperineal fistula and one with a bladderneck fistula. MRI and colostography/fistulography predicted anatomy in 88 % (29/33) and 61 % (20/33) of cases, respectively (p = 0.012). The distal end of the rectal pouch was correctly predicted in 88 % (29/33) and 67 % (22/33) of cases, respectively (p = 0.065). The length of the common channel in cloacal malformation was predicted with MRI in all (100 %, 5/5) and in 80 % of cases (4/5) with colostography/fistulography. Two bowel perforations occurred during colostography/fistulography. CONCLUSIONS: MRI provides the most accurate evaluation of ARM and should be considered a serious alternative to colostography/fistulography during preoperative work-up. KEY POINTS: * High-resolution MRI is feasible without the use of sedation or anaesthesia. * MRI is more accurate than colostography/fistulography in visualising the type of ARM. * MRI is as reliable as colostography/fistulography in predicting the level of the rectal pouch. * Colostography/fistulography can be complicated by bowel perforation. PMID- 26002130 TI - Breast MRI: EUSOBI recommendations for women's information. AB - This paper summarizes information about breast MRI to be provided to women and referring physicians. After listing contraindications, procedure details are described, stressing the need for correct scheduling and not moving during the examination. The structured report including BI-RADS(r) categories and further actions after a breast MRI examination are discussed. Breast MRI is a very sensitive modality, significantly improving screening in high-risk women. It also has a role in clinical diagnosis, problem solving, and staging, impacting on patient management. However, it is not a perfect test, and occasionally breast cancers can be missed. Therefore, clinical and other imaging findings (from mammography/ultrasound) should also be considered. Conversely, MRI may detect lesions not visible on other imaging modalities turning out to be benign (false positives). These risks should be discussed with women before a breast MRI is requested/performed. Because breast MRI drawbacks depend upon the indication for the examination, basic information for the most important breast MRI indications is presented. Seventeen notes and five frequently asked questions formulated for use as direct communication to women are provided. The text was reviewed by Europa Donna-The European Breast Cancer Coalition to ensure that it can be easily understood by women undergoing MRI. KEY POINTS: * Information on breast MRI concerns advantages/disadvantages and preparation to the examination * Claustrophobia, implantable devices, allergic predisposition, and renal function should be checked * Before menopause, scheduling on day 7-14 of the cycle is preferred * During the examination, it is highly important that the patient keeps still * Availability of prior examinations improves accuracy of breast MRI interpretation. PMID- 26002131 TI - Real-time eye lens dose monitoring during cerebral angiography procedures. AB - OBJECTIVES: To develop a real-time dose-monitoring system to measure the patient's eye lens dose during neuro-interventional procedures. METHODS: Radiation dose received at left outer canthus (LOC) and left eyelid (LE) were measured using Metal-Oxide-Semiconductor Field-Effect Transistor dosimeters on 35 patients who underwent diagnostic or cerebral embolization procedures. RESULTS: The radiation dose received at the LOC region was significantly higher than the dose received by the LE. The maximum eye lens dose of 1492 mGy was measured at LOC region for an AVM case, followed by 907 mGy for an aneurysm case and 665 mGy for a diagnostic angiography procedure. Strong correlations (shown as R(2)) were observed between kerma-area-product and measured eye doses (LOC: 0.78, LE: 0.68). Lateral and frontal air-kerma showed strong correlations with measured dose at LOC (AKL: 0.93, AKF: 0.78) and a weak correlation with measured dose at LE. A moderate correlation was observed between fluoroscopic time and dose measured at LE and LOC regions. CONCLUSIONS: The MOSkin dose-monitoring system represents a new tool enabling real-time monitoring of eye lens dose during neuro interventional procedures. This system can provide interventionalists with information needed to adjust the clinical procedure to control the patient's dose. KEY POINTS: Real-time patient dose monitoring helps interventionalists to monitor doses. Strong correlation was observed between kerma-area-product and measured eye doses. Radiation dose at left outer canthus was higher than at left eyelid. PMID- 26002132 TI - Normalizing computed tomography data reconstructed with different filter kernels: effect on emphysema quantification. AB - OBJECTIVES: To propose and evaluate a method to reduce variability in emphysema quantification among different computed tomography (CT) reconstructions by normalizing CT data reconstructed with varying kernels. METHODS: We included 369 subjects from the COPDGene study. For each subject, spirometry and a chest CT reconstructed with two kernels were obtained using two different scanners. Normalization was performed by frequency band decomposition with hierarchical unsharp masking to standardize the energy in each band to a reference value. Emphysema scores (ES), the percentage of lung voxels below -950 HU, were computed before and after normalization. Bland-Altman analysis and correlation between ES and spirometry before and after normalization were compared. Two mixed cohorts, containing data from all scanners and kernels, were created to simulate heterogeneous acquisition parameters. RESULTS: The average difference in ES between kernels decreased for the scans obtained with both scanners after normalization (7.7 +/- 2.7 to 0.3 +/- 0.7; 7.2 +/- 3.8 to -0.1 +/- 0.5). Correlation coefficients between ES and FEV1, and FEV1/FVC increased significantly for the mixed cohorts. CONCLUSIONS: Normalization of chest CT data reduces variation in emphysema quantification due to reconstruction filters and improves correlation between ES and spirometry. KEY POINTS: * Emphysema quantification is sensitive to the reconstruction kernel used. * Normalization allows comparison of emphysema quantification from images reconstructed with varying kernels. * Normalization allows comparison of emphysema quantification obtained with scanners from different manufacturers. * Normalization improves correlation of emphysema quantification with spirometry. * Normalization can be used to compare data from different studies and centers. PMID- 26002133 TI - European Guidelines for AP/PA chest X-rays: routinely satisfiable in a paediatric radiology division? AB - OBJECTIVES: Accurate collimation helps to reduce unnecessary irradiation and improves radiographic image quality, which is especially important in the radiosensitive paediatric population. For AP/PA chest radiographs in children, a minimal field size (MinFS) from "just above the lung apices" to "T12/L1" with age dependent tolerance is suggested by the 1996 European Commission (EC) guidelines, which were examined qualitatively and quantitatively at a paediatric radiology division. METHODS: Five hundred ninety-eight unprocessed chest X-rays (45% boys, 55% girls; mean age 3.9 years, range 0-18 years) were analysed with a self developed tool. Qualitative standards were assessed based on the EC guidelines, as well as the overexposed field size and needlessly irradiated tissue compared to the MinFS. RESULTS: While qualitative guideline recommendations were satisfied, mean overexposure of +45.1 +/- 18.9% (range +10.2% to +107.9%) and tissue overexposure of +33.3 +/- 13.3% were found. Only 4% (26/598) of the examined X-rays completely fulfilled the EC guidelines. CONCLUSIONS: This study presents a new chest radiography quality control tool which allows assessment of field sizes, distances, overexposures and quality parameters based on the EC guidelines. Utilising this tool, we detected inadequate field sizes, inspiration depths, and patient positioning. Furthermore, some debatable EC guideline aspects were revealed. KEY POINTS: * European Guidelines on X-ray quality recommend exposed field sizes for common examinations. * The major failing in paediatric radiographic imaging techniques is inappropriate field size. * Optimal handling of radiographic units can reduce radiation exposure to paediatric patients. * Constant quality control helps ensure optimal chest radiographic image acquisition in children. PMID- 26002134 TI - Partial splenic embolization for thrombocytopenia in liver cirrhosis: predictive factors for platelet increment and risk factors for major complications. AB - OBJECTIVES: To investigate the predictors of platelet increment and risk factors for major complications after partial splenic embolization (PSE) in cirrhosis. METHODS: Between March 2010 and June 2012, 52 cirrhotic patients with severe thrombocytopenia underwent PSE. Multiple variables were analyzed to identify the correlated factors affecting platelet increment and major complications after PSE. RESULTS: Linear mixed model analysis indicated the splenic infarction ratio (P < 0.001), non-infarcted splenic volume (P = 0.012), and cholinesterase level (P < 0.001) were significantly associated with the platelet increment after PSE. In receiver operating characteristic (ROC) analysis, the cut-off values of the splenic infarction ratio, and non-infarcted splenic volume for achieving an increment of >=60.0 * 10(9)/L in platelet counts at 1 year after PSE were 64.3% and 245.8 mL, respectively. After PSE, eight patients developed major complications. Multivariate logistic regression analysis indicated major complications were significantly associated with the infarcted splenic volume (P = 0.024) and Child-Pugh score (P = 0.018). In ROC analysis, the cut-off values of these two factors for discriminating the uncomplicated and complicated were 513.1 mL and 9.5, respectively. CONCLUSIONS: The platelet increment after PSE depends on the splenic infarction ratio, non-infarcted splenic volume and cholinesterase level. But a large infarcted splenic volume and a high Child-Pugh score may cause complications. KEY POINTS: * The platelet increment after PSE greatly depends on the splenic infarction ratio. * The non-infarcted splenic volume significantly affects the efficacy of PSE. * A high cholinesterase level contributes to the improvement of thrombocytopenia after PSE. * The non-infarcted splenic volume significantly affects the relapse of hypersplenism. * Complications are significantly associated with the infarcted splenic volume and Child-Pugh score. PMID- 26002135 TI - Comparison of post contrast CT urography phases in bladder cancer detection. AB - OBJECTIVES: The aim of this study was to investigate which post-contrast phase(s) in a four-phase CT urography protocol is (are) most suitable for bladder cancer detection. METHODS: The medical records of 106 patients with visible haematuria who underwent a CT urography examination, including unenhanced, enhancement triggered corticomedullary (CMP), nephrographic (NP) and excretory (EP) phases, were reviewed. The post-contrast phases (n = 318 different phases) were randomized into an evaluation order and blindly reviewed by two uroradiologists. RESULTS: Twenty-one patients were diagnosed with bladder cancer. Sensitivity for bladder cancer detection was 0.95 in CMP, 0.83 in NP and 0.81 in EP. Negative predictive value (NPV) was 0.99 in CMP, 0.96 in NP and 0.95 in EP. The sensitivity was higher in CMP than in both NP (p-value 0.016) and EP (p-value 0.0003). NPV was higher in CMP than in NP (p-value 0.024) and EP (p-value 0.002). CONCLUSIONS: In the CT urography protocol with enhancement-triggered scan, sensitivity and NPV were highest in the corticomedullary phase, and this phase should be used for bladder assessment. KEY POINTS: * More bladder tumours are detected during the corticomedullary phase than during other phases. * Sensitivity and NPV for bladder cancer detection were highest in corticomedullary phase. * The corticomedullary phase in CT urography should be used for bladder assessment. PMID- 26002137 TI - The use of statistics in heart rhythm research: a review. AB - In this article, we provide a brief review of key statistical concepts/methods that are commonly used in heart rhythm research, including concepts such as standard deviation, standard error, confidence interval, statistical/clinical significance, correlation coefficients, multiple comparisons, cohort and case control studies, and missing data, as well as methods such as statistical hypothesis testing, receiver operating characteristic curve, binary vs time-to event outcome, competing risk methods, and analysis of correlated data. We also make recommendations on how related statistical procedures should be applied and results should be reported. PMID- 26002136 TI - Intrahepatic mass-forming cholangiocarcinoma: prognostic value of preoperative gadoxetic acid-enhanced MRI. AB - OBJECTIVES: To assess whether gadoxetic acid-enhanced MRI could be used as a prognostic factor for intrahepatic mass-forming cholangiocarcinomas (IMCCs). METHODS: Forty-one patients with pathologically proven IMCCs who underwent preoperative gadoxetic acid-enhanced MRI were included. The signal intensity of the IMCCs on hepatobiliary phase (HBP) MRI was qualitatively analyzed by two radiologists, and categorized into intermediate or hypointense groups. Analysis of clinicopathological prognostic factors and correlations of imaging and histology were also performed. Survival time and time to recurrence (TTR) were analyzed. RESULTS: Of the 41 IMCCs, 23 were in the intermediate group and 18 were in the hypointense group on HBP MRI. IMCCs in the intermediate group were associated with shorter survival time (P = 0.048) and TTR (P = 0.002) than the IMCCs of the hypointense group. Only the intermediate group on HBP MRI had a significantly shorter TTR on multivariate analysis (P = 0.012). The IMCCs of the intermediate group showed a tendency for more abundant tumour fibrous stroma than those of the hypointense group (P = 0.027). CONCLUSIONS: The enhancement of IMCCs on HBP gadoxetic acid-enhanced MRI appears to correlate with tumour aggressiveness and outcomes due to the tumour fibrous stromal component. Thus, HBP images could be a useful prognostic factor for IMCCs after surgery. KEY POINTS: * The enhancement of IMCCs on HBP correlates with the tumour fibrous stroma. * The enhancement of IMCCs on HBP MRI appears to correlate with prognosis. * Gadoxetic acid-enhanced MRI is helpful for predicting prognosis of IMCCs after surgery. PMID- 26002138 TI - Influence of the bacterial phenotypes on the clinical manifestations in Klebsiella pneumoniae bacteremia patients: A retrospective cohort study. AB - Ninety-four episodes of Klebsiella pneumoniae bloodstream infection were identified at a university hospital in Japan. After excluding extended-spectrum beta lactamase-producing strains, 83 blood isolates from these patients were assayed in terms of their bacterial phenotypes such as the mucoid and hypermucoviscosity phenotypes. Bacterial phenotypes were correlated with the patients' clinical manifestations. The hypermucoviscosity phenotype was significantly associated with septic shock at the onset of infections (odds ratio, 15.92; 95% confidence interval, 1.27-468.12), but was not associated with liver abscess formation. Mortality was determined by the presence of septic shock. RmpA gene was associated with the induction of the hypermucoviscosity phenotype. These results reveal unique roles of bacterial phenotypes on the patient's clinical condition in K. pneumoniae bacteremia. PMID- 26002139 TI - Scaling considerations in the cardiovascular pathophysiology of obese patients. PMID- 26002140 TI - Ocriplasmin for foveal schisis in X-linked retinoschisis. AB - PURPOSE: To report a case of foveal schisis in X-linked retinoschisis treated with ocriplasmin. METHODS: Case report. RESULTS: A 27-year-old man with X-linked retinoschisis was treated with a single intravitreal injection of ocriplasmin. After injection, a posterior vitreous detachment was induced and the macular schisis cavity resolved at 1 week. Central macular thickness on optical coherence tomography decreased from 731 MUm to 185 MUm, visual acuity remained unchanged, and there were no adverse events. However, the macular schisis cavity recurred at 1 month. CONCLUSION: This is the first reported case of using ocriplasmin to treat foveal schisis in X-linked retinoschisis. Although vitreomacular traction was relieved, the schisis cavity recurred shortly after initial closure. PMID- 26002141 TI - Intravenous injection of indocyanine green results in an artificial transient desaturation by pulse oximetry. AB - PURPOSE: To describe a case series of transient oxygen desaturation measured by pulse oximetry during the intravenous infusion of indocyanine green to enhance transpupillary thermotherapy in treating retinoblastoma after ophthalmic artery chemosurgery. METHODS: Retrospective descriptive case series. RESULTS: The intravenous administration of indocyanine green for ophthalmic angiography resulted in a transient drop in oxygen saturation as measured by Nellcor fingertip pulse oximetry in three children with retinoblastoma receiving indocyanine green-guided transpupillary thermotherapy. The magnitude of reduction ranged from 92% to 94% from an initial reading of 99% to 100% in each case, with an average duration of 3 minutes. Concurrent measurement of blood pressure, pulse, and expired CO2 showed no changes during this process. CONCLUSION: Administration of intravenous indocyanine green resulted in a transient desaturation by oximetry during transpupillary thermotherapy for children with retinoblastoma under anesthesia because of the fluorescent dye's absorption of red light in a manner similar to that of deoxygenated hemoglobin, thereby leading to transient instrument misinterpretation and miscalculation of arterial oxygenation. PMID- 26002142 TI - Bacterial endophthalmitis associated with a broken and retained small-gauge vitrectomy cannula. AB - PURPOSE: To report a case of bacterial endophthalmitis associated with a retained small-gauge vitrectomy trocar. METHODS: Retrospective case report of a 66-year old woman who underwent 25-gauge vitrectomy surgery for an epiretinal membrane who presented with postoperative bacterial endophthalmitis and hand motions vision 3 weeks later. RESULTS: Aqueous and vitreous biopsy revealed Corynebacterium species sensitive to vancomycin. The patient was initially treated with intravitreal and subconjunctival injections of vancomycin, ceftazidime, and dexamethasone. Surgical exploration during a subsequent vitrectomy surgery revealed a retained, transscleral 25-gauge cannula beneath a subconjunctival abscess. The cannula was removed, and the patient was treated with vitrectomy, debridement and closure of the transscleral wound, and injection of intravitreal antibiotics. Fifteen months of follow-up revealed no recurrence of infection and improvement of vision to 20/150. CONCLUSION: Although rare, retained small-gauge vitrectomy cannulas may lead to vision threatening ocular infection. Care should be taken to inspect both the wound and the removed trocar system to ensure complete removal of this surgical device. Detailed counts of all surgical equipment should be routinely performed at the conclusion of vitrectomy surgery. PMID- 26002143 TI - Mesenchymal stem cells improve healing of the cornea after alkali injury. AB - PURPOSE: To evaluate the efficacy of mesenchymal stem cells (MSCs) to ameliorate the consequences of corneal alkali injuries. METHODS: Corneal alkali injuries were created in 30 rabbit eyes. The MSC group (n = 15) were treated with intrastromal and subconjunctival injections of phosphate-buffered saline (PBS) containing 2 * 10(6) MSCs and topical application. The control group (n = 15) was treated with PBS by the same applications forms. Drops of standard treatment (ascorbate 10 %, citrate 10 %, tobramycin, dexamethasone, Cyclogyl) were instilled for 2 weeks. Rabbits underwent slit-lamp examination, fluorescein staining, photography, and were evaluated for corneal neovascularization, opacification, and epithelial defects. Tear secretion and IOP were also evaluated. Furthermore, the concentration of Serumglutamic-pyruvic transaminase (SGPT) and vascular endothelial factor (VEGF) were measured. Immunohistochemistry was also performed for a-SMA and Ki-67. RESULTS: Eyes treated with MSCs showed better recovery. The mean neovascularized area was significantly smaller in the MSC group (p < 0.05). A significant difference in the degree of corneal opacification and re-epithelialization was also observed, as well as the IOP at 21 and 28 posttraumatic days (p < 0.05). Histology showed that MSCs resulted in almost normal architecture of eye tissues. After the MSCs infusion, SGPT and VEGF levels in cornea were significantly reduced. Immunohistochemistry demonstrated a reduction of a-SMA in the MSC group with higher mitotic-regenerative activity with the presence of Ki67. CONCLUSIONS: Our study represents a first step in understanding the possibilities of the MSC approach to treatment of alkali injuries of the cornea and shows that such an approach improves clinical outcomes and leads to better prognosis. PMID- 26002144 TI - Metabolic landscape of advanced gastric cancer according to HER2 and its prognostic implications. AB - BACKGROUND: In advanced gastric cancer (AGC), HER2 is a validated therapeutic target. However, the metabolic landscape of AGC based on HER2 status has not been reported. Furthermore, the prognostic value of HER2 in AGC is under debate. The purpose of this study was to determine the metabolic landscape and prognosis on the basis of HER2 status in AGC. METHODS: We analyzed 866 AGC patients treated with palliative chemotherapy and whose HER2 status was evaluated. HER2 positivity was defined as HER2 IHC 3+ or HER2/CEP17 ratio >=2. Among them, 363 patients were evaluated with (18)F FDG-PET before chemotherapy. We analyzed mSUV (maximal standardized uptake value) according to HER2 status and clinical outcomes. RESULTS: Among 866 patients, 225 (26.0 %) had HER2+ GC. The mSUV of HER2+ GC was significantly higher than that of HER2- GC (12.6 vs. 8.7, p < 0.001). Increased HER2 IHC positivity was correlated with increased mSUV (IHC-: 8.1, IHC 1+: 8.2, 2+: 11.4, 3+: 13.2, p < 0.001). Excluding HER2+ patients who received HER2 targeting agents, OS of patients was not different by HER2 status (12.5 vs. 11.9 months, p = 0.688). However, according to tumor metabolism, patients with higher mSUV showed worse OS regardless of HER2 positivity (mSUV < 12.8:14.8, >=12.8:8.6 months, p < 0.001). CONCLUSION: Tumor metabolism of AGC adversely influenced OS under treatment with cytotoxic chemotherapy. Tumor metabolism was higher in HER2+ AGC than HER2-. However, HER2 was not a prognostic factor in patients who received chemotherapy without HER2-targeting agents. PMID- 26002147 TI - High yields of fatty acid and neutral lipid production from cassava bagasse hydrolysate (CBH) by heterotrophic Chlorella protothecoides. AB - The fermentation process for high yields of fatty acid and neutral lipid production from cassava bagasse hydrolysate (CBH) was developed by heterotrophic Chlorella protothecoides. An efficient single-step enzymatic hydrolysis of cassava bagasse (CB) by cellulase was firstly developed to produce >30 g/L of reducing sugars. The concentrated CBH was subsequently applied in a batch culture, producing 7.9 g/L of dry biomass with yield of 0.44 g/g reducing sugar and 34.3 wt% of fatty acids and 48.6 wt% of neutral lipids. Furthermore, fed batch fermentation using CBH achieved higher yields of fatty acids (41.0 wt% and a titer of 5.83 g/L) and neutral lipids (58.4 wt% and yield of 0.22 g/g reducing sugar). Additionally, the fatty acid profile analysis showed that the intercellular lipid was suitable to prepare high-quality biodiesel. This study demonstrated the feasibility of using CBH as low-cost feedstock to produce crude algal oil for sustainable biodiesel production. PMID- 26002145 TI - Live Cell Imaging with R-GECO1 Sheds Light on flg22- and Chitin-Induced Transient [Ca(2+)]cyt Patterns in Arabidopsis. AB - Intracellular Ca(2+) transients are an integral part of the signaling cascade during pathogen-associated molecular pattern (PAMP)-triggered immunity in plants. Yet, our knowledge about the spatial distribution of PAMP-induced Ca(2+) signals is limited. Investigation of cell- and tissue-specific properties of Ca(2+) dependent signaling processes requires versatile Ca(2+) reporters that are able to extract spatial information from cellular and subcellular structures, as well as from whole tissues over time periods from seconds to hours. Fluorescence-based reporters cover both a broad spatial and temporal range, which makes them ideally suited to study Ca(2+) signaling in living cells. In this study, we compared two fluorescence-based Ca(2+) sensors: the Forster resonance energy transfer (FRET) based reporter yellow cameleon NES-YC3.6 and the intensity-based sensor R-GECO1. We demonstrate that R-GECO1 exhibits a significantly increased signal change compared with ratiometric NES-YC3.6 in response to several stimuli. Due to its superior sensitivity, R-GECO1 is able to report flg22- and chitin-induced Ca(2+) signals on a cellular scale, which allowed identification of defined [Ca(2+)]cyt oscillations in epidermal and guard cells in response to the fungal elicitor chitin. Moreover, we discovered that flg22- and chitin-induced Ca(2+) signals in the root initiate from the elongation zone. PMID- 26002146 TI - How neutrophil extracellular traps orchestrate the local immune response in gout. AB - Neutrophil granulocytes possess a large arsenal of pro-inflammatory substances and mechanisms that empower them to drive local acute immune reactions to invading microorganisms or endogenous inflammatory triggers. The use of this armory needs to be tightly controlled to avoid chronic inflammation and collateral tissue damage. In gout, inflammation arises from precipitation of uric acid in the form of needle-shaped monosodium urate crystals. Inflammasome activation by these crystals in local immune cells results in a rapid and dramatic recruitment of neutrophils. This neutrophil influx is accompanied by the infamously intense clinical symptoms of inflammation during an acute gout attack. Neutrophilic inflammation however is equipped with a built-in safeguard; activated neutrophils form neutrophil extracellular traps (NETs). At the very high neutrophil densities that occur at the site of inflammation, NETs build aggregates that densely pack the monosodium urate (MSU) crystals and trap and degrade pro-inflammatory mediators by inherent proteases. Local removal of cytokines and chemokines by aggregated NETs explains how acute inflammation can stop in the consistent presence of the inflammatory trigger. Aggregated NETs resemble early stages of the typical large MSU deposits that constitute the pathognomonic structures of gout, tophi. Although tophi contribute to muscosceletal damage and mortality in patients with chronic gout, they can therefore be considered as a payoff that is necessary to silence the intense inflammatory response during acute gout. PMID- 26002148 TI - Efficient and rapid adsorption characteristics of templating modified guar gum and silica nanocomposite toward removal of toxic reactive blue and Congo red dyes. AB - The present study highlights the potentiality of sol-gel synthesized guar gum graft-poly (acrylamide)/silica (g-GG/SiO2) hybrid nanocomposite toward the rapid removal of toxic reactive blue 4 (RB) and Congo red (CR) dyes from aqueous solution. Various physicochemical characterizations support the feasibility of the functionalized guar gum matrix as efficient template for the formation of homogeneous nanoscale silica particles. The composite demonstrates rapid and superior adsorption efficiency of RB (Qmax: 579.01 mg g(-1) within 40 min) and CR (Qmax: 233.24 mg g(-1) within 30 min) dyes from aqueous environment. Here, the pH driven adsorption process depends strongly on the ionic strength of the salt solution. The adsorption kinetics data predicts that pseudo second-order (surface adsorption) and intraparticle diffusion take place simultaneously. The adsorption equilibrium is in good agreement with the Langmuir isotherm, while the thermodynamics study confirms spontaneous nature of the adsorption process. Desorption study predicts the excellent regenerative efficacy of nanocomposite. PMID- 26002149 TI - "It's all about acceptance": A qualitative study exploring a model of positive body image for people with spinal cord injury. AB - Using modified constructivist grounded theory, the purpose of the present study was to explore positive body image experiences in people with spinal cord injury. Nine participants (five women, four men) varying in age (21-63 years), type of injury (C3-T7; complete and incomplete), and years post-injury (4-36 years) were recruited. The following main categories were found: body acceptance, body appreciation and gratitude, social support, functional gains, independence, media literacy, broadly conceptualizing beauty, inner positivity influencing outer demeanour, finding others who have a positive body image, unconditional acceptance from others, religion/spirituality, listening to and taking care of the body, managing secondary complications, minimizing pain, and respect. Interestingly, there was consistency in positive body image characteristics reported in this study with those found in previous research, demonstrating universality of positive body image. However, unique characteristics (e.g., resilience, functional gains, independence) were also reported demonstrating the importance of exploring positive body image in diverse groups. PMID- 26002150 TI - Controlled delivery of a metabolic modulator promotes regulatory T cells and restrains autoimmunity. AB - Autoimmune disorders occur when the immune system abnormally recognizes and attacks self-molecules. Dendritic cells (DCs) play a powerful role in initiating adaptive immune response, and are therefore a recent target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a small molecule glutamate receptor enhancer, alters how DCs metabolize glutamate, skewing cytokine secretion to bias T cell function. These effects provide protection in mouse models of multiple sclerosis (MS) by polarizing T cells away from inflammatory TH17 cells and toward regulatory T cells (TREG) when mice receive daily systemic injections of PHCCC. However, frequent, continued treatment is required to generate and maintain therapeutic benefits. Thus, the use of PHCCC is limited by poor solubility, the need for frequent dosing, and cell toxicity. We hypothesized that controlled release of PHCCC from degradable nanoparticles (NPs) might address these challenges by altering DC function to maintain efficacy with reduced treatment frequency and toxicity. This idea could serve as a new strategy for harnessing biomaterials to polarize immune function through controlled delivery of metabolic modulators. PHCCC was readily encapsulated in nanoparticles, with controlled release of 89% of drug into media over three days. Culture of primary DCs or DC and T cell co-cultures with PHCCC NPs reduced DC activation and secretion of pro-inflammatory cytokines, while shifting T cells away from TH17 and toward TREG phenotypes. Importantly, PHCCC delivered to cells in NPs was 36-fold less toxic compared with soluble PHCCC. Treatment of mice with PHCCC NPs every three days delayed disease onset and decreased disease severity compared with mice treated with soluble drug at the same dose and frequency. These results highlight the potential to promote tolerance through controlled delivery of metabolic modulators that alter DC signaling to polarize T cells, and suggest future gains that could be realized by engineering materials that provide longer term release. PMID- 26002151 TI - Depression, Stress, Quality of Life, and Dry Eye Disease in Korean Women: A Population-Based Study. AB - PURPOSE: To determine the relationship between dry eye disease (DED) and depressive symptoms in a nationally representative sample of Korean women. METHODS: This population-based cross-sectional study comprised 6655 women (aged 19 years or older) participating in the fifth annual Korea National Health and Nutrition Examination Survey from 2010 to 2011. Psychological problems associated with clinically diagnosed DED by ophthalmologists and symptoms of DED were assessed using questionnaires and surveys. Data were analyzed using logistic regression to determine the association of depression with allergic disease while controlling for age, lifestyle factors, and medical factors. RESULTS: Among the participants, the prevalence of clinically diagnosed DED and its symptoms was 12.3% and 20.0%, respectively. Subjects with the diagnosis had a higher likelihood of experiencing severe psychological stress [odds ratio (OR), 2.5; 95% confidential interval (CI), 1.6-4.0], depressive mood (OR, 1.5; 95% CI, 1.1-2.0), anxiety/depression problems (OR, 1.5; 95% CI, 1.1-2.0) and tended to have a history of psychological counseling (OR, 1.8; 95% CI, 1.0-3.1). Subjects with symptoms of DED showed similar patterns. CONCLUSIONS: There is a close association between depression, stress, and DED in women who have been clinically diagnosed with it or those presenting with its symptoms. PMID- 26002152 TI - Intraoperative OCT-Assisted DMEK: 14 Consecutive Cases. AB - PURPOSE: To describe the utility of a new intraoperative optical coherence tomographer (OCT) to evaluate endothelio-Descemet graft orientation during Descemet membrane endothelial keratoplasty (DMEK) procedures. METHODS: Prospective, observational, and single-center pilot case series including 14 eyes of 14 patients consecutively scheduled for DMEK surgery. After injecting the graft into the anterior chamber, the graft orientation was assessed with the help of anterior segment OCT. The surgical time and unfolding time were measured. The postoperative measurements included best-corrected visual acuity, central pachymetry, and specular microscopy at 1 month. RESULTS: Using the OCT images, it was possible to evaluate the graft orientation in all cases. The mean unfolding time was 6.1 +/- 3.0 minutes, the mean best-corrected visual acuity was 0.3 +/- 0.3 logarithm of the minimum angle of resolution, the mean decrease in central pachymetry was 213 +/- 177 MUm, and the mean central endothelial cell count was 1906 +/- 319 cells per square millimeter. CONCLUSIONS: Live intraoperative OCT is useful to visualize and assess graft orientation in DMEK surgery. It enables faster graft positioning with less graft manipulation in the presence of severe corneal edema. PMID- 26002153 TI - Cadaveric Porcine Model for Teaching and Practicing Conjunctival Autograft Creation. AB - PURPOSE: Conjunctival autografting is a technically difficult step of pterygium surgery, and novice surgeons have limited opportunities to develop and practice their surgical skills. The porcine eye model closely approximates the human eye in tissue consistency when preparing conjunctival and limbal-conjunctival grafts. This study assessed the efficacy of a cadaveric porcine model in teaching and improving a novice's skills of conjunctival autograft creation. METHODS: A novice was taught to prepare 5 * 5 mm conjunctival grafts and created 58 grafts on fresh porcine eyes. The conjunctival graft thickness was measured using standard histological techniques. RESULTS: Between grafts 1-10 and grafts 49-58, there was a statistically significant difference in both thickness (P < 0.0001; mean thickness, 133 +/- 27 and 87 +/- 23 MUm, respectively) and time of creation (P = 0.037; median time, 191 and 126 seconds, respectively). CONCLUSIONS: The cadaveric porcine model may be a useful method for teaching this important technique to novice surgeons. PMID- 26002154 TI - Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies. AB - Antibody-mediated capture of amyloid-beta (Abeta) in peripheral blood was identified as an attractive strategy to eliminate cerebral toxic amyloid in Alzheimer's disease (AD) patients and murine models. Alternatively, defective capacity of peripheral monocytes to engulf Abeta was reported in individuals with AD. In this report, we developed different approaches to investigate cellular uptake and phagocytosis of Abeta, and to examine how two immunological devices- an immunostimulatory Adjuvant System and different amyloid specific antibodies- may affect these biological events. Between one and thirteen months of age, APPswe X PS1.M146V (TASTPM) AD model mice had decreasing concentrations of Abeta in their plasma. In contrast, the proportion of blood monocytes containing Abeta tended to increase with age. Importantly, the TLR-agonist containing Adjuvant System AS01B primed monocytes to promote de novo Abeta uptake capacity, particularly in the presence of anti-Abeta antibodies. Biochemical experiments demonstrated that cells achieved Abeta uptake and internalization followed by Abeta degradation via mechanisms that required effective actin polymerization and proteolytic enzymes such as insulin-degrading enzyme. We further demonstrated that both Abeta-specific monoclonal antibodies and plasma from Abeta-immunized mice enhanced the phagocytosis of 1 MUm Abeta-coated particles. Together, our data highlight a new biomarker testing to follow amyloid clearance within the blood and a mechanism of Abeta uptake by peripheral monocytes in the context of active or passive immunization, and emphasize on novel approaches to investigate this phenomenon. PMID- 26002155 TI - Human neutrophil lipocalin in fMLP-activated whole blood as a diagnostic means to distinguish between acute bacterial and viral infections. AB - The distinction between causes of acute infections is a major clinical challenge. Current biomarkers, however, are not sufficiently accurate. Human neutrophil lipocalin (HNL) in serum distinguishes acute infections with high accuracy, but in the emergency setting the assay time should be <15-20min, which excludes the use of serum samples. The aim was therefore to develop a novel rapid assay principle and test its clinical performance. METHODS: Serum and neutrophils obtained from 84 infected and 20 healthy subjects were used in the experimental study. 725 subjects (144 healthy controls and 581 patients with signs and symptoms of acute infections) were included in the clinical study. HNL was measured in EDTA-plasma by ELISA or in heparinized whole blood after fMLP activation by a prototype point-of-care assay. RESULTS: Increased release of HNL from neutrophils after activation with fMLP was seen already after 5 min incubation. The release of HNL from purified neutrophils after 15 min incubation with fMLP was significantly correlated to the HNL concentrations in serum obtained from the same patient (r = 0.74, p < 0.001). In the distinction between healthy controls and patients with bacterial infections, the areas under the ROC curves were 0.95 (95% CI 0.91-0.97) and 0.88 (95% CI 0.84-0.91) for HNL in fMLP activated whole blood and EDTA-plasma, respectively, (p < 0.001) and in the distinction between bacterial and viral infections 0.91 (95% CI 0.86-0.95) and 0.76 (95% CI 0.70-0.81), respectively (p < 0.001). CONCLUSION: The clinical performance of HNL in fMLP-activated whole blood was superior to HNL in EDTA plasma and similar to HNL in serum. The procedure can be adopted for point-of care testing with response times of <15 min. PMID- 26002156 TI - Biological Insights from the Manduca sexta genome. Preface. PMID- 26002158 TI - Disinfection byproduct formation during biofiltration cycle: Implications for drinking water production. AB - The goal of this study was to investigate the potential of biofiltration to reduce the formation potential of disinfection byproducts (DBPs). Particularly, the work investigates the effect of the duration of the filter cycle on the formation potential of total trihalomethanes (TTHM) and five species of haloacetic acids (HAA5), dissolved oxygen (DO), organic carbon, nitrogen and total phosphorous concentrations along with biofilm coverage of the filter media and biomass viability of the attached cells. The study was conducted on a full scale biologically active filter, with anthracite and sand media, at the Britannia water treatment plant (WTP), located in Ottawa, Ontario, Canada. The formation potential of both TTHMs and HAA5s decreased due to biofiltration. However the lowest formation potentials for both groups of DBPs and or their precursors were observed immediately following a backwash event. Hence, the highest percent removal of DBPs was observed during the early stages of the biofiltration cycle, which suggests that a higher frequency of backwashing will reduce the formation of DBPs. Variable pressure scanning electron microscopy (VPSEM) analysis shows that biofilm coverage of anthracite and sand media increases as the filtration cycle progressed, while biomass viability analysis demonstrates that the percentage of cells attached to the anthracite and sand media also increases as the filtration cycle progresses. These results suggest that the development and growth of biofilm on the filters increases the DPB formation potential. PMID- 26002159 TI - Removing organic and nitrogen content from a highly saline municipal wastewater reverse osmosis concentrate by UV/H2O2-BAC treatment. AB - Reverse osmosis (RO) concentrate (ROC) streams generated from RO-based municipal wastewater reclamation processes pose potential health and environmental risks on their disposal to confined water bodies such as bays. A UV/H2O2 advanced oxidation process followed by a biological activated carbon (BAC) treatment was evaluated at lab-scale for the removal of organic and nutrient content from a highly saline ROC (TDS 16 g L(-1), EC 23.5 mS cm(-1)) for its safe disposal to the receiving environment. Over the 230-day operation of the UV/H2O2-BAC process, the colour and UV absorbance (254 nm) of the ROC were reduced to well below those of the influent to the reclamation process. The concentrations of DOC and total nitrogen (TN) were reduced by approximately 60% at an empty bed contact time (EBCT) of 60 min. The reduction in ammonia nitrogen by the BAC remained high under all conditions tested (>90%). Further investigation confirmed that the presence of residual peroxide in the UV/H2O2 treated ROC was beneficial for DOC removal, but markedly inhibited the activities of the nitrifying bacteria (i.e., nitrite oxidising bacteria) in the BAC system and hence compromised total nitrogen removal. This work demonstrated that the BAC treatment could be acclimated to the very high salinity environment, and could be used as a robust method for the removal of organic matter and nitrogen from the pre-oxidised ROC under optimised conditions. PMID- 26002157 TI - Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy. AB - The pediatric bone sarcomas osteosarcoma and Ewing sarcoma represent a tremendous challenge for the clinician. Though less common than acute lymphoblastic leukemia or brain tumors, these aggressive cancers account for a disproportionate amount of the cancer morbidity and mortality in children, and have seen few advances in survival in the past decade, despite many large, complicated, and expensive trials of various chemotherapy combinations. To improve the outcomes of children with bone sarcomas, a better understanding of the biology of these cancers is needed, together with informed use of targeted therapies that exploit the unique biology of each disease. Here we summarize the current state of knowledge regarding the contribution of receptor tyrosine kinases, intracellular signaling pathways, bone biology and physiology, the immune system, and the tumor microenvironment in promoting and maintaining the malignant phenotype. These observations are coupled with a review of the therapies that target each of these mechanisms, focusing on recent or ongoing clinical trials if such information is available. It is our hope that, by better understanding the biology of osteosarcoma and Ewing sarcoma, rational combination therapies can be designed and systematically tested, leading to improved outcomes for a group of children who desperately need them. PMID- 26002160 TI - Minimally invasive percutaneous nephrolithotomy: an effective treatment for kidney stones in infants under 1 year of age. A single-center experience. AB - We aimed to present the outcomes of PNL surgery performed in infantile patients with small renal stones who were younger than 1 year of age. A single-center prospective trial was initiated and during the period between Jan 2013 and Jan 2015, PNL was applied to 20 renal units of 16 infants (6 girls and 10 boys), including 4 patients with bilateral kidney stones. PNL was performed in patients with renal stones larger than 2 cm, as well as stones resistant to SWL or renal stones that were undetectable during SWL. The mean age of the patients was 9.55 (5-12) months. Of the 20 renal units, 1 had complete staghorn stones, 3 had partial staghorn stones, 13 had renal pelvic stones, and 3 had lower pole stones. The mean stone size was 18.5 mm (range 12-36 mm). Mean operative time for PNL was 88 (25-135 min). Mean fluoroscopy time was estimated as 3.4 min. Mean hemoglobin loss was 0.72 g/L (0.2-3). The mean hospital stay was 4.1 days (2-8 days). On postoperative day 1, a complete stone-free state was achieved in 70% of renal units (14 of 20). At the end of the first postoperative week, the remaining two patients had insignificant residual fragments of 3 mm and were followed conservatively without any specific intervention. Thus, the total SFR was 80% (16 of 20) at discharge. In infants aged less than 1 year, minimal access tract dilation during PNL, the use of smaller caliber pediatric instruments, and the realization of this procedure by surgeons with adequate experience in adults carry utmost importance. In addition, special care should be taken to avoid hypothermia and radiation exposure during PNL. PMID- 26002161 TI - Genetics: update on prenatal screening and diagnosis. AB - There have been tremendous advances in the ability to screen for the "odds" of having a genetic disorder (both mendelian and chromosomal). With microarray analyses on fetal tissue now showing a minimum risk for any pregnancy being at least 1 in 150 and ultimately greater than 1%, it is thought that all patients, regardless of age, should be offered chorionic villus sampling/amniocentesis and microarray analysis. As sequencing techniques replace other laboratory methods, the only question will be whether these tests are performed on villi, amniotic fluid cells, or maternal blood. PMID- 26002162 TI - Screening for congenital heart disease during anatomical survey ultrasonography. AB - Congenital heart disease (CHD) is among the most common congenital abnormalities. The prevalence of CHD ranges between 0.6% and 1.2% of live births. Despite its high prevalence, CHD is also among the most commonly missed abnormalities during prenatal ultrasound examination. A simple yet systematic approach to fetal heart examination, regular feedback, and implementation of training programs could improve detection rates and, in turn, neonatal outcome. PMID- 26002163 TI - What you need to know when managing twins: 10 key facts. AB - Twin pregnancies can be complicated. Early diagnosis with accurate dating, determination of chorionicity, screening for chromosomal and structural abnormalities, placental evaluation, and cervical length assessment should be completed in the first half of gestation. Routine fetal growth is recommended for all twins with serial surveillance for those complicated by anomalies, cervical shortening, growth disturbances, and amniotic fluid abnormalities. Twins with monochorionic placentation require heightened scrutiny for unequal placental sharing with discordant twin growth or selective intrauterine fetal growth restriction, twin-twin transfusion syndrome, twin anemia-polycythemia sequence, and single-fetal demise. Familiarity with essentials can assist practitioners involved in the management of twins. PMID- 26002164 TI - Short cervical length dilemma. AB - Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality. With research efforts, the rate of PTB decreased to 11.4% in 2013. Transvaginal ultrasound (TVU) cervical length (CL) screening predicts PTB. In asymptomatic singletons without prior spontaneous PTB (sPTB), TVU CL screening should be done. If the cervix is 20 mm or less, vaginal progesterone is indicated. In asymptomatic singletons with prior sPTB, serial CL screening is indicated. In multiple gestations, routine cervical screening is not indicated. In symptomatic women with preterm labor, TVU CL screening and fetal fibronectin testing is recommended. PMID- 26002165 TI - Preterm labor: approach to decreasing complications of prematurity. AB - Obstetricians play a relevant role in minimizing neonatal morbidity and mortality for women in preterm labor. Tocolytic agents can delay preterm birth for at least 2 days, thus allowing the administration of antenatal corticosteroid and in-utero transfer to appropriate neonatal health care settings, interventions that reduce neonatal mortality and morbidity. Antibiotics besides group B streptococcus prophylaxis are not indicated. The benefit/risk ratio of amniocentesis has not been assessed yet. Magnesium sulfate significantly reduces the risk of cerebral palsy. Cesarean delivery benefits fetuses in breech presentation and those severely growth restricted at <34 weeks. In preterm infants delayed clamping is associated with significant benefits. PMID- 26002166 TI - A uniform management approach to optimize outcome in fetal growth restriction. AB - A uniform approach to the diagnosis and management of fetal growth restriction (FGR) consistently produces better outcome, prevention of unanticipated stillbirth, and appropriate timing of delivery. Early-onset and late-onset FGR represent two distinct clinical phenotypes of placental dysfunction. Management challenges in early-onset FGR revolve around prematurity and coexisting maternal hypertensive disease, whereas in late-onset disease failure of diagnosis or surveillance leading to unanticipated stillbirth is the primary issue. Identifying the surveillance tests that have the highest predictive accuracy for fetal acidemia and establishing the appropriate monitoring interval to detect fetal deterioration is a high priority. PMID- 26002167 TI - Maternal early warning systems. AB - This article reviews evidence and recommendations for maternal early warning systems designed to reduce severe maternal morbidity and mortality. The clinical rationale for these systems is discussed as is research literature on early warning systems from other fields. PMID- 26002168 TI - Preeclampsia: Short-term and Long-term Implications. AB - Preeclampsia is a hypertensive disorder that affects 4% of pregnancies and has a high risk of maternal, fetal, and neonatal morbidity and mortality, as well as long-term cardiovascular risk. Recent updates in the definition, diagnosis, and management guidelines for preeclampsia warrant review by general obstetrician gynecologists. Screening and prevention algorithms for preeclampsia are available, but ultimately the cure remains delivery of the fetus and placenta. Close monitoring for the development and worsening of preeclampsia during pregnancy is essential to optimize both maternal and fetal/neonatal outcomes. PMID- 26002169 TI - Cardiac disease in pregnancy. AB - Physiologic changes in pregnancy can place extra demands on cardiac function. Preconception counseling is key to improving pregnancy outcomes. The most commonly encountered cardiac events are pulmonary edema and dysrhythmias. A team approach to antepartum care is recommended and should include maternal-fetal medicine, cardiology, and anesthesia as indicated, particularly for patients with congenital cardiac disease. PMID- 26002170 TI - Pregnancy risks associated with obesity. AB - Obesity has increased dramatically in the United States over the last several decades, with approximately 40% of pregnant women now considered overweight or obese. Obesity has been shown to be associated with numerous poor pregnancy outcomes, including increased rates of preeclampsia, gestational diabetes, fetal macrosomia, stillbirth, postterm pregnancy, and increased rates of cesarean delivery. Many of these complications have been found to increase even further with increasing body mass index in a dose-response fashion. In this review, the association of obesity with maternal, fetal, and pregnancy outcomes is discussed as are the recommendations for caring for the obese gravida. PMID- 26002171 TI - Influenza: threat to maternal health. AB - A maternal mortality rate of 1% was reported during the 2009-2010 influenza pandemic, with influenza in pregnancy posing a serious risk to maternal health. A high level of suspicion coupled with prompt diagnosis and treatment is paramount to minimizing morbidity and mortality. Vaccination during pregnancy should be of high priority to improve both maternal and neonatal outcomes. PMID- 26002172 TI - How to Approach Intrapartum Category II Tracings. AB - Since its inception, many have questioned the utility of electronic fetal heart rate (FHR) monitoring. However, it arrived without the benefit of clear, standard nomenclature, leading to difficulty interpreting studies regarding its benefit. In 2008, the National Institute of Child Health and Human Development (NICHD) developed standard nomenclature for interpreting eFHR tracings. Understanding what drives the tracings is key to managing them. Category II FHR patterns are by far the most common and most diverse patterns, leading to broad variation in care. Presented here is an algorithm for standardization of management of category II FHR tracings, based on the pathophysiology of decelerations, that can be followed in any labor unit. PMID- 26002173 TI - Prevention of the first cesarean delivery. AB - Education of providers and patients on the importance of vaginal delivery, for the current pregnancy as well as future pregnancies, is essential to reverse the current trend of primary cesareans. When discussing cesarean with patients, counseling should include the effect on subsequent pregnancy risks including the possibility of uterine rupture and placentation abnormalities. In addition, counseling must include the concept that normal labor takes time. Re-education on the natural process of labor, the importance of allowing the time needed, and patience with the duration of pregnancy and process of labor is essential. PMID- 26002174 TI - Placenta accreta spectrum: accreta, increta, and percreta. AB - Placenta accreta can lead to hemorrhage, resulting in hysterectomy, blood transfusion, multiple organ failure, and death. Accreta has been increasing steadily in incidence owing to an increase in the cesarean delivery rate. Major risk factors are placenta previa in women with prior cesarean deliveries. Obstetric ultrasonography can be used to diagnose placenta accreta antenatally, which allows for scheduled delivery in a multidisciplinary center of excellence for accreta. Controversies exist regarding optimal management, including optimal timing of delivery, surgical approach, use of adjunctive measures, and conservative (uterine-sparing) therapy. We review the definition, risk factors, diagnosis, management, and controversies regarding placenta accreta. PMID- 26002175 TI - At-risk pregnancies. PMID- 26002176 TI - At-risk pregnancies: update on management. PMID- 26002177 TI - The effects of pre-slaughter restraint (for the purpose of cattle identification) on post-slaughter responses and carcass quality following the electrical stun/killing of cattle in a Jarvis Beef stunner. AB - This study compared normal post-Jarvis stun/kill responses and carcass quality with those occurring when crush restraint was not used during pre-slaughter. The carcasses of 1065 cattle slaughtered during one week at a commercial abattoir were evaluated for quality. The post-stun/kill responses of 788 of these animals were also assessed. An additional study of data from the carcasses of 6061 cattle was further evaluated for quality findings. A significant reduction in post stun/kill limb movement, muscle tone and the expression of brainstem functions was recorded when restraint was not used. Abolishing crush restraint pre slaughter also produced a significant reduction in the incidence of blood splash. In addition, the study also showed that animal identification post-slaughter could be successfully implemented with no negative consequences to food safety or traceability. It is suggested that abolishing the use of pre-slaughter crush restraint of cattle would enhance animal welfare and operator safety in plants whether electrical, or mechanical stunning was employed. PMID- 26002178 TI - Folate and Vitamin B12 Deficiency Among Non-pregnant Women of Childbearing-Age in Guatemala 2009-2010: Prevalence and Identification of Vulnerable Populations. AB - INTRODUCTION: Information on folate and vitamin B12 deficiency rates in Guatemala is essential to evaluate the current fortification program. The objectives of this study were to describe the prevalence of folate and vitamin B12 deficiencies among women of childbearing age (WCBA) in Guatemala and to identify vulnerable populations at greater risk for nutrient deficiency. METHODS: A multistage cluster probability study was designed with national and regional representation of nonpregnant WCBA (15-49 years of age). Primary data collection was carried out in 2009-2010. Demographic and health information was collected through face-to face interviews. Blood samples were collected from 1473 WCBA for serum and red blood cell (RBC) folate and serum vitamin B12. Biochemical concentrations were normalized using geometric means. Prevalence rate ratios were estimated to assess relative differences among different socioeconomic and cultural groups including ethnicity, age, education level, wealth index and rural versus urban locality. RESULTS: National prevalence estimates for deficient serum [<10 nmol per liter (nmol/L)] and RBC folate (<340 nmol/L) concentrations were 5.1 % (95 % CI 3.8, 6.4) and 8.9 % (95 % CI 6.7, 11.7), respectively; for vitamin B12 deficiency (<148 pmol/L) 18.5 % (95 % CI 15.6, 21.3). Serum and RBC folate deficiency prevalences were higher for rural areas than for urban areas (8.0 vs. 2.0 % and 13.5 vs. 3.9 %, respectively). The prevalence of RBC folate deficiency showed wide variation by geographic region (3.2-24.9 %) and by wealth index (4.1-15.1 %). The prevalence of vitamin B12 deficiency also varied among regions (12.3-26.1 %). CONCLUSIONS: In Guatemala, folate deficiency was more prevalent among indigenous rural and urban poor populations. Vitamin B12 deficiency was widespread among WCBA. Our results suggest the ongoing need to monitor existing fortification programs, in particular regarding its reach to vulnerable populations. PMID- 26002179 TI - Letter to the editor on "Exposure to hazardous air pollutants and the risk of amyotrophic lateral sclerosis". PMID- 26002180 TI - The Pyromaniac Inside You: Salmonella Metabolism in the Host Gut. AB - A metabolically diverse microbial community occupies all available nutrient niches in the lumen of the mammalian intestine, making it difficult for pathogens to establish themselves in this highly competitive environment. Salmonella serovars sidestep the competition by using their virulence factors to coerce the host into creating a novel nutrient-niche. Inflammation-derived nutrients available in this new niche support a bloom of Salmonella serovars, thereby ensuring transmission of the pathogen to the next susceptible host by the fecal oral route. Here we review the anaerobic food chain that characterizes resident gut-associated microbial communities along with the winning metabolic strategy Salmonella serovars use to edge out competing microbes in the inflamed intestine. PMID- 26002181 TI - Postprocessing in Maxillofacial Multidetector Computed Tomography. AB - Multidetector computed tomography (CT) and volumetric rendering techniques have always been a useful support for the anatomical and pathological study of the maxillofacial district. Nowadays accessibility to multidetector CT scanners allows the achievement of images with an extremely thin collimation and with high spatial resolution, not only along the axial plane but also along the patient's longitudinal axis. This feature is the main theoretical assumption for multiplanar imaging and for an optimal 3-dimensional postprocessing. Multiplanar reconstruction (MPR) techniques permit images along any plane in the space to be obtained, including curved planes; this feature allows the representation in a single bidimensional image of different anatomical structures that develop on multiple planes. For this reason MPR techniques represent an unavoidable step for the study of traumatic pathology as well as of malformative, neoplastic, and inflammatory pathologies. Among 3-dimensional techniques, Maximum Intensity Projection and Shaded Surface Display are routinely used in clinical practice. In addition, volumetric rendering techniques allow a better efficacy in representing the different tissues of maxillofacial district. Each of these techniques give the radiologist an undoubted support for the diagnosis and the characterization of traumatic and malformative conditions, have a critical utility in the neoplastic evaluation of primary or secondary bone involvement, and are also used in the planning of the most modern radiosurgical treatments. The aim of this article is to define the main technical aspects of imaging postprocessing in maxillofacial CT and to summarize when each technique is indicated, according to the different pathologies of this complex anatomical district. PMID- 26002182 TI - The Exposure Dilemma: Qualitative Study of Medical Student Opinions and Perceptions of Radiology. AB - PURPOSE: According to a national survey of over 900 Canadian medical students, the stereotype of an isolated radiologist working in a dark room persists. The purpose of this study is to use qualitative methods to explore the ways exposure to radiology in medical school impacts students' opinions and perceptions of radiology and radiologists. METHODS: After receiving ethics approval, 4 focus groups were conducted, 1 per year of undergraduate medical training at Western University. The transcribed audio recordings and accompanying field notes, together with the open-ended questions obtained from the national survey, were analyzed using thematic analysis. RESULTS: Five hundred sixty students in medical school years 1 and 2 (preclerkship) participated in the national survey and 18 in the focus groups; 336 students in years 3 and 4 [clerkship] participated in the national survey and 10 in the focus groups. Three major findings emerged from the analysis of the data. First, stereotypes are perpetuated mainly through informal interactions. Second, there is limited exposure to radiology and radiologists in medical school, especially in preclerkship. Third, students want to know what to expect if they choose a career in radiology. CONCLUSIONS: Medical students, especially those in preclerkship, are seeking accurate information to modify or reinforce radiology stereotypes. Limited exposure makes interactions with students impactful and mentorship essential. Students want meaningful interactions with radiologists and radiology residents. PMID- 26002183 TI - Casualties of war: the infection control assessment of civilians transferred from conflict zones to specialist units overseas for treatment. AB - The casualties of global conflict attract media attention and sympathy in public, governmental, and non-governmental circles. Hospitals in developed countries offering specialist reconstructive or tertiary services are not infrequently asked to accept civilian patients from overseas conflict for complex surgical procedures or rehabilitation. Concern about the infection prevention and control risks posed by these patients, and the lack of a good evidence base on which to base measured precautions, means that the precautionary principle of accepting zero risk is usually followed. The aim of this article is to highlight infection control considerations that may be required when treating casualties from overseas conflict, based partly on our own experience. Currently there is a lack of published evidence and national consensus on how to manage these patients. The precautionary principle requires that there is an ongoing search for evidence and knowledge that can be used to move towards more traditional risk management. We propose that only by gathering the experiences of the many individual hospitals that have each cared for small numbers of such patients can such evidence and knowledge be assimilated. PMID- 26002184 TI - Published guidelines of the French Society for Hospital Hygiene and repeated national prevalence studies on healthcare-associated infections: an ecological analysis. PMID- 26002185 TI - Adequate application of recombinant thrombomodulin for sepsis-associated disseminated intravascular coagulation. PMID- 26002186 TI - Morphometric and neurochemical alterations found in l-BMAA treated rats. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis that reflects the motoneurons' degeneration. Several studies support the relationship between beta-N-methylamino-l-alanine (l BMAA), a neurotoxic amino acid produced by cyanobacteria and diatoms, and the sporadic occurrence of ALS and other neurodegenerative diseases. Therefore, the study of its neurotoxicity mechanisms has assumed great relevance in recent years. Recently, our research team has proposed a sporadic ALS animal model by l BMAA administration in rats, which displays many pathophysiological features of human ALS. In this paper, we deepen the characterization of this model corroborating the occurrence of alterations present in ALS patients such as decreased muscle volume, thinning of the motor cortex, enlarged brain's lateral ventricles, and alteration of both bulbar nuclei and neurotransmitters' levels. Therefore, we conclude that l-BMAA treated rats could be a good model which mimics degenerative features that ALS causes in humans. PMID- 26002187 TI - Taxifolin mitigates oxidative DNA damage in vitro and protects zebrafish (Danio rerio) embryos against cadmium toxicity. AB - Taxifolin (TAX) is a natural source of bioflavonoid found in various conifers. In this study, initially we investigated the antioxidant potential of TAX under in vitro assays such as 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis (3 ethylbenzthiazoline-6-sulfonic acid) (ABTS), ferric-ion reducing power (FRAP) and hydroxyl radical (OH). The activities of DPPH, ABTS, FRAP and OH radical levels were significantly inhibited by TAX with an IC50 values of 16.48, 66.34, 18.17 and 11.42MUg/ml, respectively. Secondly, TAX exhibited a strong protection against OH mediated DNA damage on pUC19 plasmid DNA at 1.0MUg/ml. Finally, we evaluated the protective mechanism of TAX against cadmium intoxicated zebrafish embryos (Danio rerio). We found that embryos exposed to 100MUM Cd exhibited significantly reduced survival, delayed hatching and phenotypic abnormalities at 24, 48, 72 and 96hours post fertilization (hpf). Similarly, Cd intoxicated embryos showed significantly increased cardiac function (131beats/min) at 60hpf. Conversely, treatment with TAX (0.1, 1.0 and 10MUM) significantly enhanced the antioxidant enzyme levels (SOD, CAT, GPx and GR) by reducing the lipid peroxidation (MDA) in zebrafish embryos. Collectively, our results concluded that TAX could act as a potent redox scavenger against oxidative DNA damage and also functions as a crucial suppressor of Cd toxicity in zebrafish embryos. PMID- 26002188 TI - Inferior Vena Cava Resection and Hemihepatectomy for Leiomyosarcoma, Utilizing Cardiopulmonary Bypass, in Situ Hepatic Perfusion, and Distal Hypothermic Circulatory Arrest. PMID- 26002189 TI - Small bowel volvulus in the adult populace of the United States: results from a population-based study. AB - BACKGROUND: Small bowel volvulus is a rare entity in Western adults. Greater insight into epidemiology and outcomes may be gained from a national database inquiry. METHODS: The Nationwide Inpatient Sample (1998 to 2010), a 20% stratified sample of United States hospitals, was retrospectively reviewed for small bowel volvulus cases (International Classification of Diseases, 9th Edition [ICD-9] code 560.2 excluding gastric/colonic procedures) in patients greater than or equal to 18 years old. RESULTS: There were 2,065,599 hospitalizations for bowel obstruction (ICD-9 560.x). Of those, there were 20,680 (1.00%) small bowel volvulus cases; 169 were attributable to intestinal malrotation. Most cases presented emergently (89.24%) and operative management was employed more frequently than nonoperative (65.21% vs 34.79%, P < .0001). Predictors of mortality included age greater than 50 years, Charlson comorbidity index greater than or equal to 1, emergent admission, peritonitis, acute vascular insufficiency, coagulopathy, and nonoperative management (P < .0001). CONCLUSION: As the first population-based epidemiological study of small bowel volvulus, our findings provide a robust representation of this rare cause of small bowel obstruction in American adults. PMID- 26002190 TI - The economic and logistical burden of care for severe work-related injuries in a level 1 tertiary care trauma referral center. AB - BACKGROUND: Work-related injuries (WRIs) represent a significant economic and logistical burden to healthcare systems. METHODS: All patients with severe WRIs (Injury Severity Score [ISS] >= 12) (1995 to 2013) were compared with patients with non-WRIs using standard methodology (P < .05). RESULTS: A total of 1,270 (8.5%) trauma admissions were for severe WRIs (mean age = 45 years, male:female ratio = 2.8:1, mean ISS = 22.7). Compared with patients with non-WRIs, WRI patients were younger, male, and had fewer comorbidities. Despite equivalent ISS, WRIs had a longer intensive care unit length of stay, length of mechanical ventilation, and number of surgical/operative procedures. Fewer patients with WRIs died in hospital and more were discharged home without support services. The acute care economic burden of WRIs was higher (because of intensive care unit and operating theatre, and physician compensation) (all analyses, P < .05). CONCLUSION: Patients with WRIs were younger, less comorbid, male, and had significantly higher utilization of acute care resources despite a similar ISS. PMID- 26002191 TI - Postoperative early thromboembolism as a prognostic indicator in patients with curatively resected pancreatic cancer. AB - BACKGROUND: Information regarding postoperative thromboembolism in curatively resected pancreatic cancer is limited. This study aimed to assess the incidence and significance of postoperative thromboembolism. METHODS: We retrospectively reviewed the medical records of 121 curatively resected pancreatic cancer patients. Early and late thromboembolisms were defined as events that occurred within 1 year and after 1 year, respectively. RESULTS: Twenty-two patients (18%) experienced thromboembolism. Seven thromboembolic events occurred within 1 month (7, 6%), and the incidence rate decreased over time. Ten (63%) of the 16 patients with early thromboembolism experienced thromboembolism before or at the same time as recurrence; however, 5 (83%) of the 6 patients with late thromboembolism experienced recurrence before thromboembolism (P = .005). A significant difference in recurrence-free survival (P = .016) and borderline difference in overall survival (P = .050) were observed between patients with early thromboembolism and others. CONCLUSIONS: Thromboembolic events after curative surgery are prevalent in pancreatic cancer, especially within 1 month. Thromboembolic events within 1 year of surgery should be cautiously monitored. PMID- 26002192 TI - Emergency department presentation, admission, and surgical intervention for colonic diverticulitis in the United States. AB - BACKGROUND: Diverticulitis in admitted inpatients is well reported. This study examined colonic diverticulitis treated in the emergency department (ED). METHODS: The 2010 Nationwide Emergency Department Sample was used to examine relationships among patient age and inpatient admission, surgical intervention, and in-hospital mortality among ED patients with a primary diagnosis of diverticulitis. RESULTS: Of 310,983 ED visits for primary diverticulitis, 53% resulted in hospitalization and 6% in surgical intervention. Most patients 65+ years old were female (69%), and most were hospitalized (63%). Seven percent of ED patients aged 65+ underwent surgery and .96% died in hospital. Patients aged less than 40 years (13% of all admissions) were mostly male (63%), 42% were hospitalized, 4% underwent surgery, and less than .01% died. Compared with patients aged less than 40 years, those 65+ demonstrated greater odds of admission (odds ratio 1.53, 95% confidence interval 1.43 to 1.64) and surgical intervention (odds ratio 1.45, 95% confidence interval 1.27 to 1.65). CONCLUSIONS: Half of ED patients were hospitalized and 6% of ED visits resulted in colectomy. Fully 13% of ED patients were less than 40 years old. Future studies examining outpatient services may further illuminate the epidemiology of diverticulitis. PMID- 26002193 TI - Measuring the detriment of treatment: number needed to harm. PMID- 26002194 TI - Life-long norepinephrine transporter (NET) knock-out leads to the increase in the NET mRNA in brain regions rich in norepinephrine terminals. AB - These studies aimed to identify the genes differentially expressed in the frontal cortex of mice bearing a life-long norepinephrine transporter knock-out (NET-KO) and wild-type animals (WT). Differences in gene expression in the mouse frontal cortex were studied using a whole-genome microarray approach. Using an alternative approach, i.e. RT-PCR (reverse transcription polymerase chain reaction) with primers complementary to various exons of the NET gene, as well as TaqMan arrays, the level of mRNA encoding the NET in other brain regions of the NET-KO mice was also examined. The analyses revealed a group of 92 transcripts (27 genes) that differentiated the NET-KO mice from the WT mice. Surprisingly, the studies have shown that the mRNA encoding NET accumulated in the brain regions rich in norepinephrine nerve endings in the NET-KO mice. Because there is no other source of NET mRNA besides the noradrenergic terminals in the brain regions studied, these results might speak in favor of the presence of mRNA in axon terminals. RNA-Binding Protein Immunoprecipitation approach indicated that mRNA encoding NET was detected in the Ago2 protein/mRNA complex. In addition, the amount of Ago2 protein in the frontal cortex was significantly higher in NET-KO mice as compared with that of the WT animals. These results are important for further characterization of the NET-KO mice, which - besides other merits - might serve as a good model to study the fate of truncated mRNA in neurons. PMID- 26002195 TI - Condition Self-Management in Pediatric Spina Bifida: A Longitudinal Investigation of Medical Adherence, Responsibility-Sharing, and Independence Skills. AB - OBJECTIVE: This study aimed to evaluate rates of medical adherence, responsibility, and independence skills across late childhood and adolescence in youth with spina bifida (SB) and to explore associations among these disease self management variables. METHOD: 111 youth with SB, their parents, and a health professional participated at two time points. Informants completed questionnaires regarding medical adherence, responsibility-sharing, and child independence skills. RESULTS: Youth gained more responsibility and independence skills across time, although adherence rates did not follow a similar trajectory. Increased child medical responsibility was related to poorer adherence, and father-reported independence skills were associated with increased child responsibility. CONCLUSIONS: This study highlights medical domains that are the most difficult for families to manage (e.g., skin checks). Although youth appear to gain more autonomy across time, ongoing parental involvement in medical care may be necessary to achieve optimal adherence across adolescence. PMID- 26002196 TI - The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight. AB - Over the past half-century, we have become increasingly aware of the ubiquity of DNA damage. Under the constant exposure to exogenous and endogenous genomic stress, cells must attempt to replicate damaged DNA. The encounter of replication forks with DNA lesions triggers several cellular responses, including the activation of translesion DNA synthesis (TLS), which largely depends upon specialized DNA polymerases with flexible active sites capable of accommodating bulky DNA lesions. A detrimental aspect of TLS is its intrinsic mutagenic nature, and thus the activity of the TLS polymerases must ideally be restricted to synthesis on damaged DNA templates. Despite their potential clinical importance in chemotherapy, TLS inhibitors have been difficult to identify since a direct assay designed to quantify genomic TLS events is still unavailable. Herein we discuss the methods that have been used to validate TLS inhibitors such as USP1, p21 and Spartan, highlighting research that has revealed their contribution to the control of DNA synthesis on damaged and undamaged templates. PMID- 26002198 TI - New structural snapshots provide molecular insights into the mechanism of high fidelity DNA synthesis. AB - Time-lapse X-ray crystallography allows visualization of intermediate structures during the DNA polymerase catalytic cycle. Employing time-lapse crystallography with human DNA polymerase beta has recently allowed us to capture and solve novel intermediate structures that are not stable enough to be analyzed by traditional crystallography. The structures of these intermediates reveals exciting surprises about active site metal ions and enzyme conformational changes as the reaction proceeds from the ground state to product release. In this perspective, we provide an overview of recent advances in understanding the DNA polymerase nucleotidyl transferase reaction and highlight both the significance and mysteries of enzyme efficiency and specificity that remain to be solved. PMID- 26002200 TI - Encounter Preparedness, Satisfaction, and Performance Effects of Influence in Assertive Community Treatment (ACT) Teams. AB - Assertive community treatment (ACT) teams are linked to high quality outcomes for individuals with severe mental illness. This paper tests arguments that influence shared between team members is associated with better encounter preparedness, higher work satisfaction, and improved performance in ACT teams. Influence is conceptualized in three ways: the average level according to team members, the team's evaluation of the dispersion of team member influence, and as the person organization fit of individual perception of empowerment. The study design is a retrospective observational design using survey data from a longitudinal study of 26 ACT teams (approximately 275 team members total) over 18 months. This study finds that average team influence and person-organization fit are positively correlated with encounter preparedness and satisfaction. Dispersion of influence was not significantly correlated with study outcomes. Influence in ACT teams has multiple dimensions, each with differential effects on team outcomes. These findings provide guidance as to how one might encourage equal and substantive contribution from ACT team members. PMID- 26002197 TI - The role of DNA base excision repair in brain homeostasis and disease. AB - Chemical modification and spontaneous loss of nucleotide bases from DNA are estimated to occur at the rate of thousands per human cell per day. DNA base excision repair (BER) is a critical mechanism for repairing such lesions in nuclear and mitochondrial DNA. Defective expression or function of proteins required for BER or proteins that regulate BER have been consistently associated with neurological dysfunction and disease in humans. Recent studies suggest that DNA lesions in the nuclear and mitochondrial compartments and the cellular response to those lesions have a profound effect on cellular energy homeostasis, mitochondrial function and cellular bioenergetics, with especially strong influence on neurological function. Further studies in this area could lead to novel approaches to prevent and treat human neurodegenerative disease. PMID- 26002201 TI - Kinetic characterization of human histone H3 lysine 36 methyltransferases, ASH1L and SETD2. AB - BACKGROUND: Dysregulation of methylation of lysine 36 on histone H3 (H3K36) have been implicated in a variety of diseases including cancers. ASH1L and SETD2 are two enzymes among others that catalyze H3K36 methylation. H3K4 methylation has also been reported for ASH1L. METHODS: Radioactivity-based enzyme assays, Western and immunoblotting using specific antibodies and molecular modeling were used to characterize substrate specificity of ASH1L and SETD2. RESULTS: Here we report on the assay development and kinetic characterization of ASH1L and SETD2 and their substrate specificities in vitro. Both enzymes were active with recombinant nucleosome as substrate. However, SETD2 but not ASH1L methylated histone peptides as well indicating that the interaction of the basic post-SET extension with substrate may not be critical for SETD2 activity. Both enzymes were not active with nucleosome containing a H3K36A mutation indicating their specificity for H3K36. Analyzing the methylation state of the products of ASH1L and SETD2 reactions also confirmed that both enzymes mono- and dimethylate H3K36 and are inactive with H3K4 as substrate, and that only SETD2 is able to trimethylate H3K36 in vitro. CONCLUSIONS: We determined the kinetic parameters for ASH1L and SETD2 activity enabling screening for inhibitors that can be used to further investigate the roles of these two proteins in health and disease. Both ASH1L and SETD2 are H3K36 specific methyltransferases but only SETD2 can trimethylate this mark. The basic post-SET extension is critical for ASH1L but not SETD2 activity. GENERAL SIGNIFICANCE: We provide full kinetic characterization of ASH1L and SETD2 activity. PMID- 26002199 TI - The Repeat Expansion Diseases: The dark side of DNA repair. AB - DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion. PMID- 26002202 TI - Actin-cytoskeleton polymerization differentially controls the stability of Ski and SnoN co-repressors in normal but not in transformed hepatocytes. AB - BACKGROUND: Ski and SnoN proteins function as transcriptional co-repressors in the TGF-beta pathway. They regulate cell proliferation and differentiation, and their aberrant expression results in altered TGF-beta signalling, malignant transformation, and alterations in cell proliferation. METHODS: We carried out a comparative characterization of the endogenous Ski and SnoN protein regulation by TGF-beta, cell adhesion disruption and actin-cytoskeleton rearrangements between normal and transformed hepatocytes; we also analyzed Ski and SnoN protein stability, subcellular localization, and how their protein levels impact the TGF beta/Smad-driven gene transcription. RESULTS: Ski and SnoN protein levels are lower in normal hepatocytes than in hepatoma cells. They exhibit a very short half-life and a nuclear/cytoplasmic distribution in normal hepatocytes opposed to a high stability and restricted nuclear localization in hepatoma cells. Interestingly, while normal cells exhibit a transient TGF-beta-induced gene expression, the hepatoma cells are characterized by a strong and sustained TGF beta-induced gene expression. A novel finding is that Ski and SnoN stability is differentially regulated by cell adhesion and cytoskeleton rearrangements in the normal hepatocytes. The inhibition of protein turnover down-regulated both Ski and SnoN co-repressors impacting the kinetic of expression of TGF-beta-target genes. CONCLUSION: Normal regulatory mechanisms controlling Ski and SnoN stability, subcellular localization and expression are altered in hepatocarcinoma cells. GENERAL SIGNIFICANCE: This work provides evidence that Ski and SnoN protein regulation is far more complex in normal than in transformed cells, since many of the normal regulatory mechanisms are lost in transformed cells. PMID- 26002203 TI - Fear Avoidance Behavior, Not Walking Endurance, Predicts the Community Reintegration of Community-Dwelling Stroke Survivors. AB - OBJECTIVE: To examine the contribution of walking endurance, subjective balance confidence, and fear avoidance behavior to community reintegration among community-dwelling stroke survivors. DESIGN: Cross-sectional study. SETTING: University-based rehabilitation center. PARTICIPANTS: Patients with chronic stroke (N=57) aged >=50 years. INTERVENTIONS: None. MAIN OUTCOME MEASURE: The Chinese version of the Community Integration Measure (CIM). RESULTS: Our correlation analyses revealed that fear avoidance behavior as measured by the Chinese version of the Survey of Activities and Fear of Falling in the Elderly (SAFE) scores had the highest significant negative correlation with CIM scores among all the variables tested. Our regression analyses also revealed that walking endurance and subjective balance confidence were not significant predictors of CIM scores. Based on scores on the number of falls in the previous 6 months, Chinese version of the Geriatric Depression Scale scores, distance covered in the 6-minute walk test, and Chinese versions of the Activities specific Balance Confidence Scale scores and SAFE scores, our final regression model predicted 49.7% of the variance in the Chinese version of the CIM scores. CONCLUSIONS: The levels of walking endurance and subjective balance confidence are not significant predictors of community reintegration of community-dwelling stroke survivors but the fear avoidance behavior. Future studies addressing fear avoidance behavior is clearly warranted for stroke rehabilitation. PMID- 26002204 TI - New Approach in Fibromyalgia Exercise Program: A Preliminary Study Regarding the Effectiveness of Balance Training. AB - OBJECTIVES: To determine the effectiveness of balance exercises on the functional level and quality of life (QOL) of patients with fibromyalgia syndrome (FMS) and to investigate the circumstances associated with balance disorders in FMS. DESIGN: Randomized controlled trial. SETTING: Physical medicine and rehabilitation clinic. PARTICIPANTS: Patients (N=57) (age range, 18-65y) with FMS were randomly assigned into 2 groups. INTERVENTIONS: Group 1 was given flexibility and balance exercises for 6 weeks, whereas group 2 received only a flexibility program as the control group. MAIN OUTCOME MEASURES: Functional balance was measured by the Berg Balance Scale (BBS), and dynamic and static balance were evaluated by a kinesthetic ability trainer (KAT) device. Fall risk was assessed with the Hendrich II fall risk model. The Nottingham Health Profile, Fibromyalgia Impact Questionnaire (FIQ), and Beck Depression Inventory (BDI) were used to determine QOL and functional and depression levels, respectively. Assessments were performed at baseline and after the 6-week program. RESULTS: In group 1, statistically significant improvements were observed in all parameters (P<.05), but no improvement was seen in group 2 (P>.05). When comparing the 2 groups, there were significant differences in group 1 concerning the KAT static balance test (P=.017) and FIQ measurements (P=.005). In the correlation analysis, the BDI was correlated with the BBS (r=-.434) and Hendrich II results (r=.357), whereas body mass index (BMI) was correlated with the KAT static balance measurements (r=.433), BBS (r=-.285), and fall frequency (r=.328). CONCLUSIONS: A 6-week balance training program had a beneficial effect on the static balance and functional levels of patients with FMS. We also observed that depression deterioration was related to balance deficit and fall risk. Higher BMI was associated with balance deficit and fall frequency. PMID- 26002205 TI - Quantitative determination of fucoidan using polyion-sensitive membrane electrodes. AB - The use of polyanion and polycation-sensitive membrane electrodes to detect five different preparations of fucoidan is described. Unlike linear polyanionic molecules previously measured with polymer membrane-based electrochemical sensors, fucoidans from marine brown algae are all highly branched, sulfated polysaccharides with varying charge densities and structures, depending on the species of seaweed, method of extraction used and extent of purification. When tridodecylmethylammonium (TDMA) was used as the ion-exchanger, a large, non equilibrium EMF response was observed over a concentration range of 0.5-50 MUg mL(-1) fucoidan. Fucoidan was also measured by titration with polycationic protamine, using a dinonylnaphthalene sulfonate (DNNS)-doped membrane electrode as the potentiometric endpoint detector. Potentiometric titration was used to determine the binding ratio between protamine and fucoidan at the neutralization endpoint for each fucoidan preparation. This binding ratio was then used to successfully determine the fucoidan content of commercially available nutritional supplements. Fucoidan was also measured in undiluted blood serum, demonstrating that this method may be applicable for measuring fucoidan for clinical applications. PMID- 26002206 TI - Analytical methods for assessing metal bioaccessibility in airborne particulate matter: A scoping review. AB - In contrast to the existence of standardized methods to assess metal bioaccessibility via the gastrointestinal route, there are no widely-accepted, established in vitro testing protocols to measure elemental solubility in the human lung. This may be attributed, in part, to the difficulty associated with simulating the lung's complex in vivo conditions. The purpose of this review is two-fold: (1) to determine how the bioaccessibility of metals associated with ambient particulate matter (PM) in the human lung has been assessed in the literature, and (2) examine the suitability and biological relevance of applied methods for the measurement of metal bioaccessibility employed to date. The review revealed that limited attention has been paid to the development and application of biologically-relevant in vitro methods to measure elemental solubility in ambient PM as a proxy for bioaccessibility in the human lung. Few studies (n=14) used synthetic lung fluids to simulate in vivo conditions, with only half extracting samples at a biologically-relevant temperature of 37 degrees C. There was limited evidence suggesting that the use of water is less effective as a leaching agent compared to simulated lung fluids. In sum, this scoping review highlights a critical need to develop standardized methods for the systematic assessment of elemental bioaccessibility via the respiratory route. Priority should be placed on the validation of biologically-relevant methods, including the use of leaching agents and extraction parameters used, which allow for testing to be conducted in a reliable, yet cost efficient, manner. PMID- 26002207 TI - Signal amplification strategies for DNA and protein detection based on polymeric nanocomposites and polymerization: A review. AB - Demand is increasing for ultrasensitive bioassays for disease diagnosis, environmental monitoring and other research areas. This requires novel signal amplification strategies to maximize the signal output. In this review, we focus on a series of significant signal amplification strategies based on polymeric nanocomposites and polymerization. Some common polymers are used as carriers to increase the local concentration of signal probes and/or biomolecules on their surfaces or in their interiors. Some polymers with special fluorescence and optical properties can efficiently transfer the excitation energy from a single site to the whole polymer backbone. This results in superior fluorescence signal amplification due to the resulting collective effort (integration of signal). Recent polymerization-based signal amplification strategies that employ atom transfer radical polymerization (ATRP) and photo-initiated polymerization are also summarized. Several distinctive applications of polymers in ultrasensitive bioanalysis are highlighted. PMID- 26002208 TI - Analytical potential of a laser ablation-glow discharge-optical emission spectrometry system for the analysis of conducting and insulating materials. AB - The analytical capabilities of a glow discharge (GD) as a secondary source for excitation/ionization of the material provided by laser ablation (LA) have been compared to conventional laser induced breakdown spectroscopy (LIBS). In LA-GD both sources can be independently adjusted to optimize the sampling process and then its subsequent excitation. This could involve a number of analytical performance advantages, such as reduced matrix dependence, greater precision and sensitivity than those encountered in LIBS. For such purpose, an ablation chamber design including two electrodes to generate the GD discharge has been built and assayed. A comparison between LIBS and LA-GD-OES has been carried out, both, under reduced argon and helium atmospheres. Different sets of samples (conducting reference materials, glass and fluorine pellets) have been used to evaluate the novel coupled technique. The LA-GD coupled system has shown to provide lower detection limits. In addition, best linear correlations between intensities and concentrations and lower matrix effects have also been found using the coupled system. Moreover, special advantages of the LA-GD-OES have also been demonstrated for the analysis of fluorine. PMID- 26002209 TI - Discrimination and classification techniques applied on Mallotus and Phyllanthus high performance liquid chromatography fingerprints. AB - Mallotus and Phyllanthus genera, both containing several species commonly used as traditional medicines around the world, are the subjects of this discrimination and classification study. The objective of this study was to compare different discrimination and classification techniques to distinguish the two genera (Mallotus and Phyllanthus) on the one hand, and the six species (Mallotus apelta, Mallotus paniculatus, Phyllanthus emblica, Phyllanthus reticulatus, Phyllanthus urinaria L. and Phyllanthus amarus), on the other. Fingerprints of 36 samples from the 6 species were developed using reversed-phase high-performance liquid chromatography with ultraviolet detection (RP-HPLC-UV). After fingerprint data pretreatment, first an exploratory data analysis was performed using Principal Component Analysis (PCA), revealing two outlying samples, which were excluded from the calibration set used to develop the discrimination and classification models. Models were built by means of Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Classification and Regression Trees (CART) and Soft Independent Modeling of Class Analogy (SIMCA). Application of the models on the total data set (outliers included) confirmed a possible labeling issue for the outliers. LDA, QDA and CART, independently of the pretreatment, or SIMCA after "normalization and column centering (N_CC)" or after "Standard Normal Variate transformation and column centering (SNV_CC)" were found best to discriminate the two genera, while LDA after column centering (CC), N_CC or SNV_CC; QDA after SNV_CC; and SIMCA after N_CC or after SNV_CC best distinguished between the 6 species. As classification technique, SIMCA after N_CC or after SNV_CC results in the best overall sensitivity and specificity. PMID- 26002210 TI - Procrustes rotation as a diagnostic tool for projection pursuit analysis. AB - Projection pursuit (PP) is an effective exploratory data analysis tool because it optimizes the projection of high dimensional data using distributional characteristics rather than variance or distance metrics. The recent development of fast and simple PP algorithms based on minimization of kurtosis for clustering data has made this powerful tool more accessible, but under conditions where the sample-to-variable ratio is small, PP fails due to opportunistic overfitting of random correlations to limiting distributional targets. Therefore, some kind of variable compression or data regularization is required in these cases. However, this introduces an additional parameter whose optimization is manually time consuming and subject to bias. The present work describes the use of Procrustes analysis as diagnostic tool that can be used to evaluate the results of PP analysis in an efficient manner. Through Procrustes rotation, the similarity of different PP projections can be examined in an automated fashion with "Procrustes maps" to establish regions of stable projections as a function of the parameter to be optimized. The application of this diagnostic is demonstrated using principal components analysis to compress FTIR spectra from ink samples of ten different brands of pen, and also in conjunction with regularized PP for soybean disease classification. PMID- 26002211 TI - Selective sorption of iodide onto organo-MnO2 film and its electrochemical desorption and detection. AB - This paper reports an electrochemically grown film consisting of layered MnO2 intercalated with hexadecylpyridinium cations (HDPy(+)), which can selectively sorb and detect iodide anions in aqueous solution amperometrically. Sorption of iodide by the HDPy/MnO2 film did not occur via ion exchange, but through hydrophobic interactions between the interlayer organic phase of the film and iodide ions in solution. The sorption rate increased with the deposited amount of MnO2. During the sorption process, the interlayer spaces expanded, and new diffraction peaks appeared that were attributed to the incorporated species. Anodic polarization of the iodide-sorbed HDPy/MnO2 film led to electron transfer from the incorporated iodide to the underlying substrate through the MnO2 sheets. The oxidized iodide was expelled from the film as molecular I2, while the expanded interlayer spaces were restored to their original state. Thus, the MnO2 layers and the incorporated HDPy can synergistically sorb/desorb iodide anions, resulting in a unique "self-cleaning" function that can operate electrochemically. This property allowed amperometric detection of iodide at a concentration as low as 0.0186 MUM, which was below the detection limits reported for previous iodide sensors. PMID- 26002212 TI - Textile-based sampling for potentiometric determination of ions. AB - Potentiometric sensing utilizing textile-based micro-volume sampling was applied and evaluated for the determination of clinically (Na(+), K(+), Cl(-)) and environmentally (Cd(2+), Pb(2+) and pH) relevant analytes. In this technological design, calibration solutions and samples were absorbed into textiles while the potentiometric cells (ion-selective electrodes and reference electrode) were pressed against the textile. Once the liquid, by wicking action, reached the place where the potentiometric cell was pressed onto the textile, hence closing the electric circuit, the potentiometric response was obtained. Cotton, polyamide, polyester and their blends with elastane were applied for micro-volume sampling. The textiles were found to influence the determination of pH in environmental samples with pH close to neutral and Pb(2+) at low analyte concentrations. On the other hand, textile-based micro-volume sampling was successfully applied in measurements of Na(+) using solid-contact sodium selective electrodes utilizing all the investigated textiles for sampling. It was found that in order to extend the application of textile-based sampling toward environmental analysis of ions it will be necessary to tailor the physio-chemical properties of the textile materials. In general, textile-based sampling opens new possibilities for direct chemical analysis of small-volume samples and provide a simple and low-cost method to screen various textiles for their effects on samples to identify which textiles are the most suitable for on-body sensing. PMID- 26002213 TI - Preparation and application of molecularly imprinted polymer for isolation of chicoric acid from Chicorium intybus L. medicinal plant. AB - Molecularly imprinted polymer (MIP) was synthesized and applied for the extraction of chicoric acid from Chicory herb (Chicorium intybus L.). A computational study was developed to find a suitable template to functional monomer molar ratio for MIP preparations. The molar ratio was chosen based on the comparison of the binding energy of the complexes between the template and functional monomers. Based on the computational results, eight different polymers were prepared using chicoric acid as the template. The MIPs were synthesized in a non-covalent approach via thermal free-radical polymerization, using two different polymerization methods, bulk and suspension. Batch rebinding experiments were performed to evaluate the binding properties of the imprinted polymers. The best results were obtained with a MIP prepared using bulk polymerization with 4-vinylpyridine (4-VP) as the functional monomer and ethylene glycol dimethacrylate (EGDMA) as the crosslinker with a molar ratio of 1:4:20. The best MIP showed selective binding ability toward chicoric acid in the presence of the template's structural analogues, caffeic acid, caftaric acid and chlorogenic acid. PMID- 26002214 TI - Magnetic graphene oxide modified with choline chloride-based deep eutectic solvent for the solid-phase extraction of protein. AB - Four kinds of green deep eutectic solvents (DESs) based on choline chloride (ChCl) have been synthesized and coated on the surface of magnetic graphene oxide (Fe3O4@GO) to form Fe3O4@GO-DES for the magnetic solid-phase extraction of protein. X-ray diffraction (XRD), vibrating sample magnetometer (VSM), Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FESEM) and thermal gravimetric analysis (TGA) were employed to characterize Fe3O4@GO-DES, and the results indicated the successful preparation of Fe3O4@GO-DES. The UV-vis spectrophotometer was used to measure the concentration of protein after extraction. Single factor experiments proved that the extraction amount was influenced by the types of DESs, solution temperature, solution ionic strength, extraction time, protein concentration and the amount of Fe3O4@GO-DES. Comparison of Fe3O4@GO and Fe3O4@GO-DES was carried out by extracting bovine serum albumin, ovalbumin, bovine hemoglobin and lysozyme. The experimental results showed that the proposed Fe3O4@GO-DES performs better than Fe3O4@GO in the extraction of acidic protein. Desorption of protein was carried out by eluting the solid extractant with 0.005 mol L(-1) Na2HPO4 contained 1 mol L(-1) NaCl. The obtained elution efficiency was about 90.9%. Attributed to the convenient magnetic separation, the solid extractant could be easily recycled. PMID- 26002215 TI - Response surface methodology toward the optimization of high-energy carotenoid extraction from Aristeus antennatus shrimp. AB - High-energy assisted extraction techniques, like ultrasound assisted extraction (UAE) and microwave assisted extraction (MAE), are widely applied over the last years for the recovery of bioactive compounds such as carotenoids, antioxidants and phenols from foods, animals and herbal natural sources. Especially for the case of xanthophylls, the main carotenoid group of crustaceans, they can be extracted in a rapid and quantitative way with the use of UAE and MAE. Response surface methodology (RSM) is used for the optimization of extraction methodologies, also being applied to optimize high energy techniques. Three independent variables, namely extraction time, ultrasound or microwave power and solvent/material ratio, were investigated for both methods by employing a 16-run three-level Box-Behnken design (BBD). Considering the extraction efficiency for carotenoids from Aristeus antennatus shrimp, the selected conditions for UAE were 5 min, 600 W and 10:1 mL g(-1). Acetone was the solvent of choice for the extraction procedure. For MAE, the best experimental values were 7 min, 30 W and 20:1 mL g(-1) using n-hexane:acetone:ethanol 2:1:1 (v/v/v) as extraction solvent. The determination of total carotenoid yield was carried out using the spectophotometric calibration curve (A=0.1646(+/-0.0061)C-0.005(+/-0.022), R(2)=0.996, n=3) of a standard mix solution of canthaxanthin, zeaxanthin and lutein at 452.1 nm. Under the selected conditions, the yield of total carotenoids for UAE was 23.4(+/-2.3) and 6.73(+/-0.56) mg of carotenoids per 100 g dry sample for the head and the body of shrimp, while for MAE was 23.92(+/-0.63) and 13.3(+/ 1.1) mg of carotenoids per 100g dry sample, respectively. The recovery of both methods was calculated between 60 and 105%. The results indicate that high-energy extraction techniques are faster, less laborious, more repeatable and reproducible methods than the conventional approaches for the quantitative recovery of sensitive bioactive compounds. Moreover, the recovery of a high-added value group of bioactive molecules from natural sources, such as carotenoids, can constitute a profitable and valuable commercial alternative, as these compounds can be used as dietary supplements, food color enhancers and additives in animal feeds, functional foods, preservatives, pharmaceuticals and cosmetics. PMID- 26002216 TI - Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity. AB - Generation of protein-derived acetaminophen-cysteine (APAP-CYS) is reported after ingestion of large and therapeutic dosages of acetaminophen in healthy and in liver-damaged patients. The incidence of protein-derived APAP-CYS adducts in repeated supratherapeutic dosages of APAP is not known. METHODS: for 12 months, a standardized and comprehensive questionnaire was used to interview every consecutive patient at a pain management clinic. Patients found to ingest more than 4 g of APAP per day for a minimum of 14 consecutive days at the time of the encounter were invited to have blood drawn for hepatic transaminases and APAP-CYS adduct levels. Twelve subjects out of 990 interviewees met inclusion criteria. Ten of the 12 had measurable protein-derived APAP-CYS, none had evidence of liver injury. Patients that ingest repeated supratherapeutic amounts of APAP over several weeks may generate APAP-CYS protein adducts in the absence of hepatic injury. PMID- 26002217 TI - Therapeutic Plasma Exchange for Refractory Hemolysis After Brown Recluse Spider (Loxosceles reclusa) Envenomation. AB - INTRODUCTION: The brown recluse spider (BRS) (Loxosceles reclusa) envenomation can lead to multiple complications, including hemolysis. We present a case of refractory hemolysis after a BRS bite treated with therapeutic plasma exchange (TPE). CASE REPORT: A 17-year-old female presented with fever, fatigue, and dyspnea. She was diagnosed with sepsis and received intravenous (IV) fluids, inotropic support, and antibiotics. On hospital day 1 she was noted to have skin lesion consistent with a BRS bite and developed hemolysis. Systemic loxoscelism with hemolysis was then suspected and methylprednisolone IV was initiated. She was discharged with a stable HGB on hospital day 3 on oral prednisolone. She was re-admitted 24 h later, with signs of worsening hemolysis. Methylprednisolone was restarted and she was transfused 4 units of packed red blood cells. TPE was initiated due to the refractory hemolysis. Shortly after the TPE session, her clinical and laboratory status improved. She required no further transfusions and was discharged on a steroid taper. DISCUSSION: TPE is an extra-corporeal method to remove substances from the blood by separating plasma from cellular blood components and replacing it with physiologic fluids. TPE has been used for snake envenomation but there are no reports detailing its use for BRS envenomations. Improvement was associated with TPE initiation and may have been due to removal of complement components activated by the spider venom. This report suggests that TPE could be a possible treatment modality for systemic loxoscelism with refractory hemolysis due to BRS envenomation. Further investigation is warranted. PMID- 26002218 TI - Identification of cold tolerance genes from leaves of mangrove plant Kandelia obovata by suppression subtractive hybridization. AB - Low temperature is a major abiotic stress that seriously limits mangrove productivity and distribution, the molecular mechanisms of cold tolerance involved in mangroves are still poorly understood at present. It was used to identify the potential cold-related genes in Kandelia obovata (K. obovata) by suppression subtractive hybridization. 334 cold-related expressed sequence tags (ESTs) out of 670 clones were isolated and sequenced. Among these ESTs, 143 unique cDNAs were identified and classified into ten groups, such as metabolism, energy, cell rescue and defense, transcription and photosynthesis according to NCBI blast. Based on bioinformatics analysis, these ESTs were mainly related to response to stimulus and metabolic process, and were included to 72 KEGG pathways. Two selected genes (e.g., aquaporin gene and zinc family protein gene) from the library were further analyzed by quantitative real-time PCR analysis. Both the two genes were found to be transcriptionally up-regulated under cold stress, which partly approve the construction of the subtractive cDNA library. The diversity of the putative functions of these genes indicated that cold stress resulted in a complex response in K. obovata. Further investigation on the functions and potential pathways of these genes will facilitate the understanding of the molecular adaptations to cold tolerance in mangrove plants. PMID- 26002219 TI - Ecophysiological differences between three mangrove seedlings (Kandelia obovata, Aegiceras corniculatum, and Avicennia marina) exposed to chilling stress. AB - Although the cold-resistant ability of mangroves varies greatly with species, the physiological mechanism remains unclear. The chilling stress effects on morphological changes, photosynthetic pigments, reactive oxygen species (ROS), malondialdehyde (MDA) and several antioxidants, were studied in leaves of three mangrove seedlings (Kandelia obovata, Aegiceras corniculatum and Avicennia marina). Results showed that both K. obovata and A. corniculatum exhibited lighter chilling damage, lower chilling injury rates and higher survival rates compared to A. marina. Reductions of chlorophylls (Chls) were observed in all the three mangroves, and the highest was detected in A. marina. Significant increases in content of ROS (hydrogen peroxide, H2O2; hydroxyl radicals, OH?) and MDA were observed in both A. marina and A. corniculatum, whereas chilling stressed K. obovata showed a decrease in H2O2 content, constant OH? level and instantaneous increase of MDA. The contents of proline and water-soluble protein exhibited similar stress-time dependent increases in all mangroves, while A. corniculatum showed the highest increase of proline and relatively higher increase of water soluble protein. The catalase activities significantly decreased with stress time in all mangroves, while K. obovata showed the least reduction. An increase in ascorbic acid (AsA) content and activities of superoxide dismutase, peroxidase (POD), and ascorbate peroxidase (APX) were also detected in all the three mangroves, while K. obovata showed the highest increases. These results indicate that chilling-tolerance of mangroves is associated with the efficiency of antioxidants, as confirmed by principal component analysis. The AsA, APX and POD in K. obovata may play more important role in control of oxidative stresses than those in the other two species. Furthermore, the higher cold-resistance of A. corniculatum compared to A. marina may be partly associated with its higher proline accumulation. The results indicate that enzymatic and non-enzymatic antioxidants (POD, APX, AsA, proline and Car) play key roles in scavenging of excess ROS in mangroves. Further studies focusing on these stress-responsive genes will enable better understanding of the cold-resistance mechanism from molecular level. PMID- 26002220 TI - Variation of phytoplankton community structure from the Pearl River estuary to South China Sea. AB - The Pearl River is located in the northern part of South China Sea. The environment of the Pearl River estuary (PRE) is significantly impacted by nutrients from anthropogenic activities. Along the anthropogenic pollution gradient from the PRE to South China Sea, the phylogenetic diversity and biomass of phytoplankton was examined in relation to physic-chemical variables. The richness of rbcL gene was higher in the open sea than the estuary, while the concentration of chlorophyll a (Chl a) was higher in the estuary than in the open sea. The cluster analysis of the sequences data resulted in seven phytoplankton community types and the dominant species of phytoplankton changed from Cryptophytes and Diatoms to Prymnesiophytes and Diatoms along the gradient. The community structure of phytoplankton was shaped by nutrients and salinity. The phytoplankton biomass was significantly positively affected by phosphorus, nitrite and ammonium (P < 0.01) but negatively by salinity (P < 0.05); the phytoplankton diversity was highly positively affected by salinity (P < 0.05) but negatively by silicate and nitrate (P < 0.01; P < 0.05, respectively). Anthropogenic activities played a critical role in the phytoplankton distribution and biomass of the study area. Further research is necessary to reveal the influence mechanism of environmental factors on the phytoplankton. PMID- 26002221 TI - Accumulation of silver by Fucus spp. (Phaeophyceae) and its toxicity to Fucus ceranoides under different salinity regimes. AB - Metals constitute an important group of abiotic stressors that elicit stress responses in marine algae that include the production of reactive oxygen species (ROS). Silver (Ag) is a highly toxic metal to organisms but despite this there are relatively few studies on how it affects marine macroalgae (seaweeds). In a landmark study published in 1977 the first information was provided on the accumulation of Ag in Fucus spp. (Phaeophyceae) from the Looe estuary, located in south-west England, an area with a long history of mining activity. In the present study, the estuary has been re-visited and the patterns of Ag accumulation in two Fucus spp. and sediment re-examined after 35 years. We conclude that Ag concentrations in sediment and macroalgae from specific sites within the catchment remain high, but more generally sediment concentrations have declined by approximately 65 % and the dissolved, bioavailable fraction by 24 % over this period. In addition, from laboratory studies we provide data on the speciation and toxic effects of Ag under different salinity regimes in the euryhaline brown seaweed, Fucus ceranoides. From these exposure experiments, it was found that with increasing Ag concentrations growth was inhibited and lipid peroxidation associated with ROS production increased. The magnitude of the toxic effects was greater at a salinity of 10 than 28 psu which reflects the greater bioavailability of the toxic species of Ag (Ag(+) and AgCl(0)) at reduced salinities. These findings emphasise the importance of investigating the effects of metal pollution in conjunction with other, natural, environmental stressors such as salinity. PMID- 26002223 TI - Readings on psychosomatic medicine: survey of resources for trainees. AB - BACKGROUND: As systems of care become more complex and comorbid medical and psychiatric illness becomes more evident, it is essential to prepare psychiatric trainees for practice in more integrated models of care. OBJECTIVE: We sought to identify readings available for residency training in consultation-liaison (C-L) psychiatry/psychosomatic medicine with the intent to help educators and trainees identify appropriate and essential learning resources within the field. METHODS: We reviewed readings available to the residents (including commonly used textbooks in C-L psychiatry and C-L training programs' required reading lists) and identified areas of consensus regarding the topics germane to the care of patients with comorbid medical and psychiatric illness (namely depression, dementia, and delirium) and the education of trainees. RESULTS: There was considerable variation in the references cited by well-regarded textbooks and by reading lists created for trainees in C-L psychiatry. In the 4 textbooks reviewed, there were 83 shared citations on delirium (including 10 citations that were common to all 4 textbooks and 17 citations shared by 3 textbooks). Markedly less overlap was noted in the chapters on depression (only 2 references cited in all of the textbooks with relevant content) and dementia (only 7 shared references). CONCLUSION: Given the paucity of overlap of citations in commonly used textbooks, we recommend that practical topical reviews or textbook chapters be used as core (required) or recommended readings for residents on C-L psychiatry rotations, supplemented by a small number of studies or case series that illustrate key teaching points on each essential topic. PMID- 26002224 TI - Changes in Depression, Health Anxiety, and Pain Catastrophizing Between Enrollment and 1 Month After a Radius Fracture. AB - OBJECTIVES: To test the difference in symptoms of (1) depression, (2) health anxiety, and (3) catastrophic thinking between 1 and 6 weeks after injury to the radius. PATIENTS AND METHODS: In total, 69 adult patients with a minimally displaced radial head or distal radius fracture were prospectively enrolled. After diagnosis, we recorded demographic variables, 11-point ordinal numerical pain score, and agreement with "no pain, no gain"; Disabilities of the Arms, Shoulder, and Hand (DASH) questionnaire; Center for Epidemiologic Studies Depression Scale; the Whiteley Index; and the Pain Catastrophizing Scale. In total, 55 patients (80%) returned after 1 month to reevaluate pain, Disabilities of the Arms, Shoulder, and Hand, Center for Epidemiologic Studies Depression, Whiteley Index, and Pain Catastrophizing Scale scores. RESULTS: Center for Epidemiologic Studies Depression scores decreased by an average of 5 +/- 9 points (p < 0.001), and Pain Catastrophizing Scale scores decreased by 2 +/- 6 points (p = 0.0041). In multivariable analysis, decrease in Center for Epidemiologic Studies Depression was associated with not having an additional pain condition, more days elapsed between injury and final evaluation, and stronger agreement with "no pain, no gain" (adjusted R(2) = 0.26, p = 0.0006). An increase in Whiteley scores was associated with fewer years of education (R = -0.34, p = 0.012). Changes in Pain Catastrophizing Scale scores were associated with marital status (single -1.7 +/- 4.3 vs married -4.6 +/- 6.0 vs separated 0.55 +/- 6.2, p = 0.040). CONCLUSIONS: Symptoms of depression and catastrophic thinking, but not health anxiety, improved during recovery after injury. If psychologic measures are used as a screening tool to predict outcome after treatment, one should account for a patient's disease phase. LEVEL OF EVIDENCE: Prognostic level I. PMID- 26002225 TI - Thiothixene in the Management of Delirium: A Case Series. AB - BACKGROUND: Pharmacologic strategies are often required to help manage agitated patients with delirium. First-and second-generation antipsychotic medications (such as haloperidol, quetiapine, and olanzapine) are commonly used. OBJECTIVE: On the psychiatric consultation service in our hospital, thiothixene has been used based on its favorable potency, sedative, and cost profiles. Little has been written about the utility of this drug for management of delirium. METHODS: We reviewed our experience with thiothixene in this setting using pharmacy records to identify patients who received at least 1 dose between July 2011 and March 2014. We scrutinized the relevant medical records (n = 111) and recorded the following data: age, sex, medical diagnoses, signs and symptoms of delirium, dosing of thiothixene, and response to thiothixene in terms of both apparent benefit as well as side effects. RESULTS: Resolution or improvement was documented in 78% of patients and good tolerability in 82% of patients. CONCLUSIONS: Although further data from a randomized, controlled trial would be ideal, our experience suggests that thiothixene could be a safe and effective pharmacologic treatment for agitation and psychosis due to delirium. PMID- 26002226 TI - Ertapenem-Induced Delirium: A Case Report and Literature Review. PMID- 26002227 TI - Immediate mechanical effects of acute left bundle branch block by speckle tracked strain. AB - INTRODUCTION: Left bundle branch block (LBBB) is a known complication of transcatheter aortic valve replacement (TAVR) and has been shown to predict worsened outcomes in TAVR patients. A regional longitudinal strain pattern, termed the "classic" pattern of left ventricular (LV) dyssynchrony, which is thought to be due to LBBB, is highly predictive of response to cardiac resynchronization therapy. Whether LBBB causes this "classic" pattern is not known. METHODS: We retrospectively studied patients undergoing TAVR who also underwent pre- and post-TAVR strain analysis to determine if the "classic" pattern arose in those who developed TAVR-induced true LBBB. After removing patients with baseline conduction abnormalities or insufficient studies 9 patients had sufficient data for analysis. Six patients developed LBBB after TAVR and 3 patients did not develop LBBB after TAVR. ECGs were analyzed for the new onset of LBBB after TAVR. Global longitudinal strain (GLS) and regional longitudinal strain patterns were analyzed for changes between pre- and immediately post-TAVR examinations. RESULTS: Patients who did not develop LBBB showed no significant changes in their regional longitudinal strain pattern. Those patients who did develop LBBB showed significant increase in their difference of time-to-onset of contraction between the septal and lateral walls post-TAVR (22 +/- 14 ms vs 111 +/- 49 ms; p=0.003) and in their difference of time-to-peak contraction between the septal and lateral walls post-TAVR (63 +/- 56 ms vs 133 +/- 46 ms; p=0.002). Early lateral wall pre-stretch and delayed lateral wall peak contraction emerged in all patients with LBBB but early septal peak contraction meeting the established criteria was present in only one patient. DISCUSSION: The onset of LBBB led to acute, measurable changes in the regional longitudinal strain pattern consisting of early lateral wall pre-stretch and delayed lateral wall peak contraction. These represent 2 of the 3 findings in the "classic" pattern of LV dyssynchrony. Early termination of septal wall contraction meeting established criteria was not routinely found. Time and/or other factors may be required to develop the full "classic" pattern. PMID- 26002228 TI - Association between childhood exposure to single general anesthesia and neurodevelopment: a systematic review and meta-analysis of cohort study. AB - OBJECTIVE: Many studies have been done to seek the relationship between general anesthesia and neurodevelopment in pediatrics. However, there is no unified conclusion, especially single anesthesia affecting a child before 3 and 4 years. The association between anesthesia and neurodevelopment is studied using a meta analysis. METHODS: We summarized the currently available evidence by searching PubMed, EMBASE, and the Cochrane library over the past 10 years. An evaluation of neurodevelopment including learning disability, behavioral disorders, and cognitive problems was conducted. We estimated the synthesized hazard ratios (HR) and 95 % confidence interval (CI) according to inter-study heterogeneity and analyzed the factors for this association using meta-regression method. RESULTS: Thirteen eligible studies met the inclusion criteria. The neurodevelopment damage was associated with single general anesthesia before age of 4 (adjusted HR 1.28 95 % CI 1.10-1.45). The pooled adjusted HR was 1.17 (95 % CI 1.07-1.28, p = 0.001) before 4 years old after the influence analysis and the adjusted HR was 1.18 (95 % CI 1.07-1.30, p = 0.001) before 3 years old. There was no significant difference between 3 and 4 years exposed to single general anesthesia (HR3/HR4 = 1.008, p = 0.9). Due to limitations of retrospective studies, prospective investigations are needed to determine whether anesthesia is causative. CONCLUSIONS: The current evidence suggests a modestly elevated risk of neurodevelopmental disorders exists in children near 3 years of age. A single general anesthesia is relatively safe after 3 years, as the outcome is very close before 3 and 4 years old. PMID- 26002229 TI - Is postoperative delirium a relevant outcome? PMID- 26002230 TI - Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1alpha. AB - PURPOSE: Hypoxia promotes the progression of lung cancer cells. Unfortunately, anesthetic technique might aggravate hypoxia of lung cancer cells. Sevoflurane is a commonly used anesthetic. Its effect on hypoxia-induced aggressiveness of lung cancer cells remains unknown. The aim of the study is to investigate the effects of sevoflurane on hypoxia-induced growth and metastasis of lung cancer cells. As hypoxia-inducible factor-1alpha (HIF-1alpha) plays a pivotal role in mediating the adaptation and tolerance of cancer cells under hypoxic microenvironment, the role of HIF-1alpha in the effect of sevoflurane on hypoxia-induced growth and metastasis has also been elucidated. METHODS: A549 cells were treated with normoxia, hypoxia, co-treatment of sevoflurane and hypoxia, and dimethyloxaloylglycine (DMOG, a HIF-1alpha agonist) for 4 h, respectively. MTT assay and colony formation assay were used to evaluate cell growth. Transwell assay was performed to detect invasion and migration ability. The protein level of HIF-1alpha, X-linked inhibitor of apoptosis protein (XIAP), survivin, fascin, heparanase (HPA), and p38 MAPK were determined by Western blotting. RESULTS: Hypoxia enhanced proliferation and metastatic potential of cells. Sevoflurane could suppress hypoxia-induced growth and metastasis ability of cells. Furthermore, HIF-1alpha, XIAP, survivin, fascin and HPA were down-regulated significantly by the co-treatment of sevoflurane and hypoxia as compared to hypoxia treatment. DMOG abolished the inhibiting effects of sevoflurane on hypoxia-induced growth and metastasis ability of cells. In addition, sevoflurane partly reversed the increase of p38 MAPK activity that was induced by hypoxia. CONCLUSIONS: Sevoflurane could suppress hypoxia-induced growth and metastasis of lung cancer cells, which might be associated with modulating HIF-1alpha and its down-stream genes. Moreover, p38 MAPK signaling pathway was involved in the regulation of HIF-1alpha by sevoflurane. PMID- 26002231 TI - Slit2 modifies VEGF-induced angiogenic responses in rabbit skeletal muscle via reduced eNOS activity. AB - AIMS: Slit2 is a possible modulator of VEGF-induced angiogenesis, but its effects have not been tested on large animal models. We studied the effect of Slit2 on therapeutic angiogenesis induced by VEGF receptor 2 (VEGFR2) ligands Vammin and VEGF-D(DeltaNDeltaC) in vivo in rabbit skeletal muscles. The Slit2 target genes were also studied by RNA sequencing in endothelial cells. METHODS AND RESULTS: Adenoviral intramuscular gene transfers were performed into New Zealand White rabbit hindlimbs. Confocal and multiphoton microscopes were used for blood vessel imaging. Signaling experiments and gene expression analyses were performed to study mechanisms of Slit2 action. Slit2 decreased VEGFR2-mediated vascular permeability. Slit2 also reduced VEGFR2-mediated increase in blood perfusion and capillary enlargement, whereas sprouting of the capillaries was increased. Slit2 gene transfer alone did not have any effects on vascular functions or morphology. VEGFR2 activation was not affected by Slit2, but eNOS phosphorylation was diminished. The transcriptome profiling showed Slit2 down-regulating angiogenesis related genes such as Nuclear receptor subfamily 4 group A member 1 (NR4A1) and Stanniocalcin-1 (STC-1) as well as genes related to endothelial cell migration and vascular permeability. CONCLUSION: Combining Slit2 with VEGFs adjusts VEGFR2 mediated angiogenic effects into a more physiological direction. This possibly allows the use of higher VEGF vector doses to achieve a more widespread vector and VEGF distribution in the target tissues leading to a better therapeutic outcome while reducing excess vascular permeability. PMID- 26002232 TI - Soft tissue and wound management of blast injuries. AB - The management of blast-related soft tissue wounds requires a comprehensive surgical approach that acknowledges extensive zones of injury and the likelihood of massive contamination. The experiences of military surgeons during the last decade of war have significantly enhanced current understandings of the optimal means of mitigating infectious complications, the timing of soft tissue coverage attempts, and the reconstructive options available for definitive wound management. Early administration of antibiotics in the setting of soft tissue wounds and associated open fractures is the single most important aspect of open fracture care. Both civilian and military reports have elucidated the incidence of invasive fungal infection in the setting of high-energy injuries with significant wound burdens, and novel treatment protocols have emerged. The type of reconstruction is predicated upon the zone of injury and location of the soft tissue defect. Multiple reports of military cohorts have suggested the equivalency of various techniques and types of soft tissue coverage. Longer-term follow-up will inform future perspectives on the durability of these surgical approaches. PMID- 26002234 TI - Letter from the Editor: Life's Pitfalls. PMID- 26002233 TI - Detection of Brain Tumors and Systemic Metastases Using NanoLuc and Fluc for Dual Reporter Imaging. AB - PURPOSE: Bioluminescence imaging (BLI) is a technique with a low background noise and high sensitivity which is widely used in mice models in oncology. We aimed to assess BLI efficiency of the new luciferase NanoLuc (Nluc) for glioblastoma cell lines and tumors, including for dual reporter applications of deep brain tumors and systemic metastasis when combined with firefly luciferase (Fluc). PROCEDURES: U87 cells were genetically modified for constitutive production of either Nluc, Fluc, or both and assayed for luciferase activity and BLI on cell lysates, living cells, subcutaneous tumors, brain tumors, and systemic metastases. RESULTS: In vitro, light production by Nluc activity is higher than Fluc. In vivo, Nluc allows for tumor detection including for deep brain tumors and systemic metastases. CONCLUSIONS: Nluc appears to be a useful tool to combine with Fluc for dual imaging in vivo using bioluminescence, allowing for the detection of distinct events in deep tissues within the same organism. PMID- 26002235 TI - Letter from the guest editor: pitfalls in thoracic and cardiovascular imaging. PMID- 26002236 TI - Pitfalls in pulmonary nodule characterization. PMID- 26002237 TI - Pitfalls and limitations in non-small cell lung cancer staging. PMID- 26002238 TI - Pitfalls in oncologic imaging: complications of chemotherapy and radiotherapy in the chest. PMID- 26002239 TI - Computed tomography imaging of lung infection in the oncologic setting: typical features and potential pitfalls. PMID- 26002240 TI - Pitfalls in chest radiographic interpretation: blind spots. PMID- 26002241 TI - Potential pitfalls in interpretation of positron emission tomography/computed tomography findings in the thorax. PMID- 26002242 TI - Multidetector computed tomography pulmonary angiography pitfalls in the evaluation of pulmonary embolism with emphasis in technique. PMID- 26002243 TI - Pulmonary cement embolism presenting with dyspnea. PMID- 26002244 TI - Pitfalls in computed tomography of the aorta. PMID- 26002245 TI - Pitfalls in oncologic imaging: pericardial recesses mimicking adenopathy. PMID- 26002246 TI - Imaging of the mediastinum: vascular lesions as a potential pitfall. PMID- 26002247 TI - Pitfalls in imaging of the chest wall. PMID- 26002248 TI - Toxicity of silver and gold nanoparticles on marine microalgae. AB - The increased use of nanomaterials in several novel industrial applications during the last decade has led to a rise in concerns about the potential toxic effects of released engineered nanoparticles (NPs) into the environment, as their potential toxicity to aquatic organisms is just beginning to be recognised. Toxicity of metallic nanoparticles to aquatic organisms, including microalgae, seems to be related to their physical and chemical properties, as well as their behaviour in the aquatic media where processes of dissolution, aggregation and agglomeration can occur. Although the production of these particles has increased considerably in recent years, data on their toxicity on microalgae, especially those belonging to marine or estuarine environments remain scarce and scattered. The literature shows a wide variation of results on toxicity, mainly due to the different methodology used in bioassays involving microalgae. These can range for up to EC50 data, in the case of AgNPs, representing five orders of magnitude. The importance of initial cellular density is also addressed in the text, as well as the need for keeping test conditions as close as possible to environmental conditions, in order to increase their environmental relevance. This review focuses on the fate and toxicity of silver, gold, and gold-silver alloy nanoparticles on microalgae, as key organisms in aquatic ecosystems. It is prompted by their increased production and use, and taking into account that oceans and estuaries are the final sink for those NPs. The design of bioassays and further research in the field of microalgae nanoecotoxicology is discussed, with a brief survey on newly developed technology of green (algae mediated) production of Ag, Au and Ag-Au bimetallic NPs, as well as some final considerations about future research on this field. PMID- 26002249 TI - Prenatal diagnosis of cystic fibrosis: 10-years experience. AB - PURPOSE: We present in this study our 10years experience in prenatal diagnosis of cystic fibrosis performed in the Tunisian population. PATIENTS AND METHODS: Based on family history, 40 Tunisian couples were selected for prenatal diagnosis. Fetal DNA was isolated from amniotic fluid collected by transabdominal amniocentesis or from chronic villi by transcervical chorionic villus sampling. The genetic analysis for cystic fibrosis mutations was performed by denaturant gradient gel electrophoresis and denaturing high-pressure liquid phase chromatography. We performed microsatellites analysis by capillary electrophoresis in order to verify the absence of maternal cell contamination. RESULTS: Thirteen fetuses were affected, 21 were heterozygous carriers and 15 were healthy with two normal alleles of CFTR gene. Ten couples opted for therapeutic abortion. The microsatellites genotyping showed the absence of contamination of the fetal DNA by maternal DNA in 93.75%. CONCLUSION: Our diagnostic strategy provides rapid and reliable prenatal diagnosis at risk families of cystic fibrosis. PMID- 26002250 TI - Genomic imprinting: A missing piece of the Multiple Sclerosis puzzle? AB - Evidence for parent-of-origin effects in complex diseases such as Multiple Sclerosis (MS) strongly suggests a role for epigenetic mechanisms in their pathogenesis. In this review, we describe the importance of accounting for parent of-origin when identifying new risk variants for complex diseases and discuss how genomic imprinting, one of the best-characterized epigenetic mechanisms causing parent-of-origin effects, may impact etiology of complex diseases. While the role of imprinted genes in growth and development is well established, the contribution and molecular mechanisms underlying the impact of genomic imprinting in immune functions and inflammatory diseases are still largely unknown. Here we discuss emerging roles of imprinted genes in the regulation of inflammatory responses with a particular focus on the Dlk1 cluster that has been implicated in etiology of experimental MS-like disease and Type 1 Diabetes. Moreover, we speculate on the potential wider impact of imprinting via the action of imprinted microRNAs, which are abundantly present in the Dlk1 locus and predicted to fine tune important immune functions. Finally, we reflect on how unrelated imprinted genes or imprinted genes together with non-imprinted genes can interact in so called imprinted gene networks (IGN) and suggest that IGNs could partly explain observed parent-of-origin effects in complex diseases. Unveiling the mechanisms of parent-of-origin effects is therefore likely to teach us not only about the etiology of complex diseases but also about the unknown roles of this fascinating phenomenon underlying uneven genetic contribution from our parents. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 26002251 TI - microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis. AB - BACKGROUND: Reports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC. METHODS: Eligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations. RESULTS: Twenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96-3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91-3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78-5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR 34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study. CONCLUSIONS: This is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use. PMID- 26002252 TI - Vacuum cleaner effect, purging effect, active and passive wash out: a new terminology in hydrodynamic stone retrival is arising--Does it affect our endourologic routine? PMID- 26002253 TI - New light on ion channel imaging by total internal reflection fluorescence (TIRF) microscopy. AB - Ion channels play pivotal roles in a wide variety of cellular functions; therefore, their physiological characteristics, pharmacological responses, and molecular structures have been extensively investigated. However, the mobility of an ion channel itself in the cell membrane has not been examined in as much detail. A total internal reflection fluorescence (TIRF) microscope allows fluorophores to be imaged in a restricted region within an evanescent field of less than 200 nm from the interface of the coverslip and plasma membrane in living cells. Thus the TIRF microscope is useful for selectively visualizing the plasmalemmal surface and subplasmalemmal zone. In this review, we focused on a single-molecule analysis of the dynamic movement of ion channels in the plasma membrane using TIRF microscopy. We also described two single-molecule imaging techniques under TIRF microscopy: fluorescence resonance energy transfer (FRET) for the identification of molecules that interact with ion channels, and subunit counting for the determination of subunit stoichiometry in a functional channel. TIRF imaging can also be used to analyze spatiotemporal Ca(2+) events in the subplasmalemma. Single-molecule analyses of ion channels and localized Ca(2+) signals based on TIRF imaging provide beneficial pharmacological and physiological information concerning the functions of ion channels. PMID- 26002254 TI - Atherosclerosis: Recent trials, new targets and future directions. AB - Mortality from cardiovascular diseases (CVD) represents the primary cause of death worldwide. Prevention or treatment of atherosclerosis and its clinical sequelae is a central goal in the management of patients with established vascular disease or those at high-risk for vascular events. This paper provides a review of the contemporary pharmacological armamentarium targeting atherosclerosis and also highlights strategies to support future clinical trial design. Powering future trials targeting LDL-cholesterol to its absolute reduction and including patients with a higher LDL-C despite optimal medical therapy (or unable to tolerate statins) will increase the odds of meaningful results. Mendelian randomization studies may identify new causal risk factors for CVD that would help in the selection of the patients most likely to benefit from a specific new compound. Furthermore, imaging techniques integrating a morphological and functional assessment such as IVUS, OCT, PET/CT and PET/MRI may represent in a near future robust "soft" endpoints to support successful translation of early research into meaningful phase III clinical outcome trials. PMID- 26002255 TI - Root growth dynamics linked to above-ground growth in walnut (Juglans regia). AB - BACKGROUND AND AIMS: Examination of plant growth below ground is relatively scant compared with that above ground, and is needed to understand whole-plant responses to the environment. This study examines whether the seasonal timing of fine root growth and the spatial distribution of this growth through the soil profile varies in response to canopy manipulation and soil temperature. METHODS: Plasticity in the seasonal timing and vertical distribution of root production in response to canopy and soil water manipulation was analysed in field-grown walnut (Juglans regia 'Chandler') using minirhizotron techniques. KEY RESULTS: Root production in walnuts followed a unimodal curve, with one marked flush of root growth starting in mid-May, with a peak in mid-June. Root production declined later in the season, corresponding to increased soil temperature, as well as to the period of major carbohydrate allocation to reproduction. Canopy and soil moisture manipulation did not influence the timing of root production, but did influence the vertical distribution of roots through the soil profile. Water deficit appeared to promote root production in deeper soil layers for mining soil water. Canopy removal appeared to promote shallow root production. CONCLUSIONS: The findings of this study add to growing evidence that root growth in many ecosystems follows a unimodal curve with one marked flush of root growth in coordination with the initial leaf flush of the season. Root vertical distribution appeared to have greater plasticity than timing of root production in this system, with temperature and/or carbohydrate competition constraining the timing of root growth. Effects on root distribution can have serious impacts on trees, with shallow rooting having negative impacts in years with limited soil water or positive impacts in years with wet springs, and deep rooting having positive impacts on soil water mining from deeper soil layers but negative impacts in years with wet springs. PMID- 26002256 TI - A lysigenic programmed cell death-dependent process shapes schizogenously formed aerenchyma in the stems of the waterweed Egeria densa. AB - BACKGROUND AND AIMS: Plant adaptation to submergence can include the formation of prominent aerenchyma to facilitate gas exchange. The aim of this study was to characterize the differentiation of the constitutive aerenchyma in the stem of the aquatic macrophyte Egeria densa (Hydrocharitaceae) and to verify if any form of cell death might be involved. METHODS: Plants were collected from a pool in a botanical garden. Aerenchyma differentiation and apoptotic hallmarks were investigated by light microscopy and terminal deoxynucleotidyl transferase mediated dUTP nick-end labelling (TUNEL) assay coupled with genomic DNA extraction and gel electrophoresis (DNA laddering assay). Cell viability and the occurrence of peroxides and nitric oxide (NO) were determined histochemically using specific fluorogenic probes. KEY RESULTS: Aerenchyma differentiation started from a hexagonally packed pre-aerenchymatic tissue and, following a basipetal and centripetal developmental pattern, produced a honeycomb arrangement. After an early schizogenous differentiation process, a late lysigenous programmed cell death- (PCD) dependent mechanism occurred. This was characterized by a number of typical apoptotic hallmarks, including DNA fragmentation, chromatin condensation, apoptotic-like bodies, partial cell wall lysis and plasmolysis. In addition, local increases in H2O2 and NO were observed and quantified. CONCLUSIONS: The differentiation of cortical aerenchyma in the stem of E. densa is a complex process, consisting of a combination of an early schizogenous differentiation mechanism and a late lysigenous PCD-dependent process. The PCD remodels the architecture of the gas spaces previously formed schizogenously, and also results in a reduction of O2-consuming cells and in recycling of material derived from the lysigenic dismantling of the cells. PMID- 26002258 TI - All plasma products are not created equal: Characterizing differences between plasma products. AB - BACKGROUND: Plasma can be manufactured by multiple methods. Few studies have compared quality parameters between plasma products that may affect efficacy and safety. METHODS: Four different plasma products were analyzed to include fresh frozen plasma (FFP), liquid plasma (LP), solvent detergent plasma (SDP), and a spray-dried, solvent detergent-treated plasma (SD-SDP) at multiple time points of storage. Parameters measured included red blood cell, platelet, and white blood cell counts; microparticle phenotypes; thrombin generation; and thrombelastography. These parameters were compared in 10 samples of each product. RESULTS: SDP and SD-SDP contained the smallest number of residual cells compared with FFP and LP. Platelets were the most common residual cell in all products and were highest in LP. FFP contained the greatest number of residual red blood cells. Total microparticle counts were elevated in LP and FFP compared with SDP and SD-SDP. Cell-derived microparticles in both LP and FFP were mostly platelet in origin. Microparticle counts in SDP and SD-SDP were negligible. Thrombelastography results demonstrated similar thrombin, fibrinogen, and platelet function on Day 28 LP compared with Day 5 thawed FFP. Thrombin generation assays revealed that the total, lag time to, and peak thrombin formation were higher in SDP and SD-SDP compared with FFP and LP. All parameters in FFP and LP products were characterized by a large degree of variability. CONCLUSION: The differences in cellular, microparticle, and functional hemostatic parameters measured between plasma products have the potential to affect efficacy and safety. Further study is needed to elucidate the potential immune effects of the cellular and microparticle differences noted as well as the clinical implications of altered thrombin generation kinetics in SD products. PMID- 26002259 TI - Blood far forward: Time to get moving! AB - In planning for future contingencies, current problems often crowd out historical perspective and planners often turn to technological solutions to bridge gaps between desired outcomes and the reality of recent experience. The US Military, North Atlantic Treaty Organization, and other allies are collectively taking stock of 10-plus years of medical discovery and rediscovery of combat casualty care after the wars in Iraq and Afghanistan. There has been undeniable progress in the treatment of combat wounded during the course of the conflicts in Southwest Asia, but continued efforts are required to improve hemorrhage control and provide effective prehospital resuscitation that treats both coagulopathy and shock. This article presents an appraisal of the recent evolution in medical practice in historical context and suggests how further gains in far forward resuscitation might be achieved using existing technology and methods based on whole-blood transfusion while research on new approaches continues. PMID- 26002260 TI - Freeze dried plasma and fresh red blood cells for civilian prehospital hemorrhagic shock resuscitation. AB - BACKGROUND: The last decade of military trauma care has emphasized the role of blood products in the resuscitation of hemorrhaging patients. Damage-control resuscitation advocates decreased crystalloid use and reintroduces blood components as primary resuscitative fluids. The systematic use of blood products have been described in military settings, but reports describing the use of freeze dried plasma (FDP) or red blood cells (RBCs) in civilian prehospital care are few. We describe our preliminary results after implementing RBCs and FDP into our Helicopter Emergency Medical Service (HEMS). METHODS: We collected data on the use of FDP (LyoPlas N-w (AB)) during a 12-month period from May 31, 2013, to May 30, 2014, before RBC (0Rh (D) negative) introduction in June 2014. FDP and RBCs were indicated in trauma and medical patients presenting with clinical significant hemorrhage on scene. Data were obtained from HEMS registry and patient records. RESULTS: Our preliminary results show that FDP was used in 16 patients (88% males) during the first year. Main patient categories were blunt trauma (n = 5), penetrating trauma (n = 4), and nontrauma (n = 7). Ten patients (62%) were hypotensive with systolic blood pressures less than 90 mm Hg on scene. The majority (75%) received tranexamic acid. Of 14 patients admitted to the hospital, 11 received emergency surgery and 8 needed additional transfusions within the first 24 hours. No transfusion-related complications were recorded. Two of the FDP patients died on scene, and the remaining 14 patients were alive after 30 days. Early results from the recent introduction of RBC show that RBCs were given to four patients. Two patients (one penetrating trauma and one blunt trauma patient) died on scene because of exsanguination, while additional two patients (one blunt trauma patient and one with ruptured aortic aneurism) survived to hospital discharge. CONCLUSION: Our small study indicates that introduction of FDP into civilian HEMS seems feasible and may be safe and that logistical and safety issues for the implementation of RBCs are solvable. FDP ensures both coagulation factors and volume replacement, has a potentially favorable safety profile, and may be superior to other types of plasma for prehospital use. Further prospective studies are needed to clarify the role of FDP (and RBCs) in civilian prehospital hemorrhagic shock resuscitation and to aid the development of standardized protocols for prehospital use of blood products. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 26002261 TI - Coagulation function of stored whole blood is preserved for 14 days in austere conditions: A ROTEM feasibility study during a Norwegian antipiracy mission and comparison to equal ratio reconstituted blood. AB - BACKGROUND: Formulation of a medical preparedness plan for treating severely bleeding casualties during naval deployment is a significant challenge because of territory covered during most missions. The aim of this study was to evaluate the concept of "walking blood bank" as a supportable plan for supplying safe blood and blood products. METHODS: In 2013, the Royal Norwegian Navy conducted antipiracy operations from a frigate, beginning in the Gulf of Aden and ending in the Indian Ocean. Crews were on 24-hour emergency alert in preparation for an enemy assault on the frigate. Under an approved command protocol, a "walking blood bank," using crew blood donations, was established for use on board and on missions conducted in rigid-hulled inflatable boats, during which freeze-dried plasma and leukoreduced, group O low anti-A/anti-B titer, cold-stored whole blood were stored in Golden Hour Boxes. Data demonstrating the ability to collect, store, and provide whole blood were collected to establish feasibility of implementing a whole blood-focused remote damage-control resuscitation program aboard a naval vessel. In addition, ROTEM data were collected to demonstrate feasibility of performing this analysis on a large naval vessel and to also measure hemostatic efficacy of cold-stored leukoreduced whole blood (CWB) stored during a period of 14 days. ROTEM data on CWB was compared with reconstituted whole blood. RESULTS: Drills simulating massive transfusion activation were conducted, in which 2 U of warm fresh whole blood with platelet sparing leukoreduction were produced in 40 minutes, followed by collection of two additional units at 15-minute increments. The ROTEM machine performed well during ship-rolling, as shown by the overlapping calculated and measured mechanical piston movements measured by the ROTEM device. Error messages were recorded in 4 (1.5%) of 267 tests. CWB yielded reproducible ROTEM results demonstrating preserved fibrinogen function and platelet function for at least 3.5 weeks and 2 weeks, respectively. The frequency of ROTEM tests were as follows: EXTEM (n = 88), INTEM (n = 85), FIBTEM (n = 82), and APTEM (n = 12). CWB results were grouped. Compared with Days 0 to 2, EXTEM maximum clot firmness was significantly reduced, beginning on Days 10 to 14; however, results through that date remained within reference ranges and were comparable with the EXTEM maximum clot firmness for the reconstituted whole blood samples containing Day 5 room temperature stored platelets. CONCLUSION: A "walking blood bank" can provide a balanced transfusion product to support damage-control resuscitation/remote damage-control resuscitation aboard a frigate in the absence of conventional blood bank products. ROTEM analysis is feasible to monitor damage-control resuscitation and blood product quality. ROTEM analysis was possible in challenging operational conditions. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 26002263 TI - Massive transfusion policies at trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program. AB - BACKGROUND: Massive transfusion protocols (MTPs) have been developed to implement damage control resuscitation (DCR) principles. A survey of MTP policies from American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) participants was performed to establish which MTP activation, hemostatic resuscitation, and monitoring aspects of DCR are included in the MTP guidelines. METHODS: On October 10, 2013, ACS-TQIP administration administered a cross sectional electronic survey to 187 ACS-TQIP participants. RESULTS: Seventy-one percent (132 of 187) of responses were analyzed, with 62% designated as Level I and 38% designated as Level II ACS-TQIP trauma centers. Sixty-nine percent of sites indicated that they have plasma immediately available for MTP activation. By policy, in the first group of blood products administered, 88% of sites target high (>=1:2) plasma-to-red blood cell (RBC) ratios and 10% target low ratios. Likewise, 79% of sites target high platelet-to-RBC ratios and 16% target low ratios. Eighteen percent of sites reported incorporating point-of-care thromboelastogram into MTP policies. The most common intravenous hemostatic adjunct incorporated into MTPs was tranexamic acid (49%). Thirty-four percent of sites reported that some or all of their emergency medical service agencies have the ability to administer blood products or hemostatic agents during prehospital transport. There were minimal differences in MTP policies or capabilities between Level I and II sites. CONCLUSION: The majority of ACS-TQIP participants reported having MTPs that support the use of DCR principles including high plasma-to-RBC and platelet-to-RBC ratios. Immediate availability of plasma and product use by emergency medical services are becoming increasingly common, whereas the incorporation of point-of-care thromboelastogram into MTP policies remains low. PMID- 26002262 TI - Acute blood loss during burn and soft tissue excisions: An observational study of blood product resuscitation practices and focused review. AB - BACKGROUND: Many military and civilian centers have shifted to a damage-control resuscitation approach, focused on providing oxygen-carrying capacity while simultaneously mitigating coagulopathy with a balanced ratio of platelets and plasma to red blood cells. It is unclear to what degree this strategy is used during burn or soft tissue excision. Here, we characterized blood product transfusion during burn and soft tissue surgery and reviewed the published literature regarding intraoperative coagulation changes. We hypothesized that blood product resuscitation during burn and soft tissue excision is not hemostatic and would be insufficient to address hemorrhage-induced coagulopathy. METHODS: Consented adult patients were enrolled into an institutional review board-approved prospective observational study. Number, component type, volume, and age of the blood products transfused were recorded during burn excision/grafting or soft tissue debridement. Component bags (packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate) were collected, and the remaining sample was harvested from the bag and tubing. Aliquots of 1/1,000th the original volume of each blood product were obtained and combined, producing an amalgam sample containing the same ratio of product transfused. Platelet count, rotational thromboelastometry, and impedance aggregometry were measured. Significance was set at p < 0.05. RESULTS: Amalgamated transfusate samples produced abnormally weak clots (p <= 0.001) particularly if they did not contain platelets. Clot strength (48.8 [2.6] mm; reference range, 49-71 mm) for platelet containing amalgams was below the lower limit of the reference range despite platelet-red blood cell ratios greater than 1:1. Platelet aggregation was abnormally low; transfused platelets were functionally inferior to native platelets. CONCLUSION: Our study and focused review demonstrate that further work is needed to fully understand the needs of patients undergoing tissue excision. The three studies reviewed and the results of our observational work suggest that coagulopathy and thrombocytopenia may contribute to intraoperative hemorrhage. Blood product resuscitation during burn and soft tissue excision is not hemostatic. LEVEL OF EVIDENCE: Epidemiologic study, level V. PMID- 26002264 TI - Update of use of hydroxyethyl starches in surgery and trauma. PMID- 26002265 TI - Prehospital point-of-care monitoring and goal-directed therapy: Does it make a difference? PMID- 26002266 TI - Postinjury fibrinolysis shutdown: Rationale for selective tranexamic acid. PMID- 26002267 TI - Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascular permeability and inflammation in hemorrhagic shock. AB - BACKGROUND: In retrospective and prospective observational studies, fresh frozen plasma (FFP) has been associated with a survival benefit in massively transfused trauma patients. A dry plasma product, such as spray-dried plasma (SDP), offers logistical advantages over FFP. Recent studies on FFP have demonstrated that FFP modulates systemic vascular stability and inflammation. The effect of SDP on these measures has not been previously examined. This study compares SDP with FFP using in vitro assays of endothelial function and in vivo assays of lung injury using a mouse model of hemorrhagic shock (HS) and trauma. METHODS: FFP, SDP, and lactated Ringer's (LR) solution were compared in vitro using assays of endothelial cell (EC) permeability, cytokine production and content, gene expression, as well as tight and adherens junction stability. All resuscitation products were also compared in a murine model of HS. Mean arterial pressures and physiologic measures were assessed. Pulmonary vascular permeability was measured using tagged dextran. Lung tissues were stained for CD68, VE-cadherin, and occludin. RESULTS: Treatment of ECs with FFP and SDP, but not LR, preserved the integrity of EC monolayers in vitro and resulted in similar EC gene expression patterns and cytokine/growth factor production. FFP and SDP also reduced HS induced pulmonary vascular permeability in vivo to the same extent. In mice with HS, mean arterial pressures and base excess were corrected by both FFP and SDP to levels observed in sham-treated mice. Treatment after HS with FFP and SDP but not LR solution reduce alveolar wall thickening, leukocyte infiltration, and the breakdown of EC junctions, as measured by staining for VE-cadherin, and occludin. CONCLUSION: Both FFP and SDP similarly modulate pulmonary vascular integrity, permeability, and inflammation in vitro and in vivo in a murine model of HS and trauma. PMID- 26002268 TI - Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: A critical appraisal of the medical literature and available alternatives. AB - BACKGROUND: Hemorrhage remains the leading cause of preventable trauma-associated mortality. Interventions that improve prehospital hemorrhage control and resuscitation are needed. Tranexamic acid (TXA) has recently been shown to reduce mortality in trauma patients when administered upon hospital admission, and available data suggest that early dosing confers maximum benefit. Data regarding TXA implementation in prehospital trauma care and analyses of alternatives are lacking. This review examines the available evidence that would inform selection of hemostatic interventions to improve outcomes in prehospital trauma management as part of a broader strategy of "remote damage-control resuscitation" (RDCR). METHODS: The medical literature available concerning both the safety and the efficacy of TXA and other hemostatic agents was reviewed. RESULTS: TXA use in surgery was studied in 129 randomized controlled trials, and a meta-analysis was identified. More than 800,000 patients were followed up in large cohort study. In trauma, a large randomized controlled trial, the CRASH-2 study, recruited more than 20,000 patients, and two cohort studies studied more than 1,000 war casualties. In the prehospital setting, the US, French, British, and Israeli militaries as well as the British, Norwegian, and Israeli civilian ambulance services have implemented TXA use as part of RDCR policies. CONCLUSION: Available data support the efficacy and the safety of TXA. High-level evidence supports its use in trauma and strongly suggests that its implementation in the prehospital setting offers a survival advantage to many patients, particularly when evacuation to surgical care may be delayed. TXA plays a central role in the development of RDCR strategies. PMID- 26002269 TI - Injectable hemostatic adjuncts in trauma: Fibrinogen and the FIinTIC study. PMID- 26002270 TI - Syndecan-1 restitution by plasma after hemorrhagic shock. PMID- 26002271 TI - Do working environment interventions reach shift workers? AB - PURPOSE: Shift workers are exposed to more physical and psychosocial stressors in the working environment as compared to day workers. Despite the need for targeted prevention, it is likely that workplace interventions less frequently reach shift workers. The aim was therefore to investigate whether the reach of workplace interventions varied between shift workers and day workers and whether such differences could be explained by the quality of leadership exhibited at different times of the day. METHODS: We used questionnaire data from 5361 female care workers in the Danish eldercare sector. The questions concerned usual working hours, quality of leadership, and self-reported implementation of workplace activities aimed at stress reduction, reorganization of the working hours, and participation in improvements of working procedures or qualifications. RESULTS: Compared with day workers, shift workers were less likely to be reached by workplace interventions. For example, night workers less frequently reported that they had got more flexibility (OR 0.5; 95 % CI 0.3-0.7) or that they had participated in improvements of the working procedures (OR 0.6; 95 % CI 0.5-0.8). Quality of leadership to some extent explained the lack of reach of interventions especially among fixed evening workers. CONCLUSIONS: In the light of the evidence of shift workers' stressful working conditions, we suggest that future studies focus on the generalizability of results of the present study and on how to reach this group and meet their needs when designing and implementing workplace interventions. PMID- 26002273 TI - Imaging Techniques in Acute Heart Failure. AB - In recent years, imaging techniques have revolutionized the diagnosis of heart failure. In patients with a clinical picture of acute decompensation, prognosis is largely determined by early implementation of general measures and treatment of the underlying cause. Given its diagnostic yield and portability, ultrasound has become an essential tool in the setting of acute heart failure, and is currently found in all medical departments involved in the care of the critically ill patient. Cardiac magnetic resonance and computed tomography allow detailed characterization of multiple aspects of cardiac structure and function that were previously unavailable. This helps guide and monitor many of the treatment decisions in the acute heart failure population in an entirely noninvasive way. This article aims to review the usefulness of the imaging techniques that are clinically relevant in the context of an episode of acute heart failure. We discuss the indications and limitations of these techniques in detail and describe the general principles for the appropriate interpretation of results. PMID- 26002272 TI - The start and development of epilepsy surgery in Europe: a historical review. AB - Epilepsy has not always been considered a brain disease, but was believed to be a demonic possession in the past. Therefore, trepanation was done not only for medical but also for religious or spiritual reasons, originating in the Neolithic period (3000 BC). The earliest documentation of trepanation for epilepsy is found in the writings of the Hippocratic Corpus and consisted mainly of just skull surgery. The transition from skull surgery to brain surgery took place in the middle of the nineteenth century when the insight of epilepsy as a cortical disorder of the brain emerged. This led to the start of modern epilepsy surgery. The pioneer countries in which epilepsy surgery was performed in Europe were the UK, Germany, and The Netherlands. Neurosurgical forerunners like Sir Victor Horsley, William Macewen, Fedor Krause, and Otfrid Foerster started with "modern" epilepsy surgery. Initially, epilepsy surgery was mainly done with the purpose to resect traumatic lesions or large surface tumours. In the course of the twentieth century, this changed to highly specialized microscopic navigation-guided surgery to resect lesional and non-lesional epileptogenic cortex. The development of epilepsy surgery in Southern Europe, which has not been described until now, will be elaborated in this manuscript. To summarize, in this paper, we provide (1) a detailed description of the evolution of European epilepsy surgery with special emphasis on the pioneer countries; (2) novel, never published information about the development of epilepsy surgery in Southern Europe; and (3) we review the historical dichotomy of invasive electrode implantation strategy (Anglo-Saxon surface electrodes versus French-Italian stereoencephalography (SEEG) model). PMID- 26002274 TI - Fully automated production of sodium [(18)F]fluoride on AllInOne and miniAllInOne synthesizers. AB - A fully automated production of the imaging agent sodium [(18)F]fluoride ([(18)F]NaF) on two different modules commercialized by Trasis(r), the AllInOne and the miniAllInOne, is reported. Both modules allow to prepare [(18)F]NaF in good radiochemical yield (around 97%) in less than 4min with the same specifications. Quality control of [(18)F]NaF produced by this way was performed according to the US and European Pharmacopeia monograph requirements. PMID- 26002275 TI - A step towards accreditation: A robustness test of etching process. AB - In the present study the robustness of the etching process used by our laboratory was assessed. The strategy followed was based on the procedure suggested by Youden. Critical factors for the process were estimated using both Lenth's method and Dong's algorithm. The robustness test evidences that particular attention needs to be paid to the control of the etching solution's temperature. PMID- 26002276 TI - (131)I-Nimotuzumab - A potential radioimmunotherapeutic agent in treatment of tumors expressing EGFR. AB - The anti-EGFR antibody Nimotuzumab was radioiodinated with I-131 by Chloramine T and Iodogen methods. The (131)I-Nimotuzumab was purified and characterized by HPLC. Purified (131)I-Nimotuzumab exhibited radiochemical purity of >95% and retained good in vitro stability upto 24h at room temperature by both the methods. Cell binding studies carried out in A431 cells expressing EGF receptors showed good immunoreactivity of the product upto 5 days post radioiodination. Biodistribution studies in normal Swiss mice showed fast clearance by both renal and gastrointestinal routes with minimal thyroid uptake. PMID- 26002277 TI - Use of Questionnaire-Based Measures in the Assessment of Listening Difficulties in School-Aged Children. AB - OBJECTIVES: In this study, the authors assessed the potential utility of a recently developed questionnaire (Evaluation of Children's Listening and Processing Skills [ECLiPS]) for supporting the clinical assessment of children referred for auditory processing disorder (APD). DESIGN: A total of 49 children (35 referred for APD assessment and 14 from mainstream schools) were assessed for auditory processing (AP) abilities, cognitive abilities, and symptoms of listening difficulty. Four questionnaires were used to capture the symptoms of listening difficulty from the perspective of parents (ECLiPS and Fisher's auditory problem checklist), teachers (Teacher's Evaluation of Auditory Performance), and children, that is, self-report (Listening Inventory for Education). Correlation analyses tested for convergence between the questionnaires and both cognitive and AP measures. Discriminant analyses were performed to determine the best combination of tests for discriminating between typically developing children and children referred for APD. RESULTS: All questionnaires were sensitive to the presence of difficulty, that is, children referred for assessment had significantly more symptoms of listening difficulty than typically developing children. There was, however, no evidence of more listening difficulty in children meeting the diagnostic criteria for APD. Some AP tests were significantly correlated with ECLiPS factors measuring related abilities providing evidence for construct validity. All questionnaires correlated to a greater or lesser extent with the cognitive measures in the study. Discriminant analysis suggested that the best discrimination between groups was achieved using a combination of ECLiPS factors, together with nonverbal Intelligence Quotient (cognitive) and AP measures (i.e., dichotic digits test and frequency pattern test). CONCLUSIONS: The ECLiPS was particularly sensitive to cognitive difficulties, an important aspect of many children referred for APD, as well as correlating with some AP measures. It can potentially support the preliminary assessment of children referred for APD. PMID- 26002278 TI - The use of a wearable camera to capture and categorise the environmental and social context of self-identified eating episodes. AB - Research investigating the influence of the environmental and social factors on eating behaviours in free-living settings is limited. This study investigates the utility of using wearable camera images to assess the context of eating episodes. Adult participants (N = 40) wore a SenseCam wearable camera for 4 days (including 1 familiarisation day) over a 15-day period in free-living conditions, and had their diet assessed using three image-assisted multiple-pass 24-hour dietary recalls. The images of participants' eating episodes were analysed and annotated according to their environmental and social contexts; including eating location, external environment (indoor/outdoor), physical position, social interaction, and viewing media screens. Data for 107 days were used, with a total of 742 eating episodes considered for annotation. Twenty nine per cent (214/742) of the episodes could not be categorised due to absent images (12%, n = 85), dark/blurry images (8%, n = 58), camera not worn (7%, n = 54) and for mixed reasons (2%, n = 17). Most eating episodes were at home (59%) and indoors (91%). Meals at food retailers were 24.8 minutes longer (95% CI: 13.4 to 36.2) and were higher in energy (mean difference = 1196 kJ 95% CI: 242, 2149) than at home. Most episodes were seated at tables (27%) or sofas (26%), but eating standing (19%) or at desks (18%) were common. Social interaction was evident for 45% of episodes and media screens were viewed during 55% of episodes. Meals at home watching television were 3.1 minutes longer (95% CI: -0.6 to 6.7) and higher in energy intake than when no screen was viewed (543 kJ 95% CI: -32 to 1120). The environmental and social context that surrounds eating and dietary behaviours can be assessed using wearable camera images. PMID- 26002279 TI - Worlds apart. Consumer acceptance of functional foods and beverages in Germany and China. AB - This study examined consumers' willingness to buy functional foods. Data were collected from an Internet survey in Germany (n = 502) and China (n = 443). The results showed that consumers in China were much more willing to buy functional foods, compared with their German counterparts. A substantial segment of the German consumers indicated lower willingness to buy functional foods, compared with the same foods without additional health benefits. The findings further showed that in both countries, the participants with higher health motivation and more trust in the food industry reported higher willingness to buy functional foods than the participants with lower health motivation and less trust in the industry. Food neophobia had a negative impact on acceptance of functional foods in the Chinese sample. No such association was observed for the German sample. The results suggest that cultural factors play a significant role in the acceptance of functional foods; therefore, caution should be exercised in generalizing research findings from Western countries to others. PMID- 26002281 TI - Vagal modulation of dispersion of repolarisation in the rabbit heart. AB - Bradycardia is a risk factor for arrhythmia in several disorders, including acquired long QT syndrome, whereby slowing of heart rate facilitates ectopic activity and torsade de pointes. Slowing of rate is associated with an increase in the spatiotemporal dispersion of ventricular repolarisation (DOR) in electrically paced hearts. However, there have been conflicting reports on the effect of the vagus nerve, which mediates the physiological slowing of heart rate, on DOR. The aim of this study was to investigate the effect of vagus nerve stimulation (VNS) on the heterogeneity of ventricular repolarisation, as assessed using the T-wave peak-to-end interval (TpTe) and monophasic action potentials (MAPs), in normal hearts and in hearts with acquired long QT syndrome. Experiments were conducted in an isolated innervated rabbit heart preparation. The effect of VNS on cardiac electrograms, MAPs and ventricular function was investigated in control and following perfusion of E4031 (50nmol/L); an inhibitor of the rapid delayed rectifying potassium current. VNS was associated with a stimulation frequency-dependent bradycardia (-74+/-6 [10Hz] vs. -25+/-4bpm [2Hz], P<0.05). VNS prolonged the TpTe interval (29+/-1 vs. 20+/-2ms, P<0.05) and increased T-wave amplitude (1.7+/-0.3 vs. 0.7+/-0.2mV, P<0.05) in association with increased apicobasal DOR. The effects of VNS were exacerbated by E4031, with a greater prolongation of TpTe (DeltaTpTe 42+/-6 vs. 8+/-1ms, P<0.05) and max-min apicobasal time of repolarisation (TRepol; 45+/-11 vs. 5+/-2ms, P<0.05). DeltaTpTe was strongly correlated with the Deltamax-minTRepol (r(2)=0.87, P<0.05) and TpTe was prolonged to a greater degree in hearts exhibiting spontaneous ventricular tachyarrhythmia. Rate dependent differences in regional action potential prolongation were replicated using computational models. These data demonstrate that VNS increases ventricular DOR and that the effects of the vagus nerve on ventricular electrophysiology are exacerbated in pharmacologically acquired long QT syndrome. PMID- 26002280 TI - Western-style diet impairs stimulus control by food deprivation state cues: Implications for obesogenic environments. AB - In western and westernized societies, large portions of the population live in what are considered to be "obesogenic" environments. Among other things, obesogenic environments are characterized by a high prevalence of external cues that are associated with highly palatable, energy-dense foods. One prominent hypothesis suggests that these external cues become such powerful conditioned elicitors of appetitive and eating behavior that they overwhelm the internal, physiological mechanisms that serve to maintain energy balance. The present research investigated a learning mechanism that may underlie this loss of internal relative to external control. In Experiment 1, rats were provided with both auditory cues (external stimuli) and varying levels of food deprivation (internal stimuli) that they could use to solve a simple discrimination task. Despite having access to clearly discriminable external cues, we found that the deprivation cues gained substantial discriminative control over conditioned responding. Experiment 2 found that, compared to standard chow, maintenance on a "western-style" diet high in saturated fat and sugar weakened discriminative control by food deprivation cues, but did not impair learning when external cues were also trained as relevant discriminative signals for sucrose. Thus, eating a western-style diet contributed to a loss of internal control over appetitive behavior relative to external cues. We discuss how this relative loss of control by food deprivation signals may result from interference with hippocampal dependent learning and memory processes, forming the basis of a vicious-cycle of excessive intake, body weight gain, and progressive cognitive decline that may begin very early in life. PMID- 26002282 TI - Macrophages and galectin 3 play critical roles in CVB3-induced murine acute myocarditis and chronic fibrosis. AB - Macrophage influx and galectin 3 production have been suggested as major players driving acute inflammation and chronic fibrosis in many diseases. However, their involvement in the pathogenesis of viral myocarditis and subsequent cardiomyopathy are unknown. Our aim was to characterise the role of macrophages and galectin 3 on survival, clinical course, viral burden, acute pathology, and chronic fibrosis in coxsackievirus B3 (CVB3)-induced myocarditis. Our results showed that C3H/HeJ mice infected with CVB3 and depleted of macrophages by liposome-encapsulated clodronate treatment compared with infected untreated mice presented higher viral titres but reduced acute myocarditis and chronic fibrosis, compared with untreated infected mice. Increased galectin 3 transcriptional and translational expression levels correlated with CVB3 infection in macrophages and in non-depleted mice. Disruption of the galectin 3 gene did not affect viral titres but reduced acute myocarditis and chronic fibrosis compared with C57BL/6J wild-type mice. Similar results were observed after pharmacological inhibition of galectin 3 with N-acetyl-d-lactosamine in C3H/HeJ mice. Our results showed a critical role of macrophages and their galectin 3 in controlling acute viral induced cardiac injury and the subsequent fibrosis. Moreover, the fact that pharmacological inhibition of galectin 3 induced similar results to macrophage depletion regarding the degree of acute cardiac inflammation and chronic fibrosis opens up the possibility of new pharmacological strategies for viral myocarditis. PMID- 26002283 TI - IDO expressing dendritic cells suppress allograft rejection of small bowel transplantation in mice by expansion of Foxp3+ regulatory T cells. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), the enzyme that catalyzes the first and rate-limiting step of tryptophan catabolism, suppresses T-cell responses by tryptophan depletion and accumulation of kynurenine metabolites. IDO prevents allograft rejection in various transplantations. METHODS: Dendritic cells (DC) highly expressing IDO (IDO(+) DC) were cultured through transduction of adenovirus vectors carrying the IDO sequence. IDO(+) DC were incubated with CD4(+) CD25(-) T cells to detect T cell proliferation. The effects of IDO(+) DC and 3-Hydroxyanthranilic acid (3-HAA) were verified in an allogeneic murine small bowel transplantation (SBT) model. Foxp3(+) Treg cells of recipient mice were detected by flow cytometry and cytokines in plasma were determined by ELISA. RESULTS: IDO(+) DC effectively suppressed proliferation of CD4(+) CD25(-) T cells in vitro, and this effect could be enhanced by adding 3-HAA. In the SBT transplantation model, both 3-HAA (P < 0.05) and IDO(+) DC (P < 0.01) prolonged the survival time of transplanted mice. Mice treated with IDO(+) DC achieved longer mean survival time than 3-HAA administrated mice (11.5d vs. 18.5d). Grafts from IDO(+) DC, 3-HAA and combination treatment group showed reduced inflammation and minimal architectural distortion. IFN-gamma production was significantly inhibited by IDO(+) DC and 3-HAA (P<0.05). The expression of IL-2 was slightly lower with 3-HAA or IDO(+) DC treatment. However, IL-10 was higher in 3-HAA, IDO(+) DC and combination treatment groups, while TGF-beta was elevated in all non-control groups. CONCLUSIONS: IDO(+) DC plus 3-HAA has an immunoprotective role and represents a potential strategy to suppress acute rejection and prolong survival of grafts in SBT. PMID- 26002284 TI - Differential expression of microRNAs in renal transplant patients with acute T cell mediated rejection. AB - BACKGROUND: MicroRNAs (miRNAs) regulate most of encoding genes and protein. In this study, we aimed to investigate the expression levels of miR-142-5p, miR-142 3p, miR-155 and miR-223 in paired biopsy and peripheral blood mononuclear cell (PBMC) samples of renal allograft recipients with acute T-cell mediated rejection (ATCMR), compared with normal allografts (NA). METHODS: In this study, the expression levels of individual miRNAs were determined in biopsy and PBMC samples of 17 recipients with ATCMR and 18 recipients with NA. RESULTS: Our results showed that the intragraft expression levels of all studied miRNAs were significantly higher in ATCMR than NA. However, regarding the PBMC samples, miR 142-3p and miR-223 were significantly increased in ATCMR than NA. Receiver operating characteristic (ROC) analysis showed that miR-142-5p, miR-142-3p, miR 155 and miR-223 in biopsy samples and miR-142-3p and miR-223 in PBMC samples could discriminate ATCMR from NA recipients. CONCLUSION: It has been reported that high intragraft expressions of miRNAs have a profound role in the pathogenesis of ATCMR process. Our results showed that high expression of all the studied miRNAs in biopsies and miR-142-3p and miR-223 in PBMC samples could be used as suggestive diagnostic tools to discriminate ATCMR patients from NA. PMID- 26002285 TI - Special Considerations in Medical Screening for Participants in Remote Endurance Events. AB - As participation at remote endurance events increases, so does the need to screen participants for potentially problematic medical conditions, but this process has been ill-defined to date. This article aims to outline a general approach to screening and discusses common or important medical conditions that may need consideration in the screening process. Medical conditions that are considered low risk may translate to high-risk conditions in the setting of a remote and austere location. Medical directors of remote endurance events should have a familiarity with assessing risks and applying informed consent principles to participation. While there are no specific standards on medical disqualification from an event based on medical history alone, several systematic considerations should be made that allow for an assessment of risk to an individual for a specific event. The medical director and event director, in discussion with the athlete and treating clinician when appropriate, should come to a consensus on participation when high-risk medical conditions become apparent during the screening process. Both modifications and accommodations to participation may be used to mitigate both clinical and medicolegal risk and allow for participation. PMID- 26002287 TI - Organochlorine pesticides and polychlorinated biphenyl congeners in wild terrestrial mammals from Croatia: Interspecies comparison of residue levels and compositions. AB - In this pilot study, we investigated levels of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in the adipose tissues of two free-ranging terrestrial carnivores from Croatia sampled in 2010 and 2011: the brown bear (Ursus arctos; N=32) and the grey wolf (Canis lupus; N=29). Concentrations of ?OCPs and SigmaPCBs ranged from 0.45 to 4.09 ng g(-1) lipid mass (lm) and from 0.93 to 8.52 ng g(-1) lm in brown bear, and from 1.18 to 5.67 ng g(-1) lm and 2.68 to 48.9 ng g(-1) lm in grey wolf adipose tissues, respectively. PCBs were dominant accounting for over 72% of total analyzed persistent organic pollutants (POPs). The sum of six indicator non-dioxin-like PCBs (Sigma6IndNDL PCBs) made up 60-93% and 58-85% of the total congener concentrations in brown bears and wolves, respectively. Although the levels of the measured parameters were significantly higher in grey wolves than in bears, the contaminant profiles of the two species were similar, with gamma-HCH, HCB, beta-HCH and DDE as major OCP contaminants, and PCB-153>PCB-180~PCB-170>PCB-138 as the dominant congeners. The sum of hexachlorocyclohexanes (SigmaHCHs) and 8 toxicologically relevant dioxin-like PCBs (Sigma8ToxDL PCBs) was higher in the males than in the females of the brown bear. Concentrations of SigmaDDTs, HCB, SigmaOCP, SigmaPCBs, Sigma6IndNDL PCBs, and toxicologically relevant non-dioxin-like PCBs (SigmaToxNDL PCBs) were significantly positively correlated with lipid content in the grey wolf. Concentrations of OCPs and PCBs in brown bears and wolves from Croatia were low and normal for large terrestrial mammals. PMID- 26002288 TI - miR-526a regulates apoptotic cell growth in human carcinoma cells. AB - MicroRNAs (miRNAs) play vital roles in the regulation of cell cycle, cell growth, apoptosis, and tumorigenesis. Our previous studies showed that miR-526a positively regulated innate immune response by suppressing CYLD expression, however, the functional relevance of miR-526a expression and cell growth remains to be evaluated. In this study, miR-526a overexpression was found to promote cancer cell proliferation, migration, and anchor-independent colony formation. The molecular mechanism(s) of miR-526a-mediated growth stimulation is associated with rapid cell cycle progression and inhibition of cell apoptosis by targeting CYLD. Taken together, these results provide evidence to show the stimulatory role of miR-526a in tumor migration and invasion through modulation of the canonical NF-kappaB signaling pathway. PMID- 26002289 TI - Practical benefits of knowing the enemy: modern molecular tools for diagnosing the etiology of bacterial diseases and understanding the taxonomy and diversity of plant-pathogenic bacteria. AB - Knowing the identity of bacterial plant pathogens is essential to strategic and sustainable disease management in agricultural systems. This knowledge is critical for growers, diagnosticians, extension agents, and others dealing with crops. However, such identifications are linked to bacterial taxonomy, a complicated and changing discipline that depends on methods and information that are often not used by those who are diagnosing field problems. Modern molecular tools for fingerprinting and sequencing allow for pathogen identification in the absence of distinguishing or conveniently tested phenotypic characteristics. These methods are also useful in studying the etiology and epidemiology of phytopathogenic bacteria from epidemics, as was done in numerous studies conducted in California's Salinas Valley. Multilocus and whole-genome sequence analyses are becoming the cornerstones of studies of microbial diversity and bacterial taxonomy. Whole-genome sequence analysis needs to become adequately accessible, automated, and affordable in order to be used routinely for identification and epidemiology. The power of molecular tools in accurately identifying bacterial pathogenesis is therefore of value to the farmer, diagnostician, phytobacteriologist, and taxonomist. PMID- 26002286 TI - Consensus Recommendations on Training and Competing in the Heat. AB - Exercising in the heat induces thermoregulatory and other physiological strain that can lead to impairments in endurance exercise capacity. The purpose of this consensus statement is to provide up-to-date recommendations to optimize performance during sporting activities undertaken in hot ambient conditions. The most important intervention one can adopt to reduce physiological strain and optimize performance is to heat acclimatize. Heat acclimatization should comprise repeated exercise-heat exposures over 1-2 weeks. In addition, athletes should initiate competition and training in an euhydrated state and minimize dehydration during exercise. Following the development of commercial cooling systems (e.g., cooling vests), athletes can implement cooling strategies to facilitate heat loss or increase heat storage capacity before training or competing in the heat. Moreover, event organizers should plan for large shaded areas, along with cooling and rehydration facilities, and schedule events in accordance with minimizing the health risks of athletes, especially in mass participation events and during the first hot days of the year. Following the recent examples of the 2008 Olympics and the 2014 FIFA World Cup, sport governing bodies should consider allowing additional (or longer) recovery periods between and during events for hydration and body cooling opportunities when competitions are held in the heat. PMID- 26002290 TI - Impact of diseases on export and smallholder production of banana. AB - Banana (Musa spp.) is one of the world's most valuable primary agricultural commodities. Exported fruit are key commodities in several producing countries yet make up less than 15% of the total annual output of 145 million metric tons (MMT). Transnational exporters market fruit of the Cavendish cultivars, which are usually produced in large plantations with fixed infrastructures and high inputs of fertilizers, pesticides, and irrigation. In contrast, smallholders grow diverse cultivars, often for domestic markets, with minimal inputs. Diseases are serious constraints for export as well as smallholder production. Although black leaf streak disease (BLSD), which is present throughout Asian, African, and American production areas, is a primary global concern, other diseases with limited distributions, notably tropical race 4 of Fusarium wilt, rival its impact. Here, we summarize recent developments on the most significant of these problems. PMID- 26002291 TI - Epidemiology and population biology of Pseudoperonospora cubensis: a model system for management of downy mildews. AB - The resurgence of cucurbit downy mildew has dramatically influenced production of cucurbits and disease management systems at multiple scales. Long-distance dispersal is a fundamental aspect of epidemic development that influences the timing and extent of outbreaks of cucurbit downy mildew. The dispersal potential of Pseudoperonospora cubensis appears to be limited primarily by sporangia production in source fields and availability of susceptible hosts and less by sporangia survival during transport. Uncertainty remains regarding the role of locally produced inoculum in disease outbreaks, but evidence suggests multiple sources of primary inoculum could be important. Understanding pathogen diversity and population differentiation is a critical aspect of disease management and an active research area. Underpinning advances in our understanding of pathogen biology and disease management has been the research capacity and coordination of stakeholders, scientists, and extension personnel. Concepts and approaches developed in this pathosystem can guide future efforts when responding to incursions of new or reemerging downy mildew pathogens. PMID- 26002292 TI - Soil health paradigms and implications for disease management. AB - Soil health has been defined as the capacity of soil to function as a vital living system to sustain biological productivity, maintain environmental quality, and promote plant, animal, and human health. Building and maintaining soil health are essential to agricultural sustainability and ecosystem function. Management practices that promote soil health, including the use of crop rotations, cover crops and green manures, organic amendments, and conservation tillage, also have generally positive effects on the management of soilborne diseases through a number of potential mechanisms, including increasing soil microbial biomass, activity, and diversity, resulting in greater biological suppression of pathogens and diseases. However, there also may be particular disease issues associated with some soil health management practices. In this review, research and progress made over the past twenty years regarding soil health, sustainability, and soil health management practices, with an emphasis on their implications for and effects on plant disease and disease management strategies, are summarized. PMID- 26002293 TI - Survival Disparity of African American Versus Non-African American Patients With ESRD Due to SLE. AB - BACKGROUND: A recent study showed an increased risk of death in African Americans compared with whites with end-stage renal disease (ESRD) due to lupus nephritis (LN). We assessed the impact of age stratification, socioeconomic factors, and kidney transplantation on the disparity in patient survival among African American versus non-African American patients with LN-caused ESRD, compared with other causes. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Using the US Renal Data System database, we identified 12,352 patients with LN caused ESRD among 1,132,202 patients who initiated maintenance dialysis therapy from January 1, 1995, through December 31, 2006, and were followed up until December 31, 2010. PREDICTORS: Baseline demographics and comorbid conditions, Hispanic ethnicity, socioeconomic factors (employment status, Medicare/Medicaid insurance, and area-level median household income based on zip code as obtained from the 2000 US census), and kidney transplantation as a time-dependent variable. OUTCOME: All-cause mortality. MEASUREMENTS: Multivariable Cox and competing-risk regressions. RESULTS: Mean duration of follow-up in the LN-caused ESRD and other-cause ESRD cohorts were 6.24+/-4.20 (SD) and 4.06+/-3.61 years, respectively. 6,106 patients with LN-caused ESRD (49.43%) and 853,762 patients with other-cause ESRD (76.24%) died during the study period (P<0.001). Patients with LN-caused ESRD were significantly younger (mean age, 39.92 years) and more likely women (81.65%) and African American (48.13%) than those with other-cause ESRD. In the fully adjusted multivariable Cox regression model, African American (vs non-African American) patients with LN-caused ESRD had significantly increased risk of death at age 18 to 30 years (adjusted HR, 1.43; 95% CI, 1.24 1.65) and at age 31 to 40 years (adjusted HR, 1.17; 95% CI, 1.02-1.34). Among patients with other-cause ESRD, African Americans were at significantly increased risk at age 18 to 30 years (adjusted HR, 1.17; 95% CI, 1.11-1.22). LIMITATIONS: We used zip code-based median household income as a surrogate for patient income. Residual socioeconomic confounders may exist. CONCLUSIONS: African Americans are at significantly increased risk of death compared with non-African Americans with LN-caused ESRD at age 18 to 40 years, a racial disparity risk that is 10 years longer than that in the general ESRD population. Accounting for area-level median household income and transplantation significantly attenuated the disparity in mortality of African American versus non-African American patients with LN-caused ESRD. PMID- 26002294 TI - Use of an uncensored primary outcome in a catheter design trial? PMID- 26002295 TI - Hemodialysis catheters: which design is more cost-effective? PMID- 26002296 TI - In reply to 'hemodialysis catheters: which design is more cost-effective?' and 'use of an uncensored primary outcome in a catheter design trial?'. PMID- 26002297 TI - Unicompartmental Knee Arthroplasty: Does a Selection Bias Exist? AB - Unicompartmental knee arthroplasty (UKA) is a minimally invasive option reported to allow a more rapid recovery and better patient outcomes. However, whether these outcomes are related to selection bias has not been fully investigated. This study examines whether a bias existed in selection of UKA candidates. We compared outcomes of patients who were scheduled for UKA but had the plan changed intraoperatively to total knee arthroplasty (TKA) to two randomly selected contemporaneous control groups: 1) patients planned as UKA who received UKA and 2) patients planned as TKA who received TKA. Our results not only showed a selection bias existed, but also showed patients converted to TKA intraoperatively had similar clinical results to patients receiving UKAs and better results than patients originally scheduled for TKA. PMID- 26002298 TI - Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis. AB - STUDY OBJECTIVE: We evaluate the incidence of complications associated with the use of nitrates in patients presenting with acute pulmonary edema and concomitant moderate or severe aortic stenosis compared with patients without aortic stenosis. Nitrates are contraindicated in severe aortic stenosis because of the theoretical yet unproven risk of precipitating profound hypotension. METHODS: A cohort design with retrospective chart review study was conducted at two Canadian hospitals. Patients with aortic stenosis (moderate or severe) and without aortic stenosis were included if they presented with acute cardiogenic pulmonary edema, received intravenous or sublingual nitroglycerin, and had an echocardiography report available. The primary outcome was clinically relevant hypotension, defined as hypotension leading to any of the following predefined events: nitroglycerin discontinuation, intravenous fluid bolus, vasopressor use, or cardiac arrest. The secondary outcome was sustained hypotension, defined as a systolic blood pressure less than 90 mm Hg and lasting greater than or equal to 30 minutes. RESULTS: The cohort consisted of 195 episodes of acute pulmonary edema, representing 65 episodes with severe aortic stenosis (N=65) and an equal number of matched episodes with moderate aortic stenosis (N=65) and no aortic stenosis (N=65). Nitroglycerin was administered intravenously only in 70% of cases, intravenously and sublingually in 25%, and sublingually only in the remaining 5%. After adjustment for sex, initial systolic blood pressure, furosemide dose, and use of noninvasive ventilation, moderate and severe aortic stenosis were not associated with clinically relevant hypotension after receipt of nitroglycerin (adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.40 to 2.37 for moderate aortic stenosis; adjusted OR 0.99, 95% CI 0.41 to 2.41 for severe aortic stenosis). The incidence of clinically relevant hypotension was 26.2% for moderate and severe aortic stenosis and 23.1% in the no aortic stenosis reference group. The secondary outcome of sustained hypotension occurred in 29.2% of patients with severe aortic stenosis, 16.9% with moderate aortic stenosis, and 13.8% in the no aortic stenosis group (adjusted OR for severe aortic stenosis 2.34; 95% CI 0.91 to 6.01). CONCLUSION: In this retrospective study, neither moderate nor severe aortic stenosis was associated with a greater risk of clinically relevant hypotension requiring intervention when nitroglycerin was used for acute pulmonary edema. Future studies should investigate safety and efficacy of nitroglycerin for patients with aortic stenosis because this study was limited by a small sample size and design limitations. Cautious use of nitroglycerin in patients with moderate or severe aortic stenosis and presenting with acute pulmonary edema may be a safer strategy than traditionally thought. PMID- 26002299 TI - Role of noroviruses as aetiological agents of diarrhoea in developing countries. AB - Diarrhoea is considered to be the second leading cause of death due to infections among children < 5 years of age worldwide that may be caused by bacteria, parasites, viruses and non-infectious agents. The major causative agents of diarrhoea in developing countries may vary from those in developed countries. Noroviruses are considered to be the most common cause of acute diarrhoea in both children and adults in industrialized countries. On the other hand, there is a lack of comprehensive epidemiological evidence from developing countries that norovirus is a major cause of diarrhoea. In these regions, asymptomatic norovirus infections are very common, and similar detection rates have been observed in patients with diarrhoea and asymptomatic persons. This review summarizes the current knowledge of norovirus infection in developing countries and seeks to position infections with noroviruses among those of other enteropathogens in terms of disease burden in these regions. PMID- 26002300 TI - Human mastadenovirus type 70: a novel, multiple recombinant species D mastadenovirus isolated from diarrhoeal faeces of a haematopoietic stem cell transplantation recipient. AB - A human mastadenovirus D (HAdV-D) isolated from diarrhoeal faeces of an allogeneic haematopoietic stem cell transplant (SCT) recipient was found to be non-typable by sequencing of loops 1 and 2 of the hexon main neutralization epitope ('imputed serology'). In contrast to HAdV-C, HAdV-D infections are rarely observed in SCT patients. Therefore, the whole genome of this isolate was sequenced and phylogenetically analysed. In addition, microneutralization testing with type-specific antisera was performed. A complete genomic sequence of 35.2 kb in length with a GC content of 57 % was obtained and found to be distantly related to HAdV-D27 (96.25 % identity). Imputed serology implicated a new type with a nucleotide sequence identity of only 96.11 % to HAdV-D37 (loop 1) and 95.76 % to HAdV-D30 and HAdV-D37 (loop 2). Microneutralization testing confirmed that this clinical isolate was not neutralized by HAdV-D37- or HAdV-D30-specific antisera. The penton base gene showed a novel sequence, which clustered with HAdV D38, but bootscan analysis indicated an intra-penton recombination event with HAdV-D60. Another recombination event was detected within the early gene region E3 with the 12.2 kDa and CR1-alpha genes derived from HAdV-D58. Moreover, the E4 region was derived from HAdV-D13, but all these genes had evolved significantly from their ancestors. By contrast, the recombinant fibre gene was almost 100 % identical to HAdV-D29. In conclusion, the genomics of this novel HAdV, designated the HAdV-D70 [P70H70F29] prototype, supported the significance of multiple recombinations in the phylogeny of HAdV-D. PMID- 26002301 TI - Possible functional co-operation of palindromes hr3 and hr4 in the genome of Cydia pomonella granulovirus affects viral replication capacity. AB - After previous studies had shown that natural transposon insertion between the two homologous regions hr3 and hr4 of the genome of the Mexican (M) strain of Cydia pomonella granulovirus (CpGV-M) resulted in a loss of viral competitiveness, the function of these homologous regions was investigated. A CpGV-based bacmid (CpBAC) was constructed and mutants with deleted hr3 and hr4 palindromes (CpBAChr3/hr4KO) and a construct (CpBAChr3-kan-hr4) with physically separated hr3 and hr4 repeats were generated to investigate their involvement in in vivo replication. Based on median lethal concentration (LC50) and median survival time (ST50) of the mutant viruses vCpBAChr3/hr4KO and vCpBAChr3-kan-hr4 it was found that the infectivity of both mutants for codling moth Cydia pomonella L. (Lep.: Tortricidae) larvae was not influenced compared with the parental virus vCpBAC. Co-infection experiments with vCpBAChr3-kan-hr4 and vCpBAC using different virus ratios revealed that vCpBAChr3-kan-hr4 was efficiently out competed by vCpBAC during in vivo replication. These findings suggested that the separation of hr3 and hr4 resulted in a replication disadvantage of the mutant similar to the observation made in previous co-infection experiments using the transposon-carrying mutant CpGV-MCp5 and WT CpGV-M. It was concluded that the palindromes hr3 and hr4 may play a non-essential but co-functional role in the replication of CpGV-M. PMID- 26002303 TI - Occipital artery: a not so poor artery for the embolization of lateral sinus dural arteriovenous fistulas with Onyx. PMID- 26002302 TI - Groin complications in endovascular mechanical thrombectomy for acute ischemic stroke: a 10-year single center experience. AB - BACKGROUND: The increasing utilization of balloon guide catheters (BGCs) in thrombectomy therapy for ischemic stroke has led to concerns about large-bore sheaths causing vascular groin complications.Objective To retrospectively assess the impact of large large-bore sheaths and vascular closure devices on groin complication rates at a comprehensive stroke center over a 10-year period. METHODS: Radiological and clinical records of patients with acute ischemic stroke who underwent mechanical endovascular therapy with an 8Fr or larger sheaths were reviewed. A groin complication was defined as the formation of a groin hematoma, retroperitoneal hematoma, femoral artery pseudoaneurysm, or the need for surgical repair. Information collected included size of sheath, type of hemostatic device, and anticoagulation status of the patient. Blood bank records were also analyzed to identify patients who may have had an undocumented blood transfusion for a groin hematoma. RESULTS: A total of 472 patients with acute ischemic stroke who underwent mechanical thrombectomy with a sheath and BGC sized 8Fr or larger were identified. 260 patients (55.1%) had tissue Plasminogen Activator (tPA) administered as part of stroke treatment. Vascular closure devices were used in 97.9% of cases (n=462). Two patients were identified who had definite groin complications and a further two were included as having possible complications. There was a very low rate of clinically significant groin complications (0.4 0.8%) associated with the use of large-bore sheaths. CONCLUSIONS: These findings suggest that concerns for groin complications should not preclude the use of BGCs and large-bore sheaths in mechanical thrombectomy for acute ischemic stroke. PMID- 26002304 TI - The impact of cancer incidence and stage on optimal utilization of radiotherapy: Methodology of a population based analysis by the ESTRO-HERO project. AB - BACKGROUND AND PURPOSE: The impact of differences in the distribution of major cancer sites and stages at diagnosis among 4 European countries on the optimal utilization proportion (OUP) of patients who should receive external beam radiotherapy was assessed within the framework of the ESTRO-HERO project. MATERIALS AND METHODS: Data from Australian Collaboration for Cancer Outcomes Research and Evaluation (CCORE) were used. Population based stages at diagnosis from the cancer registries of Belgium, Slovenia, the Greater Poland region of Poland, and The Netherlands were used to assess the OUP for each country. A sensitivity analysis was carried out. RESULTS: The overall OUP by country varied from the lowest of 48.3% in Australia to the highest of 53.4% in Poland; among European countries the variation was limited to 3%. Cancer site specific OUPs showed differences according to the variability in stage at diagnosis across countries. The most important impact on the OUP by country was due to changes in relative frequency of tumours rather than stage at diagnosis. CONCLUSIONS: This methodology can be adapted using European data, thus facilitating the planning of resources required to cope with the demand for radiotherapy in Europe, taking into account the national variability in cancer incidence. PMID- 26002305 TI - Local control rate after the combination of re-irradiation and hyperthermia for irresectable recurrent breast cancer: Results in 248 patients. AB - BACKGROUND AND PURPOSE: Randomized studies have shown that adding hyperthermia (HT) to re-irradiation (re-RT) improves treatment outcome for patients with breast cancer recurrences. We evaluated the efficacy and side effects in patients treated with re-RT and HT for irresectable locoregional breast cancer recurrences. MATERIAL AND METHODS: From September 1996 to December 2011, 248 patients with a macroscopic breast cancer recurrence were treated with re-RT and HT. Radiotherapy (RT) was applied to a dose of 32 Gy in 4 Gy fractions, twice weekly. HT was prescribed once weekly after RT. Primary endpoints for this analysis were complete response (CR) and local control (LC). Secondary endpoints were overall survival (OS), and toxicity. Patient-, tumor-, and treatment-related characteristics predictive for the endpoints were identified in univariate and multivariate analyses. RESULTS: The median follow-up period was 32 months. The CR rate was 70%. At 1, 3, and 5 years LC was 53%, 40% and 39%, and OS was 66%, 32%, and 18%, respectively. OS after 10 years was 10%. Thermal burns developed in 23% patients, healing with conservative measures. The incidence of 5 years late grade 3 toxicity was 1%. A few patients survived more than 10 years without evidence of disease. CONCLUSIONS: The combination of re-RT and HT results in a high rate of long-term LC with acceptable late toxicity, and many patients remained locally controlled for the rest of their survival period. PMID- 26002306 TI - Assessment of cumulative external beam and intracavitary brachytherapy organ doses in gynecologic cancers using deformable dose summation. AB - PURPOSE: Due to inter-fraction variation in applicator position, organ displacement and deformation, doses to targets and normal tissues may not be accurately represented by adding the doses from external beam radiation therapy (EBRT) and intracavitary brachytherapy (ICBT) using rigid image registration. Deformable image registration permits organ and applicators to be spatially matched in 3D, enabling more accurate tracking of the accumulated volumetric dose to the target as well as organs at risk (OAR). This study assesses the dosimetric impact of using deformable image registration to determine the cumulative EBRT and ICBT doses to the rectum and bladder. METHODS AND MATERIALS: Data from 20 patients with stage IB1-IVA cervical cancer were analyzed. Nine of the patients were treated with ICBT and EBRT which included a nodal or parametrium boost while eleven were treated with ICBT and EBRT with no boost. Dose summation was performed in two stages. For the first stage, only the ICBT fractional doses were added using both "parameter adding" and deformable registration techniques. In the second stage, the ICBT and EBRT doses were combined using "parameter adding" in two ways. Partial "parameter adding" considers the cumulative ICBT dose from deformable registration as one parameter while full "parameter adding" uses fractional ICBT parameters. The cumulative minimum doses to 2cc (D2cc) of the rectum and bladder were compared between deformable registration and "parameter adding" techniques. RESULTS: Dose summation of ICBT fractions only using deformable registration yielded D2cc values that were (10.1+/-9.5)% lower for the rectum and (7.2+/-6.3)% lower for the bladder compared to "parameter adding". When ICBT and EBRT doses were summed deformably, the group without EBRT boost had D2cc that were (0.0+/-4.6)% and (-1.2+/-2.9)% lower for the rectum and bladder respectively compared to partial "parameter adding". With EBRT boost, the differences were (-2.9+/-4.0)% and (-3.2+/-3.3)% for the rectum and bladder respectively. For full "parameter adding", the differences from deformable sum were (2.7+/-5.0)%, (2.6+/-5.0)% without EBRT boost and (0.6+/-4.8)%, (-1.5+/ 3.7)% with EBRT boost. CONCLUSION: Comparison of deformable dose summation with the technique of "parameter adding" suggests that "parameter adding" can be used as a good approximation of D2cc when adding ICBT and EBRT doses with or without boost. With EBRT boosts, deformable dose summation may more accurately represent dose to normal critical structures but these differences remain small compared to "parameter adding". PMID- 26002307 TI - Diffusion-weighted magnetic resonance imaging for the prediction of pathologic response to neoadjuvant chemoradiotherapy in esophageal cancer. AB - PURPOSE: To explore the value of diffusion-weighted magnetic resonance imaging (DW-MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer. MATERIAL AND METHODS: In 20 patients receiving nCRT for esophageal cancer DW-MRI scanning was performed before nCRT, after 8-13 fractions, and before surgery. The median tumor apparent diffusion coefficient (ADC) was determined at these three time points. The predictive potential of initial tumor ADC, and change in ADC (DeltaADC) during and after treatment for pathologic complete response (pathCR) and good response were assessed. Good response was defined as pathCR or near-pathCR (tumor regression grade [TRG] 1 or 2). RESULTS: A pathCR after nCRT was found in 4 of 20 patients (20%), and 8 patients (40%) showed a good response to nCRT. The DeltaADCduring was significantly higher in pathCR vs. non-pathCR patients (34.6%+/-10.7% [mean+/-SD] vs. 14.0%+/-13.1%, p=0.016), as well as in good vs. poor responders (30.5%+/-8.3% vs. 9.5%+/-12.5%, p=0.002). The DeltaADCduring was predictive of residual cancer at a threshold of 29% (sensitivity of 100%, specificity of 75%, PPV of 94%, and NPV of 100%), and for poor pathologic response at a threshold of 21% (sensitivity of 82%, specificity of 100%, PPV of 100%, and NPV of 80%). CONCLUSIONS: In this exploratory study, the treatment induced change in ADC during the first 2-3weeks of nCRT for esophageal cancer seemed highly predictive of histopathologic response. Larger series are warranted to verify these results. PMID- 26002308 TI - Validation of an automated mite counter for Dermanyssus gallinae in experimental laying hen cages. AB - For integrated pest management (IPM) programs to be maximally effective, monitoring of the growth and decline of the pest populations is essential. Here, we present the validation results of a new automated monitoring device for the poultry red mite (Dermanyssus gallinae), a serious pest in laying hen facilities world-wide. This monitoring device (called an "automated mite counter") was validated in experimental laying hen cages with live birds and a growing population of D. gallinae. This validation study resulted in 17 data points of 'number of mites counted' by the automated mite counter and the 'number of mites present' in the experimental laying hen cages. The study demonstrated that the automated mite counter was able to track the D. gallinae population effectively. A wider evaluation showed that this automated mite counter can become a useful tool in IPM of D. gallinae in laying hen facilities. PMID- 26002309 TI - Host-associated differences in morphometric traits of parasitic larvae Hirsutiella zachvatkini (Actinotrichida: Trombiculidae). AB - Examination of host-associated variation in the chigger mite Hirsutiella zachvatkini (Schluger) revealed morphological differences among larvae infesting sympatric hosts: Apodemus agrarius, Apodemus flavicollis and Myodes glareolus. The analysis included 61 variables of larvae obtained from their gnathosoma, idiosoma and legs (measurements and counts). Statistically significant differences were observed for metric characters of the legs as opposed to the scutum. In view of the conspecificity of the mites, supported by comparison of COI gene products obtained from larvae and laboratory-reared deutonymphs, the observed variation is attributed to phenotypic plasticity. The knowledge of larval morphology, including intraspecific variation of metric characters, supported by molecular and host range data, places H. zachvatkini among the most comprehensively defined members of Trombiculidae. PMID- 26002310 TI - First detection of Sarcoptes scabiei from domesticated pig (Sus scrofa) and genetic characterization of S. scabiei from pet, farm and wild hosts in Israel. AB - In this report we describe for the first time the detection of Sarcoptes scabiei type suis mites on domestic pigs in Israel and examine its genetic variation compared with S. sabiei from other hosts. Microscopic examination of skin samples from S. scabiei-infested pigs (Sus scrofa domesticus) revealed all developmental stages of S. scabiei. To detect genetic differences between S. scabiei from different hosts, samples obtained from pig, rabbits (Orictolagus cuniculus), fox (Vulpes vulpes), jackal (Canis aureus) and hedgehog (Erinaceus concolor) were compared with GenBank-annotated sequences of three genetic markers. Segments from the following genes were examined: cytochrome C oxidase subunit 1 (COX1), glutathione-S-transferase 1 (GST1), and voltage-sensitive sodium channel (VSSC). COX1 analysis did not show correlation between host preference and genetic identity. However, GST1 and VSSC had a higher percentage of identical sites within S. scabiei type suis sequences, compared with samples from other hosts. Taking into account the limited numbers of GST1 and VSSC sequences available for comparison, this high similarity between sequences of geographically-distant, but host-related populations, may suggest that different host preference is at least partially correlated with genetic differences. This finding may help in future studies of the factors that drive host preferences in this parasite. PMID- 26002311 TI - Phytoseiids in Washington commercial apple orchards: biodiversity and factors affecting abundance. AB - Galendromus occidentalis (Nesbitt) is an important biological control agent of spider mites (Acari: Tetranychidae) in Washington apple orchards. It was thought to be essentially the sole phytoseiid existing in this system, due in part to its resistance to commonly used orchard pesticides, and organophosphates in particular. To test this assumption, we conducted a survey of 102 commercial apple blocks in Washington to characterize the community of phytoseiid species. Seven phytoseiid species were found in our samples; G. occidentalis and Amblydromella caudiglans (Schuster) were found in the greatest abundance. We hypothesized that the gradual shift away from the use of organophosphates in recent decades may have caused the change in phytoseiid community structure. The survey data and information regarding the management, location, and surrounding habitat of each block were used to determine what factors affect phytoseiid abundances. Galendromus occidentalis abundance was positively affected by the use of conventional (vs. organic) spray programs, and the use of the acaricide bifenazate. Amblydromella caudiglans abundance was negatively affected by bifenazate use and positively affected by herbicide strip weediness; it was also less prevalent in 'Golden Delicious' blocks compared to other cultivars. These results indicate that A. caudiglans reaches higher abundances in orchards that lack certain agricultural disturbances, whereas G. occidentalis can survive in more disturbed environments. Surveys of this nature can provide valuable insight to potential drivers of community structure, allowing for the improvement of integrated pest management programs that incorporate conservation of newly recognized biological control agents such as A. caudiglans. PMID- 26002312 TI - A novel culture medium for isolation of rapidly-growing mycobacteria from the sputum of patients with cystic fibrosis. AB - BACKGROUND: Isolation of mycobacteria from the sputum of patients with cystic fibrosis (CF) is challenging due to the overgrowth of cultures by other bacteria and fungi. In this setting, Burkholderia cepacia selective agar (BCSA) has been recommended as a convenient and effective culture medium for the isolation of rapidly-growing, non-tuberculous mycobacteria (NTM). A novel selective culture medium (RGM medium) was evaluated for the isolation of rapidly-growing NTM from the sputum of children and adults with CF. METHODS: A total of 118 isolates of rapidly-growing mycobacteria and 98 other bacteria and fungi were inoculated onto RGM medium. These were assessed for growth at 30 degrees C over a seven day period. A total of 502 consecutive sputum samples were collected from 210 patients with CF. Each sample was homogenized and cultured onto RGM medium and also onto BCSA. Cultures were incubated for 10days at 30 degrees C. RESULTS: Of 118 isolates of mycobacteria all but one grew well on RGM medium, whereas 94% of other bacteria and fungi were inhibited. A total of 55 sputum samples (from 33 distinct patients) yielded NTM using a combination of both RGM and BCSA (prevalence: 15.7%). NTM were recovered from 54 sputum samples using RGM medium compared with only 17 samples using BCSA (sensitivity 98% vs. 31%; P<=0.0001). A total of 419 isolates of non-mycobacteria were recovered from sputum samples on BCSA compared with 46 on RGM medium. CONCLUSIONS: RGM medium offers a simple and effective culture method for the isolation of rapidly-growing mycobacteria from sputum samples from patients with CF without decontamination of samples. RGM medium allows for the systematic screening of all sputum samples routinely referred for culture from patients with CF. PMID- 26002313 TI - Sex differences in myelin-associated protein levels within and density of projections between the orbital frontal cortex and dorsal striatum of adult rats: implications for inhibitory control. AB - Impulsive actions and decisions often lead to undesirable outcomes. Lesion and neuroimaging studies have revealed that the orbital frontal cortex (OFC) and dorsal striatum (dSTR) play key roles in inhibitory control. It has been proposed that greater OFC input into the dSTR reflects enhanced top-down cognitive control and less impulsive responding. We previously reported a sex difference in inhibitory control, such that female rats make fewer impulsive errors than do male rats. The goal of the present study was to investigate differences in the OFC and dSTR of young adult male and female rats. In Experiment 1, we measured levels of two myelin-associated proteins, myelin basic protein (MBP) and myelin proteolipid protein (PLP), in the OFC and dSTR. Western blot data revealed that females had significantly higher levels of both MBP and PLP in the OFC but similar levels in the dSTR as compared to males. In Experiment 2, we infused the anterograde tracer, biotinylated dextran amine (BDA), into the OFC and measured the density of BDA in the dSTR. BDA was visualized using histochemistry followed by light microscopy imaging and densitometry analysis. Density of BDA in the dSTR was significantly greater in females as compared to males indicating that the projections from the OFC to dSTR may be greater in females as compared to males. Our results suggest a potential neuroanatomical sex difference that may contribute to the reported differences in inhibitory control levels of male and female rats. PMID- 26002314 TI - Nerve injury induces the expression of syndecan-1 heparan sulfate proteoglycan in primary sensory neurons. AB - Heparan sulfate proteoglycans (HSPGs) have important functions in development of the central nervous system; however, their functions in nerve injury are not yet fully understood. We previously reported the expression of syndecan-1, a type of HSPG, in cranial motor neurons after nerve injury, suggesting the importance of syndecan-1 in the pathology of motor nerve injury. In this study, we examined the expression of syndecan-1, a type of HSPG, in primary sensory neurons after nerve injury in mice. Sciatic nerve axotomy strongly induced the expression of syndecan 1 in a subpopulation of injured dorsal root ganglion (DRG) neurons, which were small in size and had CGRP- or isolectin B4-positive fibers. Syndecan-1 was also distributed in the dorsal horn of the spinal cord ipsilateral to the axotomy, and located on the membrane of axons in lamina II of the dorsal horn. Not only sciatic nerve axotomy, infraorbital nerve axotomy also induced the expression of syndecan-1 in trigeminal ganglion neurons. Moreover, syndecan-1 knockdown in cultured DRG neurons induced a shorter neurite extension. These results suggest that syndecan-1 expression in injured primary sensory neurons may have functional roles in nerve regeneration and synaptic plasticity, resulting in the development of neuropathic pain. PMID- 26002315 TI - Descending and tonotopic projection patterns from the auditory cortex to the inferior colliculus. AB - The inferior colliculus (IC) receives many corticofugal projections, which can mediate plastic changes such as shifts in frequency tuning or excitability of IC neurons. While the densest projections are found in the IC's external cortices, fibers originating from the primary auditory cortex (AI) have been observed throughout the IC's central nucleus (ICC), and these projections have shown to be organized tonotopically. Some studies have also found projections from other core and non-core cortical regions, though the organization and function of these projections are less known. In guinea pig, there exists a non-core ventrorostral belt (VRB) region that has primary-like properties and has often been mistaken for AI, with the clearest differentiating characteristic being VRB's longer response latencies. To better understand the auditory corticofugal descending system beyond AI, we investigated if there are projections from VRB to the ICC and if they exhibit a different projection pattern than those from AI. In this study, we performed experiments in ketamine-anesthetized guinea pigs, in which we positioned 32-site electrode arrays within AI, VRB, and ICC. We identified the monosynaptic connections between AI-to-ICC and VRB-to-ICC using an antidromic stimulation method, and we analyzed their locations across the midbrain using three-dimensional histological techniques. Compared to the corticocollicular projections to the ICC from AI, there were fewer projections to the ICC from VRB, and these projections had a weaker tonotopic organization. The majority of VRB projections were observed in the caudal-medial versus the rostral-lateral region along an isofrequency lamina of the ICC, which is in contrast to the AI projections that were scattered throughout an ICC lamina. These findings suggest that the VRB directly modulates sound information within the ascending lemniscal pathway with a different or complementary role compared to the modulatory effects of AI, which may have implications for treating hearing disorders. PMID- 26002316 TI - Effects of JIP3 on epileptic seizures: Evidence from temporal lobe epilepsy patients, kainic-induced acute seizures and pentylenetetrazole-induced kindled seizures. AB - JNK-interacting protein 3 (JIP3), also known as JNK stress-activated protein kinase-associated protein 1 (JSAP1), is a scaffold protein mainly involved in the regulation of the pro-apoptotic signaling cascade mediated by c-Jun N-terminal kinase (JNK). Overexpression of JIP3 in neurons in vitro has been reported to lead to accelerated activation of JNK and enhanced apoptosis response to cellular stress. However, the occurrence and the functional significance of stress-induced modulations of JIP3 levels in vivo remain elusive. In this study, we investigated the expression of JIP3 in temporal lobe epilepsy (TLE) and in a kainic acid (KA) induced mouse model of epileptic seizures, and determined whether down-regulation of JIP3 can decrease susceptibility to seizures and neuron damage induced by KA. We found that JIP3 was markedly increased in TLE patients and a mouse model of epileptic seizures; mice underexpressing JIP3 through lentivirus bearing LV-Letm1 RNAi showed decreased susceptibility, delayed first seizure and decreased seizure duration response to the epileptogenic properties of KA. Subsequently, a decreased activation of JNK following seizure induction was observed in mice underexpressing JIP3, which also exhibited less neuronal apoptosis in the CA3 region of the hippocampus, as assessed three days after KA administration. We also found that mice underexpressing JIP3 exhibited a delayed pentylenetetrazole (PTZ)-induced kindling seizure process. PMID- 26002317 TI - Uveitis secondary to leishmaniasis immune reconstitution syndrome in a HIV positive patient. AB - We describe the case of a HIV-positive patient treated for visceral leishmaniasis who developed uveitis as part of a leishmaniasis immune reconstitution syndrome. Visceral leishmaniasis is increasingly found in HIV-positive adults. Its ophthalmic manifestations can range from relatively minor to complicated anterior uveitis, leading to secondary glaucoma and loss of vision. Clinicians caring for people living with HIV should be alert to the complications of leishmaniasis that can occur before and during treatment. PMID- 26002318 TI - Prevalence and concordance of human papillomavirus infection at multiple anatomic sites among HIV-infected women from Chennai, India. AB - Human papillomavirus (HPV) infection at the cervix, anus and oropharynx has been rarely concurrently estimated among HIV-infected women. Using multiplex polymerase chain reaction testing, we prospectively evaluated HPV genotype distribution across three anatomic sites among 50 eligible HIV-infected women from Chennai, India, who provided biological specimens and answered a sexual behaviour questionnaire. We also assessed clinical and behavioural factors related to HPV prevalence. Oncogenic HPV prevalence was comparable between the anus and cervix at 52.2% and 52.0% and lower at the oropharynx at 13.2%; 78% of women with a cervical HPV infection had the same type in the anus. Newly acquired oncogenic HPV infections were lower at cervix (24%) than anus (35%) at three months. 'Any type' cervical HPV prevalence was higher among women with low education and less than five years since HIV diagnosis. CD4+ count and antiretroviral therapy status were not associated with HPV prevalence at the three anatomic sites; however, enrolment cervical HPV16 prevalence was elevated among women with nadir CD4+ <200 cells/uL and enrolment CD4+ <350 cells/uL. Regular cervical screening is essential in HIV-infected Indian women irrespective of CD4+ count and antiretroviral therapy status. Additional research clarifying the natural history of anal HPV infection is also needed in this population. PMID- 26002319 TI - 2015 UK National Guideline on the management of non-gonococcal urethritis. AB - We present the updated British Association for Sexual Health and HIV guideline for the management of non-gonococcal urethritis in men. This document includes a review of the current literature on its aetiology, diagnosis and management. In particular it highlights the emerging evidence that azithromycin 1 g may result in the development of antimicrobial resistance in Mycoplasma genitalium and that neither azithromycin 1 g nor doxycycline 100 mg twice daily for seven days achieves a cure rate of >90% for this micro-organism. Evidence-based diagnostic and management strategies for men presenting with symptoms suggestive of urethritis, those confirmed to have non-gonococcal urethritis and those with persistent symptoms following first-line treatment are detailed. PMID- 26002320 TI - 'Biomarking' infection during continuous renal replacement therapy: still relevant? PMID- 26002322 TI - Simultaneous topographic and recognition imaging of epidermal growth factor receptor (EGFR) on single human breast cancer cells. AB - Epidermal growth factor receptor (EGFR) plays an important role in signaling pathway of the development of breast cancer cells. Since EGFR overexpresses in most breast cancer cells, it is regarded as a biomarker molecule of breast cancer cells. Here we demonstrated a new AFM technique-topography and recognition (TREC) imaging-to simultaneously obtain highly sensitive and specific molecular recognition images and high-resolution topographic images of EGFR on single breast cancer cells. PMID- 26002321 TI - Antimicrobial peptide resistance in Neisseria meningitidis. AB - Antimicrobial peptides (AMPs) play an important role as a host defense against microbial pathogens and are key components of the human innate immune response. Neisseria meningitidis frequently colonizes the human nasopharynx as a commensal but also is a worldwide cause of epidemic meningitis and rapidly fatal sepsis. In the human respiratory tract, the only known reservoir of N. meningitidis, meningococci are exposed to human endogenous AMPs. Thus, it is not surprising that meningococci have evolved effective mechanisms to confer intrinsic and high levels of resistance to the action of AMPs. This article reviews the current knowledge about AMP resistance mechanisms employed by N. meningitidis. Two major resistance mechanisms employed by meningococci are the constitutive modification of the lipid A head groups of lipooligosaccharides by phosphoethanolamine and the active efflux pump mediated excretion of AMPs. Other factors influencing AMP resistance, such as the major porin PorB, the pilin biogenesis apparatus, and capsular polysaccharides, have also been identified. Even with an inherently high intrinsic resistance, several AMP resistance determinants can be further induced upon exposure to AMPs. Many well-characterized AMP resistance mechanisms in other Gram-negative bacteria are not found in meningococci. Thus, N. meningitidis utilizes a limited but highly effective set of molecular mechanisms to mediate antimicrobial peptide resistance. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 26002323 TI - A paper-based resonance energy transfer nucleic acid hybridization assay using upconversion nanoparticles as donors and quantum dots as acceptors. AB - Monodisperse aqueous upconverting nanoparticles (UCNPs) were covalently immobilized on aldehyde modified cellulose paper via reduction amination to develop a luminescence resonance energy transfer (LRET)-based nucleic acid hybridization assay. This first account of covalent immobilization of UCNPs on paper for a bioassay reports an optically responsive method that is sensitive, reproducible and robust. The immobilized UCNPs were decorated with oligonucleotide probes to capture HPRT1 housekeeping gene fragments, which in turn brought reporter conjugated quantum dots (QDs) in close proximity to the UCNPs for LRET. This sandwich assay could detect unlabeled oligonucleotide target, and had a limit of detection of 13 fmol and a dynamic range spanning nearly 3 orders of magnitude. The use of QDs, which are excellent LRET acceptors, demonstrated improved sensitivity, limit of detection, dynamic range and selectivity compared to similar assays that have used molecular fluorophores as acceptors. The selectivity of the assay was attributed to the decoration of the QDs with polyethylene glycol to eliminate non-specific adsorption. The kinetics of hybridization were determined to be diffusion limited and full signal development occurred within 3 min. PMID- 26002324 TI - Two decades of chemical imaging of solutes in sediments and soils--a review. AB - The increasing appreciation of the small-scale (sub-mm) heterogeneity of biogeochemical processes in sediments, wetlands and soils has led to the development of several methods for high-resolution two-dimensional imaging of solute distribution in porewaters. Over the past decades, localised sampling of solutes (diffusive equilibration in thin films, diffusive gradients in thin films) followed by planar luminescent sensors (planar optodes) have been used as analytical tools for studies on solute distribution and dynamics. These approaches have provided new conceptual and quantitative understanding of biogeochemical processes regulating the distribution of key elements and solutes including O2, CO2, pH, redox conditions as well as nutrient and contaminant ion species in structurally complex soils and sediments. Recently these methods have been applied in parallel or integrated as so-called sandwich sensors for multianalyte measurements. Here we review the capabilities and limitations of the chemical imaging methods that are currently at hand, using a number of case studies, and provide an outlook on potential future developments for two dimensional solute imaging in soils and sediments. PMID- 26002325 TI - Recent progress in applications of graphene oxide for gas sensing: A review. AB - This paper is a review of the recent progress on gas sensors using graphene oxide (GO). GO is not a new material but its unique features have recently been of interest for gas sensing applications, and not just as an intermediate for reduced graphene oxide (RGO). Graphene and RGO have been well known gas-sensing materials, but GO is also an attractive sensing material that has been well studied these last few years. The functional groups on GO nanosheets play important roles in adsorbing gas molecules, and the electric or optical properties of GO materials change with exposure to certain gases. Addition of metal nanoparticles and metal oxide nanocomposites is an effective way to make GO materials selective and sensitive to analyte gases. In this paper, several applications of GO based sensors are summarized for detection of water vapor, NO2, H2, NH3, H2S, and organic vapors. Also binding energies of gas molecules onto graphene and the oxygenous functional groups are summarized, and problems and possible solutions are discussed for the GO-based gas sensors. PMID- 26002326 TI - Chemically selective polymer substrate based direct isotope dilution alpha spectrometry of Pu. AB - Quantification of actinides in the complex environmental, biological, process and waste streams samples requires multiple steps like selective preconcentration and matrix elimination, solid source preparations generally by evaporation or electrodeposition, and finally alpha spectrometry. To minimize the sample manipulation steps, a membrane based isotope dilution alpha spectrometry method was developed for the determination of plutonium concentrations in the complex aqueous solutions. The advantages of this method are that it is Pu(IV) selective at 3M HNO3, high preconcentration factor can be achieved, and obviates the need of solid source preparation. For this, a thin phosphate-sulfate bifunctional polymer layer was anchored on the surface of microporous poly(ethersulfone) membrane by UV induced surface grafting. The thickness of the bifunctional layer on one surface of the poly(ethersulfone) membrane was optimized. The thickness, physical and chemical structures of the bifunctional layer were studied by secondary ionization mass spectrometry (SIMS), scanning electron microscopy (SEM) and SEM-EDS (energy-dispersive spectroscopy). The optimized membrane was used for preconcentration of Pu(IV) from aqueous solutions having 3-4M HNO3, followed by direct quantification of the preconcentrated Pu(IV) by isotope dilution alpha spectrometry using (238)Pu spike. The chemical recovery efficiency of Pu(IV) was found to be 86+/-3% below Pu(IV) loading capacity (1.08 MUg in 2*1 cm(2)) of the membrane sample. The experiments with single representative actinides indicated that Am(III) did not sorb to significant extent (7%) but U(VI) sorbed with 78+/ 3% efficiency from the solutions having 3M HNO3 concentration. However, Pu(IV) chemical recovery in the membrane remained unaffected from the solution containing 1:1000 wt. proportion of Pu(IV) to U(VI). Pu concentrations in the (U, Pu)C samples and in the irradiated fuel dissolver solutions were determined. The results thus obtained were found to be in good agreement with those obtained by conventional alpha spectrometry, biamperometry and thermal ionization mass spectrometry. PMID- 26002327 TI - A flexible trilinear decomposition algorithm for three-way calibration based on the trilinear component model and a theoretical extension of the algorithm to the multilinear component model. AB - There is a great deal of interest in decompositions of multilinear component models in the field of multi-way calibration, especially the three-way case. A flexible novel trilinear decomposition algorithm of the trilinear component model as a modification of an alternating least squares algorithm for three-way calibration is proposed. The proposed algorithm (constrained alternating trilinear decomposition, CATLD) is based on an alternating approximate least squares scheme, in which two extra terms are added to each loss function, making it more efficient and flexible. The analysis of simulated three-way data arrays shows that it converges fast, is insensitive to initialization, and is insensitive to the overestimated number of components used in the decomposition. The analysis of real excitation-emission matrix (EEM) fluorescence and real high performance liquid chromatography-photodiode array detection (HPLC-DAD) data arrays confirms the results of the simulation studies, and shows that the proposed algorithm is favorable not only for EEMs but also for HPLC-DAD data. The three-way calibration method based on the CATLD algorithm is very efficient and flexible for direct quantitative analysis of multiple analytes of interest in complex systems, even in the presence of uncalibrated interferents and varying background interferents. Additionally, a theoretical extension of the proposed algorithm to the multilinear component model (constrained alternating multilinear decomposition, CAMLD) is developed. PMID- 26002328 TI - Chemometric approach to open validation protocols: Prediction of validation parameters in multi-residue ultra-high performance liquid chromatography-tandem mass spectrometry methods. AB - The recent technological advancements of liquid chromatography-tandem mass spectrometry allow the simultaneous determination of tens, or even hundreds, of target analytes. In such cases, the traditional approach to quantitative method validation presents three major drawbacks: (i) it is extremely laborious, repetitive and rigid; (ii) it does not allow to introduce new target analytes without starting the validation from its very beginning and (iii) it is performed on spiked blank matrices, whose very nature is significantly modified by the addition of a large number of spiking substances, especially at high concentration. In the present study, several predictive chemometric models were developed from closed sets of analytes in order to estimate validation parameters on molecules of the same class, but not included in the original training set. Retention time, matrix effect, recovery, detection and quantification limits were predicted with partial least squares regression method. In particular, iterative stepwise elimination, iterative predictors weighting and genetic algorithms approaches were utilized and compared to achieve effective variables selection. These procedures were applied to data reported in our previously validated ultra high performance liquid chromatography-tandem mass spectrometry multi-residue method for the determination of pharmaceutical and illicit drugs in oral fluid samples in accordance with national and international guidelines. Then, the partial least squares model was successfully tested on naloxone and lormetazepam, in order to introduce these new compounds in the oral fluid validated method, which adopts reverse-phase chromatography. Retention time, matrix effect, recovery, limit of detection and limit of quantification parameters for naloxone and lormetazepam were predicted by the model and then positively compared with their corresponding experimental values. The whole study represents a proof-of concept of chemometrics potential to reduce the routine workload during multi residue methods validation and suggests a rational alternative to ever-expanding procedures progressively drifting apart from real sample analysis. PMID- 26002329 TI - Copper sulfide nanoparticle-decorated graphene as a catalytic amplification platform for electrochemical detection of alkaline phosphatase activity. AB - Copper sulfide nanoparticle-decorated graphene sheet (CuS/GR) was successfully synthesized and used as a signal amplification platform for electrochemical detection of alkaline phosphatase activity. First, CuS/GR was prepared through a microwave-assisted hydrothermal approach. The CuS/GR nanocomposites exhibited excellent electrocatalytic activity toward the oxidation of ALP hydrolyzed products such as 1-naphthol, which produced a current response. Thus, a catalytic amplification platform based on CuS/GR nanocomposite for electrochemical detection of ALP activity was designed using 1-naphthyl phosphate as a model substrate. The current response increased linearly with ALP concentration from 0.1 to 100 U L(-1) with a detection limit of 0.02 U L(-1). The assay was applied to estimate ALP activity in human serum samples with satisfactory results. This strategy may find widespread and promising applications in other sensing systems that involves ALP. PMID- 26002330 TI - An electrochemical microRNAs biosensor with the signal amplification of alkaline phosphatase and electrochemical-chemical-chemical redox cycling. AB - MicroRNAs (MiRNAs) have been regarded as clinically important biomarkers and drug discovery targets. In this work, we reported a simple and ultrasensitive electrochemical method for miRNAs detection based on single enzyme amplification and electrochemical-chemical-chemical (ECC) redox cycling. Specifically, upon contact with the target miRNAs, the hairpin structure of biotinylated DNA immobilized on gold electrode was destroyed and the biotin group in DNA was forced away from the electrode surface, allowing for the coupling of streptavidin conjugated alkaline phosphatase (SA-ALP). Then, ascorbic acid (AA, the enzymatic product of ALP) triggered the ECC redox cycling with ferrocene methanol (FcM) and tris(2-carboxyethyl)phosphine (TCEP) as the redox mediator and the chemical reducing reagent, respectively. The method was more sensitive than that with horseradish peroxidase (HRP) or glucose oxidase (GOx) triggered recycling since one ALP molecule captured by one target miRNA molecule promoted the production of thousands of AA. Analytical merits (e.g., detection limit, dynamic range, specificity, regeneration and reproducibility) were evaluated. The feasibility of the method for analysis of miRNA-21 in human serum has also been demonstrated. PMID- 26002331 TI - Electrospun polystyrene/graphene nanofiber film as a novel adsorbent of thin film microextraction for extraction of aldehydes in human exhaled breath condensates. AB - In the current study, we introduced a novel polystyrene/graphene (PS/G) composite nanofiber film for thin film microextraction (TFME) for the first time. The PS/G nanofiber film was fabricated on the surface of filter paper by a facile electrospinning method. The morphology and extraction performance of the resultant composite film were investigated systematically. The PS/G nanofiber film exhibited porous fibrous structure, large surface area and strong hydrophobicity. A new thin film microextraction-high performance liquid chromatography (TFME-HPLC) method was developed for the determination of six aldehydes in human exhaled breath condensates. The method showed high enrichment efficiency and fast analysis speed. Under the optimal conditions, the linear ranges of the analytes were in the range of 0.02-30 MUmol L(-1) with correlation coefficients above 0.9938, and the recoveries were between 79.8% and 105.6% with the relative standard deviation values lower than 16.3% (n=5). The limits of quantification of six aldehydes ranged from 13.8 to 64.6 nmol L(-1). The established method was successfully applied for the quantification of aldehyde metabolites in exhaled breath condensates of lung cancer patients and healthy people. Taken together, the TFME-HPLC method provides a simple, rapid, sensitive, cost-effective, non-invasion approach for the analysis of linear aliphatic aldehydes in human exhaled breath condensates. PMID- 26002332 TI - Mesoporous TiO2 nanoparticles for highly sensitive solid-phase microextraction of organochlorine pesticides. AB - Mesoporous TiO2 nanoparticles were synthesized with the hydrothermal method and characterized by powder X-ray diffraction (PXRD) and transmission electron microscope (TEM). Then a superior solid-phase microextraction (SPME) fiber was fabricated by sequentially coating the stainless steel fiber with silicone sealant film and mesoporous TiO2 powder. The developed fiber possessed a homogeneous surface and a long life-span up to 100 times at direct immersing (DI) extraction mode. Under the optimized conditions, the extraction efficiencies of the self-made 17 MUm TiO2 fiber for six organochlorine pesticides (OCPs) were higher than those of the two commercial fibers (65 MUm PDMS/DVB and 85 MUm PA fibers) which were much thicker than the former. As for analytical performance, low detection limits (0.08-0.60 ng L(-1)) and wide linearity (5-5000 ng L(-1)) were achieved under the optimal conditions. The repeatabilities (n=5) for single fiber were between 2.8 and 12.3%, while the reproducibilities (n=3) of fiber-to fiber were in the range of 3.7-15.7%. The proposed fiber was successfully applied to the sensitive analysis of OCPs in real water samples and four of the six analytes were detected from the rainwater and the lake water samples. PMID- 26002333 TI - Influence of oxygen and long term storage on the profile of volatile compounds released from polymeric multilayer food contact materials sterilized by gamma irradiation. AB - The profile of volatile compounds released from 13 different multilayer polymeric materials for food use, before and after their exposure to gamma radiation, has been assessed by solid-phase microextraction-gas chromatography-mass spectrometry. Thermosealed bags of different materials were filled with either air or nitrogen to evaluate the oxygen influence. One-third of the samples were analyzed without irradiation, whereas the rest were irradiated at 15 and 25 kGy. Half of the samples were processed just after preparation and the other half was stored for 8 months at room temperature prior to analysis. Very significant differences between unirradiated and irradiated bags were found. About 60-80 compounds were released and identified per sample. A huge peak of 1,3 ditertbutylbenzene was present in most of the irradiated samples. An outstanding reproducibility in all the variables evaluated (chromatograms, oxygen percentage, volume of bags) was noticed. Independently of filling gas, the results of unirradiated materials were almost identical. In contrast, the chromatographic profile and the odor of irradiated bags filled with nitrogen were completely different to those filled with air. Principal component analysis was performed and 86.9% of the accumulated variance was explained with the first two components. The migration of compounds from irradiated materials to the vapor phase was much lower than the limits established in the Commission Regulation (EU) No 10/2011. PMID- 26002334 TI - beta-CD/ATP composite materials for use in dispersive solid-phase extraction to measure (fluoro)quinolone antibiotics in honey samples. AB - A novel sorbent (beta-CD/ATP composite) for dispersive solid-phase extraction (d SPE) prepared by bonding beta-cyclodextrin to modified attapulgite via silane coupling was used to determine the concentrations of four (fluoro)quinolones (Qs) in honey samples. The subsequent quantification of the Qs (ciprofloxacin, norfloxacin, ofloxacin, and gatifloxacin) was accomplished using high-performance liquid chromatography (HPLC) with ultraviolet detection after the d-SPE procedure. Parameters that may influence the extraction efficiency, such as type and volume of the eluent, type and amount of the sorbent, times of the vortex and sonication process, and pH of the sample, were investigated using batch and column procedures. The optimal experimental conditions (5 mL sample at pH 3, 4 mg of beta-CD/ATP composite as the sorbent, 200 MUL of 40% ammonia in methanol as the eluent, with vortex time 60s and sonication time 6 min, and no addition of salt) were obtained from this statistical evaluation. The limits of detection (LODs) were determined to the range from 0.30 to 3.95 MUg L(-1). Good recoveries (83.6-88.6%) were obtained under the optimum conditions, and the relative standard deviations (RSDs), which are used to indicate reproducibility, were less than 7.4%. The method was validated with three real honey samples, and the results demonstrated that beta-CD/ATP composite possessed a high adsorption capacity for Qs. Although the LODs were slightly higher than expected, this study confirmed the possibility of using cyclodextrin grafted palygorskite in analytical applications. PMID- 26002335 TI - Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH). AB - Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article. PMID- 26002336 TI - Identifying and managing common childhood language and speech impairments. PMID- 26002337 TI - Probing competitive interactions in quaternary formulations. AB - HYPOTHESIS: The interaction of amphiphilic block copolymers of the poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) group with small molecule surfactants may be "tuned" by the presence of selected alcohols, with strong interactions leading to substantial changes in (mixed) micelle morphology, whilst weaker interactions lead to coexisting micelle types. EXPERIMENTS: The nature and the strength of the interactions between Pluronic P123 (EO20PO70EO20) and small molecule surfactants (anionic sodium dodecylsulfate, SDS, C12SO4Na), (cationic dodecyltrimethylammonium bromide, C12TAB) and (non-ionic polyoxyethylene(23)lauryl ether, Brij 35, C12EO23OH) is expected to depend on the partitioning of the short, medium and long chain alcohols (ethanol, hexanol and decanol respectively) and was probed using tensiometry, pulsed-gradient spin-echo nuclear magnetic resonance (PGSE-NMR) and small-angle neutron scattering (SANS). FINDINGS: The SANS data for aqueous P123 solutions with added alcohols were well described by a charged spherical core/shell model for the micelle morphology. The addition of the surfactants led to significantly smaller, oblate elliptical mixed micelles in the absence of alcohols. Addition of ethanol to these systems led to a decrease in the micelle size, whereas larger micelles were observed upon addition of the longer chain alcohols. NMR studies provided complementary estimates of the micelle composition, and the partitioning of the various components into the micelle. PMID- 26002338 TI - Efficient activation of peroxymonosulfate by manganese oxide for the degradation of azo dye at ambient condition. AB - This study determines the potential of manganese oxide (MnOx) nanoparticles for the activation of peroxymonosulfate (PMS). The MnOx nanoparticles were prepared by a facile co-precipitation method and the degradation rates of acid red G (ARG) by the as-prepared catalysts in the presence of PMS were measured. The results showed that the Mn3O4 nanoparticles with tetragonal structure exhibited high catalytic activity for the degradation of ARG by activating PMS to generate radicals. The effects of the operational parameters on the catalytic property of the obtained nanosized Mn3O4 catalyst were investigated in detail. The catalyst exhibits excellent catalytic activity in a wide range of pH from 2 to 12. Moreover, it still maintained high catalytic activity even after five reaction cycles, indicating the good stability of the catalyst. In addition, radical quenching studies were carried out to ascertain the dominating radical species and a proper mechanism was also proposed. PMID- 26002339 TI - Laccase immobilization over multi-walled carbon nanotubes: Kinetic, thermodynamic and stability studies. AB - The biocatalytic performance of immobilized enzyme systems depends mostly on the intrinsic properties of both biomolecule and support, immobilization technique and immobilization conditions. Multi-walled carbon nanotubes (MWCNTs) possess unique features for enzyme immobilization by adsorption. Enhanced catalytic activity and stability can be achieved by optimization of the immobilization conditions and by investigating the effect of operational parameters. Laccase was immobilized over MWCNTs by adsorption. The hybrid material was characterized by Fourier transformed infrared (FTIR) spectroscopy, scanning and transmission electron microscopy (SEM and TEM, respectively). The effect of different operational conditions (contact time, enzyme concentration and pH) on laccase immobilization was investigated. Optimized conditions were used for thermal stability, kinetic, and storage and operational stability studies. The optimal immobilization conditions for a laccase concentration of 3.75MUL/mL were a pH of 9.0 and a contact time of 30min (522 Ulac/gcarrier). A decrease in the thermal stability of laccase was observed after immobilization. Changes in DeltaS and DeltaH of deactivation were found for the immobilized enzyme. The Michaelis Menten kinetic constant was higher for laccase/MWCNT system than for free laccase. Immobilized laccase maintained (or even increased) its catalytic performance up to nine cycles of utilization and revealed long-term storage stability. PMID- 26002340 TI - Growth and properties of well-crystalline cerium oxide (CeO2) nanoflakes for environmental and sensor applications. AB - This paper reports the synthesis, characterizations and applications of well crystalline 2D-cerium oxide (CeO2) nanoflakes prepared by a rapid and facile solution combustion process. The nanoflakes were characterized in detail and applied as photocatalyst for dye-degradation and as an efficient electron mediator to fabricate high-sensitive hydroquinone chemical sensor. The detailed characterizations revealed that the prepared nanoflakes were well-crystalline and grown in very high-density. The synthesized CeO2 nanoflakes exhibited good photocatalytic activity toward the photocatalytic degradation of direct red-23 dye. Further, the synthesized nanoflakes were utilized as an efficient electron mediator to fabricate reproducible and highly sensitive hydroquinone chemical sensor. The fabricated chemical sensor exhibited a reproducible and reliable sensitivity of 2.04MUAmM(-1)cm(-2) and the detection limit of 2.914MUM with the correlation coefficient (R) of 0.98815 and good linearity from 78MUM to 12.5mM. The observed results confirmed that the CeO2 nanoflakes can efficiently be used for photocatalytic and sensing applications. PMID- 26002341 TI - Analysis of the leaching behavior of elements from coal combustion residues for better management. AB - In this study, fly ash, pond ash, bottom ash, slurry ash, raw water, pond water, and slurry samples were collected from Bokaro Thermal Power Plant, Bokaro, Jharkhand, India, and studied for the leachability of different elements by acid digestion and shake test at different liquid to solid (L/S) ratios. The raw water, pond water, slurry water, and leachates of acid digestion and shake tests were analyzed for the elements sodium (Na), potassium (K), calcium (Ca), iron (Fe), copper (Cu), cobalt (Co), manganese (Mn), cadmium (Cd), zinc (Zn), lead (Pb), nickel (Ni), and chromium (Cr). Shake test results confirmed that the water got saturated when the L/S ratio was equal to or above 10, indicating no further increase in concentration of elements at the L/S ratio of 10. Leaching behavior of Na from pond ash was not understood in the present study. In the study, the chemical composition showed that all the four types of ashes contain a small fraction of CaO (about 0.37 to 0.90 % by weight) and very high contents of SiO2 (about 55.14 to 58.34 % by weight) and Al2O3 (about 29.44 to 32.81 % by weight) that are the major composition of Portland cement. The study will help to understand the leachability potential of harmful elements present in fly ash, pond ash, bottom ash, and slurry ash under natural conditions and to take regulatory measures to protect the surface water, groundwater, and soil environment. PMID- 26002343 TI - A case of hypertensive urgency. AB - A 41-year-old male Nepalese soldier presented to the primary care medical centre with a 1-week history of fatigue and muscle aches following a trip to Nepal. His BP was 164/98 but was otherwise normal. Four days later he presented with new symptoms of sweating and palpitations and a BP of 200/127 whereupon he was admitted to hospital with the diagnosis of hypertensive crisis. Appropriate investigation and initial management were undertaken, and he was discharged after 12 h on antihypertensive treatment. This case highlights the risk of hypertensive crisis in both diagnosed and silent hypertensive disease, and the review highlights the presentations, initial investigation and different management of hypertensive crisis. PMID- 26002344 TI - Modern agriculture and food and nutrition insecurity: paradox in India. PMID- 26002342 TI - Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study. AB - BACKGROUND: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults. METHODS: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users. RESULTS: The majority of the 50 selected articles report results of cross-sectional studies (29; 58%), mainly conducted in the US (24; 48%) or Canada (15; 30%). Studies mostly focused on neighborhood environment associations with mobility (39; 78%), social participation (19; 38%), and occasionally both (11; 22%). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74%), but also 'Natural and human-made changes' (27; 54%) and 'Support and relationships' (21; 42%). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'. CONCLUSION: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults. PMID- 26002345 TI - The Hispanic health paradox across generations: the relationship of child generational status and citizenship with health outcomes. AB - OBJECTIVES: In examining the Hispanic health paradox, researchers rarely determine if the paradox persists across immigrant generations. This study examines immigrant respiratory health disparities among Hispanic children in terms of current asthma, bronchitis, and allergies using an expanded six-group immigrant cohort framework that includes citizenship and the fourth-plus generation. STUDY DESIGN: Cross-sectional primary survey data from 1568 caretakers of Hispanic schoolchildren in El Paso, Texas (USA), were utilized. METHODS: Data were analyzed using generalized linear models. RESULTS: Results indicate that a healthy immigrant advantage lasts until the 2.5 generation for bronchitis and allergies (P < 0.05), and until the third generation for asthma (P < 0.10). Citizenship was not an influence on the likelihood of a child having a respiratory health condition. CONCLUSIONS: Findings demonstrate the utility of the expanded six-group cohort framework for examining intergenerational patterns in health conditions among immigrant groups. PMID- 26002346 TI - The Teleost Intramandibular Joint: A mechanism That Allows Fish to Obtain Prey Unavailable to Suction Feeders. AB - Although the majority of teleost fishes possess a fused lower jaw (or mandible), some lineages have acquired a secondary joint in the lower jaw, termed the intramandibular joint (IMJ). The IMJ is a new module that formed within the already exceptionally complex teleost head, and disarticulation of two bony elements of the mandible potentially creates a "double-jointed" jaw. The apparent independent acquisition of this new functional module in divergent lineages raises a suite of questions. (1) How many teleostean lineages contain IMJ-bearing species? (2) Does the IMJ serve the same purpose in all teleosts? (3) Is the IMJ associated with altered feeding kinematics? (4) Do IMJ-bearing fishes experience trade-offs in other aspects of feeding performance? (5) Is the IMJ used to procure prey that are otherwise unavailable? The IMJ is probably under-reported, but has been documented in at least 10 lineages within the Teleostei. Across diverse IMJ-bearing lineages, this secondary joint in the lower jaw serves a variety of functions, including: generating dynamic out-levers that allow fish to apply additional force to a food item during jaw closing; allowing fish to "pick" individual prey items with pincer-like jaws; and facilitating contact with the substrate by altering the size and orientation of the gape. There are no consistent changes in feeding kinematics in IMJ-bearing species relative to their sister taxa; however, some IMJ-bearing taxa produce very slow movements during the capture of food, which may compromise their ability to move prey into the mouth via suction. Despite diversity in behavior, all IMJ-bearing lineages have the ability to remove foods that are physically attached to the substrate or to bite off pieces from sessile organisms. Because such prey cannot be drawn into the mouth by suction, the IMJ provides a new mechanism that enables fish to obtain food that otherwise would be unavailable. PMID- 26002347 TI - Evolution and Functional Morphology of the Proboscis in Kalyptorhynchia (Platyhelminthes). AB - Predatory flatworms belonging to the taxon Kalyptorhynchia are characterized by an anterior muscular proboscis that they use to seize prey. In many cases, the proboscis is armed with hooks, derived either from the extracellular matrix that surrounds the muscles or from intracellular deposits in the epithelium covering the proboscis. Glands associated with the proboscis reportedly are venomous; however, there are few direct tests of this hypothesis. This article reviews the structure and current knowledge of the function of the proboscis in the Kalyptorhynchia, points to areas in which the current understanding of phylogenetic relationships within this taxon is incongruent with our hypothesis of how the proboscis evolved, and addresses areas in need of further research, especially as regards functional morphology and biomechanics. PMID- 26002348 TI - Copepods' Response to Burgers' Vortex: Deconstructing Interactions of Copepods with Turbulence. AB - This study examined the behavioral response of two marine copepods, Acartia tonsa and Temora longicornis, to a Burgers' vortex intended to mimic the characteristics of a turbulent vortex that a copepod is likely to encounter in the coastal or near-surface zone. Behavioral assays of copepods were conducted for two vortices that correspond to turbulent conditions with mean dissipation rates of turbulence of 0.009 and 0.096 cm(2) s(-3) (denoted turbulence level 2 and level 3, respectively). In particular, the Burgers' vortex parameters (i.e., circulation and rate of axial strain rate) were specified to match a vortex corresponding to the median rate of dissipation due to viscosity for each target level of turbulence. Three-dimensional trajectories were quantified for analysis of swimming kinematics and response to hydrodynamic cues. Acartia tonsa did not significantly respond to the vortex corresponding to turbulence level 2. In contrast, A. tonsa significantly altered their swimming behavior in the turbulence-level-3 vortex, including increased relative speed of swimming, angle of alignment of the trajectory with the axis of the vortex, ratio of net-to-gross displacement, and acceleration during escape, along with decreased turn frequency (relative to stagnant control conditions). Further, the location of A. tonsa escapes was preferentially in the core of the stronger vortex, indicating that the hydrodynamic cue triggering the distinctive escape behavior was vorticity. In contrast, T. longicornis did not reveal a behavioral response to either the turbulence level 2 or the level 3 vortex. PMID- 26002349 TI - Molecular Evidence for Convergence and Parallelism in Evolution of Complex Brains of Cephalopod Molluscs: Insights from Visual Systems. AB - Coleoid cephalopods show remarkable evolutionary convergence with vertebrates in their neural organization, including (1) eyes and visual system with optic lobes, (2) specialized parts of the brain controlling learning and memory, such as vertical lobes, and (3) unique vasculature supporting such complexity of the central nervous system. We performed deep sequencing of eye transcriptomes of pygmy squids (Idiosepius paradoxus) and chambered nautiluses (Nautilus pompilius) to decipher the molecular basis of convergent evolution in cephalopods. RNA-seq was complemented by in situ hybridization to localize the expression of selected genes. We found three types of genomic innovations in the evolution of complex brains: (1) recruitment of novel genes into morphogenetic pathways, (2) recombination of various coding and regulatory regions of different genes, often called "evolutionary tinkering" or "co-option", and (3) duplication and divergence of genes. Massive recruitment of novel genes occurred in the evolution of the "camera" eye from nautilus' "pinhole" eye. We also showed that the type-2 co-option of transcription factors played important roles in the evolution of the lens and visual neurons. In summary, the cephalopod convergent morphological evolution of the camera eyes was driven by a mosaic of all types of gene recruitments. In addition, our analysis revealed unexpected variations of squids' opsins, retinochromes, and arrestins, providing more detailed information, valuable for further research on intra-ocular and extra-ocular photoreception of the cephalopods. PMID- 26002350 TI - The feasibility of implementing recovery, psychosocial and pharmacological interventions for psychosis: comparison study. AB - BACKGROUND: Clinical guidelines for the treatment of people experiencing psychosis have existed for over a decade, but implementation of recommended interventions is limited. Identifying influences on implementation may help to reduce this translational gap. The Structured Assessment of Feasibility (SAFE) measure is a standardised assessment of implementation blocks and enablers. The aim of this study was to characterise and compare the implementation blocks and enablers for recommended psychosis interventions. METHODS: SAFE was used to evaluate and compare three groups of interventions recommended in the 2014 NICE psychosis guideline: pharmacological (43 trials testing 5 interventions), psychosocial (65 trials testing 5 interventions), and recovery (19 trials testing 5 interventions). The 127 trial reports rated with SAFE were supplemented by published intervention manuals, research protocols, trial registrations and design papers. Differences in the number of blocks and enablers across the three interventions were tested statistically, and feasibility profiles were generated. RESULTS: There was no difference between psychosocial and recovery interventions in the number of blocks or enablers to implementation. Pharmacological interventions (a) had fewer blocks than both psychosocial interventions (chi (2)(3) = 133.77, p < 0.001) and recovery interventions (chi (2)(3) = 104.67, p < 0.001) and (b) did not differ in number of enablers from recovery interventions (chi (2)(3) = 0.74, p = 0.863) but had fewer enablers than psychosocial interventions (chi (2)(3) = 28.92, p < 0.001). Potential adverse events associated with the intervention tend to be a block for pharmacological interventions, whereas complexity of the intervention was the most consistent block for recovery and psychosocial interventions. CONCLUSIONS: Feasibility profiles show that pharmacological interventions are relatively easy to implement but can sometimes involve risks. Psychosocial and recovery interventions are relatively complex but tend to be more flexible and more often manualised. SAFE ratings can contribute to tackling the current implementation challenges in mental health services, by providing a reporting guideline structure for researchers to maximise the potential for implementation and by informing prioritisation decisions by clinical guideline developers and service managers. PMID- 26002351 TI - Management of brain arteriovenous malformations. AB - OPINION STATEMENT: Arteriovenous malformations (AVMs) pose a risk of morbidity and mortality throughout an affected patient's lifetime. Over the course of a patient's life, the risk of hemorrhage is approximately 1-4 % per year, and after an initial hemorrhage occurs, this risk may be higher. Other causes of morbidity include seizures, headaches, or progressive neurologic deficits. Once an AVM has been discovered, the utility of attempted obliteration or surgical resection compared to the risk of intervention should be entertained. The characteristics of the malformation as well as the patient's overall health status contribute to the decision to intervene on these lesions. For small lesions located in superficial areas without high-risk surgical characteristics (low-grade Spetzler Martin grades), it is reasonable to consider surgical resection. In lesions that pose high-risk of complications from surgical removal, intra-arterial embolization, radiosurgery, or a combination of the two may be reasonable treatment options. Some AVMs at traditional high surgical risk may be amenable to partial embolization, allowing initially high-risk lesions to become better candidates for surgical resection. In some patients, particularly those who are older or who have multiple medical comorbidities, the risk of intervention as compared to the annual hemorrhage risk may warrant conservative management as opposed to intervention. The overall treatment strategy must be based on patient and AVM characteristics and careful risk-benefit ratio analysis. PMID- 26002352 TI - Predictors of morbidity and mortality among patients with cervical spondylotic myelopathy treated surgically. AB - PURPOSE: The aim of this study is to report and quantify the associated factors for morbidity and mortality following surgical management of cervical spondylotic myelopathy (CSM). METHODS: The Nationwide Inpatient Sample (NIS) database was use to retrospectively review all patients over 25 years of age with a diagnosis of CSM who underwent anterior and/or posterior cervical fusion or laminoplasty between 2001 and 2010. The main outcome measures were total procedure-related complications and mortality. Multivariate regression analysis was used to identify demographic, comorbidity, and surgical parameters associated with increased morbidity and mortality risk [reported as: OR (95% CI)]. RESULTS: A total of 54,348 patients underwent surgical intervention for CSM with an overall morbidity rate of 9.83% and mortality rate of 0.43%. Comorbidities found to be associated with an increased complication rate included: pulmonary circulation disorders [6.92 (5.91-8.12)], pathologic weight loss [3.42 (3.00-3.90)], and electrolyte imbalance [2.82 (2.65-3.01)]. Comorbidities found to be associated with an increased mortality rate included: congestive heart failure [4.59 (3.62 5.82)], pulmonary circulation disorders [11.29 (8.24-15.47)], and pathologic weight loss [5.43 (4.07-7.26)]. Alternatively, hypertension [0.56 (0.46-0.67)] and obesity [0.36 (0.22-0.61)] were found to confer a decreased risk of mortality. Increased morbidity and mortality rates were also identified for fusions of 4-8 levels [morbidity: 1.55 (1.48-1.62), mortality: 1.80 (1.48-2.18)] and for age >65 years [morbidity: 1.65 (1.57-1.72), mortality: 2.74 (2.25-3.34)]. An increased morbidity rate was found for posterior-only [1.55 (1.47-1.63)] and combined anterior and posterior fusions [3.20 (2.98-3.43)], and an increased mortality rate was identified for posterior-only fusions [1.87 (1.40-2.49)]. Although revision fusions were associated with an increased morbidity rate [1.81 (1.64-2.00)], they were associated with a decreased rate of mortality [0.24 (0.10 0.59)]. CONCLUSION: The NIS database was used to provide national estimates of morbidity and mortality following surgical management of CSM in the United States. Several comorbidities, as well as demographic and surgical parameters, were identified as associated factors. PMID- 26002353 TI - A clivus plate fixation for reconstruction of ventral defect of the craniovertebral junction: a novel fixation device for craniovertebral instability. AB - PURPOSE: A fabricated mesh cage and/or posterior occipitocervical instrumentation alone has been used for reconstruction of ventral defect of the upper cervical spine. However, using a trimmed mesh cage it was hard to achieve optimal clival screw purchase and it migrated or broke. A specific instrumentation at the craniovertebral junction (CVJ) should incorporate the morphology of the CVJ and biomechanical validation. The purpose of the present study was to develop an innovative clivus plate integrated with the clinical anatomy of CVJ and to evaluate the stability of the clivus plate fixation (CPF), stand-alone or combined with a posterior occipitocervical fixation (POCF). METHODS: Dimensions relevant to the clivus plate were measured on 40 adult dry bones and CT images of 30 patients. The CPF was composed of the clivus plate and a titanium mesh cage. The clivus plate was anchored to the clivus, atlas and C3 body and connected to the mesh cage. Six fresh cadaveric head-neck specimens (Oc-C4) were used in this study (46 +/- 15 years old, 2 F/4 M). A continuous pure moment of +/-1.5 Nm was applied to the specimen in flexion, extension, lateral bending and axial rotation. The status of intact, CPF alone, and CPF plus POCF was tested on each specimen. The CPF was implanted to the specimen following resection of the C1 anterior arch, C2 vertebral body, C2-C3 disc and atlantoaxial ligaments. The POCF was applied with screws anchoring at the occiput, C1, C3 and C4. The range of motion (ROM) and neutral zone (NZ) from the occiput to C3 were calculated. RESULTS: The clivus plate was developed based on measurements of 40 adult dry bones and CT images of 30 patients. The plates were successfully applied to all specimens. No obvious loosening or mismatch was observed. The mean clival length and widest and narrowest diameter of the clivus were 26, 33 and 19 mm, respectively. The clivus screw length was 8 mm for the caudal holes and 10 mm for the cephalad hole. The CPF reduced ROMs to 3.9 degrees in flexion, 2.8 degrees in extension, 4.2 degrees in lateral bending and 6.8 degrees in axial rotation. The combined CPF and POCF constrained motion within 0.6 degrees in all directions and more than the CPF (P < 0.05). NZs after the CPF were 1.0 degrees in flexion-extension, 2.1 degrees in lateral bending and 2.2 degrees in axial rotation, respectively. NZs after the CPF plus POCF were within 0.2 degrees in all directions and less than the CPF (P < 0.05). CONCLUSION: This study demonstrated screw purchase in the adult clivus and developed an innovative clivus plate fixation for reconstructing an extensive ventral defect in the upper cervical spine. The clivus plate fixation combined a posterior instrumentation ensuring reliable upper cervical stability. PMID- 26002354 TI - Clinical and radiological outcomes of unilateral versus bilateral instrumentation in two-level degenerative lumbar diseases. AB - PURPOSE: To compare the clinical and radiological outcomes of unilateral versus bilateral instrumented in two-level degenerative lumbar diseases after minimally invasive transforaminal lumbar interbody fusion (MITLIF). METHODS: We conducted a prospective cohort study of 74 patients, who underwent unilateral or bilateral instrumented in two-level MITLIF for degenerative lumbar diseases from May 2010 to June 2012. There were 35 patients in group A undergoing unilateral pedicle screw fixation and 39 patients in group B undergoing bilateral pedicle screw fixation. Demographic data and clinical characteristics were compared between the two groups before surgery. Perioperative data, clinical and radiological outcomes of the two groups were also compared. RESULTS: The mean follow-up period was 32.1 +/- 7.5 months for group A and 31.7 +/- 8.0 months for group B (p > 0.05). Group A required a significantly shorter operating time, lower implant costs and less intraoperative blood loss and X-ray exposure time than group B (p < 0.01). However, no statistical differences were identified in the amount of transfusion and postoperative hospital stay between the two groups (p > 0.05). Clinical outcomes assessed by visual analog scores for back and leg pain (VAS-BP and VAS LP, respectively) and Oswestry Disability Index (ODI) improved significantly in both groups after surgery, and no significant differences existed between the two groups at each postoperative follow-up (p > 0.05). There were significant differences within groups for Cobb angles of the whole lumbar [Cobb (a)] and the whole lumbar lordosis at each time point before and after surgery (p < 0.05). No significant differences existed between groups in relation to Cobb (a), Cobb angle of the fused segments, lumbar lordosis and the segmental lordosis at any time point before and after surgery (p > 0.05). There were no significant differences in fusion rate and total complication rate between the two groups (p > 0.05). CONCLUSIONS: Unilateral instrumentation after two-level MITLIF provided similar clinical and radiological outcomes to bilateral fixation in two-level degenerative lumbar diseases. Compared with bilateral fixation, unilateral fixation shortens operation time, reduces intra-operative blood loss and X-ray exposure time, and saves medical expenses with similar postoperative hospital stay and complication rate. PMID- 26002355 TI - Depression is associated with increased incidence of osteoporotic thoracolumbar fracture in postmenopausal women: a prospective study. AB - PROPOSE: To determine whether depression in postmenopausal women with osteoporosis is associated with an increased risk of thoracolumbar fragility fracture. METHODS: Postmenopausal women with osteoporosis and without prior vertebral fracture history who were seen at our institution from January 2006 to January 2010 (n = 1397) were divided into depression group (n = 494) and depression-free group (n = 903). After at least 4 years the incidence of thoracolumbar osteoporotic vertebral fracture was compared between the groups. For those who developed vertebral fracture, quality of life over the subsequent 2 months and fracture pain in the subsequent 2 weeks were compared. Depression was assessed with the 21-item Beck Depression Inventory, pain intensity with the visual analogue scale and quality of life with the Medical Outcomes Study 36-item Short-Form Survey. RESULTS: The incidence of thoracolumbar fractures among women with continuous depression was higher than the group without depression (35.43 vs. 25.14 %, respectively; (P < 0.05). Osteoporotic thoracolumbar fractures were associated with significantly lower quality of life scores in women with depression than in those without depression (P < 0.05). Fracture pain was experienced by a higher percentage of patients with continuous depression than by those without depression (44.00 vs. 27.31 %; P < 0.05). CONCLUSION: Depression is associated with a higher risk of thoracolumbar fracture, with more fracture pain and with lower quality of life in the 2 months following fracture. PMID- 26002356 TI - Entry zone of iliac screw fixation to maintain proper entry width and screw length. AB - PURPOSE: To evaluate the entry zone of iliac screw fixation to maintain proper entry width and screw length. METHODS: Computed tomography images of pelvic bones from 90 human cadavers were reconstructed into 3-dimensional models. In each model, a sectional image crossing the posterior superior iliac spine (PSIS) and anterior inferior iliac spine (AIIS) and consecutive sectional images up to 20 mm superiorly and inferiorly from the PSIS with 1-mm intervals aiming the AIIS were obtained. One virtual iliac screw with 10-mm diameter was introduced onto the PSIS at the middle and at the lateral and medial 1/4 points on the prominence of the posterior iliac spine. The entry width of the bony prominence and the corresponding maximal screw length available were evaluated for each entry point. RESULTS: The entry width was smallest on the inferior 20 mm (4.7 +/- 3.0 mm) and gradually increased up to the superior 10 mm (19.1 +/- 3.9 mm) sectional images. The maximal screw length was smallest on the superior 20 mm (76.7 +/- 39.7 mm) and gradually increased down to the inferior 10 mm (112.3 +/- 15.1 mm) sectional images. The maximal screw lengths were significantly greatest at the most medial point and smallest at the most lateral point on the superior 20- and 10-mm sectional images and at the PSIS. CONCLUSIONS: The iliac screw fixation entry zone to maintain proper screw length and entry width is outlined from 20 mm superiorly to 10 mm inferiorly from the PSIS and is located more medially from the prominence of the posterior iliac spine. PMID- 26002357 TI - Impact of fast-track discharge from cardiothoracic intensive care on family satisfaction. AB - BACKGROUND: Dissatisfaction with the intensive care unit may threaten medical care. Clarifying treatment preferences can be useful in these settings, where physician direction may influence decision making and therefore medical treatment. This study aimed to evaluate whether fast-track discharge from intensive care units affects the satisfaction of family members. METHODS: We used a single-center non-randomized trial, with all eligible family members involved. To evaluate family satisfaction, we used the Society of Critical Care Family Needs Assessment questionnaire (SCCMFNAQ). We hypothesized that those discharged within 24 h of intensive care unit admission and their families would have higher levels of satisfaction. Patients were scored using the therapeutic interventions scoring system (TISS) and additive EuroSCORE. RESULTS: Two-hundred fifty-five family members were enrolled. The mean patient age was 53 years, and 92 % were male. The median satisfaction level among family members was 17.9 (range 14-31). Patients were divided into two groups, one receiving fast-track discharge (116 patients), and one whose members stayed longer (139 patients). The overall satisfaction was affected significantly by quality of the delivered care and dissatisfaction increased by lack of comfort in hospital settings, including the waiting room. No significant differences were seen between the two groups for overall satisfaction (p = 0.546) and individual components of the questionnaire. Higher satisfaction was linked to higher levels of education among family members (p = 0.045) and information being relayed by a senior physician p = 0.03 (two tailed test). CONCLUSIONS: Fast-track discharge from intensive care did not influence family satisfaction as hypothesized. Satisfaction relied on family members' level of education and the level of seniority of the physician relaying information. PMID- 26002358 TI - Anionic-nonionic mixed-surfactant-enhanced remediation of PAH-contaminated soil. AB - Soil washing is an efficient remediation technique that enhances the solubility of polycyclic aromatic hydrocarbons (PAHs) in specific surfactant to remediate PAH-contaminated soil. This study evaluated the remediation efficiency of PAH contaminated soil from a coke oven plant by comparing sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS), and Triton X-100 (TX100), as well as TX100-SDS and TX100-SDBS mixed surfactants. Results showed that SDS-TX100 and SDBS-TX100 had synergistic effects on PAH solubilization when surfactant concentrations were above their critical micelle concentration. Competitive effects of the three solubilized PAHs (phenanthrene with three rings, fluoranthene with four rings, and benzo[a]pyrene with five rings) with a particular anionic-nonionic mixed surfactant were investigated. PAHs with more rings were found to slightly decrease the solubility in surfactant solution of PAHs with fewer rings, whereas PAHs with fewer rings promoted the solubility in surfactant solution of PAHs with more rings. The removal ratios of PAHs during the remediation of actual PAH-contaminated soil were best improved by the anionic nonionic mixed surfactant TX100-SDS (9:1), followed by TX100-SDS (8:2), TX100-SDS (7:3), TX100-SDBS (7:3), TX100, SDBS, and SDS. Therefore, anionic-nonionic mixed surfactants can help improve the remediation performance of PAHs based on their application in tests of cleaning actual PAH-contaminated soil from a coke oven plant. PMID- 26002359 TI - Spatial distribution and toxicity assessment of heavy metals in sediments of Liaohe River, northeast China. AB - Twenty-four surface sediment samples were collected from Liaohe River in June 2014 for the analysis of total concentrations of Cu, Pb, Zn, Cd, Ni, Fe, and Mn. The spatial distribution of heavy metals in Liaohe River was site specific, with Hun River as the most polluted river mainly affected by industrial and human activities. The contents of acid-volatile sulfide (AVS) and simultaneously extracted metals (SEMs) in Liaohe River varied significantly, ranging from 0.03 to 19.4 MUmol/g and 0.14 to 10.8 MUmol/g, respectively. Sulfate-reducing bacteria (SRB) community size, organic matter and sulfate availability, and sediment redox status may be the main factors affecting the AVS distribution. Among all the acid extracted metals, Zn was dominant in all samples, whereas much more toxic Cd contributed less than 1.0 % to the total SEMs. Sediment quality guidelines (SQGs) and AVS-SEM models were used to predict the sediment toxicity. Results revealed that only a small portion of sites exhibited potential metal toxicity to aquatic biota, while adverse effects should rarely occur in majority of sites. Comparison of the two assessment methods showed inconsistent results, indicating that each method had its own limitations. The combination of different methods will be more convincing as to the sediment quality assessment. PMID- 26002360 TI - Influence of soil properties on the bioaccumulation and effects of arsenic in the earthworm Eisenia andrei. AB - This study aimed at assessing the influence of soil properties on the uptake and toxicity effects of arsenic in the earthworm Eisenia andrei exposed for 4 weeks to seven natural soils spiked with different arsenic concentrations. Water soluble soil concentrations (AsW) and internal As concentrations in the earthworms (AsE) were greatly different between soils. These two variables were highly correlated and were key factors in earthworm toxicity response. AsW was explained by some soil properties, such as the pH, calcium carbonate content, ionic strength, texture or oxide forms. Toxicity showed a clear variation between soils, in some cases without achieving 50 % adverse effect at the highest As concentration added (600 mg kg(-1)). Nevertheless, soil properties did not show, in general, a high relation with studied toxicity endpoints, although the high correlation with AsW could greatly reduce indirectly As bioavailability and toxicity risk for earthworms. Obtained results suggest that soil properties should be part of the criteria to establishing thresholds for contaminated soils because they will be key in controlling As availability and thus result in different degrees of toxicity. PMID- 26002361 TI - Aquifer community structure in dependence of lithostratigraphy in groundwater reservoirs. AB - Groundwater microbiology with respect to different host rocks offers new possibilities to describe and map the habitat harboring approximately half of Earths' biomass. The Thuringian Basin (Germany) contains formations of the Permian (Zechstein) and Triassic (Muschelkalk and Buntsandstein) with outcrops and deeper regions at the border and central part. Hydro(geo)chemistry and bacterial community structure of 11 natural springs and 20 groundwater wells were analyzed to define typical patterns for each formation. Widespread were Gammaproteobacteria, while Bacilli were present in all wells. Halotolerant and halophilic taxa were present in Zechstein. The occurrence of specific taxa allowed a clear separation of communities from all three lithostratigraphic groups. These specific taxa could be used to follow fluid movement, e.g., from the underlying Zechstein or from nearby saline reservoirs into Buntsandstein aquifers. Thus, we developed a new tool to identify the lithostratigraphic origin of sources in mixed waters. This was verified with entry of surface water, as species not present in the underground Zechstein environments were isolated from the water samples. Thus, our tool shows a higher resolution as compared to hydrochemistry, which is prone to undergo fast dilution if water mixes with other aquifers. Furthermore, the bacteria well adapted to their respective environment showed geographic clustering allowing to differentiate regional aquifers. PMID- 26002362 TI - Impact of a phosphate fertilizer plant on the contamination of marine biota by heavy elements. AB - Due to their toxicity, persistence, and bioaccumulation, metals are important marine environment pollutants, especially in low renewal rate water such as the Mediterranean Sea, receiving a lot of untreated industrial waste. The impact of a phosphate fertilizer plant on the marine biota metal contamination was studied. Several types of organisms: crabs, mussels, patella and fish were collected from two areas of the Lebanese coast, one subjected to the impact of the plant and another away from it; samples were analyzed for Zn, U, Cr, V, Mn, Ni, Co, Cu, As, Cd and Pb by ICP-MS. Higher accumulation was in crabs, patella, and mussels. Fish accumulated principally Zn, Cu, and Cd; a difference was observed between species and tissues. Cytosol metal fractionation using size-exclusion LC-ICP-MS showed principally Pb, As, Co, and Mn in the low molecular weight fraction (<1.8 Da); Cd, Zn, and Cu in the metallothionein fraction (1.8--18 k Da), and Ni in high molecular weight fraction (>20 kDa). PMID- 26002363 TI - Effect of Zn stresses on physiology, growth, Zn accumulation, and chlorophyll of Phyllostachys pubescen s. AB - The effects of Zinc (Zn) on lipid peroxidation, antioxidative enzymes, growth, Zn accumulation, and leaf chlorophyll of Phyllostachys pubescens (Pradelle) Mazel ex J.Houz. were investigated in two greenhouse experiments. Hydroponics experiment with Zn application of 0, 20, 100, and 400 MUM revealed that lower concentration of Zn in solution led to increased malondialdehyde (MDA) and proline contents but inhibited SOD activity in all treatments. P. pubescens had showed strong ability to accumulate Zn in stems and reached maximum level at 100 MUM with 7.91-fold increase compared with control. In pot experiment, treatment with Zn ranged from 0, 200, 400, 800, 1,600, to 3,200 mg kg(-1). Application of 800 mg kg(-1) revealed 116, 24.6, and 28.3 times increase in Zn concentration of roots, stems, and leaves, respectively. Growth and chlorophyll contents of plants in pots were better promoted at 400 mg kg(-1) Zn, with 60.5 and 30.9 % enhanced roots and shoot compared with control. The bioaccumulation factor (BAF) was in the sequence of stem > roots > leaves. The translocation factor (TF) of stem was higher than leaves. PMID- 26002364 TI - Route of electrochemical oxidation of the antibiotic sulfamethoxazole on a mixed oxide anode. AB - The appearance of pharmaceutical compounds and their bioactive transformation products in aquatic environments is becoming an issue of increasing concern. In this study, the electrochemical oxidation of the widely used antibiotic sulfamethoxazole (SMX) was investigated using a commercial mixed oxide anode (Ti/Ru0.3Ti0.7O2) and a single compartment filter press-type flow reactor. The kinetics of SMX degradation was determined as a function of electrolyte composition, applied current density, and initial pH. Almost complete (98 %) degradation of SMX could be achieved within 30 min of electrolysis in 0.1 mol L( 1) NaCl solution at pH 3 with applied current densities >=20 mA cm(-2). Nine major intermediates of the reaction were identified by LC-ESI-Q-TOF-MS (e.g., C6H9NO2S (m/z = 179), C6H4NOCl (m/z = 141), and C6H6O2 (m/z = 110)). The degradation followed various routes involving cleavage of the oxazole and benzene rings by hydroxyl and/or chlorine radicals, processes that could occur before or after rupture of the N-S bond, followed by oxidation of the remaining moieties. Analysis of the total organic carbon content revealed that the antibiotic was partially mineralized under the conditions employed and some inorganic ions, including NO3 (-) and SO4 (2-), could be identified. The results presented herein demonstrate the efficacy of the electrochemical process using a Ti/Ru0.3Ti0.7O2 anode for the remediation of wastewater containing the antibiotic SMX. PMID- 26002365 TI - Ceramics manufacturing contributes to ambient silica air pollution and burden of lung disease. AB - Inhalation of silica (SiO2) in occupational exposures can cause pulmonary fibrosis (silicosis), lung function deficits, pulmonary inflammation, and lung cancer. Current risk assessment models, however, cannot fully explain the magnitude of silica-induced pulmonary disease risk. The purpose of this study was to assess human health risk exposed to airborne silica dust in Taiwan ceramics manufacturing. We conducted measurements to characterize workplace-specific airborne silica dust in tile and commodity ceramic factories and used physiologically based alveolar exposure model to estimate exposure dose. We constructed dose-response models for describing relationships between exposure dose and inflammatory responses, by which health risks among workers can be assessed. We found that silica contents were 0.22-33.04 % with mean concentration ranges of 0.11-5.48 and 0.46-1763.30 MUg m(-3), respectively, in commodity and tile ceramic factories. We showed that granulation workers in tile ceramic factory had the highest total SiO2 lung burden (~1000 mg) with cumulative SiO2 lung burden of ~4 * 10(4) mg-year. The threshold estimates with an effect on human lung inflammation and fibrosis are 407.31 +/- 277.10 (mean +/- sd) and 505.91 +/- 231.69 mg, respectively. For granulation workers, long-term exposure to airborne silica dust for 30-45 years was likely to pose severe adverse health risks of inflammation and fibrosis. We provide integrated assessment algorithms required to implement the analyses and maintain resulting concentration of silica dust at safety threshold level in the hope that they will stimulate further analyses and interpretation. We suggest that decision-makers take action to implement platforms for effective risk management to prevent the related long term occupational disease in ceramics manufacturing. PMID- 26002366 TI - Influence of environmental contamination on pregnancy outcomes. AB - This study aims to compare pregnancy outcomes in four contaminated areas to those observed in a non-contaminated area of similar socioeconomic status. A cross sectional study was carried out. A structured and pre-tested questionnaire was administered to population-based samples of 788-920 families in each of the five studied areas. The exposure assessment used was an ecological measure. Using logistic regression, odds of several pregnancies outcomes (pregnancy occurrence, miscarriage, stillbirth, prematurity, low birth weight, congenital malformation, and multiple births) were estimated after adjustment for potential confounders such as socioeconomic, demographic, and substance abuse factors. We adopted a statistical significance level of 5 %. In three of the four exposed areas, pregnancy occurrence was reduced in comparison to the control area (Area 2, odds ratio (OR) = 0.68, 95 % CI = 0.54-0.86; Area 3, OR = 0.76, 95 % CI = 0.60-0.97; Area 4, OR = 0.71, 95 % CI = 0.56-0.90). Also, a significantly increased odds of miscarriage for living in Area 3 (OR = 1.83, 95 % CI = 1.07-3.12) was found. The other pregnancy outcomes were not significantly elevated in the exposed areas. In conclusion, this study shows evidence of reduced pregnancy occurrence and increased miscarriage occurrence in some of the contaminated areas, compared to the control area. PMID- 26002367 TI - Potential impacts of climate change on water quality in a shallow reservoir in China. AB - To study the potential effects of climate change on water quality in a shallow reservoir in China, the field data analysis method is applied to data collected over a given monitoring period. Nine water quality parameters (water temperature, ammonia nitrogen, nitrate nitrogen, nitrite nitrogen, total nitrogen, total phosphorus, chemical oxygen demand, biochemical oxygen demand and dissolved oxygen) and three climate indicators for 20 years (1992-2011) are considered. The annual trends exhibit significant trends with respect to certain water quality and climate parameters. Five parameters exhibit significant seasonality differences in the monthly means between the two decades (1992-2001 and 2002 2011) of the monitoring period. Non-parametric regression of the statistical analyses is performed to explore potential key climate drivers of water quality in the reservoir. The results indicate that seasonal changes in temperature and rainfall may have positive impacts on water quality. However, an extremely cold spring and high wind speed are likely to affect the self-stabilising equilibrium states of the reservoir, which requires attention in the future. The results suggest that land use changes have important impact on nitrogen load. This study provides useful information regarding the potential effects of climate change on water quality in developing countries. PMID- 26002368 TI - Runoff characteristics and non-point source pollution analysis in the Taihu Lake Basin: a case study of the town of Xueyan, China. AB - Non-point source pollution is a significant environmental issue in small watersheds in China. To study the effects of rainfall on pollutants transported by runoff, rainfall was monitored in Xueyan town in the Taihu Lake Basin (TLB) for over 12 consecutive months. The concentrations of different forms of nitrogen (N) and phosphorus (P), and chemical oxygen demand, were monitored in runoff and river water across different land use types. The results indicated that pollutant loads were highly variable. Most N losses due to runoff were found around industrial areas (printing factories), while residential areas exhibited the lowest nitrogen losses through runoff. Nitrate nitrogen (NO3-N) and ammonia nitrogen (NH4-N) were the dominant forms of soluble N around printing factories and hotels, respectively. The levels of N in river water were stable prior to the generation of runoff from a rainfall event, after which they were positively correlated to rainfall intensity. In addition, three sites with different areas were selected for a case study to analyze trends in pollutant levels during two rainfall events, using the AnnAGNPS model. The modeled results generally agreed with the observed data, which suggests that AnnAGNPS can be used successfully for modeling runoff nutrient loading in this region. The conclusions of this study provide important information on controlling non-point source pollution in TLB. PMID- 26002369 TI - Electrophysiological and behavioral responses of Diaphania glauculalis males to female sex pheromone. AB - The aim of this study is to identify the pheromone active component of female moths, Diaphania glauculalis, an important pest of Anthocephalus chinensis in China. The sex pheromone was extracted from sex pheromone gland extracts of virgin female moth of D. glauculalis using n-hexane, and the pheromone gland extracts of females were analyzed using coupled gas chromatography electroantennogram detection (GC-EAD) and gas chromatography-mass spectrometry (GC-MS). The sex pheromone active components were based on the comparison the retention time and mass spectrum, with suitable synthetic compounds. (E)-11 hexadecenal (E11-16:Ald) and (E,E)-10,12-hexadecadienal (E10E12-16:Ald) were identified as the major sex pheromone components in the females. Their biological activities were evaluated in a series of electroantennogram (EAG) experiments and four-arm olfactometer assays using synthetic compounds. D. glauculalis males could be attracted by any single component, but a mixture of the E11-16:Ald and E10E12-16:Ald in a ratio of 5:5 elicited a substantial response, demonstrating that the binary blend is essential in male attraction. We therefore conclude that the aldehyde compounds, a mixture of E11-16:Ald and E10E12-16:Ald, comprise the sex pheromone components of D. glauculalis, which might be applied for insect field trapping. PMID- 26002370 TI - Ecofriendly hot water treatment reduces postharvest decay and elicits defense response in kiwifruit. AB - Hot water treatment (HWT) of fruit is an effective approach for managing postharvest decay of fruits and vegetables. In the present study, the effects of HWT (45 degrees C for 10 min) on the growth of Botrytis cinerea and Penicillium expansum in vitro, and gray (B. cinerea) and blue mold (P. expansum) development in kiwifruit were investigated. HWT effectively inhibited spore germination and germ tube elongation of B. cinerea and P. expansum. Reactive oxygen species accumulation and protein impairment in the fungi triggered by HWT contributed to the inhibitory effect. Results of in vivo studies showed that HWT controlled gray and blue mold in kiwifruit stored at 4 and 25 degrees C. HWT induced a significant increase in the activity of antioxidant enzymes, including catalase and peroxidase, and the level of total phenolic compounds in kiwifruit. These findings indicate that the inhibition of postharvest decay in kiwifruit by HWT is associated with the inhibition of spore germination of both fungal pathogens and the elicitation of defense response in the kiwifruit host. Moreover, HWT used in this study did not impair fruit quality. HWT appears to represent a potential non chemical alternative for the effective management of postharvest decay of kiwifruit. PMID- 26002371 TI - Fipronil should not be categorized as a "systemic insecticide": a reply to Gibbons et al. (2015). PMID- 26002372 TI - Photodegradation of neonicotinoid insecticides in water by semiconductor oxides. AB - The photocatalytic degradation of three neonicotinoid insecticides (NIs), thiamethoxam (TH), imidacloprid (IM) and acetamiprid (AC), in pure water has been studied using zinc oxide (ZnO) and titanium dioxide (TiO2) as photocatalysts under natural sunlight and artificial light irradiation. Photocatalytic experiments showed that the addition of these chalcogenide oxides in tandem with the electron acceptor (Na2S2O8) strongly enhances the degradation rate of these compounds in comparison with those carried out with ZnO and TiO2 alone and photolytic tests. Comparison of catalysts showed that ZnO is the most efficient for the removal of such insecticides in optimal conditions and at constant volumetric rate of photon absorption. Thus, the complete disappearance of all the studied compounds was achieved after 10 and 30 min of artificial light irradiation, in the ZnO/Na2S2O8 and TiO2/Na2S2O8 systems, respectively. The highest degradation rate was noticed for IM, while the lowest rate constant was obtained for AC under artificial light irradiation. In addition, solar irradiation was more efficient compared to artificial light for the removal of these insecticides from water. The main photocatalytic intermediates detected during the degradation of NIs were identified. PMID- 26002373 TI - Chemical characterization and spatial distribution of PAHs and heavy hydrocarbons in rural sites of Campania Region, South Italy. AB - In this paper, the behaviour and distribution patterns of heavy hydrocarbons and several polycyclic aromatic hydrocarbon (PAH) priority pollutants, as listed by the US Environmental Protection Agency, were evaluated in 891 soil samples. The samples were collected in three expected polluted rural sites in Campania (southern Italy) as part of the LIFE11 ECOREMED project, funded by the European Commission, to test innovative agriculture-based soil restoration techniques. These sites have been selected because they have been used for the temporary storage of urban and building waste (Teverola), subject to illicit dumping of unknown material (Trentola-Ducenta), or suspected to be polluted by metals due to agricultural practices (Giugliano). Chemical analysis of soil samples allowed the baseline pollution levels to be determined prior to any intervention. It was found that these areas can be considered contaminated for residential use, in accordance with Italian environmental law (Law Decree 152/2006). Statistical analysis applied to the data proved that average mean concentrations of heavy hydrocarbons could be as high as 140 mg/kg of dry soil with peaks of 700 mg/kg of dry soil, for the Trentola-Ducenta site; the median concentration of analytical results for hydrocarbon (HC) concentration for the Trentola-Ducenta and Giugliano sites was 63 and 73.4 mg/kg dry soil, respectively; for Teverola, the median level was 35 mg/kg dry soil. Some PAHs (usually benzo(a)pyrene) also exceeded the maximum allowed level in all sites. From the principal component analysis applied to PAH concentrations, it emerged that pollutants can be supposed to derive from a single source for the three sites. Diagnostic ratios calculated to determine possible PAH sources suggest petroleum combustion or disposal practice. Our sampling protocol also showed large dishomogeneity in soil pollutant spatial distribution, even at a scale as small as 3.3 m, indicating that variability could emerge at very short spatial scales. PMID- 26002375 TI - Des-acyl ghrelin attenuates pilocarpine-induced limbic seizures via the ghrelin receptor and not the orexin pathway. AB - Des-acyl ghrelin, widely accepted to work independently of the ghrelin receptor, is increasingly being implicated in a number of biological functions. The involvement of des-acyl ghrelin in epilepsy has only been recently reported. In this study, apart from unravelling the effect of des-acyl ghrelin on seizure thresholds and seizure severity in two models of pilocarpine-induced seizures, we mainly attempted to unravel its anticonvulsant mechanism of action. Since it was found that des-acyl ghrelin administration affected food intake via the orexin pathway, we first determined whether this pathway was responsible for des-acyl ghrelin's seizure-attenuating properties using the dual orexin receptor antagonist almorexant. We noted that, while des-acyl ghrelin showed dose dependent anticonvulsant effects against focal pilocarpine-evoked seizures in rats, almorexant did not affect seizure severity and did not reverse des-acyl ghrelin's anticonvulsant effect. Subsequently, to investigate whether the ghrelin receptor was implicated in des-acyl ghrelin's anticonvulsant properties, we tested this peptide in ghrelin receptor deficient mice and wild type mice, all infused with pilocarpine intravenously. Unexpectedly, we found that des-acyl ghrelin significantly elevated seizure thresholds in C57Bl/6 and wild type mice but not in ghrelin receptor knock-out mice. Taken together, our results indicate the involvement of the ghrelin receptor in the anticonvulsant effects of des-acyl ghrelin on pilocarpine-induced seizures. We also show for the first time that dual antagonism of hippocampal orexin receptors does not affect seizure severity. PMID- 26002374 TI - Turkey Handwashing Survey: suggestion for taking the ecological model into better consideration. AB - OBJECTIVES: This study is aimed to find out the handwashing habits and their relations to the socio-economic variables. METHODS: The sampling is determined regarding the address-based population registration system of the country. The multi-staged stratified cluster sampling method was used. It is conducted by a face to face questionnaire with 6854 persons. 22 questions are asked whether they are washing their hands or not related to different situations, the results are graded and the "Handwashing Habits Score" (HHS) is obtained. The reasons for not handwashing were evaluated by categorizing as individual, environmental and combined reasons. RESULTS: The HHS is increasing in the older age groups (beta = 0.148, p < 0.001), females (beta = 0.306, p < 0.001), citizens of urban settlement (beta = 0.061, p < 0.001), higher education levels (beta = 0.191, p < 0.001). The reasons for not handwashing were found as 53.3 % individual, 39.2 % environmental, 7.5 % combined. The frequency of mentioning not washing hands because of the environmental reasons is getting higher in the older age groups, in the urban side, and in the higher education level (p < 0.001). CONCLUSIONS: The handwashing habits are shaped by the determinant networks which form a complex structure by intertwining individual, socio-economic and environmental factors in different sub-groups with various weights. This result might contribute to the efforts of conceptualizing the health behaviors with ecological model. PMID- 26002376 TI - Investigating dimensionality and measurement bias of DSM-5 alcohol use disorder in a representative sample of the largest metropolitan area in South America. AB - BACKGROUND: Given the recent launch of a new diagnostic classification (DSM-5) for alcohol use disorders (AUD), we aimed to investigate its dimensionality and possible measurement bias in a non-U.S. METHODS: The current analyses were restricted to 948 subjects who endorsed drinking at least one drink per week in the past year from a sample of 5037 individuals. Data came from Sao Paulo Megacity Project (which is part of World Mental Health Surveys) collected between 2005 and 2007. First, exploratory factor analysis (EFA) was carried out to test for the best dimensional structure for DSM-5-AUD criteria. Then, item response theory (IRT) was used to investigate the severity and discrimination properties of each criterion of DSM-5-AUD. Finally, differential criterion functioning (DCF) were investigated by socio-demographics (income, gender, age, employment status, marital status and education). All analyses were performed in Mplus software taking into account complex survey design features. RESULTS: The best EFA model was a one-dimensional model. IRT results showed that the criteria "Time Spent" and "Given Up" have the highest discrimination and severity properties, while the criterion "Larger/Longer" had the lowest value of severity, but an average value of discrimination. Only female gender had DCF both at criterion- and factor level, rendering measurement bias. CONCLUSION: This study reinforces the existence of a DSM-5-AUD continuum in the largest metropolitan area of South America, including subgroups that had previously higher rates of alcohol use (lower educational/income levels). Lower DSM-5-AUD scores were found in women. PMID- 26002377 TI - Further validation of a marijuana purchase task. AB - BACKGROUND: A valid measure of the relative economic value of marijuana is needed to characterize individual variation in the drug's reinforcing value and inform evolving national marijuana policy. Relative drug value (demand) can be measured via purchase tasks, and demand for alcohol and cigarettes has been associated with craving, dependence, and treatment response. This study examined marijuana demand with a marijuana purchase task (MPT). METHODS: The 22-item self-report MPT was administered to 99 frequent marijuana users (37.4% female, 71.5% marijuana use days, 15.2% cannabis dependent). RESULTS: Pearson correlations indicated a negative relationship between intensity (free consumption) and age of initiation of regular use (r=-0.34, p<0.001), and positive associations with use days (r=0.26, p<0.05) and subjective craving (r=0.43, p<0.001). Omax (maximum expenditure) was positively associated with use days (r=0.29, p<0.01) and subjective craving (r=0.27, p<0.01). Income was not associated with demand. An exponential demand model provided an excellent fit to the data across users (R(2)=0.99). Group comparisons based on presence or absence of DSM-IV cannabis dependence symptoms revealed that users with any dependence symptoms showed significantly higher intensity of demand and more inelastic demand, reflecting greater insensitivity to price increases. CONCLUSIONS: These results provide support for construct validity of the MPT, indicating its sensitivity to marijuana demand as a function of increasing cost, and its ability to differentiate between users with and without dependence symptoms. The MPT may denote abuse liability and is a valuable addition to the behavioral economic literature. Potential applications to marijuana pricing and tax policy are discussed. PMID- 26002378 TI - [Aging and age-related changes of the vitreous body]. AB - BACKGROUND AND PURPOSE: The vitreous body is the largest component of the eye. It is a colorless, gelatinous, highly hydrated matrix that fills the posterior segment of the eye between the lens, the ciliary body and the retina. Changes in vitreal structure that occur with aging, such as vitreous liquefaction and fiber aggregation (vitreous syneresis) are important in the pathogenesis of many vitreoretinal diseases. During senescence, the vitreous volume is reduced, the vitreous body collapses and the vitreal fibers are continuously thickened, become more tortuous and surrounded by liquefied vitreous. This sequence of age-related changes results from a progressive reorganization of the hyaluronic acid and collagen molecular networks. RESULTS AND DISCUSSION: Although the vitreous body may at first glance appear to be a redundant tissue than can be removed and almost normal ocular function will still be maintained, the vitreous body and the vitreoretinal interface have a crucial influence on the physiology and pathophysiology of the eye. Age-related liquefaction and vitrous syneresis play an essential pathogenetic role in the development of posterior vitreous detachment, retinal breaks and retinal detachment. PMID- 26002379 TI - [Upper eyelid swelling]. PMID- 26002381 TI - Correction. PMID- 26002380 TI - Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. AB - Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease. PMID- 26002382 TI - Testing for alcohol sensitivity of tremor amplitude in a large cohort with essential tremor. AB - BACKGROUND: Improvement of essential tremor (ET) amplitude after alcohol ingestion is usually based on patient reports but a quantitative test for large numbers of patients is lacking and the percentage of ET patients with a detectable alcohol effect is therefore unknown. METHODS: A validated and published alcohol home test was used in 104 ET patients. The Archimedes spiral was drawn before alcohol ingestion and at 4 time points after alcohol consumption and rated on a 10-point rating scale according to Bain and Findley. A second identical test without alcohol ingestion was performed by the same patients and evaluated by the same two raters to analyze the total variability of the spiral ratings. RESULTS: Alcohol reduces tremor in ET patients as a group and a rebound effect with an increase in tremor intensity was found the next morning. Sex, family history of ET, diagnosis (definite vs. probable) and medical history of alcohol responsiveness do not predict the alcohol response. The minimal detectable difference in the spiral score was 2 due to spontaneous tremor fluctuations and inter-rater differences. The test demonstrated alcohol sensitivity of the tremor in 46% of the patients. Responsivity to alcohol could only be seen in patients with spiral scores above 3. CONCLUSIONS: Alcohol sensitivity is a feature of ET in at least 46% of the patients. We could not find predictors for alcohol sensitivity. The minimal detectable change is 2 scores and alcohol responsivity was only detected in patients with baseline Archimedes spiral rating of >=3. PMID- 26002383 TI - Historical perspectives on the implantable cardioverter-defibrillator and prevention of sudden death in hypertrophic cardiomyopathy. AB - The implantable cardioverter-defibrillator (ICD) was not originally envisioned as a treatment to prevent sudden death (SD) in young people with genetic heart diseases. In the case of hypertrophic cardiomyopathy (HCM), initially it was not known whether the ICD would be effective in patients with a disease very different morphologically and functionally from coronary artery disease. Nevertheless, several observational clinical studies have shown that the ICD reliably terminates life-threatening ventricular tachyarrhythmias in HCM, and is largely responsible for reducing HCM mortality to 0.5% per year, by preventing SD and changing the natural course of the disease. PMID- 26002384 TI - Atrial and ventricular arrhythmias in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in genes coding for cardiac sarcomeres. HCM is the most common inherited heart disease, with a prevalence of 0.2%. There are multiple genetic variants that cause pleomorphic clinical attributes and disease characterized by myocardial disarray and myocardial hypertrophy. Patients are at an increased risk of atrial and ventricular arrhythmias. Management of these arrhythmias is complex. Atrial fibrillation is associated with increased mortality and thromboembolism. Ventricular arrhythmias are life threatening and best treated with an implantable defibrillator. PMID- 26002385 TI - The role of cardiovascular magnetic resonance in sudden death risk stratification in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in young patients, but current risk stratification strategies do not identify all patients at risk. Contrast-enhanced cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) can identify areas of abnormal myocardial substrate comprising fibrosis, the structural nidus for potentially life threatening ventricular arrhythmias. More recently, follow-up studies have demonstrated a strong relationship between extent of LGE in patients with HCM and increased risk of adverse disease-related events, including sudden death. PMID- 26002386 TI - Relationship between arrhythmogenic right ventricular dysplasia and exercise. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is rare cardiomyopathy associated with life-threatening arrhythmias and increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, environmental factors such as exercise have been implicated in the pathogenesis of the disease. Recent studies have shown that exercise may be associated with adverse outcomes in ARVD/C patients. Based on current evidence, ARVD/C patients are recommended to limit exercise irrespective of their mutation status. In addition, some studies have suggested the presence of an entirely acquired form of the disease caused by exercise that has been dubbed exercise-induced ARVD/C. PMID- 26002387 TI - Left ventricular hypertrophy and arrhythmogenesis. AB - Left ventricular hypertrophy (LVH) poses an independent risk of increased morbidity and mortality, including atrial arrhythmias, ventricular arrhythmias, and sudden cardiac death. The most common causes of LVH are hypertension and valvular heart disease. Electrocardiography and echocardiography are the first steps in the diagnosis and evaluation of therapy in patients with LVH. Cardiac MRI is the gold standard in diagnosis and assessment of response to therapy. Management of LVH should be based on etiology, evidence, and guideline adherence. Timely and optimal management of the underlying cause of LVH results in improvement (regression) of LVH and its related complications. PMID- 26002388 TI - Arrhythmias in dilated cardiomyopathy. AB - Patients with dilated cardiomyopathies (DCM) face a significant burden of arrhythmias, including conduction defects such as atrioventricular block and interventricular delay in the form of left bundle branch block, resulting in altered electromechanical coupling that can exacerbate heart failure. Atrial fibrillation is common and carries an adverse prognosis. Ventricular arrhythmias and sudden cardiac death generally occur late in the disease course. Sustained monomorphic ventricular tachycardia accounts for most of the sustained ventricular arrhythmias in DCM. This article summarizes common forms of arrhythmias encountered in patients with DCM, and reviews the relevant electrophysiologic basis of these arrhythmias and their management. PMID- 26002389 TI - Cardiac sarcoidosis and consequent arrhythmias. AB - Myocardial involvement in patients with sarcoidosis can be difficult to diagnose, and requires a high index of suspicion and low threshold for screening. The presentation of cardiac sarcoidosis is variable, and can range from asymptomatic electrocardiographic changes to sudden cardiac death. This review provides an overview of the arrhythmic consequences of cardiac sarcoidosis, with emphasis on the electrophysiologist's role in recognition, diagnostic testing, and management of this rare disease. PMID- 26002390 TI - Arrhythmias in chagasic cardiomyopathy. AB - Chagas disease, a chronic parasitosis caused by the protozoa Trypanosoma cruzi, is an increasing worldwide problem because of the number of cases in endemic areas and the migration of infected individuals to more developed regions. Chagas disease affects the heart through cardiac parasympathetic neuronal depopulation, immune-mediated myocardial injury, parasite persistence in cardiac tissue with secondary antigenic stimulation, and coronary microvascular abnormalities causing myocardial ischemia. A lack of knowledge exists for risk stratification, management, and prevention of ventricular arrhythmias in patients with chagasic cardiomyopathy. Catheter ablation can be effective for the management of recurrent ventricular tachycardia. PMID- 26002391 TI - Arrhythmias in viral myocarditis and pericarditis. AB - Acute viral myocarditis and acute pericarditis are self-limiting conditions that run a benign course and that may not involve symptoms that lead to medical assessment. However, ventricular arrhythmia is frequent in viral myocarditis. Myocarditis is thought to account for a large proportion of sudden cardiac deaths in young people without prior structural heart disease. Identification of acute myocarditis either with or without pericarditis is therefore important. However, therapeutic interventions are limited and nonspecific. Identifying those at greatest risk of a life-threatening arrhythmia is critical to reducing the mortality. This review summarizes current understanding of this challenging area in which many questions remain. PMID- 26002392 TI - Arrhythmias in Fabry cardiomyopathy. AB - Fabry disease is an X-linked multisystem disorder caused by deficiency of the alpha-galactosidase A enzyme. Cardiovascular manifestations include hypertension, coronary disease, arrhythmias, valvular abnormalities, heart failure, and sudden death. Bradycardia and conduction system abnormalities are related initially to abnormal accumulation of glycolipids in the lysosomes of conduction tissues. Hypertrophy and eventual fibrosis provides a substrate for persistent conduction abnormalities and ventricular arrhythmias. Sudden cardiac death can be related to bradyarrhythmias or tachycardias. Enzyme replacement therapy can improve cardiac function and clinical outcomes. Pacemakers or defibrillators are important in the treatment of patients with Fabry disease who are at risk for arrhythmias. PMID- 26002393 TI - Mitochondrial cardiomyopathy and related arrhythmias. AB - Mitochondrial dysfunction has been shown to be involved in the pathophysiology of arrhythmia, not only in inherited cardiomyopathy due to specific mutations in the mitochondrial DNA but also in acquired cardiomyopathy such as ischemic or diabetic cardiomyopathy. This article briefly discusses the basics of mitochondrial physiology and details the mechanisms generating arrhythmias due to mitochondrial dysfunction. The clinical spectrum of inherited and acquired cardiomyopathies associated with mitochondrial dysfunction is discussed followed by general aspects of the management of mitochondrial cardiomyopathy and related arrhythmia. PMID- 26002394 TI - Arrhythmias in the muscular dystrophies. AB - In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occurs with variable prevalence, mirroring the phenotypic variability seen among and within the various hereditary myopathies. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The noncardiac manifestations can lead to delayed recognition of symptoms, affect the decision to implant a prophylactic device, and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID- 26002395 TI - Arrhythmias in peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a complication of late pregnancy and the early postpartum period characterized by dilated cardiomyopathy and heart failure with reduced ejection fraction. Approximately half of women fail to recover left ventricular function. Standard management of heart failure is indicated, with some exceptions for women who are predelivery or breastfeeding. Atrial and ventricular arrhythmias are reported in PPCM, but the frequency of arrhythmias in this condition is not well characterized. Management of PPCM-associated arrhythmias may include antiarrhythmic drugs, catheter ablation, and wearable or implantable cardioverter-defibrillators. Further research is needed on the prevalence, natural history, and optimal management of arrhythmias in PPCM. PMID- 26002396 TI - Arrhythmias in left ventricular noncompaction. AB - Left ventricular noncompaction (LVNC) is a newly recognized form of cardiomyopathy that has been associated with heart failure, arrhythmias, thromboembolic events, and sudden death. Both ventricular and supraventricular arrhythmias are now well described as prominent clinical components of LVNC. Throughout the spectrum of age, these arrhythmias have been associated with prognosis and outcome, and their clinical management is therefore an important aspect of patient care. The risk of sudden death seems to be associated with ventricular dilation, systolic dysfunction, and the presence of arrhythmias. Proposed management strategies shown to have efficacy include antiarrhythmic therapy, ablation techniques, and implantable cardioverter-defibrillator implantation. PMID- 26002397 TI - Arrhythmias in takotsubo cardiomyopathy. AB - Acute emotional or physical stress can trigger a catecholamine-mediated myocardial stunning known as takotstubo cardiomyopathy (TCM). Although TCM is generally reversible, it can be associated with significant morbidity, including secondarily to cardiac arrhythmia. Lethal arrhythmias such as heart block, ventricular tachycardia, and ventricular fibrillation have been described. Repolarization abnormalities associated with TCM can lead to characteristic T wave abnormalities and QT prolongation that place patients at increased risk for ventricular arrhythmia, including torsades de pointes. This article focuses on the arrhythmic complications associated with TCM and explores the underlying etiology of these arrhythmias. PMID- 26002398 TI - QT Prolongation and Oncology Drug Development. AB - Many pharmaceutical agents interact with cardiac ion channels resulting in abnormal ventricular repolarization and prolongation of the QT interval. In rare circumstances, this has resulted in the development of the potentially life threatening arrhythmia, torsades de pointes. It is recognized, however, that accurate measurement of the QT interval is challenging, and it is a poor predictor for the development of this arrhythmia. Nevertheless, QT interval monitoring is an essential part of pharmaceutical development, and significant increases in the QT interval may prevent a drug from gaining approval. PMID- 26002400 TI - Arrhythmias in cardiomyopathies. Foreword. PMID- 26002399 TI - Arrhythmia in stem cell transplantation. AB - Stem cell regenerative therapies hold promise for treating diseases across the spectrum of medicine. While significant progress has been made in the preclinical stages, the clinical application of cardiac cell therapy is limited by technical challenges. Certain methods of cell delivery, such as intramyocardial injection, carry a higher rate of arrhythmias. Other potential contributors to the arrhythmogenicity of cell transplantation include reentrant pathways caused by heterogeneity in conduction velocities between graft and host as well as graft automaticity. In this article, the arrhythmogenic potential of cell delivery to the heart is discussed. PMID- 26002401 TI - Arrhythmias in cardiomyopathies. Preface. PMID- 26002402 TI - The clinical significance of circulating soluble RAGE in patients with severe sepsis. AB - BACKGROUND: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor involved in the pathogenesis of inflammatory diseases. However, the significance of the soluble isoform of RAGE (sRAGE) has not been clarified in critical illness. We investigated circulating sRAGE in blood samples from septic patients. METHODS: In this cross-sectional study, criteria for inclusion were patients with severe sepsis and age older than 18 years. Samples were collected within 24 hours after the diagnosis of sepsis and also from healthy volunteers. The levels of sRAGE and RAGE signaling pathway-associated biologic parameters were measured with an enzyme-linked immunosorbent assay kit. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were calculated at the time of patient enrollment. We used the International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm to assess coagulopathy. RESULTS: Included were 24 septic patients and 12 healthy volunteers. Serum sRAGE level was significantly increased in the patients compared with healthy controls. Significant correlations were found between sRAGE levels and APACHE II, SOFA, and ISTH DIC scores. The increase in sRAGE levels also correlated with the upregulation of interleukin-6, soluble vascular adhesion molecule 1, and plasminogen activator inhibitor 1 levels and a reduction in platelet count. The fraction of sRAGE other than the endogenous secreted form of RAGE (esRAGE) was augmented in the patients. CONCLUSION: We demonstrated for the first time that the serum level of sRAGE increased with the progression of DIC and the severity of sepsis, suggesting that circulating sRAGE reflects RAGE signaling pathway activity, which induces the excessive inflammatory response involved in endothelial injury and coagulopathy and that its measurement may be useful as a biomarker for sepis. LEVEL OF EVIDENCE: Prognostic study, level IV. PMID- 26002403 TI - Sex differences in heart rate variability: a longitudinal study in international elite cross-country skiers. AB - PURPOSE: Exercise-related sudden cardiac deaths (SCD) occur with a striking male predominance. A higher sympathetic tone in men has been suggested as risk factor for SCD. Elite athletes have the highest risk for exercise-related SCD. We aimed to analyze the autonomic nervous system of elite cross-country skiers from Norway, Russia and Switzerland in supine position and after orthostatic challenge in various training periods (TP). METHOD: Measurements of heart rate variability (HRV) were performed on a weekly basis over 1 year using an orthostatic challenge test with controlled breathing. Main outcome parameters were the high-frequency power in supine position (HFsupine) as marker of cardiac parasympathetic activity and the low-frequency/high-frequency power ratio after orthostatic challenge (LF/HFstand) as marker of cardiac sympathetic activation. Training intensity and duration were recorded daily and expressed as training strain. The training year was divided into three TPs. An average of weekly HRV measurements was calculated for each TP. RESULT: Female (n = 19, VO2max 62.0 +/- 4.6 ml kg(-1) min(-1), age 25.8 +/- 4.3 years) and male (n = 16, VO2max 74.3 +/- 6.3 ml kg(-1) min(-1), age 24.4 +/- 4.2 years) athletes were included. Training strain was comparable between sexes (all p > 0.05) and changed between TPs (all p < 0.05) while no HRV parameters changed over time. There were no sex differences in HFsupine while the LF/HFstand was significantly higher in male athletes in all TPs. CONCLUSION: For a comparable amount of training, male athletes showed constantly higher markers of sympathetic activity after a provocation maneuver. This may explain part of the male predominance in sports-related SCD. PMID- 26002404 TI - Potentiators for cystic fibrosis - targeting the underlying molecular defect. PMID- 26002405 TI - Middle East respiratory syndrome coronavirus "MERS-CoV": current knowledge gaps. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) that causes a severe lower respiratory tract infection in humans is now considered a pandemic threat to the Gulf region. Since its discovery in 2012, MERS-CoV has reached 23 countries affecting about 1100 people, including a dozen children, and claiming over 400 lives. Compared to SARS (severe acute respiratory syndrome), MERS-CoV appears to kill more people (40% versus 10%), more quickly, and is especially more severe in those with pre-existing medical conditions. Most MERS-CoV cases (>85%) reported thus far have a history of residence in, or travel to the Middle East. The current epidemiology is characterised by slow and sustained transmission with occasional sparks. The dromedary camel is the intermediate host of MERS-CoV, but the transmission cycle is not fully understood. In this current review, we have briefly summarised the latest information on the epidemiology, clinical features, diagnosis, treatment and prevention of MERS-CoV especially highlighting the knowledge gaps in its transmission dynamics, diagnosis and preventive strategy. PMID- 26002406 TI - Long term antihypertensive drug use and prostate cancer risk: A 9-year population based cohort analysis. AB - BACKGROUND: Recent findings from clinical trials have indicated inconsistent associations between angiotensin II receptor blockers and the risk of cancer incidence. Furthermore, the relationship between antihypertensive drugs and prostate cancer in hypertensive patients remains unclear. METHODS: From Taiwan's national health insurance database, we identified 80,299 patients diagnosed with hypertension in 2001 and matched with 321,916 subjects without hypertension by age, income, urbanization level, and index day. A total of 684 hypertensive patients without antihypertensive drug use (drug non-user subcohort) were also matched (1:4) with 2736 patients on antihypertensive medication (drug subcohort) using the same criteria. Each subject in the two study groups was followed up for a maximum of nine years, during which death was considered a competing event when performing the stratified Fine and Gray regression hazards model for the estimation of prostate cancer risk for the cohorts. Uptake of antihypertensive prescription was considered a time-dependent variable. RESULTS: Our findings indicate that patients with hypertension are at significantly increased risk for prostate cancer incidence when compared to their matched non-hypertensive counterparts (sHR=6.80, 95% CI=1.97-23.44, p=0.0024). Among hypertensive patients, those with long term antihypertensive drug use are not at elevated risk of developing prostate cancer relative to non-users of antihypertensive drugs (1 5 year vs. non-user sHR=0.99, 95% CI=0.32-3.05; >5 year vs. non-user sHR=0.88, 95% CI=0.34-2.26). CONCLUSIONS: Hypertension is considered a risk factor for prostate cancer. However, long term uptake of antihypertensive medication in male hypertensive patients should not be a concern for the development of prostate cancer. PMID- 26002407 TI - Failure mode and effects analysis of medication adherence in patients with chronic myeloid leukemia. AB - BACKGROUND: Poor adherence to ABL tyrosine kinase inhibitors (ABL TKIs) is associated with reduced treatment efficacy and increased healthcare costs. To examine the hazards associated with poor adherence, we implemented failure mode and effects analysis (FMEA). METHODS: We surveyed 54 chronic myeloid leukemia (CML) patients treated at Saga University Hospital from October 2012 to May 2014. The survey consisted of items regarding the type of ABL TKI used, adherence to ABL TKIs, the appearance of adverse effects, utilisation of the high cost medical care benefit system, and factors affecting adherence. Four factors that likely affected adherence were identified, including the level of understanding of ABL TKIs treatment outcomes, adverse effects, the high cost of medications, and careless slips in the taking of medicine. Results of the survey were analysed by FMEA. RESULTS: The risk priority number was highest for careless slips in the taking of medicine at 7.0 +/- 1.0 (mean +/- SEM), followed in descending order by the inadequate understanding of treatment outcomes (4.9 +/- 0.6), adverse effects (3.8 +/- 0.8), and high medication cost (2.2 +/- 0.5). Thus, the prevention of careless slips was the most important factor affecting adherence to ABL TKIs. Contrary to our preoccupation, FMEA revealed that high medication cost was the lowest risk factor for poor adherence. This finding may be attributed to the high utilisation (96.3 %) of the high cost medical care benefit system. CONCLUSION: These findings suggest that an inadequate medication-taking habit such as careless slips may represent a potential target to improve and maximize adherence in CML patients. PMID- 26002408 TI - Eight patients with Williams syndrome and craniosynostosis. AB - Williams syndrome (WS) is a well-known genetic syndrome caused by a microdeletion on chromosome 7q11.23 encompassing the elastin gene. It is characterized by distinctive facies, congenital cardiovascular malformations, intellectual disabilities, and various other manifestations. Some patients were reported with craniosynostosis. Here, we report 8 WS cases diagnosed with craniosynostosis using three-dimensional cranial computed tomography. These findings suggest that craniosynostosis may occur more frequently in WS patients than expected. PMID- 26002409 TI - Effect of reduced visual acuity on precision of two-dimensional tracing movements. AB - PURPOSE: We intended to assess consequences of reduced visual acuity for performance in a natural simple motor task (tracing) using objective kinematic performance measures. Specifically, we intended to elucidate the kind of relationship between the task performance and best corrected binocular visual acuity and to determine the threshold of visual acuity when task performance starts to deteriorate. METHODS: Ninety-five individuals with different best corrected visual acuity participated in the study (age 49+/-12 years, mean+/-SD, 27 men and 68 women). The participants manually traced maze-like visual patterns of different spatial complexity presented on the screen of a portable notebook computer using Clinical Kinematic Assessment Tool software. Tracing error was computed as performance measure in each trial with a spatial pattern matching technique - rigid point set registration method. RESULTS: The segmented linear regression analysis showed that the relation between visual acuity and tracing errors was best described with a regression function having a break point between two data segments. Tracing performance was unaffected by values of visual acuity below 0.2 on logMAR scale, but when logMAR values increased above this critical limit (i.e. when visual acuity is further reduced), tracing errors linearly increased. The rate of the increase of the tracing error correlated with the complexity of visual stimulus shape. CONCLUSION: Testing of fine motor functions with objective kinematic measures during visuomotor tasks may help differentiating between actual effects of reduced visual acuity on eye-hand coordination in individuals with similar levels of impairment of visual acuity. PMID- 26002410 TI - Is the prevalence of ADHD in Turkish elementary school children really high? AB - PURPOSE: Previous findings in Turkish samples of children have suggested higher prevalence of ADHD than those detected in Western cultures. Methodological problems might explain these findings. Here, we aimed to re-check the prevalence rate of Attention-Deficit/Hyperactivity Disorder (ADHD) along with other childhood psychiatric disorders in a representative school sample of elementary school children in Izmir, Turkey. METHOD: The sample consisted of 419 randomly selected primary school children aged 6-14-year-old. We were able to interview 417 cases (99.5 % of the sample). Psychiatric diagnoses in children were assessed using the K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children- Present and Lifetime Version) and an impairment criterion scale. RESULTS: The prevalence rates of ADHD were 21.8 and 12.7 % in children without and with impairment, respectively. The following major mental disorders were significantly more prevalent in ADHD cases than controls: oppositional defiant disorder (ODD) (9.4 versus 0 %), conduct disorder (15.1 versus 0 %), anxiety (17 versus 0.5 %), and mood (5.7 versus 0.8 %). CONCLUSIONS: Our results confirmed a substantially higher ADHD prevalence rate (more than double) than the suggested pooled worldwide prevalence, although similar to the one recently detected in a representative populational sample of children in the US (11 %). These findings, consistent with previous developmental epidemiology studies from Turkey, confirm that ADHD is highly prevalent in Turkish elementary school children. PMID- 26002412 TI - Predicting time to emergency department return for anxiety disorders and acute stress reactions in children and adolescents: a cohort study. AB - PURPOSE: While studies indicate that few children with anxiety disorders receive specialized mental health care, significant knowledge gaps exist for the mental health care trajectory outside of specialized care. We examined whether physician based care after an emergency department (ED) visit for mental health care predicted time to ED return. METHODS: We conducted a retrospective cohort study using administrative data from Alberta, Canada. Included in the cohort were 8075 children <18 years discharged from an ED (104 EDs in total), April 2002-September 2010, following a visit for an anxiety disorder or acute stress reaction. We used a multivariable Cox proportional hazards model to estimate time to ED return for mental health care (censored at 90 days). The variables of interest were: number and type of physician visits 30 days after index visit. We adjusted for sociodemographics, clinical acuity, comorbidity, and recent history of ED mental health care in the model. RESULTS: Within 30 days of ED discharge, multiple physician follow-up visits were associated with shorter return time (adjusted HR 1.24, 95 % CI 1.08-1.43). A single physician follow-up visit was associated with longer return time (adjusted HR 0.68, 95 % CI 0.58-0.79). Physician follow-up visits for mental health care were associated with shorter return time (adjusted HR 2.5, 95 % CI 2.21-2.83). CONCLUSIONS: Following an index visit, ED return by children with anxiety disorders or acute stress reactions is associated with specific characteristics of subsequent physician visits. Improving physician use of evidence-based treatment and family access to coordinated services may reduce costly hospital-based care. PMID- 26002411 TI - The Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort as a resource for studying psychopathology in childhood and adolescence: a summary of findings for depression and psychosis. AB - PURPOSE: The purpose of this study is to highlight the Avon Longitudinal Study of Parents and Children (ALSPAC) as a resource to study psychopathology. To demonstrate this, we review the studies related to depression and psychosis in childhood and adolescence and discuss the results in relation to the aetiology of depression and psychotic experiences (PEs) and possible underlying mechanisms. METHODS: We examined the list of publications from ALSPAC and then classified them as examining (a) the course and risk factors of maternal and paternal depression, (b) the effects of maternal and paternal depression on child development, (c) risk factors for depression in childhood and adolescence, (d) the frequency, clinical relevance and risk factors of PEs, and (e) shared risk factors for depression and PEs. RESULTS: There was evidence that environmental stressors and the way these are interpreted contribute to risk of depression and evidence that biological factors related to puberty are also likely to play a role. With regards to PEs, the findings further support the existence of 'a continuum of psychosis' while they also suggest that PEs might be of limited clinical utility in predicting psychotic disorder during adolescence and early adulthood. Finally, most risk factors examined were found to be shared between depression and PEs. CONCLUSIONS: The ALSPAC birth cohort has provided important insights for our understanding of the aetiological mechanisms underlying depression and PEs. Future research could aim to incorporate measures of automatic psychological mechanisms to provide insights into the brain mechanisms that underlie these clinical phenomena. PMID- 26002413 TI - Thyme essential oil as a defense inducer of tomato against gray mold and Fusarium wilt. AB - The potential of thyme essential oil in controlling gray mold and Fusarium wilt and inducing systemic acquired resistance in tomato seedlings and tomato grown in hydroponic system was evaluated. Thyme oil highly reduced 64% of Botrytis cinerea colonization on pretreated detached leaves compared to untreated control. Also, it played a significant decrease in Fusarium wilt severity especially at7 days post treatment when it was reduced to 30.76%. To explore the plant pathways triggered in response to thyme oil, phenolic compounds accumulation and peroxidase activity was investigated. Plant response was observed either after foliar spray or root feeding in hydroponics which was mostly attributed to peroxidases accumulation rather than phenolic compounds accumulation, and thyme oil seems to be more effective when applied to the roots. PMID- 26002414 TI - How do integrative practices influence patient-centered care?: An exploratory study comparing diabetes and mental health care. AB - BACKGROUND: Integration between organizational units to achieve common goals has been of interest to health systems because of the potential to improve patient centered care. However, the means by which integrative practices actually influence patient-centered care remain unclear. Whereas many studies claim a positive association between implementation of integrative practices and patient centered care, others raise concerns that integrative practices may not necessarily improve patient-centered care. PURPOSE: The aim of this study was to explore the mechanism by which integrative practices influence patient-centered care and to suggest a systematic approach for effective integration. APPROACH: We conducted a qualitative study comparing diabetes and mental health services through focus groups with 60 staff members from one health maintenance organization. We developed quantitative indicators to support the suggested model. FINDINGS: We identified a five-category framework of integrative practices that each directly and distinctively influences patient-centered care. Moreover, our findings suggest that integrative practices influence patient-centered care indirectly through creation of interdependent treatment competence, which enables providers to repeatedly deliver interdependent treatment in a flexible and adaptive way. PRACTICAL IMPLICATIONS: Providers should carefully implement integrative practices considering patient and disease characteristics, as our findings suggest that more implementation of integrative practices is not necessarily better for patient-centered care. Specifically, optimal implementation refers to the collective implementation of different integrative practices and thus encompasses both the extent (i.e., the amount of currently implemented practices out of those considered important to implement) and the extensiveness (i.e., the amount relative to the implementation of other practices) that may lead to interdependent treatment competence and higher patient-centered care. We suggest a creative measurement method of comparing the relative implementation of integrative practices that may assist managers and policy makers in developing interdependent treatment competence. PMID- 26002415 TI - Toward a high-performance management system in health care, part 4: Using high performance work practices to prevent central line-associated blood stream infections-a comparative case study. AB - BACKGROUND: Central line-associated bloodstream infections (CLABSIs) are among the most harmful health care-associated infections and a major patient safety concern. Nationally, CLABSI rates have been reduced through the implementation of evidence-based interventions; thus far, however, hospitals still differ substantially in their success implementing these practices. Prior research on high-performance work practices (HPWPs) suggests that these practices may explain some of the differences health systems experience in the success of their quality improvement efforts; however, these relationships have not yet been systematically investigated. PURPOSES: In this study, we sought to explore the potential role HPWPs may play in explaining differences in the success of CLABSI reduction efforts involving otherwise similar organizations and approaches. METHODOLOGY/APPROACH: To form our sample, we identified eight hospitals participating in the federally funded "On the CUSP: Stop BSI" initiative. This sample included four hospital "pairs" matched on organizational characteristics (e.g., state, size, teaching status) but having reported contrasting CLABSI reduction outcomes. We collected data through site visits as well as 194 key informant interviews, which were framed using an evidence-informed model of health care HPWPs. FINDINGS: We found evidence that, at higher performing sites, HPWPs facilitated the adoption and consistent application of practices known to prevent CLABSIs; these HPWPs were virtually absent at lower performing sites. We present examples of management practices and illustrative quotes categorized into four HPWP subsystems: (a) staff engagement, (b) staff acquisition/development, (c) frontline empowerment, and (d) leadership alignment/development. PRACTICE IMPLICATIONS: We present the HPWP model as an organizing framework that can be applied to facilitate quality and patient safety efforts in health care. Managers and senior leaders can use these four HPWP subsystems to select, prioritize, and communicate about management practices critical to the success of their CLABSI prevention efforts. PMID- 26002416 TI - Immunohistochemical distribution of neuropeptide Y, peptide YY, pancreatic polypeptide-like immunoreactivity and their receptors in the epidermal skin of healthy women. AB - Few studies have suggested that neuropeptide Y (NPY) could play an important role in skin functions. However, the expression of NPY, the related peptides, peptide YY (PYY) and pancreatic polypeptide (PP) and their receptors have not been investigated in human skin. Using specific antisera directed against NPY, PYY, PP and the Y1, Y2, Y4 and Y5 receptor subtypes, we investigated here the expression of these markers. NPY-like immunoreactivity (ir) in the epidermal skin could not be detected. For the first time we report the presence of positive PP-like ir immunofluorescent signals in epidermal cells, i.e. keratinocytes of skin from three areas (abdomen, breast and face) obtained as surgical left-overs. The immunofluorescent signal of PP-like ir varies from very low to high level in all three areas. In contrast, PYY-like ir is only expressed in some cells and with varied level of intensity. Furthermore and for the first time we observed specific Y1 and Y4 receptor-like ir in all epidermal layers, while the Y2 and Y5 subtypes were absent. Interestingly, as seen in human epidermis, in Episkin, a reconstituted human epidermal layer, we detected the presence of PP-like as well as Y1-like and Y4-like ir. These data have shown the presence and distribution of PYY, PP and Y1 and Y4 receptors in the human skin and Episkin, suggesting possible novel roles of NPY related peptides and their receptors in skin homeostasis. PMID- 26002417 TI - Pressure- and flow-controlled media perfusion differently modify vascular mechanics in lung decellularization. AB - Organ biofabrication is a potential future alternative for obtaining viable organs for transplantation. Achieving intact scaffolds to be recellularized is a key step in lung bioengineering. Perfusion of decellularizing media through the pulmonary artery has shown to be effective. How vascular perfusion pressure and flow vary throughout lung decellularization, which is not well known, is important for optimizing the process (minimizing time) while ensuring scaffold integrity (no barotrauma). This work was aimed at characterizing the pressure/flow relationship at the pulmonary vasculature and at how effective vascular resistance depends on pressure- and flow-controlled variables when applying different methods of media perfusion for lung decellularization. Lungs from 43 healthy mice (C57BL/6; 7-8 weeks old) were investigated. After excision and tracheal cannulation, lungs were inflated at 10 cmH2O airway pressure and subjected to conventional decellularization with a solution of 1% sodium dodecyl sulfate (SDS). Pressure (PPA) and flow (V'PA) at the pulmonary artery were continuously measured. Decellularization media was perfused through the pulmonary artery: (a) at constant PPA=20 cmH2O or (b) at constant V'PA=0.5 and 0.2 ml/min. Effective vascular resistance was computed as Rv=PPA/V'PA. Rv (in cmH2O/(ml/min)); mean+/-SE) considerably varied throughout lung decellularization, particularly for pressure-controlled perfusion (from 29.1+/ 3.0 in baseline to a maximum of 664.1+/-164.3 (p<0.05), as compared with flow controlled perfusion (from 49.9+/-3.3 and 79.5+/-5.1 in baseline to a maximum of 114.4+/-13.9 and 211.7+/-70.5 (p<0.05, both), for V'PA of 0.5 and 0.2 ml/min respectively. Most of the media infused to the pulmonary artery throughout decellularization circulated to the airways compartment across the alveolar capillary membrane. This study shows that monitoring perfusion mechanics throughout decellularization provides information relevant for optimizing the process time while ensuring that vascular pressure is kept within a safety range to preserve the organ scaffold integrity. PMID- 26002418 TI - The effects of barrier disruption and moisturization on the dynamic drying mechanics of human stratum corneum. AB - We study the dynamic drying mechanics of human stratum corneum, the most superficial layer of skin and essential physical and chemical barrier to the external environment. Barrier disruption caused by a depletion of lipids ordinarily found in healthy stratum corneum can occur with ageing, aggressive cleansing or with dry skin disorders and diseases such as atopic dermatitis and psoriasis. We establish the effects of severe barrier disruption on the dynamic drying mechanics of human stratum corneum by measuring variations in thickness and spatially resolved in-plane displacements in healthy and lipid depleted tissue samples drying in controlled environmental conditions. In-plane displacements recorded at regular intervals during drying are azimuthally averaged and fitted with a profile based on a linear elastic model. The measured thickness of the tissue sample is accounted for in each model fit. Dynamic variations in the drying stress and elastic modulus of the tissue are then established from the model fits. We find that barrier disruption causes dramatic reductions in drying timescales, increases in the elastic modulus of the tissue and larger drying stresses. We expect these changes to increase the propensity for cracking and chapping in skin. The maximum elastic modulus and drying stress of barrier disrupted stratum corneum (ESC=85.4+/-6.8 MPa, PSC=10.9+/-0.9 MPa) is reduced to levels comparable with stratum corneum containing lipids (ESC=26.1+/ 3.2 MPa, PSC=2.58+/-0.45 MPa) after treatment with a 5% aqueous solution of glycerol. Neither 2% nor 5% glycerol solutions slow the accelerated drying timescales in barrier disrupted stratum corneum. PMID- 26002419 TI - gamma-Fe2O3 nanoparticles filled polyvinyl alcohol as potential biomaterial for tissue engineering scaffold. AB - Maghemite (gamma-Fe2O3) nanoparticle with its unique magnetic properties is recently known to enhance the cell growth rate. In this study, gamma-Fe2O3 is mixed into polyvinyl alcohol (PVA) matrix and then electrospun to form nanofibers. Design of experiments was used to determine the optimum parameter settings for the electrospinning process so as to produce elctrospun mats with the preferred characteristics such as good morphology, Young's modulus and porosity. The input factors of the electrospinnning process were nanoparticles content (1-5%), voltage (25-35 kV), and flow rate (1-3 ml/h) while the responses considered were Young's modulus and porosity. Empirical models for both responses as a function of the input factors were developed and the optimum input factors setting were determined, and found to be at 5% nanoparticle content, 35 kV voltage, and 1 ml/h volume flow rate. The characteristics and performance of the optimum PVA/gamma-Fe2O3 nanofiber mats were compared with those of neat PVA nanofiber mats in terms of morphology, thermal properties, and hydrophilicity. The PVA/gamma-Fe2O3 nanofiber mats exhibited higher fiber diameter and surface roughness yet similar thermal properties and hydrophilicity compared to neat PVA PVA/gamma-Fe2O3 nanofiber mats. Biocompatibility test by exposing the nanofiber mats with human blood cells was performed. In terms of clotting time, the PVA/gamma-Fe2O3 nanofibers exhibited similar behavior with neat PVA. The PVA/gamma-Fe2O3 nanofibers also showed higher cells proliferation rate when MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was done using human skin fibroblast cells. Thus, the PVA/gamma-Fe2O3 electrospun nanofibers can be a promising biomaterial for tissue engineering scaffolds. PMID- 26002420 TI - Identification of peculiar and common effects of histone modifications on transcription. AB - Histone modifications (HMs) play an important role in controlling eukaryotic gene expression and next generation sequencing (NGS) has greatly advanced the research on this topic with generating many high-resolution maps for HMs. Here, we use these maps to analyze the relationship between HMs and transcription. By incorporating various segments of genes into analysis without restricting the scope only in the promoter region, we have collected more comprehensive data and captured some details of this process. A position effect of gene regions has been revealed and it can even inverse the property of some HMs from activating to repressing genes such as the cases of H3K4me3, H3K36me3 and H3K14ac. Especially H3K36me3, its dual character on gene transcription makes it able to serve as a criterion to distinguish high and low expressed genes. We also study the general property of different HMs based on the comprehensive data. Using exploratory factor analysis (EFA), we have extracted 4 latent structures underlying the HMs, which are able to represent their activating and repressing effects concisely. These 4 factors have fine properties in the aspects of distinguishing high and low expressed genes, predicting transcription level and identifying genes with unique attributes such as stable RNA generating genes found to have a close relationship with lifespan of organisms here. In summary, while the position effect associated HM peculiarities demonstrate some details of the complex HM regulation network divergently, the common factors catch the nature of the network convergently. This deepens our understanding on the HM-transcription relationship. PMID- 26002421 TI - Development of quantitative interspecies toxicity relationship modeling of chemicals to fish. AB - In this work, quantitative interspecies-toxicity relationship methodologies were used to improve the prediction power of interspecies toxicity model. The most relevant descriptors selected by stepwise multiple linear regressions and toxicity of chemical to Daphnia magna were used to predict the toxicities of chemicals to fish. Modeling methods that were used for developing linear and nonlinear models were multiple linear regression (MLR), random forest (RF), artificial neural network (ANN) and support vector machine (SVM). The obtained results indicate the superiority of SVM model over other models. Robustness and reliability of the constructed SVM model were evaluated by using the leave-one out cross-validation method (Q(2)=0.69, SPRESS=0.822) and Y-randomization test (R(2)=0.268 for 30 trail). Furthermore, the chemical applicability domains of these models were determined via leverage approach. The developed SVM model was used for the prediction of toxicity of 46 compounds that their experimental toxicities to a fish were not being reported earlier from their toxicities to D. magna and relevant molecular descriptors. PMID- 26002422 TI - Iron accumulation promotes TACE-mediated TNF-alpha secretion and neurodegeneration in a mouse model of ALS. AB - Oxidative stress contributes to degeneration of motor neurons in patients with amyotrophic lateral sclerosis (ALS) as well as transgenic mice overexpressing ALS associated human superoxide dismutase 1 (SOD1) mutants. However, the molecular mechanism by which the ALS-linked SOD1 mutants including SOD1(G93A) induce oxidative stress remains unclear. Here, we show that iron was accumulated in ventral motor neurons from SOD1(G93A)-transgenic mice even at 4 weeks of age, subsequently inducing oxidative stress. Iron chelation with deferoxamine mesylate delayed disease onset and extended lifespan of SOD1(G93A) mice. Furthermore, SOD1(G93A)-induced iron accumulation mediated the increase in the enzymatic activity of TNF-alpha converting enzyme (TACE), leading to secretion of TNF-alpha at least in part through iron-dependent oxidative stress. Our findings suggest iron as a key determinant of early motor neuron degeneration as well as proinflammatory responses at symptomatic stage in SOD1(G93A) mice. PMID- 26002423 TI - Achieving Goal Blood Pressure. AB - Both monotherapy and combination therapy options are appropriate for antihypertensive therapy according to the 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines. Most patients require more than one agent to achieve blood pressure (BP) control, and adding a second agent is more effective than doubling the dose of existing therapy. The addition of a third agent may be required to achieve adequate BP reductions in some patients. Single-pill fixed-dose combinations (FDCs) allow multiple-drug regimens to be delivered without any negative impact on patient compliance or persistence with therapy. FDCs also have documented beneficial clinical effects and use of FDCs containing two or three agents is recommended by the 2013 ESH/ESC guidelines. PMID- 26002424 TI - Application of remote sensing for the optimization of in-situ sampling for monitoring of phytoplankton abundance in a large lake. AB - Directives and legislations worldwide aim at representatively and continuously monitoring the ecological status of surface waters. In many countries, chlorophyll-a concentrations (CHL) are used as an indicator of phytoplankton abundance and the trophic level of lakes or reservoirs. In-situ measurements of water quality parameters, however, are time-consuming, costly and of unknown but naturally limited spatial representativeness. In addition, the variety of the involved lab and field measurement methods and instruments complicates comparability and reproducibility. Taking Lake Geneva as an example, 1234 satellite images from the MERIS sensor on the Envisat satellite from 2002 to 2012 are used to quantify the spatial and temporal variations of CHL concentrations. Based on histograms of spring, summer and autumn CHL estimates, the spatial representativeness of two existing in-situ measurement locations is analysed. Appropriate sampling frequencies to capture CHL peaks are examined by means of statistical resampling. The approaches proposed allow determining optimal in-situ sampling locations and frequencies. Their generic nature allows for adaptation to other lakes, especially to establish new survey programmes where no previous records are available. PMID- 26002425 TI - Espr 2015. PMID- 26002426 TI - Effect of methylated tea catechins from Chinese oolong tea on the proliferation and differentiation of 3T3-L1 preadipocyte. AB - As the important component of tea catechins in oolong tea, (-)-epigallocatechin 3 O-(3-O-methyl) gallate (EGCG3"Me) has exhibited various beneficial effects, however, little attention about its obesity prevention effect is available. In this study, the inhibitory effects of tea catechin monomers, including their methylated forms on the proliferation and differentiation of 3T3-L1 preadipocyte were studied. The major methylated tea catechins in oolong tea were identified as EGCG3"Me and ECG3"Me. The accumulation of triglyceride was significantly reduced in a concentration-dependent manner in groups treated with EGCG3"Me at concentrations of 20, 40 and 80MUg/mL, and the accumulation of lipid was decreased to 89.42+/-2.66%, 64.36+/-3.13% and 39.37+/-2.79%, respectively. Both EGCG3"Me and EGCG treatments showed a significant inhibitory effect on adipogenesis, while EGCG3"Me showed a relatively higher effect than EGCG, which was contrary to the results of cytotoxic activity. For ECG and ECG3"Me, ECG3"Me also showed a relatively higher antiobesity effect and lower cytotoxic activity. The results of activity screening showed that methylated tea catechins, including EGCG3"Me and ECG3"Me inhibited the proliferation and differentiation of 3T3-L1 preadipocyte. The difference of inhibitory effects for tested compounds may be due to their structural difference (the hydroxyl group at C-3 in D ring substituted by methoxy group). PMID- 26002427 TI - Investigation of inflammatory profile in MSUD patients: benefit of L-carnitine supplementation. AB - Maple Syrup Urine Disease (MSUD) is a metabolic disorder caused by a severe deficiency of the branched-chain alpha-keto acid dehydrogenase complex activity which leads to the accumulation of branched-chain amino acids (BCAA) leucine (Leu), isoleucine and valine and their respective alpha-keto-acids in body fluids. The main symptomatology presented by MSUD patients includes ketoacidosis, failure to thrive, poor feeding, apnea, ataxia, seizures, coma, psychomotor delay and mental retardation, but, the neurological pathophysiologic mechanisms are poorly understood. The treatment consists of a low protein diet and a semi synthetic formula restricted in BCAA and supplemented with essential amino acids. It was verified that MSUD patients present L-carnitine (L-car) deficiency and this compound has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. Since there are no studies in the literature reporting the inflammatory profile of MSUD patients and the L-car role on the inflammatory response in this disorder, the present study evaluates the effect of L-car supplementation on plasma inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interferon-gamma (INF-gamma), and a correlation with malondialdehyde (MDA), as a marker of oxidative damage, and with free L-car plasma levels in treated MSUD patients. Significant increases of IL-1beta, IL-6, and INF-gamma were observed before the treatment with L-car. Moreover, there is a negative correlation between all cytokines tested and L-car concentrations and a positive correlation among the MDA content and IL-1beta and IL-6 values. Our data show that L-car supplementation can improve cellular defense against inflammation and oxidative stress in MSUD patients and may represent an additional therapeutic approach to the patients affected by this disease. PMID- 26002428 TI - Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms in rats. AB - BACKGROUND/PURPOSE: Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. In recent years, several studies have been conducted to find agents that can prevent the development of these two phenomena. The aim of the present study is to evaluate the effect of simvastatin, a 3 hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on morphine induced tolerance and withdrawal symptoms. METHODS: Groups of male rats received daily morphine [for induction of tolerance (10 mg/kg) and for induction of dependence (additive doses: 5 mg/kg/12 h, 10 mg/kg/12 h, 15 mg/kg/12 h, 20 mg/kg/12 h, and 25 mg/kg/12 h)] in combination with propylene glycol or simvastatin [5 mg/kg, per os (p.o.), 10 mg/kg, p.o., and 20 mg/kg, p.o.]. Next, the nociception was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. The animals received additional doses of morphine for 9 days in order to induce dependency. One hour after the last dose of the morphine injection, naloxone was administered and withdrawal symptoms were recorded for 1 hour. RESULTS: The results of the present study showed that chronic morphine administration induced tolerance to the analgesic effect for 19 days, whereas simvastatin (20 mg/kg, p.o.) delayed the day of the established tolerance by 5 days. The administration of simvastatin also prevented the morphine-induced shift to the right of the 50% effective dose (ED50) in the dose-response curve. Furthermore, the results showed that simvastatin decreased the total withdrawal score significantly. CONCLUSION: We found that simvastatin attenuated morphine-induced tolerance and withdrawal symptoms. PMID- 26002429 TI - Progressive outer retinal necrosis associated with occlusive vasculitis in acquired immunodeficiency syndrome. AB - A 45-year-old man, a case of acquired immunodeficiency syndrome, received a highly active antiretroviral therapy at the outpatient service for 4 years without regular follow-up. He experienced progressively blurred vision for 6 months and a cutaneous zoster on his back 3 months ago. He was diagnosed with progressive outer retinal necrosis by polymerase chain reaction-restriction fragment length polymorphism using an aqueous humor sample, which revealed an existence of varicella zoster virus. He was given a combination of systemic, intravitreal antiviral and a highly active antiretroviral therapy. Occlusive vasculitis, an unusual finding for progressive outer retinal necrosis, developed in both eyes 1 week after the secondary intravitreal injection. Unfortunately, his vision deteriorated to no light perception in both eyes within 2 weeks. Progressive outer retinal necrosis is characterized clinically as showing minimal or no inflammation in the aqueous and vitreous humors, absence of retinal vasculitis, and patches of yellowish spots located deep in the retina. Physicians should pay attention to this rare case of progressive outer retinal necrosis associated occlusive vasculitis with very poor prognosis in spite of aggressive treatment. PMID- 26002430 TI - Risk factors for fluconazole-resistant invasive candidiasis in intensive care unit patients: An analysis from the China Survey of Candidiasis study. AB - PURPOSE: To assess the risk factors for invasive Candida infection (ICI) caused by fluconazole-resistant (Flu-R) Candida species in intensive care unit (ICU) patients. MATERIALS AND METHODS: Data from China Survey of Candidiasis study were analyzed. Patients with proven ICI were classified into fluconazole-sensitive (Flu-S) and Flu-R groups. Independent risk factors for Flu-R ICI were identified using a multivariate logistic regression. RESULTS: Forty-one percent of ICI patients were infected with Flu-R Candida. Significantly more patients had Candida colonization, intra-abdominal hypertension, and antifungal therapy at least 7 days before diagnosis; fewer patients had gastrointestinal perforation, systemic inflammatory response syndrome manifestation, and fluoroquinolone exposure in the Flu-R group. Furthermore, hospital or ICU stay before onset of infection was longer in the Flu-R group than in the Flu-S group (hospital or ICU stay: 19 vs 13 days or 10.5 vs 8 days, P < .05). Also, it was demonstrated as an independent risk factor for Flu-R Candida infection. CONCLUSION: As many as 41% of ICI patients were infected with Flu-R Candida, and the main risk factor was longer ICU stay before onset of ICI, implying that caution should be exercised when treating patients who have been long stayed in ICU with fluconazole as the first-line drug before testing isolates for drug sensitivity. PMID- 26002431 TI - The MACOCHA score is feasible to predict intubation failure of nonanesthesiologist intensive care unit trainees. AB - PURPOSE: Endotracheal intubation (ET) in intensive care unit (ICU) patients is regarded as more challenging than elective intubations in the operating room. Despite challenging conditions in ICU, trainees are often the initial operators performing ET. Because nonanesthesiologist intensivists with limited experience in ET run most of the nonsurgical ICUs, it is of exceptional importance to identify patients with predictable difficult ET in advance to prepare for a difficult airway scenario and thus avoid severe complications. METHODS: In this prospective, observational, single-center study, we used a truncated MACOCHA score to evaluate intubation performance of nonanesthesiologist ICU trainees in an interdisciplinary medical ICU. RESULTS: We show that (a) ET could be performed safely and without fatal complications in all cases; (b) the MACOCHA score is feasible on a nonanesthesiologist ICU; (c) a truncated MACOCHA score of at least 8 predicts failure of ICU trainees; and (d) availability of an ear, nose, and throat physician and an anesthesiologist is required to warrant successful management of difficult airways. CONCLUSION: Our findings are a further step to implement the MACOCHA score into the standard admission procedure of an ICU to identify early those patients in whom additional support is needed in case of ET and to improve patient safety. PMID- 26002433 TI - Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients. PMID- 26002432 TI - Text Messaging Support for Urban Adolescents and Young Adults Using Injectable Contraception: Outcomes of the DepoText Pilot Trial. AB - PURPOSE: To evaluate the feasibility, acceptability, and preliminary effectiveness of DepoText, a text messaging reminder system designed to improve moderately long-acting reversible contraception appointment attendance among young urban adolescent girls and young adult women using Depo-Provera. METHODS: Female patients aged 13-21 years willing to be randomized, using Depo-Provera, and owning a cell phone with text messaging were recruited from an urban academic practice in a community with high rates of unplanned pregnancy for this institutional review board-approved randomized controlled pilot trial. Participants completed a baseline Web-based survey and were followed for three injection cycles. Intervention participants received welcome, appointment, and healthy self-management messages using the Compliance for Life short messaging system platform over each injection cycle. Compliance for Life recorded outgoing and incoming communications, and patients were tracked for clinical behaviors. The log-transformed number of days between scheduled appointment and injection was analyzed using linear regression. RESULTS: Recruitment data show 95% eligibility and 91% enrollment rates with maximum enrollment completion in 3 months. Most were African-American and resided in low-income, single-parent, and mother-headed households. Most participants had cell phone plans that included unlimited text messaging and Internet access and completed all three Depo-Provera cycles. Intervention participants returned closer to their scheduled appointments than their control peers for the first visit (Beta = -.75; 95% confidence interval, -1.4 to .06; p = .03) but not for the second and third visits. CONCLUSIONS: The DepoText intervention is acceptable, feasible, and shows short term preliminary efficacy for improving clinic attendance for moderately long acting reversible contraception appointments. Additional research exploring the cost and longitudinal prevention effectiveness is warranted. PMID- 26002434 TI - Brain venular pattern by 7T MRI correlates with memory and haemoglobin in sickle cell anaemia. AB - Sickle cell anaemia (SCA) is a hereditary hemoglobinopathy characterised by extensive vascular dysfunction that stems from inflammation, thrombosis and occlusion of post-capillary venules. Cognitive impairment is a neurological complication of SCA whose pathogenesis is unknown. We hypothesised that cerebral venular abnormalities are linked to cognitive impairment in SCA. Thus, we employed 7T magnetic resonance imaging (MRI) to examine the association between venular density and cognitive function in homozygous SCA. We quantified the density of total, long, and short venules in pre-defined regions of interest between the frontal and occipital cornu on each hemisphere. Cognitive function was assessed using the Hopkins Verbal Learning Test - Revised (HVLT-R) test of learning and memory. Patients (n=11) were compared with race, age and gender equated controls (n=7). Compared to controls, patients had an overall venular rarefaction, with significantly lower density of long venules and greater density of short venules which was inversely related to HVLT-R performance and haemoglobin. To our knowledge, this is the first 7T MRI study in SCA and first report of associations between cerebral venular patterns and cognitive performance and haemoglobin. Future studies should examine whether these novel neuroimaging markers predict cognitive impairment longitudinally and are mechanistically linked to severity of anaemia. PMID- 26002435 TI - Photoluminescence, photocatalytic and antibacterial activities of CeO2.CuO.ZnO nanocomposite fabricated by co-precipitation method. AB - A novel tri-metallic oxide nanocomposite CeO2.CuO.ZnO has been synthesized by a simple co-precipitation method. The nanocomposite has been characterized by XRD, SEM, EDS, FTIR and PL spectra. The crystallite size of the CeO2.CuO.ZnO was calculated using XRD data. The crystallite size of the CeO2.CuO.ZnO mixed metal oxide annealed at 600 degrees C is found to be in range of 15.34-44.81 nm, with an average size of 29.51 nm. Excitation at different wavelengths showed PL in UV and visible regions. It has been found that PL behavior of CeO2.CuO.ZnO is excitation wavelength dependent. This flexible PL property is conflicting to well known Kasha's rule of excitation wavelength dependence of emission spectrum. The catalyst shows better photo-catalytic dye degradation efficiency in slightly alkaline pH in presence of H2O2. Nanocomposite CeO2.CuO.ZnO was found to be effective against pathogenic bacteria. PMID- 26002436 TI - Study of monoprotic acid-base equilibria in aqueous micellar solutions of nonionic surfactants using spectrophotometry and chemometrics. AB - Many studies have shown the distribution of solutes between aqueous phase and micellar pseudo-phase in aqueous micellar solutions. However, spectrophotometric studies of acid-base equilibria in these media do not confirm such distribution because of the collinearity between concentrations of chemical species in the two phases. The collinearity causes the number of detected species to be equal to the number of species in a homogenous solution that automatically misinterpreted as homogeneity of micellar solutions, therefore the collinearity is often neglected. This interpretation is in contradiction to the distribution theory in micellar media that must be avoided. Acid-base equilibrium of an indicator was studied in aqueous micellar solutions of a nonionic surfactant to address the collinearity using UV/Visible spectrophotometry. Simultaneous analysis (matrix augmentation) of the equilibrium and solvation data was applied to eliminate the collinearity from the equilibrium data. A model was then suggested for the equilibrium that was fitted to the augmented data to estimate distribution coefficients of the species between the two phases. Moreover, complete resolution of concentration and spectral profiles of species in each phase was achieved. PMID- 26002438 TI - Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway. AB - Thymosin alpha 1 (Talpha1), an immunoactive peptide, has been shown to inhibit cell proliferation and induce apoptosis in human leukemia, non-small cell lung cancer, melanoma, and other human cancers. However, the response and molecular mechanism of breast cancer cells exposed to Talpha1 remain unclear. PTEN, a tumor suppressor gene, is frequently mutated in a variety of human cancers. In the present study, we aimed to investigate the biological roles of PTEN in the growth inhibition of human breast cancer cells exposed to Talpha1. Using wild-type and mutant PTEN-expressing cells, we found a strong correlation between PTEN status and Talpha1-mediated growth inhibition of breast cancer cells. The growth inhibition effect was more pronounced in breast cancer cells in which Talpha1 enhanced PTEN expression, whereas endogenous PTEN knockdown reversed the growth inhibition effect of Talpha1 in breast cancer cells. Further investigation revealed that PTEN up-regulation, which was induced by Talpha1, can inhibit the activation of the PI3K/Akt/mTOR signaling pathway, leading to the growth inhibition of breast cancer cells. The addition of the synergy between Talpha1 and the inhibition of PI3K/Akt/mTOR activation could strongly block cell viability in PTEN down-regulated breast cancer cells. PTEN-overexpressing cells not only up-regulated Bax and cleaved caspase-3/9 and PARP expression but also down-regulated Bcl-2 compared to the treatment with Talpha1 alone. Together these findings suggest that PTEN mediates Talpha1-induced apoptosis through the mitochondrial death cascade and inhibition of the PI3K/Akt/mTOR signaling pathway in breast cancer cells. PMID- 26002437 TI - Amido-Schiff base derivatives as colorimetric fluoride sensor: Effect of nitro substitution on the sensitivity and color change. AB - A series of Schiff bases synthesized by the condensation of benzohydrazide and NO2 substituted benzaldehyde have been used as selective fluoride ion sensor. Test paper coated with these synthetic Schiff bases (test kits) can detect fluoride ion selectively with a drastic color change and detection can be achieved by just using the naked-eye without the help of any optical instrument. Interestingly, the position of -NO2 group in the amido Schiff bases has an effect on the sensitivity as well as on the change of color of species. PMID- 26002439 TI - [Combination of pulsed dye laser and propranolol in the treatment of ulcerated infantile haemangioma]. AB - INTRODUCTION: Ulceration is the most common complication of infantile haemangioma, with 15.8% of them usually appearing in the proliferative phase. They can be managed in several ways. We present our experience in the treatment of ulcerated haemangioma with the combination of pulsed dye laser and propranolol. MATERIAL AND METHODS: A retrospective observational study was conducted on patients with ulcerated infantile haemangioma treated with pulsed dye laser in association with propranolol. The study included 7 patients, 3 cases in labial area and 4 cases in the nappy area. A review was also performed on a historical cohort of 5 children with ulcerated haemangiomas with the same features, but treated only with propranolol, topical agents and occlusive dressings. RESULTS: The median size of the ulcer was 1.0 cm, and there was a mean time of onset pre-treatment of 2 weeks. Pain and bleeding was present in all patients. After 2 weeks of combined propranolol and laser treatment, all lesions were healed. The pain disappeared after the first laser session. Patients with ulcerative haemangioma in the labial area obtained a better response than patients with haemangioma in the nappy area. The cohort of patients treated with propranolol required a mean healing time of 5.2 weeks, with the addition of an occlusive dressing with ointment. CONCLUSIONS: We believe that our results suggest that combined treatment, laser and propranolol, has synergistic effects that accelerate the healing of ulcerated haemangioma, as observed in our patients. Further studies with larger numbers of patients are needed to confirm this fact. PMID- 26002440 TI - Bilateral Internal Mammary Artery Use for Coronary Artery Bypass Grafting Remains Underutilized: A Propensity-Matched Multi-Institution Analysis. AB - BACKGROUND: Bilateral internal mammary arterial (BIMA) grafts have repeatedly demonstrated superior outcomes compared with single IMA (SIMA) after coronary artery bypass grafting (CABG). Despite known survival benefits with BIMA use, perceived perioperative challenges often preclude BIMA use. We hypothesized that the use of BIMA remains underutilized, even in low-risk patients. METHODS: A total of 43,823 primary, isolated CABG patients in a regional Society of Thoracic Surgeons Database were evaluated. Patients were stratified by BIMA versus SIMA use. Surgical candidates considered "low risk" for BIMA use included the following: age less than 70 years; no or mild chronic lung disease; body mass index less than 30; and absence of diabetes. The BIMA patients (n = 1,333) were 1:1 propensity matched to SIMA patients (n = 1,333) and outcomes were compared. RESULTS: Overall, BIMA use was 3%; 24% (n = 10,327) of patients met "low-risk" criteria for BIMA use. Among "low-risk" patients, BIMA utilization was 6%. Propensity-matched comparisons revealed similar preoperative risk profiles between BIMA and SIMA patients (Predicted Risk of Mortality [PROM] 1.1% vs 1.1%, p > 0.05). The BIMA use was associated with longer cross-clamp time (71 vs 62 minutes, p < 0.05). Importantly, BIMA use was not associated with increased postoperative mortality, morbidity, or hospital length of stay (all p > 0.05). However, hospital readmission within 30 days was 41% greater for BIMA patients compared with SIMA patients (p = 0.01). CONCLUSIONS: Bilateral IMA graft use appears to remain underutilized in the modern surgical era, even in low surgical risk patients. The BIMA use does not appear to increase the risk of postoperative morbidity, although requires longer operative times and a higher risk for readmission. Efforts to more clearly understand surgeon motivators for the use of BIMA grafting are needed. PMID- 26002441 TI - Aortic Root Replacement With Biological Valved Conduits. AB - The execution of Bentall procedures using biological valved conduits is expanding owing to the increased incidence of aortic valve and root diseases in the aging population. To review the available data, a systematic search identified 29 studies with a total of 3,298 patients. Although evidence on short-term results suggested favorable outcomes after biological Bentall operations, data beyond 5 years are limited and highlight the urgent need for further investigations with longer follow-up. PMID- 26002442 TI - Transapical Versus Transaortic Transcatheter Aortic Valve Implantation: A Systematic Review. AB - Two alternative approaches for transcatheter aortic valve implantation (TAVI) exist for patients unsuitable for the transfemoral approach; the transapical and the transaortic approaches. It is unclear as to which approach has superior short term outcomes. A systematic review and meta-analysis was performed to answer this question. Mortality was equivalent in the 2 groups. There was a trend toward a lower rate of stroke in the transaortic group (0.9% vs 2.1%) but this was not statistically significant. Conversion to surgical aortic valve replacement, paravalvular leak, pacemaker requirement, and major bleeding occurred at equivalent rates. PMID- 26002443 TI - Resection of Primary and Secondary Tumors of the Sternum: An Analysis of Prognostic Variables. AB - BACKGROUND: We sought to determine the prognostic variables associated with overall survival (OS) and recurrence-free probability (RFP) in patients with primary and secondary sternal tumors treated with surgical resection. METHODS: A retrospective analysis of patients who underwent resection of primary or secondary sternal tumors at 2 cancer institutes between 1995 and 2013 was performed. OS and RFP were estimated using the Kaplan-Meier method, and predictors of OS and RFP were analyzed using the Cox proportional hazards model. RESULTS: Sternal resection was performed in 78 patients with curative (67 [86%]) or palliative (6 [8%]) intent. Seventy-three patients (94%) had malignant tumors, of which 28 (36%) were primary and 45 (57%) were secondary malignancies. Sternal resections were complete in 13 patients (17%) and partial in 65 (83%). There were no perioperative deaths, and grade III/IV complications were noted in 17 patients (22%). The 5-year OS was 80% for patients with primary malignant tumors, 73% for patients with nonbreast secondary malignant tumors, and 58% for patients with breast tumors (p = 0.85). In the overall cohort, R0 resection was associated with prolonged 5-year OS (84% vs 20%) on univariate (p = 0.004) and multivariate (adjusted hazard ratio, 3.37; p = 0.029) analysis. On subgroup analysis, R0 resection was associated with improved OS and RFP only for patients with primary malignant tumors. CONCLUSIONS: Sternal resection can achieve favorable OS for patients with primary and secondary sternal tumors. R0 resection is associated with improved 5-year OS and RFP in patients with primary malignant tumors. We did not detect a similar effect in patients with breast or nonbreast secondary tumors. PMID- 26002444 TI - Radical Lymph Node Dissection in Primary Esophagectomy for Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Subtotal esophagectomy with radical lymph node dissection (RLND) remains an effective therapeutic strategy for localized esophageal squamous cell carcinoma (ESCC). However, controversy exists regarding the extent to which RLND should be performed. We reappraised the prognostic impact and accurate nodal staging of RLND in ESCC. METHODS: The data from 101 ESCC patients (mean age, 57.5 years; 93 men) who underwent primary subtotal esophagectomy were retrospectively collected. Candidate variables, including the number of total dissected lymph nodes (TDLN [subgrouped into TDLN less than 13, TDLN 13 to 40, and TDLN more than 40]), were evaluated to determine their prognostic impacts and hazard ratio (HR). RESULTS: Fewer TDLN (p < 0.001; HR 9.011, 2.449, and 1.000 for TDLN less than 13, TDLN 13 to 40, and TDLN more than 40, respectively), tumor length exceeding 3.5 cm (p < 0.001; HR 3.321), resection margin invasion (p < 0.001; HR 14.493), and positive nodal status (p = 0.002; HR 2.730) were independent predictors of a poor prognosis. Considering the 54 node-negative patients, more TDLN correlated with improved survival (p = 0.001). Risk analysis demonstrated that one fewer TDLN could contribute to an increased HR of 1.047 (p = 0.014). However, RLND involving more TDLN appeared to lose the prognostic impact for the 47 node-positive patients (p = 0.072). Furthermore, the number of positive dissected lymph nodes remained at approximately 4 if the number of TDLN exceeded 20. CONCLUSIONS: For N negative or N-positive ESCC patients undergoing primary surgical resection, the number of TDLN influenced their prognosis or nodal staging accuracy, respectively. At least 20 TDLN were necessary for N-positive patients. PMID- 26002445 TI - A Prospective Clinical Trial of Telecytopathology for Rapid Interpretation of Specimens Obtained During Endobronchial Ultrasound-Fine Needle Aspiration. AB - BACKGROUND: Cytopathologic interpretation of endobronchial ultrasound with fine needle aspiration (EBUS-FNA) samples by a pathologist can be time-consuming and costly, and an onsite cytopathologist may not always be readily available. A telecytopathology system was instituted and evaluated to examine the effect on operative time for EBUS. METHODS: A prospective study was performed of sequential patients undergoing EBUS-FNA for the evaluation of mediastinal lymphadenopathy. Specimens for the control group were transported to the pathology laboratory, followed by remote cytologic interpretation. In a subsequent cohort, a telecytopathology system was used with intraoperative transmission of real-time live video microscopy to a remote cytopathologist (TCP group). The primary outcome was time to confirmation of cytology results. RESULTS: Of 46 patients entered into the study, 23 underwent traditional analysis (control group), and 20 were analyzed using telecytopathology (TCP group). Lung cancer was the most common malignancy in both groups (12 TCP, 12 control). There was no difference in mean number of lymph node stations sampled (1.3 TCP vs 1.8 control, p = 0.76). Use of TCP was associated with fewer needle passes (4.9 vs 7.3, p = 0.02) and fewer slides for interpretation (8.4 vs 13.5, p = 0.01) per procedure. Time to result confirmation was significantly shorter in the TCP group (19.0 vs 46.7 minutes, p < 0.001). A diagnostic specimen was obtained in 70% of patients in the TCP group compared with 65% in the control group (p = 0.5). False-negative rates in patients undergoing EBUS-FNA and mediastinoscopy were similar between the two groups (0 in TCP vs 2 in control, p = 0.49). Mean procedural costs (excluding cost of the telecytology system and operating room time) were equivalent between the two groups ($888 TCP vs $887 control). CONCLUSIONS: Telecytopathology provides rapid interpretation of EBUS-FNA samples with diagnostic accuracy comparable to traditional methods, shortens procedure time, and is a more efficient model for delivery of on-site EBUS-FNA interpretation. PMID- 26002446 TI - Endothelial nitric oxide synthase genotypes modulate peripheral vasodilatory properties after myocardial infarction. AB - BACKGROUND: Studies in population genetics suggest an important relationship between the eNOS G894T polymorphism and occurrence of acute myocardial infarction (AMI), with little known on its influence on the post-AMI period. AIM: To investigate the association of allelic variants produced by the G894T transversion in eNOS (rs1799983) with post-AMI variables. METHODS: Cross sectional analyses of anthropometric, clinical and laboratory assessments obtained within the first 24h and after 5 and 30 days of the AMI event across T carriers and G homozygotes of eNOS in 371 consecutive cases of AMI with ST segment elevation admitted to a Brazilian emergency service in cardiology. Genotypes were determined by polymerase chain reaction followed by enzymatic restriction. RESULTS: Despite no difference between genotypic groups on aspects as Killip-Kimbal classification scores, extension of infarcted mass, lipid profile or pattern of medication use, an increase in serum nitric oxide from admission to day 5 was higher for T carriers (p<0.001). Thirty days post-AMI, peripheral blood flow reserve was larger among T carriers either by flow- (p=0.037) and nitrate-mediated (p=0.040) dilation testing. CONCLUSION: Our results suggest an association of the eNOS 894T allele with an apparent improvement in late arterial function in post-AMI patients. PMID- 26002447 TI - Proteomics analysis of human oligodendroglioma proteome. AB - Proteomics analyses enable the identification and quantitation of proteins. From a purely clinical perspective, the application of proteomics based on innovations, may greatly affect the future management of malignant brain tumors. This optimism is based on four main reasons: diagnosis, prognosis, selection of targeted therapy based on molecular profile of the brain tumor and monitoring therapeutic response, or resistance. We extracted the proteins of tumor and normal brain tissues, and then evaluated the protein purity by Bradford test. In this study, we separated the proteins by two-dimensional (2DG) gel electrophoresis methods. Then spots were analyzed, compared using statistical data and specific software and were identified by pH isoelectric, molecular weights and data banks. The protein profiles were determined using 2D gel electrophoresis and MALDI TOF/TOF mass spectrometry approaches. Simple statistical tests were used to establish a putative hierarchy in which the change in protein level was ranked according to a cut-off point with p<0.05. The 2D gel showed a total of 1328 spots among which 157 spots were under-expressed and 276 spots were overexpressed. Most proteins are subjects to post-translational modifications, where amino acid residues may be chemically modified or conjugated by small proteins like ubiquitin. Proteomics is a powerful way to identifying multiple proteins which are altered following a neuropharmacological intervention in a CNS disease. PMID- 26002448 TI - [The healing garden, therapeutic resource: Psychopathological and phenomenological aspects, therapeutic implications]. PMID- 26002449 TI - US Guided Treat-to-Target Approach in Early RA: Implications for Uncoupling of Disease Activity and Structural Joint Damage. AB - OBJECTIVE: To assess the relationship between disease activity, measured by DAS28, and radiographic progression, using X-Ray and US as tools to evaluate structural joint damage and residual inflammation, in early RA patients. METHODS: Changes from baseline to week 52 in clinical variables and measures of radiographic progression were compared between early RA patients who received anti-TNF biologic therapy (192 patients), and those who received synthetic DMARD therapy (288 patients). Patients were stratified into: in remission, low (LDA), moderate (MDA) and high (HDA) disease activity at 52-weeks of treatment according to DAS-28 score. Radiographic progression was assessed both at baseline and at 52 weeks using modified Total Sharp Score (mTSS). In addition, US scores for number of erosions, synovial hypertrophy and vascularity were recorded. RESULTS: Whilst there was no significant radiologic progression in the patients who achieved remission, whether treated with synthetic DMARD or biologic therapy; on the other hand, there was a steady increase of joint damage in those who did not achieve remission, mainly in those treated with synthetic DMARD and in favor of the biologic therapy. On comparing the MSS scores at 52-weeks, the biologic therapy cohort who showed LDA (DAS-28: 2.6-3.1), MDA (DAS-28 score > 3.2-5.1) and HDA (>5.1) had significantly (p< 0.001) less number of erosions and joint space narrowing (P< 0.001) as well as US-GS and US-PD scores in comparison to the synthetic DMARD therapy cohort. X-Ray and US parameters showed a discriminating value regarding joint damage particularly in the patients who did not achieve remission, with US parameter showing accurate 95% CI estimate. CONCLUSION: Using US as a sensitive tool for joint affection assessment, the combination of biologic and DMARDs therapies retards joint damage, independently of its effects on disease activity, contrasting synthetic DMARDs monotherapy. PMID- 26002450 TI - Complications Encountered with Total Hip Arthroplasty in Rheumatoid Patients. AB - Rheumatoid arthritis affects around 1% of the global population with a predilection for Western societies. The treatment of the rheumatoid hip has gone through significant changes in recent years. Although osteotomies and synovectomies were previously commonplace, advances in arthroplasty technique and technology has seen these former procedures being performed less commonly. This article tackles some of the key issues with regard to the rheumatoid hip, namely the increased risk and methods of dealing with protrusio acetabuli, the risk of dislocation, infection and rates of aseptic loosening. PMID- 26002451 TI - The Peri-operative Management of the Rheumatoid Patient Undergoing Total Knee Arthroplasty: A Review of Literature. AB - Rheumatoid arthritis is the commonest inflammatory arthropathy, and affects synovium, cartilage and bone. Despite recent improvements with disease modifying biological agents, progressive joint destruction may continue eventually leading to the need for joint arthroplasty. The knee joint is involved in 90% of patients with rheumatoid arthritis, and total knee arthroplasty is being performed in many patients to alleviate pain and recover function. However, complications are not uncommon. In this review of the literature we look at pre-operative, intra operative and post-operative factor that need to be taken into account to reduce the risk of complications in these patients. Due to the systemic nature of rheumatoid arthritis, a multi-disciplinary approach is crucial. This includes addressing medical and pharmacological issues, and anesthetic concerns pre operatively, and anticipating and preventing relevant complications postoperatively. PMID- 26002452 TI - Surgical Treatment Options in Thumb Carpometacarpal Osteoarthritis: A Recent Literature Overview Searching for Practice Pattern with Special Focus on Total Joint Replacement. AB - Thumb carpometacarpal joint osteoarthritis is the most common site of non rheumatic degenerative lesion in the hand, and there are special features in rheumatic patients. None of various surgical treatment options can be declared as "gold standard" recently. The surgical treatment depends on patient's age, patient's claims in work and leisure, local bone stock, possible allergies, local comorbities, and local deformities. PMID- 26002453 TI - Inflammatory Fibromyalgia: Is it Real? AB - Fibromyalgia (FM) is a characterized by generalized pain with widespread tender points in specific areas and is frequently accompanied by fatigue, stiffness, and a non-restorative sleep pattern. In the current retrospective study, we identified a subgroup of FM patients who had clinically important markers of inflammation. The study also explored the use of the original American College of Rheumatology (ACR) criteria in the diagnosis of FM. Our data suggested there was a distinct subset of patients with FM who had positive ESR, CRP, ANA and RF; a group that we considered representative of inflammatory FM. None of the FM patients in this study developed a documented coexisting autoimmune illness during the retrospective review period. The existence of FM subgroups further puts into question the already controversial use of either the new or old ACR classification criteria in the diagnosis of FM, as they do not address the issue of systemic inflammation which appears to be significant. PMID- 26002454 TI - Periodontal Pathogens are Likely to be Responsible for the Development of Ankylosing Spondylitis. AB - The role of oral bacteria in the etiology of ankylosing spondylitis (AS) is examined in this review. Periodontitis is related to AS to a significant degree, and periodontitis is significantly more prevalent in patients with AS. Anti Pophyromonas gingivalis and anti-Prevotella intermedia antibodies titers are higher in AS patients than in healthy subjects. Eight randomized controlled trials that used sulfasalazine were reviewed. Moxifloxacin and rifamycin are significantly effective in the treatment of AS. Periodontal pathogens are likely to be responsible for the development of AS in genetically susceptible individuals. These results will guide more comprehensive and efficacious treatment strategies for AS. PMID- 26002455 TI - Pro-oxidant- Antioxidant Balance (PAB) in Rheumatoid Arthritis and its Relationship to Disease Activity. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that tends to be progressive and chronic. Previous studies showed that oxidative stress has a main role in pathology of RA. The aim of this study was the easy elucidation of oxidative stress through pro-oxidant-antioxidant balance (PAB) in these patients. METHOD: The sera of 130 RA patients and 130 age-matched healthy subjects (HS) were collected and the PAB was measured. According to the normal value of PAB in HS, the patients were divided into two groups; patients with increased serum PAB and those with normal serum PAB values. In patients with increased PAB value, the correlation of PAB value with RA disease activity [(DAS28ESR)], biochemical parameters, and BMI were determined. RESULTS: Significantly higher serum PAB values were found in the whole RA group of patients (88.69+/-39.42 HK) in comparison to HS (53.57+/-25.10 HK), p . 0.05. There was no significant correlation between PAB values and RA disease activity. In patients with elevated serum PAB value; serum cholesterol, triglycerides and BMI were significantly higher in comparison to patients with normal values. CONCLUSION: The PAB test can show the oxidative stress in RA patients. Further research should be done to determine the potency of the PAB assay as a tool for monitoring adverse effect of oxidative stress in RA, as well as the effect of antioxidant therapies in the outcomes. PMID- 26002456 TI - Imaging Methods of Joint Damage in Early Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune connective tissue disease of unknown etiology with development of persistent and erosive arthritis ultimately resulting in disability. The prevalence of RA is about 0.5-1% in adults worldwide. Radiographic changes in the joints at early stages of the disease are often absent. Accordingly, there is a need for instrumental methods of diagnosis with greater sensitivity. These include magnetic resonance imaging and ultrasound of joints. The paper reviews the instrumental methods of diagnosis of joint damage in early RA according to the existing literature of PubMed database. Selection criteria were original articles in the English language reporting "X ray", "MRI" and "ultrasound" in patients with early RA. PMID- 26002457 TI - Inflammatory Pathways in Knee Osteoarthritis: Potential Targets for Treatment. AB - Osteoarthritis (OA) of the knee is a wide-spread, debilitating disease that is prominent in Western countries. It is associated with old age, obesity, and mechanical stress on the knee joint. By examining the recent literature on the effect of the anti-inflammatory prostaglandins 15d-PGJ2 and Delta12-PGJ2, we propose that new therapeutic agents for this disease could facilitate the transition from the COX-2-dependent pro-inflammatory synthesis of the prostaglandin PGE2 (catalyzed by mPGES-1), to the equally COX-2-dependent synthesis of the aforementioned anti-inflammatory prostaglandins. This transition could be instrumental in halting the breakdown of cartilage via matrix metalloproteinases (MMPs) and aggrecanases, as well as promoting the matrix regeneration and synthesis of cartilage by chondrocytes. Another desirable property of new OA therapeutics could involve the recruitment of mesenchymal stem cells to the damaged cartilage and bone, possibly resulting in the generation of chondrocytes, synoviocytes, and, in the case of bone, osteoblasts. Moreover, we propose that research promoting this transition from pro-inflammatory to anti inflammatory prostaglandins could aid in the identification of new OA therapeutics. PMID- 26002458 TI - Development and Validation of a Patient Reported Experience Measure (PREM) for Patients with Rheumatoid Arthritis (RA) and other Rheumatic Conditions. AB - OBJECTIVES: Patient experience is not routinely measured in rheumatoid arthritis (RA) and no accepted standardised Patient Reported Experience Measures (PREM) tools currently exist. Commissioning for Quality in Rheumatoid Arthritis (CQRA) has developed, piloted and validated PREMs for RA and other rheumatic conditions. METHODS: Focus groups were held with RA patients to identify key elements of the patient experience. These were mapped against the UK Department of Health Patient Experience Framework and a PREM questionnaire developed with questions specifically relating to RA and rheumatology services. The RA PREM was piloted and Cronbach's alpha used to assess internal consistency. The PREM was modified to capture experience of patients with other rheumatic conditions and further validated. RESULTS: Ten UK sites and 524 patients were included in the RA PREM pilot and validation analysis. The RA PREM reliably captured RA patient experience and had good construct validity. Cronbach's alpha within the multiquestion domains ranged from 0.61 to 0.90 and the percentage agreement ranged from 22.5% to 70.4% with overall care. The modified PREM was evaluated in 11 UK sites and 110 patients with a range of rheumatic conditions. Cronbach's alpha ranged from 0.76 to 0.91 and the percentage agreement similarly ranged from 70% to 90% with the question on overall care. CONCLUSIONS: The RA PREM and the modified PREM provide new valuable validated tools for capturing the patient experience in a range of rheumatic conditions. The RA PREM is currently being used in a UK National Clinical Audit of Rheumatoid and Early Inflammatory Arthritis. PMID- 26002459 TI - Does metabolic syndrome or its individual components affect pain and function in knee osteoarthritis women? AB - BACKGROUND: Current studies and research support the role of metabolic syndrome (MetS) in knee osteoarthritis (OA). However, few studies have focused on its impact on knee OA parameters. The aim of this study was to investigate if metabolic syndrome or its individual components affect the intensity of pain, functional disability, and radiographic severity in knee osteoarthritis women. MATERIALS AND METHODS: We conducted a cross sectional study including confirmed radiographic knee osteoarthritis according to Kellgren and Lawrence scale, with and without metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The two groups were compared for pain Visual Analogue Scale (VAS), Lequesne index, Womac function, and radiological grade after adjusting for significant covariates. Multiple regression analysis was used to identify the independent effects of each specific component for metabolic syndrome on knee osteoarthritis parameters. RESULTS: One hundred thirty women were included. The mean age was 56.68+/-8.07 [34-75] years, and the mean BMI was 32.54+/-2.92 [23-37] kg/m2. The prevalence of metabolic syndrome was 48.5%. Women with and without metabolic syndrome had similar knee osteoarthritis parameters. However, accumulation of MetS components was associated with higher level of pain (OR = 3.7, CI = [1.5-5.9], p=0.001), independently of age and BMI. Multiple regression analyses showed, after adjusting for all covariates, that hyperglycemia had a positive impact on pain (p=0.009), waist circumference was positively associated with Lequesne index (p=0.04), high triglycerides level was significantly associated with increased pain (p=0.04) and higher Lequesne score (p=0.05), and Systolic blood pressure was positively correlated with Lequesne index (p=0.01). CONCLUSION: In addition to weight reduction, appropriate treatment of metabolic syndrome needs to become an important management strategy for knee pain and functional impairment. PMID- 26002460 TI - Stable knockdown of Kif5b in MDCK cells leads to epithelial-mesenchymal transition. AB - Polarization of epithelial cells requires vectorial sorting and transport of polarity proteins to apical or basolateral domains. Kif5b is the mouse homologue of the human ubiquitous Kinesin Heavy Chain (uKHC). To investigate the function of Kif5b in epithelial cells, we examined the phenotypes of Kif5b-deficient MDCK cells. Stable knockdown of Kif5b in MDCK cells resulted in reduced cell proliferation rate, profound changes in cell morphology, loss of epithelial cell marker, and gain of mesenchymal marker, as well as increased cell migration, invasion, and tumorigenesis abilities. E-cadherin and NMMIIA could interact with Kif5b in polarized MDCK cells, and their expression levels were decreased in Kif5b-deficient MDCK cells. Overexpression of E-cadherin and NMMIIA in Kif5b depleted MDCK cells could decrease mesenchymal marker expression and cell migration ability. These results indicate that stable knockdown of Kif5b in MDCK cells can lead to epithelial-mesenchymal transition, which is mediated by defective E-cadherin and NMMIIA expression. PMID- 26002461 TI - PCBP2 regulates hepatic insulin sensitivity via HIF-1alpha and STAT3 pathway in HepG2 cells. AB - Elevated free fatty acids (FFAs) are fundamental to the pathogenesis of hepatic insulin resistance. However, the molecular mechanisms of insulin resistance remain not completely understood. Transcriptional dysregulation, post transcriptional modifications and protein degradation contribute to the pathogenesis of insulin resistance. Poly(C) binding proteins (PCBPs) are RNA binding proteins that are involved in post-transcriptional control pathways. However, there are little studies about the roles of PCBPs in insulin resistance. PCBP2 is the member of the RNA-binding proteins and is thought to participate in regulating hypoxia inducible factor-1 (HIF-1alpha) and signal transducers and activators of transcription (STAT) pathway which are involved in regulating insulin signaling pathway. Here, we investigated the influence of PCBP2 on hepatic insulin resistance. We showed that the protein and mRNA levels of PCBP2 were down-regulated under insulin-resistant conditions. In addition, we showed that over-expression of PCBP2 ameliorates palmitate (PA)-induced insulin resistance, which was indicated by elevated phosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3beta (GSK3beta). We also found that over expression of PCBP2 inhibits HIF1alpha and STAT3 pathway. Furthermore, glucose uptake was found to display a similar tendency with the phosphorylation of Akt. The expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6 phosphatase (G6Pase), two key gluconeogenic enzymes, were down-regulated following Over-expression of PCBP2. Accordingly, PA-induced intracellular lipid accumulation was suppressed in over-expression of PCBP2 HepG2 cells. In addition, we found that over-expression of PCBP2 inhibits HIF1alpha and STAT3 pathway. Our results demonstrate that PCBP2 was involved in hepatic insulin sensitivity might via HIF-1alpha and STAT3 pathway in HepG2 cells. PMID- 26002462 TI - Absence-like seizures and their pharmacological profile in tottering-6j mice. AB - We previously showed that recessive ataxic tottering-6j mice carried a base substitution (C-to-A) in the consensus splice acceptor sequence linked to exon 5 of the alpha1 subunit of the Cav2.1 channel gene (Cacna1a), resulting in the skipping of exon 5 and deletion of part of the S4-S5 linker, S5, and part of the S5-S6 linker in domain I of the alpha1 subunit of the Cav2.1 channel. However, the electrophysiological and pharmacological consequences of this mutation have not previously been investigated. Upon whole-cell patch recording of the recombinant Cav2.1 channel in heterologous reconstitution expression systems, the mutant-type channel exhibited a lower recovery time after inactivation of Ca(2+) channel current, without any change in peak current density or the current voltage relationship. Tottering-6j mice exhibited absence-like seizures, characterized by bilateral and synchronous 5-8 Hz spike-and-wave discharges on cortical and hippocampal electroencephalograms, concomitant with sudden immobility and staring. The pharmacological profile of the seizures was similar to that of human absence epilepsy; the seizures were inhibited by ethosuximide and valproic acid, but not by phenytoin. Thus, the tottering-6j mouse is a useful model for studying Cav2.1 channel functions and Cacna1a-related diseases, including absence epilepsy. PMID- 26002463 TI - Enhancement of human mesenchymal stem cell infiltration into the electrospun poly(lactic-co-glycolic acid) scaffold by fluid shear stress. AB - The infiltration of the cells into the scaffolds is important phenomenon to give them good biocompatibility and even biodegradability. Fluid shear stress is one of the candidates for the infiltration of cells into scaffolds. Here we investigated the directional migration of human mesenchymal stem cells and infiltration into PLGA scaffold by fluid shear stress. The human mesenchymal stem cells showed directional migrations following the direction of the flow (8, 16 dyne/cm(2)). In the scaffold models, the fluid shear stress (8 dyne/cm(2)) enhanced the infiltration of cells but did not influence on the infiltration of Poly(lactic-co-glycolic acid) particles. PMID- 26002464 TI - Pannexin 1 deficiency can induce hearing loss. AB - Gap junctions play a critical role in hearing. Connexin gap junction gene mutations can induce a high incidence of hearing loss. Pannexin (Panx) gene also encodes gap junction proteins in vertebrates. Panx1 is a predominant pannexin isoform and has extensive expression in the cochlea. Here, we report that deletion of Panx1 in the cochlea could produce a progressive hearing loss. The auditory brainstem response (ABR) recording showed that hearing loss was moderate to severe and severe at high-frequencies. Distortion product otoacoustic emission (DPOAE), which reflects the activity of active cochlear mechanics that can amply acoustic stimulation to enhance hearing sensitivity and frequency selectivity, was also reduced. We further found that Panx1 deficiency could activate Caspase-3 cell apoptotic pathway in the cochlea to cause hair cells and other types of cells degeneration. These data indicate that like connexins Panx1 deficiency can also induce hearing loss. These data also suggest that pannexins play important rather than redundant roles in the cochlea and hearing. PMID- 26002465 TI - Chemoresistance of CD133(+) colon cancer may be related with increased survivin expression. AB - CD133, putative cancer stem cell marker, deemed to aid chemoresistance. However, this claim has been challenged recently and we previously reported that patients with CD133(+) colon cancer have benefit from 5-fluorouracil (5-FU) chemotherapy incontrast to no benefit in patients with CD133(-) cancer. To elucidate the role of CD133 expression in chemoresistance, we silenced the CD133 expression in a colon cancer cell line and determined its effect on the biological characteristics downstream. We comparatively analyzed the sequential changes of MDR1, ABCG2, AKT1 and survivin expression and the result of proliferation assay (WST-1 assay) with 5-FU treatment in CD133(+) and siRNA-induced CD133(-) cells, derived from Caco-2 colon cancer cell line. 5-FU treatment induced significantly increase of the mRNA expression of MDR1, ABCG2 and AKT1genes, but not protein level. CD133 had little to no effect on the mRNA and protein expression of these genes. However, survivin expression at mRNA and protein level were significantly increased in CD133(+) cells compared with siRNA-induced CD133-cells and Mock (not sorted CD133(+) cells) at 96 h after siRNA transfection. The cytotoxicity assay demonstrated notable increase of chemoresistance to 5-FU treatment (10 MUM) in CD133(+) cells at 96 h after siRNA transfection. From this study, we conclude that CD133(+) cells may have chemoresistance to 5-FU through the mechanism which is related with survivin expression, instead of MDR1, ABCG2 and AKT1 expression. Therefore a survivin inhibitor can be a new target for effective treatment of CD133(+) colon cancer. PMID- 26002466 TI - Transforming growth factor beta-activated kinase 1 negatively regulates interleukin-1alpha-induced stromal-derived factor-1 expression in vascular smooth muscle cells. AB - Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1alpha (IL-1alpha) was investigated in primary rat VSMCs. We found IL-1alpha promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein beta (C/EBPbeta) in an IkappaB kinase beta (IKKbeta) signaling-dependent manner. Moreover, IL-1alpha-induced expression of C/EBPbeta and SDF-1 was significantly potentiated by knockdown of transforming growth factor beta activated kinase 1 (TAK1), an upstream activator of IKKbeta signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negative effect on IL-1alpha-induced expression of C/EBPbeta and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1alpha-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. PMID- 26002467 TI - RACK1-mediated translation control promotes liver fibrogenesis. AB - Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1alpha1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1 stimulated collagen 1alpha1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis. PMID- 26002468 TI - Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK. AB - Palmitate (PA), one of the most prevalent saturated fatty acids, causes myocardial dysfunction. However, the mechanisms by which PA induces cell apoptosis and autophagy remain to be elucidated. We showed that autophagy was induced in an mTORC1-dependent way and played a protective role against PA induced apoptosis, which was verified by pretreatment with 3-methyladenine (3MA) and rapamycin. However, p62 began to accumulate after 18 h treatment with PA, suggesting prolonged exposure to PA lead to an impairment of autophagic flux. PA enhanced ROS production as well as activated p38-mitogen-activated protein kinase (p38 MAPK) and c-jun NH2 terminal kinases (JNKs). The antioxidant N-Acety-l Cysteine (NAC) was found to attenuate the JNK and p38 MAPK activation with a concomitant reduction of PA-induced autophagy and apoptosis. Furthermore, both JNK and p38 MAPK inhibitors were shown to directly abrogate caspase 7 cleavage as well as the conversion of LC3BI to LC3BII. Thus, we demonstrate that PA stimulates autophagy and apoptosis via ROS-dependent JNK and p38 MAPK pathways. PMID- 26002469 TI - Disruption of Smad4 in odontoblasts and dental epithelial cells influences the phenotype of multiple keratocystic odontogenic tumors. AB - Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasms with a high recurrence rate. The molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Previous research showed that specific ablation of Smad4 in odontoblasts and dental epithelia resulted in spontaneous KCOTs in mice, and that constitutively activated Hedgehog (Hh) signaling was detected in the cyst epithelia of both Smad4(Co/Co) OC-Cre and Smad4(Co/Co) K5-Cre mice. Here, we ablated Smad4 in mouse odontoblasts and dental epithelia and compared the sizes and numbers of KCOTs. Both the number and size of KCOTs in Smad4(Co/Co) OC-Cre mice were larger than those in Smad4(Co/Co) K5 Cre mice, suggesting that paracrine signals from root odontoblasts play a more important role than those from Hertwig's epithelial root sheath (HERS) cells. PMID- 26002471 TI - Extraction of climatic signals from fossil organic compounds in marine sediments up to 11.7 Ma old (IODP-U1318). AB - This study focuses on the extraction of climate signals and processes using a combined approach which includes the analysis of a high number of lipid molecules in marine sediments, and the chemometric analysis of the acquired data. Neutral and acidic fractions of marine sediments from site IODP-U1318 (south-west of the UK, Porcupine Seabight) were quantified by GC-MS. The alkenone unsaturation index, U(k')37, was estimated from the composition of C37 alkenones and it was then used for the estimation of sea surface temperatures (SST) for reference. Principal component analysis (PCA), explained 77.45% of the total data variance, and differentiated neutral fraction GC-MS total ion current (TIC) profiles according to SST values of the different sediment sections. GC-MS TIC chromatograms were correlated to sea surface temperatures (SST) by partial least squares regression (PLSR). The compounds more robustly in line with SST values at each sediment section explained 93% of the SST variance and they were identified using the variable importance in projection (VIP) scores method. The proposed approach enables an objective identification of organic compounds sensitive to SST variability throughout complete chromatographic profiles. As a result of this multivariate unbiased approach, lipid composition of sediments was differentiated between compounds of marine (long chain n-alkanes, long chain n-alkan-1-ols) and terrestrial (short chain n-alkan1-ols, alkenols, cholesterol, squalene) origin, whose concentrations were directly and inversely correlated to SST, respectively. PMID- 26002470 TI - Drosophila p24 and Sec22 regulate Wingless trafficking in the early secretory pathway. AB - The Wnt signaling pathway is crucial for development and disease. The regulation of Wnt protein trafficking is one of the pivotal issues in the Wnt research field. Here we performed a genetic screen in Drosophila melanogaster for genes involved in Wingless/Wnt secretion, and identified the p24 protein family members Baiser, CHOp24, Eclair and a v-SNARE protein Sec22, which are involved in the early secretory pathway of Wingless/Wnt. We provided genetic evidence demonstrating that loss of p24 proteins or Sec22 impedes Wingless (Wg) secretion in Drosophila wing imaginal discs. We found that Baiser cannot replace other p24 proteins (CHOp24 or Eclair) in escorting Wg, and only Baiser and CHOp24 interact with Wg. Moreover, we showed that the v-SNARE protein Sec22 and Wg are packaged together with p24 proteins. Taken together, our data provide important insights into the early secretory pathway of Wg/Wnt. PMID- 26002472 TI - A tutorial review: Metabolomics and partial least squares-discriminant analysis- a marriage of convenience or a shotgun wedding. AB - The predominance of partial least squares-discriminant analysis (PLS-DA) used to analyze metabolomics datasets (indeed, it is the most well-known tool to perform classification and regression in metabolomics), can be said to have led to the point that not all researchers are fully aware of alternative multivariate classification algorithms. This may in part be due to the widespread availability of PLS-DA in most of the well-known statistical software packages, where its implementation is very easy if the default settings are used. In addition, one of the perceived advantages of PLS-DA is that it has the ability to analyze highly collinear and noisy data. Furthermore, the calibration model is known to provide a variety of useful statistics, such as prediction accuracy as well as scores and loadings plots. However, this method may provide misleading results, largely due to a lack of suitable statistical validation, when used by non-experts who are not aware of its potential limitations when used in conjunction with metabolomics. This tutorial review aims to provide an introductory overview to several straightforward statistical methods such as principal component discriminant function analysis (PC-DFA), support vector machines (SVM) and random forests (RF), which could very easily be used either to augment PLS or as alternative supervised learning methods to PLS-DA. These methods can be said to be particularly appropriate for the analysis of large, highly-complex data sets which are common output(s) in metabolomics studies where the numbers of variables often far exceed the number of samples. In addition, these alternative techniques may be useful tools for generating parsimonious models through feature selection and data reduction, as well as providing more propitious results. We sincerely hope that the general reader is left with little doubt that there are several promising and readily available alternatives to PLS-DA, to analyze large and highly complex data sets. PMID- 26002473 TI - Detection of malathion in food peels by surface-enhanced Raman imaging spectroscopy and multivariate curve resolution. AB - An analytical methodology was developed for detection of malathion in the peels of tomatoes and Damson plums by surface-enhanced Raman imaging spectroscopy and multivariate curve resolution. To recover the pure spectra and the distribution mapping of the analyzed surfaces, non-negative matrix factorization (NMF), multivariate curve calibration methods with alternating least squares (MCR-ALS) and MCR with weighted alternating least square (MCR-WALS) were utilized. Error covariance matrices were estimated to evaluate the structure of the error over all the data. For the tomato data, NMF-ALS and MCR-ALS presented excellent spectral recovery even in the absence of initial knowledge of the pesticide spectrum. For the Damson plum data, owing to heteroscedastic noise, MCR-WALS produced better results. This methodology enabled detection below to the maximum residue limit permitted for this pesticide. This approach can be implemented for in situ monitoring because it is fast and does not require extensive manipulation of samples, making its use feasible for other fruits and pesticides as well. PMID- 26002474 TI - G-quadruplex functionalized nano mesoporous silica for assay of the DNA methyltransferase activity. AB - The abnormal level of DNA methyltransferase (MTase) may cause the aberrant DNA methylation, which has been found being associated with a growing number of human diseases, so it is necessary to create a sensitive and selective method to detect DNA MTase activity. In this paper, a new type of DNA functionalized nano mesoporous silica (MSNs) was creatively introduced to the detection of DNA MTase activity with G-quadruplex as a lock for signal molecule to release. The method was carried out by designing a particular DNA which could fold into G-quadruplex and complement with probe DNA. Next, MSNs was prepared before blocking methylene blue (MB) by G-quadruplex. Probe DNA was then fixed on gold nanoparticles modified glass carbon electrode, and the material was able to be transferred to the surface of electrode by DNA hybridization. After methylation of DNA MTase and the cutting of restriction endonuclease, the electrode was transferred to phosphate buffer solution (pH 9.0) for the releasing of MB. The response of differential pulse voltammetry was obtained from the release of MB. Consequently, the difference of signals with or without methylation could prove the assay of M. SssI MTase activity. The results showed that the responses from MB increased linearly with the increasing of the M. SssI MTase concentrations from 0.28 to 50UmL(-1). The limit of detection was 0.28UmL(-1). In addition, Zebularine, a nucleoside analog of cytidine, was utilized for studying the inhibition activity of M. SssI MTase. PMID- 26002475 TI - Sensitive determination of four camptothecins by solid-phase microextraction-HPLC based on a boronic acid contained polymer monolithic layer. AB - Camptothecin (CPT) and its derivative have been revealed to possess special anti cancer activity, extraction methods are necessary for trace determination of CPTs in complex samples. In this work, we prepared a high efficient boronic acid-based polymer monolithic layer for microextraction of CPTs. A disposable membrane filter-based extraction device was developed, and boronic acid groups were co polymerized into a polyporous polymer skeleton and served as the monolithic sorbent. The prepared poly(4-VB-MA-TRIM) showed good stability and great extraction efficiency toward four CPTs. After optimization of extraction conditions, poly(4-VB-MA-TRIM)-based solid-phase microextraction was coupled HPLC for determination of CPTs in biological samples. The method exhibited low limits of detection of 0.05-0.2 ng mL(-1), which is significantly more sensitive than reported HPLC methods. The method also showed wide linear range (0.1-100 and 0.5 200 ng mL(-1)), good linearity (R(2)>=0.9981) and good reproducibility (RSD <=3.76%). The method has been applied in plasma samples, with good selectivity and good recoveries ranging from 85.1 to 104.7%. PMID- 26002476 TI - Subcritical water extraction of organic matter from sedimentary rocks. AB - Subcritical water extraction of organic matter containing sedimentary rocks at 300 degrees C and 1500 psi produces extracts comparable to conventional solvent extraction. Subcritical water extraction of previously solvent extracted samples confirms that high molecular weight organic matter (kerogen) degradation is not occurring and that only low molecular weight organic matter (free compounds) are being accessed in analogy to solvent extraction procedures. The sedimentary rocks chosen for extraction span the classic geochemical organic matter types. A type I organic matter-containing sedimentary rock produces n-alkanes and isoprenoidal hydrocarbons at 300 degrees C and 1500 psi that indicate an algal source for the organic matter. Extraction of a rock containing type II organic matter at the same temperature and pressure produces aliphatic hydrocarbons but also aromatic compounds reflecting the increased contributions from terrestrial organic matter in this sample. A type III organic matter-containing sample produces a range of non-polar and polar compounds including polycyclic aromatic hydrocarbons and oxygenated aromatic compounds at 300 degrees C and 1500 psi reflecting a dominantly terrestrial origin for the organic materials. Although extraction at 300 degrees C and 1500 psi produces extracts that are comparable to solvent extraction, lower temperature steps display differences related to organic solubility. The type I organic matter produces no products below 300 degrees C and 1500 psi, reflecting its dominantly aliphatic character, while type II and type III organic matter contribute some polar components to the lower temperature steps, reflecting the chemical heterogeneity of their organic inventory. The separation of polar and non-polar organic compounds by using different temperatures provides the potential for selective extraction that may obviate the need for subsequent preparative chromatography steps. Our results indicate that subcritical water extraction can act as a suitable replacement for conventional solvent extraction of sedimentary rocks, but can also be used for any organic matter containing mineral matrix, including soils and recent sediments, and has the added benefit of tailored extraction for analytes of specific polarities. PMID- 26002477 TI - Rapid baculovirus titration assay based on viable cell side scatter (SSC). AB - The baculovirus expression system is one of the most powerful tools for the production of recombinant proteins on both laboratory and industrial scales. Multiplicity of infection (MOI) is the crucial parameter for efficient protein expression. To obtain an optimal MOI, it is important to determine titer of virus stock before protein production. Herein, we established a label-free, simple and rapid method for virus titration based on viable cell side scatter (SSC). Generally, the SSC of cells infected with a series of virus dilutions was measured by a flow cytometer at 48 h post-infection, and the probability of infected cells at a given dilution was estimated. For each well with the infection probabilities between 0.20 and 0.80, the range of dilutions was chosen, and virus titer was determined with a statistical method. Log-scale comparison of the results between the SSC based method and a standard plaque assay showed a good correlation (R(2)=0.9853), suggesting the fine accuracy of this proposed method. PMID- 26002478 TI - Monitoring of phthalates in foodstuffs using gas purge microsyringe extraction coupled with GC-MS. AB - Phthalate esters (PAEs) are commonly used as nonreactive plasticisers in vinyl plastics to increase the flexibility of plastic polymers. Numerous studies have indicated that the PAEs as a class of endocrine-disrupting chemicals. In addition, the studies have also shown that a major source of human exposure to phthalates is the diet. To date, the largest problem in PAEs analysis is the high blank value because PAEs are widely used in various applications and products. To overcome this shortcoming, gas purge microsyringe extraction (GP-MSE) was applied, which established a new and low-blank-value analytical method for PAE analysis to analyse PAEs in foodstuffs. In this study, GP-MSE was used as a clean up method, and the overall recoveries ranged from 85.7 to 102.6%, and the RSD was less than 10%. More importantly, this method can overcome the problem of the high blank value in PAE analysis. This method was applied for measuring PAEs in 78 foodstuffs. The results showed that a wide variety of PAE concentrations were found in the different groups, and the content of PAEs (varies from 658 to 1610 ng g(-1) fresh weight) is greatest in seafood. The concentrations were in the following order: DEHP>DBP>DEP~DMP>BBP~DNOP. Finally, the daily intake of PAEs was estimated for adults based on the levels of PAEs in foodstuffs. The total EDIdiet values of 3.2 and 12.9 MUg kg(-1) bw d(-1) were calculated for DEHP based on the mean and highest concentrations in foodstuffs, respectively. PMID- 26002479 TI - Study of blood collection and sample preparation for analysis of vitamin D and its metabolites by liquid chromatography-tandem mass spectrometry. AB - The analysis of vitamin D status, with special emphasis on 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, is gaining interest in clinical studies due to the classical and non-classical effects attributed to this prohormone. In this research, the influence of the two steps preceding determination (viz. sample collection and preparation) on the quantitative analysis of vitamin D and its more important metabolites has been studied. Two preparation approaches, deproteination and solid-phase extraction (SPE), have been evaluated in terms of sensitivity to delimit their application, thus establishing that detection of 1,25-dihydroxyvitamin D cannot be addressed by protein precipitation. Concerning sample collection, serum and plasma reported high accuracy (above 83.3%) for vitamin D and metabolites, while precision, expressed as relative standard deviation, was below 12.9% for all analytes in both samples. Statistical analysis revealed that serum and plasma provided similar physiological levels for vitamin D3, 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3, while significantly different levels were obtained for 1,25-dihydroxyvitamin D3, always higher in plasma than in serum. Sample collection and treatment have proved to be significant in the analysis of vitamin D and its relevant metabolites. PMID- 26002480 TI - Sensitive targeted multiple protein quantification based on elemental detection of quantum dots. AB - A generic strategy based on the use of CdSe/ZnS Quantum Dots (QDs) as elemental labels for protein quantification, using immunoassays with elemental mass spectrometry (ICP-MS), detection is presented. In this strategy, streptavidin modified QDs (QDs-SA) are bioconjugated to a biotinylated secondary antibody (b Ab2). After a multi-technique characterization of the synthesized generic platform (QDs-SA-b-Ab2) it was applied to the sequential quantification of five proteins (transferrin, complement C3, apolipoprotein A1, transthyretin and apolipoprotein A4) at different concentration levels in human serum samples. It is shown how this generic strategy does only require the appropriate unlabeled primary antibody for each protein to be detected. Therefore, it introduces a way out to the need for the cumbersome and specific bioconjugation of the QDs to the corresponding specific recognition antibody for every target analyte (protein). Results obtained were validated with those obtained using UV-vis spectrophotometry and commercial ELISA Kits. As expected, ICP-MS offered one order of magnitude lower DL (0.23 fmol absolute for transferrin) than the classical spectrophotometric detection (3.2 fmol absolute). ICP-MS precision and detection limits, however turned out to be compromised by procedural blanks. The full analytical performance of the ICP-MS-based immunoassay proposed was assessed for detection of transferrin (Tf), present at the low ng mL(-1) range in a complex "model" synthetic matrix, where the total protein concentration was 100 MUg mL(-1). Finally, ICP-MS detection allowed the quantitative control of all the steps of the proposed immunoassay, by computing mass balances obtained, and the development of a faster indirect immunoassay format where the plate wells were directly coated with the whole protein mixture sample. PMID- 26002481 TI - A tetraphenylimidazole-based fluorescent probe for the detection of hydrogen sulfide and its application in living cells. AB - A novel probe based on the fluorescence off-on strategy was prepared to optically detect hydrogen sulfide (H2S) via an excited state intramolecular proton transfer (ESIPT) mechanism. The probe shows high sensitivity and excellent selectivity to H2S. It also displays a large Stokes shift (~140 nm) and a remarkable quantum yield enhancement (F=0.412) after interaction with H2S. Moreover, the cellular imaging experiment demonstrated that it has potential utility for H2S sensing in biological sciences. PMID- 26002482 TI - Enzymatic cleavage and mass amplification strategy for small molecule detection using aptamer-based fluorescence polarization biosensor. AB - Fluorescence polarization (FP) assays incorporated with fluorophore-labeled aptamers have attracted great interest in recent years. However, detecting small molecules through the use of FP assays still remains a challenge because small molecule binding only results in negligible changes in the molecular weight of the fluorophore-labeled aptamer. To address this issue, we herein report a fluorescence polarization (FP) aptamer assay that incorporates a novel signal amplification strategy for highly sensitive detection of small molecules. In the absence of adenosine, our model target, free FAM-labeled aptamer can be digested by nuclease, resulting in the release of FAM-labeled nucleotide segments from the dT-biotin/streptavidin complex with weak background signal. However, in the presence of target, the FAM-labeled aptamer-target complex protects the FAM labeled aptamer from nuclease cleavage, allowing streptavidin to act as a molar mass amplifier. The resulting increase in molecular mass and FP intensity of the aptamer-target complex provides improved sensitivity for concentration measurement. The probe could detect adenosine from 0.5 MUM to 1000 MUM, with a detection limit of 500 nM, showing that the sensitivity of the probe is superior to aptamer-based FP approaches previously reported for adenosine. Importantly, FP could resist environmental interferences, making it useful for complex biological samples without any tedious sample pretreatments. Our results demonstrate that this dual-amplified, aptamer-based strategy can be used to design fluorescence polarization probes for rapid, sensitive, and selective measurement of small molecules in complicated biological environment. PMID- 26002483 TI - Fluorescent probe for turn-on sensing of L-cysteine by ensemble of AuNCs and polymer protected AuNPs. AB - A new fluorescent probe based on ensemble of gold nanoclusters (AuNCs) and polymer protected gold nanoparticles (AuNPs) for turn-on sensing of L-cysteine was designed and prepared. The AuNCs were protected by bovine serum albumin and had strong fluorescence. The polymer protected AuNPs were synthesized by a facile in situ strategy at room temperature and could quench the fluorescence of AuNCs due to the Forster resonance energy transfer. Interestingly, it has been observed that the quenched fluorescence of AuNCs was recovered by L-cysteine, which could induce the aggregation of polymer protected AuNPs by sulfur group. Then the prepared fluorescent probe was successfully used for determination of L-Cys in human urines, which would have an evolving aspect and promote the subsequent exploration. PMID- 26002484 TI - A turn-on fluorescent probe for selective and sensitive detection of hydrogen sulfide. AB - An imidazolethione based turn-on fluorescent probe was synthesized for the detection of hydrogen sulfide, a biologically relevant molecule and an important air pollutant. The probe rapidly and selectively reacted with hydrogen sulfide to produce a strongly fluorescent product, resulting in the fluorescence enhancement of the system. The detection limit was determined to be 30 nM at the probe concentration of 1.0 MUM. An indicating paper for visual detection of hydrogen sulfide gas has been fabricated by immobilizing the probe on a piece of appropriate paper substrate, and the detection limit of the visual method reached as low as 0.7 ppm. Moreover, the fluorescence turn-on/off of the system showed good reversibility when exposed alternately to hydrogen sulfide and mercuric ion, which was utilized to make an INHIBIT logic circuit for the presence of the two species. PMID- 26002485 TI - Analyte-induced photoreduction method for visual and colorimetric detection of tyrosine. AB - A new method based on photochemical formation of silver nanoparticles (AgNPs) was developed for detection of tyrosine (Tyr). To selectively detect Tyr and to simplify the detection procedure, the photoactivity of Tyr was utilized to trigger the photochemical reduction in production of AgNPs. The drastic change of solution color caused by the surface plasmon resonance (SPR) absorption band of the formed AgNPs was used to extract the quantitative information of Tyr. This developed method is simple in detection, while both the sensitivity and selectivity are significant improved. Meanwhile, the solution color was changed from colorless to dark yellow after the formation of AgNPs, which allows a much higher sensitivity in visual identification when compared with the SPR band shifting technique commonly, used in conventional colorimetric methods. To optimize the detection system and to understand the mechanism in this proposed method, parameters such as irradiation time, intensity of light source, and the concentration of Tyr were systematically examined. Results indicated that these factors mainly affected the reaction rate of photoreduction. The morphologies of the formed AgNPs were similar, but with small differences in particle sizes. In the examination of selectivity, sixteen other amino acids were examined. Results indicated that only amino acids of tryptophan, cysteine and histidine are photoactive and possess potential interferences in analysis of Tyr. Quantitative studies indicated that a linear response up to 10 MUM with a detection limit of 100 nM could be obtained. For visually detection, color change could be observed with a concentration as low as 500 nM of Tyr. PMID- 26002486 TI - Colorimetric detection of iron ions (III) based on the highly sensitive plasmonic response of the N-acetyl-L-cysteine-stabilized silver nanoparticles. AB - We report here a facile colorimetric sensor based on the N-acetyl-L-cysteine (NALC)-stabilized Ag nanoparticles (NALC-Ag NPs) for detection of Fe(3+) ions in aqueous solution. The Ag NPs with an average diameter of 6.55+/-1.0 nm are successfully synthesized through a simple method using sodium borohydride as reducing agent and N-acetyl-L-cysteine as protecting ligand. The synthesized silver nanoparticles show a strong surface plasmon resonance (SPR) around 400 nm and the SPR intensity decreases with the increasing of Fe(3+) concentration in aqueous solution. Based on the linear relationship between SPR intensity and concentration of Fe(3+) ions, the as-synthesized water-soluble silver nanoparticles can be used for the sensitive and selective detection of Fe(3+) ions in water with a linear range from 80 nM to 80 MUM and a detection limit of 80 nM. On the basis of the experimental results, a new detection mechanism of oxidation-reduction reaction between Ag NPs and Fe(3+) ions is proposed, which is different from previously reported mechanisms. Moreover, the NALC-Ag NPs could be applied to the detection of Fe(3+) ions in real environmental water samples. PMID- 26002487 TI - False positive and false negative diagnoses of prostate cancer at multi parametric prostate MRI in active surveillance. AB - MP-MRI is a critical component in active surveillance (AS) of prostate cancer (PCa) because of a high negative predictive value for clinically significant tumours. This review illustrates pitfalls of MP-MRI and how to recognise and avoid them. The anterior fibromuscular stroma and central zone are low signal on T2W-MRI/apparent diffusion coefficient (ADC), resembling PCa. Location, progressive enhancement and low signal on b >=1000 mm2/s echo-planar images (EPI) are differentiating features. BPH can mimic PCa. Glandular BPH shows increased T2W/ADC signal, cystic change and progressive enhancement; however, stromal BPH resembles transition zone (TZ) PCa. A rounded morphology, low T2 signal capsule and posterior/superior location favour stromal BPH. Acute/chronic prostatitis mimics PCa at MP-MRI, with differentiation mainly on clinical grounds. Visual analysis of diffusion-weighted MRI must include EPI and appropriate windowing of ADC. Quantitative ADC analysis is limited by lack of standardization; the ADC ratio and ADC histogram analysis are alternatives to mean values. DCE lacks standardisation and has limited utility in the TZ, where T2W/DWI are favoured. Targeted TRUS-guided biopsies of MR-detected lesions are challenging. Lesions detected on MP-MRI may not be perfectly targeted with TRUS and this must be considered when faced with a suspicious lesion on MP-MRI and a negative targeted TRUS biopsy histopathological result. KEYPOINTS: * Multi-parametric MRI plays a critical role in prostate cancer active surveillance. * Low T2W signal intensity structures appear dark on ADC, potentially simulating cancer. * Stromal BPH mimics cancer at DWI and DCE. * Long b value trace EPI should be reviewed * Targeted biopsy of MR-detected lesions using TRUS guidance may be challenging. PMID- 26002488 TI - Radiocaesium activity concentrations in parmelioid lichens within a 60 km radius of the Fukushima Dai-ichi Nuclear Power Plant. AB - Radiocaesium activity concentrations ((134)Cs and (137)Cs) were measured in parmelioid lichens collected within the Fukushima Prefecture approximately 2 y after the Fukushima Dai-ichi Nuclear Power Plant accident. A total of 44 samples consisting of nine species were collected at 16 points within a 60 km radius of the Fukushima Dai-ichi Nuclear Power Plant. The activity concentration of (134)Cs ranged from 4.6 to 1000 kBq kg(-1) and for (137)Cs ranged from 7.6 to 1740 kBq kg(-1). A significant positive correlation was found between the (137)Cs activity concentration in lichens and the (137)Cs deposition density on soil (n = 44), based on the calculated Spearman's rank correlation coefficients as r = 0.90 (P < 0.01). The two dominant species, Flavoparmelia caperata (n = 12) and Parmotrema clavuliferum (n = 11), showed strong positive correlations, for which the r values were calculated as 0.92 (P < 0.01) and 0.90 (P < 0.01) respectively. Therefore, Flavoparmelia caperata and Parmotrema clavuliferum are suggested as biomonitoring species for levels of radiocaesium fallout within the Fukushima Prefecture. PMID- 26002489 TI - Subclinical cerebrovascular disease inversely associates with learning ability: The NOMAS. AB - OBJECTIVE: Memory has been examined in subjects with imaging markers of cerebrovascular disease, but learning has been less well studied. We examined the relationship among subclinical cerebrovascular disease, cerebral volumes, and verbal learning in an ethnically and racially diverse community sample. METHODS: A clinically stroke-free subset of Northern Manhattan Study participants underwent cognitive testing and brain MRI with quantification of white matter hyperintensity volume (WMHV) and total cerebral volume (TCV) using semiautomated segmentation. We used generalized linear regression and mixed models to examine the association between imaging findings and verbal learning. RESULTS: There were 1,272 participants (61% women, mean age 70 +/- 9 years). Participants with greater WMHV and smaller TCV remembered fewer total words on a list-learning task (beta = -0.83 per SD change in WMHV, 95% confidence interval [CI] = -1.22 to 0.45, p < 0.0001; and beta = 0.48 per SD change in TCV, 95% CI = 0.05 to 0.90, p = 0.03, respectively). Subclinical brain infarction (SBI) was not associated with total words learned (beta = -0.04, 95% CI = -1.08 to 1.00, p = 0.94). Those with greater WMHV had increased odds of a flatter learning slope. After excluding participants with SBI, the association between total words learned and WMHV remained significant. All measurements were adjusted for age, education, race/ethnicity, medical insurance status, and the presence of SBI. CONCLUSIONS: White matter hyperintensities, a marker of cerebral small vessel disease, may have an impact on learning slope. This suggests that verbal learning performance can be incorporated into neuropsychological measures for vascular cognitive impairment and that cerebrovascular disease discovered on imaging affects the ability to learn new information. PMID- 26002490 TI - The relative importance of heads, bodies, and movement to person recognition across development. AB - Children have been shown to be worse at face recognition than adults even into their early teens. However, there is debate about whether this is due to face specific mechanisms or general perceptual and memory development. Here, we considered a slightly different option--that children use different cues to recognition. To test this, we showed 8-year-olds, 10-year-olds, and adults whole body, head only, and body only stimuli that were either moving or static. These were shown in two tasks, a match-to-sample task with unfamiliar people and a learning task, to test recognition of experimentally familiar people. On the match-to-sample task, children were worse overall, but the pattern of results was the same for each age group. Matching was best with all cues or head available, and there was no effect of movement. However, matching was generally slower with moving stimuli, and 8-year-olds, but not 10-year-olds, were slower than adults. In general, more cues were faster than heads or bodies alone, but 8-year-olds were surprisingly slow when still bodies were shown alone. On the learning task, again all age groups showed similar patterns, with better performance for all cues. Both 8- and 10-year-olds were more likely to say that they knew someone unfamiliar. Again, movement did not provide a clear advantage. Overall, this study suggests that any differences in face recognition between adults and children are not due to differences in cue use and that instead these results are consistent with general improvements in memory. PMID- 26002491 TI - Ethical Practice Under Accountable Care. AB - Accountable Care Organizations (ACOs) are a key mechanism of the Patient Protection and Affordable Care Act (PPACA). ACOs will influence incentives for providers, who must understand these changes to make well-considered treatment decisions. Our paper defines an ethical framework for physician decisions and action within ACOs. Emerging ethical pressures providers will face as members of an ACO were classified under major headings representing three of the four principles of bioethics: autonomy, beneficence, and justice (no novel conflicts with non-maleficence were identified). Conflicts include a bias against transient populations, a motive to undertreat conditions lacking performance measures, and the mandate to improve population health incentivizing life intrusions. After introducing and explaining each conflict, recommendations are offered for how providers ought to precede in the face of novel ethical choices. Our description of novel ethical choices will help providers know what to expect and our recommendations can guide providers in choosing well. PMID- 26002492 TI - Perception of Value and the Minimally Conscious State. AB - The "disability paradox" is the idea that for those who become severely disabled, their own quality of life (QoL) assessment remains at or slightly below the QoL assessments of normal controls. This is a source of skepticism regarding third person QoL judgments of the disabled. I argue here that this skepticism applies as well to those who are in the minimally conscious state (MCS). For rather simple means of sustaining an MCS patient's life (for example, tube feeding), the cost of being wrong that the patient would not want further support is high. Pair this cost with the reason to be skeptical of third-person judgments, and my argument suggests not withholding food and water from MCS patients. PMID- 26002493 TI - Comparison of two surgical methods for the treatment of CIN: classical LLETZ (large-loop excision of the transformation zone) versus isolated resection of the colposcopic apparent lesion - study protocol for a randomized controlled trial. AB - BACKGROUND: In compliance with national and international guidelines, non pregnant women with cervical intraepithelial neoplasia grade 3 should be treated by cervical conization. According to the definition of the large loop excision of the transformation zone (LLETZ) operation, the lesion needs to be resected, including the transformation zone. It is well known from the literature that the cone size directly correlates with the risk of preterm delivery in the course of a future pregnancy. Thus, it would be highly desirable to keep the cone dimension as small as possible while maintaining the same level of oncological safety. METHODS/DESIGN: The aim of this study is to analyze whether resection of the lesion only, without additional excision of the transformation zone, is equally as effective as the classical LLETZ operation regarding oncological outcome. We are performing this prospective, patient-blinded multicenter trial by randomly assigning women who need to undergo a LLETZ operation for cervical intraepithelial neoplasia grade 3 to either of the following two groups at a ratio of 1:1: (1) additional resection of the transformation zone or (2) resection of the lesion only. To evaluate equal oncological outcome, we are performing human papillomavirus (HPV) tests 6 and 12 months postoperatively. The study is designed to consider the lesion-only operation as oncologically not inferior if the rate of HPV high-risk test results is not higher than 5 % compared with the HPV high-risk rate of women undergoing the classical LLETZ operation. DISCUSSION: In case that non-inferiority of the "lesion-only" method can be demonstrated, this operation should eventually become standard treatment for all women at childbearing age due to the reduction in risk of preterm delivery. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) Identifier: DRKS00006169 . Date of registration: 30 July 2014. PMID- 26002494 TI - Guidelines for presymptomatic testing for Huntington's disease: past, present and future in France. AB - Huntington's disease was the first adult onset neurological disease for which presymptomatic genetic testing became possible. It served as a model for the approach which constituted a radical change in medical practice and provided an important framework for multi-step, multidisciplinary, counselling for at risk persons. We will review the historical context of guidelines and good clinical practices, the experiences of our team which covers more than 20 years of presymptomatic testing for Huntington's disease in France, and explore the impact of the new French legislation for the future of presymptomatic testing of diseases for which neither preventive measures nor curative treatments are yet available. PMID- 26002495 TI - Outline of metabolic diseases in adult neurology. AB - INTRODUCTION: Inborn errors of metabolism (IEM) are traditionally defined by enzymatic deficiencies or defects in proteins involved in cellular metabolism. Historically discovered and characterized in children, a growing number of IEM are described in adults, and especially in the field of neurology. In daily practice, it is important to recognize emergency situations as well as neurodegenerative diseases for which a metabolic disease is likely, especially when therapeutic interventions are available. OBJECTIVES: Here, the goal is to provide simple clinical, imaging and biochemical tools that can first orientate towards and then confirm the diagnosis of IEM. General guidelines are presented to treat the most common IEM during metabolic crises - acute encephalopathies with increased plasma ammonia, lactate or homocystein, as well as rhabdomyolysis. Examples of therapeutic strategies currently applied to chronic neurometabolic diseases are also provided - GLUT1 deficiency, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Niemann-Pick type C and Wilson disease. Genetic counseling is mandatory in some X-linked diseases - ornithine transcarbamylase deficiency and adrenoleukodystrophy - and recommended in maternally inherited mitochondrial diseases - mutations of mitochondrial DNA. CONCLUSION: Besides these practical considerations, the contribution of metabolism to the field of adult neurology and neurosciences is much greater: first, with the identification of blood biomarkers that are progressively changing our diagnostic strategies thanks to lipidomic approaches, as illustrated in the field of spastic paraplegia and atypical psychiatric presentations; and second, through the understanding of pathophysiological mechanisms involved in common neurological diseases thanks to the study of these rare diseases. PMID- 26002496 TI - The Ethics of Big Data: Current and Foreseeable Issues in Biomedical Contexts. AB - The capacity to collect and analyse data is growing exponentially. Referred to as 'Big Data', this scientific, social and technological trend has helped create destabilising amounts of information, which can challenge accepted social and ethical norms. Big Data remains a fuzzy idea, emerging across social, scientific, and business contexts sometimes seemingly related only by the gigantic size of the datasets being considered. As is often the case with the cutting edge of scientific and technological progress, understanding of the ethical implications of Big Data lags behind. In order to bridge such a gap, this article systematically and comprehensively analyses academic literature concerning the ethical implications of Big Data, providing a watershed for future ethical investigations and regulations. Particular attention is paid to biomedical Big Data due to the inherent sensitivity of medical information. By means of a meta analysis of the literature, a thematic narrative is provided to guide ethicists, data scientists, regulators and other stakeholders through what is already known or hypothesised about the ethical risks of this emerging and innovative phenomenon. Five key areas of concern are identified: (1) informed consent, (2) privacy (including anonymisation and data protection), (3) ownership, (4) epistemology and objectivity, and (5) 'Big Data Divides' created between those who have or lack the necessary resources to analyse increasingly large datasets. Critical gaps in the treatment of these themes are identified with suggestions for future research. Six additional areas of concern are then suggested which, although related have not yet attracted extensive debate in the existing literature. It is argued that they will require much closer scrutiny in the immediate future: (6) the dangers of ignoring group-level ethical harms; (7) the importance of epistemology in assessing the ethics of Big Data; (8) the changing nature of fiduciary relationships that become increasingly data saturated; (9) the need to distinguish between 'academic' and 'commercial' Big Data practices in terms of potential harm to data subjects; (10) future problems with ownership of intellectual property generated from analysis of aggregated datasets; and (11) the difficulty of providing meaningful access rights to individual data subjects that lack necessary resources. Considered together, these eleven themes provide a thorough critical framework to guide ethical assessment and governance of emerging Big Data practices. PMID- 26002497 TI - Strategy to increase research in Latin America: project on education in research by AOSpine Latin America. AB - BACKGROUND: The emancipatory nature of education requires research as its fundamental base, because physicians can only improve their skills and knowledge through enquiry. The number and quality of scientific publications by Latin American spine surgeons found in the Medline database was low between 2000 and 2011. Nevertheless, the research Bank Survey of AOSpine Latin America (AOSLA) members showed that 96% of responders were very interested and motivated to perform scientific research. METHODS AND POPULATION: The research officer of AOSLA together with the Country Council and the AOSpine Research Commission established a competency-based curriculum to improve understanding of what is necessary to produce research and the best methods to achieve this goal. The research curriculum was divided into four main components: (1) research educational plan, (2) performing research, (3) technical and professional support and (4) assessment. RESULTS: The competences, learning outcomes and a syllabus on knowledge in research were developed to enable the participants to understand and perform investigations effectively. The eLearning module was designed to improve the competences to access, evaluate and use scientific information available in the main databases efficiently. Research courses were given as an isolated activity four times in Brazil and Mexico and as precourse activities six times in Brazil, Mexico and Peru. The result was an increased number of articles published and works presented at congresses. CONCLUSIONS: The project of education in research can be effectively disseminated and applied across regions, across students and across specialties. PMID- 26002498 TI - The influence of budA deletion on glucose metabolism related in 2,3-butanediol production by Klebsiella pneumoniae. AB - Klebsiella pneumoniae (K. pneumoniae), which is a promising microorganism for industrial bulk production of 2,3-butanediol (2,3-BDO), naturally converts glucose to 2,3-BDO. The 2,3-BDO biosynthesis from glucose is composed of three steps; alpha-acetolactate biosynthesis by alpha-acetolactate synthase (budB); acetoin biosynthesis by alpha-acetolactate decarboxylase (budA); and 2,3-BDO biosynthesis by acetoin reductase (budC). In an effort to understand the influence of blocked 2,3-BDO pathway on K. pneumoniae glucose metabolism by budA deletion, we constructed K. pneumoniaeDeltawabGDeltabudA (SGSB106). Carbon flux distribution analysis, transcriptome analysis and extracellular amino acid concentration analysis were carried out to understand the effects of the budA deletion, and K. pneumoniaeDeltawabG (SGSB100) was used as a control strain. Approximately 50.3% decrease in CO2 emission; and approximately 3.8-fold increase in amino acid production was observed in SGSB106. In addition to, among the amino acids, valine production significantly increased, suggesting that the branched chain amino acid biosynthesis (BACC) in SGSB106 was activated by deletion of budA. Furthermore, whole genome transcriptome analysis of SGSB106 and SGSB100, correlates with the results from carbon distribution and amino acids concentration analyses. PMID- 26002499 TI - Cellulose and hemicellulose-degrading enzymes in Fusarium commune transcriptome and functional characterization of three identified xylanases. AB - Specific enzymes from plant-pathogenic microbes demonstrate high effectiveness for natural lignocellulosic biomass degradation and utilization. The secreted lignocellulolytic enzymes of Fusarium species have not been investigated comprehensively, however. In this study we compared cellulose and hemicellulose degrading enzymes of classical fungal enzyme producers with those of Fusarium species. The results indicated that Fusarium species are robust cellulose and hemicellulose degraders. Wheat bran, carboxymethylcellulose and xylan-based growth media induced a broad spectrum of lignocellulolytic enzymes in Fusarium commune. Prediction of the cellulose and hemicellulose-degrading enzymes in the F. commune transcriptome using peptide pattern recognition revealed 147 genes encoding glycoside hydrolases and six genes encoding lytic polysaccharide monooxygenases (AA9 and AA11), including all relevant cellulose decomposing enzymes (GH3, GH5, GH6, GH7, GH9, GH45 and AA9), and abundant hemicellulases. We further applied peptide pattern recognition to reveal nine and seven subfamilies of GH10 and GH11 family enzymes, respectively. The uncharacterized XYL10A, XYL10B and XYL11 enzymes of F. commune were classified, respectively, into GH10 subfamily 1, subfamily 3 and GH11 subfamily 1. These xylanases were successfully expressed in the PichiaPinkTM system with the following properties: the purified recombinant XYL10A had interesting high specific activity; XYL10B was active at alkaline conditions with both endo-1,4-beta-d-xylanase and beta-xylosidase activities; and XYL11 was a true xylanase characterized by high substrate specificity. These results indicate that F. commune with genetic modification is a promising source of enzymes for the decomposition of lignocellulosic biomass. PMID- 26002500 TI - Peptide synthesis in neat organic solvents with novel thermostable proteases. AB - Biocatalytic peptide synthesis will benefit from enzymes that are active at low water levels in organic solvent compositions that allow good substrate and product solubility. To explore the use of proteases from thermophiles for peptide synthesis under such conditions, putative protease genes of the subtilase class were cloned from Thermus aquaticus and Deinococcus geothermalis and expressed in Escherichia coli. The purified enzymes were highly thermostable and catalyzed efficient peptide bond synthesis at 80 degrees C and 60 degrees C in neat acetonitrile with excellent conversion (>90%). The enzymes tolerated high levels of N,N-dimethylformamide (DMF) as a cosolvent (40-50% v/v), which improved substrate solubility and gave good conversion in 5+3 peptide condensation reactions. The results suggest that proteases from thermophiles can be used for peptide synthesis under harsh reaction conditions. PMID- 26002501 TI - Tandem-yeast expression system for engineering and producing unspecific peroxygenase. AB - Unspecific peroxygenase (UPO) is a highly efficient biocatalyst with a peroxide dependent monooxygenase activity and many biotechnological applications, but the absence of suitable heterologous expression systems has precluded its use in different industrial settings. Recently, the UPO from Agrocybe aegerita was evolved for secretion and activity in Saccharomyces cerevisiae [8]. In the current work, we describe a tandem-yeast expression system for UPO engineering and large scale production. By harnessing the directed evolution process in S. cerevisiae, the beneficial mutations for secretion enabled Pichia pastoris to express the evolved UPO under the control of the methanol inducible alcohol oxidase 1 promoter. Whilst secretion levels were found similar for both yeasts in flask fermentation (~8mg/L), the recombinant UPO from P. pastoris showed a 27 fold enhanced production in fed-batch fermentation (217mg/L). The P. pastoris UPO variant maintained similar biochemical properties of the S. cerevisiae counterpart in terms of catalytic constants, pH activity profiles and thermostability. Thus, this tandem-yeast expression system ensures the engineering of UPOs to use them in future industrial applications as well as large scale production. PMID- 26002502 TI - Enzyme catalytic nitration of aromatic compounds. AB - Nitroaromatic compounds are important intermediates in organic synthesis. The classic method used to synthesize them is chemical nitration, which involves the use of nitric acid diluted in water or acetic acid, both harmful to the environment. With the development of green chemistry, environmental friendly enzyme catalysis is increasingly employed in chemical processes. In this work, we adopted a non-aqueous horseradish peroxidase (HRP)/NaNO2/H2O2 reaction system to study the structural characteristics of aromatic compounds potentially nitrated by enzyme catalysis, as well as the relationship between the charges on carbon atoms in benzene ring and the nitro product distribution. Investigation of various reaction parameters showed that mild reaction conditions (ambient temperature and neutral pH), plus appropriate use of H2O2 and NaNO2 could prevent inactivation of HRP and polymerization of the substrates. Compared to aqueous organic co-solvent reaction media, the aqueous-organic two-liquid phase system had great advantages in increasing the dissolved concentration of substrate and alleviating substrate inhibition. Analysis of the aromatic compounds' structural characteristics indicated that substrates containing substituents of NH2 or OH were readily catalyzed. Furthermore, analysis of the relationship between natural bond orbital (NBO) charges on carbon atoms in benzene ring, as calculated by the density functional method, and the nitro product distribution characteristics, demonstrated that the favored nitration sites were the ortho and para positions of substituents in benzene ring, similar to the selectivity of chemical nitration. PMID- 26002503 TI - Fungal demethylation of Kraft lignin. AB - Demethylation of industrial lignin has been for long coveted as a pathway to the production of an abundant natural substitute for fossil-oil derived phenol. In an attempt to possibly identify a novel Kraft lignin-demethylating enzyme, we surveyed a collection of fungi by using selected ion flow tube-mass spectrometry (SIFT-MS). This method readily identifies methanol resulting from lignin demethylation activity. Absidia cylindrospora, and unidentified Cylindrocladium sp. and Aspergillus sp. were shown to metabolize lignin via different pathways, based on the HPLC analysis of lignin fragments. Of these three, Cylindrocladium and Aspergillus were shown to retain most of the lignin intact after 3 weeks in culture, while removing about 40% of the available methoxy groups. Our results demonstrate that after optimization of culture and lignin recovery methods, biological modification of Kraft lignin may be a feasible pathway to obtaining demethylated lignin for further industrial use. PMID- 26002504 TI - Bacteriophage phi11 lysin: Physicochemical characterization and comparison with phage phi80alpha lysin. AB - Phage lytic enzymes are promising antimicrobial agents. Lysins of phages phi11 (LysPhi11) and phi80alpha (LysPhi80alpha) can lyse (destroy) cells of antibiotic resistant strains of Staphylococcus aureus. Stability of enzymes is one of the parameters making their practical use possible. The objectives of the study were to investigate the stability of lysins of phages phi11 and phi80alpha in storage and functioning conditions, to identify optimum storage conditions and causes of inactivation. Stability of the recombinant LysPhi11 and LysPhi80alpha was studied using turbidimetry. CD-spectroscopy, dynamic light scattering, and electrophoresis were used to identify causes of inactivation. At 37 degrees C, pH 7.5 and concentration of NaCl not higher than 150mM, LysPhi11 molecules contain a high percentage of random coils (43%). However, in spite of this the enzyme has high activity (0.4-0.8OD600nms(-1)mg(-1)). In storage conditions (4 degrees C and 22 degrees C, pH 6.0-9.0, 10-500mM NaCl) LysPhi11 is inactivated by a monomolecular mechanism. The optimum storage conditions for LysPhi11 (4 degrees C, pH 6.0-7.5, 10mM NaCl) were selected under which the time of the enzyme half inactivation is 120-160 days. LysPhi80alpha stability is insufficient: at 37 degrees C the enzyme loses half of its activity almost immediately; at 4 degrees C and 22 degrees C the time of half-inactivation of LysPhi80alpha varies in the range from several hours to 3 days. Despite the common properties in the manifestation of antistaphylococcal activity the kinetic behavior of the enzymes is different. LysPhi11 is a more promising candidate to be used as an antimicrobial agent. PMID- 26002505 TI - Microbial fuel cell-based diagnostic platform to reveal antibacterial effect of beta-lactam antibiotics. AB - Beta-lactam antibiotics comprise the largest group of antibacterial agents. Due to their bactericidal properties and limited toxicity to humans they are preferred in antimicrobial therapy. In most cases, therapy is empiric since susceptibility testing in diagnostic laboratories takes a relatively long time. This paper presents a novel platform that is based on the microbial fuel cell (MFC) technology and focuses on the early antibiogram determination of isolates against a series of beta-lactam antibiotics. An advantage of the system is that it can be integrated into traditional microbiological diagnostic laboratory procedures. Tested bacterium suspensions are uploaded into the anodic chambers of each miniaturized MFC unit integrated into a panel system, containing different antibiotic solutions. Electronic signals gained in each MFC unit are continuously monitored and are proportional to the metabolic activity of the presenting test bacterium. Using this method, antibiotic susceptibility can be evaluated in 2-4h after inoculation. Hereby we demonstrate the efficacy of the platform in antibiogram determination by testing the susceptibilities of Escherichia coli strain ATCC 25922 and Staphylococcus aureus strain ATCC 29213 against 10 beta lactam antibiotics (penicillin, ampicillin, ticarcillin, cefazolin, cefuroxime, cefoperazone, cefepime, cefoxitin, cefaclor, imipenem). This paper also presents the construction of the background instrumentation and the panel system into which a printed circuit board (PCB) based electrode was integrated. Our results suggest that MFC based biosensors have the potential to be used in diagnostics for antibiogram determination. PMID- 26002506 TI - Identification and characterization of three Penicillium chrysogenum alpha-l arabinofuranosidases (PcABF43B, PcABF51C, and AFQ1) with different specificities toward arabino-oligosaccharides. AB - We previously described four alpha-l-arabinofuranosidases (ABFs) secreted by Penicillium chrysogenum 31B. Here, we cloned the fifth and sixth genes (Pcabf43B and Pcabf51C) encoding the ABFs PcABF43B and PcABF51C in this strain and overexpressed these genes in Escherichia coli. The deduced amino acid sequences of PcABF43B and PcABF51C were highly similar to putative ABFs belonging to glycoside hydrolase families 43 and 51, respectively. Semiquantitative reverse transcription polymerase chain reaction indicated that both genes were induced by arabinose, arabinitol, arabinan, and arabinoxylan; however, the Pcabf51C gene was constitutively expressed at low levels in P. chrysogenum 31B. PcABF43B had optimal activity at 20 degrees C and pH 5-6, indicating that this enzyme was psychrophilic and had the lowest optimal temperature reported for ABFs. PcABF51C had optimal activity at 45 degrees C and pH 6-7. Both recombinant enzymes showed high activity on arabino-oligosaccharides, but little activity on arabinose containing polysaccharides, such as l-arabinan. Next, we compared the substrate specificities of PcABF43B, PcABF51C, and AFQ1, a P. chrysogenum ABF that preferentially degraded oligosaccharides over polysaccharides. PcABF43B was found to preferentially hydrolyze (1->3)-linkages in branched arabino-oligosaccharides and released only a small amount of arabinose from linear alpha-1,5-arabino oligosaccharides. In contrast, AFQ1 and PcABF51C showed higher activities on linear arabino-oligosaccharides than on branched arabino-oligosaccharides. AFQ1 showed high catalytic efficiencies for alpha-1,5-l-arabinofuranobiose (alpha-1,5 Ara2) and alpha-1,5-l-arabinofuranotriose (alpha-1,5-Ara3) at the same level. In contrast, intracellular PcABF51C showed much higher catalytic efficiency for alpha-1,5-Ara2 than for alpha-1,5-Ara3. PMID- 26002507 TI - Studies on the function and catalytic mechanism of O-methyltransferases SviOMT02, SviOMT03 and SviOMT06 from Streptomyces virginiae IBL14. AB - To identify the fuctions of the nine putative O-methyltransferase genes in Streptomyces virginiae IBL14, the evolutionary and functional relationship of these genes in its 8.0 Mb linear chromosome was set up via sequence comparison with those of other Streptomyces species. Further, the functions and catalytic mechanism of the three genes sviOMT02, sviOMT03 and sviOMT06 from this strain were studied through experimental and computational approaches. As a result, the nine putative O-methyltransferases belong to methyltransf_2 superfamily, amdomet MTases superfamily, and leucine carboxyl methyltransferase superfamily, and are phylogenetically close to those of Streptomyces sp. C. The products of genes sviOMT03 and sviOMT06 could catalyze O-methylation of caffeic acid to form ferulic acid. Computational analysis indicated that the O-methylation mechanism of SviOMT03 and SviOMT06 proceeds from a direct transfer of the SAM-methyl group to caffeic acid with inversion of symmetry aided by a divalent metal ion in a SN2 like mechanism. Particularly, the conservative polar amino acid residues in SviOMT03 and SviOMT06, including Lys143 that reacts with caffeic acid, Ser74, Asp140 and Tyr149 that react with S-adenosyl methionine, and His142 (SviOMT03) or His171 (SviOMT06) that transfers the 3-hydroxyl proton of substrate caffeic acid, probably be essential in their O-methylation. PMID- 26002508 TI - Drug maker must restart obesity drug study after releasing early data. PMID- 26002509 TI - Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm. AB - Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling-(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients. PMID- 26002510 TI - Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India. AB - This article describes regulatory approaches for approval of "generic" orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the "original" product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as "generic" and "reference" drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches. PMID- 26002511 TI - CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48. AB - Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1 adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents. PMID- 26002512 TI - Hyperferritinemia at diagnosis predicts relapse and overall survival in younger AML patients with intermediate-risk cytogenetics. AB - The prognostic value of ferritin level at diagnosis in AML patients is unknown. We studied 162 younger AML patients with intermediate-risk cytogenetics who received intensive chemotherapy. The median ferritin level at diagnosis was 633 MUg/L and 128 (79%) patients had a ferritin level above the upper normal limit. Hyperferritinemia was significantly associated with a higher cumulative incidence of relapse as well as poorer disease-free and overall survival. In multivariate analysis, hyperferritinemia remained an independent poor prognosis factor. The level of ferritin at diagnosis has a major impact on relapse suggesting a link between inflammation, oxidative stress and chemoresistance in AML. PMID- 26002513 TI - Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70. AB - Chronic lymphocytic leukemia is a malignancy driven by abberant B cell signaling and survival. Leukemic B cells accumulate in the peripheral blood and the lymphoid organs where contact with stromal cells and T cells provide critical survival signals. Clinical severity of CLL is associated with several prognostic markers including expression of the kinase ZAP-70. ZAP-70 expression enhances signaling via the B cell antigen receptor and is associated with increased cell adhesion and migration capacity. Here we report that ZAP-70-positive CLL patients display significantly higher expression of the TNF superfamily receptor and memory marker CD27 than do ZAP-70 negative patients. CD27 expression by CLL was acutely elevated upon BCR cross-linking, or upon ectopic expression of ZAP-70. CD27 expression correlated with functional capacity to adhere to stromal cells and antibody blockade of CD27 impaired CLL binding to stroma. These results provide the first evidence for differential expression of CD27 among CLL prognostic groups, suggest a role for ZAP-70 dependent signaling in CD27 induction and implicate CD27 in cell-cell interactions with the lymphoid tissue microenvironment. PMID- 26002514 TI - Identification of prognostic subgroups among acute myeloid leukemia patients with intermediate risk cytogenetics using a flow-cytometry-based assessment of ABC transporter function. AB - BACKGROUND: A median fluorescence intensity ratio (MFIR) which measures the efflux of mitoxantrone (an ATP Binding Cassette (ABC) transporter substrate) with and without ABC transporter inhibition correlates with expression of MDR1 and BCRP in acute myeloid leukemia (AML) blasts. METHODS: This study evaluates the impacts of the MFIR on AML outcomes and its interaction with detection of the FLT3 ITD. RESULTS: Among 200 newly diagnosed AML patients, an MFIR of >= 1.9 (MFIR+) was detected in 60 (30%) leukemic blast samples. In multivariate analysis, MFIR was an independent prognostic factor for response to induction chemotherapy (OR=7.2, P<0.00001), DFS (HR=2.3, P=0.004) and OS (HR=2.2, P=0.0005) with the main effect being in the 141 patients with intermediate risk cytogenetics. Among intermediate risk cytogenetics patients: MFIR+ outcomes were similar to unfavorable cytogenetic risk (CR, 53% vs. 52%, P=1.0; OS, 11 vs. 9 months, P=0.79). MFIR status can further stratify the prognostic risk for patients with or without FLT3 ITD mutation. CONCLUSIONS: MFIR has value in predicting outcomes including DFS and OS as well as induction failure. This is particularly true for patients with intermediate risk cytogenetics and when combined with assessment for the FLT3-ITD mutation. PMID- 26002515 TI - ICU family communication and health care professionals: A qualitative analysis of perspectives. AB - OBJECTIVES: Although ineffective communication is known to influence patient and family satisfaction with care in intensive care unit [ICU] settings, there has been little systematic analysis of the features of the perceived problem from a communication theory perspective. This study was undertaken to understand perceptions of miscommunication and the circumstances in which they present. RESEARCH METHODOLOGY AND DESIGN: Semi-structured interviews were conducted with 22 health care professionals [HCPs] in five adult ICUs at an academic medical centre in the United States. FINDINGS: From qualitative analysis of the transcribed interviews, four themes emerged, each containing multiple subthemes. Person factors are problems that originate within individuals, related to education, cultural background and emotion. Structural factors are associated with boundaries and coordination of institutional roles. Information management problems result from social and psychological processes by which HCPs and family members seek, distribute and understand information. Relationship management problems arise from difficulties in interpersonal interactions. CONCLUSIONS: Ineffective communication is not a single problem, but rather several distinct problems that exist at different levels of abstraction and vary in over-time stability. These findings provide a framework for designing interventions to improve the well-being of patients and family members. PMID- 26002516 TI - Neurognathostomiasis in a young child in India: A case report. AB - Eosinophilc meningitis is commonly associated with Angiostrongylus and Gnathostoma infection and has largely been reported from Thailand. We present the first case report of neurognathostomaisis in a pediatric patient from India. A 3.5 year old girl presented with fever, parasthesis, behavioral changes followed by flaccid quadriparesis. Neuroimaging showed haemorrhagic radiculomyelitis with cerebrospinal fluid eosinophilia. Diagnosis of Gnathostoma infection was confirmed serologically and she was treated with anthelminthic drugs and steroids. This report emphasizes the increasing importance of central nervous system helminithic infections as an alternative diagnosis to common infections like neurotuberculosis in developing countries, even in pediatric patients. Increasing intercontinental travel and migration have increased the incidence and importance in the developed world as well. PMID- 26002517 TI - Morphology, ultrastructure and phylogeny of Myxobolus curimatae n. sp. (Myxozoa: Myxosporea) a parasite of Prochilodus costatus (Teleostei: Prochilodontidae) from the Sao Francisco River, Brazil. AB - Myxobolus curimatae n. sp. has been found infecting the gill filaments of Prochilodus costatus (Prochilodontidae) from the Sao Francisco River in the state of Minas Gerais, Brazil. The prevalence of the species was 18.7%. Mature spores were rounded from a frontal view, with elongated polar capsules of equal size, and had polar filaments with 9-10 turns. Ultrastructural analysis revealed that sporogenesis patterns followed those of other Myxobolus species. The plasmodium walls had numerous invaginations and protrusions, and few pinocytic channels. Numerous mitochondria, generative cells and young pansporoblasts were observed in the peripherical areas of the plasmodia, and mature spores were found in deeper layers. A layer of collagenic fibrils surrounded the plasmodia. The morphological data and molecular analysis of the 18S rDNA identified this parasite as a new species. The maximum likelihood phylogenetic tree showed M. curimatae n. sp., as a sister species of Thelohanellus marginatus, in a basal branch of the subclade composed by parasites with tropism to different organs and host families. PMID- 26002518 TI - The metabolic rate of cultured muscle cells from hybrid Coturnix quail is intermediate to that of muscle cells from fast-growing and slow-growing Coturnix quail. AB - Growth rate is a fundamental parameter of an organism's life history and varies 30-fold across bird species. To explore how whole-organism growth rate and the metabolic rate of cultured muscle cells are connected, two lines of Japanese quail (Coturnix coturnix japonica), one that had been artificially selected for fast growth for over 60 generations and a control line were used to culture myoblasts. In line with previous work, myoblasts from the fast growth line had significantly higher rates of oxygen consumption, glycolytic flux, and higher mitochondrial volume than myoblasts from the control line, indicating that an increase in growth rate is associated with a concomitant increase in cellular metabolic rates and that mitochondrial density contributes to the differences in rates of metabolism between the lines. We reared chicks from two hybrid lines with reciprocal parental configurations for growth rate to explore the effect of maternally inherited mitochondrial DNA on rates of growth and metabolism. Growth rates of chicks, cellular basal oxygen consumption, glycolytic flux, and mitochondrial volume in myoblasts from chicks from both reciprocal crosses were intermediate to the fast and control lines. This indicates that genes in the nucleus have a strong influence on metabolic rates at the cellular level, compared with maternally inherited mitochondrial DNA. PMID- 26002519 TI - Validating the relationship between 3-dimensional body acceleration and oxygen consumption in trained Steller sea lions. AB - We tested the ability of overall dynamic body acceleration (ODBA) to predict the rate of oxygen consumption ([Formula: see text]) in freely diving Steller sea lions (Eumetopias jubatus) while resting at the surface and diving. The trained sea lions executed three dive types-single dives, bouts of multiple long dives with 4-6 dives per bout, or bouts of multiple short dives with 10-12 dives per bout-to depths of 40 m, resulting in a range of activity and oxygen consumption levels. Average metabolic rate (AMR) over the dive cycle or dive bout calculated was calculated from [Formula: see text]. We found that ODBA could statistically predict AMR when data from all dive types were combined, but that dive type was a significant model factor. However, there were no significant linear relationships between AMR and ODBA when data for each dive type were analyzed separately. The potential relationships between AMR and ODBA were not improved by including dive duration, food consumed, proportion of dive cycle spent submerged, or number of dives per bout. It is not clear whether the lack of predictive power within dive type was due to low statistical power, or whether it reflected a true absence of a relationship between ODBA and AMR. The average percent error for predicting AMR from ODBA was 7-11 %, and standard error of the estimated AMR was 5-32 %. Overall, the extensive range of dive behaviors and physiological conditions we tested indicated that ODBA was not suitable for estimating AMR in the field due to considerable error and the inconclusive effects of dive type. PMID- 26002520 TI - Feasibility, acceptability, and adherence of two educational programs for care staff concerning nursing home patients' fecal incontinence: a pilot study preceding a cluster-randomized controlled trial. AB - BACKGROUND: Fecal incontinence has a high prevalence in the nursing home population which cannot be explained by co-morbidity or anatomic and physiological changes of aging alone. Our hypothesis is that fecal incontinence can be prevented, cured, or ameliorated by offering care staff knowledge of best practice. However, it is not clear which educational model is most effective. To assess the effect of two educational programs for care staff, we planned a three armed cluster-randomized controlled trial. There is a lack of research reporting effects of interventions targeting improved continence care processes in older patients. Thus, to improve the quality of the planned trial, we decided to carry out a pilot study to investigate the feasibility of the planned design, the interventions (educational programs) and the outcome measures, and to enable a power calculation. This paper reports the results from the pilot study. METHODS: Three nursing homes, representing each arm of the planned trial, were recruited. Criteria for assessing success of feasibility were pre-specified. Methods, outcome measures, acceptability, and adherence of the components of the intervention were evaluated by descriptive statistical analyses and qualitative content analysis of one focus group interview (n = 7) and four individual interviews. RESULTS: The main study is feasible with one major and some minor modifications. Due to challenges with recruitment and indications supporting the assumption that a single intervention with one workshop is not sufficient as an implementation strategy, the main study will be reduced to two arms: a multifaceted education intervention and control. The components of the multifaceted intervention seemed to work well together and need only minor modification. Important barriers to consider were sub-optimal use of skill-mix, problems of communicating important assessments and care plans, and isolated nurses with an indistinct nurse identity. CONCLUSIONS: Overall, the main study is feasible. The pedagogical approach needs to consider the identified barriers. Thus, it is essential to empower nurses in their professional role, to facilitate clinical reasoning and critical thinking among care staff, and to facilitate processes to enable care staff to find, report, and utilize information in the electronic patient record. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01939821. PMID- 26002522 TI - Editor's Introduction. PMID- 26002521 TI - Bisecting Galactose as a Feature of N-Glycans of Wild-type and Mutant Caenorhabditis elegans. AB - The N-glycosylation of the model nematode Caenorhabditis elegans has proven to be highly variable and rather complex; it is an example to contradict the existing impression that "simple" organisms possess also a rather simple glycomic capacity. In previous studies in a number of laboratories, N-glycans with up to four fucose residues have been detected. However, although the linkage of three fucose residues to the N,N'-diacetylchitobiosyl core has been proven by structural and enzymatic analyses, the nature of the fourth fucose has remained uncertain. By constructing a triple mutant with deletions in the three genes responsible for core fucosylation (fut-1, fut-6 and fut-8), we have produced a nematode strain lacking products of these enzymes, but still retaining maximally one fucose residue on its N-glycans. Using mass spectrometry and HPLC in conjunction with chemical and enzymatic treatments as well as NMR, we examined a set of alpha-mannosidase-resistant N-glycans. Within this glycomic subpool, we can reveal that the core beta-mannose can be trisubstituted and so carries not only the ubiquitous alpha1,3- and alpha1,6-mannose residues, but also a "bisecting" beta-galactose, which is substoichiometrically modified with fucose or methylfucose. In addition, the alpha1,3-mannose can also be alpha galactosylated. Our data, showing the presence of novel N-glycan modifications, will enable more targeted studies to understand the biological functions and interactions of nematode glycans. PMID- 26002523 TI - Is there a need to standardize reporting terminology in appendicitis? AB - While computed tomography (CT) remains the most accurate and widely used modality for appendicitis imaging, ultrasound has developed its own niche role, especially in the pediatric population and in premenopausal women. Ultrasound is commonly used as the initial imaging test when available, with indeterminate or clinically equivocal cases proceeding to CT.To avoid the radiation and time and cost of CT, ultrasound needs to be improved. While previous studies have focused on improving the diagnostic accuracy of ultrasound through better patient selection and technique, relatively little attention has been brought to the ultrasound report, which often serves as the sole mode of communication between the radiologist and the clinician.Standardization of reporting and terminology has been found to improve patient outcomes and management in breast imaging. A standardized report for appendicitis has the potential to decrease confusion and increase accuracy. A potential format could include a standardized list of the presence or absence of imaging findings associated with appendicitis, with a final summary or score indicating the likelihood of appendicitis being present. Aggregation of data over time through use of a common format could help guide radiologist recommendations based on which imaging findings are present. Overall, a standardized report could help increase the value of ultrasound, leading to improved radiologist-clinician communication, better patient outcomes, and decreased costs. PMID- 26002524 TI - Sonographic findings of typical and atypical scrotal trauma. AB - This review article illustrates sonographic findings in the setting of accidental and nonaccidental scrotal trauma. Although sonographic findings may be irrespective of the type of trauma, the goals of sonographic evaluation are similar in both atypical and typical mechanisms of scrotal injury. Familiarity with findings such as disruption of testicular integrity or vascularity facilitates prompt diagnosis and plays a critical role in clinical management. PMID- 26002525 TI - Parametric mapping of contrasted ovarian transvaginal sonography. AB - The purpose of this study was to assess the accuracy of parametric analysis of transvaginal contrast-enhanced ultrasound (TV-CEUS) for distinguishing benign versus malignant ovarian masses. A total of 48 ovarian masses (37 benign and 11 borderline/malignant) were examined with TV-CEUS (Definity; Lantheus, North Billerica, MA; Philips iU22; Philips Medical Systems, Bothell, WA). Parametric images were created offline with a quantification software (Bracco Suisse SA, Geneva, Switzerland) with map color scales adjusted such that abnormal hemodynamics were represented by the color red and the presence of any red color could be used to differentiate benign and malignant tumors. Using these map color scales, low values of the perfusion parameter were coded in blue, and intermediate values of the perfusion parameter were coded in yellow. Additionally, for each individual color (red, blue, or yellow), a darker shade of that color indicated a higher intensity value. Our study found that the parametric mapping method was considerably more sensitive than standard region of interest (ROI) analysis for the detection of malignant tumors but was also less specific than standard ROI analysis. Parametric mapping allows for stricter cutoff criteria, as hemodynamics are visualized on a finer scale than ROI analyses, and as such, parametric maps are a useful addition to TV-CEUS analysis by allowing ROIs to be limited to areas of the highest malignant potential. PMID- 26002527 TI - What can we learn from the transcriptome of the resurrection plant Craterostigma plantagineum? AB - MAIN CONCLUSION: The desiccation transcriptome of the resurrection plant C. plantagineum is composed of conserved protein coding transcripts, taxonomically restricted transcripts and recently evolved non-protein coding transcripts. Research in resurrection plants has been hampered by the lack of genome sequence information, but recently introduced sequencing technologies overcome this limitation partially and provide access to the transcriptome of these plants. Transcriptome studies showed that mechanisms involved in desiccation tolerance are conserved in resurrection plants, seeds and pollen. The accumulation of protective molecules such as sugars and LEA proteins are major components in desiccation tolerance. Leaf folding, chloroplast protection and protection during rehydration must involve specific molecular mechanisms, but the basis of such mechanisms is mainly unknown. The study of regulatory regions of a desiccation induced C. plantagineum gene suggests that cis-regulatory elements may be responsible for expression variations in desiccation tolerant and non-desiccation tolerant plants. The analysis of the C. plantagineum transcriptome also revealed that part of it is composed of taxonomically restricted genes (TRGs) and non protein coding RNAs (ncRNAs). TRGs are known to code for new traits required for the adaptation of organisms to particular environmental conditions. Thus the study of TRGs from resurrection plants should reveal species-specific functions related to the desiccation tolerance phenotype. Non-protein coding RNAs can regulate gene expression at epigenetic, transcriptional and post-transcriptional level and thus these RNAs may be key players in the rewiring of regulatory networks of desiccation-related genes in C. plantagineum. PMID- 26002528 TI - Emerging therapies for the prevention of acute respiratory distress syndrome. AB - The development of acute respiratory distress syndrome (ARDS) carries significant risk of morbidity and mortality. To date, pharmacological therapy has been largely ineffective for patients with ARDS. We present our personal review aimed at outlining current and future directions for the pharmacological prevention of ARDS. Several available risk-stratification or prediction score strategies for identification of patients at risk of ARDS have been reported. Although not ready for clinical everyday use, they are and will be instrumental in the ongoing and future trials of pharmacoprevention of ARDS.Several systemic medications established the potential role in ARDS prevention based on the preclinical studies and observational data. Due to potential for systemic adverse effects to neutralize any pharmacological benefits of systemic therapy, inhaled medications appear particularly attractive candidates for ARDS prevention. This is because of their direct delivery to the site of proposed action (lungs), while the pulmonary epithelial surface is still functional.We postulate that overall morbidity and mortality rates from ARDS in the future will be contingent upon decreasing the overall incidence of ARDS through effective identification of those at risk and early application of proven supportive care and pharmacological interventions. PMID- 26002529 TI - On the collapse pressure of armored bubbles and drops. AB - Drops and bubbles wrapped in dense monolayers of hydrophobic particles are known to sustain a significant decrease of their internal pressure. Through dedicated experiments we investigate the collapse behavior of such armored water drops as a function of the particle-to-drop size ratio in the range 0.02-0.2. We show that this parameter controls the behavior of the armor during the deflation: at small size ratios the drop shrinkage proceeds through the soft crumpling of the monolayer, at intermediate ratios the drop becomes faceted, and for the largest studied ratios the armor behaves like a granular arch. The results show that each of the three morphological regimes is characterized by an increasing magnitude of the collapse pressure. This increase is qualitatively modeled thanks to a mechanism involving out-of-plane deformations and particle disentanglement in the armor. PMID- 26002530 TI - Transient dynamics of a 2D granular pile. AB - We investigate by means of Contact Dynamics simulations the transient dynamics of a 2D granular pile set into motion by applying shear velocity during a short time interval to all particles. The spreading dynamics is directly controlled by the input energy whereas in recent studies of column collapse the dynamics scales with the initial potential energy of the column. As in column collapse, we observe a power-law dependence of the runout distance with respect to the input energy with nontrivial exponents. This suggests that the power-law behavior is a generic feature of granular dynamics, and the values of the exponents reflect the distribution of kinetic energy inside the material. We observe two regimes with different values of the exponents: the low-energy regime reflects the destabilization of the pile by the impact with a runout time independent of the input energy whereas the high-energy regime is governed by the input energy. We show that the evolution of the pile in the high-energy regime can be described by a characteristic decay time and the available energy after the pile is destabilized. PMID- 26002531 TI - Motion of an elastic capsule in a constricted microchannel. AB - We study the motion of an elastic capsule through a microchannel characterized by a localized constriction. We consider a capsule with a stress-free spherical shape and impose its steady-state configuration in an infinitely long straight channel as the initial condition for our calculations. We report how the capsule deformation, velocity, retention time, and maximum stress of the membrane are affected by the capillary number, Ca , and the constriction shape. We estimate the deformation by measuring the variation of the three-dimensional surface area and a series of alternative quantities easier to extract from experiments. These are the Taylor parameter, the perimeter and the area of the capsule in the spanwise plane. We find that the perimeter is the quantity that best reproduces the behavior of the three-dimensional surface area. This is maximum at the centre of the constriction and shows a second peak after it, whose location depends on the Ca number. We observe that, in general, area-deformation-correlated quantities grow linearly with Ca , while velocity-correlated quantities saturate for large Ca but display a steeper increase for small Ca . The velocity of the capsule divided by the velocity of the flow displays, surprisingly, two different qualitative behaviors for small and large capillary numbers. Finally, we report that longer constrictions and spanwise wall bounded (versus spanwise periodic) domains cause larger deformations and velocities. If the deformation and velocity in the spanwise wall bounded domains are rescaled by the initial equilibrium deformation and velocity, their behavior is undistinguishable from that in a periodic domain. In contrast, a remarkably different behavior is reported in sinusoidally shaped and smoothed rectangular constrictions indicating that the capsule dynamics is particularly sensitive to abrupt changes in the cross section. In a smoothed rectangular constriction larger deformations and velocities occur over a larger distance. PMID- 26002532 TI - Primitive Cranial Surgery-Scythian Trepanations (500-300 b.c.). PMID- 26002533 TI - Are Nursing Students Appropriate Partners for the Interdisciplinary Training of Surgery Residents? AB - BACKGROUND: Interdisciplinary team training in a simulation center recreates clinical team interactions and holds promise in improving teamwork of clinicians by breaking down educational silos. The objective of our study was to assess the appropriateness of interdisciplinary training with general surgery residents and nursing students. METHODS: Over 2 consecutive academic years (2012-2013 and 2013 2014), general surgery residents participated in interdisciplinary team-training simulation-based sessions with senior nursing students. Scenario objectives included demonstration of appropriate teamwork and communication, and clinical decision making; sessions incorporated interdisciplinary debriefing of the scenarios. Participants were asked to assess their team-training experience and the appropriateness of their team-training partner. Responses were compared. RESULTS: A total of 16 team-training sessions were conducted during the study period. Overall, 12 surgery residents (67%) and 44 nursing students (63%) who had participated in at least 1 session responded to the survey. Although both residents and nursing students indicated that the knowledge and team skills acquired during these sessions were useful to them in clinical practice (73% vs 86%, respectively; p = not significant), residents rated their educational value lower (3.3 vs 4.3 on a 5-point scale, respectively; p < 0.01) and only 18% of the residents felt that these sessions should be continued compared with 90% of nursing students (p < 0.05). Most useful components of the sessions were participation in the scenario (73%) and debriefing (54%) for residents and for the nursing students, debriefing (91%), observation of others (68%), and interaction with resident physicians (66%) ranked highest; 48% of student nurses preferred residents as team-training partners whereas 100% residents preferred practicing nurses and 0% with nursing students owing to their limited clinical experience. CONCLUSIONS: Interdisciplinary team training and debriefing of surgery residents with nursing students is feasible and highly valued by nursing students. Nevertheless, our experience indicates that residents do not prefer nursing students as team-training partners owing to their limited clinical experience and would rather train with experienced nurses. PMID- 26002534 TI - Video Skills Curricula and Simulation: A Synergistic Way to Teach 2-Layered, Hand Sewn Small Bowel Anastomosis. AB - BACKGROUND: We sought to determine if general surgery (GS) interns could learn a side-to-side, 2-layered, hand-sewn small bowel anastomosis (HSBA) using an online instructional video and low-fidelity simulation model. METHODS: A 3-hour HSBA technical skills training session was held among GS interns. Participants were asked to write down the steps for performing a side-to-side, 2-layered HSBA (pretest). An online 13-minute instructional video on HSBA was then viewed. Low fidelity bowel simulators were then provided for deliberate practice under staff supervision. A posttest (identical to pretest) concluded the session. The maximum test score was 20 points. At 4 months later, a retention test was administered. Trainees were anonymously surveyed to determine the session's educational value. Pretest, posttest, and retention test scores were compared. RESULTS: Participants were 25 GS interns. The mean pretest score was 5 (range: 0-11). Posttest scores improved (mean = 15; range: 11-19, p = 0.016), whereas retention test scores were stable (mean = 14; range: 8-18). Of those who participated in retention testing (24/25), 7 had now performed a 2-layered HSBA, 11 had witnessed HSBA, and 6 had neither performed nor witnessed an HSBA since the educational session. Retention test scores were higher among those who had performed HSBA (mean = 16; range: 13 18) vs those who had not performed nor witnessed an HSBA (mean = 14; range: 8-18, p = 0.04). Mean Likert scores supported the educational value of the session. CONCLUSION: Initial intern performance of HSBA was abysmal. A contemporary online video skills curriculum coupled with low-fidelity bowel simulators improved trainee knowledge of how to perform a 2-layered HSBA. This effect remained stable over 4 months. PMID- 26002535 TI - Portfolios Enhance Clinical Activity in Surgical Clerks. AB - OBJECTIVES: A change in German licensing legislation imposed a portfolio for surgical clerks. We aimed to analyze whether the implementation of the portfolio changed the amount of clinical exposure and activities during surgical clerkships. DESIGN: The study was conducted with a modified pre-post design at the University Hospital of Tuebingen, Germany. Before and after the implementation of the portfolio on April 1, 2013, final-year students (n = 557) who had just finished their surgical clerkship were interviewed with an online questionnaire. A total of 21 basic surgical skills were evaluated. RESULTS: Overall, 230 questionnaires were returned and analyzed; 51% were preintervention. Overall clinical activity for the whole study cohort varied for different activities between 98% and 32%. For 16 of 21 parameters, there was more clinical activity in the postintervention (portfolio) group. This difference was statistically significant for the following 7 activities: discharge, analgesia, local infiltration, patient positioning, drain in, blood transfusion, and emergency diagnostics. CONCLUSION: The implementation of the portfolio did enhance clinical activity for surgical clerks in the study cohort. Nevertheless, overall exposure is still unsatisfactory low for some activities. Additional changes and studies are necessary to further improve surgical education. PMID- 26002536 TI - A Comparison of Teaching Modalities and Fidelity of Simulation Levels in Teaching Resuscitation Scenarios. AB - INTRODUCTION: The purpose of our study was to examine the ability of novices to learn selected aspects of Advanced Cardiac Life Support (ACLS) in training conditions that did not incorporate simulation compared to those that contained low- and high-fidelity simulation activities. We sought to determine at what level additional educational opportunities and simulation fidelity become superfluous with respect to learning outcomes. METHODS: Totally 39 medical students and physician assistant students were randomly assigned to 4 training conditions: control (lecture only), video-based didactic instruction, low-, and high-fidelity simulation activities. Participants were assessed using a baseline written pretest of ACLS knowledge. Following this, all participants received a lecture outlining ACLS science and algorithm interpretation. Participants were then trained in specific aspects of ACLS according to their assigned instructional condition. After training, each participant was assessed via a Megacode performance examination and a written posttest. RESULTS: All groups performed significantly better on the written posttest compared with the pretest (p < 0.001); however, no groups outperformed any other groups. On the Megacode performance test, the video-based, low-, and high-fidelity groups performed significantly better than the control group (p = 0.028, p < 0.001, p = 0.019). Equivalence testing revealed that the high-fidelity simulation condition was statistically equivalent to the video-based and low-fidelity simulation conditions. CONCLUSION: Video-based and simulation-based training is associated with better learning outcomes when compared with traditional didactic lectures only. Video-based, low-fidelity, and high-fidelity simulation training yield equivalent outcomes, which may indicate that high-fidelity simulation is superfluous for the novice trainee. PMID- 26002537 TI - A Novel Method for Real-Time Audio Recording With Intraoperative Video. AB - OBJECTIVE: Although laparoscopic surgery has become widespread, effective and efficient education in laparoscopic surgery is difficult. Instructive laparoscopy videos with appropriate annotations are ideal for initial training in laparoscopic surgery; however, the method we use at our institution for creating laparoscopy videos with audio is not generalized, and there have been no detailed explanations of any such method. Our objectives were to demonstrate the feasibility of low-cost simple methods for recording surgical videos with audio and to perform a preliminary safety evaluation when obtaining these recordings during operations. DESIGN: We devised a method for the synchronous recording of surgical video with real-time audio in which we connected an amplifier and a wireless microphone to an existing endoscopy system and its equipped video recording device. We tested this system in 209 cases of laparoscopic surgery in operating rooms between August 2010 and July 2011 and prospectively investigated the results of the audiovisual recording method and examined intraoperative problems. SETTING: Numazu City Hospital in Numazu city, Japan. PARTICIPANTS: Surgeons, instrument nurses, and medical engineers. RESULTS: In all cases, the synchronous input of audio and video was possible. The recording system did not cause any inconvenience to the surgeon, assistants, instrument nurse, sterilized equipment, or electrical medical equipment. Statistically significant differences were not observed between the audiovisual group and control group regarding the operating time, which had been divided into 2 slots-performed by the instructors or by trainees (p > 0.05). CONCLUSIONS: This recording method is feasible and considerably safe while posing minimal difficulty in terms of technology, time, and expense. We recommend this method for both surgical trainees who wish to acquire surgical skills effectively and medical instructors who wish to teach surgical skills effectively. PMID- 26002538 TI - UV-induced self-aggregation of E. coli after low and medium pressure ultraviolet irradiation. AB - Presence of aggregated bacteria has been shown to decrease the efficacy of ultraviolet (UV) disinfection and there is some indication that UV irradiation may promote aggregation of bacteria among themselves. This study aims to provide an in-depth understanding of the effect of UV light on inducing self-aggregation of Escherichia coli bacteria by using microscopy and particle counter analysis techniques. The bacteria were observed and quantified before and after UV irradiation by employing size and concentration parameters. Four doses of low pressure (LP) UV irradiation, 20, 40, 60 and 80 mJ/cm(2), and two doses of medium pressure (MP) UV irradiation, 40 and 80 mJ/cm(2), were tested. At all LP UV doses tested, a significant increase in particle size was observed following UV exposure, indicating UV-induced self-aggregation. However, the magnitude of UV dose did not seem to have an impact. In the MP UV experiments, only a dose of 80 mJ/cm(2) had a significant impact on the formation of aggregates upon UV exposure. Changing the light intensity and exposure time to deliver the same LP UV dose resulted in different levels of aggregation. The results indicated that UV light intensity and wavelength may play a role in aggregation of bacteria. PMID- 26002539 TI - Synthesis, spectral, thermal, fluorescence, antimicrobial, anthelmintic and DNA cleavage studies of mononuclear metal chelates of bi-dentate 2H-chromene-2-one Schiff base. AB - The Co(II), Ni(II) and Cu(II) complexes have been synthesized with Schiff base (HL), derived from 8-formyl-7-hydroxy-4-methylcoumarin with benzylamine. The Schiff base and its metal complexes were structurally characterized based on IR, (1)H NMR, (13)C NMR, UV-visible, ESR, magnetic, thermal, fluorescence, mass and ESI-MS studies. The complexes are completely soluble in DMF and DMSO. The molar conductance values indicate that, all synthesized metal complexes are non electrolytic in nature. Elemental analysis reveals [ML2(H2O)2] stoichiometry, here MCo(II), Ni(II) and Cu(II), L=deprotonated ligand. The coordination between metal ion and Schiff base was supported by IR data, through deprotonation of phenolic oxygen of coumarin and azomethine nitrogen atoms. Solution electronic spectral results unveiled that all the synthesized complexes posses six coordinated geometry around metal ion. Thermal studies suggest the presence of coordinated water molecules. The Schiff base and its metal complexes have been screened for their antibacterial (Escherichia coli, Pseudomonas aureginosa, Klebsiella pneumoniae and Staphylococcus aureus) and antifungal (Penicillium chrysogenum and Aspergillus niger), anthelmintic (Pheretima posthuma) and DNA cleavage (Calf Thymus DNA) activities. PMID- 26002540 TI - The influence of UV-irradiation on chitosan modified by the tannic acid addition. AB - The influence of UV-irradiation with the wavelength 254 nm on the properties of chitosan modified by the tannic acid addition was studied. Tannic acid was added to chitosan solution in different weight ratios and after solvent evaporation thin films were formed. The properties of the films such as thermal stability, Young modulus, ultimate tensile strength, moisture content, swelling behavior before and after UV-irradiation were measured and compared. Moreover, the surface properties were studied by contact angle measurements and by the use of atomic force microscopy. The results showed that UV-irradiation caused both, the degradation of the specimen and its cross-linking. The surface of the films made of chitosan modified by the addition of tannic acid was altered by UV irradiation. PMID- 26002541 TI - Sibling bullying is associated with anxiety, depression and self-harm. PMID- 26002542 TI - Prophylactic Interleukin-2 Treatment Prevents Fetal Gut Inflammation and Injury in an Ovine Model of Chorioamnionitis. AB - BACKGROUND: Chorioamnionitis results from an infection of the fetal membranes and is associated with fetal adverse outcomes notably in the intestine. Using a translational ovine model, we showed that intra-amniotic exposure to inflammatory stimuli decreased the regulatory/effector T (Treg/Teff) cell balance in the gut, which was accompanied by intestinal inflammation and mucosal injury. We thus aimed to augment the Treg/Teff cell ratio in the fetal gut by prophylactic IL-2 treatment and evaluate whether it is sufficient to prevent chorioamnionitis induced intestinal inflammation and mucosal injury. METHODS: Fetal sheep (122 d of gestation) were intra-amniotically exposed to lipopolysaccharide for 2 or 7 days with or without prophylactic IL-2 treatment (4 d). We evaluated the infiltration of inflammatory cells in the ileum and mesenteric lymph nodes. Cytokine gene expression was analyzed in fetal ileum and the inflammatory changes were correlated with gut wall integrity. RESULTS: IL-2 administration preferentially increased intestinal Treg cells and thus the Treg/Teff cell ratio. Prophylactic IL-2 treatment reduced the lipopolysaccharide-induced influx of neutrophils and CD3(+) T cells and decreased the messenger RNA levels of proinflammatory cytokines including IL-6 and IL-17 in the fetal ileum. Importantly, prophylactic IL-2 treatment prevented mucosal damage without inducing fetal adverse treatment outcomes. CONCLUSIONS: Our data show that prophylactic IL-2 treatment prevents fetal intestinal inflammation and mucosal injury in the context of experimental chorioamnionitis. Modulation of the Treg/Teff cell balance may contribute to the protective effects of IL-2. PMID- 26002543 TI - Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease. PMID- 26002544 TI - Reduced red blood cell deformability over time is associated with a poor outcome in septic patients. AB - BACKGROUND: To investigate changes in red blood cell (RBC) rheology over time in critically ill patients with sepsis and their relationship with outcome. METHODS: In this prospective, non-interventional study, RBC rheology was assessed using the Laser-assisted Optical Rotational Cell Analyzer in a convenience sample of intensive care unit (ICU) patients with (n=64) and without (n=160) sepsis. Results were compared to measures in healthy volunteers (n=20). RBC rheology was also assessed on days 1 and 3 of the ICU stay in 32 of the non-septic and 19 of the septic patients. RBC deformability was determined by the elongation index (EI) in relation to the shear stress (0.3 to 50Pa) applied to the RBC membrane. An aggregation index (AI) was assessed simultaneously with the same device. RESULTS: The ICU mortality rate of the septic patients was 31%. RBC deformability was already reduced in septic patients at ICU admission, an effect that persisted during the study period and worsened in the non-survivors for the large majority of shear stresses studied (e.g., EI for 50Pa of shear stress was 0.527+/-0.064 in non-survivors vs. 0.566+/-0.034 in survivors, p<0.05). These changes were not observed in non-septic patients. The AI was more elevated in septic than in non septic patients at ICU admission, but had no prognostic value. CONCLUSIONS: Alterations in RBC rheology, including reduced deformability and increased aggregation, occur early in septic patients and reductions in RBC deformability over time are associated with a poor outcome. PMID- 26002546 TI - Population genetics for 17 Y-STR loci in Mongolian ethnic minority from Liaoning Province, Northeast China. PMID- 26002547 TI - The role of memory in the relationship between attention toward thin-ideal media and body dissatisfaction. AB - PURPOSE: This study examined the causal relationship between attention and memory bias toward thin-body images, and the indirect effect of attending to thin-body images on women's body dissatisfaction via memory. METHOD: In a 2 (restrained vs. unrestrained eaters) * 2 (long vs. short exposure) quasi-experimental design, female participants (n = 90) were shown images of thin models for either 7 s or 150 ms, and then completed a measure of body dissatisfaction and a recognition test to assess their memory for the images. RESULTS: Both restrained and unrestrained eaters in the long exposure condition had better recognition memory for images of thin models than did those in the short exposure condition. Better recognition memory for images of thin models was associated with lower body dissatisfaction. Finally, exposure duration to images of thin models had an indirect effect on body dissatisfaction through recognition memory. CONCLUSIONS: These findings suggest that memory for body-related information may be more critical in influencing women's body image than merely the exposure itself, and that targeting memory bias might enhance the effectiveness of cognitive bias modification programs. PMID- 26002545 TI - Impaired coronary and retinal vasomotor function to hyperoxia in Individuals with Type 2 diabetes. AB - PURPOSE: Adults with diabetes are at a high risk of developing coronary heart disease. The purpose of this study was to assess coronary artery vascular function non-invasively in individuals with and without Type 2 diabetes and to compare these coronary responses to another microvascular bed (i.e. retina). We hypothesized that individuals with diabetes would have impaired coronary reactivity and that these impairments would be associated with impairments in retinal reactivity. METHODS: Coronary blood velocity (Transthoracic Doppler Echocardiography) and retinal diameters (Dynamic Vessel Analyzer) were measured continuously during five minutes of breathing 100% oxygen (i.e. hyperoxia) in 15 persons with Type 2 diabetes and 15 age-matched control subjects. Using fundus photographs, retinal vascular calibers were also measured (central retinal arteriole and venule equivalents). RESULTS: Individuals with diabetes compared to controls had impaired coronary (-2.34+/-16.64% vs. -14.27+/-10.58%, P=0.03) and retinal (arteriole: -0.04+/-3.34% vs. -3.65+/-5.07%, P=0.03; venule: -1.65+/ 3.68% vs. -5.23+/-5.47%, P=0.05) vasoconstrictor responses to hyperoxia, and smaller central arteriole-venule equivalent ratios (0.83+/-0.07 vs. 0.90+/-0.07, P=0.014). Coronary reactivity was associated with central retinal arteriole equivalents (r=-0.516, P=0.005) and retinal venular reactivity (r=0.387, P=0.034). CONCLUSION: Diabetes impairs coronary and retinal microvascular function to hyperoxia. Impaired vasoconstrictor responses may be part of a systemic diabetic vasculopathy, which may contribute to adverse cardiovascular events in individuals with diabetes. PMID- 26002548 TI - Elucidating how bamboo salt interacts with supported lipid membranes: influence of alkalinity on membrane fluidity. AB - Bamboo salt is a traditional medicine produced from sea salt. It is widely used in Oriental medicine and is an alkalizing agent with reported antiinflammatory, antimicrobial and chemotherapeutic properties. Notwithstanding, linking specific molecular mechanisms with these properties has been challenging to establish in biological systems. In part, this issue may be related to bamboo salt eliciting nonspecific effects on components found within these systems. Herein, we investigated the effects of bamboo salt solution on supported lipid bilayers as a model system to characterize the interaction between lipid membranes and bamboo salt. The atomic composition of unprocessed and processed bamboo salts was first analyzed by mass spectrometry, and we identified several elements that have not been previously reported in other bamboo salt preparations. The alkalinity of hydrated samples was also measured and determined to be between pH 10 and 11 for bamboo salts. The effect of processed bamboo salt solutions on the fluidic properties of a supported lipid bilayer on glass was next investigated by fluorescence recovery after photobleaching (FRAP) analysis. It was demonstrated that, with increasing ionic strength of the bamboo salt solution, the fluidity of a lipid bilayer increased. On the contrary, increasing the ionic strength of near neutral buffer solutions with sodium chloride salt diminished fluidity. To reconcile these two observations, we identified that solution alkalinity is critical for the effects of bamboo salt on membrane fluidity, as confirmed using three additional commercial bamboo salt preparations. Extended-DLVO model calculations support that the effects of bamboo salt on lipid membranes are due to the alkalinity imparting a stronger hydration force. Collectively, the results of this work demonstrate that processing of bamboo salt strongly affects its atomic composition and that the alkalinity of bamboo salt solutions contributes to its effect on membrane fluidity. PMID- 26002549 TI - Association of Genetic Factors and Gene-Environment Interactions With Risk of Developing Posttraumatic Stress Disorder in a Case-Control Study. AB - BACKGROUND: The dopamine receptor D2 (DRD2) and serotonin transporter (5-HTT) genes are associated with posttraumatic stress disorder (PTSD). However, it remains largely unknown whether these genes interact with environmental factors to affect the development of PTSD. PURPOSE: The purpose of this study was to examine the associations of gene polymorphisms and gene-environment interactions with the risk of developing PTSD among adolescent earthquake survivors. METHOD: A total of 183 adolescent survivors from an earthquake-stricken area participated in this study. Measures included a questionnaire about demographic characteristics and earthquake exposure, the PTSD Checklist-Civilian Version and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition disorders. Genotypes were analyzed by using the polymerase chain reaction-based restriction fragment length polymorphism. RESULTS: The 5-HTTLPR and 5-HTTVNTR polymorphisms and earthquake exposure had statistically significant positive effects on PTSD. The interaction effects of 5 HTTLPR * Earthquake Exposure and 5-HTTVNTR * Earthquake Exposure were statistically significant. CONCLUSION: The development of PTSD is the result not only of a genetic effect and environmental factors but also of the interactive effect between gene and environment. PMID- 26002550 TI - Systemic Inflammatory Marker CRP Was Better Predictor of Readmission for AECOPD Than Sputum Inflammatory Markers. AB - INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) readmission contributes considerably to the worse outcomes for COPD patients. Predictors for readmission include some socio-demographic variables and the severity of the underlying disease, however, few evidence suggested whether persistently heightened airway or systemic inflammation was related to recurrence of AECOPD. The aim of this study was to evaluate role of airway and systemic inflammatory biomarkers during AECOPD on predicting readmission for AECOPD. METHODS: Consecutive hospitalized patients with AECOPD were recruited. Inflammatory and clinical indices were evaluated at the day of admission before starting therapy and the day of planned discharge (day 10-14). Predictors for readmission were assessed by binary logistic regression model. RESULTS: 93 patients were included with 51 patients (54.8%) were readmitted due to AECOPD at least once during 1 year following the index admission. The logistic regression model indicated that age (OR=1.072, 95%CI: 1.012-1.135, P=.017), hs-CRP (high sensitive-C reactive protein) at day 14 (OR=1.392, 95%CI: 1.131-1.712, P=.002), CAT value at day 14 (OR=1.12, 95%CI: 1.031-1.217, P=.007) were the independent variables statistically significant in predicting rehospitalization. CONCLUSION: Systemic inflammatory marker CRP was a better predictor of readmission than sputum inflammatory markers. CAT score and age were also useful to predict readmission. PMID- 26002551 TI - Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells. AB - The deregulation of lipid metabolism is a hallmark of tumor cells, and elevated lipogenesis has been reported in prostate cancer. Metformin, a drug commonly prescribed for type II diabetes, displays antitumor properties. Here, we show that metformin inhibits lipogenesis in several prostate cancer cell lines. In LNCaP cells, this effect parallels the decrease of key lipogenic proteins: ACC (acetyl-CoA carboxylase), FASN (fatty acid synthase) and SREBP1c (sterol regulatory element binding protein-1c), whereas there is no modification in DU145 and PC3 cells. Despite the relatively high level of lipogenic proteins induced by the overexpression of a constitutively active form of SREBP1c or treatment with androgens, metformin is still able to inhibit lipogenesis. Metformin does not alter the concentration of malonyl-CoA (the fatty acid precursor), and it only slightly decreases the NADPH levels, which is a co-factor required for lipogenesis, in LNCaP. Finally, we show that the inhibitory effect of metformin on lipogenesis is primarily due to a cellular energy deficit. Metformin decreases ATP in a dose-dependent manner, and this diminution is significantly correlated with the inhibition of lipogenesis in LNCaP and DU145. Indeed, the effect of metformin is linked to changes in the ATP content rather than the regulation of protein expression. Our results describe a new mechanism of action for metformin on prostate cancer metabolism. PMID- 26002552 TI - Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer. AB - HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3 B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer. PMID- 26002553 TI - miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1. AB - Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with frequent metastatic rate and poor survival. Integrated analyses allow understanding the interplay between different levels of molecular alterations.We integrated miRNA and gene expression data from 458 ccRCC and 254 normal kidney specimens to construct a miRNA-target interaction network.We identified the downregulated miR 124-3p, -30a-5p and -200c-3p as the most influential miRNAs in RCC pathogenesis.miR-124-3p and miR-200c-3p expression showed association with patient survival, miR-30a-5p was downregulated in metastases compared to primary tumors. We used an independent set of 87 matched samples for validation. We confirmed the functional impact of these miRNAs by in vitro assays. Restoration of these miRNAs reduced migration, invasion and proliferation. miR-124-3p decreased the S phase of cell cycle, as well. We compared transcriptome profiling before and after miRNA overexpression, and validated CAV1 and FLOT1 as miR-124-3p targets. Patients with higher CAV1 and FLOT1 had lower miR-124-3p expression and shorter overall survival.We hypothesize that these three miRNAs are fundamental contributing to ccRCC aggressive/metastatic behavior; and miR-124-3p especially has a key role through regulating CAV1 and FLOT1 expression. Restoration of the levels of these miRNAs could be considered as a potential therapeutic strategy for ccRCC. PMID- 26002554 TI - Efficacy of the antimicrobial peptide TP4 against Helicobacter pylori infection: in vitro membrane perturbation via micellization and in vivo suppression of host immune responses in a mouse model. AB - Helicobacter pylori infection is marked by a strong association with various gastric diseases, including gastritis, ulcers, and gastric cancer. Antibiotic treatment regimens have low success rates due to the rapid occurrence of resistant H. pylori strains, necessitating the development of novel anti-H. pylori strategies. Here, we investigated the therapeutic potential of a novel peptide, Tilapia Piscidin 4 (TP4), against multidrug resistant gastric pathogen H. pylori, based on its in vitro and in vivo efficacy.TP4 inhibited the growth of both antibiotic-sensitive and -resistant H. pylori (CagA+, VacA+) via membrane micelle formation, which led to membrane depolarization and extravasation of cellular constituents. During colonization of gastric tissue, H. pylori infection maintains high T regulatory subsets and a low Th17/Treg ratio, and results in expression of both pro- and anti-inflammatory cytokines. Treatment with TP4 suppressed Treg subset populations and pro- and anti- inflammatory cytokines. TP4 restored the Th17/Treg balance, which resulted in early clearance of H. pylori density and recovery of gastric morphology. Toxicity studies demonstrated that TP4 treatment has no adverse effects in mice or rabbits. The results of this study indicate that TP4 may be an effective and safe monotherapeutic agent for the treatment of multidrug resistant H. pylori infections. PMID- 26002555 TI - Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma. AB - Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities.We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived.Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC. PMID- 26002556 TI - Method for sectioning and sampling hearts for histologic evaluation after delivery of biological agents by transendocardial injection. AB - The use of transendocardial (TE) injection as a validated method for delivering therapeutic agents to the diseased heart is increasing. Of the catheter systems currently available, TE injections guided by electromechanical mapping are attractive due to their minimal use of fluoroscopy and three-dimensional reconstruction capabilities that allow precise targeting of injections. We propose a method of cardiac sampling that takes advantage of the spatial accuracy of this system. Our preclinical experience with this methodology has yielded encouraging results, allowing a thorough examination of the injected areas through limited sampling. PMID- 26002557 TI - Response to the "letter regarding Interference of doxycycline pretreatment in a model of abdominal aortic aneurysms". PMID- 26002558 TI - Effect of olive leaf extract treatment on doxorubicin-induced cardiac, hepatic and renal toxicity in rats. AB - Doxorubicin (DOX) is known to increase in oxidative stress in several organs. Olive leaf extract (OLE) has potent antioxidant effects; therefore, we evaluated the ability of OLE to reduce DOX-induced toxicity in the heart, liver, and kidneys of rats. DOX (30mg/kg; i.p.) was administered to rats, which were sacrificed 4 days after DOX. The rats received OLE (6 and 12mL/L in drinking water) for 12 days. Serum cardiac troponin I (cTnI) levels, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities, urea and creatinine levels, as well as prooxidant and antioxidant status in organs were measured. DOX was found to increase serum markers that indicate tissue injury, malondialdehyde (MDA), diene conjugate (DC), and protein carbonyl (PC) levels, and to decrease glutathione (GSH) levels in organs. Histopathologic changes were also evaluated. OLE, especially OLE 1000, led to decreases in serum cTnI and urea levels, ALT and AST activities, and amelioration in histopathologic findings. Decreases in MDA, DC, and PC, and increases in GSH levels were observed in organs of DOX-treated rats due to OLE. We conclude that OLE treatment may be effective in decreasing DOX-induced cardiac, hepatic and renal oxidative stress and injury. PMID- 26002559 TI - Advances in imaging to allow personalized medicine in Crohn's disease. AB - Crohn's disease is a destructive inflammatory bowel disease of unknown origin that may lead to various complications such as strictures, stenosis, fistulas and colitis-associated neoplasias. However, the course of the disease varies substantially among patients and disease behaviour may also change with time. At diagnosis behaviour is inflammatory in the majority of patients, while penetrating or structuring behaviour become more prominent at later time points. Thus, medication in Crohn's disease needs frequent optimization over time. Therefore, new strategies for prediction of response to therapy are urgently needed. Here, recent advantages in imaging techniques for personalized medicine in Crohn's disease are reviewed. Such advantages include ultrasonography, computed tomography, magnetic resonance imaging and new endoscopic approaches such as molecular endoscopy. It is expected that these novel techniques will lead to marked improvements in the assessment of disease behaviour and the prediction of response to clinical therapy with biologicals. PMID- 26002560 TI - Antibiotic resistance of lactic acid bacteria isolated from dry-fermented sausages. AB - Dry-fermented sausages are meat products highly valued by many consumers. Manufacturing process involves fermentation driven by natural microbiota or intentionally added starter cultures and further drying. The most relevant fermentative microbiota is lactic acid bacteria (LAB) such as Lactobacillus, Pediococcus and Enterococcus, producing mainly lactate and contributing to product preservation. The great diversity of LAB in dry-fermented sausages is linked to manufacturing practices. Indigenous starters development is considered to be a very promising field, because it allows for high sanitary and sensorial quality of sausage production. LAB have a long history of safe use in fermented food, however, since they are present in human gastrointestinal tract, and are also intentionally added to the diet, concerns have been raised about the antimicrobial resistance in these beneficial bacteria. In fact, the food chain has been recognized as one of the key routes of antimicrobial resistance transmission from animal to human bacterial populations. The World Health Organization 2014 report on global surveillance of antimicrobial resistance reveals that this issue is no longer a future prediction, since evidences establish a link between the antimicrobial drugs use in food-producing animals and the emergence of resistance among common pathogens. This poses a risk to the treatment of nosocomial and community-acquired infections. This review describes the possible sources and transmission routes of antibiotic resistant LAB of dry fermented sausages, presenting LAB antibiotic resistance profile and related genetic determinants. Whenever LAB are used as starters in dry-fermented sausages processing, safety concerns regarding antimicrobial resistance should be addressed since antibiotic resistant genes could be mobilized and transferred to other bacteria. PMID- 26002561 TI - Neocaridina denticulata: A Decapod Crustacean Model for Functional Genomics. AB - A decapod crustacean model is needed for understanding the molecular mechanisms underlying physiological processes, such as reproduction, sex determination, molting and growth, immunity, regeneration, and response to stress. Criteria for selection are: life-history traits, adult size, availability and ease of culture, and genomics and genetic manipulation. Three freshwater species are considered: cherry shrimp, Neocaridina denticulata; red swamp crayfish, Procambarus clarkii; and redclaw crayfish, Cherax quadricarinatus. All three are readily available, reproduce year round, and grow rapidly. The crayfish species require more space for culture than does N. denticulata. The transparent cuticle of cherry shrimp provides for direct assessment of reproductive status, stage of molt, and tissue specific expression of reporter genes, and facilitates screening of mutations affecting phenotype. Moreover, a preliminary genome of N. denticulata is available and efforts toward complete genome sequencing and transcriptome sequencing have been initiated. Neocaridina denticulata possesses the best combination of traits that make it most suitable as a model for functional genomics. The next step is to obtain the complete genome sequence and to develop molecular technologies for the screening of mutants and for manipulating tissue specific gene expression. PMID- 26002562 TI - Stability versus Maneuvering: Challenges for Stability during Swimming by Fishes. AB - Fishes are well known for their remarkable maneuverability and agility. Less visible is the continuous control of stability essential for the exploitation of the full range of aquatic resources. Perturbations to posture and trajectory arise from hydrostatic and hydrodynamic forces centered in a fish (intrinsic) and from the environment (extrinsic). Hydrostatic instabilities arise from vertical and horizontal separation of the centers of mass (CM) and of buoyancy, thereby creating perturbations in roll, yaw, and pitch, with largely neglected implications for behavioral ecology. Among various forms of hydrodynamic stability, the need for stability in the face of recoil forces from propulsors is close to universal. Destabilizing torques in body-caudal fin swimming is created by inertial and viscous forces through a propulsor beat. The recoil component is reduced, damped, and corrected in various ways, including kinematics, shape of the body and fins, and deployment of the fins. We postulate that control of the angle of orientation, theta, of the trailing edge is especially important in the evolution and lifestyles of fishes, but studies are few. Control of stability and maneuvering are reflected in accelerations around the CM. Accelerations for such motions may give insight into time-behavior patterns in the wild but cannot be used to determine the expenditure of energy by free-swimming fishes. PMID- 26002563 TI - Handling and Use of Oxygen by Pancrustaceans: Conserved Patterns and the Evolution of Respiratory Structures. AB - The handling and use of oxygen are central to physiological function of all pancrustaceans. Throughout the Pancrustacea, ventilation is controlled by a central oxygen-sensitive pattern generator. The ancestral condition was likely to achieve ventilation of the gills via leg-associated or mouth-associated muscles, but in insects and some air-breathing crustaceans, new muscles were recruited for this purpose, including intersegmental muscles likely used previously for posture and locomotion. Many aspects of the sensing of oxygen and the occurrence of responses to hypoxia (increased ventilation, depressed growth and metabolic rate, developmental changes that enhance the delivery of oxygen) appear common across most pancrustaceans, but there is tremendous variation across species. Some of this can be explained by habitat (e.g., ventilation of the internal medium occurs in terrestrial species and of the external medium in aquatic species; rearing under hypoxia induces tracheal proliferation in terrestrial insects and hemocyanin production in aquatic crustaceans); some plausibly by evolutionary origin of some responses to hypoxia within the Pancrustacea (the most basal arthropods may lack a ventilatory response to hypoxia); and some by the availability of environmental oxygen (animals adapted to survive hypoxia turn on the response to hypoxia at a lower PO2). On average, crustaceans and insects have similar tolerances to prolonged anoxia, but species or life stages from habitats with a danger of being trapped in hypoxia can tolerate longer durations of anoxia. Lactate is the primary anaerobic end-product in crustaceans but some insects have evolved a more diverse array of anaerobic end-products, including ethanol, alanine, succinate, and acetate. Most clades of Pancrustacea are small and lack obvious respiratory structures. Gilled stem-pancrustaceans likely evolved in the Cambrian, and gills persist in large Ostracoda, Malacostraca, and Branchiopoda. Based on currently accepted phylogenies, invaginations of cuticle to form lungs or tracheae occurred independently multiple times across the Arthropoda and Pancrustacea in association with the evolution of terrestriality. However, the timing and number of such events in the evolution of tracheal systems remain controversial. Despite molecular phylogenies that place the origin of the hexapods before the appearance of land plants in the Ordovician, terrestrial fossils of Collembola, Archaeognatha, and Zygentoma in the Silurian and Devonian, and the lack of fossil evidence for older aquatic hexapods, suggest that the tracheated hexapods likely evolved from Remipedia-like ancestors on land. PMID- 26002564 TI - High neuroendocrine component is a factor for poor prognosis in gastrointestinal high-grade malignant mixed adenoneuroendocrine neoplasms. AB - BACKGROUND: High-grade malignant mixed adenoneuroendocrine carcinoma (MANEC) is a highly malignant combined neoplasm formed by an adenocarcinomatous component and a poorly differentiated (Grade 3) neuroendocrine (NE) carcinoma. METHODS: Tumors from 21 patients with gastrointestinal high-grade malignant MANECs or tumors with varying percentages of Grade 3 NE component were examined, and the NE component was confirmed by morphological analysis and immunohistochemical staining. Patients were divided into high NE (NE component > 50% in the primary tumor) and low NE (NE component <= 50% in the primary tumor) component groups. RESULTS: High NE component was a poor prognostic factor for patients with high grade MANEC (p = 0.021). Out of 13 patients with high-grade malignant MANEC, eight had a pure NE component, one had a pure adenocarcinomatous component, and four had mixed-type cancer in the metastatic lymph nodes. We further enrolled eight patients who had a Grade 3 NE component in the primary tumor and found that the pure NE component in tumor emboli and distant liver metastases were more frequent in the high NE than in the low NE component group (p = 0.012 and p = 0.046, respectively). CONCLUSION: The predominant tumor component in primary tumors was a prognostic factor and could predict tumor emboli and liver metastases pathology in high grade malignant MANECs. PMID- 26002565 TI - Identification of Deleterious SNPs and Their Effects on Structural Level in CHRNA3 Gene. AB - The aim of our study is to identify probable deleterious genetic variations that can alter the expression and the function of the CHRNA3 gene using in silico methods. Of the 2305 SNPs identified in the CHRNA3 gene, 115 were found to be non synonymous and 12 and 15 nsSNPs were found to be in the 5' and 3' UTRs, respectively. Further, out of the 115 nsSNPs investigated, eight were predicted to be deleterious by both SIFT and PredictSNP servers. The major mutations predicted to affect the structure of the protein are phenylalanine to valine (Y43V) and lysine to asparagine (K216N) as shown by the trajectory run in molecular dynamics studies. The random transition of the protein structures over the simulation period caused by these mutations hints at how the native state is distorted which could lead to the loss of structural stability and functionality of the nicotinic acetylcholine receptors subunit alpha-3 protein. Based on this work, we propose that the nsSNP with SNP id of rs75495285 and rs76821682 will have comparatively more deleterious effects than the other predicted mutations in destabilizing the protein structure. PMID- 26002566 TI - Novel self-nanoemulsifying self-nanosuspension (SNESNS) for enhancing oral bioavailability of diacerein: Simultaneous portal blood absorption and lymphatic delivery. AB - The application of self-nanoemulsified drug delivery system (SNEDDS) to improve bioavailability of diacerein (D) has been hampered by its large dose and limited solubility. This work aimed to prepare diacerein loaded self nanoemulsifying self nanosuspension (D-SNESNS) containing high drug load. D-SNESNS was prepared by homogenizing D into MaisineTM-based SNEDDS that gave the highest drug solubility. D-SNESNS was evaluated for particle size, zeta potential and in vitro dissolution. Significant increase of D solubility was observed from D-SNESNS (~ 309 MUg/mL) than traditional SNEDDS (~162MUg/mL) due to the spontaneous simultaneous formation of nanoemulsion and nanosuspension (top-down approach). When exposed to water with mild agitation, the drug microparticles in D-SNESNS are temporarily surrounded by unsaturated aqueous layer (containing optimum concentrations of surfactant and co-solvent) that facilitates the erosion of the suspended drug particles into nanosized ones. Nanoemulsion-based nanosuspension (NENS) was confirmed using transmission electron microscopy and particle size analysis. D-SNESNS equivalent to 50mg D exhibited complete and very rapid dissolution after 15 min in phosphate buffer pH 6.8 due to the existence of D as solubilized molecules inside nanoemulsion globules and nanosized suspended drug particles forming D-NENS. The relative bioavailabilities of rhein from D-SNESNS in rats with normal and blocked chylomicron flow were about 210% and 164%, respectively in comparison to aqueous D suspension. The significant increase in the dissolution, portal absorption and lymphatic delivery of D propose that SNESNS could be promising to improve oral bioavailability of poorly water soluble drugs that have limited drug load in SNEDDS. PMID- 26002567 TI - Characterization of gelation process and drug release profile of thermosensitive liquid lecithin/poloxamer 407 based gels as carriers for percutaneous delivery of ibuprofen. AB - Suitability of liquid lecithin (i.e., solution of lecithin in soy bean oil with ~ 60% w/w of phospholipids) for formation of gels, upon addition of water solution of poloxamer 407, was investigated, and formulated systems were evaluated as carriers for percutaneous delivery of ibuprofen. Formulation study of pseudo ternary system liquid lecithin/poloxamer 407/water at constant liquid lecithin/poloxamer 407 mass ratio (2.0) revealed that minimum concentrations of liquid lecithin and poloxamer 407 required for formation of gel like systems were 15.75% w/w and 13.13% w/w, respectively, while the maximum content of water was 60.62% w/w. The systems comprising water concentrations in a range from 55 to 60.62% w/w were soft semisolids suitable for topical application, and they were selected for physicochemical and biopharmaceutical evaluation. Analysis of conductivity results and light microscopy examination revealed that investigated systems were water dilutable dispersions of spherical oligolamellar associates of phospholipids and triglyceride molecules in the copolymer water solution. Rheological behavior evaluation results indicated that the investigated gels were thermosensitive shear thinning systems. Ibuprofen (5% w/w) was incorporated by dispersing into the previously prepared carriers. Drug-loaded systems were physically stable at storage temperature from 5 +/- 3 degrees C to 40 +/- 2 degrees C, for 30 days. In vitro ibuprofen release was in accordance with the Higuchi model (rH>0.95) and sustained for 12h. The obtained results implicated that formulated LLPBGs, optimized regarding drug release and organoleptic properties, represent promising carriers for sustained percutaneous drug delivery of poorly soluble drugs. PMID- 26002568 TI - LeciPlex, invasomes, and liposomes: A skin penetration study. AB - The present study compares three vesicular systems, cationic LeciPlex, invasomes, and conventional liposomes for their ability to deliver drugs deep into the skin. Skin penetration ability of the three vesicular systems was studied for two drugs namely idebenone (antioxidant/anticancer) and azelaic acid (antiacne). All systems showed sizes in nanometer range with small polydispersity indices. Vesicular systems were characterized by CryoTEM studies to understand the differences in morphology of the vesicular systems. Ex vivo human skin penetration studies suggested a pattern in penetration of drugs in different layers of the skin: LeciPlex showed higher penetration for idebenone whereas invasomes showed higher penetration of azelaic acid. Ex vivo study using a fluorescent dye (DiI) was performed to understand the differences in the penetration behavior of the three vesicular systems on excised human skin. In vitro cytotoxicity studies on B16F10 melanoma cell lines revealed, when loaded with idebenone, LeciPlex formulations had the superior activity followed by invasomes and liposomes. In vitro antimicrobial study of azelaic acid loaded systems on Propionibacterium acne revealed high antimicrobial activity for DDAB leciplex followed by almost equal activity for invasomes and CTAB LeciPlex followed by liposomes. Whereas antiacne efficacy study in rats for azelaic acid loaded systems, invasomes exhibited the best antiacne efficacy followed by liposomes and LeciPlex. PMID- 26002569 TI - Devices for oral and respiratory paediatric medicines: What do healthcare professionals think? AB - Medical devices are crucial for the proper administration of paediatric medicines to children, but handling and dosing errors commonly appear in daily practice. As both the understanding and the usage of medical devices for oral and respiratory drug administration are heterogeneous among patients and caregivers, the European Paediatric Formulation Initiative (EuPFI) consortium performed a European survey among healthcare professional stakeholders in France, Germany, Hungary, Italy, Spain and UK. The results show country- and age-dependent usage of devices for oral administration of liquid formulations, with a clear preference for oral droppers and syringes in the neonatal phase and in early infancy. In older children, spoons and cups are more frequently used although it is recognized that they may fail in delivering correct doses. The percentage of medicinal products definitely requiring an oral administration device was estimated as 68.8% by the participants. The survey elaborated a similar usage pattern for medical devices for respiratory drug delivery: in young children drug solutions are nebulized, using face-masks and subsequently valved holding chambers or spacers, with increasing age metered-dose inhalers and later dry powder inhalers are preferably used. 56% of the responding healthcare professionals believed that providing an administration device helps to ensure that the patient receives the correct dose of medicine, and 41% agreed that patients must be given an administration device with each supply of medicine. Interestingly, 6.7% thought that patients tend not to use the device provided and remarkably 25.4% stated that patients already have a device. Although there is the highest count of treated children with device supply in Germany and Hungary, there are no observed significant differences in the six investigated European countries (p=0.057). Patient difficulties in correct oral and respiratory device use were identified by respondents and potential solutions discussed. PMID- 26002570 TI - Novel doped calcium phosphate-PMMA bone cement composites as levofloxacin delivery systems. AB - Antibiotic-loaded acrylic bone cements (ALABCs) are well-established and cost effective materials to control the occurrence of bone and joint infections. However, the inexistence of alternative antibiotics other than those already commercially available and the poor ability to bind to bone tissue hampering its biological function are still major drawbacks of ALABCs clinical application. The concept of this research work is to develop a novel bone cement (BC) drug delivery system composed by Mg- and Sr-doped calcium phosphate (CaP) particles as drug carriers loaded into a lactose-modified acrylic BC, which, to the best of our knowledge, has never been reported. CaP particles are known to promote bone ingrowth and current research is focused on using these carriers as antibiotic delivery systems for the treatment of bone infections, like osteomyelitis. Levofloxacin is a fluoroquinolone with anti-staphylococcal activity and adequate penetration into osteoarticular tissues and increasingly being recommended to manage bone-related infections. Also, the lactose-modified BC matrix, with a more porous structure, has already proved to enhance antibiotic release from the BC inner matrix. This novel BC composite biomaterial has shown improved mechanical integrity, biocompatibility maintenance, and sustained release of levofloxacin, with concentrations over the minimum inhibitory concentration values after a 48h while maintaining antibacterial activity over an 8-week period against Staphyloccocus aureus and Staphyloccocus epidermidis, common pathogens associated with bone infections. PMID- 26002571 TI - Effects of acupressure on anxiety: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the evidence from randomised controlled trials (RCTs) and quantify the effects of acupressure on anxiety among adults. METHODOLOGY: RCTs published between January 1997 and February 2014, comparing acupressure with sham control, were identified from the databases Science Citation Index/Social Sciences Citation Index, Scopus, PubMed and PsycINFO. Meta-analysis of eligible studies was performed and the magnitude of the overall effect size was calculated for the anxiety outcome. Revised STRICTA (the Standards for Reporting Interventions in Clinical Trials of Acupuncture) criteria were used to appraise the acupressure procedures, and the Cochrane risk of bias tool was used to assess the methodological quality of the studies. RESULTS: Of 39 potentially relevant studies, seven RCTs met the inclusion criteria for review while five studies met the criteria for meta-analysis. All studies reported the positive effect of acupressure on relieving anxiety from the anticipation of surgery or treatment. EX-HN3 (Yintang), HT7 (Shenmen) were the commonest points selected and two studies used bilateral points. The acupressure procedure was generally well reported and studies had a low risk of bias. The combined results of the five trials showed a greater overall reduction in anxiety in the acupressure group than in the sham controls (standardised mean differences (SMD)=-1.11; 95% CI 1.61 to -0.61; p<0.0001 heterogeneity: I(2)=75%; chi(2)=16.17; p=0.003; r=0.485). CONCLUSIONS: Acupressure seems to be effective in providing immediate relief of pretreatment anxiety among adults, and has a medium effect size. However, conflicting results were found for the improvements on physiological indicators. More rigorous reporting, including allocation concealment procedure, is needed to strengthen the results. PMID- 26002572 TI - Interference with distinct steps of sphingolipid synthesis and signaling attenuates proliferation of U87MG glioma cells. AB - Glioblastoma is the most common malignant brain tumor, which, despite combined radio- and chemotherapy, recurs and is invariably fatal for affected patients. Members of the sphingolipid (SL) family are potent effectors of glioma cell proliferation. In particular sphingosine-1-phosphate (S1P) and the corresponding G protein-coupled S1P receptors transmit proliferative signals to glioma cells. To investigate the contribution to glioma cell proliferation we inhibited the first step of de novo SL synthesis in p53(wt) and p53(mut) glioma cells, and interfered with S1P signaling specifically in p53(wt) U87MG cells. Subunit silencing (RNAi) or pharmacological antagonism (using myriocin) of serine palmitoyltransferase (SPT; catalyzing the first committed step of SL biosynthesis) reduced proliferation of p53(wt) but not p53(mut) GBM cells. In U87MG cells these observations were accompanied by decreased ceramide, sphingomyelin, and S1P content. Inhibition of SPT upregulated p53 and p21 expression and induced an increase in early and late apoptotic U87MG cells. Exogenously added S1P (complexed to physiological carriers) increased U87MG proliferation. In line, silencing of individual members of the S1P receptor family decreased U87MG proliferation. Silencing and pharmacological inhibition of the ATP-dependent cassette transporter A1 (ABCA1) that facilitates S1P efflux in astrocytes attenuated U87MG growth. Glyburide-mediated inhibition of ABCA1 resulted in intracellular accumulation of S1P raising the possibility that ABCA1 promotes S1P efflux in U87MG glioma cells thereby contributing to inside-out signaling. Our findings indicate that de novo SL synthesis, S1P receptor-mediated signaling, and ABCA1-mediated S1P efflux could provide pharmacological targets to interfere with glioma cell proliferation. PMID- 26002573 TI - Postoperative dynamic changes in the concentration of CK19-2G2 in lung cancer patients and the clinical value of this marker. AB - CK19-2G2, a newly identified fragment of cytokeratin 19, is a candidate marker for the diagnosis of lung cancer and for monitoring a patient's response to lung cancer treatment. This study investigated the postoperative dynamic changes in serum CK19-2G2 concentration and the clinical value of this marker in lung cancer patients. Preoperative and postoperative concentrations of CK19-2G2 were measured in 352 lung cancer patients who had undergone pulmonary resection. Stratified analyses based on pathologic types and lymph node involvement were performed to determine their possible impacts on postoperative CK19-2G2 concentration. CK19 2G2 concentration was significantly lower after tumor resection than before tumor resection. For squamous cell carcinoma patients, the postoperative CK19-2G2 concentration had decreased significantly at 1 week after surgery and had decreased further at 1 month after surgery. For adenocarcinoma patients, there were little changes in the CK19-2G2 concentration during 1 week to 1 month after surgery. At 1 week after surgery, the CK19-2G2 concentration was slightly higher in patients with N2 stage disease than in those with N0 and N1 stage disease, and this difference increased at 1 month after surgery. Postoperative CK19-2G2 concentration may be an indicator of prognosis. An increase after the initial drop in CK19-2G2 concentration after surgery may indicate a poor prognosis. PMID- 26002574 TI - The effect of statins on cancer cells--review. AB - Statins [3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, abbreviated HMGCR) inhibitors], are well-known cholesterol-depleting agents. Since the early 1990 s, it has been known that statins could be successfully used in cancer therapy, but the exact mechanism(s) of statin activity remains unclear and is now an extensive focus of investigation. So far, it was proven that there are several mechanisms that are activated by statins in cancer cells; some of them are leading to cell death. Statins exert different effects depending on cell line, statin concentration, duration of exposure of cells to statins, and the type of statin being used. It was shown that statins may inhibit the cell cycle by influence on both expression and activity of proteins involved in cell-cycle progression such as cyclins, cyclin-dependent kinases (CDK), and/or inhibitors of CDK. Also, statins may induce apoptosis by both intrinsic and extrinsic pathways. Statin treatment may lead to changes in molecular pathways dependent on the EGF receptor, mainly via inhibition of isoprenoid synthesis. By inhibition of the synthesis of cholesterol, statins may destabilize the cell membrane. Moreover, statins may change the arrangement of transporter OATP1, the localization of HMGCR, and could induce conformational changes in GLUT proteins. In this review, we have tried to gather and compare most of the recent outcomes of the research in this field. We have also attempted to explain why hydrophilic statins are less effective than hydrophobic statins. Finally, we have gathered results from in vivo experiments, presenting the use of statins in combined therapies and discussed a number of molecular targets that could serve as biomarkers predisposing to statin therapy. PMID- 26002575 TI - RNA interference against TMEM97 inhibits cell proliferation, migration, and invasion in glioma cells. AB - Gliomas are the most common form of primary brain tumor in the adult central nervous system. Altered expression and prognostic value of transmembrane protein 97 (TMEM97) has been recently reported in different types of human tumors. However, the association of TMEM97and glioma is poorly defined. Here, we reported that TMEM97 was significantly increased in glioma tissues compared to non tumorous brain tissues. Furthermore, TMEM97 levels were progressively increased with increasing histologic tumor grade in glioma. Higher TMEM97 expression level was correlated with shorter survival time of patients with glioma. Downregulation of TMEM97 through RNA interference inhibited cell proliferation and G1/S transition in two glioma cell lines, U87 and U373. More importantly, TMEM97 silencing induced a significant decrease in the expression of G1/S transition key regulators, cyclin D1, cyclin E, CDK2, and CDK4. Additionally, downregulation of TMEM97 in glioma cells notably repressed cell migration and cell invasion. Further analysis suggested that the decreased invasion was associated with alterations in EMT markers, including E-cadherin, beta-catenin, and Twist. Since expression of TMEM97 seems to be associated with the oncogenic potential of glioma, and suppression of its expression can inhibit cancer cell growth and metastasis, TMEM97 may be a potential therapeutic target in human glioma. PMID- 26002576 TI - Elevated RABEX-5 protein expression predicts poor prognosis in combined small cell lung cancer. AB - RABEX-5 has been studied in various solid tumors, but its role in combined small cell lung cancer (C-SCLC) remains unknown. This study aimed to investigate the expression, the potential relevance to clinicopathological characters and prognostic significance of RABEX-5 in patients with C-SCLC. Fifty-two C-SCLC patients who received radical surgery were enrolled in our study. The clinicalpathological data and survival time were reviewed. The mRNA and protein expression of RABEX-5 from the paired tumor tissues and adjacent normal tissues were determined, and its relationship with clinicalpathological variables and prognosis was analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of RABEX-5 for C-SCLC. The mRNA and protein expression level of RABEX-5 was significantly elevated in C-SCLC tissues. The increased RABEX-5 protein expression was correlated with clinical stage (p = 0.011) and tumor recurrence (p = 0.006). The median OS and DFS was significantly shorter in the high RABEX-5 expression group compared to low RABEX-5 expression group (OS: 12.0 vs. 21.7 months, p = 0.014; DFS: 6.7 vs. 11.8 months, p = 0.005). Multivariate Cox analysis indicated that high RABEX-5 protein expression was an independent prognostic factor for OS and DFS (p < 0.001). RABEX-5 is a potential useful indicator and predicts a poor long-term prognosis for C-SCLC, which should be considered in defining the prognosis with other well-known prognosticators in C-SCLC patients. PMID- 26002577 TI - Serum markers in early-stage and locally advanced melanoma. AB - The identification of prognostic factors in cutaneous melanoma allows choosing the most effective treatment, especially in group of patients with locoregional disease. Markers related to carcinogenesis and angiogenesis in particular have effect on the course of the disease. The aim of this study was to evaluate clinical utility of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinase 1 (TIMP-1), and YKL-40 in serum of melanoma patients at pathological stages I-III. We included 148 adult patients with melanoma. The median follow-up was 40 months. Disease recurrence was observed in 43 patients; 3-year disease-free survival (DFS) rate was 71.7%; 35 patients died; and the 3-year overall survival (OS) rate was 85%. Concentrations of VEGF, MMP-2, MMP-9, TIMP-1, and YKL-40 were measured by ELISA kits. VEGF, MMP-9, TIMP-1, and YKL-40 were significantly higher in group of patients than in controls. Increased concentrations of TIMP-1 were related to patient survival, which in the group of lower and increased TIMP-1, disease-free survival amounted to 81 vs. 61% (p = 0.014) and overall survival -88 vs. 82% (p = 0.050), respectively. An increased concentration of YKL-40 was observed in 59% of patients with ulceration and in 26% of patients without ulceration (p = 0.012). We have found a clinically significant correlation between YKL-40 and MMP-9 (rho = 0.363; p = 0.004) as well as YKL-40 and VEGF (rho = 0.306; p = 0.018). In melanoma patients at stages I-III, the high concentrations of TIMP-1 in serum predicted adverse prognosis. YKL-40 was associated with ulceration of primary tumor, which is a very important prognostic factor. PMID- 26002579 TI - Effect of nisin and doxorubicin on DMBA-induced skin carcinogenesis--a possible adjunct therapy. AB - In view of the emergence of multidrug-resistant cancer cells, there is a need for therapeutic alternatives. Keeping this in mind, the present study was aimed at evaluating the synergism between nisin (an antimicrobial peptide) and doxorubicin (DOX) against DMBA-induced skin carcinogenesis. The possible tumoricidal activity of the combination was evaluated in terms of animal bioassay observations, changes in hisotological architecture of skin tissues, in situ apoptosis assay (TUNEL assay) and in terms of oxidant and antioxidant status of the skin tissues. In vivo additive effect of the combination was evidenced by larger decreases in mean tumour burden and tumour volume in mice treated with the combination than those treated with the drugs alone. Histological observations indicated that nisin-DOX therapy causes chromatin condensation and marginalisation of nuclear material in skin tissues of treated mice which correlated well with the results of TUNEL assay wherein a marked increase in the rate of apoptosis was revealed in tissues treated with the combination. A slightly increased oxidative stress in response to the adjunct therapy as compared to dox-alone-treated group was revealed by levels of lipid peroxidation (LPO) and nitrite generation in skin tissue-treated mice. An almost similar marginal enhancement in superoxide dismutase levels corresponding with a decrease in catalase activity could also be observed in nisin + DOX-treated groups as compared to nisin and dox-alone-treated groups. These results point towards the possible use of nisin as an adjunct to doxorubicin may help in developing alternate strategies to combat currently developing drug resistance in cancer cells. PMID- 26002578 TI - miRNA-449a is downregulated in osteosarcoma and promotes cell apoptosis by targeting BCL2. AB - Accumulating evidence reveals that miR-449a is expressed at a low level in several tumors and cancer cell lines, and acts as a tumor suppressor in several cancers. However, its role in osteosarcoma (OS) is not well understood. In the present study, we found that miR-449a was significantly downregulated in both OS tissues and cell lines. Furthermore, low expression level of miR-449a was correlated with advanced tumor stage, metastasis, and predicted a poor overall survival in OS patients. Additionally, restoration of miR-449a in OS cell lines U2OS and Saos-2 reduced cell viability, promoted cell apoptosis in vitro, and suppressed tumorigenicity in vivo. Moreover, BCL2, an antiapoptotic molecule, was identified to be a direct target of miR-449a, and the proapoptotic function of miR-449a was mainly through targeting BCL2 expression. Taken together, our results demonstrated a tumor-suppressive role of miR-449a in OS progression and suggested a potential therapeutic target for OS. PMID- 26002580 TI - miR-582-5p inhibits proliferation of hepatocellular carcinoma by targeting CDK1 and AKT3. AB - microRNAs play an important role in the progression of hepatocellular carcinoma (HCC). In this study, we found that miR-582-5p expression was downregulated in hepatoma tissues and HCC cell lines. Upregulation of miR-582-5p reduced colony number, inhibited cellular proliferation, and arrested cell cycle in G0/G1 phase. When miR-582-5p was inhibited, the colony number was increased and cellular proliferation and cell cycle were promoted. Further studies showed that miR-582 5p regulated the progression of HCC through directly inhibiting the expression of CDK1 and AKT3, and indirectly inhibiting the expression of cyclinD1. PMID- 26002581 TI - Phytobarriers: Plants capture particles containing potentially toxic elements originating from mine tailings in semiarid regions. AB - Retention of particles containing potentially toxic elements (PTEs) on plants that spontaneously colonize mine tailings was studied through comparison of washed and unwashed shoot samples. Zn, Pb, Cd, Cu, Ni, Co and Mn concentrations were determined in plant samples. Particles retained on leaves were examined by Scanning Electronic Microscopy and energy dispersive X-Ray analysis. Particles containing PTEs were detected on both washed and unwashed leaves. This indicates that the thorough washing procedure did not remove all the particles containing PTEs from the leaf surface, leading to an overestimation of the concentrations of PTEs in plant tissues. Particularly trichomes and fungal mycelium were retaining particles. The quantity and composition of particles varied among plant species and place of collection. It is obvious that plants growing on toxic mine tailings form a physical barrier against particle dispersion and hence limit the spread of PTEs by wind. PMID- 26002582 TI - Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse. AB - Acetaminophen (APAP) is widely used as a safety analgesic and antipyretic agent. Although considered safe at therapeutic doses, overdose of APAP can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. Luteolin is a naturally occurring flavonoid which is abundant in plants. The objective of this study was to investigate corresponding anti oxidative and anti-inflammatory activities of luteolin, using acetaminophen treated mice as a model system. Male C57BL/C mice were randomly divided into three groups (n=6 each). The control group was given phosphate buffered saline (PBS) orally. The APAP group was given APAP by intraperitoneal injection (i.p) at 300 mg/kg suspended in PBS. The luteolin-treated group was given APAP and luteolin (0-100 mg/kg/day, 1 or 3 days before APAP administration) suspended in PBS orally. 16 h after APAP administration, the liver and serum were collected to determine the liver injury. Luteolin administration significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), malondialdehyde (MDA) levels, as well as glutathione (GSH) depletion and decrease of superoxide dismutase (SOD). Luteolin restored SOD, GSH and GSH-px activities and depressed the expression of pro-inflammatory factors, such as inducible nitric oxide synthase (i-NOS), TNF-alpha, nuclear factor kappa B (NF kappaB), and IL-6, respectively. Moreover, luteolin down-regulated acetaminophen induced nitrotyrosine (NT) formation and endoplasmic reticulum (ER) stress. These results suggest the presence of anti-oxidative, anti-inflammatory and anti-ER stress properties of luteolin in response to acetaminophen-induced liver injury in mice. PMID- 26002583 TI - Altered ultrastructure, density and cathepsin K expression in bone of female muscarinic acetylcholine receptor M3 knockout mice. AB - High frequency of osteoporosis is found in postmenopausal women where several molecular components were identified to be involved in bone loss that subsequently leads to an increased fracture risk. Bone loss has already been determined in male mice with gene deficiency of muscarinic acetylcholine receptor M3 (M3R-KO). Here we asked whether bone properties of female 16-week old M3R-KO present similarities to osteoporotic bone loss by means of biomechanical, radiological, electron microscopic, cell- and molecular biological methods. Reduced biomechanical strength of M3R-KO correlated with cortical thickness and decreased bone mineral density (BMD). Femur and vertebrae of M3R-KO demonstrated a declined trabecular bone volume, surface, and a higher trabecular pattern factor and structure model index (SMI) compared to wild type (WT) mice. In M3R KO, the number of osteoclasts as well as the cathepsin K mRNA expression was increased. Osteoclasts of M3R-KO showed an estimated increase in cytoplasmic vesicles. Further, histomorphometrical analysis revealed up-regulation of alkaline phosphatase. Osteoblasts and osteocytes showed a swollen cytoplasm with an estimated increase in the amount of rough endoplasmatic reticulum and in case of osteocytes a reduced pericellular space. Thus, current results on bone properties of 16-week old female M3R-KO are related to postmenopausal osteoporotic phenotype. Stimulation and up-regulation of muscarinic acetylcholine receptor subtype M3 expression in osteoblasts might be a possible new option for prevention and therapy of osteoporotic fractures. Pharmacological interventions and the risk of side effects have to be determined in upcoming studies. PMID- 26002584 TI - Unbalanced acetylcholinesterase activity in larynx squamous cell carcinoma. AB - Previous reports have demonstrated that a non-neuronal cholinergic system is expressed aberrantly in airways. A proliferative effect is exerted directly by cholinergic agonists through the activation of nicotinic and muscarinic receptors. In cancer, particularly those related with smoking, the mechanism through which tumour cells respond to aberrantly activated cholinergic signalling is a key question. Fifty paired pieces of larynx squamous cell carcinoma and adjacent non-cancerous tissue were compared in terms of their acetylcholinesterase activity (AChE). The AChE activity in non-cancerous tissues (0.248 +/- 0.030 milliunits per milligram of wet tissue; mU/mg) demonstrates that upper respiratory tissues express sufficient AChE activity for controlling the level of acetylcholine (ACh). In larynx carcinomas, the AChE activity decreased to 0.157 +/- 0.024 mU/mg (p=0.009). Larynx cancer patients exhibiting low ACh degrading enzymatic activity had a significantly shorter overall survival (p=0.031). Differences in the mRNA levels of alternatively spliced AChE isoforms and molecular compositions were noted between glottic and supraglottic cancers. Our results suggest that the low AChE activity observed in larynx squamous cell carcinoma may be useful for predicting the outcome of patients. PMID- 26002585 TI - In vivo anti-apoptosis activity of novel berberine-loaded chitosan nanoparticles effectively ameliorates osteoarthritis. AB - Berberine chloride (BBR) is an isoquinoline alkaloid that possesses promising protective efficacies against osteoarthritis (OA). Nevertheless, the therapeutic agent of this substance in OA is limited by its poor aqueous solubility, low bioavailability and short biological half-life. In this study, chitosan (CS) based nanoparticles were prepared for the sustained release of BBR. Novel BBR loaded chitosan nanoparticles (CNs) were successfully synthesized by the ionic cross-linking method. BBR-loaded CNs were spherical and homogeneous in shape. Moreover, they exhibited good stability and had ideal releasing profile in vitro. After intra-articular injection of BBR-loaded CNs, the level of BBR in rat plasma decreased and the retention time in synovial fluid increased compared with free BBR solution. In vivo evaluation of BBR-loaded CNs further showed higher anti apoptosis activity in the treatment of OA compared with BBR solution at equivalent concentration. This result was evidenced by the changes of gross morphology and histological analyses in rat articular cartilage, TUNEL assay, quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical analyses of caspase-3, Bcl-2 and Bax expressions. Given these results, BBR-loaded CNs are potential therapeutic agents for OA. PMID- 26002586 TI - Deletion of muscarinic type 1 acetylcholine receptors alters splenic lymphocyte functions and splenic noradrenaline concentration. AB - The existence of interactions between the immune and the sympathetic nervous systems is well established. Noradrenaline can promote or inhibit the immune response, and conversely, the immune response itself can affect noradrenaline concentration in lymphoid organs, such as the spleen. It is also well known that acetylcholine released by pre-ganglionic neurons can modulate noradrenaline release by the postsynaptic neuron. The spleen does not receive cholinergic innervation, but it has been reported that lymphocytes themselves can produce acetylcholine, and express acetylcholine receptors and acetylcholinesterase. We found that the spleen of not overtly immunized mice in which muscarinic type 1 acetylcholine receptors have been knocked out (M1KO) has higher noradrenaline concentrations than that of the wildtype mice, without comparable alterations in the heart, in parallel to a decreased number of IgG-producing B cells. Splenic lymphocytes from M1KO mice displayed increased in vitro-induced cytotoxicity, and this was observed only when CD4(+) T cells were present. In contrast, heterozygous acetylcholinesterase (AChE+/-) mice, had no alterations in splenic noradrenaline concentration, but the in vitro proliferation of AChE+/- CD4(+) T cells was increased. It is theoretically conceivable that reciprocal effects between neuronally and non-neuronally derived acetylcholine and noradrenaline might contribute to the results reported. Our results emphasize the need to consider the balance between the effects of these mediators for the final immunoregulatory outcome. PMID- 26002587 TI - Artesunate Attenuates Lipopolysaccharide-Stimulated Proinflammatory Responses by Suppressing TLR4, MyD88 Expression, and NF-kappaB Activation in Microglial Cells. AB - Microglia are considered as a major target in the prevention of neuroinflammation by modulating the production of pro-inflammatory mediators. Artesunate, a water soluble artemisinin derivative, exerts an anti-inflammatory effect. In the present study, we showed artesunate dose-dependently suppressed the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and interleukin-1beta (IL-1beta) in BV2 microglial cells. In addition, artesunate inhibited LPS-induced expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and activation of nuclear factor kappa B (NF-kappaB) by blockade of inhibitor of NF-kappaB (IkappaB) degradation. This data indicate that artesunate attenuates the generation of proinflammatory mediators on LPS-stimulated BV-2 microglial cells. And this effect may be associated with the suppression of TLR4/MyD88/NF-kappaB signaling pathways. Therefore, artesunate may be a potential anti neuroinflammatory agent. PMID- 26002588 TI - Balloon cell nevi of the conjunctiva: Clinicopathologic correlation and literature review. AB - Balloon cell nevi are rare, benign melanocytic tumors that may involve the conjunctiva, choroid, and skin. In the ocular adnexa they typically present as raised and mobile hyperpigmented masses. Histologically, balloon cell nevi consist of large cells forming nests that usually lack melanin pigment. The balloon cells have a clear or vacuolated cytoplasm with centrally located nuclei. The vacuolated cytoplasm may be the result of defective melanin synthesis, with the accumulation of melanin precursors in premelanosomes. Balloon cells can resemble xanthoma cells, adipocytes, macrophages, sebaceous adenomas, melanoma with balloon cell changes, and metastatic renal cell carcinoma. Differentiating between these various entities via morphology and immunohistochemistry thus remains clinically significant. We report three cases of conjunctival balloon cell nevi and review the literature. PMID- 26002589 TI - Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis. AB - AIMS: Advanced glycation end products (AGEs) have been implicated in pulmonary and renal fibrosis. Herein, we investigated whether AGEs are associated with liver fibrosis and examined the underlying mechanism by focusing on hepatic stellate cell (HSC) activation and autophagy induction. METHODS: Liver fibrosis was assessed by transient elastography (FibroScan). Serum AGE levels were determined by ELISA. Rat primary HSCs and HSC-T6 were treated with BSA-AGEs, cell proliferation was examined by WST-1 assay, and cell activation was evaluated by qPCR for transcripts of alpha-SMA and collagen type Ialpha1 and by Western blotting. Autophagy was measured by detection of LC3-II lipidation, p62 degradation, and puncta GFP-LC3 formation. Receptor of AGE (RAGE)-blocking antibodies and soluble RAGE were employed to inhibit AGE-RAGE signaling. RESULTS: First, elevated AGE levels were observed in CHC patients than patients with chronic hepatitis B, especially in those with insulin resistance. Second, compared to controls, AGE-treated rat primary HSCs displayed an enhanced cell proliferation (1.39-fold), increased transcripts of alpha-SMA (2.40-fold) and proCOL1A1 (1.76-fold), and a higher level of alpha-SMA protein (1.85-fold). Moreover, AGE-induced HSC activation improved autophagy flux, as evidenced by significantly more LC3-II lipidation, p62 degradation, as well as GFP-LC3 puncta formations. In addition, our results showed that AGE-induced HSC autophagy and HSC activation could be reduced by RAGEs. CONCLUSION: AGEs were found to induce autophagy and activation of HSCs, which subsequently contributes to the fibrosis in CHC patients. Blocking AGE-RAGE signaling may be a promising way to alleviate fibrosis. PMID- 26002591 TI - A Risk Assessment Tool for the Virtual Screening of Metal Oxide Nanoparticles through Enalos InSilicoNano Platform. AB - The increasing use of Nanoparticles (NPs) in a wide range of applications has led to a rising concern on the possible toxicological effects that this use may have on human health and the environment. Since experimental toxicity evaluation for the different types of NPs already available, is often expensive and time consuming, several computational approaches are proposed for the risk assessment of NPs. In this work, we have developed a predictive classification model for the toxicological assessment of iron oxide NPs with different core, coating and surface modification based on a number of different properties including size, relaxivities, zeta potential and type of coating. The model was fully validated based on several validation measurements and was released online via Enalos InSilicoNano Platform (http://enalos.insilicotox.com/QNAR_IronOxide_Toxicity/). The developed web service gives the interested user the opportunity to insert the indicated properties and get a toxicity prediction accompanied by an indication of its reliability based on the domain of applicability. This newly introduced web service complements our previously reported efforts to extract important information from available datasets and develop user friendly applications for the toxicity assessment of NPs. PMID- 26002590 TI - Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial. AB - AIMS: Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, alpha-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized crossover pilot of alpha-tocopherol supplementation on HDL function [i.e., cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)] and lipoprotein subfractions in type 1 diabetes. METHODS: Hp genotype was assessed in members of two Allegheny County, PA, type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily alpha-tocopherol or placebo for 8 weeks with a 4-week washout. RESULTS: Baseline CE decreased with the number of Hp 2 alleles (p-trend = 0.003). There were no differences in LP or lipoprotein subfractions. In intention-to treat analysis stratified by Hp, alpha-tocopherol increased CE in Hp 2-2 (beta = 0.79, p = 0.03) and LP in Hp 1 allele carriers (beta Hp 1-1 = 0.18, p = 0.05; beta Hp 2-1 = 0.21, p = 0.07); reduced HDL particle size (beta = -0.07, p = 0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1; and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp. CONCLUSIONS: In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. alpha-Tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies. PMID- 26002592 TI - Predicting success or failure of brace treatment for adolescents with idiopathic scoliosis. AB - Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal deformity. Brace treatment is a common non-surgical treatment, intended to prevent progression (worsening) of the condition during adolescence. Estimating a braced patient's risk of progression is an essential part of planning treatment, so method for predicting this risk would be a useful decision support tool for practitioners. This work attempts to discover whether failure of brace treatment (progression) can be predicted at the start of treatment. Records were obtained for 62 AIS patients who had completed brace treatment. Subjects were labeled as "progressive" if their condition had progressed despite brace treatment and "non progressive" otherwise. Wrapper-based feature selection selected two useful predictor variables from a list of 14 clinical measurements taken from the records. A logistic regression model was trained to classify patients as "progressive" or "non-progressive" using these two variables. The logistic regression model's simplicity and interpretability should facilitate its clinical acceptance. The model was tested on data from an additional 28 patients and found to be 75 % accurate. This accuracy is sufficient to make the predictions clinically useful. It can be used online: http://www.ece.ualberta.ca/~dchalmer/SimpleBracePredictor.html . PMID- 26002593 TI - CT image-based computer-aided system for orbital prosthesis rehabilitation. AB - In this paper, a computer-aided system for orbital prosthesis rehabilitation is introduced. With the system, a 3D model of the orbital prosthesis can be easily reconstructed from the CT image of a patient by referring to the normal eye of the patient, and the rehabilitation result by the model can be simulated before the surgery. This facilitates surgeons to design appropriate orbital prosthesis and improve rehabilitation esthetics. Based on the system, the preoperative surgery planning for orbital implant can also be made. This improves the reliability, safety and intuition of the rehabilitation surgery well. The system has been applied to clinical CT images of patients, and the experimental results show effectiveness and acceptability of the system in the clinic. PMID- 26002594 TI - Rotating permanent magnet excitation for blood flow measurement. AB - A compact, portable and improved blood flow measurement system for an extracorporeal circuit having a rotating permanent magnetic excitation scheme is described in this paper. The system consists of a set of permanent magnets rotating near blood or any conductive fluid to create high-intensity alternating magnetic field in it and inducing a sinusoidal varying voltage across the column of fluid. The induced voltage signal is acquired, conditioned and processed to determine its flow rate. Performance analysis shows that a sensitivity of more than 250 mV/lpm can be obtained, which is more than five times higher than conventional flow measurement systems. Choice of rotating permanent magnet instead of an electromagnetic core generates alternate magnetic field of smooth sinusoidal nature which in turn reduces switching and interference noises. These results in reduction in complex electronic circuitry required for processing the signal to a great extent and enable the flow measuring device to be much less costlier, portable and light weight. The signal remains steady even with changes in environmental conditions and has an accuracy of greater than 95%. This paper also describes the construction details of the prototype, the factors affecting sensitivity and detailed performance analysis at various operating conditions. PMID- 26002595 TI - In vitro evaluation of low-intensity light radiation on murine melanoma (B16F10) cells. AB - Changes in the energy state of biomolecules induced by electromagnetic radiation lead to changes in biological functions of irradiated biomolecules. Using the RRM approach, it was computationally predicted that far-infrared light irradiation in the range of 3500-6000 nm affects biological activity of proto-oncogene proteins. This in vitro study evaluates quantitatively and qualitatively the effects of selected far-infrared exposures in the computationally determined wavelengths on mouse melanoma B16F10 cells and Chinese hamster ovarian (CHO) cells by MTT (thiazolyl blue tetrazolium bromide) cell proliferation assay and confocal laser scanning microscopy (CLSM). This paper also presents the findings obtained from irradiating B16F10 and CHO cells by the selected wavelengths in visible and near infrared range. The MTT results show that far-infrared wavelength irradiation induces detrimental effect on cellular viability of B16F10 cells, while that of normal CHO cells is not affected considerably. Moreover, CLSM images demonstrate visible cellular detachment of cancer cells. The observed effects support the hypothesis that far-infrared light irradiation within the computationally determined wavelength range induces biological effect on cancer cells. From irradiation of selected visible and near-infrared wavelengths, no visible changes were detected in cellular viability of either normal or cancer cells. PMID- 26002596 TI - Cognitive behaviour therapy plus aerobic exercise training to increase activity in patients with myotonic dystrophy type 1 (DM1) compared to usual care (OPTIMISTIC): study protocol for randomised controlled trial. AB - BACKGROUND: Myotonic dystrophy type 1 (DM1) is a rare, inherited chronic progressive disease as well as an autosomal dominant multi-systemic disorder. It is probably one of the most common adult forms of muscular dystrophy, with a prevalence of approximately 10 per 100,000 people affected. With 733 million people in Europe, we estimate that 75,000 people in Europe are affected with DM1. METHODS/DESIGN: OPTIMISTIC is a multi-centre, randomised trial designed to compare an intervention comprising cognitive behavioural therapy (CBT) plus graded exercise therapy against standard care. Participants will be recruited from myotonic dystrophy clinics and neuromuscular centres in France, Germany, the Netherlands and the United Kingdom. A sample size of 208 individuals is needed. To allow for some potential loss to follow-up, a total of 296 male and female patients aged 18 years and older with genetically proven classical or adult DM1 and suffering from severe fatigue (only DM1 patients with a Checklist Individual Strength (CIS) subscale fatigue severity score >= 35 are likely to benefit from the intervention), able to walk independently and able to complete the trial interventions will be included. The primary outcome of the study is the score on the DM1-Activ scale, which is a measure of activity and participation for patients with DM1. Secondary outcomes include the 6-minute walk test, objective physical activity measured with an accelerometer, quality of life and cognitive measures. The trial will also collect data on potential effect modifiers of the short- and long-term clinical response, including pain, muscular impairment and cognitive-behavioural variables. In addition, OPTIMISTIC will identify genetic factors that predict outcome and potential biomarkers as surrogate outcome measures that best explain the observed clinical variation. DISCUSSION: OPTIMISTIC will not only provide effectiveness data on an intervention that could fill a treatment-gap for DM1 patients but will also improve our understanding of the relevant determinants of the prognosis of DM1. TRIAL REGISTRATION: REGISTRATION NUMBER: Cinicaltrials.gov NCT02118779; registered 11 April 2014. PMID- 26002597 TI - Risk factors for shoulder pain in patients with spinal cord injury: a multicenter study. AB - INTRODUCTION: Shoulder pain in spinal cord injury (SCI) is common due to the repetition of the wheelchair propulsion and the increased intra-articular pressure during transfers. Known risk factors for the onset of shoulder pain are age and level of SCI. Aims of this study were to assess how body mass index affects the onset of shoulder pain and to evaluate the relationship between the age at the moment of SCI and the number of years between SCI and the onset of shoulder pain. METHODS: A retrospective study was performed including subjects with SCI between C5 and S3. Excluding criteria were spina bifida and subjects not using manual wheelchair or presenting with shoulder pain before SCI. Patients in the two spinal cord units were reviewed with a self-made questionnaire, and patients were also enrolled during sport events. Age at the moment of SCI, current age and number of years between SCI and the onset of shoulder pain were recorded. RESULTS: Ninety-six patients were enrolled: 77 men and 19 women; 46.4 % reported shoulder pain. Overweight patients who do more than 12 transfers per day showed an increased incidence of shoulder pain (p = 0.0434). A linear regression showed a significant relationship between the age of the subject at the moment of SCI and the number of years between the SCI and the onset of pain. CONCLUSION: Our study confirms that age and level of SCI are risk factors for shoulder pain, but we demonstrated also that overweight patients who do more than 12 transfers per day have higher chances of having shoulder pain. PMID- 26002598 TI - Preface. VETPATH 2014--Pathogenesis of Bacterial Infections of Animals. PMID- 26002599 TI - The impact of childhood gender expression on childhood sexual abuse and psychopathology among young men who have sex with men. AB - Young men who have sex with men (MSM) are a risk group highly vulnerable to HIV infection and psychiatric symptoms are direct predictors of sexual risk behavior in MSM. Childhood sexual abuse (CSA) is associated with psychiatric symptomology in adolescence, and MSM are disproportionately impacted by CSA compared to heterosexuals. Some evidence suggests that childhood gender nonconformity, a natural variation of human gender expression, is more common in MSM than heterosexual males and places MSM at greater risk for CSA. This study examined whether or not childhood gender expression moderated the association between incidents of unwanted, early sexual experiences occurring before age 13 (ESE) and current psychiatric symptomology in a community-based sample of 449 young MSM aged 16-20. Analyses revealed significant bivariate associations between ESE and psychological symptoms, and significant multivariable associations between ESE, gender nonconformity and psychiatric outcomes. Young MSM with childhood gender nonconformity may be disproportionately victimized by CSA thereby increasing their likelihood of developing psychiatric symptoms in adolescence. Early intervention addressing these factors may help reduce lifetime negative sequelae. PMID- 26002600 TI - Profiles and predictors of behavioral resilience among children in child welfare. AB - Children living in out-of-home care have experienced a multitude of adversities, often resulting in compromised functioning. The current study used Ontario Looking After Children (OnLAC) project data to estimate developmental trajectories of behavioral outcomes (i.e., conduct and emotional problems) over a 4-year period (i.e., ages 6-10 to 9-13) in 313 children living in out-of-home care. Predictors measured at baseline (e.g., sex) and across the subsequent 4 year period (e.g., parenting practices) were also investigated. Findings indicated that 64.2% and 58.6% followed resilient trajectories for conduct behaviors and emotional functioning, respectively. Predictors of resilient trajectories included internal developmental assets, number of children in the home, whether the child was receiving treatment, and positive parenting. Findings need to be interpreted with an understanding that children in out-of-home care have varying levels of functioning across various domains (e.g., educational, social) other than the ones measured here. Predictors were static and dynamic and cut across various contexts, emphasizing the importance of considering child functioning within an ecological model. PMID- 26002601 TI - Relationship between child abuse exposure and reported contact with child protection organizations: results from the Canadian Community Health Survey. AB - Much of what is known about child abuse in Canada has come from reported cases of child abuse and at-risk samples, which likely represent the most severe cases of child abuse in the country. The objective of the current study is to examine the prevalence of a broad range of child abuse experiences (physical abuse, sexual abuse, and exposure to IPV) and investigate how such experiences and sociodemographic variables are related to contact with child protection organizations in Canada using a representative general population sample. Data were drawn from the 2012 Canadian Community Health Survey: Mental Health collected from the 10 provinces using a multistage stratified cluster design (n=23,395; household response rate=79.8%; aged 18 years and older). Physical abuse only (16.8%) was the most prevalent child abuse experience reported with the exposure to specific combinations of two or more types of child abuse ranging from 0.4% to 3.7%. Only 7.6% of the adult population with a history of child abuse reported having had contact with child protection organizations. Experiencing all three types of child abuse was associated with the greatest odds of contact with child protection organizations (AOR=15.8; 95% CI=10.1 to 24.6). Physical abuse only was associated with one of the lowest odds of contact with child protection organizations. Preventing child abuse is widely acknowledged as an important, but challenging public health goal. Strategies to increase reporting of child abuse may help to protect children and to connect families with necessary services. One obvious priority would be physical abuse. PMID- 26002602 TI - Three-dimensional dynamic analysis of knee joint during gait in medial knee osteoarthritis using loading axis of knee. AB - We recently developed a new method for three-dimensional evaluation of mechanical factors affecting knee joint in order to help identify factors that contribute to the progression of knee osteoarthritis (KOA). This study aimed to verify the clinical validity of our method by evaluating knee joint dynamics during gait. Subjects were 41 individuals (14 normal knees; 8 mild KOAs; 19 severe KOAs). The positions of skin markers attached to the body were captured during gait, and bi planar X-ray images of the lower extremities were obtained in standing position. The positional relationship between the markers and femorotibial bones was determined from the X-ray images. Combining this relationship with gait capture allowed for the estimation of relative movement between femorotibial bones. We also calculated the point of intersection of loading axis of knee on the tibial proximal surface (LAK point) to analyze knee joint dynamics. Knee flexion range in subjects with severe KOA during gait was significantly smaller than that in those with normal knees (p=0.011), and knee adduction in those with severe KOA was significantly larger than in those with mild KOA (p<0.000). LAK point was locally loaded on the medial compartment of the tibial surface as KOA progressed, with LAK point of subjects with severe KOA rapidly shifting medially during loading response. Local loading and medial shear force were applied to the tibial surface during stance phase as medial KOA progressed. Our findings suggest that our method is useful for the quantitative evaluation of mechanical factors that affect KOA progression. PMID- 26002603 TI - Childhood obesity affects postural control and aiming performance during an upper limb movement. AB - Obesity reduces the efficiency of postural and movement control mechanisms. However, the effects of obesity on a functional motor task and postural control in standing and seated position have not been closely quantified among children. The aim of this study is to examine the effects of obesity on the execution of aiming tasks performed in standing and seated conditions in children. Twelve healthy weight children and eleven obese children aged between 8 and 11 years pointed to a target in standing and seated position. The difficulty of the aiming task was varied by using 2 target sizes (1.0 cm and 5.0 cm width; pointing to the smaller target size needs a more precise movement and constitutes a more difficult task). Hand movement time (MT) and its phases were measured to quantify the aiming task. Mean speed of the center of pressure displacement (COP speed) was calculated to assess postural stability during the movement. Obese children had significantly higher MTs compared to healthy-weight children in seated and standing conditions explained by greater durations of deceleration phase when aiming. Concerning the COP speed during the movement, obese children showed significantly higher values when standing compared to healthy-weight children. This was also observed in the seated position. In conclusion, obesity adds a postural constraint during an aiming task in both seated and standing conditions and requires obese children to take more time to correct their movements due to a greater postural instability of the body when pointing to a target with the upper limb. PMID- 26002604 TI - Accuracy of the Microsoft Kinect for measuring gait parameters during treadmill walking. AB - The measurement of gait parameters normally requires motion tracking systems combined with force plates, which limits the measurement to laboratory settings. In some recent studies, the possibility of using the portable, low cost, and marker-less Microsoft Kinect sensor to measure gait parameters on over-ground walking has been examined. The current study further examined the accuracy level of the Kinect sensor for assessment of various gait parameters during treadmill walking under different walking speeds. Twenty healthy participants walked on the treadmill and their full body kinematics data were measured by a Kinect sensor and a motion tracking system, concurrently. Spatiotemporal gait parameters and knee and hip joint angles were extracted from the two devices and were compared. The results showed that the accuracy levels when using the Kinect sensor varied across the gait parameters. Average heel strike frame errors were 0.18 and 0.30 frames for the right and left foot, respectively, while average toe off frame errors were -2.25 and -2.61 frames, respectively, across all participants and all walking speeds. The temporal gait parameters based purely on heel strike have less error than the temporal gait parameters based on toe off. The Kinect sensor can follow the trend of the joint trajectories for the knee and hip joints, though there was substantial error in magnitudes. The walking speed was also found to significantly affect the identified timing of toe off. The results of the study suggest that the Kinect sensor may be used as an alternative device to measure some gait parameters for treadmill walking, depending on the desired accuracy level. PMID- 26002605 TI - Psychophysical measurements of itch and nociceptive sensations in an experimental model of allergic contact dermatitis. AB - Allergic contact dermatitis (ACD) is a common condition that can significantly affect the quality of life. Contact with allergens results in delayed hypersensitivity reactions involving T lymphocytes, with associated skin inflammation and spontaneous itch and nociceptive sensations. However, psychophysical studies of these sensations are lacking. In the present study, we sensitized 8 healthy volunteers to squaric acid dibutyl ester (SADBE). Two weeks later, 1 volar forearm was challenged with SADBE, and the other with acetone vehicle control. Subsequently, participants rated the maximal perceived intensity of spontaneous itch, pricking/stinging, and burning every 6 to 12 hours for 1 week, using the generalized Labeled Magnitude Scale. In the laboratory, they judged stimulus-evoked sensations within and outside the chemically treated area. The SADBE- but not the acetone-treated skin resulted in 1) localized inflammation, with spontaneous itch and nociceptive sensations peaking at 24 to 48 hours after challenge, 2) alloknesis, hyperknesis, and hyperalgesia to mechanical stimuli that were reduced or eliminated by anesthetic cooling of the SADBE-treated area and restored on rewarming, suggesting that sensations and dysesthesias are dependent on ongoing peripheral neural activity, and 3) enhanced itch to intradermal injection of histamine, BAM8-22, or beta-alanine. This experimental model of T-cell-mediated inflammation may prove useful in evaluating potential treatments of itch from ACD. PERSPECTIVE: In a model of allergic contact dermatitis, experimentally applied in humans, psychophysical measurements were obtained of persistent, spontaneous itch and enhanced stimulus-evoked itch and pain sensations. These sensory measurements will be useful in the identification of the neural mechanisms underlying inflammatory itch and pain. PMID- 26002606 TI - Completely intramural bronchogenic cyst of the cervical esophagus in a neonate. AB - Bronchogenic cysts are congenital cystic lesions of foregut origin, usually intrapulmonary or mediastinal, while esophageal cysts generally originate within the esophagus. To the best of our knowledge, this is the first report of a case of a completely intramural bronchogenic cyst of the cervical esophagus in a neonate. PMID- 26002607 TI - Should docetaxel be standard of care for patients with metastatic hormone sensitive prostate cancer? Pro and contra. AB - Following the results of the TAX-327 study, questions have been raised as to whether administering chemotherapy to men with prostate cancer before symptomatic disease progression when receiving standard hormonal treatment can improve the duration and quality of patient survival. The GETUG-AFU-15 and CHAARTED studies both assessed the efficacy and tolerability of androgen deprivation therapy (ADT) with or without docetaxel in men with metastatic hormone-naive prostate cancer. Both studies included a mix of patients with de novo metastatic disease (~75%) and patients who developed metastases following treatment of localized disease. A short course of ADT was allowed in both trials prior to accrual. Key differences between the two studies include the number of patients with high-volume metastases (GETUG-AFU-15: 52%; CHAARTED: 65%) and number of docetaxel cycles (GETUG-AFU-15: up to nine cycles; CHAARTED six cycles). Both studies reported an improvement in progression-free survival with docetaxel plus ADT versus ADT alone. The GETUG-AFU-15 did not find a significant difference in the primary end point of overall survival (OS) {hazard ratio (HR) 0.9 [95% confidence interval (CI) 0.7-1.2]; P = 0.44} for ADT plus docetaxel versus ADT alone. The CHAARTED study met the primary end point of OS [HR 0.61 (95% CI 0.47-0.80); P = 0.0003], and in a subset analysis reported the greatest improvement in OS for patients with high-volume disease [HR 0.60 (95% CI 0.45-0.81); P = 0.0006]. The following article debates the results from the GETUG-AFU-15 and CHAARTED studies and asks whether medical practice should be changed for patients with metastatic hormone naive prostate cancer based on the results of one positive study. PMID- 26002608 TI - An activating ALK gene mutation in ALK IHC-positive/FISH-negative nonsmall-cell lung cancer. PMID- 26002609 TI - De-escalation attempts for adjuvant trastuzumab: longer beats shorter. PMID- 26002610 TI - Prognostic and predictive value of ERbeta1 and ERbeta2 in the Intergroup Exemestane Study (IES)-first results from PathIES?. AB - BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERbeta1 and ERbeta2 expression in primary tumours in order to determine benefit in the two treatment arms. PATIENTS AND METHODS: Primary tumour samples were available for 1256 patients (27% IES population). ERbeta1 and ERbeta2 expression was dichotomised at the median IHC score (high if ERbeta1 >= 191, ERbeta2 >= 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs. RESULTS: Neither ERbeta1 nor ERbeta2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERbeta1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERbeta1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERbeta2 expression in either DFS or OS. CONCLUSION: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERbeta1 expression but not in those with high ERbeta1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted. PMID- 26002611 TI - Does a voucher program improve reproductive health service delivery and access in Kenya? AB - BACKGROUND: Current assessments on Output-Based Aid (OBA) programs have paid limited attention to the experiences and perceptions of the healthcare providers and facility managers. This study examines the knowledge, attitudes, and experiences of healthcare providers and facility managers in the Kenya reproductive health output-based approach voucher program. METHODS: A total of 69 in-depth interviews with healthcare providers and facility managers in 30 voucher accredited facilities were conducted. The study hypothesized that a voucher program would be associated with improvements in reproductive health service provision. Data were transcribed and analyzed by adopting a thematic framework analysis approach. A combination of inductive and deductive analysis was conducted based on previous research and project documents. RESULTS: Facility managers and providers viewed the RH-OBA program as a feasible system for increasing service utilization and improving quality of care. Perceived benefits of the program included stimulation of competition between facilities and capital investment in most facilities. Awareness of family planning (FP) and gender-based violence (GBV) recovery services voucher, however, remained lower than the maternal health voucher service. Relations between the voucher management agency and accredited facilities as well as existing health systems challenges affect program functions. CONCLUSIONS: Public and private sector healthcare providers and facility managers perceive value in the voucher program as a healthcare financing model. They recognize that it has the potential to significantly increase demand for reproductive health services, improve quality of care and reduce inequities in the use of reproductive health services. To improve program functioning going forward, there is need to ensure the benefit package and criteria for beneficiary identification are well understood and that the public facilities are permitted greater autonomy to utilize revenue generated from the voucher program. PMID- 26002612 TI - A randomized, home-based, childhood obesity intervention delivered by patient navigators. AB - BACKGROUND: Although Colorado is perceived as a healthy state, in 2010, 14.1 % of children aged 2-5 were overweight and 9.1 % were obese. Despite the high prevalence of obesity in this population, evidence to support particular strategies to treat obese preschoolers is lacking. The efficacy of home-based, childhood obesity interventions to reduce a child's body mass index is inconclusive. However, this model uniquely provides an opportunity to observe and intervene with the home food and activity environment and engage the entire family in promoting changes that fit each family's unique dynamics. METHODS/DESIGN: Eligible participants are children aged 2-5 years who attended a well-child care visit at a Denver Health Community Health Service clinic within 12 months prior to recruitment and on that visit had a body mass index (BMI) >85th percentile-for-age. Participants are randomly recruited at study inception and allocated to the intervention in one of five defined 6-month stepped wedge engagements; the delayed intervention groups serves as control groups until the start of the intervention. The program is delivered by a patient navigator at the family' home and consists of a 16-session curriculum focused on 1) parenting styles, 2) nutrition, and 3) physical activity. At each visit, a portion of curriculum is delivered to guide parents and children in selecting one goal for behavior change in each of three work areas to work on during the following week. The primary study outcome measure is change in BMI z-score from baseline to post intervention period. DISCUSSION: This childhood obesity study, innovative for its home-based intervention venue, provides rich data characterizing barriers and facilitators to healthy behavior change within the home. The study population is innovative as it is focused on preschool-aged, Latino children from low-income families; this population has not typically been targeted in obesity management assessments. The home-based intervention is linked to clinical care through update letters and assessment of the program's impact to the child's medical providers. Informing primary care providers about a child's accomplishments and challenges, allows the clinician to support the health weight effort when seeing families during subsequent clinical visits. TRIAL REGISTRATION: ClinicalTrials.gov NCT02024360 Registered December 21, 2013. PMID- 26002614 TI - De novo aphasic status epilepticus presenting with frontal periodic lateralized epileptiform discharges. PMID- 26002615 TI - Small fast rhythmic eye movements (SFREM) misdiagnosed as frontal seizures. PMID- 26002613 TI - Assessment of the Sensitivity, Specificity, and Accuracy of Thermography in Identifying Patients with TMD. AB - BACKGROUND: The purpose of the present study was to evaluate the sensitivity, specificity, and accuracy of thermography in identifying patients with temporomandibular dysfunction (TMD). MATERIAL AND METHODS: The study sample consisted of 50 patients (27 women and 23 men) ages 19.2 to 24.5 years (mean age 22.43+/-1.04) with subjective symptoms of TMD (Ai II-III) and 50 patients (25 women and 25 men) ages 19.3 to 25.1 years (mean age 22.21+/-1.18) with no subjective symptoms of TMD (Ai I). The anamnestic interviews were conducted according to the three-point anamnestic index of temporomandibular dysfunction (Ai). The thermography was performed using a ThermaCAM TMSC500 (FLIR Systems AB, Sweden) independent thermal vision system. Thermography was closely combined with a 10-min chewing test. RESULTS: The results of our study indicated that the absolute difference in temperature between the right and left side (DeltaT) has the highest diagnostic value. The diagnostic effectiveness of this parameter increased after the chewing test. The cut-off points for values of temperature differences between the right and left side and identifying 95.5% of subjects with no functional disorders according to the temporomandibular dysfunction index Di (specificity 95.5%) were 0.26 degrees C (AUC=0.7422, sensitivity 44.3%, accuracy 52.4%) before the chewing test and 0.52 degrees C (AUC=0.7920, sensitivity 46.4%, accuracy 56.3%) after it. CONCLUSIONS: The evaluation of thermography demonstrated its diagnostic usefulness in identifying patients with TMD with limited effectiveness. The chewing test helped in increasing the diagnostic efficiency of thermography in identifying patients with TMD. PMID- 26002616 TI - Causal functional contributions and interactions in the attention network of the brain: an objective multi-perturbation analysis. AB - Spatial attention is a prime example for the distributed network functions of the brain. Lesion studies in animal models have been used to investigate intact attentional mechanisms as well as perspectives for rehabilitation in the injured brain. Here, we systematically analyzed behavioral data from cooling deactivation and permanent lesion experiments in the cat, where unilateral deactivation of the posterior parietal cortex (in the vicinity of the posterior middle suprasylvian cortex, pMS) or the superior colliculus (SC) cause a severe neglect in the contralateral hemifield. Counterintuitively, additional deactivation of structures in the opposite hemisphere reverses the deficit. Using such lesion data, we employed a game-theoretical approach, multi-perturbation Shapley value analysis (MSA), for inferring functional contributions and network interactions of bilateral pMS and SC from behavioral performance in visual attention studies. The approach provides an objective theoretical strategy for lesion inferences and allows a unique quantitative characterization of regional functional contributions and interactions on the basis of multi-perturbations. The quantitative analysis demonstrated that right posterior parietal cortex and superior colliculus made the strongest positive contributions to left-field orienting, while left brain regions had negative contributions, implying that their perturbation may reverse the effects of contralateral lesions or improve normal function. An analysis of functional modulations and interactions among the regions revealed redundant interactions (implying functional overlap) between regions within each hemisphere, and synergistic interactions between bilateral regions. To assess the reliability of the MSA method in the face of variable and incomplete input data, we performed a sensitivity analysis, investigating how much the contribution values of the four regions depended on the performance of specific configurations and on the prediction of unknown performances. The results suggest that the MSA approach is sensitive to categorical, but insensitive to gradual changes in the input data. Finally, we created a basic network model that was based on the known anatomical interactions among cortical tectal regions and reproduced the experimentally observed behavior in visual orienting. We discuss the structural organization of the network model relative to the causal modulations identified by MSA, to aid a mechanistic understanding of the attention network of the brain. PMID- 26002617 TI - A unique cellular scaling rule in the avian auditory system. AB - Although it is clear that neural structures scale with body size, the mechanisms of this relationship are not well understood. Several recent studies have shown that the relationship between neuron numbers and brain (or brain region) size are not only different across mammalian orders, but also across auditory and visual regions within the same brains. Among birds, similar cellular scaling rules have not been examined in any detail. Here, we examine the scaling of auditory structures in birds and show that the scaling rules that have been established in the mammalian auditory pathway do not necessarily apply to birds. In galliforms, neuronal densities decrease with increasing brain size, suggesting that auditory brainstem structures increase in size faster than neurons are added; smaller brains have relatively more neurons than larger brains. The cellular scaling rules that apply to auditory brainstem structures in galliforms are, therefore, different to that found in primate auditory pathway. It is likely that the factors driving this difference are associated with the anatomical specializations required for sound perception in birds, although there is a decoupling of neuron numbers in brain structures and hair cell numbers in the basilar papilla. This study provides significant insight into the allometric scaling of neural structures in birds and improves our understanding of the rules that govern neural scaling across vertebrates. PMID- 26002618 TI - Can colours be used to segment words when reading? AB - Rayner, Fischer, and Pollatsek (1998, Vision Research) demonstrated that reading unspaced text in Indo-European languages produces a substantial reading cost in word identification (as deduced from an increased word-frequency effect on target words embedded in the unspaced vs. spaced sentences) and in eye movement guidance (as deduced from landing sites closer to the beginning of the words in unspaced sentences). However, the addition of spaces between words comes with a cost: nearby words may fall outside high-acuity central vision, thus reducing the potential benefits of parafoveal processing. In the present experiment, we introduced a salient visual cue intended to facilitate the process of word segmentation without compromising visual acuity: each alternating word was printed in a different colour (i.e., ). Results only revealed a small reading cost of unspaced alternating colour sentences relative to the spaced sentences. Thus, present data are a demonstration that colour can be useful to segment words for readers of spaced orthographies. PMID- 26002619 TI - Views of Australian Medical Oncologists Regarding the Use of Mismatch Repair Status to Assist Adjuvant Chemotherapy Recommendations for Patients With Early Stage Colon Cancer. AB - BACKGROUND: Mismatch repair deficiency (dMMR) has been shown to confer a superior prognosis and is possibly predictive of a lack of benefit from fluoropyrimidine adjuvant chemotherapy (AC) for early-stage colon cancer (ESCC). We conducted a survey to assess medical oncologists' views regarding ESCC AC, with an emphasis on the use of MMR status to guide their recommendations. MATERIALS AND METHODS: The survey was distributed to all members of the Medical Oncology Group of Australia. Their demographic data, practice information, and views on the use of MMR status in ESCC and in 3 case scenarios were collected. The 3 case scenarios were a 68-year-old woman with moderate-risk stage II disease, who was eager to undergo AC (case 1); a 43-year-old woman with high-risk stage II disease, who was ambivalent regarding AC (case 2); and a 78-year-old woman with multiple comorbidities and high-risk stage II disease, who was eager to undergo AC. RESULTS: The survey response rate was 35% (190 of 550). Of the 190 responders, 152 (80%) routinely treated patients with colon cancer (CC) and completed the survey. For patients with stage II CC, 112 of 141 (79%) would use MMR status to assist AC recommendations, and 97 (69%) thought it changed their practice. In the case scenarios, 81% (case 1, 110 of 136), 67% (case 2, 92 of 137), and 43% (case 3, 57 of 133) used MMR status to assist AC recommendations. If dMMR was present, 78% (case 1, 86 of 110), 53% (case 2, 49 of 92), and 53% (case 3, 30 of 57) changed their initial recommendations by advising against AC. CONCLUSION: The use of MMR status to assist AC recommendations for patients with stage II CC is an accepted practice for most Australian medical oncologists who responded to our survey. PMID- 26002620 TI - Factors Associated With Healthy Lifestyle Behaviors in a Sample of Turkish Adolescents: A School-Based Study. AB - PURPOSE: This was a descriptive-correlational study designed to determine factors associated with the healthy lifestyle behaviors of high school students in Turkey. DESIGN: The study sample consisted of 812 high school adolescents. The Adolescent Lifestyle Profile scale was used to identify the healthy lifestyle behaviors of adolescents. RESULTS: The total Adolescent Lifestyle Profile mean score of 2.75 +/- 0.33 and the mean score on the Interpersonal relations subscale were found to be the highest scores while the mean score on the Health responsibility subscale was found to be the lowest. Significant predictors of healthy lifestyle behaviors of adolescents were good relationships with family and friends, having a father who was a college graduate, and good health perception. CONCLUSIONS: The study revealed similar results among adolescents of different cultures. IMPLICATIONS FOR PRACTICE: These findings can be used as a guide in developing an adolescent health promotion program for school nurses. PMID- 26002621 TI - How Does GPi-DBS Affect Speech in Primary Dystonia? AB - BACKGROUND: Globus pallidus internus deep brain stimulation (GPi-DBS) can be an effective treatment for primary dystonia. However, speech disorders have previously been reported as a common possible side effect of the treatment. OBJECTIVES: To study possible deterioration of speech after GPi-DBS and describe this in different dimensions. METHODS: Speech was systematically evaluated in 15 patients with predominant torticollis and GPi-DBS. Each patient was tested twice within one day in two stimulation conditions: ON-DBS vs. OFF-DBS. Speech analyses comprised both function-oriented (perceptual scales, acoustic analyses) and communication-related measures (intelligibility, naturalness). A control sample of 15 healthy speakers underwent the same speech assessment. RESULTS: On the group level, patients with dystonia showed mild but significant impairment on the overall dysarthria scale, the intelligibility score, and the naturalness ratings in both stimulation conditions (Mann-Whitney, P < .05). No stimulation-induced deterioration was found. A slight increase in articulation rate was measured in the ON condition. On the single-case level, effects of GPi-DBS on speech were heterogenous. In one patient we observed a deterioration of speech (dysarthria), in a second patient with a history of childhood stuttering we found an aggravation of dysfluency. Impressive benefits could be documented in another patient who also suffered from spasmodic dysphonia. CONCLUSIONS: The study provides evidence that speech impairment is not a necessary side-effect of GPi DBS in primary dystonia. Both, recurring of stuttering and a worsening of dysarthria may be seen in individual patients. The positive effects of GPi-DBS on the symptoms of spasmodic dysphonia merits further research as DBS is not commonly applied in this population. PMID- 26002622 TI - X-ray phase-contrast computed tomography of human coronary arteries. AB - OBJECTIVE: The objective of this study was to assess the potential of grating based phase-contrast computed tomography (gb-PCCT) for the detection and characterization of human coronary artery disease in an experimental ex vivo validation study. MATERIALS AND METHODS: The study was approved by the institutional review board, and informed consent was obtained from all patients. Specimens were examined using a conventional low-coherence x-ray tube (40 kV) and a Talbot-Lau grating interferometer. Histopathologic assessment was used as the standard of reference. Signal characteristics of calcified, fibrous (FIB), and lipid-rich (LIP) tissue were visually and quantitatively assessed by phase contrast Hounsfield units (HU). Conventional absorption-based HU values were also measured. Conservative measurements of diagnostic accuracy for the detection and differentiation of plaque components as well as quantitative measurements of vessel dimensions were obtained, and receiver operating characteristic curve analysis for plaque differentiation was performed. RESULTS: A total of 15 coronary arteries from 5 subjects were available for analysis (386 sections). Calcified, FIB, and LIP displayed distinct gb-PCCT signal criteria. The diagnostic accuracy of gb-PCCT was high with sensitivity, specificity, and negative and positive predictive values of 0.89 or greater for all plaque components with good interrater agreement (k >= 0.88). In addition, quantitative measurements of vessel dimensions in gb-PCCT were strongly correlated with measurements obtained from histopathology (Pearson R >= 0.86). Finally, phase contrast Hounsfield units were superior to conventional HU in differentiating FIB and LIP (receiver operating characteristic analysis, 0.86 vs. 0.77, respectively; P < 0.05). CONCLUSIONS: In an ex vivo setting, gb-PCCT provides improved differentiation and quantification of coronary atherosclerotic plaque and may thus serve as a tool for nondestructive histopathology. PMID- 26002623 TI - Advanced virtual monoenergetic computed tomography of hyperattenuating and hypoattenuating liver lesions: ex-vivo and patient experience in various body sizes. AB - OBJECTIVE: To determine the value of advanced virtual monoenergetic images (mono+) from dual-energy computed tomography (CT) of hyperattenuating and hypoattenuating liver lesions in various phantom sizes and patients in comparison with standard monoenergetic images (mono). MATERIALS AND METHODS: Anthropomorphic phantoms simulating 4 patient sizes (S, 300 * 200 mm; M, 350 * 250 mm; L, 400 * 300 mm; and XL, 600 * 450 mm) with a liver insert containing both hyperattenuating and hypoattenuating iodine-containing lesions were imaged with dose-equivalent dual-energy (100/150 Sn kilovolt [peak] [kV{p}]) and single energy (120 kV[p]) protocols on a 192-slice dual-source CT system. In addition, 4 patients with 3 hypoattenuating and 3 hyperattenuating hepatocellular carcinoma were included and underwent dual-energy CT imaging with the same scanner at similar kV(p) settings (100/150 Sn kV[p]). Images were reconstructed with standard mono and with the mono+ algorithm at 10-kiloelectron volt (keV) intervals from 40 to 190 keV. Attenuation of the liver and lesions were measured, and contrast-to-noise ratios (CNRs) were calculated. Lesion conspicuity was rated by 2 blinded independent readers in all mono and mono+ data sets from 40 to 190 keV using a 5-point Likert scale (1, lowest conspicuity; and 5, highest conspicuity). RESULTS: Attenuation in the liver and in both hyperattenuating and hypoattenuating lesions did not differ between mono and mono+ (P = 0.41-0.49). Noise on mono+ was significantly lower than on mono for all phantom sizes (P < 0.05) and was increasing with phantom size. Hyperattenuating lesion CNR was highest for mono+ images at 40 keV in the S phantom (6.73), with significantly higher CNR for mono+ than for mono and for single energy (120 kV[p]) in all phantom sizes (all P < 0.001) except for the XL phantom. Hypoattenuating lesion CNR was highest for high-keV mono+ being significantly higher than on mono and on single-energy (120 kV[p]) images (all P < 0.001), except for the XL phantom with significantly higher CNR for mono (1.3) compared with mono+ (0.47) and 120 kV(p) (1.26). In patients, CNR curves of hyperattenuating hepatocellular carcinoma were in accordance with the phantom data, whereas hypoattenuating lesions demonstrate varying curves, some being in accordance with findings in phantoms. Interreader agreement for lesion conspicuity was very good (intraclass correlation, 0.95), with higher conspicuity scores for mono+ than for mono and single energy (120 kV[p]) at all phantom sizes (all P < 0.05) and within patients. CONCLUSION: Our ex vivo and patient data demonstrate added value for imaging of both hyperattenuating and hypoattenuating liver lesions with advanced virtual monoenergetic dual-energy CT by decreased noise, increased CNR, and higher lesion conspicuity, although with limitations in XL body sizes. PMID- 26002624 TI - Mutagenicity and chemopreventive activities of Astronium species assessed by Ames test. AB - In the neotropical savannah, Astronium species are used in popular medicine to treat allergies, inflammation, diarrhea and ulcers. Given that natural products are promising starting points for the discovery of novel potentially therapeutic agents, the aim of the present study was to investigate the mutagenic and antimutagenic activities of hydroalcoholic extracts of Astronium spp. The mutagenicity was determined by the Ames test on Salmonella typhimurium strains TA98, TA97a, TA100 and TA102. The antimutagenicity was tested against the direct acting and indirect-acting mutagens. The results showed that none of the extracts induce any increase in the number of revertants, demonstrating the absence of mutagenic activity. On the other hand, the results on the antimutagenic potential showed a moderate inhibitory effect against NPD and a strong protective effect against B[a]P and AFB1. This study highlights the importance of screening species of Astronium for new medicinal compounds. The promising results obtained open up new avenues for further study and provide a better understanding the mechanisms by which these species act in protecting DNA from damage. However, further pharmacological and toxicological investigations of crude extracts of Astronium spp., as well as of its secondary metabolites, are necessary to determine the mechanism(s) of action to guarantee their safer and more effective application to human health. PMID- 26002625 TI - 3-Aminoglutarate is a "silent" false transmitter for glutamate neurons. AB - Understanding the storage and release of the excitatory neurotransmitter, L glutamate by synaptic vesicles has lagged behind receptor characterizations due to a lack of pharmacological agents. We report that the glutamate analog, 3 aminoglutarate (3-AG) is a "silent" false transmitter for glutamate neurons that may be a useful tool to study storage and release mechanisms. Like L-glutamate itself, 3-AG is a high-affinity substrate for both the plasma membrane (EAATs) and vesicular (vGLUT) glutamate transporters. As such, EAATs facilitate 3-AG entry into neuronal cytoplasm allowing 3-AG to compete with L-glutamate for transport into vesicles thus reducing glutamate content. In a synaptosomal preparation, 3-AG inhibited calcium-dependent endogenous L-glutamate release. Unlike L-glutamate, 3-AG had low affinity for both ionotropic (NMDA and AMPA) and G-protein coupled (mGlu1-8) receptors. Consequently, 3-AG behaves as a "silent" false transmitter that may be used in physiological experiments to probe synaptic vesicle storage and release mechanisms for L-glutamate. The companion paper by Wu et al. (2015) describes initial experiments that explore the effects of 3-AG on glutamate synaptic transmission under physiological and pathophysiological conditions. PMID- 26002626 TI - Effects of 3-aminoglutarate, a "silent" false transmitter for glutamate neurons, on synaptic transmission and epileptiform activity. AB - Pharmacological tools that interact with the mechanisms that regulate vesicular filling and release of the neurotransmitter L-glutamate would be of enormous value. In this study, we provide physiological evidence that the glutamate analog, 3-aminoglutarate (3-AG), acts as a false transmitter to reduce presynaptic glutamate release. 3-AG inhibits glutamate-mediated neurotransmission both in primary neuronal cultures and in brain slices with more intact neural circuits. When assayed with the low affinity glutamate receptor antagonist gamma DGG, we demonstrate that 3-AG significantly reduces the synaptic cleft glutamate concentration, suggesting that 3-AG may act as a false transmitter to compete with glutamate during vesicle filling. Furthermore, using three different epileptic models (Mg(2+)-free, 4-AP, and high K(+)), we demonstrate that 3-AG is capable of suppressing epileptiform activity both before and after its induction. Our studies, along with those of the companion paper by Foster et al. (2015) indicate that 3-AG is a "silent" false transmitter for glutamate neurons that is a useful pharmacological tool to probe the mechanisms governing vesicular storage and release of glutamate under both physiological and pathophysiological conditions. 3-AG may have potential therapeutic value in conditions where the glutamate neurotransmitter system is pathologically overactive. PMID- 26002627 TI - Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol preferring rats. AB - Alteration of glutamatergic-neurotransmission is a hallmark of alcohol dependence. We have previously reported that chronic ethanol-drinking downregulated glutamate transporter 1 (GLT-1) in nucleus accumbens (NAc) in male P rats in a manner that was reversed by ceftriaxone treatment. However, the effect of ceftriaxone on extracellular glutamate concentrations in NAc after chronic ethanol-drinking has not yet been studied. In the present study, male P rats were treated with ceftriaxone (100 mg/kg/day, i.p.) for five consecutive days following five-weeks of free choice ethanol (15% and 30%) drinking. In vivo microdialysis was performed to measure the extracellular glutamate concentrations in NAc and the effect of blockade of GLT-1 with dihydrokainic acid (DHK) on extracellular glutamate in NAc of ceftriaxone-treated rats was determined. Ceftriaxone treatment attenuated ethanol intake as well as ethanol preference. Extracellular glutamate was significantly higher in NAc after five-weeks of ethanol drinking in saline-treated compared to water control rats. Ceftriaxone treatment blocked the increase extracellular glutamate produced by ethanol intake. Blockade of GLT-1 by DHK reversed the effects of ceftriaxone on glutamate and implicated the role of GLT-1 in the normalization of extracellular glutamate by ceftriaxone. In addition, GLT-1 protein was decreased in ethanol exposed animals and ceftriaxone treatment reversed this deficit. Ceftriaxone treatment also increased glutamine synthetase activity in NAc but not in PFC as compared to ethanol drinking saline-treated rats. Our present study demonstrates that ceftriaxone treatment prevents ethanol drinking in part through normalization of extracellular glutamate concentrations in NAc of male P rats via GLT-1. PMID- 26002628 TI - The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats. AB - GABAB (gamma-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists. PMID- 26002629 TI - Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways. AB - Cadmium (Cd), a toxic environmental contaminant, contributes to neurodegeneration. Rapamycin, a macrocyclic lactone, has shown preventive effect on Cd-induced neuronal cell death. However, the underlying mechanism is not fully understood. Here, we show that rapamycin prevented Cd-induced apoptotic cell death in neuronal cells. Coincidently, rapamycin markedly blocked Cd-induced phosphorylation of Akt, S6K1 and 4E-BP1 in the cells. Expression of a rapamycin resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of Cd-induced cell death, implying that the preventive effect of rapamycin on Cd-induced neurotoxicity is mTOR kinase activity-dependent. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor, rictor or raptor/rictor enhanced rapamycin's blockage of Cd-induced cell death. Furthermore, downregulation of S6K1, ectopic expression of constitutively hypophosphorylated 4E-BP1 or dominant negative Akt, or co-treatment with Akt inhibitor also potentiated the rapamycin's inhibitory effect. The findings indicate that rapamycin prevents Cd-induced neuronal cell death via suppressing both mTORC1 and mTORC2 pathways. Our results highlight that rapamycin may be exploited for the prevention of Cd-induced neurodegenerative disorders. PMID- 26002631 TI - A chemically defined substrate for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells. AB - Due to the limitation of current pharmacological therapeutic strategies, stem cell therapies have emerged as a viable option for treating many incurable neurological disorders. Specifically, human pluripotent stem cell (hPSC)-derived neural progenitor cells (hNPCs), a multipotent cell population that is capable of near indefinite expansion and subsequent differentiation into the various cell types that comprise the central nervous system (CNS), could provide an unlimited source of cells for such cell-based therapies. However the clinical application of these cells will require (i) defined, xeno-free conditions for their expansion and neuronal differentiation and (ii) scalable culture systems that enable their expansion and neuronal differentiation in numbers sufficient for regenerative medicine and drug screening purposes. Current extracellular matrix protein (ECMP) based substrates for the culture of hNPCs are expensive, difficult to isolate, subject to batch-to-batch variations, and, therefore, unsuitable for clinical application of hNPCs. Using a high-throughput array-based screening approach, we identified a synthetic polymer, poly(4-vinyl phenol) (P4VP), that supported the long-term proliferation and self-renewal of hNPCs. The hNPCs cultured on P4VP maintained their characteristic morphology, expressed high levels of markers of multipotency, and retained their ability to differentiate into neurons. Such chemically defined substrates will eliminate critical roadblocks for the utilization of hNPCs for human neural regenerative repair, disease modeling, and drug discovery. PMID- 26002630 TI - Adrenomedullin promotes differentiation of oligodendrocyte precursor cells into myelin-basic-protein expressing oligodendrocytes under pathological conditions in vitro. AB - Oligodendrocytes, which are the main cell type in cerebral white matter, are generated from their precursor cells (oligodendrocyte precursor cells: OPCs). However, the differentiation from OPCs to oligodendrocytes is disturbed under stressed conditions. Therefore, drugs that can improve oligodendrocyte regeneration may be effective for white matter-related diseases. Here we show that a vasoactive peptide adrenomedullin (AM) promotes the in vitro differentiation of OPCs under pathological conditions. Primary OPCs were prepared from neonatal rat brains, and differentiated into myelin-basic-protein expressing oligodendrocytes over time. This in vitro OPC differentiation was inhibited by prolonged chemical hypoxic stress induced by non-lethal CoCl(2) treatment. However, AM promoted the OPC differentiation under the hypoxic stress conditions, and the AM receptor antagonist AM(22-52) canceled the AM-induced OPC differentiation. In addition, AM treatment increased the phosphorylation level of Akt in OPC cultures, and correspondingly, the PI3K/Akt inhibitor LY294002 blocked the AM-induced OPC differentiation. Taken together, AM treatment rescued OPC maturation under pathological conditions via an AM-receptor-PI3K/Akt pathway. Oligodendrocytes play critical roles in white matter by forming myelin sheath. Therefore, AM signaling may be a promising therapeutic target to boost oligodendrocyte regeneration in CNS disorders. PMID- 26002632 TI - Metabolic engineering of Clostridium tyrobutyricum for n-butanol production from maltose and soluble starch by overexpressing alpha-glucosidase. AB - Clostridium tyrobutyricum does not have the enzymes needed for using maltose or starch. Two extracellular alpha-glucosidases encoded by agluI and agluII from Clostridium acetobutylicum ATCC 824 catalyzing the hydrolysis of alpha-1,4 glycosidic bonds in maltose and starch from the non-reducing end were cloned and expressed in C. tyrobutyricum (Deltaack, adhE2), and their effects on n-butanol production from maltose and soluble starch in batch fermentations were studied. Compared to the parental strain grown on glucose, mutants expressing agluI showed robust activity in breaking down maltose and produced more butanol (17.2 vs. 9.5 g/L) with a higher butanol yield (0.20 vs. 0.10 g/g) and productivity (0.29 vs. 0.16 g/L h). The mutant was also able to use soluble starch as substrate, although at a slower rate compared to maltose. Compared to C. acetobutylicum ATCC 824, the mutant produced more butanol from maltose (17.2 vs. 11.2 g/L) and soluble starch (16.2 vs. 8.8 g/L) in batch fermentations. The mutant was stable in batch fermentation without adding antibiotics, achieving a high butanol productivity of 0.40 g/L h. This mutant strain thus can be used in industrial production of n-butanol from maltose and soluble starch. PMID- 26002633 TI - Effects of impurities in biodiesel-derived glycerol on growth and expression of heavy metal ion homeostasis genes and gene products in Pseudomonas putida LS46. AB - Biodiesel production-derived waste glycerol (WG) was previously investigated as potential carbon source for medium chain length polyhydroxyalkanoate (mcl-PHA) production by Pseudomonas putida LS46. In this study, we evaluated the effect of impurities in the WG on P. putida LS46 physiology during exponential growth and corresponding changes in transcription and protein expression profiles compared with cells grown on pure, reagent grade glycerol. High concentration of metal ions, such as Na(+), and numbers of heavy metals ion, such as copper, ion, zinc, were detected in biodiesel-derived WG. Omics analysis from the corresponding cultures suggested altered expression of genes involved in transport and metabolism of ammonia and heavy metal ions. Expression of three groups of heavy metal homeostasis genes was significantly changed (mostly upregulated) in WG cultures and included the following: copper-responded cluster 1 and 2 genes, primarily containing cusABC; two copies of copAB and heavy metal translocating P type ATPase; Fur-regulated, TonB-dependent siderophore receptor; and several cobalt/zinc/cadmium transporters. Expression of these genes suggests regulation of intracellular concentrations of heavy metals during growth on biodiesel derived glycerol. Finally, a number of genes involved in adapting to, or metabolizing free fatty acids and other nonheavy metal contaminants, such as Na(+), were also upregulated in P. putida LS46 grown on biodiesel-derived glycerol. PMID- 26002634 TI - Factors Affecting the Choice of Psychiatry as a Specialty and Satisfaction among Turkish Psychiatry Residents. AB - OBJECTIVE: This study aimed to investigate the factors affecting the choice of psychiatry among psychiatry residents, identify the fulfillment of expectations, and assess their satisfaction level. METHODS: Anonymous questionnaires were administered to 98 psychiatry residents, and sociodemographic and professional data were collected. RESULTS: Among the reasons for choosing psychiatry, the opportunity to cultivate interest in humanities, importance of social and relational issues, and intellectual challenge were most frequently selected. The opportunity for complete use of medical training, salary, and opportunity to practice psychotherapy were the expectations least met. The largest group of participants was satisfied to have chosen psychiatry (41.5%), decided on psychiatry training after medical school (35.4%), and attached importance to becoming a clinician (70.7%). CONCLUSIONS: Although the satisfaction level was high in this study, addressing the areas in which expectations were not met may increase the satisfaction of psychiatry residents and the selection of psychiatry as a specialty. PMID- 26002635 TI - A Decade of War: Adapting to Meet the Mental Health Training Demands. PMID- 26002636 TI - Artificial agents, good care, and modernity. AB - When is it ethically acceptable to use artificial agents in health care? This article articulates some criteria for good care and then discusses whether machines as artificial agents that take over care tasks meet these criteria. Particular attention is paid to intuitions about the meaning of 'care', 'agency', and 'taking over', but also to the care process as a labour process in a modern organizational and financial-economic context. It is argued that while there is in principle no objection to using machines in medicine and health care, the idea of them functioning and appearing as 'artificial agents' is problematic and attends us to problems in human care which were already present before visions of machine care entered the stage. It is recommended that the discussion about care machines be connected to a broader discussion about the impact of technology on human relations in the context of modernity. PMID- 26002637 TI - Specific and number of comorbidities are associated with increased levels of temporomandibular pain intensity and duration. AB - BACKGROUND: Temporomandibular pain disorder (TMD) is a common pain condition in the face. People with TMD report multiple pain comorbidities. The presence of fibromyalgia and migraine in people with TMD is associated with an increase in TMD pain intensity and duration. However, data on the relationship between increasing number of pain comorbidities and TMD pain are rare. The aims of this study were: firstly to evaluate the extent to which increasing number of comorbidities is associated with increasing TMD pain intensity and duration; and secondly to evaluate the extent to which the presence of specific comorbidities is associated with increasing TMD pain intensity and duration. METHODS: The sample included 180 people seeking TMD treatment at Boston and Montreal clinics. TMD was diagnosed using the Research Diagnostic Criteria for TMD. A Numerical Pain Rating Scale assessed TMD pain intensity and participants provided their TMD pain duration in a study questionnaire. The comorbidities of migraine, chronic fatigue syndrome, irritable bowel syndrome, interstitial cystitis and restless leg syndrome were diagnosed by 5 validated diagnostic questionnaires. The associations were analyzed by linear regression, controlling for confounders. RESULTS: There was a positive association between the number of comorbidities present and TMD pain intensity (p < 0.01) and between the number of comorbidities present and TMD pain duration (p < 0.01). Also, the presence of migraine was positively associated with TMD pain intensity (p < 0.01) and the presence of chronic fatigue syndrome was positively associated with TMD pain intensity (p < 0.05) and with TMD pain duration (p < 0.01). When TMD patients were separated into groups, these associations did not change for the myofascial pain group, whereas in the non-myofascial pain group, the relationship between number of comorbidities and TMD pain duration was the only one still present. CONCLUSION: This study shows that the number of comorbidities is positively associated with TMD pain duration and intensity. The presence of specific conditions, such as migraine and chronic fatigue syndrome, is associated with an increase in TMD intensity and duration. PMID- 26002638 TI - Cost-effectiveness of stimulation of the sphenopalatine ganglion (SPG) for the treatment of chronic cluster headache: a model-based analysis based on the Pathway CH-1 study. AB - BACKGROUND: In the recent Pathway CH-1 study, on-demand stimulation of the sphenopalatine ganglion (SPG) by means of an implantable neurostimulation system was proven to be a safe and effective therapy for the treatment of chronic cluster headache. Our objective was to assess the cost-effectiveness of SPG stimulation in the German healthcare system when compared to medical management. METHODS: Clinical data from the Pathway CH-1 study were used as input for a model based projection of the cost-effectiveness of SPG stimulation through 5 years. Medical management as the comparator treatment was modeled on the basis of clinical events observed during the baseline period of CH-1. The costs of treatment were derived from a previously published cluster headache costing study and 2014 medication, neurostimulator, and procedure costs. We computed the 5-year incremental cost-effectiveness ratio (ICER) in euros per quality-adjusted life year (QALY), with costs and effects discounted at 3 % per year. RESULTS: SPG stimulation was projected to add 0.325 QALYs over the study period, while adding ?889 in cost, resulting in a 5-year ICER of ?2,736 per QALY gained. Longer follow up periods, higher baseline attack frequency, and higher utilization of attack aborting medications led to overall cost savings. SPG stimulation was found either cost-effective or cost-saving across all scenarios investigated in sensitivity analyses. CONCLUSIONS: Our model-based analysis suggests that SPG stimulation for the treatment of chronic cluster headache, under the assumption of sustained therapy effectiveness, leads to meaningful gains in health-related quality of life and is a cost-effective treatment strategy in the German healthcare system. PMID- 26002639 TI - The transcriptomic response to copper exposure in the digestive gland of Japanese scallops (Mizuhopecten yessoensis). AB - The present study was conducted to elucidate the effects of copper exposure on the immune system and lipid metabolism of the Japanese scallop, Mizuhopecten yessoensis. Transcriptional levels of differentially expressed genes (DEGs)in M. yessoensis digestive gland tissue were analyzed using the deep-sequencing platform Illumina HiSeqTM 2000. In total, 841 and 877 genes were identified as significantly up- or down-regulated, respectively. In addition, significant enrichment analysis identified 3 gene ontology terms and 15 pathways involved in the response to copper exposure. Analysis of transcripts related to the immune response revealed a complex pattern of innate recognition receptors, including toll-like receptors, NOD-like receptors and downstream pathway effectors, including those involved in apoptosis. Furthermore, genomic analysis revealed that genes involved in extracellular matrix (ECM)-receptor interactions were enriched in Cu-exposed scallop glands. These results will provide a resource for subsequent gene expression studies regarding heavy metal exposure and the identification of copper-sensitive biomarkers for the aquaculture of M. yessoensis. PMID- 26002640 TI - A C1q domain containing protein from Crassostrea gigas serves as pattern recognition receptor and opsonin with high binding affinity to LPS. AB - C1q proteins serve as pattern recognition receptors and involve in the pathogen recognition and complement pathway activation. In the present study, a novel C1q domain containing protein from Crassostrea gigas (designated CgC1qDC-1) was isolated by liposaccharide-Sepharose 6B affinity chromatography. The coding sequence of CgC1qDC-1 gene was determined by performing a homologous search of eight tryptic peptides identified by MALDI-TOF/TOF-MS against the genome of C. gigas. The coding sequence of CgC1qDC-1 was of 387 bp encoding a polypeptide of 128 amino acids containing a typical globular C1q domain. The globular C1q domain possessed eight beta strands with a jelly-roll topology structure, which was similar to the structure of human gC1q domain. The mRNA transcripts of CgC1qDC-1 were dominantly expressed in mantle and hemocytes, while low expressed in hepatopancreas, gonad, gill and muscle. The expression level of CgC1qDC-1 increased drastically at 6 h after Vibrio splendidus stimulation, and then gradually fell to the normal level at about 24 h. ELISA assay quantified that CgC1qDC-1 bound to LPS with high binding affinity (Kd = 0.09 * 10(-6) M). Moreover, CgC1qDC-1 significantly enhanced the phagocytosis of oyster hemocytes towards Gram-negative bacteria Escherichia coli and V. splendidus. These results collectively indicated that CgC1qDC-1 could serve as pattern recognition receptor and opsonin in the innate immune response against invading Gram-negative bacteria. PMID- 26002663 TI - Bilateral subdural hygromas following administration of intrathecal methotrexate chemotherapy. AB - We report the case of a previously well 58-year-old man who presented with headache and confusion 4 days postadministration of intrathecal methotrexate. He was undergoing intensive chemotherapy (CODOX-M/IVAC, cyclophosphamide, doxorubicin, vincristine, methotrexate, etoposide, ifosfamide, cytarabine) for the treatment of leukaemic phase CD20 negative diffuse large B-cell lymphoma. A CT of the head demonstrated the presence of bilateral subdural hygromas complicated by haemorrhage resulting from coexisting chemotherapy induced thrombocytopenia. Surgical drainage of the hygroma was undertaken but the patient died of overwhelming sepsis. In patients with high-risk lymphoma, directed central nervous system (CNS) therapy is administered either systemically or intrathecally. It is thought that subdural hygromas result from cerebrospinal fluid (CSF) accumulation in the inner dural layers of the cerebral convexities from CSF leak and reduction in CSF pressure post-lumbar puncture. We describe a rare but potentially fatal complication of intrathecal chemotherapy that haemato oncologists need to be mindful of. PMID- 26002665 TI - Neonatal suppurative sialadenitis: an important clinical diagnosis. AB - Neonatal suppurative sialadenitis is a condition causing infection of the salivary glands, most frequently caused by Staphylococcus aureus. The vast majority of cases reported in the literature have been in infants with recognised risk factors. This report presents two cases of neonatal sialadenitis in siblings, neither of whom had any predisposing characteristics. The aetiology, diagnosis and treatment of this condition are discussed. This report will also highlight the need for awareness of this condition and its inclusion in considered differentials for neck swelling in all infants. PMID- 26002664 TI - Giant pseudoangiomatous stromal hyperplasia presenting in the breast of a prepubertal child. AB - Large benign lesions of the breasts are rare in children. We present a case of a 35 cm mass, weighing 2.7 kg in a 13-year-old girl with small developing breasts. Despite the enormity of the lesion, the patient managed to keep it concealed from her parents for 8 months. While initially suspicious of sarcoma a diagnosis of pseudoangiomatous stromal hyperplasia was suggested radiologically and confirmed histologically. Excision with reduction mammoplasty was performed, care taken not to disrupt the remaining breast tissue to facilitate future breast development. 18 months on, the cosmetic appearance of the breasts is good, with healthy underlying breast tissue developing. To the best of our knowledge this case is the largest documented breast tumour of this type in a patient of this age and illustrates the challenge of treating such tumours in the developing breast. PMID- 26002666 TI - Airway foreign body aspiration: common, yet easily overlooked! Two interesting cases. AB - Two cases: A 66-year-old woman was referred to the hospital due to dyspnoea and cough. Seven months prior to referral, the patient had choked on a chunk of nut and grain-filled bread. She had daily cough and dyspnoea. The patient was convinced of an airway foreign body and she contacted her general practitioner and the emergency service several times; they all found this unlikely. Fibre optic bronchoscopy revealed two obstructing nut-like foreign bodies in the right upper and lower lobe, respectively. A 77-year-old man with sarcoidosis developed increased dyspnoea and sputum production. Three weeks earlier, the patient had choked on a magnesium tablet. Everyone was convinced that the tablet had dissolved. Infection was suspected. Chest CT scan was performed showing no obvious signs of infection or progression in sarcoidosis. After the CT scan, the patient coughed up the remains of the tablet and his symptoms resolved. Retrospective evaluation of the CT scan revealed the tablet. PMID- 26002667 TI - Sinus thrombectomy for purulent cerebral venous sinus thrombosis utilizing a novel combination of the Trevo stent retriever and the Penumbra ACE aspiration catheter: the stent anchor with mobile aspiration technique. AB - Intracranial complications of sinusitis are rare but life threatening. We present a case of a 17-year-old woman with sinusitis who deteriorated over the course of 12 days from subdural empyema and global purulent cerebral venous sinus thrombosis. The patient was managed with surgery and mechanical thrombectomy utilizing a novel 'stent anchor with mobile aspiration technique', in which a Trevo stent retriever (Stryker) was anchored in the superior sagittal sinus (SSS) while a 5 MAX ACE reperfusion catheter (Penumbra) was passed back and forth from the SSS to the sigmoid sinus with resultant dramatic improvement in venous outflow. The patient was extubated on postoperative day 3 and was discharged with minimal lower extremity weakness on postoperative day 11. This is the first report using the Trevo stent retriever for sinus thrombosis. It is important to keep these rare complications in mind when evaluating patients with oral and facial infections. PMID- 26002668 TI - Dens invaginatus in a geminated maxillary lateral incisor. AB - Dens invaginatus (DI) and gemination are two developmental abnormalities that are well reported in the dental literature, but their coexistence in a single tooth is rare. Such situations worsen the risk factors associated with these anomalies, and the treatment plan should be customised as they possess altered morphology and anatomy. A 19-year-old girl came for evaluation of a cracked tooth in the front region of the upper jaw. The tooth showed clinical features of gemination and radiographic features of DI, and was diagnosed as DI in geminated maxillary lateral incisor. The differential diagnoses based on clinical appearance without radiographic investigation may warrant the treatment approach if these two abnormalities coexist in a single tooth. The report also highlights the importance of three-dimensional imaging in diagnosis and treatment planning of teeth with altered pulp canal anatomy. There are few reported cases in the literature detailing the treatment options for these two anomalies occurring in the same tooth. PMID- 26002669 TI - Episodic headache due to ruptured intracranial dermoid cyst. PMID- 26002670 TI - Living kidney donation following nephrectomy due to pelviureteric junction obstruction. AB - A 49-year-old man presented with a 15-year history of problematic pelviureteric junction obstruction of his left kidney. Surgical management had failed to sufficiently control his symptoms and he was keen to have the kidney removed. Following preoperative discussion, the patient consented to his kidney being used for transplant. Following a total nephrectomy, the kidney was successfully transplanted into a 61-year-old woman, with a cold ischaemic time of 3 h and 22 min. There was primary function in the transplanted kidney and creatinine at 6 weeks was 60. This case highlights the potential for using organs with pelviureteric junction obstruction for living donor transplant and thereby expanding the donor pool. PMID- 26002671 TI - An unexpected headache: pituitary apoplexy in a pregnant woman on anticoagulation. AB - Pituitary apoplexy is a rare event in which the pituitary gland undergoes infarction or haemorrhage, most commonly in the setting of an underlying tumour. We report on apoplexy of an undiagnosed pituitary adenoma precipitated both by physiological enlargement of the pituitary in pregnancy and prophylactic anticoagulation from a history of deep vein thrombosis. The haemorrhage was managed conservatively without significant complications. PMID- 26002672 TI - Not paraneoplastic pemphigus but pemphigus vulgaris in a patient with thymoma. PMID- 26002673 TI - Spectral-domain optical coherence tomography findings of peripapillary staphyloma. PMID- 26002674 TI - Late miscarriage caused by Serratia marcescens: a rare but dire disease in pregnancy. PMID- 26002675 TI - Peroneal Tendon Reconstruction and Coverage for Treatment of Septic Peroneal Tenosynovitis: A Devastating Complication of Lateral Ankle Ligament Reconstruction With a Tendon Allograft. AB - Septic peroneal tenosynovitis is a rare and significant challenge. A search of peer-reviewed published studies revealed only 5 case reports to guide treatment, none of which resulted in significant loss of both peroneal tendons necessitating reconstruction. No clear guidance is available regarding how to provide reliable reconstruction of both peroneal tendons after a significant loss secondary to septic tenosynovitis. In the present report, we describe the case of a young, active-duty soldier who underwent lateral ankle ligament reconstruction with a tendon allograft whose postoperative course was complicated by septic peroneal tenosynovitis resulting in significant loss of both peroneal tendons. Reconstruction was achieved in a staged fashion with the use of silicone rods and external fixation to maintain physiologic tension and preserve peroneal tendon function, followed by reconstruction of both peroneal tendons and the superior peroneal retinaculum with a tensor fascia lata autograft. Soft tissue coverage was obtained with an anterolateral thigh free tissue transfer and a split thickness skin graft. The patient returned to full activity as an active-duty soldier with minimal pain and no instability of the right lower extremity. The muscle strength of both peroneal tendons remained at 5 of 5, and no objective findings of ankle instability were seen at 3.5 years postoperatively. PMID- 26002676 TI - Reconstruction of the Pediatric Lateral Malleolus and Physis by Free Microvascular Transfer of the Proximal Fibular Physis. AB - Traumatic injury to the pediatric growth plate can result in growth disturbances, late angular deformity, and limb length inequalities. Complete traumatic loss the entire growth plate complex (physis, epiphysis, and distal metaphysis) of the ankle can lead to severe joint instability and loss of function. In the growing child, physeal preservation is paramount; however, the reconstructive options are limited. We report a case of post-traumatic loss of the distal fibular physis resulting in severe ankle valgus in a pediatric patient after a Gustilo grade 3B open injury. Ankle valgus secondary to post-traumatic necrosis of the lateral ankle physeal complex was successfully managed by microvascular free transfer of the ipsilateral proximal fibula physis. The 24-month follow-up examination demonstrated continued growth of the free vascularized physeal graft and a stable ankle. The donor site had healed without incident. The patient was able to return to age-appropriate play, sports, and social integration. PMID- 26002677 TI - Effects on Subtalar Joint Stress Distribution After Cannulated Screw Insertion at Different Positions and Directions. AB - We investigated the effects on subtalar joint stress distribution after cannulated screw insertion at different positions and directions. After establishing a 3-dimensional geometric model of a normal subtalar joint, we analyzed the most ideal cannulated screw insertion position and approach for subtalar joint stress distribution and compared the differences in loading stress, antirotary strength, and anti-inversion/eversion strength among lateral medial antiparallel screw insertion, traditional screw insertion, and ideal cannulated screw insertion. The screw insertion approach allowing the most uniform subtalar joint loading stress distribution was lateral screw insertion near the border of the talar neck plus medial screw insertion close to the ankle joint. For stress distribution uniformity, antirotary strength, and anti inversion/eversion strength, lateral-medial antiparallel screw insertion was superior to traditional double-screw insertion. Compared with ideal cannulated screw insertion, slightly poorer stress distribution uniformity and better antirotary strength and anti-inversion/eversion strength were observed for lateral-medial antiparallel screw insertion. Traditional single-screw insertion was better than double-screw insertion for stress distribution uniformity but worse for anti-rotary strength and anti-inversion/eversion strength. Lateral medial antiparallel screw insertion was slightly worse for stress distribution uniformity than was ideal cannulated screw insertion but superior to traditional screw insertion. It was better than both ideal cannulated screw insertion and traditional screw insertion for anti-rotary strength and anti-inversion/eversion strength. Lateral-medial antiparallel screw insertion is an approach with simple localization, convenient operation, and good safety. PMID- 26002678 TI - Percutaneous, Minimally Invasive Repair of Traumatic and Simultaneous Rupture of Both Achilles Tendons: A Case Report. AB - Achilles injury is a common musculoskeletal disorder. Bilateral rupture of the Achilles tendon, however, is much less common and usually occurs spontaneously. Complete, traumatic, and bilateral ruptures are rare and typically require long periods of immobilization before the patient can return to full weightbearing. A 52-year-old male was hospitalized for bilateral traumatic rupture to both Achilles tendons. No risk factors for tendon rupture were found. Blood samples revealed no peripheral blood pathologic features. Both tendons were repaired with percutaneous, minimally invasive surgery using the Achillon((r)) tendon suture system. Rehabilitation was begun 4 weeks later. An ankle-foot orthosis was prescribed to provide ankle support with an adjustable range of movement, and active plantar flexion was set at 0 degrees to 30 degrees . The patient remained non-weightbearing with the ankle-foot orthosis device and performed active range of-motion exercises. At 8 weeks after surgery, we recommended that he begin walking with partial weightbearing using a foot-tibial orthosis with the range of motion set to 45 degrees plantar flexion and 15 degrees dorsiflexion. At 10 weeks postoperatively, he was encouraged to return to full weightbearing on both feet. Beginning rehabilitation as soon as possible after minimally invasive surgery, compared with 6 weeks of immobilization after surgery, provided a rapid resumption to full weightbearing. We emphasize the clinical importance of a safe, simple treatment program that can be followed for a patient with damage to the Achilles tendons. To our knowledge, ours is the first report of minimally invasive repair of bilateral simultaneous traumatic rupture of the Achilles tendon. PMID- 26002679 TI - Effect of Osteogenic Progenitor Cell Concentration on the Incidence of Foot and Ankle Fusion. AB - The use of biologics, namely demineralized bone matrix, bone marrow aspirate (BMA), and other growth factors, has gained popularity in foot and ankle surgery for use in compromised hosts or high-risk situations. Our research has shown the concentration of these pluripotent cells was greatest in the iliac crest. A medical record and radiographic review was performed to compare the effect of BMA harvest site osteogenic progenitor cells on the incidence of fusion. Radiographs were reviewed for radiographic evidence of trabecular bridging in 2 or more views. If fusion occurred, the number of osteogenic progenitor cells found in the combined BMA at surgery was recorded. A total of 33 patients were included in the present study. Of the 33 patients, 32 (97.0%) had radiographic fusion at a mean of 13 +/- 6 (range 8 to 30) weeks, and 1 (3.0%) experienced nonunion and required revision. The patient procedures were as follows: 18 (54.5%) hindfoot arthrodeses, 8 (24.2%) forefoot arthrodeses, 4 (12.1%) fractures, and 3 (9.1%) isolated ankle fusions. The mean colony-forming units for the patients with fusion was 20.3 +/- 23.5 (range 0.0 to 107.0). In the patient with nonunion, it was 0.20 colony-forming unit. Our comparison of the incidence of fusion with the use of osteogenic progenitor cells from 3 anatomic sites showed a low incidence of complications and a high incidence of fusion. No association was found between the BMA concentration and the incidence of fusion, suggesting a minimum concentration and biologic potential of pluripotent cells is necessary to achieve the clinical effect of fusion. PMID- 26002680 TI - Anatomic Parameters of the Lisfranc Joint Complex in a Radiographic and Cadaveric Comparison. AB - Subtle injuries to the Lisfranc joint complex are difficult to diagnose clinically and radiographically and can ultimately result in obvious disability if misdiagnosed. However, no previous study has shown the true mean average distance between the base of the first and second metatarsals (the Lisfranc distance). Therefore, in the present study, the anatomic and radiographic parameters of the Lisfranc joint were studied in detail to assist in the evaluation of Lisfranc injuries. The parameters of the Lisfranc joint complex in 100 normal volunteers and 10 cadavers were measured, including the medial, lateral depth of the mortise joint, width and height of the second metatarsal base, and distance between the base of the first and second metatarsals. The mean average Lisfranc distance was 0.24 +/- 0.06 mm in the left foot and 0.25 +/- 0.06 mm in the right foot for the radiographic group (p = .089) and 0.39 +/- 0.04 mm in the left foot and 0.37 +/- 0.04 mm in the right foot for the cadaver group (p = .129). The medial depth and Lisfranc distance in the radiographic group were smaller than the same measurements in the cadaver group, and these differences were statistically significant (medial depth, p < .001; Lisfranc distance, p < .001). The lateral depth and second metatarsal height in the radiographic group were larger than the same measurements in the cadaver group, and these differences were statistically significant (lateral depth, p < .001; second metatarsal height, p < .001). The second metatarsal width was the same in the 2 groups (p = .651). In conclusion, if the Lisfranc distance is >3.0 mm radiographically, a subtle injury to the Lisfranc joint should be highly suspected. No test of stability was performed between shallow and narrow versus deeper and broader Lisfranc mortise configurations. We merely speculated that a deeper and wider mortise is likely to be more stable than one that is shallow and narrow, probably owing to the presence of broader ligaments. PMID- 26002681 TI - Tibiocalcaneal Arthrodesis With a Porous Tantalum Spacer and Locked Intramedullary Nail for Post-Traumatic Global Avascular Necrosis of the Talus. AB - Global avascular necrosis of the talus is a devastating complication that usually occurs as a result of a post-traumatic or metabolic etiology. When conservative options fail, tibiocalcaneal arthrodesis is generally indicated in conjunction with massive bone grafting to maintain the functional length of the extremity. Several bone grafting options are available, including the use of a freeze-dried or fresh-frozen femoral head allograft or autograft obtained from the iliac crest or fibula, all of which pose their own inherent risks. The noted complications with massive bone grafting techniques have included graft collapse, infection, immune response, donor site morbidity, and nonunion. In an effort to avoid many of these complications, we present a case report involving post-traumatic talar avascular necrosis in a 59-year-old male who was successfully treated with the use of a porous tantalum spacer, an autogenic morselized fibular bone graft, and 30 mL of bone marrow aspirate in conjunction with a retrograde tibiocalcaneal nail. Porous tantalum is an attractive substitute for bone grafting because of its structural integrity, biocompatibility, avoidance of donor site complications, and lack of an immune response. The successful use of porous tantalum has been well-documented in hip and knee surgery. We present a practical surgical approach to tibiotalocalcaneal arthrodesis with a large segmental deficit. To our knowledge, this is the first published report describing an alternative surgical technique to address global avascular necrosis of the talus that could have additional applications in salvaging the ankle with a large bone deficiency. PMID- 26002682 TI - Descriptive Quantitative Analysis of Rearfoot Alignment Radiographic Parameters. AB - Although the radiographic parameters of the transverse talocalcaneal angle (tTCA), calcaneocuboid angle (CCA), talar head uncovering (THU), calcaneal inclination angle (CIA), talar declination angle (TDA), lateral talar-first metatarsal angle (lTFA), and lateral talocalcaneal angle (lTCA) form the basis of the preoperative evaluation and procedure selection for pes planovalgus deformity, the so-called normal values of these measurements are not well established. The objectives of the present study were to retrospectively evaluate the descriptive statistics of these radiographic parameters (tTCA, CCA, THU, CIA, TDA, lTFA, and lTCA) in a large population, and, second, to determine an objective basis for defining "normal" versus "abnormal" measurements. As a secondary outcome, the relationship of these variables to the body mass index was assessed. Anteroposterior and lateral foot radiographs from 250 consecutive patients without a history of previous foot and ankle surgery and/or trauma were evaluated. The results revealed a mean measurement of 24.12 degrees , 13.20 degrees , 74.32%, 16.41 degrees , 26.64 degrees , 8.37 degrees , and 43.41 degrees for the tTCA, CCA, THU, CIA, TDA, lTFA, and lTCA, respectively. These were generally in line with the reported historical normal values. Descriptive statistical analysis demonstrated that the tTCA, THU, and TDA met the standards to be considered normally distributed but that the CCA, CIA, lTFA, and lTCA demonstrated data characteristics of both parametric and nonparametric distributions. Furthermore, only the CIA (R = -0.2428) and lTCA (R = -0.2449) demonstrated substantial correlation with the body mass index. No differentiations in deformity progression were observed when the radiographic parameters were plotted against each other to lead to a quantitative basis for defining "normal" versus "abnormal" measurements. PMID- 26002683 TI - NOTCH3 variants in patients with subcortical vascular cognitive impairment: a comparison with typical CADASIL patients. AB - Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is thought to be a common form of hereditary subcortical vascular cognitive impairment (SVCI), there is little data on the frequency of NOTCH3 variants in SVCI patients. We prospectively screened for NOTCH3 variants in consecutive SVCI patients who underwent brain magnetic resonance imaging and amyloid positron emission tomography as well as sequence analysis for mutational hotspots in the NOTCH3 gene. Among 117 patients with SVCI, 16 patients had either known mutations or variants of unknown significance in the NOTCH3 gene. There were no differences in clinical and neuroimaging features between SVCI patients with and without NOTCH3 variants, only except for a higher number of deep microbleeds in SVCI patients with NOTCH3 variants. Our findings suggest that there is a phenotypic entity of NOTCH3 variant that is similar to that of sporadic SVCI but not of typical CADASIL. Notably, 2 SVCI patients with NOTCH3 mutations showed significant amyloid burden, which challenges the prevailing concept that CADASIL represents the genetic model of pure small vessel disease. PMID- 26002685 TI - Nobiletin ameliorates cisplatin-induced acute kidney injury due to its anti oxidant, anti-inflammatory and anti-apoptotic effects. AB - Cisplatin is an effective anti-cancer drug which causes remarkable toxicity to kidney by generating reactive oxygen species and by stimulating inflammatory and apoptotic pathway. Citrus flavonoid, like nobiletin has been reported to possess anti-oxidant, anti-inflammatory and anti-apoptotic properties. Hence, the present study was aimed to evaluate these properties of nobiletin, a polymethoxy flavone in cisplatin-induced acute renal injury. Adult male albino Wistar rats were divided into 6 groups. Nobiletin was administered at the dose of 1.25, 2.5 and 5mg/kg for a period of 10 days. On 7th day, a single injection of cisplatin (8 mg/kg) was injected to rats. Cisplatin administration resulted in renal dysfunction as evident by increase in serum creatinine and BUN levels. Oxidative stress in cisplatin group was reflected by increase in MDA level, and depletion of anti-oxidants such as glutathione, superoxide dismutase and catalase in renal tissue. Furthermore, cisplatin increased the expressions of Bax, caspase-3 and DNA damage along with decreased expression of Bcl-2 in the renal tissue. Histological analysis also revealed acute tubular necrosis. However, pretreatment with nobiletin preserved renal function and restored anti-oxidant status. Nobiletin supplementation inhibited activation of apoptotic pathways and DNA damage. It also attenuated tubular injury histologically. Collectively, the result of this study suggests the nephroprotective potential of nobiletin which may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects. PMID- 26002684 TI - Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex. AB - Microglia form the immune system of the brain. Previous studies in cell cultures and animal models suggest altered activation states and cellular senescence in the aged brain. Instead, we analyzed 3 transcriptome data sets from the postmortem frontal cortex of 381 control individuals to show that microglia gene markers assemble into a transcriptional module in a gene coexpression network. These markers predominantly represented M1 and M1/M2b activation phenotypes. Expression of genes in this module generally declines over the adult life span. This decrease was more pronounced in microglia surface receptors for microglia and/or neuron crosstalk than in markers for activation state phenotypes. In addition to these receptors for exogenous signals, microglia are controlled by brain-expressed regulatory factors. We identified a subnetwork of transcription factors, including RUNX1, IRF8, PU.1, and TAL1, which are master regulators (MRs) for the age-dependent microglia module. The causal contributions of these MRs on the microglia module were verified using publicly available ChIP-Seq data. Interactions of these key MRs were preserved in a protein-protein interaction network. Importantly, these MRs appear to be essential for regulating microglia homeostasis in the adult human frontal cortex in addition to their crucial roles in hematopoiesis and myeloid cell-fate decisions during embryogenesis. PMID- 26002686 TI - Medical school-based teaching kitchen improves HbA1c, blood pressure, and cholesterol for patients with type 2 diabetes: Results from a novel randomized controlled trial. AB - AIMS: A medical school-based teaching kitchen sought to establish proof-of principle for its hands-on Mediterranean diet (MD)-based cooking and nutrition curriculum for patients with type 2 diabetes (T2D). METHODS: This pilot randomized controlled trial (RCT) allocated 27 patients with T2D between the control and GCCM arms. Mixed effects linear regression with repeated measures was used to investigate differences from baseline to 6 months. The primary and secondary endpoints were HbA1c -0.3% (-27 mmol/mol) and diastolic blood pressure (DBP) -10 mmHg and a 25% improved responses in dietary habits and attitudes and competencies in healthy nutrition. RESULTS: Compared to the control group, the GCCM group had superior HbA1c reduction (-0.4% vs. -0.3%, p = 0.575) that was not statistically significant. There were significantly greater reductions in the GCCM vs. control group for DBP (-4 vs. 7 mmHg, p=0.037) and total cholesterol ( 14 vs. 17 mg/dL, p = 0.044). There was a greater proportion increase though not significant of GCCM subjects compared to controls who mostly believed they could eat correct portions (18% vs. -11%, p = 0.124), and who used nutrition panels to make food choices (34% vs. 0%, p = 0.745). CONCLUSION: This is the first known RCT demonstrating improved biometrics using a novel MD-based hands on cooking and nutrition curriculum for patients with T2D. These results suggest subsequent clinical trials are warranted on the grounds of documented feasibility and clinical efficacy. PMID- 26002687 TI - Efficient anaerobic treatment of synthetic textile wastewater in a UASB reactor with granular sludge enriched with humic acids supported on alumina nanoparticles. AB - A novel technique to co-immobilize humus-reducing microorganisms and humic substances (HS), supported on gamma-Al2O3 nanoparticles (NP), by a granulation process in an upflow anaerobic sludge bed (UASB) reactor is reported in the present work. Larger granules (predominantly between 1 and 1.7 mm) were produced using NP coated with HS compared to those obtained with uncoated NP (mostly between 0.25 and 0.5 mm). The HS-enriched granular biomass was then tested for its capacity to achieve the reductive decolorization of the recalcitrant azo dye, reactive red 2 (RR2), in the same UASB reactor operated with a hydraulic residence time of 12 h and with glucose as electron donor. HS-enriched granules achieved higher decolorization and COD removal efficiencies, as compared to the control reactor operated in the absence of HS, in long term operation and applying high concentrations of RR2 (40-400 mg/L). This co-immobilizing technique could be attractive for its application in UASB reactors for the reductive biotransformation of several contaminants, such as nitroaromatics, poly halogenated compounds, metalloids, among others. PMID- 26002688 TI - Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue. AB - Recent animal work has suggested that cochlear synapses are more vulnerable than hair cells in both noise-induced and age-related hearing loss. This synaptopathy is invisible in conventional histopathological analysis, because cochlear nerve cell bodies in the spiral ganglion survive for years, and synaptic analysis requires special immunostaining or serial-section electron microscopy. Here, we show that the same quadruple-immunostaining protocols that allow synaptic counts, hair cell counts, neuronal counts and differentiation of afferent and efferent fibers in mouse can be applied to human temporal bones, when harvested within 9 h post-mortem and prepared as dissected whole mounts of the sensory epithelium and osseous spiral lamina. Quantitative analysis of five "normal" ears, aged 54-89 yrs, without any history of otologic disease, suggests that cochlear synaptopathy and the degeneration of cochlear nerve peripheral axons, despite a near-normal hair cell population, may be an important component of human presbycusis. Although primary cochlear nerve degeneration is not expected to affect audiometric thresholds, it may be key to problems with hearing in noise that are characteristic of declining hearing abilities in the aging ear. PMID- 26002689 TI - A quantitative analysis of the prevalence of clinical depression and anxiety in patients with prostate cancer undergoing active surveillance. AB - OBJECTIVE: To quantitatively determine the prevalence of anxiety and depression in men on active surveillance (AS). DESIGN: Cross-sectional questionnaire survey. SETTING: Secondary care prostate cancer (PCa) clinics across South, Central and Western England. PARTICIPANTS: 313 men from a total sample of 426 with a histological diagnosis of PCa currently managed with AS were identified from seven UK urology departments. The mean age of respondents was 70 (51-86) years with the majority (76%) being married or in civil partnerships. 94% of responders were of white British ethnicity. PRIMARY OUTCOME MEASURES: The prevalence of clinically meaningful depression and anxiety as assessed by the Hospital Anxiety and Depression Scale (HADS; score >=8/21). SECONDARY OUTCOME MEASURES: Patient demographic data (age, employment, relationship, ethnic and educational status). Each demographic variable was cross-tabulated against patients identified as depressed or anxious to allow for the identification of variables that were significantly associated with depression and anxiety. In order to determine predictors for depression and anxiety among the demographic variables, logistic regression analyses were conducted, with p<0.05 considered as indicating statistical significance. RESULTS: The prevalence of clinical anxiety and depression as determined via the HADS (HADS >=8) was 23% (n=73) and 12.5% (n=39), respectively. Published data from men in the general population of similar age has shown prevalence rates of 8% and 6%, respectively, indicating a twofold increase in depression and a threefold increase in anxiety among AS patients. Our findings also suggest that AS patients experience substantially greater levels of anxiety than patients with PCa treated radically. The only demographic predictor for anxiety or depression was divorce. CONCLUSIONS: Patients with PCa managed with AS experienced substantially higher rates of anxiety and depression than that expected in the general population. Strategies to address this are needed to improve the management of this population and their quality of life. PMID- 26002690 TI - Diuretic versus placebo in normotensive acute pulmonary embolism with right ventricular enlargement and injury: a double-blind randomised placebo controlled study. Protocol of the DiPER study. AB - INTRODUCTION: In acute pulmonary embolism (PE), poor outcome is usually related to right ventricular (RV) failure due to the increase in RV afterload. Treatment of PE with RV failure without shock is controversial and usually relies on fluid expansion to increase RV preload. However, several studies suggest that fluid expansion may worsen acute RV failure by increasing RV dilation and ischaemia, and increase left ventricular compression by RV dilation. By reducing RV enlargement, diuretic treatment may break this vicious circle and provide early improvement in normotensive patients referred for acute PE with RV failure. METHODS AND ANALYSIS: The Diuretic versus placebo in Pulmonary Embolism with Right ventricular enlargement trial (DiPER) is a prospective, multicentre, randomised (1:1), double-blind, placebo controlled study assessing the superiority of furosemide as compared with placebo in normotensive patients with confirmed acute PE and RV dilation (diagnosed on echocardiography or CT of the chest) and positive brain natriuretic peptide result. The primary end point will be a combined clinical criterion derived from simplified Pulmonary Embolism Severity Index (PESI) score and evaluated at 24 h. It will include: (1) urine output >0.5 mL/kg/min for the past 24 h; (2) heart rate <110 bpm; (3) systolic blood pressure >100 mm Hg and (4) arterial oxyhaemoglobin level >90%. Thirty-day major cardiac events defined as death, cardiac arrest, mechanical ventilation, need for catecholamine and thrombolysis, will be evaluated as a secondary end point. Assuming an increase of 30% in the primary end point with furosemide and a beta risk of 10%, 270 patients will be required. ETHICS AND DISSEMINATION: Ethical approval was received from the ethical committee of Ile de France (2014 001090-14). The findings of the trial will be disseminated through peer-reviewed journals, and national and international conference presentations. TRIAL REGISTRATION NUMBER: NCT02268903. PMID- 26002691 TI - Outcomes of antiretroviral treatment in HIV-infected adults: a dynamic and observational cohort study in Shenzhen, China, 2003-2014. AB - OBJECTIVES: To report 10-year outcomes of virological and immunological treatment failure rates and risk factors. DESIGN: Prospective cohort study. SETTING: Shenzhen, China. PARTICIPANTS: 2172 HIV-positive adults in the national treatment database of Shenzhen from December 2003 to January 2014. INTERVENTION: Antiretroviral therapy according to the Chinese national treatment guidelines. OUTCOME MEASURES: Virological and immunological treatment failure rates. RESULTS: Of the 3099 patients surveyed, 2172 (70.1%) were included in the study. The median age was 33 years; 78.2% were male and 51.8% were infected through heterosexual contact. The median follow-up time was 31 months (IQR, 26-38). A total of 81 (3.7%) patients died, whereas 292 (13.4%) and 400 (18.4%) patients experienced virological and immunological failures, respectively. Adjusted Cox regression analysis indicated that baseline viral load (HR=2.19, 95% CI 1.52 to 4.48 for patients with a baseline viral load greater than or equal to 1,000,000 copies/mL compared to those with less than 10,000 copies/mL) and WHO stage (HR=4.16, 95% CI 2.01 to 10.57 for patients in WHO stage IV compared with those in stage I) were significantly associated with virological failure. The strongest risk factors for immunological treatment failure were a low CD4 cell count (HR=0.46, 95% CI 0.32 to 0.66 for patients with CD4 cell counts of 50-99 cells/mm(3) compared to those with less than 50 cells/mm(3)) and higher baseline WHO stage at treatment initiation (HR=2.15, 95% CI 1.38 to 3.34 for patients in WHO stage IV compared to those in stage I). CONCLUSIONS: Sustained virological and immunological outcomes show that patients have responded positively to long term antiretroviral treatment with low mortality. This 10-year data study provides important information for clinicians and policymakers in the region as they begin to evaluate and plan for the future needs of their own rapidly expanding programmes. PMID- 26002692 TI - SurgiCal Obesity Treatment Study (SCOTS): protocol for a national prospective cohort study of patients undergoing bariatric surgery in Scotland. AB - INTRODUCTION: The efficacy of bariatric surgery for large-scale, long-term weight loss is well established. However, many questions remain over the continual benefits and cost-effectiveness of that weight loss for overall health, particularly when accounting for potential complications and adverse events of surgery. Health research institutes in the UK and the USA have called for high quality longitudinal cohort studies of patients undergoing bariatric surgery, assessing outcomes such as surgical complications, mortality, diabetes remission, microvascular complications, cardiovascular events, mental health, cost and healthcare use. METHODS AND ANALYSIS: SurgiCal Obesity Treatment Study (SCOTS) is a national, prospective, observational, cohort study of patients undergoing primary bariatric surgical procedures in Scotland. This study aims to recruit 2000 patients and conduct a follow-up for 10 years postbariatric surgery using multiple data collection methods: surgeon-recorded data, electronic health record linkage, and patient-reported outcome measures. Outcomes measured will include: mortality, weight change, diabetes, surgical, cardiovascular, cancer, behavioural, reproductive/urological and nutritional variables. Healthcare utilisation and economic productivity will be collected to inform cost effectiveness analysis. ETHICS AND DISSEMINATION: The study has received a favourable ethical opinion from the West of Scotland Research Ethics committee. All publications arising from this cohort study will be published in open-access peer-reviewed journals. All SCOTS investigators (all members of the research team at every recruiting site) will have the ability to propose research suggestions and potential publications using SCOTS data; a publications committee will approve all requests for use of SCOTS data and propose writing committees and timelines. Lay-person summaries of all research findings will be published simultaneously on the SCOTS website (http://www.scotsurgeystudy.org.uk). PMID- 26002693 TI - 1,3-Butadiene, CML and the t(9:22) translocation: A reality check. AB - Epidemiological studies of 1,3-butadiene have suggest that exposures to humans are associated with chronic myeloid leukemia (CML). CML has a well-documented association with ionizing radiation, but reports of associations with chemical exposures have been questioned. Ionizing radiation is capable of inducing the requisite CML-associated t(9:22) translocation (Philadelphia chromosome) in appropriate cells in vitro but, thus far, chemicals have not shown this capacity. We have proposed that 1,3-butadiene metabolites be so tested as a reality check on the epidemiological reports. In order to conduct reliable testing in this regard, it is essential that a positive control for induction be available. We have used ionizing radiation to develop such a control. Results described here demonstrate that this agent does in fact induce pathogenic t(9:22) translocations in a human myeloid cell line in vitro, but does so at low frequencies. Conditions that will be required for studies of 1,3-butadiene are discussed. PMID- 26002694 TI - A novel AAT-deletion mutation in the coding sequence of the BCO2 gene in yellow fat rabbits. AB - The carcasses of yellow-fat rabbits may be attractive to modern consumers, because they have a relatively high content of biologically active compounds. One of the main candidate genes associated with the yellow-fat trait is beta-carotene 9',10'-oxygenase (BCO2). This study is the first report of the novel AAT-deletion mutation at codon 248 of the BCO2 gene, which has been found in homozygous yellow fat rabbits. The deletion mutation, located at the beginning of exon 6, results in the absence of asparagine in protein. We also developed a PCR-RFLP test that supports intravital genotyping of indel polymorphism based on genomic DNA. PMID- 26002695 TI - A history of the term "DMARD". AB - The article outlines a history of the concept of "disease-modifying antirheumatic drugs" or DMARDs--from the emergence in the 1970s of the idea of drugs with decisive long-term effects on bone erosion in rheumatoid arthritis (RA), through the consolidation and popularisation in the term DMARD in 1980s and 1990s. It then examines the usage of the terms "remission-inducing drugs" (RIDs) and "slow acting anti-rheumatic drugs" (SAARDs), which for some years offered competition to the term DMARDs, thus underscoring the contingency of the establishment of DMARD as a word. Finally, it juxtaposes the apparently spontaneous emergence of the three terms DMARD, SAARD and RID, and the disappearance of the latter two, with a failed attempt in the early 1990s to replace these terms with the new term "disease-controlling antirheumatic treatment" (DC-ART). The analysis highlights the paradoxical qualities of the DMARD concept as robust albeit tension ridden, while playing down the role of identified individuals and overarching explanations of purpose. PMID- 26002696 TI - Use of Androcoll-S after thawing improves the quality of electroejaculated and epididymal sperm samples from red deer. AB - Single Layer Centrifugation is a useful technique to select sperm with good quality. The use of selection methods such as Androcoll could become an important tool to improve the quality of sperm samples and therefore to improve other artificial reproductive techniques such as sperm sex sorting, in vitro fertilization or AI. The aim of this study was to evaluate the effect of a Single Layer Centrifugation with Androcoll-S on the sperm quality of red deer sperm samples of two different origins, electroejaculated samples and epididymal samples obtained post-mortem, after thawing and after an incubation for 2h at 37 degrees C. Sperm motility, viability, membrane permeability, mitochondrial activity, acrosomal status and DNA fragmentation were determined for all samples. The samples selected by Androcoll-S showed an improvement in sperm kinematics compared to unselected samples after thawing and after incubation. The same effect was observed in parameters such as viability, mitochondrial activity or acrosomal status which were improved after the selection. In contrast, no difference was found in DNA fragmentation between selected and unselected samples within the same sperm type. We conclude that sperm selection by SLC with Androcoll-S after thawing for red deer sperm of both types is a suitable technique that allows sperm quality in both types of sperm samples to be improved, thereby improving other assisted reproductive techniques. Further studies (IVF and in vivo fertilization) are required to determine whether this improvement can increase fertility, as has been shown for other species. PMID- 26002697 TI - Material Properties and Antimicrobial Activity of Polyhydroxybutyrate (PHB) Films Incorporated with Vanillin. AB - Polyhydroxybutyrate (PHB) was produced by Bacillus mycoides DFC 1, isolated from garden soil. Antimicrobial (AM) films of PHB were prepared by incorporating vanillin (4-hydroxy-3-methoxybenzaldehyde) from 10 to 200 MUg/g of PHB. The films were assessed for antimicrobial activity against foodborne pathogens and spoilage bacteria comprising of Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Staphylococcus aureus and fungi such as Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus parasiticus, Aspergillus ochraceus, Penicillium viridicatum, and Penicillium clavigerum. The minimum concentration of vanillin required to exhibit antimicrobial activity was >=80 MUg/g PHB for bacteria and >=50 MUg/g PHB for fungi. The PHB films with and without vanillin were studied for mechanical and thermal properties such as tensile strength, Young's modulus, percentage elongation to break, melting temperature, and heat of fusion. The thermal stability of the films was studied using thermogravimetric analysis. The release kinetics of vanillin into food matrices was also checked using food stimulants. The study is intended to find applications for PHB films containing vanillin to enhance the shelf life of foods in the form of biodegradable wrapper. PMID- 26002698 TI - General properties of the acoustic plate modes at different temperatures. AB - Using acoustic plate modes with SH-polarization and quartz crystal with Euler angles 0 degrees , 132.75 degrees , 90 degrees , as an example, general properties of the acoustic plate modes at different temperatures are studied theoretically and experimentally in the range from -40 to +80 degrees C. It is shown that in addition to well-known parameters responsible for temperature characteristics of acoustic waves the temperature coefficients of the acoustic plate modes depend on the mode order n, plate thickness h/lambda, and expansion of the plate in direction of its thickness (h - thickness, lambda - acoustic wavelength). These properties permit the mode sensitivity to be increased or decreased without replacing plate material and orientation. PMID- 26002699 TI - Volumetric differences suggest involvement of cerebellum and brainstem in chronic migraine. AB - BACKGROUND: Chronic migraine (CM) is a disabling neurologic condition that often evolves from episodic migraine. There has been mounting evidence on the volumetric changes detected by magnetic resonance imaging (MRI) technique in migraineurs. These studies mainly focused on episodic migraine patients and less is known about the differences in CM patients. METHOD: A total of 24 CM patients and 24 healthy control individuals (all females) were included in this study. All participants underwent neurological examination and MRI. High-resolution anatomical MRI images were processed with an automated segmentation method (FreeSurfer). White-matter abnormalities of the brain were also evaluated with the Age-Related White-Matter-Changes Scale. RESULTS: The volumes of the cerebellum and brainstem were found to be smaller in CM patients compared to healthy controls. White-matter abnormalities were also found in CM patients, specifically in the bilateral parieto-occipital areas. There was no correlation between the clinical variables and volume decrease in these regions. CONCLUSION: CM patients showed significant volume differences in infratentorial areas and white-matter abnormalities in the posterior part of the brain. It is currently unclear whether the structural brain changes seen in migraine patients are the cause or the result of headaches. Longitudinal volumetric neuroimaging studies with larger groups, especially on the chronification of migraine, are needed to shed light on this topic. PMID- 26002702 TI - About systematic reviews. PMID- 26002700 TI - Improving the detection of chronic migraine: Development and validation of Identify Chronic Migraine (ID-CM). AB - BACKGROUND: Migraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self administered tool (ID-CM) to identify migraine and CM. METHODS: ID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3beta gold-standard clinician diagnosis. RESULTS: Stages 1 and 2 identified 20 items selected for psychometric validation in stage 3 (n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%). DISCUSSION: ID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable. PMID- 26002703 TI - Commentary. The role of arthrodesis of the wrist in spastic disorders. V. Neuhaus, J. J. Kadzielski, C. S. Mudgal. J Hand Surg Eur. 2015, 512-7. PMID- 26002704 TI - Re: Gilbert A, Valbuena S, Posso C. Obstetrical brachial plexus injuries: late functional results of the Steindler procedure. J Hand Surg Eur. 2014, 39: 868-75. PMID- 26002705 TI - Reply to: Gilbert A, Valbuena S, Posso C. Obstetrical brachial plexus injuries: late functional results of the Steindler procedure. J Hand Surg Eur. 2014, 39: 868-75. PMID- 26002706 TI - Re: Akhavani MA, McMurtrie A, Webb M, Muir L. A review of the classification of Dupuytren's Disease. J Hand Surg Eur. 2015, 40: 155-65 and Rodrigues JN, Zhang W, Scammell BE, Davis TRC. What patients want from the treatment of Dupuytren's Disease--is the Unite Rhumatologique des Affections de la Main (URAM) scale relevant? J Hand Surg Eur. 2015, 40: 150-4. PMID- 26002707 TI - Clinical research in hand surgery. PMID- 26002710 TI - Ferulic acid and Alzheimer's disease: promises and pitfalls. AB - Oxidative stress plays an important role in both initiation and progression of neurodegenerative diseases, such as Alzheimer and Parkinson. Therefore, much attention has been paid to antioxidants for developing therapeutic strategies for the neurodegenerative diseases. However, as serious adverse effects are related to synthetic antioxidants, recent research has been focused on natural products especially phenolic antioxidants. In the present article, we critically review the available literature related to the beneficial role of ferulic acid on Alzheimer's disease, since it is a natural antioxidant which is widely found in different fruits and vegetables. We also provide some informations about sources, chemical structure, bioavailability and clinical impacts of ferulic acid. PMID- 26002711 TI - Changes in volume of giant intracranial aneurysms treated by surgical strategies other than direct clipping. AB - BACKGROUND: Giant intracranial aneurysms (GIA) are often not eligible for direct clip occlusion. Surgical alternatives include partial clip occlusion or the placement of a cerebrovascular bypass or the combination of both. These alternative indirect strategies are expected to lead to a decrease in GIA volume over time rather than instantaneously. To examine whether this is the case, we analyzed follow-up imaging results 1 year after surgery. METHODS: We retrospectively screened the prospective GIA Registry's imaging database for anterior circulation GIA treated by surgical strategies other than direct clipping. We measured pre- and 1-year post-treatment GIA volume, lateral ventricle volume (LVV), and mid-line shift (MLS) in 19 cases. RESULTS: After a mean follow-up of 466 days (standard deviation +/-171) GIA volumes decreased from 9.6 cm(3) (interquartile range (IQR) 6.1-14.1) to 4.3 cm(3) (IQR 2.9-5.7; p < 0.01). Ipsilateral LVV increased from 8.6 cm(3) (IQR 6.4-24.9) to 16.0 cm(3) (IQR 9.1-27.2; p < 0.01) while contralateral LVV increased from 10.3 cm(3) (IQR 7.3 20.1) to 11.7 cm(3) (IQR 8.2-19.4; p = 0.02). MLS changed from 0.1 mm (IQR -1.9 to 2.0) to -0.9 mm (IQR -1.8 to 0.4; p = 0.03). The decrease in GIA volume correlated with the increase in ipsilateral LVV (rs = 0.60; p = 0.01) but not with the changes in MLS (rs = 0.41; p = 0.08). CONCLUSIONS: In our patient cohort, surgical strategies other that direct clipping for the treatment of anterior circulation GIA lead to a significant decrease in GIA volume over time. The resulting decrease in mass effect was more sensitively monitored by the measurement of changes in ipsilateral LVV than changes in MLS. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov . Unique identifier: NCT02066493. PMID- 26002712 TI - Microsurgical decompression for central lumbar spinal stenosis: a single-center observational study. AB - OBJECTIVE: To assess outcomes and complications in patients undergoing microsurgical decompression for central lumbar spinal stenosis (LSS) without radiologic instability. METHODS: Prospective data for patients operated at the Department of Neurosurgery, St. Olavs University Hospital, Norway, were obtained from the Norwegian Registry for Spine Surgery (NORspine) from 2007 to 2012. The primary outcome was change in Oswestry disability index (ODI) at 1 year. The secondary endpoint was perioperative complications. Complications were graded according to the Ibanez classification system. RESULTS: For all patients (n = 125), the mean improvement in ODI at 1 year was 16.9 points (95% CI 13.5-20.2, p < 0.001). Seventy-six (71.7%) patients achieved a minimal clinically important difference in ODI (defined as >=8 points improvement). The total number of complications within 3 months of surgery was 22 (17.6%). There were 14 medical and eight surgical complications, and all were Ibanez grade I or II (mild or moderate) complications. Four (3.2%) complications occurred while being admitted to the hospital and 18 (14.4%) occurred within 3 months following hospital discharge. The most common complication was urinary tract infection (n = 11, 8.8%). CONCLUSIONS: Microsurgical decompression for central LSS in the absence of radiological instability is an effective and safe treatment. PMID- 26002713 TI - Keyhole interlaminar dorsal rhizotomy for spastic diplegia in cerebral palsy. AB - BACKGROUND: The efficiency and safety of dorsal rhizotomies for cerebral palsy lie in the accuracy of radicular identification together with selectivity of root sectioning. Two different exposures are currently in use. The first is extended laminotomy/laminectomy from the upper lumbar level to the sacrum, which allows accurate identification of all L2-S2 roots/rootlets. The second is limited laminotomy exposing the conus/cauda equina at the thoracolumbar junction; this less invasive method limits accessibility to the roots. To optimize the accuracy and selectivity while minimizing invasiveness, the authors developed a tailored interlaminar procedure targeting the radicular levels involved in the harmful components of spasticity directly and individually. METHODS: Six patients with spastic diplegia at different levels of the Gross Motor Functional Classification System were selected. In each patient, two to three interlaminar spaces, preselected according to planning, were enlarged in the "keyhole" fashion, respecting the spinous processes and interspinous ligaments. Ventral root stimulation identified the radicular level. Dorsal root stimulation evaluated its implication in the hyperactive segmental circuits, helping quantify the percentage of rootlets to be cut. RESULTS: There were neither wound-related nor general complications. At 1 year of follow-up, X-ray examination did not reveal kyphosis or instability. In all children, the excess of spasticity was reduced. The Ashworth score decreased from 3.2 on average to 0.6 postoperatively (range: 2 4 to 0-2). Regarding the functional status at 1 year of follow-up for the three ambulatory children, the Gillette ability-to-walk score increased from 3/10 on average to 7.3/10 postoperatively (range: 2-4 to 7-8). For the three non ambulatory children, abnormal postures, painful contractures and ease of care were much improved. CONCLUSION: Keyhole interlaminar dorsal rhizotomy (KIDr) offers direct intradural access to each of the ventral/dorsal roots, thus maximizing the reliability of anatomical mapping and allowing individual physiological testing of all targeted roots. The interlaminar approach minimizes invasiveness by respecting the posterior spine structures. PMID- 26002714 TI - Early cholecystectomy in children with gallstone pancreatitis reduces readmissions. AB - BACKGROUND: Multiple guidelines exist in adult practice regarding the timing of cholecystectomy for gallstone pancreatitis. Current evidence to support their application to pediatric practice is minimal. This study sought to determine the effect of timing of cholecystectomy for gallstone pancreatitis in children on the risk of readmission. METHOD: All patients younger than 19years of age presenting to an acute NHS trust in England with a diagnosis of gallstone pancreatitis between 1 January 1999 and 31st December 2009 were included. Patient level data were extracted from the English Hospital Episode Statistic Database. ICD10, OPCS4.6 and hospital administrative data were used to determine: diagnosis, age, associated comorbidities and subsequent procedures performed. RESULTS: 670 cases of gallstone related pancreatitis were recorded in younger than 19 years old between 1999 and 2009 resulting in 3 deaths during this period. The majority (534/670) underwent a cholecystectomy which was performed less than two weeks from primary admission in 33% (174/534) of cases. Cholecystectomy within two weeks provides an actual risk reduction (ARR) of readmission of 57.5% (95% CI 50.1 to 64.4%, p<0.0001, NNT 2). No significant difference was identified in operative complications or mortality following early cholecystectomy in this group (p>0.05). CONCLUSIONS: Readmissions can be significantly reduced in this population by performing a cholecystectomy within two weeks with no apparent rise in surgical complications. PMID- 26002715 TI - 45,X mosaicism with Y chromosome presenting female phenotype. AB - Prophylactic gonadectomy is recommended in patients with 45,X mosaicism with the Y chromosome and presenting a female phenotype because of the risk of gonadoblastoma development. The characteristics of this disorder remain unclear because of its low incidence. We report 4 patients with 45,X mosaicism with the Y chromosome and presenting complete female external genitalia. We analyzed the characteristics and the macroscopic and histopathological findings of their gonads and performed hormonal assays of the 4 patients. All 4 patients were referred to us with short stature as the chief complaint. Chromosomal studies revealed 45,X/47,XYY in 1, and the others had a 45,X/46,XY karyotype. Three patients (6 gonads) underwent laparoscopic bilateral gonadectomy. The macroscopic appearance of gonads of 1 patient was similar to an ovary, whereas gonads of the rest appeared as streak gonads. The histopathological findings revealed bilateral gonadoblastoma in 1 patient, although the macroscopic findings did not show tumor characteristics. It is impossible to distinguish the histopathological findings of gonads according to their macroscopic appearance among patients with 45,X mosaicism with the Y chromosome and presenting a female phenotype. PMID- 26002716 TI - Dynamic changes in plasma tissue plasminogen activator, plasminogen activator inhibitor-1 and beta-thromboglobulin content in ischemic stroke. AB - The aim of this paper is to investigate the corresponding variations of plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activities, and beta-thromboglobulin (beta-TG) content in patients during different stages of ischemic stroke. Ischemic stroke is a common disease among aging people and its occurrence is associated with abnormalities in the fibrinolytic system and platelet function. However, few reports focus on the dynamic changes in the plasma fibrinolytic system and beta-TG content in patients with ischemic stroke. Patients were divided into three groups: acute, convalescent and chronic. Plasma t-PA and PAI-1 activities were determined by chromogenic substrate analysis and plasma beta-TG content was detected by radioimmunoassay. Patients in the acute stage of ischemic stroke had significantly increased levels of t-PA activity and beta-TG content, but PAI-1 activity was significantly decreased. Negative correlations were found between plasma t-PA and PAI-1 activities and between plasma t-PA activity and beta-TG content in patients with acute ischemic stroke. There were significant differences in plasma t-PA and PAI-1 activities in the aged control group, as well as in the acute, convalescent and chronic groups. It can be speculated that the increased activity of t-PA in patients during the acute stage was the result of compensatory function, and that the increase in plasma beta-TG level not only implies the presence of ischemic stroke but is likely a cause of ischemic stroke. During the later stages of ischemic stroke, greater attention is required in monitoring levels of PAI-1. PMID- 26002717 TI - Intensification and isolation: psychosocial work environment changes in Spain 2005-10. AB - BACKGROUND: Work organization in Spain has traditionally been based on a high proportion of passive work. Changes in the labour market in Europe and the economic crisis that began in 2008 may have had an impact on the pace of work in Spain. AIMS: To estimate the prevalence of exposure to high-strain work and passive work in 2010 compared with 2005 and to analyse the distribution by gender, age and occupation of workers exposed to high strain and iso-strain in 2010 compared with 2005. METHODS: Two representative samples of the Spanish working population were compared. Unweighted and weighted prevalences in 2010 were calculated and compared with those in 2005. RESULTS: In the 2010 sample of 5110 workers, 29% (95% CI 27.8; 30.7) were exposed to high strain (of whom 83% had low social support). There was an increase of 6% (95% CI 3.8; 7.1) in high strain, and of 7% (95% CI 5.2; 8.3) to iso-strain, compared with 2005 (n = 7612). In 2010, as in 2005, the proportion of manual workers exposed to strain and iso strain was more than double the corresponding proportion in non-manual workers. CONCLUSIONS: There has been an intensification of work, reduction in social support and a notable increase in exposure to high strain and iso-strain. The class inequalities reflect the segmentation of the Spanish labour market. PMID- 26002718 TI - Csr1/Zap1 Maintains Zinc Homeostasis and Influences Virulence in Candida dubliniensis but Is Not Coupled to Morphogenesis. AB - The supply and intracellular homeostasis of trace metals are essential for every living organism. Therefore, the struggle for micronutrients between a pathogen and its host is an important determinant in the infection process. In this work, we focus on the acquisition of zinc by Candida dubliniensis, an emerging pathogen closely related to Candida albicans. We show that the transcription factor Csr1 is essential for C. dubliniensis to regulate zinc uptake mechanisms under zinc limitation: it governs the expression of the zinc transporter genes ZRT1, ZRT2, and ZRT3 and of the zincophore gene PRA1. Exclusively, artificial overexpression of ZRT2 partially rescued the growth defect of a csr1Delta/Delta mutant in a zinc restricted environment. Importantly, we found that, in contrast to what is seen in C. albicans, Csr1 (also called Zap1) is not a major regulator of dimorphism in C. dubliniensis. However, although a csr1Delta/Delta strain showed normal germ tube formation, we detected a clear attenuation in virulence using an embryonated chicken egg infection model. We conclude that, unlike in C. albicans, Csr1 seems to be a virulence factor of C. dubliniensis that is not coupled to filamentation but is strongly linked to zinc acquisition during pathogenesis. PMID- 26002719 TI - The Candida albicans Exocyst Subunit Sec6 Contributes to Cell Wall Integrity and Is a Determinant of Hyphal Branching. AB - The yeast exocyst is a multiprotein complex comprised of eight subunits (Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84) which orchestrates trafficking of exocytic vesicles to specific docking sites on the plasma membrane during polarized secretion. To study SEC6 function in Candida albicans, we generated a conditional mutant strain in which SEC6 was placed under the control of a tetracycline-regulated promoter. In the repressed state, the tetR-SEC6 mutant strain (denoted tSEC6) was viable for up to 27 h; thus, all phenotypic analyses were performed at 24 h or earlier. Strain tSEC6 under repressing conditions had readily apparent defects in cytokinesis and endocytosis and accumulated both post Golgi apparatus secretory vesicles and structures suggestive of late endosomes. Strain tSEC6 was markedly defective in secretion of aspartyl proteases and lipases as well as filamentation under repressing conditions. Lack of SEC6 expression resulted in markedly reduced lateral hyphal branching, which requires the establishment of a new axis of polarized secretion. Aberrant localization of chitin at the septum and increased resistance to zymolyase activity were observed, suggesting that C. albicans Sec6 plays an important role in mediating trafficking and delivery of cell wall components. The tSEC6 mutant was also markedly defective in macrophage killing, indicating a role of SEC6 in C. albicans virulence. Taken together, these studies indicate that the late secretory protein Sec6 is required for polarized secretion, hyphal morphogenesis, and the pathogenesis of C. albicans. PMID- 26002720 TI - The NDR Kinase Cbk1 Downregulates the Transcriptional Repressor Nrg1 through the mRNA-Binding Protein Ssd1 in Candida albicans. AB - NDR (nuclear Dbf2-related) kinases are essential components for polarized morphogenesis, cytokinesis, cell proliferation, and apoptosis. The NDR kinase Cbk1 is required for the hyphal growth of Candida albicans; however, the molecular functions of Cbk1 in hyphal morphogenesis are largely unknown. Here, we report that Cbk1 downregulates the transcriptional repressor Nrg1 through the mRNA-binding protein Ssd1, which has nine Cbk1 phosphorylation consensus motifs. We found that deletion of SSD1 partially suppressed the defective hyphal growth of the C. albicans cbk1Delta/Delta mutant and that Ssd1 physically interacts with Cbk1. Cbk1 was required for Ssd1 localization to polarized growth sites. The phosphomimetic SSD1 allele (ssd1-9E) allowed the cbk1Delta/Delta mutant to form short hyphae, and the phosphodeficient SSD1 allele (ssd1-9A) resulted in shorter hyphae than did the wild-type SSD1 allele, indicating that Ssd1 phosphorylation by Cbk1 is important for hyphal morphogenesis. Furthermore, we show that the transcriptional repressor Nrg1 does not disappear during hyphal initiation in the cbk1Delta/Delta mutant but is completely absent in the cbk1Delta/Delta ssd1Delta/Delta double mutant. Deletion of SSD1 also increased Als3 expression and internalization of the cbk1Delta/Delta mutant in the human embryonic kidney cell line HEK293T. Collectively, our results suggest that one of the functions of Cbk1 in the hyphal morphogenesis of C. albicans is to downregulate Nrg1 through Ssd1. PMID- 26002722 TI - Factors associated with blood pressure control among patients attending the outpatient clinic of a South African district hospital. AB - OBJECTIVE: To determine the prevalence and factors associated with blood pressure (BP) control. METHODS: In a cross-sectional study involving 251 consecutively sampled patients, a semi-structured questionnaire collected information on socio demography, co-morbidities, hypertension treatments and BP control. Data analysis included descriptive statistics and logistic regression. RESULTS: Most participants were: on treatment for >5 years (60.6%); on three or more drugs (93.6%); treated according to guidelines (77%); and reported not missing medications in the last week (86.5%). BP control was achieved in only 31.5% and 16.7% of participants at the current and last visits, respectively. In multivariate regression analysis, a history of myocardial infarction (odd ratio [OR] = 0.41; P = 0.04) and being divorced/widowed (OR = 3.1; P = 0.01) predicted poor BP control. CONCLUSION: This study confirms the prevalent sub-optimal control of BP and suggests the need for further studies to examine the relationship between marital support, critical medical events and BP control. PMID- 26002721 TI - Auditory attention in childhood and adolescence: An event-related potential study of spatial selective attention to one of two simultaneous stories. AB - Auditory selective attention is a critical skill for goal-directed behavior, especially where noisy distractions may impede focusing attention. To better understand the developmental trajectory of auditory spatial selective attention in an acoustically complex environment, in the current study we measured auditory event-related potentials (ERPs) across five age groups: 3-5 years; 10 years; 13 years; 16 years; and young adults. Using a naturalistic dichotic listening paradigm, we characterized the ERP morphology for nonlinguistic and linguistic auditory probes embedded in attended and unattended stories. We documented robust maturational changes in auditory evoked potentials that were specific to the types of probes. Furthermore, we found a remarkable interplay between age and attention-modulation of auditory evoked potentials in terms of morphology and latency from the early years of childhood through young adulthood. The results are consistent with the view that attention can operate across age groups by modulating the amplitude of maturing auditory early-latency evoked potentials or by invoking later endogenous attention processes. Development of these processes is not uniform for probes with different acoustic properties within our acoustically dense speech-based dichotic listening task. In light of the developmental differences we demonstrate, researchers conducting future attention studies of children and adolescents should be wary of combining analyses across diverse ages. PMID- 26002723 TI - Combined thrombus aspiration and recanalization in treating Budd-Chiari syndrome with inferior vena cava thrombosis. AB - PURPOSE: To investigate the feasibility, safety, and effectiveness of combined thrombus aspiration and inferior vena cava (IVC) recanalization for Budd-Chiari syndrome (BCS) patients with IVC thrombosis. MATERIALS AND METHODS: From March 2011 to October 2014, 17 consecutive BCS patients with IVC thrombosis [male 13, female 4 (mean age 52.6 +/- 8.4 years, range 43-72 years)] treated by combined thrombus aspiration and IVC recanalization were enrolled in this retrospective study. An 8F guiding catheter was used as the aspiration catheter. During the treatment, the aspiration catheter was placed from the right femoral vein to the IVC thrombi, and a 20-ml syringe was connected with the aspiration catheter for thrombus aspiration. IVC recanalization was performed after thrombus aspiration. Data on technical success, clinical success, and follow-up were analyzed. RESULTS: Technical success was achieved in all patients. After thrombus aspiration, 12 patients had no visible thrombi on IVC venography, while 5 patients were shown to have the IVC mural thrombi. Afterwards, 13 patients were treated by IVC balloon dilation, and 4 patients were treated by IVC stent insertion. No patient experienced dyspnea after treatment. The average IVC pressure decreased from 29.8 +/- 3.4 cmH2O to 8.6 +/- 2.1 cmH2O (P < 0.001). Clinical success was achieved in all patients. The average follow-up period was 15.3 +/- 11.6 months (range 2-44 months). Long-term IVC patency was achieved in 15 of 17 patients. CONCLUSION: Combined thrombus aspiration and IVC recanalization can be a safe and effective method for BCS patients with IVC thrombosis. PMID- 26002724 TI - Moderate hypofractionation and simultaneous integrated boost by helical tomotherapy in prostate cancer: monoinstitutional report of acute tolerability assessment with different toxicity scales. AB - INTRODUCTION: Based on radiobiology evidence, hypofractionated radiotherapy has the potential of improving treatment outcome in prostate cancer patients. In this study, we evaluated the safety, in terms of acutetoxicity, of using moderate hypofractionated radiotherapy delivered with Helical Tomotherapy (HT) to treat prostate cancer patients. MATERIALS AND METHODS: Between December 2012 and April 2014, 42 consecutive patients were treated with hypofractionated radiotherapy using HT. All patients received 70 Gy in 28 fractions to PTV1, which included the prostate. In the intermediate risk group, 61.6 Gy were delivered to PTV2, which included the seminal vesicles. In high risk patients, the pelvic nodes were added (PTV3) and received 50.4 Gy. Acute toxicity was recorded prospectively with RTOG and Common Terminology Criteria for Adverse Events 3.0, retrospectively with CTCAE 4.0. Expanded Prostate Cancer Index Composite (EPIC) was measured at baseline and 3 months after end of treatment, to investigate health related quality of life with regards to bladder and gastrointestinal function. RESULTS: Acute toxicity was acceptable, independently from the system used to score side effects. Moderate genitourinary toxicity was more frequent than gastrointestinal toxicity. No correlation between acute side effects and patients' characteristics or physical dose parameters was registered. EPIC evaluation showed a negligible difference in urinary and bowel function post-treatment, that did not reach statistical significance. CONCLUSIONS: Our experience confirms the safety of moderate hypofractionation delivered with HT in prostate cancer patients with low, intermediate and high risk. PMID- 26002725 TI - Strategies to improve the credibility of meta-analyses in spine surgery: a systematic survey. AB - BACKGROUND CONTEXT: Meta-analyses are powerful tools that can synthesize existing research, inform clinical practice, and support evidence-based care. These studies have become increasingly popular in the spine surgery literature, but the rigor with which they are being conducted has not yet been evaluated. PURPOSE: Our primary objectives were to evaluate the methodological quality (credibility) of spine surgery meta-analyses and to propose strategies to improve future research. Our secondary objectives were to evaluate completeness of reporting and identify factors associated with higher credibility and completeness of reporting. STUDY DESIGN: This study is based on a systematic survey of meta analyses. OUTCOME MEASURES: We evaluated credibility according to the Users' Guide to the Medical Literature and completeness of reporting according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. METHODS: We systematically searched MEDLINE, EMBASE, and The Cochrane Library, and two reviewers independently assessed eligibility, credibility, and completeness of reporting. We used multivariable linear regression to evaluate potential associations. Interrater agreement was quantified using kappa and intraclass correlation (ICC) coefficients. RESULTS: We identified 132 eligible meta-analyses of spine surgery interventions. The mean credibility score was 3 of 7 (standard deviation [SD], 1.4; ICC, 0.86), with agreement for each item ranging from 0.54 (moderate) to 0.83 (almost perfect). Clinical questions were judged as sensible in 125 (95%), searches were exhaustive in 102 (77%), and risk of bias assessments were undertaken in 91 (69%). Seven (5%) meta-analyses addressed possible explanations for heterogeneity using a priori subgroup hypotheses and 24 (18%) presented results that were immediately clinically applicable. Investigators undertook duplicate assessments of eligibility, risk of bias, and data extraction in 46 (35%) and rated overall confidence in the evidence in 24 (18%). Later publication year, increasing Journal Impact Factor, increasing number of databases, inclusion of Randomized Controlled Trials, and inclusion of non-English studies were significantly associated with higher credibility scores (p<.05). The mean score for reporting was 18 of 27 (SD, 4.4; ICC, 0.94). CONCLUSIONS: The credibility of many current spine surgery meta-analyses is limited. Researchers can improve future meta-analyses by performing exhaustive literature searches, addressing possible explanations of heterogeneity, presenting results in a clinically useful manner, reproducibly selecting and assessing primary studies, addressing confidence in the pooled effect estimates, and adhering to guidelines for complete reporting. PMID- 26002726 TI - Impacts of information and communication technologies on nursing care: an overview of systematic reviews (protocol). AB - BACKGROUND: Information and communication technologies (ICTs) used in the health sector have well-known advantages. They can promote patient-centered healthcare, improve quality of care, and educate health professionals and patients. However, implementation of ICTs remains difficult and involves changes at different levels: patients, healthcare providers, and healthcare organizations. Nurses constitute the largest health provider group of the healthcare workforce. The use of ICTs by nurses can have impacts in their practice. The main objective of this review of systematic reviews is to systematically summarize the best evidence regarding the effects of ICTs on nursing care. METHODS/DESIGN: We will include all types of reviews that aim to evaluate the influence of ICTs used by nurses on nursing care. We will consider four types of ICTs used by nurses as a way to provide healthcare: management systems, communication systems, information systems, and computerized decision support systems. We will exclude nursing management systems, educational systems, and telephone systems. The following types of comparisons will be carried out: ICT in comparison with usual care/practice, ICT compared to any other ICT, and ICT versus other types of interventions. The primary outcomes will include nurses' practice environment, nursing processes/scope of nursing practice, nurses' professional satisfaction as well as nursing sensitive outcomes, such as patient safety, comfort, and quality of life related to care, empowerment, functional status, satisfaction, and patient experience. Secondary outcomes will include satisfaction with ICT from the nurses and patients' perspective. Reviews published in English, French, or Spanish from 1 January 1995 will be considered. Two reviewers will independently screen the title and abstract of the papers in order to assess their eligibility and extract the following information: characteristics of the population and setting, type of interventions (e.g., type of ICTs and service provided), comparisons, outcomes, and review limitations. Any disagreements will be resolved by discussion and consensus involving the two reviewers or will involve a third review author, if needed. DISCUSSION: This overview is an interesting starting point from which to compare and contrast findings of separate reviews regarding the positive and negative effects of ICTs on nursing care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014762. PMID- 26002728 TI - Anti-Inflammatory Effects of Resveratrol in Patients with Ulcerative Colitis: A Randomized, Double-Blind, Placebo-controlled Pilot Study. AB - BACKGROUND AND AIMS: Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease in which reducing pro-inflammatory and/or increasing anti-inflammatory molecules is the mainstay of treatment. The aim of this study was to evaluate the effects of supplementation with resveratrol as an antiinflammatory and antioxidant agent on inflammation and quality of life in patients with active UC. METHODS AND RESULTS: In this randomized, double-blind, placebo-controlled study, 50 eligible patients with active mild to moderate UC were supplemented with either a 500-mg resveratrol or placebo capsule for 6 weeks. Serum inflammatory markers, activity of NF-kappaB in peripheral blood mononuclear cells (PBMC) and quality of life were assessed at baseline and at the end of the study. Resveratrol supplementation led to a significant reduction in plasma levels of TNF-alpha (19.70 +/- 12.80 to 17.20 +/- 10.09 pg/mL) and hs-CRP (4764.25 +/- 2260.48 to 2584.50 +/- 1792.80 ng/mL) and activity of NF-kappaB in PBMCs (0.19 +/ 0.05 to 0.10 +/- 0.04 OD) (p <0.001), whereas there were no significant changes of these factors in placebo group. Also, the score of inflammatory bowel disease questionnaire -9 (IBDQ-9) increased, whereas the clinical colitis activity index score decreased significantly in the resveratrol group (32.72 +/- 7.52 to 47.64 +/- 8.59) (p <0.001) and when compared with the placebo group (35.54 +/- 9.50 to 41.08 +/- 6.59) (p <0.001). CONCLUSION: Our results indicate that 6 weeks supplementation with 500 mg resveratrol can improve quality of life and disease clinical colitis activity at least partially through inflammation reduction in patients with UC. Whether these effects will be continued in longer duration of treatment remains to be determined. PMID- 26002727 TI - Mapping the functional network of medial prefrontal cortex by combining optogenetics and fMRI in awake rats. AB - The medial prefrontal cortex (mPFC) plays a critical role in multiple cognitive and limbic functions. Given its vital importance, investigating the function of individual mPFC circuits in animal models has provided critical insight into the neural basis underlying different behaviors and psychiatric conditions. However, our knowledge regarding the mPFC whole-brain network stays largely at the anatomical level, while the functional network of mPFC, which can be dynamic in different conditions or following manipulations, remains elusive especially in awake rodents. Here we combined optogenetic stimulation and functional magnetic resonance imaging (opto-fMRI) to reveal the network of brain regions functionally activated by mPFC outputs in awake rodents. Our data showed significant increases in blood-oxygenation-level dependent (BOLD) signals in prefrontal, striatal and limbic regions when mPFC was optically stimulated. This activation pattern was robust, reproducible, and did not depend on the stimulation period in awake rats. BOLD signals, however, were substantially reduced when animals were anesthetized. In addition, regional brain activation showing increased BOLD signals during mPFC stimulation was corroborated by electrophysiological recordings. These results expand the applicability of the opto-fMRI approach from sensorimotor processing to cognition-related networks in awake rodents. Importantly, it may help elucidate the circuit mechanisms underlying numerous mPFC-related functions and behaviors that need to be assessed in the awake state. PMID- 26002729 TI - Promoter hypermethylation of membrane type 3 matrix metalloproteinase is associated with cell migration in colorectal adenocarcinoma. AB - The gene MT3-MMP (also known as MMP16) encodes the membrane type 3 matrix metalloproteinase, which is a member of the matrix metalloproteinase (MMP) gene family. Several MMPs are associated with migration in colorectal cancer (CRC). However, the methylation status of the MT3-MMP promoter in CRC has not been reported. The methylation status and expression levels of MT3-MMP were investigated in primary tumor tissues and adjacent normal tissues in 105 patients with CRC, one normal colon cell line (CCD18Co), and three CRC cell lines (SW480, DLD-1, and LoVo) by quantitative methylation-specific PCR and real-time PCR. MT3 MMP was hypermethylated in 82 of 105 CRC tissues (78%), 30 of 105 adjacent normal tissues (29%), and two of 11 normal colon tissues (18%). MT3-MMP mRNA was significantly reduced in CRC compared with that in adjacent normal tissues (P < 0.05). The methylation-mediated downregulation of MT3-MMP was restored by treatment with 5-aza-2'-deoxycytidine in two CRC cell lines, and MT3-MMP promoter activity was significantly reduced by methylation. The knockdown of MT3-MMP induced cell migration, but overexpressed MT3-MMP reduced cell migration in CRC cells. These results demonstrate that the MT3-MMP promoter is frequently hypermethylated in CRC and that downregulation of MT3-MMP may be important for cell migration in CRC. PMID- 26002730 TI - Monooxygenase, peroxidase and peroxygenase properties and reaction mechanisms of cytochrome P450 enzymes. AB - This review examines the monooxygenase, peroxidase and peroxygenase properties and reaction mechanisms of cytochrome P450 (CYP) enzymes in bacterial, archaeal and mammalian systems. CYP enzymes catalyze monooxygenation reactions by inserting one oxygen atom from O2 into an enormous number and variety of substrates. The catalytic versatility of CYP stems from its ability to functionalize unactivated carbon-hydrogen (C-H) bonds of substrates through monooxygenation. The oxidative prowess of CYP in catalyzing monooxygenation reactions is attributed primarily to a porphyrin pi radical ferryl intermediate known as Compound I (CpdI) (Por*+FeIV=O), or its ferryl radical resonance form (FeIV-O*). CYP-mediated hydroxylations occur via a consensus H atom abstraction/oxygen rebound mechanism involving an initial abstraction by CpdI of a H atom from the substrate, generating a highly-reactive protonated Compound II (CpdII) intermediate (FeIV-OH) and a carbon-centered alkyl radical that rebounds onto the ferryl hydroxyl moiety to yield the hydroxylated substrate. CYP enzymes utilize hydroperoxides, peracids, perborate, percarbonate, periodate, chlorite, iodosobenzene and N-oxides as surrogate oxygen atom donors to oxygenate substrates via the shunt pathway in the absence of NAD(P)H/O2 and reduction oxidation (redox) auxiliary proteins. It has been difficult to isolate the historically elusive CpdI intermediate in the native NAD(P)H/O2-supported monooxygenase pathway and to determine its precise electronic structure and kinetic and physicochemical properties because of its high reactivity, unstable nature (t1/2~2 ms) and short life cycle, prompting suggestions for participation in monooxygenation reactions of alternative CYP iron-oxygen intermediates such as the ferric-peroxo anion species (FeIII-OO-), ferric-hydroperoxo species (FeIII OOH) and FeIII-(H2O2) complex. PMID- 26002731 TI - Oxidizing intermediates in P450 catalysis: a case for multiple oxidants. AB - Cytochrome P450 (P450 or CYP) catalysis involves the oxygenation of organic compounds via a series of catalytic intermediates, namely, the ferric-peroxo, ferric-hydroperoxo, Compound I (Cpd I) and FeIII-(H2O2) intermediates. Now that the structures of P450 enzymes have been well established, a major focus of current research in the P450 area has been unraveling the intimate details and activities of these reactive intermediates. The general consensus is that the Cpd I intermediate is the most reactive species in the reaction cycle, especially when the reaction involves hydrocarbon hydroxylation. Cpd I has recently been characterized experimentally. Other than Cpd I, there is a multitude of evidence, both experimental as well as theoretical, supporting the involvement of other intermediates in various types of oxidation reactions. The involvement of these multiple oxidants has been experimentally demonstrated using P450 active-site mutants in epoxidation, heteroatom oxidation and dealkylation reactions. In this chapter, we will review the P450 reaction cycle and each of the reactive intermediates to discuss their role in oxidation reactions. PMID- 26002733 TI - Acyl-Carbon Bond Cleaving Cytochrome P450 Enzymes: CYP17A1, CYP19A1 and CYP51A1. AB - Cytochrome P450 (P450 or CYP) enzymes in their resting state contain the heme iron in a high-spin FeIII state. Binding of a substrate to a P450 enzyme allows transfer of the first electron, producing a Fe(II) species that reacts with oxygen to generate a low-spin iron superoxide intermediate (FeIII-O-O*) ready to accept the second electron to produce an iron peroxy anion intermediate (a, FeIII O-O-). In classical monooxygenation reactions, the peroxy anion upon protonation fragments to form the reactive Compound I intermediate (Por*+FeIV=O), or its ferryl radical resonance form (FeIV-O*). However, when the substrate projects a carbonyl functionality, of the type b, at the active site as is the case for reactions catalyzed by CYP17A1, CYP19A1 and CYP51A1, the peroxy anion (FeIII-O-O ) is trapped, yielding a tetrahedral intermediate (c) that fragments to an acyl carbon cleavage product (d plus an acid). Analogous acyl-carbon cleavage reactions are also catalyzed by certain hepatic P450s and CYP125A1 from Mycobacterium tuberculosis. A further improvisation on the theme is provided by aldehyde deformylases that convert long-chain aliphatic aldehydes to hydrocarbons. CYP17A1 is involved in the biosynthesis of corticoids as well as androgens. The flux toward these two classes of hormones seems to be regulated by cytochrome b 5, at the level of the acyl-carbon cleavage reaction. It is this regulation of CYP17A1 that provides a safety mechanism, ensuring that during corticoid biosynthesis, which requires 17alpha-hydroxylation by CYP17A1, androgen formation is avoided (Fig. 4.1). PMID- 26002732 TI - Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions. AB - Cytochrome P450 3A4 (CYP3A4) is the major and most important drug-metabolizing enzyme in humans that oxidizes and clears over a half of all administered pharmaceuticals. This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions. Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs. In vivo, CYP3A4 inhibition could lead to undesired drug drug interactions and drug toxicity, a major reason for late-stage clinical failures and withdrawal of marketed pharmaceuticals. Owing to its central role in drug metabolism, many aspects of CYP3A4 catalysis have been extensively studied by various techniques. Here, we give an overview of experimental and theoretical methods currently used for investigation and prediction of CYP3A4-ligand interactions, a defining factor in drug metabolism, with an emphasis on the problems addressed and conclusions derived from the studies. PMID- 26002734 TI - Regioselective Versatility of Monooxygenase Reactions Catalyzed by CYP2B6 and CYP3A4: Examples with Single Substrates. AB - Hepatic microsomal cytochrome P450 (CYP) enzymes have broad and overlapping substrate specificity and catalyze a variety of monooxygenase reactions, including aliphatic and aromatic hydroxylations, N-hydroxylations, oxygenations of heteroatoms (N, S, P and I), alkene and arene epoxidations, dehalogenations, dehydrogenations and N-, O- and S-dealkylations. Individual CYP enzymes typically catalyze the oxidative metabolism of a common substrate in a regioselective and stereoselective manner. In addition, different CYP enzymes often utilize different monooxygenase reactions when oxidizing a common substrate. This review examines various oxidative reactions catalyzed by a CYP enzyme acting on a single substrate. In the first example, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a halogenated aromatic environmental contaminant, was oxidatively biotransformed by human CYP2B6. Nine different metabolites of BDE-47 were produced by CYP2B6 via monooxygenase reactions that included aromatic hydroxylation, with and without an NIH-shift, dealkylation and debromination. In the second example, lithocholic acid (3alpha-hydroxy-5beta-cholan-24-oic acid), an endogenous bile acid, served as a substrate for human CYP3A4 and yielded five different metabolites via aliphatic hydroxylation and dehydrogenation reactions. PMID- 26002735 TI - Cytochrome p450 enzymes in the bioactivation of polyunsaturated Fatty acids and their role in cardiovascular disease. AB - Various members of the cytochrome P450 (CYP) superfamily have the capacity of metabolizing omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs). In most mammalian tissues, CYP2C and CYP2J enzymes are the major PUFA epoxygenases, whereas CYP4A and CYP4F subfamily members function as PUFA hydroxylases. The individual CYP enzymes differ in their substrate specificities as well as regio- and stereoselectivities and thus produce distinct sets of epoxy and/or hydroxy metabolites, collectively termed CYP eicosanoids. Nutrition has a major impact on the endogenous CYP-eicosanoid profile. "Western diets" rich in n 6 PUFAs result in a predominance of arachidonic acid-derived metabolites, whereas marine foodstuffs rich in n-3 PUFAs shift the profile to eicosapentaenoic and docosahexaenoic acid-derived metabolites. In general, CYP eicosanoids are formed as second messengers of numerous hormones, growth factors and cytokines regulating cardiovascular and renal function, and a variety of other physiological processes. Imbalances in the formation of individual CYP eicosanoids are linked to the development of hypertension, myocardial infarction, maladaptive cardiac hypertrophy, acute kidney injury, stroke and inflammatory disorders. The underlying mechanisms are increasingly understood and may provide novel targets for the prevention and treatment of these disease states. Suitable pharmacological agents are under development and first proofs of concept have been obtained in animal models. PMID- 26002736 TI - Monooxygenation of small hydrocarbons catalyzed by bacterial cytochrome p450s. AB - Cytochrome P450s (P450s) catalyze the NAD(P)H/O2-dependent monooxygenation of less reactive organic molecules under mild conditions. The catalytic activity of bacterial P450s is very high compared with P450s isolated from animals and plants, and the substrate specificity of bacterial P450s is also very high. Accordingly, their catalytic activities toward nonnative substrates are generally low especially toward small hydrocarbons. However, mutagenesis approaches have been very successful for engineering bacterial P450s for the hydroxylation of small hydrocarbons. On the other hand, "decoy" molecules, whose structures are very similar to natural substrates, can be used to trick the substrate recognition of bacterial P450s, allowing the P450s to catalyze oxidation reactions of nonnative substrates without any substitution of amino acid residues in the presence of decoy molecules. Thus, the hydroxylation of small hydrocarbons such as ethane, propane, butane and benzene can be catalyzed by P450BM3, a long alkyl-chain hydroxylase, using substrate misrecognition of P450s induced by decoy molecules. Furthermore, a number of H2O2-dependent bacterial P450s can catalyze the peroxygenation of a variety of nonnative substrates through a simple substrate-misrecognition trick, in which catalytic activities and enantioselectivity are dependent on the structure of decoy molecules. PMID- 26002738 TI - Cytochrome p450 enzymes and electrochemistry: crosstalk with electrodes as redox partners and electron sources. AB - The functional significance of cytochrome P450 (P450) enzymes includes their ability to catalyze the biotransformation of xenobiotics (foreign compounds) and endogenous compounds. P450 enzymes play an important role in the detoxification of exogenous bioactive compounds and hydrophobic xenobiotics (e.g. carcinogens, drugs, environment pollutants, food supplements, medicines, plant products) and in the biotransformation of endogenous bioactive compounds (e.g. amino acids, cholesterol, eicosanoids, saturated/unsaturated fatty acids, melatonin, steroid hormones). Electrode/P450 systems are analyzed in terms of the mechanisms underlying P450-catalyzed reactions. Bioelectrocatalysis-based screening of potential substrates or inhibitors of P450 enzymes, the stoichiometry of the electrocatalytic cycle, oxidation-reduction (redox) thermodynamics, and the peroxide shunt pathway are described. Electrochemical techniques are utilized for investigating the influence of (1) the vitamin B group, (2) vitamins (e.g. vitamins A and B) and antioxidants (e.g. taurine), and (3) drugs and antioxidants (e.g. mexidol, ethoxidol) on biocatalysis using P450 enzymes, and on the metabolism of drugs catalyzed by P450 3A4. The characteristics, performance and potential applications of P450 electrochemical systems are also discussed. PMID- 26002737 TI - Use of chemical auxiliaries to control p450 enzymes for predictable oxidations at unactivated C-h bonds of substrates. AB - Cytochrome P450 enzymes (P450s) have the ability to oxidize unactivated C-H bonds of substrates with remarkable regio- and stereoselectivity. Comparable selectivity for chemical oxidizing agents is typically difficult to achieve. Hence, there is an interest in exploiting P450s as potential biocatalysts. Despite their impressive attributes, the current use of P450s as biocatalysts is limited. While bacterial P450 enzymes typically show higher activity, they tend to be highly selective for one or a few substrates. On the other hand, mammalian P450s, especially the drug-metabolizing enzymes, display astonishing substrate promiscuity. However, product prediction continues to be challenging. This review discusses the use of small molecules for controlling P450 substrate specificity and product selectivity. The focus will be on two approaches in the area: (1) the use of decoy molecules, and (2) the application of substrate engineering to control oxidation by the enzyme. PMID- 26002739 TI - Mechanistic basis of electron transfer to cytochromes p450 by natural redox partners and artificial donor constructs. AB - Cytochromes P450 (P450s) are hemoproteins catalyzing oxidative biotransformation of a vast array of natural and xenobiotic compounds. Reducing equivalents required for dioxygen cleavage and substrate hydroxylation originate from different redox partners including diflavin reductases, flavodoxins, ferredoxins and phthalate dioxygenase reductase (PDR)-type proteins. Accordingly, circumstantial analysis of structural and physicochemical features governing donor-acceptor recognition and electron transfer poses an intriguing challenge. Thus, conformational flexibility reflected by togging between closed and open states of solvent exposed patches on the redox components was shown to be instrumental to steered electron transmission. Here, the membrane-interactive tails of the P450 enzymes and donor proteins were recognized to be crucial to proper orientation toward each other of surface sites on the redox modules steering functional coupling. Also, mobile electron shuttling may come into play. While charge-pairing mechanisms are of primary importance in attraction and complexation of the redox partners, hydrophobic and van der Waals cohesion forces play a minor role in docking events. Due to catalytic plasticity of P450 enzymes, there is considerable promise in biotechnological applications. Here, deeper insight into the mechanistic basis of the redox machinery will permit optimization of redox processes via directed evolution and DNA shuffling. Thus, creation of hybrid systems by fusion of the modified heme domain of P450s with proteinaceous electron carriers helps obviate the tedious reconstitution procedure and induces novel activities. Also, P450-based amperometric biosensors may open new vistas in pharmaceutical and clinical implementation and environmental monitoring. PMID- 26002740 TI - Biological diversity of cytochrome P450 redox partner systems. AB - Cytochrome P450 enzymes (P450s or CYPs) catalyze an enormous variety of oxidative reactions in organisms from all major domains of life. Their monooxygenase activity relies on the reductive scission of molecular oxygen (O2) bound to P450 heme iron, and thus on the delivery of two electrons to the heme iron at discrete points in the catalytic cycle. Early studies suggested that P450 redox partner machinery fell into only two major classes: either the eukaryotic diflavin enzyme NADPH-cytochrome P450 oxidoreductase, or bacterial/mitochondrial NAD(P)H ferredoxin reductase and ferredoxin partners. However, more recent studies, aided by genome sequence data, reveal a much more complex scenario. Several new types of P450 redox partner systems have now been characterized, including P450s naturally linked to their redox partners, or to a component protein of their P450 electron delivery system. Other P450s have evolved to bypass requirements for redox partners, and instead react directly with hydrogen peroxide or NAD(P)H to facilitate oxidative or reductive catalysis. Further P450s are fused to non-redox partner enzymes and can catalyse consecutive reactions in a common pathway. This chapter describes the biochemistry and the enormous natural diversity of P450 redox systems, including descriptions of novel P450s fused to non-redox partner proteins. PMID- 26002741 TI - Cytochrome P450cin (CYP176A1). AB - Cytochrome P450cin (P450cin) (CYP176A1) is a bacterial P450 enzyme that catalyses the enantiospecific hydroxylation of 1,8-cineole to (1R)-6beta-hydroxycineole when reconstituted with its natural reduction-oxidation (redox) partner cindoxin, E. coli flavodoxin reductase, and NADPH as a source of electrons. This catalytic system has become a useful tool in the study of P450s as not only can large quantities of P450cin be prepared and rates of oxidation up to 1,500 min(-1) achieved, but it also displays a number of unusual characteristics. These include an asparagine residue in P450cin that has been found in place of the usual conserved threonine residue observed in most P450s. In general, this conserved threonine controls oxygen activation to create the potent ferryl (Fe(IV=O) porphyrin cation radical required for substrate oxidation. Another atypical characteristic of P450cin is that it utilises an FMN-containing redoxin (cindoxin) rather than a ferridoxin as is usually observed with other bacterial P450s (e.g. P450cam). This chapter will review what is currently known about P450cin and how this enzyme has provided a greater understanding of P450s in general. PMID- 26002742 TI - Fungal unspecific peroxygenases: heme-thiolate proteins that combine peroxidase and cytochrome p450 properties. AB - Eleven years ago, a secreted heme-thiolate peroxidase with promiscuity for oxygen transfer reactions was discovered in the basidiomycetous fungus, Agrocybe aegerita. The enzyme turned out to be a functional mono-peroxygenase that transferred an oxygen atom from hydrogen peroxide to diverse organic substrates (aromatics, heterocycles, linear and cyclic alkanes/alkenes, fatty acids, etc.). Later similar enzymes were found in other mushroom genera such as Coprinellus and Marasmius. Approximately one thousand putative peroxygenase sequences that form two large clusters can be found in genetic databases and fungal genomes, indicating the widespread occurrence of such enzymes in the whole fungal kingdom including all phyla of true fungi (Eumycota) and certain fungus-like heterokonts (Oomycota). This new enzyme type was classified as unspecific peroxygenase (UPO, EC 1.11.2.1) and placed in a separate peroxidase subclass. Furthermore, UPOs and related heme-thiolate peroxidases such as well-studied chloroperoxidase (CPO) represent a separate superfamily of heme proteins on the phylogenetic level. The reactions catalyzed by UPOs include hydroxylation, epoxidation, O- and N dealkylation, aromatization, sulfoxidation, N-oxygenation, dechlorination and halide oxidation. In many cases, the product patterns of UPOs resemble those of human cytochrome P450 (P450) monooxygenases and, in fact, combine the catalytic cycle of heme peroxidases with the "peroxide shunt" of P450s. Here, an overview on UPOs is provided with focus on their molecular and catalytic properties. PMID- 26002743 TI - Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery. AB - PURPOSE: We evaluated the role of a poly(ethylene glycol) (PEG) surface coating to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung. METHODS: Three sizes of PRINT hydrogel particles (80 * 320 nm, 1.5 and 6 MUm donuts) with and without a surface PEG coating were instilled in the airways of C57/b6 mice. At time points of 1, 7, and 28 days, BALF and whole lungs were evaluated for the inflammatory cytokine Il-6 and chemokine MIP-2, histopathology, cellular populations of macrophages, dendritic cells (DCs), and granulocytes, and particulate uptake within these cells through flow cytometry, ELISAs, and fluorescent imaging. RESULTS: Particles of all sizes and surface chemistries were readily observed in the lung with minimal inflammatory response at all time points. Surface modification with PEGylation was found to significantly increase lung residence times and homogeneous lung distribution, delaying macrophage clearance of all sizes, with the largest increase in residence time observed for 80 * 320 nm particles. Additionally, it was observed that DCs were recruited to the airway following administration of unPEGylated particles and preferentially associated with these particles. CONCLUSIONS: Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics. PMID- 26002744 TI - Characterization of Contents of Distal Ileum and Cecum to Which Drugs/Drug Products are Exposed During Bioavailability/Bioequivalence Studies in Healthy Adults. AB - PURPOSE: Characterize the contents of distal ileum and cecum in healthy adults under conditions simulating the bioavailability/bioequivelance studies of drug products in fasted and fed state. METHODS: Twelve males participated in a two phase crossover study. Phase I: subjects remained fasted overnight plus 4.5 h in the morning prior to colonoscopy. Phase II: subjects remained fasted overnight, consumed breakfast in the morning, and abstain from food until colonoscopy, 4.5 h after breakfast. Upon sampling, volume, pH and buffer capacity were measured; after ultracentrifugation, supernatant was physicochemically characterized and non-liquid particles diameter was measured. RESULTS: In distal ileum, pH is ~8.1 and size of non-liquid particles is ~200 MUm, regardless of dosing conditions; in fed state, liquid fraction was lower whereas osmolality and carbohydrate content were higher. In cecum, the environment was similar with previously characterized environment in the ascending colon; in fasted state, size of non-liquid particles is smaller than in distal ileum (~70 MUm). Fluid composition in distal ileum is different from cecum, especially in fasted state. CONCLUSION: Differences in luminal environment between distal ileum and cecum may impact the performance of orally administered products which deliver drug during residence in lower intestine. Dosing conditions affect cecal environment more than in distal ileum. PMID- 26002745 TI - Photosynthetic responses of trees in high-elevation forests: comparing evergreen species along an elevation gradient in the Central Andes. AB - Plant growth at extremely high elevations is constrained by high daily thermal amplitude, strong solar radiation and water scarcity. These conditions are particularly harsh in the tropics, where the highest elevation treelines occur. In this environment, the maintenance of a positive carbon balance involves protecting the photosynthetic apparatus and taking advantage of any climatically favourable periods. To characterize photoprotective mechanisms at such high elevations, and particularly to address the question of whether these mechanisms are the same as those previously described in woody plants along extratropical treelines, we have studied photosynthetic responses in Polylepis tarapacana Philippi in the central Andes (18 degrees S) along an elevational gradient from 4300 to 4900 m. For comparative purposes, this gradient has been complemented with a lower elevation site (3700 m) where another Polylepis species (P. rugulosa Bitter) occurs. During the daily cycle, two periods of photosynthetic activity were observed: one during the morning when, despite low temperatures, assimilation was high; and the second starting at noon when the stomata closed because of a rise in the vapour pressure deficit and thermal dissipation is prevalent over photosynthesis. From dawn to noon there was a decrease in the content of antenna pigments (chlorophyll b and neoxanthin), together with an increase in the content of xanthophyll cycle carotenoids. These results could be caused by a reduction in the antenna size along with an increase in photoprotection. Additionally, photoprotection was enhanced by a partial overnight retention of de-epoxized xanthophylls. The unique combination of all of these mechanisms made possible the efficient use of the favourable conditions during the morning while still providing enough protection for the rest of the day. This strategy differs completely from that of extratropical mountain trees, which uncouple light-harvesting and energy-use during long periods of unfavourable, winter conditions. PMID- 26002746 TI - Plant communities in harsh sites are less invaded: a summary of observations and proposed explanations. AB - Plant communities in abiotically stressful, or 'harsh', habitats have been reported to be less invaded by non-native species than those in more moderate habitats. Here, we synthesize descriptive and experimental evidence for low levels of invasion in habitats characterized by a variety of environmental stressors: low nitrogen; low phosphorus; saline, sodic or alkaline soils; serpentine soils; low soil moisture; shallow/rocky soils; temporary inundation; high shade; high elevation; and high latitude. We then discuss major categories of hypotheses to explain this pattern: the propagule limitation mechanism suggests invasion of harsh sites is limited by relatively low arrival rates of propagules compared with more moderate habitats, while invasion resistance mechanisms suggest that harsh habitats are inherently less invasible due to stressful abiotic conditions and/or increased effects of biotic resistance from resident organisms. Both propagule limitation and invasion resistance may simultaneously contribute to low invadedness of harsh sites, but the management implications of these mechanisms differ. If propagule limitation is more important, managers should focus on reducing the likelihood of propagule introductions. If invasion resistance mechanisms are in play, managers should focus on restoring or maintaining harsh conditions at a site to reduce invasibility. PMID- 26002748 TI - [Strategies to promote podiatric health, after 10 years]. PMID- 26002747 TI - Multiligamentous injuries and knee dislocations. AB - Complex capsular ligamentous structures contribute to stability of the knee joint. Simultaneous injury of two or more knee ligaments, aside from concurrent tears involving the anterior cruciate and medial collateral ligaments, is considered to be associated with femorotibial knee dislocations. Proximal tibiofibular joint dislocations are not always easily recognized and may be overlooked or missed. Patellofemoral dislocations can be transient with MR imaging sometimes required to reach the diagnosis. In this article, the authors describe the mechanism of injury, ligamentous disruptions, imaging, and treatment options of various types of knee dislocations including injuries of the femorotibial, proximal tibiofibular, and patellofemoral joints. PMID- 26002749 TI - [Perceptions of patients and health professionals about the quality of care provided to chronic obstructive pulmonary disease patients]. AB - OBJECTIVE: To explore the understanding and knowledge of patients and health professionals about factors that influence the quality of care provided in Primary Care to people with Chronic Obstructive Pulmonary Disease (COPD). DESIGN: Qualitative study performed between February and March 2010. LOCATION: Primary Care Centers. PARTICIPANTS: Medical and nursing professionals and patients with COPD. METHODS: Non-probabilistic intentional sampling with representation criterion of the discourse. Two group (focus group) and 6 individual interviews were performed. The interviews were recorded, literally transcribed and interpreted by social discourse analysis. RESULTS: Patients neither identify properly the symptomatology nor they assume the COPD importance until advanced states. The lacks of knowledge about the evolution of the disease and the impact on quality of life hinders the necessary changes. Professionals reports problems with performing spirometry. Among doctors, scepticism regarding to the effectiveness of the interventions aimed at change of behaviour is identified. The existence of Clinical Guides, the improvement of the coordination between professionals and the alignment of priorities between managers and professionals stand out as organizational factors. CONCLUSIONS: The identified factors suggest the possibility of improving the health care through improved communication to motivate them to take the recommended changes and to increase the adherence to treatments. To this effect, the awareness and training of professionals, the healthcare coordination, the implementation of Clinical Guides and the use of indicators in a process of quality assessment. PMID- 26002750 TI - [The experience of women care cargivers with chronic conditions of dependent relatives]. AB - OBJECTIVE: To describe the experience of women caregivers with chronic conditions who care for a dependent relative. DESIGN: Qualitative study based on constructivist grounded theory. LOCATION: Study conducted on two Health Areas urban of the Community of Madrid. PARTICIPANTS: Thirty nine women with a chronic condition who take care of dependent relatives were selected by means of purposive sampling. METHOD: Data were collected through 23 semi-structured interviews and 2 focus groups between April 2010 and December 2011. Grounded theory procedures were used in the data analysis. RESULTS: To feel their life hampered describes the subjective experience of family caregivers with chronic conditions who take care of a dependent relative. When comparing their past life with the current life they become aware of the losses they have suffered over time. They feel less strong, sadder and less free; they worry about how to meet the demands of family care. The life they are leading makes them question the meaning of their own lives. CONCLUSIONS: This study shows the losses realized day by day by women caregivers with a chronic illness, which lead them to lose the meaning of their own lives. To know the experience of these women caregivers will help develop interventions and specific services that compensate for the losses they feel and help improve their quality of living. PMID- 26002751 TI - Oncologic results and prognostic predictors of patients with locally advanced rectal cancer showing ypN0 after radical surgery following neoadjuvant chemoradiotherapy. AB - PURPOSE: Adjuvant chemotherapy is recommended for patients with locally advanced rectal cancer after radical surgery following neoadjuvant chemoradiotherapy (NCRT) regardless of the final pathologic stage. However, the efficacy of adjuvant chemotherapy in ypN0 patients remains controversial. The aim of this study was to evaluate the oncologic outcomes and analyze the prognostic factors for ypN0 patients in order to estimate prognosis and establish an effective adjuvant chemotherapy strategy for stage 0-II rectal cancers after radical surgery following NCRT. METHODS: Between January 1999 and December 2009, the medical records of 202 patients who had been diagnosed with locally advanced rectal cancer, underwent radical surgery following NCRT, and showed ypN0 were retrospectively reviewed. RESULTS: The median follow-up period was 60.5 months. The 5-year local recurrence rate was 3.1 %. The 5-year disease-free survival and 5-year overall survival were 86.3 and 86.9 %. Postirradiation T3-4 and abdominoperineal resection (APR) were the independent prognostic indicators for disease-free survival (p = 0.001, p = 0.003) and overall survival (p = 0.001, p = 0.002). Adjuvant chemotherapy improved local recurrence in the patient with ypT3 4 and patients who had undergone APR (p = 0.014, p = 0.002). APR affected local recurrence, disease-free survival, and overall survival of ypT3-4 patients (p = 0.013. 0.029, and 0.001) CONCLUSIONS: Postirradiation T3-4 and APR are the significant prognostic factors for ypN0. Further randomized prospective study is needed to evaluate the oncologic benefit of adjuvant chemotherapy in ypN0 patients, especially those with ypT3-4 and those having undergone APR, and to confirm which chemotherapeutic agent could improve the oncologic outcomes of patients poorly responding to NCRT. PMID- 26002752 TI - Prognostic factors for overall survival in metastatic colorectal cancer using a stop-and-go FLIRI-based treatment strategy. AB - PURPOSE: To determine overall survival and baseline prognostic variables in a cohort of patients with metastatic colorectal cancer receiving a FLIRI-based stop and-go treatment strategy. METHODS: Clinical information was collected from patient files in consecutive patients treated with palliative combination chemotherapy using a stop-and-go strategy from September 2007 until June 2011. The primary outcome was overall survival. Cox regression analysis was used to examine the effect of prognostic variables on survival. Baseline variables were performance status, primary tumor site, status of primary tumor (resected or unresected), synchronous metastases, >1 metastatic site, liver-only metastases, alkaline phosphatase (>300 U/l), lactate dehydrogenase (>300 U/l), platelets (>400 * 10(9)/l), and leucocytes (>10 * 10(9)/l). RESULTS: We included 314 patients (median age 64.5 (57-70) years). Median overall survival was 20.9 (95 % confidence interval (CI), 19.1-223.4) months with a median follow-up of 21.3 months (interquartile range (IQR) 13-34.8). Independent prognostic markers of decreased survival were PS 1 and 2 vs. 0 hazard ratio (HR) 1.47 (95 % CI 1.14 1.91, p = 0.003) and HR 2.06 (95 % CI 1.19-3.56, p = 0.01), colon as the primary tumor site HR 1.43 (95 % CI 1.09-1.88, p = 0.009), unresected primary tumor HR 2.22 (95 % CI 1.61-3.07, p < 0.001), and elevated leucocytes (>10 * 10(9)/l) HR 1.53 (95 % CI 1.12-2.09, p = 0.007). CONCLUSIONS: Overall survival in metastatic colorectal cancer using a FLIRI-based stop-and-go strategy in an unselected consecutive cohort proved comparable to RCTs from the same period. Baseline prognostic markers of poorer prognosis were PS 1 or 2, colon as primary tumor site, unresected primary tumor, and leucocytes >10 * 10(9)/l. These variables are all easy accessible in daily clinical practice. PMID- 26002753 TI - Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open label, single-arm nilotinib registration study. AB - PURPOSE: Activating KIT mutations are part of the pathogenesis of systemic mastocytosis (SM). Nilotinib is a tyrosine kinase inhibitor that potently inhibits activated forms of KIT. This phase 2, open-label, single-arm study (CAMN107A2101; www.clinicaltrials.gov NCT00109707) evaluated nilotinib in patients with SM. METHODS: Patients with SM [aggressive SM (ASM), indolent SM, or other] received nilotinib 400 mg twice daily. C-findings were collected retrospectively to assess response using criteria proposed after trial initiation. Response was evaluated using improvements in laboratory findings (for all patients) and ASM response criteria (for the ASM subgroup). RESULTS: In 61 patients enrolled, the median nilotinib exposure was 232 days (range 3-1274 days) with a median follow-up of 34.7 months. In patients with ASM (n = 37), the overall response rate was 21.6 %. In the eight responders, all of whom had a KIT D816V mutation at any time, mast cell infiltration and tryptase level decreased by 70 % and 29.8 %, respectively; absolute neutrophil count increased by 94.7 %. Laboratory parameters also improved in the non-ASM subgroups. Overall survival at 24 months was 81.2 % (95 % CI 70.6-91.8 %) with median survival not yet reached. New or worsening grade 3/4 hematologic adverse events (AEs) included thrombocytopenia (10.3 %), anemia (10.0 %), and neutropenia (6.9 %). The most common grade 3/4 nonhematologic drug-related AEs were diarrhea (6.6 %) and headache (4.9 %). Eleven patients (9 with ASM, 2 with MCL) died, 10 due to progressive disease; 7 deaths occurred >=28 days after treatment discontinuation. CONCLUSIONS: Nilotinib 400 mg twice daily was effective in some patients with SM, including patients with mutated KIT D816V. PMID- 26002755 TI - Early sensory processing in right hemispheric stroke patients with and without extinction. AB - While extinction is most commonly viewed as an attentional disorder and not as a consequence of a failure to process contralesional sensory information, it has been speculated that early sensory processing of contralesional targets in extinction patients might not be fully normal. We used a masked visuo-motor response priming paradigm to study the influence of both contralesional and ipsilesional peripheral subliminal prime stimuli on central target performance, allowing us to compare the strength of the early sensory processing associated with these prime stimuli between right brain damaged patients with and without extinction as well as healthy elderly subjects. We found that the effect of an informative subliminal prime in the left contralesional visual field on central target performance was significantly reduced in both right brain damaged patients with and without extinction. The results suggest that a low-level early sensory deterioration of the neural representation for contralesional prime stimuli is a general consequence of right hemispheric brain damage unrelated to the presence or absence of extinction. This suggests that the presence of a spatial bias against contralesional information is not sufficient to elicit extinction. For extinction to occur, this spatial bias might need to be accompanied by a pathological (non-directional) reduction of attentional capacity. PMID- 26002754 TI - Relations between social-perceptual ability in multi- and unisensory contexts, autonomic reactivity, and social functioning in individuals with Williams syndrome. AB - Compromised social-perceptual ability has been proposed to contribute to social dysfunction in neurodevelopmental disorders. While such impairments have been identified in Williams syndrome (WS), little is known about emotion processing in auditory and multisensory contexts. Employing a multidimensional approach, individuals with WS and typical development (TD) were tested for emotion identification across fearful, happy, and angry multisensory and unisensory face and voice stimuli. Autonomic responses were monitored in response to unimodal emotion. The WS group was administered an inventory of social functioning. Behaviorally, individuals with WS relative to TD demonstrated impaired processing of unimodal vocalizations and emotionally incongruent audiovisual compounds, reflecting a generalized deficit in social-auditory processing in WS. The TD group outperformed their counterparts with WS in identifying negative (fearful and angry) emotion, with similar between-group performance with happy stimuli. Mirroring this pattern, electrodermal activity (EDA) responses to the emotional content of the stimuli indicated that whereas those with WS showed the highest arousal to happy, and lowest arousal to fearful stimuli, the TD participants demonstrated the contrasting pattern. In WS, more normal social functioning was related to higher autonomic arousal to facial expressions. Implications for underlying neural architecture and emotional functions are discussed. PMID- 26002756 TI - Sensorimotor and cognitive involvement of the beta-gamma oscillation in the frontal N30 component of somatosensory evoked potentials. AB - The most consistent negative cortical component of somatosensory evoked potentials (SEPs), namely the frontal N30, can be considered more multidimensional than a strict item of standard somatosensory investigation, dedicated to tracking the afferent volley from the peripheral sensory nerve potentials to the primary somatosensory cortex. In this review, we revisited its classical sensorimotor implication within the framework of the recent oscillatory model of ongoing electroencephalogram (EEG) rhythms. Recently, the N30 component was demonstrated to be related to an increase in the power of beta-gamma EEG oscillation and a phase reorganization of the ongoing EEG oscillations (phase locking) in this frequency band. Thanks to high density EEG recordings and the inverse modeling method (swLORETA), it was shown that different overlapping areas of the motor and premotor cortex are specifically involved in generating the N30 in the form of a beta gamma oscillatory phase locking and power increase. This oscillatory approach has allowed a re-investigation of the movement gating behavior of the N30. It was demonstrated that the concomitant execution of finger movements by a stimulated hand impinges the temporal concentration of the ongoing beta/gamma EEG oscillations and abolished the N30 component. It was hypothesized that the involvement of neuronal populations in both the sensorimotor cortex and other related areas were unable to respond to the phasic sensory activation so could not phase-lock their oscillatory signals to the external sensory input during the movement. In this case, the actual movement has primacy over the artificial somatosensory input. The contribution of the ongoing oscillatory activity in the N30 emergence calls for a reappraisal of fundamental and clinical interpretations of the frontal N30 component. An absent or reduced amplitude of the N30 can now be viewed not only as a deficit in the activation of the somatosensory synaptic network in response to sensory input, but also as a global alteration of the beta-gamma ongoing oscillation and/or of the phase-locking mechanism itself. In addition, it has lately been shown that the N30 amplitude increases during the observation of another person's hand movement. A new paradigm in which the experimenter's hand movement, observed by the participant, triggered the electric stimulation of the subject's hand has been introduced. This has allowed the identification of different cortical areas which are closely related to those involved in the mirror neuron system. This contribution of N30 behavior has paved the way for future investigation of the integration of sensory input into cognitive context. PMID- 26002757 TI - Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer's disease. AB - OBJECTIVES: Furthering our understanding of the relationship between amyloidosis (Abeta), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD. METHODS: A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Abeta-/ND-), Stage 1 (Abeta+/ND-), Stage 2 (Abeta+/ND+), and suspected non-Alzheimer's associated pathology (SNAP; Abeta /ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT). RESULTS: Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed. CONCLUSIONS: Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design. PMID- 26002759 TI - Characterization of the painful restless legs syndrome. PMID- 26002758 TI - Habitual sleep variability, not sleep duration, is associated with caloric intake in adolescents. AB - OBJECTIVE: The objective of this study was to investigate the associations between objectively measured habitual sleep duration (HSD), habitual sleep variability (HSV), and energy and snack intake in adolescents. METHODS: We used data from 324 adolescents who participated in the Penn State Child Cohort follow up examination. Actigraphy was used over seven consecutive nights to estimate nightly sleep duration. The seven-night mean and standard deviation of sleep duration were used to represent HSD and HSV, respectively. The Youth/Adolescent Food Frequency Questionnaire was used to obtain the daily average total energy, protein, fat, and carbohydrate intake, and number of snacks consumed. Linear regression models were used to investigate the associations between habitual sleep patterns and caloric, protein, fat, and carbohydrate intake. Proportional odds models were used to associate habitual sleep patterns with snack consumption. RESULTS: After adjusting for age, sex, race, body mass index (BMI) percentile, and smoking status, an increased HSV was associated with a higher energy intake, particularly from fat and carbohydrate. For example, with a 1-h increase in HSV, there was a 170 (66)-kcal increase in the daily total energy intake. An increased HSV was also related to increased snack consumption, especially snacks consumed after dinner. For instance, a 1-h increase in HSV was associated with 65% and 94% higher odds of consuming more snacks after dinner during school/workdays and weekends/vacation days, respectively. Neither energy intake nor snack consumption was significantly related to HSD. CONCLUSION: High habitual sleep variability, not habitual sleep duration, is related to increased energy and food consumption in adolescents. Maintaining a regular sleep pattern may decrease the risk of obesity in adolescents. PMID- 26002760 TI - Caregiver perception of sleep-disordered breathing-associated symptoms in children of rural Andean communities above 4000 masl with chronic exposure to biomass fuel. AB - BACKGROUND: Previous studies have uncovered a very high prevalence of sleep disorders in general, and of sleep-disordered breathing in particular among children exposed to indoor biomass fuel pollution. However, despite the significant symptomatology, parents are unlikely to report these issues during health-care visits. OBJECTIVE: The objective of this study was to determine whether reduced caregiver perception of sleep disorders may account for the infrequent diagnosis and treatment of such problems in children residing at high altitudes and exposed to high biomass pollution. METHODS: Parents of children aged 9-15 years of three communities residing in the Pasco region in Peru located between 3800 and 4200 meters above sea level were surveyed using a validated questionnaire instrument focused on symptoms associated with sleep-disordered breathing as well as whether caregivers perceived that their child suffered from a sleep disorder. RESULTS: Among the 77 children included, 48.1% had nocturnal awakenings and 46.8% had repetitive movements and restless sleep. Habitual snoring was present in 33.8% of all children. However, only 10.4% of mothers considered that their children had sleep problems, and all of their children had positive answers for >=4 sleep symptoms. CONCLUSIONS: Children residing at high altitudes and exposed to traditional biomass-fueled stoves exhibit an extremely high frequency of sleep symptoms that are misperceived by their mothers as being "normal." Interventions aimed at increasing parental recognition and awareness of sleep problems will be essential to foster improved diagnosis and treatment. PMID- 26002761 TI - Daytime symptoms of restless legs syndrome--clinical characteristics and rotigotine effectiveness. AB - OBJECTIVE: To elucidate the prevalence and clinical characteristics of daytime restless legs syndrome (RLS) among patients with idiopathic RLS and investigate the effectiveness of rotigotine for daytime RLS. METHODS: In 256 enrolled RLS patients, we investigated factors associated with the presence of RLS symptoms throughout the day. We also assessed the duration of daytime RLS symptoms at hourly intervals, time of initial symptom onset during the day, and associations between duration of daytime and nighttime RLS symptoms. In addition, we compared changes in duration and frequency of RLS symptoms during daytime and nighttime after randomly assigning patients to a 13-week treatment with rotigotine, a dopamine agonist patch with 24-hour action, or placebo. RESULTS: Eighty-one (31.6%) patients had daytime RLS symptoms. Only the International Restless Legs Syndrome Study Group rating scale total score was significantly associated with the presence of daytime RLS symptoms (p < 0.01) on multiple logistic regression analysis. Daytime RLS symptom onset was at 6 a.m. in 44.4% of patients; symptom duration increased significantly toward nighttime. There was a significant positive association between duration of daytime and nighttime RLS symptoms (p < 0.0001) and a greater statistically significant reduction of daytime RLS symptom duration with rotigotine treatment than with placebo (p = 0.03). CONCLUSIONS: Daytime symptoms are frequent in patients with RLS and may be associated with increased severity of the disorder and prolonged nighttime RLS symptoms. Rotigotine could become an important treatment choice for daytime symptoms. PMID- 26002763 TI - Meditation has stronger relationships with mindfulness, kundalini, and mystical experiences than yoga or prayer. AB - Contemplative practices can have profound effects on mindfulness and on physical and sensory and mystical experiences. Individuals who self-reported meditation, yoga, contemplative prayer, or a combination of practices and their patterns of practice were compared for mindfulness, kundalini effects, and mystical experiences. The results suggest that the amount of practice but not the pattern and social conditions of practice influences mindfulness and possibly mystical experiences. Meditation, yoga, contemplative prayer, or a combination of practices all were found to be associated with enhancements of mindfulness, kundalini effects, and mystical experiences, but meditation had particularly strong associations and may be the basis of the associations of yoga and prayer with these outcomes. The results further suggest that the primary association of contemplative practices is with the real time awareness and appreciation of sensory and perceptual experiences which may be the intermediary between disparate practices and mindfulness, kundalini effects, and mystical experiences. PMID- 26002762 TI - Tumor-induced loss of mural Connexin 43 gap junction activity promotes endothelial proliferation. AB - BACKGROUND: Proper functional association between mural cells and endothelial cells (EC) causes EC of blood vessels to become quiescent. Mural cells on tumor vessels exhibit decreased attachment to EC, which allows vessels to be unstable and proliferative. The mechanisms by which tumors prevent proper association between mural cells and EC are not well understood. Since gap junctions (GJ) play an important role in cell-cell contact and communication, we investigated whether loss of GJ plays a role in tumor-induced mural cell dissociation. METHODS: Mural cell regulation of endothelial proliferation was assessed by direct co-culture assays of fluorescently labeled cells quantified by flow cytometry or plate reader. Gap junction function was assessed by parachute assay. Connexin 43 (Cx43) protein in mural cells exposed to conditioned media from cancer cells was assessed by Western and confocal microscopy; mRNA levels were assessed by quantitative real-time PCR. Expression vectors or siRNA were utilized to overexpress or knock down Cx43. Tumor growth and angiogenesis was assessed in mouse hosts deficient for Cx43. RESULTS: Using parachute dye transfer assay, we demonstrate that media conditioned by MDA-MB-231 breast cancer cells diminishes GJ communication between mural cells (vascular smooth muscle cells, vSMC) and EC. Both protein and mRNA of the GJ component Connexin 43 (Cx43) are downregulated in mural cells by tumor-conditioned media; media from non-tumorigenic MCF10A cells had no effect. Loss of GJ communication by Cx43 siRNA knockdown, treatment with blocking peptide, or exposure to tumor-conditioned media diminishes the ability of mural cells to inhibit EC proliferation in co-culture assays, while overexpression of Cx43 in vSMC restores GJ and endothelial inhibition. Breast tumor cells implanted into mice heterozygous for Cx43 show no changes in tumor growth, but exhibit significantly increased tumor vascularization determined by CD31 staining, along with decreased mural cell support detected by NG2 staining. CONCLUSIONS: Our data indicate that i) functional Cx43 is required for mural cell induced endothelial quiescence, and ii) downregulation of Cx43 GJ by tumors frees endothelium to respond to angiogenic cues. These data define a novel and important role for maintained Cx43 function in regulation of vessel quiescence, and suggest its loss may contribute to pathological tumor angiogenesis. PMID- 26002764 TI - Pupil dilation patterns reflect the contents of consciousness. AB - The study of human consciousness has historically depended on introspection. However, introspection is constrained by what can be remembered and verbalized. Here, we demonstrate the utility of high temporal resolution pupillometry to track the locus of conscious attention dynamically, over a single trial. While eye-tracked, participants heard several musical clips played diotically (same music in each ear) and, later, dichotically (two clips played simultaneously, one in each ear). During dichotic presentation, participants attended to only one ear. We found that the temporal pattern of pupil dilation dynamics over a single trial discriminated which piece of music was consciously attended on dichotic trials. Deconvolving these pupillary responses further revealed the real-time changes in stimulus salience motivating pupil dilation. Taken together, these results show that pupil dilation patterns during single-exposure to dynamic stimuli can be exploited to discern the contents of conscious attention. PMID- 26002765 TI - Anti-nociceptive activity of the crude extract of Myrianthus arboreus P. Beauv (Cecropiaceae) in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Myrianthus arboreus P. Beauv (Cecropiaceae) is a shrub or a tree plant widely distributed in Tropical Africa. In the South Eastern part of Nigeria, the leaves are used in traditional medicine as an analgesic for muscular pains, and also as an enema to relieve pain in the back and loins. Although no scientific study has been performed to validate its traditional use in pain management, this study therefore aims at investigating the anti nociceptive activity of M. arboreus leaves extract in mice. MATERIALS AND METHODS: Anti-nociceptive activity of M. arboreus was investigated using acetic acid induced writhing, formalin induced paw licks, hot plate, and tail flick tests. Acute toxicity was determined using a slightly modified Lorkes method. RESULTS: The extract of M. arboreus produced a significant dose-dependent [F (4, 20)=13.48 p<0.001] inhibition of abdominal writhings induced by acetic acid. In the formalin paw licking test, it produced a significant dose-dependent inhibition of neurogenic and inflammatory pain [F (4, 17.5)=60.13 p<0.001]. It also produced a significant dose dependent [F (4, 20)=30.5 p<0.001; F (4, 20)=0.321 p<0.0001] prolongation of the latency and reaction time in the hot plate and tail immersion tests. Peak effect was observed at the highest dose (40 mg/kg). LD50 of the plant was found to be 894 mg/kg. CONCLUSION: M. arboreus possesses potent antinociceptive activity mediated centrally and peripherally, an effect which may justify its traditional use in the management of pain. PMID- 26002766 TI - A quantitative ethnozoological study of traditionally used animals in Pachamalai hills of Tamil Nadu, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The purpose of this study was designed to gather primary folk knowledge on different animal based therapies used by Malayalis in Pachamalai hills. This is the first ethnozoological study in Pachamalai hills; the data regarding the medicinal animals/animal products were documented and their usages were analyzed quantitatively. METHODS: Data was collected following the interviews from key informants (N=89) and reported diseases and health complications were classified in 18 categories. Seven quantitative indexes such as informant consensus factor (FIC), fidelity level (FL), relative frequency of citation (RFC), relative importance (RI), cultural importance index (CII), index of agreement on remedies (IAR) and cultural agreement index (CAI) were used to analyze the reported animal species. RESULTS: A total of 46 animal species belonging to 8 taxonomic groups were documented to be used in traditional medicine by Malayalis in Pachamalai hills. Animal based medicines were prepared from whole animals or their body parts or products extracted from them such as: butter, meat, milk, bones, horn, musk, skin, fin, honey, mucus, eggs, urine, excreta, hair and legs. The most encountered taxonomic group was Mammalia having 14 species. Aphrodisiac ailments (AA) (0.99), Dental care ailments (DCA) (0.99), Endocrinal disorders ailments (EDA) (0.99), Hair care ailments (HCA) (0.99), Oncology ailments (OA) (0.99) and Ortho ailments (ORTA) (0.99) gained the highest FIC value. Sus scrofa domesticus scored the highest FL (100%) for the Skeleto muscular ailments for external cause; Lissemys punctata had the highest RI value (2.00) due to its versatility and the highest frequency of citation (RFC=1.000). Gallus domesticus had the highest cultural importance (CII=8.538) and the highest CAI value (CAI=8.427). According to IAR, Plexippus paykulli (IAR=1.00), Equus ferrus caballus (IAR=1.00), Trachypithecus johnii (IAR=1.00), Oecophylla samaragdina (IAR=1.00) and Apis indica (0.990) had the highest agreement among the informants for being used for the same medicinal purpose. Furthermore, no side effects have been reported from the use of ABT. CONCLUSIONS: Our study revealed that Malayalis (Pachamalai hills) possess valuable knowledge on Malayalis' animal based therapies. It is believed that the present documentation will serve to record this vanishing knowledge before it is eroded completely from the island and to the scientific community. It is also anticipated that the present documentation will be fundamental to protect traditional knowledge, for the conservation and sustainable use of the rich biodiversity of Pachamalai hills for future generations and to ensure Pachamalai hills' sovereign rights over its genetic resources and utilization by first documenting them. In addition, further experimental investigations are required to elucidate the pharmacological properties of the reported medicinal fauna of Pachmalai hills. PMID- 26002767 TI - The significant inhibition on CYP3A caused by radix Aconiti single herb is not observed in the Wutou decoction: The necessity of combination therapy of radix Aconiti. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Wutou (WT, Radix Aconiti), the mother root of Aconitum carmichaelii Debx., is a famous Chinese herb against rheumatoid arthritis. In Chinese clinics, PWT is often prepared as a decoction in combination with other herbs, such as Wutou decoction (WTD). The present study aimed to compare the effects of PWT single herb and WTD on CYP3A activity ex vivo and in vivo. MATERIALS AND METHODS: In the ex vivo study, CYP3A activity was determined by using testosterone (Tes) as a specific probe. Levels of Tes and its metabolite 6beta-hydroxytestosterone (6beta-OH-Tes) were measured using a validated ultra-performance liquid chromatography (UPLC) method. CYP3A protein and mRNA levels were measured by using Western blot and real-time PCR, respectively. In the in vivo study, CYP3A activity was determined by using buspirone (BP) as a specific probe. The plasma concentrations of BP and its primary metabolites, namely, 1-(2-pyrimidinyl) piperazine (1-PP) and 6' hydroxybuspirone (6'-OH-BP), were determined using a validated UPLC-tandem mass spectrometry (UPLC/MS/MS) method. RESULTS: Compared with the control group, the formation rates of 6beta-OH-Tes from Tes ex vivo significantly decreased in groups treated with PWT at the tested doses, and this decrease was accompanied by a striking decrease in CYP3A protein and mRNA levels. However, a significant increase was observed in the ratios in the WTD groups compared with PWT single herb groups. In vivo, both formation ratios of 6'-OH-BP and 1-PP from BP showed no significant change in the WTD group. CONCLUSIONS: PWT can significantly inhibit CYP3A activity ex vivo at the tested doses because of the down-regulation of CYP3A protein and mRNA expression levels. WTD can significantly reverse the inhibition caused by PWT. WTD also had no significant effect on CYP3A activity in vivo. Results implied that the use of PWT as a part of the WTD prescription rather than PWT single herb is more appropriate in clinics. PMID- 26002768 TI - Antiplasmodial potential of traditional antimalarial phytotherapy remedies used by the Kwale community of the Kenyan Coast. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Kenya, 22 million people are at risk of malaria, 70% of them are in rural areas and most of these people use traditional plant based medicines to treat malaria. The aim of the study was to escalate documentation, from an earlier study of medicinal plants, traditionally used to treat malaria by the Digo community of Kwale County, taking cognizance of their pharmacological information by evaluating their antiplasmodial efficacies. MATERIALS AND METHODS: The study was carried out in Kwale County at Shimba Hills Game Reserve and adjoining part of Kinango. Traditional health practitioners (THP) were interviewed with a standard questionnaire to obtain information on medicinal plants traditionally used for management of malaria. Group interviews were also held among THPs and members of the community. The plant samples collected were tested for antiplasmodial activity against chloroquine sensitive (D6) and resistant (W2) Plasmodium falciparum using the ability of extracts, prepared from the plant species, to inhibit the incorporation of [G-3H] hypoxanthine into the malaria parasites. RESULTS: Fifty seven (57) species in forty eight (48) genera and thirty (30) families were documented and evaluated for in vitro antiplasmodial activity. Apocynaceae, Euphorbiaceae, and Rubiaceae families had each about 12% of the plant species reported as antimalarial remedy and represented the species that are most commonly used. Twelve species (21.1%) showed antiplasmodial efficacy of IC50<5ug/ml and these were Boscia salicifolia, Cissampelos mucronata, Clerodendrum myricoides, Commiphora schimperi, Flueggea virosa, Maytenus undata, Maytenus senegalensis, Maytenus putterlickioides, Vernonia amygdalina, Warburgia stuhlmannii, Zanthoxylum chalybeum and Tabernaemontana pachysiphon. CONCLUSIONS: These results seem to indicate that ethnopharmacological inquiry used in search for new herbal remedies as predictive and could form the basis of an ethnopharmacopoeia and search for new active principles. This is the first report on traditional use of T. pachysiphon for malaria and its antiplasmodial activity. PMID- 26002769 TI - Ethnoveterinary medicinal plant knowledge and practice among the tribal communities of Thakht-e-Sulaiman hills, west Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pastoralist tribal communities inhabit Thakht-e Sulaiman hills since centuries. In this remote and geographically isolated area, local people mainly rely on their natural environment for ethnoveterinary care. The area is therefore of special interest for the documentation and analysis of ethnoveterinary plant use and efficacy. MATERIALS AND METHODS: Field work was conducted from 2010-2012 and 86 informants were interviewed. First, detailed unstructured interviews and group discussions were done with key informants, and second, successive oral freelisting and semi-structured interviews were performed. The veterinary diseases as described by the informants were categorized according to the symptoms they cause and the organs they affect. Information on the cited plants, informant consensus factor (ICF) and fidelity level (FL) were calculated based on use reports. RESULTS: A total of 22 ethnoveterinary medicinal plant species, belonging to 21 genera and 20 families with 559 use reports were recorded from two different ecological zones. More species were documented from the foothills but total use reports were higher for mountain species. Mainly leaves are used to prepare decoctions which are administered orally. Most use reports concerned skeleto-muscular problems followed by gastrointestinal ailments, but ritual uses and dermatological illnesses got highest ICF. Most often cited species were Pinus gerardina, P. wallichiana and Daphne papyracea while highest FL was obtained for Salix tetrasperma, Berberis calliobotrys and Litsea monopetala. Interestingly, 50% of the species have the same or similar use for humans. CONCLUSION: According to the local people, the most often mentioned species have high medicinal potential. They show a wide acceptance, broad application, multiple ways of preparation and administration. There is a need to conserve the knowledge of medicinal plant use in the Thakht-e-Sulaiman hills for future generations and to incorporate it into existing livestock health care services. PMID- 26002771 TI - Engaging the citizenship of the homeless-a qualitative study of specialist primary care providers. AB - BACKGROUND: Homeless patients have complex health needs. They also often describe difficulty accessing and maintaining access to clinical services. Although engagement with health care has been explored from the patient perspective, little is known about how health care professionals conceptualize, assess and promote engagement with health care among homeless persons. AIM: To examine how health professionals working in services for homeless persons view their patients' engagement with health care and explore how these views influence their practice. METHODS: Semi-structured phone interviews were conducted with health professionals who had experience working with homeless patients. Purposive sampling aimed to cover a range of location, practice type and duration of professional experience. Thematic analysis was undertaken on interview transcripts. RESULTS: Thirteen interviews were conducted. Four themes were explored relating to engagement of homeless persons with health care: (i) systematic barriers to engagement; (ii) difficulties engaging with professionals; (iii) system approaches to facilitate engagement and (iv) relationship approaches to facilitate engagement. In addition, a fifth theme emerged relating to the interaction between practices and networks of homeless persons in which practices were perceived as a key resource for a citizenship of the homeless. CONCLUSION: Primary care practices providing services for homeless people aim to promote engagement with health care by maximizing flexibility and fostering relationships between patients and the clinical team. In doing so they produce a paradox, whereby they function as a key hub within a citizenship of homeless persons while simultaneously aiming to help people move out of homelessness into a more settled state. PMID- 26002770 TI - A randomised controlled trial of low-dose aspirin for the prevention of fractures in healthy older people: protocol for the ASPREE-Fracture substudy. AB - BACKGROUND: Disability, mortality and healthcare burden from fractures in older people is a growing problem worldwide. Observational studies suggest that aspirin may reduce fracture risk. While these studies provide room for optimism, randomised controlled trials are needed. This paper describes the rationale and design of the ASPirin in Reducing Events in the Elderly (ASPREE)-Fracture substudy, which aims to determine whether daily low-dose aspirin decreases fracture risk in healthy older people. METHODS: ASPREE is a double-blind, randomised, placebo-controlled primary prevention trial designed to assess whether daily active treatment using low-dose aspirin extends the duration of disability-free and dementia-free life in 19 000 healthy older people recruited from Australian and US community settings. This substudy extends the ASPREE trial data collection to determine the effect of daily low-dose aspirin on fracture and fall-related hospital presentation risk in the 16 500 ASPREE participants aged >=70 years recruited in Australia. The intervention is a once daily dose of enteric-coated aspirin (100 mg) versus a matching placebo, randomised on a 1:1 basis. The primary outcome for this substudy is the occurrence of any fracture vertebral, hip and non-vert-non-hip-occurring post randomisation. Fall-related hospital presentations are a secondary outcome. DISCUSSION: This substudy will determine whether a widely available, simple and inexpensive health intervention aspirin-reduces the risk of fractures in older Australians. If it is demonstrated to safely reduce the risk of fractures and serious falls, it is possible that aspirin might provide a means of fracture prevention. TRIAL REGISTRATION NUMBER: The protocol for this substudy is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000347561). PMID- 26002772 TI - Parental views on childhood vaccination against viral gastroenteritis-a qualitative interview study. AB - BACKGROUND: Gastroenteritis (GE) causes significant morbidity, especially in young children. A vaccine against rotavirus, a common cause of viral GE (vGE), was added to the childhood immunization schedule in the UK in July 2013 and further related vaccines are under development. AIM: To explore parents' beliefs about vGE and their attitudes towards vaccinating. DESIGN AND SETTING: Qualitative interview study with parents of children who had recently experienced an episode of GE. METHOD: Twenty-eight semi-structured interviews were conducted over the phone with parents. Interviews were audio-recorded, transcribed and analysed using standard thematic approaches. RESULTS: Parents varied in their perception of the threat posed by GE, and parents who did not perceive GE as serious were less enthusiastic about vaccines. Other parents were supportive of vaccines in general and considered benefits to their child, their family and the wider community. Many parents said that they lacked knowledge about efficacy and effectiveness of GE vaccines but their underlying belief about the seriousness of illness motivated their attitudes. CONCLUSION: Acceptability of GE vaccines to parents could be improved by providing more information on both the burden of illness and the impact of rotavirus vaccine in other comparable countries. PMID- 26002773 TI - Enrichment of circulating tumor cells in tumor-bearing mouse blood by a deterministic lateral displacement microfluidic device. AB - Concentration of real tumor cells leaking into blood from cancer was attempted by a deterministic lateral displacement (DLD) microfluidic device. Spiked cultured cell line tumor cells are often used to verify performance of the circulating tumor cells (CTCs) separation methods. Cultured tumor cells are obviously larger than most of hematocytes and considered not to be appropriate as CTC mimics, while there is uncertainty in identifying real CTCs from clinical samples and there is no practical way to examine CTCs leakage into benign cells during the sorting. In this work, blood samples were prepared from tumor-bearing mice whose tumors were induced by implanting cells with GFP expression to living mice. Therefore, CTCs were identified by their fluorescence emission. We succeeded in the enrichment of tumor cells to 0.05% from the blood, in which CTCs were negligibly detected among three million blood cells, and little loss of CTCs was observed. PMID- 26002774 TI - A microfluidic cell culture device (MUFCCD) to culture epithelial cells with physiological and morphological properties that mimic those of the human intestine. AB - Physiological and morphological properties of the human intestine cannot be accurately mimicked in conventional culture devices such as well plates and petri dishes where intestinal epithelial cells form a monolayer with loose contacts among cells. Here, we report a novel microfluidic cell culture device (MUFCCD) that can be used to culture cells as a human intestinal model. This device enables intestinal epithelial cells (Caco-2) to grow three-dimensionally on a porous membrane coated with fibronectin between two polydimethylsiloxane (PDMS) layers. Within 3 days, Caco-2 cells cultured in the MUFCCD formed villi- and crypt-like structures with small intercellular spaces, while individual cells were tightly connected to one another through the expression of the tight junction protein occludin, and were covered with a secreted mucin, MUC-2. Caco-2 cells cultured in the MUFCCD for 3 days were less susceptible to bacterial attack than those cultured in transwell plates for 21 days. MUFCCD-cultured Caco-2 cells also displayed physiologically relevant absorption and paracellular transport properties. These results suggest that our intestinal model more accurately mimics the morphological and physiological properties of the intestine in vivo than the conventional transwell culture model. PMID- 26002775 TI - Uncrossed epileptic seizures in Joubert syndrome. AB - Joubert syndrome and related disorders comprise a subgroup of ciliopathies defined by the presence of the 'molar tooth sign', a midbrain-hindbrain malformation identifiable by neuroimaging. Characteristically, the corticospinal tract and superior cerebellar peduncles do not decussate. Epileptic seizures are uncommon. We present a case of a 28-year-old man with a background of Leber's congenital amaurosis with nephronophthisis, requiring kidney transplantation, and mental retardation, who developed epileptic seizures consisting of a short muffled cry and involuntary shaking movements of the extremities beginning in the left upper limb; these episodes lasted several seconds and occurred in clusters. Simultaneous video-EEG recording showed an ictal pattern in the left frontal lobe. Brain MRI revealed the pathognomonic 'molar tooth sign'; diffusion tensor imaging (DTI)-tractography showed a lack of decussation of both corticospinal tracts. To the best of our knowledge, this is the first time that DTI tractography has been used to uncover the anatomical substrate underlying the semiology of epileptic seizures. PMID- 26002776 TI - Autoantibody-associated congenital heart block: a rare cause of persistent fetal bradycardia. AB - Persistent fetal bradycardia in early pregnancy is a rare finding and indicates towards congenital heart block. This is commonly associated with positive maternal anti-Ro/anti-La antibodies. A case of an asymptomatic primigravida with persistent fetal bradycardia on routine antenatal ultrasound is reported with special emphasis on its management options. PMID- 26002777 TI - Acute myocardial infarction due to simultaneous occlusions of the left anterior descending artery and right coronary artery. PMID- 26002778 TI - End-to-side "loop" graft for total facial nerve reconstruction: Over 10 years experience. AB - BACKGROUND: Multiple-branch reconstruction is required in order to attain facial reanimation for extensive facial nerve defects. We previously reported that end to-side nerve grafting, with the use of a single nerve graft for defect reconstruction, was easy to perform. We have also demonstrated the efficacy of end-to-side nerve suture of the recipient nerve to the donor graft nerve, in experimental rat models and clinical cases. The regenerating axons, which extended into the nerve graft, were "distributed" to multiple recipient nerves via end-to-side nerve-suture sites. METHODS: Thirty-two patients who underwent facial nerve reconstruction (five to 10 branches) had a single sural nerve graft coapted to the proximal stump of the facial nerve in an end-to-end manner, followed by end-to-side nerve suture of the recipient nerve stumps to the side of the nerve graft. In 19 patients who were expected to undergo postoperative radiotherapy and/or chemotherapy, the distal end of the graft was connected to the side of the hypoglossal nerve for "axonal supercharging," to enhance the recovery of the facial muscles. RESULTS: Initial facial movements were noted at 5 12 months postoperatively, and good recovery (House-Brackmann grade III/IV) was observed during long-term follow-up in most patients. CONCLUSION: End-to-side nerve suture of the recipient nerve stumps to the nerve graft requires less graft nerve material and less technical mastery to reconstruct multiple branches of the facial nerve. We also described the concept of "axonal supercharging," namely the connection of double-donor neural sources to the graft, and "axonal distribution," namely the reinnervation of multiple recipient nerve stumps connected to the graft in an end-to-side manner. This combination of axonal supercharging and distribution can be a useful option in facial nerve reconstruction. PMID- 26002779 TI - Reconstruction of a large soft-tissue defect in the single finger using the modified cross-finger flap. AB - BACKGROUND: Providing soft-tissue coverage for a large defect in the single finger presents marked functional and aesthetic challenges. This article describes the reconstruction of such injuries using a modified cross-finger flap, and it reports the results of the use of the flap. METHODS: Over 5 years, a retrospective study was conducted with 22 patients who had a large defect in the single finger. The mean size of soft-tissue defects was 4.3 +/- 0.4 cm in length and 1.8 +/- 0.4 cm in width. The defects were reconstructed with a modified cross finger flap. RESULTS: Full-flap survival was achieved in 20 fingers. Partial distal-flap necrosis occurred in two fingers, which healed without surgical intervention. We collected the data of the sensory restoration in 20 flaps where sensory return was considered important. Based on the modified American Society for Surgery of the Hand guidelines for the stratification of a two-point discrimination (2PD), 17 (85%) flaps achieved excellent and good results and only three (15%) flaps obtained fair result. No significant difference was found in joint motion between the donor finger and the contralateral side. According to the Michigan Hand Outcomes Questionnaire, 11 patients were satisfied, nine were somewhat satisfied and two were neither satisfied nor dissatisfied with the functional recovery of the reconstructed finger. CONCLUSIONS: The modified cross finger flap is versatile and useful for the coverage of the relatively large defect in the single finger, especially when sensory reconstruction is needed. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26002780 TI - Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy. AB - BACKGROUND: The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN: The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS: Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age >= 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS: Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS. PMID- 26002781 TI - A review of follow-up outcomes after elective endovascular repair of degenerative thoracic aortic aneurysms. AB - Long-term outcomes of elective thoracic endovascular aortic repair (TEVAR) for degenerative thoracic aortic aneurysms (TAA) are not well defined. A review of the literature on the follow-up outcomes of elective TEVAR for degenerative TAA resulted in 22 relevant articles. Two- and five-year freedom from aneurysm related death varied between 93.0% and 100.0%, and 82.4% to 92.7%, respectively. Two-year and five-year all-cause survival ranged between 68.0% and 97.2% and 47.0% to 78.0%, respectively. Follow-up ranged between 17.3 and 66.0 months. Most common endograft-related complication was endoleak, with reported rate between 1.4% and 14.8% during six months up to five years of follow-up. Endovascular reinterventions were reported in 0.0-32.3%, secondary open surgery was needed in 0.0% to 4.7% during follow-up. Aneurysm-related survival rates after elective TEVAR for degenerative TAA are acceptable. However, reported incidences of endograft-related complications vary considerably in the literature, but the majority can be managed with conservative treatment or additional endovascular procedures. PMID- 26002782 TI - Skew flap for staged below-knee amputation in sepsis. AB - Skew flap amputation was first described in the 1980s but was never as popular as the long posterior flap amputation. This report describes a staged below-knee amputation in sepsis, with pus throughout the leg and a lack of skin coverage. One benefit of skew flaps never previously published is the fact that the suture line is not directly over the tibia. Therefore, an open wound or incomplete skin coverage is not as important as in long posterior flaps where it often leads to bone exposure and revision amputation. These benefits were utilized in this case leading to stump healing. PMID- 26002783 TI - Rendezvous technique for recanalization of long-segmental chronic total occlusion above the knee following unsuccessful standard angioplasty. AB - PURPOSE: To assess the technical feasibility and efficacy of the rendezvous technique, a type of subintimal retrograde wiring, for the treatment of long segmental chronic total occlusions above the knee following unsuccessful standard angioplasty. METHODS: The rendezvous technique was attempted in eight limbs of eight patients with chronic total occlusions above the knee after standard angioplasty failed. The clinical symptoms and ankle-brachial index were compared before and after the procedure. At follow-up, pain relief, wound healing, limb salvage, and the presence of restenosis of the target vessels were evaluated. RESULTS: The rendezvous technique was performed successfully in seven patients (87.5%) and failed in one patient (12.5%). Foot pain improved in all seven patients who underwent successful treatment, with ankle-brachial indexes improving from 0.23 +/- 0.13 before to 0.71 +/- 0.09 after the procedure (P < 0.001). At the end of the follow-up period, the visual analogue scale improved from 6.86 +/- 1.57 to 1.57 +/- 1.27 (P < 0.001). Non-healing ulcers in three patients either healed (n = 2) or improved (n = 1). No major amputation was necessary. Kaplan-Meier analyses revealed that stenosis-free rate was 83.3% at six months and 41.7% at 12 months. CONCLUSION: The rendezvous technique is a feasible and effective treatment for chronic total occlusions above the knee when standard angioplasty fails. PMID- 26002784 TI - The evolution of biofilm-forming Wrinkly Spreaders in static microcosms and drip fed columns selects for subtle differences in wrinkleality and fitness. AB - Experimental evolution studies are used to investigate bacterial adaptive radiation in simple microcosms. In the case of the Wrinkly Spreader, a class of biofilm-forming adaptive mutants of Pseudomonas fluorescens SBW25, the current paradigm is that they are only evolutionarily successful in static microcosms where they outcompete other lineages for O2 at the air-liquid interface. However, we have isolated Wrinkly Spreaders from drip-fed glass bead columns as an example of parallel evolution. These mutants are adaptive, with competitive fitness advantages on columns of 1.28-1.78. This might be explained by the enhanced attachment characteristically shown by Wrinkly Spreaders, allowing them to resist liquid flow through the column pore network. A comparison of column and static microcosm-isolated Wrinkly Spreaders showed that many aspects of wrinkleality, including colony reversion, microcosm growth, biofilm strength and attachment, as well as fitness in static microcosms, were significantly different within and between the two groups of mutants. These findings indicate that the two environments had selected for Wrinkly Spreaders with subtly differing degrees of wrinkleality and fitnesses, suggesting that aspects of the Wrinkly Spreader phenotype may have different relative values in static microcosms and drip-fed columns. PMID- 26002785 TI - Factors Associated With Clopidogrel Adherence in Community-Dwelling Patients. AB - OBJECTIVE: The purpose of this study was to characterize predictors of adherence to clopidogrel therapy focusing on patients' perceptions of clopidogrel and nuisance bleeding. METHODS: This was a cross-sectional study of community dwelling cardiovascular patients with a self-reported prescription for clopidogrel. Self-report questionnaires assessed depressive symptoms, social support, nuisance bleeding, perceptions of clopidogrel, and adherence to therapy. Low, moderate, and high adherence groups based on the Morisky Medication Adherence Scale were compared and hierarchical multiple linear regression analysis was used to predict adherence. RESULTS: A total of 102 subjects were enrolled, and 55%, 28%, and 16% were classified as having low, moderate, and high adherence, respectively. Greater perceptions of clopidogrel necessity, lower perception of clopidogrel concern, and increased severity of nuisance bleeding were predictors of better adherence. CONCLUSIONS: Data from this cross-sectional study suggest that concerns about clopidogrel and feelings about its necessity play an important role in clopidogrel adherence. PMID- 26002786 TI - Randomized Comparison of 3 Hemostasis Techniques After Transradial Coronary Intervention. AB - BACKGROUND: The transradial route for coronary intervention has proven to be a safe and feasible method, and several techniques have been shown to be effective in achieving hemostasis. OBJECTIVES: The aim of this study is to evaluate the efficacy of 3 hemostasis techniques on radial artery outcomes after transradial catheterization. METHODS: A total of 1650 patients were randomly assigned to 1 of the 3 hemostasis techniques after the procedure. The outcome measures were local vascular complications, tolerance to the device, and the time taken to achieve hemostasis. RESULTS: Time taken to achieve hemostasis was significantly longer in the pressure dressing (PD) group than in the pneumatic compression device (PCD) group and rotary compression pad device (RCD) group (306 +/- 65 vs 263 +/- 62 and 237 +/- 58 minutes; P < .0001). There were also significant differences between PD, PCD, and RCD groups with respect to the incidence of oozing (8.2% vs 5.1% and 5.1%; P = .047) and discomfort level (1.68 vs 1.43 and 1.40; P < .0001). The incidence of early (24 hours after the procedure) radial artery occlusion was significantly higher in the PD group than in the PCD and RCD groups (15.6% vs 5.8% and 4.5%; P < .0001). Logistic regression analysis showed that independent predictors of radial artery occlusion at 30-day follow-up visit were diabetes (hazard ratio, 2.39), larger radial artery diameter (hazard ratio, 0.52), the use of the PCD (hazard ratio, 0.51, compared with PD) and the RCD (hazard ratio, 0.52, compared with PD), and radial artery patency during compression (hazard ratio, 0.016). CONCLUSIONS: Hemostasis devices have comparative advantages over the conventional pressure dressing. The presence of radial artery flow during compression represents a strong predictor of radial artery patency during follow up periods. PMID- 26002787 TI - Long-term culture of pluripotent stem-cell-derived human neurons on diamond--A substrate for neurodegeneration research and therapy. AB - Brain Computer Interfaces (BCI) currently represent a field of intense research aimed both at understanding neural circuit physiology and at providing functional therapy for traumatic or degenerative neurological conditions. Due to its chemical inertness, biocompatibility and stability, diamond is currently being actively investigated as a potential substrate material for culturing cells and for use as the electrically active component of a neural sensor. Here we provide a protocol for the differentiation of mature, electrically active neurons on microcrystalline synthetic thin-film diamond substrates starting from undifferentiated pluripotent stem cells. Furthermore, we investigate the optimal characteristics of the diamond microstructure for long-term neuronal sustainability. We also analyze the effect of boron as a dopant for such a culture. We found that the diamond crystalline structure has a significant influence on the neuronal culture unlike the boron doping. Specifically, small diamond microcrystals promote higher neurite density formation. We find that boron incorporated into the diamond does not influence the neurite density and has no deleterious effect on cell survival. PMID- 26002788 TI - Reactive oxygen species and glutathione dual redox-responsive micelles for selective cytotoxicity of cancer. AB - This study developed reactive oxygen species (ROS) and glutathione (GSH) dual redox-responsive micelles, which encapsulate anticancer drug camptothecin (CPT), protect CPT activity, and trigger CPT release in cancer cell H2O2- or GSH-rich surroundings. Experimental results show that CPT-loaded dual redox-responsive micelles remain stable at low levels of ROS and GSH in blood circulation, have high redox sensitivities needed to CPT release in cancer cells with high ROS or GSH (e.g., lung, gastric, and colon cancer cells), and prevent undersigned CPT toxicity in ROS/GSH balanced normal cells (e.g., fibroblast cells, etc.) or normal organs (e.g., liver, kidney, etc.). The CPT-loaded dual redox-responsive micelles also had high in vivo antitumor efficacy. This study demonstrates that ROS and GSH dual redox-responsive micelles have potential use as anticancer therapeutic nanomedicine in various cancer therapies. PMID- 26002789 TI - Sleep disturbances in menopausal women: Aetiology and practical aspects. AB - Sleep deteriorates with age. The menopause is often a turning point for women's sleep, as complaints of insomnia increase significantly thereafter. Insomnia can occur as a secondary disorder to hot flashes, mood disorders, medical conditions, psychosocial factors, underlying intrinsic sleep disorders, such as obstructive sleep apnoea (OSA) or restless legs syndrome (RLS), or it can be a primary disorder. Since unrecognized OSA can have dramatic health-related consequences, menopausal women complaining of persisting sleep disturbances suggesting primary insomnia or intrinsic sleep disorders should be referred to a sleep specialist for a comprehensive sleep assessment. Patients suffering from primary insomnia will be preferentially treated with non-benzodiazepine hypnotics or melatonin, or with cognitive behavioural therapy. Insomnia related to vasomotor symptoms can be improved with hormone replacement therapy. Gabapentin and isoflavones have also shown efficacy in small series but their precise role has yet to be established. In patients suffering from OSA, non-pharmacological therapy will be applied: continuous positive airway pressure or an oral appliance, according to the severity of the disorder. In the case of RLS, triggering factors must be avoided; dopaminergic agonists are the first-line treatment for moderate to severe disease. In conclusion, persisting sleep complaints should be addressed in menopausal women, in order to correctly diagnose the specific causal disorder and to prescribe treatments that have been shown to improve sleep quality, quality of life and long-term health status. PMID- 26002790 TI - Base-Pairing Energies of Protonated Nucleoside Base Pairs of dCyd and m(5)dCyd: Implications for the Stability of DNA i-Motif Conformations. AB - Hypermethylation of cytosine in expanded (CCG)n*(CGG)n trinucleotide repeats results in Fragile X syndrome, the most common cause of inherited mental retardation. The (CCG)n*(CGG)n repeats adopt i-motif conformations that are preferentially stabilized by base-pairing interactions of protonated base pairs of cytosine. Here we investigate the effects of 5-methylation and the sugar moiety on the base-pairing energies (BPEs) of protonated cytosine base pairs by examining protonated nucleoside base pairs of 2'-deoxycytidine (dCyd) and 5 methyl-2'-deoxycytidine (m(5)dCyd) using threshold collision-induced dissociation techniques. 5-Methylation of a single or both cytosine residues leads to very small change in the BPE. However, the accumulated effect may be dramatic in diseased state trinucleotide repeats where many methylated base pairs may be present. The BPEs of the protonated nucleoside base pairs examined here significantly exceed those of Watson-Crick dGuo*dCyd and neutral dCyd*dCyd base pairs, such that these base-pairing interactions provide the major forces responsible for stabilization of DNA i-motif conformations. Compared with isolated protonated nucleobase pairs of cytosine and 1-methylcytosine, the 2' deoxyribose sugar produces an effect similar to the 1-methyl substituent, and leads to a slight decrease in the BPE. These results suggest that the base pairing interactions may be slightly weaker in nucleic acids, but that the extended backbone is likely to exert a relatively small effect on the total BPE. The proton affinity (PA) of m(5)dCyd is also determined by competitive analysis of the primary dissociation pathways that occur in parallel for the protonated (m(5)dCyd)H(+)(dCyd) nucleoside base pair and the absolute PA of dCyd previously reported. PMID- 26002793 TI - R. Graham Cooks Elected to the National Academy of Sciences. PMID- 26002791 TI - From raw data to biological discoveries: a computational analysis pipeline for mass spectrometry-based proteomics. AB - In the last two decades, computational tools for mass spectrometry-based proteomics data analysis have evolved from a few stand-alone software solutions serving specific goals, such as the identification of amino acid sequences based on mass spectrometry spectra, to large-scale complex pipelines integrating multiple computer programs to solve a collection of problems. This software evolution has been mostly driven by the appearance of novel technologies that allowed the community to tackle complex biological problems, such as the identification of proteins that are differentially expressed in two samples under different conditions. The achievement of such objectives requires a large suite of programs to analyze the intricate mass spectrometry data. Our laboratory addresses complex proteomics questions by producing and using algorithms and software packages. Our current computational pipeline includes, among other things, tools for mass spectrometry raw data processing, peptide and protein identification and quantification, post-translational modification analysis, and protein functional enrichment analysis. In this paper, we describe a suite of software packages we have developed to process mass spectrometry-based proteomics data and we highlight some of the new features of previously published programs as well as tools currently under development. Graphical Abstract ?. PMID- 26002792 TI - MALDI-ISD Mass Spectrometry Analysis of Hemoglobin Variants: a Top-Down Approach to the Characterization of Hemoglobinopathies. AB - Hemoglobinopathies are the most common inherited disorders in humans and are thus the target of screening programs worldwide. Over the past decade, mass spectrometry (MS) has gained a more important role as a clinical means to diagnose variants, and a number of approaches have been proposed for characterization. Here we investigate the use of matrix-assisted laser desorption/ionization time-of-flight MS (MALDI-TOF MS) with sequencing using in source decay (MALDI-ISD) for the characterization of Hb variants. We explored the effect of matrix selection using super DHB or 1,5-diaminonaphthalene on ISD fragment ion yield and distribution. MALDI-ISD MS of whole blood using super DHB simultaneously provided molecular weights for the alpha and beta chains, as well as extensive fragmentation in the form of sequence defining c-, (z + 2)-, and y ion series. We observed sequence coverage on the first 70 amino acids positions from the N- and C-termini of the alpha and beta chains in a single experiment. An abundant beta chain N-terminal fragment ion corresponding to betac34 was determined to be a diagnostic marker ion for Hb S (beta6 Glu->Val, sickle cell), Hb C (beta6 Glu->Lys), and potentially for Hb E (beta26 Glu->Lys). The MALDI-ISD analysis of Hb S and HbSC yielded mass shifts corresponding to the variants, demonstrating the potential for high-throughput screening. Characterization of an alpha chain variant, Hb Westmead (alpha122 His->Gln), generated fragments that established the location of the variant. This study is the first clinical application of MALDI-ISD MS for the determination and characterization of hemoglobin variants. PMID- 26002794 TI - Urinalysis. AB - Performing a urinalysis should be part of a minimum database in addition to physical examination, historical information gathering, complete blood cell counts, and serum/plasma biochemical analysis. Urinalysis provides information on function of various organs and information on renal function. It is necessary to interpret blood urea nitrogen and serum/plasma creatinine concentrations and is useful in assessing urine concentrating and diluting ability, glomerular barrier function, tubular function, proteinuria, discolored urine, urolithiasis, and neoplasia. Performing a urinalysis is technically easy and does not require expensive equipment or disposable supplies. PMID- 26002795 TI - Cystoscopy in dogs and cats. AB - Cystoscopy has become an important and widely available component of the diagnostic evaluation of diseases of the lower urinary tract in dogs and cats. In addition, a large number of cystoscopic guided procedures have been described that can be used to treat disease processes that were previously treatable only with invasive surgical procedures. This article reviews the indications and contraindications for cystoscopy, cystoscopy equipment and techniques for male and female dogs and cats, potential complications associated with cystoscopy, and management options for these complications. PMID- 26002796 TI - Congenital diseases of the lower urinary tract. AB - Congenital lower urinary tract diseases occur with variable frequency and may result in clinical signs of urinary incontinence, urinary obstruction, or urination through abnormal openings. This article discusses diagnosis of congenital diseases of the urinary bladder and urethra and describes treatment of these disorders. PMID- 26002797 TI - Urolithiasis. AB - Uroliths occur commonly in the bladder and/or urethra of dogs and cats and can be life-threatening if urethral obstruction occurs. The majority of uroliths are composed of struvite or calcium oxalate; however, other minerals such as urate and cystine occur. Uroliths may be composed of more than one mineral. Some uroliths are amenable to medical dissolution (eg, struvite, urate, and cystine) while others (eg, calcium oxalate) are not. Medical management involves decreasing urine saturation for the minerals that form uroliths. PMID- 26002798 TI - Interventional urology: endourology in small animal veterinary medicine. AB - The use of novel image-guided techniques in veterinary medicine has become more widespread, especially in urologic diseases. With the common incidence of urinary tract obstructions, stones disease, renal disease, and urothelial malignancies, combined with the recognized invasiveness and morbidity associated with traditional surgical techniques, the use of minimally invasive alternatives using interventional radiology and interventional endoscopy techniques has become incredibly appealing to owners and clinicians. This article provides a brief overview of some of the most common procedures done in endourology in veterinary medicine to date, providing as much evidence-based medicine as possible when comparing with traditional surgical alternatives. PMID- 26002799 TI - Urology: It's Gold for a Reason! PMID- 26002800 TI - Activated platelet-T-cell conjugates in peripheral blood of patients with HIV infection: coupling coagulation/inflammation and T cells. AB - BACKGROUND: Despite successfully suppressed viremia by treatment, patients with high levels of biomarkers of coagulation/inflammation are at an increased risk of developing non-AIDS defining serious illnesses such as cardiovascular diseases. Thus, there is a relationship between persistent immune activation and coagulation/inflammation, although the mechanisms are poorly understood. Platelets play an important role in this process. Although interactions between platelets and elements of the innate immune system, such as monocytes, are well described, little is known about the interaction between platelets and the adaptive immune system. DESIGN: We investigated the interaction of a component of the coagulation system, platelets, and the adaptive immune system T cells. METHODS: Healthy controls and combination antiretroviral therapy (cART)-treated HIV-infected patients with viral loads of less than 40 copies/ml for more than 15 months were analysed for platelet-T-cell conjugate formation. RESULTS: Platelets can form conjugates with T cells and were preferentially seen in CD4 and CD8 T cell subsets with more differentiated phenotypes [memory, memory/effector and terminal effector memory (TEM)]. Compared with healthy controls, these conjugates in patients with HIV infection were more frequent, more often composed of activated platelets (CD42bCD62P), and were significantly associated with the D dimer serum levels. CONCLUSION: These data support a model in which platelet-T cell conjugates may play a critical role in the fast recruitment of antigen experienced T cells to the place of injury. This mechanism can contribute in maintaining a state of coagulation/inflammation observed in these patients contributing to the pathology of the disease. PMID- 26002801 TI - Possible mechanism for inhibition of morphine formation from 6-acetylmorphine after intake of street heroin. AB - Heroin is de-acetylated in the body to morphine in two steps. The intermediate 6 acetylmorphine (6-AM) is formed rapidly and is considered important for the pharmacological effect of heroin. In urine drug testing, an atypical pattern of morphine and 6-AM is known to occur in low frequency. The aim of this study was to investigate this atypical pattern in more detail and to identify responsible substances for a possible inhibition of the conversion from 6-AM to morphine. Urine samples were selected from a routine flow of samples sent for drug testing. Out of 695 samples containing morphine and 6-acetylmorphine, 11.5% had the atypical pattern of a 6-AM to morphine ratio above 0.26 as derived from a bimodal frequency distribution. An in vitro study of the conversion of 6-acetylmorphine to morphine in human liver homogenates demonstrated that a number of known carboxylesterase inhibitors were able to inhibit the reaction mimicking the situation in vivo. Compound 3 (3,6-Dimethoxy-4-acetoxy-5-[2-(N methylacetamido)ethyl]phenanthrene) a substance formed from thebaine during the production of heroin was found to be a strong inhibitor. Liquid chromatography mass spectrometry was used to identify possible inhibitors present in vivo. This part of the investigation demonstrated that several components may contribute to the effect. It is concluded that inhibition of liver carboxylesterase activity is a possible mechanism causing the atypical pattern and that one candidate compound is the result of the heroin production process. An inhibition of 6-AM metabolism is likely to increase the pharmacological effect of heroin and may be related to a higher risk of lethal toxicity. PMID- 26002802 TI - Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids. AB - People eating different balances of omega-3 and omega-6 nutrients develop predictably different proportions of competing highly unsaturated fatty acids (HUFA) in their tissue lipids. While epidemiological studies have associated wide differences in HUFA balance with disease severity, some clinical studies that did not examine wide differences failed to confirm the association. We examined the degree to which the relative amount of arachidonic acid, the major precursor of omega-6 eicosanoids, differs among people who have widely different dietary intakes of omega-3 and omega-6 nutrients. Gas chromatographic analyses of human blood samples describe the balance among n-3 and n-6 HUFA for different individuals. The proportion of the omega-6 arachidonic acid, from which potent eicosanoids are formed, is not constant. It ranges from 30% to 70% of HUFA while the competing n-3 HUFA range from 60% to 10% of HUFA. Significant differences in clinical outcomes between control and intervention groups have been seen when using dietary interventions that shift the balance of n-3 and n-6 nutrients far enough to create a biologically significant difference in the HUFA balance. PMID- 26002803 TI - The effect of race on long term mortality in mechanically ventilated patients. AB - OBJECTIVE: Determine the impact of race on one-year mortality following mechanical ventilation. BACKGROUND: There is a lack of prospective studies on the effect of race on survival following mechanical ventilation. METHODS: Observational study of adult patients on ventilatory support for <24 h prior to enrollment. Socioeconomic factors, laboratory and clinical data were recorded. Primary outcome was one-year mortality. RESULTS: We enrolled 178 patients; 100 African American (AA), 78 other races (OTH). One-year mortality for AA was 49% and 33% for OTH (p = 0.035). After correcting for covariates, race was not significantly associated with mortality (p = 0.42). AA patients had higher mean arterial blood pressure, serum creatinine, heart rate, and peak (p < 0.01) and mean (p = 0.05) airway pressures. CONCLUSIONS: AA patients who underwent mechanical ventilation had greater one-year mortality, although race per se was not a significant factor. It remains to be determined if strict blood pressure control and lower airway pressures may improve survival in this racial group. PMID- 26002804 TI - Combined hormonal contraceptive use among breastfeeding women: an updated systematic review. AB - BACKGROUND: Contraception is important for women who are postpartum, including those who are breastfeeding. Use of combined hormonal contraceptives (CHCs) may affect breastfeeding performance and infant health outcomes. OBJECTIVE: The objective was to identify evidence examining clinical outcomes for breastfeeding and infant health among breastfeeding women using CHCs compared to nonusers. SEARCH STRATEGY: We searched the PubMed database for all articles published from database inception through September 30, 2014. SELECTION CRITERIA: We included primary research studies that compared breastfeeding women using CHCs with breastfeeding women using nonhormonal or no contraception, or compared breastfeeding women initiating combined hormonal contraception at early versus later times postpartum. Breastfeeding outcomes of interest included duration, rate of exclusive breastfeeding and timing of supplementation. Infant outcomes of interest included growth, health and development. RESULTS: Fifteen articles describing 13 studies met inclusion criteria for this review. Studies ranged from poor to fair methodological quality and demonstrated inconsistent effects of combined oral contraceptives (COCs) on breastfeeding performance with COC initiation before or after 6 weeks postpartum; some studies demonstrated greater supplementation and decreased breastfeeding continuation among COC users compared with nonusers, and others demonstrated no effect. For infant outcomes, some studies found decreases in infant weight gain for COC users compared with nonusers when COCs were initiated at <6 weeks postpartum, while other studies found no effect. None of the studies found an effect on infant weight gain when COCs were started after 6 weeks postpartum, and no studies found an effect on other infant health outcomes regardless of time of COC initiation. CONCLUSION: Limited evidence of poor to fair quality demonstrates an inconsistent impact of COCs on breastfeeding duration and success. The evidence also demonstrated conflicting results on whether early initiation of COCs affects infant outcomes but generally found no negative impact on infant outcomes with later initiation of COCs. The body of evidence is limited by older studies using different formulations and doses of estrogen and poor methodologic quality. Given the significant limitations of this body of evidence, the importance of contraception for postpartum women and the theoretical concerns that have been raised about the use of combined hormonal contraception by women who are breastfeeding, rigorous studies examining these issues are needed. In addition, postpartum women should be counseled about the full range of safe alternative contraceptive methods, particularly during the first 6 weeks postpartum when the risk of venous thromboembolism is highest and use of estrogen may exacerbate this risk. PMID- 26002805 TI - A randomized noninferiority crossover controlled trial of the functional performance and safety of new female condoms: an evaluation of the Velvet, Cupid2, and FC2. AB - OBJECTIVES: New designs of female condoms have been developed to lower cost and/or improve acceptability. To secure regulatory approvals, clinical studies are required to verify performance. We aimed to assess the functional performance and safety of two new female condom types - Velvet and Cupid2 female condom - against the existing FC2 female condom. STUDY DESIGN: This was a three-period crossover, randomized noninferiority clinical trial with 300 women randomized to condom-type order in one South African site. Primary end points were total clinical failure and total female condom failure. Noninferiority of component modes, clinical breakage, nonclinical breakage, slippage, misdirection and invagination were also determined. Safety data were also assessed for each female condom. Participants were asked to use five of each female condom type and to collect information on use in a condom diary at home and were interviewed after use of each type. Frequencies and percentages were calculated by condom type for each failure mode, and differences in performance of the three female condoms using FC2 as reference, with 95% confidence intervals, were estimated using generalized estimating equation models. RESULTS: A total of 282 (94%) participants completed follow-up, using at least one condom of each type. Total clinical failure (clinical breakage, invagination, misdirection, slippage) was <5% for all female condoms: FC2 (4.50%), Cupid2 (4.79%) and Velvet (3.93%). Noninferiority was demonstrated for all condom failure modes for the two new female condoms with respect to FC2, within the margin of 3% difference in mean failure, at the 5% significance level. CONCLUSION: Noninferiority for the two new female condoms was demonstrated with respect to the marketed FC2. These data are used to support manufacturer dossiers for World Health Organization (WHO)/United Nations Population Fund (UNFPA) prequalification. IMPLICATIONS: Data from this study have been submitted to WHO/UNFPA and will contribute to the prequalification submission requirements for the Cupid2 and Velvet female condoms. PMID- 26002806 TI - The impact of psychiatric history on women's pre- and postabortion experiences. AB - OBJECTIVE: The objective of this study is to investigate to what extent psychiatric history affects preabortion decision difficulty, experienced burden, and postabortion emotions and coping. Women with and without a history of mental disorders might respond differently to unwanted pregnancy and subsequent abortion. STUDY DESIGN: Women who had an abortion (n=325) were classified as either with or without a history of mental disorders, using the Composite International Diagnostic Interview version 3.0. The two groups were compared on preabortion doubt, postabortion decision uncertainty, experienced pressure, experienced burden of unwanted pregnancy and abortion, and postabortion emotions, self-efficacy and coping. The study was conducted in the Netherlands. Data were collected using structured face-to-face interviews and analyzed with regression analyses. RESULTS: Compared to women without prior mental disorders, women with a psychiatric history were more likely to report higher levels of doubt [odds ratio (OR)=2.30; confidence interval (CI)=1.29-4.09], more burden of the pregnancy (OR=2.23; CI=1.34-3.70) and the abortion (OR=1.93; CI=1.12-3.34) and more negative postabortion emotions (beta=.16; CI=.05-.28). They also scored lower on abortion-specific self-efficacy (beta=-.11; CI=-.22 to .00) and higher on emotion oriented (beta=.22; .11-.33) and avoidance-oriented coping (beta=.12; CI=.01 .24). The two groups did not differ significantly in terms of experienced pressure, decision uncertainty and positive postabortion emotions. CONCLUSIONS: Psychiatric history strongly affects women's pre- and postabortion experiences. Women with a history of mental disorders experience a more stressful pre- and postabortion period in terms of preabortion doubt, burden of pregnancy and abortion, and postabortion emotions, self-efficacy and coping. IMPLICATIONS: Negative abortion experiences may, at least partially, stem from prior or underlying mental health problems. PMID- 26002807 TI - How do pregnancy intentions affect contraceptive choices when cost is not a factor? A study of privately insured women. AB - OBJECTIVE: The objective was to test the hypothesis that among privately insured women who have contraceptive coverage without cost-sharing, using prescription contraception is predicted primarily by pregnancy intentions. STUDY DESIGN: Participants are 987 women ages 18-40 who wish to avoid pregnancy for at least the next 12 months and are enrolled in Highmark Health plans in Pennsylvania. Data are from the baseline survey of MyNewOptions, an ongoing randomized controlled trial testing an intervention to help insured women make optimum contraceptive choices. Primary type of contraception used [categorized as long acting reversible contraception (LARCs), other prescription methods, nonprescription methods or no method] is modeled using multinomial logistic regression, with predictors representing the timing and strength of pregnancy intentions, pregnancy history, pregnancy risk exposure and sociodemographics. RESULTS: LARCs were used by 8.4% of the sample; other prescription methods (primarily oral contraceptives), 49.6%; nonprescription methods (primarily condoms), 30.4%; and no method, 11.5%. Pregnancy intentions predicted use of LARCs and other prescription methods compared with no method. The most consistent predictors of using all categories of contraception were pregnancy risk exposure measures (partnership type and frequency of sexual intercourse). CONCLUSIONS: In the absence of cost-sharing for contraception, women's choice of prescription contraception was a function primarily of pregnancy risk exposure rather than pregnancy intentions. IMPLICATIONS: This study is among the first to examine privately insured women's contraception choices in the context of contraceptive coverage without cost-sharing; it shows that use of prescription contraception is predicted by pregnancy risk exposure and pregnancy intentions. PMID- 26002808 TI - Mitochondrial transporters for ornithine and related amino acids: a review. AB - Among the members of the mitochondrial carrier family, there are transporters that catalyze the translocation of ornithine and related substrates, such as arginine, homoarginine, lysine, histidine, and citrulline, across the inner mitochondrial membrane. The mitochondrial carriers ORC1, ORC2, and SLC25A29 from Homo sapiens, BAC1 and BAC2 from Arabidopsis thaliana, and Ort1p from Saccharomyces cerevisiae have been biochemically characterized by transport assays in liposomes. All of them transport ornithine and amino acids with side chains terminating at least with one amine. There are, however, marked differences in their substrate specificities including their affinity for ornithine (KM values in the mM to MUM range). These differences are most likely reflected by minor differences in the substrate binding sites of these carriers. The physiological role of the above-mentioned mitochondrial carriers is to link several metabolic pathways that take place partly in the cytosol and partly in the mitochondrial matrix and to provide basic amino acids for mitochondrial translation. In the liver, human ORC1 catalyzes the citrulline/ornithine exchange across the mitochondrial inner membrane, which is required for the urea cycle. Human ORC1, ORC2, and SLC25A29 are likely to be involved in the biosynthesis and transport of arginine, which can be used as a precursor for the synthesis of NO, agmatine, polyamines, creatine, glutamine, glutamate, and proline, as well as in the degradation of basic amino acids. BAC1 and BAC2 are implicated in some processes similar to those of their human counterparts and in nitrogen and amino acid metabolism linked to stress conditions and the development of plants. Ort1p is involved in the biosynthesis of arginine and polyamines in yeast. PMID- 26002809 TI - A rapid hydrolysis method and DABS-Cl derivatization for complete amino acid analysis of octreotide acetate by reversed phase HPLC. AB - Octreotide as a synthetic cyclic octapeptide is a somatostatin analog with longer half-life and more selectivity for inhibition of the growth hormone. The acetate salt of octreotide is currently used for medical treatment of somatostatin related disorders such as endocrine and carcinoid tumors, acromegaly, and gigantism. Octreotide contains both cysteine and tryptophan residues which make the hydrolysis part of its amino acid analysis procedure very challenging. The current paper introduces a fast and additive-free method which preserves tryptophan and cysteine residues during the hydrolysis. Using only 6 M HCl, this hydrolysis process is completed in 30 min at 150 degrees C. This fast hydrolysis method followed by pre-column derivatization of the released amino acids with 4 N,N-dimethylaminoazobenzene-4'-sulfonyl chloride (DABS-Cl) which takes only 20 min, makes it possible to do the complete amino acid analysis of an octreotide sample in a few hours. The highly stable-colored DABS-Cl derivatives can be detected in 436 nm in a reversed phase chromatographic system, which eliminates spectral interferences to a great extent. The amino acid analysis of octreotide acetate including hydrolysis, derivatization, and reversed phase HPLC determination was validated according to International Conference of Harmonization (ICH) guidelines. PMID- 26002810 TI - Hydration of amino acids: FTIR spectra and molecular dynamics studies. AB - The hydration of selected amino acids, alanine, glycine, proline, valine, isoleucine and phenylalanine, has been studied in aqueous solutions by means of FTIR spectra of HDO isotopically diluted in H2O. The difference spectra procedure and the chemometric method have been applied to remove the contribution of bulk water and thus to separate the spectra of solute-affected HDO. To support interpretation of obtained spectral results, molecular dynamics simulations of amino acids were performed. The structural-energetic characteristic of these solute-affected water molecules shows that, on average, water affected by amino acids forms stronger and shorter H-bonds than those in pure water. Differences in the influence of amino acids on water structure have been noticed. The effect of the hydrophobic side chain of an amino acid on the solvent interactions seems to be enhanced because of the specific cooperative coupling of water strong H-bond chain, connecting the carboxyl and amino groups, with the clathrate-like H-bond network surrounding the hydrocarbon side chain. The parameter derived from the spectral data, which corresponds to the contributions of the population of weak hydrogen bonds of water molecules which have been substituted by the stronger ones in the hydration sphere of amino acids, correlated well with the amino acid hydrophobicity indexes. PMID- 26002811 TI - Optically active poly(amide-imide)/TiO2 nanocomposites containing amino acid moieties: synthesis and properties. AB - The novel optically active poly(amide-imide) (PAI)/TiO2 nanocomposites containing fluorene moieties have been successfully synthesized through ultrasonic irradiation. The surface of nanoparticles was chemically modified with gamma aminopropyltriethoxyl silane to enhance the compatibility with polymeric matrix and to avoid the aggregation of nanoparticles. The dispersion of surface-modified TiO2 in PAI film was confirmed by the transmission electron microscope (TEM) analysis showing the well-dispersed nanosized TiO2 nanoparticles. The thermal stabilities and optical properties of PAI/surface-modified TiO2 nanocomposite films were also investigated. The thermogravimetric analysis data showed an improvement of thermal stability of novel nanocomposite films as compared to the pure polymer. PMID- 26002812 TI - Novel bioluminescent receptor-binding assays for peptide hormones: using ghrelin as a model. AB - Peptide hormones perform important biological functions by binding specific cell membrane receptors. For hormone-receptor interaction studies, receptor-binding assays are widely used. However, conventional receptor-binding assays rely on radioactive tracers that have drawbacks. In recent studies, we established novel non-radioactive receptor-binding assays for some recombinant protein hormones based on the ultrasensitive bioluminescence of a newly developed nanoluciferase (NanoLuc) reporter. In the present work, we extended the novel bioluminescent receptor-binding assay to peptide hormones that have small size and can be conveniently prepared by chemical synthesis. Human ghrelin, a 28-amino acid peptide hormone carrying a special O-fatty acid modification, was used as a model. To prepare a bioluminescent ghrelin tracer, a chemically synthesized ghrelin analog with a unique cysteine residue at the C-terminus was site specifically conjugated with an engineered NanoLuc with a unique exposed cysteine residue at the C-terminus via a reversible disulfide linkage. The NanoLuc conjugated ghrelin retained high binding affinity with the ghrelin receptor GHSR1a (K d = 1.14 +/- 0.13 nM, n = 3) and was able to sensitively monitor the receptor-binding of various GHSR1a ligands. The novel bioluminescent receptor binding assay will facilitate the interaction studies of ghrelin with its receptor. We also proposed general procedures for convenient conjugation of other peptide hormones with NanoLuc for novel bioluminescent receptor-binding assays. PMID- 26002813 TI - Effects of 3,5-Diiodotyrosine and Potassium Iodide on Thyroid Function and Oxidative Stress in Iodine-Excess Wistar Rats. AB - The objective of this study was to investigate the effects of organic iodine (3,5 diiodotyrosine, DIT) and inorganic iodine (potassium iodine, KI) on thyroid function and oxidative stress in iodine-excess Wistar rats. Seventy-two Wistar rats were randomly divided into eight groups: normal control (NC), thyroid tablet induced hyperthyroidism model (HM), low DIT (L-DIT), medium DIT (M-DIT), high DIT (H-DIT), low KI (L-KI), medium KI (M-KI), and high KI (H-KI). All rats were fed ad libitum for 30 days. Morphological changes in the thyroid, absolute and relative weights of the thyroid, thyroid function markers free triiodothyronine (FT3) and free thyroxine (FT4), urinary iodine level, and oxidative stress indicators were measured. Compared to the HM groups, the FT3 and FT4 levels decreased in the L-DIT groups; the thyroid weight and thyroid weight/body weight values decreased markedly in the L-DIT and M-DIT groups; serum superoxide dismutase/malondialdehyde increased markedly; glutathione peroxidase activity increased markedly in the L-DIT groups; and malondialdehyde levels decreased significantly in the M-DIT groups. However, the FT3 and FT4 levels decreased and glutathione peroxidase levels increased significantly in the DIT groups compared to their corresponding KI groups. Additionally, urinary iodine levels increased significantly in both DIT and KI groups, while the highest urinary iodine excretion was showed in the DIT groups among groups. When the addition of iodine with the same doses in iodine-excess rats, although neither DIT nor KI normalized iodine levels in the iodine-excess rats, the DIT did less damage than did KI to thyroid follicular cells. Therefore, DIT rather than KI had a protective effect by balancing the antioxidant system when exposed to supraphysiological iodine. These suggest that DIT may be used as a new alternative iodized salt in the universal salt iodization to avoid the potential damage of surplus KI. PMID- 26002814 TI - Assessment of left ventricular ejection fraction using low radiation dose computed tomography. AB - BACKGROUND: Cardiac CT is a non-invasive modality with the ability to estimate LVEF. However, given its limited temporal resolution and radiation, there has been initial resistance to use CT to measure LVEF. Developing an accurate, fast, low radiation dose protocol is desirable. OBJECTIVE: The objective of this study is to demonstrate that a 'low radiation dose' 64 slice cardiac computed tomography (CT) protocol is feasible and can accurately measure left ventricular ejection fraction (LVEF) while delivering a radiation dose lower than radionuclide angiography (RNA). METHODS: Patients undergoing RNA were prospectively screened and enrolled to undergo a 'low-dose' 64 slice CT LVEF protocol. LVEF measures, duration of each study and radiation dose between CT and RNA were compared. RESULTS: A total of 77 patients (mean age = 61.8 +/- 12.2 years and 58 men) were analyzed. The mean LVEF measured by CT and RNA were 41.9 +/- 15.2% and 39.4 +/- 13.9%, respectively, (P = 0.154) with a good correlation (r = 0.863). Bland-Altman plot revealed a good agreement between the CT and RNA LVEF (mean difference of -2.4). There was good agreement between CT LVEF and RNA for identifying patients with LVEF <=30% (kappa = 0.693) and LVEF >=50% (kappa = 0.749). The mean dose estimated effective dose for CT and RNA were 4.7 +/- 1.6 and 9.5 +/- 1.0 mSv, respectively. The mean CT LVEF imaging duration (4:32 +/- 3:05 minutes) was significantly shorter than the RNA image acquisition time (9:05 +/- 2:36 minutes; p < 0.001). CONCLUSION: The results of our study suggest that low-dose CT LVEF protocol is feasible, accurate, and fast while delivering a lower radiation dose than traditional RNA. PMID- 26002815 TI - (99m)Tc-HMDP scintigraphy rectifies wrong diagnosis of AL amyloidosis. AB - A 71-year-old African man without history of cardiac disease was referred to our center for dyspnea. Transthoracic echocardiogram and cardiac MRI were suggestive of cardiac amyloidosis (CA). The diagnosis of the light-chain cardiac amyloidosis (AL-CA) was made after a first endomyocardial biopsy. Accordingly chemotherapy was started. Systematic 99mTc-HMDP scintigraphy showed moderate cardiac uptake (visual score of 2), unusual for AL-CA, and permitted to rectify the diagnosis. Hereditary transthyretin cardiac amyloidosis was confirmed by a second endomyocardial biopsy with a positive Congo-red and anti-transthyretin antibody stainings, mass spectrometry and genetic analysis (Val122Ile mutation). PMID- 26002816 TI - Patients with thoracic trauma and concomitant spinal cord injury have a markedly decreased mortality rate compared to patients without spinal cord injury. AB - INTRODUCTION: The present study was performed to compare the clinical outcome, with special focus on the mortality rate of thoracic injuries, in patients with and without spinal cord injury. MATERIALS AND METHODS: Patients who were treated for thoracic trauma at our institution between January 1998 and December 2007 were included in this retrospective cohort study. Patients were divided into two groups according to whether they had suffered a concomitant spinal cord injury (SCI) (N = 54) or not (N = 61). Survival analysis was performed using the Kaplan Meier function and the Cox proportional hazards model. Age, sex, injury severity score (ISS), Charlson comorbidity index (CCI), and infection with pneumonia were included as covariates in the final model. RESULTS: Patients with SCI have a 65 % reduction in the chance of dying compared to patients without SCI following thoracic trauma (HR = 0.35; 95%CI = 0.13-0.96; p = 0.041). Sex (HR = 0.67; 95 % CI: 0.26-1.71, P = 0.141), ISS > =25 (HR = 2.08 95 % CI: 0.58-7.49, P = 2.63) and a Charlson Comorbidity Index of 2 (HR = 1.82; 95 % CI: 0.58-7.22, P = 0.393) had no effect in the risk of dying. However, patients older than 60 years had four times the chance of dying than patients younger than 30 years (HR = 4.39; 95 % CI: 1.02-19, P = 0.048). Patients with pneumonia had a nonsignificant twofold increase in the risk of dying (HR = 2.28; 95 % CI: 0.97-5.34, P = 0.059). CONCLUSIONS: Our results demonstrate that patients with thoracic trauma and concomitant SCI had markedly decreased mortality compared to patients without SCI, even after adjusting for age, sex, injury severity, comorbidities and pneumonia infection. PMID- 26002817 TI - Generalized iterative most likely oriented-point (G-IMLOP) registration. AB - PURPOSE: The need to align multiple representations of anatomy is a problem frequently encountered in clinical applications. A new algorithm for feature based registration is presented that solves this problem by aligning both position and orientation information of the shapes being registered. METHODS: The iterative most likely oriented-point (IMLOP) algorithm and its generalization (G IMLOP) to the anisotropic noise case are described. These algorithms may be understood as probabilistic variants of the popular iterative closest point (ICP) algorithm. A probabilistic model provides the framework, wherein both position information and orientation information are simultaneously optimized. Like ICP, the proposed algorithms iterate between correspondence and registration subphases. Efficient and optimal solutions are presented for implementing each subphase of the proposed methods. RESULTS: Experiments based on human femur data demonstrate that the IMLOP and G-IMLOP algorithms provide a strong accuracy advantage over ICP, with G-IMLOP providing additional accuracy improvement over IMLOP for registering data characterized by anisotropic noise. Furthermore, the proposed algorithms have increased ability to robustly identify an accurate versus inaccurate registration result. CONCLUSION: The IMLOP and G-IMLOP algorithms provide a cohesive framework for incorporating orientation data into the registration problem, thereby enabling improvement in accuracy as well as increased confidence in the quality of registration outcomes. For shape data having anisotropic uncertainty in position and/or orientation, the anisotropic noise model of G-IMLOP enables further gains in registration accuracy to be achieved. PMID- 26002818 TI - Reduction of inappropriate ICD therapies in patients with primary prevention of sudden cardiac death: DECREASE study. AB - BACKGROUND: A significant number of patients with an implantable cardioverter/defibrillator (ICD) for primary prevention receive inappropriate shocks. Previous studies have reported a reduction of inappropriate therapies with simple modifications of ICD detection settings, however, inclusion criteria and settings varied markedly between studies. Our aim was to investigate the effect of raising the ICD detection zone in the entire primary prevention ICD population. METHODS AND RESULTS: 543 patients receiving an ICD for primary prevention were randomized to either conventional or progressive ICD programming. The detection rate was programmed at 171 bpm for ventricular tachycardia (VT) and 214 bpm for ventricular fibrillation (VF) in the Conventional group and 187 bpm for VT and 240 bpm for VF in the Progressive group. 43 % of patients received single-chamber and 57 % dual-chamber detection devices (DDD-ICD 19 %; CRT-D 38 %). The primary endpoint consisted of inappropriate therapies and untreated VT/VF. The primary endpoint was reached in 35 patients (13 %) in the Conventional group and 17 patients (6 %) in the Progressive group (p = 0.004). Progressive ICD programming led to significantly fewer amount of patients with ICD therapies (26 vs. 14 %; p < 0.001) and shocks (11 vs. 5 %; p = 0.023) compared to conventional ICD programming. Sub-analyses showed the greatest reduction of inappropriate therapies and shocks in dual-chamber detection devices with progressive compared to single-chamber detection devices with conventional ICD programming (p < 0.001). CONCLUSIONS: Progressive ICD programming reduces the number of inappropriate therapies and shocks in a broad primary prevention ICD population particularly in combination with dual-chamber detection algorithms. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov ; ClinicalTrials.gov identifier NCT01217528. PMID- 26002819 TI - Qualitative and quantitative differences of adipose-derived stromal cells from superficial and deep subcutaneous lipoaspirates: a matter of fat. AB - BACKGROUND AIMS: Subcutaneous fat represents a valuable reservoir of adipose derived stem cells (ASCs) in the stromal vascular fraction (SVF), widely exploited in regenerative medicine applications, being easily harvested through lipoaspiration. The lack of standardized procedures for autologous fat grafting guided research efforts aimed at identifying possible differences related to the harvesting site, which may affect cell isolation yield, cell growth properties and clinical outcomes. Subcutaneous fat features a complex architecture: the superficial fascia separates superficial adipose tissue (SAT) from deep layer tissue (DAT). We aimed to unravel the differences between SAT and DAT, considering morphological structure, SVF composition, and ASC properties. METHODS: SAT and DAT were collected from female donors and comparatively analyzed to evaluate cellular yield and viability, morphology, immunophenotype and molecular profile. ASCs were isolated in primary culture and used for in vitro differentiation assays. SAT and DAT from cadaver donors were also analyzed through histology and immunohistochemistry to assess morphology and cell localization within the hypoderm. RESULTS: Liposuctioned SAT contained a higher stromal tissue compound, along with a higher proportion of CD105-positive cells, compared with DAT from the same harvesting site. Also, cells isolated from SAT displayed increased multipotency and stemness features. All differences were mainly evidenced in specimens harvested from the abdominal region. According to our results, SAT features overall increased stem properties. CONCLUSIONS: Given that subcutaneous adipose tissue is currently exploited as the gold standard source for high-yield isolation of adult stem cells, these results may provide precious hints toward the definition of standardized protocols for microharvesting. PMID- 26002820 TI - Comparing image search behaviour in the ARRS GoldMiner search engine and a clinical PACS/RIS. AB - Information search has changed the way we manage knowledge and the ubiquity of information access has made search a frequent activity, whether via Internet search engines or increasingly via mobile devices. Medical information search is in this respect no different and much research has been devoted to analyzing the way in which physicians aim to access information. Medical image search is a much smaller domain but has gained much attention as it has different characteristics than search for text documents. While web search log files have been analysed many times to better understand user behaviour, the log files of hospital internal systems for search in a PACS/RIS (Picture Archival and Communication System, Radiology Information System) have rarely been analysed. Such a comparison between a hospital PACS/RIS search and a web system for searching images of the biomedical literature is the goal of this paper. Objectives are to identify similarities and differences in search behaviour of the two systems, which could then be used to optimize existing systems and build new search engines. Log files of the ARRS GoldMiner medical image search engine (freely accessible on the Internet) containing 222,005 queries, and log files of Stanford's internal PACS/RIS search called radTF containing 18,068 queries were analysed. Each query was preprocessed and all query terms were mapped to the RadLex (Radiology Lexicon) terminology, a comprehensive lexicon of radiology terms created and maintained by the Radiological Society of North America, so the semantic content in the queries and the links between terms could be analysed, and synonyms for the same concept could be detected. RadLex was mainly created for the use in radiology reports, to aid structured reporting and the preparation of educational material (Lanlotz, 2006) [1]. In standard medical vocabularies such as MeSH (Medical Subject Headings) and UMLS (Unified Medical Language System) specific terms of radiology are often underrepresented, therefore RadLex was considered to be the best option for this task. The results show a surprising similarity between the usage behaviour in the two systems, but several subtle differences can also be noted. The average number of terms per query is 2.21 for GoldMiner and 2.07 for radTF, the used axes of RadLex (anatomy, pathology, findings, ...) have almost the same distribution with clinical findings being the most frequent and the anatomical entity the second; also, combinations of RadLex axes are extremely similar between the two systems. Differences include a longer length of the sessions in radTF than in GoldMiner (3.4 and 1.9 queries per session on average). Several frequent search terms overlap but some strong differences exist in the details. In radTF the term "normal" is frequent, whereas in GoldMiner it is not. This makes intuitive sense, as in the literature normal cases are rarely described whereas in clinical work the comparison with normal cases is often a first step. The general similarity in many points is likely due to the fact that users of the two systems are influenced by their daily behaviour in using standard web search engines and follow this behaviour in their professional search. This means that many results and insights gained from standard web search can likely be transferred to more specialized search systems. Still, specialized log files can be used to find out more on reformulations and detailed strategies of users to find the right content. PMID- 26002821 TI - Ready for a fight? The physiological effects of detecting an opponent's pheromone cues prior to a contest. AB - Reception of pheromone cues can elicit significant physiological (e.g. steroid hormone levels) changes in the recipient. These pheromone-induced physiological changes have been well documented for male-female interactions, but scarcely in same-sex interactions (male-male and female-female). We sought to address this dearth in the current literature and examine whether mangrove rivulus fish (Kryptolebias marmoratus) could detect and, ultimately, mount a physiological response to the pheromone signature of a potential, same-sex competitor. We examined steroid hormone levels in mangrove rivulus exposed to one of three treatments: 1) isolation, 2) exposure to pheromones of a size-matched partner, and 3) pheromone exposure to a size-matched opponent followed by a physical encounter with the opponent. We found that exposure to a competitor's pheromone cues elicited a significant increase in testosterone levels. Increases in testosterone were similar across genetically distinct lineages derived from geographically distinct populations. Further, testosterone levels were similar between individuals only exposed to pheromone cues and individuals exposed to both pheromone cues and a subsequent physical encounter. Our findings led us to generate a number of testable predictions regarding how mangrove rivulus utilize pheromone signals in social interactions, the molecular mechanisms linking social stimuli and hormonal responses, and the possible adaptive benefits of hormonal responsiveness to receiving a potential competitor's pheromone cues. PMID- 26002823 TI - Antibiotics for acute laryngitis in adults. AB - BACKGROUND: This is an update of the original review published in 2005. Acute laryngitis is a common illness worldwide. Diagnosis is often made by case history alone and treatment often targets symptoms. OBJECTIVES: To assess the effectiveness and safety of different antibiotic therapies in adults with acute laryngitis. A secondary objective was to report the rates of adverse events associated with these treatments. SEARCH METHODS: We searched CENTRAL (2014, Issue 11), MEDLINE (January 1966 to November week 3, 2014), EMBASE (1974 to December 2014), LILACS (1982 to December 2014) and BIOSIS (1980 to December 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any antibiotic therapy with placebo for acute laryngitis. The main outcome was objective voice scores. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and synthesised data. MAIN RESULTS: We included three RCTs (351 participants) that had moderate to high risk of bias. The quality of the evidence was very low for all outcomes. We downgraded the studies because of limitations in study design or execution (risk of bias), imprecision and inconsistency of results. We included a new trial presented only as a conference abstract in this update.In one study of acute laryngitis in adults, 100 participants were randomised to receive penicillin V (800 mg twice daily for five days) or an identical placebo. A recording of each patient reading a standardised text was made at the first visit, during re-examination after one and two weeks, and at follow-up after two to six months. No significant differences were found between the groups. The trial also measured symptoms reported by participants and found no significant differences.One study investigated erythromycin for acute laryngitis in 106 adults. The mean objective voice scores measured at the first visit, at re-examination after one and two weeks, and at follow-up after two to six months did not significantly differ between the groups. At one week there were significant beneficial differences in the severity of reported vocal symptoms (slight, moderate and severe) as judged by participants (P value = 0.042). However, the rates of participants having improved voice disturbance (subjective symptoms) at one and two weeks were not significantly different among groups. Comparing erythromycin and placebo groups on the rate of persistence of cough at two weeks, the risk ratio (RR) was 0.38 (95% confidence interval (CI) 0.15 to 0.97, P value = 0.04) and the number needed to treat for an additional beneficial outcome (NNTB) was 5.87 (95% CI 3.09 to 65.55). We calculated a RR of 0.64 (95% CI 0.46 to 0.90, P value = 0.034) and a NNTB of 3.76 (95% CI 2.27 to 13.52; P value = 0.01) for the subjective voice scores at one week.A third trial from Russia included 145 patients with acute laryngitis symptoms. Participants were randomised to three treatment groups: Group 1: seven-day course of fusafungine (six times a day by inhalation); Group 2: seven-day course of fusafungine (six times a day by inhalation) plus clarithromycin (250 mg twice daily for seven days); Group 3: no treatment. Clinical cure rates were measured at days 5 +/- 1, 8 +/- 1 and 28 +/- 2. The authors reported significant differences in the rates of clinical cure at day 5 +/- 1 favouring fusafungine (one trial; 93 participants; RR 1.50, 95% CI 1.02 to 2.20; P value = 0.04) and fusafungine plus clarithromycin (one trial 97 participants; RR 1.47, 95% CI 1.00 to 2.16; P value = 0.05) when compared to no treatment. However, no significant differences were found at days 8 +/- 1 and 28 +/- 2. Also, no significant differences were found when comparing fusafungine to fusafungine plus clarithromycin at days 5 +/- 1, 8 +/- 1 and 28 +/- 2. AUTHORS' CONCLUSIONS: Antibiotics do not appear to be effective in treating acute laryngitis when assessing objective outcomes. They appear to be beneficial for some subjective outcomes. Erythromycin could reduce voice disturbance at one week and cough at two weeks when measured subjectively. Fusafungine could increase the cure rate at day five. The included RCTs had important methodological problems and these modest benefits from antibiotics may not outweigh their cost, adverse effects or negative consequences for antibiotic resistance patterns. PMID- 26002822 TI - The sweetness and bitterness of childhood: Insights from basic research on taste preferences. AB - In this article, we review findings from basic, experimental research on children that suggest that the liking of sweet and the dislike of bitter tastes reflect children's basic biology. Children are born preferring sweet tastes, which attract them to mother's milk and even act as an analgesic. They prefer higher levels of sweet than do adults, with preferences declining to adult levels during middle to late adolescence, which coincides with the cessation of physical growth. The level of sweetness most preferred by children has remained heightened relative to adults for nearly a decade, despite reductions in sugar, both consumed and in the food environment. In spite of these reductions, however, children's intake of sugar remains higher than that recommended by health organizations worldwide. In contrast to sweet taste, children dislike and reject bitter taste, which protects them from ingesting poisons. Although variation in bitter taste receptor genes such as TAS2R38 accounts for people's marked differences in perceptions of the same bitter-tasting compounds, basic research revealed that these genotype-phenotype relationships are modified with age, with children of the same genotype being more bitter sensitive than adults and the changeover occurring during mid-adolescence. This heightened bitter sensitivity is also evident in the taste of the foods (green vegetables) or medicines (liquid formulations of drugs) they dislike and reject. While bitter taste can be masked or blocked to varying degrees by sugars and salts, their efficacy in modulating bitterness is not only based on the type of bitter ligand but on the person's age. Children's heightened preference for sweet and dislike of bitter, though often detrimental in the modern food environment, reflects their basic biology. Increasing knowledge of individual variation in taste due to both age and genetics will shed light on potential strategies to promote healthier eating since chronic diseases derive in large part from poor food choice dictated by taste preferences, and will contribute to a new era of drug formulations designed especially for the taste palate of children. PMID- 26002824 TI - The expression of molecule CD28 and CD38 on CD4+/CD8+ T lymphocytes in thymus and spleen elicited by Schistosoma japonicum infection in mice model. AB - Schistosomiasis caused by human schistosomes such as Schistosoma japonicum (S. japonicum) is considered as an immune-related disease. It was demonstrated that specific cytokine antibodies' response elicited by S. japonicum infection was gradually downregulated with the progress of the disease, resulting in a Th1/Th2 polarization and suppression of immune response. CD28 (cluster of differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival, and CD38 is an activating marker of T lymphocyte with high expression in many acute or chronic infections. The immune signature of CD28null T cells in the peripheral circulation associates with chronic inflammation in many diseases, such as HIV and CMV infection. In the thymus, CD28 expression on developing thymocytes appears to play a role for their selection, and it synergizes with CD38 to induce apoptosis of DP (double positive) thymocytes. Few reports about CD28 and CD38 have been published in schistosomiasis. Here, we investigated the dynamic patterns of the expression of molecules CD28 and CD38 on CD4(+)/CD8(+) T lymphocytes of the thymus and spleen in mice model with S. japonicum infection. Our data indicated that at an early period of infection, the frequency of CD8(+)CD28(-) T cell in the spleen decreased significantly, but higher at chronic infection than that in control. However, it demonstrated an increasing trend in the thymus with the progression of infection. The frequency of CD4(+)CD28(-) T cells increased from acute infection in the thymus, while from chronic infection in the spleen. The expression of CD38 on CD8(+) T cells began to increase at 4 weeks post infection both in the thymus and spleen; its elevated expression on CD4(+) T cells emerged at 6 weeks post infection in the thymus and at 10 weeks post infection in the spleen. Praziquantel (PZQ) treatment could partially restore the frequency of CD28(+) T cell of CD4(+) T cells and CD38(+) T cell of CD8(+)/CD4(+) T cells in the spleen and CD38(+) T cell in the thymus. We hypothesized that the reactivation of S. japonicum infection may trigger expansion of CD28(-) T cells and hence mediate systemic inflammation. We speculated that CD8(+)CD28(-) T cell might be involved in immune modulation and CD8(+)CD28(-) T cell may be a crucial part in pathogenesis, which can provide further knowledge of the sophisticated mechanism of immuno-downregulation in schistosomiasis and potential treatment target. PMID- 26002825 TI - Annona muricata leaf extract-mediated silver nanoparticles synthesis and its larvicidal potential against dengue, malaria and filariasis vector. AB - Mosquitoes transmit several diseases which cause millions of deaths every year. The use of synthetic insecticides to control mosquitoes caused diverse effects to the environment, mammals, and high manufacturing cost. The present study was aimed to test the larvicidal activity of green synthesized silver nanoparticles using Annona muricata plant leaf extract against third instar larvae of three medically important mosquitoes, i.e., Aedes aegypti, Anopheles stephensi, and Culex quinquefasciatus. The different concentrations of green synthesized Ag Nanoparticles (AgNPs; 6, 12, 18, 24, 30 MUg mL(-1)) and aqueous crude leaf extract (30, 60, 90, 120, 150 MUg mL(-1)) were tested against the larvae for 24 h. Significant larval mortality was observed after the treatment of A. muricata for all mosquitoes with lowest LC50 and LC90 values, viz., A. aegypti (LC50 and LC90 values of 12.58 and 26.46 MUg mL(-1)), A. stephensi (LC50 and LC90 values of 15.28 and 31.91 MUg mL(-1)) and C. quinquefasciatus (LC50 and LC90 values of 18.77 and 35.72 MUg mL(-1)), respectively. The synthesized AgNPs from A. muricata were highly toxic than aqueous crude extract. The nanoparticle characterization was done using spectral and microscopic analysis, namely UV-visible spectroscopy which showed a sharp peak at 420 nm of aqueous medium containing AgNPs, X-ray diffraction (XRD) analysis revealed the average crystalline size of synthesized AgNPs (approximately 45 nm), and Fourier transform infrared spectroscopy (FTIR) study exhibited prominent peaks 3381.28, 2921.03, 1640.17, 1384.58, 1075.83, and 610.77 cm(-1). Particle size analysis (PSA) showed the size and distribution of AgNPs (103 nm); field emission scanning electron microscopy (FE-SEM) and high resolution transmission electron microscopy (HR-TEM) analysis showed a spherical shape, size range from 20 to 53 nm; and energy-dispersive X-ray spectroscopy (EDX) reflects the chemical composition of synthesized AgNPs. Heat stability of the AgNPs was confirmed between the temperatures 20 to 70 degrees C. The result suggests that green synthesized AgNPs from A. muricata has the potential to be used as a low-cost and eco-friendly approach for the control of selected mosquitoes. PMID- 26002826 TI - Circadian activity of Culicoides oxystoma (Diptera: Ceratopogonidae), potential vector of bluetongue and African horse sickness viruses in the Niayes area, Senegal. AB - Culicoides biting midges (Diptera: Ceratopogonidae) are important vectors of arboviruses in Africa. Culicoides oxystoma has been recently recorded in the Niayes region of Senegal (West Africa) and its high abundance on horses suggests a potential implication in the transmission of the African horse sickness virus in this region. This species is also suspected to transmit bluetongue virus to imported breeds of sheep. Little information is available on the biology and ecology of Culicoides in Africa. Therefore, understanding the circadian host seeking activity of this putative vector is of primary importance to assess the risk of the transmission of Culicoides-borne pathogens. To achieve this objective, midges were collected using a sheep-baited trap over two consecutive 24-h periods during four seasons in 2012. A total of 441 Culicoides, belonging to nine species including 418 (94.8%) specimens of C. oxystoma, were collected. C. oxystoma presented a bimodal circadian host-seeking activity at sunrise and sunset in July and was active 3 h after sunrise in April. Daily activity appeared mainly related to time periods. Morning activity increased with the increasing temperature up to about 27 degrees C and then decreased with the decreasing humidity, suggesting thermal limits for C. oxystoma activity. Evening activity increased with the increasing humidity and the decreasing temperature, comprised between 20 and 27 degrees C according to seasons. Interestingly, males were more abundant in our sampling sessions, with similar activity periods than females, suggesting potential animal host implication in the facilitation of reproduction. Finally, the low number of C. oxystoma collected render practical vector-control recommendations difficult to provide and highlight the lack of knowledge on the bio-ecology of this species of veterinary interest. PMID- 26002827 TI - Prevalence and molecular characterization of Cryptosporidium spp. in dairy cattle, northwest China. AB - Cryptosporidium spp. cause enteric diseases in a wide range of animals, including dairy cattle. However, limited information is available regarding prevalence and molecular characterization of Cryptosporidium spp. in dairy cattle in Gansu province and Ningxia Hui Autonomous Region (NXHAR), northwest China. A total of 2945 dairy feces samples (1257 from Gansu province and 1688 from NXHAR) were collected between December 2012 and March 2014 and were tested by PCR amplification of the small subunit (SSU) rRNA gene. A total of 150 (5.09 %, 58 from Gansu and 92 from NXHAR) samples were PCR-positive for Cryptosporidium, and the prevalence is associated with the region and age of dairy cattle. Species identification showed Cryptosporidium andersoni in 36 samples (24.00 %, 19 from NXHAR and 17 from Gansu), Cryptosporidium ryanae in 24 samples (16.00 %, 13 from NXHAR and 11 from Gansu), Cryptosporidium bovis in 70 samples (46.67 %, 41 from NXHAR and 29 from Gansu), and Cryptosporidium parvum in 20 samples (13.33 %, 19 from NXHAR and 1 from Gansu). A DNA sequence analysis of the gp60 gene suggested that all the 20 C. parvum isolates represented subtype IIdA15G1. These findings indicated the presence of zoonotic Cryptosporidium in Gansu and NXHAR. This is the first report of four species of Cryptosporidium (C. andersoni, C. ryanae, C. bovis, and C. parvum) infection in dairy cattle in Gansu province. This is also the first report of C. ryanae infection in dairy cattle in NXHAR. Effective control strategies should be implemented to prevent and control Cryptosporidium infection in dairy cattle and humans. PMID- 26002828 TI - Microglia activation: one of the checkpoints in the CNS inflammation caused by Angiostrongylus cantonensis infection in rodent model. AB - Angiostrongylus cantonensis (A. cantonensis) is a rodent nematode. Adult worms of A. cantonensis live in the pulmonary arteries of rats; humans are non-permissive hosts like the mice. The larva cannot develop into an adult worm and only causes serious eosinophilic meningitis or meningo-encephalitis if humans or mice eat food containing larva of A. cantonensis in the third stage. The differing consequences largely depend on differing immune responses of hosts to parasite during A. cantonensis invasion and development. To further understand the reasons why mice and rats attain different outcomes in A. cantonensis infection, we used the HE staining to observe the pathological changes of infected mice and rats. In addition, we measured mRNA levels of some cytokines (IL-5, IL-6, IL-13, Eotaxin, IL-4, IL-10, TGF-beta, IFN-gamma, IL-17A, TNF-alpha, IL-1beta, and iNOS) in brain tissues of mice and rats by real-time PCR. The result showed that brain inflammation in mice was more serious than in rats. Meanwhile, mRNA expression levels of IL-6, IL-1beta, TNF-alpha, and iNOS increased after mice were infected. In contrast, mRNA levels of these cytokines in rats brain tissues decreased at post- infection 21 days. These cytokines mostly were secreted by activated microglia in central nervous system. Microglia of mice and rats were showed by Iba-1 (microglia marker) staining. In micee brains, microglia got together and had more significant activation than in rats brains. The results demonstrate that mice and rats have different CNS inflammation after infection by A. cantonensis, and it is in line with other researchers' reported findings. In conclusion, it is suggested that microglia activation is probably to be one of the most important factors in angiostrongyliasis from our study. PMID- 26002829 TI - Coalescence vs. concatenation: Sophisticated analyses vs. first principles applied to rooting the angiosperms. AB - It has recently been concluded that phylogenomic data from 310 nuclear genes support the clade of (Amborellales, Nymphaeales) as sister to the remaining angiosperms and that shortcut coalescent phylogenetic methods outperformed concatenation for these data. We falsify both of those conclusions here by demonstrating that discrepant results between the coalescent and concatenation analyses are primarily caused by the coalescent methods applied (MP-EST and STAR) not being robust to the highly divergent and often mis-rooted gene trees that were used. This result reinforces the expectation that low amounts of phylogenetic signal and methodological artifacts in gene-tree reconstruction can be more problematic for shortcut coalescent methods than is the assumption of a single hierarchy for all genes by concatenation methods when these approaches are applied to ancient divergences in empirical studies. We also demonstrate that a third coalescent method, ASTRAL, is more robust to mis-rooted gene trees than MP EST or STAR, and that both Observed Variability (OV) and Tree Independent Generation of Evolutionary Rates (TIGER), which are two character subsampling procedures, are biased in favor of characters with highly asymmetrical distributions of character states when applied to this dataset. We conclude that enthusiastic application of novel tools is not a substitute for rigorous application of first principles, and that trending methods (e.g., shortcut coalescent methods applied to ancient divergences, tree-independent character subsampling), may be novel sources of previously under-appreciated, systematic errors. PMID- 26002830 TI - Surviving the Messinian Salinity Crisis? Divergence patterns in the genus Dendropoma (Gastropoda: Vermetidae) in the Mediterranean Sea. AB - Four genetically distinct clades were recently described under the name Dendropoma petraeum, a Mediterranean endemic vermetid gastropod. The aim of this work is to date the processes that drove to the diversification within this taxon and to relate them to the corresponding historical events occurred in the Mediterranean Sea. Sequences from mitochondrial and nuclear markers were obtained from specimens collected in 29 localities spanning over 4000km across the entire distribution range of D. petraeum species complex. The phylogenetic and coalescent-based analyses confirmed the four well-supported and largely differentiated lineages of D. petraeum, clearly delimited geographically along a west-east axis within the Mediterranean Sea: Western, Tyrrhenian-Sicilian, Ionian Aegean and Levantine lineages. Divergence time estimates, obtained using a range of known substitution rates for other marine gastropods, indicated two main stages of diversification. In the first period (between 9.5 and 4.5mya), the ancestral D. petraeum diverged into the current four lineages. The most recent period occurred between 3.72 and 0.66mya in the late Pliocene-early Pleistocene, and included the main within-lineage diversification events. Therefore, if the divergence time between the major lineages of Dendropoma in the Mediterranean actually predated or coincided with the Messinian Salinity Crisis, then they should have survived to this dramatic period within the Mediterranean, as supported by Bayes Factors model comparison. Conversely, if the divergence started after the crisis, congruent with the idea that no true marine organism survived the Messinian Salinity Crisis, then our results indicate substitution rates of Dendropoma much higher than usual (5.16% per million years for COI, 3.04% for 16S). More recent climate changes seem to have conditioned the demographic history of each lineage differently. While Western and Tyrrhenian Sicilian lineages both underwent an increase in their effective population sizes from 1.5 to 0.6mya coinciding with a long interglacial period, the Ionian-Aegean and Levantine lineages showed constant effective population sizes since 2-2.5mya, suggesting that these eastern lineages might represent small and relict populations surviving the subsequent Quaternary glaciations in isolated refugia. PMID- 26002831 TI - Evolutionary hierarchy of vertebrate-like heterotrimeric G protein families. AB - Heterotrimeric G proteins perform a crucial role as molecular switches controlling various cellular responses mediated by G protein-coupled receptor (GPCR) signaling pathway. Recent data have shown that the vertebrate-like G protein families are found across metazoans and their closest unicellular relatives. However, an overall evolutionary hierarchy of vertebrate-like G proteins, including gene family annotations and in particular mapping individual gene gain/loss events across diverse holozoan lineages is still incomplete. Here, with more expanded invertebrate taxon sampling, we have reconstructed phylogenetic trees for each of the G protein classes/families and provide a robust classification and hierarchy of vertebrate-like heterotrimeric G proteins. Our results further extend the evidence that the common ancestor (CA) of holozoans had at least five ancestral Galpha genes corresponding to all major vertebrate Galpha classes and contain a total of eight genes including two Gbeta and one Ggamma. Our results also indicate that the GNAI/O-like gene likely duplicated in the last CA of metazoans to give rise to GNAI- and GNAO-like genes, which are conserved across invertebrates. Moreover, homologs of GNB1-4 paralogon- and GNB5 family-like genes are found in most metazoans and that the unicellular holozoans encode two ancestral Gbeta genes. Similarly, most bilaterian invertebrates encode two Ggamma genes which include a representative of the GNG gene cluster and a putative homolog of GNG13. Interestingly, our results also revealed key evolutionary events such as the Drosophila melanogaster eye specific Gbeta subunit that is found conserved in most arthropods and several previously unidentified species specific expansions within Galphai/o, Galphas, Galphaq, Galpha12/13 classes and the GNB1-4 paralogon. Also, we provide an overall proposed evolutionary scenario on the expansions of all G protein families in vertebrate tetraploidizations. Our robust classification/hierarchy is essential to further understand the differential roles of GPCR/G protein mediated intracellular signaling system across various metazoan lineages. PMID- 26002832 TI - Altered long noncoding RNA expression profiles in the myocardium of rats with ischemic heart failure. AB - AIMS: Despite significant advances in the treatment of coronary artery disease, the prevalence of ischemic heart failure is still increasing rapidly. Long noncoding RNAs are a novel class of gene regulators and may contribute to disease cause. The aim of the present study was to investigate the expression profiles of long noncoding RNAs and their potential functional roles in ischemic heart failure. METHODS: We applied a well-established ischemic heart failure rat model and performed long noncoding RNA microarray experiments on the left ventricular tissue of rats with ischemic heart failure and under sham control. Differentially expressed long noncoding RNAs and mRNAs were identified through fold-change filtering. Bioinformatic analyses were performed to predict the potential biological roles of key long noncoding RNAs. RESULTS: We found that 1197 long noncoding RNAs and 2066 mRNAs were upregulated, whereas 1403 long noncoding RNAs and 2871 mRNAs were downregulated in failing hearts (fold-change > 2.0). We also identified 331 pairs of differentially expressed long noncoding RNAs and nearby coding genes, which contained 291 long noncoding RNAs and 296 mRNAs. Expression levels of four long noncoding RNA-mRNA pairs, which might be involved in the pathogenesis of ischemic heart failure were confirmed by quantitative real-time PCR. CONCLUSION: Our study identified a set of long noncoding RNAs that were aberrantly expressed in rats with ischemic heart failure and might be involved in the pathogenesis of ischemic heart failure. The results of our study may provide a novel perspective for better understanding the molecular basis of ischemic heart failure. PMID- 26002833 TI - Management and outcome of major bleeding in patients on triple therapy after coronary stenting. Clues from the WARfarin and coronary STENTing (WAR-STENT) registry. PMID- 26002834 TI - Control Solutions for Blood Glucose Meters: A Neglected Opportunity for Reliable Measurements? PMID- 26002835 TI - Evaluation of a Methodology for Estimating HbA1c Value by a New Glucose Meter. AB - BACKGROUND: Accuracy/robustness of HbA1c estimation (eA1c) with an algorithm built into the MyStar Extra blood glucose (BG) meter has been demonstrated by in silico testing. We evaluated the performance and use of eA1c in a clinical setting. METHODS: Subjects took the BG meter home for 4 months to obtain eA1c in this open-label, single-center study. Laboratory HbA1c values were obtained approximately every 2 weeks and the corresponding eA1c documented. Subjects completed a questionnaire at study end (NCT01885546). RESULTS: There were 133 enrolled subjects (mean [SD] age 60.0 [15.0] years, 69 males, 104 with diabetes, HbA1c 7.0% [1.4]). A total of 1008 pairs of eA1c and laboratory HbA1c values were available. In subjects with diabetes, 97.5% of the eA1c results fell within +/- 20% of the laboratory HbA1c, 95.0% within +/- 18%, and 90.7% within +/- 15%. When results were limited to the reportable HbA1c range of >= 6 to <= 10%, 99.3% of eA1c values fell within +/- 20% of the laboratory HbA1c, 98.5% within +/- 18%, and 96.2% within +/- 15% Most subjects agreed/strongly agreed that the eA1c section in the user guide and flash cards was easy to follow (72%), they would use the system to track their eA1c (70%), they found the eA1c tool helpful (79%), and the tool may motivate them to manage their diabetes better (83%). CONCLUSIONS: Accuracy of the eA1c feature in this clinical setting was similar to the performance in silico. The majority of subjects found this tool helpful and agreed it may motivate to manage their diabetes better. PMID- 26002836 TI - Performance and System Validation of a New Cellular-Enabled Blood Glucose Monitoring System Using a New Standard Reference Measurement Procedure of Isotope Dilution UPLC-MRM Mass Spectrometry. AB - BACKGROUND: We evaluated the accuracy, precision, and linearity of the In Touch blood glucose monitoring system (BGMS), a new color touch screen and cellular enabled blood glucose meter, using a new rapid, highly precise and accurate (13)C6 isotope-dilution liquid chromatography-mass spectrometry method (IDLC-MS). METHODS: Blood glucose measurements from the In Touch BGMS were referenced to a validated UPLC-MRM standard reference measurement procedure previously shown to be highly accurate and precise. Readings from the In Touch BGMS were taken over the blood glucose range of 24-640 mg/dL using 12 concentrations of blood glucose. Ten In Touch BGMS and 3 lots of test strips were used with 10 replicates at each concentration. A lay user study was also performed to assess the ease of use. RESULTS: At blood glucose concentrations <75 mg/dL 100% of the measurements are within +/-8 mg/dL from the true reference standard; at blood glucose levels >75 mg/dL 100% of the measurements are within +/-15% of the true reference standard. 100% of the results are within category A of the consensus grid. Within-run precision show CV < 3.72% between 24-50 mg/dL and CV<2.22% between 500 and 600 mg/dL. The results show that the In Touch meter exceeds the minimum criteria of both the ISO 15197:2003 and ISO 15197:2013 standards. The results from a user panel show that 100% of the respondents reported that the color touch screen, with its graphic user interface (GUI), is well labeled and easy to navigate. CONCLUSIONS: To our knowledge this is the first touch screen glucose meter and the first study where accuracy of a new BGMS has been measured against a true primary reference standard, namely IDLC-MS. PMID- 26002837 TI - Usability of the Gla-300 Injection Device Compared With Three Other Commercialized Disposable Insulin Pens: Results of an Interview-Based Survey. PMID- 26002838 TI - The effect of adjustable suture (Khaw) trabeculectomy on intraocular pressure: a retrospective case series. AB - The aim of the study is to investigate long-term intraocular pressure (IOP) outcome as well as complications associated with adjustable suture trabeculectomy in glaucoma patients who were uncontrolled under maximum medical therapy. In this retrospective case series, 35 eyes of 30 patients are included in the study. Adjustable suture trabeculectomy with 0.2 mg/cc mitomycin-C for 3 min was performed by the same surgeon. Subconjunctival 5-fluorouracil injection, transconjunctival suture adjustment, digital massage, and/or argon suturolysis were utilized postoperatively as needed. Complete success, qualified success, and failure were defined as IOP <= 18 mmHg without medication, IOP <= 18 mmHg with one or more medications, and IOP >18 mmHg with medication or need for additional glaucoma surgery, respectively. Of the 35 eyes, 13 had primary open angle, 18 had psuedoexfoliative, 1 had juvenile, 1 had pigmentary, 1 had uveitic, and 1 had chronic angle-closure glaucoma. Mean preoperative IOP of 30.1 +/- 10.5 mmHg dropped to 10.8 +/- 4.7 mmHg (p < 0.001) after a mean follow-up of 595 +/- 435 days. Nine eyes had the desired IOP on first postoperative day where no transconjunctival suture adjustment was performed. Remaining 26 eyes required a mean of two adjustments (range 1-7) during the first postoperative 24 days in order to achieve a desirable IOP. Complete success, qualified success, and failure were observed in 28 (80 %), 5 (14 %), and 2 (6 %) eyes, respectively. There were no serious complications related to adjustable suture trabeculectomy. We believe adjustable suture trabeculectomy to be a safe and effective alternative to standard trabeculectomy where a desirable low IOP can be achieved. PMID- 26002839 TI - Decreased reactivation of a herpes simplex virus type 1 (HSV-1) latency associated transcript (LAT) mutant using the in vivo mouse UV-B model of induced reactivation. AB - Blinding ocular herpetic disease in humans is due to herpes simplex virus type 1 (HSV-1) reactivations from latency, rather than to primary acute infection. The cellular and molecular immune mechanisms that control the HSV-1 latency reactivation cycle remain to be fully elucidated. The aim of this study was to determine if reactivation of the HSV-1 latency-associated transcript (LAT) deletion mutant (dLAT2903) was impaired in this model, as it is in the rabbit model of induced and spontaneous reactivation and in the trigeminal ganglia (TG) explant-induced reactivation model in mice. The eyes of mice latently infected with wild-type HSV-1 strain McKrae (LAT((+)) virus) or dLAT2903 (LAT((-)) virus) were irradiated with UV-B, and reactivation was determined. We found that compared to LAT((-)) virus, LAT((+)) virus reactivated at a higher rate as determined by shedding of virus in tears on days 3 to 7 after UV-B treatment. Thus, the UV-B-induced reactivation mouse model of HSV-1 appears to be a useful small animal model for studying the mechanisms involved in how LAT enhances the HSV-1 reactivation phenotype. The utility of the model for investigating the immune evasion mechanisms regulating the HSV-1 latency/reactivation cycle and for testing the protective efficacy of candidate therapeutic vaccines and drugs is discussed. PMID- 26002840 TI - Distal leg epidermal nerve fiber density as a surrogate marker of HIV-associated sensory neuropathy risk: risk factors and change following initial antiretroviral therapy. AB - Distal leg epidermal nerve fiber density (ENFD) is a validated predictor of HIV sensory neuropathy (SN) risk. We assessed how ENFD is impacted by initiation of first-time antiretroviral therapy (ART) in subjects free of neuropathy and how it is altered when mitochondrial toxic nucleoside medications are used as part of ART. Serial changes in proximal thigh and distal leg ENFD were examined over 72 weeks in 150 Thai subjects randomized to a regimen of stavudine (d4T) switching to zidovudine (ZDV) at 24 weeks vs ZDV vs tenofovir (TDF) for the entire duration of study, all given in combination with nevirapine. We found individual variations in ENFD change, with almost equal number of subjects who decreased or increased their distal leg ENFD over 72 weeks and no relationship to nucleoside backbone or to development of neuropathic signs or symptoms. Lower baseline distal leg ENFD and greater increases in mitochondrial oxidative phosphorylation complex I (CI) activity were associated with larger increases in distal leg ENFD over 72 weeks. Distal leg ENFD correlated with body composition parameters (body surface area, body mass index, height) as well as with blood pressure measurements. Assessed together with a companion cross-sectional study, we found that mean distal leg ENFD in all HIV+ subjects was lower than in HIV- subjects but similar among HIV+ groups whether ART-naive or on d4T with/without neuropathy/neuropathic symptoms. The utility of ENFD as a useful predictor of small unmyelinated nerve fiber damage and neuropathy risk in HIV may be limited in certain populations. PMID- 26002842 TI - The relationship between left ventricular deformation and different geometric patterns according to the updated classification: findings from the hypertensive population. AB - OBJECTIVE: We sought to investigate left ventricular mechanics in hypertensive patients with different geometric patterns by using two-dimensional (2DE) and three-dimensional (3DE) strain analysis. METHODS: This cross-sectional study included 197 hypertensive individuals who underwent a complete 2DE and 3DE examination. We applied the new updated criteria of left ventricular geometry that considered left ventricular mass index, left ventricular end-diastolic diameter and relative wall thickness. According to this classification the individuals were divided into six groups: normal geometry, concentric remodelling, eccentric nondilated left ventricular hypertrophy (LVH), concentric LVH, dilated LVH and concentric-dilated LVH. RESULTS: Multidirectional 2DE and 3DE left ventricular strain decreased from the hypertensive patients with normal geometry, across the individuals with left ventricular concentric remodelling, eccentric nondilated LVH, to the patients with concentric LVH and dilated LVH patterns. The reduction of left ventricular systolic and early diastolic strain rates was noticed to be heading in the same direction, as well as the elevation of late diastolic strain rates. Left ventricular twist and torsion were increased in the participants with concentric and dilated LVH patterns. Reduced 2DE and 3DE strains were associated with concentric and dilated LVH patterns independent of demographic and clinical parameters. CONCLUSION: Left ventricular deformation in hypertensive patients is significantly impacted by left ventricular geometry. Concentric and dilated LVH patterns have the greatest unfavourable effect on 2DE and 3DE left ventricular mechanics. The updated classification of left ventricular geometry provides valuable and comprehensive information about left ventricular mechanical deformation and function in hypertensive population. PMID- 26002841 TI - System-level impact of mitochondria on fungal virulence: to metabolism and beyond. AB - The mitochondrion plays wide-ranging roles in eukaryotic cell physiology. In pathogenic fungi, this central metabolic organelle mediates a range of functions related to disease, from fitness of the pathogen to developmental and morphogenetic transitions to antifungal drug susceptibility. In this review, we present the latest findings in this area. We focus on likely mechanisms of mitochondrial impact on fungal virulence pathways through metabolism and stress responses, but also potentially via control over signaling pathways. We highlight fungal mitochondrial proteins that lack human homologs, and which could be inhibited as a novel approach to antifungal drug strategy. PMID- 26002843 TI - Nitroglycerin-mediated, but not flow-mediated vasodilation, is associated with blunted nocturnal blood pressure fall in patients with resistant hypertension. AB - BACKGROUND: Endothelial function by flow-mediated (FMD) and nitroglycerin mediated vasodilations (NMD) was scarcely investigated in resistant hypertension. We aimed to assess the independent correlates of FMD and NMD in resistant hypertensive patients, particularly their associations with ambulatory blood pressures (BP) and nocturnal BP fall patterns. METHODS: In a cross-sectional study, 280 resistant hypertensive patients performed 24-h ambulatory BP monitoring, carotid-femoral pulse wave velocity, polysomnography, and brachial artery FMD and NMD by high-resolution ultrasonography. Independent correlates of FMD, NMD, and brachial artery diameter (BAD) were assessed by multiple linear and logistic regressions. RESULTS: Median (interquartile range) FMD was 0.75% (-0.6 to +4.4%) and NMD was 11.8% (7.1-18.4%). Baseline BAD and diabetes were independently associated with both FMD and NMD. Older age and prior cardiovascular diseases were associated with altered FMD, whereas higher night time SBP and lower nocturnal SBP fall were associated with impaired NMD. Moreover, there was a significant gradient of impaired NMD according to blunted nocturnal BP decline patterns. BAD was independently associated with age, sex, BMI, albuminuria, and nocturnal SBP fall. Further adjustments to blood flow velocity, aortic stiffness, plasma aldosterone concentration, and sleep apnea did not change these relationships. CONCLUSION: NMD, but not FMD, is independently associated with unfavorable night-time BP levels and nondipping patterns, and may be a better cardiovascular risk marker in patients with resistant hypertension. BAD also may provide additional prognostic information. PMID- 26002844 TI - Aortic calcification is associated with arterial stiffening, left ventricular hypertrophy, and diastolic dysfunction in elderly male patients with hypertension. AB - BACKGROUND: Stiffening of large arteries can result in changes of cardiac structure and function by increasing afterload to the left ventricle. Calcification has been proposed as a mechanism underlying progression of arterial stiffening. The aim of the current study was to investigate the relationship between aortic calcification, arterial stiffening, left ventricular hypertrophy, and diastolic dysfunction. METHODS: One hundred and sixty-four hypertensive elderly (>=65 years old) male patients with normal left ventricular systolic function (left ventricular ejection fraction >=55%) underwent transthoracic echocardiography, brachial-ankle pulse wave velocity (baPWV), and noncontrast computed tomography. Coronary artery calcium score and aorta calcium score (ACS) were measured on noncontrast computed tomography using the volume method. Left ventricular dimensions, mitral inflow velocities, and early mitral annular (E') velocity were measured using transthoracic echocardiography. The left ventricular mass index (LVMI) was calculated. RESULTS: The logACS was associated with mean baPWV (r = 0.387, P = 0.001), LVMI (r = 0.241, P < 0.002), E' velocity (r = 0.293, P < 0.001), and E/E' (r = 0.194, P = 0.013), suggesting arterial stiffening, increased left ventricular mass, and diastolic dysfunction in patients with raised ACS. On multivariate analysis, the LVMI showed an independent positive association with the logACS, even after adjusting for various clinical variables and the coronary artery calcium score (P = 0.009). Similarly, E' velocity also demonstrated an independent negative association with the logACS on multivariate analysis (P = 0.003). The mean baPWV, LVMI, and E' velocity showed similar correlations with both thoracic and abdominal ACS, even when thoracic and abdominal calcium scores were calculated separately. CONCLUSION: Heavy aortic calcification and resultant arterial stiffening might underlie left ventricular hypertrophy and diastolic dysfunction in elderly male patients with hypertension. PMID- 26002845 TI - IFI16 mediates soluble Flt-1 and endoglin production by trophoblast cells. AB - OBJECTIVES: Preeclampsia is a serious pregnancy-specific hypertensive syndrome that is characterized by widespread maternal endothelial dysfunction. Previous studies have shown that increased levels of circulating cell-free fetal DNA in women with preeclampsia correspond to the degree of disease severity; however, it is unknown whether this DNA is a key signal that contributes to the development of preeclampsia. The detection of DNA is critical to appropriate innate immune responses. The interferon-inducible protein 16 (IFI16) - a member of the HIN-200 family - is an innate immune receptor for intracellular DNA, which is implicated in the control of cell growth, apoptosis, angiogenesis, and immunomodulation; however, its role in preeclampsia remains unresolved. Here, we tested the hypothesis that this DNA can activate IFI16 in the placentas of women with preeclampsia and is sufficient to induce soluble fms-like tyrosine kinase 1 (sFlt 1) and soluble endoglin (sEng) production. METHODS: We characterized IFI16 in severe preeclamptic placentas and assessed whether DNA increased the release of sFlt-1 and sEng from trophoblast cells and placental explants. Furthermore, we determined whether IFI16 was involved in DNA-induced sFlt-1 and sEng production. RESULTS: Placental immunoreactivity and protein levels of IFI16 were significantly increased in women with preeclampsia compared to matched control women. Treatment of human trophoblasts with the IFI16 agonist poly(dA:dT) significantly increased IFI16 levels. Furthermore, poly(dA:dT) induced sFlt-1 and sEng production by human trophoblasts in an IFI16-dependent manner. CONCLUSIONS: We conclude that trophoblast cells respond to cell-free fetal DNA through the IFI16 receptor, resulting in the production of the preeclampsia-related antiangiogenic factors sFlt-1 and sEng. PMID- 26002846 TI - Hepatitis C Virus RNA Levels During Interferon-Free Combination Direct-Acting Antiviral Treatment in Registrational Trials. PMID- 26002847 TI - Reply to Harrington et al. PMID- 26002849 TI - Development of a Successful Scholarly Activity and Research Program for Subspecialty Trainees. AB - Training young physicians to perform research is challenging on many levels. Thus, many internal medicine training programs, including both core and subspecialty programs, struggle with providing a rigorous and successful research experience for their trainees. Here, the authors report on the rationale, design, practical implementation and outcome of a new program that was developed at the University Gastroenterology Fellowship Training Program. Before program inception, 33% of trainees presented original research at scientific meetings or published their work in peer-reviewed journals. After implementation, 100% of trainees accomplished these metrics. Additionally, the proportion of trainees remaining in academic medicine increased from 14% before implementation of the program to 51% after it began. Several elements were viewed to be critically important for the program including the following: communication of expectations and development of a robust program structure, dedicated protected time, a dedicated research curriculum, programmatic support, mentorship and oversight as well as accountability/tracking of accomplishments. The authors conclude that institutions able to adopt these or similar approaches will reap the many rewards of discovery research performed by trainees. PMID- 26002848 TI - Peer Victimization and Adolescent Adjustment: The Moderating Role of Sleep. AB - The present study examined multiple indices of sleep as moderators of the association between peer victimization and adjustment among typically developing adolescents. Participants included 252 adolescents (M = 15.79 years; 66 % European American, 34 % African American) and their parents. A multi-method, multi-informant design was employed to address the research questions. Sleep was assessed objectively with actigraphy (sleep minutes and sleep efficiency) and subjectively with self-reports. Adolescents reported on peer victimization and internalizing symptoms. Externalizing behaviors were examined with mother and father reports. Subjective sleep/wake problems moderated the associations between peer victimization and internalizing and externalizing symptoms. A stronger relation emerged between peer victimization and internalizing symptoms among adolescents who reported higher versus lower levels of sleep/wake problems. Adolescents with elevated sleep/wake problems had higher levels of externalizing symptoms across the range of peer victimization. However, for those with fewer sleep/wake problems, a positive relation between peer victimization and externalizing symptoms was observed. Actigraphy-based sleep minutes and sleep efficiency also moderated the relations between peer victimization and internalizing symptoms. Although peer victimization was associated with higher levels of internalizing symptoms for all youth, those who reported the lowest levels of such symptoms had longer and more efficient sleep in conjunction with low levels of peer victimization. Findings are novel and highlight the importance of considering both bioregulatory processes and peer relations in the prediction of adolescents' adjustment. PMID- 26002850 TI - Essential thrombocythemia-related stroke and improvement with tissue plasminogen activator. PMID- 26002851 TI - Indices of serum tonicity in clinical practice. AB - Although disturbances of serum tonicity (effective osmolality) may have dire consequences, only surrogate indices of tonicity are available in practice. This report identifies the appropriate index for expressing clinical states of dystonicity. Serum sodium concentration ([Na]S) and osmolality ([Osm]S) may be incongruent. When the tonicity state shown by [Osm]S is higher than [Na]S and the difference between the 2 indices is caused by an excess of solute that distributes in total body water, tonicity is described by [Na]S. When this difference results from a gain of solute with extracellular distribution like mannitol or a decrease in serum water content, causing a falsely low measurement of [Na]S, [Osm]S accurately reflects tonicity. Two indices of tonicity are applicable during hyperglycemia: the tonicity formula (2 .[Na]S + [Glucose]S/18) and the corrected [Na]S ([Na]S corrected to a normal [Glucose]S using an empirically derived coefficient). Clinicians should understand the uses and limitations of the tonicity indices. PMID- 26002852 TI - Infection Management and Health Practices Among Forensic Science Investigators in South Korea. AB - This study investigated the current status of infection management for forensic science investigators in South Korea. This study included 104 forensic science investigators, of which 97.1% were exposed to the blood or body fluids of corpses during handling. Of these investigators, 98% claimed they wore gloves, and 12.9% used double-layered gloves. A total of 70.6% of the participants with relevant work experience wore masks to reduce infection risk; 43% wore gowns and goggles when at risk of contracting an infection. Furthermore, 59.8% of the investigators with pertinent work experience sought appropriate first aid and treatment when they experienced contaminated skin cuts or stab wounds. Working conditions and other problems should be analyzed consistently with the cooperation of employees, occupational health practitioners, and relevant organizations to prevent work associated infections among forensic science investigators. PMID- 26002853 TI - Metabolic Syndrome Prevalence and Correlates in a Worksite Wellness Program. AB - The purpose of this study was to examine the prevalence of metabolic syndrome among faculty and staff who participated in a university wellness program. In addition, this study identified common correlates of metabolic syndrome in the participating employee population. Knowledge of behaviors and characteristics of individuals with metabolic syndrome is essential when developing health promotion strategies for them. Metabolic syndrome is unique in that it results from a clustering of risk factors that are difficult to address, and each additional risk factor increasingly affects health and well-being. A targeted, comprehensive approach is needed to counteract individual's predisposition to metabolic syndrome. This research identified the association between employees' metabolic risks and their demographic, physical, and psychosocial characteristics in an effort to determine metabolic syndrome prevalence, develop population-specific interventions, and decrease the risk of metabolic syndrome among workers. PMID- 26002854 TI - Underreporting of Workplace Violence: Comparison of Self-Report and Actual Documentation of Hospital Incidents. AB - This study examined differences between self-report and actual documentation of workplace violence (WPV) incidents in a cohort of health care workers. The study was conducted in an American hospital system with a central electronic database for reporting WPV events. In 2013, employees (n = 2010) were surveyed by mail about their experience of WPV in the previous year. Survey responses were compared with actual events entered into the electronic system. Of questionnaire respondents who self-reported a violent event in the past year, 88% had not documented an incident in the electronic system. However, more than 45% had reported violence informally, for example, to their supervisors. The researchers found that if employees were injured or lost time from work, they were more likely to formally report a violent event. Understanding the magnitude of underreporting and characteristics of health care workers who are less likely to report may assist hospitals in determining where to focus violence education and prevention efforts. PMID- 26002855 TI - Quantitative EEG and Low-Resolution Electromagnetic Tomography (LORETA) Imaging of Patients Undergoing Methadone Treatment for Opiate Addiction. AB - Methadone maintenance treatment (MMT) has been used as a treatment for opiate dependence since the mid-1960s. Evidence suggests that methadone binds to mu opiate receptors as do other opiates and induces changes in neurophysiological function. However, little is known, about how neural activity within the higher frequency gamma band (>30 Hz) while at rest changes in those stabilized on MMT despite its association with the excitation-inhibition balance within pyramidal interneuron networks. Our study investigated differences in resting gamma power (37-41 Hz) between patients undergoing MMT for opiate dependence, illicit opiate users, and healthy controls subjects. Electroencephalographic data were recorded from 26 sites according to the international 10-20 system. Compared with the healthy controls subjects, people either undergoing MMT (mean difference [MD] = 0.32, 95% CI = 0.09-0.55, P < .01) or currently using illicit opiates (MD = 0.31, 95% CI = 0.06-0.56, P = .01) exhibited significant increased gamma power. The sLORETA (standardized low-resolution electromagnetic tomography) between-group comparison revealed dysfunctional neuronal activity in the occipital, parietal, and frontal lobes in the patients undergoing MMT. A more severe profile of dysfunction was observed in those using illicit opiates. Our findings suggest that long-term exposure to opioids is associated with disrupted resting state network, which may be reduced after MMT. PMID- 26002856 TI - Writing a research article. PMID- 26002858 TI - NANN Shares Member Spotlight, 2015 Conference Registration Information. PMID- 26002859 TI - A 6th Vital Sign--Potential Use of Nasogastric Tube for Intra-abdominal Pressure Monitoring Method to Detect Feeding Intolerance in Very Low Birth-Weight Preterm Infants (<1500 g). AB - BACKGROUND: While various feeding strategies designed to optimize growth have been investigated and used in the clinical setting, the problem of not being able to recognize the warning signs of feeding intolerance early enough to prevent serious gastrointestinal complication commonly associated with very low birth weight (VLBW) preterm infant remains. Currently, early stages of feeding intolerance are most often identified though nurse assessments. Additional methods to predict feeding intolerance in this population are needed. Currently, intra-abdominal pressure monitoring has been an effective method to predict intolerance to enteral nutrition in the adult and pediatric populations. PURPOSE: There is supportive evidence for the use of noninvasive methods, such as nasogastric tubes, to effectively monitor IAP. While this may not be the gold standard method of using Foley catheters for measurement, it could provide predictive levels that are indicative of progression toward bowel inflammation. FINDINGS: This review shows the potential for using noninvasive nasogastric tubes for monitoring intra-abdominal pressure and may provide direction for evaluating intra-abdominal pressures in VLBW preterm infants as a reliable method for early identification of feeding intolerance. IMPLICATIONS FOR PRACTICE: The use of nasogastric tubes to monitor intra-abdominal pressure may provide an effective noninvasive tool to identify VLBW preterm infants progressing toward feeding intolerance and would add to assessment data. IMPLICATIONS FOR RESEARCH: Development and testing of a reliable nasogastric tube monitoring device in the VLBW preterm infant population and identify predictive levels that indicate progression toward feeding intolerance is needed. Once IAP predictive levels are identified, provider interventions could be developed. PMID- 26002860 TI - National Association of Neonatal Nurse Practitioners (NANNP) Workforce Survey. AB - BACKGROUND: As an integral member of a healthcare team, neonatal nurse practitioners (NNPs) provide care in a variety of settings that include but are not limited to all levels of inpatient care, transport, acute and chronic care settings; delivery rooms; and outpatient care settings. Anecdotal evidence indicates that responsibilities, practice environment, and workload vary widely between regions and practice settings. PURPOSE: Historically, the supply of neonatal nurse practitioners has rarely met the demand for services, although needs vary by region at any given time. Because the NNP role is a collaborative one, a shortage of NNPs leaves a gap in the team approach to care. In 2011, the National Association of Neonatal Nurse Practitioners (NANNP) commissioned the first national study of the current NNP workforce in the United States and Canada. In an effort to further explore the NNP workforce population, the NANNP Council partnered with the National Certification Corporation to perform a second workforce survey of NNPs in the spring of 2014. FINDINGS/RESULTS: The online survey was conducted between March and April 2014. The goal of the study was to describe the demographics, practice environment, scope of responsibilities, benefits and reimbursement, and job satisfaction for the current NNP workforce. IMPLICATIONS FOR PRACTICE/RESEARCH: Key areas of concern identified by the 2014 Neonatal Nurse Practitioner Workforce Survey include an aging workforce; the need for NNP faculty; inadequate staffing ratios; the lack of downtime during prolonged shifts; and the need to assisting practices in developing competency and mentoring programs. PMID- 26002861 TI - Facilitated tucking to reduce pain in neonates: evidence for best practice. AB - BACKGROUND: Increasing survival rates of preterm infants and a greater understanding of the long-term consequences of early exposure to pain have generated a greater need for nonpharmacologic pain management strategies in the neonatal intensive care unit (NICU) setting. Facilitated tucking supports the preterm infant and is a valuable strategy to manage neonatal pain. Alternative nonpharmacologic approaches to pain management in neonates include nonnutritive sucking and kangaroo care. CLINICAL QUESTION: In premature and critically ill infants, what is the effect of facilitated tucking on pain behaviors in those who received the intervention compared with those who did not, and what alternative interventions for nonpharmacologic pain reduction are supported by strong research evidence? SEARCH STRATEGY: Studies were identified in the PubMed database using the search terms: facilitated tucking, NICU, pain management, preterm infant, and nonpharmacologic. Studies were included if they were peer reviewed, were published in the last 5 years (or considered classic), and if they used experimental study designs. RESULTS: The studies identified demonstrate that facilitated tucking reduces the expression of pain in premature infants. As a whole, existing research supports the use of facilitated tucking for infants as early as 23 weeks' gestational age, during painful procedures including: heel stick, endotracheal suctioning, and venipuncture. IMPLICATIONS FOR PRACTICE AND RESEARCH: Pain management interventions are necessary to decrease the potentially unfavorable consequences of early exposure to pain and to promote positive outcomes. Additional research is indicated to discover the effects of nonpharmacologic interventions in neonates with severe illness, congenital abnormalities, and/or assisted breathing. PMID- 26002862 TI - 7th Edition NRP Brings Big Changes for NRP Instructors: The American Academy of Pediatrics. PMID- 26002864 TI - The Recent De Novo Origin of Protein C-Termini. AB - Protein-coding sequences can arise either from duplication and divergence of existing sequences, or de novo from noncoding DNA. Unfortunately, recently evolved de novo genes can be hard to distinguish from false positives, making their study difficult. Here, we study a more tractable version of the process of conversion of noncoding sequence into coding: the co-option of short segments of noncoding sequence into the C-termini of existing proteins via the loss of a stop codon. Because we study recent additions to potentially old genes, we are able to apply a variety of stringent quality filters to our annotations of what is a true protein-coding gene, discarding the putative proteins of unknown function that are typical of recent fully de novo genes. We identify 54 examples of C-terminal extensions in Saccharomyces and 28 in Drosophila, all of them recent enough to still be polymorphic. We find one putative gene fusion that turns out, on close inspection, to be the product of replicated assembly errors, further highlighting the issue of false positives in the study of rare events. Four of the Saccharomyces C-terminal extensions (to ADH1, ARP8, TPM2, and PIS1) that survived our quality filters are predicted to lead to significant modification of a protein domain structure. PMID- 26002865 TI - Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis. AB - RATIONALE: Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. OBJECTIVE: We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways. METHODS AND RESULTS: In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1 mediated cholesterol efflux. Specifically, anti-miR33 derepressed the novel target genes PGC-1alpha, PDK4, and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe(-/-) mice with anti miR33 oligonucleotides reduced aortic sinus lesion area compared with controls, despite no changes in high-density lipoprotein cholesterol or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared with normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1alpha, SLC25A25, NRF1, and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans. CONCLUSIONS: This study demonstrates that anti-miR33 therapy derepresses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis. PMID- 26002866 TI - Genome-Wide Mapping of Structural Variations Reveals a Copy Number Variant That Determines Reproductive Morphology in Cucumber. AB - Structural variations (SVs) represent a major source of genetic diversity. However, the functional impact and formation mechanisms of SVs in plant genomes remain largely unexplored. Here, we report a nucleotide-resolution SV map of cucumber (Cucumis sativas) that comprises 26,788 SVs based on deep resequencing of 115 diverse accessions. The largest proportion of cucumber SVs was formed through nonhomologous end-joining rearrangements, and the occurrence of SVs is closely associated with regions of high nucleotide diversity. These SVs affect the coding regions of 1676 genes, some of which are associated with cucumber domestication. Based on the map, we discovered a copy number variation (CNV) involving four genes that defines the Female (F) locus and gives rise to gynoecious cucumber plants, which bear only female flowers and set fruit at almost every node. The CNV arose from a recent 30.2-kb duplication at a meiotically unstable region, likely via microhomology-mediated break-induced replication. The SV set provides a snapshot of structural variations in plants and will serve as an important resource for exploring genes underlying key traits and for facilitating practical breeding in cucumber. PMID- 26002867 TI - The Arabidopsis R-SNARE VAMP721 Interacts with KAT1 and KC1 K+ Channels to Moderate K+ Current at the Plasma Membrane. AB - SNARE (soluble N-ethylmaleimide-sensitive factor protein attachment protein receptor) proteins drive vesicle traffic, delivering membrane and cargo to target sites within the cell and at its surface. They contribute to cell homeostasis, morphogenesis, and pathogen defense. A subset of SNAREs, including the Arabidopsis thaliana SNARE SYP121, are known also to coordinate solute uptake via physical interactions with K(+) channels and to moderate their gating at the plasma membrane. Here, we identify a second subset of SNAREs that interact to control these K(+) channels, but with opposing actions on gating. We show that VAMPs (vesicle-associated membrane proteins), which target vesicles to the plasma membrane, also interact with and suppress the activities of the inward-rectifying K(+) channels KAT1 and KC1. Interactions were evident in yeast split-ubiquitin assays, they were recovered in vivo by ratiometric bimolecular fluorescence complementation, and they were sensitive to mutation of a single residue, Tyr-57, within the longin domain of VAMP721. Interaction was also recovered on exchange of the residue at this site in the homolog VAMP723, which normally localizes to the endoplasmic reticulum and otherwise did not interact. Functional analysis showed reduced channel activity and alterations in voltage sensitivity that are best explained by a physical interaction with the channel gates. These actions complement those of SYP121, a cognate SNARE partner of VAMP721, and lead us to propose that the channel interactions reflect a "hand-off" in channel control between the two SNARE proteins that is woven together with vesicle fusion. PMID- 26002868 TI - A Gibberellin-Mediated DELLA-NAC Signaling Cascade Regulates Cellulose Synthesis in Rice. AB - Cellulose, which can be converted into numerous industrial products, has important impacts on the global economy. It has long been known that cellulose synthesis in plants is tightly regulated by various phytohormones. However, the underlying mechanism of cellulose synthesis regulation remains elusive. Here, we show that in rice (Oryza sativa), gibberellin (GA) signals promote cellulose synthesis by relieving the interaction between SLENDER RICE1 (SLR1), a DELLA repressor of GA signaling, and NACs, the top-layer transcription factors for secondary wall formation. Mutations in GA-related genes and physiological treatments altered the transcription of CELLULOSE SYNTHASE genes (CESAs) and the cellulose level. Multiple experiments demonstrated that transcription factors NAC29/31 and MYB61 are CESA regulators in rice; NAC29/31 directly regulates MYB61, which in turn activates CESA expression. This hierarchical regulation pathway is blocked by SLR1-NAC29/31 interactions. Based on the results of anatomical analysis and GA content examination in developing rice internodes, this signaling cascade was found to be modulated by varied endogenous GA levels and to be required for internode development. Genetic and gene expression analyses were further performed in Arabidopsis thaliana GA-related mutants. Altogether, our findings reveal a conserved mechanism by which GA regulates secondary wall cellulose synthesis in land plants and provide a strategy for manipulating cellulose production and plant growth. PMID- 26002870 TI - A Transcriptomic Approach to Evolutionary Genetics of Giant Horsetail. PMID- 26002869 TI - Regulation of Jasmonate-Mediated Stamen Development and Seed Production by a bHLH MYB Complex in Arabidopsis. AB - Stamens are the plant male reproductive organs essential for plant fertility. Proper development of stamens is modulated by environmental cues and endogenous hormone signals. Deficiencies in biosynthesis or perception of the phytohormone jasmonate (JA) attenuate stamen development, disrupt male fertility, and abolish seed production in Arabidopsis thaliana. This study revealed that JA-mediated stamen development and seed production are regulated by a bHLH-MYB complex. The IIIe basic helix-loop-helix (bHLH) transcription factor MYC5 acts as a target of JAZ repressors to function redundantly with other IIIe bHLH factors such as MYC2, MYC3, and MYC4 in the regulation of stamen development and seed production. The myc2 myc3 myc4 myc5 quadruple mutant exhibits obvious defects in stamen development and significant reduction in seed production. Moreover, these IIIe bHLH factors interact with the MYB transcription factors MYB21 and MYB24 to form a bHLH-MYB transcription complex and cooperatively regulate stamen development. We speculate that the JAZ proteins repress the bHLH-MYB complex to suppress stamen development and seed production, while JA induces JAZ degradation and releases the bHLH-MYB complex to subsequently activate the expression of downstream genes essential for stamen development and seed production. PMID- 26002872 TI - Mind the Gap: The Effect of Keyboard Key Gap and Pitch on Typing Speed, Accuracy, and Usability, Part 3. AB - OBJECTIVE: The aim of this study was to evaluate the effects of key gap (distance between edges of keys) on computer keyboards on typing speed, percentage error, preference, and usability. BACKGROUND: In Parts 1 and 2 of this series, a small key pitch (center-to-center distance between keys) was found to reduce productivity and usability, but the findings were confounded by gap. In this study, key gap was varied while holding key pitch constant. METHOD: Participants (N = 25) typed on six keyboards, which differed in gap between keys (1, 3, or 5 mm) and pitch (16 or 17 mm; distance between centers of keys), while typing speed, accuracy, usability, and preference were measured. RESULTS: There was no statistical interaction between gap and pitch. Accuracy was better for keyboards with a gap of 5 mm compared to a 1-mm gap (p = .04). Net typing speed (p = .02), accuracy (p = .002), and most usability measures were better for keyboards with a pitch of 17 mm compared to a 16-mm pitch. CONCLUSIONS: The study findings support keyboard designs with a gap between keys of 5 mm over 1 mm and a key pitch of 17 mm over 16 mm. APPLICATIONS: These findings may influence keyboard standards and design, especially the design of small keyboards used with portable devices, such as tablets and laptops. PMID- 26002871 TI - Horsetails Are Ancient Polyploids: Evidence from Equisetum giganteum. AB - Horsetails represent an enigmatic clade within the land plants. Despite consisting only of one genus (Equisetum) that contains 15 species, they are thought to represent the oldest extant genus within the vascular plants dating back possibly as far as the Triassic. Horsetails have retained several ancient features and are also characterized by a particularly high chromosome count (n = 108). Whole-genome duplications (WGDs) have been uncovered in many angiosperm clades and have been associated with the success of angiosperms, both in terms of species richness and biomass dominance, but remain understudied in nonangiosperm clades. Here, we report unambiguous evidence of an ancient WGD in the fern lineage, based on sequencing and de novo assembly of an expressed gene catalog (transcriptome) from the giant horsetail (Equisetum giganteum). We demonstrate that horsetails underwent an independent paleopolyploidy during the Late Cretaceous prior to the diversification of the genus but did not experience any recent polyploidizations that could account for their high chromosome number. We also discuss the specific retention of genes following the WGD and how this may be linked to their long-term survival. PMID- 26002874 TI - Toward a Clinically Meaningful Taxonomy of Violent Offenders: The Role of Anger and Thinking Styles. AB - Violent offender rehabilitation programs aim to reduce the risk of re-offending in known offenders by addressing a range of different treatments needs, often with core intervention targets of improving anger regulation and altering antisocial beliefs and thinking styles. Such programs have proven efficacy in reducing recidivism for some, but not all, violent offenders, and little is known about the effects of these programs on different offender types. This study investigates whether subtypes of violent offenders can be meaningfully identified and considers how this influences short-term treatment outcomes. Cluster analysis identified three distinctive violent offender groups within a sample of 305 male offenders who had been assessed for participation in a violent offender rehabilitation program. An "unregulated" group had high levels of anger experience and expression and low levels of anger control, and held beliefs that were strongly supportive of a criminal lifestyle. A "regulated" group demonstrated levels of anger and beliefs supporting criminal activity that were not in a range that warranted treatment. Finally, an "overregulated" group was assessed as the group at highest risk of violent re-offending and had low levels of anger experience and expression and an absence of beliefs supporting criminal activity. The unregulated group appeared to gain the most benefit from treatment, although it had the highest levels of criminal thinking and problematic anger. These findings nonetheless offer support for the hypothesis that violent offender treatment programs may be optimally effective when targeted at particular types of offenders. PMID- 26002873 TI - Developing an Integrated Violence Prevention for Men and Women in Treatment for Substance Use Disorders. AB - Rates of past-year partner and non-partner violence perpetration (VP) in substance use disorder (SUD) treatment samples exceed 50%, with studies showing rates of past-year VP exceeding 70% when considering violence occurring with either intimate partners or non-partners. However, SUD treatment programs typically do not include VP prevention interventions, and the few studies examining the impact of SUD interventions on VP have focused exclusively on partner VP. This study summarizes results of a randomized controlled pilot study of an Integrated Violence Prevention Treatment (IVPT) designed to address VP across partner and non-partner relationships as well as predictors of post treatment VP. Participants were men (70%) and women (30%) in SUD treatment reporting past-year VP who were randomized to either IVPT or a control condition. The IVPT involved a Motivational Interviewing session targeting interpersonal conflicts, followed by five cognitive-behavioral therapy sessions focusing on VP prevention skills. The control condition included a session including a videotape and discussion of anger management, followed by five psycho-educational sessions common for SUD settings. Results showed that VP (total, partner, and non-partner) and cocaine use significantly decreased between baseline and 3-month follow-up for both conditions, and the IVPT group showed a significant decline in alcohol use. Analyses focusing on VP during follow-up revealed that baseline cocaine use and drinking during the follow-up predicted post-treatment VP. Together, these findings suggest that IVPT is a promising intervention (feasible, appears to impact drinking, an important factor related to violence) but that additional continuing care approaches may be indicated to sustain positive outcomes. PMID- 26002875 TI - Preventing Interpersonal Violence on College Campuses: The Effect of One Act Training on Bystander Intervention. AB - Sexual assault, stalking, dating violence, and intimate partner violence, herein collectively termed interpersonal violence (IV), are public health problems affecting 20% to 25% of female college students. Currently, One Act is one of the few IV prevention training programs at universities that teach students bystander skills to intervene in low- and high-risk IV situations. The objectives of this study were 1) to evaluate One Act's effects on date rape attitudes and behaviors, and bystanders' confidence, willingness to help, and behavior, and 2) to compare the effects on bystander skills between One Act and Helping Advocates for Violence Ending Now (HAVEN), an IV response training program with similar participants. Data were collected over 2 years, before and after One Act and HAVEN trainings. We measured outcomes with four scales: College Date Rape Attitudes and Behaviors, Bystander Confidence, Willingness to Help, and Bystander Behavior. The analysis compared within- and between-group mean differences in scale scores pre- and post-trainings using linear mixed models. One Act showed improvements for date rape attitudes and behaviors ( p < .001), bystander's confidence ( p < .001), and willingness to help ( p < .001). One Act participants' bystander confidence improved more ( p = .006), on average, than HAVEN's. The differences in the two trainings' effects on bystander willingness to help and behavior had similar patterns but were not statistically significant. We found a larger positive impact on bystander confidence among students who participated in the bystander prevention training compared with the response training. Further research is needed to improve the measures for bystander behavior and measure the bystander trainings' larger impact on the community. PMID- 26002876 TI - Tensions and Ambivalent Feelings: Opinions of Emergency Department Employees About the Identification and Management of Intimate Partner Violence. AB - The objective of this study was to examine factors facilitating and constraining the identification and management of intimate partner violence (IPV) at an emergency department (ED). Semi-structured interviews were conducted with 18 ED employees of a university hospital in the Netherlands. All interviews were audiotaped, transcribed verbatim, and analyzed by using qualitative content analysis in Atlas.ti. Constraining factors were lack of knowledge, awareness, and resources at the ED. ED employees felt many barriers to bringing up IPV. Facilitating factors were good cooperation among staff, the involvement of one team member in producing an IPV protocol, having received training on child abuse, and private consulting rooms. The ED setting and the ED employees' task perception and attitude contained both constraining and facilitating factors: ED employees saw it as their task and responsibility to help IPV victims, but their priorities were to secure a high turnover and treat acute physical problems. Although ED employees expressed openness and willingness to help, they also took the view that victims had a considerable responsibility of their own in disclosing and managing IPV, which led to ambivalent feelings. In conclusion, ED employees faced tensions in IPV identification and management caused by lack of awareness, knowledge and resources, conflicting priorities at the ED, and ambivalent feelings. Improvements can be made by supporting ED employees with guidelines in the form of a protocol and with training that also addresses the tensions ED employees face. PMID- 26002877 TI - Parental Support Buffering the Effect of Violence on Adolescents' Depression: Gender Differences. AB - In Mexico violence across the country has increased in recent years and has become a social problem of great importance. The continuous exposure to all types of interpersonal violence leads adolescents to cope with experiences and challenges of great risk of development deviations. Trying to find a more comprehensive understanding of violence outcomes on Mexican adolescents and its moderators, the present quantitative, non-experimental, cross-sectional correlation study was performed. Parental support ( vs. other sort of social support) was proposed to be a relevant moderator factor for decreasing the negative outcomes of violence exposure on depression, and gender was predicted to play a role in this process. A two-way interaction between violence exposure and parental support was only significant in the case of adolescent girls, whereas there was no evidence of such moderation for adolescent boys. The effect of exposure to violence on girls' depression was stronger when their parental support was relatively low than when their parental support was relatively high. Parental support may serve as a protective factor of depression after violence exposure especially for girls, whereas more research should be conducted in order to detect an efficient protective mechanism for boys who are exposed to violence. PMID- 26002878 TI - Effectiveness of the IDAP Treatment Program for Male Perpetrators of Intimate Partner Violence: A Controlled Study of Criminal Recidivism. AB - Despite substantial problems with intimate partner violence (IPV) worldwide, the empirical support remains weak for the effectiveness of recidivism-reducing interventions for IPV perpetrators. We conducted a controlled study of the effectiveness of the Integrated Domestic Abuse Program (IDAP), a manual-based group intervention for adult male IPV offenders. A consecutive series of 340 convicted male IPV offenders who began IDAP in the Swedish Prison and Probation Services 2004 to 2007 were compared with 452 contemporary, convicted male IPV offender controls. We obtained follow-up reconviction data from the National Crime Register and used Cox regression to model the effectiveness of IDAP versus regular treatment. Treated and control subjects were all followed until March 2, 2011, for an average time-at-risk of 4.6 years (median 4.4, SD = 1.0). Twenty five percent ( n = 84) of IDAP participants recidivated in any violence versus 23% of controls ( n = 104); corresponding figures for IPV specifically were 19% ( n = 65) and 19% ( n = 84), respectively. Intention-to-treat analyses adjusted for individual baseline risk and follow-up time suggested marginally and non significantly lower reconviction rates in IDAP participants versus controls (hazard ratio [HR] = 0.92, 95% confidence interval [CI] = [0.69, 1.23] for any violence and HR = 0.92, 95% CI = [0.66, 1.28] for IPV, respectively). Hence, possible recidivism-reducing effects of IDAP in this cross-cultural validation were small and impossible to secure statistically. To remedy the frustrating lack of proven effective treatments for IPV offenders, better interventions should be developed and tested. Such efforts could benefit from improved knowledge about IPV-specific, causal risk factors and more powerful treatment combinations. PMID- 26002879 TI - Heavy Episodic Drinking and Sexual Aggression Among Male College Students: The Protective Influence of Church Attendance. AB - Much research has examined personal characteristics that increase the risk of men engaging in sexual aggression. Heavy episodic drinking, typically operationalized for males as consuming five or more standard drinks of alcohol in a 2-hr period, is one factor that has been found in most studies to be associated with higher risk for sexual aggression. Although relatively little empirical attention has been given to personal characteristics that can protect men from perpetrating sexual aggression, research on factors that are tied to less alcohol use may be fruitful in this regard. Accordingly, the current study examined if church attendance protected against sexual aggression perpetration by reducing heavy episodic drinking among male students who completed survey questionnaires during their first, second, and third years of college. The results showed increased church attendance over the first and second years of college was associated with lower levels of subsequent, heavy episodic drinking and sexual aggression. Moreover, the results indicated lower levels of heavy episodic drinking mediated the protective effect of church attendance on sexual aggression. These findings can inform sexual aggression prevention efforts in the male, college student population. PMID- 26002880 TI - Nucleomorph Genome Sequences of Two Chlorarachniophytes, Amorphochlora amoebiformis and Lotharella vacuolata. AB - Many algal groups acquired complex plastids by the uptake of green and red algae through multiple secondary endosymbioses. As a result of gene loss and transfer during the endosymbiotic processes, algal endosymbiont nuclei disappeared in most cases. However, chlorarachniophytes and cryptophytes still possess a relict nucleus, so-called the nucleomorph, of the green and red algal endosymbiont, respectively. Nucleomorph genomes are an interesting and suitable model to study the reductive evolution of endosymbiotically derived genomes. To date, nucleomorph genomes have been sequenced in four cryptophyte species and two chlorarachniophyte species, including Bigelowiella natans (373 kb) and Lotharella oceanica (610 kb). In this study, we report complete nucleomorph genome sequences of two chlorarachniophytes, Amorphochlora amoebiformis and Lotharella vacuolata, to gain insight into the reductive evolution of nucleomorph genomes in the chlorarachniophytes. The nucleomorph genomes consist of three chromosomes totaling 374 and 432 kb in size in A. amoebiformis and L. vacuolata, respectively. Comparative analyses among four chlorarachniophyte nucleomorph genomes revealed that these sequences share 171 function-predicted genes (86% of total 198 function-predicted nucleomorph genes), including the same set of genes encoding 17 plastid-associated proteins, and no evidence of a recent nucleomorph to-nucleus gene transfer was found. This suggests that chlorarachniophyte nucleomorph genomes underwent most of their reductive evolution prior to the radiation of extent members of the group. However, there are slight variations in genome size, GC content, duplicated gene number, and subtelomeric regions among the four nucleomorph genomes, suggesting that the genomes might be undergoing changes that do not affect the core functions in each species. PMID- 26002881 TI - Reverse engineering of logic-based differential equation models using a mixed integer dynamic optimization approach. AB - MOTIVATION: Systems biology models can be used to test new hypotheses formulated on the basis of previous knowledge or new experimental data, contradictory with a previously existing model. New hypotheses often come in the shape of a set of possible regulatory mechanisms. This search is usually not limited to finding a single regulation link, but rather a combination of links subject to great uncertainty or no information about the kinetic parameters. RESULTS: In this work, we combine a logic-based formalism, to describe all the possible regulatory structures for a given dynamic model of a pathway, with mixed-integer dynamic optimization (MIDO). This framework aims to simultaneously identify the regulatory structure (represented by binary parameters) and the real-valued parameters that are consistent with the available experimental data, resulting in a logic-based differential equation model. The alternative to this would be to perform real-valued parameter estimation for each possible model structure, which is not tractable for models of the size presented in this work. The performance of the method presented here is illustrated with several case studies: a synthetic pathway problem of signaling regulation, a two-component signal transduction pathway in bacterial homeostasis, and a signaling network in liver cancer cells. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: julio@iim.csic.es or saezrodriguez@ebi.ac.uk. PMID- 26002882 TI - PopGeV: a web-based large-scale population genome browser. AB - MOTIVATION: The development of high-throughput sequencing technology has made it possible for more and more researchers to use population sequencing data to mine genes associated with specific traits. However, the massive amounts of sequencing data have also brought new challenges to the researchers. The question of how to browse population genomic data in an easy and intuitive manner must be addressed. Web-based genome browsers allow user to conveniently view the results of genomic analyses, but heavy usage can reduce the response speed of the webpage, which limits its usefulness in the display of large-scale genome data. IndexedDB technology is a good solution to this problem; it supports web browsers and so creates local databases. In this way, data can be read from the local storage, achieving a smooth display of population genomic data. RESULTS: PopGeV has the following characteristics. First, it uses a new encoding method for compression of population SNP and INDEL data. IndexedDB technology is used to download the results to local storage so that users can browse the results smoothly even when the network traffic is heavy. Second, PopGeV identify similar genomic regions between two individuals based on SNP data. Population diversity indexes are calculated when comparing two populations. Third, user defined annotation information can be integrated for user-friendly mining of gene functions. Simulation shows that PopGeV can smoothly display analysis results of population genome containing over 500 individuals with 2 millions SNP data. AVAILABILITY AND IMPLEMENTATION: PopGeV is available at www.soyomics.com/popgev/ CONTACT: yuanxh@iga.ac.cn. PMID- 26002883 TI - pwOmics: an R package for pathway-based integration of time-series omics data using public database knowledge. AB - Characterization of biological processes is progressively enabled with the increased generation of omics data on different signaling levels. Here we present a straightforward approach for the integrative analysis of data from different high-throughput technologies based on pathway and interaction models from public databases. pwOmics performs pathway-based level-specific data comparison of coupled human proteomic and genomic/transcriptomic datasets based on their log fold changes. Separate downstream and upstream analyses results on the functional levels of pathways, transcription factors and genes/transcripts are performed in the cross-platform consensus analysis. These provide a basis for the combined interpretation of regulatory effects over time. Via network reconstruction and inference methods (Steiner tree, dynamic Bayesian network inference) consensus graphical networks can be generated for further analyses and visualization. AVAILABILITY AND IMPLEMENTATION: The R package pwOmics is freely available on Bioconductor (http://www.bioconductor.org/). CONTACT: astrid.wachter@med.uni goettingen.de. PMID- 26002884 TI - tmle.npvi: targeted, integrative search of associations between DNA copy number and gene expression, accounting for DNA methylation. AB - We describe the implementation of the method introduced by Chambaz et al. in 2012. We also demonstrate its genome-wide application to the integrative search of new regions with strong association between DNA copy number and gene expression accounting for DNA methylation in breast cancers. AVAILABILITY AND IMPLEMENTATION: An open-source R package tmle.npvi is available from CRAN (http://cran.r-project.org/). CONTACT: pierre.neuvial@genopole.cnrs.fr. PMID- 26002885 TI - Bayesian mixture analysis for metagenomic community profiling. AB - MOTIVATION: Deep sequencing of clinical samples is now an established tool for the detection of infectious pathogens, with direct medical applications. The large amount of data generated produces an opportunity to detect species even at very low levels, provided that computational tools can effectively profile the relevant metagenomic communities. Data interpretation is complicated by the fact that short sequencing reads can match multiple organisms and by the lack of completeness of existing databases, in particular for viral pathogens. Here we present metaMix, a Bayesian mixture model framework for resolving complex metagenomic mixtures. We show that the use of parallel Monte Carlo Markov chains for the exploration of the species space enables the identification of the set of species most likely to contribute to the mixture. RESULTS: We demonstrate the greater accuracy of metaMix compared with relevant methods, particularly for profiling complex communities consisting of several related species. We designed metaMix specifically for the analysis of deep transcriptome sequencing datasets, with a focus on viral pathogen detection; however, the principles are generally applicable to all types of metagenomic mixtures. AVAILABILITY AND IMPLEMENTATION: metaMix is implemented as a user friendly R package, freely available on CRAN: http://cran.r-project.org/web/packages/metaMix CONTACT: sofia.morfopoulou.10@ucl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bionformatics online. PMID- 26002886 TI - Diffusion maps for high-dimensional single-cell analysis of differentiation data. AB - MOTIVATION: Single-cell technologies have recently gained popularity in cellular differentiation studies regarding their ability to resolve potential heterogeneities in cell populations. Analyzing such high-dimensional single-cell data has its own statistical and computational challenges. Popular multivariate approaches are based on data normalization, followed by dimension reduction and clustering to identify subgroups. However, in the case of cellular differentiation, we would not expect clear clusters to be present but instead expect the cells to follow continuous branching lineages. RESULTS: Here, we propose the use of diffusion maps to deal with the problem of defining differentiation trajectories. We adapt this method to single-cell data by adequate choice of kernel width and inclusion of uncertainties or missing measurement values, which enables the establishment of a pseudotemporal ordering of single cells in a high-dimensional gene expression space. We expect this output to reflect cell differentiation trajectories, where the data originates from intrinsic diffusion-like dynamics. Starting from a pluripotent stage, cells move smoothly within the transcriptional landscape towards more differentiated states with some stochasticity along their path. We demonstrate the robustness of our method with respect to extrinsic noise (e.g. measurement noise) and sampling density heterogeneities on simulated toy data as well as two single-cell quantitative polymerase chain reaction datasets (i.e. mouse haematopoietic stem cells and mouse embryonic stem cells) and an RNA-Seq data of human pre implantation embryos. We show that diffusion maps perform considerably better than Principal Component Analysis and are advantageous over other techniques for non-linear dimension reduction such as t-distributed Stochastic Neighbour Embedding for preserving the global structures and pseudotemporal ordering of cells. AVAILABILITY AND IMPLEMENTATION: The Matlab implementation of diffusion maps for single-cell data is available at https://www.helmholtz muenchen.de/icb/single-cell-diffusion-map. CONTACT: fbuettner.phys@gmail.com, fabian.theis@helmholtz-muenchen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26002887 TI - The prevalence rate of Porphyromonas gingivalis and its association with cancer: A systematic review and meta-analysis. AB - It seems that Porphyromanas gingivalis is carcinogenic, because it activates a number of inflammatory immune responses in the host and causes disorders in bacterial clearance mechanisms. There is little information on the prevalence of this bacterium in cancer patients. The aim of this study was to evaluate and compare the prevalence of P. gingivalis in cancer patients by meta-analysis methods.Different databases including PubMed, EMBASE, the Cochrane Library, Scopus, and ISI web of Knowledge were investigated and eight relevant articles published in 2000-2013 were finally analyzed. Data were analyzed by meta-analysis method, fixed effect model. I2 statistics were calculated to examine the heterogeneity of papers. The information was analyzed by R and STATA Ver 12.2.A total of 711 people infected with P. gingivalis were included in this study. In total, the prevalence of P. gingivalis was 40.7% (95% CI, 19.3-62.1). The prevalence of P. gingivalis was evaluated in four case-control studies. The results of this study showed that P. gingivalis increased the chance of cancer development and periodontal disease as much as 1.36 times (OR, 1.36; 95%CI, 0.47 3.97).Although there was no significant correlation between P. gingivalis and cancer, this bacterium increased the chance of cancer and periodontal disease and could be considered as a main potential risk factor. PMID- 26002888 TI - Oxygen for ST-Segment-Elevation Myocardial Infarction: Still Up in the Air. PMID- 26002890 TI - Acoustic Dispensing Preserves the Potency of Therapeutic Peptides throughout the Entire Drug Discovery Workflow. AB - Routine peptide structure-activity relationship screening requires the serial dilution of peptides to produce full concentration-response curves. Established tip-based protocols involve multiple tip changes and high exposure to plasticware. In the case of peptides, this becomes a challenge, since peptides can adsorb to plastic, resulting in an observed loss of potency. Various methods can be employed to prevent peptide loss during compound handling, such as the inclusion of bovine serum albumin or solvents in assay buffer and the siliconization of plasticware, yet protein binding remains unpredictable. The degree of variation by which peptides will adhere to plasticware can confuse results and cause inaccuracies in potency predictions. We evaluated acoustic noncontact methods for peptide serial dilution and compared it with traditional tip-based methods, on the effect on potency curves for glucagon-like peptide-1 and glucagon peptide analogues. The current study demonstrates the benefits of noncontact dispensing for high-density microplate assay preparation of peptides using nanoliter droplets across our entire drug discovery workflow, from in vitro high-throughput screening to drug exposure determinations from in vivo samples. PMID- 26002889 TI - Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. AB - BACKGROUND: Oxygen is commonly administered to patients with ST-elevation myocardial infarction despite previous studies suggesting a possible increase in myocardial injury as a result of coronary vasoconstriction and heightened oxidative stress. METHODS AND RESULTS: We conducted a multicenter, prospective, randomized, controlled trial comparing oxygen (8 L/min) with no supplemental oxygen in patients with ST-elevation-myocardial infarction diagnosed on paramedic 12-lead ECG. Of 638 patients randomized, 441 patients had confirmed ST-elevation myocardial infarction and underwent primary end-point analysis. The primary end point was myocardial infarct size as assessed by cardiac enzymes, troponin I, and creatine kinase. Secondary end points included recurrent myocardial infarction, cardiac arrhythmia, and myocardial infarct size assessed by cardiac magnetic resonance imaging at 6 months. Mean peak troponin was similar in the oxygen and no oxygen groups (57.4 versus 48.0 MUg/L; ratio, 1.20; 95% confidence interval, 0.92-1.56; P=0.18). There was a significant increase in mean peak creatine kinase in the oxygen group compared with the no oxygen group (1948 versus 1543 U/L; means ratio, 1.27; 95% confidence interval, 1.04-1.52; P=0.01). There was an increase in the rate of recurrent myocardial infarction in the oxygen group compared with the no oxygen group (5.5% versus 0.9%; P=0.006) and an increase in frequency of cardiac arrhythmia (40.4% versus 31.4%; P=0.05). At 6 months, the oxygen group had an increase in myocardial infarct size on cardiac magnetic resonance (n=139; 20.3 versus 13.1 g; P=0.04). CONCLUSION: Supplemental oxygen therapy in patients with ST-elevation-myocardial infarction but without hypoxia may increase early myocardial injury and was associated with larger myocardial infarct size assessed at 6 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01272713. PMID- 26002891 TI - Feline Calicivirus, Murine Norovirus, Porcine Sapovirus, and Tulane Virus Survival on Postharvest Lettuce. AB - Human norovirus (HuNoV) is the leading cause of foodborne illnesses, with an increasing number of outbreaks associated with leafy greens. Because HuNoV cannot be routinely cultured, culturable feline calicivirus (FCV), murine norovirus (MNV), porcine sapovirus (SaV), and Tulane virus (TV) have been used as surrogates. These viruses are generated in different cell lines as infected cell lysates, which may differentially affect their stability. Our objective was to uniformly compare the survival of these viruses on postharvest lettuce while evaluating the effects of cell lysates on their survival. Viruses were semipurified from cell lysates by ultrafiltration or ultracentrifugation followed by resuspension in sterile water. Virus survival was examined before and after semipurification: in suspension at room temperature (RT) until day 28 and on lettuce leaves stored at RT for 3 days or at 4 degrees C for 7 and 14 days. In suspension, both methods significantly enhanced the survival of all viruses. On lettuce, the survival of MNV in cell lysates was similar to that in water, under all storage conditions. In contrast, the survival of FCV, SaV, and TV was differentially enhanced, under different storage conditions, by removing cell lysates. Following semipurification, viruses showed similar persistence to each other on lettuce stored under all conditions, with the exception of ultracentrifugation-purified FCV, which showed a higher inactivation rate than MNV at 4 degrees C for 14 days. In conclusion, the presence of cell lysates in viral suspensions underestimated the survivability of these surrogate viruses, while viral semipurification revealed similar survivabilities on postharvest lettuce leaves. PMID- 26002893 TI - Microbial Source Tracking in Adjacent Karst Springs. AB - Modern man-made environments, including urban, agricultural, and industrial environments, have complex ecological interactions among themselves and with the natural surroundings. Microbial source tracking (MST) offers advanced tools to resolve the host source of fecal contamination beyond indicator monitoring. This study was intended to assess karst spring susceptibilities to different fecal sources using MST quantitative PCR (qPCR) assays targeting human, bovine, and swine markers. It involved a dual-time monitoring frame: (i) monthly throughout the calendar year and (ii) daily during a rainfall event. Data integration was taken from both monthly and daily MST profile monitoring and improved identification of spring susceptibility to host fecal contamination; three springs located in close geographic proximity revealed different MST profiles. The Giach spring showed moderate fluctuations of MST marker quantities amid wet and dry samplings, while the Zuf spring had the highest rise of the GenBac3 marker during the wet event, which was mirrored in other markers as well. The revelation of human fecal contamination during the dry season not connected to incidents of raining leachates suggests a continuous and direct exposure to septic systems. Pigpens were identified in the watersheds of Zuf, Shefa, and Giach springs and on the border of the Gaaton spring watershed. Their impact was correlated with partial detection of the Pig-2-Bac marker in Gaaton spring, which was lower than detection levels in all three of the other springs. Ruminant and swine markers were detected intermittently, and their contamination potential during the wet samplings was exposed. These results emphasized the importance of sampling design to utilize the MST approach to delineate subtleties of fecal contamination in the environment. PMID- 26002892 TI - Whole-Genome Sequence Analysis and Genome-Wide Virulence Gene Identification of Riemerella anatipestifer Strain Yb2. AB - Riemerella anatipestifer is a well-described pathogen of waterfowl and other avian species that can cause septicemic and exudative diseases. In this study, we sequenced the complete genome of R. anatipestifer strain Yb2 and analyzed it against the published genomic sequences of R. anatipestifer strains DSM15868, RA GD, RA-CH-1, and RA-CH-2. The Yb2 genome contains one circular chromosome of 2,184,066 bp with a 35.73% GC content and no plasmid. The genome has 2,021 open reading frames that occupy 90.88% of the genome. A comparative genomic analysis revealed that genome organization is highly conserved among R. anatipestifer strains, except for four inversions of a sequence segment in Yb2. A phylogenetic analysis found that the closest neighbor of Yb2 is RA-GD. Furthermore, we constructed a library of 3,175 mutants by random transposon mutagenesis, and 100 mutants exhibiting more than 100-fold-attenuated virulence were obtained by animal screening experiments. Southern blot analysis and genetic characterization of the mutants led to the identification of 49 virulence genes. Of these, 25 encode cytoplasmic proteins, 6 encode cytoplasmic membrane proteins, 4 encode outer membrane proteins, and the subcellular localization of the remaining 14 gene products is unknown. The functional classification of orthologous-group clusters revealed that 16 genes are associated with metabolism, 6 are associated with cellular processing and signaling, and 4 are associated with information storage and processing. The functions of the other 23 genes are poorly characterized or unknown. This genome-wide study identified genes important to the virulence of R. anatipestifer. PMID- 26002894 TI - Mining for Nonribosomal Peptide Synthetase and Polyketide Synthase Genes Revealed a High Level of Diversity in the Sphagnum Bog Metagenome. AB - Sphagnum bog ecosystems are among the oldest vegetation forms harboring a specific microbial community and are known to produce an exceptionally wide variety of bioactive substances. Although the Sphagnum metagenome shows a rich secondary metabolism, the genes have not yet been explored. To analyze nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), the diversity of NRPS and PKS genes in Sphagnum-associated metagenomes was investigated by in silico data mining and sequence-based screening (PCR amplification of 9,500 fosmid clones). The in silico Illumina-based metagenomic approach resulted in the identification of 279 NRPSs and 346 PKSs, as well as 40 PKS-NRPS hybrid gene sequences. The occurrence of NRPS sequences was strongly dominated by the members of the Protebacteria phylum, especially by species of the Burkholderia genus, while PKS sequences were mainly affiliated with Actinobacteria. Thirteen novel NRPS-related sequences were identified by PCR amplification screening, displaying amino acid identities of 48% to 91% to annotated sequences of members of the phyla Proteobacteria, Actinobacteria, and Cyanobacteria. Some of the identified metagenomic clones showed the closest similarity to peptide synthases from Burkholderia or Lysobacter, which are emerging bacterial sources of as-yet-undescribed bioactive metabolites. This report highlights the role of the extreme natural ecosystems as a promising source for detection of secondary compounds and enzymes, serving as a source for biotechnological applications. PMID- 26002895 TI - Coupling the CRISPR/Cas9 System with Lambda Red Recombineering Enables Simplified Chromosomal Gene Replacement in Escherichia coli. AB - To date, most genetic engineering approaches coupling the type II Streptococcus pyogenes clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system to lambda Red recombineering have involved minor single nucleotide mutations. Here we show that procedures for carrying out more complex chromosomal gene replacements in Escherichia coli can be substantially enhanced through implementation of CRISPR/Cas9 genome editing. We developed a three-plasmid approach that allows not only highly efficient recombination of short single stranded oligonucleotides but also replacement of multigene chromosomal stretches of DNA with large PCR products. By systematically challenging the proposed system with respect to the magnitude of chromosomal deletion and size of DNA insertion, we demonstrated DNA deletions of up to 19.4 kb, encompassing 19 nonessential chromosomal genes, and insertion of up to 3 kb of heterologous DNA with recombination efficiencies permitting mutant detection by colony PCR screening. Since CRISPR/Cas9-coupled recombineering does not rely on the use of chromosome encoded antibiotic resistance, or flippase recombination for antibiotic marker recycling, our approach is simpler, less labor-intensive, and allows efficient production of gene replacement mutants that are both markerless and "scar"-less. PMID- 26002896 TI - Arcobacter butzleri, Arcobacter cryaerophilus, and Arcobacter skirrowii Circulation in a Dairy Farm and Sources of Milk Contamination. AB - Even though dairy cows are known carriers of Arcobacter species and raw or minimally processed foods are recognized as the main sources of human Arcobacter infections in industrialized countries, data on Arcobacter excretion patterns in cows and in milk are scant. This study aimed to identify potentially pathogenic Arcobacter species in a dairy herd and to investigate the routes of Arcobacter transmission among animals and the potential sources of cattle infection and milk contamination. A strategy of sampling the same 50 dairy animals, feed, water, and milk every month for a 10-month period, as well as the sampling of quarter milk, animal teats, the milking environment, and animals living on the farm (pigeons and cats), was used to evaluate, by pulsed-field gel electrophoresis (PFGE), the characteristic patterns in animals, their living environment, and the raw milk they produced. Of the 463 samples collected, 105 (22.6%) were positive for Arcobacter spp. by culture examination. All the matrices except quarter milk and pigeon gut samples were positive, with prevalences ranging from 15 to 83% depending on the sample. Only three Arcobacter species, Arcobacter cryaerophilus (54.2%), A. butzleri (34.2%), and A. skirrowii (32.3%), were detected. PFGE analysis of 370 isolates from positive samples provided strong evidence of Arcobacter circulation in the herd: cattle likely acquire the microorganisms by orofecal transmission, either by direct contact or from the environment, or both. Water appears to be a major source of animal infection. Raw milk produced by the farm and collected from a bulk tank was frequently contaminated (80%) by A. butzleri; our PFGE findings excluded primary contamination of milk, whereas teats and milking machine surfaces could be sources of Arcobacter milk contamination. PMID- 26002897 TI - Microbiota Dynamics Associated with Environmental Conditions and Potential Roles of Cellulolytic Communities in Traditional Chinese Cereal Starter Solid-State Fermentation. AB - Traditional Chinese solid-state fermented cereal starters contain highly complex microbial communities and enzymes. Very little is known, however, about the microbial dynamics related to environmental conditions, and cellulolytic communities have never been proposed to exist during cereal starter fermentation. In this study, we performed Illumina MiSeq sequencing combined with PCR denaturing gradient gel electrophoresis to investigate microbiota, coupled with clone library construction to trace cellulolytic communities in both fermentation stages. A succession of microbial assemblages was observed during the fermentation of starters. Lactobacillales and Saccharomycetales dominated the initial stages, with a continuous decline in relative abundance. However, thermotolerant and drought-resistant Bacillales, Eurotiales, and Mucorales were considerably accelerated during the heating stages, and these organisms dominated until the end of fermentation. Enterobacteriales were consistently ubiquitous throughout the process. For the cellulolytic communities, only the genera Sanguibacter, Beutenbergia, Agrobacterium, and Erwinia dominated the initial fermentation stages. In contrast, stages at high incubation temperature induced the appearance and dominance of Bacillus, Aspergillus, and Mucor. The enzymatic dynamics of amylase and glucoamylase also showed a similar trend, with the activities clearly increased in the first 7 days and subsequently decreased until the end of fermentation. Furthermore, beta-glucosidase activity continuously and significantly increased during the fermentation process. Evidently, cellulolytic potential can adapt to environmental conditions by changes in the community structure during the fermentation of starters. PMID- 26002898 TI - Changes in Sodium, Calcium, and Magnesium Ion Concentrations That Inhibit Geobacillus Biofilms Have No Effect on Anoxybacillus flavithermus Biofilms. AB - This study investigated the effects of varied sodium, calcium, and magnesium concentrations in specialty milk formulations on biofilm formation by Geobacillus spp. and Anoxybacillus flavithermus. The numbers of attached viable cells (log CFU per square centimeter) after 6 to 18 h of biofilm formation by three dairy derived strains of Geobacillus and three dairy-derived strains of A. flavithermus were compared in two commercial milk formulations. Milk formulation B had relatively high sodium and low calcium and magnesium concentrations compared with those of milk formulation A, but the two formulations had comparable fat, protein, and lactose concentrations. Biofilm formation by the three Geobacillus isolates was up to 4 log CFU cm(-2) lower in milk formulation B than in milk formulation A after 6 to 18 h, and the difference was often significant (P <= 0.05). However, no significant differences (P <= 0.05) were found when biofilm formations by the three A. flavithermus isolates were compared in milk formulations A and B. Supplementation of milk formulation A with 100 mM NaCl significantly decreased (P <= 0.05) Geobacillus biofilm formation after 6 to 10 h. Furthermore, supplementation of milk formulation B with 2 mM CaCl2 or 2 mM MgCl2 significantly increased (P <= 0.05) Geobacillus biofilm formation after 10 to 18 h. It was concluded that relatively high free Na(+) and low free Ca(2+) and Mg(2+) concentrations in milk formulations are collectively required to inhibit biofilm formation by Geobacillus spp., whereas biofilm formation by A. flavithermus is not impacted by typical cation concentration differences of milk formulations. PMID- 26002899 TI - Genetic Structure and Antimicrobial Resistance of Escherichia coli and Cryptic Clades in Birds with Diverse Human Associations. AB - The manner and extent to which birds associate with humans may influence the genetic attributes and antimicrobial resistance of their commensal Escherichia communities through strain transmission and altered selection pressures. In this study, we determined whether the distribution of the different Escherichia coli phylogenetic groups and cryptic clades, the occurrence of 49 virulence associated genes, and/or the prevalence of resistance to 12 antimicrobials differed between four groups of birds from Australia with contrasting types of human association. We found that birds sampled in suburban and wilderness areas had similar Escherichia communities. The Escherichia communities of backyard domestic poultry were phylogenetically distinct from the Escherichia communities sourced from all other birds, with a large proportion (46%) of poultry strains belonging to phylogenetic group A and a significant minority (17%) belonging to the cryptic clades. Wild birds sampled from veterinary and wildlife rehabilitation centers (in-care birds) carried Escherichia isolates that possessed particular virulence associated genes more often than Escherichia isolates from birds sampled in suburban and wilderness areas. The Escherichia isolates from both the backyard poultry and in-care birds were more likely to be multidrug resistant than the Escherichia isolates from wild birds. We also detected a multidrug-resistant E. coli strain circulating in a wildlife rehabilitation center, reinforcing the importance of adequate hygiene practices when handling and caring for wildlife. We suggest that the relatively high frequency of antimicrobial resistance in the in-care birds and backyard poultry is due primarily to the use of antimicrobials in these animals, and we recommend that the treatment protocols used for these birds be reviewed. PMID- 26002900 TI - Automated Sampling Procedures Supported by High Persistence of Bacterial Fecal Indicators and Bacteroidetes Genetic Microbial Source Tracking Markers in Municipal Wastewater during Short-Term Storage at 5 degrees C. AB - Because of high diurnal water quality fluctuations in raw municipal wastewater, the use of proportional autosampling over a period of 24 h at municipal wastewater treatment plants (WWTPs) to evaluate carbon, nitrogen, and phosphorus removal has become a standard in many countries. Microbial removal or load estimation at municipal WWTPs, however, is still based on manually recovered grab samples. The goal of this study was to establish basic knowledge regarding the persistence of standard bacterial fecal indicators and Bacteroidetes genetic microbial source tracking markers in municipal wastewater in order to evaluate their suitability for automated sampling, as the potential lack of persistence is the main argument against such procedures. Raw and secondary treated wastewater of municipal origin from representative and well-characterized biological WWTPs without disinfection (organic carbon and nutrient removal) was investigated in microcosm experiments at 5 and 21 degrees C with a total storage time of 32 h (including a 24-h autosampling component and an 8-h postsampling phase). Vegetative Escherichia coli and enterococci, as well as Clostridium perfringens spores, were selected as indicators for cultivation-based standard enumeration. Molecular analysis focused on total (AllBac) and human-associated genetic Bacteroidetes (BacHum-UCD, HF183 TaqMan) markers by using quantitative PCR, as well as 16S rRNA gene-based next-generation sequencing. The microbial parameters showed high persistence in both raw and treated wastewater at 5 degrees C under the storage conditions used. Surprisingly, and in contrast to results obtained with treated wastewater, persistence of the microbial markers in raw wastewater was also high at 21 degrees C. On the basis of our results, 24-h autosampling procedures with 5 degrees C storage conditions can be recommended for the investigation of fecal indicators or Bacteroidetes genetic markers at municipal WWTPs. Such autosampling procedures will contribute to better understanding and monitoring of municipal WWTPs as sources of fecal pollution in water resources. PMID- 26002901 TI - Survival of Listeria monocytogenes in Soil Requires AgrA-Mediated Regulation. AB - In a recent paper, we demonstrated that inactivation of the Agr system affects the patterns of survival of Listeria monocytogenes (A.-L. Vivant, D. Garmyn, L. Gal, and P. Piveteau, Front Cell Infect Microbiol 4:160, http://dx.doi.org/10.3389/fcimb.2014.00160). In this study, we investigated whether the Agr-mediated response is triggered during adaptation in soil, and we compared survival patterns in a set of 10 soils. The fate of the parental strain L. monocytogenes L9 (a rifampin-resistant mutant of L. monocytogenes EGD-e) and that of a DeltaagrA deletion mutant were compared in a collection of 10 soil microcosms. The DeltaagrA mutant displayed significantly reduced survival in these biotic soil microcosms, and differential transcriptome analyses showed large alterations of the transcriptome when AgrA was not functional, while the variations in the transcriptomes between the wild type and the DeltaagrA deletion mutant were modest under abiotic conditions. Indeed, in biotic soil environments, 578 protein-coding genes and an extensive repertoire of noncoding RNAs (ncRNAs) were differentially transcribed. The transcription of genes coding for proteins involved in cell envelope and cellular processes, including the phosphotransferase system and ABC transporters, and proteins involved in resistance to antimicrobial peptides was affected. Under sterilized soil conditions, the differences were limited to 86 genes and 29 ncRNAs. These results suggest that the response regulator AgrA of the Agr communication system plays important roles during the saprophytic life of L. monocytogenes in soil. PMID- 26002902 TI - Increasing Avermectin Production in Streptomyces avermitilis by Manipulating the Expression of a Novel TetR-Family Regulator and Its Target Gene Product. AB - Avermectins produced by Streptomyces avermitilis are commercially important anthelmintic agents. The detailed regulatory mechanisms of avermectin biosynthesis remain unclear. Here, we identified SAV3619, a TetR-family transcriptional regulator designated AveT, to be an activator for both avermectin production and morphological differentiation in S. avermitilis. AveT was shown to indirectly stimulate avermectin production by affecting transcription of the cluster-situated activator gene aveR. AveT directly repressed transcription of its own gene (aveT), adjacent gene pepD2 (sav_3620), sav_7490 (designated aveM), and sav_7491 by binding to an 18-bp perfect palindromic sequence (CGAAACGKTKYCGTTTCG, where K is T or G and Y is T or C and where the underlining indicates inverted repeats) within their promoter regions. aveM (which encodes a putative transmembrane efflux protein belonging to the major facilitator superfamily [MFS]), the important target gene of AveT, had a striking negative effect on avermectin production and morphological differentiation. Overexpression of aveT and deletion of aveM in wild-type and industrial strains of S. avermitilis led to clear increases in the levels of avermectin production. In vitro gel-shift assays suggested that C-5-O-B1, the late pathway precursor of avermectin B1, acts as an AveT ligand. Taken together, our findings indicate positive-feedback regulation of aveT expression and avermectin production by a late pathway intermediate and provide the basis for an efficient strategy to increase avermectin production in S. avermitilis by manipulation of AveT and its target gene product, AveM. PMID- 26002903 TI - Dual Roles of Capsular Extracellular Polymeric Substances in Photocatalytic Inactivation of Escherichia coli: Comparison of E. coli BW25113 and Isogenic Mutants. AB - The dual roles of capsular extracellular polymeric substances (EPS) in the photocatalytic inactivation of bacteria were demonstrated in a TiO2-UVA system, by comparing wild-type Escherichia coli strain BW25113 and isogenic mutants with upregulated and downregulated production of capsular EPS. In a partition system in which direct contact between bacterial cells and TiO2 particles was inhibited, an increase in the amount of EPS was associated with increased bacterial resistance to photocatalytic inactivation. In contrast, when bacterial cells were in direct contact with TiO2 particles, an increase in the amount of capsular EPS decreased cell viability during photocatalytic treatment. Taken together, these results suggest that although capsular EPS can protect bacterial cells by consuming photogenerated reactive species, it also facilitates photocatalytic inactivation of bacteria by promoting the adhesion of TiO2 particles to the cell surface. Fluorescence microscopy and scanning electron microscopy analyses further confirmed that high capsular EPS density led to more TiO2 particles attaching to cells and forming bacterium-TiO2 aggregates. Calculations of interaction energy, represented by extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) potential, suggested that the presence of capsular EPS enhances the attachment of TiO2 particles to bacterial cells via acid-base interactions. Consideration of these mechanisms is critical for understanding bacterium nanoparticle interactions and the photocatalytic inactivation of bacteria. PMID- 26002904 TI - Living-Donor Kidney Transplantation: Reducing Financial Barriers to Live Kidney Donation--Recommendations from a Consensus Conference. AB - Live-donor kidney transplantation (LDKT) is the best treatment for eligible people with late-stage kidney disease. Despite this, living kidney donation rates have declined in the United States in recent years. A potential source of this decline is the financial impact on potential and actual living kidney donors (LKDs). Recent evidence indicates that the economic climate may be associated with the decline in LDKT and that there are nontrivial financial ramifications for some LKDs. In June 2014, the American Society of Transplantation's Live Donor Community of Practice convened a Consensus Conference on Best Practices in Live Kidney Donation. The conference included transplant professionals, patients, and other key stakeholders (with the financial support of 10 other organizations) and sought to identify best practices, knowledge gaps, and opportunities pertaining to living kidney donation. This workgroup was tasked with exploring systemic and financial barriers to living kidney donation. The workgroup reviewed literature that assessed the financial effect of living kidney donation, analyzed employment and insurance factors, discussed international models for addressing direct and indirect costs faced by LKDs, and summarized current available resources. The workgroup developed the following series of recommendations to reduce financial and systemic barriers and achieve financial neutrality for LKDs: (1) allocate resources for standardized reimbursement of LKDs' lost wages and incidental costs; (2) pass legislation to offer employment and insurability protections to LKDs; (3) create an LKD financial toolkit to provide standardized, vetted education to donors and providers about options to maximize donor coverage and minimize financial effect within the current climate; and (4) promote further research to identify systemic barriers to living donation and LDKT to ensure the creation of mitigation strategies. PMID- 26002905 TI - Message from the ISCB: 2015 ISCB Accomplishment by a Senior Scientist Award: Cyrus Chothia. AB - The International Society for Computational Biology (ISCB; http://www.iscb.org) honors a senior scientist annually for his or her outstanding achievements with the ISCB Accomplishment by a Senior Scientist Award. This award recognizes a leader in the field of computational biology for his or her significant contributions to the community through research, service and education. Cyrus Chothia, an emeritus scientist at the Medical Research Council Laboratory of Molecular Biology and emeritus fellow of Wolfson College at Cambridge University, England, is the 2015 ISCB Accomplishment by a Senior Scientist Award winner.Chothia was selected by the Awards Committee, which is chaired by Dr Bonnie Berger of the Massachusetts Institute of Technology. He will receive his award and deliver a keynote presentation at 2015 Intelligent Systems for Molecular Biology/European Conference on Computational Biology in Dublin, Ireland, in July 2015. CONTACT: dkovats@iscb.org. PMID- 26002906 TI - A novel essential domain perspective for exploring gene essentiality. AB - MOTIVATION: Genes with indispensable functions are identified as essential; however, the traditional gene-level studies of essentiality have several limitations. In this study, we characterized gene essentiality from a new perspective of protein domains, the independent structural or functional units of a polypeptide chain. RESULTS: To identify such essential domains, we have developed an Expectation-Maximization (EM) algorithm-based Essential Domain Prediction (EDP) Model. With simulated datasets, the model provided convergent results given different initial values and offered accurate predictions even with noise. We then applied the EDP model to six microbial species and predicted 1879 domains to be essential in at least one species, ranging 10-23% in each species. The predicted essential domains were more conserved than either non-essential domains or essential genes. Comparing essential domains in prokaryotes and eukaryotes revealed an evolutionary distance consistent with that inferred from ribosomal RNA. When utilizing these essential domains to reproduce the annotation of essential genes, we received accurate results that suggest protein domains are more basic units for the essentiality of genes. Furthermore, we presented several examples to illustrate how the combination of essential and non-essential domains can lead to genes with divergent essentiality. In summary, we have described the first systematic analysis on gene essentiality on the level of domains. CONTACT: huilu.bioinfo@gmail.com or Long.Lu@cchmc.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26002907 TI - Epigenetic Changes in Hybrids. AB - Genome-wide approaches to the study of hybrid vigor have identified epigenetic changes in the hybrid nucleus in Arabidopsis (Arabidopsis thaliana), maize (Zea mays), and rice (Oryza sativa). DNA methylation associated with 24-nucleotide small interfering RNAs exhibits transallelic effects in hybrids of Arabidopsis and other species. Some of the transmethylation changes are inherited and some affect gene expression. Hybrids have larger leaves than those of the parents and have increases in cell size and number. The increased leaf size results in a greater photosynthetic capacity, which may support the increased vegetative and reproductive yields of the F1 hybrids. Genes and metabolic pathways that have altered expression relative to the parents include loci involved in responses to hormones and to biotic and abiotic stress. Whereas epigenetically induced changes in gene expression may contribute to hybrid vigor, the link between the transcriptional changes and the hybrid phenotype is not confirmed. Recurrent selection of high yielding F1 lines from the F2/F3 of a number of crops has fixed heterosis yields in pure breeding lines. These hybrid-like lines may have valuable applications in crop systems. PMID- 26002910 TI - Linking Health System Responsiveness to Political Rights and Civil Liberties: A Multilevel Analysis Using Data From 44 Countries. AB - Responsiveness is a dimension of health system functioning and might be dependent upon contextual factors related to politics. Given this, we performed cross national comparisons with the aim of investigating: 1) the associations of political factors with patients' reports of health system responsiveness and 2) the extent to which health input and output might explain these associations. World Health Survey data were analyzed for 44 countries (n = 103 541). Main outcomes included, respectively, 8 and 7 responsiveness domains for inpatient and outpatient care. Linear multilevel regressions were used to assess the associations of politics (namely, civil liberties and political rights), socioeconomic development, health system input, and health system output (measured by maternal mortality) with responsiveness domains, adjusted for demographic factors. Political rights showed positive associations with dignity (regression coefficient = 0.086 [standard error = 0.039]), quality (0.092 [0.049]), and support (0.113 [0.048]) for inpatient care and with dignity (0.075 [0.040]), confidentiality (0.089 [0.043]), and quality (0.124 [0.053]) for outpatient care. Positive associations were observed for civil liberties as well. Health system input and output reduced observed associations. Results tentatively suggest that strengthening political rights and, to a certain extent, civil liberties might improve health system responsiveness, in part through their effect on health system input and output. PMID- 26002912 TI - Outstanding Merit Award for 2014. PMID- 26002908 TI - TANG1, Encoding a Symplekin_C Domain-Contained Protein, Influences Sugar Responses in Arabidopsis. AB - Sugars not only serve as energy and cellular carbon skeleton but also function as signaling molecules regulating growth and development in plants. Understanding the molecular mechanisms in sugar signaling pathways will provide more information for improving plant growth and development. Here, we describe a sugar hypersensitive recessive mutant, tang1. Light-grown tang1 mutants have short roots and increased starch and anthocyanin contents when grown on high-sugar concentration medium. Dark-grown tang1 plants exhibit sugar-hypersensitive hypocotyl elongation and enhanced dark development. The tang1 mutants also show an enhanced response to abscisic acid but reduced response to ethylene. Thus, tang1 displays a range of alterations in sugar signaling-related responses. The TANG1 gene was isolated by a map-based cloning approach and encodes a previously uncharacterized unique protein with a predicted Symplekin tight-junction protein C terminus. Expression analysis indicates that TANG1 is ubiquitously expressed at moderate levels in different organs and throughout the Arabidopsis (Arabidopsis thaliana) life cycle; however, its expression is not affected by high-sugar treatment. Genetic analysis shows that PRL1 and TANG1 have additive effects on sugar-related responses. Furthermore, the mutation of TANG1 does not affect the expression of genes involved in known sugar signaling pathways. Taken together, these results suggest that TANG1, a unique gene, plays an important role in sugar responses in Arabidopsis. PMID- 26002909 TI - GENERAL CONTROL NONREPRESSED PROTEIN5-Mediated Histone Acetylation of FERRIC REDUCTASE DEFECTIVE3 Contributes to Iron Homeostasis in Arabidopsis. AB - Iron homeostasis is essential for plant growth and development. Here, we report that a mutation in GENERAL CONTROL NONREPRESSED PROTEIN5 (GCN5) impaired iron translocation from the root to the shoot in Arabidopsis (Arabidopsis thaliana). Illumina high-throughput sequencing revealed 879 GCN5-regulated candidate genes potentially involved in iron homeostasis. Chromatin immunoprecipitation assays indicated that five genes (At3G08040, At2G01530, At2G39380, At2G47160, and At4G05200) are direct targets of GCN5 in iron homeostasis regulation. Notably, GCN5-mediated acetylation of histone 3 lysine 9 and histone 3 lysine 14 of FERRIC REDUCTASE DEFECTIVE3 (FRD3) determined the dynamic expression of FRD3. Consistent with the function of FRD3 as a citrate efflux protein, the iron retention defect in gcn5 was rescued and fertility was partly restored by overexpressing FRD3. Moreover, iron retention in gcn5 roots was significantly reduced by the exogenous application of citrate. Collectively, these data suggest that GCN5 plays a critical role in FRD3-mediated iron homeostasis. Our results provide novel insight into the chromatin-based regulation of iron homeostasis in Arabidopsis. PMID- 26002916 TI - Pharmacotherapy for type 2 diabetes in very elderly patients: practicing nihilism or pragmatism? PMID- 26002918 TI - The ethics of biomedical markets. PMID- 26002919 TI - Correction. AB - Gillon R. Defending the four principles approach as a good basis for good medical practice and therefore for good medical ethics. J Med Ethics 2015;41:111-6. The author misrepresented Beauchamp and Childress when he wrote: 'My own view (unlike Beauchamp and Childress who explicitly state that they make no such claim ( p. 421)1, is that all moral agents whether or not they are doctors or otherwise involved in healthcare have these prima facie moral obligations; but in the context of answering the question 'what is it to do good medical ethics ?' my claim is limited to the ethical obligations of doctors'. The author intended and should have written the following: 'My own view, unlike Beauchamp and Childress who explicitly state that they make no such claim (p.421)1 is that these four prima facie principles can provide a basic moral framework not only for medical ethics but for ethics in general'. PMID- 26002917 TI - The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling. AB - Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding matricellular protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in the mouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These data highlight novel functions of CCN1 as a naturally optimized molecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses. PMID- 26002921 TI - Correction for Bacon et al., Biological evidence supports an early and complex emergence of the Isthmus of Panama. PMID- 26002922 TI - Colloidal test bed for universal dynamics of phase transitions. PMID- 26002923 TI - Resting heart rate and the risk of developing impaired fasting glucose and diabetes: the Kailuan prospective study. AB - BACKGROUND: To investigate the association between resting heart rate and the risk of developing impaired fasting glucose (IFG), diabetes and conversion from IFG to diabetes. METHODS: The prospective analysis included 73,357 participants of the Kailuan cohort (57,719 men and 15,638 women). Resting heart rate was measured via electrocardiogram in 2006. Incident diabetes was defined as either the fasting blood glucose (FBG) >= 7.0 mmol/l or new active use of diabetes medications during the 4-year follow-up period. IFG was defined as a FBG between 5.6 and 6.9 mmol/l. A meta-analysis including seven published prospective studies focused on heart rate and diabetes risk, and our current study was then conducted using random-effects models. RESULTS: During 4 years of follow-up, 17,463 incident IFG cases and 4,649 incident diabetes cases were identified. The corresponding adjusted hazard ratios (HRs) for each 10 beats/min increase in heart rate were 1.23 [95% confidence interval (CI): 1.19, 1.27] for incident diabetes, 1.11 (95% CI: 1.09, 1.13) for incident IFG and 1.13 (95% CI: 1.08, 1.17) for IFG to diabetes conversion. The risks of incident IFG and diabetes were significantly higher among participants aged < 50 years than those aged >= 50 years (P-interaction < 0.02 for both). A meta-analysis confirmed the positive association between resting heart rate and diabetes risk (pooled HR for the highest vs lowest heart rate quintile = 1.59, 95% CI:1.27, 2.00; n = 8). CONCLUSION: Faster resting heart rate is associated with higher risk of developing IFG and diabetes, suggesting that heart rate could be used to identify individuals with a higher future risk of diabetes. PMID- 26002925 TI - Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life. AB - BACKGROUND: We investigated the effects of fetal growth restriction (FGR) induced by maternal protein restriction on inflammatory vascular remodeling using a cuff induced vascular injury mouse model. METHODS: Dams (C57BL/6J strain mice) were fed an isocaloric diet containing 20% protein (normal protein; NP) or 8% protein (low protein; LP) from 10 weeks of age until delivery. On the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed the NP diet. When offspring were 10 weeks of age, vascular injury was induced by polyethylene cuff placement around the femoral artery. RESULTS: Birth weight in offspring from dams fed LP until delivery (LPO) was significantly lower, but body weight was the same at 2 weeks after birth compared with that in NP offspring (NPO). Arterial blood pressure at 12 weeks of age did not differ between LPO and NPO. Neointima formation was exaggerated in LPO compared with NPO and associated with an increase in cell proliferation assessed by proliferating cell nuclear antigen (PCNA) staining index. Moreover, LPO showed enhanced expression of monocyte chemotactic protein-1, interleukin (IL)-6, IL-1beta, tumor necrosis factor-alpha, and production of superoxide anion in the injured artery. Moreover, mRNA expression of isoforms of NAD(P)H oxidase subunits such as p22phox, p40phox, p47phox, p67phox, gp91phpx, and Rac1 in the injured arteries were enhanced in LPO. Furthermore, HIF-1alpha expression was increased in LPO compared with that in NPO. CONCLUSIONS: These results suggest that maternal low-protein diet-induced FGR increases susceptibility of the vasculature to postnatal injury. PMID- 26002924 TI - RAD-QTL Mapping Reveals Both Genome-Level Parallelism and Different Genetic Architecture Underlying the Evolution of Body Shape in Lake Whitefish (Coregonus clupeaformis) Species Pairs. AB - Parallel changes in body shape may evolve in response to similar environmental conditions, but whether such parallel phenotypic changes share a common genetic basis is still debated. The goal of this study was to assess whether parallel phenotypic changes could be explained by genetic parallelism, multiple genetic routes, or both. We first provide evidence for parallelism in fish shape by using geometric morphometrics among 300 fish representing five species pairs of Lake Whitefish. Using a genetic map comprising 3438 restriction site-associated DNA sequencing single-nucleotide polymorphisms, we then identified quantitative trait loci underlying body shape traits in a backcross family reared in the laboratory. A total of 138 body shape quantitative trait loci were identified in this cross, thus revealing a highly polygenic architecture of body shape in Lake Whitefish. Third, we tested for evidence of genetic parallelism among independent wild populations using both a single-locus method (outlier analysis) and a polygenic approach (analysis of covariation among markers). The single-locus approach provided limited evidence for genetic parallelism. However, the polygenic analysis revealed genetic parallelism for three of the five lakes, which differed from the two other lakes. These results provide evidence for both genetic parallelism and multiple genetic routes underlying parallel phenotypic evolution in fish shape among populations occupying similar ecological niches. PMID- 26002926 TI - Troponins and other biomarkers in the early diagnosis of acute myocardial infarction. AB - Chest pain is a common presenting symptom; however, the majority of emergency chest pain admissions are not due to acute myocardial infarction (AMI). AMI can be life threatening and early diagnosis or rule out of AMI might potentially improve morbidity and mortality, as well as reduce time to decision and therefore overall treatment costs. High-sensitivity troponin (hs-troponin) assays have been developed that enable precise quantification of extremely low troponin concentrations. Such hs-troponin assays are recommended in early rule-out protocols for AMI, when measured at presentation and again at 3-6 h. However, troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise, late peak and low specificity for coronary plaque rupture. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations. PMID- 26002927 TI - Coffee intake and risk of obesity, metabolic syndrome and type 2 diabetes: a Mendelian randomization study. AB - BACKGROUND: Coffee is one of the most widely consumed beverages. We tested the hypothesis that genetically high coffee intake is associated with low risk of obesity, metabolic syndrome and type 2 diabetes, and with related components thereof. METHODS: We included 93,179 individuals from two large general population cohorts in a Mendelian randomization study. We tested first whether high coffee intake is associated with low risk of obesity, metabolic syndrome and type 2 diabetes, and with related components thereof, in observational analyses; second, whether five genetic variants near the CYP1A1, CYP1A2 and AHR genes are associated with coffee intake; and third, whether the genetic variants are associated with obesity, metabolic syndrome and type 2 diabetes, and with related components thereof. Finally, we tested the genetic association with type 2 diabetes in a meta-analysis including up to 78,021 additional individuals from the DIAGRAM consortium. RESULTS: Observationally, high coffee intake was associated with low risk of obesity, metabolic syndrome and type 2 diabetes. Further, high coffee intake was associated with high body mass index, waist circumference, weight, height, systolic/diastolic blood pressure, triglycerides and total cholesterol and with low high-density lipoprotein cholesterol, but not with glucose levels. In genetic analyses, 9-10 vs 0-3 coffee-intake alleles were associated with 29% higher coffee intake. However, genetically derived high coffee intake was not associated convincingly with obesity, metabolic syndrome, type 2 diabetes, body mass index, waist circumference, weight, height, systolic/diastolic blood pressure, triglycerides, total cholesterol, high-density lipoprotein cholesterol or glucose levels. Per-allele meta-analysed odds ratios for type 2 diabetes were 1.01 (0.98-1.04) for AHR rs4410790, 0.98 (0.95-1.01) for AHR rs6968865, 1.01 (0.99-1.03) for CYP1A1/2 rs2470893, 1.01 (0.98-1.03) for CYP1A1/2 rs2472297 and 0.98 (0.95-1.01) for CYP1A1 rs2472299. CONCLUSIONS: High coffee intake was associated observationally with low risk of obesity, metabolic syndrome and type 2 diabetes, and was associated observationally with related components thereof, but with no genetic evidence to support corresponding causal relationships. PMID- 26002929 TI - Structures, properties, and functions of the stings of honey bees and paper wasps: a comparative study. AB - Through natural selection, many animal organs with similar functions have evolved different macroscopic morphologies and microscopic structures. Here, we comparatively investigate the structures, properties and functions of honey bee stings and paper wasp stings. Their elegant structures were systematically observed. To examine their behaviors of penetrating into different materials, we performed penetration-extraction tests and slow motion analyses of their insertion process. In comparison, the barbed stings of honey bees are relatively difficult to be withdrawn from fibrous tissues (e.g. skin), while the removal of paper wasp stings is easier due to their different structures and insertion skills. The similarities and differences of the two kinds of stings are summarized on the basis of the experiments and observations. PMID- 26002928 TI - Genetic Risk Score for Essential Hypertension and Risk of Preeclampsia. AB - BACKGROUND: Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria. Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores (GRSs) for hypertension and blood pressure are associated with preeclampsia. METHODS: Subjects consisted of 162 preeclamptic cases and 108 normotensive pregnant controls, all of Iowa residence. Subjects' DNA was extracted from buccal swab samples and genotyped on the Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Missing genotypes were imputed using MaCH and Minimac software. GRSs were calculated for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using established genetic risk loci for each outcome. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of 516 cases and 1,097 controls of European ancestry. RESULTS: GRSs for hypertension, SBP, DBP, and MAP were not significantly associated with risk for preeclampsia (P > 0.189). The results of the replication analysis also yielded nonsignificant associations. CONCLUSIONS: GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia. PMID- 26002930 TI - Matrix compliance and the regulation of cytokinesis. AB - Integrin-mediated cell adhesion to the ECM regulates many physiological processes in part by controlling cell proliferation. It is well established that many normal cells require integrin-mediated adhesion to enter S phase of the cell cycle. Recent evidence indicates that integrins also regulate cytokinesis. Mechanical properties of the ECM can dictate entry into S phase; however, it is not known whether they also can affect the successful completion of cell division. To address this issue, we modulated substrate compliance using fibronectin-coated acrylamide-based hydrogels. Soft and hard substrates were generated with approximate elastic moduli of 1600 and 34,000 Pascals (Pa) respectively. Our results indicate that dermal fibroblasts successfully complete cytokinesis on hard substrates, whereas on soft substrates, a significant number fail and become binucleated. Cytokinesis failure occurs at a step following the formation of the intercellular bridge connecting presumptive daughter cells, suggesting a defect in abscission. Like dermal fibroblasts, mesenchymal stem cells require cell-matrix adhesion for successful cytokinesis. However, in contrast to dermal fibroblasts, they are able to complete cytokinesis on both hard and soft substrates. These results indicate that matrix stiffness regulates the successful completion of cytokinesis, and does so in a cell-type specific manner. To our knowledge, our study is the first to demonstrate that matrix stiffness can affect cytokinesis. Understanding the cell-type specific contribution of matrix compliance to the regulation of cytokinesis will provide new insights important for development, as well as tissue homeostasis and regeneration. PMID- 26002931 TI - Inexhaustible hair-cell regeneration in young and aged zebrafish. AB - Animals have evolved two general strategies to counter injury and maintain physiological function. The most prevalent is protection by isolating vital organs into body cavities. However, protection is not optimal for sensory systems because their external components need to be exposed to the environment to fulfill their receptive function. Thus, a common strategy to maintain sensory abilities against persistent environmental insult involves repair and regeneration. However, whether age or frequent injuries affect the regenerative capacity of sensory organs remains unknown. We have found that neuromasts of the zebrafish lateral line regenerate mechanosensory hair cells after recurrent severe injuries and in adulthood. Moreover, neuromasts can reverse transient imbalances of Notch signaling that result in defective organ proportions during repair. Our results reveal inextinguishable hair-cell regeneration in the lateral line, and suggest that the neuromast epithelium is formed by plastic territories that are maintained by continuous intercellular communication. PMID- 26002932 TI - Dysregulated LIF-STAT3 pathway is responsible for impaired embryo implantation in a Streptozotocin-induced diabetic mouse model. AB - The prevalence of diabetes is increasing worldwide with the trend of patients being young and creating a significant burden on health systems, including reproductive problems, but the effects of diabetes on embryo implantation are still poorly understood. Our study was to examine effects of diabetes on mouse embryo implantation, providing experimental basis for treating diabetes and its complications. Streptozotocin (STZ) was applied to induce type 1 diabetes from day 2 of pregnancy or pseudopregnancy in mice. Embryo transfer was used to analyze effects of uterine environment on embryo implantation. Our results revealed that the implantation rate is significantly reduced in diabetic mice compared to controls, and the change of uterine environment is the main reason leading to the decreased implantation rate. Compared to control, the levels of LIF and p-STAT3 are significantly decreased in diabetic mice on day 4 of pregnancy, and serum estrogen level is significantly higher. Estrogen stimulates LIF expression under physiological level, but the excessive estrogen inhibits LIF expression. LIF, progesterone or insulin supplement can rescue embryo implantation in diabetic mice. Our data indicated that the dysregulated LIF-STAT3 pathway caused by the high level of estrogen results in the impaired implantation in diabetic mice, which can be rescued by LIF, progesterone or insulin supplement. PMID- 26002933 TI - Incubation temperature, morphology and performance in loggerhead (Caretta caretta) turtle hatchlings from Mon Repos, Queensland, Australia. AB - Marine turtles are vulnerable to climate change because their life history and reproduction are tied to environmental temperatures. The egg incubation stage is arguably the most vulnerable stage, because marine turtle eggs require a narrow range of temperatures for successful incubation. Additionally, incubation temperature affects sex, emergence success, morphology and locomotor performance of hatchlings. Hatchlings often experience high rates of predation in the first few hours of their life, and increased size or locomotor ability may improve their chances of survival. Between 2010 and 2013 we monitored the temperature of loggerhead (Caretta caretta; Linnaeus 1758) turtle nests at Mon Repos Rookery, and used these data to calculate a mean three day maximum temperature (T3dm) for each nest. We calculated the hatching and emergence success for each nest, then measured the mass, size and locomotor performance of hatchlings that emerged from those nests. Nests with a T3dm greater than 34 degrees C experienced a lower emergence success and produced smaller hatchlings than nests with a T3dm lower than 34 degrees C. Hatchlings from nests with a T3dm below 34 degrees C performed better in crawling and swimming trials than hatchlings from nests with a T3dm above 34 degrees C. Thus even non-lethal increases in global temperatures have the potential to detrimentally affect fitness and survival of marine turtle hatchlings. PMID- 26002935 TI - Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan. PMID- 26002936 TI - Proximal Junctional Kyphosis Following Spinal Deformity Surgery in the Pediatric Patient. AB - Proper understanding and restoration of sagittal balance is critical in spinal deformity surgery, including conditions such as adolescent idiopathic scoliosis and Scheuermann kyphosis. One potential complication following spinal reconstruction is proximal junctional kyphosis. The prevalence of proximal junctional kyphosis varies in the literature, and several patient- and surgery related risk factors have been identified. To date, the development of proximal junctional kyphosis has not been shown to lead to a negative clinical outcome following spinal fusion for adolescent idiopathic scoliosis or Scheuermann kyphosis. Treatment options range from simple observation in asymptomatic cases to revision surgery with extension of the fusion proximally. Several techniques and technologies are emerging that seek to address and prevent proximal junctional kyphosis. PMID- 26002937 TI - Transplant tourism and organ trafficking: Ethical implications for the nursing profession. AB - Organ availability for transplantation has become an increasingly complex and difficult question in health economics and ethical practice. Advances in technology have seen prolonged life expectancy, and the global push for organs creates an ever-expanding gap between supply and demand, and a significant cost in bridging that gap. This article will examine the ethical implications for the nursing profession in regard to the procurement of organs from an impoverished seller's market, also known as 'Transplant Tourism'. This ethical dilemma concerns itself with resource allocation, informed consent and the concepts of egalitarianism and libertarianism. Transplant Tourism is an unacceptable trespass against human dignity and rights from both a nursing and collective viewpoint. Currently, the Australian Nursing and Midwifery Council, the Royal college of Nursing Australia, The Royal College of Nursing (UK) and the American Nurses Association do not have position statements on transplant tourism, and this diminishes us as a force for change. It diminishes our role as advocates for the most marginalised in our world to have access to care and to choice and excludes us from a very contemporary real debate about the mismatch of organ demand and supply in our own communities. As a profession, we must have a voice in health policy and human rights, and according to our Code of Ethics in Australia and around the world, act to promote and protect the fundamental human right to healthcare and dignity. PMID- 26002934 TI - Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study. AB - OBJECTIVE: In the setting where two individuals are genetically similar, epigenetic mechanisms could account for discordance in the presence or absence of non-alcoholic fatty liver disease (NAFLD). This study investigated if serum microRNAs (miRs) could explain discordance in NAFLD. DESIGN: This is a cross sectional analysis of a prospective cohort study of 40 (n=80) twin-pairs residing in Southern California. All participants underwent a standardised research visit, liver MRI using proton-density fat fraction to quantify fat content and miR profiling of their serum. RESULTS: Among the 40 twin-pairs, there were 6 concordant for NAFLD, 28 were concordant for non-NAFLD and 6 were discordant for NAFLD. The prevalence of NAFLD was 22.5% (18/80). Within the six discordant twins, a panel of 10 miRs differentiated the twin with NAFLD from the one without. Two of these miRs, miR-331-3p and miR-30c, were also among the 21 miRs that were different between NAFLD and non-NAFLD groups (for miR-331-3p: 7.644+/ 0.091 vs 8.057+/-0.071, respectively, p=0.004; for miR-30c: 10.013+/-0.126 vs 10.418+/-0.086, respectively, p=0.008). Both miRs were highly heritable (35.9% and 10.7%, respectively) and highly correlated with each other (R=0.90, p=2.2*10( 16)) suggesting involvement in a common mechanistic pathway. An interactome analysis of these two miRs showed seven common target genes. CONCLUSIONS: Using a novel human twin-study design, we demonstrate that discordancy in liver fat content between the twins can be explained by miRs, and that they are heritable. PMID- 26002938 TI - Academic dishonesty among health science school students. AB - BACKGROUND: Academic dishonesty has become a serious problem at institutions of higher learning. RESEARCH QUESTION: What is the frequency of academic dishonesty and what factors affect the tendency of dishonesty among Turkish health science school students? RESEARCH DESIGN: This descriptive and cross-sectional study aims to evaluate academic dishonesty among university nursing, midwifery, and dietetic students. Participants and research context: The study sample consisted of 499 health science students in Turkey. The tendency toward academic dishonesty was investigated using the Academic Dishonesty Tendency Scale. Ethical considerations: Institutional review board approved the study. Written permission was obtained from the researcher to use Turkish version of the Academic Dishonesty Tendency Scale. FINDINGS: Of all the students, 80.0% claimed to refer to Internet during homework preparation and 49.1% of students reported to cite the references at the end of article on some instances. Of the students, 56.1% claimed never to have cheated in the exams. It was found that academic dishonesty was partly low (1.80-2.59) in students. For students using a library while doing their homework, mean scores were significantly lower ( p < 0.05). There were also statistically significant difference between mean scores and student's year in school, student's perception of school success, and frequency of Internet use while doing homework ( p < 0.05). DISCUSSION: The tendency of academic dishonesty was lower among students who use Internet and library more frequently. These findings are consistent with previous studies. CONCLUSION: Measurements to take against academic dishonesty should be directed toward not only students but institutions and instructors as well. PMID- 26002939 TI - Cross-cultural validation of the moral sensitivity questionnaire-revised Chinese version. AB - BACKGROUND: Ethical issues pose challenges for nurses who are increasingly caring for patients in complicated situations. Ethical sensitivity is a prerequisite for nurses to make decisions in the best interest of their patients in daily practice. Currently, there is no tool for assessing ethical sensitivity in Chinese language, and no empirical studies of ethical sensitivity among Chinese nurses. RESEARCH OBJECTIVES: The study was conducted to translate the Moral Sensitivity Questionnaire-Revised Version (MSQ-R) into Chinese and establish the psychometric properties of the Moral Sensitivity Questionnaire-Revised Version into Chinese (MSQ-R-CV). RESEARCH DESIGN: This research was a methodological and descriptive study. PARTICIPANTS AND RESEARCH CONTEXT: MSQ-R was translated into Chinese using Brislin's model, and the Translation Validity Index was evaluated. MSQ-R-CV was then distributed along with a demographic questionnaire to 360 nurses working at tertiary and municipal hospitals in Changsha, China. ETHICAL CONSIDERATIONS: This study was approved by the Institutional Review Boards of Yale University and Central South University. FINDINGS: MSQ-R-CV achieved Cronbach's alpha 0.82, Spearman-Brown coefficient 0.75, significant item discrimination (p < 0.001), and item-total correlation values ranging from 0.524 to 0.717. A two-factor structure was illustrated by exploratory factor analysis, and further confirmed by confirmatory factor analysis. Chinese nurses had a mean total score of 40.22 +/- 7.08 on the MSQ-R-CV, and sub-scores of 23.85 +/- 4.4 for moral responsibility and strength and 16.37 +/- 3.75 for sense of moral burden. DISCUSSION: The findings of this study were compared with studies from other countries to examine the structure and meaningful implications of ethical sensitivity in Chinese nurses. CONCLUSION: The two-factor MSQ-R-CV (moral responsibility and strength, and sense of moral burden) is a linguistically and culturally appropriate instrument for assessing ethical sensitivity among Chinese nurses. PMID- 26002940 TI - Ethical challenges related to next of kin - nursing staffs' perspective. AB - BACKGROUND: Patients in clinical settings are not lonely islands; they have relatives who play a more or less active role in their lives. OBJECTIVES: The purpose of this article is to elucidate the ethical challenges nursing staff encounter with patients' next of kin and to discuss how these challenges affect clinical practice. RESEARCH DESIGN: The study is based on data collected from ethical group discussions among nursing staff in a nursing home. The discussions took place in 2011 and 2012. The data were analysed and interpreted by using hermeneutic methodology. ETHICAL CONSIDERATIONS: All the data have been anonymised and handled with confidentiality. Written informed consent was obtained from all participants. FINDINGS: Ethical challenges relating to patients' next of kin were found to be an issue frequently discussed in the groups. Our findings indicate that next of kin have different characteristics, categorised as 'the professionals' and 'the shadows'. In this article, we will describe the next of kin's characteristics and the ethical challenges and practical implications that nursing staff experience in this connection. DISCUSSION: We will discuss the findings in the light of the four basic principles of medical ethics and propose interventions to help nurses manage ethical challenges related to next of kin. CONCLUSION: The study reveals the need to enhance nursing staffs' communicative and ethical skills on an individual level, but most importantly, to establish routines in clinical settings for informing and following up next of kin in a systematic and structured way. PMID- 26002941 TI - Association of oral streptococci community dynamics with severe early childhood caries as assessed by PCR-denaturing gradient gel electrophoresis targeting the rnpB gene. AB - This study sought to investigate the possible association between the dynamics of oral streptococci community profiles and severe early childhood caries (S-ECC) development, compared with caries-free (CF) controls. Supragingival plaque samples were evaluated from 8-32-month-old children who had previously been assessed for overall profiles of their oral microbial community. Twelve children were in each group. Bacterial genomic DNA was extracted and amplified using rnpB specific primers for streptococci; the products were then subjected to denaturing gradient gel electrophoresis (DGGE) and sequence analysis. We observed that the mean values for species richness (N) and diversity of oral streptococci (H') were significantly lower in the S-ECC group than in the CF group (N = 1.25 +/- 4.14 vs 14.92 +/- 2.84; H' = 1.41 +/- 0.29 vs 1.64 +/- 0.18) at 32 months of age (P < 0.05). Significantly higher detection rates of Streptococcus sanguinis and Streptococcus gordonii were found in the CF group compared with the S-ECC group at 32 months of age (P < 0.05). Cluster analysis of DGGE profiles showed that most of the clusters were constructed from one individual over time. These results suggested that the onset of S-ECC is accompanied by reduced diversity of oral streptococci, that the detection rates of S. sanguinis and S. gordonii have negative correlations with S-ECC; and that there are high levels of intra individual similarity for the oral streptococci community over time. PMID- 26002942 TI - Incidence of Burkholderia contaminans at a cystic fibrosis centre with an unusually high representation of Burkholderia cepacia during 15 years of epidemiological surveillance. AB - The Burkholderia cepacia complex (Bcc) is a heterogeneous group of bacteria comprising around 20 related species. These bacteria are important opportunistic pathogens, especially in cystic fibrosis (CF) patients, and are associated with a worse prognosis and decreased life expectancy. The taxonomic position of 20 Bcc isolates retrieved from CF patients receiving care at Hospital Santa Maria (HSM), in Lisbon, from 1995 to 2006, was re-examined in the present work. These isolates, formerly classified as Burkholderia cepacia (taxon K), are here reclassified as Burkholderia contaminans, including the former B. cepacia IST408, which was the focus of previous studies regarding the biosynthesis of the exopolysaccharide 'cepacian'. The CF population examined has been previously described as having an exceptionally high representation of B. cepacia, presumably due to a contamination arising from saline solutions for nasal application. Twenty-one additional isolates, obtained from a chronically infected patient, from 2006 to 2010, were also identified as B. contaminans. This study also provides insight into the potential clinical impact of B. contaminans, a species that is rarely associated with CF infections. Isolates belonging to this species were shown to be involved in chronic and transient respiratory infections, and were associated with severe lung function deterioration and with a case of death with cepacia syndrome. However, since the patients were co infected with Burkholderia cenocepacia and other non-Burkholderia bacteria, the role played by B. contaminans is unclear. Nevertheless, B. contaminans isolates were found to prevail over B. cenocepacia isolates during co-infection of at least one chronically infected patient. PMID- 26002943 TI - Diagnostic accuracy of a novel lateral-flow device in invasive aspergillosis: a meta-analysis. AB - A novel lateral-flow device (LFD) has been invented for use as a diagnostic tool for invasive aspergillosis (IA). We conducted a meta-analysis to assess the diagnostic accuracy of the device. Published studies that used the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria and provided sufficient data were included. Two reviewers independently collected the data from each study and assessed the risk bias using the Quality Assessment of Diagnostic Accuracy Studies-2. The pooled sensitivity, specificity and diagnostic odds ratio (DOR) were computed and reported with a 95 % confidence interval (CI). Seven studies published between 2008 and March 2015 were included. The pooled sensitivity, specificity and DOR for the proven/probable versus no IA cases were 0.86 (95 % CI, 0.76-0.93), 0.93 (95 % CI, 0.89-0.96) and 65.94 (95 % CI, 27.21-159.81) in the LFD test using bronchoalveolar lavage (BAL) fluid, and 0.68 (95 % CI, 0.52-0.81), 0.87 (95 % CI, 0.80-0.92) and 11.90 (95 % CI, 3.54 39.96) in the LFD test using serum. We concluded that the Aspergillus LFD had a good diagnostic value in immunocompromised patients at risk of IA. The BAL LFD might have a better performance than the serum LFD test. PMID- 26002944 TI - Differentiation of clinically relevant Mucorales Rhizopus microsporus and R. arrhizus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). AB - This study addresses the usefulness of matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS for reliable identification of the two most frequently occurring clinical species of Rhizopus, namely Rhizopus arrhizus with its two varieties, arrhizus and delemar, and Rhizopus microsporus. The test set comprised 38 isolates of clinical and environmental origin previously identified by internal transcribed spacer (ITS) sequencing of rDNA. Multi-locus sequence data targeting three gene markers (ITS, ACT, TEF ) showed two monophylic clades for Rhizopus arrhizus and Rhizopus microsporus (bootstrap values of 99 %). Cluster analysis confirmed the presence of two distinct clades within Rhizopus arrhizus representing its varieties arrhizus and delemar. The MALDI Biotyper 3.0 Microflex LT platform (Bruker Daltonics) was used to confirm the distinction between Rhizopus arrhizus and Rhizopus microsporus and the presence of two varieties within the species Rhizopus arrhizus. An in-house database of 30 reference main spectra (MSPs) was initially tested for correctness using commercially available databases of Bruker Daltonics. By challenging the database with the same strains of which an in-house database was created, automatic identification runs confirmed that MALDI-TOF MS is able to recognize the strains at the variety level. Based on principal component analysis, two MSP dendrograms were created and showed concordance with the multi-locus tree; thus, MALDI-TOF MS is a useful tool for diagnostics of mucoralean species. PMID- 26002945 TI - Steroid-induced glaucoma and childhood blindness. AB - AIM: To determine the prevalence, risk factors and the severity of visual loss caused by steroid-induced glaucoma (SIG) among children. METHODS: Five-year records of all paediatric glaucoma cases presenting to the glaucoma services of our tertiary care centre were evaluated. Data of children presenting with SIG were recorded with respect to their visual acuity, highest baseline intraocular pressure, cup:disc ratio, perimetry and need of glaucoma filtering surgery. Parents were interviewed to assess the indication of steroid use, type of steroid used, person prescribing it and the duration of use. The prevalence of visual impairment was calculated based on WHO criteria. RESULTS: Of 1259 cases of paediatric glaucoma presenting at our centre over 5 years, 59 children (4.7%) were diagnosed with SIG. Of these, 51 (87%) had been prescribed topical steroids for vernal keratoconjunctivitis (VKC). The median duration of steroid use was 18 months (range 1 month to 8 years). Also, 82% of children with VKC had been prescribed steroids by the treating ophthalmologist and 52% had been on topical steroids for >1 year. Glaucomatous optic neuropathy was the cause of blindness in 37.3% (22/59) and low vision in 23.7% (14/59) children. And 27% (16/59) were unilaterally blind at presentation. CONCLUSIONS: A third of the children presenting with SIG to our tertiary care centre were bilaterally blind at presentation. Ophthalmologists need to consider steroid-sparing agents to treat VKC and monitor these children closely for glaucoma if they prescribe topical steroids in order to prevent unnecessary childhood blindness. PMID- 26002946 TI - Teamwork, communication and safety climate: a systematic review of interventions to improve surgical culture. AB - OBJECTIVES: To define the target domains of culture-improvement interventions, to assess the impact of these interventions on surgical culture and to determine whether culture improvements lead to better patient outcomes and improved healthcare efficiency. BACKGROUND: Healthcare systems are investing considerable resources in improving workplace culture. It remains unclear whether these interventions, when aimed at surgical care, are successful and whether they are associated with changes in patient outcomes. METHODS: PubMed, Cochrane, Web of Science and Scopus databases were searched from January 1980 to January 2015. We included studies on interventions that aimed to improve surgical culture, defined as the interpersonal, social and organisational factors that affect the healthcare environment and patient care. The quality of studies was assessed using an adapted tool to focus the review on higher-quality studies. Due to study heterogeneity, findings were narratively reviewed. FINDINGS: The 47 studies meeting inclusion criteria (4 randomised trials and 10 moderate-quality observational studies) reported on interventions that targeted three domains of culture: teamwork (n=28), communication (n=26) and safety climate (n=19); several targeted more than one domain. All moderate-quality studies showed improvements in at least one of these domains. Two studies also demonstrated improvements in patient outcomes, such as reduced postoperative complications and even reduced postoperative mortality (absolute risk reduction 1.7%). Two studies reported improvements in healthcare efficiency, including fewer operating room delays. These findings were supported by similar results from low-quality studies. CONCLUSIONS: The literature provides promising evidence for various strategies to improve surgical culture, although these approaches differ in terms of the interventions employed as well as the techniques used to measure culture. Nevertheless, culture improvement appears to be associated with other positive effects, including better patient outcomes and enhanced healthcare efficiency. TRIAL REGISTRATION NUMBER: CRD42013005987. PMID- 26002947 TI - Infection prevention and control in nursing homes: a qualitative study of decision-making regarding isolation-based practices. AB - BACKGROUND: Isolation-based practices in nursing homes (NHs) differ from those in acute care. NHs must promote quality of life while preventing infection transmission. Practices used in NHs to reconcile these goals of care have not been characterised. PURPOSE: To explore decision-making in isolation-based infection prevention and control practices in NHs. METHODS: A qualitative study was conducted with staff (eg, staff nurses, infection prevention directors and directors of nursing) employed in purposefully sampled US NHs. Semistructured, role-specific interview guides were developed and interviews were digitally recorded, transcribed verbatim and analysed using directed content analysis. The research team discussed emerging themes in weekly meetings to confirm consensus. RESULTS: We inferred from 73 interviews in 10 NHs that there was variation between NHs in practices regarding who was isolated, when isolation-based practices took place, how they were implemented, and how they were tailored for each resident. Interviewees' decision-making depended on staff perceptions of acceptable transmission risk and resident quality of life. NH resources also influenced decision-making, including availability of private rooms, extent to which staff can devote time to isolation-based practices and communication tools. A lack of understanding of key infection prevention and control concepts was also revealed. CONCLUSIONS AND IMPLICATIONS: Current clinical guidelines are not specific enough to ensure consistent practice that meets care goals and resource constraints in NHs. However, new epidemiological research regarding effectiveness of varying isolation practices in this setting is needed to inform clinical practice. Further, additional infection prevention and control education for NH staff may be required. PMID- 26002949 TI - Site-directed mutagenesis reveals regions implicated in the stability and fiber formation of human lambda3r light chains. PMID- 26002950 TI - Differential expression of intracellular and secreted osteopontin isoforms by murine macrophages in response to Toll-like receptor agonists. PMID- 26002951 TI - Palmitoylation targets AKAP79 protein to lipid rafts and promotes its regulation of calcium-sensitive adenylyl cyclase type 8. PMID- 26002948 TI - Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission. AB - Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid beta (Abeta) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Abeta peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Abeta to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Abeta and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease. PMID- 26002952 TI - The Athlete Sleep Screening Questionnaire: a new tool for assessing and managing sleep in elite athletes. AB - BACKGROUND/AIM: The purpose of this study was to develop a subjective, self report, sleep-screening questionnaire for elite athletes. This paper describes the development of the Athlete Sleep Screening Questionnaire (ASSQ). METHODS: A convenience sample of 60 elite athletes was randomly distributed into two groups; 30 athletes completed a survey composed of current psychometric tools, and 30 athletes completed a revised survey and a sleep specialist structured clinical interview. An item analysis was performed on the revised survey with comparison to clinical decisions regarding appropriate intervention based on a sleep specialist assessment. RESULTS: A comparison of existing sleep-screening tools with determination of clinical need from a sleep specialist showed low consistency, indicating that current sleep-screening tools are unsuitable for assessing athlete sleep. A new 15-item tool was developed (ASSQ) by selecting items from existing tools that more closely associated with the sleep specialist's reviews. Based on test-retest percentage agreement and the kappa statistic, we found good internal consistency and reliability of the ASSQ. To date, 349 athletes have been screened, and 46 (13.2%) identified as requiring follow-up consultation with a sleep specialist. Results from the follow-up consultations demonstrated that those athletes identified by the ASSQ as abnormal sleepers have required intervention. CONCLUSIONS: The research developed a new athlete-specific sleep-screening questionnaire. Our findings suggest that existing sleep-screening tools are unsuitable for assessing sleep in elite athletes. The ASSQ appears to be more accurate in assessing athlete sleep (based on comparison with expert clinical assessment). The ASSQ can be deployed online and provides clinical cut-off scores associated with specific clinical interventions to guide management of athletes' sleep disturbance. The next phase of the research is to conduct a series of studies comparing results from the ASSQ to blinded clinical reviews and to data from objective sleep monitoring to further establish the validity of the ASSQ as a reliable sleep screening tool for elite athletes. PMID- 26002953 TI - Delineation of genetic relatedness and population structure of oral and enteric Campylobacter concisus strains by analysis of housekeeping genes. AB - Campylobacter concisus is an oral bacterium that has been shown to be associated with inflammatory bowel disease (IBD). In this study we examined clusters of oral C. concisus strains isolated from patients with IBD and healthy controls by analysing six housekeeping genes. In addition, we investigated the population structure of C. concisus strains. Whether oral and enteric strains form distinct clusters based on the sequences of these housekeeping genes was also investigated. The oral C. concisus strains were found to contain two genomospecies, which belong to the two genomospecies previously found in enteric C. concisus strains. C. concisus clusters formed based on the sequences of a single aspA gene were the same as that formed by using previously reported MLST schemes. The analysis of combined oral and enteric C. concisus strains found that enteric C. concisus strains did not form distinct clusters. Genetic structure analysis identified five subpopulations of C. concisus and showed that genetic recombination between C. concisus strains was common. However, genetic recombination was significantly less in oral strains isolated from patients with IBD than from healthy individuals. Previously reported oral and enteric intestinal epithelial invasive C. concisus strains were in cluster II and subpopulation III. Furthermore, this study shows that there are no distinct enteric C. concisus strain clusters or subpopulations. PMID- 26002954 TI - Effects of gender on capecitabine toxicity in colorectal cancer. AB - BACKGROUND: Capecitabine is a highly water soluble prodrug of 5-fluorouracil that is dosed by patient body surface area. Body surface area dosing makes no allowances for differences in body composition. There is mounting evidence that lean body mass is a better predictor of toxicity than body surface area for drugs which distribute into the lean compartment. Because women, on average, have lower lean body mass than men, we expect that women would experience a higher incidence of toxicity than men when body surface area dosing is used. OBJECTIVE: To determine whether female colorectal cancer patients experienced a higher incidence of dose-limiting toxicity than men when treated with adjuvant capecitabine. METHODS: We conducted a retrospective chart review of colorectal cancer patients treated with adjuvant capecitabine at our institute between 2008 and 2012. Patients receiving capecitabine were identified from the pharmacy dispensing database and then screened for inclusion. Dosing and toxicity information were gathered and dose-limiting toxicity incidence (defined as a composite endpoint of dose delay, dose reduction, or discontinuation of therapy) was compared between males and females using the chi-square test. Binary logistic regression analysis was then performed to account for differences between male and female populations. RESULTS: A total of 299 patients (163 males, 136 females) met inclusion criteria. Females had a significantly higher dose-limiting toxicity incidence than males (67.7 vs. 52.2%, p = 0.007). Relationships between gender and dose-limiting toxicity incidence remained significant after logistic regression analysis (OR: 2.04; 95% CI: 1.23-3.36). CONCLUSION: Female colorectal cancer patients experience a higher dose-limiting toxicity incidence than male patients when given adjuvant capecitabine dosed according to body surface area. PMID- 26002955 TI - Into Thin Air and Back: Deer Mouse Study Examines High-Altitude Adaptation. PMID- 26002956 TI - Most Comprehensive Study to Date Reveals Evolutionary History of Citrus. PMID- 26002957 TI - Electronic Cigarettes: A Primer for Clinicians. AB - OBJECTIVE: To introduce the otolaryngology community to the current state of research regarding electronic cigarettes, with special attention paid to mechanism, impact on health and addiction, and use in smoking cessation. DATA SOURCES: Review of Google Scholar and PubMed databases using the keywords electronic cigarettes, e-cigs, e-cigarettes, and vaping. In addition, information from media sources as well as news outlets was evaluated to gauge public perception of research findings. REVIEW METHODS: Recent research and randomized controlled trials were prioritized. CONCLUSIONS: The landscape of electronic cigarette devices is evolving, as is the research regarding their risks and benefits. Utilization is rapidly increasing. It appears that older users employ them as a smoking cessation tool compared to younger users. The data are generally inconclusive regarding the benefits of electronic cigarettes for smoking cessation compared with other methods. Furthermore, the safety profile of electronic cigarettes is dynamic and difficult to fully ascertain. IMPLICATIONS FOR PRACTICE: Patients with a variety of otolaryngologic conditions, including cancer, may benefit from frank discussion regarding electronic cigarettes. Furthermore, increasing patient inquiries regarding these devices are likely given their increasing popularity. PMID- 26002958 TI - Novel Management of Intractable Cervical Chylous Fistula with Local Application of Pseudomonas aeruginosa Injection. AB - OBJECTIVE: Cervical chylous fistula is an uncommon complication after neck dissection, but it might lead to some serious clinical outcomes. Although most cervical chylous fistulas can heal in a few days with standard treatments, some can be intractable. In this study, we describe a new method with local application of Pseudomonas aeruginosa injection for intractable cervical chylous fistula. STUDY DESIGN: Case series with chart review. SETTING: West China Hospital, Sichuan University, Chengdu, China. SUBJECTS AND METHODS: The charts of 18 patients who were treated with P aeruginosa injection (PAI) for intractable cervical chylous fistula were retrospectively reviewed. RESULTS: All patients were successfully treated with PAI. Mild fever (temperature, <38 degrees C) occurred in 9 patients, moderate fever (38 degrees C-39 degrees C) in 4 patients, and severe fever (>39 degrees C) in 5 patients. All patients had mild to severe neck pain. CONCLUSIONS: Local application of PAI is an effective method for the treatment of intractable cervical chylous fistula, of which the most common side effects are transient fever and local pain. PMID- 26002959 TI - Maid is a negative regulator of transforming growth factor-beta-induced cell migration. AB - Maternal Id-like molecule (Maid) is a dominant negative helix-loop-helix protein that has been implicated in regulating gene expression as well as cell-cycle progression. Overexpressed Maid was previously shown to inhibit certain cellular responses induced by transforming growth factor-beta (TGF-beta), such as TGF-beta induced cytostasis and cell motility, but not epithelial-mesenchymal transition (EMT). The role of endogenous Maid in regulating TGF-beta signalling, however, has not been elucidated. We have found evidence that endogenous Maid negatively regulates TGF-beta-induced cell motility. Maid knockdown enhanced TGF-beta induced cell motility as measured by chamber migration and wound healing assays but did not affect cell motility induced by bone morphogenetic protein (BMP)-4. Endogenous Maid does not appear to be involved in regulating TGF-beta-induced cytostasis, resistance to apoptosis or EMT. Notably, Maid expression was induced in the delayed phase (later than 24 h) after TGF-beta stimulation whereas the expression of two other negative feedback regulators, Smad7 and SnoN, was induced as early as 1 h after stimulation. These findings indicate that Maid is a unique negative feedback regulator of TGF-beta signalling in its mode of action as well as the timing of its induction. PMID- 26002960 TI - Mediator complex cooperatively regulates transcription of retinoic acid target genes with Polycomb Repressive Complex 2 during neuronal differentiation. AB - The Mediator complex (Mediator) plays key roles in transcription and functions as the nexus for integration of various transcriptional signals. Previously, we screened for Mediator cyclin-dependent kinase (CDK)-interacting factors and identified three proteins related to chromatin regulation. One of them, SUZ12 is required for both stability and activity of Polycomb Repressive Complex 2 (PRC2). PRC2 primarily suppresses gene expression through histone H3 lysine 27 trimethylation, resulting in stem cell maintenance and differentiation; perturbation of this process leads to oncogenesis. Recent work showed that Mediator contributes to the embryonic stem cell state through DNA loop formation, which is strongly associated with chromatin architecture; however, it remains unclear how Mediator regulates gene expression in cooperation with chromatin regulators (i.e. writers, readers and remodelers). We found that Mediator CDKs interact directly with the PRC2 subunit EZH2, as well as SUZ12. Known PRC2 target genes were deregulated by Mediator CDK knockdown during neuronal differentiation, and both Mediator and PRC2 complexes co-occupied the promoters of developmental genes regulated by retinoic acid. Our results provide a mechanistic link between Mediator and PRC2 during neuronal differentiation. PMID- 26002961 TI - Synthesis of histone proteins by CPE ligation using a recombinant peptide as the C-terminal building block. AB - The post-translational modification of histones plays an important role in gene expression. We report herein on a method for synthesizing such modified histones by ligating chemically prepared N-terminal peptides and C-terminal recombinant peptide building blocks. Based on their chemical synthesis, core histones can be categorized as two types; histones H2A, H2B and H4 which contain no Cys residues, and histone H3 which contains a Cys residue(s) in the C-terminal region. A combination of native chemical ligation and desulphurization can be simply used to prepare histones without Cys residues. For the synthesis of histone H3, the endogenous Cys residue(s) must be selectively protected, while keeping the N terminal Cys residue of the C-terminal building block that is introduced for purposes of chemical ligation unprotected. To this end, a phenacyl group was successfully utilized to protect endogenous Cys residue(s), and the recombinant peptide was ligated with a peptide containing a Cys-Pro ester (CPE) sequence as a thioester precursor. Using this approach it was possible to prepare all of the core histones H2A, H2B, H3 and H4 with any modifications. The resulting proteins could then be used to prepare a core histone library of proteins that have been post-translationally modified. PMID- 26002962 TI - Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. AB - Mastocytosis (M) is a clonal myeloid-disabling disorder for which no curative therapy is currently available. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic purine analog cytoreductive treatment, for which efficacy is mostly reported in advanced M. Here we report, with a long-term follow-up period (>10 years) efficacy and safety in 68 adult patients with M (36 [53%] had indolent M and 32 [47%] had advanced M) treated by 2-CdA (0.14 mg/kg in infusion or subcutaneously, days 1-5; repeated at 4-12 weeks until 1 to 9 courses). Median 2 CdA courses number was 3.7 (1-9). The overall response rate was 72% (complete remission [R]/major/partial R: 0%/47%/25%) and according to indolent/advanced M was 92% (major/partial R: 56%/36%) and 50% (major/partial R: 37.5%/12.5%), respectively. Clinical improvement was observed for 10 of 11 mediator release and 6 of 7 mast cell infiltration-related symptoms including urticaria pigmentosa and organomegaly (P < .02). Serum tryptase levels decreased (P = .01). Median durations of response were 3.71 (0.1-8) and 2.47 (0.5-8.6) years for indolent and aggressive M, respectively. The most frequent grade 3/4 toxicities were lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%). 2-CdA appears to provide a significant efficacy with some toxicity in various M subtypes, mostly in indolent M, refractory to multiple symptomatic therapies. PMID- 26002963 TI - How I treat Waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 * 10(9)/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T cell therapy. PMID- 26002964 TI - Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. AB - As multiple myeloma (MM) progresses, natural killer (NK)-cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for treatment of MM but its influence on NK-cell biology is unclear. Here, we report that lenalidomide lowers the threshold for NK-cell activation, causing a 66% decrease in the 50% effective concentration (EC50) for activation through CD16, and a 38% decrease in EC50 for NK group 2 member D (NKG2D)-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augments NK-cell responses, causing a twofold increase in the proportion of primary NK cells producing interferon-gamma (IFN-gamma), and a 20 fold increase in the amount of IFN-gamma produced per cell. Importantly, lenalidomide did not trigger IFN-gamma production in unstimulated NK cells. Thus, lenalidomide enhances the NK-cell arm of the immune response, without activating NK cells inappropriately. Of particular clinical importance, lenalidomide also allowed NK cells to be activated by lower doses of rituximab, an anti-CD20 monoclonal antibody (mAb) widely used to treat B-cell malignancies. This supports combined use of lenalidomide and rituximab in a clinical setting. Finally, superresolution microscopy revealed that lenalidomide increased the periodicity of cortical actin at immune synapses, resulting in an increase in the area of the actin mesh predicted to be penetrable to vesicles containing IFN-gamma. NK cells from MM patients also responded to lenalidomide in this way. This indicates that nanometer-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds. PMID- 26002966 TI - Characterization of hamster NAD+-dependent 3(17)beta-hydroxysteroid dehydrogenase belonging to the aldo-keto reductase 1C subfamily. AB - The cDNAs for morphine 6-dehydrogenase (AKR1C34) and its homologous aldo-keto reductase (AKR1C35) were cloned from golden hamster liver, and their enzymatic properties and tissue distribution were compared. AKR1C34 and AKR1C35 similarly oxidized various xenobiotic alicyclic alcohols using NAD(+), but differed in their substrate specificity for hydroxysteroids and inhibitor sensitivity. While AKR1C34 showed 3alpha/17beta/20alpha-hydroxysteroid dehydrogenase activities, AKR1C35 efficiently oxidized various 3beta- and 17beta-hydroxysteroids, including biologically active 3beta-hydroxy-5alpha/beta-dihydro-C19/C21-steroids, dehydroepiandrosterone and 17beta-estradiol. AKR1C35 also differed from AKR1C34 in its high sensitivity to flavonoids, which inhibited competitively with respect to 17beta-estradiol (Ki 0.11-0.69 MUM). The mRNA for AKR1C35 was expressed liver specific in male hamsters and ubiquitously in female hamsters, whereas the expression of the mRNA for AKR1C34 displayed opposite sexual dimorphism. Because AKR1C35 is the first 317Beta-HYDROXYSTEROID DEHYDROGENASE IN THE AKR SUPERFAMILY: , we also investigated the molecular determinants for the 3beta-hydroxysteroid dehydrogenase activity by replacement of Val54 and Cys310 in AKR1C35 with the corresponding residues in AKR1C34, Ala and Phe, respectively. The mutation of Val54Ala, but not Cys310Phe, significantly impaired this activity, suggesting that Val54 plays a critical role in recognition of the steroidal substrate. PMID- 26002967 TI - Bipolar disorder is often missed in people who misuse alcohol or drugs. PMID- 26002965 TI - CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. AB - Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-alpha, -beta, and -gamma production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide. PMID- 26002968 TI - Neighbourhood racial/ethnic composition and segregation and trajectories of cognitive decline among US older adults. AB - BACKGROUND: The influence of the sociodemographic context of one's environment on cognitive ageing is not well understood. METHODS: We examined differences in cognitive trajectories according to the racial/ethnic characteristics of the residential environment. On the basis of 63 996 person-years of data from a nationally representative cohort of 6150 adults over the age of 50 years from the Health and Retirement Study, we used multivariate linear mixed models to determine the effect of neighbourhood racial/ethnic composition and county-level segregation on cognitive function and cognitive decline over a 10-year period. RESULTS: In models adjusting for individual demographic and health characteristics, Hispanic composition had a significant positive association with cognitive function (standardised beta=0.136, p<0.05) and moderate evidence of an association with greater cognitive decline (standardised beta=-0.014, p=0.09). Greater Hispanic-white segregation was associated with statistically significant higher cognitive function at baseline (standardised beta=0.099, p<0.001) and greater cognitive decline (standardised beta=-0.011, p<0.01). For a 20 percentage point increase in Hispanic composition and segregation, the observed associations implied 1 and 1.25 additional years of cognitive ageing over 10 years, respectively. These effects did not differ by individual race/ethnicity and were not explained by neighbourhood socioeconomic status or neighbourhood selection. Black composition and black-white segregation did not have a significant influence on cognitive ageing. DISCUSSION: This study demonstrates disparities in the progression of cognitive ageing according to racial/ethnic characteristics of the neighbourhood environment. PMID- 26002969 TI - Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone. AB - Both term and preterm parturition are characterized by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or co-cultured with PHM1-41 myometrial smooth muscle cells, for 24 h. In a third set of experiments, PHM1-41 myocytes were cultured for 24 h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Co-culture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100 ng/ml). The synergistic secretion of IL-6 and IL-8 from co-cultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from co-cultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from co-cultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS, and can augment myocyte contraction. These effects are all partially inhibited by progesterone. PMID- 26002970 TI - Identification of jasmonic acid-associated microRNAs and characterization of the regulatory roles of the miR319/TCP4 module under root-knot nematode stress in tomato. AB - MicroRNAs (miRNAs) are important transcriptional and post-transcriptional modulators of gene expression that play crucial roles in the responses to diverse stresses. To explore jasmonic acid (JA)-dependent miRNA-mediated regulatory networks that are responsive to root-knot nematode (RKN), two small RNA libraries were constructed from wild-type (WT) and JA mutant (spr2) plants. A total of 263 known miRNAs and 441 novel miRNAs were significantly regulated under RKN stress in the two libraries. The spatio-temporal expression of candidate miRNAs and their corresponding targets were analysed by qRT-PCR under RKN stress. A clear negative correlation was observed between miR319 and its target TEOSINTE BRANCHED1/CYCLOIDEA/PRO-LIFERATING CELL FACTOR 4 (TCP4) in leaf, stem, and root under RKN stress, implying that the miR319/TCP4 module is involved in the systemic defensive response. Reverse genetics demonstrated that the miR319/TCP4 module affected JA synthetic genes and the endogenous JA level in leaves, thereby mediating RKN resistance. These results suggested that the action of miR319 in serving as a systemic signal responder and regulator that modulated the RKN systemic defensive response was mediated via JA. The potential cross-talk between miR319/TCP4 and miR396/GRF (GROWTH RESPONDING FACTOR) in roots under RKN invasion is discussed, and a predictive model regarding miR319/TCP4-mediated RKN resistance is proposed. PMID- 26002971 TI - Evolutionary divergence of the plant elicitor peptides (Peps) and their receptors: interfamily incompatibility of perception but compatibility of downstream signalling. AB - Plant elicitor peptides (Peps) are potent inducers of pattern-triggered immunity and amplify the immune response against diverse pathogens. Peps have been discovered and studied extensively in Arabidopsis and only recently orthologues in maize were also identified and characterized in more detail.Here, the presence of PROPEPs, the Pep precursors, and PEPRs, the Pep receptors, was investigated within the plant kingdom. PROPEPs and PEPRs were identified in most sequenced species of the angiosperms. The conservation and compatibility of the Pep-PEPR system was analysed by using plants of two distantly related dicot families, Brassicaceae and Solanaceae, and a representative family of monocot plants, the Poaceae. All three plant families contain important crop plants, including maize, rice, tomato, potato, and canola. Peps were not recognized by species outside of their plant family of origin, apparently because of a divergence of the Pep sequences. Three family-specific Pep motifs were defined and the integration of such a motif into the Pep sequence of an unrelated Pep enabled its perception. Transient transformation of Nicotiana benthamiana with the coding sequences of the AtPEPR1 and ZmPEPR1a led to the recognition of Pep peptides of Brassicaceae or Poaceae origin, respectively, and to the proper activation of downstream signalling. It was concluded that signalling machinery downstream of the PEPRs is highly conserved whereas the leucine-rich repeat domains of the PEPRs co-evolved with the Peps, leading to distinct motifs and, with it, interfamily incompatibility. PMID- 26002972 TI - Hormonal regulation of secondary cell wall formation. AB - Secondary cell walls (SCWs) have critical functional importance but also constitute a high proportion of the plant biomass and have high application potential. This is true mainly for the lignocellulosic constituents of the SCWs in xylem vessels and fibres, which form a structured layer between the plasma membrane and the primary cell wall (PCW). Specific patterning of the SCW thickenings contributes to the mechanical properties of the different xylem cell types, providing the plant with mechanical support and facilitating the transport of solutes via vessels. In the last decade, our knowledge of the basic molecular mechanisms controlling SCW formation has increased substantially. Several members of the multi-layered regulatory cascade participating in the initiation and transcriptional regulation of SCW formation have been described, and the first cellular components determining the pattern of SCW at the subcellular resolution are being uncovered. The essential regulatory role of phytohormones in xylem development is well known and the molecular mechanisms that link hormonal signals to SCW formation are emerging. Here, we review recent knowledge about the role of individual plant hormones and hormonal crosstalk in the control over the regulatory cascades guiding SCW formation and patterning. Based on the analogy between many of the mechanisms operating during PCW and SCW formation, recently identified mechanisms underlying the hormonal control of PCW remodelling are discussed as potentially novel mechanisms mediating hormonal regulatory inputs in SCW formation. PMID- 26002973 TI - Simple and robust determination of the activity signature of key carbohydrate metabolism enzymes for physiological phenotyping in model and crop plants. AB - The analysis of physiological parameters is important to understand the link between plant phenotypes and their genetic bases, and therefore is needed as an important element in the analysis of model and crop plants. The activities of enzymes involved in primary carbohydrate metabolism have been shown to be strongly associated with growth performance, crop yield, and quality, as well as stress responses. A simple, fast, and cost-effective method to determine activities for 13 key enzymes involved in carbohydrate metabolism has been established, mainly based on coupled spectrophotometric kinetic assays. The comparison of extraction buffers and requirement for dialysis of crude protein extracts resulted in a universal protein extraction protocol, suitable for the preparation of protein extracts from different organs of various species. Individual published kinetic activity assays were optimized and adapted for a semi-high-throughput 96-well assay format. These assays proved to be robust and are thus suitable for physiological phenotyping, enabling the characterization and diagnosis of the physiological state. The potential of the determination of distinct enzyme activity signatures as part of a physiological fingerprint was shown for various organs and tissues from three monocot and five dicot model and crop species, including two case studies with external stimuli. Differential and specific enzyme activity signatures are apparent during inflorescence development and upon in vitro cold treatment of young inflorescences in the monocot ryegrass, related to conditions for doubled haploid formation. Likewise, treatment of dicot spring oilseed rape with elevated CO2 concentration resulted in distinct patterns of enzyme activity responses in leaves. PMID- 26002974 TI - Light-induced STOMAGEN-mediated stomatal development in Arabidopsis leaves. AB - The initiation of stomata, microscopic valves in the epidermis of higher plants that control of gas exchange, requires a co-ordinated sequence of asymmetric and symmetric divisions, which is under tight environmental and developmental control. Arabidopsis leaves grown under elevated photosynthetic photon flux density have a higher density of stomata. STOMAGEN encodes an epidermal patterning factor produced in the mesophyll, and our observations indicated that elevated photosynthetic irradiation stimulates STOMAGEN expression. Our analysis of gain and loss of function of STOMAGEN further detailed its function as a positive regulator of stomatal formation on both sides of the leaf, not only in terms of stomatal density across the leaf surface but also in terms of their stomatal index. STOMAGEN function was rate limiting for the light response of the stomatal lineage in the adaxial epidermis. Mutants in pathways that regulate stomatal spacing in the epidermis and have elevated stomatal density, such as stomatal density and distribution (sdd1) and too many mouth alleles, displayed elevated STOMAGEN expression, suggesting that STOMAGEN is either under the direct control of these pathways or is indirectly affected by stomatal patterning, suggestive of a feedback mechanism. These observations support a model in which changes in levels of light irradiation are perceived in the mesophyll and control the production of stomata in the epidermis by mesophyll-produced STOMAGEN, and whereby, conversely, stomatal patterning, either directly or indirectly, influences STOMAGEN levels. PMID- 26002975 TI - Vitamin E gamma-Tocotrienol Inhibits Cytokine-Stimulated NF-kappaB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids. AB - NF-kappaB plays a central role in pathogenesis of inflammation and cancer. Many phytochemicals, including gamma-tocotrienol (gammaTE), a natural form of vitamin E, have been shown to inhibit NF-kappaB activation, but the underlying mechanism has not been identified. In this study, we show that gammaTE inhibited cytokine triggered activation of NF-kappaB and its upstream regulator TGF-beta-activated kinase-1 in murine RAW 264.7 macrophages and primary bone marrow-derived macrophages. In these cells, gammaTE induced upregulation of A20, an inhibitor of NF-kappaB. Knockout of A20 partially diminished gammaTE's anti-NF-kappaB effect, but gammaTE increased another NF-kappaB inhibitor, Cezanne, in A20(-/-) cells. In search of the reason for A20 upregulation, we found that gammaTE treatment increased phosphorylation of translation initiation factor 2, IkappaBalpha, and JNK, indicating induction of endoplasmic reticulum stress. Liquid chromatography tandem mass spectrometry analyses revealed that gammaTE modulated sphingolipids, including enhancement of intracellular dihydroceramides, sphingoid bases in de novo synthesis of the sphingolipid pathway. Chemical inhibition of de novo sphingolipid synthesis partially reversed gammaTE's induction of A20 and the anti NF-kappaB effect. The importance of dihydroceramide increase is further supported by the observation that C8-dihydroceramide mimicked gammaTE in upregulating A20, enhancing endoplasmic reticulum stress, and attenuating TNF-triggered NF-kappaB activation. Our study identifies a novel anti-NF-kappaB mechanism where A20 is induced by stress-induced adaptive response as a result of modulation of sphingolipids, and it demonstrates an immunomodulatory role of dihydrocermides. PMID- 26002976 TI - Dominant Suppression of Inflammation via Targeted Mutation of the mRNA Destabilizing Protein Tristetraprolin. AB - In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies. PMID- 26002977 TI - Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia. AB - Ras GTPase-activating proteins (RasGAPs) inhibit signal transduction initiated through the Ras small GTP-binding protein. However, which members of the RasGAP family act as negative regulators of T cell responses is not completely understood. In this study, we investigated potential roles for the RasGAPs RASA1 and neurofibromin 1 (NF1) in T cells through the generation and analysis of T cell-specific RASA1 and NF1 double-deficient mice. In contrast to mice lacking either RasGAP alone in T cells, double-deficient mice developed T cell acute lymphoblastic leukemia/lymphoma, which originated at an early point in T cell development and was dependent on activating mutations in the Notch1 gene. These findings highlight RASA1 and NF1 as cotumor suppressors in the T cell lineage. PMID- 26002978 TI - Quantitative TCR:pMHC Dissociation Rate Assessment by NTAmers Reveals Antimelanoma T Cell Repertoires Enriched for High Functional Competence. AB - Experimental models demonstrated that therapeutic induction of CD8 T cell responses may offer protection against tumors or infectious diseases providing that T cells have sufficiently high TCR/CD8:pMHC avidity for efficient Ag recognition and consequently strong immune functions. However, comprehensive characterization of TCR/CD8:pMHC avidity in clinically relevant situations has remained elusive. In this study, using the novel NTA-His tag-containing multimer technology, we quantified the TCR:pMHC dissociation rates (koff) of tumor specific vaccine-induced CD8 T cell clones (n = 139) derived from seven melanoma patients vaccinated with IFA, CpG, and the native/EAA or analog/ELA Melan-A(MART 1)(26-35) peptide, binding with low or high affinity to MHC, respectively. We observed substantial correlations between koff and Ca(2+) mobilization (p = 0.016) and target cell recognition (p < 0.0001), with the latter independently of the T cell differentiation state. Our strategy was successful in demonstrating that the type of peptide impacted on TCR/CD8:pMHC avidity, as tumor-reactive T cell clones derived from patients vaccinated with the low-affinity (native) peptide expressed slower koff rates than those derived from patients vaccinated with the high-affinity (analog) peptide (p < 0.0001). Furthermore, we observed that the low-affinity peptide promoted the selective differentiation of tumor specific T cells bearing TCRs with high TCR/CD8:pMHC avidity (p < 0.0001). Altogether, TCR:pMHC interaction kinetics correlated strongly with T cell functions. Our study demonstrates the feasibility and usefulness of TCR/CD8:pMHC avidity assessment by NTA-His tag-containing multimers of naturally occurring polyclonal T cell responses, which represents a strong asset for the development of immunotherapy. PMID- 26002979 TI - Unexpected Role for Adaptive alphabetaTh17 Cells in Acute Respiratory Distress Syndrome. AB - Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by increased alveolar permeability with no effective treatment beyond supportive care. Current mechanisms underlying ARDS focus on alveolar endothelial and epithelial injury caused by products of innate immune cells and platelets. However, the role of adaptive immune cells in ARDS remains largely unknown. In this study, we report that expansion of Ag-specific alphabetaTh17 cells contributes to ARDS by local secretion of IL-17A, which in turn directly increases alveolar epithelial permeability. Mice with a highly restrictive defect in Ag-specific alphabetaTh17 cells were protected from experimental ARDS induced by a single dose of endotracheal LPS. Loss of IL-17 receptor C or Ab blockade of IL-17A was similarly protective, further suggesting that IL-17A released by these cells was responsible for this effect. LPS induced a rapid and specific clonal expansion of alphabetaTh17 cells in the lung, as determined by deep sequencing of the hypervariable CD3RbetaVJ region of the TCR. Our findings could be relevant to ARDS in humans, because we found significant elevation of IL-17A in bronchoalveolar lavage fluid from patients with ARDS, and rIL-17A directly increased permeability across cultured human alveolar epithelial monolayers. These results reveal a previously unexpected role for adaptive immune responses that increase alveolar permeability in ARDS and suggest that alphabetaTh17 cells and IL-17A could be novel therapeutic targets for this currently untreatable disease. PMID- 26002980 TI - Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells. AB - The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. The expression of CCR8 during naive T cell activation is controlled by skin-specific factors derived from epidermal keratinocytes and not by resident dendritic cells. In this study, we show that the CCR8-inducing factors are heat stable and protease resistant and include the vitamin D3 metabolite 1alpha,25-dihydroxyvitamin D3 and PGE2. The effect of either metabolite alone on CCR8 expression was weak, whereas their combination resulted in robust CCR8 expression. Elevation of intracellular cAMP was essential because PGE2 could be substituted with the adenylyl cyclase agonist forskolin, and CCR8 expression was sensitive to protein kinase A inhibition. For effective induction, exposure of naive T cells to these epidermal factors needed to occur either prior to or during T cell activation even though CCR8 was only detected 4-5 d later in proliferating T cells. The importance of tissue environments in maintaining cellular immune surveillance networks within distinct healthy tissues provides a paradigm shift in adaptive immunity. Epidermal-derived vitamin D3 metabolites and PGs provide an essential cue for the localization of CCR8(+) immune surveillance T cells within healthy human skin. PMID- 26002983 TI - Correction. PMID- 26002981 TI - The Contribution of Ebola Viral Load at Admission and Other Patient Characteristics to Mortality in a Medecins Sans Frontieres Ebola Case Management Centre, Kailahun, Sierra Leone, June-October 2014. AB - This paper describes patient characteristics, including Ebola viral load, associated with mortality in a Medecins Sans Frontieres Ebola case management centre (CMC).Out of 780 admissions between June and October 2014, 525 (67%) were positive for Ebola with a known outcome. The crude mortality rate was 51% (270/525). Ebola viral load (whole-blood sample) data were available on 76% (397/525) of patients. Univariate analysis indicated viral load at admission, age, symptom duration prior to admission, and distance traveled to the CMC were associated with mortality (P < .05). The multivariable model predicted mortality in those with a viral load at admission greater than 10 million copies per milliliter (P < .05, odds ratio >10), aged >= 50 years (P = .08, odds ratio = 2) and symptom duration prior to admission less than 5 days (P = .14). The presence of confusion, diarrhea, and conjunctivitis were significantly higher (P < .05) in Ebola patients who died.These findings highlight the importance viral load at admission has on mortality outcomes and could be used to cohort cases with viral loads greater than 10 million copies into dedicated wards with more intensive medical support to further reduce mortality. PMID- 26002984 TI - Body mass index and childhood obesity classification systems: A comparison of the French, International Obesity Task Force (IOTF) and World Health Organization (WHO) references. AB - AIM: This study aims to compare three body mass index (BMI)-based classification systems of childhood obesity: the French, the International Obesity Task Force (IOTF) and the World Health Organization (WHO) references. METHODS: The study involved 1382 schoolchildren, recruited from the Lille Academic District in France in May 2009 aged 8.4+/-1.7 years (4.0-12.0 years). Their mean height and body mass were 131.5+/-10.9cm and 30.7+/-9.2kg, respectively, resulting in a BMI of 17.4+/-3.2kg/m(2). The weight status was defined according to the three systems considered in this study. The agreement between these references was tested using the Cohen's kappa coefficient. RESULTS: The prevalence of overweight was higher with the WHO references (20.0%) in comparison with the French references (13.8%; P<0.0001) and the IOTF (16.2%; P<=0.01). A similar result was found with obesity (WHO: 11.6% vs. IOTF: 6.7%; or French references: 6.7%; P<0.0001). Agreement between the three references ranged from "moderate" to "perfect" (0.43<=kappa<=1.00; P<0.0001). Kappa coefficients were higher when the three references were used to classify children as obese (0.63<=kappa<=1.00; P<0.0001) as compared to classification in the overweight (obesity excluded) category (0.43<=kappa<=0.94; P<0.0001). When sex and age categories (4-6 years vs. 7-12 years) were considered to define the overweight status, the lowest kappa coefficient was found between the French and WHO references in boys aged 7-12 years (kappa=0.28; P<0.0001), and the highest one in girls aged 7-12 years between the French references and IOTF (kappa=0.97; P<0.0001). As for obesity, agreement between the three references ranged from 0.60 to 1.00 (P<0.0001), with the lowest values obtained in the comparison of the WHO references against French references or IOTF among boys aged 7-12 years (kappa=0.60; P<0.0001). CONCLUSION: Overall, the WHO references yield an overestimation in overweight and/or obesity within this sample of schoolchildren as compared to the French references and the IOTF. The magnitude of agreement coefficients between the three references depends on of both sex and age categories. The French references seem to be in rather close agreement with the IOTF in defining overweight, especially in 7-12 year-old children. PMID- 26002985 TI - Improved frozen section examination of the retroareolar margin for prediction of nipple involvement in breast cancer. AB - INTRODUCTION: In this prospective ex vivo study, we propose a new technique for the intraoperative examination of retroareolar tissue and describe both surgical excision and pathological methods. We performed a nipple-sparing mastectomy simulation in patients selected to total mastectomy, in order to evaluate the accuracy of these new technique. MATERIALS AND METHODS: A total of 158 total mastectomy specimens from patients affected by ductal carcinoma in situ (n = 15) or invasive ductal carcinoma (stages I, II, or IIIA) (n = 143) were examined. To obtain the entire sample area, the terminal retroareolar milk duct bunch was isolated. Fragments approximately 1.5 cm in length were excised and sectioned in parallel at the base of the nipple using a cold bistoury. Three transverse histological sections (4 MUm each) at 200 MUm intervals that included the entire isolated fragments were subjected to frozen section examination. The sections were stained with hematoxylin-eosin and were evaluated. The remainder of each fragment was embedded in paraffin and 4 MUm sections were subsequently stained with hematoxylin-eosin and examined. RESULTS: There were two false-negative (1.3%) and five false-positive (3.1%) findings among the frozen and paraffin sections analyzed. A statistical analysis of the frozen section examinations showed a sensitivity of 92.0%, a specificity of 96.2%, a positive predictive value of 82.1%, a negative predictive value of 98.4%, and an accuracy of 95.4%. CONCLUSION: The frozen section examination technique described here detected nipple involvement in breast cancer with greater accuracy than the frozen section usually performed by most surgeons. PMID- 26002986 TI - Surgical and oncological outcome of robotic surgery compared to laparoscopic and abdominal surgery in the management of endometrial cancer. AB - OBJECTIVE: To compare different techniques of minimally invasive surgery (laparoscopy and robotics) to abdominal surgery in order to identify the optimal surgical technique in the treatment of endometrial cancer. METHODS AND MATERIALS: A single-institutional, matched, retrospective, cohort study was performed. All patients with clinical stage I or occult stage II endometrial cancer who underwent robotic hysterectomy, bilateral salpingo-oophorectomy +/- lymphadenectomy from August 2010 and December 2013 were identified. Surgical and oncological outcomes were compared with patients matched by age, body mass index, tumor histology, and grade, who underwent abdominal or laparoscopic surgery between January 2001 and December 2013. RESULTS: Three groups were identified: 177 laparotomies (group A), 277 laparoscopies (group B) and 72 robotics (group C). There were no statistically significant differences between the three groups in terms of age, BMI and FIGO stage. The operative time was shortest in group B (p = 0.0001). Blood loss and transfusions were equivalent in group B and C, while they were greater in group A (p = 0.0001). The intra-operative, early and late postoperative complications, rate of conversion, the re-intervention and median hospital stay were lower in group C. The rate of recurrence and death from disease was similar in all three groups. CONCLUSIONS: Minimally invasive surgery was superior to abdominal surgery in terms of surgical outcomes. Robotic surgery was superior to laparoscopy in terms of intra- and post-operative complications, conversion rates, length of hospital stay and re-interventions. In terms of oncological outcomes the three groups were equivalent. PMID- 26002987 TI - Caring for children undergoing radiotherapy treatment: Swedish radiotherapy nurses' perceptions. AB - PURPOSE: The aim was to explore radiotherapy nurses' perceptions of their experiences of caring for children undergoing radiotherapy treatment for cancer. METHOD: Semi-structured interviews of 12 nurses were conducted. The interviews were analysed using a phenomenographical approach. RESULTS: All interviewees were women, and the group's mean age was 49 years. Caring for children during radiotherapy treatment was perceived as a complex task. Their perceptions included views on providing holistic care, creating a sense of security and being committed. Through holistic care the radiotherapy nurses took responsibility regarding care for the child and family, technical aspects of the radiotherapy procedure and the development of their profession. They tried to create a sense of security through individualized information and preparation, through teamwork with the child and family, and regarding anaesthetic personnel (if needed) while balancing the care they gave related to the child, to the family, to anaesthetic personnel, and to their own tasks. The radiotherapy nurses perceived themselves as committed in their care and reported being emotionally affected by sadness, but also joy. CONCLUSIONS: By clarifying radiotherapy nurses perceptions of caring for children guidelines can be developed to lessen anxiety and increase the sense of security amongst children undergoing radiotherapy treatment and their family members. PMID- 26002988 TI - [Digestive surgical complications during pregnancy following bariatric surgery: Experience of a center for perinatology and obesity]. AB - OBJECTIVE: To describe severe complications during pregnancy requiring surgery in patients with a history of obesity surgery. MATERIEL AND METHODS: A retrospective study in a hospital with tertiary care perinatology and an obesity reference center, on all pregnancies following bariatric surgery over a 10-year period, analyzing all cases of surgical complications. RESULTS: There were 8 major complications related to the procedure in 141 pregnancies with bariatric surgery. The 2 complications in women with gastric banding were band slippage resulting in severe dysphagia, one of which leading to intractable vomiting and serious hydrolectric disorders. Among the 6 complications after bypass surgery, 4 were occlusions: 3 on internal hernias of which 2 with volvulus and 1 associated with intestinal invagination, as well as one with intestinal invagination only. One patient had a laparotomy for a suspected invagination which was not confirmed. The other surgical complications after gastric bypass were a hernia and an exploratory laparotomy for suspected intussusception which was overturned. There was no case of maternal or perinatal death. CONCLUSION: Pregnancies in patients with a history of bariatric surgery are at high risk, in particular for complications related to the surgery and thus require careful interdisciplinary surveillance, and determination of predictive factors. PMID- 26002989 TI - Biochemical and histological impact of direct renin inhibition by aliskiren on myofibroblasts activation and differentiation in bleomycin induced pulmonary fibrosis in adult mice. AB - Aliskiren is a drug classified as a direct renin inhibitor. The renin-angiotensin system plays an important role in pulmonary fibrogeneses. This study aimed to investigate the impact of aliskiren on pulmonary fibrosis induced by bleomycin. Forty adult mice were divided into group I (control), group II (aliskiren 25mg/kg/day IP), group III (bleomycin 0.035U/g intraperitoneally twice weekly for 4 weeks) and group IV (aliskiren+bleomycin). Plasma renin activity (PRA), lung content of hydroxyproline and transforming growth factor-beta1 (TGF-beta1) were assayed. Lung paraffin sections were prepared for histological study and immunohistochemical detection of alpha smooth muscle actin (alphaSMA) as a marker for myofibroblasts activation and differentiation. Bleomycin induced a significant elevation of PRA with a significant increase in hydroxyproline and TGF-beta1 in group III. Microscopically, pulmonary fibrosis was evident in the form of areas of collapsed alveoli, intense inflammatory cells infiltrations, excess accumulation of collagen, and excessively encountered alphaSMA positively immune-stained myofibroblasts, compared to a negative immune-reaction in groups I and II. In group IV, aliskiren resulted in a significant decrease in PRA, TGF beta1 and hydroxyproline, with an attenuation of pulmonary fibrosis and a decrease in alphaSMA positively immune-stained myofibroblasts. In conclusion, renin inhibition by aliskiren attenuated pulmonary fibrosis through decreasing TGF-beta1 and myofibroblasts activation and differentiation. PMID- 26002991 TI - Single-Coil Implantable Cardioverter Defibrillator Leads Remained the Preferred Option. PMID- 26002990 TI - Transfer from primary maternity unit to tertiary hospital in New Zealand - timing, frequency, reasons, urgency and outcomes: Part of the Evaluating Maternity Units study. AB - OBJECTIVES: to examine the transfers from primary maternity units to a tertiary hospital in New Zealand by describing the frequency, timing, reasons and outcomes of those who had antenatal or pre-admission birthplace plan changes, and transfers in labour or postnatally. DESIGN: mixed methods prospective (concurrent) cohort study, which analysed transfer and clinical outcome data (407 primary unit cohort, 285 tertiary hospital cohort), and data from the six week postpartum survey (571 respondents). PARTICIPANTS AND SETTING: well, pregnant women booked to give birth in a tertiary maternity hospital or primary maternity unit in one region in New Zealand (2010-2012). All women received midwifery continuity of care, regardless of their intended or actual birthplace. RESULTS: fewer than half of the women who planned a primary unit birth gave birth there (191 or 46.9%). A change of plan may have been made either antenatally or before admission in labour; and transfers were made after admission to the primary unit in labour or during the postnatal stay (about 48 hours). Of the 117 (28.5%) planning a primary unit birth who changed their planned birthplace type antenatally 73 (62.4%) were due to a clinical indication. Earthquakes accounted for 28.1% of birthplace change (during the research period major earthquakes occurred in the study region). Most (73.8%) labour changes occurred before admission in labour to the primary unit. For the 76 women who changed plan at this stage the most common reasons to do so were a rapid labour (25.0%) or prolonged rupture of membranes (23.7%). Transfers in labour from primary unit to tertiary hospital occurred for 27 women (12.6%) of whom 26 (96.3%) were having their first baby. "Slow progress" of labour accounted for 21 (77.8%) of these and 17 (62.9%) were classified as 'non-emergency'. The average transfer time for 'emergency' transfers was 58 minutes. The average time for all labour transfers from specialist consultation to birth was 4.5 hours. Nine postnatal transfers (maternal or neonatal) from a primary unit occurred (4.7%), making a total post admission transfer rate of 17.3% for the primary unit cohort. KEY CONCLUSIONS: birthplace changes were not uncommon, with many women changing their birthplace plan antenatally or prior to admission in labour and some transferring between facilities during or soon after birth. Most changes were due to the development of complications or 'risk factors'. Most transfers were not urgent and took approximately one hour from the decision to arrival at the tertiary hospital. Despite the transfers the neonatal clinical outcomes were comparable between both primary and tertiary cohorts, and there was higher maternal morbidity in the tertiary cohort. IMPLICATIONS FOR PRACTICE: although the study size is relatively small, its comprehensive documentation of transfers has the potential to inform future research and the birthplace decision-making of childbearing women and midwives. PMID- 26002992 TI - Expression profile of circulating serum microRNAs in dogs with lymphoma. AB - Serum microRNAs (miRNAs) are mediators of cell-to-cell communication and alter the cellular microenvironment; they are stable for hours under certain conditions in body fluids despite the presence of RNases. Certain miRNAs have been found to be altered in the serum or plasma of humans with various cancers and may represent promising, non-invasive biomarkers for various diseases in humans and animals. The objective of this study was to determine the expression profile of circulating miRNAs in the serum of dogs with lymphoma. Serum samples were obtained from 61 dogs with lymphoma and 40 control dogs, and real-time reverse transcription-polymerase chain reaction was used for miRNA measurement. In order to select candidate genes, a comprehensive expression analysis was undertaken prior to validation of several candidate miRNAs. Of 277 miRNAs, five (let-7b, miR 223, miR-25, miR-92a, and miR-423a) were selected as candidates. The expression levels of four miRNAs (let-7b, miR-223, miR-25, miR-92a) were significantly reduced in the lymphoma group, whereas miR-423a levels were significantly increased compared to the controls. When the lymphoma cases were categorized into high- or low-grade as well as into their anatomic form, miR-25 levels were lower in the serum samples from the lymphoma group compared to those from the control group. Although the biological function of serum miRNAs still remains unclear, determining their functional roles in serum and tissues will contribute not only to the identification of potential biomarkers but also to the elucidation of the pathogenesis of canine lymphoma. PMID- 26002993 TI - A bioinformatic approach to check the spatial epitope structure of an immunogenic protein coded by DNA vaccine plasmids. AB - In this study, we used an approach to check the Hemagglutinin antigen-antibodies interactions after fusion of one or two gene segments to Hemagglutinin gene in some influenza DNA vaccines. We designed different DNA vaccine constructs containing Hemagglutinin 9 (H9) gene fused to four or eight 29 amino acids of C3d (4/8P29C3d) and/or 3, 4 domains of the Fc part of IgY (FcIgY) coding sequences. As there are receptors for P29C3d and FcIgY on the immune cells, fused H9 are targeted to these cells. Three dimensional (3D) structures of the DNA vaccine coded proteins were modeled and docked with two antibodies (1KEN, 1QFU) to evaluate the effect of the H9 gene fusion to the other gene segments (4, 8 P29C3d and FcIgY) on the interaction of two H9 spatial epitopes. Also, we docked DNA vaccine proteins containing Fc IgY to its receptor (CHIR AB1) and compare interaction affinity of Fc IgY alone with affinity of DNA vaccines containing Fc IgY. The average of 1KEN and 1QFU interface scores were 94.89 and 93.09% of H9 DNA vaccine-antibodies interface scores, respectively. These percentages showed a little change in the H9 immunogenic parts. Also, because of spatial freedom of H9 part in all DNA vaccine proteins, added parts may not interfere with antibody antigen interactions. Once, H9+FcIgY and CHIR AB1 affinity decreased in comparison with affinity of Fc IgY alone and CHIR AB1, affinity of H9+8P29C3d+FcIgY and CHIR AB1 increased to 132%. So, this would be expectable that despite of loss of affinity in H9 and its antibodies in the H9+8P29C3d+FcIgY, dramatic increase of Fc IgY and CHIR AB1 affinity in this group, could repair the loss of H9 affinity and may lead to a better immunogenicity. PMID- 26002994 TI - Revisiting the time until fixation of a neutral mutant in a finite population - A coalescent theory approach. AB - Evaluation of the time scale of the fixation of neutral mutations is crucial to the theoretical understanding of the role of neutral mutations in evolution. Diffusion approximations of the Wright-Fisher model are most often used to derive analytic formulations of genetic drift, as well as for the time scales of the fixation of neutral mutations. These approximations require a set of assumptions, most notably that genetic drift is a stochastic process in a continuous allele frequency space, an assumption appropriate for large populations. Here equivalent approximations are derived using a coalescent theory approach which relies on a different set of assumptions than the diffusion approach, and adopts a discrete allele-frequency space. Solutions for the mean and variance of the time to fixation of a neutral mutation derived from the two approaches converge for large populations but slightly differ for small populations. A Markov chain analysis of the Wright-Fisher model for small populations is used to evaluate the solutions obtained, showing that both the mean and the variance are better approximated by the coalescent approach. The coalescence approximation represents a tighter upper bound for the mean time to fixation than the diffusion approximation, while the diffusion approximation and coalescence approximation form an upper and lower bound, respectively, for the variance. The converging solutions and the small deviations of the two approaches strongly validate the use of diffusion approximations, but suggest that coalescent theory can provide more accurate approximations for small populations. PMID- 26002995 TI - Analysis of substrate competition in regulatory network motifs: Stimulus-response curves, thresholds and ultrasensitivity. AB - In the simplest case, substrate competition arises if two ligands compete for access to a single binding site of a receptor protein (or enzyme). If the two ligands exhibit different binding affinities the competition becomes biased: as long as the receptor concentration remains lower than that of the high-affinity ligand the latter blocks all of the available binding sites so that the concentration of the complex comprising the low-affinity ligand remains low. The latter only rises if the receptor concentration is increased beyond that of the high-affinity ligand. Depending on the binding affinity of the low-affinity ligand this increase may then occur in an ultrasensitive manner. Similar behavior has been observed in a phosphorylation/dephosphorylation cycle involved in cell cycle regulation. However, a steady state analysis shows that in this case the threshold concentration is modulated by the catalytic rate constants for phosphorylation and dephosphorylation of the high-affinity substrate. As a consequence, there exists a trade-off between the dynamic range of the system as measured by the maximal phosphorylation level of the substrate and the sensitivity of the system as measured by the position of the threshold. Using the ratio of the binding affinities as a small parameter we derive explicit expressions for the stimulus-response curves as a function of the receptor (or enzyme) concentration as well as conditions for the occurrence of ultrasensitivity. Interestingly, the network motifs investigated in this study are described by structurally similar steady state equations indicating that the analysis presented here may be extendable for analyzing substrate competition in more complex regulatory networks. PMID- 26002996 TI - The flatness of Lamellipodia explained by the interaction between actin dynamics and membrane deformation. AB - The crawling motility of many cell types relies on lamellipodia, flat protrusions spreading on flat substrates but (on cells in suspension) also growing into three dimensional space. Lamellipodia consist of a plasma membrane wrapped around an oriented actin filament meshwork. It is well known that the actin density is controlled by coordinated polymerization, branching, and capping processes, but the mechanisms producing the small aspect ratios of lamellipodia (hundreds of nm thickness vs. several MUm lateral and inward extension) remain unclear. The main hypothesis of this work is a strong influence of the local geometry of the plasma membrane on the actin dynamics. This is motivated by observations of co localization of proteins with I-BAR domains (like IRSp53) with polymerization and branching agents along the membrane. The I-BAR domains are known to bind to the membrane and to prefer and promote membrane curvature. This hypothesis is translated into a stochastic mathematical model where branching and capping rates, and polymerization speeds depend on the local membrane geometry and branching directions are influenced by the principal curvature directions. This requires the knowledge of the deformation of the membrane, being described in a quasi-stationary approximation by minimization of a modified Helfrich energy, subject to the actin filaments acting as obstacles. Simulations with this model predict pieces of flat lamellipodia without any prescribed geometric restrictions. PMID- 26002997 TI - Trophic effects of adipose derived stem cells on Langerhans islets viability- Review. AB - Langerhans islets transplantation has been proposed to provide an endogenous source of insulin in Type I diabetes. However, the hypoxic stress and the receptor's immune reaction suffered by the implants cause them to fail in sustaining the insulin production along the time. Experimental studies have shown that adipose derived stem cells (ADSCs) can secrete cytokines that activate free radical scavengers, antioxidants and chaperone heat/shock proteins leading to reduction of apoptosis in damaged tissues. Therefore, using the PubMed database, we reviewed the experimental studies that investigated the trophic effects of ADSCs on Langerhans islets viability, in vitro and in vivo, from 2009 to 2014. We excluded articles that investigated the effects of other types of mesenchymal stem cells on beta-cell survival as well articles that worked in the differentiation of ADSCs into insulin producing cells. The analysis of the experiments revealed that exposure of islets to ADSCs in vitro, even for a short period of time, can enhance islet cell viability and function. In vivo studies also corroborated the trophic effects of ADSCs leading to the improvement of islet function and reduction of the number of the islets required for controlling the receptor's glucose levels. This review can contribute to guide future experiments looking for a long term diabetes treatment employing ADSC trophic effects for the enhancement of transplanted Langerhans islet viability and functioning. PMID- 26002998 TI - Understanding the poultry trade network in Kenya: Implications for regional disease prevention and control. AB - Infectious diseases in poultry can spread quickly and lead to huge economic losses. In the past decade, on multiple continents, the accelerated spread of highly pathogenic avian Influenza A (H5N1) virus, often through informal trade networks, has led to the death and culling of hundreds of millions of poultry. Endemic poultry diseases like Newcastle disease and fowl typhoid can also be devastating in many parts of the world. Understanding trade networks in unregulated systems can inform policy decisions concerning disease prevention and containment. From June to December 2008 we conducted a cross-sectional survey of backyard farmers, market traders, and middlemen in 5/8 provinces in Kenya. We administered a standardized questionnaire to each type of actor using convenience, random, snowball, and systematic sampling. Questionnaires addressed frequency, volume, and geography of trade, as well as biosecurity practices. We created a network diagram identifying the most important locations for trade. Of 380 respondents, 51% were backyard farmers, 24% were middlemen and 25% were market traders. Half (50%) of backyard farmers said they raised poultry both for household consumption and for sale. Compared to market traders, middlemen bought their poultry from a greater number of villages (median 4.2 villages for middlemen vs. 1.9 for market traders). Traders were most likely to purchase poultry from backyard farmers. Of the backyard farmers who sold poultry, 51% [CI 40-63] reported selling poultry to market traders, and 54% [CI 44-63] sold to middlemen. Middlemen moved the largest volume of poultry on a weekly basis (median purchases: 187 birds/week [IQR 206]; median sales: 188 birds/week [IQR 412.5]). The highest numbers of birds were traded in Nairobi - Kenya's capital city. Nairobi was the most prominent trading node in the network (61 degrees of centrality). Many smaller sub-networks existed as a result of clustered local trade. Market traders were also integral to the network. The informal poultry trade in Kenya is dependent on the sale of backyard poultry to middlemen and market traders. These two actors play a critical role in poultry movement in Kenya; during any type of disease outbreak middlemen should be targeted for control- and containment-related interventions. PMID- 26002999 TI - Glycan variation and evolution in the eukaryotes. AB - In this review, we document the evolution of common glycan structures in the eukaryotes, and illustrate the considerable variety of oligosaccharides existing in these organisms. We focus on the families of N- and O-glycans, glycosphingolipids, glycosaminoglycans, glycosylphosphatidylinositol (GPI) anchors, sialic acids (Sias), and cytoplasmic and nuclear glycans. We also outline similar and divergent aspects of the glycans during evolution within the groups, which include inter- and intraspecies differences, molecular mimicry, viral glycosylation adaptations, glycosyltransferase specificity relating to function, and the natural dynamism powering these events. Finally, we present an overview of the patterns of glycosylation found within the groups comprising the Eukaryota, namely the Deuterostomia, Fungi, Viridiplantae, Nematoda, and Arthropoda. PMID- 26003000 TI - Transport and Management of Patients With Confirmed or Suspected Ebola Virus Disease. AB - The foundation of safe care for patients with confirmed or suspected Ebola virus disease is effective infection control practice, which requires implementation of appropriate administrative policies, work practices, and environmental controls, accompanied by focused education, training, and supervision. In 2002, Emory University partnered with the Centers for Disease Control and Prevention to develop a capability for the evaluation and management of individuals with serious communicable disease. In 2005, the University of Nebraska developed a similar isolation capability. In each case, the hospitals partnered with emergency medical services (EMS) professionals to ensure safe out-of-hospital transport and management of their patients. The objectives of these hospital and out-of-hospital collaborations were to close education, training, and practice gaps to best facilitate the care for patients with serious communicable disease while ensuring the safety of the medics and the general public through meticulous implementation of infection control practices as recommended by Centers for Disease Control and Prevention. The description of practices implemented by EMS teams in these communities for the transport of patients with confirmed Ebola virus disease is shared so that others might more readily implement these practices, policies, and procedures as applicable to their mission requirements and system design. Transport of patients with relevant travel history and development of illness (persons under investigation) is also included. PMID- 26003001 TI - Emergency Department Processes for the Evaluation and Management of Persons Under Investigation for Ebola Virus Disease. AB - INTRODUCTION: Due to the recent Ebola virus outbreak in West Africa, patients with epidemiologic risk for Ebola virus disease and symptoms consistent with Ebola virus disease are presenting to emergency departments (EDs) and clinics in the United States. These individuals, identified as a person under investigation for Ebola virus disease, are initially screened using a molecular assay for Ebola virus. If this initial test is negative and the person under investigation has been symptomatic for < 3 days, a repeat test is required after 3 days of symptoms to verify the negative result. In the time interval before the second test result is available, manifestations of the underlying disease process for the person under investigation, whether due to Ebola virus disease or some other etiology, may require further investigation to direct appropriate therapy. MATERIALS AND METHODS: ED administrators, physicians, and nurses proposed processes to provide care that is consistent with other ED patients. Biocontainment unit administrators, industrial hygienists, laboratory directors, physicians, and other medical personnel examined the ED processes and offered biocontainment unit personal protective equipment and process strategies designed to ensure safety for providers and patients. CONCLUSION: ED processes for the safe and timely evaluation and management of the person under investigation for Ebola virus disease are presented with the ultimate goals of protecting providers and ensuring a consistent level of care while confirmatory testing is pending. PMID- 26003002 TI - Carotid Flow Time Changes With Volume Status in Acute Blood Loss. AB - STUDY OBJECTIVE: Noninvasive predictors of volume responsiveness may improve patient care in the emergency department. Doppler measurements of arterial blood flow have been proposed as a predictor of volume responsiveness. We seek to determine the effect of acute blood loss and a passive leg raise maneuver on corrected carotid artery flow time. METHODS: In a prospective cohort of blood donors, we obtained a Doppler tracing of blood flow through the carotid artery before and after blood loss. Measurements of carotid flow time, cardiac cycle time, and peak blood velocity were obtained in supine position and after a passive leg raise. Measurements of flow time were corrected for pulse rate. RESULTS: Seventy-nine donors were screened for participation; 70 completed the study. Donors had a mean blood loss of 452 mL. Mean corrected carotid artery flow time before blood loss was 320 ms (95% confidence interval [CI] 315 to 325 ms); this decreased after blood loss to 299 ms (95% CI 294 to 304 ms). A passive leg raise had little effect on mean corrected carotid artery flow time before blood loss (mean increase 4 ms; 95% CI -1 to 9 ms), but increased mean corrected carotid artery flow time after blood loss (mean increase 23 ms; 95% CI 18 to 28 ms) to predonation levels. CONCLUSION: Corrected carotid artery flow time decreased after acute blood loss. In the setting of acute hypovolemia, a passive leg raise restored corrected carotid artery flow time to predonation levels. Further investigation of corrected carotid artery flow time as a predictor of volume responsiveness is warranted. PMID- 26003003 TI - Global Emergency Medicine Journal Club: A Social Media Discussion About the Lack of Association Between Press Ganey Scores and Emergency Department Analgesia. AB - Annals of Emergency Medicine collaborated with an educational Web site, Academic Life in Emergency Medicine (ALiEM), to host a public discussion featuring the 2014 Annals article on the association between Press Ganey scores and emergency department (ED) analgesia by Schwartz et al. The objective was to curate a 14-day (December 1 through 14, 2014) worldwide academic dialogue among clinicians in regard to preselected questions about the article. Five online facilitators hosted the multimodal discussion on the ALiEM Web site, Twitter, and Google Hangout. Comments across the social media platforms were curated for this report, as framed by the 4 preselected questions. Engagement was tracked through Web analytic tools and analysis of tweets. Blog comments, tweets, and video expert commentary involving the featured article are summarized and reported. The dialogue resulted in 978 page views from 342 cities in 33 countries on the ALiEM Web site, 464,345 Twitter impressions, and 83 views of the video interview with experts. Of the unique 169 identified tweets, discussion (53.3%) and learning points (32.5%) were the most common category of tweets identified. Common themes that arose in the open-access multimedia discussions included Press Ganey data validity and the utility of patient satisfaction in determining pain treatment efficacy. This educational approach using social media technologies demonstrates a free, asynchronous means to engage a worldwide scholarly discourse. PMID- 26003004 TI - Emergency Department Crowding and Outcomes After Emergency Department Discharge. AB - STUDY OBJECTIVE: We assess whether a panel of emergency department (ED) crowding measures, including 2 reported by the Centers for Medicare & Medicaid Services (CMS), is associated with inpatient admission and death within 7 days of ED discharge. METHODS: We conducted a retrospective cohort study of ED discharges, using data from an integrated health system for 2008 to 2010. We assessed patient transit-level (n=3) and ED system-level (n=6) measures of crowding, using multivariable logistic regression models. The outcome measures were inpatient admission or death within 7 days of ED discharge. We defined a clinically important association by assessing the relative risk ratio and 95% confidence interval (CI) difference and also compared risks at the 99th percentile and median value of each measure. RESULTS: The study cohort contained a total of 625,096 visits to 12 EDs. There were 16,957 (2.7%) admissions and 328 (0.05%) deaths within 7 days. Only 2 measures, both of which were patient transit measures, were associated with the outcome. Compared with a median evaluation time of 2.2 hours, the evaluation time of 10.8 hours (99th percentile) was associated with a relative risk of 3.9 (95% CI 3.7 to 4.1) of an admission. Compared with a median ED length of stay (a CMS measure) of 2.8 hours, the 99th percentile ED length of stay of 11.6 hours was associated with a relative risk of 3.5 (95% CI 3.3 to 3.7) of admission. No system measure of ED crowding was associated with outcomes. CONCLUSION: Our findings suggest that ED length of stay is a proxy for unmeasured differences in case mix and challenge the validity of the CMS metric as a safety measure for discharged patients. PMID- 26003005 TI - Laryngospasm With Apparent Aspiration During Sedation With Nitrous Oxide. AB - Nitrous oxide and oxygen mixture has become increasingly popular for the procedural sedation and analgesia of children in the emergency department. In general, nitrous oxide is regarded as a very safe agent according to large case series. We report a case of single-agent nitrous oxide sedation of a child, complicated by laryngospasm and radiographically confirmed bilateral upper lobe pulmonary opacities. Although rarely reported with parenteral sedative agents, laryngospasm and apparent aspiration has not been previously reported in isolated nitrous oxide sedation. This case highlights that, similar to other sedative agents, nitrous oxide administration also needs to be conducted by staff and in settings in which airway emergencies can be appropriately managed. PMID- 26003006 TI - What Are the Most Useful Red Flags for Suspected Vertebral Fracture in Patients With Low Back Pain in the Emergency Department? PMID- 26003008 TI - CXC Chemokine Receptor 4 Is Expressed Paravascularly in Apical Papilla and Coordinates with Stromal Cell-derived Factor-1alpha during Transmigration of Stem Cells from Apical Papilla. AB - INTRODUCTION: Stem cells from the apical papilla (SCAPs) at the apex may be attracted into the root canal space as a cell source for pulp-dentin regeneration. To test this possibility, we used in vitro transmigration models to investigate whether SCAPs can be chemoattracted by the delivery of the chemotactic cytokine stromal cell-derived factor-1alpha (SDF-1alpha). METHODS: We first examined the expression of CXC chemokine receptor 4 (CXCR4) for SDF-1alpha in the apical papilla and in cultured SCAPs using immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and flow cytometric analyses. A standard Transwell migration assay and a 3-dimensional cell migration assay were used to analyze transmigration of SCAPs via the SDF-1alpha/CXCR4 axis. RESULTS: CXCR4 was expressed in the paravascular region of the apical papilla and detected in SCAP cultures. Most cultured SCAPs harbored intracellular CXCR4 (58%-99%, n = 4), whereas only a few cells had detectable CXCR4 on the cell surface (0.3% 2.34%, n = 4). Although SDF-1alpha had no significant effect on SCAP proliferation, it significantly promoted a higher number of migrated cells; this effect was abolished by anti-CXCR4 antibodies. Interestingly, cell surface CXCR4 on SCAPs was not detectable until after transmigration. The 3-dimensional migration assay revealed that SDF-1alpha significantly enhanced SCAP migration in the collagen gel. CONCLUSIONS: SCAPs can be chemoattracted via the SDF 1alpha/CXCR4 axis, suggesting that SDF-1alpha may be used clinically to induce CXCR4-expressing SCAPs in the apical papilla to transmigrate into the root canal space as an endogenous cell source for pulp regeneration. PMID- 26003007 TI - Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers. AB - Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. BACKGROUND: The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. PATIENTS AND METHODS: Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. RESULTS: Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed. CONCLUSION: Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naive patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results. PMID- 26003009 TI - Effects of inefficient transcription termination of rbcL on the expression of accD in plastids of Arabidopsis thaliana. AB - The plastid accD gene encodes one subunit of a multimeric acetyl-CoA carboxylase that is required for fatty acid biosynthesis. In Arabidopsis thaliana, the accD gene is transcribed by the nuclear-encoded phage-type RNA polymerase, and the accumulation of accD transcripts is subjected to a dynamic pattern during chloroplast development. However, the mechanisms underlying the regulation of accD expression remain unknown. Here, we showed that the inefficient transcription termination of rbcL due to the absence of RHON1 impaired the developmental profile of accD, resulting in the constitutive expression of accD during chloroplast development. Moreover, the accumulation of accD transcripts accordingly resulted in an increase in accD protein levels, suggesting that transcript abundance is critical for accD gene production. Our study demonstrates that the interplay between accD and upstream rbcL regulates the expression of accD and highlights the significance of transcriptional regulation in plastid gene expression in higher plants. PMID- 26003010 TI - Enhanced therapeutic anti-inflammatory effect of betamethasone on topical administration with low-frequency, low-intensity (20 kHz, 100 mW/cm(2)) ultrasound exposure on carrageenan-induced arthritis in a mouse model. AB - The purpose of this work was to investigate whether low-frequency, low-intensity (20 kHz, <100 mW/cm(2), spatial-peak, temporal-peak intensity) ultrasound, delivered with a lightweight (<100 g), tether-free, fully wearable, battery powered applicator, is capable of reducing inflammation in a mouse model of rheumatoid arthritis. The therapeutic, acute, anti-inflammatory effect was estimated from the relative swelling induced in mice hindlimb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near-infrared labeled 2-deoxyglucose. The outcome of the experiments indicated that the combination of ultrasound exposure and topical application of 0.1% (w/w) betamethasone gel resulted in statistically significantly (p < 0.05) enhanced anti-inflammatory activity in comparison with drug or ultrasound treatment alone. The present study underscores the potential benefits of low-frequency, low-intensity ultrasound-assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, tolerable low-frequency, low-intensity ultrasound-promoted non invasive drug delivery. PMID- 26003011 TI - Inflammatory genes in rat livers from cardiac- and brain death donors. AB - BACKGROUND: Liver transplantation (LT) is the only life-saving treatment for patients with end-stage liver disease. The increase in patients has prompted the use of not only donation after brain death (DBD) donors but also living donors (LD) and donation after cardiac death (DCD) donors. Donor-type affects early graft function and graft survival as evidenced by an increased risk of developing ischemic type biliary lesions and higher risk of graft loss in DCD as compared with those in DBD grafts. METHODS: Using a rat model, we used quantitative reverse transcription-polymerase chain reaction to examine expression levels of proinflammatory, cytoprotective, and injury genes and determined apoptosis in DCD and DBD livers at different time points after retrieval. RESULTS: After retrieval, early mediators of inflammation MCP-1, HMGB1, and toll-like receptor (TLR 4) were increased in DCD livers, whereas the proinflammatory genes interleukin 6, interleukin 1beta, tumor necrosis factor alpha, P-selectin, and E selectin were massively upregulated in DBD compared with those in LD livers. HO-1 was increased in both postmortem groups. After cold ischemia, DCD livers showed increased levels of MCP-1, TLR4, and HMGB1, whereas expression of proinflammatory genes in DBD liver remained high. During 12 h of cold storage, expression levels remained stable except Hif-1alpha and HMGB1. DCD showed higher number of apoptotic cells compared with DBD livers. CONCLUSIONS: Compared with LD, DCD livers showed only mild upregulation of inflammatory markers, but increased levels of MCP-1, HMGB1, and TLR4, and more apoptotic cells. In contrast, DBD livers showed a massive inflammatory response. These differences in tissue injury and inflammatory response might be relevant for the outcome after LT. PMID- 26003012 TI - Operative skill: quantifying surgeon's response to tissue properties. AB - BACKGROUND: The aim of this study was to investigate how tissue characteristics influence psychomotor planning and performance during a suturing task. Our hypothesis was that participants would alter their technique based on tissue type with each subsequent stitch placed while suturing. MATERIALS AND METHODS: Surgical attendings (n = 6), residents (n = 4), and medical students (n = 5) performed three interrupted sutures on different simulated materials as follows: foam (dense connective tissue), rubber balloons (artery), and tissue paper (friable tissue). An optical motion tracking system captured performance data from participants' bilateral hand movements. Path length and suture time were segmented by each individual stitch placed to investigate changes to psychomotor performance with subsequent stitch placements. Repeated measures analysis of variance was used to evaluate for main effects of stitch order on path length and suture time and interactions between stitch order, material, and experience. RESULTS: When participants sutured the tissue paper, they changed their procedure time (F(4,44) = 5.14, P = 0.017) and path length (F(4,44) = 4.64, P = 0.003) in a linear fashion with the first stitch on the tissue paper having the longest procedure time and path length. Participants did not change their path lengths and procedure times when placing subsequent stitches in the foam (P = 0.910) and balloon materials (P = 0.769). CONCLUSIONS: This study demonstrates quantifiable real-time adaptation by participants to material characteristics during a suturing task. Participants improved their motion-based performance with each subsequent stitch placement indicating changes in psychomotor planning or performance. This adaptation did not occur with the less difficult tasks. Motion capture technology is a promising method for investigating surgical performance and how surgeons adapt to operative complexity. PMID- 26003013 TI - Greek adaptation and validation of the Patient-Rated Tennis Elbow Evaluation (PRTEE). AB - PURPOSE OF THE STUDY: To cross-culturally adapt and validate the Greek version of the Patient-Rated Tennis Elbow Evaluation (PRTEE-G) Questionnaire. METHODS: Four bi-lingual translators were involved in the translation and cultural adaptation procedures. Eighty-two patients (61 women and 21 men) with Lateral Elbow Tendinopathy (LET) participated in the study. To establish test - retest reliability, the patients were asked to complete the PRTEE-G Questionnaire before and after the first physiotherapy treatment. Internal consistency of the translated instrument was measured using Cronbach 'alpha'. An intraclass correlation coefficient was used to assess the test - retest reliability of the PRTEE-G Questionnaire. Concurrent validity was measured by correlating the PRTEE G Questionnaire scores with the Greek version of the Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH) scores using Pearson's correlation coefficient. RESULTS: The Greek PRTEE questionnaire has acceptable internal consistency (Cronbach 'alpha' = 0.95), excellent test - retest reliability (ICC = 0.94) and demonstrates expected concurrent validity (r > 0.72). CONCLUSION: The Greek version of PRTEE Questionnaire is a reliable and valid measure when administered to patients with LET. PMID- 26003014 TI - The diagnostic accuracy of five tests for diagnosing partial-thickness tears of the supraspinatus tendon: A cohort study. AB - STUDY DESIGN: A cohort study. INTRODUCTION: The causes of the pain can be difficult for clinicians to diagnose due to the complexity of the shoulder anatomy and the wide spectrum of shoulder conditions. PURPOSE OF THE STUDY: The aim of this study was to investigate the clinical usefulness of provocative diagnostic tests, in patients with partial-thickness tears of the supraspinatus (SST) tendon. METHODS: The partial-thickness tears SST tendon group consisted of 50 patients and 50 subjects with shoulder pain. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios of five physical examination tests were calculated using a 2 * 2 table. RESULTS: All the tests exhibited clinical useful positive LR greater than 2 (all, >7.0). The Yocum, Jobe, and Hawkinse-Kennedy exhibited clinically useful negative LR of less than 0.5. CONCLUSIONS: The provocative tests examined were clinically useful in determining the presence or absence of pathology of the supraspinatus tendon. LEVEL OF EVIDENCE: 2b. PMID- 26003015 TI - Conservative treatment of mallet finger: A systematic review. AB - PURPOSE: To determine if there is a superior orthosis and wearing regimen for the conservative treatment of mallet finger injuries. The secondary purpose is to examine the current evidence to evaluate if a night orthosis is necessary following the initial immobilization phase. METHODS: A comprehensive literature search was conducted using the search terms mallet finger, splint, orthosis, and conservative treatment. RESULTS: Four randomized controlled trials (RCTs) were included in the systematic review. In all 4 RCTs mallet fingers were immobilized continuously for 6 weeks in acute injuries and 8 weeks for chronic injuries. CONCLUSIONS: Two of the three studies found a large effect size for orthotic intervention ranging from 2.17 to 12.12. Increased edema and age and decreased patient adherence seem to negatively influence DIP extension gains. Recommended immobilization duration is between 6 to 8 weeks and with additional weeks of immobilization in cases of persistent lags. LEVEL OF EVIDENCE: 1a. PMID- 26003016 TI - Single String Technique for Coronary Bifurcation Stenting: Detailed Technical Evaluation and Feasibility Analysis. AB - OBJECTIVES: The study aimed to evaluate the adequacy and feasibility of the single string bifurcation stenting technique. BACKGROUND: Double-stent techniques may be required for complex bifurcations. Currently applied methods all have their morphological or structural limitations with respect to wall coverage, multiple strut layers, and apposition rate. METHODS: Single string is a novel method in which, first, the side branch (SB) stent is deployed with a single stent cell protruding into the main branch (MB). Second, the MB stent is deployed across this protruding stent cell. The procedure is completed by final kissing balloon dilation. The single string technique was first tested in vitro (n = 20) and next applied in patients (n = 11) with complex bifurcation stenoses. RESULTS: All procedures were performed successfully, crossing a single stent cell in 100%. Procedure duration was 23.0 +/- 7.9 min, and the fluoroscopy time was 9.4 +/- 3.5 min. The results were evaluated by optical coherence tomography, showing fully apposed struts in 83.0 +/- 9.2% in the bifurcation area. Residual area obstruction in the MB was 6.4 +/- 5.6% and 25.0 +/- 16.9% in the SB, as evaluated by micro computed tomography. All the human cases were performed successfully with excellent angiographic results: the residual area stenosis was 27 +/- 8% and 29 +/- 10% in the MB and in the SB, respectively, by 3-dimensional quantitative coronary angiography. No relevant periprocedural enzyme increase was observed. During follow-up (6 +/- 4 months), no adverse clinical events (death, myocardial infarction, target vessel revascularization) were noted. CONCLUSIONS: The single string technique for complex bifurcation dilation was shown to be adequate in vitro and feasible in humans, with favorable results in terms of stent overlap, malapposition rate, and low residual obstruction in both the MB and SB. PMID- 26003017 TI - Percutaneous Closure of a Residual Left Atrial Appendage Leak After Lariat Procedure. PMID- 26003018 TI - Plaque Characterization to Inform the Prediction and Prevention of Periprocedural Myocardial Infarction During Percutaneous Coronary Intervention: The CANARY Trial (Coronary Assessment by Near-infrared of Atherosclerotic Rupture-prone Yellow). AB - OBJECTIVES: This study sought to determine whether pre-percutaneous coronary intervention (PCI) plaque characterization using near-infrared spectroscopy identifies lipid-rich plaques at risk of periprocedural myonecrosis and whether these events may be prevented by the use of a distal protection filter during PCI. BACKGROUND: Lipid-rich plaques may be prone to distal embolization and periprocedural myocardial infarction (MI) in patients undergoing PCI. METHODS: Patients undergoing stent implantation of a single native coronary lesion were enrolled in a multicenter, prospective trial. Near-infrared spectroscopy and intravascular ultrasound were performed at baseline, and lesions with a maximal lipid core burden index over any 4-mm length (maxLCBI4mm) >=600 were randomized to PCI with versus without a distal protection filter. The primary endpoint was periprocedural MI, defined as troponin or a creatine kinase-myocardial band increase to 3 or more times the upper limit of normal. RESULTS: Eighty-five patients were enrolled at 9 U.S. sites. The median (interquartile range) maxLCBI4mm was 448.4 (274.8 to 654.4) pre-PCI and decreased to 156.0 (75.6 to 312.6) post-PCI (p < 0.0001). Periprocedural MI developed in 21 patients (24.7%). The maxLCBI4mm was higher in patients with versus without MI (481.5 [425.6 to 679.6] vs. 371.5 [228.9 to 611.6], p = 0.05). Among 31 randomized lesions with maxLCBI4mm >=600, there was no difference in the rates of periprocedural MI with versus without the use of a distal protection filter (35.7% vs. 23.5%, respectively; relative risk: 1.52; 95% confidence interval: 0.50 to 4.60, p = 0.69). CONCLUSIONS: Plaque characterization by near-infrared spectroscopy identifies lipid-rich lesions with an increased likelihood of periprocedural MI after stent implantation, presumably due to distal embolization. However, in this pilot randomized trial, the use of a distal protection filter did not prevent myonecrosis after PCI of lipid-rich plaques. PMID- 26003019 TI - Clinical Events and Patient-Reported Chest Pain in All-Comers Treated With Resolute Integrity and Promus Element Stents: 2-Year Follow-Up of the DUTCH PEERS (DUrable Polymer-Based STent CHallenge of Promus ElemEnt Versus ReSolute Integrity) Randomized Trial (TWENTE II). AB - OBJECTIVES: This study assessed clinical events and patient-reported chest pain 2 years after treatment of all-comers with Resolute Integrity zotarolimus-eluting stents (Medtronic Vascular, Santa Rosa, California) and Promus Element everolimus eluting stents (Boston Scientific, Natick, Massachusetts). BACKGROUND: For both drug-eluting stents (DES), no all-comer outcome data from >12 months of follow-up have been published. Although there is increasing interest in patient-reported chest pain following stenting, data with novel DES are scarce. METHODS: The DUTCH PEERS multicenter trial (TWENTE II) (DUrable Polymer-Based STent CHallenge of Promus ElemEnt Versus ReSolute Integrity) Randomized Trial [TWENTE II]) randomized 1,811 all-comer patients to treatment with 1 type of DES. Monitoring and event adjudication were performed by independent contract research organizations. RESULTS: The 2-year follow-up of 1,810 patients (99.9%) was available. The primary composite endpoint target vessel failure occurred in 8.6% and 7.8% of patients treated with zotarolimus- and everolimus-eluting stents, respectively (p = 0.55). Rates of components of target vessel failure were: cardiac death (2.4% vs. 1.9%, p = 0.42); target vessel-related myocardial infarction (2.4% vs. 1.8%, p = 0.33); clinically-indicated target vessel revascularization (4.6% vs. 4.9%, p = 0.83). At 1- and 2-year follow-up, >80% of patients were free from chest pain (no between-stent difference). In addition, >87% of patients were either free from chest pain or experienced pain only at maximal physical exertion, but not during normal daily activities. Patients with chest pain after 12 months at no more than moderate physical effort had a higher risk of target vessel revascularization during the following year (hazard ratio: 1.89 [95% confidence interval: 1.05 to 3.39], p = 0.03). CONCLUSIONS: During the second year of follow-up, the incidence of adverse clinical endpoints remained similar and low for both DES. The vast majority of patients were free from chest pain. PMID- 26003020 TI - Impact of Strut Width in Periprocedural Myocardial Infarction: A Propensity Matched Comparison Between Bioresorbable Scaffolds and the First-Generation Sirolimus-Eluting Stent. AB - OBJECTIVES: This study aimed to assess the clinical impact of strut width (evaluated by abluminal strut surface area [ASSA]) on periprocedural myocardial infarction (PMI) and clinical outcomes in patients treated with bioresorbable scaffolds (BRS) versus first-generation sirolimus-eluting stents (SES). BACKGROUND: To date, there are no reports on the impact of ASSA on PMI and clinical outcomes. METHODS: We compared the impact of ASSA on outcomes and PMI in propensity-matched patients treated with BRS and SES. The primary outcome was the incidence of major adverse cardiac events (MACE), defined as the combination of all-cause mortality, follow-up myocardial infarction, and target vessel revascularization, at 30-days and 1-year follow-ups. The secondary endpoint was the incidence of PMI. RESULTS: After propensity-matched analysis, 499 patients (147 BRS patients vs. 352 SES patients) were evaluated. Mean ASSA was higher in patients treated with BRS versus SES (BRS: 132.3 +/- 76.7 mm(2) vs. SES: 67.6 +/- 48.4 mm(2), p < 0.001). MACE was not significantly different between groups (30 days MACE: BRS: 0% vs. SES: 1.4%, p = 0.16, and 1-year MACE: BRS: 15.7% vs. SES: 11.4%, p = 0.67). The incidence of PMI was significantly higher in the BRS group (BRS: 13.1% vs. SES: 7.5%, p = 0.05). Multivariable analyses indicated that treatment of left anterior descending artery and ASSA were independent predictors of PMI. CONCLUSIONS: BRS implantation, compared with SES implantation, was associated with a higher incidence of PMI. MACE at 30 days and 1 year were not significantly different. Left anterior descending artery percutaneous coronary intervention and ASSA were independent predictors of PMI. PMID- 26003021 TI - Continuous Left Atrial Pressure Monitoring During MitraClip: Assessing the Immediate Hemodynamic Response. PMID- 26003022 TI - Long-Term Efficacy and Safety of Paclitaxel-Eluting Balloon for the Treatment of Drug-Eluting Stent Restenosis: 3-Year Results of a Randomized Controlled Trial. AB - OBJECTIVES: This study sought to investigate the long-term comparative efficacy and safety of paclitaxel-eluting balloon (PEB), paclitaxel-eluting stent (PES), or balloon angioplasty (BA) for the treatment of drug-eluting stent restenosis. BACKGROUND: The optimal treatment of drug-eluting stent restenosis remains unknown. Although PEB has shown encouraging results, the long-term clinical efficacy and safety of PEB remains poorly defined. METHODS: A total of 402 patients with clinically significant restenosis in limus-eluting stents were randomly assigned to receive PEB (n = 137), PES (n = 131), or BA (n = 134). For this analysis, PEB versus PES and PEB versus BA were compared. The primary efficacy and safety endpoints were target lesion revascularization and the composite of death or myocardial infarction. RESULTS: At a median follow-up of 3 years, the risk of target lesion revascularization was comparable with PEB versus PES (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 0.91 to 2.33; p = 0.11) and lower with PEB versus BA (HR: 0.51, 95% CI: 0.34 to 0.74; p < 0.001). The risk of death/myocardial infarction tended to be lower with PEB versus PES (HR: 0.55, 95% CI: 0.28 to 1.07; p = 0.08), due to a lower risk of death (HR: 0.38, 95% CI: 0.17 to 0.87; p = 0.02). The risk of death/myocardial infarction was similar with PEB versus BA (HR: 0.96, 95% CI: 0.46 to 2.0; p = 0.91). CONCLUSIONS: At 3 years, the use of PEB as compared with PES to treat patients with limus-eluting stent restenosis has similar efficacy and safety. PEB remains superior to BA. The sustained efficacy without trade-off in safety supports the role of PEB as treatment option for patients with drug-eluting stent restenosis. (Intracoronary Stenting and Angiographic Results: Drug Eluting Stent In-Stent Restenosis: 3 Treatment Approaches [ISAR-DESIRE 3]; NCT00987324). PMID- 26003023 TI - Restenosis After Drug-Eluting Stent Implantation in a Patient With Polycythemia Vera: Optical Coherence Tomography and Pathological Findings. PMID- 26003024 TI - Internal Mammary Artery Atherosclerosis: Use of Optical Coherence Tomography to Characterize Lesions and Guide Intervention. PMID- 26003025 TI - Long-Term Results of Drug-Coated Balloons for Drug-Eluting In-Stent Restenosis: Gaining Perspective. PMID- 26003026 TI - The 24-Month Prognosis of Patients With Positive or Intermediate Results in the Intracoronary Ergonovine Provocation Test. AB - OBJECTIVES: This study was an observational, multicenter registry to determine clinical characteristics and 24-month prognosis of patients who underwent intracoronary ergonovine provocation tests. BACKGROUND: The clinical characteristics and prognosis of patients who underwent the ergonovine provocation for vasospastic angina were not fully elucidated. METHODS: A total of 2,129 patients in the VA-KOREA (Vasospastic Angina in Korea) registry were classified into positive (n = 454), intermediate (n = 982), and negative (n = 693) groups by intracoronary ergonovine provocation tests. The 24-month incidences of cardiac death, new-onset arrhythmia, and acute coronary syndrome were determined (mean 26.7 +/- 8.8 months). RESULTS: The number of smokers, frequency of angina before angiography, high-sensitivity C-reactive protein, and triglyceride were higher in the positive group than in other groups. The clinical characteristics of the intermediate and the negative groups were very similar. In the positive group, the incidences of diffuse, focal, and mixed spasm were 65.9%, 23.6%, and 10.6%. Coronary spasm was more frequently provoked on atherosclerotic segments. The 24-month incidences of cardiac death, arrhythmia, and acute coronary syndrome were low (0.9%, 1.6%, and 1.9%, respectively) in the positive group, and there was no cardiac death in the intermediate group (p = 0.02). In the positive group, frequent angina, current smoking, and multivessel spasm were independent predictors for adverse events. CONCLUSIONS: The 24-month prognosis of the positive group in the intracoronary ergonovine provocation test was relatively worse than that of the intermediate group. More intensive clinical attention should be paid to vasospastic angina patients with high-risk factors including frequent angina before angiography, current smoking, and multivessel spasm. PMID- 26003027 TI - Aortic Valve Cusps Decalcification Complicated by an Embolic Myocardial Infarction Treated by Transradial Intracoronary Embolectomy. PMID- 26003028 TI - A Rare Case of Spontaneous Dissection in a Left Internal Mammary Artery Bypass Graft in Acute Coronary Syndrome. PMID- 26003029 TI - Transcatheter Mitral Valve Implantation With the FORTIS Device: Insights Into the Evaluation of Device Success. PMID- 26003030 TI - Percutaneous Ventricular Septal Defect Closure After Sapien 3 Transcatheter Aortic Valve Replacement. PMID- 26003031 TI - Atrial Remodeling Following Catheter-Based Renal Denervation Occurs in a Blood Pressure- and Heart Rate-Independent Manner. AB - OBJECTIVES: This study sought to investigate left atrial (LA) remodeling in relation to blood pressure (BP) and heart rate (HR) after renal sympathetic denervation (RDN). BACKGROUND: In addition to reducing BP and HR in certain patients with hypertension, RDN can decrease left ventricular (LV) mass and ameliorate LV diastolic dysfunction. METHODS: Before and 6 months after RDN, BP, HR, LV mass, left atrial volume index (LAVI), diastolic function (echocardiography), and premature atrial contractions (PAC) (Holter electrocardiogram) were assessed in 66 patients with resistant hypertension. RESULTS: RDN reduced office BP by 21.6 +/- 3.0/10.1 +/- 2.0 mm Hg (p < 0.001), and HR by 8.0 +/- 1.3 beats/min (p < 0.001). At baseline, LA size correlated with LV mass, diastolic function, and pro-brain natriuretic peptide, but not with BP or HR. Six months after RDN, LAVI was reduced by 4.0 +/- 0.7 ml/kg/m(2) (p < 0.001). LA size decrease was stronger when LAVI at baseline was higher. In contrast, the decrease in LAVI was not dependent on LV mass or diastolic function (E/E' or E/A) at baseline. Furthermore, LAVI decreased without relation to decrease in systolic BP or HR. Additionally, occurrence of PAC (median of >153 PAC/24 h) was reduced (to 68 PAC/24 h) by RDN, independently of changes in LA size. CONCLUSIONS: In patients with resistant hypertension, LA volume and occurrence of PAC decreased 6 months after RDN. This decrease was independent of BP and HR at baseline or the reduction in BP and HR reached by renal denervation. These data suggest that there is a direct, partly BP-independent effect of RDN on cardiac remodeling and occurrence of premature atrial contractions. PMID- 26003032 TI - First-in-Man Percutaneous Transseptal Closure of Paravalvular Regurgitation After Percutaneous Valve-in-Ring Implantation. PMID- 26003033 TI - [Vulvar oedema revealing systemic mastocytosis]. AB - BACKGROUND: Systemic mastocytosis is characterised by abnormal proliferation of mast cells in various organs. We report an original case of systemic mastocytosis revealed by vulvar oedema. PATIENTS AND METHODS: A 24-year-old patient was examined in the dermatology department for vulvar oedema appearing during sexual intercourse. She presented vasomotor dysfunction of the lower limbs, urticaria on the trunk on exertion, diarrhoea and bone pains. Laboratory tests showed serum tryptase of 29.7MUg and plasma histamine at twice the normal value. Myelogram results showed infiltration by dysmorphic mast cells. Screening for c-kit D816V mutation was positive. Duodenal biopsies revealed mast-cell clusters with aggregation involving over 15 mast cells. CD2 staining was inconclusive and CD25 staining could not be done. Trabecular osteopenia was found, and we thus made a diagnosis of indolent systemic mastocytosis (ISM variant Ia) as per the WHO 2008 criteria. Symptomatic treatment was initiated (antiH1, H2, antileukotrienes) and clinical and laboratory follow-up was instituted. DISCUSSION: The cutaneous signs leading to diagnosis in this patient of systemic mastocytosis involving several organs were seemingly minimal signs associated with mastocyte degranulation. This is the third recorded case of mastocytosis revealed by vulvar oedema and the first case revealing systemic involvement. The two previously reported cases of vulvar oedema revealed cutaneous mastocytosis alone. Mastocytosis, whether systemic or cutaneous, must be included among the differential diagnoses considered in the presence of vulvar oedema. PMID- 26003034 TI - Toward a standard technique for laparoscopic distal pancreatectomy? Synthesis of the 2013 ACHBT Spring workshop. AB - Laparoscopic distal pancreatectomy is currently a commonly performed procedure. Twenty-five retrospective studies comparing laparotomy and laparoscopy have dealt with the feasibility of this approach for localized benign and malignant tumors. However, these studies report several different techniques. The aim of this review was to determine if a standardized procedure could be proposed. Based on the literature and the experience of surgeons in the French Association of Hepatobiliary Surgery and Liver Transplantation (ACBHT-Association francaise de chirurgie hepato-biliaire et de transplantation hepatique), we recommend primary control of the splenic artery, use of linear staplers for pancreatic transection, splenic vein control either at its end or its origin, and, depending on local conditions, preservation of the splenic vessels when splenic preservation is envisioned. Current data do not allow establishment of any definitive recommendations as to the ideal site of pancreatic transection, operative patient position, or the direction of dissection, which mainly depends on local practices. Control of the splenic vein remains the critical point of this procedure, and impacts the intra-operative strategy. PMID- 26003035 TI - Ecology of free-living metacercariae (Trematoda). AB - The presence of trematodes with a free-living metacercarial stage is a common feature of most habitats and includes important species such as Fasciola hepatica, Parorchis acanthus and Zygocotyle lunata. These trematodes encyst on the surface of an animal or plant that can act as a transport host, which form the diet of the target definitive host. Although these species are often considered individually, they display common characteristics in their free-living biology indicating a shared transmission strategy, yet in comparison to species with penetrative cercariae this aspect of their life cycles remains much overlooked. This review integrates the diverse data and presents a novel synthesis of free-living metacercariae using epibiosis as the basis of a new framework to describe the relationship between transport hosts and parasites. All aspects of their biology during the period that they are metabolically independent of a host are considered, from cercarial emergence to metacercarial excystment. PMID- 26003036 TI - Cross-border malaria: a major obstacle for malaria elimination. AB - Movement of malaria across international borders poses a major obstacle to achieving malaria elimination in the 34 countries that have committed to this goal. In border areas, malaria prevalence is often higher than in other areas due to lower access to health services, treatment-seeking behaviour of marginalized populations that typically inhabit border areas, difficulties in deploying prevention programmes to hard-to-reach communities, often in difficult terrain, and constant movement of people across porous national boundaries. Malaria elimination in border areas will be challenging and key to addressing the challenges is strengthening of surveillance activities for rapid identification of any importation or reintroduction of malaria. This could involve taking advantage of technological advances, such as spatial decision support systems, which can be deployed to assist programme managers to carry out preventive and reactive measures, and mobile phone technology, which can be used to capture the movement of people in the border areas and likely sources of malaria importation. Additionally, joint collaboration in the prevention and control of cross-border malaria by neighbouring countries, and reinforcement of early diagnosis and prompt treatment are ways forward in addressing the problem of cross-border malaria. PMID- 26003037 TI - Development of malaria transmission-blocking vaccines: from concept to product. AB - Despite decades of effort battling against malaria, the disease is still a major cause of morbidity and mortality. Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. In the 1950s, Huff et al. first demonstrated the induction of transmission-blocking immunity in chickens by repeated immunizations with Plasmodium gallinaceum-infected red blood cells. Since then, significant progress has been made in identification of parasite antigens responsible for transmission-blocking activity. Recombinant technologies accelerated evaluation of these antigens as vaccine candidates, and it is possible to induce effective transmission-blocking immunity in humans both by natural infection and now by immunization with recombinant vaccines. This chapter reviews the efforts to produce TBVs, summarizes the current status and advances and discusses the remaining challenges and approaches. PMID- 26003038 TI - Trunk extension exercises: How is trunk extensor muscle recruitment related to the exercise dosage? AB - Trunk extension exercises are used to train endurance and strength of the trunk extensor muscles. Appropriate exercise dosage is crucial to achieve specific training effects, however literature describing the relation between the predetermined exercise intensity and the actual trunk extensors activity is scarce and inconclusive. To examine whether the actual activity of the thoracic and lumbar extensors during extensions exercises correspond with the predetermined intensity, electromyographic evaluation of the trunk extensors was performed during trunk extension exercises at various intensities expressed as percentages of 1-RM. The 1-RM was predetermined using 2 different methods: (1) through direct estimation by determining the maximum isometric force produced during semi-seated trunk extension on a Tergumed rehabilitation device, (2) through indirect estimation calculated based on the relation between the maximum number of repetitions of trunk extension from prone lying on a variable angle chair and the submaximal resistance at which the repetitions were performed as presented on the Holten-diagram. The total trunk muscle activity during extension exercises performed semi-seated on a rehabilitation device or from prone lying corresponds with the predetermined dosage using both estimation methods. The indirect estimation method more accurately predicts the actual trunk extensor activity for low load training than for high load training. However, the direct estimation method is suitable to closely predetermine the load and actual trunk extensors activity during high load exercises. A shift from a differential recruitment between the thoracic and lumbar extensors at low intensities to a more homogenous recruitment at high intensities is observed during semi-seated trunk extension exercises. During prone extension exercises both muscle groups equally contribute to the total muscle work regardless of the exercise intensity. Based on these findings suggestions regarding the appropriate choice of estimation and performance method are made. PMID- 26003039 TI - Microneedle patch delivery to the skin of virus-like particles containing heterologous M2e extracellular domains of influenza virus induces broad heterosubtypic cross-protection. AB - A broadly cross-protective influenza vaccine that can be administrated by a painless self-immunization method would be a value as a potential universal mass vaccination strategy. This study developed a minimally-invasive microneedle (MN) patch for skin vaccination with virus-like particles containing influenza virus heterologous M2 extracellular (M2e) domains (M2e5x VLPs) as a universal vaccine candidate without adjuvants. The stability of M2e5x VLP-coated microneedles was maintained for 8weeks at room temperature without losing M2e antigenicity and immunogenicity. MN skin immunization induced strong humoral and mucosal M2e antibody responses and conferred cross-protection against heterosubtypic H1N1, H3N2, and H5N1 influenza virus challenges. In addition, M2e5x VLP MN skin vaccination induced T-helper type 1 responses such as IgG2a isotype antibodies and IFN-gamma producing cells at higher levels than those by conventional intramuscular injection. These potential immunological and logistic advantages for skin delivery of M2e5x VLP MN vaccines could offer a promising approach to develop an easy-to-administer universal influenza vaccine. PMID- 26003040 TI - Novel biodegradable polyesteramide microspheres for controlled drug delivery in Ophthalmology. AB - Most of the posterior segment diseases are chronic and multifactorial and require long-term intraocular medication. Conventional treatments of these pathologies consist of successive intraocular injections, which are associated with adverse effects. Successful therapy requires the development of new drug delivery systems able to release the active substance for a long term with a single administration. The present work involves the description of a new generation of microspheres based on poly(ester amide)s (PEA), which are novel polymers with improved biodegradability, processability and good thermal and mechanical properties. We report on the preparation of the PEA polymer, PEA microspheres (PEA Ms) and their characterization. PEA Ms (~15MUm) were loaded with a lipophilic drug (dexamethasone) (181.0+/-2.4MUg DX/mg Ms). The in vitro release profile of the drug showed a constant delivery for at least 90days. Based on the data from a performed in vitro release study, a kinetic ocular model to predict in vivo drug concentrations in a rabbit vitreous was built. According to the pharmacokinetic simulations, intravitreal injection of dexamethasone loaded PEA microspheres would provide release of the drug in rabbit eyes up to 3months. Cytotoxicity studies in macrophages and retinal pigment epithelial cells revealed a good in vitro tolerance of the microsystems. After sterilization, PEA Ms were administered in vivo by subtenon and intravitreal injections in male Sprague Dawley rats and the location of the microspheres in rat eyes was monitored. We conclude that PEA Ms provide an alternative delivery system for controlling the delivery of drugs to the eye, allowing a novel generation of microsphere design. PMID- 26003041 TI - Image-guided synergistic photothermal therapy using photoresponsive imaging agent loaded graphene-based nanosheets. AB - We report the image-guided synergistic photothermal antitumor effects of photoresponsive near-infrared (NIR) imaging agent, indocyanine green (ICG), by loading onto hyaluronic acid-anchored, reduced graphene oxide (HArGO) nanosheets. Loading of ICG onto either rGO (ICG/rGO) or HArGO (ICG/HArGO) substantially improved the photostability of photoresponsive ICG upon NIR irradiation. After 1min of irradiation, the NIR absorption peak of ICG almost disappeared whereas the peak of ICG on rGO or HArGO was retained even after 5min of irradiation. Compared with plain rGO, HArGO provided greater cellular delivery of ICG and photothermal tumor cell-killing effects upon laser irradiation in CD44-positive KB cells. The temperature of cell suspensions treated with ICG/HArGO was 2.4-fold higher than that of cells treated with free ICG. Molecular imaging revealed that intravenously administered ICG/HArGO accumulated in KB tumor tissues higher than ICG/rGO or free ICG. Local temperatures in tumor tissues of laser-irradiated KB cell-bearing nude mice were highest in those intravenously administered ICG/HArGO, and were sufficient to trigger thermal-induced complete tumor ablation. Immunohistologically stained tumors also showed the highest percentages of apoptotic cells in the group treated with ICG/HArGO. These results suggest that photoresponsive ICG-loaded HArGO nanosheets could serve as a potential theranostic nano-platform for image-guided and synergistic photothermal antitumor therapy. PMID- 26003042 TI - Vascular-targeted TNFalpha improves tumor blood vessel function and enhances antitumor immunity and chemotherapy in colorectal cancer. AB - Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. "Vascular targeting" strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor alpha (TNFalpha) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNFalpha (TCP-1/TNFalpha: 5MUg/mouse) displayed potent antitumor activity by inducing apoptosis and reducing microvessel number in tumors than unconjugated TNFalpha, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5 fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNFalpha (1ng/mouse) and to a greater extent by the same concentration of TCP 1/TNFalpha. In this regard, TCP-1/TNFalpha combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNFalpha normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFalpha in bone marrow and spleen. At the same time, TCP-1/TNFalpha significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNFalpha holds great promise for colorectal cancer therapy. PMID- 26003043 TI - A systems approach to modeling drug release from polymer microspheres to accelerate in vitro to in vivo translation. AB - Mathematical models of controlled release that span the in vitro to in vivo transition are needed to speed the development and translation of clinically relevant controlled release drug delivery systems. Fully mechanistic approaches are often challenged due to the use of highly-parameterized mathematically complex structures to capture the release mechanism. The simultaneous scarcity of in vivo data to inform these models and parameters leads to a situation where overfitting to capture observed phenomena is common. A data-driven approach to model development for controlled drug release from polymeric microspheres is taken herein, where physiological mechanisms impacting controlled release are incorporated to capture observed changes between in vitro release profiles and in vivo device dynamics. The model is generalizable, using non-specific binding to capture drug-polymer interactions via charge and molecular structure, and it has the ability to describe both inhibited (slowed) and accelerated release resulting from electrostatic or steric interactions. Reactive oxygen species (ROS)-induced degradation of biodegradable polymers was incorporated via a reaction-diffusion formalism, and this suggests that ROS may be the primary effector of the oft observed accelerated in vivo release of polymeric drug delivery systems. Model performance is assessed through comparisons between model predictions and controlled release of several drugs from various-sized microparticles in vitro and in vivo. PMID- 26003044 TI - G5-PEG PAMAM dendrimer incorporating nanostructured lipid carriers enhance oral bioavailability and plasma lipid-lowering effect of probucol. AB - This work aimed to improve the oral bioavailability and plasma lipid-lowering effect of probucol (PB) by constructing a combined drug delivery system (CDDS) composed of nanostructured lipid carrier (NLC) and PEGylated poly(amidoamine) dendrimer (PEG-PAMAM). PEG-PAMAM with dendrimer generations of 5 (G5-PEG) or 7 (G7-PEG) were incorporated in PB-NLCs to form PB-CDDSs, PB-NLCs/G5-PEG and PB NLCs/G7-PEG. The resultant two kinds of PB-CDDSs were characterized by particle size, zeta potential, drug encapsulation efficacy, PB release rates, and physical stability. Formulation effects of NLC and CDDS on the cellular uptake of hydrophobic drug were explored in Caco-2 cells by fluorescent Cy5 dye as a hydrophobic drug model. Furthermore, in vivo pharmacokinetics of the PB-CDDS composed of G5-PEG and PB-NLCs were investigated in a low density lipoprotein receptor knockout (LDLr-/-) mouse model, including plateau plasma PB concentrations after oral administration of multiple doses, and bioavailability after oral administration of a single dose of different PB formulations. In addition, lipid-lowering effect of PB-NLCs/G5-PEG was studied. The results indicate that both G5-PEG and G7-PEG significantly improved aqueous solubility of PB. The two PB-CDDSs exhibited similar particle size (around 150nm) as PB-NLCs, but slower PB burst release rate, higher total PB release amount, and better particle morphology and storage stability than PB-NLCs. In comparison with traditional NLC, CDDS dramatically enhanced cellular uptake of Cy5 into Caco-2 cells. In vivo results demonstrate that PB-NLCs/G5-PEG had the highest plateau plasma PB concentration and oral bioavailability, and the greatest cholesterol lowering effect in comparison with PB suspensions and PB-NLCs. Therefore, G5-PEG incorporating NLC can be exploited as a promising drug delivery system to improve oral bioavailability and lipid-lowering effect of PB. PMID- 26003045 TI - A systematic review of the statistical methods in prospective cohort studies investigating the effect of medications on cognition in older people. AB - BACKGROUND: There is increasing awareness that medications can contribute to cognitive decline. Prospective cohort studies are rich sources of clinical data. However, investigating the contribution of medications to cognitive decline is challenging because both medication exposure and cognitive impairment can be associated with attrition of study participants, and medication exposure status may change over time. The objective of this review was to investigate the statistical methods in prospective cohort studies assessing the effect of medications on cognition in older people. METHODS: A systematic literature search was conducted to identify prospective cohort studies of at least 12 months duration that investigated the effect of common medications or medication classes (anticholinergics, antihistamines, hypnotics, sedatives, opioids, statins, estrogens, testosterone, antipsychotics, anticonvulsants, antidepressants, anxiolytics, antiparkinson agents and bronchodilators) on cognition in people aged 65 years and older. Data extraction was performed independently by two investigators. A descriptive analysis of the statistical methods was performed. RESULTS: A total of 44 articles were included in the review. The most common statistical methods were logistic regression (24.6% of all reported methods), Cox proportional hazards regression (22.8%), linear mixed-effects models (21.1%) and multiple linear regression (14.0%). The use of advanced techniques, most notably linear mixed-effects models, increased over time. Only 6 articles (13.6%) reported methods for addressing missing data. CONCLUSIONS: A variety of statistical methods have been used for investigating the effect of medications on cognition in older people. While advanced techniques that are appropriate for the analysis of longitudinal data, most notably linear mixed-effects models, have increasingly been employed in recent years, there is an opportunity to implement alternative techniques in future studies that could address key research questions. PMID- 26003046 TI - Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene. AB - Guanidinoacetate methyltransferase (GAMT) deficiency is a neurodegenerative disease. Although no symptomatic patients on treatment achieved normal neurodevelopment, three asymptomatic newborns were reported with normal neurodevelopmental outcome on neonatal treatment. GAMT deficiency is therefore a candidate for newborn screening programs, but there are no studies for the carrier frequency of this disease in the general population. To determine carrier frequency of GAMT deficiency, we studied the variants in the GAMT gene reported in the Exome Variant Server database and performed functional characterization of missense variants. We used previously cloned GAMT transcript variant 1 (7 missense variants) and cloned a novel GAMT transcript variant 2 (5 missense variants). The latter was used in Exome Variant Server database according to recommendations of the Human Genome Variation Society. There were 4 missense variants (1 previously reported and 3 novel) with low GAMT enzyme activity indicating pathogenicity. Additionally, there was one novel frameshift and one novel nonsense variant likely pathogenic. There was no measurable GAMT enzyme activity in the wild type of GAMT transcript variant 2. We concluded that GAMT transcript variant 2 is not involved in GAMT protein synthesis. For this reason, Human Genome Variation Society should use mutation nomenclature according to the coding region of the GAMT transcript variant 1. The carrier frequency of GAMT deficiency was 0.123 % in the general population. As early diagnosis results in normal neurodevelopmental outcome, GAMT deficiency should be included in newborn screening programs to diagnose individuals at the asymptomatic stage of the disease to prevent permanent neurodevelopmental disability. PMID- 26003047 TI - A conditional transgenic mouse line for targeted expression of the stem cell marker LGR5. AB - LGR5 is a known marker of embryonic and adult stem cells in several tissues. In a mouse model, Lgr5+ cells have shown tumour-initiating properties, while in human cancers, such as basal cell carcinoma and colon cancer, LGR5 expression levels are increased: however, the effect of increased LGR5 expression is not fully understood. To study the effects of elevated LGR5 expression levels we generated a novel tetracycline-responsive, conditional transgenic mouse line expressing human LGR5, designated TRELGR5. In this transgenic line, LGR5 expression can be induced in any tissue depending on the expression pattern of the chosen transcriptional regulator. For the current study, we used transgenic mice with a tetracycline-regulated transcriptional transactivator linked to the bovine keratin 5 promoter (K5tTA) to drive expression of LGR5 in the epidermis. As expected, expression of human LGR5 was induced in the skin of double transgenic mice (K5tTA;TRELGR5). Inducing LGR5 expression during embryogenesis and early development resulted in macroscopically and microscopically detectable phenotypic changes, including kink tail, sparse fur coat and enlarged sebaceous glands. The fur and sebaceous gland phenotypes were reversible upon discontinued expression of transgenic LGR5, but this was not observed for the kink tail phenotype. There were no apparent phenotypic changes if LGR5 expression was induced at three weeks of age. The results demonstrate that increased expression of LGR5 during embryogenesis and the neonatal period alter skin development and homeostasis. PMID- 26003049 TI - Time, space and the vertebrate body axis. AB - Anterior-posterior (A-P) patterning of the vertebrate main body axis regulated by timing. Anterior structures are specified early, posterior late. (1) Timing involves timed decision points as emphasised by the Wnt studies of Sokol and colleagues. It also involves complex timers, where large parts of the axis are patterned sequentially by a common upstream mechanism (articles by Durston et al., Mullins et al., Oates et al.,). (2) A gastrula BMP-anti BMP dependent time space translation (TST) mechanism was demonstrated for the trunk section of the axis (Durston). (3) Thisses' studies emphasise the importance of BMP-anti BMP and the organiser inducing factor nodal for A-P patterning. (4) Meinhardt's interesting studies on the organiser and A-P patterning are reviewed in relation to TST. (5) Mullins' investigations show that anti-BMP dependent TST starts earlier (at the blastula stage) and extends further anteriorly (to the anterior head). Sive's studies imply it may extend further still to the "extreme anterior domain" (EAD). (6) The somitogenesis timer (clock) is presented. Stern's and Oates' findings are discussed. (7) Relations between somitogenesis and axial TST are discussed. (8) Relations of classical axial patterning pathways to TST decision points and somitogenesis are inventarised. In conclusion, all of these findings point to an integral BMP-anti BMP dependent A-P TST mechanism, running from cement gland in the EAD, Six3 and the anterior tip of the forebrain at blastula stages to Hox13 and the tip of the tail by the mid neurula stage. TST acts via sequential timed transitions between ventral (unstable, timed) and dorsal (stabilised) states. In the trunk-tail, the timer is thought to be Hox temporal collinearity and TST depends on Hox function. In the head, TST is under investigation. The somitogenesis clock is upstream of the TST timer, providing precision in the posterior part of the axis at least. Classical A-P signalling pathways: retinoids, FGFs and Wnts, change behaviour at functional decision points on the axis. PMID- 26003048 TI - CCR9-mediated signaling through beta-catenin and identification of a novel CCR9 antagonist. AB - Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of beta-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of beta-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of beta-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/beta-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/beta-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target. PMID- 26003051 TI - Secondary structure-based analysis of mouse brain small RNA sequences obtained by using next-generation sequencing. AB - In order to find novel structured small RNAs, next-generation sequencing was applied to small RNA fractions with lengths ranging from 40 to 140 nt and secondary structure-based clustering was performed. Sequences of structured RNAs were effectively clustered and analyzed by secondary structure. Although more than 99% of the obtained sequences were known RNAs, 16 candidate mouse structured small non-coding RNAs (MsncRs) were isolated. Based on these results, the merits of secondary structure-based analysis are discussed. PMID- 26003050 TI - Conceptual barriers to understanding physical barriers. AB - The members of the large family of claudin proteins regulate ion and water flux across the tight junction. Many claudins, e.g. claudins 2 and 15, accomplish this by forming size- and charge-selective paracellular channels. Claudins also appear to be essential for genesis of tight junction strands and recruitment of other proteins to these sites. What is less clear is whether claudins form the paracellular seal. While this seal is defective when claudins are disrupted, some results, including ultrastructural and biochemical data, suggest that lipid structures are an important component of tight junction strands and may be responsible for the paracellular seal. This review highlights current understanding of claudin contributions to barrier function and tight junction structure and suggests a model by which claudins and other tight junction proteins can drive assembly and stabilization of a lipid-based strand structure. PMID- 26003052 TI - Teaching residents may affect the margin status of breast-conserving operations. AB - PURPOSE: The current study was performed to evaluate the effects of teaching surgical residents on the margin status after lumpectomy. METHODS: A retrospective review of all patients from July 2006 to Nov 2009 was performed. The impact of the technical ability of surgical residents to perform lumpectomy was evaluated to determine if there was an effect on the margin status. A logistic regression analysis was performed to adjust for clinical variables known to affect the margin status. RESULTS: Of 106 patients, 19% had positive margins. Residents with unsatisfactory technical skills had a positive margin rate of 34% compared to 8% for residents with satisfactory skills (p = 0.004). In the multivariate logistic regression analysis, the operating surgeon remained significantly associated with a positive margin status. Operations performed by residents with satisfactory technical skills or by attending surgeons were less likely to have positive margins than those performed by residents with unsatisfactory technical skills (OR 0.26, 95% CI 0.08-0.86; p = 0.03). After a mean follow-up of 60 months, the breast cancer-specific survival rate was 94%, and there were no local recurrences as a first event. CONCLUSIONS: The technical ability of residents may affect the margin status after lumpectomy. The importance of teaching surgical residents needs to be considered in future quality of care evaluations. PMID- 26003053 TI - Perceived ambiguity as a barrier to intentions to learn genome sequencing results. AB - Many variants that could be returned from genome sequencing may be perceived as ambiguous-lacking reliability, credibility, or adequacy. Little is known about how perceived ambiguity influences thoughts about sequencing results. Participants (n = 494) in an NIH genome sequencing study completed a baseline survey before sequencing results were available. We examined how perceived ambiguity regarding sequencing results and individual differences in medical ambiguity aversion and tolerance for uncertainty were associated with cognitions and intentions concerning sequencing results. Perceiving sequencing results as more ambiguous was associated with less favorable cognitions about results and lower intentions to learn and share results. Among participants low in tolerance for uncertainty or optimism, greater perceived ambiguity was associated with lower intentions to learn results for non-medically actionable diseases; medical ambiguity aversion did not moderate any associations. Results are consistent with the phenomenon of "ambiguity aversion" and may influence whether people learn and communicate genomic information. PMID- 26003054 TI - Reply: To PMID 25305408. PMID- 26003056 TI - Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. PMID- 26003055 TI - The new world of the urinary microbiota in women. AB - Emerging evidence challenges the long-held paradigm that the healthy bladder is sterile. These discoveries may provide new opportunities to address important women's health conditions, which include preterm labor and delivery, urinary tract infections, and common forms of urinary incontinence. Traditional tools for urinary bacterial assessment, which includes urinary dipsticks and standard urine cultures, have significant limitations that restrict the information that is available to clinicians. For example, the standard urine culture does not detect slow-growing bacteria that die in the presence of oxygen. Two new, complementary tools, however, can detect these and other organisms, which permits a more complete characterization of bacterial communities within the female bladder. Obstetrician-gynecologists should become familiar with these new approaches (expanded quantitative urine culture and 16S ribosomal RNA gene sequencing) that can detect previously unrecognized organisms. These advances are making it possible to answer previously intractable scientific and clinical questions. Traditional nomenclature used to describe the bacterial status in the bladder is quite dated and unsuited for the emerging information about the bacterial milieu of the female urinary tract. In the context of the sterile bladder paradigm, clinicians have learned about "uropathogens," "asymptomatic bacteriuria," and "urinary tract infection." Given that the lower urinary tract is not sterile, these terms should be reevaluated. Clinicians can already benefit from the emerging knowledge regarding urinary organisms that have previously gone undetected or unappreciated. For example, in some subpopulations of women with urinary symptoms, existing data suggest that the urinary bacterial community may be associated with women's health conditions of interest. This Clinical Opinion highlights the inadequacies of the current tools for urinary bacterial assessment, describes the new assessment tools, explains the current interpretation of the resulting data, and proposes potential clinical uses and relevance. A new world is opening to our view that will give us the opportunity to better understand urinary bacteria and the bladder in which they live. This new knowledge has significant potential to improve patient care in obstetrics and gynecology. PMID- 26003057 TI - Detection of intraamniotic inflammation in fresh and processed amniotic fluid samples with the interleukin-6 point of care test. PMID- 26003060 TI - Doubtful association between progesterone therapy and fetal nuchal translucency. PMID- 26003058 TI - Intraabdominal fat, insulin sensitivity, and cardiovascular risk factors in postpartum women with a history of preeclampsia. AB - OBJECTIVE: Women who develop preeclampsia have a higher risk of future cardiovascular disease and diabetes compared to women who have uncomplicated pregnancies. We hypothesized that women with prior preeclampsia would have increased visceral adiposity that would be a major determinant of their metabolic and cardiovascular risk factors. STUDY DESIGN: We compared intraabdominal fat (IAF) area, insulin sensitivity index (SI), fasting lipids, low-density lipoprotein relative flotation rate, and brachial artery flow-mediated dilatation in 49 women with prior preeclampsia and 22 controls who were at least 8 months postpartum and matched for age, parity, body mass index, and months postpartum. Women were eligible if they did not smoke tobacco, use hormonal contraception, have chronic hypertension, or have a history of gestational diabetes. RESULTS: The groups were similar for age (mean +/- SD: prior preeclampsia 33.4 +/- 6.6 vs control 34.6 +/- 4.3 years), parity (median: 1 for both), body mass index (26.7 +/- 5.9 vs 24.0 +/- 7.3 kg/m(2)), and months postpartum (median [25th-75th percentile]: 16 [13-38] vs 16.5 [13-25]). There were no significant differences in IAF area and SI. Despite this, women with preeclampsia had lower high-density lipoprotein (46.0 +/- 10.7 vs 51.3 +/- 9.3 mg/dL; P < .05), smaller/denser low density lipoprotein relative flotation rate (0.276 +/- 0.022 vs 0.289 +/- 0.016; P = .02), higher systolic (114.6 +/- 10.9 vs 102.3 +/- 7.5 mm Hg) and diastolic (67.6 +/- 7.5 vs 60.9 +/- 3.6 mm Hg; P < .001) blood pressures, and impaired flow mediated dilatation (4.5 [2-6.7] vs 8.8 [4.5-9.1] percent change, P < .05) compared to controls. In a subgroup analysis, women with nonsevere preeclampsia (n = 17) had increased IAF (98.3 [60.1-122.2]) vs 63.1 [40.1-70.7] cm(2); P = .02) and decreased SI (4.18 [2.43-5.25] vs 5.5 [3.9-8.3] * 10(-5) min(-1)/pmol/L; P = .035) compared to the controls, whereas women with severe preeclampsia (n = 32) were not different for IAF and SI. IAF was negatively associated with SI and positively associated with cardiovascular risk factors even after adjusting for the matching variables and total body fat. CONCLUSION: Women with prior preeclampsia have an atherogenic lipid profile and endothelial dysfunction compared to matched control subjects despite having similar adiposity and insulin sensitivity, suggesting that there are mechanisms separate from obesity and insulin resistance that lead to their cardiovascular risk factors. Visceral adiposity may have a role in contributing to these risk factors in the subgroup of women who have preeclampsia without severe features. PMID- 26003059 TI - Increased 3-gram cefazolin dosing for cesarean delivery prophylaxis in obese women. AB - OBJECTIVE: The purpose of this study was to determine tissue concentrations of cefazolin after the administration of a 3-g prophylactic dose for cesarean delivery in obese women (body mass index [BMI] >30 kg/m(2)) and to compare these data with data for historic control subjects who received 2-g doses. Acceptable coverage was defined as the ability to reach the minimal inhibitory concentration (MIC) of 8 MUg/mL for cefazolin. STUDY DESIGN: We conducted a 2-phase investigation. The current phase is a prospective cohort study of the effects of obesity on tissue concentrations after prophylactic 3-g cefazolin doses at the time of cesarean delivery. Concentration data after 3-g were compared with data for historic control subjects who had received 2-g. Three grams of parenteral cefazolin was given 30-60 minutes before skin incision. Adipose samples were collected at both skin incision and closure. Cefazolin concentrations were determined with the use of a validated high-performance liquid chromatography assay. RESULTS: Twenty-eight obese women were enrolled in the current study; 29 women were enrolled in the historic cohort. BMI had a proportionally inverse relationship on antibiotic concentrations. An increase of the cefazolin dose dampened this effect and improved the probability of reaching the recommended MIC of >=8 MUg/mL. Subjects with a BMI of 30-40 kg/m(2) had a median concentration of 6.5 MUg/g (interquartile range [IQR], 4.18-7.18) after receiving 2-g vs 22.4 MUg/g (IQR, 20.29-34.36) after receiving 3-g. Women with a BMI of >40 kg/m(2) had a median concentration of 4.7 MUg/g (IQR, 3.11-4.97) and 9.6 MUg/g (IQR, 7.62 15.82) after receiving 2- and 3-g, respectively. With 2 g of cefazolin, only 20% of the cohort with a BMI of 30-40 kg/m(2) and none of the cohort with a BMI of >40 kg/m(2) reached an MIC of >=8 MUg/mL. With 3-g, all women with a BMI of 30-40 kg/m(2) reached target MIC values; 71% of the women with a BMI of >40 kg/m(2) attained this cutoff. CONCLUSION: Higher adipose concentrations of cefazolin were observed after the administration of an increased prophylactic dose. This concentration-based pharmacology study supports the use of 3 g of cefazolin at the time of cesarean delivery in obese women. Normal and overweight women (BMI <30 kg/m(2)) reach adequate cefazolin concentrations with the standard 2-g dosing. PMID- 26003061 TI - Blood pressure evaluation in children treated with laser surgery for twin-twin transfusion syndrome at 2-year follow-up. AB - OBJECTIVE: Twin survivors of twin-twin transfusion syndrome (TTTS) may be at risk for early onset of cardiovascular disease. The aim of this study was to determine prevalence and risk factors for elevated blood pressure (BP) among children treated with selective laser photocoagulation of communicating vessels. STUDY DESIGN: Data were prospectively collected from surviving children treated for TTTS with laser surgery from 2008 through 2010. Systolic BP (SBP) and diastolic BP (DBP) were obtained from 91 child survivors at age 24 months (+/-6 weeks) and evaluated based on age, sex, and height percentile. BP percentiles were calculated for each patient and categorized as normal (<95%) or abnormal (>95%). Clinical variables were evaluated using multilevel regression models to evaluate risk factors for elevated BP. RESULTS: BP was categorized as normal in 38% and abnormal in 62% of twin survivors based on percentile for sex, age, and height; a comparable distribution was found for DBP elevation. There were no differences between donor and recipient twins for absolute SBP and DBP or BP classification. In a multivariate analysis, significant risk factors for higher SBP included prematurity (beta -0.54; 95% confidence interval [CI], -0.99 to -0.09; P = .02), higher weight percentile (beta 0.24; 95% CI, 0.05-0.42; P = .01), and presence of cardiac disease (beta 0.50; 95% CI, 0.10-0.89; P = .01). Prematurity was also a significant risk for abnormal DBP (odds ratio, 0.89; 95% CI, 0.80-1.00; P = .05). CONCLUSION: Child survivors of TTTS had elevated SBP and DBP measurements at 2 years of age, with no differences seen between former donor and recipient twins. Prematurity may be a risk factor for elevated BP measurements in this population. Future studies are warranted to ascertain whether these cardiovascular findings persist over time. PMID- 26003062 TI - Postpartum contraceptive use among women with a recent preterm birth. AB - OBJECTIVE: The objective of the study was to evaluate the associations between postpartum contraception and having a recent preterm birth. STUDY DESIGN: Population-based data from the Pregnancy Risk Assessment Monitoring System in 9 states were used to estimate the postpartum use of highly or moderately effective contraception (sterilization, intrauterine device, implants, shots, pills, patch, and ring) and user-independent contraception (sterilization, implants, and intrauterine device) among women with recent live births (2009-2011). We assessed the differences in contraception by gestational age (<=27, 28-33, or 34-36 weeks vs term [>=37 weeks]) and modeled the associations using multivariable logistic regression with weighted data. RESULTS: A higher percentage of women with recent extreme preterm birth (<=27 weeks) reported using no postpartum method (31%) compared with all other women (15-16%). Women delivering extreme preterm infants had a decreased odds of using highly or moderately effective methods (adjusted odds ratio, 0.5; 95% confidence interval, 0.4-0.6) and user-independent methods (adjusted odds ratio, 0.5; 95% confidence interval, 0.4-0.7) compared with women having term births. Wanting to get pregnant was more frequently reported as a reason for contraceptive nonuse by women with an extreme preterm birth overall (45%) compared with all other women (15-18%, P < .0001). Infant death occurred in 41% of extreme preterm births and more than half of these mothers (54%) reported wanting to become pregnant as the reason for contraceptive nonuse. CONCLUSION: During contraceptive counseling with women who had recent preterm births, providers should address an optimal pregnancy interval and consider that women with recent extreme preterm birth, particularly those whose infants died, may not use contraception because they want to get pregnant. PMID- 26003063 TI - Cerebral palsy: causes, pathways, and the role of genetic variants. AB - Cerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality. CP rates have remained the same for 50 years despite a 6-fold increase in cesarean birth. Epidemiological studies have shown that the origins of most CP are prior to labor. Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are heterogeneous and require function investigations to prove causation. Whole genome sequencing, fine scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders. PMID- 26003064 TI - Reply: To PMID 25797233. PMID- 26003065 TI - A millennial view of cystic fibrosis. AB - Although only identified as a distinct disease in the 1930s, it was soon apparent that Cystic Fibrosis (CF) had been present, but unrecognised, in European populations for many years - perhaps even centuries [1] . Within a decade of the early descriptions, the autosomal recessive nature of this genetic disease had been clarified, and its clinical features had been expanded. Secondary nutritional deficiencies complicated the underlying condition: the first clear description of CF as "a new disease", which included a speculation about its genetic basis (because there were 2 pairs of sibs in the case series) was published as Vitamin A deficiency in children [2]. The diagnosis was most often made at autopsy. When it was suspected in life, the diagnostic tests used included duodenal intubation to obtain fluid which would show impaired tryptic digestion of the coating of X-Ray film in CF children, and measurement of vitamin A in the blood. Some nutritional improvement could be expected with simple, rather inefficient pancreatic enzyme preparations, but it was not until mid century that antibiotics began to treat pulmonary infections effectively. As a young doctor in the 1950s I soon became aware that the median age at death for affected children was about one year, and most died before reaching school age. . PMID- 26003066 TI - Diagnosing cystic fibrosis in newborn screening in Poland - 15 years of experience. AB - Early diagnosis of cystic fibrosis (CF) made by the introduction of CF NBS (Cystic Fibrosis Newborn Screening) provides the opportunity to undertake preventive measures and provide treatment before the development of irreversible changes in the respiratory tract and other complications. CF NBS was conducted as a pilot programme in four Polish districts in the period 1999-2003. In 2006 CF NBS started again and was gradually extended across the country. The aim of this study was to show the evolution of the Polish CF NBS strategies and assess the diagnostic consequences of this programme. MATERIAL AND METHODS: The study involved children diagnosed and treated only in the IMiD Centre. The strategy in Polish CF NBS was modified over time. Firstly, the model IRT/IRT and IRT/IRT/DNA with one mutation was implemented, which was followed by IRT/DNA with a gradually expanding number of CFTR mutations (tab. I). Newborns with positive results of CF NBS were called to the CF IMiD Centre, and sweat tests were performed. The children diagnosed and children with mutations in both alleles of the CFTR gene even if at least one of them had undefined pathogenicity) were taken under IMiD Centre care. Sensitivity, specificity and positive predictive values during subsequent stages of CF NBS were calculated (tab. III). RESULTS: During the 1999 2003 pilot study 444 063 newborns underwent CF NBS and in 74 cases CF was diagnosed. 582 693 newborns were screened from September 2006 to December 2011 in four regions and 100 children were diagnosed with CF. The frequencies of CF in the Polish population in both screening periods were 1:5767 and 1:5712 respectively. Firstly, the IRT/IRT model was implemented, but the number of newborns called to the CF Centre was high - the PPV was 7.6%. In the next step CF NBS DNA analysis was used. Here sensitivity and specificity were high - nearly 100%. In the following years the number of mutations detected was expanded (including 16 most common ones in the Polish population). Due to the panel changes, the number of calls declined and the PPV (predictive positive value) improved (to 26.1%) after the application of expanded genetic analysis. Expanding the panel of mutations resulted in an increased number of carriers and observational subjects. CONCLUSIONS: IRT/DNA strategy with expanded DNA analysis provides the opportunity for earlier CF diagnosis even in children with normal sweat test values. However, this model caused frequent carrier detection and inconclusive diagnosis in comparison to IRT/IRT or IRT/IRT/DNA with a limited number of mutations. Further research and changes in Polish CF NBS are needed to increase the PPV, while preserving high sensitivity and specificity.. PMID- 26003067 TI - Diagnostic problems in cystic fibrosis - specific characteristics of a group of infants and young children diagnosed positive through neonatal screening, in whom cystic fibrosis had not been diagnosed. AB - INTRODUCTION: Neonatal cystic fibrosis screening contributes to an early diagnosis of cystic fibrosis and to implementing appropriate therapeutic management. Long-standing screening tests have made it possible to identify a group of newborns in whom the diagnosis was ambiguous and required further specialised tests. AIM: The aim is to present cases of patients with a positive result of newborn screening for cystic fibrosis who were found to be carriers of the mutation in both alleles, however the lack of clinical symptoms and correct sweat testing values did not lead doctors to diagnosing cystic fibrosis and by the same token implementing the treatment. MATERIAL AND METHODS: The analysis encompassed a group of 22 infants and children 3 months to 3 years of age, in whom, in spite of a positive result of newborn screening for cystic fibrosis and the presence of 2 mutations in the CFTR gene, the diagnosis of cystic fibrosis was not made, and appropriate treatment was not administered because of diagnostic doubts (due to correct concentration of chlorides in sweat, correct IRT level and lack of clinical signs of cystic fibrosis). The control group consisted of 55 children treated in our centre, in whom neonatal screening for cystic fibrosis was positive and the diagnosis was confirmed by genetic testing, sweat chloride testing and IRT concentration. RESULTS: There were no differences in birth body weight between the groups. The differences in chlorideion levels in sweat secretion tests and mean IRT values were statistically significant and were: 97.5 for the control group and 26.4 for the test group. At the present time there are no clinical symptoms to give a diagnosis of cystic fibrosis and start treatment in the test group. CONCLUSIONS: Newborn screening contributes not only to an early diagnosis of cystic fibrosis but also to CFTR-related metabolic syndromes (CRMS), which is a phenomenon requiring further observation. This fact constitutes a definite psychological problem for the parents of these patients. . PMID- 26003068 TI - Meconium ileus in newborns with cystic fibrosis - results of treatment in the group of patients operated on in the years 2000-2014. AB - AIM: Evaluation of diagnostic and treatment procedures in children with cystic fibrosis (CF) operated on because of meconium ileus (MI). MATERIAL AND METHODS: The authors retrospectively reviewed the documentation of 10 CF newborn patients operated on in the years 2000-2014 because of MI. In prenatal ultrasound (US) examinations, suspicion of bowel abnormalities was raised in 2 cases, even though all the 10 mothers had a minimum of 3 US examinations during pregnancy. The mean gestational age of the newborns was 39.2 weeks - 36-41 weeks), their mean birth weight 3472g (2560-4550 g). Family history of CF was positive in two patients. Genetic testing was performed in all the children operated on. RESULTS: In all the children operated on, mutations in both alleles of the CFTR gene were found. Five patients were F508del homozygotic, 4 were heterozygotic for this mutation, one had another mutation. Sweat tests were positive in all the children. Abdominal distention was observed in 9 patients, vomiting and retention of gastric contents in 5. In 8 children meconium was not passed at all. 2 children passed a small amount of viscid meconium. Before the operation, rectal saline washouts were done in 5 newborns. Five patients were operated on during the first day of life, four on the second day and one on the third day of life. Intra operatively a simple form of MI was diagnosed in 8 cases, a complicated form in 2 cases. In patients with the simple form of MI, a Bishop-Koop stoma was created after the evacuation of meconium. Two of these children needed a resection of some centimetres of dilated terminal ileum with doubtful viability. In newborns with the complicated form of MI, the treatment was individualized, always with stoma formation. The time of postoperative meconium evacuation through enterostomy ranged from 6 to 15 days. Enteral feeding was started on average on the 9th day postoperatively. The mean hospital stay was 22.9 days. In 8 children the stoma was taken out at the mean age of 19.4 months, in one patient the stoma closed spontaneously. No disturbances in electrolyte balance or excessive fluid loss, nor any body weight deficits connected with the stoma were observed. There were no complications during stoma closure. All the patients are alive. The time of observation ranges from 7 to 146 months (average 95 months). All the patients currently present respiratory symptoms, have pancreatic insufficiency and need pancreatic enzyme supplementation. Seven do not, however, have body weight and height deficits. All the children with weight and height deficits have abnormal liver function tests. During observation two patients had MI equivalent symptoms, which was resolved by conservative treatment. CONCLUSIONS: 1. In every case of intra-operative diagnosis of MI, it is necessary to perform genetic testing and sweat tests to confirm or exclude CF. 2. Mechanical intra-operative decompression of the bowel from inspissated meconium with a temporary stoma, which makes the continuation of bowel decompression possible in the postoperative period, is an effective treatment in children with MI. 3. The Bishop-Koop stoma, permitting the passage through the whole gastrointestinal tract, is a safe option. In our material, no complications of this stoma, such as stoma care problems or dyselectrolithemia were observed. 4. The decision of stoma closure in children with MI and CF should be delayed until the moment of introducing a broadened diet and should be undertaken together with a pediatrician who is a specialist in CF therapy. . PMID- 26003069 TI - Clinical status and somatic development of patients with or without meconium ileus diagnosed through neonatal screening for cystic fibrosis. AB - The aim of the study was to compare the patients with abnormal result of newborn screening for cystic fibrosis (CF NBS), with or without meconium ileus (MI), in regard to their clinical status at the diagnosis and early childhood somatic development. MATERIAL AND METHODS: The survey comprised patients with abnormal results of CF NBS which was carried out during years 2006-2011. Cohort of 92 children remaining under care of Institute of Mother and Child was followed in the period 09.2006-12.2011. In our study there were two groups compared: 19 children with MI and 73 children without MI. Clinical characteristics and genotype were evaluated and biochemical tests assessing pancreatic insufficiency and hepatic dysfunction were performed at the time of diagnosis, then annual weight and height Z-scores as well as clinical status based on ShwachmanKulczycki score were collected. Cox proportional hazards regression model was used to assess the effect of MI and genotype on development of pancreatic insufficiency. RESULTS: MI was observed in 19 (20.6%) of 92 CF infants. MI and non-MI patients did not differ in respect of sex, gestational age and birth weight. The presence of severe genotype was more frequent in MI than non-MI group (94.7 and 64.4% respectively), whereas no significant difference was found in F508del mutation distribution. At the time of diagnosis inadequate weight gain and hepatic function disturbances prevailed more often in MI (68.4% and 31.6%) than non-MI group (39.7% and 9.6%). Pancreatic insufficiency was diagnosed in all children in MI group and in 76.1% of non-MI group and the risk of PI development was 2.3 (1.4 4.0) times higher in MI than in non-MI patients. MI children had smaller weight for-age Z-score at the age of 12 months (-0.95) when compared to non-MI children (-0.13). Weight Z-scores compared at the age of 2 and 3 years as also height-for age Z-scores did not differ significantly between groups. No statistically significant difference in clinical status according to Shwachman-Kulczycki score was found between MI and non-MI groups at the age of 12 months, 2 years and 3 years. CONCLUSIONS: Our results suggest that the history of MI in children with CF may predispose them to more severe clinical course of disease in early childhood: insufficient weight gain and liver disturbances at the time of diagnosis, higher risk of developing pancreatic insufficiency and smaller weight at the age of 12 months, although clinical status according to Shwachman Kulczycki score did not differ from non-MI group. Patients with MI, may require more intensive care and supervision in treatment. Further research is needed to asses MI impact on development of CF children in subsequent years. . PMID- 26003070 TI - Application of positive expiratory pressure *PEP* in cystic fibrosis patient inhalations. AB - Inhalations, whose aim is the liquefaction of dense viscous secretions and preparing them for evacuation from the bronchial tree by means of drainage techniques, are standard treatment procedures in cystic fibrosis. Numerous studies showed that during inhalation only a small percentage of the drug was deposited in the bronchi. The use of the so-called elevated positive expiratory pressure, or PEP system, can improve the drug deposition in the lungs and consequently have the effect of increasing the effects of physiotherapy and delay the progression of the disease. The aim of the study was a retrospective evaluation of the applicability of the PEP system in mucolytic drug inhalations in CF patients. MATERIAL AND METHODS: Analysis of the variation of selected spirometry indicators over time: FEV1, FVC, MEF 75%, 50%, 25%, performed in two groups of patients with cystic fibrosis: group I using PEP (n 29), group II without PEP (n 38). The analysis of parameter variance in time, as well as of the course taken by the changes and the difference in this respect regarding the PEP and no PEP group of patients was made by means of the analysis of linear regression for correlated data (generalized estimating equation). RESULTS: The use of the PEP system for inhalation in patients with cystic fibrosis had the greatest impact on improving the values of MEF 75%, 50%, 25%. After 18 months, observations indicated the improvement of the values by 8.1%, 10.4% and 13% respectively in the group of PEP and reduction by 6%, 4.6% and 4.5% in the group without PEP. The differences in the level of change observed between the two groups proved to be statistically significant (p=0.033, p = 0.019, p=0.006). After 18 months compared to the initial visit, the analysis of variation over time in the PEP group showed significant improvement only in the case of MEF 25% (p=0.024). CONCLUSIONS: 1) The PEP system may be applied in inhalations of mucolytic drugs in cystic fibrosis patients. 2) the application of the PEP system for inhalations in cystic fibrosis patients showed the greatest improvement in the values of MEF 75%50%25% 3) the use of PEP for inhalation of mucolytic drugs in patients with cystic fibrosis may be one of the factors affecting the delay of progression of functional changes in the lungs. 4) Long-term randomized observation should be carried out in order to confirm the retrospective study results. . PMID- 26003071 TI - Cross-infections with Pseudomonas aeruginosa in patients with cystic fibrosis attending the Warsaw Centre. AB - AIM: 1. To assess the prevalence of cross-infections with P. aeruginosa in order to evaluate the epidemiological situation of this infection in patients with cystic fibrosis attending our centre; 2. To correlate the clinical features of the patients carrying a potentially transmissible strain with the entire study group in order to determine the risk factors and possible effects of its acquisition. MATERIAL AND METHODS: 170 Pseudomonas aeruginosa strains obtained from the respiratory tract of 75 cystic fibrosis patients attending the Warsaw Centre in 2011 and 2012 were typed using restriction enzyme analysis-pulsed field gel electrophoresis (Spe I restriction enzyme was used). Simultaneously, the information concerning contacts between patients, as well as several clinical data regarding the course of the disease were collected. RESULTS: Twenty four clusters of strains were detected. The main cluster included 49 isolates derived from 21 patients. The other detected clusters included 2 to 12 isolates derived from 1 to 7 patients. Three clusters comprised the isolates derived from three pairs of siblings. There were 15 clusters containing 2 to 7 strains belonging to the same patient. The remaining 24 patients were infected with their own strains, not fitting any clonal group. Several clinical parameters showed that the 21 patients whose strains constituted the main cluster, were in worse clinical condition than the other patients in the study group. Moreover, the total duration of their hospitalizations in order to perform intravenous antibiotic treatment was longer. CONCLUSIONS: 1. Frequent hospitalizations of CF patients with a more severe course of the disease seem to be a risk factor of cross infections with P. aeruginosa. 2. Intensification of measures to prevent cross infection, such as hygienic precautions, patient segregation, introduction of home intravenous antibiotic therapy programme, as well as further education of patients and their parents should lead to the improvement of the epidemiological situation in our centre. . PMID- 26003072 TI - The clinical presentations of pulmonary aspergillosis in children with cystic fibrosis - preliminary report. AB - Pulmonary aspergillosis is a very serious complication in cystic fibrosis (CF) patients due to the great variety of its clinical presentations and the fact that it worsens the prognosis. We can distinguish the following: Aspergillus colonization (AC), Aspergillus infection (AI) and allergic bronchopulmonary aspergillosis (ABPA). Aspergillus colonization (AC) is defined as isolation of Aspergillus spp. from 50% ormore sputum samples over six months to one year without observing deterioration in lung function and an increase in such respiratory symptoms as cough. Aspergillus infection (AI) is diagnosed in subjects with Aspergillus colonization and a decline in lung function, respiratory exacerbation with and without cough or with an incomplete response to a 2-4 week course of appropriate broad-spectrum antibiotics. Aspergillus can also cause allergic bronchopulmonary aspergillosis (ABPA). The classic diagnostic criteria of allergic bronchopulmonary aspergillosis in cystic fibrosis have been established during the Cystic Fibrosis Foundation Conference in 2001. AIM: To establish the prevalence of pulmonary aspergillosis in children with cystic fibrosis under the care of our centre and to investigate the potential predisposing factors to Aspergillus infection (AI) and allergic bronchopulmonary aspergillosis (ABPA). MATERIAL AND METHODS: An analysis was conducted of the medical documentation of 374 children aged 0-18 years monitored regularly in the Cystic Fibrosis Centre of the Institute of Mother and Child in Warsaw from 01.01.2010 to 31.08.2014. We selected 13 patients who presented an evidently worsening clinical status and course of the bronchopulmonary disease (decline in lung function parameters, respiratory exacerbations with increased cough, new or recent abnormalities in chest imaging) despite standard treatment with a high calorie diet, supplementation of pancreatic enzymes and vitamins, dornase alpha, inhaled and/or oral antibiotics, inhaled or oral corticosteroids, bronchodilators, physiotherapy. In this group of 13 CF children Aspergillus fumigatus was isolated from sputum. They represented 3.5% of the patients treated in our centre. Pulmonary aspergillosis was analyzed in relation to the age, sex, genotype, exocrine pancreatic insufficiency, body mass index, pulmonary function, microbiological examination of sputum, pulmonary complications and therapies. The mean age was 10.7 years (range 4.5-16.3). Only one child was under the age of six years. Patients were divided into 3 groups: patients with Aspergillus infection (AI), patients with allergic bronchopulmonary aspergillosis (ABPA), and a patient with Aspergillus infection and bronchopulmonary aspergillosis. RESULTS: Aspergillus infection (AI) was diagnosed in 9 cases (2.4%) and allergic bronchopulmonary aspergillosis (ABPA) in 3 (0.8%). One patient was treated with corticosteroids, because of allergic bronchopulmonary aspergillosis (ABPA) and after 8 months he developed Aspergillus infection (AI).n Most of the children were homo- or heterozygous for mutation F508del. Pancreatic insufficiency was recognized in all the children with ABPA, most of those with AI (8/9) and in one boy with ABPA and AI. Most of the patients had chronic respiratory colonization of Staphylococcus aureus and Pseudomonas aeruginosa. Children with AI were older (mean age:12.4), had a worse nutritional status (three of them had aBMI 3rd percentile), poorer lung function (five had severe lung disease *FEV1 40%*, complications occurred in one of the underlying diseases *haemoptysis, CFRD - Cystic Fibrosis Related Diabetes*, two of them had vascuport inserted due to the need for frequent intravenous antibiotic therapy. All the patients received inhaled antibiotics. A long-term oral azithromycin regime was applied in all the children with allergic bronchopulmonary aspergillosis, in most of those with Aspergillus infection *6,9* and in one boy with ABPA and AI. In three patients diagnosed with Aspergillus infection, antifungal treatment did not give any clinical or radiological improvement. They underwent surgical resection in the Department of Thoracic Surgery in Rabka (Poland). One patient had pneumonectomy and two underwent lobectomies. One boy had lung transplantation in Rigshospitalet in Copenhagen nine months after being diagnosed with Aspergillus infection. CONCLUSIONS: Since pulmonary aspergillosis is a very serious complication in CF children, it seems reasonable to include screening for early detection of Aspergillus colonization in the annual assessment of CF patients who are over 6 years old. Due to the small sample size and retrospective design of our analysis, the identification of risk factors of pulmonary aspergillosis in CF children require further prospective studies. . PMID- 26003073 TI - The course of glucose intolerance in children with cystic fibrosis: a retrospective study - preliminary report. AB - Diabetes is a common and severe complication of cystic fibrosis. If unrecognized, the condition not only causes deterioration of pulmonary function and failure to gain weight, but also a six-fold increase in mortality. AIM: 1. To evaluate the course of abnormal glucose tolerance and cystic fibrosis-related diabetes (CFRD), as well as the effects of treating these conditions in children with cystic fibrosis. 2. To analyze the association between the classes of mutations in both alleles of the CFTR gene and glucose intolerance. MATERIALS AND METHODS: analysis was undertaken of the clinical records of 12 children (from the years 2002 to 2014), who were under the care of the Diabetes Outpatient Clinic at the Medical University of Warsaw and the Cystic Fibrosis Centre of the Institute of Mother and Child in Warsaw. The patients were divided into groups based on glucose tolerance categories in the Oral Glucose Tolerance Test (impaired glucose tolerance - IGT, cystic fibrosis related diabetes without fasting hyperglycemia - CFRD FH- or with fasting hyperglycemia - CFRD FH+). The mean age of the children who were referred to the Diabetes Outpatient Clinic was 12.09 +/- 3.57 years and the mean HbA1c at the baseline versus the end of the follow up was 6.16 +/- 1,77% versus 6.03 +/- 1.05%, respectively. We used the continuous glucose monitoring system (CGMS) for the diagnostics of 4 patients. The mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were investigated in all the patients. All the children had mutations in at least one allele of the CFTR gene belonging to class I or II. Six (6/12) patients were homozygous, and 3 (3/12) patients heterozygous for the Phe508del (former F508del) mutation. Three children had other mutations (1717-1G>A/2183AA-G, R553X/3380delGAAG, G542X/2143delT). RESULTS: In our study group we recognized impaired glucose tolerance (IGT) in 7 (7/12) patients and cystic fibrosis-related diabetes (CFRD) in 5 (5/12) patients; there were 4 patients with CFRD FH+ and 1 patient with CFRD FH-. During follow up we observed IGT deterioration of glucose tolerance towards CFRD FH- in 4(4/7) patients. Eight (8/12) patients were on functional insulin therapy, five of them (5/8) used insulin pumps. The remaining patients (4 individuals - 4/12), who were in good condition and on a high-glycemic index product restricted diet, did not require insulin. In the group treated with insulin we observed improvement in BMI z-scores (from-1.14 to -0.70). CONCLUSIONS: Glucose tolerance in children with cystic fibrosis deteriorates with age. Patients in a good condition and with good compliance to a low-glycemic index product diet, start insulin therapy later. Patients with a severe course of cystic fibrosis and diabetes require immediate insulin implementation. Insulin treatment improves their nutritional status. A continuous glucose monitoring system is a useful diagnostic tool which can be taken into account in therapeutic decisions. Prospective studies on the pediatric population with cystic fibrosis are needed in Poland for a better analysis of the associations between abnormal glucose tolerance, the class of mutation in the CFTR gene and the impact of glucose intolerance treatment on the clinical status of the patients. PMID- 26003074 TI - Does the mutation of the SERPINA1 gene contribute to liver damage and cholestasis in patients with diagnosed cystic fibrosis? preliminary study. AB - Mutation of the SERPINA1 gene is present in about 2% of patients with cystic fibrosis but is more common and accounts for about 5% in patients with cystic fibrosis and co-existing liver lesions. The SERPINA1 gene is responsible for the synthesis of a serine protease inhibitor. The protein related with this gene is accumulated within the endoplasmic reticulum of hepatocytes causing their damage, inflammation and cirrhosis. The aim was to assess the presumable effect of the SERPINA1 mutation gene in patients with diagnosed cystic fibrosis on damage to the liver and/or cholestasis. MATERIAL AND METHOD: The analysis included 30 children, 13 girls (43.3%) and 17 boys (56.6%), aged from 6 months to 18 years (the average age was 5.5 years) with diagnosed cystic fibrosis. All the patients have undergone a genetic test of the mutation of the SERPINA1 gene. The analysis included age, sex, clinical symptoms, type of mutation of the CFTR protein, abnormalities in laboratory tests (the activity of aminotransferases, GGTP, alkaline phosphatase , protein, the indicator of acid steatocrit, the rate of APRI) and abdominal ultrasonography. RESULTS: Symptoms of damaged liver were concluded in 9/30 patients (30%) with diagnosed cystic fibrosis. Most commonly observed were increased activities of aminotransferases in 9/30 patients (30%) and of gamma glutamyl transferase in 6/30 (20%) of the assessed patients. In 4/30 patients the abdominal ultrasonography revealed an enlarged liver and increased echogenicity. Mutation within the SERPINA1 gene was observed only in 1/30 patients (3.3%) with diagnosed cystic fibrosis. As far as the patient is concerned, currently the activities of aminotransferases, GGTP and AF are normal, but there has been a considerable increase in the intensity of symptoms from the respiratory system. No corelation between the mutation of the SERPINA1 gene and clinical symptoms, type of mutation of the CFTR protein, laboratory results of the functions and damage to the liver and the abdominal ultrasonography was observed. CONCLUSIONS: We did not find a more frequent occurrence of the SERPINA1 gene mutation in children with cystic fibrosis and coexisting features of damaged liver and cholestasis. The obtained results suggest the contribution of other than SERPINA1 gene mutation factors responsible for the development of changes in the liver in patients diagnosed with cystic fibrosis. The studies on the subject should be extended and performed on a larger group of patients. . PMID- 26003075 TI - Renal assessment in teenage patients with cystic fibrosis - preliminary report. AB - BACKGROUND: Together with increasing life expectancy of patients with cystic fibrosis *CF*, there is a growing need to deal with unforeseen problems and complications. Among others renal dysfunction has become of great concern. AIM: Evaluation of renal function in CF children. MATERIAL AND METHODS: We performed cross-sectional study on a group of 11 teenage inpatients with CF. Physical examination, past medical history analysis, renal function measurements and analysis were conducted in all of them. Renal assessment included: serum cystatin C and creatinine levels, measured and estimated creatinine clearance, estimated cystatin C clearance, urine indicators of crystallization risk and renal ultrasonography. RESULTS: One patient had elevated serum cystatin C level and diminished McIsaac equation. Renal ultrasound revealed non-congenital anomaly in 1 case - it was nephrolithiasis. All the individuals had elevated at least 1 urine indicator of crystallization risk. CONCLUSION: There is a great need of good, standardized test of renal function in cystic fibrosis patients. The focus of research should turn towards finding a tool similar to faecal elastase, which is cheap, easy to perform, sensitive and specific, and can be used to confirm the diagnosis. PMID- 26003076 TI - Dietary pattern and its relationship between bone mineral density in girls and boys with cystic fibrosis - preliminary report. AB - BACKGROUND: Nutrition influence on cystic fibrosis (CF) patients survival is well documented and dietary therapy is one of basic elements of their treatment. Prolonged survival of CF patients might yet emerge comorbidities, which include bone mineral disease. THE AIM: The assessment of the dietary pattern and its relationship between bone density in boys and girls with cystic fibrosis. MATERIAL AND METHODS: 89 patients aged 10-18 years from 3 Polish CF Centres were included into the study. To obtain a knowledge about quality of diet, a 3-day food record was assessed and percent of recommended for CF patients intake of energy, protein, carbohydrates, fat, vitamin D3, calcium, phosphorus was counted. Bone mineral density (BMD) in lumbar spine (L1-L4) was measured and expressed as a Z-score. To assess nutritional status, anthropometric measurements was evaluated (body weight, height and BMI). Descriptive methods, Mann-Whitney test, T-Student test, Spearman correlation and one-way ANOVA were used for statistical analyses. RESULTS: The patients with cystic fibrosis did not meet specific for CF nutritional guidelines. A deficiency in recommended intake was observed in energy (88%), protein (82%), calcium (78%) and vitamin D3 (71%). The intake of phosphorus was higher than recommended (142%). A nutritional status was significantly reduced, as compared with the reference group (p 0.001). Boys characterized significantly lower body weight (p=0.019) and height (p=0.036) than girls as well as worse caloric (p=0.023) and carbohydrates intake (p=0.005). However, girls had reduced vitamin D3 content in their diet (p 0.001). The bone mineral density in the whole group was reduced and Z-score amounted to -0.95 +/- 1.17. Tendency to decreasing of BMD with age was observed. BMI showed important correlation with bone mineral density both in girls (p 0.001) and in boys (p=0.020). CONCLUSION: CF patients do not follow specific for them dietary recommendations and essential differences were observed between girls and boys. Nutritional status (BMI) showed correlation with bone mineral density in CF patients. Therefore intensive nutritional therapy according to recommendations is needed. . PMID- 26003077 TI - Postural defects in children with cystic fibrosis - preliminary report. AB - Postural disturbances may cause the worsening of cardiopulmonary function in cystic fibrosis children and adolescents, as well as adversely affect their somatic and psychological development. THE AIM: Evaluation of postural defects in the population of cystic fibrosis children and adolescents. MATERIAL AND METHODS: Physical orthopedic examination of 41 cystic fibrosis patients (20 girls, 21 boys), aged 2-17 years (mean 8.1). The patients were divided into age groups: I under 5 y.o - 8 patients., II 5-9 y.o.- 6 patients, III 9-13 y.o - 11 patients, IV 13 y.o. and older - 16 patients. Postural disorders were divided into two groups. The first group included defects with a possible influence on the respiratory function of a cystic fibrosis patient: scoliosis, spine defects and chest deformities. The second group included lower extremities defects without influence on the function of the respiratory system. RESULTS: Postural as well as chest disorders were observed in 36 (87.8%) of the patients who were examined. Disorders with possible influence on respiratory system function, were observed in 13 (31.7%) of the 41 patients. Increased thoracic kyphosis (round back) was most frequent. In the group of patients aged 5 years and younger neither spinal nor chest abnormalities were observed. In the group of patients aged 5-9 years 1 (16.6%) case of congenital scoliosis and 1 (16.6%) case of plane back were found. In the group of children aged 9-13 years increased thoracic kyphosis was observed in 2 (18.1%) cases, plane back was observed in 2 (18.1%) children as well, while in 1 (9.0%) case increased lumbar lordosis was diagnosed. Barrell chest was observed in 2 (18.1%) cases. In the group of adolescents aged 13 years and more, 4 (25.0%) cases of scoliosis, 16 (100%) cases of increased thoracic kyphosis and 6 (37.5%) cases of barrel chest were observed. Because of the different methods of examination among posture studies of the healthy population, obtaining a control population is difficult. CONCLUSIONS: The number of postural defects in children with cystic fibrosis increases with age, and is becoming a significant health problem. It seems that there is a need of a deeper study on a greater population. . PMID- 26003078 TI - Surgeon's viewpoint on lung transplantation in cystic fibrosis patients - preliminary report. AB - INTRODUCTION: The surgeon's viewpoint on a patient with cystic fibrosis differs from that of a pediatrician or internist. The problems a cystic fibrosis specialist encounters are different from those faced by the surgeon who takes over the patient in a very advanced, often terminal stage of the disease. Hence, the main problem for the surgeon is the decision concerning the surgery (lung transplantation, pneumonectomy, lobectomy). It is, therefore, important to lay down fundamental and appropriate rules concerning the indications and contraindications for lung transplantation, especially in patients with cystic fibrosis. AIM: The aim of this study was to analyze the methods of qualifying and preparing patients for surgery, as well as carrying out the procedure of transplantation and postoperative short and long-term care. MATERIAL AND METHODS: The investigation was carried out on 16 patients with cystic fibrosis. Three were operated on and 10 were on the waiting list for transplantation. Two patients on the waiting list died, one patient was disqualified from transplantation. During qualification for lung transplantation, strict indications, contraindications and other factors (such as blood type, patient's height, coexisting complications) were taken under consideration. RESULTS: All the 3 patients after lung transplantation are alive and under our constant surveillance. Ten patients await transplantation, though four of them are suspended due to hepatitis C infection. Two patients on the waiting list died: one from respiratory insufficiency and the other in the course of bridge to-transplant veno-venous extracorporeal membrane oxygenation due to hepatic failure. One patient has been disqualified because of cachexia. CONCLUSIONS: Since lung transplantation is the final treatment of the end-stage pulmonary insufficiency in cystic fibrosis patients, the number of such procedures in cystic fibrosis is still too low in Poland. The fast development of these procedures is highly needed. It is necessary to develop better cooperation between different disciplines and specialists, especially between pediatricians and surgeons. The correct choice of the suitable moment for lung transplantation is crucial for the success of the procedure. PMID- 26003079 TI - Determinants of health-related quality of life in polish patients with CF - adolescents' and parents' perspectives. AB - AIM: 1. Evaluation of health-related quality of life (HRQOL) in adolescents with cystic fibrosis (CF). 2. Evaluation of HRQOL in children with CF from the parents' perspective. 3. Evaluation of the relationship between HRQOL and both medical and psychosocial factors. MATERIAL AND METHODS: Health-related quality of life was measured with the Cystic Fibrosis Questionnaire - Revised. Seventy patients with cystic fibrosis, aged 14-18 years completed the version for adolescents and adults (CFQ-R 14+ and 70 parents of children aged 6-13 years filled out the version for parents (CFQ-R 6-13). Scores ranged from 0 to 100, with higher scores indicating a better quality of life. Disease severity was assessed by lung function test, nutritional status, chronic Pseudomonas aeruginosa infection and type of CFTR gene mutation. Social indices i.e. the patient's school attendance and the parent's work status were collected. RESULTS: In the adolescents' opinion, Eating problems and Digestive functioning got the highest rate, whereas Vitality, Treatment burden, Health perceptions and Weight got the lowest. Boys estimated their Physical functioning significantly higher than girls. When evaluating their children's quality of life, parents granted the highest score to Physical, Respiratory and Digestive functioning and the lowest results were attributed to Treatment burden. Nutritional status and lung function impairment turned out to be predictors of some other domains but not psychosocial ones. The chronic Pseudomonas aeruginosa infection had an influence on several quality of life areas from the parents' perspective. School attendance had a significant impact on many aspects of the adolescents' functioning. CONCLUSIONS: 1. The study revealed that the health-related quality of life of CF children and adolescents is moderately good. 2. Digestive functioning was one of the highest scored domains, while Treatment burden was one of the lowest, according to both the adolescents' and the parents' perception. 3. The potential impact of disease severity was clearly marked in the group of younger children, whose health related quality of life was assessed by the parents. Self-evaluation conducted by adolescents was more subjective. 4. School attendace was an important factor of the quality of life. Further research is required in order to find other psychosocial indices. PMID- 26003080 TI - Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats: involvement of the INSIG/SREBP pathway. AB - Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile. PMID- 26003081 TI - Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats. AB - A wide body of preclinical and clinical data suggests that alpha 7 nicotinic acetylcholine receptors (alpha7-nAChRs) may represent useful targets for cognitive improvement in schizophrenia and Alzheimer's disease. A promising recent approach is based on the use of positive allosteric modulators (PAMs) of alpha7-nAChRs due to their several advantages over the direct agonists. Nevertheless, the behavioural effects of this class of compounds, particularly with regard to higher-order cognitive functions, have not been broadly characterised. The aim of the present study was to evaluate the procognitive efficacies of type I and type II alpha7-nAChRs PAMs, N-(4-chlorophenyl)-[[(4 chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and N-(5 Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) in the novel object recognition task (NORT), attentional set-shifting task (ASST) and five-choice serial reaction time task (5-CSRTT) in rats. Additionally, the effects of galantamine, an acetylcholinesterase inhibitor that also allosterically modulates nAChRs, were assessed. We report that CCMI (0.3-3mg/kg), PNU-120596 (0.3-3mg/kg) and galantamine (1-3mg/kg) attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. Methyllycaconitine (3mg/kg) blocked the actions of CCMI, PNU-120596 and galantamine in the NORT and ASST, suggesting that the procognitive effects of these compounds are alpha7-nAChRs-dependent. However, none of the compounds tested affected the rats' attentional performance in the 5-CSRTT. The present findings confirm and extend the observations indicating that the positive allosteric modulation of alpha7-nAChRs enhances recognition memory and cognitive flexibility in preclinical tasks. Therefore, the present study supports the utility of alpha7-nAChRs PAMs as a potential cognitive enhancing therapy. PMID- 26003082 TI - Different mechanisms of extracellular adenosine accumulation by reduction of the external Ca(2+) concentration and inhibition of adenosine metabolism in spinal astrocytes. AB - Extracellular adenosine is a neuromodulator in the central nervous system. Astrocytes mainly participate in adenosine production, and extracellular adenosine accumulates under physiological and pathophysiological conditions. Inhibition of intracellular adenosine metabolism and reduction of the external Ca(2+) concentration ([Ca(2+)]e) participate in adenosine accumulation, but the precise mechanisms remain unclear. This study investigated the mechanisms underlying extracellular adenosine accumulation in cultured rat spinal astrocytes. The combination of adenosine kinase and deaminase (ADK/ADA) inhibition and a reduced [Ca(2+)]e increased the extracellular adenosine level. ADK/ADA inhibitors increased the level of extracellular adenosine but not of adenine nucleotides, which was suppressed by inhibition of equilibrative nucleoside transporter (ENT) 2. Unlike ADK/ADA inhibition, a reduced [Ca(2+)]e increased the extracellular level not only of adenosine but also of ATP. This adenosine increase was enhanced by ENT2 inhibition, and suppressed by sodium polyoxotungstate (ecto-nucleoside triphosphate diphosphohydrolase inhibitor). Gap junction inhibitors suppressed the increases in adenosine and adenine nucleotide levels by reduction of [Ca(2+)]e. These results indicate that extracellular adenosine accumulation by ADK/ADA inhibition is due to the adenosine release via ENT2, while that by reduction of [Ca(2+)]e is due to breakdown of ATP released via gap junction hemichannels, after which ENT2 incorporates adenosine into the cells. PMID- 26003083 TI - Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells. AB - Connexin (Cx) makes up a type of intercellular channel called gap junction (GJ). GJ plays a regulatory role in cellular physiology. The Cx expression level is often decreased in cancer cells compared to that in healthy ones, and the restoration of its expression has been shown to exert antiproliferative effects. This work aims to evaluate the effect of the restoration of connexin 43 (Cx43) (the most ubiquitous Cx subtype) expression on sunitinib (SU)-induced cytotoxicity in malignant mesothelioma (MM) cells. Increased Cx43 expression in an MM cell line (H28) improved the ability of SU to inhibit receptor tyrosine kinase (RTK) signaling. Moreover, higher Cx43 expression promoted SU-induced apoptosis. The cell viability test revealed that Cx43 enhanced the cytotoxic effect of SU in a GJ-independent manner. The effect of Cx43 on a proapoptotic factor, Bax, was then investigated. The interaction between Cx43 and Bax was confirmed by immunoprecipitation. Furthermore, higher Cx43 expression increased the production of a cleaved (active) form of Bax during SU-induced apoptosis with no alteration in total Bax expression. These findings indicate that Cx43 most likely increases sensitivity to SU in H28 through direct interaction with Bax. In conclusion, we found that Cx43 overcame the chemoresistance of MM cells. PMID- 26003084 TI - Anti-inflammatory effects of glaucocalyxin B in microglia cells. AB - Over-activated microglia is involved in various kinds of neurodegenerative process including Parkinson, Alzheimer and HIV dementia. Suppression of microglial over activation has emerged as a novel strategy for treatment of neuroinflammation-based neurodegeneration. In the current study, anti inflammatory and neuroprotective effects of the ent-kauranoid diterpenoids, which were isolated from the aerial parts of Rabdosia japonica (Burm. f.) var. glaucocalyx (Maxim.) Hara, were investigated in cultured microglia cells. Glaucocalyxin B (GLB), one of five ent-kauranoid diterpenoids, significantly decreased the generation of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in the lipopolysaccharide (LPS)-activated microglia cells. In addition, GLB inhibited activation of nuclear factor-kappaB (NF-kappaB), p38 mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS) in LPS-activated microglia cells. Furthermore, GLB strongly induced the expression of heme oxygenase (HO)-1 in BV-2 microglia cells. Finally, GLB exhibited neuroprotective effect by preventing over-activated microglia induced neurotoxicity in a microglia/neuron co-culture model. Taken together, the present study demonstrated that the GLB possesses anti-nueroinflammatory activity, and might serve as a potential therapeutic agent for treating neuroinflammatory diseases. PMID- 26003085 TI - EGCG synergizes the therapeutic effect of cisplatin and oxaliplatin through autophagic pathway in human colorectal cancer cells. AB - Application of the platinum-based chemotherapy for colorectal cancer is restricted due to its severe cytotoxic effects. In this study we used synergistic strategies by combining (-)-Epigallocatechin gallate (EGCG) with cisplatin or oxaliplatin to minimize the ill effects of platinum-based therapy. MTS assay was used to examine the effect of EGCG, cisplatin and oxaliplatin on the proliferation of human colorectal cancer DLD-1 and HT-29 cells. Autophagic process was evaluated by detection of LC3-II protein, autophagosome formation, and quantification of Acidic Vesicular. Treatment of DLD-1 and HT-29 cells with EGCG plus cisplatin or oxaliplatin showed a synergistic effect on inhibition of cell proliferation and induction of cell death. EGCG enhanced the effect of cisplatin and oxaliplatin-induced autophagy in DLD-1 and HT-29 cells, as characterized by the accumulation of LC3-II protein, the increase of acidic vesicular organelles (AVOs), and the formation of autophagosome. In addition, transfection of DLD-1 and HT-29 cells with siRNA against ATG genes reduced EGCG synergistic effect. Our findings suggest that combining EGCG with cisplatin or oxaliplatin could potentiate the cytotoxicity of cisplatin and oxaliplatin in colorectal cancer cells through autophagy related pathway. PMID- 26003086 TI - In vitro characterization of luseogliflozin, a potent and competitive sodium glucose co-transporter 2 inhibitor: Inhibition kinetics and binding studies. AB - In this study, we evaluated an inhibition model of luseogliflozin on sodium glucose co-transporter 2 (SGLT2). We also analyzed the binding kinetics of the drug to SGLT2 protein using [(3)H]-luseogliflozin. Luseogliflozin competitively inhibited human SGLT2 (hSGLT2)-mediated glucose uptake with a Ki value of 1.10 nM. In the absence of glucose, [(3)H]-luseogliflozin exhibited a high affinity for hSGLT2 with a Kd value of 1.3 nM. The dissociation half-time was 7 h, suggesting that luseogliflozin dissociates rather slowly from hSGLT2. These profiles of luseogliflozin might contribute to the long duration of action of this drug. PMID- 26003088 TI - Evaluating the risk of mixtures in the indoor air of primary school classrooms. AB - In school environments, children are constantly exposed to mixtures of airborne substances, derived from a variety of sources, both in the classroom and in the school surroundings. It is important to evaluate the hazardous properties of these mixtures, in order to conduct risk assessments of their impact on children's health. Within this context, through the application of a maximum cumulative ratio approach, this study aimed to explore whether health risks due to indoor air mixtures are driven by a single substance or are due to cumulative exposure to various substances. This methodology requires knowledge of the concentration of substances in the air mixture, together with a health-related weighting factor (i.e. reference concentration or lowest concentration of interest), which is necessary to calculate the hazard index. Maximum cumulative ratio and hazard index values were then used to categorise the mixtures into four groups, based on their hazard potential and therefore appropriate risk management strategies. Air samples were collected from classrooms in 25 primary schools in Brisbane, Australia. Analysis was conducted based on the measured concentration of these substances in about 300 air samples. The results showed that in 92 % of the schools, indoor air mixtures belonged to the 'low concern' group, and therefore, they did not require any further assessment. In the remaining schools, toxicity was mainly governed by a single substance, with a very small number of schools having a multiple substance mix which required a combined risk assessment. The proposed approach enables the identification of such schools and thus aids in the efficient health risk management of pollution emissions and air quality in the school environment. PMID- 26003087 TI - Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. AB - Epilepsy and other neurological deficits are common, disabling manifestations of the genetic disorder, tuberous sclerosis complex (TSC). Brain inflammation has been implicated in contributing to epileptogenesis in acquired epilepsy due to brain injury, but the potential role of inflammatory mechanisms in genetic epilepsies is relatively unexplored. In this study, we investigated activation of inflammatory mediators and tested the effects of anti-inflammatory treatment on epilepsy in the Tsc1-GFAP conditional knock-out mouse model of TSC (Tsc1(GFAP)CKO mice). Real-time quantitative RT-PCR, immunohistochemistry, and Western blotting demonstrated increased expression of specific cytokines and chemokines, particularly IL-1beta and CXCL10, in the neocortex and hippocampus of Tsc1(GFAP)CKO mice, which was reversed by treatment with a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Double-labeling immunohistochemical studies indicated that the increased IL-1beta was localized primarily to astrocytes. Importantly, the increase in inflammatory markers was also observed in astrocyte culture in vitro and at 2 weeks of age in Tsc1(GFAP)CKO mice before the onset of epilepsy in vivo, indicating that the inflammatory changes were not secondary to seizures. Epicatechin-3-gallate, an inhibitor of IL-1beta and CXCL10, at least partially reversed the elevated cytokine and chemokine levels, reduced seizure frequency, and prolonged survival of Tsc1(GFAP)CKO mice. These findings suggest that mTOR-mediated inflammatory mechanisms may be involved in epileptogenesis in the genetic epilepsy, TSC. PMID- 26003089 TI - Degradation of four organophosphorous pesticides catalyzed by chitosan-metal coordination complexes. AB - Three types of chitosan with high (3.40 * 10(6)), medium (2.11 * 10(5)), and low (5.89 * 10(4)) molecular weights were chosen as ligands to synthesize chitosan magnesium, calcium, iron(III), and zinc coordination complexes. Degradation of four organophosphorous pesticides (dichlorvos, omethoate, dimethoate, and chlorpyrifos) by the above complexes in a heterogeneous system was studied using solid-phase extraction (SPE) and gas chromatography (GC). The degradation effect is related to the different types of chitosan, metal, and organophosphorus pesticides (OPs). Complexes of transition metals and the low molecular weight chitosan showed high hydrolytic activity. The chitosan-iron(III) complex was further used to study its catalytic kinetics on the hydrolysis of OPs. At pH 7.0 and 20 degrees C, the half-life of dichlorvos hydrolyzed by chitosan iron(III) was 52 h, whereas that of spontaneous dichlorvos hydrolysis was 105 h. The degradation ratio of omethoate and dimethoate increased to 38 and 52 %, respectively, which were 34 and 48 % higher than the control after 6 days at pH 7.0 and 20 degrees C. For all tested conditions, an increase of pH and temperature resulted in a higher degradation rate. PMID- 26003090 TI - Comparison of microhabitats and foraging strategies between the captive-born Zhangxiang and wild giant pandas: implications for future reintroduction. AB - The female giant panda Zhangxiang (pedigree number 826) was born on August 20, 2011 in Wolong Nature Reserve, China. On November 6, 2013, Zhangxiang was transported into the acclimatization enclosure in the Liziping Nature Reserve. Before Zhangxiang left the enclosure into the wild, we conducted the first study to compare microhabitats and foraging strategies between Zhangxiang in the enclosure and giant pandas in the wild. Compared with the latter, microhabitats of Zhangxiang in the enclosure are characteristic of gentler slope, more trees, higher canopy, smaller tree DBH, and lower density of living bamboos. Diet composition and foraging behaviors significantly differed between Zhangxiang and wild giant pandas, perhaps reflecting the combined consequence of environmental conditions (e.g., bamboo species) and individual status (e.g., age, mastication ability, etc.). The difference in microhabitats and foraging strategies between Zhangxiang and wild giant pandas implied that after being released into the natural habitat in the reserve, Zhangxiang will have to adapt to the environmental conditions once again. For future reintroduction, the enclosure can be extended to the Bashania spanostachya forest in the reserve, and captive giant pandas for release can thus normally transit into the wild without human intervention during acclimatization period. For other acclimatization enclosures to be constructed in the future, ecological environment inside, including topography, forests, and bamboos as well, should as possible as can match the habitat that the giant panda to-be-reinforced populations inhabit. PMID- 26003092 TI - Adopting child restraint laws to address child passenger injuries: Experience from high income countries and new initiatives in low and middle income countries. PMID- 26003091 TI - Urban and rural habitats differ in number and type of bird feeders and in bird species consuming supplementary food. AB - Bird feeding is one of the most widespread direct interactions between man and nature, and this has important social and environmental consequences. However, this activity can differ between rural and urban habitats, due to inter alia habitat structure, human behaviour and the composition of wintering bird communities. We counted birds in 156 squares (0.25 km(2) each) in December 2012 and again in January 2013 in locations in and around 26 towns and cities across Poland (in each urban area, we surveyed 3 squares and also 3 squares in nearby rural areas). At each count, we noted the number of bird feeders, the number of bird feeders with food, the type of feeders, additional food supplies potentially available for birds (bread offered by people, bins) and finally the birds themselves. In winter, urban and rural areas differ in the availability of food offered intentionally and unintentionally to birds by humans. Both types of food availability are higher in urban areas. Our findings suggest that different types of bird feeder support only those species specialized for that particular food type and this relationship is similar in urban and rural areas. PMID- 26003093 TI - Selection and validation of reliable reference genes in Gossypium raimondii. AB - OBJECTIVE: To identify reliable reference genes for gene expression analysis in Gossypium raimondii. RESULTS: Five different software tools, geNorm, NormFinder, BestKeeper, ReFinder and ?Ct method were employed to analyze the qRT-PCR data systematically of 12 housekeeping genes. SAD and TUA11 showed relatively stable expression levels in all tissues (i.e. leaves, shoots, buds, and sepals). We then limited our analysis to each plant part and identified tissue-specific reference genes. Our results showed TUA11, TUB6 and EF1a, EF1a, MZA and GAPC2, MZA, GAPC2, SAD and TUA11, and UBQ and MZA were reliable reference genes in leaves, shoots, buds, and sepals, respectively. CONCLUSION: Some genes were commonly identified as candidate reference genes in more than two tissue, while others were tissue specific. Thus, our study allows choosing an appropriate control gene based on sampling for gene expression analysis. PMID- 26003094 TI - Antifungal activity and mechanism of tea polyphenols against Rhizopus stolonifer. AB - OBJECTIVE: To investigate the antifungal activity and possible mechanism of tea polyphenols (TPs) against Rhizopus stolonifer, the agent of rotting in nectarines and peaches. RESULTS: TP inhibited both mycelial growth and spore germination in vitro in a dose-dependent manner, and the morphological changes of the treated hyphae with TP, such as irregularly swollen, increased branching, wrinkled, entwining, collapse and breakage, and of the treated spores, such as swelling of germ tube tips, exfoliation of the surface layer and disorganization of cell organelles, were observed using optical microscopy, scanning electron microscopy and transmission electron microscopy. TP also significantly decreased rhizopus rot on inoculated nectarines and induced the activities of phenylalanine ammonia lyase, polyphenol oxidase, peroxidase, chitinase, and beta-1,3-glucanase. CONCLUSION: The mechanism of action might be attributed to direct damage of the mycelium and spore and indirect induction of defensive enzyme activities. TP has the potential to be developed as an alternative to control post-harvest disease of fruit caused by R. stolonifer. PMID- 26003095 TI - Cold adaptation of a psychrophilic chaperonin from Psychrobacter sp. and its application for heterologous protein expression. AB - OBJECTIVES: A chaperonin, PsyGroELS, from the Antarctic psychrophilic bacterium Psychrobacter sp. PAMC21119, was examined for its role in cold adaptation when expressed in a mesophilic Escherichia coli strain. RESULTS: Growth of E. coli harboring PsyGroELS at 10 degrees C was increased compared to the control strain. A co-expression system using PsyGroELS was developed to increase productivity of the psychrophilic enzyme PsyEst9. PsyEst9 was cloned and expressed using three E. coli variants that co-expressed GroELS from PAMC21119, E. coli, or Oleispira antarctica RB8(T). Co-expression with PsyGroELS was more effective for the production of PsyEst9 compared tothe other chaperonins. CONCLUSION: PsyGroELS confers cold tolerance to E. coli, and shows potential as an effective co-expression system for the stable production of psychrophilic proteins. PMID- 26003096 TI - New opportunities for the regulation of secondary metabolism in plants: focus on microRNAs. AB - Plant cell cultures are of particular interest in industrial applications as a source of biologically active substances. It is difficult, however, to achieve stable production of secondary metabolites for many plant cell cultures using classical techniques. Novel approaches should be developed for removal of the inhibitor blocks that prevent pathway activation and shift the regulatory balance to the activation of entire biosynthetic pathways. MicroRNAs (miRNAs) are small RNAs that play important regulatory roles in various biological processes. Only recently miRNAs have been demonstrated as active in secondary metabolism regulation. In this work, we summarize recent data on the emerging approaches based on regulation of secondary metabolism by miRNAs. PMID- 26003097 TI - An unusual breast malignancy. AB - We describe an extramedullary plasmacytoma of both breasts in a 35-year-old woman. No other involvement was detected in the bone marrow or in any other site . Extramedullary plasmacytomas of the breast are extremely rare, especially those that are not associated with multiple myeloma. PMID- 26003098 TI - Nuchal Fibroma : A rare entity of neck masses. AB - A nuchal fibroma is a rare benign mass; it is a fibrolipoma-like soft tissue mass, usually located in the lower back and the neck. Males are affected far more often than females. It can occur extranuchally. It is a slow growing tumor and usually asymptomatic. We present a rare case of a 39-year old female who was diagnosed with nuchal-type fibroma on final pathology. The proper management for this type of tumor is complete excision. PMID- 26003099 TI - Epinephrine-secreting large incidental pheochromocytoma in a normotensive male with stormy intraoperative hemodynamics. AB - Pheochromocytoma is a rare tumour which is usually suggested by sustained or paroxysmal hypertension however the spectrum of the presentation of pheochromocytoma continues to expand and hypertension may be absent despite excess catecholamine secretion. The normotensive pheochromocytoma is a distinct entity and as in the case we report the presentation was quite unique as well as the intraoperative behaviour was stormy. PMID- 26003100 TI - Everolimus induced Pneumonitis. AB - Everolimus (RAD 001) is an orally administered inhibitor of mTOR (mammalian target of rapamycin), a central regulator of intracellular signaling pathways involved in cell growth and proliferation, cellular metabolism and angiogenesis. Drug is currently in use to prevent allograft rejection after solid organ transplantation and in treatment of advanced renal cell carcinoma (RCC). Noninfectious pneumonitis is rare adverse reaction associated with rapamycin and rapamycin analogues. Awareness of this toxicity and appropriate management is important to optimize patient safety. Here we report a case of everolimus induced pneumonitis in a 72 years old male with metastatic renal cell carcinoma (mRCC) after 4 months of commencement of everolimus. Drug was discontinued and patient was treated accordingly and discharged after 10 days of hospital admission. PMID- 26003101 TI - Primary mantle cell lymphoma of appendix. AB - We present a case of immunohistochemically proven primary mantle cell lymphoma of appendix that presented as a mass in right iliac fossa. The usual presentation of gastrointestinal mantle cell lymphoma is in the form of multiple lymphomatous polyposis. Mantle cell lymphoma has a unique immunohistochemistry and genetic abnormality. PMID- 26003102 TI - A Rare Variant of Multiple Myeloma; Non-Secretory Myeloma with diffuse osteolytic lesions. AB - Non-secretory myeloma is a very rare entity of plasma cell dyscrasia. It is delineated as symptomatic myeloma without detectable monoclonal immunoglobulin peak on serum or urine electrophoresis with normal immunoquantification. Due to the inability to detect monoclonality often it is difficult to ascertain an early and accurate diagnosis. Misdiagnosing results to undue delay in therapeutic intervention. Consequently extensive imaging studies, serum free light chains detection and morphological confirmation are mandatory. Lytic bone lesions are less frequently seen in this type of myeloma. Here we report the case of a patient with this rare variant having diffuse osteolytic lesions in whom we established the diagnosis by bone marrow examination and document light chain restriction by immunophenotyping. Patient is classified as stage III according to Durie and Salmon criteria in view of anemia and multiple lytic lesions observed. PMID- 26003103 TI - Pain and Cancer: A systematic review. AB - Pain is the most common symptoms in patients with cancer, a significant number of cases it is undiagnosed and under treated. It is important to understand the nature of the pain experienced by patients, to distinguish between nociceptive and neuropathic pain. Successful management of cancer pain requires a good knowledge of the causes of pain and various treatment available and information to manage their side effects. Pain has a significant negative impact on the patient and his family, therefore it needs to be managed urgently and appropriately. PMID- 26003104 TI - Tumor Thickness: A predictor of nodal disease in early squamous cell carcinomas of buccal mucosa. AB - Squamous cell carcinomas of buccal mucosa is one the highest number of malignancies seen in the Southeast Asian region. It is related to chewing a combination of tobacco mixed with betel leaves, areca nut, and lime shell called quid. As it is most commonly due to substance abuse and affects younger population, it has tremendous economical and social consequences. Surgery is the most successful modality of management in these patients. The surgery involves wide excision of the diseased mucosa and neck dissection. Neck dissection is associated with certain morbidities, but is routinely practiced in some centers like ours. We have attempted to evaluate the occurrence of the nodal disease in relation to the thickness of the tumor in cases of early cancers of buccal mucosa (stage I and II). We have used ultrasound of the lesion as our modality to assess the tumor thickness preoperatively. AJCC 7th edition was used to assess the clinical and pathological stage of the disease. We have studied 52 patients of early buccal mucosal squamous cell carcinoma, and we observed that tumors thicker than 7mm (p-0.05) have highest co-relation with nodal metastases. This study also recommends that neck dissection should be prophylactically performed for tumors thicker than 4mm. Tumor characteristics such as grade, perineural invasion, and lymphatic invasion should be considered as predictors for early nodal involvement. PMID- 26003105 TI - Hypofractionated Simultaneous Integrated Boost (SIB) versus Conventional Fractionation in Localized Prostate Cancer: A Randomized Pilot Study. AB - PURPOSE: Radical prostatectomy or radiotherapy has comparable results in the treatment of localized prostate cancer. High dose external irradiation entails a prolonged 7-8 weeks of treatment with significant inconvenience to elderly patients. Hypofractionated regimen in prostate cancer depends on the distinctive radiobiological properties of prostate cancer cells; their relative low alpha beta ratio compared to that for late-reacting rectal tissue allows for significant dose escalation per fraction without expected increase in late normal tissue reaction. PATIENTS AND MATERIALS: Between July 2012 and December 2013, twenty patients were blindly randomized into two groups. The planning target volume in the study group received 65Gy to 67.5Gy/25 fractions over 5 weeks. The patients in the control arm received 74Gy to 78Gy in 2Gy/fraction. Cost-benefit was evaluated for both regimens. RESULTS: Both groups were comparable regarding risk factors, with no significant statistical differences. Four patients in the study group developed grade 2 urinary toxicity and one patient had grade 3 during treatment. At six months no patient had urinary symptoms. In the control arm 4 patients have grade 2 toxicity during treatment which disappeared at six months. The two groups showed no statistical difference in the mean quality of life. Serum PSA reached a nadir value of 0.02 and 0.04 in the study and control groups respectively at 3 month post-treatment. The cost of treatment for the study group was 25000 L.E. per patient compared to 40000 L.E. in the control group. The hypofractionated group consumed 31138 MU compared to 45611 MU for the control group with a p-value of 0.015. CONCLUSION: Hypofractionated IMRT with concomitant boost for localized cancer prostate is a feasible option with lesser cost and comparable toxicities. Longer followup is required to assess the late effects before recommending it as a standard of care. PMID- 26003106 TI - Quantitative evaluation of the dosimetric effects of balloon deformation and source position in high-dose rate mammosite breast brachytherapy. AB - PURPOSE: To investigate quantitatively the deformation of the mammosite balloon, eccentricity of the source position and their effects on the dose delivered to the tumor lumpectomy site and critical structures. MATERIALS AND METHODS: The distances of the brachytherapy source to the surface of the mammosite balloon were measured in using radiographic images for fractions 1 to 10 for twelve patients. The dose at the balloon surface (nearly 680cGy) and prescription dose of 340cGy at 1cm from the balloon surface were calculated for the different fractions and their dependence on the balloon volume and source position were investigated. RESULTS: The position of the source can be offset from the center of the mammosite balloon by up to 6mm. Deformation of the balloon led to variations in its dimensions by up to 8mm. The dose at 1cm from the balloon surface that covers the lumpectomy site varied by up to 19% from 340cGy along the elongated diameter of the balloon and by up to 40% along the short diameter. Maximal doses to the skin, ribs and lung were 420cGy, 630cGy and 500cGy per fraction, respectively, which depended mostly on their distance from the balloon surface. CONCLUSION: The geometric variations in the shape of the balloon and position of the source can cause lack of dose coverage to the lumpectomy site or create hot dose spots in the surrounding normal tissue that might compromise intended clinical goals. Users as well as vendors should consider correction measures for the deformation of the balloons and the eccentricity of the position of the high dose source. PMID- 26003107 TI - Spectrum of ovarian tumors: Histopathological study of 218 cases. AB - BACKGROUND: Ovarian tumors are a group of neoplasms that have diverse spectrum of features according to the particular tumor entity. Ovarian cancer is the leading cause of death in females. The aim of this study is to determine the frequency of ovarian tumors and its distribution according to cell of origin and age group. MATERIAL AND METHOD: This is a retrospective study of all cases of ovarian tumors collected during a period of 9 years from the Histopathology Department of Al Gamhuria Teaching Hospital from 1993-1996 and Ibn Sina laboratory in Aden Governorate from 2009- 2013. RESULTS: The tumors are grouped according to the nature of tumor whether benign, borderline or malignant, and according to cell of origin and age group. Benign tumors are the most frequent (86.7%), and malignant are less (13.3%). The total surface epithelial tumors are 63.7%, benign serous tumors are the most common (44%), followed by mucinous t mors (9.6%), serous tadenocarcinoma (2.8%), mucinous cystadenocarcinoma (1.8%), serous cystadenoma borderline (1.4%), and endometrioid adenocarcinoma (1.4%). The least frequent tumors are mucinous cystadenoma borderline and poorly differentiated carcinoma at 0.9% each. Tumors derived from sex cord stromal tissue as benign fibroma and thecoma comprise 5%, while malignant tumors are granulosa cell tumor (1.4%) and androblast ma moderately differentiated (0.5%). Tumors derived from germ cell as benign cystic teratoma are 26.6% while malignant tumors were dysgerminoma (0.9%) and malignant teratoma (0.5%). CONCLUSION: Benign tumors outnumber the malignant tumors. Surface epithelial tumors are the most common class of tumors. Bilateral tumors are not frequent. The high death rates are due to advanced malignancy during the time of diagnosis from the majority of cases. PMID- 26003108 TI - Rare chromosome structural aberration characterizing oncology malignancy. AB - Ring chromosome aberration are rare abnormality potentially involving any chromosome in patients diagnosing in Oncology. The present review and case study has focused on the ring chromosome associated with oncology malignancies. MATERIAL AND METHODS: An electronic peer review article search was performed systematically to obtain relevant literature with the CINAHL, Google scholar, and Pub Med databases. The keywords included marker, abnormalities, structural, Ring chromosome. The inclusion criteria for the review were that the documents were original quantitative research and published in English. This was also initiated using Medline, Mitelman database (http://cgap.nci.nih.gov/Chromosomes/Mitelman), Danish cytogenetic register and other pertinent web references on ring chromosomes in Oncology malignancies. Articles that were not directly relevant to the present objective were excluded. Also the un-stimulated bone marrow specimen of present case manipulated with Methotrexate cells culture synchronization and finally was treated by GTGbanding technique. RESULTS: Ring chromosome was observed in 10% of the total cells. Cytogenetic analysis demonstrated apparently ring (15) 46, XY, r(15) karyotype. The clinical findings revealed history of nausea, loss of appetite, diarrhea, night sweats, and a weight loss, anemia and diagnosed as accelerated CML. CONCLUSION: Our finding adds to the spectrum of both morphology and genetic rearrangements in oncology malignancies. Additional future analyses in similar subject will be necessary to draw firm conclusions. PMID- 26003109 TI - Infectious complications after allogeneic bone marrow transplantation: Sheikha Badryia Center, Kuwait. AB - OBJECTIVE: To present our experience of post-transplant infections in allogeneic stem cell transplants at Sheikha Badryia Stem Cell Transplant Centre, Kuwait. METHODS: Retrospective analysis of 21 consecutive patients with malignant and non malignant hematological disorders who received a transplant of an unmanipulated bone marrow graft from an HLAidentical sibling donor from November 2011 to December 2013. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. Bone marrow stem cells were used as the stem cell source. Cyclosporin and methotrexate with or without mycophenolate mofetil/methylprednisolone were used as graftversus-host disease (GVHD) prophylaxis. The engraftment was monitored with molecular analysis. Survival was calculated from the date of transplant to death or last follow-up. RESULTS: Twenty-one patients received allogeneic stem cell transplants from HLA- matched siblings for various hematological disorders. Twelve patients were female. The median age of the patient cohort was 34 years (range 3-41 years). All patients and donors were cytomegalovirus (CMV) IgG-positive. Seventeen patients (80.95%) developed febrile episodes in different phases of post-transplant recovery. Posttransplant infections were confirmed in 20 patients (90.2%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections and chronic graft versus host disease was one patient (4.8%). CONCLUSION: 90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively. PMID- 26003110 TI - Simulation-based training in robot-assisted surgery: current evidence of value and potential trends for the future. AB - Robot-assisted surgery has changed the landscape of surgery. Implementation of robotics into most surgical specialties has left many educators challenged to develop the tools necessary to train and credential surgeons. Advances in robot assisted surgery have led to the development of simulators and tools to assess skills that transfer to surgical practice. We report on current trends in robot assisted surgical training, focus on simulation-based education, and anticipate future developments. PMID- 26003111 TI - Sequence-based ultra-dense genetic and physical maps reveal structural variations of allopolyploid cotton genomes. AB - BACKGROUND: SNPs are the most abundant polymorphism type, and have been explored in many crop genomic studies, including rice and maize. SNP discovery in allotetraploid cotton genomes has lagged behind that of other crops due to their complexity and polyploidy. In this study, genome-wide SNPs are detected systematically using next-generation sequencing and efficient SNP genotyping methods, and used to construct a linkage map and characterize the structural variations in polyploid cotton genomes. RESULTS: We construct an ultra-dense inter-specific genetic map comprising 4,999,048 SNP loci distributed unevenly in 26 allotetraploid cotton linkage groups and covering 4,042 cM. The map is used to order tetraploid cotton genome scaffolds for accurate assembly of G. hirsutum acc. TM-1. Recombination rates and hotspots are identified across the cotton genome by comparing the assembled draft sequence and the genetic map. Using this map, genome rearrangements and centromeric regions are identified in tetraploid cotton by combining information from the publicly-available G. raimondii genome with fluorescent in situ hybridization analysis. CONCLUSIONS: We report the genotype-by-sequencing method used to identify millions of SNPs between G. hirsutum and G. barbadense. We construct and use an ultra-dense SNP map to correct sequence mis-assemblies, merge scaffolds into pseudomolecules corresponding to chromosomes, detect genome rearrangements, and identify centromeric regions in allotetraploid cottons. We find that the centromeric retro element sequence of tetraploid cotton derived from the D subgenome progenitor might have invaded the A subgenome centromeres after allotetrapolyploid formation. This study serves as a valuable genomic resource for genetic research and breeding of cotton. PMID- 26003112 TI - Second generation physical and linkage maps of yellowtail (Seriola quinqueradiata) and comparison of synteny with four model fish. AB - BACKGROUND: Physical and linkage maps are important aids for the assembly of genome sequences, comparative analyses of synteny, and to search for candidate genes by quantitative trait locus analysis. Yellowtail, Seriola quinqueradiata, is an economically important species in Japanese aquaculture, and genetic information will be useful for DNA-assisted breeding. We report the construction of a second generation radiation hybrid map, its synteny analysis, and a second generation linkage map containing SNPs (single nucleotide polymorphisms) in yellowtail. RESULTS: Approximately 1.4 million reads were obtained from transcriptome sequence analysis derived from 11 tissues of one individual. To identify SNPs, cDNA libraries were generated from a pool of 500 whole juveniles, and the gills and kidneys of 100 adults. 9,356 putative SNPs were detected in 6,025 contigs, with a minor allele frequency >= 25%. The linkage and radiation hybrid maps were constructed based on these contig sequences. 2,081 markers, including 601 SNPs markers, were mapped onto the linkage map, and 1,532 markers were mapped in the radiation hybrid map. CONCLUSIONS: The second generation linkage and physical maps were constructed using 6,025 contigs having SNP markers. These maps will aid the de novo assembly of sequencing reads, linkage studies and the identification of candidate genes related to important traits. The comparison of marker contigs in the radiation hybrid map indicated that yellowtail is evolutionarily closer to medaka than to green-spotted pufferfish, three-spined stickleback or zebrafish. The synteny analysis may aid studies of chromosomal evolution in yellowtail compared with model fish. PMID- 26003113 TI - Correlation of cadmium and aluminum in blood samples of kidney disorder patients with drinking water and tobacco smoking: related health risk. AB - The combined exposure to aluminum (Al) and cadmium (Cd) causes more pronounced adverse health effects on humans. The kidneys are the main organs affected by internal exposure to Cd and Al via food and non-food items. The objective of present study was to measure the Al and Cd concentrations in cigarettes tobacco (branded and non-branded) and drinking water (domestic treated, ground and lake water) samples in southern part of Pakistan, to assess the risk due to ingestion of water and inhalation of cigarettes smoke containing high concentrations of both elements. The study population (kidney disorder and healthy) divided into two group based on consuming lake and ground water, while smoking non-branded cigarette as exposed, while drinking domestic treated water and smoking branded cigarette as non-exposed. Electrothermal atomic absorption spectrometry was used to determined Cd and Al concentrations in tobacco, drinking water and blood samples. The resulted data indicated that the levels of Al and Cd in lake and underground water were higher than the permissible limit in drinking water recommended by the World Health Organization. The biochemical parameters of exposed and referent patients, especially urinary N-acetyl-h-glucosaminidase, were used as a biomarkers of kidney disorder. Exposed kidney disorder patients have higher levels of Cd and Al than the exposed referents subjects, while difference was significant when compared to resulted data of non-exposed patients and referents (p = 0.01-0.001). The pearson correlation showed positive correlation between both toxic element concentrations in water, cigarettes versus blood samples of exposed subjects (r = 0.20-0.67 and 0.71-0.82), while lower values were observed for non-exposed subjects (r = 0.123-0.423 and 0.331-0.425), respectively. PMID- 26003114 TI - Potentiation of hypericin-mediated photodynamic therapy cytotoxicity by MK-886: focus on ABC transporters, GDF-15 and redox status. AB - BACKGROUND: Pretreatment with 5-LOX pathway inhibitor MK-886 potentiates cytotoxic effects of photodynamic therapy mediated by natural photosensitizer, hypericin. In this study, we focused on elucidating mechanisms beyond the increased efficacy of combined treatment. METHODS: Metabolic activity/viability, caspase-3 activation/mitochondrial membrane potential dissipation, intracellular hypericin level, glutathione level and redox status (NAD(P)H/oxidized flavins ratio) analyses, as well as drug efflux assays, were performed by flow cytometry. Changes in protein expression of ATP-binding cassette transporters, GDF-15 and other selected proteins were evaluated by Western blotting. Silencing of gdf-15 was carried out to verify its role in response to treatment. RESULTS: MK-886 pretreatment led to a concentration-dependent increase in intracellular hypericin content, accompanied by changes in ATP-binding cassette transporters levels and efflux efficiency. Intracellular accumulation of cytokine GDF-15 correlated with increased cell death markers; however, the impact of gdf-15 silencing on the evaluated markers was negligible. A marked decrease in the glutathione level of a majority of cells was observed after more toxic combination treatment. CONCLUSION: The significant increase in cell death markers after combination treatment confirms the potentiating effect of MK-886 on hypericin-mediated photodynamic therapy in HT-29 and MCF-7 cells. Although BCRP downregulation was not confirmed as leading mechanism responsible for elevated levels of hypericin content, changes in expression and efflux activity of ABC transporters caused by MK-886 suggest its potential in combination treatment with drugs that are substrates of these transporters, predominantly MRP1. However, complex cellular response to MK-886 pretreatment needs to be considered and further elucidated. PMID- 26003115 TI - Laparoscopic colorectal surgery is safe and benefits octogenarian patients with malignant disease: a matched case-control study comparing laparoscopic and open colorectal surgery. AB - PURPOSE: Increased physiological stress from laparoscopic surgery and the lower physiological reserves in the elderly are causes for concern. This study aims to compare the outcomes between laparoscopic and open colorectal surgery in octogenarians. METHODS: Octogenarians who underwent elective colorectal resections from 2000 to 2011 were reviewed. Patients who underwent laparoscopic surgery were matched for comorbidities, T-staging and type of resection performed to patients with open surgery. RESULTS: Each group had 36 patients. Both groups were comparable for median age (85 vs 83, p = 0.43), gender (21 vs 18 males, p = 0.64) and the American Society of Anaesthesiologists (ASA) score (p = 0.486). Both groups had comparable median maximal tumour dimensions (4.75 vs 4.25 cm, p = 0.38) and median number of lymph nodes harvested (15 vs 14, p = 0.94). The laparoscopic group had, however, a longer median operative time (167.5 vs 124.5 min, p < 0.001). Both groups had comparable median length of hospitalisation (8 vs 7, p = 0.83), number of complications with a grade of complication (GOC) of >=3 (5 vs 7, p = 0.75) and 30-day mortality rates (8.3 vs 5.6%, p = 1.00). One year survival rate for the open group was lower (75.0 vs 94.4%, p = 0.09). CONCLUSIONS: Despite a longer operating time, laparoscopic surgery had comparable short-term outcomes and might have a long-term survival benefit. PMID- 26003117 TI - Clinicopathological attributes and outcomes of treatment in young-onset rectal cancer. PMID- 26003116 TI - Surgical diverticulitis is not associated with defects in the expression of wound healing genes. AB - PURPOSE: The development of diverticuli may represent defects in collagen vascular tissue integrity possibly from a genetic predisposition. We evaluated the tissue expression of wound healing genes in sigmoid tissue from youthful patients undergoing surgery for diverticulitis and thus would more likely suffer from a genetic predisposition (SD mean age 39 +/- 0.9) versus controls in the form of patients over the age of 50 (mean age 52.9 +/- 10.5 years) without evidence of diverticular disease. METHODS: The mRNA expression of 84 genes associated with the extracellular matrix, cellular adhesion, growth factors, inflammatory cytokines, and signal transduction was evaluated in 16 SD and 15 control tissues using a Qiagen Wound Healing Array. Vitronectin, the gene protein with the highest potential significance on raw analysis, was further investigated using a Taqman assay with an additional 11 SD (total n = 27) and four control (total n = 19) samples. Statistics were by Student's t and Mann-Whitney tests with Bonferroni correction. RESULTS: No significant differences in mRNA expression between the SD and control tissue in the 84 measured genes were demonstrated after correction. Vitronectin mRNA expression was downregulated 2.7 fold in SD tissue vs. tissue from non-neoplastic control patients (p = 0.001 raw/0.08 corrected). However, on vitronectin TaqMan analysis, no difference in expression was seen in SD vs. all controls or in all subset comparisons. CONCLUSIONS: The lack of significant alteration in mRNA expression of traditionally associated wound healing genes/proteins in young SD patients suggests that such genes play a minor role in the genetic predisposition to youthful diverticulitis. PMID- 26003118 TI - Sphincterotomy for anal fissure in Crohn's disease: is it dangerous? PMID- 26003119 TI - The use of topical 10% metronidazole in the treatment of non-healing pilonidal sinus wounds after surgery. PMID- 26003120 TI - Burn care delivery in a sub-saharan african unit: A cost analysis study. AB - INTRODUCTION: There are significant resource challenges to burn surgical care delivery in low and middle-income countries at baseline and only a few burn cost analysis studies from sub-Saharan Africa have been performed. METHODS: This is a retrospective database analysis of prospectively collected data from all patients recorded in the burn registry between June 2011 and August 2014 located at the Kamuzu Central Hospital Burn Unit in Lilongwe, Malawi. We utilized activity-based costing, a bottom-up cost analysis methodology with cost allocation that allows determination of unit cost or cost per service. RESULTS: 905 patients were admitted to the burn unit during the study period. The calculated total monthly burn expenditure for all cost centers was $11,622.66. Per day, the total unit cost was $387.42 with a mean daily per-patient cost of $24.26 (SD +/- $6.44). Consequently, the mean cost per in-patient admission was $559.85 (SD +/- $736.17). The mean daily cost per 1% total burn surface per patient at our center is $2.65 (SD +/- $3.01). DISCUSSION: This burn care cost analysis study helps quantify the relative contribution of differing cost centers that comprise burn care delivery and hospital costs in a sub-Saharan African setting. Accurate and relevant cost information on hospital services at the patient level is therefore fundamental for policy makers, payers, and hospitals. CONCLUSION: Our study has demonstrated that comprehensive burn care is possible at a cost much lower than found in other burn centers in low or middle-income countries and can be sustained with moderate funding. PMID- 26003121 TI - Antibiotic prophylaxis audit and questionnaire study: Traffic Light Poster improves adherence to protocol in gastrointestinal surgery. AB - OBJECTIVE: To measure adherence to antibiotic prophylaxis (AP) protocol amongst surgeons and anesthetists and explore their understanding of AP prescribing in practice. DESIGN: A prospective audit of AP in gastrointestinal surgery and re audit after intervention. A questionnaire survey of practice. RESULTS: 58 (38%- clean; 62%- clean contaminated) operations were audited and 73 (48%-clean; 51% clean contaminated) operations were re-audited after intervention with "Traffic Light Poster" (TFP) .55 colleagues (32 consultants and 23 trainees) were recruited for questionnaire survey in three West Midlands hospitals. Audit and Re Audits. Only 31% of procedures followed the protocol correctly in the initial audit and this increased to 73% in the re-audit. 73% of patients undergoing clean procedures received AP inappropriately in the initial audit but reduced significantly to 20% (p < 0.002) in the re-audit. In the initial audit, 62% of clean contaminated procedures did not receive the appropriate first line AP but this fell to 35% (p < 0.05) in the re-audit. Questionnaire Survey- Only 30% of respondents would not give AP in clean surgery as recommended. 45% would use appropriate AP for clean-contaminated wounds. 73% of respondents will give AP at induction, 20% 1 h pre op and 7% just before incision. CONCLUSION: There is poor compliance with AP protocols in gastrointestinal surgery in part due to general lack of awareness. An educational intervention in the form of a 'Traffic Light Poster' improved adherence to AP protocol two fold. There was improved rationalizing of AP. Clean procedures, in particular, had less inappropriate prescribing. PMID- 26003122 TI - Tensile test and interface retention forces between wires and composites in lingual fixed retainers. AB - INTRODUCTION: In daily orthodontic clinical practice retention is very important, and lingual retainers are part of this challenge. The failure of lingual retainers may be due to many factors. The aim of this study was to assess the retention forces and mechanical behavior of different types of wires matched with different kinds of composites in lingual retainers. METHODS: A tensile test was performed on cylindrical composite test specimens bonded to orthodontic wires. The specimens were constructed using four different wires: a straight wire (Remanium .016*.022" Dentaurum), two round twisted wires (Penta One .0215" Masel, Gold Penta Twisted .0215" Gold N'braces) and a rectangular braided wire (D-Rect .016*.022" Ormco); and three composites: two micro-hybrids (Micro-Hybrid Enamel Plus HFO Micerium, and Micro-Hybrid SDR U Dentsply) and a micro-nano-filled composite (Micro-Nano-Filled Transbond LR 3M). The test was performed at a speed of 10mm/min on an Instrom device. The wire was fixed with a clamp. RESULTS: The results showed that the bonding between wires and composites in lingual fixed retainers seemed to be lowest for rectangular smooth wires and increased in round twisted and rectangular twisted wires where the bonding was so strong that the maximum tension/bond strength was greater than the ultimate tensile strength of the wire. The highest values were in rectangular twisted wires. Concerning the composites, hybrid composites had the lowest interface bonding values and broke very quickly, while the nano- and micro-composites tolerated stronger forces and displayed higher bonding values. The best results were observed with the golden twisted wire and reached 21.46 MPa with the Transbond composite. With the rectangular braided wire the retention forces were so high that the Enamel Plus composite fractured when the load exceeded 154.6 N/MPa. When the same wire was combined with the Transbond LR either the wire or the composite broke when the force exceeded 240 N. CONCLUSIONS: The results of this study show that, when selecting a lingual retainer in daily clinical practice, not only must the patient's compliance and dependability be considered but also the mechanical properties and composition of different combinations of composites and wires. PMID- 26003124 TI - 5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats. AB - Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3+/-1.0, 43.7+/-2.7 and 66.7+/-4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1MUg/kg each) or l-694,247 (5-HT1D agonist; 0.0125MUg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists alpha-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125MUg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release. PMID- 26003125 TI - Sound-evoked vestibular stimulation affects the anticipation of gravity effects during visual self-motion. AB - Humans anticipate the effects of gravity during visually simulated self-motion in the vertical direction. Here we report that an artificial vestibular stimulation consisting of short-tone bursts (STB) suppresses this anticipation. Participants pressed a button upon entering a tunnel during virtual-reality roller coaster rides in downward or forward directions. In different trials, we delivered STB, pulsed white noise (WN), or no sound (NO). In the control conditions (WN, NO), participants responded earlier during downward than forward motion irrespective of true kinematics, consistent with the a priori expectation that downward but not forward motion is accelerated by gravity. STB canceled the difference in response timing between the two directions, without affecting overall task performance. Thus, we argue that vestibular signals play a role in the anticipation of visible gravity effects during self-motion. PMID- 26003126 TI - Group membership and social status modulate joint actions. AB - The ability to form shared task representations is considered a keystone of social cognition. It remains, however, contentious if, and to what extent, social categorization impacts on shared representations. In the present study, we address the possibility of the modulation of action co-representation by social categorization, such as group membership and social status, as indexed by the social Simon effect. Italian participants were requested to perform a social Simon task, along with either an Italian (high-status in-group) or an Albanian (low-status out-group) participant. Results show that Italian participants co represented the action of their partner when paired with a high-status in-group participant. Conversely, this effect was absent when they performed the task with a low-status out-group participant. Furthermore, the Albanian participants co represented the action of their partner when paired with an Italian participant. These results suggest that group membership modulates action co-representation through the varying of the groups' relative status. The impact of this issue is boundless given the increasing multicultural nature of our society. Indeed, if multiculturalism fails, modern society does likewise. PMID- 26003127 TI - Exercise intensity modulates the change in cerebral blood flow following aerobic exercise in chronic stroke. AB - The mechanisms supporting functional improvement by aerobic exercise following stroke remain incompletely understood. This study investigated how cycling intensity and aerobic fitness influence cerebral blood flow (CBF) following a single exercise session. Thirteen community-living stroke survivors performed 20 min of semi-recumbent cycling at low and moderate intensities (40-50 and 60-70 % of heart rate reserve, respectively) as determined from an exercise stress test. CBF was quantified by arterial spin labeling MRI at baseline, as well as 30 and 50 min post-exercise. An intensity-dependent effect was observed in the right post-central and supramarginal gyri up to 50 min after exercise (uncorrected p < 0.005, cluster size >=10). Regional CBF was increased 18 +/- 17 % and reduced 8 +/- 12 % following moderate- and low-intensity cycling, respectively. In contrast, CBF changes were similar between sessions in the right lentiform nucleus and mid-frontal gyrus, as well as the left temporal and parietal gyri. Aerobic fitness was directly related to posterior cingulate and thalamic CBF, and inversely related to precuneal CBF at rest (R (2) >= 0.75); however, no relationship between fitness and the post-exercise change in CBF was observed. Divergent changes in regional CBF were observed in the right parietal cortex following low- and moderate-intensity exercise, which suggests that intensity of prescribed exercise may be useful in optimizing rehabilitation. PMID- 26003128 TI - A dedicated system for topographical working memory: evidence from domain specific interference tests. AB - In the present study, we used single- and dual-task conditions to investigate the nature of topographical working memory to better understand what type of task can hamper performance during navigation. During dual-task conditions, we considered four different sources of interference: motor (M), spatial motor (SM), verbal (i.e. articulatory suppression AS) and spatial environmental (SE). In order to assess the nature of topographical working memory, we used the Walking Corsi Test, asking the participants to perform two tasks simultaneously (M, SM, AS and SE). Our results showed that only spatial-environmental interference hampers the execution of a topographical working memory task, suggesting a task-domain specific effect. We also found general gender differences in the topographical working memory capabilities: men were more proficient than women, regardless of the type of interferences. However, like men, women performed worse when a spatial-environmental interference was present. PMID- 26003129 TI - Hitting moving targets with a continuously changing temporal window. AB - Hitting a moving target requires that we do not miss the target when it is around the aimed position. The time available for us not to miss the target when it is at the position of interest is usually called the time window and depends on target's speed and size. These variables, among others, have been manipulated in previous studies but kept constant within the same trial or session. Here, we present results of a hitting task in which targets underwent simple harmonic motion, which is defined by a sinusoidal function. Target velocity changes continuously in this motion and so does the time window which is shorter in the centre (peak velocity) and longer at the turning points (lowest velocity) within a single trial. We studied two different conditions in which the target moved with a reliable (across trials) amplitude displacement or reliable peak velocity, respectively, and subjects were free to decide where and when to hit it. Results show that subjects made a compromise between maximum and minimum target's speed, so that they did hit the target at intermediate speed values. Interestingly, the reliability of target peak velocity (or displacement) modulated the point of interception. When target's peak velocity was more reliable, subjects intercepted the target at positions with smaller temporal windows and the reverse was true when displacement was reliable. Subjects adapted the interceptive behaviour to the underlying statistical structure of the targets. Finally, in a control condition in which the temporal window also depended on the instant size and not only on speed, subjects intercepted the target when it moved at similar speeds than when the size was constant. This finding suggests that velocity rather than the temporal window contributed more to controlling the interceptive movements. PMID- 26003130 TI - Carry-over coarticulation in joint angles. AB - Coarticulation indicates a dependence of a movement segment on a preceding segment (carry-over coarticulation) or on the segment that follows (anticipatory coarticulation). Here we study coarticulation in multidegrees of freedom human arm movements. We asked participants to transport a cylinder from a starting position to a center target and on to a final target. In this naturalistic setting, the human arm has ten degrees of freedom and is thus comfortably redundant for the task. We studied coarticulation by comparing movements between the same spatial locations that were either preceded by different end-effector paths (carry-over coarticulation) or followed by different end-effector paths (anticipatory coarticulation). We found no evidence for coarticulation at the level of the end-effector. We found very clear evidence, however, for carry-over, not for anticipatory coarticulation at the joint level. We used the concept of the uncontrolled manifold to systematically establish coarticulation as a form of motor equivalence, in which most of the difference between different movement contexts lies within the uncontrolled manifold that leaves the end-effector invariant. The findings are consistent with movement planning occurring at the level of the end-effector, and those movement plans being transformed to the joint level by a form of inverse kinematics. The observation of massive self motion excludes an account that is solely based on a kinematic pseudo-inverse. PMID- 26003131 TI - Efficient health research and improving Europeans' health. PMID- 26003132 TI - Effects of food price inflation on infant and child mortality in developing countries. AB - BACKGROUND: After a historic low level in the early 2000s, global food prices surged upwards to bring about the global food crisis of 2008. High and increasing food prices can generate an immediate threat to the security of a household's food supply, thereby undermining population health. This paper aims to assess the precise effects of food price inflation on child health in developing countries. METHODS: This paper employs a panel dataset covering 95 developing countries for the period 2001-2011 to make a comprehensive assessment of the effects of food price inflation on child health as measured in terms of infant mortality rate and child mortality rate. RESULTS: Focusing on any departure of health indicators from their respective trends, we find that rising food prices have a significant detrimental effect on nourishment and consequently lead to higher levels of both infant and child mortality in developing countries, and especially in least developed countries (LDCs). DISCUSSION: High food price inflation rates are also found to cause an increase in undernourishment only in LDCs and thus leading to an increase in infant and child mortality in these poorest countries. This result is consistent with the observation that, in lower-income countries, food has a higher share in household expenditures and LDCs are likely to be net food importing countries. CONCLUSIONS: Hence, there should be increased efforts by both LDC governments and the international community to alleviate the detrimental link between food price inflation and undernourishment and also the link between undernourishment and infant mortality. PMID- 26003133 TI - High-throughput screening system for inhibitors of human Heat Shock Factor 2. AB - Development of novel anti-cancer drug leads that target regulators of protein homeostasis is a formidable task in modern pharmacology. Finding specific inhibitors of human Heat Shock Factor 1 (hHSF1) has proven to be a challenging task, while screening for inhibitors of human Heat Shock Factor 2 (hHSF2) has never been described. We report the development of a novel system based on an in vivo cell growth restoration assay designed to identify specific inhibitors of human HSF2 in a high-throughput format. This system utilizes a humanized yeast strain in which the master regulator of molecular chaperone genes, yeast HSF, has been replaced with hHSF2 with no detrimental effect on cell growth. This replacement preserves the general regulatory patterns of genes encoding major molecular chaperones including Hsp70 and Hsp90. The controlled overexpression of hHSF2 creates a slow-growth phenotype, which is the basis of the growth restoration assay used for high-throughput screening. The phenotype is most robust when cells are cultured at 25 degrees C, while incubation at temperatures greater than 30 degrees C leads to compensation of the phenotype. Overexpression of hHSF2 causes overexpression of molecular chaperones which is a likely cause of the slowed growth. Our assay is characterized by two unique advantages. First, screening takes place in physiologically relevant, in vivo conditions. Second, hits in our screen will be of medically relevant potency, as compounds that completely inhibit hHSF2 function will further inhibit cell growth and therefore will not be scored as hits. This caveat biases our screening system for compounds capable of restoring hHSF2 activity to a physiologically normal level without completely inhibiting this essential system. PMID- 26003134 TI - A Protocol to Collect Specific Mouse Skeletal Muscles for Metabolomics Studies. AB - Due to the highly sensitive nature of metabolic states, the quality of metabolomics data depends on the suitability of the experimental procedure. Metabolism could be affected by factors such as the method of euthanasia of the animals and the sample collection procedures. The effects of these factors on metabolites are tissue-specific. Thus, it is important to select proper methods to sacrifice the animal and appropriate procedures for collecting samples specific to the tissue of interest. Here, we present our protocol to collect specific mouse skeletal muscles with different fiber types for metabolomics studies. We also provide a protocol to measure lactate levels in tissue samples as a way to estimate the metabolic state in collected samples. PMID- 26003135 TI - Enhanced visual exploration for real objects compared to pictures during free viewing in the macaque monkey. AB - The question of whether animals perceive pictures as representation of real objects remains still unsolved. Object-picture perception is generally studied requiring animals to learn some information about real objects and transfer that knowledge to the pictorial domain, or vice versa. Here, we tackle the issue of object-picture perception from a different perspective, examining visual exploration behavior of two naive macaque monkeys during free-viewing of objects and pictures of these objects on a computer monitor. Our main finding is that monkeys looked spontaneously longer at object rather than picture stimuli. However, we find striking similarities in temporal dynamics of gaze allocation within the time course of a single stimulus presentation, as well as in habituation rates within and across behavioral sessions. We also highlight differences between stimulus types in terms of spatial gaze patterns and looking strategies. Stimulus features that attract overt attention during spontaneous visual exploration are thus better predicted for object stimuli by a visual saliency model. Moreover, we provide evidence for a consistency in stimulus preference for objects and pictures, suggesting a correspondence of in how macaques perceive objects and their pictorial stimuli. Taken together, our data suggest that macaque monkeys exhibit evidence for correspondence between objects and pictures. This validates spontaneous visual exploration as a method for studying object-picture correspondence without a need for extensive behavioral training. We discuss the potential advantages of using object over picture stimuli in the context of studies on visual cognition. PMID- 26003136 TI - A transactional analysis of changes in parent and chick behaviour prior to separation of Herring Gulls (Larus Argentatus): A three-term contingency model. AB - The effect of the passage of time on parent-offspring behaviour of urban Herring Gulls (Larus Argentatus) was studied and analysed using a three-term contingency model. A behavioural sequence was initiated by the arrival of a parental adult gull, which would lead to feeding in the chick. However, with the passage of time, and approach of the separation period, this pattern changed. Chicks' begging became more intense, and parent gulls more often withheld food. However, the chicks' begging became directed at a wider range of adults over the observation period. These activities are placed within a three-term contingency model, which may have implications for understanding some behavioural processes involved in parent-offspring separation. PMID- 26003137 TI - The function and meaning of female rat paracopulatory (proceptive) behaviors. AB - Female paracopulatory behavior is believed to incite the male to start copulation and to allow the female control over the pace of sexual interaction. It is also supposed to represent female sexual motivation. However, there is little direct experimental evidence for these presumed functions. In the present study, we determined the temporal relationship between female paracopulatory behavior, male pursuit of the female, and male copulatory acts. Groups of 4 intact female and 3 male Wistar rats were housed in a seminatural environment for 8 days. Sociosexual behavior during the entire period of behavioral estrus was analyzed. All episodes of paracopulatory behavior were identified, and the male behavior occurring up to 10s before or after each episode was determined. Most paracopulatory behaviors were unrelated to male copulatory acts or male pursuit. To the contrary, 96% of copulatory acts occurred within 5s of female paracopulatory behavior and 83% within 5s of male pursuit of the female. Sexual interaction was initiated by a male as often as it was initiated by a female. The duration of an episode of paracopulatory behavior or male pursuit was an important determinant of the likelihood that a copulatory act would follow. Copulatory acts were a consequence of a subtle interaction between the male and the female, with the behavior of both being equally important. No support was obtained for the notion that sexual interactions are mainly controlled by the female. PMID- 26003138 TI - Behavioural responses of feral and domestic guppies (Poecilia reticulata) to predators and their cues. AB - Predation is an important factor during adaptation to novel environments, and the feralisation of introduced domestic species often involves responding appropriately to allopatric predators despite a background of domestication and inbreeding. Twenty years ago, domestic guppies were introduced to a semi-natural environment at Burgers' Zoo in the Netherlands, where they have since been exposed to avian predation. We compared predation-linked behaviours in this feral population and in domestic guppies akin to the original founders. We found that both populations responded to a novel predator and to conspecific alarm cues. However, shoaling, an important anti-predator behaviour, was higher among feral guppies both at baseline and when exposed to the novel predator. We did not observe a linked suite of anti-predator behaviours across shoaling, predator inspection, alarm substance sensitivity and boldness, suggesting that these responses may be decoupled from one another depending on local predation regimes. As we compared two populations, we cannot identify the causal factors determining population differences, however, our results do suggest that shoaling is either a particularly consequential anti-predator adaptation or the most labile of the behaviours we tested. Finally, the behavioural adaptability of domestic guppies may help to explain their success as an invasive species. PMID- 26003139 TI - Intratesticular alpha1-adrenergic receptors mediate stress-disturbed transcription of steroidogenic stimulator NUR77 as well as steroidogenic repressors DAX1 and ARR19 in Leydig cells of adult rats. AB - The aim of the present study was to define the role of testicular alpha1 adrenergic receptors (alpha1-ADRs) in stress-triggered adaptation of testosterone producing Leydig cells of adult rats. Results showed that in vivo blockade of testicular alpha1-ADRs prevented partial recovery of circulating androgen levels registered after 10* repeated immobilization stress (10 * IMO). Moreover, alpha1 ADR-blockade diminished 10 * IMO-triggered recovery of Leydig cell androgen production, and abolished mitochondrial membrane potential recovery. In the same cells, 10 * IMO-induced increase in Star transcript was abolished, Lhcgr transcript decreased, while transcription of other steroidogenic proteins was not changed. alpha1-ADR-blockade recovered stress-induced decrease of Nur77, one of the main steroidogenic stimulator, while significantly reduced 10 * IMO-increased in the transcription of the main steroidogenic repressors, Arr19 and Dax1. In vitro experiments revealed an adrenaline-induced alpha1-ADR-mediated decrease in Nur77 transcription in Leydig cells. Adrenaline-induced increase of repressor Dax1 also involves ADRs in Leydig cells. Accordingly, alpha1-ADRs participate in some of the stress-triggered effects on the steroidogenic machinery of Leydig cells. PMID- 26003140 TI - Streptozotocin induces endoplasmic reticulum stress and apoptosis via disruption of calcium homeostasis in mouse pancreas. AB - Calcium homeostasis refers to the regulation of calcium ion concentration in the body. This concentration is tightly controlled by a stabilizing system consisting of calcium channels and calcium buffering proteins. Calcium homeostasis is crucial for cell survival. Various forms of cell death (e.g., necrosis and apoptosis) also share calcium signaling pathways and molecular effectors. Calcium acts not only as a ubiquitous second messenger involved in apoptosis along with various cell death inducers but also a regulator for the synthesis of enzymes/hormones such as insulin. We hypothesized that streptozotocin disrupts calcium homeostasis and the altered intracellular calcium levels may induce cell death. After streptozotocin administration, blood glucose level was increased while insulin levels decreased. The expression of insulin response markers also decreased relative to the vehicle group. L-type voltage-gated calcium channel expression and sarcoplasmic reticulum Ca(2+) ATPase were increased by streptozotocin. Calcium buffering protein calbindin-D9k and calmodulin family members were also increased. The expression of genes involved in transporting calcium ions to the endoplasmic reticulum (ER) was decrease while the expression of those affecting the removal of calcium from the ER was increased. Depletion of calcium from the ER leads to ER-stress and can induce apoptosis. In the streptozotocin-treatment group, apoptosis markers were increased. Taken together, these results imply that the disruption of calcium homeostasis by streptozotocin induces ER-stress and leads to the apoptosis of pancreatic cells. Additionally, findings from this study suggest that imbalances in calcium homeostasis could promote pancreatic beta cell death and result in type I diabetes. PMID- 26003141 TI - Identification of polymorphic genes for use in assemblage B genotyping assays through comparative genomics of multiple assemblage B Giardia duodenalis isolates. AB - Giardia duodenalis assemblage B is potentially a zoonotic parasite. The characterisation and investigation of isolates has been hampered by greater genetic diversity of assemblage B, limiting the application and utility of current genotyping loci. Since whole genome sequencing is the optimal high throughput method for gene identification, the present study sequenced assemblage B isolate BAH15c1 and compared the sequence to the draft GS references to identify polymorphic genes for potential use in genotyping assays. The majority of the genome sequence was conserved between the two isolates, producing 508 contigs of 10.4 Mb with 4968 genes. Seventy polymorphic genes for potential use in genotyping assays were identified ranging in variation from elongation factor 1 alpha, which was the most conserved, through to triose phosphate isomerase, which was the most variable. PMID- 26003142 TI - Neo-adjuvant chemotherapy does not increase the rate of complete resection and does not significantly reduce the morbidity of Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer. AB - OBJECTIVE: To measure the efficacy and the safety of Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer and to compare the outcomes before and after chemotherapy. METHODS: Between 2008 and 2013, 200 consecutive patients were offered VPD for stage IIIC/IV ovarian cancer. Exclusion criteria were: metastases in the lungs or 3 liver segments at CT review and/or disease on small bowel serosa or encasing the porta hepatis at explorative laparoscopy. The endpoints were efficacy (rate of complete resection, CR) and safety (morbidity and mortality). The results were compared between patients in group 1 (upfront surgery) and group 2 (during or after chemotherapy). RESULTS: Ninety-eight patients were in group 1 and 102 in group 2. Twenty out of 200 patients (10%) did not have VPD, 180 out of 200 patients (90%) had VPD and CR: 90.8% in group 1, 89.8% in group 2. The mortality (1%) and intra-operative complication rate (3.3%) were similar. Post-operative complications rate was 34.8% in group 1 vs. 30.7% in group 2 (P=0.669). The difference in grade III (15.7% vs. 5.5%, P=0.053) and grade IIIb complications (13.4% vs. 4.4%, P=0.062) approached statistical significance. All other outcomes were not significantly different in the 2 groups. CONCLUSION: VPD achieved CR in 90% of the patients. Neo-adjuvant chemotherapy did not increase the rate of CR and did not significantly decrease the morbidity or the complexity of the surgery. PMID- 26003143 TI - Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up. AB - Optimal management of women with early stage granulosa cell tumours (GCT) presents a management conundrum - they have excellent prognosis but a third will relapse. Advances uncovering the molecular characteristics of GCT have not been matched by improvements in our understanding and treatment. METHODS: Stage I GCT patients referred to Auckland City Hospital (1955-2012) and Princess Margaret Cancer Centre (1992-2012) were identified. Baseline characteristics, histopathology and outcomes were recorded retrospectively. RESULTS: One hundred and sixty stage I GCT patients were identified with a median age of 49 years. Median follow-up was 7.0 years (range 0.1-44.2 years). Fifty-one patients (32%) relapsed with a median time to relapse (TTR) of 12.0 years (1.3-17.7 years) - 20 initial relapses occurred 10 years post-diagnosis. Higher relapse rates (43% vs. 24% p=0.02) and shorter TTR (10.2 vs. 16.2 years p=0.007) were seen with stage Ic versus stage Ia disease. Cyst rupture was associated with increased relapse (p=0.03). Surgery was the main therapeutic modality at relapse. Eighty six percent of patients received non-surgical management at least once post-relapse. Clinical benefit rate was 43% with chemotherapy, 61% with hormonal therapy and 86% with radiation. Five- and 10-year overall survival (OS) were 98.5 and 91.6%, respectively. Median OS was similar in patients with (24.3 years) and without relapse (22.3 years). CONCLUSION: Surgery remains fundamental at diagnosis and relapse. Caution should be exercised in recommending adjuvant chemotherapy at initial diagnosis given median OS was greater than 20 years even with relapse. Hormonal therapy at relapse appears encouraging but needs further assessment. Novel treatment strategies need exploration with international collaboration essential for this. PMID- 26003144 TI - Experience with androgen deprivation therapy for prostate cancer in Japan and future perspectives. AB - Novel anti-androgens and androgen biosynthesis inhibitors have been developed to treat castration-resistant prostate cancer. However, knowledge of androgen deprivation therapy (ADT) has not been developed in the criticism, including information regarding the adverse effects of hormonal therapy. We hypothesize that there are ethnic differences in the efficacy and adverse effects of ADT; therefore, this review summarizes the experience of ADT, mainly in Japan. A risk stratification instrument, the Japan Cancer of the Prostate Risk Assessment (J CAPRA) score, was developed based on the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. It revealed that clinical outcomes were substantially better for males treated with ADT in Japan compared with those in the United States. Moreover, there were small survival differences in patients with localized and locally advanced cancer who received local therapy and primary ADT in another Japanese cohort study. In terms of adverse effects, including bone loss and cardiovascular risk, ADT appears to be better tolerated in Japanese populations than in Western cohorts. An ongoing randomized controlled trial of a trimodality treatment comprising brachytherapy, external beam radiation therapy, and neoadjuvant with or without adjuvant ADT in patients with localized high-risk prostate cancer will provide novel insights regarding adjuvant ADT. As a future perspective, the optimal selection of the type of primary ADT, including combining androgen blockade and novel hormonal compounds, adjusted according to each patient's clinicopathological background, may provide better clinical outcomes in patients with advanced prostate cancer. PMID- 26003145 TI - Leucopenia and treatment efficacy in advanced nasopharyngeal carcinoma. AB - BACKGROUND: Leucopenia or neutropenia during chemotherapy predicts better survival in several cancers. We aimed to assess whether leucopenia could be a biological measure of treatment and a marker of efficacy in advanced nasopharyngeal carcinoma (ANPC). METHODS: We retrospectively analyzed 3826 patients with ANPC who received chemoradiotherapy. Leucopenia was categorised on the basis of worst grade during treatment according to the National Cancer Institute Common Toxicity Criteria version 4.0: no leucopenia (grade 0), mild leucopenia (grade 1-2), and severe leucopenia (grade 3-4). Associations between leucopenia and survival were estimated by Cox proportional hazards model. RESULTS: Of the 3826 patients, 2511 (65.6 %) developed mild leucopenia (grade 1 2) and 807 (21.1 %) developed severe leucopenia (grade 3-4) during treatment; 508 (13.3 %) did not. A multivariate Cox model that included leucopenia determined that the hazard ratios (HR) of death for patients with mild and severe leucopenia were 0.69 [95 % confidence interval (95 %CI) 0.56-0.85, p < 0.001] and 0.75 (95 %CI 0.59-0.95, p = 0.019), respectively; the HR of distant metastasis for patients with mild and severe leucopenia were 0.77 (95 %CI 0.61-0.96, p = 0.023) and 0.99 (95 %CI 0.77-1.29, p = 0.995), respectively. Leucopenia had no effect on locoregional relapse. CONCLUSIONS: Our results indicate that mild leucopenia during chemoradiotherapy is associated with improved overall survival and distant metastasis-free survival in ANPC. Mild leucopenia may indicate appropriate dosage of chemotherapy. We can identify the patients who may benefit from chemotherapy if they experienced leucopenia during the treatment. Prospective trials are required to assess whether dosing adjustments based on leucopenia may improve chemotherapy efficacy. PMID- 26003146 TI - Echocardiographic evaluation of prosthetic heart valves. AB - The specific flow pattern and imaging features of prosthetic heart valves poses major challenges for the Doppler echocardiographic assessment of prosthetic valve structure and function. A comprehensive approach that integrates several semi quantitative and quantitative parameters obtained from multiple views is key to appropriately detect and quantitate prosthetic valve dysfunction and complications. In patients with prosthetic valves, and particularly in those with mitral prostheses, transesophageal echocardiography is often required to confirm and/or complement information obtained by transthoracic echocardiography. Three dimensional echocardiography may provide incremental information for the identification of the underlying etiology of prosthetic valve stenosis or regurgitation. Transcatheter aortic valve implantation has rapidly expanded in the past 10 years and paravalvular regurgitation is frequent following this procedure. Given that paravalvular regurgitant jets are often multiple, irregular, and eccentric, the grading of this type of regurgitation is particularly challenging and requires an integrative multiwindow, multiplane, multiparametric approach. PMID- 26003147 TI - Predictive value for paravalvular regurgitation of 3-dimensional anatomic aortic annulus shape assessed by multidetector computed tomography post-transcatheter aortic valve replacement. AB - AIMS: Paravalvular regurgitation (PAR) remains a serious complication after trans catheter aortic valve replacement (TAVR). Multidetector computed tomography (MDCT)-based measurements of the aortic basal virtual ring (BVR) are considered the gold standard for trans-catheter heart valve (THV) sizing. However, the real anatomic aortic annulus is a 3-dimensional structure. To compare measurement of 3D-anatomic annulus with BVR and secondly to assess independent predictive parameters that may impact on PAR > mild post-TAVR (PAR+). METHODS AND RESULTS: MDCT was performed in 92 patients before and after balloon or self-expandable TAVR. 3D-AA shape was obtained point by point following the semilunar attachment of aortic cusps (Osirix-MD 2.8.2). 3D-oversizing index (nominal THV area/3D-AA area - 1) * 100 was calculated as well as 2D-oversizing index using BVR area instead of 3D-AA area. PAR was quantified by planimetry of vena-contracta in transthoracic echocardiography short-axis view. Valvular calcium volume and annulus calcium area were measured using Hounsfield-intensity detection. ROC curves and logistic regression for PAR(+) were performed. BVR area overall underestimated 3D-AA area by 19 +/- 9% (P< 0.001), significantly more in PAR(+) (26 +/- 7%) vs. PAR(-) (17 +/- 9%, P< 0.001). 3D-oversizing index had greater predictive value for PAR > mild (area under the curve, AUC = 0.88) with 88% sensibility (Se) and 82% specificity (Sp) than 2D-oversizing index (AUC = 0.68) with 84% Se, but only 41% Sp (P< 0.0001). Also, valvular calcium volume and annulus calcium area were less predictors for PAR > mild (AUC = 0.68, respectively, AUC = 0.75, P = 0.002). In a multivariate analysis, only 3D oversizing index showed an independent value for PAR > mild (OR = 18.6, P< 0.001). CONCLUSION: Basal ring CT measurement significantly underestimated the real 3D-anatomic aortic annulus area. This may impact on THV sizing and PAR incidence. 3D-oversizing index is the most predictive factor for PAR > mild. PMID- 26003148 TI - Inverted left atrial appendage after cardiac procedure. PMID- 26003149 TI - Congenital defects of the pericardium: a review. AB - Pericardial defects are a rare disorder that can be characterized as acquired or congenital. Congenital defects can be further characterized by location and size of the defect, e.g. left- or right-sided and partial or complete absence of the pericardium. While physical examination and electrocardiogram are not diagnostic, chest radiographs and echocardiography have findings that should alert the clinician to the absence of the pericardium as a possible diagnosis. Despite its limitations with visualizing the normal pericardium in areas of minimal adipose, cardiac magnetic resonance is currently the gold standard for diagnosing the congenital absence of the pericardium. Patients have a similar life expectancy to those without pericardial defects; however in certain cases, herniation and strangulation of cardiac chambers can be life threatening and lead to sudden cardiac death. Treatment is tailored to the patient's symptoms, presentation, and the size and location of the defect. PMID- 26003150 TI - Right ventricular embolization of laser catheter fragment. PMID- 26003151 TI - Transcatheter pulmonic valve replacement in carcinoid heart disease. PMID- 26003154 TI - Pharmacist-led educational and error notification interventions on prescribing errors in family medicine clinic. AB - OBJECTIVES: To determine the rate of prescribing errors in a family medicine clinic and the subsequent impact of pharmacist-led educational and error notification interventions on prescribing errors. DESIGN: Single site, pre-post study design. SETTING: An outpatient academic family medicine clinic serving pediatric and adult populations in Oklahoma from March 1, 2011, through April 30, 2012. PARTICIPANTS: 24 resident physicians who prescribed medications during routine outpatient visits. INTERVENTION: A prescribing educational program, audit and feedback methods, and weekly newsletter. MAIN OUTCOMES MEASURE: Percentage of prescription errors and physician error rate before and after intervention among pediatric and adult populations. RESULTS: During the two assessment periods, 24 resident physicians wrote 2,753 prescriptions for 394 pediatric and 899 adult patients. The overall percentage of prescription errors decreased from 18.6% during March 2011 to 14.5% during April 2012 (P = 0.004). Errors were more commonly seen with prescriptions written for pediatric patients (24.9%) than for adult patients (13.9%) (P = 0.001). Individual physician error rates ranged from 5% to 36% (mean +/- SD 16.5% +/- 8.1). Physicians committed significantly fewer prescribing errors during the postintervention assessment period (14.9%) than during the preintervention assessment period (20.9%) (P = 0.002). Controlling for time, pediatric prescription error rates among physicians who participated in the educational intervention were 36% lower than the error rates among physicians who did not participate (rate ratio 0.64 [95% CI 0.45, 0.91], P = 0.01). CONCLUSION: The pharmacist-led educational program was effective in reducing pediatric prescribing errors among resident physicians in a family medicine clinic. PMID- 26003152 TI - Multi-phase rotational angiography of the left ventricle to assist ablations: feasibility and accuracy of novel imaging. AB - AIMS: Interventional left ventricular (LV) procedures integrating static 3D anatomy visualization are subject to mismatch with dynamic catheter movements due to prominent LV motion. We aimed to evaluate the accuracy of a recently developed acquisition and post-processing protocol for low radiation dose LV multi-phase rotational angiography (4DRA) in patients. METHODS AND RESULTS: 4DRA image acquisition of the LV was performed as investigational acquisition in patients undergoing left-sided ablation (11 men; BMI = 24.7 +/- 2.5 kg/m2). Iodine contrast was injected in the LA, while pacing from the RA at a cycle length of 700 ms. 4DRA acquisition and reconstruction were possible in all 11 studies. Reconstructed images were post-processed using streak artefact reduction algorithms and an interphase registration-based filtering method, increasing contrast-to-noise ratio by a factor 8.2 +/- 2.1. This enabled semi-automatic segmentation, yielding LV models of five equidistant phases per cardiac cycle. For evaluation, off-line 4DRA fluoroscopy registration was performed, and the 4DRA LV contours of the different phases were compared with the contours of five corresponding phases of biplane LV angiography, acquired in identical circumstances. Of the distances between these contours, 95% were <4 mm in both incidences. Effective radiation dose for 4DRA, calculated by patient-specific Monte-Carlo simulation, was 5.1 +/- 1.1 mSv. CONCLUSION: Creation of 4DRA LV models in man is feasible at near-physiological heart rate and with clinically acceptable radiation dose. They showed high accuracy with respect to LV angiography in RAO and LAO. The presented technology not only opens perspectives for full cardiac cycle dynamic anatomical guidance during interventional procedures, but also for 3DRA without need for very rapid pacing. PMID- 26003155 TI - TransitionRx: Impact of community pharmacy postdischarge medication therapy management on hospital readmission rate. AB - OBJECTIVES: To determine if a community pharmacy-based transition of care (TOC) program that included the full scope of medication therapy management (MTM) services (TransitionRx) decreased hospital readmissions, resolved medication related problems, and increased patient satisfaction. DESIGN: Prospective, quasi experimental study. SETTING: Nine Kroger Pharmacies located in Western Cincinnati. PATIENTS: Patients older than 18 years of age and discharged from two local hospitals with a diagnosis of congestive heart failure, chronic obstructive pulmonary disease, or pneumonia. Patients were recruited from two local hospitals and referred to the community pharmacy for MTM services with the pharmacist within 1 week of discharge. MAIN OUTCOME MEASURES: Pharmacists reconciled the patients' medications, identified drug therapy problems, recommended changes to therapy, and provided self-management education. At 30 days after discharge, research personnel conducted telephone surveys, using a previously validated survey instrument, to assess hospital readmissions and patient satisfaction. Pharmacist interventions and medication-related problems were documented. RESULTS: A total of 90 patients completed the study. Of these, 20% of patients in the usual care group were admitted to the hospital within 30 days compared with 6.9% of patients in the intervention group (P = 0.019). In the 30 patients who received MTM services from the pharmacist, 210 interventions were made. The overall mean patient satisfaction with the TOC process was not significantly different between patients who were seen by the pharmacist and those who were not seen by the pharmacist. CONCLUSION: Community pharmacies successfully collaborated with hospitals to develop a referral process for TOC interventions. Patients who received MTM services from the pharmacist experienced significantly fewer readmissions than patients who received usual care. PMID- 26003156 TI - Young women's perceptions and experiences with contraception supply in community pharmacies. AB - BACKGROUND: Unintended pregnancy is a major public health problem in the United States.Correct contraceptive use can reduce the rate of unintended pregnancy. Community pharmacies are well positioned to provide contraceptives and advice about contraception. OBJECTIVES: To determine young women's perceptions and experiences with contraception supply in community pharmacies and to identify whether pharmacy characteristics predicted very positive experiences. DESIGN: This study comprised two cross-sectional surveys including an online women's pharmacy perceptions and experiences (PPE) survey and a faxed/observed survey of community pharmacies. SETTING: One county in Michigan. PARTICIPANTS: Young women and community pharmacies. MAIN OUTCOME MEASURE: The two surveys were merged to explore pharmacy characteristics that may impact women's perceptions and experiences with community pharmacies. Multiple logistic regression analysis was used to explore relationships between pharmacy characteristics and positive outcomes. RESULTS: The response rate for the PPE survey was 54% (n = 343/637). Data from all community pharmacies in the county was retrieved via fax (n = 41/94, 43.6%) or observation (n = 53/94, 56.4%). Women were included in this analysis if they indicated a regular pharmacy (one they go to most often) in the county of interest (n = 210). More than 50% of women (n = 125/210) visited a pharmacy more than once per month. Sixty percent of women were currently using something to prevent pregnancy (n = 124/210, 60.8%). Thirty-five percent of women had a positive experience (n = 73/210, 34.8%). In the multiple logistic regression, women who visited a chain pharmacy had almost 65% lower odds of an overall positive experience with their regular pharmacy compared with women who visited a grocery or mass merchandise pharmacy (odds ratio 0.35 [95% CI 0.16], P = 0.75). CONCLUSION: Young women visit community pharmacies and use contraceptives frequently. Interventions need to be developed and implemented to improve young women's perceptions and experiences with contraception at community pharmacies. PMID- 26003157 TI - Access to patients' health records for drug therapy problem determination by pharmacists. AB - OBJECTIVES: To evaluate differences in the number and type of drug therapy problems (DTPs) identified by pharmacists with and without access to patients' primary care health records; determine the confidence level of pharmacists in their assessment of DTPs with and without access to health records; and determine the type of information pharmacists need to confirm their assessment. METHODS: The study design was an exploratory and comparative evaluation of comprehensive medication management assessments. Pharmacists initially completed patient assessments without access to the patient's primary care health record. Pharmacists documented the visit according to the standard of care and documented the assessment in a standardized study form. Pharmacists then reviewed the patient's primary care health record and documented a revised assessment in the standardized study form. The standardized form included sections about the number of DTPs, the classification of DTPs, the pharmacist's confidence level in identifying DTPs, and the information needed to increase the pharmacist's confidence level in identifying DTPs. RESULTS: Pharmacists evaluated 24 patients and identified 132 DTPs. After reviewing patients' primary care health records, 31 DTPs were deemed "false DTPs," 3 DTPs were recategorized, and 9 new DTPs were identified. Practitioner confidence levels in DTP determination improved after reviewing patients' primary care health records. The health information most frequently identified as desirable after the initial review was laboratory tests. CONCLUSION: Pharmacists identified more DTPs with lower confidence levels without access to patients' primary care health records. Fewer DTPs were deemed "confirmed DTPs" and confidence in the practitioners' assessments improved after review of the primary care health records. Access to primary care health records can help community pharmacists build an efficient and comprehensive medication management practice. PMID- 26003158 TI - Project DIS-IMPACT: Drug information in English and Spanish to improve patient preparation before colonoscopy. AB - OBJECTIVE: To create culturally appropriate colonoscopy education services and handouts for the Hispanic population undergoing a colonoscopy procedure to ensure correct bowel preparation. SETTING: Project DIS-IMPACT was conducted at a federally qualified, nonprofit community health center along the United States Mexico border. PRACTICE DESCRIPTION: Patients identified in the study included those who were at least 50 years of age and had not received a colonoscopy between July 1, 2012, and February 28, 2013. Participants included uninsured Hispanics, able to speak English or Spanish, registered with the clinic, and referred by a provider working at the health center. PRACTICE INNOVATION: The process of evaluating and developing colonoscopy screening education included creating a standing order, developing medication education handouts in both English and Spanish, and documenting areas of improvement at monthly pharmacy staff meetings. MAIN OUTCOME MEASURES: Outcomes of the program included a descriptive statistics analysis of the served population and culturally appropriate counseling recommendations used in the medication (polyethylene glycol electrolyte solution) education handouts. RESULTS: A total of 143 participants received colonoscopy, including 49 men and 94 women. As the classes were conducted, the patient information handouts were adapted accordingly based on culturally appropriate recommendations from participants and providers. CONCLUSION: Pharmacists played a unique role in providing culturally appropriate precolonoscopy education material to assist in successful colonoscopy preparation. PMID- 26003159 TI - Evaluation of a pharmacist-performed tuberculosis testing initiative in New Mexico. AB - OBJECTIVE: To report experiences of the New Mexico pharmacist tuberculosis (TB) testing program. SETTING: Community pharmacies in New Mexico interested in participating in the TB testing initiative from March 2011 to August 2013. PRACTICE INNOVATION: To expand accessibility of TB testing, New Mexico pharmacists were granted the authority to prescribe, administer, and read tuberculin skin tests (TSTs) in March 2011. To receive this special prescriptive authority, pharmacists had to complete a New Mexico Department of Health training program in accordance with the Centers for Disease Control and Prevention guidelines. EVALUATION: Data were collected on the number of TSTs performed and the TST reading follow-up rate. Patient data collected were demographic information, reason for obtaining a TST (e.g., immigration, school, or work), TB risk factors, and TST results. RESULTS: In New Mexico, 43 pharmacists were certified for TB testing during the evaluation period, 25 of whom were actively prescribing and performing TB testing at eight community pharmacies. There were 606 tests administered to 578 patients; 70.9% women, median age 31 years (4-93 years). Employment and school were the main reasons for obtaining a TB test. A total of 578 of 623 (92.8%) patients followed up to have their TSTs read. A total of 18 positive tests (3.1% positivity rate) were identified and appropriate referrals were made. CONCLUSION: New Mexico expanded the scope of practice for pharmacists. Pharmacist-performed TB testing had a valuable public health benefit. TB testing follow-up rates at community pharmacies in New Mexico were high, most likely due to convenient hours, accessible locations, and no required appointments. PMID- 26003160 TI - Incidence and cost of medications dispensed despite electronic medical record discontinuation. AB - OBJECTIVE: To determine the incidence and cost of medications dispensed despite discontinuation (MDDD) of the medications in the electronic medical record within an integrated health care organization. SETTING: Dean Health System, with medical clinics and pharmacies linked by an electronic medical record, and a shared health plan and pharmacy benefits management company. PRACTICE DESCRIPTION: Pharmacist-led quality improvement project using retrospective chart review. PRACTICE INNOVATION: Electronic medical records, pharmacy records, and prescription claims data from patients 18 years of age or older who had a prescription filled for a chronic condition from June 2012 to August 2013 and submitted a claim through the Dean Health Plan were aggregated and cross referenced to identify MDDD. MAIN OUTCOME MEASURES: Descriptive statistics were used to characterize demographics and MDDD incidence. Fisher's exact test and independent samples t tests were used to compare MDDD and non-MDDD groups. Wholesale acquisition cost was applied to each MDDD event. RESULTS: 7,406 patients met inclusion criteria. For 223 (3%) patients with MDDD, 253 independent events were identified. In terms of frequency per category, antihypertensive agents topped the list, followed, in descending order, by anticonvulsants, antilipemics, antidiabetics, and anticoagulants. Nine medications accounted for 59% (150 of 253) of all MDDD events; these included (again in descending order): gabapentin, atorvastatin, simvastatin, hydrochlorothiazide, lisinopril, warfarin, furosemide, metformin, and metoprolol. Mail-service pharmacies accounted for the highest incidence (5.3%) of MDDD, followed by mass merchandisers (4.6%) and small chains (3.9%). The total cost attributable to MDDD was $9,397.74. CONCLUSION: Development of a technology-based intervention to decrease the incidence of MDDD may be warranted to improve patient safety and decrease health care costs. PMID- 26003161 TI - Rhabdomyolysis precipitated by possible interaction of ticagrelor with high-dose atorvastatin. AB - OBJECTIVE: To report a case of rhabdomyolysis possibly caused by interaction of ticagrelor with high-dose atorvastatin. SUMMARY: A 62-year-old woman originally from India underwent uncomplicated percutaneous coronary intervention following ST-elevation myocardial infarction. The patient was discharged on a secondary prevention drug regimen that included ticagrelor 90 mg twice daily, atorvastatin 80 mg once daily, metoprolol 25 mg twice daily, and aspirin 81 mg daily. Two months later, the patient was readmitted with complaints of muscle pain, nausea, vomiting, and poor oral intake. The patient was diagnosed with rhabdomyolysis based on her symptoms combined with elevated creatine kinase, urine myoglobin, and serum creatinine. Intravenous fluids were initiated and atorvastatin held. Throughout the second hospital stay, serial laboratory values revealed a decrease in creatine kinase and resolution of acute kidney injury and muscle pain. The patient was discharged on aspirin and clopidogrel. Low-dose statin therapy was started at a follow-up appointment with close monitoring without recurrence of rhabdomyolysis. RESULTS: A drug interaction between the cytochrome P450 3A4 inhibitor ticagrelor and substrate atorvastatin 80 mg may have precipitated development of rhabdomyolysis in this patient. The probability of this drug interaction is rated as "possible" on both the Naranjo Adverse Drug Reaction Probability Scale and the Drug Interaction Probability Scale. CONCLUSION: Rhabdomyolysis was observed possibly because of a drug interaction between once daily ticagrelor and atorvastatin 80 mg. Clinicians need to be aware of this possible drug interaction via CYP3A4 and potential complications. PMID- 26003162 TI - Something important is missing in the ACC/AHA cholesterol treatment guidelines. AB - OBJECTIVE: To discuss factors surrounding development of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines and reasons they have not yet been adopted by clinicians. SUMMARY: The new ACC/AHA cholesterol guidelines were released in November 2013. The guidelines are based on randomized controlled trial evidence and, if fully implemented, are likely to result in a reduction of atherosclerotic cardiovascular disease (ASCVD) in Americans. Despite this, the guidelines have not been adopted by clinicians. This is because the guidelines are missing something very important-guidance for the clinician and the public. Guidelines are supposed to give guidance to clinicians on how to manage the various clinical presentations encountered in daily practice and to help them translate science into practice. Guidelines are also supposed to help the public define dyslipidemias in a way they can understand and thus seek treatment and actively follow the progress of their treatment. CONCLUSION: The National Lipid Association (NLA) stepped in to help fill the void in the ACC/AHA cholesterol guidelines and offered recommendations for treating individual patients who have increased risk of ASCVD. The NLA recommendations give clinicians the expert guidance and LDL-C goal rudder they need to successfully manage their patient's cholesterol. PMID- 26003163 TI - Meningococcal disease: A brief primer. PMID- 26003164 TI - Caring for the boomers. PMID- 26003165 TI - MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression. AB - The transcription factor MYC is a proto-oncogene regulating cell proliferation, cell cycle, apoptosis and metabolism. The recent identification of MYC-regulated long noncoding RNAs (lncRNAs) expands our knowledge of the role of lncRNAs in MYC functions. Here, we identify MYC-repressed lncRNAs named MYCLo-4, -5 and -6 by comparing 3 categories of lncRNAs (downregulated in highly MYC-expressing colorectal cancer, up-regulated by MYC knockdown in HCT116, upregulated by MYC knockdown in RKO). The MYC-repressed MYCLos are implicated in MYC-modulated cell proliferation through cell cycle regulation. By screening cell cycle-related genes regulated by MYC and the MYC-repressed MYCLos, we identified the MYC repressed gene GADD45A as a target gene of the MYC-repressed MYCLos such as MYCLo 4 and MYCLo-6. PMID- 26003167 TI - Challenges for Fish Foodborne Parasitic Zoonotic Diseases. PMID- 26003166 TI - The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide and its advanced status is frequently resistant to conventional chemotherapeutic agents and radiation. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperactivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia. We analyzed the drug activity in both normoxia and hypoxia conditions, the latter playing often a relevant role in the induction of chemoresistance and angiogenesis.In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle, induced apoptosis and autophagy at low concentrations. Interestingly the drug inactivated p-Akt and p-S6 at < 10 nM concentration.In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration as documented by MTT assays and Western blot analysis. Moreover, the drug showed in hypoxia inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1alpha and of VEGF.Our results indicate that NVP BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therapy. PMID- 26003168 TI - Systemic attenuation of the TGF-beta pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. AB - Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor beta (TGF-beta) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-beta signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-beta1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of beta2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-beta1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-beta1 signaling normalized B2M to young levels in both studied tissues. PMID- 26003169 TI - Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial. AB - BACKGROUND: Chromosomal instability (CIN) has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer we have previously demonstrated that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on tumour fitness and growth. The aim of this current study was to validate this finding using previously defined CIN thresholds in a much larger prospective cohort from a randomised, controlled, clinical trial. PATIENTS AND METHODS: As a surrogate measurement of CIN, dual centromeric fluorescence in situ hybridisation was performed for both chromosomes 2 and 15 on 1173 tumours from the breast cancer TACT trial (CRUK01/001). Each tumour was scored manually and the mean percentage of cells deviating from the modal centromere number was used to define four CIN groups (MCD1-4), where tumours in the MCD4 group were defined as having extreme CIN. RESULTS: In a multivariate analysis of disease-free survival, with a median follow-up of 91 months, increasing CIN was associated with improved outcome in patients with ER-negative cancer (P trend = 0.03). A similar pattern was seen in ER-negative/HER2-negative cancers (Ptrend = 0.007). CONCLUSIONS: This prospective validation cohort study further substantiated the association between extreme CIN and improved outcome in ER-negative breast cancers. Identifying such patients with extreme CIN may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification in this aggressive breast cancer subtype. PMID- 26003170 TI - Cocaine-induced delayed recurrent vasculitis: a 4-year follow-up. AB - BACKGROUND: Cocaine is a highly abused substance in United States with almost 70 % of cocaine adulterated with levamisole. It is known to cause vasculitis involving multiple organs due to its direct toxic effect and by the contribution of levamisole or a combined effect of both. CASE REPORT: A 51-year-old woman complained of painful erythematous rash in her hands and lower extremities that started few hours after smoking cocaine and progressed to blistering dark lesions in her lower extremities. She denied any other systemic complaints. Although she has been smoking cocaine for more than 35 years, these skin eruptions started only 4 years ago. Examination revealed tender retiform purpura in the hand and tender retiform purpura with hemorrhagic bulla in the legs. Initially, she had only a significantly positive atypical p-ANCA and later developed combined positivity of both Myeloperoxidase (MPO) and Anti-proteinase-3(PR3) antibodies with a p-ANCA pattern on immunofluorescence. We report a unique case of cocaine (likely contaminated with levamisole)-induced delayed recurrent vasculitis with varying vasculitic antibodies over the years. CONCLUSIONS: This case highlights the fact that patients can develop cocaine-related vasculitis after many years of uneventful abuse. Cocaine, with its adulterant levamisole, has the propensity to trigger diverse immunological reactions, which is evident by the varying antibody profile seen in the same patient over time. PMID- 26003171 TI - The Role of CD36 in the Effect of Arginine in Atherosclerotic Rats. AB - BACKGROUND: The aim of this study was to investigate the effects of arginine in the development of atherosclerosis in rats fed a high-fat diet supplemented with arginine and to evaluate the role of CD36 in this process. MATERIAL AND METHODS: A total of 40 Sprague-Dawley rats were randomly assigned to 4 groups: control group, fat diet group, simvastatin group, and arginine group. They were fed for 12 weeks and were then sacrificed. Immunohistochemical CD36 expression and pathology was investigated in the aorta; CD36 expression in mononuclear cells was detected by Western blot and RT-PCR. RESULTS: The thickness of the aortal intima, media, and I/M significantly decreased in the arginine group rats compared with those in the fat diet group (P<0.05). CD36 expression was up-regulated in rats in the fat diet group compared with the control group and was down-regulated in rats in the arginine group compared with rats in the fat diet group. CONCLUSIONS: The addition of arginine has a significant effect on reducing rat atherosclerosis development, which may be attributed to both the down-regulation of CD36 expression in rat aortic endothelial and blood mononuclear cells and the NO pathway. PMID- 26003172 TI - Are Flow Diverting Stents a Treatment Option in Acutely Ruptured Complex A1-A2 Junction Aneurysms? PMID- 26003173 TI - Overexpression of Enterococcus faecalis elr operon protects from phagocytosis. AB - BACKGROUND: Mechanisms underlying the transition from commensalism to virulence in Enterococcus faecalis are not fully understood. We previously identified the enterococcal leucine-rich protein A (ElrA) as a virulence factor of E. faecalis. The elrA gene is part of an operon that comprises four other ORFs encoding putative surface proteins of unknown function. RESULTS: In this work, we compared the susceptibility to phagocytosis of three E. faecalis strains, including a wild type (WT), a DeltaelrA strain, and a strain overexpressing the whole elr operon in order to understand the role of this operon in E. faecalis virulence. While both WT and DeltaelrA strains were efficiently phagocytized by RAW 264.7 mouse macrophages, the elr operon-overexpressing strain showed a decreased capability to be internalized by the phagocytic cells. Consistently, the strain overexpressing elr operon was less adherent to macrophages than the WT strain, suggesting that overexpression of the elr operon could confer E. faecalis with additional anti-adhesion properties. In addition, increased virulence of the elr operon-overexpressing strain was shown in a mouse peritonitis model. CONCLUSIONS: Altogether, our results indicate that overexpression of the elr operon facilitates the E. faecalis escape from host immune defenses. PMID- 26003174 TI - Increased plasma BMP-2 levels are associated with atherosclerosis burden and coronary calcification in type 2 diabetic patients. AB - BACKGROUND: Although Bone morphogenetic protein-2 (BMP-2) is a known mediator of bone regeneration and vascular calcification, to date no study has investigated the relationship between BMP-2 and type 2 diabetes mellitus (T2DM) and its possible role in coronary artery disease (CAD). The purpose of this study is to evaluate the relationship of BMP-2 with atherosclerosis and calcification in patients with T2DM. METHODS: 124 subjects were enrolled in this study: 29 patients with T2DM and CAD; 26 patients with T2DM and without CAD; 36 patients with CAD and without T2DMand 34 without T2DM or CAD (control group). Severity of coronary lesions was assessed using coronary angiography and intravascular ultrasound (IVUS). Plasma BMP-2 levels were quantified using a commercially available ELISA kit. RESULTS: Compared to the control group, the mean plasma BMP 2 level was significantly higher in T2DM patients with or without CAD (20.1 +/- 1.7 or 19.3 +/- 1.5 pg/ml, vs 17.2 +/- 3.3 pg/ml, P < 0.001). In a multivariable linear regression analysis, both T2DM and CAD were significantly and positively associated with BMP-2 (Estimate, 0.249; standard error (SE), 0.063; p <0.0001; Estimate, 0.400; SE, 0.06; p < 0.0001). Plasma BMP-2 was also strongly correlated with glycosylated hemoglobin A1c (HbA1c) (Spearman rho = -0.31; p = 0.0005). SYNTAX score was also significantly associated with BMP-2 (Spearman rho = 0.46; p = 0.0002). Using the results from IVUS, plasma BMP-2 levels were shown to positively correlate with plaque burden (Spearman rho = 0.38, P = 0.002) and plaque calcification (Spearman rho =0.44, P = 0.0003) and to negatively correlate with lumen volume (Spearman rho =0.31, P = 0.01). CONCLUSIONS: Our study demonstrates that patients with T2DM had higher circulating levels of BMP-2 than normal controls. Plasma BMP-2 levels correlated positively with plaque burden and calcification in patients with T2DM. PMID- 26003175 TI - Evaluation of afoxolaner chewables to control flea populations in naturally infested dogs in private residences in Tampa FL, USA. AB - BACKGROUND: A study was conducted to evaluate the effectiveness of afoxolaner chewables to control flea populations in naturally infested dogs in private residences in Tampa FL, USA. Evaluations of on-animal and premises flea burdens, flea sex structure and fed-unfed premises flea populations were conducted to more accurately assess flea population dynamics in households. METHODS: Thirty seven naturally flea infested dogs in 23 homes in Tampa, FL were enrolled in the study and treated with afoxolaner chewables. Chewables (NexGard(r) Chewables; Merial) were administered according to label directions by study investigators on study day 0 and once again between study days 28 and 30. Flea infestations on pets were assessed using visual area thumb counts and premises flea infestations were assessed using intermittent-light flea traps on days 0, 7, 14, 21, and once between study days 28-30, 40-45, and 54-60. RESULTS: Within 7 days of administration of afoxolaner chewable tablets, flea counts on dogs were reduced by 99.3%. By one month post-treatment, total flea counts on dogs were reduced by 99.9%, with 97.3% (36/37) of the dogs being flea free. Following the second dosing on study day 28-30, total on-dog flea burden was reduced by 100% on days 40-45 and 54-60. On day 0, the traps collected a geometric mean of 18.2 fleas. Subsequent reductions in emerging flea populations were 97.7 and 100% by days 28 30 and 54-60, respectively. There were 515 total fleas (Ctenocephalides felis felis) collected in the intermittent light flea traps on day 0, and 40.4% of those fleas displayed visual evidence of having fed. Seven days after initial treatment, only 13.1% of the fleas contained blood and by day 14 only 4.9% of the fleas collected in traps displayed evidence of having fed. On day 0, prior to treatment, 60% of the unfed fleas collected in intermittent-light flea traps were females, but by days 28-30, unfed males accounted for 78% of the population. CONCLUSIONS: This in-home investigation conducted during the summer of 2014 in subtropical Tampa, FL demonstrated that afoxolaner chewables rapidly and effectively eliminated flea populations in infested dogs and homes. PMID- 26003176 TI - Reduction of Phytate in Soy Drink by Fermentation with Lactobacillus casei Expressing Phytases From Bifidobacteria. AB - Plant-based food products can be modified by fermentation to improve flavour and the concentration of some biologically active compounds, but also to increase the mineral availability by eliminating anti-nutrient substances such as phytates. The objective of this study was to develop a fermented soybean drink with improved nutritional quality and source of probiotic bacteria by including as starter for fermentation Lactobacillus casei strains modified to produce phytase enzymes from bifidobacteria. The L. casei strains showed a good adaptation to develop in the soy drink but they needed the addition of external carbohydrates to give rise to an efficient acidification. The strain expressing the Bifidobacterium pseudocatenulatum phytase was able to degrade more than 90 % phytate during product fermentation, whereas expression of Bifidobacterium longum spp. infantis phytase only led to 65 % hydrolysis. In both cases, accumulation of myo-inositol triphosphates was observed. In addition, the hydrolysis of phytate in soy drink fermented with the L. casei strain expressing the B. pseudocatenulatum phytase resulted in phytate/mineral ratios for Fe (0.35) and Zn (2.4), which were below the critical values for reduced mineral bioavailability in humans. This investigation showed the ability of modified L. casei to produce enzymes with technological relevance in the design of new functional foods. PMID- 26003177 TI - Expression and localization of the diacylglycerol kinase family and of phosphoinositide signaling molecules in adrenal gland. AB - Adrenal glands play a central role in the secretion of steroid hormones and catecholamines. Previous studies have revealed that molecules engaged in phosphoinositide (PI) turnover are expressed in the adrenal gland, suggesting the importance of PI signaling in adrenal signal transduction. Diacylglycerol kinase (DGK) catalyzes the phosphorylation of diacylglycerol (DG), a major second messenger in the PI signaling cascade. The DGK family is expressed in distinct patterns in endocrine organs at the mRNA and protein levels. Nevertheless, little is known about the characteristics and morphological aspects of DGKs in the adrenal gland. We have performed immunohistochemical analyses to investigate the expression and localization of DGK isozymes, together with PI signaling molecules, in the adrenal gland at the protein level. Our results show that the DGK family and a set of PI signaling molecules are expressed intensely in zona glomerulosa cells and medullary chromaffin cells in the adrenal gland. In adrenal cells, DGKgamma localizes to the Golgi complex, DGKepsilon to the plasma membrane, and DGKzeta to the nucleus. These findings show the distinct expression and subcellular localization of DGK isozymes and PI signaling molecules in the adrenal gland, suggesting that each DGK isozyme has a role in signal transduction in adrenal cells, especially in the zona glomerulosa and medulla. PMID- 26003178 TI - Lack of galectin-3 up-regulates IgA expression by peritoneal B1 lymphocytes during B cell differentiation. AB - Galectin-3 is a beta-galactoside-binding protein with an inhibitory role in B cell differentiation into plasma cells in distinct lymphoid tissues. We use a model of chronic schistosomiasis, a well-characterized experimental disease hallmarked by polyclonal B cell activation, in order to investigate the role of galectin-3 in controlling IgA production through peritoneal B1 cells. Chronically infected, galectin-3-deficient mice (Lgals3(-/-)) display peritoneal fluid hypercellularity, increased numbers of atypical peritoneal IgM(+)/IgA(+) B1a and B1b lymphocytes and histological disturbances in plasma cell niches when compared with Lgals3(+/+) mice. Similar to our infection model, peritoneal B1 cells from uninfected Lgals3(-/-) mice show enhanced switching to IgA after in vitro treatment with interleukin-5 plus transforming growth factor-beta (IL-5 + TGF beta1). A higher number of IgA(+) B1a lymphocytes was found in the peritoneal cavity of Lgals3(-/-)-uninfected mice at 1 week after i.p. injection of IL-5 + TGF-beta1; this correlates with the increased levels of secreted IgA detected in the peritoneal fluid of these mice after cytokine treatment. Interestingly, a higher number of degranulated mast cells is present in the peritoneal cavity of uninfected and Schistosoma mansoni-infected Lgals3(-/-) mice, indicating that, at least in part, mast cells account for the enhanced differentiation of B1 into IgA producing B cells found in the absence of galectin-3. Thus, a novel role is revealed for galectin-3 in controlling the expression of surface IgA by peritoneal B1 lymphocytes; this might have important implications for manipulating the mucosal immune response. PMID- 26003179 TI - Comparison of I-123 MIBG planar imaging and SPECT for the detection of decreased heart uptake in Parkinson disease. AB - Decreased myocardial uptake of I-123 metaiodobenzylguanidine (MIBG) is an important finding for diagnosis of Parkinson's disease (PD). This study compared I-123 MIBG SPECT and planar imaging with regard to their diagnostic yield for PD. 52 clinically diagnosed PD patients who also had decreased striatal uptake on FP CIT PET/CT were enrolled. 16 normal controls were also included. All underwent cardiac MIBG planar scintigraphy and SPECT separately. Myocardial I-123 MIBG uptake was interpreted on planar and SPECT/CT images separately by visual and quantitative analysis. The final diagnosis was made by consensus between two readers. Kappa analyses were performed to determine inter-observer agreement for both methods. Sensitivity, specificity, and accuracy were compared with McNemar's test. The sensitivity, specificity, and accuracy were 84.6, 100, and 88.2% for planar images and 96.2, 100 and 97.1% for SPECT, respectively, with a significant difference between the two imaging methods (p < 0.031). All inter-observer agreements were almost perfect (planar scintigraphy: kappa = 0.82; SPECT: kappa = 0.93). Heart-to-mediastinum ratios from PD patients with negative planar and positive SPECT scans (group A) and patients with positive planar and positive SPECT scans (group B) were 1.69 +/- 0.16 (1.59-1.85) and 1.41 +/- 0.15 (1.20 1.53), respectively, and showed significant difference (p = 0.023). Lung-to mediastinum ratios for groups A and B were 2.16 +/- 0.20 (1.96-2.37) and 1.6 +/- 0.19 (1.3-1.78), respectively, and were significantly higher in the former (p = 0.001). I-123 MIBG SPECT has a significantly higher diagnostic performance for PD than planar images. Increased lung uptake may cause false-negative results on planar imaging. PMID- 26003180 TI - Contrasting Patterns of Diterpene Acid Induction by Red Pine and White Spruce to Simulated Bark Beetle Attack, and Interspecific Differences in Sensitivity Among Fungal Associates. AB - Conifers possess a suite of physiochemical defenses that protect their subcortical tissues from bark beetle - fungal complexes. These defenses include rapid induction of terpenoids and phenolics at the site of attack. Studies of the distribution, induction, and bioactivity of conifer terpenoids have focused heavily on monoterpenes. We assessed induction of diterpene acids in white spruce (Picea glauca) and red pine (Pinus resinosa) to fungal associates of two bark beetles, and the responses of four spruce beetle (Dendroctonus rufipennis) associated fungi to three diterpene acids. Constitutive phloem contents differed between species, in that red pine had extremely low concentrations of diterpene acids, whereas white spruce had substantial constitutive levels. Induction differed quantitatively. Both red pine and white spruce exhibited marked increases, but red pine underwent greater increases and achieved higher concentrations than white spruce. Induction also differed qualitatively in that red pine showed lower diversity and fewer compositional changes during induction than white spruce. In red pine,fungal inoculation accompanying wounding elicited greater increases than wounding alone, but in white spruce total concentrations were higher following wounding alone. Spruce beetle fungal symbiont growth varied among species and compounds. Some diterpenes elicited both stimulatory and inhibitory effects on fungi, depending on concentration. All four fungi exhibited higher tolerances compared to those associated with pine bark beetles in previous studies. Variation in tolerances to, and potentially metabolism of, diterpene acids by symbionts may reflect differences in constitutive levels between spruce and pine, and partially explain differences in concentrations achieved during induction. PMID- 26003181 TI - Comment to: Posterior component separation with transversus abdominis release successfully addresses recurrent ventral hernias following anterior component separation. Pauli EM et al. Hernia 2015; 19: 285-291. PMID- 26003182 TI - Management of urogenital atrophy in breast cancer patients: a systematic review of available evidence from randomized trials. AB - Symptoms of urogenital atrophy are common in breast cancer survivors. Its optimal management is currently unknown. A systematic review of randomized controlled trials (RCTs) evaluating treatments for urogenital atrophy in breast cancer patients was performed. EMBASE, Ovid Medline and the Cochrane Library were searched from 1946 to November 2014. Outcomes included improvements in both vaginal symptoms (e.g., dryness, pain, dyspareunia and itching) and vaginal hormone response measured by validated scales [e.g., Vaginal Health Index (VHI) and Vaginal Maturation Index (VMI)]. Of 430 unique citations identified, 4 studies (n = 196) met inclusion criteria. Interventions included pH-balanced gel, Replens((r)), lidocaine, Estring((r)) and Vagifem((r)). Sample sizes ranged from 7 to 98 patients. Given the heterogeneity of the studies, a narrative synthesis of results was performed. One study of 98 patients suggested that vaginal pH balanced gel (mean VHI 5.00 +/- 0.816, mean VMI 51.18 +/- 3.753) was more efficient than placebo (VHI 16.98 +/- 3.875, p < 0.001, VMI 47.87 +/- 2.728, p < 0.001) at 12 weeks in providing vaginal symptom relief. In patients who used lidocaine, 90 % had reduced dyspareunia compared to saline in a study of 46 patients. Although increased serum estradiol occurred, both Estring((r)) and Vagifem((r)) were shown to improve quality of life and VMI in a study of seven patients. Treatment of urogenital atrophy remains a challenging issue and there is a paucity of RCT evidence addressing this knowledge gap. It is evident that more prospective trials are needed. PMID- 26003183 TI - A new way to visualize DNA's base succession: the Caenorhabditis elegans chromosome landscapes. AB - In the eukaryotic genomes, the genetic diseases are generally associated with the tandem repeats. These repeats seem to appear frequently. In this paper, we are describing a wavelet transform technique which provides a new way to represent the DNA succession bases as a DNA progression images. These images offer DNA landscapes, visualizing and following up periodicities through genomes. We investigated in a structural coding technique the Pnuc. Then, we illustrated, with time-frequency representation, the existence and the superposition of the periodicities in some biological features, their locations and the different ways in which they appear. The representations generated showed that one periodicity can sometimes be alone, but generally, it is incorporated to others. These periodicities associations create, in the Caenorhabditis elegans chromosome, a precise structural image of biological features, such as CeRep, Helitrons, repeats and satellites. PMID- 26003184 TI - Assessment of nitrate leakage and N2O emission from five environmental-friendly agricultural practices using fuzzy logic method and empirical formula. AB - Agricultural nonpoint source pollution in China has been the major environmental problem, so environmental-friendly agricultural practices (EAPs) must be promoted to improve environmental quality. However, the most suitable practices for each agricultural region must first be identified. Thus, in the presented study a fuzzy-logic method and a revised empirical formula were used to assess nitrate leakage and N2O emissions, respectively, and to compare five EAPs in Xinxiang, a major grain-producing county in Henan Province, China. The required information was collected in face-to-face interviews with 10 extension service experts from the county, using a questionnaire to explore their opinions of the EAPs currently adopted by smallholder farmers, as well as the amounts, frequencies, varieties and proportions of nitrogen fertilizers applied annually. The results indicate that reduced tillage, soil testing and fertilizer recommendations would be the most appropriate practices to initially promote on a large scale in Xinxiang. PMID- 26003185 TI - The development of allergic inflammation in a murine house dust mite asthma model is suppressed by synbiotic mixtures of non-digestible oligosaccharides and Bifidobacterium breve M-16V. AB - PURPOSE: The incidence and severity of allergic asthma is rising, and novel strategies to prevent or treat this disease are needed. This study investigated the effects of different mixtures of non-digestible oligosaccharides combined with Bifidobacterium breve M-16V (BB) on the development of allergic airway inflammation in an animal model for house dust mite (HDM)-induced allergic asthma. METHODS: BALB/c mice were sensitized intranasally (i.n.) with HDM and subsequently challenged (i.n.) with PBS or HDM while being fed diets containing different oligosaccharide mixtures in combination with BB or an isocaloric identical control diet. Bronchoalveolar lavage fluid (BALF) inflammatory cell influx, chemokine and cytokine concentrations in lung homogenates and supernatants of ex vivo HDM-restimulated lung cells were analyzed. RESULTS: The HDM-induced influx of eosinophils and lymphocytes was reduced by the diet containing the short-chain and long-chain fructo-oligosaccharides and BB (FFBB). In addition to the HDM-induced cell influx, concentrations of IL-33, CCL17, CCL22, IL-6, IL-13 and IL-5 were increased in supernatants of lung homogenates or BALF and IL-4, IFN-gamma and IL-10 were increased in restimulated lung cell suspensions of HDM-allergic mice. The diet containing FFBB reduced IL-6, IFN gamma, IL-4 and IL-10 concentrations, whereas the combination of galacto oligosaccharides and long-chain fructo-oligosaccharides with BB was less potent in this model. CONCLUSION: These findings show that synbiotic dietary supplementation can affect respiratory allergic inflammation induced by HDM. The combination of FFBB was most effective in the prevention of HDM-induced airway inflammation in mice. PMID- 26003187 TI - Assessment of Sediment Risk in the North End of Tai Lake, China: Integrating Chemical Analysis and Chronic Toxicity Testing with Chironomus dilutus. AB - Whole life-cycle bioassays with Chironomus dilutus were performed to evaluate sediment toxicity in Tai Lake, a typical freshwater lake in China. Meanwhile, contaminants of concern were analyzed in sediment. The sediments in Tai Lake showed no acute mortality in 10-day testing to C. dilutus. After chronic exposure to the sediments, however, adverse effects-including decreased survival and sublethal impairments of growth, emergence, and fecundity-were observed at most sites in Tai Lake. A variety of contaminants were detected in sediment with the total concentrations in the range of 504-889 ng/g dry weight (dw) for polycyclic aromatic hydrocarbons, 0.56-1.81 ng/g dw for polychlorinated biphenyls, 38.6-87.8 ng/g dw for polybrominated diphenyl ethers, 8.34-14.2 ng/g dw for organochlorine pesticides, 1.27-2.95 ng/g dw for organophosphate pesticides, 0.11-0.21 ng/g dw for pyrethroid pesticides, and 332-609 ug/g dw for metals. Finally, a canonical correlation analysis was applied to link chronic sediment toxicity to the toxic units of individual contaminants. Results suggested that two pesticides (hexachlorocyclohexane and chlorpyrifos) and two metals (chromium and nickel) in sediments from Tai Lake were the potential contributors to the noted toxicity in C. dilutus in the life-cycle toxicity testing. In conclusion, acute bioassays with the benthos were not sensitive enough to assess sediment toxicity in freshwater lakes in China, and it is desirable to integrate chronic toxicity testing with chemical analysis to better understand sediment risk. PMID- 26003186 TI - Moderate alcohol consumption diminishes the development of non-alcoholic fatty liver disease (NAFLD) in ob/ob mice. AB - PURPOSE: Using ob/ob mice as a model of non-alcoholic fatty liver disease (NAFLD), we investigated the effect of moderate alcohol intake on the development of NAFLD and molecular mechanisms involved. METHODS: Ob/ob mice were fed water or ethanol solution (2.5 g/kg body weight/day) for 6 weeks, and markers of liver injury, insulin signalling and adiponectin in visceral adipose tissue were determined. RESULTS: Whereas bodyweight and the degree of liver steatosis did not differ among ob/ob mouse groups, those consuming ethanol had markedly less macrovesicular hepatic fat accumulation, inflammatory alterations and significantly lower transaminase levels. Despite similarly elevated protein levels of tumour necrosis factor alpha, protein concentrations of plasminogen activator inhibitor 1 were significantly lower in livers of ob/ob mice consuming ethanol in comparison with controls. The hepato-protective property of moderate alcohol ingestion in ob/ob mice was associated with an induction of the sirtuin 1/adiponectin-signalling cascade in visceral fat tissue and an activation of Akt in the liver. Similar effects of moderate alcohol exposure were also found in vitro in 3T3-L1 and AML-12 cells. CONCLUSION: These data suggest that moderate alcohol intake may diminish the development of NAFLD through sirtuin-1/ adiponectin-dependent signalling cascades. PMID- 26003188 TI - CTLA-4 affects expression of key cell cycle regulators of G0/G1 phase in neoplastic lymphocytes from patients with chronic lymphocytic leukaemia. AB - Previously, we showed that cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is overexpressed in chronic lymphocytic leukaemia (CLL) and its expression is correlated with the expression of the major regulators of G1 phase progression: cyclins D2 and D3, and cyclin-dependent kinase inhibitory protein 1 (p27 (KIP1) ). In the present study, we blocked CTLA-4 on the surface of both CLL cells and normal B lymphocytes to investigate the impact of CTLA-4 on the expression of the mentioned G1 phase regulators. We found that in CLL patients and in healthy individuals, the median proportions of cyclin D2-positive cells as well as cyclin D3(+) cells significantly decreased following CTLA-4 blockade. Moreover, CTLA-4 blockade led to an increase in the median frequencies of p27 (KIP1) -positive cells, although this increase was marked only in CLL patients. Our study showed that CTLA-4 affects the expression of the key regulators of G1 phase progression in CLL cells as well as in normal B lymphocytes and may contribute to a better understanding of the role of CTLA-4 in the regulation of G1 phase progression. PMID- 26003189 TI - Characterization of Individuals Taking Part in Low Dose Computed Tomography (LDCT) Screening Program. AB - In the past years the participation rate in conventional voluntary x-ray lung screening has been around 22 % in Somogy County in Hungary. Due to the high morbidity and mortality rates of lung cancer, low participation rate of the high risk individuals on the screening is a primary question in Hungary. To obtain an effectively high level of participation in our ongoing low dose CT screening program, we had to emphasize the benefits of participation for the targeted individuals. As a first step, our aim was to gather information on the aspects affecting the individuals' will for participation. We used the most accessible source of information: individuals over the age of 50, who attended the conventional voluntary lung screening, were approached to fill a questionnaire on their habits relating to smoking, health issues and their prior participation of lung screening. 1080 adults anonymously completed the questionnaire. Analyzing the results, beside other findings, we found a unique variable factor, which altered negatively the compliance for the screening: older individuals, who started participating in the screening in obligation to the health regulations, took part in the voluntary screening programs at a significantly lower rate. Our findings led us to better understanding the complexity of decision making affecting the individual's participation and attitudes toward health issues. TRIAL REGISTRATION: IG/03833/2012. PMID- 26003190 TI - Microchimeric Cells, Sex Chromosome Aneuploidies and Cancer. AB - The phenomenon of feta-maternal microchimerisms inspires numerous questions. Many questions remain to be answered regarding this new avenue of genetics. The X and Y chromosomes have been associated with malignancy in different types of human tumors. We aimed to investigate the numerical aberrations of chromosomes X and Y in lung cancer (LC) and bladder cancer (BC) and review recent evidence for possible roles of microchimeric cells (McCs) in these cancers. We carried out cytogenetic analysis of the tumor and blood sampling in 52 cases of people with BC and LC, and also with 30 healthy people. A total of 48 (92.3 %) of the patients revealed sex chromosome aneuploidies (SCAs). A total SCAs was found in 9.8 % of 2282 cells that were analyzed as one or more cells in each case. The 68 and 95 SCAs were found in the 1952 (8.4 %) cells in peripheral blood, and 41 and 19 SCAs in the 330 (18.2 %) cells in the tumoral tissues respectively. There was a significant difference in the frequencies of SCAs between the patients and the control groups determined by the Fischer's Exact Test (p < 0.0001). The frequencies of SCAs were higher in the tumoral tissues than in the blood (p < 0.0001). There was a significant difference in the frequencies of SCAs between the tumor and blood tissues, and this was higher in the tumor tissue (p < 0.0001). In general, 78.9 % (41) of the 52 patients with LC and BC had X and Y chromosome monosomies. Largely a Y chromosome loss was present in 77.8 % of the men, and the 47, XXY karyotype was found in 33.3 % of them. The second most common SCA was monosomy X, and was found in 71.4 % of the women. McCs were observed in 26.9 % of the 52 patients, and the frequencies of McCs were higher in the blood than in the tissues (p < 0.0001). XY cells were identified in the lung and bladder tissues of the women who had been pregnant with boys, but not in those who had not. There was a significant difference in the frequencies of McCs between the LC and BC patients (p < 0.0005). We speculate that the microchimerism could have a general beneficial role in cancer, in which some sites may not be evident because of an allogeneic maternal immune reaction that hastens cancer development. A further understanding of McCs may help in anticipating its implications in cancer. Our results may suggest that SCAs may be contributing factors in the development of LC and BC, and aneuploidies of X and Y chromosomes play a role in the pathogenesis of cancers. PMID- 26003191 TI - Genetic diversity and genome-wide association analysis of cooking time in dry bean (Phaseolus vulgaris L.). AB - KEY MESSAGE: Fivefold diversity for cooking time found in a panel of 206 Phaseolus vulgaris accessions. Fastest accession cooks nearly 20 min faster than average. SNPs associated with cooking time on Pv02, 03, and 06. Dry beans (Phaseolus vulgaris L.) are a nutrient dense food and a dietary staple in parts of Africa and Latin America. One of the major factors that limits greater utilization of beans is their long cooking times compared to other foods. Cooking time is an important trait with implications for gender equity, nutritional value of diets, and energy utilization. Very little is known about the genetic diversity and genomic regions involved in determining cooking time. The objective of this research was to assess cooking time on a panel of 206 P. vulgaris accessions, use genome- wide association analysis (GWAS) to identify genomic regions influencing this trait, and to test the ability to predict cooking time by raw seed characteristics. In this study 5.5-fold variation for cooking time was found and five bean accessions were identified which cook in less than 27 min across 2 years, where the average cooking time was 37 min. One accession, ADP0367 cooked nearly 20 min faster than average. Four of these five accessions showed close phylogenetic relationship based on a NJ tree developed with ~5000 SNP markers, suggesting a potentially similar underlying genetic mechanism. GWAS revealed regions on chromosomes Pv02, Pv03, and Pv06 associated with cooking time. Vis/NIR scanning of raw seed explained 68 % of the phenotypic variation for cooking time, suggesting with additional experimentation, it may be possible to use this spectroscopy method to non-destructively identify fast cooking lines as part of a breeding program. PMID- 26003192 TI - Mesenchymal stromal cells to halt the progression of type 1 diabetes? AB - No treatment to halt the progressive loss of insulin-producing beta-cells in type 1 diabetes mellitus has yet been clinically introduced. Strategies tested have at best only transiently preserved beta-cell function and in many cases with obvious side effects of drugs used. Several studies have suggested that mesenchymal stromal cells exert strong immunomodulatory properties with the capability to prevent or halt diabetes development in animal models of type 1 diabetes. A multitude of mechanisms has been forwarded to exert this effect. Recently, we translated this strategy into a first clinical phase I/IIa trial and observed no side effects, and preserved or even increased C-peptide responses to a mixed meal tolerance test during the first year after treatment. Future blinded, larger studies, with extended follow-up, are clearly of interest to investigate this treatment concept. PMID- 26003193 TI - 3.0T MR imaging of the ankle: Axial traction for morphological cartilage evaluation, quantitative T2 mapping and cartilage diffusion imaging-A preliminary study. AB - PURPOSE: To determine the impact of axial traction during high resolution 3.0T MR imaging of the ankle on morphological assessment of articular cartilage and quantitative cartilage imaging parameters. MATERIALS AND METHODS: MR images of n=25 asymptomatic ankles were acquired with and without axial traction (6kg). Coronal and sagittal T1-weighted (w) turbo spin echo (TSE) sequences with a driven equilibrium pulse and sagittal fat-saturated intermediate-w (IMfs) TSE sequences were acquired for morphological evaluation on a four-point scale (1=best, 4=worst). For quantitative assessment of cartilage degradation segmentation was performed on 2D multislice-multiecho (MSME) SE T2, steady-state free-precession (SSFP; n=8) T2 and SSFP diffusion-weighted imaging (DWI; n=8) images. Wilcoxon-tests and paired t-tests were used for statistical analysis. RESULTS: With axial traction, joint space width increased significantly and delineation of cartilage surfaces was rated superior (P<0.05). Cartilage surfaces were best visualized on coronal T1-w images (P<0.05). Differences for cartilage matrix evaluation were smaller. Subchondral bone evaluation, motion artifacts and image quality were not significantly different between the acquisition methods (P>0.05). T2 values were lower at the tibia than at the talus (P<0.001). Reproducibility was better for images with axial traction. CONCLUSION: Axial traction increased the joint space width, allowed for better visualization of cartilage surfaces and improved compartment discrimination and reproducibility of quantitative cartilage parameters. PMID- 26003194 TI - Hypertrophic cardiomyopathy: Cardiac structural and microvascular abnormalities as evaluated with multi-parametric MRI. AB - PURPOSE: To determine the relationship between myocardial structural and microvascular abnormality in hypertrophic cardiomyopathy (HCM) by multi parametric cardiac MRI. MATERIALS AND METHODS: Twenty-four HCM and eighteen controls were retrospectively included. Left ventricle mass (LVM), LV end systolic and end-diastolic volume (LVESV, LVEDV), LV ejection fraction (LVEF), and 16-segment wall thickness at ES and ED (SESWT, SEDWT) were assessed with a 2D cine-MRI. Myocardial perfusion (reflected by K(trans)), interstitial volume (Ve) and mean transmit time (MTT) were evaluated with a model-dependent dynamic contrast-enhanced MRI. Myocardial fibrosis was assessed with late gadolinium enhancement (LGE) imaging. RESULTS: K(trans) was significantly decreased in LGE present (0.74+/-0.15mL/g/min) against LGE-absent (0.55+/-0.14mL/g/min, p=0.030) and normal group (0.81+/-0.32mL/g/min, p<0.001), but was unchanged in LGE-absent against normal group (p>0.05). Ve and MTT were significantly increased in LGE present (Ve: 26.7+/-15.7%; MTT: 28.6+/-21.3s) against LGE-absent (37.6+/-18.3%; 49.8+/-30.5s) and normal group (19.7+/-6.9%; 15.1+/-3.9s; all p<0.001), and were significantly increased in LGE-absent against normal group (p<0.001). LGE significantly correlated to K(trans), Ve, MTT, and SESWT (rho=0.232, -0.247, 0.443, and -0.207, respectively). K(trans) negatively correlated to SEDWT and SESWT (rho=-0.224 and -0.231). Ve and MTT positively correlated to SEDWT (Ve: rho=0.223; MTT: rho=0.239) and SESWT (Ve: rho=0.248; MTT: rho=0.254). CONCLUSIONS: Consistent relationship was determined between myocardial structural abnormality and microvascular dysfunction in HCM. PMID- 26003195 TI - [Simulation training in pulmonary medicine: Rationale, review of the literature and perspectives]. AB - Training in pulmonary medicine requires the acquisition of a great deal of knowledge, but also technical know-how and interpersonal skills. The prevailing teaching pattern is mentorship. It implies a direct transmission of knowledge, but also entails some drawbacks such as disparity in learning opportunities, subjective evaluation of the trainee and potential risks for patients. There is growing interest in simulation training as a teaching technique, where students practice their skills in a secure environment, then analyse their performance in a debriefing session. It is complementary to other learning methods (abstraction, observation or mentorship) and forms part of an ethical approach: 'never practice on a real patient for the first time'. We have reviewed the literature related to simulation training in pulmonary medicine and in particular for physical examination, technical skills, pathologies, communication with patients and therapeutic education. In most of the studies, simulation training is a way of speeding up students' training - without necessarily yielding better results - and of respecting the procedures. We then present the French regulations and official guidelines regarding the use of this training method in the teaching of medicine. Finally, we shall consider some prospects of this approach for the community of pulmonologists. PMID- 26003196 TI - [National consensus regarding azithromycin use in cystic fibrosis]. AB - AIM: To propose a formalized consensus agreement regarding the prescription of azithromycin in cystic fibrosis (CF). MATERIAL AND METHODS: Application of the Delphi method in 5 thematic fields: indications, contra-indications, dosage, precautions for use and treatment follow-up. RESULTS: Thirty identified French CF centers participated in the process on 49 (61%), which comprised 3 rounds. Experts validated azithromycin as a long-term anti-inflammatory agent in children aged over 6 years, presenting with the classical form of CF, irrespective of the bacteriological status of the patient (except for non-tuberculous mycobacteria). Azithromycin administration should not be routine in the milder forms of the disease, and avoided in the presence of severe hepatic or renal involvement. In children whose weight is below 40 kg, a strong consensus recommended a single daily oral dose, administered three times weekly. However, in adults, the level of agreement was weaker. Minimal duration of treatment is 6 months, after which the drug should be discontinued if no observable effect is noted on clinical parameters, exacerbation rate and/or FEV1. Clinical monitoring of treatment tolerance is recommended (nausea, diarrhea, skin rash, tinnitus, deafness, arthropathy), without increasing the frequency of surveillance of sputum bacteria. However, it is essential to monitor sputum for fungi (expectoration, Aspergillus, broncho-pulmonary allergic aspergillosis). CONCLUSION: This consensus statement defines an area for the prescription of azithromycin in CF, with the aim of better harmonization of its use. PMID- 26003197 TI - [Pulmonary manifestations of Langerhans cell histiocytosis]. AB - Pulmonary Langerhans cell histiocytosis is a rare diffuse cystic interstitial pneumonia of unknown etiology that occurs selectively in young smokers of both genders. The multicenter studies conducted by the reference center have better defined the short and medium terms natural history of the disease and the clinical management of patients. A substantial proportion of patients experience a dramatic decline in their lung function soon after diagnosis. Importantly, smoking cessation is associated with a decreased risk of subsequent deterioration. Cladribine, a purine analogue, chemotherapy may dramatically improve lung function in patients with progressive pulmonary Langerhans cell histiocytosis, but this treatment should be used only in the setting of clinical research. Specific pulmonary hypertension therapies (anti-endothelin receptors, inhibitors of phosphodiesterases) may be used with caution in specialized centres for patients with severe pulmonary hypertension, and seem to be well tolerated. The recent identification of the V600E mutation of the BRAF oncogene in approximately half of the Langerhans cell histiocytosis lesions, including pulmonary granulomas, represents an important step forward in the understanding of the pathogenesis of Langerhans cell histiocytosis. Potentially it opens the way to targeted therapies. PMID- 26003198 TI - Changes in center of pressure displacement with the use of a foot drop stimulator in individuals with stroke. AB - BACKGROUND: Center of pressure measured during gait can provide information about underlying control mechanisms and the efficacy of a foot drop stimulator. This investigation evaluated changes in center of pressure displacement in individuals with stroke with and without a foot drop stimulator. METHODS: Individuals with stroke-related foot drop (n=11) using a foot drop stimulator and healthy controls (n=11). Walking speed and bilateral center of pressure variables: 1) net displacement; 2) position and maximum displacement; and 3) mean velocity during walking. FINDINGS: On the affected limb with the foot drop stimulator as compared to the affected limb without the foot drop stimulator: 1) increased anterior/posterior maximum center of pressure excursion 8% during stance; 2) center of pressure at initial contact was 6% more posterior; 3) medial/lateral mean, maximum and minimum center of pressure position during stance all significantly decreased; 4) anterior/posterior net displacement increased during stance and single support; and 5) anterior/posterior velocity of the center of pressure increased during stance. INTERPRETATION: Individuals with stroke using a foot drop stimulator contacted the ground more posterior at initial contact and utilized more of the anterior/posterior plantar surface of the foot on the affected limb during stance. With the foot drop stimulator there was a shift in center of pressure toward the medial side possibly indicating an improvement in equinovarus gait where there is a tendency to load the lateral foot throughout stance. For individuals with stroke a foot drop stimulator can improve displacement of the center of pressure which indicates improved forward progression and stability during walking. PMID- 26003199 TI - Interleukin-1beta, Interleukin1-Ra, Interleukin-10, and tumor necrosis factor alpha polymorphisms in Tunisian patients with rheumatoid arthritis. AB - OBJECTIVES: The aim of this study was to investigate the role of IL-1beta ( 511C>T), TNFalpha (-308 G>A), IL-10 (-1082 G>A) and IL-1RN VNTR polymorphisms in the susceptibility to rheumatoid arthritis (RA) in Tunisians. PATIENTS AND METHODS: Using PCR-based methods, 104 RA patients and 150 healthy controls were investigated. We compared allele and genotype frequencies in RA patients versus controls and analyzed their correlations with erosive form (EF). RESULTS: IL1-RN VNTR A1A3 genotype is associated with higher risk of RA (P=0.012, OR=4.31). Among the cases, males who carry this genotype were more exposed to RA (P=0.044, OR=8, 47). For IL1- beta gene, a significantly higher frequency of the -511C/C genotype was observed in RA patients in comparison to controls (P=0.013, OR=2.45). This higher frequency was especially observed in women (P=0,003, OR=3.42). In contrast, IL10-1082G/G genotype was less common in patients (P=0.046, OR=0.46). According to EF, men carrying IL1-RN VNTR A1A3 (P=0.005 OR=5.28) and IL1-beta 511C/C (P=0.015 OR=2.61) genotypes develop non EF of RA. Moreover, TNFalpha-308 A allele (P=0.024, OR=1.84) and A/A genotype (P=0.033, OR=3.1) were positively associated to EF of RA. However, G allele (P=0.024, OR=0.31) and GG genotype (P=0.31, OR=0.031) of the TNFalpha-308 were protectors. CONCLUSION: Our results indicated that IL-1RN VNTR, IL-1beta (-511C>T) and IL-10 (-1082 G>A) are associated with susceptibility to RA, and that IL-1RN VNTR, IL-1beta (-511C>T) and TNFalpha (-308 G>A) are associated with severity of RA. PMID- 26003200 TI - A cost analysis of a pancreatic cancer screening protocol in high-risk populations. AB - BACKGROUND: Pancreatic cancer is the 4th leading cause of cancer death in the United States. A screening protocol is needed to catch early-stage, resectable disease. This study suggests a protocol for high-risk individuals and assesses the cost in the context of the Affordable Care Act. METHODS: Medicare and national average pricing were used for cost analysis of a protocol using magnetic resonance imaging/MRCP biannually in high-risk groups. RESULTS: Costs per year of life added" based on Medicare and national average costs, respectively, are as follows: $638.62 and $2,542.37 for Peutz-Jeghers syndrome, $945.33 and $3,763.44 for hereditary pancreatitis, $1,141.77 and $4,545.45 for familial pancreatic cancer and "p16-Leiden" mutations, and $356.42 and $1,418.92 for new-onset diabetes over age 50 with weight loss or smoking. CONCLUSIONS: A screening program using magnetic resonance imaging/MRCP is affordable in high-risk populations. The United States Preventive Services Task Force must re-evaluate its pancreatic cancer screening guidelines to make screening more cost-effective for the individual. PMID- 26003201 TI - Enhanced recovery in emergency surgery: validity and generalizability of a randomized trial. PMID- 26003202 TI - Local pancreatic head resection: the search for optimal indications through quality of life assessments. AB - BACKGROUND: Local pancreatic head resection (LPHR) for chronic pancreatitis has had limited adoption in the United States perhaps because of sparse outcomes and quality of life data. METHODS: Forty-four patients underwent LPHR and retrospective evaluation of patient outcomes and quality of life assessment was performed. RESULTS: The mean age was 49 +/- 11 years (50% men) with chronic alcohol use as the etiology in 79% of patients. One patient (2%) died within 90 days. The intensive care unit stay was 1.8 +/- 3.1 days and postoperative length of stay was 12.6 +/- 9.4 days with 96% of patients discharged home. Ten (22%) patients had major perioperative complications. Biliary stricture was the most common late complication (14%). Quality of life assessment results showed that global status (47/100) and physical (66/100), cognitive (68/100), and social (52/100) functions were acceptable. Prevalent postoperative symptoms were pain (52/100), insomnia (56/100), and digestive disturbance (60/100). CONCLUSIONS: LPHR is safe and effective for a substantial proportion of patients with chronic pancreatitis. Further refinement in the selection of patients most likely to benefit from this operation is warranted. PMID- 26003203 TI - Does lymph node ratio affect prognosis in gastroesophageal cancer? AB - BACKGROUND: Increasing evidence suggests that the ratio of number of nodes harboring metastatic cancer to the total number of lymph nodes examined (lymph node ratio, LNR) may affect survival after esophagogastric resection for cancer. We analyzed the impact of LNR in overall survival in patients undergoing esophagogastric resection for cancer. METHODS: Patients who underwent gastroesophageal resection for cancer (1998 to 2008) were categorized into 4 groups according to their LNR: 113 patients had negative nodes (N0), 86 LNR less than .3, 40 LNR .31 to .6, and 47 LNR greater than .6. Study endpoint was overall median survival. RESULTS: Higher LNR was associated (P < .001) with more advanced stage and adverse pathologic features (eg, grading, venous/perineural invasion). Multivariate analysis demonstrated that LNR is an independent predictor of survival. CONCLUSION: In our experience, LNR correlates with adverse pathologic features and is a negative prognostic factor in patients undergoing radical resection for gastroesophageal cancer. PMID- 26003205 TI - Repeat Excision and Primary Anastomotic Urethroplasty for Salvage of Recurrent Bulbar Urethral Stricture. AB - PURPOSE: We compared the results of initial excision and primary anastomosis urethroplasty to the excision and primary anastomosis outcomes of other challenging reoperative clinical settings, including secondary cases (prior urethroplasty of any technique other than excision and primary anastomosis) and repeat cases (prior excision and primary anastomosis). MATERIALS AND METHODS: We reviewed our database of patients who underwent excision and primary anastomosis urethroplasty for bulbar urethral stricture at our tertiary referral center from 2007 to 2014. Patients without available data and those with a history of lichen sclerosus, radiation, pelvic fracture urethral injuries, distal strictures and/or hypospadias were excluded from analysis. Patient characteristics and outcomes were compared between those undergoing initial, secondary, and repeat excision and primary anastomosis urethroplasty for bulbar urethral stricture. RESULTS: Among 898 urethroplasties performed during the study period we identified 305 men who underwent excision and primary anastomosis urethroplasty of the bulbar urethra, including an initial procedure in 268 of 305 (88%) and reoperation in 37 (12%). Of patients with reoperation 18 of 37 (49%) underwent secondary excision and primary anastomosis following a different type of prior urethroplasty and 19 (51%) underwent repeat excision and primary anastomosis. Repeat excision and primary anastomosis in the bulbar urethra was successful in 18 of 19 patients (95%), which was comparable to the success rate of initial bulbar excision and primary anastomosis (251 of 268 or 94%) as well as secondary bulbar excision and primary anastomosis (17 of 18 or 94%, p = 0.975) with a similar mean stricture length. Mean followup for all patients was 41.5 months (range 6 to 90) and mean followup in each group was greater than 30 months. CONCLUSIONS: Repeat excision and primary anastomosis urethroplasty has excellent results for short bulbar strictures, comparable to those achieved in the initial and secondary setting. PMID- 26003206 TI - Natural History of Pathologically Benign Cancer Suspicious Regions on Multiparametric Magnetic Resonance Imaging Following Targeted Biopsy. AB - PURPOSE: We determined the natural history of pathologically benign cancer suspicious regions on multiparametric magnetic resonance imaging following targeted biopsy. MATERIALS AND METHODS: Between January 2012 and September 2014, 330 men underwent prostate multiparametric magnetic resonance imaging. A total of 533 cancer suspicious regions were identified and scored on a Likert scale of 1 to 5 based on suspicion for malignancy with 5 indicating the highest suspicion level. Following multiparametric magnetic resonance imaging all men underwent magnetic resonance imaging-ultrasound fusion targeted prostate biopsy using ProFuse software and the ei-Nav|Artemis system (innoMedicus, Cham, Switzerland), and a computer generated 12-core random biopsy. We analyzed a cohort of 34 men with a total of 51 cancer suspicious regions who had benign prostate biopsies and underwent repeat multiparametric magnetic resonance imaging and prostate specific antigen testing at 1 year. Changes in the greatest linear measurement, the suspicion score and serum prostate specific antigen were ascertained. RESULTS: During 1 year the suspicion score distribution and the mean greatest linear measurement of the cancer suspicious regions decreased significantly (p <0.0001) while mean prostate specific antigen did not significantly change (p = 0.632). Two (3.9%), 15 (29.4%) and 34 cancer suspicious regions (66.7%) showed an increase, no change and decrease in suspicion score, respectively. No (0%), 21 (42.0%) and 29 cancer suspicious regions (58.0%) showed an increase of 20% or greater, no change and a decrease of 20% or greater in greatest linear measurement, respectively. Of the 2 cancer suspicious regions exhibiting an increased suspicion score neither showed a prostate specific antigen increase of 0.5 ng/ml or greater. CONCLUSIONS: Our study provides compelling evidence that few benign cancer suspicious regions increase in suspicion score and/or the greatest linear measurement within 1 year independent of the baseline suspicion score. Therefore, routinely repeating multiparametric magnetic resonance imaging at 1 year in men with pathologically benign cancer suspicious regions should be discouraged since it is unlikely to influence management decisions. PMID- 26003204 TI - NetworkPainter: dynamic intracellular pathway animation in Cytobank. AB - BACKGROUND: High-throughput technologies such as flow and mass cytometry have the potential to illuminate cellular networks. However, analyzing the data produced by these technologies is challenging. Visualization is needed to help researchers explore this data. RESULTS: We developed a web-based software program, NetworkPainter, to enable researchers to analyze dynamic cytometry data in the context of pathway diagrams. NetworkPainter provides researchers a graphical interface to draw and "paint" pathway diagrams with experimental data, producing animated diagrams which display the activity of each network node at each time point. CONCLUSION: NetworkPainter enables researchers to more fully explore multi parameter, dynamical cytometry data. PMID- 26003207 TI - Redefining the Autonomic Nerve Distribution of the Bladder Using 3-Dimensional Image Reconstruction. AB - PURPOSE: We sought to create a 3-dimensional reconstruction of the autonomic nervous tissue innervating the bladder using male and female cadaver histopathology. MATERIALS AND METHODS: We obtained bladder tissue from a male and a female cadaver. Axial cross sections of the bladder were generated at 3 to 5 mm intervals and stained with S100 protein. We recorded the distance between autonomic nerves and bladder mucosa. We manually demarcated nerve tracings using ImageScope software (Aperio, Vista, California), which we imported into BlenderTM graphics software to generate 3-dimensional reconstructions of autonomic nerve anatomy. RESULTS: Mean nerve density ranged from 0.099 to 0.602 and 0.012 to 0.383 nerves per mm2 in female and male slides, respectively. The highest concentrations of autonomic innervation were located in the posterior aspect of the bladder neck in the female specimen and in the posterior region of the prostatic urethra in the male specimen. Nerve density at all levels of the proximal urethra and bladder neck was significantly higher in posterior vs anterior regions in female specimens (0.957 vs 0.169 nerves per mm2, p<0.001) and male specimens (0.509 vs 0.206 nerves per mm2, p=0.04). CONCLUSIONS: Novel 3 dimensional reconstruction of the bladder is feasible and may help redefine our understanding of human bladder innervation. Autonomic innervation of the bladder is highly focused in the posterior aspect of the proximal urethra and bladder neck in male and female bladders. PMID- 26003208 TI - Omission of radiotherapy in elderly patients with early breast cancer: 15-Year results of a prospective non-randomised trial. AB - BACKGROUND: Whether radiotherapy (RT) is beneficial in elderly (? 70 years) patients undergoing conservative surgery for early breast cancer has long been controversial. Recent randomised trials show that most elderly patients do not benefit from RT. We started a prospective non-randomised trial to address this issue in 1987 and now present results for the 627 consecutive pT1/2cN0 patients recruited, and treated by conservative surgery (quadrantectomy) and tamoxifen, and assigned non-randomly to RT or no RT. METHODS: We used multivariate competing risks models to estimate 15-crude cumulative incidence (CCI) of ipsilateral breast tumour recurrence (IBTR), distant metastasis and breast cancer mortality. The models incorporated a propensity score as a measure of probability of receiving RT based on baseline characteristics, to account for the lack of randomisation. RESULTS: For pT1 patients, 15-year CCIs of IBTR, distant metastasis and breast cancer death were indistinguishable in the RT and no RT groups. For pT2 patients, 15-year CCI of IBTR was much higher in those not given RT (14.6% versus 0.8%, p = 0.004), although breast cancer mortality and distant metastasis did not differ significantly between RT and no RT. CONCLUSIONS: Consistent with the findings of recent randomised trials, our long-term data indicate that most elderly, ER-positive patients with pT1 cN0 breast cancer treated by quadrantectomy do not benefit from RT. The 14.6% CCI of IBTR in our pT2 patients is an additional finding not presented in the trials and suggests that RT should be administered to elderly patients with pT2 disease. PMID- 26003209 TI - Plant diterpene synthases: exploring modularity and metabolic diversity for bioengineering. AB - Plants produce thousands of diterpenoid natural products; some of which are of significant industrial value as biobased pharmaceuticals (taxol), fragrances (sclareol), food additives (steviosides), and commodity chemicals (diterpene resin acids). In nature, diterpene synthase (diTPS) enzymes are essential for generating diverse diterpene hydrocarbon scaffolds. While some diTPSs also form oxygenated compounds, more commonly, oxygenation is achieved by cytochrome P450 dependent mono-oxygenases. Recent genome-, transcriptome-, and metabolome-guided gene discovery and enzyme characterization identified novel diTPS functions that form the core of complex modular pathway systems. Insights into diterpene metabolism may translate into the development of new bioengineered microbial and plant-based production systems. PMID- 26003210 TI - [Pathology of the mediastinum. Introduction]. PMID- 26003211 TI - [Handling of paraffin-embedded tissue]. PMID- 26003212 TI - [Pathology of the mediastinum. Case 7. Small cell neuroendocrine carcinoma]. PMID- 26003213 TI - [Pathology of the mediastinum. Pre-test answers]. PMID- 26003214 TI - The cemented twin-peg Oxford partial knee replacement survivorship: a cohort study. AB - BACKGROUND: A new twin-peg version of the Oxford knee was introduced in 2003. However, until now there has been no information about its survivorship. The aim of this study was to determine the survivorship, and the patients' perception of outcome over time. METHODS: A cohort of all patients treated from 2003 until 2009 using the twin-peg Oxford partial knee was contacted. The main indication for treatment was anteromedial osteoarthritis (AMOA). The Oxford Knee Score (OKS), American Knee Society Functional (AKS-F) score and satisfaction rate were obtained, and the time-to-failure was used to perform a survival analysis. RESULTS: There were 249 patients treated, with 288 medial cemented implants. Of these, 248 patients with 287 implants could be contacted and implant survival or failure was verified. Their mean age was 67years (range: 34-94). The mean follow up time was 5.1years (maximum: 9.2). The nine years cumulative implant survival rate for all cases using revision for any reason to define failure was 98% (95% CI, 84 to 100). There were no cases of femoral loosening. The mean OKS was 22 pre operatively, 41 at two years, and 41 at final review, at which point 96% of patients were very or fairly pleased with the result. CONCLUSION: The survivorship of the twin-peg knee was better than that of the single peg knee at our centre, and appeared no worse than the results of the single peg knee at the originating centre. It can offer secure femoral fixation, sustained clinical benefit and patient satisfaction. LEVEL OF EVIDENCE: Level IV case-series. PMID- 26003215 TI - A new technique using mesh for extensor reconstruction after proximal tibial resection. AB - BACKGROUND: Proximal tibial reconstruction following wide resection in both malignant and benign tumors presents difficulties mainly due to both patellar tendon reconstruction and high risk of infection. The purpose of this study is to determine the efficacy of a new technique using a mesh for extensor reconstruction. METHODS: We retrospectively reviewed nine consecutive patients who underwent resection of the proximal tibia with prosthetic reconstruction and reconstruction of the extensor using a mesh between 2009 and 2012. The surgical technique included the attachment of the mesh to the tibial component with a band of meshes looped over the patella and a gastrocnemius flap for coverage. RESULTS: One patient had an above-the-knee amputation due to infection. Eight patients were followed up for 33 months (range, 20-50). In the eight patients, extensor lag had a mean of 5 degrees (range, 0 to 20). Active flexion had a mean of 96.25 degrees (range, 80 to 120) and ISOLS scores had a mean of 21/30 (range, 18 to 26). All patients were able to ambulate without crutches at the latest follow-up. CONCLUSION: Extensor lag was significantly less compared to previous reports. No complications were observed in eight patients. Utilization of the mesh for extensor reconstruction after the proximal tibial resection is a simple, reliable and successful method. PMID- 26003216 TI - Quadriceps tendon repair using hamstring, prolene mesh and autologous conditioned plasma augmentation. A novel technique for repair of chronic quadriceps tendon rupture. AB - BACKGROUND: Several techniques have been described for the primary repair of quadriceps tendon ruptures but there is a paucity of literature on operative management of chronic/recurrent quadriceps tendon ruptures. We describe a novel technique for the revision of quadriceps tendon ruptures which uses hamstring, prolene mesh and autologous conditioned plasma augmentation. METHODS: Our patient was an independently mobile, active 61 year-old man who sustained staggered, bilateral quadriceps tendon ruptures. He had two failed direct repairs on the left side. The patient was unable to actively extend his knee. On the third attempt, despite maximising quadriceps tendon length using the Codivilla technique the gap remained significant. The left and right semitendinosus and left gracilis tendons were thus harvested and used to augment our repair. A prolene mesh, sized to fit the whole length quadriceps tendon and patella, was then secured to the repair to reinforce it. The repair site was finally injected with autologous conditioned plasma. RESULTS: Satisfactory post-operative outcomes were achieved. The patient was pain-free and able to maintain straight leg raise with a 10 degrees extensor lag at his four months review in clinic. CONCLUSIONS: We were able to achieve a stable construct with combination of both well established and novel tendon lengthening techniques, in addition to mesh and biological augmentation. In our experience this surgical procedure is suitable for the treatment of a large tendon gap defect and will withstand high force transmission. PMID- 26003217 TI - Film-based delivery quality assurance for robotic radiosurgery: Commissioning and validation. AB - PURPOSE: Robotic radiosurgery demands comprehensive delivery quality assurance (DQA), but guidelines for commissioning of the DQA method is missing. We investigated the stability and sensitivity of our film-based DQA method with various test scenarios and routine patient plans. We also investigated the applicability of tight distance-to-agreement (DTA) Gamma-Index criteria. METHODS AND MATERIAL: We used radiochromic films with multichannel film dosimetry and re calibration and our analysis was performed in four steps: 1) Film-to-plan registration, 2) Standard Gamma-Index criteria evaluation (local-pixel-dose difference <=2%, distance-to-agreement <=2 mm, pass-rate >=90%), 3) Dose distribution shift until maximum pass-rate (Maxgamma) was found (shift acceptance <1 mm), and 4) Final evaluation with tight DTA criteria (<=1 mm). Test scenarios consisted of purposefully introduced phantom misalignments, dose miscalibrations, and undelivered MU. Initial method evaluation was done on 30 clinical plans. RESULTS: Our method showed similar sensitivity compared to the standard End-2-End Test and incorporated an estimate of global system offsets in the analysis. The simulated errors (phantom shifts, global robot misalignment, undelivered MU) were detected by our method while standard Gamma-Index criteria often did not reveal these deviations. Dose miscalibration was not detected by film alone, hence simultaneous ion-chamber measurement for film calibration is strongly recommended. 83% of the clinical patient plans were within our tight DTA tolerances. CONCLUSION: Our presented methods provide additional measurements and quality references for film-based DQA enabling more sensitive error detection. We provided various test scenarios for commissioning of robotic radiosurgery DQA and demonstrated the necessity to use tight DTA criteria. PMID- 26003219 TI - Organogenesis in plants: initiation and elaboration of leaves. AB - Plant organs initiate from meristems and grow into diverse forms. After initiation, organs enter a morphological phase where they develop their shape, followed by differentiation into mature tissue. Investigations into these processes have revealed numerous factors necessary for proper development, including transcription factors such as the KNOTTED-LIKE HOMEOBOX (KNOX) genes, the hormone auxin, and miRNAs. Importantly, these factors have been shown to play a role in organogenesis in various diverse model species, revealing both deep conservation of regulatory strategies and evolutionary novelties that led to new plant forms. We review here recent work in understanding the regulation of organogenesis and in particular leaf formation, highlighting how regulatory modules are often redeployed in different organ types and stages of development to achieve diverse forms through the balance of growth and differentiation. PMID- 26003218 TI - It's more than stamp collecting: how genome sequencing can unify biological research. AB - The availability of reference genome sequences, especially the human reference, has revolutionized the study of biology. However, while the genomes of some species have been fully sequenced, a wide range of biological problems still cannot be effectively studied for lack of genome sequence information. Here, I identify neglected areas of biology and describe how both targeted species sequencing and more broad taxonomic surveys of the tree of life can address important biological questions. I enumerate the significant benefits that would accrue from sequencing a broader range of taxa, as well as discuss the technical advances in sequencing and assembly methods that would allow for wide-ranging application of whole-genome analysis. Finally, I suggest that in addition to 'big science' survey initiatives to sequence the tree of life, a modified infrastructure-funding paradigm would better support reference genome sequence generation for research communities most in need. PMID- 26003220 TI - Effects of transforming growth factor beta-1 infected human bone marrow mesenchymal stem cells on high- and low-metastatic potential hepatocellular carcinoma. AB - BACKGROUND: This study investigates the effects of human bone marrow-derived mesenchymal stem cell (hMSC) on migration and proliferation ability of hepatocellular carcinoma (HCC) with high- and low-metastatic potential. METHODS: The hMSC and transforming growth factor-beta1 (TGFbeta-1) gene infected hMSC were co-cultured with hepatoma cells. The ability of cells migration was assessed by Transwell assay. The ability of cells proliferation was detected using CCK-8 assay. The mice were engrafted with hMSC and TGFbeta-1 gene infected hMSC, respectively, after hepatoma cells inoculation 15 days, twice a week for 6 weeks successively. The tumor inhibition rate was calculated. TGFbeta-1, osteopontin (OPN), and programmed cell death protein 4 (PDCD4) genes expression of hepatoma cells were detected by quantitative real-time polymerase chain reaction (qPCR) before and after co-cultured experiments. RESULTS: TGFbeta-1 infected hMSC or hMSC co-culture with hepatoma cells groups can significantly promote hepatoma cells proliferation (P < 0.05). The migration numbers of hepatoma cells with TGFbeta-1 infected hMSC co-culture groups were significantly reduced compared with the other two groups (P < 0.05). The tumors weight inhibition rates of MHCC97-H and MHCC97-L animal models were the highest in the third week by hMSC engraftment. But the highest tumor inhibition rate of MHCC97-H animal models was observed in the fourth week and MHCC97-L animal models in the fifth week after TGFbeta-1 infected hMSC engraftment. OPN gene relative quantitative expression of hepatoma cells was significantly down-regulated after co-cultured with hMSC and TGFbeta-1 gene infected hMSC groups (P < 0.05). TGFbeta-1 gene relative quantitative expression of MHCC97-H and MHCC97-L cells was significantly up regulated after co-cultured with TGFbeta-1 gene infected hMSC groups (P < 0.05). PDCD4 expression had no statistical differences among groups. CONCLUSIONS: hMSC and TGFbeta-1 gene infected hMSC can promote hepatoma cells proliferation and inhibit hepatoma cells migration. hMSC and TGFbeta-1 gene infected hMSC exhibit anti-tumor activity in a time-dependent manner. TGFbeta-1 cytokine may be the main factor in HCC proliferation. OPN makes a significant contribution to the changes of hepatoma cells metastasis. PMID- 26003221 TI - Changes in Functional Activity of JEG-3 Trophoblast Cell Line in the Presence of Factors Secreted by Placenta. AB - BACKGROUND AND AIMS: Cells in the maternal-fetal interface secrete cytokines that regulate proliferation, migration, and trophoblast invasion during the first trimester of pregnancy and the limitation of these processes during the third trimester. The aim of the study was to evaluate the influence of factors secreted by human placenta during the first and third trimester of pregnancy on cytokine receptor expression and proliferative and migratory activity of JEG-3 trophoblast cells. METHODS: The research was conducted using the explant conditioned media of placentas obtained from healthy women with elective termination of pregnancy at 9 11 weeks and placentas of women whose pregnancy progressed without complications at 38-39 weeks. Assessment of surface molecule expression was performed using FACS Canto II flow cytometer (BD, USA). The proliferative activity of JEG-3 trophoblast cells was evaluated by dyeing with crystal violet vital dye. The migration activity of JEG-3 was evaluated using 24-well insert plates with polycarbonate inserts (pore size 8 microns). RESULTS: Expression of CD116, CD118, CD119, IFNgamma-R2, CD120b, CD183, CD192, CD295, EGFR, and TGFbeta-R2 on JEG-3 was higher when the cells were incubated in the presence of the third trimester placental factors in comparison with the first trimester placental factors. Factors secreted by the placenta during the third trimester of pregnancy had more pronounced stimulatory effect on the proliferation and migration of trophoblast in comparison with baseline levels and with the effect of the first trimester placental factors. CONCLUSIONS: The findings suggest that the behavior of trophoblasts in vitro might not be representative of in vivo behavior in the absence of additional local factors that influence the trophoblast in vivo. PMID- 26003222 TI - Pathologic Lymph Node-positive Prostate Cancer: Some Answers ... with Many More Questions. PMID- 26003223 TI - Treatment of the Primary Tumor in Metastatic Prostate Cancer: Current Concepts and Future Perspectives. AB - CONTEXT: Multimodal treatment for men with locally advanced prostate cancer (PCa) using neoadjuvant/adjuvant systemic therapy, surgery, and radiation therapy is being increasingly explored. There is also interest in the oncologic benefit of treating the primary tumor in the setting of metastatic PCa (mPCa). OBJECTIVE: To perform a review of the literature regarding the treatment of the primary tumor in the setting of mPCa. EVIDENCE ACQUISITION: Medline, PubMed, and Scopus electronic databases were queried for English language articles from January 1990 to September 2014. Prospective and retrospective studies were included. EVIDENCE SYNTHESIS: There is no published randomized controlled trial (RCT) comparing local therapy and systemic therapy to systemic therapy alone in the treatment of mPCa. Prospective studies of men with locally advanced PCa and retrospective studies of occult node-positive PCa have consistently shown the addition of local therapy to a multimodal treatment regimen improves outcomes. Molecular and genomic evidence further suggests the primary tumor may have an active role in mPCa. CONCLUSIONS: Treatment of the primary tumor in mPCa is being increasingly explored. While preclinical, translational, and retrospective evidence supports local therapy in advanced disease, further prospective studies are under way to evaluate this multimodal approach and identify the patients most likely to benefit from the inclusion of local therapy in the setting of metastatic disease. PATIENT SUMMARY: In this review we explored preclinical and clinical evidence for treatment of the primary tumor in metastatic prostate cancer (mPCa). We found evidence to support clinical trials investigating mPCa therapy that includes local treatment of the primary tumor. Currently, treating the primary tumor in mPCa is controversial and lacks high-level evidence sufficient for routine recommendation. PMID- 26003224 TI - Evidence for a common founder effect amongst South African and Zambian individuals with Spinocerebellar ataxia type 7. AB - Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by the expansion of a CAG repeat within the ataxin 7 gene, leading to a pathogenic polyglutamine tract within the ataxin 7 protein. SCA7 patients suffer from progressive cerebellar ataxia and macular degeneration. SCA7 is considered to be rare, although founder effects have been reported in South Africa, Scandinavia and Mexico. The South African SCA7-associated haplotype has not been investigated in any other populations, and there have been limited reports of SCA7 patients from other African countries. Here, we describe the first two ethnic Zambian families with confirmed SCA7. Haplotype analysis showed that the South African SCA7 haplotype alleles were significantly associated with the pathogenic expansion in affected Zambian individuals, providing strong evidence for a shared founder effect between South African and Zambian SCA7 patients. PMID- 26003225 TI - Prophylactic treatment in menstrual migraine: A proof-of-concept study. AB - The present study aimed to investigate the efficacy of repetitive cathodal direct current stimulation (rctDCS) over the visual cortex as a prophylactic treatment in patients with menstrual migraine. 20 female patients were recruited in this double-blind, placebo-controlled study and were assigned to receive either cathodal or sham stimulation. Over 3 menstrual cycles, tDCS with 2mA intensity and 20 min duration was applied to the visual cortex of the patients, in 5 consecutive sessions 1-5 days prior to the first day of their menstruation. The primary endpoint of the study was the frequency of the migraine attacks at the end of the treatment period, however, additional parameters, such as the number of migraine related days and the intensity of pain were also recorded 3 months before, during and 3 months post-treatment. Visual cortex excitability was determined by measuring the phosphene thresholds (PTs) using single pulse transcranial magnetic stimulation (TMS) over the visual cortex. Sixteen patients completed the study. A significant decrease in the number of migraine attacks (p=0.04) was found in the cathodal group compared to baseline but not compared to sham (p=0.053). In parallel the PTs increased significantly in this group, compared to the sham group (p<0.05). Our results indicate that prophylactic treatment with rctDCS over the visual cortex might be able to decrease the number of attacks in patients with menstrual migraine, probably by modifying cortical excitability. PMID- 26003226 TI - JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration. AB - JC virus (JCV) infection of glial cells can lead to progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. A newly described phenotype of the infection is infection of neurons. This distinct clinical and radiological syndrome is named JCV granule cell neuronopathy, characterized by exclusive or predominant cerebellar atrophy. We report the clinical and radiological longitudinal findings of 5 HIV-infected patients referred to us between September 2004 and November 2011 who exhibited JCV granule cell neuronopathy (4 probable cases and 1 possible). The association of immunocompromised status, progressive cerebellar syndrome, MRI abnormalities with cortical cerebellar atrophy and cerebrospinal fluid positive for JCV on PCR allowed for a highly probable diagnosis. The reversal of the immunocompromised status is the only way to stop the disease evolution. Motor functioning can remain impaired, but the illness itself, unlike progressive multifocal leukoencephalopathy, does not seem to threaten life. PMID- 26003227 TI - Common variants of ATP1A3 but not ATP1A2 are associated with Chinese genetic generalized epilepsies. AB - OBJECTIVE: ATP1A2 and ATP1A3 are genes that code for catalytic subunits of Na/K ATPases, which play important roles in the basal electrophysiological states of nerve cells. The aim of this study was to investigate whether genetic polymorphisms of ATP1A2 and ATP1A3 influence susceptibility to genetic generalized epilepsies (GGEs) and the efficacy of anti-epileptic drugs in a Chinese population. METHOD: Six ATP1A2 tagged single-nucleotide polymorphisms (tagSNPs) and two ATP1A3 tagSNPs were were genotyped by allele-specific MALDI-TOF mass spectrometry in 484 Chinese GGE patients (280 drug-responsive and 204 drug resistant patients) and 284 healthy controls. RESULTS: Significant differences were found in the frequencies of the ATP1A3 rs8107107 C allele and the CC genotype between the GGEs and the healthy controls (11% vs. 15%, odds ratio (OR)=0.807 (0.68-0.960), p=0.021 and 0.4% vs. 3.2%, OR=0.121 (0.026-0.565), p=0.002, respectively). The frequency of the rs8107107 CT+CC genotype was significantly lower among the GGE patients than among the healthy controls (15% vs. 26.8%, OR=0.327 (0.248-0.942), p=0.001). No significant differences in the frequencies of six ATP1A2 tagSNPs or ATP1A2 haplotypes were found between the GGEs and the healthy controls. No tagSNPs were involved in anti-epileptic drug resistance. CONCLUSION: Our findings demonstrated that common variants of ATP1A3 but not ATP1A2 were associated with the susceptibility to GGEs in a Chinese population, which indicates that the ATP1A3 gene plays a significant role in the pathophysiology of genetic generalized epilepsies. PMID- 26003228 TI - Permanent reversal of essential tremor following a frontal lobe stroke. AB - Following a right prerolandic stroke, a 76 year old woman with bilateral upper extremity essential tremor (ET) recovered permanently from the latter contralaterally to the affected hemisphere. The ischemic stroke likely interrupted the cortical component of the ET network. Given the magnitude of neuronal loss, post-stroke cortical reorganization was unable to restore this important component of the ET network, accounting for the permanent nature of ET suppression. PMID- 26003229 TI - Impaired sleep-associated modulation of post-exercise corticomotor depression in multiple sclerosis. AB - OBJECTIVE: To compare the beneficial effect of nap versus rest on the recovery of motor evoked potentials (MEPs) after a fatiguing exercise performed in patients with multiple sclerosis (MS) and healthy controls. METHODS: In 12 MS patients and 12 healthy controls, MEPs were recorded from the adductor pollicis muscle before, 10 and 60 min (T0, T10, and T60) after an effort of thumb adduction at 25% of maximal voluntary contraction force for 24 min. After the effort, the subject was maintained at rest or invited to have a nap while monitored with polysomnography. The two sessions (nap and rest) were randomly performed in each subject during the same day. The impact of nap and rest on post-exercise changes in MEP amplitude were studied in each group (patients and controls) and then compared between the two groups. RESULTS: Although MEP amplitude at baseline was lower in MS patients than in controls, post-exercise corticomotor depression (PECD), expressed as T10/T0 MEP amplitude ratio, was similar in both groups. Regarding MEP amplitude recovery at T60, nap was significantly more beneficial than rest in healthy subjects, but not in MS patients. CONCLUSION: Motor recovery from PECD following a fatiguing exercise can be enhanced by sleep (at least a short nap) in healthy subjects. In MS patients, sleep restorative effect is reduced or lost, maybe contributing to the excessive fatigue or fatigability characterized in these patients. PMID- 26003230 TI - Fracture toughness testing: A discriminatory mechanical testing performance indicator for glass-ionomer restoratives? AB - OBJECTIVES: To investigate the single-edge notched (SEN) bend fracture toughness (KIC) testing methodology as a reproducible and discriminatory mechanical testing protocol for encapsulated and hand-mixed glass-ionomers (GI). METHODS: SEN bend test-pieces (35.0+/-0.1mm length, 6.0+/-0.1mm width, 3.0+/-0.1mm thickness with a sharp notch formed at mid-length by embedding a scalpel blade) were prepared for KIC testing using three encapsulated GI products (Chemfil Rock, Fuji IXGP Fast Capsule and Ionofil Molar AC). In addition, test-pieces were prepared from a hand mixed GI product (Ionofil Molar) which contained between 100% and 20% of the manufacturer's recommended powder content (in 10% decrements) for a constant weight of liquid. Groups of 20 test-pieces were prepared for each encapsulated GI product (n=3) and hand-mixed GI powder:liquid mixing ratio (n=9). Data were statistically analyzed and the coefficients of variation (CoV) determined for each encapsulated GI product and hand-mixed GI powder:liquid mixing ratio. RESULTS: The KIC testing methodology failed to discriminate between the encapsulated GI products that were investigated (p=0.225). For the hand-mixed GI, the KIC testing methodology also failed to discriminate between the powder:liquid mixing ratios investigated (R(2)=0.576). The pooled CoV (10%) for the encapsulated GI products and for the powder:liquid mixing ratio groups (12%) identified the reproducibility of the test for this experiment. For the hand mixed GI mixing ratio groups with between 100% to 50% of the recommended powder content, no trend could be discerned. SIGNIFICANCE: The KIC testing methodology failed to discriminate between different encapsulated GI products and hand-mixed GI powder:liquid mixing ratio groups investigated, despite KIC being an intrinsic material property and the coefficient of variation being acceptable. PMID- 26003231 TI - Influence of the resin cement thickness on the fatigue failure loads of CAD/CAM feldspathic crowns. AB - OBJECTIVES: to evaluate the influence of the occlusal resin cement thickness on the cyclic loads-to-failure of feldspathic crowns and to compare the results to data from monotonic tests. A large range of cement thickness (50MUm and 500MUm) was tested, in order to better measure the influence of this variable. METHODS: Feldspathic ceramic crowns (Vita Mark II blocks, Vita Zahnfabrik) were bonded to dentin analog dies (G10 (NEMA grade G10, International Paper), with occlusal resin cement thicknesses of 50MUm and 500MUm (Multilink Automix, Ivoclar). The dies were prepared with microchannels for water transport to the cement layer. After 96-h water storage, the specimens (n=20) were submitted to cyclic loads (500,000 cycles at 20Hz; initial maximum load=40% of monotonic load, from previous data) following a staircase sensitivity design (step size=25N). Failure loads at 500,000 cycles were compared to monotonic failure loads (from a previous study with specimens produced by the same author, using the same materials, specimen configuration and cementation protocol). RESULTS: Crowns with an occlusal cement layer of 50MUm were more resistant than those cemented with 500MUm (246.4+/-22.9N vs. 158.9+/-22.9N), under wet cyclic testing conditions (p<0.001). The fatigue failure loads were reduced compared to monotonic loads: to 37% of monotonic for 50MUm; to 53% of monotonic for 500MUm. SIGNIFICANCE: An occlusal cement thickness of 50MUm was more favorable for the structural performance of feldspathic crowns than was 500MUm. Cyclic fatigue reduced failure loads well below those found under monotonic loading. PMID- 26003232 TI - Effect of polyacrylic acid on dentin protease activities. AB - OBJECTIVE: This study tested whether treatment of demineralized dentin with polyacrylic acid (PAA) has any activatory or inhibitory activity on dentin matrix metalloproteinases (MMP)s or cathepsin K (CAT-K). METHODS: Dentin beams (1mm*2mm*6mm; n=10) were completely demineralized with EDTA. After initial dry mass assessment, the beams were dipped into 37% phosphoric acid (PA), PA+2% benzalkonium chloride (BAC), PA+2% chlorhexidine digluconate (CHX), 10% PAA, PAA+BAC or PAA+CHX for 20s. Demineralized beams without treatment served as control. All beams were incubated in simulated body fluid (SBF) for 1 week and the dry mass loss was evaluated. Aliquots of SBF were used to analyze solubilized telopeptide fragments using ICTP as indicator of MMP-mediated collagen degradation and CTX for CAT-K-mediated degradation. Additional demineralized beams (n=10) were used to measure the influence of different chemical treatments on total MMP activity of EDTA-demineralized dentin using generic MMP assay. Data were analyzed by ANOVA (alpha=0.05). RESULTS: Dry mass loss ranged from 6% (PA) to 2% for (PA-BAC) or (PAA-BAC) (p<0.05). ICTP release of PAA-treated group was significantly higher (p<0.05) than the control, and not significantly different from the PA group (p>0.05). PA+CHX or PAA+CHX and PAA+BAC showed significantly lower ICTP than PA or PAA groups (p<0.05). CAT-K activity increased significantly after 10% PAA treatment compared to control (p<0.05) or to PA postreatment. SIGNIFICANCE: Demineralized dentin treated with 10% polyacrylic acid activated CAT-K more than 37% phosphoric acid; 2% chlorhexidine digluconate seems to be a better inhibitor of MMPs and CAT-K than 2% benzalkonium chloride. PMID- 26003233 TI - Anaphylaxis to medications containing meat byproducts in an alpha-gal sensitized individual. PMID- 26003234 TI - Introducing a standard of legal insanity: The case of Sweden compared to The Netherlands. AB - A recent governmental report has suggested that the notion of insanity, which has not been a relevant concept in Swedish criminal law for the last 50years, should be reintroduced into the criminal justice system. This move has generated a debate over the most appropriate criteria to be included in a legal standard for insanity. We consider the fundamental question of whether a legal standard is required when introducing insanity, by looking at a legal system in which legal insanity is available but where no standard is used: The Netherlands. Overall, a review of advantages and disadvantages leads to the conclusion that such a standard is necessary. What exactly should that standard be? Is the development of different "grades" of insanity desirable? Legal considerations concerning what is essentially a legal notion should predominate in making these determinations informed by psychiatric and other relevant scientific findings. PMID- 26003235 TI - Introduction. AB - This volume of the Handbook of Clinical Neurology deals with neurologic disorders of sex and bladder. Sexuality is for the large majority of humans a component of a fulfilled life, even though it is not "vital" in the usual sense of the word. However, dysfunctions of the lower urinary tract (LUT) are vital, as they may lead to chronic infection, dilatation of the upper urinary tract, renal insufficiency, and death. Sexual disorders and LUT are often mentioned in ancient literature, but most contemporary methods of diagnosis and treatment were only introduced in the 20th century. Despite the relatively high prevalence of these disorders, most physicians are ill prepared to discuss them with their patients, let alone to diagnose and treat them. It is the aim of this volume of the Handbook to try to reverse this attitude and convince neurologists that sexual and LUT function need to be addressed in their patients, for reasons of correct diagnosis and possible therapeutic consequences, as well as gaining overall trust from the patient. PMID- 26003236 TI - Human sexual response. AB - The human sexual response to sexually arousing stimuli is a motivational incentive-based cycle comprising subjective experience and physiologic changes. Clinical and empirical data support a circular model of overlapping phases of variable order. Brain imaging data of sexual arousal identify areas of cerebral activation and inhibition reflecting a complex network of cognitive, motivational, emotional, and autonomic components. Psychologic and biologic factors influence the brain's appraisal and processing of sexual stimuli to allow or disallow subsequent arousal. The sexual and non-sexual outcomes influence motivation to future sexual intimacy. Variability is marked both between individuals and within a person's sexual life, influenced by multiple factors, including stage of life cycle, mental health, and relationship happiness. Neurologic disease can interrupt the cycle at many points: by limiting motivation, reducing ability to attend to and feel sexual stimuli, and accomplishing the movements needed to stimulate and experience intercourse. Impairments to genital congestion, penile erection, and orgasm may also occur. Disease-associated changes to the interpersonal relationship and self-image plus frequently comorbid depression will tend to lessen motivation and temper the brain's appraisal of sexual stimuli, so precluding arousal. Therapy begins by explaining the sexual response cycle, clarifying the points of interruption in the patient's own cycle so as to guide treatment. PMID- 26003237 TI - Anatomy and physiology of genital organs - men. AB - Male sexual functions involve a number of organs and structures in genitalia whose role is to produce fertilizing gametes and to allow female-partner insemination. The testes belong to the reproductive and endocrine systems as they synthesize spermatozoa and androgens, and are under finely regulated hormonal control by the hypothalamopituitary axis. Sexual responses are controlled by a complex and coordinated interplay of both the somatic and the autonomic nervous system in multiple components of the brain, spinal cord, and relevant peripheral organs. Erectile bodies are an essential element of the penis and engorgement of the penis with blood leads to penile tumescence. Blood engorgement is due to relaxation of smooth-muscle cells of erectile tissue and endothelium of the penile arteries. The penis gains additional rigidity when the ischiocavernosus muscles contract. Stimuli from peripheral and/or central origins activate particular spinal nuclei, causing penile erection. Ejaculation consists of two phases, emission and expulsion, which correspond, respectively, to secretion of the different components of the semen by sex glands and forceful expulsion of semen due to rhythmic contractions of the bulbospongiosus muscle. A spinal generator of ejaculation integrates genital stimuli and sexual cues and, when the excitatory threshold is reached, triggers ejaculation by orchestrating the activation of autonomic and somatic pathways commanding the peripheral events of ejaculation. PMID- 26003238 TI - Anatomy and physiology of genital organs - women. AB - "Anatomy is destiny": Sigmund Freud viewed human anatomy as a necessary, although not a sufficient, condition for understanding the complexity of human sexual function with a solid biologic basis. The aim of the chapter is to describe women's genital anatomy and physiology, focusing on women's sexual function with a clinically oriented vision. Key points include: embryology, stressing that the "female" is the anatomic "default" program, differentiated into "male" only in the presence of androgens at physiologic levels for the gestational age; sex determination and sex differentiation, describing the interplay between anatomic and endocrine factors; the "clitoral-urethral-vaginal" complex, the most recent anatomy reading of the corpora cavernosa pattern in women; the controversial G spot; the role of the pelvic floor muscles in modulating vaginal receptivity and intercourse feelings, with hyperactivity leading to introital dyspareunia and contributing to provoked vestibulodynia and recurrent postcoital cystitis, whilst lesions during delivery reduce vaginal sensations, genital arousability, and orgasm; innervation, vessels, bones, ligaments; and the physiology of women's sexual response. Attention to physiologic aging focuses on "low-grade inflammation," genital and systemic, with its impact on women sexual function, especially after the menopause, if the woman does not or cannot use hormone replacement therapy. PMID- 26003239 TI - Anatomy and physiology of the lower urinary tract. AB - Functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. Neural control of micturition is organized as a hierarchic system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily during the early postnatal period, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults cause re-emergence of involuntary micturition, leading to urinary incontinence. The mechanisms underlying these pathologic changes are discussed. PMID- 26003240 TI - Human sexual behavior related to pathology and activity of the brain. AB - Reviewed in this chapter are: (1) correlations among human sexual behavior, brain pathology, and brain activity, including caveats regarding the interpretation of "cause and effect" among these factors, and the degree to which "hypersexuality" and reported changes in sexual orientation correlated with brain pathology are uniquely sexual or are attributable to a generalized disinhibition of brain function; (2) the effects, in some cases inhibitory, in others facilitatory, on sexual behavior and motivation, of stroke, epileptic seizures, traumatic brain injury, and brain surgery; and (3) insights into sexual motivation and behavior recently gained from functional brain imaging research and its interpretive limitations. We conclude from the reviewed research that the neural orchestra underlying the symphony of human sexuality comprises, rather than brain "centers," multiple integrated brain systems, and that there are more questions than answers in our understanding of the control of human sexual behavior by the brain - a level of understanding that is still in embryonic form. PMID- 26003241 TI - Functional imaging of structures involved in neural control of the lower urinary tract. AB - Recent functional brain imaging studies, building on earlier observations, suggest a working model of brain control of the lower urinary tract. It comprises a few cerebral neural circuits that, during the storage phase, act on the midbrain periaqueductal gray to inhibit the long-loop, spinobulbospinal voiding reflex, thus promoting continence. Circuit 1, centered on the medial prefrontal cortex, appears to be concerned with conscious control of both continence and voiding. Circuit 2, centered on the dorsal anterior cingulate (midcingulate) and supplementary motor area, is concerned with emotional aspects of bladder control: desire to void or urgency with concomitant urethral sphincter activation to delay leakage. A subcortical circuit 3 has been less well studied. Circuit 1 is bilateral with a right-sided preference. Scattered studies of the connectivity of the control network suggest that white-matter damage may contribute to urinary incontinence. A few studies confirm that isolated cerebral lesions, if in the medial prefrontal cortex or its connecting pathways, may lead to incontinence. Lower urinary tract dysfunction in other neurologic diseases (normal-pressure hydrocephalus, Parkinson's disease, and multiple systems atrophy) appears consistent with the working model, and even spinal or peripheral lesions have central effects. However, this model omits the contributions of brain regions already observed in some imaging studies and therefore is certainly oversimplified. PMID- 26003242 TI - Approach to the male patient with sexual dysfunction. AB - The management of the male patient with sexual dysfunction (SD) requires special knowledge and abilities. Generally, SD is best approached from the physiologic perspective, keeping in mind that sexual functioning has important psychosocial dimensions. The history obtained from the patient and, if possible, from his partner should seek information not only on the SD, but also on coexisting neurologic or medical disorders. A list of drugs should be obtained, as many prescription drugs, even in low doses, can influence sexual function. The clinical examination, including sensory, motor, and reflex testing of the lumbosacral segments, may reveal pertinent somatic abnormalities, which in the case of a suspected peripheral nervous system lesion may be supported by clinical neurophysiologic testing. The first-line diagnostic approach includes defining the type of sexual dysfunction to allow the most appropriate therapy. Metabolic and other systemic diseases need to be ruled out. Patients suspected of having psychologic, structural, urologic, endocrinologic, or vascular etiology of SD should be referred to the appropriate specialist. PMID- 26003243 TI - Approach to the male patient with lower urinary tract dysfunction. AB - History and physical examination are the cornerstones of evaluation of the male patient with lower urinary tract (LUT) symptoms and (suspected) neurologic disorder, both to diagnose the nervous system lesion, and to get insight into the type of LUT dysfunction (LUTD). Non-neurologic LUTD needs to be ruled out. Laboratory testing is necessary to diagnose urinary infection. In those in whom neurogenic LUTD is probable, postvoid residual urine and urinary flow measurement generally rule out significant outflow obstruction and allow for basic symptomatic management. If symptomatology is complex or severe, or the pathophysiology uncertain, or invasive treatment planned, urodynamic or videourodynamic measurements should be performed to inform on bladder sensation, detrusor contractility, pressures generated in the bladder, as well as the behavior of bladder neck, the striated urethral sphincter, and urinary flow. This information is paramount to the clinician to plan management and consider prognosis. Assessment needs to be repeated, as chronic neurogenic LUTD is not a stable condition; in progressive neurologic diseases the nature of LUTD itself may change. The upper urinary tract needs to be checked and followed up regularly, particularly in patient groups in which high intravesical pressures may be generated. PMID- 26003244 TI - Sexual and bladder comorbidity in women. AB - Sexual dysfunction in women is defined as disorders of sexual desire, arousal, orgasm, and/or sexual pain, which result in significant personal distress and may have a negative effect on a woman's health and an impact on her quality of life. A comprehensive understanding of the anatomic, neurobiologic, and psychologic mechanisms behind women's sexual function and dysfunction is of paramount importance. This chapter reviews the most frequent comorbid conditions related to urinary tract symptoms (thus including symptoms related to overactive bladder syndrome and urinary incontinence) and sexual dysfunction in women. Likewise, it considers the different disorders from the point of view of daily clinical practice. PMID- 26003245 TI - Sexual dysfunction in patients with peripheral nervous system lesions. AB - Peripheral nervous system (PNS) disorders may cause sexual dysfunction (SD) in patients of both genders. These disorders include mainly polyneuropathies (particularly those affecting the autonomic nervous system (ANS)) and localized lesions affecting the innervation of genital organs. Impaired neural control may produce a malfunction of the genital response consisting of loss of genital sensitivity, erectile dysfunction, loss of vaginal lubrication, ejaculation disorder, and orgasmic disorder. In addition, there is often a loss of desire which actually has a complex pathogenesis, which goes beyond the mere loss of relevant nerve function. In patients who have no manifest health problems - particularly men with erectile dysfunction - one should always consider the possibility of an underlying polyneuropathy; in patients with SD after suspected denervation lesions of the innervation of genital organs within the lumbosacral spinal canal and in the pelvis, clinical neurophysiologic testing may clarify the PNS involvement. SD can alter self-esteem and lower patients' quality of life; opening up a discussion on sexual issues should be a part of the management of patients with PNS disorders. They may greatly benefit from counseling, education on coping strategies, and specific treatments. PMID- 26003246 TI - Lower urinary tract dysfunction in patients with peripheral nervous system lesions. AB - The prevalence of lower urinary tract (LUT) dysfunction in peripheral nervous system (PNS) disorders is larger than in comparable control populations. This is particularly true for polyneuropathies with autonomic nervous system involvement, and for localized lesions with LUT innervation. LUT symptoms may be the guide to the diagnosis of processes localized in the lumbosacral spinal canal (as in cauda equina syndrome), and in the pelvis. Typical LUT dysfunctions (LUTD) caused by PNS involvement include bladder and sphincter hypoactivity with poor emptying, and incontinence. Paradoxically, bladder overactivity may also occur in pure PNS lesions. The acute cauda equina syndrome is an emergency requiring magnetic resonance imaging and surgery; in chronic neurogenic LUTD due to PNS involvement, the diagnosis of the lesion may be clarified by clinical neurophysiologic testing. Other important causes of neurogenic LUT dysfunction are perineoabdominal and pelvic surgeries. Surgeons are devising nerve-sparing techniques to prevent such major and often persistent complications in patients who are otherwise cured of the underlying disease. LUTD significantly affects the quality of life in patients and may lead to recurring urinary infections and upper urinary tract involvement. Thorough assessment of LUT function by urodynamics may be necessary in patients who are not improved by simple conservative measures. PMID- 26003247 TI - Sexual dysfunction in patients with spinal cord lesions. AB - Many aspects of sexuality can be disrupted following a spinal cord lesion (SCL). It can alter an individual's self-esteem and body image, interfere with positioning and mobility, introduce unexpected problems with incontinence and spasticity, decrease pleasure, and delay orgasm. Sexual concerns in men can involve erectile function, essential for intercourse, ejaculation function, necessary for fertility, and the ability to reach orgasm. In women they can involve concerns with vaginal lubrication, genital congestion, and vaginal infections, which can all go unnoticed, and orgasm, which may be lost. All of these concerns must be addressed during rehabilitation as individuals with SCL continue to live an active sexual life, and consider sexuality among their top priority for quality of life. This chapter describes the impact of SCL on various phases of men's and women's sexual responses and on various aspects of sexuality. Treatments are described in terms of what is currently available and what is specific to the SCL population. New approaches in particular for women are described, along with tips from sexual counseling which consider an overall approach, taking into account the primary, secondary, and tertiary consequences of the SCL on the individual's sexuality. Throughout the chapter, attempts are made to integrate neurophysiologic knowledge, findings from the literature on SCL, and clinical experience in sexual rehabilitation. PMID- 26003248 TI - Dysfunction of lower urinary tract in patients with spinal cord injury. AB - Over the past 50 years, the mortality for urorenal cause in patients with spinal cord injuries (SCI) has decreased from over 75% to 2.3%, as a result of dramatic improvements in the diagnosis and management of lower urinary tract dysfunction (LUTD). The aims of this chapter are to assess the physiopathology of upper and lower motor neuron lesion on bladder and sphincter function after SCI, to give an overview of required clinical and instrumental examination and to discuss treatment modalities. Videourodynamic examination plays a key role in the assessment and follow-up of LUTD in SCI patients, in conjunction with neurophysiological and radiological examinations. The cornerstone of bladder management in SCI is clean intermittent self-catheterization, but often other treatments are needed to achieve full continence, to reduce infections and stone formation, to protect the upper urinary tract from excessive bladder pressure, and to prevent chronic renal failure. Treatments may be pharmacologic (i.e., anticholinergic drugs and botulinum toxin) or surgical (by enterocystoplasty or urinary diversion). In selected cases, neuromodulation and sacral root stimulation can be used to reduce detrusor overactivity and empty the bladder. Management of LUTD in SCI patients requires a deep knowledge of spinal cord medicine and functioning of patients with neurologic disability. PMID- 26003249 TI - Lower urinary tract dysfunction in patients with brain lesions. AB - Stroke and brain tumor are well-known brain diseases. The incidence of lower urinary tract dysfunction (LUTD) in these patients ranges from 14% to 53%, mostly overactive bladder (OAB), and is higher when the frontal cortex is involved. This presumably reflects damage at the prefrontal cortex, cingulate cortex, and other areas that regulate (mainly inhibit) the micturition reflex. White-matter disease (WMD) is a chronic, bilateral form of cerebrovascular disease, leading to a high prevalence of OAB (up to 90%). Since WMD is particularly common in the elderly, WMD may be one of the anatomic substrates for elderly OAB. Traumatic brain injury and normal-pressure hydrocephalus are rather diffuse brain diseases, which cause OAB with a prevalence rate of 60-95%. Recent neuroimaging studies have shown a relationship between LUTD and the frontal cortex in these diseases. Data on other brain diseases, particularly affecting deep brain structures, are limited. Small infarctions, tumors, or inflammatory diseases affecting the basal ganglia, hypothalamus, and cerebellum lead to mainly OAB. In contrast, similar diseases affecting the brainstem lead to either OAB or urinary retention. The latter reflects damage at the periaqueductal gray and the pontine micturition center that directly relay and modulate the micturition reflex. Urinary incontinence (UI) in brain disease can be divided into two types: neurogenic UI (due to OAB) and functional UI (immobility and loss of initiative/cognition). These two types of UI may occur together, but management differs significantly. Management of neurogenic UI includes anticholinergic drugs that do not penetrate the blood brain barrier easily. Management of functional UI includes behavioral therapy (timed/prompted voiding with physical assistance and bladder/pelvic floor training) and drugs to treat gait as well as cognition that facilitate continence. These treatments will maximize the quality of life in patients with brain diseases. PMID- 26003250 TI - Sexual function after strokes. AB - Strokes are the second leading cause of death and the third leading cause of disability worldwide. Thanks in part to better and more available diagnosis, treatment, and rehabilitation, the vast majority of stroke patients tend to survive strokes, particularly in the industrialized world. Motor disability and cognitive changes such as aphasia and visuospatial disorders are most often considered among the major contributors to stroke burden. This chapter discusses disorders of sexual functions as another frequent sequel of strokes. Strokes generally induce hyposexuality, but in some instances they may be followed by hypersexuality. There is some evidence suggesting that lesions of either hemisphere affect sexual activities, but for different reasons: aphasia and depression after left-hemisphere lesions, a deficit in arousal and perhaps visuospatial disorders after right-hemisphere lesions. Psychologic, psychosocial, and physical factors, as well as medications, play an important role. A better understanding of the psychosocial and physiologic mechanisms underlying sexual functioning can provide insight into improving sexual activity and therefore quality of life in patients affected by strokes and other brain lesions. PMID- 26003251 TI - Sexuality in patients with Parkinson's disease, Alzheimer's disease, and other dementias. AB - Sexual dysfunction (SD) is common among patients with Parkinson's disease (PD), Alzheimer's disease (AD), and other dementias. Sexual functioning and well-being of patients with PD and their partners are affected by many factors, including motor disabilities, non-motor symptoms (e.g., autonomic dysfunction, sleep disturbances, mood disorders, cognitive abnormalities, pain, and sensory disorders), medication effects, and relationship issues. The common sexual problems are decreased desire, erectile dysfunction, difficulties in reaching orgasm, and sexual dissatisfaction. Hypersexuality is one of a broad range of impulse control disorders reported in PD, attributed to antiparkinsonian therapy, mainly dopamine agonists. Involvement of a multidisciplinary team may enable a significant management of hypersexuality. Data on SD in demented patients are scarce, mainly reporting reduced frequency of sex and erectile dysfunction. Treatment of SD is advised at an early stage. Behavioral problems, including inappropriate sexual behavior (ISB), are distressing for patients and their caregivers and may reflect the prevailing behavior accompanying dementia (disinhibition or apathy associated with hyposexuality). The neurobiologic basis of ISB is still only vaguely understood but assessment and intervention are recommended as soon as ISB is suspected. Management of ISB in dementia demands a thorough evaluation and understanding of the behavior, and can be treated by non pharmacologic and pharmacologic interventions. PMID- 26003252 TI - Relationship satisfaction and sexuality in Huntington's disease. AB - Huntington's disease (HD) is a chronic disabling disease that inflicts a considerable burden on patients and their families for a variety of reasons. These reasons include cognitive impairment and motor dysfunction, personality changes, and knowledge of possible genetic transmission of the disease to their children. Thus, the decision to take a genetic test for individuals at risk for HD is often associated with family planning and relationship stress. However, for most individuals, a positive genetic test does not alter family planning with regard to their decision to have children. HD has also been associated with abnormal sexual behaviors, although only a few studies have explored sexuality and sexual dysfunction in HD. Up to 85% of men and 75% of women experience sexual problems, including hypoactive sexual disorder in some cases and increased sexual interest and paraphilia in others. Psychologic support should involve the communication of realistic expectations about the progression of the disorder and potential consequences on the children. PMID- 26003253 TI - Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders. AB - Progressive neurodegenerative disorders are devastating diseases with often fatal outcomes. Lower urinary tract symptoms (LUTS) add to morbidity and increase the risk of becoming dependent on the help of others (e.g., nursing-home referral). In Parkinson's disease (PD), the specific loss of dopaminergic neurons in the substantia nigra and possibly also in the ventral tegmental area induces loss of neurogenic bladder control through dysfunction of a complex network in which selective disinhibition of bladder reflexes is lost. In PD, more than 60% of patients have troublesome bladder symptoms, and 30% experience incontinence, though not daily. In atypical parkinsonism, including multiple system atrophy, LUTS are highly prevalent, and the onset of LUTS in comparison to other autonomic symptoms and motor symptoms may serve as a diagnostic marker. Less is known about the pathophysiology of incontinence in Alzheimer's disease, but higher cognitive function including attention and self-management may play a role. Incontinence is a major risk factor for loss of independence. The complex pathophysiologic mechanisms of neurodegenerative disorders and hence complex symptoms play important roles in LUTS and patient quality of life. Nocturia, incontinence, and urgency as well as poor bladder emptying are the most common symptoms. These symptoms may interact with the core symptoms of the disorders, increasing the risk of incontinence and infection. In rarer neurogenerative disorder LUTS may be present, most commonly in disorders with spinal cord involvement. The systematic and careful tracking of symptoms, evaluation using non-invasive techniques, and conservative management including pharmacologic treatments can often markedly improve the lives of patients and their caregivers. PMID- 26003254 TI - Sexual dysfunction in patients with multiple sclerosis. AB - Multiple sclerosis (MS) can affect patients' sexuality and sexual relationships in many ways. Sexual dysfunctions (SDs) are highly prevalent in MS patients and include diminished desire, arousal/erectile dysfunction, and orgasmic/ejaculatory dysfunction. SDs can be caused by damage to the brain, to the spinal cord areas, and to the peripheral neurons engaged in sexual response; by specific MS symptoms (e.g., spasticity, fatigue, incontinence) that interfere with sexual functioning, and finally by the psychosocial impact of the chronic illness (especially mood disorders, cognitive impairment, and couple issues). SDs are highly underdiagnosed in MS patients and have a negative influence on their quality of life. Talking with patients about their sexual issues may bring considerable benefits and reinforce the therapeutic alliance. Many interventions such as education and some coping strategies can be implemented by all healthcare providers. Whenever possible, patients should be referred to a specialist for more specific treatments or counseling. Other important interventions include diagnosing and treating mood disorders, as well as tailoring other MS treatments so that they interfere as little as possible with sexual functioning. PMID- 26003255 TI - Lower urinary tract dysfunction in patients with multiple sclerosis. AB - Lower urinary tract (LUT) dysfunction is common in multiple sclerosis (MS), and has a considerable impact on quality of life. It most often results from involvement of the spinal cord, which results in detrusor overactivity and detrusor sphincter dyssynergia. LUT symptoms may change with time, paralleling the dynamic course of MS, and therefore the need for regular follow-up assessments is essential. A formal evaluation includes history taking, measurement of the postvoid residual volume (PVR), testing for urinary tract infections and urodynamic studies in select cases. If the PVR is elevated, incomplete bladder emptying is best managed by intermittent self-catheterization. Several options exist for managing the overactive bladder, including antimuscarinics, desmopressin, tibial nerve stimulation, and botulinum toxin A. A stepwise approach is adopted for managing LUT dysfunction in MS. PMID- 26003256 TI - Sexual dysfunction in patients with epilepsy. AB - Sexuality is an important and private aspect of life and sexuality and epilepsy have been intimately linked since ancient time. Disturbances of reproductive and sexual health are common in men and women with epilepsy. Multiple causes may lead to sexual dysfunction. The basis for hyposexuality has been attributed to both epilepsy and antiepileptic drug use, making it difficult to distinguish between the illness-specific and pharmacologic impacts on sexual functioning. Low levels of androgens are associated with sexual arousal insufficiency and sexual dysfunction. Data from animal studies support the hypothesis that hyposexuality occurs as a result of epileptiform activity in the temporal lobe, but not in the motor cortex. Enzyme-inducing antiepileptic drugs are metabolized in the hepatic P 450 system (e.g., 3A4, 2C9, 2C19), induce hepatic enzymes, increase the hepatic synthesis of sex hormone-binding globulin (SHBG), and increase the metabolism of sex hormones that might have an additional influence on sexuality in patients with epilepsy. When examining sexual dysfunction in men and women with epilepsy, the Arizona Sexual Experience Scale may be helpful in evaluating sexual function. Laboratory tests for estrogen, free and total testosterone, and serum SHBG may also be useful in evaluating sexual health. PMID- 26003257 TI - Genital and sexual pain in women. AB - This chapter discusses the all too common problem of sex-related pain in women. Pain is a complex perceptive experience, involving biologic as well as psychologic and relational meanings. They become increasingly important with the chronicity of pain. Neurologists are quite aware of the painful aspect of many neurologic disorders, but lifelong and acquired genital and sexual pain is still neglected in a consistent percentage of women. One reason is the view - still held by many - that psychologic factors play the most important role in sex related pain complaints. The consequences of diagnostic delay can be dramatic. Persisting tissue inflammation induces pain to change from acute and "nociceptive," which indicates a "friendly signal," alerting one to ongoing tissue damage, to chronic and "neuropathic," a disease per se. Whilst the primary disease is progressing and neuroinflammation becomes a prominent feature, affected women have to bear years of pain and distress, huge quantifiable and non quantifiable costs, and a progressive deterioration of personal and relational health and happiness. The scenario is even more dramatic when pain complicates an already disabling disease. The main aspects considered in this chapter include neuroinflammation as a key feature of pain; genital and sexual pain as part of neurologic diseases; and genital and sexual pain syndrome (dyspareunia and vaginismus) as primary problems, and their pelvic comorbidities (bladder pain syndrome, endometriosis, irritable bowel syndrome, provoked vestibulodynia/vulvodynia). Finally, we discuss iatrogenic pain, i.e., genital and sexual pain caused by ill-conceived medical, surgical, pharmacologic or radiologic therapeutic interventions. PMID- 26003258 TI - Management and rehabilitation of neurologic patients with sexual dysfunction. AB - Neurologic disease frequently negatively affects sexual experience in multiple ways. The patient's sexual self-image, sexual function, propensity to sexual pain, and motivation to be sexually active may be impacted, as may the sexual experiences of the partner. Difficulties with mobility can limit both partners' sexual arousal and pleasure. Conditions associated with chronic pain or continence concerns add further distress. Thus sexual rehabilitation needs to address many areas. Comorbid depression is common and needs to be stabilized before definitive treatment of sexual dysfunction. Management strategies include cognitive behavioral therapy, mindfulness-based cognitive therapy, and sex therapy and, for erectile dysfunction and premature ejaculation, pharmacotherapy can be added. Benefit from all these modalities is confirmed in the general population but only pharmacologic treatment of erectile dysfunction has been studied in neurologic patients, where benefit is also seen. Testosterone is indicated only for comorbid testosterone deficit: very occasionally the neurologic condition causes secondary male hypogonadism. No androgen deficiency state has been identified in women. Results of testosterone treatment in women are conflicting: recruited women were not clearly dysfunctional and women with neurologic conditions have not been studied. Future research involving both partners using combined medical and psychologic therapy as followed in clinical practice is advocated. PMID- 26003259 TI - Management of male neurologic patients with infertility. AB - Many aspects of fertility rely on intact neurologic function and thus neurologic diseases can result in infertility. While research into general female fertility and alterations in male semen quality is limited, we have an abundance of knowledge regarding ejaculatory dysfunction following nerve injury. Normal ejaculation is the result of coordinated reflex activity involving both the sympathetic and somatic nervous systems. Nerve injury can result in retrograde ejaculation, and anejaculation. With retrograde ejaculation, the ejaculate is propelled into the bladder instead of out through the urethra. In mild cases this condition can be reversed by sympathomimetic medications and, in more severe cases, sperm cells can be extracted from the bladder following ejaculation. With anejaculation, the ejaculatory reflex is not activated by normal sexual stimulation. In such cases, the first choice of treatment is assisted ejaculation, preferably by penile vibratory stimulation. If vibratory stimulation is unsuccessful, then ejaculation can almost always be induced by electroejaculation. In cases where assisted ejaculation fails, sperm can be retrieved surgically from either the epididymis or from the testis. Once viable sperm cells have been obtained, these are used in assisted reproductive techniques, including intravaginal insemination, intrauterine insemination, and in vitro fertilization/intracytoplasmic sperm injection. PMID- 26003260 TI - Management and rehabilitation of neurologic patients with lower urinary tract dysfunction. AB - Diverse lower urinary tract problems arise in neurologic disease, caused by dysfunctions of the bladder and outlet, both during urine storage and voiding. Most neurologic diseases cause some lower urinary tract dysfunction (LUTD), and the type of dysfunction is related to the location of the nervous system lesion. Clinical evaluation requires identification of risk factors for major morbidity, particularly renal dysfunction, and mechanisms underlying symptoms. A holistic approach is needed to cover influential aspects (e.g., cognitive function, mobility, and urinary tract infections) and related issues (e.g., sexual function, bowel function, and autonomic dysreflexia), requiring a multidisciplinary team. Comprehensive history and examination are supported by a bladder diary, urinalysis, and renal assessment, supplemented by urodynamic tests. The simplest classification of neurogenic LUTD describes both bladder and sphincter function, cataloging each structure as normal, overactive, or underactive. Treatment aims to protect life expectancy and improve quality of life, noting the possibility of neurologic disease progression and comorbid disorders. Conservative measures include fluid advice and assessment of suitable containment products. Urine storage can be improved with antimuscarinic medications, bladder injections with botulinum neurotoxin A, and less established methods such as nerve stimulation, intravesical instillations, and beta-3 agonist. For severe storage dysfunction, sacral neuromodulation or surgery to improve reservoir function, increase outlet resistance, or divert the urinary tract may be needed. Voiding is usually replaced by intermittent or indwelling catheterization, which has largely superseded triggered reflex voiding, bladder expression, or sphincterotomy. Treatment selection is hampered by a limited, low quality evidence base. PMID- 26003261 TI - Psychiatric disorders and sexual dysfunction. AB - Sexual problems are highly prevalent among patients with psychiatric disorders. They may be caused by the psychopathology of the psychiatric disorder but also by its pharmacotherapy. Both positive symptoms (e.g., psychosis, hallucinations) as well as negative symptoms (e.g., anhedonia) of schizophrenia may negatively interfere with interpersonal and sexual relationships. Atypical antipsychotics have fewer sexual side-effects than the classic antipsychotics. Mood disorders may affect libido, sexual arousal, orgasm, and erectile function. With the exception of bupropion, agomelatine, mirtazapine, vortioxetine, amineptine, and moclobemide, all antidepressants cause sexual side-effects. Selective serotonin reuptake inhibitors (SSRIs) may particularly delay ejaculation and female orgasm, but also can cause decreased libido and erectile difficulties. SSRI-induced sexual side-effects are dose-dependent and reversible. Very rarely, their sexual side-effects persist after SSRI discontinuation. This is often preceded by genital anesthesia. Some personality characteristics are a risk factor for sexual dysfunction. Also patients with eating disorders may suffer from sexual difficulties. So far, research into psychotropic-induced sexual side-effects suffers from substantial methodologic limitations. Patients tend not to talk with their clinician about their sexual life. Psychiatrists and other doctors need to take the initiative to talk about the patient's sexual life in order to become informed about potential medication-induced sexual difficulties. PMID- 26003262 TI - Preface. PMID- 26003263 TI - Foreword. PMID- 26003264 TI - The Effect of Psychological Intervention on Thirst and Interdialytic Weight Gain in Patients on Chronic Hemodialysis: A Randomized Controlled Trial. AB - OBJECTIVE: Patients on hemodialysis (HD) are unable to eliminate excess fluid and must adhere to a regimen of dietary fluid restriction to prevent volume overload. Thirst represents a major obstacle to the achievement of such a goal. The aim of our study was (1) to assess the association of thirst and xerostomia, measured by validated questionnaires, Dialysis Thirst Inventory and Xerostomia Inventory with interdialytic weight gain (IDWG) and (2) to evaluate in a randomized controlled trial (RCT), the effect of psychological intervention on IDWG and thirst. STUDY DESIGN: Cross-sectional evaluation of association of thirst and IDWG and single blind RCT of psychological intervention on IDWG management. SETTING: Outpatient dialysis unit. SUBJECTS: The cross-sectional evaluation included 117 patients on HD (age, 71 +/- 13 years); among these, 54 were selected for the RCT. INTERVENTION: The questionnaires were administered to all the participating patients; IDWG (4-week average), Kt/V, predialysis blood pressure, dialyzate sodium, hematocrit, serum electrolytes, parathyroid hormone, and patients' medications were recorded. Fifty-four patients were randomized on a 1:1 basis to usual treatment (including dietary advice) or psychological intervention, consisting of group sessions, held once a week for 5 weeks; IDWG and all the other parameters were rechecked after 6 weeks and 6 months. MAIN OUTCOME MEASURE: IDWG change from baseline. RESULTS: Dialysis Thirst Inventory score was correlated with IDWG (rho = 0.575; P < .001), body mass index (rho = 0.257; P = .005), and inversely with age (rho = -0.344; P < .001). A small but significant decrease of IDWG compared to baseline was observed in the intervention group (baseline 1332 +/- 338 g/day; at 6 weeks, 1183 +/- 258 g/day; at 6 months, 1203 +/- 284 g/day; P < .001). No IDWG changes with respect to baseline occurred in controls (baseline 1310 +/- 333 g/day; at 6 weeks, 1336 +/- 340 g/day; at 6 months, 1323 +/- 328 g/day; P = .57). The secondary outcomes were not affected by the intervention. CONCLUSIONS: The findings of our study show that a psychological support may help managing IDWG in HD patients. PMID- 26003265 TI - Informed consent for live liver donors: A qualitative, prospective study. AB - BACKGROUND & AIMS: Adult-to-adult live donor liver transplantation (LDLT) poses serious health risks and no direct health benefits to donors. Ensuring live donors' autonomy through informed consent is critical. We assessed live liver donors' (LD) comprehension, information needs, risk perceptions, and demographics. METHODS: Semi-structured interviews were prospectively conducted with LDs after completing donor evaluation and informed consent at our transplant center. Likert scales measured informed consent domains. Open-ended responses underwent thematic analysis. RESULTS: Thirty LDs participated (100% participation rate). Although 90% of LDs reported being informed about donation 'a great deal', only 66% reported understanding information about donation 'a great deal.' Many (40%) reported difficulty understanding medical terminology. Information LDs most desired to feel comfortable with their decision included: incidence and type of donor complications (67%), description of donation procedure (57%), and the process of donor preparation (43%). Most (83%) LDs rated risks to themselves as 'not at all' to 'somewhat' risky, and minimized these risks. CONCLUSIONS: Although LDs perceived that they were adequately informed, their actual comprehension about donation was inadequate. Findings suggest the value of informed consent for preparation for the procedure and potential periprocedural risks rather than for decision-making. More comprehensible information disclosure may optimize informed consent. PMID- 26003266 TI - The effect of polyunsaturated fatty acids on obesity through epigenetic modifications. AB - BACKGROUND AND PURPOSE: In recent years it has been demonstrated that polyunsaturated fatty acids (PUFA) have anti-inflammatory and as regulators of lipid metabolism. However, the epigenomic mechanisms involved in these processes are not known in depth. The aim of this review was to describe the scientific evidence supports that regular consumption of PUFA may reduce obesity and overweight by altering epigenetic marks. MATERIAL AND METHODS: A search of recent publications was carried out in human clinical trials, as well as animal model and in vitro experiments. RESULTS: Exist a possible therapeutic effect of PUFAs on the prevention and development of obesity due to their ability to reversively modify the methylation of the promoters of genes associated with lipid metabolism and to modulate the activity of certain microRNAs. CONCLUSIONS: A better knowledge and understanding of the PUFAs role in epigenetic regulation of obesity is possible with the current published results. The PUFAs may modulate the promotor epigenetic marks in several adipogenic genes and regulate the expression of several miRNAs. PMID- 26003267 TI - Whole Pelvis Versus Prostate-Only Radiotherapy With or Without Short-Course Androgen Deprivation Therapy and Mortality Risk. AB - BACKGROUND: The purpose of the study was to determine whether the extent of prostate radiotherapy (ie, whole-pelvic radiotherapy [WPRT] vs. prostate and seminal vesicle radiotherapy [PSVRT]) is associated with all-cause mortality (ACM) in men treated with or without androgen deprivation therapy (ADT). PATIENTS AND METHODS: A multiple-institution cohort of 3709 prostate cancer patients was prospectively assembled from 1991 to 2006. The median age was 72 years and all patients had T1c-T3N0M0 adenocarcinoma of the prostate. Patients were treated with WPRT or PSVRT followed by a brachytherapy boost, with or without neoadjuvant ADT (median duration, 4.2 months). Seventy percent of patients had unfavorable risk disease (Gleason score >= 7; prostate-specific antigen >= 10 ng/mL; or stage >= T2b). Cox regression was applied to determine whether the radiation treatment volume affected the risk of ACM. The interaction between radiation volume and ADT use was assessed. RESULTS: After a median follow-up of 3.3 years, 561 deaths were observed. A decreased risk of ACM was noted with the use of WPRT versus PSVRT (adjusted hazard ratio [AHR], 0.58; 95% confidence interval [CI], 0.38-0.89; P = .01), or with ADT use (AHR, 0.71; 95% CI, 0.58-0.90; P = .004). However, a combination of WPRT and ADT did not further improve ACM compared with either WPRT alone or PSVRT with ADT. Moreover, there was a significant interaction between the radiotherapeutic treatment volume and ADT (AHR, 1.61; 95% CI, 1.004-2.58; P = .048). CONCLUSION: Treatment with WPRT or short-course ADT is associated with a decreased risk of ACM, although a combination of the two does not yield greater benefit. This observation suggests a shared mechanism for this risk reduction, which we hypothesize to be via the treatment of micrometastatic disease within the pelvic lymph nodes. PMID- 26003268 TI - Multimodal Therapy in the Treatment of Prostate Sarcoma: The Johns Hopkins Experience. AB - BACKGROUND: The objective of this study was to evaluate the use of neoadjuvant chemoradiation in patients with prostate sarcoma treated at our institution and report oncological outcomes. MATERIALS AND METHODS: The records of patients with intermediate- or high-grade prostate sarcoma treated with curative intent at our institution from 1993 to 2013 were reviewed. Patient demographic information, tumor characteristics, and treatment modalities used were assessed. Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were calculated. RESULTS: Eight patients met inclusion criteria. The mean age at presentation was 64 years, and urinary obstruction was the most common presenting symptom. All patients underwent surgical resection and neoadjuvant radiation and 6 had concurrent chemotherapy. Four patients received intraoperative radiation. With a median follow-up of 36 months, there were no local recurrences, 6 metastases, 4 deaths from disease, and no deaths from other causes. The median OS and CSS was 67.8 months, with actuarial OS and CSS rates of 100% at 1 year, 75% at 2 years, 62.5% at 3 years, and 62.5% at 5 years. Median RFS was 14.2 months, with actuarial RFS rate of 75% at 1 year, 37.5% at 2 years, and 25% at 3 years. CONCLUSION: Prostate sarcomas are rarely cured using surgical resection alone. Our cohort treated with a multimodality approach had favorable CSS and RFS compared with historic and contemporary series of surgery alone and no local recurrences. Most patients developed metastatic recurrence, highlighting the aggressive nature of this disease. PMID- 26003269 TI - Antimullerian hormone levels and antral follicle count as prognostic indicators in a personalized prediction model of live birth. AB - OBJECTIVE: To compare antimullerian hormone (AMH) and antral follicle count (AFC) separately and in combination with clinical characteristics for the prediction of live birth after controlled ovarian stimulation. DESIGN: Retrospective development and temporal external validation of prediction model. SETTING: Outpatient IVF clinic. PATIENT(S): We applied the boosted tree method to develop three prediction models incorporating clinical characteristics plus AMH or AFC or the combination on 2,124 linked IVF cycles from 2006 to 2010 and temporally externally validated predicted live-birth probabilities with an independent data set comprising 1,121 cycles from 2011 to 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Predictive power (posterior log of odds ratio compared to age, or PLORA), reclassification, receiver operator characteristic analysis, calibration, dynamic range. RESULT(S): Predictive power, was highest for the AMH model (PLORA = 29.1), followed by the AMH-AFC model (PLORA = 28.3) and AFC model (PLORA = 22.5). The prediction errors were 1% to <5% in each prognostic tier for all three models, except for the predicted live-birth probabilities of <10% in the AFC model, where the prediction error was 8%. The improvement in predictive power was highest for the AMH model: 76.2% improvement over age alone relative to 59% improvement for AFC and 73.3% for the combined model. Receiver operating characteristic analysis demonstrated that the AMH and the combined model had comparable discrimination (area under the curve = 0.716) and similar prediction error for high and low strata of live-birth prediction, with an improvement of 6.3% over age alone. CONCLUSION(S): The validated prediction model confirmed that AMH when combined with clinical characteristics can accurately identify the likelihood of live birth with a low prediction error. AFC provided no added predictive value beyond AMH. PMID- 26003270 TI - In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment. AB - OBJECTIVE: To study the in vivo mechanisms of action of ulipristal acetate (UPA) on uterine myomas. DESIGN: Retrospective histologic and immunohistochemical (IHC) study of myomas. SETTING: Academic research unit. PATIENT(S): Among 59 women with symptomatic myomas who underwent myomectomy, 42 were treated preoperatively with UPA, while 17 were not. INTERVENTION(S): Histology and IHC were analyzed on tissue microarrays obtained from surgical specimens. MAIN OUTCOME MEASURE(S): Proliferation, apoptosis, extracellular matrix (ECM) remodeling, and matrix metalloproteinase 2 (MMP-2) expression. RESULT(S): Proliferation was low in all conditions, with no statistical difference between groups. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay showed an increase in cell death in UPA-treated myomas compared with untreated myomas, but only after short-term treatment; this was not associated with elevated levels of cleaved caspase-3. After long-term treatment, cell density was higher and the ECM volume fraction lower in UPA-treated myomas than in untreated myomas. MMP-2 expression was found to be increased after treatment, showing the highest level after long-term treatment, compared with untreated myomas. CONCLUSION(S): Regarding sustained clinical volume reduction of myomas, this study strongly points to multifactorial mechanisms of action of UPA, involving: 1) a persistently low cell proliferation rate; 2) a limited period of cell death; and 3) ECM remodeling concomitant with stimulation of MMP-2 expression. PMID- 26003271 TI - First contact: the intersection of demographics, knowledge, and appraisal of treatment at the initial infertility visit. AB - OBJECTIVE: To determine the impact of the initial infertility visit on treatment related knowledge, patient anxiety, and appraisals of treatment. DESIGN: Prospective survey. SETTING: Academic medical center. PATIENT(S): Two hundred thirty-four English-speaking women aged 18-50 years attending their first infertility visit. INTERVENTION(S): Participants completed a survey assessing health literacy, knowledge, anxiety, and appraisals of the treatment process before and after their infertility visit. MAIN OUTCOME MEASURE(S): Knowledge of infertility and treatment and anxiety and appraisal scores. RESULT(S): Most participants were white and earned >$100,000/year and had at least a college education. Baseline knowledge of reproductive anatomy, assisted reproductive technology (ART), and fertility factors was modest but improved after the initial visit. Factors associated with higher knowledge included higher education and income, white or Asian ethnicity, and English as a primary language. Patient appraisals of treatment represented by the positive (Challenge) and negative (Threat and Loss) subscale scores on the Appraisal of Life Events (ALE) scale changed over time Negative appraisals of treatment and anxiety scores decreased and positive appraisals of treatment increased after the initial visit. Lower knowledge was associated with higher positive appraisal scores; lower health literacy was associated with higher anxiety and appraisal scores (positive and negative) after the visit. Black women had higher Challenge scores compared with white and Asian women. Hispanic women had higher anxiety scores than non-Hispanic women. CONCLUSION(S): Infertility patients have modest baseline knowledge of fertility and infertility treatment. The initial infertility visit can improve this knowledge and decrease both negative appraisals of treatment and anxiety levels. Differences in knowledge and appraisal were seen across ethnic groups and other demographic variables. Physicians should individualize patient counseling to improve patients' knowledge and provide realistic treatment expectations while also reducing patient anxiety. PMID- 26003272 TI - Interferometric phase microscopy for label-free morphological evaluation of sperm cells. AB - OBJECTIVE: To compare label-free interferometric phase microscopy (IPM) to label free and label-based bright-field microscopy (BFM) in evaluating sperm cell morphology. This comparison helps in evaluating the potential of IPM for clinical sperm analysis without staining. DESIGN: Comparison of imaging modalities. SETTING: University laboratory. PATIENT(S): Sperm samples were obtained from healthy sperm donors. INTERVENTION(S): We evaluated 350 sperm cells, using portable IPM and BFM, according to World Health Organization (WHO) criteria. The parameters evaluated were length and width of the sperm head and midpiece; size and width of the acrosome; head, midpiece, and tail configuration; and general normality of the cell. MAIN OUTCOME MEASURE(S): Continuous variables were compared using the Student's t test. Categorical variables were compared with the chi(2) test of independence. Sensitivity and specificity of IPM and label-free BFM were calculated and compared with label-based BFM. RESULT(S): No statistical differences were found between IPM and label-based BFM in the WHO criteria. In contrast, IPM measurements of head and midpiece width and acrosome area were different from those of label-free BFM. Sensitivity and specificity of IPM were higher than those of label-free BFM for the WHO criteria. CONCLUSION(S): Label free IPM can identify sperm cell abnormalities, with an excellent correlation with label-based BFM, and with higher accuracy compared with label-free BFM. Further prospective clinical trials are required to enable IPM as part of clinical sperm selection procedures. PMID- 26003273 TI - Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization. AB - OBJECTIVE: To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN: Phase 3 randomized, double-blind, noninferiority trial. SETTING: Multicenter trial. PATIENT(S): A total of 1,390 women aged 35-42 years. INTERVENTION(S): A single injection of 150 MUg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach >=17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S): Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S): Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S): Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: NCT01144416. PMID- 26003274 TI - Formoterol synergy with des-ciclesonide inhibits IL-4 expression in IgE/antigen induced mast cells by inhibiting JNK activation. AB - Inhaled corticosteroid (ICS) therapy in combination with long-acting beta adrenergic agonists (LABA) is the most important treatment for allergic asthma, although the mechanism still remains unclear. However, mast cells play a central role in the pathogenesis of asthma. In this study, we explored the sole or synergetic effects of des-ciclesonide (ICS) and formoterol (LABA) on the cytokines IL-4 and IL-13 and on histamine release from mast cells (RBL-2H3 cells). We found that des-ciclesonide (0.1, 1 and 10nM) and formoterol (0.1, 1 and 10MUM) alone attenuated DNP-BSA-induced IL-4 and IL-13 production, respectively, in a concentration-dependent manner in DNP-IgE-sensitized mast cells. Des-ciclesonide (0.2nM) and formoterol (1MUM) alone also reduced histamine production. However, the combination of des-ciclesonide (0.2nM) and formoterol (1MUM) had a synergistic inhibition effect on IL-4 mRNA expression and protein production but not IL-13 and histamine release. The JNK inhibitor SP600125 (10MUM) inhibited antigen-induced mRNA expression and protein production of IL-4. Des-ciclesonide and formoterol alone inhibited the activation of JNK in a concentration-dependent manner, and the combination of des-ciclesonide (0.2nM) and formoterol (1MUM) exhibited greater inhibition effect compared with des ciclesonide (0.2nM) or formoterol (1MUM) alone. Taken together, these synergistic effects on mast cells might provide the rationale for the development of the most recent ICS/LABA combination approved for asthma therapy. PMID- 26003275 TI - Frizzleds and WNT/beta-catenin signaling--The black box of ligand-receptor selectivity, complex stoichiometry and activation kinetics. AB - The lipoglycoproteins of the mammalian WNT family induce beta-catenin-dependent signaling through interaction with members of the Class Frizzled receptors and LDL receptor-related protein 5/6 (LRP5/6) albeit with unknown selectivity. The 10 mammalian Frizzleds (FZDs) are seven transmembrane (7TM) spanning receptors and have recently been classified as G protein-coupled receptors (GPCRs). This review summarizes the current knowledge about WNT/FZD selectivity and functional selectivity, the role of co-receptors for signal specification, the formation of receptor complexes as well as the kinetics and mechanisms of signal initiation with focus on WNT/beta-catenin signaling. In order to exploit the true therapeutic potential of WNT/FZD signaling to treat human disease, it is clear that substantial progress in the understanding of receptor complex formation and signal specification has to precede a mechanism-based drug design targeting WNT receptors. PMID- 26003276 TI - Circadian activation of the hypothalamic-pituitary-adrenal axis may affect central, but not peripheral, effect of lithium in conditioned taste aversion learning in rats. AB - Activation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in conditioned taste aversion (CTA) learning induced by lithium chloride. This study investigated if circadian activation of the HPA axis affects the lithium induced CTA formation. The pairing of conditioned stimulus (sucrose) and unconditioned stimulus (lithium chloride) was performed at night (shortly after light-off) when the HPA activity shows its circadian increase. Intraperitoenal injection of lithium chloride (0.15M, 3ml/kg or 12ml/kg) at night induced CTA formation and the HPA axis activation and increased c-Fos expression in both the parabrachial nucleus (PBN) and the nucleus tractus of solitarius (NTS) in a dose dependent manner. However, intracerebroventricular lithium (0.6M, 5ul) at night failed to induce CTA or the HPA axis activation, although it increased c-Fos expression in the PBN and NTS. Results suggest that circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA formation, and the lithium-induced c-Fos expression in brain regions may not be effective to induce CTA unless it is coupled with the HPA axis activation. It is concluded that the HPA axis activation may play an important role mediating not only peripheral but also central effect of lithium in CTA formation. PMID- 26003277 TI - The unusual suspects: cytokines in taste perception and beyond. PMID- 26003278 TI - Trends in length of stay, mortality and readmission among patients with community acquired bacteraemia. AB - In patients hospitalized with severe infection, premature discharge may lead to increased risk of readmission and death. We conducted this population-based cohort study to examine trends in length of stay (LOS) and 30-day mortality and hospital readmission rates after bacteraemia from 1994 through 2013. We used Cox regression to compute hazard ratios (HRs) for 30-day mortality and 30-day postdischarge readmission rates by calendar period and quintiles of LOS, adjusting for age, sex and comorbidity. Among 7618 patients hospitalized with community-acquired bacteraemia during the study period, median LOS decreased from 12 days (quartiles 7-21 days) in 1994-1998 to 9 days (quartiles 6-16 days) in 2009-2013 (25% relative reduction). The 30-day mortality fell from 16.7% to 15.0%, yielding an adjusted 30-day HR of 0.80 (95% confidence interval (CI) 0.68 0.95). Almost one fifth (19.4%) of patients discharged alive were readmitted within 30 days. Concurrently, the adjusted HR of readmission tended to increase (adjusted HR 1.09, 95% CI 0.93-1.28) in 2009-2013 compared with 1994-1998. Compared with the middle quintile of LOS (9-12 days), the risk of readmission was slightly higher for patients discharged within 5 days (adjusted HR 1.12, 95% CI 0.92-1.37), especially for readmission due to infection (adjusted HR 1.38, 95% CI 1.03-1.85). Readmission risk was lowest for 6 to 8 days LOS (adjusted HR 0.80, 95% CI 0.67-0.95) and highest for LOS >=23 days (adjusted HR 1.30, 95% CI 1.11 1.53). The declining LOS after community-acquired bacteraemia between 1994 and 2013 was not accompanied by increased 30-day mortality but by slightly increased readmission rates. PMID- 26003279 TI - Improving predictions of the risk of resistance development against new and old antibiotics. AB - The methods used today by academic researchers and the pharmaceutical industry to assess the risk of emergence of resistance, for example during development of new antibiotics or when assessing an old antibiotic, are sub-optimal. Even though easy to perform, the presently used serial passage procedures, minimal prevention concentration measurements and determination of mutation rates in vitro are generally providing inadequate knowledge for risk assessment and making decisions to continue/discontinue drug development. These methods need to be complemented and replaced with more relevant methods such as determination of whether resistance genes already pre-exist in various metagenomes, and the likelihood that these genes can transfer into the relevant pathogens and be stably maintained. Furthermore, to determine the risk of emergence of mutationally conferred resistance the fitness effect of the resistance mechanism is key, as this parameter will determine the ability of the resistant mutants to be maintained and enriched in the host after they have emerged. This information combined with knowledge of bacterial population sizes and growth and killing dynamics at relevant infection sites should allow for better forecasting of the risk of resistance emerging in clinical settings. PMID- 26003280 TI - Variability of human immunodeficiency virus-1 in the female genital reservoir during genital reactivation of herpes simplex virus type 2. AB - Clinical and subclinical genital herpes simplex virus type 2 (HSV-2) reactivations have been associated with increases in human immunodeficiency virus (HIV)-1 genital shedding. Whether HSV-2 shedding contributes to the selection of specific genital HIV-1 variants remains unknown. We evaluated the genetic diversity of genital and blood HIV-1 RNA and DNA in 14 HIV-1/HSV-2-co-infected women, including seven with HSV-2 genital reactivation, and seven without as controls. HIV-1 DNA and HIV-1 RNA env V1-V3 sequences in paired blood and genital samples were compared. The HSV-2 selection pressure on HIV was estimated according to the number of synonymous substitutions (dS), the number of non synonymous substitutions (dN) and the dS/dN ratio within HIV quasi-species. HIV-1 RNA levels in cervicovaginal secretions were higher in women with HSV-2 replication than in controls (p0.02). Plasma HIV-1 RNA and genital HIV-1 RNA and DNA were genetically compartmentalized. No differences in dS, dN and the dS/dN ratio were observed between the study groups for either genital HIV-1 RNA or plasma HIV-1 RNA. In contrast, dS and dN in genital HIV-1 DNA were significantly higher in patients with HSV-2 genital reactivation (p <0.01 and p <0.05, respectively). The mean of the dS/dN ratio in genital HIV-1 DNA was slightly higher in patients with HSV-2 genital replication, indicating a trend for purifying selection (p 0.056). HSV-2 increased the genetic diversity of genital HIV-1 DNA. These observations confirm molecular interactions between HSV-2 and HIV-1 at the genital tract level. PMID- 26003281 TI - Staphylococcus aureus in former Portuguese colonies from Africa and the Far East: missing data to help fill the world map. AB - The aim of the present study was to determine the prevalence and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage among patients and healthcare workers in Angola (ANG), Sao Tome and Principe (STP), Cape Verde (CV) and East Timor (ET), and to characterize the antimicrobial susceptibility, virulence content and population structure of all S. aureus. Despite the importance of MRSA as a major human pathogen, data from these former Portuguese colonies in Africa and Asia are scarce. A total of 2065 nasal swabs recovered between 2010-14 were included in the study. Antimicrobial susceptibility testing and molecular characterization of S. aureus showed: (i) a very high MRSA prevalence in ANG (61.6%), moderate in STP (25.5%), low in CV (5.6%) and null in ET; (ii) a high prevalence of Panton-Valentine leukocidin in STP (36.8%), ET (29.2%) and CV (28.3%) contrasting with ANG (7.9%); (iii) ST5-SCCmecIVa, ST8-IV/V and ST5-VI were the major MRSA clones in ANG (65.2%), STP (44.8%) and CV (50%), respectively; (iv) a high resistance to trimethoprim-sulfamethoxazole in ANG (66.5%) and STP (50.9%), to rifampin in ANG (77.3%), and to tetracycline in STP (26.3%) and ET (20.8%); (v) three major methicillin-susceptible S. aureus clones (ST15, ST508, ST152) were present in all four countries. Age <18 years (OR 2.03, 95% CI 1.24-3.31), previous surgery (OR 2.45, 95% CI 1.24-4.83), no smoking (OR 4.04, 95% CI 1.05-15.50), and longer hospitalization (OR 2.53, 95% CI 1.49-4.28) were risk factors for MRSA carriage. This study provided the first comprehensive overview on MRSA in former Portuguese colonies in Africa and Asia, missing data in the world map. PMID- 26003282 TI - Impact of fluoroquinolone resistance in Gram-negative bloodstream infections on healthcare utilization. AB - There has been a concerning increase in fluoroquinolone resistance among Gram negative bloodstream isolates. This retrospective cohort study examines the implications of fluoroquinolone resistance on use of healthcare resources in patients with Gram-negative bloodstream infections (BSI). Hospitalized adults with first episodes of community-onset Gram-negative BSI from 2010 to 2012 at Palmetto Health Hospitals in Columbia, SC, USA were identified. Multivariate linear regression was used to examine risk factors for prolonged hospital length of stay (HLOS) in survivors of Gram-negative BSI. Among 474 unique patients, 384 (81%) and 90 (19%) had BSI due to fluoroquinolone-susceptible (FQ-S) and fluoroquinolone non-susceptible (FQ-NS) Gram-negative bacilli, respectively. The FQ-NS bloodstream isolates, particularly Escherichia coli, were more likely than FQ-S isolates to be multi-drug resistant (56% versus 6%, p < 0.001). Compared with patients with BSI due to FQ-S bloodstream isolates, those with FQ-NS isolates were more likely to receive inappropriate empirical antimicrobial therapy (26% versus 3%, p < 0.001), have longer mean HLOS (11.6 versus 9.3 days, p 0.03) and treatment duration with intravenous antibiotics during hospitalization (9.1 versus 7.1 days, p 0.001), and use outpatient intravenous antibiotics at hospital discharge (15% versus 8%, p 0.05). After adjustments in the multivariate model, inappropriate empirical antimicrobial therapy was an independent risk factor for prolonged HLOS in survivors of Gram-negative BSI (parameter estimate 3.65 days, 95% CI 0.43-6.86). Multi-drug resistance among FQ NS bloodstream isolates limits both empirical and definitive antimicrobial treatment options and poses excessive burdens on the healthcare system. PMID- 26003283 TI - Relationship between GII.3 norovirus infections and blood group antigens in young children in Tunisia. AB - Noroviruses (NoVs) constitute a major cause of gastroenteritis in Tunisia. One hundred and fourteen matched saliva and stool samples were collected from children (n = 114) suffering from acute gastroenteritis at the hospital of Monastir during the winter season 2011-2012. For 98 of 114 children, blood samples were collected for secretor genotyping. NoVs were associated with 36.8% (n = 42/114) of the gastroenteritis cases. The GII.3 genotype was the most common (69% of all NoVs). For patients who were phenotyped (n = 114) for human blood group antigens (HBGAs), the secretor and non-secretor phenotypes represented 79% and 21%, respectively. Of the NoV infections, 83% were detected in all ABO groups. Five GII.3 isolates, one GII.1 isolate and one GII.7 isolate were detected in Lewis-positive non-secretors, confirmed by genotyping of the FUT2 gene. Even though our data showed that GII.3 NoVs could infect non-secretors, no binding was observed with saliva and GII.3 baculovirus-expressed virus-like particles from the same symptomatic non-secretor individual. This suggests that other factors might also participate in NoV attachment in children and newborns. PMID- 26003284 TI - Molecular methods for identification and characterization of novel papillomaviruses. AB - Papillomaviruses (PV) are a remarkably heterogeneous family of small DNA viruses that infect a wide variety of vertebrate species and are aetiologically linked with the development of various neoplastic changes of the skin and mucosal epithelia. Based on nucleotide similarity, PVs are hierarchically classified into genera, species and types. Novel human PV (HPV) types are given a unique number only after the whole genome has been cloned and deposited with the International HPV Reference Center. As of 9 March 2015, 200 different HPV types, belonging to 49 species, had been recognized by the International HPV Reference Center. In addition, 131 animal PV types identified from 66 different animal species exist. Recent advances in molecular techniques have resulted in an explosive increase in the identification of novel HPV types and novel subgenomic HPV sequences in the last few years. Among PV genera, the gamma-PV genus has been growing most rapidly in recent years with 80 completely sequenced HPV types, followed by alpha-PV and beta-PV genera that have 65 and 51 recognized HPV types, respectively. We reviewed in detail the contemporary molecular methods most often used for identification and characterization of novel PV types, including PCR, rolling circle amplification and next-generation sequencing. Furthermore, we present a short overview of 12 and 10 novel HPV types recently identified in Sweden and Slovenia, respectively. Finally, an update on the International Human Papillomavirus Reference Center is provided. PMID- 26003285 TI - Evaluation of Sleep Disorders in Patients With Severe Traumatic Brain Injury During Rehabilitation. AB - OBJECTIVE: To explore the presence and types of sleep disorders in chronic patients with severe traumatic brain injury (TBI) undergoing inpatient rehabilitation using formal diagnostic criteria based on the International Classification of Sleep Disorders, 2nd edition. DESIGN: Cross-sectional study. SETTING: Inpatient brain injury rehabilitation units. PARTICIPANTS: Chronic inpatients with severe TBI (N=30) were evaluated during rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants wore an actiwatch for 7 days and completed self-report measures on sleep, mood, fatigue, pain, and daytime sleepiness. RESULTS: Twenty participants (67%) had a sleep-wake cycle disturbance, of which 15 (50%) met diagnostic criteria for a sleep disorder. Diagnosed sleep disorders in the sample were insomnia (26.7%), posttraumatic hypersomnia (6.7%), delayed sleep phase syndrome (10%), irregular sleep-wake pattern disorder (3.3%), and periodic limb movement disorder (3.3%). Sleep quality was estimated by senior clinical staff as interfering with rehabilitation in 36.6% of the sample. Poor sleep quality was associated with greater anxiety, fatigue, and daytime sleepiness. CONCLUSIONS: Consistent with previous studies, the present study showed high levels of sleep-wake cycle disturbances in patients with severe TBI undergoing rehabilitation, which were associated with anxiety, fatigue, and daytime sleepiness. These findings highlight the importance of assessing and treating sleep problems in patients with TBI undergoing rehabilitation. PMID- 26003286 TI - A novel method for discrimination between innocent and pathological heart murmurs. AB - This paper presents a novel method for discrimination between innocent and pathological murmurs using the growing time support vector machine (GTSVM). The proposed method is tailored for characterizing innocent murmurs (IM) by putting more emphasis on the early parts of the signal as IMs are often heard in early systolic phase. Individuals with mild to severe aortic stenosis (AS) and IM are the two groups subjected to analysis, taking the normal individuals with no murmur (NM) as the control group. The AS is selected due to the similarity of its murmur to IM, particularly in mild cases. To investigate the effect of the growing time windows, the performance of the GTSVM is compared to that of a conventional support vector machine (SVM), using repeated random sub-sampling method. The mean value of the classification rate/sensitivity is found to be 88%/86% for the GTSVM and 84%/83% for the SVM. The statistical evaluations show that the GTSVM significantly improves performance of the classification as compared to the SVM. PMID- 26003287 TI - Swallowing accelerometry signal feature variations with sensor displacement. AB - Dual-axis accelerometry has recently shown promise as a non-invasive method for detecting swallowing impairment using signal processing and pattern classification algorithms. However, it is unknown whether variations in sensor placement alter signal characteristics, threatening the accuracy of signal processing classifiers for aspiration detection. To address this question, water swallows were recorded in 14 healthy adults using a dual-axis accelerometer in 13 different positions (baseline, and 2, 4, 6 and 8 mm above, below and to the right of baseline). The baseline position was midline, immediately below the thyroid cartilage during quiet breathing. After segmentation and pre-processing, signal features were extracted in multiple domains (time, frequency, time-frequency). The effect of sensor position on signal feature distributions was examined with non-parametric statistical analysis. The analysis showed that the sensor could be displaced by as much as 4 mm inferior and lateral to the baseline position and by up to 6 mm above the baseline location without significantly altering time frequency features. In other words, when considering the baseline position as the origin, the admissible region for sensor placement spans 10 mm in the superior inferior axis and 8 mm in the medial-lateral direction. Results of this study suggest that time-frequency representations of accelerometry signals are most robust to sensor placement variations around the baseline position. The implication of this finding is that a swallowing accelerometry classifier based on time-frequency features can likely tolerate small variations in sensor location without degradation in classification performance. PMID- 26003288 TI - The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis. AB - Canonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably beta-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs. PMID- 26003289 TI - Letter to the editor on "The combined abdominal and perineal approach for dissection of the lower rectum. The development of new indications". How can we describe the anatomical and surgical basis of the combined abdominal and perineal approaches in lower rectal cancer surgery? PMID- 26003291 TI - The best anesthesia regimen for patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. PMID- 26003290 TI - The preoperative level of physical activity is associated to the postoperative recovery after elective cholecystectomy - A cohort study. AB - INTRODUCTION: There is an increasing interest in the role of preoperative physical activity for postoperative recovery. The effect of preoperative physical activity and recovery after cholecystectomy is unknown. The aim of this study was to evaluate the association of self-reported leisure-time preoperative physical activity with postoperative recovery and complications after elective cholecystectomy due to gallstone disease. METHODS: Prospective observational cohort study with 200 patients scheduled to undergo elective cholecystectomy. Level of self-assessed leisure-time physical activity was compared with recovery. RESULTS: Regular physical activity was associated with a higher degree of return to work within three weeks post-operatively (relative chance (RC) 1.26, p = 0.040); with a higher chance of leaving hospital within one day post-op (RC 1.23, p = 0.001), as well as with better mental recovery (RC 1.18, p = 0.049), compared to physically inactive. No statistically significant association was seen with return to work within one week or with self-assessed physical recovery. DISCUSSION: In clinical practice, evaluating the patients' level of physical activity is feasible, and may potentially be used to identify patients being more suitable for same-day surgery. Given the study design, the results from this study cannot prove causality. CONCLUSION: The present study shows that the preoperative leisure-time physical activity-level, is positively associated with less sick leave, a shorter hospital stay and with better mental recovery, three weeks post-elective cholecystectomy. We recommend assessing the physical activity level preoperatively for prognostic reasons. If preoperative/postoperative physical training will increase recovery remains to be shown in a randomized controlled study. PMID- 26003292 TI - Effect of TP53 16-bp and beta-TrCP 9-bp INS/DEL polymorphisms in relation to risk of breast cancer. AB - P53 as a tumor suppressor and an apoptosis modulator, is the regulator of the cell cycle and apoptosis, and contributes to mammary gland development and breast cancer (BC) progression. BTRC gene (Homo sapiens beta-transducing repeat containing E3 ubiquitin protein ligase) encoded protein, beta-TrCP, is a novel regulator of p53. The current study aimed to assess the possible effects of TP53 IVS3 16 bp (rs17878362) and beta-TrCP 9 bp (rs16405) INS/DEL polymorphisms on BC risk in an Iranian population. A total of 439 women including 236 BC patients and 203 healthy women were recruited. The TP53 and beta-TrCP INS/DEL polymorphisms were genotyped by allele-specific polymerase chain reaction method. Our data demonstrated that the TP53 16-bp INS/DEL variation was associated with an increased risk of BC in codominant (INS/INS vs. DEL/DEL: OR=1.82; 95% CI=1.02 3.23; P=0.042) and dominant (Del/INS+INS/INS vs. DEL/DEL: OR=1.48; 95% CI=1.03 2.21; P=0.044) models. Additionally, the variant allele (INS) of TP53 DEL/INS polymorphism with a relatively higher frequency in cases than in controls (35.6 vs. 27.8) was a risk factor for BC (OR=1.43; 95% CI=1.06-1.93; P=0.017). With respect to beta-TrCP INS/DEL polymorphism, our study failed to find any difference in allele and genotype distribution between BC patients and controls in codominant, dominant and recessive tested inheritance models (P>0.05). Furthermore, no significant association among the beta-TrCP and TP53 genotype distribution and clinical characteristics of BC patients were found (P>0.05). Our findings suggest that the TP53 16-bp INS/INS and DEL/INS+INS/INS genotypes as well as the INS allele could be genetic factors related to BC risk. PMID- 26003293 TI - Genome-wide analysis of long noncoding RNA expression profile in papillary thyroid carcinoma. AB - Long noncoding RNAs (lncRNAs) have been proved to play important roles in cancer biology. To understand their expression profile and potential functions in papillary thyroid carcinoma (PTC), we investigated the lncRNA and mRNA expression in PTC and paired adjacent noncancerous thyroid tissue using microarray. Quantitative real time polymerase chain reaction (qRT-PCR) was used to validate 10 differentially expressed lncRNAs. Gene ontology (GO) analysis and pathway analysis were also used to investigate the gene function. Potential target genes of lncRNAs were predicted according to two independent algorithms. The microarray revealed thousands of significantly differentially expressed lncRNAs and mRNAs in PTC relative to noncancerous thyroid tissue. The results of qRT-PCR were consistent with those of the microarray, in that all 10 lncRNAs were differentially expressed with the same trend (up- or down-regulated) (P<0.05). Significantly enriched GO terms and pathways among differentially expressed mRNAs were identified. Many of these pathways were linked to cancer, such as "p53 signaling pathway" (associated with 25 genes), "pathways in cancer" (associated with 75 genes), "MAPK signaling pathway" (associated with 50 genes) and "PPAR signaling pathway" (associated with 16 genes). 1805 dysregulated lncRNAs were found to have cis or trans target genes. 463 of the cis target genes were found to be differentially expressed and might be regulated by lncRNAs in the tumorigenesis of PTC. Our study provides a genome-wide screening and analysis of lncRNA expression profile in PTC for the first time and lays the foundation for further investigation of lncRNAs related to PTC. PMID- 26003294 TI - Multiple non-coding exons and alternative splicing in the mouse Mas protooncogene. AB - The Mas protooncogene encodes a G protein-coupled receptor with the common seven transmembrane domains, expressed mainly in the testis and brain. We provided evidence that Mas is a functional angiotensin-(1-7) receptor and can interact with the angiotensin II type 1 (AT1) receptor. The gene is transcriptionally regulated during development in the brain and testis, but its structure was unresolved. In this study we used 5'- and 3'-RACE, RT-PCR, and RNase-protection assays to elucidate the complete Mas gene structure and organization. We identified 12 exons in the mouse Mas gene with 11 in the 5' untranslated mRNA, which can be alternatively spliced. We also showed that Mas transcription can start from 4 tissue-specific promoters, whereby testis-specific Mas mRNA is transcribed from two upstream promoters, and the expression of Mas in the brain starts from two downstream promoters. Alternative splicing and multiple promoter usage result in at least 12 Mas transcripts in which different 5' untranslated regions are fused to a common coding sequence. Moreover, termination of Mas mRNA is regulated by two different polyadenylation signals. The gene spans approximately 27 kb, and the longest detected mRNA contains 2,451 bp. Thus, our results characterize the Mas protooncogene as the gene with the most complex gene structure of all described members of the gene family coding for G protein coupled receptors. PMID- 26003295 TI - Isolation, characterization and functional analysis of full length p53 cDNA from Bubalus bubalis. AB - p53 plays a pivotal role in maintaining the genomic integrity of the cell and has an important role in cellular transformation. We isolated and cloned a full length p53 cDNA (Bp53) from water buffalo in expression vectors designed to generate tagged proteins with FLAG or GFP. Bp53 was found to be 1161 nucleotide long and codes for 386 amino acid residues with 79% homology with human p53 containing 393 amino acids. Although Bp53 has some inherent differences in amino acid composition in different functional domains as compared to human p53 but the total electrostatic charge of amino acids has been maintained. Bp53 cDNA was transiently transfected in a p53 null human NSCLC cell line and as expected, it was predominantly localized in the nucleus. Besides, Bp53 effectively transactivates a number of target genes similar to human p53 and exerts most of its anti-tumorigenic potential in culture as observed in clonogenic and cell viability assays. Like human p53 mutants, core domain mutant version of Bp53 was found to be mis-localized to cytoplasm with diminished tumor suppressor activity. However, Bp53 appeared to be more sensitive to mdm2 mediated degradation and as a result, this protein was less stable as compared to human p53. For the first time we have characterized a functionally efficient wild-type p53 from buffalo having lower stability than human p53 and thus, buffalo p53 could be used as a model system for further insight to the molecular basis of wild-type p53 instability. PMID- 26003296 TI - Lack of relationship between the P413L chromogranin B variant and a SALS Italian cohort. AB - Chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). Particularly, a variation c.1238C>T (p.Pro413Leu) in the chromogranin B gene, CHGB, has been associated with an earlier age at onset in both familial and sporadic ALS in French/French-Canadian populations studied. The aim of our study was to evaluate the P413L chromogranin variation in Italian patients with sporadic ALS. The study included 366 Italian patients with sporadic ALS and 382 control subjects. Genotyping of the polymorphism P413L in the CHGB gene was performed and the clinical characteristics of patients were analyzed in relation to their genotype. Our study on a cohort of Italian patients with SALS and controls failed to confirm an increased frequency of the 413L variant in SALS patients. Furthermore, we did not confirm the previous observation of a difference of age at onset between T-allele carriers and non-carriers (median age of onset 58.5 vs. 60.2years of age, respectively). Our findings do not support the 413L variant as a risk factor for sporadic ALS in the Italian population. PMID- 26003297 TI - The identification of loci for polydactyly in chickens using a genome-wide association study. AB - Polydactyly is a commonly observed limb malformation in humans and other vertebrates. The Beijing-You chicken expressing the polydactyly phenotype provides an opportunity to investigate the potential cause for polydactyly. Here we extensively exploited genetic determinants of the chicken polydactyly in a genome wide association study using over 580,000 SNPs characterized in a Beijing You * Lohmann F1 cross, consisting of 79 animals. A total of 10 loci clustered on the short arm of chromosome 2 were identified to be significantly associated with the trait. Among the 10 significant SNPs, 7 were located in a linkage disequilibrium block of 1737kb. The strongest association signal (rs317674023, P=5.48*10(-8)) residing nearby Bone Morphogenetic Protein Receptor-Associated Molecule 1 (BRAM1) was identified in the genomic region. Our results provide insights to the genetic basis underlying chicken polydactyly and may facilitate studies of the limb malformation in humans and other species. PMID- 26003298 TI - Green synthesis of gold nanoparticles using chlorogenic acid and their enhanced performance for inflammation. AB - Here we developed a novel green synthesis method for gold nanoparticles (CGA AuNPs) using chlorogenic acid (CGA) as reductants without the use of other chemicals and validated the anti-inflammatory efficacy of CGA-AuNPs in vitro and in vivo. The resulting CGA-AuNPs appeared predominantly spherical in shape with an average diameter of 22.25+/-4.78nm. The crystalline nature of the CGA-AuNPs was confirmed by high-resolution X-ray diffraction and by selected-area electron diffraction analyses. High-resolution liquid chromatography/electrospray ionization mass spectrometry revealed that the caffeic acid moiety of CGA forms quinone structure through a two-electron oxidation causing the reduction of Au(3+) to Au(0). When compared to CGA, CGA-AuNPs exhibited enhanced anti inflammatory effects on NF-kappaB-mediated inflammatory network, as well as cell adhesion. Collectively, green synthesis of CGA-AuNPs using bioactive reductants and mechanistic studies based on mass spectrometry may open up new directions in nanomedicine and CGA-AuNPs can be an anti-inflammatory nanomedicine for future applications. FROM THE CLINICAL EDITOR: Gold nanoparticles (Au NPs) have been shown to be very useful in many applications due to their easy functionalization capability. In this article, the authors demonstrated a novel method for the synthesis of gold nanoparticles using chlorogenic acid (CGA) as reductants. In vitro experiments also confirmed biological activity of the resultant gold nanoparticles. Further in-vivo studies are awaited. PMID- 26003299 TI - Pilot in vivo investigation of cerium oxide nanoparticles as a novel anti-obesity pharmaceutical formulation. AB - Obesity is a worldwide pathological condition that strongly impairs human health, and, to date, no effective therapy against excessive fat accumulation has been found yet. Since overweight correlates with an increased oxidative stress, our aim is to investigate the antioxidant effects of cerium oxide nanoparticles (nanoceria) as a potential pharmaceutical approach for the treatment of obesity. Nanoceria were tested both in vitro and in vivo; they were proven to interfere with the adipogenic pathway by reducing the mRNA transcription of genes involved in adipogenesis, and by hindering the triglycerides accumulation in 3T3-L1 pre adipocytes. Nanoceria, intraperitonally injected in Wistar rats, did not show appreciable toxic effects, but instead efficiently contributed in reducing the weight gain and in lowering the plasma levels of insulin, leptin, glucose and triglycerides. FROM THE CLINICAL EDITOR: Obesity is now a significant problem worldwide. To date, obesity surgery remains the best treatment for weight reduction. Much research has been conducted to discover an effective pharmacological treatment against obesity. In this article, the authors continued their previous work in studying the anti-adipogenic properties of cerium oxide nanoparticles. The antioxidant effects of nanoceria were studied in in vitro and in vivo experiments. It was shown in animal model that nanoceria could reduce body weight effectively. These promising results may provide a novel treatment in the clinical setting in the future. PMID- 26003300 TI - Different states of integrin LFA-1 aggregation are controlled through its association with tetraspanin CD9. AB - The tetraspanin CD9 has been shown to interact with different members of the beta1 and beta3 subfamilies of integrins, regulating through these interactions cell adhesion, migration and signaling. Based on confocal microscopy co localization and on co-immunoprecipitation results, we report here that CD9 associates with the beta2 integrin LFA-1 in different types of leukocytes including T, B and monocytic cells. This association is resistant to stringent solubilization conditions which, together with data from chemical crosslinking, in situ Proximity Ligation Assays and pull-down experiments, suggest a primary/direct type of interaction mediated by the Large Extracellular Loop of the tetraspanin. CD9 exerts inhibitory effects on the adhesive function of LFA-1 and on LFA-1-dependent leukocyte cytotoxic activity. The mechanism responsible for this negative regulation exerted by CD9 on LFA-1 adhesion does not involve changes in the affinity state of this integrin but seems to be related to alterations in its state of aggregation. PMID- 26003301 TI - Study of multi-functional electrospun composite nanofibrous mats for smart wound healing. AB - Composite nanofibers derived from synthetic and natural polymers normally show desirable characteristics in biomedical applications. In this study, composite nanofibrous mats (denoted as CNMs) with diameters of around 300 nm were fabricated facilely using blends of chitosan, gelatin and shape memory polyurethane (SMPU) by electrospinning and subsequent post-treatment with a silver nitrate solution. The obtained CNMs have shape memory effect and show desirable water vapor transmission ratio, surface wettability, satisfactory biological properties including antibacterial activity against the common Gram negative and Gram-positive bacteria, cytocompatibility demonstrated to fibroblast, and the hemostatic property through a whole-blood clotting test. In addition, such CNMs can possibly benefit the wound healing through shape fixation assisted easy processing and shape recovery-assisted closure of cracked wounds, which can be fine-tuned by pre-programming. Therefore, the CNMs presented in this study can be used as potential smart wound dressings. PMID- 26003302 TI - Fungus Cerrena unicolor as an effective source of new antiviral, immunomodulatory, and anticancer compounds. AB - In the report, three bioactive fractions from Cerrena unicolor: laccase (LAC), endopolysaccharides (c-EPL), and low molecular weight (ex-LMS) were tested for the first time towards their antiviral, immunostimulatory, cytotoxic and antiproliferative effect. The immunomodulatory activity was studied by means of THP-1-derived macrophages able to synthesize and secrete IL-6 and TNF-alpha. We used cervical carcinoma cell lines SiHa (ATCC, HTB-35) and CaSki (ATCC, CRL 1550) to determine antitumor activity and human skin fibroblasts (HSF) as a control. SiHa and L929 cell lines were used in the antiviral activity assay to propagate HHV-1 and EMCV, respectively. LAC was the most active against HSV at an early stage of viral replication, whereas the activity of laccase against EMCV was evident after incubation of the virus with LAC before and after the adsorption step. Moreover, the investigations showed that the fungal c-EPL fraction stimulated the production and secretion of TNF-alpha and IL-6 by THP-1-derived macrophages up to a level of 2000 pg/ml and 400 pg/ml, respectively. It was indicated for the first time that the LAC and ex-LMS fractions exhibited anticancer activity. This resulted from their cytotoxic or antiproliferative action against the investigated tumor cells at concentrations above 250 MUg/ml and 10 MUg/ml, respectively. PMID- 26003303 TI - Investigation of curcumin release from chitosan/cellulose micro crystals (CMC) antimicrobial films. AB - Following the novel 'vapor induced phase inversion' (VIPI) method, we have prepared curcumin loaded chitosan/cellulose micro crystals composite films and characterized them by thermo gravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopy (SEM). The equilibrium moisture absorption behavior of these films was investigated under different relative humidity (RH) environments and the data obtained was interpreted by the GAB isotherm model successfully. The films were also studied for their curcumin release behavior in the physiological fluid (PF) at 37 degrees C and the kinetic data obtained was best interpreted by Higuchi model. Finally, the films showed fair antimicrobial action against bacteria and fungi. PMID- 26003304 TI - Absolute and relative educational inequalities in obesity among adults in Tehran: Findings from the Urban HEART study-2. AB - BACKGROUND: The prevalence of obesity is increasing in Iran. Previous studies showed mixed results in relation to association between socioeconomic status and obesity in the country. The current study aimed to examine educational inequalities among adults in Tehran in 2011. METHOD: Data on 90,435 persons 18 years and older from Urban Health Equity Assessment and Response Tool (Urban HEART-2) were analyzed. The Slope Index of Inequality (SII) and the Relative Index of Inequality (RII) were used for assessing educational inequalities in obesity. These measures were quantified using generalized linear models for the binomial family adjusted for sex and age. Subgroup analysis was conducted across sex, age groups and the 22 districts of Tehran. RESULTS: Both SII and RII showed substantial educational inequalities in obesity in favour of more educated adults [RII and SII (95% CI were equal to 2.91 (2.71-3.11) and 0.12 (0.12-0.13)), respectively]. These educational inequalities were persistent even after adjusting for employment, marital status and smoking. Subgroup analysis revealed that educational inequalities were more profound among women. While among men educational inequalities were generally increasing with age, an inverse trend was observed among women. Educational inequalities were observed within all 22 districts of Tehran and generally there were no statistically significant differences between districts. CONCLUSION: An inverse association between education and obesity was observed in the current study. To decrease educational inequalities in Tehran, priority should be given to younger women and older men. Further analyses are needed to explain these inequalities. PMID- 26003305 TI - The association of gray matter volumes in the frontoparietal attention network with temperamental effortful control in young adults: a voxel-based morphometry study. AB - Structural MRI studies have identified a link between cortical maturation and temperamental effortful control (EC), which is a trait-like risk factor for psychopathology during adolescence. However, little research has explored the underlying neural basis of EC in adults. We aimed to examine the relationship between EC and brain structure in young adults. High-resolution T1-weighted images were acquired from 27 undergraduates who completed the Adult Temperament Questionnaire-short form. The data were analyzed with SPM8 using voxel-based morphometry (VBM). A priori region of interest (ROI) analyses indicated that EC was positively associated with gray matter volumes in brain regions that included the bilateral dorsolateral prefrontal cortex, the left supplementary motor area, the right orbitofrontal cortex, the left anterior cingulate cortex, and the left superior and inferior parietal lobes. These results suggest that temperamental EC in young adults is related to variations in gray matter volumes, particularly within the frontoparietal attention network, and yield insight into the relation between the vulnerability to psychopathology and the neurobiological basis of individual differences in temperamental EC. PMID- 26003306 TI - Recent advances and current issues in single-cell sequencing of tumors. AB - Intratumoral heterogeneity is a recently recognized but important feature of cancer that underlies the various biocharacteristics of cancer tissues. The advent of next-generation sequencing technologies has facilitated large scale capture of genomic data, while the recent development of single-cell sequencing has allowed for more in-depth studies into the complex molecular mechanisms of intratumoral heterogeneity. In this review, the recent advances and current challenges in single-cell sequencing methodologies are discussed, highlighting the potential power of these data to provide insights into oncological processes, from tumorigenesis through progression to metastasis and therapy resistance. PMID- 26003307 TI - Expression of Peroxiredoxin 1 After Traumatic Spinal Cord Injury in Rats. AB - Reactive astrogliosis and microgliosis after spinal cord injury (SCI) contribute to glial scar formation that impedes axonal regeneration. The mechanisms underlying reactive astrocyte and microglia proliferation upon injury remain partially understood. Peroxiredoxin 1 (PRDX1) is an antioxidant participating in cell proliferation, differentiation, and apoptosis. However, PRDX1 functions in SCI-induced astrocyte and microglia proliferation are unknown. In this study, we established an acute spinal cord contusion injury model in adult rats to investigate the potential role of PRDX1 during the pathological process of SCI. We found the palpable expression increase of PRDX1 after SCI by western blot and immunohistochemistry staining. Double immunofluorescence staining showed that PRDX1 expression mainly increased in astrocytes and microglia. In addition, PRDX1/proliferating cell nuclear antigen (PCNA) colocalized in astrocytes and microglia. Furthermore, PCNA expression also elevated after SCI, as well as was positively correlated with PRDX1 expression. In vitro, PRDX1 expression in primary rat spinal cord astrocytes and microglia changed in a concentration- and time-dependent manner according to LPS treatment. In addition, PRDX1 knockdown in astrocytes and microglia resulted in the decrease of PCNA expression after LPS stimulation, showing that PRDX1 promoted astrocyte and microglia proliferation after inflammation. Our results suggested that PRDX1 might play a crucial role in astrocyte and microglia proliferation after SCI. PMID- 26003308 TI - The demographic consequences of mutualism: ants increase host-plant fruit production but not population growth. AB - The impact of mutualists on a partner's demography depends on how they affect the partner's multiple vital rates and how those vital rates, in turn, affect population growth. However, mutualism studies rarely measure effects on multiple vital rates or integrate them to assess the ultimate impact on population growth. We used vital rate data, population models and simulations of long-term population dynamics to quantify the demographic impact of a guild of ant species on the plant Ferocactus wislizeni. The ants feed at the plant's extrafloral nectaries and attack herbivores attempting to consume reproductive organs. Ant guarded plants produced significantly more fruit, but ants had no significant effect on individual growth or survival. After integrating ant effects across these vital rates, we found that projected population growth was not significantly different between unguarded and ant-guarded plants because population growth was only weakly influenced by differences in fruit production (though strongly influenced by differences in individual growth and survival). However, simulations showed that ants could positively affect long-term plant population dynamics through services provided during rare but important events (herbivore outbreaks that reduce survival or years of high seedling recruitment associated with abundant precipitation). Thus, in this seemingly clear example of mutualism, the interaction may actually yield no clear benefit to plant population growth, or if it does, may only do so through the actions of the ants during rare events. These insights demonstrate the value of taking a demographic approach to studying the consequences of mutualism. PMID- 26003309 TI - Do exotic plants lose resistance to pathogenic soil biota from their native range? A test with Solidago gigantea. AB - Native plants commonly suffer from strong negative plant-soil feedbacks. However, in their non-native ranges species often escape from these negative feedbacks, which indicates that these feedbacks are generated by at least partially specialized soil biota. If so, introduced plants might evolve the loss of resistance to pathogens in their former native range, as has been proposed for the loss of resistance to specialized herbivores. We compared the magnitude of plant-soil feedbacks experienced by native and exotic genotypes of the perennial forb, Solidago gigantea. Feedbacks were assessed in soil collected across 14 sites sampled across the western part of Solidago's native range in the US. Both native and exotic genotypes of Solidago suffered consistently negative and broadly similar plant-soil feedbacks when grown in North American soil. Although there was substantial variation among soils from different sites in the strength of feedbacks generated, the magnitude of feedbacks generated by North American genotypes of S. gigantea were strongly correlated with those produced in the same soil by European genotypes. Our results indicate that Solidago experiences strong negative soil feedbacks in native soil and that introduced genotypes of Solidago have not lost resistance to these negative effects of soil biota. Both genotypic and landscape-level effects can be important sources of variation in the strength of plant-soil feedbacks. PMID- 26003310 TI - Prevalence of chronic pulmonary aspergillosis in patients with tuberculosis from Iran. AB - In patients with preexisting lung disease, especially a cavity, Aspergillus can infect the surface of the cavity, causing chronic cavitary pulmonary aspergillosis (CCPA), and may form an aspergilloma, collectively called chronic pulmonary aspergillosis (CPA). In the present study, we assessed tuberculosis (TB) patients for CPA based on culture and serological methods. During a period of 1 year (from March 2013 to March 2014), we studied 124 patients with TB (94 with current TB and 30 with previous TB) at Masih Daneshvari Hospital in Tehran, Iran. Sputum specimens were analyzed by direct microscopic examination (DME) and fungal culture. The clinical and radiological features of all patients were recorded, to categorize the patients into CCPA and aspergilloma. All patients were screened for serum-specific IgG against A. fumigatus, by enzyme-linked immunosorbent assay (ELISA). Out of 124 patients with TB (66 male, age range: 10 91 years), 48 patients (38.7 %) exhibited residual cavities. Eighteen (14.5 %) patients had cavities with pleural thickening. A round-shaped mass lesion was detected in six patients (6.8 %). DME was positive in ten patients for septate fungal hyphae. A. fumigatus was grown from 14 samples. Fifty-five (44.3 %) cases were positive for serum-specific IgG against A. fumigatus. Of 124 patients with TB, 3 (2.4 %) met criteria for aspergilloma and 14 (11.3 %) for CCPA. CPA is a common clinical presentation in individuals with healed TB in Iran, as reported by previous studies from other countries. PMID- 26003311 TI - Neonatal urinary tract infection may increase the risk of childhood asthma. AB - The aim of this population-based retrospective cohort study was to investigate the onset of urinary tract infection in newborns and the associated risks of childhood asthma. Children with neonatal UTI (n = 3,312) and randomly selected controls (n = 13,243) were enrolled for our analysis. We calculated the follow-up person-years for each participant from the index date until the diagnosis of asthma, the end of 2008, or withdrawal from the insurance system (because of death or loss to follow-up). Furthermore, we compared the risk of asthma between non-UTI and UTI cohorts by using Cox proportional hazards model analysis, the adjusted hazard ratio (aHR), and a 95 % confidence interval (95 % CI). The overall asthma incidence rate was found to be 1.53-fold significantly higher in the UTI cohort than in the non-UTI cohort (70.3 vs 45.8 per 1000 person-years). After we adjusted for potential risk factors, the overall risk of asthma remained higher in the UTI cohort (aHR = 1.47, 95 % CI = 1.35-1.59). The incidence rate was higher in boys than in girls. Overall, patients suffering from UTI may have a greater risk of developing asthma than patients without UTI. This nationwide retrospective cohort study demonstrates that neonatal UTI may increase the risk of childhood asthma. PMID- 26003312 TI - Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NC 6H 4Me-4] for R = Me, Et and iPr, induce apoptosis, cell cycle arrest and inhibit cell invasion of HT-29 colon cancer cells through modulation of the nuclear factor-kappaB activation pathway and ubiquitination. AB - The phosphanegold(I) carbonimidothioates, Ph3PAu{SC(OR)=NC6H4Me-4} for R = Me (1), Et (2) and iPr (3), feature linear P-Au-S coordination geometries and exhibit potent in vitro cytotoxicity against HT-29 colon cancer cells in both monolayer and multi-cellular spheroid models (e.g., IC50 = 11.9 +/- 0.4 and 20.3 +/- 0.3 MUM for 2, respectively). Both intrinsic and extrinsic pathways of apoptosis are demonstrated by human apoptosis PCR array analysis, caspase activities, DNA fragmentation and cell apoptotic assays. Compounds 1-3 induce an extrinsic pathway that leads to down-regulation of NFkappaB. Compound 2 also exhibits an extrinsic apoptotic pathway involving the activation of both p53 and p73, whereas 3 activates p53 only. Lys48- and Lys63-linked polyubiquitination are also promoted by 1-3. Each of cytotoxic Ph3PAu{SC(OR)=NC6H4Me-4}, for R = Me (1), Et (2) and iPr (3), induce an intrinsic apoptotic pathway as well as an extrinsic pathway leading to down-regulation of NFkappaB. Lys48- and Lys63-linked polyubiquitination are promoted by 1-3 and these are able to inhibit cell invasion and to suppress the activity of TrxR. PMID- 26003313 TI - Benefit finding predicts depressive and anxious symptoms in women with breast cancer. AB - PURPOSE: The aims of this study were to examine the psychometric properties of Chinese version of the Benefit Finding Scale (BFS-C) and to evaluate the effect of benefit finding on depressive and anxious symptoms in Chinese women with breast cancer. METHODS: The English version of the Benefit Finding Scale was translated and back-translated prior to its administration. At the baseline assessment (T1), 658 women with breast cancer completed a demographic form, BFS C, and Hospital Anxiety and Depression Scale (HAD). Then, 4 weeks later (T2), all the participants finished HAD again, and the BFS-C was re-administered to 100 patients who were randomly selected from the total sample. RESULTS: The BFS-C exhibited moderate internal consistency and test-retest reliability. Five factors were extracted by principal component analysis: personal growth, worldview, family relationship, social relationship, and acceptance, and confirmatory factor analyses supported this five-factor model. Regression analyses showed that more benefit finding at T1 could predict less depressive and anxious symptoms at T2, accounting for 21.1 % and 15.3 % of variance, respectively. More worldview, family relationship, social relationship, and acceptance at T1 were associated with less depressive symptoms at T2, and more personal growth, worldview, family relationship, and acceptance at T1 were associated with less anxious symptoms at T2. CONCLUSIONS: BFS-C is of good reliability and validity, and appropriate for assessing benefit finding in women with breast cancer. Worldview, family relationship, and acceptance are important contributing factors to depressive and anxious symptoms, which may be beneficial for women with breast cancer. PMID- 26003314 TI - Predicting factors of health-related quality of life in octogenarians: a 3-year follow-up longitudinal study. AB - PURPOSE: The proportion of very old people is rising, and so, describing their health-related quality of life (HRQoL) is an important point of interest. The aim of this study was to analyse the predictive factors on HRQoL throughout a 3-year follow-up period, in a community-based cohort of octogenarian people. METHODS: From 290 subjects aged 85 and over, sociodemographic and geriatric data, including levels of frailty phenotype assessment, and HRQoL using the EuroQol 5D3L (EQ-5D) instrument were collected. A longitudinal analysis was performed by generalized estimating equations (jointly testing the bivariate effect of variables and its time dependence) and regression mixed models to evaluate the adjusted effect of variables on HRQoL after a 3-year follow-up. RESULTS: In the EQ-5D baseline assessment, the average visual analogue self-rating scale value was 63.82 (SD +/- 19.45), the EQ-5D index was 0.67 (0.34) and the most significant issues were pain/discomfort (61.2 %), depression (45.3 %) and mobility (44.6 %). The third year index was 0.55 (0.38). Independent predictive factors of a lower HRQoL identified by the regression mixed models were female gender (marginal effect ME = -0.101; p = 0.003), being pre-frail (ME = -0.142; p = 0.011) or frail (ME = -0.071; p = 0.030), having heart failure (ME = -0.081; p = 0.037) and having a high social risk score (ME = -0.020; p = 0.015). In contrast, higher functional status (ME = 0.050; p < 0.001) and nutritional score (ME = 0.013; p = 0.011) appeared to be predictive factors of an enhanced HRQoL. The adjusted effect of "time of follow-up" had no statistical significance. CONCLUSION: Frail individuals at baseline have a significant lower HRQoL, whereas a higher functional status and nutritional status are independent predicting factors of an enhanced HRQoL after 3 years of follow-up. These findings may encourage clinicians in order to asses HRQoL. PMID- 26003315 TI - The development of summary components for the Disablement in the Physically Active scale in collegiate athletes. AB - PURPOSE: The Disablement in the Physically Active scale (DPA) is a generic patient-reported outcome designed to evaluate constructs of disability in physically active populations. The purpose of this study was to analyze the DPA scale structure for summary components. METHODS: Four hundred and fifty-six collegiate athletes completed a demographic form and the DPA. A principal component analysis (PCA) was conducted with oblique rotation. Factors with eigenvalues >1 that explained >5 % of the variance were retained. RESULTS: The PCA revealed a two-factor structure consistent with paradigms used to develop the original DPA. Items 1-12 loaded on Factors 1 and Items 13-16 loaded on Factor 2. Items 1-12 pertain to impairment, activity limitations, and participation restrictions. Items 13-16 address psychosocial and emotional well-being. Consideration of item content suggested Factor 1 concerned physical function, while Factor 2 concerned mental well-being. Thus, items clustered around Factor 1 and 2 were identified as physical (DPA-PSC) and mental (DPA-MSC) summary components, respectively. Together, the factors accounted for 65.1 % of the variance. CONCLUSIONS: The PCA revealed a two-factor structure for the DPA that resulted in DPA-PSC and DPA-MSC. Analyzing the DPA as separate constructs may provide distinct information that could help to prescribe treatment and rehabilitation strategies. PMID- 26003316 TI - How well are we measuring postoperative "recovery" after abdominal surgery? AB - PURPOSE: The content validity of patient-reported outcomes (PROs) commonly used to measure postoperative recovery is unknown. The objective of this study was to develop a conceptual framework for recovery after abdominal surgery and to analyze the content of PRO instruments against this conceptual framework. METHODS: Qualitative methods were used to develop a conceptual framework for recovery. Patients undergoing abdominal surgery and healthcare professionals were interviewed. Recovery-related concepts were identified using a thematic analysis, and concepts were then linked to the International Classification of Functioning, Disability and Health (ICF). The contents of eight PRO instruments that have been used to measure recovery were then examined using this conceptual framework. RESULTS: A total of 17 patients and 15 healthcare professionals were interviewed. A total of 22 important recovery-related concepts were identified and linked to the ICF. The four most important concepts were "Energy level," "Sensation of pain," "General physical endurance," and "Carrying out daily routine." The number of important recovery-related concepts covered by each instrument ranged from 1 to 22 (mean 7.3 concepts). The SF36 (n = 22), European Organization for the Treatment and Research of Cancer Quality-of-Life Questionnaire-C30 (n = 20), and the Gastrointestinal Quality-of-Life Index (n = 19) covered the greatest number of important recovery concepts. No instrument covered all of the important concepts. CONCLUSIONS: The comparison of the contents of PRO instruments commonly used to measure postoperative recovery after abdominal surgery demonstrated major gaps in the representation of concepts that are important to patients and healthcare professionals. PMID- 26003317 TI - Short-term quality of life in patients undergoing colonic surgery using enhanced recovery after surgery program versus conventional perioperative management. AB - OBJECTIVE: Enhanced recovery after surgery (ERAS) integrates evidence-based interventions to reduce surgical stress and accelerate rehabilitation. Our study was to compare the short-term quality of life (QOL) in patients undergoing open colonic surgery using ERAS program or conventional management. METHODS: A prospective study of 57 patients using ERAS program and 60 patients using conventional management was conducted. The clinical characteristics of all patients were recorded. QOL was evaluated longitudinally using the questionnaires (EORTC QLQ-C30 and QLQ-CR29) pre- and postoperatively. Generalized estimating equation was used to do the analysis in order to determine the effective impact of correlative factors on the postoperative QOL, including age, sex, BMI, ASA grade, tumor location, tumor size, pTNM stage, recovery program and length of time after surgery. RESULTS: The morbidity in ERAS and control group was 17.5 versus 26.7 % (p = 0.235). The patients in ERAS group had much faster rehabilitation and less hospital stay. In the primary statistical analysis, the scores of global QOL (on POD3, POD6, POD10, POD14, POD21), physical functioning (on POD3, POD6, POD10, POD14, POD21), role functioning (on POD6, POD10, POD14, POD21), emotional functioning (on POD3, POD6, POD10, POD14, POD21), cognitive functioning (on POD3, POD6) and social functioning (on POD3, POD6, POD10, POD14, POD21, POD28) were higher in ERAS group than in control group, which suggested that the patients in ERAS group had a better life status. However, the scores of pain (on POD10, POD14, POD21), appetite loss (on POD3, POD6), constipation (on POD3, POD6, POD10), diarrhea (on POD3, POD10), financial difficulties (on POD10, POD14, POD21), perspective of future health (on POD6, POD10, POD14), gastrointestinal tract problems (on POD3, POD6, POD10) and defecation problems (on POD6, POD10, POD14) were lower in ERAS group than in control group, which revealed that the patients in ERAS group suffered less symptoms. In the further generalized estimating equation analysis, the result showed that recovery program and length of time after surgery had independently positive impact on the patient's postoperative QOL. CONCLUSION: Short-term QOL in patients undergoing colonic cancer using ERAS program was better than that using conventional management. PMID- 26003318 TI - Factors Associated with Having a Medical Home for Children At-Risk of Experiencing Negative Events: Results from a National Study. AB - OBJECTIVES: Although the Patient Centered Medical Home is a considered an optimal model for care, some children still do not receive care in this model. Beyond the clinical and practitioner factors known to affect having a medical home, family and environmental risks [referred to as adverse childhood experiences (ACE)] may also be associated with having a medical home. This study's purpose was to examine whether family and environment risks are associated with children having a medical home. METHODS: Data from the nationally representative, cross-sectional 2011-2012 National Survey of Children's Health telephone survey were used (N = 95,677). Analyses were conducted to describe the sample characteristics and determine the association between family and environmental risks and whether a child has a medical home. A subset of risks were modeled from the seminal study of ACEs. RESULTS: Nearly one-quarter of parents reported that their children experienced at-least one ACE. Compared to children who experienced no ACEs, children who experienced at least one ACE, or other family and environmental risks, had lower odds of having a medical home than those whom did not. Logistic regressions showed that cumulative ACEs (odds ratio (OR) 0.76; 95 % confidence interval (CI) 0.65-0.90) as well as other family and environmental risks (OR 0.36, 95 % CI 0.26-0.51) were related to lower odds of having a medical home. CONCLUSIONS: This study suggests that family and environmental risks, including ACEs, impact parental report of a child having a medical home and that a dosage effect may exist. ACEs and other risk factors must be considered when providers care for children at-risk of experiencing negative events, particularly multiple negative events. PMID- 26003320 TI - The aggregation of "native" human serum albumin. AB - Recombinant fully deuterated, defatted human serum albumin in heavy water was found to be about 90% aggregated before final fractionation. For comparison and to establish a datum for this isotope effect, the extent of aggregation is reported for "native" defatted and fatted human serum albumin solutions in phosphate buffered 1 mg/ml in heavy and light water at 25 degrees C and at 4 degrees C. The extent of aggregation is small over a month at these temperatures, but extensive when the solutions are subjected to repeated freeze-thawing from 18 to 25 degrees C in both D2O and H2O. PMID- 26003321 TI - Creating impact with operations research in health: making room for practice in academia. AB - Operations research (OR)-based analyses have the potential to improve decision making for many important, real-world health care problems. However, junior scholars often avoid working on practical applications in health because promotion and tenure processes tend to value theoretical studies more highly than applied studies. This paper discusses the author's experiences in using OR to inform and influence decisions in health and provides a blueprint for junior researchers who wish to find success by taking a similar path. This involves selecting good problems to study, forming productive collaborations with domain experts, developing appropriate models, identifying the most salient results from an analysis, and effectively disseminating findings to decision makers. The paper then suggests how journals, funding agencies, and senior academics can encourage such work by taking a broader and more informed view of the potential role and contributions of OR to solving health care problems. Making room in academia for the application of OR in health follows in the tradition begun by the founders of operations research: to work on important real-world problems where operations research can contribute to better decision making. PMID- 26003319 TI - Open questions and novel concepts in oral cancer surgery. AB - The persistence of cancerous cells after surgery in oral squamous cell carcinoma (OSCC) represents a major challenge, as it often leads to local recurrences and secondary primary tumors, which are eventually responsible for a large proportion of deaths. This persistence is currently evaluated by histological analyses. In this review we discuss some important pitfalls of the histopathological analysis, such as margin evaluation, specimen shrinkage and T staging. In addition, we critically analyze the appropriateness of current surgical techniques in relation to the concept of field cancerization. Finally, we describe some novel imaging and molecular approaches, which might be useful in tailoring surgical resections and encourage the use of OSCC animal models to explore and provide proof of concept of the feasibility and potential clinical utility of innovative surgical protocols. PMID- 26003322 TI - Root distribution of Nitraria sibirica with seasonally varying water sources in a desert habitat. AB - In water-limited environments, the water sources used by desert shrubs are critical to understanding hydrological processes. Here we studied the oxygen stable isotope ratios (delta (18)O) of stem water of Nitraria sibirica as well as those of precipitation, groundwater and soil water from different layers to identify the possible water sources for the shrub. The results showed that the shrub used a mixture of soil water, recent precipitation and groundwater, with shallow lateral roots and deeply penetrating tap (sinker) roots, in different seasons. During the wet period (in spring), a large proportion of stem water in N. sibirica was from snow melt and recent precipitation, but use of these sources declined sharply with the decreasing summer rain at the site. At the height of summer, N. sibirica mainly utilized deep soil water from its tap roots, not only supporting the growth of shoots but also keeping the shallow lateral roots well hydrated. This flexibility allowed the plants to maintain normal metabolic processes during prolonged periods when little precipitation occurs and upper soil layers become extremely dry. With the increase in precipitation that occurs as winter approaches, the percentage of water in the stem base of a plant derived from the tap roots (deep soil water or ground water) decreased again. These results suggested that the shrub's root distribution and morphology were the most important determinants of its ability to utilize different water sources, and that its adjustment to water availability was significant for acclimation to the desert habitat. PMID- 26003323 TI - A 1-Year Quantitative Survey of Noro-, Adeno-, Human Boca-, and Hepatitis E Viruses in Raw and Secondarily Treated Sewage from Two Plants in Norway. AB - A study of enteric viruses in raw and treated sewage from two secondary treatment plants, which received sewage from Oslo city (plant A) and small municipalities in Hedmark county in Norway (plant B), showed high levels of noro-, adeno-, and bocavirus throughout the year. A seasonal variation was observed for adeno- and GII norovirus with higher levels during winter and bocavirus that had more positive samples during winter. The virus concentrations in raw sewage were comparable in the two plants, with medians (log10 genome copies per liter) of 6.1, 6.3, 6.0, and 4.5 for noro GI, noro GII, adeno-, and bocavirus, respectively. The level of hepatitis E virus was not determined as it was below the limit of quantification. The mean log10 virus reduction was 0.55 (plant A) and 1.44 (plant B) with the highest reduction found in the plant with longer hydraulic retention time. The adenoviruses were dominantly serotype 41, while serotype 12 appeared sporadically. Of the 102 raw and treated sewage samples that were tested, eight were positive for hepatitis E virus of which four were from treated sewage. Two of the four obtained gene sequences from hepatitis E virus originated from the rural sewage samples and showed high similarity with a genotype 3 strain of hepatitis E virus detected in local piglets. Two other hepatitis E virus sequences obtained from urban sewage samples showed high similarities with genotype 3 strains isolated from urban sewage in Spain and a human genotype 1 isolate from India. The study gives information on the levels of noroviruses in raw and treated sewage, which is valuable to risk assessment, information indicating that some infections with hepatitis E viruses in Norway have a regional origin and that human bocavirus 2 and 3 are prevalent in the Norwegian population. PMID- 26003324 TI - Insulin-induced changes in skeletal muscle microvascular perfusion are dependent upon perivascular adipose tissue in women. AB - AIMS/HYPOTHESIS: Obesity increases the risk of cardiovascular disease and type 2 diabetes, partly through reduced insulin-induced microvascular vasodilation, which causes impairment of glucose delivery and uptake. We studied whether perivascular adipose tissue (PVAT) controls insulin-induced vasodilation in human muscle, and whether altered properties of PVAT relate to reduced insulin-induced vasodilation in obesity. METHODS: Insulin-induced microvascular recruitment was measured using contrast enhanced ultrasound (CEU), before and during a hyperinsulinaemic-euglycaemic clamp in 15 lean and 18 obese healthy women (18-55 years). Surgical skeletal muscle biopsies were taken on a separate day to study perivascular adipocyte size in histological slices, as well as to study ex vivo insulin-induced vasoreactivity in microvessels in the absence and presence of PVAT in the pressure myograph. Statistical mediation of the relation between BMI and microvascular recruitment by PVAT was studied in a mediation model. RESULTS: Obese women showed impaired insulin-induced microvascular recruitment and lower metabolic insulin sensitivity compared with lean women. Microvascular recruitment was a mediator in the association between obesity and insulin sensitivity. Perivascular adipocyte size, determined in skeletal muscle biopsies, was larger in obese than in lean women, and statistically explained the difference in microvascular recruitment between obese and lean women. PVAT from lean women enhanced insulin-induced vasodilation in isolated skeletal muscle resistance arteries, while PVAT from obese women revealed insulin-induced vasoconstriction. CONCLUSIONS/INTERPRETATION: PVAT from lean women enhances insulin-induced vasodilation and microvascular recruitment whereas PVAT from obese women does not. PVAT adipocyte size partly explains the difference in insulin-induced microvascular recruitment between lean and obese women. PMID- 26003326 TI - Future of muscle research in diabetes: a look into the crystal ball. AB - In type 2 diabetes, skeletal muscle is not only responsible for early metabolic abnormalities, but its contractile activity also offers an efficient prevention and treatment strategy. This outlook into the coming decades summarises challenges and opportunities for translational research on skeletal muscle in diabetes and related diseases. Currently, our understanding of the interactions between myocellular networks, the master regulators of resting metabolism, and muscle's position within multi-organ crosstalk, is incomplete. In the face of an ageing population, changes within muscle tissue appear to be the predominant mechanisms responsible for sarcopenia, but the relative roles of obesity and ageing as driving forces of its development are less clear. To address these research questions, innovative approaches to optimising exercise training or minimising sedentarism will need to be devised and tested in large-scale standardised prospective studies. Finally, another major challenge will be the identification and evaluation of muscle targets to prevent and treat metabolic diseases. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). PMID- 26003325 TI - Sick of sitting. AB - Sitting too much kills. Epidemiological, physiological and molecular data suggest that sedentary lifestyle can explain, in part, how modernity is associated with obesity, more than 30 chronic diseases and conditions and high healthcare costs. Excessive sitting--sitting disease--is not innate to the human condition. People were designed to be bipedal and, before the industrial revolution, people moved substantially more throughout the day than they do presently. It is encouraging that solutions exist to reverse sitting disease. Work environments, schools, communities and cities can be re-imagined and re-invented as walking spaces, and people thereby offered more active, happier, healthier and more productive lives. PMID- 26003327 TI - Insulin is a key determinant of elevated retinal arteriolar flicker response in insulin-resistant individuals. AB - AIMS/HYPOTHESIS: Insulin may link metabolic disorders to retinal microvascular pathology. The aim of the present study was to investigate the impact of early insulin resistance on retinal microcirculation. METHODS: Retinal diameter responses to flicker-light stimulation were investigated in 81 clinically healthy participants (32 +/- 6 years [mean +/- SD], 59% women) who were recruited according to their BMI. All participants underwent an OGTT and euglycaemic hyperinsulinaemic clamp (40 mU/m(2) . min(-1) insulin dose). After stratification by low and high insulin sensitivity based on a clamp-derived glucose disposal rate of <= or >4.9 mg/kg body mass, respectively, baseline retinal diameters and their relative changes to flicker stimulation were compared while controlling for mean arterial pressure, BMI and sex. RESULTS: The arterial vasodilator response at the end of flicker stimulation (p = 0.044) and the area under the arterial reaction curve during flicker stimulation (p = 0.015) were significantly higher in individuals with low vs high insulin sensitivity. Vasodilatory responses of retinal veins to flicker stimulation and baseline retinal diameters did not differ between insulin-sensitive and insulin-resistant participants (p > 0.05). In a stepwise linear regression analysis, fasting insulin remained the only predictor of the arterial vasodilator response to flicker-light (p < 0.01). Waist circumference also contributed, although to a lesser extent, to the arterial vasodilator response (p = 0.023). CONCLUSIONS/INTERPRETATION: Insulin sensitivity is an important determinant of retinal microvascular function. We propose that the elevated arterial flicker response in insulin-resistant states is a result of higher circulating insulin levels. PMID- 26003329 TI - Optimizing Quality and Efficiency of Healthcare Delivery in Hematopoietic Cell Transplantation. AB - Hematopoietic cell transplantation is a complex and resource intense procedure that can be associated with high risks of treatment failure due to disease relapse or complications. There also exists considerable variability among transplant centers with respect to the number of procedures performed, available resources and personnel, patient selection, transplant practices, and supportive care. Hematopoietic cell transplantation as a specialty has been a pioneer in incorporating the constructs of quality and efficiency routinely in patient care. However, several challenges still remain. Harmonization of data collection and reporting, use of innovative technological tools, evidence-based practice supported by clinical trials, better efforts towards care coordination and transition of care, and reduction of variation will facilitate these efforts and will lead to improved experience and outcomes for hematopoietic cell transplant recipients. PMID- 26003328 TI - Characterization of Cellobiose Dehydrogenase from a Biotechnologically Important Cerrena unicolor Strain. AB - Cellobiose dehydrogenase (CDH), a secreted flavocytochrome produced by a number of wood-degrading fungi, was detected in the culture supernatant of a biotechnologically important strain of Cerrena unicolor grown in a modified cellulose-based liquid medium. The enzyme was purified as two active fractions: CuCDH-FAD (flavin domain) (1.51-fold) with recovery of 8.35 % and CuCDH (flavo heme enzyme) (21.21-fold) with recovery of 73.41 %. As CDH from other wood rotting fungi, the intact form of cellobiose dehydrogenase of C. unicolor is a monomeric protein containing one flavin and one heme b with molecular mass 97 kDa and pI = 4.55. The enzyme is glycosylated (8.2 %) mainly with mannose and glucosamine residues. Moreover, the cellobiose dehydrogenase gene cdh1 and its corresponding cDNA from the fungus C. unicolor were isolated, cloned, and characterized. The 2316-bp full-length cDNA of cdh1 encoded a mature CDH protein containing 771 amino acids preceded by a signal peptide consisting of 18 amino acids. Moreover, both active fractions were characterized in terms of kinetics, temperature and pH optima, and antioxidant properties. PMID- 26003330 TI - Vector-transmitted disease vaccines: targeting salivary proteins in transmission (SPIT). AB - More than half the population of the world is at risk for morbidity and mortality from vector-transmitted diseases, and emerging vector-transmitted infections are threatening new populations. Rising insecticide resistance and lack of efficacious vaccines highlight the need for novel control measures. One such approach is targeting the vector-host interface by incorporating vector salivary proteins in anti-pathogen vaccines. Debate remains about whether vector saliva exposure exacerbates or protects against more severe clinical manifestations, induces immunity through natural exposure or extends to all vector species and associated pathogens. Nevertheless, exploiting this unique biology holds promise as a viable strategy for the development of vaccines against vector-transmitted diseases. PMID- 26003331 TI - Bacterial Endocarditis Manifesting as Outflow Tract Obstruction in Two Patients Implanted With Percutaneous Prosthetic Pulmonary Valves. AB - Recent reports on bacterial infections occurring in patients with transcatheter implanted pulmonary valves have raised concerns about higher than previously perceived occurrences of these events. We report on 2 patients who presented with right ventricular outflow tract obstruction secondary to prosthetic pulmonary valve endocarditis involving the valve's periphery, a rarely described and uncommon manifestation. One patient had an acute and rapidly deteriorating disease course, whereas the other had a more chronic and indolent course. Both patients were treated in the catheterization laboratory to relieve the obstructions, treatments which resulted in satisfactory acute results. PMID- 26003332 TI - Quantification of wastewater sludge dewatering. AB - Quantification and comparison of the dewatering characteristics of fifteen sewage sludges from a range of digestion scenarios are described. The method proposed uses laboratory dewatering measurements and integrity analysis of the extracted material properties. These properties were used as inputs into a model of filtration, the output of which provides the dewatering comparison. This method is shown to be necessary for quantification and comparison of dewaterability as the permeability and compressibility of the sludges varies by up to ten orders of magnitude in the range of solids concentration of interest to industry. This causes a high sensitivity of the dewaterability comparison to the starting concentration of laboratory tests, thus simple dewaterability comparison based on parameters such as the specific resistance to filtration is difficult. The new approach is demonstrated to be robust relative to traditional methods such as specific resistance to filtration analysis and has an in-built integrity check. Comparison of the quantified dewaterability of the fifteen sludges to the relative volatile solids content showed a very strong correlation in the volatile solids range from 40 to 80%. The data indicate that the volatile solids parameter is a strong indicator of the dewatering behaviour of sewage sludges. PMID- 26003333 TI - Degradation kinetics and pathways of three calcium channel blockers under UV irradiation. AB - Calcium channel blockers (CCBs) are a group of pharmaceuticals widely prescribed to lower blood pressure and treat heart diseases. They have been frequently detected in wastewater treatment plant (WWTP) effluents and downstream river waters, thus inducing a potential risk to aquatic ecosystems. However, little is known about the behavior and fate of CCBs under UV irradiation, which has been adopted as a primary disinfection method for WWTP effluents. This study investigated the degradation kinetics and pathways of three commonly-used CCBs, including amlodipine (AML), diltiazem (DIL), and verapamil (VER), under UV (254 nm) irradiation. The chemical structures of transformation byproducts (TBPs) were first identified to assess the potential ecological hazards. On that basis, a generic solid-phase extraction method, which simultaneously used four different cartridges, was adopted to extract and enrich the TBPs. Thereafter, the photo degradation of target CCBs was performed under UV fluences typical for WWTP effluent disinfection. The degradation of all three CCBs conformed to the pseudo first-order kinetics, with rate constants of 0.031, 0.044 and 0.011 min(-1) for AML, DIL and VER, respectively. By comparing the MS(2) fragments and the evolution (i.e., formation or decay) trends of identified TBPs, the degradation pathways were proposed. In the WWTP effluent, although the target CCBs could be degraded, several TBPs still contained the functional pharmacophores and reached peak concentrations under UV fluences of 40-100 mJ cm(-2). PMID- 26003334 TI - Paleolithic nutrition improves plasma lipid concentrations of hypercholesterolemic adults to a greater extent than traditional heart-healthy dietary recommendations. AB - Recent research suggests that traditional grain-based heart-healthy diet recommendations, which replace dietary saturated fat with carbohydrate and reduce total fat intake, may result in unfavorable plasma lipid ratios, with reduced high-density lipoprotein (HDL) and an elevation of low-density lipoprotein (LDL) and triacylglycerols (TG). The current study tested the hypothesis that a grain free Paleolithic diet would induce weight loss and improve plasma total cholesterol, HDL, LDL, and TG concentrations in nondiabetic adults with hyperlipidemia to a greater extent than a grain-based heart-healthy diet, based on the recommendations of the American Heart Association. Twenty volunteers (10 male and 10 female) aged 40 to 62 years were selected based on diagnosis of hypercholesterolemia. Volunteers were not taking any cholesterol-lowering medications and adhered to a traditional heart-healthy diet for 4 months, followed by a Paleolithic diet for 4 months. Regression analysis was used to determine whether change in body weight contributed to observed changes in plasma lipid concentrations. Differences in dietary intakes and plasma lipid measures were assessed using repeated-measures analysis of variance. Four months of Paleolithic nutrition significantly lowered (P < .001) mean total cholesterol, LDL, and TG and increased (P < .001) HDL, independent of changes in body weight, relative to both baseline and the traditional heart-healthy diet. Paleolithic nutrition offers promising potential for nutritional management of hyperlipidemia in adults whose lipid profiles have not improved after following more traditional heart-healthy dietary recommendations. PMID- 26003335 TI - The effects of Present Hedonistic Time Perspective and Past Negative Time Perspective on substance use consequences. AB - BACKGROUND: The overuse of substances can lead to economic, physical, and social consequences. Previous research has demonstrated associations between time perspective and frequency of substance use, but no studies have investigated time perspective's effect on substance use consequences. This study aimed to fill this gap in the literature. METHODS: Using an MTurk sample (N=531), latent factor models tested the hypothesis that both Present Hedonistic Time Perspective (PrHTP) and Past Negative Time Perspective PaNTP positively predict alcohol and illicit drug use consequences. Bootstrap analyses were then used to test the hypothesis that PrHTP indirectly affected the relationship between PaNTP and alcohol and illicit drug use consequences. RESULTS: PrHTP significantly predicted alcohol and illicit drug use consequences. PaNTP also significantly predicted alcohol and illicit drug use consequences. PrHTP was found to indirectly affect the relationship between PaNTP and substance use consequences for both alcohol and illicit drugs. CONCLUSIONS: The findings are consistent with previous research and introduce time perspective as an individual differences risk factor for substance use consequences. The partial and full indirect effects are consistent with the idea that individuals with a PaNTP may develop a PrHTP, placing them at risk for substance use consequences. PMID- 26003336 TI - Serum level of vascular endothelial growth factor decreased in chronic ketamine abusers. AB - AIMS: To evaluate the serum level of vascular endothelial growth factor (VEGF) in a group of chronic ketamine abusers in comparison to healthy controls. METHODS: Eighty-one ketamine abusers who were hospitalized for the treatment of ketamine dependence and 39 healthy controls were recruited. Serum VEGF level was measured by enzyme linked immunosorbent assay (ELISA). Psychopathological symptoms were assessed using Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). RESULTS: Serum level of VEGF was significantly lower in chronic ketamine abusers compared to healthy controls (64.6+/-42.1 vs. 92.4+/-59.4pg/ml, F=7.243, p=0.008). CONCLUSIONS: Serum level of VEGF decreased in chronic ketamine abusers compared to healthy controls. PMID- 26003337 TI - Handling healthcare workforce planning with care: where do we stand? AB - BACKGROUND: Planning the health-care workforce required to meet the health needs of the population, while providing service levels that maximize the outcome and minimize the financial costs, is a complex task. The problem can be described as assessing the right number of people with the right skills in the right place at the right time, to provide the right services to the right people. The literature available on the subject is vast but sparse, with no consensus established on a definite methodology and technique, making it difficult for the analyst or policy maker to adopt the recent developments or for the academic researcher to improve such a critical field. METHODS: We revisited more than 60 years of documented research to better understand the chronological and historical evolution of the area and the methodologies that have stood the test of time. The literature review was conducted in electronic publication databases and focuses on conceptual methodologies rather than techniques. RESULTS: Four different and widely used approaches were found within the scope of supply and three within demand. We elaborated a map systematizing advantages, limitations and assumptions. Moreover, we provide a list of the data requirements necessary to implement each of the methodologies. We have also identified past and current trends in the field and elaborated a proposal on how to integrate the different methodologies. CONCLUSION: Methodologies abound, but there is still no definite approach to address HHR planning. Recent literature suggests that an integrated approach is the way to solve such a complex problem, as it combines elements both from supply and demand, and more effort should be put in improving that proposal. PMID- 26003338 TI - Sex matters to the heart: A special issue dedicated to the impact of sex related differences of cardiovascular diseases. PMID- 26003339 TI - From AChE to BACE1 inhibitors: The role of the amine on the indanone scaffold. AB - In recent years, a progressive increase in age-related disorders could be observed in most western countries, among which Alzheimer's disease (AD) is one of the most challenging. BACE1 could be seen as an attractive target to develop disease-modifying compounds, and in this context, a new series of hybrid molecules was designed and synthesized, based on a previously identified multitarget lead compound. In particular, the amino side chain was appropriately modified to fit BACE1 as additional target. In vitro testing results pointed out compound 8 (IC50=2.49+/-0.08 MUM), bearing the bulky bis(4 fluorophenyl)methyl)piperazine substituent, as the most potent BACE1 inhibitor of the series. PMID- 26003340 TI - Rectal bleeding after radiation therapy for endometrial cancer. AB - BACKGROUND AND PURPOSE: The goals of this study were to determine the rate and risk factors of rectal bleeding (RB) after external beam radiotherapy and vaginal brachytherapy (EBRT +VB), and to compare these data to previously unreported RB rates from PORTEC-2 patients receiving EBRT or VB alone. MATERIALS AND METHODS: Retrospective chart review identified 212 endometrial cancer patients receiving adjuvant EBRT+VB between 2006 and 2013. Patient-reported RB data were also obtained from PORTEC-2 patients randomized to EBRT (n=166) or VB (n=182). The two populations were compared using an RB scale of symptom severity. RESULTS: After a median 35months, 17.9% of EBRT+VB patients (n=38) experienced any RB with 1.9% (n=4) having bleeding requiring intervention. Age ?70years was the only predictor of RB (OR 2.8; 95% CI 1.1-8.7; p=0.027). Rates of patient-reported RB after EBRT were similar with 15.0% (n=25) having any RB and 0.6% (n=1) having "very much" bleeding. On regression analysis, any EBRT (either EBRT alone or EBRT+VB) increased the risk of RB compared to those who received VB alone (OR 3.0; p=0.0028; 95% CI 1.4-6.7). The rates of more severe RB were low and did not significantly differ between treatments. CONCLUSIONS: Significant RB is rare after radiation. EBRT has higher rates of rectal bleeding than VB. The addition of VB to EBRT does not significantly alter bleeding rates. PMID- 26003341 TI - Synthesis of C-5" and C-6"-modified alpha-GalCer analogues as iNKT-cell agonists. AB - Alpha-galactosyl ceramide (alpha-GalCer) is a prototypical synthetic ligand of invariant natural killer T (iNKT) cells. Upon presentation by the MHC class I like molecule CD1d, this glycolipid stimulates iNKT cells to secrete a vast amount of both pro-inflammatory Th1 and anti-inflammatory Th2 cytokines. Recently, we discovered that selected 6"-modified alpha-GalCer analogues may produce markedly Th1-biased responses due to the formation of either an additional anchor with CD1d or by establishing extra interactions with the T-cell receptor of iNKT cells. Here, we report a practical synthesis towards 6"-O carbamate and galacturonamide analogues of alpha-GalCer and their evaluation as iNKT cell agonists in mice. PMID- 26003342 TI - Combination of 4-anilinoquinazoline and rhodanine as novel epidermal growth factor receptor tyrosine kinase inhibitors. AB - A type of novel rhodanine-based 4-anilinoquinazoline, which designed the combination between quinazoline as the backbone and various substituted biological rhodanine groups as the side chain, have been synthesized, and their antiproliferative activities were also evaluated firstly. These compounds displayed good antiproliferative activity and EGFR-TK inhibitory activity. Among them, compound 8d showed good inhibitory activity (IC50=2.7MUM for Hep G2, IC50=3.1MUM for A549) and molecular docking of 8d into EGFR TK active site was also performed, this inhibitor well fitting the active site might well explain its excellent inhibitory activity. PMID- 26003343 TI - Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators. AB - Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), (E/Z)-4-(1-{4-[2 (dodecylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ERalpha via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs. PMID- 26003345 TI - Properties of protease-treated maize starches. AB - Commercially produced maize starches were treated with protease (Promod 25P) and their composition and properties were compared with untreated controls. It was found that, although protease treatment reduced the starch protein contents by 41%, 21% and 37% for the waxy, normal and amylomaize starches, respectively, it also caused some pits on the granule surfaces, which were evident by scanning electron microscopy (SEM), but no obvious decrease in granule dimensions (Coulter Counter Multisizer). The protein extraction was associated with decreases in starch lipid content by 42%, 40% and 45% (waxy, normal and amylomaize starches, respectively) and a decrease in total amylose content (30.7-26.0%) for the normal maize starch. The gelatinisation parameters of the starches by differential scanning calorimetry (DSC) in water, 0.001M HCl or NaOH were less obviously affected by protease treatment in common with the swelling factors at 80 degrees C. The amount of alpha-glucan leached by the swollen (80 degrees C) granules was, however, increased by the protease treatment by factors of 3.8, 1.4, and 1.1, for the waxy, normal and amylomaize starches, respectively. Although proteases provide a useful tool for the purification of native starches, commercial protease preparations need to be controlled in terms of amylase content to prevent modifications to starch structure and properties during industrial processing. PMID- 26003344 TI - Isolation of cholinesterase and beta-secretase 1 inhibiting compounds from Lycopodiella cernua. AB - Three new serratene-type triterpenoids (1-3) and a new hydroxy unsaturated fatty acid (13) together with nine known compounds (4-12) were isolated from Lycopodiella cernua. The chemical structures were established using NMR, MS, and Mosher's method. Compound 13 showed the most potent inhibitory activity against acetylcholinesterase (AChE) with an IC50 value of 0.22MUM. For butyrylcholinesterase (BChE) inhibitory activity, 5 showed the most potent activity with an IC50 value of 0.42MUM. Compound 2 showed the most potent activity with an IC50 of 0.23MUM for BACE-1 inhibitory activity. The kinetic activities were investigated to determine the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 4, 5, and 13 were mixed; BChE inhibition by 5 was competitive, while 2 and 6 showed mixed-types. In addition, molecular docking studies were performed to investigate the interaction of these compounds with the pocket sites of AChE. The docking results revealed that the tested inhibitors 3, 4, and 13 were stably present in several pocket domains of the AChE residue. PMID- 26003346 TI - Preparation and stability of the inclusion complex of astaxanthin with hydroxypropyl-beta-cyclodextrin. AB - The inclusion complex of astaxanthin (ASX) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was prepared. Infrared spectroscopy (IR) proved the formation of the inclusion complex. The water solubility of the inclusion complex was >1.0mg/ml, which is much better than that of ASX. The solid state thermal behaviour of the inclusion complex was investigated by thermogravimetric/differential thermal analysis (TG/DTA). The starting decomposition temperature of ASX was enhanced to about 290 degrees C. The stability of the inclusion complex in solution was also tested. Forming of the inclusion complex greatly enhanced the stability of ASX against light and oxygen. Furthermore, the release of ASX from the inclusion complex was controlled. PMID- 26003347 TI - Spectroscopic, stability and radical-scavenging properties of a novel pigment from gardenia. AB - A novel pigment, named gardecin, has been isolated from gardenia fruits, together with another five known crocins. The pigment, which possessed a structure which is unique among crocins, was characterised using spectrometric techniques, particularly 1D and 2D NMR. The NMR assignments were based on data from (1)H NMR, (13)C NMR, DEPT, (1)H-(1)H COSY, NOESY, HMQC and HMBC measurements. The five known crocins were identified on the basis of MS, UV/visible and 1D NMR data. Chemical stability and antioxidant ability of gardecin in comparison with the other five crocins were studied. The stronger DPPH free radical-scavenging ability of gardecin compared, with the other crocins, was observed. Kinetic studies have shown that all crocins were unstable under various conditions, but surprisingly gardecin was fairly stable. PMID- 26003348 TI - Enrichment of isoflavone aglycones in soymilk by fermentation with single and mixed cultures of Streptococcus infantarius 12 and Weissella sp. 4. AB - Soymilk was fermented with either Streptococcus infantarius 12 (Si 12), Weissella sp. 4 (Ws 4), or their mixed cultures with different mixing ratios (Si 12:Ws 4=1:1, 1:3, 1:5, and 1:10, v/v) for 12h at 37 degrees C. All cultures in soymilk readily proliferated and reached about 10(8-9)CFU/mL. After 12h, pH and titratable acidity of soymilk ranged 4.19-4.47 and 0.57%-0.64%, respectively. The pH of soymilk fermented with Si 12 was the lowest while that obtained with Ws 4 the highest. A sharp increase in beta-glucosidase (beta-glu) activity corresponded well with a rapid decrease in isoflavone glucosides and an increase in aglycone contents. The rate of hydrolysis of isoflavone glucosides was the least with Si 12 while the highest with Ws 4, resulting in about 23%-33% and 98% 99% hydrolysis of the glucosides with Si 12 and Ws 4, respectively, after 12h. Mixed cultures with 1:3, 1:5, and 1:10 ratios seem to be more effective starters for bioactive fermented soymilk with more aglycones and appropriate acidity in a short time than single cultures. PMID- 26003349 TI - Antioxidant properties of extracts from fermented and cooked seeds of Polish cultivars of Lathyrus sativus. AB - Antiradical and total antioxidant activities of extracts from raw, prepared for inoculation, fermented (tempeh) and cooked seeds of grass pea (Lathyrus sativus Krab and Derek cultivars) were measured. Tempeh fermentation with Rhizopus oligosporus resulted in higher scavenging activity towards DPPH and ABTS(+) radicals which correlated well with the content of total phenols. In Derek cultivar, fermentation caused a significant inhibition of linoleic acid oxidation by methanol extracts. In buffer extracts the highest TAA values were observed in raw seeds. Cooking of seeds lowered RSA values as compared to fermentation, especially for the DPPH assay. Methanol and buffer extracts from cooked seeds showed prooxidant activity towards linoleic acid. PMID- 26003350 TI - Salicylaldehyde is a characteristic aroma component of buckwheat groats. AB - Salicylaldehyde (2-hydroxybenzaldehyde) was identified as a characteristic component of buckwheat groats aroma by a sensory analysis guided fractionation of the extract. The extract with the strongest odour was prepared by petroleum ether extraction of water soaked groats. This extract was further extracted with sodium hydrogen carbonate solution and purified by a preparative layer chromatography and identified by NMR, MS and IR spectroscopy. A capillary electrophoresis method was developed and used to determine salicylaldehyde content in buckwheat groats and flour samples. Traditionally dehulled buckwheat grain, which had the strongest odour, contained the highest concentration (1.6ppm) of salicylaldehyde with an odour activity value (OAV) of 216. PMID- 26003351 TI - Terpenes and fatty acid profiles of milk fat and "Bitto" cheese as affected by transhumance of cows on different mountain pastures. AB - The evolution of fatty acid (FA) and terpenoid profiles was studied in milk (n=20) and "Bitto" (n=3), a protected designation of origin cheese produced in a restricted Italian alpine area. Milk came from 25 Italian Brown cows successively grazing pastures at 1400, 2100 and 2200m during transhumance in June-September 2006. The fat matter was analyzed for FAs and terpenes by means of gas chromatography and purge & trap/gas chromatography-mass spectrometry, respectively. FA composition of milk fat varied significantly (p<0.0001) in relation to contents of conjugated linoleic acid (CLA), stearic, linoleic and trans-vaccenic acids. Similar monoterpene profiles characterized milk fat from cows grazing the different pastures and the highest amount of terpenes was measured in milk coming from cows grazing at 1400m. High levels of delta3-carene in milk fat were likely related to the important presence of Ligusticum mutellina in the pasture. Only negligible amounts of sesquiterpenes were detected in milk fat whereas they were the most abundant class in fodder. Both FA and terpene profiles of ripened (70 days) cheeses resembled those of the original milks. Overall, results confirm the influence of the botanical composition of mountain pastures both in enhancing the ruminal synthesis of CLA and in modifying the FA and terpenoid profiles of milk and "Bitto" cheese. Nevertheless, neither the FA nor the terpenoid profiles revealed here can be considered as "unique" to "Bitto" cheese and, for this reason, they can hardly be assumed to be biomarkers for defining a specific relationship among grazing area, milk and "Bitto" cheese. They better represent the chemical fingerprint of the cow feeding, adopted in mountain areas. PMID- 26003352 TI - Stability of antioxidants in an apple polyphenol-milk model system. AB - The stability of antioxidants in an apple polyphenol-milk model system was examined. The model system consisted of skim milk fortified with pH-neutralised apple polyphenols (AP, 0-200mg per 100ml milk), with or without ascorbic acid (100mg per 100ml milk). Physical and chemical changes were evaluated after thermal treatment (120 degrees C, 5min) and oxidative storage (20 degrees C and 38 degrees C, up to 12 weeks). Antioxidant capacity was determined using both oxygen radical absorbance capacity (ORAC) assay and ferric reducing antioxidant power (FRAP) assay. Significant antioxidant capacity was detected in the presence of milk. Antioxidant capacity was retained during thermal treatment but decreased slowly during storage. The concentration of ascorbic acid decreased rapidly, and was close to zero after 2-week storage at 38 degrees C or 10-week storage at 20 degrees C. The brownness of the polyphenol-milk system increased over storage duration of 0-12 weeks; this effect was retarded by the addition of ascorbic acid. This high polyphenol-milk has demonstrated good physical stability. PMID- 26003353 TI - Effects of reactive oxygen species on cellular wall disassembly of banana fruit during ripening. AB - Fruit softening is generally attributed to cell wall disassembly. Experiments were conducted to investigate effects of various reactive oxygen species (ROS) on in vitro cellular wall disassembly of harvested banana fruit. The alcohol extracted insoluble residue (AEIR) was obtained from the pulp tissues of banana fruit at various ripening stages and then used to examine the disassembly of cellular wall polysaccharides in the presence of superoxide anion (O2(-)), hydrogen peroxide (H2O2) or hydroxyl radical (OH) and their scavengers. The presence of OH accelerated significantly disassembly of cellular wall polysaccharides in terms of the increase in contents of total sugars released and uronic acid, and the decrease in molecular mass of soluble polysaccharides, using gel permeation chromatography. However, the treatment with H2O2 or O2(-) showed no significant effect on the disassembly of cellular wall polysaccharides. Furthermore, the degradation of the de-esterified AEIR was more susceptible to OH attack than the esterified AEIR. In addition, the effect of OH could be inhibited in the presence of OH scavenger. This study suggests that disassembly of cellular wall polysaccharides could be initiated by OH as the solublisation of the polysaccharides increased, which, in turn, accelerated fruit softening. PMID- 26003354 TI - Distribution of phenolic compounds in the graded flours milled from whole buckwheat grains and their antioxidant capacities. AB - Whole buckwheat grains were milled into 16 flour fractions using the gradual milling system and the phenolic compounds and the antioxidant capacity of each flour fraction were investigated. The phenolic and flavonoid contents of both free and bound phenolic extracts of buckwheat flour fractions significantly increased in the order from the fraction number 1 (phenolics less rich fraction) to the fraction number 16 (phenolics rich fraction). The phenolic compounds in buckwheat existed primarily in free form, whereas the flavonoids existed in grain in insoluble bound forms, bound to cell wall materials. The amounts of ferulic acid and rutin increased from 2.5 and 2.5MUg/g flour of the phenolics less rich fraction to 609.5 and 389.9MUg/g flour of the phenolics rich fraction of grain, respectively. The higher phenolic contents in the phenolics rich fractions exhibited the stronger antioxidant capacity than the phenolics less rich fractions. As a result, the flour milled from the outer layers of buckwheat grains with large amount of phenolic compounds and antioxidant capacity are considered to have significant health benefits. PMID- 26003355 TI - Gelation properties of previously cooked minced meat from Jonah crab (Cancer borealis) as affected by washing treatment and salt concentration. AB - The influence of washing treatment (dewatered only, one wash, and three washes) and sodium chloride (NaCl) concentration (0%, 2%, and 4%) on the gelation properties of crab mince was investigated. This previously cooked muscle mince is a low-value by-product of the crab processing industry, considered to have little or no functional properties. Crab mince gels were produced and tested for water holding capacity (WHC), gel strength, colour, and electrophoretic profile. Wash treatment and NaCl concentration significantly affected gelation. Washed samples exhibited significantly higher WHC than dewatered samples. The 4% NaCl treatment decreased WHC compared to lower NaCl levels. Multiple washing steps increased the force to gel deformation. Wash treatment and NaCl concentration also affected the colour of gels. Based on these results, cooked crab meat mince treated with three washes and 0% NaCl resulted in the strongest gels with the best water-holding capacity, which can be used in the development of value-added products. PMID- 26003356 TI - Assessment of polyphenolic content and in vitro antiradical characteristics of apple pomace. AB - Apple pomaces, a by-product in the apple juice processing, were subjected to evaluation as potential sources of antioxidant phytochemicals on the basis of their total content of phenolics (from 4.22 to 8.67mg/g), total flavonoids (from 0.45 to 1.19mg/g) and total flavan-3-ols (from 2.27 to 9.51mg/g), and in vitro antiradical activities. Some individual phenolic compounds including caffeic and chlorogenic acids, (+)-catechin and (-)-epicatechin, rutin, quercetin glycosides and phloridzin were identified and quantified by HPLC. The antiradical activity of apple pomaces was tested by measuring their ability to scavenge DPPH and hydroxyl radicals by ESR spectroscopy. The highest DPPH (EC50(DPPH)=6.33mg/ml) and hydroxyl (EC50(OH)=26.11mg/ml) radical scavenging activities were obtained in the case of Reinders pomace. The regression analysis produced moderate to high correlation coefficients between the antiradical activities (1/EC50(DPPH) and 1/EC50(OH)), and total phenolics, total flavonoids, total flavan-3-ols, and some individual phenolic compounds. PMID- 26003357 TI - Human health risk of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in edible fish from Huairou Reservoir and Gaobeidian Lake in Beijing, China. AB - Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured by a gas chromatography-mass spectometry (GC-MS) in some edible fish from Huairou Reservoir and Gaobeidian Lake in Beijing, China. The concentrations of OCPs and PCBs were higher in fish (except Misgurnus anguillicaudatus) from Gaobeidian Lake than in those from Huairou Reservoir. The average concentrations of HCHs, DDTs and PCBs in fish ranged from 0.58 to 8.48, 7.54 to 88.3, below limit of detection (nd) to 22.7ng/g wet weight, respectively. beta-HCH, p,p'-DDE and PCB153 were the most abundant compounds among HCHs, DDTs and PCBs, respectively. Risk assessments of OCPs and PCBs for humans were estimated according to three different guidelines. The results indicated that fish intake would not pose a health risk to humans with a consumption of 7.4+/-8.6g/person day according to the acceptable daily intake (ADI) and minimal risk level (MRL) in the two environments. However, the hazardous ratio of the 95th percentile for PCBs in fish from Gaobeidian Lake exceeded 1, which suggested that daily exposure to PCBs had a lifetime cancer risk of greater than 1 in 1,000,000. PMID- 26003358 TI - Dissipation of organophosphorus pesticides in wheat during pasta processing. AB - For investigating the carryover of some organophosphorus pesticide residues in the cereal food chain from grain to consumer, a study was set up on durum wheat, semolina and pasta. Pesticide-free durum wheat was placed into a small-scale model of a commercial storage vessel and treated with pesticides (malathion, fenitrothion, chlorpyrifos methyl, and pirimiphos methyl) according to the raw material legislation of Turkey. The residue levels of insecticides were determined in wheat, semolina, and spaghetti produced from stored wheat at various time intervals during five months of storage. A multiresidue analysis was performed using GC equipped with an NPD. The confirmation was performed by GC-MS. The residue levels of insecticides in wheat exceeded the maximum residue limits (MRLs) for wheat. The storage period was generally not effective enough to reduce the residues in wheat to levels below the MRLs. Although a considerable amount of the insecticides remained in the semolina, spaghetti processing significantly reduced residue concentrations in general. Pirimiphos methyl was the most persistent of the insecticides and comparatively less substantial loss occurred during milling and spaghetti processing due to its physicochemical properties. PMID- 26003359 TI - Effect of the long-term intake of an egg white hydrolysate on the oxidative status and blood lipid profile of spontaneously hypertensive rats. AB - This paper examines the effects of the long-term consumption of egg white hydrolysed with pepsin (hEW) on the antioxidant status and lipid profile of spontaneously hypertensive rats (SHR). The antioxidant capacity was measured by the oxygen radical absorbance capacity (ORAC) and the oxidative status by the malon-dialdehyde (MDA) assay. The lipid profile was analysed spectrophotometrically. The radical-scavenging capacity of the plasma was increased and the MDA concentration in the aorta was decreased in the SHR treated with 0.5g/kg/day of hEW. Our findings indicate that hEW played an important role in antioxidative defence of SHR and exerted a beneficial effect on the lipid profile, lowering triglycerides and total cholesterol without changing HDL levels. Therefore, hEW may be useful to prevent or reverse abnormalities associated with the metabolic syndrome and its complications, such as hypertension, oxidative stress and hyperlipidemia. PMID- 26003360 TI - Firming of fruit tissues by vacuum-infusion of pectin methylesterase: Visualisation of enzyme action. AB - Apple pieces were vacuum-impregnated with either a pectin methylesterase (PME) and calcium solution or with water prior to pasteurization. Pasteurized apple pieces impregnated with PME and calcium showed a significantly higher firmness. Moreover, solid state (13)C NMR spectroscopy of apple cell wall residues revealed an increase of their molecular rigidity. Exogenous PME addition involved a decrease from 82% to 45% of apple pectin degree of methyl-esterification. Microscopic observations of apple slices immunolabelled with antibodies specific for pectins showed that (i) demethyl-esterification was more intense in the cell wall region lining intercellular spaces (demonstrating a key role for these intercellular channels in the enzyme penetration in the tissue during vacuum infusion) and that (ii) the number of calcium-dimerized deesterified homogalacturonan chains increased. The results corroborate the hypothesis that vacuum-impregnated PME action liberates free carboxyl groups along pectin chains that could interact with calcium, increasing the rigidity of pectins and finally the mechanical rigidity of apple tissue. PMID- 26003361 TI - Antibrowning activity of MRPs in enzyme and fresh-cut apple slice models. AB - The present study examined various types of Maillard reaction products (MRPs) for their inhibitory effect on mushroom tyrosinase. Results showed that monosaccharide-GSH (glutathione) but not polysaccharide-GSH derived MRPs were more active than GSH in inhibiting mushroom tyrosinase. However, in fresh-cut apple slice model, surprisingly GSH performed much better than sucrose-GSH derived MRPs when the apple slices were stored at room temperature for 24h. Further time-course study did find deterioration in tyrosinase mushroom inhibitory activity of sugar-GSH derived MRPs over time, suggesting the formed tyrosinase inhibitors in MRPs are unstable. Different combinations of chemical agents with sucrose-GSH derived MRPs were also investigated on apple slices. A synergistic effect was observed when sucrose-GSH derived MRPs (3.125mM) were applied in combination with 0.5% ascorbic acid. Apart from instability of principal inhibitors, observation of an unpleasant odor from apple slices treated with MRPs raised another concern about the probable negative impact of these inhibitors on the sensory quality of food products. Our research indicates the limited application of MRPs as antibrowning agents for food products. PMID- 26003362 TI - The effect of asparaginase on acrylamide formation in French fries. AB - Acrylamide formation in French fries was investigated in relation to blanching and asparaginase soaking treatments before final frying. Par-fried potatoes of Bintje variety were prepared by cutting strips (0.8*0.8*5cm) which were blanched at 75 degrees C for 10min. Unblanched strips were used as the control. Control or blanched strips were then dried at 85 degrees C for 10min and immediately partially fried at 175 degrees C for 1min. Finally, frozen par-fried potatoes were fried at 175 degrees C for 3min to obtain French fries. Pre-drying of raw or blanched potato strips did not generate acrylamide formation as expected. Partial frying of pre-dried control potato strips generated 370MUg/kg of acrylamide and the final frying determined French fries with 2075MUg/kg of acrylamide. When control potato strips were treated with a 10000 ASNU/l asparaginase solution at 40 degrees C for 20min, the acrylamide formation in French fries was reduced by 30%. When blanched potato strips were treated in the same way, the produced French fries have 60% less acrylamide content than blanched strips without the enzyme treatment. Soaking of blanched potato strips (75 degrees C, 10min) in an 10000 ASNU/l asparaginase solution at 40 degrees C for 20min is an effective way to reduce acrylamide formation after frying by reducing the amount of one of its important precursors such as asparagine. PMID- 26003363 TI - Effect of hydrothermal treatment on the antioxidant properties of broccoli (Brassica oleracea var. botrytis italica) florets. AB - In the extracts of fresh raw and frozen broccoli, caffeic, ferulic, sinapinic acids and kaempferol were identified. Boiling reduced the amounts of caffeic acid and kaempferol in both samples. The concentration of polyphenols was 2.69mg/g fresh mass and 0.96mg/fresh mass in fresh raw broccoli and frozen raw broccoli, respectively. Boiling significantly decreased the amounts of phenolic compounds in fresh broccoli (1.58mg/g of fresh mass). In the case of frozen broccoli, boiling increased the concentration of polyphenols by 38%. Fresh broccoli extract neutralized free radicals by 19.87%. Boiling significantly reduced its antiradical activity (to 15.06%). Samples of frozen broccoli had a 27.06% antiradical ability. Boiling did not change the antiradical activity in frozen broccoli case. Hydrothermal processing significantly influenced on the ability of the extracts to inhibit the decolorization of beta-carotene emulsion. The extract of fresh broccoli had a higher activity when uncooked. Boiling seemed to increase this activity in the case of frozen broccoli samples. The results of the studies on the ability of broccoli extracts to inhibit linoleic acid autooxidation were ambiguous and depended on the method applied. No correlation was found between the content of phenolic compounds and the antioxidant activity of the extracts, regardless of the experimental variant and technique used. PMID- 26003364 TI - Combined effect of temperature and pulsed electric fields on apple juice peroxidase and polyphenoloxidase inactivation. AB - Pulsed electric fields (PEF) were applied to freshly prepared apple juice using a laboratory scale continuous PEF system to study the feasibility of inactivating peroxidase (POD) and polyphenoloxidase (PPO). Square wave PEF using different combinations of electric field strength, pre-treatment temperature and treatment time were evaluated in this study and compared to conventional pasteurisation (72 degrees C; 26s). Inactivation curves for the enzyme were plotted for each parameter and inactivation kinetics were calculated. Results showed the highest level of decrease in the enzymatic activity of 71% and 68%, for PPO and POD, respectively, were obtained by using a combination of preheating to 50 degrees C, and a PEF treatment time of 100MUs at 40kV/cm. This level of inactivation was significantly higher (P<0.05) than that recorded in juice processed by conventional mild pasteurisation where the activity of PPO and POD decreased by 46% and 48%, respectively. The kinetic data for the inactivation of both enzymes could be described using a 1st-order model (P<0.001). PMID- 26003365 TI - Inactivation of soybean lipoxygenase in soymilk by pulsed electric fields. AB - The inactivation of soybean lipoxygenase by pulsed electric fields (PEF) was studied. Effects of PEF parameters (treatment time, pulse strength, pulse frequency and pulse width) were evaluated. Soymilk was exposed to pulsed strengths from 20 to 42kV/cm for up to 1036MUs treatment time in square wave pulse of bipolar mode. Moreover, pulse frequency (100-600Hz) and pulse width (1 5MUs) was also tested at constant pulsed treatment time of 345MUs and strength of 30kV/cm. Residual activity of soybean lipoxygenase decreased with the increase of treatment time, pulse strength, pulse frequency and pulse width. The maximum inactivation of soybean lipoxygenase by PEF achieved 88% at 42kV/cm for 1036MUs with 400Hz of pulse frequency and 2MUs of pulse width at 25 degrees C. Inactivation of soybean lipoxygenase by pulsed electric fields was modeled using several kinetic models. Weibull distribution function was most suitable model describing the inactivation of soybean LOX as a function of pulsed electric fields process parameters. Moreover, reduction of soybean LOX activity related to the electric field strength could be well described by the Fermi model. PMID- 26003366 TI - Antioxidant flavonoid glycosides from the leaves of Ficus pumila L. AB - The Okinawan folks in Japan use Ficus pumila L. as a beverage or herbal medicine to treat diabetes and high blood pressure. Four flavonoid glycosides were isolated and identified as rutin (1 and 3), apigenin 6-neohesperidose (2), kaempferol 3-robinobioside (4) and kaempferol 3-rutinoside (5). Among these compounds, rutin exhibited the strongest antioxidant activity in DPPH radical scavenging assay and superoxide radical inhibition assay. The preparation of Ooitabi leaves in water provide sufficient amount of flavonoid glycosides to the Okinawan although 50% of aqueous ethanol extracted these flavonoid glycosides more effectively. These results show the potential of Ooitabi leaves as a natural source of antioxidant for health management. PMID- 26003367 TI - The formation of potentially harmful compounds in churros, a Spanish fried-dough pastry, as influenced by deep frying conditions. AB - Colour, moisture, hydroxymethylfurfural (HMF) and acrylamide (AA) were investigated in traditional Spanish churros. Samples were deep-fried in sunflower oil at lab-scale temperatures of 180, 190 and 200 degrees C and for frying times of 2, 3, 5 and 7min. Fresh made churros were also obtained from local producers. HMF ranged from 1.2+/-0.02 to 221.4+/-2.02mg/kg for lab-scale experiments and an average of 74.3+/-47.5mg/kg was recorded in commercial samples. AA ranged from below the limit of quantitation to 90+/-0.6MUg/kg for lab-scale experiments and an average of 46+/-24.5MUg/kg was measured in commercial samples. Temperatures between 185 and 200 degrees C are commonly used to obtain churros with an acceptable palatability and a crispy surface. However, HMF and AA levels increased nearly two-fold from 190 to 200 degrees C at the same frying times, indicating that a more precise control of frying temperatures is required to minimize their formation. PMID- 26003368 TI - Study of polyphenol content in the seeds of red grape (Vitis vinifera L.) varieties cultivated in Turkey and their antiradical activity. AB - The polyphenolic content and antioxidant capacity in the seeds of 11 red grape varieties (five international and six native) widely cultivated in Turkey were investigated. Total phenolic, total flavanol and total polymeric procyanidin content ranged from 79.2 to 154.6, 89.2 to 179.4, and 27.0 to 43.3mg/g seed, respectively. While (+)-catechin (4.71-23.8mg/g seed) was found as main flavanol, galloylated catechin monomer and dimeric procyanidin amounts varied between 2.89 17.2 and 0.97-2.97mg/g seed, respectively. All seed extracts showed remarkable DPPH radical scavenging activity (EC50) and oxygen radical scavenging capacity (ORAC) ranging from 2.71 to 4.62MUg/mL and 1425.9 to 3009.2MUmol Trolox equivalent/g seed, respectively. With high amount of total phenolic content and antioxidant activity, seeds of Okuzgozu, Papaz Karasi, Ada Karasi and Kalecik Karasi varieties could be evaluated as dietary supplement. PMID- 26003369 TI - Simultaneous kinetic-spectrophotometric determination of maltol and ethyl maltol in food samples by using chemometrics. AB - A fast and accurate procedure has been researched and developed for the simultaneous determination of maltol and ethyl maltol, based on their reaction with iron(III) in the presence of o-phenanthroline in sulfuric acid medium. This reaction was the basis for an indirect kinetic spectrophotometric method, which followed the development of the pink ferroin product (lambdamax=524nm). The kinetic data were collected in the 370-900nm range over 0-30s. The optimized method indicates that individual analytes followed Beer's law in the concentration range of 4.0-76.0mgL(-1) for both maltol and ethyl maltol. The LOD values of 1.6mgL(-1) for maltol and 1.4mgL(-1) for ethyl maltol agree well with those obtained by the alternative high performance liquid chromatography with ultraviolet detection (HPLC-UV). Three chemometrics methods, principal component regression (PCR), partial least squares (PLS) and principal component analysis radial basis function-artificial neural networks (PC-RBF-ANN), were used to resolve the measured data with small kinetic differences between the two analytes as reflected by the development of the pink ferroin product. All three performed satisfactorily in the case of the synthetic verification samples, and in their application for the prediction of the analytes in several food products. The figures of merit for the analytes based on the multivariate models agreed well with those from the alternative HPLC-UV method involving the same samples. PMID- 26003370 TI - Determination of carotenoids in Dunaliella salina cultivated in Taiwan and antioxidant capacity of the algal carotenoid extract. AB - A simple HPLC method with good separation efficiency was developed to determine all-trans and cis forms of carotenoids in Dunaliella salina cultivated in Taiwan. The analysis used a C30 column (250*4.6mm, 5MUm) and an isocratic solvent system (flow rate=1mL/min) mixing methanol-acetonitrile-water (84/14/2, v/v/v) and methylene chloride, (75/25, v/v). Carotenoids were detected at 450nm. Moreover, the antioxidant capacities of the algal carotenoid extract were also evaluated with Trolox equivalent antioxidant capacity (TEAC) assay, reducing power and 2,2 diphenyl-2-picrylhydrazyl hydrate (DPPH) radical scavenging assay. Results showed that 7 carotenoids in the algal extract could be separated simultaneously within 30min and the total amount of them was 290.77mg/g algae. The contents of all trans-beta-carotene and 9- or 9'-cis-beta-carotene, the major carotenoids in the algae, were 138.25 and 124.65mg/g algae, respectively. The contents of all-trans lutein, all-trans-zeaxanthin, 13- or 13'-cis-beta-carotene, all-trans-alpha carotene and 9- or 9'-cis-alpha-carotene were 6.55, 11.27, 4.95, 2.69, and 2.41mg/g algae, respectively. The algal carotenoid extract had significantly higher antioxidant activity than all-trans forms of alpha-carotene, beta carotene, lutein and zeaxanthin in all antioxidant assays. The cis forms of carotenoids, especially 9- or 9'-cis-beta-carotene, might play crucial roles for the antioxidant capacities of the algal extract. PMID- 26003371 TI - Determination of the fruit content of apricot and strawberry jams and spreads and apricot and peach fruit preparations by gravimetric quantification of hemicellulose. AB - An innovative method developed for fruit content determination based on the quantification of hemicellulose was applied to apricot and peach fruit preparations, apricot and strawberry jams and spreads. For this purpose, the hemicellulose fraction was isolated from the alcohol-insoluble residue from peaches, apricots, and strawberries, yielding the amount of the respective fresh fruit per gram hemicellulose. Fruit preparations from peaches with 34.4%, 47.2% and 66.4% fruit content were produced using pectin and carrageenan, xanthan or starch, respectively, as hydrocolloids. Jams from apricots and strawberries were prepared with pectin. Fruit contents of apricot jams were 34.1% and 48.2%, and 36.6% and 46.4% in strawberry jams, respectively. Furthermore, a range of commercial apricot spreads and jams and one strawberry spread as well as apricot and peach fruit preparations were examined. The fruit content was calculated based on the amount of hemicellulose. Calculated fruit contents were in good agreement with the respective product specifications (e.g. 62.6% vs. 66.4%, 35.2% vs. 34.1%, 67.5% vs. 70.0% and 54.0% vs. 53.7%, respectively) with deviations ranging between 0.3% and 4.2%. Maximal deviation was found only in the case of a self-made peach fruit preparation (40.9% vs. 34.4%), where interference of added hydrocolloids and fruit ingredients probably resulted in significant overestimation of the fruit content. Although sample preparation needed to be adapted to different fruit matrices, this novel method proved to be suitable for the determination of fruit contents of fruit preparations, spreads and jams. For the first time, this method was successfully applied to industrially manufactured fruit products without knowledge of fruit specification and the complex recipes of jams, spreads, and fruit preparations, respectively. PMID- 26003372 TI - High throughput flow injection bioluminometric method for olive oil antioxidant capacity. AB - This paper describes a rapid flow injection automated method for the determination of olive oil total antioxidant capacity. The chemistry involved is the horseradish peroxidase (HRP) catalysed oxidation of luminol by hydrogen peroxide. Oxidation results in light emission (bioluminescence) that is enhanced using p-iodophenol sensitizer. Olive oil (0.7mL) is extracted with two 0.7mL aliquots of 80-20% (v/v) methanol-water solvent. A 17MUL aliquot of the extract containing hydrophilic antioxidants is injected in a phosphate buffer channel that subsequently merges with a luminol-HRP-p-iodophenol reagent stream. Bioluminescence resulting after merging the mixture with a hydrogen peroxide stream is suppressed upon increasing antioxidants' concentration resulting in negative peaks due to hydrogen peroxide consumption by antioxidants. The method has been optimized on (a) number of manifold channels, (b) flow rates, (c) coil length and (d) HRP, hydrogen peroxide and p-iodophenol concentrations. Detection limit is calculated at 1.5*10(-7)M gallic acid, linear range is between 1.0*10( 6) and 1*10(-4)M and precision is better than 2.8% RSD (n=4). The fully automated method is achieving a rate of sampling equal 180 probes per hour. The proposed method is applied for the assessment of 50 extra-virgin olive oil samples of different Greek cultivars and regions. PMID- 26003373 TI - HPLC analysis and safety assessment of coumarin in foods. AB - Coumarin is a component of natural flavourings including cassia, which is widely used in foods and pastries. The toxicity of coumarin has raised some concerns and food safety authorities have set a maximum limit of 2mg/kg for foods and beverages in general, and a maximum level of 10mg/l for alcoholic beverages. An efficient method for routine analysis of coumarin is liquid chromatography with diode array detection. The optimal sample preparation for foods containing cinnamon was investigated and found to be cold extraction of 15g sample with 50mL of methanol (80%, v/v) for 30min using magnetic stirring. In the foods under investigation, appreciable amounts of coumarin were found in bakery products and breakfast cereals (mean 9mg/kg) with the highest concentrations up to 88mg/kg in certain cookies flavoured with cinnamon. Other foods such as liqueurs, vodka, mulled wine, and milk products did not have coumarin concentrations above the maximum level. The safety assessment of coumarin containing foods, in the context of governmental food controls, is complicated as a toxicological basis for the maximum limits appears to be missing. The limits were derived at a time when a genotoxic mechanism was assumed. However, this has since been disproven in more recent studies. Our exposure data on coumarin in bakery products show that there is still a need for a continued regulation of coumarin in foods. A toxicological re-evaluation of coumarin with the aim to derive scientifically founded maximum limits should be conducted with priority. PMID- 26003374 TI - Geographical origin of polished rice based on multiple element and stable isotope analyses. AB - We determined carbon and nitrogen contents (C and N contents) and stable carbon, nitrogen, and oxygen isotopic compositions (delta(13)C, delta(15)N, and delta(18)O) of polished rice in order to develop a simple method to discriminate its geographical origin. As a first attempt, we examined a single cultivar, Koshihikari rice, from 14 different cultivation areas including Australia (n=1), Japan (n=12), and USA (n=1). For all rice samples, C and N contents and the isotopic compositions are consistent with those of general plant materials, being 37.2-40.0% (C content), 0.8-1.4% (N content), -27.1 to -25.4% (delta(13)C), +0.4 to +9.0% (delta(15)N), and +18.8 to +22.9% (delta(18)O). However, its cultivated area is clearly distinguished by a pentagonal radar plot based on the elemental and isotopic compositions. Thus, the comparison of C and N contents and delta(13)C, delta(15)N, and delta(18)O values would potentially be useful for rapid and routine discrimination of geographical origin of the polished rice. PMID- 26003375 TI - Platelet miRNAs and cardiovascular diseases. AB - Activated platelets play a critical role in the acute complications of atherosclerosis that cause life-threatening ischemic events at late stages of the disease. The miRNAs are a novel class of small, non-coding RNAs that play a significant role in both inflammatory and cardiovascular diseases. The miRNAs are known to be present in platelets and exert important regulatory functions. Here we systematically examine the genes that are regulated by platelet miRNAs (miRNA 223,miRNA-126,miRNA-21, miRNA-24 and miRNA-197) and the association with cardiovascular disease risks. Platelet-secreted miRNAs could be novel biomarkers associated with cardiovascular diseases. PMID- 26003376 TI - [Cutaneous lesions in a woman treated with adalimumab]. PMID- 26003378 TI - Lithium therapy in bipolar disorder: a balancing act? PMID- 26003377 TI - [Appropriate medication prescribing in older people]. AB - Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists. PMID- 26003379 TI - Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. AB - BACKGROUND: Lithium is a widely used and highly effective treatment for mood disorders, but causes poorly characterised adverse effects in kidney and endocrine systems. We aimed to analyse laboratory information system data to determine the incidence of renal, thyroid, and parathyroid dysfunction associated with lithium use. METHODS: In a retrospective analysis of laboratory data from Oxford University Hospitals National Health Service Trust (Oxfordshire, UK), we investigated the incidence of renal, thyroid, and parathyroid dysfunction in patients (aged >=18 years) who had at least two creatinine, thyrotropin, calcium, glycated haemoglobin, or lithium measurements between Oct 1, 1982, and March 31, 2014, compared with controls who had not had lithium measurements taken. We used survival analysis and Cox regression to estimate the hazard ratio (HR) for each event with lithium use, age, sex, and diabetes as covariates. FINDINGS: Adjusting for age, sex, and diabetes, presence of lithium in serum was associated with an increased risk of stage three chronic kidney disease (HR 1.93, 95% CI 1.76-2.12; p<0.0001), hypothyroidism (2.31, 2.05-2.60; p<0.0001), and raised total serum calcium concentration (1.43, 1.21-1.69; p<0.0001), but not with hyperthyroidism (1.22, 0.96-1.55; p=0.1010) or raised adjusted calcium concentration (1.08, 0.88 1.34; p=0.4602). Women were at greater risk of development of renal and thyroid disorders than were men, with younger women at higher risk than older women. The adverse effects occurred early in treatment (HR <1 for length of treatment with lithium). Higher than median lithium concentrations were associated with increased risk of all adverse outcomes. INTERPRETATION: Lithium treatment is associated with a decline in renal function, hypothyroidism, and hypercalcaemia. Women younger than 60 years and people with lithium concentrations higher than median are at greatest risk. Because lithium remains a treatment of choice for bipolar disorder, patients need baseline measures of renal, thyroid, and parathyroid function and regular long-term monitoring. FUNDING: None. PMID- 26003381 TI - Climate and health: mortality attributable to heat and cold. PMID- 26003382 TI - Social cognition in simple action coordination: A case for direct perception. AB - In this paper we sketch the outlines of an account of the kind of social cognition involved in simple action coordination that is based on direct social perception (DSP) rather than recursive mindreading. While we recognize the viability of a mindreading-based account such as e.g. Michael Tomasello's, we present an alternative DSP account that (i) explains simple action coordination in a less cognitively demanding manner, (ii) is better able to explain flexibility and strategy-switching in coordination and crucially (iii) allows for formal modeling. This account of action coordination is based on the notion of an agent's field of affordances. Coordination ensues, we argue, when, given a shared intention, the actions of and/or affordances for one agent shape the field of affordances for another agent. This a form of social perception since in particular perceiving affordances for another person involves seeing that person as an agent. It is a form of social perception since it involves perceiving affordances for another person and registering how another person's actions influence one's own perceived field of affordances. PMID- 26003380 TI - Mortality risk attributable to high and low ambient temperature: a multicountry observational study. AB - BACKGROUND: Although studies have provided estimates of premature deaths attributable to either heat or cold in selected countries, none has so far offered a systematic assessment across the whole temperature range in populations exposed to different climates. We aimed to quantify the total mortality burden attributable to non-optimum ambient temperature, and the relative contributions from heat and cold and from moderate and extreme temperatures. METHODS: We collected data for 384 locations in Australia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, and USA. We fitted a standard time-series Poisson model for each location, controlling for trends and day of the week. We estimated temperature-mortality associations with a distributed lag non-linear model with 21 days of lag, and then pooled them in a multivariate metaregression that included country indicators and temperature average and range. We calculated attributable deaths for heat and cold, defined as temperatures above and below the optimum temperature, which corresponded to the point of minimum mortality, and for moderate and extreme temperatures, defined using cutoffs at the 2.5th and 97.5th temperature percentiles. FINDINGS: We analysed 74,225,200 deaths in various periods between 1985 and 2012. In total, 7.71% (95% empirical CI 7.43-7.91) of mortality was attributable to non-optimum temperature in the selected countries within the study period, with substantial differences between countries, ranging from 3.37% (3.06 to 3.63) in Thailand to 11.00% (9.29 to 12.47) in China. The temperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas to about the 80-90th percentile in temperate regions. More temperature-attributable deaths were caused by cold (7.29%, 7.02-7.49) than by heat (0.42%, 0.39-0.44). Extreme cold and hot temperatures were responsible for 0.86% (0.84-0.87) of total mortality. INTERPRETATION: Most of the temperature-related mortality burden was attributable to the contribution of cold. The effect of days of extreme temperature was substantially less than that attributable to milder but non-optimum weather. This evidence has important implications for the planning of public-health interventions to minimise the health consequences of adverse temperatures, and for predictions of future effect in climate-change scenarios. FUNDING: UK Medical Research Council. PMID- 26003383 TI - Marine oil spill risk mapping for accidental pollution and its application in a coastal city. AB - Accidental marine oil spill pollution can result in severe environmental, ecological, economic and other consequences. This paper discussed the model of Marine Oil Spill Risk Mapping (MOSRM), which was constructed as follows: (1) proposing a marine oil spill risk system based on the typical marine oil spill pollution accidents and prevailing risk theories; (2) identifying suitable indexes that are supported by quantitative sub-indexes; (3) constructing the risk measuring models according to the actual interactions between the factors in the risk system; and (4) assessing marine oil spill risk on coastal city scale with GIS to map the overall risk. The case study of accidental marine oil spill pollution in the coastal area of Dalian, China was used to demonstrate the effectiveness of the model. The coastal areas of Dalian were divided into three zones with risk degrees of high, medium, and low. And detailed countermeasures were proposed for specific risk zones. PMID- 26003384 TI - The management in response to marine oil spill from ships in China: A systematic review. AB - Historical trends about marine ship-source oil spill incidents from 1990 to 2010 in China were analyzed, and it provided an overview of the status quo of China's management in response to marine oil spill from ships. The Chinese government has issued a series of laws on marine environmental protection since 1982, and promulgated many regulations to prevent and tackle ship-source oil spill. At present, the oil spill emergency response system established in China has five levels: the national level, sea level, provincial level, port level, and ship level. China has demonstrated its ability to control and remove small-scale oil spill from ships in port area and near-shore coastal waters, and also paid attention to related research and development projects. Although China has made significant progress in managing shipping oil spill, challenges still exist, including strengthening oil spill emergency cooperation, enhancing China's response capability, and improving relevant research and development projects. PMID- 26003385 TI - Nutrients and clam contamination by Escherichia coli in a meso-tidal coastal lagoon: Seasonal variation in counter cycle to external sources. AB - The clam Ruditapes decussatus was transplanted from a natural recruitment area of Ria Formosa to three sites, surveyed for nutrients in water and sediments. Specimens were sampled monthly for determination of Escherichia coli, condition index and gonadal index. Higher nutrient values in low tide reflect drainage, anthropogenic sources or sediment regeneration, emphasising the importance of water mixing in the entire lagoon driven by the tide. Despite the increase of effluent discharges in summer due to tourism, nutrient concentrations and E. coli in clams were lower in warmer periods. The bactericide effect of temperature and solar radiation was better defined in clams from the inlet channel site than from sites closer to urban effluents. High temperature in summer and torrential freshwater inputs to Ria Formosa may anticipate climate change scenarios for south Europe. Seasonal variation of nutrients and clam contamination may thus point to possible alterations in coastal lagoons and their ecosystem services. PMID- 26003386 TI - Biotope map of the German Baltic Sea. AB - Full-coverage maps on the distribution of marine biotopes are a necessary basis for Nature Conservation and Marine Spatial Planning. Yet biotope maps do not exist in many regions. We are generating the first full-coverage biotope map for the German Baltic Sea according to the HELCOM Underwater biotope and habitat classification system (HUB). Species distribution modelling is applied to create full-coverage spatial information of biological features. The results of biomass modelling of twelve target taxa and presence/absence modelling of three target taxa enabled the identification of biological levels up to HUB level 6. Environmental data on bathymetry, light penetration depth and substrate are used to identify habitat levels. HUB biotope levels were combined with HUB habitat levels to create a biotope map. Altogether, 68 HUB biotopes are identified in the German Baltic Sea. The new biotope map combining substrate characteristics and biological communities will facilitate marine management in the area. PMID- 26003387 TI - Improving outcomes in prolonged mechanical ventilation: a road map. PMID- 26003388 TI - Transcriptional phenotyping of fibrotic lung disease: a new gold standard? PMID- 26003389 TI - Classification of usual interstitial pneumonia in patients with interstitial lung disease: assessment of a machine learning approach using high-dimensional transcriptional data. AB - BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that distorts pulmonary architecture, leading to hypoxia, respiratory failure, and death. Diagnosis is difficult because other interstitial lung diseases have similar radiological and histopathological characteristics. A usual interstitial pneumonia pattern is a hallmark of idiopathic pulmonary fibrosis and is essential for its diagnosis. We aimed to develop a molecular test that distinguishes usual interstitial pneumonia from other interstitial lung diseases in surgical lung biopsy samples. The eventual goal of this research is to develop a method to diagnose idiopathic pulmonary fibrosis without the patient having to undergo surgery. METHODS: We collected surgical lung biopsy samples from patients with various interstitial lung diseases at 11 hospitals in North America. Pathology diagnoses were confirmed by an expert panel. We measured RNA expression levels for 33 297 transcripts on microarrays in all samples. A classifier algorithm was trained on one set of samples and tested in a second set. We subjected a subset of samples to next-generation RNA sequencing (RNAseq) generating expression levels on 55 097 transcripts, and assessed a classifier trained on RNAseq data by cross-validation. FINDINGS: We took 125 surgical lung biopsies from 86 patients. 58 samples were identified by the expert panel as usual interstitial pneumonia, 23 as non-specific interstitial pneumonia, 16 as hypersensitivity pneumonitis, four as sarcoidosis, four as respiratory bronchiolitis, two as organising pneumonia, and 18 as subtypes other than usual interstitial pneumonia. The microarray classifier was trained on 77 samples and was assessed in a test set of 48 samples, for which it had a specificity of 92% (95% CI 81-100) and a sensitivity of 82% (64-95). Based on a subset of 36 samples, the RNAseq classifier had a specificity of 95% (84-100) and a sensitivity of 59% (35-82). INTERPRETATION: Our results show that the development of a genomic signature that predicts usual interstitial pneumonia is feasible. These findings are an important first step towards the development of a molecular test that could be applied to bronchoscopy samples, thus avoiding surgery in the diagnosis of idiopathic pulmonary fibrosis. FUNDING: Veracyte. PMID- 26003390 TI - Long-term survival of critically ill patients treated with prolonged mechanical ventilation: a systematic review and meta-analysis. AB - BACKGROUND: Prolonged dependence on mechanical ventilation after critical illness is an emerging public health challenge; however, long-term outcomes are incompletely understood. We aimed to systematically analyse long-term survival of critically ill patients treated with prolonged mechanical ventilation. METHODS: We searched PubMed, CINAHL, and the Cochrane Library between 1988 and Nov 6, 2013, with no language restrictions, for studies on prolonged mechanical ventilation. We included studies of adult populations treated with mechanical ventilation for more than 14 days, who were admitted to a ventilator weaning unit, or who had a tracheostomy for acute respiratory failure. We abstracted data with a standardised collection template and assessed study quality (ie, risk of bias) using a customised Newcastle-Ottawa Scale. We did a stratified analysis based on study setting (eg, acute vs post-acute care hospitals), and used a random-effects model to calculate pooled statistics (proportions with 95% CIs) for all outcomes. We did sensitivity analyses based on study quality (ie, high quality studies only) and country of origin (USA vs non-USA and USA vs UK). The primary outcome was mortality at 1 year. Secondary outcomes were in-hospital mortality, discharge destination among survivors, successful liberation from mechanical ventilation while in hospital, and mortality at timepoints longer than 1 year. FINDINGS: Of 6326 studies identified, 402 underwent full manuscript review, and 124 studies from 16 countries met the inclusion criteria. 39 studies reported mortality at 1 year, which was 59% (95% CI 56-62). Among the 29 high quality studies, the pooled mortality at 1 year was 62% (95% CI 57-67). Pooled mortality at hospital discharge was 29% (95% CI 26-32). However, only 19% (16-24) were discharged to home and only 50% (47-53) were successfully liberated from mechanical ventilation. For studies in post-acute care hospitals, outcomes were worse in the USA than internationally (mortality at 1 year was 73% [95% CI 67-78] in the USA vs 47% [29-65] in non-USA countries; in-hospital mortality was 31% [26 37] vs 18% [14-24]; and liberation from ventilation was 47% [42-51] vs 63% [59 68]; p<0.0001 for all). INTERPRETATION: Although a high proportion of patients survived to hospital discharge, fewer than half of patients survived beyond 1 year. Future studies should focus on optimum patient selection for prolonged mechanical ventilation and integration of long-term outcome information into clinical decision making. FUNDING: Cooper University Health Care and Cooper Medical School of Rowan University. PMID- 26003391 TI - Comparison of single questions and brief questionnaire with longer validated food frequency questionnaire to assess adequate fruit and vegetable intake. AB - OBJECTIVE: The aim of this study was to determine if a single question (SQ) for fruit and a SQ or five-item questionnaire for vegetable consumption (VFQ) could replace a longer food frequency questionnaire (FFQ) to screen for inadequate versus adequate intakes in populations. METHODS: Participants (109) completed three test screeners: fruit SQ, vegetable SQ, and a five-item VFQ followed by the reference 74-item FFQ (version 2 of the Dietary Questionnaire for Epidemiological Studies [DQESv2]) including 13 fruit and 25 vegetable items. The five-item VFQ asked about intake of salad vegetables, cooked vegetables, white potatoes, legumes, and vegetable juice. The screeners were compared with the reference (DQESv2 FFQ) for sensitivity, specificity, and positive and negative predictive powers (PPV, NPV) to detect intakes of two or more servings of fruit and three or more servings of vegetables. Relative validity was examined using Bland-Altman statistics. RESULTS: The fruit SQ showed a PPV of 56% and an NPV of 83%. The PPV for the vegetable SQ was 30% and the NPV was 89%. For the five-item VFQ, the PPV was 39% and the NPV was 85%. Bland-Altman plots and linear regression equations showed that although the screener showed good agreement for fruit (unstandardized b1 coefficient = 0.04) for vegetable intake the difference between methods increased at higher intake levels (unstandardized b1 coefficients = -0.3 for the SQ, b1 = -0.6 for five-item VFQ). CONCLUSION: The fruit SQ and the five-item VFQ are suitable replacements for longer FFQs to detect inadequate intake and assess population mean but not individual intakes. PMID- 26003392 TI - Bariatric surgery may not achieve intended outcomes in all patients. PMID- 26003393 TI - eNutrition: An extension of teleintensive care. AB - The aim of this brief report was to introduce the term eNutrition and to describe our new initiatives expanding the traditional role of existing telemedicine systems to provide nutrition support services. This is especially useful at institutions that still do not have a physician or dietitian with specialized knowledge and clinical expertise in nutrition-related issues. We also describe details of the various components of our eNutrition program, including early assessments and optimal provision of enteral and parenteral nutrition, many of which can be used with minimal investment in computer software and hardware. PMID- 26003394 TI - Transition of gastroenterological patients from paediatric to adult care: A position statement by the Italian Societies of Gastroenterology. AB - In 2013, four Italian Gastroenterological Societies (the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition, the Italian Society of Hospital Gastroenterologists and Endoscopists, the Italian Society of Endoscopy, and the Italian Society of Gastroenterology) formed a joint panel of experts with the aim of preparing an official statement on transition medicine in Gastroenterology. The transition of adolescents from paediatric to adult care is a crucial moment in managing chronic diseases such as celiac disease, inflammatory bowel disease, liver disease and liver transplantation. Improved medical treatment and availability of new drugs and surgical techniques have improved the prognosis of many paediatric disorders, prolonging survival, thus making the transition to adulthood possible and necessary. An inappropriate transition or the incomplete transmission of data from the paediatrician to the adult Gastroenterologist can dramatically decrease compliance to treatment and prognosis of a young patient, particularly in the case of severe disorders. For these reasons, the Italian gastroenterological societies decided to develop an official shared transition protocol. The resulting document discusses the factors influencing the transition process and highlights the main points to accomplish to optimize compliance and prognosis of gastroenterological patients during the difficult transition from childhood to adolescence and adulthood. PMID- 26003395 TI - Helicobacter infections with rare bacteria or minimal gastritis: Expecting the unexpected. AB - BACKGROUND: The routine use of special stains for detection of Helicobacter remains controversial. AIMS: To determine the frequency of histologically atypical Helicobacter infection. METHODS: All gastric biopsies received at a large pathology reference laboratory over a 6-month period were stained for Helicobacter, and the histologic and clinicopathologic parameters evaluated. RESULTS: Amongst 7663 Helicobacter-positive biopsies, 823 (10.7%) did not show typical chronic active gastritis with numerous Helicobacter organisms, and were therefore considered histologically atypical. Rare Helicobacter pylori organisms accounted for 58.0% of all atypical infections; the next most common atypical Helicobacter infection was that with minimal or no gastric inflammation (23.3% of atypical infections). Patients in these groups did not differ demographically from those with other forms of atypical or typical Helicobacter infection, although a small subgroup (6%) was more likely to have had a previously treated infection. CONCLUSIONS: In many of these atypical infections, Helicobacter would not have been suspected based on the histologic findings alone, and would have been missed without routine special stains. Performing a sensitive stain could prevent additional testing and allow prompt treatment of the affected patients, thus substantially reducing the risk for peptic ulcer and gastric cancer and preventing the transmission of the infection to family members. PMID- 26003396 TI - What is the real relevance of endogenous ghrelin? AB - Ghrelin is a pleiotropic and ubiquitous gastric hormone implicated in body physiology. Ghrelin exhibits potent orexigenic actions and increases body weight and adiposity. Ghrelin is also involved in other metabolic functions among which we can highlight the GH releasing activity and the regulation of glucose homeostasis. Ghrelin needs the enzyme GOAT to be acylated, a step essential for binding to the GHSR1a receptor to exert its functions. Genetic animal models emerge as important tools to delineate the physiological relevance of ghrelin on energy balance. Despite the numerous reports using different genetically engineered mouse models targeting the ghrelin system, its endogenous relevance in metabolism seems to be less important than its pharmaceutical options. PMID- 26003397 TI - Paralytic peptide activates insect humoral immune response via epidermal growth factor receptor. AB - Paralytic peptide (PP) activates innate immunity of silkworm Bombyx mori, inducing production of anti-microbial peptides (AMPs) and phagocytosis-related proteins; however the signal pathways of PP-dependent immune responses are not clear. In present study, we characterized BmE cells as a PP-responsive cell line by examining the expression of AMP genes and activation of p38 mitogen-activated protein kinase (p38 MAPK) under PP stimulation, and we also found PP directly binds to BmE cell membrane. Then we found that PP-dependent expression of AMP genes is suppressed by tyrosine kinase inhibitor (genistein) both in BmE cells and in fat body of silkworm larvae. Moreover, the specific tyrosine kinase epidermal growth factor receptor (EGFR) inhibitor (AG1478) attenuates PP-induced expression of AMP genes in BmE cells and fat body of silkworm and RNA interference (RNAi) to BmEGFR also suppresses PP-induced expression of AMP genes. Furthermore, the PP-induced p38 MAPK phosphorylation is inhibited by AG1478. Our results suggest that BmE cells can be used as a cell model to investigate the signal pathway of PP-dependent humoral immune response and receptor tyrosine kinase EGFR/p38 MAPK pathway is involved in the production of AMPs induced by PP. PMID- 26003398 TI - Editorial overview: Preventive and therapeutic vaccines (B cell epitope vaccine). PMID- 26003400 TI - Multiple paternity and sperm storage in captive Hermann's tortoises, Testudo hermanni boettgeri determined from amniotic fluid adhering to the eggshell. AB - We identified multiple paternity in 52.9% of the clutches of Hermann's tortoise Testudo hermanni boettgeri using polymorphic microsatellite markers. In addition we demonstrated sperm storage across seasons. DNA was extracted from the amniotic fluid adhering to the eggshell's inner surface, a procedure suitable for easy, non-invasive DNA sampling in conservation and breeding programs. To improve the informative value of monomorphic single tandem repeat (STR) markers we additionally analyzed single nucleotide polymorphism (SNP) variability. PMID- 26003399 TI - Modeling glaucoma in rats by sclerosing aqueous outflow pathways to elevate intraocular pressure. AB - Injection of hypertonic saline via episcleral veins toward the limbus in laboratory rats can produce elevated intraocular pressure (IOP) by sclerosis of aqueous humor outflow pathways. This article describes important anatomic characteristics of the rat optic nerve head (ONH) that make it an attractive animal model for human glaucoma, along with the anatomy of rat aqueous humor outflow on which this technique is based. The injection technique itself is also described, with the aid of a supplemental movie, including necessary equipment and specific tips to acquire this skill. Outcomes of a successful injection are presented, including IOP elevation and patterns of optic nerve injury. These concepts are then specifically considered in light of the use of this model to assess potential neuroprotective therapies. Advantages of the hypertonic saline model include a delayed and relatively gradual IOP elevation, likely reproduction of scleral and ONH stresses and strains that may be important in producing axonal injury, and its ability to be applied to any rat (and potentially mouse) strain, leaving the unmanipulated fellow eye as an internal control. Challenges include the demanding surgical skill required by the technique itself, a wide range of IOP response, and mild corneal clouding in some animals. However, meticulous application of the principles detailed in this article and practice will allow most researchers to attain this useful skill for studying cellular events of glaucomatous optic nerve damage. PMID- 26003401 TI - Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing. AB - Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS. PMID- 26003402 TI - Recurrent null mutation in SPG20 leads to Troyer syndrome. AB - Troyer syndrome is an autosomal recessive form of complex hereditary spastic paraplegia. To date, the disorder has only been described in the Amish and in kindred from Oman. In Amish, all affected individuals have a homozygous one nucleotide deletion; c.1110delA. In the Omani kindred, all affected have a homozygous two nucleotides deletion; c.364_365delTA (p.Met122ValfsTer2). Here we report the results of homozygosity mapping and whole exome sequencing in two siblings of a consanguineous Turkish family with mild intellectual disability, spastic paraplegia, and muscular dystrophy. We identified the same deletion that has been identified in the Omani kindred, but haplotype analysis suggests a recurrent event, and not a founder mutation. We summarize current knowledge of Troyer syndrome, and propose wider use of whole exome sequencing in routine diagnostics. This applies in particular to nonspecific phenotypes with high heterogeneity, such as spastic paraplegia, intellectual disability, and muscular dystrophy, since in such cases the assignment of a definite diagnosis is frequently delayed. PMID- 26003403 TI - The impact of Clostridium difficile infection on resource use and costs in hospitals in Spain and Italy: a matched cohort study. AB - OBJECTIVE: To assess the impact of Clostridium difficile infection (CDI) on hospital resources and costs in Spain and Italy. METHODS: CDI data were collected from institutions in Spain and Italy. Each patient was matched with two randomly selected uninfected controls in the same institution. Patient outcomes were assessed for the first and second episodes of CDI and for patients aged <=65 and >65 years. The impact of CDI on hospital length of stay (LOS) was used to calculate CDI-attributable costs. A multivariate analysis using duration of stay as the continuous outcome variable assessed the independent effect of CDI on hospital costs and LOS. RESULTS: LOS attributable to CDI ranged from 7.6-19.0 days in adults and was 5.0 days in children; the increases were greater in adults in Italy than in Spain. Attributable costs per adult patient ranged from ?4396 in Madrid to ?14 023 in Rome, with the majority of the cost being due to hospitalization. For children, the total attributable cost was ?3545/patient. CONCLUSIONS: These data show that the burden of CDI is considerable in Spain and Italy. Treatments that can reduce LOS, disease severity, and recurrence rates, as well as effective infection control measures to prevent transmission, have the potential to reduce the burden of CDI. PMID- 26003404 TI - Impact of tuberculosis treatment and antiretroviral therapy on serial RD-1 specific quantitative T-cell readouts (QuantiFERON-TB Gold In-Tube), and relationship to treatment-related outcomes and bacterial burden. AB - BACKGROUND: The impact of anti-tuberculosis treatment with and without antiretroviral therapy (ART) on standardized interferon gamma release assay (IGRA) readouts has been studied inadequately in high-burden countries. METHODS: The QuantiFERON-TB Gold In-Tube (QFT-GIT) test was used to evaluate interferon gamma (IFN-gamma) responses longitudinally (0, 3, 6, and 12 months post initiation of tuberculosis (TB)-HIV co-treatment or ART alone) in 82 HIV-infected patients. RESULTS: Of the 65 evaluable participants, 30 were co-infected on ART, 17 were co-infected but not on ART, and 18 were HIV-infected alone and on ART. In HIV-infected and HIV-TB-infected patients on ART, IFN-gamma responses increased, whilst they decreased in those not on ART. However, baseline, month 3, and month 6 IFN-gamma responses, irrespective of ART, did not differ in TB-HIV co-infected patients who culture-converted compared to those who did not (1.25 vs. 1.05, p=0.5 at baseline; 3.76 vs. 1.15, p=0.2 for month 3; 0.06 vs. 0.7, p=0.3 for month 6). IFN-gamma levels did not correlate with the magnitude of sputum bacillary load, smear status, or liquid culture time-to-positivity. CONCLUSION: As IGRAs do not correlate with 2- or 6-month culture conversion or with markers of bacillary burden, they are unlikely to be useful for the prognostication of treatment outcome in co-infected patients. PMID- 26003405 TI - Better short-term efficacy of treating severe flail chest with internal fixation surgery compared with conservative treatments. AB - BACKGROUND: The objective of the study is to provide evidence for selecting the best treatment approach for severe flail chest by comparing surgical and conservative treatments. METHODS: This is a retrospective study in which 32 patients with severe flail chest were treated in the Fujian Provincial Hospital (China) between July 2007 and July 2012 with surgical internal rib fixation (n = 17) or conservative treatments (n = 15). Mechanical ventilation time, intensive care unit (ICU) stay time, pulmonary infection, antibiotic treatment duration, acute physiology and chronic health evaluation II (APACHE II) scores 7 and 14 days after trauma, rate of tracheostomy, and rate of endotracheal re-intubation were compared. RESULTS: One patient died in the conservative treatment group. Better short-term outcomes were observed in the surgery group, such as total mechanical ventilation time (10.5 +/- 3.7 vs. 13.7 +/- 4.4 days, P = 0.03), ICU stay (15.9 +/- 5.0 vs. 19.6 +/- 5.0 days, P = 0.05), pulmonary infection rate (58.8 % vs. 93.3 %, P = 0.02), and APACHE II scores on the 14th day (6.5 +/- 3.8 vs. 10.1 +/- 4.7, P = 0.02). No difference was observed in the therapeutic time of antibiotics, rate of tracheostomy, and the rate of endotracheal re-intubation between the two groups. CONCLUSIONS: Results suggest that internal fixation surgery resulted in better outcomes in the management of severe flail chest compared with conservative treatments. PMID- 26003406 TI - Physical activity during pregnancy and maternal-child health (PAMELA): study protocol for a randomized controlled trial. AB - BACKGROUND: Preterm birth is associated with most cases of neonatal deaths and negative health outcomes, and hypertensive disorders. Hypertension is influenced by maternal behavior, such as physical activity. Physical activity is associated with better outcomes for mother and fetus, besides healthier weight gains during pregnancy. Few women are physically active during pregnancy and few clinical trials have been carried out with pregnant women. The aim of this paper is to describe the protocol of a controlled trial evaluating whether regular exercise during pregnancy may result in improved maternal-child health and neonatal outcomes. METHODS/DESIGN: The PAMELA (Physical Activity for Mothers Enrolled in Longitudinal Analysis) trial is a randomized controlled trial nested in a birth cohort study. Eligible women belonging to the birth cohort will be invited (between the 16th and 20th week of gestation) to enroll in the trial. Baseline data (blood and urine samples, anthropometry and pulmonary function) will be collected at enrollment. The same assessments will be repeated eight and 16 weeks after baseline. After randomization, women will be allocated into either one of these groups: control, 426 women who will be advised to keep their usual daily activities; and intervention, 213 women who will engage in an exercise program, three sessions a week. At least 70 % attendance over 16 weeks will be required to be considered compliant to the intervention. Exercise protocol will include aerobics, strength and flexibility training. Maternal and child outcomes will be measured at the 36th week of gestation, at birth and at three, 12, 24 and 48 months postpartum. An intention-to-treat analysis will be performed. DISCUSSION: Few women are active during pregnancy and a vast majority decrease their activities or even quit exercising. We present a population-based regular exercise intervention focused on the prevention of hypertension, pre-eclampsia and preterm birth. Data on the underlying cohort will allow future analysis using different outcomes with low probability of recall bias or misclassification of exposure status. Results will potentially influence prenatal care counseling in regards to physical activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02148965 , registered on 22 May 2014. PMID- 26003407 TI - Muscle strength and areal bone mineral density at the hip in women: a cross sectional study. AB - BACKGROUND: Muscle strengthening exercises are promoted for building and maintaining a healthy skeleton. We aimed to investigate the relationship between muscle strength and areal bone mineral density (BMD) at the hip in women aged 26 97 years. METHODS: This cross-sectional study utilises data from 863 women assessed for the Geelong Osteoporosis Study. Measures of hip flexor and abductor strength were made using a hand-held dynamometer (Nicholas Manual Muscle Tester). The maximal measure from three trials on each leg was used for analyses. BMD was measured at the hip using dual energy x-ray absorptiometry (DXA; Lunar DPX-L). Total lean mass, body fat mass and appendicular lean mass were determined from whole body DXA scans. Linear regression techniques were used with muscle strength as the independent variable and BMD as the dependent variable. Models were adjusted for age and indices of body composition. RESULTS: Measures of age adjusted hip flexor strength and hip abductor strength were positively associated with total hip BMD. For each standard deviation (SD) increase in hip flexor strength, the increase in mean total hip BMD (SD) was 10.4 % (p = 0.009). A similar pattern was observed for hip abductor strength, with an increase in mean total hip BMD of 22.8 % (p = 0.025). All associations between hip muscle strength and total hip BMD were independent of height, but were nullified after adjusting for appendicular lean mass or total lean mass. CONCLUSIONS: There was a positive association observed between muscle strength and BMD at the hip. However, this association was explained by measures of lean mass. PMID- 26003408 TI - A qualitative assessment of practitioner perspectives post-introduction of the first continuous professional competence (CPC) guidelines for emergency medical technicians in Ireland. AB - BACKGROUND: In November 2013, the Irish Regulator for emergency medical technicians (EMTs) introduced the first mandatory requirement for registrants to demonstrate evidence of continuous professional development (CPD)/continuous professional competence (CPC). This qualitative study assessed the experience of practitioners with CPC-related materials provided to them by the Regulator in addition to identifying perceived or encountered practical challenges and suggested improvements six months following introduction of the requirement. METHODS: Five fora were utilised, comprising two distinct groupings: a group of student EMTs (n = 62) and four discrete groups of qualified EMTs (total n = 131) all of whom had commenced the newly-introduced CPC process. All 193 volunteers were members of the Civil Defence (an auxiliary/voluntary organisation) and represented a nationwide distribution of personnel. Responses were categorised as 'perceived' challenges to CPC, relating to student EMTs, and 'experienced' challenges to CPC, relating to qualified EMTs. Responses also included suggestions from both groups of EMTs on how to improve the current system and guidance material. Audio/visual recordings were made, transcribed and then analysed using NVivo (version 10). A coding framework was developed which identified unifying themes. RESULTS: All participants agreed that CPC for pre hospital practitioners was a welcomed initiative believing that CPC activities would help ensure that EMTs maintain or enhance their skills and be better enabled to provide quality care to the patients they might encounter. Two specific areas were identified by both groups as being challenging: 1) the practicalities of completing CPC and 2) the governance and administration of the CPC process. Challenging practicalities included: ability of voluntary EMTs to gain access to operational placements with paramedics and advanced paramedics; the ability to experience the number of patient contacts required and the definition of what constitutes a 'patient contact'. With regard to the governance and administration of CPC, it was suggested that in order to enhance the process, the Regulator should provide: an outline of the CPC audit process; examples of cases studies and reflective practice; templates for portfolios; and should establish a central hub for CPC information. CONCLUSION: These groups of Irish EMTs appeared keen to participate in continuous professional competence activities. In addition, these EMTs identified areas that, in their opinion, required clarification by the Regulator related to the practicalities of CPC and the governance and administration of CPC. More information, dissemination of sample requirements and further effective engagement with the Regulator could be used to refine the current CPC requirements for EMTs. PMID- 26003409 TI - Echinenone vibrational properties: From solvents to the orange carotenoid protein. AB - Orange carotenoid protein (OCP) is a cyanobacterial photoactive protein which binds echinenone as a chromophore; it is involved in photoprotection of these photosynthetic organisms against intense illumination. In its resting state, OCP appears orange (OCPo), and turns into a red form (OCPr) when exposed to blue green light. Here we have combined resonance Raman spectroscopy and molecular modeling to investigate the mechanisms underlying the electronic absorption properties of the different forms of OCP. Our results show that there are at least two carotenoid configurations in the OCPo, suggesting that it is quite flexible, and that the OCPo to OCPr transition must involve an increase of the apparent conjugation length of the bound echinenone. Resonance Raman indicates that this chromophore must be in an all-trans configuration in OCPo. Density functional theory (DFT) calculations, in agreement with the Raman spectra of both OCP forms, show that the OCPo to OCPr transition must involve either an echinenone s-cis to s-trans isomerization which would affect the position of its conjugated end-chain rings, or a bending of the echinenone rings which would bring them from out of the plane of the CC conjugated plane in the OCPo form into the CC plane in the OCPr form. PMID- 26003410 TI - Long-term response to continuous duodenal infusion of levodopa/carbidopa gel in patients with advanced Parkinson disease: The Barcelona registry. AB - INTRODUCTION: Continuous infusion of levodopa/carbidopa intestinal gel (LCIG) is an effective treatment for patients with advanced Parkinson Disease (PD) that cannot be further improved by oral therapy. METHODS: We conducted an observational, prospective, and multicenter study to collect, in a large sample of PD treated with LCIG, long-term information about the outcome and safety of the treatment. The assessments were performed before LCIG, 1, 3, 6 months after, and ever since, every 6 months. RESULTS: We studied 72 patients with a mean observation time of 22 months and a maximum of 48 months. During follow-up 28 patients discontinued the treatment, especially for lack of efficacy or adverse events related to the drug. We obtained a significant improvement of motor and non-motor fluctuations, mean off time and some non-motor symptoms. A significant increase in the percentage of time with dyskinesias was found in patients having less than 50% of the day with dyskinesias before LCIG. However, patients having already many dyskinesias before LCIG experienced a significant decrease of the troublesome dyskinesias, meaning that outcomes might be different depending on specific clinical characteristics. Adverse effects were in general minor but one case of intestinal perforation and one of abdominal cellulite were observed. CONCLUSIONS: We confirmed that LCIG is a very effective treatment option for advanced PD; however considering the findings that dyskinesia can increase and the potential for serious side effects, we suggest the necessity for development of guidelines that better define the profile of responders. PMID- 26003411 TI - Abnormal thermography in Parkinson's disease. AB - BACKGROUND: An autonomic denervation and abnormal vasomotor reflex in the skin have been described in Parkinson's disease (PD) and might be evaluable using thermography with cold stress test. METHODS: A cross-sectional pilot study was undertaken in 35 adults: 15 patients with PD and abnormal [(123)I] metaiodobenzylguanidine cardiac scintigraphy and 20 healthy controls. Baseline thermography of both hands was obtained before immersing one in cold water (3 +/- 1 degrees C) for 2 min. Continuous thermography was performed in: non-immersed hand (right or with lesser motor involvement) during immersion of the contralateral hand and for 6 min afterward; and contralateral immersed hand for 6 min post-immersion. The region of interest was the dorsal skin of the third finger, distal phalanx. RESULTS: PD patients showed a lower mean baseline hand temperature (p = 0.037) and greater thermal difference between dorsum of wrist and third finger (p = 0.036) and between hands (p = 0.0001) versus controls, regardless of the motor laterality. Both tests evidenced an adequate capacity to differentiate between groups: in the non-immersed hand, the PD patients did not show the normal cooling pattern or final thermal overshoot observed in controls (F = 5.29; p = 0.001), and there was an AUC of 0.897 (95%CI 0.796-0.998) for this cooling; in the immersed hand, thermal recovery at 6 min post-immersion was lesser in patients (29 +/- 17% vs. 55 +/- 28%, p = 0.002), with an AUC of 0.810 (95%CI 0.662-0.958). CONCLUSIONS: PD patients reveal abnormal skin thermal responses in thermography with cold stress test, suggesting cutaneous autonomic dysfunction. This simple technique may be useful to evaluate autonomic dysfunction in PD. PMID- 26003412 TI - External validation of a simple clinical tool used to predict falls in people with Parkinson disease. AB - BACKGROUND: Assessment of fall risk in an individual with Parkinson disease (PD) is a critical yet often time consuming component of patient care. Recently a simple clinical prediction tool based only on fall history in the previous year, freezing of gait in the past month, and gait velocity <1.1 m/s was developed and accurately predicted future falls in a sample of individuals with PD. METHODS: We sought to externally validate the utility of the tool by administering it to a different cohort of 171 individuals with PD. Falls were monitored prospectively for 6 months following predictor assessment. RESULTS: The tool accurately discriminated future fallers from non-fallers (area under the curve [AUC] = 0.83; 95% CI 0.76-0.89), comparable to the developmental study. CONCLUSION: The results validated the utility of the tool for allowing clinicians to quickly and accurately identify an individual's risk of an impending fall. PMID- 26003413 TI - NDP-alpha-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors. AB - Melanocortins exert neuroprotection in a variety of experimental neurodegenerative disorders, including Alzheimer's disease (AD). Further, in previous research we showed that these endogenous peptides stimulate neurogenesis in an acute neurodegenerative disorder such as ischemic stroke. In the present research, we investigated the potential neurogenic effect of melanocortins in AD using APPSwe transgenic mice (Tg2576). To this purpose, 24week-old animals were prepared for 5-bromo-2'-deoxyuridine (BrdU) labeling of proliferating cells on days 1-11 of the study. Treatment of Tg2576 mice with nanomolar doses of the melanocortin analog [Nle(4),D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP alpha-MSH), administered once daily from day 1 to 50, improved brain histology and cognitive functions relative to saline-treated Tg2576 animals. No signs of toxicity were observed. Immunohistochemical examination of the hippocampus at the end of the study (day 50) showed that NDP-alpha-MSH-treated Tg2576 mice had a greater number of BrdU immunoreactive cells colocalized with NeuN (an indicator of mature neurons) and Zif268 (an indicator of functionally integrated neurons) in the dentate gyrus, relative to saline-treated Tg2576 animals; no newly formed astrocytes were found. Animal pretreatment with the selective melanocortin MC4 receptor antagonist HS024 before each NDP-alpha-MSH administration prevented all the beneficial effects of the peptide. The present data indicate that MC4 receptor stimulation by a melanocortin prevents cognitive decline in experimental AD, this effect being associated not only with neuroprotection but also with an intense neurogenesis. MC4 receptor agonists could be innovative and safe candidates to counteract AD progression in humans. PMID- 26003414 TI - The ROR2 tyrosine kinase receptor regulates dendritic spine morphogenesis in hippocampal neurons. AB - Wnt signaling regulates synaptic development and function and contributes to the fine-tuning of the molecular and morphological differentiation of synapses. We have shown previously that Wnt5a activates non-canonical Wnt signaling to stimulate postsynaptic differentiation in excitatory hippocampal neurons promoting the clustering of the postsynaptic scaffold protein PSD-95 and the development of dendritic spines. At least three different kinds of Wnt receptors have been associated with Wnt5a signaling: seven trans-membrane Frizzled receptors and the tyrosine kinase receptors Ryk and ROR2. We report here that ROR2 is distributed in the dendrites of hippocampal neurons in close proximity to synaptic contacts and it is contained in dendritic spine protrusions. We demonstrate that ROR2 is necessary to maintain dendritic spine number and morphological distribution in cultured hippocampal neurons. ROR2 overexpression increased dendritic spine growth without affecting the density of dendritic spine protrusions in a form dependent on its extracellular Wnt binding cysteine rich domain (CRD) and kinase domain. Overexpression of dominant negative ROR2 lacking the extracellular CRD decreased spine density and the proportion of mushroom like spines, while ROR2 lacking the C-terminal and active kinase domains only affected spine morphology. Our results indicate a crucial role of the ROR2 in the formation and maturation of the postsynaptic dendritic spines in hippocampal neurons. PMID- 26003415 TI - Array-based DNA methylation analysis in individuals with developmental delay/intellectual disability and normal molecular karyotype. AB - Despite recent progress in molecular karyotyping and clinical sequencing the cause of intellectual disability in a considerable subset of individuals affected by this phenotype remains elusive. As intellectual disability is also a feature of various imprinting disorders and some monogenic forms of intellectual disability are caused by epigenetic modifiers we hypothesized that changes in DNA methylation might be associated with or even causative in some cases of intellectual disability. Therefore, we performed a DNA methylation analysis of peripheral blood samples from 82 patients with intellectual disability and additional features using the HumanMethylation450 BeadChip. The findings were compared to that of 19 normal controls. Differentially methylated loci were validated by bisulfite pyrosequencing. On a global level, we failed to detect a robust DNA methylation signature segregating individuals with intellectual disability from controls. Using an individual approach, we identified 157 regions showing individual DNA methylation changes in at least one patient. These correlated to 107 genes including genes linked to conditions associated with intellectual disability, namely COLEC11, SHANK2, GLI2 and KCNQ2, as well as imprinted genes like FAM50B and MEG3. The latter was suggestive of an undiagnosed Temple syndrome which could be confirmed by diagnostic tests. Subsequent in-depth analysis of imprinted loci revealed DNA methylation changes at additional imprinted loci, i.e. PPIEL, IGF2R, MEG8 and MCTS2/HM13, in up to five patients. Our findings indicate that imprinting disorders are rare but probably under diagnosed in patients with intellectual disability and moreover point to DNA methylation changes as potential alternative means to identify deregulated genes involved in the pathogenesis of intellectual disability. PMID- 26003416 TI - Probing the effects of fish oil on the delivery and inflammation-inducing potential of imiquimod. AB - Imiquimod is a chemotherapeutic agent for many skin-associated diseases, but it has also been associated with inflammatory side effects. The aim of this study was to prevent the inflammatory effect of commercial imiquimod (Aldara((r))) by controlled release of imiquimod through a hydrogel/oleogel colloidal mixture (CA bigel) containing fish oil as an anti-inflammatory agent. Imiquimod permeability from Aldara(r) cream and bigel through mice skin was evaluated, and the drug content residing in the skin via the tape stripping technique was quantified. The fish oil fatty acid content in skin along with its lipophilic environment was also determined. An inflammation study was conducted using animal models, and Aldara((r)) cream was found to potentially cause psoriasis-like inflammation, which could be owing to prolonged application and excessive drug permeation. Controlled release of imiquimod along with fish oil through CA bigel may have caused reduced imiquimod inflammation. NMR studies and computerized molecular modeling were also conducted to observe whether the fish oil and imiquimod formed a complex that was responsible for improving imiquimod transport and reducing its side effects. NMR spectra showed dose-dependent chemical shifts and molecular modeling revealed pi-sigma interaction between EPA and imiquimod, which could help reduce imiquimod inflammation. PMID- 26003417 TI - Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol. AB - The present case study focuses on the crystallization kinetics and molecular mobility of an amorphous mouth and throat drug namely Biclotymol, through differential scanning calorimetry (DSC), temperature resolved X-ray powder diffraction (TR-XRPD) and hot stage microscopy (HSM). Kinetics of crystallization above the glass transition through isothermal and non-isothermal cold crystallization were considered. Avrami model was used for isothermal crystallization process. Non-isothermal cold crystallization was investigated through Augis and Bennett model. Differences between crystallization processes have been ascribed to a site-saturated nucleation mechanism of the metastable form, confirmed by optical microscopy images. Regarding molecular mobility, a feature of molecular dynamics in glass-forming liquids as thermodynamic fragility index m was determined through calorimetric measurements. It turned out to be around m=100, describing Biclotymol as a fragile glass-former for Angell's classification. Relatively long-term stability of amorphous Biclotymol above Tg was analyzed indirectly by calorimetric monitoring to evaluate thermodynamic parameters and crystallization behavior of glassy Biclotymol. Within eight months of storage above Tg (T=Tg+2 degrees C), amorphous Biclotymol does not show a strong inclination to crystallize and forms a relatively stable glass. This case study, involving a multidisciplinary approach, points out the importance of continuing looking for stability predictors. PMID- 26003418 TI - Effect of hydrophobic scaffold on the cellular uptake and gene transfection activities of DNA-encapsulating liposomal nanoparticles via intracerebroventricular administration. AB - Efficient DNA carriers are needed as a gene medication for curing brain disorders. In the present study, the function of a neutral lipid envelope-type nanoparticle (LNP) encapsulating pDNA was evaluated after intracerebroventricular administration. The lipid envelope was composed of a series of SS-cleavable and pH-activated lipid like materials (ssPalm) including myristic acid, vitamin A and vitamin E in the hydrophobic scaffold (LNPssPalmM, LNPssPalmA, LNPssPalmE, respectively). The LNPssPalmA and LNPssPalmE were extensively distributed in the corpus callosum, and then gene expression occurred mainly astrocytes in this region, while not in LNPssPalmM. The recombinant human ApoE3-dependent enhancement of the uptake into an astrocyte-derived cell line (KT-5) was observed in LNPssPalmA and LNPssPalmE. Thus, ApoE in the brain plays a key role in the cellular uptake of these particles by astrocytes, and this uptake is dependent on the structure of the hydrophobic scaffold. PMID- 26003419 TI - School-Based Interventions for Anxious Children: Long-Term Follow-Up. AB - This study examined the long-term outcomes of a nonclinical sample of anxious children (N = 61) who were randomized by school to 9 weeks of group cognitive behavioral therapy (CBT) for children, group CBT for children plus parent training, or no-treatment control. Parents and children completed measures of anxiety symptoms at baseline, posttreatment, and at 3-, 6-, 12-month, 2-, and 3 year posttreatment follow-ups. Piecewise longitudinal growth curve analyses were applied to the data. When the two CBT groups were combined and compared with control, the combined treatment group showed significantly greater reduction in children's anxiety severity based on the parent ratings in the first longitudinal phase. However, on the parent Clinician Severity Rating, gains were maintained to 3 years. Child report revealed no significant differences between groups on anxiety reduction. This study maintained a small no-treatment control group during the entire follow-up period. From parental perspective only, school-based group CBT appeared to be beneficial in decreasing severity of anxiety symptoms and maintaining gains over time. PMID- 26003420 TI - Sleep-Wake Patterns of Adolescents with Borderline Personality Disorder and Bipolar Disorder. AB - Sleep-wake patterns are rarely examined in adolescents with borderline personality disorder (BPD) or bipolar disorder (BD). Within a developmental perspective, this study explores the sleep-wake cycle of adolescents aged 12-17 years with BPD or BD and healthy controls (HC) during periods with and without entrainment by school/work schedules. Eighteen euthymic BPD, six euthymic BD, and 20 HC adolescents wore wrist actigraphy during nine consecutive days to assess sleep-wake patterns. During school/work days, BPD adolescents spent more time awake when they were in bed compared to HC and BD adolescents (p = 0.039). On schedule-free days, BPD and BD youths spent more time in bed compared to HC adolescents (p = 0.015). BPD adolescents woke up over 1 h later compared to HC (p = 0.003). Total sleep time was more variable between nights in BPD adolescents compared to the HC group (p = 0.031). Future research should explore if sleep wake pattern disruptions are a cause or a consequence of BPD symptomatology in adolescents. Addressing sleep-wake pattern during clinical assessment and treatment of BPD adolescents may potentially reduce their symptoms; this therapeutic effect still needs to be evaluated. PMID- 26003422 TI - Impact of admission to hospice on pain intensity and type of pain therapies administered. AB - PURPOSE: The primary aim of this study was to evaluate pain intensity changes in patients admitted to a hospice. The secondary objective was to evaluate whether these changes in pain were accompanied by modifications in therapies and drugs used to treat pain. PATIENTS AND METHODS: This retrospective study included 96 patients admitted to a hospice for a minimum of 7 days who received pain therapy. An 11-point (0-10) numerical rating scale (NRS) was used to assess pain on a daily basis. A repeated measures analysis of variance was performed to evaluate pain intensity changes over time. RESULTS: Mean +/- SD pain NRS values of the entire group were 2.58 +/- 2.61 on day 1 and 1.40 +/- 1.72 on day 7 (P = 0.002). Restricting the analysis to patients with moderate to severe pain at the time of hospice admission, results were even more significant. In fact, mean +/- SD pain NRS was 5.51 +/- 1.24 for patients with pain >=4 at admission and 1.76 +/- 1.91 for the same patients after 7 days (P < 0.001). A significant increase in the number of patients receiving morphine was observed from day 1 to day 7 (24 to 41, respectively, P = 0.001) and in those receiving drugs via parenteral routes (subcutaneous or intravenous) from 10 to 27 (P = 0.002) CONCLUSIONS: Admission to a hospice and the hospice environment led to a significant reduction in reported pain intensity for the patients included in this study, mainly those with moderate to severe pain at the time of admission. This decrease in pain was accompanied by a significant increase in the use of morphine, especially via parenteral routes, but not by a higher mean equivalent daily dose of oral morphine per patient. PMID- 26003421 TI - Cancer's positive flip side: posttraumatic growth after childhood cancer. AB - BACKGROUND: Surviving childhood cancer may result in positive psychological changes called posttraumatic growth (PTG). Knowing about the possibility of positive changes may facilitate survivors' reintegration in daily life. We aimed to (1) describe PTG in Swiss childhood cancer survivors including the most and the least common PTG phenomena on the subscale and item levels and (2) determine factors associated with PTG. METHOD: Within the Swiss Childhood Cancer Survivor Study (SCCSS), we sent two questionnaires to childhood cancer survivors registered in the Swiss Childhood Cancer Registry (SCCR). Eligible survivors were diagnosed after 1990 at age <=16 years, survived >=5 years, and were aged >=18 years at the time the second questionnaire was sent. We included the Posttraumatic Growth Inventory (PTGI) to assess five areas of PTG. We investigated the association of PTG with socio-demographic characteristics, self reported late effects, and psychological distress, which were assessed in the SCCSS and clinical variables extracted from the SCCR. We used descriptive statistics to describe PTG and linear regressions to investigate factors associated with PTG. RESULTS: We assessed PTG in 309 childhood cancer survivors. Most individuals reported to have experienced some PTG. The most endorsed change occurred in "relation with others," the least in "spiritual change." PTG was significantly higher in survivors with older age at diagnosis (p = 0.001) and those with a longer duration of treatment (p = 0.042), while it was lower in male survivors (p = 0.003). CONCLUSIONS: Supporting experiences of PTG during follow up may help survivors successfully return to daily life. PMID- 26003423 TI - Meaning of work and the process of returning after head and neck cancer. AB - PURPOSE: The purposes of this study were (1) to investigate employment status at diagnosis, sick leave, and returning to work patterns in correlation to quality of life, anxiety, and depression in patients treated for head and neck cancer (HNC) and (2) to explore patients' experiences of the process of returning to work. METHODS: Sixty-six patients with HNC (aged 34-66 years) were repeatedly interviewed over a period of 24 months. Interview responses that concerned the patients' experiences and ideas about work were categorised using the similarities-differences technique. Questionnaires on quality of life, anxiety, and depression were used to describe the patient characteristics and the differences between groups. RESULTS: In total, 53% of the patients had returned to work at 24 months after treatment, and 17% were deceased. Several quality of life parameters were significantly worse for patients not working at 24 months after treatment. Nine categories were found to describe the return-to-work process starting with symptoms causing sick leave, thoughts about the sick leave, and ending with the return to work and/or retirement. CONCLUSIONS: Returning to work is an important part of life because it structures everyday life and strengthens the individual's identity. The quality of life results showed significant differences between workers and non-workers at the 24-month follow up. The patients need to be both physically and mentally prepared for the process of returning to work. It is important to take an individual rehabilitation approach to guide and support the patients in returning to work and regaining an important aspect of their everyday life. In such an approach, it is vital to understand the patients' overall life context and the patients' own perspective on the process and meaning associated with work. PMID- 26003424 TI - Indigenous cancer patient and staff attitudes towards unmet needs screening using the SCNAT-IP. AB - INTRODUCTION: Indigenous Australians have a higher cancer incidence, worse mortality and are less likely to receive optimal cancer treatment compared with non-Indigenous Australians. Culturally appropriate supportive care helps ensure that Indigenous patients engage in and receive optimal care. However, many existing supportive care needs tools lack cultural relevance for Indigenous people, and their feasibility with Indigenous people has not been demonstrated. The Supportive Care Needs Assessment Tool for Indigenous People (SCNAT-IP) assesses the unmet supportive care needs of Indigenous cancer patients. PURPOSE: This descriptive study evaluates the clinical implementation of the SCNAT-IP in routine care. METHODS: Two large tertiary cancer treatment centres and two regional oncology clinics participated. Participants included 10 clinical staff and 36 adult Indigenous cancer patients (mean age 54 years). Patients and clinicians completed brief, purpose-designed questionnaires and interviews. RESULTS: Patients reported high ratings (means >8/10) for acceptability, helpfulness and timing items. The majority (>=80%) of staff agreed that the SCNAT IP was useful to clinical practice, should be used in routine care and was acceptable to their patients. CONCLUSIONS: The study provides empirical support for the feasibility and acceptability of the SCNAT-IP in routine cancer care with Indigenous Australians. Routine screening with the SCNAT-IP has the potential to improve cancer care for Indigenous people with cancer. PMID- 26003425 TI - Evaluation of the validity of chemotherapy-induced nausea and vomiting assessment in outpatients using the Japanese version of the MASCC antiemesis tool. AB - PURPOSE: The Multinational Association of Supportive Care in Cancer (MASCC) developed the MASCC antiemesis tool (MAT) as a tool for chemotherapy-induced nausea and vomiting (CINV) assessment and subsequently published its Japanese version in 2010. We evaluated the validity of CINV assessment in outpatients using the Japanese version of MAT. METHODS: Patients administered highly or moderately emetogenic chemotherapy in the outpatient chemotherapy unit of our hospital were included in the study. The study was designed as a prospective two period crossover observational study to evaluate the correlation between the daily patient diary and the Japanese version of MAT in terms of CINV onset. We examined with a focus on reliability of the Japanese version of MAT particularly in the description of the delayed phase of nausea and vomiting. RESULTS: Patient descriptions of CINV onset in a total of 116 cycles in 58 patients (two cycles/patient) were analyzed. The CINV incidence indicated by the patient diary was similar to that by the Japanese version of MAT. The concordance rate between the two tools in the same patients was 86.2 % for CINV onset in the delayed phase. The nausea score was also similar between the two tools regarding the mean and variance, showing a strong correlation with a correlation coefficient of 0.71. CONCLUSIONS: The results of the study showed that the Japanese version of MAT is a highly reliable tool for CINV assessment, indicating that it is valid for assessing CINV in outpatients. PMID- 26003426 TI - The effects of resistance exercise on physical performance and health-related quality of life in prostate cancer patients: a systematic review. AB - PURPOSE: Physical exercise has been shown to be an effective, safe, and quite inexpensive method to reduce cardiovascular and metabolic risk factors and is currently in the process of establishing its relevance for cancer specific morbidity and mortality. The aim of this systematic review was to focus on specific effects of resistance exercise (RE) in the adjuvant therapy and rehabilitation of prostate cancer patients (PCaPs) receiving or having received androgen deprivation therapy (ADT). METHODS: A systematic literature search focusing on relevant and peer-reviewed studies published between 1966 and September 2014, using PubMed, EMBASE, MEDLINE, SCOPUS, and Cochrane Library databases, was conducted. RESULTS: The majority of studies demonstrated RE as an effective and safe intervention to improve muscular strength and performance, fatigue and quality of life (QoL) in PCaPs, while there is inconclusive evidence concerning cardiovascular performance, body composition, blood lipids, bone mineral density (BMD), and immune response. CONCLUSION: Existing evidence leads to the conclusion that RE seems to be a safe intervention in PCaPs with beneficial effects on physical performance capacity and QoL. Nevertheless, further research in this field is urgently needed to increase understanding of exercise interventions in PCaPs. PMID- 26003427 TI - Layer-resolved colorectal tissues using nonlinear microscopy. AB - In this work, multiphoton microscopy (MPM), based on the nonlinear optical processes two-photon excited fluorescence (TPEF) and second harmonic generation (SHG), was extended to evaluate the feasibility of using MPM to distinguish layers of the bowel wall. It was found that MPM has the ability to identify the four-layer microstructures of colorectal tissues including mucosa, submucosa, muscularis propria, and serosa as there are many intrinsic signal sources in each layer. Our results also showed the capability of using the quantitative analyses of MPM images for quantifying some feature parameters including the nuclear area, nuclear-to-cytoplasmic ratio, and optical redox ratio. This work demonstrates that MPM has the potential in noninvasively monitoring the development and progression of colorectal diseases and then guiding effective treatment. PMID- 26003428 TI - Small copper-doped silicon clusters CuSin (n = 4-10) and their anions: structures, thermochemistry, and electron affinities. AB - The structures and energies of copper-doped small silicon clusters CuSi n (n = 4 10) and their anions were investigated systematically using CCSD(T)/aug-cc-pVTZ DK//MP2/6-31G(2df,p), G4//MP2/6-31G(2df,p), and the B3LYP/6-311+G* basis set. The performance of the methods used for the prediction of energetic and thermodynamic properties was evaluated. Comparing experimental [Xu et al. (2012) J Chem Phys 136:104308] and theoretical calculations, it was concluded that the CCSD(T) results are very accurate and exhibit the best performance; the mean absolute deviation from experimental data was 0.043 eV. The excellent agreement of vertical detachment energy (VDE) between experimental results and CCSD(T) calculations indicates that the ground state structures of CuSi n (-) (n = 4-10) presented in this paper are reliable. For CuSi10, assigning 2.90+/-0.08 eV to the experimental adiabatic electron affinity (AEA) and 3.90+/-0.08 eV to the VDE is more reasonable than to 3.46+/-0.08 eV and 3.62+/-0.08 eV, respectively, based on the CCSD(T) calculations and the previous photoelectron spectrum of CuSi10 (-) (Xu et al., op. cit.). The AEAs of CuSi n (n = 4-10), excluding CuSi7, are in excellent agreement with experimental data, showing that the ground state structures of CuSi n (n = 4-6, 8-10) reported in this paper are reliable. CuSi10 is suggested to be the smallest endohedral ground state structure. However, adding an additional electron to CuSi10 pulls out the Cu atom from the center location, forming an exohedral ground state structure of CuSi10 (-). The charge transfer and dissociation energy of Cu from CuSi n and their anions determined to examine the nature of bonding and their relative stabilities. PMID- 26003429 TI - Distribution of infective gastrointestinal helminth larvae in tropical erect grass under different feeding systems for lambs. AB - This study examined tropical pasture contamination dynamics under different feeding systems for finishing lambs. The experiment aimed to evaluate the vertical distribution of gastrointestinal helminth infective larvae (L3) in erect grass subjected to grazing and to assess the parasite load and its impact on lamb performance in three production systems. Three treatments based on Aruana grass (Panicum maximum cv. IZ-5) were as follows: T1, grass only; T2, grass with 1.5% of body weight (BW) nutrient concentrate supplementation; and T3, grass with 2.5% BW concentrate supplementation. The randomized block design had three replicates of three treatments, with six lambs per replicate. L3 were recovered from three pasture strata (upper, middle, and bottom), each representing one third of the sward height, and correlated with microclimatic data. Significant differences (P < 0.05) were observed among treatments in the L3 recovery. Despite different grass heights between treatments and microclimates within the sward, the L3 concentration generally did not differ significantly among the three strata within a treatment (P > 0.05). Pasture microclimate did not correlate with larval recovery. At the end of the experiment, the animal fecal egg count was similar among treatments (P > 0.05). The results indicated that different lamb feeding systems in a tropical erect grassland caused differences in grass height but did not affect the distribution of infective larvae among strata. Larvae were found from the base to the top of the grass sward. PMID- 26003430 TI - Fucosylated clusterin in semen promotes the uptake of stress-damaged proteins by dendritic cells via DC-SIGN. AB - STUDY QUESTION: Could seminal plasma clusterin play a role in the uptake of stress-damaged proteins by dendritic cells? SUMMARY ANSWER: Seminal plasma clusterin, but not serum clusterin, promotes the uptake of stress-damaged proteins by dendritic cells via DC-SIGN. WHAT IS KNOWN ALREADY: Clusterin is one of the major extracellular chaperones. It interacts with a variety of stressed proteins to prevent their aggregation, guiding them for receptor-mediated endocytosis and intracellular degradation. The concentration of clusterin in semen is almost 20-fold higher than that found in serum, raising the question about the role of seminal plasma clusterin in reproduction. No previous studies have analyzed whether seminal plasma clusterin has chaperone activity. We have previously shown that seminal plasma clusterin, but not serum clusterin, expresses an extreme abundance of fucosylated glycans. These motifs enable seminal plasma clusterin to bind DC-SIGN with very high affinity. STUDY DESIGN, SIZE, DURATION: In vitro experiments were performed to evaluate the ability of seminal plasma clusterin to inhibit the precipitation of stressed proteins, promoting their uptake by dendritic cells via DC-SIGN (a C-type lectin receptor selectively expressed on dendritic cells (DC)). Moreover, the ability of seminal plasma clusterin to modulate the phenotype and function of DCs was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clusterin was purified from human semen and human serum. Catalase, bovine serum albumin, glutathione S-transferase, and normal human serum were stressed and the ability of seminal plasma clusterin to prevent the precipitation of these proteins, guiding them to DC-SIGN expressed by DCs, was evaluated using a fluorescence-activated cell sorter (FACS). Endocytosis of stressed proteins was analyzed by confocal microscopy and the ability of seminal plasma clusterin-treated DCs to stimulate the proliferation of CD25+FOXP3+CD4+ T cells was also evaluated by FACS. MAIN RESULTS AND THE ROLE OF CHANCE: Seminal plasma clusterin interacts with stressed proteins, inhibits their aggregation (P < 0.01) and efficiently targets them to dendritic cells via DC SIGN (P < 0.01). DCs efficiently endocytosed clusterin-client complexes and sorted them to degradative compartments involved in antigen processing and presentation. Moreover, we also found that the interaction of seminal plasma clusterin with DC-SIGN did not change the phenotype of DCs, but stimulates their ability to induce the expansion of CD25+FOXP3+CD4+ T lymphocytes (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: All the experiments were performed in vitro; hence the relevance of our observations should be validated in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that by inducing the endocytosis of stress-damaged proteins by DCs via DC-SIGN, seminal plasma clusterin might promote a tolerogenic response to male antigens, thereby contributing to female tolerance to seminal antigens. STUDY FUNDING/COMPETING INTERESTS: The present research was supported by the Consejo Nacional de Investigaciones Cientificas y Tecnicas, the Buenos Aires University School of Medicine, and the Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina). The authors have no conflicts of interest to declare. PMID- 26003431 TI - NEDD8-mediated neddylation is required for human endometrial stromal proliferation and decidualization. AB - STUDY QUESTION: Does NEDD8-mediated neddylation regulate human endometrial stromal proliferation and decidualization? SUMMARY ANSWER: Neddylation inhibition by a selective NEDD8-activating enzyme inhibitor, MLN4924, significantly impairs human endometrial stromal cell (HESC) proliferation and decidualization and facilitates cell senescence, via p21 accumulation. WHAT IS KNOWN ALREADY: Neddylation regulates cell proliferation and tissue remodeling during embryogenesis and tumorigenesis, while human endometrial stroma undergoes sequential proliferation, differentiation, as well as dynamic tissue remodeling during each menstrual cycle. STUDY DESIGN, SIZE, DURATION: We first analyzed the expression of NEDD8 in human endometrial tissues from 50 subjects, and then explored the consequence of neddylation inhibition by MLN4924 on HESCs proliferation, decidualization and cellular senescence. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected 50 dated human endometrial tissues from early proliferative stage to late secretory phase of the menstrual cycle and analyzed the NEDD8 expression and cellular location in human endometrium by employing quantitative real-time PCR (qRT-PCR) and immunohistochemistry staining. Similar approaches were also used to explore the mRNA and protein expression of NEDD8 in an immortalized human endometrial stromal cell line (HESC) during proliferation and decidualization (N = 6). An MTS assay was performed to evaluate the effects of neddylation inhibition by MLN4924 on HESC proliferation. Flow cytometry and BrdU incorporation assay were conducted to determine the HESC cell cycle progression in response to MLN4924 exposure during proliferation. We also analyzed F-actin distribution by phalloidin staining and decidual marker gene expression by qRT-PCR to accesses the consequence of neddylation inhibition on HESC decidualization. Immunoblotting analysis of cullin1 and p21, and SA-beta Galactosidase staining were performed to reveal the potential molecular basis for the impaired HESC proliferation, decidualization and cellular senescence. The siRNA technique was applied to knockdown p21 expression to test whether a clearance of p21 accumulation would correct the HESC defects from neddylation inhibition. MAIN RESULTS AND THE ROLE OF CHANCE: We demonstrated that NEDD8 is ubiquitously expressed in human endometrium including luminal epithelium, glandular epithelium and the stromal cells during the menstrual cycle, as well as in the HESCs during proliferation and differentiation in culture. Employing multiple molecular, cellular and pharmacological approaches, we further observed that neddylation inhibition by MLN4924 significantly attenuates HESC proliferation (P-value < 0.05), impairs decidual transformation (P-value < 0.05), and facilitates cellular senescence. These abnormal HESC activities upon MLN4924 exposure were accompanied with reduced cullin1 neddylation and an aberrant accumulation of p21. While a clearance of p21 accumulation by siRNA knockdown could partially restore HESC proliferation and cellular viability, it failed to correct the decidualization defects. LIMITATIONS, REASONS FOR CAUTION: Since NEDD8 was also intensely expressed in the endometrial epithelium, it is interesting to further study its potential role in stroma-epithelial interactions through isolating and culturing epithelial cells. p21 siRNA knockdown experiments revealed that there are differential molecular machineries, other than p21, that are subject to neddylation regulation during HESC proliferation compared with differentiation. This alternative mechanism warrants further investigation in future. WIDER IMPLICATIONS OF THE FINDINGS: Our findings add novel evidence showing, for what we believe the first time, that NEDD8-mediated neddylation is required for normal human endometrial functions, which raises the possibility of approaching the neddylation system for diagnosis and treatment of infertility in women. STUDY FUNDING/COMPETING INTERESTS: This work was supported in parts by the National Basic Research Program of China (2011CB944400 to H.W.) and the National Natural Science Foundation (81130009, 81330017 to H.W., 81170575 to S.Q. and 31471106 to S.Z.). The author declares that there is no conflict of interest. PMID- 26003432 TI - Advances in the meta-analysis of heterogeneous clinical trials II: The quality effects model. AB - This article examines the performance of the updated quality effects (QE) estimator for meta-analysis of heterogeneous studies. It is shown that this approach leads to a decreased mean squared error (MSE) of the estimator while maintaining the nominal level of coverage probability of the confidence interval. Extensive simulation studies confirm that this approach leads to the maintenance of the correct coverage probability of the confidence interval, regardless of the level of heterogeneity, as well as a lower observed variance compared to the random effects (RE) model. The QE model is robust to subjectivity in quality assessment down to completely random entry, in which case its MSE equals that of the RE estimator. When the proposed QE method is applied to a meta-analysis of magnesium for myocardial infarction data, the pooled mortality odds ratio (OR) becomes 0.81 (95% CI 0.61-1.08) which favors the larger studies but also reflects the increased uncertainty around the pooled estimate. In comparison, under the RE model, the pooled mortality OR is 0.71 (95% CI 0.57-0.89) which is less conservative than that of the QE results. The new estimation method has been implemented into the free meta-analysis software MetaXL which allows comparison of alternative estimators and can be downloaded from www.epigear.com. PMID- 26003433 TI - Rationale and design of the RT-AF study: Combination of rivaroxaban and ticagrelor in patients with atrial fibrillation and coronary artery disease undergoing percutaneous coronary intervention. AB - OBJECTIVE: Optimal antithrombotic strategy for patients with concomitant coronary artery disease and atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) is still controversial, and the role of novel antithrombotic agents has nerve been tested. Therefore, the aim of this study is to evaluate and overall safety and efficacy profile of the combination of rivaroxaban and ticagrelor in this particular population. DESIGN: The RT-AF study is an open label, randomized, active-controlled, multicenter clinical trial with up to 420 subjects enrolled in 5 centers. Eligible patients, who have a history or new onset paroxysmal, persistent, or permanent non-valvular AF, referred to the study centers with indications for PCI will be randomly assigned to receive triple therapy (including warfarin, clopidogrel and aspirin) or dual therapy (rivaroxaban and ticagrelor). All subjects will have clinical follow-up at discharge, at 30 days, 6 months and 12 months. The primary end point is major or clinically relevant non-major bleeding events at 12 months. The major secondary end point is the composite efficacy outcome of death, myocardial infarction, stent thrombosis and ischemic stroke. CONCLUSION: The study will be sufficiently powered to provide data primarily regarding the safety of dual therapy with rivaroxaban and ticagrelor over the traditional triple therapy in patients with AF undergoing PCI at 12 months. It will also provide important information regarding the efficacy of the two different antithrombotic regimens. (ClinicalTrials.gov identifier: NCT02334254). PMID- 26003434 TI - Design challenges in transdiagnostic psychotherapy research: Comparing Transdiagnostic Behavior Therapy (TBT) to existing evidence-based psychotherapy in veterans with affective disorders. AB - BACKGROUND: To address the limitations of disorder-specific approaches, newer transdiagnostic approaches to psychotherapy have been developed to provide a single treatment that is capable of addressing several, related disorders. However, the recruitment of multiple diagnoses presents many challenges to the traditional design of psychotherapy randomized controlled trials (RCTs). OBJECTIVE: The goal of the manuscript is to present the challenges and rationale for designing a RCT for transdiagnostic treatment to inform and aid in the development of future investigations. METHODS: A recently funded and ongoing RCT for Transdiagnostic Behavior Therapy (TBT) is used as an example to discuss the related design challenges. The TBT study involves the recruitment of 96 veteran participants with any of the following eight principal diagnoses: posttraumatic stress disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, generalized anxiety disorder, specific phobia, major depressive disorder, or persistent depressive disorder. Within the TBT study, participants will complete a semi-structured diagnostic interview and a series of transdiagnostic self-report measures to determine eligibility and assess baseline symptomatology. Qualifying participants will be randomized to TBT or control psychotherapy. Additional assessments will be completed at post-treatment and 6 month follow-up. CONCLUSIONS: Due to the transdiagnostic nature of the sample, adjustments to the recruitment and randomization procedures, selection of measures, selection of control psychotherapy, and analysis plan were required. These adjustments have implications to future trials on transdiagnostic psychotherapy protocols as well as future research in line with the transdiagnostic focus of the National Institute of Mental Health's Research Domain Criteria (RDoC) funding strategy. PMID- 26003435 TI - Advances in the meta-analysis of heterogeneous clinical trials I: The inverse variance heterogeneity model. AB - This article examines an improved alternative to the random effects (RE) model for meta-analysis of heterogeneous studies. It is shown that the known issues of underestimation of the statistical error and spuriously overconfident estimates with the RE model can be resolved by the use of an estimator under the fixed effect model assumption with a quasi-likelihood based variance structure - the IVhet model. Extensive simulations confirm that this estimator retains a correct coverage probability and a lower observed variance than the RE model estimator, regardless of heterogeneity. When the proposed IVhet method is applied to the controversial meta-analysis of intravenous magnesium for the prevention of mortality after myocardial infarction, the pooled OR is 1.01 (95% CI 0.71-1.46) which not only favors the larger studies but also indicates more uncertainty around the point estimate. In comparison, under the RE model the pooled OR is 0.71 (95% CI 0.57-0.89) which, given the simulation results, reflects underestimation of the statistical error. Given the compelling evidence generated, we recommend that the IVhet model replace both the FE and RE models. To facilitate this, it has been implemented into free meta-analysis software called MetaXL which can be downloaded from www.epigear.com. PMID- 26003436 TI - The Telehealth Enhancement of Adherence to Medication (TEAM) in pediatric IBD trial: Design and methodology. AB - Medication nonadherence is a significant health care issue requiring regular behavioral treatment. Lack of sufficient health care resources and patient/family time commitment for weekly treatment are primary barriers to receiving appropriate self-management support. We describe the methodology of the Telehealth Enhancement of Adherence to Medication (TEAM) trial for medication nonadherence in pediatric inflammatory bowel disease (IBD). For this trial, participants 11-18 years of age will be recruited from seven pediatric hospitals and will complete an initial 4-week run in to assess adherence to a daily medication. Those who take less than 90% of their prescribed medication will be randomized. A total of 194 patients with IBD will be randomized to either a telehealth behavioral treatment (TBT) arm or education only (EO) arm. All treatments will be delivered via telehealth video conferencing. The patients will be assessed at baseline, post-treatment, 3, 6, and 12 months. We anticipate that participants in the TBT arm will demonstrate a statistically significant improvement at post-treatment and 3-, 6-, and 12-month follow-up compared to participants in the EO arm for both medication adherence and secondary outcomes (i.e., disease severity, patient quality of life, and health care utilization). If efficacious, the TEAM intervention could be disseminated broadly and reduce health care access barriers so that the patients could receive much needed self management intervention. PMID- 26003437 TI - LFP-20, a porcine lactoferrin peptide, ameliorates LPS-induced inflammation via the MyD88/NF-kappaB and MyD88/MAPK signaling pathways. AB - LFP-20 is one of the 20 amino acid anti-microbial peptides identified in the N terminus of porcine lactoferrin. Apart from its extensively studied direct anti bacterial activity, its potential as an activator of immune-related cellular functions is unknown. Therefore, this study investigated its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated pig alveolar macrophages in vitro and systemic inflammation in an in vivo mouse model. We found that the inhibitory effects of LFP-20 on production of pro-inflammatory cytokines were independent of its LPS-binding activity. However, they were associated with NF-kappaB and MAPK dependent signaling. Furthermore, LFP-20 might directly influence MyD88 levels to block its interaction with NF-kappaB and MAPK-dependent signaling molecules that might alter LPS-mediated inflammatory responses in activated macrophages. Taken together, our data indicated that LFP-20 prevents the LPS-induced inflammatory response by inhibiting MyD88/NF-kappaB and MyD88/MAPK signaling pathways, and sheds light on the potential use of LFP-20 in the therapy of LPS-mediated sepsis. PMID- 26003438 TI - Highly specific and rapid immuno-fluorescent visualization and detection of E. coli O104:H4 with protein-A coated magnetic beads based LST-MUG assay. AB - A method combining immunomagnetic separation and fluorescent sensing was developed to detect Escherichia coli (E. coli) O104:H4. The antibody specific to E. coli O104:H4 was immobilized on protein A-coated magnetic beads. This protein A-anti E. coli O104:H4 complex was used to bind Fluorescein IsoThioCyanate (FITC) labeled E. coli O104:H4 antigen (whole cell) on it. The goal was to achieve a fluorescently detectable protein-A-anti E. coli O104:H4-E. coli O104:H4 complex on the magnetic beads. Fluorescent microscopy was used to image the magnetic beads. The resulting fluorescence on the beads was due to the FITC labeled antigen binding on the protein-A-anti E. coli O104:H4 immobilized magnetic beads. This visually proves the antigen-antibody binding. The fluorescent imaging results were obtained in 2 h if the minimum available bacteria in the sample were at least 10(5) CFU/ml. If no fluorescence was observed on the magnetic beads during fluorescent imaging, it indicates the bacterial concentration in the sample to be too low for it to have bound to the magnetic beads and hence no detection was possible. To detect bacterial concentration less than 10(5) CFU/ml in the sample, an additional step was required for detection. The magnetic bead complex was added to the LST-MUG (lauryl sulfate tryptose-4-methylumbelliferyl beta-D-glucuronide), a signaling reporter. The E. coli O104:H4 grows in LST-MUG and releases beta-glucuronidase enzyme. This enzyme cleaves the MUG substrate that produces 4-methylumbelliferone, a highly fluorescent species. This fluorescence was detected using a spectrofluorometer. The emission peak in the fluorescent spectrum was found to be at 450 nm. The lower and upper detection range for this LST-MUG assay was found to be 2.05*10(5)-4.09*10(8) CFU/ml. The results for the LST-MUG assay for concentrations below 10(5) CFU/ml were ascertained in 8h. The advantages of this technique include the specific detection of bacteria without an enrichment step and allowing the procedure to be completed in hours rather than days. PMID- 26003439 TI - Development of selective and differential medium for Shigella sonnei using three carbohydrates (lactose, sorbitol, and xylose) and X-Gal. AB - The aim of this study was to develop a new selective and differential medium for isolating Shigella sonnei (designated 3SD medium). The new medium was based on three carbohydrates (lactose, sorbitol, and xylose) and a chromogenic substrate (5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside, X-Gal). S. sonnei cannot ferment lactose, sorbitol, or xylose, but can ferment X-Gal, which generates turquoise-blue colonies with rough edges. Other bacteria (54 strains of foodborne pathogens and spoilage bacteria) produced visually distinct colonies on 3SD medium (colorless or pink-violet colonies), or their growth was inhibited on 3SD medium. The optimum concentration of 50 mg/L X-Gal was selected because it yielded the highest level of morphological discrimination between S. sonnei and other bacteria, and this concentration was cost-effective. Bile salt concentration optimization was performed using healthy, heat-injured, and acid injured S. sonnei. The recovery rate differed significantly depending on the bile salt concentration; media containing >1.0 g/L bile salt showed significantly lower recovery of stress-injured cells than medium containing 0.5 g/L bile salt (P<0.05). Growth of all Gram-positive bacteria was inhibited on medium containing 0.5 g/L bile salt; therefore, this concentration was used as the optimal concentration. Previous media used to isolate Shigella spp. (MacConkey, xylose lysine desoxycholate, and Salmonella-Shigella agar) showed poor performance when used to support the growth of injured S. sonnei cells, whereas 3SD medium supported a high growth rate of injured and healthy cells (equivalent to that obtained with nutrient-rich tryptic soy agar). To validate the performance of 3SD medium with real specimens, S. sonnei and other bacteria were spiked into samples such as untreated water, carrot, salad, and oyster. 3SD medium showed superior specificity (100%) and sensitivity (100%) for S. sonnei, and yielded no false positive or false-negative results. Thus, the novel 3SD medium described herein is a powerful tool for the rapid and efficient selective isolation of S. sonnei in research and clinical laboratories, and the food industry. PMID- 26003440 TI - Simple and rapid preparation of red fluorescence and red color S. aureus derived nanobioparticles for pathogen detection. AB - In this study, a simple and rapid method was developed to transform protein A producing Staphylococcus aureus cells into red color and red fluorescent nanobioparticles, which were homogeneous, dispersive and relatively stable with a uniform size of 800 nm. The method consists of reaction with a monotetrazolium redox dye at 25 degrees C for 15 min and heat inactivation at 65 degrees C for 30 min. This method provided the first S. aureus nanobioparticles with the dual property of red color and red fluorescence. Attributed to the IgG binding site known as protein A on their surface, the nanobioparticles could be used as vectors for immunoassays of many bacteria and viruses. Coagglutination test of Escherichia coli O157:H7 observed by naked eyes showed that the detection limitation of the nanobioprobes was 1*10(6) CFU/ml, which was about 100 times more sensitive than the natural uncolored S. aureus bioprobes. Red fluorescence detection and analysis of the coagglutination product by a microplate reader lowered the detection limit to 2.5*10(4) CFU/ml. PMID- 26003441 TI - Effects of flavonoids on expression of genes involved in cell cycle regulation and DNA replication in human fibroblasts. AB - Flavonoids have been studied as potential agents in medicine for many years. Among them, genistein was found to be active in various biological systems, mainly in prevention of cancer. Our recent work supported the idea that genistein also impacts multiple cellular processes in healthy fibroblasts; however, its effects on cell cycle-related pathways remained to be elucidated. Thus, in this work, high throughput screening with microarrays coupled to real-time quantitative Reverse Transcription PCR analyses was employed to study the changes in expression of key genes associated with cell cycle regulation and/or DNA replication in response to genistein, kaempferol, daidzein, and mixtures of genistein and either kaempferol or daidzein. Among them, genistein was found as the most significantly modulating, in a time- and dose-dependent manner, compound of activity of studied genes, whose products are involved in different phases of the cell cycle and/or in regulatory processes important for DNA replication and cell growth. It considerably reduced the efficiency of expression of genes coding for MCM2-7 and MCM10 helicases, as well as some other proteins involved in the S phase control. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and GADD45A genes, as well as down-regulation of several mRNAs specific for this stage, demonstrated by transcriptomic assessments. We believe that studies described in this paper will be helpful in elucidating molecular mechanisms of action of genistein as modulator of cell cycle and inhibitor of DNA replication in humans. PMID- 26003442 TI - Targeting CD151 by lentivirus-mediated RNA interference inhibits luminal and basal-like breast cancer cell growth and invasion. AB - CD151 is a member of the tetraspanin family, which is involved in diverse cellular processes, including proliferation, motility, and invasion. However, the role of CD151 in breast cancer especially luminal and basal-like subtype breast cancer remains obscure. Here, we report the role of CD151 in the biological behaviors of luminal and basal-like subtype cell lines and the underlying molecular mechanism. A eukaryotic expression vector expressing both CD151 shRNA and GFP was transfected into MCF-7 and MDA-MB-468 cells. The CD151 gene-silencing effect is authenticated by real-time PCR and Western blot. Our data show that the capacity for proliferation, migration, and invasion of two kinds of cells is diminished after Knockdown of CD151 via lentivirus-mediated CD151 specific shRNA. Tumor cells are arrested in G0/G1 phase. Apoptosis is increased. Moreover, we also demonstrate that the expressions of mmp26 and CD147 are inhibited by knockdown of CD151. But the inhibition depends on the cell type. We can conclude that silencing gene CD151 inhibits expression of properties that are associated with the malignant phenotype of MCF-7 and MDA-MB-468 cells. It may become a potential target in breast cancer therapy especially for luminal and basal subtypes. PMID- 26003443 TI - Body weight estimation based on postmortem CT data--validation of a multiplication factor. AB - Postmortem computed tomography (pmCT) is increasingly applied in forensic medicine as a documentation and diagnostic tool. The present study investigated if pmCT data can be used to estimate the corpse weight. In 50 forensic cases, pmCT examinations were performed prior to autopsy and the pmCT data were used to determine the body volume using an automated segmentation tool. PmCT was performed within 48 h postmortem. The body weights assessed prior to autopsy and the body volumes assessed using the pmCT data were used to calculate individual multiplication factors. The mean postmortem multiplication factor for the study cases was 1.07 g/ml. Using this factor, the body weight may be estimated retrospectively when necessary. Severe artifact causing foreign bodies within the corpses limit the use of pmCT data for body weight estimations. PMID- 26003444 TI - Review and status report of pediatric left ventricular systolic strain and strain rate nomograms. AB - Interest in strain (epsilon) and strain rate (SR) for the assessment of pediatric left ventricular (LV) myocardial function has increased. However, the strengths and limitations of published pediatric nomograms have not been critically evaluated. A literature search was conducted accessing the National Library of Medicine using the keywords myocardial velocity, strain, strain rate, pediatric, reference values, and nomograms. Adding the following keywords, the results were further refined: neonates, infants, adolescents, range/intervals, and speckle tracking. Ten published studies evaluating myocardial velocities, epsilon, or SR nomograms were analyzed. Sample sizes were limited in most of these studies, particularly in terms of neonates. Heterogeneous methods-tissue Doppler imaging, two- and three-dimensional speckle tracking-were used to perform and normalize measurements. Although most studies adjusted measurements for age, classification by specific age subgroups varied. Few studies addressed the relationships of epsilon and SR measurements to body size and heart rate. Data have been generally expressed by mean values and standard deviations; Z scores and percentiles that are commonly employed for pediatric echocardiographic quantification have been never used. Reference values for epsilon and SR were found to be reproducible in older children; however, they varied significantly in neonates and infants. Pediatric nomograms for LV epsilon and SR are limited by (a) small sample sizes, (b) inconsistent methodology used for derivation and normalization, and (c) scarcity of neonatal data. Some of the studies demonstrate reproducible patterns for systolic deformation in older children. There is need for comprehensive nomograms of myocardial epsilon and SR involving a large population of normal children obtained using standardized methodology. PMID- 26003446 TI - Environmental enrichment blocks reinstatement of ethanol-induced conditioned place preference in mice. AB - This study aimed to explore the effect of environmental enrichment (EE) on the reinstatement of ethanol-induced conditioned place preference (CPP) in C57Bl/6J mice. To investigate the effect of training dose on the extinction and relapse of ethanol-induced CPP, doses of ethanol were applied and we found 0.8 g/kg and 1.6 g/kg training doses lead to significant CPP. In the reinstatement procedure, previously extinguished 1.6 g/kg ethanol CPP could be markedly reinstated by a priming injection of 0.8 g/kg. In contrast, priming with 0.4 g/kg of ethanol failed to reinstate the CPP induced by 0.8 g/kg. To investigate whether concomitant EE exposure could prevent the reinstatement of ethanol-induced CPP, one half of the mice were housed in standard environment (SE) and the other half in EE during the extinction and reinstatement session in the second experiment. Our study showed that reinstatement of ethanol-induced CPP was blocked by EE and the extinction rate was the same between SE and EE mice. These findings suggest that EE can block reinstatement of ethanol-induced CPP in mice, and aiding in the identification of new therapeutic strategies for alcohol addiction. PMID- 26003445 TI - Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses. AB - Synapses mediate information flow between neurons and undergo plastic changes in response to experience, which is critical for learning and memory. Conversely, synaptic defects impair information processing and underlie many brain pathologies. Rho-family GTPases control synaptogenesis by transducing signals from extracellular stimuli to the cytoskeleton and nucleus. The Rho-GTPases Rac1 and Cdc42 promote synapse development and the growth of axons and dendrites, while RhoA antagonizes these processes. Despite its importance, many aspects of Rho-GTPase signaling remain relatively unknown. Rho-GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). Though the number of both GEFs and GAPs greatly exceeds that of Rho-GTPases, loss of even a single GEF or GAP often has profound effects on cognition and behavior. Here, we explore how the actions of specific GEFs and GAPs give rise to the precise spatiotemporal activation patterns of Rho-GTPases in neurons. We consider the effects of coupling GEFs and GAPs targeting the same Rho-GTPase and the modular pathways that connect specific cellular stimuli with a given Rho-GTPase via different GEFs. We discuss how the creation of sharp borders between Rho-GTPase activation zones is achieved by pairing a GEF for one Rho GTPase with a GAP for another and the extensive crosstalk between different Rho GTPases. Given the importance of synapses for cognition and the fundamental roles that Rho-GTPases play in regulating them, a detailed understanding of Rho-GTPase signaling is essential to the progress of neuroscience. PMID- 26003447 TI - Extracellular matrix protein reelin regulate dendritic spine density through CaMKIIbeta. AB - Reelin, an extracellular matrix protein, plays an important role in brain development as well as synaptic plasticity. Interestingly, several recent studies have found that Reelin is important for dendritic spine formation in vitro and in vivo. However, the molecular mechanism by which Reelin regulates the dendritic spine density has not been studied well yet. In this study, we found that exogenous Reelin treatment was significantly increased the dendritic spine density in the primary hippocampal neurons. In addition, Reelin was increased the puncta numbers of synaptophysin and PSD-95. Moreover, we found that Reelin modulated the levels of CaMKIIbeta, and CaMKIIbeta siRNA prevented Reelin's effect on the dendritic spine density. Overall, our results are the first to demonstrate that CaMKIIbeta might be required to enable Reelin to alter the dendritic spine density. PMID- 26003448 TI - Temporal and spatial organization of gait-related electrocortical potentials. AB - To advance gait rehabilitation research it is of great importance to understand the supraspinal control of walking. In this study, the temporal and spatial characteristics of averaged electrocortical activity during treadmill walking in healthy subjects was assessed. Electroencephalography data were recorded from 32 scalp locations, averaged across trials, and related to phases of the gait cycle based on the detection of left heel strike. A characteristic temporal pattern of positive and negative potentials, similar to movement-related cortical potentials, and related to the gait cycle was observed over the cortical leg representation area. Source localization analysis revealed that mainly the primary somatosensory, somatosensory association, primary motor and cingulate cortex were activated during walking. The negative peaks of the gait-related cortical potential were associated with activity predominantly in the cingulate and prefrontal cortex, while the primary motor, primary somatosensory and somatosensory association cortex were mainly active during the positive peaks. This study identified gait-related cortical potentials during walking. The results indicate a widely distributed cortical network involved in gait control. PMID- 26003449 TI - Challenging gait leads to stronger lower-limb kinematic synergies: The effects of walking within a more narrow pathway. AB - Previous studies using the uncontrolled manifold (UCM) analysis demonstrated that during the swing phase of gait, multi-joint kinematic synergies act to stabilize, i.e., minimize the variance of, the mediolateral trajectory of the swinging limb. Importantly, these synergies are strongest during midswing, suggesting that during gait, individuals may employ strategies to avoid collisions between the limbs at this instance. The purpose of the current study was to test this hypothesis by quantifying whether the synergy index (DeltaV) during the middle period of the swing phase of treadmill walking was affected when the width of the treadmill belt was narrowed, a task expected to increase the risk of limb collisions. Eleven healthy young adults walked on a dual-belt treadmill under two conditions: (1) dual-belt - both belts of the treadmill moved at 1.2 m/s (total width: 62.5 cm) and the subject walked with one foot on each of the moving belts and (2) single-belt - one treadmill belt moved at 1.2m/s while the other belt remained stationary and the subject walked with both feet on the moving belt (total width: 30.5 cm). During both conditions, motion capture recorded the positions of 22 passive reflective markers from which UCM analysis was used to quantify DeltaV in the joint configuration space. Results indicate that DeltaV during the middle-third of swing phase significantly increased by 20% during single-belt walking (p<.01). We interpret this as evidence that the stronger synergies at midswing are needed to stabilize the limb trajectory in order to reduce the risk of between-limb collisions during a period when the lower limbs are nearest each other in the frontal plane. PMID- 26003450 TI - Alterations in white matter integrity in first-episode, treatment-naive patients with somatization disorder. AB - White matter (WM) abnormality in somatization disorder (SD) has not been reported yet. This study was designed to elucidate the alterations in WM integrity in SD. A total of 25 patients with SD and 28 healthy controls were enrolled in the study. WM integrity was analyzed using tract-based spatial statistics. No differences were found between the patients and the controls for fractional anisotropy (FA) values, mean diffusivity (MD), axial diffusivity, and radial diffusivity values at the corrected p<0.05 level. Patients with SD had significantly decreased FA values in the cingulum and inferior fronto-occipital fasciculus, and significantly increased MD values in the anterior thalamic radiation and corticospinal tract compared with the controls at the uncorrected p<0.005 level. Somatization severity was correlated with the FA values of the cingulum and inferior fronto-occipital fasciculus in the patients. The patients exhibit suggestive alterations in WM integrity in the cingulum, inferior fronto occipital fasciculus, anterior thalamic radiation, and corticospinal tract. PMID- 26003451 TI - Limited hair cell induction from human induced pluripotent stem cells using a simple stepwise method. AB - Disease-specific induced pluripotent stem cells (iPS) cells are expected to contribute to exploring useful tools for studying the pathophysiology of inner ear diseases and to drug discovery for treating inner ear diseases. For this purpose, stable induction methods for the differentiation of human iPS cells into inner ear hair cells are required. In the present study, we examined the efficacy of a simple induction method for inducing the differentiation of human iPS cells into hair cells. The induction of inner ear hair cell-like cells was performed using a stepwise method mimicking inner ear development. Human iPS cells were sequentially transformed into the preplacodal ectoderm, otic placode, and hair cell-like cells. As a first step, preplacodal ectoderm induction, human iPS cells were seeded on a Matrigel-coated plate and cultured in a serum free N2/B27 medium for 8 days according to a previous study that demonstrated spontaneous differentiation of human ES cells into the preplacodal ectoderm. As the second step, the cells after preplacodal ectoderm induction were treated with basic fibroblast growth factor (bFGF) for induction of differentiation into otic placode-like cells for 15 days. As the final step, cultured cells were incubated in a serum free medium containing Matrigel for 48 days. After preplacodal ectoderm induction, over 90% of cultured cells expressed the genes that express in preplacodal ectoderm. By culture with bFGF, otic placode marker-positive cells were obtained, although their number was limited. Further 48-day culture in serum free media resulted in the induction of hair cell-like cells, which expressed a hair cell marker and had stereocilia bundle-like constructions on their apical surface. Our results indicate that hair cell-like cells are induced from human iPS cells using a simple stepwise method with only bFGF, without the use of xenogeneic cells. PMID- 26003452 TI - Does ovarian stimulation for IVF increase gynaecological cancer risk? A systematic review and meta-analysis. AB - The aim of this study was to evaluate whether ovarian stimulation for IVF increases the risk of gynaecological cancer, including ovarian, endometrial, cervical and breast cancers, as an independent risk factor. A systematic review and meta-analysis was conducted. Clinical trials that examined the association between ovarian stimulation for IVF and gynaecologic cancers were included. The outcomes of interest were incidence rate of gynaecologic cancers. Twelve cohort studies with 178,396 women exposed to IVF were included; 10 studies were used to analyse ovarian (167,640 women) and breast (151,702 women) cancers, and six studies were identified in the analysis of endometrial (116,672 women) and cervical cancer (114,799 women). Among these studies, 175 ovarian, 48 endometrial, 502 cervical and 866 cases of breast cancer were reported. The meta analysis found no significant association between ovarian stimulation for IVF and increased ovarian, endometrial, cervical and breast cancer risk (odds ratio [OR] 1.06, 95% confidence interval [CI] 0.85 to 1.32; OR 0.97, 95% CI 0.58 to 1.63; OR 0.43, 95% CI 0.30 to 0.60; OR 0.69, 95% CI 0.63 to 0.76, respectively). Ovarian stimulation for IVF, therefore, does not increase the gynaecologic cancer risk, whether hormone-dependent endometrial and breast cancer or non-hormone-dependent ovarian and cervical cancer. PMID- 26003454 TI - A novel bio-functional material based on mammalian cell aggresomes. AB - Aggresomes are protein aggregates found in mammalian cells when the intracellular protein degradation machinery is over-titered. Despite that they abound in cells producing recombinant proteins of biomedical and biotechnological interest, the physiological roles of these protein clusters and the functional status of the embedded proteins remain basically unexplored. In this work, we have determined for the first time that, like in bacterial inclusion bodies, deposition of recombinant proteins into aggresomes does not imply functional inactivation. As a model, human alpha-galactosidase A (GLA) has been expressed in mammalian cells as enzymatically active, mechanically stable aggresomes showing higher thermal stability than the soluble GLA version. Since aggresomes are easily produced and purified, we propose these particles as novel functional biomaterials with potential as carrier-free, self-immobilized catalyzers in biotechnology and biomedicine. PMID- 26003453 TI - Accumulation and metabolism of selenium by yeast cells. AB - This paper examines the process of selenium bioaccumulation and selenium metabolism in yeast cells. Yeast cells can bind elements in ionic from the environment and permanently integrate them into their cellular structure. Up to now, Saccharomyces cerevisiae, Candida utilis, and Yarrowia lipolytica yeasts have been used primarily in biotechnological studies to evaluate binding of minerals. Yeast cells are able to bind selenium in the form of both organic and inorganic compounds. The process of bioaccumulation of selenium by microorganisms occurs through two mechanisms: extracellular binding by ligands of membrane assembly and intracellular accumulation associated with the transport of ions across the cytoplasmic membrane into the cell interior. During intracellular metabolism of selenium, oxidation, reduction, methylation, and selenoprotein synthesis processes are involved, as exemplified by detoxification processes that allow yeasts to survive under culture conditions involving the elevated selenium concentrations which were observed. Selenium yeasts represent probably the best absorbed form of this element. In turn, in terms of wide application, the inclusion of yeast with accumulated selenium may aid in lessening selenium deficiency in a diet. PMID- 26003455 TI - Clinical Experience with Pulse Dose Rate Brachytherapy for Conservative Treatment of Penile Carcinoma and Comparison with Historical Data of Low Dose Rate Brachytherapy. AB - AIMS: To assess the efficacy of pulse dose rate (PDR) interstitial brachytherapy in the treatment of carcinoma of the penis and to compare with historical data of low dose rate (LDR) brachytherapy. MATERIALS AND METHODS: We reviewed the clinical records of 27 consecutive patients treated in our institution with exclusive PDR brachytherapy for a squamous cell carcinoma of the penis. The median tumour greatest diameter was 20 mm (range: 10-50 mm). Twenty-three patients (85%) had tumours limited to the glans and/or prepuce and four patients (15%) also had inguinal lymph node metastases. Implantations were carried out according to the Paris system and treatments were delivered with PDR brachytherapy. RESULTS: The median brachytherapy dose was 60 Gy (range: 60-70 Gy). The median treated volume was 28 cm(3) (range: 8-62 cm(3)). The median reference isodose rate was 0.4 Gy/pulse/h (range: 0.4-0.5 Gy/pulse/h). The median number of pulses was 150 (range: 120-175 pulses). With a median follow-up of 33 months (range: 6-64 months), tumour relapses in the penis were reported in four patients (15%). All patients with only local relapse (n = 3) were successfully salvaged with partial amputation. The estimated overall survival rate at 3 years was 95% (95% confidence interval: 83-100%). No grade 3 or more acute reaction was observed. Delayed ulcerations and stenoses requiring at least one meatal dilatation were reported in two (9%) and five (22%) patients without local relapse. The treated volume was significantly correlated to the risk of clinically relevant delayed toxicity. CONCLUSIONS: The efficacy/toxicity results of PDR brachytherapy for the treatment of penile carcinoma are comparable with those obtained with LDR brachytherapy in historical cohorts. PMID- 26003456 TI - Successful treatment of a Musculoskeletal Tumor Society grade 3 aneurysmal bone cyst with N-butyl cyanoacrylate embolization and percutaneous cryoablation. AB - This report presents a 13-year-old girl with an aggressive skeletal lesion involving the posterior elements of the cervicothoracic junction. The lesion was determined to be a Musculoskeletal Tumor Society grade 3 aneurysmal bone cyst based on imaging and pathologic findings. The cyst was treated with endovascular n-butyl cyanoacrylate embolization and percutaneous cryoablation with sensory and motor-evoked potential monitoring. Follow-up imaging at 16 months demonstrated significant reduction in the size of the lesion, with no evidence of recurrence. PMID- 26003457 TI - CT during Arteriography to Visualize the Right Adrenal Vein for Adrenal Venous Sampling. AB - The present report describes 6 cases of adrenal venous sampling (AVS) in patients who underwent computed tomography (CT) during arteriography because cannulation of right adrenal veins was otherwise difficult. CT was performed during arteriography to obtain information on the location and direction of the right adrenal vein. Two right adrenal veins were visualized in 1 case. The right central adrenal vein was not visualized in 1 case owing to an injury from a previous unsuccessful AVS procedure, but the right renal capsular vein was well visualized. CT during arteriography could contribute to a high AVS success rate. PMID- 26003458 TI - Anaphylactic reaction to bovine thrombin in ultrasound-guided treatment of femoral pseudoaneurysm. PMID- 26003459 TI - Hybrid Microsurgical Reconstruction and Percutaneous Endovascular Stent Placement for Management of Dissected Graft Hepatic Artery during Living Donor Liver Transplantation. PMID- 26003460 TI - Endurant endograft limb occlusion associated with a floating thrombus: a word of caution. PMID- 26003461 TI - Percutaneous embolization of a post-thoracic endovascular aortic repair aortic sac-bronchial fistula with N-butyl cyanoacrylate. PMID- 26003462 TI - Rare ringlike hepatic arterial anastomoses in the hepatoduodenal ligament. PMID- 26003463 TI - Delayed benign massive pneumoperitoneum associated with tunneled peritoneal drainage catheter placement. PMID- 26003464 TI - Liquid Embolic Onyx Reflux to Basilar Artery Retrieved by Solitaire AB Stent in the Treatment of Arteriovenous Malformations. PMID- 26003465 TI - Delayed Cardiac Tamponade following Injury during Retrieval of a Superior Vena Caval Filter. PMID- 26003466 TI - Hypertensive pneumoperitoneum treated with minimally invasive percutaneous drainage. PMID- 26003467 TI - Use of a transjugular needle to cross a benign ureteric stricture. PMID- 26003468 TI - Improved surveillance for carbapenem-resistant Enterobacteriaceae using chromogenic media with a broth enrichment. AB - In this study, 238 rectal screening swabs for carbapenem-resistant Enterobacteriaceae (CRE) were compared using chromID CARBA plates and the CDC reference method. Direct inoculation of chromID CARBA plates only identified 53% of CRE, whereas meropenem broth enrichment increased the positive agreement to 88% and identified additional cases of CRE. Additionally, the chromID CARBA method allowed for faster results and decreased the number of colonies further tested. PMID- 26003469 TI - Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis. AB - The activity of ceftolozane/tazobactam was tested against 50 nonduplicate Pseudomonas aeruginosa from 18 cystic fibrosis children collected in 2012-2014. These isolates were multidrug resistant with susceptibility to meropenem, ceftazidime, and piperacillin/tazobactam of 46%, 58%, and 50%, respectively. Ceftolozane/tazobactam was the most active with MIC50, MIC90, and percent susceptibility of 2mg/L, 8 mg/L, and 86%. PMID- 26003470 TI - Closed-system 'economic' models for psychiatric disorders: Western atomism and its culture-bound syndromes. AB - The stabilization of human cognition via feedback from embedding social and cultural contexts is a dynamic process deeply intertwined with it, constituting, in a sense, the riverbanks directing the flow of a stream of generalized consciousness at different scales: Cultural norms and social interaction are synergistic with individual and group cognition and their disorders. A canonical failure mode in atomistic cultures is found to be a 'ground state' collapse well represented by atomistic models of economic interaction that are increasingly characterized as divorced from reality by heterodox economists. That is, high rates of psychopathic and antisocial personality disorder and obsessive compulsive disorder emerge as culture-bound syndromes particular to Western or Westernizing societies, or to those undergoing social disintegration. PMID- 26003471 TI - The Role of PCR in the Diagnosis of Candida Vulvovaginitis-a New Gold Standard? AB - PCR is recognized as a reliable technique for detection of all types of microorganisms. Being highly objective and reproducible also sensitive and specific, PCR is now widely used for sexually transmitted infection (STI) diagnosis. Potential, however, exists for detecting non-pathogens, and not identifying a pathogenic state decreases specificity or clinical significance. PCR Candida tests of vaginal specimens are now widely available and frequently used offering a modest to moderate increase in sensitivity and are likely to replace traditional culture and DNA homology testing. Nevertheless, there remain considerable gaps in our knowledge regarding the usefulness and applications of these expensive tests. PMID- 26003472 TI - Association of Drug Effects on Serum Parathyroid Hormone, Phosphorus, and Calcium Levels With Mortality in CKD: A Meta-analysis. AB - BACKGROUND: Serum parathyroid hormone (PTH), phosphorus, and calcium levels are surrogate outcomes that are central to the evaluation of drug treatments in chronic kidney disease (CKD). This systematic review evaluates the evidence for the correlation between drug effects on biochemical (PTH, phosphorus, and calcium) and all-cause and cardiovascular mortality end points in adults with CKD. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adults with CKD. SELECTION CRITERIA FOR STUDIES: Randomized trials reporting drug effects on biochemical and mortality end points. INTERVENTION: Drug interventions with effects on serum PTH, phosphorus, and calcium levels, including vitamin D compounds, phosphate binders, cinacalcet, bisphosphonates, and calcitonin. OUTCOMES: Correlation between drug effects on biochemical and all-cause and cardiovascular mortality. RESULTS: 28 studies (6,999 participants) reported both biochemical and mortality outcomes and were eligible for analysis. Associations between drug effects on surrogate biochemical end points and corresponding effects on mortality were weak and imprecise. All correlation coefficients were less than 0.70, and 95% credible intervals were generally wide and overlapped with zero, consistent with the possibility of no association. The exception was an inverse correlation between drug effects on serum PTH levels and all-cause mortality, which was nominally significant (-0.64; 95% credible interval, -0.85 to -0.15), but the strength of this association was very imprecise. Risk of bias within available trials was generally high, further reducing confidence in the summary correlations. Findings were robust to adjustment for age, baseline serum PTH level, allocation concealment, CKD stage, and drug class. LIMITATIONS: Low power in analyses and combining evidence from many different drug comparisons with incomplete data across studies. CONCLUSIONS: Drug effects on serum PTH, phosphorus, and calcium levels are weakly and imprecisely correlated with all cause and cardiovascular death in the setting of CKD. Risks of mortality (patient level outcome) cannot be inferred from treatment-induced changes in biochemical outcomes in people with CKD. Similarly, existing data do not exclude a mortality benefit with treatment. Trials need to address patient-centered outcomes to evaluate drug effectiveness in this setting. PMID- 26003473 TI - Share your passion for nephrology: ten tips to invigorate attending rounds and precepting sessions. AB - Although there have been mounting concerns over the decline in applicants to nephrology training programs, strategies to entice students and trainees to pursue a career in nephrology are lacking. Furthermore, the complex factors that contribute to career decisions and the lag between a positive interaction and a decision to pursue nephrology make such strategies difficult to assess. Nevertheless, it is still important to continue efforts to mentor and inspire. This article offers 10 strategies to help nephrologists share passion for nephrology in the clinical arena. These include the excitement of the dialysis unit, ethical dilemmas, pearls for the bedside, and questions "on the fly." PMID- 26003474 TI - Quantitative evaluation of a pediatric rheumatology transition program. AB - BACKGROUND: Transition from pediatric to adult care can be a challenging process which leaves young people vulnerable to interruptions of care and worsening disease status. Efforts to improve transition processes and outcomes have included development of individualized transition plans, creation of transition clinics, and utilization of transition coordinators. Few interventions have assessed transition outcomes quantitatively. METHODS: We assessed transition outcome and satisfaction of a social worker-centered transition program in a pediatric rheumatology clinic. The social worker met with patients who were 16 years or older and their families, provided transition education materials, assisted patients in developing an individualized transition plan, assisted in making appointments with an adult rheumatologist at time of transfer of care, and followed up with patients to assess transition outcomes. Patients were contacted 6-8 months after initial appointment with the adult rheumatologist to assess whether they remained in the care of the adult provider. Participants then completed a questionnaire to rate their satisfaction with the transition program. RESULTS: 210 adolescents and young adults participated in the transition program. Twenty-six similarly aged patients were eligible for transition services but did not participate in the program and were used as controls. Of the patients who participated in the program, 42% were considered to have transitioned successfully to adult care compared to 23% of controls (p-value = 0.002) of all patients. In the survey of satisfaction, 81% of participants said that they were satisfied with the transition process. CONCLUSIONS: This study shows that a social worker transition coordinator can significantly improve the rate of pediatric rheumatology patients who successfully transition to adult care. Furthermore, patients are largely satisfied with this process. PMID- 26003475 TI - Effects of Oestrogen Treatment on Skeletal Response to Exercise in the Hips and Spine in Postmenopausal Women: A Meta-Analysis. AB - BACKGROUND: It is recognized that low oestrogen status impairs the skeletal response to mechanical loading in elderly women; therefore, oestrogen administration is expected to increase the osteogenic response to mechanical strain. OBJECTIVES: This meta-analysis aimed to evaluate the combined effects of hormone replacement therapy (HRT) and exercise on femoral neck and lumbar spine bone mineral density (BMD) in postmenopausal women, in comparison with the effects of exercise-only intervention. METHODS: A systematic literature search was conducted in PubMed, Embase, SPORTDiscus and ProQuest up to May 1, 2014, to ascertain the influence of oestrogen administration and exercise on BMD in postmenopausal women. The study quality and potential publication bias of the included trials were evaluated. The primary end point was the change in BMD from baseline to follow-up. The effect sizes were estimated in terms of the standardized mean difference (SMD). Subgroup analysis was conducted on the basis of exercise categories. RESULTS: Six studies with a total of 764 postmenopausal women (aged between 51.8 +/- 2.9 and 68.0 +/- 3.0 years) met the inclusion criteria. The included studies had low and high levels of heterogeneity of hip outcomes (I2 = 0.0 %) and spine outcomes (I2 = 80.8%), respectively. Fixed- and random-effects models were used for calculating the effect size estimates. The pooled effect sizes associated with the combined interventions of HRT and exercise were significant for femoral neck BMD (SMD 0.220, 95% confidence interval [CI] 0.011-0.429, p = 0.039) and lumbar spine BMD (SMD 0.729, 95% CI 0.186-1.273, p = 0.009) in comparison with the exercise-only intervention. The mixed loading exercise programmes were sensitive to HRT in preventing postmenopausal bone loss in the spine (SMD 1.073, 95% CI 0.140-2.005, p = 0.024) in comparison with single-mode exercise. CONCLUSIONS: Our findings indicate that oestrogen treatment significantly increases the skeletal response to exercise training in both the hips and the spine in postmenopausal women, which implies that the combination of oestrogen administration and exercise may generate greater effects. PMID- 26003476 TI - Severity of delirium in the ICU is associated with short term cognitive impairment. A prospective cohort study. AB - OBJECTIVES: To examine the hypothesis that severity of delirium in the intensive care unit (ICU) is positively associated with cognitive impairment at the time of hospital discharge. DESIGN: A prospective cohort study. SETTING: Adult medical and surgical ICU of a tertiary-care teaching hospital in Japan in ICU patients who were enrolled and admitted for more than 48hours. METHODS: Severity of delirium was represented as a score of the Intensive Care Delirium Screening Checklist (ICDSC) during the patients' stay in the ICU under the assumption that higher ICDSC score indicated severe delirium. After discharge from the ICU, the patients were followed up for cognitive impairment using the Mini-Mental State Examination (MMSE). RESULTS: Of the 79 patients enrolled, 50 (63.3%) developed delirium during their stay in the ICU. Patients who developed delirium had higher rates of cognitive impairment (28.0% vs. 3.4%, p=0.03). After adjusting for covariates, the averaged ICDSC score during the ICU stay indicated a positive association between severity of delirium and cognitive impairment at the time of hospital discharge (adjusted odds ratio (OR) 1.6; 95% confidential interval (CI), 1.02-2.54; p=0.041). CONCLUSIONS: Our findings indicate that severity of delirium during ICU stay may be associated with cognitive impairment at the time of discharge from the hospital in ICU survivors. PMID- 26003477 TI - Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations. AB - We aimed to determine the frequency of mutations, carrier rates and the association of rare mutations with Familial Mediterranean Fever (FMF) symptoms. There is a need to evaluate as many different populations as possible in order to determine either specific rare mutations or a range of disease-associated mutations. The demographic data and FMF symptoms related to MEFV gene mutations were collected from 731 participants. Exon 2 and exon 10 of the MEFV gene were tested by DNA sequencing. The rare mutations were identified as: M694I (1.1%, n=12), E148V (0.6%, n=6), T267I (0.5%, n=5), L110P (0.2%, n=2), E167D (0.2%, n=2), K695R (0.1%, n=1) and an insertion G (Guanine) mutation (0.4%, n=4) at the 777th codon of exon 10. We used routine comprehensive detection systems such as Sanger sequence that can catch rare mutations, for definite diagnosis and treatment of FMF disease. PMID- 26003478 TI - Mitochondrial estrogen receptor beta2 drives antiapoptotic pathways in advanced serous ovarian cancer. AB - We previously showed an unfavorable prognostic role of the cytoplasmic estrogen receptor beta2 (cERbeta2) in serous ovarian cancer. Here we aimed to investigate molecular determinants in cell survival function of cERbeta2 in this malignant disease. We used immunohistochemistry to evaluate differences in apoptosis (quantified by the expression of cleaved caspase-3) and cell proliferation (quantified by the expression of Ki-67) in 56 advanced serous ovarian cancer cases, stratified according to the absence or presence of estrogen receptor beta2 (ERbeta2) protein in the cytoplasmic compartment (31 cERbeta2- and 25 cERbeta2+ cases, respectively). Thereafter, by immunofluorescence, we visualized the subcellular distribution of ERbeta2, and by the proximity ligation assays, we characterized in situ its ability to interact with other proteins specifically involved in the apoptosis cascade. Finally, we assessed cytochrome c expression by immunohistochemistry. We demonstrated that, although not affecting tumor proliferation, cytoplasmic ERbeta2 expression was indeed associated to a lower apoptotic rate in ovarian cancer cases. Then, we proved that cERbeta2 is targeted to mitochondria where it interacts as a binding partner with BAD (B-cell lymphoma [Bcl] 2-associated death promoter). This interaction, precluding the Bcl-xL (B cell lymphoma extra large)/BAD heterodimer formation, inhibited Bax (Bcl-2-like protein 4) oligomerization, the release of cytochrome c, and ultimately apoptosis. In conclusion, we provide in vivo mechanistic evidence for an antiapoptotic function of mitochondrial ERbeta2, a finding supporting the value of its cytoplasmic expression as an unfavorable prognostic biomarker for serous ovarian cancer. PMID- 26003479 TI - Genomic Copy Number Signatures Uncovered a Genetically Distinct Group from Adenocarcinoma and Squamous Cell Carcinoma in Non-Small Cell Lung Cancer. AB - Adenocarcinoma (AC) and squamous cell carcinoma (SCC) of non-small cell lung carcinoma (NSCLC) have different clinical presentations, morphologies, treatments, and prognoses. Recent studies suggested that fundamental genetic alterations related to carcinogenesis of each tumor type may be different. In this study, we investigated the genomic alterations of 47 primary NSCLC samples (22 ACs and 25 SCCs) as well as the corresponding normal tissue using array comparative genomic hybridization. Frequent copy number alterations (CNAs), which were identified in more than 68% of all of the cases, were evaluated in each subtype (SCC and AC), and a CNA signature was established. Among these CNAs, 37 genes from the SCCs and 15 genes from the ACs were located in a region of gain, and 4 genes from the SCCs and 13 genes from the ACs were located in a region of loss. The most frequent gain was located on 3q26-29 including the gene TP63 in SCCs and 7q11.23 and 7q36.3 in ACs. Moreover, we identified 3 genetically distinct groups (group I [16 SCC] with CNA signature of SCC; group II [7 SCC + 8 AC], which has a genetically distinctive CNA signature from SCC and AC; and group III [2 SCC + 14 AC] with CNA signature of AC) by gene clustering extracted from CNAs, which are associated with a prognosis. The present study contributed to the molecular characterization of AC and SCC of NSCLC and showed a subtype of tumor that has a unique genetic CNA signature. However, further study about the significance of these 3 distinct groups and their usefulness as a diagnostic marker of identified CNAs is necessary. PMID- 26003480 TI - Diagnosis and treatment of anteroinferior capsular redundancy associated with anterior shoulder instability using an open Latarjet procedure and capsulorrhaphy. AB - PURPOSE: There is a paucity of data detailing management of anterior capsular redundancy (ACR) when using the Latarjet procedure for unidirectional instability. This study aimed to describe the surgical management and to assess the clinical profile of patients presenting with anterior capsular redundancy [ACR(+)] with anterior shoulder instability. METHODS: Seventy-seven patients who had a Latarjet procedure were followed for a 55-month period. Per-operative ACR was assessed during surgery. ACR was considered present if the inferior capsular flap of a Neer T-shaft capsulorrhaphy was able to cover the superior capsular flap with the arm in the neutral position. Patients with ACR(+) received an additional Neer capsulorrhaphy, while patients with ACR(-) did not. This per operative finding was correlated with demographics, clinical, radiological pre operative data and surgical outcome. RESULTS: Patients presenting with a per operative ACR(+) were significantly associated with a sulcus sign (P < 0.001), a Beighton score >4 (P < 0.01), a low-energy instability history (P < 0.05), a predominant history of subluxations (P < 0.05), fewer Hill-Sachs lesion (P < 0.05) and a female gender (P < 0.05), but not significantly with external rotation >85 degrees . Open standard Latarjet procedures with Neer capsulorrhaphy in ACR(+) patients showed excellent or good results and stability rate of 95 %. All patients except four who presented with a new dislocation after surgery were satisfied with their outcome. Thirteen patients (16 %) had a persistent apprehension sign at the last follow-up. ACR(+) and ACR(-) groups did not show significant difference in the mean values of Rowe, Walch-Duplay and Constant Murley scores. CONCLUSION: ACR correlated with a sulcus sign, Beighton score and instability history. In anterior shoulder instability associated with ACR, the Latarjet procedure with a Neer capsulorrhaphy appears a satisfactory treatment alternative to arthroscopic or open capsular shift. It decreased apprehension in comparison with Latarjet procedures without capsular repair. LEVEL OF EVIDENCE: Cases series, treatment study, Level IV. PMID- 26003481 TI - The comparison between the different generations of autologous chondrocyte implantation with other treatment modalities: a systematic review of clinical trials. AB - PURPOSE: This paper aims to review the current evidence for autologous chondrocyte implantation (ACI) generations relative to other treatment modalities, different cell delivery methods and different cell source application. METHODS: Literature search was performed to identify all level I and II studies reporting the clinical and structural outcome of any ACI generation in human knees using the following medical electronic databases: PubMed, EMBASE, Cochrane Library, CINAHL, SPORTDiscus and NICE healthcare database. The level of evidence, sample size calculation and risk of bias were determined for all included studies to enable quality assessment. RESULTS: Twenty studies were included in the analysis, reporting on a total of 1094 patients. Of the 20 studies, 13 compared ACI with other treatment modalities, seven compared different ACI cell delivery methods, and one compared different cell source for implantation. Studies included were heterogeneous in baseline design, preventing meta-analysis. Data showed a trend towards similar outcomes when comparing ACI generations with other repair techniques and when comparing different cell delivery methods and cell source selection. Majority of the studies (80 %) were level II evidence, and overall the quality of studies can be rated as average to low, with the absence of power analysis in 65 % studies. CONCLUSION: At present, there are insufficient data to conclude any superiority of ACI techniques. Considering its two-stage operation and cost, it may be appropriate to reserve ACI for patients with larger defects or those who have had inadequate response to other repair procedures until hard evidence enables specific clinical recommendations be made. LEVEL OF EVIDENCE: II. PMID- 26003483 TI - A Hertzian contact mechanics based formulation to improve ultrasound elastography assessment of uterine cervical tissue stiffness. AB - Clinical practice requires improved techniques to assess human cervical tissue properties, especially at the internal os, or orifice, of the uterine cervix. Ultrasound elastography (UE) holds promise for non-invasively monitoring cervical stiffness throughout pregnancy. However, this technique provides qualitative strain images that cannot be linked to a material property (e.g., Young's modulus) without knowledge of the contact pressure under a rounded transvaginal transducer probe and correction for the resulting non-uniform strain dissipation. One technique to standardize elastogram images incorporates a material of known properties and uses one-dimensional, uniaxial Hooke's law to calculate Young's modulus within the compressed material half-space. However, this method does not account for strain dissipation and the strains that evolve in three-dimensional space. We demonstrate that an analytical approach based on 3D Hertzian contact mechanics provides a reasonable first approximation to correct for UE strain dissipation underneath a round transvaginal transducer probe and thus improves UE derived estimates of tissue modulus. We validate the proposed analytical solution and evaluate sources of error using a finite element model. As compared to 1D uniaxial Hooke's law, the Hertzian contact-based solution yields significantly improved Young's modulus predictions in three homogeneous gelatin tissue phantoms possessing different moduli. We also demonstrate the feasibility of using this technique to image human cervical tissue, where UE-derived moduli estimations for the uterine cervix anterior lip agreed well with published, experimentally obtained values. Overall, UE with an attached reference standard and a Hertzian contact-based correction holds promise for improving quantitative estimates of cervical tissue modulus. PMID- 26003482 TI - The role of tendon and subacromial bursa in rotator cuff tear pain: a clinical and histopathological study. AB - PURPOSE: To evaluate a possible association of shoulder pain with the clinical features and the histopathological changes occurring in the ruptured tendon and subacromial bursa of patients with rotator cuff tear. METHODS: One hundred and eighty patients were clinically evaluated with the constant score and the visual analogue pain scale. Radiographs and MRI were performed. The chronology of the rupture, the muscle fatty degeneration according to Goutallier's scale and the tear size were evaluated. For each patient, a biopsy of the supraspinatus tendon and subacromial bursa was performed during arthroscopic rotator cuff tear repair and the specimens were histopathologically analysed. RESULTS: Clinically, the shoulder was more painful in females, in the presence of a chronic cuff lesion and a low Goutallier's grade (P < 0.05). No association was found between pain and age of the patient and between pain and tear size. Histologically, hypertrophy and inflammation of the tendon and hypertrophy, inflammation, oedema and necrosis of the subacromial bursa were directly associated with pain (P < 0.05). Pain decreased significantly in the presence of fatty metaplasia and necrosis of the tendon (P < 0.05). CONCLUSIONS: This study defines the main clinical and histopathological features of painful rotator cuff tear. In particular, a greater association of pain was observed with the histopathological changes in the bursa compared with those in the rotator cuff. Considering that the bursa plays also an essential role during the healing process, this "new" role of the subacromial bursa as pain generator has important repercussions in both pharmacological and surgical treatments of rotator cuff tears. LEVEL OF EVIDENCE: IV. PMID- 26003484 TI - Hoof position during limb loading affects dorsoproximal bone strains on the equine proximal phalanx. AB - Sagittal fractures of the proximal phalanx (P1) in the racehorse appear to be associated with turf racing surfaces, which are known to restrict forward slide of the foot at impact. We hypothesized that restriction of forward foot slip would result in higher P1 bone strains during metacarpophalangeal joint (MCPJ) hyperextension. Unilateral limbs from six equine cadavers were instrumented with strain gauges and bone reference markers to measure dorsoproximal P1 bone strains and MCPJ extension, collateromotion and axial rotation during in vitro limb loading to 10,500 N. By limiting movement of the distal actuator platform, three different foot conditions (forward, free, and restricted) were applied in a randomised block design. Bone reference markers, recorded by video, were analyzed to determine motion of P1 relative to MC3. Rosette strain data were reduced to principal and shear magnitudes and directions. A mixed model ANOVA determined the effect of foot position on P1 bone strains and MCPJ angles. At 10,000 N load, the restricted condition resulted in higher P1 axial compressive (p=0.015), maximum shear (p=0.043) and engineering shear (p=0.046) strains compared to the forward condition. The restricted condition had higher compressive (p=0.025) and lower tensile (p=0.043) principal strains compared to the free condition. For the same magnitude of principal or shear strains, axial rotation and collateromotion angles were greatest for the restricted condition. Therefore, the increase in P1 principal compressive and shear bone strains associated with restricted foot slip indicate that alterations in foot:ground interaction may play a role in fracture occurrence in horses. PMID- 26003485 TI - Validating Dual Fluoroscopy System Capabilities for Determining In-Vivo Knee Joint Soft Tissue Deformation: A Strategy for Registration Error Management. AB - Knee osteoarthritis (OA) causes structural and mechanical changes within tibiofemoral (TF) cartilage affecting tissue load deformation behavior. Quantifying in-vivo TF soft tissue deformations in healthy and early OA may provide a novel biomechanical marker, sensitive to alterations occurring prior to radiographic change. Dual Fluoroscopy (DF) allows accurate in-vivo TF soft tissue deformation assessment but requires validation. In-vivo healthy and early OA TF cartilage deforms 0.3-1.2mm during static standing full body-weight loading. Our aim was to establish minimum detectable displacement (MDD) for femoral translation in a DF system using a marker-based and markerless approach with variable image intensifier magnifications. An instrumented frame allowed controlled femur specimen translations. Bone positions were reconstructed from DF data using centroids of affixed steel beads (marker-based) and 2D-3D bone feature registration (markerless). Statistical analyses included independent samples t tests and reliability analysis. Markerless measurements by three trained operators had large variations making it prudent to have an appropriate error management strategy when performing 2D-3D registration. Marker-based MDD improved with image resolution and was 0.05 mm at 3.2 LP/mm (LP: line pairs). Markerless MDD at 3.2 LP/mm was 0.08 mm. Average femur and tibia 2D-3D registrations yielded excellent reliability (84.4%). Therefore, DF images acquired at resolution greater than 3.2 LP/mm would be capable for determining accurate and reliable in vivo healthy and early OA TF soft tissue deformation. This study provides a registration error management strategy for in-vivo TF soft tissue deformation assessment that could be applied for future clinical applications to establish non-invasive biomechanical markers for early OA diagnosis. PMID- 26003486 TI - Progressive changes in artistic performance of a Chinese master with Alzheimer's disease. AB - We report on the paintings of a Chinese artist before and after he developed Alzheimer's dementia (AD). PMID- 26003487 TI - Cooperation between neuropsychology researchers and ethical committees: Room for improvement? PMID- 26003488 TI - A commentary on Karlebach and Francks, (2015). PMID- 26003489 TI - Combined eye tracking and fMRI reveals neural basis of linguistic predictions during sentence comprehension. AB - It is widely agreed upon that linguistic predictions are an integral part of language comprehension. Yet, experimental proof of their existence remains challenging. Here, we introduce a new predictive eye gaze reading task combining eye tracking and functional magnetic resonance imaging (fMRI) that allows us to infer the existence and timing of linguistic predictions via anticipatory eye movements. Participants read different types of word sequences (i.e., regular sentences, meaningless jabberwocky sentences, non-word lists) up to the pre-final word. The final target word was displayed with a temporal delay and its screen position was dependent on the syntactic word category (nouns vs verbs). During the delay, anticipatory eye-movements into the correct target word area were indicative of linguistic predictions. For fMRI analysis, the predictive sentence conditions were contrasted to the non-word condition, with the anticipatory eye movements specifying differences in timing across conditions. A conjunction analysis of both sentence conditions revealed the neural substrate of word category prediction, namely a distributed network of cortical and subcortical brain regions including language systems, basal ganglia, thalamus, and hippocampus. Direct contrasts between the regular sentence condition and the jabberwocky condition indicate that prediction of word category in meaningless jabberwocky sentences relies on classical left-hemispheric language systems involving Brodman's area 44/45 in the left inferior frontal gyrus, left superior temporal areas, and the dorsal caudate nucleus. Regular sentences, in contrast, allowed for the prediction of specific words. Word-specific predictions were specifically associated with more widely distributed temporal and parietal cortical systems, most prominently in the right hemisphere. Our results support the presence of linguistic predictions during sentence processing and demonstrate the validity of the predictive eye gaze paradigm for measuring syntactic and semantic aspects of linguistic predictions, as well as for investigating their neural substrates. PMID- 26003490 TI - Preclinical refinements of a broadly protective VLP-based HPV vaccine targeting the minor capsid protein, L2. AB - An ideal prophylactic human papillomavirus (HPV) vaccine would provide broadly protective and long-lasting immune responses against all high-risk HPV types, would be effective after a single dose, and would be formulated in such a manner to allow for long-term storage without the necessity for refrigeration. We have developed candidate HPV vaccines consisting of bacteriophage virus-like particles (VLPs) that display a broadly neutralizing epitope derived from the HPV16 minor capsid protein, L2. Immunization with 16L2 VLPs elicited high titer and broadly cross-reactive and cross-neutralizing antibodies against diverse HPV types. In this study we introduce two refinements for our candidate vaccines, with an eye towards enhancing efficacy and clinical applicability in the developing world. First, we assessed the role of antigen dose and boosting on immunogenicity. Mice immunized with 16L2-MS2 VLPs at doses ranging from 2 to 25 MUg with or without alum were highly immunogenic at all doses; alum appeared to have an adjuvant effect at the lowest dose. Although boosting enhanced antibody titers, even a single immunization could elicit strong and long-lasting antibody responses. We also developed a method to enhance vaccine stability. Using a spray dry apparatus and a combination of sugars & an amino acid as protein stabilizers, we generated dry powder vaccine formulations of our L2 VLPs. Spray drying of our L2 VLPs did not affect the integrity or immunogenicity of VLPs upon reconstitution. Spray dried VLPs were stable at room temperature and at 37 degrees C for over one month and the VLPs were highly immunogenic. Taken together, these enhancements are designed to facilitate implementation of a next-generation VLP-based HPV vaccine which addresses U.S. and global disparities in vaccine affordability and access in rural/remote populations. PMID- 26003491 TI - Indirect Toll-like receptor 5-mediated activation of conventional dendritic cells promotes the mucosal adjuvant activity of flagellin in the respiratory tract. AB - The Toll-like receptor 5 (TLR5) agonist flagellin is an effective adjuvant for vaccination. Recently, we demonstrated that the adaptive responses stimulated by intranasal administration of flagellin and antigen were linked to TLR5 signaling in the lung epithelium. The present study sought to identify the antigen presenting cells involved in this adjuvant activity. We first found that the lung dendritic cells captured antigen very efficiently in a process independent of TLR5. However, TLR5-mediated signaling specifically enhanced the maturation of lung dendritic cells. Afterward, the number of antigen-bound and activated conventional dendritic cells (both CD11b(+) and CD103(+)) increased in the mediastinal lymph nodes in contrast to monocyte-derived dendritic cells. These data suggested that flagellin-activated lung conventional dendritic cells migrate to the draining lymph nodes. The lymph node dendritic cells, in particular CD11b(+) cells, were essential for induction of CD4 T-cell response. Lastly, neutrophils and monocytes were recruited into the lungs by flagellin administration but did not contribute to the adjuvant activity. The functional activation of conventional dendritic cells was independent of direct TLR5 signaling, thereby supporting the contribution of maturation signals produced by flagellin-stimulated airway epithelium. In conclusion, our results demonstrated that indirect TLR5-dependent stimulation of airway conventional dendritic cells is essential to flagellin's mucosal adjuvant activity. PMID- 26003492 TI - Assessment of the impact of manufacturing changes on the physicochemical properties and biological activity of Her1-ECD vaccine during product development. AB - Vaccine preparations based on the extracellular domain of Her1 (Her1-ECD) have demonstrated, in vitro and in vivo, a potent antimetastatic effect on EGFR(+) Lewis lung carcinoma model, while associated side effects were absent. The Her1 ECD is a glycoprotein with a molecular weight of 105 kDa and has 11 potential sites for N-glycosylation. Currently Her1-ECD based vaccine has been evaluated in patients with hormone refractory prostate cancer. Her1-ECD molecule used for in clinical trials was obtained from culture supernatant of HEK 293 transfectomes used the protein free culture media and is purified by immunoaffinity chromatography. In order to increase the cell growth and productivity, new defined culture media have been developed (alternative culture media) in Her1-ECD vaccine production process. In this work, a comparability study was performed to evaluate the impact of process changes in the characteristics physic-chemical and biologicals of the Her1-ECD protein and the degree of similitude between both variants. Techniques such as: SDS-PAGE, SEC-HPLC, isoelectric point, peptide mapping, mass spectrometric, SCX-HPLC, oligosaccharide map, ELISA and flow cytometric were used with this aim. Results indicated that this process change decreases the degree of sialylation of the protein but does not affect its biological activity (measured as titers of Abs and recognition for A431 cell line). PMID- 26003493 TI - Barriers to childhood immunisation: Findings from the Longitudinal Study of Australian Children. AB - OBJECTIVES: To examine barriers to childhood immunisation experienced by parents in Australia. DESIGN: Cross-sectional analysis of secondary data. SETTING: Nationally representative Longitudinal Study of Australian Children (LSAC). PARTICIPANTS: Five thousand one hundred seven infants aged 3-19 months in 2004. MAIN OUTCOME MEASURE: Maternal report of immunisation status: incompletely or fully immunised. RESULTS: Overall, 9.3% (473) of infants were incompletely immunised; of these just 16% had mothers who disagreed with immunisation. Remaining analyses focussed on infants whose mother did not disagree with immunisation (N=4994) (of whom 8% [398] were incompletely immunised). Fifteen variables representing potential immunisation barriers and facilitators were available in LSAC; these were entered into a latent class model to identify distinct clusters (or 'classes') of barriers experienced by families. Five classes were identified: (1) 'minimal barriers', (2) 'lone parent, mobile families with good support', (3) 'low social contact and service information; psychological distress', (4) 'larger families, not using formal childcare', (5) 'child health issues/concerns'. Compared to infants from families experiencing minimal barriers, all other barrier classes had a higher risk of incomplete immunisation. For example, the adjusted risk ratio (RR) for incomplete immunisation was 1.51 (95% confidence interval: 1.08-2.10) among those characterised by 'low social contact and service information; psychological distress', and 2.47 (1.87-3.25) among 'larger families, not using formal childcare'. CONCLUSIONS: Using the most recent data available for examining these issues in Australia, we found that the majority of incompletely immunised infants (in 2004) did not have a mother who disagreed with immunisation. Barriers to immunisation are heterogeneous, suggesting a need for tailored interventions. PMID- 26003494 TI - Physical activity and dietary behavior with red blood cell distribution width. AB - BACKGROUND: No studies, to date, have examined the concurrent effects of physical activity and healthy eating on red blood cell distribution width. PURPOSE: Examine the association between accelerometer-determined physical activity and daily dietary patterns with red blood cell distribution width (RDW). METHODS: Data from the 2003-2006 NHANES were used. 4538 participants provided data on the study variables. Physical activity was assessed over a 7-day period via accelerometry. Dietary behavior was assessed using 2 recall surveys. Multivariable linear regression analysis was used to examine the association between physical activity and diet with RDW (outcome variable). RESULTS: Independent of established CVD risk factors, physical activity (beta=-0.07, p=0.002), but not diet (beta=-0.05, p=0.13), was associated with lower RDW. There was no evidence of multiplicative interaction (interaction term: beta=0.02, p=0.65). CONCLUSION: Physical activity, but not diet, was inversely associated with RDW. If confirmed by prospective studies, adoption of regular physical activity may help to prevent cardiovascular disease and mortality via changes in RDW. PMID- 26003496 TI - Electrophysiological and behavioural responses of turbot (Scophthalmus maximus) cooled in ice water. AB - Behavioural, neural and physiological aspects related to pre-slaughter cooling of turbot habituated to two environmental temperatures (18.7 and 12.0 degrees C) were investigated. Six fish in both treatments were immersed in ice water for 75 min. For control, four fish were immersed in water under their habituated environmental temperature. Turbot did not show a quick reduction of overall power in the EEG (electroencephalogram) to less than 10%, nor did the turbot show a shift in brain wave predominance from high to low frequency waves. At 15 min after immersion in ice water at least 7 out of 12 fish still showed total power values over 10% of pre-immersion values. Significant reductions in responsiveness to needle scratches and reduced breathing after immersion in ice water were observed, but none of these parameters had dropped to 0 even after 75 min in ice water. A significant reduction in gill score was found at 2 and 5 min after immersion in ice water compared to the control fish (p<0.05). Heart rates significantly increased immediately after immersion in ice water and then decreased to a low basal value 30 min after immersion. The heart beat did not show major changes in regularity over time. Finally, at 15 and 75 min the turbot in ice water were significantly more responsive to vibration than to needle scratches. From these results we conclude that immersion in ice water may not induce unconsciousness, however, the brain activity does decrease to a lower level. The implication of this low brain activity with respect to welfare is not clear. Increased heart rates and maintained low brain activity and response to needle scratches during early immersion in ice water are indicative of a stress response appearing to affect welfare negatively. PMID- 26003495 TI - Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice. AB - The oral and post-oral actions of sugar and fat stimulate intake and condition flavor preferences in rodents through a process referred to as appetition. Ghrelin is implicated in food reward processing, and this study investigated its involvement in nutrient conditioning in mice. In Exp. 1 ghrelin receptor-null (GHSR-null) and C57BL/6 wildtype (WT) mice learned to prefer a flavor (CS+) mixed into 8% glucose over another flavor (CS-) mixed into a "sweeter" but non nutritive 0.1% sucralose+saccharin (S+S) solution. In Exp. 2 treating WT mice with a ghrelin receptor antagonist [(D-Lys3)-GHRP-6] during flavor training did not prevent them from learning to prefer the CS+ glucose over the CS-S+S flavor. GHSR-null and WT mice were trained in Exp. 3 to drink a CS+ paired with intragastric (IG) infusion of 16% glucose and a CS- paired with IG water. Both groups drank more CS+ than CS- in training and preferred the CS+ to CS- in a choice test. The same (Exp. 4) and new (Exp. 5) GHSR-null and WT mice learned to prefer a CS+ flavor paired with IG fat (Intralipid) over a CS- flavor paired with IG water. GHSR-null and WT mice also learned to prefer a CS+ flavor added to 8% fructose over a CS- added to water. Together, these results indicate that ghrelin receptor signaling is not required for flavor preferences conditioned by the oral or post-oral actions of sugar and fat. This contrasts with other findings implicating ghrelin signaling in food reward processing and food-conditioned place preferences. PMID- 26003497 TI - Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice. AB - Recently, oestrogen receptors (ERs) have been implicated in rapid learning processes. We have previously shown that 17beta-estradiol, ERalpha and ERbeta agonists can improve learning within 40 min of drug administration in mice. However, oestrogen action at the classical receptors may only in part explain these rapid learning effects. Chronic treatment of a G-protein coupled oestrogen receptor (GPER) agonist has been shown to affect learning and memory in ovariectomized rats, yet little is known about its rapid learning effects. Therefore we investigated whether the GPER agonist G-1 at 1 MUg/kg, 6 MUg/kg, 10 MUg/kg, and 30 MUg/kg could affect social recognition, object recognition, and object placement learning in ovariectomized CD1 mice within 40 min of drug administration. We also examined rapid effects of G-1 on CA1 hippocampal dendritic spine density and length within 40 min of drug administration, but in the absence of any learning tests. Results suggest a rapid enhancing effect of GPER activation on social recognition, object recognition and object placement learning. G-1 treatment also resulted in increased dendritic spine density in the stratum radiatum of the CA1 hippocampus. Hence GPER, along with the classical ERs, may mediate the rapid effects of oestrogen on learning and neuronal plasticity. To our knowledge, this is the first report of GPER effects occurring within a 40 min time frame. PMID- 26003498 TI - Mentoring matters. PMID- 26003499 TI - Tuning Nursing Educational in an Italian academic context. AB - BACKGROUND: The European Union Bologna Process has laid the foundation for a common European competence-based educational framework. In many countries, nursing education is in transition from vocational to higher education, with many diverse systems. The competence-based approach provided by the project Tuning Educational Structures offers a common and coherent framework able to facilitate the implementation of the principles underpinning the Bologna Process reform. OBJECTIVES: This study aimed to ascertain the relevance that Italian nursing university lecturers attributed to the 40 competences of the Italian version of the nursing Bachelor's and Master's Degrees. These competences were developed through adoption of the Tuning Methodology in the nursing context. SETTING: The study was conducted in the 4 universities of one region of Italy which offer nursing Bachelor's and Master's Degrees. PARTICIPANTS: A total of 164 Italian university nursing lecturers. METHODS: Using a four point scale, a cross sectional survey was conducted from March 2011 to April 2012. Participants evaluated each competence according to its relevance for Bachelor's or Master's Education. Frequency analysis was conducted. RESULTS: The significance for each competence of Tuning was rated very high by Italian lecturers and appeared to overlap partially with the original European study. In Italy, the most relevant competences for Bachelor's Degree were the skills associated with the use of appropriate interventions, activities and skills in nursing and the skills associated with nursing practice and clinical decision-making. For Master's Degree, leadership, management and team competences were the most important. CONCLUSIONS: The Tuning Nursing Project was accepted by the Italian lecturers. The competence-based approach was considered by Italian lectures as a support enabling to reflect on the current Italian nursing education cycles of study and to ensure shared visions and common approaches between Italian and European lecturers. PMID- 26003500 TI - The role of chorionic cytotrophoblasts in the smooth chorion fusion with parietal decidua. AB - BACKGROUND/PURPOSE: Human placenta and chorion are rapidly growing transient embryonic organs built from diverse cell populations that are of either, ectodermal [placenta and chorion specific trophoblast (TB) cells], or mesodermal origin [villous core and chorionic mesenchyme]. The development of placenta and chorion is synchronized from the earliest phase of implantation. Little is known about the formative stages of the human chorion, in particular the steps between the formation of a smooth chorion and its fusion with the parietal decidua. METHODS: We examined the available histological material using immunohistochemistry, and further analyzed in vitro the characteristics of the recently established and reported human self-renewing trophoblast progenitor cells (TBPC) derived from chorionic mesoderm. RESULTS: Here, we provided evidence that the mechanism by which smooth chorion fuses with parietal decidua is the invasion of smooth chorionic cytotrophoblasts (schCTBs) into the uterine wall opposite to the implantation side. This process, which partially replicates some of the mechanisms of the blastocyst implantation, leads to the formation of a new zone of contacts between fetal and maternal cells. CONCLUSION: We propose the schCTBs invasion of the parietal decidua as a mechanism of 'fusion' of the membranes, and that schCTBs in vivo contribute to the pool of the invasive schCTB. PMID- 26003501 TI - Getting to goal in newly diagnosed type 2 diabetes using combination drug "subtraction therapy". AB - BACKGROUND: The treatment of newly diagnosed type 2 diabetes mellitus is diverse, with no clear consensus regarding the initial drug regimen or dosing to achieve optimal glycemic control. METHODS: We treated 44 consecutive patients with newly diagnosed type 2 diabetes with maximally tolerated doses of pioglitazone 45 mg/day, metformin 1000-2000 mg/day, and repaglinide 1-4 mg before meals. The doses and drugs were subsequently decreased ("subtraction therapy") to achieve optimal glycemic control and minimize side effects. Three primary outcomes were measured: the short term HbA1c response, the long term HbA1c response, and the incidence of hypoglycemia. RESULTS: All 44 patients responded with a rapid, progressive decline in their HbA1c levels from 11.43+/-2.3% to 6.17+/-0.72% (101+/-25.1 mmol/mol to 44+/-7.9 mmol/mol) by three months, and remained stable thereafter. An HbA1c <=7.0% (<=53 mmol/mol) was reached within 1-4 months in 42 of 44 patients, and in every patient by 12 months. Each patient's lowest HbA1c level, 5.65+/-0.6% (38+/-6.6 mmol/mol), was reached over 6.3+/-2.9 months. Patients with initial HbA1c levels >10% (>86 mmol/mol) (n=33) responded similarly as those with HbA1c levels <10% (<86 mmol/mol) (n=11). Combination drug therapy maintained HbA1c levels between 5.0 and 7.0% (31 and 53 mmol/mol) for up to 14.83 years. Only one clinically significant hypoglycemic event occurred during 261.08 person-years of follow-up. CONCLUSIONS: In our experience, combination drug "subtraction therapy" was safe and effective for treating all newly diagnosed type 2 diabetic patients. PMID- 26003502 TI - Prediction of risk of lung cancer in populations and in pulmonary nodules: Significant progress to drive changes in paradigms. AB - The ability to estimate the risk of lung cancer is important in three common clinical scenarios: the management of pulmonary nodules, the selection of people for screening with computed tomography and in the early identification of symptomatic disease. The risk prediction models that have been developed have similar themes owing to the strongest risk factors dominating the model. In the management of pulmonary nodules, there is a need to ensure that models reliably predict the chance of malignancy by performing validation studies in the population in which the models will be used. Two models stand out as the better ones in validation studies, one best used for smaller nodules and the other for larger ones. To maximise the cost effectiveness of screening with computed tomography, it is essential to select a population at high enough risk. A number of risk models have been developed, of varying complexity. Simpler models may be easier to use in practice but may miss a minority at high risk who have less common but important risk factors. Identification of early symptomatic lung cancer is important to improve early survival and reduce emergency presentations but single symptoms are non-specific. Risk prediction can improve the targeting of investigation and potentially identify patients early. Clinicians need to embrace the concept of estimating the risk of lung cancer in these three important areas because the evidence is strong enough to support a change in the clinical paradigm. PMID- 26003503 TI - The incidence and clinical impact of bone metastases in non-small cell lung cancer. AB - INTRODUCTION: Non-small cell lung cancer (NSCLC) is the leading global cause of cancer death. While bone metastases (BM) commonly cause morbidity, bone-targeted agent (BTA) use is variable. We investigated the incidence and impact of BM among unselected NSCLC patients. METHODS: A retrospective chart review of all NSCLC patients seen at a single institution from January 2007 to January 2008 was performed. Various clinical and pathology data were collected. In BM patients, skeletal related events (SRE), interventions and outcomes were recorded. RESULTS: We identified 383 patients; median age 68 (IQR 60-76); 54% female. Initially 156 patients (41%) were treated with curative intent of whom 91 subsequently relapsed; 227 (59%) were considered palliative from time of diagnosis, including 22 with early stage disease not amenable to radical therapy. Of 296 patients with advanced NSCLC, common metastatic sites were: lung/pleura (80%), mediastinal nodes (69%), bone (39%), brain (30%), and liver (24%). Of 118 patients with BM, 69 (59%) had >=1 SREs (range 1-18). Common SREs were radiotherapy (63%), pathologic fractures (22%), spinal cord compression (6%) or surgery to bone (5%). Opioid analgesia was required in 69% of BM patients, only 6% of patients with BM received BTA. Overall survival (OS) in pts with mNSCLC was 7.3 months (IQR 3.1 20.5). Pts with BM had significantly shorter OS compared to those without BM (5.8 versus 10.2 months, p=0.03). CONCLUSIONS: BM are common in patients with advanced NSCLC and associated with shorter survival. In this cohort, despite SREs occurred in many patients, BTA were rarely used. PMID- 26003505 TI - Enzymatic cybernetics: an unpublished work by Jacques Monod. AB - In 1959, Jacques Monod wrote a manuscript entitled Cybernetique enzymatique [Enzymatic cybernetics]. Never published, this unpublished manuscript presents a synthesis of how Monod interpreted enzymatic adaptation just before the publication of the famous papers of the 1960s on the operon. In addition, Monod offers an example of a philosophy of biology immersed in scientific investigation. Monod's philosophical thoughts are classified into two categories, methodological and ontological. On the methodological side, Monod explicitly hints at his preferences regarding the scientific method in general: hypothetical deductive method, and use of theoretical models. He also makes heuristic proposals regarding molecular biology: the need to analyse the phenomena in question at the level of individual cells, and the dual aspect of all biological explanation, functional and evolutionary. Ontological issues deal with the notions of information and genetic determinism, "cellular memory", the irrelevance of the notion of "living matter", and the usefulness of a cybernetic comprehension of molecular biology. PMID- 26003504 TI - Adherence to the ESC Heart Failure Treatment Guidelines in Spain: ESC Heart Failure Long-term Registry. AB - INTRODUCTION AND OBJECTIVES: To estimate the percentage of heart failure patients in Spain that received the European Society of Cardiology recommended treatments, and in those that did not, to determine the reasons why. METHODS: The study included 2834 consecutive ambulatory patients with heart failure from 27 Spanish hospitals. We recorded general information, the treatment indicated, and the reasons why it was not prescribed in some cases. In patients who met the criteria to receive a certain drug, true undertreatment was defined as the percentage of patients who, without justification, did not receive the drug. RESULTS: In total, 92.6% of ambulatory patients with low ejection fraction received angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 93.3% beta blockers, and 74.5% mineralocorticoid receptor antagonists. The true undertreatment rates were 3.4%, 1.8%, and 19.0%, respectively. Target doses were reached in 16.2% of patients receiving angiotensin converting enzyme inhibitors, 23.3% of those with angiotensin receptor blockers, 13.2% of those prescribed beta blockers, and 23.5% of those with mineralocorticoid receptor antagonists. Among patients who could benefit from ivabradine, 29.1% received this drug. In total, 36% of patients met the criteria for defibrillator implantation and 90% of them had received the device or were scheduled for implantation, whereas 19.6% fulfilled the criteria for resynchronization therapy and 88.0% already had or would soon have the device. In patients who met the criteria, but did not undergo device implantation, the reasons were not cost-related. CONCLUSIONS: When justified reasons for not administering heart failure drugs were taken into account, adherence to the guideline recommendations was excellent. Exclusive use of the percentage of treated patients is a poor indicator of the quality of healthcare in heart failure. Measures should be taken to improve the attainment of optimal dosing in each patient. PMID- 26003506 TI - Geschwind's syndrome in a patient with schizophrenia. PMID- 26003507 TI - Contemporary models of pediatric obsessive-compulsive disorder: An evaluation with a large clinical sample. AB - We evaluated the construct validity of the Child Yale-Brofwn Obsessive-Compulsive Scale (CYBOCS) in a large clinical sample (N=730) using confirmatory factor analysis. Results found inadequate fit for a priori models, though a model accounting for overlapping item content displayed good fit. Parallel obsessions/compulsions items may provide largely redundant information on the CYBOCS. Findings suggest modifying the CYBOCS to reduce burden on researchers, patients, and clinicians, and to more accurately measure pediatric obsessive compulsive disorder (OCD). PMID- 26003508 TI - MDMA, cannabis, and cocaine produce acute dissociative symptoms. AB - Some drugs of abuse may produce dissociative symptoms, but this aspect has been understudied. We explored the dissociative potential of three recreational drugs (3,4-methylenedioxymethamphetamine (MDMA), cannabis, and cocaine) during intoxication and compared their effects to literature reports of dissociative states in various samples. Two placebo-controlled studies were conducted. In Study 1 (N=16), participants received single doses of 25, 50, and 100 mg of MDMA, and placebo. In Study 2 (N=21), cannabis (THC 300 ug/kg), cocaine (HCl 300 mg), and placebo were administered. Dissociative symptoms as measured with the Clinician-Administered Dissociative States Scale (CADSS) significantly increased under the influence of MDMA and cannabis. To a lesser extent, this was also true for cocaine. Dissociative symptoms following MDMA and cannabis largely exceeded those observed in schizophrenia patients, were comparable with those observed in Special Forces soldiers undergoing survival training, but were lower compared with ketamine-induced dissociation. Cocaine produced dissociative symptoms that were comparable with those observed in schizophrenia patients, but markedly less than those in Special Forces soldiers and ketamine users. Thus, MDMA and cannabis can produce dissociative symptoms that resemble dissociative pathology. The study of drug induced dissociation is important, because it may shed light on the mechanisms involved in dissociative psychopathology. PMID- 26003509 TI - Behavioral and emotional responses to interpersonal stress: A comparison of adolescents engaged in non-suicidal self-injury to adolescent suicide attempters. AB - Prominent theoretical models and existing data implicate interpersonal factors in the development and maintenance of suicidal behavior and non-suicidal self-injury (NSSI). However, no known study has yet used computerized behavioral tasks to objectively assess responses to interpersonal conflict/collaboration among teens engaged in NSSI or having made a suicide attempt. The current study, therefore, compared interpersonal functioning indexed by the Prisoner's Dilemma (PD) task among three mutually exclusive groups, adolescents (ages 13-17): engaged in NSSI only without history of a suicide attempt (n=26); who made a suicide attempt without history of NSSI (n=26); and typically developing controls (n=26). Participants also completed the Interpersonal Sensitivity Measure to assess their general sensitivity to/awareness of others' behaviors and feelings. No significant between-group differences were found in PD task performance; however, compared to typically developing control participants and those who had made a suicide attempt, the NSSI group reported significantly more stress during the task. Additionally, NSSI participants rated themselves as more interpersonally sensitive compared to both attempters and typically developing controls. Given the lack of knowledge about whether these groups either differentially activate the same circuitry during stressful interpersonal interactions or instead rely on alternative, compensatory circuits, future work using event-related functional magnetic resonance imaging is warranted. PMID- 26003510 TI - Google Trends: Ready for real-time suicide prevention or just a Zeta-Jones effect? An exploratory study. AB - Two studies have shown that increasing the consultation of the word "suicide" in the Google search engine was associated with a subsequent increase in the prevalence of suicide attempts. The main goal of this article was to explore the trends generated by a key-word search associated with suicide, depression and bipolarity in an attempt to identify general trends (disorders epidemics in the population/"real events" vs newsworthy advertisement/"media event"). Based on previous studies, the frequency of the search words "how to suicide" and "commit suicide" were analyzed for suicide, as well as "depression" (for depressive disorders) and "bipolar disorder". Together, these analyses suggest that the search for the words "how to suicide" or "commit suicide" on the Google search engine may be a good indicator for suicide prevention policies. However, the tool is not developed enough to date to be used as a real time dynamic indicator of suicide epidemics. The frequency of the search for the word "suicide" was associated with those for "depression" but not for "bipolar disorder", but searches for psychiatric conditions seem to be influenced by media events more than by real events in the general population. PMID- 26003511 TI - Association between null alleles of GSTM1 and GSTT1 and dependence to heroin and opium. PMID- 26003512 TI - Novel analytical method to measure formaldehyde release from heated hair straightening cosmetic products: Impact on risk assessment. AB - Hair straightening cosmetic products may contain formaldehyde (FA). In Europe, FA is permitted for use in personal care products at concentrations ? 0.2g/100g. According to the Cosmetic Ingredient Review (CIR) Expert Panel products are safe when formalin (a 37% saturated solution of FA in water) concentration does not exceed 0.2g/100g (0.074 g/100g calculated as FA). The official method of reference does not discriminate between "free" FA and FA released into the air after heating FA donors. The method presented here captures and collects the FA released into the air from heated cosmetic products by derivatization with 2,4 dinitrophenylhydrazine and final analysis by UPLC/DAD instrument. Reliable data in terms of linearity, recovery, repeatability and sensitivity are obtained. On a total of 72 market cosmetic products analyzed, 42% showed FA concentrations very close to or above the threshold value (0.074 g/100g calculated as FA) suggested by the Cosmetic Ingredient Review committee, whereas 11 products, negative using the official method of reference, were close to or above the threshold value (0.074 g/100g calculated as FA). This may pose a health problem for occasional users and professional hair stylists. PMID- 26003513 TI - A strategy for structuring and reporting a read-across prediction of toxicity. AB - Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested. PMID- 26003514 TI - In vitro metabolism of rebaudioside E under anaerobic conditions: Comparison with rebaudioside A. AB - The hydrolysis of the steviol glycosides rebaudioside (Reb) A and E, as well as steviolbioside (a metabolic intermediate) to steviol was evaluated in vitro using human fecal homogenates from healthy Caucasian and Asian donors. Incubation of each of the Rebs in both groups resulted in a rapid hydrolysis to steviol. Metabolism of 0.2mg/mL sample was complete within 24h, with the majority occurring within the first 16 h. There were no clear differences in the rate or extent of metabolism of Reb E relative to the comparative control Reb A. The hydrolysis of samples containing 2.0mg/mL of steviol glycosides Reb A and Reb E tended to take slightly longer than 0.2mg/mL samples. Herein, we report for the first time that there were no apparent gender or ethnicity differences in the rate of metabolism of any of the Rebs, regardless of the concentrations tested. Steviolbioside, an intermediate in the hydrolysis of Reb E to steviol was also found to be rapidly degraded to steviol. These results demonstrate Reb E is metabolized to steviol in the same manner as Reb A. These data support the use of toxicology data available on steviol, and on steviol glycosides metabolized to steviol (i.e., Reb A) to underpin the safety of Reb E. PMID- 26003515 TI - Novel database for exposure to fragrance ingredients in cosmetics and personal care products. AB - Exposure of fragrance ingredients in cosmetics and personal care products to the population can be determined by way of a detailed and robust survey. The frequency and combinations of products used at specific times during the day will allow the estimation of aggregate exposure for an individual consumer, and to the sample population. In the present study, habits and practices of personal care and cosmetic products have been obtained from market research data for 36,446 subjects across European countries and the United States in order to determine the exposure to fragrance ingredients. Each subject logged their product uses, time of day and body application sites in an online diary for seven consecutive days. The survey data did not contain information on the amount of product used per occasion or body measurements, such as weight and skin surface area. Nevertheless, this was found from the literature where the likely amount of product used per occasion or body measurement could be probabilistically chosen from distributions of data based on subject demographics. The daily aggregate applied consumer product exposure was estimated based on each subject's frequency of product use, and Monte Carlo simulations of their likely product amount per use and body measurements. Statistical analyses of the habits and practices and consumer product exposure are presented, which show the robustness of the data and the ability to estimate aggregate consumer product exposure. Consequently, the data and modelling methods presented show potential as a means of performing ingredient safety assessments for personal care and cosmetics products. PMID- 26003516 TI - Challenges in using the ToxRefDB as a resource for toxicity prediction modeling. AB - Developing and evaluating toxicity prediction models requires selection and use of datasets of known positive and negative agents for the endpoint(s) of interest. EPA's Toxicity Reference Database (ToxRefDB) is a publicly available dataset containing detailed study and effect information on more than 400 chemicals, and it has been used by EPA researchers to develop toxicity prediction models. During an initial evaluation of reproductive toxicity, however, limitations were uncovered in applying data from ToxRefDB that involved interpretation of toxicity effects and designation of toxicity endpoints, core attributes of the database that are critical to its use. These limitations for reproductive toxicity were found to be related, at least in part, to challenges faced in (1) evaluating the source of the original study data (EPA Data Evaluation Records (DERs)) for input into ToxRefDB and (2) interpretation of the biological significance of responses. These limitations of the ToxRefDB have important implications for the wider use of the database as it currently exists. Our results point to a need for improvements to the existing ToxRefDB and/or for researchers to independently evaluate, assign and verify positive or negative designations to data from ToxRefDB before use in development or validation of prediction models or testing frameworks. PMID- 26003517 TI - Developmental toxicity assessment of the new turf herbicide, methiozolin ([5-(2,6 difluorobenzyl)oxymethyl-5-methyl-3,3(3-methylthiophen-2-yl)-1,2-isoxazoline]), in rabbits. AB - Methiozolin is a new herbicide to control annual bluegrass (Poa annua L.) and large crabgrass (Digitaria sanguinalis (L.) Scop.) in various turfgrasses. The potential of methiozolin to induce maternal and developmental toxicity was investigated in the pregnant New Zealand White Rabbits. Methiozolin was, at dose levels of 0, 125, 250 and 500 mg/kg/day, administered by oral gavage to artificially inseminated rabbits (25 females per group) from days 6 to 28 of gestation. All does were subjected to Cesarean section on day 29 of gestation. At 500 mg/kg/day, treatment-related toxicities including abortion (10/22), decreased mean body weight, weight gain, net body weight change, reduced food consumption and decreased fetal weight were observed. At 125 and 250 mg/kg/day, no signs of maternal and developmental toxicity were observed. There were no treatment related external, visceral and skeletal abnormalities of fetuses at all doses tested. In the current experimental conditions, the no observed adverse effect levels (NOAELs) of methiozolin are considered to be 250 mg/kg/day for does and prenatal development. PMID- 26003518 TI - The keratocystic odontogenic tumour (KCOT)--an odyssey. AB - The most appropriate management for the lesion now known as the keratocystic odontogenic tumour (previously known as the odontogenic keratocyst) remains controversial. This article reviews the different management protocols adopted by one surgical unit over the last 30 years and the results obtained from the different treatment modalities. A current treatment protocol consisting of initial decompression followed by aggressive curettage and peripheral ostectomy with methylene blue staining appears to be successful, but our longest follow-up is only 6 years. PMID- 26003519 TI - The distribution pattern of alpha2,3- and alpha2,6-linked sialic acids affects host cell preference in Toxoplasma gondii. AB - Tachyzoites of Toxoplasma gondii, an obligate intracellular parasite, actively invade almost all types of nucleated cells. However, T. gondii tachyzoites preferentially infect particular types of animal tissue cells. The mechanism underlying the host cell preference of T. gondii is not yet known. In this study, we found that enzymatic removal of alpha2,3- but not alpha2,6-linked sialic acids on the surface of Vero cells decreased T. gondii tachyzoite adhesion or invasion to the treated cells. Although Chinese hamster ovary (CHO) cells express only alpha2,3-linked sialic acid, a genetically modified CHO cell line constructed by transfection with the alpha2,6-sialiltransferase gene contains subpopulations with a variety of expression patterns of alpha2,3- and alpha2,6-linked sialic acids. When T. gondii tachyzoites were added to the modified CHO cells, the tachyzoites preferentially attached to cells belonging to a subpopulation of cells that highly expressed alpha2,3-linked sialic acids. Additionally, multiple regression analysis performed to analyse the relationship between the amount of alpha2,3-linked/alpha2,6-linked sialic acids and parasite-expressed fluorescence intensity suggested that more tachyzoites adhered to individual alpha2,3-linked sialic acid rich-cells than to alpha2,3-linked sialic acid-poor/null cells. The results of confocal laser microscopy confirmed this finding. These results indicate that the host cell preference of T. gondii was, at least partially, affected by the distribution pattern of alpha2,3-, but almost never alpha2,6 linked sialic acids on host cells. PMID- 26003520 TI - Crosstalk between Nrf2 and Notch signaling. AB - The transcription factor Nrf2 (nuclear factor, erythroid derived 2, like 2) belongs to the CNC-bZip protein family, forming a transcriptosome with its direct heterodimer partner, sMaf, and co-factors such as CBP/p300. Nrf2 binds to one or more AREs (antioxidant response elements) that are located in the gene regulatory regions of the hundreds of Nrf2 target genes. The AREs are key enhancers that are activated in response to endogenous or exogenous stresses to maintain cellular and tissue homeostasis. Data emanating from gene expression microarray analyses comparing Nrf2-disrupted and wild-type mouse embryonic fibroblasts (MEF) showed that expression of Notch1 and Notch-signaling-related genes were decreased in Nrf2-disrupted cells. This observation triggered our research on Nrf2-Notch crosstalk. A functional ARE has been identified upstream of the Notch1 major transcription start site. Furthermore, an Rbpjkappa binding site is conserved on the promoters of Nrf2 among animal species. Notch1 is one of the transmembrane Notch family receptors that drive Notch signaling, together with the Rbpjkappa transcription factor. After canonically accepting ligands such as Jags and Deltas, the receptor undergoes cleavage to yield the Notch intracellular domain, which translocates to the nucleus. Recent studies using conditional knockout mice indicate that Notch1 as well as Notch2 plays an important role postnatally in liver development and in maintenance of hepatic function. In this review, we summarize current understanding of the role of reciprocal transcriptional regulation between Nrf2 and Notch in adult liver from studies using Nrf2, Keap1, and Notch1 genetically engineered mice. PMID- 26003522 TI - P20A inhibits HIV-1 fusion through its electrostatic interaction with the distal region of the gp41 fusion core. AB - We previously identified an HIV-1 fusion inhibitor P20A targeting HIV-1 gp41 6-HB fusion core. Using alanine scanning mutagenesis, we investigated the effect of 6 HB surface residue mutations on the binding affinity between P20A and 6-HB. Substitution of positively or negatively charged residues in the distal region of 6-HB with alanines resulted in significant decrease or increase of its binding affinity to P20A, respectively. The 6-HB with E630K, D632K, or E634K mutation exhibited enhanced binding affinity with P20A, suggesting that P20A blocks HIV-1 fusion through electrostatic interaction with the positively charged residues in the distal region of the gp41 fusion core. PMID- 26003521 TI - Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption. AB - Cytochrome P450 2E1 (CYP2E1) induction and oxidative metabolism of ethanol in hepatocytes inflame and damage liver. Chronic ethanol ingestion also induces kidney dysfunction, which is associated with mortality from alcoholic hepatitis. Whether the kidney is directly affected by ethanol or is secondary to liver damage is not established. We found that CYP2E1 was induced in kidney tubules of mice chronically ingesting a modified Lieber-deCarli liquid ethanol diet. Phospholipids of kidney tubules were oxidized and fragmented in ethanol-fed mice with accumulation of azelaoyl phosphatidylcholine (Az-PC), a nonbiosynthetic product formed only by oxidative truncation of polyunsaturated phosphatidylcholine. Az-PC stimulates the inflammatory PAF receptor (PTAFR) abundantly expressed by neutrophils and kidney tubules, and inflammatory cells and myeloperoxidase-containing neutrophils accumulated in the kidneys of ethanol fed mice after significant hysteresis. Decreased kidney filtration and induction of the acute kidney injury biomarker KIM-1 in tubules temporally correlated with leukocyte infiltration. Genetic ablation of PTAFR reduced accumulation of PTAFR ligands and reduced leukocyte infiltration into kidneys. Loss of this receptor in PTAFR(-/-) mice also suppressed oxidative damage and kidney dysfunction without affecting CYP2E1 induction. Neutrophilic inflammation was responsible for ethanol induced kidney damage, because loss of neutrophil myeloperoxidase in MPO(-/-) mice was similarly protective. We conclude that ethanol catabolism in renal tubules results in a self-perpetuating cycle of CYP2E1 induction, local PTAFR ligand formation, and neutrophil infiltration and activation that leads to myeloperoxidase-dependent oxidation and damage to kidney function. Hepatocytes do not express PTAFR, so this oxidative cycle is a local response to ethanol catabolism in the kidney. PMID- 26003523 TI - Blue marble health and "the big three diseases": HIV/AIDS, tuberculosis, and malaria. PMID- 26003525 TI - Expression, purification and preliminary crystallographic studies of human glutamate oxaloacetate transaminase 1 (GOT1). AB - Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l aspartate and alpha-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. In this work, human GOT1 was expressed in Escherichia coli periplasmic space, and purified by a combination of His-tag immobilized metal-ion affinity chromatography and anion exchange chromatography. Optimal activity of the enzyme occurred at a temperature of 37 degrees C and a pH of 7.5. Cations such as Na(+), K(+) and Mg(2+) slightly inhibited the activity of recombinant human GOT1, while Zn(2+), Mn(2+), Cu(2+), Ni(2+), Co(2+) and Ca(2+) had stronger inhibitory effects. Crystals of human GOT1 were grown using the hanging-drop vapor diffusion method at 4 degrees C with 0.1M Bis-Tris pH 6.0% and 21% (w/v) PEG 3350. The crystals diffracted to 2.99A resolution and belonged to space group P43212 with the unit cell parameters a = b = 93.4, c = 107.4A, alpha = beta = gamma = 90 degrees . PMID- 26003524 TI - Therapeutic targeting of acute lung injury and acute respiratory distress syndrome. AB - There is no Food and Drug Administration-approved treatment for acute respiratory distress syndrome (ARDS), in spite of the relatively large number of patients with the diagnosis. In this report, we provide an overview of preclinical studies and a description of completed and future clinical trials in humans with ARDS. Preclinical studies dealing with acute lung injury have suggested roles for complement and complement receptors, as well as the evolving role of histones, but details of these pathways are inadequately understood. Anti-inflammatory interventions have not been convincingly effective. Various cell growth factors are being considered for clinical study. Interventions to block complement activation or its products are under consideration. Stem cell therapies have shown efficacy in preclinical studies, which have motivated phase I/II trials in humans with ARDS. PMID- 26003526 TI - Expression and purification of biologically active recombinant human paraoxonase 1 from inclusion bodies of Escherichia coli. AB - Human PON1 (h-PON1) is a Ca(2+)-dependent serum enzyme and can hydrolyze (and inactivate) a wide range of substrates. It is a multifaceted enzyme and exhibit anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti microbial, and organophosphate (OP)-detoxifying properties. Thus, h-PON1 is a strong candidate for the development of therapeutic intervention against these conditions in humans. Insufficient hydrolyzing activity of native h-PON1 against desirable substrate affirms the urgent need to develop improved variant(s) of h PON1 having enhanced activity. Production of recombinant h-PON1 (rh-PON1) using an Escherichia coli expression system is a key to develop such variant(s). However, generation of rh-PON1 using E. coli expression system has been elusive until now because of the aggregation of over-expressed rh-PON1 protein in inactive form as inclusion bodies (IBs) in the bacterial cells. In this study, we have over-expressed rh-PON1(wt) and rh-PON1(H115W;R192K) proteins as IBs in E. coli, and refolded the inactive enzymes present in the IBs to their active form using in vitro refolding. The active enzymes were isolated from the refolding mixture by ion-exchange chromatography. The catalytic properties of the refolded enzymes were similar to their soluble counterparts. Our results show that the pure and the active variant of rh-PON1 enzyme having enhanced hydrolyzing activity can be produced in large quantities using E. coli expression system. This method can be used for the industrial scale production of rh-PON1 enzymes and will aid in developing h-PON1 as a therapeutic candidate. PMID- 26003527 TI - The muscarinic system, cognition and schizophrenia. AB - An increasing body of evidence has implicated the central muscarinic system as contributing to a number of symptoms of schizophrenia and serving as a potential target for pharmaceutical interventions. A theoretical review is presented that focuses on the central muscarinic system's contribution to the cognitive symptoms of schizophrenia. The aim is to bridge the void between pertinent neuropsychological and neurobiological research to provide an explanatory account of the role that the central muscarinic system plays in the symptoms of schizophrenia. First, there will be a brief overview of the relevant neuropsychological schizophrenia literature, followed by a concise introduction to the central muscarinic system. Subsequently, we will draw from animal, neuropsychological and pharmacological literature, and discuss the findings in relation to cognition, schizophrenia and the muscarinic system. Whilst unifying the multiple domains of research into a concise review will act as a useful line of enquiry into the central muscarinic systems contribution to the symptoms of schizophrenia, it will be made apparent that more research is needed in this field. PMID- 26003528 TI - Cohesion and the aneuploid phenotype in Alzheimer's disease: A tale of genome instability. AB - Neurons are postmitotic cells that are in permanent cell cycle arrest. However, components of the cell cycle machinery that are expressed in Alzheimer's disease (AD) neurons are showing features of a cycling cell and those attributed to a postmitotic cell as well. Furthermore, the unique physiological operations taking place in neurons, ascribed to "core cell cycle regulators" are also key regulators in cell division. Functions of these cell cycle regulators include neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. In this review, we focus on cohesion and cohesion related proteins in reference to their neuronal functions and how impaired centromere/cohesion dynamics may connect cell cycle dysfunction to aneuploidy in AD. PMID- 26003529 TI - Attenuation of hearing loss in DBA/2J mice by anti-apoptotic treatment. AB - DBA/2J mice are characterized by early onset hearing loss at about 3-4 weeks of age. Mutations in cadherin 23 (Cdh23) and fascin-2 (Fscn2) are responsible for the phenotypes, but the underlying mechanism is unknown. In the present study, DBA/2J mice displayed progressive hair cell loss and degeneration of spiral ganglion neurons (SGNs) after 2 weeks of age; however, the mRNA level of Caspase 3 in the inner ears was much higher at 2 weeks of age than that at 4 or 8 weeks of age. Moreover, transcriptional levels of Caspase-3 and Caspase-9 in the inner ears of DBA/2J mice were significantly higher than those of C57BL/6J mice at 2 or 8 weeks of age. Immunohistochemistry localized Caspase-3 and Caspase-9 mainly to the hair cells, SGNs and stria vascularis of the cochleae. To determine the significance of caspase-dependent apoptosis in the hearing loss, the pan-caspase inhibitor Z-VAD-FMK was given intraperitoneally to DBA/J2 mice over an 8-week period starting at one week of age. Blockage of caspases preserved hearing in the mice by more than 10 dB (dB) sound pressure level (SPL) of the ABR thresholds and significantly reduced outer hair cell loss at the basal turns of the cochleae. These results demonstrate that apoptosis in the cochleae of DBA/J2 mice contributes to the early onset of hearing loss, which can be attenuated by anti apoptotic treatment. PMID- 26003530 TI - Cellular proteome alterations in response to enterovirus 71 and coxsackievirus A16 infections in neuronal and intestinal cell lines. AB - Hand, foot and mouth disease is mainly caused by enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16), but EV-A71 is also associated with severe neurological complications. Host factors may contribute to the different clinical outcomes of EV-A71 and CV-A16 infections. A neurovirulent EV-A71 strain (EV A71/UH1) from a fatal case, a non-neurovirulent EV-A71 strain (EV-A71/Sha66) and a CV-A16 strain (CV-A16/22159) from cases of uncomplicated HFMD were used. Replication of the viruses in SK-N-MC (neuronal) and HT-29 (intestinal) cell lines correlated with the severity of clinical disease associated with each virus. EV-A71/UH1 showed the greatest replication in neuronal cells. In HT-29 cells, both EV-A71 strains replicated well, but CV-A16/22159 showed no effective replication. The proteomes of mock and infected SK-N-MC and HT-29 cell lines were compared by 2D-SDS-PAGE. The differentially expressed proteins were identified by MALDI-TOF/TOF analysis. There were 46 and 44 differentially expressed proteins identified from SK-N-MC and HT-29 cells, respectively, categorized under apoptosis, stress, cytoskeletal, energy metabolism proteins and others. Western blot validation showed that EV-A71/UH1 and CV-A16 also differentially induced proteins involved in viral RNA translation and host cell stress responses in neuronal and intestinal cell lines. PMID- 26003531 TI - Automating mass spectrometry-based quantitative glycomics using aminoxy tandem mass tag reagents with SimGlycan. AB - Protein glycosylation is a common post-translational modification, which serves critical roles in the biological processes of organisms. Monitoring of changes in the abundance and structure of glycans may be necessary to explain the correlations between protein glycosylation and various diseases. Hence, the growing importance of glycoproteomics necessitates in-depth qualitative and quantitative studies of glycans. One of the emerging trends in glycomics research is the innovation related to accurate mass spectrometry based quantitative analysis of glycans. Recently, we have introduced aminoxyTMT reagents, which enable efficient relative quantitation of carbohydrates, improved glycan ionization efficiency and increased analytical throughput. These reagents can be used for quantitative analysis of N-glycans by direct infusion or liquid chromatography (LC)-coupled to electrospray ionization mass spectrometry (ESI MS). However, unlike in proteomics, one of the major challenges left unaddressed is the lack of informatics tools to automate the qualitative and quantitative analysis of generated data. This analysis typically includes identification/quantitation of glycans using MS/MS data and differential analysis across biological samples. We have developed software modules to streamline such protocols for quantitative analysis of aminoxyTMT labeled-glycans derived from complex mixtures. This article is part of a Special Issue entitled: Proteomics in India. PMID- 26003532 TI - Functions of Fibroblast Growth Factor Receptors in cancer defined by novel translocations and mutations. AB - The four receptor tyrosine kinases (RTKs) within the family of Fibroblast Growth Factor Receptors (FGFRs) are critical for normal development but also play an enormous role in oncogenesis. Mutations and/or abnormal expression often lead to constitutive dimerization and kinase activation of FGFRs, and represent the primary mechanism for aberrant signaling. Sequencing of human tumors has revealed a plethora of somatic mutations in FGFRs that are frequently identical to germline mutations in developmental syndromes, and has also identified novel FGFR fusion proteins arising from chromosomal rearrangements that contribute to malignancy. This review details approximately 200 specific point mutations in FGFRs and 40 different fusion proteins created by translocations involving FGFRs that have been identified in human cancer. This review discusses the effects of these genetic alterations on downstream signaling cascades, and the challenge of drug resistance in cancer treatment with antagonists of FGFRs. PMID- 26003533 TI - Round Ligament Technique and Use of a Vessel-sealing Device to Facilitate Complete Salpingectomy at the Time of Vaginal Hysterectomy. AB - Prophylactic salpingectomy at the time of hysterectomy has been recommended for women at average risk for ovarian cancer. Vaginal hysterectomy is considered the preferred approach to a benign hysterectomy, and adnexectomy should not be considered a contraindication to this approach. This paper with accompanying video describes and demonstrates the round ligament technique and use of a vessel sealing device to facilitate removal of the entire fallopian tube at the time of vaginal hysterectomy. PMID- 26003534 TI - Antagonistic effects of alpha-tocopherol and ursolic acid on model bacterial membranes. AB - alpha-tocopherol (Toc), the most active component of vitamin E can exert antagonistic effects disabling the therapy of cancers and bacterial infections. Such antagonisms were observed also between Toc and bioactive pentacyclic triterpenes (PT) exhibiting anticancer and antibacterial properties. Both Toc and PT are water-insoluble membrane active substances. Thus, our idea was to emulate their interactions with model Escherichia coli membranes. E. coli inner membranes were selected for the experiments because their lipid composition is quite simple and well characterized and the two main components are phosphatidylethanolamine and phosphatidylglycerol. As a model of E. coli membranes we applied Langmuir monolayers formed by the E. coli total extract of polar lipids (Etotal) as well as by the main lipid components: phosphatidylethanolamine (POPE) and phosphatidylglycerol (ECPG). The antagonistic effects of ursolic acid (Urs) and Toc were investigated with the application of ternary Langmuir monolayers formed by Urs, Toc and one of the phospholipids POPE or ECPG. Our studies indicated that the affinities of Urs and Toc towards the POPE molecule are comparable; whereas there are profound differences in the interactions of Urs and Toc with ECPG. Thus, the model experiments prove that in the case of E. coli membrane, the differences in the interactions between Urs and Toc with the anionic bacterial phosphatidylglycerol can be the key factor responsible for the antagonistic effects observed between PT and Toc in vivo. PMID- 26003535 TI - Riccardin C derivatives cause cell leakage in Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major problem in clinical settings, and because it is resistant to most antimicrobial agents, MRSA infections are difficult to treat. We previously reported that synthetic macrocyclic bis(bibenzyl) derivatives, which were originally discovered in liverworts, had anti-MRSA activity. However, the action mechanism responsible was unclear. In the present study, we elucidated the action mechanism of macrocyclic bis(bibenzyl) RC-112 and its partial structure, IDPO-9 (2-phenoxyphenol). Survival experiments demonstrated that RC-112 had a bactericidal effect on MRSA, whereas IDPO-9 had bacteriostatic effects. IDPO-9-resistant mutants exhibited cross-resistance to triclosan, but not to RC-112. The mutation was identified in the fabI, enoyl-acyl carrier protein reductase gene, a target of triclosan. We have not yet isolated the RC-112-resistant mutant. On the other hand, the addition of RC-112, unlike IDPO-9, caused the inflow of ethidium and propidium into S. aureus cells. RC-112-dependent ethidium outflow was observed in ethidium loaded S. aureus cells. Transmission electron microscopy also revealed that S. aureus cells treated with RC-112 had intracellular lamellar mesosomal-like structures. Intracellular Na+ and K+ concentrations were significantly changed by the RC-112 treatment. These results indicated that RC-112 increased membrane permeability to ethidium, propidium, Na+, and K+, and also that the action mechanism of IDPO-9 was different from those of the other compounds. PMID- 26003536 TI - The combination of insulin-like growth factor 1 and erythropoietin protects against ischemic spinal cord injury in rabbits. AB - INTRODUCTION: Insulin-like growth factor 1 (IGF-1) and erythropoietin (EPO) have been reported to independently protect against ischemic spinal cord injury in rabbits. In the present study, we investigated whether the combination of IGF-1 and EPO protects against ischemic spinal cord injury in rabbits. METHODS: Animals were assigned to 1 of 4 groups (n = 6 in each): a control group (saline), an IGF 1 group (IGF-1 0.3 mg/kg), an EPO group (EPO 800 U/kg), or an IGF-1 + EPO group (IGF-1 0.3 mg/kg + EPO 800 U/kg). Spinal cord ischemia was produced by occluding the abdominal aorta for 15 min. Saline, IGF-1, and EPO were administered intravenously just after the start of reperfusion. Hindlimb motor function was assessed daily for 7 days, after which histopathological evaluation was performed. To analyze phosphorylation of signal transduction molecules, animals were assigned to 1 of the 4 groups (n = 8 in each). Spinal cord ischemia and the treatment were the same as those described above. The spinal cords were removed at 15 or 30 min after reperfusion and used to analyze phosphorylation of signal transduction molecules. Four animals served as the preischemic control, and the spinal cord was removed just before the start of ischemia. RESULTS: In the IGF-1 + EPO group, both neurological and histopathological outcomes were significantly improved as compared to the control group, which was consistent with the increase of Janus kinase-2 (JAK2) phosphorylation. CONCLUSIONS: The combination of IGF-1 and EPO protects against ischemic spinal cord injury in rabbits. JAK2 might contribute to the protective effect. PMID- 26003537 TI - Effects of selective cleavage of high-mannose-type glycans of Maackia amurensis leukoagglutinin on sialic acid-binding activity. AB - BACKGROUND: Maackia amurensis leukoagglutinin (MAL) is a glycoprotein and sialic acid-binding lectin that is used widely in the detection and characterization of sialoglycoconjugates and human cancer cells. However, its N-linked glycan structure and role have yet to be determined. METHODS: The N-linked glycans were analyzed using high-performance liquid chromatography with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and the secondary structure was investigated using circular dichroism analysis. A hemagglutination assay was performed. Furthermore, surface plasmon resonance analysis, and fluorescence microscopy and fluorescence-activated cell-sorting analysis were conducted to assess the sialoglycoprotein-binding ability and its usefulness in the detection of human breast cancer MCF-7 cells, respectively. RESULTS: Analysis of the N-linked glycan structure of MAL confirmed the presence of eight glycans, comprising two alpha1,3-fucosylated paucimannosidic-type and six high-mannose type glycans. Glycan analysis of MAL that had been treated with peptide N glycosidase F (de-M-MAL) revealed that while the two alpha1,3-fucosylated paucimannosidic glycans remained attached following the treatment, the six high mannose-type glycans had been completely cleaved from the original MAL. There were almost no secondary structural changes between MAL and de-M-MAL; however, the lectin activities exhibited by MAL, such as hemagglutination and binding to a sialoglycoprotein, were completely absent in de-M-MAL, and the ability to detect human breast cancer MCF-7 cells was 77% lower in de-M-MAL than in MAL. CONCLUSION: The high-mannose-type glycans in intact MAL are closely associated with its lectin activities. GENERAL SIGNIFICANCE: This is the first report of the N-linked glycan structure of MAL and the effect of high-mannose-type glycans on lectin activities. PMID- 26003538 TI - The Shark Strikes Twice: Hypervariable Loop 2 of Shark IgNAR Antibody Variable Domains and Its Potential to Function as an Autonomous Paratope. AB - In this present study, we engineered hypervariable loop 2 (HV2) of the IgNAR variable domain in a way that it solely facilitates antigen binding, potentially functioning as an autonomous paratope. For this, the surface-exposed loop corresponding to HV2 was diversified and antigen-specific variable domain of IgNAR antibody (vNAR) molecules were isolated by library screening using yeast surface display (YSD) as platform technology. An epithelial cell adhesion molecule (EpCAM)-specific vNAR was used as starting material, and nine residues in HV2 were randomized. Target-specific clones comprising a new HV2-mediated paratope were isolated against cluster of differentiation 3epsilon (CD3epsilon) and human Fcgamma while retaining high affinity for EpCAM. Essentially, we demonstrate that a new paratope comprising moderate affinities against a given target molecule can be engineered into the vNAR scaffold that acts independent of the original antigen-binding site, composed of complementarity-determining region 3 (CDR3) and CDR1. PMID- 26003539 TI - Correlation between BRCA1 and TopBP1 protein expression and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. AB - PURPOSE: To investigate the correlation between protein expression of breast cancer susceptibility gene 1 (BRCA1) and topoisomerase IIbeta-binding protein 1 (TopBP1) and clinical outcome of non-small cell lung cancer treated with platinum based chemotherapy. METHODS: Immunohistochemical staining was conducted to detect the protein expression of BRCA1 and TopBP1 in 101 cases of NSCLC and to correlate these with clinical features, disease progression, and patient survival. Chi square test (chi (2)-test) was used to evaluate categorical variables. Spearman's rank order correlation was used to analyze continuous variables. Overall survival rate of NSCLC patients was analyzed by Kaplan-Meier survival curve and log-rank test. Relevant factors affecting the survival of patients with advanced NSCLC were analyzed by COX proportional hazards regression model. RESULTS: A total of 101 NSCLC patients were included in the present study. In tumor tissue specimens, positive expression rates of BRCA1 and TopBP1 proteins were 51.5 and 57.4 %, respectively. A significant correlation between the positive expression of BRCA1 and the positive expression of TopBP1 was observed (P < 0.001, r = 0.326). No significant correlation between BRCA1/TopBP1 and age, gender, smoking status, performance status score, pathohistological type, or clinical stage was detected (P > 0.05). During the follow-up period, 65 patients died, and 86 patients showed progression at the end of the study. The survival rate of patients with negative BRCA1 protein expression was higher than that in patients with positive BRCA1 protein expression [median overall survival (OS) 34 vs. 21 months, HR 1.913, 95 % CI 1.161-3.150, P = 0.011]. Similarly, the survival rate of patients with negative TopBP1 expression was higher than that in patients with positive TopBP1 (median OS 36 vs. 23 months, HR 1.931, 95 % CI 1.157-3.224, P = 0.012). No significant correlation between protein expression of BRCA1 or TopBP1 with NSCLC disease progression was observed (P > 0.05). CONCLUSIONS: The present study indicates NSCLC patients with negative BRCA1 and TopBP1 expression showed better prognosis than those with positive protein expression. PMID- 26003540 TI - Phase II study of erlotinib in elderly patients with non-small cell lung cancer harboring epidermal growth factor receptor mutations. AB - PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are key drugs in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. We assessed the efficacy and safety of one EGFR tyrosine kinase inhibitor, erlotinib, in elderly Japanese patients with EGFR-mutated NSCLC. METHODS: Elderly patients aged 75 or older with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) were enrolled in this prospective phase II trial. Patients received 150 mg erlotinib per day orally. The primary end point was the overall response rate. RESULTS: Between March 2013 and November 2014, 32 patients were enrolled with median age 80 years. All tumors had adenocarcinoma histology, and 20 patients (62.5 %) had an L858R mutation. The response rate was 56.3 % [95 % confidence interval (CI) 39.4-72.0 %], and the disease control rate was 90.6 % (95 % CI 75.2-97.6 %). Median progression-free survival was 15.5 months (95 % CI 11.2-not reached). Skin disorder was the most common adverse event, and grade 4 drug-related interstitial lung disease occurred in one patient. CONCLUSIONS: Erlotinib is effective and tolerated in elderly patients with EGFR mutation-positive NSCLC. PMID- 26003541 TI - Optimal site for facial nerve transection and neurorrhaphy: a randomized prospective animal study. AB - BACKGROUND: Since the first facial allograft transplantation was performed, several institutions have performed the procedure with the main objectives being restoration of the aesthetic appearance and expressive function of the face. The optimal location to transect the facial nerve during flap harvest in transplantation to preserve facial movement function is currently unknown. There are currently two primary methods to perform facial nerve neurorrhaphy between the donor and recipient-one protocol involves transection and repair of the facial nerve at the main trunk while the another protocol advocates for the neurorrhaphy to be performed distally at the main branches. The purpose of this study is to establish the optimal location for transection and repair of the facial nerve to optimize functional recovery of facial movement. METHODS: A prospective randomized controlled trial using a rat model was performed. Two groups of 12 rats underwent facial nerve transection and subsequent repair either at the main trunk of the nerve (group 1) or 2 cm distally, at the main bifurcation (group 2). Primary outcome of nerve functional recovery was measured using a previously validated laser curtain model, which measured amplitude of whisking at 2, 4, and 6 post-operatively. The deflection of the laser curtain sent a digital signal that was interpreted by central computer software. RESULTS: At week 2 post-nerve surgery, the average amplitude observed for group 1 and 2 was 4.4 and 10.8 degrees, respectively. At week 4, group 1 showed improvement with an average amplitude of 9.7 degrees, while group 2 displayed an average of 10.2 degrees. The week 6 results showed the greatest improvement from baseline for group 1. Group 1 and 2 had average amplitudes of 17.2 and 6.9 degrees, respectively. There was no statistically significant difference between the two groups at 2, 4, and 6 weeks after facial nerve surgery (p > 0.05). CONCLUSIONS: We found no statistical difference between these two locations of nerve repair using identical methods. Therefore, the authors recommend a single versus multiple nerve repair technique. This finding has potential implications for future facial allograft transplantations and at minimum necessitates further study with long-term follow-up data. PMID- 26003542 TI - Immunization of sheep with DNA coding for the variable region of anti-idiotypic antibody generates humoral and cell mediated immune responses specific for peste des petits ruminants virus. PMID- 26003543 TI - Consent to epistemic interventions: a contribution to the debate on the right (not) to know. AB - The debate on the 'right (not) to know' has simmered on for over 30 years. New examples where a right to be informed is contrasted to a right to be kept in ignorance occasionally surface and spark disagreement on the extent to which patients and research subjects have a right to be self-determining concerning the health related information they receive. Up until now, however, this debate has been unsatisfactory with regard to the question what type of rights-if any-are in play here and to what extent they can provide a normative basis for informed consent. This paper provides an analysis of informed consent in the context of 'epistemic interventions': interventions which involve the communication of (health-related) information. First, I offer an analysis of the concept of a 'right not to know' in the context of consent to epistemic interventions. I argue that the scope of the consent is determined by the extent to which this intervention can be seen as an infringement of the private sphere. After that I show how this analysis affects the scope and standards of informed consent. PMID- 26003544 TI - Pretreatment with Evans blue, a stimulator of BK(Ca) channels, inhibits compound 48/80-induced shock, systemic inflammation, and mast cell degranulation in the rat. AB - The present study demonstrated that intravenous injection of a high dose of compound 48/80 to the rat induced 50% drop, within a few min, in the mean arterial pressure and pulse pressure as well as systemic inflammatory plasma leakage that might lead to circulatory and respiratory failure. We also investigated whether pretreatment with Evans blue, a stimulator of BK(Ca) channels, could exert inhibitory effect against compound C48/80-induced allergic circulatory shock and systemic inflammation. Different groups of Sprague-Dawley rats received an intravenous injection of a dose of Evans blue (0, 5, 10, or 50 mg/kg) just 20 s prior to injection of compound 48/80 (200 MUg/kg, over 2 min). The present study found that pretreatment with Evans blue in a dose of 10 or 50 mg/kg exerted acute inhibitory effect on compound 48/80-induced sudden drop in mean arterial and pulse pressures. We also showed that pretreatment with Evans blue in a dose of 5, 10, or 50 mg/kg significantly inhibited compound 48/80 induced extensive plasma extravasation, mast cell degranulation, and edema formation in various organs including the airways, esophagus, and skin. Pretreatment with Evans blue 50 mg/kg 1 h earlier exhibited longer-term inhibitory effect on compound 48/80-induced arterial hypotension and systemic inflammation. We concluded that Evans blue pretreatment prevented rats from compound 48/80-triggered allergic shock and systemic inflammation, possibly mainly through inhibition of mast cell degranulation. Evans blue might be potentially useful in elucidating the mechanism and acting as a therapeutic agent of allergic shock and systemic inflammation. PMID- 26003545 TI - PReVENT--protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial. AB - BACKGROUND: It is uncertain whether lung-protective mechanical ventilation using low tidal volumes should be used in all critically ill patients, irrespective of the presence of the acute respiratory distress syndrome (ARDS). A low tidal volume strategy includes use of higher respiratory rates, which could be associated with increased sedation needs, a higher incidence of delirium, and an increased risk of patient-ventilator asynchrony and ICU-acquired weakness. Another alleged side-effect of low tidal volume ventilation is the risk of atelectasis. All of these could offset the beneficial effects of low tidal volume ventilation as found in patients with ARDS. METHODS/DESIGN: PReVENT is a national multicenter randomized controlled trial in invasively ventilated ICU patients without ARDS with an anticipated duration of ventilation of longer than 24 hours in 5 ICUs in The Netherlands. Consecutive patients are randomly assigned to a low tidal volume strategy using tidal volumes from 4 to 6 ml/kg predicted body weight (PBW) or a high tidal volume ventilation strategy using tidal volumes from 8 to 10 ml/kg PBW. The primary endpoint is the number of ventilator-free days and alive at day 28. Secondary endpoints include ICU and hospital length of stay (LOS), ICU and hospital mortality, the incidence of pulmonary complications, including ARDS, pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives and neuromuscular blocking agents, incidence of ICU delirium, and the need for decreasing of instrumental dead space. DISCUSSION: PReVENT is the first randomized controlled trial comparing a low tidal volume strategy with a high tidal volume strategy, in patients without ARDS at onset of ventilation, that recruits a sufficient number of patients to test the hypothesis that a low tidal volume strategy benefits patients without ARDS with regard to a clinically relevant endpoint. TRIAL REGISTRATION: The trial is registered at www.clinicaltrials.gov under reference number NCT02153294 on 23 May 2014. PMID- 26003547 TI - Encapsulated Thyroid Carcinoma of Follicular Cell Origin. AB - Encapsulated carcinomas of follicular cell origin are subject to considerable controversies. This group includes an encapsulated/well-circumscribed (E/WC) follicular variant of papillary carcinoma (FVPTC) and encapsulated follicular and Hurthle cell carcinoma (EFC, EHC respectively). FVPTC usually presents as an E/WC tumor and less commonly as an infiltrative neoplasm. E/WC FVPTC rarely metastasizes to lymph nodes, whereas infiltrative tumors often present with cervical nodal metastases. Many studies revealed FVPTC in general to be genetically close to the follicular adenomas (FA)/EFC group of tumors. This is particularly true for the E/WC FVPTC which has a high rate of RAS and lack BRAFV600E mutations. Infiltrative FVPTC has an opposite molecular profile closer to classical papillary carcinoma than to FA/EFC (BRAFV600E > RAS mutations). Noninvasive E/WC FVPTCs are extremely indolent even if treated with lobectomy alone. While EFC and EHC with capsular invasion only have an excellent outcome, those with extensive (>=4 foci) lymphovascular invasion (LVI) have a significant rate of distant recurrence. The prognosis of those with focal LVI seems good, but more studies are needed to confirm their behavior. In EHC, those with extensive/significant LVI have a different RNA expression profile than those with less LVI. EHC appear to recur earlier, are less RAI avid, and have a different mutation profile than EFC. Noninvasive E/WC FVPTC should be treated conservatively. There is therefore a need to reclassify the E/WC FVPTC in order to prevent overtreatment. In view of their molecular and behavioral differences, EHC should not be considered a subset of EFC. PMID- 26003546 TI - A randomised controlled trial investigating the effects of Mediterranean diet and aerobic exercise on cognition in cognitively healthy older people living independently within aged care facilities: the Lifestyle Intervention in Independent Living Aged Care (LIILAC) study protocol [ACTRN12614001133628]. AB - BACKGROUND: The rapid ageing of the population is becoming an area of great concern, both globally and in Australia. On a societal level, the cost of supporting an ageing demographic, particularly with their associated medical requirements, is becoming an ever increasing burden that is only predicted to rise in the foreseeable future. The progressive decline in individuals' cognitive ability as they age, particularly with respect to the ever increasing incidence of Alzheimer's Disease (AD) and other cognitive complications, is in many respects one of the foundation stones of these concerns. There have been numerous observational studies reporting on the positive effects that aerobic exercise and the Mediterranean diet appear to have on improving cognitive ability. However, the ability of such interventions to improve cognitive ability, or even reduce the rate of cognitive ageing, has not been fully examined by substantial interventional studies within an ageing population. METHODS: The LIILAC trial will investigate the potential for cognitive change in a cohort of cognitively healthy individuals, between the ages of 60 and 90 years, living in independent accommodation within Australian aged care facilities. This four-arm trial will investigate the cognitive changes which may occur as a result of the introduction of aerobic exercise and/or Mediterranean diet into individuals' lifestyles, as well as the mechanisms by which these changes may be occurring. Participants will be tested at baseline and 6 months on a battery of computer based cognitive assessments, together with cardiovascular and blood biomarker assessments. The cardiovascular measures will assess changes in arterial stiffness and central pulse pressures, while the blood measures will examine changes in metabolic profiles, including brain derived neurotrophic factor (BDNF), inflammatory factors and insulin sensitivity. CONCLUSION: It is hypothesised that exercise and Mediterranean diet interventions, both individually and in combination, will result in improvements in cognitive performance compared with controls. Positive findings in this research will have potential implications for the management of aged care, particularly in respect to reducing the rate of cognitive decline and the associated impacts both on the individual and the broader community. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry- ACTRN12614001133628. PMID- 26003549 TI - Endoscopic Sleeve Gastroplasty: How I Do It? AB - BACKGROUND: Primary endoscopic weight loss therapies are of interest for access, simplicity, and economy. The objective of this manuscript is to describe the endoscopic sleeve gastroplasty used in 50 patients. METHODS: The goal of this procedure is to reduce the gastric lumen into a tubular configuration, with the greater curvature modified by a line of sutured plications. General anesthesia with endotracheal intubation is needed. An endoscopic suturing system requiring a specific double-channel endoscope delivers full-thickness sets of running sutures from the antrum to the fundus. Patients are admitted and observed, with discharge planned within 24 h. Post-procedure outpatient care includes diet instruction with intensive follow-up by a multidisciplinary team. Voluntary oral contrast and endoscopy studies are scheduled to assess the gastroplasty at 3, 6, and 12 months. RESULTS: The technique was applied in 50 patients (13 men) with an average body mass index (BMI) of 37.7 kg/m(2) (range 30-47) with 13 having reached 1 year. Procedure duration averaged 66 min during which six to eight sutures on average were placed. All patients were discharged in less than 24 h. There were no major intra-procedural, early, or delayed adverse events. Weight loss parameters were satisfactory, mean BMI changes from 37.7 +/- 4.6 to 30.9 +/- 5.1 kg/m(2) at 1 year, and mean %TBWL was 19.0 +/- 10.8. Oral contrast studies and endoscopy revealed sleeve gastroplasty configuration at least until 1 year of follow-up. CONCLUSION: Endoscopic sleeve gastroplasty is a safe, effective, and reproducible primary weight loss technique. PMID- 26003548 TI - Utility of Ultrasound, Transaminases, and Visual Inspection to Assess Nonalcoholic Fatty Liver Disease in Bariatric Surgery Patients. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common in adults with extreme obesity and can impact long-term health and survival. Liver biopsy is the only accurate test for diagnosis and staging, but is invasive and costly. Non invasive testing offers an attractive alternate, but the overall accuracy remains a significant issue. This study was conducted to determine the accuracy and clinical utility of pre-operative ultrasound and liver transaminase levels, as well as intra-operative hepatic visual inspection, for assessing presence of NAFLD as confirmed by hepatic histology. METHODS: Data was collected prospectively from 580 morbidly obese adult patients who underwent Roux-en-Y gastric bypass surgery with intraoperative wedge biopsy between January 2004 and February 2009. Complete data for ultrasound, ALT and AST levels, and documented visual inspection was available for 513 patients. RESULTS: The prevalence of NAFLD was 69 % and that of NASH was 32 %. The individual non-invasive clinical assessments demonstrated low sensitivity, specificity, and accuracy for detecting the presence of steatosis, steatohepatitis, or fibrosis. The combination of normal or abnormal results for all tests improved predictive utility. Abnormal tests with all three assessments had a sensitivity of 95-98 % and a specificity of 28-48 % for major histologic findings in NAFLD/NASH. Normal tests with all three assessments had a sensitivity of 12-22 % and a specificity of 89-97 % for major histologic findings in NAFLD/NASH. CONCLUSIONS: Although individual clinical tests for NAFLD have limited accuracy, the use of combined clinical tests may prove useful. PMID- 26003550 TI - Changes in Health-Related Quality of Life After Gastric Bypass in Patients With and Without Obesity-Related Disease. AB - BACKGROUND: A substantial proportion of severely obese patients undergoing bariatric surgery have not developed disease as a consequence of obesity. Little is known about the effects of bariatric surgery on health-related quality of life (HRQL) in this patient group. In a prospective study at a public hospital, we compared HRQL in gastric bypass patients with and without obesity-related disease before and 2 years after surgery. METHODS: HRQL was assessed in 232 severely obese patients before, 1 year, and 2 years after Roux-en-Y gastric bypass. We used a general HRQL questionnaire, the Short Form 36, and an obesity-specific questionnaire, the Obesity-related Problems scale. The patients were divided into two groups based on the presence of obesity-related disease (n = 146) or not (n = 86) before surgery. We defined obesity-related disease as having at least one of the following conditions: type 2 diabetes mellitus, hypertension, dyslipidemia, coronary heart disease, obstructive sleep apnea, gastroesophageal reflux disease, or osteoarthritis. Linear mixed models were used to analyze the HRQL outcomes. RESULTS: Before surgery, patients with no obesity-related disease reported equal HRQL compared with patients with obesity-related disease. Two years after gastric bypass, substantial improvements in all subscales of Short Form 36 and in Obesity related Problems scale were observed in both groups, and the improvements were similar in 7 out of 8 subscales of Short Form 36 as well as for the Obesity related Problems scale. CONCLUSIONS: Baseline HRQL was similar in patients with and without obesity-related disease prior to gastric bypass. After surgery, patients with no comorbidity had similar positive changes in HRQL as patients with one or several comorbidities. These findings indicate that other factors than obesity-related disease are at least as important for severely obese patients' impaired HRQL. PMID- 26003551 TI - "Normal Values of 24H Multichannel Intraluminal Impedance pH-Metry in a Greek Obese Population Based on Montreal Definition of Gerd". AB - BACKGROUND: Although several studies reporting normal values of 24h multichannel intraluminal impedance pH (MIIpH) have been published, none of them has ever studied obese individuals. The purpose of this study is to determine overall frequency and duration of reflux episodes (acid and non-acid, supine-upright, post and preprandial) in obese asymptomatic volunteers. METHODS: Obese volunteers were enlisted during their preoperative evaluation for bariatric surgery. Volunteers had no gastroesophageal reflux disease (GERD) symptoms and no evidence of esophageal mucosal injury on endoscopy. Participants underwent a 24h MIIpH. RESULTS: In this prospective observational study, data of 22 obese individuals were analyzed. Mean age was 41.9 years and mean BMI was 47.1 kg/m(2). Mean total reflux episodes was 55.6 and 95th percentile was 99.7. Mean percentage of total time with pH <4 was 2.59 % and 95th percentile was 8.57 %. Mean percentage of bolus exposure was 1.84 % with 95th percentile being 4.47 %. Postprandial acid reflux episodes were statistical significant more frequent in comparison to preprandial acid reflux episodes (19.41 vs. 15, p = 0.008). Mean acid clearance duration was 3.6 times higher than median bolus clearance duration (56.05 and 15.55 s, respectively, p = 0.868). CONCLUSION: Our study is the first to provide normal values of 24h MIIpH of asymptomatic obese. Normal values of 24h MIIpH of obese asymptomatic individuals differ from the reported normal values of non obese healthy individuals; having more reflux episodes and equal or slightly higher median bolus exposure and acid clearance. Our results imply that new cut off values should be employed in order to define GERD in obese individuals. PMID- 26003552 TI - Results of Implementing an Enhanced Recovery After Bariatric Surgery (ERABS) Protocol. AB - BACKGROUND: With the increasing prevalence of morbid obesity and healthcare costs in general, interest is shown in safe, efficient, and cost-effective bariatric care. This study describes an Enhanced Recovery After Bariatric Surgery (ERABS) protocol and the results of implementing such protocol on procedural times, length of stay in hospital (LOS), and the number of complications, such as readmissions and reoperations. METHODS: Results of implementing an ERABS protocol were analyzed by comparing a cohort treated according to the ERABS protocol (2012 2014) with a cohort treated before implementing ERABS (2010-2012). Differences between both cohorts were analyzed using independent t tests and chi-squared tests. RESULTS: A total of 1.967 patients (mean age 43.3 years, 80% female) underwent a primary bariatric procedure between 2010 and 2014, of which 1.313 procedures were performed after implementation of ERABS. A significant decrease of procedural times and a significantly decreased LOS, from 3.2 to 2.0 nights (p < 0.001), were seen after implementation of ERABS. Significantly more complications were seen post-ERABS (16.1 vs. 20.7%, p = 0.013), although no significant differences were seen in the number of major complications. CONCLUSION: Implementation of ERABS can result in shorter procedural times and a decreased LOS, which may lead to more efficient and cost-effective bariatric care. The increase in complications was possibly due to better registration of complications. The main goal of an ERABS protocol is efficient, safe, and evidence-based bariatric care, which can be achieved by standardization of the total process. PMID- 26003553 TI - Looking for a precursor of spontaneous Sleep Slow Oscillations in human sleep: The role of the sigma activity. AB - Sleep Slow Oscillations (SSOs), paradigmatic EEG markers of cortical bistability (alternation between cellular downstates and upstates), and sleep spindles, paradigmatic EEG markers of thalamic rhythm, are two hallmarks of sleeping brain. Selective thalamic lesions are reportedly associated to reductions of spindle activity and its spectrum ~14 Hz (sigma), and to alterations of SSO features. This apparent, parallel behavior suggests that thalamo-cortical entrainment favors cortical bistability. Here we investigate temporally-causal associations between thalamic sigma activity and shape, topology, and dynamics of SSOs. We recorded sleep EEG and studied whether spatio-temporal variability of SSO amplitude, negative slope (synchronization in downstate falling) and detection rate are driven by cortical-sigma-activity expression (12-18Hz), in 3 consecutive 1s-EEG-epochs preceding each SSO event (Baselines). We analyzed: (i) spatial variability, comparing maps of baseline sigma power and of SSO features, averaged over the first sleep cycle; (ii) event-by-event shape variability, computing for each electrode correlations between baseline sigma power and amplitude/slope of related SSOs; (iii) event-by-event spreading variability, comparing baseline sigma power in electrodes showing an SSO event with the homologous ones, spared by the event. The scalp distribution of baseline sigma power mirrored those of SSO amplitude and slope; event-by-event variability in baseline sigma power was associated with that in SSO amplitude in fronto-central areas; within each SSO event, electrodes involved in cortical bistability presented higher baseline sigma activity than those free of SSO. In conclusion, spatio-temporal variability of thalamocortical entrainment, measured by background sigma activity, is a reliable estimate of the cortical proneness to bistability. PMID- 26003554 TI - Delayed Bleeding Rate According to the Forrest Classification in Second-Look Endoscopy After Endoscopic Submucosal Dissection. AB - BACKGROUND AND AIM: Forrest classification is a valid tool to predict rebleeding rate in peptic ulcer, not in post-endoscopic resection ulcer. We evaluated the delayed bleeding rate in Forrest classification II and III lesions when they were not treated in second-look endoscopy. METHODS: Between July 2011 and February 2012, 706 lesions in 656 consecutive patients who underwent second-look endoscopy performed on the second day after endoscopic submucosal dissection (ESD) were prospectively investigated. Endoscopic findings were described according to Forrest classification, and late delayed bleeding was defined as bleeding from second-look endoscopy to 1 month. We evaluated the rate of late delayed bleeding in untreated Forrest classification II and III lesions during second-look endoscopy. RESULTS: Among the 706 gastric tumors analyzed, late delayed bleeding after ESD occurred in 29 lesions (4.1%). At second-look endoscopy, Forrest I lesions (immediately treated by endoscopic hemostasis) were found in 63 cases [Ia, 8 lesions (1.1%); Ib, 55 lesions (7.8%)]; there was no further bleeding after discharge. Forrest II and III lesions (not treated in second-look endoscopy) were found in 643 cases [IIa, 62 lesions (8.8%); IIb, 119 lesions (16.9%); IIc, 460 lesions (65.2 %); III, 2 lesions (0.3%)]; and there was no significant difference in the late delayed bleeding rate between these groups [IIa, 2/62 (3.2%); IIb, 5/119 (4.2%); IIc and III, 22/462 (4.8%); P = 1.000]. CONCLUSIONS: The rate of late delayed bleeding of post-ESD ulcers with non bleeding visible vessels was not significantly different from that of ulcers with non-visible vessels ( http://cris.nih.go.kr , identifier KCT0000268). PMID- 26003556 TI - An intimate cause of proctocolitis. PMID- 26003555 TI - Long-Term Administration of Fibroblast Growth Factor 21 Prevents Chemically Induced Hepatocarcinogenesis in Mice. AB - PURPOSE: In this study, we explored whether treatment with FGF-21 could prevent diethylnitrosamine (DEN) induced hepatocarcinogenesis in mice. METHODS & RESULTS: Hepatoma was induced by injection of DEN every three days for 18 weeks. For the prophylactic experiment, mice were firstly injected with FGF-21 for 2 weeks, then FGF-21 was administered to the mice once daily in association with DEN injection till the end of the experiment. The hepatoma incidence of mice treated with FGF 21 was 13.3%, while the incidence of mice treated with saline was 61.5%. To understand the mechanisms, we compared the expression of betaklotho (KLB) and oxidative stress level in the livers between the mice treated with FGF-21 and saline. We found that FGF-21 could suppress DEN-induced oxidative stress and up regulate the expression of KLB in the livers. To confirm these results, we compared the expression of KLB in L02 cells stimulated with or without FGF-21. Besides, we established DEN-induced oxidative stress cell model to affirm the relationship between FGF-21 and DEN-induced oxidative stress in vitro. Results showed that FGF-21 increased the expression of KLB and diminished the DEN-induced oxidative stress in vitro in a dose dependent manner. CONCLUSION: Systemic administration of FGF-21 can prevent DEN-induced hepatocarcinogenesis via suppressing oxidative stress and increasing the expression of KLB. PMID- 26003558 TI - Mesenchymal Stem Cells in IBD: unMaSCing Their Therapeutic Mechanisms. PMID- 26003557 TI - Analysis of Familial Tendencies in Transferrin Saturation in a Korean Population. AB - BACKGROUND: Despite the high transferrin saturation (TS) level in Koreans, the p.Cys282Tyr and p.His63Asp mutations are markedly less frequent than in Caucasians. We aimed to determine TS levels and their familial tendencies in a Korean population using nationwide data from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1 2010). METHODS: A total of 4904 subjects without a history of hepatitis B and C virus infection, or liver cirrhosis, and who were negative for anemia and hepatitis B antigen were enrolled. A familial tendency analysis was performed in 260 families. Parents were grouped into four quartiles based on their TS levels. Offspring were categorized according to the mean parental TS four quartile scores (1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0). A familial tendency was evaluated by comparing the mean TS of offspring in seven parental groups. RESULTS: The mean TS was 39.3 +/- 15.6% for Korean males and 33.2 +/- 12.9% for Korean females, and both were significantly higher than those of Caucasians reported in the HEIRS study (30.6 +/- 11.0% for male, 25.6 +/- 10.6% for female, P < 0.001). The 260 families showed statistically significant familial tendencies of TS values (P < 0.001). The mean TS of offspring in parental group 1.0, 1.5, 2.0, and 2.5 showed a lower value than that in higher group 3.0, 3.5, and 4.0. In contrast, there were no significant differences in age, daily dietary iron intake, and AST or ALT value among seven groups. CONCLUSIONS: These findings suggest unidentified genetic variations on high TS in Koreans beyond the p.Cys282Tyr and p.His63Asp mutations commonly identified in Caucasians. PMID- 26003559 TI - Erratum: What is the impact of primary care model type on specialist referral rates? A cross-sectional study. PMID- 26003561 TI - Many-Body Perturbation Theory (MBPT) and Time-Dependent Density-Functional Theory (TD-DFT): MBPT Insights About What Is Missing In, and Corrections To, the TD-DFT Adiabatic Approximation. AB - In their famous paper, Kohn and Sham formulated a formally exact density functional theory (DFT) for the ground-state energy and density of a system of N interacting electrons, albeit limited at the time by certain troubling representability questions. As no practical exact form of the exchange correlation (xc) energy functional was known, the xc-functional had to be approximated, ideally by a local or semilocal functional. Nowadays, however, the realization that Nature is not always so nearsighted has driven us up Perdew's Jacob's ladder to find increasingly nonlocal density/wavefunction hybrid functionals. Time-dependent (TD-) DFT is a younger development which allows DFT concepts to be used to describe the temporal evolution of the density in the presence of a perturbing field. Linear response (LR) theory then allows spectra and other information about excited states to be extracted from TD-DFT. Once again the exact TD-DFT xc-functional must be approximated in practical calculations and this has historically been done using the TD-DFT adiabatic approximation (AA) which is to TD-DFT very similar to what the local density approximation (LDA) is to conventional ground-state DFT. Although some of the recent advances in TD-DFT focus on what can be done within the AA, others explore ways around the AA. After giving an overview of DFT, TD-DFT, and LR-TD-DFT, this chapter focuses on many-body corrections to LR-TD-DFT as one way to build hybrid density-functional/wavefunction methodology for incorporating aspects of nonlocality in time not present in the AA. PMID- 26003560 TI - Frailty assessment based on trunk kinematic parameters during walking. AB - BACKGROUND: Physical frailty has become the center of attention of basic, clinical and demographic research due to its incidence level and gravity of adverse outcomes with age. Frailty syndrome is estimated to affect 20 % of the population older than 75 years. Thus, one of the greatest current challenges in this field is to identify parameters that can discriminate between vulnerable and robust subjects. Gait analysis has been widely used to predict frailty. The aim of the present study was to investigate whether a collection of parameters extracted from the trunk acceleration signals could provide additional accurate information about frailty syndrome. METHODS: A total of 718 subjects from an elderly population (319 males, 399 females; age: 75.4 +/- 6.1 years, mass: 71.8 +/- 12.4 kg, height: 158 +/- 6 cm) volunteered to participate in this study. The subjects completed a 3-m walk test at their own gait velocity. Kinematic data were acquired from a tri-axial inertial orientation tracker. FINDINGS: The spatio temporal and frequency parameters measured in this study with an inertial sensor are related to gait disorders and showed significant differences among groups (frail, pre-frail and robust). A selection of those parameters improves frailty classification obtained to gait velocity, compared to classification model based on gait velocity solely. INTERPRETATION: Gait parameters simultaneously used with gait velocity are able to provide useful information for a more accurate frailty classification. Moreover, this technique could improve the early detection of pre frail status, allowing clinicians to perform measurements outside of a laboratory environment with the potential to prescribe a treatment for reversing their physical decline. PMID- 26003562 TI - Heterojunctions in Composite Photocatalysts. AB - Combining different light-absorbing materials for the formation of semiconductor heterojunctions is a very effective strategy for preparing highly active photocatalyst and photoelectrochemical systems. Moreover, the combination of solid state semiconductors with polymers or molecular absorbers expands the possible combinations of materials to alter light absorption and optimize charge carrier separation. In this chapter, different strategies to prepare such composites are presented, highlighting the necessity of intimate interfacial contact for optimum charge carrier transfer. Moreover, the most recent developments and improvements in the formation of heterojunctions and composite photocatalyst systems based on semiconductor solids are presented. PMID- 26003563 TI - Physical Limits of Solar Energy Conversion in the Earth System. AB - Solar energy provides by far the greatest potential for energy generation among all forms of renewable energy. Yet, just as for any form of energy conversion, it is subject to physical limits. Here we review the physical limits that determine how much energy can potentially be generated out of sunlight using a combination of thermodynamics and observed climatic variables. We first explain how the first and second law of thermodynamics constrain energy conversions and thereby the generation of renewable energy, and how this applies to the conversions of solar radiation within the Earth system. These limits are applied to the conversion of direct and diffuse solar radiation - which relates to concentrated solar power (CSP) and photovoltaic (PV) technologies as well as biomass production or any other photochemical conversion - as well as solar radiative heating, which generates atmospheric motion and thus relates to wind power technologies. When these conversion limits are applied to observed data sets of solar radiation at the land surface, it is estimated that direct concentrated solar power has a potential on land of up to 11.6 PW (1 PW=10(15) W), whereas photovoltaic power has a potential of up to 16.3 PW. Both biomass and wind power operate at much lower efficiencies, so their potentials of about 0.3 and 0.1 PW are much lower. These estimates are considerably lower than the incoming flux of solar radiation of 175 PW. When compared to a 2012 primary energy demand of 17 TW, the most direct uses of solar radiation, e.g., by CSP or PV, have thus by far the greatest potential to yield renewable energy requiring the least space to satisfy the human energy demand. Further conversions into solar-based fuels would be reduced by further losses which would lower these potentials. The substantially greater potential of solar-based renewable energy compared to other forms of renewable energy simply reflects much fewer and lower unavoidable conversion losses when solar radiation is directly converted into renewable energy. PMID- 26003564 TI - Computational Molecular Electronic Spectroscopy with TD-DFT. AB - In this chapter we present applications of TD-DFT aiming at reproducing and rationalizing the optical signatures of molecules, and, more precisely, the absorption and fluorescence spectra of conjugated compounds belonging to both organic and inorganic families. We particularly focus on the computations going beyond the vertical approximation, i.e., on the calculation of 0-0 energies and vibronic spectra with TD-DFT, and on large applications performed for "real-life" structures (organic and inorganic dyes, optimization of charge-transfer structures, rationalization of excited-state proton transfer, etc.). We present a series of recent applications of TD-DFT methodology for these different aspects. The main conclusions of TD-DFT benchmarks aiming at pinpointing the most suited exchange-correlation functionals are also discussed. PMID- 26003565 TI - Vitamin B12 and omega-3 fatty acids together regulate lipid metabolism in Wistar rats. AB - Our recent study indicates that maternal vitamin B12 and omega-3 fatty acid status influence plasma and erythrocyte fatty acid profile in dams. The present study examines the effects of prenatal and postnatal vitamin B12 and omega-3 fatty acid status on lipid metabolism in the offspring. Pregnant dams were divided into five groups: Control; Vitamin B12 deficient (BD); Vitamin B12 supplemented (BS); Vitamin B12 deficient group supplemented with omega-3 fatty acids (BDO); Vitamin B12 supplemented group with omega-3 fatty acids (BSO). The offspring were continued on the same diets till 3 month of age. Vitamin B12 deficiency increased cholesterol levels (p<0.01) but reduced docosahexaenoic acid (DHA) (p<0.05), liver mRNA levels of acetyl CoA carboxylase-1 (ACC-1) (p<0.05) and carnitine palmitoyltransferase-1 (CPT-1) (p<0.01) in the offspring. Omega-3 fatty acid supplementation to this group normalized cholesterol but not mRNA levels of ACC-1 and CPT-1. Vitamin B12 supplementation normalized the levels cholesterol to that of control but increased plasma triglyceride (p<0.01) and reduced liver mRNA levels of adiponectin, ACC-1, and CPT-1 (p<0.01 for all). Supplementation of both vitamin B12 and omega-3 fatty acid normalized triglyceride and mRNA levels of all the above genes. Prenatal and postnatal vitamin B12 and omega-3 fatty acids together play a crucial role in regulating the genes involved in lipid metabolism in adult offspring. PMID- 26003566 TI - Detection and quantification of bovine papillomavirus type 2 in urinary bladders and lymph nodes in cases of Bovine Enzootic Hematuria from the endemic region of Azores. AB - Bovine Enzootic Hematuria (BEH) is a disease with a severe impact on production indexes and characterized by the development of bovine urinary bladder tumors, particularly in the Azores archipelago. The purpose of this study was to investigate and quantify BPV2 tissue distribution in bovine urinary bladder tumors, normal bladders, and iliac lymph nodes of cattle from the Azores. A real time PCR system targeting the L1 gene was developed and allowed for the specific detection of the virus. BPV2 DNA was detected in a large proportion of the samples tested, both from neoplastic and healthy tissues, indicating that this virus is very prevalent in the bovine population of the Azores. Moreover, all types of tissues tested were positive, confirming a wide viral distribution within the infected animal. Bovine cutaneous papillomas sampled from Portuguese mainland dairy cattle were used as controls. Viral load ranged between 2.2*10(4) copies/cell in the skin papillomas, and 0.0002 copies/cell in the urinary bladders tumors from the Azores. This is the first report presenting quantitative data on BPV2 infection in bovine urinary bladder lesions from the Azores. This approach will provide a useful tool to evaluate the role of BPV2 not only in the pathogenesis BEH but also in cell transformation mechanisms. PMID- 26003567 TI - Admissions for imported and non-imported parasitic diseases at a General Hospital in Spain: A retrospective analysis. AB - OBJECTIVE: To analyze imported and non-imported parasitic diseases as a cause of admission to a general hospital. METHODS: A retrospective analysis of hospital admissions for parasitic diseases between 2004 and 2013 performed by means of hospital information systems at a public hospital in the city of Castellon (Spain). RESULTS: During the period covered in this study, there were 204,349 admissions, 213 of which were for parasitic diseases (prevalence: 1.04/1000 admission). 129 were neglected parasitic tropical diseases and 61 were imported parasitic diseases. The main parasitic diseases were hydatidosis (24.9%), visceral leishmaniasis (22.5%) and malaria (12.2%). There was a decrease in admissions for visceral leishmaniasis in the 2004-2008 period from 27.7% to 15.9% in the 2009-2013 period (p < 0.001), and an increase in admissions for malaria from 5.0% to 21.3% (p < 0.001). 38 (20.3%) of the 187 patients with parasitic diseases were HIV infected. HIV infection was more common in patients with toxoplasmosis (94.1%; p < 0.001), cryptosporidiosis (66.7%; p < 0.02) and visceral leishmaniasis (46.4%; p = 0.003). There were 34 (18.2%) children with parasitic diseases. Twelve of the 28 patients with visceral leishmaniasis (42.9%; p < 0.001), and 11 of the 17 patients with soil-transmitted diseases were children (64.7%; p < 0.001). The cause of death in eight patients was parasitic disease related (mortality rate: 4.3%). The mortality rate for visceral leishmaniasis was significantly higher (14.3%; p = 0.01). CONCLUSION: The main cause is endemic parasitic diseases such as hydatidosis. Visceral leishmaniasis decreased during the period covered by the study, but malaria increased. PMID- 26003568 TI - Non-homologous functions of the AlkB homologs. AB - The DNA repair enzyme AlkB was identified in E. coli more than three decades ago. Since then, nine mammalian homologs, all members of the superfamily of alpha ketoglutarate and Fe(II)-dependent dioxygenases, have been identified (designated ALKBH1-8 and FTO). While E. coli AlkB serves as a DNA repair enzyme, only two mammalian homologs have been confirmed to repair DNA in vivo. The other mammalian homologs have remarkably diverse substrate specificities and biological functions. Substrates recognized by the different AlkB homologs comprise erroneous methyl- and etheno adducts in DNA, unique wobble uridine modifications in certain tRNAs, methylated adenines in mRNA, and methylated lysines on proteins. The phenotypes of organisms lacking or overexpressing individual AlkB homologs include obesity, severe sensitivity to inflammation, infertility, growth retardation, and multiple malformations. Here we review the present knowledge of the mammalian AlkB homologs and their implications for human disease and development. PMID- 26003569 TI - Elucidation of drivers of high-level production of lactates throughout a cancer development. AB - Lactates play key roles in facilitating or protecting the development of a cancer in most cancer types. While its beneficial effects to cancer development have been extensively studied, very little is known about what derives the high-level production of lactates in a cancer throughout its entire development. Here we present a novel computational analysis of transcriptomic data of nine primary cancer types, plus a few precancerous and metastatic cancer, to address this issue. Our approach is to identify stress types, which are known to play key roles in cancer development and show strong co-expressions with lactate dehydrogenase-A (LDHA), at different stages of cancer development. A number of interesting observations are made through our analyses, including (i) all nine primary cancer types show similar association patterns between stresses and LDHA, namely the strengths of the associations increase from early- to intermediate stage cancer tissues but then make a substantial down turn at the most advanced stage; (ii) while the detailed stress types associated with LDHA may vary across different cancer types, stresses induced by apoptosis and adaptive immune responses are present universally, suggesting that these two stresses are possibly two key drivers to keep the high-level production of lactates; and (iii) there is a clear distinction between stress types associated with LDHA in precancerous tissues vs. cancer and metastasis tissues. We anticipate that the analyses can provide highly useful information for designing personalized treatments for different cancers at different stages, as stopping lactate production could have devastating effects on a cancer development. PMID- 26003571 TI - Moving research on puberty forward: measures are the key component. PMID- 26003572 TI - Obesity prevention in childhood and cardiovascular health later in life: we need to get the ball rolling. PMID- 26003573 TI - College sexual assault: a call for trauma-informed prevention. PMID- 26003574 TI - The Youth Readiness Intervention for war-affected youth. AB - PURPOSE: Mental disorders are among the largest contributors to the global burden of disease. Since the cessation of the Sierra Leonean civil war in 2002, there have been few mental health resources available for war-affected youth. Co occurring psychological problems are commonly reported by youth in the post conflict setting, suggesting a need for evidence-based interventions that cater to comorbid psychological difficulties. This feasibility study outlines the implementation and evaluation of a mixed-methods approach for developing and piloting a culturally grounded group mental health treatment-the Youth Readiness Intervention (YRI)-for war-affected Sierra Leonean youth. METHODS: Participating youth (N = 32; 50% female; ages, 15-24 years) were allocated to one of four gender- and age-stratified groups, facilitated by gender-matched Sierra Leonean interventionists. The intervention comprised adapted cognitive behavioral therapy techniques to address issues pertinent to war-affected youth. Analyses comprised assessments of reliable symptom change, mental health, functional adaptation, and interventionist fidelity outcomes. RESULTS: The YRI was found to be acceptable, feasible and associated with reliable changes in internalizing and externalizing symptoms and improvements in functional impairments and emotion regulation (mean effect size, d = .64). CONCLUSIONS: Youth struggling with the mental health consequences of past trauma due to war merit special attention. The YRI presents a feasible and acceptable intervention for use in this low resource setting. A randomized controlled trial is planned to further test intervention effectiveness and scalability. PMID- 26003575 TI - Key elements for, and indicators of, a successful transition: an international Delphi study. AB - PURPOSE: The purpose of this study was to reach an international consensus to determine what key elements should be part of a transition program and what indicators could be used to assess its success. METHODS: For this purpose, a Delphi study including an international panel of 37 experts was carried out. The study consisted of three rounds, with response rates ranging from 86.5% to 95%. At each round, experts were asked to assess key elements (defined as the most important elements for the task) and indicators (defined as quantifiable characteristics). At each round, panelists were contacted via e-mail explaining them the tasks to be done and giving them the Web link where to complete the questionnaire. At Round 3, each key element and indicator was assessed as essential, very important, important, accessory, or unnecessary. A 70% agreement was used as cutoff. RESULTS: At Round 3, more than 70% of panelists agreed on six key elements being essential, with one of them (Assuring a good coordination between pediatric and adult professionals) reaching an almost complete consensus (97%). Additionally, 11 more obtained more than 70% agreement when combined with the Very important category. Among indicators, only one (Patient not lost to follow-up) was considered almost unanimously (91%) as essential by the panelists and seven others also reached consensus when the Very important category was included. CONCLUSIONS: Using these results as a framework to develop guidelines at local, national, and international levels would allow better assessing and comparing transition programs. PMID- 26003576 TI - Masculine discrepancy stress, teen dating violence, and sexual violence perpetration among adolescent boys. AB - PURPOSE: Addressing gender norms is integral to understanding and ultimately preventing violence in both adolescent and adult intimate relationships. Males are affected by gender role expectations which require them to demonstrate attributes of strength, toughness, and dominance. Discrepancy stress is a form of gender role stress that occurs when boys and men fail to live up to the traditional gender norms set by society. Failure to live up to these gender role expectations may precipitate this experience of psychological distress in some males which, in turn, may increase the risk to engage in physically and sexually violent behaviors as a means of demonstrating masculinity. METHODS: Five-hundred eighty-nine adolescent males from schools in Wayne County, Michigan completed a survey assessing self-perceptions of gender role discrepancy, the experience of discrepancy stress, and history of physical and sexual dating violence. RESULTS: Logistic regression analyses indicated boys who endorsed gender role discrepancy and associated discrepancy stress were generally at greater risk to engage in acts of sexual violence but not necessarily physical violence. CONCLUSIONS: Boys who experience stress about being perceived as "sub-masculine" may be more likely to engage in sexual violence as a means of demonstrating their masculinity to self and/or others and thwarting potential "threats" to their masculinity by dating partners. Efforts to prevent sexual violence perpetration among male adolescents should perhaps consider the influence of gender socialization in this population and include efforts to reduce distress about masculine socialization in primary prevention strategies. PMID- 26003577 TI - Elucidating the mechanisms linking early pubertal timing, sexual activity, and substance use for maltreated versus nonmaltreated adolescents. AB - PURPOSE: To test models linking pubertal timing, peer substance use, sexual behavior, and substance use for maltreated versus comparison adolescents. Three theoretical mechanisms were tested: (1) peer influence links early pubertal timing to later sexual behavior and substance use; (2) early maturers engage in substance use on their own and then select substance-using friends; or (3) early maturers initiate sexual behaviors which lead them to substance-using peers. METHODS: The data came from a longitudinal study of the effects of child maltreatment on adolescent development (303 maltreated and 151 comparison adolescents; age, 9-13 years at initial wave). Multiple-group structural equation models tested the hypotheses across three time points including variables of pubertal timing, perception of peer substance use, sexual behavior, and self reported substance use. RESULTS: Early pubertal timing was associated with substance-using peers only for maltreated adolescents, indicating the mediation path from early pubertal timing through substance-using peers to subsequent adolescent substance use and sexual behavior only holds for maltreated adolescents. Mediation via sexual behavior was significant for both maltreated and comparison adolescents. This indicates that sexual behavior may be a more universal mechanism linking early maturation with risky friends regardless of adverse life experiences. CONCLUSIONS: The findings are a step toward elucidating the developmental pathways from early puberty to risk behavior and identifying early experiences that may alter mediation effects. PMID- 26003578 TI - Chasing the bean: prescription drug smoking among socially active youth. AB - PURPOSE: Alternative consumption practices of prescription drug misuse have been less well monitored than general prevalence. We describe prescription drug smoking among socially active youth and highlight correlates of this practice. We also examine its association with drug problems, drug dependence, and mental health. METHODS: We surveyed 404 young adults recruited from nightlife venues in New York via time-space sampling. We use linear and logistic regression models to examine the probability of smoking prescription drugs and its association with drug problems, dependence, and mental health. Qualitative findings supplement the survey data. RESULTS: Males have higher odds than females (odds ratio [OR] = 3.4), and heterosexuals have higher odds than sexual minority youth (OR = 2.3) of smoking prescription drugs. Those involved in electronic dance music nightlife have higher odds (OR = 2.1) than those who do not participate in that scene, whereas those in college bar scenes have lower odds (OR = .4) of having smoked prescription drugs. Prescription drug smokers report more drug problems (beta = .322) and greater symptoms of dependence net (beta = .298) of the frequency of misuse and other characteristics. Prescription drug smokers do not report greater mental health problems. Qualitative interview data support these survey findings. CONCLUSIONS: Prescription drug smoking is a significant drug trend among socially active youth. It is associated with drug problems and symptoms of dependence net of frequency of misuse. Prevention and intervention efforts for youth who misuse prescription drugs should address the issue of prescription drug smoking, and this may be an area for clinicians to address with their adolescent patients. PMID- 26003579 TI - Alcohol use at the cusp of adolescence: a prospective national birth cohort study of prevalence and risk factors. AB - PURPOSE: To estimate the prevalence of alcohol use at the age of 10-11 years and document variation by early sociodemographic and concurrent alcohol-specific risk factors. METHODS: The Millennium Cohort Study is a prospective, nationally representative study of live births in the United Kingdom across 12 months. A random sample of electoral wards was stratified to adequately represent U.K. countries, economically deprived areas, and areas with high concentrations of Asian and Black British families. A total of 12,305 child-mother pairs provided self-report data at 9 months (mother's marital status, age, education, occupational level; child gender, ethnicity, country) and age 10-11 years (adolescent alcohol use and attitudes). RESULTS: After adjusting for attrition and sampling design, 13.4% of 10- to 11-year-olds had had an alcoholic drink (more than few sips), 1.2% had felt drunk, and .6% had five or more drinks at a time. Odds of ever drinking were higher among boys (1.47, 95% confidence interval, 1.29-1.68) and lower among early adolescents who were Asian British (vs. white; .09, .05-.17) or Black British (.42, .29-.62). Beyond sociodemographic differences, more positive attitudes about alcohol were associated with greater odds of drinking (1.70, 1.51-1.91), feeling drunk (2.96, 2.07-4.24), and having five or more drinks (4.20, 2.66-6.61). CONCLUSIONS: Alcohol use in the last year of primary school was identified but not common. Its use varied by sociodemographic groups; early adolescents with more positive alcohol attitudes had especially high risks of early alcohol initiation. Results support calls for increased surveillance and screening for very early drinking. PMID- 26003580 TI - Underage college students' alcohol displays on Facebook and real-time alcohol behaviors. AB - PURPOSE: College is often a time of alcohol use initiation and displayed Facebook alcohol references. The purpose of this longitudinal study was to determine associations between initial references to alcohol on social media and college students' self-reported recent drinking, binge drinking, and excessive drinking. METHODS: First-year students from two U.S. public universities were randomly selected from registrar lists for recruitment. Data collection included 2 years of monthly Facebook evaluation. When an initial displayed Facebook alcohol reference was identified, these "New Alcohol Displayers" were contacted for phone interviews. Phone interviews used the validated timeline followback method to evaluate recent alcohol use, binge episodes, and excessive drinking. Analyses included calculation of positive predictive value and Poisson regression. RESULTS: A total of 338 participants were enrolled; 56.1% participants were female, 74.8% were Caucasian, and 58.8% were from the Midwestern University. A total of 167 (49.4%) participants became new alcohol displayers during the first 2 years of college. Among new alcohol displayers, 78.5% reported past 28-day alcohol use. Among new alcohol displayers who reported recent alcohol use, 84.9% reported at least one binge episode. Posting an initial Facebook alcohol reference as a profile picture or cover photo was positively associated with excessive drinking (risk ratio = 2.34; 95% confidence interval, 1.54-3.58). CONCLUSIONS: Findings suggest positive associations between references to alcohol on social media and self-reported recent alcohol use. Location of initial reference as a profile picture or cover photo was associated with problematic drinking and may suggest that a student would benefit from clinical investigation or resources. PMID- 26003581 TI - Mood disturbance in adolescents screened by the Mood Disorder Questionnaire predicts poorer social adjustment. AB - PURPOSE: Early-onset bipolar disorder is associated with a more severe illness course and poorer outcome. Its identification in adolescents may provide the opportunity for adequate intervention to improve global functioning and long-term prognosis. Thus, this study aimed to screen mood disturbance in a sample of high school students using Mood Disorder Questionnaire (MDQ) and follow up their adaptive functioning 1 year later. METHODS: In the first year, adolescents aged 15-17 years old from a Taiwanese senior high school (N = 1,151) completed the Chinese version of MDQ, the Impulsiveness Scale, and a set of questions about risky behaviors. A subgroup of respondents (N = 184) picked randomly were interviewed to validate the diagnosis of bipolar disorder. In the second year, the Social Adjustment Inventory for Children and Adolescents was applied for the same sample of subjects for the measurement of their adaptive functions. RESULTS: The intraclass correlation coefficient and the Cronbach alpha coefficient of the MDQ were .68 and .61, respectively. MDQ score of at least 7 showed modest sensitivity (.57) and specificity (.64) for bipolar disorder. Higher MDQ score predicted risky behaviors in adolescents at baseline measurement. MDQ score was found significantly correlated with Impulsiveness Scale total score. In follow-up evaluation, participants with an MDQ score of >=7 had poorer social adjustment. CONCLUSIONS: Our findings suggest that untreated mood disturbance among adolescents leads to impaired social adaptive functioning in the next year. The application of MDQ in adolescents may help clinicians in early intervention for their emotional disturbance. PMID- 26003582 TI - Providing long-acting reversible contraception services in Seattle school-based health centers: key themes for facilitating implementation. AB - PURPOSE: The purpose of this study was to describe the implementation of a program that provides long-acting reversible contraception (LARC) services within school-based health centers (SBHCs) and to identify barriers and facilitators to implementation as reported by SBHC clinicians and administrators, public health officials, and community partners. METHODS: We conducted 14 semistructured interviews with key informants involved in the implementation of LARC services. Key informants included SBHC clinicians and administrators, public health officials, and community partners. We used a content analysis approach to analyze interview transcripts for themes. We explored barriers to and facilitators of LARC service delivery across and within key informant groups. RESULTS: The most cited barriers across key informant groups were as follows: perceived lack of provider procedural skills and bias and negative attitudes about LARC methods. The most common facilitators identified across groups were as follows: clear communication strategies, contraceptive counseling practice changes, provider trainings, and stakeholder engagement. Two additional barriers emerged in specific key informant groups. Technical and logistical barriers to LARC service delivery were cited heavily by SBHC administrative staff, community partners, and public health officials. Expense and billing was a major barrier to SBHC administrative staff. CONCLUSIONS: LARC counseling and procedural services can be implemented in an SBHC setting to promote access to effective contraceptive options for adolescent women. PMID- 26003583 TI - Distressed and looking for help: Internet intervention support for arthritis self management. AB - PURPOSE: Focusing on youth with juvenile arthritis (JA), this study investigates eHealth interventions as a means to develop services to improve the health of youth with chronic conditions. Internet use and preferences for Internet-based interventions were compared among youth with high and low psychosocial quality of life (PS-QL) scores. METHODS: Youth with JA (n = 134; high PS-QL, n = 67; low PS QL, n = 67) completed the MyRheum online survey, which assessed physical functioning, psychosocial health, Internet usage, and amount of time spent using social networking Web sites. Youth indicated their choice, interest, and preferences in using a Web site for youth with JA. The t tests, chi-squared tests, and Fisher exact tests were used to assess significance between high and low PS-QL groups. RESULTS: Youth with lower PS-QL reported greater intrusiveness of their condition across life's activities than did youth with higher PS-QL. Low PS-QL was associated with spending more than 1 hour per day using social networking sites and having used the Internet to find information on various health and substance use topics. Youth with lower PS-QL expressed more interest in messaging others, online forums, building personal profiles, and networking with other teens than did youth with higher PS-QL. Both those with high and low PS-QL preferred online to in-person support groups. CONCLUSIONS: Many youth with JA report low PS-QL and identify interest in Internet-based supportive interventions. The next generation of eHealth interventions for youth with JA, and possibly other chronic conditions, may better address their needs by recognizing the diversity of experiences and tailoring intervention strategies accordingly. PMID- 26003584 TI - Effects of a workplace intervention on sleep in employees' children. AB - PURPOSE: The implications of sleep patterns for adolescent health are well established, but we know less about larger contextual influences on youth sleep. We focused on parents' workplace experiences as extrafamilial forces that may affect youth sleep. METHODS: In a group-randomized trial focused on employee work groups in the information technology division of a Fortune 500 company, we tested whether a workplace intervention improved sleep latency, duration, night-to-night variability in duration, and quality of sleep of employees' offspring, aged 9-17 years. The intervention was aimed at promoting employees' schedule control and supervisor support for personal and family life to decrease employees' work family conflict and thereby promote the health of employees, their families, and the work organization. Analyses focused on 93 parent-adolescent dyads (57 dyads in the intervention and 46 in the comparison group) that completed baseline and 12-month follow-up home interviews and a series of telephone diary interviews that were conducted on eight consecutive evenings at each wave. RESULTS: Intent to-treat analyses of the diary interview data revealed main effects of the intervention on youth's sleep latency, night-to-night variability in sleep duration, and sleep quality, but not sleep duration. CONCLUSIONS: The intervention focused on parents' work conditions, not on their parenting or parent-child relationships, attesting to the role of larger contextual influences on youth sleep and the importance of parents' work experiences in the health of their children. PMID- 26003585 TI - Incapacitated and forcible rape of college women: prevalence across the first year. AB - PURPOSE: The purpose of this study was to document the point and cumulative prevalence of incapacitated rape (IR) and forcible rape (FR) among first-year college women. METHODS: Female students (N = 483) completed a health questionnaire (1) on arrival on campus; (2) at the end of the fall semester; (3) at the end of the spring semester; and (4) at the end of the summer following their first year of college. RESULTS: Before entering college, 18% reported IR (attempted and/or completed), and 15% reported FR (attempted and/or completed). During the first year of college, 15% reported IR (attempted or completed) and 9% reported FR (attempted or completed). By the start of the second year (lifetime prevalence), 26% and 22% had experienced IR and FR (attempted or completed), respectively. CONCLUSIONS: Both incapacitated and forcible sexual assaults and rape have reached epidemic levels among college women. Interventions to address sexual violence on campus are urgently needed. PMID- 26003586 TI - The important role of nursing in primary care exploring knowledge about human immunodeficiency virus and other sexually transmitted diseases in adolescents. PMID- 26003587 TI - Infrared Thermal Analysis and Individual Differences in Skin Temperature Asymmetry in Rett Syndrome. AB - PURPOSE: We evaluated the feasibility of using a portable infrared thermal camera to quantify the degree of thermal dysregulation (cold hands/feet) and test for naturally occurring within-patient skin temperature asymmetry in Rett syndrome. PROCEDURES: Infrared thermal images were acquired passively from 15 patients (mean age = 13.7 years, range 4-47) with clinical diagnoses of Rett. Images were acquired using a FLIR T400 infrared thermal camera (still images recorded at 5 Hz, resolution of 320 * 240 pixels, thermal sensitivity = 0.05 degrees C; capture session lasted approximately 3 minutes). The infrared thermal camera was orthogonal to the body part (hands, feet) and positioned approximately 1 meter from the skin's surface. RESULTS: There were large intraindividual left/right differences in temperature. Seven (47%) and eight (53%) patients had statistically significant (P <0.05) left/right asymmetries between hands (mean difference = 0.87 degrees C, standard deviation = 1.21) and feet (mean difference = 1.73 degrees C, standard deviation = 3.03), respectively. Coders were reliable (intraclass correlations 0.97-0.99) on temperatures and selection of anatomical regions of interest. CONCLUSIONS: The degree of thermal asymmetry may reflect prolonged activity of the sympathetic nervous system and individual differences in sympathetic regulation. As clinical trials emerge and endpoints are considered, portable infrared thermal camera may provide one noninvasive means of evaluating changes in sympathetic regulation. PMID- 26003588 TI - The Effect of Faster Reporting Speed for Imaging Studies on the Number of Misses and Interpretation Errors: A Pilot Study. AB - PURPOSE: The purpose of the study was to determine if increasing radiologist reading speed results in more misses and interpretation errors. METHODS: We selected a sample set of 53 abdomen-pelvis CT scans of variable complexity performed at a teaching hospital during the study period. We classified the CT scans into 4 categories based on their level of difficulty, with level 4 representing the most-complex cases. Five attending radiologists participated in the study. We initially established an average baseline reporting time for each radiologist. Radiologists were randomly assigned a set of 12 studies, of varying complexity, to dictate at their normal speed, and a separate set of 12 studies, of similar complexity, to read at a speed that was twice as fast as their normal speed. The major and minor misses were recorded and analyzed. A chi(2) analysis was used to compare the results. RESULTS: Reading at the faster speed resulted in more major misses for 4 of the 5 radiologists. The total number of major misses for the 5 radiologists, when they reported at the faster speed, was 16 of 60 reported cases, versus 6 of 60 reported cases at normal speed; P = .032. The average interpretation error rate of major misses among the 5 radiologists reporting at the faster speed was 26.6%, compared with 10% at normal speed. CONCLUSIONS: Our pilot study found a significant positive correlation between faster reading speed and the number of major misses and interpretation errors. PMID- 26003589 TI - CT Radiation Dose Optimization and Tracking Program at a Large Quaternary-Care Health Care System. AB - PURPOSE: The authors report the implementation and outcomes of a CT radiation dose optimization and tracking program at a large quaternary-care health care system. METHODS: A committee reviewed, optimized, and released standardized imaging protocols for the most common CT examinations across the health system. Volume CT dose index and dose-length product (DLP) diagnostic reference levels (DRLs) were established, with the goal of decreasing the percentage of outliers (CT scans with DLPs greater than the established DRLs) to <5% of tracked CT examinations. Baseline radiation dose data were manually extracted for 5% of total examinations. A semiautomated process to analyze all DLP data was then implemented to monitor outliers. RESULTS: The baseline percentage of outliers was slightly higher than 10% for pediatric scans but nearly 26.5% for adult scans. Over the first year, after standardized protocols were distributed, the percentage of outliers decreased for pediatric brain (from 22% to 6%), adult brain (from 23% to 3%), and adult chest (from 22% to 11%) examinations. Over the next 2 years, after the dose-tracking program was implemented, the percentage of outliers decreased for adult (brain, from 3% to 1%; chest, from 11% to 1%; abdomen, from 24% to 1%) and pediatric (brain, from 6% to 2%; chest, from 11% to 0%; abdomen, from 7% to 1%) examinations. CONCLUSIONS: The reported CT protocol optimization and dose-tracking program enabled a sustainable reduction in the proportion of CT examinations being performed above established DRLs from as high as 26% to <1% over a period of 2 years. PMID- 26003590 TI - Workplace-based assessment: a review of user perceptions and strategies to address the identified shortcomings. AB - Workplace based assessments (WBAs) are now commonplace in postgraduate medical training. User acceptability and engagement is essential to the success of any medical education innovation. To this end, possessing an insight into trainee and trainer perceptions towards WBAs will help identify the major problems, permitting strategies to be introduced to improve WBA implementation. A review of literature was performed to identify studies examining trainee and trainer perceptions towards WBAs. Studies were excluded if non-English or sampling a non medical/dental population. The identified literature was synthesised for the purpose of this critical narrative review. It is clear that there is widespread negativity towards WBAs in the workplace. This has negatively impacted on the effectiveness of WBA tools as learning aids. This negativity exists in trainees but also to an extent in their trainers. Insight gained from the literature reveals three dominant problems with WBA implementation: poor understanding as to the purpose of WBAs; insufficient time available for undertaking these assessments; and inadequate training of trainers. Approaches to addressing these three problems with WBA implementation are discussed. It is likely that a variety of solutions will be required. The prevalence of negativity towards WBAs is substantial in both trainees and trainers, eroding the effectiveness of learning that is consequent upon them. The educational community must now listen to the concerns being raised by the users and consider the range of strategies being proposed to improve the experiences of trainees, and their trainers. PMID- 26003592 TI - A perspective on toxicology of Conus venom peptides. AB - The evolutionarily unique and ecologically diverse family Conidae presents fundamental opportunities for marine pharmacology research and drug discovery. The focus of this investigation is to summarize the worldwide distribution of Conus and their species diversity with special reference to the Indian coast. In addition, this study will contribute to understanding the structural properties of conotoxin and therapeutic application of Conus venom peptides. Cone snails can inject a mix of various conotoxins and these venoms are their major weapon for prey capture, and may also have other biological purposes, and some of these conotoxins fatal to humans. Conus venoms contain a remarkable diversity of pharmacologically active small peptides; their targets are an iron channel and receptors in the neuromuscular system. Interspecific divergence is pronounced in venom peptide genes, which is generally attributed to their species specific biotic interactions. There is a notable interspecific divergence observed in venom peptide genes, which can be justified as of biotic interactions that stipulate species peculiar habitat and ecology of cone snails. There are several conopeptides used in clinical trials and one peptide (Ziconotide) has received FDA approval for treatment of pain. This perspective provides a comprehensive overview of the distribution of cone shells and focus on the molecular approach in documenting their taxonomy and diversity with special reference to geographic distribution of Indian cone snails, structure and properties of conopeptide and their pharmacological targets and future directions. PMID- 26003591 TI - Modified surgical techniques for total alloplastic temporomandibular joint replacement: One institution's experience. AB - OBJECTIVE: To present three modified techniques of total alloplastic temporomandibular joint replacement (TMJ TJR) and to evaluate the outcomes regarding prosthesis stability and heterotopic bone formation. MATERIAL AND METHODS: A total of 15 patients (19 joints), treated with the Biomet stock prosthesis from May 2006 to May 2013, were retrospectively analyzed. Surgical procedures were performed with the following three modifications: bone grafting of the glenoid fossa; salvage of TMJ discs; and harvesting of retro-mandibular subcutaneous fats. The glenoid fossa depth was measured preoperatively by Surgicase 5.0 software. All patients were evaluated by radiographic examination and surgical observation. RESULTS: The fossa was grafted with an autogenous bone in 15 joints (78.9%). In 4 joints (21.1%), only bone repair was performed. Radiographic evaluation revealed a good integration between the autogenous and host bones. All patients showed postoperative occlusal stability. In 5 joints (26.3%), the discs were salvaged. Both bleeding and operation time were reduced. Fat grafts were harvested in 17 joints (89.5%), in which there were no abnormalities in the periprosthetic bone structure. In 2 joints (10.5%), with no fat grafting, heterotopic bone formation was found. CONCLUSIONS: The modified techniques of TJR help to improve prostheses stability, reducing heterotopic bone formation and avoiding additional scars. PMID- 26003593 TI - Anti-chikungunya activity of luteolin and apigenin rich fraction from Cynodon dactylon. AB - OBJECTIVE: To obtain luteolin and apigenin rich fraction from the ethanolic extract of Cynodon dactylon (L.) (C. dactylon) Pers and evaluate the fraction's cytotoxicity and anti-Chikungunya potential using Vero cells. METHODS: The ethanolic extract of C. dactylon was subjected to silica gel column chromatography to obtain anti-chikungunya virus (CHIKV) fraction. Reverse phase HPLC and GC-MS studies were carried out to identify the major phytochemicals in the fraction using phytochemical standards. Cytotoxicity and the potential of the fraction against CHIKV were evaluated in vitro using Vero cells. Reduction in viral replication was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) after treating the viral infected Vero cells with the fraction. RESULTS: Reverse Phase-HPLC and GC-MS studies confirmed the presence of flavonoids, luteolin and apigenin as major phytochemicals in the anti-CHIKV ethanolic fraction of C. dactylon. The fraction was found to exhibit potent viral inhibitory activity (about 98%) at the concentration of 50 ug/mL as observed by reduction in cytopathic effect, and the cytotoxic concentration of the fraction was found to be 250 ug/mL. RT-PCR analyses indicated that the reduction in viral mRNA synthesis in fraction treated infected cells was much higher than the viral infected control cells. CONCLUSIONS: Luteolin and apigenin rich ethanolic fraction from C. dactylon can be utilized as a potential therapeutic agent against CHIKV infection as the fraction does not show cytotoxicity while inhibiting the virus. PMID- 26003594 TI - Hypolipidemic, antioxidant and anti-atherosclerogenic effects of aqueous extract of Zanthoxylum heitzii stem bark in diet-induced hypercholesterolemic rats. AB - OBJECTIVE: To evaluate anti-dyslipidemic, antioxidant and anti-atherosclerogenic properties of this extract in diet-induced hypercholesterolemic rat, a model of metabolic syndrome-induced atherosclerosis and associated cardiovascular diseases. METHODS: Normocholesterolemic (NC) male rats were divided into six groups (n=10) and fed a high-cholesterol (HC) diet for 30 days (5 groups), or normal rat chow (normal control group). Rats given a HC diet also received distilled water (disease control), the potent hypocholesterolemic agent with anti atherosclerotic activity atorvastatin (2 mg/kg, positive control), or one of the three doses of Zanthoxylum heitzii stem bark aqueous extract tested (225, 300 and 375 mg/kg) concomitantly for four months. Signs of general toxicity, body temperature and weight, and water and food intake were monitored in live animals. After sacrifice, lipid profiles and oxidative stress markers were assessed in the blood and liver, aorta, and feces, and histopathological analysis of aorta was performed. RESULTS: Plant extract prevented the elevation of aortic total cholesterol and triglycerides, and hepatic low density lipoprotein, very low density lipoprotein, and total cholesterol. Lipid peroxidation (TBARS) was decreased and aortic atherosclerotic plaque formation prevented. CONCLUSIONS: These observations strongly suggest that stem bark aqueous extract of Zanthoxylum heitzii has anti-atherosclerogenic properties, at least partly mediated by antioxidant and hypolipidemic effects. PMID- 26003595 TI - Challenging loop-mediated isothermal amplification (LAMP) technique for molecular detection of Toxoplasma gondii. AB - OBJECTIVE: To compare analytical sensitivity and specificity of a newly described DNA amplification technique, LAMP and nested PCR assay targeting the RE and B1 genes for the detection of Toxoplasma gondii (T. gondii) DNA. METHODS: The analytical sensitivity of LAMP and nested-PCR was obtained against10-fold serial dilutions of T. gondii DNA ranging from 1 ng to 0.01 fg. DNA samples of other parasites and human chromosomal DNA were used to determine the specificity of molecular assays. RESULTS: After testing LAMP and nested-PCR in duplicate, the detection limit of RE-LAMP, B1-LAMP, RE-nested PCR and B1-nested PCR assays was one fg, 100 fg, 1 pg and 10 pg of T. gondii DNA respectively. All the LAMP assays and nested PCRs were 100% specific. The RE-LAMP assay revealed the most sensitivity for the detection of T. gondii DNA. CONCLUSIONS: The obtained results demonstrate that the LAMP technique has a greater sensitivity for detection of T. gondii. Furthermore, these findings indicate that primers based on the RE are more suitable than those based on the B1 gene. However, the B1-LAMP assay has potential as a diagnostic tool for detection of T. gondii. PMID- 26003596 TI - Evidence of increasing risk of schistosomiasis among school-age children in municipality of Calatrava, Province of Negros Occidental, Philippines. AB - OBJECTIVE: To explore risk of school-age children being infected with schistosomiasis in selected villages in the municipality of Calatrava, province of Negros Occidental, Philippines. METHODS: As part of the monitoring and evaluation of the helminth control program in the province of Negros Occidental, parasitological monitoring, through the use microscopy of stool samples processed using Kato-Katz technique, was conducted to describe the baseline and follow-up parasitological status of school-age children in 2010 and 2012, respectively. Seven villages from the municipality of Calatrava were selected as study sites. RESULTS: During baseline assessment, only one case of schistosomiasis was reported from the village of Marcelo. During follow-up assessment, 32 cases (6.9%) of schistosomiasis were reported and the prevalence of moderate-heavy intensity infection was 1.3% in six villages. Among the seven villages included in the follow-up, Minapasuk had the highest prevalence at 14.6%, while San Isidro reported no case of schistosomiasis. CONCLUSIONS: Non-endemic villages, which have reported positive cases in school-age children, may need to be assessed for possible endemicity for schistosomiasis. Transmission of the disease may need to be determined in these villages through active parasitological and malacological surveillance. Other non-endemic villages adjacent to or share river networks with endemic villages in Calatrava may need to be explored for possible introduction of the disease, especially after typhoons and flooding. Establishing endemicity for schistosomiasis in these villages will help infected and at risk individuals to receive yearly treatment to reduce morbidities caused by this disease. PMID- 26003597 TI - Role of epidermal growth factor in pathogenesis of uterine leiomyomas. AB - OBJECTIVE: To investigate the role of epidermal growth factor (EGF) in the pathogenesis of uterine leiomyomas. METHODS: Human myometrial smooth muscle cells (HM-SMCs) and smooth muscle cells of human uterine leiomyomas (HL-SMCs) were separated from patients' specimens and cultured. After processed by EGF or PD98059 (inhibitor of MKK/MEK) +EGF, the proliferation rate of both SMCs was detected by BrdU method and the phosphorylation level of p44/42 mitogen-activated protein kinase (MAPK) was determined by Western-blot. After different processing time by EGF, the phosphorylation levels of p44/42 MAPK and AKT and p27 expression level in both SMCs were detected by Western-blot. RESULTS: EGF could significantly promote HL-SMCs proliferation and PD98059 could inhibit this effect (P<0.05); besides, PD98059 could inhibit the increase of the phosphorylation level of p44/42 MAPK in both SMCs induced by EGF. When the processing time by EGF was over 15min, the phosphorylation levels of p44/42 MAPK and AKT in both SMCs decreased sharply and were close to zero; p27 expression in HM-SMCs raised significantly while the upregulation in HL-SMCs was little. CONCLUSIONS: EGF could not cause activation of EGFR because of the dephosphorylation of p44/42 MAPK and AKT in HL-SMCs, which caused p27 expression insufficiently and cell cycle dysregulation. PMID- 26003598 TI - Causes of immune dysfunction in hyperbilirubinemia model rats. AB - OBJECTIVE: To explore the causes of immune dysfunction in neonatal rats with hyperbilirubinemia. METHODS: A total of 60 newborn SD rats were equally randomized into normal saline (NS) group, LPS control group, bilirubin control group, low-dose group and high-dose group. After anesthesia, 0.1 mL NS was given to the NS and LPS control group and different doses of bilirubin for the other groups; 1 h later, the NS and bilirubin control group received the intraperitoneal injection of 0.05 mL NS and 1mg/kg LPS for the other groups. After 5 or 24 hours of model establishment, spleens were collected for detecting the expression levels of MyD88 and p-TAK1 protein and the spleen cells apoptosis by immunohistochemmistry and TUNEL method. After 24 hours of model establishment, serum inflammatory factors levels and T cell subsets distribution were determined by ELISA and flow cytometry. RESULTS: In contrast to low-dose bilirubin, high dose bilirubin could induce spleen cells apoptosis in coordination with LPS. After 5 hours of model establishment, compared with NS group, MyD88 expression level in low-dose group elevated while p-TAK1 level in high-dose group reduced (P<0.05). In high-dose group, inflammotory factors levels and CD8(+) T cells percentage were all higher than LPS control and NS group (P<0.05), while CD4(+) T cells percentage was lower than NS group (P<0.05). CONCLUSIONS: High concentration plasma bilirubin in coordination with LPS could inhibit NF-kappaB signal pathways activation and aggravate inflammatory reaction, thus caused immunosuppression with inflammation cascade, which resulted in the immune dysfunction. PMID- 26003599 TI - Correlation between expression of 1 alpha -hydroxylase and hypocalcaemia in rats with severe pancreatitis. AB - OBJECTIVE: To investigate the essential biochemical indices like 1 -hydroxylase and hypocalcaemia in the rats with severe acute pancreatitis and explore the correlation between them. METHODS: A total of 120 SPF grade Wistar male rats which were in similar physiological status were selected and randomly divided into two groups: sham group (SO group) and severe acute pancreatitis group (SAP group). Then they were divided into 1 h, 3 h, 6 h, and 12 h subgroups according to the killing time. The severe acute pancreatitis model was established by retrograde injection of 5% sodium taurocholate. Serum calcium, serum creatinine, serum urea nitrogen and serum amylase were measured at different time. Serum 1, 25 dihydroxy vitamin D3 level was determined by enzyme linked immunosorbentassay. The expression of 1-hydroxylase protein in the kidney tissue was determined with Western blotting and immunohistochemistry to observe its location. The pathologic features of the kidney tissue section was observed under light microscope and submicroscopic structure of the proximal convoluted tubule epithelial cell was observed under transmission electron microscope. RESULTS: Compared with the SO group, rats in the SAP group showed continuous pathological injury as time went by. There was significant increase in serum creatinine, serum urea nitrogen and serum amylase in SAP group compared with the SO group 1, 3, 6, 12 hours after the operation (P<0.05). There was significant decrease in serum calcium and 1, 25 dihydroxy vitamin D3 3, 6, 12 hours after the operation (P<0.05). It also showed that the expression of the 1-hydroxylase protein in kidney tissues was upregulated at 1 h, 3 h and decreased at 6 h, 12 h compared with the SO group. The serum calcium, 1, 25 dihydroxy vitamin D3 and the expression of the 1 hydroxylase protein in kidney tissues of the SAP group showed sustaining decrease. Western blotting showed positive correlation between the 1-hydroxylase expression and serum calcium at 3 h, 6 h and 12 h (r=0.976, P<0.001; r=0.948, P<0.001; r=0.742, P=0.001) and also positive correlation between the 1 hydroxylase expression and serum 1, 25 dihydroxy vitamin D3 at 1 h, 3 h, 6 h and 12 h (r=0.935, P<0.001; r=0.952, P<0.001; r=0.917, P<0.001; r=0.874, P<0.001). CONCLUSIONS: At the early stage of the kidney injury, the expression of 1 hydroxylase in the kidney tissue is reduced with the progress of the disease and the decrease in its activity has a correlation with the hypocalcaemia. PMID- 26003600 TI - Effects and mechanism of miR-214 on hepatocellular carcinoma. AB - OBJECTIVE: To explore the role of miR-214 in the progression of hepatocellular carcinoma (HCC) and its inhibitory mechanisms in depressing the signaling pathway of beta-catenin, this study was conducted. METHODS: We ectopically expressed miR 214 in HepG2 cells to obtain cell lines Lv-miR-214-HepG2 and their control Lv control-HepG2. Differences between the two cell lines were compared in cell growth, proliferation, colony forming ability and cell cycles. RT-PCR method was applied for the quantification of beta-catenin mRNA expression. Western-blot method was applied for the determination of the protein level of beta-catenin and their downstream targets (ie. Cyclin D1, c-Myc and TCF-1). The effect of miR-214 on cells was further explored through RNA interference and restoring miR-214 expression. RESULTS: In comparison with negative (Lv-control-HepG2) and blank (HepG2) control, a significant inhibition of cell growth and proliferation caused by miR-214 was observed after 48~72h of cell culture experiments (P<0.05). The miR-214 treatment resulted in a colony forming efficiency of (23.28+/-3.26)%, which was significantly lower than that of negative control [(51.31+/-3.97)%] (P<0.05). According to FCM results, the experimental group, compared with control, showed a higher proportion of cells in G0/G1 phase [(70.32+/-3.12)%] but a lower proportion in S phase [(18.42+/-2.90)%] (P<0.05). The MTT assay demonstrated a significant inhibition of the proliferation and beta-catenin expression of HCC cells compared with control (P<0.05), while no significant difference was observed after HCC cells being transfected with beta-catenin overexpression plasmid (P>0.05). By comparing to the RT-PCR and Western-blot results of control, the miR-214 treatment led to a slightly decrease in the beta catenin mRNA expression (P>0.05), but an extremely inhibition in the protein level of beta-catenin and its downstream targets Cyclin D1, c-Myc, and TCF-1 (P<0.05). CONCLUSIONS: miR-214 functions as a suppressor during the progression of HCC, and its inhibitory role was achieved by down-regulating beta-catenin signaling pathway. PMID- 26003601 TI - Mechanism of Profilin-1 in regulating eNOS/NO signaling pathway and its role in hypertensive myocardial hypertension. AB - OBJECTIVE: To explore the mechanism of Profilin-1 in regulating eNOS/NO pathway and its role in the development of myocardial hypertrophy. METHODS: Spontaneously hypertensive rats (SHR) aged 5 weeks were injected with different adenovirus vectors to induce Profilin-1 expression knockdown (SHR-I) or over express (SHR-H) or to use as control (SHR-C). All these treatment were compared with Wistar-Kyoto rats (SKY) treated with control adenovirus vectors (WKY-C). The same injection was executed at the sixth week during the experiment of 12 weeks. After experiment, the left ventricular weight-to-heart weight ratio (LVW/HW) and left ventricular long axis (LVLA) were measured. Meanwhile, NO contents in blood and myocardium, Profilin-1, eNOS and Caveolin-3 mRNA and protein levels and phosphorylated eNOS (P-eNOS) protein level in myocardium were determined. RESULTS: Compared with WKY-C group, the SHR-C group was statistically higher in LVW/HW (0.79+/-0.03), LVLA (11.82+/-0.58 mm) and Profilin-1 mRNA and protein level (P<0.05), but lower in NO content [(18.63+/-6.23) MUmol/L] in blood and [(2.71+/-0.17) MUmol/L] in myocardium), eNOS activity and Caveolin-3 expression (P<0.05). The over expressing Profilin-1 led SHR-H group to a higher value of LVW/HW [(0.93+/-0.03) mm and LVLA (14.17+/-0.69) mm] in comparison with SHR-C group (P<0.05), and to a lower value of NO content (in myocardium), eNOS activity and Caveolin-3 expression (P<0.05); however, this phenomenon was reversed by the knockdown Profilin-1 expression (SHR-I group). CONCLUSIONS: Profilin-1 expression, being negative in regulating Caveolin-3 expression and eNOS/NO pathway activity, promotes the development of myocardial hypertrophy which can be reversed by Profilin-1 silencing. PMID- 26003602 TI - Effect of down-regulation of voltage-gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain. AB - OBJECTIVE: To evaluate the effect of down-regulation of Nav1.7 on the activation of astrocytes and microglia in DRG of rats with cancer pain, and explore the transmission of the nociceptive information. METHODS: Lentiviral vector harboring RNAi sequence targeting the Nav1.7 gene was constructed, and Walker 256 breast cancer cell and morphine was injected to build the bone cancer pain model and morphine tolerance model in rats. Lentiviral vector was injected. Rats in each model were divided into 4 groups: model group, PBS group, vehicle group and LV Nav1.7 group. The expression levels of GFAP and OX42 in dorsal root ganglia (DRG) were measured. RESULTS: After the animal model was built, the level of Nav1.7, GFAP and OX42 was improved obviously with the time prolonged, which was statistically significant (P<0.05). The expression level of GFAP and OX42 in the DRG in the LV-Nav1.7 group declined obviously compared to the model group, PBS group and vehicle group (P<0.05). CONCLUSIONS: Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7 and inhibit the activation of astrocytes and microglia in DRG. The effort is also effective in morphine tolerance bone cancer pain model rats. PMID- 26003603 TI - BMP-4 induced proliferation and oriented differentiation of rat hepatic oval cells into hepatocytes. AB - OBJECTIVE: To explore the role of bone morphogenetic protein 4 (BMP-4) in hepatic progenitor cells (HPCs). METHODS: The effect of BMP-4 on rat hepatic oval cells was examined by using the WB-F344 rat hepatocytic epithelial stem-cell-like cell line. This hepatocytic cell line could exert various hepatocyte functions including the secretion of albumin and urea. Immunohistochemistry was used to examine the effects of BMP-4 and its antagonist, Noggin, on the proliferation and differentiation of these cells, cellular uptake and excretion of indocyanine green, the periodic acid-schiff (PAS) assay for glycogen storage and the expression of hepatic markers. RESULTS: Our results showed for the first time that BMP-4 may acted as a potential inducer of hepatic differentiation in rat hepatic oval cells. CONCLUSIONS: This cell source offers a much-needed attractive and expandable source for future investigations of drug screening, stem cell technologies and cellular transplantation, in a society with increasing levels of liver disease and damage. PMID- 26003604 TI - HS-4, a highly potent inhibitor of cell proliferation of human cancer cell. AB - OBJECTIVE: To investigate the antitumor activity of the compound HS-4 and the action mechanism. METHODS: MTT method was used to test in vitro antitumor activity of the compound HS-4. Orthotopic xenotransplantation tumor model of liver cancer was established in nude mice, and, in vivo antitumor activity of compound HS-4 was tested with a small animal in-vivo imaging system. Sequencing of small RNA library and RNA library was performed in HS-4 treated tumor cell group and control group to investigate the anti-cancer mechanism of HS-4 at level of functional genomics, using high-throughput sequencing technology. RESULTS: HS 4 was found to have relatively high in-vitro antitumor activity against liver cancer cells, gastric cancer cells, renal cancer cells, lung cancer cells, breast cancer cells and colon cancer cells. The IC50 values against SMMC-7721 and Bel 7402 of liver cancer cells were 0.14 and 0.13 nmol/L respectively, while the IC50 values against MGC-803 and SGC-7901 of gastric cancer cells were 0.19 and 0.21 nmol/L, respectively. It was demonstrated that HS-4 possessed a better therapeutic effect in liver cancer. CONCLUSIONS: A new reliable orthotopic xenotransplantation tumor model of liver cancer in nude mice is established. The new compounds HS-4 was found to possess relatively high in vivo and in vitro antitumor activity against liver cancer cells. PMID- 26003605 TI - High-throughput assessment of bacterial ecology in hog, cow and ovine casings used in sausages production. AB - Natural casings derived from different intestine portions have been used for centuries in the production of fresh and dry-fermented sausages. Here we analysed by means of culture-dependent methods and Illumina high-throughput sequencing of 16S rRNA amplicons the bacterial ecology of hog, cow and ovine casings at different stages of their preparation for sausages production. Several strains of Staphylococcus, Lactobacillus, Bifidobacterium, Vagococcus and Clostridium were counted, isolated and characterised at phylogenetic level. High-throughput sequencing analyses revealed a high bacterial diversity, which differed strongly between casings of different animal species. The technological processes involved in the preparation for casing had also a strong impact on the casings bacterial ecology, with a significant reduction of undesired microorganisms, and an increase in the proportion of lactobacilli and staphylococci. Natural casings were demonstrated to be complex ecological environments, whose role as microbiological inoculants in the production of sausages should not be underestimated. PMID- 26003606 TI - [North-South cooperation on transfusion and hematology teaching: A Benin experience]. AB - Hematologic diseases are a significant part of health disorders in Benin. As an example, anemia is the second cause of hospitalization, measuring up to 7.9% all over the country (National Plan of Sanitary Development, 2009-2018). By contrast, there is only one active hematologist in the country. Thanks to two partnerships, on one hand between the health sciences faculty in Cotonou (Benin) and the medicine one in Tours (France), and on the other hand between the Beninese Blood Transfusion National Agency and the French Blood Establishment, a first blood transfusion and hematology formation was held in Cotonou on December 2014. Among other benefits, was created an hematology-transfusion network in order to facilitate relations between Beninese hospital doctors, with the support of the two French partner institutions. The article describes this progress. PMID- 26003607 TI - Acute Response to Tolvaptan in ADPKD: A Window to Predict Long-term Efficacy? PMID- 26003608 TI - Evaluating the Merits of CKD Patient Educational Materials: Readability Is Necessary But Not Sufficient. PMID- 26003609 TI - Dialysate fluid endotoxin: assaying claims to cleanliness. PMID- 26003610 TI - Decreasing Exposure to Hemodialysis Catheters in ESRD--More Work to Be Done. PMID- 26003611 TI - Renal Handling of beta-Trace Protein: Interpreting the Evidence. PMID- 26003612 TI - In Reply to 'Renal Handling of beta-Trace Protein: Interpreting the Evidence'. PMID- 26003613 TI - Quiz page June 2015: a young woman with hypertension. PMID- 26003614 TI - The influence of slope and peatland vegetation type on riverine dissolved organic carbon and water colour at different scales. AB - Peatlands are important sources of fluvial carbon. Previous research has shown that riverine dissolved organic carbon (DOC) concentrations are largely controlled by soil type. However, there has been little work to establish the controls of riverine DOC within blanket peatlands that have not undergone major disturbance from drainage or burning. A total of 119 peatland catchments were sampled for riverine DOC and water colour across three drainage basins during six repeated sampling campaigns. The topographic characteristics of each catchment were determined from digital elevation models. The dominant vegetation cover was mapped using 0.5m resolution colour infrared aerial images, with ground-truthed validation revealing 82% accuracy. Forward and backward stepwise regression modelling showed that mean slope was a strong (and negative) determinant of DOC and water colour in blanket peatland river waters. There was a weak role for plant functional type in determining DOC and water colour. At the basin scale, there were major differences between the models depending on the basin. The dominance of topographic predictors of DOC found in our study, combined with a weaker role of vegetation type, paves the way for developing improved planning tools for water companies operating in peatland catchments. Using topographic data and aerial imagery it will be possible to predict which tributaries will typically yield lower DOC concentrations and which are therefore more suitable and cost-effective as raw water intakes. PMID- 26003615 TI - Current research on experimental and applied animal sciences. PMID- 26003617 TI - Denosumab for the prevention of skeletal complications in metastatic castration resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events. PMID- 26003616 TI - Does interim PET increase the value of ABVD in advanced-stage Hodgkin lymphoma? PMID- 26003618 TI - This, that, or something different? AB - A 72-year-old man presented after a single choroidal mass was incidentally detected on fundus examination of his right eye. The patient has a history of multiple myeloma and neuroendocrine thymoma diagnosed 6 and 10 years before presentation, respectively. Fine-needle aspiration biopsy revealed metastatic choroidal carcinoid tumor. The patient was subsequently treated with brachytherapy (iodine-125). PMID- 26003619 TI - Malignant lymphoma of the conjunctiva. AB - Conjunctival lymphomas constitute 25% of all ocular adnexal lymphomas. The majority are B-cell non-Hodgkin lymphomas (NHLs) (98%), whereas conjunctival T cell NHLs are rare (2%). The most frequent subtype of conjunctival B-cell lymphoma is extranodal marginal zone lymphoma (EMZL; 81%), followed by follicular lymphoma (8%), diffuse large B-cell lymphoma (3%), and mantle cell lymphoma (3%). Extranodal marginal zone lymphoma occurs slightly more often in women and, along with follicular lymphoma, presents late in the seventh decade of life, whereas diffuse large B-cell lymphoma and especially mantle cell lymphoma have a predilection for the male gender and typically present in the eighth decade. Extranodal marginal zone lymphoma and follicular lymphoma present most frequently in the forniceal and bulbar conjunctiva. Conjunctival diffuse large B-cell lymphoma, mantle cell lymphoma and T-cell NHLs are characterized by a short duration of symptoms before the first ophthalmologic consultation. External beam radiotherapy is the treatment of choice for extranodal marginal zone lymphoma and follicular lymphoma, whereas diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell NHLs are mainly treated with chemotherapy. Conjunctival T-cell NHLs are associated with a particularly poor prognosis, with 50% of patients having progression or recurrence during a 1-year follow-up period. PMID- 26003620 TI - A microdestructive capillary electrophoresis method for the analysis of blue-pen ink strokes on office paper. AB - This manuscript describes the development of a capillary electrophoresis (CE) method for the detection of acid and basic dyes and its application to real samples, blue-pen-ink strokes on office paper. First, a capillary zone electrophoresis (CZE) method was developed for the separation of basic and acid dyes, by studying the separation medium (buffer nature, pH and relative amount of additive) and instrumental parameters (temperature, voltage and capillary dimensions). The method performance was evaluated in terms of selectivity, resolution (above 5 and 2 for acid dyes and basic dyes, respectively, except for two basic dye standards), LOD (lower than 0.4 mg/L) and precision as intraday and interday RSD values of peak migration times (lower than 0.6%). The developed method was then applied to 34 blue pens from different technologies (rollerball, ballpoint, markers) and with different ink composition (gel, water-based, oil based). A microdestructive sample treatment using a scalpel to scratch 0.3mg of ink stroke was performed. The entire electropherogram profile allowed the visual discrimination between different types of ink and brands, being not necessary a statistical treatment. A 100% of discrimination was achieved between pen technologies, brands, and models, although non-reproducible zones in the electropherograms were found for blue gel pen samples. The two different batches of blue oil-based pens were also differentiated. Thus, this method provides a simple, microdestructive, and rapid analysis of different blue pen technologies which may complement the current analysis of questioned documents performed by forensic laboratories. PMID- 26003621 TI - Temperature control in large-internal-diameter scaffolded monolithic columns operated at ultra-high pressures. AB - Scaffolding makes it feasible to create organic-polymer monoliths in large confinements, such as wide-bore columns. By creating the scaffold from a metal good heat conductivity inside the column is obtained, which renders the relatively large columns (comparable with 4.6 mm i.d.) suitable for application under ultra-high-pressure LC conditions. It was anticipated that the metal scaffold would allow accurate control of the temperature within the columns, but the temperature profiles within the columns could not be characterized using the previously available small-internal-diameter scaffolded columns. In the current study the internal diameter of the scaffolded columns was increased up to square conduits of 4*4 mm. Prior to the formation of the stationary phase the heating efficiency in the empty scaffolded conduits was addressed. The performance of stationary phases created in the large scaffolds was investigated using the kinetic performance approach and the results were compared to those of the previous studies. Finally, scaffolded columns were tested under ultra-high pressure LC conditions, where good temperature control is essential. PMID- 26003622 TI - Method transfer from high-pressure liquid chromatography to ultra-high-pressure liquid chromatography. II. Temperature and pressure effects. AB - The importance of the generated temperature and pressure gradients in ultra-high pressure liquid chromatography (UHPLC) are investigated and compared to high pressure liquid chromatography (HPLC). The drug Omeprazole, together with three other model compounds (with different chemical characteristics, namely uncharged, positively and negatively charged) were used. Calculations of the complete temperature profile in the column at UHPLC conditions showed, in our experiments, a temperature difference between the inlet and outlet of 16 degrees C and a difference of 2 degrees C between the column center and the wall. Through van't Hoff plots, this information was used to single out the decrease in retention factor (k) solely due to the temperature gradient. The uncharged solute was least affected by temperature with a decrease in k of about 5% while for charged solutes the effect was more pronounced, with k decreases up to 14%. A pressure increase of 500 bar gave roughly 5% increase in k for the uncharged solute, while omeprazole and the other two charged solutes gave about 25, 20 and 15% increases in k, respectively. The stochastic model of chromatography was applied to estimate the dependence of the average number of adsorption/desorption events (n) and the average time spent by a molecule in the stationary phase (taus) on temperature and pressure on peak shape for the tailing, basic solute. Increasing the temperature yielded an increase in n and decrease in taus which resulted in less skew at high temperatures. With increasing pressure, the stochastic modeling gave interesting results for the basic solute showing that the skew of the peak increased with pressure. The conclusion is that pressure effects are more pronounced for both retention and peak shape than the temperature effects for the polar or charged compounds in our study. PMID- 26003623 TI - ALCOHOL DEPENDENCE AND ANOREXIA NERVOSA: INDIVIDUAL AUTONOMY AND THE JURISDICTION OF THE COURT OF PROTECTION: An NHS Foundation Trust v Ms X [2014] EWCOP 35; (2014) 140 BMLR 41. PMID- 26003624 TI - A novel image-based quantitative method for the characterization of NETosis. AB - NETosis is a newly recognized mechanism of programmed neutrophil death. It is characterized by a stepwise progression of chromatin decondensation, membrane rupture, and release of bactericidal DNA-based structures called neutrophil extracellular traps (NETs). Conventional 'suicidal' NETosis has been described in pathogenic models of systemic autoimmune disorders. Recent in vivo studies suggest that a process of 'vital' NETosis also exists, in which chromatin is condensed and membrane integrity is preserved. Techniques to assess 'suicidal' or 'vital' NET formation in a specific, quantitative, rapid and semiautomated way have been lacking, hindering the characterization of this process. Here we have developed a new method to simultaneously assess both 'suicidal' and 'vital' NETosis, using high-speed multi-spectral imaging coupled to morphometric image analysis, to quantify spontaneous NET formation observed ex-vivo or stimulus induced NET formation triggered in vitro. The use of imaging flow cytometry allows automated, quantitative and rapid analysis of subcellular morphology and texture, and introduces the potential for further investigation using NETosis as a biomarker in pre-clinical and clinical studies. PMID- 26003625 TI - Decreased PBRM1 expression predicts unfavorable prognosis in patients with clear cell renal cell carcinoma. AB - AIMS: PBRM1 is one of the histone and chromatin regulators. A mutation in PBRM1 was recently identified in clear cell renal cell carcinoma (ccRCC). The aim of this study was to determine the clinicopathologic and prognostic significance of PBRM1 expression in ccRCC. METHODS AND RESULTS: Immunohistochemistry was performed for PBRM1 in 657 ccRCC cases. The number of positive cells was determined using image analyzer after virtual microscope scanning. There was a strong correlation between decreased PBRM1 expression and old age, increased tumor size, higher Fuhrman grade, higher pT stage, and higher stage (all P <0.001). Patients with decreased PBRM1 expression showed significantly worse cancer-specific survival (CSS) and progression-free survival (PFS) (both P<0.001). In multivariate analysis, PBRM1 expression was an independent predictor of shorter PFS (P = 0.007). In lower-stage group (stages I and II), decreased expression of PBRM1 exhibited significantly worse CSS and PFS (both P<0.001) but not in higher-stage group (stages III and IV). In multivariate analysis of lower stage group, decreased expression of PBRM1 was significantly associated with both poor CSS and PFS (P = 0.038 and 0.003, respectively). CONCLUSIONS: Decreased expression of PBRM1 predicts unfavorable clinical outcome in patients with ccRCC. PMID- 26003626 TI - Response to the Letter to the Editor regarding "Protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells". PMID- 26003627 TI - The occurrence of auditory dysfunction in children with TB receiving ototoxic medication at a TB hospital in South Africa. AB - OBJECTIVES: to describe the auditory dysfunction of children with tuberculosis receiving ototoxic medication at a residential TB hospital in the Cape Town metropolitan area. METHODS: A descriptive survey research design was adopted. The auditory status of participants was evaluated by otoscopy, immittance, audiometry or OAE and AABR (depending on the age). STUDY SAMPLE: 29 in-patients (7 months to 16.6 years). RESULTS: Fifty five percent of participants presented with middle ear abnormalities (n=16) and 48% (n=12) had sensorineural or mixed hearing loss. The degree of hearing loss ranged from mild to profound in 16% of the ears. The conventional pure-tone average of .5, 1, & 2 kHz did not allow for the determination of the degree of hearing loss in the remaining 18% which had high frequency hearing loss. CONCLUSIONS: The high occurrence of hearing loss necessitates the implementation of monitoring program for children receiving ototoxic medication. Consideration should be given to using the average of hearing thresholds at 4, 6 and 8 kHz to determine the classification of degree of hearing loss in cases of ototoxicity. PMID- 26003628 TI - Qualitative and Semiquantitative Analysis of Fecal Bifidobacterium Species in Centenarians Living in Bama, Guangxi, China. AB - Centenarians constitute a significant subpopulation in the Bama County of Guangxi province in China. The beneficial effects of intestinal microbiota, especially bifidobacteria of centenarians, have been widely accepted; however, knowledge about Bifidobacterium species in centenarians is not adequate. The aim of this study was to investigate the quantity and prevalence of fecal Bifidobacterium in healthy longevous individuals. Fecal samples from eight centenarians from Bama (aged 100 to 108 years), eight younger elderlies from Bama (aged 80 to 99 years), and eight younger elderlies from Nanning (aged 80 to 99 years) were analyzed using denaturing gradient gel electrophoresis, species-specific clone library, and quantitative polymerase chain reaction technology (qPCR). A total of eight different Bifidobacterium species were detected. B. dentium, B. longum, B. thermophilum, B. pseudocatenulatum/B. catenulatum, and B. adolescentis were common in fecal of centenarians and young elderly. B. minimum, B. saecularmay/B. pullorum/B. gallinarum, and B. mongoliense were found in centenarians but were absent in the younger elderlies. In addition, Bifidobacterium species found in centenarians were different from those found in Bama young elderly and Nanning young elderly, and the principal differences were the significant increase in the population of B. longum (P < 0.05) and B. dentium (P < 0.05) and the reduction in the frequency of B. adolescentis (P < 0.05), respectively. Centenarians tend to have more complex fecal Bifidobacterium species than young elderlies from different regions. PMID- 26003629 TI - Waterborne Leptospirosis: Survival and Preservation of the Virulence of Pathogenic Leptospira spp. in Fresh Water. AB - Many studies have implicated fresh water as a source of leptospirosis outbreaks. To estimate the survival and the preservation of the virulence of pathogenic Leptospira spp. maintained in water, we selected five still waters with various pH and mineral profiles. The water samples were artificially inoculated with a culture of a pathogenic strain belonging to serovar Icterohaemorrhagiae. Samples were stored for 20 months at 4, 20 or 30 degrees C. The survival and preservation of virulence of this pathogenic strain was estimated by subculturing these stored samples. After 14 and 20 months of storage, the strain Icterohaemorrhagiae was re-isolated, and its virulence was determined using an animal model. In these waters, the mean survival was 130 days for storage at 4 degrees C, 263 days at 20 degrees C, and 316 days at 30 degrees C. Unexpectedly, the mean survival was 344 days for a final pH < 7 and 129 days for pH >= 7. Moreover, the pathogenic strain remained fully virulent and was able to induce a lethal disease in gerbils even when the pH of the contaminated waters decreased to <6. These data showed that despite unfavourable storage conditions such as cold, nutrient-poor acidic waters, the survival and virulence of pathogenic Leptospira spp. was fully preserved over at least 20 months. PMID- 26003630 TI - Social evolution and genetic interactions in the short and long term. AB - The evolution of social traits remains one of the most fascinating and feisty topics in evolutionary biology even after half a century of theoretical research. W.D. Hamilton shaped much of the field initially with his 1964 papers that laid out the foundation for understanding the effect of genetic relatedness on the evolution of social behavior. Early theoretical investigations revealed two critical assumptions required for Hamilton's rule to hold in dynamical models: weak selection and additive genetic interactions. However, only recently have analytical approaches from population genetics and evolutionary game theory developed sufficiently so that social evolution can be studied under the joint action of selection, mutation, and genetic drift. We review how these approaches suggest two timescales for evolution under weak mutation: (i) a short-term timescale where evolution occurs between a finite set of alleles, and (ii) a long term timescale where a continuum of alleles are possible and populations evolve continuously from one monomorphic trait to another. We show how Hamilton's rule emerges from the short-term analysis under additivity and how non-additive genetic interactions can be accounted for more generally. This short-term approach reproduces, synthesizes, and generalizes many previous results including the one-third law from evolutionary game theory and risk dominance from economic game theory. Using the long-term approach, we illustrate how trait evolution can be described with a diffusion equation that is a stochastic analogue of the canonical equation of adaptive dynamics. Peaks in the stationary distribution of the diffusion capture classic notions of convergence stability from evolutionary game theory and generally depend on the additive genetic interactions inherent in Hamilton's rule. Surprisingly, the peaks of the long-term stationary distribution can predict the effects of simple kinds of non-additive interactions. Additionally, the peaks capture both weak and strong effects of social payoffs in a manner difficult to replicate with the short-term approach. Together, the results from the short and long-term approaches suggest both how Hamilton's insight may be robust in unexpected ways and how current analytical approaches can expand our understanding of social evolution far beyond Hamilton's original work. PMID- 26003633 TI - [Continuous renal replacement therapy and negative fluid balance improves renal function and prognosis of patients with acute kidney injury in sepsis]. AB - OBJECTIVE: To investigate the influence of fluid balance and model of renal replacement therapy (RRT) on renal function and prognosis of patients suffering from septic acute kidney injury (AKI). METHODS: A retrospective cohort analysis of 117 septic AKI patients who had undergone RRT between January 2009 and December 2014 was performed in the Second Affiliated Hospital of Nanjing Medical University. The patients were divided into positive fluid balance group (n = 52) and negative fluid balance group (n = 65) according to the total amount of fluid calculated from the difference between fluid administered and fluid lost during the first 1 week of RRT. The incidence of renal recovery and death of the patients by 60 days as the endpoint events were taken to judge the prognosis of two groups. RRT strategies included continuous renal replacement therapy (CRRT) and intermittent renal replacement therapy (IRRT). Multiple factors including estimated glomerular filtration rate (eGFR), sequential organ failure assessment (SOFA) score, RRT model, the accumulation of fluid before initiation of RRT, and negative fluid balance during RRT were analyzed for outcome predictors by Cox proportional hazards model. RESULTS: There were no differences between two groups regarding clinical characteristics. The percentage of receiving CRRT in the negative fluid balance group was slightly higher than that of the positive fluid balance group (52.31% vs. 36.54%, chi2 = 2.899, P = 0.089). With Kaplan-Meier survival curves, it was shown that the patients of negative fluid balance group had a higher rate of recovery of renal function (chi2 = 4.803, P = 0.028) and significantly lower mortality rate (chi2 = 9.505, P = 0.002). The rate of recovery of renal function by 60 days was higher in the negative fluid balance group than that in the positive fluid balance group (47.69% vs. 28.85%, chi2 = 3.991, P = 0.046), while the mortality rate was significantly lowered in the negative fluid balance group compared with that of the positive fluid balance group (40.00% vs. 67.31%, chi2 = 4.378, P = 0.036). Cox multivariate regression was used for excluding confounding factors. After adjusting for the clinically relevant variables, RRT negative fluid balance was significantly associated with recovery of renal function [ hazard ratios (HR) = 2.440, 95% confidence intervals (95%CI) = 1.089-5.464, P = 0.030] and mortality (HR = 0.443, 95%CI = 0.238-0.822, P = 0.010]. Higher eGFR before RRT and CRRT were independent favorable factors for recovery of renal function (HR = 1.014, 95%CI = 1.003-1.026, P = 0.012; HR = 3.138, 95%CI = 1.765-7.461, P = 0.002), and higher SOFA score was associated with a significantly higher risk of death (HR = 1.115, 95%CI = 1.057-1.177, P < 0.001). CONCLUSIONS: Once the patients with septic AKI showed the signs of fluid overload, timely RRT and effective removal of excessive liquid may reverse the adverse prognosis. RRT with negative fluid balance is beneficial for the recovery of renal function, and reduce the mortality in patients with septic AKI, and CRRT model is a good choice. PMID- 26003634 TI - [Correlation of kidney injury and inflammatory response in rats with classic severe heatstroke]. AB - OBJECTIVE: To investigate the temporal features of renal injury in rats with severe heat stroke (SHS) and their relationship with inflammatory response. METHODS: Fifty-six male Wistar rats were randomly divided into normal control group and SHS for 0, 2, 6, 24, 48, 72 hours group (SHS-0, 2, 6, 24, 48, 72 h groups), with 8 rats in each group. Rats were placed in an artificial climate chamber [ temperature (39.5+/-0.2) centigrade, humidity (60+/-5)% ] to induce SHS model, and the criterion for successful model reproduction was the onset of lowering peak systolic blood pressure ( SBP ). Then the rats were transferred to room temperature (23.0+/-0.2) centigrade after successful reproduction of the model. The rats of normal control group were kept in room temperature of (23.0+/ 0.2) centigrade. Heart blood and renal tissue samples were harvested, and the levels of serum creatinine (SCr) and blood urea nitrogen (BUN) were determined by automatic biochemistry analyzer. The levels of myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in renal tissue specimens were determined by enzyme linked immunosorbent assay (ELISA). The changes in histopathology in kidney were observed with light microscopy, and Paller scores were used to assess the degree of renal injury. RESULTS: Compared with normal control group, the levels of SCr and BUN in serum, and MPO, TNF-alpha and IL-6 in the renal tissue homogenate were significantly increased in SHS-6 h group [SCr (MUmol/L): 174.0+/-27.0 vs. 68.0+/-11.3, BUN (mmol/L): 12.6+/-2.3 vs. 4.3+/-1.2, MPO: (203.0+/-38.0)% vs. (100.0+/-1.4 )%, TNF-alpha: (121.0+/-16.0)% vs. (100.0+/-1.4 )%, IL-6: (118.0+/-19.0)% vs. (100.0+/-1.3)%, all P < 0.05], and they peaked at 24 hours [SCr (MUmol/L): 489.0+/-96.0 vs. 68.0+/-11.3, BUN (mmol/L): 19.3+/-5.7 vs. 4.3+/-1.2, MPO: (511.0+/-41.0)% vs. (100.0+/-1.4)%, TNF alpha: (399.0+/-47.0)% vs. (100.0+/-1.4)%, IL-6: (473.0+/-56.0)% vs. (100.0+/ 1.3)%, all P < 0.01], then declined to the normal levels at 72 hours. Under light microscopy, tissue edema and necrosis of renal tubules were found, and leukocyte infiltration was found to be most profuse at 24 hours, then they returned to normal levels at 72 hours. Paller scores in SHS-6 h group were significantly higher than those of the normal control group (75.45+/-9.70 vs. 14.23+/-3.26, P < 0.01), and it peaked at 24 hours (186.00+/-14.25 vs. 14.23+/-3.26, P < 0.01), followed by a gradual lowering, back to normal level at 72 hours. CONCLUSIONS: The results suggest that progressive renal damage occurred in the rats with SHS within 24 hours, and it was accompanied with elevated levels of MPO, TNF-alpha and IL-6 in the kidney homogenate, suggesting that inhibition of neutrophil activation and the release of IL-6, TNF-alpha may protect the SHS associated renal injury. PMID- 26003631 TI - Adaptive potential of genomic structural variation in human and mammalian evolution. AB - Because phenotypic innovations must be genetically heritable for biological evolution to proceed, it is natural to consider new mutation events as well as standing genetic variation as sources for their birth. Previous research has identified a number of single-nucleotide polymorphisms that underlie a subset of adaptive traits in organisms. However, another well-known class of variation, genomic structural variation, could have even greater potential to produce adaptive phenotypes, due to the variety of possible types of alterations (deletions, insertions, duplications, among others) at different genomic positions and with variable lengths. It is from these dramatic genomic alterations, and selection on their phenotypic consequences, that adaptations leading to biological diversification could be derived. In this review, using studies in humans and other mammals, we highlight examples of how phenotypic variation from structural variants might become adaptive in populations and potentially enable biological diversification. Phenotypic change arising from structural variants will be described according to their immediate effect on organismal metabolic processes, immunological response and physical features. Study of population dynamics of segregating structural variation can therefore provide a window into understanding current and historical biological diversification. PMID- 26003635 TI - [A mathematic analysis of different manners of replacement fluid infusion in continuous veno-venous hemofiltration]. AB - OBJECTIVE: To establish a mathematical formula for choosing the manner of replacement fluid infusion in continuous renal replacement therapy (CRRT), so as to provide the basis for improving the treatment effect. METHODS: A mathematical formula for choosing the manner of replacement fluid infusion with continuous veno-venous hemofiltration (CVVH) was taken as an example, and it was compared with the result of standard replacement fluid in order to analyze the effect of different manners of infusion. (1) Comparison parameters: the plasma volume ("Vreturn") and some electrolyte concentration ("Creturn") in back way of CRRT ( if other thing was solute, filter coefficient should be 1.0). (2) Research objects: the actual replacement fluid (for example, the most complex should be sorted into A and B type) mode (pre or post) was compared with the standard replacement fluid (the A and B in one). (3) Based on the formula of standard replacement, four equations in different conditions were derived: pre-dilution and post-dilution mode; same direction and same ratio; same direction and different ratio; different direction and same ratio; different direction and different ratio. RESULTS: The calculated results of "Vreturn" (except hematocrit) and "Creturn" were same to the standard only following the rule of same direction and ratio for A and B no matter pre-dilution mode or post-dilution mode, and it was different from the standard in others. In pre-dilution mode and post-dilution mode, it showed: (1) A and B in same direction and different ratio: "Vreturn" and "Creturn" were different from the standard for the alterative ratio of B. (2) A and B in different direction and same ratio: "Vreturn" was same to the standard, but "Creturn" was different from the standard for the completely different and more complex computational formula. (3) A and B in different direction and different ratio: both "Vreturn" and "Creturn" were different from the standard. The different "Vreturn" was due to the different ratio of B. The different "Creturn" was caused by different ratio of B and the completely different computational formula. CONCLUSIONS: (1) For parts of replacement fluid which must be separated (for example, bicarbonate formula), the result is same to the standard, and is predicted and mastered only following the rule of same direction and ratio. Otherwise, we need to calculate the two parameters over and over again. The result will run out of our judgment. The wrongness of losing water and electrolyte disorders maybe come out. (2) Accordingly,the formula could be used to analyze the same case like the separated replacement infusion, for example, a large number of citrates as regional anticoagulation were infused only in the front of filter, while the replacement fluid can be done in varied forms. PMID- 26003636 TI - [Investigation regarding the correlation between hydroxyethyl starch administration and acute kidney injury in critically ill patients]. AB - OBJECTIVE: To explore the risk factors of the occurrence of acute kidney injury (AKI) in critically ill patients, and to investigate the effect of hydroxyethyl starch (HES) on renal function in these patients. METHODS: A prospective investigation was conducted. Critically ill patients admitted to Department of Critical Care Medicine of People's Hospital of Huangshan, Wannan Medical College from March 2012 to October 2013 were enrolled. For all the patients under observation, the following data were collected: demography, comorbidities, clinical presentation, severity of illness, and the use of blood product and drugs. All patients were divided into AKI group and non-AKI group by means of Acute Kidney Injury Network (AKIN) criteria, then the risk factors of AKI were investigated by means of univariate and multivariate logistic regression analysis. The effect of HES 130/0.4 administration on renal function in critically ill patients was evaluated. RESULTS: 314 patients were enrolled for study out of 1 152 patients admitted. Among these patients enrolled, 89 of them were found to suffer from AKI. AKI was classified as stage 1 in 59 patients, stage 2 in 19 patients, and stage 3 in 11 patients. It was shown by the univariate analysis that 12 variables were the risk factors of AKI, including age, hypertension, diabetes mellitus, acute physiology and chronic health evaluation II (APACHEII) score, sequential organ failure assessment (SOFA) score, coagulation SOFA score, neurological SOFA score, cardiovascular SOFA score, blood pH on intensive care unit (ICU) admission, blood glucose on ICU admission, accumulating dose of HES, and presence of shock (P < 0.05 or P < 0.01). However, HES administration and daily maximum dose of HES were not the risk factors of AKI in critically ill patients (both P > 0.05). Using the multivariate logistic regression analysis, it was shown that total SOFA score [ odds ratio (OR) = 1.20, 95% confidence interval (95%CI) = 1.09-1.32, P < 0.001 ], hypertension (OR = 2.44, 95%CI = 1.22-4.89, P = 0.012), blood glucose level on ICU admission (OR = 1.85, 95%CI = 1.32-2.59, P < 0.001), and presence of shock (OR = 3.81, 95%CI = 1.93-7.53, P < 0.001) were independent predictors of AKI in critically ill patients, however, the cumulative dose of HES was not independent risk factor for AKI (OR = 0.77, 95%CI = 0.68-0.87, P < 0.001). CONCLUSIONS: Total SOFA score, hypertension, blood glucose level on ICU admission, and presence of shock were independent risk factors for AKI in critically ill patients. HES administration may not be a causative factor of an increased risk of AKI in the ICU. PMID- 26003632 TI - RecBCD is required to complete chromosomal replication: Implications for double strand break frequencies and repair mechanisms. AB - Several aspects of the mechanism of homologous double-strand break repair remain unclear. Although intensive efforts have focused on how recombination reactions initiate, far less is known about the molecular events that follow. Based upon biochemical studies, current models propose that RecBCD processes double-strand ends and loads RecA to initiate recombinational repair. However, recent studies have shown that RecBCD plays a critical role in completing replication events on the chromosome through a mechanism that does not involve RecA or recombination. Here, we examine several studies, both early and recent, that suggest RecBCD also operates late in the recombination process - after initiation, strand invasion, and crossover resolution have occurred. Similar to its role in completing replication, we propose a model in which RecBCD is required to resect and resolve the DNA synthesis associated with homologous recombination at the point where the missing sequences on the broken molecule have been restored. We explain how the impaired ability to complete chromosome replication in recBC and recD mutants is likely to account for the loss of viability and genome instability in these mutants, and conclude that spontaneous double-strand breaks and replication fork collapse occur far less frequently than previously speculated. PMID- 26003637 TI - [The effect of AN69 ST membrane on filter lifetime in continuous renal replacement therapy without anticoagulation in patients with high risk of bleeding]. AB - OBJECTIVE: To evaluate whether AN69 ST membrane would prolong filter lifetime in continuous renal replacement therapy (CRRT) without anticoagulation in patients with high risk of bleeding. METHODS: A single-center, prospective, randomized, double-blind control trial with crossover design was conducted. From March 1st to December 31st in 2013, patients who were admitted to Department of Critical Care Medicine of the Fourth Hospital of Hebei Medical University meeting CRRT treatment indications, but could not receive systemic anticoagulation because of high risk of bleeding were studied. The selected patients were randomly divided into two groups according to a random number table, and four filters consisting of two AN69 ST100 membrane filters (A) and two traditional AN69 M100 membrane filters (B) were used for them. Group I with the filter order of A-B-A-B, and group II with the order of B-A-B-A. The clinical data of patients was recorded in detail, and conventional AN69 ST and AN69 membrane filter lifetime, their influence on coagulability, and the incidence of bleeding complications were compared. RESULTS: Seventeen patients were enrolled, with 10 in groupI, and 7 in group II. The basic medical characteristics including gender, age, acute physiology and chronic health evaluation II ( APAECH II) score, sequential organ failure score (SOFA), Acute Renal Injury Network (AKIN) stage, activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR), platelet count (PLT), and use of mechanical ventilation were not significantly different between two groups. But the use of vasoactive drug was more frequent in group IIcompared with that of group I[ 100.0% (7/7) vs. 30.0% (3/10), chi2 = 8.330, P = 0.010]. AN69 ST filter lifetime (n = 34) was (15.92+/ 2.10) hours, there was no statistically significant difference compared with that of AN69 membrane (t = 0.088, P = 0.942), filter lifetime of which (n = 34) was (16.12+/-1.38) hours. It was also found by Kaplan-Meier survival analysis that there was no significant difference between the two membrane filter lifetime (chi2 =1.589, P = 0.208). Logistic regression analysis showed that the life of the first filter was not correlated with coagulation indicators, including APTT, PT, INR, and PLT [ APTT: odds ratio (OR) = 0.977, 95% confidence interval (95%CI) = 0.892-1.071, P = 0.623; PT: OR = 1.001, 95%CI = 0.901-1.109, P = 0.988; INR: OR = 1.078, 95%CI = 0.348-3.340, P = 0.896; PLT: OR = 0.996, 95%CI = 0.974-1.019, P = 0.735]. The application rate of vasoactive drugs, which was different between two groups for basic medical indications showed no effect on filter life time (OR = 2.541, 95%CI = 0.239-26.955, P = 0.439). Reasons of clotting in filters were also analyzed, and it was found that blood coagulation in the filter ranked the top (88.2%), and the other reasons were catheter-related problems, death, and unscheduled transport. No difference in blood coagulation function was found in both groups after treatment for 12 hours, and there was no bleeding complication. CONCLUSIONS: During the CRRT without systemic anticoagulant, both surface treatment with polyethyleneimine AN69 and AN69 ST membrane cannot prolong filter lifetime. PMID- 26003638 TI - [Analysis of the characteristics of patients suffering from acute kidney injury following severe trauma receiving renal replacement therapy]. AB - OBJECTIVE: To analyze the characteristics of severe trauma patients with acute kidney injury (AKI) receiving renal replacement therapy (RRT), in order to look for the risk factors of AKI and the opportune time for the initiation of RRT on prognosis. METHODS: A retrospective cohort study involving consecutive patients with severe trauma in emergency intensive care unit (ICU) in the Second Affiliated Hospital of Zhejiang University School of Medicine, from August 2011 to December 2014, was conducted. Inclusion criteria included age>=18 years, injury severity score (ISS) > 16, AKI receiving RRT, and the duration of hospital stay > 24 hours. The general data, the risk factors of AKI, the prognostic indicators, and the information of RRT were recorded. All patients were divided into two groups according to the prognosis, the time of onset of AKI and the initiation time of RRT. The independent risk factors for prognosis were screened by binary logistic regression analysis. RESULTS: Seventy-three patients were eligible for enrollment, including 48 deaths ( 65.8% ); 49 patients suffered from AKI<=48 hours after trauma (early stage group), and in 24 patients it was longer than 48 hours (late stage group). In 55 patients RRT was routinely started (routine RRT group), 18 patients underwent RRT ahead of routine criteria decided by the judgment of the attending doctor ( earlier RRT group). The main risk factors of RRT in traumatic patients with AKI were shock and sepsis, each accounted for 90.4% and 53.4%. Compared with survival group, in death group, the proportion of male patients was lower (70.8% vs. 100.0%, chi2 = 7.238, P = 0.007), acute physiology and chronic health evaluation II ( APACHEII) scores were higher (23.7+/-5.1 vs. 14.4+/-3.7, t = 8.031, P < 0.001), Glasgow coma score (GCS) was lower [5.0 (3.0, 15.0) vs. 15.0 (8.0, 15.0 ), U = 320.000, P = 0.001 ], incidence of shock and sepsis was higher (97.9% vs. 76.0%, chi2 = 6.755, P = 0.009; 64.6% vs. 32.0%, chi2 = 7.014, P = 0.008), the rate of use of contrast medium was lower (27.1% vs. 56.0%, chi2 = 5.898, P = 0.015), the time for the diagnosis of AKI post trauma was delayed [ days: 2 (1, 5) vs. 2 (1, 2), U = 762.000, P = 0.049 ], the time for the initiation of RRT post trauma was later [ days: 6.0 (3.0, 12.0) vs. 3.0 (2.0, 4.5), U = 868.500, P = 0.002 ], the recovery rate of renal function at discharge was lower (10.4% vs. 100.0%, chi2 = 54.497, P < 0.001). Compared with late stage group, in early stage group, the mortality was lower (55.1% vs. 87.5%, chi2 = 7.509, P = 0.006 ), and the incidence of sepsis before AKI was also lower (38.8% vs. 83.3%, chi2 = 12.854, P < 0.001). Compared with routine RRT group, the recovery of renal function at discharge was better with a lower mortality rate in the earlier RRT group, but the difference was considered to be insignificant ( 55.6% vs. 36.4%, chi2 = 2.064, P = 0.151; 50.0% vs. 70.9%, chi2 = 2.633, P = 0.105). Logistic regression analysis showed GCS [odds ratio (OR) = 0.852, 95% confidence interval (95%CI) = 0.747-0.972, P = 0.017], shock before AKI (OR = 85.350, 95%CI = 5.682-1 282.073, P = 0.001), and sepsis before AKI (OR = 11.499, 95%CI = 2.127 - 62.161, P = 0.005) were independent risk factors for the judgment of prognosis. CONCLUSIONS: Shock and sepsis are the major risk factors of RRT in trauma patients with AKI. Shock, sepsis and traumatic brain injury are the independent risk factors of death. Perhaps early initiation of routine RRT cannot improve the outcome of the patients with posttraumatic renal insuficiency. PMID- 26003639 TI - [The study of cause of early death and a matched study for the risk factors in patients undergoing maintenance hemodialysis]. AB - OBJECTIVE: To explore the cause of early death (death within 3-12 months after hemodialysis) and the related influencing factors patients undergoing maintenance hemodialysis (MHD) as to provide a scientific basis for the prevention of early death. METHODS: A retrospective matched controlled study was conducted. Fifty-one patients who underwent MHD from January 2004 to April 2014 and died within 3-12 months after hemodialysis in hemodialysis center of the 174th Chinese People's Liberation Army Hospital were included in the case group by retrospective analysis method. According to 1:2 matched controls, 102 patients underwent hemodialysis in the same period (+/-2 months) and survived over 12 months were selected as control group. All patients received regular hemodialysis (dialysis 2 3 times per week), with conventional limitation of water and sodium intake, routine treatments such as control of blood pressure, treatment of anemia and disorders of calcium and phosphorus contents. Causes of short-term death were analyzed. Clinical and biochemical parameters of two groups were collected when dialysis was started, and the single factor and multiple factors logistic regression was used to analyze the related risk factors when dialysis was started. Receiver operating characteristic curve (ROC) was plotted to evaluate the value of above parameters in predicting the early death in patents with MHD. RESULTS: The main causes of early death of 51 patients with MHD were mainly cardiovascular and cerebrovascular diseases (27 cases, 52.9%), and infections (15 cases, 29.4%). It was shown by single factor analysis that the age [odds ratio (OR) = 6.625, 95% confidence interval (95%CI) = 3.232-13.580, P = 0.000 ], diabetes (OR = 3.875, 95%CI = 0.654 - 10.622, P = 0.031), specialist intervention time before dialysis (OR = 0.349, 95%CI = 0.287 - 0.572, P = 0.004), the emergence of cardiovascular and cerebrovascular events before dialysis (OR = 9.667, 95%CI = 4.632 - 20.174, P = 0.000), the first dialysis for emergency dialysis (OR = 3.875, 95%CI = 1.713 - 8.765, P = 0.005), blood albumin level (OR = 0.294, 95%CI = 0.068 - 0.550, P = 0.008), leukocyte count (OR = 6.286, 95%CI = 1.648 - 23.982, P = 0.026), neutrophil count (OR = 2.833, 95%CI = 1.630 - 4.923, P = 0.001) might be the factors correlating with early death. Eight independent factors were statistically significant, and their effect on the MHD patients was analyzed by logistic regression analysis in alpha = 0.05 level. The results showed that patients with old age (OR = 1.054, 95%CI = 1.019-1.090, P = 0.002), and the emergence of cardio-cerebrovascular events (OR = 7.469, 95%CI = 2.474 - 22.545, P = 0.000) were early death risk factors of MHD patients, and early specialist intervention before dialysis was a protective factor (OR = 0.286, 95%CI = 0.113-0.722, P = 0.008). ROC curve showed that age had moderate diagnostic value for early death of MHD [area under ROC curve (AUC) = 0.756], the cut-off value was 59.0 years old, the sensitivity was 66.7%, and the specificity was 77.5%. The diagnostic value of early specialist intervention before dialysis was relatively low (AUC = 0.36), the cut-off value was 0.875 years, the sensitivity was 39.2%, and the specificity was 33.3%. CONCLUSIONS: Old age, the emergency of cardiovascular and cerebrovascular events before dialysis is associated with early death, and specialist intervention ahead of dialysis can reduce the risk of early death. PMID- 26003640 TI - [Effect of continuous renal replacement therapy on the plasma concentration of imipenem in severe infection patients with acute renal injury]. AB - OBJECTIVE: To investigate the extracorporeal clearance rate of imipenem in severe infection patients in the mode of continuous vena-venous hemofiltration (CVVH) during continuous renal replacement therapy (CRRT), in order to approach if the concentration of imipenem in plasma could achieve effective levels of anti infection, and to explore the effect of time and anticoagulation measure on imipenem clearance during CRRT treatment. METHODS: A prospective observational study was conducted. All adult severe infection patients complicating acute kidney injury (AKI) in the Department of Critical Care Medicine of the Fourth Hospital of Hebei Medical University from March 2013 to September 2014, who were prescribed imipenem as part of their required medical care, and CRRT for treatment of AKI were enrolled. 0.5 g doses of imipenem was administered intravenously every 6 hours or 8 hours according to random number table, and infused over 0.5 hour. The unfractionated heparin was used for anticoagulation in the patients without contraindications, and no anticoagulation strategy was used in the patients with high risk of bleeding. At 24 hours after first time of administration, postfilter venous blood and ultrafiltrate samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 5, 6, and 8 hours after imipenem administration. The concentration of imipenem in above samples was determined with liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS). RESULTS: A total of 25 patients were enrolled. Thirteen patients received imipenem intravenously every 6 hours, and 12 patients, every 8 hours. The anticoagulation was conducted with heparin in 13 cases, and 12 cases without anticoagulation. The intra-day precision, inter-day precision, matrix effect, and recovery rate in low, medium, and high concentration of plasma and ultrafiltrate, and the stability of samples under different conditions showed a good result, the error of accuracy was controlled in the range of +/-15%. With the application of Prismaflex blood filtration system and AN69-M100 filter, under the mode with CVVH, the total clearance rate of imipenem was (8.874+/-2.828) L/h when the actual dose of replacement fluid was (31.63+/-1.48) mL*kg-1*h-1, the total CRRT clearance rate of imipenem in vitro was (2.211+/-0.539) L/h, which accounting for (30.1+/-15.7)% of the total drug clearance. In 6 hours interval dosage regimen, the percentages of the time > 4* minimum inhibitory concentration (MIC) at specific 4*MIC of 2, 4, 6, and 8 MUg/mL of imipenem were more than 40% of the dosing interval. But in the 8 hours interval dosage regimen, when the level was above the 4*MIC of 4 MUg/mL, maintaining time would drop below 40% of the dosing interval, with significant differences compared with that in 6 hours interval dosage regimen [4*MIC = 2 MUg/mL: (60.84+/-20.25)% vs. (94.01+/-12.46)%, t = 4.977, P = 0.001; 4*MIC = 4 MUg/mL: (39.85+/-15.88)% vs. (68.74+/-9.57)%, t = 5.562, P = 0.000; 4*MIC = 6 g/mL: (27.58+/-13.70)% vs. (53.97+/-8.36)%, t = 5.867, P = 0.000; 4*MIC = 8 MUg/mL: ( 8.87+/-12.43)% vs. (43.48+/-7.83)%, t = 5.976, P = 0.000]. No significant change in sieving coefficient of imipenem was found within a short time (6 hours), which indicated that there was no effect of anticoagulation on clearance of imipenem by AN69-M100 filter, and no statistical significance was found with repeated measure analysis (F = 0.186, P > 0.05 ). CONCLUSIONS: The clearance rate of imipenem is increased significantly in vitro under the mode of CVVH with the actual dose of replacement fluid was (31.63+/-1.48) mL*kg-1*h-1 in severe infective patients with severe sepsis complicating AKI, affecting the level of plasma drug concentration, need to adjust the dosage regimen. When the time of the dosing interval was shortened, the concentration of imipenem in patients' plasma could be increased significantly. In a short period of time, the sieving coefficient of imipenem through AN69 filter is not affected by anticoagulation measures and time cleaning efficiency will not decline. PMID- 26003641 TI - [Risk and harm of contrast induced nephropathy in critically ill patients]. AB - OBJECTIVE: To assess whether intravenous contrast medium would result in acute kidney injury (AKI), and to determine the risk factors associated with contrast induced AKI (CI-AKI) and its outcome. METHODS: A retrospective observational study was conducted in intensive care unit (ICU) of Fuyang People's Hospital in Zhejiang Province from January 1st 2011 to December 31st 2014. All enrolled critically ill patients had accepted CT scan, and the hospital length of stay was longer than 48 hours, and the patients who needed renal replacement treatment were excluded. Patients were divided into contrast medium group and control group. AKI was defined according to Acute Kidney Injury Network (AKIN) criteria ( serum creatinine content over 26.4 MUmol/L or 50% increase of it from baseline within 48 hours). The incidence of AKI was compared between the two groups, and risk factors for CI-AKI were determined by multiple logistic regression analysis. The relationship of CI-AKI and outcomes were also analyzed. RESULTS: A total of 2 370 critically ill patients were enrolled during the period. 474 (20.0%) of the 2 370 patients received contrast medium, and 70 of them suffered from CI-AKI ( 14.8% ). In 1 896 patients who did not receive contrast medium, 235 of them suffered from AKI (12.4%). There was no significant difference in the incidence of AKI between two groups ( chi2 = 1.905, P = 0.168). After several confounding factors were adjusted, multiple logistic regression analysis showed that contrast medium was not found to associate with AKI in critically ill patients [ odds ratio (OR) = 1.66, 95% confidence interval ( 95%CI) = 0.72-3.90,P = 0.201 ], and high acute physiology and chronic health evaluation II ( APACHEII) score ( OR = 1.70, 95%CI = 1.33-2.40, P < 0.001), sepsis (OR = 8.06, 95%CI = 3.28-17.80, P < 0.001), shock (OR = 3.57, 95%CI = 1.73-8.01, P < 0.001) and use of nephrotoxic agent (OR = 1.96, 95%CI = 1.25-2.63, P = 0.015) were risk factors of CI-AKI. Ten of 70 patients with CI-AKI died (14.3%), and 21 out of 404 patients without CI AKI, died (5.2%). There was no significant difference in the mortality rate (chi2 = 8.060, P = 0.005 ). It was shown by multiple logistic regression analysis that age (OR=1.30, 95%CI = 1.05-1.71, P = 0.027), male sex (OR = 1.13, 95%CI = 1.05 1.20, P = 0.039), APACHEII score (OR = 1.07, 95%CI = 1.03-1.18, P < 0.001), and sepsis ( OR = 3.29, 95%CI = 1.92-6.46, P < 0.001) were highly associated with mortality of critically ill patients in whom contrast medium was used. However, the occurrence of CI-AKI showed no influence on the mortality rate (OR = 1.70, 95%CI = 0.88-3.56, P = 0.227). CONCLUSIONS: The use of contrast medium is not a risk factor of CI-AKI in critically ill patients. CI-AKI will not raise mortality rate in ICU patients. PMID- 26003642 TI - [A clinical research on renal protective effect of Xuebijing injection in patients with sepsis]. AB - OBJECTIVE: To evaluate the protective effect of Xuebijing injection against renal injury in patients with sepsis, and to explore its possible mechanism. METHODS: A prospective randomized controlled trial (RCT) was conducted in which 62 severe patients with sepsis and septic shock admitted in Department of Critical Care Medicine of Jiangsu Province Traditional Chinese Medicine Hospital from June 2013 to December 2013 were randomly divided into control group and Xuebijing group, with 31 patients in each group. The patients in both groups received basic treatment for sepsis, and the patients in Xuebijing group were additionally given intravenous injection of Xuebijing 100 mL once a day for 7 days. In both groups, the changes in acute physiology and chronic health evaluation II (APACHE II) score were observed before treatment and 1, 3, 7 days after treatment, and the changes in the levels of interleukins (IL-6, IL-10), prothrombin time (PT), fibrinogen (Fib), activated partial thromboplastin time (APTT), serum creatinine (SCr), and Cystain C (Cys C) were determined before treatment and 1 day and 3 days after treatment. RESULTS: There was no statistically significant difference in APACHE II score before treatment between two groups, however, the APACHE II scores were significantly decreased in both groups 3 days and 7 days after treatment compared with those before treatment, and the degree of decrease in Xuebijing group was more obvious 7 days after treatment (13.61+/-7.62 vs. 16.34+/ 8.70, P < 0.05). Serum concentrations of Cys C, SCr, IL-6, IL-10, PT, APTT, and Fib showed no difference between two groups before treatment (all P > 0.05), while after treatment the degrees of improvement of above indexes in Xuebijing group were obviously superior to those in control group, especially 3 days after treatment[Cys C (mg/L): 1.12+/-0.11 vs. 1.35+/-0.14, SCr (MUmol/L): 115.0+/-31.0 vs. 135.0+/-24.0, IL-6 (ng/L): 54.27+/-28.79 vs. 73.35+/-31.01, PT (s): 13.50+/ 0.11 vs. 15.71+/-0.11, APTT (s): 43.66+/-0.31 vs. 48.03+/-0.55, Fib (g/L): 1.91+/ 0.51 vs. 1.51+/-0.52, P < 0.05 or P < 0.01]. CONCLUSIONS: Xuebijing injection has certain renal protective effect in patients with sepsis, and its mechanism is possibly related to the regulation and improvement of uncontrolled inflammatory response and coagulation function in sepsis. PMID- 26003643 TI - [Risk factors of acute kidney injury in patients with acute lung injury]. PMID- 26003644 TI - [Five-year analysis of bedside blood filtration in the department of emergency of a large general hospital]. PMID- 26003645 TI - [The relationship between acute kidney injury patients with continuous renal replacement therapy center ejection index and the inferior vena cava respiratory variation index]. PMID- 26003646 TI - [The relationship between acute kidney injury following traffic trauma with the injury score and prognosis]. PMID- 26003647 TI - [The retrospective analysis of risk factor of acute kidney injury after bee sting]. PMID- 26003648 TI - [Diagnostic value of urinary kidney injury molecule-1 for acute kidney injury in septic rats]. PMID- 26003649 TI - [Effect observation of continuous blood purification in treatment of sepsis complicated with intra-abdominal hypertension]. PMID- 26003650 TI - [Advances in research into proteomics of urinary biomarkers in acute kidney injury]. PMID- 26003651 TI - [Effect of blood purification on precision of measurement of hemodianics with thernodilution method in patients with septic shock]. PMID- 26003652 TI - Angiopoietin-like protein 2 may mediate the inflammation in murine mastitis through the activation of interleukin-6 and tumour necrosis factor-alpha. AB - Mastitis is the inflammation of the mammary gland. Recent research has shown that Angiopoietin-like protein 2 (ANGPTL2) is a key inflammatory mediator. In the present study, we tested whether there is a correlation between increased ANGPTL2 expression and inflammation in response to Staphylococcus aureus in murine mastitis and the mechanisms involved. Thirty mice were divided into two groups: blank control group, challenged group. The entire infused mammary glands were removed to observe the changes of histopathology, myeloperoxidase (MPO) activity, production of tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, and genes expression of ANGPTL2, TNF-alpha and IL-6. In challenged group, the structure of mammary glands was damaged and the large areas of cell fragments were observed. The MPO activity, IL-6 and TNF-alpha concentrations, ANGPTL2, IL 6, and TNF-alpha mRNA levels were significantly elevated in challenged group compared with blank control group. The present findings indicate ANGPTL2 may mediate the inflammation in murine mastitis through the activation of IL-6 and TNF-alpha. PMID- 26003653 TI - Effects of MAL61 and MAL62 overexpression on maltose fermentation of baker's yeast in lean dough. AB - The predominant fermentable sugar in lean dough is maltose. To improve the leavening ability of baker's yeast in lean dough, maltose metabolism should be improved. Maltase (alpha-glucosidase, encoded by MAL62) and maltose permease (encoded by MAL61) are the major factors involved in maltose metabolism. The major rate-limiting factor in maltose metabolism and leavening ability of baker's yeast remains unclear. In this work, MAL61 and/or MAL62 overexpression strains were constructed to investigate the decisive factor for maltose metabolism of industrial baker's yeast in lean dough. Our results show that elevated maltose permease activity by MAL61 overexpression yielded less improvement in maltose fermentation compared to elevated maltase activity by MAL62 overexpression. Significant increase in maltase activity by MAL62 overexpression could result in a 44% increase in leavening ability of industrial baker's yeast in lean dough and a 39% increase in maltose metabolism in a medium containing glucose and maltose. Thus, maltase was the rate-limiting factor in maltose fermentation of industrial baker's yeast in lean dough. This study lays a foundation for breeding of industrial baker's yeast for quick dough leavening. PMID- 26003654 TI - Closing the knowledge gap in secondhand smoke exposure among children: employment of a five-minute household survey in China. AB - OBJECTIVE: The 2010 Global Burden of Disease study unexpectedly reports no health burden associated with secondhand smoke (SHS) exposure in children 5-17 years of age. One possible reason for this error is that children under 13 years of age are not considered in standard community surveys of SHS exposure. This study aims to use a 5-min household survey to estimate the prevalence of SHS exposure among children in urban and rural China. STUDY DESIGN: Cross-sectional survey. METHODS: A multi-stage stratified sample of 1120 urban and rural households with 3073 residents from the Ningbo, China, was identified and one adult member from each household was administered a brief survey about the demographic characteristics and smoking status of all household residents. RESULTS: Adjusting for the sampling design and clustering within households, 63% of children less than 7 years of age, 53% of the children 7-12 years of age, and 54% of the children 13 17 years of age were living in households with daily smokers. Controlling for the number of male residents, significantly more households with daily smokers were located in rural areas (p < 0.001) and the average education level of adults in households with daily smokers was significantly lower than that among adults in households without daily smokers (p = 0.007). CONCLUSION: The heavy household exposure of children in China to SHS is an unrecognized public health problem that demands urgent policy and programmatic responses. The brief household survey developed for this study is an easy method for monitoring the prevalence of SHS exposure of children over time that could be useful in community-based tobacco control initiatives. PMID- 26003655 TI - Longevity of posterior resin composite restorations in adults - A systematic review. AB - OBJECTIVE: To conduct a systematic review of the literature on the longevity of posterior resin composite restorations in adults. MATERIAL AND METHODS: A systematic literature search was conducted according to pre-determined criteria for inclusion and exclusion. The studies selected were prospective clinical trials with a minimum follow-up time of 4 years, 40 restorations per experimental group and an annual attrition rate of less than 5%. Initially, abstracts and full text articles were assessed independently and the assessment was subsequently agreed on by five reviewers. The methodological quality of the studies was assessed according to the Swedish Council on Health Technology Assessment (SBU) standard checklist for determining the extent to which studies meet basic quality criteria. RESULTS: In all, the literature search identified 4275 abstracts and 93 articles were read in full-text. There were eighteen studies which met the criteria for inclusion, eight of which were included in the analysis. There were 80 failures of restorations with a total follow-up time at risk for failure of 62,030 months. The overall incidence rate for all causes of failure was 1.55 lost restorations per 100 restoration years. The most common biological reason for failure (a total of 31 restorations) was secondary caries, with or without fracture of the restoration. The quality of the evidence was low. CONCLUSIONS: In an efficacy setting, the overall survival proportion of posterior resin composite restorations is high. The major reasons for failure are secondary caries and restoration fracture which supports the importance of adequate follow-up time. CLINICAL SIGNIFICANCE: The overall survival proportion of posterior composite restorations was high, but the results cannot be extrapolated to an effectiveness setting. The importance of adequate follow-up time is supported by the finding that secondary caries often occurred after 3 years or later. PMID- 26003657 TI - Lack of carbon air filtration impacts early embryo development. AB - PURPOSE: To assess human fertilization and preimplantation embryo development in the presence and in the absence of carbon filtration METHODS: This is a retrospective cohort analysis of fresh, controlled ovarian hyperstimulation cycles as well as previously cryopreserved pronuclear stage embryo transfer cycles in a single IVF center. Embryo development and cycle-based outcomes were compared among three groups: 1) when carbon filtration was present, 2) when carbon filtration was absent, and 3) when carbon filtration had been restored. RESULTS: A total of 524 fresh cycles and 156 cryopreserved embryo cycles were analyzed. Fertilization, cleavage, and blastocyst conversion rates for fresh cycles all declined during the period of absent carbon filtration and recovered after the restoration of carbon filtration. Cryopreserved embryos that were thawed and cultured during the period of absent filtration did not have changes in cleavage or blastocyst conversion rates compared to periods where carbon filtration was present. Clinical pregnancy and live birth rates were unchanged among the three time periods. CONCLUSIONS: The absence of carbon filtration in an IVF laboratory air handler is associated with poor fertilization and early embryo development for fresh cycles. Because development of previously frozen pronuclear stage embryos was unaffected, the lack of carbon filtration may preferentially affect embryos in the peri-fertilization period. Carbon filtration is an integral part to a successful human in-vitro fertilization laboratory. PMID- 26003656 TI - Effect of Anti-Mullerian hormone (AMH) and bone morphogenetic protein 15 (BMP-15) on steroidogenesis in primary-cultured human luteinizing granulosa cells through Smad5 signalling. AB - PURPOSE: To determine if there is any effect of AMH and BMP-15 on estradiol and progesterone production from primary-cultured human luteinizing granulosa cells, to delineate what is the effect of FSH on their actions and which are the possible mechanisms involved. METHODS: Luteinizing granulosa cells (GCs), obtained from follicular fluid of 30 women undergoing in vitro fertilization, were cultured, after a short 24-h preincubation period, in serum-free medium for 24 or/and 48 h in the presence/absence of various concentrations of AMH, BMP-15 and FSH alone or in combinations. Estradiol and progesterone production, SMAD5 phosphorylation and StAR expression were studied in parallel. Steroids were measured in culture-supernatant using enzyme-immunoassays, while Smad5-signaling pathway activation and StAR protein expression were assessed immunocytochemically. RESULT(S): We found that the treatment of AMH in GCs for 24/48 h attenuated FSH-induced estradiol production (p < 0.001), had no effect on basal estradiol levels, decreased basal progesterone production (p < 0.001) and FSH-induced StAR expression (p < 0.001). On the other hand, BMP-15 decreased basal estradiol levels (p < 0.001) and attenuated FSH-induced estradiol production (p < 0.001). Furthermore, BMP-15 reduced progesterone basal secretion (p < 0.001), an effect that was partially reversed by FSH (p < 0.01), probably via increasing StAR expression (p < 0.001). FSH-induced StAR expression was also attenuated by BMP-15 (p < 0.001). FSH, AMH and BMP-15 activated Smad-signaling pathway, as confirmed by the increase of phospo-Smad5 protein levels (p < 0.001 compared to control). CONCLUSION(S): AMH and BMP-15 by interacting with FSH affect the production of estradiol and progesterone from cultured luteinizing granulosa cells possibly via Smad5-protein phosphorylation. PMID- 26003658 TI - Does company-sponsored egg freezing promote or confine women's reproductive autonomy? AB - PURPOSE: A critical ethical analysis of the initiative of several companies to cover the costs of oocyte cryopreservation for their healthy employees. The main research question is whether such policies promote or confine women's reproductive autonomy. RESULTS: A distinction needs to be made between the ethics of AGE banking in itself and the ethics of employers offering it to their employees. Although the utility of the former is expected to be low, there are few persuasive arguments to deny access to oocyte cryopreservation to women who are well informed about the procedure and the success rates. However, it does not automatically follow that it would be ethically unproblematic for employers to offer egg banking to their employees. CONCLUSIONS: For these policies to be truly 'liberating', a substantial number of conditions need to be fulfilled, which can be reduced to three categories: (1) women should understand the benefits, risks and limitations, (2) women should feel no pressure to take up the offer; (3) the offer should have no negative effect on other family-friendly policies and should in fact be accompanied by such policies. Fulfilling these conditions may turn out to be impossible. Thus, regardless of companies' possible good intentions, women's reproductive autonomy is not well served by offering them company sponsored AGE banking. PMID- 26003659 TI - Prenatally buprenorphine-exposed children: health to 3 years of age. AB - Our prospective study is among the first attempts to examine the health of prenatally buprenorphine-exposed children after neonatal age and to determine the types of child maltreatment in this patient group. The study population included 102 children (61/41 Caucasian males/females) who had a positive urine screen for buprenorphine as a newborn. In addition to buprenorphine, the children were also prenatally exposed to other substances. The data were collected by pediatricians in follow-up visits until 3 years of age and from medical records. Ten prenatally buprenorphine-exposed children (10 %) had some birth defect. The study children had slightly more major anomalies than newborns on average in Finland (3.4 %). Eye disorders (nystagmus, opticus atrophy, and strabismus) occurred in 11 % of children. One child was diagnosed with hepatitis C transmission. One female died of sudden infant death syndrome (SIDS), and one male died of congenital heart disease. Pediatricians submitted altogether 70 reports to child welfare services of suspected maltreatment. Of these reports, 45 (64 %) involved medical neglect. Physical abuse was suspected in four reports. CONCLUSION: We suggest that prenatally buprenorphine-exposed children have several types of problems with their health at toddler age and that they are susceptible to child maltreatment, especially to medical neglect. PMID- 26003660 TI - Reply to correspondence letter "Krakow's children cohort and long term follow-up of thimerosal exposure--design and statistics". PMID- 26003661 TI - Clinical characteristics and molecular epidemiology of Enterovirus infection in infants <3 months in a referral paediatric hospital of Barcelona. AB - Enterovirus (EV) infection is common in infants, but the information with regard to the molecular epidemiology and the associations between types and clinical variables is very scarce. This study includes 195 children <3 months old with fever, attended from March 2010 to December 2012 in an emergency department of a tertiary paediatric hospital in whom EV infection was confirmed by real-time PCR in blood and/or cerebrospinal fluid. Clinical and epidemiological data was prospectively collected. In 152 (77.9 %) patients, EVs could be typed. The most common type was Echovirus-5 (E5; 32, 21.1 %), followed by Echovirus-11 (E11; 18, 11.8 %), Echovirus-21 and Echovirus-25 (E21, E25; 11 each one, 7.2 %) and Coxsackievirus-B4 (CVB4; 6, 6.6 %). The majority of types appeared in spring, but E5 and E25 were found mainly during summer (p < 0.01). E21 was associated with high-grade fever (p < 0.01); E5 with exanthema (p = 0.03) and CVB4 tended to cause meningitis more often than the other types (p = 0.07). CONCLUSION: The most common EV types were Echovirus-5 and Echovirus-11. Some significant associations between types and epidemiologic and clinical findings were observed. What is Known-What is New * Enteroviruses cause a normally benign illness in young infants, except in some cases. * The molecular epidemiology of Enterovirus infection is not well known in European countries. * This study describes a large number of infants with Enterovirus infection and shows the seasonality of different types, and their associations with epidemiologic and clinical variables. PMID- 26003662 TI - In Memoriam: Wayne Katon, MD (1950-2015). AB - The following is a memorial of Dr. Wayne J. Katon, MD, FAPM, the former editor-in chief of General Hospital Psychiatry. He passed away on March 1, 2015. PMID- 26003663 TI - Survey of collaborative mental health providers in cystic fibrosis centers in the United States. PMID- 26003664 TI - A randomized trial of a depression self-care toolkit with or without lay telephone coaching for primary care patients with chronic physical conditions. AB - OBJECTIVE: The aim of this study was to compare outcomes of use of a depression self-care toolkit with and without lay telephone coaching among primary care patients 40 years and older with depressive symptoms and comorbid chronic physical conditions. METHOD: A single blind, individually randomized, pragmatic trial of a depression self-care toolkit (Toolkit) with or without lay telephone coaching was conducted among primary care adults with depressive symptoms and comorbid chronic physical conditions. Eligible patients were randomized to receive the Toolkit with (intervention) or without (control) telephone coaching provided by trained lay coaches. The primary outcome was depression severity [Patient Health Questionnaire (PHQ-9)] at 6 months. Secondary outcomes were self efficacy, satisfaction, and use of health services at 6 months. RESULTS: A total of 223 patients were randomized, and 172 (77.1%) completed 6-month follow-ups. PHQ-9 scores improved significantly in both groups over the 6-month follow-up; the differences in PHQ-9 scores between intervention and control groups were statistically significant at 3 months [effect size = 0.44; 95% confidence interval (CI) = 0.16-0.72] but not at 6 months (effect size = 0.24; 95% CI = 0.01 to 0.60). Patients with moderate depression severity (PHQ-9 10-19) and high self-efficacy at baseline were most likely to benefit from the intervention. There was no significant effect of the intervention on the secondary outcomes. CONCLUSIONS: The incremental value of lay telephone coaching of a Toolkit appears short-lived. Targeting of coaching to those with moderate depression severity may be indicated. PMID- 26003665 TI - Interactive effects of juvenile defoliation, light conditions, and interspecific competition on growth and ectomycorrhizal colonization of Fagus sylvatica and Pinus sylvestris seedlings. AB - Seedlings of forest tree species are exposed to a number of abiotic (organ loss or damage, light shortage) and biotic (interspecific competition) stress factors, which may lead to an inhibition of growth and reproduction and, eventually, to plant death. Growth of the host and its mycorrhizal symbiont is often closely linked, and hence, host damage may negatively affect the symbiont. We designed a pot experiment to study the response of light-demanding Pinus sylvestris and shade-tolerant Fagus sylvatica seedlings to a set of abiotic and biotic stresses and subsequent effects on ectomycorrhizal (ECM) root tip colonization, seedling biomass, and leaf nitrogen content. The light regime had a more pronounced effect on ECM colonization than did juvenile damage. The interspecific competition resulted in higher ECM root tip abundance for Pinus, but this effect was insignificant in Fagus. Low light and interspecific competition resulted in lower seedling biomass compared to high light, and the effect of the latter was partially masked by high light. Leaf nitrogen responded differently in Fagus and Pinus when they grew in interspecific competition. Our results indicated that for both light-demanding (Pinus) and shade-tolerant (Fagus) species, the light environment was a major factor affecting seedling growth and ECM root tip abundance. The light conditions favorable for the growth of seedlings may to some extent compensate for the harmful effects of juvenile organ loss or damage and interspecific competition. PMID- 26003666 TI - Higher busulfan dose intensity appears to improve leukemia-free and overall survival in AML allografted in CR2: An analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - Allogeneic hematopoietic cell transplantation is a potentially curative treatment in patients with acute myeloid leukemia. Recent advances in the field of hematopoietic cell allografting have resulted in a practice shift, favoring less intense preparative regimens. We present results of a retrospective comparative analysis of two preparative regimens, namely FB2 (IV fludarabine plus IV busulfan 6.4mg/kg+/-10%) and FB4 (IV fludarabine plus IV busulfan 12.8mg/kg +/-10%), in patients with acute myeloid leukemia undergoing hematopoietic cell allografting in second complete remission at EBMT participating centers. Between 2003 and 2010, 128 AML patients in second complete remission were allografted following a preparative regimen of FB2 (n=88) or FB4 (n=40). The median time-to-neutrophil engraftment was similar whether patients received FB2 (16 (5-38) days) or FB4 (16 (9-29) days), p=0.45. A multivariate analysis showed that use of FB4 resulted in improved 2-year leukemia-free (HR=0.44 (95%CI=0.21, 0.94), p=0.03) and overall survival (HR=0.38 (95%CI=0.16, 0.86), p=0.02). Cumulative incidence of non relapse mortality (2-year) for all patients was 21% (95%CI=14-28%). Our analysis suggests that FB4 improves 2-year leukemia-free and overall survival in AML allografted in second complete remission. A confirmatory randomized controlled trial that compares these two preparative regimens (FB2 vs. FB4) in AML in CR2 is definitely warranted. PMID- 26003667 TI - High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents. AB - Global obesity is a pandemic status, estimated to affect over 2 billion people, that has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing the broader scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. To this end, the emphasis is once again placed on the experimental animal models of the disease. In the current study, we have focused on the effects of a high-fat diet (HFD) on hippocampal-dependent memory in C57/Bl6 Wild type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. Our results indicate that the continuous HFD administration starting at the time of weaning is sufficient to produce beta-amyloid-independent, hippocampal-dependent memory deficits measured by a 2-object novel-object recognition test (NOR) in mice as early as 6months of age. Furthermore, the resulting metabolic syndrome appears to have direct effects on brain insulin regulation and mitochondrial function. We have observed pathological changes related to both the proximal and distal insulin signaling pathway in the brains of HFD-fed WT and APP/PS1 mice. These changes are accompanied by a significantly reduced OXPHOS metabolism, suggesting that mitochondria play an important role in hippocampus-dependent memory formation and retention in both the HFD-treated and AD-like rodents at a relatively young age. PMID- 26003668 TI - Mites associated with sugarcane crop and with native trees from adjacent Atlantic forest fragment in Brazil. AB - In some Brazilian regions the Atlantic forest biome is currently restrict to fragments occurring amid monocultures, as sugarcane crops in the Northeast region. Important influence of forest remnants over mite fauna of permanent crops have been showed, however it has been poorly explored on annual crops. The first step for understanding ecological relationship in an agricultural systems is known its composition. The objective of this study was to investigate the plant inhabiting mite fauna associated with sugarcane crop (Saccharum officinarum L.) (Poaceae) and caboata (Cupania oblongifolia Mart.) (Sapindaceae) trees in the state of Alagoas, Brazil. Sugarcane stalks and sugarcane and caboata apical, middle and basal leaves were sampled. A total of 2565 mites were collected from sugarcane and classified into seven families of Trombidiformes and Mesostigmata orders, with most individuals belonging to the Eriophyidae, Tetranychidae and Tarsonemidae families. Among predatory mites, the Phytoseiidae were the most common. A total of 1878 mites were found on C. oblongifolia and classified into 13 families of Trombidiformes and Mesostigmata orders. The most abundant phytophagous mite family on caboata was also Eriophyidae. In contrast to sugarcane, Ascidae was the most common predatory mite family observed in caboata. No phytophagous species were common to both sugarcane and C. oblongifolia. However two predatory mites were shared between host plants. Although mites associated with only one native species in the forest fragment were evaluated in this study, our preliminary results suggest Atlantic forest native vegetation can present an important role in the sugarcane agricultural system as a source of natural enemies. PMID- 26003669 TI - The role of wild canids and felids in spreading parasites to dogs and cats in Europe. Part I: Protozoa and tick-borne agents. AB - Over the last few decades, the world has witnessed radical changes in climate, landscape, and ecosystems. These events, together with other factors such as increasing illegal wildlife trade and changing human behaviour towards wildlife, are resulting into thinning boundaries between wild canids and felids and their domestic counterparts. As a consequence, the epidemiology of diseases caused by a number of infectious agents is undergoing profound readjustements, as pathogens adapt to new hosts and environments. Therefore, there is a risk for diseases of wildlife to spread to domestic carnivores and vice versa, and for zoonotic agents to emerge or re-emerge in human populations. Hence, the identification of the hazards arising from the co-habitation of these species is critical in order to plan and develop adequate control strategies against these pathogens. In the first of this two-part article, we review the role that wild canids and felids may play in the transmission of protozoa and arthropod-borne agents to dogs and cats in Europe, and provide an account of how current and future progress in our understanding of the ecology and epidemiology of parasites, as well as of host parasite interactions, can assist efforts aimed at controlling parasite transmission. PMID- 26003670 TI - Systemic endothelial function in cases with wet-type age-related macular degeneration. AB - BACKGROUND: Choroidal endothelial dysfunction plays key role in wet-type age related macular degeneration (AMD). Peripheral vascular endothelial function is not known in wet AMD. OBJECTIVE: We aimed to analyze peripheral vascular endothelial function in cases with wet-type age-related macular degeneration by measuring flow-mediated dilatation (FMD). MATERIALS AND METHODS: The study included 20 cases with wet AMD (Group 1, mean age 65.9 +/- 7.2 years) and 24 healthy individuals (Group 2, mean age 62.0 +/- 11.9 years). In all cases, a cardiologist assessed the responses of endothelial function by measuring the FMD following brachial artery occlusion. RESULTS: Mean FMD, an indicator of endothelial function was found to be 6.4 +/- 2.7 % in Group 1 and 15.6 +/- 7.3 % in Group 2 (p < 0.001). There was no significant difference between patient and control groups regarding age, sex, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, ESR and CRP. CONCLUSION: Reduced FMD is present in patients with wet AMD, suggesting that impaired peripheral endothelial function may be involved in its pathogenesis. PMID- 26003671 TI - Olfaction deterioration in cognitive disorders in the elderly. AB - BACKGROUND: Parkinson's and Alzheimer's diseases are widespread neurodegenerative pathologies. Parkinson's disease affects about 1 % of the population over the age of 65 years, while Alzheimer is considered the most common cause of dementia, with an annual incidence of 1 % in persons aged 65 years. It has been demonstrated that both these neurodegenerative diseases are associated with smell dysfunction. AIM: The aim of the present review is to describe briefly modern olfactory evaluation tools as well as the importance of olfactory sensitivity screening in the elderly, especially where cognitive disorders, such as Alzheimer's or Parkinson's diseases, are suspected. METHODS: A brief literature review focusing on the basic principle of smell tests is illustrated together with their application in elderly patients affected by cognitive disorders, in particular Parkinson's and Alzheimer's diseases. RESULTS/CONCLUSIONS: Alzheimer's and Parkinson's diseases are both neurodegenerative disorders typically found in the elderly. As both diseases are characterized by the early presence of dysosmia, simple validated smell tests could very well help clinicians in the early diagnosis of these neuropathological conditions. Elderly patients complaining of smell loss and found to be dysosmic, by means of validated olfactory tests, should be neurologically evaluated as early as possible to detect slight motor abnormalities in an at-risk population. PMID- 26003672 TI - Advance directives in mental health: Facts and values. PMID- 26003673 TI - Pathological response after neoadjuvant bevacizumab- or cetuximab-based chemotherapy in resected colorectal cancer liver metastases. AB - Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated. PMID- 26003674 TI - A first online intervention to increase patients' perceived ability to act in situations of abuse in health care: reports of a Swedish pre-post study. AB - BACKGROUND: Efforts to counteract abuse in health care, defined as patient experienced abuse, have mainly focused on interventions among caregivers. This study is the first to test an online intervention focusing on how patients can counteract such abuse. The intervention aimed at increasing patients' intention and perceived ability to act in future situations where they risk experiencing abuse. METHODS: Participants were recruited through a nephrology clinic in Sweden. The intervention consisted of an online program that aimed to stimulate patients to think of possible actions in situations in which they risk experiencing abuse. The program comprised stories and exercises in text and comic form. The participants filled out a questionnaire immediately before and after going through the program, as well as during follow-up four to eight weeks later. RESULTS: Forty-eight patients (39 %) participated in the study and spent, on average, 41 min responding to questions and going through the program. Both men and women, of various ages and educational backgrounds, participated. An increase in participants' self-reported ability to identify opportunities to act in a given situation was seen immediately afterwards, as well as during follow up. CONCLUSION: The current study suggests that it is feasible and most likely useful to a variety of patients to work with the provided material that has the aim of counteracting abuse in health care. It would be of interest to further develop ways of using comics and to test similar interventions in other health care settings. PMID- 26003675 TI - Rapid assessment of antibody-induced ricin neutralization by employing a novel functional cell-based assay. AB - Ricin is one of the most potent and lethal toxins known against which there is no available antidote. Currently, the most promising countermeasures against the toxin are based on neutralizing antibodies elicited by active vaccination or administered passively. A cell-based assay is widely applied for the primary screening and evaluation of anti-ricin antibodies, yet such assays are usually time-consuming (18-72 h). Here, we report of a novel assay to monitor ricin activity, based on HeLa cells that stably express the rapidly-degraded ubiquitin luciferase (Ub-FL, half-life of 2 min). Ricin-induced arrest of protein synthesis could be quantified within 3 to 6h post intoxication (IC90 of 300 and 100 ng/ml, respectively). Furthermore, by stabilizing the intracellular levels of Ub-FL in the last hour of the assay, a 3-fold increase in the assay sensitivity was attained. We applied this assay to monitor the efficacy of a ricin holotoxin based vaccine by measuring the formation of neutralizing antibodies throughout the immunization course. The potency of anti-ricin monoclonal antibodies (directed to either subunit of the toxin) could also be easily and accurately measured in this assay format. Owing to its simplicity, this assay may be implemented for high-throughput screening of ricin-neutralizing antibodies and for identification of small-molecule inhibitors of the toxin, as well as other ribosome-inactivating toxins. PMID- 26003676 TI - A neutralizing scFv antibody against infectious bursal disease virus screened by flow cytometry. AB - Infectious bursal disease (IBD) is considered a vital viral disease that threatens the poultry industry worldwide. In this study, a recombinant single chain variable fragment (scFv) antibody library derived from chickens immunized with VP2 protein of infectious bursal disease virus (IBDV) was constructed. The library was subjected to three rounds of screening by flow cytometry (FCM) against VP2/IBDV through a bacteria display technology, resulting in the enrichment of scFvs. Three scFv clones with different fluorescence intensity were obtained by colony pick up at random. The obtained scFv antibodies were expressed and purified. Relative affinity assay showed the three clones had different sensitivity to VP2, in accordance with fluorescence activity cell sorting analysis (FACS). The potential use of the isolated IBDV-specific scFv antibodies was demonstrated by the successful application of these antibodies in Western blotting and ELISA assay. What's more, in vitro neutralization measurement showed that one of the three isolated antibodies possessed the neutralization function against IBDV. This study provides new strategies for screening of antibody library, and scFv antibodies isolated in this study may be utilized as lead candidates for further development of diagnostic or therapeutic antibodies for detection and treatment of IBDV infection. PMID- 26003677 TI - 53rd Symposium of International Society for Clinical Electrophysiology of Vision (ISCEV), 23-27 June 2015, Ljubljana, Slovenia. PMID- 26003678 TI - ISCEV symposium program listing (in chronological order). PMID- 26003679 TI - What should be the preferred choice of hemiarthroplasty technique in American Society of Anesthesiologists (ASA) class III patients with femoral neck fractures? Cemented or cementless. AB - The hypothetical basis of this trial specifies that hemiarthroplasty applications without cement will prove to be superior to applications with cement in terms of survival, complications, clinical and radiological improvements in the early stages of femoral neck fracture cases, which belongs to the Society of Anesthesiologists (ASA) class III group. Society of Anesthesiologists (ASA) class III elderly patients (minimum 70 years of age), who had undergone surgical interventions for femoral neck fractures were classified into two groups as those undergoing the intervention without cement (Group A) and those undergoing the procedure with cement (Group B), and these were retrospectively evaluated. The patients were followed up for a mean duration of 47.4 and 44.8 months, respectively. Survival in the early stage, duration of stay in the intensive care, intraoperative cardiac indexes, complications, clinical and radiological parameters were the main factors used in the evaluation and comparisons. The mean duration of operation in Group B cases was determined to be statistically significantly longer than that of Group A (p<0.001). The postoperative stay at the intensive care unit in both groups and the rate of mortality for 6 months in Group B were determined to be statistically significantly high (p<0.05). In group B, significant depressive findings were determined in the comparison of the intra operative pre-and post-cement cardiac indexes. In the clinical assessment, no statistically significant results were obtained, although higher final Harris scores were determined in Group A cases (p=0.581). In the treatment of femoral neck fractures, bipolar hemiarthroplasty applications without cement provide favourable early and short-term results, which are at least as effective as the applications with cement. PMID- 26003680 TI - Cross-cultural adaptation of the spinal cord lesion-related coping strategies questionnaire for use in Iran. AB - INTRODUCTION: This study examined the validity and reliability of the Iranian version of the spinal cord lesion-related coping strategies questionnaire (SCL CSQ-I) in persons with spinal cord injury (SCI). METHODS: Consecutive patients with SCI (n=220) were recruited into the study. A standard forward-backward translation procedure was used to translate the SCL CSQ from English into Persian. Participants also completed the Short Form Health Survey (SF-12), Hospital Anxiety and Depression Scale (HADS), Spinal Cord Independence Measure (SCIM III), Community Integration Questionnaire (CIQ), and SCL CSQ-I. Psychometric properties examined were internal consistency, test-retest reliability, convergent validity, discriminant validity, and construct validity. RESULTS: Cronbach alphas for the SCL CSQ-I subscales ranged from 0.68 to 0.89, indicating acceptable internal reliability, and intraclass correlation coefficients ranged from 0.74 to 0.89, indicating good test-retest reliability. The SCL CSQ-I subscales significantly correlated with scores on the SF-12, HADS, SCIM III and CIQ, indicating solid convergent validity. Each item of the SCL CSQ I within a hypothesized dimension correlated strongly with the total score for that dimension. Exploratory and confirmatory factor analyses identified a three factor model. The SCL CSQ-I subscales correlated significantly with clinical and socio-demographic characteristics. CONCLUSION: The Iranian version of the SCL CSQ is a reliable and valid tool for measuring coping strategies in persons with SCI. PMID- 26003681 TI - Late amputation may not reduce complications or improve mental health in combat related, lower extremity limb salvage patients. AB - INTRODUCTION: Following severe lower extremity trauma, patients who undergo limb reconstruction and amputations both endure frequent complications and mental health sequelae. The purpose of this study is to assess the extent to which late amputation following a period of limb salvage impacts the evolution of the clinical variables that can affect the patient's perception of his or her limb: ongoing limb associated complications and mental health conditions. PATIENTS AND METHODS: A case series of US service members who sustained a late major extremity amputation from September 2001 through July 2011 were analysed. Pre- and post amputation complications, mental health conditions, and reason(s) for desiring amputation were recorded. RESULTS: Forty-four amputees with detailed demographic, injury and treatment data were identified. The most common reasons for desiring a late amputation were pain and being dissatisfied with the function of the salvage limb. An average of 3.2 (range 1-10) complications were reported per amputee prior to undergoing late amputation and an average of 1.8 (range 0-5) complications reported afterwards. The most common complication prior to and after late amputation was soft tissue infection (24 (17%) and 9 (22%), respectively). Twenty-nine (64%) late amputees were diagnosed with a mental health condition prior to undergoing their amputation and 27 (61%) late amputees were diagnosed with mental conditions after late amputation. Only three of the 15 patients who did not have a mental health condition documented prior to their late amputation remained free of a documented mental health condition after the amputation. DISCUSSION: Ongoing complications and mental health conditions can affect how a patient perceives and copes with his or her limb following severe trauma. Patient dissatisfaction following limb reconstruction can influence the decision to undergo a late amputation. Patients with a severe, combat related lower extremity injury that are undergoing limb salvage may not have a reduction in their overall complication rate, a resolution of specific complications or an improvement of their mental health after undergoing late amputation. CONCLUSION: Surgeons caring for limb salvage patients should counsel appropriately when managing expectations for a patient who desires a late amputation. PMID- 26003682 TI - Evolutionary trajectories of two distinct avian influenza epidemics: Parallelisms and divergences. AB - Influenza A virus can quickly acquire genetic mutations that may be associated with increased virulence, host switching or antigenic changes. To provide new insights into the evolutionary dynamics and the adaptive strategies of distinct avian influenza lineages in response to environmental and host factors, we compared two distinct avian influenza epidemics caused by the H7N1 and H7N3 subtypes that circulated under similar epidemiological conditions, including the same domestic species reared in the same densely populated poultry area for similar periods of time. The two strains appear to have experienced largely divergent evolution: the H7N1 viruses evolved into a highly pathogenic form, while the H7N3 did not. However, a more detailed molecular and evolutionary analysis revealed several common features: (i) the independent acquisition of 32 identical mutations throughout the entire genome; (ii) the evolution and persistence of two sole genetic groups with similar genetic characteristics; (iii) a comparable pattern of amino acid variability of the HA proteins during the low pathogenic epidemics; and (iv) similar rates of nucleotide substitutions. These findings suggest that the evolutionary trajectories of viruses with the same virulence level circulating in analogous epidemiological conditions may be similar. In addition, our deep sequencing analysis of 15 samples revealed that 17 of the 32 parallel mutations were already present at the beginning of the two epidemics, suggesting that fixation of these mutations may occur with different mechanisms, which may depend on the fitness gain provided by each mutation. This highlighted the difficulties in predicting the acquisition of mutations that can be correlated to viral adaptation to specific epidemiological conditions or to changes in virus virulence. PMID- 26003683 TI - Conjugated Linoleic Acid Supplementation has no Impact on Aerobic Capacity of Healthy Young Men. AB - This study investigated the effect of conjugated linoleic acid (CLA) on the aerobic capacity and anthropometric measurements of humans. Although this effect has been shown in animal studies, human studies have reported controversial results. In this double-blind, placebo-controlled, randomized clinical trial, 80 non-trained healthy young men received a 50:50 mixture of cis-9,trans-11 and trans-10 cis-12 CLA (CLA 4 * 0.8 g day(-1)) ora placebo (PLA; soybean oil) in an 8-week intervention. Maximal oxygen consumption (VO2 max), time to exhaustion, weight, body mass index (BMI) and waist circumference (WC) were measured. CLA had no effect on VO2 max (p = 0.5) also no change was seen in time to exhaustion (p = 0.51), weight (p = 0.7), BMI (p = 0.7) and WC (p = 0.8) vs PLA. Our results suggest that CLA has no significant effect on VO2 max, time to exhaustion and anthropometric measurements in untrained healthy young male students. PMID- 26003684 TI - More from ecologists to support natural history museums. PMID- 26003685 TI - Analysis of illegal peptide biopharmaceuticals frequently encountered by controlling agencies. AB - Recent advances in genomics, recombinant expression technologies and peptide synthesis have led to an increased development of protein and peptide therapeutics. Unfortunately this goes hand in hand with a growing market of counterfeit and illegal biopharmaceuticals, including substances that are still under pre-clinical and clinical development. These counterfeit and illegal protein and peptide substances could imply severe health threats as has been demonstrated by numerous case reports. The Belgian Federal Agency for Medicines and Health Products (FAMHP) and customs are striving, together with their global counterparts, to curtail the trafficking and distributions of these substances. At their request, suspected protein and peptide preparations are analysed in our Official Medicines Control Laboratory (OMCL). It stands to reason that a general screening method would be beneficiary in the battle against counterfeit and illegal peptide drugs. In this paper we present such general screening method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the identification of counterfeit and illegal injectable peptide preparations, extended with a subsequent quantification method using ultra-high performance liquid chromatography with diode array detection (UHPLC-DAD). The screening method, taking only 30 min, is able to selectively detect 25 different peptides and incorporates the proposed minimum of five identification points (IP) as has been recommended for sports drug testing applications. The group of peptides represent substances which have already been detected in illegal and counterfeit products seized by different European countries as well as some biopharmaceutical peptides which have not been confiscated yet by the controlling agencies, but are already being used according to the many internet users forums. Additionally, we also show that when applying the same LC gradient, it is also possible to quantify these peptides without the need for derivatization or the use of expensive labelled peptides. This quantification method was successfully validated for a representative subset of 10 different peptides by using the "total error" approach in accordance with the validation requirements of ISO 17025. PMID- 26003686 TI - Enzymatic amplification-free nucleic acid hybridisation sensing on nanostructured thick-film electrodes by using covalently attached methylene blue. AB - Amplification-free (referring to enzymatic amplification step) detection methodologies are increasing in biosensor development due to the need of faster and simpler protocols. However, for maintaining sensitivity without this step, highly detectable molecules or very sensitive detection techniques are required. The nanostructuration of transducer surfaces with carbon nanotubes (CNTs), gold nanoparticles (AuNPs) or both in nanohybrid configurations has been employed in this work for DNA hybridisation sensing purposes. Methylene blue (MB), covalently attached to single stranded DNA, (ssDNA) was incubated with a complementary sequence immobilized on nanostructured screen-printed electrodes (AuSPEs). Although CNTs can increase notoriously the signal of the marker, adsorptive properties should also be considered when bioassays are performed because non specific adsorption (NSA) phenomena are magnified. In this work, strategies for decreasing NSA were thoroughly evaluated for the detection of Mycoplasma pneumoniae (MP) on CNTs-nanostructured screen-printed electrodes. Among them, the employ of UV-radiation or long incubation times (72h) allowed obtaining higher signals for the complementary strand with respect to the non-complementary one. The use of CNTs/AuNPs nanohybrids, together with the use of streptavidin-biotin (ST-B) interaction allows the higher differentiation (with a 3.5 ratio) in the genosensing of M. pneumoniae. PMID- 26003687 TI - HPLC-HRMS method for fast phytochelatins determination in plants. Application to analysis of Clinopodium vulgare L. AB - An optimized analytical method based on C8 core-shell reverse phase chromatographic separation and high resolution mass spectral (HRMS) detection is developed for a fast analysis of unbound phytochelatins (PCs) in plants. Its application to analysis of Clinopodium vulgare L. is demonstrated where proper PCs liberating and preservation conditions were employed using dithiotreitol in the extraction step. A baseline separation of glutathione (GSH) and phytochelatins from 2 to 5 (PC2-PC5) for 3 min was achieved at conventional HPLC backpressure, with detection limits from 3 ppt (for GSH) to 2.5 ppb (for PC5). It is shown, that the use of HRMS with tandem mass spectral (MS/MS) capabilities permits additional wide range screening ability for iso-phytochelatins and PC similar compounds, based on exact mass and fragment spectra in a post acquisition manner. PMID- 26003688 TI - A comprehensive study of the enantioseparation of chiral drugs by cyclodextrin using capillary electrophoresis combined with theoretical approaches. AB - Four chiral drugs were enantioseparated by native beta-cyclodextrin (beta-CD) and negatively charged carboxymethyl-beta-cyclodextrin (CM-beta-CD) using capillary electrophoresis coupled with electrochemiluminescence detection (CE-ECL). Using 50 mM pH 5.5 Tris-H3PO4 with 10 mM CM-beta-CD as a running buffer, high resolution efficiency could be obtained. With the help of isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) and molecular modeling, the chiral recognition mechanism was comprehensively investigated. Thermodynamic parameters data from ITC revealed that CM-beta-CD exhibited stronger binding affinity with analytes than beta-CD, and that the driving forces of CM-beta-CD responsible for chiral recognition were mainly electrostatic interactions between negatively charged CM-beta-CD and positively charged analytes. In addition, from both a macroscopic and microscopic point of view, the results of NMR and molecular modeling investigation adequately confirm the conclusion by comparing the stereochemical structures of complexes. Combination of ITC, NMR and molecular modeling techniques not only can assist CE to investigate the chiral discrimination mechanism, but also can predict and guide CE enantioseparation efficiency conversely. PMID- 26003689 TI - Flow-injection amperometric determination of glucose using a biosensor based on immobilization of glucose oxidase onto Au seeds decorated on core Fe3O4 nanoparticles. AB - An amperometric biosensor based on chemisorption of glucose oxidase (GOx) on Au seeds decorated on magnetic core Fe3O4 nanoparticles (Fe3O4@Au) and their immobilization on screen-printed carbon electrode bulk-modified with manganese oxide (SPCE{MnO2}) was designed for the determination of glucose. The Fe3O4@Au/GOx modified SPCE{MnO2} was used in a flow-injection analysis (FIA) arrangement. The experimental conditions were investigated in amperometric mode with the following optimized parameters: flow rate 1.7 mL min(-1), applied potential +0.38 V, phosphate buffer solution (PBS; 0.1 mol L(-1), pH 7.0) as carrier and 3.89 unit mm(-2) enzyme glucose oxidase loading on the active surface of the SPCE. The designed biosensor in FIA arrangement yielded a linear dynamic range for glucose from 0.2 to 9.0 mmol L(-1) with a sensitivity of 2.52 uA mM(-1) cm(-2), a detection limit of 0.1 mmol L(-1) and a quantification limit of 0.3 mmol L(-1). Moreover, a good repeatability of 2.8% (number of measurements n=10) and a sufficient reproducibility of 4.0% (number of sensors n=3) were achieved. It was found that the studied system Fe3O4@Au facilitated not only a simpler enzyme immobilization but also provided wider linear range. The practical application of the proposed biosensor for FIA quantification of glucose was tested in glucose sirup samples, honeys and energy drinks with the results in good accordance with those obtained by an optical glucose meter and with the contents declared by the producers. PMID- 26003690 TI - Dynamic microwave assisted extraction coupled with dispersive micro-solid-phase extraction of herbicides in soybeans. AB - Non-polar solvent dynamic microwave assisted extraction was firstly applied to the treatment of high-fat soybean samples. In the dispersive micro-solid-phase extraction (D-u-SPE), the herbicides in the high-fat extract were directly adsorbed on metal-organic frameworks MIL-101(Cr). The effects of several experimental parameters, including extraction solvent, microwave absorption medium, microwave power, volume and flow rate of extraction solvent, amount of MIL-101(Cr), and D-u-SPE time, were investigated. At the optimal conditions, the limits of detection for the herbicides ranged from 1.56 to 2.00 MUg kg(-1). The relative recoveries of the herbicides were in the range of 91.1-106.7%, and relative standard deviations were equal to or lower than 6.7%. The present method was simple, rapid and effective. A large amount of fat was also removed. This method was demonstrated to be suitable for treatment of high-fat samples. PMID- 26003691 TI - Dielectric barrier discharge-assisted one-pot synthesis of carbon quantum dots as fluorescent probes for selective and sensitive detection of hydrogen peroxide and glucose. AB - In this work, we proposed a dielectric barrier discharge (DBD)-assisted one-pot strategy to fabricate carbon quantum dots (CQDs) using only one reagent N, N dimethylformamide (DMF) at atmospheric pressure and room temperature. The experimental conditions were carefully investigated, and the prepared CQDs were characterized by using UV-vis spectrophotometer, fluorescence spectrophotometer, Fourier transform infrared (FTIR) spectrometer, transmission electron microscopy (TEM) and X-ray photoelectron spectrometer (XPS). The CQDs have an average size of 3.6 nm in diameter with narrow size distribution, and can be used as highly selective and sensitive fluorescence probes for hydrogen peroxide and glucose, with limits of detection of 3.8 MUM and 3.5 MUM, respectively. PMID- 26003692 TI - Portable gliadin-immunochip for contamination control on the food production chain. AB - Celiac disease (CD) is one of the most common digestive disorders caused by an abnormal immune reaction to gluten. So far there are no available therapies, the only solution is a strict gluten-free diet, which however could be very challenging as gluten can be hidden in many food products. Furthermore an additional problem is related to cross-contamination of nominal gluten-free foods with gluten-based ones during manufacturing. Here we propose a lab on chip platform as a powerful tool to help food manufacturers to evaluate the real amount of gluten in their products by an accurate in-situ control of the production chain and maybe to specify the real gluten content in packages labeling. Our portable gliadin-immunochips, based on an electrochemical impedance spectroscopy transduction method, were first calibrated and then validated for both liquid and solid food matrixes by analyzing different beers and flours. The high specificity of our assay was also demonstrated by performing control experiments on rice and potatoes flours containing prolamin-like proteins. We achieved limit of quantification of 0.5 ppm for gliadin that is 20 times lower than the worldwide limit established for gluten-free food while the method of analysis is faster and cheaper than currently employed ELISA-based methods. Moreover our results on food samples were validated through a mass spectrometry standard analysis. PMID- 26003693 TI - Novel and rapid method for determination of organophosphorus pesticide residues in edible fungus using direct gas purge microsyringe extraction coupled on-line with gas chromatography-mass spectrometry. AB - In this work a new analytical method for a rapid and simultaneous determination of 28 organophosphorus pesticides (OPPs) residues in edible fungus using gas purge microsyringe extraction (GP-MSE), coupled with on-line gas chromatography mass spectrometry (GP-MSE-GC-MS) has been developed and optimized. GP-MSE, a novel gas flow liquid-phase microextraction technique, has been then fruitfully used as innovative and one-step extraction procedure, allowing a direct injection into the gas chromatograph coupled with a mass spectrometry detector (GC-MS) system without any further cleaning step. Once optimized, the GP-MSE-GC-MS analysis procedure showed reproducibility values, resolutions, linear responses, detection and quantification limits that allowed to consider this method suitable for the analysis of the 28 OPPs in real samples. Furthermore, OPP recoveries and the relative standard deviations (RSDs) ranged from 85.26% to 100.21%, and from 1.6% to 6.9%, respectively. This procedure was then used for the analysis of real samples and the obtained results were compared with those of ultrasonic extraction-solid phase extraction. Among the 28 OPPs, 14 of them were found in Lentinus edodes and Enoki mushrooms fungus samples, with a total concentrations of 112.7 and 210.7 MUg kg(-1), respectively. This work demonstrated then that GP MSE-GC-MS provided a highly efficient, solvent-saving, accurate and sensitive quantitative analysis method for a rapid determination of OPPs in edible fungus. PMID- 26003694 TI - Designing valid and optimised standard addition calibrations: Application to the determination of anions in seawater. AB - A strategy for designing valid standard addition calibrations and for optimising their uncertainty is presented. The design of calibrations involves the development of models of the sensitivity and precision of the instrumental signal, in a wide range of analyte concentration (or any other studied quantity), and the definition of sample dilution and standard addition procedures that allow fulfilling the assumptions of the linear unweighted regression model in, typically, a smaller range of standard addition calibrations. Calibrators are prepared by diluting the sample and adding analyte with negligible uncertainty to fit in a concentration range where signals are homoscedastic. The minimisation of the uncertainty is supported on detailed measurement uncertainty models function of the calibrators preparation procedure and of analytical instrumentation performance. The number of collected signals replicates is defined by balancing their impact on the estimated expanded uncertainty, the resources needed and the target (maximum) uncertainty for the intended use of measurements. The calibration design strategy was successfully applied to the determination of the mass concentration (mg L(-1)) of Cl(-), Br(-), NO3(-) and SO4(-2) in seawater by ion chromatography. A target expanded uncertainty of 20% was defined for the determination of Cl(-), NO3(-) and SO4(-2), or 40% for the determination of the smaller mass concentration of Br(-). The developed measurement model produced reliable predictions of the measurement uncertainty from approximate concentration of the analyte in the sample, before its accurate quantification, thus proving optimisation is effective. Predictions are more prone to the variability of the measurement uncertainty estimation if based on low number of calibrators signals. The reported relative expanded uncertainty ranged from 7.1% to 49%. PMID- 26003695 TI - Solvent bar micro-extraction: Improving hollow fiber liquid phase micro extraction applicability in the determination of Ni in seawater samples. AB - During the last decade, hollow fiber liquid phase micro-extraction (HF-LPME) has become an attractive alternative in sample treatment for the analysis of trace metals in seawater. If compared with other similar methodologies, its main advantages are associated to a higher stability of the organic solution contained into the pores of the fiber, which acts as a lipophilic membrane during the extraction process. However there are some remaining problems that makes its use difficult, mostly related to the need of increasing the rate of analysis and improving portability. In this paper a novel three phase solvent bar micro extraction (3PSBME) for the fiber device has been proposed. Its main advantage is that the 3PSBME device can be left free in the sample. This way the system is portable, and no special support is needed leading to the possibility of simultaneous extraction of several samples. In this work, multivariate central composite design of experiment has been carried out to optimize Ni pre concentration using di-2-ethylhexyl phosphoric acid (DEHPA) as extractant and HNO3 as acceptor agent. Factors influencing extraction have been the pH in the sample and the fiber length. For seawater samples, Ni can be pre-concentrated 11 times in 140 min. The method presents RSD 9.42% and limit of detection 44 ng L( 1), using GFAAS for instrumental determination. It has been applied for determination of Ni in seawater, including a reference material CRM-403 proving its applicability. PMID- 26003696 TI - Microchip electrophoretic separation and fluorescence detection of chelerythrine and sanguinarine in medicinal plants. AB - A new method has been developed for separation of chelerythrine and sanguinarine in medicinal plants used in traditional Chinese medicine (TCM). The separation is achieved by microchip electrophoresis (CE) using laser-induced fluorescence detection. The CE separation is achieved by using a hydro-organic medium as the electrolyte buffer. The experimental results are consistent with the prediction by theory in terms of resolution and migration speed because of the low Joule heat generated in microchip CE. In addition, formamide was found to have a potential for separation of molecules with similar chemical structures. Based on these findings, a run buffer containing 50% formamide was used to separate chelerythrine (CHE) and sanguinarine (SAN). The influencing factors, such as solvent of run buffer, pH of buffer, separation distance, and separation voltage, were optimized. Baseline separation of chelerythrine and sanguinarine was achieved within 120 s under an electrical voltage of 1.8 kV. Good linearity was observed in the concentration range of 0.15-550 MUg mL(-1) (r=0.9993) for CHE and in the range of 0.3-600 MUg mL(-1) (r=0.9998) for SAN. A low limit of detection (LOD) was achieved because of the high sensitivity achieved by laser-induced fluorescence detection (i.e. 5.0 ng mL(-1) and 2.0 ng mL(-1) for CHE and SAN, respectively). The contents of CHE are found to be 641.8+/-7.5 and 134.0+/-2.3 mg/kg in extracts of Macleaya cordata and Chelidonium majus, respectively, with good recovery of above 99%. The corresponding values for SAN found in these Chinese herbal extracts are 681.8+/-7.9 mg/kg and 890.5+/-8.9 mg/kg, respectively. PMID- 26003697 TI - Simultaneous determination of four trace level endocrine disrupting compounds in environmental samples by solid-phase microextraction coupled with HPLC. AB - A simple, rapid, sensitive and effective method for the simultaneous determination of four endocrine disrupting compounds (EDCs) (bisphenol A (BPA), bisphenol F (BPF), bisphenol AF (BPAF) and bisphenol AP (BPAP)) in environment water samples based on solid-phase microextraction (SPME) coupled with high performance liquid chromatography (HPLC) was developed. Multi-wall carbon nanotubes (MWCNTs) adsorbents showed a good affinity to the target analytes. These compounds were rapidly extracted within 10 min. Various experimental parameters that could affect the extraction efficiencies had been investigated in detail. Under the optimum conditions, the enrichment factors of the method for the target EDCs were found to be 500. Satisfactory precision and accuracy of the method were obtained in a low concentration range of 2.0-500.0 ng mL(-1). The method detection limits were in the range of 0.10-0.30 ng mL(-1). The high pre concentration rate and efficiency of the method ensure its successful application in extraction of trace EDCs from large volumes of environmental water samples. The extraction recoveries in real samples ranged from 85.3% to 102.5% with the relative standard deviations (n=5) less than 3.74%. PMID- 26003698 TI - Use of ZIF-8-derived nanoporous carbon as the adsorbent for the solid phase extraction of carbamate pesticides prior to high-performance liquid chromatographic analysis. AB - In this work, a chemically and thermally robust and highly porous zeolite-type metal-organic framework, zeolitic imidazolate framework-8 (ZIF-8), was used as both a precursor and a template and furfuryl alcohol as a second precursor to synthesize a nanoporous carbon. The prepared ZIF-8-derived nanoporous carbon was used as the solid-phase extraction adsorbent for the extraction of carbamate pesticides from cabbage and water samples. The adsorbed analytes were eluted with acetonitrile for the determination by high performance liquid chromatography ultraviolet detection. The high surface area, high porosity, good stability and fast adsorption/desorption kinetics of the material enabled it to have a high adsorption capacity and good adsorption performance. Under optimum conditions, good linearity for the analytes in the range of 0.5-100 ng g(-1) and 0.05-20 ng mL(-1) existed for cabbage and water samples with the correlation coefficients of 0.9968-0.9980 and 0.9990-0.9995, respectively. The limits of detection (S/N=3) for the analytes were in the range of 0.25-0.1 ng g(-1) and 0.01-0.02 ng mL(-1) for the cabbage and water samples, respectively. The relative standard deviations (RSDs) for intra-day and the inter-day determinations of the analytes were below 7.0% and 12.5%, respectively. PMID- 26003699 TI - Exploration of attenuated total reflectance mid-infrared spectroscopy and multivariate calibration to measure immunoglobulin G in human sera. AB - Immunoglobulin G (IgG) is crucial for the protection of the host from invasive pathogens. Due to its importance for human health, tools that enable the monitoring of IgG levels are highly desired. Consequently there is a need for methods to determine the IgG concentration that are simple, rapid, and inexpensive. This work explored the potential of attenuated total reflectance (ATR) infrared spectroscopy as a method to determine IgG concentrations in human serum samples. Venous blood samples were collected from adults and children, and from the umbilical cord of newborns. The serum was harvested and tested using ATR infrared spectroscopy. Partial least squares (PLS) regression provided the basis to develop the new analytical methods. Three PLS calibrations were determined: one for the combined set of the venous and umbilical cord serum samples, the second for only the umbilical cord samples, and the third for only the venous samples. The number of PLS factors was chosen by critical evaluation of Monte Carlo-based cross validation results. The predictive performance for each PLS calibration was evaluated using the Pearson correlation coefficient, scatter plot and Bland-Altman plot, and percent deviations for independent prediction sets. The repeatability was evaluated by standard deviation and relative standard deviation. The results showed that ATR infrared spectroscopy is potentially a simple, quick, and inexpensive method to measure IgG concentrations in human serum samples. The results also showed that it is possible to build a united calibration curve for the umbilical cord and the venous samples. PMID- 26003700 TI - Preparation and properties of a new solid state arsenate As(V) ion selective electrode and its application. AB - In this study a new solid-state ion selective electrode which is easy to prepare and sensitive to arsenate ion concentration is prepared. The solid salts used in the electrode composition were Cu2S, Ag3AsO4 and Ag2S. The principal component of the electrode was Ag3AsO4. The measurements were made in constant ionic strength using 0.1M NaNO3 and at room temperature. The potentiometric response of electrodes prepared in various compositions was investigated against arsenate ion concentration. The highest slope was obtained with 40% Ag3AsO4, 30% Cu2S and 30% Ag2S. This electrode showed linear response for arsenate ion in the 10(-5)-10(-1) M concentration range. An analytically useful potential change occurred, from 1*10(-6) to 1*10(-1) M arsenate. The slope of the linear portion was about 19+/-2 mV/10-fold change in arsenate concentration. The lifetime of the electrode was more than two years, when used at least 4-5 times a day, and the response time was about 20-30s depending on the concentration changes. The interference of most common ions and the effect of pH (6-10) have been investigated. This electrode has been used for the determination of arsenate ion in beer sample. PMID- 26003701 TI - An on-line SPE-HPLC method for effective sample preconcentration and determination of fenoxycarb and cis, trans-permethrin in surface waters. AB - A new on-line SPE-HPLC method using fused-core columns for on-line solid phase extraction and large volume sample injection for increasing the sensitivity of detection was developed for the determination of insecticides fenoxycarb and cis , trans-permethrin in surface waters. The separation was carried out on fused core column Phenyl-Hexyl (100*4.6 mm), particle size 2.7 um with mobile phase acetonitrile:water in gradient mode at flow rate 1.0 mL min(-1), column temperature 45 degrees C. Large volume sample injection (1500 uL) to the extraction dimension using short precolumn Ascentis Express RP C-18 (5*4.6 mm); fused-core particle size 2.7 um allowed effective sample preconcentration and efficient ballast sample matrix removal. The washing mobile phase consisting of a mixture of acetonitrile:water; 30:70, (v/v) was pumped at flow rate of 0.5 mL min(-1) through the extraction precolumn to the waste. Time of the valve switch for transferring the preconcentrated sample zone from the extraction to the separation column was set at 3rd min. Elution of preconcentrated insecticides from the extraction precolumn and separation on the analytical column was performed in gradient mode. Linear gradient elution started from 40% of acetonitrile at time of valve switch from SPE column (3rd min) to 95% of acetonitrile at 7th min. Synthetic dye sudan I was chosen as an internal standard. UV detection at wavelength 225 nm was used and the method reached the limits of detection (LOD) at ng mL(-1) levels for both insecticides. The method showing on-line sample pretreatment and preconcentration with highly sensitive determination of insecticides was applied for monitoring of fenoxycarb and both permethrin isomers in different surface water samples in Czech Republic. The time of whole analysis including on-line extraction, interferences removal, chromatography separation and system equilibration was less than 8 min. PMID- 26003702 TI - One-pot green synthesis of oxygen-rich nitrogen-doped graphene quantum dots and their potential application in pH-sensitive photoluminescence and detection of mercury(II) ions. AB - Nitrogen doping has been a powerful method to modulate the properties of carbon materials for various applications, and N-doped graphene quantum dots (GQDs) have gained remarkable interest because of their unique chemical, electronic, and optical properties. Herein, we introduce a facile one-pot solid-phase synthesis strategy for N-doped GQDs using citric acid (CA) as the carbon source and 3,4 dihydroxy-L-phenylalanine (L-DOPA) as the N source. The as-prepared N-GQDs with oxygen-rich functional groups are uniform with an average diameter of 12.5 nm. Because of the introduction of nitrogen atoms, N-GQDs exhibit excitation wavelength-independent fluorescence with the maximum emission at 445 nm, and a high quantum yield of 18% is achieved at an excitation wavelength of 346 nm. Furthermore, a highly efficient fluorosensor based on the as-prepared N-GQDs was developed for the detection of Hg(2+) because of the effective quenching effect of metal ions via nonradiative electron transfer. This fluorosensor exhibits high sensitivity toward Hg(2+) with a detection limit of 8.6 nM. The selectivity experiments reveal that the fluorescent sensor is specific for Hg(2+). Most importantly, the practical use of the sensor based on N-GQDs for Hg(2+) detection was successfully demonstrated in river-water samples. PMID- 26003703 TI - A gas-diffusion flow injection method coupled with online solid-liquid extraction for the determination of ammonium in solid samples. AB - A simple, rapid and reliable gas-diffusion flow injection (GD-FI) method for ammonium determination in building materials has been developed. It is based on leaching ammonium from a ground solid sample into an alkaline solution with subsequent ammonia gas generation. Ammonia is then transported in a nitrogen stream to the GD cell of the FI system where it is absorbed into its acceptor solution containing a mixture of the acid-base indicators cresol red and thymol blue. The maximum increase in the absorbance of the acceptor solution at 580 nm is related to the ammonium concentration in the solid sample. The proposed method is characterized by a linear concentration range of 0.1-5.0 mg NH4(+) kg(-1), a limit of detection of 8 MUg NH4(+) kg(-1) and a sample throughput of 10h(-1). A successful application of this method for the determination of ammonium in building materials such as concrete, cement and sand is reported. PMID- 26003704 TI - Immunochromatographic assay for quantitative and sensitive detection of hepatitis B virus surface antigen using highly luminescent quantum dot-beads. AB - Hepatitis B virus infection is one of the major causes of hepatitis, liver cirrhosis and liver cancer. In this study, we used highly luminescent quantum dot beads (QBs) as signal amplification probes in the sandwich immunochromatographic assay (ICA) for ultrasensitive and quantitative detection of hepatitis B virus surface antigen (HBsAg) in human serum. Various parameters that influenced the sensitivity and stability of the QB-based ICA (QB-ICA) sensor were investigated. Two linear independent regression equations for detection of serum HBsAg were expressed with Y=0.3361X-0.0059 (R(2)=0.9983) for low HBsAg concentrations between 75 pg mL(-1) and 4.8 ng mL(-1), and Y=0.8404 X-2.9364 (R(2)=0.9939) for high HBsAg concentrations in the range from 4.8 ng mL(-1) to 75 ng mL(-1). The detection limit of the proposed ICA sensor achieved was 75 pg mL(-1), which is much higher than that of the routinely-used gold nanoparticle based ICA. The intra- and inter-assays recovery rates for spiked serum samples at HBsAg concentrations of 75 pg mL(-1), 3.75 ng mL(-1) and 18.75 ng mL(-1) ranged from 90.14% to 97.6%, and coefficients of variation were all below 7%, indicating that the QB-ICA sensor has an acceptable accuracy for HBsAg detection. Additionally, the quantitative method developed showed no false positive results in an analysis of 49 real HBsAg-negative serum samples, and exhibited excellent agreement (R(2)=0.9209) with a commercial chemiluminescence immunoassay kit in identifying 47 HBsAg-positive serum samples. In summary, due to its high fluorescence intensity, the sandwich QB-ICA sensor is a very promising point-of-care test for rapid, simple and ultrasensitive detection of HBsAg, as well as other disease related protein biomarkers. PMID- 26003705 TI - Application of an HS-MS for the detection of ignitable liquids from fire debris. AB - In arson attacks, accelerants such as ignitable liquids are commonly used to initiate or accelerate a fire. The detection of ignitable liquid residues at fire scenes is therefore a key step in fire investigations. The most widely used analytical technique for the analysis of accelerants is GC-MS. However, pre concentration of the ignitable liquid residues is required prior to the chromatographic analysis. The standard method, ASTM E1412, involves passive headspace concentration with activated charcoal strips as a method to isolate the ignitable liquid residues from fire debris and these residues are subsequently desorbed from the carbon strip with solvents such as carbon disulfide. In the work described here, an alternative analytical technique based on an HS-MS (headspace mass spectrometry) has been developed for the thermal desorption of the carbon strips and analysis of different ignitable liquid residues in fire debris. The working conditions for the HS-MS analytical procedure were optimized using different types of fire debris (pine wood burned with gasoline and diesel). The optimized variables were desorption temperature and desorption time. The optimal conditions were 145 degrees C and 15 min. The optimized method was applied to a set of fire debris samples. In order to simulate post burn samples several accelerants (gasoline, diesel, citronella, kerosene, paraffin, and alcohol) were used to ignite different substrates (wood, cotton, cork, paper, and paperboard). chemometric methods (cluster analysis and discriminant analysis) were applied to the total ion spectrum obtained from the MS (45-200 m/z) to discriminate between the burned samples according to the accelerant used. The method was validated by analyzing all samples by GC-MS according to the standard methods ASTM E1412 and ASTM E1618. The results obtained on using the method developed in this study were comparable to those obtained with the reference method. However, the newly developed HS-MS method is faster, safer, and more environmental friendly than the standard method. PMID- 26003706 TI - A categorical review on electroanalytical determination of non-narcotic over-the counter abused antitussive drugs. AB - Dextromethorphan (DXM) and diphenhydramine (DPH) are two commonly used over-the counter non-narcotic antitussive drugs. Recent reports reveal the widespread abuse of DXM and DPH due to their euphoric and alcohol-like effects. Due to their medicinal importance as well as the apparent increase in their use as abused drugs, it has become critical to determine them in samples of biological, clinical and pharmaceutical interest. The electrochemical techniques for drug analysis have gathered considerable attention due to their pronounced selectivity, sensitivity and simplicity. The given review presents a compilation of published voltammetric and potentiometric methods developed for determination of DXM and DPH. It critically highlights the analytical performances, revealing the recent trends and progress in the specified approach for their analysis. The review forms a basis for further progress in this field and development of improved electrochemical sensors to determine the drug. PMID- 26003707 TI - Simultaneous speciation analysis of chromate, molybdate, tungstate and vanadate in welding fume alkaline extracts by HPLC-ICP-MS. AB - A novel analytical procedure was developed for the simultaneous speciation analysis of chromate, molybdate, tungstate and vanadate by anion-exchange high performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Linear gradient elution from 100% water to 100% 0.7 M NaCl was applied for chromatographic separation of metal species. In standard aqueous solution at neutral pH molybdate, tungstate and vanadate exist in several aqueous species, while chromate is present as a single CrO4(2-) species. Consequently, only chromate can be separated from this solution in a sharp chromatographic peak. For obtaining sharp chromatographic peaks for molybdate, tungstate and vanadate, the pH of aqueous standard solutions was raised to 12. At highly alkaline conditions single CrO4(2-), MoO4(2-) and WO4(2-) are present and were eluted in sharp chromatographic peaks, while VO4(3-) species, which predominates at pH 12 was eluted in slightly broaden peak. In a mixture of aqueous standard solutions (pH 12) chromate, molybdate, tungstate and vanadate were eluted at retention times from 380 to 420 s, 320 to 370 s, 300 to 350 s and 240 to 360 s, respectively. Eluted species were simultaneously detected on-line by ICP-MS recording m/z 52, 95, 182 and 51. The developed procedure was successfully applied to the analysis of leachable concentrations of chromate, molybdate, tungstate and vanadate in alkaline extracts (2% NaOH+3% Na2CO3) of manual metal arc (MMA) welding fumes loaded on filters. Good repeatability and reproducibility of measurement (RSD+/-3.0%) for the investigated species were obtained in both aqueous standard solutions (pH 12) and in alkaline extracts of welding fumes. Low limits of detection (LODs) were found for chromate (0.02 ng Cr mL(-1)), molybdate (0.1 ng Mo mL(-1)), tungstate (0.1 ng W mL(-1)) and vanadate (0.2 ng V mL(-1)). The accuracy of analytical procedure for the determination of chromate was checked by analysis of CRM 545, Cr(VI) in welding dust loaded on a filter. Good agreement between determined and reported certified values was obtained. For molybdate, tungstate and vanadate the assessment of accuracy was performed by spiking welding fume filters. Good recoveries for all investigated species (98-101%) confirmed the accuracy of the analytical procedure. PMID- 26003708 TI - Rapid screening of aflatoxin B1 in beer by fluorescence polarization immunoassay. AB - This manuscript describes the development of a sensitive, fast and easily performed fluorescence polarization immunoassay (FPIA) for the mycotoxin aflatoxin B1 (AFB1) in various beer samples, both lager and dark. The highest sensitivity was determined for six poly- and monoclonal antibodies selective towards aflatoxins. The sample pretreatment design was emphasized since beer samples are characterized by extremely diverse matrices. Herein, the choice of sorbent for effective removal of matrix interferences prior to analysis was crucial. The samples were diluted with a borate buffer solution containing 1% PEG 6000 and passed through the clean-up column packed with NH2-derivated silica. This sample pretreatment technique was perfectly suitable for the FPIA of lager beer samples, but for dark beer and ale it did not suffice. An artificial matrix was constructed to plot a calibration curve and quantify the results of the latter samples. The developed immunoassay was characterized by a limit of detection of 1 ng mL(-1). Apparent recovery values of 89-114% for lager and 80 125% for dark beer were established. The FPIA data for AFB1 was characterized by elevated linear regression coefficients, 0.9953 for spiked lager and 0.9895 for dark beer samples respectively. PMID- 26003709 TI - Sensitive fluorescent assay for copper (II) determination in aqueous solution using copper-specific ssDNA and Sybr Green I. AB - This paper reports a fluorescent turn-off assay for sensitive detection of Cu(2+) in an aqueous solution by using a copper-specific ssDNA Cu100 and Sybr Green I. By monitoring the fluorescence changes arose from different interactions of Sybr Green I with Cu100 and Cu100/Cu(2+) complex, the Cu(2+) could be linearly detected from 5.57 to 250 ppb, with a detection limit of 5.57 ppb. The feasibility of this assay was demonstrated by detecting Cu(2+) in certified reference materials and spiked water samples with satisfactory results. PMID- 26003710 TI - A label-free impedimetric immunosensor for direct determination of the textile dye Disperse Orange 1. AB - A strategy for a label-free impedimetric immunosensor is described for detection of the textile dye Disperse Orange 1 (DO1). The compounds 1,12-diaminododecane (DADD) and then 1,7-diaminoheptane (DAH) were firstly successively grafted onto a glassy carbon electrode (GCE) surface by electro-oxidation of one amino group, while the other terminal amino group was modified with the antibody anti-DO1. The construction process of the immunosensor was characterized by cyclic voltammetry, electrochemical impedance spectroscopy and capacitance measurements. The electron transfer resistance (Rct) exhibited an effective response to the affinity between the immobilized antibody and the antigen in solution. The linear range for the target compound was from 5.0 nmol L(-1) to 0.5 MUmol L(-1) (R=0.9980), and the limit of detection (LOD) was 7.56 nmol L(-1). The proposed impedimetric immunosensor has the advantages of simplicity, cost-effectiveness, and sensitivity. PMID- 26003712 TI - Prediction of the distillation temperatures of crude oils using 1H NMR and support vector regression with estimated confidence intervals. AB - This paper aims to estimate the temperature equivalent to 10% (T10%), 50% (T50%) and 90% (T90%) of distilled volume in crude oils using (1)H NMR and support vector regression (SVR). Confidence intervals for the predicted values were calculated using a boosting-type ensemble method in a procedure called ensemble support vector regression (eSVR). The estimated confidence intervals obtained by eSVR were compared with previously accepted calculations from partial least squares (PLS) models and a boosting-type ensemble applied in the PLS method (ePLS). By using the proposed boosting strategy, it was possible to identify outliers in the T10% property dataset. The eSVR procedure improved the accuracy of the distillation temperature predictions in relation to standard PLS, ePLS and SVR. For T10%, a root mean square error of prediction (RMSEP) of 11.6 degrees C was obtained in comparison with 15.6 degrees C for PLS, 15.1 degrees C for ePLS and 28.4 degrees C for SVR. The RMSEPs for T50% were 24.2 degrees C, 23.4 degrees C, 22.8 degrees C and 14.4 degrees C for PLS, ePLS, SVR and eSVR, respectively. For T90%, the values of RMSEP were 39.0 degrees C, 39.9 degrees C and 39.9 degrees C for PLS, ePLS, SVR and eSVR, respectively. The confidence intervals calculated by the proposed boosting methodology presented acceptable values for the three properties analyzed; however, they were lower than those calculated by the standard methodology for PLS. PMID- 26003711 TI - Rapid analysis of synthetic cannabinoids using a miniature mass spectrometer with ambient ionization capability. AB - Synthetic cannabinoids are an emerging class of drugs of abuse and are of a great concern for transport control and usage regulation. In this study, we have developed rapid analytical methods using a miniature mass spectrometer for the identification of synthetic cannabinoids, as the traces of bulk powders on surfaces or substances in blood and urine. Significantly simplified work flows were developed by employing two ambient ionization methods, the paper spray and extraction spray ionization. Using five synthetic cannabinoids as examples, a limit of detection of 2 ng was estimated for the detection of trace powders on a bench surface and limits of quantitation as good as 10 ng/mL were obtained for the analysis of blood and urine samples. PMID- 26003713 TI - Detection of aflatoxin B1 with immunochromatographic test strips: Enhanced signal sensitivity using gold nanoflowers. AB - Immunochromatographic test strips (ICTS) are commonly limited to higher concentrations of analytes. This limitation stems from the relatively low sensitivity of conventional gold nanospheres (AuNSs with a diameter of 20 nm) to emit detectable brightness values. The larger multi-branched gold nanoflowers (AuNFs) with a higher optical brightness as well as good colloidal stability exhibit significant improvements over conventional AuNSs for enhanced sensitivity of ICTS. In this study, blue AuNFs with an average diameter of 75+/-5 nm were synthetized and employed as a signal amplification probe for ultrasensitive and quantitative detection of aflatoxin B1 (AFB1) in rice. A portable optical strip reader was used to record the optical densities of test and control lines of the strip. Under the optimal conditions, the AuNF based ICTS system accurately detected AFB1 linearly and dynamically over the range of 0.5-25 pg/mL with a half maximal inhibitory concentration at 4.17 pg/mL. The inhibitory concentration was achieved 10 times lower than that of the traditional AuNS based ICTS systems (41.25 pg/mL). The limit of detection for AFB1 in rice extract was achieved at 0.32 pg/mL. In summary, AuNFs are a novel probe that exhibited excellent sensitivity in the ICTS system and could be used for ultrasensitive detection of other analytes in food safety monitoring, and even medical diagnostics. PMID- 26003714 TI - Simultaneous speciation of inorganic arsenic, selenium and tellurium in environmental water samples by dispersive liquid liquid microextraction combined with electrothermal vaporization inductively coupled plasma mass spectrometry. AB - A new method based on dispersive liquid liquid microextraction (DLLME) combined with electrothermal vaporization inductively coupled plasma mass spectrometry (ETV-ICP-MS) was developed for the simultaneous speciation of inorganic arsenic (As), selenium (Se) and tellurium (Te) with sodium diethyldithiocarbamate (DDTC) as both chelating reagent and chemical modifier. As(III), Se(IV) and Te(IV) were transformed into DDTC-chelates at pH 7 and extracted into the fine droplets formed by injecting the binary solution of bromobenzene (extraction solvent) and methanol (dispersive solvent) into the sample solution. After phase separation by centrifugation, As(III), Se(IV) and Te(IV) preconcentrated in the organic phase were determined by ETV-ICP-MS. Total inorganic As, Se and Te were obtained by reducing As(V), Se(VI) and Te(VI) to As(III), Se(IV) and Te(IV) with L-cysteine, which were then subjected to the same DLLME-ETV-ICP-MS process. The concentration of As(V), Se(VI), Te(VI) were calculated by subtracting the concentration of As(III), Se(IV) and Te(IV) from the total inorganic As, Se and Te, respectively. The main factors affecting the microextraction efficiency and the vaporization behavior of target species were investigated in detail. Under the optimal conditions, the limits of detection were 2.5, 8.6 and 0.56 ng L(-1) for As(III), Se(IV) and Te(IV), respectively, with the relative standard deviations (n=7) of 8.5-9.7%. The developed method was applied to the speciation of inorganic As, Se and Te in Certified Reference Materials of GSBZ50004-88, GBW(E)080395 and GBW(E)080548 environmental waters, and the determined values are in good agreement with the certified values. The method was also successfully applied to the simultaneous speciation of inorganic As, Se and Te in different environmental water samples with the recoveries in the range of 86.3-107% for the spiked samples. PMID- 26003715 TI - Sensitive voltammetric determination of lead released from ceramic dishes by using of bismuth nanostructures anchored on biochar. AB - A simple and sensitive electroanalytical method was developed for determination of nanomolar levels of Pb(II) based on the voltammetric stripping response at a carbon paste electrode modified with biochar (a special charcoal) and bismuth nanostructures (nBi-BchCPE). The proposed methodology was based on spontaneous interactions between the highly functionalized biochar surface and Pb(II) ions followed by reduction of these ions into bismuth nanodots which promote an improvement on the stripping anodic current. The experimental procedure could be summarized in three steps: including an open circuit pre-concentration, reduction of accumulated lead ions at the electrode surface and stripping step under differential pulse voltammetric conditions (DPAdSV). SEM images revealed dimensions of bismuth nanodots ranging from 20 nm to 70 nm. The effects of main parameters related to biochar, bismuth and operational parameters were examined in detail. Under the optimal conditions, the proposed sensor has exhibited linear range from 5.0 to 1000 nmol L(-1) and detection limit of 1.41 nmol L(-1) for Pb(II). The optimized method was successfully applied for determination of Pb(II) released from overglaze-decorated ceramic dishes. Results obtained were compared with those given by inductively coupled plasma optical emission spectroscopy (ICP OES) and they are in agreement at 99% of confidence level. PMID- 26003716 TI - Determination of malachite green in fish based on magnetic molecularly imprinted polymer extraction followed by electrochemiluminescence. AB - A novel procedure for selective extraction of malachite green (MG) from fish samples was set up by using magnetic molecularly imprinted polymers (MMIP) as the solid phase extraction material followed by electrochemiluminescence (ECL) determination. MMIP was prepared by using Fe3O4 magnetite as magnetic component, MG as template molecule, methacrylic acid (MAA) as functional monomer and ethylene glycol dimethacrylate (EGDMA) as crosslinking agent. MMIP was characterized by SEM, TEM, FT-IR, VSM and XRD. Leucomalachite green (LMG) was oxidized in situ to MG by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). And then MMIP was successfully used to selectively enrich MG from fish samples. Adsorbed MG was desorbed and determined by ECL. Under the optimal conditions, calibration curve was good linear in the range of 0.29-290 MUg/kg and the limit of detection (LOD) was 7.3 ng/kg (S/N=3). The recoveries of MMIP extraction were 77.1-101.2%. In addition, MMIP could be regenerated. To the best of our knowledge, MMIP coupling with ECL quenching of Ru(bpy)3(2+)/TPA for the determination of MG has not yet been developed. PMID- 26003717 TI - Design of a dual-function peptide probe as a binder of angiotensin II and an inducer of silver nanoparticle aggregation for use in label-free colorimetric assays. AB - Label-free colorimetric assays using metallic nanoparticles have received much recent attention, for their application in simple and sensitive methods for detection of biomolecules. Short peptide probes that can bind to analyte biomolecules are attractive ligands in molecular nanotechnology; however, identification of biological recognition motifs is usually based on trial-and error experiments. Herein, a peptide probe was screened for colorimetric detection of angiotensin II (Ang II) using a mechanism for non-crosslinking aggregation of silver nanoparticles (AgNPs). The dual-function peptides, which bind to the analyte and induce AgNP aggregation, were identified using a two-step strategy: (1) screening of an Ang II-binding peptide from an Ang II receptor sequence library, using SPOT technology, which enable peptides synthesis on cellulose membranes via an Fmoc method and (2) selection of peptide probes that effectively induce aggregation of AgNPs using a photolinker modified peptide array. Using the identified peptide probe, KGKNKRRR, aggregation of AgNPs was detected by observation of a pink color in the absence of Ang II, whereas AgNPs remained dispersed in the presence of Ang II (yellow). The color changes were not observed in the presence of other hormone molecules. Ang II could be detected within 15 min, with a detection limit of 10 uM, by measuring the ratio of absorbance at 400 nm and 568 nm; the signal could also be observed with the naked eye. These data suggest that the peptide identified here could be used as a probe for simple and rapid colorimetric detection of Ang II. This strategy for the identification of functional peptides shows promise for the development of colorimetric detection of various diagnostically important biomolecules. PMID- 26003718 TI - HPLC-UV method validation for the identification and quantification of bioactive amines in commercial eggs. AB - A quantitative and confirmatory high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method for the determination of bioactive amines in the albumen and yolk of commercial eggs was developed, optimized and validated by analyte extraction with trichloroacetic acid and pre-column derivatization with dansyl chloride. Phenylethylamine, putrescine, cadaverine, histamine, tyramine, spermidine and spermine standards were used to evaluate the following performance parameters: limit of detection (LoD), limit of quantification (LoQ), selectivity, linearity, precision, recovery and ruggedness. The LoD of the method was defined from 0.2 to 0.3 mg kg(-1) for the yolk matrix and from 0.2 to 0.4 mg kg(-1) for the albumen matrix; the LoQ was from 0.7 to 1.0 mg kg(-1) for the yolk matrix and from 0.7 to 1.1 mg kg(-1) for the albumen matrix. The validated method exhibited excellent selectivity and separation of all amines with coefficients of determination higher than 0.99. The obtained recovery values were from 90.5% to 108.3%, and the relative standard deviation (RSD) was lower than 10% under repeatability conditions for the studied analytes. The performance parameters show the validated method to be adequate for the determination of bioactive amines in egg albumen and yolk. PMID- 26003719 TI - Construction of effective disposable biosensors for point of care testing of nitrite. AB - In this paper we aim to demonstrate, as a proof-of-concept, the feasibility of the mass production of effective point of care tests for nitrite quantification in environmental, food and clinical samples. Following our previous work on the development of third generation electrochemical biosensors based on the ammonia forming nitrite reductase (ccNiR), herein we reduced the size of the electrodes' system to a miniaturized format, solved the problem of oxygen interference and performed simple quantification assays in real samples. In particular, carbon paste screen printed electrodes (SPE) were coated with a ccNiR/carbon ink composite homogenized in organic solvents and cured at low temperatures. The biocompatibility of these chemical and thermal treatments was evaluated by cyclic voltammetry showing that the catalytic performance was higher with the combination acetone and a 40 degrees C curing temperature. The successful incorporation of the protein in the carbon ink/solvent composite, while remaining catalytically competent, attests for ccNiR's robustness and suitability for application in screen printed based biosensors. Because the direct electrochemical reduction of molecular oxygen occurs when electroanalytical measurements are performed at the negative potentials required to activate ccNiR (ca.-0.4V vs Ag/AgCl), an oxygen scavenging system based on the coupling of glucose oxidase and catalase activities was successfully used. This enabled the quantification of nitrite in different samples (milk, water, plasma and urine) in a straightforward way and with small error (1-6%). The sensitivity of the biosensor towards nitrite reduction under optimized conditions was 0.55 A M(-1) cm(-2) with a linear response range 0.7-370 MUM. PMID- 26003720 TI - New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants. AB - Platinum drugs have been widely used for the treatment of several solid tumors. Although DNA has been recognized as the primary cellular target for these agents, there are unresolved issues concerning their effects and the molecular mechanisms underlying the antitumor efficacy. These cytotoxic agents interact with sub cellular compartments other than the nucleus. Here, we review how such emerging phenomena contribute to the pharmacologic activity as well as to drug resistance phenotypes. DNA-unrelated effects of platinum drugs involve alterations at the plasma membrane and in endo-lysosomal compartments. A direct interaction with the mitochondria also appears to be implicated in drug-induced cell death. Moreover, the pioneering work of a few groups has shown that platinum drugs can act on the tumor microenvironment as well, and potentiate antitumor activity of the immune system. These poorly understood aspects of platinum drug activity sites may be harnessed to enhance their antitumor efficacy. A complete understanding of DNA unrelated effects of platinum compounds might reveal new aspects of drug resistance allowing the implementation of the antitumor therapeutic efficacy of platinum compound-based regimens and minimization of their toxic side effects. PMID- 26003721 TI - Insertion of central venous catheter in cachectic patients. PMID- 26003722 TI - Galleria mellonella Larvae as an Infection Model for Penicillium marneffei. AB - Penicillium marneffei, the only known dimorphic and pathogenic species in the genus of Penicillium, is responsible for severe to deadly infection in immunocompromised patients. In this study, P. marneffei was able to infect the greater wax moth Galleria mellonella. The increasing inoculum doses of P. marneffei cells resulted in greater larval mortality, and the larval mortality rate also depended on the incubation temperature after P. marneffei infection and different P. marneffei strains. Moreover, the phagocytosis of hemocytes to P. marneffei was investigated, and it showed that the phagocytosis was increasing during the infection. These results demonstrated that G. mellonella can be effectively used to facilitate the in vivo study of P. marneffei infection and hemocytes are the key component of the larvae's immune defenses. PMID- 26003723 TI - The traditional herbal medicine, Ge-Gen-Tang, inhibits pacemaker potentials by nitric oxide/cGMP dependent ATP-sensitive K(+) channels in cultured interstitial cells of Cajal from mouse small intestine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ge-Gen-Tang (GGT) is a traditional Chinese medicinal formula composed of Puerariae radix (Pueraria lobata Ohwi), Ephedrae Herba (Ephedra sinica Stapf), Cinnamomi Ramulus (Cinnamomum cassia Blume), Paeoniae Radix (Paeonia lactiflora Pallas), Glycyrrhizae Radix preparata (Glycyrrhiza uralensis Fischer), Zingiberis Rhizoma (Zingiber officinale Roscoe), and Zizyphi Fructus (Ziziphus jujuba Mill. var. inermis Rehder) and is widely used to ameoliorate the symptoms of gastrointestinal (GI) disorders related to diarrhea and intestinal mucosal immunity and for anti-cold, antipyretic and analgesic in Eastern Asia. AIM OF THE STUDY: Interstitial cells of Cajal (ICCs) are pacemaker cells in the GI tract that generate rhythmic oscillations in membrane potentials known as slow waves. We investigated the effects of GGT on pacemaker potentials in cultured ICCs from the mouse small intestine, and sought to identify the receptors and the action mechanisms involved. MATERIALS AND METHODS: Enzymatic digestions were used to dissociate ICCs from mouse small intestine tissues. All experiments on ICCs were performed on within 12h after culture. A whole-cell patch-clamp configuration was used to record potentials (current clamp) from cultured ICCs. Intracellular Ca(2+) ([Ca(2+)]i) increase was studied in cultured ICCs using fura-2AM. All of the experiments were performed at 30-32 degrees C. RESULTS: Under the current clamping mode, GGT decreased the amplitude and frequency of pacemaker potentials; however, these effects were blocked by intracellular GDPbetaS, a G-protein inhibitor, and glibenclamide, a specific ATP-sensitive K(+) channels blocker. Prazosin (alpha1-adrenoceptor antagonist) and butoxamine (beta2-adrenoceptor antagonist) did not block the GGT induced effects, whereas atenolol (beta1-adrenoceptor antagonist) blocked the GGT induced effects. Also, yohimbine (alpha2-adrenoceptor antagonist) partially blocked the GGT-induced effects. Pretreatment with SQ-22536, an adenylate cyclase inhibitor, did not block the GGT-induced effects, whereas pretreatment with ODQ, a guanylate cyclase inhibitor, or L-NAME, an inhibitor of nitric oxide (NO) synthase, did. Additionally, [Ca(2+)]i analysis showed that GGT decreased [Ca(2+)]i. CONCLUSION: These results suggest that GGT inhibits pacemaker potentials in ICCs in a G protein-, cGMP- and NO-dependent manner through stimulation of alpha2 and beta1-adrenoceptors. PMID- 26003724 TI - Ammonia-induced oxidative damage in neurons is prevented by resveratrol and lipoic acid with participation of heme oxygenase 1. AB - Ammonia is a metabolite that, at high concentrations, is implicated in neurological disorders, such as hepatic encephalopathy (HE), which is associated with acute or chronic liver failure. Astrocytes are considered the primary target of ammonia toxicity in the central nervous system (CNS) because glutamine synthetase (GS), responsible for ammonia metabolism in CNS, is an astrocytic enzyme. Thus, neuronal dysfunction has been associated as secondary to astrocytic impairment. However, we demonstrated that ammonia can induce direct effects on neuronal cells. The cell viability was decreased by ammonia in SH-SY5Y cells and cerebellar granule neurons. In addition, ammonia induced increased reactive oxygen species (ROS) production and decreased GSH intracellular content, the main antioxidant in CNS. As ammonia neurotoxicity is strongly associated with oxidative stress, we also investigated the potential neuroprotective roles of the antioxidants, resveratrol (RSV) and lipoic acid (LA), against ammonia toxicity in cerebellar granule neurons. RSV and LA were able to prevent the oxidative damage induced by ammonia, maintaining the levels of ROS production and GSH close to basal values. Both antioxidants also decreased ROS production and increased GSH content under basal conditions (in the absence of ammonia). Moreover, we showed that heme oxygenase 1 (HO1), a protein associated with protection against stress conditions, is involved in the beneficial effects of RSV and LA in cerebellar granule neurons. Thus, this study reinforces the neuroprotective effects of RSV and LA. Although more studies in vivo are required, RSV and LA could represent interesting therapeutic strategies for the management of HE. PMID- 26003725 TI - Mutational analysis of Mycobacterium tuberculosis lysine E-aminotransferase and inhibitor co-crystal structures, reveals distinct binding modes. AB - Lysine E-aminotransferase (LAT) converts lysine to alpha-aminoadipate-delta semialdehyde in a PLP-mediated reaction. We mutated active-site T330, N328 and E243, and structurally rationalized their properties. T330A and T330S mutants cannot bind PLP and are inactive. N328A although inactive, binds to PLP. E243A retains activity, but binds alpha-ketoglutarate in a different conformation. We had earlier identified 2-aminomethyl piperidine derivative as a LAT inhibitor. The co-crystal structure reveals that it mimics binding of C5 substrates and exhibits two binding modes. E243, that shields R422 in the apo enzyme, exhibits conformational changes to permit the binding of the inhibitor in one of the binding modes. Structure-based analysis of bound water in the active site suggests optimization strategies for synthesis of improved inhibitors. PMID- 26003726 TI - Expression of REST4 in human gliomas in vivo and influence of pioglitazone on REST in vitro. AB - The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have a role of antineoplastic in various tumor cells, which including glioma cells. Moreover, study indicated that PPARgamma agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down regulating REST mRNA level but not by inducing alternative splicing of REST pre mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma. PMID- 26003727 TI - MicroRNA-204 suppresses trophoblast-like cell invasion by targeting matrix metalloproteinase-9. AB - Preeclampsia is a devastating pregnancy-related syndrome characterized by the onset of hypertension, proteinuria and edema. Insufficient invasion of trophoblasts is well-known to be correlated with preeclampsia development. The present study was performed to investigate the functional role microRNA (miRNA) 204 in trophoblastic invasion in vitro. We here found that the invasive capabilities of BeWo and JEG3 trophoblast-like cells were suppressed by miR-204 mimics, whereas enhanced by its inhibitor. Matrix metalloproteinase-9 (MMP9) was first confirmed to play a role in regulating trophoblast invasion through loss- or gain-of-function experiment. Notably, we demonstrated MMP9 as a direct target of miR-204 in BeWo cells by using the dual-luciferase assay. Moreover, forced overexpression of MMP9 was noted to partly attenuate the inhibitory effects of miR-204 on BeWo cell invasion. Taken together, our study indicates that miR-204 may contribute to the development of preeclampsia by inhibiting trophoblastic invasion, and that MMP9 is involved in miR-204-mediated trophoblast cell invasion. Our study suggests miR-204 as a novel therapeutic target for preeclampsia. PMID- 26003728 TI - Heat shock-induced interactions among nuclear HSFs detected by fluorescence cross correlation spectroscopy. AB - The cellular response to stress is primarily controlled in cells via transcriptional activation by heat shock factor 1 (HSF1). HSF1 is well-known to form homotrimers for activation upon heat shock and subsequently bind to target DNAs, such as heat-shock elements, by forming stress granules. A previous study demonstrated that nuclear HSF1 and HSF2 molecules in live cells interacted with target DNAs on the stress granules. However, the process underlying the binding interactions of HSF family in cells upon heat shock remains unclear. This study demonstrate for the first time that the interaction kinetics among nuclear HSF1, HSF2, and HSF4 upon heat shock can be detected directly in live cells using dual color fluorescence cross-correlation spectroscopy (FCCS). FCCS analyses indicated that the binding between HSFs was dramatically changed by heat shock. Interestingly, the recovery kinetics of interaction between HSF1 molecules after heat shock could be represented by changes in the relative interaction amplitude and mobility. PMID- 26003729 TI - Historical perspective: An interview with renowned Immunologist Dr. Michael Sela. PMID- 26003730 TI - Crystal structure of the death effector domains of caspase-8. AB - Caspase-8 is a key mediator in various biological processes such as apoptosis, necroptosis, inflammation, T/B cells activation, and cell motility. Caspase-8 is characterized by the N-terminal tandem death effector domains (DEDs) and the C terminal catalytic protease domain. The DEDs mediate diverse functions of caspase 8 through homotypic interactions of the DEDs between caspase-8 and its partner proteins. Here, we report the first crystal structure of the DEDs of caspase-8. The overall structure of the DEDs of caspase-8 is similar to that of the DEDs of vFLIP MC159, which is composed of two tandem death effector domains that closely associate with each other in a head-to-tail manner. Structural analysis reveals distinct differences in the region connecting helices alpha2b and alpha4b in the second DED of the DEDs between caspase-8 and MC159, in which the helix alpha3b in MC159 is replaced by a loop in caspase-8. Moreover, the different amino acids in this region might confer the distinct features of solubility and aggregation for the DEDs of caspase-8 and MC159. PMID- 26003731 TI - Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer. AB - Dysregulation of PI3K-AKT-mTOR pathway has been reported in various pathologies, such as cancer and insulin resistance. The proline-rich AKT substrate of 40-kDa (PRAS40), also known as AKT substrate 1 (AKT1S1), lies at the crossroads of these cascades and inhibits the activity of the mTOR complex 1 (mTORC1) kinase. This review discusses the role of PRAS40 and possible feedback mechanisms, and alterations in AKT/PRAS40/mTOR signaling that have been implicated in the pathogenesis of tumor progression. Additionally, we probed new datasets extracted from Oncomine, a cancer microarray database containing datasets derived from patient samples, to further understand the role of PRAS40 (AKT1S1). These data strongly supports the hypothesis that PRAS40 may serve as a potential therapeutic target for various cancers. PMID- 26003732 TI - Osteomodulin regulates diameter and alters shape of collagen fibrils. AB - Osteomodulin (OMD) is a member of the small leucine-rich repeat proteoglycan family, which is involved in the organization of the extracellular matrix. OMD is located in bone tissue and is reportedly important for bone mineralization. However, the details of OMD function in bone formation are poorly understood. Using the baculovirus expression system, we produced recombinant human OMD and analyzed its interaction with type I collagen, which is abundant in bone. In this result, OMD directly interacted with purified immobilized collagen and OMD suppressed collagen fibril formation in a turbidity assay. Morphological analysis of collagen in the presence or absence of OMD demonstrated that OMD reduces the diameter and changes the shape of collagen fibrils. We conclude that OMD regulates the extracellular matrix during bone formation. PMID- 26003733 TI - Epigenetic control of EMT/MET dynamics: HNF4alpha impacts DNMT3s through miRs-29. AB - BACKGROUND AND AIMS: Epithelial-to-mesenchymal transition (EMT) and the reverse mesenchymal-to-epithelial transition (MET) are manifestations of cellular plasticity that imply a dynamic and profound gene expression reprogramming. While a major epigenetic code controlling the coordinated regulation of a whole transcriptional profile is guaranteed by DNA methylation, DNA methyltransferase (DNMT) activities in EMT/MET dynamics are still largely unexplored. Here, we investigated the molecular mechanisms directly linking HNF4alpha, the master effector of MET, to the regulation of both de novo of DNMT 3A and 3B. METHODS: Correlation among EMT/MET markers, microRNA29 and DNMT3s expression was evaluated by RT-qPCR, Western blotting and immunocytochemical analysis. Functional roles of microRNAs and DNMT3s were tested by anti-miRs, microRNA precursors and chemical inhibitors. ChIP was utilized for investigating HNF4alpha DNA binding activity. RESULTS: HNF4alpha silencing was sufficient to induce positive modulation of DNMT3B, in in vitro differentiated hepatocytes as well as in vivo hepatocyte specific Hnf4alpha knockout mice, and DNMT3A, in vitro, but not DNMT1. In exploring the molecular mechanisms underlying these observations, evidence have been gathered for (i) the inverse correlation between DNMT3 levels and the expression of their regulators miR-29a and miR-29b and (ii) the role of HNF4alpha as a direct regulator of miR-29a-b transcription. Notably, during TGFbeta-induced EMT, DNMT3s' pivotal function has been proved, thus suggesting the need for the repression of these DNMTs in the maintenance of a differentiated phenotype. CONCLUSIONS: HNF4alpha maintains hepatocyte identity by regulating miR-29a and 29b expression, which in turn control epigenetic modifications by limiting DNMT3A and DNMT3B levels. PMID- 26003734 TI - alpha-Synuclein-induced internalization of NMDA receptors in hippocampal neurons is associated with reduced inward current and Ca(2+) influx upon NMDA stimulation. AB - Abnormal alpha-synuclein (alpha-syn) expression and aggregation have been implicated in the pathogenesis of Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's disease (AD). These neurodegenerative disorders, collectively known as synucleinopathies, are usually associated with cognitive impairment that could be caused by impaired hippocampal function. Although abnormal expressions of alpha-syn and N-methyl-d-aspartate (NMDA) receptor are frequently observed in the hippocampus of patients with synucleinopathies, how these proteins interact with each other in hippocampal neurons remains poorly understood. In the present study, primary cultures of hippocampal neurons and alpha-syn transgenic mice were used to investigate the effect of alpha-syn on NMDA receptors. Neurons were treated either by direct addition of recombinant human alpha-syn (halpha-syn) to the medium, or by infection with the halpha-syn gene, to increase intracellular levels of alpha-syn. In both cases, NMDA receptor NR1 subunits on the cell surface were reduced while the total amount of NR1 was unchanged, indicating an internalization of NR1 subunits. Neurons with elevated alpha-syn also showed a profound increase in Rab5B, an isoform of the small GTPases essential for NMDA receptor endocytosis. Knockdown of Rab5B expression by siRNA inhibited the alpha-syn-induced reduction in surface NR1. The in vitro findings were confirmed in alpha-syn transgenic mice, showing that increased alpha-syn expression was accompanied by reduced levels of surface NR1 and increased expression of Rab5B. Due to the essential role of NR1 subunits for assembling a complete NMDA receptor, its reduction on the cell surface indicated impaired receptor function. This was demonstrated by observations that neurons with elevated alpha-syn showed profound reductions in NMDA-elicited Ca(2+) influx and inward current, which were also inhibited by knockdown of Rab5B expression. Our data suggest that increased alpha-syn expression may impair NMDA receptor function in the hippocampus by reducing the density of NR1 subunits on the cell surface. PMID- 26003735 TI - Innervation changes induced by inflammation of the rat thoracolumbar fascia. AB - Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors. PMID- 26003737 TI - Modulation of immunity and gut microbiota after dietary administration of alginate encapsulated Shewanella putrefaciens Pdp11 to gilthead seabream (Sparus aurata L.). AB - The potential benefits of probiotics when administering to fish could improve aquaculture production. The objective of this study was to examine the modulation of immune status and gut microbiota of gilthead seabream (Sparus aurata L.) specimens by a probiotic when administered encapsulated. Commercial diet was enriched with Shewanella putrefaciens Pdp11 (SpPdp11, at a concentration of 10(8) cfu g(-1)) before being encapsulated in calcium alginate beads. Fish were fed non supplemented (control) or supplemented diet for 4 weeks. After 1, 2 and 4 weeks the main humoral and cellular immune parameters were determined. Furthermore, gene expression profile of five immune relevant genes (il1beta, bd, mhcIIalpha, ighm and tcrbeta) was studied by qPCR in head kidney. On the other hand, intestinal microbiota of fish was analysed at 7 and 30 days by DGGE. Results demonstrated that administration of alginate encapsulated SpPdp11 has immunostimulant properties on humoral parameters (IgM level and serum peroxidase activity). Although no immunostimulant effects were detected on leucocyte activities, significant increases were detected in the level of mRNA of head kidney leucocytes for mhcIIalpha and tcrbeta after 4 weeks of feeding the encapsulated-probiotic diet. The administration of SpPdp11 encapsulated in alginate beads produced important changes in the DGGE patterns corresponding to the intestinal microbiota. Predominant bands related to lactic acid bacteria, such as Lactococcus and Lactobacillus strains, were sequenced from the DGGE patterns of fish fed the probiotic diet, whereas they were not sequenced from fish receiving the control diet. The convenience or not of probiotic encapsulation is discussed. PMID- 26003738 TI - Research findings from the use of probiotics in tilapia aquaculture: A review. AB - This study aims to present research findings from the use of probiotics in tilapia aquaculture. In omnivorous species of tilapia aquaculture, intestines and gonads, rearing water and sediments or even commercial products, can be sources for acquiring appropriate probiotics. Administration of probiotics varies from direct oral/water routine to feed additives, of which the latter is most commonly used. Probiotic applications can be either mono or multiple strains. Dosage and duration of time are significant factors in providing desired results. As probiotics have been proven to be either immune enhancers and/or growth promoters in aquatic animals, several modes of actions of probiotics in enhancement of immune responses, and an improvement of growth and survival rates of tilapia are presented, while the effects of others are not yet understood to the same degree as for other fish species. Some points extracted from the research findings are emphasised for further investigation and development. PMID- 26003736 TI - The biology of aging and lymphoma: a complex interplay. AB - The probability to develop non-Hodgkin lymphoma grows with age. The biological links between aging and lymphoma are not well described in the literature, and different hypothesis may be raised to explain this complex relationship. First, the impact of chronological age favoring the accumulation of genetic alterations can contribute to the multisteps proces of lymphomagenesis. Then, the age-related defects in cancer protection and the age-related clonal restriction in hematopoietic stem cell may also promote lymphoma development. Finally, the senescent and immunosenescence phenotype might represent a key process explaining this link. In this review, we will explore the current available clinical data and their ability to apply to age-related regulation pathways. PMID- 26003739 TI - Combining eicosapentaenoic acid, decosahexaenoic acid and arachidonic acid, using a fully crossed design, affect gene expression and eicosanoid secretion in salmon head kidney cells in vitro. AB - Future feed for farmed fish are based on untraditional feed ingredients, which will change nutrient profiles compared to traditional feed based on marine ingredients. To understand the impact of oils from different sources on fish health, n-6 and n-3 polyunsaturated fatty acids (PUFAs) were added to salmon head kidney cells, in a fully crossed design, to monitor their individual and combined effects on gene expression. Exposing salmon head kidney cells to single fatty acids, arachidonic acid (AA) or decosahexaenoic acid (DHA), resulted in down regulation of cell signaling pathway genes and specific fatty acid metabolism genes as well as reduced prostaglandin E2 (PGE2) secretion. Eicosapentaenoic acid (EPA) had no impact on gene transcription in this study, but reduced the cell secretion of PGE2. The combined effect of AA + EPA resulted in up-regulation of eicosanoid pathway genes and the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), Bclx (an inducer of apoptosis) and fatty acid translocase (CD36) as well as increased cell secretion of PGE2 into the media. Adding single fatty acids to salmon head kidney cells decreased inflammation markers in this model. The combination AA + EPA acted differently than the rest of the fatty acid combinations by increasing the inflammation markers in these cells. The concentration of fatty acid used in this experiment did not induce any lipid peroxidation responses. PMID- 26003741 TI - The Trumorph(r) system: The new universal technique for the observation and analysis of the morphology of living sperm. [corrected]. AB - Evaluation of sperm morphology is a fundamental component of semen analysis, but its real significance has been obscured by a plethora of techniques that involve fixation and staining procedures that induce artefacts. Here we describe Trumorph(p)(r), a new method for sperm morphology assessment that is based upon examination of wet preparations of living spermatozoa immobilized by a short 60 degrees C shock using negative phase contrast microscopy. We have observed samples from five animals of the following species: bull, boar, goat and rabbit. In every case, all the components of the sperm head and tail were perfectly defined, including the acrosome and midpiece (in all its length, including cytoplasmic droplets). A range of morphological forms was observed, similar to those found by conventional fixed and stained preparations, but other forms were found, distinguishable only by the optics used. The ease of preparation makes it a robust method applicable for analysis of living unmodified spermatozoa in a range of situations. Subsequent studies on well-characterized samples are required to describe the morphology of potentially fertilizing spermatozoa. PMID- 26003742 TI - Effects of a subconvulsive dose of kainic acid on the gene expressions of the arginine vasopressin, oxytocin and neuronal nitric oxide synthase in the rat hypothalamus. AB - Arginine vasopressin (AVP) synthesis in the hypothalamo-neurohypophysial system (HNS) is up-regulated by kainic acid (KA)-induced seizure in rats. However, it remains unknown whether a subconvulsive dose of KA affects the HNS. Here we examined the effects of subcutaneous (s.c.) administration of a low dose of KA (4 mg/kg) on the gene expressions of the AVP, oxytocin (OXT) and neuronal nitric oxide synthase (nNOS) in the supraoptic (SON) and paraventricular nuclei (PVN) of the rat hypothalamus, using in situ hybridization histochemistry. The expression of the AVP gene in the SON and PVN was judged to be up-regulated in KA-treated rats in comparison with saline-treated rats as controls. Next, the expression of the OXT gene was significantly increased in the SON at 6-24h and in the PVN at 6 and 12h after s.c. administration of KA. Finally, the expression of the nNOS gene was significantly increased in the SON and PVN at 3 and 6h after s.c. administration of KA. These results suggest that up-regulation of the gene expressions of the AVP, OXT and nNOS in the rat hypothalamus may be differentially affected by peripheral administration of a subconvulsive dose of KA. PMID- 26003743 TI - Gene expression in the CNS of lactating rats with different patterns of maternal behavior. AB - For most mammalian species, maternal behavior has an essential role in the development of the offspring. The frequency of licking/grooming (LG) the pups has been used as a parameter to evaluate maternal care, having mothers with high (HL) or low (LL) frequencies of LG. This study aimed to analyze the gene expression of the receptors for dopamine (Drd1a), prolactin (Prlr), serotonin (Htr1a, Htr1b), estrogen (Esr1, Esr2), and of Bdnf in the olfactory bulb (OB), hippocampus (HP), prefrontal cortex (PFC), and striatum (ST) of Wistar rats from three groups: LL (n = 8); HL (n = 8); virgin females in diestrus (D; n = 6). Maternal behavior was studied between the 1st and 7th postpartum days. Brain parts were analyzed by qRT PCR. LL showed a decrease in the frequency of nursing, and an increase of remaining off the pups. There was an increase in gene expression of Drd1a, Prlr, Htr1a, Htr1b and Esr1 in the OB of HL, compared to LL. In the HP, Drd1a, Prlr and Htr1a were differently expressed when comparing HL, or LL, with D. The main finding is that HL had higher gene expression levels in the OB, which is a crucial structure to promote behavioral differences. PMID- 26003740 TI - Association of DNA methylation in the brain with age in older persons is confounded by common neuropathologies. AB - DNA methylation plays a crucial role in the regulation of gene expression, cell differentiation and development. Previous studies have reported age-related alterations of methylation levels in the human brain across the lifespan, but little is known about whether the observed association with age is confounded by common neuropathologies among older persons. Using genome-wide DNA methylation data from 740 postmortem brains, we interrogated 420,132 CpG sites across the genome in a cohort of individuals with ages from 66 to 108 years old, a range of ages at which many neuropathologic indices become quite common. We compared the association of DNA methylation prior to and following adjustment for common neuropathologies using a series of linear regression models. In the simplest model adjusting for technical factors including batch effect and bisulfite conversion rate, we found 8156 CpGs associated with age. The number of CpGs associated with age dropped by more than 10% following adjustment for sex. Notably, after adjusting for common neuropathologies, the total number of CpGs associated with age was reduced by approximately 40%, compared to the sex adjusted model. These data illustrate that the association of methylation changes in the brain with age is inflated if one does not account for age-related brain pathologies. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 26003744 TI - Lipid emulsion therapy given intraosseously in massive verapamil overdose. AB - Intravenous fat emulsion (IFE) therapy has been widely used in the emergency department (ED) for treating various medication overdoses. The standard recommended route to administer IFE therapy is intravenously through a peripheral or central vein. No reports of intraosseous (IO) administration in humans could be found in the literature after a brief search. We report of a patient emergently receiving IFE through the IO route. A 24-year-old woman presented to ED after a massive deliberate verapamil overdose. A decision was then made to start both vasopressors and 20% IFE therapy. Central access was established, and a norepinephrine drip was started. Intravenous fat emulsion was to be started, but peripheral access was lost at that time and not able to be reestablished. An IO line was then placed without difficulty in the left proximal tibia using an EZ IO system. Approximately half way during the bolus administration, the intravenous pump began to alarm that the infusion was not flowing adequately. At this point, peripheral access was obtained, and IFE infusion was moved to that site. We believe that this is the first report of IFE administered via the IO route in a human. This case report illustrates a novel way of administering IFE therapy in an emergency situation where intravenous access may be difficult to obtain. PMID- 26003745 TI - Lung ultrasound and pulmonary consolidations. PMID- 26003746 TI - Bilateral lower extremity swelling: black pearl. AB - Iatrogenic pneumothorax secondary to thoracentesis is relatively uncommon but does present to the emergency department (ED). Iatrogenic pneumothoraces developing tension physiology are rare. We report a case of an elderly female patient presenting to the ED with an isolated chief complaint of bilateral leg swelling, beginning the day after a thoracentesis, which was performed 3 days prior for pleural effusions secondary to lung cancer. Given that the patient was hemodynamically stable, not hypoxic, and had a history of chronic obstructive pulmonary disease and recent history of pleural effusions with diminished lung sounds throughout, this was a radiologic diagnosis. Immediately upon diagnosis, a 10F intrapleural catheter was inserted at the second intercostal space in the midclavicular line with successful resolution of the tension phenomenon. The patient tolerated the procedure well, and the catheter was removed on hospital day 2 without recurrence of the pneumothorax. She experienced resolution of her lower extremity swelling and was discharged from the hospital 2 days later. Isolated inferior vena cava syndrome secondary to a subacute tension pneumothorax was likely the cause of the patient's symptoms. This presentation is very rare and is undocumented in the literature. A high degree of suspicion for acute chest pathology should exist in every patient presenting to the ED with history of recent pleural violation. PMID- 26003747 TI - Digitally assisted bougie intubation: a novel technique for difficult airway management. AB - Management of the difficult airway is a relatively common problem in emergency medicine. A popular adjunct technique is the use of a tracheal introducer (sometimes called a "bougie"). Blind digital intubation is also described. There is no discussion in the literature about the use of digital assistance for endotracheal tube delivery after successful laryngoscopy. PMID- 26003748 TI - Evolution of bacterial transcription factors: how proteins take on new tasks, but do not always stop doing the old ones. AB - Many bacterial transcription factors do not behave as per the textbook operon model. We draw on whole genome work, as well as reported diversity across different bacteria, to argue that transcription factors may have evolved from nucleoid-associated proteins. This view would explain a large amount of recent data gleaned from high-throughput sequencing and bioinformatic analyses. PMID- 26003750 TI - A Picture Is Worth a Thousand Words: Customizing MyPlate for Low-Literate, Low Income Families in 4 Steps. PMID- 26003749 TI - Maternal Feeding Goals Described by Low-Income Mothers. AB - OBJECTIVE: To identify maternal feeding goals and examine associations of number and type of goals with mother and child characteristics. DESIGN: Qualitative interviews about child feeding and quantitative assessment of goal prevalence and associations with mother and child characteristics. SETTING: Southeastern Michigan. PARTICIPANTS: A total of 287 low-income mothers (31% Hispanic or non white) and their children ages 4 to 8 years. MAIN OUTCOME MEASURE: Maternal feeding goals. ANALYSIS: Themes were generated using the constant comparative method, individual interviews were coded, and the prevalence of feeding goals was determined. Regression analyses examined associations of mother and child characteristics with the number and type of feeding goals. RESULTS: Thirteen maternal feeding goals were identified. The most prevalent were to restrict less nutrient-dense food (60%), promote autonomy around eating (54%), prevent obesity (53%), and promote fruits or vegetables (52%). A child who was female and heavier with an older, non-Hispanic white, more educated mother with less chaos in the home predicted more maternal feeding goals (all P < .05). Specific maternal and child characteristics were associated with individual feeding goals. CONCLUSIONS AND IMPLICATIONS: Depending on their current goals for child feeding, some mothers may benefit from interventions focused on goal development, whereas other mothers may benefit from interventions designed to facilitate goal implementation. PMID- 26003751 TI - Poor mental health in diabetes: still a neglected comorbidity. PMID- 26003752 TI - Endemic diabetes in the world's poorest people. PMID- 26003753 TI - In defence of NICE draft type 2 diabetes guidelines. PMID- 26003754 TI - In defence of NICE draft type 2 diabetes guidelines--Author's reply. PMID- 26003755 TI - Metyrapone stimulation test to diagnose central adrenal insufficiency. PMID- 26003756 TI - Fixed dose combinations for type 2 diabetes. PMID- 26003757 TI - Nigel Unwin: battling non-communicable diseases. PMID- 26003758 TI - Assessment of interleukin 28B genotype as a predictor of response to combined therapy with pegylated interferon plus ribavirin in HCV infected Egyptian patients. AB - BACKGROUND AND AIM: Single nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) gene is associated with spontaneous clearance and variable response to combined therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C virus (HCV) infected patients. This study aimed at assessing the value of IL28B rs8099917 gene polymorphism in predicting sustained virological response (SVR) among HCV infected Egyptian patients treated with PEG IFN and RBV. METHODS: Our study was conducted on 153 chronic HCV infected patients treated with PEG-IFN and RBV. Genotyping of rs8099917 near the IL-28B gene was performed by Real Time PCR using Taq-Man probe assay. RESULTS: The overall SVR was achieved in 49.6% of patients. Patients with TT genotype showed significantly higher SVR rate than minor allele (TG/GG) carriers (74% vs. 26%, P=0.004). Logistic regression analysis revealed that TT carriers had 2.8 higher chance for SVR achievement than G allele carriers TG/GG (OR=2.8, 95% CI=1.4-5.6, P=0.004). Younger age, male sex and low activity grading were significant predictors of SVR (P=0.003, P=<0.001 and P<0.001 respectively). High pretreatment AST levels and advanced liver fibrosis were negative predictors of SVR (P=0.04 and P<0.001 respectively). CONCLUSION: IL28B genotype is a significant pre treatment predictor of response to PEG-IFN/RBV in HCV infected Egyptian patients. PMID- 26003759 TI - Islet antigen-pulsed dendritic cells expressing ectopic IL-35Ig protect nonobese diabetic mice from autoimmune diabetes. AB - Dendritic cells (DCs) are professional antigen presenting cells capable of orchestrating either stimulatory or regulatory immune responses mediated by T cells. Interleukin 35 (IL-35) is an immunosuppressive, heterodimeric cytokine belonging to the IL-12 family and known to be produced by regulatory T cells but not DCs. In this study, we explored the possible immunosuppressive effect of IL 35 ectopically expressed by splenic DCs from nonobese diabetic (NOD) mice, a prototypical model of autoimmune diabetes. After pulsing with the IGRP peptide (a dominant, diabetogenic autoantigen in NOD mice) and transfer in vivo, IL-35Ig- but not Ig-transfected DCs suppressed antigen specific, T cell-mediated responses in a skin test assay. More importantly, transfer of IL-35Ig-transfected, IGRP pulsed DCs into prediabetic NOD mice induced a delayed and less severe form of diabetes, an effect accompanied by the increase of CD4(+)CD39(+) suppressive T cells in pancreatic lymph nodes. Our data therefore suggest that DCs overexpressing ectopic IL-35Ig might represent a powerful tool in negative vaccination strategies. PMID- 26003761 TI - Renewing perianesthesia passion... inspiring excellence. PMID- 26003762 TI - Focus issue: innovations in pain management: guest editorial. PMID- 26003760 TI - Hokkaido genotype of Puumala virus in the grey red-backed vole (Myodes rufocanus) and northern red-backed vole (Myodes rutilus) in Siberia. AB - Three species of Myodes voles known to harbor hantaviruses include the bank vole (Myodes glareolus), which serves as the reservoir host of Puumala virus (PUUV), the prototype arvicolid rodent-borne hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in Europe, and the grey red-backed vole (Myodes rufocanus) and royal vole (Myodes regulus) which carry two PUUV-like hantaviruses, designated Hokkaido virus (HOKV) and Muju virus (MUJV), respectively. To ascertain the hantavirus harbored by the northern red-backed vole (Myodes rutilus), we initially screened sera from 233 M. rutilus, as well as from 90 M. rufocanus and 110 M. glareolus, captured in western and eastern Siberia during June 2007 to October 2009, for anti-hantaviral antibodies. Thereafter, lung tissues from 44 seropositive voles were analyzed for hantavirus RNA by reverse transcription-polymerase chain reaction. Partial L-, M- and S-segment sequences, detected in M. rutilus and M. rufocanus, were closely related to HOKV, differing from previously published L-, M- and S-segment sequences of HOKV by 17.8-20.2%, 15.9-23.4% and 15.0-17.0% at the nucleotide level and 2.6-7.9%, 1.3-6.3% and 1.2 4.0% at the amino acid level, respectively. Alignment and comparison of hantavirus sequences from M. glareolus trapped in Tyumen Oblast showed very high sequence similarity to the Omsk lineage of PUUV. Phylogenetic analysis, using neighbor-joining, maximal likelihood and Bayesian methods, showed that HOKV strains shared a common ancestry with PUUV and exhibited geographic-specific clustering. This report provides the first molecular evidence that both M. rutilus and M. rufocanus harbor HOKV, which might represent a genetic variant of PUUV. PMID- 26003763 TI - Pain Management for Older African Americans in the Perianesthesia Setting: The "Eight I's". AB - National legislation (Affordable Care Act) emphasizes quality and equitable pain care for all patient populations, but frequently, pain management is not effective and equitable in African American (AA) elders, placing them at higher risk for severe pain and persistent pain. Research shows that AAs are less likely to receive guideline-based pain care. This underscores the need for perianesthesia nurses to be knowledgeable and capable of integrating cultural practices and evidence-based recommendations into their care of older AAs to ensure adequate pain management in this vulnerable population. This article describes differences and disparities in pain management in AA older adults and provides a cultural framework to guide perianesthesia pain management. PMID- 26003764 TI - Perioperative ketamine for acute postoperative analgesia: the Mayo Clinic-Florida experience. AB - Many common elective surgeries are associated with moderate-to-severe postoperative pain. These common surgeries include total knee and total hip arthroplasty, thoracotomy, and multilevel lumbar spine surgery. Unfortunately, many patients requiring these surgeries are already in moderate-to-severe pain, necessitating high doses of oral or transdermal opioids preoperatively. This is an established risk factor for difficult-to-control postoperative pain.(1,2) Opioid-sparing interventions are important elements in these patients to promote convalescence and reduce common opioid side effects such as constipation, confusion, pruritus, nausea, vomiting, and urinary retention. Potential interventions to reduce postoperative pain can include nonsteroidal anti inflammatory drugs, acetaminophen, gabapentin, and even invasive therapies such as epidural or peripheral nerve blockade. Ketamine is a well-known anesthetic agent that has opioid-sparing analgesic properties, is noninvasive, and in analgesic doses, has few contraindications. This article will review the basic science behind ketamine, some of the evidence supporting its perioperative use, and the logistics of how the Department of Anesthesia at Mayo Clinic in Jacksonville, Florida rolled out a hospital-wide ketamine infusion protocol. PMID- 26003765 TI - The Michigan Opioid Safety Score (MOSS): A Patient Safety and Nurse Empowerment Tool. AB - Safely treating postsurgical pain continues to be a challenge, despite more than a decade of focus on its appropriate management. Overuse of opioids and undertreatment of pain continues, as does insufficient monitoring of patients at risk for opioid and pain-related complications. It is clear that relying only on numeric subjective pain scores is inadequate when treating pain. Appropriate bedside evaluation should also include measures of respiration and sedation. Furthermore, assessment of risk should be done with initial pain assessment and continued throughout the pain management course. The recently developed Michigan Opioid Safety Score integrates health risks and objective measures of respiratory rate and sedation, while encouraging the use of multimodal analgesia for all patients. PMID- 26003766 TI - Promoting the use of capnography in acute care settings: an evidence-based practice project. AB - Opioid-induced respiratory depression (OIRD) is a life-threatening complication of opioid analgesia. End-tidal carbon dioxide monitoring (capnography) has been shown to detect early signs of OIRD earlier than other commonly used monitoring methods. The goal of this evidence-based practice project was to promote the standardized use of capnography to reduce the incidence of OIRD. The project included an updated nursing protocol, an electronic order trigger, improved access to capnography monitors, and staff education about OIRD risk assessment and the use of capnography. A survey of registered nurses was also conducted to gather their perceptions on the ease of use and effectiveness of capnography. Twelve months after introducing the intervention there was an increase in monitoring frequency, with 2.56 times more patients at high risk for OIRD being monitored with capnography than at baseline. Of the 171 registered nurses surveyed during this project, 99% perceived the portable capnography monitors as easy to use and interpret. However, 71% reported systems issues in obtaining the monitoring equipment, and 65% reported problems with patient adherence. The intervention succeeded in increasing the number of high-risk patients being monitored with capnography and reducing the number of cases of OIRD. PMID- 26003767 TI - Specially trained registered nurses can safely manage epidural analgesia infusion in laboring patients. AB - PURPOSE: To discover evidence for defining the registered nurse's (RN's) role in the management of epidural analgesia in the labor and delivery setting. DESIGN: The Labor Epidural Nurse Safety (LENS) study consisted of two parts. The first part was a 10-year retrospective review of the outcomes of 2,568 laboring women for whom epidural catheters had been placed and verified by an anesthesiologist or certified registered nurse anesthetist, then continuous epidural infusion initiated, and basal rate or patient-controlled epidural analgesia (PCEA) dose increased, if needed, within specified parameters by specially trained labor and delivery RNs. The second part compared the outcomes of the neonates born to the 2,568 women in the first part of the study with neonates born to mothers who received PCEA with a continuous infusion initiated and managed exclusively by anesthesiologists and/or certified registered nurse anesthetists at two control sites. METHODS: Maternal outcomes were quantified by incidences of clinically significant hypotension and sentinel events, such as respiratory distress, cardio/respiratory distress, loss of consciousness, and seizures. Evidence of neonatal outcomes was collected by comparing Apgar scores. FINDINGS: No sentinel events occurred, and there was no increase in maternal hypotensive events in the RN-managed group. There were no statistically significant differences in Apgar scores between the experimental and control groups. CONCLUSION: Specially trained RNs can safely initiate continuous infusions and increase the basal rate of epidural analgesia infusions or PCEA doses administered to laboring women, after insertion and confirmation of correct catheter placement by a qualified anesthesia provider, without adversely affecting maternal and fetal/neonatal outcomes. PMID- 26003768 TI - Rescue dose orders as an alternative to range orders: an evidence-based practice project. AB - Relief of pain is a fundamental aspect of optimal patient care. However, pain management in the inpatient setting is often constrained by concerns related to regulatory oversight, particularly with regard to the use of opioid dose range orders. These concerns can inadvertently result in the development of policies and practices that can negatively impact the health care team's ability to deliver optimal and individualized pain management. An evidence-based practice project was undertaken to address concerns about regulatory oversight of pain management processes by changing the way pain was managed in a large academic hospital setting. A novel pain management approach using rescue dose medications was established as an alternative to opioid dose range orders. The use of the rescue dose protocol was successfully implemented. Outcomes included an overall reduction in the administration of inappropriate intravenous opioids and opioid acetaminophen combination medications, with a subsequent increase in single entity first-line opioid analgesics. Rescue dose protocols may offer an alternative to opioid dose range orders as a means of effectively managing pain. PMID- 26003769 TI - Preoperative pain management education: a quality improvement project. AB - The management of pain is one of the greatest clinical challenges for nurses who care for patients during the postoperative period. It can be even more challenging for patients who must manage their own pain after discharge from the health care facility. Research shows that postoperative pain continues to be undermanaged despite decades of education and evidence-based guidelines. Ineffective management of postoperative pain can negatively impact multiple patient outcomes. The purpose of this quality improvement project was to evaluate the effectiveness of a preoperative pain management patient education intervention on improving patients' postoperative pain management outcomes. The project was conducted with patients undergoing same-day laparoscopic cholecystectomy in an outpatient general surgery service at a teaching institution. Patients in the intervention and comparison groups completed the American Pain Society Patient Outcome Questionnaire-Revised during their first postoperative clinic visit 2 weeks after surgery. Results showed that patients who received the preoperative education intervention reported less severe pain during the first 24 hours postoperatively, experienced fewer and less severe pain medication side effects, returned to normal activities sooner, and used more nonpharmacologic pain management methods postoperatively compared with those who did not receive the education. PMID- 26003770 TI - The effect of combined stimulation of external cold and vibration during immunization on pain and anxiety levels in children. AB - PURPOSE: Procedures involving needles are the most common and major sources of pain in children. External cold and vibration via Buzzy (MMJ Labs, Atlanta, GA) is a method that combines cooling and vibration. DESIGN: This study investigated the effect of the combined stimulation of skin with external cold and vibration via Buzzy on the pain and anxiety levels in children during immunization. METHODS: This study was a prospective, randomized controlled trial. Children were randomized into two groups: experimental (external cold and Buzzy) and control (no intervention). The pain and anxiety levels of the children were assessed using the Wong-Baker FACES scale and Children Fear Scale. FINDING: The experimental group showed significantly lower pain and anxiety levels than the control group during immunization. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The combined stimulation of skin with external cold and vibration can be used to reduce pain and anxiety during pediatric immunization. PMID- 26003771 TI - How tuned in are you to the patient experience? PMID- 26003772 TI - Pain quality and outcome measurement in the electronic health record. PMID- 26003773 TI - Rescheduling of hydrocodone combination products: potential impact and alternatives for postoperative pain management. PMID- 26003774 TI - Postoperative pain control after tonsillectomy. PMID- 26003775 TI - Why is pain... still a pain? PMID- 26003776 TI - Effects of Volatile Anesthetics on Oral Tissue Blood Flow in Rabbits: A Comparison Among Isoflurane, Sevoflurane, and Desflurane. AB - PURPOSE: The aim of this study was to compare the concentration-dependent effects of isoflurane, sevoflurane, and desflurane on oral tissue blood flow. MATERIALS AND METHODS: Thirty male Japan White rabbits were randomized to receive 1 of 3 volatile anesthetics: isoflurane (group Iso), sevoflurane (group Sevo), or desflurane (group Des). The end-tidal concentration of each volatile anesthetic was regulated to 0.5, 1, and 1.5 minimum alveolar concentrations (MACs). The observed variables were heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, common carotid arterial blood flow, tongue mucosal blood flow, mandibular bone marrow blood flow (BBF), masseter muscle blood flow (MBF), upper alveolar tissue blood flow, and lower alveolar tissue blood flow (LBF). RESULTS: The blood pressure in each group tended to decrease depending on the concentration of each volatile anesthetic, with the smallest effect in group Des. BBF and MBF in group Iso were higher than those in group Des at 1 MAC, and MBF and LBF in group Iso were highest at 1.5 MAC. CONCLUSION: The results of this study suggest that each volatile anesthetic produced unique effects on blood flow in oral tissues and circulatory parameters. Among the 3 volatile anesthetics, desflurane produced the smallest effects on oral tissue blood flow. PMID- 26003777 TI - Understandability of Speech Predicts Quality of Life Among Maxillectomy Patients Restored With Obturator Prosthesis. AB - PURPOSE: Maxillary malignant tumor resection by maxillectomy might lead to defects that can be repaired by prosthetic obturation. The aim of this study was to associate quality of life (QoL) and the Obturator Functioning Scale (OFS) with functional performance and salivary flow rate in Brazilian patients rehabilitated with an obturator prosthesis. PATIENTS AND METHODS: This retrospective cross sectional study included patients who underwent surgical resection with or without radiotherapy or without chemotherapy and the rehabilitation with an obturator prosthesis at the Fundacao Oncocentro de Sao Paulo (Sao Paulo, Brazil). The predictor variables were Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) domains and clinical evaluation of salivary flow rate. The outcome variables were overall scores obtained by the University of Washington QoL Scale (UWQOL) and the OFS. Sociodemographics (gender and age) and clinical characteristics (postoperative radiotherapy, tumor stage, classification of maxillary defect, tooth in maxilla, and type of obturator) also were evaluated. Univariate and multivariate analyses were performed to determinate whether PSS-HN domains and salivary flow were predictors of overall QoL and overall OFS. RESULTS: The sample was composed of 73 patients with a mean age of 62 years and 51% were men. According to the PSS-HN domains, some patients (5%) always ate alone, 87% reported that speech is usually or always understandable, and 56% had no dietary restrictions. Sixty-one patients (65%) reported some degree of hyposalivation. The mean overall QoL score was 76.5 (standard deviation, 5.3). Patients with compromised PSS-HN domains had significantly worse overall UWQOL scores (P = .001, P < .001, and P = .006, respectively). In multiple regression analyses, understandability of speech was the only predictor of overall QoL scores. CONCLUSION: The results of this study showed that understandability of speech was the only predictor of overall QoL scores. PMID- 26003778 TI - Externalizing spectrum or spectra? Underlying dimensions of the externalizing spectrum. AB - BACKGROUND: Major psychiatric disorders have been conceptualized to comprise of two dimensions namely, the internalizing and externalizing spectrum. Externalizing spectrum disorders consist of childhood disruptive behaviour disorders (DBD), antisocial personality disorder (ASPD) and substance use disorders. They are supposed to share common underlying personality traits. However, there is a need to explore the underlying dimensionality of externalizing spectrum of both disorders and traits in a mixed clinical and nonclinical sample from a non-western cultural-ethnic backdrop. MATERIALS AND METHODS: One hundred consecutive subjects with alcohol dependence (AD) and an equal number of biologically unrelated non-substance-dependent control subjects were recruited for the study. Subjects were examined for evidence of DBD and ASPD using Semi-Structured Assessment for Genetics of Alcoholism (SSAGA-IV). Validated instruments were used for the assessment of impulsivity, sensation seeking and hostility. Continuous scores generated from these instruments were converted to standardized Z scores to ensure comparability among different types of scales. Data were tested for normality of distribution by Kolmogorov-Smirnov test. Analysis was done by using principal component factor analysis with varimax rotation. RESULTS: Factor analysis revealed two broad factors underlying the externalizing spectrum. The first factor included conduct, antisocial personality and oppositional defiant disorder. This factor was labelled as disruptive dissocial. The second factor, which included AD and all personality traits, was labelled as impulsive-hostile. CONCLUSION: Within the externalizing spectrum, there are at least two distinct underlying dimensions: disruptive-dissocial and impulsive-hostile. If confirmed in other samples as well, this may have important implications for understanding and managing psychiatric and psychological issues. PMID- 26003779 TI - Translation of the Broad Autism Phenotype Questionnaire to an Indian language: A description of the process. AB - The Broad Autism Phenotype Questionnaire (BAPQ) which is a reliable, efficient and easy to administer instrument is used to assess the Broad Autism Phenotype (BAP). In order to understand cross cultural perspectives using this instrument, a key process is translation of the instrument. The process of translation is often overlooked and hence the quality of the translated instrument may suffer. This paper highlights the robust process adopted for translating the BAPQ into one of the Indian languages - Kannada, using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and World Health Organisation (WHO) guidelines. The translated instrument was tested on a pilot sample of parents of 10 children with ASD and parents of 11 typically developing children. The results are in congruence with the published literature. PMID- 26003780 TI - Peer kidney care initiative 2014 report: dialysis care and outcomes in the United States. PMID- 26003781 TI - Laparoscopic sacrocolpopexy with a vaginal prosthetic adhesive. AB - STUDY OBJECTIVE: To evaluate the efficacy and safety of vaginal prosthetic adhesive (VPA) during laparoscopic sacrocolpopexy. DESIGN: Retrospective analysis of 35 first consecutive cases. SETTING: Gynecology Surgery Unit, Bouchard Clinic, Marseille, France. PATIENTS: Thirty-five women (age range: 35-85 years; average 60.8 years) presenting a genital prolapse assessed by a Pelvic Organ Prolapse Quantification (POP-Q) Score (stage 2 to 4). PROCEDURES: Modified laparoscopic sacrocolpopexy using a synthetic glue (IfabondTM, Peters Surgical((r))) to fix the mesh to the vagina (anterior and posterior) and to the levator ani. Two non absorbable knots are used to secure the anterior mesh to the isthmus and to the promontory. MEASUREMENTS AND MAIN RESULTS: The average operating time was 68.4 minutes (45-115 min). No complications occurred during the procedure and early postoperative course. One patient (2.8%) experienced mesh exposure, and one patient (2.8%) experienced a subacute intestinal obstruction, which was resolved by a medical treatment. During a median follow-up at 13.2 months (range: 6-24.7 months), the surgical success rate (POP-Q<2) was 94.2% (two recurrences). The patient satisfaction rate was 87%. CONCLUSIONS: The VPA during laparoscopic sacrocolpopexy seems to be safe and effective at short term. This new procedure due to adhesive opens up a new path for the widespread use of sacrocolpopexy and for reduced operating times, which is often one obstacle with the dissection in the development of this technique. PMID- 26003782 TI - Preoperative platelet aggregation predicts perioperative blood loss and rethoracotomy for bleeding in patients receiving dual antiplatelet treatment prior to coronary surgery. AB - INTRODUCTION: Patients scheduled for coronary artery bypass graft surgery (CABG) are commonly treated with clopidogrel. We sought to assess the relation between preoperative platelet aggregation and bleeds in CABG patients on clopidogrel. MATERIAL AND METHODS: In a case-control study, we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy. Platelet aggregation induced by 10MUmol/l adenosine di-phosphate (ADP) in platelet-rich plasma was measured in subjects on clopidogrel within 5days prior to surgery. ADP-induced aggregation of >=50% was used to define subjects with satisfactory inhibition of platelet reactivity. RESULTS: In 29 patients with preoperative ADP-induced aggregation >=50%, compared with 23 subjects with aggregation <50%, lower chest-tube drainage volumes (after 6h, p=0.002; and 12h, p=0.001) and fewer rethoracotomies were observed (p=0.03). The former group was characterized with lower transfusion rates of packed red blood cells (p=0.009), platelet concentrate (p=0.04) and fresh frozen plasma (p=0.001). Patients with ADP-induced aggregation >=50% did not differ from untreated controls regarding the postoperative drainage, transfusions and rethoracotomy. The incidence of thromboembolic events and death during perioperative period were similar in all groups. Multivariate logistic regression identified ADP-induced aggregation <50% as the only independent predictor of rethoracotomy (OR=2.94 [1.12-7.75], p=0.029). CONCLUSIONS: Patients on aspirin and clopidogrel <5days before CABG who had preoperative ADP-induced platelet aggregation >=50% have bleeding risk similar to those receiving aspirin monotherapy. Reduced platelet reactivity to ADP can predict postoperative bleeding in CABG patients on dual antiplatelet therapy. PMID- 26003783 TI - The Vena Tech LP Permanent Caval Filter: Effectiveness and Safety in the Clinical Setting in Three Chinese Medical Centers. AB - OBJECTIVE: The effectiveness, safety, and patient outcomes after Vena Tech LP caval filter placement were evaluated retrospectively in China. METHODS AND RESULTS: From January 2002 to January 2013, 1,200 patients received Tech LP caval filters to prevent PE at three Beijing University medical centers. The patients' general condition, reasons for DVT formation, filter placement method, indication for filter placement, complications, safety of the filter, treatment post-filter, and follow-up were recorded. The patients' mean age was 65 (range, 19-87) years, and 840 were males. Before filter placement, all had ultrasonic-diagnosed DVT, 84% (1008/1200) were assessed for PE, and 73% (736/1008) had PE. Filters were placed via the femoral or jugular vein, with 62 placements at the SVC and 1,138 at the IVC. Filter placement via various venous access routes was 100% successful. Anticoagulation therapy was continued in 88% patients (n=1056) for >=6 months after filter placement. Follow-up was accomplished in 80% (n=960) of patients for an average of 6 years (range, 3 months to 10 years). The patency rate of the vena cava was 90% at 5 years. The morbidity was 2% and the mortality was 0.5% during 30 days post-filter placement. After 30 days, the mortality rate was 2.4%, no PE reoccurred, and there were no other clinical adverse events. CONCLUSION: Vena Tech LP caval filter placement was effective and safe, with demonstrated stability and a good long-term patency rate at the IVC and SVC in China. PMID- 26003784 TI - GDF11 and the Mythical Fountain of Youth. AB - Identifying candidates that rejuvenate aged muscle stem cells is an important strategy toward developing therapies to treat age-related diseases. In this issue, Egerman et al. (2015) re-investigate the activity of GDF11 in myogenesis, recently suggested as an anti-aging agent, and instead find a potent inhibitory effect on skeletal muscle regeneration. PMID- 26003785 TI - Developing a targeted, theory-informed implementation intervention using two theoretical frameworks to address health professional and organisational factors: a case study to improve the management of mild traumatic brain injury in the emergency department. AB - BACKGROUND: Despite the availability of evidence-based guidelines for the management of mild traumatic brain injury in the emergency department (ED), variations in practice exist. Interventions designed to implement recommended behaviours can reduce this variation. Using theory to inform intervention development is advocated; however, there is no consensus on how to select or apply theory. Integrative theoretical frameworks, based on syntheses of theories and theoretical constructs relevant to implementation, have the potential to assist in the intervention development process. This paper describes the process of applying two theoretical frameworks to investigate the factors influencing recommended behaviours and the choice of behaviour change techniques and modes of delivery for an implementation intervention. METHODS: A stepped approach was followed: (i) identification of locally applicable and actionable evidence-based recommendations as targets for change, (ii) selection and use of two theoretical frameworks for identifying barriers to and enablers of change (Theoretical Domains Framework and Model of Diffusion of Innovations in Service Organisations) and (iii) identification and operationalisation of intervention components (behaviour change techniques and modes of delivery) to address the barriers and enhance the enablers, informed by theory, evidence and feasibility/acceptability considerations. We illustrate this process in relation to one recommendation, prospective assessment of post-traumatic amnesia (PTA) by ED staff using a validated tool. RESULTS: Four recommendations for managing mild traumatic brain injury were targeted with the intervention. The intervention targeting the PTA recommendation consisted of 14 behaviour change techniques and addressed 6 theoretical domains and 5 organisational domains. The mode of delivery was informed by six Cochrane reviews. It was delivered via five intervention components : (i) local stakeholder meetings, (ii) identification of local opinion leader teams, (iii) a train-the-trainer workshop for appointed local opinion leaders, (iv) local training workshops for delivery by trained local opinion leaders and (v) provision of tools and materials to prompt recommended behaviours. CONCLUSIONS: Two theoretical frameworks were used in a complementary manner to inform intervention development in managing mild traumatic brain injury in the ED. The effectiveness and cost-effectiveness of the developed intervention is being evaluated in a cluster randomised trial, part of the Neurotrauma Evidence Translation (NET) program. PMID- 26003786 TI - Sleep quality of mother-caregivers of Duchenne muscular dystrophy patients. AB - BACKGROUND: Sleep disturbance is a common problem for caregivers. In general, patients with Duchenne muscular dystrophy (DMD) use noninvasive ventilation to maintain quality of life and improve survival. OBJECTIVE: The aim of this study was to evaluate the sleep quality of caregiver-mothers of sons with DMD and factors that are associated with their sleep quality. METHODS: We evaluated 32 caregiver-mothers of sons with DMD and 32 mothers of sons without any neuromuscular or chronic disease (control-CTRL group). The evaluation of quality of sleep was made using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Caregiver-mothers had poor sleep quality, specifically longer sleep latency and reduced sleep efficiency. The impaired sleep quality of the caregiver-mothers was associated with the length of time of noninvasive ventilation used by their sons. CONCLUSIONS: Our results suggest that caregiver-mothers of sons with DMD have poor quality of sleep, and the length of use of noninvasive ventilation of their sons is associated with better sleep of caregiver-mothers. PMID- 26003787 TI - Left ventricular subclinical dysfunction associated with myocardial deformation changes in obstructive sleep apnea patients estimated by real-time 3D speckle tracking echocardiography. AB - BACKGROUND: Previous studies have demonstrated that patients with obstructive sleep apnea (OSA) may develop left ventricular (LV) diastolic dysfunction. We aimed to study whether OSA patients have LV regional systolic dysfunction with myocardial deformation changes, despite a normal LV ejection fraction, using real time 3D speckle-tracking echocardiography (Rt3D-STE). METHODS: Seventy-eight patients with OSA and no comorbidities were studied. They were divided into the following three groups according to the apnea-hypopnea index (AHI): 5~15/h as group I (mild OSA, 26 cases), 15~30/h as group II (moderate OSA, 29 cases), and >=30/h as group III (severe OSA, 23 cases). Thirty gender-age-matched normal subjects were included as controls. The parameters of LV diastolic function were acquired with traditional echocardiography. The LV myocardial deformation parameters were obtained, including the longitudinal (LS), circumferential (CS), radial (RS), and area (AS) strains, with Rt3D-STE. RESULTS: LV global systolic function was normal in all patients, but diastolic function was impaired in groups II and III (E/E' was 9.6 +/- 2.8 and 10.4 +/- 2.5, respectively, p < 0.0001). The global LS and AS were significantly reduced in groups II and III compared with the controls and group I (LS 15.9 +/- 1.4 % and 14.8 +/- 1.5 % vs 18.2 +/- 1.7 % and 17.8 +/- 1.5 %; AS 27.4 +/- 1.8 % and 24.9 +/- 2.3 % vs 33.4 +/- 2.2 % and 32.7 +/- 2.9 %, respectively, p < 0.0001), but the global CS and RS were significantly reduced only in group III (17.3 +/- 1.4 % and 43.1 +/- 6.5 % vs 19.6 +/- 1.6 % and 55.4 +/- 4.0 %, respectively, <0.0001). The severity of OSA was significantly associated with the LV global AS value (r = -0.80, p < 0.0001), LS (r = -0.64, p < 0.0001), CS (r = -0.51, p < 0.0001), and RS (r = -0.62, p < 0.0001). CONCLUSIONS: Patients with moderate and severe OSA tended to have both LV diastolic dysfunction and abnormalities in regional systolic function with myocardial deformation changes, in spite of the normal LV ejection fraction. Myocardial strains of the LV were negatively correlated with the AHI. Rt-3DST had important clinical significance in the early evaluation of cardiac dysfunction in OSA patients. PMID- 26003788 TI - Restless leg syndrome and multiple sclerosis: a case-control study in China. AB - BACKGROUND: As a common neurological movement disorder, restless leg syndrome (RLS) is often seen in patients with multiple sclerosis (MS). However, the relationship between RLS and MS is still unclear. This case-control study aimed to measure RLS prevalence and uncover its association with MS, as well as to identify possible associated risk factors. METHODS: Six hundred and ninety-five patients were randomly selected from a cohort of patients with MS at the Neurology Department of our hospital, and a group of age- and sex-matched healthy controls (n = 603) was enrolled from the general population. Using a face-to-face interview questionnaire, we collected data on RLS incidence in participants with or without MS. We further assessed sleep quality in all the participants. RESULTS: We found there to be a significantly higher prevalence of RLS among patients with MS compared to healthy controls (odds ratio [OR], 3.8; P < 0.001). Risk factors such as an older MS age at onset and a longer MS duration were significantly associated with the presence of RLS. Furthermore, patients with both MS and RLS were more likely to suffer from sleep complaints compared to patients with MS without RLS. CONCLUSIONS: RLS was significantly associated with MS and was found to have a significant impact on sleep quality, particularly in patients with MS. PMID- 26003789 TI - Cost-effectiveness modelling in diagnostic imaging: a stepwise approach. AB - Diagnostic imaging (DI) is the fastest growing sector in medical expenditures and takes a central role in medical decision-making. The increasing number of various and new imaging technologies induces a growing demand for cost-effectiveness analysis (CEA) in imaging technology assessment. In this article we provide a comprehensive framework of direct and indirect effects that should be considered for CEA in DI, suitable for all imaging modalities. We describe and explain the methodology of decision analytic modelling in six steps aiming to transfer theory of CEA to clinical research by demonstrating key principles of CEA in a practical approach. We thereby provide radiologists with an introduction to the tools necessary to perform and interpret CEA as part of their research and clinical practice. KEY POINTS: * DI influences medical decision making, affecting both costs and health outcome. * This article provides a comprehensive framework for CEA in DI. * A six-step methodology for conducting and interpreting cost effectiveness modelling is proposed. PMID- 26003790 TI - 3D rotational angiography in the endovascular treatment of visceral aneurysms: preliminary experience in a single centre. AB - OBJECTIVES: Endovascular embolization is a valid option for the management of visceral artery aneurysms. Imaging is crucial for providing anatomical assessments, but preoperative non-invasive investigations may not be exhaustive. The aim of this work is to present preliminary experience with the use of three dimensional rotational angiography (3DRA) in this particular theatre. METHODS: Seven patients were treated for eight visceral aneurysms (six splenic and two renal) by endovascular embolization. 3DRA was performed before the treatment using a standard protocol. Different parameters (location of the lesion, the afferent and efferent vessels, aneurysm neck, vascular diameters, working incidence) were analyzed. RESULTS: 3DRA was successfully accomplished in all procedures. Mean aneurysm diameter was 23 mm and mean C-arm working incidence was 29 degrees (R-L) and 9 degrees (C-C). The sandwich technique was used in four lesions and the packing in the remaining four. Technical success was 100 %. The mean radiation dose per procedure was 291 600 mGy.cm(2). The mean procedural time was 2.25 hours. There were no immediate or short-term complications. CONCLUSIONS: 3DRA could be an interesting intraoperative tool to provide anatomical and technical assessments of the visceral arteries necessary for endovascular treatment, especially when information from preoperative imaging is not exhaustive. KEY POINTS: Endovascular embolization is a valid alternative solution for visceral artery aneurysm treatment. Imaging is crucial for anatomical assessments and treatment guidance. 3DRA can contribute to endovascular treatment in lieu of preoperative imaging. PMID- 26003793 TI - Depuration and anatomical distribution of domoic acid in the surf clam Mesodesma donacium. AB - In northern Chile, domoic acid (DA) has been detected in several bivalve species. In Mesodesma donacium, one of the most important commercial species for local fishermen, no information is available on depuration, or on the anatomical distribution of this toxin and its potential use as a palliative measure to minimize the consequences of ASP outbreaks. Deputation of DA is very fast in M. donacium, and can be adequately described by means of a two-compartment model. The estimated rates for the first and second compartments were 1.27 d(-1) and 0.24 d(-1), respectively, with a transfer rate between compartments of 0.75. Having high depuration rates protects this species from being affected by Pseudo nitzschia blooms for an extended period of time. Taking this into account, the time in which the bivalves are unsafe for consumers is very short, and therefore the economic losses that could result by the DA outbreaks in local fisheries should be moderate. In relation to anatomical distribution, at least during the uptake phase, the toxin was evenly distributed within the soft tissues, with a total toxin burden corresponding to 27%, 32% and 41% for Digestive Gland (DG), Foot (FT) and Other Body Fractions (OBF), respectively. Since the contribution of each organ to the toxin concentration is a function of both weight contribution and toxin burden, the pattern of toxin distribution showed the following trend: "all other body fractions" (OBF) > Foot (FT) > Digestive Gland (DG). Thus, the highest concentration of DA, with a contribution close to 72%, corresponds to the edible tissues (OBF + FT), while the DG (non-edible tissue) only contributes the remaining 28%. Consequently, in view of the anatomical distribution of domoic acid in M. donacium, the elimination of the digestive gland does not substantially reduce the toxicity of the final product and therefore selective evisceration would not improve their quality for human consumption. PMID- 26003791 TI - Apparent diffusion coefficient values of diffusion-weighted imaging for distinguishing focal pulmonary lesions and characterizing the subtype of lung cancer: a meta-analysis. AB - OBJECTIVES: The potential performance of apparent diffusion coefficient (ADC) values for distinguishing malignant and benign pulmonary lesions, further characterizing the subtype of lung cancer was assessed. METHODS: PubMed, EMBASE, Cochrane Library, EBSCO, and three Chinese databases were searched to identify eligible studies on diffusion-weighted imaging (DWI) of focal pulmonary lesions. ADC values of malignant and benign lesions were extracted by lesion type and statistically pooled based on a linear mixed model. Further analysis for subtype of lung cancer was also performed. The methodological quality was assessed using the quality assessment of diagnostic accuracy studies tool. RESULTS: Thirty-four articles involving 2086 patients were included. Malignant pulmonary lesions have significantly lower ADC values than benign lesions [1.21 (95% CI, 1.19-1.22) mm(2)/s vs. 1.76 (95% CI, 1.72-1.80) mm(2)/s; P < 0.05]. There is a significant difference between ADC values of small cell lung cancer and non-small cell lung cancer (P < 0.05), while the differences were not significant among histological subtypes of lung cancer. The methodological quality was relatively high, and the data points from Begg's test indicated that there was probably no obvious publication bias. CONCLUSIONS: The ADC value is helpful for distinguishing malignant and benign pulmonary lesions and provides a promising method for differentiation of SCLC from NSCLC. KEY POINTS: * This meta-analysis assesses the role of DWI in pulmonary lesions. * Differentiation and classification subtype of lung cancer is essential for treatment decision-making. * ADC values can help distinguish between malignant and benign lesions. * ADC values might help characterize the subtype of lung cancer. PMID- 26003792 TI - 128-slice CT angiography of the aorta without ECG-gating: efficacy of faster gantry rotation time and iterative reconstruction in terms of image quality and radiation dose. AB - OBJECTIVE: To evaluate image quality and radiation dose of non ECG-gated 128 slice CT angiography of the aorta (CTAA) with fast gantry rotation time and iterative reconstruction. METHODS: Four hundred and eighty patients underwent non ECG-gated CTAA. Qualitative and quantitative image quality assessments were performed. Radiation dose was assessed and compared with the dose of patients who underwent ECG-gated CTAA (n = 126) and the dose of previous CTAA performed with another CT (n = 339). RESULTS: Image quality (aortic root-ascending portion) was average-to-excellent in more than 94% of cases, without any non-diagnostic scan. For proximal coronaries, image quality was average-to-excellent in more than 50%, with only 21.5% of non-diagnostic cases. Quantitative analysis results were also good. Mean radiation dose for thoracic CTAA was 5.6 mSv versus 20.6 mSv of ECG gated protocol and 20.6 mSv of 16-slice CTAA scans, with an average dose reduction of 72.8% (p < 0.001). Mean radiation dose for thoracic-abdominal CTAA was 9.7 mSv, versus 20.9 mSv of 16-slice CTAA scans, with an average dose reduction of 53.6% (p < 0.001). CONCLUSIONS: Non ECG-gated 128-slice CTAA is feasible and able to provide high quality visualization of the entire aorta without significant motion artefacts, together with a considerable dose and contrast media volume reduction. KEY POINTS: * CT image quality of aortic root ascending aorta is challenging. * Non ECG-gated scans are often limited by pulsatility artefacts. * ECG-gated examinations are usually limited by high radiation doses. * Non ECG-gated 128-slice low dose CTAA provides high quality images. * 128-slice CTAA low dose protocol could frequently replace ECG-gated CTAA. PMID- 26003794 TI - Intracranial haemorrhages associated with venom induced consumption coagulopathy in Australian snakebites (ASP-21). AB - Intracranial haemorrhage (ICH) is a rare life-threatening consequence of venom induced consumption coagulopathy in snake-bite. It is unclear why certain patients haemorrhage. We aimed to investigate ICH in snake envenoming. Cases of venom-induced consumption coagulopathy from July 2005-June 2014 were identified from the Australian Snakebite Project, a prospective multicentre cohort of snake bites. Cases with venom-induced consumption coagulopathy were extracted with data on the snake-bite, clinical effects, laboratory investigations, treatment and outcomes. 552 cases had venom-induced consumption coagulopathy; median age, 40 y (2-87 y), 417 (76%) males, 253 (46%) from brown snakes and 17 died (3%). There were 6/552 (1%) cases of ICH; median age, 71 y (59-80 y), three males and five from brown snakes. All received antivenom and five died. All six had a history of hypertension. Time to onset of clinical effects consistent with ICH was 8-12 h in four cases, and within 3 h in two. Difficult to manage hypertension and vomiting were common. One patient had a normal cerebral CT on presentation and after the onset of focal neurological effects a repeat CT showed an ICH. ICH is rare in snake-bite with only 1% of patients with coagulopathy developing one. Older age and hypertension were associated with ICH. PMID- 26003795 TI - Influence of thyroid states on the local effects induced by Bothrops envenoming. AB - Bothrops leucurus venom causes significant local effects, such as necrosis, pain, hemorrhage and edema. These effects are important because of their high frequency and severity. The treatment of these local effects is not simple because of their quick triggering and a variety of components that induce these effects. Myonecrosis, dermonecrosis and edema are primarily caused by the action of hemorrhagins and myotoxins. A number of investigators have demonstrated the influence of thyroid hormones on inflammatory processes, particularly on wound healing. We investigated the edematogenic, hemorrhagic and necrotic activity of the B. leucurus venom in the hypothyroid, hyperthyroid and euthyroid of rats. The CK (creatine kinase) plasma level decreased in the animals in a hypothyroid state. The hypothyroid condition also significantly reduced the hemorrhagic and dermonecrotic area compared to the euthyroidism and hyperthyroidism states. It also mitigated the rat paw edema compared to that found in the euthyroid and hyperthyroid animals. The hyperthyroid animals showed no significant differences in the three treatments compared to the euthyroid animals. Our results suggest that the triggering of local effects induced by envenomation by B. leucurus is attenuated in hypothyroid animals, possibly by the effect of hypothyroidism on the immune system and blood flow. PMID- 26003796 TI - Occurrence and profiles of lipophilic toxins in shellfish harvested from Argentina. AB - The presence of phytoplankton responsible for the production of lipophilic marine biotoxins is well recognised throughout parts of South America. To date, the quantitation of lipophilic toxins in Argentinean shellfish has been limited to select and highly focussed geographical studies. This work reports the analysis for lipophilic marine biotoxins in shellfish harvested across five regions of Argentina between 1992 and 2012. LC-MS/MS analysis was used for the quantitation of all regulated lipophilic toxins. High concentrations of okadaic acid group toxins were quantified, with a clear dominance of the parent okadaic acid and more than 90% of the toxin present as esters. Results showed DSP toxins in shellfish from the Buenos Aires Province during 2006 and 2007, earlier than previously described. There was also strong evidence linking the presence of okadaic acid to human intoxications. Other lipophilic toxins detected were yessotoxin, pectenotoxin-2 and 13-desMeC spirolide. With evidence published recently for the presence of azaspiracid producers, this work reports the detection of low concentrations of azaspiracid-2 in shellfish. As such the data provides the first published evidence for yessotoxins and azaspiracids in Argentinean shellfish and further evidence for the continuing presence of lipophilic marine toxins in Argentinean waters. PMID- 26003797 TI - Multiple simultaneous primary oral squamous cell carcinomas: a previously unreported presentation. AB - The simultaneous occurrence of a second oral squamous cell carcinoma, or in rare cases more, is well known, but to our knowledge, the presentation of 5 primary oral cancers at once has not previously been reported. We discuss this exceptional case and offer a possible explanation for its cause. PMID- 26003798 TI - Re: 'long-term results of a randomized controlled trial analyzing the role of systematic pre-operative coronary angiography before elective carotid endarterectomy in patients with asymptomatic coronary artery disease'--reply. PMID- 26003799 TI - Where now for Endovascular Repair of Ruptured AAA? PMID- 26003800 TI - Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. AB - INTRODUCTION: Many pathways have been reported involving the effect of hydrogen rich saline on protecting skin flap partial necrosis induced by the inflammation of ischemia/reperfusion injury. This study focused on the influence of hydrogen rich saline treatment on apoptosis pathway of ASK-1/JNK and Bcl-2/Bax radio in I/R injury of skin flaps. METHODS: Adult male Sprague-Dawley rats were divided into three groups. Group 1 was sham surgery group, Group 2 and 3 were ischemia/reperfusion surgery treated with physiological saline and hydrogen-rich saline respectively. Blood perfusion of flap was measured by Laser doppler flowmeters. Hematoxylin and eosin staining was used to observe morphological changes. Early apoptosis in skin flap was observed through TUNEL staining and presented as the percentage of TUNEL-positive cells of total cells. pASK-1, pJNK, Bcl-2 and Bax were examined by immunodetection. In addition Bcl-2, Bax and caspase-3 were detected by qPCR. Caspase-3 activity was also measured. RESULTS: Compared to the Group 2, tissues from the group 3 were observed with a high expression of Bcl-2 and a low expression of pASK-1, pJNK, and Bax, a larger survival area and a high level of blood perfusion. Hydrogen-rich saline ameliorated inflammatory infiltration and decreased cell apoptosis. CONCLUSION: The results indicate that hydrogen-rich saline could ameliorate ischemia/reperfusion injury and improve flap survival rate by inhibiting the apoptosis factor and, at the same time, promoting the expression of anti apoptosis factor. PMID- 26003802 TI - IVIg for relapsing-remitting multiple sclerosis: promises and uncertainties. AB - Despite promising clinical trials, intravenous immunoglobulin (IVIg) therapy in relapsing-remitting multiple sclerosis (MS) has met with uncertainties that might be attributed to small patient cohorts, heterogeneity in the patients, dose of IVIg, or the duration and window of treatment. PMID- 26003801 TI - Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy. AB - Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches. SIGNIFICANCE: This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention. PMID- 26003803 TI - Tetrapleura tetraptera spice attenuates high-carbohydrate, high-fat diet-induced obese and type 2 diabetic rats with metabolic syndrome features. AB - BACKGROUND: Tetrapleura tetraptera, a seasoning and nutritive spice is also used in western African folk medicine in the management of wide variety of diseases including diabetes, inflammation and hypertension. Flavonoids and saponins are some abundant secondary metabolic constituents in the fruits of this plant. This study aimed at evaluating the potential therapeutic action of the polyphenol-rich hydroethanolic extract (HET) of this fruit in experimentally induced obese and type 2 diabetic rats (T2DM) with characteristic metabolic syndrome (MetS). METHODS: MetS was induced in rats by high-carbohydrate, high-fat diet and administration of low-dose streptozotocin. Then different oral doses of HET (200 and 400 mg/kg) were administered to T2DM rats for 28 days. A standard antidiabetic drug, metformin (300 mg/kg), was used for comparison. The body weight, systolic blood pressure, oxidative stress and metabolic parameters were then assessed to evaluate the effect of HET on MetS. RESULTS: HET reduced weight gain, fasting blood glucose and plasma insulin levels as well as homeostasis model assessment of insulin resistance (HOMA-IR) and alleviated obesity and T2DM associated oxidative stress and hypertension in rats. Moreover, a significantly hypolipidemic property and an attenuation of liver injury and tissue steatosis was observed after HET administration. HET further demonstrated its anti inflammation effect via down regulation of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), C-reactive protein (CRP), leptin and an increase in adiponectin. The HET exhibited dose-dependent effects which were comparable to that of metformin. CONCLUSIONS: The present study thereby demonstrates the anti insulin resistance, antilipidemic, anti-obesity, hypotensive and anti inflammatory properties of HET; hence it has the potential to be further developed for the management of MetS such as obesity, T2DM and hypertension. PMID- 26003806 TI - Epilepsy genetics: the ongoing revolution. AB - Epilepsies have long remained refractory to gene identification due to several obstacles, including a highly variable inter- and intrafamilial expressivity of the phenotypes, a high frequency of phenocopies, and a huge genetic heterogeneity. Recent technological breakthroughs, such as array comparative genomic hybridization and next generation sequencing, have been leading, in the past few years, to the identification of an increasing number of genomic regions and genes in which mutations or copy-number variations cause various epileptic disorders, revealing an enormous diversity of pathophysiological mechanisms. The field that has undergone the most striking revolution is that of epileptic encephalopathies, for which most of causing genes have been discovered since the year 2012. Some examples are the continuous spike-and-waves during slow-wave sleep and Landau-Kleffner syndromes for which the recent discovery of the role of GRIN2A mutations has finally confirmed the genetic bases. These new technologies begin to be used for diagnostic applications, and the main challenge now resides in the interpretation of the huge mass of variants detected by these methods. The identification of causative mutations in epilepsies provides definitive confirmation of the clinical diagnosis, allows accurate genetic counselling, and sometimes permits the development of new appropriate and specific antiepileptic therapies. Future challenges include the identification of the genetic or environmental factors that modify the epileptic phenotypes caused by mutations in a given gene and the understanding of the role of somatic mutations in sporadic epilepsies. PMID- 26003804 TI - Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial. AB - BACKGROUND: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. METHODS/DESIGN: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42 43 degrees C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. DISCUSSION: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. TRIAL REGISTRATION NUMBER: NCT02231086 (Clinicaltrials.gov). PMID- 26003805 TI - Challenges in essential tremor genetics. AB - The field of essential tremor (ET) genetics remains extremely challenging. The relative lack of progress in understanding the genetic etiology of ET, however, does not reflect the lack of a genetic contribution, but rather, the presence of substantial phenotypic and genotypic heterogeneity. A meticulous approach to phenotyping is important for genetic research in ET. The only tool for phenotyping is the clinical history and examination. There is currently no ET specific serum or imaging biomarker or defining neuropathological feature (e.g., a protein aggregate specific to ET) that can be used for phenotyping, and there is considerable clinical overlap with other disorders such as Parkinson's disease (PD) and dystonia. These issues greatly complicate phenotyping; thus, in some studies, as many as 30-50% of cases labeled as "ET" have later been found to carry other diagnoses (e.g., dystonia, PD) rather than ET. A cursory approach to phenotyping (e.g., merely defining ET as an "action tremor") is likely a major issue in some family studies of ET, and this as well as lack of standardized phenotyping across studies and patient centers is likely to be a major contributor to the relative lack of success of genome wide association studies (GWAS). To dissect the genetic architecture of ET, whole genome sequencing (WGS) in carefully characterized and well-phenotyped discovery and replication datasets of large case-control and familial cohorts will likely be of value. This will allow specific hypotheses about the mode of inheritance and genetic architecture to be tested. There are a number of approaches that still remain unexplored in ET genetics, including the contribution of copy number variants (CNVs), 'uncommon' moderate effect alleles, 'rare' variant large effect alleles (including Mendelian and complex/polygenic modes of inheritance), de novo and gonadal mosaicism, epigenetic changes and non-coding variation. Using these approaches is likely to yield new ET genes. PMID- 26003807 TI - Impact of cardiac resynchronization therapy-defibrillator implantation on the association between body mass index and prognosis in patients with heart failure. AB - PURPOSE: This study aimed to examine the association between body mass index (BMI) and prognosis in heart failure patients after cardiac resynchronization therapy-defibrillator (CRT-D) implantation. METHODS: We retrospectively investigated 125 patients (33 overweight [BMI >=25 kg/m(2)], 75 normal weight [BMI 18.5-24.9 kg/m(2)], and 17 underweight patients [BMI <18.5 kg/m(2)]) who underwent CRT-D implantation. The clinical outcome endpoints were all-cause death and appropriate shock therapy. RESULTS: During the follow-up period (mean 3.1 +/- 1.8 years), 23 patients died (1 [3.0 %] overweight, 17 [22.7 %] normal weight, and 5 [29.4 %] underweight patients), and appropriate shock events were observed in 14 patients (2 [6.1 %] overweight, 10 [13.3 %] normal weight, and 2 [11.8 %] underweight patients). All patients survived shock therapy. After adjusting for confounding factors, overweight patients had significantly fewer outcomes relating to all-cause death and appropriate shock events (hazard ratio 0.27, 95 % confidence interval 0.08-0.91, p = 0.034) than normal weight patients. However, the prognostic difference between overweight and normal weight patients could be diminished as a result of the successful shock therapies (p = 0.067). Additionally, prognosis did not differ between overweight and normal weight patients among the responders, but did differ among the non-responders. The underweight patients had a poorer prognosis after CRT-D implantation compared with the other groups. CONCLUSIONS: Although high BMI was associated with better outcomes among heart failure patients with CRT-D implantations, the difference in the prognosis between overweight and normal weight patients was reduced because of defibrillator therapy and the improvement in cardiac function provided by CRT D implantation. PMID- 26003808 TI - A low fibrillatory wave amplitude predicts sinus node dysfunction after catheter ablation in patients with persistent atrial fibrillation. AB - BACKGROUND: Concealed sinus node dysfunction (SND) may become manifest after restoration of sinus rhythm by ablation in patients with persistent atrial fibrillation (AF). The purpose of this study was to investigate the predictors of SND after catheter ablation of persistent AF. METHODS: Two hundred two consecutive patients who underwent ablation for persistent AF were enrolled. Ipsilateral pulmonary vein isolation followed by, if necessary, electrical cardioversion were performed in all patients. SND was defined when temporary and/or permanent pacemakers were needed due to sinus bradycardia after ablation. RESULTS: SND developed in 12 (5.9 %) patients. There was no difference between the patients with and without SND in terms of the age (with SND, 67 +/- 9 and without, 66 +/- 10 years old, P = 0.599) and sex (male; 58 vs. 79 %, P = 0.186). However, the patients with SND had a lower amplitude of the fibrillatory waves (0.115 +/- 0.086 vs. 0.176 +/- 0.077 mV, P = 0.009) and larger left atrial volume index (LAVI; 66 +/- 31 vs. 34 +/- 13, P = 0.007) than those without. A receiver operating characteristic curve identified a fibrillatory wave amplitude of 0.145 mV (AUC = 0.742; sensitivity = 65 %; specificity = 83 %) and LAVI of 47.5 ml/m(2) (AUC = 0.837; sensitivity = 82 %; specificity = 87 %) as the optimal cutoff values for predicting SND. A multivariate analysis revealed that the amplitude of the fibrillatory waves (odds ratio = 0.84 for 0.010 mV increase, 95 % CI = 0.71 0.98, P = 0.031) and LAVI (odds ratio = 1.08 for 1.0 cm(3)/m(2) increase, 95 % CI = 1.04-1.12, P < 0.001) were independent risk factors for SND. CONCLUSIONS: A low amplitude of the fibrillatory waves and a large LAVI were predictors of SND after restoration of sinus rhythm by ablation in patients with persistent AF. PMID- 26003809 TI - Acaricidal effect and histological damage induced by Bacillus thuringiensis protein extracts on the mite Psoroptes cuniculi. AB - BACKGROUND: The mite Psoroptes cuniculi is a common worldwide ectoparasite and the most frequently found in rabbit farms. It causes significant economic losses on commercial rabbit breeding associated with poor leather quality, reduced conception rates, weight loss, poor growth and death. Several strategies have been proposed for the treatment of mange caused by this mite, ranging from the use of acaricides, entomopathogenic fungi, essential oils and vaccines. However, therapy and control of both human scabies and animal mange are still based mainly on the use of drugs and chemicals such as ivermectin, which involves disadvantages including genotoxic and cytotoxic effects, resistance and environmental damage. Bacillus thuringiensis is a bacterium, innocuous for human being, domestic animals and plants that produces highly biodegradable proteins, and has been used worldwide for biological control. The aim of this work was to find an alternative treatment based on biological control for scabies caused by Psoroptes cuniculi, using protein extracts from strains of Bacillus thuringiensis. METHODS: P. cuniculi mites were obtained from naturally infected New Zealand rabbits, and different doses of protein from B. thuringiensis were added to the mites. We measured mortality and obtained the median lethal concentration and median lethal times. For histological analysis, the mites were fixed in 10% formalin, processed according to the paraffin embedded tissue technique. Sections were stained with hematoxylin-eosin to observe the general histological structure. RESULTS: We report here for the first time evidence about the in vitro acaricidal effect caused by the strain GP532 of B. thuringiensis on the mite Psoroptes cuniculi, with an LC50 of 1.3 mg/ml and a LT50 of 68 h. Histological alterations caused by B. thuringiensis on this mite, included the presence of dilated intercellular spaces in the basal membrane, membrane detachment of the peritrophic matrix and morphological alterations in columnar cells of the intestine. CONCLUSIONS: Since this mite is an obligate ectoparasite that affects rabbits, goats, horses, cows and sheep, B. thuringiensis protein extracts are proposed as a potential treatment for biological control of mange in farm animals. PMID- 26003810 TI - Regulated C-C motif ligand 2 (CCL2) in luteal cells contributes to macrophage infiltration into the human corpus luteum during luteolysis. AB - Intense macrophage infiltration is observed during luteolysis in various animals including women; however, we still do not know how macrophage infiltration into the human corpus luteum (CL) during luteolysis is regulated. In this study, we examined the expression, localization and regulation of an important chemokine for the recruitment of monocyte/macrophage lineages, C-C motif ligand 2 (CCL2), in the human CL across the luteal phase and in cultured human luteinized granulosa cells (LGCs), with special reference to the number of infiltrating macrophages and luteal cell function. CCL2 mRNA increased in the non-functional regressing CL during menstruation (P < 0.01), corresponding to an elevated mRNA expression of a macrophage-derived cytokine, tumor necrosis factor (TNF), and an increased number of infiltrating macrophages positively stained with a macrophage marker, CD68. CCL2 protein was immunohistochemically localized to the cytoplasm of granulosa-lutein and theca-lutein cells, and CCL2 mRNA was significantly reduced by hCG both in vivo (P < 0.05) and in vitro (P < 0.01). CCL2 was also down-regulated by luteotrophic prostaglandin (PG) E (P < 0.0001), but up regulated by luteolytic PGF (P < 0.05) in vitro. Administration of TNF significantly enhanced the CCL2 mRNA expression in cultured LGCs (P < 0.01). A greater abundance of infiltrating macrophages were found around granulosa-lutein cells lacking 3beta-HSD or PGE synthase (PGES) immunostaining. CCL2 mRNA expression was negatively correlated with both HSD3B1 and PGES, suggesting that locally produced progesterone and PGE suppress macrophage infiltration into the CL. Taken together, the infiltration of macrophages in the human CL is regulated by endocrine and paracrine molecules via regulation of the CCL2 expression in luteal cells. PMID- 26003811 TI - Effect of juvenoids pyriproxyfen and diofenolan on embryogenesis and postembryonic development of blow fly Chrysomya megacephala (Diptera: Calliphoridae) following egg treatment. AB - The blow fly Chrysomya megacephala is a serious medico-veterinary pest causing myiasis in humans and animals apart from transmitting various disease-causing pathogens. Being an economically important pest, it warrants successful control in the early stages without affecting the host, environment, and non-target organisms. Juvenoids being safe, species and stage selective, biodegradable, and harmless to beneficial non-target organisms. Treatment of freshly laid eggs of C. megacephala with juvenoids pyriproxyfen and diofenolan (50 and 100 MUg/cm(2)) by contact method for 1-60 min severely derailed the embryogenesis and postembryonic development. The results included the following: reduced eclosion, dead, non viable eggs, undeveloped embryos of various stages, and fully developed embryos entrapped in chorion and unable to eclose. Several latent effects of juvenoids were also observed like larval mortality in the first instar, abnormal pupariation, reduced normal pupariation, formation of pupal-adult mosaics, suppression of adult emergence, and emergence of only deformed adults. Diofenolan was found to be more potent than pyriproxyfen in suppressing embryogenesis. These results show that the juvenoids pyriproxyfen and diofenolan have the potential to be judiciously used along with other bio-rational methods for the successful control of C. megacephala. PMID- 26003812 TI - Socioeconomic factors associated with outcome after cardiac arrest in patients under the age of 65. AB - AIM: In a prior study of seven North American cities Pittsburgh had the highest crude rate of cardiac arrest deaths in patients 18 to 64 years of age, particularly in neighborhoods with lower socioeconomic status (SES). We hypothesized that lower SES, associated poor health behaviors (e.g., illicit drug use) and pre-existing comorbid conditions (grouped as socioeconomic factors [SE factors]) could affect the type and severity of cardiac arrest, thus outcomes. METHODS: We retrospectively identified patients aged 18 to 64 years treated for in-hospital (IHCA) and out-of hospital arrest (OHCA) at two Pittsburgh hospitals between January 2010 and July 2012. We abstracted data on baseline demographics and arrest characteristics like place of residence, insurance and employment status. Favorable cerebral performance category [CPC] (1 or 2) was our primary outcome. We examined the associations between SE factors, cardiac arrest variables and outcome as well as post-resuscitation care. RESULTS: Among 415 subjects who met inclusion criteria, unfavorable CPC were more common in patients who were unemployed, had a history of drug abuse or hypertension. In OHCA, favorable CPC was more often associated with presentation with ventricular fibrillation/tachycardia (OR 3.53, 95% CI 1.43-8.74, p = 0.006) and less often associated with non-cardiovascular arrest etiology (OR 0.22, 95% CI 0.08-0.62, p = 0.004). We found strong associations between specific SE factors and arrest factors associated with outcome in OHCA patients only. Significant differences in post-resuscitation care existed based on injury severity, not on SES. CONCLUSIONS: SE factors strongly influence type and severity of OHCA but not IHCA resulting in an association with outcomes. PMID- 26003813 TI - Growing trend of China's contribution to the field of spine: a 10-year survey of the literature. AB - PURPOSE: China, as a rapidly developing country with the largest population including over 50,000 orthopaedic surgeons, has an increasing importance in the field of spine. However, the quantity and quality of research production in the field of spine in the major regions of China-Mainland China, Taiwan, and Hong Kong is unclear. This study aimed to investigate the contribution of China to the field of spine. METHODS: Articles published in the 5 major spine journals originating from Mainland China, Taiwan and Hong Kong in 2004-2013 were retrieved from the database of Web of Science. The number of articles, impact factors, citations, article type, city, institution, funding source and conflict of interest were analyzed. RESULTS: There were 1006 publications in the 5 spine journals between 2004 and 2013 from China, including 706 from Mainland China, 210 from Taiwan, and 90 from Hong Kong. The time trend of the number of articles from these three regions showed a significant increase of 8.74-fold (from 23 to 201) between 2004 and 2013 (p = 0.000). From 2006, the number of publications from Mainland China exceeded Taiwan and Hong Kong. Mainland China had the highest total impact factors (1686.54) and total citations (4214), followed by Taiwan (498.93; 2009) and Hong Kong (222.89; 1311). Hong Kong had the highest mean impact factor (2.48) and mean citations (14.46), followed by Mainland China (2.40; 10.26) and Taiwan (2.38; 10.14). The journal Spine published the largest number of articles (470), followed by European Spine Journal (268). CONCLUSIONS: Chinese contributions to the field of spine have a significant increase during the past 10 years, particularly from Mainland China. Hong Kong had the highest quality research output in terms of mean impact factor and mean citation per article. PMID- 26003814 TI - Trends analysis of rhBMP utilization in single-level posterior lumbar fusion (PLF) in the United States. AB - PURPOSE: A retrospective database review was carried out to evaluate the trends and demographics of rhBMP utilization in single-level posterior lumbar fusion (PLF) in the United States. METHODS: Patients who underwent single-level PLF from 2005 to 2011 were identified by searching ICD-9 diagnosis and procedure codes in the PearlDiver Patient Records Database (PearlDiver Technologies, Fort Wayne, IN, USA), a national database of orthopaedic insurance records. The year of procedure, age, gender, and region of the United States were recorded for each patient. Results were reported for each variable as the incidence of procedures identified per 100,000 patients searched in the database. RESULTS: Totally 5158 patients had single-level PLF in this study. The average rate of single-level PLF with rhBMP utilization maintained at a relatively stable level (19.1-23.5%) from 2005 to 2009, but sharply decreased to 6.8% in 2010 and 6.9% in 2011. The overall incidence of single-level PLF without rhBMP (1.37 cases per 100,000 patients) was more than five times of the incidence of single-level PLF with rhBMP (0.27 cases per 100,000 patients) (P < 0.01). The average rate of single-level PLF with rhBMP utilization is highest in Midwest (18.7%), followed by West (18.4%), South (16.4%) and Northeast (11.5%). The highest incidence of single-level PLF with rhBMP was observed in the group aged 70-74 years with an incidence of 0.33 per 100,000 patients. CONCLUSIONS: The incidence of rhBMP utilization in single-level PLF increased from 2006 to 2009, but dropped to a low level in 2010 and 2011. The Northeast region had the lowest incidence of rhBMP utilization. The group aged 70 74 years trended to have the higher incidence of single-level PLF with rhBMP utilization. PMID- 26003815 TI - Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method. AB - The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems. PMID- 26003816 TI - Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency. AB - Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are activated and contribute to neuronal cell death. We can thus hypothesise that the use of microglial activation blockers could prevent this additional neuronal death. PMID- 26003817 TI - The Integrated Gateway Model: a catalytic approach to behavior change. AB - OBJECTIVES: To develop and test an Integrated Gateway Model of behaviors and factors leading to subsequent positive reproductive, maternal, and child health behaviors. METHODS: A secondary analysis was conducted using previously published household survey data collected from men (n=5551; 2011) and women (n=16144; 2011) in Nigeria and women in Egypt (n=2240; 2004-2007). The number of health behaviors each potential gateway behavior predicted was assessed by multivariate regression, adjusting for potential confounders. The influence of gateway factors on gateway behaviors was tested via interaction terms. Gateway behaviors and factors were ranked by the number of health outcomes predicted, both separately and synergistically. RESULTS: The key gateway behavior identified in both datasets was spousal communication about family planning, whereas the key gateway factor was exposure to family planning messages. CONCLUSIONS: The model could facilitate innovative research and programming that in turn might promote cascades of positive behaviors in reproductive, maternal, and child health. PMID- 26003818 TI - The Effect of Resident Involvement on Perioperative Outcomes in Transurethral Urologic Surgeries. AB - OBJECTIVE: To conduct the first study of intra- and postoperative outcomes related to intraoperative resident involvement in transurethral resection procedures for benign prostatic hyperplasia and bladder cancer in a large, multi institutional database. DESIGN: Relying on the American College of Surgeons National Surgical Quality Improvement Program Participant User Files (2005-2012), we abstracted all cases of endoscopic prostate surgery (EPS) for benign prostatic hyperplasia and transurethral resection of bladder tumors (TURBTs). Multivariable logistic regression models were constructed to assess the effect of trainee involvement (postgraduate year [PGY] 1-2: junior, PGY 3-4: senior, PGY >= 5: chief or fellow) vs attending only on operative time and length of hospital stay, as well as 30-day complication, reoperation, and readmission rates. RESULTS: In all, 5093 EPS and 3059 TURBTs for a total of 8152 transurethral resection procedures were performed during the study period for which data on resident involvement were available. In multivariable analyses, resident involvement in EPS or TURBT was associated with increased odds of prolonged operative times and hospital readmissions in 30 days independent of resident level of training. Resident involvement was not associated with overall complications or reoperation rates. CONCLUSIONS: Resident involvement in lower urinary tract surgeries is associated with increased readmissions. Strategies to optimize resident teaching of these common urologic procedures in order to minimize possible risks to patients should be explored. PMID- 26003819 TI - Childhood sexual abuse by representatives of the Roman Catholic Church: a prevalence estimate among the Dutch population. AB - Estimates of the extent of childhood sexual abuse (CSA) within in the Roman Catholic Church (RCC) in the general population are difficult to find. The independent Commission of Inquiry into sexual abuse of minors in the RCC in the Netherlands collected population-based data to estimate its prevalence. A large random online population sample was surveyed using a two-phase stratified sampling procedure. In Phase 1, 34,267 subjects aged 40 years and older were screened for childhood exposure to sexual abuse by non-family members, a history of institutionalization and a Roman Catholic upbringing. In Phase 2, a stratified subset of 2,462 subjects was assessed to obtain more detailed target information about sexual abuse reports within the RCC. We employed multiple imputation for the estimation of RCC CSA in the original Phase 1 sample. The prevalence of non familial CSA in general (14.0%) was higher among women (17.2%) than among men (10.6%). The prevalence of CSA within the Dutch RCC (1.7%) was higher among men (2.7%) than among women (0.7%). As expected, older subjects reported more often CSA in the RCC than their younger counterparts. Respondents who stayed for some time in RCC run institutions for education or child protection had a higher risk to report sexual abuse. Although sexual abuse of minors by representatives of the RCC was a structural problem during a period that the Church was highly influential in the Netherlands, the estimated prevalence of the phenomenon is only a fraction of the prevalence rate of non-familial CSA. PMID- 26003820 TI - The exposure of children to intimate partner violence: Potential bridges between two fields in research and psychosocial intervention. Research and interventions often focus on a specific form of violence without considering other forms of victimization. PMID- 26003821 TI - Previous maltreatment and present mental health in a high-risk adolescent population. AB - Childhood maltreatment is known to increase the risk of future psychiatric disorders. In the present study, we explored the impact of experienced maltreatment on the prevalence and comorbidity of psychiatric disorders in a high risk population of adolescents in residential care units. We also studied the impact of poly-victimization. The participants of the study were adolescents in residential care units in Norway (n=335, mean age 16.8 years, girls 58.5%). A diagnostic interview (Child and Adolescent Psychiatric Assessment Interview) was used, yielding information about previous maltreatment (witnessing violence, victim of family violence, community violence, sexual abuse) and DSM-IV diagnoses present in the last three months. Exposure to maltreatment was reported by 71%, and in this group, we found significantly more Asperger's syndrome (AS) (p=.041), conduct disorder (CD) (p=.049), major depressive disorder (MDD) (p=.001), dysthymia (p=.030), general anxiety disorder (GAD) (p<.001), and having attempted suicide (p=.006). We found significantly more comorbid disorders in the maltreated group. Poly-victimization was studied by constructing a scale comprised of witnessing violence, victim of family violence, victim of sexual abuse and household dysfunction. We found that poly-victimization was associated with significantly increased risk of MDD, GAD, AS, CD, and having attempted suicide (p<.01). The complexity of the clinical outcomes revealed in this study suggest that longer-term treatment plans and follow-up by psychiatric services might be needed to a greater extend than for the rest of the child and adolescent population, and that trauma informed care is essential for adolescents in residential youth care. PMID- 26003822 TI - Buriti oil (Mauritia flexuosa L.) negatively impacts somatic growth and reflex maturation and increases retinol deposition in young rats. AB - Buriti oil contains nutrients such as essential fatty acids and vitamins, which are directly involved with neonates' development. However, the refining process of this oil can change its nutrient profile. This study investigated the effects of maternal consumption of Buriti oil (crude or refined), on reflex and somatic development and retinol levels in neonatal rats. Thirty-six Wistar male neonate rats born from mothers who consumed diet with 7% lipids during gestation and lactation were used. Rats were randomized into three groups: rats receiving diet added of soybean oil (control-CG), crude Buriti oil (CB) and refined Buriti oil (RB). Offspring weight, tail length, reflex ontogeny and somatic maturation were assessed during lactation. At the end of the experiment, serum and liver retinol concentrations were measured. Animals from CB and RB groups showed delayed onset of palm grasp, righting reflex and cliff avoidance reflexes compared to the control group (CG). However, animals from RB group showed anticipation of auditory startle compared to those from BC group. Regarding somatic maturation indicators, animals from RB group showed delayed eye opening and eruption of superior and inferior incisors in relation to control and anticipation in the auditory conduit opening in relation to CB group. Rats from CB and RB groups showed higher serum and liver vitamin A contents. Buriti oil delays physical parameters and reflex maturation and increases serum and liver retinol deposition among neonatal rats. PMID- 26003823 TI - Development and applications of Ray's fluid thioglycollate media for detection and manipulation of Perkinsus spp. pathogens of marine molluscs. AB - During the early 1950s, Sammy M. Ray discovered that his high-salt modification of fluid thioglycollate sterility test medium caused dramatic in vitro enlargement of Perkinsus marinus (=Dermocystidium marinum) cells that coincidentally infected several experimentally cultured oyster gill tissue explants. Subsequent testing confirmed that the enlarged cells among some oyster tissues incubated in Ray's fluid thioglycollate medium (RFTM) were those of that newly described oyster pathogen. Non-proliferative in vitro enlargement, cell wall thickening, and subsequent blue-black iodine-staining of hypertrophied trophozoites (=hypnospores=prezoosporangia) following incubation in RFTM are unique characteristics of confirmed members of the protistan genus Perkinsus. A number of in vitro assays and manipulations with RFTM have been developed for selective detection and enumeration of Perkinsus sp. cells in tissues of infected molluscs, and in environmental samples. RFTM-enlarged Perkinsus sp. cells from tissues of infected molluscs also serve as useful inocula for initiating in vitro isolate cultures, and cells of several Perkinsus spp. from both in vitro cultures and infected mollusc tissues may be induced to zoosporulate by brief incubations in RFTM. DNAs from RFTM-enlarged Perkinsus sp. cells provide useful templates for PCR amplifications, and for sequencing and other assays to differentiate and identify the detected Perkinsus species. We review the history and components of fluid thioglycollate and RFTM media, and the characteristics of numerous RFTM based diagnostic assays that have been developed and used worldwide since 1952 for detection and identification of Perkinsus spp. in host mollusc tissues and environmental samples. We also review applications of RFTM for in vitro manipulations and purifications of Perkinsus sp. pathogen cells. PMID- 26003824 TI - Immune responses to infectious diseases in bivalves. AB - Many species of bivalve mollusks (phylum Mollusca, class Bivalvia) are important in fisheries and aquaculture, whilst others are critical to ecosystem structure and function. These crucial roles mean that considerable attention has been paid to the immune responses of bivalves such as oysters, clams and mussels against infectious diseases that can threaten the viability of entire populations. As with many invertebrates, bivalves have a comprehensive repertoire of immune cells, genes and proteins. Hemocytes represent the backbone of the bivalve immune system. However, it is clear that mucosal tissues at the interface with the environment also play a critical role in host defense. Bivalve immune cells express a range of pattern recognition receptors and are highly responsive to the recognition of microbe-associated molecular patterns. Their responses to infection include chemotaxis, phagolysosomal activity, encapsulation, complex intracellular signaling and transcriptional activity, apoptosis, and the induction of anti-viral states. Bivalves also express a range of inducible extracellular recognition and effector proteins, such as lectins, peptidoglycan recognition proteins, thioester bearing proteins, lipopolysaccharide and beta1,3 glucan-binding proteins, fibrinogen-related proteins (FREPs) and antimicrobial proteins. The identification of FREPs and other highly diversified gene families in bivalves leaves open the possibility that some of their responses to infection may involve a high degree of pathogen specificity and immune priming. The current review article provides a comprehensive, but not exhaustive, description of these factors and how they are regulated by infectious agents. It concludes that one of the remaining challenges is to use new "omics" technologies to understand how this diverse array of factors is integrated and controlled during infection. PMID- 26003825 TI - Reduced expression of THRbeta in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression. AB - PURPOSE: Down-regulation of thyroid hormone receptor beta (THRbeta) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRbeta mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical-biological features. METHODS: Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRbeta gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRbeta. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. RESULTS: THRbeta transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRbeta expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. CONCLUSIONS: Our results demonstrate that down-regulation of THRbeta is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis. PMID- 26003826 TI - Relation of resistin to proprotein convertase subtilisin-kexin type 9 levels in coronary artery disease patients with different nutritional status. AB - OBJECTIVE: To investigate the association of resistin with proprotein convertase subtilisin-kexin type 9 (PCSK9) levels, another novel regulator of atherosclerosis, in the condition of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: We prospectively enrolled a total of 356 consecutive stable CAD patients who were not treated with lipid-lowering drugs in the present study. The baseline clinical characteristics were collected. Plasma PCSK9 and resistin levels were determined by ELISA. The relationship between plasma PCSK9 and resistin levels was investigated. RESULTS: Overall, plasma resistin exhibited a positive nonparametric correlation with PCSK9 levels (r = 0.123, p = 0.02). When the patients were classified into groups based on body mass index (BMI), the resistin correlated significantly to the PCSK9 levels in patients with BMI < 25 kg/m(2) (r = 0.162, p = 0.026) but not in patients with BMI >= 25 kg/m(2) (r = 0.087, p = 0.205). Multivariate regression analysis corroborated the relation between the PCSK9 and an elevated resistin level in patients with BMI < 25 kg/m(2) independently of traditional parameters including age, sex, BMI, smoking, family history of CAD, systolic blood pressure, glucose, low density lipoprotein cholesterol, white blood cell, neutrophil to lymphocyte ratio, and high-sensitive C-reactive protein. CONCLUSIONS: Plasma resistin was positively related to PCSK9 levels in CAD patients with normal weight, suggesting that the circulating resistin might represent a link with PCSK9 level variations in CAD progression of normal body weight. PMID- 26003828 TI - More on homeopathy. PMID- 26003827 TI - Nonalcoholic fatty liver disease and decreased bone mineral density: is there a link? AB - PURPOSE: Liver diseases are associated with decreased bone mineral density (BMD) and evidence suggests that nonalcoholic fatty liver disease (NAFLD) affects several extra-hepatic organs, interacting with the regulation of multiple endocrine and metabolic pathways. This review focuses on the rapidly expanding body of evidence that supports a strong association between NAFLD and the risk of decreased BMD, expression of low bone mass (osteoporosis), or reduced mineralization (osteomalacia). METHODS: We identified studies by searching PubMed for original articles published in English through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "bone mineral density", "osteoporosis", or "osteomalacia". RESULTS: Recent cross-sectional and case-control studies involving both adults and children have consistently shown that patients with NAFLD exhibit a greater prevalence of decreased BMD compared with age-, sex-, and body mass index-matched healthy controls. Accumulating clinical and experimental evidence suggests that NAFLD may contribute to the pathophysiology of low BMD, possibly through the direct contribution of NAFLD to whole-body and hepatic insulin resistance and/or the systemic release of multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators. CONCLUSIONS: Although more research is needed before firm conclusions can be drawn, it appears that there is a non-chance, statistical association between NAFLD and low BMD. This finding argues for more careful monitoring and evaluation of BMD among patients with NAFLD. The potential contribution of NAFLD itself to the development and progression of decreased BMD warrants further study. PMID- 26003829 TI - Etiology of phantom limb syndrome: Insights from a 3D default space consciousness model. AB - In this article, we examine phantom limb syndrome to gain insights into how the brain functions as the mind and how consciousness arises. We further explore our previously proposed consciousness model in which consciousness and body schema arise when information from throughout the body is processed by corticothalamic feedback loops and integrated by the thalamus. The parietal lobe spatially maps visual and non-visual information and the thalamus integrates and recreates this processed sensory information within a three-dimensional space termed the "3D default space." We propose that phantom limb syndrome and phantom limb pain arise when the afferent signaling from the amputated limb is lost but the neural circuits remain intact. In addition, integration of conflicting sensory information within the default 3D space and the loss of inhibitory afferent feedback to efferent motor activity from the amputated limb may underlie phantom limb pain. PMID- 26003830 TI - Treatment of Ebola virus infections with inhibitors of TLR4. AB - Ebola virus (EBOV) infection is associated with modulation of cytokine expression in infected patients. EBOV has been shown to interact directly with immune cells (at minimum with macrophages and dendritic cells) and modulation of cytokine expression has also been observed in vitro, which is similar to that in vivo. The modulation of cytokine expression observed in vitro was independent of virus infection and the glycoprotein GP1,2 was shown to be necessary and sufficient for cytokine modulation. Interestingly, similar changes in gene expression were observed in cells treated with lipopolysaccharide (LPS). As evidence suggests that GP1,2 and LPS use the same receptor, it is tempting to evaluate whether compounds that can inhibit signal transduction by LPS, e.g., TAK-242, can also reduce EBOV-induced pathogenesis. PMID- 26003831 TI - Is magnetic resonance imaging of human brain is harmful? AB - In human brains, there are a lot of macroscopic (~100 nm) magnetite granules. Exposure of the patient's head in high strength magnetic fields could lead to penetrance of those particles into brain neurons and their staying there for a long period. That conclusion is the consequence of calculations based on the equations describing the dynamics of those particles under the action of ponderomotive magnetic, elastic and viscous forces. The role of iron in brain metabolism is not conclusively clear but there is evidence of the connection between excess iron and neurodegenerative diseases. In this regard, we consider it necessary to look more carefully at the matter of safety for brain magnetic resonance imaging. PMID- 26003832 TI - Brown Adipose Tissue: A Human Perspective. AB - Since 2009, the presence of brown adipose tissue (BAT) in adult humans has been irrefutably proven. It is estimated that active BAT can contribute up to 2.5-5% of resting metabolic rate in humans, suggesting that sustained activation of BAT may alleviate obesity and associated disorders. In the current chapter, the discovery of BAT in adult humans will be discussed. Furthermore, the characteristics of human BAT, methods to visualize the tissue as well as physiological and pharmacological methods to enhance its activity will be stressed. PMID- 26003833 TI - Population level effects of multiwalled carbon nanotubes in Daphnia magna exposed to pulses of triclocarban. AB - Due to the rapid increase of carbon nanotubes (CNT) applications and their inevitable release into the aquatic environment, CNT may interact with and further influence the fate and transport of other pollutants such as triclocarban (TCC). TCC is a high-production-volume chemical that is widely used as an antimicrobial agent, is continually released into the aquatic environment, and is biologically active and persistent. In the present study, the population test with Daphnia magna was performed over 93 days. Different treatments were examined: (a) control, (b) solvent control, (c) 1 mg CNT/L from the beginning, (d) 1 mg CNT/L as of day 14, (e) control with a 2-day pulse of 25 ug TCC/L on day 14, 41 ug TCC/L (day 54), and 61 ug TCC/L (day 68) and (f) same pulses of TCC with co-exposure to 1 mg CNT/L. Significant changes in all three size classes were observed as a result of the long-term exposure to 1 mg CNT/L. Increasing in number of neonates, and decreasing in number of juveniles and adults were observed. Moreover, daphnids were significantly smaller when they were exposed to MWCNT. The exposure with TCC led to size-dependent mortality in Daphnia magna populations and a subsequent recovery. Lower toxicity of TCC was observed, with the presence of MWCNT in the medium. The reported effects of TCC on population level were compared to the output of an individual-based Daphnia magna population model, in order to verify the model predictions with laboratory data. PMID- 26003834 TI - Acute toxicity of selected organic pollutants to saltwater (mysid Siriella armata) and freshwater (cladoceran Daphnia magna) ecotoxicological models. AB - The acute toxicity of three organophosphate pesticides (diazinon, chlorpyrifos, pirimiphos-methyl) two chlorinated biocides (endosulfan, pentachlorophenol) and a nonsteroidal anti-inflammatory drug (diclofenac) was tested on <24 h neonates of saltwater mysidacea (Siriella armata) in laboratory acute toxicity test. The 50 and 10 % lethal effective concentrations (LC(50) and LC(10)), NOEC and LOEC values were calculated. The three organophosphate pesticides showed an apparently biphasic dose-response profile, supporting that its mechanism of action in crustaceans differ from other organic compounds. The biphasic pattern of response was confirmed using the common aquatic ecotoxicological model Daphnia magna. According to the 96-h LC(50) values for S. armata, the ranking of toxicity was chlorpyrifos (0.13 ug/L) < pirimiphos-methyl (1.3 ug/L) < endosulfan (3.2 ug/L) < diazinon (4.03 ug/L) < pentachlorophenol (262.2 ug/L) < diclofenac (2919 ug/L). In general, mysids resulted at least one order of magnitude more sensitive than model daphnia, which stresses the need for using marine species for the derivation of seawater quality standards. PMID- 26003835 TI - Evolution of cadmium tolerance and associated costs in a Gammarus fossarum population inhabiting a low-level contaminated stream. AB - Deciphering evolutionary processes occurring within long-term contaminated wild populations is essential for the ecological risk assessment of persistent chemical contaminations. Using field populations of Gammarus, a commonly-used genus in aquatic ecotoxicology, the present study sought to gain insights into the extent to which long-term exposure to metals in the field could effectively lead to shifts in toxicological sensitivities. For this, we identified a Gammarus population inhabiting a stream contaminated by cadmium (Cd). We compared the Cd exposure and Cd-sensitivity of this population to those of five reference populations. Active biomonitoring determined in different years and seasons that significant levels of Cd were bioavailable in the contaminated site. Laboratory sensitivity tests under common garden conditions established that this long-term field exposure led to the development of a moderate Cd tolerance, which was maintained after a 3-week acclimatization in the laboratory, and transmitted to offspring produced under clean conditions. The potential physiological costs of tolerance were assessed by means of feeding rate measurements (in the laboratory and in situ). They revealed that, unlike for reference populations, the feeding activity of organisms from the tolerant population was greatly decreased when they were maintained under laboratory conditions, potentially indicating a high population vulnerability to environmental perturbations. Because dissolved Cd concentrations in water from the contaminated site were low (averaging 0.045 ug L(-1)) and below the current European environmental quality standard for Cd for inland surface waters (fixed at 0.08 ug L(-1) in soft water environments), this case study sheds light onto the extent to which current environmental quality standards are protective against potential adverse outcomes of adaptive and micro evolutionary processes occurring in contaminated environments. PMID- 26003836 TI - Antimicrobial susceptibility monitoring of mastitis pathogens isolated from acute cases of clinical mastitis in dairy cows across Europe: VetPath results. AB - VetPath is an ongoing pan-European antimicrobial susceptibility monitoring programme collecting pathogens from diseased cattle, pigs and poultry not recently treated with antibiotics. Non-replicate milk samples were collected from cows with acute clinical mastitis in eight countries. Escherichia coli, Staphylococcus aureus and Streptococcus uberis were isolated by standardised methods. Antimicrobial susceptibility was determined in a central laboratory by CLSI broth microdilution methodology; results were interpreted using clinical breakpoints where available. Among E. coli (n=280), resistance to tetracycline (14.3%) and cefapirin (11.1%) were most common. Resistance to other beta-lactam antibiotics was absent (ceftiofur) or very low (cefalexin, amoxicillin/clavulanic acid). The MIC90 of enrofloxacin and marbofloxacin was 0.03 and 0.06MUg/mL, respectively, with 0.7% of strains displaying a deviating high MIC. Staphylococcus aureus (n=250) were susceptible to most antibiotics tested, although 36.0% were resistant to penicillin G. For other beta-lactam antibiotics where a CLSI breakpoint was available, no resistance was detected. Tetracycline resistance was low (5.2%). Streptococcus uberis (n=282) were susceptible to all beta-lactam antibiotics, although 29.8% were intermediately susceptible to penicillin G; 18.8% of strains were resistant to erythromycin and 28.7% to tetracycline. This European study shows that bacteria associated with acute clinical mastitis are susceptible to most antibiotics with the exception of penicillin G against S. aureus, and erythromycin and tetracycline against S. uberis. The results of this study should serve as a reference baseline. This work also highlights the urgent need to set additional clinical breakpoints for antibiotics frequently used to treat mastitis. PMID- 26003837 TI - Is acromioplasty necessary in the setting of full-thickness rotator cuff tears? A systematic review. AB - BACKGROUND: The benefits of acromioplasty in treating rotator cuff disease have been debated. We systematically reviewed the literature regarding whether acromioplasty with concomitant coracoacromial (CA) release is necessary for the successful treatment of full-thickness rotator cuff tears. MATERIALS AND METHODS: We identified randomized controlled trials that reported on patients who underwent rotator cuff repair with or without acromioplasty and used descriptive statistics to summarize the findings. RESULTS: Four studies fulfilled the inclusion criteria. They reported on 354 patients (mean age, 59 years; range 3-81 years) with a mean follow-up of 22 months (range 12-24 months). There were two level-I and two level-II studies. Two studies compared rotator cuff repair with versus without acromioplasty, and two studies compared rotator cuff repair with versus without subacromial decompression (acromioplasty, CA ligament resection, and bursectomy). The procedures were performed arthroscopically, and the CA ligament was released in all four studies. There were no statistically significant differences in clinical outcomes between patients treated with acromioplasty compared with those treated without acromioplasty. CONCLUSIONS: This systematic review of the literature does not support the routine use of partial acromioplasty or CA ligament release in the surgical treatment of rotator cuff disease. In some instances, partial acromioplasty and release of the CA ligament can result in anterior escape and worsening symptoms. Further research is needed to determine the optimum method for the operative treatment of full thickness rotator cuff tears. LEVEL OF EVIDENCE: Level I, systematic review of level I and II studies. PMID- 26003838 TI - Self or non-self? The multifaceted role of the microbiota in immune-mediated diseases. PMID- 26003839 TI - Left atrial dissection. AB - Left atrial (LA) dissection is a rare complication and is defined as a gap from the mitral or tricuspid annular area to the interatrial septum or left atrial wall. Because of its low incidence, this entity is not fully understood. LA dissection is related to mitral valve surgery as well as coronary artery disease, arrhythmia, trauma, tumor, and spontaneous occurrence. Transesophageal echocardiography is the most useful diagnostic modality for LA dissection, but multimodality investigation supports accurate diagnosis. There are two treatment options for LA dissection: surgical repair and close observation. Surgical repair involves entry closure and internal drainage. The indication for surgery should be based on the clinical presentation. PMID- 26003840 TI - Lipopolysaccharide of Aggregatibacter actinomycetemcomitans induces the expression of chemokines MCP-1, MIP-1alpha, and IP-10 via similar but distinct signaling pathways in murine macrophages. AB - Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium frequently isolated from lesions of patients with localized aggressive periodontitis. Lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, stimulates innate immune cells via Toll-like receptor 4 (TLR4) to initiate inflammatory responses. In this study, we purified LPS from A. actinomycetemcomitans (AaLPS) and investigated its ability to induce the expression of chemokines, which play an important role in recruitment of leukocytes to the infection site. AaLPS induced the expression of chemokines, MCP 1, MIP-1alpha, and IP-10 in murine macrophages, leading to the infiltration of peripheral blood mononuclear cells in a transwell system. Although TLR4 was essential for the induction of all these chemokines by AaLPS, MCP-1 and MIP 1alpha expressions were MyD88-dependent, but IP-10 expression was MyD88 independent, as determined using macrophages from mice deficient in TLR4 or MyD88. Furthermore, the activation of ERK and JNK were necessary for the expression of MCP-1 and MIP-1alpha, whereas p38 MAP kinase and JNK activations were required for IP-10 expression. In addition, IFN-beta/STAT1 signaling was exclusively involved in IP-10 expression but not in MCP-1 or MIP-1alpha expression. AaLPS also activated the transcription factors, NF-kappaB, AP-1, NF IL6, and ISRE, all of which are involved in chemokine gene expression. These results suggest that AaLPS induces the expression of chemokines MCP-1, MIP 1alpha, and IP-10 through TLR4 in murine macrophages. Further, the induction of MCP-1 and MIP-1alpha requires MyD88, ERK, and JNK, whereas the induction of IP-10 requires JNK, p38 MAP kinase, and IFN-beta/STAT1. PMID- 26003841 TI - The roles of ribosomal protein S19 C-terminus in a shortened neutrophil lifespan through delta lactoferrin. AB - Cell lifespan is partially regulated by a balance between survival signals via constitutively active G protein-coupled receptors (GPCRs) and death signals via death receptors. We have demonstrated that neutrophils produce a mimic ligand of G protein-coupled C5a receptor (C5aR), ribosomal protein S19 (RP S19) polymer. In contrast to an original ligand C5a, RP S19 polymer induces not only inhibition of the guanine nucleotide exchange factor activity but also initiation of the regulator of G protein signaling 3 (RGS3) promoter in a RP S19 C-terminus dependent manner. To examine an antagonistic effect of the RP S19 C-terminus on G proteins, His-S-tagged C5a or C5a/RP S19, in which an RP S19 C-terminus is bound to the C5a C-terminus, was incubated with neutrophils, and a transcription factor delta lactoferrin (deltaLf) was identified as a specific binding protein via pull down experiments. The S-tagged C5a-induced agonistic effects on chemotaxis, cytoplasmic Ca(2+) influx and p38 mitogen-activated protein kinase phosphorylation were not changed by Lf knockdown and deltaLf overexpression in neutrophil-like or macrophage-like cells, which were differentiated into mature cells from human promyelocytic leukemia HL-60 cells by dimethyl sulfoxide and phorbol-12-myristate-13-acetate, respectively. While, the S-tagged C5a/RP S19 induced antagonistic or agonistic effects on mature HL-60 neutrophil-like or macrophage-like cells were reversed by Lf knockdown and deltaLf overexpression, respectively. Moreover, RGS3 expression was increased in another HL-60 neutrophil like cells under spontaneous apoptosis induced by an apoptotic inducer MnCl2. The RGS3 expression in apoptotic neutrophil-like cells was delayed not only by Lf knockdown but also by neutralization of the RP S19 polymer or C5aR. The inhibitory extension from G protein of C5aR to Galpha subsets of constitutively active GPCRs along with the RP S19 polymer-induced translocation of deltaLf from the cytoplasmic face of the plasma membrane to the nucleus seems to shorten the neutrophil cell lifespan. PMID- 26003842 TI - Testing Theories about Ethnic Markers: Ingroup Accent Facilitates Coordination, Not Cooperation. AB - In recent years, evolutionary psychologists and anthropologists have debated whether ethnic markers have evolved to solve adaptive problems related to interpersonal coordination or to interpersonal cooperation. In the present study, we add to this debate by exploring how individuals living in a modern society utilize the accents of unfamiliar individuals to make social decisions in hypothetical economic games that measure interpersonal trust, generosity, and coordination. A total of 4603 Danish participants completed a verbal-guise study administered over the Internet. Participants listened to four speakers (two local and two nonlocal) and played a hypothetical Dictator Game, Trust Game, and Coordination Game with each of them. The results showed that participants had greater faith in coordinating successfully with local speakers than with nonlocal speakers. The coordination effect was strong for individuals living in the same city as the particular speakers and weakened as the geographical distance between the participants and the speakers grew. Conversely, the results showed that participants were not more generous toward or more trusting of local speakers compared with nonlocal speakers. Taken together, the results suggest that humans utilize ethnic markers of unfamiliar individuals to coordinate behavior rather than to cooperate. PMID- 26003843 TI - The microbiome and autoimmune disease: Report from a Noel R. Rose Colloquium. AB - Although the mechanisms by which the human microbiome influences the onset and progression of autoimmune diseases remain to be determined, established animal models of autoimmune diseases indicate that local and systemic bidirectional interactions with the microbiome play a signaling or promoting role through the immune system. Whether alterations in the microbiome are a pathogenic cause or simply an effect of inflammation and autoimmune disease remains an essential question to be addressed in disease-specific research, as well as whether particular conditions of the microbiome promote health or promote disease. Future research in this area needs to account for sex differences in microbiome composition because autoimmune diseases disproportionately affect women. Probiotic and other treatments that manipulate assemblage of the microbiome may offer methods of preventing or mitigating the effects of autoimmune disease. PMID- 26003845 TI - Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-kB signaling pathway. AB - Garlic and its active constituents have shown versatile medicinal activities in the prevention and treatment of various disorders. Allyl methyl disulfide (AMDS) was identified as one of the major bioactive components in an effective inhalation fork remedy using fresh garlic paste in our previous study. In this work, we investigated the immunological properties of AMDS to elucidate the underlying mechanisms of the fork inhalation treatment using fresh garlic. The inhibition effect of AMDS on TNF-alpha-induced IL-8 and IP-10 production in intestinal epithelial cell lines HT-29 and Caco-2 was first evaluated. Pretreatment of the cells with AMDS attenuated IL-8 and IP-10 secretion induced by TNF-alpha in a dose-dependent manner in the non-cytotoxic concentration range of 20 to 150 MUM. Mechanistic studies revealed that AMDS suppressed the accumulation of IL-8 mRNA and inhibited IkBalpha degradation and NF-kB p65 translocation into the nucleus at both the transcriptional and translational levels, suggesting that the attenuation effort of AMDS on cytokine IL-8 secretion might at least be partially related to the NF-kappaB signaling pathway. These results suggest that AMDS may be a promising phytochemical agent in the treatment of immunological disorders, such as ulcerative colitis, Crohn's disease, intestinal inflammatory diseases and others. In addition, the mechanistic study data indicated that immune modulation could be one of the therapeutic mechanisms of the effective fork treatment containing AMDS as one of the major components. PMID- 26003844 TI - Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays. AB - The proprotein convertase furin is implicated in a variety of pathogenic processes such as bacterial toxin activation, viral propagation, and cancer. Several groups have identified non-peptide compounds with high inhibitory potency against furin in vitro, although their efficacy in various cell-based assays is largely unknown. In this study we show that certain guanidinylated 2,5 dideoxystreptamine derivatives exhibit interesting ex vivo properties. Compound 1b (1,1'-(4-((2,4-diguanidino-5-(4-guanidinophenoxy)cyclohexyl)oxy)-1,3 phenylene)diguanidine) is a potent and cell-permeable inhibitor of cellular furin, since it was able to retard tumor cell migration, block release of a Golgi reporter, and protect cells against Bacillus anthracis (anthrax) and Pseudomonas aeruginosa intoxication, with no evident cell toxicity. Other compounds based on the 2,5-dideoxystreptamine scaffold, such as compound 1g (1,1'-(4,6-bis(4 guanidinophenoxy)cyclohexane-1,3-diyl)diguanidine) also efficiently protected cells against anthrax, but displayed only moderate protection against Pseudomonas exotoxin A and did not inhibit cell migration, suggesting poor cell permeability. Certain bis-guanidinophenyl ether derivatives such as 2f (1,3-bis(2,4 diguanidinophenoxy) benzene) exhibited micromolar potency against furin in vitro, low cell toxicity, and highly efficient protection against anthrax toxin; this compound only slightly inhibited intracellular furin. Thus, compounds 1g and 2f both represent potent furin inhibitors at the cell surface with low intracellular inhibitory action, and these particular compounds might therefore be of preferred therapeutic interest in the treatment of certain bacterial and viral infections. PMID- 26003846 TI - Obaculactone exerts a novel ameliorating effect on contact dermatitis through regulating T lymphocyte. AB - It is still deficient that an immunosuppressant with a negligible toxicity for patients suffering from contact hypersensitivity. In the present study, we identified a natural occurring compound named obaculactone that effectively alleviated the macroscopic and microscopic appearances of the contact hypersensitivity, while it scarcely possessed toxic effect on mice at 5-20mg/kg. The mRNAs of IL-2, IL-17a, TNF-alpha and IFN-gamma expressed in lymph nodes of mice with dermatitis were also decreased by obaculactone in a dose-dependent manner. Moreover, the hypersensitivity couldn't be adoptively transferred from obaculactone-treated donor mice to normal mice. In vitro study, proliferation arrest in activated hapten-specific T cells and anti-CD3/CD28 stimulated T cells were observed in obaculactone-treated groups. In addition, the enhanced expressions of CD25 and CD69 in activated T cells were reduced by obaculactone. Meanwhile, obaculactone caused G0/G1 phase arrest and up-regulated the levels of cleaved-caspases and cleaved-PARP inducing apoptosis in activated T cells. Taken together, suppressing cell growth in activated T lymphocytes may contribute to the novel ameliorating effect for obaculactone against the contact hypersensitivity. PMID- 26003848 TI - Bubble size on detachment from the luminal aspect of ovine large blood vessels after decompression: The effect of mechanical disturbance. AB - Bubbles nucleate and develop after decompression at active spots on the luminal aspect of ovine large blood vessels. Series of bubbles were shown to detach from the active spot with a mean diameter of 0.7-1.0mm in calm conditions. The effect of mechanical disturbance (striking the bowl containing the vessel or tangential flow) was studied on ovine blood vessels stretched on microscope slides and photographed after hyperbaric exposure. Diameter on detachment after a heavy blow to the bowl was 0.87 +/- 0.43 mm (mean +/- SD), no different from bubbles which detached without striking the bowl (0.86 +/- 0.28 mm). Bubble diameter on detachment during pulsatile tangential flow at 234 cm/min, 0.99 +/- 0.36 mm, was not smaller than that seen in the same blood vessels in calm conditions (0.81 +/- 0.34 mm). The active spots were stained for lipids, proving their hydrophobicity. The most abundant active spots, which produced only a few bubbles, did not stain for lipids thereafter. The possibility that phospholipids were removed along with detached bubbles may correlate with acclimation to diving. The finding of bubble production at the active spots matches observed phenomena in divers: variable sensitivity to decompression, acclimation to diving, the effect of elevated gas load on increased bubble formation, a higher bubble score in the second dive on the same day, and unexplained neurological symptoms after decompression. Large bubbles released from the arterial circulation give serious cause for concern. PMID- 26003847 TI - Gut feeling: MicroRNA discriminators of the intestinal TLR9-cholinergic links. AB - The intestinal tissue notably responds to stressful, cholinergic and innate immune signals by microRNA (miRNA) changes, but whether and how those miRNA regulators modify the intestinal cholinergic and innate immune pathways remained unexplored. Here, we report changes in several miRNA regulators of cholinesterases (ChEs) and correspondingly modified ChE activities in intestine, splenocytes and the circulation of mice exposed to both stress and canonical or alternative Toll-Like Receptor 9 (TLR9) oligonucleotide (ODN) aptamer activators or blockers. Stressful intraperitoneal injection of saline, the anti-inflammatory TLR9 agonist mEN101 aptamer or the inflammation-activating TLR9 aptamer ODN 1826 all increased the expression of the acetylcholinesterase (AChE)-targeting miR 132. In comparison, mEN101 but neither ODN 1826 nor saline injections elevated intestinal miR-129-5p, miR-186 and miR-200c, all predicted to target both AChE and the homologous enzyme butyrylcholinesterase (BChE). In cultured immune cells, BL-7040, the human counterpart of mEN101, reduced AChE activity reflecting inflammatory reactions in a manner preventable by the TLR9 blocking ODN 2088. Furthermore, the anti-inflammatory BL-7040 TLR9 aptamer caused reduction in nitric oxide and AChE activity in both murine splenocytes and human mononuclear cells at molar concentrations four orders of magnitude lower than ODN 1826. Our findings demonstrate differential reaction of cholinesterase-targeting miRNAs to distinct TLR9 challenges, indicating upstream miRNA co-regulation of the intestinal alternative NFkappaB pathway and cholinergic signaling. TLR9 aptamers may hence potentiate miRNA regulation that enhances cholinergic signaling and the resolution of inflammation, which opens new venues for manipulating bowel diseases. PMID- 26003849 TI - The effect of selective antagonist of H4 receptor JNJ7777120 on nasal symptoms, cough, airway reactivity and inflammation in guinea pigs. AB - The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30 min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by Pennock's method as baseline, during AR and after JNJ7777120 treatment. Leucocyte count in BAL and blood was analyzed. JNJ7777120 (5mg/kg) significantly suppressed nasal symptoms and the number of coughs. This compound significantly inhibited airway reactivity to histamine, but not methacholine. Pre-treatment with JNJ7777120 5mg/kg did not influence significantly the leucocyte count in BAL and blood except for a significant decrease in monocyte count in blood compared to the control group (p<0.05). We conclude that the antitussive action of JNJ7777120 is peripheral. The primary effect of the compound is anti-inflammatory, and the suppression of cough is a consequence of reduced airway inflammation. PMID- 26003850 TI - Semi-automated assessment of transdiaphragmatic pressure variability across motor behaviors. AB - We developed and tested a semi-automated algorithm to generate large data sets of ventilatory information (amplitude, premotor drive and timing) across a range of motor behaviors. Adult spontaneously breathing, anesthetized mice (n = 27) underwent measurements of transdiaphragmatic pressure (Pdi) during eupnea, hypoxia-hypercapnia, and tracheal occlusion with values ranging from 8 +/- 1 to 9 +/- 2 to 44 +/- 3 cmH2O, respectively. Premotor drive to phrenic motor neurons (estimated by the rate of rise during initial 60 ms) was ~ 5-fold greater during tracheal occlusion compared to other behaviors. Variability in Pdi amplitude (normalized to spontaneously occurring sighs for each animal) displayed minimal evidence of complex temporal structure or dynamic clustering across the entire period of examination. Using a deterministic model to evaluate predictor variables for Pdi amplitude between successive inspiratory events, there was a large correlation for premotor drive and preceding Pdi amplitude vs. Pdi amplitude (r = 0.52). These findings highlight substantial variability in Pdi amplitude that primarily reflects linear components rather than complex, dynamic effects over time. PMID- 26003851 TI - Behaviour and prefrontal protein differences in C57BL/6N and 129 X1/SvJ mice. AB - Experimental animals provide valuable opportunities to establish aetiological mechanisms and test new treatments for neurodevelopmental psychiatric conditions. However, it is increasingly appreciated that inter-strain differences cannot be neglected in the experimental design. In addition, the importance of including females in preclinical - but also clinical - research is now recognised. Here, we compared behaviour and prefrontal protein differences in male and female C57BL/6N and 129X1/SvJ mice as both are commonly used experimental rodents. Relative to 129X1/SvJ mice, both sexes of C57BL/6N mice had weaker sensorimotor gating, measured in the prepulse inhibition (PPI) of startle paradigm, and were more sensitive to amphetamine challenge in the open field. The pattern of protein expression in the prefrontal cortex of C57BL6N mice was also clearly distinct from 129X1/SvJ mice. Proteins differentially expressed were those associated with oxidative metabolism, receptor protein signalling, cell communication and signal transduction and energy pathways. We suggest that the C57BL/6N mouse may usefully proxy features of the neurodevelopmental disorders and could have application in pre-translational screening of new therapeutic approaches. The 129X1/SvJ strain in contrast, might be better suited to experimental studies of causal risk factors expected to lower PPI and increase amphetamine sensitivity. PMID- 26003852 TI - Lipids generated during acute pancreatitis increase inflammatory status of macrophages by interfering with their M2 polarization. AB - BACKGROUND: Necrosis of adipose tissue is a common complication of acute pancreatitis. The areas of steatonecrosis become a source of inflammatory mediators, including chemically modified fatty acids which could influence the progression of the systemic inflammation. In an experimental model of acute pancreatitis we analyzed the effects of lipids generated by two representative areas of adipose tissue on the switch to the M1 phenotype in macrophages. METHODS: Pancreatitis was induced in rats by intraductal administration of 5% taurocholate and after 6 h, lipids from retroperitoneal, mesenteric or epididymal adipose tissues were collected. Lipid uptake, phenotype polarization and the activation of PPARgamma and NFkappaB were evaluated in macrophages treated with these lipids. RESULTS: After induction of pancreatitis, lipids from visceral adipose tissue promote the switch to an increased pro-inflammatory phenotype in macrophages. This effect is not related with a higher activation of NFkappaB but with an interfering effect on the activation of M2 phenotype. CONCLUSIONS: During acute pancreatitis, lipids generated by some areas of adipose tissue interfere on the M2 polarization of macrophages, thus resulting in a more intense pro inflammatory M1 response. PMID- 26003853 TI - T-cell populations in chronic pancreatitis. PMID- 26003855 TI - Human aging alters the neural computation and representation of space. AB - The hippocampus and striatum are core neural circuits involved in spatial learning and memory. Although both neural systems support spatial navigation, experimental and theoretical evidence indicate that they play different roles. In particular, whereas hippocampal place cells generate allocentric neural representations of space that are sensitive to geometric information, striatum dependent learning is influenced by local landmarks. How human aging affects these different neural representations, however, is still not well understood. In this paper, we combined virtual reality, computational modeling, and neuroimaging to investigate the effects of age upon the neural computation and representation of space in humans. We manipulated the geometry and local landmarks of a virtual environment and examined the effects on memory performance and brain activity during spatial learning. In younger adults, both behavior and brain activity in the medial-temporal lobe were consistent with predictions of a computational model of hippocampus-dependent boundary processing. In contrast, older adults' behavior and medial-temporal lobe activity were primarily influenced by local cue information, and spatial learning was more associated with activity in the caudate nucleus rather than the hippocampus. Together these results point to altered spatial representations and information processing in the hippocampal striatal circuitry with advancing adult age, which may contribute to spatial learning and memory deficits associated with normal and pathological aging. PMID- 26003854 TI - The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking. AB - Novelty seeking (NS) is a personality trait important for adaptive functioning, but an excessive level of NS has been linked to psychiatric disorders such as ADHD and substance abuse. Previous research has investigated separately the neural and genetic bases of the NS trait, but results were mixed and neural and genetic bases have yet to be examined within the same study. In this study, we examined the interrelationships among the dopamine beta-hydroxylase (DBH) gene, brain structure, and the NS trait in 359 healthy Han Chinese subjects. We focused on the DBH gene because it encodes a key enzyme for dopamine metabolism, NS is believed to be related to the dopaminergic system and has been reported associated with DBH variation. Results showed a significant positive association between the cortical surface area of the left insula and NS score. Furthermore, the DBH genetic polymorphism at the SNP rs7040170 was strongly associated with both the surface area of the left insula and NS score, with G carriers having a larger left insula surface area and a higher NS score than AA homozygotes. Subsequent path analysis suggested that the insula partially mediated the association between the DBH gene and the NS trait. Our data provided the first evidence for the involvement of the insula in the dopamine-NS relationship. Future studies of molecular mechanisms underlying the NS personality trait and related psychiatric disorders should consider the mediation effect of the neural structure. PMID- 26003856 TI - A reliable spatially normalized template of the human spinal cord--Applications to automated white matter/gray matter segmentation and tensor-based morphometry (TBM) mapping of gray matter alterations occurring with age. AB - Recently, a T2*-weighted template and probabilistic atlas of the white and gray matter (WM, GM) of the spinal cord (SC) have been reported. Such template can be used as tissue-priors for automated WM/GM segmentation but can also provide a common reference and normalized space for group studies. Here, a new template has been created (AMU40), and accuracy of automatic template-based WM/GM segmentation was quantified. The feasibility of tensor-based morphometry (TBM) for studying voxel-wise morphological differences of SC between young and elderly healthy volunteers was also investigated. Sixty-five healthy subjects were divided into young (n=40, age<40years old, mean age 28+/-5years old) and elderly (n=25, age>50years old, mean age 57+/-5years old) groups and scanned at 3T using an axial high-resolution T2*-weighted sequence. Inhomogeneity correction and affine intensity normalization of the SC and cerebrospinal fluid (CSF) signal intensities across slices were performed prior to both construction of the AMU40 template and WM/GM template-based segmentation. The segmentation was achieved using non-linear spatial normalization of T2*-w MR images to the AMU40 template. Validation of WM/GM segmentations was performed with a leave-one-out procedure by calculating DICE similarity coefficients between manual and automated WM/GM masks. SC morphological differences between young and elderly healthy volunteers were assessed using the same non-linear spatial normalization of the subjects' MRI to a common template, derivation of the Jacobian determinant maps from the warping fields, and a TBM analysis. Results demonstrated robust WM/GM automated segmentation, with mean DICE values greater than 0.8. Concerning the TBM analysis, an anterior GM atrophy was highlighted in elderly volunteers, demonstrating thereby, for the first time, the feasibility of studying local structural alterations in the SC using tensor-based morphometry. This holds great promise for studies of morphological impairment occurring in several central nervous system pathologies. PMID- 26003857 TI - Neural dynamics in motor preparation: From phase-mediated global computation to amplitude-mediated local computation. AB - Oscillatory activity plays a critical role in the brain. Here, we illustrate the dynamics of neural oscillations in the motor system of the brain. We used a non directional cue to instruct participants to prepare a motor response with either the left or the right hand and recorded electroencephalography during the preparation of the response. Consistent with previous findings, the amplitude of alpha-band (8-14Hz) oscillations significantly decreased over the motor region contralateral to the hand prepared for the response. Prior to this decrease, there were a number of inter-regional phase synchronies at lower frequencies (2 4Hz; delta band). Cross-frequency coupling was quantified to further explore the direct link between alpha amplitudes and delta synchrony. The cross-frequency coupling of showed response-specific modulation, whereby the motor region contralateral to the preparation hand exhibited an increase in coupling relative to the baseline. The amplitude of alpha oscillations had an unpreferred and a preferred delta phase, in which the amplitude was modulated negatively and positively, respectively. Given the amplitude of alpha-band oscillations decreased over the analyzed period, the alpha amplitude might be down-regulated by the phase-amplitude coupling, although we do not have direct evidence for that. Taken together, these results show global-to-local computation in the motor system, which started from inter-regional delta phase synchrony and ended at an effector-specific decrease in the amplitude of alpha-band oscillations, with phase-amplitude coupling connecting both computations. PMID- 26003858 TI - Dependence of BOLD signal fluctuation on arterial blood CO2 and O2: Implication for resting-state functional connectivity. AB - Blood oxygenation level dependent (BOLD) functional MRI signal is known to be modulated by the CO2 level. Typically only end-tidal CO2, rather than the arterial partial pressure of CO2 (paCO2), was measured while the arterial partial pressure of O2 (paO2) level was not controlled due to free breathing, making their contribution not separable. Especially, the influences of paO2 and paCO2 on resting-state functional connectivity are not well studied. In this study, we investigated the relationship between paCO2 and resting as well as stimulus evoked BOLD signals under hyperoxic and hypercapnic manipulation with tight control of arterial paO2. Rats under isoflurane anesthesia were subjected to six inspired gas conditions: 47% O2 in air (Normal), adding 1%, 2% or 5% CO2, carbogen (95% O2/5% CO2), and 100% O2. Somatosensory BOLD activation was significantly increased under 100% O2, while reduced with increased paCO2 levels. However, while resting BOLD connectivity pattern expanded and bilateral correlation increased under 100% O2, the correlation coefficient between the left and right somatosensory cortex was generally not dependent on paCO2 or paO2. Interestingly, the correlation in 0.04-0.07Hz range significantly increased with CO2 levels. Intracortical electrophysiological recordings showed a similar trend as the BOLD but the neurovascular coupling varied. The results suggest that paO2 and paCO2 together rather than paCO2 alone alter the BOLD signal. The response is not purely vascular in nature but has strong neuronal origins. This should be taken into consideration when designing calibrated BOLD experiment and interpreting functional connectivity data especially in aging, under drug, or neurological disorders. PMID- 26003859 TI - Regional gray matter density is associated with morningness-eveningness: Evidence from voxel-based morphometry. AB - Diurnal preference (morningness-eveningness) is known to be associated with several individual characteristics that are important in the fields of sociology, education, and psychiatry. Despite this importance, the anatomical correlates of individual differences in morningness-eveningness are unknown, and these were investigated in the present study. We used voxel-based morphometry and a questionnaire to determine individual morningness-eveningness and its association with brain structures in 432 healthy men and 344 healthy women (age, 20.7+/ 1.8years). We demonstrated that morningness (less eveningness) was associated with (a) lower regional gray matter density (rGMD) in the precuneus and adjacent areas, (b) lower rGMD in the left posterior parietal cortex and adjacent areas, and (c) higher rGMD in the bilateral orbitofrontal cortex. Further, our exploratory analyses revealed that (d) higher rGMD in hypothalamic areas around the bilateral suprachiasmatic nuclei were associated with morningness. These findings demonstrate that variations in morningness-eveningness reflect the GM structures of focal regions across the cortex, and suggest a structural basis for individual morningness-eveningness and its association with a wide range of psychological variables distributed across different GM areas of the brain. PMID- 26003860 TI - Generating original ideas: The neural underpinning of originality. AB - One of the key aspects of creativity is the ability to produce original ideas. Originality is defined in terms of the novelty and rarity of an idea and is measured by the infrequency of the idea compared to other ideas. In the current study we focused on divergent thinking (DT) - the ability to produce many alternate ideas - and assessed the neural pathways associated with originality. Considering that generation of original ideas involves both the ability to generate new associations and the ability to overcome automatic common responses, we hypothesized that originality would be associated with activations in regions related to associative thinking, including areas of the default mode network (DMN) such as medial prefrontal areas, as well as with areas involved in cognitive control and inhibition. Thirty participants were scanned while performing a DT task that required the generation of original uses for common objects. The results indicate that the ability to produce original ideas is mediated by activity in several regions that are part of the DMN including the medial prefrontal cortex (mPFC) and the posterior cingulate cortex (PCC). Furthermore, individuals who are more original exhibited enhanced activation in the ventral anterior cingulate cortex (vACC), which was also positively coupled with activity in the left occipital-temporal area. These results are in line with the dual model of creativity, according to which original ideas are a product of the interaction between a system that generates ideas and a control system that evaluates these ideas. PMID- 26003861 TI - Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Extant data from in vivo animal models and postmortem studies indicate that Alzheimer's disease (AD) pathology is associated with reduction of the brain antioxidant glutathione (GSH), yet direct clinical evidence has been lacking. In this study, we investigated GSH modulation in the brain with AD and assessed the diagnostic potential of GSH estimation in hippocampi (HP) and frontal cortices (FC) as a biomarker for AD and its prodromal stage, mild cognitive impairment (MCI). METHODS: Brain GSH levels were measured in HP of 21 AD, 22 MCI, and 21 healthy old controls (HC) and FC of 19 AD, 19 MCI, and 28 HC with in vivo proton magnetic resonance spectroscopy. The association between GSH levels and clinical measures of AD progression was tested. Linear regression models were used to determine the best combination of GSH estimation in these brain regions for discrimination between AD, MCI, and HC. RESULTS: AD-dependent reduction of GSH was observed in both HP and FC (p < .001). Furthermore, GSH reduction in these regions correlated with decline in cognitive functions. Receiver operator characteristics analyses evidenced that hippocampal GSH robustly discriminates between MCI and healthy controls with 87.5% sensitivity, 100% specificity, and positive and negative likelihood ratios of 8.76/.13, whereas cortical GSH differentiates MCI and AD with 91.7% sensitivity, 100% specificity, and positive and negative likelihood ratios of 9.17/.08. CONCLUSIONS: The present study provides compelling in vivo evidence that estimation of GSH levels in specific brain regions with magnetic resonance spectroscopy constitutes a clinically relevant biomarker for MCI and AD. PMID- 26003862 TI - A quantitative approach to developing Parkinsonian monkeys (Macaca fascicularis) with intracerebroventricular 1-methyl-4-phenylpyridinium injections. AB - BACKGROUND: Non-human primate Parkinson's disease (PD) models are essential for PD research. The most extensively used PD monkey models are induced with 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the modeling processes of developing PD monkeys cannot be quantitatively controlled with MPTP. Therefore, a new approach to quantitatively develop chronic PD monkey models will help to advance the goals of "reduction, replacement and refinement" in animal experiments. NEW METHOD: A novel chronic PD monkey models was reported using the intracerebroventricular administration of 1-methyl-4-phenylpyridinium (MPP(+)) in Cynomolgus monkeys (Macaca fascicularis). RESULTS: This approach successfully produced stable and consistent PD monkeys with typical motor symptoms and pathological changes. More importantly, a sigmoidal relationship (Y=8.15801e( 0.245/x); R=0.73) was discovered between PD score (Y) and cumulative dose of MPP(+) (X). This relationship was then used to develop two additional PD monkeys under a specific time schedule (4 weeks), with planned PD scores (7) by controlling the dose and frequency of the MPP(+) administration as an independent validation of the formula. COMPARISON WITH EXISTING METHOD(S): We developed Parkinsonian monkeys within controlled time frames by regulating the accumulated dose of MPP(+) intracerebroventricular administered, while limiting side effects often witnessed in models developed with the peripheral administration of MPTP, makes this model highly suitable for treatment development. CONCLUSIONS: This novel approach provides an edge in evaluating the mechanisms of PD pathology associated with environmental toxins and novel treatment approaches as the formula developed provides a "map" to control and predict the modeling processes. PMID- 26003863 TI - Effects of environmental and pharmacological manipulations on a novel delayed nonmatching-to-sample 'working memory' procedure in unrestrained rhesus monkeys. AB - BACKGROUND: Working memory is a domain of 'executive function.' Delayed nonmatching-to-sample (DNMTS) procedures are commonly used to examine working memory in both human laboratory and preclinical studies. NEW METHOD: The aim was to develop an automated DNMTS procedure maintained by food pellets in rhesus monkeys using a touch-sensitive screen attached to the housing chamber. Specifically, the DNMTS procedure was a 2-stimulus, 2-choice recognition memory task employing unidimensional discriminative stimuli and randomized delay interval presentations. RESULTS: DNMTS maintained a delay-dependent decrease in discriminability that was independent of the retention interval distribution. Eliminating reinforcer availability during a single delay session or providing food pellets before the session did not systematically alter accuracy, but did reduce total choices. Increasing the intertrial interval enhanced accuracy at short delays. Acute Delta(9)-THC pretreatment produced delay interval-dependent changes in the forgetting function at doses that did not alter total choices. Acute methylphenidate pretreatment only decreased total choices. COMPARISON WITH EXISTING METHODS: All monkeys were trained to perform NMTS at the 1s training delay within 60 days of initiating operant touch training. Furthermore, forgetting functions were reliably delay interval-dependent and stable over the experimental period (~6 months). CONCLUSIONS: Consistent with previous studies, increasing the intertrial interval improved DNMTS performance, whereas Delta(9) THC disrupted DNMTS performance independent of changes in total choices. Overall, the touchscreen-based DNMTS procedure described provides an efficient method for training and testing experimental manipulations on working memory in unrestrained rhesus monkeys. PMID- 26003865 TI - Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes. AB - We used a combined approach of whole-exome sequencing and candidate mutation validation to identify the disease-causing gene in a hereditary spastic paraplegia (HSP) patient with lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. HSP is a clinically and genetically heterogeneous neurodegenerative disorder characterized by degeneration of the corticospinal tract motor neurons and resulting in progressive lower limb spasticity, often with a complicated phenotype. We identified novel compound heterozygous mutations in the SPG11 gene in this patient as follows: a mutation in exon 32, c.6194C > G transition (p.S2056X) and a novel c.5121+1C > T splicing mutation. Our finding suggests that these novel compound heterozygous mutations in SPG11 are associated with HSP and lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. This study also demonstrates that exome sequencing is an efficient and rapid diagnostic tool for identifying the causes of some complex and genetically heterogeneous neurodegenerative diseases. PMID- 26003864 TI - Fibrosis in the lens. Sprouty regulation of TGFbeta-signaling prevents lens EMT leading to cataract. AB - Cataract is a common age-related condition that is caused by progressive clouding of the normally clear lens. Cataract can be effectively treated by surgery; however, like any surgery, there can be complications and the development of a secondary cataract, known as posterior capsule opacification (PCO), is the most common. PCO is caused by aberrant growth of lens epithelial cells that are left behind in the capsular bag after surgical removal of the fiber mass. An epithelial-to-mesenchymal transition (EMT) is central to fibrotic PCO and forms of fibrotic cataract, including anterior/posterior polar cataracts. Transforming growth factor beta (TGFbeta) has been shown to induce lens EMT and consequently research has focused on identifying ways of blocking its action. Intriguingly, recent studies in animal models have shown that EMT and cataract developed when a class of negative-feedback regulators, Sprouty (Spry)1 and Spry2, were conditionally deleted from the lens. Members of the Spry family act as general antagonists of the receptor tyrosine kinase (RTK)-mediated MAPK signaling pathway that is involved in many physiological and developmental processes. As the ERK/MAPK signaling pathway is a well established target of Spry proteins, and overexpression of Spry can block aberrant TGFbeta-Smad signaling responsible for EMT and anterior subcapsular cataract, this indicates a role for the ERK/MAPK pathway in TGFbeta-induced EMT. Given this and other supporting evidence, a case is made for focusing on RTK antagonists, such as Spry, for cataract prevention. In addition, and looking to the future, this review also looks at possibilities for supplanting EMT with normal fiber differentiation and thereby promoting lens regenerative processes after cataract surgery. Whilst it is now known that the epithelial to fiber differentiation process is driven by FGF, little is known about factors that coordinate the precise assembly of fibers into a functional lens. However, recent research provides key insights into an FGF-activated mechanism intrinsic to the lens that involves interactions between the Wnt Frizzled and Jagged/Notch signaling pathways. This reciprocal epithelial-fiber cell interaction appears to be critical for the assembly and maintenance of the highly ordered three-dimensional architecture that is central to lens function. This information is fundamental to defining the specific conditions and stimuli needed to recapitulate developmental programs and promote regeneration of lens structure and function after cataract surgery. PMID- 26003866 TI - Divergent regulation of distinct glucocorticoid systems in alcohol dependence. AB - Chronic alcohol consumption disrupts glucocorticoid signaling at multiple physiological levels to interact with several disease-related processes associated with neuroendocrine and psychiatric disorders. Excessive alcohol use produces stress-related neuroadaptations at the level of the hypothalamic pituitary-adrenal (HPA) axis as well as within central (extra-hypothalamic) neural circuitry, including the central amygdala (CeA) and prefrontal cortex (PFC). Altered glucocorticoid receptor (GR) signaling in these areas following excessive alcohol exposure is postulated to mediate the transition from recreational drinking to dependence, as well as the manifestation of a host of cognitive and neurological deficits. Specifically, a bidirectional regulation of stress systems by glucocorticoids leads to the development of an HPA axis tolerance and a concomitant sensitization of cortical and subcortical circuitries. A greater understanding of how hypothalamic and extra-hypothalamic glucocorticoid systems interact to mediate excessive drinking and related pathologies will lead to more effective therapeutic strategies for alcohol use disorder (AUD) and closely related comorbidities. PMID- 26003867 TI - Current knowledge on procaspase-1 variants with reduced or abrogated enzymatic activity in autoinflammatory disease. AB - Caspase-1 is a proinflammatory enzyme that is essential in many inflammatory conditions including infectious, autoimmune, and autoinflammatory disorders. The inflammation is mainly mediated by the generation of inflammasomes that activate caspase-1 and subsequently interleukin (IL)-1beta and IL-18. In addition, homotypic CARD/CARD interaction of procaspase-1 with RIP2 and thereby activation of the NF-kappaB pathways may play some role in the inflammation. However, normally, this pathway seems to become downregulated rapidly by the cleavage and excretion of RIP2 by active (pro-)caspase-1. In patients with unexplained recurrent systemic inflammation, CASP1 variants were detected, which often destabilized the caspase-1 dimer interface. Obviously, the resulting decreased or abrogated enzymatic activity and IL-1beta production did not prevent the febrile episodes. As an unexpected finding, the inactive procaspase-1 variants significantly enhanced proinflammatory signaling by increasing RIP2 mediated NF kappaB activation in an in vitro cell transfection model. A likely reason is the failure of inactive procaspase-1 to cleave bound RIP2 and also to mediate its excretion out of the intracelluar space thereby keeping the RIP2-NF-kappaB pathway upregulated. Hence, proinflammatory effects of enzymatically inactive procaspase-1 variants may partially explain the inflammatory episodes of the patients. PMID- 26003868 TI - Sonographically Guided Semimembranosus Bursa Injection: Technique and Validation. AB - OBJECTIVES: To describe and validate a sonographically guided (SG) semimembranosus (SM) bursa injection technique in an unembalmed cadaveric model. DESIGN: Prospective, cadaveric laboratory investigation. SETTING: Academic institution procedural skills laboratory. SUBJECTS: Ten unembalmed cadaveric thigh-knee-ankle-foot specimens from 4 male and 6 female donors ages 55-92 years (mean 76.2 years) with body mass indices of 15.4-31.8 kg/m(2) (mean 21.9 kg/m(2)). METHODS: A single, experienced operator completed SG SM bursa injections in 10 unembalmed cadaveric knees using 3 mL of diluted colored latex. At a minimum of 2 days after the injection, co-investigators dissected the specimens to assess the distribution of latex with respect to the SM bursa. MAIN OUTCOME: Injections were graded for accuracy as follows: accurate (all latex contained within the SM bursa), accurate with overflow (latex within the SM bursa and extending into regions other than the needle track), or inaccurate (no latex within the SM bursa). RESULTS: All 10 injections (100%) accurately placed latex within the SM bursa and resulted in proximal spread to at least the level of the knee joint. Eight of 10 injections (80%) demonstrated minimal (<1 mL) extrabursal flow without extension into the intra-articular space. No neurovascular injury occurred in any specimen. CONCLUSIONS: SG SM injections are feasible and accurate and may be considered for diagnostic and therapeutic injections in patients with suspected distal SM disorders. Injection volumes less than 3 mL should be considered to reduce extrabursal spread as clinically indicated. PMID- 26003869 TI - Disability Stage is an Independent Risk Factor for Mortality in Medicare Beneficiaries Aged 65 Years and Older. AB - BACKGROUND: Stages of activity limitation based on activities of daily living (ADLs) and instrumental activities of daily living (IADLs) have been found to predict mortality in persons aged 70 years and older but have not been examined in Medicare beneficiaries aged 65 years and older using data that are routinely collected. OBJECTIVE: To examine the association between functional stages based on items of ADLs and IADLs with 3-year mortality in Medicare beneficiaries aged 65 years and older, accounting for baseline sociodemographics, health status, smoking, subjective health, and psychological well-being. DESIGN: A cohort study using the Medicare Current Beneficiary Survey (MCBS) and associated health care utilization data. SETTING: Community administered survey. PARTICIPANTS: The study included 9698 Medicare beneficiaries aged 65 years and older who participated in the MCBS in 2005-2007. MAIN OUTCOME MEASURES: Death within 3 years of cohort entry. RESULTS: The overall mortality rate was 3.6 per 100 person years, and 3 year cumulative mortality was 10.3%. Unadjusted 3-year mortality was monotonically associated with both ADL stage and IADL stage. Adjusted 3-year mortality was associated with ADL and IADL stages, except that in some models the hazard ratio for stage III (which includes persons with atypical activity limitation patterns) was numerically lower than that for stage II. CONCLUSION: We found nearly monotonic relationships between ADL and IADL stage and adjusted 3 year mortality. These findings could aid in the development of population health approaches and metrics for evaluating the success of alternative economic, social, or health policies on the longevity of older adults with activity limitations. PMID- 26003870 TI - Prevalence of Posterior Shoulder Subluxation in Children With Neonatal Brachial Plexus Palsy After Early Full Passive Range of Motion Exercises. AB - BACKGROUND: Children with neonatal brachial plexus palsy (NBPP) are often prescribed shoulder range of motion (ROM) exercises; however, the extent and timing of exercise implementation remains controversial in the context of shoulder joint integrity. The association of ROM exercises to delayed posterior shoulder subluxation (PSS) is unknown. OBJECTIVE: To determine prevalence of PSS in children with NBPP who began full passive ROM exercises before 6 months of age, and characteristics associated with development or absence of PSS in children. DESIGN: Cross-sectional study. SETTING: Tertiary care NBPP referral center. PARTICIPANTS: Forty-six children with NBPP, aged 24-57 months, who began full ROM exercises before 6 months of age. METHODS: One radiologist conducted bilateral shoulder ultrasound (US) on each child to evaluate for PSS. One occupational therapist evaluated each child clinically for PSS using defined parameters without knowledge of US results. MAIN OUTCOME MEASURES: By US, 20% of children had PSS; 46% had PSS by clinical examination. Shoulder active ROM limitations and history of shoulder surgery were associated with presence of PSS. Extent of NBPP was not associated with PSS. RESULTS: Nine of 46 children (20%) met US criteria for PSS; alpha angle was 58 degrees +/- 21 degrees (mean +/- standard deviation [SD]). Twenty-one children (46%) met clinical criteria. Mean age at examination was 35 +/- 10 months. Shoulder active ROM (P <= .004) was associated with PSS, whereas passive ROM was not (P >= .08). History of secondary shoulder surgery and primary nerve graft repair were associated with PSS (P = .04). Extent of NBPP by Narakas classification was not associated with PSS (P = .48). CONCLUSIONS: Early use of full-arc passive ROM home exercise program is not associated with increased prevalence of PSS in children with NBPP compared to prevalence of PSS in published literature. We suggest careful clinical examination, based on defined criteria, provides a reasonable screening examination for evaluating PSS that can be confirmed by noninvasive US. PMID- 26003871 TI - Relationships Between Capsular Stiffness and Clinical Features in Adhesive Capsulitis of the Shoulder. AB - BACKGROUND: Tightening and contracture of the joint capsule are hallmarks of adhesive capsulitis of the shoulder (ACS). However, quantification of capsular stiffness and its relation to clinical features have not been investigated thoroughly. OBJECTIVES: To quantify capsular stiffness during intra-articular hydraulic distension (IHD) and to investigate its relationships with pain severity, symptom duration, range of motion (ROM), gender, and diabetes status. DESIGN: Case series. SETTING: University outpatient clinic of physical medicine and rehabilitation. PARTICIPANTS: A total of 107 consecutive patients with ACS who underwent IHD. METHODS: Pressure-volume monitoring data during IHD, pain severity, symptom duration, shoulder ROM, and diabetes status were obtained by retrospective chart review. Capsular stiffness (Kcap) was measured by calculating the slope of the elastic phase in pressure-volume curves. ROM was evaluated in 3 directions (flexion, abduction, and external rotation) with a goniometer, and the sum of the 3 ROMs was calculated. MAIN OUTCOME MEASUREMENTS: Pearson correlation coefficients and comparisons of averages were used to analyze the relationships between Kcap and clinical features. RESULTS: The mean Kcap of the total group of participants was 26.0 +/- 14.2 mmHg/mL. Shoulder pain in motion or rest did not correlate with Kcap. Patients with stiffer capsules had smaller sums of ROMs (r = -.298, P = .002), with distinct limitations in external rotation and abduction (r = -.278, P = .004 and r = -.313, P = .001, respectively). Women had significantly stiffer capsules than men (29.5 +/- 14.3 versus 20.2 +/- 12.1 mmHg/mL, P = .001). Diabetes status had no significant effect on capsular stiffness. CONCLUSIONS: Capsular stiffness of the glenohumeral joint significantly correlated with limitation in shoulder ROM, especially in the abduction and external rotation directions, whereas there were no meaningful relationships with shoulder pain during motion or rest. This is the first study to reveal the relationships between in vivo quantified capsular stiffness and shoulder ROM limitations. PMID- 26003872 TI - Acceleration and Orientation Jumping Performance Differences Among Elite Professional Male Handball Players With or Without Previous ACL Reconstruction: An Inertial Sensor Unit-Based Study. AB - BACKGROUND: Handball is one of the most challenging sports for the knee joint. Persistent biomechanical and jumping capacity alterations can be observed in athletes with an anterior cruciate ligament (ACL) injury. Commonly identified jumping biomechanical alterations have been described by the use of laboratory technologies. However, portable and easy-to-handle technologies that enable an evaluation of jumping biomechanics at the training field are lacking. OBJECTIVE: To analyze unilateral/bilateral acceleration and orientation jumping performance differences among elite male handball athletes with or without previous ACL reconstruction via a single inertial sensor unit device. DESIGN: Case control descriptive study. SETTING: At the athletes' usual training court. PARTICIPANTS: Twenty-two elite male (6 ACL-reconstructed and 16 uninjured control players) handball players were evaluated. METHODS: The participants performed a vertical jump test battery that included a 50-cm vertical bilateral drop jump, a 20-cm vertical unilateral drop jump, and vertical unilateral countermovement jump maneuvers. MAIN OUTCOME MEASUREMENTS: Peak 3-dimensional (X, Y, Z) acceleration (m.s(-2)), jump phase duration and 3-dimensional orientation values ( degrees ) were obtained from the inertial sensor unit device. Two-tailed t-tests and a one way analysis of variance were performed to compare means. The P value cut-off for significance was set at P < .05. RESULTS: The ACL-reconstructed male athletes did not show any significant (P < .05) residual jumping biomechanical deficits regarding the measured variables compared with players who had not suffered this knee injury. A dominance effect was observed among non-ACL reconstructed controls but not among their ACL-reconstructed counterparts (P < .05). CONCLUSIONS: Elite male handball athletes with previous ACL reconstruction demonstrated a jumping biomechanical profile similar to control players, including similar jumping performance values in both bilateral and unilateral jumping maneuvers, several years after ACL reconstruction. These findings are in agreement with previous research showing full functional restoration of abilities in top-level male athletes after ACL reconstruction, rehabilitation and subsequent return to sports at the previous level. PMID- 26003873 TI - The Effects of Volitional Preemptive Abdominal Contraction on Postural Control Responses in Healthy Subjects. AB - OBJECTIVE: To investigate the effect of volitional preemptive abdominal contraction by using an abdominal bracing maneuver (ABM) on postural control responses. DESIGN: A within-subjects, repeated-measure, experimental design. SETTING: Laboratory. PARTICIPANTS: Sixty-five healthy subjects between 18 and 50 years of age. METHODS: Subjects performed ABM alternating with No-ABM during 2 rounds of 2 Neurocom computed dynamic posturography tests: the Motor Control Test (MCT) and conditions 1 (eyes open), 2 (eyes closed), and 5 (eyes closed, sway referenced support) of the Sensory Organization Test (SOT). MAIN OUTCOME MEASUREMENTS: (1) MCT Response Latency (milliseconds) and Response Scaling (magnitude of active postural correction) and (2) SOT Equilibrium Scores and 2 Dimensional Sway ( degrees /second), and SOT Movement Strategy, which measure postural sway and movement strategies (ankle versus hip strategy), respectively. RESULTS: The use of ABM (versus No-ABM) produced: (1) a small but statistically significant decrease in SOT Equilibrium Score for condition 2 (-1.0%; P = .004); (2) an increase in SOT 2-Dimensional Sway ( degrees /second) during conditions 1 (16.9%; P = .0001) and 2 (15.0%; P = .0001); (3) a small decrease in SOT Movement Strategy scores during condition 1 (-0.5%; P = .001) and condition 2 (-1.0%; P = .017); and (4) a reduction of MCT Response Latency by 3 milliseconds (-2.1%; P = .005) and reduction of Response Scaling by 0.33 degrees /second (-9.2%; P = .001). CONCLUSION: Individuals can incorporate the ABM without substantively altering postural control. Although selected SOT and MCT scores exhibited small decreases in postural response integrity, those outcomes did not reflect functionally meaningful changes. These findings can enhance clinicians' confidence in prescribing the ABM as a means to protectively stabilize the spine and potentially prevent injury in healthy subjects without concern for reducing postural control, especially during more complex postural perturbations that introduce sensory conflict. PMID- 26003874 TI - In honor of the 75th birthday of Kuanyshbek Bituovich Musabekov. PMID- 26003875 TI - Electrostatic interaction of soft particles. AB - Theories of the electrostatic interaction between two soft particles (i.e., particles covered with an ion-penetrable surface layer of polyelectrolytes) in an electrolyte solution are reviewed. Interactions of soft particles after contact of their surface layers are particularly discussed. Interaction in a salt-free medium and the discrete-charge effect are also treated. PMID- 26003876 TI - Rapid dissemination of granular cell astrocytoma arising from periventricular stem cell regions in chronic multiple sclerosis. PMID- 26003877 TI - Recent trends in incidence, geographical distribution, and survival of papillary thyroid cancer in France. AB - BACKGROUND: Over the past few decades, the incidence of thyroid cancer has dramatically increased in many countries. This increase was mainly seen in papillary cancer. The role of diagnostic practices and the effects of other risk factors were suggested to explain this increase. We provide a descriptive analysis in terms of changes in incidence, geographical distribution, and survival to check the relevance of assumptions about the increase. METHODS: A detailed analysis of changes in incidence recorded in French cancer registries between 1982 and 2010 was performed taking into account age, period, and birth cohort. The geographical distribution of the incidence in the 2006-2010 period was estimated from the standardized incidence ratios. The net survival was estimated to evaluate the effects of sex, age, and period of diagnosis in patients diagnosed between 1989 and 2004 and followed-up until 2013. RESULTS: The incidence of papillary cancer has increased sharply over the 1982-2010 period; the average annual rate of increase was 7.8% in men and 7.2% in women. The increase has slowed in the recent period in people aged less than 50 at the time of diagnosis. It has also slowed in the cohorts born 1945 and after. There was a strong geographic disparity in incidence between areas covered by cancer registries. Finally, the net survival was very high; the 10-year net survival was 96% and improved progressively from 82% in patients diagnosed between 1989 and 1993 to 95% in those diagnosed between 1999 and 2004. CONCLUSION: The increased incidence results most probably from the effect of medical practice, although other risk factors seem also involved, but to a lesser extent. The increase seems to have slowed down in the recent years, especially in the youngest age groups. This observation suggests a recent trend towards saturation of the effects of medical practices in post-1945 cohorts associated with an effect of the gradual dissemination of the recommendations relative to the management of thyroid nodules. PMID- 26003878 TI - Possible role of apoptosis in pathogenesis of adenoid hypertrophy and chronic adenoiditis: Prospective case-control study. AB - OBJECTIVE: Apoptosis is a programmed cell death; it provides an important balance between lymphocytes in adenoid tissue. The aim of this study is to investigate the role of apoptosis in chronic adenoiditis and adenoid hypertrophy. This is the first study in the literature about apoptosis in adenoid hypertrophy and chronic adenoiditis. METHODS: Prospective case-control study in a tertiary referral university hospital was conducted. 46 patients who had chronic adenoiditis and adenoid hypertrophy underwent adenoidectomy. Adenoids were evaluated for apoptosis and assembled into groups according to their size. Apoptotic cells were counted in three different microscopic fields and their average was taken for every microcompartment. As a result of immunohistochemical staining, specimens were compared for their apoptotic cell rate. RESULTS: The difference in apoptosis of chronic adenoiditis and adenoid hypertrophy groups is statistically significant (p<0.05). The age 6 was used as a cut-off to compare apoptosis in adenoid tissue. The difference was not statistically significant for patients at and below 6 years of age; however, the difference was statistically significant for patients above 6 years of age. The comparison of apoptosis in microcompartments of adenoid tissue (intrafollicular, interfollicular, subepithelial and intraepithelial) between chronic adenoiditis and adenoid hypertrophy groups revealed significant differences for intrafollicular and intraepithelial areas, and insignificant differences for interfollicular and subepithelial areas. CONCLUSION: Although apoptosis could not totally explain the pathogenesis of chronic adenoiditis and adenoid hypertrophy, it appeared to play an important role in it. Apoptosis functions to limit adenoid hypertrophy. Adenoid apoptosis appears to be age-dependent. PMID- 26003879 TI - Proton pump (H+/K+-ATPase) expression in human larynx. AB - OBJECTIVE: The goal of our study was to investigate and to identify the existence of proton pump in different parts of larynx. The presence of acidic content in this area is known to be connected to several laryngeal diseases. It is mostly developed by upward recurrence of acidic gastric content, but there are some signs that the acid can be produced in the larynx as well, because of the proton pump activity in laryngeal mucosa. METHODS: The study was performed on two types of specimens: (1) 50 cadaver larynges and (2) 11 surgical larynges obtained after laryngectomy. Samples were taken from supraglottis, glottis and subglottic areas and immunohistochemistry for the beta subunit of the proton pump was done. RESULTS: The presence of proton pump was proved in seromucous glands in laryngeal supraglottic area, but it was also, for the first time, found in human chondrocytes in the thyroid and epiglottic cartilage. CONCLUSION: These new findings could encourage further research that would illuminate better the etiopathogenesis not only of laryngopharyngeal reflux, but also the pathophysiology of cartilaginous disorders. PMID- 26003880 TI - A case of hypertrophic cranial pachymeningitis associated with invasive Aspergillus mastoiditis. AB - We report a rare case of hypertrophic cranial pachymeningitis (HCP) associated with invasive Aspergillus mastoiditis. A 63-year-old man with diabetes mellitus underwent mastoidectomy because of chronic discharge from his left ear. The mastoidectomy was unsuccessful in resolving purulent otorrhea; moreover, 7 months later, the patient developed left abducens nerve palsy. Magnetic resonance imaging revealed HCP at the left middle cranial fossa. Although the pathogen could not be identified, an Aspergillus infection was considered based on elevated serum beta-d-glucan and a positive Aspergillus antigen test result. Voriconazole treatment resolved diplopia and left otorrhea and dramatically improved HCP. PMID- 26003881 TI - Inverse Relationship between Cardio-Ankle Vascular Index and Body Mass Index in Healthy Children. AB - OBJECTIVE: To establish reference scores for cardio-ankle vascular index (CAVI), a noninvasive measure of vascular function, which reflects the stiffness of arteries, in healthy children, to test for racial and ethnic differences, and to compare CAVI scores between overweight and normal weight children. STUDY DESIGN: Subjects included 292 children aged 10-18 years: 100 non-Hispanic whites, 89 non Hispanic blacks, and 103 Hispanics. Subjects were grouped as normal weight (body mass index [BMI] <85th percentile for age) and overweight (BMI >85th percentile for age). Blood pressure (BP) and CAVI scores were measured in all subjects. RESULTS: After controlling for age, sex, and BMI, normal weight black males had a higher CAVI score (indicating stiffer arteries) in comparison with Hispanic males and white males (5.53 +/- 0.15 vs 5.13 +/- 0.15 vs 5.02 +/- 0.15, P = .04). BMI had an inverse association on the CAVI score (r = -0.335, P < .0001). In multivariable analysis, BMI and average CAVI scores were significant predictors of each other (R(2) = 0.37, P < .0001, R(2) = 0.21, P < .0001). There was no significant correlation between CAVI scores and resting BP values, confirming that CAVI scores were independent of concurrent BP values. CONCLUSIONS: Significant differences in vascular function exist among ethnic groups of children. Overweight children had lower CAVI scores, suggestive of vascular adaptation to obesity in early life. CAVI, by providing a noninvasive measure of vascular health, may help identify children at increased risk for cardiovascular disease. PMID- 26003882 TI - Supreme Laryngeal Mask Airway versus Face Mask during Neonatal Resuscitation: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the effectiveness of supreme laryngeal mask airway (SLMA) over face mask ventilation for preventing need for endotracheal intubation at birth. STUDY DESIGN: We report a prospective, randomized, parallel 1:1, unblinded, controlled trial. After a short-term educational intervention on SLMA use, infants >=34-week gestation and/or expected birth weight >=1500 g requiring positive pressure ventilation (PPV) at birth were randomized to resuscitation by SLMA or face mask. The primary outcome was the success rate of the resuscitation devices (SLMA or face mask) defined as the achievement of an effective PPV preventing the need for endotracheal intubation. RESULTS: We enrolled 142 patients (71 in SLMA and 71 in face mask group, respectively). Successful resuscitation rate was significantly higher with the SLMA compared with face mask ventilation (91.5% vs 78.9%; P = .03). Apgar score at 5 minutes was significantly higher in SLMA than in face mask group (P = .02). Neonatal intensive care unit admission rate was significantly lower in SLMA than in face mask group (P = .02). No complications related to the procedure occurred. CONCLUSIONS: In newborns with gestational age >=34 weeks and/or expected birth weight >=1500 g needing PPV at birth, the SLMA is more effective than face mask to prevent endotracheal intubation. The SLMA is effective in clinical practice after a short-term educational intervention. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT01963936. PMID- 26003883 TI - Selection of DNA aptamers against Human Cardiac Troponin I for colorimetric sensor based dot blot application. AB - Troponin T and I are ideal markers which are highly sensitive and specific for myocardial injury and have shown better efficacy than earlier markers. Since aptamers are ssDNA or RNA that bind to a wide variety of target molecules, the purpose of this research was to select an aptamer from a 79bp single-stranded DNA (ssDNA) random library that was used to bind the Human Cardiac Troponin I from a synthetic nucleic acids library by systematic evolution of ligands exponential enrichment (Selex) based on several selection and amplification steps. Human Cardiac Troponin I protein was coated onto the surface of streptavidin magnetic beads to extract specific aptamer from a large and diverse random ssDNA initial oligonucleotide library. As a result, several aptamers were selected and further examined for binding affinity and specificity. Finally TnIApt 23 showed beast affinity in nanomolar range (2.69nM) toward the target protein. A simple and rapid colorimetric detection assay for Human Cardiac Troponin I using the novel and specific aptamer-AuNPs conjugates based on dot blot assay was developed. The detection limit for this protein using aptamer-AuNPs-based assay was found to be 5ng/ml. PMID- 26003884 TI - Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. AB - CRISPR-Cas9 systems provide a platform for high efficiency genome editing that are enabling innovative applications of mammalian cell engineering. However, the delivery of Cas9 and synthesis of guide RNA (gRNA) remain as steps that can limit overall efficiency and ease of use. Here we describe methods for rapid synthesis of gRNA and for delivery of Cas9 protein/gRNA ribonucleoprotein complexes (Cas9 RNPs) into a variety of mammalian cells through liposome-mediated transfection or electroporation. Using these methods, we report nuclease-mediated indel rates of up to 94% in Jurkat T cells and 87% in induced pluripotent stem cells (iPSC) for a single target. When we used this approach for multigene targeting in Jurkat cells we found that two-locus and three-locus indels were achieved in approximately 93% and 65% of the resulting isolated cell lines, respectively. Further, we found that the off-target cleavage rate is reduced using Cas9 protein when compared to plasmid DNA transfection. Taken together, we present a streamlined cell engineering workflow that enables gRNA design to analysis of edited cells in as little as four days and results in highly efficient genome modulation in hard-to-transfect cells. The reagent preparation and delivery to cells is amenable to high throughput, multiplexed genome-wide cell engineering. PMID- 26003885 TI - A plant cell model of polyglutamine aggregation: Identification and characterisation of macromolecular and small-molecule anti-protein aggregation activity in vivo. AB - In vitro studies have shown that LEA proteins from plants and invertebrates protect and stabilise other proteins under conditions of water stress, suggesting a role in stress tolerance. However, there is little information on LEA protein function in whole plants or plant cells, particularly with respect to their anti aggregation activity. To address this, we expressed in tobacco BY-2 suspension cells an aggregation-prone protein based on that responsible for Huntington's disease (HD). In HD, abnormally long stretches of polyglutamine (polyQ) in huntingtin (Htt) protein cause aggregation of Htt fragments within cells. We constructed stably transformed BY-2 cell lines expressing enhanced green fluorescent protein (EGFP)-HttQ23 or EGFP-HttQ52 fusion proteins (encoding 23 or 52 glutamine residues, pertaining to the normal and disease states, respectively), as well as an EGFP control. EGFP-HttQ52 protein aggregated in the cytoplasm of transformed tobacco cells, which showed slow growth kinetics; in contrast, EGFP-HttQ23 or EGFP did not form aggregates and cells expressing these constructs grew normally. To test the effect of LEA proteins on protein aggregation in plant cells, we constructed cell lines expressing both EGFP-HttQ52 and LEA proteins (PM1, PM18, ZLDE-2 or AavLEA1) or a sHSP (PM31). Of these, AavLEA1 and PM31 reduced intracellular EGFP-HttQ52 aggregation and alleviated the associated growth inhibition, while PM18 and ZLDE-2 partially restored growth rates. Treatment of EGFP-HttQ52-expressing BY2 cells with the polyphenol epigallocatechin-3-gallate (EGCG) also reduced EGFP-HttQ52 aggregation and improved cell growth rate. The EGFP-HttQ52 cell line therefore has potential for characterising both macromolecular and small molecule inhibitors of protein aggregation in plant cells. PMID- 26003886 TI - Quantification of Vocal Fold Vibration in Various Laryngeal Disorders Using High Speed Digital Imaging. AB - OBJECTIVE: To quantify vibratory characteristics of various laryngeal disorders seen by high-speed digital imaging (HSDI). METHODS: HSDI was performed on 78 patients with various laryngeal disorders (20 with polyp, 16 with carcinoma, 13 with leukoplakia, 6 with vocal fold nodule, and 33 with others) and 29 vocally healthy subjects. Obtained data were quantitatively evaluated by frame-by-frame analysis, laryngotopography, digital kymography, and glottal area waveform. RESULTS: Overall, patients with laryngeal pathologies showed greater asymmetry in amplitude, mucosal wave and phase, smaller mucosal wave, and poorer glottal closure than vocally healthy subjects. Furthermore, disease-specific vibratory disturbances that generally agreed with the findings in the literature were quantified: comparing polyp with nodule, differences were noted in longitudinal phase difference, amplitude, and mucosal wave. In comparison with leukoplakia and cancer, nonvibrating area was more frequently noted in cancer. CONCLUSIONS: The HSDI analysis of various voice disorders using multiple methods can help phonosurgeons to properly diagnose various laryngeal pathologies and to estimate the degree of their vocal disturbances. PMID- 26003887 TI - Normative Values of Voice Analysis Parameters With Respect to Menstrual Cycle in Healthy Adult Turkish Women. AB - OBJECTIVE/HYPOTHESIS: Objective measurements are quite important for assessment of voice disorders. The first aim of this study was to establish a prototype database of normative values of voice analysis parameters in healthy Turkish adult female population. The second aim was to evaluate the variations of these parameters during physiological menstrual cycle. STUDY DESIGN: This is a prospective, single-blind study. METHODS: Eighty-nine healthy women (mean age, 31.5 +/- 6.0 years) with normal physical findings and without vocal abuse or dysphonia were participated. Detailed physical and videostroboscopic larynx examination was done. Participants' voice samples of sustained /a/ and /i/ vowels were recorded, and voice analysis was done. GRBAS scale was done by four otolaryngologists, and subjects were asked to score their own voice quality using Voice Handicap Index-10 (VHI-10) at the premenstruation, during menstruation, and postmenstruation periods. RESULTS: Eighty-nine healthy Turkish women's some normative acoustic vocal parameters of three different phases of menstrual cycle were reported. The data indicated that during the premenstruation period; the mean jitter %, shimmer % and noise-to-harmonic ratio values were significantly higher than that of other two periods. Variations of computerized acoustic vocal analysis parameters through menstruation cycle were in concordance with the perceptual voice assessment (GRBAS) and the questionnaire of subjects' perception of their own voices (VHI-10). CONCLUSIONS: In this study the normative values of voice analysis parameters of healthy adult Turkish women was reported. Adding computerized voice analysis parameters may improve the assessment and screening of voice in routine clinical practice because this is a simple and reliable method. Evaluation of voice can be performed regardless of the phases of menstrual cycle, but not performing acoustic analysis during the premenstrual period may prevent some of the unintended errors. PMID- 26003888 TI - Incidence of hypoglycemia in patients with type 2 diabetes treated with gliclazide versus DPP-4 inhibitors during Ramadan: A meta-analytical approach. AB - AIM: Hypoglycemia can be a concern for patients with type 2 diabetes when fasting during Ramadan. In this analysis, we assessed the incidence of symptomatic hypoglycemic events in fasting patients treated with gliclazide or dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: A systematic literature review was performed to identify randomized clinical trials comparing the efficacy and safety of gliclazide with DPP-4 inhibitors when treating adults with type 2 diabetes fasting during Ramadan. The primary endpoint of all included studies was the incidence of symptomatic hypoglycemic events. RESULTS: The pooled analysis included three randomized trials. There was no evidence of heterogeneity between the studies (I(2)=0%). There was no significant difference in the incidence of symptomatic hypoglycemic events in patients fasting during Ramadan treated with either a DPP-4 inhibitor or gliclazide (5.6% versus 7.2%, risk ratio 1.12, 95% CI 0.73-1.73, p=0.61). CONCLUSION: Patients treated with either gliclazide or DPP-4 inhibitors while fasting during Ramadan have similarly low risks of experiencing symptomatic hypoglycemia. Gliclazide is an effective oral antidiabetic that may be suitable for the management of patients with type 2 diabetes during Ramadan. Individualized Ramadan-focused advice and evening intake of treatment may improve the management of patients with diabetes during Ramadan. PMID- 26003889 TI - Comparison of vildagliptin as an add-on therapy and sulfonylurea dose-increasing therapy in patients with inadequately controlled type 2 diabetes using metformin and sulfonylurea (VISUAL study): A randomized trial. AB - The aim of present study is to compare the efficacy and safety of adding vildagliptin with sulfonylurea dose-increasing as an active comparator in patients who had inadequately controlled type 2 diabetes mellitus (T2DM) using metformin plus sulfonylurea in real clinical practice. Patients using metformin plus sulfonylurea were assigned to either vildagliptin add-on (50 mg twice a day, n=172) or sulfonylurea dose-increasing by 50% (n=172) treatment groups. The primary endpoint was a change in HbA(1c) after 24 weeks. The secondary endpoints were patients achieving HbA(1c)<=7.0% (53 mmol/mol) and changes in the fasting plasma glucose (FPG), 2-h postprandial glucose (2pp), lipid profiles, and urine albumin-to-creatinine ratio. Body weight and hypoglycemia were also investigated. The mean HbA(1c) at baseline was 8.6% (70 mmol/mol) in both groups. At week 24, the adjusted mean HbA(1c) levels decreased by -1.19% (-13.09 mmol/mol) with vildagliptin add-on and -0.46% (-5.06 mmol/mol) with sulfonylurea (P<0.001). Significantly more vildagliptin add-on patients achieved HbA(1c)<=7.0% (53 mmol/mol) than did sulfonylurea patients (40.1% vs. 7.9%; P<0.001). Greater reductions in FPG and 2pp were observed with vildagliptin add-on than with sulfonylurea (P<0.001). The vildagliptin add-on group exhibited no clinically relevant weight gain and had a lower incidence of hypoglycemia compared with the sulfonylurea group. Vildagliptin add-on therapy might be a suitable option for patients with T2DM that is controlled inadequately by metformin and sulfonylurea, based on its greater glucose control and better safety profile (ClinicalTrial.gov: NCT01099137). PMID- 26003890 TI - Organic cation transporter Octn1-mediated uptake of food-derived antioxidant ergothioneine into infiltrating macrophages during intestinal inflammation in mice. AB - OCTN1/SLC22A4 is expressed on apical membranes of small intestine, and is involved in gastrointestinal absorption of its substrates, including the food derived antioxidant ergothioneine (ERGO). ERGO concentration in circulating blood of patients with inflammatory bowel disease (Crohn's disease) is lower than that in healthy volunteers; thus, circulating ERGO is a potential diagnostic marker, although the mechanisms underlying low ERGO concentration in patients are unknown. Here, we focused on intestinal macrophages, which infiltrate sites of inflammation, and examined possible first-pass uptake of ERGO by macrophages. ERGO concentration in blood was lower in mice with dextran sodium sulfate (DSS) induced colitis than in controls. On the other hand, expression of octn1 gene product and ERGO concentration in intestinal tissues of DSS-treated mice were higher than in controls. Interestingly, lamina propria mononuclear cells (LPMCs) isolated from DSS-treated mice contained ERGO and showed [(3)H]ERGO uptake and Octn1 expression, whereas ERGO was undetectable in LPMCs of control mice. Functional expression of OCTN1 was also confirmed in LPS-stimulated human macrophage-like cell line, THP-1. In conclusion, OCTN1 is functionally expressed on activated intestinal macrophages, and ERGO uptake into these immune cells could contribute at least in part to the altered disposition of ERGO in intestinal inflammation. PMID- 26003891 TI - Reduced folate carrier 1 gene expression levels are correlated with methotrexate efficacy in Japanese patients with rheumatoid arthritis. AB - Responsiveness to methotrexate (MTX), the "anchor drug" for treating rheumatoid arthritis (RA), varies among individual patients. In this study we investigated the effects of folate transporter gene expression levels on disease activity among 56 Japanese patients with RA who were undergoing MTX therapy. We also assessed gene expression levels for 15 healthy control subjects. The mRNA expression levels of reduced folate carrier 1 (RFC1) and proton-coupled folate transporter (PCFT) in PBMCs from these patients and controls were determined using real-time quantitative polymerase chain reaction (PCR). Compared with PCFT, there were large individual differences in RFC1 mRNA expression levels in both RA patients and healthy controls. RFC1 mRNA expression levels and RA disease activity scores were significantly negatively correlated, as disease activity scores were lower for patients with higher RFC1 mRNA expression levels. However, RFC1 mRNA levels were not correlated with MTX doses. Thus, the clinical efficacy of MTX for Japanese RA patients was associated with the expression level of a folate transporter gene. Increased RFC1 expression may increase MTX uptake by immune cells, such as lymphocytes, and as a result, RA disease activity would be reduced. PMID- 26003892 TI - Bowel obstruction rates in antecolic/antegastric versus retrocolic/retrogastric Roux limb gastric bypass: a meta-analysis. AB - BACKGROUND: Previous literature is varied with regard to rates of bowel obstruction after laparoscopic Roux-en-Y gastric bypass (LRYGB). Internal herniation through mesenteric defects is a common cause of bowel obstructions. There are advantages and disadvantages to routing the Roux limb via a retrocolic/retrogastric (RC/RG) versus an antecolic/antegastric (AC/AG) position. OBJECTIVE: To review the literature comparing obstruction rates in RYGB using the antecolic versus retrocolic approach. SETTING: Community-based integrated multispecialty health system with a teaching hospital serving 19 counties over a 3-state region. METHODS: A literature search for articles published from 1994 2013 was completed. Articles were included if they reported an n>25, Roux limb route, obstruction rate by route, and follow-up duration. Statistical analysis included chi(2) test by patient number. RESULTS: The initial search identified 241 articles; 8 met inclusion criteria. There were 4805 patients in the AC/AG group, and 2238 in the RC/RG group. Follow-up ranged from 0 to 68 months. A linear stapled technique was reported in 4231 (88%) patients in the AC/AG group and 1541 (69%) of RC/RG group. Handsewn closure of mesenteric defects was reported in 2152 (45%) patients in the AC/AG group and 1012 (45%) patients in the RC/RG group. Bowel obstructions occurred in 68 (1.4%) patients in the AC/AG group and 117 (5.2%) patients in the RC/RG group (P<.001). Internal hernias were reported in 65 (1.3%) patients in the AC/AG group and 52 (2.3%) patients in the RC/RG group (P<.001). Two mortalities were reported in the AC/AG group. CONCLUSIONS: Increased rates of bowel obstruction and internal hernia were observed in the RC/RG group compared with the AC/AG group. A prospective, randomized trial would be necessary to definitively determine the impact of Roux limb position and routine closure of mesenteric defects on bowel obstruction rates after gastric bypass. PMID- 26003893 TI - Comment on: Should metabolic surgery be offered in morbidly obese patients with type I diabetes? PMID- 26003894 TI - Laparoscopic sleeve gastrectomy leads the U.S. utilization of bariatric surgery at academic medical centers. AB - BACKGROUND: Analysis of a recent single state bariatric surgery registry revealed that laparoscopic sleeve gastrectomy was the most common bariatric procedure starting in 2012. The objective of this study was to examine the trend in utilization of laparoscopic sleeve gastrectomy performed at academic medical centers in the United States. METHODS: Using ICD-9 diagnosis and procedure codes, clinical data obtained from the University HealthSystem Consortium database for all bariatric procedures performed for the treatment of severe obesity between October 1, 2011, and June 30, 2014. Quarterly trends in utilization for the 4 most commonly performed bariatric operations were examined, and comparisons between procedures were performed. RESULTS: A total of 54,953 bariatric procedures were performed. Utilization of laparoscopic sleeve gastrectomy increased from 23.7% of all bariatric procedures during the fourth quarter of 2011 to 60.7% during the second quarter of 2014 while laparoscopic gastric bypass decreased from 62.2% to 37.0%, respectively. Utilization of laparoscopic sleeve gastrectomy surpassed that of laparoscopic gastric bypass in the second quarter of 2013 (50.6% versus 45.8%). During the same time period, utilization of open gastric bypass fell from 6.6% to 1.5%, and the use of laparoscopic adjustable gastric banding decreased from 7.5% to .8%. CONCLUSIONS: Within the context of U.S. academic medical centers, there has been a significant increase in the utilization of laparoscopic sleeve gastrectomy, which has surpassed laparoscopic gastric bypass utilization since 2013. Laparoscopic sleeve gastrectomy is now the most commonly performed bariatric procedure at the national level within academic centers. PMID- 26003895 TI - Laparoscopic cyst-gastrostomy after laparoscopic sleeve gastrectomy. PMID- 26003896 TI - Surgical management of gastrogastric fistula. AB - BACKGROUND: Gastrogastric fistula (GGF) is a rare complication after Roux-en-Y gastric bypass (RYGB) that can be challenging to treat. OBJECTIVE: The aim of this study is to examine our surgical experience in the management of GGF after RYGB. SETTING: Academic center, United States. METHODS: We report a consecutive series of 36 patients who underwent surgery for GGF at our institution between 2005 and 2013. RESULTS: The cohort had a mean age of 48.0+/-10.8 years, mean body mass index (BMI) of 34.6+/-11.3 kg/m(2), and an average number of 5.0+/-2.0 co morbidities at the time of GGF revision. Of the 36 patients, 16 (44.4%) had previous open RYGB. Endoscopy confirmed GGF in 26 patients (72.2%), whereas upper gastrointestinal (GI) series indicated GGF in 21 of 30 cases (70.0%). The GGF surgery was on average 6.4+/-3.8 years after the primary procedure. All patients underwent surgical management either in the form of a redo gastrojejunal anastomosis with excision of fistula (77.7%) or a remnant gastrectomy with excision of fistula (22.2%). Mean operative time, blood loss, and length of stay were 248.4+/-103.3 minutes, 232.7+/-270.2 mL, and 8.5+/-8.6 days, respectively. One major intraoperative and 6 early postoperative complications occurred. After a mean follow-up of 38.4+/-30.0 months, the mean BMI was 35.5+/-6.2 kg/m(2) in patients with weight regain before GGF revision (P<.05) versus 25.0+/-6.1 kg/m(2) in patients without weight regain (P = .7). CONCLUSION: GGF is a rare complication of RYGB. Surgical treatment should be tailored to the presenting symptoms and associated anatomic abnormality. Anastomotic revisions are associated with higher complication rates. PMID- 26003897 TI - The effect of surgically induced weight loss on nonalcoholic fatty liver disease in morbidly obese Indians: "NASHOST" prospective observational trial. AB - BACKGROUND: Surgically induced weight loss improves nonalcoholic fatty liver disease (NAFLD) in morbidly obese Caucasian patients. Similar data are lacking from India. OBJECTIVE: To compare the histologic features of NAFLD in morbidly obese Indian patients before and 6 months after bariatric surgery. Histologic changes were also separately assessed according to the type of bariatric intervention. SETTING: Teaching institution, India; private practice. METHODS: All patients undergoing bariatric surgery from July 2012 to July 2013 underwent a routine liver biopsy at the time of bariatric surgery. If the biopsy specimen indicated NAFLD, patients were asked to undergo a second biopsy after 6 months. Baseline anthropometry, clinical data, biochemistry, and pathology were recorded and repeated at follow-up. RESULTS: Eighty-eight of 134 index biopsy specimens indicated NAFLD. Thirty patients had paired liver biopsies. Steatosis was present in all, 14 had lobular inflammation, 10 had ballooning degeneration, and 14 had fibrosis. Mean time between the biopsies was 7.1 months (range 6-8 months). At the second biopsy, steatosis had resolution in 19 and improvement in 11, lobular inflammation had resolution in 12 and improvement in 2, ballooning had resolution in 9 and improvement in 1 and fibrosis had resolution in 11 and improvement in 3 (P<0.05 for all). Improvement was greater among those who underwent a sleeve gastrectomy in comparison to a Roux-en-Y gastric bypass, although this difference was not statistically significant. None had worsening of liver histologic results. CONCLUSIONS: Surgically induced weight loss significantly and rapidly improves liver histology in morbidly obese Indians with NAFLD. PMID- 26003899 TI - Comment on: Vertical sleeve gastrectomy specimens have a high prevalence of unexpected histopathologic findings requiring additional clinical management. PMID- 26003898 TI - Using presurgical psychological testing to predict 1-year appointment adherence and weight loss in bariatric surgery patients: predictive validity and methodological considerations. AB - BACKGROUND: Previous studies suggest that presurgical psychopathology accounts for some of the variance in suboptimal weight loss outcomes among Roux-en-Y gastric bypass (RYGB) patients, but research has been equivocal. OBJECTIVES: The present study seeks to extend the past literature by examining associations between presurgical scale scores on the broadband Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and suboptimal weight loss and poor adherence to follow-up 1 year postoperatively after accounting for several methodologic considerations. SETTING: Cleveland Clinic Bariatric and Metabolic Institute, Cleveland, Ohio, USA. METHODS: The sample consisted of 498 RYGB patients, who produced a valid presurgical MMPI-2-RF protocol at program intake. The sample was primarily female (72.9%), Caucasian (64.9%), and middle aged (mean = 46.4 years old; standard deviation [SD] = 11.6). The mean presurgical body mass index (BMI) was 47.4 kg/m(2) (SD = 8.2) and mean percent weight loss (%WL) at 1 year postoperatively was 31.18 %WL (SD = 8.44). RESULTS: As expected, scales from the Behavioral/Externalizing Dysfunction (BXD) domain of the MMPI-2-RF were associated with worse weight loss outcomes and poor adherence to follow-up, particularly after accounting for range restriction due to underreporting. Individuals producing elevated scores on these scales were at greater risk for achieving suboptimal weight loss (<50% excess weight loss) and not following up with their appointment compared with those who scored below cut offs. CONCLUSIONS: Patients who are more likely to engage in undercontrolled behavior (e.g., poor impulse control), as indicated by presurgical MMPI-2-RF findings, are at greater risk for suboptimal weight loss and poor adherence to follow-up following RYGB. Objective psychological assessments should also be conducted postoperatively to ensure that intervention is administered in a timely manner. Future research in the area of presurgical psychological screening should consider the impact of underreporting and other discussed methodologic issues in predictive analyses. PMID- 26003900 TI - Conversion of Nissen fundoplication to laparoscopic gastric bypass: video case report and literature review. PMID- 26003901 TI - Lack of evidence of increased risk of bacterial transmission during cystic fibrosis educational programmes. AB - BACKGROUND: Educational and rehabilitation programmes increase the quality-of life of patients with cystic fibrosis, but patients are discouraged to participate because of the risk of cross-infections. METHODS: Isolates of Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae cultured one year before to one year after attendance were investigated by pulsed field gel electrophoresis, multilocus sequence typing and/or spa-typing. RESULTS: We typed 984 bacterial isolates cultured from 46 patients aged 5-18 years attending educational programmes at Aarhus University Hospital during 2009-2011. There were no cross-infections with P. aeruginosa. Six cases of S. aureus or H. influenzae strain replacement with a new strain-type shared with a fellow attendee were found. However, the probability of acquiring a shared strain of S. aureus or H. influenzae was not increased for patients attending educational programmes. CONCLUSIONS: Transmission of P. aeruginosa, S. aureus and H. influenzae related to attendance to the investigated educational programmes could not be documented. PMID- 26003902 TI - Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease. AB - OBJECTIVES: To further characterize the echocardiographic anatomy of the canine mitral valve apparatus in normal dogs and in dogs affected by myxomatous mitral valve disease (MMVD). ANIMALS: Twenty-two normal dogs and 60 dogs with MMVD were prospectively studied. METHODS: The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet were measured in the control group and the affected group, as were the diameters of the mitral valve annulus in diastole (MVAd) and systole (MVAs). The dogs with MMVD were staged based on American College of Veterinary Internal Medicine (ACVIM) guidelines and separated into groups B1 and B2/C. All measurements were indexed to body weight based on empirically defined allometric relationships. RESULTS: There was a statistically significant relationship between all log10 transformed mitral valve dimensions and body weight. The AMVL, AMVW, AMVA, MVAd and MVAs were all significantly greater in the B2/C group compared to the B1 and control groups. The AMVW was also significantly greater in the B1 group compared to the control group. Interobserver % coefficient of variation (% CV) was <10% for AMVL, AMVA, MVAd and MVAs, but was 29.6% for AMVW. Intraobserver % CV was <10.4% for all measurements. CONCLUSIONS: Measurements of the anterior mitral valve leaflet and the mitral valve annulus in the dog can be indexed to body weight based on allometric relationships. Preliminary reference intervals have been proposed over a range of body sizes. Relative to normal dogs, AMVL, AMVW, AMVA, MVAd and MVAs are greater in patients with advanced MMVD. PMID- 26003903 TI - Fungal myocarditis and pericardial effusion secondary to Inonotus tropicalis (phylum Basidiomycota) in a dog. AB - Fungal disease is a rare cause of pericardial effusion in dogs. This report describes the first case of fungal pericardial effusion and myocarditis secondary to the fungal organism Inonotus tropicalis. A 9-year-old female spayed French bulldog with a multi-year history of treatment with glucocorticoids for management of atopy was presented for exercise intolerance, ascites and weight loss. Physical examination and thoracic imaging revealed enlarged peripheral and cranial mediastinal lymph nodes, left ventricular thickening and cardiac tamponade secondary to pericardial effusion. Fine needle aspiration of the cranial mediastinal lymph node showed pyogranulomatous inflammation with short, thin and poorly septated hyphae. Culture of the aspirate yielded a fungal isolate identified as Inonotus tropicalis based on morphologic features and rRNA gene sequencing. Postmortem examination showed myocardial thickening with multifocal to coalescing, firm, white, ill-defined nodules. Histology confirmed the presence of disseminated fungal infection with extensive myocardial involvement. Inonotus tropicalis is an opportunistic poroid wood-decaying basidiomycete. Infection in this dog was likely the result of chronic immunosuppressive therapy. PMID- 26003904 TI - Late-life depression: Burden, severity and relationship with social support dimensions in a West African community. AB - OBJECTIVES: The occurrence of depression in old age is often linked with grave consequences. The purpose of this study is to investigate the burden of depression and its relationship with perceived social support among the elderly in a West African community setting. METHODS: In this cross-sectional study, participants made up of 350 elders aged 60 years and above were selected through multi-stage random sampling technique. All participants were interviewed with designed questionnaire, multidimensional scale of perceived social support (MSPSS) and Geriatric Depression Scale (GDS) to elicit socio-demographic profile, social support and depressive psychopathology respectively. RESULTS: The participants were largely females (52.9%) and their mean age was 68.8+/-7.3 years. A little above one-quarter (26.4%) had depressive episode, and mild severity was preponderant. Low level of social support was associated with depression (chi(2)=8.418, p=0.004); especially low social supports from significant others (chi(2)=3.989, p=0.046) and family members (chi(2)=4.434, p=0.035). Similarly, severity of depression in the elderly correlated negatively with availability of social support from significant others (chi(2)=5.495, p=0.019) and family members (chi(2)=5.149, p=0.023). CONCLUSION: Considering the burden of depression in this elderly population and the influential roles of social support especially from family and significant others on depression; strengthening of informal social support and formal social support for the elders is advocated. In addition, design of community based geriatric mental health with social services and articulation of public policy to address old age needs are implied. PMID- 26003905 TI - Hormonal factors and incident asthma and allergic rhinitis during puberty in girls. AB - BACKGROUND: Accumulating evidence is indicating that hormonal factors play a role in new-onset allergic rhinitis and asthma after puberty. OBJECTIVE: To determine whether age at menarche and use of hormonal contraceptives predict new-onset allergic rhinitis and asthma after puberty in young German women. METHODS: A prospective community-based cohort study followed 1,191 girls 9 to 11 years old to early adulthood (19-24 years old). Self-administrated questionnaires concerning age at menarche, use of hormonal contraceptives, and status and age at onset of physician-diagnosed allergic rhinitis and asthma were collected at 16 to 18 and 19 to 24 years of age. Logistic regression models were used to analyze the incidence of asthma and allergic rhinitis after puberty and pooled estimates were obtained from the final model. RESULTS: Eleven percent of girls developed allergic rhinitis after menarche and 3% reported new-onset asthma. Late menarche (>13 years of age) was statistically significantly inversely related to allergic rhinitis (adjusted odds ratio [OR] 0.32, 95% confidence interval [CI] 0.14-0.74) but did not reach the level of statistical significance for asthma (OR 0.32, 95% CI 0.07-1.42). Use of hormonal contraceptives was inversely associated with new onset allergic rhinitis (OR 0.14, 95% CI 0.08-0.23) and asthma (OR 0.27, 95% CI 0.12-0.58) after puberty. CONCLUSION: This study shows that girls with late onset of menarche are less likely to develop allergic rhinitis after puberty compared with those who have menarche at an average age. These findings also suggest that, in addition to endogenous hormones, hormonal contraceptives play a role and might protect young women from allergies and asthma. PMID- 26003906 TI - Racial disparities in surgical outcomes: Does the level of resident surgeon play a role? AB - BACKGROUND: Despite recognition of racial/ethnic surgical disparities, few studies have considered the role of surgical residents. This study aimed to elucidate whether disparities in postoperative outcomes are associated with the presence/level of surgical residents involved in procedures. METHODS: Patients who were classified as having laparoscopic cholecystectomy, laparoscopic appendectomy, and open hernia repair in the 2005-2010 American College of Surgeons National Surgical Quality Improvement Program database were compared by level of provider (junior residents postgraduate year 1-2, senior residents, attending alone) for differences in patient demographics, clinical case-mix, and postoperative outcome information by the use of descriptive statistics and multivariable logistic regression. RESULTS: A total of 196,770 patients met inclusion criteria. Attendings performed 43.0% of operations alone (senior residents 37.5%, junior residents 20.1%), They operated on 44.1% white, 30.1% black, and 43.9% Hispanic patients compared with 35.5%, 48.7%, and 41.3% and 20.4%, 21.3%, and 14.8% for senior and junior residents, respectively. Compared with attendings alone, senior residents were more likely to operate on black patients (adjusted odds ratio [OR] 2.02, 95% confidence interval [95% CI] 1.95 2.09) and have major (OR 1.13, 95% CI 1.06-1.21) and minor complications (OR 1.20, 95% CI 1.11-1.31). Junior residents also were more likely to operate on black patients but did not experience significantly worse outcomes. CONCLUSION: Greater risk-adjusted odds of complications among patients treated by senior residents need to be carefully weighed given the group's higher likelihood of operating on minority patients. PMID- 26003907 TI - Intracorporeal suturing: Transfer from Fundamentals of Laparoscopic Surgery to cadavers results in substantial increase in mental workload. AB - INTRODUCTION: A spatial secondary task developed by the authors was used to measure the mental workload of the participant when transferring suturing skills from a box simulator to more realistic surgical conditions using a fresh cadaver. We hypothesized that laparoscopic suturing on genuine bowel would be more challenging than on the Fundamentals of Laparoscopic Surgery (FLS)-simulated bowel as reflected in differences on both suturing and secondary task scores. METHODS: We trained 14 surgical assistant students to FLS proficiency in intracorporeal suturing. Participants practiced suturing on the FLS box for 30 minutes and then were tested on both the FLS box and the bowel of a fresh cadaver using the spatial, secondary dual-task conditions developed by the authors. RESULTS: Suturing times increased by >333% when moving from the FLS platform to the cadaver F(1,13) = 44.04, P < .001. The increased completion times were accompanied by a 70% decrease in secondary task scores, F(1,13) = 21.21, P < .001. CONCLUSION: The mental workload associated with intracorporeal suturing increases dramatically when trainees transfer from the FLS platform to human tissue under more realistic conditions of suturing. The increase in mental workload is indexed by both an increase in suturing times and a decrease in the ability to attend to the secondary task. PMID- 26003908 TI - Serum transthyretin is a predictor of clinical outcomes in critically ill trauma patients. AB - BACKGROUND: In surgery patients, low preoperative serum transthyretin (TTR) level is associated with greater rates of infection and mortality. However, the predictive value of TTR on surgical outcomes after major trauma has not yet been studied. METHODS: Critically ill trauma patients who underwent surgery for trauma and had TTR preoperatively measured after admission to the surgical intensive care unit (ICU) at the LAC+USC Medical Center (01/2008-05/2014) were identified retrospectively. Univariable and multivariable regression analyses determined the significance of TTR on outcomes. RESULTS: We identified 348 patients. Univariable analysis indicated that patients with lower TTR had more infections (P < .001), higher mortality (P = .007), longer hospital stay (P < .001), longer ICU stay (P < .001), and increased ventilator days (P < .001). Even after adjusting for differences in patient characteristics, lower TTR level was associated with greater infectious complication rates (P = .001), greater mortality (P = .005), longer hospital stay (P = .013), longer ICU stay (P = .030), and increased ventilator days (P = .044). CONCLUSION: In critically ill trauma patients, low serum TTR level is associated with poorer clinical outcomes, and its prognostic utility warrants further study. PMID- 26003909 TI - Impact of gastrectomy procedural complexity on surgical outcomes and hospital comparisons. AB - BACKGROUND: Most risk adjustment approaches adjust for patient comorbidities and the primary procedure. However, procedures done at the same time as the index case may increase operative risk and merit inclusion in adjustment models for fair hospital comparisons. Our objectives were to evaluate the impact of surgical complexity on postoperative outcomes and hospital comparisons in gastric cancer surgery. METHODS: Patients who underwent gastric resection for cancer were identified from a large clinical dataset. Procedure complexity was characterized using secondary procedure CPT codes and work relative value units (RVUs). Regression models were developed to evaluate the association between complexity variables and outcomes. The impact of complexity adjustment on model performance and hospital comparisons was examined. RESULTS: Among 3,467 patients who underwent gastrectomy for adenocarcinoma, 2,171 operations were distal and 1,296 total. A secondary procedure was reported for 33% of distal gastrectomies and 59% of total gastrectomies. Six of 10 secondary procedures were associated with adverse outcomes. For example, patients who underwent a synchronous bowel resection had a higher risk of mortality (odds ratio [OR], 2.14; 95% CI, 1.07 4.29) and reoperation (OR, 2.09; 95% CI, 1.26-3.47). Model performance was slightly better for nearly all outcomes with complexity adjustment (mortality c statistics: standard model, 0.853; secondary procedure model, 0.858; RVU model, 0.855). Hospital ranking did not change substantially after complexity adjustment. CONCLUSION: Surgical complexity variables are associated with adverse outcomes in gastrectomy, but complexity adjustment does not affect hospital rankings appreciably. PMID- 26003910 TI - The use of error analysis to assess resident performance. AB - BACKGROUND: The aim of this study was to assess validity of a human factors error assessment method for evaluating resident performance during a simulated operative procedure. METHODS: Seven postgraduate year 4-5 residents had 30 minutes to complete a simulated laparoscopic ventral hernia (LVH) repair on day 1 of a national, advanced laparoscopic course. Faculty provided immediate feedback on operative errors and residents participated in a final product analysis of their repairs. Residents then received didactic and hands-on training regarding several advanced laparoscopic procedures during a lecture session and animate lab. On day 2, residents performed a nonequivalent LVH repair using a simulator. Three investigators reviewed and coded videos of the repairs using previously developed human error classification systems. RESULTS: Residents committed 121 total errors on day 1 compared with 146 on day 2. One of 7 residents successfully completed the LVH repair on day 1 compared with all 7 residents on day 2 (P = .001). The majority of errors (85%) committed on day 2 were technical and occurred during the last 2 steps of the procedure. There were significant differences in error type (P <= .001) and level (P = .019) from day 1 to day 2. The proportion of omission errors decreased from day 1 (33%) to day 2 (14%). In addition, there were more technical and commission errors on day 2. CONCLUSION: The error assessment tool was successful in categorizing performance errors, supporting known-groups validity evidence. Evaluating resident performance through error classification has great potential in facilitating our understanding of operative readiness. PMID- 26003911 TI - Readmissions after major cancer surgery among older adults. AB - BACKGROUND: Decreasing readmissions has become a focus of emerging efforts to improve the quality and affordability of health care. However, little is known about reasons for readmissions after major cancer surgery in the expanding elderly population (>=65 years) who are also at increased risk of adverse operative events. We sought to identify (1) the extent to which older age impacts readmissions and (2) factors predictive of 30- and 90-day readmissions after major cancer surgery among older adults. METHODS: We identified 2,797 older adults who underwent 1 of 7 types of major thoracic or abdominopelvic cancer surgery within a large multihospital system from 2003 to 2012. Multivariate logistic regression analyses were conducted to identify predictors of 30- and 90 day readmission controlling for covariates. RESULTS: Overall 30- and 90-day readmission rates were 16% and 24% with the majority of readmissions occurring within 15-days of discharge. Principal diagnoses of 30-day readmissions included gastrointestinal, pulmonary, and infections complications. The 30-day readmissions were associated with >2 comorbid conditions and >=2 postoperative complications. Readmissions varied significantly according to cancer surgery type and across treating hospitals. Readmissions did not vary by increasing age. Factors associated with 90-day readmission were comparable to those observed at 30 days. CONCLUSION: In this large, multihospital study of older adults, multiple morbidities, procedure type, greater number of complications, and the treating hospital predicted 30- and 90-day readmissions. These findings point toward the potential impact of hospital-level factors behind readmission. Our results also heighten the importance of assessing the influence of readmission on other important cancer care metrics, namely, patient-reported outcomes and the completion of adjuvant systemic therapies. PMID- 26003912 TI - Preservation solution impacts physiologic function and cellular viability of human saphenous vein graft. AB - INTRODUCTION: Recent clinical data suggest intraoperative preservation of human saphenous vein (HSV) in normal saline is associated with vein graft failure. We evaluated the influence of several preservation media on acute physiologic function and cellular viability of HSV conduit. METHODS: Unprepared (UP) HSV obtained from coronary artery bypass graft patients was characterized on a muscle bath after 2-hour storage in 6 solutions: Plasma-Lyte A, 0.9% NaCl (normal saline), University of Wisconsin solution, Celsior solution, autologous whole blood, or glutathione-ascorbic acid L-arginine (GALA) solution. Vascular smooth muscle contractility was assessed after exposure to depolarizing KCl and phenylephrine. The relaxation of phenylephrine-precontracted HSV to sodium nitroprusside and carbachol (endothelial-independent and -dependent relaxation, respectively) was also assessed. Cellular viability was determined via the methyl thiazolyl tetrazolium (MTT) assay. Rat aortae were used to assess the effect of pH during graft preservation on endothelial-dependent relaxation. RESULTS: Preservation of HSV in normal saline and autologous whole blood impaired contractile responses to KCl relative to UP tissues, whereas preservation in University of Wisconsin solution and Celsior solution enhanced contractile responses (P < .05). Relative to UP tissues, responses to phenylephrine were decreased with preservation in normal saline, whereas preservation in University of Wisconsin solution, Celsior solution, and GALA all potentiated these responses (P < .05). Only preservation in normal saline impaired endothelial-independent relaxation (P = .005). Preservation in Plasma-Lyte A (P = .02), normal saline (P = .002), and University of Wisconsin solution (P = .02) impaired endothelial dependent relaxation. Normal saline preservation decreased MTT viability index relative to UP tissues (0.02 +/- 0.002 mg(-1)0.5 mL(-1) vs 0.033 +/- 0.005 mg( 1)0.5 mL(-1); P = .03). Endothelial function was impaired by acidic pH in rat aorta. CONCLUSION: Preservation of HSV in normal saline causes graft injury leading to impaired physiologic function and decreased viability of the HSV. This harm is mitigated by the use of buffered salt solutions as preservation media. PMID- 26003914 TI - Determining the 'point of change' in the patient's history-the delta rule. PMID- 26003913 TI - The impact of resident involvement on surgical outcomes among patients undergoing hepatic and pancreatic resections. AB - BACKGROUND: Resident participation during hepatic and pancreatic resections varies. The impact of resident participation on surgical outcomes in hepatic and pancreatic operations is poorly defined. METHODS: We identified 25,511 patients undergoing a hepatic or pancreatic resection between 2006 and 2012 using the American College of Surgeons National Surgical Quality Improvement Program database. Multivariate regression models were constructed to determine any association between resident participation and surgical outcomes. RESULTS: Pancreatic resections (n = 16,045; 62.9%) were more common than liver resections (n = 9,466; 37%). Residents participated in the majority of cases (n = 21,857; 86%), with most involvement at the senior level (postgraduate year >= 3, n = 21,147; 97%). Resident participation resulted in slightly longer mean operative times (hepatic, 9 minutes; pancreatic, 22 minutes; both P < .01). Need for perioperative transfusion, hospital duration of stay, and reoperation rates were unaffected by resident participation (all P > .05). Resident participation resulted in a higher risk of overall morbidity (odds ratio [OR], 1.14; 95% CI, 1.05-1.24; P = .001), but not major morbidity (OR, 1.05; 95% CI, 0.93-1.20; P = .40) after liver and pancreas resection. Resident participation resulted in lower odds of 30-day mortality after liver and pancreas resections (OR, 0.75; 95% CI, 0.60-0.94; P = .01). CONCLUSION: Although resident participation resulted in slightly longer operative times and a modest increase in overall complications after liver and pancreatic resection, other metrics such as duration of stay, major morbidity, and mortality were unaffected. These data have important implications for educating patients regarding resident participation in these complex cases. PMID- 26003915 TI - Conflict adaptation within but not across NoGo decision criteria: Event-related potential evidence of specificity in the contextual modulation of cognitive control. AB - From the standpoint of conflict-monitoring theory (Botvinick et al., 2001), detecting an incident of information-processing conflict should attenuate the disruptive influence of information-processing conflicts encountered subsequently, by which time cognitive-control operations will have been engaged. To examine the generality of this conflict-adaptation process across task dimensions, the present research analyzed event-related potentials in a Go/NoGo task that randomly varied the NoGo decision criterion applied across trials. Sequential analyses revealed reduced-amplitude fronto-central N2 and NoGo P3 responses on the second of two consecutive NoGo trials. Importantly, both of these conflict-adaptation effects were present only when the same NoGo decision criterion was applied across trials n and n-1. These findings support the theory that encountering information-processing conflict focuses attention on specific stimulus-response contingencies (Verguts & Notebaert, 2009) rather than engages general cognitive-control mechanisms (Freitas & Clark, 2015). Further implications for the generality of cognitive control are discussed. PMID- 26003916 TI - A comprehensive transcriptomic view of renal function in the malaria vector, Anopheles gambiae. AB - Renal function is essential to maintain homeostasis. This is particularly significant for insects that undergo complete metamorphosis; larval mosquitoes must survive a freshwater habitat whereas adults are terrestrial, and mature females must maintain ion and fluid homeostasis after blood feeding. To investigate the physiological adaptations required for successful development to adulthood, we studied the Malpighian tubule transcriptome of Anopheles gambiae using Affymetrix arrays. We assessed transcription under several conditions; as third instar larvae, as adult males fed on sugar, as adult females fed on sugar, and adult females after a blood meal. In addition to providing the most detailed transcriptomic data to date on the Anopheles Malpighian tubules, the data provide unique information on the renal adaptations required for the switch from freshwater to terrestrial habitats, on gender differences, and on the contrast between nectar-feeding and haematophagy. We found clear differences associated with ontogenetic change in lifestyle, gender and diet, particularly in the neuropeptide receptors that control fluid secretion, and the water and ion transporters that impact volume and composition. These data were also combined with transcriptomics from the Drosophila melanogaster tubule, allowing meta analysis of the genes which underpin tubule function across Diptera. To further investigate renal conservation across species we selected four D. melanogaster genes with orthologues highly enriched in the Anopheles tubules, and generated RNAi knockdown flies. Three of these genes proved essential, showing conservation of critical functions across 150 million years of phylogenetic separation. This extensive data-set is available as an online resource, MozTubules.org, and could potentially be mined for novel insecticide targets that can impact this critical organ in this pest species. PMID- 26003917 TI - Patterns of expression of odorant receptor genes in a Chagas disease vector. AB - Rhodnius prolixus is a triatomine bug acting as a relevant vector of Chagas disease for which the genome sequence has been recently made available. Based on this information, a set of olfactory (ORs) and ionotropic receptor (IRs) genes potentially related to olfactory processes was characterized, and the expression patterns along bug development and in different structures potentially involved in promoting chemosensory-mediated behaviors were studied. For this, diverse bioinformatic procedures were used to validate gene models analyzing their structural and functional features and designing specific primers. Evolutionary relationships among R. prolixus olfactory coreceptors (RproOrco, RproIR25a, RproIR8a and RproIR76b) and their orthologues from other insects were shown to have mostly good bootstrap support values in phylogenetic trees. Moreover, antennal expression was confirmed for most genes included in the study. Both ORs and IRs showed antennal expression along the whole development of bugs of this species, with few exceptional receptors showing gradually increasing expression or expression restricted to the antennae of adult bugs. Finally, the expression of most of the selected genes was confirmed in other structures, such as rostri, tarsi, tibial pads and genitalia, which are potentially involved in promoting chemosensory-mediated behaviors. These results are discussed in terms of their relevance to advance in the understanding of the molecular bases of triatomine behavior. PMID- 26003918 TI - Patients' experiences of in-hospital care when nursing staff were engaged in a practice development programme to promote person-centredness: A narrative analysis study. AB - BACKGROUND: The drive towards person-centred approaches to care delivery has been increasingly promoted. This is in response to the significant challenges within health and social care organisations, which impact on the care experience for patients and their families. OBJECTIVE: The aim of this paper is to illuminate the experiences of patients of care received in hospital wards during the intervention phase of a programme to develop person-centred practice. DESIGN: A narrative enquiry study was conducted which is a particular way of exploring complex cultural or social patterns. Structural narrative analysis was used to generate explanation and interpretation of in-hospital patients' care experience. SETTING: Recruitment was from four different hospital sites in one health care organisation, focussing on patients who were admitted to the nine wards/units where the nursing teams were participating in a practice development programme that had the intention of promoting person-centredness. PARTICIPANTS: Participants were people aged over 18 and receiving care and treatment in the identified wards/units. Twenty-six patients were recruited. METHODS: Narrative interviews were audio-recorded at four month intervals and transcribed. The records were subjected to a process of structural analysis. RESULTS: The findings offer insight into patients' experiences of care in a range of clinical settings in which an explicit intervention to promote person-centred practice was underway. There was one overriding theme formulated: Vulnerability at the junctures of systems, care processes and nurses' responses. From this main theme, we derived four sub-themes: (1) confronting vulnerability, (2) experiencing exemplary care, (3) experiencing misalignments in systems, care processes and nurses' responses, and (4) sharing in a sense of belonging with ward nurses. CONCLUSIONS: In-hospital patients are exposed to vulnerability in the care experience. They placed value on exemplary care. Experiences of misalignments in systems, care processes and nurses' responses disempower patients and heighten a sense of vulnerability. The ward nursing teams were generating a family like atmosphere. Patients responded by sharing a sense of belonging with ward nurses. These findings confirm components that have influenced the development of person centred practice, such as the importance of the context and culture of care. They also offer new insights that may contribute to on-going practice development work. PMID- 26003919 TI - INTroducing A Care bundle To prevent pressure injury (INTACT) in at-risk patients: A protocol for a cluster randomised trial. AB - BACKGROUND: Pressure injuries are a significant clinical and economic issue, affecting both patients and the health care system. Many pressure injuries in hospitals are facility acquired, and are largely preventable. Despite growing evidence and directives for pressure injury prevention, implementation of preventative strategies is suboptimal, and pressure injuries remain a serious problem in hospitals. OBJECTIVES: This study will test the effectiveness and cost effectiveness of a patient-centred pressure injury prevention care bundle on the development of hospital acquired pressure injury in at-risk patients. DESIGN: This is a multi-site, parallel group cluster randomised trial. The hospital is the unit of randomisation. METHODS: Adult medical and surgical patients admitted to the study wards of eight hospitals who are (a) deemed to be at risk of pressure injury (i.e. have reduced mobility), (b) expected to stay in hospital for >=48h, (c) admitted to hospital in the past 36h; and (d) able to provide informed consent will be eligible to participate. Consenting patients will receive either the pressure injury prevention care bundle or standard care. The care bundle contains three main messages: (1) keep moving; (2) look after your skin; and (3) eat a healthy diet. Nurses will receive education about the intervention. Patients will exit the study upon development of a pressure injury, hospital discharge or 28 days, whichever comes first; transfer to another hospital or transfer to critical care and mechanically ventilated. The primary outcome is incidence of hospital acquired pressure injury. Secondary outcomes are pressure injury stage, patient participation in care and health care costs. A health economic sub-study and a process evaluation will be undertaken alongside the trial. Data will be analysed at the cluster (hospital) and patient level. Estimates of hospital acquired pressure injury incidence in each group, group differences and 95% confidence interval and p values will be reported. DISCUSSION: To our knowledge, this is the first trial of an intervention to incorporate a number of pressure injury prevention strategies into a care bundle focusing on patient participation and nurse-patient partnership. The results of this study will provide important information on the effectiveness and cost effectiveness of this intervention in preventing pressure injuries in at-risk patients. If the results confirm the utility of the developed care bundle, it could have a significant impact on clinical practice worldwide. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613001343796. PMID- 26003920 TI - Periatrial epicardial adipose tissue thickness is an independent predictor of atrial fibrillation recurrence after cryoballoon-based pulmonary vein isolation. AB - BACKGROUND: Epicardial adipose tissue (EAT) is a metabolically active fat depot. Studies have investigated the effect of EAT thickness on outcomes of radiofrequency catheter ablation of atrial fibrillation (AF). However, data on the relationship between EAT thickness and outcome of cryoballoon-based pulmonary vein isolation (PVI) are lacking. OBJECTIVE: In this study, we investigate the association between EAT thickness and AF recurrence after cryoballoon-based PVI. METHODS: Patients with symptomatic paroxysmal or persistent AF despite >=1 antiarrhythmic drug(s) were scheduled for cryoballoon-based PVI for AF per the recent recommendations. Periatrial, periventricular, and total EAT thickness measurements were obtained from preprocedural multidetector CT scans. RESULTS: A total of 249 patients (55.6 +/- 10.7 years; 48.2% male; 18.5% persistent AF) were involved in the study. Patients were followed-up for 29 months (8-48 months). When blanking period was considered, freedom from AF after the ablation procedure was 75.9% at a median follow-up of 29 months. Total periatrial EAT thickness (18.1 +/- 6.2 vs. 14.7 +/- 4.7 mm; P < .001) was greater in patients with late AF recurrence when compared to those without. On the other hand, periventricular or total EAT thickness measurements did not differ between both groups (P > .05). Multivariate Cox proportional hazard regression analysis showed that periatrial EAT thickness (hazard ratio, 1.086; P = .001) and left atrial volume index (hazard ratio, 1.144; P < .001) were independent predictors for late AF recurrence. CONCLUSION: Quantification of EAT thickness from preprocedural multidetector CT scans may serve as a beneficial parameter for prediction of AF recurrence after cryoballoon-based PVI. PMID- 26003921 TI - CLASP2 Has Two Distinct TOG Domains That Contribute Differently to Microtubule Dynamics. AB - CLIP-associated proteins CLASPs are mammalian microtubule (MT) plus-end tracking proteins (+TIPs) that promote MT rescue in vivo. Their plus-end localization is dependent on other +TIPs, EB1 and CLIP-170, but in the leading edge of the cell, CLASPs display lattice-binding activity. MT association of CLASPs is suggested to be regulated by multiple TOG (tumor overexpressed gene) domains and by the serine arginine (SR)-rich region, which contains binding sites for EB1. Here, we report the crystal structures of the two TOG domains of CLASP2. Both domains consist of six HEAT repeats, which are similar to the canonical paddle-like tubulin-binding TOG domains, but have arched conformations. The degrees and directions of curvature are different between the two TOG domains, implying that they have distinct roles in MT binding. Using biochemical, molecular modeling and cell biological analyses, we have investigated the interactions between the TOG domains and alphabeta-tubulin and found that each domain associates differently with alphabeta-tubulin. Our findings suggest that, by varying the degrees of domain curvature, the TOG domains may distinguish the structural conformation of the tubulin dimer, discriminate between different states of MT dynamic instability and thereby function differentially as stabilizers of MTs. PMID- 26003922 TI - Folding Optimization In Vivo Uncovers New Chaperones. AB - By employing a genetic selection that forces the cell to fold an unstable, aggregation-prone test protein in order to survive, we have generated bacterial strains with enhanced periplasmic folding capacity. These strains enhance the soluble steady-state level of the test protein. Most of the bacterial variants we isolated were found to overexpress one or more periplasmic proteins including OsmY, Ivy, DppA, OppA, and HdeB. Of these proteins, only HdeB has convincingly been previously shown to function as chaperone in vivo. By giving bacteria the stark choice between death and stabilizing a poorly folded protein, we have now generated designer bacteria selected for their ability to stabilize specific proteins. PMID- 26003924 TI - The First Crystal Structure of the UP1 Domain of hnRNP A1 Bound to RNA Reveals a New Look for an Old RNA Binding Protein. AB - The heterogeneous nuclear ribonucleoprotein (hnRNP) A1 protein is a multifunctional RNA binding protein implicated in a wide range of biological functions. Mechanisms and putative hnRNP A1-RNA interactions have been inferred primarily from the crystal structure of its UP1 domain bound to ssDNA. RNA stem loops represent an important class of known hnRNP A1 targets, yet little is known about the structural basis of hnRNP A1-RNA recognition. Here, we report the first high-resolution structure (1.92A) of UP1 bound to a 5'-AGU-3' trinucleotide that resembles sequence elements of several native hnRNP A1-RNA stem loop targets. UP1 interacts specifically with the AG dinucleotide sequence via a "nucleobase pocket" formed by the beta-sheet surface of RRM1 and the inter-RRM linker; RRM2 does not contact the RNA. The inter-RRM linker forms the lid of the nucleobase pocket and we show using structure-guided mutagenesis that the conserved salt bridge interactions (R75:D155 and R88:D157) on the alpha-helical side of the RNA binding surface stabilize the linker in a geometry poised to bind RNA. We further investigated the structural basis of UP1 binding HIViSL3(ESS3) by determining a structural model of the complex scored by small-angle X-ray scattering. UP1 docks on the apical loop of SL3(ESS3) using its RRM1 domain and inter-RRM linker only. The biophysical implications of the structural model were tested by measuring kinetic binding parameters, where mutations introduced within the apical loop reduce binding affinities by slowing down the rate of complex formation. Collectively, the data presented here provide the first insights into hnRNP A1 RNA interactions. PMID- 26003925 TI - The 'BlueScreen HC' assay as a decision making test in the genotoxicity assessment of flavour and fragrance materials. AB - The genotoxicity of a library of 70 flavour and fragrance substances having a high proportion of in vivo and/or carcinogenicity test data has been assessed using the GADD45a-GLuc 'BlueScreen HC' genotoxicity assay, with and without exogenous metabolic activation. There are only limited genotoxicity and carcinogenicity study data for compounds in this applicability domain, but this study allowed the following conclusions: (i) The BlueScreen HC results are highly predictive of positive results from regulator-required in vitro genotoxicity assays for the test set of materials; the moderate negative predictivity of BlueScreen HC from the in vitro test set of material is mainly due to the high rate of false positive in regulatory in vitro mammalian tests. (ii) BlueScreen HC negative results are predictive of negative in vivo results and provide a specific prediction of in vivo genotoxicity assay results. (iii) In this applicability domain, which comprises a large proportion of relatively low molecular weight molecules, a 1mM testing limit maintains the sensitivity of the assay, and increases specificity. (iv) The predictive capacity and specificity to in vivo genotoxins and carcinogens, coupled to a microplate format with low compound requirement supports further investigation of the BlueScreen HC assay as a useful tool in prioritizing the assessment of new F&F materials and in filling data gaps on materials with no or limited regulatory test data for genotoxicity. PMID- 26003926 TI - High prevalence of previous arrests for illicit drug use and/or impaired driving among drivers killed in motor vehicle crashes in Sweden with amphetamine in blood at autopsy. AB - BACKGROUND: Amphetamine, and to a lesser extent the secondary amine methamphetamine, are major recreational drugs of abuse in Sweden. These central stimulant amines are identified in blood from roughly 50% of people arrested for driving under the influence of drugs (DUID). However, much less information is available about the presence of amphetamine in blood of drivers killed in road traffic crashes. METHODS: This retrospective 10-year study (2001-2010) used a forensic toxicology database (TOXBASE) to retrieve information about road-traffic crashes when the driver had amphetamine and/or methamphetamine in autopsy blood. Forensic toxicology results were available from over 95% of all drivers killed on Swedish roads during this 10-year period. RESULTS: Amphetamine was present in the blood of 106 drivers (3.9%) either alone or together with other psychoactive substances (e.g. alcohol, cannabis, diazepam, alprazolam, etc.). The vast majority of fatalities were male (95%) with a mean age (+/-standard deviation) of 37+/-11.4 years (range 16-67 years). The mean (median) and highest concentrations of amphetamine in femoral blood were 1.36 mg/L (1.0mg/L) and 6.74 mg/L, respectively. Many of the victims (75%) had been arrested previously for use of illicit drugs or DUID. The median number of previous arrests was 4 (range 0-83) and amphetamine or methamphetamine were among the drugs identified in blood samples from 89% of cases (0-100%). CONCLUSION: The high prevalence of repeat DUID offending and/or use of illicit drugs among the drivers killed in road traffic crashes suggests that an early intervention and treatment for stimulant abuse might have been more beneficial than conventional punishments for such drug related crimes. PMID- 26003923 TI - The Chemical Biology of Molecular Chaperones--Implications for Modulation of Proteostasis. AB - Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein-folding landscape, which results in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation, and aberrant regulation of cell stress responses. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis. PMID- 26003927 TI - Stigma as a public health tool: Implications for health promotion and citizen involvement - A response to Bayer and Fairchild. PMID- 26003928 TI - Emerging patterns of crack use in Mexico City. AB - BACKGROUND: Recent studies in Mexico have documented a significant increase in crack cocaine use, indicating the potential for an emerging drug epidemic. METHODS: Ethnographic observations and interviews were used describe the profiles and patterns of use among street-recruited crack users in Mexico City. The data came from an international research collaboration funded by the National Institutes of Health. RESULTS: A polythetic typology was developed based on five dimensions central to categorizing patterns of crack use behavior: frequency of use, duration of use, context, social networks, and social contracts. Four types of users were discovered applying these dimensions: dabblers, stable users, crack heads, and old heads. Although several similarities were documented between patterns of crack use in Mexico and those in the United States and Western Europe, several key aspects distinguished crack users in this population: (1) self-regulated use; (2) non-linear progression of crack; and (3) the influence of the dimensions pertaining to setting, social networks, and social contract as contributing to understanding of the previous two. Further, we provide a discussion of how specific contextual factors in Mexico may be giving rise to these emerging patterns. CONCLUSION: Compared to the U.S. and Europe, this study finds that the majority of crack users were able to self-regulate their use without major disruption to daily social functioning. As crack use spreads in Mexico and other Latin American countries, we need to recognize the importance of social context in developing more tailored health and social responses that are specific to these developing countries. PMID- 26003929 TI - Alcohol and drug use by Spanish drivers: Comparison of two cross-sectional road side surveys (2008-9/2013). PMID- 26003930 TI - Current and recent drug use intensifies sexual and structural HIV risk outcomes among female sex workers in the Russian Federation. AB - BACKGROUND: Female sex workers (FSW) and people who inject drugs (PWID) are at high risk for HIV infection, with FSW-PWID at even greater risk. HIV-related research often focuses on the primary mode of transmission - sexual or parenteral transmission for FSW and PWID, respectively - with less known on how sex work and injection drug use (IDU) are collectively associated with the risk environment experienced by sex workers. We investigated this relationship among FSW in three Russian cities. METHODS: In 2011, FSWs (N=754) in Tomsk, Krasnoyarsk, and Kazan were recruited via respondent-driven sampling and completed a survey and rapid HIV screening. Multivariable models evaluated the role of injection history (classified as active: last 6 months, former: prior to last 6 months, and never) with a set of sexual and structural HIV risk outcomes. RESULTS: IDU was common: 11% actively injected drugs and 11% were former injectors. HIV infection was most prevalent among active injectors (AOR: 6.7; 95% CI: 2.4-18.9) and former injectors (AOR:4.5; 95%CI: 1.7-11.6), compared to non-injectors. Some 6-8% of non injecting FSWs reported recent physical or sexual client violence and 23% police extortion. Compared to these non-injectors, active injecting was associated with unprotected anal sex (AOR: 2.8, 95%CI: 1.2-6.4), client violence (AOR: 7.3, 95%CI: 2.1-24.7), and police extortion (AOR: 3.0 95%CI: 1.5-5.9%). Self-reported sexual and structural risk outcomes were also more prevalent among active compared to former injectors; however, few differences existed between former and non-injectors. CONCLUSIONS: FSW experience sexual, structural, and HIV risk outcomes and these risks are amplified for actively injecting FSWs. FSW who stopped injecting drugs demonstrated risk profiles closer to those of sex workers who had no history of injection. HIV prevention programs and outreach can provide opportunities to include harm reduction interventions and linkage to treatment for FSW to move FSWs towards lower risk environments. PMID- 26003931 TI - Clinical and functional outcome of assertive outreach for patients with schizophrenic disorder: Results of a quasi-experimental controlled trial. AB - BACKGROUND: The majority of studies support modern assertive health service models. However, the evidence is limited for parts of continental Europe, as well as for the pharmacological adherence outcome parameter. METHOD: We conducted a quasi-experimental controlled trial including adult patients with a schizophreniform disorder and a maximum of 60 points on the Global Assessment of Functioning Scale (GAF). Interventions (n=176) and controls (TAU, n=142) were assessed every six-month within one year in 17 study practices in rural areas. Mental and functional state were rated using the Brief Psychiatric Rating Scale (BPRS) and the GAF. Functional limitations and pharmacological adherence were patient-rated using the WHO-Disability Assessment Schedule II (WHODAS-II) and the Medication Adherence Report Scale (MARS). We computed multilevel mixed models. RESULTS: The GAF and BPRS of both groups improved significantly, yet the increase in the intervention group was significantly higher. In contrast, patient-rated variables - WHODAS-II and MARS - neither showed a stable temporal improvement nor a difference between groups. CONCLUSION: Our findings only partly support the investigated AO intervention, because of conflicting results between clinician- and patient-ratings. Accordingly, the benefits of AO need to be further evaluated. PMID- 26003932 TI - The genus Geobacillus and their biotechnological potential. AB - The genus Geobacillus comprises a group of Gram-positive thermophilic bacteria, including obligate aerobes, denitrifiers, and facultative anaerobes that can grow over a range of 45-75 degrees C. Originally classified as group five Bacillus spp., strains of Bacillus stearothermophilus came to prominence as contaminants of canned food and soon became the organism of choice for comparative studies of metabolism and enzymology between mesophiles and thermophiles. More recently, their catabolic versatility, particularly in the degradation of hemicellulose and starch, and rapid growth rates have raised their profile as organisms with potential for second-generation (lignocellulosic) biorefineries for biofuel or chemical production. The continued development of genetic tools to facilitate both fundamental investigation and metabolic engineering is now helping to realize this potential, for both metabolite production and optimized catabolism. In addition, this catabolic versatility provides a range of useful thermostable enzymes for industrial application. A number of genome-sequencing projects have been completed or are underway allowing comparative studies. These reveal a significant amount of genome rearrangement within the genus, the presence of large genomic islands encompassing all the hemicellulose utilization genes and a genomic island incorporating a set of long chain alkane monooxygenase genes. With G+C contents of 45-55%, thermostability appears to derive in part from the ability to synthesize protamine and spermine, which can condense DNA and raise its Tm. PMID- 26003933 TI - The Escherichia coli Acid Stress Response and Its Significance for Pathogenesis. AB - Escherichia coli has a remarkable ability to survive low pH and possesses a number of different genetic systems that enable it to do this. These may be expressed constitutively, typically in stationary phase, or induced by growth under a variety of conditions. The activities of these systems have been implicated in the ability of E. coli to pass the acidic barrier of the stomach and to become established in the gastrointestinal tract, something causing serious infections. However, much of the work characterizing these systems has been done on standard laboratory strains of E. coli and under conditions which do not closely resemble those found in the human gut. Here we review what is known about acid resistance in E. coli as a model laboratory organism and in the context of its lifestyle as an inhabitant-sometimes an unwelcome one-of the human gut. PMID- 26003934 TI - Challenges for the production of bioethanol from biomass using recombinant yeasts. AB - Lignocellulose biomass, one of the most abundant renewable resources on the planet, is an alternative sustainable energy source for the production of second generation biofuels. Energy in the form of simple or complex carbohydrates can be extracted from lignocellulose biomass and fermented by microorganisms to produce bioethanol. Despite 40 years of active and cutting-edge research invested into the development of technologies to produce bioethanol from lignocellulosic biomass, the process remains commercially unviable. This review describes the achievements that have been made in generating microorganisms capable of utilizing both simple and complex sugars from lignocellulose biomass and the fermentation of these sugars into ethanol. We also provide a discussion on the current "roadblocks" standing in the way of making second-generation bioethanol a commercially viable alternative to fossil fuels. PMID- 26003935 TI - Modulation of bacterial proliferation as a survival strategy. AB - The cell cycle is one of the most fundamental processes in biology, underlying the proliferation and growth of all living organisms. In bacteria, the cell cycle has been extensively studied since the 1950s. Most of this research has focused on cell cycle regulation in a few model bacteria, cultured under standard growth conditions. However in nature, bacteria are exposed to drastic environmental changes. Recent work shows that by modulating their own growth and proliferation bacteria can increase their survival under stressful conditions, including antibiotic treatment. Here, we review the mechanisms that allow bacteria to integrate environmental information into their cell cycle. In particular, we focus on mechanisms controlling DNA replication and cell division. We conclude this chapter by highlighting the importance of understanding bacterial cell cycle and growth control for future research as well as other disciplines. PMID- 26003936 TI - Cyparissins A and B, jatrophane diterpenes from Euphorbia cyparissias as Pgp inhibitors and cytotoxic agents against ovarian cancer cell lines. AB - From the whole plant of Euphorbia cyparissias, two new diterpenes based on jatrophane skeleton, named cyparissins A and B (1 and 2) were isolated. Their chemical structures were established through a combination of nuclear magnetic resonance spectroscopy and mass spectrometric methods. The new cyparissins A and B were tested to evaluate their ability to inhibit P-glycoprotein-mediated multidrug resistance and their cytotoxic activity against A2780 human ovarian cancer cells, both WT and ADR. Compounds 1 and 2 showed moderate inhibitory effects on P-glycoprotein while showing a significant concentration-depending cytotoxic activity for both cancer cell lines. These isolated compounds are based on a new chemical structure that expands the knowledge base for this class of bioactive metabolites. PMID- 26003937 TI - Changes in the gene expression of estrogen receptors involved in the protective effect of estrogen in rat's trumatic brain injury. AB - It has been demonstrated that estradiol has neuroprotective effects after traumatic brain injury (TBI) in female rats. Since estrogen receptors have an important role in estradiol effects at the cellular level and the exact mechanism(s) of estradiol-induced neuroprotection has not yet been fully clarified, the present study was designed to determine the changes in the levels of estrogen receptors mRNAs and proteins involved in this phenomenon. All experiments were carried out on female Wistar rats. The brain edema and blood brain-barrier (BBB) disruption were assessed. The TBI method was diffuse type and induced by the Marmarou method. Semiquantitative RT-PCR and immunoblotting were used to assess ERalpha and ERbeta gene expression. The data showed that the level of brain water content was significantly increased in TBI group. The increased water content was significantly attenuated in estradiol-treated (1mg/kg) TBI rats. Disruption of BBB after TBI was significantly inhibited just by estradiol treatment. Estrogen-treated animals showed a significant increase in ERalpha mRNA (18%) and protein (35%) levels in the brain tissue. Furthermore, in the brain injured rats the levels of ERbeta mRNA were lower than those in control rats. Following estrogen treatment, the protein levels of ERbeta were closed to those in control group. In conclusion, the data demonstrate that estrogen treatment can protect brain against traumatic brain injury. Estrogen treatment increases ER mRNA and protein levels which were coincident with its protective effects. It seems that such phenomenon participates in the induction of neuroprotective effects of estrogen. This article is part of a Special Issue entitled 1618. PMID- 26003938 TI - Automatic endpoint detection to support the systematic review process. AB - Preparing a systematic review can take hundreds of hours to complete, but the process of reconciling different results from multiple studies is the bedrock of evidence-based medicine. We introduce a two-step approach to automatically extract three facets - two entities (the agent and object) and the way in which the entities are compared (the endpoint) - from direct comparative sentences in full-text articles. The system does not require a user to predefine entities in advance and thus can be used in domains where entity recognition is difficult or unavailable. As with a systematic review, the tabular summary produced using the automatically extracted facets shows how experimental results differ between studies. Experiments were conducted using a collection of more than 2million sentences from three journals Diabetes, Carcinogenesis and Endocrinology and two machine learning algorithms, support vector machines (SVM) and a general linear model (GLM). F1 and accuracy measures for the SVM and GLM differed by only 0.01 across all three comparison facets in a randomly selected set of test sentences. The system achieved the best performance of 92% for objects, whereas the accuracy for both agent and endpoints was 73%. F1 scores were higher for objects (0.77) than for endpoints (0.51) or agents (0.47). A situated evaluation of Metformin, a drug to treat diabetes, showed system accuracy of 95%, 83% and 79% for the object, endpoint and agent respectively. The situated evaluation had higher F1 scores of 0.88, 0.64 and 0.62 for object, endpoint, and agent respectively. On average, only 5.31% of the sentences in a full-text article are direct comparisons, but the tabular summaries suggest that these sentences provide a rich source of currently underutilized information that can be used to accelerate the systematic review process and identify gaps where future research should be focused. PMID- 26003939 TI - Years of life lost and morbidity cases attributable to transportation noise and air pollution: A comparative health risk assessment for Switzerland in 2010. AB - BACKGROUND: There is growing evidence that chronic exposure to transportation related noise and air pollution affects human health. However, health burden to a country of these two pollutants have been rarely compared. AIMS: As an input for external cost quantification, we estimated the cardiorespiratory health burden from transportation related noise and air pollution in Switzerland, incorporating the most recent findings related to the health effects of noise. METHODS: Spatially resolved noise and air pollution models for the year 2010 were derived for road, rail and aircraft sources. Average day-evening-night sound level (Lden) and particulate matter (PM10) were selected as indicators, and population weighted exposures derived by transportation source. Cause-specific exposure response functions were derived from a meta-analysis for noise and literature review for PM10. Years of life lost (YLL) were calculated using life table methods; population attributable fraction was used for deriving attributable cases for hospitalisations, respiratory illnesses, visits to general practitioners and restricted activity days. RESULTS: The mean population weighted exposure above a threshold of 48dB(A) was 8.74dB(A), 1.89dB(A) and 0.37dB(A) for road, rail and aircraft noise. Corresponding mean exposure contributions were 4.4, 0.54, 0.12MUg/m(3) for PM10. We estimated that in 2010 in Switzerland transportation caused 6000 and 14,000 YLL from noise and air pollution exposure, respectively. While there were a total of 8700 cardiorespiratory hospital days attributed to air pollution exposure, estimated burden due to noise alone amounted to 22,500 hospital days. CONCLUSIONS: YLL due to transportation related pollution in Switzerland is dominated by air pollution from road traffic, whereas consequences for morbidity and indicators of quality of life are dominated by noise. In terms of total external costs the burden of noise equals that of air pollution. PMID- 26003940 TI - Noise and somatic symptoms: A role for personality traits? AB - OBJECTIVES: We investigated the role of a stress-sensitive personality on relations between noise, noise annoyance and somatic symptom reporting. First, we investigated the cross-sectional association of road traffic noise exposure and somatic symptoms, and its modification by hostility and vulnerability to stress. Second, we investigated the cross-sectional association of noise annoyance from eight sources (e.g. road traffic, aircraft, neighbours) and somatic symptoms, and it's confounding by hostility and vulnerability to stress. METHODS: Data were obtained from LifeLines, a general population cohort from the Netherlands. Road traffic noise was estimated using the Common Noise Assessment Methods in Europe (CNOSSOS-EU) noise model. Noise annoyance, hostility, vulnerability to stress, and somatic symptoms were assessed with validated questionnaires. RESULTS: Poisson regression models adjusted for demographic and socioeconomic variables indicated no association of noise exposure and somatic symptoms (incidence rate ratio (IRR) 1.001; 95% confidence interval (CI) 1.000-1.001; n=56,937). Interactions of noise exposure and hostility and vulnerability to stress were not statistically significant. Small positive associations were found for noise annoyance from each of the eight sources and somatic symptoms, when adjusted for demographic and socioeconomic variables (e.g. for road traffic noise annoyance IRR 1.014, 95% CI 1.011-1.018; n=6177). Additional adjustment for hostility and vulnerability to stress resulted in small decreases of the IRRs for noise annoyance from each of the eight sources, but the associations remained statistically significant. CONCLUSIONS: Personality facets hostility and vulnerability to stress did not modify the relation between road traffic noise exposure and somatic symptom reporting, or confound relations between noise annoyance and symptoms. PMID- 26003941 TI - Foldase and inhibitor functionalities of the pepsinogen prosegment are encoded within discrete segments of the 44 residue domain. AB - Pepsin is initially produced as the zymogen pepsinogen, containing a 44 residue prosegment (PS) domain. When folded without the PS, pepsin forms a thermodynamically stable denatured state (refolded pepsin, Rp). To guide native folding, the PS binds to Rp, stabilizes the folding transition state, and binds tightly to native pepsin (Np), thereby driving the folding equilibrium to favor the native state. It is unknown whether these functionalities of the PS are encoded within the entire sequence or within discrete segments. PS residues 1p 29p correspond to a highly conserved region in pepsin-like aspartic proteases and we hypothesized that this segment is critical to PS-catalyzed folding. This notion was tested in the present study by characterizing the ability of various truncated PS peptides to bind Rp, catalyze folding from Rp to Np, and to inhibit Np. Four PS truncations were examined, corresponding to PS residues 1p-16p (PS1 16), 1p-29p (PS1-29), 17p-44p (PS17-44) and 30p-44p (PS30-44). The three PS functionalities could be ascribed primarily to discrete regions within the highly conserved motif: 1p-16p dictated Rp binding, 17p-29p dictated Np binding/inhibition, while the entire 1p-29p dictated transition state binding/catalyzing folding. Conversely, PS30-44 played no obvious role in PS catalyzed folding; it is hypothesized that this more variable region may serve as a linker between PS1-29 and the mature domain. The high sequence conservation of PS1-29 and its role in catalyzing pepsin folding strongly suggest that there is a conserved PS-catalyzed folding mechanism shared by pepsin-like aspartic proteases with this motif. PMID- 26003942 TI - Chronic variable stress exposure in male Wistar rats affects the first step of olfactory detection. AB - For most animal species, olfaction plays a paramount role in their perception of the environment. Odours are initially detected in neurons located in the olfactory mucosa. This tissue is regulated by several physiological signals and can be altered in pathology. A number of clinical studies suggest an association between depressive disorders and olfactory sensory loss. In rodents, depressive like states can be observed in models of chronic stress. We tested the hypothesis that olfactory function might be altered in a rat model of depression, induced by chronic variable stress (CVS). While CVS rats exhibited several symptoms consistent with chronic stress exposure and depressive-like states (increased sucrose intake in sucrose preference test, increased immobility in forced swim test, hyperlocomotion), their odorant responses recorded at the olfactory mucosa level by electro-olfactogram were decreased. In addition we observed increased apoptosis markers in the olfactory mucosa using Western Blot. Our data are consistent with reduced olfactory capacities in a laboratory rat model of chronic stress and depression, in agreement with human clinical data; this warrants further mechanistic studies. Furthermore, this works raises the possibility that altered olfactory function might be a confounding factor in the behavioural testing of chronically stressed or depressed rats. PMID- 26003943 TI - Pavlovian conditioning to food reward as a function of eating disorder risk. AB - The aim of this experiment was to examine the extent to which eating disorder risk affects the strength of food-reward conditioning. Eighty food-restricted undergraduates were placed into a VR environment consisting of two visually distinct rooms. Participants underwent multiple pairing sessions in which they were confined into one of the two rooms and explored a VR environment. Room A was paired with real-life M&Ms for three sessions, and Room B was paired with no food for three sessions. After a short delay, a test session was administered, and participants were given free access to the entire VR environment for 5 min. Participants also completed the Eating Attitudes Test (EAT-26; [11]), which is a standard screening tool of eating disorder risk. Participants displayed a significant conditioned place preference for the VR room previously paired with food, and they displayed a significant explicit preference for the M&M-paired room in a forced-choice test. There was a significant positive correlation between place preference strength and scores on the dieting subscale of the EAT 26. Additionally, ratings of the no-food room were significantly lower as dieting scores increased. This suggests that components of eating disorder risk can influence basic conditioning strength to places associated with food reward. For both males and females, additional correlations between eating disorder risk subscales and conditioning variables are discussed, and implications for future research are proposed in hopes of understanding how conditioning paradigms can provide insight into treating and preventing eating disorders. PMID- 26003944 TI - Positive and negative emotional contexts unevenly predict episodic memory. AB - The aim of this study was to investigate whether the recognition of faces with neutral expressions differs when they are encoded under different emotional contexts (positive, negative or non-emotional). The effects of the emotional valence context on the subsequent memory effect (SME) and the autonomic responses were also examined. Twenty-eight participants performed a betting-game task in which the faces of their virtual opponents were presented in each trial. The probability of winning or losing was manipulated to generate positive or negative contexts, respectively. Additionally, the participants performed the same task without betting as a non-emotional condition. After the encoding phase, an old/new paradigm was performed for the faces of the virtual opponents. The recognition was superior for the faces encoded in the positive contexts than for the faces encoded in the non-emotional contexts. The skin conductance response amplitude was equivalent for both of the emotional contexts. The N170 and P300 components at occipital sites and the frontal slow wave manifested SMEs that were modulated by positive contexts; neither negative nor non-emotional contexts influenced these effects. The behavioral and neurophysiological data demonstrated that positive contexts are stronger predictors of episodic memory than negative or non-emotional contexts. PMID- 26003945 TI - Absence of rapid eye movements during sleep in adult zebrafish. AB - Sleep is not a uniform phenomenon, but is organized in alternating, fundamentally different states, rapid eye movement sleep and non-rapid eye movement sleep. Zebrafish (Danio rerio) have recently emerged as an excellent model for sleep research. Zebrafish are well characterized in terms of development, neurobiology and genetics. Moreover, there are many experimental tools not easily applied in mammalian models that can be readily applied to zebrafish, making them a valuable additional animal model for sleep research. Sleep in zebrafish is defined behaviorally and exhibits the hallmarks of mammalian sleep (e.g. sleep homeostasis and pressure). To our knowledge no attempts have been made to discern if sleep in zebrafish entails alternations of REM-NREM sleep cycles which are critical for further development of the model. In the current experiment we quantify two key REM sleep components, rapid eye movements and respiratory rates, across sleep-wake cycles. We find no sleep-related rapid eye movements. During sleep respiratory rates, however, are reduced and become less regular, further establishing that the behavioral definition used truly captures a change in the fish's physiology. We thus fail to find evidence for REM-NREM sleep cycles in zebrafish but demonstrate a physiological change that occurs concomitantly with the previously defined behavioral state of sleep. We do not rule out that other phasic REM components (e.g. atonia, cardiac arrhythmias, myoclonic twitches or desynchronized EEG) are coherently expressed during sleep but we conclude that adult zebrafish do not have REM-sleep-related rapid eye movements. PMID- 26003946 TI - A therapeutic combination of metyrapone and oxazepam increases brain levels of GABA-active neurosteroids and decreases cocaine self-administration in male rats. AB - In rodents, the behavioral and neurochemical effects resulting from the pharmacological blockade of the hypothalamo-pituitary-adrenal (HPA) axis are unclear. Metyrapone, a corticosterone synthesis inhibitor, has been demonstrated to reduce cocaine-related behaviors, especially in a low-dose combination with oxazepam, a benzodiazepine. Although this combination therapy (MET/OX) also reduces drug-taking and drug-seeking behaviors in both rodents and cocaine dependent humans, these effects are not correlated with plasma glucocorticoid levels. In this brief report, we present data demonstrating that this MET/OX combination enhances brain levels of the GABA-active steroid metabolites, tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone. Male rats, trained to self-administer cocaine or that received yoked-saline infusions, were pretreated with MET/OX, at doses that reduced cocaine-motivated responding, or vehicle. Allopregnanolone and THDOC were measured using liquid chromatography-mass spectroscopy (LC-MS/MS) in the prefrontal cortex and amygdala in the brains from these rats. THDOC levels were enhanced following MET/OX pretreatment in both brain regions, regardless of cocaine self-administration experience. However, allopregnanolone was selectively enhanced in the rats that self-administered cocaine, but not in rats in the yoked-saline group. Thus, the MET/OX combination increased neurosteroid content in brain regions important for drug addiction. These neurosteroids have been shown to reduce cocaine-related behaviors and may contribute to the behavioral effects of MET/OX combination therapy. PMID- 26003947 TI - Is long-term physical activity safe for older adults with knee pain?: a systematic review. AB - OBJECTIVE: To determine whether long-term physical activity is safe for older adults with knee pain. DESIGN: A comprehensive systematic review and narrative synthesis of existing literature was conducted using multiple electronic databases from inception until May 2013. Two reviewers independently screened, checked data extraction and carried out quality assessment. Inclusion criteria for study designs were randomised controlled trials (RCTs), prospective cohort studies or case control studies, which included adults of mean age over 45 years old with knee pain or osteoarthritis (OA), undertaking physical activity over at least 3 months and which measured a safety related outcome (adverse events, pain, physical functioning, structural OA imaging progression or progression to total knee replacement (TKR)). RESULTS: Of the 8614 unique references identified, 49 studies were included in the review, comprising 48 RCTs and one case control study. RCTs varied in quality and included an array of low impact therapeutic exercise interventions of varying cardiovascular intensity. There was no evidence of serious adverse events, increases in pain, decreases in physical function, progression of structural OA on imaging or increased TKR at group level. The case control study concluded that increasing levels of regular physical activity was associated with lower risk of progression to TKR. CONCLUSIONS: Long-term therapeutic exercise lasting 3 to 30 months is safe for most older adults with knee pain. This evidence supports current clinical guideline recommendations. However, most studies investigated selected, consenting older adults carrying out low impact therapeutic exercise which may affect result generalizability. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2014:CRD42014006913. PMID- 26003948 TI - Validity and sensitivity to change of three scales for the radiographic assessment of knee osteoarthritis using images from the Multicenter Osteoarthritis Study (MOST). AB - OBJECTIVES: The purpose of this study was to assess the concurrent validity and sensitivity to change of three knee osteoarthritis (OA) grading scales. The Kellgren-Lawrence (KL) and the Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) grading scales are well-established. The third scale, the compartmental grading scale for OA (CG) is a novel scale which grades JSN, femoral osteophytes, tibial erosion and subluxation to create a total score. METHODS: One sample of 72 posteroanterior (PA) fixed-flexion radiographs displaying mild to moderate knee OA was selected from the Multicenter Osteoarthritis Study (MOST) to study validity. A second sample of 75 radiograph pairs, which showed an increase in OA severity over 30 months, was selected to study sensitivity to change. The three radiographic grading scales were applied to each radiograph in both samples. Spearman's rank correlation coefficients were used to correlate the radiographic grades and the change in grades over 30 months with a Whole-organ Magnetic Resonance Imaging Score (WORMS)-based composite score which included five articular features of knee OA. RESULTS: Correlations between the KL, OARSI JSN and CG grading scales and the magnetic resonance image (MRI) based score were 0.836, 0.840 and 0.773 (P < 0.0001) respectively while correlations between change in the radiographic grading scales and change in the MRI-based score were 0.501, 0.525 and 0.492 (P < 0.0001). CONCLUSIONS: All three radiographic grading scales showed high validity and are suitable to assess knee OA severity. They showed moderate sensitivity to change; therefore caution should be taken when using ordinal radiographic grading scales to monitor knee OA over time. PMID- 26003949 TI - ADAMTS-4 activity in synovial fluid as a biomarker of inflammation and effusion. AB - OBJECTIVE: To evaluate the potential of ADAMTS-4 (aggrecanase -1) activity in synovial fluid (SF) as a biomarker of knee injury and joint disease. DESIGN: We have measured ADAMTS-4 activity in the synovial fluid of 170 orthopaedic patients with different degrees of joint pathology, using a commercial ADAMTS-4 fluorescence resonance energy transfer (FRET) substrate assay. Patients were classified at arthroscopy as (i) macroscopically normal, (ii) with an injury of the meniscus, anterior cruciate ligament or chondral/osteochondral defects or (iii) with osteoarthritis, and the influence of independent factors (age, patient group, effusion and synovial inflammation) on ADAMTS-4 activity levels was assessed. RESULTS: In most patients (106/170) ADAMTS-4 activity was undetectable; ADAMTS-4 ranged from 0 to 2.8 ng/mL in synovial fluid from patients with an injury, 0-4.1 ng/mL in osteoarthritic patients and 4.0-12.3 ng/mL in patients with large effusions. Four independent variables each significantly influenced ADAMTS-4 activity in synovial fluid (all P < 0.001): age (concordance = 0.69), presence of osteoarthritis (OA) (concordance = 0.66), level of effusion (concordance = 0.78) and inflammation (concordance = 0.68). Not only did effusion influence the amount of ADAMTS-4 activity most strongly, but it also did this in an ordered manner (P < 0.001). CONCLUSIONS: The main finding of this study is that ADAMTS-4 levels in synovial fluid are most strongly correlated with inflammation and severity of effusion in the knee. Further study is required to determine if it could provide a useful tool to aid clinical diagnoses, indicate treatment, to monitor progression of joint degeneration or OA or alternatively the success of treatment. PMID- 26003952 TI - Insecticide resistance in vector Chagas disease: evolution, mechanisms and management. AB - Chagas disease is a chronic parasitic infection restricted to America. The disease is caused by the protozoa Trypanosoma cruzi, which is transmitted to human through the feces of infected triatomine insects. Because no treatment is available for the chronic forms of the disease, vector chemical control represents the best way to reduce the incidence of the disease. Chemical control has been based principally on spraying dwellings with insecticide formulations and led to the reduction of triatomine distribution and consequent interruption of disease transmission in several areas from endemic region. However, in the last decade it has been repeatedly reported the presence triatomnes, mainly Triatoma infestans, after spraying with pyrethroid insecticides, which was associated to evolution to insecticide resistance. In this paper the evolution of insecticide resistance in triatomines is reviewed. The insecticide resistance was detected in 1970s in Rhodnius prolixus and 1990s in R. prolixus and T. infestans, but not until the 2000s resistance to pyrthroids in T. infestans associated to control failures was described in Argentina and Bolivia. The main resistance mechanisms (i.e. enhanced metabolism, altered site of action and reduced penetration) were described in the T. infestans resistant to pyrethrods. Different resistant profiles were demonstrated suggesting independent origin of the different resistant foci of Argentina and Bolivia. The deltamethrin resistance in T. infestans was showed to be controlled by semi-dominant, autosomally inherited factors. Reproductive and developmental costs were also demonstrated for the resistant T. infestans. A discussion about resistance and tolerance concepts and the persistence of T. infestans in Gran Chaco region are presented. In addition, theoretical concepts related to toxicological, evolutionary and ecological aspects of insecticide resistance are discussed in order to understand the particular scenario of pyrethroid resistance in triatomines. PMID- 26003950 TI - Non-invasive mouse models of post-traumatic osteoarthritis. AB - Animal models of osteoarthritis (OA) are essential tools for investigating the development of the disease on a more rapid timeline than human OA. Mice are particularly useful due to the plethora of genetically modified or inbred mouse strains available. The majority of available mouse models of OA use a joint injury or other acute insult to initiate joint degeneration, representing post traumatic osteoarthritis (PTOA). However, no consensus exists on which injury methods are most translatable to human OA. Currently, surgical injury methods are most commonly used for studies of OA in mice; however, these methods may have confounding effects due to the surgical/invasive injury procedure itself, rather than the targeted joint injury. Non-invasive injury methods avoid this complication by mechanically inducing a joint injury externally, without breaking the skin or disrupting the joint. In this regard, non-invasive injury models may be crucial for investigating early adaptive processes initiated at the time of injury, and may be more representative of human OA in which injury is induced mechanically. A small number of non-invasive mouse models of PTOA have been described within the last few years, including intra-articular fracture of tibial subchondral bone, cyclic tibial compression loading of articular cartilage, and anterior cruciate ligament (ACL) rupture via tibial compression overload. This review describes the methods used to induce joint injury in each of these non invasive models, and presents the findings of studies utilizing these models. Altogether, these non-invasive mouse models represent a unique and important spectrum of animal models for studying different aspects of PTOA. PMID- 26003951 TI - Determining collagen distribution in articular cartilage using contrast-enhanced micro-computed tomography. AB - OBJECTIVE: Collagen distribution within articular cartilage (AC) is typically evaluated from histological sections, e.g., using collagen staining and light microscopy (LM). Unfortunately, all techniques based on histological sections are time-consuming, destructive, and without extraordinary effort, limited to two dimensions. This study investigates whether phosphotungstic acid (PTA) and phosphomolybdic acid (PMA), two collagen-specific markers and X-ray absorbers, could (1) produce contrast for AC X-ray imaging or (2) be used to detect collagen distribution within AC. METHOD: We labeled equine AC samples with PTA or PMA and imaged them with micro-computed tomography (micro-CT) at pre-defined time points 0, 18, 36, 54, 72, 90, 180, 270 h during staining. The micro-CT image intensity was compared with collagen distributions obtained with a reference technique, i.e., Fourier-transform infrared imaging (FTIRI). The labeling time and contrast agent producing highest association (Pearson correlation, Bland-Altman analysis) between FTIRI collagen distribution and micro-CT -determined PTA distribution was selected for human AC. RESULTS: Both, PTA and PMA labeling permitted visualization of AC features using micro-CT in non-calcified cartilage. After labeling the samples for 36 h in PTA, the spatial distribution of X-ray attenuation correlated highly with the collagen distribution determined by FTIRI in both equine (mean +/- S.D. of the Pearson correlation coefficients, r = 0.96 +/- 0.03, n = 12) and human AC (r = 0.82 +/- 0.15, n = 4). CONCLUSIONS: PTA induced X-ray attenuation is a potential marker for non-destructive detection of AC collagen distributions in 3D. This approach opens new possibilities in development of non-destructive 3D histopathological techniques for characterization of OA. PMID- 26003953 TI - Subtle changes in bone mineralization density distribution in most severely affected patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with low aBMD as measured by DXA and altered microstructure as assessed by bone histomorphometry and microcomputed tomography. Knowledge of bone matrix mineralization is lacking in COPD. Using quantitative backscatter electron imaging (qBEI), we assessed cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) in 19 postmenopausal women (62.1 +/- 7.3 years of age) with COPD. Eight had sustained fragility fractures, and 13 had received treatment with inhaled glucocorticoids. The BMDD outcomes from the patients were compared with healthy reference data and were correlated with previous clinical and histomorphometric findings. In general, the BMDD outcomes for the patients were not significantly different from the reference data. Neither the subgroups of with or without fragility fractures or of who did or did not receive inhaled glucocorticoid treatment, showed differences in BMDD. However, subgroup comparison according to severity revealed 10% decreased cancellous mineralization heterogeneity (Cn.CaWidth) for the most severely affected compared with less affected patients (p=0.042) and compared with healthy premenopausal controls (p=0.021). BMDD parameters were highly correlated with histomorphometric cancellous bone volume (BV/TV) and formation indices: mean degree of mineralization (Cn.CaMean) versus BV/TV (r=0.58, p=0.009), and Cn.CaMean and Ct.CaMean versus bone formation rate (BFR/BS) (r=-0.71, p<0.001). In particular, those with lower BV/TV (<50th percentile) had significantly lower Cn.CaMean (p=0.037) and higher Cn.CaLow (p=0.020) compared with those with higher (>50th percentile) BV/TV. The normality in most of the BMDD parameters and bone formation rates as well as the significant correlations between them suggests unaffected mineralization processes in COPD. Our findings also indicate no significant negative effect of treatment with inhaled glucocorticoids on the bone mineralization pattern. However, the observed concomitant occurrence of relatively lower bone volumes with lower bone matrix mineralization will both contribute to the reduced aBMD in some patients with COPD. PMID- 26003955 TI - The human cytomegalovirus non-coding Beta2.7 RNA as a novel therapeutic for Parkinson's disease--Translational research with no translation. AB - Human cytomegalovirus (HCMV) encodes abundant numbers of microRNAs (miRNAs) and other non-coding RNAs (ncRNAs) whose functions are presently under intense investigation. In this chapter, we discuss the function of one of the more well characterised virus-encoded ncRNAs, derived from the viral major early gene (Beta2.7). This RNA plays an anti-apoptotic role during infection by directly interacting with mitochondrial complex I to help maintain high levels of ATP production and by preventing the stress induced re-localisation of retinoid/interferon-induced mortality-19 protein, GRIM-19. We then go on to describe how an 800 nucleotide sub-domain of the Beta2.7 transcript, p137, has been exploited in the development of a novel therapeutic for the treatment of Parkinson's disease. PMID- 26003954 TI - Isolation and propagation of a Spiroplasma sp. from Slovakian Ixodes ricinus ticks in Ixodes spp. cell lines. AB - Ixodes spp. ticks are known to occasionally harbour spiroplasmas - helical mycoplasmas in the class Mollicutes; a previous study in Slovakia reported an overall prevalence of Spiroplasma ixodetis of 3% in Ixodes ricinus. In the present study, extracts of unfed adult I. ricinus ticks collected from vegetation in south-western Slovakia were added to a panel of cell lines derived from I. ricinus and Ixodes scapularis embryos. The cultures were monitored by preparation and examination of Giemsa-stained cytocentrifuge smears at intervals over the subsequent 16-18 months. Spiroplasma-like microorganisms were detected in cultures of both tick species after 2-3 months and subcultured onto fresh, uninfected cells of the appropriate cell line up to seven times. Molecular analysis using PCR assays targeting fragments of the 16S rRNA, ITS and rpoB genes confirmed the identity of the microorganisms as a Spiroplasma sp., with between 98.9% and 99.5% similarity to S. ixodetis. The sequences of the spiroplasmas isolated from three different pools of ticks collected on two different occasions were identical for all three genes tested. PMID- 26003956 TI - Oki stenting for anastomotic bronchomalacia in lung transplantation. AB - Anastomotic airway complications are a frequent cause of disease in lung transplantation. However, there is no consensus on the type of treatment to be performed with prosthetic devices. While some recent gadgets such as the Oki stent have been proposed for main right bronchus stenosis, there are no reports of stenting using this prosthesis in cases where the main complication is malacia rather than stenosis. We present 2 patients diagnosed with main right bronchus bronchomalacia, also involving bronchius intermedius. After several attempts to bypass the anastomosis employing different types of stent, including a T-tube Montgomery device, normal sputum drainage was not possible. Oki stenting was performed without complications, with a remarkable reduction in endoscopic procedures as well as important functional improvement. For both stenosis and bronchomalacia in lung transplantation, we propose Oki stenting as the first choice of treatment. PMID- 26003957 TI - North American trial results at 1 year with the Sorin Freedom SOLO pericardial aortic valve. AB - OBJECTIVES: A North American prospective, 15-centre Food and Drug Administration (FDA) valve trial was designed to assess the safety and effectiveness of the Freedom SOLO stentless pericardial aortic valve in the treatment of surgical aortic valve disease. METHODS: Beginning in 2010, 251 patients (mean: 74.7 +/- 7.5 years), were recruited in the Freedom SOLO aortic valve trial. One hundred eighty-nine patients have been followed for at least 1 year and are the basis for this review. Preoperatively, 54% of patients had NYHA functional class III or IV symptoms, and the majority of patients had a normal ejection fraction (EF) (median EF = 61%). Concomitant procedures were performed in 61.9% of patients, with coronary artery bypass grafting (CABG) (48.7%) being the most common followed by a MAZE procedure (13.7%). Reoperations were performed in 8.5% of patients in the study. RESULTS: The entire cohort of 251 patients enrolled had 7 deaths prior to 30 days, 2 of which were valve-related (aspiration pneumonia and sudden death) and 5 were not valve-related. There were 11 deaths after 30 days, 1 valve-related (unknown cardiac death) and 10 not valve-related. Five valves were explanted, 3 early (endocarditis, acute insufficiency and possible root dissection) and 2 late (endocarditis). Thirty-day adverse events include arrhythmias requiring permanent pacemaker (4.2%), thromboembolic events (3.7%) and thrombocytopenia (7.4%). One-year follow-up of all 189 patients demonstrated mean gradients for valve sizes 19, 21, 23, 25 and 27 mm of 11.7, 7.8, 6.3, 4.6 and 5.0 mmHg, respectively. Effective orifice areas for the same valve sizes were 1.2, 1.3, 1.6, 1.8 and 1.9 cm(2), respectively. Ninety-six percent of patients (181/189) were in NYHA class I or II at the 1-year follow-up. CONCLUSIONS: The Freedom SOLO stentless pericardial aortic valve demonstrated excellent haemodynamics and a good safety profile out to the 1 year of follow-up. PMID- 26003958 TI - Coronary artery bypass surgery without cardioplegia: hospital results in 8515 patients?. AB - OBJECTIVES: Cardioplegic myocardial protection is used in most cardiac surgical procedures. However, other alternatives have proved useful. We analysed the perioperative results in a large series of patients undergoing coronary artery bypass (CABG) using cardiopulmonary bypass (CPB) and non-cardioplegic methods. METHODS: From January 1992 to October 2013, 8515 consecutive patients underwent isolated CABG with CPB without cardioplegia, under hypothermic ventricular fibrillation and/or an empty beating heart. The mean age was 61.9 +/- 9.5 years, 12.4% were women, 26.3% diabetic, 64% hypertensive; and 9.6% had peripheral vascular disease, 7.8% cerebrovascular disease and 54.3% previous acute myocardial infarction (AMI). One-third of patients were in Canadian Cardiovascular Society Class III/IV. Three-vessel disease was present in 76.5% of the cases and 10.9% had moderate/severe left ventricle (LV) dysfunction (ejection fraction <40%). A multivariate analysis was made of risk factors associated to in hospital mortality and three major morbidity complications [cerebrovascular accident, mediastinitis and acute kidney injury (AKI)], as well as for prolonged hospital stay. RESULTS: The mean CPB time was 58.2 +/- 20.7 min. The mean number of grafts per patient was 2.7 +/- 0.8 (arterial: 1.2 +/- 0.5). The left internal thoracic artery (ITA) was used in 99.4% of patients and both ITAs in 23.1%. The in-hospital mortality rate was 0.7% (61 patients), inotropic support was required in 6.6% and mechanical support in 0.8, and 2.0% were re-explored for bleeding and 1.3% for sternal complications (mediastinitis, 0.8%). AKI, the majority transient, occurred in 1595 patients (18.9%). The incidence rates of stroke/transient ischemic attack (TIA) and acute myocardial infarction (AMI) were 2.6 and 2.5%, respectively, and atrial fibrillation/flutter occurred in 22.6% of cases. Age, LV dysfunction, non-elective surgery, previous cardiac surgery, peripheral vascular disease and CPB time were independent risk factors for mortality and major morbidity. The mean hospital stay was 7.2 +/- 5.7 days. CONCLUSIONS: Isolated CABG with CPB using non-cardioplegic methods proved very safe, with low mortality and morbidity. These methods are simple and expeditious and remain as very useful alternative techniques of myocardial preservation. PMID- 26003959 TI - Direct reperfusion of the right common carotid artery prior to cardiopulmonary bypass in patients with brain malperfusion complicated with acute aortic dissection. AB - The cases of 3 patients with brain malperfusion secondary to acute aortic dissection who underwent preoperative perfusion of the right common carotid artery are presented. The patients were 64, 65 and 72 years old and 2 were female. All were in a comatose or semi-comatose state with left hemiplegia. The right common carotid artery was exposed and directly cannulated, using a 12-Fr paediatric arterial cannula. The right common femoral artery was chosen for arterial drainage, using a 14-Fr double-lumen cannula. The circuit contained a small roller pump and heat exchanger coil. Target flow was set at 90 ml/min and blood temperature at 30 degrees C. Durations of right carotid perfusion were 120, 100 and 45 min, respectively. All underwent partial arch replacement and survived. Postoperative neurological sequelae were minimal in all cases. PMID- 26003960 TI - The effects of using a radial artery in patients already receiving bilateral internal mammary arteries during coronary bypass grafting: 30-day outcomes and 14 year survival in a propensity-matched cohort. AB - OBJECTIVES: Recent studies have demonstrated the superiority of bilateral internal mammary arteries (BIMAs) as conduit material for coronary artery bypass grafting (CABG) surgery. However, there is limited research on the effects of other graft conduits used in patients who require additional bypasses. The goal of this study was to evaluate the impact of the radial artery (RA) when used in conjunction with the BIMAs. METHODS: From the beginning of 2000 to the end of 2013, 4370 patients underwent CABG for three or more vessels at our institution. There were 568 and 183 patients who received BIMA + saphenous vein graft (SVG) and BIMA + radial +/- SVG, respectively. Propensity matching was used to create a balanced cohort from these patients, which resulted in two groups of 183 patients. Thirty-day outcomes and long-term survival were compared between the two groups. Long-term follow-up was generated using the Social Security Death Index. RESULTS: There were no significant differences in preoperative characteristics. For 30-day outcomes, the BIMA + radial +/- SVG group had more postoperative atrial fibrillation (24.6 vs 12.0%; P = 0.001) and a longer median postoperative length of stay (6 vs 5 days; interquartile range = 2; P = 0.016) than BIMA + SVG patients. There was no significant difference in long-term survival between the two groups over the 14-year period. However, before year 10, the BIMA + SVG group had a trend towards higher survival, whereas on follow-up after 10 years, there was a trend that favoured the BIMA + radial +/- SVG patients. Cox regression analysis using a time-dependent covariate demonstrated that when the groups were split at 10 years, there was a statistically significant improvement in survival of the BIMA + radial +/- SVG group [adjusted hazard ratio 0.254 95% confidence interval (CI) 0.062-0.977; P = 0.048] over BIMA + SVG patients between 10 and 14 years. CONCLUSIONS: Overall, there were no statistically significant differences in survival between the BIMA + SVG and BIMA + radial +/- SVG groups over the 14 years. However, further analysis demonstrated that while the BIMA + radial +/- SVG group had a trend towards decreased survival before 10 years, use of the RA in conjunction with BIMAs was associated with significantly increased survival in the later years. A larger cohort of patients with longer follow-up is needed to assess the outcomes of CABG using BIMA + radial +/- SVG. PMID- 26003961 TI - Thoracoscopic surgical ablation versus catheter ablation for atrial fibrillation. AB - For patients with atrial fibrillation (AF) who are refractory to anti-arrhythmic drugs (AADs), minimally invasive video-assisted thoracoscopic surgical ablation (SA) and catheter ablation (CA) are potential alternative treatment options. The recent FAST randomized study suggested that thoracoscopic SA was superior to CA in achieving freedom of AF in patients who have failed at least one prior AAD. To assess the relative merits and risks of SA versus CA, a systematic review and meta-analysis was conducted. Electronic searches were performed using six databases from their inception to December 2014. Relevant studies comparing thoracoscopic SA and CA were identified; data were extracted and analysed according to predefined clinical endpoints. Relative risk (RR) and weighted mean difference were used as summary statistics. Freedom from AF/arrhythmias was significantly higher in SA versus CA at 12-month off-AAD (78.4 vs 53%; RR, 1.54; P < 0.0001) and on-AAD (82.6 vs 45.7%; RR, 1.85; P < 0.00001). This difference was maintained in paroxysmal and persistent AF subgroups. The SA cohort had a significantly lower requirement for repeat ablations compared with the CA cohort (4.7 vs 24.4%; RR, 0.21; P = 0.0001). However, major complications were significantly higher in the SA group (28.2 vs 7.8%; RR, 3.30; P = 0.0003), driven by pleural effusion and pneumothorax. SA may be more efficacious than CA treatment in a selected patient population with refractory AF and prior failed catheter intervention. Improved freedom from arrhythmias at up to 12-month follow up is counterbalanced by higher procedural complication rates. PMID- 26003962 TI - Revised medical criteria for evaluating cancer (malignant neoplastic diseases). Final rule. AB - We are revising the criteria in parts A and B of the Listing of Impairments (listings) that we use to evaluate claims involving cancer (malignant neoplastic diseases) under titles II and XVI of the Social Security Act (Act). These revisions reflect our adjudicative experience, advances in medical knowledge, recommendations from medical experts we consulted, and public comments we received in response to a Notice of Proposed Rulemaking (NPRM). PMID- 26003963 TI - Response from Kelly and Flint. PMID- 26003964 TI - James (Jim) Escott Church. PMID- 26003965 TI - Medicare and Medicaid programs: revisions to deeming authority survey, certification, and enforcement procedures. Final rule. AB - This final rule revises the survey, certification, and enforcement procedures related to CMS oversight of national accrediting organizations (AOs). The revisions implement certain provisions under the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA). The revisions also clarify and strengthen our oversight of AOs that apply for, and are granted, recognition and approval of an accreditation program in accordance with the statute. The rule also extends some provisions, which are applicable to Medicare-participating providers, to Medicare-participating suppliers subject to certification requirements, and clarifies the definition of "immediate jeopardy." PMID- 26003966 TI - Requirements for blood and blood components intended for transfusion or for further manufacturing use. Final rule. AB - The Food and Drug Administration (FDA) is amending the regulations applicable to blood and blood components, including Source Plasma, to make the donor eligibility and testing requirements more consistent with current practices in the blood industry, to more closely align the regulations with current FDA recommendations, and to provide flexibility to accommodate advancing technology. In order to better assure the safety of the nation's blood supply and to help protect donor health, FDA is revising the requirements for blood establishments to test donors for infectious disease, and to determine that donors are eligible to donate and that donations are suitable for transfusion or further manufacture. FDA is also requiring establishments to evaluate donors for factors that may adversely affect the safety, purity, and potency of blood and blood components or the health of a donor during the donation process. Accordingly, these regulations establish requirements for donor education, donor history, and donor testing. These regulations also implement a flexible framework to help both FDA and industry to more effectively respond to new or emerging infectious agents that may affect blood product safety. PMID- 26003967 TI - [Exudative otitis media in the childhood]. AB - This review article was designed to systematize the literature data concerning etiology, pathogenesis, diagnostics and treatment of exudative otitis media (EOM) in the children. The review is focused on the prevailing current tendencies in the approaches to the problems of etiology, diagnostics, and treatment of EOM in the children as exemplified by the publications in the foreign and Russian speaking literature. The special emphasis is laid on the description of the therapeutic and surgical methods for the management of EOM. PMID- 26003968 TI - [Prospects for the application of bacteriophages in otorhinolaryngology]. AB - The objective of the present work was to summarize the available literature data concerning the importance of and prospects for for the application of bacteriophages for the treatment of the most common diseases of the upper respiratory tract and the ear. PMID- 26003969 TI - [Surgeon and noblesse]. PMID- 26003970 TI - Conference reenergizes focus on engaging the younger generation of perioperative nurses. PMID- 26003971 TI - Complementary care interventions. PMID- 26003972 TI - Using simulation training to improve OR team response. PMID- 26003973 TI - Managing medical device alarms in the hospital setting. PMID- 26003974 TI - Evidence appraisal of Vogus TJ, Cooil B, Sitterding M, Everett LQ. Safety organizing, emotional exhaustion, and turnover in hospital nursing units. PMID- 26003975 TI - Transmission and Scanning Electron Microscopy of the Accessory Cells and Chorion During Development of Ciona intestinalis Type B Embryos and the Impact of Their Removal on Cell Morphology. AB - Spawned ascidian oocytes are surrounded by a membrane called the chorion (or vitelline coat) and associated with two populations of maternally-supplied cells. Outside the chorion are follicle cells, which may affect the buoyancy of eggs. Inside the chorion are test cells, which during oogenesis provision the egg and which after fertilisation contribute to the larval tunic. The structure of maternal cells may vary between species. The model ascidian Ciona intestinalis has been recently split into two species, currently named type A and type B. The ultrastructure of extraembryonic cells and structures from type A embryos has been reported. Here we describe the ultrastructure of follicle and test cells from C. intestinalis type B embryos. Test cells are about 5 um in diameter and line the inside of the chorion of developing embryos in a dense sheet. Follicle cells are large (> 100 um long) and spike-shaped, with many large vesicles. Terminal electron dense granules are found towards the tips of spikes, adjacent to cytoplasm containing numerous small electron dense bodies connected by filaments. These are probably vesicles containing material for the terminal granules. Removal of maternal structures and cells just after fertilisation, as commonly used in many experiments manipulating C. intestinalis development, has been reported to affect embryonic patterning. We examined the impact of this on embryonic ectoderm cells by scanning electron microscopy. Cells of embryos that developed without maternal structures still developed cilia, but had indistinct cell boundaries and a more flattened appearance than those that developed within the chorion. PMID- 26003976 TI - Formation of a new limb bud at the boundary between a transplanted limb bud and the tail surface of Xenopus tadpoles. AB - Through transplantation experiments with Xenopus laevis tadpoles, we found a new morphogenetic phenomenon consisting of limb bud formation at the boundary between transplanted whole limb buds and the tail surface. This phenomenon occurs without limb-limb stump interaction and has a number of unique features: (1) Only one extra limb bud was formed per transplant and the new limb and the transplanted limb were bilaterally symmetrical, forming a pair of limb girdles. (2) Extra new limb bud formation occurred not only at the tail but also at other non-limb regions, including abdominal and head surfaces. (3) Successful limb formation required the presence of basal 1/4 region (presumptive limb girdle) of a limb bud explant. (4) New limb formation was host-stage-dependent: before metamorphosis, limb bud formation ratio was high (> 90%), but as the host tadpole entered metamorphosis, this potential declined and morphological abnormalities of new limbs increased. (5) Cell lineage analysis showed that epidermis of the new limb bud always contained many (about 60%) host-derived cells, while new limb cartilage cells were completely graft-derived. These results suggest that heterotopic new limb formation occurs through interaction between graft mesenchyme and host epidermis. Thus, the present study has clarified the two important aspects of limb ontogeny: the importance of presumptive limb girdle for the limb bud initiation and the relationship between limb bud formation potential and metamorphic tissue remodeling. The present experimental system may help to improve our understanding of epithelial-mesenchymal interaction during limb bud initiation and subsequent limb cell differentiation during metamorphosis. PMID- 26003977 TI - The Lycaenid Central Symmetry System: Color Pattern Analysis of the Pale Grass Blue Butterfly Zizeeria maha. AB - The nymphalid groundplan has been proposed to explain diverse butterfly wing color patterns. In this model, each symmetry system is composed of a core element and a pair of paracore elements. The development of this elemental configuration has been explained by the induction model for positional information. However, the diversity of color patterns in other butterfly families in relation to the nymphalid groundplan has not been thoroughly examined. Here, we examined aberrant color pattern phenotypes of a lycaenid butterfly, Zizeeria maha, from mutagenesis and plasticity studies as well as from field surveys. In several mutants, the third and fourth spot arrays were coordinately positioned much closer to the discal spot in comparison to the normal phenotype. In temperature-shock types, the third and fourth array spots were elongated inwardly or outwardly from their normal positions. In field-caught spontaneous mutants, small black spots were located adjacent to normal black spots. Analysis of these aberrant phenotypes indicated that the spots belonging to the third and fourth arrays are synchronously changeable in position and shape around the discal spot. Thus, these arrays constitute paracore elements of the central symmetry system of the lycaenid butterflies, and the discal spot comprises the core element. These aberrant phenotypes can be explained by the black-inducing signals that propagate from the prospective discal spot, as predicted by the induction model. These results suggest the existence of long-range developmental signals that cover a large area of a wing not only in nymphalid butterflies, but also in lycaenid butterflies. PMID- 26003978 TI - Phylogeny and Differentiation of Wide-Ranging Ryukyu Kajika Frog Buergeria japonica (Amphibia: Rhacophoridae): Geographic Genetic Pattern Not Simply Explained by Vicariance Through Strait Formation. AB - To investigate geographic genetic structures and taxonomic relationships among isolated populations of Buergeria japonica, occurring very widely in various habitats of the Ryukyu Archipelago and Taiwan, we conducted phylogenetic and demographic analyses among individuals from various localities, representing their entire distributional ranges. Buergeria japonica is genetically greatly differentiated and comprises three major clades (the Southern Taiwan [ST] clade, the Northern Taiwan + Southern Ryukyu [NT/SR] clade, and the Central + Northern Ryukyu [CR/NR] clade), each of which seems to represent independent species. The first divergence in the species is estimated to have occurred in the middle to late Miocene in areas of current Taiwan, then eastern periphery of the Asian continent. Split of the ST and the remaining clades, and subsequent divergence between the NT/SR and the CR/NR clades in the latter, indicate consecutive south to north vicariant diversifications. However, these vicariances are not always associated with formation of significant barriers such as deep straits. Less but still prominently diverged subclades (the Amami + Tokara [AM/TK] and the Okinawa [ON] subclades) in the CR/NR clade were recognized in spite of the absence of an intervening deep strait. Contrariwise, individuals from Amami and Tokara Groups formed the AM/TK subclade in spite of the presence of the intervening Tokara Gap (a long-standing deep tectonic strait). Furthermore, in the AM/TK subclade, low but definite genetic divergence was found between the Northern Amami + Tokara (NAM/TK) lineage and the Southern Amami (SAM) lineage. Estimated divergence time and gene flow rate within the NAM/TK lineage indicate that this species reached northern Tokara from the south by overseas dispersal over the Tokara Gap long after its formation, but not by more recent artificial transportation. This overseas dispersal would have been facilitated by its more frequent occurrence around coastal habitats than other frogs. PMID- 26003979 TI - Chironomid midges (Diptera, chironomidae) show extremely small genome sizes. AB - Chironomid midges (Diptera; Chironomidae) are found in various environments from the high Arctic to the Antarctic, including temperate and tropical regions. In many freshwater habitats, members of this family are among the most abundant invertebrates. In the present study, the genome sizes of 25 chironomid species were determined by flow cytometry and the resulting C-values ranged from 0.07 to 0.20 pg DNA (i.e. from about 68 to 195 Mbp). These genome sizes were uniformly very small and included, to our knowledge, the smallest genome sizes recorded to date among insects. Small proportion of transposable elements and short intron sizes were suggested to contribute to the reduction of genome sizes in chironomids. We discuss about the possible developmental and physiological advantages of having a small genome size and about putative implications for the ecological success of the family Chironomidae. PMID- 26003980 TI - The Japanese Marten Favors Actinidia arguta, a Forest Edge Liane as a Directed Seed Disperser. AB - This study demonstrates the potential of the Japanese marten (Martes melampus) to serve as a directed seed disperser of Actinidia arguta, a representative forest edge liane. Fecal compositions of the Japanese marten in a western part of Tokyo, Japan were analyzed by the point-frame method. It fed on fruits in autumn (73.1%) and winter (63.0%), and the seeds of A. arguta were most frequently eaten (47.4%). Although the vegetation in the study area was dominated by forest (95.5%), seeds found in the marten feces were dominated by those of forest edge plants (92.1%), suggesting a strong selective bias, both habitat and food, toward these species. The density of marten feces was also higher at forest edges than forest interiors. A. arguta plants were more abundant at forest edges than within the forest at Afan Wood, Nagano Prefecture. These results suggest that the Japanese marten selectively uses forest edges as a location for feeding and defecation and thus functions as a directed seed disperser of A. arguta. PMID- 26003981 TI - Growth of the Coconut Crab, Birgus latro, at Its Northernmost Range Estimated from Mark-Recapture Using Individual Identification Based on Carapace Grooving Patterns. AB - Although populations of the coconut crab, Birgus latro, have declined in the tropical Indo-Pacific region, insufficient knowledge exists for the management of this species. We investigated the growth of the northernmost coconut crab population, located at Ocean Expo Park, Okinawa, southern Japan, using a mark recapture method based on the identification of individual carapace grooving patterns. Of the 485 crabs photographed (264 males, 221 females; 14.3-68.8 mm thoracic length [ThL]), 64 males and 62 females were recaptured (recapture rate 26%). The liberty period ranged from two to 2384 days. The annual data indicated that most crabs molted during winter, except for juveniles and crabs near the maximum size. Using the GROTAG program, the asymptotic ThL (Linfinity) was estimated as 80.72 and 49.89 mm for males and females, respectively. The Brody growth coefficient (K) was 0.063 for both sexes. The growth curves from these parameters showed that males grew larger than females because of a difference in growth speed. Longevity was estimated at approximately 50 years for both sexes. The growth data obtained in the present study, which are the most precise gathered for the coconut crab to date, can be compared with the results of studies performed in other regions. PMID- 26003982 TI - Effects of Photoperiod and Temperature on Growth and Development in Clouded Salamander (Hynobius nebulosus) Larvae. AB - Day length is one of the most important factors that organisms use to predict seasonal changes in their environment. Several amphibians regulate their growth and development in response to photoperiod. However, many studies have not focused on the ecological effects of the photoperiodic response on growth and development because they use tropical animals, animals from a commercial source or from unknown localities, or extreme light regimens for experiments. In the present study, we examined the effects of photoperiod on growth and development in the clouded salamander (Hynobius nebulosus) by raising larvae under different photoperiods and at different temperatures in the laboratory. The average larval period under a long-day photoperiod of L16:D8 was longer than that under L12:D12 at 15 degrees C or 20 degrees C, although the difference between the photoperiods was only significant for 15 degrees C. Juveniles weighed more at metamorphosis under L16:D8 than those under L12:D12, irrespective of temperature, suggesting that a longer developmental period results in a heavier body weight. The head width of juveniles did not differ for different photoperiods at either temperature. However, the growth rate of the head width under L12:D12 was faster than that under L16:D8 at 15 degrees C. Long day length appears to produce larger H. nebulosus juveniles in a relatively stable aquatic environment with a low population density. Thus, development may be accelerated when the day length becomes shorter as winter approaches, and larvae may have increased the growth rate of their head widths to compensate for the shorter growing period under shorter day lengths. PMID- 26003983 TI - Effect of Thyroid Function on MNU-Induced Mammary Carcinogenesis. AB - Mammary cancer is a disease that affects many women. Extensive research has been conducted to elucidate which variables are involved in the development of this cancer. Studies have highlighted thyroid function as a modulator of tumor growth and development. Thyroxine and 3,3',5-triiodothyronine are responsible for regulating the development, differentiation, homeostasis, and metabolism of cells in the body including mammary tissue. Thyroid hormones also have estrogen-like effects on mammary cancer cell growth by regulating the estrogen receptor. The present study was designed to determine whether medically induced hyperthyroidism increases the multiplicity, prevalence, and mammary tumor burden in rats; and to elucidate whether surgically induced hypothyroidism conversely attenuates the rate of mammary cancer cell growth. Female Sprague-Dawley rats were randomly divided into three groups (euthyroid-control, hyperthyroid, and hypothyroid). Hyperthyroidism was induced via oral administration of levothyroxine; whereas, hypothyroidism was induced by thyroidectomy. Mammary carcinogenesis was induced with a single intraperitoneal injection of N-methyl-N-nitrosurea (MNU). Rats were sacrificed at 38 weeks, and the mammary tumors were excised, fixed for histology and analyzed. Analysis included evaluation of malignancy and immunohistochemistry for ER. MNU-induced mammary carcinogenesis among the groups resulted in a significant difference in tumor burden. The hyperthyroid group had a statistically higher tumor burden than did the euthyroid group, and the hypothyroid group had no tumors of mammary tissue origin at 38 weeks. All excised mammary tumors were ER alpha negative. These data support the hypothesis that thyroid function is one of potentially many factors that contribute to modulation of MNU-induced mammary tumor growth. PMID- 26003984 TI - Exoskeleton Morphology of Three Species of Preponini, with Discussion of Morphological Similarities among Neotropical Charaxinae (Lepidoptera: Nymphalidae)-I. Head, Cephalic Appendages, and Cervix. AB - The present study compares the morphology of the head, appendages, and cervical region of three species of the butterflies Archaeoprepona demophon demophon (Linnaeus, 1758), Archaeoprepona licomedes licomedes (Cramer, 1777), and Prepona pylene pylene Hewitson, [1854], through descriptions, illustrations, and scanning electron micrographs. The results are compared with Prepona claudina annetta (Gray, 1832), Memphis moruus stheno Hubner, [1819], and Zaretis itys itylus (Westwood, 1850), showing unique characteristics for each species and/or genus, or characteristics shared among the species analyzed. The detailed morphology of these three species was previouslyunknown. PMID- 26003985 TI - Exoskeleton Morphology of Three Species of Preponini, with Discussion of Morphological Similarities among Neotropical Charaxinae (Lepidoptera: Nymphalidae)-II. Thorax and Thoracic Appendages. AB - The present report, the second part of a study of the external morphology of Preponini, compares the thorax and thoracic appendages of Archaeoprepona demophon demophon (Linnaeus, 1758), Archaeoprepona licomedes licomedes (Cramer, 1777) and Prepona pylene pylene Hewitson, [1854], through descriptions and illustrations. The results are compared with three other species, Prepona claudina annetta (Gray, 1832), Memphis moruus stheno Hubner, [1819] and Zaretis itys itylus (Westwood, 1850), revealing previously unrecognized similarities among species of Charaxinae. PMID- 26003986 TI - Exoskeleton Morphology of Three Species of Preponini, with Discussion of Morphological Similarities among Neotropical Charaxinae (Lepidoptera: Nymphalidae)-III. Abdomen and Genitalia. AB - The present paper is the final part of a study of the external morphology of Preponini, which compares the abdomen and genitalia of Archaeoprepona demophon demophon (Linnaeus, 1758), Archaeoprepona licomedes licomedes (Cramer, 1777) and Prepona pylene pylene Hewitson, [1854], through descriptions and illustrations. The results are compared with three other species, Prepona claudina annetta (Gray, 1832), Memphis moruus stheno Hubner, [1819] and Zaretis itys itylus (Westwood, 1850). The abdomen is commonly the most informative tagma for butterflies. In Charaxinae, this tagma supports diagnoses of both genera and species, besides providing a solid morphological base for recent molecular findings for Preponini. PMID- 26003987 TI - Molecular Identification of Ptychodera flava (Hemichordata: Enteropneusta): Reconsideration in Light of Nucleotide Polymorphism in the 18S Ribosomal RNA Gene. AB - Seven nuclear and mitochondrial DNA markers were examined in 12 specimens of Ptychodera flava, a model acorn worm used in molecular biology, collected in Japan from three local populations with different modes of living. A comparison of intraspecific results did not show genetically isolated populations despite the species' enclave habitats and asexual reproduction. Moreover, both the nuclear 18S ribosomal RNA gene and mitochondrial 16S ribosomal RNA gene sequences were identical to those from Moorea in French Polynesia, nearly 10,000 kilometers away from Japan. I also provide the first definitive information regarding polymorphisms in 18S ribosomal RNA gene, the external transcribed spacer (ETS), internal transcribed spacers (ITS), and mitochondrial cytochrome c oxidase subunit 1 (mtCO1) sequence in hemichordates using newly designed primer sets, and I show both high larval vagility and certain criteria for the molecular identification of this species. PMID- 26003988 TI - Is a Gall an Extended Phenotype of the Inducing Insect? A Comparative Study of Selected Morphological and Physiological Traits of Leaf and Stem Galls on Machilus thunbergii (Lauraceae) Induced by Five Species of Daphnephila (Diptera: Cecidomyiidae) in Northeastern Taiwan. AB - Mature galls induced by Daphnephila truncicola, D. taiwanensis, D. sueyenae, D. stenocalia, and D. ornithocephala on Machilus thunbergii in northern Taiwan were examined to verify the dictum that the morphology of galls is an expression of the extended phenotype of the respective gall-inducing insect. Based on their length-width ratio, the materials were grouped into either fleshy (those induced by D. taiwanensis and D. sueyenae) or slim galls (those induced by D. truncicola, D. stenocalia, and D. ornithocephala). Stem galls induced by D. truncicola showed an energy level of 0.0178 kJ/g. Among leaf galls, the greatest energy level was in the one induced by D. stenocalia (0.0193 kJ/g), followed by D. sueyenae (0.0192 kJ/g), D. taiwanensis (0.0189 kJ/g), and D. ornithocephala (0.0160 kJ/g). The numbers of reserve and nutritive cell layers in galls were greater in the stem galls induced by D. truncicola, similar to those in the fleshy leaf galls, than in the slim leaf galls. Based on the fungal taxa isolated from the larval chambers and considering the similarities and divergences among gall characteristics, the galls induced by D. truncicola and D. taiwanensis clustered into one, whereas those of D. sueyenae aligned with the 'D. stenocalia-D. ornithocephala' cluster. The present study verified that shapes, structure, nutritive tissues, energy levels, and multiple coexisting fungal taxa within galls reinforce that they are extended phenotypes of the respective gall-inducing Daphnephila species and they represent adaptive evolution of Daphnephila on M. thunbergii. PMID- 26003989 TI - Weighted protein residue networks based on joint recurrences between residues. AB - BACKGROUND: Weighted and un-weighted protein residue networks can predict key functional residues in proteins based on the closeness centrality C and betweenness centrality B values for each residue. A static snapshot of the protein structure, and a cutoff distance, are used to define edges between the network nodes. In this work we apply the weighted network approach to study the beta-Lactamase Inhibitory Protein (BLIP). Joint recurrences extracted from molecular dynamics MD trajectory positions of the protein residue carbon alpha atoms are used to define edge weights between nodes, and no cutoff distance is used. The results for B and C from our approach are compared with those extracted from an un-weighted network, and a weighted network that uses interatomic contacts to define edge weights between nodes, respectively. RESULTS: The joint recurrence weighted network approach performs well in pointing out key protein residues. Furthermore, it seems to emphasize residues with medium to high relative solvent accessibility that lie in loop regions between secondary structure elements of the protein. CONCLUSIONS: Protein residue networks that use joint recurrences extracted from molecular dynamics simulations of a solvated protein perform well in pointing to hotspot residues and hotspot clusters. This approach uses no distance cutoff threshold, and does not exclude any interactions between the residues, including water-mediated interactions. PMID- 26003990 TI - Progression of gyrate atrophy measured with ultra-wide-field imaging. AB - The study aims to determine the progression of gyrate atrophy by measuring the area growth of chorioretinal atrophic lesions using ultra-wide-field images (UWFI). A retrospective, observational, and comparative study was conducted and UWFI (200 degrees ) were obtained from two patients with gyrate atrophy at baseline and follow-up. Measurements of atrophy were obtained for three types of lesions: Solitary atrophic lesions (SAL), De novo solitary lesions (DNSL), and peripapillary atrophy (PPA). Comparison of baseline and follow-up was done using t tests. Two patients with gyrate atrophy were included. Patient 1 presented 16 SAL, 5 DNSL, and PPA measured for both eyes (BE). Overall area growth (OAG) for SAL (expressed in decimals) presented a mean of 3.41, sigma 3.07. DNSL area for BE presented a mean of 1586.08 P (2), sigma 1069.55. OAG for PPA presented a mean of 1.21, sigma 0.17. Patient 2 presented 5 SAL, no DNSL, and PPA was measured for BE. OAG for SAL presented a mean of 1.58, sigma 1.05 (range 1.02-3.47). OAG for PPA presented a mean of 1.05, sigma 0.001. Gyrate atrophy progression can be determined by measuring the changes in area using UWFI. PMID- 26003991 TI - Safety and efficacy of adjunctive intranasal mitomycin C and triamcinolone in endonasal endoscopic dacryocystorhinostomy. AB - One of the common causes of failure in dacryocystorhinostomy for nasolacrimal duct obstruction (NLDO) is mucosal scarring and fibrosis around the ostium. Steroid and mitomycin C (MMC) can potentially reduce scarring by their action on the inflammatory and proliferative phase of wound healing, respectively. The purpose of this study is to evaluate the safety and efficacy of combined usage of adjunctive MMC and intranasal triamcinolone (TA) in endonasal endoscopic dacryocystorhinostomy (EE-DCR). This is a retrospective interventional case series. All patients underwent mechanical EE-DCR in two regional hospitals in Hong Kong from January 2005 to December 2006 were included. All received intraoperative MMC application for 5 min and gelfoam soaked with TA onto the ostium. Main outcome measures include the anatomical and functional success rate at follow-up at least 6 months after operation. Other outcomes include complications occurred during and after operation. A total of 73 EE-DCR were performed in 69 patients. Three patients had simultaneous bilateral DCR; one had sequential DCRs for both sides. At the last follow-up, anatomical success was achieved in 68 cases (93 %) and both anatomical with functional success in 67 cases (92 %). No major complication was observed. Minor complications included asymptomatic mucosal adhesion between the nasal septum and lateral nasal wall in one patient and moderate secondary hemorrhage in another. EE-DCR with adjunctive MMC and TA is a safe and successful procedure for the treatment of NLDO. PMID- 26003992 TI - Motor outcome of deep intracerebral haemorrhage in diffusion tensor imaging: comparison of data from different locations along the corticospinal tract. AB - OBJECTIVES: Although diffusion tensor imaging (DTI) is widely studied to assess the motor outcome after ischaemic stroke, there is paucity of data regarding outcomes of intracerebral haemorrhage (ICH). The aim of this study was to determine the DTI data from different locations along the corticospinal tract (CST) and association to motor outcome. METHODS: We prospectively recruited patients with deep ICH admitted to our hospital from November 2010 to July 2012.Diffusion tensor imaging was performed within 14 days after the onset of ICH. Fractional anisotropy (FA) was measured along the CST at corona radiata, perihaematomal oedema, cerebral peduncle and pons. Corticospinal tract integrity was classified into three types by diffusion tensor tractography (DTT): type A with preserved CST, type B with partially interrupted CST and type C with completely interrupted CST. Motor outcome was assessed by Motricity index (MI) at admission, after 1 and 3 months. RESULTS: Forty-eight patients were enrolled with a mean age of 62 years. The median time interval from onset of ICH to DTI study was 7 days. The patients in type C had significantly worse MI at admission (P < 0.001), after 1 month (P < 0.001) and after 3 months (P < 0.001) as compared to those with type A and type B. Lower rFA at the corona radiata was significantly correlated with poorer motor outcome at admission, after 1 month and after 3 months. DISCUSSION: Clinical motor outcome of ICH within 2 weeks can be identified with a statistically significant decrease in rFA at the corona radiata. PMID- 26003993 TI - Performance analysis of active disturbance rejection tracking control for a class of uncertain LTI systems. AB - The paper considers the tracking problem for a class of uncertain linear time invariant (LTI) systems with both uncertain parameters and external disturbances. The active disturbance rejection tracking controller is designed and the resulting closed-loop system's characteristics are comprehensively studied. In the time-domain, it is proven that the output of closed-loop system can approach its ideal trajectory in the transient process against different kinds of uncertainties by tuning the bandwidth of extended state observer (ESO). In the frequency-domain, different kinds of parameters' influences on the phase margin and the crossover frequency of the resulting control system are illuminated. Finally, the effectiveness and robustness of the controller are verified through the actuator position control system with uncertain parameters and load disturbances in the simulations. PMID- 26003994 TI - Sampled data observer based inter-sample output predictor for Electro-Hydraulic Actuators. AB - In this paper, a Sampled Data Disturbance Observer which simultaneously estimates the unmeasurable states and the uncertainties for the Electro-Hydraulic Actuators systems are presented. The novelty of our approach is the use of an inter-sample output predictor which allows the user to increase the frequency acquisition of the piston position sensor without affecting the convergence performance. The stability analysis of the proposed observer is proved using the Lyapunov function adapted to hybrid systems. To show the efficiency of the proposed observer, numerical simulations of a control application which combine the proposed observer and a Proportional Integral controller for the purpose of piston position tracking problem are presented. PMID- 26003995 TI - Reply: To PMID 25454934. PMID- 26003996 TI - Stopping Parenteral Nutrition for 3 Hours Reduces False Positives in Newborn Screening. AB - OBJECTIVE: To evaluate effects of holding parenteral nutrition (PN) for 3 hours prior to newborn screening (NBS) on false-positive NBS rate for amino acids (AAs) in very low birth weight (VLBW) infants (birth weight <1500 g). STUDY DESIGN: We analyzed data from 12 567 consecutive births in 1 hospital between May 2010 and June 2013. VLBW infants were stratified into 3 groups: (1) infants without PN before NBS (no-PN group); (2) infants with early PN running at the time of NBS (early-PN group); and (3) infants with early-PN that were temporarily replaced by dextrose-containing intravenous fluid 3 hours prior to NBS (stop-PN group). We compared the false-positive rate for AA and cost effectiveness between the groups. RESULTS: The false-positive rate for AA among 413 VLBW infants was significantly higher than infants with birth weight >1500 g (7.62% vs 0.05%; P < .001). There were no false-positive results for AA in the no-PN group. The false positive rate for AA in the stop-PN group (2/65) was significantly lower than the early-PN group (29/245) (3.1% vs 11.8%; P = .037). The stop-PN group was more cost effective than early-PN group, saving $17.27 per infant screened ($5.53 vs $22.80) or $192.54 for each false-positive result for AA averted. Further reductions in inconclusive samples were also noted. CONCLUSIONS: VLBW and early PN are significant factors for false-positive results for AA. Holding PN containing AAs for 3 hours before NBS collection is a practical and cost effective method to significantly reduce the false-positive rate for AA in VLBW infants. PMID- 26003998 TI - MORFAN Syndrome: An Infantile Hypoinsulinemic Hypoketotic Hypoglycemia Due to an AKT2 Mutation. AB - We report a child with hypoinsulinemic hypoglycemia and distinctive facies, with a diagnosis of the previously described MORFAN (Mental retardation, pre- and post natal Overgrowth, Remarkable Face, and Acanthosis Nigricans) syndrome of unknown etiology. Whole-exome sequencing revealed a de novo AKT2 mutation. Although AKT2 has been implicated in four patients with hypoinsulinemic hypoglycemia, our report expands phenotypic spectrum to include MORFAN syndrome characteristics. PMID- 26003997 TI - Sympathetic Activity Assessed during Exercise Recovery in Young Obese Females. AB - OBJECTIVE: To evaluate differences in sympathetic activity, as assessed by an exercise recovery index (ERI; heart rate/oxygen consumption [VO2] plateau), between black and white obese female adolescents. An additional aim was to determine the association of ERI with insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]), cardiovascular fitness per fat-free mass (VO2 per fat-free mass), systolic blood pressure (SBP), and percent body fat (%FAT) in both black and white obese adolescents. STUDY DESIGN: Sixty-one females volunteered to participate in this study. HOMA-IR, SBP, and %FAT were assessed during resting conditions in black (n = 49, 13.7 +/- 1.6 years, 38.1 +/- 6.1 kg/m(2)) and white (n = 12, 13.3 +/- 2.2 years, 34.3 +/- 4.9 kg/m(2)) obese adolescents. An ERI was calculated during a 5-minute passive recovery period immediately following a graded treadmill exercise test to exhaustion. RESULTS: The ERI was significantly greater in black compared with white obese adolescent females (29.8 +/- 6.4 vs 24.1 +/- 3.1 bpm.mLO2(-1).min(-1), P = .004). Using multiple linear regression modeling, there was a significant independent association between ERI and VO2 per fat-free mass (r = -0.310, P = .027) and %FAT (r = 0.326, P = .020) in black obese adolescents after controlling for HOMA-IR and SBP. CONCLUSIONS: These results suggest that black obese adolescent females have greater sympathetic activity, as assessed by an ERI, than white obese adolescent females. These findings support the need for weight management efforts aimed at both reducing %FAT and improving fitness in obese adolescents, specifically black females. TRIAL REGISTRATION: Registered with Clinicaltrials.gov: NCT00562293. PMID- 26003999 TI - Public Discourse on Measles, A Shot in the Arm for Vaccination. PMID- 26004000 TI - Mediastinal Lipomatosis Presenting as Persistent Pneumonia. PMID- 26004001 TI - Biocompatible anionic polyelectrolyte for improved liposome based gene transfection. AB - Cationic liposomes have been widely used as efficient gene carriers. However, the serious cytotoxicity caused by exposed positive charges restricts the further application of those kinds of gene vectors. Thus, it is challenging to develop biocompatiable non-positive charge carriers to achieve high gene transfection efficiencies. Herein, we report a novel design by pasting biocompatible anionic polyelectrolyte, namely alginic acid, hyaluronic acid, pectin and polyglutamic acid, to the positive charge surface of liposome/pDNA complex. Through shielding the positive charges, the new gene carriers show decreased cytotoxicity while still maintaining high transfection efficiency. To be noted, the complex formed by coating polyglutamic acid to the surface of liposome/pDNA greatly enhanced the transfection efficiency in HepG2 cells, and the use of pectin shows increased transfection in MCF-7 cells. Hemolysis assay proved a possible mechanism that when the new gene complex was internalized into cells, as acidity increases, more side chains become hydrophobic, and thus destabilizing the endosomal membrane to accelerate DNA escape. The present results suggest that such anionic polyelectrolyte covered liposome based carrier possess promising application for clinical gene delivery. PMID- 26004002 TI - An injectable liquid crystal system for sustained delivery of entecavir. AB - Liquid crystal (LC) technology has attracted much interest for new injectable sustained-release (SR) formulations. In this study, an injectable liquid crystal forming system (LCFS) including entecavir was prepared for the treatment of hepatitis B. In particular, an anchoring effect was introduced because LCFSs are relatively hydrophobic while entecavir is a slightly charged drug. The physicochemical properties of LCFSs were investigated by cryo-transmission electron microscopy (cryo-TEM), polarized optical microscopy, and small-angle X ray scattering (SAXS), showing typical characteristics of the liquid crystalline phase, which was classified as the hexagonal phase. A pharmacokinetic study in rats showed sustained release of entecavir for 3-5 days with a basic LCFS formulation composed of sorbitan monooleate (SMO), phosphatidyl choline (PC), and tocopherol acetate (TA) as the main LC components. 1,2-Dipalmitoyl-sn-glycero-3 phosphatidic acid (DPPA), an anionic phospholipid, was added to increase the anchoring effect between the cationic entecavir and the anionic DPPA, which resulted in a 1.5-times increase in half-life in rats. In addition, anchoring was strengthened by optimizing the pH to 2.5-4.5, increasing the half-life in the rat and dog. Also, due to the increasing terminal half-life from rat to dog resulting from species differences, LCFS produced one week delivery of entecavir in rat and two weeks delivery in dog. Therefore, LCFS injection using the anchoring effect for entecavir can potentially be used to deliver the drug over more than 2 weeks or even 1 month for the treatment of hepatitis B. PMID- 26004003 TI - Dual targeting for metastatic breast cancer and tumor neovasculature by EphA2 mediated nanocarriers. AB - EphA2 is a transmembrane receptor tyrosine kinase that is highly expressed on both tumor neovasculature and some kinds of tumor cells. Here, a homing peptide with a sequence of YSAYPDSVPMMSK (YSA) that binds specifically with EphA2 was utilized to modify the stealth liposomes (YSA-LP). With a particle size of about 85 nm, this functionalized nanocarrier was loaded with fluorescent probe or doxorubicin (DOX) and investigated in vitro and in vivo. In the cellular endocytosis studies in vitro, coumarin-6 loaded YSA-LP exhibited significant specificity to both EphA2-overexpressing tumor cells (MDA-MB-231) and human umbilical vein endothelial cells (HUVEC) via a YSA mediated interaction. In a MDA MB-231 xenograft tumor mouse model, DiR-loaded YSA-LP showed more lasting accumulation in tumor tissue by small animal imaging compared to unmodified liposomes (LP). Further, YSA-LP greatly facilitated the efficacy of DOX loaded against both tumor cells and tumor angiogenesis in the same mouse model, evidenced by inhibiting tumor growth, metastasis and CD31 expression as well as inducing cancer cell apoptosis. Additionally, YSA-LP (DOX) showed relatively low systemic and cardiac toxicity compared with control groups. In conclusion, YSA might be a promising targeting motif for EphA2-overexpressing tumor cells and tumor neovasculature, which could be used to mediate drug delivery for chemotherapy agents. PMID- 26004004 TI - Topical and transdermal delivery of caffeine. AB - Caffeine is administered topically and transdermally for a variety of pharmaceutical and cosmetic applications and it is also used as a model hydrophilic compound in dermal risk assessment studies. This review considers the physicochemical and permeation properties of caffeine with reference to its delivery to and through the skin. Since it has been used as a model compound the findings have implications for the delivery of many hydrophilic compounds having similar properties. Various passive and active formulation strategies to promote enhanced skin permeation of caffeine are considered. Models to study percutaneous caffeine penetration are also discussed in detail. PMID- 26004005 TI - Quaternary polymethacrylate-magnesium aluminum silicate films: Water uptake kinetics and film permeability. AB - The aim of this study was to investigate the impact of the addition of different amounts of magnesium aluminum silicate (MAS) to polymeric films based on quaternary polymethacrylates (QPMs, here Eudragit RS and RL). MAS contains negatively charged SiO(-) groups, while QPM contains positively charged quaternary ammonium groups. The basic idea is to be able to provide desired water and drug permeability by simply varying the amount of added MAS. Thin, free films of varying composition were prepared by casting and exposed to 0.1M HCl and pH 6.8 phosphate buffer. The water uptake kinetics and water vapor permeability of the systems were determined gravimetrically. The transport of propranolol HCl, acetaminophen, methyl-, ethyl- and propylparaben across thin films was studied using side-by-side diffusion cells. A numerical solution of Fick's second law of diffusion was applied to determine the apparent compound diffusion coefficients, partition coefficients between the bulk fluids and the films as well as the apparent film permeability for these compounds. The addition of MAS resulted in denser inner film structures, at least partially due to ionic interactions between the positively charged quaternary ammonium groups and the negatively charged SiO(-) groups. This resulted in lower water uptake, reduced water vapor permeability and decreasing apparent compound diffusivities. In contrast, the affinity of the investigated drugs and parabens to the films substantially increased upon MAS addition. The obtained new knowledge can be helpful for the development of novel coating materials (based on QPM-MAS blends) for controlled release dosage forms. PMID- 26004006 TI - Characterization of 9-nitrocamptothecin-in-cyclodextrin-in-liposomes modified with transferrin for the treating of tumor. AB - Encapsulation of hydrophobic drugs in the form of drug-cyclodextrin (CD) complex in liposomes has been applied as a novel strategy to combine the relative advantages of CDs and liposomes into one system, naming drug-in-CD-in-liposome (DCL). In the present study, soluble 9-NC/hydroxypropyl-beta-cyclodextrin (HP beta-CD) inclusion complexes were prepared using the freeze-drying technique. Then 9-NC inclusion complexes were further encapsulated into liposomes by ethanol injection method and transferrin (Tf) was conjugated to the surface of 9-NC DCL to obtain Tf modified 9-NC DCL (Tf-9-NC-CL). Compared to PEGylated 9-NC DCL (P-9 NC-CL), the lactone stability and vesicle stability of Tf-9-NC-CL were significantly increased. Both 9-NC and HP-beta-CD were found to release from the DCL and Tf modification resulted in reduced release of them. The enhanced targeting efficiency of the Tf-modified liposomes was demonstrated by flow cytometry and confocal microscopy. In vivo pharmacokinetics in rats showed improved lactone stability of 9-NC following intravenous injection of Tf-9-NC-CL. The cytotoxicity of Tf-9-NC-CL against tumor cells and normal cells was investigated in vitro and the antitumor efficacy was evaluated in S180 tumor bearing mice in vivo. Compared with free 9-NC, 9-NC inclusion complexes and P-9 NC-CL, Tf-9-NC-CL demonstrated the strongest cytotoxicity to tumor cells. And the inhibitory rate of tumor (IRT) values were determined to be 43.08%, 56.92%, 67.69% and 80.00% for 9-NC solution, inclusion complexes, P-9-NC-CL and Tf-9-NC CL, respectively. In conclusion, Tf modification can be useful in increasing vesicle stability, targeting drug delivery efficiency and antitumor efficacy of DCL containing hydrophobic antitumor drugs, such as 9-NC. PMID- 26004007 TI - Use of whole genome DNA spectrograms in bacterial classification. AB - A spectrogram reflects the arrangement of nucleotides through the whole chromosome or genome. Our previous study suggested that the spectrogram of whole genome DNA sequences is a suitable tool for the determination of relationships among bacteria. Related bacteria have similar spectrograms, and similarity in spectrograms was measured using a color layout descriptor. Several parameters, such as the mapping of four bases into a spectrogram, the number of considered elements in the color layout descriptor, the color model of the image and the building tree method, can be changed. This study addresses the use of parameter selection to ensure the best classification results. The quality of the classification was measured by Matthew's correlation coefficient (MCC). The proposed method with optimal parameters (called SpectCMP-Spectrogram CoMParison method) achieved an average MCC of 0.73 at the phylum level. The SpectCMP method was also tested at the order level; the average MCC in the classification of class Gammaproteobacteria was 0.76. The success of a classification with respect to the correct phyla was compared to three methods that are used in bacterial phylogeny: the CVTree method, OGTree method and moment vector method. The results show that the SpectCMP method can be used in bacterial classification at various taxonomic levels. PMID- 26004008 TI - Targeting of the EGFR/beta1 integrin connecting proteins PINCH1 and Nck2 radiosensitizes three-dimensional SCC cell cultures. AB - Epidermal growth factor receptor (EGFR) signaling plays an important role in tumor cell resistance to therapy. In addition to ligand binding, mutual and cooperative interactions of EGFR with integrin cell adhesion receptors critically influence proper downstream signaling through a number of bridging adapter proteins. In the present study, we analyzed the role of two of these adapter proteins, called PINCH1 and Nck2, for cellular radioresistance in combination with EGFR-targeting using the monoclonal antibody cetuximab. siRNA-mediated knockdown of PINCH1 or Nck2 resulted in enhanced radiosensitivity of 3D grown human squamous cell carcinoma cell lines FaDu (head and neck) and A431 (epidermis) comparable with effects seen after cetuximab treatment. Combination of knockdown and cetuximab did not result in additive nor synergistic effects regarding clonogenic radiation survival. Modifications in MAPK, Akt and FAK phosphorylation occurred upon cetuximab treatment as well as PINCH1 or Nck2 depletion. We further found this tumor cell radiosensitization to be due to attenuated repair of DNA double strand breaks and altered Rad50 and Nbs1 expression but without changes in other DNA repair proteins such as ATM, DNA-PK and Mre11. Our data suggest that the adaptor proteins PINCH1 and Nck2 critically contribute to cellular radioresistance and proper EGFR signaling in 3D lrECM grown human squamous cell carcinoma cells. Further investigations are warranted to identify the intracellular signaling network controlled by EGFR, PINCH1 and Nck2. PMID- 26004009 TI - Evaluation of the sensitivity and reliability of primary rainbow trout hepatocyte vitellogenin expression as a screening assay for estrogen mimics: Methodological issues. PMID- 26004010 TI - Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential. AB - INTRODUCTION: The purpose of this study was (i) to evaluate the gastrointestinal behavior of micro- and nanosized fenofibrate in humans and (ii) to develop a simple yet qualitatively predictive in vitro setup that simulates the observed absorption-determining factors. MATERIALS AND METHODS: Commercially available micro- and nanoparticles of fenofibrate (Lipanthyl(r) and Lipanthylnano(r), respectively) were administered orally to five healthy volunteers in fasting and postprandial conditions. Intraluminal and systemic drug concentrations were determined as reference data for the development of a predictive in vitro setup. To capture the observed solubility/permeability interplay, in vitro dissolution testing was performed in the presence of a permeation bag with sink conditions. RESULTS: In fasting conditions, intake of nanosized fenofibrate generated increased duodenal concentrations compared to microsized fenofibrate, which was reflected in an improved systemic exposure. In postprandial conditions, duodenal concentrations were greatly enhanced for both formulations, however without an accompanying increase in systemic exposure. It appeared that micellar encapsulation of the highly lipohilic fenofibrate limited its potential to permeate from fed state intestinal fluids. To capture these in vivo observations in an in vitro setup, classic dissolution testing was combined with permeation assessment into a permeation bag with sink conditions. In case of fasting conditions, the dissolution/permeation approach allowed for an improved discriminative power between micro- and nanosized fenofibrate by better simulating the dynamic interplay of dissolution and absorption. In case of postprandial conditions, the observed solubility-permeability interplay could be simulated using the dissolution/permeation approach in combination with biorelevant media (FeSSGFFortimel and FeSSIF-V2) to mimic micellar entrapment and reduced permeation potential of fenofibrate. CONCLUSION: For the first time, reduced permeation of a lipophilic drug despite increased intraluminal concentrations, was demonstrated in humans. Dissolution testing using biorelevant media in combination with permeation assessment into a sink permeation bag appeared to be a simple yet pragmatic approach to capture this solubility permeability interplay in early formulation evaluation. PMID- 26004011 TI - ODM2CDA and CDA2ODM: tools to convert documentation forms between EDC and EHR systems. AB - BACKGROUND: Clinical trials apply standards approved by regulatory agencies for Electronic Data Capture (EDC). Operational Data Model (ODM) from Clinical Data Interchange Standards Consortium (CDISC) is commonly used. Electronic Health Record (EHR) systems for patient care predominantly apply HL7 standards, specifically Clinical Document Architecture (CDA). In recent years more and more patient data is processed in electronic form. RESULTS: An open source reference implementation was designed and implemented to convert forms between ODM and CDA format. There are limitations of this conversion method due to different scope and design of ODM and CDA. Specifically, CDA has a multi-level hierarchical structure and CDA nodes can contain both XML values and XML attributes. CONCLUSIONS: Automated transformation of ODM files to CDA and vice versa is technically feasible in principle. PMID- 26004012 TI - Two myeloid differentiation factor 88 (MyD88) isoforms identified in ducks. AB - MyD88 is an adaptor protein involved in the interleukin-1 receptor-induced and Toll-like receptor (TLR)-induced activation of nuclear factor-kappaB (NF-kappaB). In this study, we identified two isoforms of MyD88 gene, designated DuMyD88-X1 and DuMyD88-X2, from duck cells. Both variants were determined to have a death domain at the N-terminal and a Toll/IL-1R (TIR) domain at the C-terminal; however, the TIR domain of DuMyD88-X2 was incomplete and was 81 amino acids shorter than DuMyD88-X1. Quantitative real-time reverse transcription PCR revealed broad expression of both MyD88s. During Newcastle disease virus (NDV) challenge experiments, expression of the two genes increased significantly, with DuMyD88-X1 having a larger amplitude and longer duration. Overexpression of DuMyD88-X1 and DuMyD88-X2 induced the activation of NF-kappaB and IL-6 in vitro, suggesting that DuMyD88-X1 and DuMyD88-X2 may be important in the innate immune response. The results verify the existence of a MyD88-dependent signaling pathway in ducks and contribute to understanding the potential role of MyD88s in the innate immune response. PMID- 26004013 TI - Double-Patterned Sidewall Directed Self-Assembly and Pattern Transfer of Sub-10 nm PTMSS-b-PMOST. AB - The directed self-assembly (DSA) of two sub-20 nm pitch silicon-containing block copolymers (BCPs) was accomplished using a double-patterned sidewall scheme in which each lithographic prepatterned feature produced two regions for pattern registration. In doing so, the critical dimension of the lithographic prepatterns was relaxed by a factor of 2 compared to previously reported schemes for DSA. The key to enabling the double-patterned sidewall scheme is the exploitation of the oxidized sidewalls of cross-linked polystyrene formed during the pattern transfer of the resist via reactive ion etching. This results in shallow trenches with two guiding interfaces per prepatterned feature. Electron loss spectroscopy was used to study and confirm the guiding mechanism of the double-patterned sidewalls, and pattern transfer of the BCPs into a silicon substrate was achieved using reactive ion etching. The line edge roughness, width roughness, and placement error are near the target required for bit-patterned media applications, and the technique is also compatible with the needs of the semiconductor industry for high-volume manufacturing. PMID- 26004014 TI - Symptomatic cytomegalovirus gastrointestinal infection with positive quantitative real-time PCR findings in apparently immunocompetent patients: a case series. AB - Cytomegalovirus (CMV) gastrointestinal disease rarely occurs in immunocompetent patients, and is mainly diagnosed on the basis of histopathological findings. Real-time PCR for CMV DNA quantification is considered to be a useful diagnostic tool, but its place in the diagnostic strategy is not clearly defined. The goal of the study was to describe the clinical and paraclinical features of apparently immunocompetent patients with CMV gastrointestinal disease diagnosed according to quantitative PCR results. In this retrospective study conducted in a 1500-bed tertiary-care centre, we reviewed the case records of apparently immunocompetent patients with positive findings of CMV DNA in gastrointestinal biopsies with compatible symptoms and endoscopic findings. A total of 13 patients were included between January 2007 and December 2010. The median age was 81 years, and 54% of patients had underlying immune-modulating conditions. Diarrhoea, haematochezia and dysphagia were the main reported symptoms, and ulcers were the main endoscopic findings. The mean value of CMV DNA load in gastrointestinal biopsies was 3845 copies/MUg total DNA (range, 15-15 500 copies/MUg total DNA). The highest values were found in two patients who were diagnosed with adenocarcinoma in the subsequent course of CMV infection. Clinical features were similar to those in previous series in which diagnosis was based on histopathological analysis. Elderly people are more commonly affected, and a link with immune senescence is possible. Quantification of CMV DNA seems to be a useful tool for diagnosis when combined with clinical and endoscopic findings, but further studies are necessary to interpret quantitative values. PMID- 26004015 TI - NMDA and D1 receptors are involved in one-trial tolerance to the anxiolytic-like effects of diazepam in the elevated plus maze test in rats. AB - The elevated plus maze (EPM) test is used to examine anxiety-like behaviors in rodents. One interesting phenomenon in the EPM test is one-trial tolerance (OTT), which refers to the reduction in the anxiolytic-like effects of benzodiazepines when rodents are re-exposed to the EPM. However, the underlying mechanism of OTT is still unclear. In this study, we reported that OTT occurred when re-exposure to the EPM (trial 2) only depended on the prior experience of the EPM (trial 1) rather than diazepam treatment. This process was memory-dependent, as it was prevented by the N-methyl-D-aspartate (NMDA) receptors antagonist MK-801 1.5h before trial 2. In addition, OTT was maintained for at least one week but was partially abolished after an interval of 28 days. Furthermore, the administration of the D1-like receptors agonist SKF38393 to the bilateral dorsal hippocampus largely prevented OTT, as demonstrated by the ability of the diazepam treatment to produce significant anxiolytic-like effects in trial 2 after a one-day interval. These findings suggest that OTT to the EPM test may occur via the activation of NMDA receptors and the inactivation of D1-like receptors in certain brain regions, including the hippocampus. PMID- 26004018 TI - Age-related prefrontal impairments implicate deficient prediction of future reward in older adults. AB - Foresighted decision-making depends on the ability to learn the value of future outcomes and the sequential choices necessary to achieve them. Using a 3-stage Markov decision task and functional magnetic resonance imaging, we investigated age differences in the ability to extract state transition structures while learning to predict future reward. In younger adults learning was associated with enhanced activity in the prefrontal cortex (PFC). In older adults (OA) we found no evidence for PFC recruitment. However, high-performing OA showed enhanced striatal activity, suggesting that they may engage in a model-free (experience based) learning strategy. Change point analyses revealed that in younger adults learning was characterized by distinct and abrupt shifts in PFC activity, which were predictive of behavioral change points. In OA PFC activity was less pronounced and not predictive of behavior. Our findings suggest that age-related impairments in learning future reward value can be attributed to a deficit in extracting sequential state transition structures. This deficit may lead to myopic decisions in OA if contextual information has to be temporally integrated. PMID- 26004019 TI - Knowing the patient: A qualitative study on care-taking and the clinical pharmacist-patient relationship. AB - BACKGROUND: Previous studies have found clinical pharmacists (CPs) and clinical pharmacy specialists (CPSs) in direct patient care have positive effects across various patient outcomes. However, there are also other kinds of care-taking occurring in pharmacy-run clinic appointments that produce value for patients. OBJECTIVE: To identify and characterize how CPs/CPSs in direct care clinics develop and practice care-taking behaviors which advance the pharmacist-patient relationship. METHODS: Semi-structured CP/CPS interviews were conducted once per year for two years (46 year 1, 50 year 2) along with direct observations of clinical pharmacy work as part of an anticoagulation improvement intervention. Participants were from Veterans Health Administration (VHA) medical centers and VHA community-based outpatient clinics in the Northeastern U.S. Interviews were transcribed verbatim and thematically analyzed using NVIVO 10 software. RESULTS: It was found that CPs/CPSs practice "knowing the patient" in ways related to, but distinct from this practice in the nursing literature. For CPs/CPSs, knowing the patient occurred over time, and it produced familiarity and trust between CPs/CPs and patients. A reciprocal relationship developed in which patients came to rely on CP/CPSs for other types of assistance. Patterns of knowing the patient and being known by the patient manifested in three distinct ways: 1) identifying the patient's unmet needs, 2) explaining other medications, and 3) helping the patient navigate the system. CONCLUSION: This research identifies an action, knowing the patient, whereby CPs use their knowledge of the patient to deliver individualized care. This study contributes to the developing literature on pharmacist-patient relationships and pharmacist-patient communication. PMID- 26004016 TI - Brain network alterations and vulnerability to simulated neurodegeneration in breast cancer. AB - Breast cancer and its treatments are associated with mild cognitive impairment and brain changes that could indicate an altered or accelerated brain aging process. We applied diffusion tensor imaging and graph theory to measure white matter organization and connectivity in 34 breast cancer survivors compared with 36 matched healthy female controls. We also investigated how brain networks (connectomes) in each group responded to simulated neurodegeneration based on network attack analysis. Compared with controls, the breast cancer group demonstrated significantly lower fractional anisotropy, altered small-world connectome properties, lower brain network tolerance to systematic region (node), and connection (edge) attacks and significant cognitive impairment. Lower tolerance to network attack was associated with cognitive impairment in the breast cancer group. These findings provide further evidence of diffuse white matter pathology after breast cancer and extend the literature in this area with unique data demonstrating increased vulnerability of the post-breast cancer brain network to future neurodegenerative processes. PMID- 26004017 TI - Changes in Abeta biomarkers and associations with APOE genotype in 2 longitudinal cohorts. AB - Apolipoprotein E (APOE) genotype influences onset age of Alzheimer's disease but effects on disease progression are less clear. We investigated amyloid-beta (Abeta) levels and change in relationship to APOE genotype, using 2 different measures of Abeta in 2 different longitudinal cohorts. Abeta accumulation was measured using positron emission tomography (PET) imaging and (11)C-Pittsburgh compound-B (PiB) in 113 Baltimore Longitudinal Study of Aging participants (mean age 77.3 years; 107 normal, 6 cognitively impaired) and cerebral spinal fluid (CSF) Abeta1-42 assays in 207 BIOCARD study participants (mean age 62 years; 195 normal, 12 cognitively impaired). Participants in both cohorts had up to 7 serial assessments (mean 2.3-2.4). PET-PiB retention increased and CSF Abeta1-42 declined longitudinally. APOE epsilon4 was significantly associated with higher PET-PiB retention and lower CSF Abeta1-42, independent of age and sex, but APOE genotype did not significantly affect Abeta change over time. APOE epsilon4 carriers may be further along in the disease process, consistent with earlier brain Abeta deposition and providing a biological basis for APOE genotype effects on onset age of Alzheimer's disease. PMID- 26004020 TI - Surface Laplacians (SL) and phase properties of EEG rhythms: Simulated generators in a volume-conduction model. AB - Surface Laplacian (SL) methods offer advantages in spectral analysis owing to the well-known implications of volume conduction. Although recognition of the superiority of SL over reference-dependent measures is widespread, well-reasoned cautions have precluded their universal adoption. Notably, the expected selectivity of SL for superficial rather than deep generators has relegated SL to the role of an add-on to conventional analyses, rather than as an independent area of inquiry, despite empirical findings supporting the consistency and replicability of physiological effects of interest. It has also been reasoned that the contrast-enhancing effects of SL necessarily make it insensitive to broadly distributed generators, including those suspected for oscillatory rhythms such as EEG alpha. These concerns are further exacerbated for phase-sensitive measures (e.g., phase-locking, coherence), where key features of physiological generators have yet to be evaluated. While the neuronal generators of empirically derived EEG measures cannot be precisely known due to the inverse problem, simple dipole generator configurations can be simulated using a 4-sphere head model and linearly combined. We simulated subdural and deep generators and distributed dipole layers using sine and cosine waveforms, quantified at 67-scalp sites corresponding to those used in previous research. Reference-dependent (nose, average, mastoids reference) EEG and corresponding SL topographies were used to probe signal fidelity in the topography of the measured amplitude spectra, phase and coherence of sinusoidal stimuli at and between "active" recording sites. SL consistently outperformed the conventional EEG measures, indicating that continued reluctance by the research community is unfounded. PMID- 26004021 TI - Social communication with virtual agents: The effects of body and gaze direction on attention and emotional responding in human observers. AB - In social communication, the gaze direction of other persons provides important information to perceive and interpret their emotional response. Previous research investigated the influence of gaze by manipulating mutual eye contact. Therefore, gaze and body direction have been changed as a whole, resulting in only congruent gaze and body directions (averted or directed) of another person. Here, we aimed to disentangle these effects by using short animated sequences of virtual agents posing with either direct or averted body or gaze. Attention allocation by means of eye movements, facial muscle response, and emotional experience to agents of different gender and facial expressions were investigated. Eye movement data revealed longer fixation durations, i.e., a stronger allocation of attention, when gaze and body direction were not congruent with each other or when both were directed towards the observer. This suggests that direct interaction as well as incongruous signals increase the demands of attentional resources in the observer. For the facial muscle response, only the reaction of muscle zygomaticus major revealed an effect of body direction, expressed by stronger activity in response to happy expressions for direct compared to averted gaze when the virtual character's body was directed towards the observer. Finally, body direction also influenced the emotional experience ratings towards happy expressions. While earlier findings suggested that mutual eye contact is the main source for increased emotional responding and attentional allocation, the present results indicate that direction of the virtual agent's body and head also plays a minor but significant role. PMID- 26004022 TI - Association of the angiopoietin-like protein 8 rs2278426 polymorphism and several environmental factors with serum lipid levels. AB - The present study was performed to examine the association of the angiopoietin like protein 8 (ANGPTL8) rs2278426 single nucleotide polymorphism (SNP) and several environmental factors with serum lipid profiles in the Mulao and Han populations. A total of 879 individuals of the Mulao ethnic group and 865 individuals of the Han Chinese ethnic group were included. The serum apolipoprotein (Apo) B level was higher, however the serum ApoA1 level was lower in the Mulao individuals than in the Han individuals (P<0.05 and P<0.001, respectively). The genotypic and allelic frequencies, and the association with the ANGPTL8 rs2278426 SNP were different between the Mulao and Han populations. The frequency of the A allele was 17.80% in Han individuals and 23.04% in Mulao individuals (P<0.001). The frequencies of GG, GA and AA genotypes were 68.79, 26.82 and 4.39% in the Han population, and 60.64, 32.65 and 6.71% in the Mulao population (P<0.005), respectively. A significant association between the SNP and serum lipid traits was only detected in Han females and not in Han males or in the Mulao population. The subjects with GA/AA genotypes had lower low-density lipoprotein cholesterol (LDL-C) and ApoB levels, and higher ApoA1 levels with a higher ApoA1/ApoB ratio than the subjects with the GG genotype in the Han population. Subgroup analyses revealed that the subjects with the GA/AA genotype had lower levels of total cholesterol, LDL-C and ApoB, and a higher ApoA1/ApoB ratio than the subjects with the GG genotype in Han females (P<0.05-P<0.001). Serum lipid parameters were also associated with several environmental factors, including dietary patterns, lifestyle, obesity, physical inactivity and hypertension, in the two ethnic groups (P<0.05-0.001). These findings suggest that there may be an ethnic- and gender-specific association of the rs2278426 SNP and serum lipid parameters. PMID- 26004023 TI - [Squirting and female ejaculation in 2015?]. AB - Since Antiquity, women who expulse a large quantity of liquid during sexual stimulation have remained a mystery. This phenomena is usually called "squirting". Many physicians have proposed different explications, however, there are very few scientific publications and their conclusions are discordant. Today, squirting is fashionable in the media, and some recent studies have brought new information. Through medical publications, we present the conclusions concerning the origin and the nature of squirting, the psychological experience of these squirting women and the feelings of their partners. PMID- 26004024 TI - [Hedrocele, an unknown pelvic organ prolapse]. AB - Pelvic floor disorders are frequent and source of symptoms which can be invalidating for patients. Between them, hedrocele is a pathology often unknown and clinically difficult to diagnose. It is a herniation of fat pad, small bowel or sigmoid colon in the recto-uterine pouch (cul-de-sac of Douglas) exercising a mass effect on the anterior wall of the rectum. Pelvic magnetic resonance imaging with morphological sequences and dynamic sequences in thrust can be very useful, allowing a comprehensive study of pelvic floor dysfunction and confirming the complete diagnosis, especially before surgery. We suggest you some examples to illustrate this pathology in order to emphasize the importance of its diagnosis, especially preoperative. A better understanding of this pelvic floor dysfunction would improve the care of patients. PMID- 26004025 TI - [Off-label use--or science before the law]. PMID- 26004026 TI - [Efficacy of a medical device containing liposomal hyaluronic acid against vulvo vaginal dryness]. AB - OBJECTIVES: Hyaluronic acid (HA) is present in the vulval and vaginal conjonctive tissue. It possesses hydrating and healing properties and is indicated to treat menopause induced vulvo-vaginal atrophy. The goal of this study is to evaluate the efficacy of a medical device containing liposomal HA upon patients of different ages suffering from vulvo-vaginal dryness (VVD). METHODS: Tested product Mucogyne(r) was applied 3 times a week for 84 days by 47 patients, 28 premenopausal young women (mean age: 32 years old) and 19 post-menopausal women (mean age: 57.5 years old) all suffering from VVD associated to spontaneous pain and dyspareunia. Clinical evaluations and Vaginal Health Index (VHS) were calculated at 0, 1 and 3 months. RESULTS: A significant clinical improvement (P<0.001) occurred at 1 month (-25 % for dryness and -46 % for pain) and at 3 months (respectively -86 and -79 %). VHS was significantly improved (P<0.001) from 30 % at 1 month to 72 % after 3 months. CONCLUSION: Liposomal AH significantly decreases symptoms and clinical signs of VVD at all ages and represents a safe and efficient alternative to topical and/or systemic hormonal therapy after menopause. PMID- 26004027 TI - Use of a 1.0 Tesla open scanner for evaluation of pediatric and congenital heart disease: a retrospective cohort study. AB - BACKGROUND: Open cardiovascular magnetic resonance (CMR) scanners offer the potential for imaging patients with claustrophobia or large body size, but at a lower 1.0 Tesla magnetic field. This study aimed to evaluate the efficacy of open CMR for evaluation of pediatric and congenital heart disease. METHODS: This retrospective, cross-sectional study included all patients <=18 years old or with congenital heart disease who underwent CMR on an open 1.0 Tesla scanner at two centers from 2012-2014. Indications for CMR and clinical questions were extracted from the medical record. Studies were qualitatively graded for image quality and diagnostic utility. In a subset of 25 patients, signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were compared to size- and diagnosis-matched patients with CMR on a 1.5 Tesla scanner. RESULTS: A total of 65 patients (median 17.3 years old, 60% male) were included. Congenital heart disease was present in 32 (50%), with tetralogy of Fallot and bicuspid aortic valve the most common diagnoses. Open CMR was used due to scheduling/equipment issues in 51 (80%), claustrophobia in 7 (11%), and patient size in 3 (5%); 4 patients with claustrophobia had failed CMR on a different scanner, but completed the study on open CMR without sedation. All patients had good or excellent image quality on black blood, phase contrast, magnetic resonance angiography, and late gadolinium enhancement imaging. There was below average image quality in 3/63 (5%) patients with cine images, and 4/15 (27%) patients with coronary artery imaging. SNR and CNR were decreased in cine and magnetic resonance angiography images compared to 1.5 Tesla. The clinical question was answered adequately in all but 2 patients; 1 patient with a Fontan had artifact from an embolization coil limiting RV volume analysis, and in 1 patient the right coronary artery origin was not well seen. CONCLUSIONS: Open 1.0 Tesla scanners can effectively evaluate pediatric and congenital heart disease, including patients with claustrophobia and larger body size. Despite minor artifacts and differences in SNR and CNR, the majority of clinical questions can be answered adequately, with some limitations with coronary artery imaging. Further evaluation is necessary to optimize protocols and image quality. PMID- 26004028 TI - Correlation between laryngobronchoscopy and pepsin in the diagnosis of extra oesophageal reflux. AB - OBJECTIVE: This study aimed to investigate pepsin as a marker of extra oesophageal reflux disease by examining its presence in tracheal aspirates and correlating it with macroscopic changes on laryngobronchoscopy, along with the results of standard tests for gastro-oesophageal reflux disease and clinical features. METHODS: A retrospective review was undertaken of a cohort of 188 paediatric patients who underwent laryngobronchoscopy at a tertiary children's hospital and for whom pepsin assay results of tracheal aspirates were available. An association analysis was performed. RESULTS: The mean patient age was 3.99 (3.40-4.58) years, with a male preponderance (55 per cent). Positive changes on laryngobronchoscopy were significantly associated with positive tracheal pepsin findings (p < 0.0001) but not with positive standard gastro-oesophageal reflux disease investigations. A positive pepsin assay was significantly associated with a history of recurrent croup (p = 0.0385) and a diagnosis of cystic fibrosis (p = 0.0232). CONCLUSION: Macroscopic changes on laryngobronchoscopy were significantly associated with positive tracheal pepsin findings in this paediatric population, suggesting that extra-oesophageal reflux disease may be a contributing aetiology. PMID- 26004029 TI - Low-dose SoluMatrix diclofenac : a review of safety across two Phase III studies in patients with acute and osteoarthritis pain. AB - INTRODUCTION: Similar to other NSAIDs, diclofenac is associated with serious dose related cardiovascular, gastrointestinal, and renal adverse events. Low-dose SoluMatrix diclofenac , containing submicron particles of diclofenac, was developed to provide effective analgesia at lower drug doses compared with currently available NSAIDs. AREAS COVERED: The efficacy and safety of low-dose SoluMatrix diclofenac was evaluated in two randomized, placebo-controlled Phase III studies: a study in patients with acute pain following bunionectomy surgery and a study in patients with osteoarthritis pain of the hip or knee. In this review article, we summarize safety data from these studies. EXPERT OPINION: The safety results from the Phase III studies indicate that all dosing regimens of low-dose SoluMatrix diclofenac up to 12 weeks are generally well tolerated. Few serious gastrointestinal, cardiovascular, renal, or hepatic adverse events commonly associated with NSAID use were reported in these studies. Although not directly compared, the safety of SoluMatrix diclofenac was similar to findings for other diclofenac drug products. The potential for safe and effective management of acute and chronic pain at reduced NSAID doses is attractive; definitive characterization of SoluMatrix diclofenac safety requires confirmation by long-term studies. PMID- 26004030 TI - ROOTS: A multicenter study in Belgium to evaluate the effectiveness and safety of liraglutide (Victoza(r)) in type 2 diabetic patients. AB - AIMS: The ROOTS study was an observational study to evaluate the effectiveness and safety of liraglutide (Victoza((r))), a GLP-1 receptor analog, in a cohort of patients with type 2 diabetes with inadequate glycaemic control despite conventional antihyperglycaemic dual therapy. The primary objective was to assess glycaemic control while using liraglutide under normal clinical practice conditions. The primary endpoint was to estimate the proportion of patients achieving improved glycaemic control defined as a HbA1c<7% or with a decrease of >=1% after 12 months. MATERIAL AND METHODS: The study included 245 subjects. They received liraglutide in addition to their usual dual therapy (metformin and sulfonylureas or pioglitazone). Age and duration (mean+/-SD) of diabetes were 58+/-10 and 9+/-5 years respectively. Body mass index was 33.9+/-6.2 kg/m(2). RESULTS: HbA1c decreased from 9.12%+/-1.28 at baseline to 7.54%+/-1.12 after one year follow-up (p<0.001). The primary endpoint was achieved in 66.5% of patients. In parallel, we observed a reduction of BMI from baseline 33.9+/-6.2 to 32.8+/ 6.3 kg/m(2) (p<0.001). At 12 months, 64.6% of the patients received liraglutide at a dosage of 1.2 mg/day, 32.7% received 1.8 mg and 2.7% 0.6 mg. Adverse drug reactions were present in 24% of subjects, most frequently gastrointestinal disorders (11.4%), mainly nausea (6.9%) and no pancreatic events. CONCLUSIONS: Treatment with liraglutide was associated with a marked improvement in glycaemic control in daily routine practice as well as with a reduction of weight, without major side effects. PMID- 26004031 TI - Improving rehabilitation after critical illness through outpatient physiotherapy classes and essential amino acid supplement: A randomized controlled trial. AB - PURPOSE: Patients recovering from critical illness may be left with significant muscle mass loss. This study aimed to evaluate whether a 6-week program of enhanced physiotherapy and structured exercise (PEPSE) and an essential amino acid supplement drink (glutamine and essential amino acid mixture [GEAA]) improves physical and psychological recovery. MATERIALS AND METHODS: Intensive care patients aged 45 years or older, with a combined intensive care unit stay/pre-intensive care unit stay of 5 days or more were recruited to a randomized controlled trial examining the effect of PEPSE and GEAA on recovery. The 2 factors were tested in a 2 * 2 factorial design: (1) GEAA drink twice daily for 3 months and (2) 6-week PEPSE in first 3 months. Primary efficacy outcome was an improvement in the 6-minute walking test at 3 months. RESULTS: A total of 93 patients were randomized to the study. Patients receiving the PEPSE and GEA had the biggest gains in distance walked in 6-minute walking test (P < .0001). There were also significant reductions in rates of anxiety in study groups control supplement/PEPSE (P = .047) and GEAA supplement/PEPSE (P = .036) and for GEAA supplement/PEPSE in depression (P = .0009). CONCLUSION: Enhanced rehabilitation combined with GEAA supplement may enhance physical recovery and reduce anxiety and depression. PMID- 26004032 TI - Emerging intracellular receptors for hemorrhagic fever viruses. AB - Ebola virus and Lassa virus belong to different virus families that can cause viral hemorrhagic fever, a life-threatening disease in humans with limited treatment options. To infect a target cell, Ebola and Lassa viruses engage receptors at the cell surface and are subsequently shuttled into the endosomal compartment. Upon arrival in late endosomes/lysosomes, the viruses trigger membrane fusion to release their genome into the cytoplasm. Although contact sites at the cell surface were recognized for Ebola virus and Lassa virus, it was postulated that Ebola virus requires a critical receptor inside the cell. Recent screens for host factors identified such internal receptors for both viruses: Niemann-Pick disease type C1 protein (NPC1) for Ebola virus and lysosome associated membrane protein 1 (LAMP1) for Lassa virus. A cellular trigger is needed to permit binding of the viral envelope protein to these intracellular receptors. This 'receptor switch' represents a previously unnoticed step in virus entry with implications for host-pathogen interactions and viral tropism. PMID- 26004033 TI - Microdissecting the role of microRNAs in the pathogenesis of prostate cancer. AB - MicroRNAs (miRNAs) are naturally occurring, small, non-coding RNA molecules that post-transcriptionally regulate the expression of a large number of genes involved in various biological processes, either through mRNA degradation or through translation inhibition. Since the discovery of miRNAs, a vast amount of research has implicated the deregulated expression of miRNAs in different malignancies, including prostate cancer (PCa). Different miRNA expression profiles are reportedly associated with the development, progression, and emergence of castration-resistant PCa (CRPC), suggesting their use in the diagnosis, prognosis, and development of anti-cancer treatment models directed against this disease. However, before their exploitation in terms of therapeutics, a thorough understanding and in-depth mechanistic studies of these miRNAs and the gene networks they orchestrate are necessary for ascertaining their definitive role in the development and progression of PCa. This review attempts to extensively summarize the current knowledge of aberrantly expressed miRNAs and their mode of action in PCa, while highlighting the existing discrepancies and future research warranted. PMID- 26004034 TI - Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis. AB - Atherosclerosis is a lipid-driven chronic inflammatory disorder. Monocytes and macrophages are key immune cells in the development of disease and clinical outcome. It is becoming increasingly clear that epigenetic pathways govern many aspects of monocyte and macrophage differentiation and activation. The dynamic regulation of epigenetic patterns provides opportunities to alter disease associated epigenetic states. Therefore, pharmaceutical companies have embraced the targeting of epigenetic processes as new approaches for interventions. Particularly histone deacetylase (Hdac) inhibitors and DNA-methyltransferase inhibitors have long received attention and several of them have been approved for clinical use in relation to hematological malignancies. The key focus is still on oncology, but Alzheimer's disease, Huntington's disease and inflammatory disorders are coming in focus as well. These developments raise opportunities for the epigenetic targeting in cardiovascular disease (CVD). In this review we discuss the epigenetic regulation of the inflammatory pathways in relation to atherosclerosis with a specific attention to monocyte- and macrophage-related processes. What are the opportunities for future therapy of atherosclerosis by epigenetic interventions? PMID- 26004036 TI - Stiffness of cancer cells measured with an AFM indentation method. AB - The stiffness of cancer cells and its changes during metastasis are very important for understanding the pathophysiology of cancer cells and the mechanisms of metastasis of cancer. As the first step of the studies on the mechanics of cancer cells during metastasis, we determined the elasticity and stiffness of cancer cells with an indentation method using an atomic force microscope (AFM), and compared with those of normal cells. In most of the past AFM studies, Young's elastic moduli of cells have been calculated from force indentation data using Hertzian model. As this model is based on several important assumptions including infinitesimal strain and Hooke's linear stress strain law, in the exact sense it cannot be applied to cells that deform very largely and nonlinearly. To overcome this problem, we previously proposed an equation F=a[exp(bdelta)-1] to describe relations between force (F) and indentation (delta), where a and b are parameters relating with cellular stiffness. In the present study, we applied this method to cancer cells instead of Young's elastic modulus. The conclusions obtained are: 1) AFM indentation test data of cancer cells can be very well described by the above equation, 2) cancer cells are softer than normal cells, and 3) there are no significant locational differences in the stiffness of cancer cells between the central and the peripheral regions. These methods and results are useful for studying the mechanics of cancer cells and the mechanisms of metastasis. PMID- 26004035 TI - Decidual natural killer cells regulate vessel stability: implications for impaired spiral artery remodelling. AB - Decidual NK (dNK) cells are present during uterine spiral artery remodelling, an event that is crucial for successful placentation and the provision of an adequate blood supply to the developing fetus. Spiral artery remodelling is impaired in the pregnancy complication pre-eclampsia. Although dNK cells are known to play active roles at the maternal-fetal interface, little is known about their effect on endothelial integrity, an important component of vessel stability. We present a study in which we have modelled dNK-endothelium interactions, using first-trimester dNK cells isolated from both normal pregnancies and those with impaired spiral artery remodelling. dNK cells were isolated from first-trimester pregnancies, screened by uterine artery Doppler ultrasound to determine resistance indices (RI) that relate to the extent of spiral artery remodelling. dNK culture supernatant from normal-RI pregnancies (but not high-RI pregnancies) destabilised endothelial tube-like structures in Matrigel, and normal-RI dNK cells induced endothelial intercellular adhesion molecule-1 and tumour necrosis factor-alpha expression to a greater extent than high-RI dNK cells. We have established a functional role for dNK cells in the disruption of endothelial structures and have suggested how impairment of this process may be contributing to the reduced vessel remodelling in pregnancies with a high uterine artery resistance index. These findings have implications for our understanding of the pathology of pre-eclampsia and other pregnancy disorders where remodelling is impaired. PMID- 26004037 TI - Alteration of spontaneous neuronal activity in young adults with non-clinical depressive symptoms. AB - Non-clinical depressive symptoms (nCDSs) are highly prevalent in young adults and may be associated with the risk of developing full-fledged depressive disorders. However, the neural basis underlying nCDSs remains unknown. To explore the alteration of spontaneous brain activity in individuals with nCDSs compared with healthy controls (HCs), we investigated resting-state brain activity using the amplitude of low-frequency fluctuations (ALFF) in subjects with nCDSs (n=17) and HCs (n=20). All subjects were drawn from a sample of 1105 college students participating in a survey assessing depressive symptoms. We determined that nCDSs can lead to reduced ALFF in the right ventral lateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC) and to increased ALFF in the left fusiform, left posterior cerebellum, right cuneus, left inferior parietal lobule, right supramarginal gyrus and bilateral precuneus. In addition, with respect to Beck Depression Inventory (BDI) scores and ALFF values in subjects with nCDSs, a positive correlation was discovered in the right DLPFC, while a negative correlation was identified in left posterior cerebellum and bilateral precuneus after correction. These results indicate that nCDSs are characterized by altered spontaneous activity in several important functional regions. We suggest that altered ALFFs in the right DLPFC, left posterior cerebellum and bilateral precuneus may be biomarkers that are related to the pathophysiology of nCDSs in young adults. PMID- 26004038 TI - Spectroscopic XPEEM of highly conductive SI-doped GaN wires. AB - Using soft X-ray photoelectron emission microscopy (XPEEM), complemented by scanning Auger microscopy (SAM) and scanning capacitance microscopy, we have quantitatively studied the incorporation of silicon and band bending at the surface (m-facet) of an individual, highly conductive Si-doped GaN micro-wires (Tchoulfian et al., Applied Physics Letters 102 (12), 2013). Electrically active n-dopants Si atoms in Ga interstitial sites are detected as nitride bonding states in the high-resolution Si2p core level spectra, and represent only a small fraction (<10%) of the overall Si surface concentration measured by SAM. The derived carrier concentration of 2*10(21) at cm(-3) is in reasonable agreement with electrical measurements. A consistent surface band bending of ~1 eV is directly evidenced by surface photo-voltage measurements. Such an approach combining different surface-sensitive microscopies is of interest for studying other heavily doped semiconducting wires. PMID- 26004039 TI - Resected gastric cancer with D2 dissection: advances in adjuvant chemoradiotherapy and radiotherapy techniques. AB - Surgery is the main treatment option for locally advanced gastric cancer. D2 dissection has been recommended worldwide as standard lymphadenectomy for resectable gastric cancer. Furthermore, the role of peri- or postoperative chemotherapy for D2-dissected gastric cancer has been established in both Western and European countries. It has been disputed whether adding radiotherapy to chemotherapy could further benefit those patients. Until recently, studies from Korea and China may have made it clear. In North America, however, the INT-0116 trial does not rule out that chemoradiotherapy is effective in patients with D2 dissection, but the ongoing CRITICS trial will, hopefully, clarify this. In addition, literature published in the past decade supports the theory that improved radiotherapy techniques are likely to accurately deliver radiation dose and significantly reduce radiation toxicity. Finally, the status of E2F-1 and HER 2 may be associated with efficacy of radiotherapy based on retrospective studies. PMID- 26004040 TI - Rodeo athletes: management of shoulder instability. AB - BACKGROUND: The aim of this study was to describe epidemiological data and evaluate the clinical results of traumatic anterior glenohumeral instability in rodeo athletes. METHODS: Thirteen patients, all male, with a mean age of 23.2 (18 31) years old, with anterior glenohumeral instability were include in this study. In 9 patients, the right side was affected. The mean time elapsed between injury and undergoing surgery was 56 months (24-120 months). The surgical technique used (arthroscopic or open bone block procedure) was chosen based on the ISIS (Instability Severity Index Score). Only professional athletes who had been in the sport for at least 60 months were included. Functional evaluation was conducted using the UCLA scale, after a 24-month follow-up period. RESULTS: The number of dislocation episodes varied from 10 to 100 (mean 27 episodes). All of the patients were submitted a surgical treatment open bone block procedure, due to their degree of sport participation, type of sport (forced overhead and collision) and the presence of associated bone defect lesions. According to UCLA criteria, the results were excellent in 12 patients and good in one. The mean time elapsed before returning to the sport was five months, varying between two and ten months. Complications included one patient developing axillary neuropraxia, which was completely resolved six months after the operation, and another patient developed a superficial skin infection. CONCLUSIONS: The rodeo athletes with anterior shoulder instability had serious associated bony lesions and has good outcome after bone block procedure. PMID- 26004041 TI - The effects of regular supplementary flexibility training on physical fitness performance of young high-level soccer players. AB - BACKGROUND: The present study examined the effect of regular static flexibility training on selective physical fitness components in young high-level soccer players. METHODS: Twenty three players (mean+/-SD) were randomly assigned into flexibility (Flex) and control (Con) groups (Flex group: N.=12, age 16.1+/-0.6 years; height 1.71+/-.06 m; body mass 62.4+/-7.5 kg; peak oxygen uptake [VO2peak] 55.8+/-4.1 ml.kg-1.min-1; Con group: N.=11, age 15.9+/-0.6 years; height 1.73+/ .07 m; body mass 61.5+/-5.6 kg; VO2peak 54.2+/-5.2 mL.kg-1.min-1). The Flex group performed a specific static stretching training-program before and after each training session, for four weeks (4 days/week). The two groups performed two series of anthropometrics and physical-fitness tests prior to and following the application of the stretching training performed on the Flex group. RESULTS: There were initially no main treatment effects on aerobic capacity (VO2peak), on 10-m sprint and on Broad-jump. However, sit-and-reach flexibility, 35m sprint and agility (P<0.05) performance, and when results corrected with Delta (magnitude of changes), Delta flexibility, Delta 35m-sprint, Delta agility and Delta Broad jump (P<.05) scores were significantly improved in Flex group compared with Con group. CONCLUSIONS: The present results suggest that regular specific supplementary application of static stretching training is effective in improving flexibility, 35-m speed, explosiveness and agility performance in young high-level soccer players. PMID- 26004042 TI - Tactical swimming activity and heart rate aspects of youth water polo game. AB - BACKGROUND: Although physical demands could differently occur during particular phases of the youth water polo game, at present, literature lacks of time-motion and heart rate data referred to specific tactical situation. Therefore, the present study aimed to analyze a youth water polo game, specifying heart rate, and swimming activity aspects in relation to game situations. METHODS: Twenty-six youth male players (15.6+/-0.5 years old) voluntary played a friendly game, which was tactically analyzed (offensive and defensive Even and Counterattack situation, and Power-play, Inferiority and Game Breaks) using notational analysis procedures. Successively, the heart rate (aerobic, anaerobic) and time motion (horizontal, vertical, and duel swimming patterns, with and without ball possession, backstroke) analyses were applied only to six (3 for team) players because they performed at list half of the total game duration. The tactical scenarios were mainly characterized by offensive (33%) and defensive (33%) even possessions, and game breaks (23%). RESULTS: No effect emerged between situations in terms of heart rate distribution, because it principally resulted as aerobic (range: 58-97%). The swimming activity analysis mainly showed differences (P<=0.05) between offensive counterattack and power-play in terms of distance (1 min of game, single pattern), time duration (1 min of game), and speed (single pattern) related to the horizontal activity. Repeated high intensity activities were performed 3.0+/-2.8 (range: 1-7) during the game. CONCLUSIONS: The findings of the present study provide important information for the planning of youth water polo training, with specific reference to playing situations. PMID- 26004043 TI - Effect of the Pilates method on physical conditioning of healthy subjects: a systematic review and meta-analysis. AB - INTRODUCTION: Physical conditioning consists of a variety of health-related attributes and Pilates exercises are described as a form of this conditioning. The objective of this systematic review was to determine the effect of the Pilates method on health and ability outcome of the physical conditioning of healthy individuals. EVIDENCE ACQUISITION: The search was performed in the following databases: Medline, Cinahl, Embase, Lilacs, Scielo, Web of Science, PEDro, Cochrane Controlled Trials Register Library, Scopus, Science Direct and Google Scholar. (1950-2014). Included studies were randomized controlled trials (RCTs) that assessed the effects of the Pilates method on healthy subjects. EVIDENCE SYNTHESIS: Nine RCTs met the inclusion criteria. Pilates improved abdominal muscular endurance when compared with no exercises (mean difference [MD]=9.53%; 95% CI: 2.41, 16.43; P=0.009), however, there was no difference in flexibility (MD=4.97; 95% CI: -0.53, 10.47; P=0.08). Some positive effects (up to 6 months) of the Pilates practice were found in some RCTs' results as follows: Improvement of dynamic balance, quality of life and back muscle flexibility. CONCLUSIONS: The results indicate the Pilates exercises performed on the mat or apparatus 2 to 3 times a week, for 5 to 12 weeks, improves abdominal muscular endurance (on average, 10 more abdominals curls in 1-minute sit-up test) for both genders, when compared to no exercises. PMID- 26004044 TI - The effects of modified exponential tapering technique on perceived exertion, heart rate, time trial performance, VO2max and power output among highly trained junior cyclists. AB - BACKGROUND: The present study investigated the effects of a 2-week modified exponential taper on physiological adaptation and time trial performance among junior cyclists. METHODS: Participants (N.=27) with the mean age of 16.95+/-0.8 years, height of 165.6+/-6.1 cm and weight of 54.19+/-8.1 kg were matched into either modified exponential taper (N.=7), normal exponential taper (N.=7), or control (N.=7) groups using their initial VO2max values. Both experimental groups followed a 12-week progressive endurance training program and subsequently, a 2 week tapering phase. A simulated 20-km time trial performance along with VO2max, power output, heart rate and rating of perceived exertion were measured at baseline, pre and post-taper. One way ANOVA was used to analyze the difference between groups before the start of the intervention while mixed factorial ANOVA was used to analyze the difference between groups across measurement sessions. When homogeneity assumption was violated, the Greenhouse-Geisser Value was used for the corrected values of the degrees of freedom for the within subject factor the analysis. RESULTS: Significant interactions between experimental groups and testing sessions were found in VO2max (F=6.67, df=4, P<0.05), power output (F=5.02, df=4, P<0.05), heart rate (F=10.87, df=2.51, P<0.05) rating of perceived exertion (F=13.04, df=4, P<0.05) and 20KM time trial (F=4.64, df=2.63, P<0.05). Post-hoc analysis revealed that both types of taper exhibited positive effects compared to the non-taper condition in the measured performance markers at post taper while no different were found between the two taper groups. CONCLUSIONS: It was concluded that both taper protocols successfully inducing physiological adaptations among the junior cyclists by reducing the volume and maintaining the intensity of training. PMID- 26004045 TI - Biliary collateral veins and associated biliary abnormalities of portal hypertensive biliopathy in patients with cavernous transformation of portal vein. AB - PURPOSE: The purpose was to investigate magnetic resonance imaging (MRI) features of biliary collateral veins and associated biliary abnormalities of portal hypertensive biliopathy (PHB). MATERIALS AND METHODS: Thirty-six patients including 18 patients with abnormal biliary changes and 18 patients as control group were involved in this study. MRI features of biliary collateral veins were analyzed. RESULTS: Stenosis with dilated proximal bile ducts occurred in 33.3% of patients, 27.8% of patients had irregular ductal walls, 22.2% of patients had thickened ductal walls, 16.7% of patients had angulated ductal walls, and 44.4% of patients had thickened gallbladder walls. CONCLUSIONS: Biliary collateral veins and associated biliary abnormalities of PHB can be detected by MRI. PMID- 26004046 TI - Celiac Disease - A Case Series from North India. PMID- 26004047 TI - Co-production in practice: how people with assisted living needs can help design and evolve technologies and services. AB - BACKGROUND: The low uptake of telecare and telehealth services by older people may be explained by the limited involvement of users in the design. If the ambition of 'care closer to home' is to be realised, then industry, health and social care providers must evolve ways to work with older people to co-produce useful and useable solutions. METHOD: We conducted 10 co-design workshops with users of telehealth and telecare, their carers, service providers and technology suppliers. Using vignettes developed from in-depth ethnographic case studies, we explored participants' perspectives on the design features of technologies and services to enable and facilitate the co-production of new care solutions. Workshop discussions were audio recorded, transcribed and analysed thematically. RESULTS: Analysis revealed four main themes. First, there is a need to raise awareness and provide information to potential users of assisted living technologies (ALTs). Second, technologies must be highly customisable and adaptable to accommodate the multiple and changing needs of different users. Third, the service must align closely with the individual's wider social support network. Finally, the service must support a high degree of information sharing and coordination. CONCLUSIONS: The case vignettes within inclusive and democratic co-design workshops provided a powerful means for ALT users and their carers to contribute, along with other stakeholders, to technology and service design. The workshops identified a need to focus attention on supporting the social processes that facilitate the collective efforts of formal and informal care networks in ALT delivery and use. PMID- 26004048 TI - Design, Synthesis, In Silico and In Vitro Studies of Substituted 1, 2, 3, 4- Tetrahydro Pyrimidine Phosphorus Derivatives. AB - Molecular docking studies of the designed two series (4a-l, 6a-l, 9 and 10) of novel substituted phosphorylated 1, 4-dihydropyridine and 1,2,3,4 tetrahydropyrimidine derivatives against the drug targets of DHFR from Bacillus cereus, LpxC from Pseudomonas aeruginosa, IDH from E. coli and MurB from Staphylococcus aureus were encouraged for their synthesis. These compounds were synthesized from substituted aromatic aldehydes, thiourea/urea and ethyl acetoacetate in the presence of polyphosphoric acid (PPA). These were further phosphorylated with diethyl (2-chloroethoxy) methyl phosphonate to get the desired products. In vitro anti-bacterial activity against the specified bacterial strains related to docked protein exhibited good inhibitory activity at different dose concentrations. Quantitative Structure Activity Relationship (QSAR) descriptors of the designed structures have demonstrated their satisfactory drug like properties. The results from Molecular Docking, QSAR descriptors and in vitro anti-bacterial activities led to the identification of safer and potential antibacterial agents of the title compounds screened. Compounds 4a, 4d, 4i, 6a, 6d, 9 and 10 were found to be potent antibacterial agents. PMID- 26004049 TI - Simple and Efficient Route Toward Ambient Preparation of Pyrimido[b]Quinolinetriones Using Copper (I) Iodide Nanoparticles in Aqueous Media. AB - A simple and efficient synthesis of pyrimido[b]quinolinetriones is introduced using copper (I) iodide nanoparticles (CuI NPs) as an efficient heterogeneous catalyst in green media-water. The catalyst was prepared through the simple precipitation route and well characterized by various techniques such as XRD and SEM. The mild reaction conditions, using aqueous medium, reusability of the catalyst, simple reaction work-up and excellent yields of products make the present protocol sustainable and advantageous compared to the conventional methods. PMID- 26004050 TI - Classification of Breast Cancer Resistant Protein (BCRP) Inhibitors and Non Inhibitors Using Machine Learning Approaches. AB - The breast cancer resistant protein (BCRP) is an important transporter and its inhibitors play an important role in cancer treatment by improving the oral bioavailability as well as blood brain barrier (BBB) permeability of anticancer drugs. In this work, a computational model was developed to predict the compounds as BCRP inhibitors or non-inhibitors. Various machine learning approaches like, support vector machine (SVM), k-nearest neighbor (k-NN) and artificial neural network (ANN) were used to develop the models. The Matthews correlation coefficients (MCC) of developed models using ANN, k-NN and SVM are 0.67, 0.71 and 0.77, and prediction accuracies are 85.2%, 88.3% and 90.8% respectively. The developed models were tested with a test set of 99 compounds and further validated with external set of 98 compounds. Distribution plot analysis and various machine learning models were also developed based on druglikeness descriptors. Applicability domain is used to check the prediction reliability of the new molecules. PMID- 26004051 TI - Synthesis of 9H-furo [2,3-f]Chromene Derivatives by Promoting ZnO Nanoparticles. AB - Three- component reactions of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1 ethanone, aldehydes and malononitrile or ethyl cyanoacetate in the presence of nanoparticles of ZnO as catalyst are explained as effective and green synthetic method for generating 9H- furo[2,3-f]chromenes in good yield. PMID- 26004052 TI - Advanced biomaterials and their potential applications in the treatment of periodontal disease. AB - Periodontal disease is considered as a widespread infectious disease and the most common cause of tooth loss in adults. Attempts for developing periodontal disease treatment strategies, including drug delivery and regeneration approaches, provide a useful experimental model for the evaluation of future periodontal therapies. Recently, emerging advanced biomaterials including hydrogels, films, micro/nanofibers and particles, hold great potential to be utilized as cell/drug carriers for local drug delivery and biomimetic scaffolds for future regeneration therapies. In this review, first, we describe the pathogenesis of periodontal disease, including plaque formation, immune response and inflammatory reactions caused by bacteria. Second, periodontal therapy and an overview of current biomaterials in periodontal regenerative medicine have been discussed. Third, the roles of state-of-the-art biomaterials, including hydrogels, films, micro/nanofibers and micro/nanoparticles, developed for periodontal disease treatment and periodontal tissue regeneration, and their fabrication methods, have been presented. Finally, biological properties, including biocompatibility, biodegradability and immunogenicity of the biomaterials, together with their current applications strategies are given. Conclusive remarks and future perspectives for such advanced biomaterials are discussed. PMID- 26004053 TI - Effect of race on outcomes (stroke and death) in patients >65 years with atrial fibrillation. AB - Atrial fibrillation (AF) is associated with stroke and death. We sought to determine whether there are any racial differences in the outcomes of death and stroke in patients with AF. We used Medicare administrative data from January 1, 2010, to December 31, 2011, to identify 517,941 patients with newly diagnosed AF. Of these, 452,986 patients (87%) were non-Hispanic white, 36,425 (7%) were black, and 28,530 (6%) were Hispanic. The association between race and outcomes of death and stroke were measured using Cox proportional hazard models. Over a median follow-up period of 20.3 months, blacks had a significantly higher hazard of death (hazard ratio [HR] = 1.46; 95% confidence interval [CI] 1.43 to 1.48; p <0.001) and stroke (HR = 1.66; 95% CI 1.57 to 1.75; p <0.001), compared with white patients. After controlling for pre-existing co-morbidities, the higher hazard of death in blacks was eliminated (HR 0.95; 95% CI 0.93 to 0.96; p <0.001) and the relative hazard of stroke was reduced (HR = 1.46; 95% CI 1.38 to 1.55; p <0.001). Similarly, Hispanics had a higher risk of death (HR = 1.11; 95% CI 1.09 to 1.14; p <0.001) and stroke (HR = 1.21; 95% CI 1.13 to 1.29; p <0.001) compared with whites. The relative hazard of death was lower in Hispanics (HR 0.82; 95% CI 0.80 to 0.84; p <0.001) compared with whites, after controlling for pre-existing co-morbidities, and the relative hazard of stroke was also attenuated (HR = 1.11; 95% CI 1.03 to 1.18; p <0.001). In conclusion, in patients >65 years with newly diagnosed AF, the risks of death and stroke are higher in blacks and Hispanics compared with whites. The increased risk was eliminated or significantly reduced after adjusting for pre-existing co-morbidities. AF may be a marker for underlying co-morbidities in black and Hispanic patients who may be at a higher mortality risk. PMID- 26004054 TI - A monograph on the remediation of hazardous phthalates. AB - Phthalates or phthalic acid esters are a group of xenobiotic and hazardous compounds blended in plastics to enhance their plasticity and versatility. Enormous quantities of phthalates are produced globally for the production of plastic goods, whose disposal and leaching out into the surroundings cause serious concerns to the environment, biota and human health. Though in silico computational, in vitro mechanistic, pre-clinical animal and clinical human studies showed endocrine disruption, hepatotoxic, teratogenic and carcinogenic properties, usage of phthalates continues due to their cuteness, attractive chemical properties, low production cost and lack of suitable alternatives. Studies revealed that microbes isolated from phthalate-contaminated environmental niches efficiently bioremediate various phthalates. Based upon this background, this review addresses the enumeration of major phthalates used in industry, routes of environmental contamination, evidences for health hazards, routes for in situ and ex situ microbial degradation, bacterial pathways involved in the degradation, major enzymes involved in the degradation process, half-lives of phthalates in environments, etc. Briefly, this handy module would enable the readers, environmentalists and policy makers to understand the impact of phthalates on the environment and the biota, coupled with the concerted microbial efforts to alleviate the burden of ever increasing load posed by phthalates. PMID- 26004055 TI - BRCA-associated pancreatico-biliary neoplasms: Four cases illustrating the emerging clinical impact of genotyping. PMID- 26004056 TI - Virtually-induced threat in Parkinson's: Dopaminergic interactions between anxiety and sensory-perceptual processing while walking. AB - Research evidence has suggested that anxiety influences gait in PD, with an identified dopa-sensitive gait response in highly anxious PD. It has been well established that accurate perception of the environment and sensory feedback is essential for gait. Arguably since sensory and perceptual deficits have been noted in PD, anxiety has the potential to exacerbate movement impairments, since one might expect that reducing resources needed to overcome or compensate for sensory-perceptual deficits may lead to even more severe gait impairments. It is possible that anxiety in threatening situations might consume more processing resources, limiting the ability to process information about the environment or one's own movement (sensory feedback) especially in highly anxious PD. Therefore, the current study aimed to (i) evaluate whether processing of threat-related aspects of the environment was influenced by anxiety, (ii) evaluate whether anxiety influences the ability to utilize sensory feedback in PD while walking in threatening situations, and (iii) further understand the role of dopaminergic medication on these processes in threatening situations in PD. Forty-eight participants (24 HC; 12 Low Anxious [LA-PD], 12 Highly Anxious [HA-PD]) completed 20 walking trials in virtual reality across a plank that was (i) located on the ground (GROUND) (ii) located above a deep pit (ELEVATED); while provided with or without visual feedback about their lower limbs (+VF; -VF). After walking across the plank, participants were asked to judge the width of the plank they had just walked across. The plank varied in size from 60-100 cm. Both ON and OFF dopaminergic medication states were evaluated in PD. Gait parameters, judgment error and self-reported anxiety levels were measured. Results showed that HA-PD reported greater levels of anxiety overall (p<0.001) compared to HC and LA-PD, and all participants reported greater anxiety during the ELEVATED condition compared to GROUND (p=0.01). PD had similar judgment error as HC. Additionally, medication state did not significantly influence judgment error in PD. More importantly, HA-PD were the only group that did not adjust their step width when feedback was provided during the GROUND condition. However, medication facilitated a reduction in ST-CV when visual feedback was available only in the HA-PD group. Therefore, the current study provides evidence that anxiety may interfere with information processing, especially utilizing sensory feedback while walking. Dopaminergic medication appears to improve utilization of sensory feedback in stressful situations by reducing anxiety and/or improving resource allocation especially in those with PD who are highly anxious. PMID- 26004057 TI - Pattern reactivation co-varies with activity in the core recollection network during source memory. AB - Neuroimaging studies of episodic memory have consistently demonstrated that memory retrieval involves reactivating patterns of neural activity that were present during encoding, and these effects are thought to reflect the qualitative retrieval (recollection) of information that is specific to the content of an episode. By contrast, recollection is also accompanied by other neural correlates that generalize across episodic content and are consequently referred to as the "core recollection network". The neural mechanism by which these specific and core effects interact to give rise to episodic memory retrieval is largely unknown. The current study addressed this issue by testing for correlations (connectivity) between pattern reactivation and activity in the core recollection network. Subjects encoded a series of words with different tasks and then completed a two-step source memory test, whereby they identified the task (source) previously associated with the word and the confidence of that judgment. Multivariate pattern analysis (MVPA) was used in combination with fMRI to first identify encoding-related neural patterns and then test for their reactivation during retrieval. Consistent with prior findings, the magnitude of reactivation increased with source-memory confidence. Moreover, individual-trial measures of reactivation exhibited positive correlations with activity in multiple regions of the core recollection network. Importantly, evidence of functional connectivity between pattern reactivation and a region of left posterior parietal cortex supports the role of this region in tracking the retrieval of episodic information in service of making subjective memory decisions. PMID- 26004058 TI - Distinct brain signatures of content and structure violation during action observation. AB - Sentences, musical phrases and goal-directed actions are composed of elements that are linked by specific rules to form meaningful outcomes. In goal-directed actions including a non-canonical element or scrambling the order of the elements alters the action's content and structure, respectively. In the present study we investigated event-related potentials of the electroencephalographic (EEG) activity recorded during observation of both alterations of the action content (obtained by violating the semantic components of an action, e.g. making coffee with cola) and alterations of the action structure (obtained by inverting the order of two temporally adjacent pictures of sequences depicting daily life actions) interfering with the normal flow of the motor acts that compose an action. Action content alterations elicited a bilateral posterior distributed EEG negativity, peaking at around 400 ms after stimulus onset similar to the ERPs evoked by semantic violations in language studies. Alteration of the action structure elicited an early left anterior negativity followed by a late left anterior positivity, which closely resembles the ERP pattern found in language syntax violation studies. Our results suggest a functional dissociation between the processing of action content and structure, reminiscent of a similar dissociation found in the language or music domains. Importantly, this study provides further support to the hypothesis that some basic mechanisms, such as the rule-based structuring of sequential events, are shared between different cognitive domains. PMID- 26004059 TI - Impaired auditory selective attention ameliorated by cognitive training with graded exposure to noise in patients with traumatic brain injury. AB - Patients who suffer traumatic brain injury frequently report difficulty concentrating on tasks and completing routine activities in noisy and distracting environments. Such impairments can have long-term negative psychosocial consequences. A cognitive control function that may underlie this impairment is the capacity to select a goal-relevant signal for further processing while safeguarding it from irrelevant noise. A paradigmatic investigation of this problem was undertaken using a dichotic listening task (study 1) in which comprehension of a stream of speech to one ear was measured in the context of increasing interference from a second stream of irrelevant speech to the other ear. Controls showed an initial decline in performance in the presence of competing speech but thereafter showed adaptation to increasing audibility of irrelevant speech, even at the highest levels of noise. By contrast, patients showed linear decline in performance with increasing noise. Subsequently attempts were made to ameliorate this deficit (study 2) using a cognitive training procedure based on attention process training (APT) that included graded exposure to irrelevant noise over the course of training. Patients were assigned to adaptive and non-adaptive training schedules or to a no-training control group. Results showed that both types of training drove improvements in the dichotic listening and in naturalistic tasks of performance in noise. Improvements were also seen on measures of selective attention in the visual domain suggesting transfer of training. We also observed augmentation of event-related potentials (ERPs) linked to target processing (P3b) but no change in ERPs evoked by distractor stimuli (P3a) suggesting that training heightened tuning of target signals, as opposed to gating irrelevant noise. No changes in any of the above measures were observed in a no-training control group. Together these findings present an ecologically valid approach to measure selective attention difficulties after brain injury, and provide a means to ameliorate these deficits. PMID- 26004060 TI - Distinctive laterality of neural networks supporting action understanding in left and right-handed individuals: An EEG coherence study. AB - Prior work has demonstrated that perspective and handedness of observed actions can affect action understanding differently in right and left-handed persons, suggesting potential differences in the neural networks underlying action understanding between right and left-handed individuals. We sought to evaluate potential differences in these neural networks using electroencephalography (EEG). Right- and left-handed participants observed images of tool-use actions from egocentric and allocentric perspectives, with right- and left-handed actors performing the actions. Participants judged the outcome of the observed actions, and response accuracy and latency were recorded. Behaviorally, the highest accuracy and shortest latency was found in the egocentric perspective for right- and left-handed observers. Handedness of subject showed an effect on accuracy and latency also, where right-handed observers were faster to respond than left handed observers, but on average were less accurate. Mu band (8-10 Hz) cortico cortical coherence analysis indicated that right-handed observers have coherence in the motor dominant left parietal-premotor networks when looking at an egocentric right or allocentric left hands. When looking in an egocentric perspective at a left hand or allocentric right hand, coherence was lateralized to right parietal-premotor areas. In left-handed observers, bilateral parietal premotor coherence patterns were observed regardless of actor handedness. These findings suggest that the cortical networks involved in understanding action outcomes are dependent on hand dominance, and notably right handed participants seem to utilize motor systems based on the limb seen performing the action. The decreased accuracy for right-handed participants on allocentric images could be due to asymmetrical lateralization of encoding action and motoric dominance, which may interfere with translating allocentric limb action outcomes. Further neurophysiological studies will determine the specific processes of how left- and right-handed participants understand actions. PMID- 26004061 TI - Increased motor preparation activity during fluent single word production in DS: A correlate for stuttering frequency and severity. AB - Abnormal speech motor preparation is suggested to be a neural characteristic of stuttering. One of the neurophysiological substrates of motor preparation is the contingent negative variation (CNV). The CNV is an event-related, slow negative potential that occurs between two defined stimuli. Unfortunately, CNV tasks are rarely studied in developmental stuttering (DS). Therefore, the present study aimed to evaluate motor preparation in DS by use of a CNV task. Twenty five adults who stutter (AWS) and 35 fluent speakers (FS) were included. They performed a picture naming task while an electro-encephalogram was recorded. The slope of the CNV was evaluated at frontal, central and parietal electrode sites. In addition, a correlation analysis was performed with stuttering severity and frequency measures. There was a marked increase in CNV slope in AWS as compared to FS. This increase was observed over the entire scalp with respect to stimulus onset, and only over the right hemisphere with respect to lip movement onset. Moreover, strong positive correlations were found between CNV slope and stuttering frequency and severity. As the CNV is known to reflect the activity in the basal ganglia-thalamo-cortical-network, the present findings confirm an increased activation of this loop during speech motor preparation in stuttering. The more a person stutters, the more neurons of this cortical-subcortical network seem to be activated. Because this increased CNV slope was observed during fluent single word production, it is discussed whether or not this observation refers to a successful compensation strategy. PMID- 26004062 TI - Functional brain networks involved in reality monitoring. AB - Source monitoring refers to the recollection of variables that specify the context and conditions in which a memory episode was encoded. This process involves using the qualitative and quantitative features of a memory trace to distinguish its source. One specific class of source monitoring is reality monitoring, which involves distinguishing internally generated from externally generated information, that is, memories of imagined events from real events. The purpose of the present study was to identify functional brain networks that underlie reality monitoring, using an alternative type of source monitoring as a control condition. On the basis of previous studies on self-referential thinking, it was expected that a medial prefrontal cortex (mPFC) based network would be more active during reality monitoring than the control condition, due to the requirement to focus on a comparison of internal (self) and external (other) source information. Two functional brain networks emerged from this analysis, one reflecting increasing task-related activity, and one reflecting decreasing task related activity. The second network was mPFC based, and was characterized by task-related deactivations in areas resembling the default-mode network; namely, the mPFC, middle temporal gyri, lateral parietal regions, and the precuneus, and these deactivations were diminished during reality monitoring relative to source monitoring, resulting in higher activity during reality monitoring. This result supports previous research suggesting that self-referential thinking involves the mPFC, but extends this to a network-level interpretation of reality monitoring. PMID- 26004063 TI - Shared neural substrates of apraxia and aphasia. AB - Apraxia is regularly associated with aphasia, but there is controversy whether their co-occurrence is the expression of a common basic deficit or results from anatomical proximity of their neural substrates. However, neither aphasia nor apraxia is an indivisible entity. Both diagnoses embrace diverse manifestations that may occur more or less independently from each other. Thus, the question whether apraxia is always accompanied by aphasia may lead to conflicting answers depending on which of their manifestations are considered. We used voxel based lesion symptom mapping (VLSM) for exploring communalities between lesion sites associated with aphasia and with apraxia. Linguistic impairment was assessed by the Aachen Aphasia Test (AAT) subtests naming, comprehension, repetition, written language, and Token Test. Apraxia was examined for imitation of meaningless hand and finger postures and for pantomime of tool use. There were two areas of overlap between aphasia and apraxia. Lesions in the anterior temporal lobe interfered with pantomime of tool use and with all linguistic tests. In the left inferior parietal lobe there was a large area where lesions were associated with defective imitation of hand postures and with poor scores on written language and the Token Test. Within this large area there were also two spots in supramarginal and angular gyrus where lesions were also associated with defective pantomime. We speculate that the coincidence of language impairment and defective pantomime after anterior temporal lesions is due to impaired access to semantic memory. The combination of defective imitation of hand postures with poor scores on Token Test and written language is not easily compatible with a crucial role of parietal regions for the conversion of concepts of intended actions into motor commands. It accords better with a role of left inferior parietal lobe regions for the categorical perception of spatial relationships. PMID- 26004064 TI - Spatial attention systems in spatial neglect. AB - It has been established that processes relating to 'spatial attention' are implemented at cortical level by goal-directed (top-down) and stimulus-driven (bottom-up) networks. Spatial neglect in brain-damaged individuals has been interpreted as a distinguished exemplar for a disturbance of these processes. The present paper elaborates this assumption. Functioning of the two attentional networks seem to dissociate in spatial neglect; behavioral studies of patients' orienting and exploration behavior point to a disturbed stimulus-driven but preserved goal-directed attention system. When a target suddenly appears somewhere in space, neglect patients demonstrate disturbed detection and orienting if it is located in contralesional direction. In contrast, if neglect patients explore a scene with voluntarily, top-down controlled shifts of spatial attention, they perform movements that are oriented into all spatial directions without any direction-specific disturbances. The paper thus argues that not the top-down control of spatial attention itself, rather a body-related matrix on top of which this process is executed, seems affected. In that sense, the traditional role of spatial neglect as a stroke model for 'spatial attention' requires adjustment. Beyond its insights into the human stimulus-driven attentional system, the disorder most notably provides vistas in how our brain encodes topographical information and organizes spatially oriented action - including the top-down control of spatial attention - in relation to body position. PMID- 26004065 TI - Effectively engaging the private sector through vouchers and contracting - A case for analysing health governance and context. AB - Health systems of low and middle income countries in the Asia Pacific have been described as mixed, where public and private sector operate in parallel. Gaps in the provision of primary health care (PHC) services have been picked up by the private sector and led to its growth; as can an enabling regulatory environment. The question whether governments should purchase services from the private sector to address gaps in service provision has been fiercely debated. This purposive review draws evidence from systematic reviews, and additional published and grey literature, for input into a policy brief on purchasing PHC-services from the private sector for underserved areas in the Asia Pacific region. Additional published and grey literature on vouchers and contracting as mechanisms to engage the private sector was used to supplement the conclusions from systematic reviews. We analysed the literature through a policy lens, or alternatively, a 'bottom-up' approach which incorporates components of a realist review. Evidence indicates that both vouchers and contracting can improve health service outcomes in underserved areas. These outcomes however are strongly influenced by (1) contextual factors, such as roles and functions attributable to a shared set of key actors (2) the type of delivered services and community demand (3) design of the intervention, notably provider autonomy and trust (4) governance capacity and provision of stewardship. Examining the experience of vouchers and contracting to expand health services through engagement with private sector providers in the Asia Pacific found positive effects with regards to access and utilisation of health services, but more importantly, highlighted the significance of contextual factors, appropriate selection of mechanism for services provided, and governance arrangements and stewardship capacity. In fact, for governments seeking to engage the private sector, analysis of context and capacities are potentially a more useful frame than generalizable outcomes of effectiveness. PMID- 26004066 TI - Prevalence of eae-positive, lactose non-fermenting Escherichia albertii from retail raw meat in China. AB - Escherichia albertii is a newly emerging enteric pathogen that has been associated with gastroenteritis in humans. Recently, E. albertii has also been detected in healthy and sick birds, animals, chicken meat and water. In the present study, the prevalence and characteristics of the eae-positive, lactose non-fermenting E. albertii strains in retail raw meat in China were evaluated. Thirty isolates of such strains of E. albertii were identified from 446 (6.73%) samples, including duck intestines (21.43%, 6/28), duck meat (9.52%, 2/21), chicken intestines (8.99%, 17/189), chicken meat (5.66%, 3/53), mutton meat (4.55%, 1/22) and pork meat (2.44%, 1/41). None was isolated from 92 samples of raw beef meat. Strains were identified as E. albertii by phenotypic properties, diagnostic PCR, sequence analysis of the 16S rRNA gene, and housekeeping genes. Five intimin subtypes were harboured by these strains. All strains possessed the II/III/V subtype group of the cdtB gene, with two strains carrying another copy of the I/IV subtype group. Pulsed-field gel electrophoresis showed high genetic diversity of E. albertii in raw meats. Our findings indicate that E. albertii can contaminate various raw meats, posing a potential threat to public health. PMID- 26004067 TI - DNA Demethylation Dynamics in the Human Prenatal Germline. AB - Global DNA demethylation in humans is a fundamental process that occurs in pre implantation embryos and reversion to naive ground state pluripotent stem cells (PSCs). However, the extent of DNA methylation reprogramming in human germline cells is unknown. Here, we performed whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq) of human prenatal germline cells from 53 to 137 days of development. We discovered that the transcriptome and methylome of human germline is distinct from both human PSCs and the inner cell mass (ICM) of human blastocysts. Using this resource to monitor the outcome of global DNA demethylation with reversion of primed PSCs to the naive ground state, we uncovered hotspots of ultralow methylation at transposons that are protected from demethylation in the germline and ICM. Taken together, the human germline serves as a valuable in vivo tool for monitoring the epigenome of cells that have emerged from a global DNA demethylation event. PMID- 26004068 TI - RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma. AB - For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular understanding of these distinct disease manifestations can critically inform patient management. Using genetically engineered mouse models, we show that heterozygous mutation of Dpc4/Smad4 attenuates the metastatic potential of Kras(G12D/+);Trp53(R172H/+) pancreatic ductal adenocarcinomas while increasing their proliferation. Subsequent loss of heterozygosity of Dpc4 restores metastatic competency while further unleashing proliferation, creating a highly lethal combination. Expression levels of Runx3 respond to and combine with Dpc4 status to coordinately regulate the balance between cancer cell division and dissemination. Thus, Runx3 serves as both a tumor suppressor and promoter in slowing proliferation while orchestrating a metastatic program to stimulate cell migration, invasion, and secretion of proteins that favor distant colonization. These findings suggest a model to anticipate likely disease behaviors in patients and tailor treatment strategies accordingly. PMID- 26004069 TI - Structural Insights into Bunyavirus Replication and Its Regulation by the vRNA Promoter. AB - Segmented negative-strand RNA virus (sNSV) polymerases transcribe and replicate the viral RNA (vRNA) within a ribonucleoprotein particle (RNP). We present cryo EM and X-ray structures of, respectively, apo- and vRNA bound La Crosse orthobunyavirus (LACV) polymerase that give atomic-resolution insight into how such RNPs perform RNA synthesis. The complementary 3' and 5' vRNA extremities are sequence specifically bound in separate sites on the polymerase. The 5' end binds as a stem-loop, allosterically structuring functionally important polymerase active site loops. Identification of distinct template and product exit tunnels allows proposal of a detailed model for template-directed replication with minimal disruption to the circularised RNP. The similar overall architecture and vRNA binding of monomeric LACV to heterotrimeric influenza polymerase, despite high sequence divergence, suggests that all sNSV polymerases have a common evolutionary origin and mechanism of RNA synthesis. These results will aid development of replication inhibitors of diverse, serious human pathogenic viruses. PMID- 26004071 TI - Cytokeratin localization and basal cell differentiation in the epididymal epithelium during postnatal development of the mouse. AB - The epididymis is a male genital organ that has plays various functions, including sperm concentration, maturation, and storage. The epididymal epithelium consists of principal cells, clear cells, and basal cells. To comprehensively understand the occurrence and morphological differentiation of basal cells, we examined the expression and localization of cytokeratins (CKs) in the epididymal epithelium during postnatal development of the mouse. Immunohistochemical staining showed that, in adult mice, CK5 and CK14 were exclusively expressed in the cytoplasm of basal cells. During postnatal development, basal cells that stained positive for CK5 and CK14 first appeared in immature columnar epithelial cells in mice aged 1 week. The immunoreactivity became progressively stronger in mice aged 2-3 weeks. In mice aged 3 weeks, the immunoreactivity was strong in regions IV and V. In mice aged >= 4 weeks, strong immunoreactivity was observed in all epididymal regions. CK5 and CK14 could be useful markers of differentiation in epididymal basal cells. These basal cells originate from immature columnar epithelial cells and are of two types-dome-shaped and flask shaped-. The flask-shaped cells are mainly located in the initial segment of the mouse epididymis. PMID- 26004072 TI - Lectin-binding sites in epithelial cells of the mouse prostate gland. AB - The prostate is an exocrine gland in the male reproductive tract that secretes seminal fluids. To gain insight into the cytochemical properties of prostatic epithelial cells, the characteristics of glycoconjugates in mouse prostate sections were examined by lectin histochemistry and immunohistochemistry. Characteristic staining patterns were observed, depending on the type of lectins present in the epithelia. Luminal cells reacted specifically with mannose-binding lectins (Galanthus nivalis lectin, Hippeastrum hybrid lectin, Narcissus pseudonarcissus lectin) and Maclura pomifera lectin in all lobes of the prostate. Luminal cells also expressed galactose, N-acetyl-D-galactosamine (GalNAc), N acetyl-D-glucosamine (GlcNAc), and fucose residues in the lateral and ventral lobes. Basal cells expressed GlcNAc and fucose, and reacted with Datura stramonium lectin and Aleuria aurantia lectin in all lobes. These results indicate that in the mouse prostate, the selectivity of lectin-binding sites for distinct cell types and lobe-dependent staining may relate to cellular and regional differences in function. Furthermore, some lectins selectively bound to prostatic epithelial cells, indicating their potential use as markers for the histopathological evaluation of prostatic diseases, cancer diagnosis, or male infertility. PMID- 26004073 TI - Chemoarchitecture of glial fibrillary acidic protein (GFAP) and glutamine synthetase in the optic nerve of the monkey (Macaca fuscata): An immunohistochemical study. AB - An immunohistochemical analysis of the chemoarchitecture of glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) was conducted in the monkey optic nerve. The optic nerve has been divided into 3 regions: the prelaminar, lamina cribrosa, and retrolaminar regions. However, it currently remains unclear whether the chemoarchitecture of GFAP and GS is homogeneously organized, especially in the retrolaminar region. Strong-to-moderate GFAP immunoreactivity was observed in all 3 regions. The retrolaminar region was further divided into anterior (RLa) and posterior (RLp) retrolaminar regions. More GFAP immunoreactive punctations were observed in the RLa region than in the RLp region. Regarding GS immunoreactivity, moderately GS immunoreactive glial cells were observed in the prelaminar and retrolaminar regions. In the retrolaminar region, there were more of these cells in the RLa region than in the RLp region. GS immunoreactivity was markedly weaker in the prelaminar and retrolaminar regions than in the retina. Thus, the chemoarchitecture of GFAP and GS was heterogeneously organized in the retrolaminar region, and the RLa region was the main GS distribution site in the retrolaminar region. Since GS is a key enzyme of glutamate metabolism, these results may provide clues as to how glutamate is metabolized in the primate optic nerve. PMID- 26004070 TI - Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors. AB - The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene restricted ontogenies. PMID- 26004074 TI - Photopic full-field electroretinography and optical coherence tomography in type 1 diabetic retinopathy. AB - PURPOSE: The purpose of this study was to evaluate the role of photopic full field electroretinography (ERG) and retinal thickness measurements by spectral domain optical coherence tomography (SD-OCT) in the assessment of disease severity in type 1 diabetic retinopathy. METHODS: A population-based cohort of 151 patients with type 1 diabetes underwent a complete ophthalmic examination, including photopic full-field ERG and SD-OCT for retinal thickness measurements. Stereoscopic fundus photographs were taken according to the Early Treatment Diabetic Retinopathy Study protocol, and the classification of diabetic retinopathy was based on the International Clinical Diabetic Retinopathy Disease Severity Scale. Associations between photographically determined retinopathy level, b-wave amplitude and peak time of the photopic single-flash and 30-Hz flicker ERG, and central retinal thickness parameters were evaluated. RESULTS: For all ERG measurements, the amplitude decreased and peak time increased with progression of the disease, but these associations lost statistical significance after adjusting for age and excluding laser-treated patients. Mean retinal thickness was significantly associated with the b-wave amplitude of photopic single-flash and 30-Hz flicker responses (r(2) = 0.08, p = 0.006; and r(2) = 0.05, p = 0.025, respectively), but revealed no association with retinopathy level. CONCLUSIONS: Photopic full-field ERG and SD-OCT-derived retinal thickness parameters have limited clinical value in the staging of diabetic retinopathy. However, thinning of the central retina leads to significant functional impairment and may reflect an ongoing neurodegenerative process in the retinal tissue. PMID- 26004075 TI - Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma. AB - PURPOSE: To evaluate the retinal function and the neural conduction along the visual pathways after treatment with citicoline eye drops in patients with open angle glaucoma (OAG). METHODS: Fifty-six OAG patients (mean age 52.4 +/- 4.72 years, IOP <18 mmHg with beta-blocker monotherapy only) were enrolled. Of these, 47 eyes completed the study: 24 OAG eyes were treated with topical citicoline (OMK1(r), Omikron Italia, 3 drops/day) (GC eyes) over a 4-month period (month 4) followed by a 2-month period of citicoline wash-out (month 6), and another 23 OAG eyes were only treated with beta-blocker monotherapy (GP eyes). In GC and GP eyes, pattern electroretinogram (PERG) and visual evoked potentials (VEP) were assessed at baseline and at months 4 and 6 in both groups. RESULTS: At baseline, similar (ANOVA, p > 0.01) PERG and VEP values in GC and GP eyes were observed. After treatment with topical citicoline, a significant (p < 0.01) increase of PERG P50-N95 and VEP N75-P100 amplitudes, and a significant (p < 0.01) shortening of VEP P100 implicit times were found. In GC eyes, the shortening of VEP P100 implicit times was correlated significantly (p < 0.01) with the increase of PERG P50-N95 amplitudes. After a 2-month period of topical Citicoline wash-out, PERG and VEP values were similar (p > 0.01) to baseline ones. GP eyes showed not significant changes of PERG and VEP values during the entire follow-up. CONCLUSIONS: Topical treatment with citicoline in OAG eyes induces an enhancement of the retinal bioelectrical responses (increase of PERG amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex (shortening and increase of VEP implicit time and amplitude, respectively). PMID- 26004076 TI - Malignant optic glioma - the spectrum of disease in a case series. AB - PURPOSE: Malignant optic glioma of adulthood is a rare, invasive neoplasm of the anterior visual pathway with 66 cases reported in the literature. It presents as anaplastic astrocytoma (WHO grade III) or glioblastoma (WHO grade IV). The present case series covers the spectrum of disease manifestations, discusses neuroradiological findings, and reviews the current literature. METHODS: Retrospective case series of five patients from three tertiary referral centers and literature review. RESULTS: Visual loss with or without pain was the presenting symptom in all patients (two women, three men). Two patients were initially misdiagnosed as optic neuritis, and one patient as atypical non arteritic anterior ischemic optic neuropathy (NAION). A neoplastic disease was suspected in the two remaining patients. MRI features were iso- to hypointensity on T1-weighted native images, contrast enhancement, and hyperintensity on T2 weighted images. Biopsy was generally diagnostic; however, one patient required two biopsies for diagnosis. The series includes an exceptional case of intraocular tumor extension and vitreous spread. The disease was lethal within one to two years in all patients. CONCLUSIONS: Malignant optic glioma is a diagnostic challenge and remains a devastating and lethal disease. Advances in the understanding of tumor biology have yet failed to translate into effective treatment regimens. PMID- 26004077 TI - Management of diffuse choroidal hemangioma in Sturge-Weber syndrome with Ruthenium-106 plaque radiotherapy. AB - PURPOSE: To evaluate Ruthenium-106 plaque radiotherapy in the treatment of diffuse choroidal hemangioma (DCH) associated with serous retinal detachment. METHODS: A retrospective analysis was performed in five patients treated for DCH associated with Sturge-Weber syndrome (SWS). In all cases, Ruthenium-106 plaque therapy with a target apex dose of 30.98-47.36 Gy (mean:38.9 Gy) was performed. The outcomes of treatment were regression of DCH, assessed by B-scan ultrasonography; resolution of serous retinal detachment, measured by B-scan ultrasonography and optical coherence tomography (OCT); changes in best corrected visual acuity (BCVA) and the development of radiation-related complications. All investigations were repeated 3 months after treatment and then at six monthly intervals within 22-122 months (mean: 62 months) of follow-up. RESULTS: The initial BCVA of the affected eyes ranged from counting fingers at 1 m to 0.1 by the Snellen chart. Mean tumor basal diameter was 16.7 mm (range: 13.8 to 18.5 mm) and mean tumor thickness was 4.4 mm (range: 2.4 to 5.8 mm). Tumor regression was found in all cases with the prompt resolution of subretinal fluid. In three patients, BCVA improved and in two it remained stable. During the follow-up period, in one case secondary glaucoma was treated with transscleral cyclophotocoagulation, and in another case, recurrence of the hemangioma was treated with repeated Ruthenium-106 plaque irradiation and transpupillary therapy. CONCLUSION: Ruthenium-106 plaque radiotherapy is an effective and safe treatment option for DCH associated with SWS. Brachytherapy led to tumor regression and resolution of serous retinal detachments, and visual stabilization was achieved in most cases. PMID- 26004078 TI - Postmortem heart weight modelled using piecewise linear regression in 27,645 medicolegal autopsy cases. AB - The interpretation of postmortem heart weight is often difficult, and references for normal heart weight are important. However, to assess the cause of death at a medicolegal autopsy it is also important to have references based on an unselected population of medicolegal autopsy cases with non-natural causes of death (not due directly to disease). We aimed at studying and deriving references for adult heart weight by considering sex, age and body size in cases with an external cause of death. We identified all medicolegal autopsies in Sweden from 1999 to 2013 (n=79,778) and included 27,645 cases. We applied multivariate piecewise linear regression models in three strata of body mass-underweight, normal-/overweight and obesity. We observed that approximately 50% of the variation in heart weight was explained by age, sex and body size. These variables were slightly less important in explaining the variation in heart weight in the underweight and obese compared to in those normal or overweight. Based on the linear regression models we present equations to calculate the predicted heart weight with reference intervals using age, sex, body weight and height. We provide an online heart weight calculator (http://lundforensicmedicine.com) based on these equations. In the forensic interpretation of postmortem heart weights, we suggest that heart weight references derived in cases with an external cause of death is an important complement to references solely based on healthy and normal hearts. Furthermore, the heart weight references presented are derived from a large population, with sufficient numbers for separate models in underweight, normal-/overweight and obese populations. PMID- 26004079 TI - Proposed criteria for the identification of polycystic ovary syndrome following menopause: An ancillary study of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - OBJECTIVES: To propose plausible criteria with which to identify menopausal women with PCOS. STUDY DESIGN: A cross-sectional study involving the baseline data of 713 menopausal women at admission to the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) in Salvador, Bahia, Brazil. MAIN OUTCOME MEASURES: PCOS was identified by the presence of two of three criteria. (1) A history of amenorrhea or oligomenorrhea (OL) (regular intermenstrual intervals >=35 days during reproductive life); (2) clinical or biochemical hyperandrogenism (HA), identified by a score >=5 points in a hirsutism questionnaire constructed and validated for women in this age group, or total or free testosterone >= the 95th percentile for women considered normal; (3) insulin resistance (IR) (a homeostatic model assessment [HOMA] index>=2.2). Validation was performed using probable epidemiological endpoints. RESULTS: According to these criteria, 7.6% of the women in the sample had PCOS. Of these, 7.4% had HA and OL, 72.2% had HA and IR, 14.8% had OL and IR and 5.6%, had HA, OL and IR. Women with PCOS were younger, had had fewer pregnancies and entered menopause earlier. Positive associations were found between PCOS and overweight (PR: 1.31; 95%CI: 1.18-1.46), obesity (1.44; 1.01-2.06), carbohydrate metabolism disorders (impaired glucose tolerance and diabetes mellitus) (1.30; 1.03-1.65), and with diabetes alone (1.41; 0.83 2.39), although this latter association failed to reach statistical significance. CONCLUSION: The women selected in accordance with these criteria had the characteristics of PCOS that are not only expected, but also widely associated with this disorder. PMID- 26004080 TI - Phantom Eye Syndrome: Patient Experiences after Enucleation for Uveal Melanoma. AB - PURPOSE: Patients undergoing enucleation for uveal melanoma need to be informed of the possibility of phantom eye syndrome (PES). The number with uveal melanoma in PES studies has been small. Aims were to: (1) determine the prevalence, symptoms, and characteristics of PES and to test associations of PES symptoms with sociodemographic and clinical characteristics; (2) examine the interrelatedness of PES symptoms; and (3) explore the emotional valence of PES and the relationship to anxiety and depression. DESIGN: Cross-sectional questionnaire. PARTICIPANTS: Patients (n = 179) with uveal melanoma enucleated 4 to 52 months previously. METHODS: Questionnaire on PES. Responses to a routine audit of mood obtained from clinical records. MAIN OUTCOME MEASURES: Patients were asked about 3 symptoms: pain, visual sensations, and a feeling of seeing through the removed eye. Mood was assessed by the Hospital Anxiety and Depression Scale. RESULTS: Of 179 respondents, 108 (60.3%) experienced symptoms: 86 reported (48%) visual sensations, 50 reported (28%) seeing, and 42 reported (23%) pain; 14 (7.8%) reported all 3 symptoms. At the time of the questionnaire, 31 (17%) experienced 1 or more symptoms daily. Women were more likely to report pain (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.08-4.40). Younger patients at enucleation were more likely to report pain (t = 4.13; degrees of freedom (df), 177; P < 0.001) and visual sensations (t = 2.11; df, 177; P < 0.05). Patients studied sooner after enucleation were more likely to report seeing (Mann-Whitney U, 2343; P < 0.05). Pain and seeing were intercorrelated (chi-square, 5.47; Phi = 0.18; df, 1; P < 0.05), pain with visual sensations (chi-square, 3.91; Phi = 0.15; df, 1; P < 0.05) and seeing with visual sensations (chi-square, 34.22; Phi = 0.45; df, 1; P < 0.001). Twenty of 108 patients (18.5%) found symptoms disturbing, and 21 of 108 (19.4%) pleasurable. Patients reporting pain were more anxious (OR, 3.53; 95% CI, 1.38-9.03) and depressed (OR, 13.26; 95% CI, 3.87 46.21). CONCLUSIONS: Patients should be informed of PES symptoms. Pain may indicate anxiety or depression; this needs research to determine cause and effect. PMID- 26004081 TI - Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci. AB - Genome-wide association studies have identified twenty loci associated with late onset Alzheimer disease (LOAD). We examined each of the twenty loci, specifically the +/-50kb region surrounding the most strongly associated variant, for changes in gene(s) transcription specific to LOAD. Post-mortem human brain samples were examined for expression, methylation, and splicing differences. LOAD specific differences were detected by comparing LOAD to normal and "disease" controls. Eight loci, prominently ABCA7, contain LOAD specific differences. Significant changes in the CELF1 and ZCWPW1 loci occurred in genes not located nearest the associated variant, suggesting that these genes should be investigated further as LOAD candidates. PMID- 26004082 TI - The fixed combination efficacy assessment in patients with secondary neovascular glaucoma and diabetes mellitus. AB - PURPOSE: To assess IOP-lowering efficacy of bimatoprost/timolol fixed combination (Ganfort(r)) in patients with diabetes mellitus (DM) and uncontrolled secondary neovascular glaucoma (NG). MATERIALS AND METHODS: Fifty patients (51 eyes) with uncontrolled secondary neovascular glaucoma and diabetes mellitus were enrolled in the study. All patients with an uncontrolled IOP have been proposed to switch current IOP-lowering therapy to Ganfort(r). In case target IOP level was not reached filtration surgery was recommended. Ganfort(r) administration - once a day in the morning. RESULTS: IOP-lowering has been observed in all patients when switched to Ganfort(r). Mean IOP level was almost 3-x lower versus baseline in 72.5% of patients (37 eyes). The patients achieved target IOP of 15-17 mmHg. As a result, no surgical intervention was required. Significant IOP-lowering has been observed in another group of patients (14 eyes, 27.5 %) nevertheless due to glaucoma progression, these patients are still subjected to surgical treatment. CONCLUSION: IOP-lowering fixed combination Ganfort(r) (Allergan) can be used in patients with secondary neovascular glaucoma and diabetes mellitus as a drug of choice to control the IOP level. Even in cases when target IOP is not achieved, Ganfort(r) can be administered in pre-operative period and helps to reduce postoperative complications. PMID- 26004083 TI - BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential. AB - Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability. BRCA1-mutated tumors have a specific pattern of genomic copy number aberrations that can be used to classify tumors as BRCA1-like or non BRCA1-like. BRCA1 mutation, promoter methylation, BRCA1-like status and genome wide expression data was determined for 112 TN breast cancer samples with long term follow-up. Mutation status for 21 known DNA repair genes and PIK3CA was assessed. Gene expression and mutation frequency in BRCA1-like and non-BRCA1-like tumors were compared. Multivariate survival analysis was performed using the Cox proportional hazards model. BRCA1 germline mutation was identified in 10% of patients and 15% of tumors were BRCA1 promoter methylated. Fifty-five percent of tumors classified as BRCA1-like. The functions of genes significantly up regulated in BRCA1-like tumors included cell cycle and DNA recombination and repair. TP53 was found to be frequently mutated in BRCA1-like (P < 0.05), while PIK3CA was frequently mutated in non-BRCA1-like tumors (P < 0.05). A significant association with worse prognosis was evident for patients with BRCA1-like tumors (adjusted HR = 3.32, 95% CI = 1.30-8.48, P = 0.01). TN tumors can be further divided into two major subgroups, BRCA1-like and non-BRCA1-like with different mutation and expression patterns and prognoses. Based on these molecular patterns, subgroups may be more sensitive to specific targeted agents such as PI3K or PARP inhibitors. PMID- 26004084 TI - Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer. AB - Metastatic colorectal cancer (CRC) is complex clinical challenge for which there are limited treatment options. Chemotherapy with or without surgery provides moderate improvements in overall survival and quality of life; nevertheless the 5 year survival remains below 30%. Oncolytic vaccinia virus (VV) shows strong anti tumour activity in models of CRC, however transient delays in disease progression are insufficient to lead to long-term survival. Here we examined the efficacy of VV with oxaliplatin or SN-38 (active metabolite of irinotecan) in CRC cell lines in vitro and VV with irinotecan in an orthotopic model of metastatic CRC. Synergistic improvements in in vitro cell killing were observed in multiple cell lines. Combination therapy was well tolerated in tumour-bearing mice and the median survival was significantly increased relative to monotherapy despite a drug-dependent decrease in the mean tumour titer. Increased apoptosis following in vitro and in vivo combination therapy was observed. In vitro cell cycle analysis showed increases in S-phase cells following infection occurred in both infected and uninfected cell populations. This corresponded to a 4-fold greater increase in apoptosis in the uninfected compared to infected cells following combination therapy. Combination treatment strategies are among the best options for patients with advanced cancers. VV is currently under clinical investigation in patients with CRC and the data presented here suggest that its combination with irinotecan may provide benefit to a subset of CRC patients. Further, investigation of this combination is necessary to determine the tumour characteristics responsible for mediating synergy. PMID- 26004085 TI - Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo. AB - Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells. Here, we assessed genetic alterations of the retinoblastoma gene (RB1) and its key regulators: Cyclin D and E as well as their inhibitors p16 and p27. In an exploratory cohort of 69 patients selected from two prospective studies treated with either doxorubicin monotherapy or 5-FU and mitomycin for locally advanced breast cancers, we found defects in the pRB-pathway to be associated with therapy resistance (p-values ranging from 0.001 to 0.094, depending on the cut-off value applied to p27 expression levels). Although statistically weaker, we observed confirmatory associations in a validation cohort from another prospective study (n = 107 patients treated with neoadjuvant epirubicin monotherapy; p-values ranging from 7.0 * 10(-4) to 0.001 in the combined data sets). Importantly, inactivation of the p53-and the pRB-pathways in concert predicted resistance to therapy more strongly than each of the two pathways assessed individually (exploratory cohort: p-values ranging from 3.9 * 10(-6) to 7.5 * 10(-3) depending on cut-off values applied to ATM and p27 mRNA expression levels). Again, similar findings were confirmed in the validation cohort, with p-values ranging from 6.0 * 10(-7) to 6.5 * 10(-5) in the combined data sets. Our findings strongly indicate that concomitant inactivation of the p53- and pRB- pathways predict resistance towards anthracyclines and mitomycin in breast cancer in vivo. PMID- 26004087 TI - Randomized phase II trial comparing amrubicin with re-challenge of platinum doublet in patients with sensitive-relapsed small-cell lung cancer: North Japan Lung Cancer Study Group trial 0702. AB - PURPOSE: Amrubicin and re-challenge of platinum doublet are both effective treatments for sensitive-relapsed small-cell lung cancer (SCLC). However, no comparative study of these treatments has been reported. This randomized study was conducted to select the most suitable regimen for future evaluation. PATIENTS AND METHODS: SCLC patients who had relapsed more than 90 days after their first line platinum-doublet regimen were randomized to receive amrubicin (40mg/m(2), days 1-3) or re-challenge with platinum doublet. Primary endpoint was objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival and toxicity profiles. We assumed that an ORR of 50% indicates potential usefulness, while that of 30% would constitute the lower limit of interest (alpha 0.1; beta 0.1). Initial estimated accrual was 28 patients to each arm. RESULTS: From February 2008 to June 2013, 60 patients were enrolled and 57 patients (27 amrubicin and 30 re-challenge) were found to be evaluable for efficacy and safety. The ORR and PFS were 67% (90% confidence interval, 52-82) and 5.4 months in the amrubicin group, and 43% (90% confidence interval, 28-58) and 5.1 months in the re-challenge group, respectively. Although grade 3 febrile neutropenia was observed in 19% of patients in the amrubicin group, these episodes were transient and manageable. Non-hematological toxicities were generally moderate and no treatment-related death was observed in either group. CONCLUSION: Only amrubicin met the primary endpoint. Moreover, amrubicin demonstrated superior efficacy over re-challenge of platinum with acceptable levels of toxicity. Further evaluation of amrubicin for sensitive-relapsed SCLC is warranted. PMID- 26004086 TI - TIPIN depletion leads to apoptosis in breast cancer cells. AB - Triple-negative breast cancer (TNBC) is the breast cancer subgroup with the most aggressive clinical behavior. Alternatives to conventional chemotherapy are required to improve the survival of TNBC patients. Gene-expression analyses for different breast cancer subtypes revealed significant overexpression of the Timeless-interacting protein (TIPIN), which is involved in the stability of DNA replication forks, in the highly proliferative associated TNBC samples. Immunohistochemistry analysis showed higher expression of TIPIN in the most proliferative and aggressive breast cancer subtypes including TNBC, and no TIPIN expression in healthy breast tissues. The depletion of TIPIN by RNA interference impairs the proliferation of both human breast cancer and non-tumorigenic cell lines. However, this effect may be specifically associated with apoptosis in breast cancer cells. TIPIN silencing results in higher levels of single-stranded DNA (ssDNA), indicative of replicative stress (RS), in TNBC compared to non tumorigenic cells. Upon TIPIN depletion, the speed of DNA replication fork was significantly decreased in all BC cells. However, TIPIN-depleted TNBC cells are unable to fire additional replication origins in response to RS and therefore undergo apoptosis. TIPIN knockdown in TNBC cells decreases tumorigenicity in vitro and delays tumor growth in vivo. Our findings suggest that TIPIN is important for the maintenance of DNA replication and represents a potential treatment target for the worst prognosis associated breast cancers, such as TNBC. PMID- 26004088 TI - Visualizing nucleic acid metabolism using non-natural nucleosides and nucleotide analogs. AB - Nucleosides and their corresponding mono-, di-, and triphosphates play important roles in maintaining cellular homeostasis. In addition, perturbations in this homeostasis can result in dysfunctional cellular processes that cause pathological conditions such as cancer and autoimmune diseases. This review article discusses contemporary research areas applying nucleoside analogs to probe the mechanistic details underlying the complexities of nucleoside metabolism at the molecular and cellular levels. The first area describes classic and contemporary approaches used to quantify the activity of nucleoside transporters, an important class of membrane proteins that mediate the influx and efflux of nucleosides and nucleobases. A focal point of this section is describing how biophotonic nucleosides are replacing conventional assays employing radiolabeled substrates to study the mechanism of these proteins. The second section describes approaches to understand the utilization of nucleoside triphosphates by cellular DNA polymerases during DNA synthesis. Emphasis here is placed on describing how novel nucleoside analogs such as 5-ethynyl-2' deoxyuridine are being used to quantify DNA synthesis during normal replication as well as during the replication of damaged DNA. In both sections, seminal research articles relevant to these areas are described to highlight how these novel probes are improving our understanding of these biological processes. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions. PMID- 26004089 TI - Kinetic properties and heme pocket structure of two domains of the polymeric hemoglobin of Artemia in comparison with the native molecule. AB - In this project, we studied some physicochemical properties of two different globin domains of the polymeric hemoglobin of the brine shrimp Artemia salina and compared them with those of the native molecule. Two domains (AsHbC1D1 and AsHbC1D5) were cloned and expressed in BL21(DE3)pLysS strain of Escherichia coli. The recombinant proteins as well as the native hemoglobin (AfHb) were purified from bacteria and frozen Artemia, respectively by standard chromatographic methods and assessed by SDS-PAGE. The heme environment of these proteins was studied by optical spectroscopy and ligand-binding kinetics (e.g. CO association and O2 binding affinity) were measured for the two recombinant proteins and the native hemoglobin. This indicates that the CO association rate for AsHbC1D1 is higher than that of AsHbC1D5 and AfHb, while the calculated P50 value for AsHbC1D1 is lower than that of AsHbC1D5 and AfHb. The geminate and bimolecular rebinding parameters indicate a significant difference between both domains. Moreover, EPR results showed that the heme pocket in AfHb is in a more closed conformation than the heme pocket in myoglobin. Finally, the reduction potential of -0.13V versus the standard hydrogen electrode was determined for AfHb by direct electrochemical measurements. It is about 0.06V higher than the potential of the single domain AsHbC1D5. This work shows that each domain in the hemoglobin of Artemia has different characteristics of ligand binding. PMID- 26004091 TI - Spontaneous regional brain activity links restrained eating to later weight gain among young women. AB - Theory and prospective studies have linked restrained eating (RE) to risk for future weight gain and the onset of obesity, but little is known about resting state neural activity that may underlie this association. To address this gap, resting fMRI was used to test the extent to which spontaneous neural activity in regions associated with inhibitory control and food reward account for potential relations between baseline RE levels and changes in body weight among dieters over a one-year interval. Spontaneous regional activity patterns corresponding to RE were assessed among 50 young women using regional homogeneity (ReHo) analysis, which measured temporal synchronization of spontaneous fluctuations within a food deprivation condition. Analyses indicated higher baseline RE scores predicted more weight gain at a one-year follow-up. Furthermore, food-deprived dieting women with high dietary restraint scores exhibited more spontaneous local activity in brain regions associated with the expectation and valuation for food reward [i.e., orbitofrontal cortex (OFC)/ventromedial prefrontal cortex (VMPFC)] and reduced spontaneous local activity in inhibitory control regions [i.e., bilateral dorsal-lateral prefrontal cortex (DLPFC)] at baseline. Notably, the association between baseline RE and follow-up weight gain was mediated by decreased local synchronization of the right DLPFC in particular and, to a lesser degree, increased local synchronization of the right VMPFC. In conjunction with previous research, these findings highlight possible neural mechanisms underlying the relation between RE and risk for weight gain. PMID- 26004092 TI - New views of the Toxoplasma gondii parasitophorous vacuole as revealed by Helium Ion Microscopy (HIM). AB - The Helium Ion Microscope (HIM) is a new technology that uses a highly focused helium ion beam to scan and interact with the sample, which is not coated. The images have resolution and depth of field superior to field emission scanning electron microscopes. In this paper, we used HIM to study LLC-MK2 cells infected with Toxoplasma gondii. These samples were chemically fixed and, after critical point drying, were scraped with adhesive tape to expose the inner structure of the cell and parasitophorous vacuoles. We confirmed some of the previous findings made by field emission-scanning electron microscopy and showed that the surface of the parasite is rich in structures suggestive of secretion, that the nanotubules of the intravacuolar network (IVN) are not always straight, and that bifurcations are less frequent than previously thought. Fusion of the tubules with the parasite membrane or the parasitophorous vacuole membrane (PVM) was also infrequent. Tiny adhesive links were observed for the first time connecting the IVN tubules. The PVM showed openings of various sizes that even allowed the observation of endoplasmic reticulum membranes in the cytoplasm of the host cell. These findings are discussed in relation to current knowledge on the cell biology of T. gondii. PMID- 26004093 TI - Nitrergic system and plasmatic methylarginines: Evidence of their role in the perinatal programming of cardiovascular diseases. AB - Atherosclerosis, in turn preceded by endothelial dysfunction, underlies a series of important cardiovascular diseases. Reduced bioavailability of endothelial nitric oxide, by increasing vascular tone and promoting platelet aggregation, leukocyte adhesion, and smooth muscle cell proliferation, plays a key role in the onset of the majority of cardiovascular diseases. In addition, high blood levels of asymmetric dimethylarginine, a potent inhibitor of nitric oxide synthesis, are associated with future development of adverse cardiovascular events and cardiac death. Recent reports have demonstrated that another methylarginine, i.e., symmetric dimethylarginine, is also involved in the onset of endothelial dysfunction and hypertension. Almost a decade ago, prematurity at birth and intrauterine growth retardation were first associated with a potential negative influence on the cardiovascular apparatus, thus constituting risk factors or leading to early onset of cardiovascular diseases. This condition is referred to as cardiovascular perinatal programming. Accordingly, cardiovascular morbidity and mortality are higher among former preterm adults than in those born at term. The aim of this paper was to undertake a comprehensive literature review focusing on cellular and biochemical mechanisms resulting in both reduced nitric oxide bioavailability and increased methylarginine levels in subjects born preterm. Evidence of the involvement of these compounds in the perinatal programming of cardiovascular risk are also discussed. PMID- 26004094 TI - The birth and future health of DOHaD. AB - Professor David Barker, CBE, FRS, made an enormous contribution to biomedical research, which helped to change its direction and assisted translation to clinical medicine in the area of non-communicable disease (NCD). In this paper, I briefly note some of the studies, which led to his work, and describe how the underlying mechanisms came to be investigated by fetal physiologists. This is a unique aspect of the change in scientific emphasis, from a gene-centric and adult lifestyle view of NCD to a more holistic perspective, which placed emphasis on the importance of development that took place in the late 20th century. Early this century, the DOHaD Society was formed: I discuss some aspects of the formation of the Society and note the important role it is now playing in addressing the need to find early-life interventions to reduce NCD. This forms part of the unique legacy that David Barker has left to science and medicine. PMID- 26004095 TI - (R)-(-)-2-Pyrrolidinemethanol: A combined experimental and DFT vibrational analysis of monomers, dimers and hydrogen bonding. AB - Experimental IR and solution phase spectra of (R)-(-)-2-Pyrrolidinemethanol showing evidence of hydrogen bonding have been interpreted by computing vibrational modes of monomers and dimers with the molecular species due to intra- and inter-molecular hydrogen bonding, at B3LYP/6-311+G(d,p) level density functional theoretical calculations. Computed vibrational frequencies of Boltzmann population-weighted dimers for stretching and bending of O-H and N-H modes associated with the inter-molecular N-H?O and O-H?O hydrogen bonding are in good agreement with the measured IR absorption, Raman and solution-phase IR values near 3289 cm(-1), 3450 cm(-1) and 1400-1300 cm(-1). Further, the H?O length is shorter in O-H?O than in N-H?O by ~10% suggesting that O-H?O is a stronger bond. While the solution-phase IR spectral features suggest strong inter molecular associations, it is short of demonstrating which type of bonding is dominant factor. We conclude that the measured IR, Raman and solution-phase IR spectral features indicate the presence of both types of hydrogen bonds. PMID- 26004096 TI - Polarity dependent photoisomerization of ether substituted azodyes: Synthesis and photoswitching behavior. AB - Two new ether substituted azodyes were synthesized and characterized by different spectral analysis such as (1)H NMR, (13)C NMR, FTIR and UV/Vis. Synthesized compounds were used to study the photoisomerization phenomenon by using UV-Vis spectro-photometer. Interesting polarity dependent effect is observed for the first time on these materials. Trans-cis (E-Z) and cis-trans (Z-E) conversion occurred within 41 s and 445 min, respectively for both the compounds in solutions. Polarizing optical microscopy studies revealed that there is no liquid crystal phase for both the compounds. The dramatic variation in the optical property is speculated to be the polarity of the chemical species. These derivatives are useful to fabricate optical data storage devices. PMID- 26004097 TI - Supramolecular self-organisation and conformational isomerism of a binuclear O,O' dipropyl dithiophosphate gold(I) complex, [Au2{S2P(OC3H7)2}2]: Synthesis, (13)C and (31)P CP/MAS NMR spectroscopy, single-crystal X-ray diffraction study and thermal behaviour. AB - Crystalline one-dimensional polymeric catena-poly[bis(MU2-O,O' dipropyldithiophosphato-S,S')digold(I)] (Au-Au) (1) was prepared and studied using (13)C and (31)P CP/MAS NMR spectroscopy and single-crystal X-ray diffraction. To elucidate the structural function of Dtph ligands in crystalline gold(I) O,O'-dipropyl dithiophosphate, the chemical shift anisotropy parameters (deltaaniso and eta) were calculated from spinning sideband manifolds in (31)P MAS NMR spectra. A novel structure of the gold(I) compound comprises two isomeric, non-centrosymmetric binuclear molecules of [Au2{S2P(OC3H7)2}2] (isomers 'A' and 'B'), whose four Dtph groups display structural inequivalence. In each isomeric binuclear molecule of 1, a pair of MU2-bridging dipropyl Dtph ligands almost symmetrically links two neighbouring gold atoms, forming an extensive eight-membered metallocycle [Au2S4P2], while the intramolecular aurophilic Au?Au bond additionally stabilises this central cyclic moiety. At the supramolecular level of complex 1, intermolecular aurophilic Au?Au bonds yield almost linear infinite polymeric chains (?'A'?'B'?'A'?'B'?)n. The thermal behaviour of this compound was studied by the simultaneous thermal analysis (STA) technique (a combination of TG and DSC) under an argon atmosphere. PMID- 26004098 TI - Spectrophotometric evidence to the formation of AuCl4-CTA complex and synthesis of gold nano-flowers with tailored surface textures. AB - In this paper we report the UV-visible and transmission electron microscopy (TEM) evidence to the formation of stable yellow-orange colored complex, which is attributed to the formation of ion-pair between sub-aggregates of cetyltrimethylammonium bromide (CTAB) and gold at room temperature. The position of wavelength maxima (lambdamax) and shape of the spectra strongly depends on the reaction conditions, i.e., [HAuCl4] and [CTAB]. As the reaction proceeds, typical two bands (one peak and one shoulder) at ca. 409 nm and 470 nm appears and the intensities increase with the time. TEM photographs indicate that the gold-CTA complex consist of aggregated nano-flower like gold with particle size range ca. 40-60 nm. N-(4-hydroxyphenyl)ethanamide (paracetamol) was used to the reduction of resulting gold-CTA complex which leads to the formation of beautiful nano flower, branched-leaves, and bird-plume like AuNPs. Paracetamol concentrations have marked influence on the morphology (shape, size and the size distribution) and nature of the surface resonance plasmon band of AuNPs whereas [CTAB] have no impact on their spectra. Suitable mechanism have been proposed and discussed to the AuNPs formation. PMID- 26004099 TI - Optical properties of Ce(3+)-Nd(3+) co-doped YAG nanoparticles for visual and near-infrared biological imaging. AB - Ce(3+)-Nd(3+) co-doped Y3Al5O12 (YAG) nanoparticles, an average size of 20-30 nm clusters aggregated by 8-10 nm YAG nanoparticles, were synthesized by a solvothermal method. When excited by blue irradiation source, strong and broad yellow luminescence (centered at 526 nm) from Ce(3+) as well as near-infrared (NIR) luminescence (890, 1066 and 1335 nm) of Nd(3+) was observed simultaneously. It occurred by the effective dipole-dipole energy transfer from Ce(3+) to Nd(3+). Energy transfer efficiency from Ce(3+) to Nd(3+) was also calculated to be 50%. The optical property suggests that Ce(3+)-Nd(3+) co-doped YAG nanoparticles can be used as an efficient fluorescence imaging agent for not only visual but also near-infrared imaging. PMID- 26004100 TI - Characterization of sprayed TiO2 on ITO substrates for solar cell applications. AB - Titanium dioxide (TiO2) thin films had been deposited with various substrate temperatures by spray pyrolysis technique onto ITO substrates. All films exhibited polycrystalline nature with the preferred orientation along (101) plane. At the substrate temperature 450 degrees C, the film favored the formation of anatase phase. The higher substrate temperature (475 degrees C) favored the appearance of rutile structure. The SEM image of the film at substrate temperature (Ts=450 degrees C) showed high structural quality with the porous nature. The typical AFM image of TiO2 film deposited at the substrate temperature, 450 degrees C depicted the regular arrangement of fine closely packed tetragonal structured grains. The transmittance of the spectra exhibited above 85% with energy band gap of 3.6 eV. From the study of photoluminescence, the emission at 417 nm, 437 nm and with weak emission at 551 nm was observed, which confirmed the lesser defects in the samples. The electrical resistivity was found to be 6.856*10(1) Omega cm for the substrate temperature 450 degrees C. The efficiency of anatase TiO2 photoelectrode deposited at the substrate temperature 450 degrees C based cell was much higher than the efficiency of TiO2 photoelectrode deposited at the substrate temperature 475 degrees C based cell. PMID- 26004101 TI - Ag@Au core-shell nanoparticles synthesized by pulsed laser ablation in water: Effect of plasmon coupling and their SERS performance. AB - Ag@Au core-shell nanoparticles are synthesised by pulsed laser ablation in water using low energy laser pulses. The plasmon characteristics of these core-shell nanoparticles are found to be highly sensitive to the thickness of Au coating. In the synthesis, at first silver nanocolloid was prepared by ablating Ag target and then it is followed by ablation of Au target for different time durations to form Ag@Au core-shell nanostructures. The effect of plasmon-plasmon coupling on the absorption spectra is investigated by decreasing the effective distance between the nanoparticles. This is achieved by reducing the total volume of the colloidal suspension by simple evaporation of water, the solvent used. The suitability of these core-shell nanostructures for application as surface enhanced Raman scattering substrates are tested with crystal violet as probe molecules. Influence of plasmon coupling on the enhancement of Raman bands is found to be different for different bands. PMID- 26004102 TI - (13)C NMR substituent-induced chemical shifts in 4-(substituted phenyl)-3-phenyl 1,2,4-oxadiazol-5(4H)-ones (thiones). AB - In the present, study mostly novel ten 4-(substituted phenyl)-3-phenyl-1,2,4 oxadiazol-5(4H)-ones and ten 4-(substituted phenyl)-3-phenyl-1,2,4-oxadiazol 5(4H)-thiones were synthesized. These oxadiazole derivatives were characterized by IR, (1)H NMR, (13)C NMR and elemental analyses. Their (13)C NMR spectra were measured in Deuterochloroform (CDCl3). The correlation analysis for the substituent-induced chemical shift (SCS) with Hammett substituent constants (sigma), Brown Okamoto substituent constants (sigma(+), sigma(-)), inductive substituent constants (sigmaI) and different of resonance substituent constants (sigmaR, sigmaR(o)) were performed using SSP (single substituent parameter), DSP (dual substituent parameter) and DSP-NLR (dual substituent parameter-non-linear resonance) methods, as well as single and multiple regression analysis. Negative rho values were found for all correlations (reverse substituent effect). The results of all statistical analyses, (13)C NMR chemical shift of CN, CO and CS carbon of oxadiazole rings have shown satisfactory correlation. PMID- 26004103 TI - Simple spectrophotometric determination of monopersulfate. AB - A simple, sensitive and accurate spectrophotometric method has been developed and validated for the determination of monopersulfate (MPS) which is an active part of potassium monopersulfate triple salt that has the commercial name - Oxone. This work proposes a spectrophotometric determination of monopersulfate based on modification of the iodometric titration method. The analysis of absorption spectra was made for the concentration range from 1.35 to 13.01 ppm of MPS (with a detection and quantification limit of 0.41 and 1.35 ppm, respectively) and different pH values. The influence of several anions on the measurement was also investigated. Furthermore, the absorbance of iron and cobalt (often used as free radical initiators) proved to have no effect on the measurement of MPS concentrations. On the basis of the conducted studies, we propose 395 nm as an optimal wavelength for the determination of MPS concentrations. PMID- 26004104 TI - Constitutive expression of IRF-5 in HTLV-1-infected T cells. AB - Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of T cells. Interferon regulatory factor (IRF)-5 plays a critical role in the induction of interferon genes in viral infected cells. We examined the specific mechanisms underlying the expression and regulation of IRF-5 in HTLV-1-infected T cells. IRF-5 was constitutively transcribed into three distinct alternatively spliced isoforms (V1, V3 and V4) in HTLV-1-infected T-cell lines but not in uninfected T-cell lines. IRF-5 was also upregulated in HTLV-1-infected T-cell lines at protein level. Nuclear IRF-5 expression was noted in ATL cells present in lymph nodes and skin lesions. IRF-5 mRNA expression was induced following infection of T cells with HTLV-1, and specifically by viral oncoprotein Tax. Tax also activated V3 promoter. Microarray analysis of IRF-5-expressing uninfected T cells demonstrated that IRF-5 induced the expression of tumor necrosis factor family cytokines. The results suggest that IRF-5 is a Tax-regulated gene, and its expression may be associated with the pathogenesis of ATL. PMID- 26004105 TI - A Giant Thoracic Duct Cyst as the Cause of Abdomen Pain: A Case Report and Review of the Literature. AB - Thoracic duct cysts, which may be of congenital or degenerative origin, are very rare lesions. Most patients are asymptomatic, but when symptoms are present they include cough, dyspnea, dysphagia and chest pain. However, in this case report a 35-year-old male patient presented to us with intermittent abdomen pain. Clinical symptoms and radiographic findings helped to identify a giant thoracic duct cyst in this patient. Surgical resection of the cyst resolved the abdominal symptoms. This was the first case reported in the literature of a thoracic duct cyst with the symptoms of abdominal pain. PMID- 26004106 TI - "Pouch Technique" Makes Proximal Anastomosis of Free Internal Thoracic Artery Graft to Ascending Aorta Easy and Safe in Coronary Artery Bypass Surgery. AB - PURPOSE: The proximal anastomosis of free right internal thoracic artery to ascending aorta is technically difficult when the caliber is not enough. METHODS: We incise the proximal stump of the graft longitudinally for 10 mm. One side of start point of longitudinal incision is sewn to the end point of incision by 7-0 polypropylene. The folded sideline (5 mm length) is then closed with a running suture, then formation of pouch like anastomotic end is accomplished. RESULTS: We used this technique in consecutive 34 patients who underwent coronary artery bypass surgery including revascularization to circumflex arteries. Postoperative angiography revealed 97% patency. It does not need another graft material like saphenous vein or radial artery, and possible not only in on pump surgery but also in off pump. CONCLUSION: This new "Pouch technique" will make it easy to use right internal thoracic artery as a free graft in coronary artery bypass surgery. PMID- 26004107 TI - Cystic Hydatidosis of the Rib-Case Report and Review of the Literature. AB - The hydatid disease is a zoonosis endemic to rural countries, such as those in the Mediterranean region, South America, North Africa, Central Asia and China. Hydatid cysts commonly affect liver and lungs, but less than 100 cases of costal hydatidosis have been reported in the literature. While diagnosis of the disease in commonly affected organs is relatively easy, uncommon locations can prove to be challenging as is the case with costal hydatidosis. Imaging techniques can suggest the diagnosis, but sometimes it remains uncertain until surgery. The treatment is surgical, assisted by long-time Albendazole chemotherapy. We present a rare case of costal hydatidosis, the first one to be reported in Romania according to our review of the literature. PMID- 26004108 TI - Two Cases of Single-Stage Closure of a Bronchopleural Fistula Using Latissimus Dorsi Musculocutaneous Flaps after Lung Surgery. AB - Two cases of successful primary closure of a bronchopleural fistula with favorable infection control using latissimus dorsi musculocutaneous flaps are reported. Case 1 was a 70-year-old man who underwent resection of the right lower pulmonary lobe due to right lung metastasis of sigmoid colon cancer. A bronchopleural fistula was found on day 28 after surgery. Infection was controlled by antibiotic administration and tube drainage. Closure of the bronchopleural stump, thoracoplasty and plombage of latissimus dorsi muscles were performed for single-stage closure without open treatment, based on a negative pleural effusion culture. Case 2 was a 64-year-old man who underwent right lower pulmonary lobe resection due to right lung cancer. A bronchopleural fistula was found on day 14 after surgery. In single-stage closure, thoracoplasty and plombage of latissimus dorsi muscles were performed due to infection control and a negative pleural effusion culture. Both cases had a good postoperative course. PMID- 26004109 TI - Risk and Outcome of Aortic Valve Surgery in the Transcatheter Valve Era: The Gender Aspect. AB - OBJECTIVES: In 2009, a transcatheter valve intervention program was introduced at our centre. The aim of this single-centre retrospective study was to evaluate gender-specific risk profiles and outcome of patients undergoing surgical aortic valve replacement before and after 2009. METHODS: We assessed the preoperative logistic EuroSCORE and age, gender and 30-day-survival of 357 patients diagnosed with symptomatic severe aortic stenosis that underwent primary isolated surgical aortic valve replacement in 2007-2008 (group I, n = 191, 47% female) and 2010 2011 (group II, n = 166, 40% female). Survival follow up data was 100% complete. RESULTS: Women in group II were significantly younger (71.6 +/- 9.0 years; p = 0.004) and showed significantly lower risk profiles (logistic EuroSCORE: 9.6 +/- 9.9%; p = 0.04) than women in group I (age: 75.6 +/- 8.5 years, logistic EuroSCORE: 13.9 +/- 15.9). Men's age and risk profiles remained similar in both groups. Observed survival at 30 days was 98.8% in group II and 95.8% in group I which represented a statistical trend (p = 0.09). Female survival in group I was 92.2% and significantly worse as compared to 99% male survival in group I (p = 0.03). This significant difference in gender ratio of mortality was not detected in group II (female survival 97%, male survival 100%; p = 0.2). Being female was a significant risk factor in group I (odds ratio; 8.4; p = 0.03) but not in group II any longer (odds ratio: 1.0; p = 0.2). CONCLUSIONS: The possibility of transcatheter aortic valve replacement for therapy of aortic stenosis has led to a lower risk and improved outcome of surgical aortic valve replacement especially for women. PMID- 26004110 TI - Bilateral Internal Thoracic Artery Grafting: Is It Reasonable in Octogenarians? AB - PURPOSE: The feasibility of using bilateral internal thoracic artery (BITA) grafts for coronary artery bypass grafting (CABG) in octogenarians is not clear. This study aimed to compare outcomes between use of BITA and single internal thoracic artery (SITA) grafts in octogenarians undergoing isolated CABG. METHODS: Isolated CABG was performed in 1,566 patients at the Sakakibara Heart Institute between September 2004 and December 2012. Of these, 125 consecutive octogenarians were included and divided into two groups, according to the use of BITA grafts (101 subjects) or SITA grafts (24 subjects). Early and late outcomes were compared between groups. RESULTS: The preoperative patient characteristics were similar between the two groups. Early outcomes were similar, including hospital death or deep sternal infection. The estimated 5-year survival rate was similar in the BITA and SITA groups (78% vs 62%, p = 0.269). Freedom from major adverse cardiac or cerebrovascular events was significantly higher in the BITA group than in the SITA group after 5 years (90% vs 75%, p = 0.032). CONCLUSIONS: Our results suggest that use of BITA grafts for CABG is feasible and beneficial in octogenarians, resulting in improved late outcomes without increased operative risk. PMID- 26004111 TI - The Effect of Circadian Melatonin Levels on Inflammation and Neurocognitive Functions Following Coronary Bypass Surgery. AB - PURPOSE: In this study, the relationship between the plasma levels of melatonin and intercellular adhesion molecule-1 (ICAM-1), which plays role in several intercellular interactions including inflammatory and immune responses, and early neurocognitive functions associated with ischaemia-reperfusion injury during open heart surgery is examined. METHODS: Forty patients who were to undergo elective coronary artery bypass grafting (CABG) were divided into two groups, those who underwent their operations at 8 AM (group I; n = 20) and those who underwent their operations at 1 PM (group II; n = 20). Blood samples were collected prior to surgery (S1), when the aortic cross clamp was removed (S2) and 4 (S3) and 24 h after the surgery (S4). Neuropsychiatric assessment was conducted one day before and seven days after surgery. RESULTS: Melatonin levels measured during and after surgery were also significantly higher in Group 1. ICAM-1 levels were significantly lower in Group 1 at S2 and S3. Significant deterioration was observed in postoperative neurocognitive function compared with preoperative functions in Group 2 more than Group 1. CONCLUSION: We hypothesise that the greater preservation of neurocognitive functions in the morning patients is associated with elevated melatonin levels, which reduce the damage from ischaemia reperfusion injury. PMID- 26004112 TI - Analysis of Pneumonectomy for Benign Disease: A Single Institution Retrospective Study on 59 Patients. AB - INTRODUCTION: Pneumonectomy is the only curative treatment for some benign diseases but the operation is a challenging procedure. Herein, we present our experiences of pneumonectomy for 59 patients. METHODS: The medical records of 59 patients who undergone pneumonectomy for benign lung diseases from 2008 to 2013 at the Division of Thoracic Surgery in Beijing Chest Hospital were retrospectively reviewed. RESULTS: There were 23 male and 36 female patients. Three procedures including pneumonectomy, pleuropneumonectomy and completion pneumonectomy were used. The operative time and intraoperative blood loss were statistically different in the patients who undergone different operations. The operative time of the patients with and without tuberculosis had no difference but the intraoperative blood loss was more in the patients with tuberculosis (P = 0.035). The operative type, age and operative blood loss were relevant with the morbidity, the P value were 0.024, 0.042 and 0.027 respectively. CONCLUSIONS: Pneumonectomy for patients with benign disease may be more difficult than for patients with lung cancer, mean while pleuropneumonectomy and completion pneumonectomy may be greater challenges. But with careful patient selection and operative technique, it is a satisfactory treatment method for benign lung disease. The morbidity is acceptable and associated with operative type, age and operative blood loss. PMID- 26004113 TI - Two Different Minimally Invasive Techniques for Female Patients with Atrial Septal Defects: Totally Thoracoscopic Technique and Right Anterolateral Thoracotomy Technique. AB - BACKGROUND: To compare the outcomes of totally thoracoscopic technique (TTS) vs. right anterolateral thoracotomy technique (RALT) in female patients undergoing minimal invasive atrial septal defect (ASD) correction. METHODS: From March 2011 to January 2013, 125 female patients underwent minimally invasive atrial septal defect closure, of whom 62 patients were in the TTS group and 63 were in the RALT group. RESULTS: Procedures were performed successfully in all patients without in hospital mortality or major complications. cardiopulmonary bypass (CPB) time were 48.95 +/- 15.63 min in TTS group, 31.4 +/- 8.04 min in RALT group (p <0.001); the cross-clamp time were 26.92 +/- 11.84 min in TTS group and 18.51 +/- 6.11 min in RALT group (p <0.001). The length of incision in RALT group (6.02 +/- 1.03 cm) was longer than TTS group (5.31 +/- 0.68 cm) and the difference was significant (p <0.001). The overall satisfaction rate for the cosmetic results of TTS was 100% and was 96.83% (61/63 patients) in RALT patients. During follow-up, all patients in TTS group were satisfied expect two patients complained that scar was too long at groin. Reasons for a lower score in RALT group included the long scar in the chest; a RALT incision that was located too medially (coming off the bra line) and asymmetrical breast development. CONCLUSIONS: Both TTS and RALT are valid and reliable cosmetic surgical techniques for repairing ASDs in female patients. Both techniques allow excellent cosmetic and functional results in most female patients. The totally thoracoscopic technique may gain shorter incision and cosmetic results compared with RALT. PMID- 26004114 TI - Surgical Outcome of Video-Assisted Thoracoscopic Surgery vs. Thoracotomy for Primary Lung Cancer >5 cm in Diameter. AB - OBJECTIVES: The indications for video-assisted thoracoscopic surgery (VATS) for advanced-stage lung cancer are expanding, but the criteria vary among institutions. This study compared the minimal invasiveness and oncologic validity of VATS lobectomy and thoracotomy lobectomy for the treatment of large-diameter primary lung cancer. METHODS: We retrospectively reviewed clinical features and surgical outcomes of 68 patients who underwent anatomical pulmonary resection for primary lung cancer of >5-cm diameter from July 2006 to March 2013. The patients were divided into a VATS group (Group V, n = 35) and a thoracotomy group (Group T, n = 33). RESULTS: Group V exhibited less intraoperative bleeding (p = 0.012) and had a shorter length of postoperative hospital stay (p = 0.024). The 1- and 5 year overall survival rates were 91.3% and 39.3% in Group V and 84.8% and 56.9% in Group T, respectively (p = 0.48). Multivariate analysis showed that limited lymph node dissection contributed to local recurrence. The extraction bag lavage cytology in Group V revealed that the positivity rate was 35.7%. CONCLUSIONS: VATS for primary lung cancer of >5-cm diameter is similar to thoracotomy in terms of surgical outcomes. Large tumors must be carefully maneuvered during VATS to prevent cancer cell spillage. PMID- 26004115 TI - Initial Experience of Modified Four-Branched Graft Technique and Antegrade TEVAR in Acute Type A Aortic Dissection. AB - BACKGROUND: We report the initial experience of modified four-branched graft technique for proximal aorta and arch repair, feasibly combined with antegrade thoracic endovascular aortic repair (TEVAR) to extend distal aortic reconstruction in acute type A aortic dissection. METHODS: From 2011 to 2013, 12 consecutive patients with acute type A aortic dissection were indicated for arch surgery and underwent surgical replacement of proximal aorta, arch replacement or debranching procedure, and concomitant TEVAR for distal aortic repair. RESULTS: A good surgical field was obtained in all patients. No major complications developed but two hospital deaths were attributed to end-organs damage preoperatively. Good and fast remodeling of thoracic descending aorta was demonstrated in 11 patients in postoperative CT imaging and no aneurysmal dilatation of visceral aorta had been observed in 10 patients during follow-up periods. CONCLUSION: Modified four-branched graft technique facilitated proximal aorta and arch repair, and provided excellent neurological outcome and favorable short-term results. Single-stage operation combined with antegrade TEVAR is feasible and effective to extend the repair down to the descending aorta, and thus achieved good remodeling of thoracic descending aorta. PMID- 26004116 TI - Video-Assisted Thoracoscopic Surgery after Preoperative CT-Guided Lipiodol Marking of Small or Impalpable Pulmonary Nodules. AB - PURPOSE: Small pulmonary lesions that include ground-glass attenuation have been increasingly discovered because of progressive imaging diagnostic technologies. Despite the detection of such small lesions, sometimes it is quite difficult to localize them because of their size or considerable depth from the visceral pleura. In the present study, we examined the usefulness of computed tomography guided lipiodol marking for thoracoscopic resection of impalpable pulmonary nodules. METHODS: Fifty-six patients with an undiagnosed peripheral lesion(s) of the lung who had undergone preoperative computed tomography-guided lipiodol marking followed by video-assisted thoracoscopic surgery were studied. RESULTS: All of the nodules were successfully marked by computed tomography-guided lipiodol marking, and all except for one case were localized by means of intraoperative fluoroscopy as clear spots. With regard to complications, pneumothorax occurred in 21 patients (37.5%), and only one patient required transient drainage. Although hemorrhaging in the lung parenchyma and hemosputum occurred in nine patients (16.1%) and one patient (1.8%), respectively, no patients were in serious condition. No intra- or postoperative mortality or morbidity was observed. CONCLUSION: Preoperative computed tomography-guided lipiodol marking of small or impalpable pulmonary nodules is a safe and useful procedure for thoracoscopic resection of the lung. PMID- 26004117 TI - Long-Term Outcome of Prosthetic Valve Replacement in Japanese Patients Aged 65 Years or Older: Are Guidelines for Prosthetic Valve Selection Based on Overseas Data Appropriate for Japanese Patients? AB - BACKGROUND: Based on the revised AHA/ACC guidelines, it might be necessary to take into consideration the average life expectancy of Japanese people and revise the Japanese guidelines accordingly. Accordingly, we performed the present study to compare the long-term outcome in patients aged 65 years or older who underwent prosthetic valve replacement at our hospital using mechanical valves or biological valves. METHODS: We have performed valve replacement in 416 patients aged 65 years or older (mechanical: 157; biological: 244). RESULTS: There was no significant difference between the mechanical and biological valve for the actuarial survival rate. As for the valve-related complication free rate, in the mechanical valve group, the rates were significantly higher for all patients, aortic valve replacement (AVR) patients, and mitral valve replacement (MVR) patients. CONCLUSIONS: Following revision of the AHA/ACC guidelines for selection of prosthetic valves, it is necessary to investigate whether patients aged 60-70 represent the gray zone for selecting valves as in US and European guidelines, or whether a higher age is more appropriate in view of the longer average life expectancy in Japan. Accordingly, further evaluation of the long-term outcome for mechanical and biological valves in Japanese patients is needed to obtain evidence for preparation of original Japanese guidelines on prosthetic valve selection. PMID- 26004118 TI - Early and Long-Term Outcomes in Japanese Patients Aged 80 Years or Older Undergoing Conventional Aortic Valve Replacement. AB - In this study, we investigated the early and long-term results of conventional aortic valve replacement (AVR) in very old patients. METHODS: Seventy-five patients with aortic stenosis underwent conventional AVR for patients aged 80 years.We examined early death and major adverse cardiovascular and cerebrovascular event (MACCE). RESULTS: The operative mortality was 0% for isolated AVR and 19.2% for concomitant surgery. The postoperative survival rate and MACCE free-rate were no significant differences between the isolated AVR and the concomitant surgery. Univariate analysis confirmed that cardiac dysfunction, severe chronic kidney disease (CKD), hemodialysis, + coronary artery bypass grafting, and norepinephrine use were risk factor of early death. Univariate analysis confirmed that severe CKD, BNP >1000 pg/ml, aortic cross clamping time (ACCT) >180 min, and non-use carperitide and multivariate analysis confirmed that ACCT >180 min, and non-use carperitide were risk factor of MACCE. CONCLUSIONS: This study showed that the results of conventional AVR in very old patients were not satisfactory. However, the results obtained with isolated AVR were favorable with no operative deaths. The present study demonstrated that preoperative cardiac function, preoperative renal function, and operative factors have an important impact on early mortality and MACCE. PMID- 26004119 TI - Biogeographic specializations of two large hypotrich ciliates: Australocirrus shii and A. australis and proposed synonymy of Australocirrus and Cyrtohymenides. AB - Using standard methods, we studied the morphology and distribution of an Australian population of Australocirrus shii (Shi et al., 1997) nov. comb. and a Jamaican population of A. australis (Foissner, 1995) nov. comb. We identified three features, not or rarely used earlier, that distinguish Australocirrus shii from A. australis: the distance between the anterior pretransverse cirrus and the anteriormost transverse cirrus (5-8% vs. 1.5-1.7% of body length), the arrangement of the transverse cirri (3+2 vs. an oblique row), and the resting cyst macronuclear nodules (separate vs. fused). Australocirrus shii has been reported from Asia and Australia while A. australis is possibly restricted to the Neotropic. Because of problems in getting voucher materials of A. shii, we emphasise that permanent slides should be deposited in international repositories. Based on previous studies and new data, especially a refined interpretation of the shape of the paroral membrane, we suggest synonymy of Cyrtohymenides and Australocirrus. Thus, Cyrtohymena (Cyrtohymenides) shii, C. (Cyrtohymenides) aspoecki, and C. (Cyrtohymenides) australis are transferred to Australocirrus which is, inter alia, defined by a moderately to distinctly curved, but not recurved, paroral membrane, multiple fragmentation of dorsal kinety 3 and three or more dorsomarginal kineties. PMID- 26004120 TI - Foot orthoses do not affect crank power output during maximal exercise on a cycle ergometer. AB - OBJECTIVES: To investigate the effects of custom-made foot orthoses on the torque and power-cadence relationships and perceived comfort during maximal cycling exercises in a population of competitive road cyclists. DESIGN: Randomised, repeated measures, participant-blinded controlled study. METHODS: Twenty-four competitive road cyclists (22 males, 2 females; aged 18-53 years) with mobile feet performed the torque-velocity test with custom-made and sham foot orthoses. For both conditions, the maximal power, optimal cadence, optimal torque, maximal torque, and maximal cadence were extracted from the individual torque- and power cadence relationships. Comfort was assessed on a 150mm visual analogue scale. Paired-samples t-tests were used for comparison of means between conditions. RESULTS: No differences were observed between the custom-made and sham foot orthoses for any of the key variables extracted: maximal power (1022+/-180 vs. 1020+/-172W; p=0.794), optimal cadence (118+/-10 vs. 119+/-9rpm; p=0.682), optimal torque (82+/-10 vs. 82+/-11Nm; p=0.559), maximal torque (157+/-23 vs. 159+/-20 Nm; p=0.665) and maximal cadence (220+/-22 vs. 221+/-20rpm; p=0.935). There was no difference in comfort between custom-made and sham foot orthoses (106+/-30.5 vs. 116+/-25.0mm; p=0.995). CONCLUSIONS: Compared to the sham foot orthoses, the custom-made foot orthoses did not significantly affect the torque and power generating capacities or comfort during a maximal exercise performed on a stationary cycle ergometer. PMID- 26004121 TI - Re-irradiation with cetuximab or cisplatin-based chemotherapy for recurrent squamous cell carcinoma of the head and neck. AB - PURPOSE: Locoregional recurrence remains the main pattern of failure after primary combined modality treatment of squamous cell carcinoma of the head and neck (SCCHN). We compared the efficacy and toxicity of either cisplatin or cetuximab in combination with re-irradiation (ReRT) for recurrent unresectable SCCHN. Various clinicopathological factors were investigated to establish a prognostic score. PATIENTS AND METHODS: Between 2007 and 2014, 66 patients with recurrent SCCHN originating in a previously irradiated area received cetuximab (n = 33) or cisplatin-based chemotherapy (n = 33) concomitant with ReRT. Toxicity was evaluated weekly and at every follow-up visit. Physical examination, endoscopy, CT or MRI scans were used to evaluate response and disease control. RESULTS: With a mean follow-up of 18.3 months, the 1-year overall survival (OS) rates for Re-RT with cetuximab and cisplatin-based chemotherapy were 44.4 and 45.5% (p = 0.352), respectively. At 1 year, local control rates (LCR) were 46.4 and 54.2% (p = 0.625), freedom from metastases (FFM) rates 73.6 and 81% (p = 0.842), respectively. Haematological toxicity >= grade 3 occurred more often in the cisplatin group (p < 0.001), pain >= grade 3 was increased in the cetuximab group (p = 0.034). A physiological haemoglobin level and a longer interval between primary RT and ReRT, proved to be significant prognostic factors for OS (multivariate: p = 0.003, p = 0.002, respectively). Site of the recurrence and gross target volume (GTV) did not show a significant impact on OS in multivariate analysis (p = 0.160, p = 0.167, respectively). A prognostic-score (1-4 points) based on these four variables identified significantly different subgroups: 1 year OS for 0/1/2/3/4 prognostic points: 10, 38, 76, 80 and 100%, respectively (p < 0.001). CONCLUSION: Both cetuximab- and cisplatin-based ReRT of SCCHN recurrences are feasible and effective treatment options with comparable results in terms of tumour control and survival. Acute adverse events may differ slightly. Our prognostic score could help to identify appropriate patients for ReRT and stratify patients within future clinical trials. PMID- 26004122 TI - Stability of Disruptive Mood Dysregulation Disorder Symptoms (Irritable-Angry Mood and Temper Outbursts) Throughout Childhood and Adolescence in a General Population Sample. AB - DSM-5 Disruptive Mood Dysregulation Disorder (DMDD) is a controversial new diagnosis. The DSM-5 conceptualizes DMDD as persistent and chronic, but the stability of the two DMDD symptoms (irritable-angry mood and temper outbursts) over time is not known. Mothers rated DMDD symptoms in a population-based sample of 376 children (54 % male) evaluated at 6-12 years (M 9) and again an average of 8 years later (M 16). Mean scores on irritable-angry mood plus temper outbursts at baseline and follow-up were below sometimes a problem, but were higher at baseline than follow-up. Irritable-angry mood and temper outbursts were both often or very often a problem for 9 % of children at baseline, 6 % at follow-up, and 3 % at baseline and follow-up. Only 29 % of children whose baseline symptoms were often or very often continued to have follow-up symptoms at this level (remission rate 71 %). Less than half (45 %) of the children whose symptoms were often or very often at follow-up had these symptoms 8 years earlier (55 % new cases). Our finding of 71 % remission and 55 % new cases indicates instability of DMDD symptoms over an 8-year period. However, the finding that 29 % still had symptoms often or very often 8 years later is clinically significant. DMDD symptoms were found in only one child who did not have symptoms of oppositional defiant disorder (ODD), conduct disorder, ADHD, anxiety, or depression. This suggests that DMDD symptoms are a feature of multiple disorders, particularly ODD, and do not occur in isolation, questioning the validity of DMDD as a unique and independent diagnosis. PMID- 26004123 TI - Too much anticipation? Large anticipatory adjustments of grasping movements to minimal object manipulations. AB - When humans grasp objects, the grasps foreshadow the intended object manipulation. It has been suggested that grasps are selected that lead to medial arm postures, which facilitate movement speed and precision, during critical phases of the object manipulation. In Experiment 1, it has been tested whether grasp selections lead to medial postures during rotations of a dial. Participants twisted their arms considerably before grasping the dial, even when the upcoming dial rotation was minimal (5 degrees ). Participants neither assumed a medial posture at any point during a short rotation, nor did they assume any of the postures involved in short rotations in the opposite direction. Thus, grasp selections did not necessarily lead to specific postures at any point of the object manipulation. Experiment 2 examined the effect of various grasps on the speed of dial rotations. A medial initial grasp resulted in the fastest dial rotations for most rotation angles. Spontaneously selected grasps were more excursed than necessary to maximize dial rotation speed. This apparent overshot might be explained by participants' sensitive to the variability of their grasps and is in line with the assumption that grasps facilitate control over the grasped object. PMID- 26004124 TI - MicroRNA-148a inhibits the proliferation and promotes the paclitaxel-induced apoptosis of ovarian cancer cells by targeting PDIA3. AB - MicroRNAs (miRs) are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. miR-148a has been suggested to be associated with human ovarian cancer, however, the detailed functions of miR-148a in ovarian cancer remain to be fully elucidated. The present study aimed to investigate the regulatory mechanism of miR-148a in ovarian cancer cells. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were conducted to examine the RNA and protein levels, respectively. The luciferase reporter assay was used to determine the target relationship. Cell proliferation and apoptosis assays were additionally conducted. The present study demonstrated that miR-148a inhibited cell proliferation and promoted the paclitaxel-induced apoptosis of ovarian cancer cells. Furthermore, protein disulfide isomerase family A, member 3 (PDIA3) was identified as a target gene of miR-148a. A fluorescent reporter assay was performed to confirm that miR-148a was able to directly bind to the 3'-untranslated region of PDIA3 mRNA. In addition, miR-148a was frequently downregulated in ovarian cancer tissue, whereas the expression levels of PDIA3 were increased. Knockdown of PDIA3 significantly inhibited the proliferation and promoted the paclitaxel-induced apoptosis of the ovarian cancer cells, whereas overexpression of PDIA3 had the opposite effects. Therefore, the results of the present study suggested that miR-148a inhibited the proliferation and promoted the paclitaxel-induced apoptosis of ovarian cancer cells, and this may be partly attributed to direct targeting of PDIA3. PMID- 26004125 TI - Neutral heel lateral push test: The first clinical examination of spring ligament integrity. AB - INTRODUCTION: The spring (calcaneonavicular) ligament is an intricate multiligament complex whose primary role is to stabilise the medial longitudinal arch and head of talus. Clinical suspicion of a spring ligament injury in isolation is roused when persistent medial midfoot pain is present with associated pes planus following trauma. METHOD: We undertook a cadaveric study on 21 specimens to assess the use of a neutral heel lateral push test to examine the spring ligament in a standardised procedure, measuring lateral translation with graduated antegrade and retrograde defunctioning of surrounding structures and the spring ligament. RESULTS: In all specimens, a significant displacement occurred on incision of the spring ligament regardless of order of dissection. The degree of displacement increased by an insignificant amount as surrounding structures were incised at each incremental force applied. DISCUSSION: The neutral heel push test is the first clinical examination to be described to determine integrity of the spring ligament complex. Our study objectively demonstrates that lateral displacement in relation to the mid and hind-foot is influenced most significantly by the integrity of the spring ligament and to a lesser extent by tibialis posterior and flexor digitorum longus. PMID- 26004126 TI - Bilateral heel pain in a patient with Diamond-Blackfan anaemia. AB - A rare case of bilateral calcaneal stress fractures in a patient with Diamond Blackfan anaemia is described. This has not been previously reported in the literature. A calcaneal stress fracture is an important differential diagnosis in a patient presenting with heel pain. Bilaterality of symptoms should not exclude this diagnosis and clinicians should be especially vigilant with predisposed patients. PMID- 26004128 TI - Tretinoin-loaded liposomal formulations: from lab to comparative clinical study in acne patients. AB - Topical tretinoin is the most commonly used retinoid for acne. However, its irritative potential on the applied area and the barrier properties of the stratum corneum limit its use. The objective of the present study was to formulate tretinoin liposomal gel to obtain a formula with lower skin irritation potential and greater clinical effect. A statistical 2(4) factorial design was adopted. Sixteen formulae prepared and were properly evaluated. A candidate formula (F13G) prepared with 0.025% tretinoin, phospholipid- cholesterol dicetylphosphate (9:1:0.01) and incorporated in 1% carbopol gel was selected for skin irritation test. Clinical study was conducted on acne patients and compared to marketed product. All liposomes formulations were spherical in shape. The addition of cholesterol in the film hydration method significantly decreased the vesicle size, and increased the percentage of incorporation efficiency at (p < 0.05). The presence of dicetylphosphate significantly increased drug release but did not affect the percentage of incorporation efficiency and vesicle size. The results of the clinical study in acne patients revealed that F13G showed significantly higher efficacy when compared to marketed product (p < 0.05). PMID- 26004129 TI - Enhanced tolerance and antitumor efficacy by docetaxel-loaded albumin nanoparticles. AB - Docetaxel is one of the most active chemotherapeutic agents for cancer treatment. The traditional docetaxel injection (TAXOTERE(r)) is currently formulated in the surfactant polysorbate 80, which has been associated with severe adverse reactions. To avoid the use of polysorbate 80 as well as to reduce the systemic toxicity of docetaxel, in this study, docetaxel-loaded albumin nanoparticles were fabricated by a novel simple self-assembly method. The resulting nanoparticles showed a mean diameter size of 150 nm. After being encapsulated into nanoparticles, docetaxel displayed similar cytotoxicity to traditional injection. Since polysorbate 80 was not involved in nanoparticles, the hemolysis was completely eliminated. The maximal tolerance dose of nanoparticles was also increased, which allowed a higher dose to be safely intravenously injected and produced ideal antitumor effects. The 150 nm diameter also allowed the nanoparticles to accumulate in tumor tissue via the enhanced permeability and retention effect. The passive targeting ability further caused the higher antitumor effects of nanoparticles than that of traditional injection at the same dose (7.5 mg/kg). Therefore, docetaxel-loaded albumin nanoparticles fabricated by our strategy showed higher promise in their safety and effectiveness than the traditional docetaxel injection. PMID- 26004127 TI - Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase. AB - Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel(r) matrix-coated Transwell(r) chamber assays; leukemic cell lines treated with doxycycline (1 ug/ml) or anti beta1-integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, incubation with blocking anti-beta1-integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia. PMID- 26004131 TI - Is there gender bias in the peer-review process in several Elsevier's marine journals? PMID- 26004130 TI - Timing and context: important considerations in the return of genetic results to research participants. AB - General consensus exists that clinically significant germline genetic research results should be fed back to research participants. A body of literature is emerging about Australian research participants' experiences of feedback of genetic research results and factors that influence a participant's actions after receiving such information. This exploratory qualitative study conducted interviews with 11 participants from the International Sarcoma Kindred Study, four probands and seven of their relatives. They had been informed by letter of the availability of clinically significant germline TP53 mutations identified through research. We examined the participants' views about the feedback of these genetic test results. Thematic (inductive) analysis was used to analyse the data. A number of factors influenced participants' responses following notification. This included participants' understanding of the notification letter and their perception of the relevance of the information for them and/or their family. Most notably, timing of the letter in the context of an individual's current life experiences was important. Timing and context are novel factors identified that may impact on research participants' understanding or their ability to access clinically significant research results. We outline strategies for disseminating results to research participants and their next of kin that may reduce their uncertainty around the receipt of research results. PMID- 26004132 TI - Recurrent respiratory papillomatosis in northern Sweden: clinical characteristics and practical guidance. AB - CONCLUSION: Recurrent respiratory papillomatosis (RRP) patients with high surgical treatment frequency (>= 1/year, HF) were significantly younger and had a more widespread laryngeal disease compared to a low frequency treated group (< 1 treatment/year, LF). This study confirms the existence of a clinical RRP group, not primarily related to HPV sub-type, but more care-intensive and in need of more vigilant follow-up. OBJECTIVES: RRP is associated with high morbidity due to its influence on breathing and voice. The purpose of this study was to characterize RRP patients in northern Sweden and investigate possible predictor factors affecting therapeutic needs. METHOD: Patients from the regional referral area (northern Sweden) were categorized for age, disease duration, juvenile or adult onset, profile of disease development, number of surgical sessions in relation to disease duration, laryngeal deposition of papilloma, gender, and HPV sub-types, in order to identify patients with increased need for frequent surgical treatment. RESULTS: The median age of the RRP patients (n = 48) was 44.5 years; 34 (71%) were males and 14 (29%) females, most were infected with HPV 6. Patients with high surgical treatment frequency/year were significantly younger and showed more widespread papillomatous vegetation in the larynx, compared to the low frequency treated group. PMID- 26004133 TI - NextSearch: A Search Engine for Mass Spectrometry Data against a Compact Nucleotide Exon Graph. AB - Proteogenomics research has been using six-frame translation of the whole genome or amino acid exon graphs to overcome the limitations of reference protein sequence database; however, six-frame translation is not suitable for annotating genes that span over multiple exons, and amino acid exon graphs are not convenient to represent novel splice variants and exon skipping events between exons of incompatible reading frames. We propose a proteogenomic pipeline NextSearch (Nucleotide EXon-graph Transcriptome Search) that is based on a nucleotide exon graph. This pipeline consists of constructing a compact nucleotide exon graph that systematically incorporates novel splice variations and a search tool that identifies peptides by directly searching the nucleotide exon graph against tandem mass spectra. Because our exon graph stores nucleotide sequences, it can easily represent novel splice variations and exon skipping events between incompatible reading frame exons. Searching for peptide identification is performed against this nucleotide exon graph, without converting it into a protein sequence in FASTA format, achieving an order of magnitude reduction in the size of the sequence database storage. NextSearch outputs the proteome-genome/transcriptome mapping results in a general feature format (GFF) file, which can be visualized by public tools such as the UCSC Genome Browser. PMID- 26004134 TI - Targeting of cancer stem cells by inhibitors of DNA and histone methylation. AB - INTRODUCTION: Curative chemotherapy should target cancer stem cells (CSCs). The key characteristics of CSCs are a block in differentiation and an epigenetic signature similar to embryonic stem cells (ESCs). Differentiation by ESCs and CSCs is suppressed by gene silencing through the polycomb repressive complex 2 (PRC2) and/or DNA methylation. PRC2 contains the EZH2 subunit, which catalyzes the trimethylation of histone 3 lysine 27, a gene silencing marker. It is possible to reverse this 'double lock' mechanism using a combination of inhibitors of EZH2 and DNA methylation (5-aza-2'-deoxycytidine), which exhibits remarkable synergistic antineoplastic activity in preclinical studies. AREAS COVERED: The authors discuss several specific EZH2 inhibitors that have been synthesized with antineoplastic activity. One such inhibitor, EPZ-6438 (E7438), has been shown to be effective against lymphoma in a Phase I study. The indirect EZH2 inhibitor, 3-deazaneplanocin-A (DZNep), also exhibits remarkable anticancer activity due to its inhibition of methionine metabolism. EXPERT OPINION: Agents that target EZH2 warrant Phase I trials. Due to its positive pharmacodynamics, DZNep merits a high priority for clinical investigation. Agents that show positive results in Phase I studies should be advanced to clinical trials for use in combination with 5-aza-2'-deoxycytidine due to the interesting potential of this epigenetic therapy to target CSCs. PMID- 26004135 TI - Rich1 negatively regulates the epithelial cell cycle, proliferation and adhesion by CDC42/RAC1-PAK1-Erk1/2 pathway. AB - Rich1, a previously identified Rho GTPase-activating protein (RhoGAP), was found to have close relationship with Rho GTPase family members in multiple cellular processes in nervous cells and platelets. But the exact role of Rich1 in epithelial cells remains obscure. The present investigation demonstrated that up regulation of Rich1 could cause S-phase arrest, proliferation inhibition and adhesion decline with F-actin amount decrease in epithelial cells. Further exploration in hepatocyte HL7702 revealed that overexpression of Rich1 could greatly elevate the intrinsic GTPase activities on both of CDC42 and RAC1 by stimulating GTP hydrolysis, which consequently attenuated the activities of the Rho proteins and the phosphorylation level of those in PAK1-ERK1/2 signaling cascade. While the GAP domain deleted Rich1 variant or silence of endogenous Rich1 expression could not result in any of the biological effects. It is indicated that Rich1, completely different from in other types of cells, might act as a crucial upstream negative regulator via its GAP domain in control of epithelial cell cycle, proliferation and focal adhesion through CDC42/RAC1-PAK1 ERK1/2 signaling pathway and F-actin dynamics. PMID- 26004136 TI - Oncostatic effects of fluoxetine in experimental colon cancer models. AB - Colon cancer is one of the most common tumors in the human population. Recent studies have shown a reduced risk for colon cancer in patients given the antidepressant fluoxetine (FLX). The exact mechanism by which FLX might protect from colon cancer remains however controversial. Here, FLX reduced the development of different colon tumor xenografts, as well as proliferation in hypoxic tumor areas within them. FLX treatment also decreased microvessel numbers in tumors. Although FLX did not increase serum and tumor glucose levels as much as the colon chemotherapy gold standard Fluorouracil did, lactate levels were significantly augmented within tumors by FLX treatment. The gene expression of the MCT4 lactate transporter was significantly downregulated. Total protein amounts from the third and fifth mitochondrial complexes were significantly decreased by FLX in tumors. Cell culture experiments revealed that FLX reduced the mitochondrial membrane potential significantly and disabled the reactive oxygen species production of the third mitochondrial complex. Furthermore, FLX arrested hypoxic colon tumor cells in the G0/G1 phase of the cell-cycle. The expression of key cell-cycle-related checkpoint proteins was enhanced in cell culture and in vivo experiments. Therefore, we suggest FLX impairs energy generation, cell cycle progression and proliferation in tumor cells, especially under condition of hypoxia. This then leads to reduced microvessel formation and tumor shrinkage in xenograft models. PMID- 26004137 TI - CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and betaTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells. AB - Both Cluster of Differentiation 166 (CD166) and Melanoma Cell Adhesion Molecule (MCAM) play critical roles in maintaining transformative phenotype of Hepatocellular Carcinoma (HCC) cells. However, the relationship between these two membrane proteins remains unknown. Here, we found that CD166 has a positive impact on the expression of MCAM, while MCAM has no feedback on CD166. Tissue microarray analysis (TMA) also showed a positive correlation between CD166 and MCAM. Depletion of CD166-induced anti-carcinogenic phenotype could be reversed by overexpression of MCAM, suggesting MCAM is functional important in the CD166 induced liver tumorigenesis. Furthermore, we found CD166 regulates MCAM mainly through protecting MCAM from ubiquitin-mediated protein degradation. Mechanically, CD166 down-regulated two ubiquitin E3 ligases, betaTrCP and Smurf1, which play critical roles in the destability of MCAM protein. In addition, overexpression of betaTrCP and Smurf1-reduced transformative phenotype could be partially reversed by MCAM, providing evidence that MCAM is a target of betaTrCP and Smurf1. Moreover, we identified c-Raf/MEK/ERK signaling acts as a downstream effecter of CD166/PI3K/AKT axis to stimulate ubiquitination and destability of betaTrCP and Smurf1. Taken together, we establish a model that CD166 regulates MCAM through a signaling flow from activation of PI3K/AKT and c-Raf/MEK/ERK signaling to the inhibition of potential MCAM ubiquitin E3 ligases, betaTrCP and Smurf1, blockage of this signaling cascade may be useful in the treatment of CD166 and MCAM-dependent HCC. PMID- 26004138 TI - Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells. AB - The present study investigated 1,2-diarachidonoyl-sn-glycero-3 phosphoethanolamine (DAPE)-induced cell death in malignant pleural mesothelioma (MPM) cells. DAPE reduced cell viability in NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H MPM cell lines in a concentration (1-100MUM)-dependent manner. In the flow cytometry using propidium iodide (PI) and annexin V (AV), DAPE significantly increased the population of PI-positive and AV-negative cells, corresponding to primary necrosis, and that of PI-positive and AV-positive cells, corresponding to late apoptosis/secondary necrosis, in NCI-H28 cells. DAPE-induced reduction of NCI-H28 cell viability was partially inhibited by necrostatin-1, an inhibitor of RIP1 kinase to induce necroptosis, or knocking-down RIP1. DAPE generated reactive oxygen species (ROS) followed by disruption of mitochondrial membrane potentials in NCI-H28 cells. DAPE-induced mitochondrial damage was attenuated by cyclosporin A, an inhibitor of cyclophilin D (CypD). DAPE did not affect expression and mitochondrial localization of p53 protein in NCI-H28 cells. DAPE significantly decreased intracellular ATP concentrations in NCI-H28 cells. Overall, the results of the present study indicate that DAPE induces necroptosis and necrosis of MPM cells; the former is mediated by RIP1 kinase and the latter is caused by generating ROS and opening CypD-dependent mitochondrial permeability transition pore, to reduce intracellular ATP concentrations. PMID- 26004139 TI - Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis. AB - Aging is associated with alterations of lipid metabolism and increased prevalence of non alcoholic hepatic steatosis. Nevertheless, the mechanisms by which fat is accumulated in the liver during aging remain incompletely understood. In the present study, we investigated potential alterations that might contribute to the development of hepatic steatosis with aging. To this end, we analyzed the expression and the subcellular localization of key transcriptional factors involved in lipid metabolism such as ChREBP, Foxo1, Foxa2 and SREBP-1c in the liver of 3- and 24-month old Wistar rats. In addition, we studied the intracellular redistribution of ChREBP in response to fasting/refeeding transition. Old rats were characterized by hepatic steatosis, low serum ketone body levels and postprandial hyperinsulinemia. These observations were paralleled by the cytoplasmic localization and decreased expression of Foxa2, while ChREBP expression was markedly up-regulated and mainly localized in the nucleus. Consequently, the expression of lipogenic and beta-oxidation genes was up regulated or down-regulated, respectively. Besides, the intracellular redistribution of ChREBP in response to fasting/refeeding transition was also impaired in old animals. Additionally, a negative correlation between serum ketone body levels and the nuclear localization of ChREBP was observed only in adult but not in old rats. Taken together, these data suggest that an age-related dysfunctional adaptation of ChREBP, in response to changes in the nutritional state, might contribute to the development of liver steatosis with aging. PMID- 26004141 TI - Quality evaluation of randomized controlled trials reports of laparoscopy compared with open colorectal resection for colorectal cancer. AB - OBJECTIVES: Previously, there were no data looking at the quality evaluation of randomized controlled trials (RCTs) on effect comparison of laparoscopic surgery and open surgery for colorectal cancer in China. Here, we evaluate the completeness and transparency of RCT reports in this field. METHODS: The following databases were searched: Medline, EMbase, SCI Expanded, China National Knowledge Infrastructure, the Chinese Biological Medicine Database, VIP database and Wan Fang databases) to search RCT reports on the effect comparison of laparoscopic surgery and open surgery for colorectal cancer in China. Our study evaluated the reporting quality of RCTs based on 22 standards of Consolidated Standards for Reporting Trials (CONSORT) 2010 Statement. Two reviewers responded with 'yes' or 'no' to each standard to judge whether the authors had reported or had recorded concrete details of the reports accomplished in accordance with the requirement of each standard. RESULTS: A total of 40 relevant RCTs were included in the final analysis. For the 'Title and abstract', only three articles (7.5%) could be identified directly from its title as the report of RCTs. For the 'Methods', only three articles (7.5%) applied the method of random allocation of sequences; only two articles (5%) mentioned the type of randomization or gave the description of the mechanism of allocation concealment; no article referred the concrete implementation of random method. Only one article (2.5%) applied the method of blinding or sample size calculation; no article had analysis about the metaphase of an experiment or an explanation of its interruption. For 'results', only one article (2.5%) described participant flow, primary and secondary outcomes with estimated effect size or ancillary analyses. Only 13 articles (32.5%) showed baseline demographic and clinical characteristics, 10 (25%) referred to intention-to-treat analysis, and 12 (30%) mentioned important harms or unintended effects. For the 'discussion', only eight articles (20%) gave the description of trials' limitations and 13 (32.5%) presented the generalizability (external validity, applicability) of the trial findings. CONCLUSION: The quality of the RCT reports on effect comparison of laparoscopic surgery and open surgery for colorectal cancer in China is poor. The reporting of RCTs in this field should be standardized, according to the specifications of the CONSORT 2010. PMID- 26004140 TI - Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction. AB - A platform technology has been developed and tested for delivery of intracellular acting peptides through electrostatically complexed nanoparticles, or nano polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides. PMID- 26004142 TI - Treatment of childhood anxiety disorder in the context of maternal anxiety disorder: a randomised controlled trial and economic analysis. AB - BACKGROUND: Cognitive-behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder. OBJECTIVES: This study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated. DESIGN: Participants were randomised to receive (i) child cognitive-behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive-behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother-child interactions (MCIs) (CCBT + MCI). SETTING: A NHS university clinic in Berkshire, UK. PARTICIPANTS: Two hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder. INTERVENTIONS: All families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact. MAIN OUTCOME MEASURES: Primary clinical outcomes were the child's primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost-utility analysis framework with associated uncertainty. RESULTS: MCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62, p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67, p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59, p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53, p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%. CONCLUSIONS: Good outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19762288. FUNDING: This trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership (09/800/17) and will be published in full in Health Technology Assessment; Vol. 19, No. 38. PMID- 26004145 TI - Evaluation of a nasal surgical questionnaire designed for monitoring surgical outcomes and comparing different techniques. AB - OBJECTIVE: This study evaluated a nasal surgical questionnaire designed for monitoring surgical outcomes and comparing different techniques. METHODS: Eighty three healthy volunteers answered the same questionnaire twice with a minimum interval of five weeks. Three visual analogue scale items were used to assess nasal obstruction during the day, at night and during exercise. Respondents rated nasal obstruction severity by marking on a 10 cm line, with scores ranging from 0 to 100 (measured in millimetres). Other nasal symptoms, considered secondary outcomes, were graded using four-point Likert scales. RESULTS: Mean visual analogue scale scores for nasal obstruction severity experienced during the day, at night and during exercise at initial assessment were 9.99, 12.95 and 11.67, respectively. Thirty-eight per cent of scores indicated no obstruction (scores of 0), 47 per cent indicated mild obstruction (scores 1-30), 13 per cent indicated moderate obstruction (scores 31-70) and 2 per cent indicated severe obstruction (scores 71-100). Males had higher scores than females. The scores for the first and second assessment did not differ, except at night for obstruction in allergic individuals which was considered clinically unimportant. CONCLUSION: The questionnaire reliably assesses nasal symptoms and may be useful for prospective studies of nasal surgery. PMID- 26004144 TI - Asymmetric and unilateral hearing loss in children. AB - Asymmetric and unilateral hearing losses in children have traditionally been underappreciated, but health care practitioners are now beginning to understand their effect on development and the underlying pathophysiologic mechanisms. The common wisdom among medical and educational professionals has been that at least one normal-hearing or near-normal-hearing ear was sufficient for typical speech and language development in children. The objective of this review is to illustrate, to the non-otolaryngologist, the consequences of asymmetric and unilateral hearing loss in children on developmental and educational outcomes. Etiology, detection, and management are also discussed. Lastly, implications for further research are considered. PMID- 26004143 TI - Endoplasmic reticulum stress-mediated inflammatory signaling pathways within the osteolytic periosteum and interface membrane in particle-induced osteolysis. AB - Aseptic loosening secondary to periprosthetic inflammatory osteolysis results from the biological response to wear particles and is a leading cause of arthroplasty failure. The origin of this inflammatory response remains unclear. We aim to validate the definite link between endoplasmic reticulum (ER) stress and particle-induced inflammatory signaling pathways in periprosthetic osteolysis. We examine the histopathologic changes of osteolysis and the expression of specific biomarkers for ER-stress-mediated inflammatory signaling pathways (IRE1alpha, GRP78/Bip, c-Fos, NF-kappaB, ROS and Ca(2+)). Moreover, pro inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and osteoclastogenic molecules (VEGF, OPG, RANKL and M-CSF) were assessed in clinical interface membranes and murine periosteum tissues. We found wear particles to be capable of inducing ER stress in macrophages within clinical osteolytic interface membranes and murine osteolytic periosteum tissues and to be associated with the inflammatory response and osteoclastogenesis. Blocking ER stress with sodium 4 phenylbutyrate (4-PBA) results in a dramatic amelioration of particle-induced osteolysis and a significant reduction of ER-stress intensity. Simultaneously, this ER-stress blocker also lessens inflammatory cell infiltration, diminishes the capability of osteoclastogenesis and reduces the inflammatory response by lowering IRE1alpha, GRP78/Bip, c-Fos, NF-kappaB, ROS and Ca(2+) levels. Thus, ER stress plays an important role in particle-induced inflammatory osteolysis and osteoclastogenic reactions. The pharmacological targeting of ER-stress-mediated inflammatory signaling pathways might be an appealing approach for alleviating or preventing particle-induced osteolysis in at-risk patients. PMID- 26004146 TI - Effects of intrathecal injection of rapamycin on pain threshold and spinal cord glial activation in rats with neuropathic pain. AB - OBJECTIVE: To evaluate the effects of intrathecal injection of rapamycin on pain threshold and spinal cord glial activation in rats with neuropathic pain. METHODS: Healthy 30 male Sprague Dawley (SD) rats were randomly divided into six groups (n = 5 in each group): (1) control group without any treatments; (2) chronic constriction injury (CCI) group; (3) Early-rapamycin group with intrathecal injection of rapamycin 4 hours after CCI days; (4) Early-vehicle group with intrathecal injection of DMSO; (5) Late-rapamycin group with intrathecal injection of rapamycin 7 days after CCI; (6) Late-vehicle group with intrathecal injection of DMSO 7 days after CCI. Rapamycin or DMSO was injected for 3 consecutive days. Mechanical and thermal threshold were tested before and after the CCI operation. Lumbar segment of spinal cords was tested for glial fibrillary acidic protein (GFAP) by immunohistochemistry on 14th day after operation. RESULTS: Mechanical and thermal hyperalgesia emerged on fourth day were maintained till fourteenth day after operation. After intrathecal injection of rapamycin 4 hours or 7 days after CCI, mechanical and thermal threshold significantly increased compared to injection of DMSO. The area of GFAP positive and the mean density of GFAP positive area in the dorsal horn of the ipsilateral side greatly increased in rapamycin-treated groups. CONCLUSIONS: Intrathecal injection of rapamycin may attenuate CCI-induced hyperalgesia and inhibit the activation of astrocyte. PMID- 26004147 TI - The impact of phosphorus on the immune system and the intestinal microbiota with special focus on the pig. AB - There is increasing interest in dietary ingredients that are appropriate to support digestive and immune functions, but also maintain a stable microbial ecosystem in the gastrointestinal tract (GIT), particularly in weaned pigs. P is an essential nutrient for both microbes and their host, as it is involved, for example, in bone formation, energy metabolism, cellular signalling and stabilisation of cell membranes. Non-ruminant animals have limited access to phytate, the main storage form of P in plant seeds. The release of P bound to phytate requires phytase activity of plant or microbial origin, resulting in the formation of variable phosphorylated inositol phosphates (InsPs). The present review focuses on interactions between variations in dietary P supply, the immune system of the host, and the intestinal microbial ecosystem. Although results on the interaction between P and the immune system are inconsistent, several studies in different species have shown a positive impact of dietary P and phytase addition on the adaptive immune response. Recent studies with pigs suggest that P supply may influence intestinal microbial composition and activity. Individual InsPs or phosphate may also affect properties of pathogenic micro-organisms, such as metabolism or virulence. In conclusion, P may be considered as part of an integrated approach to support immune functions and maintain a stable microbial ecosystem in the GIT, thereby providing a barrier against potential pathogens. Within this regard, differences in phytate-P content and intrinsic phytase activity of plant feedstuffs, as well as the formation of individual InsPs, have to be taken into account. PMID- 26004148 TI - Increased plasmacytoid dendritic cells in Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is a post-infectious autoimmune disease. Dendritic cells (DCs) can recognize the pathogen and modulate the host immune response. Exploring the role of DCs in GBS will help our understanding of the disease development. In this study, we aimed to analyze plasmacytoid and conventional DCs in peripheral blood of patients with GBS at different stages of the disease: acute phase as well as early and late recovery phases. There was a significant increase of plasmacytoid DCs in the acute phase (p=0.03 vs healthy donors). There was a positive correlation between percentage of plasmacytoid DCs and the clinical severity of patients with GBS (r=0.61, p<0.001). Quantitative polymerase chain reaction and flow cytometry confirmed the aberrant plasmacytoid DCs in GBS. Thus, plasmacytoid DCs may participate in the development of GBS. PMID- 26004149 TI - Remarkably increased resistin levels in anti-AChR antibody-positive myasthenia gravis. AB - Resistin is a pro-inflammatory cytokine involved in the pathogenesis of autoimmune diseases. To investigate serum resistin levels in patients with myasthenia gravis (MG) and determine if there are associations between resistin levels and disease severity, we measured serum resistin levels in 102 patients with anti-acetylcholine receptor antibody-positive MG (AChR-MG). We further analyzed associations between serum resistin levels and clinical variables in patients with MG. Our findings demonstrate that serum resistin levels are elevated in patients with AChR-generalized MG and AChR-MG with thymoma and are correlated with disease severity. Resistin has potential as a useful serum biomarker for inflammation in AChR-MG. PMID- 26004150 TI - The role of laquinimod in modulation of the immune response in relapsing remitting multiple sclerosis: Lessons from gene expression signatures. AB - Laquinimod, is a potential oral immunomodulatory drug, for relapsing-remitting multiple sclerosis (RRMS). We analyzed the blood-transcriptional changes in RRMS patients (who participated in the ALLEGRO clinical trial) at one and six months after laquinimod treatment using gene expression microarrays. The molecular effects of laquinimod were enhanced by duration of treatment and showed down regulation of inflammatory responses mainly via TGFb signaling, and of pro inflammatory cytokines as well as of cellular movement, including adhesion, migration and leukocyte extravasation signaling. Our results demonstrate that laquinimod suppresses inflammation through down-regulation of inflammatory cytokines and arrest of leukocyte extravasation and thereby could attenuate disease activity in RRMS patients. PMID- 26004151 TI - Circulating lymphocyte and T memory subsets in glucocorticosteroid versus IVIG treated patients with CIDP. AB - The present study compared lymphocyte and T memory subsets in currently untreated patients with chronic inflammatory demyelinating polyneuropathy (CIDP) to glucocorticosteroid (GS) and intravenous immunoglobulin (IVIG) treated patients. Peripheral blood from 48 CIDP patients (21 untreated who were either treatment naive or without treatment during the last 3 months, 17 IVIG and 10 GS treatment) and from 12 age-matched controls was evaluated using flow cytometric analysis. Our data demonstrate that long-term GS treatment is associated with reduced frequencies of total CD4+ T cells, CD4+ memory subsets and NK cells while long term IVIG treatment is associated with alterations of the CD8+ memory compartment. Reduction of CD4+ naive T cell counts may explain the observation that GS treatment induces prolonged clinical remission compared to IVIG treatment. PMID- 26004152 TI - Methyl CpG binding protein 2 deficiency enhances expression of inflammatory cytokines by sustaining NF-kappaB signaling in myeloid derived cells. AB - Knocking down methyl CpG binding protein 2 (MeCP2) enhances NF-kappaB activation in human peripheral blood mononuclear cells (PBMC). In this study, we examined whether this caused the expression of cytokines to be elevated. Increased levels of TNFalpha, IL-6, and IL-3 mRNAs were observed in human PBMC made MeCP2 deficient with a lentiviral shRNA MeCP2 vector and in splenocytes from MeCP2-null mice. TNFalpha neutralizing antibody attenuated expression of IL-6 and TNFalpha but did not affect expression of IL-3. Lipopolysaccharide-mediated increases in TNFalpha, IL-6, and IL-3 mRNAs were also enhanced in MeCP2-deficient PBMC. Two inhibitors of NF-kappaB blocked the increased levels of IL-6, TNFalpha, and IL-3 in MeCP2-deficient PBMC treated with lipopolysaccharide. MeCP2 deficiency also enhanced expression of IL-6 and TNFalpha mRNAs in the THP1 human monocyte cell line, which were also attenuated by the NF-kappaB inhibitors. In chromatin immunoprecipitation assays, the binding of the NF-kappaB family member p65 and acetylated H3 to the TNFalpha promoter was greater after treatment with LPS in MeCP2-deficient THP1 cells. MeCP2 did not bind to the TNFalpha promoter. In summary, the data indicates that MeCP2 deficiency increases expression of TNFalpha and other inflammatory cytokines by enhancing NF-kappaB signaling. PMID- 26004153 TI - GABAergic neurons in cerebellar interposed nucleus modulate cellular and humoral immunity via hypothalamic and sympathetic pathways. AB - Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3 MP), a glutamic acid decarboxylase antagonist that reduces gamma-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways. PMID- 26004154 TI - Relation between plasmatic and cerebrospinal fluid oxidative stress biomarkers and intrathecal Ig synthesis in Multiple Sclerosis patients. AB - The aim of this study was to evaluate if cerebrospinal fluid (CSF) oxidative stress biomarkers were related to plasmatic levels and to intrathecal Ig synthesis in 51 patients with Multiple Sclerosis (MS) or clinically isolated syndrome (CIS). Plasmatic and CSF ferric reducing ability (FRA) showed a significant positive correlation (rho 0.28, p=0.04), while advanced oxidation protein products (AOPPs) did not. A negative correlation was found between IgG synthesis index and CSF FRA levels. No difference in CSF AOPPs or FRA was observed between patients with and without intrathecal IgM synthesis. Our results indicate that plasmatic and CSF FRA are strictly linked, while CSF oxidative stress biomarkers are not related to intrathecal Ig synthesis. PMID- 26004155 TI - In vivo and systems biology studies implicate IL-18 as a central mediator in chronic pain. AB - Inflammation is associated with peripheral neuropathy, however the interplay among cytokines, chemokines, and neurons is still unclear. We hypothesized that this neuroinflammatory interaction can be defined by computational modeling based on the dynamics of protein expression in the sciatic nerve of rats subjected to chronic constriction injury. Using Dynamic Bayesian Network inference, we identified interleukin (IL)-18 as a central node associated with neuropathic pain in this animal model. Immunofluorescence supported a role for inflammasome activation and induction of IL-18 at the site of injury. Combined in vivo and in silico approaches may thus highlight novel targets in peripheral neuropathy. PMID- 26004156 TI - The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2 macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease. AB - Alzheimer's disease (EOAD, LOAD), mild cognitive impairment (MCI), Parkinson's disease (PD) and healthy controls were included to determine the serum interleukin-1s (IL-1alpha, IL-1beta), IL-6 and alpha-2-macroglobulin (alpha2M) levels using ELISA. IL-6 might be a significant contributor to the inflammatory response in LOAD. The MCI data indicate that IL-1s, alpha2M and BDNF are somehow related, and this relationship might allow MCI patients to be more similar to the healthy controls. A correlation analysis of multiple biomarkers in different neurodegenerative disorders might be more useful than determining the levels of a single cytokine in a single disorder. PMID- 26004158 TI - Does enzyme replacement therapy enhance brain-derived neurotrophic factor expression in Gaucher disease? PMID- 26004157 TI - Immunohistochemical screening for antibodies in recent onset type 1 narcolepsy and after H1N1 vaccination. AB - Narcolepsy type 1 patients typically have undetectable hypocretin-1 levels in the cerebrospinal fluid (CSF), as a result of a selective loss of the hypocretin containing neurons in the hypothalamus. An autoimmune attack targeting hypothalamic hypocretin (orexin) neurons is hypothesised. So far, no direct evidence for an autoimmune attack was found. One of the major limitations of previous studies was that none included patients close to disease onset. We screened serum of 21 narcolepsy type 1 patients close to disease onset (median 11 months), including 8 H1N1 vaccinated patients, for antibodies against hypocretin neurons using immunohistochemistry. No autoantibodies against hypocretin neurons could be detected. PMID- 26004159 TI - Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis. AB - Cerebrospinal fluid (CSF) CXCL13 was shown to correlate with markers of intrathecal inflammation and CSF oligoclonal IgM bands (IgMOB) have been associated with a more severe Multiple Sclerosis (MS) course. We correlated CSF CXCL13 levels with clinical, MRI and CSF parameters, including CSF IgMOB, in 110 Clinically Isolated Syndrome (CIS) patients. CSF CXCL13 levels correlated with CSF cell count, total protein, IgG Index and with the presence of CSF IgGOB and IgMOB. CSF CXCL13 levels >=15.4 pg/ml showed a good positive predictive value and specificity for a MS diagnosis and for a clinical relapse within one year from onset. PMID- 26004160 TI - Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica. AB - Depression and chronic fatigue are frequently present in multiple sclerosis (MS); however, the prevalence rates have not been investigated in neuromyelitis optica (NMO). Thirty-nine consecutive NMO and 75 MS patients were compared using self rating questionnaires for depressive states, daily activity, and fatigue, as well as serum carnitine levels. A subgroup of patients with low carnitine levels were re-evaluated regarding depression and fatigue after levocarnitine treatment. Depression and fatigue were equally prevalent in MS and NMO and were strongly correlated with one another. Measurement of the serum carnitine levels and the administration of levocarnitine did not appear to be beneficial. PMID- 26004162 TI - Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study. AB - BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS: A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 +/- 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 +/- 2.2) and at follow-up (16.2 +/- 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS: Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups. PMID- 26004161 TI - DMF, but not other fumarates, inhibits NF-kappaB activity in vitro in an Nrf2 independent manner. AB - Fumarate-containing pharmaceuticals are potent therapeutic agents that influence multiple cellular pathways. Despite proven clinical efficacy, there is a significant lack of data that directly defines the molecular mechanisms of action of related, yet distinct fumarate compounds. We systematically compared the impact of dimethyl fumarate (DMF), monomethyl fumarate (MMF) and a mixture of monoethyl fumarate salts (Ca(++), Mg(++), Zn(++); MEF) on defined cellular responses. We demonstrate that DMF inhibited NF-kappaB-driven cytokine production and nuclear translocation of p65 and p52 in an Nrf2-independent manner. Equivalent doses of MMF and MEF did not affect NF-kappaB signaling. These results highlight a key difference in the biological impact of related, yet distinct fumarate compounds. PMID- 26004163 TI - Preoperative multivariable prognostic models for prediction of survival and major complications following surgical resection of renal cell carcinoma with suprahepatic caval tumor thrombus. AB - OBJECTIVE: Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi. METHODS: We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien >= 3A). Nomograms were internally calibrated by bootstrap resampling method. RESULTS: A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio = 2.52, P = 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio = 1.84, P<0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio = 8.45, P<0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications. CONCLUSIONS: We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention. PMID- 26004164 TI - Percentage of sarcomatoid component as a prognostic indicator for survival in renal cell carcinoma with sarcomatoid dedifferentiation. AB - OBJECTIVE: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with higher stage of presentation and worse survival. The objective of this study was to examine the clinicopathologic characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC). METHODS: We reviewed clinicopathologic data for all nephrectomized patients with confirmed sRCC. Histologic slides were rereviewed by dedicated genitourinary pathologists to ascertain PSC. Patient characteristics were tabulated overall and by disease stage. Cutpoints in the PSC providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA). Factors selected included age group, gender, race, clinical stage, tumor histology, presurgical systemic therapy, lymphovascular invasion, and tumor size. The Kaplan-Meier method and log-rank test were used to assess differences in OS. RESULTS: Among 186 patients with sRCC, 64 (34%) had localized, and 122 (66%) had metastatic disease at presentation. Patients had primarily clear cell histology (73%). Median follow-up was 12.1 months (range: 0.1-242.2mo). Median OS was 12.6 months (95% CI: 10.7-14.9mo). Univariate RPA identified a PSC cutpoint of 10% as prognostically significant. Patients with PSC>10% were at higher risk of death when compared with patients with PSC<=10% (45% vs. 61% 1-y OS; P = 0.04). Multivariate RPA revealed that tumor size, presence of metastatic disease, and PSC were significantly associated with OS. Among 4 identified groups, patients with localized disease and tumor size<=10cm were most likely to be alive at 1 year (89%), and patients with metastatic disease and PSC>40% were least likely to be alive at 1 year (28%; P<0.001). CONCLUSION: PSC appears to be a prognostic factor in patients with sRCC, with larger percentage of involvement portending a worse survival, especially in patients with metastatic disease. PMID- 26004165 TI - The prognostic effect of prostate-specific antigen half-life at the first follow up visit in newly diagnosed metastatic prostate cancer. AB - PURPOSE: Several prostate-specific antigen (PSA) kinetics parameters such as nadir PSA level and time to nadir PSA level are used commonly as predictive prognostic factors for patients with metastatic prostate cancer (mPCa) who have undergone androgen deprivation therapy. However, based on the limitations of these factors, earlier and more clinically available prognostic factors are needed. Therefore, we examined the PSA half-life (PSAHL) estimated at the first follow-up visit as a prognostic factor of newly diagnosed mPCa. METHODS: We performed a retrospective review of 309 patients with newly diagnosed mPCa who had undergone androgen deprivation therapy. After categorizing the included patients to short and long PSAHL groups, based on the median PSAHL value, Cox regression analyses were performed to identify independent prognostic factors of newly diagnosed mPCa. The Kaplan-Meier method was used for detecting differences in survival between both the groups. RESULTS: The median follow-up period was 44 months, and the prostate cancer-specific mortality (PCSM)-free survival length was 65 months in all included patients. Long PSAHL group (hazard ratio [HR] = 2.383, P<0.001), nadir PSA level (HR = 1.004, P<0.001), time to nadir PSA level (HR = 0.856; P<0.001), and Gleason score 8 to 10 relative to 6 to 7 (HR = 2.025; P = 0.008) were found to be independent predictors of the PCSM. By the Kaplan Meier method, the median PCSM-free survival of the short PSAHL group was 73.7 (95% CI: 54.8-92.6) and of the long PSAHL group was 52.5 months (95% CI: 33.4 71.6). This difference between both the groups was found to be statistically significant (P = 0.014, log rank test). CONCLUSIONS: PSAHL estimated at the first follow-up visit is an independent prognostic factor for newly diagnosed mPCa. If the prospective validation test is performed on a large scale, it may demonstrate that PSAHL is an early surrogate prognostic factor of newly diagnosed mPCa. PMID- 26004166 TI - Carbohydrate-rich breakfast attenuates glycaemic, insulinaemic and ghrelin response to ad libitum lunch relative to morning fasting in lean adults. AB - Breakfast omission is associated with obesity and CVD/diabetes, but the acute effects of extended morning fasting upon subsequent energy intake and metabolic/hormonal responses have received less attention. In a randomised cross over design, thirty-five lean men (n 14) and women (n 21) extended their overnight fast or ingested a typical carbohydrate-rich breakfast in quantities relative to RMR (i.e. 1963 (sd 238) kJ), before an ad libitum lunch 3 h later. Blood samples were obtained hourly throughout the day until 3 h post-lunch, with subjective appetite measures assessed. Lunch intake was greater following extended fasting (640 (sd 1042) kJ, P< 0.01) but incompletely compensated for the omitted breakfast, with total intake lower than the breakfast trial (3887 (sd 1326) v. 5213 (sd 1590) kJ, P< 0.001). Systemic concentrations of peptide tyrosine-tyrosine and leptin were greater during the afternoon following breakfast (both P< 0.05) but neither acylated/total ghrelin concentrations were suppressed by the ad libitum lunch in the breakfast trial, remaining greater than the morning fasting trial throughout the afternoon (all P< 0.05). Insulin concentrations were greater during the afternoon in the morning fasting trial (all P< 0.01). There were no differences between trials in subjective appetite during the afternoon. In conclusion, morning fasting caused incomplete energy compensation at an ad libitum lunch. Breakfast increased some anorectic hormones during the afternoon but paradoxically abolished ghrelin suppression by the second meal. Extending morning fasting until lunch altered subsequent metabolic and hormonal responses but without greater appetite during the afternoon. The present study clarifies the impact of acute breakfast omission and adds novel insights into second-meal metabolism. PMID- 26004167 TI - Independent and joint associations of race/ethnicity and educational attainment with sleep-related symptoms in a population-based US sample. AB - OBJECTIVE: Prior studies have documented disparities in short and long sleep duration, excessive daytime sleepiness, and insomnia by educational attainment and race/ethnicity separately. We examined both independent and interactive effects of these factors with a broader range of sleep indicators in a racially/ethnically diverse sample. METHODS: We analyzed 2012 National Health Interview Survey data from 33,865 adults aged >=18years. Sleep-related symptomatology included short sleep duration (<=6h), long sleep duration (>=9h), fatigue >3days, excessive daytime sleepiness, and insomnia. Bivariate analyses with chi-square tests and log-linear regression were performed. RESULTS: The overall age-adjusted prevalence was 29.1% for short sleep duration, 8.5% for long sleep duration, 15.1% for fatigue, 12.6% for excessive daytime sleepiness, and 18.8% for insomnia. Educational attainment and race/ethnicity were independently related to the five sleep-related symptoms. Among Whites, the likelihood of most sleep indicators increased as educational attainment decreased; relationships varied for the other racial/ethnic groups. For short sleep duration, the educational attainment-by-race/ethnicity interaction effect was significant for African Americans (p<0.0001), Hispanics (p<0.0001), and Asians (p=0.0233) compared to Whites. For long sleep duration, the interaction was significant for Hispanics only (p=0.0003). CONCLUSIONS: Our results demonstrate the importance of examining both educational attainment and race/ethnicity simultaneously to more fully understand disparities in sleep health. Increased understanding of the mechanisms linking sociodemographic factors to sleep health is needed to determine whether policies and programs to increase educational attainment may also reduce these disparities within an increasingly diverse population. PMID- 26004168 TI - Microvascular reconstruction of complex foot defects, a new anatomo-functional classification. AB - Up until recently severe foot defects have been underestimated and amputation considered the treatment of choice. Inadequate treatment of foot defects is generally responsible for impaired deambulation resulting in physical and psychological handicap to the patient and producing a negative impact on social life. Foot reconstruction represents a recent advancement but is still a great challenge to the plastic surgeon; indeed the absence of a comprehensive anatomical classification of foot defects makes sharing clinical experiences difficult, slowing down the progress in this field. We report a single surgeon experience on a consecutive series of 47 complex foot reconstructions performed on 45 patients with microvascular free flaps over a 27-year period. A retrospective review of the cases was performed, a detailed analysis of the defects is presented and possible solutions debated so as to outline the key points in the diagnosis and treatment of foot defects. In the decision making process, soft tissue defect location, dimension, and functional relevance have proven to be as important as the exact definition of the bone defect. A new anatomical classification scheme for composite defects of the foot, involving both bone and soft tissue, is proposed in order to allow for a correct evaluation of the wound and an easier identification of the ideal treatment. PMID- 26004169 TI - Excretion patterns of solute and different-sized particle passage markers in foregut-fermenting proboscis monkey (Nasalis larvatus) do not indicate an adaptation for rumination. AB - Behavioral observations and small fecal particles compared to other primates indicate that free-ranging proboscis monkeys (Nasalis larvatus) have a strategy of facultative merycism(rumination). In functional ruminants (ruminant and camelids), rumination is facilitated by a particle sorting mechanism in the forestomach that selectively retains larger particles and subjects them to repeated mastication. Using a set of a solute and three particle markers of different sizes (b2, 5 and 8mm),we displayed digesta passage kinetics and measured mean retention times (MRTs) in four captive proboscis monkeys (6-18 kg) and compared the marker excretion patterns to those in domestic cattle. In addition, we evaluated various methods of calculating and displaying passage characteristics. The mean +/- SD dry matter intake was 98 +/- 22 g kg-0.75 d-1, 68 +/- 7% of which was browse. Accounting for sampling intervals in MRT calculation yielded results that were not affected by the sampling frequency. Displaying marker excretion patterns using fecal marker concentrations (rather than amounts) facilitated comparisons with reactor theory outputs and indicated that both proboscis and cattle digestive tracts represent a series of very few tank reactors. However, the separation of the solute and particle marker and the different-sized particle markers, evident in cattle, did not occur in proboscis monkeys, in which all markers moved together, at MRTs of approximately 40 h. The results indicate that the digestive physiology of proboscis monkeys does not show typical characteristics of ruminants, which may explain why merycism is only a facultative strategy in this species. PMID- 26004170 TI - A warmer indoor environment in the evening and shorter sleep onset latency in winter: The HEIJO-KYO study. AB - Difficulty in initiating sleep is an important problem because it is associated with an increased incidence of depression, diabetes, myocardial infarction, and higher all-cause mortality. Although experimental studies in controlled settings have shown that warm skin temperature of the extremities (feet and hands) before bedtime is associated with shorter sleep onset latency (SOL), evidence from real life situations is limited. We assessed the relationship between indoor temperatures in the evening (2h before bedtime) and SOL among 861 home-dwelling elderly participants. Subjective SOL was determined according to a self administered sleep diary. Actigraphic (objective) SOL, indoor temperature, and bed temperature were simultaneously measured at participants' homes for 48h during the colder seasons (October-April). The association between evening indoor temperature and SOL was assessed using a multilevel linear regression model with random intercept for individual participants. Evening indoor temperature showed a significant inverse association with log-transformed subjective SOL (beta=-0.021, P<0.01) and actigraphic SOL (beta=-0.019, P<0.01), independent of potential confounders including gender, insomnia medication, evening physical activity, and bedtime. Higher bed temperature during the 2h after bedtime was significantly associated with shorter log-transformed actigraphic SOL (beta=-0.028, P<0.01). These significant associations were maintained even after adjustment for evening outdoor temperature. The clinically important findings of the present study indicate that SOL may be shortened by modification of evening indoor temperature and bed temperature for 2h after bedtime. PMID- 26004171 TI - Spread of imipenem-resistant Acinetobacter baumannii co-expressing OXA-23 and GES 11 carbapenemases in Lebanon. AB - OBJECTIVES: The acquisition of carbapenemases by Acinetobacter baumannii is reported increasingly worldwide, but data from Lebanon are limited. The aims of this study were to evaluate the prevalence of imipenem-resistant A. baumannii in Lebanon, identify resistance determinants, and detect clonal relatedness. METHODS: Imipenem-resistant A. baumannii were collected from nine Lebanese hospitals during 2012. Antimicrobial susceptibility, the cloxacillin effect, and ethylenediaminetetraacetic acid (EDTA) synergy were determined. Genes encoding carbapenemases and insertion sequence ISAba1 were screened via PCR sequencing. ISAba1 position relative to genes encoding Acinetobacter-derived cephalosporinases (ADCs) and OXA-23 was studied by PCR mapping. Clonal linkage was examined by enterobacterial repetitive intergenic consensus PCR (ERIC-PCR). RESULTS: Out of 724 A. baumannii isolated in 2012, 638 (88%) were imipenem resistant. Of these, 142 were analyzed. Clavulanic acid-imipenem synergy suggested carbapenem-hydrolyzing extended-spectrum beta-lactamase. A positive cloxacillin test indicated ADCs, while EDTA detection strips were negative. Genotyping indicated that 90% of isolates co-harbored blaOXA-23 and blaGES-11. The remaining strains had blaOXA-23, blaOXA-24, blaGES-11, or blaOXA-24 with blaGES-11. ISAba1 was located upstream of blaADC and blaOXA-23 in 97% and 100% of isolates, respectively. ERIC-PCR fingerprinting revealed 18 pulsotypes spread via horizontal gene transfer and clonal dissemination. CONCLUSION: This survey established baseline evidence of OXA-23 and GES-11-producing A. baumannii in Lebanon, indicating the need for further surveillance. PMID- 26004172 TI - Xpert MTB/RIF and GenoType MTBDRplus assays for the rapid diagnosis of bone and joint tuberculosis. AB - BACKGROUND: Bone and joint tuberculosis (BJTB) constitutes about 10-20% of the extrapulmonary tuberculosis (EPTB) cases in China. The GenoType MTBDRplus assay (MTBDR) has been endorsed by the World Health Organization (WHO) for the diagnosis of pulmonary TB (PTB), while the Xpert MTB/RIF assay (Xpert) has also been endorsed by the WHO for the diagnosis of both PTB and EPTB. The diagnostic utility of these two techniques for BJTB was investigated prospectively. METHODS: Sixty pus specimens were obtained from orthopedic patients. Smear, culture, Xpert, and MTBDR assays were performed for each specimen, and MGIT 960-based drug susceptibility testing (DST) was conducted for all of the isolates recovered. The diagnostic efficiency of Xpert and MTBDR was evaluated on the basis of bacteriological examination and the composite reference standard (CRS). RESULTS: Fifty of the 60 patients were considered to have BJTB according to the CRS. The sensitivities of smear, culture, Xpert, and MTBDR were 26% (13/50), 48% (24/50), 82% (41/50), and 72% (36/50) respectively, while the specificities of all of the tests were 100% (10/10). Xpert was 100% concordant with MGIT 960-based DST for the detection of rifampicin resistance. MTBDR had a sensitivity of 83.3% and a specificity of 100% for the detection of rifampicin resistance and a sensitivity of 85.7% and specificity of 100% for the detection of isoniazid resistance. CONCLUSION: With their high sensitivities, short turnaround times, and ability to diagnose TB and detect drug resistance simultaneously, both Xpert and MTBDR are feasible as diagnostic tools for BJTB in clinical practice. PMID- 26004173 TI - Evaluation of various treatment modalities in sleep bruxism. AB - STATEMENT OF PROBLEM: Sleep bruxism (SB) is an oral condition that is associated with tooth wear, orofacial pain, and interference with sleep. The most recommended management technique is the use of an occlusal splint. Although the mandibular advancement device (MAD) has shown good results, few well-designed randomized controlled trials are available with which to compare these treatment options. Therefore, an evaluation of the effect of these 2 appliances on SB is needed. PURPOSE: The purpose of this study was to evaluate the effect of a MAD and a maxillary occlusal splint (MOS) on the sleep quality and SB activity of participants with SB. MATERIAL AND METHODS: In this randomized controlled trial, 28 participants were randomly supplied with either a MAD or MOS. The sleep quality of the participants was evaluated with the Pittsburgh Sleep Quality Index (PSQI) and their SB activity with electromyographic activity of the masseter with polysomnography. These variables were measured at baseline, 1 month, and 3 months. RESULTS: Of 32 participants, 28 had data available for statistical analysis, as 4 participants did not return for follow-up examination. Both the MOS and MAD significantly reduced the PSQI and SB episodes and bursts in participants after 3 months (P<.05). The MAD provided greater reduction in SB episodes per hour after 3 months compared to the MOS. Participants supplied with a MAD reported more discomfort in their feedback form than participants using a MOS. CONCLUSIONS: Both the MAD and MOS provided significantly improved sleep quality and a decrease in SB episodes at 3 months. PMID- 26004174 TI - Editorial overview: Antiviral strategies. PMID- 26004175 TI - Nationwide surveillance of 6 otorhinolaryngological infectious diseases and antimicrobial susceptibility pattern in the isolated pathogens in Japan. AB - The Japanese Three Academic Societies Joint Antimicrobial Susceptibility Surveillance Committee has conducted a nationwide surveillance on antimicrobial susceptibility patterns and rates of isolation in 6 otolaryngological diseases. The surveillance program was conducted in the otorhinolaryngological departments of 29 universities, and their 26 affiliated hospitals. Patients suffering from acute otitis media, chronic otitis media, acute nasal sinusitis, chronic nasal sinusitis, acute tonsillitis, and peritonsillar abscess between January 2011 and June 2012 were investigated. The collected swab or incision samples were cultivated for microbial identification, and the drug susceptibility of detected bacteria was measured at the Kitasato University Research Center for Infections and Antimicrobials. The surveillance focused on three gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus), three gram-negative bacteria (Haemophilus influenzae, Moraxella Catarrhalis, and Pseudomonas aeruginosa), and three anaerobic bacteria (Peptostreptococcus spp., Prevotella spp., and Fusobacterium spp.). Bacterial susceptibility to 39 antimicrobial drugs was investigated. We compared bacterial isolation ratio of each disease in this surveillance from those of past 4 times surveillance which we performed formerly, and we also compared percentage of main drug resistant strains from those of past 4 times surveillance. The age composition between this time and former surveillances was not statistically significant by student-t test. We were unable to completely resolve the rise in resistant bacteria, such as methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, penicillin-intermediate resistant S. pneumoniae, beta-lactamase non-producing ampicillin-resistant H. influenzae, beta-lactamase producing ampicillin-resistant H. influenzae, and beta-lactamase producing amoxicillin clavulanic acid-resistant H. influenzae. We suggest promoting the proper usage of antimicrobial drugs in order to avoid the spread of these bacteria. PMID- 26004176 TI - Removal of O-GlcNAcylation is important for pig preimplantation development. AB - Glucose has been recognized as an energy source for a long time, but it has recently been suggested that the hexosamine biosynthesis pathway (HBP) and downstream protein O-GlcNAcylation have important functions in mouse preimplantation development. Thus, whether or not O-GlcNAcylation was present and what functions O-GlcNAcylation has in pig preimplantation development were investigated in the present study. The expressions of mRNA of glutaminefructose-6 phosphate aminotransferase (Gfpt), O-GlcNAc transferase (Ogt) and O-GlcNAcase (Oga), which are involved in the HBP and O-GlcNAc cycling, were examined in pig parthenogenetic diploids at each preimplantation developmental stage. Gfpt and Ogt were detected in diploids at all stages. Though Oga was detected at all stages except the 4-cell stage, OGA proteins were detected in diploids from the 2 cell to blastocyst stage. Furthermore, O-GlcNAcylated proteins in MII oocytes and diploids were also detected by immunofluorescence at every stage. Inhibition of OGT by 4.0 mM BADGP did not affect development up to the blastocyst stage, while inhibition of OGA by 300 uM PUGNAc decreased the proportion of diploids beyond the 4-cell stage. Four-cell diploids cultured with PUGNAc until 48 h developed to the blastocyst stage after culture in a PUGNAc-free medium until 144 h after electrostimulation. RNA polymerase II (Pol II) phosphorylation, which indicates the onset of mRNA transcription, was detected in nuclei of diploids in the control group at 48 h but not in the PUGNAc-treated group. These results indicate that HBP and O-GlcNAcylation have important functions in pig preimplantation development and that inhibition of OGA is fatal for development. It is also suggested that OGA inhibition disrupts normal Pol II regulation and may cause a zygotic gene activation error. PMID- 26004177 TI - Wnt Signaling Translocates Lys48-Linked Polyubiquitinated Proteins to the Lysosomal Pathway. AB - Cellular proteins are degraded in either proteasomes or lysosomes depending on the types of ubiquitin chains that covalently modify them. It is not known whether the choice between these two pathways is physiologically regulated. The Lys48-polyubiquitin chain is the major signal directing proteins for degradation in proteasomes. Here, we report the unexpected finding that canonical Wnt signaling translocates some K48-linked polyubiquitinated proteins to the endolysosomal pathway. Proteasomal target proteins, such as b-catenin, Smad1, and Smad4, were targeted into endolysosomes in a process dependent on GSK3 activity. Relocalization was also dependent on Axin1 and the multivesicular body (MVB) proteins HRS/Vps27 and Vps4. The Wnt-induced accumulation of K48-linked polyubiquitinated proteins in endolysosomal organelles was accompanied by a transient decrease in cellular levels of free mono-ubiquitin, which may contribute to Wnt-regulated stabilization of proteins (Wnt/ STOP). We conclude that Wnt redirects Lys48-polyubiquitinated proteins that are normally degraded in proteasomes to endolysosomes. PMID- 26004178 TI - T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens. AB - T lymphocytes' ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However, recent studies have suggested that the output of this discrimination process is conditioned by environmental cues. Here, we demonstrate how the IL-2 cytokine, collectively generated by strongly activated T cell clones, can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues, including local cues such as antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines. PMID- 26004179 TI - Mir-17~92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN. AB - Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17~92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17~92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17~92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17~92 responsible for LMC-MN degeneration. Additionally, mir-17~92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival. PMID- 26004180 TI - Histone H3 Serine 28 Is Essential for Efficient Polycomb-Mediated Gene Repression in Drosophila. AB - Trimethylation at histone H3K27 is central to the polycomb repression system. Juxtaposed to H3K27 is a widely conserved phosphorylatable serine residue (H3S28) whose function is unclear. To assess the importance of H3S28, we generated a Drosophila H3 histone mutant with a serine-to-alanine mutation at position 28. H3S28A mutant cells lack H3S28ph on mitotic chromosomes but support normal mitosis. Strikingly, all methylation states of H3K27 drop in H3S28A cells, leading to Hox gene derepression and to homeotic transformations in adult tissues. These defects are not caused by active H3K27 demethylation nor by the loss of H3S28ph. Biochemical assays show that H3S28A nucleosomes are a suboptimal substrate for PRC2, suggesting that the unphosphorylated state of serine 28 is important for assisting in the function of polycomb complexes. Collectively, our data indicate that the conserved H3S28 residue in metazoans has a role in supporting PRC2 catalysis. PMID- 26004181 TI - Single Transcription Factor Conversion of Human Blood Fate to NPCs with CNS and PNS Developmental Capacity. AB - The clinical applicability of direct cell fate conversion depends on obtaining tissue from patients that is easy to harvest, store, and manipulate for reprogramming. Here, we generate induced neural progenitor cells (iNPCs) from neonatal and adult peripheral blood using single-factor OCT4 reprogramming. Unlike fibroblasts that share molecular hallmarks of neural crest, OCT4 reprogramming of blood was facilitated by SMAD+GSK-3 inhibition to overcome restrictions on neural fate conversion. Blood-derived (BD) iNPCs differentiate in vivo and respond to guided differentiation in vitro, producing glia (astrocytes and oligodendrocytes) and multiple neuronal subtypes, including dopaminergic (CNS related) and nociceptive neurons (peripheral nervous system [PNS]). Furthermore, nociceptive neurons phenocopy chemotherapy-induced neurotoxicity in a system suitable for high-throughput drug screening. Our findings provide an easily accessible approach for generating human NPCs that harbor extensive developmental potential, enabling the study of clinically relevant neural diseases directly from patient cohorts. PMID- 26004182 TI - A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP Dependent Recruitment of Transcription Factors. AB - Localization to sites of DNA damage is a hallmark of DNA damage response (DDR) proteins. To identify DDR factors, we screened epitope-tagged proteins for localization to sites of chromatin damaged by UV laser microirradiation and found >120 proteins that localize to damaged chromatin. These include the BAF tumor suppressor complex and the amyotrophic lateral sclerosis (ALS) candidate protein TAF15. TAF15 contains multiple domains that bind damaged chromatin in a poly-(ADP ribose) polymerase (PARP)-dependent manner, suggesting a possible role as glue that tethers multiple PAR chains together. Many positives were transcription factors; > 70% of randomly tested transcription factors localized to sites of DNA damage, and of these, ~90% were PARP dependent for localization. Mutational analyses showed that localization to damaged chromatin is DNA-binding-domain dependent. By examining Hoechst staining patterns at damage sites, we see evidence of chromatin decompaction that is PARP dependent. We propose that PARP regulated chromatin remodeling at sites of damage allows transient accessibility of DNA-binding proteins. PMID- 26004183 TI - Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. AB - AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2alpha/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. PMID- 26004184 TI - The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX 7/L1CAM-EGL-15/FGFR Receptor Complex. AB - Neurite branching is essential for correct assembly of neural circuits, yet it remains a poorly understood process. For example, the neural cell adhesion molecule KAL-1/anosmin-1, which is mutated in Kallmann syndrome, regulates neurite branching through mechanisms largely unknown. Here, we show that KAL 1/anosmin-1 mediates neurite branching as an autocrine co-factor with EGL-17/FGF through a receptor complex consisting of the conserved cell adhesion molecule SAX 7/L1CAM and the fibroblast growth factor receptor EGL-15/FGFR. This protein complex, which appears conserved in humans, requires the immunoglobulin (Ig) domains of SAX-7/L1CAM and the FN(III) domains of KAL-1/anosmin-1 for formation in vitro as well as function in vivo. The kinase domain of the EGL-15/FGFR is required for branching, and genetic evidence suggests that ras-mediated signaling downstream of EGL-15/FGFR is necessary to effect branching. Our studies establish a molecular pathway that regulates neurite branching during development of the nervous system. PMID- 26004185 TI - Mutational Analysis of Measles Virus Suggests Constraints on Antigenic Variation of the Glycoproteins. AB - Measles virus undergoes error-prone replication like other RNA viruses, but over time, it has remained antigenically monotypic. The constraints on the virus that prevent the emergence of antigenic variants are unclear. As a first step in understanding this question, we subjected the measles virus genome to unbiased insertional mutagenesis, and viruses that could tolerate insertions were rescued. Only insertions in the nucleoprotein, phosphoprotein, matrix protein, as well as intergenic regions were easily recoverable. Insertions in the glycoproteins of measles virus were severely under-represented in our screen. Host immunity depends on developing neutralizing antibodies to the hemagglutinin and fusion glycoproteins; our analysis suggests that these proteins occupy very little evolutionary space and therefore have difficulty changing in the face of selective pressures. We propose that the inelasticity of these proteins prevents the sequence variation required to escape antibody neutralization in the host, allowing for long-lived immunity after infection with the virus. PMID- 26004186 TI - The CREB Coactivator CRTC2 Is a Lymphoma Tumor Suppressor that Preserves Genome Integrity through Transcription of DNA Mismatch Repair Genes. AB - The CREB-regulated transcription coactivator CRTC2 stimulates CREB target gene expression and has a well-established role in modulating glucose and lipid metabolism. Here, we find, unexpectedly, that loss of CRTC2, as well as CREB1 and its coactivator CREB-binding protein (CBP), results in a deficiency in DNA mismatch repair (MMR) and a resultant increased mutation frequency. We show that CRTC2, CREB1, and CBP are transcriptional activators of well-established MMR genes, including EXO1, MSH6, PMS1, and POLD2. Mining of expression profiling databases and analysis of patient samples reveal that CRTC2 and its target MMR genes are downregulated in specific T cell lymphoma subtypes, which are microsatellite unstable. The levels of acetylated histone H3 on the CRTC2 promoter are significantly reduced in lymphoma in comparison to normal tissue, explaining the decreased CRTC2 expression. Our results establish a role for CRTC2 as a lymphoma tumor suppressor gene that preserves genome integrity by stimulating transcription of MMR genes. PMID- 26004187 TI - The Cell-Intrinsic Circadian Clock Is Dispensable for Lymphocyte Differentiation and Function. AB - Circadian rhythms regulate many aspects of physiology, ranging from sleep-wake cycles and metabolic parameters to susceptibility to infection. The molecular clock, with transcription factor BMAL1 at its core, controls both central and cell-intrinsic circadian rhythms. Using a circadian reporter, we observed dynamic regulation of clock activity in lymphocytes. However, its disruption upon conditional Bmal1 ablation did not alter T- or B-cell differentiation or function. Although the magnitude of interleukin 2 (IL-2) production was affected by the time of bacterial infection, it was independent of cell-intrinsic expression of BMAL1. The circadian gating of the IL-2 response was preserved in Bmal1-deficient T cells, despite a slight reduction in cytokine production in a competitive setting. Our results suggest that, contrary to the prevailing view, the adaptive immune response is not affected by the cell-intrinsic clock but is likely influenced by cell-extrinsic circadian cues operating across multiple cell types. PMID- 26004189 TI - About DNA databasing and investigative genetic analysis of externally visible characteristics: A public survey. AB - During the last decade, DNA profiling and the use of DNA databases have become two of the most employed instruments of police investigations. This very rapid establishment of forensic genetics is yet far from being complete. In the last few years novel types of analyses have been presented to describe phenotypically a possible perpetrator. We conducted the present study among German speaking Swiss residents for two main reasons: firstly, we aimed at getting an impression of the public awareness and acceptance of the Swiss DNA database and the perception of a hypothetical DNA database containing all Swiss residents. Secondly, we wanted to get a broader picture of how people that are not working in the field of forensic genetics think about legal permission to establish phenotypic descriptions of alleged criminals by genetic means. Even though a significant number of study participants did not even know about the existence of the Swiss DNA database, its acceptance appears to be very high. Generally our results suggest that the current forensic use of DNA profiling is considered highly trustworthy. However, the acceptance of a hypothetical universal database would be only as low as about 30% among the 284 respondents to our study, mostly because people are concerned about the security of their genetic data, their privacy or a possible risk of abuse of such a database. Concerning the genetic analysis of externally visible characteristics and biogeographical ancestry, we discover a high degree of acceptance. The acceptance decreases slightly when precise characteristics are presented to the participants in detail. About half of the respondents would be in favor of the moderate use of physical traits analyses only for serious crimes threatening life, health or sexual integrity. The possible risk of discrimination and reinforcement of racism, as discussed by scholars from anthropology, bioethics, law, philosophy and sociology, is mentioned less frequently by the study participants than we would have expected. A national DNA database and the widespread use of DNA analyses for police and justice have an impact on the entire society. Therefore the concerns of lay persons from the respective population should be heard and considered. The aims of this study were to draw a broader picture of the public opinion on DNA databasing and to contribute to the debate about the possible future use of genetics to reveal phenotypic characteristics. Our data might provide an additional perspective for experts involved in regulatory or legislative processes. PMID- 26004188 TI - Assessing the influence of obesity on longitudinal executive functioning performance in patients with obstructive sleep apnea syndrome. AB - OBJECTIVE: To investigate longitudinal performance on an executive functioning task among individuals with obstructive sleep apnea syndrome (OSAS) and the impact of obesity on performance. METHODS: Participants completed the Trail Making Test Part B (TMT-B), which is an executive functioning task that measured cognitive flexibility, at baseline, 3-, 6-, and 12-month follow-ups. Hierarchical linear modeling (HLM) analyses were used to assess participants' initial performance on the task, as well the trajectories of growth on the task across time points. Additionally, body mass index (BMI) was included in the estimations of fixed and random effects as a predictor of performance. RESULTS: There were no significant differences between obese and non-obese individuals on the cognitive flexibility task at baseline. However, obese and non-obese individuals differed significantly in their linear and quadratic rates of growth across time points. CONCLUSIONS: This study suggests that obese and non-obese individuals may differentially respond to Continuous Positive Airway Pressure (CPAP) treatment (as related to cognitive flexibility). Future research should examine the impact of weight loss on the neuropsychological sequelae of obese individuals with OSAS. PMID- 26004190 TI - [Evaluation of pain during mobilization and endotracheal aspiration in critical patients]. AB - OBJECTIVES: 1) To assess the prevalence of pain during nursing care procedures, and 2) to evaluate the usefulness of certain vital signs and the bispectral index (BIS) in detecting pain. METHODS: A prospective, observational analytical study was made of procedures (endotracheal aspiration and mobilization with turning) in critically ill sedated patients on mechanical ventilation. The Behavioral Pain Scale was used to assess pain, with scores of >=3 indicating pain. Various physiological signs and BIS values were recorded, with changes of >10% being considered clinically relevant. RESULTS: A total of 146 procedures in 70 patients were analyzed. Pain prevalence during the procedures was 94%. Vital signs and BIS values increased significantly during the procedures compared to resting conditions, but only the changes in BIS were considered clinically relevant. In the subgroup of patients receiving preemptive analgesia prior to the procedure, pain decreased significantly compared to the group of patients who received no such analgesia (-2 [IQR: {-5}-0] vs. 3 [IQR: 1-4]; P<.001, respectively). CONCLUSIONS: The procedures evaluated in this study are painful. Changes in vital signs are not good indicators of pain. Changes in BIS may provide useful information about pain, but more research is needed. The administration of preemptive analgesia decreases pain during the procedures. PMID- 26004191 TI - A Glance at... Broccoli, glucoraphanin, and sulforaphane. PMID- 26004192 TI - Antibiotic overuse and Clostridium difficile infections: the Indian paradox and the possible role of dietary practices. AB - Antibiotic abuse is rampant in India, such that one may expect to see an increase of Clostridium difficile infections (CDI). However, we found that the incidence of CDI in India (1.67%) is no different from that reported in USA (1.6%) using similar techniques of detection (polymerase chain reaction test). We offer a possible explanation for this paradox. It is likely that a diet rich in fiber, yogurt, and possibly turmeric may have a protective role in decreasing the incidence of CDIs in India. PMID- 26004193 TI - Vitamin A supplementation leads to increases in regulatory CD4+Foxp3+LAP+ T cells in mice. AB - Dietary compounds, including micronutrients such as vitamin A and its metabolite retinoic acid, directly influence the development and function of the immune system. In this study, we show that either dietary deficiency of or supplementation with vitamin A had immunologic effects in mice that were fed these diets during their development (for 8 wk during the postweaning period). Deficient mice presented higher levels of interferon-gamma, interleukin (IL)-6, transforming growth factor-beta, IL-17, and IL-10 in the gut-associated lymphoid tissues and draining lymph nodes, indicating a proinflammatory shift in the gut mucosa. Serum immunoglobulin G levels also were elevated in these mice. Conversely, supplemented mice showed higher frequencies of CD4+Foxp3+LAP+ regulatory T cells in gut lymphoid tissues and spleen, suggesting that vitamin A supplementation in the diet may be beneficial in pathologic situations such as inflammatory bowel diseases. PMID- 26004195 TI - First identification of Porcine Circovirus Type 2b mutant in pigs from Uruguay. AB - Porcine Circovirus Type 2 (PCV2) is a worldwide distributed virus and is considered an important emerging pathogen related to several distinct disease syndromes in pigs. PCV2 strains are classified into three genotypes: PCV2a, with five subtypes (2A-2E), PCV2b with three subtypes (1A-1C) and PCV2c, only found in Denmark. Recently, several reports suggested the circulation of newly emerging PCV2b mutants (mPCV2b) isolated from pigs with PCVAD in cases of suspected vaccine failure. In this work, we report for the first time the identification of mPCV2b in pigs from Uruguay, providing an additional evidence of a global circulation. Complete genome characterization and phylogenetic analysis reveal that Uruguayan strains, as well as mPCV2b previously reported are closely related to other sequences already classified as PCV2b-1C. Furthermore, results showed that mPCV2b presented different genetic markers in the capsid protein compared with classical PCV2a/b strains. Further investigation about antigenic shift of the mPCV2b strains including the Uruguayan isolates is needed. PMID- 26004196 TI - Diabetes in pregnancy. AB - Diabetes in pregnancy is still considered a high-risk condition for both mother and baby. Even in the best centres, malformation and mortality rates are reportedly twofold to fivefold higher than in the background population, and pregnancy planning rates remain obstinately poor. Increasing global rates of type 2 diabetes are now extending into pregnancy, with similarly poor outcomes to type 1 diabetes, and excess maternal weight is adding to the complexity of management. Over the last 5-10 years, several randomised trials have offered new insight into the role of oral hypoglycaemic drugs and insulin analogues in pregnancy, while continuous subcutaneous insulin infusion (CSII) pumps and continuous glucose monitors (CGMs) are under scrutiny. The relevance of minor degrees of hyperglycaemia to adverse pregnancy outcome was clearly demonstrated by the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study, but translation of these data into clinical practice has proved challenging because of the continuum of risk. Long-term metabolic and cardiovascular implications of hyperglycaemia during pregnancy for mother and child are now generally recognised with major implications for public health. PMID- 26004194 TI - First insights into circulating Mycobacterium tuberculosis complex lineages and drug resistance in Guinea. AB - In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 "orphan" and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs. PMID- 26004197 TI - Reconstruction of a quadriceps tendon tear using Polyvinylidene fluoride sutures and patellar screw fixation: A biomechanical study. AB - BACKGROUND: Acute quadriceps tendon tears are infrequent injuries requiring surgical treatment. Improved stability after surgical repair may allow for earlier weight-bearing and range of motion. Therefore, a new implant was tested and compared with the "gold standard", using transosseous sutures. METHODS: Quadriceps tendon tears were constructed using a cadaveric model of 12 fresh matched-pair specimens (aged 61-97; mean age: 82 years). The biomechanical testing compared non-absorbable suture anchors (Polyvinylidene fluoride) versus transosseous absorbable sutures (Polydioxanon). Following anatomic reconstruction, the repaired specimens were loaded until they failed (testing machine: Hounsfield H10KM, Redhill, United Kingdom; maximum force: 1000 N; load speed: 25 mm/min; maximum test length: 150 mm; pre-load: 5 N). Values for load until tear displacement, maximum load until complete failure of the construct (pullout or breakage of the sutures or anchors) and stiffness of the reconstruction were recorded. RESULTS: The stiffness found in the Polyvinylidene fluoride reconstruction (mean 9.83 N/mm) (standard deviation (SD) 7.75) showed a significant increase compared to the Polydioxanon reconstruction (mean 6.66 N/mm (SD 3.32); P=0.045). Transosseous fixation showed comparable results to the suture anchor system. There was no significant difference found in the maximum load to tear displacement (PVDF: 290.88 N (SD 106.01) vs. PDS: 266.75 N (SD 82.61); P=0.358). CONCLUSIONS: Using the Polyvinylidene fluoride thread showed comparable results to the established method in reconstruction of ruptured quadriceps tendon. Stiffness of the Polyvinylidene fluoride thread reconstruction was even greater than Polydioxanon thread. CLINICAL RELEVANCE: Improved stiffness may facilitate healing and is suggested as clinical relevance in reconstruction. PMID- 26004198 TI - Construction and characterization of an infectious cDNA clone of Echovirus 25. AB - Echovirus 25 (E-25) is a member of the enterovirus family and a common pathogen that induces hand, foot, and mouth disease (HFMD), meningitis, skin rash, and respiratory illnesses. In this study, we constructed and characterized an infectious full-length E-25 cDNA clone derived from the XM0297 strain, which was the first subgenotype D6 strain isolated in Xiamen, China. The 5'-Untranslated Regions (5'-UTR), P3 (3A-3B, 3D) and P3 (3C) regions of this E-25 (XM0297) strain were highly similar to EV-B77, E-16 and E-13, respectively. Our data demonstrate that the rescued E-25 viruses exhibited similar growth kinetics to the prototype virus strain XM0297. We observed the rescued viral particles using transmission electron microscope (TEM) and found them to possess an icosahedral structure, with a diameter of approximately 30 nm. The cross neutralization test demonstrated that the E-25 (XM0297) strain immune serum could not neutralize EV A71, CV-A16 or CV-B3; likewise, the EV-A71 and CV-A16 immune serum could not neutralize E-25 (XM0297). The availability of this infectious clone will greatly enhance future virological investigations and possible vaccine development against E-25. PMID- 26004199 TI - Recessive mutations in the alpha3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. AB - Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis. PMID- 26004200 TI - Jump from pre-mutation to pathologic expansion in C9orf72. AB - An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ~70 repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ~1,750-repeat allele). Epigenetic and RNA expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ~70 repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ~70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre mutations" to reflect their propensity to expand in the next generation. Follow up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects). PMID- 26004201 TI - Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. AB - Arthrogryposis multiplex congenita is defined by the presence of contractures across two or more major joints and results from reduced or absent fetal movement. Here, we present three consanguineous families affected by lethal arthrogryposis multiplex congenita. By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126. GPR126 encodes G protein-coupled receptor 126, which has been shown to be essential for myelination of axons in the peripheral nervous system in fish and mice. A previous study reported that Gpr126(-/-) mice have a lethal arthrogryposis phenotype. We have shown that the peripheral nerves in affected individuals from one family lack myelin basic protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral axons during fetal development. Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling, and our biochemical assays indicated that the missense substitution (p.Val769Glu [c.2306T>A]) impairs autoproteolytic cleavage of GPR126. Our data indicate that GPR126 is critical for myelination of peripheral nerves in humans. This study adds to the literature implicating defective axoglial function as a key cause of severe arthrogryposis multiplex congenita and suggests that GPR126 mutations should be investigated in individuals affected by this disorder. PMID- 26004202 TI - Evidence-based hand and upper extremity surgery. PMID- 26004203 TI - Radioscaphoid articulation incongruity in Kienbock disease. PMID- 26004204 TI - Letter regarding "biomechanical analysis of flexor tendon repair using knotted kessler and bunnell techniques and the knotless bunnell technique". PMID- 26004205 TI - Pregnancy rates and serum 13,14-dihydro-15-keto-PGF2alpha concentrations in recipient Nelore heifers treated with meloxicam after the transfer of in vitro produced embryos. AB - This study aimed to determine if the administration of meloxicam, a cyclooxygenase 2 inhibitor, to Nelore (Bos taurus indicus) heifers, in which embryo transfer is more difficult and requires a greater manipulation of the reproductive tract than in Bos taurus females, would improve the pregnancy rates by decreasing serum PGFM concentrations. After estrous synchronization, multiparous recipient heifers (n = 85) were selected as embryo recipients and were randomly allocated into two groups: CON (n = 42), the control group, in which animals received 10 mL of saline intramuscularly (the same volume of meloxicam), and MEL (n = 43), the group in which animals were treated with meloxicam. According to the degree of passing the catheter, recipients from both groups were classified as grade I (easy; <80 seconds) and grade II (difficult; >80 seconds). One hour before embryo transfer, MEL recipients received an injection of 200 mg of meloxicam. Blood samples were collected from all heifers 1 hour before embryo transfer and 4 and 8 hours after embryo transfer to determine the serum concentrations of 13,14-dihydro-15-keto-PGF2alpha (PGFM), a PGF2alpha metabolite. A significant difference in the pregnancy rates on Day 30 was observed in MEL animals between those classified as grade I and II (90.48% vs. 54.54%, respectively; P < 0.01). Considering the animals from CON, the pregnancy rates were similar between grades I and II. Serum concentrations of PGFM from samples collected 4 and 8 hours after embryo transfer were lower in pregnant animals from MEL grade I than in pregnant animals from MEL grade II. Considering the pregnant females from CON, no difference was observed from samples collected 4 and 8 hours after embryo transfer. Interestingly, no difference in PGFM serum concentrations was observed between the pregnant females from MEL grade II and pregnant females from CON (P < 0.05). Thus, we conclude that meloxicam had a positive effect on the pregnancy rates of grade I Nelore heifers. PMID- 26004206 TI - Effect of oxytocin and PGF2alpha on chlortetracycline absorption from the uterus of early postpartum camels (Camelus dromedarius). AB - Fifteen parturient camels given chlortetracycline (CTC) as intrauterine pessaries (3 g/head) were divided into the control group (n = 5), which remained untreated, oxytocin-treated group (50 IU, intramuscular; n = 5), and cloprostenol-treated group (Estrumate, 500 MUg, intramuscular; n = 5). Serum samples were collected at 0, 1, 2, 4, 8, 24, 48, and 72 hours after treatment and CTC was determined. The CTC appeared in blood within 1 hour. The maximum concentration of CTC was detected in blood after 72 (543.58 +/- 117.85 MUg/L), 8 (520.48 +/- 13.65 MUg/L), and 1 hour (831.98 +/- 111.01 MUg/L) of administration in control, oxytocin-, and PGF2alpha-treated camels, respectively. There was a high significant effect of time (P < 0.001) and treatment-by-time interaction (P < 0.001) on serum CTC concentration. In the control group, there was a significant (P < 0.05) increase in CTC concentrations at 72 hours compared to the other times. In the oxytocin group, there was a significant (P < 0.05) decrease in CTC concentrations at 24, 48, and 72 hours compared to its level after 1 or 8 hours. In PGF2alpha, there was a significant (P < 0.001) decrease in CTC concentrations at 2, 4, 8, 24, 48, and 72 hours compared to its level after 1 hour. Treatment contrast at different time points showed a significant (P < 0.001) increase in CTC concentration after 1 hour in the PGF2alpha-treated group compared to oxytocin and control groups. By 72 hours, CTC concentrations were significantly (P < 0.05) lower in PGF2alpha and oxytocin groups than in the control group. In conclusion, serum CTC concentration in dromedary camels increases within 1 hour after intrauterine administration and remains elevated for at least 72 hours in control, oxytocin-, and PGF2alpha treated animals. PMID- 26004207 TI - Self-reported health and socio-economic inequalities in England, 1996-2009: Repeated national cross-sectional study. AB - Tackling social inequalities in health has been a priority for recent UK governments. We used repeated national cross-sectional data for 155,311 participants (aged >=16 years) in the Health Survey of England to examine trends in socio-economic inequalities in self-reported health over a recent period of sustained policy focus by successive UK governments aimed at tackling social inequalities in health. Socio-economic related inequalities in self-reported health were estimated using the Registrar General's occupational classification (1996-2009), and for sensitivity analyses, the National Statistics Socio-Economic Classification (NS-SEC; 2001-2011). Multi-level regression was used to evaluate time trends in General Health Questionnaire (GHQ-12) scores and bad or very bad self-assessed health (SAH), as well as EQ-5D utility scores. The study found that the probability of reporting GHQ-12 scores >=4 and >= 1 was higher in those from lower social classes, and decreased for all social classes between 1997 and 2009. For SAH, the probability of reporting bad or very bad health remained relatively constant for social class I (professional) [0.028 (95%CI: 0.026, 0.029) in 1996 compared to 0.028 (95%CI: 0.024, 0.032) in 2009], but increased in lower social classes, with the greatest increase observed amongst those in social class V (unskilled manual) [0.089 (95%CI: 0.085, 0.093) in 1996 compared to 0.155 (95%CI: 0.141, 0.168) in 2009]. EQ-5D utility scores were lower for those in lower social classes, but remained comparable across survey years. In sensitivity analyses using the NS-SEC, health outcomes improved from 2001 to 2011, with no evidence of widening socio-economic inequalities. Our findings suggest that socio-economic inequalities have persisted, with evidence of widening for some adverse self reported health outcomes. PMID- 26004208 TI - The SPIRIT Action Framework: A structured approach to selecting and testing strategies to increase the use of research in policy. AB - The recent proliferation of strategies designed to increase the use of research in health policy (knowledge exchange) demands better application of contemporary conceptual understandings of how research shapes policy. Predictive models, or action frameworks, are needed to organise existing knowledge and enable a more systematic approach to the selection and testing of intervention strategies. Useful action frameworks need to meet four criteria: have a clearly articulated purpose; be informed by existing knowledge; provide an organising structure to build new knowledge; and be capable of guiding the development and testing of interventions. This paper describes the development of the SPIRIT Action Framework. A literature search and interviews with policy makers identified modifiable factors likely to influence the use of research in policy. An iterative process was used to combine these factors into a pragmatic tool which meets the four criteria. The SPIRIT Action Framework can guide conceptually informed practical decisions in the selection and testing of interventions to increase the use of research in policy. The SPIRIT Action Framework hypothesises that a catalyst is required for the use of research, the response to which is determined by the capacity of the organisation to engage with research. Where there is sufficient capacity, a series of research engagement actions might occur that facilitate research use. These hypotheses are being tested in ongoing empirical work. PMID- 26004209 TI - "It's safer to ..." parent consulting and clinician antibiotic prescribing decisions for children with respiratory tract infections: An analysis across four qualitative studies. AB - This paper reports a cross-study analysis of four studies, aiming to understand the drivers of parental consulting and clinician prescribing behaviour when children under 12 years consult primary care with acute respiratory tract infections (RTI). Qualitative data were obtained from three primary studies and one systematic review. Purposeful samples were obtained for (i) a focus group study of parents' information needs and help seeking; (ii) an interview study of parents' experiences of primary health care (60 parents in total); and (iii) an interview study of clinicians' experiences of RTI consultations for children (28 clinicians). The systematic review synthesised parent and clinician views of prescribing for children with acute illness. Reoccurring themes and common patterns across the whole data set were noted. Through an iterative approach involving re-examination of the primary data, translation of common themes across all the studies and re-organisation of these themes into conceptual groups, four overarching themes were identified. These were: the perceived vulnerability of children; seeking safety in the face of uncertainty; seeking safety from social disapproval; and experience and perception of safety. The social construction of children as vulnerable and normative beliefs about the roles of parents and clinicians were reflected in parents' and clinicians' beliefs and decision making when a child had an RTI. Consulting and prescribing antibiotics were both perceived as the safer course of action. Therefore perception of a threat or uncertainty about that threat tended to lead to parental consulting and clinician antibiotic prescribing. Clinician and parent experience could influence the perception of safety in either direction, depending on whether previous action had resulted in perceived increases or decreases in safety. Future interventions aimed at reducing unnecessary consulting or antibiotic prescribing need to consider how to make the desired action fit with social norms and feel safer for parents and clinicians. PMID- 26004210 TI - Causal effects of socioeconomic status on central adiposity risks: Evidence using panel data from urban Mexico. AB - Associated with overweight, obesity and chronic diseases, the nutrition transition process reveals important socioeconomic issues in Mexico. Using panel data from the Mexican Family Life Survey, the purpose of the study is to estimate the causal effect of household socioeconomic status (SES) on nutritional outcomes among urban adults. We divide the analysis into two steps. First, using a mixed clustering procedure, we distinguish four socioeconomic classes based on income, educational and occupational dimensions: (i) a poor class; (ii) a lower-middle class; (iii) an upper-middle class; (iv) a rich class. Second, using an econometric framework adapted to our study (the Hausman-Taylor estimator), we measure the impact of belonging to these socioeconomic groups on individual anthropometric indicators, based on the body-mass index (BMI) and the waist-to height ratio (WHtR). Our results make several contributions: (i) we show that a new middle class, rising out of poverty, is the most exposed to the risks of adiposity; (ii) as individuals from the upper class seem to be fatter than individuals from the upper-middle class, we can reject the assumption of an inverted U-shaped relationship between socioeconomic and anthropometric status as commonly suggested in emerging economies; (iii) the influence of SES on central adiposity appears to be particularly strong for men. PMID- 26004211 TI - Carbapenemase-producing Enterobacteriaceae in Sweden 2007-2013: Experiences from seven years of systematic surveillance and mandatory reporting. AB - Carbapenemase-producing Enterobacteriaceae (CPE) are increasing worldwide, and are a major threat to healthcare systems. Recent European data support that many countries have interregional spread of CPE or an endemic situation. In Sweden mandatory laboratory reporting of CPE of both colonisation and infection has been practiced since 2007 and since 2012 also by treating physicians. Between 2007 and 2013, 94 cases of CPE were detected in Sweden, out of which 24 were considered to cause clinical infections (bloodstream infection (n=4), urinary tract infection (n=12), wound infection (n=4), respiratory tract infection (n=2) and catheter related (n=2). The majority were detected in the hospital setting through faecal screening or as probable colonisers in clinical cultures. Travel abroad was observed in the majority of the patients (81%), and among them 84% had been hospitalised. During the study period only two chains of transmissions in Swedish hospitals were reported, involving four patients. Klebsiella pneumoniae was the primarily isolated species (n=57) followed by Escherichia coli (n=29). blaNDM was the predominant carbapenemase gene (n=36), followed by blaOXA-48-group, blaKPC and blaVIM. In 26/94 cases (28%) isolates were categorised as possible XDR (extensively drug-resistant). CPE are increasing in Sweden, but are still at a comparably low level. PMID- 26004212 TI - Lack of Rev7 function results in development of tubulostromal adenomas in mouse ovary. AB - Rev7 is a subunit of Polzeta, one of the translesion DNA synthesis (TLS) polymerases involved in DNA damage repair. We recently found that Rev7 is also essential for germ cell development in mouse. In the present study, we found the development of ovarian tumors in Rev7 mutant mouse, suggesting the involvement of TLS deficiency in the etiology of ovarian tumor. The Rev7 mutant mice showed complete lack of oocytes and follicles in the ovary. The lack of follicles causes a significant increase of gonadotropin level and an increase in the proliferation of ovarian cells. As a result, the weight of the ovaries of Rev7 mutant mice increased with age and they developed tubulostromal adenomas. However, the remarkable overgrowth of ovaries occurred after gonadotropin level decreases at older ages, suggesting gonadotropin-independent progression of the ovarian tumors. In addition, the Rev7 mutant fibroblasts and ovarian cells showed significant accumulation of DNA damage. These findings suggest that not only increased gonadotropin levels but also lack of DNA damage repair function could be responsible for the development of ovarian tumors in the Rev7 mutant mouse. PMID- 26004213 TI - X-linked lymphocyte regulated gene 5c-like (Xlr5c-like) is a novel target of progesterone action in granulosa cells of periovulatory rat ovaries. AB - Progesterone (P4), acting through its nuclear receptor (PGR), plays an essential role in ovulation by mediating the expression of genes involved in ovulation and/or luteal formation. To identify ovulatory specific PGR-regulated genes, a preliminary microarray analysis was performed using rat granulosa cells treated with hCG +/- RU486 (PGR antagonist). The transcript most highly down-regulated by RU486 was an EST (expressed sequence tag) sequence (gb: BI289578.1) that matches with predicted sequence for Xlr5c-like mRNA. Since nothing is known about Xlr5c like, we first characterized the expression pattern of Xlr5c-like mRNA in the rat ovary. The level of mRNA for Xlr5c-like is transiently up-regulated in granulosa cells of periovulatory follicles after hCG stimulation in PMSG-primed rat ovaries. The transient induction of Xlr5c-like mRNA was mimicked by hCG treatment in cultured granulosa cells from preovulatory ovaries. We further demonstrated that the LH-activated PKA, MEK, PI3K, and p38 signaling is involved in the increase in Xlr5c-like mRNA. The increase in Xlr5c-like mRNA was abolished by RU486. The inhibitory effect of RU486 was reversed by MPA (synthetic progestin), but not by dexamethasone (synthetic glucocorticoid). Furthermore, mutation of SP1/SP3 and PGR response element sites in the promoter region of Xlr5c-like decreased Xlr5c-like reporter activity. RU486 also inhibited Xlr5c-like reporter activity. ChIP assay verified the binding of PGR and SP3 to the Xlr5c-like promoter in periovulatory granulosa cells. Functionally, siRNA-mediated Xlr5c like knockdown in granulosa cell cultures resulted in reduced levels of mRNA for Snap25, Cxcr4, and Adamts1. Recombinant Xlr5c-like protein expressed using an adenoviral approach was localized predominantly to the nucleus and to a lesser extent to the cytoplasm of rat granulosa cells. In conclusion, this is the first report showing the spatiotemporally regulated expression of Xlr5c-like mRNA by hCG in rat periovulatory ovaries. P4/PGR mediates the LH-induced increase in Xlr5c-like mRNA. In turn, Xlr5c-like is involved in regulating the expression of specific ovulatory genes such as Snap25, Cxcr4, and Adamts1, possibly acting in the nucleus of periovulatory granulosa cells. PMID- 26004214 TI - Mg(II) and Ni(II) induce aggregation of poly(rA)poly(rU) to either tetra aggregate or triplex depending on the metal ion concentration. AB - The ability of magnesium(II) and nickel(II) to induce dramatic conformational changes in the synthetic RNA poly(rA)poly(rU) has been investigated. Kinetic experiments, spectrofluorometric titrations, melting experiments and DSC measurements contribute in shedding light on a complex behaviour where the action of metal ions (Na(+), Mg(2+), Ni(2+)), in synergism with other operators as the intercalating dye coralyne and temperature, all concur in stabilising a peculiar RNA form. Mg(2+) and Ni(2+) (M) bind rapidly and almost quantitatively to the duplex (AU) to give a RNA/metal ion complex (AUM). Then, by the union of two AUM units, an unstable tetra-aggregate (UAUA(M2)*) is formed which, in the presence of a relatively modest excess of metal, evolves to the UAUM triplex by releasing a single AM strand. On the other hand, under conditions of high metal content, the UAUA(M2)* intermediate rearranges to give a more stable tetra-aggregate (UAUA(M2)). As concerns the role of coralyne (D), it is found that D strongly interacts with UAUA(M2). Also, in the presence of coralyne, the ability of divalent ions to promote the transition of AUD into UAUD is enhanced, according to the efficiency sequence [Ni(2+)]?[Mg(2+)]?[Na(+)]. PMID- 26004215 TI - The impact of symptoms, irritable bowel syndrome pattern and diagnostic investigations on the diagnostic delay of Crohn's disease: A prospective study. AB - BACKGROUND: We investigated symptoms and tests performed prior to a formal diagnosis of Crohn's disease and the reasons for diagnostic delay. METHODS: Consecutive patients recently diagnosed with Crohn's disease were enrolled between October 2012 and November 2013. Clinical data, symptoms including Rome III criteria at onset and at diagnosis, location and disease phenotype were recorded. Faecal calprotectin, radiological and endoscopic examinations performed prior to diagnosis were analysed. Diagnostic delay, stratified into tertiles and median time, was analysed using parametric and nonparametric tests. RESULTS: 83 patients (49.4% males, median age 31 years) were enrolled. The median diagnostic delay was 8 (0-324) months. Twenty-six patients did not consult a general practitioner until diagnosis (31.3%), 18 presented to the emergency department (21.7%) and 8 directly to a gastroenterologist (9.6%). Diagnostic delay was not associated with specific symptoms. However, patients with bloating at presentation had a longer delay compared to those who did not (median, 6.1 vs. 16.8 months, respectively; p=0.016). Nineteen patients underwent incomplete ileocolonoscopies (22.9%) and 7 had no biopsies (8.4%), with a consequent diagnostic delay (median, 24 and 24 vs. 6 months, respectively; p=0.025 and p=0.008). CONCLUSION: Diagnostic delay for Crohn's disease is significantly associated with incomplete ileocolonoscopies, but not with symptoms, except bloating at presentation. PMID- 26004216 TI - Plasminogen activation system in oral cancer: Relevance in prognosis and therapy (Review). AB - Research on carcinogenesis and progress in cancer treatment have reduced mortality of cancer patients. Mortality rates decreased by 1.5% per year from 2001 through 2010 for most types of cancer in men and women. However, oral cancer is still a significant global health problem since incidence and mortality rates are increasing. Oral cavity cancer is ranked the 8th in men and the 14th in women based on data collected between 2006 and 2010 by the National Institute of Health. Furthermore, an increasing incidence of head and neck neoplasms, particularly the tongue cancer among young adults has been reported recently. It is most likely due to increasing human papillomavirus (HPV) infection or the early start of tobacco and alcohol consumption. Treatment of oral cancer patients is mainly surgical and often leads to esthetic and functional deformities, with severe impact on the quality of life. Thus, novel form of treatments and selection of patients with high and low risk of mortality is of high priority for clinical studies. The expression of proteolytic enzymes in tumor and stromal tissues has been shown to have prognostic significance in many human cancers and inhibiting proteolysis can reduce tumor growth in many in vivo and in vitro models. Plasmin, with its activators and inhibitors are of great importance in many human malignances and collectively are called plasminogen activation system (PAS). In this comprehensive review we examine expression, possible prognostic markers and importance for therapy of the PAS members in oral cancer. Literature review suggests that overexpression of urokinase and its receptor are markers of poor outcome, thus, their inhibition can be explored in oral cancer therapy. Role of plasminogen activator inhibitor (PAI-1) is complex and depends on its concentration. Overexpression of PAI-1 favors angiogenesis, metastasis and poor prognosis, although when applied in very high concentrations it inhibits angiogenesis and tumor growth, the phenomenon is described as the PAI-1 paradox. PMID- 26004217 TI - Can a computerised training paradigm assist people with intellectual disabilities to learn cognitive mediation skills? A randomised experiment. AB - AIMS: The aim was to examine whether specific skills required for cognitive behavioural therapy (CBT) could be taught using a computerised training paradigm with people who have intellectual disabilities (IDs). Training aimed to improve: a) ability to link pairs of situations and mediating beliefs to emotions, and b) ability to link pairs of situations and emotions to mediating beliefs. METHOD: Using a single-blind mixed experimental design, sixty-five participants with IDs were randomised to receive either computerised training or an attention-control condition. Cognitive mediation skills were assessed before and after training. RESULTS: Participants who received training were significantly better at selecting appropriate emotions within situation-beliefs pairs, controlling for baseline scores and IQ. Despite significant improvements in the ability of those who received training to correctly select intermediating beliefs for situation feelings pairings, no between-group differences were observed at post-test. CONCLUSIONS: The findings indicated that computerised training led to a significant improvement in some aspects of cognitive mediation for people with IDs, but whether this has a positive effect upon outcome from therapy is yet to be established. PMID- 26004218 TI - A drug carrier targeting murine uPAR for photodynamic therapy and tumor imaging. AB - Photodynamic therapy (PDT) has been used as an effective therapeutical modality for tumors. In PDT, a photosensitizer was used to capture the light of specific wavelength, leading to the generation of reactive oxygen species and cytotoxicity surrounding the photosensitizer. Modifications of photosensitizers to enhance tumor specificity are common approaches to increase the efficacy and reduce the side effects of PDT. Previously, we developed a human serum albumin (HSA)-based drug carrier fused with the human amino-terminal fragment (hATF), which binds to a tumor surface marker (urokinase receptor, uPAR). However, hATF-HSA binds to murine uPAR much weaker (79-fold) than to human uPAR, and is not optimal for applications on murine tumor models. In this study, we developed a murine version of the drug carrier (mATF-HSA). A photosensitizer (mono-substituted beta-carboxy phthalocyanine zinc, CPZ) was loaded into this carrier, giving a rather stable macromolecule (mATF-HSA:CPZ) that was shown to bind to murine uPAR in vitro. In addition, we evaluated both the photodynamic therapy efficacy and tumor retention capability of the macromolecule (at a dose of 0.05mg CPZ/kg mouse body weight) on murine hepatoma-22 (H22) tumor bearing mouse model. mATF-HSA:CPZ showed more accumulation in tumors compared to its human counterpart (hATF-HSA:CPZ) measured by quantitative fluorescence molecular tomography (FMT). Besides, mATF-HSA:CPZ exhibited a higher tumor killing efficacy than hATF-HSA:CPZ. Together, the macromolecule mATF-HSA is a promising tumor-specific drug carrier on murine tumor models and is an useful tool to study tumor biology on murine tumor models. PMID- 26004219 TI - Sustained intravitreal delivery of dexamethasone using an injectable and biodegradable thermogel. AB - Delivery of therapeutic agents to posterior segment of the eyes is challenging due to the anatomy and physiology of ocular barriers and thus long-acting implantable formulations are much desired. In this study, a thermogelling system composed of two poly(lactic acid-co-glycolic acid)-poly(ethylene glycol) poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was developed as an injectable matrix for intravitreal drug delivery. The thermogel was prepared by mixing a sol and a precipitate of PLGA-PEG-PLGA triblock copolymers with different block ratios, among which a hydrophobic glucocorticoid, dexamethasone (DEX), was incorporated. The DEX-loaded thermogel was a low-viscous liquid at low temperature and formed a non-flowing gel at body temperature. The in vitro release rate of DEX from the thermogel could be conveniently modulated by varying the mixing ratio of the two copolymers. The long-lasting intraocular residence of the thermogel was demonstrated by intravitreal injection of a fluorescence-labeled thermogel to rabbits. Compared with a DEX suspension, the intravitreal retention time of DEX increased from a dozen hours to over 1week when being loaded in the thermogel. Additionally, intravitreal administration of the thermogel did not impair the morphology of retina and cornea. This study reveals that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for sustained delivery of bioactive agents into the eyes, and provides an alternative approach for treatment of posterior segment diseases. PMID- 26004220 TI - First-principles calculations of divalent substitution of Ca(2+) in tricalcium phosphates. AB - First-principles calculations were carried out to reveal local atomic arrangements and thermodynamic stability of substitutional divalent cations of Mg(2+), Zn(2+), Sr(2+) and Ba(2+) in tricalcium phosphates (TCPs). There are two modifications of alpha-TCP and beta-TCP, and a number of inequivalent Ca sites are present in the crystal structures. It was found that each divalent cation has energetically preferential Ca sites for substitution. For instance, Mg(2+) and Zn(2+) favor the substitution at the Ca-5 site of beta-TCP while Sr(2+) and Ba(2+) tend to occupy Ca-3 and Ca-4 in the beta-type crystal structure. The calculated site preference of these cations was in reasonable agreement with available experimental data. Moreover, it was found that these cations have negative formation energies at specific Ca sites especially in beta-TCP, indicating the stabilization of the beta phase. PMID- 26004221 TI - The biological response to nanometre-sized polymer particles. AB - Recently, nanometre-sized UHMWPE particles generated from hip and knee replacements have been identified in vitro and in vivo. UHMWPE particles in the 0.1-1.0MUm size range have been shown to be more biologically active than larger particles, provoking an inflammatory response implicated in late aseptic loosening of total joint replacements. The biological activity of nanometre-sized particles has not previously been studied. The biological response to clinically relevant UHMWPE wear particles including nanometre-sized and micrometre-sized, along with polystyrene particles (FluoSpheres 20nm, 60nm, 200nm and 1.0MUm), and nanometre-sized model polyethylene particles (Ceridust 3615(r)), was determined in terms of osteolytic cytokine release from primary human peripheral blood mononuclear cells (PBMNCs). Nanometre-sized UHMWPE wear particles, nanometre sized Ceridust 3615(r) and 20nm FluoSpheres had no significant effect on TNF alpha, IL-1beta, IL-6 and IL-8 release from PBMNCs at a concentration of 100MUm(3) particles per cell after 12 and 24h. The micrometre-size UHMWPE wear particles (0.1-1.0MUm) and 60nm, 200nm and 1.0MUm FluoSpheres caused significantly elevated osteolytic cytokine release from PBMNCs. These results indicated that particles below circa 50nm fail to activate PBMNCs and that particle size, composition and morphology played a crucial role in cytokine release by particle stimulated macrophages. PMID- 26004222 TI - BMP delivery complements the guiding effect of scaffold architecture without altering bone microstructure in critical-sized long bone defects: A multiscale analysis. AB - Scaffold architecture guides bone formation. However, in critical-sized long bone defects additional BMP-mediated osteogenic stimulation is needed to form clinically relevant volumes of new bone. The hierarchical structure of bone determines its mechanical properties. Yet, the micro- and nanostructure of BMP mediated fast-forming bone has not been compared with slower regenerating bone without BMP. We investigated the combined effects of scaffold architecture (physical cue) and BMP stimulation (biological cue) on bone regeneration. It was hypothesized that a structured scaffold directs tissue organization through structural guidance and load transfer, while BMP stimulation accelerates bone formation without altering the microstructure at different length scales. BMP loaded medical grade polycaprolactone-tricalcium phosphate scaffolds were implanted in 30mm tibial defects in sheep. BMP-mediated bone formation after 3 and 12 months was compared with slower bone formation with a scaffold alone after 12 months. A multiscale analysis based on microcomputed tomography, histology, polarized light microscopy, backscattered electron microscopy, small angle X-ray scattering and nanoindentation was used to characterize bone volume, collagen fiber orientation, mineral particle thickness and orientation, and local mechanical properties. Despite different observed kinetics in bone formation, similar structural properties on a microscopic and sub-micron level seem to emerge in both BMP-treated and scaffold only groups. The guiding effect of the scaffold architecture is illustrated through structural differences in bone across different regions. In the vicinity of the scaffold increased tissue organization is observed at 3 months. Loading along the long bone axis transferred through the scaffold defines bone micro- and nanostructure after 12 months. PMID- 26004223 TI - Crosstalk between focal adhesions and material mechanical properties governs cell mechanics and functions. AB - Mechanical properties of materials strongly influence cell fate and functions. Focal adhesions are involved in the extremely important processes of mechanosensing and mechanotransduction. To address the relationship between the mechanical properties of cell substrates, focal adhesion/cytoskeleton assembly and cell functions, we investigated the behavior of NIH/3T3 cells over a wide range of stiffness (3-1000kPa) using two of the most common synthetic polymers for cell cultures: polyacrylamide and polydimethylsiloxane. An overlapping stiffness region was created between them to compare focal adhesion characteristics and cell functions, taking into account their different time dependent behavior. Indeed, from a rheological point of view, polyacrylamide behaves like a strong gel (elastically), whereas polydimethylsiloxane like a viscoelastic solid. First, focal adhesion characteristics and dynamics were addressed in terms of material stiffness, then cell spreading area, migration rate and cell mechanical properties were correlated with focal adhesion size and assembly. Focal adhesion size was found to increase in the whole range of stiffness and to be in agreement in the overlapping rigidity region for the investigated materials. Cell mechanics directly correlated with focal adhesion lengths, whereas migration rate followed an inverse correlation. Cell spreading correlated with the substrate stiffness on polyacrylamide hydrogel, while no specific trend was found on polydimethylsiloxane. Substrate mechanics can be considered as a key physical cue that regulates focal adhesion assembly, which in turn governs important cellular properties and functions. PMID- 26004224 TI - Biodegradable soy wound dressings with controlled release of antibiotics: Results from a guinea pig burn model. AB - There is growing interest in the development of biodegradable materials from renewable biopolymers, such as soy protein, for biomedical applications. Soy protein is a major fraction of natural soybean and has the advantages of being economically competitive, biodegradable and biocompatible. It presents good water resistance as well as storage stability. In the current study, homogenous antibiotic-loaded soy protein films were cast from aqueous solutions. The antibiotic drug gentamicin was incorporated into the films in order to inhibit bacterial growth, and thus prevent or combat infection, upon its controlled release to the surrounding tissue. The current in vivo study of the dressing material in contaminated deep second-degree burn wounds in guinea pigs (n=20) demonstrated its ability to accelerate epithelialization with 71% epithelial coverage compared to an unloaded format of the soy material (62%) and a significant improved epithelial coverage as compared to the conventional dressing material (55%). Our new platform of antibiotic-eluting wound dressings is advantageous over currently used popular dressing materials that provide controlled release of silver ions, due to its gentamicin release profile, which is safer. Another advantage of our novel concept is that it is based on a biodegradable natural polymer and therefore does not require bandage changes and offers a potentially valuable and economic approach for treating burn-related infections. PMID- 26004225 TI - Comparative pharmacokinetic profiles of tectorigenin in rat plasma by UPLC-MS/MS after oral administration of Iris tectorum Maxim extract and pure tectoridin. AB - Iris tectorum Maxim, a well-known herb medicine, is commonly used for treatment of inflammation, cough, and pharyngitis for a long time in China. Tectoridin, main active ingredient of Iris tectorum Maxim, is often used for its quality control. This study was aimed to analyze the pharmacokinetic profile of tectorigenin (the metabolite of tectoridin) after oral administration of I. tectorum Maxim extract, and to compare the pharmacokinetic characterization of tectorigenin after oral administration of I. tectorum Maxim extract (ITME) and pure tectoridin (PT) in rats. In addition, a simple, reliable and sensitive UPLC MS/MS method was developed for determination of tectorigenin in rat plasma, using kaempferol as internal standard. The processed samples were separated on a Poroshell 120 SB-C18 column and detected by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The method validation results indicated that the established method was simple, specific and reliable. The pharmacokinetic results showed that the plasma concentration of tectorigenin in ITME group was much higher than that of the PT group (p<0.01). Moreover, compared to PT group, t1/2 value and AUC(0-infinity) value were also notably increased in ITME group (p<0.01). In conclusion, potential interaction exists between those chemical components in ITME, and the co-existing components in ITME could notably promote the absorption of tectoridin in rats, however, the exact compound(s) which enhance the absorption of tectoridin should be investigated in future study. PMID- 26004226 TI - Protonation-deprotonation and structural dynamics of antidiabetic drug metformin. AB - Since the late 1950s, metformin is the worldwide first-line pharmacologic treatment for type 2 diabetes. Beyond the fact that the mode of action of this drug has always been very difficult to elucidate, little is known about its physicochemical properties in aqueous solution. Herein, we focus on the protonation-deprotonation features of metformin by using jointly Raman scattering and theoretical calculations. Vibrational markers evidence the fact that within a wide pH interval extended at either side of the physiological one, i.e. ~7 +/- 4, metformin is mainly monoprotonated. Although the biprotonated form appears as major population at very low pH values (<1.5), Raman markers of neutral species do not dominate even at very high pH values (>13), presumably because of the extreme basicity of metformin as described by recent NMR measurements. Density functional theory calculations using both explicit and implicit hydration models, have led to presume a possible coexistence of two possible monoprotonated forms in aqueous environment. In conclusion, the biophysical features of this molecule and the amount used in clinical practice might certainly explain the pleiotropic actions toward several targets where metformin could be a permanent cationic partner, a proton donor/acceptor, as well as a good candidate for stabilizing the so-called pi->pi interactions. PMID- 26004227 TI - GC-MS based metabolomics study of stems and roots of Ephedra sinica. AB - Therapeutic effects of herbal medicines differ greatly due to the use of different anatomical parts or processing methods in traditional Chinese medicine, and Ephedra sinica (ES) is just a case in point. To better understand different traditional uses of the stems (known as Mahuang, MH) and roots (known as Mahuanggen, MHG) of ES, their therapeutic material basis should be investigated. In this study, ephedrine alkaloids were profiled simultaneously with primary metabolites using GC-MS based metabolomics. Ephedrine (E) has been reported to be the major bioactive constituent in MH for the treatment of asthma. The results showed that compared with MH, MHG contained much lower levels of five ephedrine alkaloids, which may well explain that MHG has not been used as an antiasthmatic. Additionally, these pharmacologically important ephedrine alkaloids exhibited strong positive correlation with five primary metabolites. In conclusion, this study facilitates better understanding of different traditional uses of MH and MHG. PMID- 26004228 TI - Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis. AB - Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis. PMID- 26004229 TI - Calibrating ChIP-Seq with Nucleosomal Internal Standards to Measure Histone Modification Density Genome Wide. AB - Chromatin immunoprecipitation (ChIP) serves as a central experimental technique in epigenetics research, yet there are serious drawbacks: it is a relative measurement, which untethered to any external scale obscures fair comparison among experiments; it employs antibody reagents that have differing affinities and specificities for target epitopes that vary in abundance; and it is frequently not reproducible. To address these problems, we developed Internal Standard Calibrated ChIP (ICeChIP), wherein a native chromatin sample is spiked with nucleosomes reconstituted from recombinant and semisynthetic histones on barcoded DNA prior to immunoprecipitation. ICeChIP measures local histone modification densities on a biologically meaningful scale, enabling unbiased trans-experimental comparisons, and reveals unique insight into the nature of bivalent domains. This technology provides in situ assessment of the immunoprecipitation step, accommodating for many experimental pitfalls as well as providing a critical examination of untested assumptions inherent to conventional ChIP. PMID- 26004230 TI - Autophagic Degradation of the 26S Proteasome Is Mediated by the Dual ATG8/Ubiquitin Receptor RPN10 in Arabidopsis. AB - Autophagic turnover of intracellular constituents is critical for cellular housekeeping, nutrient recycling, and various aspects of growth and development in eukaryotes. Here we show that autophagy impacts the other major degradative route involving the ubiquitin-proteasome system by eliminating 26S proteasomes, a process we termed proteaphagy. Using Arabidopsis proteasomes tagged with GFP, we observed their deposition into vacuoles via a route requiring components of the autophagy machinery. This transport can be initiated separately by nitrogen starvation and chemical or genetic inhibition of the proteasome, implying distinct induction mechanisms. Proteasome inhibition stimulates comprehensive ubiquitylation of the complex, with the ensuing proteaphagy requiring the proteasome subunit RPN10, which can simultaneously bind both ATG8 and ubiquitin. Collectively, we propose that Arabidopsis RPN10 acts as a selective autophagy receptor that targets inactive 26S proteasomes by concurrent interactions with ubiquitylated proteasome subunits/targets and lipidated ATG8 lining the enveloping autophagic membranes. PMID- 26004231 TI - Distinct but milder phenotypes with choreiform movements in siblings with compound heterozygous mutations in the transcription preinitiation mediator complex subunit 17 (MED17). AB - Two siblings born to non-consanguineous parents showed nystagmus and sudden opistotonic posturing from the early infancy, and subsequent developmental delay and marked choreiform movements with hypotonia in the childhood. The brother had a mild postnatal microcephaly. Brain MRI of the sister showed mild delay of myelination, dilated anterior horn and mild cerebellar atrophy. Whole exome sequencing (WES) revealed compound heterozygous mutations in MED17 gene in both siblings: c.1013-5A>G and c.1484T>G mutations transmitted from their father and mother, respectively. The c.1013-5A>G mutation caused insertion of 4 bases of intron 6 in the transcript, resulting in frameshift (p. Ser338Asnfs*15), and mutant transcript underwent nonsense-mediated mRNA decay in lymphoblastoid cells derived from two siblings. The c.1484T>G mutation substituted a leucine residue, which is highly conserved among the vertebrates, and was predicted to be damaging by in silico analysis programs. Both mutations were not registered in dbSNP data and in our 575 control exomes. These results suggest that the siblings' mutations are likely to be pathogenic. This is the second case report concerning MED17 mutations. Compared with the first reported cases of Caucasian Jewish origin, the clinical symptoms and courses are much milder and slower, respectively, in our cases. Genotype difference (a homozygous mutation versus compound heterozygous mutations) might explain these clinical differences between two cases, though early-onset nystagmus and later choreiform movements were unique in our cases. Clinical spectrum and phenotype-genotype correlations in this rare mutation should be further elucidated. PMID- 26004232 TI - Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis. AB - In this study, we have shown for the first time the effectiveness of a non-viral gene transfection strategy to re-polarize macrophages from M1 to M2 functional sub-type for the treatment of rheumatoid arthritis (RA). An anti-inflammatory (IL 10) cytokine encoding plasmid DNA was successfully encapsulated into non condensing alginate based nanoparticles and the surface of the nano-carriers was modified with tuftsin peptide to achieve active macrophage targeting. Enhanced localization of tuftsin-modified alginate nanoparticles was observed in the inflamed paws of arthritic rats upon intraperitoneal administration. Importantly, targeted nanoparticle treatment was successful in reprogramming macrophage phenotype balance as ~66% of total synovial macrophages from arthritic rats treated with the IL-10 plasmid DNA loaded tuftsin/alginate nanoparticles were in the M2 state compared to ~9% of macrophages in the M2 state from untreated arthritic rats. Treatment significantly reduced systemic and joint tissue pro inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) expression and prevented the progression of inflammation and joint damage as revealed by magnetic resonance imaging and histology. Treatment enabled animals to retain their mobility throughout the course of study, whereas untreated animals suffered from impaired mobility. Overall, this study demonstrates that targeted alginate nanoparticles loaded with IL-10 plasmid DNA can efficiently re-polarize macrophages from an M1 to an M2 state, offering a novel treatment paradigm for treatment of chronic inflammatory diseases. PMID- 26004233 TI - Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine. AB - The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan-graft-PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy. PMID- 26004234 TI - Spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo. AB - Cells and tissues are intrinsically adapted to molecular gradients and use them to maintain or change their activity. The effect of such gradients is particularly important for cell populations that have an intrinsic capacity to differentiate into multiple cell lineages, such as bone marrow derived mesenchymal stromal cells (MSCs). Our results showed that nutrient gradients prompt the spatiotemporal organization of MSCs in 3D culture. Cells adapted to their 3D environment without significant cell death or cell differentiation. Kinetics data and whole-genome gene expression analysis suggest that a low proliferation activity phenotype predominates in stromal cells cultured in 3D, likely due to increasing nutrient limitation. These differences implied that despite similar surface areas available for cell attachment, higher cell concentrations in 3D reduced MSCs proliferation, while activating hypoxia related pathways. To further understand the in vivo effects of both proliferation and cell concentrations, we increased cell concentrations in small (1.8 MUl) implantable wells. We found that MSCs accumulation and conditioning by nutrient competition in small volumes leads to an ideal threshold of cell-concentration for the induction of blood vessel formation, possibly signaled by the hypoxia related stanniocalcin-1 gene. PMID- 26004235 TI - Coaxial nozzle-assisted 3D bioprinting with built-in microchannels for nutrients delivery. AB - This study offers a novel 3D bioprinting method based on hollow calcium alginate filaments by using a coaxial nozzle, in which high strength cell-laden hydrogel 3D structures with built-in microchannels can be fabricated by controlling the crosslinking time to realize fusion of adjacent hollow filaments. A 3D bioprinting system with a Z-shape platform was used to realize layer-by-layer fabrication of cell-laden hydrogel structures. Curving, straight, stretched or fractured filaments can be formed by changes to the filament extrusion speed or the platform movement speed. To print a 3D structure, we first adjusted the concentration and flow rate of the sodium alginate and calcium chloride solution in the crosslinking process to get partially crosslinked filaments. Next, a motorized XY stages with the coaxial nozzle attached was used to control adjacent hollow filament deposition in the precise location for fusion. Then the Z stage attached with a Z-shape platform moved down sequentially to print layers of structure. And the printing process always kept the top two layers fusing and the below layers solidifying. Finally, the Z stage moved down to keep the printed structure immersed in the CaCl2 solution for complete crosslinking. The mechanical properties of the resulting fused structures were investigated. High strength structures can be formed using higher concentrations of sodium alginate solution with smaller distance between adjacent hollow filaments. In addition, cell viability of this method was investigated, and the findings show that the viability of L929 mouse fibroblasts in the hollow constructs was higher than that in alginate structures without built-in microchannels. Compared with other bioprinting methods, this study is an important technique to allow easy fabrication of lager-scale organs with built-in microchannels. PMID- 26004236 TI - Bioactive nanofibers enable the identification of thrombospondin 2 as a key player in enamel regeneration. AB - Tissue regeneration and development involves highly synchronized signals both between cells and with the extracellular environment. Biomaterials can be tuned to mimic specific biological signals and control cell response(s). As a result, these materials can be used as tools to elucidate cell signaling pathways and candidate molecules involved with cellular processes. In this work, we explore enamel-forming cells, ameloblasts, which have a limited regenerative capacity. By exposing undifferentiated cells to a self-assembling matrix bearing RGDS epitopes, we elicited a regenerative signal at will that subsequently led to the identification of thrombospondin 2 (TSP2), an extracellular matrix protein that has not been previously recognized as a key player in enamel development and regeneration. Targeted disruption of the thrombospondin 2 gene (Thbs2) resulted in enamel formation with a disordered architecture that was highly susceptible to wear compared to their wild-type counterparts. To test the regenerative capacity, we injected the bioactive matrix into the enamel organ and discovered that the enamel organic epithelial cells in TSP-null mice failed to polarize on the surface of the artificial matrix, greatly reducing integrin beta1 and Notch1 expression levels, which represent signaling pathways known to be associated with TSP2. These results suggest TSP2 plays an important role in regulating cell matrix interactions during enamel formation. Exploiting the signaling pathways activated by biomaterials can provide insight into native signaling mechanisms crucial for tooth development and cell-based strategies for enamel regeneration. PMID- 26004238 TI - Effectiveness of Repeat Radiotherapy for Painful Bone Metastases in Clinical Practice: A 10 Year Historical Cohort Study. AB - AIMS: Repeat radiotherapy for palliation of painful bone metastases is often prescribed to non-responders or those with recurrent pain, although studies on retreatment remain scarce. We assessed the effectiveness of retreatment for painful bone metastases in terms of pain relief in everyday clinical practice and identified factors associated with response. MATERIALS AND METHODS: We carried out a single-institution 10 year retrospective cohort study among 247 patients retreated for painful bone metastases. Response was defined as a decrease in pain between 2 and 12 weeks after retreatment. The overall pain response rate was calculated in an evaluable-patients-only analysis and a worst-case analysis. Multivariate logistic regression analyses were used to identify factors associated with pain response. RESULTS: A follow-up of >=2 weeks was available in 162 of 247 patients (65%). The overall pain response was 66% (95% confidence interval 58-73%) in an evaluable-patients-only analysis and 43% (95% confidence interval 37-50%) in a worst-case analysis. Response to first irradiation (odds ratio 2.16, P = 0.049) and use of systemic therapy (odds ratio 0.39, P = 0.037) were independently associated with the response to retreatment. The median overall survival was 7.1 months. CONCLUSION: In everyday clinical practice, retreatment for painful bone metastases leads to pain reduction in 66% of evaluable patients and 43% of patients in a worst-case analysis. Patients who responded to initial radiotherapy were more likely to respond again and those on systemic therapy were less likely to respond. Overall, repeat radiotherapy should be considered in patients with persisting bone pain. PMID- 26004237 TI - Engineered composite tissue as a bioartificial limb graft. AB - The loss of an extremity is a disastrous injury with tremendous impact on a patient's life. Current mechanical prostheses are technically highly sophisticated, but only partially replace physiologic function and aesthetic appearance. As a biologic alternative, approximately 70 patients have undergone allogeneic hand transplantation to date worldwide. While outcomes are favorable, risks and side effects of transplantation and long-term immunosuppression pose a significant ethical dilemma. An autologous, bio-artificial graft based on native extracellular matrix and patient derived cells could be produced on demand and would not require immunosuppression after transplantation. To create such a graft, we decellularized rat and primate forearms by detergent perfusion and yielded acellular scaffolds with preserved composite architecture. We then repopulated muscle and vasculature with cells of appropriate phenotypes, and matured the composite tissue in a perfusion bioreactor under electrical stimulation in vitro. After confirmation of composite tissue formation, we transplanted the resulting bio-composite grafts to confirm perfusion in vivo. PMID- 26004239 TI - Muscle Monitoring and Maintenance as an End Point for Patients Treated for Cancer. PMID- 26004240 TI - Effects of vitrification on ram spermatozoa using free-egg yolk extenders. AB - The present study aimed to examine the behavior of ram spermatozoa subjected to a vitrification process in free-egg yolk diluents in relation with conventional diluents and cryopreservation protocol used in this species. Previously it was investigated the toxicity of cryoprotectants, sucrose and glycerol, based on different concentrations (sucrose at 0.03 M, 0.05 M, 0.15 M and 0.25 M; and glycerol at 3%, 7%, 14% and 18%) compared to a commercial extender (Biladyl(r) with 20% egg yolk and 7% glyerol). Cryoprotectants which reported less toxicity were chosen to perform the vitrification and results were compared with the conventional cryopreservation. Semen from three rams was collected by electroejaculation. The sperm evaluation was carried out at 0, 2 and 4h through the incubation time at 37 degrees C for the experiment of toxicity and, at thawing when cryopreservation was performed. The sperm quality throughout the incubation time always resulted lower (P?0.05) for the free-egg yolk diluents in relation to Biladyl(r) (control), obtaining the lowest values of sperm quality with the highest concentrations of sucrose and glycerol. The vitrification was carried out with combinations of sucrose and glycerol (sucrose at 0.03 and 0.05 M with 3% and 7% of glycerol, respectively) and with Biladyl(r) (at different sperm concentrations). The vitrification decreased drastically (P?0.05) the sperm quality when combinations of sucrose and glycerol were used. Nevertheless, the sperm samples vitrified with Biladyl(r) at the lowest sperm concentration showed acceptable values of viability, acrosome integrity and DFI, although the sperm motility was strongly decreased. In conclusion, the use of vitrification with diluents based on combinations of sucrose and glycerol did not work for semen cryopreservation of ram. Promising results were obtained when diluents with egg yolk were used in the vitrification procedure, although more studies are necessary to improve this technique and the use of diluents without egg yolk. PMID- 26004246 TI - Functional analysis of microRNA activity in Brugia malayi. AB - The complement of the Brugia malayi microRNA-71 was inserted into the 3' untranslated region of a reporter plasmid, resulting in a decrease in reporter activity. Mutation of the seed sequence restored activity. Insertion of the 3' untranslated regions from two algorithm-predicted putative target genes into the reporter resulted in a similar decrease in activity; mutation of the predicted target sequences restored activity. These experiments demonstrate that B. malayi microRNA targets may be predicted using current algorithms and describe a functional assay to confirm predicted targets. PMID- 26004247 TI - The relationship between top-down attentional control and changes in weight. AB - AIM: To investigate the relationship between top-down attentional control in the presence of food cues and weight change over a 3-month period. METHOD: A Stroop task adapted to include background images of high-fat food and neutral items was completed by participants (N=60). Top-down attentional control was assessed by adaptation effects (Stroop effect is smaller when the previous trial is incongruent). To assess weight change, measurements were taken immediately after the Stroop task (T1) and again 3-months later (T2). Differences in weight between T1 and T2 were calculated and three groups formed: weight gain (n=20); weight loss (n=20); and no change in weight (n=20). RESULTS: Differences in top-down attentional control were observed according to weight change. Participants who demonstrated reduced top-down attentional control also exhibited changes in weight (both loss and gain) over the 3-months. In contrast, the weight of participants who maintained top-down attentional control in the Stroop task remained stable. CONCLUSIONS: Findings suggest that attentional control may have a role to play in actual eating behavior. Individuals who demonstrated reduced levels across of top-down attentional control also experienced changes in their weight over the 3-month period. Whether individuals lost or gained weight attentional control was reduced. This reduction was, however, not specific to high-fat food cues, but a general reduction in attentional control across both image conditions. PMID- 26004248 TI - Two facets of stress and indirect effects on child diet through emotion-driven eating. AB - OBJECTIVE: Stress has been associated with high-calorie, low-nutrient food intake (HCLN) and emotion-driven eating (EDE). However, effects on healthy food intake remain unknown. This study examined two facets of stress (self-efficacy, perceived helplessness) and food consumption, mediated by EDE. METHODS: Cross sectional data from fourth-graders (n=978; 52% female, 28% Hispanic) in an obesity intervention used self-report to assess self-efficacy, helplessness, EDE, fruit/vegetable (FV) intake, and high-calorie/low-nutrient (HCLN) food. RESULTS: Higher stress self-efficacy was associated with higher FV intake, beta=.354, p<0.001, and stress perceived helplessness had an indirect effect on HCLN intake through emotion-driven eating, indirect effect=.094, p<0.001; chi(2)(347)=659.930, p<0.001, CFI=0.940, TLI=0.930, RMSEA=0.030, p=1.00, adjusting for gender, ethnicity, BMI z-score, and program group. CONCLUSIONS AND IMPLICATIONS: Stress self-efficacy may be more important for healthy food intake and perceived helplessness may indicate emotion-driven eating and unhealthy snack food intake. Obesity prevention programs may consider teaching stress management techniques to avoid emotion-driven eating. PMID- 26004249 TI - DNA barcoding and the identification of tree frogs (Amphibia: Anura: Rhacophoridae). AB - The DNA barcoding gene COI (cytochrome c oxidase subunit I) effectively identifies many species. Herein, we barcoded 172 individuals from 37 species belonging to nine genera in Rhacophoridae to test if the gene serves equally well to identify species of tree frogs. Phenetic neighbor joining and phylogenetic Bayesian inference were used to construct phylogenetic trees, which resolved all nine genera as monophyletic taxa except for Rhacophorus, two new matrilines for Liuixalus, and Polypedates leucomystax species complex. Intraspecific genetic distances ranged from 0.000 to 0.119 and interspecific genetic distances ranged from 0.015 to 0.334. Within Rhacophorus and Kurixalus, the intra- and interspecific genetic distances did not reveal an obvious barcode gap. Notwithstanding, we found that COI sequences unambiguously identified rhacophorid species and helped to discover likely new cryptic species via the synthesis of genealogical relationships and divergence patterns. Our results supported that COI is an effective DNA barcoding marker for Rhacophoridae. PMID- 26004250 TI - Effect of aging process on adsorption of diethyl phthalate in soils amended with bamboo biochar. AB - Biochar is a carbonaceous sorbent and can be used as a potential material to reduce the bioavailability of organic pollutants in contaminated soils. In the present study, the adsorption and desorption of diethyl phthalate (DEP) onto soils amended with bamboo biochar was investigated with a special focus on the effect of biochar application rates and aging conditions on the adsorption capacity of the soils. Biochar amendment significantly enhanced the soil adsorption of DEP that increased with increasing application rates of biochar. However, the adsorption capacity decreased by two aging processes (alternating wet and dry, and constantly moist). In the soil with low organic carbon (OC) content, the addition of 0.5% biochar (without aging) increased the adsorption by nearly 98 times compared to the control, and exhibited the highest adsorption capacity among all the treatments. In the soil with high OC content, the adsorption capacity in the treatment of 0.5% biochar without aging was 3.5 and 3 times greater than those of the treatments of biochar aged by alternating wet and dry, and constantly moist, respectively. Moreover, constantly moist resulted in a greater adsorption capacity than alternating wet and dry treatments regardless of biochar addition. This study revealed that biochar application enhanced soil sorption of DEP, however, the enhancement of the adsorption capacity was dependent on the soil organic carbon levels, and aging processes of biochar. PMID- 26004251 TI - Complete genome sequence and integrated protein localization and interaction map for alfalfa dwarf virus, which combines properties of both cytoplasmic and nuclear plant rhabdoviruses. AB - We have determined the full-length 14,491-nucleotide genome sequence of a new plant rhabdovirus, alfalfa dwarf virus (ADV). Seven open reading frames (ORFs) were identified in the antigenomic orientation of the negative-sense, single stranded viral RNA, in the order 3'-N-P-P3-M-G-P6-L-5'. The ORFs are separated by conserved intergenic regions and the genome coding region is flanked by complementary 3' leader and 5' trailer sequences. Phylogenetic analysis of the nucleoprotein amino acid sequence indicated that this alfalfa-infecting rhabdovirus is related to viruses in the genus Cytorhabdovirus. When transiently expressed as GFP fusions in Nicotiana benthamiana leaves, most ADV proteins accumulated in the cell periphery, but unexpectedly P protein was localized exclusively in the nucleus. ADV P protein was shown to have a homotypic, and heterotypic nuclear interactions with N, P3 and M proteins by bimolecular fluorescence complementation. ADV appears unique in that it combines properties of both cytoplasmic and nuclear plant rhabdoviruses. PMID- 26004252 TI - Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain. AB - Interferon-alpha (IFNalpha) can effectively inhibit or abort a viral infection within the host. It has been reported that IFN induction and production is hindered during classical swine fever virus (CSFV) infection. Most of those studies have been performed in vitro, making it difficult to elucidate the actual role of IFNs during CSFV infection in swine. Here, we report the effect of IFNalpha treatment (delivered by a replication defective recombinant human adenovirus type 5, Ad5) in swine experimentally infected with highly virulent CSFV strain Brescia. Treatment with two different subtypes of IFNalpha delayed the appearance of CSF-related clinical signs and virus replication although it did not prevent lethal disease. This is the first report describing the effect of IFNalpha treatment during CSFV infection in swine. PMID- 26004254 TI - EF-hand domains are involved in the differential cellular distribution of dystrophin Dp40. AB - Dp40 is the shortest DMD gene product that has been reported to date. It is encoded by exons 63-70, a region required for a beta-dystroglycan interaction. Its expression has been identified in rat, mouse, and human; however, its function remains unknown. To explore the expression of Dp40 transcript and subcellular localization of epitope-tagged Dp40 proteins, RT-PCR and immunofluorescence assays were performed in PC12 cells. The expression of Dp40 mRNA was found in undifferentiated and nerve growth factor-differentiated PC12 cells. According to immunofluorescence analyses, the recombinant protein Dp40 was mainly localized in the cell periphery/cytoplasm of undifferentiated and differentiated PC12 cells, a small amount of this protein is localized to the nucleus of differentiated cells. With the aim to identify the amino acids involved in the nuclear localization of Dp40, an in silico analysis was performed and it predicted that prolines 93 and 170, located within EF1 and EF2-hand domains, are involved in the nuclear localization of this protein. This prediction was confirmed by site-directed mutagenesis, the Dp40-L93P mutant was localized to the nucleus and cell periphery, while Dp40-L170P and Dp40-L93/170P showed mainly a nuclear localization. Dp40 co-localizes with beta-dystroglycan and the co-localization score was statistically reduced in Dp40-L93P, Dp40-L170P and Dp40-L93/170P mutants. PMID- 26004255 TI - X-chromosome inactivation: new insights into cis and trans regulation. AB - X-chromosome inactivation (XCI) is a developmentally associated process that evolved in mammals to enable gene dosage compensation between XX and XY individuals. In placental mammals, it is triggered by the long noncoding RNA Xist, which is produced from a complex regulatory locus, the X-inactivation centre (Xic). Recent insights into the regulatory landscape of the Xic, including its partitioning into topological associating domains (TADs) and its genetic dissection, have important implications for the monoallelic regulation of Xist. Here, we present some of the latest studies on X inactivation with a special focus on the regulation of Xist, its various functions and the putative role of chromosome conformation in regulating the dynamics of this locus during development and differentiation. PMID- 26004253 TI - Conformational changes required for reovirus cell entry are sensitive to pH. AB - During cell entry, reovirus particles disassemble to generate ISVPs. ISVPs undergo conformational changes to form ISVP(*) and this conversion is required for membrane penetration. In tissues where ISVP formation occurs within endosomes, ISVP-to-ISVP(*) conversion occurs at low pH. In contrast, in tissues where ISVP formation occurs extracellularly, ISVP-to-ISVP(*) transition occurs at neutral pH. Whether these two distinct pH environments influence the efficiency of cell entry is not known. In this study, we used Ouabain to lower the endosomal pH and determined its effect on reovirus infection. We found that Ouabain treatment blocks reovirus infection. In cells treated with Ouabain, virus attachment, internalization, and ISVP formation were unaffected but the efficiency of ISVP(*)s formation was diminished. Low pH also diminished the efficiency of ISVP-to-ISVP(*) conversion in vitro. Thus, the pH of the compartment where ISVP-to-ISVP(*) conversion takes place may dictate the efficiency of reovirus infection. PMID- 26004256 TI - [A case of encephalitis with hyperfamiliarity for faces]. AB - A 21-year-old right-handed woman was admitted to our hospital with fever, headache, and seizures. On admission, she showed anterograde and retrograde amnesia. These features, together with mild pleocytosis in the cerebrospinal fluid, led to the diagnosis of encephalitis. Brain MRI was normal. EEG revealed small spike waves in the left temporal lobe. There were no recurrent convulsions. Five days later, she stated she had hyperfamiliarity for faces of people she had never met before. She reported that many people appeared familiar regardless of age, sex, and profession; however, feelings of likes and dislikes did not accompany these symptoms. This symptom lasted for 20 days. Her ability to recognize known faces was normal, and prosopagnosia was not present. Neuropsychological tests indicated that her verbal memory was impaired. The retrograde amnesia remained until discharge. Considering the psychological findings attributable to left temporal lobe dysfunction, as well as previous reports on similar cases, our case suggests a possible relationship between lesions of the left temporal lobe and hyperfamiliarity for faces. PMID- 26004257 TI - [Left-sided metamorphopsia of the face and simple objects caused by an infarction at the right side of the splenium of the corpus callosum]. AB - A 78-year-old woman noticed that people's eyes and the right nasal foramens located in her left visual field looked smaller than those observed in the right. The woman reported no change in shape regarding facial outlines or scenic objects. Magnetic resonance imaging revealed an acute infarction of the right side of the splenium of the corpus callosum. Close examination revealed that her metamorphopsia affected the left side of her visual field, especially influencing facial components, particularly the eye. The woman had similar reactions to photographs of several kinds of animals, realistic portraits of humans, and caricatured humans. Meanwhile, presentings caricature human face at a 90 degrees rotation elicited metamorphopsia in eyebrows located on the left side of a picture, but not the eyes. She also reported a change of shape or color tone for geometric objects. The patient's only symptom was metamorphopsia, and she did not show any other neurological defects such as callosal disconnection syndrome. Furthermore, objects that were affected by the patient's metamorphopsia (e.g. facial component especially the eye, and simple geometric figures) may be easy images to use in order to detect this type of distorted vision. PMID- 26004258 TI - [Angiographically documented hemorrhagic transformation of embolic stroke: A case report]. AB - A 81-year-old man with rheumatoid vasculitis presented with total aphasia followed by right hemiplegia. The NIHSS score was 24. Diffusion weighted magnetic resonance imaging (DWI) demonstrated an acute infarct in the left middle cerebral artery (MCA) territory, and magnetic resonance angiogram (MRA) revealed left MCA M1 occlusion. We administrated recombinant tissue plasminogen activator (rt-PA) at 132 min after symptom onset, but symptom was not improved. Emergency neuroendovascular recanalization was conducted with Penumbra((r)) system. After MCA was recanalized partially, extravasations appeared on left lenticulostriate arteries territory at 376 min from symptom onset. Multiple extravasations spread over perforating branches, and ventricular rupture recognized angiographically. After the procedure, head CT demonstrated hematoma on left basal ganglia territory with intraventricular bleeding. Rheumatoid vasculitis might affect hemorrhagic infarction in emergency neuroendovascular recanalization procedure, and careful choice of treatment would be required. PMID- 26004259 TI - [Opalski syndrome caused by vertebral artery dissection]. AB - A 52-year-old man developed sudden occipital headache followed by vomiting and vertigo. On admission, he displayed right Horner syndrome with ipsilateral reduced facial sensation to pain and temperature that crossed in the body, affecting the left limbs. In addition, he had right hemiparesis. Diffusion weighted magnetic resonance images showed a high intensity lesion localized in the lower and right lateral medulla oblongata. Magnetic resonance angiography showed severe luminal stenosis in the right vertebral artery and T2-weighted sampling perfection with application optimized contrasts using different flip angle evolution (SPACE) showed arterial wall expansion. T1-weighted SPACE showed subacute intramural hematoma at that point, suggesting arterial dissection. First described in 1946, Opalski syndrome is considered a variant of Wallenberg syndrome with ipsilateral hemiparesis. This motor impairment is considered as a result of extension of the ischemia from the lateral medulla to the upper cervical cord involving corticospinal fibers caudal to pyramidal decussation. This case adds information regarding the anatomy of the pyramidal decussation. PMID- 26004260 TI - Report on an Investigation into an Entry Level Clinical Doctorate for the Genetic Counseling Profession and a Survey of the Association of Genetic Counseling Program Directors. AB - The master's degree is the required entry-level degree for the genetic counseling profession in the US and Canada. In 2012 the Association of Genetic Counseling Program Directors (AGCPD) passed resolutions supporting retention of the master's as the entry-level and terminal degree and opposing introduction of an entry level clinical doctorate (CD) degree. An AGCPD workgroup surveyed directors of all 34 accredited training programs with the objective of providing the Genetic Counseling Advanced Degrees Task Force (GCADTF) with information regarding potential challenges if master's programs were required to transition to an entry level CD. Program demographics, projected ability to transition to an entry-level CD, factors influencing ability to transition, and potential effects of transition on programs, students and the genetic counseling workforce were characterized. Two programs would definitely be able to transition, four programs would close, thirteen programs would be at risk to close and fourteen programs would probably be able to transition with varying degrees of difficulty. The most frequently cited limiting factors were economic, stress on clinical sites, and administrative approval of a new degree/program. Student enrollment under an entry-level CD model was projected to decrease by 26.2 %, negatively impacting the workforce pipeline. The results further illuminate and justify AGCPD's position to maintain the master's as the entry-level degree. PMID- 26004261 TI - MicroRNA-148a inhibits migration and invasion of ovarian cancer cells via targeting sphingosine-1-phosphate receptor 1. AB - MicroRNAs, a group of small non-coding RNA molecules that are involved in gene silencing, function as fine-tuning regulators during cancer progression. MicroRNA (miR)-148a has previously been demonstrated to be associated with ovarian cancer. However, whether miR-148a influences the migration and invasion of ovarian cancer cells has remained elusive. In the present study, reverse transcription quantitative polymerase chain reaction and western blotting were conducted to examine mRNA and protein expression levels, respectively. Luciferase reporter assay was used to determine target relationship, and a Transwell assay was used to study cell migration and invasion. The results of the present study indicated that miR-148a expression was markedly downregulated in ovarian cancer tissues compared with that of their matched normal adjacent tissues. In addition, miR 148a expression levels were reduced in three ovarian cancer cell lines, SKOV3, OVCAR and A2780, when compared with those of HUM-CELL-0088 normal ovarian epithelial cells. Furthermore, sphingosine-1-phosphate receptor 1 (S1PR1), which is upregulated in ovarian cancer tissues and cell lines, was identified as a novel target of miR-148a in SKOV3 ovarian cancer cells. The protein expression of S1PR1 was negatively regulated by miR-148a in SKOV3 cells. Furthermore, overexpression of miR-148a or inhibition of S1PR1 suppressed SKOV3 cell migration and invasion, while restoration of S1PR1 expression reversed the suppressive effect of miR-148a upregulation on SKOV3 cell migration and invasion. In conclusion, it was hypothesized that miR-148a may potentially be used as a molecular agent for the prevention and treatment of invasion and metastasis in ovarian cancer, while S1PR1 may present a promising target for clinical applications. PMID- 26004262 TI - Vaccination with ubiquitin-hepatitis B core antigen-cytoplasmic transduction peptide enhances the hepatitis B virus-specific cytotoxic T-lymphocyte immune response and inhibits hepatitis B virus replication in transgenic mice. AB - Chronic hepatitis B virus (HBV) infection is characterized by functionally impaired type 1 T-helper cell (Thl) immunity and poor HBV-specific T-cell responses. Ubiquitin (Ub), a highly conserved small regulatory protein, commonly serves as a signal for target proteins that are recognized and degraded in proteasomes. The rapid degradation of Ub-mediated antigens results in efficient stimulation of cell-mediated immune responses. Thus, the Ub-HBV core antigen (HBcAg)-cytoplasmic transduction peptide (CTP) fusion protein was designed for specific delivery of a foreign modified antigen to the cytoplasm of antigen presenting cells. HBV transgenic mice were used to determine whether Ub-HBcAg-CTP would restore HBV-specific immune responses and anti-viral immunity in these animals. The results demonstrated that synthesized Ub-HBcAg-CTP not only significantly increased the levels of interleukin-2 and interferon (IFN)-gamma compared with those in the HBcAg-CTP, IFN-alpha, Ub-HBcAg, HBcAg and phosphate buffered saline groups, but additionally induced the highest IFN-gamma+ CD8+ T cell numbers and HBV-specific cytotoxic T lymphocyte (CTL) responses, indicating a strong immune response. In addition, enhancement of specific CTL activity provoked by the fusion protein reduced hepatitis B surface antigen (HBsAg) and HBV DNA serum levels and diminished the expression of HBsAg and HBcAg in liver tissue of HBV transgenic mice, suggesting that there was a therapeutic effect. In conclusion, the present study provided evidence that Ub-HBcAg-CTP activated the Th1-dependent immunity, triggered functional T cell responses and subsequently inhibited viral replication in HBV transgenic mice. These observations suggested that the fusion protein may represent an innovative and promising candidate for active immunotherapy during chronic and persistent HBV. PMID- 26004264 TI - Helping enhances productivity in campo flicker (Colaptes campestris) cooperative groups. AB - Reproductive adults in many bird species are assisted by non-breeding auxiliary helpers at the nest, yet the impact of auxiliaries on reproduction is variable and not always obvious. In this study, we tested Hamilton's rule and evaluated the effect of auxiliaries on productivity in the facultative cooperative breeder campo flicker (Colaptes campestris campestris). Campo flickers have a variable mating system, with some groups having auxiliaries and others lacking them (i.e., unassisted pairs). Most auxiliaries are closely related to the breeding pair (primary auxiliaries), but some auxiliaries (secondary auxiliaries) are unrelated females that joined established groups. We found no effect of breeder quality (body condition) or territory quality (food availability) on group productivity, but the presence of auxiliaries increased the number of fledglings produced relative to unassisted pairs. Nonetheless, the indirect benefit of helping was small and did not outweigh the costs of delayed breeding and so seemed insufficient to explain the evolution of cooperative breeding in campo flickers. We concluded that some ecological constraints must limit dispersal or independent breeding, making staying in the group a "best-of-a-bad-job" situation for auxiliaries. PMID- 26004263 TI - Infection and Atherosclerosis Development. AB - Atherosclerosis is a chronic disease hallmarked by chronic inflammation, endothelial dysfunction and lipid accumulation in the vasculature. Although lipid modification and deposition are thought to be a major source of the continuous inflammatory stimulus, a large body of evidence suggests that infectious agents may contribute to atherosclerotic processes. This could occur by either direct effects through infection of vascular cells and/or through indirect effects by induction of cytokine and acute phase reactant proteins by infection at other sites. Multiple bacterial and viral pathogens have been associated with atherosclerosis by seroepidemiological studies, identification of the infectious agent in human atherosclerotic tissue, and experimental studies demonstrating an acceleration of atherosclerosis following infection in animal models of atherosclerosis. This review will focus on those infectious agents for which biological plausibility has been demonstrated in animal models and on the challenges of proving a role of infection in human atherosclerotic disease. PMID- 26004266 TI - Thermoregulation of individual paper wasps (Polistes dominula) plays an important role in nest defence and dominance battles. AB - Paper wasps, like Polistes dominula, are considered as primitively eusocial. Hence, they are often used as model species for studies about the evolution of eusociality and dominance hierarchies. However, our knowledge about basic physiological processes in these wasps remains limited. In particular, the thermoregulation of individual wasps in their natural habitat has not yet been investigated in detail. We conducted a comprehensive field study to test their ability to respond to external hazards with elevated thorax temperatures. We presented artificial threats by applying smoke or carbon dioxide simulating fire and predator attacks, respectively, and monitored the thorax temperature of wasps on the nest using infrared thermography. We found that P. dominula workers recognized smoke and CO2 and reacted almost instantaneously and simultaneously with an increase of their thorax temperature. The maximal thorax temperature was reached about 65 s after the application of both stressors, but subsequently, the wasps showed a different behaviour pattern. No rise of the thorax temperature was detectable after an air blast was applied or in wasps resting on the nest. These observations provide evidence that P. dominula is able to heat up its thorax and that thermoregulation is employed in escape and defence reactions. Additionally, we investigated the thorax temperatures of queens during dominance battles. We found that the thorax temperature of the dominant queens rose up to 5 degrees C compared to that of subordinate queens that attacked the former, suggesting that the dominant queen defends herself as well as her nest. PMID- 26004265 TI - How territoriality and host-tree taxa determine the structure of ant mosaics. AB - Very large colonies of territorially dominant arboreal ants (TDAAs), whose territories are distributed in a mosaic pattern in the canopies of many tropical rainforests and tree crop plantations, have a generally positive impact on their host trees. We studied the canopy of an old Gabonese rainforest (ca 4.25 ha sampled, corresponding to 206 "large" trees) at a stage just preceding forest maturity (the Caesalpinioideae dominated; the Burseraceae were abundant). The tree crowns sheltered colonies from 13 TDAAs plus a co-dominant species out of the 25 ant species recorded. By mapping the TDAAs' territories and using a null model co-occurrence analysis, we confirmed the existence of an ant mosaic. Thanks to a large sampling set and the use of the self-organizing map algorithm (SOM), we show that the distribution of the trees influences the structure of the ant mosaic, suggesting that each tree taxon attracts certain TDAA species rather than others. The SOM also improved our knowledge of the TDAAs' ecological niches, showing that these ant species are ecologically distinct from each other based on their relationships with their supporting trees. Therefore, TDAAs should not systematically be placed in the same functional group even when they belong to the same genus. We conclude by reiterating that, in addition to the role played by TDAAs' territorial competition, host trees contribute to structuring ant mosaics through multiple factors, including host-plant selection by TDAAs, the age of the trees, the presence of extrafloral nectaries, and the taxa of the associated hemipterans. PMID- 26004267 TI - Effectiveness of inactivation of foodborne pathogens during simulated home pan frying of steak, hamburger or meat strips. AB - In order to evaluate the effect of simulated home pan frying of raw meat and meat preparations of different animal species on the thermal inactivation of pathogens, the heat resistance (D-value) of three strains of Campylobacter jejuni, Escherichia coli O157:H7, Salmonella spp., Listeria monocytogenes and two strains of generic E. coli was validated in BHI and adjusted BHI (i.e. pH5.6 and 1.5% NaCl) at 60 degrees C. The D-values were obtained of the linear phase of the survivor curves created in GInaFiT, a freeware tool to fit models to experimental data. The obtained D-values corresponded to those previously published in literature and confirmed L. monocytogenes to be the most heat resistant pathogen among them. Heat treatment in adjusted BHI significantly increased heat resistance of E. coli O157:H7 and generic E. coli. Subsequently, the thermal inactivation of L. monocytogenes, Salmonella spp., C. jejuni and E. coli O157:H7 was evaluated using a standardized procedure simulating commonly used home pan frying of various types of meat including steaks or filets, hamburgers and meat strips from various animal species such as pork, beef, chicken, lamb and some turkey, horse, kangaroo and crocodile meat. Corresponding F70-values were calculated based upon measured core time/temperature profiles. It was noted that a core temperature of 70 degrees C was not always achieved and, moreover, a heat treatment equivalent to 2 min at 70 degrees C was also not always obtained. This was in particular noted in hamburgers although the meat was visually judged well done. On several occasions, residual survivors of the initial inoculated (4 logCFU/g) food borne pathogens could be recovered either by enumeration (limit of detection 1 logCFU/g) or by the presence/absence testing per 25 g. Pan frying of hamburgers yielded the highest number of surviving pathogenic bacteria (46%), followed by well-done filets and steaks (13%) and meat strips (12%). Taking only steaks (beef, horse, kangaroo, crocodile and turkey) into account, residual detection of pathogens occurred for all levels of doneness: 18% for well-done, 71% for medium and even 90% for rare steaks. Numbers of L. monocytogenes recovered after heat treatment ranged from <1 logCFU/g to 2.6 logCFU/g. Although, the prevalence of pathogens in meat might be low, and the numbers present in case of natural contamination are probably lower than the current used inoculum of 4 logCFU/g, consumers could still be exposed to surviving food borne pathogens in case of these commonly used pan frying of raw meat and meat preparations at consumer's home. PMID- 26004268 TI - Editorial overview: New protein production tools for structural biology. PMID- 26004269 TI - Phospholipid structured microemulsion as effective carrier system with potential in methicillin sensitive Staphylococcus aureus (MSSA) involved burn wound infection. AB - Burn wounds are foremost site for bacterial colonization and multiplication. Staphylococcus aureus is one of the most predominant pathogen found in burn wounds. Fusidic acid (FA) is widely employed in the treatment of complicated skin infections caused by Staphylococcus aureus. Hence, the aim of this study was to investigate the usefulness and efficacy of topical FA (2% w/w) loaded biocompatible microemulsion-based-system (FA-ME) in eradicating MSSA bacterial infections which otherwise was less effective when dealt with conventional formulations. For construction of pseudoternary phase diagram, ratio of oil (IPM):water:Smix is 20:30:50% w/w and proportion of Smix (Phospholipid:Tween 80 (T80):Ethanol) is in the ratio of 1:2:1, respectively. The hypothesis relates here to the role of phospholipids as part of the nano-scale structure of microemulsion systems to overcome the hurdles of drug delivery. The prepared FA ME system was evaluated for its therapeutic efficacy and carrier-specific characteristics such as globule size, % transmittance, transmission electron microscopy, drug content and stability. Selected microemulsion system was incorporated into gel form and evaluated for texture analysis, drug permeation in 24 h and treatment of burn wounds. Burn wound infection was established with MSSA ATCC 25923 in BALB/c mice and the process of wound healing as well as bacterial loading in the wound was estimated. The developed nanosized FA-ME system demonstrated improved wound healing, better spreadability and enhanced therapeutic efficacy due to the changes in the behavior of the drug molecules by way of carrier-characteristics. PMID- 26004270 TI - Pharmacokinetic and pharmacodynamic evaluation of telaprevir for the treatment of hepatitis C. AB - INTRODUCTION: Telaprevir is one of the first direct-acting antiviral drugs approved for the treatment of the hepatitis C virus (HCV) genotype 1. Following its approval in 2011, new data regarding the pharmacokinetics and pharmacodynamics were reported, leading to important clinical applications. AREAS COVERED: This article reviews the pharmacokinetic and pharmacodynamic properties of telaprevir for the treatment of the HCV. The areas covered include data regarding the drug's absorption, distribution, metabolism and excretion, in addition to the antiviral activity strategy such as the clinical dose selection and treatment duration. EXPERT OPINION: Telaprevir presents several pharmacological properties that could limit its administration such a high-fat, high-calorie meal; the need to be administrated with pegylated IFN plus ribavirin; and the drug-drug interaction profile. As a consequence and considering the new therapeutic arsenal against the HCV, the use of telaprevir as part of HCV therapy will be limited. PMID- 26004271 TI - [Vogt-Koyanagi-Harada disease]. PMID- 26004272 TI - [Nicolau syndrome after glatiramer acetate injection]. PMID- 26004273 TI - [Clinical equipoise and systematic reviews of randomized controlled trials]. PMID- 26004274 TI - [Tongue angioedema as an adverse effect to mycophenolate]. PMID- 26004275 TI - [Cholesterol associated to low density lipoproteins (LDL) and vascular risk reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9): A new therapeutic target]. PMID- 26004276 TI - [Hip fracture incidence in Spain]. PMID- 26004277 TI - [Non-alcoholic fatty liver disease. Role of primary care physicians]. PMID- 26004278 TI - [Vulgaris verruca on a tatoo]. PMID- 26004279 TI - [Sacral rib]. PMID- 26004280 TI - [Medicine and robotics]. PMID- 26004282 TI - First trial response to sudden support surface displacement: the effect of vestibular compensation. AB - CONCLUSION: The effect of visual condition is more intense in the first trial response in normal subjects and patients and in last trial response only in patients. The first trial effect is more evident in compensated patients in the eyes open condition with any type of perturbation, and in non-compensated patients with the angular displacements in either visual condition. OBJECTIVE: The study of body reaction to FTR can help to understand the complex mechanisms involved in the postural response and to develop new therapies to improve stability and prevent falls in unilateral vestibular deficit (UVD). This work describes the adaptation effect and the visual influence on the postural response to repetitive balance perturbation stimulus in normal subjects, compensated, and uncompensated UVD patients. METHODS: The magnitude of displacement has been measured when the support surface is linearly or angularly displaced. The differences between results in the first and late trial, and the differences between the eyes open and eyes closed situation have been compared. RESULTS: Compensated patients recover the adaptation ability to unexpected changes on the support surface through visual preference mechanism. Not compensated patients present hypermetric postural response with greater instability in the eyes open and eyes closed situations. PMID- 26004281 TI - Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke. AB - Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan's proangiogenic potential. PMID- 26004284 TI - Feasibility study of high-resolution DCE-MRI for glomerular filtration rate (GFR) measurement in a routine clinical modal. AB - Dynamic contrast enhanced (DCE) MR renography has been identified as an interesting tool to determine single-kidney GFR. However, a fundamental issue for the applicability of MR-based estimate of single-kidney GFR is selecting a balance between spatial and temporal resolution of DCE-MRI data. The purpose is to assess the feasibility of GFR estimate from high-resolution (HR) dynamic contrast-enhanced (DCE) MRI in a routine clinical modal. Standard MR renography (2.4s/phase, total 4min; 4-ml Gd) and five-phase, HR-based imaging protocol (0, 30, 70, 120, and 240s; 0.05mmol/kg Gd) were prospectively performed in twelve volunteers who were scheduled for routine renal MRI. Data were plotted with Patlak, two-compartment modified Tofts model (2CTM), and two-compartment filtration model (2CFM) for GFR estimate. During all the measurements, only the signal intensities in the aorta and whole kidney parenchyma were considered. Standard 2CFM and 2CTM produced lower residuals over the fitted interval than HR based measures (p<0.05); and HR-bases 2CFM and 2CTM did not reflect significant correlation to standard values. Standard Patlak plots with 0-240s data points produced significantly lower GFR and higher residuals than that plots with 0-120s data points (p<0.05). HR-based Patlak plots with 0, 30, 70, and 120s data points significantly correlated with reference values (Pearson rho=0.97, p<0.01), and produced a 33.2% underestimation of reference value, which was better than that plots with 0, 30, 70, 120, and 240s data points (rho=0.92, p<0.01; 58.6% underestimation of reference value). It concludes that it is feasible to estimate GFR with HR-based DCE-MRI and appreciate kinetic model. Patlak plots from 0, 30, 70, and 120s data points is better than plots from 0, 30, 70, 120, and 240s data points. PMID- 26004283 TI - Host adaption to the bacteriophage carrier state of Campylobacter jejuni. AB - The carrier state of the foodborne pathogen Campylobacter jejuni represents an alternative life cycle whereby virulent bacteriophages can persist in association with host bacteria without commitment to lysogeny. Host bacteria exhibit significant phenotypic changes that improve their ability to survive extra intestinal environments, but exhibit growth-phase-dependent impairment in motility. We demonstrate that early exponential phase cultures become synchronised with respect to the non-motile phenotype, which corresponds with a reduction in their ability to adhere to and invade intestinal epithelial cells. Comparative transcriptome analyses (RNA-seq) identify changes in gene expression that account for the observed phenotypes: downregulation of stress response genes hrcA, hspR and per and downregulation of the major flagellin flaA with the chemotactic response signalling genes cheV, cheA and cheW. These changes present mechanisms by which the host and bacteriophage can remain associated without lysis, and the cultures survive extra-intestinal transit. These data provide a basis for understanding a critical link in the ecology of the Campylobacter bacteriophage. PMID- 26004285 TI - Access to, and use of, water by populations living in a schistosomiasis and fascioliasis co-endemic area of northern Cote d'Ivoire. AB - Water is an essential element of life, but it can also be a source of disease. Apart from direct consumption of unsafe water, direct contact and indirect consumption puts people at risk of many different types of pathogens. Employing a mixed methods approach, consisting of questionnaires and direct observations, we assessed access to, and use of, different water sources by the participants of the district des Savanes in northern Cote d'Ivoire. The use of water sources was put in relation to the potential risk of acquiring schistosomiasis and fascioliasis. Overall, 489 people aged 8 to 82 years participated. While all participants had access to safe water, 63% were in direct contact with unimproved water and 31% directly consumed unsafe water. More than a third of the people who otherwise reported using only improved water for all activities came in contact with unimproved water through crossing open water when going to their workplace, school or other destinations. Self-reported blood in urine - a marker for Schistosoma haematobium with reasonable sensitivity and specificity - was reported by 6% (n=30), self-reported blood in stool - an unspecific marker for Schistosoma mansoni - was reported by 7% (n=35), while blood co-occurring in both urine and stool was reported by another 10% (n=48) of participants. Accessing unimproved water for any activity (including crossing) was associated with higher odds of reporting blood in urine and/or blood in stool (odds ratio: 1.90; 95% confidence interval: 1.07-3.36). Our results have important rami-fications for intervention programmes targeting neglected tropical diseases, and emphasize the need for a wider supply of safe water to rural populations, since the water supply at the workplace needs to be considered as well next to the water supply at home. Crossing of open water sources is an important risk factor for sustained transmission of schistosomiasis. PMID- 26004286 TI - Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells. AB - Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44(+) cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients. PMID- 26004287 TI - Novel approaches to pediatric leukemia treatment. AB - Despite remarkable improvements in the treatment of pediatric acute leukemia (AL) over the last decades, relapse still carries a poor prognosis with significant morbidity and mortality. Novel targeted therapies are currently being investigated in an attempt to reduce adverse events and improve survival outcomes. This review summarizes recent data from the literature regarding advances in drug discovery based on biological evidence and the novel targeted drug therapies for childhood AL. Significant challenges still remain for novel drug development in childhood AL. However, first results combined with a large number of new agents currently being investigated are very encouraging. Furthermore, therapeutic advances will depend upon combination strategies using the specific action of each agent and their complementary effects on leukemia cells. PMID- 26004288 TI - The Queensland Health Ministerial Taskforce on health practitioners' expanded scope of practice: consultation findings. AB - OBJECTIVE: Queensland Health established a Ministerial Taskforce to consult on and make recommendations for the expansion of the scope ofpractice of allied health roles. This paper describes the findings from the stakeholder consultation. METHODS: The Ministerial Taskforce was chaired by the Assistant Minister for Health and included high-level representation from allied health, nursing, medicine, unions, consumers and universities. Widespread engagement was undertaken with stakeholders representing staff from a wide cross-section of health service provision, training and unions. Participants also tendered evidence of models incorporating full-scope and extended scope tasks undertaken by allied health professionals. RESULTS: The consultation incorporated 444 written submissions and verbal feedback from over 200 participants. The findings suggest that full scope of practice is often restricted within the Queensland public health system, resulting in underuse of allied health capacity and workforce inefficiencies. However, numerous opportunities exist to enhance patient care by extending current roles, including prescribing and administering medications, requesting investigations, conducting procedures and reporting results. The support needed to realise these opportunities includes: designing patient-centred models of service delivery (including better hours of operation and delegation to support staff); leadership and culture change; funding incentives; appropriate education and training; and clarifying responsibility, accountability and liability for outcomes. The taskforce developed a series of recommendations and an implementation strategy to operationalise the changes. CONCLUSIONS: The Ministerial Taskforce was an effective and efficient process for capturing broad-based engagement for workforce change while ensuring high-level support and involving potential adversaries in the decision-mking processes. What is known about the topic? Anecdotal evidence exists to suggest that allied health professionals do not work to their full scope of practice and there is potential to enhance health service efficiencies by ensuring practitioners are supported to work to their full scope of practice. What does this paper add? This paper presents the findings from a large-scale consultation, endorsed by the highest level of state government, that reinforces the perceptions that allied health professionals do not work to full scope of practice, identifies several barriers to working to full scope and extended scope of practice, and opportunities for workforce efficiencies arising from expanding scope of practice. The top-down engagement process should expedite the implementation of workforce change. What are the implications for practitioners? High-level engagement and support is an effective and efficient way to broker change and overcome intraprofessional barriers to workforce change policies. However, practitioners are often prevented from expanding their roles through an implied need to 'ask for permission', when, in fact, the only barriers to extending their role are culture and historical practice. PMID- 26004289 TI - Surgical treatment of head and neck cancers in the ancient world. AB - OBJECTIVE: This paper attempts to chart the history of head and neck cancers and their surgical treatment, starting from ancient Egypt and concluding with Galen. CONCLUSION: The ancient Egyptians appear to have treated head and neck cancers with local applications. The ancient Greek corpus contains a reference to treating pharyngeal carcinoma with cautery, but the description is too vague to establish the diagnosis conclusively. The ancient Romans moved away from surgical treatments, with Galen establishing a prejudice against surgery that would last through the Middle Ages. PMID- 26004290 TI - The effects of a multi-component dyadic intervention on the psychological distress of family caregivers providing care to people with dementia: a randomized controlled trial. AB - BACKGROUND: Earlier research showed that multi-component dyadic interventions - including a combination of intervention strategies and addressing both the person with dementia and caregiver - have a beneficial impact on the mental and physical health of people with dementia and their family caregivers. A randomized controlled trial (RCT) of a multi-component dyadic intervention, which is a translated and adapted version of an intervention that has been shown to be effective in the US by Teri et al. (2003), was performed. The effects on caregivers' mood (primary outcome), burden, general health, and salivary cortisol levels (secondary outcomes) were studied. METHODS: Community-dwelling people with dementia and their family caregivers (N = 111 dyads) were randomly assigned. The experimental group received eight home visits during three months, combining physical exercise and support (psycho-education, communication skills training, and planning of pleasant activities). Both the physical exercise and support component were directed at both the person with dementia and the caregiver. The comparison group received monthly information bulletins and phone calls. There were three measurements at baseline (prior to the intervention), at three months, and at six months into the intervention. Data were analyzed with Generalized Estimating Equations (GEE) based on an intention-to-treat analysis of all available data. RESULTS: All analyses showed no benefits of the intervention over time on any of the outcomes. CONCLUSION: The negative results might be explained by the translation and adaptation of the intervention that has been shown to be effective in the US: the intervention was shortened and did not include cognitive reframing. However, only the health effects on people with dementia and not on caregivers were studied in the US. Several other factors might also have played a role, which are important for future studies to take into account. These are: the usual health care in the country or region of implementation; the wishes and needs of participants for specific intervention components; the room for improvement regarding these components; the inclusion of positive outcome measures, such as pleasure, and the quality of the relationship. PMID- 26004291 TI - C-reactive protein gene polymorphisms and gene-environment interactions in ischaemic stroke. AB - Ischaemic stroke is a heterogeneous, multifactorial disease caused by the combination of certain risk factors and genetic factors. Several single nucleotide polymorphisms (SNPs) of C-reactive protein (CRP) have been reported to be associated with serum CRP levels. However, genetic association studies have produced conflicting results regarding the association between these SNPs and ischaemic stroke. In this paper, we conducted a population-based case-control study to determine whether two SNPs of CRP (rs1800947 and rs3093059) are associated with ischaemic stroke in Chinese Han population and to evaluate their interaction with environmental risk factors. We found that the rs1800947 GC genotype is significantly associated with the risk of ischaemic stroke, particularly the small-vessel disease and its subtype. Crossover analysis revealed that patients with the rs1800947 GC genotype and habits of smoking or drinking were more susceptible to ischaemic stroke. No association was found between the rs3093059 and ischaemic stroke. PMID- 26004292 TI - What do community health workers have to say about their work, and how can this inform improved programme design? A case study with CHWs within Kenya. AB - BACKGROUND: Community health workers (CHWs) are used increasingly in the world to address shortages of health workers and the lack of a pervasive national health system. However, while their role is often described at a policy level, it is not clear how these ideals are instantiated in practice, how best to support this work, or how the work is interpreted by local actors. CHWs are often spoken about or spoken for, but there is little evidence of CHWs' own characterisation of their practice, which raises questions for global health advocates regarding power and participation in CHW programmes. This paper addresses this issue. DESIGN: A case study approach was undertaken in a series of four steps. Firstly, groups of CHWs from two communities met and reported what their daily work consisted of. Secondly, individual CHWs were interviewed so that they could provide fuller, more detailed accounts of their work and experiences; in addition, community health extension workers and community health committee members were interviewed, to provide alternative perspectives. Thirdly, notes and observations were taken in community meetings and monthly meetings. The data were then analysed thematically, creating an account of how CHWs describe their own work, and the tensions and challenges that they face. RESULTS: The thematic analysis of the interview data explored the structure of CHW's work, in terms of the frequency and range of visits, activities undertaken during visits (monitoring, referral, etc.) and the wider context of their work (links to the community and health service, limited training, coordination and mutual support through action and discussion days, etc.), and provided an opportunity for CHWs to explain their motivations, concerns and how they understood their role. The importance of these findings as a contribution to the field is evidenced by the depth and detail of their descriptive power. One important aspect of this is that CHWs' accounts of both successes and challenges involved material elements: leaky tins and dishracks evidenced successful health interventions, whilst bicycles, empty first aid kits and recruiting stretcher bearers evidenced the difficulties of resourcing and geography they are required to overcome. CONCLUSION: The way that these CHWs described their work was as healthcare generalists, working to serve their community and to integrate it with the official health system. Their work involves referrals, monitoring, reporting and educational interactions. Whilst they face problems with resources and training, their accounts show that they respond to this in creative ways, working within established systems of community power and formal authority to achieve their goals, rather than falling into a 'deficit' position that requires remedial external intervention. Their work is widely appreciated, although some households do resist their interventions, and figures of authority sometimes question their manner and expertise. The material challenges that they face have both practical and community aspects, since coping with scarcity brings community members together. The implication of this is that programmes co-designed with CHWs will be easier to implement because of their relevance to their practices and experiences, whereas those that assume a deficit model or seek to use CHWs as an instrument to implement external priorities are likely to disrupt their work. PMID- 26004293 TI - Erratum to: Autologous blood injection for treatment of chronic recurrent TMJ dislocation: is it successful? Is it safe enough? A systematic review. PMID- 26004294 TI - A Periscope-Based Parallel Endografting Approach Can Successfully Exclude an Aneurysm of the Left Subclavian Artery Origin. PMID- 26004295 TI - Effect of abomasal or ruminal administration of citrus pulp and soybean oil on milk fatty acid profile and antioxidant properties. AB - Soybean oil (SBO) is rich in polyunsaturated fatty acids (FA) and rumen bypass of SBO can contribute to increase the polyunsaturated FA proportion in milk fat. Citrus pulp (CPP) is a source of antioxidants but there is little information on the effects of CP administration on milk properties. This study was performed to determine the role of rumen microorganisms in the transfer of antioxidants from CPP into milk when cows receive SBO as a source of polyunsaturated FA. Four ruminally fistulated lactating Holstein cows were assigned to a 4 * 4 Latin square design with a 2 * 2 factorial arrangement of treatments: (1) SBO administered in the rumen; (2) SBO infused in the abomasum; (3) SBO + CPP administered in the rumen; and (4) SBO + CPP infused in the abomasum. Product and site of administration had no effect on yield of milk components. Concentrations of total polyphenols and flavonoids, reducing power and production of conjugated diene (CD) hydroperoxides in milk were not affected by products, but infusion in the abomasum compared with administration in the rumen increased production of CD. Milk fat FA profile was not affected by products. However, cows infused in the abomasum compared with those administered in the rumen showed lower proportions of short-chain and monounsaturated FA and higher proportions of polyunsaturated, omega 3 and omega 6 FA in milk fat, which resulted in enhanced health-promoting index of milk. Administration of SBO and CPP (0.2 + 1.0 kg/d) in the rumen or the abomasum resulted in similar milk antioxidant properties, thus suggesting that the rumen microbes have little involvement in the metabolism of antioxidants from CPP. PMID- 26004296 TI - Dietary Sodium and Blood Pressure: How Low Should We Go? AB - BACKGROUND: Sodium intake in the United States exceeds recommended amounts across all age, gender and ethnic groups. National dietary guidelines advocate reduced intake by at least 1,000mg per day or more, but whether there is population-wide benefit from further reductions to levels of 1500mg per day remains controversial. METHODS AND RESULTS: A brief review of current evidence-based dietary guidelines is provided and key prospective, randomized studies that report dietary and urinary sodium data are summarized. Dietary sources of sodium and eating patterns that offer nutritiously sound approaches to nutrient dense, reduced sodium intake are compared. CONCLUSIONS: No studies suggest that high sodium intake at the levels of the population's current diet is optimal. On the contrary, national and international evidence and systematic reviews consistently recommend reducing sodium intake overall, generally by 1000mg/day. Recommendations to reduce intakes to 2400mg/d are generally accepted as beneficial. Whether further reductions to 1500mg/d are useful, feasible and safe among specific subgroups in the population who are at increased risk of hypertension or stroke remains controversial and requires individualized consideration by patients and their health care providers. PMID- 26004297 TI - Biomarker-driven diagnosis of diffuse gliomas. AB - The diffuse gliomas are primary central nervous system tumors that arise most frequently in the cerebral hemispheres of adults. They are currently classified as astrocytomas, oligodendrogliomas or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), grade IV, is the highest grade and most common form. The diagnosis of diffuse gliomas has historically been based primarily on histopathologic features, yet these tumors have a wide range of biological behaviors that are only partially explained by morphology. Biomarkers have now become an established component of the neuropathologic diagnosis of gliomas, since molecular alterations aid in classification, prognostication and prediction of therapeutic response. Isocitrate dehydrogenase (IDH) mutations are frequent in grades II and III infiltrating gliomas of adults, as well as secondary GBMs, and are a major discriminate of biologic class. IDH mutant infiltrating astrocytomas (grades II and III), as well as secondary GBMs, are characterized by TP53 and ATRX mutations. Oligodendrogliomas are also IDH mutant, but instead are characterized by 1p/19q co-deletion and mutations of CIC, FUBP1, Notch1 and the TERT promoter. Primary GBMs typically lack IDH mutations and demonstrate EGFR, PTEN, TP53, PDGFRA, NF1 and CDKN2A/B alterations and TERT promoter mutations. Pediatric gliomas differ in their spectrum of disease from those in adults; high grade gliomas occurring in children frequently have mutations in H3F3A, ATRX and DAXX, but not IDH. Circumscribed, low grade gliomas, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma and ganglioglioma, need to be distinguished from diffuse gliomas in the pediatric population. These gliomas often harbor mutations or activating gene rearrangements in BRAF. PMID- 26004299 TI - Trajectory classes of violent behavior and their relationship to lipid levels in schizophrenia inpatients. AB - OBJECTIVE: To characterize the trajectory patterns of violence in schizophrenia inpatients, examine the relationships between the violence trajectories and baseline clinical features and lipid levels, and generate a model to predict the more violent trajectories. METHODS: In a sample of 107 consecutively admitted patients with schizophrenia spectrum disorders, violent behavior was weekly rated using the Violence Scale. The patients' blood levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured at admission. A trajectory analysis was used to classify the patients' longitudinal courses in violence, and the correlates of these trajectories were assessed using multinomial logistic regression analyses. A stepwise logistic regression was used to select the best predictor variables for the more violent trajectories. RESULTS: Four violence trajectories of inpatients were obtained: class 1 (no violence, 37.4%), class 2 (low-leveling off, 39.2%), class 3 (high-falling sharply, 10.3%), and class 4 (high-falling slowly, 13.1%). Although the relationship between decreasing TC and TG levels and increased violence in the trajectory classes did not reach statistical significance, a decreasing trend in the proportion of high dichotomized-TG levels was significantly associated with more violence in the trajectory classes (p = 0.04). A five-variable model consisting of female gender, early onset, higher scores of positive symptoms, lower scores of negative symptoms, and low dichotomized-TC levels had a predictive accuracy of 0.85 (95% CI = 0.72-0.97). CONCLUSIONS: Distinct violence trajectories exist in schizophrenia inpatients, and the more violent trajectories can be predicted using baseline clinical features and lipid levels. PMID- 26004298 TI - Enhancer of zeste homolog 2 depletion induces cellular senescence via histone demethylation along the INK4/ARF locus. AB - Polycomb group proteins are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. As a member of PcG proteins, enhancer of zeste homolog 2 (EZH2) targets cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. In previous work, we reported that EZH2 depletion functionally induced cellular senescence in human gastric cancer cells with mutant p53. However, whether EZH2 expression contributes to the change of key cell cycle regulators and the mechanism involved are still unclear. To address this issue, we investigated the effects of EZH2 depletion on alteration of histone methylation pattern. In gastric cancer cells, INK4/ARF locus was activated to certain extent in consequence of a decrease of H3K27me3 along it caused by EZH2 silence, which contributed substantially to an increase in the expression of p15(INK4b), p14(ARF) and p16(INK4a) and resulted in cellular senescence ultimately. Furthermore, MKN28 cells, which did not express p16(INK4a) and p21(cip), could be induced to senescence via p15(INK4b) activation and suppression of p15(INK4b) reversed senescence progression induced by EZH2 downregulated. These data unravel a crucial role of EZH2 in the regulation of INK4/ARF expression and senescence procedure in gastric cancer cells, and show that the cellular senescence could just depend on the activation of p15(INK4b)/Rb pathway, suggesting the cell-type and species specificity involved in the mechanisms of senescence inducement. PMID- 26004300 TI - Schizoaffective disorder and metabolic syndrome: A meta-analytic comparison with schizophrenia and other non-affective psychoses. AB - People with psychotic disorders, including schizophrenia (SCZ), schizoaffective disorder (SD), or other non-affective psychoses (ONAP), have a higher risk of metabolic syndrome (MetS) than general population. However, previous meta analyses failed to explore if people with SD are more likely to suffer from MetS than SCZ and ONAP. We carried out a systematic review and meta-analysis comparing rates of MetS in SD with those in SCZ or ONAP. We searched main electronic databases for relevant articles published up to January 2015, and for unpublished data, contacting corresponding authors, to minimize selective reporting bias. Odds ratios (ORs) based on random effects models, with 95% confidence intervals (CIs), and heterogeneity (I(2)), were estimated. We performed leave-one-out, quality-based, and subgroups analyses to check findings validity. Testing for publication bias, Egger's test estimates were reported. We included 7616 individuals (1632 with SD and 5984 with SCZ/ONAP) from 30 independent samples. SD, as compared with SCZ/ONAP, had a random-effect pooled OR (95%CI) for MetS of 1.41 (1.23-1.61; p < 0.001; I(2) = 5%). No risk of publication bias was found (p = 0.85). Leave-one-out, sensitivity, and subgroups analyses confirmed the association. To our knowledge, this is the first meta-analysis comparing MetS comorbidity between individuals with SD and those with SCZ or ONAP. SD subjects are more likely to suffer from MetS, with consistent findings across the studies included. However, the role of explanatory factors of this association, and the relative contribution of MetS subcomponents, deserve further research. PMID- 26004301 TI - Effect of Allogeneic Intraoperative Blood Transfusion on Survival in Patients Treated With Radical Cystectomy for Nonmetastatic Bladder Cancer: Results From a Single High-Volume Institution. AB - BACKGROUND: Previous studies have demonstrated that perioperative blood transfusion (BT) is associated with a significantly increased risk of cancer recurrence and mortality after radical cystectomy (RC). Recently, it was shown for the first time that intraoperative transfusion has a detrimental effect on cancer survival. The aim of the current study was to validate this finding in a single European institution. PATIENTS AND METHODS: The study focused on 1490 consecutive nonmetastatic bladder cancer patients treated with RC at a single tertiary care referral center between January 1990 and August 2013. Kaplan-Meier analyses and Cox regression analyses were used to assess the effect of timing of BT administration (no transfusion vs. intraoperative transfusion vs. postoperative transfusion vs. intraoperative and postoperative transfusion) on cancer-specific mortality (CSM), overall mortality (OM), and disease recurrence. RESULTS: Mean age at the time of RC was 67 years. Overall, 322 (21.6%) patients received intraoperative BT and 97 (6.5%) received postoperative BT. At a mean follow-up time of 125 months (median, 110 months), the 5- and 10-year CSM rate was 846 (58%) and 715 (48%), respectively. In multivariable analyses patients who received intraoperative BT had greater risk of disease recurrence (hazard ratio [HR], 1.24; P < .04), CSM (HR, 1.60; P < .02), and OM (HR, 1.45; P < .03). Conversely, this effect disappears with postoperative BT (all P > .2). CONCLUSION: Our study confirms that intraoperative, but not postoperative BT, are related to a detrimental effect on survival after RC. These results should be take into account by physicians to administer BT using the correct timing. PMID- 26004302 TI - Central estrogen action sites involved in prepubertal restraint of pulsatile luteinizing hormone release in female rats. AB - The present study aimed to determine estrogen feedback action sites to mediate prepubertal restraint of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release in female rats. Wistar-Imamichi strain rats were ovariectomized (OVX) and received a local estradiol-17beta (estradiol) or cholesterol microimplant in several brain areas, such as the medial preoptic area (mPOA), paraventricular nucleus, ventromedial nucleus and arcuate nucleus (ARC), at 20 or 35 days of age. Six days after receiving the estradiol microimplant, animals were bled to detect LH pulses at 26 or 41 days of age, representing the pre- or postpubertal period, respectively. Estradiol microimplants in the mPOA or ARC, but not in other brain regions, suppressed LH pulses in prepubertal OVX rats. Apparent LH pulses were found in the postpubertal period in all animals bearing estradiol or cholesterol implants. It is unlikely that pubertal changes in responsiveness to estrogen are due to a change in estrogen receptor (ER) expression, because the number of ERalpha-immunoreactive cells and mRNA levels of Esr1, Esr2 and Gpr30 in the mPOA and ARC were comparable between the pre- and postpubertal periods. In addition, kisspeptin or GnRH injection overrode estradiol-dependent prepubertal LH suppression, suggesting that estrogen inhibits the kisspeptin-GnRH cascade during the prepubertal period. Thus, estrogen responsive neurons located in the mPOA and ARC may play key roles in estrogen dependent prepubertal restraint of GnRH/LH secretion in female rats. PMID- 26004303 TI - Detection of carbon monoxide poisoning that occurred before a house fire in three cases. AB - In our institutes, we perform a quantitative evaluation of volatile hydrocarbons in post-mortem blood in all fatal fire-related cases using headspace gas chromatography mass spectrometry. We previously reported that benzene concentrations in the blood were positively correlated with carbon monoxide hemoglobin (CO-Hb) concentrations in fire-related deaths. Here, we present 3 cases in which benzene concentrations in the blood were not correlated with CO-Hb concentrations. A high CO-Hb concentration without a hydrocarbon component, such as benzene, indicates that the deceased inhaled carbon monoxide that was not related to the smoke from the fire. Comparing volatile hydrocarbons with CO-Hb concentrations can provide more information about the circumstances surrounding fire-related deaths. We are currently convinced that this is the best method to detect if carbon monoxide poisoning occurred before a house fire started. PMID- 26004305 TI - Considerations About Pollen Used for the Production of Allergen Extracts. AB - Pollen is a biological product obtained to manufacture tree, weed, and grass allergen extracts, used to diagnose and treat allergies. Genetic and environmental factors affect the composition of pollen, e.g., the plant varieties from which pollen are obtained, weather, and levels of air pollution during plant growth. Therefore, appropriate guidelines and training of personnel to perform the activities associated with pollen are essential to produce appropriate allergen extracts. Various regulatory institutions, which vary in different countries, including the Food and Drug Administration (FDA) in the USA, control how such products should be produced. For example, the FDA regulates the manufacturing of pollen extracts but not the quality of the pollen used to prepare them, relying on each manufacturer to set its own standards to do so. To the contrary, European regulatory agencies, including the European Medicines Agency, control both the quality of the pollen and the manufacturing process to produce pollen extracts. Regulatory agencies, allergen manufacturers, scientific institutions, and pollen collection entities should collaborate to develop and implement guidelines appropriate for worldwide use for both the collection and processing of pollen raw materials. This article provides an overview of the subject of pollen for use in allergen extracts. PMID- 26004307 TI - Structural insights into viral IRES-dependent translation mechanisms. AB - A diverse group of viruses subvert the host translational machinery to promote viral genome translation. This process often involves altering canonical translation initiation factors to repress cellular protein synthesis while viral proteins are efficiently synthesized. The discovery of this strategy in picornaviruses, which is based on the use of internal ribosome entry site (IRES) elements, opened new avenues to study alternative translational control mechanisms evolved in different groups of RNA viruses. IRESs are cis-acting RNA sequences that adopt three-dimensional structures and recruit the translation machinery assisted by a subset of translation initiation factors and various RNA binding proteins. However, IRESs present in the genome of different RNA viruses perform the same function despite lacking conservation of primary sequence and secondary RNA structure, and differing in host factor requirement to recruit the translation machinery. Evolutionary conserved motifs tend to preserve sequences impacting on RNA structure and RNA-protein interactions important for IRES function. While some motifs are found in various picornavirus IRESs, others occur only in one type reflecting specialized factor requirements. This review is focused to describe recent advances on the principles and RNA structure features of picornavirus IRESs. PMID- 26004306 TI - Non respiratory symptoms in asthma as possible predictors of exacerbations. PMID- 26004304 TI - Obstructive Sleep Apnea Risk, Asthma Burden, and Lower Airway Inflammation in Adults in the Severe Asthma Research Program (SARP) II. AB - BACKGROUND: Obstructive sleep apnea (OSA) may worsen asthma, but large studies are lacking and the underlying mechanisms are unknown. OBJECTIVE: The objective of this study was to determine the prevalence of OSA risk among patients with asthma of different severity compared with normal controls (NC), and among asthmatics, to test the relationship of OSA risk with asthma burden and airway inflammation. METHODS: Subjects with severe (SA, n = 94) and nonsevere asthma (NSA, n = 161), and NC (n = 146) were recruited in an add-on substudy, to the observational Severe Asthma Research Program (SARP) II; subjects completed sleep quality, sleepiness and OSA risk (Sleep Apnea scale of the Sleep Disorders Questionnaire [SA-SDQ]) questionnaires, and clinical assessments. Sputum was induced in a subset of asthmatics. RESULTS: Relative to NC, despite similar sleep duration, the subjects with SA and NSA had worse sleep quality, were sleepier, and had higher SA-SDQ scores. Among asthmatics, higher SA-SDQ was associated with increased asthma symptoms, beta-agonist use, health care utilization, and worse asthma quality of life. A significant association of SA-SDQ with sputum polymorphonuclear cells% was noted: each increase in SA-SDQ by its standard deviation (6.85 units) was associated with a rise in % sputum neutrophils of 7.78 (95% CI 2.33-13.22, P = .0006), independent of obesity and other confounders. CONCLUSIONS: OSA symptoms are more prevalent among asthmatics, in whom they are associated with higher disease burden. OSA risk is associated with a neutrophilic airway inflammation in asthma, which suggests that OSA may be an important contributor to the neutrophilic asthma. Further studies are necessary to confirm these findings and better understand the mechanistic underpinnings of this relationship. PMID- 26004308 TI - [Pathology of the mediastinum. Case 1. Primary mediastinal large B-cell lymphoma]. PMID- 26004309 TI - [An unexpected Warthin's tumor]. PMID- 26004310 TI - [Pathology of the mediastinum. Case 4. Type B2 thymoma]. PMID- 26004311 TI - Effects of orthognathic surgery on psychological status of patients with jaw deformities. AB - The purpose of this study was to determine the effect of orthognathic surgery on psychological status. The subjects were 119 patients (38 males and 81 females, mean age 25.5+/-9.4 years) who underwent orthognathic surgery. They were divided into class III (84 patients), class II (20 patients), and class I (15 patients) groups according to the anteroposterior skeletal pattern, and they were also divided into an asymmetry group (51 patients) and a symmetry group (68 patients). We assessed psychological status using the Minnesota Multiphasic Personality Inventory (MMPI) before surgery and at more than 6 months after surgery. The MMPI scores for the depression, hysteria, psychasthenia, and social introversion scales were significantly higher than standard values before surgery, and the hypomania scale significantly lower. The cannot say scale, depression scale, and hysteria scale decreased significantly after surgery. A comparison of MMPI scores among the groups showed the depression scale in the class III group to be higher than those in the class I and II groups; there was no significant difference between the asymmetry and symmetry groups. In conclusion, orthognathic surgery has a positive influence on the psychological status of patients with jaw deformities, especially patients with skeletal class III malocclusion. PMID- 26004312 TI - Acute non-occlusive uterine ischemia: a rare complication of coronary bypass surgery. PMID- 26004314 TI - A novel use for testosterone to treat central sensitization of chronic pain in fibromyalgia patients. AB - Fibromyalgia is a diffuse chronic pain condition that occurs predominantly in women and may be under-reported in men. Symptoms include a loss of feeling of well-being and generalized widespread flu-like muscle aches and pain that fail to resolve due to central sensitization of nociceptive neurons. It has commonalities with a myriad of other chronic pain conditions which include PTSD, "Gulf War Syndrome", and various stress-induced conditions caused, for example, by viral infection, emotional or physical stress, trauma, combat, accident or surgery. It is not understood why some individuals are susceptible to this condition and others are not. White et al., elsewhere in this issue, present a clinical feasibility study designed to test the hypothesis that 1) low or deficient testosterone serum levels are linked to a high risk for an inflamed nociceptive nervous system and resultant chronic pain states, and 2) a testosterone transdermal gel applied once a day by fibromyalgia patients can be an effective therapeutic against chronic pain. Here, a short profile of fibromyalgia is provided along with a brief summary of best practices currently recommended by clinical specialists. The link between testosterone and pain is then discussed, with an overview of scientific studies that lay the foundation for testosterone as a possible important additional therapeutic that has the potential to be safely administered and effective but also avoid the adverse effects of other therapeutics. Finally, novel mechanisms by which testosterone therapy is likely to down-modulate pain signaling are proposed. PMID- 26004313 TI - Ganoderic acid C1 isolated from the anti-asthma formula, ASHMITM suppresses TNF alpha production by mouse macrophages and peripheral blood mononuclear cells from asthma patients. AB - Asthma is a heterogeneous airway inflammatory disease, which is associated with Th2 cytokine-driven inflammation and non-Th2, TNF-alpha mediated inflammation. Unlike Th2 mediated inflammation, TNF-alpha mediated asthma inflammation is generally insensitive to inhaled corticosteroids (ICS). ASHMITM, aqueous extract of three medicinal herbs-Ganoderma lucidum (G. lucidum), Sophora flavescens Ait (S. flavescens) and Glycyrrhiza uralensis Fischer (G. uralensis), showed a high safety profile and was clinically beneficial in asthma patients. It also suppresses both Th2 and TNF-alpha associated inflammation in murine asthma models. We previously determined that G. uralensis flavonoids are the key active compounds responsible for ASHMITM suppression of Th2 mediated inflammation. Until now, there are limited studies on anti-TNF-alpha compounds presented in ASHMITM. The objective of this study was to isolate and identify TNF-alpha inhibitory compounds in ASHMITM. Here we report that G. lucidum, but not the other two herbal extracts, S. flavescens or G. uralensis inhibited TNF-alpha production by murine macrophages; and that the methylene chloride (MC)-triterpenoid-enriched fraction, but not the polysaccharide-enriched fraction, contained the inhibitory compounds. Of the 15 triterpenoids isolated from the MC fraction, only ganoderic acid C1 (GAC1) significantly reduced TNF-alpha production by murine macrophages (RAW 264.7 cells) and peripheral blood mononuclear cells (PBMCs) from asthma patients. Inhibition was associated with down-regulation of NF-kappaB expression, and partial suppression of MAPK and AP-1 signaling pathways. Ganoderic acid C1 may have potential for treating TNF-alpha mediated inflammation in asthma and other inflammatory diseases. PMID- 26004315 TI - Suppression of the TRIF-dependent signaling pathway of Toll-like receptor by CDr10b in RAW264.7 macrophages. AB - Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. TLR signaling pathways can be largely classified as either myeloid differential factor 88 (MyD88)- or toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent pathways. Compound of Designation red 10 binding (CDr10b) was synthesized to investigate its role in neuroinflammatory diseases. This study was conducted to determine whether CDr10b can affect TLR signaling pathways. CDr10b suppressed NF-kappaB activation as well as COX-2 and iNOS expression induced by TLR3 or TLR4 agonists. CDr10b also suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. These results indicate that CDr10b can modulate the TRIF-dependent pathway of TLRs and has the potential to become a new therapeutic drug for chronic inflammatory diseases. PMID- 26004316 TI - Perfluorooctane sulfonate mediates microglial activation and secretion of TNF alpha through Ca2+-dependent PKC-NF-kB signaling. AB - Perfluorooctane sulfonate (PFOS), a ubiquitous pollutant widely found in the environment and biota, can cause numerous adverse effects on human health. In recent years, PFOS's toxic effects on the central nervous system (CNS) have been shown. However, we still have a lot to study in the underlying molecular mechanism of PFOS's neurotoxicity. Microglia, the innate immune cells of CNS, are critically implicated in various neurological diseases caused by pro-inflammatory mediators. In our research, we found that HAPI microglia secreted tumor necrosis factor-alpha (TNF-alpha) after PFOS exposure in time-dependent and dose-dependent way. We also discovered that intracellular concentration of free Ca(2+) ([Ca(2+)]i) significantly increased after PFOS treatments. It was noteworthy here the secretion of TNF-alpha mediated by PFOS was blocked by Ca(2+) inhibitor and protein kinase C (PKC) inhibitor. Besides these, we had learned as well that PFOS brought about the up-regulation of phosphorylated nuclear factor kappa B (NF-kB) p65 expression and accelerated degradation of NF-kappaB inhibitor alpha (IkBalpha), however, these effects could be attenuated or blocked by Ca(2+) inhibitor and PKC inhibitor. Finally, through treating SH-SY5Y cells with PFOS treated microglial conditioned medium, we demonstrated that TNF-alpha mediated neuronal apoptosis. To sum up, our research had shown, for the first time, that the distinct TNF-alpha secretion brought by PFOS in HAPI microglia, was achieved through the Ca(2+)-dependent PKC-NF-kB signaling, subsequently participating in neuronal loss. PMID- 26004317 TI - Treatment of pain in fibromyalgia patients with testosterone gel: Pharmacokinetics and clinical response. AB - To test our hypothesis that testosterone deficiency plays an important role in chronic pain, a Phase I/II pilot study was initiated with 12 fibromyalgia patients to verify that a daily dose for 28days with transdermal testosterone gel would 1) significantly and safely increase mean serum testosterone concentrations from low baseline levels to mid/high-normal levels, and 2) effectively treat the pain and fatigue symptoms of fibromyalgia. Pharmacokinetic data confirmed that serum free testosterone concentrations were raised significantly above baseline levels, by assessment of maximum hormone concentration (Cmax) and area under the curve (AUC) parameters: free testosterone Cmax was significantly raised from a mean of 2.64pg/mL to 3.91pg/mL (p<0.05), and 24hour free testosterone AUC was significantly raised from a mean of 35.0pg-hr/mL to 53.89pg-hr/mL. Assessment of the typical symptoms of fibromyalgia by patient questionnaire and tender point exam demonstrated significant change in: decreased muscle pain, stiffness, and fatigue, and increased libido during study treatment. These results are consistent with the hypothesized ability of testosterone to relieve the symptoms of fibromyalgia. Symptoms not tightly related to fibromyalgia were not improved. PMID- 26004318 TI - Transcriptome analysis reveals strong and complex antiviral response in a mollusc. AB - Viruses are highly abundant in the oceans, and how filter-feeding molluscs without adaptive immunity defend themselves against viruses is not well understood. We studied the response of a mollusc Crassostrea gigas to Ostreid herpesvirus 1 uVar (OsHV-1MUVar) infections using transcriptome sequencing. OsHV 1MUVar can replicate extremely rapidly after challenge of C. gigas as evidenced by explosive viral transcription and DNA synthesis, which peaked at 24 and 48 h post-inoculation, respectively, accompanied by heavy oyster mortalities. At 120 h post-injection, however, viral gene transcription and DNA load, and oyster mortality, were greatly reduced indicating an end of active infections and effective control of viral replication in surviving oysters. Transcriptome analysis of the host revealed strong and complex responses involving the activation of all major innate immune pathways that are equipped with expanded and often novel receptors and adaptors. Novel Toll-like receptor (TLR) and MyD88 like genes lacking essential domains were highly up-regulated in the oyster, possibly interfering with TLR signal transduction. RIG-1/MDA5 receptors for viral RNA, interferon-regulatory factors, tissue necrosis factors and interleukin-17 were highly activated and likely central to the oyster's antiviral response. Genes related to anti-apoptosis, oxidation, RNA and protein destruction were also highly up-regulated, while genes related to anti-oxidation were down-regulated. The oxidative burst induced by the up-regulation of oxidases and severe down regulation of anti-oxidant genes may be important for the destruction of viral components, but may also exacerbate oyster mortality. This study provides unprecedented insights into antiviral response in a mollusc. The mobilization and complex regulation of expanded innate immune-gene families highlights the oyster genome's adaptation to a virus-rich marine environment. PMID- 26004319 TI - Temperature regulates circadian rhythms of immune responses in red swamp crayfish Procambarus clarkii. AB - As an ectothermic animal, crayfish immunity and their resistance to pathogen can be significantly affected by environmental factors such as light and temperature. It has been found for a long time that multiple immune parameters of animals and human are circadian-regulated by light-entrained circadian rhythm. Whether temperature also affects the immune rhythm of animals still remains unclear. In the present study, we investigated the effect of temperature cycles on the rhythm of crayfish immunity and their resistance. Survival experiments demonstrated that temperature cycles of 24 degrees C and 18 degrees C effectively entrained the circadian rhythm of crayfish resistance to Aeromonas hydrophila in constant dark. After being exposed to temperature cycles, the crayfish injected at different time points exhibited significant difference in resistance to A. hydrophila. Bacterial growth and total hemocyte count (THC) also showed circadian variation in crayfish subjected to temperature cycles, but phenoloxidase (PO) activity didn't show rhythmic change under the same conditions. Quantitative real-time PCR revealed that basal expression of crustin1 and astacidin in crayfish subjected to temperature cycles was circadian-rhythmic, but induced expression by A. hydrophila didn't show the same rhythm. In contrast, crayfish maintained at constant temperature showed completely arrhythmic in bacterial resistance, immune parameters mentioned above and the expression of antimicrobial peptides. The results present here collectively indicated that temperature cycles entrained circadian rhythm of some immune parameters and shaped crayfish resistance to bacteria. PMID- 26004320 TI - Prospective assessment and validation of rhythmic and periodic pattern detection in NeuroTrend: A new approach for screening continuous EEG in the intensive care unit. AB - BACKGROUND: NeuroTrend is a computational method that analyzes long-term scalp EEGs in the ICU according to ACNS standardized critical care EEG terminology (CCET) including electrographic seizures. At present, it attempts to become a screening aid for continuous EEG (cEEG) recordings in the ICU to facilitate the review process and optimize resources. METHODS: A prospective multicenter study was performed in two neurological ICUs including 68 patients who were subjected to video-cEEG. Two reviewers independently annotated the first minute of each hour in the cEEG according to CCET. These segments were also screened for faster patterns with frequencies higher than 4 Hz. The matching annotations (2911 segments) were then used as gold standard condition to test sensitivity and specificity of the rhythmic and periodic pattern detection of NeuroTrend. RESULTS: Interrater agreement showed substantial agreement for localization (main term 1) and pattern type (main term 2) of the CCET. The overall detection sensitivity of NeuroTrend was 94% with high detection rates for periodic discharges (PD = 80%) and rhythmic delta activity (RDA = 82%). Overall specificity was moderate (67%) mainly because of false positive detections of RDA in cases of general slowing. In contrast, a detection specificity of 88% for PDs was reached. Localization revealed only a slight agreement between reviewers and NeuroTrend. CONCLUSIONS: NeuroTrend might be a suitable screening tool for cEEG in the ICU and has the potential to raise efficiency of long-term EEG monitoring in the ICU. At this stage, pattern localization and differentiation between RDA and general slowing need improvement. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26004321 TI - Low frequency nonevolving generalized periodic epileptiform discharges and the borderland of hypoxic nonconvulsive status epilepticus in comatose patients after cardiac arrest. AB - To explore the EEG boundary of nonconvulsive status epilepticus (NCSE) and the concept of "possible NCSE", we studied 14 consecutive patients with <= 2-Hz nonevolving periodic generalized epileptiform discharges (GPDs) in their first EEG after out of hospital cardiac arrest (OHCA). The pattern was associated with myoclonus in 11 patients. EG reactivity to antiseizure drugs (benzodiazepines and propofol), but without clinical improvement, was noted in 8 patients, satisfying the diagnostic criteria of "possible NCSE". Resolution of GPDs and emergence of physiological rhythms in follow-up EEGs and/or subsequent clinical improvement were noted in 6 of them, strongly suggesting that the initial slow nonevolving GPD pattern reflected NCSE significantly contributing to their coma. Background rhythms from 10 to 90% of the periods between GPDs were noted in 9 patients and appeared to correlate with reactivity of the GPD pattern to antiseizure drugs when 20% or more. Ten patients died, and four were discharged to longer care rehabilitation centers. Although based on few observations, preliminary evidence appears to indicate that in this context, nonevolving GPD frequencies as low as 0.8 Hz can reflect clinically significant NCSE and, therefore, warrant appropriate testing for possible reactivity. There is also some preliminary indication that background rhythms may be another important diagnostic and, perhaps, prognostic indicator, but this needs to be tested in large prospective studies. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26004322 TI - A single-cell model of PIP3 dynamics using chemical dimerization. AB - Most cellular processes are driven by simple biochemical mechanisms such as protein and lipid phosphorylation, but the sum of all these conversions is exceedingly complex. Hence, intuition alone is not enough to discern the underlying mechanisms in the light of experimental data. Toward this end, mathematical models provide a conceptual and numerical framework to formally evaluate the plausibility of biochemical processes. To illustrate the use of these models, here we built a mechanistic computational model of PI3K (phosphatidylinositol 3-kinase) activity, to determine the kinetics of lipid metabolizing enzymes in single cells. The model is trained to data generated upon perturbation with a reversible small-molecule based chemical dimerization system that allows for the very rapid manipulation of the PIP3 (phosphatidylinositol 3,4,5-trisphosphate) signaling pathway, and monitored with live-cell microscopy. We find that the rapid relaxation system used in this work decreased the uncertainty of estimating kinetic parameters compared to methods based on in vitro assays. We also examined the use of Bayesian parameter inference and how the use of such a probabilistic method gives information on the kinetics of PI3K and PTEN activity. PMID- 26004323 TI - Enzyme-functionalized vascular grafts catalyze in-situ release of nitric oxide from exogenous NO prodrug. AB - Nitric oxide (NO) is an important signaling molecule in cardiovascular system, and the sustained release of NO by endothelial cells plays a vital role in maintaining patency and homeostasis. In contrast, lack of endogenous NO in artificial blood vessel is believed to be the main cause of thrombus formation. In this study, enzyme prodrug therapy (EPT) technique was employed to construct a functional vascular graft by immobilization of galactosidase on the graft surface. The enzyme-functionalized grafts exhibited excellent catalytic property in decomposition of the exogenously administrated NO prodrug. Localized and on demand release of NO was demonstrated by in vitro release assay and fluorescent probe tracing in an ex vivo model. The immobilized enzyme retained catalytic property even after subcutaneous implantation of the grafts for one month. The functional vascular grafts were implanted into the rat abdominal aorta with a 1 month monitoring period. Results showed effective inhibition of thrombus formation in vivo and enhancement of vascular tissue regeneration and remodeling on the grafts. Thus, we create an enzyme-functionalized vascular graft that can catalyze prodrug to release NO locally and sustainably, indicating that this approach may be useful to develop new cell-free vascular grafts for treatment of vascular diseases. PMID- 26004324 TI - SMFM Statement: benefit of antihypertensive therapy for mild-to-moderate chronic hypertension during pregnancy remains uncertain. AB - Chronic hypertension is present in up to 5% of pregnant women and constitutes a major cause of maternal and neonatal morbidity and mortality. The purpose of this document is to summarize the current recommendations regarding use of antihypertensive medications during pregnancy for women with mild-to-moderate chronic hypertension in the setting of the recently published Control of Hypertension in Pregnancy Study (CHIPS). The recently published CHIPS trial was a multicenter international randomized controlled trial comparing "less tight control" to "tight control" of blood pressure for pregnant women with hypertension. The most updated recommendations regarding management of pregnant women with hypertension are found from the American Congress of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy, which are endorsed by the Society of Maternal-Fetal Medicine (SMFM). SMFM recommends that clinicians continue to follow existing guidelines for management of pregnant women with mild to-moderate chronic hypertension due to the fact that the benefits and risks of pharmacologic treatment for these women remain uncertain, and adequately powered randomized controlled trials are needed to address the less common but clinically significant nonsurrogate perinatal outcomes. PMID- 26004325 TI - Discussion. PMID- 26004326 TI - Discussion. PMID- 26004327 TI - The First-in-Man "Si Se Puede" Study for the use of micro-oxygen sensors (MOXYs) to determine dynamic relative oxygen indices in the feet of patients with limb threatening ischemia during endovascular therapy. AB - OBJECTIVE: Patients with limb-threatening ischemia exhibit uneven patterns of perfusion in the foot, which makes it challenging to determine adequate topographic perfusion by angiography alone. This study assessed the feasibility of reporting dynamic relative oxygen indices and tissue oxygen concentration from multiple locations on the foot during endovascular therapy using a novel micro oxygen sensor (MOXY; PROFUSA, Inc, South San Francisco, Calif) approach. METHODS: A prospective, 28-day, single-arm, observational study was performed in 10 patients who underwent endovascular therapy for limb-threatening ischemia. At least 24 hours before therapy, four microsensors were injected in each patient (one in the arm, three in the treated foot). The optical signal from the microsensors corresponded to tissue oxygen concentration. A custom detector on the surface of the skin was used to continuously and noninvasively measure the signals from the microsensors. The ability to locate and read the signal from each injected microsensor was characterized. Oxygen data from the microsensors were collected throughout the revascularization procedure. The timing of therapy deployment was recorded during the procedure to assess its relationship with the microsensor oxygen data. Oxygen data collection and clinical evaluation were performed immediately postoperatively as well as postoperatively on days 7, 14, 21, and 28. RESULTS: The study enrolled 10 patients (50% male) with ischemia (30% Rutherford class 4, 70% Rutherford class 5). Patients were a mean age of 70.7 years (range, 46-90 years), and all were Hispanic of varying origin. Microsensors were successfully read 206 of 212 times (97.2%) in all patients during the course of the study. Microsensors were compatible with intraoperative use in the interventional suite and postoperatively in an office setting. In nine of 10 revascularization procedures, at least one of the three MOXYs showed an immediate change in the dynamic relative oxygen index, correlating to deployed therapy. Moreover, there was a statistically significant increase in the concentration of oxygen in the foot in preoperative levels compared with postoperative levels. No adverse events occurred related to the microsensor materials. CONCLUSIONS: This MOXY approach appears to be safe when implanted in patients with limb-threatening ischemia undergoing endovascular recanalization and is effective in reporting local tissue oxygen concentrations over a course of 28 days. Further testing is needed to determine its potential effect on clinical decision making, both acutely on-table and chronically as a surveillance modality, which ultimately can lead to improved healing and limb salvage. PMID- 26004328 TI - Discussion. PMID- 26004329 TI - Discussion. PMID- 26004330 TI - Ectopic internal carotid artery causing oropharyngeal obstruction. PMID- 26004331 TI - Spontaneous isolated abdominal aortic dissection involving the celiac, superior mesenteric, inferior mesenteric, right renal, left iliac, and right superficial femoral arteries. PMID- 26004333 TI - Is medical advertising always unethical, or does it just seem to be? AB - Dr C. Lever is the undisputed expert in a new endovascular procedure he developed and brought to fruition over the years. Other professionals publishing their results call it by his name, although he has strictly avoided that nomenclature. Lever is at a medical center with several participating hospitals, which boast aggressive ultracompetitive marketing departments. His hospital wants to concentrate on him as proof that the best care is available at their facility. A successful campaign certainly would add to Lever's and perhaps to his group's referrals. He looks at the first advertisement and a Greek god would have been less vaunted but nothing said is untrue. What should he do? A. Ask that all advertising identifying him be discontinued immediately. B.Tell them to hype it up. C. Ask that marketing stick to the facts completely sans hype. D. Check with the Ethics Committee of the hospital. E. Check with the Ethics Committee of the American Medical Association (AMA) or American College of Surgeons or the appropriate surgical subspecialty professional association. PMID- 26004332 TI - Update on intervention versus medical therapy for atherosclerotic renal artery stenosis. AB - Atherosclerotic renal artery stenosis is known to be one of the most common causes of secondary hypertension, and early nonrandomized studies suggested that renal artery stenting (RASt) improved outcomes. The vascular community embraced this less invasive treatment alternative to surgery, and RASt increased in popularity during the late 1990s. However, recent randomized studies have failed to show a benefit regarding blood pressure or renal function when RASt was compared with best medical therapy, creating significant concerns about procedural efficacy. In the wake of these randomized trial results, hypertension and renal disease experts along with vascular interventional specialists now struggle with how to best manage atherosclerotic renal artery stenosis. This review objectively analyzes the current literature and highlights each trial's design weaknesses and strengths. We have provided our recommendations for contemporary treatment guidelines based on our interpretation of the available empirical data. PMID- 26004334 TI - Debate: Whether carotid endarterectomy is safer than stenting in the hyperacute period after onset of symptoms. AB - The carotid artery has been a regular battleground for debates regarding many issues, including appropriate management of symptomatic and asymptomatic lesions, the conduct, timing, and safety of such interventions, and now, whether endarterectomy or stenting is safer in the hyperacute period. Our discussants agree that, as a prophylactic procedure, a carotid intervention should occur early after index symptoms to prevent as many strokes as possible. However, which intervention is best? PMID- 26004335 TI - Editor's commentary. PMID- 26004336 TI - Reply. PMID- 26004337 TI - Regarding "Significant long-term predictors of reintervention following percutaneous subclavian artery revascularization". PMID- 26004338 TI - Regarding "Analysis of EndoAnchors for endovascular aneurysm repair by indications for use". PMID- 26004339 TI - Cushing's syndrome. AB - Chronic exposure to excess glucorticoids results in diverse manifestations of Cushing's syndrome, including debilitating morbidities and increased mortality. Genetic and molecular mechanisms responsible for excess cortisol secretion by primary adrenal lesions and adrenocorticotropic hormone (ACTH) secretion from corticotroph or ectopic tumours have been identified. New biochemical and imaging diagnostic approaches and progress in surgical and radiotherapy techniques have improved the management of patients. The therapeutic goal is to normalise tissue exposure to cortisol to reverse increased morbidity and mortality. Optimum treatment consisting of selective and complete resection of the causative tumour is necessay to allow eventual normalisation of the hypothalamic-pituitary-adrenal axis, maintenance of pituitary function, and avoidance of tumour recurrence. The development of new drugs offers clinicians several choices to treat patients with residual cortisol excess. However, for patients affected by this challenging syndrome, the long-term effects and comorbidities associated with hypercortisolism need ongoing care. PMID- 26004340 TI - The quality of paper-based versus electronic nursing care plan in Australian aged care homes: A documentation audit study. AB - INTRODUCTION: The nursing care plan plays an essential role in supporting care provision in Australian aged care. The implementation of electronic systems in aged care homes was anticipated to improve documentation quality. Standardized nursing terminologies, developed to improve communication and advance the nursing profession, are not required in aged care practice. The language used by nurses in the nursing care plan and the effect of the electronic system on documentation quality in residential aged care need to be investigated. PURPOSE: To describe documentation practice for the nursing care plan in Australian residential aged care homes and to compare the quantity and quality of documentation in paper based and electronic nursing care plans. METHODS: A nursing documentation audit was conducted in seven residential aged care homes in Australia. One hundred and eleven paper-based and 194 electronic nursing care plans, conveniently selected, were reviewed. The quantity of documentation in a care plan was determined by the number of phrases describing a resident problem and the number of goals and interventions. The quality of documentation was measured using 16 relevant questions in an instrument developed for the study. RESULTS: There was a tendency to omit 'nursing problem' or 'nursing diagnosis' in the nursing process by changing these terms (used in the paper-based care plan) to 'observation' in the electronic version. The electronic nursing care plan documented more signs and symptoms of resident problems and evaluation of care than the paper-based format (48.30 vs. 47.34 out of 60, P<0.01), but had a lower total mean quality score. The electronic care plan contained fewer problem or diagnosis statements, contributing factors and resident outcomes than the paper-based system (P<0.01). Both types of nursing care plan were weak in documenting measurable and concrete resident outcomes. CONCLUSIONS: The overall quality of documentation content for the nursing process was no better in the electronic system than in the paper based system. Omission of the nursing problem or diagnosis from the nursing process may reflect a range of factors behind the practice that need to be understood. Further work is also needed on qualitative aspects of the nurse care plan, nurses' attitudes towards standardized terminologies and the effect of different documentation practice on care quality and resident outcomes. PMID- 26004341 TI - The effect of provider characteristics on the responses to medication-related decision support alerts. AB - BACKGROUND: Improving the quality of prescribing and appropriate handling of alerts remains a challenge for design and implementation of clinical decision support (CDS) and comparatively little is known about the effects that provider characteristics have on how providers respond to medication alerts. OBJECTIVES: To investigate the relationship between provider characteristics and their response to medication alerts in the outpatient setting. DESIGN AND PARTICIPANTS: Retrospective observational study using a prescription log from the automated electronic outpatient system for each of 478 providers using the system at primary care practices affiliated with 2 teaching hospitals, from 2009 to 2011 for six types of alerts. Provider characteristics were obtained from the hospital credentialing system and the Massachusetts Board of Registration in Medicine. MAIN MEASURES: Override rates per 100 prescriptions and 100 alerts. RESULTS: The providers' mean override rates per 100 prescriptions and per 100 alerts were 0.52 (95% confidence interval (CI), 0.46-0.58) and 0.42 (95% CI, 0.38-0.44) respectively. The physicians (n=422) on average overrode drug alerts with rates of 0.48 per 100 drugs and 0.44 per 100 warnings. Univariate analysis revealed that six physician characteristics (physician type, age, number of encounters, medical school ranking, residency hospital ranking, and acceptance of Medicaid) were significantly related to the override rate. Multiple regression showed that house staff were more likely to override than staff physicians (p<0.001), physicians with fewer than 13 average daily encounters were more likely to override than others with more than 13 encounters (p (range), <0.001-0.05), and graduates of the top 5 medical schools were more likely to override than the others (p=0.04). All six predictors together explained 30% and 50% of the variance in override rates, respectively. CONCLUSIONS: Consideration of six specific physician characteristics may help inform interventions to improve prescriber decision-making. PMID- 26004342 TI - Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets. AB - Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), found in cooked meat, is a known food carcinogen that causes several types of cancer, including breast cancer, as PhIP metabolites produce DNA adduct and DNA strand breaks. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity. To date, no study has examined the interaction of PhIP with curcumin in breast epithelial cells. The present study demonstrates the mechanisms by which curcumin inhibits PhIP-induced cytotoxicity in normal breast epithelial cells (MCF-10A). Curcumin significantly inhibited PhIP-induced DNA adduct formation and DNA double stand breaks with a concomitant decrease in reactive oxygen species (ROS) production. The expression of Nrf2, FOXO targets; DNA repair genes BRCA-1, H2AFX and PARP-1; and tumor suppressor P16 was studied to evaluate the influence on these core signaling pathways. PhIP induced the expression of various antioxidant and DNA repair genes. However, co-treatment with curcumin inhibited this expression. PhIP suppressed the expression of the tumor suppressor P16 gene, whereas curcumin co-treatment increased its expression. Caspase-3 and -9 were slightly suppressed by curcumin with a consequent inhibition of cell death. These results suggest that curcumin appears to be an effective anti-PhIP food additive likely acting through multiple molecular targets. PMID- 26004345 TI - Complement genetics and susceptibility to inflammatory disease. Lessons from genotype-phenotype correlations. AB - Different genome-wide linkage and association studies performed during the last 15 years have associated mutations and polymorphisms in complement genes with different diseases characterized by tissue damage and inflammation. These are complex disorders in which genetically susceptible individuals usually develop the pathology as a consequence of environmental triggers. Although complement dysregulation is a common feature of these pathologies, how the disease phenotype is determined is only partly understood. One way to advance understanding is to focus the research in the analysis of the peculiar genotype-phenotype correlations that characterize some of these diseases. I will review here how understanding the functional consequences of these disease-associated complement genetic variants is providing us with novel insights into the underpinning complement biology and a better knowledge of the pathogenic mechanisms underlying each of these pathologies. These advances have important therapeutic and diagnostic implications. PMID- 26004343 TI - Three-dimensional (3D) culture of bone-derived human 786-O renal cell carcinoma retains relevant clinical characteristics of bone metastases. AB - Bone metastases from renal cell carcinoma (RCC) are typically lytic, destructive, and resistant to treatment regimens. Current in vitro models for studying metastasis introduce artifacts that limit their usefulness. Many features of tumors growing in bone are lost when human RCC cells are cultured in two dimensional (2D) plastic substrata. In this study, we established that RCC spheroids, consisting of aggregates of cells, can be grown in a three-dimensional (3D) hyaluronate hydrogel-based culture system. The bone-derived human 786-O RCC subline proliferated and survived long term in these hydrogels. Additionally, RCC spheroids in 3D hydrogels demonstrated lower proliferation rates than their counterparts grown in 2D. Overall, gene expression patterns of RCC spheroids in 3D more closely mimicked those observed in vivo than did those of cells grown in 2D. Of particular importance, selected adhesion molecules, angiogenesis factors, and osteolytic factors that have been shown to be involved in RCC bone metastasis were found to be expressed at higher levels in 3D than in 2D cultures. We propose that the 3D culture system provides an improved platform for RCC bone metastasis studies compared with 2D systems. PMID- 26004346 TI - A nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates GVHD in allogeneic bone marrow transplantation. AB - GVHD is a crucial mortality factor in allogeneic bone marrow transplantation (ABMT). In this paper, we show that dehydroxymethylepoxyquinomicin (DHMEQ), a novel inhibitor of nuclear factor-kappaB, suppresses GVHD, resulting in an improved mortality rate in a mouse ABMT model. Bone marrow cells from C57BL/6 mice (B6 mice) were transplanted into lethally irradiated BALB/c mice. Two weeks later, spleen cells from B6 mice were transplanted into the irradiated BALB/c mice. From one week after the injection of spleen cells, when the mice started to show GVHD, the mice were also injected intraperitoneally daily with DHMEQ or vehicle only (DMSO) for 4 weeks. By 80 days after the ABMT, 6/14 of the vehicle injected mice (43%) had died because of GVHD, whereas all DHMEQ-injected mice survived this observation period and developed milder GVHD than the vehicle injected mice. When regulatory T cells were reduced by the injection of anti folate receptor 4 (FR4) antibody, the effects of DHMEQ were reduced. These findings suggest that administration of DHMEQ could become a new strategy for preventing fatalities from GVHD. PMID- 26004344 TI - Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism. AB - One of the proposed mechanisms for tumor proliferation involves redox signaling mediated by reactive oxygen species such as superoxide and hydrogen peroxide generated at moderate levels. Thus, the antiproliferative and anti-tumor effects of certain antioxidants were attributed to their ability to mitigate intracellular reactive oxygen species (ROS). Recent reports support a role for mitochondrial ROS in stimulating tumor cell proliferation. In this study, we compared the antiproliferative effects and the effects on mitochondrial bioenergetic functions of a mitochondria-targeted cationic carboxyproxyl nitroxide (Mito-CP), exhibiting superoxide dismutase (SOD)-like activity and a synthetic cationic acetamide analog (Mito-CP-Ac) lacking the nitroxide moiety responsible for the SOD activity. Results indicate that both Mito-CP and Mito-CP Ac potently inhibited tumor cell proliferation. Both compounds altered mitochondrial and glycolytic functions, and intracellular citrate levels. Both Mito-CP and Mito-CP-Ac synergized with 2-deoxy-glucose (2-DG) to deplete intracellular ATP, inhibit cell proliferation and induce apoptosis in pancreatic cancer cells. We conclude that mitochondria-targeted cationic agents inhibit tumor proliferation via modification of mitochondrial bioenergetics pathways rather than by dismutating and detoxifying mitochondrial superoxide. PMID- 26004347 TI - Strain differences in the immune mechanisms of resistance of immunocompetent rats to pulmonary aspergillosis. AB - Although the relevance of genetically-based variations in susceptibility to pulmonary aspergillosis was shown in immunocompromised mice and is indicated in humans, there is virtually no information concerning variations in antifungal immune responses in resistant individuals. We have shown recently the relevance of proinflammatory cytokine (interferon-gamma/IFN-gamma and interleukin-17/IL-17) responses in resistance to sublethal Aspergillus fumigatus infection of non suppressed Dark Agouti (DA) rats (strain known of a substantial immune reactivity to noxious insults). In this study, anti-fungal immune activities of leukocytes recovered from lungs by enzyme digestion (phagocytosis, oxidative activity, hyphal killing, CD11b expression, as well as production of IFN-gamma, IL-17 and Th2/anti-inflammatory cytokines interleukin-4/IL-4 and interleukin-10/IL-10) were investigated in less reactive Albino Oxford (AO) and compared to DA rats. Elimination of fungus from lungs of AO rats was associated with lower degree of leukocyte infiltration and of the majority of their basic effector activities in comparison to DA rats. Lower production of IFN-gamma by pulmonary leukocytes was observed early (day 1) post infection (p.i.) in AO compared to DA rats, but without changes in IL-4. Both strains responded to infection by an increase of IL 17 and IL-10, but production of cytokines was higher (from days 7 p.i. and 3 p.i. for IL-17 and IL-10, respectively) in AO compared to DA rats. The levels and pattern of IFN-gamma and IL-4 responses by draining lymph node (dLN) cells were similar in both strains and basically corresponded to those of lung leukocytes. In contrast, similar levels of draining lymph node cell production of IL-17 and IL-10 were observed in both strains with lack of changes in mRNA, what suggests additional stimulation of these cytokines in lungs of AO rats. The knowledge of strain differences in the immune-based strategies in response of immunocompetent hosts to A. fumigatus might contribute to our understanding of variations in underlying mechanisms that enable of resistance to this fungus. PMID- 26004348 TI - Mutation analysis of two families with inherited congenital cataracts. AB - The present study aimed to identify the genetic mutations in two families affected with congenital cataracts. Detailed family histories and clinical data of the family members were recorded. The family members with affected phenotypes were recruited, and candidate gene sequencing was performed to determine the disease-causing mutation. Bioinformatics analysis was performed to predict the function of the mutant gene. Green fluorescent protein-tagged human wild-type CRYAA and GJA8 were sub-cloned, and the mutants were generated by site-directed mutagenesis. A novel mutation, c.416T>C (p.L139P), in CRYAA and a known mutation, c.139G>A (p.D47N), in GJA8 were identified. These mutations co-segregated with all affected individuals in each family and were not observed in the unaffected family members or in unrelated controls. The results of the bioinformatics analysis indicated that the amino acid at position 139 was highly conserved and that the p.L139P mutation was predicted to be damaging, as with p.D47N. Finally, overexpression of the two mutants revealed marked alterations, compared with the wild-type proteins. These results extend the mutation spectrum of CRYAA and provides further evidence that the p.D47N mutation in GJA8 is a hot-spot mutation. PMID- 26004349 TI - Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa. AB - Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides l-fucose and d-mannose and conjugates thereof. Previously, d mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because d-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended d-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl alpha-d-mannoside. PMID- 26004350 TI - Systematic review and meta-analysis of enhanced recovery programmes in gastric cancer surgery. AB - This systematic review and meta-analysis was performed to determine the influence of enhanced recovery programmes (ERPs) on outcomes after gastric cancer surgery. Medline, Embase, the Cochrane library and ClinicalTrials.gov were searched for studies on outcomes of gastrectomy in enhanced recovery or fast-track programmes. The primary outcome measure was post-operative duration of hospital stay (LOHS), and secondary outcome measures were selected based inclusion in two or more studies. Statistical analysis was performed using standardized mean difference (SMD) and odds ratio (OR) as the summary statistics. Fourteen studies, totalling 1676 patients with gastric cancer were analysed, including nine randomized trials. LOHS was significantly shorter after ERP when compared with control patients (CON, SMD -1.10, 95% confidence interval -1.56 to -0.65, p < 0.001), but with significant heterogeneity between studies (I(2) = 93%, p < 0.001). ERP was also associated with reduced serum inflammatory response (CRP: SMD -0.68 (-1.16 to -0.19), p = 0.007; IL-6: SMD -0.62 (-0.94 to -0.29), p < 0.001), less weight loss (SMD -0.79 (-1.11 to -0.46), p < 0.001), and lower cost (SMD -1.02 (-1.59 to -0.45), p < 0.001), as well as a trend toward shorter duration of intravenous infusion (SMD -2.70 (-5.35 to -0.05), p = 0.05). Inclusion in an ERP was not associated with increased post-operative morbidity (OR 0.83 (0.65 to 1.06), p = 0.13) or hospital readmission (OR 1.67 (0.88 to 3.19), p = 0.12). From this review the authors concluded that multimodal, standardized perioperative gastrectomy care appears feasible, safe and cost effective. PMID- 26004351 TI - Effects of microbeam radiation therapy on normal and tumoral blood vessels. AB - Microbeam radiation therapy (MRT) is a new form of preclinical radiotherapy using quasi-parallel arrays of synchrotron X-ray microbeams. While the deposition of several hundred Grays in the microbeam paths, the normal brain tissues presents a high tolerance which is accompanied by the permanence of apparently normal vessels. Conversely, the efficiency of MRT on tumor growth control is thought to be related to a preferential damaging of tumor blood vessels. The high resistance of the healthy vascular network was demonstrated in different animal models by in vivo biphoton microscopy, magnetic resonance imaging, and histological studies. While a transient increase in permeability was shown, the structure of the vessels remained intact. The use of a chick chorioallantoic membrane at different stages of development showed that the damages induced by microbeams depend on vessel maturation. In vivo and ultrastructural observations showed negligible effects of microbeams on the mature vasculature at late stages of development; nevertheless a complete destruction of the immature capillary plexus was found in the microbeam paths. The use of MRT in rodent models revealed a preferential effect on tumor vessels. Although no major modification was observed in the vasculature of normal brain tissue, tumors showed a denudation of capillaries accompanied by transient increased permeability followed by reduced tumor perfusion and finally, a decrease in number of tumor vessels. Thus, MRT is a very promising treatment strategy with pronounced tumor control effects most likely based on the anti-vascular effects of MRT. PMID- 26004352 TI - Preliminary background indoor EMF measurements in Greece. AB - The main purpose of this work was to investigate the fluctuation of Greek indoor electromagnetic field (EMF) intensity values and identify peaks that might occur. The scientific interest is mainly focused on the bands of extremely low-frequency (ELF) magnetic fields and radiofrequency (RF) electric fields which have been suggested to be possibly carcinogenic to humans by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Electromagnetic radiation (EMR) measurements were performed in a variety of indoor dwellings, in Attica and in the islands of Zakynthos and Lesvos. A total number of 4540 measurements were taken in a wide frequency range (50 Hz-2100 MHz) of which 3301 in Attica, 963 in Lesvos and 276 in Zakynthos. Statistical analysis of the data revealed specific statistically significant differences between the mean values of the electric (ELF and RF) but not the magnetic (ELF) field strengths measured at different distances from the EMF source, as well as between some of the mean values of the RF electric field at different bands. Some statistically significant differences between mean electric field values at different geographic locations were also identified. As far as the RF electric field is concerned, the maximum values, in most cases, were below 0.5 V/m, however increased values above 1 V/m and up to 5.6 V/m were occasionally observed. The ELF magnetic field values were lower than 1 MUT. It may be concluded that overall, the observed indoor EMF intensity values remained well below domestic and European established limits. PMID- 26004353 TI - In vitro activity of colistin against biofilm by Pseudomonas aeruginosa is significantly improved under "cystic fibrosis-like" physicochemical conditions. AB - The impact of physicochemical conditions observed in cystic fibrosis (CF) lung on colistin activity against both planktonic and biofilm P. aeruginosa cells was evaluated. MIC, minimum bactericidal concentration (MBC), and minimum biofilm eradication concentration (MBEC) values were assessed against 12 CF strains both under "CF-like" (anaerobiosis, pH6.4) and "standard" (aerobiosis, pH7.4) conditions. The activity of colistin was significantly higher under "CF-like" conditions compared to "standard" ones, both against planktonic (MIC90: 1 and 4 MUg/mL, respectively) and biofilm (MBEC90: 512 and 1.024 MUg/mL, respectively) cells, as confirmed by scanning electron microscopy. Improved activity was not related to biofilm matrix amount. It may be necessary to adequately "rethink" the protocols used for in vitro assessment of colistin activity, by considering physicochemical and microbiological features in the CF lung at the site of infection. This could provide a more favorable therapeutic index, rationale for administration of lower doses, probably resulting in reduced toxicity and emergence of resistant clones. PMID- 26004354 TI - Integrated sediment quality assessment through biomarker responses and bioavailability measurements: Application in Tai Lake, China. AB - A weight of evidence (WoE) framework has been applied to assess sediment quality of a typical freshwater lake, Tai Lake in China, where the sediments were contaminated by various chemicals but showed no acute lethality to the benthic invertebrate, Chironomus dilutus. A quantitative scoring method was employed to integrate three lines of evidence (LoE), including adverse effects in life cycle bioassays, biomarker responses, and bioavailability-based chemical analysis. Six biomarkers were determined in C. dilutus after the exposure to the sediments from Tai Lake and provided sensitive indication of sublethal effects at the molecular level. The biomarkers included cytochrome P450, glutathione S-transferase, carboxylesterase, acetylcholinesterase, catalase, and lipid peroxidation. The changes of the biomarkers were summarized for individual sampling sites by computing the integrated biomarker response (IBR) indices. Complementary information was also confirmed by the interrelationship of the LoEs. The IBR indices gained before pupation correlated well with the impairments of emergence of the midges, and altered acetylcholinesterase was corroborated by the detection of chlorpyrifos, an organophosphate pesticide. The relationship between bioavailable toxic units estimated by Tenax extractable concentrations of chemicals in sediment and the observed toxicity in the midges helped to identify the putative toxicity contributors to C. dilutus. Overall, the WoE method clearly distinguished the contaminated sites and ranked them by the level of contamination. Sediment-associated pesticides, particularly gamma hexachlorocyclohexane and chlorpyrifos, were the possible contributors to chronic toxicity to the midges. PMID- 26004355 TI - Physicochemical and microbiological characterization of cement kiln dust for potential reuse in wastewater treatment. AB - Cement kiln dust (CKD), a byproduct of cement manufacturing process, was collected from Misr Cement Co. at Qena, Egypt. CKD was characterized by X-ray diffraction and FTIR analysis. This byproduct was investigated for its physical chemical characters, antibacterial activities on sewage water and the presence of nematode, parasites and algae in the treated water. The efficiency of CKD-treated water was also examined on Hibiscus sabdarriffa seed germination. Total bacteria, total and fecal coliform, as well as fecal streptococci were completely inhibited by CKD. Interestingly, zinc, manganese, iron, nickel and lead were completely absent from sewage water as these metals precipitated after treatment with 10gl( 1) CKD. On the other hand, among all the tested plant criteria, only root length was significantly reduced by 55% and 15% after zero and 3 days of CKD addition respectively compared to control. Furthermore, plant lipid peroxidation showed no significant differences between treated sewage water and control after zero and 3 days time addition of CKD. Catalase enzyme activity showed significant decrease by 56% and 64%, while peroxidase activity significantly increased up to 49% and 63% compared to untreated sewage after zero and 3 days of treatment, respectively. The absorption of lead, iron and copper by treated and untreated plants showed no significant differences. Chromium ions were highly absorbed (0.075mgl(-1)) by plants irrigated only with treated sewage water at zero time, and decreased gradually to 0.018mgl(-1) after 3 days of CKD addition. This study highlighted the efficiency of cement kiln dust as an antibacterial agent and its ability of scavenging heavy metals leading to the use of treated sewage water in activities such as crop irrigation. PMID- 26004356 TI - Effects of oil spill related chemical pollution on helminth parasites in Mexican flounder Cyclopsetta chittendeni from the Campeche Sound, Gulf of Mexico. AB - During an environmental impact study of an accidental oil spill in the Campeche Sound in October 2007, we examined the helminth parasites of the benthic flatfish Cyclopsetta chittendeni as well as the concentrations of hydrocarbons and heavy metals in the sediment. The aim of this study was to determine the potential effects of these contaminants on the helminth communities of the flatfish. A total of 427 hosts were examined, and 16,895 helminths, representing 17 species, were obtained from two surveys (March and July, 2008). Statistically significant negative associations were observed between the hydrocarbons and helminth parasite abundances using multivariate methods. The results suggest that in October 2007, the oil spill had a strong negative effect on these helminth communities. However, after five months, the impacted stations were re-populated by both the flatfish and helminths. The most likely explanation for this rapid recovery is the rescue effect from non-impacted habitats to impacted stations. PMID- 26004357 TI - Evaluation of proteome alterations induced by cadmium stress in sunflower (Helianthus annuus L.) cultures. AB - The present study evaluates, at a proteomic level, changes in protein abundance in sunflower leaves in the absence or presence (at 50 or 700mg) of cadmium (as CdCl2). At the end of the cultivation period (45 days), proteins are extracted from leaves with phenol, separated by two-dimensional difference gel electrophoresis (2-D DIGE), and excised from the gels. The differential protein abundances (for proteins differing by more than 1.8 fold, which corresponds to 90% variation) are characterized using nESI-LC-MS/MS. The protein content decreases by approximately 41% in plants treated with 700mg Cd compared with control plants. By comparing all groups of plants evaluated in this study (Control vs. Cd-lower, Control vs. Cd-higher and Cd-lower vs. Cd-higher), 39 proteins are found differential and 18 accurately identified; the control vs. Cd higher treatment is that presenting the most differential proteins. From identified proteins, those involved in energy and disease/defense (including stress), are the ribulose bisphosphate carboxylase large chain, transketolase, and heat shock proteins are the most differential abundant proteins. Thus, at the present study, photosynthesis is the main process affected by Cd in sunflowers, although these plants are highly tolerant to Cd. PMID- 26004358 TI - Modulation of cadmium toxicity and enhancing cadmium-tolerance in wheat seedlings by exogenous application of polyamines. AB - Cadmium (Cd) stress causes several negative physiological, biochemical and structural changes due to the oxidative stress caused through the generation of ROS, leading to a reduction in plant growth. To look for an effective method to increase Cd tolerance of wheat seedlings, the effect of presoaking Triticum aestivum L. seeds in spermidine (Spd; 2mM) or spermine (Spm; 2mM) on seedling growth, physiological attributes and antioxidant defence system under 1mM Cd stress were investigated. Spm or Spd alleviated the adverse effects of Cd stress to convergent degrees. Presoaking wheat seeds in either polyamine increased the seedling growth and the activities of antioxidant enzymes compared to the control, but other attributes were slightly affected. Under Cd stress, presoaking seeds in either polyamine significantly increased seedling growth, membrane stability index, relative water content, concentrations of protein, starch, ascorbic acid, total glutathione, Spm and Spd, and the activities of superoxide dismutase and catalase. In contrast, electrolyte leakage, concentrations of proline, total soluble sugars, malondialdehyde, hydrogen peroxide and Cd(2+), and the activities of peroxidase and ascorbate peroxidase were reduced compared to the control. These results are important as the potential of Spd or Spm to alleviate the harmful effects of Cd stress offer an opportunity to increase the resistance of wheat seedlings to growth under Cd stress conditions. PMID- 26004359 TI - Mechanisms of silicon-mediated alleviation of heavy metal toxicity in plants: A review. AB - In present era, heavy metal pollution is rapidly increasing which present many environmental problems. These heavy metals are mainly accumulated in soil and are transferred to food chain through plants grown on these soils. Silicon (Si) is the second most abundant element in the soil. It has been widely reported that Si can stimulate plant growth and alleviate various biotic and abiotic stresses, including heavy metal stress. Research to date has explored a number of mechanisms through which Si can alleviate heavy metal toxicity in plants at both plant and soil levels. Here we reviewed the mechanisms through which Si can alleviate heavy metal toxicity in plants. The key mechanisms evoked include reducing active heavy metal ions in growth media, reduced metal uptake and root to-shoot translocation, chelation and stimulation of antioxidant systems in plants, complexation and co-precipitation of toxic metals with Si in different plant parts, compartmentation and structural alterations in plants and regulation of the expression of metal transport genes. However, these mechanisms might be associated with plant species, genotypes, metal elements, growth conditions, duration of the stress imposed and so on. Further research orientation is also discussed. PMID- 26004365 TI - Antigen-based immunotherapy (AIT) for autoimmune and allergic disease. AB - Autoimmune and allergic diseases are major causes of morbidity. Antigen-based immunotherapy (AIT) is immunologically the most satisfying means of specifically targeting only those T cells driving disease, thereby inducing antigen-specific immune tolerance, with the lowest adverse risk profile. AIT is highly effective in rodent models of T cell-driven inflammation and is now in clinical trials. The range of approaches to applying AIT in the clinic prevents a consensus on the molecular basis for this form of tolerance. In particular, there has been a paucity of information on how pre-activated effector and memory T cells respond to AIT. New, advanced murine models of AIT are beginning to deliver such information at the cellular, biochemical, transcriptional and epigenetic levels. PMID- 26004360 TI - Polo-like kinase 2 regulates angiogenic sprouting and blood vessel development. AB - Angiogenesis relies on specialized endothelial tip cells to extend toward guidance cues in order to direct growing blood vessels. Although many of the signaling pathways that control this directional endothelial sprouting are well known, the specific cellular mechanisms that mediate this process remain to be fully elucidated. Here, we show that Polo-like kinase 2 (PLK2) regulates Rap1 activity to guide endothelial tip cell lamellipodia formation and subsequent angiogenic sprouting. Using a combination of high-resolution in vivo imaging of zebrafish vascular development and a human umbilical vein endothelial cell (HUVEC) in vitro cell culture system, we observed that loss of PLK2 function resulted in a reduction in endothelial cell sprouting and migration, whereas overexpression of PLK2 promoted angiogenesis. Furthermore, we discovered that PLK2 may control angiogenic sprouting by binding to PDZ-GEF to regulate RAP1 activity during endothelial cell lamellipodia formation and extracellular matrix attachment. Consistent with these findings, constitutively active RAP1 could rescue the endothelial cell sprouting defects observed in zebrafish and HUVEC PLK2 knockdowns. Overall, these findings reveal a conserved PLK2-RAP1 pathway that is crucial to regulate endothelial tip cell behavior in order to ensure proper vascular development and patterning in vertebrates. PMID- 26004364 TI - Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome. AB - Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism. PMID- 26004366 TI - New technologies for monitoring human antigen-specific T cells and regulatory T cells by flow-cytometry. AB - T cells orchestrate and execute immune responses against certain antigens recognized by their antigen receptor. They can acquire a highly divers set of functional properties, which provide the basis for immune protection, but also for immune-pathologies and thus represent highly specific diagnostic and therapeutic targets. New cytometric technologies now allow identification and precise characterization of human conventional and regulatory T cells against basically any antigen and even within naive donors. These provide the basis for thorough analyses of immune protection against infections and to tackle unmet challenges such as T cell responses involved in tolerance and/or directed against undefined or complex antigens, that is, in autoimmunity or allergy. Together with the parallel evolution of single cell multi-parameter approaches this has revolutionized the quantitative and qualitative characterization of human T cells, bearing important diagnostic, prognostic or therapeutic potential. PMID- 26004367 TI - Mass transport model through the skin by microencapsulation system. AB - Skin drug delivery can be subdivided into topical and transdermal administration. Transdermal administration can take advantage of chemical and physical strategies that can improve skin permeability and allow drug penetration. In this study, the development of a skin penetration profile was carried out by an in vitro technique for a microencapsulated system of ibuprofen. Release experiments were performed using percutaneous absorption tests to determine the evolution of the principle present in each of the different skin compartments as a function of time. A general kinetic model for a microencapsulated structure as a mass transport system through the skin was applied: [Formula: see text] This model could predict the penetration profile of encapsulated substances through skin from biofunctional textiles as well as estimate the dosage profile of the active principle. The apparent diffusion coefficients found were 1.20 * 10(-7 )cm/s for the stratum corneum and higher for the rest of the skin 6.67 * 10(-6 )cm/s. PMID- 26004368 TI - Microencapsulation of probiotic bacteria using thermo-sensitive sol-gel polymers for powdered infant formula. AB - In this study the application of thermo-sensitive sol-gel polymers in microencapsulation formulation of probiotic bacteria, Bifidobacterium animalis spp lactis, for powdered infant formula (PIF), which is reconstituted at 70 degrees C, has been assessed. A double-layered microcapsule containing hydroxypropyl methyl cellulose (HPMC) as an inner layer and an outer layer, as the smart coating layer, based on a combination of hydroxypropyl cellulose (HPC) and poloxamer was designed. Generally, this specific microencapsulation provided superior protection against the reconstitution temperature. A high molecular weight of HPC and a greater thickness of the smart coating layer resulted in a delayed release of the bacteria from the microcapsules especially in the PIF composition. However, this was compensated by a high stability of the bacteria at 70 degrees C. Both the surface texture and particle size distribution of microcapsules have been respectively characterised by scanning electron microscopy and particle size analysis. PMID- 26004369 TI - Enhanced dissolution and stability of artemisinin by nano-confinement in ordered mesoporous SBA-15 particles. AB - Dissolution of poorly water-soluble drug, Artemisinin (ART), was enhanced by encapsulating the drug particles inside pore channels of ordered mesoporous silica, SBA-15, via co-spray drying. The drug release profiles of ART were investigated by using flow-through cell (USP IV) and in vitro dissolution tester (USP II). The co-spray-dried ART/SBA-15 samples demonstrated significantly improved dissolution rates and supersaturation compared to the untreated ART. The low cytotoxicity effect of ART and SBA-15 on Caco-2 cells after 24 h incubation demonstrated the biocompatibility of ART/SBA-15. Finally, the storage stability of the samples was investigated for 6 months under five different storage conditions. Overall, the solid dispersions exhibited excellent physical stability; however, their chemical stability was affected by humidity regardless of storage temperatures. The formulation of solid dispersions of ART/SBA-15 is potentially safe and an effective approach to enhance the solubility of poorly water-soluble ART. PMID- 26004370 TI - Preparation and cellular targeting study of VEGF-conjugated PLGA nanoparticles. AB - Vascular endothelial growth factor receptor (VEGFR) is over-expressed on a variety of tumour cells and tumour neovasculature, and so becomes well-documented target for cancer treatment. This study was designed to evaluate the cellular targeting and anti-tumor potency of VEGF-conjugated nanoparticles (VEGF-NPs). The poly-lactic-co-glycolic acid nanoparticles were prepared using the emulsion solvent evaporation method and the VEGF was conjugated on surface of nanoparticles by covalent coupling method. The obtained particles were found to be of spherical shape exhibiting a size of 710 nm and VEGF conjugation efficiency was 16.6%. The results in vitro test showed that VEGF-NPs were more associated to Human Umbilical Vein Endothelial Cells by binding to VEGFR. In vitro cell proliferation test, IC50 showed the superior antiproliferative activity of paclitaxel-loaded VEGF-NPs over unconjugated nanoparticles and native paclitaxel due to higher cellular association on tumour cells. So, the VEGF-NPs offer a promising active targeting carrier for tumour selective treatment. PMID- 26004372 TI - A morphologic reappraisal of endoscopically but not histologically apparent polyps and the emergence of the overlooked goblet cell--rich hyperplastic polyp. AB - Goblet cell--rich hyperplastic polyps (GCRHP) are morphologically subtle compared to microvesicular hyperplastic polyps (MVHP) and are believed to be the most commonly unrecognized serrated polyp, though this has not been systematically studied. We hypothesize that a gastrointestinal pathologist's review of endoscopically but not histologically apparent polyps will identify previously missed GCRHPs, a finding that may be clinically significant if the addition of this subtype of serrated polyp contributes to sufficient numeric criteria for a clinical diagnosis of serrated polyposis syndrome (SPS). Two blinded reviews were performed on 160 endoscopically but not histologically apparent polyps by a gastrointestinal pathologist, separated by a 6 month "washout period." A final review diagnosis of GCRHP was applied to all polyps with complete agreement on both reviews. Patient records were then searched to determine if the addition of a GCRHP resulted in sufficient numeric criteria for a clinical diagnosis of SPS. Fourteen (9%) polyps were reclassified as GCRHPs. The majority (n = 12, 86%) were originally called "colonic mucosa with surface hyperplastic change (CMWSHC)." Two polyps (1%) were re-classified as MVHPs. No other serrated or adenomatous polyps were identified. For each patient, the addition of a hyperplastic polyp did not result in a clinical diagnosis of SPS, though one patient fell short of this diagnosis by only one polyp. GCRHPs are the most commonly underdiagnosed serrated polyp and are often called CMWSHC. The addition of previously missed GCRHPs is unlikely to contribute to a diagnosis of SPS in an individual patient. PMID- 26004371 TI - Distinctive role of SIRT1 expression on tumor invasion and metastasis in breast cancer by molecular subtype. AB - The aim of this study was to evaluate silent mating type information regulation 2 homolog 1 (SIRT1) expression levels by subtype and evaluate its predictive power of axillary lymph node metastasis (LNM) and its association with clinical outcome. A total of 427 patients diagnosed with invasive ductal carcinoma were chosen, immunohistochemical staining for SIRT1 expression was performed on tissue microarrays, and in vitro experiments with each intrinsic subtype of human breast cancer cell line were carried out. Increased expression of SIRT1 in hormone receptor-positive breast cancer and HER2 breast cancer subtype significantly correlated with lower risks of LNM. On the contrary, in triple-negative breast cancer, increased SIRT1 expression was more frequently observed in LNM-positive subgroup than LNM-negative subgroup. Combination of statistically significant, independent parameters including SIRT1 revealed predictive performance for LNM with area under the curve of 0.602, 0.587, and 0.726 for hormone receptor positive breast cancer, HER2 breast cancer, and triple-negative breast cancer subtype, respectively. Inhibition of SIRT1 expression with small interfering RNA suppressed tumor invasion in MDA-MB-231, specifically. This is the first study to examine SIRT1 expression in breast cancer by subtype, and we have observed the potentially different role of SIRT1 gene having tumor-suppressive or tumor promoting influence depending on the subtype; thus, different associations between SIRT1 expression and prognosis by subtype should be considered in its target therapy. PMID- 26004373 TI - WHO includes 16 new cancer drugs on list of essential medicines. PMID- 26004374 TI - Androgen deprivation therapy and cognitive impairment? PMID- 26004375 TI - TAS-102 for metastatic refractory colorectal cancer. PMID- 26004376 TI - Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/W(v) mutant mouse colon. AB - Interstitial cells of Cajal (ICC) are mesenchymal cells that are distributed along the gastrointestinal tract and function as pacemaker cells or intermediary cells between nerves and smooth muscle cells. ICC express a receptor tyrosine kinase c-Kit, which is an established marker for ICC. The c-kit gene is allelic with the murine white-spotting locus (W), and some ICC subsets were reported to be missing in heterozygous mutant W/W(v) mice carrying W and W(v) mutated alleles. In this study, the characterization of interstitial cells in the subserosal layer of W/W(v) mice was analyzed by immunohistochemistry and electron microscopy. In the proximal and distal colon of W/W(v) mutant mice, no c-Kit positive cells were detected in the subserosal layer by immunohistochemistry. By electron microscopy, the interstitial cells, which were characterized by the existence of caveolae, abundant mitochondria and gap junctions, were observed in the W/W(v) mutant colon. The morphological characteristics were comparable to those of the multipolar c-Kit positive ICC seen in the subserosa of proximal and distal colon of wild-type mice. Fibroblasts were also located in the same layers, but the morphology of the fibroblasts was distinguishable from that of ICC in wild type mice or of ICC-like cells in W/W(v) mutant mice. Collectively, it is concluded that c-Kit-negative interstitial cells showing a typical ICC ultrastructure exist in the proximal and distal colon of W/W(v) mutant mice. PMID- 26004377 TI - Force-inhibiting effect of Ser/Thr protein phosphatase 2A inhibitors on bovine ciliary muscle. AB - Ciliary muscle is a smooth muscle characterized by a rapid response to muscarinic receptor stimulation and sustained contraction. Although it is evident that these contractions are Ca(2+)-dependent, detailed molecular mechanisms are still unknown. In order to elucidate the role of Ser/Thr protein phosphatase 2A (PP2A) in ciliary muscle contraction, we examined the effects of okadaic acid and other PP2A inhibitors on contractions induced by carbachol (CCh) and ionomycin in bovine ciliary muscle strips (BCM). Okadaic acid inhibited ionomycin-induced contraction, while it did not cause significant changes in CCh-induced contraction. Fostriecin showed similar inhibitory effects on the contraction of BCM. On the other hand, rubratoxin A inhibited both ionomycin- and CCh-induced contractions. These results indicated that PP2A was involved at least in ionomycin-induced Ca(2+)-dependent contraction, and that BCM had a unique regulatory mechanism in CCh-induced contraction. PMID- 26004379 TI - The Link Between Community-Based Violence and Intimate Partner Violence: the Effect of Crime and Male Aggression on Intimate Partner Violence Against Women. AB - Both intimate partner violence (IPV) and community violence are prevalent globally, and each is associated with serious health consequences. However, little is known about their potential links or the possible benefits of coordinated prevention strategies. Using aggregated data on community violence from the Sao Paulo State Security Department (INFOCRIM) merged with WHO multi country study on women's health and domestic violence data, random intercept models were created to assess the effect of crime on women's probability of experiencing IPV. The association between IPV and male aggression (measured by women's reports of their partner's fights with other men) was examined using logistic regression models. We found little variation in the likelihood of male IPV perpetration related to neighborhood crime level but did find an increased likelihood of IPV experiences among women whose partners were involved in male-to male violence. Emerging evidence on violence prevention has suggested some promising avenues for primary prevention that address common risk factors for both perpetration of IPV and male interpersonal violence. Strategies such as early identification and effective treatment of emotional disorders, alcohol abuse prevention and treatment, complex community-based interventions to change gender social norms and social marketing campaigns designed to modify social and cultural norms that support violence may work to prevent simultaneously male-on male aggression and IPV. Future evaluations of these prevention strategies should simultaneously assess the impact of interventions on IPV and male interpersonal aggression. PMID- 26004380 TI - Conversion of polar and non-polar algae oil lipids to fatty acid methyl esters with solid acid catalysts--A model compound study. AB - Bio-based fuels are becoming more and more important due to the depleting fossil resources. The production of biodiesel from algae oil is challenging compared to terrestrial vegetable oils, as algae oil consists of polar fatty acids, such as phospholipids and glycolipids, as well as non-polar triglycerides and free fatty acids common in vegetable oils. It is shown that a single sulphonated solid acid catalyst can perform the esterification and transesterification reactions of both polar and non-polar lipids. In mild reaction conditions (60-70 degrees C) Nafion NR50 catalyst produces methyl palmitate (FAME) from the palmitic acid derivatives of di-, and tri-glyceride, free fatty acid, and phospholipid with over 80% yields, with the glycolipid derivative giving nearly 40% yields of FAME. These results demonstrate how the polar and non-polar lipid derivatives of algal oil can be utilised as feedstocks for biodiesel production with a single catalyst in one reaction step. PMID- 26004378 TI - Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents. AB - Type 2 diabetic men commonly experience erectile dysfunction for which phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) are often recommended. By preventing degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, these inhibitors also enhance arterial vasorelaxant effects of nitric oxide donors (which stimulate cGMP synthesis). In the present work, we confirmed this enhancing effect after co-administration of sildenafil with nitroprusside to freshly-isolated rat tail arterial tissues. However, in the same tissues we also observed that sildenafil does not enhance but rather attenuates vasorelaxant effects of three commonly-used antidiabetic drugs, i.e. the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone. Indeed, sildenafil completely blocked vasorelaxant effects of low concentrations of these drugs. In addition, we found that this same novel anti vasorelaxant interaction of sildenafil with these agents was abolished by either 1) omitting extracellular glucose or 2) inhibiting specific smooth muscle glycolytic pathways; pathways known to preferentially utilize extracellular glucose to fuel certain adenosine triphosphate (ATP)-dependent ion transporters: e.g. ATP-sensitive K channels, sarcoplasmic reticulum Ca-ATPase, plasma membrane Ca-ATPase and Na/K-ATPase. Accordingly, we suspect that altered activity of one or more of these ion transporters mediates the observed attenuating (anti vasorelaxant) interaction of sildenafil with the antidiabetic drugs. The present results are relevant because hypertension is so common and difficult to control in Type 2 diabetes. The present data suggest that sildenafil might interfere with the known antihypertensive potential of metformin and the thiazolidinediones. However, they do not suggest that it will interact with them to cause life threatening episodes of severe hypotension, as can occur when it is co administered with nitrates. PMID- 26004382 TI - Effects of the pretreatment method on high solids enzymatic hydrolysis and ethanol fermentation of the cellulosic fraction of sugarcane bagasse. AB - This work evaluated ethanol production from sugarcane bagasse at high solids loadings in the pretreatment (20-40% w/v) and hydrolysis (10-20% w/v) stages. The best conditions for diluted sulfuric acid, AHP and Ox-B pretreatments were determined and mass balances including pretreatment, hydrolysis and fermentation were calculated. From a technical point of view, the best pretreatment was AHP, which enabled the production of glucose concentrations near 8% with high productivity (3.27 g/Lh), as well as ethanol production from 100.9 to 135.4 kg ethanol/ton raw bagasse. However, reagent consumption for acid pretreatment was much lower. Furthermore, for processes that use pentoses and hexoses separately, this pretreatment produces the most desirable pentoses liquor, with higher xylose concentration in the monomeric form. PMID- 26004381 TI - A comparative study of biodiesel production using methanol, ethanol, and tert butyl methyl ether (MTBE) under supercritical conditions. AB - In this study, biodiesel production under supercritical conditions among methanol, ethanol, and tert-butyl methyl ether (MTBE) was compared in order to elucidate the differences in their reaction behavior. A continuous reactor was employed, and experiments were conducted at various reaction temperatures (270 400 degrees C) and reaction times (3-30 min) and at a fixed pressure of 20 MPa and an oil-to-reactant molar ratio of 1:40. The results showed that under the same reaction conditions, the supercritical methanol method provided the highest yield of biodiesel. At 350 degrees C and 20 MPa, canola oil was completely converted to biodiesel after 10, 30, and 30 min in the case of - supercritical methanol, ethanol, and MTBE, respectively. The reaction kinetics of biodiesel production was also compared for supercritical methanol, ethanol, and MTBE. PMID- 26004383 TI - Borna disease virus infection impacts microRNAs associated with nervous system development, cell differentiation, proliferation and apoptosis in the hippocampi of neonatal rats. AB - MicroRNAs (miRNAs) regulate gene expression by inhibiting transcription or translation and are involved in diverse biological processes, including development, cellular differentiation and tumor generation. miRNA microarray technology is a high-throughput global analysis tool for miRNA expression profiling. Here, the hippocampi of four borna disease virus (BDV)-infected and four non-infected control neonatal rats were selected for miRNA microarray and bioinformatic analysis. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was subsequently performed to validate the dysregulated miRNAs. Seven miRNAs (miR-145*, miR-146a*, miR-192*, miR-200b, miR 223*, miR-449a and miR-505), showed increased expression, whereas two miRNAs (miR 126 and miR-374) showed decreased expression in the BDV-infected group. By RT qPCR validation, five miRNAs (miR-126, miR-200b, miR-374, miR-449a and miR-505) showed significantly decreased expression (P<0.05) in response to BDV infection. Biocarta pathway analysis predicted target genes associated with 'RNA', 'IGF1mTOR', 'EIF2', 'VEGF', 'EIF', 'NTHI', 'extrinsic', 'RB', 'IL1R' and 'IGF1' pathways. Gene Ontology analysis predicted target genes associated with 'peripheral nervous system development', 'regulation of small GTPase-mediated signal transduction', 'regulation of Ras protein signal transduction', 'aerobic respiration', 'membrane fusion', 'positive regulation of cell cycle', 'cellular respiration', 'heterocycle metabolic process', 'protein tetramerization' and 'regulation of Rho protein signal transduction' processes. Among the five dysregulated miRNAs identified by RT-qPCR, miR-126, miR-200b and miR-449a showed a strong association with nervous system development, cell differentiation, proliferation and apoptosis. PMID- 26004384 TI - Identification of a microRNA signature in endothelial cells with mechanical stretch stimulation. AB - The current study aimed to verify an miRNA signature in endothelial cells undergoing mechanical stretch stimulation. In the present study, microarray profiling was conducted in order to identify the differential expression of miRNAs in endothelial cells undergoing mechanical stimulation, compared with unstimulated endothelial cells. The microarray data was then validated by reverse transcription-quantitative polymerase chain reaction. Genes and signaling pathways regulated by the miRNAs were investigated in silico using Gene Ontology and the Kyoto Encyclopedia of Genes or Genomes, which are ontological and network mapping algorithms. The microarray data collected demonstrated that 38 miRNAs exhibited significant differential expression in endothelial cells with mechanical stretch stimulation. Of these, 20 were upregulated and 18 were downregulated. The results from the in silico analysis indicated that the miRNAs identified were participants in mechanical stretch-induced endothelial dysfunction. During the initial stage of vein graft failure, which is induced by endothelial dysfunction, a unique miRNA signature was identified. The identified miRNAs are suggested to be involved in the pathological processes of traumatic injury. PMID- 26004385 TI - The characteristics of intrinsic complex micro-contractile activity in isolated strips of the rat bladder. AB - In the resting and un-stimulated state, the bladder wall is not quiescent and discrete contractile events, microcontractions, can be recorded in almost all species. This activity contributes to the active element of compliance and to the basal resting tension. This intrinsic activity underpins the more complex phasic activity, non-voiding activity (NVA) that can be seen to increase progressively as the bladder is filled. The NVA represents the motor component of a motor sensory system that relays information to the CNS on bladder volume. Despite the importance of this intrinsic motor activity, little is known about the mechanisms involved in its generation and modulation. The present experiments were done on isolated hemi-bladders from normal rats and measurements made of the intrinsic motor activity. Detailed analysis of the resting state reveals the presence of discrete phasic contractile events, micro-contractions that range in amplitude from 0.1-0.6 mN. These events seem to occur randomly and the basal activity has the appearance of 'noise'. An analysis of the frequency amplitude distribution of the contractile events, reveals that the total activity appears to be the sum of a number of discrete contractile units, each generating a phasic contraction about a specific mean value and with characteristic frequency. In a hemi-bladder, there are between 20-30 units generating the activity at rest. Using the timed integral of the activity (product of amplitude and frequency), it was noted that the activity was increased by the muscarinic agonist carbachol, but it was decreased by the beta-adrenergic agonist isoprenaline. Stretching the preparations also increased the activity. Using these observations, a simple model of the structural and functional organisation of the isolated rat bladder is proposed: the wall appears to be arranged into a number of discrete motor units acting independently. However, the activity can be stimulated or inhibited by pharmacological agents and mechanically (stretch). The possible relevance of this activity, its relationship to NVA and in relation to the mode of action of drugs are discussed. [Corrected] PMID- 26004386 TI - Combined effect of chilling and desiccation on survival of Escherichia coli suggests a transient loss of culturability. AB - Dry air carcass chilling regimes used in some Australian meat works, which not only rapidly reduce the temperature of the carcasses but also dry the meat surface initially, are reported to cause reductions in the number of Escherichia coli present on carcasses after processing. This study used a laboratory broth model system to systematically investigate the basis of such reductions by simulating chilling and desiccation profiles observed on carcasses separately and, finally, in combination. Observed growth was compared to the predictions generated by a strain-specific modification of a validated E. coli growth model (Mellefont et al., 2003; Performance evaluation of a model describing the effects of temperature, water activity, pH and lactic acid concentration on the growth of E. coli). Good agreement between observed and predicted growth was evident when chilling or desiccation profiles were simulated individually. However, when chilling and desiccation profiles were applied simultaneously the observed population kinetics deviated from those predicted by the model. An initial reduction in cell numbers, not predicted by the model, was observed followed by an anomalously rapid increase in population density before growth resumed at a rate expected for the conditions imposed. From our analysis of the kinetics of the population changes, we suggest that the initial decrease in cell numbers was unlikely due to cell death, because conditions were growth permissive. Considering all possible explanations from the observed population kinetics, we propose that a temporary loss of the ability to produce colonies on agar plates may occur. These results may explain reports of increases in E. coli numbers two to three days after commencement of chilling, compared to those observed after 16 24h, despite the imposition of growth-preventing temperatures. PMID- 26004388 TI - Bispecific antibodies, nanoparticles and cells: bringing the right cells to get the job done. AB - Pre-arming therapeutic cells with bispecific antibodies (BiAbs) before infusion can home the cells to specific tissue antigens in the body. With the development of nanotechnology, we developed a novel strategy, namely magnetic bispecific cell engager (MagBICE), that combines BiAbs with biodegradable iron nanoparticles. Compared to conventional BiAbs, the latter enables magnetic targeting and imaging. This editorial discusses current knowledge of BiAbs and their applications in targeting activated T cells to cancerous tissues or targeting bone marrow-derived stem cells to myocardial infarction. We will also discuss the fabrication of MagBICE and its application in treating rodents with myocardial infarction. PMID- 26004389 TI - Effects of intermittent aeration on pollutants removal in subsurface wastewater infiltration system. AB - In this study, the pollutant removal performances in two pilot-scale subsurface wastewater infiltration systems (SWISs) with and without intermittent aeration were investigated. Matrix oxidation reduction potential (ORP) results showed that intermittent aeration well developed aerobic conditions in upper matrix and anoxic or anaerobic conditions in the subsequent sections, which resulted in high NH4(+)-N and TN removal. Moreover, intermittent aeration increased removal rates of COD and TP. Microbial populations and enzyme activities analysis proved that intermittent aeration not only obviously boosted the growth and reproduction of bacteria, fungus, actinomyces, nitrifying bacteria and denitrifying bacteria, but also successfully increased nitrate reductase (NR) and nitrite reductase (NIR) in the depth of 80 and 110 cm. The results suggest that the intermittent aeration could be a widespread research and application strategy for achieving the high removal performance in SWISs. PMID- 26004387 TI - Lipoprotein-associated phospholipase A2 and risk of incident cardiovascular disease in a multi-ethnic cohort: The multi ethnic study of atherosclerosis. AB - OBJECTIVE: Prospective studies reporting a positive association of lipoprotein associated phospholipase A2 (Lp-PLA2) mass and activity with incident cardiovascular disease (CVD) have included primarily white individuals. We evaluated associations of Lp-PLA2 and first-time cardiovascular events in a healthy multi-ethnic cohort characterized by presence or absence of baseline subclinical atherosclerosis. METHODS: Lp-PLA2 mass and activity were measured at baseline in 5456 participants in the Multi-Ethnic Study of Atherosclerosis. Individuals were characterized for presence of baseline subclinical disease (coronary artery calcium score > 0 or carotid intima-media thickness value > 80th percentile) and followed prospectively for development of CVD events (coronary heart disease, ischemic stroke, and cardiovascular death). RESULTS: 516 incident CVD events occurred over median follow-up of 10.2 years. In adjusted Cox proportional hazards models, each higher standard deviation of both Lp-PLA2 activity and mass was associated with an increased risk of cardiovascular events; hazard ratios (HR; 95% confidence intervals (CI)) 1.12 (1.01-1.26) for Lp-PLA2 activity and 1.10 (1.01-1.21) for mass. Associations did not differ by subclinical disease status (p-value for interaction 0.99 for Lp-PLA2 activity and 0.32 for Lp-PLA2 mass) and there was no confounding by subclinical atherosclerosis measures. Associations of Lp-PLA2 activity but not mass were weaker in Chinese participants but there were relatively few events among Chinese in race-stratified analysis. CONCLUSION: In this multi-ethnic cohort, Lp-PLA2 was positively associated with CVD risk, regardless of the presence of coronary artery calcium or a thickened carotid-intimal media. PMID- 26004390 TI - Micronutrient dynamics after thermal pretreatment of olive mill solid waste. AB - This study investigated metal dynamics, and their bioavailability, before and after thermal pretreatment of olive mill solid waste (OMSW), using a sequential metal extraction scheme. The 11.5% increase of cobalt in the most available fraction after the pretreatment coupled to the increase of methane production rate have been a good indicator that the OMSW anaerobic digestion might be metal limited due to the lack of cobalt. PMID- 26004391 TI - Screening for aortic aneurysms in patients with coronary artery disease: should it be done? AB - Aneurysmal dilation of the aorta is a clinically silent disease that often presents first with a catastrophic event. As a result, several clinician societies and organizations have recommended screening to detect aneurysms before they rupture. Although screening may reduce mortality, the implementation of screening has been poor. Cardiologists are uniquely positioned to improve this gap as they handle patients with typical risk factors for aneurysmal diseases of the aorta and can endorse and implement screening in a high-risk population. The following article attempts to concisely give a navigational tool to the cardiovascular specialist for her/his role in the diagnosis and management of thoracic and abdominal aortic aneurysms, citing evidence as well as stating opinions on how to improve outcomes in this unique patient population. PMID- 26004392 TI - Low blood and vitreal BDNF, LXA4 and altered Th1/Th2 cytokine balance are potential risk factors for diabetic retinopathy. AB - OBJECTIVE: The study was conducted to observe the serum and vitreous levels of LXA4, BDNF and Th1/Th2 cytokines in type 2 diabetes mellitus (DM) and changes associated with diabetic retinopathy (DR). Further, the in vitro study was performed to analyze the exposure of BDNF and LXA4 on LPS-induced pro inflammatory state in ARPE 19 cells. MATERIALS AND METHODS: Totally 114 individuals were recruited in a prospective case control study. Of these, 27 were type 2 DM cases with no complications, 30 cases were type 2 DM with non proliferative diabetic retinopathy (NPDR), 30 were type 2 DM with proliferative diabetic retinopathy (PDR), and 27 were healthy control. ELISA was done to estimate the serum and vitreous levels of BDNF, VEGF and PEDF. FACS cytometric Bead Array system was used to analyze the serum cytokines. RESULTS: The serum BDNF and LXA4 levels were significantly reduced in both NPDR and PDR cases compared to control (p=0.005, 0.01; p=0.033, 0.015). Serum IL-6 was significantly increased in the PDR group (p=0.04). BDNF showed a significant negative correlation with VEGF levels (r=-0.522, p<0.01) and positive correlation with IL 10 (r=0.67, p<0.05) in serum. A significant odds ratio for the serum BDNF (OR: 3.20, p=0.025) as well as serum IL-6 (OR: 1.244, p=0.042) indicated them as potential risk factors for progression of type 2 DM to DR. A significant decrease in both the LXA4 (p=0.013) and BDNF (p=0.0008) with increase in cytokines IL-6 and IL-10 levels were observed in the vitreous of PDR cases ((p=0.04, 0.01). In vitro studies showed that both LXA4 (10 nmol/L) and BDNF (500 pg) decreased the IL-6 levels (p=0.036, 0.0002), in LPS induced pro-inflammatory condition in ARPE 19 cells, thereby their anti-inflammatory effect. CONCLUSIONS: This study reports that low serum BDNF and higher IL-6 levels are potential risk factors for DR in type 2 DM. This study supports the role of BDNF in modulating the pro- and anti inflammatory cytokines, and low level of BDNF is associated with development of diabetic retinopathy. PMID- 26004393 TI - How long should we continue S-1 as adjuvant chemotherapy for squamous cell carcinoma of the head and neck? AB - CONCLUSION: It appears that patients with SCCHN should be recommended to take S-1 for more than 1 year and, if possible, more than 2 years, as adjuvant chemotherapy for SCCHN. OBJECTIVES: There is no established consensus on the duration of administration of S-1 as adjuvant chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Since it might be difficult to undergo prospective randomized study to identify the optimal duration of the administration period of S-1 without a standard, the authors have undergone a retrospective clinical study to decide the tentative standard of therapeutic duration of S-1 as adjuvant chemotherapy for SCCHN. METHODS: The clinical records of 89 patients with SCCHN who underwent adjuvant chemotherapy with S-1 were investigated. RESULTS: The median duration of S-1 administration as adjuvant chemotherapy for SCCHN was 7 months (range = 0.1-58 months). Disease-free survivals (DFSs) were generally longer when S-1 administration periods were longer. After adjusting for prognostic factors, S-1 administration periods of 24 months or longer showed significantly lower hazard ratios (HRs) than 0-12 months. PMID- 26004394 TI - Mechanotransduction pathways in bone pathobiology. AB - The skeleton is subject to dynamic changes throughout life and bone remodeling is essential for maintenance of bone functionality. The cell populations which predominantly participate in bone and cartilage remodeling, namely osteocytes, osteoblasts, osteoclasts and chondrocytes sense and respond to external mechanical signals and via a series of molecular cascades control bone metabolism and turnover rate. The aforementioned process, known as mechanotransduction, is the underlying mechanism that controls bone homeostasis and function. A wide array of cross-talking signaling pathways has been found to play an important role in the preservation of bone and cartilage tissue health. Moreover, alterations in bone mechanotransduction pathways, due to genetic, hormonal and biomechanical factors, are considered responsible for the pathogenesis of bone and cartilage diseases. Extensive research has been conducted and demonstrated that aberrations in mechanotransduction pathways result in disease-like effects, however only few signaling pathways have actually been engaged in the development of bone disease. The aim of the present review is to present these signaling molecules and cascades that have been found to be mechano-responsive and implicated in bone disease development, as revealed by research in the last five years. In addition, the role of these molecules as prognostic or diagnostic disease markers and their potential as therapeutic targets are also discussed. PMID- 26004395 TI - Adenomatous polyposis coli (APC)-induced apoptosis of HT29 colorectal cancer cells depends on mitochondrial oxidative metabolism. AB - Adenomatous polyposis coli (APC) is a tumor suppressor involved in the Wnt signaling, the primary driving force of the intestinal epithelium homeostasis. Alterations of components of the Wnt pathway, and in most cases mutations of APC, have been reported to promote colorectal cancer (CRC). During differentiation the enterocytes migrate from the crypt to the tip of the villus where they undergo apoptosis thus ensuring the continual renewal of the intestinal mucosa. The differentiation process is characterized by an activation gradient of the Wnt signaling pathway accompanied by a metabolic switch from glycolysis to mitochondrial oxidative phosphorylation along the crypt-villus axis. In the present work, we study the relationship between the expression of wild type APC protein and mitochondrial oxidative metabolism in HT29 colorectal cancer cells, originally carrying endogenous inactive APC alleles. By generating mtDNA-depleted (rho0) APC-inducible HT29 cells, we demonstrate for the first time that the APC dependent apoptosis requires the production of reactive oxygen species (ROS) by the mitochondrial respiratory chain. The possible role of mitochondria as putative target in the prevention and/or therapy of colorectal cancer is herein discussed. PMID- 26004398 TI - Histological grading in colorectal cancer: new insights and perspectives. AB - Poor histological differentiation is currently considered among the adverse histopathological factors associated with unfavourable clinical course of colorectal carcinoma (CRC). At present, the histological grade of CRC is assessed based on the percentage of glandular differentiation in the tumor according to the World Health Organization (WHO) criteria. However the prognostic value of the WHO grading system is limited by significant inter-observer variability in its assessment. In addition, the prognostic significance of WHO grading seems to depend on the microsatellite instability (MSI) status of the tumor. Finally, this grading does not apply to rarer histotypes of colorectal adenocarcinomas, such as the micropapillary, medullary, mucinous and signet ring cell variants. Recently a novel grading system based on the counting of clusters of five or more cells lacking a glandular structure (poorly differentiated clusters) and set in the tumor stroma or at invasive edge has been proposed in CRC. There is evidence that grading based on poorly differentiated clusters (PDC) is more reproducible and has more robust prognostic significance compared to WHO grading in CRC. In the present review we discuss the morphological features, criteria for the assessment, prognostic significance and correlation with biomolecular profiles of grading based on PDC counting in CRC. PMID- 26004399 TI - Use of the Preparedness for Caregiving Scale in Palliative Care: A Rasch Evaluation Study. AB - CONTEXT: Studies have shown that family carers who feel more prepared for the caregiver role tend to have more favorable experiences. Valid and reliable methods are needed to identify family carers who may be less prepared for the role of supporting a person who needs palliative care. OBJECTIVES: The aim of this study was to evaluate the measurement properties of the original English version and a Swedish version of the Preparedness for Caregiving Scale (PCS). METHODS: The sample (n = 674) was taken from four different intervention studies from Australia and Sweden, all focused on improving family carers' feelings of preparedness. Family carers of patients receiving palliative home care were selected, and baseline data were used. The measurement properties of the PCS were evaluated using the Rasch model. RESULTS: Both the English and Swedish versions of the PCS exhibit sound measurement properties according to the Rasch model. The items in the PCS captured different levels of preparedness. The response categories were appropriate and corresponded to the level of preparedness. No significant differential item functioning for age and sex was detected. Three items demonstrated differential item functioning by language but did not impact interpretation of scores. Reliability was high (>0.90) according to the Person Separation Index. CONCLUSION: The PCS is valid for use among family carers in palliative care. Data provide support for its use across age and gender groups as well as across the two language versions. PMID- 26004400 TI - Caregiver Expectations: Predictors of a Worse Than Expected Caregiving Experience at the End of Life. AB - CONTEXT: The gap between informal caregivers' expectations of caregiving at the end of life and their actual caregiving experience has important affective and behavioral consequences. OBJECTIVES: This study analyzes for the first time the characteristics of those caregivers who report a worse or much worse than expected caregiving experience, providing a potential for future targeted intervention into the caregiving experience. METHODS: The South Australian Health Omnibus is an annual, random, face-to-face, and cross-sectional survey. From 2000 to 2007, respondents were asked a range of questions about end-of-life care, including in several years a question about how the caregiving experience compared with caregivers' expectation(s). Family members and friends who reported a worse or much worse than expected caregiving experience were the focus of this analysis. Univariable and multivariable logistic regression models were created to better define this group. RESULTS: Of the 1628 active caregivers for people at the end of life, almost half (48.3%) reported a worse or much worse than expected caregiving experience. A worse or much worse than expected caregiving experience was significantly associated with gender and with level of care provided. Women who provided daily hands-on care were significantly more likely to have a worse than expected experience compared with women who provided intermittent care (odds ratio [OR] 0.65; 95% CI 0.48-0.88; P = 0.005) or rare care (OR 0.39; 95% CI 0.27 0.56; P < 0.001). Of all those providing rare care, women were significantly less likely than men to report a worse than expected caregiving experience (OR 0.61; 95% CI 0.41-0.93; P = 0.020). CONCLUSION: Caregiver expectations represent a novel and important focus for investigation into the caregiver experience. Explicitly eliciting expectations may in future lead to ways of better supporting caregivers. PMID- 26004402 TI - A Multitargeted Treatment Approach for Anemia and Cachexia in Metastatic Castration-Resistant Prostate Cancer. PMID- 26004401 TI - Practical Dyspnea Assessment: Relationship Between the 0-10 Numerical Rating Scale and the Four-Level Categorical Verbal Descriptor Scale of Dyspnea Intensity. AB - CONTEXT: Measurement of dyspnea is important for clinical care and research. OBJECTIVES: To characterize the relationship between the 0-10 Numerical Rating Scale (NRS) and four-level categorical Verbal Descriptor Scale (VDS) for dyspnea assessment. METHODS: This was a substudy of a double-blind randomized controlled trial comparing palliative oxygen to room air for relief of refractory breathlessness in patients with life-limiting illness. Dyspnea was assessed with both a 0-10 NRS and a four-level categorical VDS over the one-week trial. NRS and VDS responses were analyzed in cross section and longitudinally. Relationships between NRS and VDS responses were portrayed using descriptive statistics and visual representations. RESULTS: Two hundred twenty-six participants contributed responses. At baseline, mild and moderate levels of breathlessness were reported by 41.9% and 44.6% of participants, respectively. NRS scores demonstrated increasing mean and median levels for increasing VDS intensity, from a mean (SD) of 0.6 (+/-1.04) for VDS none category to 8.2 (1.4) for VDS severe category. The Spearman correlation coefficient was strong at 0.78 (P < 0.0001). Based on the distribution of NRS scores within VDS categories, we calculated test characteristics of two different cutpoint models. Both models yielded 75% correct translations from NRS to VDS; however, Model A was more sensitive for moderate or greater dyspnea, with fewer misses downcoded. CONCLUSION: There is strong correlation between VDS and NRS measures for dyspnea. Proposed practical cutpoints for the relationship between the dyspnea VDS and NRS are 0 for none, 1 4 for mild, 5-8 for moderate, and 9-10 for severe. PMID- 26004404 TI - In vitro anti-inflammatory and immunomodulatory properties of umbelliprenin and methyl galbanate. AB - Ferula species (Apiaceae) are considered important medicinal plants. The present in vitro study sought to investigate the immunomodulatory and anti-inflammatory properties of terpenoid coumarins isolated from Ferula szowitsiana on immune cells isolated from naive mice and to elucidate possible underlying mechanisms of action. With splenocytes, effects of the agents on PHA-induced proliferation and interleukin (IL)-4 and interferon (IFN)-gamma release were assessed. With peritoneal macrophages, anti-inflammatory potentials were evaluated in lipopolysaccharide (LPS)/IFNgamma-stimulated cells via measures of changes in nitric oxide (NO) and PGE(2) secretion. Expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was also determined via Western blot analysis. The results indicated that umbelliprenin (UMB) and methyl galbanate (MG) reduced remarkably PHA-induced splenocyte proliferation and both preferentially induced T(H)2 IL-4 and suppressed T(H)1 IFNgamma secretion. Each also significantly suppressed LPS-induced production of NO and PGE(2) apparently and also led to reductions in inducible iNOS and COX-expression. To the authors' knowledge, the present study is the first to report on anti-inflammatory and immunomodulatory effects of UMB and MG in vitro. The present results suggest that each could potentially be exploited as a natural immunosuppressant against inflammatory and autoimmune diseases once substantial further toxicological analyses have been done to confirm overall safety in vivo. PMID- 26004403 TI - Characteristics of Hospice Programs With Problematic Live Discharges. AB - CONTEXT: Little is known about how hospice live discharges vary by hospice providers' tax status and chain affiliation. OBJECTIVES: To characterize hospices with high rates of problematic patterns of live discharges. METHODS: Three hospice-level patterns of live discharges were defined as problematic when the facility rate was at the 90th percentile or higher. A hospice with a high rate of patients discharged, hospitalized, and readmitted to hospice was considered to have a problematic live discharge pattern, which we have referred to as burdensome transition. The two other problematic live discharge patterns examined were live discharge in the first seven days of a hospice stay and live discharge after 180 days in hospice. A multivariate logistic model examined variation in the hospice-level rate of each discharge pattern by the hospice's chain affiliation and profit status. This model also adjusted for facility rates of medical diagnoses, nonwhite patients, average age, and the state in which the hospice program is located. RESULTS: In 2010, 3028 hospice programs had 996,208 discharges, with 18.0% being alive. Each proposed problematic pattern of live discharge varied by chain affiliation. For-profit providers without a chain affiliation had a higher rate of burdensome transitions than did for-profit providers in national chains (18.2% vs. 12.1%, P < 0.001), whereas not-for-profit providers had the lowest rate of burdensome transitions (1.4%). About one in three (33.8%) for-profit providers exhibited one or more of these discharge patterns compared with 9.0% of not-for-profit providers. CONCLUSION: Problematic patterns of live discharges are higher among for-profit providers, especially those not affiliated with a hospice chain. PMID- 26004405 TI - Ganglion Cell-Inner Plexiform Layer Thickness in Retinal Diseases: Repeatability Study of Spectral-Domain Optical Coherence Tomography. AB - PURPOSE: To analyze the repeatability of measuring the thickness of the ganglion cell-inner plexiform layer using spectral-domain optical coherence tomography by auto-segmentation in various retinal diseases. DESIGN: Test-retest reliability analysis. METHODS: A total of 180 patients who visited our clinic between April and December 2013 were included. An experienced examiner obtained 2 consecutive measurements from a macular cube 512 * 128 scan. The patients were divided into 3 groups according to central macular thickness. Repeatability was determined by comparing the average, minimum, and 6 sectoral ganglion cell-inner plexiform layer thickness values among groups. RESULTS: Data from 165 of the 180 patients were included in the analysis. Measurement errors occurred in 3 patients (6%) in the macular atrophy group and 12 (20%) in the edema group. The measurement repeatability for ganglion cell-inner plexiform layer thickness was high in the normal eye group (average intraclass correlation coefficient [ICC], 0.994; coefficient of variation [COV], 0.7%; and test-retest variability, 1.1 MUm), relatively low in the macular edema group (average ICC, 0.845; COV, 18.7%; and test-retest variability, 27.8 MUm), and lowest in the macular atrophy group (ICC, 0.610; COV, 30.4%; and test-retest variability, 29.2 MUm) compared to the normal eye group. CONCLUSIONS: The repeatability of ganglion cell-inner plexiform layer thickness measurements was lower in the macular edema and atrophy groups. The impact of changes in macular shape caused by various retinal diseases should be taken into consideration when measuring ganglion cell-inner plexiform layer thickness in other diseases such as glaucoma and neuro-ophthalmology. PMID- 26004406 TI - Inter-expert and intra-expert agreement on the diagnosis and treatment of retinopathy of prematurity. AB - PURPOSE: To evaluate inter-expert and intra-expert agreement on the diagnosis and treatment of retinopathy of prematurity (ROP). DESIGN: Prospective intra- and inter-rater reliability analysis. METHODS: In this multicenter study, 260 wide field digital photographs of 52 patients were presented to 7 recognized ROP experts on 2 consecutive assessment days 8 weeks apart. Experts were asked to assess the patients for ROP stage, presence of plus disease, presence of aggressive posterior ROP, necessity for treatment, and suggested treatment. Agreement levels were measured with Fleiss' kappa and Cohen's kappa. RESULTS: Inter-expert agreement was fair for the ROP stage (kappa = 0.24), plus disease (kappa = 0.32), and aggressive posterior ROP (kappa = 0.35); moderate for the necessity for treatment (kappa = 0.41); and fair for the kind of treatment (kappa = 0.38). Perfect inter-expert agreement was found in 9.6% of all patients for ROP stage 0-5, 45.1% for >= stage 2 ROP, 17.3% for plus disease, 57.7% for aggressive posterior ROP, and 25% for the necessity for treatment. Intra-expert agreement was higher than inter-expert agreement and was moderate for the ROP stage (kappa = 0.56) and plus disease (kappa = 0.51), moderate to substantial for aggressive posterior ROP (kappa = 0.60), moderate for the necessity for treatment (kappa = 0.47), and substantial for the kind of treatment (kappa = 0.63). CONCLUSIONS: ROP diagnosis and treatment decisions differ between experts and by 1 expert made on different days, indicating that the grading process is subjective and there is an observer bias when diagnosing ROP. These results could influence current practice in ROP assessment and training, and prompt further refinement of international ROP guidelines. PMID- 26004408 TI - The regulation of miRNAs in inflammation-related carcinogenesis. AB - Chronic inflammation plays important roles in the initiation and development of various cancers, particularly gastrointestinal cancer. Cancer is characterized by stepwise accumulation of genetic and epigenetic alterations of genes. As a high risk factor for cancer, chronic inflammatory response produces great amount of mediators, including cytokines, reactive oxygen and nitrogen species, proteinases, which can induce genetic and epigenetic changes of cancer-associated genes and pathways. Furthermore, inflammation also modulates the expression of miRNAs that not only regulate the expression of tumor-related proteins but also enhance the tumor-promoting inflammatory process. In the current review, we summarize the mechanisms by which inflammatory mediators and signaling regulate the biosynthesis of miRNAs, as well as the involvement of miRNAs in the feedback loops promoting inflammation-associated carcinogenesis. PMID- 26004409 TI - Hydrogen sulfide-based anti-inflammatory and chemopreventive therapies: an experimental approach. AB - Hydrogen sulfide has potent anti-inflammatory and cytoprotective properties. In the gastrointestinal tract, hydrogen sulfide contributes significantly to mucosal defence and responses to injury. This includes promotion of resolution of inflammation and healing. Inhibition of hydrogen sulfide synthesis increases the susceptibility of the gastrointestinal mucosa to injury and delays healing processes. The beneficial effects of hydrogen sulfide have been exploited in the design of novel anti-inflammatory drugs that cause negligible gastrointestinal damage. Nonsteroidal anti-inflammatory drugs are known to be effective, when used chronically, in reducing the incidence of several types of cancer. However, the toxicity of these drugs, particularly in the gastrointestinal tract, greatly limits this use. On the other hand, the gastrointestinal-safe, hydrogen sulfide releasing anti-inflammatories show great promise for chemoprevention of cancers. This paper reviews the evidence supporting important anti-inflammatory and cytoprotective effects of hydrogen sulfide, particularly in the gastrointestinal tract. Also reviewed are the approaches taken to develop safer anti-inflammatory and cancer chemopreventive drugs by exploiting the beneficial effects of hydrogen sulfide. PMID- 26004407 TI - Inflammation fuels tumor progress and metastasis. AB - Inflammation is a beneficial response that can remove pathogens, repair injured tissue and restore homeostasis to damaged tissues and organs. However, increasing evidence indicate that chronic inflammation plays a pivotal role in tumor development, as well as progression, metastasis, and resistance to chemotherapy. We will review the current knowledge regarding the contribution of inflammation to epithelial mesenchymal transition. We will also provide some perspectives on the relationship between ER-stress signals and metabolism, and the role of these processes in the development of inflammation. PMID- 26004410 TI - Regulatory mechanism of the gastric hyperemic response following barrier disruption: roles of cyclooxygenase-1, the prostaglandin E2/EP1 receptor and sensory neurons. AB - We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E2, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice. This hyperemic response in the rat stomach was inhibited by indomethacin without affecting acid back-diffusion, which resulted in the aggravation of lesions. The effect of indomethacin was mimicked by loxoprofen and the selective COX-1 inhibitor, SC-560, but not by the selective COX-2 inhibitor, celecoxib. The GMBF responses induced by TC were similarly observed in the stomachs of wild-type mice and EP3 receptor knockout mice, but not in mice lacking the EP1 receptor or pretreated with an EP1 antagonist. The increase in the GMBF response associated with acid back-diffusion after the TC treatment was also inhibited by the chemical ablation of capsaicin-sensitive afferent neurons, but not capsazepine, a TRPV1 antagonist. Thus, endogenous PGE2 produced by COX-1 plays a role in the gastric hyperemic response following barrier disruption of the stomach by interacting with capsaicin-sensitive afferent neurons, mainly through EP1 receptors, and facilitating the GMBF response to acid back-diffusion. These findings have also contributed to a deeper understanding of mucosal defensive mechanisms following barrier disruption and the development of new strategies for the treatment of gastrointestinal diseases. PMID- 26004411 TI - New molecules as drug candidates for the treatment of upper and lower GI tract ulcers. AB - Ulcers in the stomach, duodenum, ileum/jejunum and colon may look alike grossly and microscopically, but they have very different etiologies and pathogenesis. Unfortunately, there is virtually no etiologic treatment for any of these lesions which are also accompanied by limited or extensive inflammation. This article reviews four groups of new antiulcer drugs discovered and patented in our lab in Boston and Long Beach/Irvine (Table 1). Actually, the first group, pyrazole and its derivatives can be used for prevention, i.e., long lasting protection of gastric mucosa against alcohol- or NSAID-induced erosions. Dopamine seems to be a new etiologic treatment for both upper and lower GI tract ulcers. Angiogenic growth factors like bFGF or PDGF (daily administration as peptides orally or by rectal enemas, or as single or double-dose of gene therapy) accelerated the healing of gastroduodenal ulcers and UC, while VEGF seems to be effective only for upper GI tract ulcers. Last but not least, a novel group of angiogenic steroids which not only stimulate new blood vessel formation and granulation tissue production (essential elements of healing of ulcer types) but may also exert mild or prominent antiinflammatory action and seem to be ideal drugs for the treatment of IBD. PMID- 26004412 TI - Proteases and their receptors as mediators of inflammation-associated colon cancer. AB - Chronic inflammation increases the risk of developing cancer. For example, patients with severe and prolonged inflammatory bowel disease, particularly ulcerative colitis, have a significantly higher risk of developing colorectal cancer. Serine proteases coordinating the coagulation cascade and immune cell proteases play important roles in regulating the inflammatory response through their actions on protease-activated receptors (PAR). PARs and their activating proteases have also been implicated in many cancers, including CRC. Importantly, the actions of proteases could be important for mediating the transition from chronic inflammation to cancer. PAR activation has been shown to have pro tumourigenic effects including the production of matrix metalloproteinases that can promote tumour cell growth and metastasis, and transactivation of the epidermal growth factor receptor, which is a main target for cancer treatment. Additionally, PAR activation can also result in increased expression of cyclooxygenase (COX)-2, an important enzyme mediating inflammation, resolution, and cancer progression. In this review, we will highlight our current knowledge about the effects of proteases and their receptors on intestinal inflammation and cancer, and explore the potential role of PAR-induced COX-2 on colitis-associated cancer. PMID- 26004413 TI - Beyond COX-inhibition: 'side-effects' of ibuprofen on neoplastic development and progression. AB - Ibuprofen is a non-steroidal anti-inflammatory drug of generalized use with over the-counter availability. Population-based studies have provided evidence that its long-term use is associated with a 30-60% decrease in the risk of developing major types of cancer. Initially, the underlying molecular mechanism was thought to be exclusively dependent on its inhibitory effect on cyclooxygenase activity, which is involved in the inflammatory response. However, numerous studies have now shown that the cancer chemopreventive properties of ibuprofen are much more complex and likely involve multiple COX-2-independent effects. Here we review the current knowledge on COX-independent effects of ibuprofen, which affect changes in gene expression or alternative splicing and act through various cell cycle- and apoptosis-regulating pathways, including beta-catenin, NF-kappaB, PPARgamma and p53. PMID- 26004414 TI - Inflammatory and non-inflammatory roles for Toll-like receptors in gastrointestinal cancer. AB - Collectively, cancers of the gastrointestinal (GI) tract (including the esophagus, stomach, duodenum, colon, rectum, liver, gall bladder and bile ducts) are the most prevalent and deadly worldwide. A common denominator in the pathogenesis of these GI tract cancers is chronic inflammation, as evidenced by the fact that sufferers of inflammatory bowel disease (IBD) are significantly more susceptible to colon cancer than healthy individuals. However, since only a relatively small proportion of individuals with chronic inflammatory conditions such as IBD go on to develop cancer, research has focused on identifying discrepancies in the host immune system that may be responsible for promoting carcinogenesis in inflamed tissue. To this end, molecular pathways linking inflammation and cancer are emerging, with one series of candidates being members of the Toll-like receptor family. PMID- 26004415 TI - Chronic inflammation and colorectal cancer: the role of vascular endothelial growth factor. AB - Colorectal cancer (CRC) is the third most frequently diagnosed cancer in males and the second in females worldwide. Accumulating evidence has demonstrated that patients with chronic inflammation in bowels have an increased risk to develop CRC. Various inflammatory cells and mediators produced during chronic inflammation are orchestrated through different molecular signaling pathways and lead to the formation of a microenvironment in favor of tumorigenesis. Vascular endothelial growth factor (VEGF), which can be induced by chronic inflammation, plays a pivotal role in tumor angiogenesis as well as tumor growth and metastasis. Antiangiogenic therapy targeting VEGF and its signaling pathways represents a promising strategy to inhibit colorectal tumorigenesis. Indeed, anti angiogenic agents modulating VEGF ligands and their receptors have already exhibited great potential in treating patients with CRC, especially when combined with conventional chemotherapeutic agents. This review discusses the promoting role of chronic inflammation in colorectal tumorigenesis at different stages including tumor initiation, promotion, progression and metastasis, highlighting the contributory role of VEGF in angiogenesis during the development from chronic inflammation to CRC. It also describes the clinical significance of anti- VEGF therapy in the treatment of such disease. PMID- 26004416 TI - PPARdelta signaling regulates colorectal cancer. AB - Peroxisome proliferator-activated receptordelta (PPARdelta) belongs to the PPARs receptor family including PPARalpha, PPARdelta, and PPARgamma. PPARdelta is a ligand-activated transcription factor that plays a critical role in regulating cancer progression. PPARdelta-linked tumorigenesis was first identified in colorectal cancer, which is demonstrated by the following evidences, so PPARepsilon is a potential drug target for colorectal cancer. In contrast, some observations show that PPARdelta negatively regulates colorectal cancer event. In the present review, the recent progress of PPARdelta signaling-mediated colorectal cancer is covered. PMID- 26004417 TI - Targeting epithelial-mesenchymal transition phenotype for gastro-intestinal cancer. AB - Gastrointestinal (G-I) cancers are one of the most common malignant tumors worldwide. Symptoms relate to the organ affected in the G-I tract are non specific, making early detection and effective treatment difficult to achieve. Epithelial-mesenchymal transition (EMT), a reversible and dynamical process, can disperse cells in embryos, form mesenchymal cells in injured tissues, and regulate embryonic stem cell differentiation. A variety of signaling molecules and distinct pathways are involved in the initiation and progression of EMT. Recent evidence has established that EMT may endow G-I cancer cells with the capacity to invade surrounding tissues, resist apoptosis, migrate to distant organs, and develop chemoresistance. Targeting these signaling molecules and pathways associated with EMT may provide clinicians with a new approach to the treatment of G-I malignancy. PMID- 26004418 TI - The genetic landscapes of inflammation-driven gastrointestinal tract cancers. AB - Gastrointestinal (GI) tract cancers account for a significant proportion of human malignancies. While classical multistep carcinogenesis is characterized by the stochastic accumulation of genetic mutations, additional extrinsic factors can also contribute to tumor promotion. Inflammation plays a critical role in cancers of the GI tract, for which the two major etiological factors are tissue injuries and altered microbiota. Together with infiltrating immune cells, all of these components generate a dynamic tumor microenvironment that inevitably induces malignant progression and metastatic growth. Crosstalk between tumor and immune cells is mediated by a multitude of pro- and anti- inflammatory cytokines. Their biological actions are propagated in both tumor and immune cells through an intricate network of intracellular signaling pathways that ultimately modulate essential cellular functions such as tumorigenic properties and lineage specification. Using the vast amount of information stored in the database on genetic changes associated with human cancers that has been collected over the past decades, this book chapter will first profile the genomic and transcriptomic landscapes of some of the major GI tract cancers. Critical driver genes and pro inflammatory cytokines will be discussed in detail. The mechanisms by which genetic mutations in cancer cells can provoke inflammation and vice versa will be explored. The way in which the symbiotic relationship between cancer cells and chronic inflammation can modulate tumor cell behavior will be examined. We will present some of the most recent advancements in the targeting of inflammation for the treatment of GI tract cancers. PMID- 26004419 TI - The current role and therapeutic targets of vitamin D in gastrointestinal inflammation and cancer. AB - Vitamin D, beyond its classical roles in the regulation of calcium and phosphorus homeostasis and bone metabolism, has been implicated in multiple pathological processes, including progression from inflammation to cancer development and also involvement in autoimmune diseases as well as cardiovascular disorders. In this review, we shall discuss the different roles of vitamin D and its therapeutic targets in different gastrointestinal diseases, focusing on colorectal cancer (CRC) and inflammatory bowel disease (IBD). To this end, vitamin D deficiency has been identified as a risk factor of CRC. On the other hand the active metabolite of vitamin D, 1, 25- dihydroxyvitamin D3 (1, 25(OH)2D3) has multiple anti cancerous benefits including inhibition of proliferation, induction of apoptosis, promotion of differentiation and suppression of angiogenesis in tumors. In IBD, vitamin D is involved in the pathogenic process through the normalization of immune responses in the colon. With these experimental findings, well-designed and large-scale clinical trials are warranted to further define the therapeutic action of vitamin D in the prevention and/or treatment of IBD and further on CRC in humans. PMID- 26004420 TI - Inhibitors of the renal outer medullary potassium channel: a patent review. AB - INTRODUCTION: Hypertension represents a substantial cardiovascular risk factor. Among anti-hypertensive drugs, diuretics play an important role. Nevertheless, they present adverse effects such as hypokalemia or hyperkalemia. In this panorama, inhibitors of the renal outer medullary potassium (ROMK) channels are emerging because they are predicted to give a diuretic/natriuretic activity higher than that provided by loop diuretics, without hypokaliemic and hyperkaliemic side effects. AREAS COVERED: This article reviews the current literature, including all the patents published in the field of inhibitors of the ROMK channels for the treatment of hypertension, heart failure and correlated diseases. The patent examination has been carried out using electronic databases Espacenet. EXPERT OPINION: Although anti-hypertensive drugs armamentarium enumerates a plethora of therapeutic classes, including diuretics, the novel class of ROMK inhibitors may find a place in this crowded market, because of the diuretic/natriuretic effects, devoid of worrying influence on potassium balance. The patent examination highlights, as a strength, the individuation of a successful template: almost all the compounds show noteworthy potency. However, only few selected compounds underwent an in vivo investigation of diuretic and anti-hypertensive activities, and no data on the hERG channel are given in these patents. PMID- 26004421 TI - The Feasibility and Acceptability to Service Users of CIRCuiTS, a Computerized Cognitive Remediation Therapy Programme for Schizophrenia. AB - BACKGROUND: Cognitive remediation (CR) is a psychological therapy, effective in improving cognitive performance and functioning in people with schizophrenia. As the therapy becomes more widely implemented within mental health services its longevity and uptake is likely to depend on its feasibility and acceptability to service users and clinicians. AIMS: To assess the feasibility and acceptability of a new strategy-based computerized CR programme (CIRCuiTS) for people with psychosis. METHOD: Four studies were conducted using mixed methods. Perceptions of attractiveness, comprehensibility, acceptability and usability were assessed using self-report questionnaires in 34 non-clinical participants (study 1), and five people with a schizophrenia diagnosis and three experienced CR therapists (studies 2 and 3). The ease with which pre-specified therapy programmes could be assembled was also assessed by three therapists (Study 2). Finally, the satisfaction of 20 service users with a diagnosis of schizophrenia regarding their experience of using CIRCuiTS in the context of a course of the CR therapy was assessed in a qualitative interview study (study 4). RESULTS: Ratings of perceived attractiveness, comprehensibility, acceptability and usability consistently exceeded pre-set high targets by non-clinical, clinical and therapist participants. Qualitative analysis of satisfaction with CIRCuiTS showed that receiving the therapy was generally seen to be a positive experience, leading to perceptions that cognitive functioning had improved and attempts to incorporate new strategy use into daily activities. CONCLUSIONS: CIRCuiTS demonstrates high acceptability and ease of use for both service users with a schizophrenia diagnosis and clinicians. PMID- 26004422 TI - Chlorine functionalization of a model phenolic C8-guanine adduct increases conformational rigidity and blocks extension by a Y-family DNA polymerase. AB - Certain phenoxyl radicals can attach covalently to the C8-site of 2' deoxyguanosine (dG) to afford oxygen-linked C8-dG adducts. Such O-linked adducts can be chemically synthesized through a nucleophilic displacement reaction between a phenolate and a suitably protected 8-Br-dG derivative. This permits the generation of model O-linked C8-dG adducts on scales suitable for insertion into oligonucleotide substrates using solid-phase DNA synthesis. Variation of the C8 aryl moiety provides an opportunity to derive structure-activity relationships on adduct conformation in duplex DNA and replication bypass by DNA polymerases. In the current study, the influence of chlorine C8-dG functionalization on in vitro DNA replication by Klenow fragment exo(-) (Kf(-)) and the Y-family polymerase (Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4)) has been determined. Model O-linked C8-dG adducts derived from the pentachlorophenoxyl radical ([PCP]G) and 2,4,6-trichlorophenoxyl radical ([TCP]G) were inserted into the reiterated G3 position of the NarI sequence (12-mer, NarI(12); and 22-mer, NarI(22)), which is a known hotspot for frameshift mutations mediated by N-linked polycyclic C8-dG adducts in bacterial mutagenesis. Within the NarI(12) duplex, the unsubstituted C8-phenoxy-dG ([PhO]G) adduct adopts a minimally perturbed B-form helix. Chlorination of [PhO]G to afford [PCP]G does not significantly change the adduct conformation within the NarI(12) duplex, as predicted by molecular dynamics simulations. However, when using NarI(22) for DNA synthesis in vitro, the chlorinated [PCP]G and [TCP]G lesions significantly block DNA replication by Kf( ) and Dpo4, whereas [PhO]G is readily bypassed. These findings highlight the impact that chlorine substituents impart to bulky C8-dG lesions. PMID- 26004423 TI - Robotic thyroidectomy versus conventional open thyroidectomy for differentiated thyroid cancer: meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis to compare the short-term outcomes of robotic thyroidectomy and conventional open thyroidectomy for differentiated thyroid cancer. METHODS: Medline, Embase, Science Citation Index Expanded and the Cochrane Library databases were searched for relevant literature. The evaluated endpoints were intra-operative and post-operative outcomes. RESULTS: Twelve eligible, non-randomised comparative studies involving 2513 patients were included, with 923 patients in the robotic thyroidectomy group and 1590 patients in the conventional open thyroidectomy group. Meta-analysis results revealed that robotic thyroidectomy was associated with significantly longer operative time and a lower number of retrieved central lymph nodes, as compared with conventional open thyroidectomy. No significant differences were found between robotic thyroidectomy and conventional open thyroidectomy in terms of post-operative outcomes. CONCLUSION: Robotic thyroidectomy appears to be a feasible and safe surgical procedure for patients with differentiated thyroid cancer. However, more high-quality randomised clinical trials should be undertaken to confirm these findings. PMID- 26004424 TI - Response to: Studying the role of dystrophin-associated proteins in influencing Becker muscular dystrophy disease severity. PMID- 26004425 TI - Forced oscillometry track sites of airway obstruction in bronchial asthma. AB - BACKGROUND: Spirometry is the most commonly used method for assessment of airway function in bronchial asthma but has several limitations. Forced oscillometry was developed as a patient-friendly test that requires passive cooperation of the patient breathing normally through the mouth. OBJECTIVE: To compare spirometry with forced oscillometry to assess the role of forced oscillometry in the detection of the site of airway obstruction. METHODS: This case-and-control study included 50 patients with known stable asthma and 50 age- and sex-matched healthy subjects. All participants underwent spirometry (ratio of force expiration volume in 1 second to forced vital capacity, percentage predicted for forced expiration volume in 1 second, percentage predicted for forced vital capacity, percentage predicted for vital capacity, and forced expiratory flow at 25-75%) and forced oscillometry (resistance at 5, 20, and 5-20 Hz). RESULTS: By spirometry, all patients with asthma had airway obstruction, 8% had isolated small airway obstruction, 10% had isolated large airway obstruction, and 82% had large and small airway obstruction. By forced oscillometry, 12% had normal airway resistance, 50% had isolated small airway obstruction with frequency-dependent resistance, and 38% had large and small airway obstruction with frequency independent resistance. There was significant difference between techniques for the detection of the site of airway obstruction (P = .012). Forced oscillometry indices were negatively correlated with spirometric indices (P < .01). CONCLUSION: Forced oscillometry as an effortless test, conducted during quiet tidal breathing, and does not alter airway caliber; thus, it can detect normal airway function better than spirometry in patients with asthma. Forced oscillometry detects isolated small airway obstruction better than spirometry in bronchial asthma. PMID- 26004426 TI - Serum vitamin D levels in a cohort of adult and pediatric patients with eosinophilic esophagitis. AB - BACKGROUND: Vitamin D deficiency has been associated with increased risk for severe asthma, challenge-proven food allergy, and severe atopic dermatitis. Vitamin D levels have not been reported in patients with eosinophilic esophagitis (EoE). OBJECTIVE: To determine levels of 25-hydroxyvitamin D in a cohort of patients with EoE. METHODS: Total serum 25-hydroxyvitamin D was measured using liquid chromatography with tandem mass spectroscopy in adults (n = 35) and children (n = 34) with EoE. Results were compared with patient demographics, EoE specific disease parameters, markers of sensitization, and features of severity using multivariable logistic regression. RESULTS: The median vitamin D level was 28.9 ng/mL. Patients with insufficient vitamin D (<30 ng/mL) were older (median 25.5 vs 16.2 years) and had a higher body mass index (median 25.2 vs 19.8 kg/m(2)). Peak median esophageal eosinophil counts were not significantly different for vitamin D insufficient and sufficient patient groups; however, higher vitamin D levels correlated with higher histologic eosinophil counts (R = 0.61, P = .03). Although there were no statistical differences in total IgE or levels of specific IgE between patients with vitamin D insufficiency and those with sufficiency, a positive skin prick test reaction to peanut was more common in patients who had vitamin D insufficiency (adjusted odds ratio 7.57, P = .009). Vitamin D insufficiency was not associated with surrogate markers of severity (dilation in adults or hospitalization or emergency visits in children). CONCLUSION: In these patients with EoE, vitamin D levels were low overall (median <30 ng/mL). The only marker of sensitization associated with insufficient vitamin D in these patients with EoE was a positive skin prick test reaction to peanut. PMID- 26004427 TI - Approaching Etuaptmumk--introducing a consensus-based mixed method for health services research. AB - With the recognized need for health systems' improvements in the circumpolar and indigenous context, there has been a call to expand the research agenda across all sectors influencing wellness and to recognize academic and indigenous knowledge through the research process. Despite being recognized as a distinct body of knowledge in international forums and across indigenous groups, examples of methods and theories based on indigenous knowledge are not well documented in academic texts or peer-reviewed literature on health systems. This paper describes the use of a consensus-based, mixed method with indigenous knowledge by an experienced group of researchers and indigenous knowledge holders who collaborated on a study that explored indigenous values underlying health systems stewardship. The method is built on the principles of Etuaptmumk or two-eyed seeing, which aim to respond to and resolve the inherent conflicts between indigenous ways of knowing and the scientific inquiry that informs the evidence base in health care. Mixed methods' frameworks appear to provide a framing suitable for research questions that require data from indigenous knowledge sources and western knowledge. The nominal consensus method, as a western paradigm, was found to be responsive to embedding of indigenous knowledge and allowed space to express multiple perspectives and reach consensus on the question at hand. Further utilization and critical evaluation of this mixed methodology with indigenous knowledge are required. PMID- 26004428 TI - Illicit tobacco trade in the firing line. PMID- 26004429 TI - Synthesis and antitumor evaluation of novel hybrids of phenylsulfonylfuroxan and epiandrosterone/dehydroepiandrosterone derivatives. AB - Thirteen novel furoxan-based nitric oxide (NO) releasing hybrids (14a-e, 15a-e, 17b-d) of 16,17-pyrazo-annulated steroidal derivatives were synthesized and evaluated against the MDA-MB-231, HCC1806, SKOV-3, DU145, and HUVEC cell lines for their in vitro anti-proliferative activity. Most of the compounds displayed potent anti-proliferative effects. Among them, 17c exhibited the best activity with IC50 values of 20-1.4nM against four cell lines (MDA-MB-231, SKOV-3, DU145, and HUVEC), and 1.03MUM against a tamoxifen resistant breast cancer cell line (HCC1806). Furthermore, five compounds (14a, 15a, 17b-d) were selected to screen for VEGF inhibitory activity. Compounds 15a, 17b,c showed obviously better activity than 2-Methoxyestradiol (2-ME) on reducing levels of VEGF secreted by MDA-MB-231 cell line. In a Capillary-like Tube Formation Assay, compounds 17b,c exhibited a significant suppression of the tubule formation in the concentration of 1.75nM and 58nM, respectively. The preliminary SAR showed that steroidal scaffolds with a linker in 3-position were favorable moieties to evidently increase the bioactivities of these hybrids. Overall, these results implied that 17c merited to be further investigated as a promising anti-cancer candidate. PMID- 26004430 TI - The characteristic of cognitive function in Type 2 diabetes mellitus. AB - AIM: To identify characteristics of neuropsychological function among elderly individuals with Type 2 diabetes mellitus with mild cognitive impairment (T2DM MCI) and evaluate domain-specific effects of T2DM on cognition. METHODS: This was a cross-sectional study conducted in Tianjin, China. MCI subjects (n=246) and controls were identified in elderly individuals with diabetes, and groups were matched in a 1:1 ratio for sex, age and educational level. Cognitive function was assessed using WAIS-III (block design, digit span), Trail Making Test A, Trail Making Test B, WMS-III (word list learning, logical memory), verbal fluency and MMSE. We used multivariable logistic regression to find diabetic factors associated with MCI. RESULTS: The mean MMSE score was 22.73 +/- 2.32 in subjects with T2DM-MCI, versus 26.71 +/- 2.43 in subjects cognitive normal (P<0.001). Executive and visuospatial functions were more impaired in individuals with T2DM MCI than in those without, as assessed using block design (P<0.001), digit span test (P<0.001), and Trails B (P<0.001). For memory, subjects with T2DM-MCI did worse than those cognitive normal on the word learning list delayed recall (P=0.015). Diabetic-related factors such as longer duration of T2DM, higher HbA1c, insulin treatment was associated with a lower level of cognitive functioning using MMSE, block design, delayed recall and Trails B test. CONCLUSIONS: T2DM should be considered a risk factor for MCI. This risk may be associated with duration of diabetes, use of glucose-lowering medications, degree of glucose control. To decrease risk of MCI, it is important to monitor glucose control and adjust medications appropriately in elderly patients. PMID- 26004431 TI - SLC47A1 gene rs2289669 G>A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients. AB - AIMS: The SLC47A1 gene encodes the multi-drug and toxic excretion-1(MATE1) protein, which plays a key role in the transport and excretion of metformin. This study is to clarify the influence of variants in SLC47A1 (rs2289669 G->A) on metformin pharmacokinetics and the long-term glucose-lowering effect of metformin. METHODS: A total of 220 newly diagnosed type 2 diabetes patients were recruited, genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, A/A). Ten patients in each group were randomly selected for metformin pharmacokinetics. All the participants received metformin oral treatment and were followed for one year. RESULTS: After one-year follow-up, the decline of HbA1c level was significantly greater in subjects with variant genotype (AA) than other two groups (-2.32% [-25.4 mmol/mol] in AA vs. -1.16% [-12.7 mmol/mol] in GA, 1.07% [-11.7 mmol/mol] in GG, P<0.05). Then taking GG genotype as the referent, the association between AA genotype and change of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and diabetes duration (P<0.05). Pharmacokinetic parameters of metformin indicated that patients carrying MATE1 homozygous A had higher area under the plasma concentration versus time curve (AUC12h), but lower renal clearance (CLR) and renal clearance by secretion (CLSR) than other patients (all P<0.01). Multivariate lineal stepwise analysis further revealed that SLC47A1 genotype was an independent impact factor for urine excretion of metformin (P<0.01). CONCLUSIONS: SLC47A1 rs2289669 G>A variants improve the glucose-lowering effect of metformin through slowing its excretion in type 2 diabetes populations. PMID- 26004432 TI - Oral hirudiniasis in a stray dog, first report in Italy. AB - In June 2014, a male stray dog was recovered at Ente Nazionale di Protezione Animali (ENPA) kennel of Manfredonia, Apulia region, showing oral bleeding and physical prostration. The dog fell in a water canal and was trapped. During the clinical examination, a specimen of leech was revealed into its oral cavity. The parasite, probably entered by drinking unfiltered and contaminated water, has been identified as an adult of aquatic leech Limnatis nilotica. Leeches could overrun wide variety of animals, and few reports about blood sucking leech infestations in mammals are available in literature. This paper describes here the first oral hirudiniasis in a dog in Italy and highlights the possibility of human nasopharyngeal leech-related infection in Apulia region. PMID- 26004433 TI - Bone morphological analyses in Spontaneously Diabetic Torii (SDT) fatty rats. AB - The Spontaneously Diabetic Torii (SDT) fatty rat, a model for obese type 2 diabetes, shows bone quantitative abnormalities, namely low bone mineral density (BMD). The objective of this study was to evaluate bone morphological changes, in particular identifying the bone qualitative abnormalities, in the SDT fatty rat. Male SDT fatty rats showed increases in total trabecular area and trabecular number and decreases in trabecular thickness in cancellous bones of the proximal tibia, indicating trabecular miniaturization. The SDT fatty rat is useful for investigation of pathophysiological changes in bone quality in diabetic osteoporosis. PMID- 26004434 TI - Production of lactulose oligosaccharides by isomerisation of transgalactosylated cheese whey permeate obtained by beta-galactosidases from dairy Kluyveromyces. AB - beta-Galactosidases from Kluyveromyces lactis and Kluyveromyces marxianus isolated from artisanal ewes' milk cheeses, were used to transgalactosylate lactose from cheese whey permeate (WP). The content of galactooligosaccharides (GOS) obtained by transgalactosylation was comparable with that formed using pure lactose as substrate. In order to obtain a mixture with higher prebiotic oligosaccharide content, isomerisation of the transgalactosylated WP was carried out using sodium aluminate as catalyst. The transgalactosylated mixtures at 6 h of reaction contained amounts of prebiotic carbohydrates (tagatose, lactulose, GOS and oligosaccharides derived from lactulose, OsLu) close to 50 g/100 g of total carbohydrates for all the strains tested, corresponding to 322 g prebiotics/kg whey permeate. Thus, the suitability of this methodology to produce mixtures of dietary non-digestible carbohydrates with prebiotic properties from WP has been demonstrated, which is interesting for the food industry since it increases the value and the applicability of this by-product from cheese manufacture. PMID- 26004435 TI - The high-throughput phenotyping of the viscoelastic behavior of whole mouse intervertebral discs using a novel method of dynamic mechanical testing. AB - Intervertebral disc (IVD) degeneration is highly correlated with lower back pain, and thus understanding the mechanisms of IVD degeneration is critical for the treatment of this disease. Utilizing mouse models to probe the mechanisms of degeneration is especially attractive due to the ease of manipulating mouse models and the availability of transgenics. Yet characterizing the mechanical behavior of mice IVDs remain challenging due to their minute size (approximately 540 MUm in height and 1080 MUm(2) in cross sectional area). We have thus developed a simple method to dynamically characterize the mechanical properties of intact mouse IVDs. The IVDs were dissected with the endplates intact, and dynamically compressed in the axial direction at 1% and 5% peak strains at 1 Hz. Utilizing this novel approach, we examined the effects of in vitro ribosylation and trypsin digestion for 24 or 72 h on the viscoelastic behavior of the whole murine IVD. Trypsin treatment resulted in a decrease of proteoglycans and loss of disc height, while ribosylation had no effect on structure or proteoglycan composition. The 72 h ribosylation group exhibited a stiffening of the disc, and both treatments significantly reduced viscous behavior of the IVDs, with the effects being more pronounced at 5% strain. Here we demonstrate a novel high throughput method to mechanically characterize murine IVDs and detect strain dependent differences in the elastic and the viscous behavior of the treated IVDs due to ribose and trypsin treatments. PMID- 26004436 TI - Developing effective assignment feedback for an interprofessional learning module An action research project. AB - BACKGROUND: The first year interprofessional learning module at University Campus Suffolk (UCS) is delivered to 300 students and the students' assignments are marked by 20 members of staff from different health and social care professions. We were keen to find a way to reduce any inconsistencies and work with both staff and students to ensure that the essay and subsequent feedback were useful for all involved. AIMS: The aims of the project were to evaluate the current marking process and feedback sheets used for year one inter-professional learning (IPL) marking, and to develop an appropriate marking tool and feedback sheet that would enable markers to provide more consistent feedback to the students. METHODS: Participatory action research was used with both students and staff members being involved. Focus group and questions were used to ascertain views about the assignment feedback. CONCLUSIONS: The feedback from this action learning project helped us to enhance the feedback for students. There was also an increase in engagement with the assessment and feedback process amongst both staff and students. PMID- 26004437 TI - Tools to reduce first year nursing students' anxiety levels prior to undergoing objective structured clinical assessment (OSCA) and how this impacts on the student's experience of their first clinical placement. AB - BACKGROUND: One form of assessment that tests students' theoretical skills and confidence in their clinical practice is known as the Objective Structured Clinical Assessment (OSCA). Traditionally it was first launched from medical education, and is now being incorporated by other disciplines, such as nursing. OBJECTIVES: This review seeks to present the best available evidence into strategies that help reduce first year nursing students' anxiety levels prior to undergoing OSCA and clinical placement. SEARCH STRATEGY: A systematic literature search was performed using Medline and CINAHL. SELECTION CRITERIA: This review considered any English language original research published between 2005 and 2013. RESULTS: A literature search located 117 articles. Eight articles were identified as meeting the inclusion in criteria. Majority of studies reported simulation session prior to the OSCA increased students confidence and reduced their anxiety levels. This resulted in students' reporting that they valued the OSCA as a worthwhile assessment. However there were four major themes: that students were anxious about attending the OSCA; that adequate preparation was seen as a coping strategy; that simulation was a further cause for anxiety; and that the simulation experience could also be used as an OSCA tool. CONCLUSIONS: Students who have been exposed to simulation scenarios before the OSCA are able to cope much better during the OSCA. Therefore, it is highly recommended to incorporate simulation scenarios into the nursing curricula for first year nursing students' clinical units to help reduce their anxiety levels prior to OCSA. PMID- 26004438 TI - A medical instrumentation laboratory dedicated to cardiovascular nurse training. PMID- 26004439 TI - Molecular mechanism of resolving trinucleotide repeat hairpin by helicases. AB - Trinucleotide repeat (TNR) expansion is the root cause for many known congenital neurological and muscular disorders in human including Huntington's disease, fragile X syndrome, and Friedreich's ataxia. The stable secondary hairpin structures formed by TNR may trigger fork stalling during replication, causing DNA polymerase slippage and TNR expansion. Srs2 and Sgs1 are two helicases in yeast that resolve TNR hairpins during DNA replication and prevent genome expansion. Using single-molecule fluorescence, we investigated the unwinding mechanism by which Srs2 and Sgs1 resolves TNR hairpin and compared it with unwinding of duplex DNA. While Sgs1 unwinds both structures indiscriminately, Srs2 displays repetitive unfolding of TNR hairpin without fully unwinding it. Such activity of Srs2 shows dependence on the folding strength and the total length of TNR hairpin. Our results reveal a disparate molecular mechanism of Srs2 and Sgs1 that may contribute differently to efficient resolving of the TNR hairpin. PMID- 26004440 TI - Structural dynamics of ribosome subunit association studied by mixing-spraying time-resolved cryogenic electron microscopy. AB - Ribosomal subunit association is a key checkpoint in translation initiation but its structural dynamics are poorly understood. Here, we used a recently developed mixing-spraying, time-resolved, cryogenic electron microscopy (cryo-EM) method to study ribosomal subunit association in the sub-second time range. We have improved this method and increased the cryo-EM data yield by tenfold. Pre equilibrium states of the association reaction were captured by reacting the mixture of ribosomal subunits for 60 ms and 140 ms. We also identified three distinct ribosome conformations in the associated ribosomes. The observed proportions of these conformations are the same in these two time points, suggesting that ribosomes equilibrate among the three conformations within less than 60 ms upon formation. Our results demonstrate that the mixing-spraying method can capture multiple states of macromolecules during a sub-second reaction. Other fast processes, such as translation initiation, decoding, and ribosome recycling, are amenable to study with this method. PMID- 26004441 TI - Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal alpha7 from Muscle alpha1(2)betagammadelta nAChRs. AB - Pinnatoxins are macrocyclic imine phycotoxins associated with algal blooms and shellfish toxicity. Functional analysis of pinnatoxin A and pinnatoxin G by binding and voltage-clamp electrophysiology on membrane-embedded neuronal alpha7, alpha4beta2, alpha3beta2, and muscle-type alpha12betagammadelta nicotinic acetylcholine receptors (nAChRs) reveals high-affinity binding and potent antagonism for the alpha7 and alpha12betagammadelta subtypes. The toxins also bind to the nAChR surrogate, acetylcholine-binding protein (AChBP), with low Kd values reflecting slow dissociation. Crystal structures of pinnatoxin-AChBP complexes (1.9-2.2 A resolution) show the multiple anchoring points of the hydrophobic portion, the cyclic imine, and the substituted bis-spiroketal and cyclohexene ring systems of the pinnatoxins that dictate tight binding between the opposing loops C and F at the receptor subunit interface, as observed for the 13-desmethyl-spirolide C and gymnodimine A congeners. Uniquely, however, the bulky bridged EF-ketal ring specific to the pinnatoxins extends radially from the interfacial-binding pocket to interact with the sequence-variable loop F and govern nAChR subtype selectivity and central neurotoxicity. PMID- 26004442 TI - Functional dynamics in replication protein A DNA binding and protein recruitment domains. AB - Replication Protein A (RPA) is an essential scaffold for many DNA processing machines; its function relies on its modular architecture. Here, we report (15)N nuclear magnetic resonance heteronuclear relaxation analysis to characterize the movements of single-stranded (ss) DNA binding and protein interaction modules in the RPA70 subunit. Our results provide direct evidence for coordination of the motion of the tandem RPA70AB ssDNA binding domains. Moreover, binding of ssDNA substrate is found to cause dramatic reorientation and full coupling of inter domain motion. In contrast, the RPA70N protein interaction domain remains structurally and dynamically independent of RPA70AB regardless of binding of ssDNA. This autonomy of motion between the 70N and 70AB modules supports a model in which the two binding functions of RPA are mediated fully independently, but remain differentially coordinated depending on the length of their flexible tethers. A critical role for linkers between the globular domains in determining the functional dynamics of RPA is proposed. PMID- 26004444 TI - Enclaves of opportunity or "ghettos of last resort?" Assessing the effects of immigrant segregation on violent crime rates. AB - A growing body of research indicates that immigration to the U.S. has crime reducing effects on aggregate levels of violence, which researchers have often attributed to the protective and revitalizing effects of immigrants settling in spatially concentrated neighborhoods. However, recent scholarship suggests that growing shares of the foreign-born population are bypassing these segregated immigrant enclaves and are dispersing more widely to other urban neighborhoods. Moreover, some scholars suggest that spatially isolating immigrant populations may not always be protective, but could actually contribute to social problems like crime, particularly in disadvantaged contexts. The current study offers one of the first analyses exploring the way that segregation of immigrant populations (relative to the U.S.-born) is related to year 2000 violent crime rates for nearly 500 census places in California and New York. Results of our analysis reveal no direct link between immigrant segregation and macro-level violence, but instead show that these effects are highly contextualized and depend on the resources present in locales. Specifically, immigrant segregation contributes to violence in highly disadvantaged places but is linked to lower violence in areas with greater resources. PMID- 26004443 TI - NMR Structure of Francisella tularensis Virulence Determinant Reveals Structural Homology to Bet v1 Allergen Proteins. AB - Tularemia is a potentially fatal bacterial infection caused by Francisella tularensis, and is endemic to North America and many parts of northern Europe and Asia. The outer membrane lipoprotein, Flpp3, has been identified as a virulence determinant as well as a potential subunit template for vaccine development. Here we present the first structure for the soluble domain of Flpp3 from the highly infectious Type A SCHU S4 strain, derived through high-resolution solution nuclear magnetic resonance (NMR) spectroscopy; the first structure of a lipoprotein from the genus Francisella. The Flpp3 structure demonstrates a globular protein with an electrostatically polarized surface containing an internal cavity-a putative binding site based on the structurally homologous Bet v1 protein family of allergens. NMR-based relaxation studies suggest loop regions that potentially modulate access to the internal cavity. The Flpp3 structure may add to the understanding of F. tularensis virulence and contribute to the development of effective vaccines. PMID- 26004445 TI - Paternal incarceration and child-reported behavioral functioning at age 9. AB - Within the last few decades our understanding of the importance of non-cognitive skills for socioeconomic success has grown along with our knowledge of the deleterious impacts of paternal incarceration for child wellbeing. Given the importance of early skills and that elementary-aged children constitute the majority of children with incarcerated parents, understanding the connection between paternal incarceration and the socio-emotional component of children's non-cognitive development is pressing. Using matching models, data from the newest wave of the Fragile Families and Child Wellbeing Study, and exploring a larger range of behavioral skills than previous literature, this paper provides estimates of the impact of paternal incarceration on children's behavioral functioning at age 9 using children's own self-reports. Comparisons to oft-used parent reports are made and heterogeneity by gender is explored. Findings suggest the incarceration of a father increases the antisocial behaviors children self report, but has null effects on prosocial skill development. PMID- 26004446 TI - Why has medicine expanded? The role of consumers. AB - In the past 50years, the field of medicine has expanded dramatically in many Western societies. Despite substantial improvements in objective health measures, there has not been a commensurate increase in assessments of subjective health. We hypothesize that medical expansion may lower people's subjective health perceptions, leading to an increase in health care utilization, and, in turn, fueling further medical expansion. We use OECD (Organization for Economic Co operation and Development) Health Data, World Development Indicators, the World Values Survey, and the European Values Study to fit a difference-in-differences model that removes unobserved cross-national heterogeneity and any period trend that is shared across nations. We find that three dimensions of medical expansion at the societal level (medical investment, medical professionalization/specialization, and an expanded pharmaceutical industry) negatively affect individual subjective health. These findings are robust to different model specifications. We conclude by discussing possible explanations for the adverse effect of medical expansion on subjective health, and how this effect may be related to other mechanisms through which medicine expands. PMID- 26004447 TI - A propensity score matching analysis of the relationship between victim sex and capital juror decision-making in North Carolina. AB - A small body of prior research has examined the impact of victim sex on jury death penalty decision-making and the majority of this research has demonstrated some evidence of a "female victim effect" such that cases involving a female victim are more likely to receive the death penalty than similarly situated cases with a male victim. However, within this line of research studies have suggested that victim sex may work in conjunction with other case characteristics. In order to further explore this phenomenon, the current study examines a near-population of death penalty cases from North Carolina (n=1069) from 1977-2009 using propensity score matching. Results demonstrate that once cases are matched on more than 50 legal and extralegal case characteristics, there is no statistically significant or substantive link between victim sex and death penalty decision making. Findings suggest that it is concrete differences in the legal and extralegal factors observed in cases with female victims compared to male victims that shape jury death sentence decisions rather than a direct effect of victim sex (before matching: OR=1.53; 95% CI=1.20-1.95; p<.001/after matching: OR=0.90; 95% CI=0.66-1.24; p=.52). Study limitations and implications are also discussed. PMID- 26004448 TI - Social context and sexual intercourse among first-year students at selective colleges and universities in the United States. AB - Most examinations of sexual behavior ignore social context. Using panel data from the National Longitudinal Study of Freshmen, a panel study of 3924 students at 28 selective colleges and universities, I examine how institutional and peer-group characteristics influence the incidence of sexual intercourse among students during their freshman year. Students who enter college as virgins are more likely to have sexual intercourse on campuses where women comprise a higher proportion of the campus population and on campuses that are more academically rigorous. Students who had sex prior to college are less likely to have sex in college when campuses are more residential. Moreover, having friends who value religion and partying affects the likelihood that a student will have sex irrespective of their prior virginity status. These findings highlight the importance of social context for sexual behavior among college students and in the general population. PMID- 26004449 TI - Effects of relationship duration, cohabitation, and marriage on the frequency of intercourse in couples: Findings from German panel data. AB - Research into the changes in the frequency of sexual intercourse is (with few exceptions) limited to cross-sectional analyses of marital duration. We investigate the frequency of intercourse while taking into account relationship duration as well as the duration of cohabitation and marriage, effects of parenthood, and relationship quality. For the analysis we apply fixed effects regression models using data from the German Family Panel (pairfam), a nationwide randomly sampled German panel survey. Our findings imply that the drop in sex frequency occurs early in the relationship, whereas neither cohabitation nor marriage affects the frequency of intercourse to a significant extent. Sex frequency is reduced during pregnancy and as long as the couple has small children, but becomes revived later on. Relationship quality is found to play a role as well. These results are contrary to the honeymoon effect found in earlier research, but indicate that in times of postponed marriage an analogous effect may be at work in the initial period of the relationship. PMID- 26004450 TI - What drives the gender gap in charitable giving? Lower empathy leads men to give less to poverty relief. AB - We draw upon past research on gender and prosocial emotions in hypothesizing that empathy can help explain the gender gap in charitable giving. In a nationally representative survey, we found that men reported less willingness to give money or volunteer time to a poverty relief organization, gaps that were mediated by men's lower reported feelings of empathy toward others. We also experimentally tested how effective a variety of different ways of framing poverty relief were for promoting giving. Framing poverty as an issue that negatively affects all Americans increased men's willingness to donate to the cause, eliminating the gender gap. Mediation analysis revealed that this "aligned self-interest" framing worked by increasing men's reported poverty concern, not by changing their understanding of the causes of poverty. Thus, while men were generally less motivated by empathy, they responded to a framing that recast charitable giving as consistent with their self-interest. Exposure to the same framing, however, led women to report lower willingness to volunteer time for poverty relief, suggesting that framing giving as consistent with self-interest may discourage those who give because of an empathic response to poverty. PMID- 26004451 TI - Why bother with testing? The validity of immigrants' self-assessed language proficiency. AB - Due to its central role in social integration, immigrants' language proficiency is a matter of considerable societal concern and scientific interest. This study examines whether commonly applied self-assessments of linguistic skills yield results that are similar to those of competence tests and thus whether these self assessments are valid measures of language proficiency. Analyses of data for immigrant youth reveal moderate correlations between language test scores and two types of self-assessments (general ability estimates and concrete performance estimates) for the participants' first and second languages. More importantly, multiple regression models using self-assessments and models using test scores yield different results. This finding holds true for a variety of analyses and for both types of self-assessments. Our findings further suggest that self assessed language skills are systematically biased in certain groups. Subjective measures thus seem to be inadequate estimates of language skills, and future research should use them with caution when research questions pertain to actual language skills rather than self-perceptions. PMID- 26004452 TI - Contextual influence on condom use in commercial sex venues: A multi-level analysis among female sex workers and gatekeepers in Guangxi, China. AB - This study aims to assess the influence of commercial sex venues on consistent condom use among female sex workers (FSWs) and to examine associations between individual and venue level factors and consistent condom use with clients. Analysis was based on a sample of 637 FSWs and 123 gatekeepers from 51 venues in Guangxi, China. Multi-level logistic regression using Bayesian simulation via Markov Chain Monte Carlo was applied to investigate whether FSWs' individual propensity to use condom with clients was statistically dependent on the venue of working. Multi-level modeling revealed considerable variability across venues in the likelihood of consistent condom use with clients among FSWs. Characteristics at both individual and venue levels helped to explain the observed variation. Certain venue-level factors exerted their influence on condom use over and above the effect of individual-level characteristics. The contextual influence exerted on condom use behaviors among FSWs may imply a potential to harness the path to individual behaviors from a higher and more dominant level, and shed light on the design of more effective sexual risk reduction intervention among venue-based FSWs. PMID- 26004453 TI - English, Spanish and ethno-racial receptivity in a new destination: A case study of Dominican immigrants in Reading, PA. AB - Scant information is available on experiences with language among immigrant populations in new destinations. This study provides a multi-dimensional portrait of the linguistic incorporation of Dominican immigrants in the "majority minority" city of Reading, Pennsylvania. The results show that daily life for most largely occurs in a Spanish-language milieu, but English proficiency and use in social networks is primarily a function of exposure to the United States. This is consistent with the standard narrative of assimilation models. At the same time, negative experiences with the use of both English and Spanish suggest that the linguistic context of reception is inhospitable for a substantial share of this population. Negative experiences with English are particularly likely to be mentioned by those with dark skin and greater cumulative exposure. Lastly, language plays an important role in experiences with ethno-racial enmity more broadly. Nonetheless, the persistent effect of skin tone indicates that such experiences are not reducible to language per se. PMID- 26004454 TI - Legislative responses to wrongful conviction: Do partisan principals and advocacy efforts influence state-level criminal justice policy? AB - The number of discovered wrongful criminal convictions (and resulting exonerations) has increased over the past decade. These cases erode public confidence in the criminal justice system and trust in the rule of law. Many states have adopted laws that aim to reduce system errors but no study has examined why some states appear more willing to provide due process protections against wrongful convictions than others. Findings from regression estimates suggest that states with a Republican controlled legislature or more Republican voters are less likely to pass these laws while the presence of advocacy organizations that are part of the 'innocence movement' make legislative change more likely. We thus identify important differences in the political and social context between U.S. states that influence the adoption of criminal justice policies. PMID- 26004455 TI - Does it pay to attend a for-profit college? Vertical and horizontal stratification in higher education. AB - Despite the recent growth of for-profit colleges, scholars are only beginning to understand the labor market consequences of attending these institutions. Using data from the National Longitudinal Survey of Youth 1997, I find that for-profit associate's degree holders encounter lower hourly earnings than associate's degree holders educated at public or private, nonprofit colleges, and earnings that are not significantly different than high school graduates. However, individuals who complete a bachelor's degree by attending college in either the for-profit or nonprofit sectors encounter positive returns. These findings, robust to model selection, suggest that the distinction between for-profit and nonprofit colleges constitutes an important axis in the horizontal dimension of education at the sub-baccalaureate level, and complicate notions of vertical stratification such that higher levels of educational attainment do not necessarily guarantee a wage premium. PMID- 26004456 TI - Income inequality, distributive fairness and political trust in Latin America. AB - In the wake of rising levels of income inequality during the past two decades, widespread concerns emerged about the social and political consequences of the widening gap between the poor and the rich that can be observed in many established democracies. Several empirical studies substantiate the link between macro-level income inequality and political attitudes and behavior, pointing at its broad and negative implications for political equality. Accordingly, these implications are expected to be accentuated in contexts of high inequality, as is the case in Latin America. Despite these general concerns about the consequences of income inequality, few studies have accounted for the importance of individual perceptions of distributive fairness in regard to trust in political institutions. Even less is known about the extent to which distributive fairness perceptions co-vary with objective indicators of inequality. Moreover, the research in this area has traditionally focused on OECD countries, which have lower indexes of inequality than the rest of the world. This study aims at filling this gap by focusing on the relevance of distributive fairness perceptions and macro-level inequality for political trust and on how these two levels interact in Latin American countries. The analyses are based on the Latinobarometer survey 2011, which consists of 18 countries. Multilevel estimations suggest that both dimensions of inequality are negatively associated with political trust but that higher levels of macro-level inequality attenuate rather than increase the strength of the negative association between distributive fairness perceptions and political trust. PMID- 26004457 TI - A natural experiment of peer influences on youth alcohol use. AB - This study estimates peer effects on alcohol use, drawing from a database of about 2000 randomly-assigned roommates on a college campus. The estimation of peer influences also takes into consideration ego's history of alcohol use and friendship with the peer. College students averaged an additional two-fifths of a binge drinking episode per month and an additional one-half of a drinking episode per month when randomly assigned a roommate who drank in high school than when assigned a roommate who did not drink in high school. An individual's prior history of alcohol use proves important. Peer effects on binge drinking as well as drinking for those who already drank in high school were about twice as large as average peer effects. When one did not have a history of alcohol use, negative peer influences were absent. Also important is the friendship between peers. When a peer is considered a best friend, the step-up effect (or positive interaction effect) increased by 1.25-1.61 drinking episodes per month. However, even when a peer is not considered a best friend, a drinking peer still increased ego's drinking episodes by 0.75-1.00 per month. PMID- 26004458 TI - Gender and class housework inequalities in the era of outsourcing hiring domestic work in Spain. AB - Many households regularly outsource unpaid domestic labor by purchasing services and products to help with cleaning, cooking, ironing, and other chores. Despite the prevalence of this practice, scholars know little about how it affects inequalities in the time spent on housework. Drawing on data on 3540 dual-earner households in Spain, this article examines the relationship between hiring domestic work and both the within-household gender gap in housework and the class gap in housework among women. I find that women who hire do about 30min less housework per day than non-hiring women, but in relation to their partners these women continue to do the same share of housework. Using counterfactual analysis, I find that the absence of paid domestic work is associated with a 20% decline in the class gap in housework among Spanish women. PMID- 26004459 TI - No place like home? Familism and Latino/a-white differences in college pathways. AB - Recent research has argued that familism, defined as a cultural preference for privileging family goals over individual goals, may discourage some Latino/a youth from applying to and attending college, particularly if they must leave home (Desmond and Lopez Turley, 2009). Using data from the Education Longitudinal Study, we find that Latino/a students and parents indeed have stronger preferences than white students and parents for living at home during college. For students, most differences in preferences for proximate colleges are explained by socioeconomic status, academic achievement and high school/regional differences. Moreover, controlling for socioeconomic background and prior achievement explains most racial/ethnic gaps in college application and attendance among high school graduates, suggesting that familism per se is not a significant deterrent to college enrollment above and beyond these more primary factors. However, results indicate generational differences; cultural factors may contribute to racial/ethnic gaps in parental preferences for children to remain at home. PMID- 26004460 TI - Does relative out-group size in neighborhoods drive down associational life of Whites in the U.S.? Testing constrict, conflict and contact theories. AB - We test whether a larger percentage of non-Whites in neighborhoods decreases associational involvement and build on earlier research in three ways. First, we explicitly consider the ethnic composition of organizations, distinguishing involvement in bridging (with out-group members) and bonding (only in-group members) organizations. Second, we start from constrict theory and test competing sets of predictions derived from conflict and contact theories to explain these relationships. Third, we examine whether relative out-group size affects involvement in different types of voluntary organizations equally. Using data from the 2005 U.S. 'Citizenship, Involvement, Democracy' survey, the percentage of non-Whites in neighborhoods is largely unrelated with associational involvement or perceived ethnic threat. However, perceiving ethnic threat is consistently negatively related with involvement in bridging organizations. Simultaneously, a larger percentage of non-Whites fosters intergroup contact, which is negatively related with perceptions of ethnic threat and involvement in bonding leisure organizations. Our results shed more light on the relationship between the relative out-group size in neighborhoods and associational involvement as well as underlying explanations for this link. PMID- 26004461 TI - Income inequality and educational assortative mating: Evidence from the Luxembourg Income Study. AB - Though extensive research has explored the prevalence of educational assortative mating, what causes its variation across countries and over time is not well understood. Using data from the Luxembourg Income Study Database, I investigate the hypothesis that assortative mating by income is influenced by income inequality between educational strata. I find that in countries with greater returns to education, the odds of any sort of union that crosses educational boundaries is substantially reduced. However, I do not find substantial evidence of an effect of changes in returns to education on marital sorting within countries. Educational and labor market parity between males and females appear to be negatively related to marital sorting. PMID- 26004462 TI - Relational skill assets and anti-immigrant sentiments. AB - This study introduces the role of relational skill assets in accounting for attitudes toward immigrants: relational skill assets. Drawing upon stratification researchers' notion of "non-cognitive skills," we build a theoretical framework highlighting the role of occupational skill requirements in explaining anti immigrant sentiment. Then, utilizing two occupation-specific measures, interpersonal skill requirement and instrumental skill requirement, we construct an explanatory factor, relational skill specificity. We test its effect on anti immigrant attitudes as well as on the concentration of foreign-born workers in occupations, using the 2004 national identity module of General Social Survey. The findings confirm our argument that workers with a higher possession of interpersonal skill assets relative to instrumental skill assets are exposed to less intense competitions with immigrants, and are therefore less likely to express anti-immigrant sentiments. Our findings suggest that occupational-level relational skill assets based on sociocultural differences play an important role in shaping native workers' attitudes' toward immigrants. PMID- 26004463 TI - Parent-child leisure activities and cultural capital in the United Kingdom: The gendered effects of education and social class. AB - This article uses data on couples from the 2000 UK Time Use Survey (N=610) to analyze how social position influences parents' leisure activities with children. The study is the first using representative data to investigate this fundamental question to understand social inequalities in family life and children's life chances. Results reveal that social position intersects with gender in influencing parent-child leisure activities with implications on children's cultural capital. Three are the main findings: (1) social position has significant positive effects on cultural activities with children and negative on parent-child television watching among mothers, but moderate differences are observed for fathers; (2) father-child leisure is strongly influenced by the spouse's social position, but not mother-child leisure; (3) education and social class show complex differences in affecting parent-child leisure, suggesting that future studies should include these two variables when analyzing parent-child time and family life. PMID- 26004464 TI - Civic communities and urban violence. AB - Civic communities have a spirit of entrepreneurialism, a locally invested population and an institutional structure fostering civic engagement. Prior research, mainly confined to studying rural communities and fairly large geographic areas, has demonstrated that civic communities have lower rates of violence. The current study analyzes the associations between the components of civic communities and homicide rates for New Orleans neighborhoods (census tracts) in the years following Hurricane Katrina. Results from negative binomial regression models adjusting for spatial autocorrelation reveal that community homicide rates are lower where an entrepreneurial business climate is more pronounced and where there is more local investment. Additionally, an interaction between the availability of civic institutions and resource disadvantage reveals that the protective effects of civic institutions are only evident in disadvantaged communities. PMID- 26004465 TI - How do we assign ourselves social status? A cross-cultural test of the cognitive averaging principle. AB - Subjective social status (SSS), or one's perceived social standing, is linked robustly to mental and physical health and is thought to be determined in part by a cognitive average of one's past, present and expected socioeconomic status. However, this averaging principle awaits a formal test. Further, cultures differ with regard to how they perceive and discount time. In this study, I draw upon cross-sectional data from the United States and Japan (2005 MIDUS non-Hispanic whites and 2008 MIDJA), which measured subjective status in terms of one's perceived standing within a personally defined community. I compare equal and unequal cognitive averaging models for their goodness of fit relative to a traditional present-based model. Socioeconomic status is assessed broadly, in terms of past, present and expected overall work and financial situations. In the United States, averaging models do not fit the data consistently better than a present-based model of SSS. However, in Japan, averaging models do fit SSS consistently better. These fit conclusions are robust to controlling for negative affect. PMID- 26004466 TI - Do information, price, or morals influence ethical consumption? A natural field experiment and customer survey on the purchase of Fair Trade coffee. AB - We address ethical consumption using a natural field experiment on the actual purchase of Fair Trade (FT) coffee in three supermarkets in Germany. Based on a quasi-experimental before-and-after design the effects of three different treatments - information, 20% price reduction, and a moral appeal - are analyzed. Sales data cover actual ethical purchase behavior and avoid problems of social desirability. But they offer only limited insights into the motivations of individual consumers. We therefore complemented the field experiment with a customer survey that allows us to contrast observed (ethical) buying behavior with self-reported FT consumption. Results from the experiment suggest that only the price reduction had the expected positive and statistically significant effect on FT consumption. PMID- 26004467 TI - Does residential mobility improve educational outcomes? Evidence from the Netherlands. AB - This paper explores the impact of residential mobility on educational outcomes. By considering a large Dutch city with substantial internal residential mobility, we examine how residential mobility influences the decision of students to drop out of school. The paper exploits a rich administrative dataset with extensive information on educational, individual, family, housing and moving characteristics of students. It combines a matching design with a multivariate regression analysis, such that the evaluation draws on a well-comparable control group for the treated students. Accounting for individual, family, educational, neighborhood and housing characteristics, as well as for school and year fixed effects, we observe that residential mobility increases the probability of school dropout in the first few years after moving. The estimated effect changes, however, to a lower risk of early school leaving after an initial period, and then changes again to a higher risk after 6years. This effect remains, regardless the level of education the students attended, or whether the student moves to a better or a worse neighborhood. PMID- 26004468 TI - Clues of subjective social status among young adults. AB - We investigate determinants of subjective social status (SSS) as measured by respondents placing themselves on a ten-rung ladder from least to most "money", "education" and "respected job", in a large sample of young adults. The most potent clues of SSS are proximate in the life course, reflecting educational attainment and current socioeconomic and job situation, rather than distal characteristics such as family background, although relatively distal High school GPA has a lingering effect. Additional analyses reveal that College selectivity has a substantial impact on SSS, net of other variables in the model; Currently married does not significantly contribute to SSS, but contrary to some expectations Number of children significantly lowers SSS. We find no evidence of greater "status borrowing" by women as associations of SSS with shared household characteristics (Household income, Household assets, Home ownership) do not differ by gender. Our findings for these young adults support the conclusion of earlier research that SSS reflects a "cognitive averaging" of standard dimensions of socioeconomic status. PMID- 26004469 TI - Asian children's verbal development: A comparison of the United States and Australia. AB - Using longitudinal cohort studies from Australia and the United States, we assess the pervasiveness of the Asian academic advantage by documenting White-Asian differences in verbal development from early to middle childhood. In the United States, Asian children begin school with higher verbal scores than Whites, but their advantage erodes over time. The initial verbal advantage of Asian American children is partly due to their parent's socioeconomic advantage and would have been larger had it not been for their mother's English deficiency. In Australia, Asian children have lower verbal scores than Whites at age 4, but their scores grow a faster rate and converge towards those of Whites by age 8. The initial verbal disadvantage of Asian Australian children is partly due to their mother's English deficiency and would have been larger had it not been for their Asian parent's educational advantage. Asian Australian children's verbal scores grow at a faster pace, in part, because of their parent's educational advantage. PMID- 26004470 TI - Understanding the devaluation of vulnerable groups: A novel application of Institutional Anomie Theory. AB - Prejudices legitimize the discrimination against groups by declaring them to be of unequal, especially of less, worth. This legitimizing power is highly relevant in social conflicts of modern societies that are governed by market-oriented value systems. However, prejudice research has yet to be linked to sociological discourses on the marketization of society. We argue that Institutional Anomie Theory (IAT), a theory originally developed to explain crime rates, offers a fruitful macro-sociological framework for a better understanding of micro-social prejudices that emerge along with processes of marketization. Extending IAT to explain prejudices in a German study based on survey data offers a first attempt to underpin our theoretical hypotheses with empirical data. Although the results need to be interpreted with due caution, they suggest that the extended IAT model can be usefully applied to explain how a marketized mentality is related to different forms of institutional integration, and how it is conducive to specific prejudices that emerge in market-dominated societies against purported economically burdening social groups. PMID- 26004472 TI - Walking ATMs and the immigration spillover effect: The link between Latino immigration and robbery victimization. AB - Media reports and prior research suggest that undocumented Latino migrants are disproportionately robbed because they rely on a cash-only economy and they are reluctant to report crimes to law-enforcement (the Walking ATM phenomenon). From this we generate two specific research questions. First, we probe for an immigration spillover effect - defined as increased native and documented Latino robbery victimization due to offenders' inability to distinguish between the statuses of potential victims. Second, we examine the oft-repeated claim that Blacks robbers disproportionately target Latino victims. Using National Incident Based Reporting System (NIBRS) data from 282 counties, results show (1) support for an immigration spillover effect but, (2) no support for the claim that Latinos are disproportionately singled out by Black robbers. We discuss the implications of our findings. PMID- 26004471 TI - Nurture net of nature: Re-evaluating the role of shared environments in academic achievement and verbal intelligence. AB - Prominent authors in the behavioral genetics tradition have long argued that shared environments do not meaningfully shape intelligence and academic achievement. However, we argue that these conclusions are erroneous due to large violations of the additivity assumption underlying behavioral genetics methods - that sources of genetic and shared and nonshared environmental variance are independent and non-interactive. This is compounded in some cases by the theoretical equation of the effective and objective environments, where the former is defined by whether siblings are made more or less similar, and the latter by whether siblings are equally subject to the environmental characteristic in question. Using monozygotic twin fixed effects models, which compare outcomes among genetically identical pairs, we show that many characteristics of objectively shared environments significantly moderate the effects of nonshared environments on adolescent academic achievement and verbal intelligence, violating the additivity assumption of behavioral genetic methods. Importantly, these effects would be categorized as nonshared environmental influences in standard twin models despite their roots in shared environments. These findings should encourage caution among those who claim that the frequently trivial variance attributed to shared environments in behavioral genetic models means that families, schools, and neighborhoods do not meaningfully influence these outcomes. PMID- 26004473 TI - On the move: Incarceration, race, and residential mobility. AB - The present study examines the relationship between incarceration and post-prison residential mobility. In spite of recent research examining the residential context following incarceration, we know little about if or how incarceration affects individual patterns of residential mobility. This study starts to fill this gap in knowledge by drawing on nationally representative data from the 1979 National Longitudinal Survey of Youth (NLSY79). I find that individuals with a history of incarceration are more likely to move after prison than they are before prison. This relationship holds even after accounting for various time varying and time-stable sources of spuriousness, including other known correlates of mobility. Additional analyses suggest that this effect is strongest early in the reentry period, and that there exists important racial variation in the relationship between incarceration and mobility. These results imply that, while housing stability is an important feature of successful prisoner reentry, incarceration contributes to larger patterns of residential instability. PMID- 26004474 TI - Field of study variation throughout the college pipeline and its effect on the earnings gap: Differences between ethnic and immigrant groups in Israel. AB - This study demonstrates the analytical leverage gained from considering the entire college pipeline-including the application, admission and graduation stages-in examining the economic position of various groups upon labor market entry. The findings, based on data from three elite universities in Israel, reveal that the process that shapes economic inequality between different ethnic and immigrant groups is not necessarily cumulative. Field of study stratification does not expand systematically from stage to stage and the position of groups on the field of study hierarchy at each stage is not entirely explained by academic preparation. Differential selection and attrition processes, as well as ambition and aspirations, also shape the position of ethnic groups in the earnings hierarchy and generate a non-cumulative pattern. These findings suggest that a cross-sectional assessment of field of study inequality at the graduation stage can generate misleading conclusions about group-based economic inequality among workers with a bachelor's degree. PMID- 26004475 TI - Should we trust survey data? Assessing response simplification and data fabrication. AB - While many factors, such as unit- and item nonresponse, threaten data quality, we focus on data contamination that arises primarily from task simplification processes. We argue that such processes can occur at two levels. First, respondents themselves may engage in various response strategies that minimize their time and effort in completing the survey. Second, interviewers and other employees of the research institute might take various shortcuts to reduce their time and/or to fulfill the requirements of their contracts; in the simplest form this can be done via copy-and-paste procedures. This paper examines the cross national quality of the reports from principals of schools participating in the 2009 PISA. We introduce two measures of data quality to document that extreme response simplification characterizes the behavior of substantial numbers of school principals in numerous countries. Additionally, we discovered strong evidence of data fabrication in several countries. PMID- 26004476 TI - Social interactions and college enrollment: A combined school fixed effects/instrumental variables approach. AB - This paper provides some of the first evidence of peer effects in college enrollment decisions. There are several empirical challenges in assessing the influences of peers in this context, including the endogeneity of high school, shared group-level unobservables, and identifying policy-relevant parameters of social interactions models. This paper addresses these issues by using an instrumental variables/fixed effects approach that compares students in the same school but different grade-levels who are thus exposed to different sets of classmates. In particular, plausibly exogenous variation in peers' parents' college expectations are used as an instrument for peers' college choices. Preferred specifications indicate that increasing a student's exposure to college going peers by ten percentage points is predicted to raise the student's probability of enrolling in college by 4 percentage points. This effect is roughly half the magnitude of growing up in a household with married parents (vs. an unmarried household). PMID- 26004477 TI - Training in two-tier labor markets: The role of job match quality. AB - This study examines training investments in two-tier labor markets, focusing on the role of job match quality. Temporary workers are in general more likely than permanent workers to leave their employer and therefore are less likely to receive employer-funded training. However, as firms prefer to continue productive job matches, we hypothesize that the negative effect of holding a temporary contract on the probability to be trained diminishes with the quality of the job match. Using a recent longitudinal survey from the Netherlands, we find that temporary workers indeed participate less frequently in firm-sponsored training. However, this effect is fully driven by mismatches: holding a temporary contract does not significantly decrease the probability to receive training for workers in good job matches. Depending on match quality, a temporary job can either be a stepping stone or a dead-end. PMID- 26004478 TI - Selling students short: Racial differences in teachers' evaluations of high, average, and low performing students. AB - Education scholars document notable racial differences in teachers' perceptions of students' academic skills. Using data from the Early Childhood Longitudinal Study-Kindergarten Cohort, this study advances research on teacher perceptions by investigating whether racial differences in teachers' evaluations of first grade students' overall literacy skills vary for high, average, and low performing students. Results highlight both the overall accuracy of teachers' perceptions, and the extent and nature of possible inaccuracies, as demonstrated by remaining racial gaps net literacy test performance. Racial differences in teachers' perceptions of Black, non-White Latino, and Asian students (compared to White students) exist net teacher and school characteristics and vary considerably across literacy skill levels. Skill specific literacy assessments appear to explain the remaining racial gap for Asian students, but not for Black and non White Latino students. Implications of these findings for education scholarship, gifted education, and the achievement gap are discussed. PMID- 26004479 TI - Her earnings: Exploring variation in wives' earning contributions across six major Asian groups and Whites. AB - Previous research on understanding race-ethnic differentials in employment and economic contributions by married women has primarily focused on Blacks, Hispanics, or Whites. This study investigates variations in wives' earning contributions as measured by wives earnings as a proportion of total annual household earnings among six Asian groups, Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese relative to native born non-Hispanic White. I disaggregate the six Asian groups by their ethnicity and nativity status. Using pooled data from 2009-2011 American Community Survey, the findings show significance of human capital, hours of paid labor market engagement and nativity status. There is strong and negative association between husbands' human capital and labor supply with wives' earning contributions suggesting near universality of male-breadwinner status. Notwithstanding the commonalities, there is significant intergroup diversity. While foreign born and native born Filipina wives despite their spouses' reasonably high human capital and work hours, contribute one of the highest shares, the same cannot be said for the Asian Indians and Japanese. For foreign born Asian Indian and to some extent Japanese women, their high human capital is not translated to high earning contribution after controlling for husband's human capital. Further, nativity status impacts groups differentially. Native born Vietnamese wives contribute the greatest. Overall, the findings underscore the relevance of employing multiple conceptual frameworks in understanding earning contributions of foreign and native born Asian wives belonging to the six Asian groups, Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese. PMID- 26004480 TI - Explanations of changes in church attendance between 1970 and 2009. AB - We deduce hypotheses from theories on religious change to explain changes in church attendance rates. Using a new dataset with 51 countries across a long period we apply panel regression models, which enable us to test well-known theories in a more strict and dynamic fashion than do cross-sectional studies. Our results provide new evidence for a few old ideas, but also show striking lack of evidence for ideas that appear well-accepted. Tertiary education proved to be a strong predictor of changes in church attendance. Theories about individualization were also supported. The evidence of existential insecurity as a cause of change was ambiguous: economic development and life expectancy showed significant effects but income inequality did not. We found no support for theories on social globalization and social benefit policy. Finally, we found that income inequality and urbanization were driving forces of change during the 70s and 80s, but not since 1990. PMID- 26004481 TI - The consequences of job displacement for health: moderating influences of economic conditions and educational attainment. AB - This paper examines the impact of worker displacement on health in the United States from 1975-2004, especially the extent to which the impact of displacement on health varies according to the economic conditions in the year of displacement and the education level of the displaced worker. Findings from ordered probit and fixed effects models suggest that the negative impact of displacement on health is exacerbated by a higher unemployment rate at the time of displacement and for displaced workers with a college degree. PMID- 26004482 TI - Primary status, complementary status, and organizational survival in the U.S. venture capital industry. AB - We introduce a distinction between two kinds of status and examine their effects on the exit rates of organizations investing in the U.S. venture capital industry. Extending past work on status-based competition, we start with a simple baseline: we describe primary status as a network-related signal of an organization's quality in a leadership role, that is, as a function of the degree to which an organization leads others that are themselves well regarded as lead organizations in the context of investment syndicates. Combining Harary's (1959) image of the elite consultant with Goffman's (1956) concept of "capacity-esteem," we then discuss complementary status as an affiliation-based signal of an organization's quality in a supporting role. We measure complementary status as a function of the extent to which an organization is invited into syndicates by well-regarded lead organizations-that is, by those possessing high levels of primary status. Findings show that, conditioning on primary status, complementary status reduces the rate at which venture capital organizations exit the industry. Consistent with the premise that these kinds of status correspond to different roles and market identities, we also find that complementary status attenuates (and ultimately reverses) the otherwise favorable effect of primary status on an organization's life chances. Theoretically and methodologically oriented scope conditions, as well as implications for future research, are discussed. PMID- 26004483 TI - Risk factors for family time burdens providing and arranging health care for children with special health care needs: Lessons from nonproportional odds models. AB - We identify need, enabling, and predisposing factors for high family time burdens associated with the health care of chronically-ill children, using data from the U.S. 2009-2010 National Survey of Children with Special Health Care Needs (NS CSHCN), a population-based survey of 40,242 children with special health care needs (CSHCN). We estimate generalized ordered logistic multivariable regressions of time spent (1) providing health care for the child at home, (2) arranging/coordinating health care, and (3) combined time. Factors associated with higher time burdens included child's functional limitations, severe or unstable health conditions, public health insurance, lack of a medical home, low family income, low adult education, and non-white race. Nonproportional odds models revealed associations between risk factors and time burden that were obscured by binary and standard ordered logistic models. Clinicians and policymakers can use this information to design interventions to alleviate this important family stressor. PMID- 26004484 TI - Measurement, methods, and divergent patterns: Reassessing the effects of same-sex parents. AB - Scholars have noted that survey analysis of small subsamples-for example, same sex parent families-is sensitive to researchers' analytical decisions, and even small differences in coding can profoundly shape empirical patterns. As an illustration, we reassess the findings of a recent article by Regnerus regarding the implications of being raised by gay and lesbian parents. Taking a close look at the New Family Structures Study (NFSS), we demonstrate the potential for misclassifying a non-negligible number of respondents as having been raised by parents who had a same-sex romantic relationship. We assess the implications of these possible misclassifications, along with other methodological considerations, by reanalyzing the NFSS in seven steps. The reanalysis offers evidence that the empirical patterns showcased in the original Regnerus article are fragile-so fragile that they appear largely a function of these possible misclassifications and other methodological choices. Our replication and reanalysis of Regnerus's study offer a cautionary illustration of the importance of double checking and critically assessing the implications of measurement and other methodological decisions in our and others' research. PMID- 26004485 TI - Curricular policy as a collective effects problem: A distributional approach. AB - Current educational policies in the United States attempt to boost student achievement and promote equality by intensifying the curriculum and exposing students to more advanced coursework. This paper investigates the relationship between one such effort - California's push to enroll all 8th grade students in Algebra - and the distribution of student achievement. We suggest that this effort is an instance of a "collective effects" problem, where the population level effects of a policy are different from its effects at the individual level. In such contexts, we argue that it is important to consider broader population effects as well as the difference between "treated" and "untreated" individuals. To do so, we present differences in inverse propensity score weighted distributions investigating how this curricular policy changed the distribution of student achievement. We find that California's attempt to intensify the curriculum did not raise test scores at the bottom of the distribution, but did lower scores at the top of the distribution. These results highlight the efficacy of inverse propensity score weighting approaches for examining distributional differences, and provide a cautionary tale for curricular intensification efforts and other policies with collective effects. PMID- 26004486 TI - Unemployment scarring by gender: Human capital depreciation or stigmatization? Longitudinal evidence from the Netherlands, 1980-2000. AB - Using longitudinal data from the Dutch Labor Force Supply Panel (OSA), this article examines how unemployment scarring (i.e., wage setbacks following unemployment) and its underlying mechanisms operate across gender in the Netherlands over the period 1985-2000. A series of fixed effect panel models that correct for unobserved heterogeneity, reveal a notable disparity in unemployment scarring by gender. Interestingly, while unemployment scarring is short-lived and partly conditional upon human capital differences among women, it is strongly persistent among men and contingent upon old age, ethnicity, and tight economic conditions. Our findings provide new evidence regarding unemployment scarring by gender while they support the hypothesis that among women the effects of unemployment scarring are predominantly driven by human capital depreciation, while among men stigma effects dominate. PMID- 26004487 TI - Small groups, contexts, and civic engagement: A multilevel analysis of United States Congregational Life Survey data. AB - Prior research suggests that church-goers are more civically engaged than their non-church-going counterparts. Little is known, however, about how the popular phenomenon of small groups factors into this equation. In the present study, we examine relationships between small group participation at individual and congregation levels and civic engagement. Using multilevel modeling and national data on congregations and individuals from the U.S. Congregational Life Study (n=82,044), we find that: (1) individual-level small group involvement is associated with four measures of civic engagement; (2) congregation-level small group participation is associated with both lower and higher civic engagement in the case of two outcomes; and (3) in the case of three civic outcomes, congregation-level small group participation moderates individual-level small group involvement such that small group members' civic activity more closely resembles the lower civic engagement of small group nonparticipants. In the case of one civic outcome, at high levels of overall small group participation, small group members' civic engagement drops below that of small group nonparticipants. Explanations for these findings, including a "crowding out" effect, are examined including their complex implications for debates regarding small groups, religious involvement, and civic engagement. PMID- 26004488 TI - When children affect parents: Children's academic performance and parental investment. AB - Sociologists have extensively documented the ways that parent resources predict children's achievement. However, less is known about whether and how children's academic performance shapes parental investment behaviors. I use data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K) and longitudinal fixed effects models to examine how changes in teacher assessments are related to changes in the conferral of various parent resources. Overall, I find that the relationship between achievement and investment varies based on the directionality in children's achievement and the type of resource at hand. Children whose performance improves receive a broad range of enrichment resources, while declines in performance are met with corrective educational resources. Results are largely consistent whether language or math assessments are used to predict investment, and also among children whose achievement does not change over time. I discuss these patterns, along with implications for the use of parent resources in education and family research. PMID- 26004489 TI - Thinkers and feelers: Emotion and giving. AB - Voluntary organizations, such as religious congregations, ask their members to contribute money as a part of membership and rely on these contributions for their survival. Yet often only a small cadre of members provides the majority of the contributions. Past research on congregational giving focuses on cognitive rational processes, generally neglecting the role of emotion. Extending Collins' (2004) interaction ritual theory, I predict that individuals who experience positive emotions during religious services will be more likely to give a higher proportion of their income to their congregation than those who do not. Moreover, I argue that this effect will be amplified in congregational contexts characterized by high aggregate levels of positive emotion, strictness, dense congregational networks, and expressive rituals. Using data from the 2001 U.S. Congregational Life Survey and multilevel modeling, I find support for several of these hypotheses. The findings suggest that both cognitive and emotional processes underlie congregational giving. PMID- 26004490 TI - Losing confidence in medicine in an era of medical expansion? AB - Has the expansion of the medical field inspired more or less confidence in medicine among the American public? This study investigates how confidence in medicine has changed over the past three decades, whether this trend is uniform across social groups and which aspects of medicine are most affected. Data are from repeated cross-sectional U.S. General Social Surveys spanning the years 1973 2008, including the 2002 Doctors and Patients Module and the 1998 Pressing Issues in Health and Medical Care Module. Americans' confidence in medicine has declined continuously over the past three decades, and the extent of this decline did not vary by gender, age group, cohort, or income level. Analysis of differences across socio-demographic groups suggests that confidence in medicine is related to trust in doctors' ethics but different from obedience to doctors' authority. Therefore, the downward trend in confidence in medicine may suggest a decline in public trust in doctors' ethics, but not necessarily a decline in obedience to doctors' authority. PMID- 26004491 TI - "Double-dose" English as a strategy for improving adolescent literacy: Total effect and mediated effect through classroom peer ability change. AB - "Double-dose" coursework has become an increasingly popular strategy to assist low-performing students succeed in academic coursework. Chicago implemented a "double-dose" English policy in 2003. This policy not only provided additional instructional time to struggling readers, but also intensified skill-based sorting in English classes. I use policy-induced variation to infer the policy effect on students' reading achievement and the effect mediated by classroom peer ability change. Results show very weak, but positive effects of taking double dose English for students with average skills. However, potential benefits of doubled instructional time are likely to be offset by negative effects of declines in classroom peer ability. Students with very weak skills experienced minimal change in classroom peer ability, and two-period coursework is likely to benefit these students. PMID- 26004492 TI - Abstracts of the 2015 Vascular Annual Meeting. Chicago, Illinois. June 17-20, 2015. PMID- 26004494 TI - Characterization of cell death caused by diplodiatoxin and dipmatol, toxic metabolites of Stenocarpella maydis. AB - Diplodiosis, a neuromycotoxicosis of cattle and sheep grazing on mouldy cobs infected by Stenocarpella maydis, is considered the last major veterinary mycotoxicosis for which the causative mycotoxin is still unknown. The current study was aimed at characterizing the cell death observed in mouse neuroblastoma (Neuro-2a), Chinese hamster ovary (CHO-K1) and Madin-Darby bovine kidney (MDBK) cell lines exposed to the S. maydis metabolites (i.e. diplodiatoxin and dipmatol) by investigating the roles of necrosis and apoptosis. Necrosis was investigated using the lactate dehydrogenase (LDH) leakage and propidium iodide (PI) flow cytometry assays and apoptosis was evaluated using the caspase-3/7 and Annexin V flow cytometry assays. In addition, transmission electron microscopy (TEM) was used to correlate the cell death pathways observed in this study with their typical morphologies. Both diplodiatoxin and dipmatol (750 MUM) induced necrosis and caspase-dependent apoptosis in Neuro-2a, CHO-K1 and MDBK cells. Ultrastructurally, the two mycotoxins induced mitochondrial damage, cytoplasmic vacuolation and nuclear fragmentation in the three cell lines. These findings have laid a foundation for future studies aimed at elucidating in detail the mechanism of action of the S. maydis metabolites. PMID- 26004495 TI - Saturated hydrogen saline attenuates endotoxin-induced lung dysfunction. AB - BACKGROUND: Acute lung injury induced by lipopolysaccharides (LPSs) is caused by pulmonary inflammation and pulmonary vascular permeability. Activation of p38 mitogen-activated protein kinase causes inflammation, and proinflammatory cytokines and oxidative stress induce autophagy, a catabolic mechanism responsible for protein degradation and recycling of damaged proteins and cytoplasmic organelles. If not controlled, excessive autophagy responses can result in cell death. MATERIALS AND METHODS: In this study, we pretreated rats with saturated hydrogen saline, and examined the molecular mechanism by which saturated hydrogen saline attenuates LPS-induced acute lung dysfunction. Sixty four male Sprague-Dawley rats were randomly assigned to one of three groups--a control group, an LPS group, or an LPS plus saturated hydrogen saline (LPS + H2) group. RESULTS: Treatment with saturated hydrogen saline prolonged the median survival time of rats and reduced lung dysfunction induced by LPS. Moreover, saturated hydrogen saline significantly attenuated LPS-mediated induction of serum tumor necrosis factor alpha, interleukin 6, myeloperoxidase, and malondialdehyde (P < 0.05). CONCLUSIONS: Autophagosomes were found in the cytoplasm of type II alveolar epithelial cells of LPS-treated rats, and light chain 3 protein (LC3)I/II was increased by LPS treatment. In contrast, saturated hydrogen saline decreased the number of autophagosomes and LC3I/II expression. Saturated hydrogen saline also attenuated the LPS-mediated increase in apoptosis and p38 expression. Taken together, saturated hydrogen saline may attenuate LPS induced acute lung dysfunction in rats by reducing inflammation, autophagy, and apoptosis involving the p38 mitogen-activated protein kinase signaling pathway. PMID- 26004496 TI - Predicting postoperative atrial fibrillation using CHA2DS2-VASc scores. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is the most frequent complication of cardiac surgery and is associated with increased morbidity and mortality. Pharmacologic prophylaxis is the main method of preventing POAF but needs to be targeted to patients at high risk of developing POAF. The CHA2DS2 VASc scoring system is a clinical guideline for assessing ischemic stroke risk in patients with atrial fibrillation. The present study evaluated the utility of this scoring system in predicting the risk of developing de novo POAF in cardiac surgery patients. MATERIALS AND METHODS: A total of 2385 patients undergoing cardiac surgery at our institution from 2008-2014 were identified for analysis. Each patient was assigned a CHA2DS2-VASc score and placed into a low- (score of 0), intermediate- (1), or high-risk (>=2) group. A multivariate regression model was created to control for known risk factors of atrial fibrillation. RESULTS: POAF occurred in 380 of 2385 patients (15.9%). Mean CHA2DS2-VASc scores among patients with POAF and without POAF were 3.6 +/- 1.7 and 2.8 +/- 1.7, respectively (P < 0.0001). Using multivariate analysis, as a patient's CHA2DS2 VASc score rose from 0-9, the risk of developing POAF increased from 8.2%-42.3%. Each point increase was associated with higher odds of developing POAF (adjusted odds ratio, 1.27; 95% confidence interval, 1.18-1.36, P < 0.0001). Compared with low-risk patients, patients in the high-risk group were 5.21 times more likely to develop POAF (P < 0.0001). CONCLUSIONS: The CHA2DS2-VASc algorithm is a simple risk-stratification tool that could be used to direct pharmacologic prophylaxis toward patients most likely to experience POAF. PMID- 26004493 TI - Mechanisms and therapeutic potential of microRNAs in hypertension. AB - Hypertension is the major risk factor for the development of stroke, coronary artery disease, heart failure and renal disease. The underlying cellular and molecular mechanisms of hypertension are complex and remain largely elusive. MicroRNAs (miRNAs) are short, noncoding RNA fragments of 22-26 nucleotides and regulate protein expression post-transcriptionally by targeting the 3' untranslated region of mRNA. A growing body of recent research indicates that miRNAs are important in the pathogenesis of arterial hypertension. Herein, we summarize the current knowledge regarding the mechanisms of miRNAs in cardiovascular remodeling, focusing specifically on hypertension. We also review recent progress of the miRNA-based therapeutics including pharmacological and nonpharmacological therapies (such as exercise training) and their potential applications in the management of hypertension. PMID- 26004497 TI - Obstructing ventral hernias are not independently associated with surgical site infections. AB - BACKGROUND: Delayed operative intervention in the setting of adhesive bowel obstruction has been recently shown to increase the rate of surgical site infection (SSI), raising the concern for bacterial translocation. The effect of obstruction on SSI rate in patients with ventral hernia is unknown. The aim of this study was to assess the association between bowel obstruction and SSI in patients undergoing ventral hernia repair (VHR). MATERIALS AND METHODS: This study is a retrospective database review. Patients undergoing isolated VHR from 2005-2011 were identified from the American College of Surgeons' National Surgical Quality Improvement Program database. Demographics, comorbidities, and 30-d outcomes were analyzed. Multivariate logistic regression was used for variables with a P value of <0.1. RESULTS: A total of 68,811 patients underwent isolated VHR; 53.1% were male with mean age of 53 +/- 15 y and body mass index of 32 +/- 8. Hernia-related obstruction was found in 17,058 (24.8%). In patients with obstruction, SSI was more frequent (3.2% versus 2.6%, P < 0.001). Obesity, advanced age, vascular, pulmonary, hepatic, renal disease, and diabetes were more prevalent. After controlling for confounding baseline variables, bowel obstruction was not independently associated with SSI (odds ratio, 0.983, 95% confidence interval, 0.872-1.107). Subgroup analysis of clean classified cases also demonstrated the lack of independent association between obstruction and SSI. CONCLUSIONS: Obstruction in patients undergoing VHR is not independently associated with SSI. Our results suggest that mesh implantation remains a viable option in this setting. Other confounding comorbid conditions should be assessed at the time of surgical intervention to identify patients appropriate for mesh repair. PMID- 26004499 TI - A novel integrin function in innate immunity from Chinese mitten crab (Eriocheir sinensis). AB - Integrins belong to a superfamily of conserved alpha beta heterodimeric cell surface receptors that have critical function in cell migration, differentiation, and survival. In this study, an integrin called EsIntegrin was identified from Chinese mitten crab Eriocheir sinensis. EsIntegrin cDNA is 4415 bp long with a 2457 bp open reading frame that encodes an 818 amino acid protein. EsIntegrin contains a signal peptide, an integrin beta subunit (N-terminal portion of extracellular region) INB domain, an epidermal growth factor (hEGF) domain, an integrin B tail domain, a transmembrane region, and an integrin b cyt domain. EsIntegrin was mainly expressed in hemocytes and the heart, with a relatively lower expression level in gills, nerves, intestine, hepatopancreas, muscles, and eyestalk. When healthy crabs were challenged with LPS, PGN, Staphyloccocus aureus, or Vibrio parahaemolyticus, EsIntegrin expression level was upregulated significantly. Recombinant EsIntegrin has agglutination activity to Gram-positive (e.g., S. aureus and Bacillus subtilis) and Gram-negative bacteria (e.g., V. parahaemolyticus and Aeromonas hydrophila) in the presence of calcium. Furthermore, rEsIntegrin could not only bind to various bacteria such as S. aureus, Micrococcus luteus, B. subtilis, Bacillus megaterium, Bacillus thuringiensis, V. parahaemolyticus, Vibrio anguillarum, A. hydrophila, Vibrio natriegens, and Escherichia coli, but this compound also helped crabs in clearing virulent Gram-negative bacterium, V. parahaemolyticus, in vivo. These data suggested that EsIntegrin might function as cellular receptor that is involved in anti-bacterial immunity from E. sinensis. PMID- 26004500 TI - Plasmodium berghei induced priming in Anopheles albimanus independently of bacterial co-infection. AB - Priming in invertebrates is the acquired capacity to better combat a pathogen due to a previous exposure to sub-lethal doses of the same organism. It is proposed to be functionally analogous to immune memory in vertebrates. Previous studies with Anopheles gambiae mosquitoes provide evidence that the inhibitory response to a second challenge by the malaria parasite Plasmodium berghei resulted from a sustained activation of hemocytes by midgut bacteria. These bacteria probably accessed the hemolymph during a first aborted infection through lesions produced by parasites invading the midgut. Since the mosquito immune responses to midgut bacteria and Plasmodium overlap, it is difficult to determine the priming responses of each. We herein document priming induced in the aseptic An. albimanus midgut by P. berghei, probably independent of the immune response induced by midgut bacteria. This idea is further evidenced by experiments with Pbs 25-28 knock out parasites (having an impaired capacity for invading the mosquito midgut) and dead ookinetes. Priming protection against a homologous challenge with P. berghei lasted up to 12 days. There was greater incorporation of 5-bromo-2'-deoxyuridine into midgut cell nuclei (indicative of DNA synthesis without mitosis) and increased transcription of hnt (a gene required for the endocycle of midgut cells) in primed versus unprimed mosquitoes, suggesting that endoreplication was the underlying mechanism of priming. Moreover, the transcription of hnt and antimicrobial peptides related to an anti-Plasmodium response (attacin, cecropin and gambicin) was enhanced in a biphasic rather than sustained response after priming An. albimanus with P. berghei. PMID- 26004498 TI - Progress and problems with the use of suicide genes for targeted cancer therapy. AB - Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated. PMID- 26004501 TI - Test-retest reliability of dynamic causal modeling for fMRI. AB - Dynamic causal modeling (DCM) is a Bayesian framework for inferring effective connectivity among brain regions from neuroimaging data. While the validity of DCM has been investigated in various previous studies, the reliability of DCM parameter estimates across sessions has been examined less systematically. Here, we report results of a software comparison with regard to test-retest reliability of DCM for fMRI, using a challenging scenario where complex models with many parameters were applied to relatively few data points. Specifically, we examined the reliability of different DCM implementations (in terms of the intra-class correlation coefficient, ICC) based on fMRI data from 35 human subjects performing a simple motor task in two separate sessions, one month apart. We constructed DCMs of motor regions with fair to excellent reliability of conventional activation measures. Using classical DCM (cDCM) in SPM5, we found that the test-retest reliability of DCM results was high, both concerning the model evidence (ICC=0.94) and the model parameter estimates (median ICC=0.47). However, when using a more recent DCM version (DCM10 in SPM8), test-retest reliability was reduced notably. Analyses indicated that, in our particular case, the prior distributions played a crucial role in this change in reliability across software versions. Specifically, when using cDCM priors for model inversion in DCM10, this not only restored reliability but yielded even better results than in cDCM. Analyzing each component of the objective function in DCM, we found a selective change in the reliability of posterior mean estimates. This suggests that tighter regularization afforded by cDCM priors reduces the possibility of local extrema in the objective function. We conclude this paper with an outlook to ongoing developments for overcoming the software-dependency of reliability observed in this study, including global optimization and empirical Bayesian procedures. PMID- 26004502 TI - In vivo histology of the myelin g-ratio with magnetic resonance imaging. AB - The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment. PMID- 26004503 TI - Connectivity-based fixel enhancement: Whole-brain statistical analysis of diffusion MRI measures in the presence of crossing fibres. AB - In brain regions containing crossing fibre bundles, voxel-average diffusion MRI measures such as fractional anisotropy (FA) are difficult to interpret, and lack within-voxel single fibre population specificity. Recent work has focused on the development of more interpretable quantitative measures that can be associated with a specific fibre population within a voxel containing crossing fibres (herein we use fixel to refer to a specific fibre population within a single voxel). Unfortunately, traditional 3D methods for smoothing and cluster-based statistical inference cannot be used for voxel-based analysis of these measures, since the local neighbourhood for smoothing and cluster formation can be ambiguous when adjacent voxels may have different numbers of fixels, or ill defined when they belong to different tracts. Here we introduce a novel statistical method to perform whole-brain fixel-based analysis called connectivity-based fixel enhancement (CFE). CFE uses probabilistic tractography to identify structurally connected fixels that are likely to share underlying anatomy and pathology. Probabilistic connectivity information is then used for tract-specific smoothing (prior to the statistical analysis) and enhancement of the statistical map (using a threshold-free cluster enhancement-like approach). To investigate the characteristics of the CFE method, we assessed sensitivity and specificity using a large number of combinations of CFE enhancement parameters and smoothing extents, using simulated pathology generated with a range of test statistic signal-to-noise ratios in five different white matter regions (chosen to cover a broad range of fibre bundle features). The results suggest that CFE input parameters are relatively insensitive to the characteristics of the simulated pathology. We therefore recommend a single set of CFE parameters that should give near optimal results in future studies where the group effect is unknown. We then demonstrate the proposed method by comparing apparent fibre density between motor neurone disease (MND) patients with control subjects. The MND results illustrate the benefit of fixel-specific statistical inference in white matter regions that contain crossing fibres. PMID- 26004505 TI - The response decrease of auditory evoked potentials by repeated stimulation--Is there evidence for an interplay between habituation and sensitization? AB - OBJECTIVES: To assess whether the response decrement of auditory evoked potentials (AEPs) after stimulus repetition is affected by an interplay between sensitization and habituation. METHODS: AEPs were recorded in 18 healthy participants. Stimulation consisted of trains with eight tones. The 6th stimulus of each train was a frequency deviant. The N100 amplitude to the 1st stimulus of the train was quantified in each trial. Trials with initially strong N100 responses and with initially weak N100 responses were averaged separately. RESULTS: For the total trial sample, the N100 and P200 amplitudes decreased from the 1st to the 2nd stimulus of the train but not thereafter. Trials with an initially strong N100 response were qualified by likewise larger N100 amplitudes to the 2nd stimulus, as compared to trials with initially weak N100 responses, and were characterized by a pronounced N100 amplitude decrease from standards to deviants. CONCLUSION: Our findings are difficult to reconcile with the view that the response decrement of AEP components after stimulus repetition is modulated by sensitization and habituation, as no evidence for either of these two processes could be obtained. SIGNIFICANCE: The study provides further evidence against habituation as underlying mechanism for the AEP decrement after stimulus repetition. PMID- 26004504 TI - Review: Puberty as a time of remodeling the adult response to ovarian hormones. AB - During pubertal development, an animal's response to stress changes and sexual differentiation of the brain and behavior continue. We discovered that particular stressors, such as shipping from suppliers or an immune challenge with lipopolysaccharide, during the prolonged pubertal period of female mice result in long-term changes in behavioral responsiveness of the brain to estradiol assessed in adulthood. All behaviors influenced by estradiol and/or progesterone that we have studied are compromised by a stressor during pubertal development. Depending on the behavior, immune challenge or shipping from suppliers during pubertal development decreases, eliminates, or even reverses the effects of estradiol. Shipping during this period causes changes in the number of estrogen receptor immunoreactive cells in key brain areas suggesting one cellular mechanism for this remodeling of the brain's response to hormones. We suggest that particular adverse experiences in girls may cause long-term alterations in the brain's response to estradiol and/or progesterone via activation of the immune system. This in turn could lead to an alteration in any aspect of mental health that is influenced by estradiol. PMID- 26004506 TI - On growth measurements of abdominal aortic aneurysms using maximally inscribed spheres. AB - The maximum diameter, total volume of the abdominal aorta, and its growth rate are usually regarded as key factors for making a decision on the therapeutic operation time for an abdominal aortic aneurysm (AAA) patient. There is, however, a debate on what is the best standard method to measure the diameter. Currently, two dominant methods for measuring the maximum diameter are used. One is measured on the planes perpendicular to the aneurism's central line (orthogonal diameter) and the other one is measured on the axial planes (axial diameter). In this paper, another method called 'inscribed-spherical diameter' is proposed to measure the diameter. The main idea is to find the diameter of the largest sphere that fits within the aorta. An algorithm is employed to establish a centerline for the AAA geometries obtained from a set of longitudinal scans obtained from South Korea. This centerline, besides being the base of the inscribed spherical method, is used for the determination of orthogonal and axial diameter. The growth rate parameters are calculated in different diameters and the total volume and the correlations between them are studied. Furthermore, an exponential growth pattern is sought for the maximum diameters over time to examine a nonlinear growth pattern of AAA expansion both globally and locally. The results present the similarities and discrepancies of these three methods. We report the shortcomings and the advantages of each method and its performance in the quantification of expansion rates. While the orthogonal diameter measurement has an ability of capturing a realistic diameter, it fluctuated. On the other hand, the inscribed sphere diameter method tends to underestimate the diameter measurement but the growth rate can be bounded in a narrow region for aiding prediction capability. Moreover, expansion rate parameters derived from this measurement exhibit good correlation with each other and with growth rate of volume. In conclusion, although the orthogonal method remains the main method of measuring the diameter of an abdominal aorta, employing the idea of maximally inscribed spheres provides both a tool for generation of the centerline, and an additional parameter for quantification of aneurysmal growth rates. PMID- 26004507 TI - Mitotic Control of Planar Cell Polarity by Polo-like Kinase 1. AB - During cell division, polarized epithelial cells employ mechanisms to preserve cell polarity and tissue integrity. In dividing cells of the mammalian skin, planar cell polarity (PCP) is maintained through the bulk internalization, equal segregation, and polarized recycling of cortical PCP proteins. The dramatic redistribution of PCP proteins coincides precisely with cell-cycle progression, but the mechanisms coordinating PCP and mitosis are unknown. Here we identify Plk1 as a master regulator of PCP dynamics during mitosis. Plk1 interacts with core PCP component Celsr1 via a conserved polo-box domain (PBD)-binding motif, localizes to mitotic endosomes, and directly phosphorylates Celsr1. Plk1 dependent phosphorylation activates the endocytic motif specifically during mitosis, allowing bulk recruitment of Celsr1 into endosomes. Inhibiting Plk1 activity blocks PCP internalization and perturbs PCP asymmetry. Mimicking dileucine motif phosphorylation is sufficient to drive Celsr1 internalization during interphase. Thus, Plk1-mediated phosphorylation of Celsr1 ensures that PCP redistribution is precisely coordinated with mitotic entry. PMID- 26004509 TI - Dynein-Based Accumulation of Membranes Regulates Nuclear Expansion in Xenopus laevis Egg Extracts. AB - Nuclear size changes dynamically during development and has long been observed to correlate with the space surrounding the nucleus, as well as with the volume of the cell. Here we combine an in vitro cell-free system of Xenopus laevis egg extract with microfluidic devices to systematically analyze the effect of spatial constraints. The speed of nuclear expansion depended on the available space surrounding the nucleus up to a threshold volume in the nanoliter range, herein referred to as the nuclear domain. Under spatial constraints smaller than this nuclear domain, the size of microtubule-occupied space surrounding the nucleus turned out to be limiting for the accumulation of membranes around the nucleus via the motor protein dynein, therefore determining the speed of nuclear expansion. This mechanism explains how spatial information surrounding the nucleus, such as the positioning of the nucleus inside the cell, can control nuclear expansion. PMID- 26004508 TI - Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear beta-Catenin. AB - In the absence of Wnt activation, cytosolic beta-catenin is degraded through GSK3/CK1-mediated phosphorylation at the N terminus. Here, we show that, upon Wnt activation, the stability of nuclear beta-catenin is regulated via methylation/demethylation. The protein lysine demethylases Kdm2a and Kdm2b regulate the turnover of non-phosphorylated beta-catenin specifically within the nucleus via direct interaction with the fourth and fifth armadillo repeats. The lysine residues within this region are required for the methylation of non phosphorylated beta-catenin, which is demethylated by Kdm2a/b and subsequently ubiquitylated. During Xenopus embryogenesis, kdm2a/b genes are transcribed during early embryogenesis and are required for the specification of the body axis. Kdm2a/b knockdown in Xenopus embryos leads to increases in non-phosphorylated and methylated beta-catenin, concurrent with the upregulation of beta-catenin target genes. This mechanism is required for controlling the output of the Wnt/beta catenin signaling pathway to maintain normal cellular functions. PMID- 26004510 TI - Lipid Droplets Are Essential for Efficient Clearance of Cytosolic Inclusion Bodies. AB - Exposing cells to folding stress causes a subset of their proteins to misfold and accumulate in inclusion bodies (IBs). IB formation and clearance are both active processes, but little is known about their mechanism. To shed light on this issue, we performed a screen with over 4,000 fluorescently tagged yeast proteins for co-localization with a model misfolded protein that marks IBs during folding stress. We identified 13 proteins that co-localize to IBs. Remarkably, one of these IB proteins, the uncharacterized and conserved protein Iml2, exhibited strong physical interactions with lipid droplet (LD) proteins. Indeed, we here show that IBs and LDs are spatially and functionally linked. We further demonstrate a mechanism for IB clearance via a sterol-based metabolite emanating from LDs. Our findings therefore uncover a function for Iml2 and LDs in regulating a critical stage of cellular proteostasis. PMID- 26004512 TI - Usefulness of atrial function for risk stratification in asymptomatic severe aortic stenosis. AB - AIM: We aimed to evaluate the usefulness of left atrial (LA) mechanics and stiffness over global left ventricular (LV) longitudinal strain (GLS) for risk stratification in severe aortic stenosis (AS). METHODS: From a cohort of 89 prospective asymptomatic patients with severe AS and normal LV ejection fraction, 82 (32 men, mean age 73+/-10 years) truly asymptomatic patients, scheduled after a negative exercise echocardiogram, were enrolled. Forty age- and gender-matched prospective, asymptomatic subjects served as controls. Predefined end points were the occurrence of symptoms (dyspnea, angina, syncope), and death during follow up. RESULTS: At study entry, patients had: impaired LV GLS (p=0.001), reduced LA reservoir (p<0.001), high LA stiffness (p<0.001), and increased valvulo-arterial impedance (p<0.001) compared to controls. During follow-up [16+/-14.9 months (ranging from 1 month to 4.2 years)], 53 patients (64.6%) reached one of the endpoints. Patients with events showed lower LV GLS (p>0.001), lower LA reservoir (p<0.001), and greater LA stiffness (p<0.001) than those asymptomatic. On univariate Cox regression analysis, LV GLS (p<0.001), LA reservoir (p<0.001), and LA stiffness (p=0.004) were strong predictors of adverse events. Kaplan-Meier curves showed that event-free survival was significantly higher in patients with a LV GLS >=16.8% [p<0.001; area under the curve (AUC)=0.922; sensitivity=86%, specificity=80%], a LA reservoir >=19.8% (p=0.001; AUC=0.860, sensitivity=71%, specificity=84%), and a LA stiffness <0.78 (p<0.001; AUC 0.819, sensitivity 70%, specificity 89%). On multivariate analysis, only LV GLS remained significantly associated with patients' prognosis (hazard ratio=1.49, 95% CI=1.11-2.01, p=0.008). CONCLUSIONS: In asymptomatic patients with severe AS, an efficient cardiovascular system is based on an effective atrial-ventricular interplay. LA function assessment is useful for early identification of risk in these patients. LV GLS however was confirmed to be the best predictor of patients' outcome. PMID- 26004513 TI - Purinergic transmission in blood vessels. AB - There are nineteen different receptor proteins for adenosine, adenine and uridine nucleotides, and nucleotide sugars, belonging to three families of G protein coupled adenosine and P2Y receptors, and ionotropic P2X receptors. The majority are functionally expressed in blood vessels, as purinergic receptors in perivascular nerves, smooth muscle and endothelial cells, and roles in regulation of vascular contractility, immune function and growth have been identified. The endogenous ligands for purine receptors, ATP, ADP, UTP, UDP and adenosine, can be released from different cell types within the vasculature, as well as from circulating blood cells, including erythrocytes and platelets. Many purine receptors can be activated by two or more of the endogenous ligands. Further complexity arises because of interconversion between ligands, notably adenosine formation from the metabolism of ATP, leading to complex integrated responses through activation of different subtypes of purine receptors. The enzymes responsible for this conversion, ectonucleotidases, are present on the surface of smooth muscle and endothelial cells, and may be coreleased with neurotransmitters from nerves. What selectivity there is for the actions of purines/pyrimidines comes from differential expression of their receptors within the vasculature. P2X1 receptors mediate the vasocontractile actions of ATP released as a neurotransmitter with noradrenaline (NA) from sympathetic perivascular nerves, and are located on the vascular smooth muscle adjacent to the nerve varicosities, the sites of neurotransmitter release. The relative contribution of ATP and NA as functional cotransmitters varies with species, type and size of blood vessel, neuronal firing pattern, the tone/pressure of the blood vessel, and in ageing and disease. ATP is also a neurotransmitter in non-adrenergic non-cholinergic perivascular nerves and mediates vasorelaxation via smooth muscle P2Y-like receptors. ATP and adenosine can act as neuromodulators, with the most robust evidence being for prejunctional inhibition of neurotransmission via A1 adenosine receptors, but also prejunctional excitation and inhibition of neurotransmission via P2X and P2Y receptors, respectively. P2Y2, P2Y4 and P2Y6 receptors expressed on the vascular smooth muscle are coupled to vasocontraction, and may have a role in pathophysiological conditions, when purines are released from damaged cells, or when there is damage to the protective barrier that is the endothelium. Adenosine is released during hypoxia to increase blood flow via vasodilator A2A and A2B receptors expressed on the endothelium and smooth muscle. ATP is released from endothelial cells during hypoxia and shear stress and can act at P2Y and P2X4 receptors expressed on the endothelium to increase local blood flow. Activation of endothelial purine receptors leads to the release of nitric oxide, hyperpolarising factors and prostacyclin, which inhibits platelet aggregation and thus ensures patent blood flow. Vascular purine receptors also regulate endothelial and smooth muscle growth, and inflammation, and thus are involved in the underlying processes of a number of cardiovascular diseases. PMID- 26004511 TI - Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling. AB - Recent studies in humans and in genetic mouse models have identified Slit- and NTRK-like family (Slitrks) as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis, and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates brain-derived neurotrophic factor (BDNF)-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a transsynaptic binding partner, protein tyrosine phosphatase delta (PTPdelta); however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling. PMID- 26004514 TI - Rasch analysis and impact factor methods both yield valid and comparable measures of health status in interstitial lung disease. AB - OBJECTIVES: Rasch analysis has largely replaced impact factor methodology for developing health status measures. The aim of this study was to develop a health status questionnaire for patients with interstitial lung disease (ILD) using impact factor methodology and to compare its validity with that of another version developed using Rasch analysis. STUDY DESIGN AND SETTING: A preliminary 71-item questionnaire was developed and evaluated in 173 patients with ILD. Items were reduced by the impact factor method (King's Brief ILD questionnaire, KBILD I) and Rasch analysis (KBILD-R). Both questionnaires were validated by assessing their relationship with forced vital capacity (FVC) and St Georges Respiratory Questionnaire (SGRQ) and by evaluating internal reliability, repeatability, and longitudinal responsiveness. RESULTS: The KBILD-R and KBILD-I comprised 15 items each. The content of eight items differed between the KBILD-R and KBILD-I. Internal and test-retest reliability was good for total scores of both questionnaires. There was a good relationship with SGRQ and moderate relationship with FVC for both questionnaires. Effect sizes were comparable. Both questionnaires discriminated patients with differing disease severity. CONCLUSION: Despite considerable differences in the content of retained items, both KBILD-R and KBILD-I questionnaires demonstrated acceptable measurement properties and performed comparably in a clinical setting. PMID- 26004515 TI - A randomized trial of fellowships for early career researchers finds a high reliability in funding decisions. AB - OBJECTIVES: Funding for early career researchers in Australia's largest medical research funding scheme is determined by a competitive peer-review process using a panel of four reviewers. The purpose of this experiment was to appraise the reliability of funding by duplicating applications that were considered by separate grant review panels. STUDY DESIGN AND METHODS: Sixty duplicate applications were considered by two independent grant review panels that were awarding funding for Australia's National Health and Medical Research Council. Panel members were blinded to which applications were included in the experiment and to whether it was the original or duplicate application. Scores were compared across panels using Bland-Altman plots to determine measures of agreement, including whether agreement would have impacted on actual funding. RESULTS: Twenty-three percent of the applicants were funded by both panels and 60 percent were not funded by both, giving an overall agreement of 83 percent [95% confidence interval (CI): 73%, 92%]. The chance-adjusted agreement was 0.75 (95% CI: 0.58, 0.92). CONCLUSION: There was a comparatively high level of agreement when compared with other types of funding schemes. Further experimental research could be used to determine if this higher agreement is due to nature of the application, the composition of the assessment panel, or the characteristics of the applicants. PMID- 26004516 TI - Long noncoding RNAs: Lessons from genomic imprinting. AB - Genomic imprinting has been a great resource for studying transcriptional and post-transcriptional-based gene regulation by long noncoding RNAs (lncRNAs). In this article, I overview the functional role of intergenic lncRNAs (H19, IPW, and MEG3), antisense lncRNAs (Kcnq1ot1, Airn, Nespas, Ube3a-ATS), and enhancer lncRNAs (IG-DMR eRNAs) to understand the diverse mechanisms being employed by them in cis and/or trans to regulate the parent-of-origin-specific expression of target genes. Recent evidence suggests that some of the lncRNAs regulate imprinting by promoting intra-chromosomal higher-order chromatin compartmentalization, affecting replication timing and subnuclear positioning. Whereas others act via transcriptional occlusion or transcriptional collision based mechanisms. By establishing genomic imprinting of target genes, the lncRNAs play a critical role in important biological functions, such as placental and embryonic growth, pluripotency maintenance, cell differentiation, and neural related functions such as synaptic development and plasticity. An emerging consensus from the recent evidence is that the imprinted lncRNAs fine-tune gene expression of the protein-coding genes to maintain their dosage in cell. Hence, lncRNAs from imprinted clusters offer insights into their mode of action, and these mechanisms have been the basis for uncovering the mode of action of lncRNAs in several other biological contexts. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26004517 TI - [Total reverse shoulder replacement. Evaluation of the clinical results and complications in a series of 52 cases]. AB - OBJECTIVE: To evaluate the clinical results and analyse the complications of total reverse shoulder replacement performed in our centre over an 8 year period. MATERIAL AND METHOD: A retrospective study was conducted on 50 patients (52 shoulders), with a mean age of 70.15 years (range 51 to 84 years) between December 2004 and December 2012, who received a total reverse shoulder replacement, all performed by the same surgeon. The results have been evaluated according to clinical data, radiography study, a satisfaction scale, and the Constant scale, with a minimum follow-up of 16 months. Five of the cases (9.62%) had been intervened due to fractures of the proximal end of the humerus, 6 cases (11.53%) as surgical consequence of a prosthesis revision, 10 cases (19.23%) due to fracture sequelae, and 30 cases (59.62%) were patients with arthropathy due to a massive fracture of the rotator cuff. RESULTS: After a mean follow up of 35.78 months (range, 16-82), satisfactory clinical results were obtained in 80% of cases, with a mean preoperative Constant of 27.7 points, and reaching 67.1 points 12 months after the operation. On the visual analogue scale, 8.25 points were obtained before the surgery, which decreased to 2.25 points 12 months later. The complications rate was 15.38%, which were due to an intra-operative fracture (1.92%), deep infection (3.84%), instability (3.84%), and early mechanical loosening (3.84%). Scapular notching was observed in the radiographic study in 9 (17.3%) cases. DISCUSSION AND CONCLUSIONS: After the results obtained, it could be said that total reverse shoulder replacement achieved encouraging results in the short term for the treatment of glenohumeral arthrosis and massive tears of the rotary cuff. On analysing our series, it can be seen that the complications rate is much higher when it is used to treat fracture sequelae in which there is a loss of proximal humerus bone stock. PMID- 26004518 TI - HIFs genes expression and hematology indices responses to different oxygen treatments in an ovoviviparous teleost species Sebastes schlegelii. AB - Hypoxia-inducible factors (HIFs) are transcription factors considered as a respond factor to oxygen tension. By using quantitative real-time PCR, expression files of HIF-1alpha and HIF-2alpha mRNA were detected in the Korean rockfish ovary, liver, gill and spleen after 30 min and 60 min acute hypoxia exposure. Meanwhile, the cortisol levels, white blood cells and several serum biochemical values of Korean rockfish under different oxygen concentration treatments were also detected. All the results might be helpful for further understanding of the potential effect of hypoxia in ovoviviparous fish. PMID- 26004519 TI - Effects of thermal stress on the growth of an intertidal population of Ellisolandia elongata (Rhodophyta) from N-W Mediterranean Sea. AB - Coralline algae are calcareous algae able to build biogenic structures, thus playing a key-role as marine biodiversity promoters and calcium carbonate producers. The aim was to estimate the growth of Ellisolandia elongata under thermal stress. E. elongata were cultured for 2, 4 and 6 months under "natural" temperature (Tc) and increased temperature (Ti = Tc + 3 degrees C). In order to determine a possible culturing effect, growth in the field was also measured. For the first time, Alizarin Red S dye was used in high energy shallow water environments. Thallus linear extension was higher in the cultured specimens (Tc and Ti) compared to the field specimens. The carbonate mass in the field was higher than in Ti and Tc after 2, 4 months but decreased after 6 months. Partly unknown in situ environmental factors could have affected growth and calcification rates in the field while thermal adaptation could explain growth rates in the culturing experiment. PMID- 26004520 TI - Cardiovascular comorbidities in patients with rosacea: A nationwide case-control study from Taiwan. AB - BACKGROUND: Rosacea is a chronic inflammatory skin disease. Inflammation plays a prominent role in atherosclerosis and its complications. OBJECTIVE: We sought to investigate the associations of rosacea with cardiovascular disease risk factors and cardiovascular diseases from a nationwide population-based database. METHODS: A total of 33,553 patients with rosacea and 67,106 age- and gender-matched control subjects were identified from the National Health Insurance Research Database in Taiwan from 1997 to 2010. Multivariate logistic regressions were performed to compare the odds of comorbidities between the 2 groups. RESULTS: Dyslipidemia (odds ratio 1.41; 95% confidence interval 1.36-1.46), coronary artery disease (odds ratio 1.35, 95% confidence interval 1.29-1.41), and hypertension (odds ratio 1.17, 95% confidence interval 1.12-1.21) were significantly associated with rosacea. Coronary artery disease remained independently associated with rosacea after adjustment for hypertension, diabetes mellitus, and dyslipidemia. Male patients with rosacea had higher risks for all comorbidities than female patients with rosacea. LIMITATIONS: The National Health Insurance Research Database does not contain information regarding rosacea subtypes or disease severity, or laboratory data. CONCLUSION: Patients with rosacea are more likely to have dyslipidemia and hypertension. They are also at increased risk of coronary artery disease after adjustment for cardiovascular disease risk factors. PMID- 26004521 TI - MicroRNA-338-3p suppresses tumor growth of esophageal squamous cell carcinoma in vitro and in vivo. AB - Accumulating evidence has shown that microRNAs (miRNAs) are aberrantly expressed in human esophageal squamous cell carcinoma (ESCC) and are crucial in tumorigenesis, among which miR-338-3p has been examined to be downregulated in patients with ESCC. However, the role of miR-338-3p in ESCC remains to be elucidated. In the present study, the role of miR-338-3p on the growth and survival of an ESCC cell line was determined with several in vitro approaches and in nude mouse models. It was determined that miR-338-3p expression was frequently downregulated in ESCC tissue compared with corresponding adjacent non-tumor tissue, and that its expression was significantly correlated with tumor stage and metastasis. Overexpression of miR-338-3p in ESCC cells suppressed cell proliferation, colony formation, migration and invasion, and induced cell arrest at the G0/G1 stage and cell apoptosis in vitro. In addition, it was demonstrated that overexpression of miR-338-3p significantly suppresses tumor growth of xenograft tumors in mice (P<0.05). These findings revealed that miR-338-3p may act as a tumor suppressor in ESCC, and its dysregulation may be involved in the initiation and development of human ESCC. In addition, it was suggested that miR 338-3p may be a potential therapeutic agent for treatment of ESCC. PMID- 26004522 TI - Energy dispersive X-ray analysis on an absolute scale in scanning transmission electron microscopy. AB - We demonstrate absolute scale agreement between the number of X-ray counts in energy dispersive X-ray spectroscopy using an atomic-scale coherent electron probe and first-principles simulations. Scan-averaged spectra were collected across a range of thicknesses with precisely determined and controlled microscope parameters. Ionization cross-sections were calculated using the quantum excitation of phonons model, incorporating dynamical (multiple) electron scattering, which is seen to be important even for very thin specimens. PMID- 26004523 TI - Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes. AB - Ischemia/reperfusion (I/R)-induced autophagy increases the severity of cardiomyocyte injury. The aim of this study was to investigate the effects of berberine, a natural extract from Rhizoma coptidis, on the I/R-induced excessive autophagy in in vitro and in vivo models. Autophagy was increased both in H9c2 myocytes during hypoxia/reoxygenation (H/R) injury and in mouse hearts exposed to I/R. And the expression level of p-AMPK and p-mTORC2 (Ser2481) were increased during H/R period. In addition, the increased autophagy level was correlated with reduced cell survival in H9c2 myocytes and increased infarct size in mouse hearts. However, berberine treatment significantly enhanced the H/R-induced cell viability and reduced I/R-induced myocardial infarct size, which was accompanied by improved cardiac function. The beneficial effect of berberine is associated with inhibiting the cellular autophagy level, due to decreasing the expression level of autophagy-related proteins such as SIRT1, BNIP3, and Beclin-1. Furthermore, both the level of p-AMPK and p-mTORC2 (Ser2481) in H9c2 myocytes exposed to H/R were decreased by berberine. In summary, berberine protects myocytes during I/R injury through suppressing autophagy activation. Therefore, berberine may be a promising agent for treating I/R-induced cardiac myocyte injury. PMID- 26004524 TI - A novel mechanism of hepatocellular carcinoma cell apoptosis induced by lupeol via Brain-Derived Neurotrophic Factor Inhibition and Glycogen Synthase Kinase 3 beta reactivation. AB - Lupeol is a naturally available triterpenoid with selective anticancerous potential on various human cancer cells. The present study shows that lupeol can inhibit cell proliferation of hepatocellular carcinoma (HCC) HCCLM3 cells in a time- and dose-dependent manner, through caspase-3 dependent activation and Poly ADP-Ribose Polymerase (PARP) cleavage. Lupeol-induced cell death is associated with a marked decrease in the protein expression of Brain-Derived Neurotrophic Factor (BDNF) and ser-9-phosphoryltion of Glycogen Synthase Kinase 3 Beta (GSK 3beta), with concomitant suppression of Akt1, phosphatidyl inositol 3-kinase (PI3K), beta-catenin, c-Myc and Cyclin D1 mRNA expression. Suppressing overexpression of BDNF by lupeol results in decreased protein expression of p-Akt and PI3K (p110alpha), as well as reactivation of GSK-3beta function in HepG2 cells. Lupeol treatment also inhibits LiCl-induced activation of Wnt signaling pathway and exerts the in vitro anti-invasive activity in Huh-7 cells. LiCl triggered high expression of beta-catenin, c-Myc and Cyclin D1 protein is reduced followed by lupeol exposure. The findings suggest a mechanistic link between caspase dependent pathway, BDNF secretion and Akt/PI3K/GSK-3beta in HCC cells. These results indicate that lupeol can suppress HCC cell proliferation by inhibiting BDNF secretion and phosphorylation of GSK-3beta(Ser-9), cooperated with blockade of Akt/PI3K and Wnt signaling pathway. PMID- 26004525 TI - Geraniol attenuates fibrosis and exerts anti-inflammatory effects on diet induced atherogenesis by NF-kappaB signaling pathway. AB - Atherosclerosis is now generally accepted as a chronic inflammatory condition. The transcription factor nuclear factor kappa B (NF-kappaB) is a key regulator of inflammation, immune responses, cell survival and cell proliferation. Tissue remodeling plays a significant role during the phase of inflammation and oxidative stress. In our study we have evaluated the effect of geraniol (GOH), a natural terpenoid on oxidative stress, inflammation and tissue remodeling in experimental animals. Experimental animals (hamsters) were divided into four groups; group 1 were control animals; group 2 were animals fed GOH alone (100mg/kg b.w. p.o); group 3 were animals fed atherogenic diet (standard pellet diet+10% coconut oil+0.25% cholesterol); group 4 animals were fed atherogenic diet as in group 3+GOH (100mg/kg b.w). At the end of the experimental period animals were killed and liver, heart and aorta tissues were analyzed for lipid peroxidation markers, non enzymic antioxidants and collagen distribution using histological studies like Milligan's trichrome and Picrosirius red staining. As inflammation plays a key role in tissue remodeling we also targeted the key inflammatory cytokine, NF-kappaB. GOH supplementation greatly prevented the remodeling of tissues by enhancing the free radical scavenging and anti inflammatory effects. Thus in conclusion it can be suggested that GOH (100mg/kg b.w) prevents the atherogenic diet induced fibrosis in experimental hamsters. PMID- 26004526 TI - Some implications of melatonin use in chronopharmacology of insomnia. AB - The last decade has witnessed the emergence of new chronopharmacological perspectives. In the case of sleep disorders, the accumulating evidence suggests that even a minor dysfunction in the biological clock can impact broadly upon body physiology causing increases in sleep onset latency, phase delays or advances in sleep initiation, frequent nocturnal awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep and increased periodic leg movements, among others. Thus, restoration of the adequate circadian pattern of proper sleep hygiene, targeted exposure to light and the use of chronobiotic drugs, such as melatonin, which affect the output phase of clock-controlled circadian rhythms, can help to recover the sleep-wake cycle. The optimization of drug effects and/or minimization of toxicity by timing medications with regard to biological rhythms is known as chronotherapeutics. While chronotherapeutical approaches have been particularly successful in the treatment of hypertension, allergies and some forms of cancer, a time-dependent pharmacological approach can be also effective when dealing with sleep disruptions like insomnia. A large proportion of patients under benzodiazepine (BZD)/Z drug treatment fail to achieve a complete and sustained recovery and are left with residual symptoms, like tolerance or dependency, that make relapse or recurrence more likely, and poorer quality of life a reality. Thus the chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. This short review discusses available data on the efficacy of melatonin to reduce chronic BZD use in insomnia patients. PMID- 26004527 TI - Macranthol promotes hippocampal neuronal proliferation in mice via BDNF-TrkB PI3K/Akt signaling pathway. AB - Macranthol is a lignans natural product isolated from Illicium dunnianum Tutch. Our previous study has demonstrated that macranthol exerted an antidepressant like effect in mice, at least in part, by increasing expression of hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the relationship between macranthol and BDNF downstream signaling pathway in the hippocampus remains unknown. The aim of this present study was to explore the mechanism of macranthol-modulated BDNF signaling pathway in a depression-like model of chronic unpredictable mild stress. Our results found that pharmacological inhibition of tropomyosin related kinase B (TrkB) with K252a abolished the improvement of macranthol on sucrose preference and immobility time, and attenuated the stimulatory effect of macranthol on hippocampal BDNF and phospho-Akt. Furthermore, K252a also reversed the improvement of macranthol on hippocampal Bcl 2, caspase-3 expression and hippocampal neuronal cell proliferation. Therefore, our findings verify that macranthol-mediated antidepressant-like action is associated with BDNF-TrkB and downstream activation of PI3K/Akt-Bcl-2/caspase-3 signaling pathway. PMID- 26004529 TI - Taurine zinc solid dispersions protect against cold-restraint stress-induced gastric ulceration by upregulating HSP70 and exerting an anxiolytic effect. AB - Pharmacological effects of solid dispersions (SDs) of a taurine zinc complex on gastric ulceration and anxiety were investigated. Pretreatment with taurine zinc (50, 100 or 200mg/kg) SDs dose-dependently protected rat gastric mucosa against cold-restraint stress (CRS)-induced gastric injury, and significantly attenuated increases in gastric mucosal H(+)K(+)-ATPase activity and lipid peroxidation and enhanced SOD activity. Taurine zinc also inhibited CRS-induced elevation of the serum stress hormones adrenocorticotropic hormone and corticosterone and upregulated HSP70 expression in the gastric mucosa. Moreover, taurine zinc (200mg/kg) SDs more potently protected the gastric mucosa from ulceration than the same dose of taurine, which may be attributed to a synergistic effect between taurine and zinc. Behavioral experiments in mice showed that taurine zinc SDs significantly increased the number of entries and time spent on the open arms in the elevated plus-maze test, time spent in the central area and total distance traveled in the open field test, and time spent and number of entries into the light compartment in the light/dark box test, indicative of reduced anxiety-like behaviors. This study demonstrates taurine zinc protected the gastric mucosa against CRS-induced gastric damage by decreasing oxidative stress, promoting endogenous HSP70 expression and attenuating psychological stress. PMID- 26004530 TI - Emerging role of neurotensin in regulation of the cardiovascular system. AB - There is increasing evidence in support of an important role played by neurotensin (NT), a tridecapeptide originally found in bovine hypothalamus, in regulation of cardiovascular system. Elevated systemic levels of NT may contribute to pathogenesis of acute circulatory disoders, and predict the risk for cardiovascular morbidity and mortality in population-based studies. Within cardiovascular system, NT-containing neural fibers are found in close contact with atrial and ventricular cardiac myocytes, cardiac conduction system, intracardiac ganglia, as well as coronary vessels in humans and various animal species. The density of NT-immunoreactive innervation is reduced in cardiac disease. NT produces a variety of cardiovascular actions including effects on heart rate, myocardial contractility, systemic blood pressure, coronary vascular tone, venous smooth muscle tone, and regional blood flow in gastrointestinal tract, cutaneous and adipose tissue. NT could trigger cardiovascular reflexes by stimulating primary visceral afferents synaptically connected with preganglionic sympathetic neurons at the spinal cord. Structural determinants of biological activity of NT reside primarily in the C-terminal portion of its molecule which is responsible for receptor activation. NT effects are mediated via activation of NT receptors, or produced indirectly via stimulation of release of various endogenous neuromodulators/neurotransmitters such as histamine, catecholamines and prostaglandins. Three subtypes of NT receptor (NTS1, NTS2 and NTS3) have been shown to be expressed in the myocardium. NTS1, a high-affinity NT binding site coupled to phospholipase C-inositoltrisphosphate transduction pathway, is thought to mediate NT-induced cardiovascular responses. PMID- 26004528 TI - Characterization of pulmonary sigma receptors by radioligand binding. AB - This study establishes the expression of appreciable populations of sites on mouse lung membranes that exhibit radioligand binding properties and pharmacology consistent with assignment as sigma1 and sigma2 receptors. Specific binding of the sigma1 receptor radioligand [(3)H](+)-pentazocine reached steady state within 6h at 37 degrees C. Saturation studies revealed high affinity binding to a single class of sites (Kd 1.36+/-0.04nM; Bmax 967+/-11fmol/mg protein). Inhibition studies showed appropriate sigma1 receptor pharmacology, including higher affinity for (+)-N-allylnormetazocine with respect to the (-)-enantiomer, and positive allosteric modulation of dextromethorphan binding by phenytoin. Using [(3)H]1,3-di(2-tolyl)guanidine in the presence of (+)-pentazocine to assess sigma2 receptor binding, steady state was achieved within 2min at 25 degrees C. Cold saturation studies revealed one high affinity, low capacity binding site (Kd 31.8+/-8.3nM; Bmax 921+/-228fmol/mg protein) that displayed sigma2 receptor pharmacology. A very low affinity, high capacity interaction also was observed that represents saturable, but not sigma receptor specific, binding. A panel of ligands showed rank order inhibition of radioligand binding appropriate for the sigma2 receptor, with ifenprodil displaying the highest apparent affinity. In vivo, dextromethorphan inhibited the specific binding of a radioiodinated sigma1 receptor ligand in lung with an ED50 of 1.2MUmol/kg, a value near the recommended dosage for the drug as a cough suppressant. Overall, the present work provides a foundation for studies of drug interactions with pulmonary sigma1 and sigma2 receptors in vitro and in vivo. PMID- 26004531 TI - Epidermal growth factor induces Ca(2+) sensitization through Rho-kinase-dependent phosphorylation of myosin phosphatase target subunit 1 in vascular smooth muscle. AB - We previously found that the protein tyrosine phosphatase inhibitor orthovanadate evoked a vasoconstrictor effect in rat aortas via Rho-kinase-dependent inactivation of myosin light chain phosphatase (MLCP) downstream of epidermal growth factor (EGF) receptor signaling. To determine whether the direct activation of EGF receptor by EGF also induces Rho-kinase-dependent vasoconstriction, isometric tension changes were measured in rat aortic rings without endothelium. Although EGF did not produce a contractile effect, the Ca(2+)-induced force in Ca(2+)-depleted rings significantly increased after treatment with 100nM EGF, suggesting that EGF induces Ca(2+) sensitization by MLCP inactivation. In addition, EGF induced the activation of Rho-kinase and phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in rat aortic smooth muscle cells (VSMCs). The effects of EGF on Ca(2+) sensitivity in aortas and MYPT1 phosphorylation in VSMCs were blocked by inhibitors of EGF receptor (AG1478), Rho-kinase (Y27632), extracellular signal-regulated kinase 1/2 (Erk1/2; FR180204), and mitogen/extracellular signal-regulated kinase (MEK; PD98059), but not by inhibitors of p38 kinase (SB203580) and c-Jun amino-terminal kinase (AS601245). EGF-induced Erk1/2 phosphorylation was not abrogated by the Rho kinase inhibitor, suggesting that Rho-kinase-dependent phosphorylation of MYPT1 is downstream of EGF receptor/MEK/Erk1/2 signaling. These results suggest that EGF induces Ca(2+) sensitization in vascular smooth muscle by Rho-kinase dependent inactivation of MLCP mediated by the EGF receptor/MEK/Erk1/2 pathway. PMID- 26004532 TI - Gabapentin inhibits the activity of the rat excitatory glutamate transporter 3 expressed in Xenopus oocytes. AB - Gabapentin, a derivative of gamma-aminobutyric acid (GABA), is used to treat epilepsy and neuropathic pain. The pharmacological mechanisms for gabapentin effects are not completely elucidated. We investigated the effect of gabapentin on the activity of excitatory amino acid transporter 3 (EAAT3) that can regulate extracellular glutamate concentrations. EAAT3 was expressed in Xenopus oocytes. Membrane currents were recorded after application of l-glutamate in the presence or absence of different concentrations of gabapentin (1-300MUM) by using a two electrode voltage clamp. To determine the effect of gabapentin on Vmax and Km of EAAT3 for l-glutamate, l-glutamate at 3-300MUM was used. To study the effects of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) on gabapentin induced changes in EAAT3 activity, oocytes were incubated with the PKC activator (Phorbol 12-myristate 13-acetate, PMA), the PKC inhibitors (chelerythrine or staurosporine), and the PI3K inhibitor wortmannin. Gabapentin decreased EAAT3 activity in a concentration-dependent manner and EAAT3 activity was significantly inhibited by 10-300MUM gabapentin. Gabapentin significantly decreased Vmax without affecting Km. PMA increased EAAT3 activity; however, gabapentin attenuated the PMA-induced increase in EAAT3 activity. Pre-incubation of oocytes with chelerythrine, staurosporine, or wortmannin decreased basal EAAT3 activity, which was further reduced by gabapentin. We conclude that gabapentin decreases EAAT3 activity at clinically relevant and higher concentrations, in which PKC and PI3K may not be involved. The results suggest that EAAT3 might not be a target for the anticonvulsant action of gabapentin. PMID- 26004533 TI - Chronic imipramine treatment differentially alters the brain and plasma amino acid metabolism in Wistar and Wistar Kyoto rats. AB - In the present study, the amino acids which have the possibility for the therapeutic efficacy of imipramine were explored and compared between Wistar Kyoto rats, an animal model of depression, and Wistar rats as a normal model. The antidepressant-like effect caused by chronic imipramine treatment was confirmed by decreased immobility in the forced swimming test. Chronic imipramine administration altered the amino acid dynamics in the brain. In the striatum, the concentrations of asparagine, glutamine and methionine were significantly increased by chronic imipramine administration. In the thalamus and hypothalamus, chronic imipramine administration significantly decreased the valine concentration. On the other hand, no amino acid was altered by chronic imipramine administration in the hippocampus, brain stem and cerebellum. In addition, lower concentration of asparagine in the prefrontal cortex of WKY rats was improved by chronic imipramine administration. This amelioration only in WKY rats may be a specific effect of chronic imipramine administration under the depressive state. In conclusion, chronic imipramine administration altered the several amino acid dynamics in the brain. Modification of the amino acid metabolism in the brain may provide a new strategy in the development of therapeutic treatment of major depression. PMID- 26004534 TI - Physical exercise versus fluoxetine: antagonistic effects on cortical spreading depression in Wistar rats. AB - The antidepressant fluoxetine and physical exercise exert similar effects on the serotoninergic system by increasing brain serotonin availability, and both show antagonistic action on cortical excitability. Here we provide the first assessment of the interaction of the two together on cortical spreading depression (CSD) in young adult rats. Wistar rats (40-60 days of life) received fluoxetine (10mg/kg/d, orogastrically) or an equivalent volume of water. Half of the animals from each condition were assigned to perform physical exercise in a treadmill, and the other half formed the sedentary (non-treadmill) control groups. Body parameters (Lee index and thoracic and abdominal circumferences) and the velocity of CSD propagation were investigated. Fluoxetine+exercise animals had less weight gain (78.68+/-3.19g) than either the fluoxetine-only (93.34+/ 4.77g) or exercise-only group (97.04+/-3.48g), but body parameters did not differ among them. The velocity of CSD propagation was reduced in the fluoxetine-only and exercise-only groups compared to sedentary water controls (3.24+/ 0.39mm/min). For the fluoxetine+exercise group, CSD velocity values were significantly lower (2.92+/-0.22mm/min) than for fluoxetine only (3.03+/ 0.35mm/min); however, they were similar to values for the exercise-only group (2.96+/-0.23mm/min). These findings confirm the similar effects of fluoxetine and exercise and suggest a greater effect of physical exercise in reducing brain excitability. PMID- 26004535 TI - Non-uniform changes in membrane receptors in the rat urinary bladder following outlet obstruction. AB - The aim of the present study was to investigate the expression and distribution of membrane receptors after bladder outlet obstruction (BOO). Partial bladder outlet obstruction (BOO) was induced in female rats and bladders were harvested after either 10 days or 6 weeks of BOO. The expression of different receptors was surveyed by microarrays and corroborated by immunohistochemistry and western blotting. A microarray experiment identified 10 membrane receptors that were differentially expressed compared to sham-operated rats including both upregulated and downregulated receptors. Four of these were selected for functional experiments on the basis of magnitude of change and relevance to bladder physiology. At 6 weeks of BOO, maximal contraction was reduced for neuromedin B and vasopressin (AVP), consistent with reductions of receptor mRNA levels. Glycine receptor-induced contraction on the other hand was increased and receptor mRNA expression was accordingly upregulated. Maximal relaxation by the beta3-adrenergic receptor agonist CL316243 was reduced as was the receptor mRNA level. Immunohistochemistry supported reduced expression of neuromedin B receptors, V1a receptors and beta3-adrenergic receptors, but glycine receptor expression appeared unchanged. Western blotting confirmed repression of V1a receptors and induction of glycine receptors in BOO. mRNA for vasopressin was detectable in the bladder, suggesting local AVP production. We conclude that changes in receptor expression following bladder outlet obstruction are non uniform. Some receptors are upregulated, conferring increased responsiveness to agonist, whereas others are downregulated, leading to decreased agonist-induced responses. This study might help to select pharmacological agents that are effective in modulating lower urinary tract symptoms in BOO. PMID- 26004536 TI - Metabolic consequences of the occlusion of the main pancreatic duct with acrylic glue after pancreaticoduodenectomy. AB - BACKGROUND: Pancreaticoduodenectomy represents the major treatment for pancreatic and periampullary neoplasms. Complications related to pancreaticojejunostomy are still the leading cause of morbidity and mortality. A solution proposed by some surgeons is the occlusion of main pancreatic duct by acrylic glue, avoiding pancreaticojejunostomy. Nevertheless, the consequences of this procedure on glucose metabolism are not well-defined. METHODS: We retrospectively analyzed a cohort of 50 patients who underwent pancreaticoduodenectomy and had metabolic assessments available. The metabolic evaluation included the following: body composition and clinical evaluation, an oral glucose tolerance test, and an hyperinsulinemic euglycemic clamp procedure. RESULTS: Twenty-three patients underwent pancreatic duct occlusion and were compared with 27 patients, well matched controls, who underwent pancreaticojejunostomy. Pancreatic duct occlusion leads to a greater impairment in insulin secretion compared with classic pancreaticojeunostomy. CONCLUSION: Pancreatic duct occlusion is associated with a greater reduction in insulin secretion but does not lead to meaningful differences in the management of patients with diabetes. PMID- 26004538 TI - The influence of flavonoid amendment on the absorption of cadmium in Avicennia marina roots. AB - Flavonoid is a key factor for the tolerance to cadmium in plants. Concentration dependent kinetics experiment was conducted to investigate the influence of flavonoid amendment on the Cd(2+) uptake in Avicennia marina (Forsk) Vierh. roots. We found that compared with the control, saturation concentration and maximal absorption rate of Cd was higher under flavonoid amendment (p<0.05). When roots were exposed to ion transport inhibitor (LaCl3), flavonoid amendment also facilitated Cd transport in roots. Flavonoids had no influence on Cd(2+) uptake in root cell walls. In conclusion, flavonoids enhance the tolerance to Cd and have a significant stimulative effect on symplasm transport of Cd in A. marina roots. Ca(2+)-channel was not the unique means of symplasm transport for Cd(2+) absorption. PMID- 26004539 TI - A critical review of arsenic exposures for Bangladeshi adults. AB - Groundwater, the most important source of water for drinking, cooking, and irrigation in Bangladesh, is a significant contributor to the daily human intake of arsenic. Other arsenic intake pathways, established as relevant for Bangladeshi adults through this review, include consumption of contaminated edible plant parts and animal-origin food, inhalation of contaminated air, soil ingestion, betel quid chewing, and tobacco smoking. This review qualifies and quantifies these arsenic intake pathways through analysis of the range of arsenic levels observed in different food types, water, soil, and air in Bangladesh, and highlights the contributions of dietary intake variation and cooking method in influencing arsenic exposures. This study also highlights the potential of desirable dietary patterns and intakes in increasing arsenic exposure which is relevant to Bangladesh where nutritional deficiencies and lower-than-desirable dietary intakes continue to be a major concern. PMID- 26004537 TI - cAMP signalling in trypanosomatids: role in pathogenesis and as a drug target. AB - Despite recent research linking cAMP signalling to virulence in trypanosomatids and detailed studies of trypanosomatid adenylyl cyclases (ACs) and phosphodiesterases (PDEs) since their discoveries 40 years ago, downstream components of the pathway and their biological functions have remained remarkably elusive. However, in recent years, significant discoveries have been made: a role for parasite ACs has been proposed in cytokinesis, evasion of the host immune response, and social motility. cAMP phosphodiesterases PDEB1 and PDEB2 were found to be essential for survival and virulence of Trypanosoma brucei and, in Trypanosoma cruzi, PDEC2 was shown to be required for normal osmoregulation. As we discuss here, these breakthroughs have led to an ongoing surge in the development of PDE inhibitors as lead compounds for trypanocidal drugs. PMID- 26004541 TI - Biomechanical Origins of Muscle Stem Cell Signal Transduction. AB - Skeletal muscle, the most abundant and widespread tissue in the human body, contracts upon receiving electrochemical signals from the nervous system to support essential functions such as thermoregulation, limb movement, blinking, swallowing and breathing. Reconstruction of adult muscle tissue relies on a pool of mononucleate, resident muscle stem cells, known as "satellite cells", expressing the paired-box transcription factor Pax7 necessary for their specification during embryonic development and long-term maintenance during adult life. Satellite cells are located around the myofibres in a niche at the interface of the basal lamina and the host fibre plasma membrane (i.e., sarcolemma), at a very low frequency. Upon damage to the myofibres, quiescent satellite cells are activated and give rise to a population of transient amplifying myogenic progenitor cells, which eventually exit the cell cycle permanently and fuse to form new myofibres and regenerate the tissue. A subpopulation of satellite cells self-renew and repopulate the niche, poised to respond to future demands. Harnessing the potential of satellite cells relies on a complete understanding of the molecular mechanisms guiding their regulation in vivo. Over the past several decades, studies revealed many signal transduction pathways responsible for satellite cell fate decisions, but the niche cues driving the activation and silencing of these pathways are less clear. Here we explore the scintillating possibility that considering the dynamic changes in the biophysical properties of the skeletal muscle, namely stiffness, and the stretch and shear forces to which a myofibre can be subjected to may provide missing information necessary to gain a full understanding of satellite cell niche regulation. PMID- 26004540 TI - Negative Epistasis and Evolvability in TEM-1 beta-Lactamase--The Thin Line between an Enzyme's Conformational Freedom and Disorder. AB - Epistasis is a key factor in evolution since it determines which combinations of mutations provide adaptive solutions and which mutational pathways toward these solutions are accessible by natural selection. There is growing evidence for the pervasiveness of sign epistasis--a complete reversion of mutational effects, particularly in protein evolution--yet its molecular basis remains poorly understood. We describe the structural basis of sign epistasis between G238S and R164S, two adaptive mutations in TEM-1 beta-lactamase--an enzyme that endows antibiotics resistance. Separated by 10 A, these mutations initiate two separate trajectories toward increased hydrolysis rates and resistance toward second and third-generation cephalosporins antibiotics. Both mutations allow the enzyme's active site to adopt alternative conformations and accommodate the new antibiotics. By solving the corresponding set of crystal structures, we found that R164S causes local disorder whereas G238S induces discrete conformations. When combined, the mutations in 238 and 164 induce local disorder whereby nonproductive conformations that perturb the enzyme's catalytic preorganization dominate. Specifically, Asn170 that coordinates the deacylating water molecule is misaligned, in both the free form and the inhibitor-bound double mutant. This local disorder is not restored by stabilizing global suppressor mutations and thus leads to an evolutionary cul-de-sac. Conformational dynamism therefore underlines the reshaping potential of protein's structures and functions but also limits protein evolvability because of the fragility of the interactions networks that maintain protein structures. PMID- 26004542 TI - Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native beta-Sheet Topology. AB - 3D domain-swapping proteins form multimers by unfolding and then sharing of secondary structure elements, often with native-like interactions. Runaway domain swapping is proposed as a mechanism for folded proteins to form amyloid fibres, with examples including serpins and cystatins. Cystatin C amyloids cause a hereditary form of cerebral amyloid angiopathy whilst cystatin B aggregates are found in cases of Unverricht-Lundborg Syndrome, a progressive form of myoclonic epilepsy. Under conditions that favour fibrillisation, cystatins populate stable 3D domain-swapped dimers both in vitro and in vivo that represent intermediates on route to the formation of fibrils. Previous work on cystatin B amyloid fibrils revealed that the alpha-helical region of the protein becomes disordered and identified the conservation of a continuous 20-residue elongated beta-strand (residues 39-58), the latter being a salient feature of the dimeric 3D domain swapped structure. Here we apply limited proteolysis to cystatin B amyloid fibrils and show that not only the alpha-helical N-terminal of the protein (residues 1-35) but also the C-terminal of the protein (residues 80-98) can be removed without disturbing the underlying fibril structure. This observation is incompatible with previous models of cystatin amyloid fibrils where the beta sheet is assumed to retain its native antiparallel arrangement. We conclude that our data favour a more generic, at least partially parallel, arrangement for cystatin beta-sheet structure in mature amyloids and propose a model that remains consistent with available data for amyloids from either cystatin B or cystatin C. PMID- 26004543 TI - A gustatory second-order neuron that connects sucrose-sensitive primary neurons and a distinct region of the gnathal ganglion in the Drosophila brain. AB - Although the gustatory system provides animals with sensory cues important for food choice and other critical behaviors, little is known about neural circuitry immediately following gustatory sensory neurons (GSNs). Here, we identify and characterize a bilateral pair of gustatory second-order neurons (G2Ns) in Drosophila. Previous studies identified GSNs that relay taste information to distinct subregions of the primary gustatory center (PGC) in the gnathal ganglia (GNG). To identify candidate G2Ns, we screened ~5,000 GAL4 driver strains for lines that label neural fibers innervating the PGC. We then combined GRASP (GFP reconstitution across synaptic partners) with presynaptic labeling to visualize potential synaptic contacts between the dendrites of the candidate G2Ns and the axonal terminals of Gr5a-expressing GSNs, which are known to respond to sucrose. Results of the GRASP analysis, followed by a single-cell analysis by FLP-out recombination, revealed a pair of neurons that contact Gr5a axon terminals in both brain hemispheres and send axonal arborizations to a distinct region outside the PGC but within the GNG. To characterize the input and output branches, respectively, we expressed fluorescence-tagged acetylcholine receptor subunit (Dalpha7) and active-zone marker (Brp) in the G2Ns. We found that G2N input sites overlaid GRASP-labeled synaptic contacts to Gr5a neurons, while presynaptic sites were broadly distributed throughout the neurons' arborizations. GRASP analysis and further tests with the Syb-GRASP method suggested that the identified G2Ns receive synaptic inputs from Gr5a-expressing GSNs, but not Gr66a-expressing GSNs, which respond to caffeine. The identified G2Ns relay information from Gr5a expressing GSNs to distinct regions in the GNG, and are distinct from other, recently identified gustatory projection neurons, which relay information about sugars to a brain region called the antennal mechanosensory and motor center (AMMC). Our findings suggest unexpected complexity for taste information processing in the first relay of the gustatory system. PMID- 26004544 TI - The Dmca1D channel mediates Ca(2+) inward currents in Drosophila embryonic muscles. AB - We studied, in a genetic model organism, Drosophila melanogaster, the channel mechanisms underlying membrane excitation in the embryonic body wall muscle whose biophysical properties have been poorly characterized. The inward current underlying the action potential was solely mediated by a high-threshold class of voltage-gated Ca(2+) channels, which exhibited slow inactivation, Ca(2+) permeability with saturation at high [Ca(2+)]OUT, and sensitivity to a Ca(2+) channel blocker, Cd(2+). The Ca(2+) current in the embryonic muscle was completely eliminated in Dmca1D mutants, indicating that the Dmca1D-encoded Ca(2+) channel is the major mediator of inward currents in the body wall muscles throughout the embryonic and larval stages. PMID- 26004545 TI - Clinical characteristics of combined cases of spinocerebellar ataxia types 6 and 31. AB - This study reports the first family in which spinocerebellar ataxia type 6 (SCA6) and spinocerebellar ataxia type 31 (SCA31) mutations were seen. An index patient first presented to our hospital due to gait and speech disturbances. Subsequent clinical investigation of this patient and her family members revealed consistent pure cerebellar ataxia transmitted in an autosomal-dominant manner. Genetic examination unexpectedly demonstrated that two of the five affected individuals had expansions of SCA6 and SCA31, while two others had SCA31 alone and the remaining had SCA6. Clinical manifestations were more severe in individuals with combined mutations relative to those with single mutation, suggesting that the SCA6 and SCA31 mutations have a cumulative pathogenic effect. PMID- 26004546 TI - [Therapeutic options for synovial sarcoma]. AB - Synovial sarcomas account for approximately 5 to 10% of soft tissue sarcomas and 0.05 to 0.1% of all malignant neoplasms. They predominantly affect the extremities but can occur in any part of the body. More than 50% of the patients are expected to develop metastatic disease within 3-5 years. In some patients disease recurrence may develop after 20 years. The 5-year overall survival rate is 10% for patients with metastatic disease and 76% for patients with localized one. Age, tumour size, histological subtype, and adjuvant radiotherapy influence prognosis. The role of adjuvant chemotherapy has not been proven yet. There are several ongoing clinical trials to determine the efficacy of active agents used for therapy of locally advanced, relapsed/refractory or metastatic disease. Better understanding of the biological behaviour of synovial sarcomas would provide the future way for the targeted therapy in combination with conventional treatments. PMID- 26004547 TI - [Conceptual framework of integrated care and options for integration in primary care]. AB - Nowadays, several countries' health governments have recognized that the complex treatment of chronic diseases, prevention and rehabilitation requires a new approach. This study presents the possible solution of integrated service delivery in health and other sectors. Furthermore, it shows how the integration of primary care services was implemented and how the integration of different levels of providers changes the organization of care. This study is based on an overview of the relevant international literature, as well as the 5th European Primary Care Forum. The comprehensive approach of integrated care and adaption of the needs of local communities encourage the development of new organizational forms and services in primary care. The integrated service forms are more suitable to satisfy the needs of patients and communities and provide wide range of services, but it is important to find the appropriate dimensions of integration which would fit our goals. PMID- 26004548 TI - [Metabolic complications of obesity during adolescence, particularly regarding elevated uric acid levels]. AB - INTRODUCTION: Obesity is a social problem worldwide that leads to several diseases, including metabolic syndrome, hypertension and cardiovascular diseases. It is known that hyperuricemia in adults may be associated with these disorders. AIM: The aim of the authors was to investigate the frequency of metabolic syndrome and hyperuricemia and their relationship among obese adolescents. METHOD: This was a cross-sectional study. The authors analysed the data of 162 overweight or obese adolescents (100 boys and 62 girls) who were previously investigated in a paediatric endocrinology consultation. Anthropometric and metabolic parameters were evaluated in all subjects. Healthy, age-matched, non obese girls (n = 20) and boys (n = 26) were used as controls. The age of overweight or obese boys was: 12 +/- 2.1 and overweight or obese girls was 11 +/- 2.5 years. In the control group the age of boys was 12.9 +/- 2.5 years and the age of girls was 13.2 +/- 1.6 years. Linear regression was used to evaluate associations between uric acid and clinical and laboratory findings associated with metabolic syndrome. RESULTS: Obese or overweight subjects had greater BMI SDS (boys, 3.4 +/- 1.3 vs 0.05 +/- 0.4 in controls, p<0.0001; girls, 3.75 +/- 1.4 vs 0.72 +/- 0.9 in controls, p = 0.0001), waist circumference (boys, 90.1 +/- 9.2 vs 82.3 +/- 6.4 cm in controls; girls, 90.2 +/- 8.6 vs 78.1 +/- 7.2 cm in controls, p<0.001), higher systolic blood pressure (boys, 125 +/- 14.3 vs 118.2 +/- 10.8 mmHg in controls, p = 0.02; girls, 125.8 +/- 11.8 vs 119.8 +/- 8.8 mmHg in controls, p<0.01), diastolic blood pressure (boys, 78.4 +/- 9.1 vs 71.2 +/- 8.0 mmHg in controls, p = 0.0003; girls, 76.45 +/- 7.2 vs 73.2 +/- 6.3 mmHg in controls, p = 0.0453). The prevalence of metabolic syndrome was 45/162 (27.8%) and the prevalence of hyperuricemia was 62/162 (38.3%). Of the 45 subjects with metabolic syndrome, 30 (66.7%) had hyperuricemia. CONCLUSIONS: It can be concluded that hyperuricemia is strongly associated with metabolic syndrome. The high concentration of uric acid predicts cardiovascular risk in adulthood. It is important for paediatricians to determine and assess uric acid levels in overweight or obese adolescents. PMID- 26004549 TI - [Infective endocarditis caused by Chlamydia pneumoniae after liver transplantation. Case report]. AB - The incidence of infective endocarditis is underestimated in solid organ transplant recipients. The spectrum of pathogens is different from the general population. The authors report the successful treatment of a 58-year-old woman with infective endocarditis caused by atypical microorganism and presented with atypical manifestations. Past history of the patient included alcoholic liver cirrhosis and cadaver liver transplantation in February 2000. One year after liver transplantation hepatitis B virus infection was diagnosed and treated with antiviral agents. In July 2007 hemodialysis was started due to progressive chronic kidney disease caused by calcineurin toxicity. In November 2013 the patient presented with transient aphasia. Transesophageal echocardiography revealed vegetation in the aortic valve and brain embolization was identified on magnetic resonance images. Initial treatment consisted of a 4-week regimen with ceftriaxone (2 g daily) and gentamycin (60 mg after hemodialysis). Blood cultures were all negative while serology revealed high titre of antibodies against Chlamydia pneumoniae. Moxifloxacin was added as an anti-chlamydial agent, but neurologic symptoms returned. After coronarography, valvular surgery and coronary artery bypass surgery were performed which resulted in full clinical recovery of the patient. PMID- 26004550 TI - [Criminal caesarean section]. PMID- 26004551 TI - [Embryonal varicella. To the Editors]. PMID- 26004552 TI - CORRIGENDUM: Intracranial Hemorrhage Caused by Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) - Multicenter Retrospective Cohort Study in Japan - . PMID- 26004555 TI - Inhibition of SHP-2 promotes radiosensitivity in glioma. AB - As a phosphatase, SHP-2 has been identified to be involved in regulating several cell functions, including growth, division, adhesion and motility. Therefore, SHP 2 may affect the response of glioma to radiotherapy, such as via enhancing angiogenesis. The present study aimed to investigate the function of SHP-2, a protein tyrosine phosphatase, in the radiosensitivity of glioma. U251, U87 and SHG44 glioma cell lines were transfected with small interfering (si)RNA against SHP-2 and cell proliferation was assessed using a cell counting kit 8 assay, cell apoptosis was assessed by fluorescence-activated cell sorting and immunoblotting, cell invasion was determined by an invasion assay, and the vasculogenic mimicry capacity was assessed by a tube formation assay. SHP-2 siRNA transfection reduced the proliferation and increased apoptosis in the glioma cell lines. Downregulation of SHP-2 suppressed glioma cell invasion and vasculogenic mimicry. These results demonstrated that no significant difference was observed between glioma tissues and normal brain tissues, however, silencing of SHP-2 inhibited cell proliferation, invasion and vasculogenic mimicry in the glioma cell lines. SHP-2 may be a novel therapeutic target for glioma. PMID- 26004556 TI - TG/DSC-FTIR and Py-GC investigation on pyrolysis characteristics of petrochemical wastewater sludge. AB - The pyrolysis characteristics of petrochemical wastewater sludge (PS) were evaluated using TG/DSC-FTIR and fixed-bed reactor with GC. TGA experiments indicated that the pyrolysis of PS proceeded in three phases, and the thermographs shifted to higher temperatures with increasing heating rate. Chars FTIR showed that the absorption of O-H, C-H, C=O and C-C decreased with pyrolysis temperatures increasing. Gases FTIR correspondingly showed that H2O, CO, and CH4 generated at higher temperatures. For the fixed-bed reactor tests, H2 and CO were relatively higher in the pyrolysis gases, and CH4 was negligible at 436K. The kinetic triplets of PS pyrolysis were estimated by Flynn-Wall-Ozawa, Kissinger Akahira-Sunose, and integral master-plots method. The results suggested that the most potential kinetic models for the first and second phase were the order reaction model, while the random nucleation and nuclei growth model for the third phase. PMID- 26004557 TI - Enhancing hemicelluloses removal from a softwood sulfite pulp. AB - Hemicelluloses removal is highly desirable in many biomass processes, including the pretreatment steps of the bioconversion for ethanol production, production of high-quality dissolving pulps. In this study, a sequential treatment consisting of pulp fractionation, followed by caustic treatment to remove hemicelluloses from a softwood sulfite pulp, was investigated. The long-fiber fraction obtained after pulp fractionation, had a lower hemicelluloses content and smaller specific surface area, but larger pore diameter than the short-fiber fraction. The fiber fractions were subsequently treated in a cold caustic extraction (CCE) or hot caustic extraction (HCE). Results showed that hemicelluloses removal in the long fiber fraction was more pronounced than the short-fiber fraction in both CCE and HCE processes. Other parameters, such as hemicelluloses removal selectivity, yield were studied. The underlying explanations were given. PMID- 26004558 TI - Alumina supported molybdenum catalyst for lignin valorization: Effect of reduction temperature. AB - Alumina supported molybdenum catalysts were prepared with an impregnation method. The activity of the catalyst in the ethanolysis of Kraft lignin to C6-C11 molecules, i.e. alcohols, esters, monophenols, benzyl alcohols and arenes, was tested in a batch reactor at 280 degrees C with initial 0 MPa nitrogen. The complete conversion of lignin to small molecular chemicals was achieved without the formation of tar or char. The reduction temperature during the catalyst preparation was proved to have a profound effect on the activity of the catalyst. The overall product yield firstly increases and then decreases with the increase of the reduction temperature in a range of 500-800 degrees C. The maximum yield up to 1390 mg/g lignin was obtained with the catalyst reduced at 750 degrees C. Furthermore, the catalyst showed an excellent recyclability, where no significant loss of the catalytic activity was exhibited after 5 runs. PMID- 26004559 TI - Glucose-6-phosphate dehydrogenase deficiency and Alzheimer's disease: Partners in crime? The hypothesis. AB - Alzheimer's disease is a multifaceted brain disorder which involves various coupled irreversible, progressive biochemical reactions that significantly reduce quality of life as well as the actual life expectancy. Aging, genetic predispositions, head trauma, diabetes, cardiovascular disease, deficiencies in insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, high cholesterol level, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic dysfunction, high blood pressure, obesity, dietary habits, exercise, social engagement, and mental stress are noted among the risk factors of this disease. In this hypothesis review I would like to draw the attention on glucose-6 phosphate dehydrogenase deficiency and its relationship with Alzheimer's disease. This enzymopathy is the most common human congenital defect of metabolism and defined by decrease in NADPH+H(+) and reduced form of glutathione concentration and that might in turn, amplify oxidative stress due to essentiality of the enzyme. This most common enzymopathy may manifest itself in severe forms, however most of the individuals with this deficiency are not essentially symptomatic. To understand the sporadic Alzheimer's disease, the writer of this paper thinks that, looking into a crystal ball might not yield much of a benefit but glucose-6 phosphate dehydrogenase deficiency could effortlessly give some clues. PMID- 26004560 TI - Pro-apoptotic and anti-proliferative effects of 3,3'-diindolylmethane in nasopharyngeal carcinoma cells via downregulation of telomerase activity. AB - The pro-apoptotic and anti-proliferative effects of 3,3'-diindolylmethane (DIM) in various tumor cell types have been widely investigated. The underlying mechanisms were suggested to include cell cycle arrest, cell signaling inhibition and downregulation of the androgen receptor. The present study demonstrated that DIM induced apoptosis and inhibited proliferation in nasopharyngeal carcinoma cells by downregulating the activity of telomerase. The nasopharyngeal carcinoma cell line 5-8F was selected for this purpose. A cell counting kit-8 assay and flow cytometry were performed to detect apoptosis and proliferation of 5-8F cells, respectively, which revealed the pro-apoptotic and anti-proliferative effects of DIM. Telomerase activity was detected using a telomeric repeat amplification protocol assay, which revealed that the telomerase activity was inhibited by DIM in a dose-dependent manner. Reverse transcription polymerase chain reaction was used to detect the mRNA expression levels of human telomerase reverse transcriptase (hTERT) and human telomerase RNA (hTR), and western blot analysis was used to detect the protein expression of hTERT. The results showed that the mRNA and protein expression of hTERT were downregulated in 5-8F cells following treatment with DIM; however, the mRNA expression of hTR remained unchanged, suggesting that hTERT was the target of DIM. To further identify the target, the length of telomeres was continually measured using a telomere length detection kit, revealing that the telomeres were shortened by DIM in an concentration-dependent manner. The present study confirmed that DIM had pro apoptotic and anti-proliferative effects in nasopharyngeal carcinoma cells by regulating telomerase. PMID- 26004561 TI - Trace metal concentrations and their transfer from sediment to leaves of four common aquatic macrophytes. AB - In the present study, the concentrations of trace and alkali metals in leaves of four common helophytes, Sparganium erectum, Glyceria maxima, Phalaris arundinacea, and Phragmites australis, as well as in corresponding water and bottom sediments were investigated to ascertain plant bioaccumulation ability. Results showed that Mn and Fe were the most abundant trace metals in all plant species, while Co and Pb contents were the lowest. Leaves of species studied differed significantly in respect of element concentrations. The highest concentrations of Mg, Na, Fe, Mn, Cu, Pb, and Ni were noted in S. erectum while the highest contents of Co, Ca, Zn, and Cr in Phalaris arundinacea. Phragmites australis contained the lowest amounts of most elements. Concentrations of Co, Cr, Fe, and Mn in all species studied and Ni in all except for Phragmites australis were higher than natural for hydrophytes. The leaves/sediment ratio was more than unity for all alkali metals as well as for Cu and Mn in Phragmites australis; Cr, Co, and Zn in Phalaris arundinacea; Cr and Mn in S. erectum; and Cr in G. maxima. High enrichment factors and high levels of toxic metals in the species studied indicated a special ability of these plants to absorb and store certain non-essential metals and, consequently, their potential for phytoremediation of contaminated aquatic ecosystems. PMID- 26004562 TI - Health risk assessment of toxic VOCs species for the coal fire well drillers. AB - In this study, the health risk of toxic volatile organic compounds (VOCs) species for well drillers, working at an exposure site around a well of underground coal fire site, was presented in a case of Shanxi province. The samples were collected by Teflon sampling bags and measured by gas chromatography-mass spectrometry (GC MS). The results showed that isopropyl alcohol was the most abundant compound of VOCs, with the geometric mean concentrations of 1700.38 MUg/m(3). The geometric mean concentrations of individual BTEX compounds obtained in all of the sampling campaign were 131.64, 10.15, 15.53, and 25.38 MUg/m(3) for benzene, toluene, ethyl-benzene, and xylenes, respectively. Relative proportion of BTEX averaged as 8.5:0.7:1:1.6. High B/T ratio (13.0) and low T/E ratio (0.7) was observed in this study. For non-cancer risk in this study, the hazardous quotient (HQ) of 1,2 dibromoethane, 1,3-butadiene, and benzene was 17.91, 1.71, and 43.88, respectively, mean their non-cancer risk was at the level of definite concern. The HQ sum of 20 VOCs was 64.94, much higher than 1. The cancer risk values of benzene (7.01E-04), 1,2-dibromoethane (1.91E-04), carbon tetrachloride (1.55E 04), and 1,3-butadiene (1.09E-04) were greater than 10(-4), indicating that they were all definite risk. The total cancer risk of all VOCs species was 1.39E-03, almost 14 times more than the level of definite risk. The stochastic exposure assessment of all VOCs species total cancer risk using the Monte Carlo simulation analysis shows that 5 and 95 % cancer risks were predicted to be 7.60E-04 and 2.75E-03, respectively. The cancer risk for all VOCs species is unacceptable. The results of sensitivity analysis show that benzene, carbon tetrachloride, and 1,3 butadiene exposure account for more than 98 % contributions to the estimated risk for drillers, indicating that those VOCs species exposure has greater impact than other species on risk assessment. Both combined effects and independent effects of each VOCs species have to be considered. PMID- 26004563 TI - The capacity of biochar made from common reeds to neutralise pH and remove dissolved metals in acid drainage. AB - We tested the capacity of biochar (made at 450 degrees C from a common reed species) to neutralise pH and remove metals in two acid drainage waters (pH 2.6 and 4.6) using column leaching and batch mixing experiments. In the column experiments, the acid drainage water was neutralised upon passage through the biochar with substantial increases (4-5 pH units) in the leachate pH. In the batch experiments, the leachate pH remained above 6.5 when the drainage:biochar ratio was less than approximately 700:1 (L acid drainage:kg biochar) and 20:1 for the pH 4.6 and pH 2.6 drainage waters, respectively. Dissolved metal concentrations were reduced by 89-98 % (Fe ~ Al > Ni ~ Zn > Mn) in the leachate from the biochar. A key mechanism of pH neutralisation appears to be solid carbonate dissolution as calcite (CaCO3) was identified (via X-ray diffraction) in the biochar prior to contact with acid drainage, and dissolved alkalinity and Ca was observed in the leachate. Proton and metal removal by cation exchange, direct binding to oxygen-containing functional groups, and metal oxide precipitation also appears important. Further evaluation of the treatment capacity of other biochars and field trials are warranted. PMID- 26004564 TI - Accumulation, availability, and uptake of heavy metals in a red soil after 22 year fertilization and cropping. AB - Fertilization is important to increase crop yields, but long-term application of fertilizers probably aggravated the risk of heavy metals in acidic soils. In this study, the effect of 22-year fertilization and cropping on accumulation, availability, and uptake of heavy metals in red soil was investigated. The results showed that pig manure promoted significantly cadmium (Cd) accumulation (average 1.1 mg kg(-1)), nearly three times higher than national soil standards and, thus, increased metal availability. But the enrichment of heavy metals decreased remarkably by 50.5 % under manure fertilization, compared with CK (control without fertilization). On the contrary, chemical fertilizers increased greatly lead (Pb) availability and Cd activity; in particular, exceeding 85 % of soil Cd became available to plant under N (nitrogen) treatment during 9-16 years of fertilization, which correspondingly increased their enrichment by 29.5 %. Long-term application of chemical fertilizers caused soil acidification and manure fertilization led to the increase in soil pH, soil organic matter (SOM), and available phosphorus (Olsen P), which influenced strongly metal behavior in red soil, and their effect had extended to deeper soil layer (20~40 cm). It is advisable to increase application of manure alone with low content of heavy metals or in combination with chemical fertilizers to acidic soils in order to reduce toxic metal risk. PMID- 26004565 TI - Heavy metal exposure from ingesting rice and its related potential hazardous health risks to humans. AB - Different types of rice grains imported from 11 different countries and available on the Kuwaiti retail market were collected for heavy metal analysis. The surveyed rice samples were grouped according to their country of origin into four different regions namely Asia, Europe, Middle East, and North America. The samples were analyzed for total arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg) using inductively coupled plasma mass spectrometry (ICP-MS). The data showed that the highest geometric means (GMs) of total As, Cd, Pb, and Hg contents were in rice samples imported from Europe, Asia, Europe, and the Middle East, respectively. The total As, Cd, Pb, and Hg concentrations in the analyzed rice samples were compared to the heavy metal content of 5800 rice samples from 25 different countries reported in the literature; furthermore, the heavy metal (total As, Cd, Pb, and Hg) concentrations determined in this study were implemented to calculate the daily dietary intake of toxic metals for the general population in the state of Kuwait, while the collected ones from the literature were implemented to calculate and then compare the daily dietary intake of toxic metals for the general population in 29 different countries around the world. PMID- 26004566 TI - Measuring the impact of energy consumption and air quality indicators on climate change: evidence from the panel of UNFCC classified countries. AB - This study examines the relationship between energy consumption, air pollution, and climate change in the panel of six economically diversified countries classified by the United Nations Framework Convention on Climate Change (UNFCC) as industrialized countries and economies in transition nations by using the panel econometric techniques for the period of 1990-2012. The results of pooled least square regression show that both the energy consumption and air quality indicators have a positive and significant relationship with the climate change, i.e., 1 % increase in energy consumption increases greenhouse gas emissions by 0.124 %, carbon dioxide emissions increase by 0.652 %, methane emissions increase by 0.123 %, and nitrous oxide emissions increase greenhouse gas emissions by 0.105 % age points. The results of fixed-effect regression and random-effect regression confirmed the deteriorating impact of air quality indicators on climate change; however, the results failed to show any significant association between energy consumption and climate change when absorbing country-specific shocks and time-variant shocks during the study time period. PMID- 26004567 TI - [Recommendations for management of acute pharyngitis in adults]. AB - Acute pharyngitis in adults is one of the most common infectious diseases seen in general practitioners' consultations. Viral aetiology is the most common. Among bacterial causes, the main agent is Streptococcus pyogenes or group A beta haemolytic streptococcus (GABHS), which causes 5%-30% of the episodes. In the diagnostic process, clinical assessment scales can help clinicians to better predict suspected bacterial aetiology by selecting patients who should undergo a rapid antigen detection test. If these techniques are not performed, an overdiagnosis of streptococcal pharyngitis often occurs, resulting in unnecessary prescriptions of antibiotics, most of which are broad spectrum. Consequently, management algorithms that include the use of predictive clinical rules and rapid tests have been set up. The aim of the treatment is speeding up symptom resolution, reducing the contagious time span and preventing local suppurative and non-suppurative complications. Penicillin and amoxicillin are the antibiotics of choice for the treatment of pharyngitis. The association of amoxicillin and clavulanate is not indicated as the initial treatment of acute infection. Neither are macrolides indicated as first-line therapy; they should be reserved for patients allergic to penicillin. The appropriate diagnosis of bacterial pharyngitis and proper use of antibiotics based on the scientific evidence available are crucial. Using management algorithms can be helpful in identifying and screening the cases that do not require antibiotic therapy. PMID- 26004568 TI - Deaths following vaccination: What does the evidence show? AB - Vaccines are rigorously tested and monitored and are among the safest medical products we use. Millions of vaccinations are given to children and adults in the United States each year. Serious adverse reactions are rare. However, because of the high volume of use, coincidental adverse events including deaths, that are temporally associated with vaccination, do occur. When death occurs shortly following vaccination, loved ones and others might naturally question whether it was related to vaccination. A large body of evidence supports the safety of vaccines, and multiple studies and scientific reviews have found no association between vaccination and deaths except in rare cases. During the US multi-state measles outbreak of 2014-2015, unsubstantiated claims of deaths caused by measles, mumps, and rubella (MMR) vaccine began circulating on the Internet, prompting responses by public health officials to address common misinterpretations and misuses of vaccine safety surveillance data, particularly around spontaneous reports submitted to the US Vaccine Adverse Event Reporting System (VAERS). We summarize epidemiologic data on deaths following vaccination, including examples where reasonable scientific evidence exists to support that vaccination caused or contributed to deaths. Rare cases where a known or plausible theoretical risk of death following vaccination exists include anaphylaxis, vaccine-strain systemic infection after administration of live vaccines to severely immunocompromised persons, intussusception after rotavirus vaccine, Guillain-Barre syndrome after inactivated influenza vaccine, fall related injuries associated with syncope after vaccination, yellow fever vaccine associated viscerotropic disease or associated neurologic disease, serious complications from smallpox vaccine including eczema vaccinatum, progressive vaccinia, postvaccinal encephalitis, myocarditis, and dilated cardiomyopathy, and vaccine-associated paralytic poliomyelitis from oral poliovirus vaccine. However, making general assumptions and drawing conclusions about vaccinations causing deaths based on spontaneous reports to VAERS - some of which might be anecdotal or second-hand - or from case reports in the media, is not a scientifically valid practice. PMID- 26004569 TI - Are consumers ready to take part in the Pharmacovigilance System?--a Portuguese preliminary study concerning ADR reporting. AB - BACKGROUND: New pharmacovigilance legislation allows consumers to report adverse drug reactions (ADRs) directly to competent authorities in all European Union countries. Consumer reporting is available in Portugal since July 2012. In 2013, the National Pharmacovigilance System (SNF) had received 3461 spontaneous ADR reports, of which only 1.4% (n = 50) were from consumers. Consumer reporting could be one opportunity to reduce underreporting. AIM: The aim of this study was to describe the attitudes and knowledge of the general public regarding spontaneous reporting and the reasons and opinions that can influence consumers' ADR underreporting. METHODS: A descriptive-correlational study was performed looking for consumers' attitudes and knowledge regarding spontaneous reporting. A 6-month survey was conducted from June to November 2013 in general adult consumers from a community pharmacy in Coimbra, Portugal, who used prescribed medicines or over-the-counter (OTC) drugs. Attitudes and opinions were surveyed by personal interview in a closed-answer questionnaire using a Likert scale. Questionnaires from healthcare professionals or incomplete ones were not considered. Data were analyzed using descriptive statistics, chi-square (chi(2)) tests, and Spearman's correlation coefficients. RESULTS: One thousand eighty-four questionnaires were collected (response rate of 81.1%) and 948 completed were selected for analysis. Of the respondents, 44.1% never heard about SNF. Younger people and those with a higher education were significantly more likely to be aware of SNF. Only one consumer had previously reported directly an ADR. Reporting ADRs indirectly through a healthcare professional (HCP) was preferred by 62.4%. The main reasons for consumers reporting spontaneous ADR would be the severity of reactions (81.1% agreed or strongly agreed) and worries about their situation (73.4% agreed or strongly agreed). Only weak and moderate correlations were found between studied statements.. CONCLUSIONS: Consumers are more likely to do spontaneous report about severe reactions or if they are worried about the symptoms. Tailored and proactive information on ADR reporting and educational interventions on consumers could increase the number of reports from consumers in Portugal. PMID- 26004570 TI - Healthcare costs associated with elderly chronic pain patients in primary care. AB - OBJECTIVE: This study aimed to estimate the total healthcare costs associated with elderly chronic pain (CP) patients, define cost-related factors in this population, and examine cost evolution over two years. METHOD: This is an ancillary study from the CP S.AGE subcohort, including non-institutionalized patients aged over 65 suffering from CP. 1190, 1108, 1042, and 950 patients were reviewed with available healthcare data at follow-up visits at 6, 12, 18, and 24 months, respectively. Healthcare components included medical and paramedical visits, medication prescription, and hospitalization. RESULT: The mean total cost in the first semester was estimated at 2548 +/- 8885 per patient. Hospitalization represented the largest cost component (50%) followed by paramedical care (24%), medications (21%), and medical visits (5%). Significant cost-associated factors were comorbidity (OR 1.49, 95% CI 1.35-1.64), dependency in daily activities (OR 1.85, 95% CI 1.39-2.47), probable depression (OR 1.71, 95% CI 1.09-2.69), permanent pain (OR 1.48, 95% CI 1.18-1.86), neuropathic pain (OR 1.94, 95% CI 1.38-2.73), living alone (OR 1.45, 95% CI 1.16-1.82), chronic back pain (OR 1.35, 95% CI 1.07-1.71), and vertebral fracture/compression (OR 1.47, 95% CI 1.08-2.01). Healthcare costs increased significantly by 48% (p < 0.0001) during follow-up namely due to hospitalizations. Elevated costs were associated with a higher risk of future hospitalization (OR 1.95, CI 95% 1.33 2.87). CONCLUSION: Healthcare costs increased rapidly over time, largely due to hospitalization. Prevention strategies to limit hospitalizations in elderly appear to be the most useful in order to achieve cost savings in the future. PMID- 26004571 TI - Development of a reduced-graphene-oxide based superparamagnetic nanocomposite for the removal of nickel (II) from an aqueous medium via a fluorescence sensor platform. AB - Reduced-graphene-oxide based superparamagnetic nanocomposite (GC) was fabricated and applied for the remediation of Ni(II) from an aqueous medium. The as-prepared GC was extensively characterized by Raman, TEM, AFM, SEM-EDX, SQUID, and BET analyses. Quantitative immobilization of Ni(II) in an aqueous solution by the fluorescent sensor platform of GC was explored at varying pH, doses, contact times, and temperatures. The pseudo-second-order kinetics equation governed the overall sorption process at optimized pH of 5 (+/-0.2). The superior monolayer sorption capacity was 228mgg(-1) at 300K. Negative DeltaG(0) indicated the spontaneous sorption nature, whereas the positive DeltaH(0) resulted from an increase in entropy (positive DeltaS(0)) at the solid-liquid interface during the endothermic reaction. The lower enthalpy agreed with the relatively high regeneration (approximately 91%) of the GC by 0.1M HCl, because of the formation of stable tetrahedral complex. The physisorption was well corroborated by calculated sorption energy (EDR ~7kJmol(-1)) and the nature of the Stern-Volmer plot of the fluorescence-quenching data with reaction time. The GC played a pivotal role as a static fluorescent sensor platform (fluorophore) for Ni(II) adsorption. Magnetic property also indicated that GC could be easily separated from fluids by exploiting its superparamagnetic property. PMID- 26004572 TI - Engineering filamentous bacteriophages for enhanced gold binding and metallization properties. AB - Filamentous bacteriophages are nanowire-like virion molecules consisting of a single stranded DNA (ssDNA) as the genomic material packed in a protein cage. In this study, Tyr containing 5-mer peptides were displayed on phage filaments for enhanced Au binding and reduction properties. Wild type fd (AEGDD) and engineered YYYYY, AYSSG and AYGDD phages were investigated by Quartz crystal microbalance (QCM), Atomic force microscopy (AFM), Scanning electron microscopy (SEM) and Energy dispersive X-ray spectroscopy (EDX) analyses. Presence of only one Tyr unit on five aa flexible region of p8 coat proteins increased Au binding affinities of engineered phages. YYYYY phages were shown to have the strongest Au surface and AuNP binding affinities. Recombinant phages were shown to be coated with Au clusters after one-step metallization reaction. With further genetic modifications, phages can be programmed to function as site specific self assembling biotemplates for bottom-up manufacturing in nanoelectronics and biosensor application studies. PMID- 26004573 TI - Role of textile substrate hydrophobicity on the adsorption of hydrosoluble nonionic block copolymers. AB - The adsorption of polyalkylene glycols and co-polymers of ethylene oxide and propylene oxide on substrates relevant to textiles with varying surface energies (cellulose, polypropylene, nylon and polyester) was studied by using quartz crystal microgravimetry. Langmuirian-type isotherms were observed for the adsorption profiles of nonionic block polymers of different architectures. The affinity with the surfaces is discussed based on experimental observations, which highlights the role of hydrophobic effects. For a given type of block polymer, micellar and monomeric adsorption is governed by the balance of polymer structure (mainly, chain length of hydrophobic segments) and substrate's surface energy. PMID- 26004574 TI - Impact of confinement on proteins concentrated in lithocholic acid based organic nanotubes. AB - Organic nanotubes form in aqueous solution near physiological pH by self-assembly of lithocholic acid (LCA) with inner diameters of 20-40nm. The encapsulation of enhanced green fluorescent protein (eGFP) and resultant confinement effect for eGFP within these nanotubes is studied via confocal microscopy. Timed release rate studies of eGFP encapsulated in LCA nanotubes and fluorescence recovery after photobleaching (FRAP) indicate that the diffusive transport of eGFP out of and/or within the nanotubes is very slow, in contrast to the rapid introduction of eGFP into the nanotubes. By encapsulating two fluorescent proteins in LCA nanotubes, eGFP and mCherry, as a fluorescence resonance energy transfer (FRET) pair, the FRET efficiencies are determined using FRET imaging microscopy at three different protein concentrations with a fixed donor-to-acceptor ratio of 1:1. Forster theory reveals that the proteins are spatially separated by 4.8-7.2nm in distance inside these nanotubes. The biomimetic nanochannels of LCA nanotubes not only afford a confining effect on eGFP that results in enhanced chemical and thermal stability under conditions of high denaturant concentration and temperature, but also function as protein concentrators for enriching protein in the nanochannels from a diluted protein solution by up to two orders of magnitude. PMID- 26004575 TI - Skin transport of PEGylated poly(epsilon-caprolactone) nanoparticles assisted by (2-hydroxypropyl)-beta-cyclodextrin. AB - The aim of this work was to investigate the potential of small nanoparticles (NPs) made of a poly(ethylene glycol)-poly(epsilon-caprolactone)-amphiphilic diblock copolymer (PEG-b-PCL, PEG=2kDa and PCL=4.2kDa) as drug carrier system through the skin. Zinc(II) phthalocyanine (ZnPc), selected as lipophilic and fluorescent model molecule, was loaded inside NPs by a melting/sonication procedure. Loaded NPs with a hydrodynamic diameter around 60nm, a slightly negative zeta potential and a ZnPc entrapment dependent on polymer/ZnPc ratio were obtained. Spectroscopic investigations evidenced that ZnPc was entrapped in monomeric form maintaining its emission properties. The transport of ZnPc through porcine ear skin was evaluated on Franz-type diffusion cells after treatment with different vehicles (water or PEG 0.4kDa) containing free ZnPc or ZnPc-loaded NPs without and with (2-hydroxypropyl)-beta-cyclodextrin (HPbetaCD) as permeation enhancer. Independently of the sample tested, ZnPc was transported in the skin without reaching receptor compartment. On the other hand, ZnPc was found in the skin in large amount and also in the viable epidermis when delivered through NPs associated with HPbetaCD, especially in conditions limiting water evaporation. Fluorescence images of skin samples after 24h of permeation were in line with ZnPc dosage in the skin and demonstrated the ability of NPs covalently tagged with rhodamine to penetrate the skin and to locate in the intercellular spaces. Insight into skin chemical properties upon application of NPs by confocal Raman spectroscopy demonstrated that HPbetaCD caused an alteration of water profile in the skin, highly reducing the degree of hydration at stratum corneum/viable epidermis interface which can promote NP transport. Taken together, these results highlight PEG-b-PCL NPs coupled with HPbetaCD as a novel vehicle for the skin delivery of highly lipophilic compounds paving the way to several applications. PMID- 26004576 TI - Multipronged approach for engineering novel peptide analogues of existing lantibiotics. AB - INTRODUCTION: Lantibiotics are a class of ribosomally and post-translationally modified peptide antibiotics that are active against a broad spectrum of Gram positive bacteria. Great efforts have been made to promote the production of these antibiotics, so that they can one day be used in our antimicrobial arsenal to combat multidrug-resistant bacterial infections. AREAS COVERED: This review provides a synopsis of lantibiotic research aimed at furthering our understanding of the structural limitation of lantibiotics as well as identifying structural regions that can be modified to improve the bioactivity. In vivo, in vitro and chemical synthesis of lantibiotics has been useful for engineering novel variants with enhanced activities. These approaches have provided novel ways to further our understanding of lantibiotic function and have advanced the objective to develop lantibiotics for the treatment of infectious diseases. EXPERT OPINION: Synthesis of lantibiotics with enhanced activities will lead to the discovery of new promising drug candidates that will have a long lasting impact on the treatment of Gram-positive infections. The current body of literature for producing structural variants of lantibiotics has been more of a 'proof-of principle' approach and the application of these methods has not yet been fully utilized. PMID- 26004577 TI - Synthesis and structure-activity relationships of novel cationic lipids with anti inflammatory and antimicrobial activities. AB - Certain membrane-active cationic steroids are known to also possess both anti inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired. PMID- 26004578 TI - Inhibitory activities of biflavonoids against amyloid-beta peptide 42 cytotoxicity in PC-12 cells. AB - A major hallmark of Alzheimer's disease is the cerebral accumulation and resulting cytotoxicity of amyloid-beta peptides, particularly Abeta42. In this study, we used an MTT assay to investigate the inhibitory activity of biflavonoids 1-22 against Abeta42 cytotoxicity in PC-12 cell cultures. Cytoprotective effects were observed for the following amentoflavone type biflavonoids: podocarpusflavone B 8, isoginkgetin 10, sciadopitysin 13, and kayaflavone 15. These biflavonoids exhibited strong activity in tested compounds, with EC50 values of 5.18, 10.77, 9.84, and 5.29 MUM, respectively. Cell viability tests of PC-12 cells revealed that biflavonoids 13 and 15 had stronger inhibitory activities than apigenin 23 and (-)-epigallocatechin gallate 24. PMID- 26004579 TI - Recent advances for FLAP inhibitors. AB - A number of FLAP inhibitors have been progressed to clinical trials for respiratory and other inflammatory indications but so far no drug has reached the market. With this Digest we assess the opportunity to develop FLAP inhibitors for indications beyond respiratory disease, and in particular for atherosclerotic cardiovascular disease. We also show how recently disclosed FLAP inhibitors have structurally evolved from the first generation FLAP inhibitors paving the way for new compound classes. PMID- 26004580 TI - An unprecedented dual antagonist and agonist of human Transglutaminase 2. AB - Transglutaminase 2 (TG2) is a ubiquitously expressed, Ca(2+)-activated extracellular enzyme in mammals that is maintained in a catalytically dormant state by multiple mechanisms. Although its precise physiological role in the extracellular matrix remains unclear, aberrantly up-regulated TG2 activity is a hallmark of several maladies, including celiac disease. Previously, we reported the discovery of a class of acylideneoxoindoles as potent, reversible inhibitors of human TG2. Detailed analysis of one of those inhibitors (CK-IV-55) led to an unprecedented and striking observation. Whereas this compound was a non competitive inhibitor (3.3+/-0.9 MUM) of human TG2 at saturating Ca(2+) concentrations, it activated TG2 in the presence of sub-saturating but physiologically relevant Ca(2+) concentrations (0.5-0.7 mM). This finding was validated in a cellular model of TG2 activation and inhibition. Mutant TG2 analysis suggested that CK-IV-55 and its analogs bound to a low-affinity Ca(2+) binding site on the catalytic core of TG2. A mechanistic model for the dual agonistic/antagonistic action of CK-IV-55 on TG2 is presented, and the pathophysiological implications of basal activation of intestinal TG2 by small molecules are discussed. PMID- 26004581 TI - Natural phenolic metabolites from endophytic Aspergillus sp. IFB-YXS with antimicrobial activity. AB - Prompted by the pressing necessity to conquer phytopathogenic infections, the antimicrobial compounds were characterized with bioassay-guided method from the ethanol extract derived from the solid-substrate fermentation of Aspergillus sp. IFB-YXS, an endophytic fungus residing in the apparently healthy leave of Ginkgo biloba L. The aim of this work was to evaluate the antimicrobial activity and mechanism(s) of these bioactive compounds against phytopathogens. Among the compounds, xanthoascin (1) is significantly inhibitory on the growth of the phytopathogenic bacterium Clavibacter michiganense subsp. Sepedonicus with a minimum inhibitory concentration (MIC) value of 0.31MUg/ml, which is more potent than streptomycin (MIC 0.62MUg/ml), an antimicrobial drug co-assayed herein as a positive reference. Moreover, terphenyl derivatives 3, 5 and 6 are also found to be active against other phytopathogens including Xanthomonas oryzae pv. oryzae Swings, Xanthomonas oryzae pv. oryzicola Swings, Erwinia amylovora and Pseudomonas syringae pv. lachrymans etc. The antibacterial mechanism of xanthoascin (1) was addressed to change the cellular permeability of the phytopathogens, leading to the remarkable leakage of nucleic acids out of the cytomembrane. The work highlights the possibility that xanthoascin (1), an analogue of xanthocillin which is used to be an approved antibiotic, may find its renewed application as a potent antibacterial agrichemical. This study contributes to the development of new antimicrobial drugs, especially against C. michiganense subsp. Sepedonicus. PMID- 26004582 TI - Innate lymphoid cells are pivotal actors in allergic, inflammatory and autoimmune diseases. AB - Innate lymphoid cells (ILCs) are lymphoid cells that do not express V(D)J rearranged receptors and play a role in the innate immune system. ILCs are categorized into three groups with respect to their function in the immune system. ILC1 induces production of IFN-gamma via T-box expressed on T cells, ILC2 promotes production of type 2 cytokines via GATA-binding protein-3 and ILC3 promotes IL-17 and IL-22 production via retinoic acid receptor-related orphan receptor-gammat. ILCs can maintain homeostasis in epithelial surfaces by responding to locally produced cytokines or direct recognition of danger patterns. Altered epithelial barrier function seems to be a key point in inappropriate activation of ILCs to promote inflammatory and allergic responses. ILCs play an essential role in initiation and maintenance of defense against infections as well as immune-mediated diseases. In this paper, we discuss the role of ILCs in inflammatory, allergic and autoimmune diseases. PMID- 26004583 TI - Physiotherapy clinical educators' perceptions and experiences of clinical prediction rules. AB - OBJECTIVES: Clinical prediction rules (CPRs) are widely used in medicine, but their application to physiotherapy practice is more recent and less widespread, and their implementation in physiotherapy clinical education has not been investigated. This study aimed to determine the experiences and perceptions of physiotherapy clinical educators regarding CPRs, and whether they are teaching CPRs to students on clinical placement. DESIGN: Cross-sectional observational survey using a modified Dillman method. PARTICIPANTS: Clinical educators (n=211, response rate 81%) supervising physiotherapy students from 10 universities across 5 states and territories in Australia. RESULTS: Half (48%) of respondents had never heard of CPRs, and a further 25% had never used CPRs. Only 27% reported using CPRs, and of these half (51%) were rarely if ever teaching CPRs to students in the clinical setting. However most respondents (81%) believed CPRs assisted in the development of clinical reasoning skills and few (9%) were opposed to teaching CPRs to students. Users of CPRs were more likely to be male (p<0.001), have post-professional qualifications (p=0.020), work in private practice (p<0.001), and work in the area of musculoskeletal physiotherapy (p<0.001) compared with non-users. The CPRs most commonly known, used and taught were the Ottawa Ankle Rule, the Ottawa Knee Rule, and Wells' Rule for Deep Vein Thrombosis. CONCLUSIONS: Students are unlikely to be learning about CPRs on clinical placement, as few clinical educators use them. Clinical educators will require training in CPRs and assistance in teaching them if students are to better learn about implementing CPRs in physiotherapy clinical practice. PMID- 26004584 TI - Qualitative and quantitative analysis of amorfrutins, novel antidiabetic dietary natural products, by HPLC. AB - CONTEXT: Initially isolated from fruits of Amorpha fruticosa L. (Fabaceae), amorfrutins are promising antidiabetic natural products as selective peroxisome proliferator-activated receptor gamma-agonists. OBJECTIVE: The objective of this study is to develop a sensitive and convenient HPLC method to analysis amorfrutins in plant materials derived from genera Amorpha and Glycyrrhiza. MATERIALS AND METHODS: The reference compounds were isolated from fruits of A. fruticosa and characterized by UV, HR-ESI-MS, and NMR spectrometric techniques. Three amorfrutins were analyzed by HPLC on a Hypersil BDS C18 column (Waters Corporation, Milford, MA) within a gradient elution of acetonitrile and 0.2% glacial acetic acid. HR-ESI-MS spectra were acquired on a quadrupole-time-of flight (Q-TOF) mass spectrometer. RESULTS: Three amorfrutins showed good linearity (r(2 )> 0.999) in the ranges of 4.2-84.5, 4.5-90.2, and 4.6-92.7 MUg/mL. The amorfrutins were only detected in fruits of A. fruticosa with the contents of 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl, amorfrutin A, and amorfrutin B in the ranges of 1.31-7.43, 0.54-3.52, and 0.64-4.63 mg/g, respectively. No amorfrutin was detected in fruits of Amorpha canescens Pursh and roots of Glycyrrhiza uralensis Fisch. (Fabaceae), Glycyrrhiza inflate Bat., or Glycyrrhiza glabra L. DISCUSSION AND CONCLUSION: A novel HPLC method was developed, validated, and applied to identify and quantify amorfrutins in complex botanic matrixes and the characteristic MS fragmentation behaviors of amorfrutins were revealed for the first time. The analytical method presented in this study could be used for the quality control of related plant materials and amorfrutin based nutraceuticals. PMID- 26004585 TI - Cistanche tubulosa ethanol extract mediates rat sex hormone levels by induction of testicular steroidgenic enzymes. AB - CONTEXT: Plants of the genus Cistanche Hoffmg. et Link (Orobanchaceae) are usually used as ethno-medicine in Eastern Asia. Pharmacology studies have shown that Cistanche possesses an androgen-like effect; however, the exact mechanism is unclear. OBJECTIVE: The present study determines the effect of ethanol extract of Cistanche tubulosa (Schenk) R. Wight stem (CTE) on hormone levels and testicular steroidogenic enzymes in rats. MATERIALS AND METHODS: Phenylethanoid glycoside content of CTE was detected by UV spectrophotometry. Rats were fed with different doses of CTE (0.2, 0.4, and 0.8 g/kg) by intragastric administration for 20 d. Sperm parameters were measured by staining and counting method. The level of progesterone and testosterone in serum was quantified by radioimmunoassay. The expression levels of cholesterol side-chain cleavage enzyme (CYP11A1), 17alpha hydroxylase/17, 20-lyase (CYP17A1), and a liver metabolic enzyme (CYP3A4) in the microsome were assessed by immunohistochemical staining or/and western blot analysis. RESULTS: The study illustrates that the administration of CTE (0.4 and 0.8 g/kg) increased sperm count (2.3- and 2.7-folds) and sperm motility (1.3- and 1.4-folds) and decreased the abnormal sperm (0.76- and 0.6-folds). The serum level of progesterone and testosterone in rats was also increased by CTE administration (p < 0.05). Results of immunohistochemistry and western blot analysis confirmed that the expression of CYP11A1, CYP17A1, and CYP3A4 was enhanced by CTE (p < 0.05). It was also found that high-dose of CTE can cause mild hepatic edema. CONCLUSION: Our results suggest that the increase in sex hormone levels could be mediated by the induction of testicular steroidogenic enzymes. PMID- 26004589 TI - Hyperuricemia and tissue monourate deposits: prospective therapeutic considerations. PMID- 26004590 TI - Less invasive surgery in idiopathic scoliosis: a case report. PMID- 26004591 TI - Comparison of the effects of water and traditional delivery on birthing women and newborns. AB - OBJECTIVE: The objective our study was to compare the respective effects of water and traditional delivery on birthing women and newborns. PATIENTS AND METHODS: 120 primiparas with singlet pregnancy, head-down foetus position, and term delivery were randomly divided into two groups. Sixty birthing women were included in traditional delivery group, while other sixty women underwent water delivery. The duration of labour and the volume of blood lost within 24 hours were compared between both groups. Furthermore, perineum condition, degree of delivery pain, and Apgar scores (1st and 5th minute) were also compared. RESULTS: The total duration of labour and the volume of lost blood were comparable between both delivery methods. The perineum integrity and episiotomy rates were significantly (p < 0.05 for both comparisons) better in water delivery group (respectively, 25.00% vs. 8.33% and 1.67% vs. 20% in traditional delivery group). Furthermore, the degree of delivery pain was also more favourable in water delivery group. The Apgar scores were comparable between both delivery methods. CONCLUSIONS: Water delivery can reduce delivery pain without increasing the risk to birthing women and newborns. PMID- 26004592 TI - Efficacy of Tadalafil once daily versus Fesoterodine in the treatment of overactive bladder in older patients. AB - OBJECTIVE: Several studies have suggested that phosphodiesterase type 5 inhibitors (5-PDEi) show a potential therapeutic use in the treatment of overactive bladder (OAB) and male lower urinary tract symptoms (LUTS). The aim of this study was to evaluating the efficacy on OAB symptoms, impact on quality of life and sexual function of tadalafil 5mg once daily in older patients versus fesoterodine 8 mg. PATIENTS AND METHODS: 108 consecutive patients diagnosed with OAB were divided into 2 groups: Group A: 56 patients treated with tadalafil 5 mg once daily; Group B: 52 patients treated with fesoterodine 8 mg, both groups treated for a period of 12 weeks. Eligible patients were men aged >= 65 years with OAB symptoms, including urgency and increased frequency during a period of >= 1 year and urgency urinary incontinence during a period of >= 6 months before enrolment. Patients were asked to complete the 3-day voiding diary prior each scheduled visit at weeks 0, 4 and 12. During these visits, they were administered: Overactive Bladder Symptom Score (OABSS), International Prostate Symptoms Score (IPSS), International Index of Erectile Function (IIEF-5) and Quality of life (QoL). RESULTS: Not statistically significant differences emerged between the two groups at baseline, both patient groups had similar age and BMI; in each treatment group, the proportion of men >= 75 years was approximately 65%. From the results of our study, we can say that a treatment once a day with tadalafil improves not only significantly: micturition/24 hours (p < 0.001), urgency episodes/24 hours (p < 0.003), and urge incontinence episodes (p < 0.001) compared to fesoterodine treatment, but also the quality of life (p < 0.001) and sexual function (p < 0.001) in older patients. CONCLUSIONS: These analyses demonstrate that tadalafil 5 mg once daily vs. fesoterodine 8 mg is efficacious in the treatment of the symptoms of OAB in older adults, improving also the quality of life and sexual and social life. PMID- 26004593 TI - Retinal nerve fiber layer thickness in the acute phase of sildenafil treatment. AB - OBJECTIVE: To evaluate the early effect of sildenafil on the retinal nerve fiber layer (RNFL) thickness. PATIENTS AND METHODS: Sixty eyes of 60 patients were enrolled in the study. The patients underwent RNFL analysis by scanning laser polarimetry (Nerve Fiber Analyzer, GDx VCC:5.3.3; Laser Diagnostic Technologies, San Diego, CA, USA) before and after a single 100 mg dose of sildenafil. Sixty eyes of 60 volunteers of similar age and sex distribution were taken as the control group. The RNFL thickness parameters evaluated included temporal, superior, nasal, inferior, temporal (TSNIT) average, superior average (SA), inferior average (IA), TSNIT standard deviation (SD), and nerve fiber index (NFI). RESULTS: The mean age of the patients was 53,52 +/- 9,26 years. The mean pre- and post-treatment TSNIT, SA, IA, TSNIT SD, and NFI of the patients were 57.46 +/- 4.94 u versus 56.90 +/- 4.59 microns (u), 68.93 +/- 6,12 u versus 67,79 +/- 5,49 u, 66,71 +/- 7.10 u versus 66.31 +/- 6.82 u, 24 +/- 3.86 u versus 23.40 +/- 4.05 u, and 16.50 +/- 6.08 u versus 14.92 +/- 6.76 u, respectively. There were no statistically significant differences between pre- and post-treatment RNFL thicknesses (p = 0.527, p = 0.281, p = 0.754, p = 0.416, p = 0.185, respectively). CONCLUSIONS: A single 100 mg dose of sildenafil seems to have no unfavorable effect on RNFL thickness in the acute phase of treatment. PMID- 26004594 TI - Effect of argon protection on the biological activity of acid etched titanium surface. AB - OBJECTIVE: As the contamination of implant surface seriously affects the early osseointegration of implants and reduces the survival rate of implants, it has attracted wide attention of researchers. The most oral titanium implants used in current clinical applications are stored in sealed packages. During the process of packaging, storage and usage, the implants inevitably contact air, which results in the surface contamination. As an inert gas, the argon has very inactive chemical properties and is routinely used as a protective gas to cut air pollution. In this study, we investigated whether argon protection can cut air pollution and maintain lasting surface biological activity of titanium implants. MATERIALS AND METHODS: We prepared sandblasting etched titanium samples under air protection or under argon protection. The samples prepared under air protection were used as the control. With the scanning electron microscopy, the contact angle measurements and the X-ray photoelectron spectroscopy, we examined surface morphology, hydrophilicity, chemical structures and components of the implants prepared under two gas protections. By using beagles as the animal model, we assessed the bone guide of the implants prepared under argon protection and morphological changes of surrounding tissues. RESULTS: While compared with those implants prepared under air protection, the surface morphology of implants prepared under argon protection did not change, which had preferable hydrophilicity, and there were differences in percentage of surface chemical elements and chemical structure. After 4 weeks, the bone-implant contact (BIC) in argon protection group was twice of the control group and the difference was statistically significant (p < 0.01). The Implant Niuchu experiments also proved that under argon protection, the implants would have good integration with the surrounding bone tissues. CONCLUSIONS: This study revealed the implants prepared under argon can cut air pollution and have high bone guide property and biological activity. PMID- 26004595 TI - Ankle-brachial index, risk of clinical fractures, mortality and low bone mass in nursing home residents. AB - OBJECTIVE: To assess whether the ankle-brachial index is related to functional impairment, clinical fractures and mortality in nursing home residents, and whether this effect is associated or not with low bone mass. PATIENTS AND METHODS: Prospective, observational, non-interventional cohort study in non dependent nursing home residents. The following determinations were made: BUN, creatinine, cholesterol, triglycerides, calcium, phosphorous 25-hydroxyvitamin D, parathyroid hormone and cystatin C in blood and microalbuminuria in urine. Bone mass was determined by measuring the peripheral densitometry of the calcaneus. The Katz Index of independence, the Tinetti Balance and Gait evaluation and functional tests were administered. The ankle-brachial index was measured and patients divided into three groups (ankle-brachial index > 1.40, 1.40-0.90, and < 0.90). Clinical fractures and general and vascular mortality were measured for 20 months. RESULTS: Seventy-two patients were included. There was an inverse relationship between age and the ankle-brachial index (p = 0.022) but no association with bone mass, biochemical tests, clinical fractures and the degree of independence. There was increased mortality in patients with increased or reduced ABI. CONCLUSIONS: An altered ankle-brachial index is a marker of vascular mortality in elderly nursing home residents. PMID- 26004596 TI - Efficacy of low-dose rituximab in combination with recombinant human thrombopoietin in treating ITP. AB - OBJECTIVE: This work aims to observe the efficacy and safety of low-dose rituximab in combination with recombinant human thrombopoietin in treating immune thrombocytopenia (ITP). PATIENTS AND METHODS: Fourteen ITP patients were treated four times with 100 mg qw of rituximab in combination with 300 ug/kg/d ih recombinant human thrombopoietin (rhTPO) for 14 d. Platelet count in peripheral blood, serum immunoglobulin, and lymphocyte subgroups by flow cytometry were detected regularly both pre- and post-treatment. RESULTS: Among the 14 patients, seven complete responses, six responses, and one no response were obtained, with an overall response of 93%. CONCLUSIONS: Low-dose rituximab in combination with rhTPO is effective in treating ITP. PMID- 26004597 TI - Diagnosis of bowel and mesenteric blunt trauma with multidetector CT. AB - OBJECTIVE: To assess the examination methods, the multidetector CT (MDCT), and findings of bowel and mesenteric injuries in blunt trauma and the evaluation for clinical management. PATIENTS AND METHODS: Retrospectively analysis examination methods, image reformation, the sensitivity and specificity of variant appearance in MDCT of 43 cases of bowel and mesenteric injuries which were conformed by operation. RESULTS: Contrast enhancement thin CT with multi-plannar reconstruction MPR can improve the sensitivity of bowel and mesenteric injuries. Appearance of bowel and mesenteric injuries in MDCT included below: patchy or focal bowel wall thickening in 67.4%, intraperitoneal free air in 25.6%, mesenteric infiltration in 90.7%, and intraperitoneal fluid in 81.4%. Bowel wall discontinuity and intraperitoneal free air are specific to bowel injuries, whereas asymmetric bowel wall thickening, irregular enhancement of bowel wall, blurred serous membrane, and fluid of intestinal loop are strongly suggestive to bowel and mesenteric injuries. CONCLUSIONS: Contrast enhancement thin CT with MPR can help improve to show direct and indirect sigh of bowel and mesenteric injuries with higher sensitivity and specificity. PMID- 26004598 TI - Predictive value of bedside tests for difficult intubations. AB - OBJECTIVE: The aim of this study is to find the ideal test(s) for the prediction of difficult laryngoscopic intubation. PATIENTS AND METHODS: One hundred and twenty patients were selected at random for this prospective observational study. The patients' preoperative exams include the assessment of Mallampati classification, thyromental, sternomental, interincisor distances and neck circumference. The laryngoscopy was evaluated with using the Cormack Lehane classification. The sensitivity, specificity, positive and negative predictive values and accuracy of tests, alone and in combination, were assessed. RESULTS: No statistically significant difference was found between the difficult and easy intubation cases. Sternomental distance showed the highest sensitivity (76%) and positive predictor value (54%). As the critical value of neck circumference was set to 35 cm and above, the sensitivity was 74% and positive predictive value, 53%. For the neck circumference and sternomental distance combination, which is determined to be the most reliable and accurate criteria, the sensitivity was 62% and positive predictive value, 42%. CONCLUSIONS: The findings suggest that the sternomental distance and neck circumference combination may be a more accurate predictor of difficult intubation. PMID- 26004599 TI - Polyurethane foam-covered breast implants: a justified choice? AB - OBJECTIVE: Even if the safety of the polyurethane prosthesis has been the subject of many studies and professional and public controversies. Nowadays, polyurethane covered implants are very popular in plastic surgery for the treatment of capsular contracture. MATERIALS AND METHODS: We have identified 41 papers (1 is a communication of the FDA) by using search browsers such as Pubmed, Medline, and eMedicine. Eleven manuscripts have been used for an introduction, and the remaining thirty have been subdivided into three tables whose results have been summarized in three main chapters: (1) capsular formation and contracture, (2) complications, (3) biodegradation and cancer risk. RESULTS: (1) The polyurethanic capsule is a well defined foreign body reaction characterized by synovial metaplasia, a thin layer of disarranged collagen fibers and a high vascularization. These features make possible a "young" capsule and a low occurrence of capsular contracture even over a long period (10 years); (2) the polyurethane implants may be difficult to remove but there is no evidence that they cause an increase in the other complications; (3) there is no evidence of polyurethane related cancer in long-term studies (after 5 years). CONCLUSIONS: Polyurethane foam covered breast implants remain a valid choice for the treatment of capsular contracture even if it would be very useful to verify the ease of removal of the prosthesis and to continue investigations on biodegradation products. PMID- 26004600 TI - Therapeutic challenge during the long-term follow-up of a patient with indolent systemic mastocytosis with extensive cutaneous involvement. AB - From a dermatological aspect, it posed a considerable challenge the skin-limited form of mastocytosis, urticaria pigmentosa and indolent systemic mastocytosis (ISM) with cutaneous lesions. Despite the favourable prognosis, lifelong dermatological control is needed, during which the average symptomatic therapy does not always seem adequate. We report here the case of a female ISM patient with recurrent cutaneous symptoms that impaired her quality of life, with a follow-up time of 27 years. During this long follow-up period, the cutaneous lesions could be controlled by antihistamines, leukotriene antagonists, glucocorticoids, local immunosuppressants or local UV radiation for only relatively short periods. Imatinib mesylate was, therefore, introduced in an attempt to control the cutaneous lesions. Tyrosine kinase inhibition is an unusual dermatological therapeutic option. This case illustrates that imatinib mesylate was a good choice with which to achieve a reduction of the skin lesions in this KIT D816V mutation-negative disease: it led to a temporary appreciable improvement of the patient's quality of life. PMID- 26004601 TI - The economic burden of HCV-induced diseases in Italy. A probabilistic cost of illness model. AB - OBJECTIVE: The hepatitis C virus (HCV) induces several pathological conditions worldwide, with a substantial medical and economic burden. The objective of this study was to estimate the average annual cost incurred by the National Health Service (NHS), as well as society, due to HCV in Italy. METHODS: A probabilistic incidence-based cost of illness model was developed to estimate an aggregate measure of the economic burden associated with HCV-induced diseases either in terms of direct or indirect costs. Indirect costs were calculated on the basis of lost productivity according to the human capital approach. A systematic literature review was carried out to identify epidemiological and economic data which were used to inform the model. Furthermore, a one-way probabilistic sensitivity analysis with 5,000 Monte Carlo simulations was performed, in order to test the robustness of the results and define the proper 95% Confidence Interval (CE). RESULTS: Overall, the total economic burden associated with HCV induced diseases was estimated in ?1.06 billion (95%CI: ?0.61-?1.63). A percentage of 60.6% was associated with indirect costs (95% CI: ?0.37-?0.99 billion) and 39.4% with direct costs (95% CI: ?0.23-?0.65 billion). In chronic hepatitis C, cirrhosis, hepatocellular carcinoma (HCC), liver transplantation and HCV-induced deaths, an average annual economic burden amounting to ?0.26 (95%CI: ?0.14-?0.41), ?0.56 (95%CI: ?0.30-?0.89), ?0.051 (95%CI: ?0.0007-?0.25), ?0.05 (95%CI: ?0.03-?0.08) and ?0.15 (95%CI: ?0.07-?0.27) billion respectively, was estimated. CONCLUSIONS: Italy is one of the European countries with the highest number of people affected by chronic HCV infection, the leading cause of cirrhosis, HCC and liver-related death. HCV-induced diseases generate high costs to Italian NHS. These highly debilitating and life-threatening complications generate a rather large amount of indirect costs for the Italian society as well. PMID- 26004602 TI - Complications and risk factors of a large series of percutaneous liver biopsies in patients with liver transplantation or liver disease. AB - OBJECTIVE: Liver biopsy is a very important investigation in Hepatology. The aim of this retrospective study was to assess the prevalence of complications after Percutaneous Liver Biopsy (PLB), performed in two groups of patients with liver transplantation or with liver disease. We compared our results with those most representative of the literature and discussed about indications, advantages and disadvantages in relation to the different modes for the execution of this procedure, with particular regard to the use of ultrasound guidance. PATIENTS AND METHODS: We analyzed the results of 847 PLB performed with the Menghini technique between January 2004 and December 2013 at the Transplant Unit of the University of Rome Tor Vergata. The indications for biopsy were: follow-up liver transplantation, HBV, HCV and HBV/HCV related liver disease, alcohol related liver disease and HIV coinfected with HBV or HCV. Our patients were classified into two groups according to specific indication: patients with liver transplantation (group A) and patients with liver disease (group B). The procedure was always performed in the Day Hospital regimen. After the biopsy, the patients remained in bed for about 4-6 hours. In absence of complications, they were then discharged in the same day. RESULTS: The most frequent complication was pain after biopsy (group A n. 45, 7.9%; group B n. 85, 30.9%), requiring analgesics administration, hypotension as a result of a vasovagal reaction resolved spontaneously (group A n. 6, 1.0%; group B n. 6, 2.2%), and bleeding (group A n. 1, 0.2%; group B n. 6, 2.2%), which, however, has never necessitated surgery, except in one case of hemothorax. Two cases of pneumothorax were resolved with chest tube. Other complications did not have a significant impact. CONCLUSIONS: Liver biopsy is not replaceable investigation to diagnose several liver diseases and their course and also to monitor the condition of the hepatic parenchyma after transplantation. Among the various methods we preferred the Menghini technique with percutaneous transcostal approach, because less traumatic. This procedure presents low occurrence of various problems. We reviewed the literature regarding the major complications related to the technique and the use of ultrasound guidance. Based on our case series and data reported by the main Authors, we believe that ultrasound guidance is not decisive in the prevention of major complications. It is useful if done in the days or weeks prior to biopsy only in order to know any anatomical abnormalities or rather diseases that may pose a specific indication for the procedure with ultrasound guidance. PMID- 26004603 TI - Role of micro-RNA (miRNA) in pathogenesis of glioblastoma. AB - Glioblastoma (GBM) is a very lethal form of human brain cancer, which is characterized by rapid diffuse, infiltrative growth and high level of cellular heterogeneity. Such cancer patients usually survive for one year under treatment. Recently, the role of small non-coding RNA known as microRNAs (miRNA), have been suggested to be involved in the pathogenesis of glioblastoma, as miRNAs play a critical role in the tumor-forming processes. The change in expression levels of several miRNAs has been found in GBM patients within last 10 years. It is evident now that impairment of miRNA regulation is one of the key mechanisms in GBM pathogenesis. The miRNA deregulation is involved in many processes, such as cell proliferation, cell cycle regulation, apoptosis, invasion, glioma stem cell behavior, and angiogenesis. GBM is also known as Grade IV astrocytoma, a rare disease with an incidence of 2-3 cases per 100,000 people in Europe and North America, and 50% with GBM die within 1 year, while 90% within 3 years. The treatments of GBM involve chemotherapy, radiation and surgery. The median survival with standard radiation and chemotherapy with Temozolomide is 1 year and 3 months, and median survival without treatment is four and a half months. In this article, symptoms of GBM, treatments, the role of miRNAs, gene expressions, types of miRNAs, neoplasms and glioblastomas, the miRNA biogenesis pathways, deregulation of miRNAs, and care of GBM have been described. PMID- 26004604 TI - Improvement of survival in patients with melanoma and non-melanoma skin cancers compared to patients without double cutaneous malignancies. AB - OBJECTIVE: The worldwide incidence of cutaneous malignant melanoma (MM) has been rising steadily over the past 30 years. At the same time non-melanoma skin cancers (NMSC) are the most prevalent type of cancer in United States and Europe. Up to date, no paper has explored the influence on the general survival in patients with MM and NMSC. We decided to perform a study with the aim to evaluate the different survival in patients with MM-NMSC compared to control patients (MM CTRL). PATIENTS AND METHODS: To evaluate prognosis in both groups, we analyzed disease-free survival (DFS) and overall survival (OS).Kaplan-Meier product was performed for the survival analysis. Median DFS was 73 months in group and 72 months in MM-CTRL patients (p = 0.4); while, median OS was 74.2 months in MM-NMSC patients and 63.1 in MM-CTRL (p < 0.001). Also at Odds-Ratio (OR), the statistical significance was maintained (p < 0.007) with a better prognostic value for MM-NMSC. RESULTS: Among group patients, the ones with a basal cell carcinoma showed a batter behavior, than the ones with squamous cell carcinoma (p = 0.01). CONCLUSIONS: Patients with MM-NMSC showed a better survival than MM-CTRL patients (p < 0.001). The causes of this improved survival are still unknown; probably the endogenous immune response can play a pivotal role in this class of patients. However, further studies are necessary to better understand this phenomenon, not yet explored in literature. PMID- 26004605 TI - Preoperative staging of colorectal cancer using virtual colonoscopy: correlation with surgical results. AB - OBJECTIVE: The aim of this study was to evaluate the clinical usefulness of computed tomography colonography (CTC) in the preoperative staging in patients with abdominal pain for occlusive colorectal cancer (CRC) and to compare the results of CTC with the surgical ones. PATIENTS AND METHODS: 127 patients with abdominal pain, iron deficiency anemia and occlusive CRC underwent a CTC examination in prone position without intravenous contrast agent and in prone position after administration of intravenous contrast medium. All the patients underwent surgery after CTC. Two radiologists with different experience analyzed the images first independently and then by consensus. They evaluated the location of the lesion, the depth of the invasion of the colon-rectal wall (T stage), lymph node involvement (N stage) and the presence or absence of distant metastasis (M stage). CTC findings were correlated with surgical outcomes. RESULTS: The overall accuracy values for tumour localization according to consensus reading of CTC examinations in comparison to surgical results were 100% (K = 1, p = 0.0001). The overall accuracy values of agreement for T staging of reader 1, reader 2 and consensus reading of CTC examinations in comparison to surgical results were respectively 95.5% (K = 0.876, p = 0.0035), 93.3% (K = 0.858, p = 0.0037) and 97.7% (K = 0.926, p = 0.0014) for <= T2; 91.3% (K = 0.839, p = 0.0027), 88.3% (K = 0.817, p = 0.0031), and 92.9% (K = 0.894, p = 0.0025) for T3; 89.6% (K = 0.825, p = 0.0037), 86.2% (K = 0.837, p = 0.0032) and 89.6% (K = 0.821, p = 0.0023) for T4. The overall accuracy values for N staging for reader 1, reader 2 and consensus reading was 90.2% (K = 0.865, p = 0.0029). The overall accuracy values for M staging of reader 1, reader 2 and consensus reading was 92% (K = 0.875, p = 0.0019). CONCLUSIONS: CTC with is a very useful tool for accurate pre-treatment staging and localization of occlusive CRC. PMID- 26004606 TI - Pathway analysis of differentially expressed genes in human esophageal squamous cell carcinoma. AB - OBJECTIVE: Esophageal Squamous Cell Carcinoma (ESCC) is one of the most common human cancers with a particularly high incidence in certain regions of China. Differentially expressed genes (DEG) between the esophageal squamous carcinoma tissues and matched normal esophageal mucosal epithelial tissues can be detected by employing the gene microarray technology. This can aid the analysis of the underlying disease mechanism and can help to identify potentially critical genes as well as related molecular signalling pathways. MATERIALS AND METHODS: The potentially critical genes and related signal pathways are examined by bioinformatics analysis including Gene Ontology (GO) analysis, pathway analysis and signal transduction networks. Here, we performed microarray analysis with 8 pairs of ESCC and normal esophageal mucosal epithelial tissues. RESULTS: Compared to the control group, 347 and 203 genes were found to be up-regulated and down regulated in the experimental group, respectively. Based on pathway analysis, 52 and 51 signal transduction pathways were involved in the up-regulated and the down-regulated genes, respectively. SLC27A6, RAB11A, ABCA8, JAM2, HNMT, GSTM1, and CDKN3, which play critical roles in regulating the expression of ESCC, were identified among the key genes involved in the signal transduction networks. CONCLUSIONS: Investigation of the mechanism underlying ESCC can provide a direction for the clinical prevention and treatment of ESCC. PMID- 26004607 TI - Connexin evolution ameliorates the risk of various cancers. AB - OBJECTIVE: Connexins can affect many cancers, but the relationship of many connexins is confused and the functions in cancers are unknown. MATERIALS AND METHODS: With conservative domains of connexins, the phylogenetic tree was constructed and all connexins could be divided into five groups (I, II, III, IV and V). The clock analysis showed that group V appeared earlier than group IV, which was earlier than group III, which was earlier than group I and II in the evolution. Group I involves in colorectal, lung, breast, pancreatic, gastric, colon, bladder and ovarian cancers. Group II affects bladder, breast, lung, gastric, colorectal, prostate, esophageal, renal, head and neck cancers. Group III affects bladder and breast cancer. The function of group IV and V has not been reported. RESULTS: When HT1376 bladder cancer cells were transfected with Cx31.9 (Group IV), the growth rate was inhibited by 17%. Inversely, when HT1376 cells were transfected with Cx31.9 RNAi, the growth rate was increased by 21%. For Cx23 (Group V), it could not affect the growth rate. CONCLUSIONS: The results suggested that ancient connexins did not involve in cancers. Recent connexins have developed the functions for inhibiting the progression of cancers in the evolution. PMID- 26004608 TI - The association of ICAM E469K with cardiovascular characteristics of acromegaly. AB - OBJECTIVE: It has been shown that genetic factors have a role in the development of acromegaly. We aimed to investigate the association between intercellular adhesion molecule (ICAM)-1 E469K polymorphism and some cardiovascular clinical parameters of acromegalic patients. PATIENTS AND METHODS: We included 41 patients with acromegaly and 65 healthy subjects with similar age and sex to the study. Fasting plasma glucose (FPG), high-density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglyceride (TG) were analyzed. Genotyping was made by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of genotype and allel ICAM-1 E469K was not significantly different between control and patients (p > 0.05). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and FPG levels were significantly higher, and HDL-C was significantly lower in patients with KK genotypes compared to patients with EE genotype in acromegaly group (p < 0.05). CONCLUSIONS: This is the first study to investigate the role of ICAM gene polymorphism in acromegaly and its cardiovascular characteristics. ICAM E469K may not be a risk factor for the acromegaly in Turkish population but may be associated with hypertension, higher FPG and lower HDL-C in acromegalic patients. PMID- 26004609 TI - Association of Rho/Rho-kinase gene polymorphisms and expressions with obesity related metabolic syndrome. AB - OBJECTIVE: The metabolic syndrome (MetS) is a common multicomponent condition including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The aim of this study was to investigate the associations of Rho GTPase and Rho kinase (ROCK) gene polymorphisms and expressions with MetS in a Turkish population. PATIENTS AND METHODS: A total of 141 obese MetS patients and 163 healthy controls with similar age and sex were included to this study. Polymorphisms were analyzed in genomic DNA using a BioMark 96.96 dynamic array system. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for gene expressions. RESULTS: We observed that genotype (CC, 18.1%; CA, 13.4%, and AA, 68.5%) and allele (C, 24.8%; A, 75.2%) frequencies for the rs35996865 polymorphism of the ROCK1 gene in patients were markedly different from controls (CC, 84.2%; CA, 2.9%, and AA, 12.9%; C, 85.6%; A, 14.4%, p < 0.0001). In the rs2230774 (Thr431Asn) polymorphism of the ROCK2 gene, there were increases in the CC genotype (16.5%) and C allele frequencies (20.4%) in MetS patients when compared with the control group (CC, 6.0%, p = 0.0009, and C, 6.7%, p < 0.0001). However, no associations with the other 18 polymorphisms studied were found. Although there were an increase in peripheral blood mRNA RhoH expressions, marked decreases in RhoC, RhoBTB1, RhoV, Rnd1, and CDC42 gene expressions were noted in MetS patients. CONCLUSIONS: This is the first study to provide evidence that ROCK gene polymorphisms and gene expressions of the Rho GTPase proteins may modify individual susceptibility to MetS in the Turkish population. PMID- 26004610 TI - Cardiac autonomic dysfunction in young obese males is not associated with disturbances in pituitary-thyroid axis hormones. AB - OBJECTIVE: Obesity has been associated with hypothyroidism and cardiac autonomic dysfunction. The present study aimed to investigate whether cardiac autonomic dysfunction in young obese males might be related to an underlying thyroid disturbance. PATIENTS AND METHODS: On the basis of body mass index (BMI), 40 participants were grouped into normal weight group (NW; BMI = 18.5-25 kg/m(2); n = 15), over weight group (OW; BMI = 25-29.9 kg/m(2); n = 12) and obese group (OB; BMI >= 30 kg/m(2); n = 13). Electrocardiogram was recorded using PowerLab system and the time and frequency domain measures of heart rate variability (HRV) were calculated. Fasting blood samples were drawn for measurement of serum thyroid stimulating hormone (TSH), total thyroxin (TT4) and total triiodothyronine (TT3) concentrations. RESULTS: The levels of TSH, TT4 and TT3 were not significantly different between the groups. The frequency domain HRV parameter reflecting parasympathetic tone (high-frequency normalized units, HFnu) was significantly reduced in OB group. The parameters which reflect sympathetic activation (Heart rate, low-frequency normalized units; LFnu and the LF/HF ratio) were significantly increased in the OB group. HFnu was significantly and negatively correlated with BMI, waist hip ratio and body fat percentage, whereas LFnu and LF/HF ratio were significantly and positively correlated with the above mentioned parameters. No significant relationships were noted between the HRV parameters and the levels of TSH or thyroid hormones. CONCLUSIONS: Cardiac autonomic dysfunction in obese young adult males is not linked with underlying thyroid disturbance. PMID- 26004611 TI - Ultrasound-guided botulinum toxin injections and EMG biofeedback therapy the lower limb muscle spasm after cerebral infarction. AB - OBJECTIVE: To evaluate the clinical efficacy under ultrasound-guided injection of botulinum toxin-A (BTX-A) and EMG biofeedback treatment of the lower limb muscle spasm after cerebral infarction. PATIENTS AND METHODS: Thirty-six cases of lower limb muscle spasm after cerebral infarction hemiplegia were randomly divided into two groups, the treatment group and the control group respectively including 18 cases. Both groups of patients were injected with BTX-A at different sites on spastic muscles. Twenty-four hours later, the treatment group was administered EMG biofeedback. Then, the modified Ashworth scoring was employed to observe the curative effect of the two groups. RESULTS: After six weeks' injection, the treatment group scored better than the control group (p < 0.05). CONCLUSIONS: Ultrasound-guided injection of botulinum toxin type A at various sites with EMG biofeedback treatment of the lower limb muscle spasms after cerebral infarction is efficient and conducive to the rehabilitation of patients' motor functions. PMID- 26004612 TI - Neither insufficiency nor overexpression of sac1 affects the accumulation of Abeta42 in Drosophila expressing Ab42. AB - OBJECTIVE: We investigated the effects of genetic down- and up-regulation of sac1 expression on Abeta42 accumulation and the associated neural deficits in flies with direct expression of arctic mutant Abeta42 (Abetaarc) in the neurons of GF pathway. MATERIALS AND METHODS: We genetically down-regulated and up-regulated the level of sac1, encoding a major phosphoinositide phosphatases in a disease model, in which arctic mutant Abeta42 is directly expressed in the neurons of a neural pathway of adult fruit flies. RESULTS: We conducted a time-course analysis of Abeta42 level in the model and found an age-dependent elevation of Abeta42 accumulation, closely correlated to the age-dependent decline of climbing ability in the model flies. Neither sac1 insufficiency nor sac1 over-expression significantly changed the three phenotypes. CONCLUSIONS: We found that the alterations of sac1 expression did not change Abeta42 accumulation and neural deficits in the model. PMID- 26004613 TI - Pleural effusion adenosine deaminase is not accurate in diagnosis of pediatric tuberculous pleural effusion: a retrospective study. AB - OBJECTIVE: Pleural effusion (PE) adenosine deaminase (ADA) has good performance in detection of tuberculous pleural effusion (TPE). However, few study was conducted for its value in pediatric patients. To evaluate PE ADA in diagnosis of pediatric TPE, a retrospective study was performed. PATIENTS AND METHODS: 204 pediatric PE patients were enrolled, and then were grouped into TPE group (77 cases, aged 11.51 +/- 0.40 years) and non-TPE group (127 cases, aged 6.39 +/- 0.35 years). Man-Whitney U test was used to compare difference in pleural ADA between the two groups. The correlation between age and ADA activity was analyzed by Spearman's correlation coefficient analysis. RESULTS: In our study, there was no difference in pleural ADA between TPE (62.1 +/- 4.2 U/L) and non-TPE patients (87.7 +/- 10.0 U/L). Compared with empyema patients (183.8 +/- 30.0 U/L), pleural ADA was lower in parapneumonic effusion (PPE) patients (63.4 +/- 3.8, p < 0.01), or TPE patients (p <0.01). Correlation analysis showed that there were no correlation between age and pleural ADA within TPE, PPE or both patients (all p > 0.05). Meanwhile, there was no significant difference in PE ADA level between genders. CONCLUSIONS: Considering the fact that the majority of pediatric PEs is TPE and PPE, our study suggests that PE ADA isn't accurate in detection of pediatric TPE. Meanwhile, an extremely high ADA activity should raise suspicion of empyema or lymphoma. PMID- 26004614 TI - Local sympathetic stimulation not only have local effects in patients with Raynaud's phenomenon. AB - OBJECTIVE: Many other organs and system can be affected in the course of Primary Raynaud's Phenomenon (RP). Simultaneously increased vasospasm in the pulmonary vascular bed may likely affect the pulmonary function. Therefore, we investigated the effect of Raynaud's phenomenon on the respiratory functions in this study. PATIENTS AND METHODS: Between March 2014 and December 2014, 30 patients with the diagnosis of PRP more than two years and 32 age-sex matched healthy controls were enrolled into this study. Cold stimulation test (CST) was performed. Pulmonary function test were performed following 30 minutes after CST and spirometric measurements were calculated. RESULTS: There were no statistically significant differences between two groups regarding their demographic and clinical data. Mean duration of symptoms from onset to present was 3.01 +/- 1.05 years. Patients with Primary RP had significantly lower FVC and higher FEV1/FVC values compared to the control groups (p = 0.015 and p=0.045, respectively). CONCLUSIONS: We found that statistically significant decrease of FVC values in patients with Primary RP compared to the healthy controls could be a impaired innervation of pulmonary system and a predictor of pulmonary vasospasm and/or pulmonary Raynaud's phenomenon, which may develop in future periods. PMID- 26004615 TI - Plasma levels of TNF-alpha and MMP-9 in patients with silicosis. AB - OBJECTIVE: Silicosis is usually recognized at later stages of the disease, and early biomarkers for silicosis will be useful for timely diagnosis. We aimed at examining plasma levels of TNF-alpha and MMP-9, and correlation between these, in patients with different stages of silicosis in order to test suitability of these inflammatory factors as early biomarkers for silicosis. PATIENTS AND METHODS: TNF alpha and MMP-9 were quantified by ELISA in plasma specimens from 30 healthy individuals (control group), 28 individuals exposed to silica dust but without clinical disease, and 30 patients with silicosis. RESULTS: Plasma levels of TNF alpha and MMP-9 were increased in individuals exposed to silica dust (p < 0.05 vs. control individuals) and were further elevated in patients with silicosis (p < 0.05 vs. control individuals and individuals exposed to silica dust). There was a significant correlation between plasma levels of TNF-alpha and MMP-9 both in individuals exposed to silica dust (r = 0.696, p < 0.01) and patients with silicosis (r = 0.768, p < 0.01). CONCLUSIONS: Plasma levels of TNF-alpha and MMP 9 are increased prior to development of clinically recognized silicosis, suggesting that these biomarkers are involved in the onset and development of silicosis. Combined detection of TNF-alpha and MMP-9 may be useful for early diagnosis of silicosis. PMID- 26004617 TI - Susac syndrome--clinical insight and strategies of therapy. AB - Susac syndrome is an uncommon autoimmune microangiopathy characterized mainly by neurological disorders and, to date, 304 clinical cases have been described. The background of this syndrome is an immune-mediated endotheliopathy that affects the microvasculature of the brain, retina, and inner ear resulting in encephalopathy, hearing loss, and branch retinal artery occlusions. However, the cause and the pathogenesis of this microangiopathy remain unclear. Magnetic resonance imaging, retinal fluorescein angiography, and audiography findings enable the diagnosis of this syndrome. In this review, we have demonstrated the epidemiology and pathology of Susac syndrome with detailed description of clinical signs, diagnostic procedures and therapeutic possibilities. PMID- 26004616 TI - The serum copeptin levels in obstructive sleep apnea patients with prehypertensive. AB - OBJECTIVE: Copeptin is a precursor of AVP, an antidiuretic hormone, plays a pivotal role in the maintenance of cardiovascular homeostasis. Obstructive sleep apnea syndrome (OSAS) is related to cardiovascular disease. We sought to evaluate the serum copeptin levels in newly diagnosed prehypertensive patients with OSAS. PATIENTS AND METHODS: Eighty-four prehypertensive patients were evaluated using polysomnography and were divided into two groups, an OSAS (n = 41) group and a control (n = 43) group. Serum copeptin levels were measured using the ELISA method. RESULTS: Copeptin levels were significantly higher in the OSAS group compared to the control group (146 [93-739] pg/ml vs. 111 [33-253] pg/ml, respectively, p < 0.001). A regression analysis revealed that the apnea hypopnea index (AHI) and the lowest SpO2 were related to serum copeptin levels (unstandardized beta = 1.02 +/- 0.40, p = 0.014 and unstandardized beta = -3.1 +/ 0.9, p = 0.048 respectively). CONCLUSIONS: According to the results of our study, serum copeptin levels are higher in the prehypertensive patients with OSAS compared to those in the control group. Therefore, in assessing the severity of OSAS, serum copeptin levels can be a candidate for a biochemical marker in addition to polysomnographic findings. PMID- 26004618 TI - Protective effects of curcumin and quercetin during benzo(a)pyrene induced lung carcinogenesis in mice. AB - OBJECTIVE: Phytochemicals is one such family of chemopreventive agents that is being researched extensively the world over for its efficacies against several cancer pathways. Curcumin and quercetin belong to the family of phytochemicals and have anti-oxidative and anti-carcinogenic properties. In the present study, chemopreventive efficacy of curcumin and quercetin was investigated against benzo(a)pyrene (BP) induced lung carcinogenesis. MATERIALS AND METHODS: The mice were segregated into five groups which included normal control, BP treated, BP+curcumin treated, BP+quercetin treated and BP+curcumin+quercetin treated groups. Lung carcinogenesis was induced by a single intra-peritoneal (IP) injection of BP (100 mg/kg body weight). Curcumin was supplemented to mice at a dose level of 60 mg/kg body weight in drinking water and quercetin was given at a dose level of 40 mg/kg body wt in drinking water. RESULTS: The BP treatment resulted in a significant increase in LPO and ROS levels. GSH levels and the activities of SOD, GST as well as GR were found to be significantly decreased following BP treatment. Further, BP treatment brought about a significant increase in the activities of drug metabolizing enzymes (cytochrome P450 and b5). Curcumin and quercetin treatments to mice were able to decrease significantly the levels of LPO, ROS, as well as activities of SOD, GST. Also, the activities of drug metabolizing were markedly decreased by the administration of phytochemicals. CONCLUSIONS: The results of this study suggest that combined treatment with curcumin and quercetin proved beneficial on antioxidant status and drug metabolizing enzymes during experimentally induced lung carcinogenesis in mice. PMID- 26004619 TI - Role of GDF15 (growth and differentiation factor 15) in pulmonary oxygen toxicity. AB - GDF15 (growth and differentiation factor 15) is a secreted cytokine, a direct target of p53 and plays a role in cell proliferation and apoptosis. It is induced by oxidative stress and has anti-apoptotic effects. The role of GDF15 in hyperoxic lung injury is unknown. We tested the hypothesis that GDF15 will be induced in vitro, in a model of pulmonary oxygen toxicity, and will play a critical role in decreasing cell death and oxidative stress. BEAS-2B (human bronchial epithelial cells) and human pulmonary vascular endothelial cells (HPMEC) were exposed to hyperoxia, and expression of GDF15 and effect of GDF15 disruption on cell viability and oxidative stress was determined. Furthermore, we studied the effect of p53 knockdown on GDF15 expression. In vitro, both BEAS-2B and HPMEC cells showed a significant increase in GDF15 expression upon exposure to hyperoxia. After GDF15 knockdown, there was a significant decrease in cell viability and increase in oxidative stress compared to control cells transfected with siRNA with a scrambled sequence. Knockdown of p53 significantly decreased the induction of GDF15 by hyperoxia. In conclusion, we show that GDF15 has a pro survival and anti-oxidant role in hyperoxia and that p53 plays a key role in its induction. PMID- 26004621 TI - Phylogeography of Francisella tularensis subspecies holarctica in Finland, 1993 2011. AB - BACKGROUND: Finland repeatedly reports some of the highest incidences of tularaemia worldwide. To determine genetic diversity of the aetiologic agent of tularaemia, Francisella tularensis, a total of 76 samples from humans (n = 15) and animals (n = 61) were analysed. METHODS: We used CanSNPs and canINDEL hydrolysis or TaqMan MGB probes for the analyses, either directly from the clinical tissue samples (n = 21) or from bacterial isolates (n = 55). RESULTS: The genotypes of the strains were assigned to three previously described basal subspecies holarctica clades. The majority of strains (n = 67) were assigned to B.12, a clade reported to dominate in Scandinavia and Eastern Europe. A single strain was assigned to clade B.4, previously reported from North America, Europe and China. The remaining strains (n = 8) were members of clade B.6. Importantly, new diversity was discovered in clade B.6. We describe two newly designed TaqMan MGB probe assays for this new B.6 subclade B.70, and its previously identified sister clade B.11, a clade dominantly found in Western Europe. CONCLUSIONS: The high genetic diversity of F. tularensis subspecies holarctica present in Finland is consistent with previous findings in Sweden. The results suggest a northern and southern division of the B.6 subclade B.10, where B.11 predominates in Western and Central Europe and B.70 is found in Fennoscandia. Further research is required to define whether the vast diversity of genotypes found is related to different habitats or reservoir species, their different postglacial immigration routes to Fennoscandia, or dynamics of the reservoir species. PMID- 26004620 TI - Down-regulation of peroxisome proliferator activated receptor gamma coactivator 1alpha induces oxidative stress and toxicity of 1-(4-Chlorophenyl)-benzo-2,5 quinone in HaCaT human keratinocytes. AB - Peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator that is known to regulate oxidative stress response by enhancing the expression of antioxidant genes. We have shown previously that 1-(4-Chlorophenyl)-benzo-2,5-quinone (4-ClBQ), a quinone metabolite of 4-monochlorobiphenyl (PCB3) induces oxidative stress and toxicity in human skin keratinocytes, and breast and prostate epithelial cells. In this study, we investigate whether PGC-1alpha regulates oxidative stress and toxicity in 4-ClBQ treated HaCaT human keratinocytes. Results showed significant down regulation in the expression of PGC-1alpha and catalase in 4-ClBQ treated HaCaT cells. Down-regulation of PGC-1alpha expression was associated with 4-ClBQ induced increase in the steady-state levels of cellular reactive oxygen species (ROS) and toxicity. Overexpression of pgc-1alpha enhanced the expression of catalase and suppressed 4-ClBQ induced increase in cellular ROS levels and toxicity. These results suggest that pgc-1alpha mediates 4-ClBQ induced oxidative stress and toxicity in HaCaT cells presumably by regulating catalase expression. PMID- 26004622 TI - Ageing well: a review of sarcopenia and frailty. AB - 'Ageing well' has been declared a global health priority by the World Health Organisation and the role of sarcopenia and frailty in late-life health is receiving increasing attention. Frailty is the decline in an individual's homeostatic function, strength and physiologic reserves leading to increased vulnerability, while sarcopenia describes the loss of muscle mass and function with age. The conceptual definitions of these conditions have been widely agreed but there is a lack of consensus on how to measure them. We review the different operational definitions described in the literature and the evidence that, whatever definition used, the prevalence and clinical impact of these conditions is high. We also consider the commonality of low physical function to both conditions, a feature which could provide a pragmatic way forward in terms of identifying those at risk. Objective measures of physical function such as usual walking speed are simple and feasible measures, extensively validated against health outcomes. Additionally, clinical applications of sarcopenia and frailty are reviewed with particular consideration to their potential role in the management of older people undergoing surgery. Frailty appears to outperform traditional anaesthetic and surgical risk scores in terms of its association with post-operative complications, length of hospital stay, institutionalisation and mortality. However, even within this sub-specialty area there is wide variation in the approaches used to measure frailty and there is an urgent need for studies to utilise established, validated and reproducible methods to identify sarcopenia and frailty in their study participants, in order to expedite scientific development. PMID- 26004623 TI - Thyroid hormone in the frontier of cell protection, survival and functional recovery. AB - Thyroid hormone (TH) exerts important actions on cellular energy metabolism, accelerating O2 consumption with consequent reactive oxygen species (ROS) generation and redox signalling affording cell protection, a response that is contributed by redox-independent mechanisms. These processes underlie genomic and non-genomic pathways, which are integrated and exhibit hierarchical organisation. ROS production led to the activation of the redox-sensitive transcription factors nuclear factor-kappaB, signal transducer and activator of transcription 3, activating protein 1 and nuclear factor erythroid 2-related factor 2, promoting cell protection and survival by TH. These features involve enhancement in the homeostatic potential including antioxidant, antiapoptotic, antiinflammatory and cell proliferation responses, besides higher detoxification capabilities and energy supply through AMP-activated protein kinase upregulation. The above aspects constitute the molecular basis for TH-induced preconditioning of the liver that exerts protection against ischemia-reperfusion injury, a strategy also observed in extrahepatic organs of experimental animals and with other types of injury, which awaits application in the clinical setting. Noteworthy, re adjusting TH to normal levels results in several beneficial effects; for example, it lengthens the cold storage time of organs for transplantation from brain-dead donors; allows a superior neurological outcome in infants of <28 weeks of gestation; reduces the cognitive side-effects of lithium and improves electroconvulsive therapy in patients with bipolar disorders. PMID- 26004624 TI - Lubricant use at last sexual encounter with a male partner: findings from a nationally representative sample of self-identified gay and bisexual men in the United States. AB - Background There is a lack of research that examines event-level lubricant use and outcomes among gay and bisexual men, with the majority of current research addressing lubricant use within the context of sexual risk. Most studies examining sexual health among gay and bisexual men have relied on convenience sampling strategies for participant recruitment. METHODS: Data were collected from the 2012 wave of the National Survey of Sexual Health and Behaviour (NSSHB), which involved the administration of an online questionnaire to a nationally representative probability sample of women and men in the United States aged 18 years and older, including an oversampling of self-identified gay and bisexual men and women. The findings from gay (n=307) and bisexual (n=25) participants who reported sexual behaviours with other male partners during their last sexual encounter are included in this paper. Post-stratification data weights were applied to the data to maximise the generalisability of the findings. RESULTS: Men who reported lubricant use during their last sexual event with a male partner (n=163) were significantly more likely to be non-White, Hispanic and between 30 and 39 years old. Bisexual men had lower odds of using lubricant than gay identified men. The majority of men reported using lubricant during anal intercourse, along with lower numbers with a range of other sexual behaviours. CONCLUSION: Public health promotion specialists should consider recommending continued lubricant use as a part of comprehensive sexual health promotion efforts for gay and bisexual men, including that it reduces pain and maximises pleasure. PMID- 26004626 TI - Disruption of type 2 iodothyronine deiodinase activity in cultured human glial cells by polybrominated diphenyl ethers. AB - Polybrominated diphenyl ether (PBDE) flame retardants are endocrine disruptors and suspected neurodevelopmental toxicants. While the direct mechanisms of neurodevelopmental toxicity have not been fully elucidated, it is conceivable that alterations in thyroid hormone levels in the developing brain may contribute to these effects. Cells within the brain locally convert thyroxine (T4) to the biologically active triiodothyronine (T3) through the action of the selenodeiodinase type 2 iodothyronine deiodinase (DIO2). Previous studies have demonstrated that PBDEs can alter hepatic deiodinase activity both in vitro and in vivo; however, the effects of PBDEs on the deiodinase isoforms expressed in the brain are not well understood. Here, we studied the effects of several individual PBDEs and hydroxylated metabolites (OH-BDEs) on DIO2 activity in astrocytes, a specialized glial cell responsible for production of more than 50% of the T3 required by the brain. Primary human astrocytes and H4 glioma cells were exposed to individual PBDEs or OH-BDEs at concentrations up to 5 MUM. BDE-99 decreased DIO2 activity by 50% in primary astrocyte cells and by up to 80% in the H4 cells at doses of >=500 nM. 3-OH-BDE-47, 6-OH-BDE-47, and 5'-OH-BDE-99 also decreased DIO2 activity in cultured H4 glioma cells by 45-80% at doses of approximately 1-5 MUM. Multiple mechanisms appear to contribute to the decreased DIO2 activity, including weakened expression of DIO2 mRNA, competitive inhibition of DIO2, and enhanced post-translational degradation of DIO2. We conclude that decreases in DIO2 activity caused by exposure to PBDEs may play a role in the neurodevelopmental deficits caused by these toxicants. PMID- 26004625 TI - Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy. AB - INTRODUCTION: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy. AREA COVERED: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated. EXPERT OPINION: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed. PMID- 26004627 TI - Involvement of mitochondrial proteins in calcium signaling and cell death induced by staurosporine in Neurospora crassa. AB - Staurosporine-induced cell death in Neurospora crassa includes a well defined sequence of alterations in cytosolic calcium levels, comprising extracellular Ca(2+) influx and mobilization of Ca(2+) from internal stores. Here, we show that cells undergoing respiratory stress due to the lack of certain components of the mitochondrial complex I (like the 51kDa and 14kDa subunits) or the Ca(2+)-binding alternative NADPH dehydrogenase NDE-1 are hypersensitive to staurosporine and incapable of setting up a proper intracellular Ca(2+) response. Cells expressing mutant forms of NUO51 that mimic human metabolic diseases also presented Ca(2+) signaling deficiencies. Accumulation of reactive oxygen species is increased in cells lacking NDE-1 and seems to be required for Ca(2+) oscillations in response to staurosporine. Measurement of the mitochondrial levels of Ca(2+) further supported the involvement of these organelles in staurosporine-induced Ca(2+) signaling. In summary, our data indicate that staurosporine-induced fungal cell death involves a sophisticated response linking Ca(2+) dynamics and bioenergetics. PMID- 26004628 TI - A preliminary investigation of reproducibility of EMG signals during daytime masticatory muscle activity using a portable EMG logging device. AB - Continuous parafunctional masseter muscle activities (MMA) that are associated with daytime bruxism have been suspected to be one of the main pathoetiology for orofacial pain. The purpose of this study was to examine the long-term stability and reliability of daytime EMG measurement of MMA using a portable device (Actiwave; CamNtech Ltd). Daytime masseter muscle EMG of five subjects were recorded for four days in their normal living environment. There was no significant time dependent effect on EMG amplitude during recording period. A total of 4923 MMA events were detected in all analysis periods (129.4h) and classified into phasic type (1209 events, 24.6%), tonic type (1759 events, 37.0%), and mixed type (1377 events, 28.0%). There was no significant difference in the number of occurrence among three MMA types. With respect to the duration and peak MMA, there were significant differences among three MMA types. The result of this study indicated that Actiwave can be used to measure MMA events during daytime with high stability and reliability under the normal living environment and it was suspected that parafunctional habits may be associated with the occurrence patterns of MMA during daytime. PMID- 26004629 TI - Reliability and fatigue characteristics of a standing hip isometric endurance protocol. AB - Muscle fatigue is a common consideration when evaluating and rehabilitating athletic injuries. The presence of muscular fatigue has been previously determined by quantifying median frequency (MF) through a power spectral analysis on EMG signals collected throughout an endurance task. Research has not yet determined if a prolonged isometric test in a standing position generates muscular fatigue of the hip. The purpose of this study was to determine the reliability and fatigue characteristics of a standing hip isometric endurance test. Twenty healthy participants completed one 60-s Maximum Voluntary Isometric Contraction of standing hip flexion, extension, adduction, and abduction. MF of the participants' dominant limb rectus femoris (RF), biceps femoris (BF), gluteus maximus (GMax), gluteus medius (GMed) and adductor longus (ADD) was determined via surface electromyography during two sessions, 30-min apart. Reliability values (ICC2,1) were moderate-to-excellent for all time intervals of each action (FlexionRF: >0.80; ExtensionBF: >0.89; ExtensionGMax: >0.60; AdductionADD: >0.78; AbductionGMed: >0.60) and MF significantly decreased over time for all actions. Results suggest the endurance test is a reliable technique to generate muscular fatigue for hip flexion, extension, adduction and abduction. It can be used as a time efficient fatigue protocol specific to the RF, BF, GMax, ADD and GMed. PMID- 26004630 TI - Transcriptome Signature and Regulation in Human Somatic Cell Reprogramming. AB - Reprogramming of somatic cells produces induced pluripotent stem cells (iPSCs) that are invaluable resources for biomedical research. Here, we extended the previous transcriptome studies by performing RNA-seq on cells defined by a combination of multiple cellular surface markers. We found that transcriptome changes during early reprogramming occur independently from the opening of closed chromatin by OCT4, SOX2, KLF4, and MYC (OSKM). Furthermore, our data identify multiple spliced forms of genes uniquely expressed at each progressive stage of reprogramming. In particular, we found a pluripotency-specific spliced form of CCNE1 that is specific to human and significantly enhances reprogramming. In addition, single nucleotide polymorphism (SNP) expression analysis reveals that monoallelic gene expression is induced in the intermediate stages of reprogramming, while biallelic expression is recovered upon completion of reprogramming. Our transcriptome data provide unique opportunities in understanding human iPSC reprogramming. PMID- 26004631 TI - hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature. AB - To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC), not the neural tube (NT). Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC)-secreted nitric oxide (NO) and direct contact with vascular smooth muscle cells (VSMCs) via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning. PMID- 26004632 TI - Identification of the Common Origins of Osteoclasts, Macrophages, and Dendritic Cells in Human Hematopoiesis. AB - Osteoclasts (OCs) originate from the myeloid cell lineage, but the successive steps in their lineage commitment are ill-defined, especially in humans. To clarify OC origin, we sorted cell populations from pediatric bone marrow (BM) by flow cytometry and assessed their differentiation potential in vitro. Within the CD11b(-)CD34(+)c-KIT(+) BM cell population, OC-differentiation potential was restricted to FLT3(+) cells and enriched in an IL3 receptor (R)alpha(high) subset that constituted less than 0.5% of total BM. These IL3Ralpha(high) cells also generated macrophages (MPhis) and dendritic cells (DCs) but lacked granulocyte (GR)-differentiation potential, as demonstrated at the clonal level. The IL3Ralpha(low) subset was re-defined as common progenitor of GR, MPhi, OC, and DC (GMODP) and gave rise to the IL3Ralpha(high) subset that was identified as common progenitor of MPhi, OC, and DC (MODP). Unbiased transcriptome analysis of CD11b( )CD34(+)c-KIT(+)FLT3(+) IL3Ralpha(low) and IL3Ralpha(high) subsets corroborated our definitions of the GMODP and MODP and their developmental relationship. PMID- 26004633 TI - Monosynaptic Tracing using Modified Rabies Virus Reveals Early and Extensive Circuit Integration of Human Embryonic Stem Cell-Derived Neurons. AB - Human embryonic stem cell (hESC)-derived dopamine neurons are currently moving toward clinical use for Parkinson's disease (PD). However, the timing and extent at which stem cell-derived neurons functionally integrate into existing host neural circuitry after transplantation remain largely unknown. In this study, we use modified rabies virus to trace afferent and efferent connectivity of transplanted hESC-derived neurons in a rat model of PD and report that grafted human neurons integrate into the host neural circuitry in an unexpectedly rapid and extensive manner. The pattern of connectivity resembled that of local endogenous neurons, while ectopic connections were not detected. Revealing circuit integration of human dopamine neurons substantiates their potential use in clinical trials. Additionally, our data present rabies-based tracing as a valuable and widely applicable tool for analyzing graft connectivity that can easily be adapted to analyze connectivity of a variety of different neuronal sources and subtypes in different disease models. PMID- 26004634 TI - Erratum to: Excess wing in glass-forming glycerol and LiCl-glycerol mixtures detected by neutron scattering. PMID- 26004635 TI - A single charge in the actin binding domain of fascin can independently tune the linear and non-linear response of an actin bundle network. AB - Actin binding proteins (ABPs) not only set the structure of actin filament assemblies but also mediate the frequency-dependent viscoelastic moduli of cross linked and bundled actin networks. Point mutations in the actin binding domain of those ABPs can tune the association and dissociation dynamics of the actin/ABP bond and thus modulate the network mechanics both in the linear and non-linear response regime. We here demonstrate how the exchange of a single charged amino acid in the actin binding domain of the ABP fascin triggers such a modulation of the network rheology. Whereas the overall structure of the bundle networks is conserved, the transition point from strain-hardening to strain-weakening sensitively depends on the cross-linker off-rate and the applied shear rate. Our experimental results are consistent both with numerical simulations of a cross linked bundle network and a theoretical description of the bundle network mechanics which is based on non-affine bending deformations and force-dependent cross-link dynamics. PMID- 26004636 TI - Radiolabeled Sugars Used for PET and SPECT Imaging. AB - There are new efforts to develop "sugar" probes for molecular imaging focusing on human clinical studies. Radiolabeled carbohydrates are used as substrate probes for studying specific processes in tissues and organisms. The best application case is 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG), which is incorporated by cancer cells. The introduction of ltF-FDG has advanced enormously human Positron Emission Tomography (PET). This review focuses on the importance of 18FFDG and other sugars as imaging probes in PET and Single Photon Emission Computed Tomography (SPECT) imaging. In conclusion, new radiolabeled molecules that can be used as radiopharmaceuticals also would possibly help in the treatment of cancer cells in human patients. PMID- 26004638 TI - Low Serum Levels of ABCA1, an ATP-Binding Cassette Transporter, Are Predictive of Preeclampsia. AB - Preeclampsia is a pregnancy-specific disorder characterized by hypertension and proteinuria, but the exact cause of preeclamptic hypertension remains unknown. ATP-binding cassette subfamily A member 1 (ABCA1) reverses cholesterol transport and eliminates excess cholesterol from tissues, whereas higher levels of cholesterol may lead to hypertension. Thus, ABCA1 affects the blood lipid profile. We have hypothesized that serum ABCA1 levels may influence the onset of hypertension and increase the risk of preeclampsia. To test this hypothesis, we measured serum ABCA1 levels in 50 normal pregnancies, 36 preeclamptic pregnancies, and 24 small-for-gestational-age (SGA) pregnancies during three trimesters. We also measured the concentrations of serum ABCA1 in non-pregnant women (n = 60), showing its normal ranges of 0.16 to 0.52 ng/ml. Importantly, the serum levels of ABCA1 were similar among non-pregnant women, normal pregnancies and SGA pregnancies. In contrast, the serum ABCA1 levels were significantly lower in preeclamptic pregnancies (0.06 +/- 0.03 ng/ml) than those in non-pregnant women, and normal and SGA pregnancies (P < 0.05). Low serum ABCA1 levels were associated with the increases in the concentrations of blood lipid (low density lipoprotein cholesterol, total cholesterol and triglycerides) and with the decrease in the concentration of high-density lipoprotein cholesterol (P < 0.01), all of which may contribute to the onset of hypertension and eventually preeclampsia. Moreover, the preeclamptic pregnancy was diagnosed with high sensitivity from the nulliparous pregnancies if the cutoff value for serum ABCA1 was 0.06 ng/ml. Thus, low serum levels of ABCA1 are predictive of preeclampsia. PMID- 26004637 TI - Prevalence and behavioural risks for HIV and HCV infections in a population of drug users of Dakar, Senegal: the ANRS 12243 UDSEN study. AB - OBJECTIVES: Data on the extent of drug use and associated HIV, hepatitis C and hepatitis B infection in West Africa are lacking. The objectives of ANRS12244 UDSEN study were to estimate the size of the heroin and/or cocaine drug user (DU) population living in the Dakar area (Senegal), and assess the prevalence and risk factors of HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV), including behavioural determinants in this population, in order to set up an integrated prevention and treatment programme for DUs. DESIGN AND METHODS: A capture recapture method was applied for population size estimation, whereas the respondent-driven sampling (RDS) method was used to recruit a sample of DUs living in the Dakar area and determine HIV, HBV and HCV prevalence. Behavioural data were gathered during face-to-face interviews, and blood samples were collected on dried blood spots for analysis in a central laboratory. Data analysis was performed using the RDS analysis tool, and risk factors were determined by logistic regression. Access to laboratory results was organized for the participants. RESULTS: The size of the DU population in the Dakar area was estimated to reach 1324 (95% confidence interval (95% CI: 1281-1367)). Based on the 506 DUs included in the study, the HIV, HCV and HBV prevalence were 5.2% (95% CI: 3.8-6.3), 23.3% (95% CI: 21.2-25.2) and 7.9% (95% CI: 5.2-11.1), respectively. In people who inject drugs (PWID), prevalence levels increased to 9.4% for HIV and 38.9% for HCV (p=0.001 when compared to those who never injected). Women were more at risk of being HIV infected (prevalence: 13.04% versus 2.97% in males, p=0.001). Being PWID was a risk factor for HCV and HIV infection (odds ratio, OR: 2.7, 95% CI: 1.7-4.3, and OR: 4.3, 95% CI: 1.7-10.7, respectively), whereas older age and female sex were additional risk factors for HIV infection (10% increase per year of age, p=0.03 and OR: 4.9, 95% CI: 1.6-156, respectively). No specific determinant was associated with the risk of HBV infection. CONCLUSIONS: High HIV and HCV prevalence were estimated in this population of DUs (including non-injectors) living in the Dakar area, Senegal, whereas HBV prevalence was close to that of the global Senegalese population, reflecting a risk of infection independent of drug use. Women seem to be highly vulnerable and deserve targeted interventions for decreasing exposure to HIV, while behavioural risk factors for HIV and HCV include the use of unsafe injections, reflecting the urgent need for developing harm reduction interventions and access to opioid substitution therapy services. PMID- 26004639 TI - Case report of a p16INK4A-positive branchial cleft cyst. AB - OBJECTIVE: To report the occurrence of a concurrent oropharyngeal papilloma and branchial cleft cyst linked by p16(INK4A) and human papillomavirus immunohistochemistry. CASE REPORT: A 42-year-old woman presented with a 1-month history of a left lateral neck mass. Contrast enhanced computed tomography showed a hypodense lesion 20 mm in diameter anteromedial to the left sternocleidomastoid muscle. Ultrasound-guided fine needle aspiration suggested a branchial cleft cyst. Panendoscopy was performed at the time of neck mass removal, and a papillomatous lesion was removed from the left hypopharynx. Histopathological analysis showed the neck lesion to be a branchial cyst containing lymphoid tissue, and the oral lesion to be a squamous papilloma. Immunohistochemical analysis showed both the branchial cleft cyst and papilloma to be positive for p16(INK4A) expression and human papillomavirus DNA. CONCLUSION: Histological and immunohistochemical analyses support the cystic transformation of lymph nodes, or the 'Inclusion Theory', as the aetiology of branchial apparatus anomalies, and raise the possibility that human papillomavirus infection may play a much larger role in disease of the head and neck than previously supposed. PMID- 26004641 TI - Shiga Toxin Producing Escherichia coli. AB - Shiga toxin-producing Escherichia coli (STEC) is among the common causes of foodborne gastroenteritis. STEC is defined by the production of specific toxins, but within this pathotype there is a diverse group of organisms. This diversity has important consequences for understanding the pathogenesis of the organism, as well as for selecting the optimum strategy for diagnostic testing in the clinical laboratory. This review includes discussions of the mechanisms of pathogenesis, the range of manifestations of infection, and the several different methods of laboratory detection of Shiga toxin-producing E coli. PMID- 26004642 TI - Vibriosis. AB - Vibriosis is a group of intestinal and extraintestinal infections caused by marine-dwelling bacteria of the genus Vibrio. Infections range from indolent illnesses to fulminant diseases, including cholera and necrotizing fasciitis. Most illnesses result from direct contact with the marine environment or consumption of shellfish, especially oysters. In the United States vibrio infections are increasing but are underreported because of lack of clinical recognition and appropriate detection in the microbiology laboratory. Recent advances to aid in the detection and identification of vibrio illnesses in the laboratory include rapid identification tests, new media, and molecular identification systems. PMID- 26004640 TI - Salmonella, Shigella, and yersinia. AB - Salmonella, Shigella, and Yersinia cause a well-characterized spectrum of disease in humans, ranging from asymptomatic carriage to hemorrhagic colitis and fatal typhoidal fever. These pathogens are responsible for millions of cases of food borne illness in the United States each year, with substantial costs measured in hospitalizations and lost productivity. In the developing world, illness caused by these pathogens is not only more prevalent but also associated with a greater case-fatality rate. Classic methods for identification rely on selective media and serology, but newer methods based on mass spectrometry and polymerase chain reaction show great promise for routine clinical testing. PMID- 26004643 TI - Campylobacter. AB - Campylobacter continues to be one of the most common bacterial causes of diarrheal illness in the United States and worldwide. Infection with Campylobacter causes a spectrum of diseases including acute enteritis, extraintestinal infections, and postinfectious complications. The most common species of Campylobacter associated with human illness is Campylobacter jejuni, but other Campylobacter species can also cause human infections. This comprehensive review includes discussion of the taxonomy, clinical manifestations of infection, epidemiology and the different methods of laboratory detection of Campylobacter. PMID- 26004644 TI - Optimizing the Laboratory Diagnosis of Clostridium difficile Infection. AB - The best laboratory diagnostic approach to detect Clostridium difficile infection (CDI) is the subject of ongoing debate. In the United States, nucleic acid amplification tests (NAAT) have become the most widely used tests for making this diagnosis. Detection of toxin in stool may be a better predictor of CDI disease and severity. Laboratories that have switched from toxin-based to NAAT-based methods have significantly higher CDI detection rates. The important issue is whether all NAAT-positive patients have CDI or at least some of those patients are excretors of the organism and do not have clinical disease. PMID- 26004645 TI - Antimicrobial susceptibility testing of bacteria that cause gastroenteritis. AB - Gastroenteritis due to enteric pathogens is generally a self-limiting disease for which antimicrobial treatment is not required. However, treatment should be considered for cases of severe or prolonged diarrhea, extraintestinal isolation of bacteria, or diarrhea in immunocompromised hosts, the elderly, and infants. Various resistance trends and current issues concerning antimicrobial susceptibility testing of enteric pathogens are reviewed in this article, including Campylobacter, Salmonella, Shigella, Vibrio, Aeromonas, Plesiomonas, and Clostridium difficile. Updated interpretive criteria from breakpoint-setting organizations are reviewed, along with explanations for recent changes in antimicrobial breakpoints. PMID- 26004646 TI - Markers of intestinal inflammation for the diagnosis of infectious gastroenteritis. AB - Infectious diarrhea is a major cause of morbidity. A rapid and inexpensive assay for the diagnosis of infectious gastroenteritis would expedite appropriate therapy and prevent unnecessary and potentially invasive testing. This article summarizes assays for the diagnosis of infectious gastroenteritis based on the host response to bacterial, viral, or parasitic infection. This includes both systemic biomarkers (such as C-reactive protein, erythrocyte sedimentation rate, and serum cytokines) and fecal biomarkers (such as lactoferrin, fecal leukocyte analysis, and calprotectin). Although some of these assays have value as adjunct diagnostics, they lack sensitivity and specificity as stand-alone tests in this setting. PMID- 26004647 TI - Laboratory diagnosis of noroviruses: present and future. AB - Norovirus is an important cause of gastroenteritis outbreaks globally and the most prevalent cause of sporadic gastroenteritis in many regions. Rapid and accurate identification of causative viral agents is critical for outbreak investigation, disease surveillance, and management. Because norovirus is not cultivable and has a highly diversified and variable genome, it is difficult to develop diagnostic assays. Detection methods have evolved from electron microscopy to conventional end-point reverse transcription polymerase chain reaction (RT-PCR), immunoassay, real-time RT-PCR, other molecular technologies, and nanotechnology array-based assays. The status and features of various testing methods are summarized in this review. PMID- 26004648 TI - Rotavirus. AB - Group A rotavirus (RVA) is the major cause of acute gastroenteritis (AGE) in young children worldwide. Introduction of two live, attenuated rotavirus vaccines, Rotarix(r) and RotaTeq(r), has dramatically reduced RVA-associated AGE and mortality. High-throughput, sensitive and specific techniques are required to rapidly diagnose and characterize rotavirus strains in stool samples for proper patient treatment and to monitor circulating vaccine and wild-type rotavirus strains. New molecular assays are rapidly developed that are more sensitive and specific than the conventional assays for detection, genotyping and full genome characterization of circulating rotavirus wild-type and vaccine (Rotarix(r) and RotaTeq(r)) strains causing AGE. PMID- 26004649 TI - Intestinal amebae. AB - Among the Entamoeba species that infect humans, Entamoeba histolytica causes diseases, Entamoeba dispar is a harmless commensal, Entamoeba moshkovskii seems to be a pathogen, and the pathogenicity of Entamoeba bangladeshi remains to be investigated. Species-specific detection needed for treatment decisions and for understanding the epidemiology and pathogenicity of these amebae. Antigen-based detection methods are needed for E dispar, E moshkovskii, and E bangladeshi; and molecular diagnostic test capable of detecting E histolytica, E dispar, E moshkovskii, and E bangladeshi simultaneously in clinical samples. Next generation sequencing of DNA from stool is needed to identify novel species of Entamoeba. PMID- 26004651 TI - Intestinal microsporidiosis. AB - Infection by the ingested pathogens of microsporidia occur primarily in immunosuppressed patients (including untreated HIV/AIDS) and are diagnosed by stool examination, small bowel biopsy with special stains, or electron microscopy (for definitive speciation), or by various molecular techniques. Although electron microscopy has been the definitive diagnostic tool for speciation, genetic sequencing increasingly provides the definitive diagnosis for new species, such as Anncaliia algerae. Further genetic sequencing of the common pathogens may allow for the development of advanced molecular diagnostics providing high diagnostic sensitivity and throughput. PMID- 26004650 TI - Infections by Intestinal Coccidia and Giardia duodenalis. AB - The coccidians Cryptosporidium spp, Cyclospora cayetanensis, and Cystoisospora belli and the flagellate Giardia duodenalis are pathogenic protozoa associated with gastrointestinal manifestations. Diagnosis relies heavily on microscopy, and although ova-and-parasite examinations can detect Giardia and Cystoisospora, Cryptosporidium and Cyclospora often require specific diagnostic requests. Approved non-microscopy methods are available for Giardia and Cryptosporidium, although negative results are frequently followed by microscopic assays. Polymerase chain reaction-based methods are not frequently used for diagnosis of Giardia and Cryptosporidium and have been used primarily for epidemiologic or outbreak investigations of Giardia and Cryptosporidium. PMID- 26004653 TI - Preface. Diagnostic testing for enteric pathogens. PMID- 26004652 TI - Multiplex polymerase chain reaction tests for detection of pathogens associated with gastroenteritis. AB - A wide range of enteric pathogens can cause infectious gastroenteritis. Conventional diagnostic algorithms are time-consuming and often lack sensitivity and specificity. Advances in molecular technology have provided new clinical diagnostic tools. Multiplex polymerase chain reaction (PCR)-based testing has been used in gastroenterology diagnostics in recent years. This article presents a review of recent laboratory-developed multiplex PCR tests and current commercial multiplex gastrointestinal pathogen tests. It focuses on two commercial syndromic multiplex tests: Luminex xTAG Gastrointestinal Pathogen Panel and BioFire FilmArray gastrointestinal test. Multiplex PCR tests have shown superior sensitivity to conventional methods for detection of most pathogens. PMID- 26004654 TI - Online open-tubular fractionation scheme coupled with push-pull perfusion sampling for profiling extravasation of gold nanoparticles in a mouse tumor model. AB - The extravasation of administered nano-drug carriers is a critical process for determining their distributions in target and non-target organs, as well as their pharmaceutical efficacies and side effects. To evaluate the extravasation behavior of gold nanoparticles (AuNPs), currently the most popular drug delivery system, in a mouse tumor model, in this study we employed push-pull perfusion (PPP) as a means of continuously sampling tumor extracellular AuNPs. To facilitate quantification of the extravasated AuNPs through inductively coupled plasma mass spectrometry, we also developed a novel online open-tubular fractionation scheme to allow interference-free determination of the sampled extracellular AuNPs from the coexisting biological matrix. After optimizing the flow-through volume and flow rate of this proposed fractionation scheme, we found that (i) the system's temporal resolution was 7.5h(-1), (ii) the stability presented by the coefficient of variation was less than 10% (6-h continuous measurement), and (iii) the detection limits for the administered AuNPs were in the range 0.057-0.068MUgL(-1). Following an intravenous dosage of AuNPs (0.3mgkg( 1) body weight), in vivo acquired profiles indicated that the pegylated AuNPs (PEG-AuNPs) had greater tendency toward extravasating into the tumor extracellular space. We also observed that the accumulation of nanoparticles in the whole tumor tissues was higher for PEG-AuNPs than for non-pegylated ones. Overall, pegylation appears to promote the extravasation and accumulation of AuNPs for nano-drug delivery applications. PMID- 26004655 TI - Precision medicine for child and adolescent psychiatry. PMID- 26004656 TI - Being mindful of mindfulness: past, present, and future of mindfulness in child and adolescent psychiatry. PMID- 26004657 TI - Want change? Try honey instead of vinegar. PMID- 26004658 TI - Longitudinal cortical thinning in adolescents with autism: good or bad? PMID- 26004659 TI - Clinic- and home-based contingency management plus parent training for adolescent cannabis use disorders. AB - OBJECTIVE: The aim of this study was to conduct a randomized test comparing 2 multicomponent, contingency management interventions, 1 with and 1 without a full parent training curriculum, and an individual treatment for adolescent cannabis use disorders. METHOD: A total of 153 adolescents who met DSM-IV criteria for cannabis abuse or dependence were randomized to motivational enhancement therapy/cognitive-behavioral therapy (MET/CBT), MET/CBT+abstinence-based contingency management (CM), or MET/CBT+CM+Parent Training (PT). RESULTS: Overall, during treatment, abstinence was greater for youth receiving clinic- and home-based CM without PT compared to those who received individual MET/CBT. There was no additional benefit of the full PT curriculum on marijuana use, youth externalizing problems, or parenting. CONCLUSION: These results suggest that clinic- plus home-based CM for cannabis use disorders can increase rates of abstinence during treatment over and above an evidence-based treatment (individual MET/CBT), but in this study the addition of a comprehensive parenting training curriculum did not further enhance efficacy. CLINICAL TRIAL REGISTRATION INFORMATION: Treatment for Adolescent Marijuana Abuse; http://clinicaltrials.gov; NCT00580671. PMID- 26004662 TI - Can parents' concerns predict autism spectrum disorder? A prospective study of high-risk siblings from 6 to 36 months of age. AB - OBJECTIVE: This prospective study characterized parents' concerns about infants at high risk for developing autism spectrum disorder (ASD; each with an older sibling with ASD) at multiple time points in the first 2 years, and assessed their relation to diagnostic outcome at 3 years. METHOD: Parents of low-risk controls (LR) and high-risk infant siblings (HR) reported any concerns that they had regarding their children's development between 6 and 24 months of age regarding sleep, diet, sensory behavior, gross/fine motor skills, repetitive movements, communication, communication regression, social skills, play, and behavioral problems, using a parent concern form designed for this study. At 3 years of age, an independent, gold-standard diagnostic assessment for ASD was conducted for all participants. RESULTS: As predicted, parents of HR children who received an ASD diagnosis reported more concerns than parents of LR and HR children who did not have ASD. The total number of concerns predicted a subsequent diagnosis of ASD as early as 12 months within the HR group. Concerns regarding sensory behavior and motor development predicted a subsequent diagnosis of ASD as early as 6 months, whereas concerns about social communication and repetitive behaviors did not predict diagnosis of ASD until after 12 months. CONCLUSION: Parent-reported concerns can improve earlier recognition of ASD in HR children. PMID- 26004660 TI - Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study. AB - OBJECTIVE: The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child's gender, type of anxiety disorder, initial severity and comorbidity, and parents' psychopathology would significantly predict outcome. METHOD: A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. RESULTS: Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. CONCLUSION: SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes. PMID- 26004661 TI - Longitudinal cortical development during adolescence and young adulthood in autism spectrum disorder: increased cortical thinning but comparable surface area changes. AB - OBJECTIVE: Prior reports suggest that autism spectrum disorder (ASD) is associated with atypically excessive early brain growth. Recent cross-sectional studies suggest that later cortical development during adolescence/adulthood might also be aberrant, although longitudinal designs are required to evaluate atypical growth trajectories. The present study sought to examine longitudinal changes in cortical thickness and surface area among adolescents and young adults with ASD. METHOD: Two high-resolution anatomic magnetic resonance imaging scans approximately 2 years apart were acquired from 17 adolescents with ASD and 18 typically developing (TD) adolescents, matched on age (range = 14-24 years), IQ, sex ratio, and handedness (70 scans total). The FreeSurfer image analysis suite was used to quantify longitudinal changes in cortical thickness and surface area. RESULTS: Accelerated cortical thinning for the ASD group as compared to the TD group was found in 2 areas in the left hemisphere, the posterior portion of ventral temporal cortex and superior parietal cortex (cluster corrected p < .01). For ventral temporal cortex, cortical thinning was associated with everyday executive function impairments, and thinner cortex at time 2 was correlated with ASD social symptoms. Differences in surface area changes were not detected. CONCLUSION: The present longitudinal study extends prior cross-sectional research by demonstrating increased cortical thinning (in portions of temporal and parietal cortex) but comparable surface area growth rates in participants with ASD compared to TD controls during adolescence and into young adulthood. These findings provide further evidence for atypical cortical development beyond the early years in ASD, marked by increased cortical thinning in late adolescence/young adulthood. PMID- 26004663 TI - Examining and comparing social perception abilities across childhood-onset neurodevelopmental disorders. AB - OBJECTIVE: Several neurodevelopmental disorders are associated with social processing deficits. The objective of this study was to compare patterns of social perception abilities across obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and control participants. METHOD: A total of 265 children completed the Reading the Mind in the Eyes Test-Child Version (RMET). Parents or caregivers completed established trait/symptom scales. The predicted percentage of accuracy on the RMET was compared across disorders and by item difficulty and item valence (i.e., positive/negative/neutral mental states), then analyzed for associations with trait/symptom scores. RESULTS: The percentage of correct RMET scores varied significantly between diagnostic groups (p < .0001). On pairwise group comparisons controlling for age and sex, children with ADHD and ASD scored lower than the other groups (p < .0001). When IQ was also controlled for in the model, participants with OCD performed better than controls (p < .001), although differences between other groups were less pronounced. Participants with ASD scored lowest on easy items. Those with ASD and ADHD scored significantly lower than other groups on items with positive valence (p < .01). Greater social communication impairment and hyperactivity/impulsivity, but not OCD traits/symptoms, were associated with lower scores on the RMET, irrespective of diagnosis. CONCLUSION: Social perception abilities in neurodevelopmental disorders exist along a continuum. Children with ASD have the greatest deficits, whereas children with OCD may be hypersensitive to social information. Social communication deficits and hyperactive/impulsive traits are associated with impaired social perception abilities; these findings highlight overlapping cognitive and behavioral manifestations across disorders. PMID- 26004664 TI - Parental age and the risk of attention-deficit/hyperactivity disorder: a nationwide, population-based cohort study. AB - OBJECTIVE: An increasing number of studies has shown an association between parental age and psychiatric disorders. However, there are inconsistent results regarding whether age at parenthood is associated with attention deficit/hyperactivity disorder (ADHD). The aim of this study is to examine whether low or advanced parental age is associated with ADHD. METHOD: In this nested case-control study, we identified 10,409 individuals with ADHD born in Finland during 1991 to 2005 and diagnosed with ADHD between 1995 and 2011, along with 39,125 controls matched on sex, date, and place of birth, from nationwide population-based registers. Conditional logistic regression was used to examine the association between parental age and ADHD in offspring, adjusting for potential confounding due to parental psychiatric history, maternal socioeconomic status, marital status, maternal smoking during pregnancy, number of previous births, and birth weight for gestational age. RESULTS: Fathers younger than 20 years had a 1.5-fold (odds ratio [OR] = 1.55, 95% CI = 1.11-2.18, p = .01) increased risk of having offspring with ADHD as compared to fathers aged 25 to 29 years. Mothers of the same age group had a 1.4-fold (OR = 1.41, 95% CI = 1.15 1.72, p =.0009) increased risk. Advanced maternal age was inversely associated with ADHD (OR = 0.79, 95% CI = 0.64-0.97, p = .02). CONCLUSION: ADHD was associated with young fathers or mothers at the time of birth. Health professionals working with young parents should be aware of the increased risk of ADHD in offspring. This will improve early detection; however, for the development of preventive measures and appropriate interventions, more information on the developmental pathways is needed. PMID- 26004665 TI - Maternal history of autoimmune disease and later development of tourette syndrome in offspring. AB - OBJECTIVE: In a nationwide prospective cohort study, we examined the possible association between maternal autoimmune disease (AD) and later diagnosis of Tourette syndrome (TS) in offspring. METHOD: Data from national Danish health registers identified a cohort consisting of all children born in Denmark between 1990 and 2007 (n = 1,116,255), followed prospectively from birth until 2011, date of TS diagnosis, death, or emigration/disappearance, whichever came first. The incidence rate ratio (IRR) of TS, dependent on whether or not the mother had a prior diagnosis of AD, was estimated by Poisson regression with 95% CIs and adjusted for age, calendar time, place of birth, maternal and paternal age, parental psychiatric diagnoses other than TS, and parental TS. RESULTS: The cohort contributed a total of 13,000,162 person years and 2,442 participants with a diagnosis of TS (414 females and 2,028 males). Prior maternal AD was found in 110 of the 2,442 children with TS, corresponding to an increased risk of TS, with an adjusted IRR of 1.22 (95% CI = 1.01-1.48). Maternal history of a prior AD increased the risk of TS in males, with an adjusted IRR of 1.29 (95% CI = 1.05 1.58), but not in females, with an adjusted IRR of 0.89 (95% CI = 0.52-1.52). CONCLUSION: Maternal AD was associated with a 29% increased incidence rate of TS in male offspring. This finding supports the hypothesis that neuroimmunological disorders may act as a component in the etiology of a subset of TS. PMID- 26004666 TI - Practice parameter for the assessment and management of youth involved with the child welfare system. AB - This Practice Parameter presents principles for the mental health assessment and management of youth involved with the child welfare system. Important definitions, background, history, epidemiology, mental health care use, and functional outcomes are described. Practical guidance regarding child welfare related considerations for evaluation and management are discussed. PMID- 26004668 TI - In vivo study on splenomegaly inhibition by genistein in Plasmodium berghei infected mice. AB - Spleen plays an important role in removing old and damaged red blood cells and malaria-infected erythrocytes. When malaria parasites invade the spleen and induce splenomegaly, splenic function tends to be impaired. Thus, the inhibition of splenomegaly is strongly required to protect the spleen. In this study, malaria-induced splenomegaly is inhibited by injecting genistein into a Plasmodium berghei-infected ICR mouse. To explain this phenomenon, the effect of genistein in spleen and liver of malaria-infected mice was evaluated by histological examination. Malaria parasites disrupted splenic architecture. After treating genistein, the disrupted architecture in which red and white pulp regions were clearly separated in recovered to uninfected ones. Changes in biophysical properties of blood were studied by measuring the viscosity of blood collected from malaria-infected and uninfected mice using a microfluidic viscometer. Genistein also had a negligible influence on variation in blood viscosity. The enzymatic activity and expression pattern of proteins were then investigated to explain the genistein effect on malaria-induced splenomegaly. Genistein is a potential drug for splenomegaly in P. berghei-infected mouse. PMID- 26004669 TI - Performance of 2-D shear wave elastography in liver fibrosis assessment compared with serologic tests and transient elastography in clinical routine. AB - Liver stiffness values assessed with 2-D shear wave elastography (SWE), transient elastography (TE) and simple serologic tests were compared with respect to non invasive assessment in a cohort of 127 consecutive patients with chronic liver diseases. The rate of reliable liver stiffness measurements was significantly higher with 2-D SWE than with TE: 99.2% versus 74.8%, p < 0.0001 (different reliability criteria used, according to current recommendations). In univariate analysis, liver stiffness measured with 2-D SWE correlated best with fibrosis stage estimated with TE (r = 0.699, p < 0.0001), followed by Forns score (r = 0.534, p < 0.0001) and King's score (r = 0.512, p < 0.0001). However, in multivariate analysis, only 2-D SWE-measured values remained correlated with fibrosis stage (p < 0.0001). The optimal 2-D SWE cutoff values for predicting significant fibrosis were 8.03 kPa for fibrosis stage >=2 (area under the receiver operating characteristic curve = 0.832) and 13.1 kPa for fibrosis stage 4 (area under the receiver operating characteristic curve = 0.915), respectively. In conclusion, 2-D SWE can be used to obtain reliable liver stiffness measurements in almost all patients and performs very well in predicting the presence of liver cirrhosis. PMID- 26004670 TI - Development of an ultrasonic method to detect cervical remodeling in vivo in full term pregnant women. AB - The objective of this study was to determine whether estimates of ultrasonic attenuation could detect changes in the cervix associated with medically induced cervical remodeling. Thirty-six full-term pregnant women underwent two transvaginal ultrasonic examinations separated in time by 12 h to determine cervical attenuation, cervical length and changes thereof. Ultrasonic attenuation and cervical length data were acquired from a zone (Zonare Medical Systems, Mountain View, CA, USA) ultrasound system using a 5-9 MHz endovaginal probe. Cervical attenuation and cervical length significantly decreased in the 12 h between the pre-cervical ripening time point and 12 h later. The mean cervical attenuation was 1.1 +/- 0.4 dB/cm-MHz before cervical ripening agents were used and 0.8 +/- 0.4 dB/cm-MHz 12 h later (p < 0.0001). The mean cervical length also decreased from 3.1 +/- 0.9 cm before the cervical ripening was administered to 2.0 +/- 1.1 cm 12 h later (p < 0.0001). Cervical attenuation and cervical length detected changes in cervical remodeling 12 h after cervical ripening administration. PMID- 26004671 TI - Prevalence and socio-demographic correlates of time spent cooking by adults in the 2005 UK Time Use Survey. Cross-sectional analysis. AB - This study aimed to document the prevalence and socio-demographic correlates of time spent cooking by adults in the 2005 UK Time-Use Survey. Respondents reported their main activities, in 10 minute slots, throughout one 24 hour period. Activities were coded into 30 pre-defined codes, including 'cooking, washing up'. Four measures of time spent cooking were calculated: any time spent cooking, 30 continuous minutes spent cooking, total time spent cooking, and longest continuous time spent cooking. Socio-demographic correlates were: age, employment, social class, education, and number of adults and children in the household. Analyses were stratified by gender. Data from 4214 participants were included. 85% of women and 60% of men spent any time cooking; 60% of women and 33% of men spent 30 continuous minutes cooking. Amongst women, older age, not being in employment, lower social class, greater education, and living with other adults or children were positively associated with time cooking. Few differences in time spent cooking were seen in men. Socio-economic differences in time spent cooking may have been overstated as a determinant of socio-economic differences in diet, overweight and obesity. Gender was a stronger determinant of time spent cooking than other socio-demographic variables. PMID- 26004672 TI - The MARK-AGE extended database: data integration and pre-processing. AB - MARK-AGE is a recently completed European population study, where bioanalytical and anthropometric data were collected from human subjects at a large scale. To facilitate data analysis and mathematical modelling, an extended database had to be constructed, integrating the data sources that were part of the project. This step involved checking, transformation and documentation of data. The success of downstream analysis mainly depends on the preparation and quality of the integrated data. Here, we present the pre-processing steps applied to the MARK AGE data to ensure high quality and reliability in the MARK-AGE Extended Database. Various kinds of obstacles that arose during the project are highlighted and solutions are presented. PMID- 26004673 TI - Is it safe to drive after acute mild stroke? A preliminary report. AB - BACKGROUND: Most guidelines recommend that patients should refrain from driving for at least one month after stroke. Despite these guidelines, and the fact that patients post-stroke may be at an increased risk for driving impairment, many patients report resuming driving within the acute phase of injury. The aim of this study was to investigate the driving performance of patients with acute mild stroke. METHODS: The current study compared the driving simulator performance of ten patients with acute mild ischemic stroke (>48 h and <7 days) to that of ten healthy, age- and education-matched controls. RESULTS: During the City Driving and Bus Following Scenarios, patients on average committed over twice as many errors (e.g., collisions, center line crossings, speed exceedances) as controls (12.4 vs. 6.0, t(18)=2.77, p<0.01; and 8.2 vs. 2.1, t(17)=2.55, p<0.05; respectively). Although there was no difference between patients and controls in the number of errors committed during simple right and left turns, patients committed significantly more errors than controls during left turns with traffic (0.49 vs. 0.26, U=26.5, p<0.05). CONCLUSION: Results suggest that patients with acute mild ischemic stroke may be able to maintain driving performance during basic tasks (e.g., straight driving, right turns) and that deficits may become apparent during more complex tasks (e.g., left turns with traffic, bus following). The results highlight the importance of healthcare professionals providing driving advice to their patients post-stroke, particularly in the acute phase of injury. PMID- 26004674 TI - About invasive cervical cancer: a French population based study between 1998 and 2010. AB - OBJECTIVES: The new French cancer plan provides the implementation of organized screening. To make an assessment of the situation, we aim to describe clinical, tumor and survival characteristics of patients with invasive cervical cancer. STUDY DESIGN: Data on women suffering from invasive cervical cancer and diagnosed from 1998 to 2010 were provided by the Cote d'Or breast cancer registry. Survival was described using the Kaplan-Meier method and prognostic factors of survival were estimated in a Cox proportional hazard model. RESULTS: On the whole, 1019 cancers have been collected including 311 (30.5%) invasive ones. The peak incidence was between 40 and 49 years, with an average age of 52 years (SD=16.4). Cancers were mostly squamous cell carcinoma (80.1%) and diagnosed at a localized stage (53.7%). Only 49% (71/145) of our population were up to date on their Pap smear follow up with lower rates in deprived women. The 5-year survival rate was 62% (15% for women with FIGO stage IV and 91% for women with FIGO stage I) with a median survival of 12.3 years [95% CI: 6.6-NR]. Multivariate analysis showed that risk of death was the highest for group age 50-59 (OR=4.93; 95% CI: [1.55-15.70]) compared to women aged less than 40, advanced stage (OR=3.12; 95% CI [1.82 5.35]), and non accurate follow up (OR=2.81; 95% CI [1.32-5.97]). After cancer diagnosis, no impact of the deprivation index on survival was found. CONCLUSION: This study confirms the poor outcome of advanced invasive cervical cancer and the importance of early detection of cervical cancer. Preventive communication should be even more developed and the implementation of a screening program may go through the provision of improved screening tools. PMID- 26004675 TI - MRI and oxidative stress markers in neurological worsening of Wilson disease following penicillamine. AB - BACKGROUND AND AIM: There is no report of MRI correlation with neurological worsening following chelating treatment in Wilson disease with neurological manifestation (WDN). We report radiological changes in four patients with WDN who worsen after penicillamine. METHODS: WDN was diagnosed on the basis of clinical, KF ring, serum ceruloplasmin and 24h urinary copper. Hematological, biochemical and cranial MRI were repeated at the time of clinical deterioration following chelating treatment. RESULTS: Four WDN patients had neurological deterioration within 4-8 weeks of penicillamine therapy. This was associated with new lesions in white matter, thalamus, pons and mid brain and these lesions showed diffusion restriction. The neurologic deterioration was associated with increased free serum copper and malanodialdehyde and reduced glutathione. Clinical conditions stabilized after few weeks of penicillamine discontinuation. CONCLUSION: Neurological worsening was associated with new lesions on MRI which revealed diffusion restriction. Increased free copper induced oxidative stress may be responsible for these changes. PMID- 26004676 TI - A frontal dopamine system for reflective exploratory behavior. AB - The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants' exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naive Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions. PMID- 26004677 TI - Limits on movement integration in children: The concatenation of trained subsequences into composite sequences as a specific experience-triggered skill. AB - Complex movement sequences may be easier to acquire in sub-segments. Nevertheless, the neuro-behavioral constraints on assembling short multi-element movement segments, acquired piecemeal and serially, into larger, composite units of action, are not clear. Here we examined the ability of children to combine movement subsequences into longer, composite, sequences. Eleven-year-olds were trained in the performance of two, 3-elements, finger-to-thumb opposition movement sequences and were tested, overnight, in the performance of composite, 6 elements, sequences. Two experiments were compared, differing only in whether or not a brief test for integration into a composite sequence was afforded immediately post-training. This composite sequence (Full) was a direct forward integration of the two subsequences, maintaining the order in which the two subsequences were trained. In both experiments, overnight performance of movement elements within the composite sequences was better than naive performance, but slower and less accurate compared to the performance of the identical movement elements in the context of the trained subsequences. Integration was as effective in the Full sequence as when the order between subsequences was switched (Reversed). However, the early test for subsequence integration was critical in inducing clear between-session ('offline') gains, as expressed in overnight performance, in both the Full and Reversed sequences. Without this brief experience in integration, no overnight gains were expressed in any of the 6 elements sequences. Moreover, the immediate post-training test resulted in a relative advantage of the Full and Reversed sequences over a 6-element sequence in which the order of the elements was mirror-reversed within each subsequence. Thus, training on subsequences may not spontaneously lead to an advantage in the performance of composite sequences, in children. However, an early brief experience with a composite sequence can suffice to trigger the establishment and consolidation of an integration routine. This routine is specific for the order of movement within the trained subsequences, but not for the order in which the subsequences were practiced. PMID- 26004678 TI - Sex differences in cerebellar mechanisms involved in pain-related safety learning. AB - Recent studies have suggested that the cerebellum contributes to the central processing of pain, including pain-related learning and memory processes. As a complex experience with multiple emotional and cognitive facets, the response to pain and its underlying neural correlates differ between men and women. However, it remains poorly understood whether and to what extent sex differences exist in the cerebellar contribution to pain-related associative learning processes. In the present conditioning study with experimental abdominal pain as unconditioned stimuli (US), we assessed sex-dependent differences in behavioral and neural responses to conditioned warning and safety cues in healthy volunteers. The results revealed that in response to visual stimuli signaling safety from abdominal pain (CS(-)), women showed enhanced cerebellar activation in lobules I IV, V, VI, VIIIa, IX and X as well as Crus II and the dentate nucleus, which are mostly representative of somatomotor networks. On the other hand, men showed enhanced neural activation in lobules I-IV, VI, VIIb, VIIIb, IX as well as Crus I and II in response to CS(-), which are representative of frontoparietal and ventral attention networks. No sex differences were observed in response to pain predictive warning signals (CS(+)). Similarly, men and women did not differ in behavioral measures of conditioning, including conditioned changes in CS valence and contingency awareness. Together, we could demonstrate that the cerebellum is involved in associative learning processes of conditioned anticipatory safety from pain and mediates sex differences in the underlying neural processes. Given the high prevalence of chronic pain conditions in women, these results may contribute to improve our understanding of the acquisition and manifestation of chronic abdominal pain syndromes. PMID- 26004679 TI - Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury. AB - Secondary death of neural cells plays a key role in the physiopathology and the functional consequences of traumatic spinal cord injury (SCI). Pharmacological manipulation of cell death pathways leading to the preservation of neural cells is acknowledged as a main therapeutic goal in SCI. In the present work, we hypothesize that administration of the neuroprotective cell-permeable compound ucf-101 will reduce neural cell death during the secondary damage of SCI, increasing tissue preservation and reducing the functional deficits. To test this hypothesis, we treated mice with ucf-101 during the first week after a moderate contusive SCI. Our results reveal that ucf-101 administration protects neural cells from the deleterious secondary mechanisms triggered by the trauma, reducing the extension of tissue damage and improving motor function recovery. Our studies also suggest that the effects of ucf-101 may be mediated through the inhibition of HtrA2/OMI and the concomitant increase of inhibitor of apoptosis protein XIAP, as well as the induction of ERK1/2 activation and/or expression. In vitro assays confirm the effects of ucf-101 on both pathways as well as on the reduction of caspase cascade activation and apoptotic cell death in a neuroblastoma cell line. These results suggest that ucf-101 can be a promising therapeutic tool for SCI that deserves more detailed analyses. PMID- 26004680 TI - EEG topography during sleep inertia upon awakening after a period of increased homeostatic sleep pressure. AB - OBJECTIVE: Behavioral and physiological indexes of high sleep inertia (SI) characterize the awakening from recovery (REC) sleep after prolonged wakefulness, but the associated electroencephalogram (EEG) topography has never been investigated. Here, we compare the EEG topography following the awakening from baseline (BSL) and REC sleep. METHODS: We have recorded the EEG waking activity of 26 healthy subjects immediately after the awakening from BSL sleep and from REC sleep following 40 h of prolonged wakefulness. In both BSL and REC conditions, 12 subjects were awakened from stage 2 sleep, and 14 subjects from rapid eye movement (REM) sleep. The full-scalp waking EEG (eyes closed) was recorded after all awakenings. RESULTS: Subjects awakened from REC sleep showed a reduction of fronto-central alpha and beta-1 activities, while no significant effects of the sleep stage of awakening have been observed. Positive correlations between pre- and post-awakening EEG modifications following REC sleep have been found in the posterior and lateral cortices in the frequency ranges from theta to beta-2 and (only for REM awakenings) extending to the fronto-central regions in the beta-1 band, and in the midline central and parietal derivations for the alpha and delta bands, respectively. CONCLUSIONS: These findings suggest that the higher SI after REC sleep may be due to the fronto-central decrease of alpha and beta-1 activity and to the persistence of the sleep EEG features after awakening in the posterior, lateral, and fronto-central cortices, without influences of the sleep stage of awakening. PMID- 26004681 TI - Catathrenia: respiratory disorder or parasomnia? AB - BACKGROUND: The International Classification of Sleep Disorders-Third Edition (ICSD-3) classifies catathrenia among the respiratory disorders and not as a parasomnia as in ICSD-2. Few patients have been reported during these years, and the clinical description of the sound is different from group to group. In fact, there is no full agreement about its nature, origin, meaning, and treatment. METHODS AND RESULTS: In this paper we review the literature on catathrenia focusing on the characteristics of the sound, demographics of the patients, aetiology, response to treatment, etc., in order to support its classification as a respiratory disorder or a parasomnia. We also discuss the possibility of Catathrenia being not one disorder but two variants or two different disorders. PMID- 26004682 TI - First-in-human cell transplant trials in Parkinson's disease: The need for an improved informed consent process. AB - First-in-human clinical trials of innovative medical procedures, such as cell transplantation for Parkinson's disease, present a variety of ethical challenges. In an era of rapidly developing stem cell technologies likely to be translated into clinical trials over the next few years, it is critical that ethical concerns be fully considered. One important undertaking is ensuring that research participants give free and truly informed consent. This will necessitate adequate disclosure of risks and benefits at a time when these are incompletely defined; ensuring understanding of a complex research protocol when there is significant possibility of therapeutic misconception; and careful determination of capacity for informed consent in patients with a neurodegenerative disorder that is known to affect cognition. Here we call attention to the ethical issues that researchers conducting these types of trials will face when trying to obtain a genuinely informed consent, and we suggest possible solutions. PMID- 26004683 TI - Neuroimaging correlates of cognitive impairment and dementia in Parkinson's disease. AB - There has been a gradual shift in the definition of Parkinson's disease, from a movement disorder to a neurodegenerative condition affecting multiple cognitive domains. Mild cognitive impairment (PD-MCI) is a frequent comorbidity in PD that is associated with progression to dementia (PDD) and debilitating consequences for patients and caregivers. At present, the pathophysiology underpinning cognitive impairment in PD is not established, although emerging evidence has suggested that multi-modal imaging biomarkers could be useful in the early diagnosis of PD-MCI and PDD, thereby identifying at-risk patients to enable treatment at the earliest stage possible. Structural MRI studies have revealed prominent grey matter atrophy and disruptions of white matter tracts in PDD, although findings in non-demented PD have been more variable. There is a need for further longitudinal studies to clarify the spatial and temporal progression of morphological changes in PD, as well as to assess their underlying involvement in the evolution of cognitive deficits. In this review, we discuss the aetiology and neuropsychological profiles of PD-MCI and PDD, summarize the putative imaging substrates in light of evidence from multi-modal neuroimaging studies, highlight limitations in the present literature, and suggest recommendations for future research. PMID- 26004685 TI - Comorbidity between anxiety disorders and recent-onset psychotic disorders. PMID- 26004684 TI - Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy. AB - The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a small-molecule Bcl2 BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer xenografts derived from cell lines and patient without significant normal tissue toxicity at effective doses. mTOR inhibition upregulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome. PMID- 26004686 TI - Metabolic syndrome in drug-naive and drug-free patients with schizophrenia and in their siblings. AB - OBJECTIVES: We tested the hypothesis that metabolic disturbances in people with schizophrenia exist as a part of the schizophrenic syndrome, even when the antipsychotic drug effect is eliminated. We aimed to determine the prevalence of metabolic syndrome among patients with schizophrenia who were antipsychotic drug naive or drug-free and their siblings for comparison with healthy controls. METHODS: One-hundred-two patients with schizophrenia (drug-naive or drug-free), 64 siblings and 70 age-matched healthy subjects were recruited for this case control study. Metabolic syndrome was assessed based on Adult Treatment Panel (ATP) III, adapted ATP III and International Diabetes Federation criteria. Student's t-tests, chi-squared tests, Kruskal-Wallis tests and Bonferroni corrections were used as appropriate. RESULTS: The diagnoses of metabolic syndrome and metabolic disturbances as a subsyndromal state were found to be significantly more frequent in patients and their siblings than in the controls. Low levels of high-density lipoprotein cholesterol and disturbances in blood pressure put the patient group at risk for metabolic syndrome even before they were exposed to antipsychotic drugs. CONCLUSIONS: Although antipsychotic drugs have consistently been related to disturbances of glucose and lipid metabolism in patients with schizophrenia, this study showed that patients with schizophrenia and their siblings are already at a high risk for metabolic syndrome independent of any antipsychotic effects. These individuals should be monitored regularly following a diagnosis of schizophrenia. PMID- 26004687 TI - Brown Norway rats, a putative schizophrenia model, show increased electroencephalographic activity at rest and decreased event-related potential amplitude, power, and coherence in the auditory sensory gating paradigm. AB - In recent schizophrenia clinical research, electroencephalographic (EEG) oscillatory activities induced by a sensory stimulus or behavioral tasks have gained considerable interest as functional and pathophysiological biomarkers. The Brown Norway (BN) rat is a putative schizophrenia model that shows naturally low sensorimotor gating and deficits in cognitive performance, although other phenotypes have not been studied. The present study aimed to investigate the neurophysiological features of BN rats, particularly EEG/event-related potential (ERP). EEG activity was recorded at rest and during the auditory sensory gating paradigm under an awake, freely moving condition. Frequency and ERP analysis were performed along with time-frequency analysis of evoked power and intertrial coherence. Compared with Wistar-Kyoto rats, a well-documented control line, BN rats showed increased EEG power at rest, particularly in the theta and gamma ranges. In ERP analysis, BN rats showed reduced N40-P20 amplitude but normal sensory gating. The rats also showed reduced evoked power and intertrial coherence against auditory stimuli. These results suggest that BN rats show features of EEG/ERP measures clinically relevant to schizophrenia and may provide additional opportunities for translational research. PMID- 26004688 TI - Genetic variants in long non-coding RNA MIAT contribute to risk of paranoid schizophrenia in a Chinese Han population. AB - The heritability of schizophrenia has been reported to be as high as ~80%, but the contribution of genetic variants identified to this heritability remains to be estimated. Long non-coding RNAs (LncRNAs) are involved in multiple processes critical to normal cellular function and dysfunction of lncRNA MIAT may contribute to the pathophysiology of schizophrenia. However, the genetic evidence of lncRNAs involved in schizophrenia has not been documented. Here, we conducted a two-stage association analysis on 8 tag SNPs that cover the whole MIAT locus in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Shanxi Province: 1093 patients with paranoid schizophrenia and 1180 control subjects; replication cohort from Jilin Province: 1255 cases and 1209 healthy controls). In discovery stage, significant genetic association with paranoid schizophrenia was observed for rs1894720 (chi(2)=74.20, P=7.1E-18), of which minor allele (T) had an OR of 1.70 (95% CI=1.50-1.91). This association was confirmed in the replication cohort (chi(2)=22.66, P=1.9E-06, OR=1.32, 95%CI 1.18 1.49). Besides, a weak genotypic association was detected for rs4274 (chi(2)=4.96, df=2, P=0.03); the AA carriers showed increased disease risk (OR=1.30, 95%CI=1.03-1.64). No significant association was found between any haplotype and paranoid schizophrenia. The present studies showed that lncRNA MIAT was a novel susceptibility gene for paranoid schizophrenia in the Chinese Han population. Considering that most lncRNAs locate in non-coding regions, our result may explain why most susceptibility loci for schizophrenia identified by genome wide association studies were out of coding regions. PMID- 26004689 TI - Cytokines in schizophrenia: methodological issues. PMID- 26004690 TI - Dysfunctional glycosynapses in schizophrenia: disease and regional specificity. AB - BACKGROUND: Our previous lipidomics studies demonstrated elevated sulfatides, plasmalogens, and N-acylphosphatidylserines in the frontal cortex of schizophrenia subjects. These data suggest that there may be an abnormal function of glycosynapses in schizophrenia. We further examined the disease and anatomical specificity of these observations. METHODS: We undertook a targeted lipidomics analysis of plasmalogens, sulfatides, and N-acyl-phosphatidylserines in the frontal cortex obtained from schizophrenia, bipolar, and ALS subjects and the cerebellum of schizophrenia subjects. RESULTS: We demonstrate that sulfatides, plasmalogens, and N-acyl-phosphatidylserines are significantly elevated in the frontal cortex of patients suffering from schizophrenia and bipolar depression but not in ALS patients. These lipids were unchanged in the cerebellum of subjects with schizophrenia. CONCLUSIONS: Our data suggest that dysfunction of oligodendrocyte glycosynapses may be specific to limbic circuits in schizophrenia and that this dysfunction is also detected in bipolar depression, suggesting that these disorders possess several common pathophysiological features. PMID- 26004691 TI - Specificity and sensitivity of visual evoked potentials in the diagnosis of schizophrenia: rethinking VEPs. AB - Alterations of the visual evoked potential (VEP) component P1 at the occipital region represent the most extended functional references of early visual dysfunctions in schizophrenia (SZ). However, P1 deficits are not reliable enough to be accepted as standard susceptibility markers for use in clinical psychiatry. We have previously reported a novel approach combining a standard checkerboard pattern-reversal stimulus, spectral resolution VEP, source detection techniques and statistical procedures which allowed the correct classification of all patients as SZ compared to controls. Here, we applied the same statistical approach but to a single surface VEP - in contrast to the complex EEG source analyses in our previous report. P1 and N1 amplitude differences among spectral resolution VEPs from a POz-F3 bipolar montage were computed for each component. The resulting F-values were then Z-transformed. Individual comparisons of each component of P1 and N1 showed that in 72% of patients, their individual Z-score deviated from the normal distribution of controls for at least one of the two components. Crossvalidation against the distribution in the SZ-group improved the detection rate to 93%. In all, six patients were misclassified. Clinical validation yielded striking positive (78.13%) and negative (92.69%) predictive values. The here presented procedure offers a potential clinical screening method for increased susceptibility to SZ which should then be followed by high density electrode array and source detection analyses. The most important aspect of this work is represented by the fact that this diagnostic technique is low-cost and involves equipment that is feasible to use in typical community clinics. PMID- 26004692 TI - Cognitive insight in first-episode schizophrenia: further evidence for a role of the ventrolateral prefrontal cortex. AB - In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self Reflectiveness in FES. PMID- 26004693 TI - Examination of the validity of the Brief Neurocognitive Assessment (BNA) for schizophrenia. AB - BACKGROUND: Although many comprehensive batteries exist to evaluate the nature and degree of cognitive impairments in patients with schizophrenia, short batteries hold promise for rapidly screening and estimating deficits in global cognition. Recently, the Brief Neurocognitive Assessment (BNA) was established and has been shown to have similar validity and utility to a more comprehensive battery of cognitive tests in evaluating global cognitive impairments in patients with schizophrenia. The present study sought to further establish the validity of the BNA by comparing it with the MATRICS Consensus Cognitive Battery (MCCB). METHODS: One-hundred seventy-six patients with schizophrenia and 300 healthy volunteers participated in the present study. Global cognition was evaluated using the MCCB composite score and estimated using the BNA. To examine practice effects and test-retest reliability, patients were re-assessed after 4weeks. RESULTS: The BNA was highly correlated with global cognition as evaluated by the MCCB in both the schizophrenia (r=0.82) and healthy control samples (r=0.75). Both instruments were similarly sensitive to deficits in global cognition in patients with schizophrenia relative to healthy controls. The BNA also demonstrated high test-retest reliability in patients with schizophrenia (r=0.87), comparable to the level observed with the MCCB (r=0.91). In addition, both the BNA and MCCB showed a similar level of practice effects (both Cohen's d=0.11), and both instruments demonstrated equivalent sensitivities to longitudinal change. Furthermore, scores from the BNA and MCCB were related to symptom severity and functional capacity to a similar degree. CONCLUSIONS: The BNA provides clinicians and researchers with an efficient and reliable means by which to evaluate global neurocognitive impairments in patients with schizophrenia by allowing estimation of performance on a more comprehensive standardized battery. PMID- 26004694 TI - Reduced maternal levels of common viruses during pregnancy predict offspring psychosis: potential role of enhanced maternal immune activity? AB - Viral infections during the prenatal or early childhood periods are one of the environmental factors which might play an etiological role in psychoses. Several studies report higher antibody levels against viruses during pregnancy in blood of mothers of offspring with psychotic disorders, but the presence of such viruses has never been demonstrated. The goal of this study was to investigate the potential association between viral infections during pregnancy and progeny with psychotic disorders and, for this purpose, we performed a nested case control study involving pregnant mothers of offspring with schizophrenia or bipolar disorder with psychotic features (cases, N=43) and pregnant women with healthy offspring (controls, N=95). Since several potential viral candidates have been suggested in prior work, a broad-spectrum virus detection system was necessary. A metagenomic analysis performed with the virus discovery method VIDISCA-454 revealed only common blood-associated viruses in all cohorts. However, a significantly lower viral prevalence was detected in the group of cases and in the sub-population of pregnant mothers of offspring with schizophrenia (p<0.05). Consistent with the existing inverse correlation between the level of these viruses and the immunocompetence of an individual, we hypothesized the presence of a higher immune activity during pregnancy in mothers whose offspring later develop a psychotic disorder as compared to controls. Combining our results with previously available literature data on antibody levels during the gestation period suggests that a more prominent maternal immune activity can be considered a risk factor for developing psychosis. PMID- 26004695 TI - Preliminary investigation into sources of uncertainty in quantitative imaging features. AB - Several recent studies have demonstrated the potential for quantitative imaging features to classify non-small cell lung cancer (NSCLC) patients as high or low risk. However applying the results from one institution to another has been difficult because of the variations in imaging techniques and feature measurement. Our study was designed to determine the effect of some of these sources of uncertainty on image features extracted from computed tomography (CT) images of non-small cell lung cancer (NSCLC) tumors. CT images from 20 NSCLC patients were obtained for investigating the impact of four sources of uncertainty: Two region of interest (ROI) selection conditions (breathing phase and single-slice vs. whole volume) and two imaging protocol parameters (peak tube voltage and current). Texture values did not vary substantially with the choice of breathing phase; however, almost half (12 out of 28) of the measured textures did change significantly when measured from the average images compared to the end-of-exhale phase. Of the 28 features, 8 showed a significant variation when measured from the largest cross sectional slice compared to the entire tumor, but 14 were correlated to the entire tumor value. While simulating a decrease in tube voltage had a negligible impact on texture features, simulating a decrease in mA resulted in significant changes for 13 of the 23 texture values. Our results suggest that substantial variation exists when textures are measured under different conditions, and thus the development of a texture analysis standard would be beneficial for comparing features between patients and institutions. PMID- 26004696 TI - Is Only Stabilization the Ideal Treatment for Ossified Posterior Longitudinal Ligament? Report of Early Results with a Preliminary Experience in 14 Patients. AB - BACKGROUND AND OBJECTIVE: Surgical treatment of ossified posterior longitudinal ligament (OPLL) continues to be wrought with confusion, debate, and arguments. We report our experience with an alternative form of treatment that involves only fixation of the involved spinal segments. We report and put on record our remarkably gratifying clinical experience in 13 of 14 patients having OPLL after surgery that involved only facetal fixation and aimed at arthrodesis of involved spinal segments. No direct bone, ligament, or disc resection was done for decompression of the spinal dural tube or root canal. The OPLL was not directly handled during the surgical procedure. The rationale of the proposed treatment is discussed. METHODS: During the period June 2012 to August 2014, 14 patients having OPLL were treated by facetal transarticular screw fixation technique. The Japanese Orthopaedic Association score, visual analogue scale, and Odom's criteria were used as indices to monitor the clinical status. RESULTS: The procedure resulted in firm stabilization and fixation of the spinal segments and provided a ground for arthrodesis. During an average follow-up period of 17 months, there was immediate postoperative and progressive recovery in symptoms in 13 patients. There were no surgery or implant-related mechanical or infective complications. CONCLUSIONS: Instability could be the defining phenomenon in pathogenesis of clinical symptoms related to OPLL. The clinical outcome in our patients suggests that only fixation of the spinal segments can be a simple, safe, and rationale form of treatment for the complex pathology of OPLL. PMID- 26004697 TI - Predicting Outcomes After Glioma Surgery: Model Behavior. PMID- 26004698 TI - Multicentric Low-Grade Gliomas. AB - BACKGROUND: Multicentric low-grade gliomas are rare entities that occur in disparate regions of the brain. They can present with distinct pathologic and imaging findings and may harbor a worse prognosis. We present a case of multicentric low-grade gliomas and highlight their pathogenesis, imaging characteristics, and molecular signatures, with implications for clinical management. CASE: A 49-year-old man presented with left-sided headaches for 3 months. Magnetic resonance imaging revealed concurrent non-enhancing lesions in the left medial temporal lobe and superior cerebellum. Increased size and the development of contrast enhancement in the temporal lesion promoted a left temporal craniotomy. Pathology revealing a grade II ganglioglioma. Three months later, the cerebellar lesion also acquired new contrast enhancement and was found to be a grade II astrocytoma following a supracerebellar infratentorial approach for resection. At 2 years follow-up, the patient remains clinically stable, receiving adjuvant chemotherapy for new non-enhancing, unresectable pontine lesion. CONCLUSION: Tumor growth rate, detailed pathologic findings, imaging characteristics, and molecular signatures influence the clinical course of multicentric low-grade gliomas. PDGFRA amplifications and IDH1 wild-type status may act in a concerted fashion to produce an accelerated course of radiologic changes and tumor recurrence, as noted in our case. Additional research is needed to stratify the risk of transformation in patients with multicentric low-grade glioma and to guide management strategies. PMID- 26004699 TI - Cohort Study on the Association Between Helmet Use and Traumatic Brain Injury in Snowboarders From a Swiss Tertiary Trauma Center. AB - BACKGROUND: Since the introduction of helmets in winter sports there is on-going debate on whether they decrease traumatic brain injuries (TBI). METHODS: This cohort study included 117 adult (>= 16 years) snowboarders with TBI admitted to a level I alpine trauma center in Switzerland between 2000/2001 and 2010/2011. The primary objective was to examine the association between helmet use and moderate to-severe TBI. Secondary objectives were to describe the epidemiology of TBI during the past decade in relation to increased helmet use. RESULTS: Of 691 injured snowboarders evaluated, 117 (17%) suffered TBI. Sixty-six percent were men (median age, 23 years). Two percent of accidents were fatal. Ninety-two percent of patients sustained minor, 1% moderate, and 7% severe TBI according to the Glasgow coma scale. Pathologic computed tomography findings were present in 16% of patients, 26% of which required surgery. Eighty-three percent of TBIs occurred while riding on-slope. There was no trend in the TBI rate during the studied period, although helmet use increased from 10% to 69%. Comparing patients with and without a helmet showed no significant difference in odds ratios for the severity of TBI. However, of the 5 patients requiring surgery only 1 was wearing a helmet. Off-piste compared with on-slope snowboarders showed an odds ratio of 26.5 (P = 0.003) for sustaining a moderate-to-severe TBI. CONCLUSIONS: Despite increased helmet use we found no decrease in TBI among snowboarders. The possibility of TBI despite helmet use and the dangers of riding off-piste should be a focus of future prevention programs. PMID- 26004700 TI - Patient Age, Hemorrhage Patterns, and Outcomes of Arteriovenous Malformation. AB - BACKGROUND: The angioarchitecture and presentation of arteriovenous malformations (AVMs) associated with AVM hemorrhage may vary with patient age. Our aim was to determine the influence of patient age at diagnosis on hemorrhage patterns and outcomes. METHODS: A consecutive case series of 267 cases of ruptured AVMs was retrospectively analyzed. Hemorrhage patterns (intracerebral hemorrhage, subarachnoid hemorrhage, and intraventricular hemorrhage) were confirmed based on computed tomography imaging at initial diagnosis. Clinical outcomes were classified with a modified Rankin Score. These cases were analyzed with respect to age at diagnosis, hemorrhage patterns, Spetzler-Martin grades, and their clinical outcomes. RESULTS: During a mean 22.2 months follow-up time (range, 7 hours to 10 years), 212 cases (79.4%) were favorable (modified Rankin Score <=2) and 55 cases (21.6%) were unfavorable (modified Rankin Score >=3). The mean age was higher in patients with an unfavorable outcome at follow-up. In univariate analyses, different age groups were significantly associated with bleeding patterns (P = 0.022). Unfavorable outcome was associated with intracerebral hemorrhage (odds ratio, 0.330; 95% confidence interval, 0.142-0.768; P = 0.008) and evacuation of hematoma (odds ratio, 0.195; 95% confidence interval, 0.044 0.867; P = 0.025), whereas intraventricular hemorrhage, subarachnoid hemorrhage, and intraventricular drainage were significantly associated with a favorable outcome. Different age groups were not significantly associated with bleeding patterns, sex, and the location of the AVM, and Spetzler-Martin grades did not show a significant association with the severity of outcomes. CONCLUSIONS: Different age groups were significantly associated with bleeding patterns. Higher patient age, intracerebral hemorrhage, and evacuation of hematoma seem to be associated with an unfavorable outcome after AVM rupture. PMID- 26004701 TI - Reducing seed dependent variability of non-uniformly sampled multidimensional NMR data. AB - The application of NMR spectroscopy to study the structure, dynamics and function of macromolecules requires the acquisition of several multidimensional spectra. The one-dimensional NMR time-response from the spectrometer is extended to additional dimensions by introducing incremented delays in the experiment that cause oscillation of the signal along "indirect" dimensions. For a given dimension the delay is incremented at twice the rate of the maximum frequency (Nyquist rate). To achieve high-resolution requires acquisition of long data records sampled at the Nyquist rate. This is typically a prohibitive step due to time constraints, resulting in sub-optimal data records to the detriment of subsequent analyses. The multidimensional NMR spectrum itself is typically sparse, and it has been shown that in such cases it is possible to use non Fourier methods to reconstruct a high-resolution multidimensional spectrum from a random subset of non-uniformly sampled (NUS) data. For a given acquisition time, NUS has the potential to improve the sensitivity and resolution of a multidimensional spectrum, compared to traditional uniform sampling. The improvements in sensitivity and/or resolution achieved by NUS are heavily dependent on the distribution of points in the random subset acquired. Typically, random points are selected from a probability density function (PDF) weighted according to the NMR signal envelope. In extreme cases as little as 1% of the data is subsampled. The heavy under-sampling can result in poor reproducibility, i.e. when two experiments are carried out where the same number of random samples is selected from the same PDF but using different random seeds. Here, a jittered sampling approach is introduced that is shown to improve random seed dependent reproducibility of multidimensional spectra generated from NUS data, compared to commonly applied NUS methods. It is shown that this is achieved due to the low variability of the inherent sensitivity of the random subset chosen from a given PDF. Finally, it is demonstrated that metrics used to find optimal NUS distributions are heavily dependent on the inherent sensitivity of the random subset, and such optimisation is therefore less critical when using the proposed sampling scheme. PMID- 26004702 TI - In vitro bactericidal activity of cefepime and cefpirome against clinical isolates at Karachi. AB - Antibiotics not only support to alleviate the infections but also facilitate to avert the multiplication of microbes. Due to the irrational use of antibiotics, the resistance of antibiotics has been augmented which results may increase in morbidity and mortality with the span of time. World renowned regulatory bodies like Food and Drug Administration (FDA), Center of Disease Control and Prevention (CDC), and World Health Organization (WHO) vigorously advocate the surveillance of the resistance of antibiotics. During the present study by Kirby-Bauer disk diffusion method 141 clinical isolates of Staphylococcus aureus (n=47, 33.34%), Escherichia coli (n=54, 38.3%), Proteus species (n=26, 18.4%), and Klebsiella pneumoniae (n=14, 9.92%) are evaluated against cefepime and cefpirome which comes of fourth generation cephalosporin. It has been found that cefpirome has better bactericidal activity than cefepime against E. coli and K. pneumoniae while cefepime has been possessed better antibacterial activity against S. aureus and Proteus species which were isolated from respiratory tract infections, blood stream infection, intra-abdominal and urinary tract infections, and skin and soft tissue infections. K. pneumoniae, E. coli, Proteus species, and S. aureus were 34.8%, 26.3%, 11.3%, and 37.7% resistance against cefepime respectively. S. aureus, E. coli, K. pneumoniae, Proteus species has shown 41.4%, 21.7%, 17.6%, and 8.9% resistance against cefpirome correspondingly. PMID- 26004703 TI - Statistical study of the risk factors of myocardial infarction in the patients of district Muzaffarabad capital of Azad Jammu and Kashmir. AB - Coronary artery disease (CAD) is a leading cause of mortality in the developing countries. The aim of the study was to check the association of Myocardial infarction (MI) with several factors such as smoking & smoking exposure, blood pressure, sugar & cholesterol level, stress, anxiety & lifestyle. A cross sectional community based survey was conducted involving 469 patients having one or more risk factors or having complains regarding MI & already diagnosed MI, was taken using Multistage sampling technique from Sheikh Zaid Hospital & Abbas Institute of Medical Sciences. The Chi-square test was used to check the association of different risk factors with myocardial infarction. The multivariate Logistic regression model was also applied to find out the most significant risk factors of MI. The results revealed that MI was strongly associated with following risk factors family size (p=0.04), profession of respondent (p=0.026), smoking (p=0.028) & smoking exposure (p=0.043). The finding also showed significant association of MI in study population with diastolic blood pressure (p=0.03), cholesterol (p=0.047), blood sugar (p=0.008), stress (p=0.036), anxiety (p=0.044) and lifestyle (p=0.015). The study revealed that family size, family history, smoking & its smoking exposure, cholesterol, blood sugar, diastolic blood pressure, stress and anxiety are the major contributing risk factors of MI in the community, whereas age and gender elucidated minor contributions in the development of MI. PMID- 26004704 TI - Inhibitory effect of Aristolochia fruit on Cytochrome P450 isozymes in vitro and in vivo. AB - The mature fruits of Aristolochia debilis, known in China by the name, "Madouling" has been popularly prescribed in Asia, particularly in China, to treat a range of conditions including gynaecological problems, arthritis and wound healing. This study was aimed to evaluate the potential effect of Madouling on the cytochrome P450 (CYP) isozymes in vitro in microsomal fractions and in vivo in rats. The influence of Madouling on CYPs activity was first explored by an in vitro method of estimating levels of four respective metabolites in rat liver microsomes. The results were re-examined in vivo in rats by using a cocktail approach involving the probe drugs theophylline, tolbutamide, chlorzoxazone and dapsone. Pharmacokinetics of the four substrates was used to analyze the activities of the targeting isozymes. In vitro study revealed that Madouling decreased the activity of CYP1A2, 3A1 and 2E1. However, no significant influence on CYP2C6 was found. These results coincided with those of in vivo study to a great degree except that in vivo estimation the herb didn't inhibit CYP1A2 significantly. From the data obtained, Madouling is suggested as a candidate for clinically significant CYP interactions. Drug co-administrated with Madouling may need dose adjustment. PMID- 26004705 TI - Antimicrobial, antitumor and brine shrimp lethality assay of Ranunculus arvensis L. extracts. AB - To investigate the antitumor activity, brine shrimp lethality assay, antibacterial and antifungal activity of Methanol Extract (ME), Water Extract (WE), Acetone Extract (AE), Chloroform Extract (CE), Methanol-Water Extract (MWE), Methanol-Acetone Extract (MAE), Methanol-Chloroform Extract (MCE) of Ranunculus arvensis (L.). Antitumor activity was evaluated with Agrobacterium tumefaciens (At10) induced potato disc assay. Cytotoxicity was evaluated with brine shrimp lethality assay. Antibacterial activity was evaluated with six bacterial strains including Escherichia coli, Enterobacter aerogenes, Bordetella bronchiseptica, Klebsiella pneumoniae, Micrococcus luteus and Streptococcus anginosus and antifungal screening was done against five fungal strains including Aspergillus niger, A. flavus, A. fumigates, Fusarium solani and Mucor species by using disc diffusion method. Best antitumor activity was obtained with ME and WE, having highest IC50 values 20.27 +/- 1.62 and 93.01 +/- 1.33MUg/disc. Brine shrimp lethality assay showed LC50 values of AE, MAE and ME were obtained as 384.66 +/- 9.42MUg/ml, 724.11 +/- 8.01MUg/ml and 978.7 +/-8.01 MUg/ml respectively. WE of R. arvensis revealed weak antimicrobial result against the tested microorganisms. On the other hand, the antifungal activity of the plant extracts was found to be insignificant. These findings demonstrate that extracts of R. arvensis possesses significant antitumor activity. Further extensive study is necessary to assess the therapeutic potential of the plant. PMID- 26004706 TI - Hepatoprotective activity of hepatoplus on isonaizid and rifampicin induced hepatotoxicity in rats. AB - Present study deals with the hepatoprotective activity of polyherbal formulation Hepatoplus (HP) as an oral supplement to the INH and RIF induced hepatitis in experimental rats. Rats treated with INH and RIF show abnormal liver function with significant increase in serum transaminases, bilirubin and clotting time (CT) and significant decrease in total protein and Albumin, which is brings to near normal levels by HP and LIV 52 treatments. Rats treated with INH and RIF suffer from oxidative stress in the hepatocytes, due to the decrease in Glutathione (GSH), Glutathione peroxidase (GPX), Catalase (CAT), Super oxide dismutase (SOD) and significant increase in Lipid Per oxidation (LPO). HP decreases the oxidative stress and protects the liver cells membrane from LPO. 85% of DNA damage (comet tail) seen with RIF and INH treatment is reduced to 34.1% on HP application. A decrease of hepatocytes mitochondrial dehydrogenase activity is observed in INH and RIF treatment is restored by HP supplementation. Hepatic apoptotic and CYP2E1 gene expressions were also studied, BAX, p53, Caspase 3 and CYP2E1 were significantly up regulated and Bcl2 was down- regulated in INH and RIF treated rats. Concomitant application of HP prevents the modulation of these gene expressions. It is concluded that high dose of HP (100mg/kg) supplemented along with INH and RIF effectively prevents the toxicity induced by INH and RIF, as effective as 100mg/kg of LIV52. PMID- 26004707 TI - Report-The fatty acid composition and physicochemical properties of the underutilised Cassia abbreviata seed oil. AB - The fatty acid composition of the underutilised Cassia abbreviata seed oil was determined using gas chromatographic methods. C. abbreviata seeds yielded 9.53% of yellowish-green oil consisting mainly of oleic acid (37.8%), palmitic acid (26.5%), linoleic acid (26.7%), stearic acid (4.1%) and elaidic acid (2.1%). The oil was solid at room temperature, had a saponification value of 376.16 mg KOH/g and an iodine value of 26.48 g I2/100g oil. The fatty acid composition and saponification value of the C. abbreviata seed oil suggest that it may find application in both cosmetic and pharmaceutical natural product formulations. PMID- 26004708 TI - Review-An overview of Pistacia integerrima a medicinal plant species: Ethnobotany, biological activities and phytochemistry. AB - Pistacia integerrima with a common name crab's claw is an ethnobotanically important tree native to Asia. Traditionally plant parts particularly its galls have been utilized for treatment of cough, asthma, dysentery, liver disorders and for snake bite. Plant mainly contains alkaloids, flavonoids, tannins, saponins and sterols in different parts including leaf, stem, bark, galls and fruit. A number of terpenoids, sterols and phenolic compounds have been isolated from Pistacia integerrima extracts. Plant has many biological activities including anti-microbial, antioxidant, analgesic, cytotoxicity and phytotoxicity due to its chemical constituents. This review covers its traditional ethnomedicinal uses along with progresses in biological and phytochemical evaluation of this medicinally important plant species and aims to serve as foundation for further exploration and utilization. PMID- 26004709 TI - Review-Vitamin D and the prevention of preeclampsia: A systematic review. AB - To identify the effect of Vitamin D in reducing the risk of preeclampsia in pregnant women. The review was conducted from December 2011 to March 2012 at the University of Sheffield. Studies were included from the Medline data base, Web of Science (Web of Knowledge), Ovid database and Google Scholar. Studies were limited to published literature only; published between January 1992 to March 2012. A total of seven studies were selected for this review based on the inclusion criteria. One was non-randomized clinical trial, three were cohort studies and three were nested case-control studies. The clinical trial showed a positive association between Vitamin D supplements and the reduction of preeclampsia risk in pregnant women. In addition, one large cohort and two nested case-control studies also showed a protective effect of vitamin D in preventing the risk of preeclampsia. However, the other two cohort studies and a nested case control study could not find any association between vitamin D levels and the risk of preeclampsia in pregnant women. The studies included in this review show conflicting results about the association of vitamin D levels and the risk of preeclampsia. However, in this review more than half of the studies showed a positive link between Vitamin D deficiencies and Preeclampsia. There is a clear need for further trials and other robust studies to identify the effect of Vitamin D on preeclampsia. PMID- 26004710 TI - Review-Epigenetic therapy for cancer. AB - Epigenetics means the study of alterations in the genetic material that affect the phenotype but does not affect the genotype. Epigenetics cause alterations in cell properties, which are inherited; but it does not cause alterations in DNA sequence. Epigenetic mediated silencing of gene is of four types, which are DNA methylation, histone deacetylation, RNA associated silencing and Genomic imprinting. Other factors (environmental and xenobiotics) can also cause gene silencing but DNA methytlation and changes in histones of chromatin are two important changes, which are responsible for malignant diseases. Two groups of drugs are under development, which corrects the epigenetic alterations. These are histone deacetylation (HDAC) inhibitors and DNA methytransferase (DNMT) inhibitors. These drugs may be used in cancer because in cancer, hypermethylation of cancer suppressor gene causes gene silencing. Epigenetic therapy scope is likely to increase in future. PMID- 26004711 TI - Review-Factors involving in fluctuation of trace metals concentrations in bovine milk. AB - Milk makes a significant contribution to human diet through provision of macronutrients, vitamins and minerals. The exact composition of milk varies with species among domestic animals according to their neonatal needs. It is recognized that imbalance in the quantity of minerals and trace elements is a serious health hazard especially for infants. Many studies reported the fluctuation in the level of metals in milk due to the influence of several factors such as geographical and exposure to environmental pollution caused by anthropogenic activity. Amongst all sources, industries take lion's share to alter the metal content in milk. The importance of different nutritional and toxic metals in milk from different geographical areas is discussed. PMID- 26004712 TI - Pharmacokinetic and imaging evaluation of (99m)Tc-HBIDP as a potential bone imaging agent. AB - Developing novel superior bone-seeking radiopharmaceutical for the detection of malignant bone lesions could further improve the diagnostic value of routine bone scanning and shorten the interval between injection and imaging. In order to further evaluate the bone imaging efficiency of (99m)Tc-HBIDP (1-hydroxy-2-(1 butyl-imidazol-2-yl)-ethane-1,1-diphosphonic acid), the pharmacokinetic in mice and single photon emission computed tomography (SPECT) bone scanning in rabbit for (99m)Tc-HBIDP was investigated. Kinetics of blood clearance showed that the distribution half-life (T(1/2a)) and elimination half-life (T(1/2 beta)) of (99m)Tc-HBIDP are 2.73 and 24.87 min, respectively. Excellent bone images can be obtained at 1 h post injection with SPECT bone scanning, which is clearer and quicker than (99m)Tc-ZL (zoledronate) and (99m)Tc-MDP (methylenediphosphonate). All results indicate that (99m)Tc-HBIDP holds great potential as a novel improved bone imaging agent. PMID- 26004713 TI - Potential antibacterial activity of coumarin and coumarin-3-acetic acid derivatives. AB - Coumarin and coumarin-3-acetic acid derivatives were synthesized by reacting phenols with malic acid, ethyl acetoacetate and ethyl acetylsuccinate in appropriate reaction conditions. All synthesized compounds were subjected to test for their antimicrobial activities against variety of gram positive (Bacillus subtilis, Staphylococcus aureus) and gram negative bacterial stains (Shigella sonnei, Escherichia coli) by agar dilution method. Several of them exhibited appreciable good antibacterial activity against the different strains of gram positive and gram negative bacteria. These findings suggest a great potential of these compounds for screening and use as antibacterial agents for further studies with a battery of bacteria. PMID- 26004714 TI - Sensitive, resistant and multi-drug resistant Acinetobacter baumanii at Saudi Arabia hospital eastern region. AB - Since the Physicians start use of antibiotics long ago with un-notice drug resistance. However actual problem was recognized about 85 years ago. Antibiotic resistant and Multi-drug resistant bacterial strains are at rise throughout the world. It is physicians and researchers to take scientific research based appropriate action to overcome this ever-spreading problem. This study is designed to find out sensitive (S), resistant (R) and multi-drug resistant (MDR) Acinetobacter baumanii strain along with other isolates in the resident patients of Eastern Region of Saudi Arabia. Pseudomonas aeruginosa is excluded from other gram-negative organisms isolated from different sites as it will be dealt separately. This study is based in was retrospective observations designed to collect data of different stains of Acinetobacter baumanii with reference to their Sensitivity (S), Resistance (R), Multi-Drug Resistance (MDR) along with other Gram negative isolated from different sites (from 1st January 2004 to 31st December 2011) at King Abdulaziz Hospital located Eastern Region of Kingdom of Saudi Arabia (KSA). All necessary techniques were used to culture and perform sensitivity of these isolates. There were 4532 isolates out of which 3018 (67%) were from patients. Out of Acinetobacter baumanii infected were 906 (20%) while other 3626 (80%) isolates were miscellaneous. Numbers of patients or cases were 480 (53%) out of 906 isolates and numbers of patients or cases in other organisms were 2538 (70%) out of 3626 isolates. Acinetobacter baumanii infected patients 221 (46%) were male and 259 (54%) were female and the male and female ratio of 1:1.2. In other organisms this male female ratio was almost same. There was steady rise in number of patients and the hence the isolates from 2004 to 2011. Majority of the bacterial strains were isolated as single organism but some were isolated as double or triple or quadruple or more organisms from different sites. Sensitive, Resistant and Multi-Drug Resistant Acinetobacter baumanii have been isolated from different sites. The other Gram negative isolates included Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Klebsiella oxytoca, Serratia marcescens and Stenotrophomonas maltophilia. A significant rise in R and MDR but there is rise in R and MDR Acinetobacter baumanii Strains has been interceded other isolates. It is important to adopt proper and sustainable policies and guideline regarding antibiotics prescription and used. We should also check our infection control practices in our hospital or healthcare settings. We should start antibiotics stewardship in our hospital in order to reducing or overcoming antibiotics Resistant (R) and Multi-Drug Resistant (MDR) strains prevalence. PMID- 26004715 TI - Antimicrobial potentials of Catharanthus roseus by disc diffusion assay. AB - The present research work investigates the in vitro antimicrobial activity of different solvent extracted samples from the aerial parts (stem, leaf, fruit and flower) of C. roseus against different microbial species using disc diffusion assay at two different concentrations of 1 and 2 mg disc-1. Hexane extracted samples inhibited the growth of all tested microbial strains except S. typhi. Similarly, ethyl acetate extracted samples was effective to control the activity of all the tested microbial strains. E. coli and S. typhi showed resistance to chloroform extracted samples and the remaining eight microbial strains were susceptible to the same extract. Butanol extracted samples did not inhibit the growth of K. pneumonia and S. typhi at low concentration, however, at higher concentration the same extract reduced the growth of different microbes. Methanol extracted samples effectively controlled the growth of all tested microbes at both concentrations except for S. typhi. Water extracted samples did not inhibit the growth at low concentration except E. coli, K. pneumonia and S. aureus and were ineffective against P. aeroginosa at both concentration. C. albicans, showed resistance against chloroform and water extracted samples at low concentration and susceptible to other solvent extracted samples at both concentration. All fractions were effective against plant pathogens i.e. E. carotovora and A. tumefaciens. PMID- 26004716 TI - Evaluation of antimicrobial activity of extracts of in vivo and in vitro grown Vinca rosea L. (Catharanthus roseus) against pathogens. AB - The antimicrobial activity of Vinca rosea was evaluated against pathogenic bacterial strains (Bacillus subtilis, B. licheniformis and Azotobacter sp.) and fungal strains (Asprgillus niger, Alternaria solani and Rhizopus oryzae) using agar well diffusion method. Methanolic extracts of in vivo leaf, in vitro leaf, in vitro calluses of leaf, nodal and fruit explants were used and exhibited antimicrobial activity as indicated by minimum inhibitory concentration (MIC). In vitro extracts showed better results as compared to the in vivo extracts for both the antibacterial as well as the antifungal activity. Among all the extracts, maximum zone of inhibition (30.3 mm +/- 0.58(a)) was formed by in vitro leaf callus extract concentration of 2.0mg/ml against B. licheniformis. Similarly in case of antifungal activity, maximum zone of inhibition (34.6mm +/- 0.57(a)) was formed by in vitro leaf callus extract and MIC value is 6.0mg/ml against A. niger. Hence these results clearly depicts that V. rosea possess a great strength to fight against the microbial activity and can be used against various infections. PMID- 26004717 TI - Formulation of bi-layer matrix tablets of tramadol hydrochloride: Comparison of rate retarding ability of the incorporated hydrophilic polymers. AB - Bi-layer tablets of tramadol hydrochloride were prepared by direct compression technique. Each tablet contains an instant release layer with a sustained release layer. The instant release layer was found to release the initial dose immediately within minutes. The instant release layer was combined with sustained release matrix made of varying quantity of Methocel K4M, Methocel K15MCR and Carbomer 974P. Bi-layer tablets were evaluated for various physical tests including weight variation, thickness and diameter, hardness and percent friability. Drug release from bi-layer tablet was studied in acidic medium and buffer medium for two and six hours respectively. Sustained release of tramadol hydrochloride was observed with a controlled fashion that was characteristic to the type and extent of polymer used. % Drug release from eight-hour dissolution study was fitted with several kinetic models. Mean dissolution time (MDT) and fractional dissolution values (T25%, T50% and T80%) were also calculated as well, to compare the retarding ability of the polymers. Methocel K15MCR was found to be the most effective in rate retardation of freely water-soluble tramadol hydrochloride compared to Methocel K4M and Capbomer 974P, when incorporated at equal ratio in the formulation. PMID- 26004718 TI - Comparative clinical evaluation on herbal formulation Pepsil, Safoof-e-Katira and Omeprazole in gastro esophageal reflux disease. AB - This study was conducted to evaluate the role of Unani herbal drugs Pepsil and Safoof-e-katira on the gastro esophageal reflux disease (GERD). This was multicentre randomized case control study conducted at Matab Hakeem Muhammad Noor ud-din, Burewala; Aziz Muhammad din Medical and Surgical Centre, Burewala and Shifa-ul-mulk Memorial Hospital, Hamdard University Karachi. The patients were selected according to inclusion and exclusion criteria. In test group-1 the male female ratio was 40%, 60%; test group-2 was 42%, 58% and in control group was 44%, 56% respectively. The observed symptoms in the study were increased appetite (TG-1-95%, TG-2-95% and CG-89%), difficulty in swallowing (TG-1-93%, TG-2-96% and TC-94%), belching/burping (TG-1-97%, TG-2-97% and CG-95%), vomiting (TG-1-90%, TG 2-96% and CG-89%), heart burn (TG-1-100%, TG-2-100% and CG-98%), palpitation (TG 1-100%, TG-2-100% and CG-97%), epigastric pain (TG-1-97%, TG-2-97% and CG-90%), abdominal cramps (TG-1-97%, TG-2-98% and CG-95%), tenesmus (TG-1-100%, TG-2-100% and CG-97%), flatulence (TG-1-100%, TG-2-75% and CG-95%), wakeup during sleep (TG 1-94%, TG-2-87% and CG-94%). The p-value of the results of the symptoms was 0.000 except flatulence where the value was 0.001. The statistical results of the study prescribed that all the drugs studied (Pepsil, Safoof-e-katira and Omeprazole) are highly significant. The herbal coded drug Pepsil showed no side effects and unani herbal drug safoof-e-katira showed minimum result of 75% in the patients while Omeprazole resulted with some side effects. In the result it can be concluded that the herbal coded drug Pepsil is a potent herbal drug for gastro esophageal reflux disease. PMID- 26004719 TI - The hypolipidemic effect of artesunate and ursolic acid in rats. AB - To find the novel hypolipidemic agents, the effects of ursolic acid and artesunate on hyperlipidemia were determined in rats fed a Western-type diet developed a hyperlipidemia. Rats received ursolic acid (50 mg/kg) or artesunate (50 mg/kg) alone, or in combination (25 +/- 25 mg/kg and 50 +/- 50 mg/kg), to prevent hyperlipidemia. Ursolic acid or artesunate alone significantly decreased the plasma triglyceride, but had no effect on the levels of cholesterol. The combination of ursolic acid and artesunate can reduce both triglyceride and cholesterol, and the effects were more potent than either agent alone, which indicates a strong synergistic effect. The hypolipidemic effect of artesunate is firstly reported. Its combination with ursolic acid might have the potential to further develop for the treatment of hyperlipidemia. PMID- 26004720 TI - Improved limit of detection and quantitation development and validation procedure for quantification of zinc in Insulin by atomic absorption spectrometry. AB - A simple and expeditious analytical method for determination of zinc in human insulin isophane suspension by flame atomic absorption spectrophotometer (FAAS) was validated. The method was carried out on atomic absorption spectrometer with 0.4 nm bandwidth, 1.0 filter factor on deuterium (D2) background correction. The integration time was set at 3.0 second with 5.0 mA lamp current. The parameters of method validation showed adequate linearity, efficiency and relative standard deviation values were between 0.64%-1.69% (n=7), 1.31%-1.58% (n=10) for repeatability and intermediate precision respectively. The limit of detection 0.0032 MUg/mL, 0.0173 MUg/mL, 0.0231 MUg/mL and limit of quantitation 0.0107MUg/mL, 0.0578 MUg/mL, 0.0694 MUg/mL based on signal to noise (SN), calibration curve method (CCM) and fortification of blank (FB) were obtained respectively. The percentages of recovery for low, medium and high spiked concentration levels of zinc in human insulin were 99.38 +/- 0.04 to 100.3 +/- 0.03, 98.45 +/- 0.38 to 100.3 +/- 0.07 and 99.42 +/- 0.03 to 99.42 +/- 0.08 respectively. With the use of this method, five samples from each vial of human insulin isophane suspension were analyzed and the zinc content was determined. The zinc content were 22.1 +/- 0.025 MUg/mL and 24.3 +/- 0.028 MUg/mL which compliance the British Pharmacopoeia standard. PMID- 26004721 TI - Serum haematological and biochemical indices of oxidative stress and their relationship with DNA damage and homocysteine in Pakistani type II diabetic patients. AB - Diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by chronic hyperglycaemia, higher glycated hemoglobin (HbA1C) as well as protein. Oxidative stress can cause damage to leukocytic DNA and enhancement of homocysteine (Hcy) level in sera of type 2 diabetic patients. Haematological and biochemical parameters are severely affected by oxidative stress, which results in damages to DNA and Hcy in these patients. Eighty DM patients and 80 normal subjects, after having their consent, were selected for the present study. Leukocytes were characterized for DNA damage by comet assay kit while, blood plasma was taken into account for biochemical indices using commercial test kits. Results indicated that DNA damage was strongly linked with erythrocyte sedimentation rate (ESR) (P<0.01), glycated hemoglobin (HbA1C) (P<0.0001), glycated serum protein (P<0.005), cholesterol (P<0.011), triglycerides (P<0.001), albumin (P<0.001), creatinine (P<0.006), urea (P<0.007) and ALT (P<0.02), and negatively associated with packed cell volume (PCV) (P<0.002) and hemoglobin (P<0.001). Homocysteine was strongly linked with ESR, HbA1C, glycated protein (P<0.002), cholesterol (P<0.016), triglycerides (P<0.0001), albumin, creatinine, urea, ALT and AST in diabetic patients. Hyc and DNA damages both were negatively linked with total hemoglobin and PCV. Both of these even in their normal range may have a role in the endothelium damage. Nutritional intervention to lower down Hyc and DNA damages in the Pakistani population may mitigate their effect and guarantee in maintenance of a healthy nation. PMID- 26004722 TI - Effect of different doses of Manuka honey in experimentally induced mouse typhoid. AB - Typhoid fever is a major cause of morbidity and mortality in the developing world. Data from World Health Organization (WHO) shows that 21 million cases of typhoid occur globally every year and over 200,000 die each year; most of them at a very young age. The situation in Pakistan is similar. Typhi and other typhoidal salmonellae have developed resistance to chloramphenicol and other first line anti-typhoid. There is a rapid increase in multi-drug resistance (MDR) throughout the world. There is an urgent need to find out alternative medicine to sort out this problem. This study was conducted to establish preventive as well as therapeutic potential of Manuka honey. A total of eighty pathogen free BALB/C mice between 8 weeks to 12 weeks of age, weighing 25-30 grams were taken and divided into 4 groups. Group A, B and C were infected through oral route with 10(8) colony forming unit (CFU) of Salmonella typhimurium ATCC 14028 to produce typhoid like disease in mice. Group A, which comprised of 20 mice was further divided in A1 and A2 given Manuka honey at a dose of 15ml/kg and 20 ml/kg respectively. Group B, which comprised of 20 mice was further divided in B1 and B2 was given Manuka honey at dose of 20ml/kg and 25ml/kg respectively. Clinical features of mouse typhoid, like body temperature, respiratory rate, number of stools and general behavior were recorded twice daily. Blood cultures of mice in different groups were taken at different days to evaluate the establishment of infection as well as to observe the therapeutic and preventive potential of Manuka honey in mouse typhoid. Fisher's Exact, Chi- Square and t-test were used to analyze the data. Significant association was observed in the ultimate fate of mice in Group A1 and Group A2 (P<0.001), showing that from a total of 20 mice in both groups, 10 mice fall in Group A1 of which 10 (100%) developed infection as it was not prevented by honey at a dose of 15ml/kg body weight (15.00+/-0.00) in Group A1 and ten mice fall in Group A2 of which 10(100%) did not developed an infection as it was prevented by honey at a dose of 20ml/kg body weight (20.00+/ 0.00) in Group A2. Significant association was observed in the ultimate fate of mice in Group B1 and Group B2 (P<0.001) showing that from a total of 20 mice in both groups, 10 mice fall in Group B1 of which 10 (100%) had an infection, which was not treated by honey at a dose of 20 ml/kg body weight. Ten mice fall in Group B2 of which 10 (100%) had an infection, which was treated by honey at a dose of 25 ml/kg body weight (25.00+/-0.00). Results of the present study suggest that Manuka honey (UMF25+/-) has a potent anti-typhoid activity in vivo as well. There is an intense need for a carefully designed clinical trial in which this therapeutic potential of Manuka honey should be further evaluated. There is also need for the search of local honeys comparable to Manuka honey as a therapeutic option for typhoid fever. PMID- 26004723 TI - The investigation of inhibiting quorum sensing and methicillin-resistant Staphylococcus aureus biofilm formation from Liriodendron hybrid. AB - The quorum sensing (QS) of pathogens has been found to affect their biofilm forming ability, making it a potential target for anti-microbial therapy. The present research aimed to evaluate the anti-QS activities of different extracts and isolated phytochemicals from Liriodendron hybrid barks and their roles in the inhibition of the growth and biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA). The assays on the inhibition of QS by the five extracts (n-hexane, dichloromethane, ethyl acetate, acetone, and methanol) and eight isolated compounds were carried out by using both the indicator strains Chromobacrerium violaceum CV026 and C. violaceum ATCC12472. The in vitro effects of the five extracts and eight isolated compounds on MRSA biofilm were also preliminarily evaluated using crystal violet micro titer plate assays. The results suggested that the dichloromethane extract showed anti-QS and MRSA biofilm inhibitory activities and the n-hexane extract possessed only MRSA biofilm inhibitory effect. The dichloromethane extract could serve as a source for developing bacterial intervention strategies targeting microbial QS system. All eight isolated compounds showed no anti-QS and biofilm formation inhibiting activities. So further researches are still being required to purify and identify the compounds possessing anti-QS and biofilm inhibitory effects from the dichloromethane and n-hexane extracts. PMID- 26004724 TI - Comparative studies of binding potential of Prunus armeniaca and Prunus domestica gums in tablets formulations. AB - The current study was undertaken to compare the binding potential of Prunus armeniaca L. and Prunus domestica L. gums in tablets' formulations. Tablet batches (F-1 to F-9) were prepared Diclofenac sodium as model drug using 5%, 7.5% and 10% of each Prunus armeniaca L., Prunus domestica L. gums as binder. PVP K30 was used as a standard binder. Magnesium stearate was used as lubricant. Flow properties of granules (like bulk density, tapped density, Carr's index, Hausner's ratio, angle of repose) as well as the physical parameters of compressed tablets including hardness, friability, thickness and disintegration time were determined. Flow parameters of granules of all the batches were found good. Physical parameters (drug content, weight variation, thickness, hardness, friability, disintegration time) of formulated tablets were found within limit when tested. The dissolution studies showed that tablets formulations containing each Prunus domestica showed better binding capacity compared to Prunus armeniaca gum. The binding potential increased as the concentration of gums increased. The FTIR spectroscopic investigation showed that the formulations containing plant gum are compatible with the drug and other excipients used. PMID- 26004725 TI - Free radical scavenging, antidiarrheal and anthelmintic activity of Pistia stratiotes L. extracts and its phytochemical analysis. AB - In this phyto-pharmacological screening of Pistia stratiotes L leaf and root extracts each separately in two different solvents demonstrated its potential medicinal value. Apparent antioxidant value is demonstrated by DPPH, Nitric oxide scavenging and Ferric ion reducing method. Additionally, total flavonoid and phenolic compounds were measured. The leaf methanolic extract scavenged both nitric oxide (NO) and DPPH radical with a dose dependent manner. But the pet ether fraction of root was found to have highest efficacy in Fe(3+/-) reducing power assay. Flavonoid was found to contain highest in the pet ether fraction of root (411.35mg/g) in terms of quercetin equivalent, similarly highest amount (34.96mg/g) of total phenolic compounds (assayed as gallic acid equivalents) were found to contain in the same fraction. The methanolic fractions appeared less cytotoxic compared to pet ether extracts. The plant extracts caused a dose dependent decrease in faecal droppings in both castor oil and magnesium sulphate induced diarrhea, where as leaf extracts in each solvent appeared most effective. Also, the plant extracts showed anthelmintic activity in earthworm by inducing paralysis and death in a dose dependent manner. At highest doses (50 mg/ml) all fractions were almost effective as the positive control piperazine citrate (10 mg/ml). Thus, besides this cytotoxic effect it's traditional claim for therapeutic use can never be overlooked. PMID- 26004726 TI - Effectiveness and safety of a 10mg warfarin initiation nomogram in Asian population. AB - Anticoagulant responses to warfarin vary among patients, based on genetic factors, diet, concomitant medications, and disease state. We evaluated the effectiveness and safety of a 10mg warfarin initiation nomogram in an Asian population. Retrospective cross-sectional audit studies were conducted from March 2009 to March 2010. The use of a 10mg-loading dose to initiate warfarin treatment resulted in 33(84.6%) patients attaining a therapeutic INR within four days (mean time, 2.6 days). There was no significant correlation between age, gender, race, and serum albumin for the time to reach a therapeutic INR. A significant correlation was noted for patient's baseline INR and time to reach a therapeutic INR (P<0.05). No significant differences were observed in time to reach a therapeutic INR in patients treated with specific class of concomitant drugs or patients with specific disease states. The overall incidence of over anticoagulation was 35.9%; however, no bleeding episodes were encountered. In conclusion, the use of a 10mg warfarin nomogram was effective in rapidly achieving a therapeutic INR. However, the nomogram's safety is debatable owing to the high over-anticoagulation rate warfarin-administered patients. Caution is recommended in the initiation of warfarin treatment using the 10mg nomogram. PMID- 26004727 TI - Various fractions of Hypericum x moserianum and Hypericum ericoides possess antiglycation, anti-lipid peroxidation, antioxidative activities and non-toxic effects in vitro. AB - In the present study, two species Hypericum x moserianum and Hypericum ericoides which belong to genus Hypericum were evaluated for their potential antiglycation, antioxidant, anti lipid peroxidation and cytotoxic activities. These species are widely used in folk medicine and to the best of our knowledge there were no previous reports regarding antioxidant, anti-glycation and cytotoxicity studies of these species. Among the crude methanol extracts and fractions of both the species, the ethyl acetate fraction of H. x moserianum exhibited promising antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with IC50 129.084+/-1.215MUg/ml, followed by methanol extract (IC50=232.083 +/- 1.215MUg/ml) and aqueous fraction (IC50=266.962 +/-2.213 MUg/ml). The ethyl acetate fraction of H. ericoides exhibited IC50 value of 295.088 +/- 2.320 MUg/ml. In antiglycation assay, the ethyl acetate fraction of H. x moserianum showed 52.096% inhibition at 500MUg/ml. For lipid peroxidation assay, the dichloromethane, aqueous and n-hexane fractions of H. x moserianum showed 67.241, 66.147 and 64.213% inhibition respectively, while aqueous fraction of H. ericoides exhibited 67.404% inhibition at 500MUg/ml. In cytotoxicity assay, all fractions of both the species were found to be non-toxic on mouse fibroblast 3T3 cells with IC50 value greater than 30MUg/ml as compared to cycloheximide with IC50 value 0.073+/-0.1MUg/ml used as a standard. It was concluded from the study that among the two species, crude methanolic and ethyl acetate fractions were more active regarding the antioxidant, anti-glycation activities while dichloromethane, aqueous and n-hexane fractions possessed anti-lipid peroxidation activity. PMID- 26004728 TI - Evidences of hepatoprotective and antioxidant effect of Citrullus colocynthis fruits in paracetamol induced hepatotoxicity. AB - The objective of present study was to explore the hepatoprotective and antioxidant profile of Citrullus colocynthis fruits. Hepatoprotective profile of methanolic extract of Citrullus colocynthis fruits (MECCF) was investigated on rats, which were made hepatotoxic using paracetamol. The antioxidant profile of MECCF was evaluated by conducting Catalase, Super oxide Dismutase, Lipid Peroxidation and Diphenyl Picryl Hydrazyl tests. During hepatoprotective investigation, the Paracetamol treated group II showed significant increase in total bilirubin (TB), serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) and alkaline phosphatase (ALP) level. The results so obtained showed that pretreatment of rats with MECCF 300mg/kg p.o. decreases the elevated TB, SGOT, SGPT and ALP serum levels. Also, MECCF inhibitory profile was found comparable with toxicant group (Paracetamol 2g/kg, p.o.). The present study concludes that MECCF fruit possess significant hepatoprotective and antioxidant activity. PMID- 26004729 TI - Parasiticidal and brine shrimp cytotoxicity potential of crude methanolic extract of rind of Punica granatum Linn against round worms and tape worms. AB - Rind of Punica granatum is traditionally used for anthelmintic purposes. The current work describes the possible anthelmintic activity of crude methanolic extract of Punica granatum (Pg. Cr) against round worms (Ascaridia galli) and the tape worms (Raillietina spiralis). Brine shrimp cytotoxicity is also performed. Brine shrimp cytotoxic activity was tested using different concentrations (1000 MUg/mL, 100 MUg/mL and 10 MUg/mL) of Pg.Cr. In vitro anthelmintic activity of Pg. Cr was determined against the parasites using albendazole and piperazine citrate as standard anthelmintic drugs in concentration 10 mg/ml. LC50 value for Brine shrimp cytotoxicity was 189.44 +/-28 MUg/mL. In test concentration of 40mg/ml of the Pg. Cr, Raillietina spiralis was paralyzed in 23 minutes. However, for parasiticidal activity (death of the parasite), it took less time (40 minutes) as compared to standard Albendazole. Time taken for death of the parasite Raillietina spiralis, in concentration 40 mg /ml, is 40 min. While standard drugs took more time to kill the Raillietina spiralis. Pg. Cr took 19 minutes to paralyze the Ascaridia galli at concentration 40 mg/ml whereas; it took 48 minutes for to kill the parasite Ascaridia galli. The current work confirms the traditional use of rind of Punica granatum as anthelmintic against Raillietina spiralis and Ascaridia galli. Results of brine shrimp cytotoxicity assay warrant for the isolation of cytotoxic compounds. List of abbreviation- Pg. Cr = Crude methanolic extract of Punica granatum. PMID- 26004730 TI - Potential cardioprotective effects of Ginseng preparations. AB - Ginseng has shown potential cardioprotective effects by way of anti-oxidative, anti-arrhythmic, calcium- channel antagonistic, anti-inflammatory and anti apoptotic properties. The underlying mechanisms may also lie in certain complex signaling pathways. Clinical evidence seemed to be less convincing as the potential cardioprotective effects of Ginseng have been investigated by using combined preparations rather than by purified bioactive ingredients in most occasions. The exact actions of Ginseng verified by using its individual bioactive ingredients will be our future research work. PMID- 26004731 TI - Anticancer activity of Cinnamon tamala leaf constituents towards human ovarian cancer cells. AB - Bioassay guided fractionation of Cinnamon tamala leaf extracts yielded bornyl acetate (1), caryophylene oxide (2), p-coumaric acid (3) and vanillic acid (4) using A-2780 human ovarian cancer cell lines. The structures of the isolated compounds were confirmed through spectroscopic techniques (EIMS, (1)H and (13)C NMR). Compound 1 exhibited highest cytotoxicity with 90.16 +/- 1.06% inhibition (IC50=5.30 x 10(-4) mg/ml) followed by compound 2 (84.40+/-1.53% inhibition; IC50=8.94 x 10(-3)mg/ml), while compounds 3 and 4 were inactive in the bioassay. PMID- 26004732 TI - Honey bee is a potential antioxidant against cyclophosphamide-induced genotoxicity in albino male mice. AB - The protective effects of honey bee (HB) and pollen grains against cyclophosphamide (CPM) -induced cytotoxic and genotoxic effects in mice were investigated. This was achieved through study the effects of CPM and HB on oxidative status, chromosomal aberrations and gene expression of the tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interleukin-1beta (IL1beta), interleukin 17A (IL-17A) and interferon-gamma (IFN-gamma) in mice. In addition, the levels of reduced glutathione (GSH) and malondialdehyde were determined. The results of this study revealed that CPM decrease in GSH level and increase in malondialdehyde (MDA) level in the liver and kidney tissues. Moreover, CPM induced sperm abnormality, chromosomal aberrations and down regulated the expression of the studied cytokine genes. HB treatment in association with CPM ameliorates GSH, MDA, chromosomal aberrations and regulated the expression of IL-1-beta, IL-17A, IL-6, TNF-alpha and IFN-gamma. Thus, HB inhibits the cytotoxic and genotoxic risks associated with CPM treatment in mice. PMID- 26004733 TI - Short communication-Evaluation of antianxiety and antidepressant properties of Carthamus tinctorius L. (Safflower) petal extract. AB - Nowadays anxiety and depression are most commonly encountered diseases. They are not only difficult to diagnose but even difficult to treat since both are sometimes seen together or one predisposes the other. Apart from this side effect profile of these drugs is also high; hence there is immense scope for the herbal drugs to treat these disorders. Present study was therefore performed to evaluate the antianxiety and antidepressant effect of Carthamus tinctorius petal extract. 28 white albino rats bred in the animal house of Department of Pharmacology, University of Karachi weighing 180-220gm were randomly divided into four groups (n=7/group) to assess behavioral effects. The anxiolytic and antidepressant effects of Carthamus tinctorius petal extract were evaluated using elevated plus maize and forced swim test respectively at100 and 200mg/kg. These effects were compared with standard drugs Diazepam (anxiolytic) 2mg/kg and Nortriptyline (antidepressant) 12.5mg/kg. Results show that CT produced highly significant anxiolytic and anti-depressant effects at both doses as compared to control, similar to standard anxiolytic and antidepressant drugs diazepam and nortriptyline. It increased the latency of first entry to closed arms and the time spent in open arms very significantly at both doses while entries to open arm were increased significantly at 100mg/kg and very significantly at 200mg/kg in EPM test and increased the immobility time very significantly in FST. Hence it can be concluded that CT may be used as an alternative therapeutic agent while treating patients with anxiety and depressive disorders. PMID- 26004734 TI - Report-Isolation identification and control of vancomycin resistant Staphylococcus aureus. AB - Vancomycin resistant Staphylococcus aureus (VRSA) has been reported from many parts of the world including Asian countries. Hence, main objective of study was to evaluate the possible occurrence of VRSA in hospitals of Lahore city and to ensure the effectiveness of various substitute therapeutic options. A total of 150 samples of pus/wounds were collected from three hospitals of the city and VRSA were isolated and confirmed through recommended method of Clinical and Laboratory Standards Institute. Out of 51 (49.04%) methicillin resistant S. aureus (MRSA) isolates, 5 (9.8%) were found resistant to vancomycin. Minimum inhibitory concentration (MIC) of Linezolid (LZD), Moxifloxacin (MFX) and Clindamycin (CD) were calculated against VRSA isolates by broth microdilution test. All 5 (100%) isolates were susceptible to Linezolid and Clindamycin, while 4 (80%) were susceptible to Moxifloxacin. Ethanolic extracts of Turmeric, Mint, Coriander, Garlic, Kalonji, Cinnamon and Cloves illustrate average MIC values of 140.8 MUg/mL, 563.2 MUg/mL, 486.4 MUg/mL, 614.4 MUg/mL, 409.6 MUg/mL, 281.6 MUg/mL and 64 MUg/mL, respectively against 5 VRSA strains. Concentration dependent increase in growth inhibition zones of ethanolic plant extract was recorded by agar well diffusion test. This study was helpful to find out the effective antibiotic against VRSA. Plant extracts encompass anti-staphylococcal activity and this finding demands necessity of further exploration of potential found in these natural herb. PMID- 26004735 TI - Aging of intrauterine tissues in spontaneous preterm birth and preterm premature rupture of the membranes: A systematic review of the literature. AB - BACKGROUND: Many adverse pregnancy outcomes (APOs), including spontaneous preterm birth (PTB), are associated with placental dysfunction. Recent clinical and experimental evidences suggest that premature aging of the placenta may be involved in these events. Although placental aging is a well-known concept, the mechanisms of aging during normal pregnancy and premature aging in APOs are still unclear. This review was conducted to assess the knowledge on placental aging related biochemical changes leading to placental dysfunction in PTB and/or preterm premature rupture of membranes (pPROM). METHODS: We performed a systematic review of studies published over the last 50 years in two electronic databases (Pubmed and Embase) on placental aging and PTB or pPROM. RESULTS: The search yielded 554 citations, 30 relevant studies were selected for full-text review and three were included in the review. Only one study reported oxidative stress-related aging and degenerative changes in human placental membranes and telomere length reduction in fetal cells as part of PTB and/or pPROM mechanisms. Similarly, two animal studies reported findings of decidual senescence and referred to PTB mechanisms. CONCLUSION: Placental and fetal membrane oxidative damage and telomere reduction are linked to premature aging in PTB and pPROM but the risk factors and biomolecular pathways causing this phenomenon are not established in the literature. However, no biomarkers or clinical indicators of premature aging as a pathology of PTB and pPROM have been reported. We document major knowledge gaps and propose several areas for future research to improve our understanding of premature aging linked to placental dysfunction. PMID- 26004736 TI - The role of red blood cells in cardiovascular disease. PMID- 26004737 TI - Improved assay performance of single nucleotide polymorphism array over conventional karyotyping in analyzing products of conception. AB - BACKGROUND: Conventional karyotyping has been a routine method to identify chromosome abnormalities in products of conception. However, this process is being transformed by single nucleotide polymorphism (SNP) array, which has advantages over karyotyping, including higher resolution and dispensing with cell culture. Therefore, the purpose of this study was to evaluate the advantage of high-resolution SNP array in identifying genetic aberrations in products of conception. METHODS: We consecutively collected 155 products of conception specimens, including 139 from first-trimester miscarriage and 16 from second trimester miscarriage. SNP array was performed on these samples in parallel with G-banded karyotyping. RESULTS: The test success rate was 98.1% (152/155) using SNP array, which was higher than that using karyotyping (133/155, 85.8%). It yielded a 63.8% (97/152) abnormality rate, and the frequency of various chromosome abnormalities was in agreement with other previous studies. The results between array and karyotyping demonstrated a 94.0% (125/133) concordance. SNP array obtained additional aberrations in 3.8% (5/133) of those cases unidentified by karyotyping, which included three cases with whole-genome uniparental disomy, one with pathogenic copy number variation, and one with del(4)(q35.1q35.2) and dup(12)(q24.31q24.33). However, chromosome translocations presented in two cases and tetraploidy presented in one case were detected by karyotyping instead of array. Additionally, two out of three cases with mosaic trisomy were revealed by array but recognized as pure trisomy by karyotyping. CONCLUSION: This study demonstrated that SNP array had certain advantages over G banded karyotyping, including a higher success rate, additional detection of copy number variations and uniparental disomy, and improved sensitivity to mosaicism. Therefore, it would be an alternative method to karyotyping in clinical genetic practice. PMID- 26004738 TI - Detection of chromosome abnormalities: Beyond conventional karyotyping. PMID- 26004739 TI - Why do head and neck cancer patients visit the emergency department? PMID- 26004740 TI - Does the presence of microplastics influence the acute toxicity of chromium(VI) to early juveniles of the common goby (Pomatoschistus microps)? A study with juveniles from two wild estuarine populations. AB - Toxicological interactions between microplastics (MP) and other environmental contaminants are of grave concern. Here, the potential influence of MP in the short-term toxicity of chromium to early juveniles of Pomatoschistus microps was investigated. Three null hypotheses were tested: (1) exposure to Cr(VI) concentrations in the low ppm range does not induce toxic effects on juveniles; (2) the presence of microplastics in the water does not influence the acute toxicity of Cr(VI) to juveniles; (3) the environmental conditions of the natural habitat where fish developed do not influence their sensitivity to Cr(VI)-induced acute stress. Fish were collected in the estuaries of Minho (M-est) and Lima (L est) Rivers (NW Iberian Peninsula) that have several abiotic differences, including in the water and sediment concentrations of various environmental contaminants. After acclimatization to laboratory conditions, two 96h acute bioassays were carried out with juveniles from both estuaries to: (i) investigate the effects of Cr(VI) alone; (ii) investigate the effects of Cr(VI) in the presence of MP (polyethylene spheres 1-5MUm ?). Cr(VI) alone induced mortality (96h-LC50s: 14.4-30.5mg/l) and significantly decreased fish predatory performance (<=74%). Thus, in the range of concentrations tested (5.6-28.4mg/l) Cr(VI) was found to be toxic to P. microps early juveniles, therefore, we rejected hypothesis 1. Under simultaneous exposure to Cr(VI) and MP, a significant decrease of the predatory performance (<=67%) and a significant inhibition of AChE activity (<=31%) were found. AChE inhibition was not observed in the test with Cr(VI) alone and MP alone caused an AChE inhibition <=21%. Mixture treatments containing Cr(VI) concentration >=3.9mg/l significantly increased LPO levels in L-est fish, an effect that was not observed under Cr(VI) or MP single exposures. Thus, toxicological interactions between Cr(VI) and MP occurred, therefore, we rejected hypothesis 2. In the presence of MP, the negative effect caused by high concentrations of Cr(VI) on the predatory performance was significantly reduced in L-est fish but not in M-est fish, and Cr(VI) concentrations higher than 3.9mg/l caused oxidative damage in L-est fish but not in M-est fish. The acclimatization and test conditions were similar for fish from the two estuaries and these ecosystems have environmental differences. Thus, long term exposure to distinct environmental conditions in the natural habitat during previous developmental phases influenced the sensitivity and responses of juveniles to Cr(VI), therefore, we rejected hypothesis 3. Overall, the results of this study indicate toxicological interactions between MP and Cr(VI) highlighting the importance of further investigating the combined effects of MP and other common contaminants. PMID- 26004741 TI - Loquat (Eriobotrya japonica) extract prevents dexamethasone-induced muscle atrophy by inhibiting the muscle degradation pathway in Sprague Dawley rats. AB - In the Orient, loquat (Eriobotrya japonica) extract (LE) is widely used in teas, food and folk medicines. The leaves of the loquat tree have been used for generations to treat chronic bronchitis, coughs, phlegm production, high fever and gastroenteric disorders. One of the major active components of loquat leaves is ursolic acid, which was recently investigated in the context of preventing muscle atrophy. The present study investigated the therapeutic potential of LE on dexamethasone-induced muscle atrophy in rats. Daily intraperitoneal injections of dexamethasone caused muscle atrophy and evidence of muscle atrophy prevention by LE was demonstrated using various assays. In particular, dexamethasone-induced grip strength loss was alleviated by LE and the increase in serum creatine kinase activity, a surrogate marker of muscle damage, caused by dexamethasone injection was reduced by LE. Western blot analysis and immunoprecipitation demonstrated that dexamethasone markedly increased the protein expression levels of muscle ring finger 1 (MuRF1), which causes the ubiquitination and degradation of myosin heavy chain (MyHC), and decreased the protein expression levels of MyHC as well as increased the ubiquitinated MyHC to MyHC ratio. However, LE reduced the dexamethasone-induced protein expression levels of MuRF1 and ubiquitinated MyHC. Additional experiments revealed that LE supplementation inhibited the nuclear translocation of FoxO1 induced by dexamethasone. These findings suggested that LE prevented dexamethasone-induced muscle atrophy by regulating the FoxO1 transcription factor and subsequently the expression of MuRF1. PMID- 26004742 TI - Mitochondrial apoptotic pathway activation in the atria of heart failure patients due to mitral and tricuspid regurgitation. AB - Apoptosis occurs in atrial cardiomyocytes in mitral and tricuspid valve disease. The purpose of this study was to examine the respective roles of the mitochondrial and tumor necrosis factor-alpha receptor associated death domain (TRADD)-mediated death receptor pathways for apoptosis in the atrial cardiomyocytes of heart failure patients due to severe mitral and moderate-to severe tricuspid regurgitation. This study comprised eighteen patients (7 patients with persistent atrial fibrillation and 11 in sinus rhythm). Atrial appendage tissues were obtained during surgery. Three purchased normal human left atrial tissues served as normal controls. Moderately-to-severely myolytic cardiomyocytes comprised 59.7+/-22.1% of the cardiomyocytes in the right atria and 52.4+/-12.9% of the cardiomyocytes in the left atria of mitral and tricuspid regurgitation patients with atrial fibrillation group and comprised 58.4+/-24.8% of the cardiomyocytes in the right atria of mitral and tricuspid regurgitation patients with sinus rhythm. In contrast, no myolysis was observed in the normal human adult left atrial tissue samples. Immunohistochemical analysis showed expression of cleaved caspase-9, an effector of the mitochondrial pathways, in the majority of right atrial cardiomyocytes (87.3+/-10.0%) of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial cardiomyocytes (90.6+/-31.4%) and left atrial cardiomyocytes (70.7+/-22.0%) of mitral and tricuspid regurgitation patients with atrial fibrillation. In contrast, only 5.7% of cardiomyocytes of the normal left atrial tissues showed strongly positive expression of cleaved caspase-9. Of note, none of the atrial cardiomyocytes in right atrial tissue in sinus rhythm and in the fibrillating right and left atria of mitral and tricuspid regurgitation patients, and in the normal human adult left atrial tissue samples showed cleaved caspase-8 expression, which is a downstream effector of TRADD of the death receptor pathway. Immunoblotting of atrial extracts showed that there was enhanced expression of cytosolic cytochrome c, an effector of the mitochondrial pathways, but no expression of membrane TRADD and cytosolic caspase-8 in the right atrial tissue of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial and left atrial tissues of mitral and tricuspid regurgitation patients with atrial fibrillation. Taken together, this study showed that mitochondrial pathway for apoptosis was activated in the right atria in sinus rhythm and in the left and right atria in atrial fibrillation of heart failure patients due to mitral and tricuspid regurgitation, and this mitochondrial pathway activation may contribute to atrial contractile dysfunction and enlargement in this clinical setting. PMID- 26004743 TI - Prognostic value of multidimensional indices in ambulatory COPD patients. PMID- 26004744 TI - A care improvement program acting as a powerful learning environment to support nursing students learning facilitation competencies. AB - Change management is an important area of training in undergraduate nursing education. Successful change management in healthcare aimed at improving practices requires facilitation skills that support teams in attaining the desired change. Developing facilitation skills in nursing students requires formal educational support. A Dutch Regional Care Improvement Program based on a nationwide format of change management in healthcare was designed to act as a Powerful Learning Environment for nursing students developing competencies in facilitating change. This article has two aims: to provide comprehensive insight into the program components and to describe students' learning experiences in developing their facilitation skills. This Dutch Regional Care Improvement Program considers three aspects of a Powerful Learning Environment: self regulated learning; problem-based learning; and complex, realistic and challenging learning tasks. These three aspects were operationalised in five distinct areas of facilitation: increasing awareness of the need for change; leadership and project management; relationship building and communication; importance of the local context; and ongoing monitoring and evaluation. Over a period of 18 months, 42 nursing students, supported by trained lecturer-coaches, took part in nine improvement teams in our Regional Care Improvement Program, executing activities in all five areas of facilitation. Based on the students' experiences, we propose refinements to various components of this program, aimed at strengthenin the learning environment. There is a need for further detailed empirical research to study the impact this kind of learning environment has on students developing facilitation competencies in healthcare improvement. PMID- 26004745 TI - Impact of client feedback on clinical outcomes for young people using public mental health services: A pilot study. AB - This paper reports on research conducted in public health settings with young people who have serious mental health issues. An easy to use feedback system for clinicians providing psychotherapy was assessed against treatment as usual. Data were collected on four widely used outcome measures. There has been little previous research in this area. We found evidence for treatment effects. There was some evidence supportive of the feedback system but further study is needed. PMID- 26004746 TI - Common rather than unique aspects of repetitive negative thinking are related to depressive and anxiety disorders and symptoms. AB - Repetitive Negative Thinking (RNT) is assumed to be a transdiagnostic factor in depressive and anxiety disorders. We hypothesized that an underlying common dimension of RNT will be more strongly associated with each of the anxiety and depressive disorders, with comorbidity among disorders and with symptom severity than unique aspects of rumination and worry. In a cross-sectional study, 2143 adults diagnosed according to DSM-IV criteria completed questionnaires for content-independent RNT, rumination and worry. 84% of the shared variance of worry and rumination overlapped with content-independent RNT. The common dimension of RNT was significantly associated with each of the depressive and anxiety disorders, comorbidity among emotional disorders and the common core of depressive, anxiety and avoidance symptoms. The unique portion of rumination showed a significant relationship with Major Depressive Disorder and depressive comorbidity and the unique portion of worry with Generalized Anxiety Disorder. These findings are particularly relevant for clinical practice as generic interventions to reduce RNT are currently being tested. PMID- 26004747 TI - Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: Meta analysis of randomized controlled trials: Comment. PMID- 26004748 TI - Pre-procedural dual antiplatelet therapy and bleeding events following transcatheter aortic valve implantation (TAVI). AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is associated with bleeding that increases mortality. Dual antiplatelet therapy (DAPT) is recommended in TAVI, however little is known about pre-procedural DAPT use and its impact on hemostasis. We sought to determine the frequency, predictors and bleeding events in patients receiving DAPT before TAVI. METHODS: Three-hundred and-three (n=303, 78.6+/-7.6years, 49% female, EuroScore 23.1+/-16.9) consecutive patients undergoing TAVI were prospectively analyzed and followed for in-hospital events. According to pre-procedural antiplatelet status study population was divided into 2 groups: patients receiving aspirin and clopidogrel (DAPT) and those on aspirin only or no antiplatelet therapy (noDAPT). RESULTS: Pre procedural DAPT was used in 139 cases (46%). Previous PCI (OR 4.8, [2.8-8.3], p<0.0001), implantation of self-expandable prosthesis (OR 2.2, [1.2-4], p=0.007) femoral access (OR 2.2, [1.1-4.5], p=0.029) and platelet count (OR 1.006, [1.002 1.01], p=0.002) were identified as independent predictors of pre-procedural DAPT. No difference was observed in the rates of any bleeding (23% in DAPT vs. 24.4% in noDAPT, p=0.930) or major/life-threatening bleeding (12.2% in DAPT vs. 14.7% in noDAPT, p=0.715). Propensity-score matching analysis did not alter the results. GFR <30ml/min was the strongest predictor of bleeding (OR 4.3, [1.9-9.9], p=0.0005). There was a trend towards lower frequency of MI and stroke/TIA in DAPT as compared with noDAPT (3.6% vs. 9.8%, p=0.082). CONCLUSIONS: Pre-procedural DAPT is frequent and does not increase short-term bleeding complications or need for transfusion following TAVI. Possible impact of DAPT use before TAVI on ischemic complications needs to be investigated in larger populations. PMID- 26004749 TI - Evolutionary dynamics of fairness on graphs with migration. AB - Individual migration plays a crucial role in evolutionary dynamics of population on networks. In this paper, we generalize the networked ultimatum game by diluting population structures as well as endowing individuals with migration ability, and investigate evolutionary dynamics of fairness on graphs with migration in the ultimatum game. We first revisit the impact of node degree on the evolution of fairness. Interestingly, numerical simulations reveal that there exists an optimal value of node degree resulting in the maximal offer level of populations. Then we explore the effects of dilution and migration on the evolution of fairness, and find that both the dilution of population structures and the endowment of migration ability to individuals would lead to the drop of offer level, while the rise of acceptance level of populations. Notably, natural selection even favors the evolution of self-incompatible strategies, when either vacancy rate or migration rate exceeds a critical threshold. To confirm our simulation results, we also propose an analytical method to study the evolutionary dynamics of fairness on graphs with migration. This method can be applied to explore any games governed by pairwise interactions in finite populations. PMID- 26004751 TI - The influence of fluorine position on the properties of fluorobenzoxaboroles. AB - 5-Fluoro-2,1-benzoxaborol-1(3H)-ol, a potent antifungal drug also known as Tavaborole or AN2690, has been compared with its three isomers in terms of its activity against several fungi as well as pKa and multinuclear NMR characterization. The molecular and crystal structure of 6-fluoro-2,1 benzoxaborol-1(3H)-ol was determined and compared with that of AN2690. PMID- 26004752 TI - Mild traumatic brain injuries in early adolescent rugby players: Long-term neurocognitive and academic outcomes. AB - BACKGROUND: Information is scant concerning enduring brain injury effects of participation in the contact sport of Rugby Union (hereafter rugby) on early adolescents. OBJECTIVE: The objective was prospectively to investigate differences between young adolescent male rugby players and non-contact sports controls on neurocognitive test performance over 3 years and academic achievement over 6 years. METHOD: A sample of boys from the same school and grade was divided into three groups: rugby with seasonal concussions (n = 45), rugby no seasonal concussions (n = 21) and non-contact sports controls (n = 30). Baseline neurocognitive testing was conducted pre-season in Grade 7 and post-season in Grades 8 and 9. Year-end academic grades were documented for Grades 6-9 and 12 (pre-high school to year of school leaving). A mixed model repeated measures ANOVA was conducted to investigate comparative neurocognitive and academic outcomes between the three sub-groups. RESULTS: Compared with controls, both rugby groups were significantly lower on the WISC-III Coding Immediate Recall sub test. There was a significant interaction effect on the academic measure, with improved scores over time for controls, that was not in evidence for either rugby group. CONCLUSIONS: Tentatively, the outcome suggests cognitive vulnerability in association with school level participation in rugby. PMID- 26004753 TI - Effect of soccer heading ball speed on S100B, sideline concussion assessments and head impact kinematics. AB - OBJECTIVE: To examine the effect of soccer heading ball speed on S-100B serum concentration, concussion sideline assessments and linear head impact acceleration. METHODS: Sixteen division I soccer players participated in this pre test post-test design study. Athletes performed five standing headers over a 10 minute period at 30 (n = 5), 40 (n = 5) or 50 (n = 6) miles per hour (mph) (randomized). S-100B serum concentration (ng mL-1) and sideline concussion assessments were measured prior to and post-heading. Peak resultant linear head acceleration (gravitational units; g) was measured during soccer heading. RESULTS: No statistically significant interaction effects were identified between ball velocity groups over time on S100B (effect sizes ranged from 0.03-0.23) or concussion assessments tests. There was a non-significant increase (p = 0.06) in head impact acceleration from the 30 (30.6; SD = 6.2 g) to 50 mph (50.7; SD = 7.7 g) ball speed. CONCLUSIONS: In this controlled setting, an acute bout of soccer heading across various ball velocities did not affect S100B or concussion assessment test scores. These findings are preliminary, as the small sample size in each group may have played a role in the lack of significant findings. PMID- 26004754 TI - Determinants of participation of youth with acquired brain injury: A systematic review. AB - OBJECTIVES: Participation is considerably restricted in children and adolescents with acquired brain injury (ABI) as compared to their healthy peers. This systematic review aims to identify which factors are associated with participation in children and adolescents with ABI. METHODS: A systematic search in Medline and various other electronic databases from January 2001-November 2014 was performed. All clinical studies describing determinants of participation at least 1 year after the diagnosis of ABI by means of one or more pre-defined instruments in patients up to 18 years of age were included. Extracted data included study characteristics, patient characteristics, participation outcome and determinants of participation (categorized into: health conditions (including characteristics of ABI), body functions and structures, activities, personal factors and environmental factors). The methodological quality of the studies was evaluated based on three quality aspects (selection, information and statistical analysis bias) and scored as low, moderate or high. RESULTS: Eight studies using an explicit participation outcome measure were selected after review, including a total of 1863 patients, with a follow-up ranging from 1 up to 288 months. Three studies included patients with a traumatic or a non-traumatic brain injury (TBI or NTBI) and five studies with only TBI patients. Factors consistently found to be associated with more participation restrictions were: greater severity of ABI, impaired motor, cognitive, behavioural and/or sensory functioning, limited accessibility of the physical environmentand worse family functioning. Fewer participation problems were associated with a supportive/nurturing parenting style, higher household income, acceptance and support in the community and availability of special programmes. The overall methodological quality of the included studies was high in two and moderate in six studies. CONCLUSION: This systematic review shows that only a few, moderate quality, studies on the determinants of participation after paediatric ABI using recommended explicit measurement instruments are available. Various components of the ICF model: health condition, body functions and structures and environmental factors were consistently found to be associated with participation. More methodologically sound studies, using the recommended explicit outcome measures, a standardized set of potential determinants and long-term follow-up are suggested to increase the knowledge on participation in children and youth with ABI. PMID- 26004750 TI - Prognostic Impact of Diabetes Mellitus in Chronic Heart Failure According to Presence of Ischemic Heart Disease - With Special Reference to Nephropathy. AB - BACKGROUND: It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy. METHODS AND RESULTS: We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c >=6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio >=30 mg/g or urine dipstick test >=(+/-) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy. CONCLUSIONS: The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy. PMID- 26004755 TI - Outpatient follow-up and return to school after emergency department evaluation among children with persistent post-concussion symptoms. AB - OBJECTIVE: To describe differences in outpatient follow-up and academic accommodations received by children with and without persistent post-concussion symptoms (PPCS) after emergency department (ED) evaluation. It was hypothesized that children with PPCS would have more outpatient visits and receive academic accommodations more often than children without PPCS and that follow-up would be positively associated with receiving accommodations. METHODS: Children aged 8-18 years with acute (<=6hours) concussion at time of presentation to a paediatric ED were enrolled in an observational study. Outcomes were assessed through a telephone survey 30 days after injury. RESULTS: Of 234 enrolled participants, 179 (76%) completed follow-up. PPCS occurred in 21%. Only 45% of subjects had follow up visits after ED discharge. Follow-up visit rates were similar for those with and without PPCS (58% vs. 41%, respectively; p = 0.07). Children with PPCS missed twice as many school days as those without (3 vs. 1.5; p < 0.001), but did not differ in receiving academic accommodations (36% vs. 53%; p = 0.082). Outpatient follow-up was associated with receiving academic accommodations (RR = 2.2; 95% CI = 1.4-3.5). CONCLUSIONS: Outpatient follow-up is not routine for concussed children. Despite missing more school days, children with PPCS do not receive academic accommodations more often. Outpatient follow-up may facilitate academic accommodations. PMID- 26004756 TI - Ultrastructure of antennal and posterior abdominal sensilla in Chlorophorus caragana females. AB - Chlorophorus caragana Xie & Wang is a destructive wood-boring beetle that damages Caragana spp. bushes and is distributed in desert areas in north-west China. Using scanning electron microscopy and transmission electron microscopy, we observed the morphology and ultrastructure of antennal and posterior abdominal sensilla in C. caragana females, to discuss the putative functions of these sensilla in host location and oviposition behaviors. In total, seven types (24 subtypes) of sensilla were located on the antenna and posterior abdomen. On the antenna, there were Bohm's bristles (BB.); four subtypes of sensilla chaetica (Ch.1-Ch.4) characterized by non-porous surfaces and sensillum-lymph cavities without dendrites; two subtypes of sensilla trichodea (Tr.1 and Tr.2) with a tip pore and dendrites surrounded by dendritic sheaths; dome-shaped sensilla (Dom.) emerging from a deep cavity with one tip pore; four subtypes of sensilla basiconica (Ba.1-Ba.4) and one type of sensilla auricillica (Au.) with a porous cuticular surface and dendrites in the sensillum-lymph cavity; and one type of sensilla styloconica (Sty.) with grooves on the cuticular wall. On the posterior abdomen, there were four subtypes of sensilla chaetica (Ch.5-Ch.8); three subtypes of sensilla trichodea (Tr.3-Tr.5); and three subtypes of sensilla basiconica (Ba.5-Ba.7; Ba.5 had no groove in the cuticular wall, Ba.6 had one tip pore, and Ba.7 was located in a cuticular cavity). The antennal sensilla were believed to be mechanosensitive, chemosensitive, and sensitive to humidity and temperature, and to play roles in mating, host location and oviposition. The abdominal sensilla are believed to be related to oviposition behaviors. PMID- 26004757 TI - Dextromethorphan provides neuroprotection via anti-inflammatory and anti excitotoxicity effects in the cortex following traumatic brain injury. AB - Traumatic brain injury (TBI) is caused by primary and secondary injury mechanisms. TBI induces a certain amount of inflammatory responses and glutamate excitotoxicity that are believed to participate in the pathogenesis of secondary injury. The non-narcotic anti-tussive drug dextromethorphan (DM) has been reported to have a high safety profile in humans and its neuroprotective against a variety of disorders, including cerebral ischemia, epilepsy and acute brain injury. However, few studies have explored the underlying mechanisms of the neuroprotective effects of DM in animals in the setting of TBI. The aim of the present study was to investigate the neuroprotective effects of DM on TBI and to determine the underlying mechanisms. Rats were subjected to a controlled cortical impact (CCI) injury and randomly divided into three groups: Sham-operated, TBI and DM treatment groups. The DM treatment group was administered DM (30 mg/kg of body weight, intraperitoneally) immediately after injury. It was identified that DM treatment following TBI significantly reduced brain edema and neurological deficits, as well as increased neuronal survival. These effects correlated with a decrease of tumor necrosis factor alpha, interleukin-1beta (IL-1beta) and IL-6 protein expression and an increase of glutamate/aspartate transporter and glutamate transporter-1 in the cortex of the brain. These results provided in vivo evidence that DM exerts neuroprotective effects via reducing inflammation and excitotoxicity induced following TBI. The present study has shed light on the potential use of DM as a neuroprotective agent in the treatment of cerebral injuries. PMID- 26004758 TI - Aetiological diagnosis of middle-aged and elderly cryptogenic ischaemic cerebral vascular disease. AB - Although tremendous efforts have been made to explore the potential aetiologies of cryptogenic ischaemic cerebral vascular disease (CICVD), it remains a great challenge for neurologists to get a comprehensive picture of CICVD across the world. Part of the reason why is that the vast majority of studies have focussed on CICVD in young stroke patients while the underlying causes of CICVD in middle aged or elderly stroke population have not been fully investigated. The focus of this paper has been dedicated to review the different studies that explore the aetiologies of CICVD cases in this patient population. While there is a set of heterogeneous causes that can lead to CICVD in middle-aged and elderly patients, our review reveals that emboli originated from or across occult places within the heart or produced by transient arrhythmias could possibly be the main culprit. Dislodged aortic plaques might also account for certain CICVD cases and in fewer cases, hereditary arteriopathy and thrombophilia can also play a role. The aforementioned factors have similar roles in middle-aged and elderly CICVD patients as in their younger counterparts. However, more studies are needed to explore the role of these factors in older patients. PMID- 26004759 TI - Transcriptional regulation via nuclear receptor crosstalk required for the Drosophila circadian clock. AB - Circadian clocks in large part rely on transcriptional feedback loops. At the core of the clock machinery, the transcriptional activators CLOCK/BMAL1 (in mammals) and CLOCK/CYCLE (CLK/CYC) (in Drosophila) drive the expression of the period (per) family genes. The PER-containing complexes inhibit the activity of CLOCK/BMAL1 or CLK/CYC, thereby forming a negative feedback loop [1]. In mammals, the ROR and REV-ERB family nuclear receptors add positive and negative transcriptional regulation to this core negative feedback loop to ensure the generation of robust circadian molecular oscillation [2]. Despite the overall similarities between mammalian and Drosophila clocks, whether comparable mechanisms via nuclear receptors are required for the Drosophila clock remains unknown. We show here that the nuclear receptor E75, the fly homolog of REV-ERB alpha and REV-ERB beta, and the NR2E3 subfamily nuclear receptor UNF are components of the molecular clocks in the Drosophila pacemaker neurons. In vivo assays in conjunction with the in vitro experiments demonstrate that E75 and UNF bind to per regulatory sequences and act together to enhance the CLK/CYC-mediated transcription of the per gene, thereby completing the core transcriptional feedback loop necessary for the free-running clockwork. Our results identify a missing link in the Drosophila clock and highlight the significance of the transcriptional regulation via nuclear receptors in metazoan circadian clocks. PMID- 26004760 TI - Short-term monocular deprivation alters GABA in the adult human visual cortex. AB - Neuroplasticity is a fundamental property of the nervous system that is maximal early in life, within the critical period [1-3]. Resting GABAergic inhibition is necessary to trigger ocular dominance plasticity and to modulate the onset and offset of the critical period [4, 5]. GABAergic inhibition also plays a crucial role in neuroplasticity of adult animals: the balance between excitation and inhibition in the primary visual cortex (V1), measured at rest, modulates the susceptibility of ocular dominance to deprivation [6-10]. In adult humans, short term monocular deprivation strongly modifies ocular balance, unexpectedly boosting the deprived eye, reflecting homeostatic plasticity [11, 12]. There is no direct evidence, however, to support resting GABAergic inhibition in homeostatic plasticity induced by visual deprivation. Here, we tested the hypothesis that GABAergic inhibition, measured at rest, is reduced by deprivation, as demonstrated by animal studies. GABA concentration in V1 of adult humans was measured using ultra-high-field 7T magnetic resonance spectroscopy before and after short-term monocular deprivation. After monocular deprivation, resting GABA concentration decreased in V1 but was unaltered in a control parietal area. Importantly, across participants, the decrease in GABA strongly correlated with the deprived eye perceptual boost measured by binocular rivalry. Furthermore, after deprivation, GABA concentration measured during monocular stimulation correlated with the deprived eye dominance. We suggest that reduction in resting GABAergic inhibition triggers homeostatic plasticity in adult human V1 after a brief period of abnormal visual experience. These results are potentially useful for developing new therapeutic strategies that could exploit the intrinsic residual plasticity of the adult human visual cortex. PMID- 26004761 TI - A comparative analysis of spindle morphometrics across metazoans. AB - Cell division in all eukaryotes depends on function of the spindle, a microtubule based structure that segregates chromosomes to generate daughter cells in mitosis or haploid gametes in meiosis. Spindle size adapts to changes in cell size and shape, which vary dramatically across species and within a multicellular organism, but the nature of scaling events and their underlying mechanisms are poorly understood. Cell size variations are most pronounced in early animal development, as egg diameters range from tens of microns up to millimeters across animal phyla, and decrease several orders of magnitude during rapid reductive divisions. During early embryogenesis in the model organisms X. laevis and C. elegans, the spindle scales with cell size [1, 2], a phenomenon regulated by molecules that modulate microtubule dynamics [3-6], as well as by limiting cytoplasmic volume [7, 8]. However, it is not known to what extent spindle scaling is conserved across organisms and among different cell types. Here we show that in a range of metazoan phyla, mitotic spindle length decreased with cell size across an ~30-fold difference in zygote size. Maximum spindle length varied, but linear spindle scaling occurred similarly in all species once embryonic cell diameter reduced to 140 MUm. In contrast, we find that the female meiotic spindle does not scale as closely to egg size, adopting a more uniform size across species that most likely reflects its specialized function. Our analysis reveals that spindle morphometrics change abruptly, within one cell cycle, at the transition from meiosis to mitosis in most animals. PMID- 26004762 TI - Ancient homology of the mitochondrial contact site and cristae organizing system points to an endosymbiotic origin of mitochondrial cristae. AB - Mitochondria are eukaryotic organelles that originated from an endosymbiotic alpha-proteobacterium. As an adaptation to maximize ATP production through oxidative phosphorylation, mitochondria contain inner membrane invaginations called cristae. Recent work has characterized a multi-protein complex in yeast and animal mitochondria called MICOS (mitochondrial contact site and cristae organizing system), responsible for the determination and maintenance of cristae [1-4]. However, the origin and evolution of these characteristic mitochondrial features remain obscure. We therefore conducted a comprehensive search for MICOS components across the major groups that encompass eukaryotic diversity to determine the extent of conservation of this complex. We detected homologs for the majority of MICOS components among opisthokonts (the group containing animals and fungi), but only Mic60 and Mic10 were consistently identified outside this group. The conservation of Mic60 and Mic10 in eukaryotes is consistent with their central role in MICOS function [5-7], indicating that the basic mechanism for cristae determination arose early in evolution and has remained relatively unchanged. We found that eukaryotes with ultrastructurally simplified anaerobic mitochondria that lack cristae have also lost MICOS. We then searched for a prokaryotic MICOS and identified a homolog of Mic60 present only in alpha proteobacteria, providing evidence for the endosymbiotic origin of mitochondrial cristae. Our study clarifies the origins of mitochondrial cristae and their subsequent evolutionary history, provides evidence for a general mechanism of cristae formation and maintenance in eukaryotes, and points to a new potential factor involved in membrane differentiation in prokaryotes. PMID- 26004764 TI - A 425-million-year-old silurian pentastomid parasitic on ostracods. AB - Pentastomids (tongue worms) are worm-like arthropods known today from ~140 species [1]. All but four are parasitic on vertebrates. Their life cycle typically involves larval development in an intermediate host followed by maturation in the respiratory tract of a definitive terrestrial host. Fossil pentastomids are exceedingly rare and are known only from isolated juveniles [2 6]. The identity of the possible hosts of fossil pentastomids and the origin of their lifestyle have generated much debate. A new, exceptionally preserved species, described based on adults from 425-million-year-old marine rocks, is the only known fossil pentastomid associated with a host, in this case a species of ostracod crustacean. The pentastomids are preserved near eggs within the ostracod and also, uniquely for any fossil or living pentastomid, are attached externally to the host. This discovery affirms the origin of pentastomids as ectoparasitic on marine invertebrates. The terrestrialization of pentastomids may have occurred in parallel with the vertebrate invasion of land. PMID- 26004763 TI - Selective activation of a putative reinforcement signal conditions cued interval timing in primary visual cortex. AB - As a consequence of conditioning visual cues with delayed reward, cue-evoked neural activity that predicts the time of expected future reward emerges in the primary visual cortex (V1). We hypothesized that this reward-timing activity is engendered by a reinforcement signal conveying reward acquisition to V1. In lieu of behavioral conditioning, we assessed in vivo whether selective activation of either basal forebrain (BF) or cholinergic innervation is sufficient to condition cued interval-timing activity. Substituting for actual reward, optogenetic activation of BF or cholinergic input within V1 at fixed delays following visual stimulation entrains neural responses that mimic behaviorally conditioned reward timing activity. Optogenetically conditioned neural responses express cue-evoked temporal intervals that correspond to the conditioning intervals, are bidirectionally modifiable, display experience-dependent refinement, and exhibit a scale invariance to the encoded delay. Our results demonstrate that the activation of BF or cholinergic input within V1 is sufficient to encode cued interval-timing activity and indicate that V1 itself is a substrate for associative learning that may inform the timing of visually cued behaviors. PMID- 26004765 TI - Ancient wolf genome reveals an early divergence of domestic dog ancestors and admixture into high-latitude breeds. AB - The origin of domestic dogs is poorly understood [1-15], with suggested evidence of dog-like features in fossils that predate the Last Glacial Maximum [6, 9, 10, 14, 16] conflicting with genetic estimates of a more recent divergence between dogs and worldwide wolf populations [13, 15, 17-19]. Here, we present a draft genome sequence from a 35,000-year-old wolf from the Taimyr Peninsula in northern Siberia. We find that this individual belonged to a population that diverged from the common ancestor of present-day wolves and dogs very close in time to the appearance of the domestic dog lineage. We use the directly dated ancient wolf genome to recalibrate the molecular timescale of wolves and dogs and find that the mutation rate is substantially slower than assumed by most previous studies, suggesting that the ancestors of dogs were separated from present-day wolves before the Last Glacial Maximum. We also find evidence of introgression from the archaic Taimyr wolf lineage into present-day dog breeds from northeast Siberia and Greenland, contributing between 1.4% and 27.3% of their ancestry. This demonstrates that the ancestry of present-day dogs is derived from multiple regional wolf populations. PMID- 26004766 TI - Activity-dependent transmission and integration control the timescales of auditory processing at an inhibitory synapse. AB - To capture the context of sensory information, neural networks must process input signals across multiple timescales. In the auditory system, a prominent change in temporal processing takes place at an inhibitory GABAergic synapse in the dorsal nucleus of the lateral lemniscus (DNLL). At this synapse, inhibition outlasts the stimulus by tens of milliseconds, such that it suppresses responses to lagging sounds, and is therefore implicated in echo suppression. Here, we untangle the cellular basis of this inhibition. We demonstrate with in vivo whole-cell patch clamp recordings in Mongolian gerbils that the duration of inhibition increases with sound intensity. Activity-dependent spillover and asynchronous release translate the high presynaptic firing rates found in vivo into a prolonged synaptic output in acute slice recordings. A key mechanism controlling the inhibitory time course is the passive integration of the hyperpolarizing inhibitory conductance. This prolongation depends on the synaptic conductance amplitude. Computational modeling shows that this prolongation is a general mechanism and relies on a non-linear effect caused by synaptic conductance saturation when approaching the GABA reversal potential. The resulting hyperpolarization generates an efficient activity-dependent suppression of action potentials without affecting the threshold or gain of the input-output function. Taken together, the GABAergic inhibition in the DNLL is adjusted to the physiologically relevant duration by passive integration of inhibition with activity-dependent synaptic kinetics. This change in processing timescale combined with the reciprocal connectivity between the DNLLs implements a mechanism to suppress the distracting localization cues of echoes and helps to localize the initial sound source reliably. PMID- 26004767 TI - Drug exposure in a metastatic human lung adenocarcinoma cell line gives rise to cells with differing adhesion, proliferation, and gene expression: Implications for cancer chemotherapy. AB - The Am1010 cell line was previously established from a metastatic deposit in an arm muscle from a patient with lung adenocarcinoma who had undergone four cycles of chemotherapy with cisplatin and taxol. Am1010 cells were labeled with red fluorescent protein or green fluorescent protein. A total of eight sublines were isolated following in vitro exposure to cisplatin or taxol. The sublines differed with regard to their adhesion and proliferation properties, with certain sublines exhibiting an increased proliferation rate and/or decreased surface adhesion. Gene expression assays demonstrated that tenascin C; cyclin D1; collagen, type 1, alpha2; integrin alpha1; related RAS viral (r-ras) oncogene homolog 2; platelet derived growth factor C; and Src homolog 2 domain containing in the focal adhesion pathway, and intercellular adhesion molecule 1, F11 receptor, claudin 7 and cadherin 1 in the cell adhesion pathway, varied in expression among the sublines. The results of the present study suggested that drug exposure may alter the aggressiveness and metastatic potential of cancer cells, which has important implications for cancer chemotherapy. PMID- 26004769 TI - The Altmetric Score: A New Measure for Article-Level Dissemination and Impact. PMID- 26004770 TI - Major Adverse Events One Year After Acute Kidney Injury After Contrast-Enhanced Computed Tomography. AB - STUDY OBJECTIVE: Recent studies have demonstrated that a single episode of acute kidney injury from a number of causes can increase the risk of severe long-term outcomes, including major cardiovascular events and death. We tested the hypothesis that patients who develop acute kidney injury consistent with contrast induced nephropathy after contrast-enhanced computed tomography (CT) imaging are at increased risk of major adverse events at 1 year. METHODS: We followed a prospective, heterogeneous cohort of consecutive emergency department patients undergoing contrast-enhanced CT for the outcomes of acute kidney injury consistent with contrast-induced nephropathy and major adverse events, defined as the combined outcome of death (all cause), renal failure, myocardial infarction, and stroke or other arterial vascular events, in any anatomic territory, requiring invention within 1 year. The primary outcome, major adverse events, was determined by the consensus of 2 of 3 blinded adjudicators. RESULTS: We followed 633 patients undergoing contrast-enhanced CT, of whom 11% developed acute kidney injury consistent with contrast-induced nephropathy and 15% (95/633; 95% confidence interval [CI] 12% to 18%) experienced at least 1 major adverse event within 1 year, including 7% (46/633; 95% CI 5% to 9%) who died. The development of acute kidney injury after contrast-enhanced CT was associated with an increased risk of 1-year major adverse event: the incident risk ratio was 4.01 (95% CI 2.61 to 6.05) and was 2.36 (95% CI 1.49 to 3.75) after adjusting for age, existing coronary artery disease, active malignancy, and 1 or more additional exposures to intravascular iodinated contrast media. CONCLUSION: The development of acute kidney injury after contrast-enhanced CT was associated with a 2-fold increase in 1-year major adverse events. Further research is needed to validate this observation. PMID- 26004772 TI - Anti-inflammatory Treatment for Seemingly Non-inflammatory Disorders. Editorial. PMID- 26004771 TI - Treatment of boundary conditions in through-diffusion: A case study of (85)Sr(2+) diffusion in compacted illite. AB - Valuable techniques to measure effective diffusion coefficients in porous media are an indispensable prerequisite for a proper understanding of the migration of chemical-toxic and radioactive micropollutants in the subsurface and geosphere. The present article discusses possible pitfalls and difficulties in the classical through-diffusion technique applied to situations where large diffusive fluxes of cations in compacted clay minerals or clay rocks occur. The results obtained from a benchmark study, in which the diffusion of (85)Sr(2+) tracer in compacted illite has been studied using different experimental techniques, are presented. It is shown that these techniques may yield valuable results provided that an appropriate model is used for numerical simulations. It is further shown that effective diffusion coefficients may be systematically underestimated when the concentration at the downstream boundary is not taken adequately into account in modelling, even for very low concentrations. A criterion is derived for quasi steady-state situations, by which it can be decided whether the simplifying assumption of a zero-concentration at the downstream boundary in through diffusion is justified or not. The application of the criterion requires, however, knowledge of the effective diffusion coefficient of the clay sample. Such knowledge is often absent or only approximately available during the planning phase of a diffusion experiment. PMID- 26004773 TI - Drug Targeting Based on a New Concept-Targeting Against TLR4 as an Example. AB - TLRs are very important players to regulate innate immune responses. TLR4 controls the host defense by sensing an exotic pathogen, such as lipopolysaccharides. At the same time, some endogenous proteins, including HMGB1 and S100A8, could also function to be a ligand to elicit inflammatory reactions. These facts make TLR4 signaling system very complicated. For instance, the application of TLR4 ligands in cancer therapies is desirable for enhancement of anti-tumor immunity in terms of its reparative nature, but undesirable for enhancement of metastatic growth of cancer cells. In this manuscript, in order to make a novel molecular design to disrupt an interaction between TLR4/MD-2 and endogenous ligands, we provide a potential binding style of the TLR4/MD-2 complex with HMGB1 by using their 3D structural data and docking simulations, and also discuss S100A8 binding to TLR4/MD-2. PMID- 26004768 TI - Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy. AB - BACKGROUND: In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy. METHODS: Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib. CONCLUSIONS: In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive. PMID- 26004774 TI - Maternal mortality in Africa: investigating more, acting more. PMID- 26004775 TI - Maternal mortality and distance to facility-based obstetric care in rural southern Tanzania: a secondary analysis of cross-sectional census data in 226 000 households. AB - BACKGROUND: Access to skilled obstetric delivery and emergency care is deemed crucial for reducing maternal mortality. We assessed pregnancy-related mortality by distance to health facilities and by cause of death in a disadvantaged rural area of southern Tanzania. METHODS: We did a secondary analysis of cross sectional georeferenced census data collected from June to October, 2007, in five rural districts of southern Tanzania. Heads of georeferenced households were asked about household deaths in the period June 1, 2004, to May 31, 2007, and women aged 13-49 years were interviewed about birth history in the same time period. Causes of death in women of reproductive age were ascertained by verbal autopsy. We also asked for sociodemographic information. Multilevel logistic regression was used to analyse the effects of distance to health facilities providing delivery care on pregnancy-related mortality (direct and indirect maternal and coincidental deaths). FINDINGS: The study included 818 583 people living in 225 980 households. Pregnancy-related mortality was high at 712 deaths per 100 000 livebirths, with haemorrhage being the leading cause of death. Deaths due to direct causes of maternal mortality were strongly related to distance, with mortality increasing from 111 per 100 000 livebirths among women who lived within 5 km to 422 deaths per 100 000 livebirths among those who lived more than 35 km from a hospital (adjusted odds ratio 3.68; 95% CI 1.37-9.88). Neither pregnancy-related nor indirect maternal mortality was associated with distance to hospital. Among women who lived within 5 km of a hospital, pregnancy-related mortality was 664 deaths per 100 000 livebirths even though 72% gave birth in hospital and 8% had delivery by caesarean section. INTERPRETATION: Large distances to hospital contribute to high levels of direct obstetric mortality. High pregnancy-related mortality in those living near to a hospital suggests deficiencies in quality of care. FUNDING: Bill & Melinda Gates Foundation. PMID- 26004776 TI - The Kinetic Reaction Mechanism of the Vibrio cholerae Sodium-dependent NADH Dehydrogenase. AB - The sodium-dependent NADH dehydrogenase (Na(+)-NQR) is the main ion transporter in Vibrio cholerae. Its activity is linked to the operation of the respiratory chain and is essential for the development of the pathogenic phenotype. Previous studies have described different aspects of the enzyme, including the electron transfer pathways, sodium pumping structures, cofactor and subunit composition, among others. However, the mechanism of the enzyme remains to be completely elucidated. In this work, we have studied the kinetic mechanism of Na(+)-NQR with the use of steady state kinetics and stopped flow analysis. Na(+)-NQR follows a hexa-uni ping-pong mechanism, in which NADH acts as the first substrate, reacts with the enzyme, and the oxidized NAD leaves the catalytic site. In this conformation, the enzyme is able to capture two sodium ions and transport them to the external side of the membrane. In the last step, ubiquinone is bound and reduced, and ubiquinol is released. Our data also demonstrate that the catalytic cycle involves two redox states, the three- and five-electron reduced forms. A model that gathers all available information is proposed to explain the kinetic mechanism of Na(+)-NQR. This model provides a background to understand the current structural and functional information. PMID- 26004777 TI - Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1). AB - Ovarian cancer is a lethal gynecological disease that is characterized by peritoneal metastasis and increased resistance to conventional chemotherapies. This increased resistance and the ability to spread is often attributed to the formation of multicellular aggregates or spheroids in the peritoneal cavity, which seed abdominal surfaces and organs. Given that the presence of metastatic implants is a predictor of poor survival, a better understanding of how spheroids form is critical to improving patient outcome, and may result in the identification of novel therapeutic targets. Thus, we attempted to gain insight into the proteomic changes that occur during anchorage-independent cancer cell aggregation. As such, an ovarian cancer cell line, OV-90, was cultured in adherent and non-adherent conditions using stable isotope labeling with amino acids in cell culture (SILAC). Anchorage-dependent cells (OV-90AD) were grown in tissue culture flasks, whereas anchorage-independent cells (OV-90AI) were grown in suspension using the hanging-drop method. Cellular proteins from both conditions were then identified using LC-MS/MS, which resulted in the quantification of 1533 proteins. Of these, 13 and 6 proteins were up-regulated and down-regulated, respectively, in aggregate-forming cells compared with cells grown as monolayers. Relative gene expression and protein expression of candidates were examined in other cell line models of aggregate formation (TOV 112D and ES-2), which revealed an increased expression of calcium-activated chloride channel regulator 1 (CLCA1). Moreover, inhibitor and siRNA transfection studies demonstrated an apparent effect of CLCA1 on cancer cell aggregation. Further elucidation of the role of CLCA1 in the pathogenesis of ovarian cancer is warranted. PMID- 26004778 TI - Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta. AB - Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2alpha, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen. PMID- 26004782 TI - Recent Updates on Peroxisome Proliferator-Activated Receptor delta Agonists for the Treatment of Metabolic Syndrome. AB - Metabolic syndrome is a disorder described by reduced insulin sensitivity, overweight, hyperlipidaemia, high blood pressure and myocardial disorders, mainly due to high fat diet and lack of physical activity. The peroxisome proliferator activated receptors (PPARs) are type II nuclear hormone receptors that regulate a number of processes in living systems, such as metabolism of carbohydrates and fatty acids, growth and differentiation of cell, and inflammatory reactions. Alpha, gamma and delta are the three distinct isoforms of PPAR. The stimulation of PPARdelta alters body's energy fuel preference from glucose to fat. The PPARdelta isoform is expressed ubiquitously in all tissues, especially in those tissues which involved in metabolism of lipids like adipose tissue, liver, kidney, and muscle. Currently, PPARdelta is an emerging therapeutic target for the pharmacological therapy of disorders associated with metabolic syndrome. Several PPARdelta selective agonists had been reported in last ten years, many of them had been advanced into the late phase of clinical trials such as Endurobol (GW501516). However, no PPARdelta agonists are yet approved for human use. The present work had been planned to cover wide variety of PPARdelta agonists reported till now along with their potential role to tackle various metabolic disorders. The present review has been planned to focus mainly the most popular PPARdelta agonists. PMID- 26004780 TI - Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem Cell Populations. AB - Heterogeneity within the self-renewal durability of adult hematopoietic stem cells (HSCs) challenges our understanding of the molecular framework underlying HSC function. Gene expression studies have been hampered by the presence of multiple HSC subtypes and contaminating non-HSCs in bulk HSC populations. To gain deeper insight into the gene expression program of murine HSCs, we combined single-cell functional assays with flow cytometric index sorting and single-cell gene expression assays. Through bioinformatic integration of these datasets, we designed an unbiased sorting strategy that separates non-HSCs away from HSCs, and single-cell transplantation experiments using the enriched population were combined with RNA-seq data to identify key molecules that associate with long term durable self-renewal, producing a single-cell molecular dataset that is linked to functional stem cell activity. Finally, we demonstrated the broader applicability of this approach for linking key molecules with defined cellular functions in another stem cell system. PMID- 26004781 TI - Efficient Detection and Purification of Cell Populations Using Synthetic MicroRNA Switches. AB - Isolation of specific cell types, including pluripotent stem cell (PSC)-derived populations, is frequently accomplished using cell surface antigens expressed by the cells of interest. However, specific antigens for many cell types have not been identified, making their isolation difficult. Here, we describe an efficient method for purifying cells based on endogenous miRNA activity. We designed synthetic mRNAs encoding a fluorescent protein tagged with sequences targeted by miRNAs expressed by the cells of interest. These miRNA switches control their translation levels by sensing miRNA activities. Several miRNA switches (miR-1-, miR-208a-, and miR-499a-5p-switches) efficiently purified cardiomyocytes differentiated from human PSCs, and switches encoding the apoptosis inducer Bim enriched for cardiomyocytes without cell sorting. This approach is generally applicable, as miR-126-, miR-122-5p-, and miR-375-switches purified endothelial cells, hepatocytes, and insulin-producing cells differentiated from hPSCs, respectively. Thus, miRNA switches can purify cell populations for which other isolation strategies are unavailable. PMID- 26004783 TI - Animal models for ebolavirus countermeasures discovery: what defines a useful model? AB - INTRODUCTION: Ebolaviruses are highly pathogenic filoviruses, which cause disease in humans and nonhuman primates (NHP) in Africa. The Zaire ebolavirus outbreak in 2014, which continues to greatly affect Western Africa and other countries to which the hemorrhagic fever was exported due to travel of unsymptomatic yet infected individuals, was complicated by the lack of available licensed vaccines or therapeutics to combat infection. After almost a year of research at an increased pace to find and test vaccines and therapeutics, there is now a deeper understanding of the available disease models for ebolavirus infection. Demonstration of vaccine or therapeutic efficacy in NHP models of ebolavirus infection is crucial to the development and eventual licensure of ebolavirus medical countermeasures, so that safe and effective countermeasures can be accelerated into human clinical trials. AREAS COVERED: The authors describe ebolavirus hemorrhagic fever (EHF) disease in various animal species: mice, guinea pigs, hamsters, pigs and NHP, to include baboons, marmosets, rhesus and cynomolgus macaques, as well as African green monkeys. Because the NHP models are supremely useful for therapeutics and vaccine testing, emphasis is placed on comparison of these models, and their use as gold-standard models of EHF. EXPERT OPINION: Animal models of EHF varying from rodents to NHP species are currently under evaluation for their reproducibility and utility for modeling infection in humans. Complete development and licensure of therapeutic agents and vaccines will require demonstration that mechanisms conferring protection in NHP models of infection are predictive of protective responses in humans, for a given countermeasure. PMID- 26004784 TI - SNPscan as a high-performance screening tool for mutation hotspots of hearing loss-associated genes. AB - In the present study, to assess the feasibility of the SNPscan technique for mutation screening in patients with nonsyndromic hearing loss (NSHL) and neonatus in China, the SNPscan technique was compared with the SNaPshot screening system. Chinese patients (162) with NSHL were used as the experimental group and 276 children without HL were used as the control group, respectively. SNPscan detected molecular defects in 112 patients (68.5%). In this technique, 83 patients (51.2%) with homozygous or compound heterozygous had confirmed molecular etiology in the GJB2, SLC26A4, and MT-RNR1 genes. By contrast, SNaPshot detected molecular defects in 103 patients (63.6%). In this method, 72 subjects (44.4%) with HL were confirmed to have NSHL caused by these mutations. This study demonstrates that SNPscan performs equally well or better than earlier routine genotyping method for genetic hearing loss, with possibility of detecting a larger variety of mutation. PMID- 26004785 TI - Validation of the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E) in West China. AB - OBJECTIVE: We aimed to validate the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) for Chinese people with epilepsy (PWE). METHODS: The NDDI-E was translated into a Chinese version. A consecutive cohort of PWE from West China Hospital was recruited to test the reliability and validity of the Chinese version of the NDDI-E (C-NDDI-E). Each patient underwent the Mini International Neuropsychiatric Interview (MINI) and C-NDDI-E. RESULTS: A total of 202 PWE completed the psychiatric evaluation. The C-NDDI-E was easily comprehended and quickly completed by all participants. Fifty-four patients (26.7%) had current major depressive disorder (MDD) according to the MINI criteria. The Cronbach's alpha coefficient for the C-NDDI-E was 0.825. Receiver operating characteristic analyses showed an area under the curve of 0.936 (95% CI=0.904-0.968). At a cutoff score of >12, the C-NDDI-E had a sensitivity of 0.926, a specificity of 0.804, a positive predictive value of 0.633, and a negative predictive value of 0.967. CONCLUSION: The C-NDDI-E is a valuable instrument for screening MDD in Chinese PWE. PMID- 26004786 TI - Characterization of a surface reaction by means of atomic force microscopy. AB - We study a thermally activated on-surface planarization reaction by a detailed analysis of the reactant and reaction products from atomically resolved atomic force microscopy (AFM) images and spectroscopy. The three-dimensional (3D) structure of the reactant, a helical diphenanthrene derivative, requires going beyond constant-height imaging. The characterization in three dimensions is enabled by acquisition and analysis of the AFM signal in a 3D data set. This way, the structure and geometry of nonplanar molecules as well as their reaction products on terraces and at step edges can be determined. PMID- 26004787 TI - 'O' blood type is associated with larger grey-matter volumes in the cerebellum. AB - Recent evidence indicated higher incidence of cognitive deficits in ABO blood type system 'AB' individuals. Since this statistical difference might originate from the lack of protective effects exerted by 'O' alleles on the brain via vascular or non-vascular routes, this study investigated volumetric differences in grey matter between 'O' and non-'O' adults to explore the possibility of a structural endophenotype visible in 'O' adults without cognitive impairment or neurodegeneration. A large sample of cognitively healthy adults who had previously undergone structural MRI for research purposes were contacted telephonically and enquired about their ABO blood type. Out of the 189 individuals who were able to retrieve and communicate this information, 'O' (n=76) and 'A' adults (n=65) were included in Model 1. In Model 2, all non-'O' (n=113) were instead collapsed in a single group. Voxel-Based Morphometry analyses were carried out on three-dimensional T1-weighted scans, and between sample t tests were run to compare the maps of grey-matter volumes of the subgroups of interest, controlling for major nuisance variables. In Model 1, 'O' adults had larger grey-matter volumes in two symmetrical clusters within the posterior ventral portion of the cerebellum. This was confirmed in Model 2. Additionally, non-'O' adults showed lower volume values in temporal and limbic regions, including the left hippocampus. The cerebellar clusters were located in regions previously found to be part of a network responsible for sensorimotor integration. It is speculated that the structural reductions seen in non-'O' adults might result in a susceptibility to down-regulation of this network. This occurrence is likely to intensify along the ageing process and may contribute to foster cognitive decline. Although Model 2 seems to suggest that having a 'O' blood type might play a role in protection against those conditions in which temporal and mediotemporal volumetric loss is observed (Alzheimer's disease), additional supporting evidence is needed. A number of potential biological processes might sustain these between-group differences, including sensorimotor ontogenesis, hormonal function, and a regional impact of cerebral amyloid angiopathy. These findings identify the cerebellar tissue as a candidate for further studying ABO function, and support a general association between ABO blood type and variance in the development of the nervous system. PMID- 26004788 TI - Vitamin C reverses lead-induced deficits in hippocampal synaptic plasticity in rats. AB - Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity. PMID- 26004789 TI - Identifying human microRNA-disease associations by a new diffusion-based method. AB - Identifying the microRNA-disease relationship is vital for investigating the pathogenesis of various diseases. However, experimental verification of disease related microRNAs remains considerable challenge to many researchers, particularly for the fact that numerous new microRNAs are discovered every year. As such, development of computational methods for disease-related microRNA prediction has recently gained eminent attention. In this paper, first, we construct a miRNA functional network and a disease similarity network by integrating different information sources. Then, we further introduce a new diffusion-based method (NDBM) to explore global network similarity for miRNA disease association inference. Even though known miRNA-disease associations in the database are rare, NDBM still achieves an area under the ROC curve (AUC) of 85.62% in the leave-one-out cross-validation in improving the prediction accuracy of previous methods significantly. Moreover, our method is applicable to diseases with no known related miRNAs as well as new miRNAs with unknown target diseases. Some associations who strongly predicted by our method are confirmed by public databases. These superior performances suggest that NDBM could be an effective and important tool for biomedical research. PMID- 26004790 TI - Annotating risk factors for heart disease in clinical narratives for diabetic patients. AB - The 2014 i2b2/UTHealth natural language processing shared task featured a track focused on identifying risk factors for heart disease (specifically, Cardiac Artery Disease) in clinical narratives. For this track, we used a "light" annotation paradigm to annotate a set of 1304 longitudinal medical records describing 296 patients for risk factors and the times they were present. We designed the annotation task for this track with the goal of balancing annotation load and time with quality, so as to generate a gold standard corpus that can benefit a clinically-relevant task. We applied light annotation procedures and determined the gold standard using majority voting. On average, the agreement of annotators with the gold standard was above 0.95, indicating high reliability. The resulting document-level annotations generated for each record in each longitudinal EMR in this corpus provide information that can support studies of progression of heart disease risk factors in the included patients over time. These annotations were used in the Risk Factor track of the 2014 i2b2/UTHealth shared task. Participating systems achieved a mean micro-averaged F1 measure of 0.815 and a maximum F1 measure of 0.928 for identifying these risk factors in patient records. PMID- 26004791 TI - When to conduct probabilistic linkage vs. deterministic linkage? A simulation study. AB - INTRODUCTION: When unique identifiers are unavailable, successful record linkage depends greatly on data quality and types of variables available. While probabilistic linkage theoretically captures more true matches than deterministic linkage by allowing imperfection in identifiers, studies have shown inconclusive results likely due to variations in data quality, implementation of linkage methodology and validation method. The simulation study aimed to understand data characteristics that affect the performance of probabilistic vs. deterministic linkage. METHODS: We created ninety-six scenarios that represent real-life situations using non-unique identifiers. We systematically introduced a range of discriminative power, rate of missing and error, and file size to increase linkage patterns and difficulties. We assessed the performance difference of linkage methods using standard validity measures and computation time. RESULTS: Across scenarios, deterministic linkage showed advantage in PPV while probabilistic linkage showed advantage in sensitivity. Probabilistic linkage uniformly outperformed deterministic linkage as the former generated linkages with better trade-off between sensitivity and PPV regardless of data quality. However, with low rate of missing and error in data, deterministic linkage performed not significantly worse. The implementation of deterministic linkage in SAS took less than 1min, and probabilistic linkage took 2min to 2h depending on file size. DISCUSSION: Our simulation study demonstrated that the intrinsic rate of missing and error of linkage variables was key to choosing between linkage methods. In general, probabilistic linkage was a better choice, but for exceptionally good quality data (<5% error), deterministic linkage was a more resource efficient choice. PMID- 26004792 TI - Identifying synonymy between relational phrases using word embeddings. AB - Many text mining applications in the biomedical domain benefit from automatic clustering of relational phrases into synonymous groups, since it alleviates the problem of spurious mismatches caused by the diversity of natural language expressions. Most of the previous work that has addressed this task of synonymy resolution uses similarity metrics between relational phrases based on textual strings or dependency paths, which, for the most part, ignore the context around the relations. To overcome this shortcoming, we employ a word embedding technique to encode relational phrases. We then apply the k-means algorithm on top of the distributional representations to cluster the phrases. Our experimental results show that this approach outperforms state-of-the-art statistical models including latent Dirichlet allocation and Markov logic networks. PMID- 26004793 TI - A New Fractionation and Recovery Method of Viral Genomes Based on Nucleic Acid Composition and Structure Using Tandem Column Chromatography. AB - Metagenomic studies have revealed the unexplored diversity of the environmental virosphere. However, most studies are biased towards specific types of viral genomes due to the absence of universal methods to access all viral genome types. In the present study, we established a novel system to efficiently separate single- and double-stranded DNA/RNA viral genomes using hydroxyapatite and cellulose chromatography. This method will allow us to quantitatively and simultaneously access four types of viral genomes and will provide important clues to further understand previously unexplored environmental viral populations and obtain potentially unbiased libraries from environmental viral communities. PMID- 26004794 TI - Effect of Probiotics/Prebiotics on Cattle Health and Productivity. AB - Probiotics/prebiotics have the ability to modulate the balance and activities of the gastrointestinal (GI) microbiota, and are, thus, considered beneficial to the host animal and have been used as functional foods. Numerous factors, such as dietary and management constraints, have been shown to markedly affect the structure and activities of gut microbial communities in livestock animals. Previous studies reported the potential of probiotics and prebiotics in animal nutrition; however, their efficacies often vary and are inconsistent, possibly, in part, because the dynamics of the GI community have not been taken into consideration. Under stressed conditions, direct-fed microbials may be used to reduce the risk or severity of scours caused by disruption of the normal intestinal environment. The observable benefits of prebiotics may also be minimal in generally healthy calves, in which the microbial community is relatively stable. However, probiotic yeast strains have been administered with the aim of improving rumen fermentation efficiency by modulating microbial fermentation pathways. This review mainly focused on the benefits of probiotics/prebiotics on the GI microbial ecosystem in ruminants, which is deeply involved in nutrition and health for the animal. PMID- 26004796 TI - Management of small renal mass: an opportunity to address a growing problem in early stage kidney cancer. PMID- 26004795 TI - Biotechnological Aspects of Microbial Extracellular Electron Transfer. AB - Extracellular electron transfer (EET) is a type of microbial respiration that enables electron transfer between microbial cells and extracellular solid materials, including naturally-occurring metal compounds and artificial electrodes. Microorganisms harboring EET abilities have received considerable attention for their various biotechnological applications, in addition to their contribution to global energy and material cycles. In this review, current knowledge on microbial EET and its application to diverse biotechnologies, including the bioremediation of toxic metals, recovery of useful metals, biocorrosion, and microbial electrochemical systems (microbial fuel cells and microbial electrosynthesis), were introduced. Two potential biotechnologies based on microbial EET, namely the electrochemical control of microbial metabolism and electrochemical stimulation of microbial symbiotic reactions (electric syntrophy), were also discussed. PMID- 26004797 TI - Renal Tumor Biopsy: More Dogma Belied. PMID- 26004798 TI - Improving what matters. PMID- 26004799 TI - Reply to Pranav Sharma, Asad Sawar and Philippe Spiess' letter to the editor re: re: Craig Rogers, Ravi Barod, Scott Schwartz, Mani Menon. Endovascular extraction of caval tumor thrombus to facilitate minimally invasive cytoreductive nephrectomy for metastatic kidney cancer. Eur Urol 2015;68:167-8. PMID- 26004800 TI - Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. AB - BACKGROUND: Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. OBJECTIVE: To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. DESIGN, SETTING, AND PARTICIPANTS: A total of 680 men who received adjuvant radiation therapy (n=105) or salvage radiation therapy (n=575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. INTERVENTION: RT was delivered using three-dimensional conformal or intensity-modulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin releasing hormone agonist with or without a nonsteroidal antiandrogen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. RESULTS AND LIMITATIONS: Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8-10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0-23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p=0.003) and DM (HR: 2.48; p=0.03) compared with patients receiving >=12 mo of ADT. The 5 yr rates of DM were 6.0% and 23% for >=12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p=0.0004), DM (HR: 0.88; p=0.0004), and PCSM (HR: 0.90; p=0.037). These findings are limited by the retrospective nature of our analysis. CONCLUSIONS: For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT >=12 mo may be preferable. Validation of our findings is needed. PATIENT SUMMARY: We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes. PMID- 26004801 TI - MARK-AGE data management: Cleaning, exploration and visualization of data. AB - Databases are an organized collection of data and necessary to investigate a wide spectrum of research questions. For data evaluation analyzers should be aware of possible data quality problems that can compromise results validity. Therefore data cleaning is an essential part of the data management process, which deals with the identification and correction of errors in order to improve data quality. In our cross-sectional study, biomarkers of ageing, analytical, anthropometric and demographic data from about 3000 volunteers have been collected in the MARK-AGE database. Although several preventive strategies were applied before data entry, errors like miscoding, missing values, batch problems etc., could not be avoided completely. Such errors can result in misleading information and affect the validity of the performed data analysis. Here we present an overview of the methods we applied for dealing with errors in the MARK AGE database. We especially describe our strategies for the detection of missing values, outliers and batch effects and explain how they can be handled to improve data quality. Finally we report about the tools used for data exploration and data sharing between MARK-AGE collaborators. PMID- 26004803 TI - Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3 oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir. AB - tert-Butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) is a valuable chiral synthon, which is used for the synthesis of the cholesterol-lowering drugs atorvastatin and rosuvastatin. To date, only the alcohol dehydrogenases from Lactobacillus brevis (LbADH) and Lactobacillus kefir (LkADH) have demonstrated catalytic activity toward the asymmetric reduction of tert-butyl 6-chloro-3,5 dioxohexanoate (CDOH) to (S)-CHOH. Herein, a tetrad mutant of LkADH (LkTADH), A94T/F147L/L199H/A202L, was screened to be more efficient in this bioreduction process, exhibiting a 3.7- and 42-fold improvement in specific activity toward CDOH (1.27 U/mg) over LbADH (0.34 U/mg) and wild-type LkADH (0.03 U/mg), respectively. The molecular basis for the improved catalytic activity of LkTADH toward CDOH was investigated using homology modeling and docking analysis. Two major issues had a significant impact on the biocatalytic efficiency of this process, including (i) the poor aqueous stability of the substrate and (ii) partial substrate inhibition. A fed-batch strategy was successfully developed to address these issues and maintain a suitably low substrate concentration throughout the entire process. Several other parameters were also optimized, including the pH, temperature, NADP(+) concentration and cell loading. A final CDOH concentration of 427 mM (100 g/L) gave (S)-CHOH in 94 % yield and 99.5 % e.e. after a reaction time of 38 h with whole cells expressing LkTADH. The space time yield and turnover number of NADP(+) in this process were 10.6 mmol/L/h and 16,060 mol/mol, respectively, which were the highest values ever reported. This new approach therefore represents a promising alternative for the efficient synthesis of (S)-CHOH. PMID- 26004802 TI - Metabolism of beta-valine via a CoA-dependent ammonia lyase pathway. AB - Pseudomonas species strain SBV1 can rapidly grow on medium containing beta-valine as a sole nitrogen source. The tertiary amine feature of beta-valine prevents direct deamination reactions catalyzed by aminotransferases, amino acid dehydrogenases, and amino acid oxidases. However, lyase- or aminomutase-mediated conversions would be possible. To identify enzymes involved in the degradation of beta-valine, a PsSBV1 gene library was prepared and used to complement the beta valine growth deficiency of a closely related Pseudomonas strain. This resulted in the identification of a gene encoding beta-valinyl-coenzyme A ligase (BvaA) and two genes encoding beta-valinyl-CoA ammonia lyases (BvaB1 and BvaB2). The BvaA protein demonstrated high sequence identity to several known phenylacetate CoA ligases. Purified BvaA enzyme did not convert phenyl acetic acid but was able to activate beta-valine in an adenosine triphosphate (ATP)- and CoA-dependent manner. The substrate range of the enzyme appears to be narrow, converting only beta-valine and to a lesser extent, 3-aminobutyrate and beta-alanine. Characterization of BvaB1 and BvaB2 revealed that both enzymes were able to deaminate beta-valinyl-CoA to produce 3-methylcrotonyl-CoA, a common intermediate in the leucine degradation pathway. Interestingly, BvaB1 and BvaB2 demonstrated no significant sequence identity to known CoA-dependent ammonia lyases, suggesting they belong to a new family of enzymes. BLAST searches revealed that BvaB1 and BvaB2 show high sequence identity to each other and to several enoyl CoA hydratases, a class of enzymes that catalyze a similar reaction with water instead of amine as the leaving group. PMID- 26004804 TI - Probiotic attributes of Lactobacillus fermentum isolated from human feces and dairy products. AB - The objective of this study was to characterize native Lactobacillus fermentum isolates for their probiotic attributes. Accordingly, 12 L. fermentum isolates selected from indigenous fermented dairy products and infant fecal samples were evaluated for their probiotic properties by in vitro and PCR methods. The cultures exhibited high tolerance to acid and bile as well as survival in simulated transit fluids (above 70 %). Cell surface hydrophobicity was in the range of 0.55-57.69 % for xylene and 0.45-77.12 % for hexadecane, whereas auto aggregation ranged between 9 and 62 %. Isolates exhibited efficient binding to mucin and fibronectin, bile salt hydrolase activity, cholesterol assimilation (49 76 %), and radical scavenging activity (37-77 %). The isolates demonstrated antibacterial activity against Listeria monocytogenes Scott A and Micrococcus luteus ATCC 9341. Molecular fingerprinting and identification of the isolates were achieved by PCR with GTG5 as well as 16S rRNA, phenylalanyl-tRNA synthetase alpha subunit (pheS), and RNA polymerase alpha subunit (rpoA) genes. This revealed the genomic diversity of the isolates from the two sources. Gene specific amplification of probiotic marker genes was attained by PCR-based methods, and resultant products were sequenced. Multiple sequence alignment of the probiotic marker genes using bioinformatics revealed similarity to completely sequenced genomes of L. fermentum CECT 5716 and IFO 3956 with a few variations in mucin-binding protein gene sequences. Isolates designated as L. fermentum MCC 2759 and L. fermentum MCC 2760 showed the best probiotic attributes with high survival in simulated gastrointestinal fluids, in vitro adhesion, cholesterol reduction, and high antioxidative potential. Thus, these cultures could be potential probiotic candidates for application as functional foods. PMID- 26004805 TI - Phosphorylation of Ser-204 and Tyr-405 in human malonyl-CoA decarboxylase expressed in silkworm Bombyx mori regulates catalytic decarboxylase activity. AB - Decarboxylation of malonyl-CoA to acetyl-CoA by malonyl-CoA decarboxylase (MCD; EC 4.1.1.9) is a vital catalytic reaction of lipid metabolism. While it is established that phosphorylation of MCD modulates the enzymatic activity, the specific phosphorylation sites associated with the catalytic function have not been documented due to lack of sufficient production of MCD with proper post translational modifications. Here, we used the silkworm-based Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid system to express human MCD (hMCD) and mapped phosphorylation effects on enzymatic function. Purified MCD from silkworm displayed post-translational phosphorylation and demonstrated coherent enzymatic activity with high yield (-200 MUg/silkworm). Point mutations in putative phosphorylation sites, Ser-204 or Tyr-405 of hMCD, identified by bioinformatics and proteomics analyses reduced the catalytic activity, underscoring the functional significance of phosphorylation in modulating decarboxylase-based catalysis. Identified phosphorylated residues are distinct from the decarboxylation catalytic site, implicating a phosphorylation-induced global conformational change of MCD as responsible in altering catalytic function. We conclude that phosphorylation of Ser-204 and Tyr-405 regulates the decarboxylase function of hMCD leveraging the silkworm-based BmNPV bacmid expression system that offers a fail-safe eukaryotic production platform implementing proper post translational modification such as phosphorylation. PMID- 26004806 TI - Clinical characteristics of acute lacunar stroke in young adults. AB - INTRODUCTION: Acute lacunar stroke in subjects under 55 years of age has been poorly characterized. METHODS: We assessed the clinical features of lacunar stroke in 51 patients aged <=55 years (84.5% men, mean standard deviation [SD] age 49.8 [5.2] years) collected from a prospective hospital-based stroke registry in Barcelona, Catalonia, Spain. RESULTS: This subset of young lacunar stroke patients accounted for only 5.2% of all lacunar strokes, 1.2% of all ischemic strokes, and 1.1% of all acute strokes included in the registry over a 24-year period. In the multivariate analysis, factors independently associated with acute lacunar stroke in patients aged <=55 years were alcohol consumption (>60 g/day) (odds ratio [OR] = 6.67), heavy smoking (>20 cigarettes/day) (OR = 3.02), obesity (OR = 2.81), essential etiology (OR = 2.73), and headache at stroke onset (OR = 2.45). CONCLUSION: Characterization of the clinical profile of acute lacunar stroke in younger patients contributes to a better knowledge of the full clinical expression of this ischemic stroke subtype. PMID- 26004807 TI - Osseous and dental outcomes of primary gingivoperiosteoplasty with iliac bone graft: A radiological evaluation. AB - Primary alveolar cleft repair has two main purposes: to restore normal morphology and normal function. Gingivoperiosteoplasty with bone grafting in mixed dentition has been a well-established procedure. We hypothesized that 1) performance of this surgery in deciduous dentition would provide favorable bone graft osseointegration, and 2) would improve the support of incisor teeth eruption, thereby avoiding maxillary growth disturbances. We conducted a retrospective study of clinical and tridimensional radiological data for 73 patients with alveolar clefts (with or without lip and palate clefts) who underwent gingivoperiosteoplasty with iliac bone graft in deciduous dentition. Pre- and post-operative Cone Beam Computed Tomography (CBCT) comparison allowed evaluation of the ratio between bone graft volume and initial cleft volume (BGV/ICV ratio), and measurement of central incisor teeth movements. This series of 73 patients included 44 males and 29 females, with a mean age of 5.5 years. Few complications were observed. Post-operative CBCT was performed at 7.4 months. The mean BGV/ICV ratio was 0.62. Axial rotation was significantly improved post-operatively (p = 0.004). Gingivoperiosteoplasty with iliac bone graft is safe when performed in deciduous dentition and results in a sufficient bone graft volume to support lateral incisor eruption and upper central incisor tooth position improvement. PMID- 26004808 TI - Microfluidic analysis of pressure drop and flow behavior in hypertensive micro vessels. AB - The retinal arterial network is the only source of the highly nutrient consumptive retina, thus any insult on the arteries can impair the retinal oxygen and nutrient supply and affect its normal function. The aim of this work is to study the influences of vascular structure variation on the flow and pressure characteristics via microfluidic devices. Two sets of micro-channel were designed to mimic the stenosed microvessels and dichotomous branching structure in the retinal arteries. Three working fluids including red blood cell (RBC) suspension were employed to investigate the pressure drop in the stenosed channel. The flow behaviors of RBC suspensions inside the micro channels were observed using high speed camera system. Pressure drop of different working fluids and RBC velocity profiles in the stenosed channel were obtained. Moreover, hematocrit levels of RBC suspensions inside the bifurcated channels were analyzed from the sequential images of RBC flow. The results of the flow in the stenosed channel show that RBCs drift from the center of the channels, and RBC velocity is influenced not only by the inlet flow rate but also the interaction between RBCs. The measured pressure drops in the stenosed channel increase notably with the increase of fluid viscosity. Furthermore, the dimensionless pressure drop due to the stenosis decreases with Reynolds number. On the other hand, the results of flow through the bifurcated channels show that as the ratio of the daughter-branch width to the mother-channel width increases, the ratio of hematocrit in two connected branches (Ht/Hd) decreases, which is in favorable agreement with the available analysis results. PMID- 26004809 TI - NUP98/11p15 translocations affect CD34+ cells in myeloid and T lymphoid leukemias. AB - We assessed lineage involvement by NUP98 translocations in myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML), and T-cell acute lymphoblastic leukaemia (T-ALL). Single cell analysis by FICTION (Fluorescence Immunophenotype and Interphase Cytogenetics as a Tool for Investigation of Neoplasms) showed that, despite diverse partners, i.e. NSD1, DDX10, RAP1GDS1, and LNP1, NUP98 translocations always affected a CD34+/CD133+ hematopoietic precursor. Interestingly the abnormal clone included myelomonocytes, erythroid cells, B- and T- lymphocytes in MDS/AML and only CD7+/CD3+ cells in T-ALL. The NUP98-RAP1GDS1 affected different hematopoietic lineages in AML and T-ALL. Additional specific genomic events, were identified, namely FLT3 and CEBPA mutations in MDS/AML, and NOTCH1 mutations and MYB duplication in T-ALL. PMID- 26004810 TI - Expression and localisation of brain-type organic cation transporter (BOCT/24p3R/LCN2R) in the normal rat hippocampus and after kainate-induced excitotoxicity. AB - The iron siderophore binding protein lipocalin 2 (LCN2, also known as 24p3, NGAL and siderocalin) may be involved in iron homeostasis, but to date, little is known about expression of its putative receptor, brain-type organic cation transporter (BOCT, also known as BOCT1, 24p3R, NGALR and LCN2R), in the brain during neurodegeneration. The present study was carried out to elucidate the expression of LCN2 and BOCT in hippocampus after excitotoxicity induced by the glutamate analog, kainate (KA) and a possible role of LCN2 in neuronal injury. As reported previously, a rapid and sustained induction in expression of LCN2 was found in the hippocampus after intracerebroventicular injection of KA. BOCT was expressed in neurons of the saline-injected control hippocampus, and immunolabel for BOCT protein was preserved in pyramidal neurons of CA1 at 1 day post-KA injection, likely due to the delayed onset of neurodegeneration after KA injection. At 3 days and 2 weeks after KA injections, loss of immunolabel was observed due to degenerated neurons, although remaining neurons continued to express BOCT, and induction of BOCT was found in OX-42 positive microglia. This resulted in an overall decrease in BOCT mRNA and protein expression after KA treatment. Increased expression of the pro-apoptotic marker, Bim, was found in both neurons and microglia after KA injection, but TUNEL staining indicating apoptosis was found primarily in Bim-expressing neurons, but not microglia. Interaction between LCN2 and BOCT was found by DuoLink assay in cultured hippocampal neurons. Apo-LCN2 without iron caused no significant differences in neuronal Bim expression or cell survival, whereas holo-LCN2 consisting of LCN2:iron:enterochelin complex increased Bim mRNA expression and decreased neuronal survival. Together, results suggest that LCN2 and BOCT may have a role in neuronal injury. PMID- 26004811 TI - Targeting TRAIL in the treatment of cancer: new developments. AB - INTRODUCTION: While apoptosis is critical for maintaining homeostasis in normal cells, defective apoptosis contributes to the survival of cancer cells. TNF related apoptosis-inducing ligand (TRAIL)-targeted therapy has attracted significant effort for treating cancer, but the clinical results have revealed limitations. The authors review the current status of development of TRAIL targeted therapy with an outlook towards the future. AREAS COVERED: Recombinant human proteins, small molecules and agonistic monoclonal antibodies targeting death receptors that trigger TRAIL-mediated apoptosis are covered in this article. The authors review both intrinsic and extrinsic apoptotic pathways, highlighting how the apoptosis serves as a promising therapeutic target. They also review different categories of TRAIL pathway targeting agents and provide a brief overview of clinical trials using these agents. The authors discuss the limitations of conventional approaches for targeting the TRAIL pathway as well as future directions. EXPERT OPINION: The development of better combination partners for pro-apoptotic TRAIL pathway modulators including novel agents inhibiting anti apoptotic molecules or targeting alternative resistance pathways may improve the chances for anti-tumor responses in the clinic. Developing predictive biomarkers via circulating tumor cells/DNA, apoptosis signal products, and genetic signatures/protein biomarkers from tumor tissue are also suggested as future directions. PMID- 26004812 TI - Is practice rate rather than exercise intensity more important in health benefits of moderately obese postmenopausal women? AB - OBJECTIVE: The aim of this study was to evaluate the impact of brisk walking on physical fitness, body composition and fasting lipid-lipoprotein profile of women 50-65 years-old, once adherence or exercise intensity is considered. METHODS: A sample of 159 healthy, sedentary, obese postmenopausal women (body mass index [BMI]=29-35 kg/m2) was subjected to 3 sessions/week of 45 min-walking, at 60% of heart rate reserve (HRR), during 16 weeks. Body composition, physical fitness and fasting lipid-lipoprotein profile were assessed before and after the intervention. RESULTS: Among the three tertiles of adherence to exercise sessions (<71%, 71-87%,>87%) women displaying the greatest one were characterized by the highest reduction in body weight (-1.9+/-2.7 kg) (mean+/-SD), fat mass (-2.0+/ 2.3 kg) and waist girth (-4.4+/-3.4 cm) and the best improvement in physical fitness (7.3+/-3.5 mL O2/kg/min), (P<0.0001). A comparable analysis based on tertiles of walking intensity (<56%, 56-63%,>63% HRR) did not show between-group differences in body composition or physical fitness. Also, the fasting lipid lipoprotein profile was improved by a reduction of cholesterol, LDL cholesterol, and triglyceride levels and by an increase in HDL cholesterol, irrespective of the participants' adherence (0.053 ng/mL for 2 successive measurements; the study population was categorized as early (n=47) or late (n=40) OLA, using the median value of 21 DIM as the cutoff. Further milk samples were collected 6 times weekly, from morning and afternoon milkings, these were pooled by WIM, and one proportional sample was analyzed fresh for fat, protein, and lactose content by the dairy company Tine SA, using traditional FTIR spectrography in the wet phase of milk. Daily energy-balance calculations were performed in 42 lactations and averaged by WIM. Animals experiencing late OLA had a more negative energy balance in WIM 1, 3, 4, and 5, with the greatest differences been seen in WIM 3 and 4. A higher proportion of the fatty acids were medium chained, C14:0 and C16:0, in the early than in the late OLA group from WIM 1. In WIM 4, the proportion of total fatty acid content that was C16:0 predicted late OLA, with 74% sensitivity and 80% specificity. The long-chain proportion of the fatty acids C18:0 and cis-9 C18:1 were lower in the early than in the late OLA group. Differences were greatest in WIM 4 and 5. Differences in concentrations of cis-9 C18:1 were seen between the groups from WIM 1. No relationship was seen between OLA and milk concentrations of either protein or fat, or between OLA and the milk fat:protein ratio. The differences in milk fatty acid proportions between the 2 groups are most likely related to differences in energy balance. The study shows that frozen milk samples can be tested for fatty acids by FTIR spectroscopy and that FTIR spectroscopy of milk can be used to provide real-time information about cow reproductive function. PMID- 26004833 TI - Dietary Maillard reaction products and their fermented products reduce cardiovascular risk in an animal model. AB - This study examined the effects of Maillard reaction products (MRP) and MRP fermented by lactic acid bacteria on antioxidants and their enhancement of cardiovascular health in ICR mouse and rat models. In previous in vitro studies, the selected lactic acid bacteria were shown to significantly affect the activity of MRP. The expression of genes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) related to antioxidant activity was upregulated by Maillard-reacted sodium caseinate (cMRP), and cMRP fermented by Lactobacillus fermentum H9 (F-cMRP) synergistically increased the expression of catalase and superoxide dismutase when compared with the high-cholesterol-diet group. Bleeding time, the assay for determination of antithrombotic activity, was significantly prolonged by Maillard-reacted whey protein concentration (wMRP) and wMRP fermented by Lactobacillus gasseri H10 (F-wMRP), similar to the bleeding time of the aspirin group (positive control). In addition, the acute pulmonary thromboembolism-induced mice overcame severe body paralysis or death in both the wMRP and the F-wMRP groups. In the serum-level experiment, cMRP and F-cMRP significantly reduced the serum total and low-density lipoprotein cholesterol levels and triglycerides but had only a slight effect on high-density lipoprotein cholesterol. The levels of aspartate transaminase and alanine transaminase also declined in the cMRP and F-cMRP intake groups compared with the high-cholesterol diet group. In particular, F-cMRP showed the highest reducing effects on triglycerides, aspartate transaminase, and alanine transaminase. Moreover, the expression of cholesterol-related genes in the F-cMRP group demonstrated greater effects than for the cMRP group in the level of cholesterol 7 alpha-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), and low-density lipoprotein receptors compared with the high-cholesterol-diet group. The protective role of cMRP and F-cMRP in the high-cholesterol group may have been the result of an antioxidative defense mechanism that regulated cholesterol synthesis and metabolism. Therefore, F-cMRP and cMRP have the potential to play preventive and therapeutic roles in the management of cardiovascular disease. PMID- 26004834 TI - The effects of a garlic oil chemical compound, propyl-propane thiosulfonate, on ruminal fermentation and fatty acid outflow in a dual-flow continuous culture system. AB - The ban on the use of antibiotics as growth promoters in animal feeds in the European Union has stimulated research on potential alternatives. Recently, propyl-propane thiosulfonate (PTSO), a stable organosulfurate compound of garlic, was purified. The objectives of the current study were to investigate the potential effects of PTSO on rumen microbial fermentation and to define effective doses. Two experiments were conducted using dual-flow continuous culture fermenters in 2 replicated periods. Each experimental period consisted of 5 d for adaptation of the ruminal fluid and 3 d for sampling. Temperature (39 degrees C), pH (6.4), and liquid (0.10 h(-1)) and solid (0.05 h(-1)) dilution rates were maintained constant. Samples were taken 2 h after feeding and from the 24-h effluent. Samples were analyzed for volatile fatty acids (VFA) and nitrogen fractions, and degradation of nutrients was calculated. In addition, 24-h effluents from experiment 2 were analyzed for their fatty acid (FA) profile. Treatments in experiment 1 included a negative control without additive, a positive control with monensin (12mg/L), and PTSO at 30 and 300mg/L. The addition of 30mg/L did not affect any of the measurements tested. The addition of 300mg/L reduced microbial fermentation, as suggested by the decreased total VFA concentration, true degradation of organic matter and acid detergent fiber, and a tendency to decrease neutral detergent fiber degradation. Experiment 2 was conducted to test increasing doses of PTSO (0, 50, 100, and 150mg/L) on rumen microbial fermentation. At 2 h postfeeding, total VFA and molar proportion of propionate responded quadratically, with higher values in the intermediate doses. Molar proportions of butyrate increased and branched-chain VFA decreased linearly as the dose of PTSO increased. In the 24-h effluents, total VFA, acetate, and branched-chain VFA concentrations decreased linearly and those of propionate responded cubically with the highest value at 100mg/L. Saturated FA decreased and unsaturated FA increased linearly with increasing dose of PTSO. The concentration of trans-10,cis-12 conjugated linoleic acid decreased by 78.5% with addition of PTSO at the highest dose (150mg/L). Results suggest the potential of PTSO to modify ruminal fermentation in a direction consistent with higher propionate molar proportion, higher outflow of unsaturated FA, and low trans-10,cis-12 conjugated linoleic acid in an effective dose between 50 and 100mg/L. PMID- 26004835 TI - Carryover of bovine leukemia virus antibodies in samples from shared milk meters. AB - Screening for infectious diseases of cattle using milk from the dairy herd improvement (DHI) sampling process is very convenient. However, when samples from shared milk meters are used, carryover of antibodies or other diagnostic targets can complicate the interpretation of the diagnostic test results for diseases, including bovine leukosis. The objectives of this study were (1) to assess the potential for carryover of antibodies against bovine leukemia virus (BLV) in milk samples obtained from shared meters, and (2) to determine if adjustment of the diagnostic test cut-off value would improve the test characteristics for meter collected milk ELISA results. Eight dairy farms were randomly selected from herds with a wide range of BLV prevalence levels in Prince Edward Island, Canada. Within each chosen farm, 2 to 4milk meters were randomly selected. During the routine procedures of DHI sampling, 2 simultaneous milk samples, 1 hand-collected at the beginning of milking (after udder preparation) and the other from the corresponding milk meter, were taken from all lactating cows (n=236) that were milked at the selected meters (n=26). The sequence of cows using each meter was recorded. All samples were tested for BLV antibodies using a commercial indirect ELISA. Antibody carryover potential was assessed in meter-collected samples which were preceded by other cows using the same meters. Applying the hand-collected sample results as our reference standard, a new cut-off was defined for meter collected samples to optimize the test characteristics. At the standard cut-off value of the diagnostic test, 110 (46.6%) of the hand-collected and 136 (57.6%) of the meter-collected samples were positive. For low-titer cows (e.g., true negatives), the likelihood of antibody carryover significantly increased as the titer of preceding cows increased, whereas this change was not substantial for high-titer cows. The odds of obtaining false diagnoses in meter-positive samples became larger with increase in the titer of preceding cows. A suspicious category for meter ELISA results was defined, and a retest was recommended for the cows falling into this category. This strategy effectively assisted in reducing the number of consequent false-positive results. When DHI-collected samples are used, carryover can affect the interpretation of dichotomous test results and may require adjustment of assay cut-off values. PMID- 26004837 TI - Examination of weekly mammary parenchymal area by ultrasound, mammary mass, and composition in Holstein heifers reared on 1 of 3 diets from birth to 2 months of age. AB - Monitoring in vivo growth of mammary parenchyma (PAR) has historically been difficult, necessitating slaughter studies to measure PAR quantity. Advances in ultrasound (US) technology warrant revisiting its use as a noninvasive tool to monitor PAR growth in vivo. The level of nutrient intake during the first 2mo of life may affect measures of mammary growth and composition. Objectives were to examine the utility of US as an in vivo tool to quantify PAR cross-sectional area in Holstein heifers reared on 1 of 3 diets from birth to 2mo of age, assessing potential dietary effects; assess the relationships between weekly US measurements, teat length, manual palpation of PAR scores, and PAR mass at 2mo of age; and examine mammary composition in experimental animals. Holstein heifers (n=24; 41+/-1kg of initial body weight) from a single farm were randomly assigned to 1 of 3 milk replacers that differed in source and amount of fat. Milk replacer was fed at 660g of dry matter/d until weaning at 42 d. Heifers had ad libitum access to a common calf starter (20% crude protein) and water for the duration of the 56-d trial. Teat length and palpation scores were obtained weekly. A real time B-mode US with a 7.5-MHz convex probe was used to examine 2-dimensional PAR area in all 4 glands of heifers once weekly from 2 to 3 d of age to harvest at 56 d. The left front and left rear glands were also examined by US 24h postharvest to validate final US measurements, and then bisected to produce a sagittal plane view of PAR for comparison with US images. Mass and composition of mammary gland tissue were determined at 8 wk using standard methodology. Over the course of this 8-wk trial, average teat length increased from 11 to 17mm. The PAR area started small (6.6+/-3.2mm(2) per gland) and increased to 42.1+/-2.5mm(2) per gland by the end of the trial. As anticipated, based on measurements obtained at slaughter, US measurements were more related to amount of PAR (r=0.74) than either teat length (r=0.34) or palpation scoring (r=0.63). Importantly, US is quantitative, whereas palpation scoring is subjective. Diet did not affect mass or composition of PAR in young heifers; total udder PAR mass averaged 1.40+/ 0.80g. In conclusion, we showed that in heifers younger than 2mo of age, obtaining weekly PAR measurements via ultrasound is an effective quantitative tool for measuring changes in PAR area in vivo. Future studies may incorporate and expand upon the methods developed here to determine what quantitative evaluation of PAR in young heifers can reveal about milk production capacity. PMID- 26004838 TI - Estimating genetic parameters for fertility in dairy cows from in-line milk progesterone profiles. AB - The aim of this study was to define endocrine fertility traits from in-line milk progesterone (P4) records and to estimate genetic parameters for these traits. Correlations of classical fertility (calving interval and calving to first service) and milk production traits with endocrine fertility traits were also estimated. In-line milk P4 records (n=160,952) collected from June 2009 through November 2013 for 2,273 lactations of 1,561 Holstein-Friesian cows in 12 commercial herds in the Netherlands were analyzed for (the log of) the number of days from calving till commencement of luteal activity (lnC-LA), proportion of samples between 25 and 60 d in milk with luteal activity (PLA), presence or absence of luteal activity for a cow between 25 and 60 d in milk, interval from commencement of luteal activity to first service (CLAFS), first luteal phase length, length of first interluteal interval, and length of first interovulatory interval. Milk P4 records were sampled, on average, every 2 d. Genetic parameters were estimated using a mixed linear animal model. Heritability estimates (+/-SE) of endocrine fertility traits were 0.12+/-0.05 for lnC-LA, 0.12+/-0.05 for PLA, and 0.11+/-0.06 for CLAFS, and their repeatability estimates were 0.29+/-0.04, 0.21+/-0.04, and 0.15+/-0.06, respectively. The genetic correlation of lnC-LA with PLA was -0.91+/-0.06 and with CLAFS was -0.56+/-0.25. The genetic correlations of lnC-LA were 0.26+/-0.33 with calving interval and 0.37+/-0.21 with calving to first service. Genetic correlations of the milk production traits with lnC-LA ranged from 0.04 to 0.18 and 0.07 to 0.65 with classical fertility traits. The phenotypic correlations of all endocrine fertility traits with milk production traits were close to zero (0.01 to 0.07). This study shows that in line P4 records can be used to define and explore several heritable endocrine fertility traits in dairy cows and might help in selection for improved fertility. PMID- 26004839 TI - The role of solid feed amount and composition and of milk replacer supply in veal calf welfare. AB - Diets used in veal production were linked with welfare problems: that is, behavioral and gastrointestinal health disorders. This study aimed to determine how indicators of calf welfare, that is, behavior and some characteristics of the feces reflecting gastrointestinal health status, are affected by (1) different amounts and compositions of solid feed (SF), (2) the addition of ad libitum long straw to a typical veal diet, and (3) milk replacer (MR) being fed via automated milk dispensers (AMD). Two-week-old Holstein-Friesian bull calves (n=270) were used in this study. In a 4*2 factorial design, 32 pens (5 calves per pen) were allocated to different levels of SF (SF1, SF2, SF3, or SF4) and roughage-to concentrate ratios (20:80 or 50:50). The experimental period (13 to 29wk of age) was preceded by an adaptation period (3 to 12wk of age). Targeted total dry matter (DM) intake from SF during the experimental period was 20 kg of DM for SF1, 100 kg of DM for SF2, 180 kg of DM for SF3, and 260 kg of DM for SF4. The roughage part of the SF was 50% maize silage and 50% chopped wheat straw (on a DM basis). Ten additional pens were allocated to 2 treatments with ad libitum SF, with either (1) SF components in separate troughs (SEP) or (2) SF components mixed, with the composition being equal to the choice of SEP calves in the preceding week (MIX). Another 4 pens were fitted with racks filled with long wheat straw (STR) and fed SF2 with a roughage-to-concentrate ratio of 20:80. All the aforementioned pens received MR in buckets. Finally, 8 pens were allocated to 1 of 2 SF levels: SF1 or SF2 (with a roughage-to-concentrate ratio of 50:50) and fed MR via an AMD. Milk replacer provision was adjusted every 2wk to achieve similar rates of carcass gain across treatments (excluding SEP, MIX, and STR). Behavior was recorded at 15 and 24wk using instantaneous scan sampling. The prevalence of diarrhea and clay-like feces, which signal ruminal drinking, was monitored at 14 and 25wk. More roughage, but not concentrate, increased rumination and decreased tongue playing. The STR calves had higher rumination and lower abnormal behavior levels compared with calves without ad libitum straw. Offering MR via an AMD reduced tongue playing at 15wk. Tongue playing frequency was related to both roughage amount and AMD feeding, suggesting 2 separate motivations (i.e., rumination and sucking) underlying the development of this behavior. Only SF amount affected aspects of feces: SF1 calves had the highest diarrhea incidence. No effect of diet was found on clay-like feces. PMID- 26004836 TI - Molecular identification and quantification of lactic acid bacteria in traditional fermented dairy foods of Russia. AB - Russian traditional fermented dairy foods have been consumed for thousands of years. However, little research has focused on exploiting lactic acid bacteria (LAB) resources and analyzing the LAB composition of Russian traditional fermented dairy foods. In the present study, we cultured LAB isolated from fermented mare and cow milks, sour cream, and cheese collected from Kalmykiya, Buryats, and Tuva regions of Russia. Seven lactobacillus species and the Bifidobacterium genus were quantified by quantitative PCR. The LAB counts in these samples ranged from 3.18 to 9.77 log cfu/mL (or per gram). In total, 599 LAB strains were obtained from these samples using de Man, Rogosa, and Sharpe agar and M17 agar. The identified LAB belonged to 7 genera and 30 species by 16S rRNA and murE gene sequencing and multiplex PCR assay. The predominant LAB isolates were Lactobacillus helveticus (176 strains) and Lactobacillus plantarum (63 strains), which represented 39.9% of all isolates. The quantitative PCR results revealed that counts of 7 lactobacilli species and Bifidobacterium spp. of 30 fermented cow milk samples ranged from 1.19+/-0.34 (Lactobacillus helveticus in Tuva) to 8.09+/-0.71 (Lactobacillus acidophilus in Kalmykiya) log cfu/mL of fermented cow milk (mean +/- standard error). The numbers of Bifidobacterium spp., Lb. plantarum, Lb. helveticus, and Lb. acidophilus revealed no significant difference between the 3 regions; nevertheless, Lactobacillus paracasei, Lactobacillus fermentum, Lactobacillus sakei, and Lactobacillus delbrueckii ssp. bulgaricus exhibited different degrees of variation across 3 regions. The results demonstrate that traditional fermented dairy products from different regions of Russia have complex compositions of LAB species. The diversity of LAB might be related to the type of fermented dairy product, geographical origin, and manufacturing process. PMID- 26004840 TI - How cholesterol interacts with proteins and lipids during its intracellular transport. AB - Sterols, as cholesterol in mammalian cells and ergosterol in fungi, are indispensable molecules for proper functioning and nanoscale organization of the plasma membrane. Synthesis, uptake and efflux of cholesterol are regulated by a variety of protein-lipid and protein-protein interactions. Similarly, membrane lipids and their physico-chemical properties directly affect cholesterol partitioning and thereby contribute to the highly heterogeneous intracellular cholesterol distribution. Movement of cholesterol in cells is mediated by vesicle trafficking along the endocytic and secretory pathways as well as by non vesicular sterol exchange between organelles. In this article, we will review recent progress in elucidating sterol-lipid and sterol-protein interactions contributing to proper sterol transport in living cells. We outline recent biophysical models of cholesterol distribution and dynamics in membranes and explain how such models are related to sterol flux between organelles. An overview of various sterol-transfer proteins is given, and the physico-chemical principles of their function in non-vesicular sterol transport are explained. We also discuss selected experimental approaches for characterization of sterol protein interactions and for monitoring intracellular sterol transport. Finally, we review recent work on the molecular mechanisms underlying lipoprotein-mediated cholesterol import into mammalian cells and describe the process of cellular cholesterol efflux. Overall, we emphasize how specific protein-lipid and protein protein interactions help overcoming the extremely low water solubility of cholesterol, thereby controlling intracellular cholesterol movement. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 26004841 TI - ["History of Latin America's contribution to the scientific development and institutional world of neurosurgery" 56th week National and International Surgical Week, Mexico City September 24 2014]. PMID- 26004842 TI - Role of hypofractionated radiotherapy in breast locoregional radiation. AB - Long-term results of randomised trials have confirmed the safety and efficacy of hypofractionated radiotherapy using approximately 2.6 Gy per fraction to lower total doses of 40-42.6 Gy delivered over 3 weeks, for postoperative treatment of early breast cancer. In these trials, hypofractionated radiotherapy was predominantly used for breast only treatment, while there are fewer trials that specifically examined hypofractionated radiotherapy to the breast plus regional nodes. Hypofractionated locoregional radiation is considered a standard of care in the United Kingdom and in some parts of Canada. We aim to review the radiobiology and normal tissue effects of hypofractionated locoregional radiation and to summarize available published clinical experiences using this treatment strategy as adjuvant therapy after breast conserving surgery or mastectomy for women with early breast cancer. PMID- 26004843 TI - [Which node area should be irradiated after neoadjuvant chemotherapy in breast cancer?]. AB - In addition to achieve breast conserving surgery after neoadjuvant chemotherapy, its indications are growing, especially in Her2 overexpressing and triple negative breast cancers owing to the emergence of new targeted therapies. Radiotherapy belongs to breast cancer management. However, some questions are still unresolved regarding nodes area irradiation after neoadjuvant chemotherapy. This short communication reviews indications of radiotherapy of node areas in breast cancer after neoadjuvant chemotherapy. PMID- 26004844 TI - Swiss popular initiative for a single health insurer... once again! AB - The article describes a recent Swiss popular initiative, aiming to replace the current system of statutory health insurance run by 61 competing private insurers with a new system run by a single public insurer. Despite the rejection of the initiative by 62% of voters in late September 2014, the campaign and ballot results are interesting because they show the importance of (effective) public communication in shaping the outcome of a popular ballot. The relevance of the Swiss case goes beyond the peculiarities of its federalism and direct democracy and might be useful for other countries debating the pros and cons of national unitary health insurance systems versus models using multiple insurers. After this electoral ballot, the project to establish a public sickness fund in Switzerland seems definitely stopped, at least for the next decade. Insurers, who opposed the initiative, have effectively fed the "fear of change" of the population and have stressed the good outcomes of the Swiss healthcare system. However, the political pressure favoured by the popular initiative opened a "windows of opportunity" and led the federal Parliament to pass a stricter regulation of health insurers, improving in this way the current system. PMID- 26004846 TI - Quantitative lipidomic analysis of plasma and plasma lipoproteins using MALDI-TOF mass spectrometry. AB - Knowledge of the plasma lipid composition is essential to clarify the specific roles of different lipid species in various pathophysiological processes. In this study, we developed an analytical strategy combining high-performance liquid chromatography with evaporative light scattering detection (HPLC-ELSD) and off line coupling with matrix-assisted laser desorption/ionization with time-of flight mass spectrometry (MALDI-TOF/MS) to determine the composition of plasma and major lipoproteins at two levels, lipid classes and lipid species. We confirmed the suitability of MALDI-TOF/MS as a quantitative measurement tool studying the linearity and repeatability for triglycerides (TG), phosphatidylethanolamine (PE) and phosphatidylcholine (PC). Moreover, data obtained with this method were correlated with other lipid classes and species measurements using currently available technologies. To establish the potential utility of our approach, human plasma very low density- (VLDL), low density- (LDL) and high density- (HDL) lipoproteins from 10 healthy donors were separated using ultracentrifugation, and compositions of nine lipid classes, cholesteryl esters (CE), TG, free cholesterol (FC), PE, phosphatidylinositol (PI), sulfatides (S), PC, lysophosphatidylcholine (LPC) and sphingomyelin (SM), analyzed. In total, 157 lipid species in plasma, 182 in LDL, 171 in HDL, and 148 in VLDL were quantified. The lipidomic profile was consistent with known differences in lipid classes, but also revealed unexpected differences in lipid species distribution of lipoproteins, particularly for LPC and SM. In summary, the methodology developed in this study constitutes a valid approach to determine the lipidomic composition of plasma and lipoproteins. PMID- 26004845 TI - Leaders' experiences and perceptions implementing activity-based funding and pay for-performance hospital funding models: A systematic review. AB - INTRODUCTION: Providing cost-effective, accessible, high quality patient care is a challenge to governments and health care delivery systems across the globe. In response to this challenge, two types of hospital funding models have been widely implemented: (1) activity-based funding (ABF) and (2) pay-for-performance (P4P). Although health care leaders play a critical role in the implementation of these funding models, to date their perspectives have not been systematically examined. PURPOSE: The purpose of this systematic review was to gain a better understanding of the experiences of health care leaders implementing hospital funding reforms within Organisation for Economic Cooperation and Development countries. METHODS: We searched literature from 1982 to 2013 using: Medline, EMBASE, CINAHL, Academic Search Complete, Academic Search Elite, and Business Source Complete. Two independent reviewers screened titles, abstracts and full texts using predefined criteria. We included 2 mixed methods and 12 qualitative studies. Thematic analysis was used in synthesizing results. RESULTS: Five common themes and multiple subthemes emerged. Themes include: pre-requisites for success, perceived benefits, barriers/challenges, unintended consequences, and leader recommendations. CONCLUSIONS: Irrespective of which type of hospital funding reform was implemented, health care leaders described a complex process requiring the following: organizational commitment; adequate infrastructure; human, financial and information technology resources; change champions and a personal commitment to quality care. PMID- 26004847 TI - Potential of N-acetylated-para-aminosalicylic acid to accelerate manganese enhancement decline for long-term MEMRI in rodent brain. AB - BACKGROUND: Manganese (Mn(2+))-enhanced MRI (MEMRI) is a valuable imaging tool to study brain structure and function in normal and diseased small animals. The brain retention of Mn(2+) is relatively long with a half-life (t1/2) of 51-74 days causing a slow decline of MRI signal enhancement following Mn(2+) administration. Such slow decline limits using repeated MEMRI to follow the central nervous system longitudinally in weeks or months. This is because residual Mn(2+) from preceding administrations can confound the interpretation of imaging results. We investigated whether the Mn(2+) enhancement decline could be accelerated thus enabling repeated MEMRI, and as a consequence broadens the utility of MEMRI tests. NEW METHODS: We investigated whether N-acetyl-para aminosalicylic acid (AcPAS), a chelator of Mn(2+), could affect the decline of Mn(2+) induced MRI enhancement in brain. RESULTS AND CONCLUSION: Two-week treatment with AcPAS (200mg/kg/dose*3 daily) accelerated the decline of Mn(2+) induced enhancement in MRI. In the whole brain on average the enhancement declined from 100% to 17% in AcPAS treated mice, while in PBS controls the decline is from 100% to 27%. We posit that AcPAS could enhance MEMRI utility for evaluating brain biology in small animals. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, no method exists to accelerate the decline of the Mn(2+) induced MRI enhancement for repeated MEMRI tests. PMID- 26004848 TI - Total protein is an effective loading control for cerebrospinal fluid western blots. AB - BACKGROUND: Cerebrospinal fluid (CSF) has been used to identify biomarkers of neurological disease. CSF protein biomarkers identified by high-throughput methods, however, require further validation. While Western blotting (WB) is well suited to this task, the lack of a validated loading control for CSF WB limits the method's accuracy. NEW METHOD: We investigated the use of total protein (TP) as a CSF WB loading control. Using iodine-based reversible membrane staining, we determined the linear range and consistency of the CSF TP signal. We then spiked green fluorescent protein (GFP) into CSF to create defined sample-to-sample differences in GFP levels that were measured by WB before and after TP loading correction. Levels of CSF complement C3 and cystatin C measured by WB with TP loading correction and ELISA in amyotrophic lateral sclerosis and healthy control CSF samples were then compared. RESULTS: CSF WB with the TP loading control accurately detected defined differences in GFP levels and corrected for simulated loading errors. Individual CSF sample Western blot and ELISA measurements of complement C3 and cystatin C were significantly correlated and the methods showed a comparable ability to detect between-groups differences. COMPARISON WITH EXISTING METHOD: CSF TP staining has a greater linear dynamic range and sample-to sample consistency than albumin, a commonly used CSF loading control. The method accurately corrects for simulated errors in loading and improves the sensitivity of CSF WB compared to using no loading control. CONCLUSIONS: The TP staining loading control improves the sensitivity and accuracy of CSF WB results. PMID- 26004849 TI - Full correlation matrix analysis (FCMA): An unbiased method for task-related functional connectivity. AB - BACKGROUND: The analysis of brain imaging data often requires simplifying assumptions because exhaustive analyses are computationally intractable. Standard univariate and multivariate analyses of brain activity ignore interactions between regions and analyses of interactions (functional connectivity) reduce the computational challenge by using seed regions of interest or brain parcellations. NEW METHOD: To meet this challenge, we developed full correlation matrix analysis (FCMA), which leverages and optimizes algorithms from parallel computing and machine learning to efficiently analyze the pairwise correlations of all voxels in the brain during different cognitive tasks, with the goal of identifying task related interactions in an unbiased manner. RESULTS: When applied to a localizer dataset on a small compute cluster, FCMA accelerated a naive, serial approach by four orders of magnitude, reducing running time from two years to one hour. In addition to this performance gain, FCMA emphasized different brain areas than existing methods. In particular, beyond replicating known category selectivity in visual cortex, FCMA also revealed a region of medial prefrontal cortex whose selectivity derived from differential patterns of functional connectivity across categories. COMPARISON WITH EXISTING METHOD(S): For benchmarking, we started with a naive approach and progressively built up to the complete FCMA procedure by adding optimized classifier algorithms, multi-threaded parallelism, and multi node parallelism. To evaluate what can be learned with FCMA, we compared it against multivariate pattern analysis of activity and seed-based analysis of functional connectivity. CONCLUSIONS: FCMA demonstrates how advances in computer science can alleviate computational bottlenecks in neuroscience. We have released a software toolbox to help others evaluate FCMA. PMID- 26004850 TI - Simultaneous monitoring of Staphylococcus aureus growth in a multi-parametric microfluidic platform using microscopy and impedance spectroscopy. AB - We describe the design, construction, and characterization of a scalable microfluidic platform that allows continuous monitoring of biofilm proliferation under shear stress conditions. Compared to other previous end-point assay studies, our platform offers the advantages of integration into multiple environments allowing simultaneous optical microscopy and impedance spectroscopy measurements. In this work we report a multi-parametric sensor that can monitor the growth and activity of a biofilm. This was possible by combining two interdigitated microelectrodes (IDuEs), and punctual electrodes to measure dissolved oxygen, K+, Na+ and pH. The IDuE has been optimized to permit sensitive and reliable impedance monitoring of Staphylococcus aureus V329 growth with two- and four-electrode measurements. We distinguished structural and morphological changes on intact cellular specimens using four-electrode data modeling. We also detected antibiotic mediated effects using impedance. Results were confirmed by scanning electrode microscopy and fluorescence microscopy after live/dead cell staining. The bacitracin mediated effects detected with impedance prove that the approach described can be used for guiding the development of novel anti-biofilm agents to better address bacterial infection. PMID- 26004851 TI - Injury Patterns and Help-seeking Behavior in Hong Kong Male Intimate Partner Violence Victims. AB - BACKGROUND: Few studies have focused on the characteristics of male victims of intimate partner violence (IPV). Providers of care lack knowledge on the pathognomonic features to identify male IPV victims, who tend to be hidden. OBJECTIVES: This study investigated the injury patterns of male IPV victims and their help-seeking characteristics. METHODS: A retrospective cohort study was carried out in two regional hospitals in Hong Kong. Data were collected from the hospital computer databases (i.e., the Accident & Emergency Information System and the Clinical Data Analysis and Reporting System) and the medical charts completed by physicians. RESULTS: Medical records were retrieved from August 1, 2009 to December 31, 2011 for all IPV victims presenting at the accident and emergency departments. There were 372 cases in total, including 54 male and 318 female cases. Male victims were more likely to have abrasions/scrapes (66.7%), human bites (20.4%), and laceration/cutting (18.5%) than female victims (31.4%, 1.3%, 6.9%; p < 0.001, p < 0.01, p < 0.001, respectively). More male victims received dressing (38.9%) and injection (13.0%) than female victims (14.5%, 3.5%; p < 0.001, p < 0.01, respectively). Fewer male victims attended consultation by the medical social worker (MSW; 5.6%) than female victims (21.7%). CONCLUSION: Abrasion wounds are the most common in male victims of IPV. Male victims have lower rates of seeking help from MSWs, and most are aged 40 years or above. This study has identified important characteristics of male victims to aid the development of a comprehensive program for early IPV detection and management. PMID- 26004852 TI - Interruptions of Trauma Resuscitations for Radiographic Procedures. AB - BACKGROUND: Although x-ray studies provide important diagnostic information during trauma resuscitations, they may also lead to significant interruptions in care. OBJECTIVES: We sought to determine the frequency and duration of interruptions for chest x-ray studies (CXR) and pelvic x-ray studies (PXR) and the frequency of lead apron use among providers who exited trauma rooms during resuscitation. METHODS: Using a convenience sampling method, we conducted a prospective, observational study from August 2013 to March 2014, enrolling adult trauma patients at a Level I trauma center who received CXR and PXR in the first 30 min of evaluation. An observer stood outside resuscitation rooms and recorded the time elapsed from the first provider exiting the room to the last provider returning. We recorded how many exiting providers wore lead aprons and whether unused aprons were available. RESULTS: Of the 156 trauma cases observed, 67.3% were of male patients with a mean age of 52 years (interquartile range [IQR] 34 67 years); 97.4% (184/189) of radiographs resulted in interruptions of trauma evaluation. Mean and median interruption times were 67 s and 50 s, respectively (IQR 25-95) for CXR; 37 s and 27 s, respectively (IQR 16-43) for PXR; and 160 s and 180 s, respectively (IQR 120-180) for combined CXR/PXR. A mean of 3.5 providers (IQR 3-5) left the immediate bedside and exited the room during x-ray studies. Most (91%) providers leaving the room were not wearing lead aprons, and extra aprons were available in the room 91% (167/184) of the time. CONCLUSIONS: Radiographic procedures often result in interruptions of trauma resuscitations despite the availability of lead aprons. PMID- 26004853 TI - Extracorporeal Membrane Oxygenation Support for Hypokalemia-induced Cardiac Arrest: A Case Report and Review of the Literature. AB - BACKGROUND: Hypokalemia is a reversible cause of cardiac arrest in patients presenting to the emergency department (ED). Extracorporeal membrane oxygenation (ECMO) is an established technology for cardiopulmonary support with emerging roles in resuscitation. Here, we review the literature of hypokalemic-induced cardiac arrests and discuss one such case successfully managed with ECMO. CASE REPORT: A 23-year-old Central American man who presented to a community ED under federal custody with several days of nausea and vomiting was found to have a serum potassium level of 1.5 mEq/L. Repeat serum potassium level was 1.1 mEq/L upon arrival to our facility. Within 2 h of arrival, despite electrolyte repletion, he suffered cardiac arrest. Advanced cardiac life support was performed for 45 min. ECMO was initiated while active chest compressions were performed. After aggressive potassium repletion, return of spontaneous circulation was achieved and ECMO was eventually discontinued. Further investigation ultimately confirmed the presence of a potassium-wasting nephropathy, for which the patient had been treated with chronic potassium supplementation prior to entering federal custody. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ECMO is a well-established modality for cardiopulmonary support, with an emerging role for patients in undifferentiated cardiac arrest presenting to the ED. There is a growing interest in the utility of ECMO in these circumstances. This report highlights hypokalemia as an important cause of cardiac arrest, reviews the treatment and causes of hypokalemia, and demonstrates a potential role for ECMO as a critical temporizing measure to provide time for potassium repletion. PMID- 26004854 TI - Luxatio Erecta Humeri: Hands-up Dislocation. PMID- 26004855 TI - Immersion Foot: A Case Report. AB - BACKGROUND: Immersion foot (commonly called "trench foot") was originally described in the military literature during World War I. Since that time, the emergency department (ED) has become a common setting where this injury presents. However, this topic is neglected in the emergency medicine literature. The purpose of this case report is to present trench foot in a way that is relevant to emergency physicians and to provide an up-to-date summary of the history, case reports, physiology, clinical presentation, and treatment of this injury. CASE REPORT: Here we present the case of a homeless, schizophrenic patient who presented to one Midwestern ED in January for immersion foot. Photos of the actual patient are shown to illustrate the case. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Due to unfamiliarity, immersion foot can go undiagnosed during assessment of patients exposed to moist environments. In addition, patients at increased risk for developing immersion foot are frequently encountered in EDs. Most importantly, the appropriate treatment for immersion foot is different than the treatment for other freezing cold injuries. PMID- 26004856 TI - Nuclear organization in DNA end processing: Telomeres vs double-strand breaks. AB - Many proteins ligands are shared between double-strand breaks and natural chromosomal ends or telomeres. The structural similarity of the 3' overhang, and the efficiency of cellular DNA end degradation machineries, highlight the need for mechanisms that resect selectively to promote or restrict recombination events. Here we examine the means used by eukaryotic cells to suppress resection at telomeres, target telomerase to short telomeres, and process broken ends for appropriate repair. Not only molecular ligands, but the spatial sequestration of telomeres and damage likely ensure that these two very similar structures have very distinct outcomes with respect to the DNA damage response and repair. PMID- 26004858 TI - Geostatistical modelling of schistosomiasis prevalence. PMID- 26004857 TI - Co-occurrence between mental distress and poly-drug use: a ten year prospective study of patients from substance abuse treatment. AB - INTRODUCTION: Longitudinal research investigating psychiatric trajectories among patients with poly-drug use patterns remains relatively scant, even though this specific population is at elevated risk for multiple negative outcomes. The present study examined temporal associations between poly-drug use (i.e. heroin, cannabis, tranquilizers, and amphetamines) and mental distress over a 10-year period. METHODS: A clinical cohort of 481 patients was recruited from substance use treatment facilities in Norway, and prospectively interviewed 1, 2, 7 and 10years after the initial data collection at treatment admission. At each assessment participants completed a questionnaire addressing their substance use and mental distress. Longitudinal growth models were used to examine whether, and if so, how, levels of drug use were associated with the level and rate of change in mental distress over time. RESULTS: Results from the longitudinal growth models showed a co-occurrence between active poly-drug use and mental distress, such that there was a dose-response effect where mental distress increased both in magnitude and over time with the number of drugs used. Reduction in mental distress during the 10-year study period was evident only in the no-drug use condition. Use of multiple drugs and mental distress appear strongly co-related over time. CONCLUSIONS: Pre-treatment assessment should carefully identify individuals manifesting poly-drug use and mental disorders. Treatment and follow up services should be tailored to their specific needs. PMID- 26004860 TI - Association between Hypertriglyceridemia and Lacunar Infarction in Type 2 Diabetes Mellitus. AB - BACKGROUND: Although recent studies have shown that the elevation of serum triglyceride (TG) is related to the increased incidence of ischemic stroke, the relationship between hypertriglyceridemia and subtypes of ischemic stroke is largely unknown. This study attempted to evaluate whether hypertriglyceridemia is associated with lacunar stroke in diabetes mellitus (DM). METHODS: A total of 2141 consecutive patients with acute ischemic stroke were enrolled from March 2005 to April 2014, excluding the subjects with undetermined/other determined etiology or no lipid data. We compared the lipid profiles among stroke subtypes. The estimated serum TG levels and the interaction between DM and stroke subtypes were determined by analysis of covariance (ANCOVA) and Tukey's multiple comparison. RESULTS: In ANCOVA test, the difference of estimated TG between DM and non-DM patients was largest in small-vessel occlusion (SVO; 159.7 [95% confidence interval {CI}, 143.2-176.2] versus 122.4 [95% CI, 106.1-138.7]), and a significant interaction was observed between DM and stroke subtypes for TG levels (P = .013) but not for total cholesterol (P = .363), low-density lipoprotein cholesterol (P = .171), or high-density lipoprotein cholesterol (P = .231). By Tukey's multiple comparison, SVO was consistently associated with DM for serum TG levels (P < .001). CONCLUSIONS: In acute ischemic stroke with DM, serum TG level was significantly associated with lacunar infarction adjusting for other lipid profiles and vascular risk factors. Further studies are warranted to reveal the pathophysiologic implication of hypertriglyceridemia for lacunar infarction in type 2 DM. PMID- 26004861 TI - The Efficacy and Safety of Granulocyte Colony-Stimulating Factor for Patients with Stroke. AB - BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has been shown to reduce lesion volume and improve functional outcome in experimental stroke models. However, whether G-CSF plays a role currently in patients with stroke remains uncertain. Our study aimed at examining the efficacy and safety of G-CSF in patients with acute ischemic stroke. METHODS: A comprehensive search was conducted in 5 online databases up to April 2014, and 10 studies with 711 patients met the criteria. RESULTS: The results showed that G-CSF was beneficial in improving the National Institutes of Health Stroke Scale (standardized mean difference [SMD], .43; 95% confidence interval [CI], .03-.82; P = .04) and modified Rankin Scale (mRS) scores (SMD, .72; 95% CI, .51-.93; P = .01), and elevating CD34(+) count (P < .001). No treatment effects were found in Barthel Index scores (SMD, -.13; 95% CI, -.61 to .35; P = .59), serious adverse events (relative ratio [RR], 1.12; 95% CI, .91-1.38; P = .28), or the death of serious adverse events (RR, 1.25; 95% CI, .82-1.91; P = .30) between groups at day 90. Adverse effect on vascular complications was not detected to be increased although G-CSF produced a marked elevation in the total leukocyte count (SMD, 3.52; 95% CI, 2.54-4.49; P < .001). CONCLUSIONS: In conclusion, G-CSF is effective at mobilizing bone marrow-derived CD34(+) stem cells to the peripheral blood. It also seems to improve the National Institutes of Health Stroke Scale and mRS scores. The administration of G-CSF appears to be safe and well tolerated. Further studies need to be done on a large sample to verify or fully characterize the results. PMID- 26004859 TI - Spatial distribution of schistosomiasis and treatment needs in sub-Saharan Africa: a systematic review and geostatistical analysis. AB - BACKGROUND: Schistosomiasis affects more than 200 million individuals, mostly in sub-Saharan Africa, but empirical estimates of the disease burden in this region are unavailable. We used geostatistical modelling to produce high-resolution risk estimates of infection with Schistosoma spp and of the number of doses of praziquantel treatment needed to prevent morbidity at different administrative levels in 44 countries. METHODS: We did a systematic review to identify surveys including schistosomiasis prevalence data in sub-Saharan Africa via PubMed, ISI Web of Science, and African Journals Online, from inception to May 2, 2014, with no restriction of language, survey date, or study design. We used Bayesian geostatistical meta-analysis and rigorous variable selection to predict infection risk over a grid of 1 155 818 pixels at 5 * 5 km, on the basis of environmental and socioeconomic predictors and to calculate the number of doses of praziquantel needed for prevention of morbidity. FINDINGS: The literature search identified Schistosoma haematobium and Schistosoma mansoni surveys done in, respectively, 9318 and 9140 unique locations. Infection risk decreased from 2000 onwards, yet estimates suggest that 163 million (95% Bayesian credible interval [CrI] 155 million to 172 million; 18.5%, 17.6-19.5) of the sub-Saharan African population was infected in 2012. Mozambique had the highest prevalence of schistosomiasis in school-aged children (52.8%, 95% CrI 48.7-57.8). Low-risk countries (prevalence among school-aged children lower than 10%) included Burundi, Equatorial Guinea, Eritrea, and Rwanda. The numbers of doses of praziquantel needed per year were estimated to be 123 million (95% CrI 121 million to 125 million) for school-aged children and 247 million (239 million to 256 million) for the entire population. INTERPRETATION: Our results will inform policy makers about the number of treatments needed at different levels and will guide the spatial targeting of schistosomiasis control interventions. FUNDING: European Research Council, China Scholarship Council, UBS Optimus Foundation, and Swiss National Science Foundation. PMID- 26004862 TI - Trains of electrical stimulation of the trapezius muscles redistribute the frequencies of body oscillations during stance. AB - We investigated the postural effects of trains of electrical stimulation (TES) applied unilaterally or bilaterally on the trapezius muscle in 20 healthy subjects (mean age: 23.1 +/- 1.33 years; F/M: 8/12). The anterior-posterior (AP) displacements (AP axis), medio-lateral displacements (ML axis) and total travelled distances (TTW) of the centre of pressure (COP) remained unchanged with TES. However, detailed spectral analysis of COP oscillations revealed a marked decrease of the magnitudes of peak power spectral density (peak PSD) following application of TES. Peak PSD was highly correlated with the intensity of stimulation (P < 0.001 both the AP and ML axes). For the AP axis, the integrals of the sub-bands 0-0.4, 0.4-1.5, 1.5-3 Hz were significantly decreased (P < 0.001), the integrals of the sub-bands 3-5 and 5-8 Hz were not significantly affected (P>0.30) and the integrals of the sub-band 8-10 Hz were significantly increased (P < 0.001). The ratios of the integrals of sub-bands 8-10 Hz/0-3 Hz were markedly enhanced with bilateral TES (P < 0.001). For the ML axis, the effects were striking (P < 0.001) for the sub-bands 0-0.4, 0.4-1.5 and 8-10 Hz. For both the AP and ML axes, a significant inverse linear relationship was found between the intensity of TES and the average speed of COP. We show that TES applied over the trapezius muscles exerts significant and so far unrecognised effects upon oscillations of the COP, decreasing low-frequency oscillations and enhancing high-frequency oscillations. Our data unravel a novel property of the trapezius muscles upon postural control. We suggest that this muscle plays a role of a distributor of low-frequency versus high-frequency sub-bands of frequency during stance. Previous studies have shown that patients with supra-tentorial stroke show an increased peak PSD in low frequencies of body oscillations. Therefore, our findings provide a rationale to assess neurostimulation of the trapezius muscle in the rehabilitation of postural deficits in supra-tentorial stroke. PMID- 26004863 TI - BII stability and base step flexibility of N6-adenine methylated GATC motifs. AB - The effect of N6-adenine methylation on the flexibility and shape of palindromic GATC sequences has been investigated by molecular dynamics simulations. Variations in DNA backbone geometry were observed, which were dependent on the degree of methylation and the identity of the bases. While the effect was small, more frequent BI to BII conversions were observed in the GA step of hemimethylated DNA. The increased BII population of the hemimethylated system positively correlated with increased stacking interactions between methylated adenine and guanine, while stacking interactions decreased at the TC step for the fully methylated strand. The flexibility of the AT and TC steps was marginally affected by methylation, in a fashion that was correlated with stacking interactions. The facilitated BI to BII conversion in hemimethylated strands might be of importance for SeqA selectivity and binding. PMID- 26004864 TI - Activation of P2Y6 Receptors Facilitates Nonneuronal Adenosine Triphosphate and Acetylcholine Release from Urothelium with the Lamina Propria of Men with Bladder Outlet Obstruction. AB - PURPOSE: Deregulation of purinergic bladder signaling may contribute to persistent detrusor overactivity in patients with bladder outlet obstruction. Activation of uridine diphosphate sensitive P2Y6 receptors increases voiding frequency in rats indirectly by releasing adenosine triphosphate from the urothelium. To our knowledge this mechanism has never been tested in the human bladder. MATERIALS AND METHODS: We examined the role of the uridine diphosphate sensitive P2Y6 receptor on tetrodotoxin insensitive nonneuronal adenosine triphosphate and [(3)H]acetylcholine release from the human urothelium with the lamina propria of control organ donors and patients with benign prostatic hyperplasia. RESULTS: The adenosine triphosphate-to-[(3)H]acetylcholine ratio was fivefold higher in mucosal urothelium/lamina propria strips from benign prostatic hyperplasia patients than control men. The selective P2Y6 receptor agonist PSB0474 (100 nM) augmented by a similar amount adenosine triphosphate and [(3)H]acetylcholine release from mucosal urothelium/lamina propria strips from both groups of individuals. The facilitatory effect of PSB0474 was prevented by MRS2578 (50 nM) and by carbenoxolone (10 MUM), which block P2Y6 receptor and pannexin-1 hemichannels, respectively. Blockade of P2X3 (and/or P2X2/3) receptors with A317491 (100 nM) also attenuated release facilitation by PSB0474 in control men but not in patients with benign prostatic hyperplasia. Immunolocalization studies showed that P2Y6, P2X2 and P2X3 receptors were present in choline acetyltransferase positive urothelial cells. In contrast to P2Y6 staining, choline acetyltransferase, P2X2 and P2X3 immunoreactivity decreased in the urothelium of benign prostatic hyperplasia patients. CONCLUSIONS: Activation of P2Y6 receptor amplifies mucosal adenosine triphosphate release underlying bladder overactivity in patients with benign prostatic hyperplasia. Therefore, we propose selective P2Y6 receptor blockade as a novel therapeutic strategy to control persistent storage symptoms in obstructed patients. PMID- 26004865 TI - PRPS2 Expression Correlates with Sertoli-Cell Only Syndrome and Inhibits the Apoptosis of TM4 Sertoli Cells. AB - PURPOSE: Sertoli-cell only syndrome is one of the reasons for male infertility but its pathogenesis remains unclear. PRPS2, a subset of PRS, is reported to be a potential protein associated with Sertoli-cell only syndrome. In this study we further investigated the correlation between PRPS2 and Sertoli-cell only syndrome, and evaluated the effect of PRPS2 expression on apoptosis of TM4 Sertoli cells. MATERIALS AND METHODS: PRPS2 expression was detected in patients with Sertoli-cell only syndrome and normal spermatogenesis, and in Sertoli-cell only syndrome mouse models by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and Western blot. PRPS2 expression in TM4 Sertoli cells was then down-regulated and up-regulated by lentivirus vectors. The effect of PRPS2 expression on cell apoptosis and cell cycle transition was evaluated by flow cytometry. RESULTS: PRPS2 expression in patients with Sertoli cell only syndrome was significantly greater than in those with normal spermatogenesis. A significant increase in PRPS2 expression was observed in Sertoli-cell only syndrome mouse models. PRPS2 over expression significantly inhibited cell apoptosis and promoted cell cycle transition in TM4 Sertoli cells. However, PRPS2 down-regulation showed a reverse effect. Moreover, results revealed that PRPS2 over expression inhibited cell apoptosis via the p53/Bcl 2/caspase-9/caspase-3/caspase-6/caspase-7 signaling pathway. CONCLUSIONS: PRPS2 expression correlates with Sertoli-cell only syndrome and inhibits the apoptosis of TM4 Sertoli cells via the p53/Bcl-2/caspases signaling pathway. PMID- 26004869 TI - Primed and ready: understanding lineage commitment through single cell analysis. AB - Regulation of lineage commitment in multipotential cells is key to maintaining a balanced hematopoietic output throughout life while retaining the capacity to respond to stress and infection. Cell fate decisions are made by individual stem cells, but population-level analysis obscures the mechanics of cell fate choice by averaging the molecular and functional heterogeneity that exists even in the most highly purified stem cell populations. Therefore, single cell analysis of both molecular and cellular phenotypes is crucial to delineate and interrogate the process of lineage commitment. We review recent single cell expression profiling, imaging, and clonal tracking studies that have provided new insights into commitment, focusing on the hematopoietic system, and suggest how new technologies may illuminate our understanding of lineage commitment in the near future. PMID- 26004866 TI - Microsurgical Spermatic Cord Denervation as a Treatment for Chronic Scrotal Content Pain: A Multicenter Open Label Trial. AB - PURPOSE: We prospectively evaluated the results of microsurgical spermatic cord denervation in a series of patients with chronic scrotal content pain in a multicenter study, including 1 center in Germany and 3 centers in Chile. MATERIALS AND METHODS: A total of 50 patients with chronic scrotal content pain more than 3 months in duration were prospectively selected for standardized operative microsurgical spermatic cord denervation as pain treatment. In all patients preoperative management included a positive response to a spermatic cord block test with local anesthesia. Pain severity was assessed using an analog visual pain scale (range 0 to 10) for 30 consecutive days. A total of 52 testicular units were operated on using a subinguinal approach. In all cases a surgical microscope was used to identify the arteria testicularis. RESULTS: No intraoperative complications were observed and no testicular units were lost. Two reoperations were performed, including 1 for hematocele and 1 for hydrocele. Six months after surgery 40 patients (80%) were completely pain-free. In 6 patients (12%) intermittent testicular discomfort persisted, which could be managed by acetaminophen on demand. Four patients (8%) had no change in pain severity after surgery. CONCLUSIONS: After proper selection of patients microsurgical spermatic cord denervation seems to be a safe and efficient procedure to treat chronic scrotal content pain. Considering the limitations of the study, a randomized, controlled trial with longer followup is highly warranted. PMID- 26004870 TI - The crucial role of mast cells in blood-brain barrier alterations. AB - Mast cells are critical regulators of the pathogenesis of the central nervous system diseases, including stroke, multiple sclerosis, and traumatic brain injury, and brain tumors. Here, we have summarized the literature data concerning the involvement of mast cells in blood-brain barrier alterations, and we have suggested a possible role of angiogenic mediators stored in mast cell granules in the vasoproliferative reactions occurring in these pathological conditions. It is conceivable to hypothesize that mast cells might be regarded in a future perspective as a new target for the adjuvant treatment of neurodegenerative diseases and brain tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, favoring the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression. PMID- 26004871 TI - Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells. AB - BACKGROUND: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin resistance. METHODS: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72h on expression and cisplatin cytotoxicity was tested. RESULTS: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. CONCLUSIONS: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin resistance of NSCLC and MPM cells. Tumour cell resistance to MDR1 inhibitors of cell surface MDR1 and Gb3 could explain the aggressiveness of NSCLC and MPM. Therapy with GCS activity inhibitors or toxin targeting of the Gb3 receptor may substantially reduce acquired cisplatin drug resistance of NSCLC and MPM cells. PMID- 26004872 TI - Novel CO2 removal device driven by a renal-replacement system without hemofilter. A first step experimental validation. AB - OBJECTIVES: To study the technical effectiveness of a novel extracorporeal CO2 removal device in removing CO2 from blood. STUDY DESIGN: Prospective animal study. ANIMALS: Five adult female healthy pigs. METHODS: Hypercapnic pigs were equipped with a low-flow CO2 removal device (PrismaLung((r)), Hospal((r))) integrated on a CRRT platform. The rate of CO2 elimination was examined in vivo using a hollow fiber gas exchanger under various conditions (blood flow rates: 200, 300 and 400 mL/min; sweep gas flows: 2, 5, 10 and 50 L/min; FsO2: 0.21 and 1). Statistical analysis was performed with Student t-test. RESULTS: The extracorporeal device produced CO2 removal rates ranging from 35 to 75 mL/min. Efficiency was increased with higher blood and sweep gas flows: reduction of PCO2 of 40.2 +/- 13.0 mmHg (relative decrease of 46%, P < 0.001) and increase in pH of 0.24 +/- 0.06 (7.21 before and 7.46 after filter, P < 0.001). Animals' blood gases were significantly modified after 10 minutes of treatment: PaCO2 decreased from 81.2 to 70.0 mmHg (relative decrease of 14%, P < 0.001) and pH increased from 7.17 to 7.22 (P < 0.001). No significant changes in arterial blood oxygenation were observed when using pure oxygen (increase of PaO2 from 106 to 107 mmHg, P = 0.36), allowing the use of ambient air as sweep gas through the membrane. CONCLUSIONS: A device based on a Prismaflex((r)) platform was technically effective in removing CO2 from the blood, thus decreasing PaCO2 and acidosis in hypercapnic pigs. PMID- 26004873 TI - One half of patients reports persistent pain three months after orthopaedic surgery. AB - OBJECTIVE: To determine persistent post-surgical pain prevalence after orthopaedic surgery with its impact on patient quality of life and to assess factors related to it. STUDY DESIGN: Cross-sectional cohort study. PATIENTS: A questionnaire was mailed to 2100 patients undergoing orthopaedic surgery in our teaching hospital. METHODS: Pain prevalence 3 months after surgery, pain intensity, a neuropathic pain component using the DN4 questionnaire and its impact on patient quality of life were assessed. RESULTS: One thousand two hundred and ninety-two patients answered our questionnaire. Among them, 48% suffered from chronic pain. This pain had a neuropathic component in 43%, which was responsible for analgesic overconsumption and increases in sleep disturbance and sick leave. Arthrodesis, knee arthroplasty and leg fracture were linked to increased chronic post-surgical pain (OR=2.7, OR=1.8, OR=1.9, respectively; P<0.05). Elbow surgery, meniscectomy, amputation and neurolysis were linked to increased neuropathic pain. CONCLUSIONS: Chronic, post-surgical pain is common after orthopaedic surgery, leading to analgesic consumption and sleep disturbance. Patients at high risk for developing chronic post-surgical pain must be identified preoperatively. The development of postoperative pain clinics should be one way to respond to this public health problem. PMID- 26004874 TI - Use of aztreonam in association with cefepime for the treatment of nosocomial infections due to multidrug-resistant strains of Pseudomonas aeruginosa to beta lactams in ICU patients: A pilot study. AB - OBJECTIVES: Resistance to all beta-lactams is emerging among Pseudomonas aeruginosa (PA) clinical isolates. Aztreonam and cefepime act synergistically in vitro against AmpC overproducing PA isolates. The objective of this study was to evaluate the clinical efficacy of this treatment in ICU patients infected with multidrug-resistant PA. MATERIAL AND METHODS: Retrospective study (2 years, 2 ICUs) in a tertiary university hospital. Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all beta-lactams and treated with the association of at least aztreonam plus cefepime. Treatment was considered effective for pneumonia using CPIS scores at the end of treatment and for other infections, using the SOFA score and signs of infection improvement at the end of treatment. Infectious episodes were classified as cure or failure. RESULTS: Thirteen patients were included (10 nosocomial pneumonia, 3 nosocomial intra-abdominal infections). The median [25th-75th percentiles] admission SAPS2 score was 54 [51-69] and the median SOFA score at the beginning of infection was 7 [4-8]. The median CPIS scores for pneumonia at the beginning and end of treatment were 9 [7-10.5] and 2 [0.75-5.5]. The duration of treatment with the combination of aztreonam plus cefepime was 14 days [9.5-16]. Nine episodes were classified as cures and 4 as failures, indicating a clinical efficacy of 69.2%. Overall mortality was 38.5%. DISCUSSION: These data suggest that the association of cefepime plus aztreonam could be an attractive alternative in the treatment of infections with multidrug-resistant PA to all beta-lactams with a clinical efficacy rate of 69%. PMID- 26004875 TI - ECLS indication for a case of stress myocardiopathy associated with severe asthma. PMID- 26004876 TI - Anaphylactic reaction and cardiac arrest due to gadobenate dimeglumine. PMID- 26004877 TI - A survey of the administration of prednisolone versus ibuprofen analgesic protocols after ambulatory tonsillectomy. AB - INTRODUCTION: Postoperative pain, nausea and vomiting are frequent symptoms after tonsillectomy. There have been controversies concerning the advantages and drawbacks of different analgesics in this setting, especially non-steroidal anti inflammatory drugs, because of potential side effects. We have evaluated the effectiveness and safety of a shift from prednisolone to ibuprofen for postoperative analgesia after tonsillectomy. PATIENTS AND METHODS: Data from 1231 children scheduled for tonsillectomy over a period of 30 months were analysed. During the first period, children received a combination of paracetamol prednisolone with codeine as a rescue therapy; in the second period, they received paracetamol and ibuprofen, with tramadol as a rescue therapy. All children received IV dexamethasone at 0.1mg/kg for antiemetic prophylaxis. The primary end-point was the incidence of severe pain defined as an Objective Pain Scale (OPS) score>=6 at the seventh postoperative day (POD7). Other end-points were postoperative nausea or emesis (PONV), sleep disturbance, oral intake and postoperative haemorrhage and reoperation. RESULTS: Six hundred and seventy-two and 559 children were included in the prednisolone and ibuprofen groups respectively. OPS scores>=6 were observed in 3.1% of cases (95% confidence interval, 2.3-4.2%) on POD7 for the entire study population. Ibuprofen reduced the incidence of OPS scores>=6 on POD7 (relative risk 0.37, 95% CI: 0.18-0.78; P=0.009), OPS scores in the ambulatory unit (P<0.001) and POD1 (P<0.001), nalbuphine requirements (RR 0.42, 95% CI, 0.34-0.5, P<0.0001), and PONV (P=0.01) compared with prednisolone. Ibuprofen enhanced sleep quality on POD0 (P<0.0001) and POD7 (P=0.02), and oral intake on POD1 (P<0.0001). The incidence of bleeding requiring reoperation was comparable between the two groups (RR 0.8 [95% CI, 0.13 4.78], p=0.8). Predictive factors for an OPS score>=6 at POD7 were OPS score>4 on the morning and the evening of POD1 (OR 1.24, 95% CI 1.02-1.49, P=0.03 and OR 1.30, 95% CI 1.12-1.55, P=0.008, respectively) and prednisolone use (OR 2.37, 95% CI 1.06-5.31, P=0.04). CONCLUSION: The administration of ibuprofen compared to prednisolone improves postoperative comfort in children undergoing ambulatory tonsillectomy without increasing the incidence of side effects. PMID- 26004878 TI - Confirmation of brain death diagnosis: A study on French practice. AB - INTRODUCTION: In France, brain death diagnosis is regulated by law and mandates the use of confirmatory tests (electroencephalogram or angiography). No data are available on this practice and the possible influence of medical history. STUDY DESIGN: National survey using an e-mail questionnaire after phone agreement. PATIENTS AND METHODS: A questionnaire was sent to intensive care units allowed to practice organ harvesting. It assessed the use of supplementary tests, the reasons behind the choice of a confirmatory test, as well as the influence of medical history on decision-making. RESULTS: Eighty-two out of 188 intensive care units (ICU) answered the questionnaire. Most of them (80%) performed supplementary tests, mainly transcranial Doppler. Computed tomography (CT) angiography was the only confirmatory test available in all ICUs, and this without interruption for 94% of them. Electroencephalogram (EEG) availability was usually restricted to weekdays. Most ICUs confirmed brain death by a CT angiography (95%), less frequently by EEG (54%) and rarely by arteriography (12%). These tests were usually performed within 1 to 6 hours after clinical diagnosis. Results from imaging tests were obtained within 15 minutes in the majority of ICUs (59%), whereas the time for EEG results was more frequently between 15 and 60 minutes (62%). The choice of confirmatory test was guided by its availability (43%), or protocol driven (20%), or a combination of both of the latter criteria (35%). Medical history had no influence on this choice for 63% of respondents. DISCUSSION: CT-angiography is currently the privileged confirmatory test for the diagnosis of brain death in France. Availability is the main reason behind this choice. The EEG is the second most commonly used test. Transcranial Doppler helps to determine when to perform confirmatory tests. PMID- 26004879 TI - Levobupivacaine for continuous femoral nerve block in paediatric patients: A plasma concentration analysis report on safety. PMID- 26004880 TI - Epidural analgesia in the intensive care unit: An observational series of 121 patients. AB - BACKGROUND: Epidural analgesia (EA) has been more investigated during the perioperative period than in the intensive care unit (ICU) setting. Recent studies support beneficial effects for EA beyond analgesia itself. However, data on feasibility and safety are still lacking in the ICU. Our goal was to assess the feasibility and practice of EA in ICU patients. METHODS: Multicentre observational study in 3 ICUs over a 10-month period. Goals were to report the incidence of EA-related complications and EA duration. All ICU patients receiving EA were included, whether EA was initiated in the ICU or elsewhere, e.g. in the operating room. Demographics, clinical and biological data were prospectively recorded. Epidural catheter tips were sent to the microbiology laboratory for culture. RESULTS: One hundred and twenty-one patients were included (mean age 60 years), with mean SOFA and median SAPS II scores of 3.2 and 32, respectively. Reasons for EA initiation included trauma (14%), postoperative pain management after major surgery (42%), and pancreatitis (31%). No EA-related neurologic complication was recorded, and one case of epidural abscess is discussed. No other EA-related infectious complications were observed. Median duration of EA was 11 days. Reasons for EA discontinuation included efficient analgesia without EA (60%) and accidental catheter removal (17%). 22% of epidural catheter cultures were positive for skin flora bacteria. CONCLUSION: EA seems feasible in the ICU. Its apparent safety should be further validated in larger cohorts, but these preliminary results may stimulate more interest in the assessment of potential benefits associated with EA in the ICU setting. PMID- 26004881 TI - Use of volatile anaesthetic agents in anaesthesia: A survey of practice in France in 2012. AB - Volatile anaesthetic agents are used in the vast majority of general anaesthesias performed in France. We assessed the degree of understanding of French anaesthetists with regard to the general pharmacology of these products and their understanding of the factors that govern selection of the different agents available for use in adults. A validated 13-item questionnaire was sent electronically in 2012 using files from the Societe francaise d'anesthesie et de reanimation (Sfar). It covered four categories: general characteristics of the respondent; practical aspects of anaesthesia with volatile agents; pharmacological properties and criteria for choosing a volatile agent; risk of intra-operative awareness. Among the 981 respondents, the anaesthetic technique used by 50% was that of an intravenous induction followed by maintenance with sevoflurane. The concepts relating to the practical use of these products are well known. A fresh gas flow of less than 2 L/min is used by 96% of the respondents. However, knowledge levels are often inadequate (rate of correct answers often<50%). This lack of knowledge pertains to current themes (climate pollution), those of debatable clinical significance, e.g. pre-conditioning, hypoxic vasoconstriction and those that concern scientific theory (medullary action). However, a lack of knowledge is also observed with regard to basic pharmacology (respiratory, vascular, neurological or pharmacokinetic effects). There is no significant difference in the mode of practice. The experience of the anaesthetist (measured by number of years post diploma) resulted in a number of differences in response to many aspects of the questionnaire but these were minor. These results suggest the need for an improvement both in the initial and continued training of anaesthetists with respect to volatile anaesthetic agents. PMID- 26004883 TI - Wernicke's encephalopathy: A rare complication of hyperemesis gravidarum. PMID- 26004882 TI - Sedative premedication before surgery--A multicentre randomized study versus placebo. AB - OBJECTIVE: Anxiolytic premedication before non-ambulatory surgery in adult patients may have become of less importance in an era of better preoperative patient information. Moreover, an oral hypnotic given the night before surgery may be as efficient as an anxiolytic for relieving patient anxiety. These two strategies were compared for superiority to a placebo and to each other for non inferiority. STUDY DESIGN: Double-blind, randomized, multicentre study versus placebo. Eight hospitals in France. June 2011 to February 2013. PATIENTS: Non ambulatory consecutive surgical patients undergoing general surgery. METHODS AND INTERVENTIONS: Patients received either zopiclone 7.5mg the night before surgery (n=204), or alprazolam 0.5mg the morning of surgery (n=206) and controls received placebo (n=68). Demographic data, preoperative anxiety, fear of surgery and anaesthesia, and mood were assessed the day before surgery using a visual analogue scale, the Spielberger scale and the APAIS scale. In the operating room, anxiety and comfort were assessed in addition to physiological data. RESULTS: Preoperative data did not differ between groups. In the operating room, anxiety and comfort were moderate and did not differ significantly between groups on a 1 10 scale (median [25-75 percentile]): zopiclone: 2 [1-4] and 2.5 [1-5]; alprazolam: 2 [1,4] and 2 [1-5]; placebo: 3 [1-5] and 3 [1-5]. The patients who were more anxious preoperatively remained so in the operating room, irrespective of the treatment received (r=0.31, p<0.001). A placebo effect was observed in 38% of patients in the corresponding group. Patients receiving zopiclone reported a significantly better sleep the night before surgery compared to other groups (median: 2 vs. 1, p<0.001). CONCLUSIONS: Premedication in non-ambulatory surgery is no more effective than a placebo, owing to the very moderate level of anxiety experienced by patients. PMID- 26004884 TI - Needle-free delivery of macromolecules through the skin using controllable jet injectors. AB - INTRODUCTION: Transdermal delivery of drugs has a number of advantages in comparison to other routes of administration. The mechanical properties of skin, however, impose a barrier to administration and so most compounds are administered using hypodermic needles and syringes. In order to overcome some of the issues associated with the use of needles, a variety of non-needle devices based on jet injection technology has been developed. AREAS COVERED: Jet injection has been used primarily for vaccine administration but has also been used to deliver macromolecules such as hormones, monoclonal antibodies and nucleic acids. A critical component in the more recent success of jet injection technology has been the active control of pressure applied to the drug during the time course of injection. EXPERT OPINION: Jet injection systems that are electronically controllable and reversible offer significant advantages over conventional injection systems. These devices can consistently create the high pressures and jet speeds necessary to penetrate tissue and then transition smoothly to a lower jet speed for delivery of the remainder of the desired dose. It seems likely that in the future this work will result in smart drug delivery systems incorporated into personal medical devices and medical robots for in-home disease management and healthcare. PMID- 26004885 TI - Selenium speciation in human serum and its implications for epidemiologic research: a cross-sectional study. AB - Observational studies addressing the relation between selenium and human health, particularly cancer risk, yielded inconsistent results, while most recent randomized trials showed a fairly consistent pattern suggesting null or adverse effects of the metalloid. One of the most plausible explanations for such inconsistencies is inadequate exposure assessment in observational studies, commonly carried out by measuring total Se content without taking into account the specific exposure to the individual chemical forms of the metalloid, whose toxic and nutritional properties may vary greatly. Data on the distribution of these species in human blood and their correlation with overall selenium levels are very limited. The concentrations of organic and inorganic selenium species were analyzed in serum of fifty subjects sampled from the general population of the municipality of Modena, northern Italy, aged from 35 to 70 years. Samples were collected during a 30-month period, and determinations of selenium species were carried out using high pressure liquid chromatography coupled with inductively coupled plasma dynamic reaction cell mass spectrometry. The majority of selenium was found to be present as organic species, but the inorganic forms showed higher levels than expected. These species showed limited correlations with age, sex and body mass index, while the organic forms increased in subjects consuming selenium-containing dietary supplements and decreased in smokers. The length of the sample storage period strongly influenced the distribution of selenium compounds, with a clear tendency towards higher inorganic and lower organic selenium levels over time. In multivariate analysis adjusting for potential confounders, total serum selenium correlated with human serum albumin bound selenium and, in males, with two organic species of the metalloid (selenocysteine and glutathione peroxidase-bound selenium), while little association existed with the other organic forms and the inorganic ones. These findings highlight the potential for exposure misclassification of observational epidemiologic investigations based on overall selenium content in blood and possibly other tissues, and the critical role of the storage conditions for speciation analysis. PMID- 26004887 TI - Normal intellectual development in children born from women with hypothyroxinemia during their pregnancy. AB - Proper maternal thyroid function is known to be essential for neural differentiation and migration in the fetus during the first half of pregnancy. The objectives of this study were to assess the relationship between thyroxin levels, in pregnant women with no thyroid disease and the intellectual development of their offspring in a non-iodine-deficient area, and to know specifically whether or not isolated hypothyroxinemia during pregnancy was associated with a lower intelligence in the offspring. Previously we had publicated values TSH, FT4, free T3 (FT3), anti-thyroid peroxidase antibodies (TPO Abs) and urinary iodine concentration (UIC) in 1322 pregnant women in our hospital area. Now we presented results of intelligence quotient in children born from these pregnancies. We assessed 455 children at one year of age using Brunet Lezine scale. Of these, 289 children were evaluated again at 6-8 years of age using the WISC-IV. From the total group of children recruited, we established as control subgroup, children born of rigorously normal pregnancies (women with UIC > 150 MUg/L, FT4>10th percentile and TPO-Ab negative in both trimesters). The remaining children were divided into two subgroups: those born to mothers with FT4 below the 10th percentile and the rest. No correlation was found between FT4 maternal levels, in either of trimesters studied, and the intellectual scores of offspring. No differences were found in intellectual scores comparing children born to mothers with hypothyroxinemia and those whose mothers were euthyroxinemic in both trimesters, or with the control subgroup. As conclusions we did not find any association between the levels of maternal FT4 during pregnancy and the subsequent intellectual development the offspring from these pregnancies. We attribute this result to the fact that all the pregnant women included had normal thyroid function. PMID- 26004886 TI - Counteract of bone marrow of blotchy mice against the increases of plasma copper levels induced by high-fat diets in LDLR-/- mice. AB - BACKGROUND: Bone marrow of blotchy mouse (blotchy marrow) reflects the function of transmembrane domain and relevant intramembrane sites of ATP7A in myeloid cells. By chronic infusion of angiotensin II, we previously found that blotchy marrow plays a minor role in regulating plasma copper. Moreover, the recipients of blotchy marrow presented a moderate reduction of plasma lipids and inflammatory mediator production. Little is known about whether these changes are a specific response to angiotensin II or reveal a more general role of ATP7A. OBJECTIVE AND DESIGN: We investigated if blotchy marrow reduces plasma lipids and inflammatory mediators induced by high-fat diets. To test this hypothesis, blotchy and control marrows were reconstituted to the recipient mice (irradiated male LDLR-/- mice), followed by high-fat-diet feeding for 4 months. At the end points, plasma metals (copper, zinc and iron), lipid profiling (cholesterol, triglyceride, phospholipids and lipoprotein) and six inflammatory mediators (lymphotacin, MCP3, MCP5, TIMP1, VEGF-A and IP-10) were measured. Parallel experiments were performed using male LDLR-/- mice fed either high-fat diets or chow diets for 4 months. RESULTS: In addition to hyperlipidemia and low-grade inflammation, high-fat diets selectively increased plasma copper concentration compared to chow diets in LDLR-/- mice. After high-fat-diet feeding, the recipients with blotchy marrow showed a decrease in plasma copper (p < 0.01) and an increase in plasma iron (p < 0.05). The recipients with blotchy marrow also presented decreases in cholesterol (p < 0.01) and phospholipids (p < 0.05) in plasma. Surprisingly, plasma levels of MCP3 (p < 0.05), MCP5 (p < 0.05), TIMP1 (p < 0.01), VEGF-A (p < 0.01) and IP-10 (p < 0.01) were significantly increased in the recipients with blotchy marrow compared to controls; the increased levels of MCP3, MCP5 and TIMP1 were more than 50%. CONCLUSION: Our studies showed that blotchy marrow counteracts the increased copper levels induced by high-fat diets, indicating that circulating myeloid cells can regulate blood copper levels via ATP7A. Moreover, transplantation of blotchy marrow followed by high-fat diets leads to a decrease in lipid profile and an increase in inflammatory mediator production. Overall, blotchy marrow mediates divergent responses to angiotensin II and high-fat diets in vivo. PMID- 26004888 TI - Biomarkers in critically ill patients with systemic inflammatory response syndrome or sepsis supplemented with high-dose selenium. AB - OBJECTIVE: Low levels of selenium (Se) and glutathione peroxidase (GSHPx), a key selenoenzyme, were documented in systemic inflammatory response syndrome (SIRS) and sepsis, both associated with high mortality. Se supplementation had mixed effects on outcome. We hypothesized that Se supplementation could have a different impact on biomarkers and 28-day mortality in patients with SIRS vs. sepsis. METHODS: Adult patients with SIRS or sepsis were randomized to either high-dose (Se+, n = 75) or standard-dose (Se-, n = 75) Se supplementation. Plasma Se, whole blood GSHPx activity, C-reactive protein (CRP), procalcitonin (PCT), prealbumin, albumin and cholesterol levels were measured serially up to day 14. RESULTS: There was no difference in mortality between Se- (24/75) vs. Se+ group (19/75; p = 0.367) or between SIRS and septic patients (8/26 vs. 35/124; p = 0.794). There was a trend to reduced mortality in SIRS patients in the Se+ vs. Se group (p = 0.084). Plasma Se levels increased in the Se+ group only in patients with sepsis but not in patients with SIRS. Plasma Se levels correlated with GSHPx. In SIRS/Se+ group, Se correlated only with GSHPx. In SIRS/Se- group, Se correlated with cholesterol but not with other biomarkers. In sepsis patients, Se levels correlated with cholesterol, GSHPx and prealbumin. Cholesterol levels were higher in survivors in the Se- group. CONCLUSIONS: Se levels correlated with GSHPx activity and other nutritional biomarkers with significant differences between SIRS and sepsis groups. High-dose Se supplementation did not affect mortality but a strong trend to decreased mortality in SIRS patients warrants further studies in this population. PMID- 26004889 TI - Functional characterization of new mutations in Wilson disease gene (ATP7B) using the yeast model. AB - The Wilson disease gene, a copper transporting ATPase (Atp7b), is responsible for the sequestration of Cu into secretory vesicles, and this function is exhibited by the orthologous Ccc2p in the yeast. In this study, we aimed to characterize clinically relevant new mutations of human ATP7B (p.T788I, p.V1036I and p.R1038G fsX83) in yeast lacking the CCC2 gene. Expression of human wild type ATP7B gene in ccc2Delta mutant yeast restored the growth deficiency and copper transport activity; however, expression of the mutant forms did not restore the copper transport functions and only partially supported the cell growth. Our data support that p.T788I, p.V1036I and p.R1038G-fsX83 mutations cause functional deficiency in ATP7B functions and suggest that these residues are important for normal ATP7B function. PMID- 26004890 TI - Plasma and mitochondrial membrane perturbation induced by aluminum in human peripheral blood lymphocytes. AB - Aluminum is a redox-inert element that could induce cell damage via activation of oxidative stress. In this work, the effect of aluminum on different cellular compartments of human peripheral blood lymphocytes was studied. The presence of aluminum induced a lipid peroxidation and physico-chemical modifications at the membrane level. A decrease in fluorescence anisotropy of TMA-DPH and in the polarity of the lipid bilayer with a concomitant shift toward a gel phase was observed, while the pyrene excimerization coefficient (Kex) increased. Flow cytometry measurements, using JC-1, Rhodamine 123 and H2-DCFDA as fluorescent probes, indicated that aluminum induces a slight mitochondrial membrane depolarization that was associated with a moderate increase in reactive oxygen species production. A significative influence on these parameters was measured only at high aluminum concentration. PMID- 26004891 TI - Prevention of cell death by the zinc ion chelating agent TPEN in cultured PC12 cells exposed to Oxygen-Glucose Deprivation (OGD). AB - To elucidate the role of Zn(2+)-associated glutamate signaling pathway and voltage-dependent outward potassium ion currents in neuronal death induced by hypoxia-ischemia, PC12 cells were exposed to Oxygen-Glucose Deprivation (OGD) solution mimicking the hypoxic-ischemic condition in neuron, and the effect of N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a specific Zn(2+) chelating agent on OGD-induced neuronal death was assessed in the present study. The cell survival rate, apoptosis status, potassium channel currents, intracellular free glutamate concentration and GluR2 expression in PC12 cells exposed to OGD in the absence or presence of TPEN for different time were investigated. The results showed that OGD exposure increased apoptosis, reduced the cell viability (P < 0.01 at 3h, 6h and 24h, respectively compared to control), changed the voltage-dependent outward potassium ion current (increase at 1h, but decrease at 3h) and decreased the concentration of intracellular glutamate (P < 0.05 at 3h and 6h, P < 0.01 at 24h respectively compared to control) and GluR2 expression (P < 0.05 at 3h, 6h and 24h, respectively compared to control) in PC12 cells. TPEN partially reversed the influence resulted from OGD. These results suggest that OGD-induced cell apoptosis and/or death is mediated by the alteration in glutamate signaling pathway and the voltage dependent outward potassium ion currents, while TPEN effectively prevent cell apoptosis and/or death under hypoxic-ischemic condition. PMID- 26004892 TI - Hesperidin ameliorates heavy metal induced toxicity mediated by oxidative stress in brain of Wistar rats. AB - Cadmium (Cd) induces neurotoxicity owing to its highly deleterious capacity to cross the blood brain barrier (BBB). Recent studies have provided insights on antioxidant properties of bioflavonoids which have emerged as potential therapeutic and nutraceutical agents. The aim of our study was to examine the hypothesis that hesperidin (HP) ameliorates oxidative stress and may have mitigatory effects in the extent of heavy metal-induced neurotoxicity. Cd (3mg/kg body weight) was administered subcutaneously for 21 days while HP (40 mg/kg body weight) was administered orally once every day. The results of the current investigation demonstrate significant elevated levels of oxidative stress markers such as lipid peroxidation (LPO) and protein carbonyl (PC) along with significant depletion in the activity of non-enzymatic antioxidants like glutathione (GSH) and non-protein thiol (NP-SH) and enzymatic antioxidants in the Cd treated rats' brain. Activity of neurotoxicity biomarkers such as acetylcholinesterase (AchE), monoamine oxidase (MAO) and total ATPase were also altered significantly and HP treatment significantly attenuated the altered levels of oxidative stress and neurotoxicity biomarkers while salvaging the antioxidant sentinels of cells to near normal levels thus exhibiting potent antioxidant and neuroprotective effects on the brain tissue against oxidative damage in Cd treated rodent model. PMID- 26004893 TI - Development of thyroid dysfunction among women with excessive iodine intake--A 3 year follow-up. AB - OBJECTIVES: Thyroid dysfunction can be a result of excessive iodine intake, which may have adverse health consequences, particularly for women in fertile age. In 2010, we conducted a cross-sectional study among lactating women with excessive iodine intake in the Saharawi refugee camps in Algeria and found a high prevalence of thyroid dysfunction. Three years later, we conducted a follow-up study to monitor the iodine situation and explore whether thyroid dysfunction still was highly prevalent when the women no longer were post-partum. None of the women were treated for hyper- or hypothyroidism between baseline and follow-up. METHODS: In 2013, we were able to recapture 78 of the 111 women from the baseline. Thyroid hormones and antibodies were measured in serum and thyroid size was assessed by palpation. Urinary iodine concentration (UIC) and drinking water iodine concentration were measured. RESULTS: The overall prevalence of thyroid dysfunction and/or positive antibodies was 34.3% and was not significantly changed from baseline. Of the non-pregnant women we reexamined, 17 had hypo- or hyperthyroidism in 2010; among these, 12 women still had abnormal thyroid function at follow-up. In addition, we found 9 new cases with marginally abnormal thyroid function. Women with thyroid dysfunction and/or positive antibodies had significantly higher BMI and thyroglobulin than women with normal thyroid function. We also found that women with high breast milk iodine concentration (BMIC) at baseline had more thyroid dysfunction at follow-up than the women with lower BMIC at baseline. CONCLUSIONS: At follow-up, the prevalence of thyroid dysfunction was still high and had not changed during the 3 years between studies and from a postpartum period. The women still had a high iodine intake indicated by high UIC. Breast milk iodine concentration from baseline predicted thyroid dysfunction at follow-up. PMID- 26004894 TI - Essential metals profile of the hair and nails of patients with laryngeal cancer. AB - Trace elements have an impact on numerous physiological processes. The monitoring of their levels in the organism allows you to detect not only their deficiencies, but also several illnesses. The aim of this study was to compare the levels of essential elements (calcium, magnesium, zinc, copper, iron, manganese) in hair, nails and serum of both patients with laryngeal cancer and healthy people. The determination of six metals was performed by an inductively coupled plasma mass spectrometry (ICP-MS) and an inductively coupled plasma optical emission spectrometry (ICP-OES). The concentration of essential elements in hair and nails of the control group was statistically significantly higher than in the group of patients with laryngeal cancer. In the case of serum, differences were found between the patients and controls in respect of the level of three metals. The results of principal component analysis (PCA) revealed the strong and similar clustering behavior of essential elements in hair and nails. The metals did not correlate between two alternative materials. The present study indicated that, using the level of essential elements in hair and nails as a basis, it is possible to distinguish cancer patients from healthy people. The alternative materials are independent of homeostasis and therefore seem to be more useful in the detection of diseases and mineral deficiencies in human than the classical biological materials, such as blood. PMID- 26004895 TI - Do soft drinks affect metal ions release from orthodontic appliances? AB - OBJECTIVE: The effect of orange juice and Coca Cola((r)) on the release of metal ions from fixed orthodontic appliances. MATERIALS AND METHODS: A continuous flow system designed for in vitro testing of orthodontic appliances was used. Orange juice/Coca Cola((r)) was flowing through the system alternately with artificial saliva for 5.5 and 18.5h, respectively. The collected samples underwent a multielemental ICP-OES analysis in order to determine the metal ions release pattern in time. RESULTS: The total mass of ions released from the appliance into orange juice and Coca Cola((r)) (respectively) during the experiment was calculated (MUg): Ni (15.33; 37.75), Cr (3.604; 1.052), Fe (48.42; >= 156.1), Cu (57.87, 32.91), Mn (9.164; 41.16), Mo (9.999; 30.12), and Cd (0.5967; 2.173). CONCLUSIONS: It was found that orange juice did not intensify the release of metal ions from orthodontic appliances, whereas Coca Cola((r)) caused increased release of Ni ions. PMID- 26004896 TI - Association of plasma manganese levels with chronic renal failure. AB - Manganese (Mn) is an essential trace element involved in the formation of bone and in amino acid, lipid and carbohydrate metabolism. Mn excess may be neurotoxic to humans, affecting specific areas of the central nervous system. However, relatively little is known about its physiological and/or toxicological effects, and very few data are available concerning the role of Mn in chronic renal failure (CRF). This paper describes a 12-month study of the evolution of plasma Mn levels in predialysis patients with CRF and the relationship with energy and macronutrient intake. The participants in this trial were 64 patients with CRF in predialysis and 62 healthy controls. Plasma levels of creatinine, urea, uric acid, total protein and Mn were measured. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault index. The CRF patients had higher plasma levels of creatinine, urea, uric acid and Mn and a lower GFR than the controls. Plasma Mn was positively correlated with creatinine, plasma urea and plasma uric acid and was negatively correlated with the GFR and the intake of energy and macronutrients. In conclusion, CRF in predialysis patients is associated with increases in circulating levels of Mn. PMID- 26004897 TI - Involvement of caspases and their upstream regulators in myocardial apoptosis in a rat model of selenium deficiency-induced dilated cardiomyopathy. AB - Keshan disease is an endemic dilated cardiomyopathy (DCM) which is closely related with selenium-deficient diet in China. In the previous study, we reported that the low selenium status plays a pivotal role in the myocardial apoptosis in the DCM rats, however, the underlying mechanism remains unclear. The present study aimed to determine whether the intrinsic, extrinsic pathways and the upstream regulators were involved in the myocardial apoptosis of selenium deficiency-induced DCM rats. Therefore, the rat model of endemic DCM was induced by a selenium-deficient diet for 12 weeks. Accompanied with significant dilation and impaired systolic function of left ventricle, an enhanced myocardial apoptosis was detected by TUNEL assay. Western blot analysis showed remarkably increased protein levels of cleaved caspase-3, caspase-8, caspase-9, and cytosolic cytochrome c released from the mitochondria. In addition, the immunoreactivities of p53 and Bax were significantly up-regulated, while the anti apoptotic Bcl-2 family members Bcl-2 and Bcl-X(L) were down-regulated. Furthermore, appropriate selenium supplement for another 4 weeks could partially reverse all the above changes. In conclusion, the intrinsic, extrinsic pathways and the upstream regulators such as p53, Bax, Bcl-2, and Bcl-X(L )were all involved in selenium deficiency-induced myocardial apoptosis. PMID- 26004898 TI - Cadmium-induced formation of sulphide and cadmium sulphide particles in the aquatic hyphomycete Heliscus lugdunensis. AB - Freshwater fungi which can survive under metal exposure receive increasing scientific attention. Enhanced synthesis of sulphide and glutathione but no phytochelatin synthesis in response to cadmium (up to 80 MUM Cd(2+) in the medium) was measured in the aquatic hyphomycete Heliscus lugdunensis. Up to 25 MUmol g(-1) dry mass the fungus formed sulphide in an exponentially Cd(2+) concentration-dependent manner. Using light microscopy, precipitates were observed outside of the hyphae which could be determined as amorphous particles by X-ray diffraction (XRD). Energy dispersive X-ray spectroscopy (EDS) analysis indicated that these particles were mainly composed of Cd and S with an atomic ratio of 1:1, but some elements of the culture medium such as P and Cl were also present. Fungal cells exposed to Cd(2+) accumulated 12-28 MUmol metal g(-1) dry mass over a period of 7-28 days. The results may indicate that sulphide could sequester excess Cd(2+) under oxygen deprived conditions and thereby reduce its toxicity via an additional avoidance mechanism of this fungus. PMID- 26004899 TI - Content of trace elements and chromium speciation in Neem powder and tea infusions. AB - Total concentrations of selected trace elements in Neem powder and in Neem tea were determined by inductively coupled plasma mass spectrometry (ICP-MS). The data revealed that despite high total concentrations of the potentially toxic elements Al and Ni in Neem powder, their amounts dissolved in Neem tea were low. Total concentrations of the other toxic elements Pb, As and Cd were also very low and do not represent a health hazard. In contrast, total concentrations of the essential elements Fe, Cu, Zn, Se Mo and Cr in Neem powder were high and also considerable in Neem tea. Consuming one cup of Neem tea (2g per 200 mL of water) covers the recommended daily intakes for Cr and Se and represents an important source of Mo and Cu. Speciation analysis of Cr by high performance liquid chromatography (HPLC) coupled to ICP-MS with the use of enriched Cr isotopic tracers to follow species interconversions during the analytical procedure demonstrated that toxic Cr(VI) was not present either in Neem powder or in Neem tea. Its concentrations were below the limits of detection of the HPLC-ICP-MS procedure applied. The speciation analysis data confirmed that even Cr(VI) was added, it was rapidly reduced by the presence of antioxidants in Neem leaves. By the use of enriched Cr isotopic spike solutions it was also demonstrated that for obtaining reliable analytical data it is essential to apply the extraction procedures which prevent Cr species interconversions, or to correct for species transformation. PMID- 26004900 TI - Mangiferin ameliorates aluminium chloride-induced cognitive dysfunction via alleviation of hippocampal oxido-nitrosative stress, proinflammatory cytokines and acetylcholinesterase level. AB - Mangiferin is a phytochemical primarily present in the stem, leaves and bark of Mangifera indica. It offers neuroprotection mainly through inhibition of oxidative stress, and decreasing proinflammatory cytokines level in the brain. Aluminium has been reported to cause oxidative stress-associated damage in the brain. In the present investigation, protective effect of mangiferin against aluminium chloride (AlCl3)-induced neurotoxicity and cognitive impairment was studied in male Swiss albino mice. AlCl3 (100 mg/kg) was administered once daily through oral gavage for 42 days. Mangiferin (20 and 40 mg/kg, p.o.) was given to mice for last 21 days of the study. We found cognitive dysfunction in AlCl3 treated group, which was assessed by Morris water maze test, and novel object recognition test. AlCl3-treated group showed elevated level of oxidative stress markers, proinflammatory cytokines level and lowered hippocampal brain-derived neurotrophic factor (BDNF) content. Mangiferin (40 mg/kg) prevented the cognitive deficits, hippocampal BDNF depletion, and biochemical anomalies induced by AlCl3 treatment. In conclusion, our data demonstrated that mangiferin offers neuroprotection in AlCl3-induced neurotoxicity and it may be a potential therapeutic approach in the treatment of oxido-nitrosative stress and inflammation-associated neurotoxicity. PMID- 26004901 TI - Plasma levels of trace elements and exercise induced stress hormones in well trained athletes. AB - This study analyzed the variation and relationship of several trace elements, metabolic substrates and stress hormones activated by exercise during incremental exercise. Seventeen well-trained endurance athletes performed a cycle ergometer test: after a warm-up of 10 min at 2.0 W kg(-1), the workload was increased by 0.5 W kg(-1) every 10 min until exhaustion. Prior diet, activity patterns, and levels of exercise training were controlled, and tests timed to minimize variations due to the circadian rhythm. Oxygen uptake, blood lactate concentration, plasma ions (Zn, Se, Mn and Co), serum glucose, non-esterified fatty acids (NEFAs) and several hormones were measured at rest, at the end of each stage and 3, 5 and 7 min post-exercise. Urine specific gravity was measured before and after the test, and participants drank water ad libitum. Significant differences were found in plasma Zn and Se levels as a function of exercise intensity. Zn was significantly correlated with epinephrine, norepinephrine and cortisol (r = 0.884, P < 0.01; r = 0.871, P < 0.01; and r = 0.808, P = 0.05); and Se showed significant positive correlations whit epinephrine and cortisol (r = 0.743, P < 0.05; and r = 0.776, P < 0.05). Neither Zn nor Se levels were associated with insulin or glucagon, and neither Mn nor Co levels were associated with any of the hormones or substrate metabolites studied. Further, while Zn levels were found to be associated only with lactate, plasma Se was significantly correlated with lactate and glucose (respectively for Zn: r = 0.891, P < 0.01; and for Se: r = 0.743, P < 0.05; r = 0.831, P < 0.05). In conclusion, our data suggest that there is a positive correlation between the increases in plasma Zn or Se and stress hormones variations induced by exercise along different submaximal intensities in well-hydrated well-trained endurance athletes. PMID- 26004902 TI - Encapsulated boron as an osteoinductive agent for bone scaffolds. AB - The aim of this study was to develop boron (B)-releasing polymeric scaffold to promote regeneration of bone tissue. Boric acid-doped chitosan nanoparticles with a diameter of approx. 175 nm were produced by tripolyphosphate (TPP)-initiated ionic gelation process. The nanoparticles strongly attached via electrostatic interactions into chitosan scaffolds produced by freeze-drying with approx. 100 MUm pore diameter. According to the ICP-OES results, following first 5h initial burst release, fast release of B from scaffolds was observed for 24h incubation period in conditioned medium. Then, slow release of B was performed over 120 h. The results of the cell culture studies proved that the encapsulated boron within the scaffolds can be used as an osteoinductive agent by showing its positive effects on the proliferation and differentiation of MC3T3-E1 preosteoblastic cells. PMID- 26004904 TI - Vacation ease: travelling with an insulin pump. AB - BACKGROUND: Vacation travel is a welcome retreat from our everyday world. Whether the trip is trekking in Nepal, a ski vacation in the western Rockies or a beach holiday to the Caribbean, the insulin pump is a constant companion for many people with diabetes. As a healthcare professional assisting individuals in their travel plans, we can contribute to the success of their trip by encouraging early preparation and by sharing practical and timely tips. PURPOSE: To provide current information and practical insights for healthcare professionals (HCP) who are counseling patients with diabetes travelling with an insulin pump. LIMITATIONS: There are numerous suggestions for all patients with diabetes who travel. This article will focus on travel recommendations specific to the pump user. Due to the lack of research in this area the information shared is based on evidence where possible and otherwise patient experience. CONCLUSION: Insulin pump users can enjoy any type of vacation travel. Certain destinations require more preparation than others but regardless of the choice of venue, preplanning in collaboration with a knowledgeable health care provider can contribute to a successful experience. PMID- 26004903 TI - High intrinsic aerobic capacity and pomegranate juice are protective against macrophage atherogenecity: studies in high- vs. low-capacity runner (HCR vs. LCR) rats. AB - We studied the rat model system of high- vs. low-capacity runner (HCR vs. LCR) rats to question the atherogenic properties (oxidative stress, triglycerides and cholesterol metabolism) in the rat macrophages, serum, liver and heart. Half of the LCR or HCR rats consumed pomegranate juice (PJ; 15 MUmol of gallic acid equivalents/rat/day) for 3 weeks and were compared to placebo-treated rats. At the end of the study blood samples, peritoneal macrophages (RPM), livers, and hearts were harvested from the rats. RPM harvested from HCR vs. LCR demonstrated reduced cellular oxidation (21%), increased paraoxonase 2 activity (28%) and decreased triglycerides mass (44%). Macrophage uptake rates of fluorescein isothiocyanate-labeled low-density lipoprotein (LDL) or oxidized LDL were significantly lower, by 37% or by 18%, respectively, in HCR vs. LCR RPM. PJ consumption significantly decreased all the above atherogenic parameters with more substantial beneficial effects observed in the LCR vs. the HCR rats (~80% vs. ~40% improvement, respectively). Similar hypo-triglyceridemic pattern was noted in serum from HCR vs. LCR. In contrast to the above results, liver oxidation and triglycerides mass were both minimally increased in HCR vs. LCR rats by 31% and 28%, respectively. In the heart, lipid content was very low, and interestingly, an absence of any significant oxidative stress, along with modest triglyceride accumulation, was observed. We conclude that HCR vs. LCR rats demonstrate reduced atherogenicity, mostly in their macrophages. PJ exerts a further improvement, mostly in macrophages from LCR rats. PMID- 26004905 TI - How can diabetes applications be better? PMID- 26004906 TI - Clinical diabetes research using data mining: a Canadian perspective. AB - With the advent of the digitization of large amounts of information and the computer power capable of analyzing this volume of information, data mining is increasingly being applied to medical research. Datasets created for administration of the healthcare system provide a wealth of information from different healthcare sectors, and Canadian provinces' single-payer universal healthcare systems mean that data are more comprehensive and complete in this country than in many other jurisdictions. The increasing ability to also link clinical information, such as electronic medical records, laboratory test results and disease registries, has broadened the types of data available for analysis. Data-mining methods have been used in many different areas of diabetes clinical research, including classic epidemiology, effectiveness research, population health and health services research. Although methodologic challenges and privacy concerns remain important barriers to using these techniques, data mining remains a powerful tool for clinical research. PMID- 26004907 TI - Estimating central line-associated bloodstream infection incidence rates by sampling of denominator data: A prospective, multicenter evaluation. AB - BACKGROUND: Large-scale, prospective, evaluation of sampling for central line associated bloodstream infection (CLABSI) denominator data was necessary prior to National Healthcare Safety Network (NHSN) implementation. METHODS: In a sample of volunteer hospitals from states in the Emerging Infections Program, prospective collection of CLABSI denominators (patient days, central line days [CLDs]) was performed in eligible locations for >=6 and <=12 consecutive months using the current NHSN method (daily collection) and also by a second data collector who sampled the denominator data 1 d/wk. The quality of the sampled data was evaluated and used to calculate estimated CLDs and CLABSI rates, which were compared with actual CLDs and CLABSI rates (daily counts). RESULTS: In total, 89 locations in 66 acute care hospitals participated. Sampled data were collected as intended 88% of the time; the quality of the data was comparable with the data collected daily. In locations with higher CLDs per month (>=75), estimated CLDs and CLABSI rates were similar to actual CLDs and CLABSI rates; however, there were significant differences in actual and estimated values among locations with lower (<=74) CLDs per month.Sampling was successfully implemented, but significant differences in the accuracy of estimated CLDs and CLABSI rates, based on the actual number of CLDs per month, were noted. CONCLUSION: For locations with a higher number of CLDs per month, sampling 1 d/wk is a valid and accurate alternative to daily collection of CLABSI denominator data. PMID- 26004908 TI - Association of C7673T polymorphism in apolipoprotein B gene with ischemic stroke in the Chinese population: a meta-analysis. AB - BACKGROUND: Epidemiological studies have evaluated the association between the C7673T polymorphism in apolipoprotein B (apoB) gene and ischemic stroke (IS), but the results are still debatable even in the Chinese population. This meta analysis was therefore designed to clarify these controversies. METHODS: All of the relevant studies were identified from PubMed, Embase, Chinese National Knowledge Infrastructure database and Chinese Wanfang database up to 31 October 2014. Statistical analyses were conducted with Revman 5.2 and STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. A fixed or random effect model was selected for pooling data based on the heterogeneity test. Publication bias was assessed by Begg's test and Egger's test. RESULTS: A significant association was found between the C7673T polymorphism in apoB gene and IS under the heterozygous genetic model (OR = 1.868, 95% CI = 1.160-3.007) and the allelic genetic model (OR = 1.742, 95% CI = 1.294-2.346), respectively. In the subgroup analysis by the geographic region, T allele could increase the risk of IS in northern Chinese (OR = 2.359, 95% CI: 1.425-3.907), but not in southern Chinese individuals (OR = 1.485, 95% CI: 0.778-2.832). Further stratification for source of controls showed that statistical significance was found among the population-based studies. CONCLUSION: Our meta-analysis revealed that C7673T polymorphism in apoB gene was significantly associated with increased IS risk in the Chinese population. PMID- 26004909 TI - Important considerations for case-control study conduct and reporting. PMID- 26004910 TI - Association between PDE4D gene and ischemic stroke: recent advancements. AB - Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome. PMID- 26004912 TI - Heterologous expression of ACC deaminase from Trichoderma asperellum improves the growth performance of Arabidopsis thaliana under normal and salt stress conditions. AB - Transgenic Arabidopsis thaliana plants expressing the 1-aminocyclopropane-1 carboxylate deaminase gene (ACCD) of Trichoderma asperellum ACCC30536 (TaACCD) were created and their growth performance was assessed under normal and salt stress conditions. In order to characterize their growth, root length, root number, fresh weight (FW), relative water content (RWC), seed production, and seed number were measured. Under normal growing condition, all growth parameters except for dry weight (DW) of the transgenic plants increased significantly compared to WT plants. Furthermore, the transgenic line also exhibited higher tolerance and faster growth than WT plants in the presence of 150 mM NaCl. The increased salt stress tolerance of the transgenic plants is attributed to a greater RWC, root weight, root length, root number and FW under salt stress, and to reduced reactive oxygen species (ROS) level, cell death and electrolyte leakage compared to WT plants. The reduction in ROS levels could be explained by increased activity of several antioxidant enzymes, including peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT). Thus, we propose that heterologous expression of TaACCD could be used to improve salt stress tolerance in plants. PMID- 26004911 TI - Reduced plasma taurine level in Parkinson's disease: association with motor severity and levodopa treatment. AB - PURPOSE: This study aimed to evaluate the level of taurine in plasma, and its association with the severity of motor and non-motor symptoms (NMS) and chronic levodopa treatment in Parkinson's disease (PD). PATIENTS AND METHODS: Plasma taurine level was measured in treated PD (tPD), untreated PD (ntPD) and control groups. Motor symptoms and NMS were assessed using the Unified Parkinson's Disease Rating Scale, the short form of the McGill Pain Questionnaire, the Hamilton Depression Scale, the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms and the Pittsburgh Sleep Quality Index. Longtime exposure to levodopa was indicated by its approximate cumulative dosage. RESULTS: The plasma taurine levels of PD patients were decreased when compared with controls and negatively associated with motor severity but not NMS. Moreover, tPD patients exhibited lower levels of plasma taurine than ntPD patients. Interestingly, plasma taurine levels negatively correlated with cumulative levodopa dosage in tPD. After controlling for potential confounders, the association between taurine and levodopa remained significant. CONCLUSION: Our study supports that taurine may play important roles in the pathophysiology of PD and the disturbances caused by chronic levodopa administration. PMID- 26004913 TI - Shoot ionome to predict the synergism and antagonism between nutrients as affected by substrate and physiological status. AB - The elemental composition of a tissue or organism is defined as ionome. However, the combined effects on the shoot ionome determined by the taxonomic character, the nutrient status and different substrates have not been investigated. This study tests the hypothesis that phylogenetic variation of monocots and dicots grown in iron deficiency can be distinguished by the shoot ionome. We analyzed 18 elements in barley, cucumber and tomato and in two substrates (hydroponic vs soil) with different nutritional regimes. Multivariate analysis evidenced a clear separation between the species. In hydroponic conditions the main drivers separating the species are non essential-nutrients as Ti, Al, Na and Li, which were positively correlated with macro- (P, K) and micronutrients (Fe, Zn, Mo, B). The separation between species is confirmed when plants are grown on soil, but the distribution is determined especially by macronutrients (S, P, K, Ca, Mg) and micronutrients (B). A number of macro (Mg, Ca, S, P, K) and micronutrients (Fe, Mn, Zn, Cu, Mo, B) contribute to plant growth and several other important physiological and metabolic plant activities. The results reported here confirmed that the synergism and antagonism between them and other non-essential elements (Ti, Al, Si, Na) define the plant taxonomic character. The ionome profile might thus be exploited as a tool for the diagnosis of plants physiological/nutritional status but also in defining biofortification strategies to optimize both mineral enrichment of staple food crops and the nutrient input as fertilizers. PMID- 26004915 TI - A Top-Down Cortical Circuit for Accurate Sensory Perception. AB - A fundamental issue in cortical processing of sensory information is whether top down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-range reciprocal projection between M2 secondary motor cortex and S1 primary somatosensory cortex. In vivo physiological recordings revealed that sensory stimulation induced sequential S1 to M2 followed by M2 to S1 neural activity. The top-down projection from M2 to S1 initiated dendritic spikes and persistent firing of S1 layer 5 (L5) neurons. Optogenetic inhibition of M2 input to S1 decreased L5 firing and the accurate perception of tactile surfaces. These findings demonstrate that recurrent input to sensory areas is essential for accurate perception and provide a physiological model for one type of top-down control circuit. PMID- 26004916 TI - Response to Letter to the Editor Re: "Determining the level of evidence for the effectiveness of spinal manipulation in the upper limb: A systematic review meta analysis". PMID- 26004914 TI - Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. AB - Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability. PMID- 26004917 TI - Taxane induced neuropathy in patients affected by breast cancer: Literature review. AB - Taxane induced neuropathy (TIN) is the most limiting side effect of taxane based chemotherapy, relative to the majority of breast cancer patients undergoing therapy with both docetaxel and paclitaxel. The symptoms begin symmetrically from the toes, because the tips of the longest nerves are affected for first. The patients report sensory symptoms such as paresthesia, dysesthesia, numbness, electric shock-like sensation, motor impairment and neuropathic pain. There is a great inter-individual variability among breast cancer women treated with taxanes, in fact 20-30% of them don't develop neurotoxicity. Actually, there is no standard therapy for TIN, although many medications, antioxidants and natural substances have been tested in vitro and in vivo. We will summarize all most recent literature data on TIN prevention and treatment, in order to reach an improvement in TIN management. Further studies are needed to evaluate new therapies that restore neuronal function and improve life quality of patients. PMID- 26004918 TI - The functional muscle-bone unit in patients with osteogenesis imperfecta type I. AB - CONTEXT: Osteogenesis imperfecta (OI) type I is a heritable bone fragility disorder that is caused by mutations affecting collagen type I. We recently showed that patients with OI type I frequently have muscle weakness. As muscle force and bone mass are usually closely related, we hypothesized that muscle weakness in OI type I could contribute to increase bone mass deficit in the lower extremities. OBJECTIVE: To assess the muscle-bone relationship in the lower extremities of children and adolescents with OI type I. SETTING: The study was carried out in the outpatients department of a pediatric orthopedic hospital. Patients and other participants Thirty children and adolescents with OI type I (20 females; mean age [SD]: 11.2 years [3.9]) were compared with 30 healthy age- and sex-matched controls (mean age [SD]: 11.1 years [4.5]). MAIN OUTCOME MEASURES: Tibia bone mineral content (BMC; mg/mm) was measured by peripheral quantitative computed tomography to estimate bone strength at the 4% and 14% sites. Lower extremity peak force (kN) was measured by mechanography using the multiple two-legged hopping test. RESULTS: Compared with age- and sex-matched controls, patients with OI type I had 17% lower peak force (1.3 kN vs. 1.7 kN; p=0.002) as well as a 22% lower BMC (128 mg/mm vs. 165 mg/mm; p<0.001). Stepwise regression analysis showed that muscle force and tibia length were positively related to bone strength (r(2)=0.90, p<0.001) whereas there was no effect of the disease status (OI vs. control). CONCLUSIONS: These results suggest that the muscle-bone relationship is similar between children and adolescents with OI type I and healthy age and sex-matched controls. It also suggests that muscle weakness may contribute to decreased bone strength in individuals with OI type I. PMID- 26004919 TI - How B cells remember? A sophisticated cytoplasmic tail of mIgG is pivotal for the enhanced transmembrane signaling of IgG-switched memory B cells. AB - Antibody memory is critical for protection against many human infectious diseases and is the basis for nearly all current human vaccines. Isotype switched immunoglobulin (Ig) G-expressing memory B cells are considered as one of the fundaments for the rapid, high affinity and high-titered memory antibody response. The detailed molecular mechanism of the enhanced activation of IgG switched memory B cells upon BCR engagement with antigens has been an elusive question in immunology. In this review, we tried to discuss all the exciting new advances revealing the molecular mechanisms of the transmembrane signaling through mIgG cytoplasmic tail in IgG-switched memory B cells. PMID- 26004920 TI - Lipoprotein apheresis. AB - Lipoprotein apheresis is an extracorporeal therapy whereby apo B-containing lipoproteins (LDL, vLDL, and Lp(a)) are selectively removed from the plasma of a patient. It is a variation of plasma exchange, which non-selectively removes all plasma proteins. Lipoprotein apheresis is most commonly used to treat patients with familial hypercholesterolemia, but is also often used for other hyperlipidemic patients, including those with elevated Lp(a), to limit and/or reverse the atherosclerotic complications of high cholesterol. Herein, we provide an overview of lipoprotein apheresis including indications, techniques, efficacy, and adverse events, as well as guidelines and other considerations important for selection of patients for this therapy. PMID- 26004922 TI - Is Video-Assisted Thoracoscopic Surgery Adequate in Treatment of Pulmonary Hydatidosis? AB - BACKGROUND: Surgical management of pulmonary hydatid cyst disease has been well established. However, there are still limited data on the role of video-assisted thoracoscopic surgery in treatment of this disease. The aim of this study is to identify the advantages and disadvantages of minimally invasive surgery and compare the outcomes with patients undergoing thoracotomy in this parasitic disease. METHODS: The medical records of 77 patients (53 male, 24 female) undergoing surgery for pulmonary hydatid cyst disease between January 2011 and January 2014 were reviewed. Removal of the hydatid cyst was completed using video assisted thoracoscopic surgery in 39% (n = 30) of the patients, whereas open thoracotomy was used in 61% (n = 47). Conversion rate was 21%. Statistical analysis was used to assess differences in drainage amount, time to drain removal, length of surgery, length of hospital stay, and pain scores. Probability values of less than 0.05 were considered significant. RESULTS: The drainage amount, time to drain removal, length of surgery, duration of narcotic analgesics usage, and visual analog scale scores in the thoracotomy group were significantly longer than those of the thoracoscopy group. Postoperative complications occurred in 4.3% of thoracotomy and in 13.3% of thoracoscopy patients. There was no mortality in either group. During the follow-up period, no recurrence was detected. CONCLUSIONS: Video-assisted thoracoscopy for surgery of pulmonary hydatid cyst disease is superior to open thoracotomy causing less postoperative pain, a better cosmetic result, a shorter surgical time, a lower drainage volume, and a shorter time to drain removal in a selected group of patients. The fear of recurrence because of incomplete isolation of the cyst during removal was not a concern regarding our technique. PMID- 26004921 TI - Primary and secondary prevention of ischemic heart disease in women. AB - Cardiovascular disease remains the number one cause of mortality among women. With increasing awareness of heart disease in women and increasing focus on including more women in trials, mortality from cardiovascular disease has fallen. Despite this, more women than men die from cardiovascular disease, and increasing cardiovascular disease is seen in young women. Preventive therapies have been the focus of recent guidelines to close this gap. In this review, data for primary and secondary prevention therapies for ischemic heart disease in women will be reviewed. PMID- 26004923 TI - Valved Polytetrafluoroethylene Conduits for Right Ventricular Outflow Tract Reconstruction. AB - BACKGROUND: The purposes of this study were to review our early outcomes using valved expanded polytetrafluoroethylene (ePTFE) conduits, with or without bulging sinus structure, for right ventricular outflow tract reconstruction and to examine the mechanical properties of the ePTFE material after bulging sinuses were created. METHODS: A retrospective review was performed of all patients who received the valved ePTFE conduit between 2008 and 2014 at a single institution. The surface morphologies and the mechanical strengths of the ePTFE conduit with bulging sinuses examined by scanning electron microscopy and unidirectional pull test were compared with those of the original ePTFE material. RESULTS: There were 120 operations with the valved ePTFE conduit (60 with bulging sinuses). The patients median age and weight were 6.9 years and 23.7 kg. The conduits were a median size of 22 mm. At 5 years, freedom from conduit reoperation was 92.7% (95% confidence interval, 82.7% to 97.0%), and freedom from severe conduit insufficiency or more than a 50 mm Hg gradient was 74.8% (95% confidence interval, 60.8% to 84.4%). No significant differences in the surface morphologies were observed by the scanning electron microscopy or in the maximum tolerated loads obtained by the pull test between the original ePTFE material and the ePTFE with bulging sinuses (121 and 122 N in longitudinal direction and 115 and 121 N in circumferential direction; p = 0.88 and p = 0.68). CONCLUSIONS: The valved ePTFE conduits demonstrated excellent early clinical outcomes. The mechanical property examinations showed no obvious difference after bulging sinuses were created on the ePTFE material. PMID- 26004924 TI - The Impact of a Frailty Education Module on Surgical Resident Estimates of Lobectomy Risk. AB - BACKGROUND: Frailty is a risk factor for adverse events after surgery. Residents' ability to recognize frailty is underdeveloped. We assessed the influence of a frailty education module on surgical residents' estimates of lobectomy risk. METHODS: Traditional track cardiothoracic surgery residents were randomly allocated to take an online short course on frailty (experimental group) or to receive no training (control group). Residents read a clinical vignette, made an initial risk estimate of major complications for lobectomy, and rated clinical factors on their importance to their estimates. They viewed a video of a standardized patient portraying the patient in the vignette, randomly selected to exhibit either vigorous or frail behavior, and provided a final risk estimate. After rating five vignettes, they completed a test on their frailty knowledge. RESULTS: Forty-one residents participated (20 in the experimental group). Initial risk estimates were similar between the groups. The experimental group rated clinical factors as "very important" in their initial risk estimates more often than did the control group (47.6% versus 38.5%; p < 0.001). Viewing videos resulted in a significant change from initial to final risk estimates (frail 50% +/- 75% increase, p = 0.008; vigorous 14% +/- 32% decrease, p = 0.043). The magnitude of change in risk estimates was greater for the experimental group (10.0 +/- 8.1 versus 5.1 +/- 7.7; p < 0.001). The experimental group answered more frailty test questions correctly (93.7% versus 75.2%; p < 0.001). CONCLUSIONS: A frailty education module improved resident knowledge of frailty and influenced surgical risk estimates. Training in frailty may help educate residents in frailty recognition and surgical risk assessment. PMID- 26004925 TI - Thoracic Revised Cardiac Risk Index Is Associated With Prognosis After Resection for Stage I Lung Cancer. AB - BACKGROUND: The objective of this investigation is to evaluate whether the Thoracic Revised Cardiac Risk Index (ThRCRI) is an independent prognostic factor after lung resection for early-stage lung cancer. METHODS: Observational analysis performed on 1,370 patients (from 2000 to 2011) undergoing anatomic lung resection for pathologic stage I non-small cell lung cancer in three thoracic surgery units. Survival was calculated by the Kaplan-Meier method. The association between survival and several clinical variables was determined by Cox multivariate analysis. RESULTS: Median follow-up was 77 months. Patients were assigned to risk classes according to their ThRCRI score: class A (score, 0 to 1), 1,062 patients; class B (score, 1.5 to 2.5), 284 patients; class C (score, >2.5), 24 patients. Patients in class A had a longer 5-year overall survival (66%) compared w those in classes B (53%) and C (35%; log-rank test, p < 0.0001). The ThRCRI remained an independent prognostic factor after Cox regression analysis (hazard ratio, 1.2; p = 0.001) along with age (hazard ratio, 1.03; p < 0.0001), pT stage (hazard ratio, 1.6; p < 0.0001), and forced expiratory volume in 1 second (hazard ratio, 0.98; p < 0.0001). Five-year cancer-specific survival was longer in patients with ThRCRI class A (77%) compared with classes B (75%) and C (55%; log-rank test, p = 0.05). Mortality from cardiac events occurring during follow-up was 1.5% in class A, 7% in class B, and 13% in class C (p < 0.0001). CONCLUSIONS: The ThRCRI is a useful prognostic score in patients undergoing resection for early-stage lung cancer. Patients with a score greater than 2.5 should be counseled about their increased risk of major perioperative cardiac events and their expected decreased long-term survival. PMID- 26004926 TI - Aortic Implantation of Anomalous Origin of the Left Coronary Artery From the Pulmonary Artery: Long-Term Outcomes. AB - BACKGROUND: Since 1989 all patients with anomalous origin of the left coronary artery from the pulmonary artery at our institution have been treated with aortic implantation. The purpose of this review was to assess the late outcomes of these patients, especially regarding left ventricular (LV) function and mitral valve insufficiency. METHODS: Between 1989 and 2014, 36 patients had aortic implantation of anomalous origin of the left coronary artery from the pulmonary artery. Mean age at surgery was 2.5 +/- 5.1 years (median, 0.5 years). Operative strategy included antegrade cold-blood cardioplegia, main pulmonary artery transection, aortic implantation with a large button of pulmonary artery, pulmonary reconstruction with fresh autologous pericardium, and prolonged postoperative inotropic and ventilator support. Mitral regurgitation and LV dysfunction were graded as 0 to 4 (0 = none, 1 = trivial, 1.5 = trivial-mild, 2 = mild, 2.5 = mild-moderate, 3 = moderate, 3.5 = moderate-severe, and 4 = severe). RESULTS: Mean mitral regurgitation grade preoperatively was 2.95 +/- 0.95. Mean LV dysfunction grade was 3.14 +/- 1.27. Mean cross-clamp and cardiopulmonary bypass times were 49.1 +/- 18 minutes (median, 48.5 minutes) and 147.5 +/- 45 minutes (median, 139 minutes), respectively. There was no operative or late mortality. Four patients had delayed sternal closure. Mean duration of ventilator support was 11 +/- 6.6 days (median, 9 days). Two patients required 3 and 6 days of postoperative extracorporeal mechanical circulatory support. Mean length of stay was 25 +/- 18 days (median, 19 days). No patient has required reoperation for supravalvar pulmonary stenosis, coronary stenosis, or mitral valve repair or replacement. Late echocardiographic follow-up shows a mean mitral regurgitation grade of 1.67 +/- 1.05 and a mean LV dysfunction grade of 0.23 +/- 0.68. CONCLUSIONS: Aortic implantation is our procedure of choice for patients with anomalous origin of the left coronary artery from the pulmonary artery. No patient required mitral valve repair or transplant. There was marked improvement of mitral regurgitation grade, return to essentially normal LV function, and no mortality during a 25-year period. PMID- 26004927 TI - Early diagnosis of HIV among men who have sex with men in Western Australia: impact of a peer-led sexually transmissible infection testing service. AB - Background In July 2010, the Western Australian AIDS Council established the 'M Clinic', a peer-led STI testing service for MSM. This study describes trends in HIV notifications among MSM in WA from 2004 to 2013, particularly the impact of the M Clinic on newly acquired HIV diagnoses. METHODS: The number and proportion of MSM HIV cases with newly acquired infection were compared for the 2004-2006, 2007-2009 and 2011-2013 time periods. Data from 2010 were excluded as the M Clinic opened in July 2010. RESULTS: Between the 2004-2006 and 2007-2009 periods, the number of MSM with newly acquired HIV increased by 50% (23 to 33 cases) and the number of newly acquired cases as a proportion of all new HIV diagnoses among MSM increased from 27% to 35% (30% increase) (P=0.25). In the 2011-2013 period, the number of newly acquired HIV cases among MSM more than doubled to 70 cases and comprised 53% of all new HIV diagnoses among MSM (P<0.05). Of the 70 newly acquired HIV cases in the 2011-2013 period, 30% (n=21) were diagnosed at the M Clinic. CONCLUSIONS: The proportion of MSM HIV notifications that were newly acquired increased between 2004 and 2013 in WA, with the greatest increase seen after the M Clinic commenced operation. A peer-led approach to HIV testing should be considered in order to achieve early diagnosis and treatment of HIV among MSM. PMID- 26004928 TI - Resonant Infrared Multiple Photon Dissociation Spectroscopy of Anionic Nucleotide Monophosphate Clusters. AB - We report mid-infrared spectra and potential energy surfaces of four anionic, 2' deoxynucleotide-5'-monophosphates (dNMPs) and the ionic DNA pairs [dGMP-dCMP-H](1 ), [dAMP-dTMP-H](1-) with a total charge of the complex equal to -1. We recorded IR action spectra by resonant IR multiple-photon dissociation (IRMPD) using the FELIX free electron laser. The potential energy surface study employed an on-the fly molecular dynamics quenching method (MD/Q), using a semiempirical AM1 method, followed by an optimization of the most stable structures using density functional theory. By employing infrared multiple-photon dissociation (IRMPD) spectroscopy in combination with high-level computational methods, we aim at a better understanding of the hydrogen bonding competition between the phosphate moieties and the nucleobases. We find that, unlike in multimer double stranded DNA structures, the hydrogen bonds in these isolated nucleotide pairs are predominantly formed between the phosphate groups. This intermolecular interaction appears to exceed the stabilization energy resulting from base pairing and directs the overall cluster structure and alignment. PMID- 26004929 TI - Practice-level quality improvement interventions in primary care: a review of systematic reviews. AB - AIM: To present an overview of effective interventions for quality improvement in primary care at the practice level utilising existing systematic reviews. BACKGROUND: Quality improvement in primary care involves a range of approaches from the system-level to patient-level improvement. One key setting in which quality improvement needs to occur is at the level of the basic unit of primary care--the individual general practice. Therefore, there is a need for practitioners to have access to an overview of the effectiveness of quality improvement interventions available in this setting. METHODS: DESIGN: A tertiary evidence synthesis was conducted (a review of systematic reviews). A systematic approach was used to identify and summarise published literature relevant to understanding primary-care quality improvement at the practice level. Quality assessment was via the Critical Appraisal Skills Programme tool for systematic reviews, with data extraction identifying evidence of effect for the examined interventions. SCOPE: Included reviews had to be relevant to quality improvement at the practice level and relevant to the UK primary-care context. Reviews were excluded if describing system-level interventions. OUTCOME MEASURES: A range of measures across care structure, process and outcomes were defined and interpreted across the quality improvement interventions. FINDINGS: Audit and feedback, computerised advice, point-of-care reminders, practice facilitation, educational outreach and processes for patient review and follow-up all demonstrated evidence of a quality improvement effect. Evidence of an improvement effect was higher where baseline performance was low and was particularly demonstrated across process measures and measures related to prescribing. Evidence was not sufficient to suggest that multifaceted approaches were more effective than single interventions. CONCLUSION: Evidence exists for a range of quality improvement interventions at the primary-care practice level. More research is required to determine the use and impact of quality improvement interventions using theoretical frameworks and cost-effectiveness analysis. PMID- 26004930 TI - What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? AB - The kynurenine pathway has received increasing attention as its connection to inflammation, the immune system and neurological conditions has become more apparent. It is the primary route for tryptophan catabolism in the liver and the starting point for the synthesis of nicotinamide adenine dinucleotide in mammals. Dysregulation or overactivation of this pathway can lead to immune system activation and accumulation of potentially neurotoxic compounds. These aspects make the kynurenine pathway a promising target for therapeutic development to treat inflammation and disease with neurological aspects, especially in cancer patients undergoing chemotherapy. PMID- 26004931 TI - Thrombolytic and Antiplatelet Effects of a Novel Plasminogen Activator from the Venom of Gloydius Brevicaudus Viper. AB - AIM: To investigate the thrombolytic and antiplatelet effects of a novel plasminogen activator from the venom of the Gloydius brevicaudus viper (GBV-PA) in vitro and in vivo. METHODS: Thrombolytic experiments were performed in rabbit models of ear vein thrombosis and carotid artery thrombosis and in dog model of acute cerebral infarction. Inhibition of thrombus formation was evaluated in rat inferior vena cava thrombosis model and ferric chloride-induced arterial thrombosis. In vitro, we assayed the antithrombotic effect of GBV-PA on rabbit blood clots, euglobulin lysis time (ELT) of rabbit plasma, and ADP-induced platelet aggregation. RESULTS: GBV-PA intravenous administration significantly reduced vascular recanalization times of rabbit ear veins thrombosis and thrombus weight of rabbit carotid artery thrombosis. The arterial recanalization rates were dose- and time-dependently improved after the administration of GBV-PA in canine acute cerebral infarction model. Thrombus length and weight were significantly reduced by GBV-PA both in rat inferior vena cava and ferric chloride-induced arterial thrombosis models. Thrombus formation in the blood of rabbits that were administered of GBV-PA was also inhibited. GBV-PA radically reduced plasma ELT of the rabbit's blood clots. ADP-induced platelet aggregation was inhibited by GBV-PA in a dose-dependent manner with a half-maximal inhibitory concentration of 19.9 MUg/mL. CONCLUSION: This study demonstrates that GBV-PA is a thrombolytic and antiplatelet agent. It has significant antithrombotic effects on various in vitro and in vivo experimental models of thrombosis. The mechanisms that underline its antithrombotic effects were related to GBV-PA's capabilities of increasing fibrinolytic activity and inhibition of platelet aggregation. PMID- 26004932 TI - Modified L-shaped surgical approach to excision of the sublingual gland. AB - We present a series of 1131 patients who were treated between 1981 and 2013 using the modified L-shaped angular surgical approach to excision of the sublingual gland, and describe the risks and benefits compared with the conventional approach. A total of 365 patients were treated with the conventional approach, while the other 766 have been treated since 1991 using the modified approach. There were no serious complications or recurrences during or after the operation in the modified series. There were significant differences between the two approaches in terms of injuries to the submandibular duct (p=0.03), incidence of ranula on the opposite side (p=0.02), amount of intraoperative bleeding (p=0.000), and duration of operation (p=0.000). The modified L-shaped incision is both viable and safe, and simplifies excision of the sublingual gland while protecting the submandibular duct. PMID- 26004933 TI - Relevance of psychosocial factors to quality of life in oral cancer and oral lichen planus: a prospective comparative study. AB - We can improve our understanding of how patients cope with oral squamous cell carcinoma (SCC) by making a comparison with their processes of coping and those used in other conditions. We have therefore compared quality of life (QoL), severity of symptoms, coping strategies, and factors that influence coping between patients with oral SCC and those with oral lichen planus. We asked 104 patients with oral SCC and 51 with oral lichen planus to complete questionnaires about their coping strategies, social support, locus of control, spirituality, QoL, and severity of symptoms. The outcome was that patients with oral SCC were far more likely to resort to coping strategies such as depressive coping, distraction, and self-motivation. The groups also differed regarding QoL and severity of symptoms. Patients with oral SCC had a poorer QoL and higher depression scores, whereas patients with oral lichen planus had better scores in the social support and spirituality categories. Patients with oral SCC generally had more distress than those with oral lichen planus. Not only did the former resort to depressive coping strategies, but they also had poorer QoL and higher values for depression. For the patients with oral lichen planus, social support and spirituality were protective, whereas they were associated with distress by patients with oral SCC. PMID- 26004934 TI - Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBV-encoded RNA (EBER) expression in Hodgkin lymphoma. AB - Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are new targets in cancer immunotherapy. PD-1 protein is an immune checkpoint expressed in many tumors. Epstein-Barr virus (EBV) is present in malignant Hodgkin/Reed-Sternberg (HRS) cells in approximately 40-50 % of Hodgkin lymphoma (HL). The aim of this study is to evaluate the clinical and prognostic importance of PD-1 and/or PD-L1 in HL and also to determine the association between EBV-encoded RNA (EBER) and PD 1/PD-L1. Formalin-fixed, paraffin-embedded tissue samples from 87 cases with HL were analyzed in this study. Immunohistochemical staining was performed to detect the PD-1 and PD-L1 expressions. Chromogenic in situ hybridization for EBER was performed using fluorescein-labeled oligonucleotide probes. PD-1 and PD-L1 expressions were found in 20 % of the cases. The EBER positivity was found in 40 cases (45 %). It has been found that co-expression of PD-1 and PD-L1 was associated with shorter survival although PD-1 or PD-L1 expressions were not found to be related with survival. Overall survival (OS) and disease-free survival (DFS) in cases without PD-1 and PD-L1 expressions were 135 and 107 months, respectively. OS and DFS in cases with co-expression for PD-1 and PD-L1 were 24 and 20 months, respectively, and these differences were found to be statistically significant for both OS and DFS (p = 0.002 and p = 0.003, respectively). Cox regression analysis showed that co-expression of PD-1 and PD L1 was found to be an independent risk factor for prognosis (OR 6.9, 95 % CI 1.9 24.3). Targeting PD-1 and/or PD-L1 is meaningful due to the 20 % expression of each in HL, and we did not find an important association between PD-1 and PD-L1 and EBER expression in HL. Very poor outcome in cases with co-expression of PD 1/PD-L1 suggests new avenues to detect the new prognostic markers and also therapeutic approaches in HL. PMID- 26004935 TI - Angina pectoris in patients without flow-limiting coronary artery disease (cardiac syndrome X). A forest of a variety of trees. AB - Coronary heart disease (CHD) represents an important problem worldwide. At present, more women than men are evaluated for CHD and it has been recognized that the prevalence of this pathology in women is at least the same as in men. We have learned that cardiac syndrome X (CSX) is frequent because worldwide each year millions of people (mostly women) with angina pectoris without flow-limiting epicardial pathology are identified. Data from large myocardial infarction registries suggest a 5% to 25% prevalence of cases without flow-limiting coronary pathology. It must, however, be considered that these people are said to have normal coronary arteries by visual analysis of biplane coronarography. On the other hand, as demonstrated from autopsy, and in vivo by ultrasound intravascular studies, it would be more appropriate to say that in the majority of these cases no obstructive or flow-limiting coronary pathology was detected by coronarography. In CSX, endothelial dysfunction and microvascular dysfunction, sometimes with coronary microvascular spasm and epicardial coronary artery spasm, have been recognized as pathophysiologic mechanisms. In CSX, symptoms and pathologic signs are the same in patients with flow-limiting coronary pathology. The difference lies in the fact that the mechanisms of myocardial ischemia are microvascular and flow-limiting epicardial coronary pathology is absent. By interplay, the pathologic entities at work in CSX are linked with poor long-term outcome. The prevalence of these outcomes is probably smaller than in patients with flow-limiting coronary pathology but we lack precise values. Nonetheless, severe cardiovascular complications are frequent in CSX and it is thus the pathology is not benign. Drugs used in coronary ischemic disease are empirically prescribed to treat CSX, but we lack data from specific trials. It seems that statins and ranolazine might exert positive effects. However, specific research to target interventions in CSX would be necessary. PMID- 26004936 TI - The Polish MacNew heart disease heath-related quality of life questionnaire: a validation study. AB - BACKGROUND: The MacNew health-related quality of life questionnaire was designed to assess feelings about how heart disease affects their daily physical, emotional and social functioning in patients with 1 of the 3 major coronary artery diagnoses, stable coronary artery disease (CAD) with angina, ST-elevation myocardial infarction (STEMI), and ischemic heart failure (HF). The aim of this study was to determine the reliability and validity of the Polish version of the MacNew in patients with CAD. METHODS: Patients with CAD completed a self-report sociodemographic and clinical ques-tionnaire: the MacNew, the Short-Form 36 Health Survey, and HADS at baseline; 10% of the patients completed each questionnaire 2 weeks later. RESULTS: We studied patients with stable CAD with angina (n = 115), with STEMI (n = 112), and with ischemic HF (n = 105). Internal consistency reliability was demonstrated with Cronbach's a from 0.86 to 0.95 for the MacNew global scale and subscales. The original 3-factor structure was confirmed for the Polish version of the MacNew explaining 53.5% of the variance. Convergent validity of similar MacNew and SF-36 subscales was confirmed in the total group and in each diagnosis. Discriminant validity with the SF-36 health transition was fully confirmed in the total group and in patients with HF and partially confirmed in patients with stable CAD with angina or myocardial infarction. CONCLUSIONS: The Polish MacNew health-related quality of life questionnaire can be recommended in patients with stable CAD with angina, myocardial infarction and HF. PMID- 26004938 TI - Impact of transcatheter aortic valve implantation on the left ventricular mass. AB - BACKGROUND: Aortic stenosis (AS) induces pressure overload of the left ventricle (LV) and results in left ventricular hypertrophy. The remodeling of the LV in patients with AS is a com-plex process including structural and functional disturbances. After aortic valve replacement, reverse remodeling of LV begins. The aim of this study was to evaluate the impact of transcatheter aortic valve implantation (TAVI) on LV mass (LVM) in early and mid-term follow-ups after the procedure. METHODS AND RESULTS: We enrolled consecutive 75 patients who underwent successful TAVI. Transthoracic echocardiography was performed prior to TAVI and at hospital discharge, in the 1st month and 6th month of the follow-ups. The mean LV ejection fraction improved significantly after TAVI (54.2 +/- 15.0% to 57.3 +/ 11.7%, p < 0.001). There were no significant changes between the baseline and discharge mean LVM and LVM index values (LVMI; p = 0.1). However, LVMI decreased significantly in the 1st month of follow-up compared to baseline (123.3 +/- 20.3 to 127.9 +/- 21.3 g/m2, respectively, p < 0.001). Also, significant regression of LVM was observed at the 1st month of follow-up compared to baseline (228.3 +/- 33.5 g vs. 236.5 +/- 34.2 g, respectively, p < 0.001). Furthermore, the significant regression in both of LVM and LVMI continued at 1st and 6th months of the follow-ups (p < 0.001). CONCLUSIONS: A significant regression of LVM was observed after TAVI. These changes may have prognostic value in patients with severe AS. PMID- 26004937 TI - Mortality in low- and very low-risk patients undergoing cardiac surgery: evaluation according to the EuroSCORE II as a new standard. AB - BACKGROUND: Only a few reports have analyzed low-risk patient outcomes and in every case, the risk was based on a logistic EuroSCORE <= 2. Since this original EuroSCORE overestimates surgical risk, we developed this study to prospectively evaluate the immediate results of cardiac surgery in patients with an expected mortality risk <= 2% according to the EuroSCORE II as a new gold standard. We also examined the cause of death and whether it could be considered preventable. METHODS: A prospective risk stratification of all cardiac surgical patients treated at the Bue-nos Aires University Hospital of Argentina was performed between 2012 and 2014 using the EuroSCORE II. Causes of death were classified as preventable or not preventable. RESULTS: From a total of 990 patients, 63.2% had EuroSCORE II <= 2 (low-risk group) and 32.5% EuroSCORE II < 1 (very low-risk group). In the low-risk group, in-hospital mortal-ity was 1.8%, whereas predicted mortality was 1.04% (AUC 0.765). The observed/expected ratio was 1.73 (95% CI 0.68-4.43) and the observed-expected difference was 0.76 (95% CI -0.68-2.10). Fifty-four percent of deaths were considered preventable. CONCLUSIONS: We propose to use and further validate the EuroSCORE II as a new standard for assessing low risk patients. This model proved to be useful in evaluating the quality standards of local cardiac surgery. The review of cause of death in low-risk patients provided valuable information, which revealed potentially correctable issues. Adoption of a more demanding standard, as the EuroSCORE II to identify low-risk patients, avoids the sense of safety offered by previous versions of the score. PMID- 26004939 TI - Short-term effects of transcatheter aortic valve implantation on left atrial appendage function. AB - BACKGROUND: The beneficial effects of the transcatheter aortic valve implantation (TAVI) on echocardiographic parameters including left atrial (LA) and left ventricular (LV) functions were described by previous studies. The aim of this study was to analyze the effects of TAVI on left atrial appendage (LAA) function assessed by transthoracic and transesophageal echocar-diography. METHODS: Fifty five patients with severe symptomatic aortic stenosis were included in this prospective study. LAA early and late emptying velocities, LAA filling velocity, peak early diastolic (EM), late diastolic (AM), and systolic (SM) velocities were measured with pulsed wave Doppler and tissue Doppler imaging, and E/Em ratio was calculated before and 7.1 +/- 2.8 days after TAVI. A subgroup analysis was performed in accordance with the left ventricular ejection fraction (LVEF) of the patients and the severity of their LV diastolic dysfunction. RESULTS: Although the post-procedure peaks and mean gradients of the patients decreased sig nificantly, the LVEF increased significantly in those who had low LVEF before the procedure. The post-procedure E/Em ratio decreased significantly (p < 0.001). The post-procedural LAA mean filling velocity and EM velocity were significantly higher than the pre-procedural filling velocity (p < 0.001, p = 0.002, respectively). In the subgroup analysis, the post-procedural LAA filling velocity, early and late LAA emptying velocities, in addition to the mean velocity of the EM, AM, and SM were significantly higher than before the procedure in patients with LVEF of < 50% and E/Em ratios of > 15. CONCLUSIONS: LAA function improved soon after the TAVI procedure, especially in patients with low LVEF and marked LV diastolic dysfunction. PMID- 26004940 TI - Significance of ST-segment deviation in patients with acute pulmonary embolism and negative T waves. AB - BACKGROUND: Common electrocardiogram (ECG) manifestations in acute pulmonary em bolism (APE) include ST-segment deviation (STDV) along with negative T-waves (NTW). STDV could occur in 3 typical ischemic patterns: (i) the left ventricular (LV) subendocardial ischemic pattern; (ii) the right ventricular (RV) transmural ischemic pattern; and (iii) the LV subendocardial plus RV transmural ischemic pattern. The purpose of this study was to evalu-ate the relationship of STDV and adverse clinical outcomes and to identify the relationship of relatively normal ECG and favorable clinical outcomes. METHODS: Retrospective analysis of electronic charts in APE patients was performed in a tertiary hospital. ECGs on admission were obtained and classified as with or without STDV. Adverse clinical outcomes were defined as need to intensify therapy and 30-day mortality. Relatively normal ECG was defined as without any STDV, abnormal QRS morphology in lead V1 and S1Q3T3. RESULTS: From a total of 210 patients with NTW, 131 had STDV >= 0.1 mV, while 79 did not. Patients with STDV had worse evolution: higher incidence of dyspnea, hypotension, cardiogen-ic shock, intensification of therapy, and death compared to patients without STDV (p = 0.001 for each variable). The majority (89%) of the patients with STDV presented with 1 of the 3 typical ischemic ECG patterns. LV subendocardial ischemic pattern (OR = 4.963, p = 0.004), RV transmural ischemic pattern (OR = 3.128, p = 0.021) and LV subendocardial plus RV transmural ischemic pattern (OR = 3.036, p = 0.017) independently predicted the need to intensify therapy. RV transmural ischemic pattern (OR = 4.227, p = 0.031) and LV subendocardial plus RV transmural ischemic pattern (OR = 4.022, p = 0.032) independently predicted 30-day mortality. Compared to the patients with abnormal ECG, the patients with relatively normal ECG had a significant lower incidence of death (0% vs. 16%; p = 0.001) and need to intensify therapy during hospitalization (6% vs. 30%; p = 0.002). CONCLUSIONS: Ischemic ECG patterns are common ECG manifestations of APE and predict worse evolution and 30-day mortality. Additionally, relatively normal ECGs may associate with favorable clinical outcomes. PMID- 26004941 TI - Safety and efficacy of pulmonary vein isolation using a circular, open-irrigated mapping and ablation catheter: A multicenter registry. AB - BACKGROUND: Pulmonary vein (PV) isolation is the cornerstone of catheter ablation in patients with atrial fibrillation (AF). "Single-shot" ablation devices have been recently engineered. OBJECTIVES: We report on the safety and efficacy of a novel ablation catheter for PV isolation in patients with AF. METHODS: One hundred eighty consecutive patients (58 +/- 10 years, 125 male, 31% with structural heart disease) referred for paroxysmal (140) or persistent (40) AF underwent PV isolation by an open-irrigated mapping and radiofrequency (RF) decapolar ablation catheter in 7 centers. Ablation was guided by electroanatomic mapping, allowing RF energy delivery in the antral region of PVs from 10 irrigated electrodes simultaneously. RESULTS: Mean overall procedure time was 113 +/- 53 minutes with a mean fluoroscopy time of 13.1 +/- 8.4 minutes. The use of a preablation PV imaging related to a significant reduction in fluoroscopy time (from 14.7 +/- 9.7 to 8.7 +/- 6.6, P < .001). Mean ablation time was 12.5 +/- 5.1 minutes, and 98% of the targeted veins were isolated with a mean of 23.4 +/- 6.3 RF pulses per patient. In only 4 patients (2.2%) a single-point ablation strategy was required to achieve PV isolation. One groin hematoma and 1 PV stenosis were reported. During a mean follow-up of 13.9 +/- 8.2 months 38 of 140 patients (27%) with paroxysmal AF and 12 of 40 patients (30%) with persistent AF had an atrial arrhythmia relapse (P = .671). CONCLUSIONS: In this multicenter registry, irrigated multielectrode RF ablation proved feasible, achieving a high rate of isolated PVs. Procedural and fluoroscopy times and success rates were comparable with other techniques, with a low complication rate. PMID- 26004942 TI - Myocardial scar predicts monomorphic ventricular tachycardia but not polymorphic ventricular tachycardia or ventricular fibrillation in nonischemic dilated cardiomyopathy. AB - BACKGROUND: The relation between myocardial scar and different types of ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy (NIDCM) is unknown. OBJECTIVES: The purpose of this study was to analyze the effect of myocardial scar, assessed by late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR), on the occurrence and type of ventricular arrhythmia in patients with NIDCM. METHODS: Consecutive patients with NIDCM who underwent LGE-CMR and implantable cardioverter-defibrillator (ICD) implantation at either of 2 centers were included. LGE was defined by signal intensity >=35% of maximal signal intensity, subdivided into core and border zones (>=50% and 35% 50% of maximal signal intensity, respectively), and categorized according to location (basal or nonbasal) and transmurality. ICD recordings and electrocardiograms were reviewed to determine the occurrence and type of ventricular arrhythmia during follow-up. RESULTS: Of 87 patients (age 56 +/- 13 y, 62% male, left ventricular ejection fraction 29% +/- 12%), 55 (63%) had LGE (median 6.3 g, interquartile range 0.0-13.8 g). During a median follow-up of 45 months, monomorphic ventricular tachycardia (VT) occurred in 18 patients (21%) and polymorphic VT/ventricular fibrillation (VF) in 10 (11%). LGE predicted monomorphic VT (log-rank, P < .001), but not polymorphic VT/VF (log-rank, P = .40). The optimal cutoff value for the extent of LGE to predict monomorphic VT was 7.2 g (area under curve 0.84). Features associated with monomorphic VT were core extent, basal location, and area with 51%-75% LGE transmurality. CONCLUSIONS: Myocardial scar assessed by LGE-CMR predicts monomorphic VT, but not polymorphic VT/VF, in NIDCM. The risk for monomorphic VT is particularly high when LGE shows a basal transmural distribution and a mass >=7.2 g. Importantly, patients without LGE on CMR remain at risk for potentially fatal polymorphic VT/VF. PMID- 26004943 TI - Developing a preventive immunization approach against insect bite hypersensitivity using recombinant allergens: A pilot study. AB - Insect bite hypersensitivity (IBH) is an allergic dermatitis of horses caused by bites of midges (Culicoides spp.). IgE-mediated reactions are often involved in the pathogenesis of this disease. IBH does not occur in Iceland due to the absence of Culicoides, but it occurs with a high frequency in Icelandic horses exported to mainland Europe, where Culicoides are present. We hypothesize that immunization with the Culicoides allergens before export could reduce the incidence of IBH in exported Icelandic horses. The aim of the present study was therefore to compare intradermal and intralymphatic vaccination using four purified recombinant allergens, in combination with a Th1 focusing adjuvant. Twelve horses were vaccinated three times with 10MUg of each of the four recombinant Culicoides nubeculosus allergens. Six horses were injected intralymphatically, three with and three without IC31((r)), and six were injected intradermally, in the presence or absence of IC31((r)). Antibody responses were measured by immunoblots and ELISA, potential sensitization in a sulfidoleukotriene release test and an intradermal test, cytokine and FoxP3 expression with real time PCR following in vitro stimulation of PBMC. Immunization with the r-allergens induced a significant increase in levels of r allergen-specific IgG1, IgG1/3, IgG4/7, IgG5 and IgG(T). Application of the r allergens in IC31((r)) adjuvant resulted in a significantly higher IgG1, IgG1/3, IgG4/7 allergen-specific response. Intralymphatic injection was slightly more efficient than intradermal injection, but the difference did not reach significance. Testing of the blocking activity of the sera from the horses immunized intralymphatically with IC31((r)) showed that the generated IgG antibodies were able to partly block binding of serum IgE from an IBH-affected horse to these r-allergens. Furthermore, IgG antibodies bound to protein bands on blots of C. nubeculosus salivary gland extract. No allergen-specific IgE was induced and there was no indication of induction of IgE-mediated reactions, as horses neither responded to Culicoides extract stimulation in a sulfidoleukotriene release test, nor developed a relevant immediate hypersensitivity reaction to the recombinant allergens in skin test. IL-4 expression was significantly higher in horses vaccinated intralymphatically without IC31((r)), as compared to horses intradermally vaccinated with IC31((r)). Both routes gave higher IL-10 expression with IC31((r)). Both intralymphatic and intradermal vaccination of horses with recombinant allergens in IC31((r)) adjuvant induced an immune response without adverse effects and without IgE production. The horses were not sensitized and produced IgG that could inhibit allergen-specific IgE binding. We therefore conclude that both the injection routes and the IC31((r)) adjuvant are strong candidates for further development of immunoprophylaxis and therapy in horses. PMID- 26004944 TI - Adjuvant-dependent immunogenicity of Staphylococcus aureus Efb and Map proteins in chickens. AB - The avian IgY antibodies generated in hens and isolated from egg yolk have gained in popularity as they present an alternative source of antibodies for diagnostic as well as therapeutic applications. One of the advantages of IgY technology are the large amounts of produced antibodies from a single animal combined with their high reactivity representing an attractive alternative for mammalian antibodies. Despite many known protocols for the immunization of chickens, the administration of new antigens often requires additional modification such as antigen dose or use of an adjuvant in order to elicit a significant immune response. We investigated the immunogenicity of three Staphylococcus aureus antigens including two extracellular proteins Map and Efb and one selected Efb105-124 epitope conjugated to KLH that were administered to the animals. Additionally, the immunization protocol included two adjuvant systems: Freund's complete adjuvant and Emulsigen-D. The results demonstrated a high immunostimulatory potency of Freund's complete adjuvant, especially in case of Efb compared to the immune response elicited by Emulsigen-D. However, after immunization with the KLH-Efb105 124 conjugate, the obtained antibodies showed similar reactivity regardless of adjuvant system used with the only exception being their avidity. PMID- 26004945 TI - The systemic multiplication of Gallibacterium anatis in experimentally infected chickens is promoted by immunosuppressive drugs which have a less specific effect on the depletion of leukocytes. AB - The progression of Gallibacterium anatis infection in immunosuppressed versus immunocompetent chickens was investigated. Before experimental infection, birds were treated with corticosterone for general immunosuppression, or 5 fluorouracil, cyclosporine-A, cyclophosphamide for depletion of specific leukocyte populations. Necropsy and sampling were performed at 0, 3, 7, 10 and 28 days post infection. The used drugs did not cause selected depletion of B cells, T cells, heterophils and monocytes/macrophages, as determined by quantification of leukocytes in blood and lymphoid organs using different technologies. Bacterial re-isolation and counts of colony forming units (CFU) showed that G. anatis colonization pattern in various organs, and the numbers of bacteria in trachea were not affected by immunosuppression. However, the treatments acutely increased CFU counts derived from the spleen, which demonstrates that chemically induced immunosuppression intensifies systemic multiplication of G. anatis in chickens. PMID- 26004946 TI - Gene analysis of signal-joint T cell receptor excision circles and their relationship to age in dogs. AB - The quantification of DNA excision circles produced during T cell receptor (TCR) rearrangement, termed signal joint TCR rearrangement excision circles (sjTRECs), has been employed as a measure of age and thymic function in humans and animals. deltaRec-psiJalpha sjTRECs are ring-shaped DNAs that are generated during TCRdelta locus deletion that occurs at a late stage of T cell development. In this study, the nucleotide sequences of deltaRec-psiJalpha signal joints of canine deltaRec-psiJalpha sjTRECs were analyzed. The gene structure of canine deltaRec-psiJalpha signal joints was found to be similar to that of humans and mice. However, diversity of signal joints was detected and found to derive from N nucleotide insertions, recombination signal sequence combinational diversity and single-base substitutions at the recombination signal sequence. In addition, an adenine insertion or deletion was found approximately 280 bases from the psiJalpha signal end. Blood samples were collected from 46 dogs, ranging in age from 3 to 192 months, with a mean age of 96.4 and a SD of 51.5 months. Although deltaRec-psiJalpha sjTRECs were detectable in most of the dogs evaluated, the level did not significantly correlate with age. These results indicated that deltaRec-psiJalpha sjTREC levels were ineffective as a measure of age in dogs. PMID- 26004947 TI - Predictors and consequences of hemodynamic instability after carotid artery stenting. AB - BACKGROUND: The purpose of this study was to determine the predictors and consequences of hemodynamic instability (HI) after carotid artery stenting (CAS). METHODS: The records of all patients undergoing CAS in a single institution were reviewed. Patient demographics and risk factors were recorded. Indications for CAS, medications including statins, atropine, and beta blockers, anatomic risk factors, balloon and stent length and diameter, and degree of stenosis were noted. The presence of periprocedural hypertension (systolic blood pressure [SBP] >160), hypotension (SBP <90), and bradycardia (heart rate <60) lasting longer than 1 hr was documented, as was more transient HI. Rates of transient ischemic attack (TIA), stroke, myocardial infarction (MI), and death within 30 days of the procedure were calculated. Chi-squared analysis was used to determine the role of periprocedural factors in predicting the risk of HI and to determine if patients experiencing HI were more likely to experience major adverse events (MAEs) than those who did not. RESULTS: Between 2005 and 2012, 199 CAS were performed in 191 patients. One hundred seventeen were men and 74 were women. Their ages ranged from 46 to 92 years (mean, 73.6 years). Eighty-seven percent had hypertension, 48.5% were smokers, 48% had coronary disease, and 38% were diabetic. CAS was performed for asymptomatic stenosis in 55% of patients, 24% had previous TIA, and 20% previous stroke. Sixty-three percent of patients were on statins, 41.4% on beta blockers, and 92% received atropine before balloon dilatation or stent placement. Overall, 130 (65.3%) patients experienced HI and 67 patients (33.7%) experienced HI lasting longer than 1 hr. Octogenarians were more likely to experience both transient and prolonged HI, whereas angina or contralateral occlusion was predictive of any HI, and female sex was predictive of prolonged HI. Transient HI was not predictive of MAE. Patients with HI persisting longer than 1 hr were more likely to experience a TIA than those who did not (P = 0.045), but they were no more likely to experience stroke, MI, or death (P > 0.35 for each). CONCLUSIONS: Periprocedural HI occurs frequently during CAS even with prophylactic atropine administration. Although patients experiencing HI were more likely to experience a TIA, its presence is not associated with an increase in stroke, MI, or death. PMID- 26004948 TI - Reversion-inducing-cysteine-rich protein with Kazal motif is involved in intimal hyperplasia in carotid arteries: a new insight in the prevention of restenosis after vascular angioplasty. AB - BACKGROUND: Overexpression of matrix metalloproteinase (MMP) has been implicated in the incidence of restenosis after vascular angioplasty. Reversion-inducing cysteine-rich protein with kazal motifs (RECK) is a membrane-anchored glycoprotein that negatively regulates the activity of MMPs, such as MMP-9 and MMP-2, which play a key role in the angiogenesis during tumor growth. This study was designed to investigate the potential association between RECK and restenosis after vascular angioplasty. METHODS: Balloon-injured rabbit carotid arterial models were established. Arterial morphology was assessed by hematoxylin-eosin staining. The area of intimal hyperplasia was measured using image microscopy and image analyzer. The messenger RNA (mRNA) expression levels of RECK, MMP-9, and MMP-2 were detected using reverse transcription-polymerase chain reaction (RT PCR) at 7, 14, and 21 days. Vascular smooth muscle cells (VSMCs) were transfected with RECK small interfering RNA (siRNA). VSMC proliferation rate was detected by MTT assay at 24, 48 and 72 hr. The protein expression of RECK, MMP-9, and MMP-2 was determined by Western blot. RESULTS: MMP-2 and MMP-9 in carotid artery of rats were significantly overexpressed in the injured-artery group, compared with unmanipulated control and contralateral uninjured groups (P < 0.05). With the time of the injury extended, MMP-2 and MMP-9 mRNA levels gradually increased. RECK showed a marked peak of mRNA level at 7 days after injury, compared with unmanipulated control and contralateral uninjured groups (P < 0.001). However, the increasing trend gradually decreased at 14 days after the balloon surgery. RECK mRNA was still detectable at 21 days postoperatively, but the expression level of RECK mRNA in injured and contralateral uninjured groups was significantly lower than that in unmanipulated control group (P < 0.001). The expression level of RECK protein in VSMCs in transfected group was significantly lower compared with that in untransfected group, whereas the expression of MMP-2 and MMP-9 proteins in transfected group was significantly higher compared with that in untransfected group. Over the extension of transfection time, the proliferation of VSMCs in transfected group was increased gradually, compared with negative and blank plasmid controls (P < 0.05). CONCLUSIONS: RECK, as siRNA mediated RECK silencing regulation of MMP-9 and MMP-2, plays an important role in intimal hyperplasia, which provides a new target for prevention and treatment of restenosis after vascular angioplasty. PMID- 26004949 TI - Influence of statin therapy on type 2 endoleak evolution. AB - BACKGROUND: Endovascular repair (EVAR) for abdominal aortic aneurysm (AAA) is widely adopted; however, the procedure may be jeopardized by type 2 endoleak (T2E). Most T2Es regress over time, but their evolution is unpredictable. There is some evidence about the pleiotropic statin effect on AAA and thrombus stabilization, but there are no data on the influence of statins on T2E. The study's aim is therefore to evaluate a possible effect of statins on T2E evolution. METHODS: A retrospective analysis of patients discharged from 2008 to 2013 with T2E after EVAR was performed. Patients were followed up with duplex ultrasound and computed tomography angiography and divided on statin and no statin users. The primary end point was to evaluate the T2E persistence at 6 months and during follow-up. The secondary end points were to compare the shrinkage (median and rate), the sac increasing rate, and reintervention at 6 months and during follow-up. RESULTS: In the period examined, 756 EVARs were performed and 85 (11%) had T2E at discharge. Thirty-two (37%) patients with T2E were on statins. The median follow-up was 19 (interquartile range [IQR] 7) months. Statin and no statin patients had similar clinical and anatomical characteristics, endoprosthesis type, and medical therapy. At 6 months, patients on statins had lower T2E persistence ([26] 81% vs. [49] 93%, P = 0.16), reaching the significance at 36 months (11 +/- 9% vs. 64 +/- 7%, P = 0.001). By Cox analysis, statins are independently associated with T2E regression (hazard ratio 0.40, 95% confidence interval 0.020-0.81, P = 0.01), other characteristics are: >2 lumbar arteries or inferior mesenteric artery patency or oral anticoagulant therapy did not reduce T2E. At 6 months, statin patients had higher shrinkage rate and diameter reduction compared with no statin patients (18% vs. 3%, P = 0.03 and 11 mm (IQR 4) vs. 6 mm (IQR 4), P = 0.05, respectively). Freedom from growth diameter and reintervention rate were not significantly different (85 +/- 9% vs. 81 +/- 14%, P = 0.10 and 75 +/- 17% vs. 37 +/- 16%, P = 0.13, respectively). CONCLUSION: Statin therapy seems to influence T2E regression and aortic sac stabilization after EVAR in the early medium follow-up; however, prospective studies need to confirm the present results. PMID- 26004950 TI - The age effect in increasing operative mortality following delay in elective abdominal aortic aneurysm repair. AB - BACKGROUND: Elective repair of large abdominal aortic aneurysms (AAAs) is associated with the risk of significant perioperative mortality. When abdominal aneurysm repair is delayed, patients with asymptomatic large AAAs face the risk of death from rupture. In addition to the risk of rupture, the advancing age of the patients adds a future operative risk. This risk has been historically documented in age groups. However, a more accurate representation of the increasing operative risk with age is needed. METHODS: We analyzed all patients in the American College of Surgeons National Surgical Quality Improvement Program database who underwent endovascular or open repair for asymptomatic infrarenal AAA between 2005 and 2012. Multivariable logistic regression was used to evaluate the effect of increasing age and operative delay on 30-day postoperative mortality. RESULTS: There were 27,576 patients who underwent AAA repair during the study period (mean age 73.5 years, standard deviation 8.6, 80% male, 24% open repair). There was a linear relative increase of 5% (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.04-1.06, P < 0.001) in the odds of operative death after AAA repair with each year of operative delay irrespective of treatment approach. There was a linear relative increase of 4% for endovascular aneurysm repair (OR 1.04, 95% CI 1.02-1.05, P < 0.001) and 6% for open repair (OR 1.06, 95% CI 1.04-1.08, P < 0.001) with each year of delay in repair. CONCLUSIONS: Because of increasing age, delay in surgery is associated with uniform increase in the risk of perioperative mortality in asymptomatic patients who meet criteria for AAA repair. It is important for surgeons to incorporate this more accurate estimation of operative risk into discussions with patients who qualify for treatment yet decide to forgo surgery for the repair of their AAA. PMID- 26004951 TI - Long-term clinical outcomes and cardiovascular events after carotid endarterectomy. AB - BACKGROUND: Long-term atherosclerotic adverse events are anticipated in patients undergoing carotid endarterectomy (CEA); however, their incidence and risk predictors remain unknown. METHODS: A consecutive cohort of CEAs between 1/1/2000 12/31/2007 was analyzed. End points were any stroke, coronary event (myocardial infarction, coronary bypass, or stenting), vascular interventions for critical limb ischemia, aortic aneurysm or carotid disease, and death. Survival analysis and Cox regression models were used to identify clinical predictors. RESULTS: A total of 1,136 CEAs (bilateral, 89; mean age, 71.2 +/- 9.2 years; 56.5% male; 36.3% symptomatic, and 3.9% combined with coronary bypass) were performed during the study period with a mean clinical follow-up of 60 months (0-155 months). The postoperative combined stroke and/or death rate was 2.7% and 1.9% for asymptomatic and 4.1% for symptomatic patients. Five and 10-year risks of the end points were 7.2% and 16.1% for stroke, 18.4% and 31.5% for coronary interventions, 20.6% and 28.5% for major vascular interventions, and 25.8% and 50.1% for death. Statins conferred a significant protective effect for stroke (hazard ratio [HR], 0.53; P = 0.016) and death (HR, 0.66; P < 0.0001). Baseline vascular disease predicted future vascular interventions: aortic aneurysm (HR, 1.90; P = 0.003), peripheral arterial disease (HR, 2.03; P < 0.0001), and contralateral internal carotid artery (ICA) stenosis >=50% (HR, 4.61; P < 0.0001). Renal insufficiency predicted worse outcomes for all other end points (HR, 2.21; P = 0.023 for stroke; HR, 1.62; P = 0.008 for coronary events; HR, 2.38; P < 0.0001 for death). CONCLUSIONS: Patients undergoing CEA continue to derive long-term low stroke rate benefit but still sustain major coronary events and require vascular interventions, indicating a need for more intensive medical treatment and rigorous follow-up. PMID- 26004952 TI - Does the technique of carotid endarterectomy determine postoperative hypertension? AB - BACKGROUND: Hypertension (HT) after carotid endarterectomy (CEA) is a risk factor for postoperative myocardial infarction, stroke, and neck hematoma. We compared the incidence of postoperative HT within the week after eversion CEA (e-CEA) and patch closure CEA (p-CEA). Postoperative HT was defined as a systolic blood pressure (sBP) >= 160 mm Hg and/or the need for postoperative vasodilatators. The aim of our study was to determine if the technique of CEA had an effect on postoperative HT. METHODS: Between January 2010 and June 2011, we prospectively reviewed 560 consecutive endarterectomies (340 p-CEAs and 220 e-CEAs) performed in 443 patients under general anesthesia. All had >70% stenoses, 119 were symptomatic, and 441 asymptomatic. We compared preoperative, peroperative, and postoperative sBP and diastolic blood pressure, carotid sinus nerve block, postoperative intravenous and oral antihypertensive medications, neurologic and cardiac complications, and mortality. RESULTS: The e-CEA group had a higher incidence of women (36.4% vs. 21.8%, P = 0.0002) and HT (85.0% vs. 78.2%, P = 0.04). The e-CEAs had a significantly higher incidence of carotid sinus nerve block (93.6% vs. 15.6%, P < 0.0001). The incidence of postoperative HT was not significantly different between the 2 groups (75.9% in the e-CEA group versus 68.5% in the p-CEA group, P = 0.06). The average postoperative sBP between postoperative hour (H) 2 and H12 was significantly higher in the e-CEA group but <160 mm Hg. The sBP dropped between H2 and H6, and this decrease was greater in the p-CEA group (30% vs. 15% in the e-CEA group). The need for postoperative antihypertensive medication was not different between the 2 groups. One independent risk factor of postoperative HT was identified: history of HT. The rate of postoperative complications was not significantly different between the 2 groups. CONCLUSIONS: The e-CEA technique is not a risk factor and does not have an effect on postoperative HT. The postoperative sBP was more stable in this group. Eversion carotid endarterectomy has been considered, in the literature, as a risk factor of postoperative hypertension. We conducted a large prospective and comparative study of the endarterectomy technique by eversion and with conventional patch closure. The primary end point was the blood pressure value and the administration of antihypertensive treatment. Our study shows that postoperative hypertension after carotid endarterectomy is not related to the surgical technique. Changes in blood pressure after carotid endarterectomy by eversion are lower than those observed after conventional endarterectomy with patch closure. This technique prevents the occurrence of possible hypotension occurrence, which can be the cause of perioperative complications. PMID- 26004953 TI - Surgical repair of descending thoracic and thoracoabdominal aortic aneurysms in patients with human immunodeficiency virus infection: a 10-patient series. AB - BACKGROUND: Major surgery in patients with human immunodeficiency virus (HIV) infection increases the risk of complications such as cardiovascular morbidity and opportunistic infections. METHODS: This study reports our experience with open surgical repair of 10 descending thoracic and thoracoabdominal aortic aneurysms in patients with HIV. RESULTS: Seven were men, and their median age was 49 years. All patients were controlled with highly active antiretroviral therapy (mean CD4+: 613/mm(3)). Three patients died (1 preoperatively, 1 after rupture, and 1 after elective surgery). No patient had spinal cord ischemia or infectious complications, either early or after a median follow-up of 29 months. Bacteriologic and histologic analyses did not determine any specific etiology for the aneurysms. CONCLUSIONS: Surgical repair of descending thoracic and thoracoabdominal aortic aneurysms in patients with HIV infection is feasible and may not lead to remote infectious complications. PMID- 26004954 TI - A diagnostic evolution: surgical experience with popliteal artery entrapment syndrome at a military tertiary referral center. AB - BACKGROUND: Popliteal artery entrapment syndrome (PAES) is an increasingly encountered disorder that typically presents as claudication in young and active individuals. However, despite the increased recognition, accurate preoperative diagnosis can be difficult. The objective of this study was to describe the surgical assessment and outcomes of patients treated for PAES. METHODS: Retrospective case series of all patients managed surgically for a diagnosis of PAES at the San Antonio Military Medical Center from 2005 to 2013. RESULTS: Over 8 years, PAES was surgically treated in 25 consecutive limbs of 15 patients (mean age, 35; range, 21-49) in a military tertiary medical center. Type III was the most common variant (n = 13, 52%), followed by type VI (n = 7, 28%). Most patients presented with class I or II ischemia (88%), with anterolateral symptoms (56%), and were referred by orthopedics (66%). Diagnostic work-up included stress ankle-brachial indices, magnetic resonance imaging (MRI) and provocative angiography. Sixty-three percent of limbs with negative MRI demonstrated findings consistent with either type III or V PAES. Tendon release was used in those with types III and V, whereas liberal myectomy was used in those with types I, II, or VI. Two patients required revascularization. At a median follow-up of 126 days (range, 25 days-7 years), 83% of patients with type III demonstrated partial resolution of symptoms. Only 27% of patients without an identifiable muscle slip had clinical improvement. CONCLUSIONS: Despite modern imaging, open surgical exploration remains the definitive diagnostic modality for PAES. Patients with a muscular or tendinous slip identified intraoperatively have the best clinical outcomes. Those with no identifiable muscle slip (functional entrapment) are less likely to demonstrate clinical improvement. Further evaluation on outcomes in the management in PAES is warranted. PMID- 26004955 TI - Vascular access thrombosis in France: incidence and treatment patterns. AB - BACKGROUND: Vascular access thrombosis lacks the implementation of a treatment algorithm at large scale, involving all the actors. We aimed to determine a better understanding of the current practice patterns around vascular access thrombosis in France, with 4 axes: incidence, surveillance protocol, treatment, and time to treatment. METHODS: A comprehensive survey of all the nephrologists staffing all hemodialysis centers in France during April 2013 included 266 of 269 (99%) centers, treating 27,798 patients with arteriovenous fistula or graft. RESULTS: In 104 centers treating 11,088 patients, there were 905 documented episodes of vascular access thrombosis (8.8%) in 1 year; in the other 162 centers that supplied a range of events, the mean incidence was 8.4%. Use of in-line access flow monitoring as part of surveillance program was not correlated with better outcome compared with Doppler ultrasound (thrombosis: 7.9% vs. 10%, respectively, P = 0.09). Fifty-three percent of centers referred the patients to a vascular surgeon and 32% to an interventional radiologist (2% to urologist and 13% variable referral depending on the case complexity). Time to treatment was <24 hr in 58% and <48 hr in 91% of the centers; treatment >48 hr (9%) occurred mainly in rural zones (P = 0.04). The specialty of the treating physician did not influence time to treatment (P > 0.05). CONCLUSIONS: In France, vascular access thrombosis rate is low and not influenced by surveillance protocol type. Most patients can receive timely treatment by vascular surgeons or interventional radiologists. PMID- 26004956 TI - Agreements and discrepancies between the estimated walking distance, nongraded and graded treadmill testing, and outside walking in patients with intermittent claudication. AB - BACKGROUND: Disease severity in patients with intermittent claudication (IC) is often assessed using walking distances and treadmill tests. The aim of this study was to determine the agreement between walking distance as estimated by the patient, as measured during outside walking, and as determined using a nongraded treadmill protocol (NGTP), and an incremental graded (Gardner-Skinner) treadmill protocol (GSP). METHODS: In this prospective observational study, 30 patients with IC estimated their maximal walking distance (MWD) and completed a "Walking Impairment Questionnaire" (WIQ). Outside walking was determined using a measuring wheel and a GSP controlled device. Primary outcomes were differences in MWD and variability (coefficient of variation, COV). Secondary outcomes were results of WIQ and differences in walking speed. RESULTS: Estimated walking distance was significantly higher than MWD as objectively measured during outside walking (400 m vs. 309 m, respectively, P = 0.02). A substantial variability (COV = 55%) was found between both parameters. A small 35-m MWD difference between outside walking and GSP was found with a substantial scatter (COV = 42%). In contrast, a much larger 122-m MWD difference was present between outside walking and NGTP (COV = 89%). Patients walked significantly faster in the open air than on treadmills (median outside walking speed = 3.8 km/hr, GSP = 3.2 km/hr, NGTP = 2.8 km/hr; P < 0.001). CONCLUSIONS: An incremental graded (Gardner-Skinner) treadmill protocol demonstrated the best agreement to outside walking. Discrepancies between treadmill tests and outside walking may be explained by a difference in walking speed. A single determination of a walking distance is a poor reflection of true walking capacity. PMID- 26004957 TI - Increased prevalence of preeclampsia among women undergoing procedural intervention for renal artery fibromuscular dysplasia. AB - BACKGROUND: Renal artery fibromuscular dysplasia (RA-FMD) has a higher prevalence among women and a presumed hormonal etiology. Although preeclampsia has a clinical presentation similar to symptomatic RA-FMD and occurs exclusively in women, associations between these 2 diseases have not been characterized. To explore epidemiologic associations between RA-FMD and preeclampsia, we administered a validated screening instrument for preeclampsia to a cohort of women with a history of pregnancy who had previously been treated with procedural intervention for symptomatic RA stenosis. METHODS: Women with a history of pregnancy who had previously undergone procedural intervention (including angioplasty and/or bypass) for symptomatic RA stenosis were identified from a prospectively maintained operative registry and screened for remote history of preeclampsia using a validated survey instrument. Univariable associations between RA-FMD and preeclampsia among participants with a history of pregnancy were evaluated using t-tests for continuous factors and chi-squared tests for dichotomous factors. Multivariable associations were evaluated using logistic regression models. RESULTS: A total of 144 women were identified who met the study inclusion criteria, including 94 with atherosclerotic RA stenosis and 50 with RA-FMD. Sixty-nine patients were contacted, 59 consented to participate, and 52 had a history of pregnancy (and therefore were at risk for preeclampsia). Participants completed the survey instrument at a mean of 7.1 +/- 3.1 vs. 6.9 +/- 3.6 years after RA procedural intervention, respectively. Survey responses indicated a history of preeclampsia in 19/52 (36.5%) of participants overall, including 14/27 (51.9%) with RA-FMD versus 5/20 (20.0%) with RA atherosclerosis (P = 0.02). Preeclampsia remained associated with FMD in a multivariable model adjusting for smoking status, age at time of surgery, and estimated glomerular filtration rate (odds ratio [OR] 9.51, 95% confidence interval [CI] 1.49-60.6, P = 0.017); age at the time of surgery (OR 2.78, 95% CI 1.04-7.42, P = 0.041) and estimated glomerular filtration rate (OR 3.31, 95% CI 1.29-8.52, P = 0.013) were also associated with FMD in the multivariable model. CONCLUSIONS: Women with a history of procedural intervention for symptomatic RA stenosis have an overall prevalence of preeclampsia which greatly exceeds that expected in the general population, and our results suggest that preeclampsia is specifically associated with RA-FMD. Further investigation is needed to characterize the mechanistic relationships between FMD and preeclampsia and may have potential to decrease related cardiovascular morbidity and mortality. PMID- 26004958 TI - Application of unibody single-branch endografts in Stanford type B dissections with primary entry tear adjacent to the left subclavian artery: a computed tomography-based planning study. AB - BACKGROUND: A custom-made unibody single-branch endograft (USBE) could provide great gains in the landing zone, while maintaining a left subclavian artery (LSA) perfusion in some patients with Stanford type B dissections (TBADs). We performed a computed tomography (CT)-based planning study to determine the proportion of TBAD patients who could benefit from this custom-made USBE and ascertained the possibility of an off-the-shelf USBE in an emergency setting. METHODS: We carried out a retrospective study of TBAD patients with optimal CT scans at our center from 2007 to 2013. Patients' CT scans were analyzed using 3-dimensional reconstruction software. After generating a centerline of flow, measurements (including numerous morphologic characteristics of anatomy) were evaluated. A selected subset of patients suitable for USBE was determined. Finally, the most frequently used configurations of endografts were figured out by subgroup analysis. RESULTS: A total of 314 patients with optimal digital imaging communications in medicine (DICOM) data were included in our study. The main primary entry tears (MPETs) were located at 22.8 +/- 17.3 and 36.3 +/- 18.6 mm distal to the LSA and the left common carotid artery, respectively. Overall, 169 (54.2%) patients with MPET distal to LSA (>20 mm) could be treated by tubular stent grafts. Of the 143 patients who had intimal tears adjacent to the LSA (<=20 mm), there were 111 (35.4%) patients who could benefit from treatment using USBE based on our selection criteria. Subgroup analysis estimated the number of graft configurations needed to treat a proportion of patients: 1 design would treat 6.7% of the population, 5 designs would treat 23.1%, 10 designs would treat 37.6%, and 20 configurations would treat 54.8% . CONCLUSIONS: In all, 35.4% patients with TBAD could potentially benefit from USBE. The use of off-the-shelf endografts might be possible in cases of emergency, given the evidence of recurrent configurations. PMID- 26004959 TI - Relation between tensile tests and compliance in polyester textile vascular prostheses. AB - BACKGROUND: Compliance is one of the mechanical features of a vascular prosthesis (VP) that influences its performances. The goal of the present in vitro study was to attempt characterizing textile VP compliance through mechanical tests proposed in the standards. METHODS: Three different models of commercially available knitted VP (P1, P2, and P3) were studied using longitudinal and circumferential traction tests on coated and uncoated samples. Five samples of each model were considered for each test. The Young modulus was then calculated to indirectly predict the longitudinal and radial compliance of the VP. Moreover, actual compliance was measured on a specific device that regulates the intraluminal pressure of a fluid maintained in the tested VP at 37 degrees C. VP dilatation under pressure load was measured with a digital camera system. RESULTS: The Young modulus variations from one VP to the other were compared with the differences between effective compliance values at radial, longitudinal, and volume level. Although the presented results show differences among the VP, one can observe that the graft materials' Young modulus and the compliance properties are linked together in general. CONCLUSIONS: Although VPs are subjected to multidirectional stresses ex vivo, unidirectional standard mechanical tests, through the measurement of the materials Young modulus, can help predicting their compliance, however, in a limited frame. PMID- 26004960 TI - The impact of body mass index on lower extremity duplex ultrasonography for deep vein thrombosis diagnosis. AB - BACKGROUND: This study aimed to determine the body mass index (BMI) at which duplex ultrasonography does not accurately detect deep vein thrombosis. METHODS: This is a retrospective review of all patients who underwent lower extremity venous duplex examination at a single institution, tertiary vascular laboratory from January 2011 to June 2011. Demographics, BMI, operator years of experience, and duplex ultrasound study quality were recorded. Duplex ultrasound study quality was divided into "adequate" or "inadequate." RESULTS: A total of 495 patients were included in this study, of which 435 (88%) patients were adequate and 60 (12%) inadequate. One hundred ninety-eight (40%) patients of the overall study cohort were men and 297 (60%) women. Limited studies were performed in 21 (11%) men and 39 (13%) women (P = 0.48). There was an inverse relationship between the years of operator experience and the percent of studies classified as limited (P < 0.01). The mean BMI of patients in the adequate group versus the inadequate group was 30.3 +/- 8.9 (median 28.9) versus 39.8 +/- 15.1 (median 38.4), respectively (P < 0.0001). Univariate analysis identified tech A (least experience) (3*) and increased BMI > 40 (6*) as independent variables associated with having a limited duplex ultrasound study. CONCLUSION: These results suggest that patients with BMI > 40 may require an alternative imaging modality to objectively diagnose the presence of venous thromboembolism as an increased BMI is associated with an indeterminate study. PMID- 26004961 TI - Fast-track in abdominal aortic surgery: experience in over 1,000 patients. AB - BACKGROUND: Fast-track recovery programs have led to reduced patient morbidity and mortality after surgery. Minimally invasive surgery and anesthesia, with programs of early postoperative recovery are the main aspects of fast-track recovery programs. The optimization of pain control, early mobilization, and oral feeding allows for a rapid functional rehabilitation, which leads to minor morbidity and early discharge from the hospital to home. METHODS: We enrolled all nonemergent patients treated for elective abdominal aortic surgery for an aneurysm or obstructive disease from April 2000 to June 2014. The fast-track protocol was applied to all these patients. A transperitoneal aortic approach was used through a left subcostal incision and was complemented with epidural anesthesia-analgesia and a protocol of early rehabilitation. RESULTS: A total of 1,014 patients were treated for elective aortic surgery. For 980 patients (96.6%), clear liquids followed by a semisolid diet were tolerated starting on the afternoon of the day of intervention (day 0). Nine hundred eighty-seven patients (97.3%) began early ambulation on day 0, and for 81.2% of the population, regular colonic function returned within the second postoperative day. Seventeen deaths (1.7%) occurred. Nine hundred ten patients (89.7%) had no complications. The median hospital length of stay was 3 days for the entire series, and 80.4% of patients (n = 815) were discharged to their homes between the second and fifth days after surgery. CONCLUSIONS: The fast-track program can be efficiently and safely applied to aortic surgery and that this program improves surgical outcomes, allows for earlier discharge, and reduces costs. PMID- 26004962 TI - Endovascular chimney technique for juxtarenal abdominal aortic aneurysm: a systematic review using pooled analysis and meta-analysis. AB - BACKGROUND: To evaluate the safety and efficacy of chimney endovascular abdominal aortic repair (Ch-EVAR) for juxtarenal abdominal aortic aneurysm. METHODS: Electronic literature published between 2003 and 2014 were searched from MEDLINE and EMBASE online databases. Inclusion criteria for articles included that more than 3 patients were enrolled, chimney graft techniques were used, and the basic outcomes, such as indications, mortality within 30-day or during follow-up, complications, endoleaks, and branch vessel patency were collected. The data were pooled for analysis. Meta-analysis was performed using Stata version 11 and heterogeneity was estimated using Cochrane Q statistic and I(2) statistic. RESULTS: In total, 12 electronic literature met the inclusion criteria and 236 patients (mean age, 73.9 years) undergone Ch-EVAR were collected. A total of 335 chimney grafts were implanted, including 288 to the renal arteries and 47 to superior mesenteric arteries. Mortality (<30 days) and mortality (during follow up; a mean of 12 months) were 3.8% (9/236) and 10.6% (25/236), respectively. The rate of type I, II and III endoleaks during follow-up was 11.8% (28/236), 8.1% (19/236), and 0.4% (1/236), respectively. The chimney graft patency at 6 month was 96.6%. Meta-analysis showed that the rates of endoleaks (during follow-up), mortality (<30 days) and mortality (during follow-up) were 18%, 7% and 13%, respectively. CONCLUSIONS: Chimney graft is an efficient therapy with high initial technical success rate and favorable rates for perioperative outcomes. PMID- 26004963 TI - Clinical efficacy of infrapopliteal endovascular procedures for hemodialysis patients with critical limb ischemia. AB - PURPOSE: To investigate 5-year clinical outcomes after infrapopliteal endovascular therapy (EVT) for critical limb ischemia (CLI) patients on or not on hemodialysis (HD), and compare the clinical efficacy of EVT between the 2 groups. METHODS: The subjects were 1091 CLI patients (1310 limbs) who underwent EVT for isolated infrapopliteal lesions from 2004 to 2012, and were classified into 2 groups for comparative study: the patients on HD group (670 patients, 830 limbs) and not on HD group (421 patients, 480 limbs). RESULTS: The HD group had a significantly lower rate of freedom from major adverse limb events or perioperative death (HD 78.4% vs. non-HD 86.0% at 1 year, HD 70.3% vs. non-HD 82.4% at 5 years, P = 0.01), or amputation-free survival (AFS) rate (HD 65.7% vs. non-HD 78.7% at 1 year, HD 34.4% vs. non-HD 59.8% at 5 years, P < 0.01) after EVT compared with the non-HD group. Independent predictors of AFS in HD patients were nonambulatory, diabetes mellitus, albumin <3.0 g/dL, ejection fraction <=0.48, and no patent pedal arch arteries before EVT. AFS at 1 year was 81% in patients with 0 or 1 predictor, surpassing the suggested AFS objective performance goal (OPG) end points of 68%, but AFS in patients with 2 or more predictors failed to reach the OPG. CONCLUSIONS: In comparison with non-HD patients, the clinical efficacy of infrapopliteal EVT for HD patients was poor. Preoperative risk stratification based on AFS predictors can be used as an index for predicting the prognosis. PMID- 26004964 TI - A pulseless limb poorly predicts an arterial injury in combat trauma. AB - BACKGROUND: A pulseless limb is considered a hard sign of an arterial injury after penetrating trauma in the civilian population. However, the reliability of this finding has never been examined in combat trauma. The purpose of this study was to examine the reliability of the pulseless limb in the combat trauma population. Reasons for false positive physical examination findings were also identified. METHODS: The Joint Theater Trauma Registry identified all patients who presented to a military treatment facility (MTF) in Kandahar, Afghanistan, with a penetrating extremity injury over a 2-year period. Patients found to have a pulse deficit on initial physical examination were followed, and the results of the subsequent computed tomographic angiogram or arteriogram recorded. Patient demographics, injury patterns, and physiological data were examined. Standard statistical analysis was performed. RESULTS: From 2011 to 2012, 644 patients were treated at a single MTF for lower extremity penetrating injuries. The most common mechanisms of injury were explosions (62%) and gunshot wounds (20%). Of the 577 patients with complete medical records, 448 patients (78%) presented with palpable pulses, 115 patients (20%) presented with a pulseless limb, and 14 (2%) presented with hard signs of vascular injury. Of those with a pulseless limb and abnormal ankle-brachial index (ABI) or no ABI obtained who underwent further radiologic imaging, 38 patients (77%) had no arterial injury identified. Compared with those with a palpable pulse, patients with a pulseless limb without an arterial injury were more likely to have a higher Injury Severity Score (ISS), lower hematocrit, lower pH, greater base deficit, higher heart rate, more frequent use of tranexamic acid, and received greater volumes of packed red blood cells, plasma, and crystalloids. CONCLUSIONS: Our results demonstrate that a pulseless limb is a poor predictor of arterial injury and should not be considered a hard sign of vascular injury in the combat population. Variables including a high ISS, anemia, acidosis, and need for resuscitation products, each a surrogate for injury severity, may contribute to the decreased accuracy of the physical examination in our troops. This may translate into unnecessary immediate exploration or other interventions in patients who present with more significant injuries from the battlefield. Future studies must continue to focus on improved algorithms for diagnostic accuracy of extremity vascular injuries in this population. PMID- 26004965 TI - Female and obese patients might have higher risk from surgical repair of asymptomatic carotid artery stenosis. AB - BACKGROUND: To investigate the results after carotid endarterectomy performed for asymptomatic carotid stenosis (ACS) in a single high-volume center and define the factors that increase perioperative stroke and mortality rate. METHODS: This observational study that analyzes prospectively collected data includes 1,567 patients with ACS operated in the period between 2007 and 2012. RESULTS: Most patients were male, 1,037 (66.18%), with mean age of 63.6 years. Perioperative death rate was 0.38%. The most frequent causes of death were stroke and myocardial infarction. The total perioperative stroke/transient ischemic attack rate was 2.81%. Logistic regression analysis confirmed that females (P = 0.028) and obese (P = 0.060) patients have higher risk of perioperative stroke after surgical repair of ACS with odds ratio (OR) of 2.008 and 2.342. The early mortality was significantly higher in candidates for coroanary artery bypass grafting (P = 0.018). Stroke and mortality are related to obesity and ischemic heart disease with OR of 2.407 and 2.097, respectively. CONCLUSIONS: According to our results, female and obese patients are prone to stroke after carotid endarterectomy. Further study of the effects of female gender and obesity on surgical outcomes is warranted before medical therapy is considered the preferred treatment for these patients. PMID- 26004966 TI - Less painful tumescent solution for patients undergoing endovenous laser ablation of the saphenous vein. AB - BACKGROUND: This study aims to investigate the efficacy of lidocaine, prilocaine, and bupivacaine used in tumescent solution during endovenous laser treatment (EVLT) on intraoperative and postoperative pain. METHODS: This prospective randomized study included 90 patients. The patients were divided into 3 groups including 30 patients in each group, according to the content of local anesthetics in tumescent solution. All patients received EVLT treatment with lidocaine in group 1, prilocaine in group 2, and bupivacaine in group 3. Visual analog scale was used for the evaluation of intraoperative and postoperative pain. RESULTS: The mean intraoperative pain score was 2.27 +/- 1.53 in group 1, 1.97 +/- 1.54 in group 2, and 3.05 +/- 0.73 in group 3. On the first day postoperatively, the mean pain score was 2.57 +/- 1.7 in group 1, 3.27 +/- 1.23 in group 2, and 1.13 +/- 0.94 in group 3 (P = 0.0001). Intraoperative and postoperative mean pain scores during first day follow-up were significantly lower in group 3. CONCLUSIONS: Tumescent anesthesia is the most critical component of EVLT to improve comfort by reducing the pain. Therefore, we conclude that bupivacaine is an optimal alternative to lidocaine and prilocaine in tumescent anesthesia and can be used safely. PMID- 26004967 TI - Permacol interposition graft as an alternative to vein in contaminated wounds using a rabbit model. AB - BACKGROUND: Vascular injuries are common in trauma and often involve massive soft tissue injury and segmental arterial loss. Current practice uses either autogenous vein or polytetrafluorethylene (PTFE) for interposition grafting in arterial injuries. Decision making between autogenous or synthetic conduit pivots around the physiological state of the trauma patient. Vein is known to increase operative times in an already physiologically depleted patient, whereas synthetic graft can be simply pulled from the shelf. However, when used in contaminated wounds, PTFE is prone to chronic infection and subsequent graft failure. An alternative synthetic conduit resistant to infection would be ideal for such situations. Permacol (Tissue Science Laboratories, Inc, Andover, MA), a biosynthetic material, has demonstrated resistance to bacterial contamination in contaminated hernia repairs. When fashioned into a tubular structure, this material may be useful as an alternative vascular conduit in contaminated trauma wounds. METHODS: New Zealand white rabbits were randomized to one of 4 groups: Permacol graft (P) without bacterial contamination (n = 9), Permacol graft with bacterial contamination (CP; n = 9), autogenous vein graft without bacterial contamination (V; n = 9), or autogenous vein with bacterial contamination (CV; n = 9). All groups then underwent interposition grafting of the right common carotid artery. Grafts were contaminated by applying Staphylococcus aureus (1 * 10(5) colonies/0.1 mL) directly to the exposed surface of the graft on completion of the arterial repair. Each graft was then excised at day 42, and segments were collected for histologic evaluation, bacterial counts, and real-time polymerase chain reaction. RESULTS: Of the 36 rabbits used in this study, 3 animals in the CV group died within 72 hr of surgery. There was no difference in early mortality between P and V (0% vs. 0%; P = 1.0); however, early mortality was higher in the CV compared with the CP group (33% vs. 0%; P = 0.023). At 42 days, histologic evaluation of graft patency demonstrated no difference between P and V (67% vs. 33%; P = 0.157); however, patency was higher in CP than CV (56% vs. 12%; P = 0.040). In addition, no difference was found between the 2 contaminated groups in regard to the number of bacteria present on each graft material. CONCLUSIONS: Permacol as an interposition graft is a feasible alternative to vein in a contaminated setting and shows resistance to infection in a rabbit model. Future studies are needed to evaluate this material in larger animal models. PMID- 26004968 TI - A prospective randomized study comparing polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer. AB - BACKGROUND: To compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and active ulcer treated at a single vascular center. METHODS: Fifty-eight limbs of 56 patients with active ulcers were prospectively randomized to undergo either surgical treatment or foam sclerotherapy. Patients completed the Aberdeen Varicose Veins Questionnaire (AVVQ), the Venous Clinical Severity Score (VCSS), and Venous Disability Score (VDS). The follow-up was 502 +/- 220 days. RESULTS: The ulcer healed in 100% and 91.3% of patients treated with surgery or foam sclerotherapy, respectively (P > 0.05). There were no significant differences in AVVQ, VCSS, and VDS between the 2 groups after the procedures (P = 0.45, 0.58, and 0.66, respectively; Mann-Whitney U test). Complications occurred in 14.2% and 13.0% in the surgical and foam sclerotherapy groups, respectively. CONCLUSIONS: Surgical treatment and foam sclerotherapy achieved high rates of ulcer healing, without a statistically significant difference. Both treatments led to significant improvements in VCSS, VDS, AVVQ scores, demonstrating improvements in clinical outcomes and quality of life. PMID- 26004969 TI - Detecting disease genes of non-small lung cancer based on consistently differential interactions. AB - Systematic identification of causal disease genes can shed light on the mechanisms underlying complex diseases and provide crucial information to develop efficient biomarkers or design suitable therapies. The present paper describes a novel approach to detect potential disease genes for lung cancer, based on consistently differential interaction (CDI) scheme from heterogeneous disease datasets. In particular, reliable disordered regulations in disease states were discovered by identifying the CDIs, from which the disease genes were further detected based on their topological structures on the network. As an application of the CDI-based method, the RNA-seq data of two subtypes of non-small lung cancer were used to identify CDIs from normal to cancer onset. The results of analysis well agree with the prior knowledge as well as the experiments, thereby implying the predictive power of the CDI-based method. The comparison with other approaches also indicated the superiority of the CDI-based method in terms of accuracy and effectiveness on detecting disease-specific genes for lung cancer and metastasis. In contrast to conventional molecular biomarkers, the identified CDIs as novel network biomarkers or edge biomarkers can be applied to predict patient survival for both subtypes of lung cancers, and the interactions among CDIs can be further used as new edgetic targets for network drug design. In addition, a potential molecular mechanism was developed to explain the key roles of the identified CDIs in lung cancer and metastasis from a network perspective. PMID- 26004970 TI - The Joys of English: Lexemes, P12, Innumeracy, and Other Profundities or Absurdities. PMID- 26004971 TI - Beyond medical care. PMID- 26004972 TI - Accommodations Use Patterns in High School and Postsecondary Settings for Students Who Are d/Deaf or Hard of Hearing. AB - Using data from the second National Longitudinal Transition Study (Newman et al., 2011), the authors investigated longitudinal patterns of educational accommodations use in secondary and, later, postsecondary settings by students who are d/Deaf or hard of hearing (SDHH). The study focused on language and communication (LC) accommodations used primarily by SDHH, plus non-LC accommodations typically used by a broad range of students. Both LC accommodations for standardized testing and instruction showed decreased use in postsecondary settings compared with high school. After student demographic characteristics were controlled for, no relationships were found between types of accommodations students used in high school and those they later used in postsecondary settings. Student accommodations use in postsecondary settings was not significantly predictive of retention or degree completion. However, several student- and parent-level demographic characteristics were predictive of accommodations use in postsecondary settings. Implications and future research directions are discussed. PMID- 26004973 TI - Attitudes toward the capabilities of deaf and hard of hearing adults: insights from the parents of deaf and hard of hearing children. AB - Children who are d/Deaf and hard of hearing (DHH) grow up in environments influenced by their parents' attitudes, which may facilitate or impede these children's development and participation (World Health Organization, 2007). The attitudes of 152 Australian parents of DHH children ages 3 years 7 months to 9 years 5 months (M = 6 years 5 months) were investigated with the Opinions About Deaf People Scale (Berkay, Gardner, & Smith, 1995a). The parents' responses showed very positive attitudes toward the capabilities of DHH adults, particularly on items describing their intellectual and vocational capabilities. Parents' responses to most of the items on the scale were positively skewed, raising questions about its validity as a research tool when used with parents of DHH children. The study findings suggest that for these children, parents' attitudes may facilitate rather than present an environmental barrier to their development. PMID- 26004974 TI - American sign language and deaf culture competency of osteopathic medical students. AB - The study examined the effectiveness of a workshop on Deaf culture and basic medical American Sign Language for increasing osteopathic student physicians' confidence and knowledge when interacting with ASL-using patients. Students completed a pretest in which they provided basic demographic information, rated their confidence levels, took a video quiz on basic medical signs, and experienced a practical standardized encounter with a Deaf patient. They then attended a 4-hour workshop and, 2 weeks later, completed a posttest. Thirty-three students completed the pretest; 29 attended the workshop; 26 completed the posttest. Video quiz scores increased significantly from pretest to posttest, as did scores for the standardized patient encounter after completion of the workshop. Students also reported increased levels of confidence in interactions with the Deaf community. The results suggest that a single workshop was effective in increasing both confidence and short-term knowledge in interactions with Deaf patients. PMID- 26004975 TI - A reversed-typicality effect in pictures but not in written words in deaf and hard of hearing adolescents. AB - Two experiments investigated Chinese deaf and hard of hearing (DHH) adolescents' recognition of category names in an innovative task of semantic categorization. In each trial, the category-name target appeared briefly at the screen center followed by two words or two pictures for two basic-level exemplars of high or middle typicality, which appeared briefly approximately where the target had appeared. Participants' reaction times when they were deciding whether the target referred to living or nonliving things consistently revealed the typicality effect for the word, but a reversed-typicality effect for picture-presented exemplars. It was found that in automatically processing a category name, DHH adolescents with natural sign language as their first language evidently activate two sets of exemplar representations: those for middle-typicality exemplars, which they develop in interactions with the physical world and in sign language uses; and those in written-language learning. PMID- 26004976 TI - Career-related parental support of adolescents with hearing loss: relationships with parents' expectations and occupational status. AB - The study examined the contribution of parents' occupational status and expectations regarding persons with hearing loss to career-related support they provide their deaf and hard of hearing (dhh) adolescent children. Thirty-eight parents completed the Evaluation of Occupational Competence Scale (Weisel & Cinamon, 2005), the Evaluation of Family Competence Scale (Caprara, Regalia, Scabini, Barbaranelli, & Bandura, 2004), the Career-Related Parent Support Scale (Turner, Alliman-Brissett, Lapan, Udipi, & Ergun, 2003), and a background questionnaire. Parents' occupational expectations were positively correlated with their family expectations regarding deaf persons. Parents' occupational status contributed to expectations of success for deaf persons in prestigious occupations with high communication demands. Different types of expectations contributed to career-related parental support. Implications for theory and practice are discussed. PMID- 26004977 TI - The effects of reference genes in qRT-PCR assays for determining the immune response of bovine cells (MDBK) infected with the Bovine Viral Diarrhea Virus 1 (BVDV-1). AB - The bovine viral diarrhea virus (BVDV) causes significant economic losses to the dairy industry worldwide, and understanding its infection mechanisms would be extremely useful in designing new and efficient treatments. Due to the limited number of specific antibodies against bovine proteins, differential gene expression analyses are vital for researching host immune responses to viral infection. qRT-PCR provides a sensitive platform to conduct such gene expression analyses, but suitable housekeeping genes are needed for accurate transcript normalization. The present study assessed nine reference genes in bovine kidney cells under conditions of BVDV-1 infection, incubation with pathogen-associated molecular patterns, and co-incubation with BAY117085, a pharmacological inhibitor of the NF-kappaB signaling pathway. Analyses of Ct values using the BestKeeper and Normfinder programs ranked CD81, RPL4, and GAPDH as the most reliable reference genes. This determination of a stable set of reference genes in this culture system will facilitate analyses of expression levels for genes of interest. PMID- 26004978 TI - Further development of the theory and mathematical description of combined toxicity: An approach to classifying types of action of three-factorial combinations (a case study of manganese-chromium-nickel subchronic intoxication). AB - For characterizing the three-factorial toxicity, we proposed a new health risk oriented approach, the gist of which is a classification of effects depending on whether a binary combined toxicity's type remains virtually the same or appears to be either more or less adverse when modeled against the background of a third toxic. To explore possibilities of this approach, we used results of an experiment in which rats had been injected ip 3 times a week (up to 20 injections) with a water solution of either one of the toxics (Mn, Ni or Cr-VI salts) in a dose equivalent to 0.05 LD50, or any two of them, or all the three in the same doses, the controls receiving injections of the same volume of distilled water (4mL per rat). Judging by more than 30 indices for the organism's status, all exposures caused subchronic intoxication of mild to moderate strength. For each two-factorial exposure, we found by mathematical modeling based on the isobolograms that the binary combined subchronic toxicity either was of additive type or departed from it (predominantly toward subadditivity) depending on the effect assessed, dose, and effect level. For the three-factorial combination, different classes of effects were observed rather consistently: class A - those regarding which the third toxic's addition made the binary toxicity type more unfavorable for the organism, class B - those regarding which the result was opposite, and class C - those regarding which the type of binary combined toxicity on the background of a third toxic virtually remained the same as in its absence. We found a complicated reciprocal influence of combined metals on their retention in kidneys, liver, spleen and brain which might presumably be one of the possible mechanisms of combined toxicity, but the lack of an explicit correspondence between the above influence and the influence on toxicity effects suggests that this mechanism is not always the most important one. The relevance of the proposed classification to health risk analysis and management is briefly discussed. PMID- 26004979 TI - Metabolic profile of Diane-35 versus Diane-35 plus metformin in Chinese PCOS women under standardized life-style changes. AB - OBJECTIVE: The aim of this study was to compare the effect of Diane-35 versus Diane-35 + metformin on metabolic parameters in Chinese PCOS patients. METHODS: Patients getting individualized life-style modification were treated with Diane 35. Metformin was added according to its indication. Within a 3-month prospective study, metabolic parameters were assessed. RESULTS: Eighty-three patients were recruited, 45 using Diane-35 and 38 Diane-35 plus metformin. Using Diane-35, triglycerides (TG) (p < 0.05) and tendencially (p < 0.1) total cholesterol (TC) increased, but significant positive effects on BMI, high-density lipoprotein cholesterol (HDL-C), and HDL-C/TC ratio were observed. Other lipids and the parameters for glucose metabolism remained unchanged. In the combination group, no negative effect on TG and TC was seen, other lipid fractions improved, as well as BMI, % body fat, and all parameters for glucose metabolism like fasting plasma glucose (FPG), fasting insulin, HOMA-insulin-resistance index, and insulin sensitivity index (ISI), whereby the beneficial effect of metformin got significance compared with Diane-35 for BMI, FPG, and ISI. CONCLUSION: With the exception of increasing triglycerides, Diane-35 had no relevant negative effects in the metabolic system. It does not negatively impact the beneficial effects of metformin in lipids and glucose metabolism. Diane-35 plus metformin is effective in improving the metabolic profile of Chinese PCOS patients. PMID- 26004980 TI - Treatment adherence in schizophrenia: a patient-level meta-analysis of combined CATIE and EUFEST studies. AB - The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) obtained a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) studied a sample of 498 patients. We have combined these two samples to study the predictors and correlates of adherence to treatment. Here we report on adherence to pharmacological treatment at the six and twelve month assessments of these trials with a combined subsample of 1154 schizophrenia patients. Individual patients' data were used for analyses. We used logistic regression to examine the effects of substance use, akathisia, parkinsonism, dyskinesia, hostility, and insight on pharmacological adherence. The results showed that reduced adherence to pharmacological treatment was associated with substance use (p=0.0003), higher levels of hostility (p=0.0002), and impaired insight (p<0.0001). Furthermore, poor adherence to study medication was associated with earlier discontinuation in the combined data. The clinical implications of the results point to the importance of routine assessments and interventions to address patients' insight and comorbid substance use and the establishment of therapeutic alliance. PMID- 26004981 TI - Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics. AB - Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alters the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non functional spines. Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network. PMID- 26004982 TI - Cadmium accumulation in leaves of leafy vegetables. AB - Leafy vegetables have a relatively high potential for Cd uptake and translocation, and are thus considered Cd accumulators. For this reason, leaves and roots of lettuce (Lactuca sativa L.) and endive (Cichorium endivia L.) plants, grown on different agricultural soils in Campania region (southern Italy), subjected to different fertilisation treatments (unfertilisation, compost amendment and mineral fertilisation), were analysed for Cd concentrations. Moreover, to clarify if the highest concentrations found are linked to older and inedible or to younger and edible leaves, external and internal endive leaves were separately analysed. All the leafy vegetables analysed showed on average 2 fold higher Cd concentrations in leaves than in roots. Leaf Cd concentrations in both lettuce and endive plants significantly differed among fertilisation treatments, with values highest in the plants grown on mineral fertilised soils. Apart from the soil fertilisation treatments, however, Cd leaf concentrations were often higher (up to 4-fold) than the threshold deduced by the EU 420/2011 Regulation, although the plants grew on unpolluted soils. Anyway, external leaves of endive plants showed significantly higher concentrations than internal leaves (in some cases the values were 3-fold higher), partly reassuring on the consumption of the younger leaves. Moreover, this study points out two major drawbacks in the Italian and European regulatory frameworks: (1) metal concentration (as total and/or available fraction) limits in agricultural soils are lacking; (2) metal concentration thresholds (currently existing only for Cd and Pb in crops) reported in the EU 420/2011 Regulation, expressed on the fresh weight basis rather than on the dry weight basis, appear not suitable. PMID- 26004983 TI - Racial disparities in the optimal for induction of labor in low-risk term pregnancies: a national population-based study. AB - OBJECTIVE: The recommendation for elective induction of labor (IOL) is to await >= 39 weeks. Studies show earlier maturity of Blacks compared to Whites. The objective was to examine the effect of the Black race on the risk of intrapartum and neonatal complications after IOL. METHODS: Black women with non-indicated IOL at 37-42 weeks were selected from the CDC-Birth Cohorts 2007-2010. Congenital anomalies, hypertension/diabetes, low-birth weight, breech presentation, previous cesarean and premature rupture of membranes were excluded. Intrapartum/neonatal complications were analyzed. Logistic regression was used to calculate adjusted odds ratios, using 39 weeks as reference. RESULTS: 311,264 black were compared with 2,451,774 deliveries of other races. For Blacks, the risks of cesarean delivery and intrapartum complications were lower at 38 weeks. Chance of vaginal delivery was greater at 38 weeks. Risks of neonatal complications was not increased at 38 compared to 39 weeks. CONCLUSIONS: Intrapartum complications were lower at 38 than at 39 weeks in Blacks with no increased risk of neonatal complications. Meconium staining and fetal distress were higher as early as at 40 weeks, perhaps due to accelerated maturation. While a 39-week goal is simple and benefits many patients, a more "personalized medicine" approach may benefit even more mothers and babies. PMID- 26004984 TI - The impact of prior medical termination of pregnancy on the mother's early relationship with a subsequent infant. AB - OBJECTIVE: There is insufficient research on the mother's early relationship with a child born subsequent to a previous medical termination of pregnancy (TOP). This study explores mother-infant interactions following prior TOP and the impact on the infant's development. METHODS: Being an exploratory research comprising 12 mother-infant (6-7 months old) couples, following prior TOP, and five controls, this study uses a descriptive methodology and a qualitative approach. The Greenspan and Lieberman Observation Scale (GLOS) and the Stern's "R"-Interview were employed to investigate the mother-infant relationship. We used the Brunet Lezine's Revised Scales (BL-R) and the Projective Kit for Early Childhood (PKEC) to assess the infant's development. Grief resolution was taken into account (Perinatal Grief Scale, semi-structured interview). RESULTS: The later the perinatal loss, the less likely children are to express their emotions and respond contingently (GLOS). Their psychomotor (BL-R) and emotional (PKEC) development remains adequate. Unresolved grief is associated with more pronounced disturbances: no dyadic exchange (GLOS), language disruptions (BL-R), and withdrawal from the environment (PKEC). CONCLUSIONS: This study suggests that mother-infant interactions following a prior late TOP could undergo disturbances, which do not lead systematically to pathogenic effect on the subsequent child. Nevertheless, unresolved grief could lead to adverse effects. PMID- 26004985 TI - Lactate versus pH levels in fetal scalp blood during labor--using the Lactate Scout System. AB - OBJECTIVE: To assess if lactate measured with the Scout Lactate System is a reliable alternative to pH in intrapartum monitoring of the fetus. METHODS: A prospective study analyzing (1) the correlation between scalp lactate measured by the Scout Lactate System and the Automatic Blood Laboratory (ABL), (2) the correlation between lactate and pH measured in scalp blood and (3) the correlation between fetal scalp lactate and umbilical cord SBE. The sensitivity/specificity and positive/negative predictive values of lactate in predicting low pH were analyzed and expressed as Receiver Operating Curves (ROC). RESULTS: Lactate measured by the Scout Lactate System and the ABL correlated well (r(2)=0.85). Both lactate and pH were measured in 1009 scalp blood samples. The sensitivity and specificity of lactate >= 4.8 mmol/l in predicting a pH <7.20 were 0.63 and 0.85, respectively. The correlation between scalp lactate measured within 15 min prior to delivery and the umbilical cord SBE was low. CONCLUSION: Monitoring non-reassuring deliveries with scalp lactate instead of pH would have resulted in more (155 instead of 56) instrumental deliveries with no decrease in newborns with severe metabolic acidosis. PMID- 26004986 TI - Placental telomere shortening in stillbirth: a sign of premature senescence? AB - OBJECTIVE: The objective of this study is to investigate placental telomere shortening in unexplained stillbirths (SBs) as an indication of premature senescence. METHODS: Placentas were collected from 42 unexplained SB (>22 weeks), 43 term and 15 preterm live births, at the Policlinico Hospital of Modena (Italy). DNA extracted from placentae was studied for telomere length by real time PCR. Standard curves were generated for telomere lengths from single copy gene amplifications using a reference DNA. The telomere length for each sample was derived based on the ratio of telomere length between the sample and single copy gene standard (T/S ratio). The mean ratio of placental telomere in term live births was 5.181 +/- 3.841. RESULTS: A twofold decrease in telomere length was seen in SBs (over all 2.455 +/- 1.239; p < 0.001). For early SBs (above 34 weeks), the T/S was 2.8884 +/- 1.224 and for late SBs, the T/S was 2.207 +/- 1.201, both lower than term live births (both p < 0.01). T/S remained lower both in small for gestational age-SB (2.639 +/- 1.619) and appropriate for gestational age-SB (2.653 +/- 1.335) with no difference between these subgroups (p = ns). T/S was lower in SB compared with spontaneous preterm births (PTBs) (6.382 +/- 5.525; p < 0.01), whereas SBs telomere length were similar to those of preterm premature rupture of membranes (pPROM) (3.296 +/- 3.599; p = ns). CONCLUSIONS: Substantial reduction in telomere length in SBs is indicative of placental senescence. These data provide mechanistic insights that premature aging may lead to placental dysfunction as an initiator of fetal demise in unexplained SBs. PMID- 26004987 TI - Vitamin D is significantly associated with total testosterone and sex hormone binding globulin in Malaysian men. AB - OBJECTIVE: Cross-sectional studies in the Caucasian population have shown a significant relationship between vitamin D and testosterone levels, but data in the Asian population are limited. This study aimed to determine the association between vitamin D and testosterone levels in Malaysian men. METHODS: Chinese and Malay men (n = 382) aged 20 years or above residing in the Klang Valley, Malaysia were recruited. Their fasting blood was collected for serum testosterone, sex hormone-binding globulin (SHBG) and 25-hydroxyvitamin D (25(OH)D) assays. Relationship between 25(OH)D and testosterone levels was analyzed using multiple regression analysis. Testosterone and SHBG levels among subjects with different vitamin D status were compared using univariate analysis. Confounders such as age, ethnicity and body mass index (BMI) were adjusted. RESULTS: 25(OH)D was significantly and positively associated with total testosterone and SHBG levels before and after adjustment for age and ethnicity (p < 0.05). Only association with SHBG remained significant after further adjustment for BMI (p < 0.05). Total testosterone and SHBG values displayed an increasing trend from subjects with vitamin D deficiency to those with optimal level (p < 0.05). The trend was attenuated after adjustment for BMI (p > 0.05). CONCLUSION: 25(OH)D is significantly associated with total testosterone and SHBG in Malaysian men but this association is BMI-dependent. PMID- 26004988 TI - Androgen deprivation therapy, diabetes and poor physical performance status increase fracture risk in Chinese men treated for prostate cancer. AB - We investigated the fracture risk after androgen deprivation therapy (ADT) for prostate cancer in the Chinese population. All Chinese prostate cancer patients who were treated primarily by radical prostatectomy or radiotherapy, with or without further ADT, from year 2000 to 2009 were reviewed. We compared the fracture risk in patients who were given ADT (ADT group) with those who were not given any ADT (non-ADT group). Potential risk factors including age, diabetes mellitus, hypertension, hyperlipidemia, ischemic heart disease and performance status were reviewed. The fracture risk was analyzed with Kaplan-Meier and multivariate Cox regression analyses. Our cohort consisted of 200 patients in the non-ADT group and 252 patients in the ADT group. The ADT group was shown to have higher fracture risk (p = 0.036) upon Kaplan-Meier analysis. Upon multivariate Cox regression analyses, diabetes mellitus (HR 4.39, 95% CI 1.08-17.83, p = 0.039), poor performance status (HR 3.14, 95% CI 1.24-8.00, p = 0.016) and the use of ADT (HR 4.89, 95% CI 1.03-23.17, p = 0.045) were associated with increased fracture risk. In conclusion, the fracture risk should be considered while deciding on ADT in Chinese men, especially in diabetic patients with poor performance status. PMID- 26004989 TI - Diversity and movement of indoor Alternaria alternata across the mainland USA. AB - Alternaria spp. from sect. Alternaria are frequently associated with hypersensitivity pneumonitis, asthma and allergic fungal rhinitis and sinusitis. Since Alternaria is omnipresent in the outdoor environment, it is thought that the indoor spore concentration is mainly influenced by the outdoor spore concentration. However, few studies have investigated indoor Alternaria isolates, or attempted a phylogeographic or population genetic approach to investigate their movement. Therefore, the aim of the current study was to investigate the molecular diversity of indoor Alternaria isolates in the USA, and to test for recombination, using these approaches. Alternaria isolates collected throughout the USA were identified using ITS, gapdh and endoPG gene sequencing. This was followed by genotyping and population genetic inference of isolates belonging to Alternaria sect. Alternaria together with 37 reference isolates, using five microsatellite markers. Phylogenetic analyses revealed that species of Alternaria sect. Alternaria represented 98% (153 isolates) of the indoor isolates collected throughout the USA, of which 137 isolates could be assigned to A. alternata, 15 to the A. arborescens species complex and a single isolate to A. burnsii. The remaining 2% (3 isolates) represented sect. Infectoriae (single isolate) and sect. Pseudoulocladium (2 isolates). Population assignment analyses of the 137 A. alternata isolates suggested that subpopulations did not exist within the sample. The A. alternata isolates were thus divided into four artificial subpopulations to represent four quadrants of the USA. Forty-four isolates representing the south-western quadrant displayed the highest level of uniqueness based on private alleles, while the highest level of gene flow was detected between the south eastern (32 isolates) and south-western quadrants. Genotypic diversity was high for all quadrants, and a test for linkage disequilibrium suggested that A. alternata has a cryptic sexual cycle. These statistics could be correlated with environmental factors, suggesting that indoor A. alternata isolates, although extremely diverse, have a continental distribution and high levels of gene flow over the continent. PMID- 26004990 TI - Optimal uptake rates for initial treatments for cervical cancer in concordance with guidelines in Australia and Canada: Results from two large cancer facilities. AB - BACKGROUND: Prior work estimating optimal treatment utilisation rates for cervical cancer has focused on radiotherapy or chemotherapy, using proportions of patients with clinical indications for specific treatment strategies which were obtained from the published literature. OBJECTIVES: To estimate optimal uptake rates for surgery, radiotherapy, chemotherapy and chemo-radiotherapy for cervical cancer treatment in Australia and Canada, and to quantify the differences in the optimal and the observed treatment utilisation rates in a large cancer facility from each country. METHODS: A decision tree was constructed to reflect treatments according to guidelines and current practice (in 1999-2008) in each setting. Detailed patterns of care data from a large cancer facility in each country were obtained, and the observed stage distribution and proportions of patients with each clinical indication were used as inputs. RESULTS: The estimated overall optimal treatment rates for cervical cancer in Australia and Canada differed, largely due to the difference in the stage distribution at diagnosis in the two settings; 72% vs 54% with FIGO IA-IIA disease, respectively. The estimated optimal rates for surgery, radiotherapy, chemotherapy and chemo-radiotherapy in Australia were 63% (95% credible interval: 61-64%), 52% (53-56%), 36% (35-38%) and 36% (35-38%), respectively. The corresponding rates in Canada were 38% (36 39%), 68% (68-71%), 51% (49-52%) and 50% (49-51%), respectively. The absolute differences between the optimal and the observed rates were similar between the two settings; the absolute differences for chemotherapy and chemo-radiotherapy uptake were more pronounced (9-15% less than optimal) than those for surgery and radiotherapy uptake (within 5% of optimal). CONCLUSIONS: This is the first study to use detailed patterns of care data in multiple settings to compare optimal and observed rates for all cervical cancer treatment modalities. We found optimal treatment rates were largely dependent on the overall stage distribution. In Australia and Canada, observed surgery rates, as measured in the two large cancer facilities, were similar to the estimated optimal rates, whereas radiotherapy, chemotherapy and chemo-radiotherapy appeared to be under-utilised. PMID- 26004991 TI - No progression of the alterations in the cortical thickness of individuals with schizophrenia-spectrum disorder: a three-year longitudinal magnetic resonance imaging study of first-episode patients. AB - BACKGROUND: Cortical thickness measurement offers an index of brain development processes. In healthy individuals, cortical thickness is reduced with increasing age and is related to cognitive decline. Cortical thinning has been reported in schizophrenia. Whether cortical thickness changes differently over time in patients and its impact on outcome remain unanswered. METHOD: Data were examined from 109 patients and 76 healthy controls drawn from the Santander Longitudinal Study of first-episode schizophrenia for whom adequate structural magnetic resonance imaging (MRI) data were available (n = 555 scans). Clinical and cognitive assessments and MRIs were acquired at three regular time points during a 3-year follow-up period. We investigated likely progressive cortical thickness changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The effects of cortical thickness changes on cognitive and clinical variables were also examined along with the impact of potential confounding factors. RESULTS: There were significant diagnoses * scan time interaction main effects for total cortical thickness (F 1,309.1 = 4.60, p = 0.033) and frontal cortical thickness (F 1,310.6 = 5.30, p = 0.022), reflecting a lesser thinning over time in patients. Clinical and cognitive outcome was not associated with progressive cortical changes during the early years of the illness. CONCLUSIONS: Cortical thickness abnormalities do not unswervingly progress, at least throughout the first years of the illness. Previous studies have suggested that modifiable factors may partly account for cortical thickness abnormalities. Therefore, the importance of implementing practical actions that may modify those factors and improve them over the course of the illness should be highlighted. PMID- 26004992 TI - Cleaning-induced arsenic mobilization and chromium oxidation from CCA-wood deck: Potential risk to children. AB - Concern about children's exposure to arsenic (As) from wood treated with chromated-copper-arsenate (CCA) led to its withdrawal from residential use in 2004. However, due to its effectiveness, millions of American homes still have CCA-wood decks on which children play. This study evaluated the effects of three deck-cleaning methods on formation of dislodgeable As and hexavalent chromium (CrVI) on CCA-wood surfaces and in leachate. Initial wipes from CCA-wood wetted with water showed 3-4 times more dislodgeable As than on dry wood. After cleaning with a bleach solution, 9.8-40.3MUg/100cm(2) of CrVI was found on the wood surface, with up to 170MUg/L CrVI in the leachate. Depending on the cleaning method, 699-2473mg of As would be released into the environment from cleaning a 18.6-m(2)-deck. Estimated As doses in children aged 1-6 after 1h of playing on a wet CCA-wood deck were 0.25-0.41MUg/kg. This is the first study to identify increased dislodgeable As on wet CCA-wood and to evaluate dislodgeable CrVI after bleach application. Our data suggest that As and CrVI in 25-year old CCA-wood still show exposure risks for children and potential for soil contamination. PMID- 26004993 TI - Adapting the McMaster-Ottawa scale and developing behavioral anchors for assessing performance in an interprofessional Team Observed Structured Clinical Encounter. AB - BACKGROUND: Current scales for interprofessional team performance do not provide adequate behavioral anchors for performance evaluation. The Team Observed Structured Clinical Encounter (TOSCE) provides an opportunity to adapt and develop an existing scale for this purpose. We aimed to test the feasibility of using a retooled scale to rate performance in a standardized patient encounter and to assess faculty ability to accurately rate both individual students and teams. METHODS: The 9-point McMaster-Ottawa Scale developed for a TOSCE was converted to a 3-point scale with behavioral anchors. Students from four professions were trained a priori to perform in teams of four at three different levels as individuals and teams. Blinded faculty raters were trained to use the scale to evaluate individual and team performances. G-theory was used to analyze ability of faculty to accurately rate individual students and teams using the retooled scale. RESULTS: Sixteen faculty, in groups of four, rated four student teams, each participating in the same TOSCE station. Faculty expressed comfort rating up to four students in a team within a 35-min timeframe. Accuracy of faculty raters varied (38-81% individuals, 50-100% teams), with errors in the direction of over-rating individual, but not team performance. There was no consistent pattern of error for raters. CONCLUSION: The TOSCE can be administered as an evaluation method for interprofessional teams. However, faculty demonstrate a 'leniency error' in rating students, even with prior training using behavioral anchors. To improve consistency, we recommend two trained faculty raters per station. PMID- 26004994 TI - Mirror movements in unilateral spastic cerebral palsy: Specific negative impact on bimanual activities of daily living. AB - AIM: Mirror movements are involuntary movements of the other hand during voluntary unimanual movements. Some, but not all children with unilateral spastic cerebral palsy (USCP) show this phenomenon. In this observational study, we investigated whether these mirror movements have a specific negative impact on bimanual activities of daily living. METHODS: Eighteen children (six girls; age range, 6-16 years; mean age, 12 years 1 month; SD, 3 years 3 month) with USCP, nine with and nine without mirror movements, underwent the Jebsen Taylor Hand Function Test (unimanual capacity) and the Assisting Hand Assessment (bimanual performance). In addition, we measured the time the participants needed for the completion of five activities we had identified as particularly difficult for children with mirror movements. RESULTS: Multivariate analysis demonstrated that mirror movements indeed have a specific negative impact on bimanual performance (Assisting Hand Assessment) and on the time needed for the completion of these five particularly difficult activities. This effect was independent from unimanual capacity. CONCLUSION: Functional therapies in children with USCP and mirror movements should address this phenomenon. PMID- 26004995 TI - Cerebellar swelling due to familial hemophagocytic lymphohistiocytosis: An unusual presentation. AB - BACKGROUND: Cerebellar swelling with obstructive hydrocephalus is a rare but life threatening condition, associated with different etiologies, familial hemophagocytic lymphohistiocytosis (HLH) being rarely one of them. PATIENT: 2 year-7-month old boy presented with irritability, cerebellar dysfunction, and somnolence. Brain MRI showed marked diffuse cerebellar swelling and obstructive hydrocephalus with mild tonsillar herniation. Laboratory testing revealed pancytopenia, elevated liver enzymes, elevated ferritin and triglycerides levels and decreased fibrinogen. The diagnosis of familial HLH was confirmed by the presence of homozygous missense mutation of Syntaxin 11 gene. The child was treated with HLH-2004 protocol of chemotherapy followed by allogenic stem cell transplantation. His neurological condition improved significantly after treating the underlying disease. CONCLUSION: Cerebellar swelling is a rare manifestation of familial HLH. High degree of clinical suspicion may allow a timely diagnosis and appropriate therapy. PMID- 26004996 TI - [Digital block with or without the addition of epinephrine in the anesthetic solution]. AB - BACKGROUND AND OBJECTIVES: Review of various techniques for digital blocks with local anesthetic, with or without epinephrine. CONTENTS: Description of various procedures and comparison of results reported in the literature, mainly on latency and quality of anesthesia, details on vasoconstrictor effect of epinephrine, intraoperative bleeding, necessity of tourniquet use, duration of anesthesia and postoperative analgesia, blood flow and digital SpO2 behavior, local and systemic complications, and also approaches and drugs to be used in certain situations of ischemia. CONCLUSIONS: The advantages of adding epinephrine to the anesthetic solution are minor when compared to the risks of the procedure, and it seems dangerous to use a vasoconstrictor in the fingers, unless the safety of the technique and the possibility of discarding the tourniquet are definitely proven. PMID- 26004997 TI - Modulating human sense of agency with non-invasive brain stimulation. AB - Human voluntary actions are accompanied by a distinctive subjective experience termed "sense of agency". We performed three experiments using transcranial direct current stimulation (tDCS) to modulate brain circuits involved in control of action, while measuring stimulation-induced changes in one implicit measure of sense of agency, namely the perceived temporal relationship between a voluntary action and tone triggered by the action. Participants perceived such tones as shifted towards the action that caused them, relative to baseline conditions with tones but no actions. Actions that caused tones were perceived as shifted towards the tone, relative to baseline actions without tones. This 'intentional binding' was diminished by anodal stimulation of the left parietal cortex [targeting the angular gyrus (AG)], and, to a lesser extent, by stimulation targeting the left dorsolateral prefrontal cortex (DLPFC), (Experiment 1). Cathodal AG stimulation had no effect (Experiment 2). Experiment 3 replicated the effect of left anodal AG stimulation for actions made with either the left or the right hand, and showed no effect of right anodal AG stimulation. The angular gyrus has been identified as a key area for explicit agency judgements in previous neuroimaging and lesion studies. Our study provides new causal evidence that the left angular gyrus plays a key role in the perceptual experience of agency. PMID- 26004998 TI - Electronic personal maternity records: Both web and smartphone services. AB - This study develops an antenatal care information system to assist women during pregnancy. We designed and implemented the system as both a web-based service and a multi-platform application for smartphones and tablets. The proposed system has three novel features: (1) web-based maternity records, which contains concise explanations of various antenatal screening and diagnostic tests; (2) self-care journals, which allow pregnant women to keep track of their gestational weight gains, blood pressure, fetal movements, and contractions; and (3) health education, which automatically presents detailed information on antenatal care and other pregnancy-related knowledge according to the women's gestational age. A survey was conducted among pregnant women to evaluate the usability and acceptance of the proposed system. In order to prove that the antenatal care was effective, clinical outcomes should be provided and the results are focused on a usability evaluation. PMID- 26004999 TI - Abdominal surgery process modeling framework for simulation using spreadsheets. AB - We provide a continuation of the existing Activity Table Modeling methodology with a modular spreadsheets simulation. The simulation model developed is comprised of 28 modeling elements for the abdominal surgery cycle process. The simulation of a two-week patient flow in an abdominal clinic with 75 beds demonstrates the applicability of the methodology. The simulation does not include macros, thus programming experience is not essential for replication or upgrading the model. Unlike the existing methods, the proposed solution employs a modular approach for modeling the activities that ensures better readability, the possibility of easily upgrading the model with other activities, and its easy extension and connectives with other similar models. We propose a first-in-first served approach for simulation of servicing multiple patients. The uncertain time duration of the activities is modeled using the function "rand()". The patients movements from one activity to the next one is tracked with nested "if()" functions, thus allowing easy re-creation of the process without the need of complex programming. PMID- 26005000 TI - The multiple myeloma bone eco-system and its relation to oncogenesis. AB - Pure lytic bone lesions are the hallmark of myeloma (MM). MM is the only hematological malignancy associated with lytic bone lesions and the mechanisms of bone destruction are well documented both at the cellular and molecular levels. An uncoupling bone process characterizes MM, with stimulation of bone resorption and inhibition of bone formation. The capacity of MM cells to directly or indirectly inhibit bone formation is specific of MM, although many carcinomas have the capacity to stimulate bone resorption, directly or indirectly in a similar way to MM. Few MM do not develop bone lesions, while true sclerotic MM remain exceptional. Inhibition of bone formation is the major event explaining the transition from MGUS to overt MM. It is now well documented that bone cells regulate MM cell growth, osteoclast stimulating MM cell growth and osteoblasts inhibiting it. Progression of MM from MGUS is characterized by the selection of MM clones able to inhibit osteoblasts, favoring tumor growth. These data underline the interest of new treatments able to regenerate bone. PMID- 26005001 TI - Feasibility of radiation dose reduction using AIDR-3D in dynamic pulmonary CT perfusion. AB - AIM: To assess the feasibility of radiation dose reduction with adaptive iterative dose reduction (AIDR-6 3D) reconstruction in dynamic pulmonary CT perfusion. MATERIALS AND METHODS: CTP examinations of 10 patients acquired at 100 kVp/50 mAs were reconstructed with filtered back projection (FBP) and AIDR-3D. Artificial noise was added to raw data (pre-reconstruction projection data) to simulate lower tube current scanning. Radiodensity (in Hounsfield units), noise, and perfusion values were compared. RESULTS: There was no significant difference in noise between the full and simulated reduced tube current with AIDR-3D reconstruction (p = 1). There was significantly lower noise in lung tissue with AIDR-3D images when compared to reconstructions without AIDR-3D (p = 0.005) and no significant change in the radiodensity (p = 1; mean difference <6 HU). Mean perfusion values increased significantly at lower tube currents (25 and 12.5 mAs), compared to 50 mAs (p = 0.005). This effect was significantly greater in larger patients compared to thin patients. CONCLUSION: AIDR-3D produced significantly lower noise images than FBP-based algorithms and maintained consistent noise levels in lung at 12.5 mAs, indicating this algorithm is suitable for reduced dose lung perfusion imaging. Iterative reconstruction allows significant radiation dose reduction of up to fourfold in smaller patients, and up to twofold in the medium/large size patients. The increase in perfusion values at 25% simulated tube currents is attributed to attenuation bias. PMID- 26005002 TI - Expression patterns of long noncoding RNAs from Dlk1-Dio3 imprinted region and the potential mechanisms of Gtl2 activation during blastocyst development. AB - The function of long noncoding RNAs (lncRNAs) in cell differentiation and development have begun to be revealed in recent years. However, the expression pattern and mechanisms regulating lncRNAs are largely unknown during mammalian preimplantation development. LncRNAs expressed from Dlk1-Dio3 imprinted region have been linked to pluripotency of induced pluripotent cells (iPSCs). In this study we show that these lncRNAs (Gtl2, Rian and Mirg) are first expressed at the morula stage and gradually restricted to the inner cell mass (ICM) as the embryo differentiates into the blastocyst. Analysis of DNA methylation at IG-DMR and Gtl2-DMR showed no change during preimplantation while the presence of the activating histone modification H3K4me3 increased significantly from 8-cell to blastocyst stage, which may explain the expression activation. Additionally, knockdown of transcription factors (Oct4, Sox2 and Nanog) in blastocyst reduced the expression of Gtl2, indicating pluripotency factors regulate transcription of these lncRNAs. This study provides the spatiotemporal expression and dynamic changes of lncRNAs from Dlk1-Dio3 imprinted region in mouse preimplantation stage embryos and offers insight into the potential mechanisms responsible for Gtl2 activation. PMID- 26005003 TI - Enhanced expression of the Erns protein of classical swine fever virus in yeast and its application in an indirect enzyme-linked immunosorbent assay for antibody differentiation of infected from vaccinated animals. AB - Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is a devastating disease of swine worldwide. Although a mandatory vaccination with the modified live vaccine C-strain has been implemented in China for decades, CSF remains a serious threat to the swine industry. To facilitate the control and eradication of CSF in China, the E2-based marker vaccine rAdV-SFV-E2, an adenovirus-delivered, alphavirus replicon-vectored vaccine, has been developed. Accordingly, an accompanying discriminatory test that allows differentiating infected from vaccinated animals (DIVA) is required. Here, the enhanced expression of E(rns) protein of CSFV was achieved in the methyltropic yeast Pichia pastoris by codon-optimization of the E(rns) gene, and an indirect enzyme linked immunosorbent assay (iELISA) based on the yeast-expressed E(rns) (yE(rns)) was developed and evaluated. The optimized iELISA was able to detect CSFV specific antibodies in the serum samples from the CSFV-infected pigs as early as 6 days post-infection, and discriminate the CSFV-infected pigs from those vaccinated with rAdV-SFV-E2. The iELISA was evaluated using a panel of swine sera, and showed comparable sensitivity (94.6%) and specificity (97.1%), and the consistence rates with the virus neutralization test were 96.8% for CSFV-infected swine sera, 83.3% for C-strain-vaccinated swine sera, and 95.0% for field swine sera. In addition, the iELISA showed higher sensitivity (90.4%) compared with PrioCHECK CSFV E(rns) (59.6%). Taken together, the yE(rns)-based iELISA is specific and sensitive, representing a promising DIVA test for E2-based marker vaccines against CSF. PMID- 26005004 TI - Global asymptotical omega-periodicity of a fractional-order non-autonomous neural networks. AB - We study the global asymptotic omega-periodicity for a fractional-order non autonomous neural networks. Firstly, based on the Caputo fractional-order derivative it is shown that omega-periodic or autonomous fractional-order neural networks cannot generate exactly omega-periodic signals. Next, by using the contraction mapping principle we discuss the existence and uniqueness of S asymptotically omega-periodic solution for a class of fractional-order non autonomous neural networks. Then by using a fractional-order differential and integral inequality technique, we study global Mittag-Leffler stability and global asymptotical periodicity of the fractional-order non-autonomous neural networks, which shows that all paths of the networks, starting from arbitrary points and responding to persistent, nonconstant omega-periodic external inputs, asymptotically converge to the same nonconstant omega-periodic function that may be not a solution. PMID- 26005005 TI - Periodic synchronization control of discontinuous delayed networks by using extended Filippov-framework. AB - This paper is concerned with the periodic synchronization problem for a general class of delayed neural networks (DNNs) with discontinuous neuron activation. One of the purposes is to analyze the problem of periodic orbits. To do so, we introduce new tools including inequality techniques and Kakutani's fixed point theorem of set-valued maps to derive the existence of periodic solution. Another purpose is to design a switching state-feedback control for realizing global exponential synchronization of the drive-response network system with periodic coefficients. Unlike the previous works on periodic synchronization of neural network, both the neuron activations and controllers in this paper are allowed to be discontinuous. Moreover, owing to the occurrence of delays in neuron signal, the neural network model is described by the functional differential equation. So we introduce extended Filippov-framework to deal with the basic issues of solutions for discontinuous DNNs. Finally, two examples and simulation experiments are given to illustrate the proposed method and main results which have an important instructional significance in the design of periodic synchronized DNNs circuits involving discontinuous or switching factors. PMID- 26005006 TI - Inspiratory muscle strength relative to disease severity in adults with stable cystic fibrosis. AB - BACKGROUND: Due to heterogeneity in pulmonary disease, current literature may misrepresent inspiratory muscle involvement in cystic fibrosis (CF). This study investigated inspiratory muscle strength (IMS) relative to disease severity in adults with CF. METHODS: Maximal inspiratory pressure (MIP) was assessed in 58 adults with stable CF grouped by disease severity (20 mild, 20 moderate, 18 severe) and compared to 20 controls. Relationships between MIP, lung function, dyspnea and anthropometrics were evaluated using multivariable linear models. RESULTS: MIP in cmH2O and %-predicted was decreased in advanced CF lung disease as compared to mild disease and healthy controls (p<0.05). Disease severity accounted for 24% of the variance in IMS after controlling for confounding variables (p<0.001). CONCLUSIONS: IMS is decreased in some adults with stable CF with moderate and severe pulmonary disease, and is related to dyspnea. Future studies should determine if decreased IMS contributes inefficient breathing patterns, respiratory pump dysfunction, and/or exercise intolerance in advanced CF. PMID- 26005007 TI - New endoscopic suturing method: slip knot clip suturing. PMID- 26005008 TI - Symptomatic pancreatic duct stone formation in the disconnected bile duct. PMID- 26005009 TI - EUS-guided gastroduodenostomy for gastric outlet obstruction related to chronic pancreatitis. PMID- 26005010 TI - Suture material in the common bile duct causing recurrent stones. PMID- 26005011 TI - Finding a needle in a haystack: use of volumetric laser endomicroscopy in targeting focal dysplasia in long-segment Barrett's esophagus. PMID- 26005012 TI - Assessment of mucosal healing in inflammatory bowel disease: review. AB - BACKGROUND AND AIMS: Mucosal healing is an important treatment end-point in inflammatory bowel disease, and achieving mucosal healing has been demonstrated to improve disease-related outcomes. Considerable uncertainty exists, however, regarding the optimal approach for the assessment of mucosal healing. AIMS: To compare currently available diagnostic tools for the assessment of mucosal healing and outline the ideal approach to integrating these tools into clinical trials and clinical practice. METHODS: Review article. RESULTS: Endoscopy represents the criterion standard for the assessment of mucosal healing, and frequent endoscopic assessment is associated with a higher rate of achieving mucosal healing. The use of mucosal biopsy allows for the identification of persistent histologic disease activity, but the incremental clinical benefit of achieving histologic healing is yet to be determined. Magnetic resonance enterography has a high sensitivity for ulcer healing in endoscopically inaccessible disease activity. However, the presence of mucosal lesions cannot be reliably excluded based on this modality alone, and further small-bowel endoscopy should be considered in symptomatic patients. Video capsule endoscopy or device assisted enteroscopy can be used, with device-assisted enteroscopy being preferred in stricturing Crohn's disease because of the risk of capsule retention or in patients in whom small-bowel malignancy is a possibility. CONCLUSIONS: Endoscopy remains the criterion standard for the assessment of mucosal healing. Several alternative diagnostic modalities have become available that can be of value in specific clinical circumstances, particularly in patients with small bowel involvement. PMID- 26005013 TI - In vivo and ex vivo needle-based confocal endomicroscopy of intraductal papillary mucinous neoplasm of the pancreas. PMID- 26005014 TI - Endoscopically placed guidewire-assisted seton for an ileal pouch-pouch fistula. PMID- 26005015 TI - Endoscopic closure of acute perforations of the GI tract: a systematic review of the literature. AB - BACKGROUND: Surgical repair of endoscopic perforations of the GI tract used to be the standard, but immediate, secure endoscopic closure has become an attractive alternative treatment with the potential to reduce morbidity and mortality. OBJECTIVE: We aimed to perform a systematic review of the medical literature on endoscopic closure of acute iatrogenic perforations of the GI tract. DESIGN: A systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. SETTING: Available medical literature from 1966 through November 2013. PATIENTS: Patients with an acute perforation after an endoscopic procedure that was closed endoscopically. INTERVENTIONS: Endoscopic closure of an acute perforation of the GI tract. MAIN OUTCOME MEASUREMENTS: Clinically successful endoscopic closure. RESULTS: In our search, we identified 726 studies, 702 of which had to be excluded. Twenty-four cohort studies (21 retrospective, 3 prospective) were included in the analysis. No randomized trials were identified. Overall, the methodological quality was low. The 24 studies included described 466 acute perforations in which endoscopic closure was attempted. Successful endoscopic closure was achieved in 419 cases (89.9%; 95% CI, 87%-93%). Successful closure was achieved in 90.2% (n = 359; 95% CI, 87%-93%) of cases by using endoclips, in 87.8% (n = 58; 95% CI, 78%-95%) by using the over-the-scope-clip, and in 100% (n = 2) by using a metal stent. LIMITATIONS: Low methodological quality of included studies. CONCLUSION: This systematic review suggests that endoscopic perforation closure is a safe and effective alternative for surgical intervention in selected cases; however, the overall methodological quality was low. Prospective, true consecutive studies are needed to define the definitive role of endoscopic closure of perforations. PMID- 26005016 TI - Mass spectrometric identification, characterization and validation of the haptoglobin beta-chain protein as a lung cancer serum biomarker. AB - Lung cancer is the major contributor to overall cancer-related mortality. Biomarkers are important in early detection and prognosis, in addition to developing treatment regimes, which may improve the patient survival rates. Biomarkers may also assist in investigating the in depth metabolic pathways and in establishing a set of therapeutic agents leading to early detection of the disease. The present study was designed to identify and confirm a lung cancer protein biomarker and to correlate the differential expression of the protein to a particular histological disease type. A total of 100 lung cancer patients and 50 healthy controls were included in the present study and were categorized into the two main histological types of lung cancer; non-small cell lung cancer (NSCLC; n=88) and small cell lung cancer (SCLC; n=12). NSCLC was further subclassified into three histological types; adenocarcinoma (n=34), squamous cell carcinoma (n=48) and large cell carcinoma (n=6). The patient and control serum samples underwent sodium dodecyl sulphate polyacrylamide gel electrophoresis characterization followed by two-dimensional gel electrophoresis. Following mass spectrometry, human haptoglobin was identified with a mass of ~42-46 kDa and an isoelectric point (pI) of ~5.5-6.2. The experimental mass of the protein was found to be 45.8 kDa with a pI of 6.13. The matrix-assisted laser desorption/ionization time-of-flight/time-of-flight data exhibited spectral peaks of 1146.134, 1724.191, 1345.339 and 2210.319 m/z and Mascot search analysis identified these peaks as haptoglobin (accession no. P00738; Mascot score 87; sequence coverage 23%). This protein was significantly overexpressed in squamous cell carcinoma and adenocarcinoma, as compared with the control. The present study described differentially expressed human haptoglobin as a lung cancer serum protein biomarker, which may serve as a diagnostic and therapeutic target and set a standard criteria for the evaluation of histological types of lung cancer compared with other disease types. PMID- 26005017 TI - Incidence, admission rates, and economic burden of pediatric emergency department visits for urinary tract infection: data from the nationwide emergency department sample, 2006 to 2011. AB - BACKGROUND: The Emergency Department (ED) is being increasingly utilized as a pathway for management of acute conditions such as the urinary tract infections (UTIs). OBJECTIVE: We sought to assess the contemporary trends in pediatric UTI associated ED visits, subsequent hospitalization, and corresponding financial expenditure, using a large nationally representative pediatric cohort. Further, we describe the predictors of admission following a UTI associated ED visit. METHODS: The Nationwide Emergency Department Sample (NEDS; 2006-2011) was queried to assess temporal-trends in pediatric (age <=17 years) ED visits for a primary diagnosis of UTI (ICD9 CM code 590.X, 595.0, and 599.0), subsequent hospital admission, and total charges. These trends were examined using the estimated annual percent change (EAPC) method. Multivariable regression models fitted with generalized estimating equations (GEE) identified the predictors of hospital admission. RESULTS: Of the 1,904,379 children presenting to the ED for management of UTI, 86 042 (4.7%) underwent hospital admission. Female ED visits accounted for almost 90% of visits and increased significantly (EAPC 3.28%; p = 0.003) from 709 visits per 100 000 in 2006 to 844 visits per 100 000 in 2011. Male UTI incidence remained unchanged over the study-period (p = 0.292). The overall UTI associated ED visits also increased significantly during the study-period (EAPC 3.14%; p = 0.006) because of the increase in female UTI associated ED visits. Overall hospital admissions declined significantly over the study-period (EAPC 5.59%; p = 0.021). Total associated charges increased significantly at an annual rate of 18.26%, increasing from 254 million USD in 2006 to 464 million USD in 2011 (p < 0.001; Figure). This increase in expenditure was likely driven by increased utilization of diagnostic CT scanning in these patients (EAPC 22.86%; p < 0.001). Ultrasonography (p = 0.805), X-ray (p = 0.196), and urine analysis/culture use (p = 0.121) did not change over the study-period. In multivariable analysis, the independent predictors of admission included younger age (p < 0.001), male gender (OR = 2.05, p < 0.001), higher comorbidity status (OR = 14.81, p < 0.001), pyelonephritis (OR = 4.45, p < 0.001) and concurrent hydronephrosis (OR = 49.42, p < 0.001), stone disease (OR = 6.44, p < 0.001), or sepsis (OR = 18.83, p < 0.001). DISCUSSION: We show that the incidence of ED visits for pediatric UTI is on the rise. This rise in incidence could be due to several factors, including increasing prevalence of metabolic conditions such as obesity, diabetes and metabolic syndrome in children predisposing them to infections, or could be secondary to increasing sexual activity amongst adolescents and changing patterns of contraceptive use (increased use of OCP in place of condoms), or more simply might just be a reflection of changing practice patterns. Second, we demonstrate that total charges for management of UTI in the ED setting are increasing rapidly; the increase is primarily driven by increasing utilization of diagnostic imaging in the ED setting, as has been demonstrated in other ED based studies as well. CONCLUSIONS: In children presenting to the ED with a primary diagnosis of UTI, total ED charges are increasing at an alarming rate not commensurate with the increase in overall ED visits. While the preponderance of children presenting to the ED for UTI are treated and discharged, 4.7% of patients were admitted to the hospital for further management. The strongest predictors of inpatient admission were pyelonephritis, younger age, male gender, higher comorbidity status, and concurrent hydronephrosis, stone disease, or sepsis. Managing these at-risk patients more aggressively in the outpatient setting may prevent unnecessary ED visits and subsequent hospitalizations, and reduce associated healthcare costs. PMID- 26005018 TI - Evaluation of transcranial surgical decompression of the optic canal as a treatment option for traumatic optic neuropathy. AB - PURPOSE: Traumatic optic neuropathy (TON) is a serious complication of head trauma, with the incidence rate ranging from 0.5% to 5%. The two treatment options widely practiced for TON are: (i) high-dose corticosteroid therapy and (ii) surgical decompression. However, till date, there is no consensus on the treatment protocol. This study aimed to evaluate the therapeutic efficacy of transcranial decompression of optic canal in TON patients. METHODS: A total of 39 patients with visual loss resulting from TON between January 2005 and June 2013 were retrospectively reviewed for preoperative vision, preoperative image, visual evoked potential (VEP), surgical approach, postoperative visual acuity, complications, and follow-up results. RESULTS: All these patients underwent transcranial decompression of optic canal. During the three-month follow-up period, among the 39 patients, 21 showed an improvement in their eyesight, 6 recovered to standard logarithmic visual acuity chart "visible," 10 could count fingers, 2 could see hand movement, and 3 regained light sensation. CONCLUSION: Visual evoked potential could be used as an important preoperative and prognostic evaluation parameter for TON patients. Once TON was diagnosed, surgery is a promising therapeutic option, especially when a VEP wave is detected, irrespective of the HRCT scan findings. Operative time between trauma and operation is not necessary reference to assess the therapeutic effect of surgical decompression. The poor results of this procedure may be related to the severity of optic nerve injury. The patient's age is an important factor affecting the surgical outcomes. PMID- 26005019 TI - Thrombolytic treatment decreases glutamate/GABA ratio in serum during acute ischaemic stroke: a pilot study. AB - There is no information about possible effect of recombinant tissue plasminogen activator (rtPA) therapy on excitotoxic/neuroprotective amino acids during acute phase of ischaemic stroke (IS). Our purpose was to evaluate iv thrombolytic treatment on glutamate (Glu) and gamma-aminobutyric acid (GABA) serum levels during acute IS. Eleven thrombolytic (rtPA group) and 12 non-thrombolytic (non rtPA group) patients with acute IS were enrolled. The serum samples were obtained at three time points for rtPA group (time point 0: first to fourth hour of stroke; time point 1: immediately after rtPA administration; time point 2: on days 5-7 from stroke onset). The remaining patients had blood collection at two time points: time point 1: 5(th)-10(th) hour of stroke and time point 2: on days 5-7 of stroke. Glutamate and GABA were determined by the automated ion-exchange chromatography using Amino Acids Analyser (AAA 400) by INGOS Corp., Praha, Czech Republic. The statistically significant elevation of GABA serum level was noticed directly after thrombolysis (time point 1) in comparison to the corresponding time point in non-rtPA group [0.016 (0.002-0.032) MUM/ml vs 0.001 (0.001-0.004) MUM/ml for rtPA vs non-rtPA groups, respectively, median (first to third quartile), P < 0.05]. At the same time point, the Glu/GABA ratio was significantly decreased in rtPA group (P < 0.05) suggesting the decrease of excitotoxicity biomarkers in the blood after thrombolysis. Considering the beneficial effect of GABA receptor agonists, the elevation of GABA by rtPA should bring an additional positive features of thrombolytic treatment. PMID- 26005020 TI - The Impact of Fluid Balance on the Detection, Classification and Outcome of Acute Kidney Injury After Cardiac Surgery. AB - OBJECTIVE: To assess whether or not a positive fluid balance masks acute kidney injury (AKI) and is associated with adverse outcomes after cardiac surgery. DESIGN: Retrospective analysis. SETTING: Tertiary university-affiliated metropolitan hospital: single center. PARTICIPANTS: Three thousand two hundred seven consecutive cardiac surgical patients admitted to the ICU from July 1, 2004 to June 30, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors used AKI Network criteria to classify AKI. They then adjusted creatinine levels for weight-corrected fluid balance and categorized patients into 3 groups: group A (No AKI); group B (AKI only after adjustment); group C (AKI before and after adjustment). No patients had "AKI" before but "No AKI" after adjustment. Among 2,171 patients with weight and baseline creatinine available, after adjusting for fluid balance, the proportion of patients classified with AKI increased from 25.3% to 37.2% (p<0.001). In patients with AKI only after adjustment (group B), ICU mortality approximated that of group C (1.9% v 3.1%, p = 0.35) but was almost 3 times greater than group A (1.9% v 0.7%, p = 0.04). For group B, use of renal replacement therapy also was greater than group A (4.3% v 1.5%, p = 0.004) but less than group C (4.3% v 14.4%, p<0.001). The same trend was found for ICU length of stay (p<=0.001) and other adverse outcomes. CONCLUSIONS: Patients with AKI diagnosed after correction for the effect of a positive fluid balance on serum creatinine concentration have more adverse outcomes than patients without AKI by conventional criteria, but fewer than patients with AKI by conventional criteria. PMID- 26005021 TI - Physiological and clinically attainable concentrations of 1,25-dihydroxyvitamin D3 suppress proliferation and extracellular matrix protein expression in mouse pancreatic stellate cells. AB - BACKGROUND/OBJECTIVES: Vitamin D is an antiproliferative and differentiation promoting secosteroid hormone with pleiotropic homeostatic functions in bone and extraskeletal tissues. Signaling of vitamin D is mediated via its ubiquitously expressed nuclear receptor, the vitamin D receptor (VDR). Pancreatic stellate cells have recently been identified as targets of vitamin D action. Our aim was to elucidate the effectiveness of the most potent endogenous vitamin D metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the proliferation and extracellular matrix (ECM) protein expression in pancreatic stellate cells (PSCs) using concentrations of the compound from the physiological and clinically attainable range in humans. METHODS: Culture-activated mouse PSCs were exposed to 1,25(OH)2D3 concentrations ranging from 0.1 nM to 10 nM for 7 days and subjected to colorimetric crystal violet assay for cell growth assessment and to Western blot and immunohistochemical analyses of VDR, fibronectin and collagen I using protein-specific antibodies. Immunohistochemical localization of VDR was performed on mouse pancreatic tissue and on a set of human specimens obtained at pancreatic surgery. RESULTS: A low basal level of VDR was detected in PSCs that was strongly induced in the presence of ligand. Cell growth was suppressed dose dependently by 1,25(OH)2D3, the mean percentages of inhibition ranging from 24% at the physiological 0.1 nM concentration to around 60% at 10 nM. Significant 48% and 40% reductions in fibronectin expression were seen at 0.5 nM and 1 nM 1,25(OH)2D3. A minor decrease in collagen I expression was detected at 5 nM. VDR was predominantly localized in the islets of Langerhans in mouse and human tissues. In the latter VDR was expressed also in the exocrine tissue showing individual variation in its cellular distribution. CONCLUSIONS: Mouse PSCs express VDR protein and are sensitive 1,25(OH)2D3 target cells with low levels of 1,25(OH)2D3 exerting antiproliferative and antifibrotic effects on activated PSCs in vitro. PMID- 26005022 TI - Synthesis and antiproliferative activity of alpha-branched alpha,beta-unsaturated ketones in human hematological and solid cancer cell lines. AB - A series of alpha-branched alpha,beta-unsaturated ketones were prepared via boron trifluoride etherate mediated reaction between arylalkynes and carboxaldehydes. The evaluation of the antiproliferative activity over hematological (NB4) and solid cancer (A549, MCF-7) cell lines provided a structure-activity relationship. 5-Parameter QSAR equations were built which were able to explain 80%-92% of the variance in activity. The resulting selective lead compound showed IC50 value 0.6 MUM against the hematological cell line and did not cause apoptosis, but blocked cell cycle in G0/G1. Moreover, it was demonstrated that this compound enhances and accelerates retinoic acid induced granulocytic differentiation. PMID- 26005023 TI - (+/-) cis-Bisamido epoxides: A novel series of potent FXIII-A inhibitors. AB - A novel class of potent FXIII-A inhibitors containing a (+/-) cis-bisamido epoxide pharmacophore is described. The compounds display highly potent inhibition of FXIII-A (IC50 = 5-500 nM) in an in vitro assay. In contrast to other types of previously described covalent transglutaminase inhibitors, the bis amido epoxides exhibited no measurable reactivity with glutathione, therefore possibly rendering this class of compounds suitable for future in vivo investigations. Additionally, the compounds show selective inhibition for FXIII-A against the cysteine protease, cathepsin S although they proved to have similar potency with a closely related transglutaminase, TGII, to that observed for FXIII A. PMID- 26005024 TI - Discovery of novel non-covalent inhibitors selective to the beta5-subunit of the human 20S proteasome. AB - A series of linear peptides (6a-6o) were designed based on the known non-covalent 20S proteasome inhibitors TMC-95A and compound 5 via a fragment-based approach. These compounds were synthesized and evaluated against the chymotrypsin-like activity of the human 20S proteasome. Three of them (6d, 6e and 6k) were potent inhibitors with IC50 values at the submicromolar level. These three compounds were selective to the beta5-subunit and showed no obvious inhibition against trypsin-like and caspase-like activities of the human 20S proteasome. Docking study of the most potent compound 6e revealed its key interactions with the beta5 subunit of the 20S proteasome. These findings have provided a new chemical template for non-covalent proteasome inhibitors, which is ready for further structural optimization to improve both potency and subunit selectivity. PMID- 26005025 TI - Discovery of 5-(2',4'-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis. AB - To improve the inhibitory potency of lead compound NDMC101 on RANKL-induced osteoclastogenesis, a series of new 5-(2',4'-difluorophenyl)-salicylanilide derivatives were synthesized and evaluated for osteoclast inhibition by using TRAP-staining assay. Among them, both of compounds 6d and 6i showed three-fold increase in osteoclast-inhibitory activities compared to NDMC101 at half inhibitory concentration. Further, the mechanistic study showed that 6d and 6i could suppress RANKL-induced osteoclastogenesis-related genes, such as NFATc1, c fos, TRAP, and cathepsin K. Their inhibitory activities were further confirmed by including specific inhibition of NF-kappaB and NFATc1 expression levels in nucleus. In addition, 6d and 6i also could significantly attenuate bone-resorbing activity of osteoclasts by performing pit formation assay. Thus, a new class of 5 (2',4'-difluorophenyl)-salicylanilide derivatives may be considered as essential lead structures for the further development of anti-resorptive agents. PMID- 26005026 TI - Synthesis, characterization, hypoglycemic and aldose reductase inhibition activity of arylsulfonylspiro[fluorene-9,5'-imidazolidine]-2',4'-diones. AB - A series of 3-arylsulfonylspiroimidazolidine-2,4-diones (2a-g) and their corresponding rearranged products, 1-arylsulfonylspiroimidazolidine-2,4-diones (3a-g) were synthesized and evaluated for antidiabetic and aldose reductase inhibition activity. Three of the compounds (2b, 2c and 3c) were found more potent in-vivo hypoglycemic agents than the commercial drug glibenclamide. The free energy of binding (DeltaG) values showed that the compounds are active against aldose reductase and aldehyde reductase enzymes, which was also estimated using molecular mechanics Poisson-Boltzmann surface area method. Of the tested compounds, 2b was found to be the most potent in-vitro selective inhibitor of ALR2 possessing an IC50 value of 0.89 MUm. Structure activity relationship and molecular docking revealed the importance of substitution features of aryl group of aryllsulfonylimidazolidine-2,4-dione scaffold. It was observed that the substitution with a halogen at para position of the aryl group had a remarkable effect on ALR2 inhibition potency. PMID- 26005027 TI - HIV-1 antiviral behavior of anionic PPI metallo-dendrimers with EDA core. AB - The development of novel strategies to prevent HIV-1 infection is of outstanding relevance. Metal complexes of Cu(2+), Ni(2+), Co(2+) and Zn(2+) derived from sulfonated and carboxylated poly(propylene imine) dendrimers with ethylenediamine core were evaluated as tunable antiviral agents against HIV-1. After demonstrating their biocompatibility, specific trends in the antiviral properties were found, related to both the dendritic scaffold (peripheral group, generation) and the bound metal ions (sort, amount). In HEC-1A and VK-2 cell lines, as model of the first barrier against HIV-1 infection, a high preventive inhibitory action was found, which also avoided virus internalization inside cells and inhibited both CCR5 and CXCR4 HIV-1 strains. In peripheral blood mononuclear cells (PBMC), as model of the second barrier, a dual preventive and therapeutic behavior was observed. A rational design of such metallodendrimers opens new avenues for the production of versatile and efficient treatments against HIV-1 infection. PMID- 26005028 TI - Effects of alkylation and immunopotentiation against Ehrlich ascites murine carcinoma in vivo using novel tetra-O-acetate haloacetamido carbohydrate analogs. AB - Tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) are novel alkylating agents that appear to have alkylating activity at the plasma membrane, specificity against neoplastic cells, and may potentiate host leukocyte influx. This study sought to characterize the chemical attributes and in vivo activity of Tet-OAHCs. Four Tet-OAHCs were assessed for their partition coefficient and alkylating activity to determine cellular environments where adduct formation would be favorable. In vitro, IC50 values of all four Tet-OAHCs were determined against Ehrlich ascites murine carcinoma, as well as two leukemias (U937 human monocytic leukemia and L1210 murine lymphoid leukemia) to assess their cytotoxicity in multiple neoplastic cell lines. In vivo, B6D2F1 and CD2F1 mice were challenged i.p. with Ehrlich ascites carcinoma prior to, or after being treated with a single dose of one of the analogs. Finally, a quantitative comparison of host leukocyte influx between Tet-OAHCs and other alkylating agents was performed to confirm previous in vivo observations that the tetra-O-acetate carbohydrate moiety is important for inducing a host leukocyte response in murine models. The results can be summarized as follows: 1) Tet-OAHCs appear to demonstrate high alkylating activity in amphiphilic environments. 2) All four congeners have comparable in vitro cytotoxicities against the neoplastic cell lines examined. 3) The analogs demonstrate marked in vivo activity in both B6D2F1 and CD2F1 mice challenged with a lethal dose of Ehrlich ascites carcinoma, and frequently produce long term survival at 60 days, which is not observed in simple halo derivatives or two currently approved antineoplastic agents (daunorubicin and mechlorethamine). These effects are observed when the agents are administered either before or after the tumor challenge. 4) The carbohydrate moiety appears to be important for potentiating host leukocyte influx, as Tet-OAHCs, but not other alkylating agents demonstrated such activity in vivo. PMID- 26005029 TI - Exact solutions for the selection-mutation equilibrium in the Crow-Kimura evolutionary model. AB - We reformulate the eigenvalue problem for the selection-mutation equilibrium distribution in the case of a haploid asexually reproduced population in the form of an equation for an unknown probability generating function of this distribution. The special form of this equation in the infinite sequence limit allows us to obtain analytically the steady state distributions for a number of particular cases of the fitness landscape. The general approach is illustrated by examples; theoretical findings are compared with numerical calculations. PMID- 26005031 TI - Technical refinement of hepatic vein reconstruction in living donor liver transplantation using left liver graft. AB - BACKGROUND: In adult living donor liver transplantation (LDLT), left liver graft is generally safer for the donor. The aim of this study was to demonstrate a technical refinement for achieving sufficient outflow using left liver graft. MATERIAL AND METHODS: Forty-seven cases using left liver were divided into 2 groups according to the procedures of hepatic vein reconstruction: the side-clamp group (21 cases), and the cross-clamp group (26 cases), to sufficiently enlarge the diameter of the hepatic vein with excising the inferior vena cava (IVC). RESULTS: The liver function tests at 7 days after LDLT were not significantly different between the 2 groups, but the median amount of ascites was significantly greater in the side-clamp group (1250 ml; range, 484-3690) than in the cross-clamp group (582 ml; 190-2785). When we selected the patients with the ratio of graft weight to recipient standard liver volume less than 30%, the 1 year patient survival after transplantation was significantly better in the cross clamp group than in the side-clamp group (90% in cross-clamp group vs. 71% in side-clamp group, P<0.05). CONCLUSIONS: In conclusion, hepatic vein reconstruction with cross-clamping of the IVC can secure a sufficient outflow in LDLT using left liver graft. PMID- 26005033 TI - Unconventional implant placement. V: Implant placement through impacted teeth; results from 10 cases with an 8- to 1-year follow-up. AB - The aim of this paper is to document additional cases to an unconventional protocol published in 2009. In 9 patients, sites rendered edentulous by the presence of an impacted maxillary canine were treated with 12 implants placed through the impacted canines. In another patient, 3 implants were inserted in the mandible to rehabilitate a failing bridge. Implants were placed encroaching upon either the root or the crown. No postoperative pain was reported. Healing was uneventful in all but one patient; the latter underwent soft tissue infection 2 weeks after implant placement and was successfully treated. All implants were restored; no implant failed during the 1- to 8-year follow-up. Before implementing this protocol on a routine basis, more implants and a longer follow up are required. However, it opens intriguing treatment possibilities. It also suggests that there is still room for shifting a well-anchored paradigm in dental implantology. PMID- 26005034 TI - Contributors to fatigue in patients receiving mechanical ventilatory support: A descriptive correlational study. AB - OBJECTIVES: To describe levels of fatigue and explore clinical factors that might contribute to fatigue in critically ill patients receiving mechanical ventilation. RESEARCH METHODOLOGY/DESIGN: Descriptive, correlational design. Sample was a sub-set of patients enrolled in a randomised clinical trial testing patient-directed music for anxiety self-management. Clinical factors included age, gender, length of ICU stay, length of ventilatory support, illness severity (APACHE III), and sedative exposure (sedation intensity and frequency). Descriptive statistics and mixed models were used to address the study objectives. SETTING: Medical and surgical intensive care units in the Midwestern United States. MAIN OUTCOME MEASURES: Fatigue was measured daily via a 100-mm Visual Analogue Scale, up to 25 days. RESULTS: A sample of 80 patients (50% female) receiving ventilatory support for a median 7.9 days (range 1-46) with a mean age of 61.2 years (SD 14.8) provided daily fatigue ratings. ICU admission APACHE III was 61.5 (SD 19.8). Baseline mean fatigue ratings were 60.7 (SD 27.9), with fluctuations over time indicating a general trend upward. Mixed models analysis implicated illness severity (beta(se(beta))=.27(.12)) and sedation frequency (beta(se(beta))=1.2(.52)) as significant contributors to fatigue ratings. CONCLUSION: Illness severity and more frequent sedative administration were related to higher fatigue ratings in these mechanically ventilated patients. PMID- 26005035 TI - Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation. AB - Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels mediate pacemaker currents in the atrium. The microRNA (miR) families miR-1 and miR-133 regulate the expression of multiple genes involved in myocardial function, including HCN channels. It was hypothesized that age-dependent changes in HCN2, HCN4, miR-1 and miR-133 expression may contribute to age-associated atrial fibrillation, and therefore the correlation between expression levels, among adult (<=65 years) and aged patients (>=65 years), and sinus rhythm was determined. Right atrial appendage samples were collected from 60 patients undergoing coronary artery bypass grafting. Reverse transcription-quantitative polymerase chain reaction (PCR) and western blot analyses were performed in order to determine target RNA and protein expression levels. Compared with aged patients with sinus rhythm, aged patients with atrial fibrillation exhibited significantly higher HCN2 and HCN4 channel mRNA and protein expression levels (P<0.05), but significantly lower expression levels of miR-1 and miR-133 (P<0.05). In addition, aged patients with sinus rhythm exhibited significantly higher expression levels of HCN2 and HCN4 channel mRNA and protein (P<0.05), but significantly lower expression levels of miR-1 and -133 (P<0.05), compared with those of adult patients with sinus rhythm. Expression levels of HCN2 and HCN4 increased with age, and a greater increase was identified in patients with age associated atrial fibrillation compared with that in those with aged sinus rhythm. These electrophysiological changes may contribute to the induction of ectopic premature beats that trigger atrial fibrillation. PMID- 26005036 TI - Calcium carbonate nanoparticles as cancer drug delivery system. AB - INTRODUCTION: Calcium carbonate (CaCO3) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO3 nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO3 matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration. AREAS COVERED: Development of drug delivery carriers using CaCO3 nanoparticles has been reviewed. The current state of CaCO3 nanoparticles as cancer drug delivery systems with focus on their special properties like pH sensitivity and biodegradability has also been evaluated. EXPERT OPINION: According to our review, CaCO3 nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future. PMID- 26005037 TI - Beyond viral response: A prospective evaluation of a community-based, multi disciplinary, peer-driven model of HCV treatment and support. AB - BACKGROUND: Although the majority of new cases of hepatitis C (HCV) occur among people who inject drugs, very few receive treatment. In response, low-barrier, multidisciplinary models of HCV treatment have emerged in recent years to serve illicit drug users and have demonstrated comparable outcomes to the care delivered in tertiary care settings. However, few studies have measured comprehensive outcomes of these models. METHODS: The Toronto Community Hep C Program (TCHCP) is a community-based partnership between three primary health care centres with integrated specialist support. Program clients were interviewed using standardized questionnaires at three time points (baseline, post completion of HCV support group, and one year post group completion). The primary outcome of this study was self-reported overall health. Secondary outcomes included mental health, substance use, housing and income stability, and access to health care. RESULTS: TCHCP clients reported high rates of poverty, histories of trauma and incarceration. Physical and mental health co-morbidities were also very common; 78% reported having at least one chronic medical problem in addition to HCV and 41% had a lifetime history of hospitalization for mental health reasons. Participation in the program improved access to HCV care. Prior to joining the TCHCP, only 15% had been assessed by a HCV specialist. By the end of the study period this had increased significantly to 54%. Self-reported overall health did not improve during the study period. Housing status and income showed significant improvement. The proportion of participants with stable housing increased from 54% to 76% during the study period (p=0.0017) and the proportion of patients receiving income from provincial disability benefits also increased significantly (55% vs 75%, p=0.0216). CONCLUSION: This study demonstrated that a multi disciplinary, community-based model of HCV treatment improves participant's lives in ways that extend beyond hepatitis C. PMID- 26005038 TI - Hepatitis C Virus seroconversion among persons who inject drugs in relation to primary care physician visiting: The potential role of primary healthcare in a combined approach to Hepatitis C prevention. AB - BACKGROUND: Meaningful reductions in Hepatitis C Virus (HCV) transmission rates among persons who inject drugs (PWID) require a comprehensive prevention approach, including access to harm reduction measures and to healthcare-related interventions, such as HCV screening, testing and antiviral treatment. Little is known, however, about the role of visiting a primary care physician (PCP) in relation to HCV infection risk among PWID, when integrated within a combined prevention approach. This study assessed the association between PCP visiting and HCV seroconversion among PWID attending needle exchange programs (NEP). METHODS: A prospective cohort study, HEPCO, was conducted among active PWID in Montreal (2004-2013). Interviews scheduled at 3- or 6-month intervals included completion of an interviewer-administered questionnaire, and collection of blood samples for HCV antibody testing. HCV-seronegative participants who reported NEP attendance at baseline and had at least one follow-up visit were eligible for this study. HCV incidence was calculated using the person-time method. Time-varying Cox regression modeling was conducted to evaluate the relationship between self reported recent PCP visiting and HCV incidence. RESULTS: At baseline assessment, of 226 participants (80.5% male; median age: 30.6 years), 37.2% reported having recently visited a PCP. During 449.6 person-years of follow-up, 79 participants seroconverted to HCV [incidence rate: 17.6 per 100 person-years, 95% confidence interval (CI): 14.0-21.8]. Covariate-adjusted analyses indicated that visiting a PCP was associated with a lower risk of HCV infection [Adjusted Hazard Ratio: 0.54, 95% CI: 0.31-0.93]. Other independent predictors of HCV infection included unstable housing, cocaine injection and prescription opioid injection. CONCLUSION: Among PWID attending NEP, visiting a PCP was associated with a lower risk of HCV infection. Yet, only a minority of participants reported PCP visiting. Efforts to intensify engagement with PCP among PWID could potentially contribute to lower HCV transmission when integrated within a combined approach to prevention. PMID- 26005039 TI - Drugs and discretionary power in prisons: The officer's perspective. AB - BACKGROUND: Drugs play an increasing role in contemporary prison life. Prisoners' drug use, drug smuggling and drug selling have also had a growing impact on the work routines and practices of prison officers. This has led to critiques that prison staff have become 'too lenient' regarding drug use. METHODS: Based on observational data, qualitative interviews and survey data, this study examines the role of drugs in the way Danish prison officers exercise power. RESULTS: Two forms of power are analysed: institutional power, by which the officers can sanction or reward inmates in everyday prison life, and personal power, by which the officers' personal authority and skills can reduce the more intrusive aspects of prison control. These forms of power are applied by officers' use of discretion in order to maintain what they consider to be adequate levels of peace and order in the prison wings. It is shown that officers are highly ambivalent towards the presence of drugs in prisons. On the one hand, they support the stricter drug policies implemented over the past two decades. On the other hand, they are aware that drug use can have a positive function in the everyday running of the prison. Officers' acceptance of inmates' drug use (mainly cannabis), therefore, is not necessarily a sign of leniency but one way in which prison officers exercise their power in prison settings. CONCLUSIONS: It is concluded that discretionary power is still very central to the officers' work. This conclusion contradicts recent arguments that prison officers' agency is being threatened or restricted by 'neoliberal' management reforms. The prison officers' discretion and informal power is the key to understanding their acceptance of inmates' drug use. PMID- 26005040 TI - Aberrant activity in retinal degeneration impairs central visual processing and relies on Cx36-containing gap junctions. AB - In retinal degenerative disease (RD), the diminished light signal from dying photoreceptors has been considered the sole cause of visual impairment. Recent studies show a 10-fold increase in spontaneous activity in the RD network, challenging this paradigm. This aberrant activity forms a new barrier for the light signal, and not only exacerbates the loss of vision, but also may stand in the way of visual restoration. This activity originates in AII amacrine cells and relies on excessive activation of gap junctions. However, it remains unclear whether aberrant activity affects central visual processing and what mechanisms lead to this excessive activation of gap junctions. By combining genetic manipulation with electrophysiological recordings of light-induced activity in both living mice and isolated wholemount retina, we demonstrate that aberrant activity extends along retinotectal projections to alter activity in higher brain centers. Next, to selectively eliminate Cx36-containing gap junctions, which are the primary type expressed by AII amacrine cells, we crossed rd10 mice, a slow degenerating model of RD, with Cx36 knockout mice. We found that retinal aberrant activity was reduced in the rd10/Cx36KO mice compared to rd10 controls, a direct evidence for involvement of Cx36-containing gap junctions in generating aberrant activity in RD. These data provide an essential support for future experiments to determine if selectively targeting these gap junctions could be a valid strategy for reducing aberrant activity and restoring light responses in RD. PMID- 26005041 TI - Illicit drug use among rave attendees in a nationally representative sample of US high school seniors. AB - BACKGROUND: The popularity of electronic dance music and rave parties such as dance festivals has increased in recent years. Targeted samples of party-goers suggest high rates of drug use among attendees, but few nationally representative studies have examined these associations. METHODS: We examined sociodemographic correlates of rave attendance and relationships between rave attendance and recent (12-month) use of various drugs in a representative sample of US high school seniors (modal age: 18) from the Monitoring the Future study (2011-2013; Weighted N=7373). RESULTS: One out of five students (19.8%) reported ever attending a rave, and 7.7% reported attending at least monthly. Females and highly religious students were less likely to attend raves, and Hispanics, students residing in cities, students with higher income and those who go out for fun multiple times per week were more likely to attend. Rave attendees were more likely than non-attendees to report use of an illicit drug other than marijuana (35.5% vs. 15.6%, p<0.0001). Attendees were more likely to report use of each of the 18 drugs assessed, and attendees were more likely to report more frequent use (>=6 times) of each drug (ps<0.0001). Controlling for sociodemographic covariates, frequent attendance (monthly or more often) was associated with higher odds of use of each drug (ps<0.0001). Frequent attendees were at highest risk for use of "club drugs." DISCUSSION: Findings from this study can help inform prevention and harm reduction among rave attendees at greatest risk for drug use. PMID- 26005042 TI - Anabolic steroids and cardiovascular risk: A national population-based cohort study. AB - BACKGROUND: Non-therapeutic use of anabolic androgenic steroids (AAS) has been associated with various adverse effects; one of the most serious being direct cardiovascular effects with unknown long-term consequences. Therefore, large studies of the association between AAS and cardiovascular outcomes are warranted. We investigated cardiovascular morbidity and mortality in individuals who tested positive for AAS. METHODS AND RESULTS: Between 2002 and 2009, a total of 2013 men were enrolled in a cohort on the date of their first AAS test. Mortality and morbidity after cohort entry was retrieved from national registries. Of the 2013 individuals, 409 (20%) tested positive for AAS. These men had twice the cardiovascular morbidity and mortality rate as those with negative tests (adjusted hazard ratio (aHR) 2.0; 95% confidence interval (CI) 1.2-3.3). Compared to the Swedish population, all tested men had an increased risk of premature death from all causes (standardized mortality ratio for AAS-positive: 19.3, 95% CI 12.4-30.0; for AAS-negative: 8.3, 95% CI 6.1-11.0). CONCLUSION: Non therapeutic exposure to AAS appears to be an independent risk factor for cardiovascular morbidity and premature death. PMID- 26005044 TI - Hollywood's guidance for improving the quality of plastic surgery articles. PMID- 26005043 TI - Measurement of multiple nicotine dependence domains among cigarette, non cigarette and poly-tobacco users: Insights from item response theory. AB - BACKGROUND: Nicotine dependence (ND) is a key construct that organizes physiological and behavioral symptoms associated with persistent nicotine intake. Measurement of ND has focused primarily on cigarette smokers. Thus, validation of brief instruments that apply to a broad spectrum of tobacco product users is needed. METHODS: We examined multiple domains of ND in a longitudinal national study of the United States population, the United States National Epidemiological Survey of Alcohol and Related Conditions (NESARC). We used methods based in item response theory to identify and validate increasingly brief measures of ND that included symptoms to assess ND similarly among cigarette, cigar, smokeless, and poly tobacco users. RESULTS: Confirmatory factor analytic models supported a single, primary dimension underlying symptoms of ND across tobacco use groups. Differential Item Functioning (DIF) analysis generated little support for systematic differences in response to symptoms of ND across tobacco use groups. We established significant concurrent and predictive validity of brief 3- and 5 symptom indices for measuring ND. CONCLUSIONS: Measuring ND across tobacco use groups with a common set of symptoms facilitates evaluation of tobacco use in an evolving marketplace of tobacco and nicotine products. PMID- 26005045 TI - Factors associated with post-stroke depression and emotional incontinence: lesion location and coping styles. AB - Post-stroke depression (PSD) and post-stroke emotional incontinence (PSEI) have attracted worldwide interest in recent years. These emotional disturbances have a negative impact on the rehabilitation process and the associated worse outcome. Consequently, defining the risk factors for development of PSD and PSEI is important. In this study, we evaluated 368 consecutive patients with acute ischemic stroke at admission and at three months later. PSD was evaluated by using the Beck Depression Inventory, and PSEI was evaluated using Kim's criteria. The Social Support Rating Scale and Medical Coping Modes Questionnaire were also used as measurement tools. Multivariate analyses showed that anterior cortex infarction was associated with PSEI three months after stroke occurrence. The appearance of PSD was not related to lesion location. Both motor and sensory dysfunctions was independently associated with PSD at admission, whereas low degree of social utilization was the independent factor associated with PSD 3 months after stroke. Acceptance-resignation is related to PSD and PSEI both at admission and 3 months after stroke. Avoidance was the independent factor related to PSD at 3 months after stroke onset. PMID- 26005046 TI - Quantitative assessment of brain shifting in the late phase postevacuation in unilateral and bilateral chronic subdural hematomas. AB - AIM OF THE STUDY: Recurrence is more common in bilateral chronic subdural hematomas (CSDHs) than in unilateral. Our aim was to quantitatively compare the late phase of brain shifting postevacuation in unilateral and bilateral CSDHs. MATERIALS AND METHODS: We reviewed computed tomography (CT) scans and medical records of consecutive patients with CSDHs who underwent burr hole drainage. CT scan images (preoperative and postoperative days [PODs] 30 and 60) were imported to Adobe Photoshop, and temporal and spatial changes in brain shifting between PODs 30 and 60, and also the subdural space on POD 60, were analyzed. RESULTS: The bilateral group exhibited a significantly greater late phase of brain shifting than the unilateral group between PODs 30 and 60 (P < 0.001). The median late phase of brain shifting of the bilateral group was 8.9 mm (interquartile range [IQR]: 8.3-9.0 mm) between PODs 30 and 60, while that of the unilateral group was 1.8 mm (IQR: 1.3-2.5 mm). CONCLUSIONS: The postevacuation late phase of brain shifting is statistically greater in bilateral CSDHs than in unilateral CSDHs, which might facilitate bridging vein tearing and consequent rebleeding. This may be one factor accounting for the higher recurrence rate of bilateral CSDHs. PMID- 26005047 TI - In vitro cytotoxcity and interaction of new steroidal oxadiazinanones with calf thymus DNA using molecular docking, gel electrophoresis and spectroscopic techniques. AB - Herein we report synthesis of new steroidal oxadiazinanones from steroidal ketones. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were carried out by UV-vis, fluorescence spectroscopy and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 1.8*10(4) M(-1), 2.2*10(4) M(-1) and 2.6*10(4) M(-1), respectively, indicating the higher binding affinity of compound 6 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compound 6 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322 and it seems to follow the mechanistic pathway involving generation of hydroxyl radicals that are responsible for initiating DNA strand scission. Molecular simulations suggest that compounds binds through minor groove of DNA. MTT assay depicted promising anticancer activity of compound 5 and 6 particularly against HL-60 and MCF-7. The apoptotic degradation of DNA was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). The results revealed that compound 6 has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations. PMID- 26005048 TI - Inflammasomes and human autoimmunity: A comprehensive review. AB - Inflammasomes are multi-protein complexes composed of a NOD-like receptor (NLR)/an AIM-like receptor (ALR), the adapter molecule apoptosis-associated speck like protein that contains a CARD (ASC), and caspase-1. Active caspase-1 cleaves pro-IL-1beta and pro-IL-18 to IL-1beta and IL-18, resulting in inflammation. Genetic mutations in inflammasomes were first recognized to result in autoinflammatory diseases, which are characterized by the absence of both autoantibodies and autoreactive-T/B cells. However, there is increasing attention being placed on genetic polymorphisms that are involved in the components of inflammasomes, and these have implications for innate immunity and the natural history of autoimmune diseases. For example, while the NOD-like receptor family, pyrin domain containing 1 (NLRP1) haplotypes contributes to susceptibility to developing vitiligo; there are other single nucleotide polymorphisms (SNPs) that alters the susceptibility and severity of rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Indeed, there are multiple factors that contribute to lowering the threshold of immunity and inflammasomes play a key role in this threshold. For example, IL-1beta and IL-18 further perpetuate Th17 responses and endothelial cell damage, which potentiate a number of autoimmune diseases, including synovitis in RA, cardiovascular disease, and systemic lupus erythematosus (SLE). There is also increasing data on the role of innate immunity in experimental autoimmune encephalomyelitis (EAE), in lupus nephritis, and in a variety of autoimmune pathologies in which activation of the innate immune system is the driver for the adaptive system. Indeed, it is likely that the chronic pathology of autoimmunity is mediated in part by otherwise innocent bystander cells, augmented by inflammasomes. PMID- 26005049 TI - The molecular basis for development of proinflammatory autoantibodies to progranulin. AB - Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCbeta1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the conversion of PGRN, and is strongly associated with the occurrence of neutralizing, proinflammatory PGRN antibodies, indicating immunogenicity of this alternative secondary modification. PMID- 26005050 TI - Renal involvement in lupus is characterized by unique DNA methylation changes in naive CD4+ T cells. AB - Systemic lupus erythematosus is a multi-system disease characterized by wide spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naive CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 * 10(-6)). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus. PMID- 26005052 TI - Hemostatic control of inferior vena cava with tape traction maneuver in the presence of bulky metastatic paraaortic lymph nodes. PMID- 26005051 TI - Overexpression of caudal-related homeobox transcription factor 2 inhibits the growth of transplanted colorectal tumors in nude mice. AB - Caudal-related homeobox transcription factor 2 (CDX2) is a transcription factor, which is specifically expressed in the adult intestine. It is essential for the development and homeostasis of the intestinal epithelium and its functions as a tumor suppressor have been demonstrated in the adult colon. The present study aimed to examine the inhibitory effects of the overexpression of CDX2 on subcutaneously-transplanted tumors, derived from LoVo colon cancer cells, in nude mice, and to provide experimental evidence for the biotherapy of colon cancer. A pEGFP-C1-CDX2 eukaryotic expression vector was transfected into the LoVo cells via lipofection, and LoVo cells stably-expressing CDX2 (pEGFP-C1-CDX2 cells) were obtained using G418 selection. A nude mouse subcutaneously-transplanted tumor model was established by inoculating the nude mice with the pEGFP-C1-CDX2 cells, and the effects of overexpression of CDX2 on transplanted tumor growth in the LoVo cells were observed. Western blotting results demonstrated that the protein expression of CDX2 in the LoVo cells was higher in the pEGFP-C1-CDX2 cell group, compared with that in the pEGFP-C1 cell group and the untreated cell group. At 20 days post-inoculation with either pEGFP-C1-CDX2 or pEGFP-C1, the transplanted tumor masses were significantly lower in the pEGFP-C1-CDX2 group, compared with those in the pEGFP-C1 and untreated groups. Immunohistochemistry revealed that the expression levels of CDX2 and matrix metalloproteinase-2 (MMP-2) were detected in each group, and the protein expression of CDX2 was increased in the tumor tissues from the nude mice in the pEGFP-C1-CDX2 group. However the expression of MMP-2 was downregulated in the tumor tissues of the nude mice in the pEGFP-C1-CDX2 group. Taken together, these data suggested that pEGFP-C1-CDX2 cells exhibited suppressed tumor growth in vivo. Overexpression of CDX2 was observed in transplanted tumors in the pEGFP-C1-CDX2 group, and the gene expression of MMP-2 was reduced. These results indicate that CDX2 inhibited the growth of colorectal tumor cells, possibly by downregulating the gene expression. PMID- 26005053 TI - Epidemiology in ovarian carcinoma: Lessons from autopsy. AB - OBJECTIVE: We challenge epidemiologic knowledge regarding ovarian carcinoma (OC) by bridging the gap between clinical and autopsy data. METHODS: Autopsy reports, histological slides and clinical files from 660 patients in whom OC was diagnosed from 1975-2005 were studied (autopsy cohort, n=233; Clinical Cancer Registry from the local gyneco-oncologic center, n=427). RESULTS: Out of the autopsy cohort, we identified four distinct subgroups of patients: 1) OC was diagnosed before autopsy, n=156 (67.0%). 2) OC was an incidental finding, n=16 (6.8%). 3) The ovarian tumors were not primary OC but rather metastases from other primary tumors; this revised diagnosis was first made by using current histopathological knowledge/techniques, n=24 (10.3%). 4) Death was directly due to OC in its final stage and OC was first diagnosed by autopsy, n=37 (15.9%); when these cases were added to the Clinical Cancer Registry to an adjusted OC incidence model, the autopsy cases comprised 8.8% of the adjusted cohort and almost doubled the percentage of oldest patients (>=80 years at diagnosis) from 4.9% to 9.3% (p=0.013). CONCLUSIONS: Epidemiological data from the 1970s-1990s may overestimate true incidence because up to 10% of carcinomas in the ovary were not properly classified. Patients who were first diagnosed with OC by autopsy comprise a distinct subgroup. These are patients who have not been seen by specialized oncologists and thus play no role in their perception of the disease. Nevertheless, these cases have impact on prevalence and incidence data of OC and in an era of reduced autopsy rates will probably be overlooked. PMID- 26005055 TI - Comparison of novice and full-licenced driver common crash types in New South Wales, Australia, 2001-2011. AB - OBJECTIVE: To examine the circumstances of passenger vehicle crashes for novice licenced drivers aged 17-25 years and to compare the crash circumstances of the most common crash types for novices to a sample of full-licence drivers aged 40 49 years. METHOD: A retrospective analysis was conducted of passenger vehicle crashes involving novice and full-licenced drivers during 1 January 2001 to 31 December 2011 in New South Wales (NSW), Australia. RESULTS: There were 4113 injurious crashes of novice drivers. Almost half the novice driver crashes involved a single vehicle. Vehicle speed (33.2%), fatigue (15.6%) and alcohol (12.6%) were identified risk factors in novice driver crashes. Correspondence analysis for 4 common crash types for novice drivers revealed that the crash characteristics between novice and full-licenced drivers were similar. CONCLUSIONS: Similarities exist between novice driver and full-licenced driver crash risk for common crash types. Preventive strategies aimed at crash risk reduction for novice drivers may also benefit all drivers. PMID- 26005054 TI - Differential cytotoxicity of long-chain bases for human oral gingival epithelial keratinocytes, oral fibroblasts, and dendritic cells. AB - Long-chain bases are present in the oral cavity. Previously we determined that sphingosine, dihydrosphingosine, and phytosphingosine have potent antimicrobial activity against oral pathogens. Here, we determined the cytotoxicities of long chain bases for oral cells, an important step in considering their potential as antimicrobial agents for oral infections. This information would clearly help in establishing prophylactic or therapeutic doses. To assess this, human oral gingival epithelial (GE) keratinocytes, oral gingival fibroblasts (GF), and dendritic cells (DC) were exposed to 10.0-640.0 MUM long-chain bases and glycerol monolaurate (GML). The effects of long-chain bases on cell metabolism (conversion of resazurin to resorufin), membrane permeability (uptake of propidium iodide or SYTOX-Green), release of cellular contents (LDH), and cell morphology (confocal microscopy) were all determined. GE keratinocytes were more resistant to long chain bases as compared to GF and DC, which were more susceptible. For DC, 0.2 10.0 MUM long-chain bases and GML were not cytotoxic; 40.0-80.0 MUM long-chain bases, but not GML, were cytotoxic; and 80.0 MUM long-chain bases induced cellular damage and death in less than 20 min. The LD50 of long-chain bases for GE keratinocytes, GF, and DC were considerably higher than their minimal inhibitory concentrations for oral pathogens, a finding important to pursuing their future potential in treating periodontal and oral infections. PMID- 26005056 TI - Lead Exposure in Different Organs of Mammals and Prevention by Curcumin Nanocurcumin: a Review. AB - Chronic lead exposure is related to many health diseases in mammals. Exposure to lead forms reactive oxygen species reducing body antioxidant enzymes inflicting injury to numerous macromolecules or cell necrosis. Recent studies have revealed oxidative stress as the vital mechanism for lead toxicity. Lead is found to be toxic to several organ systems such as hematopoietic, skeletal, renal, cardiac, hepatic, and reproductive systems and extremely toxic to the central nervous system (CNS). Curcumin, an active ingredient of the dietary spice, and nanocurcumin, a nanoform of curcumin, are found to decrease toxicity due to lead in various organ systems in mouse models. Higher bioavailability, chelating property, and retention time of nanocurcumin over bulk curcumin may pave the way to expand the utility of nanocurcumin to remove lead toxicity from various organ systems within humans. PMID- 26005057 TI - The evolution of IL-4 and IL-13 and their receptor subunits. AB - This review will outline what is known about the origins and evolution of type 2 cytokines and their receptors in vertebrates. It takes advantage of the recent advances made in gene identification from the many vertebrate genomes that have now been sequenced. It will also describe what functional studies have been performed to date, giving clues to the role of these molecules and signalling pathways in non-mammalian vertebrates. PMID- 26005058 TI - Perception of primary male sexual partners' characteristics and women's history of sexually transmissible infections in Ho Chi Minh City, Vietnam. AB - Background Evidence regarding whether male partners' characteristics can influence women's likelihood of getting sexually transmissible infections (STIs) is insufficient and inconsistent. Our study examined associations between women's perception of primary male partners' demographic and behavioural characteristics and women's history of bacterial STI diagnoses among 126 women at risk for STIs in Ho Chi Minh City, Vietnam. METHODS: All variables were obtained by women's self-report. Due to the excess zeroes of the number of bacterial STI diagnoses for women, we used Zero-Inflated Poisson regression to examine associations of interest. RESULTS: Among women who had one lifetime male partner (n=49), the partner's number of female sexual partners [prevalence ratio (PR)=4.63, 95%CI=1.44-14.88] and number of STI diagnoses (PR=27.32, 95%CI=1.56-477.70) were associated with the woman's number of bacterial STI diagnoses, after adjusting for women's education level. For women who had >1 lifetime male partner (n=77), a greater number of women's bacterial STI diagnoses was also associated with their partners' STI history (PR=9.12, 95% CI=2.44-34.11). CONCLUSIONS: An increased risk for STIs in women was associated with both individual characteristics and their primary male partner's behavioural risk factors. Therefore, primary male partners' risk factors should be included in STI risk assessments, treatment and interventions for women. PMID- 26005059 TI - Defining indications for selective chest radiography in the first 24 hours after cardiac surgery. AB - OBJECTIVE: In the intensive-care unit (ICU), chest radiographs (CXRs) are frequently obtained routinely for postoperative cardiac surgery patients, despite the fact that the efficacy of routine CXRs is known to be low. We investigated the efficacy and safety of CXRs performed after cardiac surgery for specified indications only. METHODS: In this observational cohort study, we prospectively included all patients who underwent conventional major cardiac surgery by median sternotomy in the year 2012. On-demand CXRs could be obtained during the first postoperative period for specified indications only. A routine control CXR was performed on the morning of the first postoperative day for all patients who had not undergone a CXR before that time. The diagnostic and therapeutic efficacy values were calculated for all CXRs. Differences were tested using Fisher's exact test or chi(2) analysis. RESULTS: A total of 1102 consecutive cardiac surgery patients were included in this study. The diagnostic efficacy of CXRs for major abnormalities was higher for the postoperative on-demand CXRs (n = 301; 27%) than for the routine CXRs taken the morning after surgery (n = 801; 73%) (6.6% vs 2.7%, P = .004). The therapeutic efficacy was higher for the on-demand CXRs, whereas the need for intervention after the next-morning, routine CXRs was limited to 5 patients (4.0% vs 0.6%, P < .001). None of these patients experienced a major adverse event. CONCLUSIONS: Defining clear indications for selective CXRs after cardiac surgery is effective and seems to be safe. This approach may significantly reduce the total number of CXRs performed, and will increase their efficacy. PMID- 26005060 TI - The impact of surgical strategy on survival after repair of type A aortic dissection. AB - OBJECTIVE: A diverse group of operative strategies are utilized for treatment of acute Stanford type A aortic dissection. We hypothesized that a surgical strategy to prevent cross-clamp injury or false lumen pressurization would be associated with reduced morbidity, mortality, persistent false lumen patency, and improved survival. This study was designed to determine the differences in outcomes between operative techniques. METHODS: Outcomes and postoperative imaging were compared in patients who underwent surgery for acute type A aortic dissection. Two groups were compared, based on operative strategy. The surgical strategy for group 1 consisted of no aortic cross-clamp use, use of deep hypothermic circulatory arrest, and use of only antegrade perfusion after aortic replacement. The surgical strategy for group 2 consisted of any other combination that lacked 1 of these 3 technical steps. RESULTS: Between January 1, 1996, and December 31, 2012, a total of 196 patients underwent surgery for acute type A aortic dissection. Operative mortality and postoperative morbidity were not statistically different between groups. Mean follow-up time was 3.95 (range: 0 15.4) years. Persistence of a false lumen was not statistically different between groups (P = .78). Overall survival was significantly better in group 1, versus group 2 (P = .0020). Multivariate Cox regression identified preoperative renal failure, chronic lung disease, greater number of packed red blood cells transfused, and being in group 2 as risk factors for poor long-term survival. CONCLUSIONS: The operative strategy of group 1 (no cross-clamp, use of DHCA and antegrade perfusion) was associated with a highly significant improvement in survival, despite a lack of statistical difference in the incidence of persistent false aortic lumen between groups. PMID- 26005061 TI - The process of dying: whose business is it anyway? Reflecting on 'Stealing on insensibly: end-of-life politics in the United States'. PMID- 26005062 TI - Platelets and physics: How platelets "feel" and respond to their mechanical microenvironment. AB - During clot formation, platelets are subjected to various different signals and cues as they dynamically interact with extracellular matrix proteins such as von Willebrand factor (vWF), fibrin(ogen) and collagen. While the downstream signaling of platelet-ligand interactions is well-characterized, biophysical cues, such as hydrodynamic forces and mechanical stiffness of the underlying substrate, also mediate these interactions and affect the binding kinetics of platelets to these proteins. Recent studies have observed that, similar to nucleated cells, platelets mechanosense their microenvironment and exhibit dynamic physiologic responses to biophysical cues. This review discusses how platelet mechanosensing is affected by the hydrodynamic forces that dictate vWF platelet interactions and fibrin polymerization and network formation. The similarities and differences in mechanosensing between platelets and nucleated cells and integrin-mediated platelet mechanosensing on both fibrin(ogen) and collagen are then reviewed. Further studies investigating how platelets interact with the mechanical microenvironment will improve our overall understanding of the hemostatic process. PMID- 26005063 TI - Interaction Forces and Aggregation Rates of Colloidal Latex Particles in the Presence of Monovalent Counterions. AB - Force profiles and aggregation rates involving positively and negatively charged polystyrene latex particles are investigated in monovalent electrolyte solutions, whereby the counterions are varied within the Hofmeister series. The force measurements are carried out with the colloidal probe technique, which is based on the atomic force microscope (AFM), while the aggregation rates are measured with time-resolved multiangle light scattering. The interaction force profiles cannot be described by classical DLVO theory, but an additional attractive short ranged force must be included. An exponential force profile with a decay length of about 0.5 nm is consistent with the measured forces. Furthermore, the Hamaker constants extracted from the measured force profiles are substantially smaller than the theoretical values calculated from dielectric spectra. The small surface roughness of the latex particles (below 1 nm) is probably responsible for this deviation. Based on the measured force profiles, the aggregation rates can be predicted without adjustable parameters. The measured absolute aggregation rates in the fast regime are somewhat lower than the calculated ones. The critical coagulation concentration (CCC) agrees well with the experiment, including the respective shifts of the CCC within the Hofmeister series. These shifts are particularly pronounced for the positively charged particles. However, the consideration of the additional attractive short-ranged force is essential to quantify these shifts correctly. In the slow regime, the calculated rates are substantially smaller than the experimental ones. This disagreement is probably related to surface charge heterogeneities. PMID- 26005064 TI - HOMA-IR Values are Associated With Glycemic Control in Japanese Subjects Without Diabetes or Obesity: The KOBE Study. AB - BACKGROUND: Several studies have reported that insulin resistance was a major risk factor for the onset of type 2 diabetes mellitus in individuals without diabetes or obesity. We aimed to clarify the association between insulin resistance and glycemic control in Japanese subjects without diabetes or obesity. METHODS: We conducted a community-based cross-sectional study including 1083 healthy subjects (323 men and 760 women) in an urban area. We performed multivariate regression analyses to estimate the association between the homeostasis model assessment of insulin resistance (HOMA-IR) values and markers of glycemic control, including glycated haemoglobin (HbA1c), 1,5-anhydroglucitol (1,5-AG), and fasting plasma glucose (FPG) levels, after adjustment for potential confounders. RESULTS: Compared with the lowest tertile of HOMA-IR values, the highest tertile was significantly associated with HbA1c and FPG levels after adjustment for potential confounders, both in men (HbA1c: beta = 1.83, P = 0.001; FPG: beta = 0.49, P < 0.001) and women (HbA1c: beta = 0.82, P = 0.008; FPG: beta = 0.39, P < 0.001). The highest tertile of HOMA-IR values was inversely associated with 1,5-AG levels compared with the lowest tertile (beta = -18.42, P = 0.009) only in men. CONCLUSIONS: HOMA-IR values were associated with markers of glycemic control in Japanese subjects without diabetes or obesity. Insulin resistance may influence glycemic control even in a lean, non-diabetic Asian population. PMID- 26005065 TI - Prevalence and Socio-Demographic Determinants of Overweight and Obesity in a Nigerian Population. AB - OBJECTIVE: This survey explored prevalence of overweight and obesity and their associations with socio-demographic variables in a Nigerian population. METHODS: This cross-sectional survey involved 1521 adults in Nnewi. Age, sex, educational and occupational status, and BMI were recorded. RESULTS: Prevalence of overweight was higher in males (32.3%; 95% CI, 29.5%-35.2%) than in females (29.8%; 95% CI, 26.8%-33.0%); the reverse was the case for prevalence of obesity (19.6%; 95% CI, 17.3%-22.2% in males and 36.0%; 95% CI, 32.8%-39.4% in females). Higher odds ratios (ORs) for overweight and obesity were observed in participants aged 41-60 years (OR 2.03; 95% CI, 1.57-2.61 for overweight and OR 4.29; 95% CI, 3.25-5.67 for obesity) and those >60 years (OR 1.72; 95% CI, 1.21-2.43 for overweight and OR 4.21; 95% CI, 2.86-6.19 for obesity) compared to those aged 18-40 years. Female sex was associated with higher ORs for overweight (OR 1.20; 95% CI, 0.96 1.51) and obesity (OR 2.21; 95% CI, 1.73-2.83). Participants with secondary education had marginally higher ORs for overweight (OR 1.15; 95% CI, 0.88-1.51) and obesity (OR 1.17; 95% CI, 0.86-1.59) than those with tertiary education, and so were those with primary education for obesity (OR 1.19; 95% CI, 0.74-1.89) but higher OR for overweight (OR 1.44; 95% CI, 0.98-2.13). Unskilled participants had about the same OR for overweight and obesity as professionals, and while skilled participants had about the same OR for overweight as professionals, their OR for obesity (OR 1.27; 95% CI, 0.67-2.43) was fairly higher than that for professionals. CONCLUSIONS: Prevalence of overweight is higher in males than in females, but the reverse is the case for prevalence of obesity. Older age and female sex are associated with increased risk of overweight and obesity, while working at a skilled occupation is associated with obesity, and tertiary educational attainment is associated with overweight. PMID- 26005066 TI - Socioeconomic Status and Overweight: A Population-Based Cross-Sectional Study of Japanese Children and Adolescents. AB - BACKGROUND: Socioeconomic status (SES) as a determinant of obesity has received scant attention in Japan. This study examined the association between SES and overweight among Japanese children and adolescents. METHODS: Cross-sectional analyses of a representative sample of Japanese children (6-11 years: n = 397) and adolescents (12-18 years: n = 397) were performed, with measured heights and weights from the 2010 National Health and Nutrition Examination Survey and the 2010 Comprehensive Survey of Living Conditions. Overweight, including obesity, was defined by International Obesity Task Force cut-offs. SES indicators included household income, equivalent household expenditure, parental educational attainment, and parental occupational class. RESULTS: Overweight prevalence was 12.3% in children and 9.1% in adolescents. Adolescents living in middle-income households were more likely to be overweight than those living in high-income households (OR 2.26, 95% CI, 1.01-5.67) after adjustment for age, sex, and parental weight status. Similarly, adolescents living in households with low expenditure levels were more likely to be overweight than those living in households with high expenditure levels (OR 3.40, 95% CI, 1.20-9.60). In contrast, no significant association was observed among children. CONCLUSIONS: Our results indicated that low household economic status was associated with being overweight, independent of parental weight status, among Japanese adolescents. PMID- 26005067 TI - Changes in Waist Circumference and the Incidence of Type 2 Diabetes in Community Dwelling Men and Women: The Suita Study. AB - BACKGROUNDS: The association between weight gain and the incidence of type 2 diabetes is well known. The aim of our study was to investigate the relationship between change in waist circumference (WC) and type 2 diabetes incidence. METHODS: The participants in the Suita Study, a population-based cohort study in an urban area of Japan, underwent a baseline survey between 1989 and 1994 (Exam 1) and were examined at follow-up every 2 years. We performed a 9.3-year cohort study of 946 men and 1327 women with no history of diabetes who underwent Exam 1 and Exam 2 (between 1997 and 1999). Participants were stratified by sex and median WC at Exam 1, and, in each stratum, participants were further classified into three categories by tertile of WC change per year between Exam 1 and Exam 2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for type 2 diabetes incidence were calculated by Cox proportional hazard models. The endpoints were first diagnosis of type 2 diabetes or March 2011. RESULTS: During follow-up, 287 participants developed type 2 diabetes. In both sexes with median WC or higher, participants in the highest tertile of WC change had a significantly higher risk of developing type 2 diabetes. Multivariable adjusted HRs were 1.84 (95% CI, 1.10 3.08) in men and 2.30 (95% CI, 1.31-4.04) in women. No significant association was observed among participants with WC below median. CONCLUSIONS: Preventing WC gain is important in preventing type 2 diabetes in the Japanese population, especially among individuals with a relatively high WC. PMID- 26005068 TI - Epidemiologic Study on Social Determinants of Health: What's Next? PMID- 26005069 TI - Quantification of biopharmaceuticals and biomarkers in complex biological matrices: a comparison of liquid chromatography coupled to tandem mass spectrometry and ligand binding assays. AB - The quantification of proteins (biopharmaceuticals or biomarkers) in complex biological samples such as blood plasma requires exquisite sensitivity and selectivity, as all biological matrices contain myriads of proteins that are all made of the same 20 proteinogenic amino acids, notwithstanding post-translational modifications. This review describes and compares the two main approaches, namely, ligand binding assays (LBAs) and liquid chromatography coupled to tandem mass spectrometry in the selected reaction monitoring (SRM) mode. While LBAs remain the most widely used approach, SRM assays are gaining interest due to their generally better analytical performance (precision and accuracy) and their capacity for multiplex analyses. This article focuses on the possible reasons for the discrepancies between results obtained by LBAs and SRM assays. PMID- 26005070 TI - Taxonomic assessment of Culicoides brunnicans, C. santonicus and C. vexans (Diptera: Ceratopogonidae) in France: Implications in systematics. AB - Culicoides brunnicans Edwards, 1939, Culicoides santonicus, Callot et al., 1966, and Culicoides vexans (Staeger, 1839) belong to the Vexans group of the subgenus Oecacta. These species had never been studied by molecular methods and their distribution in Western Europe overlapped. C. brunnicans and C. santonicus are two closely related species and their diagnoses are based on the wing pattern only. An integrative taxonomic approach was conducted on females of the Vexans group, Culicoides furens (the type species of the subgenus Oecacta), and Culicoides nubeculosus (as outgroup) using sequences of D1D2 rDNA domains, sequences of COI mtDNA, and wing morphometrics. Species of the Vexans group were discriminated by all traits, and were closely related in the phylogeny. Their taxonomic status and their relation to C. furens were re-evaluated. PMID- 26005071 TI - [Prevalence and associated factors of anger post stroke: a systematic review]. AB - INTRODUCTION: Stroke is one of the main causes of death and disability and has a high economic cost. Anger after stroke is common and worsens functionality and quality of life. The study of this comorbidity has been hampered by the lack of standardization in anger's evaluation. AIM: To show the current evidence of anger's prevalence and anger's associated factors after stroke. MATERIALS AND METHODS: Medline systematic review of original papers studying prevalence and associated factors of anger after stroke. RESULTS: Post-stroke anger has a high prevalence (15-57.2%). Most studies have found a lack of association between irritability and sex, age, type, size, laterality and severity of the stroke and functionality. Occasionally anger has been associated with frontal infarcts and aphasia. Data regarding the association between anger and motor deficits and cognitive impairment has been inconclusive while the association between anger and psychiatric history, post stroke emotional incontinence and post stroke depression has been widely replicated. Environmental factors have been difficult to study but may be relevant. CONCLUSION: There is a high prevalence of anger post stroke. Psychiatric factors have been associated to it, while other associations are less conclusive. To improve anger knowledge and management, it would be necessary to improve its definition and assessment. PMID- 26005072 TI - [Spinal cord injury in patients over 65 years of age]. AB - INTRODUCTION: Physically active population over 65 years old is increasing, they are at risk of falls and spinal cord injury in a range of age with significant presence of chronic pathology. AIM: To review the incidence, type of injury, associated complications and functional recovey of spinal cord injury in patients over 65 years. PATIENTS AND METHODS: Retrospective descriptive study about patients over 65 years admitted in Hospital Nacional de Paraplejicos with spinal cord injury from January 2010 to December 2011. Demographic and lesion data, complications during admission and fuctional recovery measured with SCIM III (Spinal Cord Independence Measure) and WISCI II scales (Walking Index Spinal Cord Injury) were reviewed. RESULTS: 111 patients were included, mean age was 72.5 years, 33.3% were cervical injury and 66.7% were incomplete injuries, medical disease was more frequent than traumatic disease. Only 5% did not present other associated diseases. Up to 97% suffered some complications. SCIM III average was 42 points and only 35% got walking function. CONCLUSIONS: There has been an increase in aging spinal cord injury patients in recent years. Unlike general population traumatic etiology is not more frequent than medical. Incomplete injuries are common and usually associated with more comorbility, getting poorer functional recovery despite neurological improvement. PMID- 26005073 TI - [Angular gyrus connectivity model for language: a functional neuroimaging meta analysis]. AB - INTRODUCTION: Modern functional neuroimaging techniques permit the analysis of the simultaneous activation of diverse brain areas to suggest cognitive connectivity models related to specific cognitive functions. AIM: To analyze the functional networks of the angular gyrus (Brodmann area 39) related to language functions. MATERIALS AND METHODS: The database of BrainMap was used to analyze the activation coordinates of the angular gyrus and brain related areas while performing different language tasks. Eight articles were selected that included 13 experiments, 155 participants and 265 loci. RESULTS: Sixteen activation clusters made a network that included the activation of the two angular gyri, the superior right parietal lobe and right supramarginal gyri; the superior left temporal lobe (middle lateral and medial inferior), and the frontal lobe (bilateral premotor and left prefrontal). CONCLUSIONS: Our findings are in agreement with previous findings using structural connectivity techniques and support the integrative role of the angular gyrus in language functions. PMID- 26005075 TI - [Occipital nerve stimulation for refractory chronic migraine]. AB - INTRODUCTION: Occipital nerve stimulation (ONS) is an emerging and promising preventive treatment for refractory chronic migraine. AIM: To evaluate the mechanisms of actions, clinical studies, implantation techniques and inclusion criteria of the ONS as a preventive treatment for migraine. DEVELOPMENT: This work includes a non-systematic review of the literature on the above-mentioned aspects of ONS as a treatment for refractory chronic migraine. This disease affects approximately 2% of the population and results in a significant impairment in quality of life, economic burden and interference with labor and social activities. ONS is an emerging and promising therapy for the treatment of chronic migraine with greater than 50% pain reduction in most of open-label studies and published clinical trials. Although the mechanisms of action remain unknown, there seem to be a neuromodulation of the transmitted nociceptive trigeminal information in the trigeminal caudal nucleus, what could be explained by means of the Melzack and Wall pain gate theory. ONS is a safe and well tolerated treatment, and its most frequent side effects are usually local such as electrodes displacement or infections of the surgical incision. These complications do not usually require the electrodes withdrawal. CONCLUSIONS: ONS is an effective, well tolerated and safe treatment for the prevention of chronic migraine and could emerge as a useful option for those patients with medically refractory chronic migraine. PMID- 26005074 TI - [Lymphocytic hypophysitis and hypertrophic pachymeningitis: description of a possible case associated to IgG4 pathologies]. AB - INTRODUCTION: Pathologies related to lymphocyte infiltration and inflammatory cells are classified, according to their topography, into idiopathic orbital pathology, idiopathic hypertrophic pachymeningitis, Tolosa-Hunt syndrome and lymphocytic hypophysitis. Here we review the case of a female patient who began with lymphocytic hypophysitis eight years ago and has since presented several episodes of hypertrophic pachymeningitis in a variety of locations. CASE REPORT: Our study involves a 55-year-old female, being monitored owing to a two-month history of headaches, who was admitted to hospital as the result of a deterioration of her clinical signs and symptoms with paralysis of the whole right-side third cranial nerve, watery eyes and rhinorrhea. A magnetic resonance brain scan revealed the presence of a sellar lesion consistent with lymphocytic hypophysitis. Treatment was established with corticoids with an improvement at first, but two years later the patient's clinical features worsened, with headaches and periocular paraesthesias on the right-hand side. Another MRI scan was performed and several extra-axial lesions were observed, the results of the other studies being normal. Idiopathic hypertrophic pachymeningitis was therefore diagnosed and treatment with corticoids was started again. In the ensuing follow up the patient presented new lesions in different locations and poor pain control, and so immunomodulator treatment was thus added. Given the association between lymphocytic hypophysitis and hypertrophic pachymeningitis, the study was completed with determination of the IgG4 in serum, which was negative. CONCLUSIONS: The association of lymphocytic hypophysitis and hypertrophic pachymeningitis with IgG4-related pathologies have recently been reported. Although the diagnosis has not been confirmed in our patient, this relationship must be taken into account in these idiopathic cases and, above all, if they are associated with other systemic manifestations. PMID- 26005076 TI - [Deficiency, disability, neurology and television series]. AB - INTRODUCTION: The portrayal of neurological disability and deficiency on television has not always been approached in the same way, but has instead tended to reflect the standpoint taken by society with regard to these issues and how they are dealt with according to the prevailing conceptions and values at each particular time. AIMS: To address the appearance of neurological pathologies in television series and to ponder on the image they have in such contexts. DEVELOPMENT: Deficiency and disability of neurological origin have often been depicted on television in series, telefilms and documentaries, and in a wide variety of ways. Here we examine different television series and how they have dealt with neurological pathology, its diagnosis and its treatment, as well as the figure of the healthcare professional and social-familial adaptation. Examples cited include series such as House MD, Glee, American Horror Story, Homeland or Game of Thrones. CONCLUSIONS: Television series are a useful tool for making some neurological pathologies better known to the public and for dispelling the myths surrounding others, provided that the pathologies are dealt with in a realistic manner, which is not always the case. More care should be taken with regard to the way in which health professionals are portrayed in television series, as it is not always done correctly and may mislead viewers, who take what they see on the TV as being real. PMID- 26005077 TI - [Viral meningitis in adults in a district hospital]. PMID- 26005078 TI - Extreme differences in SLCO1B3 functional polymorphisms in Roma and Hungarian populations. AB - Variants in SLCO1B3 transporter are linked to disposition and uptake of drugs and show high degree of heterogeneity between populations. A total of 467 Roma and 448 Hungarian subjects were genotyped for SLCO1B3 c.334T>G and c.1683-5676A>G variant alleles by PCR-RFLP assay and direct sequencing. We found significant differences in the frequencies of homozygous variant genotypes of SLCO1B3 334GG (41.54% vs. 8.04%, p<0.001) and 1683-5676GG (0.43% vs. 2.01%, p=0.028) between Romas and Hungarians. A significantly increased prevalence was found in SLCO1B3 1683-5676G allele frequency in Hungarians compared to the Roma population (15.07% vs. 3.43%, p<=0.001). The frequency of SLCO1B3 334G allele was significantly increased in Roma population compared to Hungarians (70.56% vs. 52.23%, p=0.001). The LD values between the examined SNPs were 80 and 90 in Roma and in Hungarian samples, respectively. Our results highlight notable pharmacogenetic differences between Roma and Hungarian populations, which may have therapeutic implications. PMID- 26005079 TI - Neural tube defect family with recessive trait linked to chromosome 9q21.12 21.31. AB - PURPOSE: Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. METHODS: We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. RESULTS: A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. CONCLUSIONS: Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene. PMID- 26005080 TI - Targeting SREBPs for treatment of the metabolic syndrome. AB - Over the past few decades, mortality resulting from cardiovascular disease (CVD) steadily decreased in western countries; however, in recent years, the decline has become offset by the increase in obesity. Obesity is strongly associated with the metabolic syndrome and its atherogenic dyslipidemia resulting from insulin resistance. While lifestyle treatment would be effective, drugs targeting individual risk factors are often required. Such treatment may result in polypharmacy. Novel approaches are directed towards the treatment of several risk factors with one drug. Studies in animal models and humans suggest a central role for sterol regulatory-element binding proteins (SREBPs) in the pathophysiology of the metabolic syndrome. Four recent studies targeting the maturation or transcriptional activities of SREBPs provide proof of concept for the efficacy of SREBP inhibition in this syndrome. PMID- 26005082 TI - Four paradigms: traffic safety in the twentieth-century United States. AB - Traffic safety, once neglected within the larger history of the automobile in the United States, has finally been getting the attention it always deserved. Nevertheless, historians still sometimes misappraise traffic safety in one era by the standards of another. Ahistorical assumptions have contributed to misinterpretations-for example, that Americans of the 1920s were extraordinarily tolerant of traffic casualties because they did not respond to them as more recent traffic-safety paradigms would prescribe. As a corrective, four paradigms, approximately sequential, are proposed: Safety First, Control, Crashworthiness, and Responsibility. Historians are invited to borrow, modify, or replace them, and to consider their applicability to other countries. Whether these particular paradigms survive review or not, historians who are alert to safety paradigms will produce more reliable scholarship on the history of traffic safety. PMID- 26005083 TI - This hill is dangerous. AB - The introduction of cyclists' "danger boards" in the United Kingdom in the 1880s established a new form of road sign aimed at private, mechanized transport that redefined ideas of safety on the road. This article explores the implications of this for established road users. In particular it considers the transfer of responsibility for erecting signs from private clubs to the state in the context of cycling's eclipse by motoring in the early twentieth century. It uses the design development of road signs as a marker of changing power structures in road use. PMID- 26005084 TI - Knights of death: introducing bicycles and motor vehicles to Turin, 1890-1907. AB - The aim of this article is to investigate, through a case study from the city of Turin, the reaction to the arrival of bicycles and automobiles in Italy. It focuses on the early years of bicycle and automobile use, using municipal council minutes, local newspapers, and satirical magazines as sources. The introduction of velocipedes and cars disrupted the traditional use of roads as public spaces, generating protests against the new transport devices, especially with regard to safety concerns resulting from the transgression of traditional uses of urban streets, the speed of vehicles, and the anonymity of riders and drivers. PMID- 26005085 TI - Safety or efficiency?: strategies and conflicting interests in Belgian road safety policy, 1920-1940. AB - After World War I, automobile ownership became a mass phenomenon in Belgium, as in most other industrialized countries. Unfortunately, road-casualty figures soon followed. By the mid-1930s, traffic accidents had become the main cause of accidental deaths. There was clearly a need for a renewed road-safety policy. Public authorities in Belgium, however, were suspiciously reluctant to take new measures. While there was a public outcry for more severe regulation of motorized traffic and several MPs backed bills to this effect, motoring associations lobbied against traffic legislation reforms. In order to understand the Belgian government's hesitation, this article looks at the key strategies of the actors involved in the decision-making process concerning traffic policy. Such strategies included, among others: the creation of detailed traffic-accident statistics, revision of traffic legislation, and support for mass traffic education campaigns. Eventually, public officials stepped in and created a new technocratic traffic regime in the 1930s, yet their prime concern was not road user safety, but the efficiency of traffic streams. PMID- 26005086 TI - "Taking the problem to the people": traffic safety from public relations to political theory, 1937-1954. AB - The slogan "taking the problem to the people" nicely summarizes U.S. traffic safety campaigns of the 1950s. It refers to the goal of awareness and self discipline for drivers through education and law enforcement. A detailed analysis of the campaigns, however, shows a subtler objective of the motor interests that promoted it. They wanted to overcome political indifference through a civic mobilization of drivers as citizens, persuading drivers to lobby for traffic control. The analysis of their efforts leads us to question the role-or lack of role-of politicians in scientific and technological controversies. PMID- 26005087 TI - Delegating to the automobile: experimenting with automotive restraints in the 1970s. AB - This article explores the attempts in the United States in the 1970s to implement a new paradigm for automobile safety-crashworthiness, the idea that automobile passengers should be protected in the event of a crash. A large number of strategies were proposed, including air bags, seatbelt modifications, mandatory belt-use laws, and ignition interlocks. Many of these did not initially come to fruition, but they did give the automobile safety community a chance to experiment with different ways of distributing responsibilities between automobile occupants, automobile manufacturers, and, to a lesser extent, government agencies. These experiments helped pave the way for the successful implementation of a number of new strategies in the 1980s, 1990s, and 2000s. PMID- 26005088 TI - Arrive alive: road safety in Kenya and South Africa. AB - This article is among the first historical considerations of road safety in Africa. It argues that race and class, as colonial dualisms, analytically frame two defining moments in the development of African automobility and its infrastructure-"Africanization" in the first decade of Kenya's political independence from Britain, 1963-75, and democratization in postapartheid South Africa. We argue that recent road safety interventions in both countries exemplify an "epidemiological turn" influenced by public health constructions of the HIV/AIDS epidemic. African states' framing of road safety in behaviorist terms has obscured larger debates around redressing the historical legacies of racialized access to roads and the technopolitics of African automobility. Civic involvement in road safety initiatives has tended to be limited, although the specter of road carnage has entered into the public imagination, largely through the death of high profile Africans. However, some African road users continue to pursue alternative, and often culturally embedded, strategies to mitigate the dangers posed by life "on the road." PMID- 26005089 TI - The history of traffic safety: describing 100 years. PMID- 26005090 TI - Promoting road safety. PMID- 26005091 TI - A crooked path. AB - This is a printed version of Pamela O. Long's talk at the 2014 Society for the History of Technology annual meeting, on the occasion of receiving the Leonardo da Vinci award. It provides a synoptic intellectual autobiography of the author, treating the development of her work on Vitruvianism, ideas concerning contextualism, some of the scholars that have most influenced her work, and her present project on engineering in sixteenth-century Rome. PMID- 26005094 TI - Biosensors for waterborne viruses: Detection and removal. AB - Detection of waterborne viruses is important to eliminate and control their harmful effect as pathogens. Hence, the use of rapid and sensitive detection technologies is critically important as they can aid in investigating outbreaks and help in developing prevention strategies. To date range of viruses can contaminate drinking water sources, causing illnesses such as diarrhoea, pneumonia and gastroenteritis which can result in death. Due to their small size (nm) their complete removal from water can be difficult with current water treatment processes while being resistant to disinfectants. Available techniques for virus detection include filtration technologies, enzyme-linked immunosorbent assays and polymerase chain reaction. Although each technique has limitations, the use of biosensor technology with smart affinity materials and nanomaterials can show great potential in sensing viruses in water samples. This review reports on the latest technologies used for waterborne virus removal and detection with focus on rapid detection using biosensors. PMID- 26005095 TI - Restoration of the di-myo-inositol-phosphate pathway in the piezo hyperthermophilic archaeon Thermococcus barophilus. AB - Most Thermococcales accumulate di-myo-inositol-phosphate (DIP) as an organic solute as a response to heat stress. We have studied the accumulation of this osmolyte in the high-hydrostatic pressure adapted hyperthermophile Thermococcus barophilus. We found no accumulation of DIP under any of the stress conditions tested, although this archaeon harbors the 3 DIP synthesis genes. Lack of synthesis is due to the lack of expression of TERMP_01135 coding for the second step of DIP synthesis. In contrast to other species, the T. barophilus synthesis operon is interrupted by a four gene locus, in reverse orientation. Restoring an operon like structure at the DIP locus restored DIP synthesis, but did not have an impact on growth characteristics, suggesting that other mechanisms have evolved in this organism to cope with heat stress. PMID- 26005096 TI - Adipose tissue Mest and Sfrp5 are concomitant with variations of adiposity among inbred mouse strains fed a non-obesogenic diet. AB - The expression of a subset of genes including mesoderm specific transcript (Mest), secreted frizzled-related protein 5 (Sfrp5) and bone morphogenetic protein 3 (Bmp3) in adipose tissue biopsies of C57BL/6J mice before exposure to an obesogenic diet were shown to be predictive for the development of obesity in mice after feeding a high fat diet for 8 weeks. This observation led to the supposition that adipose tissue expression of this subset of genes within inbred strains of mice could be associated with their susceptibility in the development of adiposity when fed a low fat diet. The analyses of male mice from 5 inbred strains showed average bodyweights ranging from 25.82 to 36.58 g at 16 weeks of age. Bodyweight was highest for AKR/J and adiposity correlated highly with bodyweight for all strains. Analyses of epididymal fat gene expression showed Mest, Sfrp5 and Bmp3 to be highly concomitant with adiposity across all strains of mice. Naked 1 (Nkd1), a gene previously shown to be associated with variations of adiposity in mice fed a high fat diet, but not predictive for the development of adiposity, showed no correlation with adiposity. In addition, the expression of Mest and Sfrp5 were tightly associated across the 5 mouse strains with the highest and lowest expression occurring in DBA/2J and C57BL/6J (B6) respectively suggesting a common mechanism for their regulation. Surprisingly, when independent cohorts for these 2 strains were fed high fat diet for 8 weeks, DBA/2J showed no further increase in Sfrp5 expression whereas expression levels for B6 mice were induced almost 20-fold. Analyses of (B6 x DBA2/J) F1 mice fed a low fat diet for 8 weeks showed intermediate levels of adiposity and gene expression for Sfrp5 and Mest suggesting a strong genetic basis for these differences. PMID- 26005097 TI - Lycopene induces apoptosis in Candida albicans through reactive oxygen species production and mitochondrial dysfunction. AB - Lycopene, a well-known carotenoid pigment found in tomatoes, has shown various biological functions. In our previous report, we showed that lycopene induces two apoptotic hallmarks, plasma membrane depolarization and G2/M cell cycle arrest, in Candida albicans. In this study, we investigated the ability of lycopene to induce apoptosis, and the mechanism by which it regulates apoptosis. FITC-Annexin V staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis, and 4',6-diamidino-2-phenylindole (DAPI) assay showed that lycopene exerted its antifungal activity during the early and late stages of apoptosis in C. albicans. During apoptosis, intracellular reactive oxygen species (ROS) were increased, and specifically the hydroxyl radicals contributed to the fungal cell death. Furthermore, lycopene treatment caused intracellular Ca(2+) overload and mitochondrial dysfunction, such as mitochondrial depolarization and cytochrome c release from the mitochondria to the cytoplasm. At last caspase activation was triggered. In summary, lycopene exerted its antifungal effects against C. albicans by inducing apoptosis via ROS production and mitochondrial dysfunction. PMID- 26005098 TI - Incubation at 32.5 degrees C and above causes malformations in the zebrafish embryo. AB - Zebrafish embryos are increasingly used for developmental toxicity screening of candidate drugs and are occasionally co-incubated with a metabolic activation system at 32 degrees C for 1, 2 or 4h, depending on their developmental stage. As this temperature is higher than the optimal temperature for zebrafish embryonic development (26-28.5 degrees C), we investigated whether continuous incubation of zebrafish embryos from 2.5 until 96h post fertilization (hpf) at high temperatures (30.5-36.5 degrees C) causes malformations. At 32.5 degrees C tail malformations were observed as early as 24hpf, and these became even more prominent at 34.5 and 36.5 degrees C. Cardiovascular and head malformations, edema and blood accumulations throughout the body were present at 36.5 degrees C. Finally, temperatures higher than 28.5 degrees C accelerated embryonic development except for 36.5 degrees C, at which a lower hatching rate and hatching enzyme activity were observed. In conclusion, incubation of zebrafish embryos at 32.5 degrees C and above from 2.5 until 96hpf causes malformations as early as 24hpf. PMID- 26005099 TI - Estimating Large-Scale Network Convergence in the Human Functional Connectome. AB - The study of resting-state networks provides an informative paradigm for understanding the functional architecture of the human brain. Although investigating specialized resting-state networks has led to significant advances in our understanding of brain organization, the manner in which information is integrated across these networks remains unclear. Here, we have developed and validated a data-driven methodology for describing the topography of resting state network convergence in the human brain. Our results demonstrate the importance of an ensemble of cortical and subcortical regions in supporting the convergence of multiple resting-state networks, including the rostral anterior cingulate, precuneus, posterior cingulate cortex, posterior parietal cortex, dorsal prefrontal cortex, along with the caudate head, anterior claustrum, and posterior thalamus. In addition, we have demonstrated a significant correlation between voxel-wise network convergence and global brain connectivity, emphasizing the importance of resting-state network convergence in facilitating global brain communication. Finally, we examined the convergence of systems within each of the individual resting-state networks in the brain, revealing the heterogeneity by which individual resting-state networks balance the competing demands of specialized processing against the integration of information. Together, our results suggest that the convergence of resting-state networks represents an important organizational principle underpinning systems-level integration in the human brain. PMID- 26005100 TI - Unique Aspects of Coronary Artery Disease in Indian Women. AB - PURPOSE: Epidemiologic and clinical research suggests important gender-related differences in the prevalence, presentation, associated conventional and non conventional risk factors, management and outcomes of coronary heart disease (CHD) patients. Adequate data is not available for Indian population where prevalence of CHD and depression is high. METHOD: We conducted an observational, single-center, study from January 2010 to December 2011 on 10450 consecutive patients visiting a tertiary care center, Ahmedabad, Gujarat, India who presented with complaints related to CHD. RESULTS: Of these, 6867 patients had coronary artery disease (CAD) as confirmed by angiographic investigation; 5678 were males, and 1189 were females with similar mean age. As compared to males, females had higher prevalence of hypertension, diabetes and obesity while males had higher prevalence of smoking. Invasive treatment options like Coronary Artery Bypass Grafting (p < 0.001) and Percutaneous Coronary Intervention (p = 0.001) were used less often to treat females, and medical therapy (p < 0.001) was the preferred treatment option irrespective of the contributing risk factors/extent of CAD. Depression was observed in 39.8% of acute coronary syndrome patients (n = 1648) as assessed by MARDS scale. It was higher in female patients and in low socioeconomic strata (p < 0.001).At 12 and 36 months, rates of revascularization (p < 0.001) and mortality (p < 0.005) were higher with poor quality of life (QoL) (P < 0.001) in depressed CAD patients. CONCLUSION: In India, women appear to have a higher prevalence of hypertension, diabetes, obesity, and family history of CHD. Yet women get invasive treatments less often than men. Depression is also more common in women and is associated with poor QoL and early mortality than men. PMID- 26005101 TI - Are ERAD components involved in cross-presentation? AB - A long unanswered question in the antigen presentation field is how exogenous antigens cross-presented by Major Histocompatibility Complex class I (MHC-I) molecules to CD8(+) T cells are translocated into the cytosol. Here we discuss the known mechanisms involved in this process with a focus on the hypothesized role of the machinery that functions in endoplasmic reticulum-associated degradation (ERAD). Other potential mechanisms of antigen entry to the cytosol are also discussed. PMID- 26005102 TI - Comparing the associations between three types of adolescents' romantic involvement and their engagement in substance use. AB - Using data on 838 middle adolescents, the current study compared the associations between three types of romantic involvement and alcohol, tobacco, and marijuana use. Off-time (i.e., serious romantic relationships) but not on-time (i.e., romantic socializing and dating) types of involvement were expected to be associated with increased odds of using each substance. Participating in romantic socializing was unrelated to substance use and dating was only positively associated with alcohol use. Participation in serious romantic relationships, however, was associated with an increased likelihood of having used each substance. Associations did not differ between males and females. Based on these results some but not all forms of romantic involvement may place middle adolescents at risk for substance use. Implications for parents and relationship education are discussed. PMID- 26005103 TI - Direct vision in minimally invasive epicardial procedures: preliminary tests of prototype instrumentation. AB - This study investigated the use of direct visualization to enhance minimally invasive epicardial procedures. A commercially available miniature camera was placed in a prototype subxiphoid introducer needle and bench top, in vitro and in vivo tests of system performance were made during simulated and actual attempts at pericardial access and cardio-endoscopy. This system had an unshielded field of view of 100 degrees and a resolution of 220 * 224 pixels. When a sleeve used to maintain depth of field was slid past the distal tip of the camera probe, the field of view would decrease by ~15 degrees per millimetre of sleeve extension, but without loss of image quality. While tests during in vivo subxiphoid access in a porcine model revealed that the pericardial membrane was difficult to localize, the results also showed excellent resolution of the coronary arteries on the epicardial surface. These findings and potential improvements are discussed in detail. PMID- 26005104 TI - Differential impacts of elevated CO2 and acidosis on the energy budget of gill and liver cells from Atlantic cod, Gadus morhua. AB - Ocean acidification impacts fish and other marine species through increased seawater PCO2 levels (hypercapnia). Knowledge of the physiological mechanisms mediating effects in various tissues of fish is incomplete. Here we tested the effects of extracellular hypercapnia and acidosis on energy metabolism of gill and liver cells of Atlantic cod. Exposure media mimicked blood conditions in vivo, either during normo- or hypercapnia and at control or acidic extracellular pH (pHe). We determined metabolic rate and energy expenditure for protein biosynthesis, Na(+)/K(+)-ATPase and H(+)-ATPase and considered nutrition status by measurements of metabolic rate and protein biosynthesis in media with and without free amino acids (FAA). Addition of FAA stimulated hepatic but not branchial oxygen consumption. Normo- and hypercapnic acidosis as well as hypercapnia at control pHe depressed metabolic stimulation of hepatocytes. In gill cells, acidosis depressed respiration independent of PCO2 and FAA levels. For both cell types, depressed respiration was not correlated with the same reduction in energy allocated to protein biosynthesis or Na(+)/K(+)-ATPase. Hepatic energy expenditure for protein synthesis and Na(+)/K(+)-ATPase was even elevated at acidic compared to control pHe suggesting increased costs for ion regulation and cellular reorganization. Hypercapnia at control pHe strongly reduced oxygen demand of branchial Na(+)/K(+)-ATPase with a similar trend for H(+)-ATPase. We conclude that extracellular acidosis triggers metabolic depression in gill and metabolically stimulated liver cells. Additionally, hypercapnia itself seems to limit capacities for metabolic usage of amino acids in liver cells while it decreases the use and costs of ion regulatory ATPases in gill cells. PMID- 26005105 TI - Workers on transformation of the shelter object of the Chernobyl nuclear power plant into an ecologically-safe system show qEEG abnormalities and cognitive dysfunctions: A follow-up study. AB - OBJECTIVES: The present study aimed at assessing bioelectric activity and cognitive functions in the workers on the conversion project of the "Shelter" object (SO) of the Chernobyl nuclear power plant into an environmentally safe system. METHODS: A total of 196 men were included and examined before (t0) and after (t1) working on the SO in the period 2004-2008. They underwent a qEEG and a battery of neuropsychological and psychiatric assessments. RESULTS: At t1, the organized type of qEEG shifted towards the disorganized one. An increase of spectral delta-power in the left frontotemporal area, of theta- and alpha-power in the left temporal area, with redistribution of alpha-activity to the front and reduction of dominant frequency in the left temporal area, were registered. Further, neurocognitive tests revealed the presence of mild cognitive disorders at t1. Interestingly, those subjects previously exposed to radiation with no consequences, were more resistant to these detrimental effects. CONCLUSIONS: Taken together, the disturbances observed may be considered as cognitive symptoms of a chronic fatigue syndrome resulting from the exposure to ionizing radiation. Simple and non-invasive assessments, such as those performed by us, may be helpful to detect early brain changes caused by the presence of radiological risk factors. PMID- 26005106 TI - Broad diversity of host responses of the white-footed mouse Peromyscus leucopus to Borrelia infection and antigens. AB - Peromyscus leucopus, the white-footed mouse, is one of the more abundant mammals of North America and is a major reservoir host for at least five tickborne diseases of humans, including Lyme disease and a newly-recognized form of relapsing fever. In comparison to Mus musculus, which is not a natural reservoir for any of these infections, there has been little research on experimental infections in P. leucopus. With the aim of further characterizing the diversity of phenotypes of host responses, we studied a selection of quantitative traits in colony-bred and -reared outbred P. leucopus adults that were uninfected, infected with the relapsing fever agent Borrelia hermsii alone, or infected after immunization with Lyme disease vaccine antigen OspA and keyhole limpet hemocyanin (KLH). The methods included measurements of organ weights, hematocrits, and bleeding times, quantitative PCR for bacterial burdens, and enzyme immunoassays for serum antibodies against both the immunization proteins and cellular antigens of the infecting organism. The results included the following: (i) uninfected animals displayed wide variation in relative sizes of their spleens and in their bleeding times. (ii) In an experiment with matched littermates, no differences were observed between females and males at 7 days of infection in bacterial burdens in blood and spleen, relative spleen size, or antibody responses to the B. hermsii specific-antigen, FbpC. (iii) In studies of larger groups of males or females, the wide variations between bacterial burdens and in relative spleen sizes between individuals was confirmed. (iv) In these separate groups of males and females, all animals showed moderate-to-high levels of antibodies to KLH but wide variation in antibody levels to OspA and to FbpC. The study demonstrated the diversity of host responses to infection and immunization in this species and identified quantitative traits that may be suitable for forward genetics approaches to reservoir-pathogen interactions. PMID- 26005107 TI - Review: Sentinels of tick-borne encephalitis risk. AB - Tick-borne encephalitis (TBE) is a viral zoonotic disease endemic in many regions of Eurasia. The definition of TBE risk areas is complicated by the focal nature of the TBE virus transmission. Furthermore, vaccination may reduce case numbers and thus mask infection risk to unvaccinated persons. Therefore, additional risk indicators are sought to complement the current risk assessment solely based on human incidence. We reviewed studies published over the past ten years investigating potential new sentinels of TBE risk to understand the advantages and disadvantages of the various sentinel animal surveys and surrogate indicator methods. Virus prevalence in questing ticks is an unsuitable indicator of TBE infection risk as viral RNA is rarely detected even in large sample sizes collected at known TBE endemic areas. Seroprevalence in domestic animals, on the other hand, showed good spatial correlation with TBE incidence in humans and might also uncover presently unknown TBEV foci. PMID- 26005108 TI - Incremental effect of natural tick challenge on the infection and treatment method-induced immunity against T. parva in cattle under agro-pastoral systems in Northern Tanzania. AB - This study was conducted to assess the incremental effect of natural tick challenge on the infection and treatment method-induced immunity against T. parva under agro-pastoral systems in Simanjiro district, Northern Tanzania. T. parva specific antibody percent positivity and prevalence of T. parva parasites were studied in relation to duration post vaccination and proximity to Tarangire National park. A total of 381 cattle were included in this study, of which 127 were unvaccinated and 254 had been vaccinated at different time points between 2008 and 2014. Antibody percent positivity (PP) determined by the PIM-based T. parva ELISA and the prevalence of T. parva parasites detected by a nested PCR based on the p104 gene were used to compare vaccinated and unvaccinated cattle. Results showed that seroprevalence was significantly higher in vaccinated than unvaccinated cattle (OR 10.89, p = 0.0341). Only 1.6% (6/381) of all cattle were seronegative and 5/6 of these were unvaccinated. Prevalence of T. parva parasites was significantly higher in vaccinated (50.39%) than unvaccinated (19.69%) cattle (OR 2.03, p = 0.0144). While there was a positive association between PP and duration post vaccination but the latter was inversely associated with T. parva parasite prevalence. This study also showed that cattle which were closer to the park had higher antibody PP and T. parva prevalence. It is concluded that duration post vaccination as well as proximity from the wildlife in Tarangire National park together may exert an incremental effect on the outcome of ECF vaccination by influencing stronger antibody immunity of cattle and ability to withhold high T. parva infection pressure under constant field tick challenge. Further, the high seroprevalence in vaccinated and unvaccinated cattle suggests a likely state of endemic stability to T. parva in the study area. PMID- 26005109 TI - Updating the research domain criteria: the utility of a motor dimension. AB - Within the NIMH Research Domain Criteria (RDoC) framework, dimensions of behavior are investigated across diagnoses with the goal of developing a better understanding of their underlying neural substrates. Currently, this framework includes five domains: cognitive, social, arousal/regulatory, negative, and positive valence systems. We argue that the inclusion of a motor systems domain is sorely needed as well. Independent of medication, distinct areas of motor dysfunction (e.g. motor planning/inhibition/learning/coordination, involuntary movements) commonly appear across a number of mental disorders (e.g. schizophrenia, bipolar disorder, autism, attention deficit hyperactivity disorder, Alzheimer's disease, depression) as well as neurological disorders accompanied by significant psychological symptoms (e.g. Parkinson's disease). In addition, motor systems are amenable to study across multiple levels of analysis from the cellular molecular level focusing on cytoarchitechtonics and neurotransmitter systems, to networks and circuits measured using neuroimaging, and finally at the level of overt behavioral performance. Critically, the neural systems associated with motor performance have been relatively well defined, and different circuits have been linked to distinct aspects of motor behavior. As such, they may also be differentially associated with symptoms and motor dysfunction across diagnoses, and be uniquely informative about underlying etiology. Importantly, motor signs can change across stages of illness; they are also often present in the prodromal phases of disease and closely linked with course, suggesting that these behaviors represent a core feature reflective of pathogenic processes. The inclusion of a motor domain would allow researchers to better understand psychopathology more broadly, and may also reveal important contributions to disease processes across diagnoses. PMID- 26005111 TI - Prevalence of suicide attempts among Chinese adolescents: A meta-analysis of cross-sectional studies. AB - OBJECTIVE: According to World Health Organization, for every committed suicide there were 20 suicide attempts at least. In the last decade, despite the increasing awareness on suicide attempts among adolescents in China, there has been no comprehensive system reporting vital statistics. Consequently, the prevalence of suicide attempts reported in some studies ranged variedly. Therefore, the purpose of this study was to provide the first meta-analysis of cross-sectional studies of suicide attempts to fill this gap. METHODS: Two reviewers independently screened potentially relevant cross-sectional studies of suicide attempts through PubMed-Medline, Embase, Wanfang Data, Chongqing VIP and Chinese National Knowledge Infrastructure databases using the core terms 'suicid*'/'suicide attempt*'/'attempted suicide' and 'adolescen*'/'youth'/'child*'/'student*' and 'China'/'Chinese' in the article titles, abstracts and keywords. Chi-square based Q test and I(2) statistic assessed the heterogeneity. Forest plot was used to display results graphically. Potential publication bias was assessed by the funnel plot, Begg's and Egger's test. RESULTS: In total, 43 studies with 200,124 participants met the eligibility criteria. The pooled prevalence of suicide attempts among Chinese adolescents was 2.94% (95% CI: 2.53%-3.41%). Substantial heterogeneity in prevalence estimates was revealed. Subgroup analyses showed that the prevalence for males was 2.50% (95% CI: 2.08%-3.01%), and for females was 3.17% (95% CI: 2.56%-3.91%). CONCLUSIONS: In sum, abstracting across the literatures, the prevalence of suicide attempts among Chinese adolescents was moderate compared with other countries around the world. Necessary measures should be set out prevent them in the future. PMID- 26005110 TI - Active phagocytosis of Mycobacterium tuberculosis (H37Ra) by T lymphocytes (Jurkat cells). AB - This study aimed to co-culture Jurkat T lymphocytes with inactivated Mycobacterium tuberculosis (Mtb H37Ra), explore whether T lymphocytes could phagocytose H37Ra cells, and determine the underlying mechanism. Jurkat T lymphocytes were co-cultured with H37Ra cells, and confocal laser scanning microscopy, electron microscopy, and flow cytometry techniques were used to identify phagocytosis and elucidate its mechanism. After Jurkat T lymphocytes phagocytosed H37Ra cells, the cell body became larger, with abundant cytoplasm, the portion of the nucleus closest to the bacterium deformed, long and short pseudopodia were extended, and the folds of the cell membrane formed depressions that created phagocytic vesicles surrounding the bacterium. The macropinocytosis inhibitor amiloride and the cytoskeletal inhibitor cytochalasin D were found to inhibit phagocytic efficacy; serum complements might enhance phagocytosis through opsonization. Jurkat T lymphocytes could actively phagocytose inactivated Mtb via the macropinocytotic mechanism. Actin remodeling played an important role in the macropinocytotic process. Serum complements may regulate phagocytosis. PMID- 26005112 TI - Anaplastic lymphoma kinase gene expression in small round cell tumors of childhood--a comparative immunohistochemical study. AB - The focus of this study was to investigate anaplastic lymphoma kinase (ALK) expression by immunohistochemistry using a highly specific antibody. Distribution and frequency of ALK expression may provide a clue for ALK inhibitor use in small round cell tumors of childhood. The study group involved 76 small round cell tumors of childhood, which composed of 11 rhabdomyosarcomas, 13 Wilms tumors, 7 Ewing sarcoma/primitive neuroectodermal tumors, 34 peripheral neuroblastic tumors, and 11 acute lymphoblastic lymphoma. Anaplastic lymphoma kinase protein expression in small round cell tumors of childhood is poorly described in the literature. The findings of our study highlight a potential and possible role of targeting ALK in pediatric solid tumors by using ALK immunohistochemistry. Anaplastic lymphoma kinase may also have an oncogenic role in rhabdomyosarcomas and peripheral neuroblastic tumors, and they may possibly be treated with ALK inhibitors. Anaplastic lymphoma kinase expression in Wilms tumors is not reported in the literature, previously. Our study evaluated ALK expression in Wilms tumor samples. PMID- 26005113 TI - Neural syntax in mental disorders. PMID- 26005115 TI - Part One: For the Motion. Carotid Endarterectomy is Safer than Stenting in the Hyperacute Period After Onset of Symptoms. PMID- 26005114 TI - Dynamic network communication as a unifying neural basis for cognition, development, aging, and disease. AB - Perception, cognition, and social interaction depend upon coordinated neural activity. This coordination operates within noisy, overlapping, and distributed neural networks operating at multiple timescales. These networks are built upon a structural scaffolding with intrinsic neuroplasticity that changes with development, aging, disease, and personal experience. In this article, we begin from the perspective that successful interregional communication relies upon the transient synchronization between distinct low-frequency (<80 Hz) oscillations, allowing for brief windows of communication via phase-coordinated local neuronal spiking. From this, we construct a theoretical framework for dynamic network communication, arguing that these networks reflect a balance between oscillatory coupling and local population spiking activity and that these two levels of activity interact. We theorize that when oscillatory coupling is too strong, spike timing within the local neuronal population becomes too synchronous; when oscillatory coupling is too weak, spike timing is too disorganized. Each results in specific disruptions to neural communication. These alterations in communication dynamics may underlie cognitive changes associated with healthy development and aging, in addition to neurological and psychiatric disorders. A number of neurological and psychiatric disorders-including Parkinson's disease, autism, depression, schizophrenia, and anxiety-are associated with abnormalities in oscillatory activity. Although aging, psychiatric and neurological disease, and experience differ in the biological changes to structural gray or white matter, neurotransmission, and gene expression, our framework suggests that any resultant cognitive and behavioral changes in normal or disordered states or their treatment are a product of how these physical processes affect dynamic network communication. PMID- 26005116 TI - Part Two: Against the Motion. Carotid Endarterectomy is not Safer than Stenting in the Hyperacute Period After Onset of Symptoms. PMID- 26005117 TI - Comparing de novo and reference-based transcriptome assembly strategies by applying them to the blood-sucking bug Rhodnius prolixus. AB - High Throughput Sequencing capabilities have made the process of assembling a transcriptome easier, whether or not there is a reference genome. But the quality of a transcriptome assembly must be good enough to capture the most comprehensive catalog of transcripts and their variations, and to carry out further experiments on transcriptomics. There is currently no consensus on which of the many sequencing technologies and assembly tools are the most effective. Many non-model organisms lack a reference genome to guide the transcriptome assembly. One question, therefore, is whether or not a reference-based genome assembly gives better results than de novo assembly. The blood-sucking insect Rhodnius prolixus a vector for Chagas disease-has a reference genome. It is therefore a good model on which to compare reference-based and de novo transcriptome assemblies. In this study, we compared de novo and reference-based genome assembly strategies using three datasets (454, Illumina, 454 combined with Illumina) and various assembly software. We developed criteria to compare the resulting assemblies: the size distribution and number of transcripts, the proportion of potentially chimeric transcripts, how complete the assembly was (completeness evaluated both through CEGMA software and R. prolixus proteome fraction retrieved). Moreover, we looked for the presence of two chemosensory gene families (Odorant-Binding Proteins and Chemosensory Proteins) to validate the assembly quality. The reference-based assemblies after genome annotation were clearly better than those generated using de novo strategies alone. Reference-based strategies revealed new transcripts, including new isoforms unpredicted by automatic genome annotation. However, a combination of both de novo and reference-based strategies gave the best result, and allowed us to assemble fragmented transcripts. PMID- 26005118 TI - Parental RNA interference of genes involved in embryonic development of the western corn rootworm, Diabrotica virgifera virgifera LeConte. AB - RNA interference (RNAi) is being developed as a potential tool for insect pest management and one of the most likely target pest species for transgenic plants that express double stranded RNA (dsRNA) is the western corn rootworm. Thus far, most genes proposed as targets for RNAi in rootworm cause lethality in the larval stage. In this study, we describe RNAi-mediated knockdown of two developmental genes, hunchback (hb) and brahma (brm), in the western corn rootworm delivered via dsRNA fed to adult females. dsRNA feeding caused a significant decrease in hb and brm transcripts in the adult females. Although total oviposition was not significantly affected, there was almost complete absence of hatching in the eggs collected from females exposed to dsRNA for either gene. These results confirm that RNAi is systemic in nature for western corn rootworms. These results also indicate that hunchback and brahma play important roles in rootworm embryonic development and could provide useful RNAi targets in adult rootworms to prevent crop injury by impacting the population of larval progeny of exposed adults. The ability to deliver dsRNA in a trans-generational manner by feeding to adult rootworms may offer an additional approach to utilizing RNAi for rootworm pest management. The potential to develop parental RNAi technology targeting progeny of adult rootworms in combination with Bt proteins or dsRNA lethal to larvae may increase opportunities to develop sustainable approaches to rootworm management involving RNAi technologies for rootworm control. PMID- 26005119 TI - Functions of nuclear receptor HR3 during larval-pupal molting in Leptinotarsa decemlineata (Say) revealed by in vivo RNA interference. AB - Our previous results revealed that RNA interference-aided knockdown of Leptinotarsa decemlineata FTZ-F1 (LdFTZ-F1) reduced 20E titer, and impaired pupation. In this study, we characterized a putative LdHR3 gene, an early-late 20E-response gene upstream of LdFTZ-F1. Within the first, second and third larval instars, three expression peaks of LdHR3 occurred just before the molt. In the fourth (final) larval instar 80 h after ecdysis and prepupal stage 3 days after burying into soil, two LdHR3 peaks occurred. The LdHR3 expression peaks coincide with the peaks of circulating 20E level. In vitro midgut culture and in vivo bioassay revealed that 20E and an ecdysteroid agonist halofenozide (Hal) enhanced LdHR3 expression in the final larval instars. Conversely, a decrease in 20E by feeding a double-stranded RNA (dsRNA) against an ecdysteroidogenesis gene Ldshd repressed the expression. Moreover, Hal rescued the transcript levels in the Ldshd-silenced larvae. Thus, 20E peaks activate the expression of LdHR3. Furthermore, ingesting dsRNA against LdHR3 successfully knocked down the target gene, and impaired pupation. Finally, knockdown of LdHR3 upregulated the transcription of three ecdysteroidogenesis genes (Ldphm, Lddib and Ldshd), increased 20E titer, and activated the expression of two 20E-response genes (LdEcR and LdFTZ-F1). Thus, LdHR3 functions in regulation of pupation in the Colorado potato beetle. PMID- 26005120 TI - Shifts in metabolomic profiles of the parasitoid Nasonia vitripennis associated with elevated cold tolerance induced by the parasitoid's diapause, host diapause and host diet augmented with proline. AB - The ectoparasitoid wasp, Nasonia vitripennis can enhance its cold tolerance by exploiting a maternally-induced larval diapause. A simple manipulation of the fly host diapause status and supplementation of the host diet with proline also dramatically increase cold tolerance in the parasitoid. In this study, we used a metabolomics approach to define alterations in metabolite profiles of N. vitripennis caused by diapause in the parasitoid, diapause of the host, and augmentation of the host's diet with proline. Metabolic profiles of diapausing and nondiapausing parasitoid were significantly differentiated, with pronounced distinctions in levels of multiple cryoprotectants, amino acids, and carbohydrates. The dynamic nature of diapause was underscored by a shift in the wasp's metabolomic profile as the duration of diapause increased, a feature especially evident for increased concentrations of a suite of cryoprotectants. Metabolic pathways involved in amino acid and carbohydrate metabolism were distinctly enriched during diapause in the parasitoid. Host diapause status also elicited a pronounced effect on metabolic signatures of the parasitoid, noted by higher cryoprotectants and elevated compounds derived from glycolysis. Proline supplementation of the host diet did not translate directly into elevated proline in the parasitoid but resulted in an alteration in the abundance of many other metabolites, including elevated concentrations of essential amino acids, and reduction in metabolites linked to energy utilization, lipid and amino acid metabolism. Thus, the enhanced cold tolerance of N. vitripennis associated with proline augmentation of the host diet appears to be an indirect effect caused by the metabolic perturbations associated with diet supplementation. PMID- 26005121 TI - Urban air pollution, poverty, violence and health--Neurological and immunological aspects as mediating factors. AB - Rapid rural-urban migration has created overcrowded areas characterized by concentrated poverty and increases in indoor and outdoor air pollutants. These "hotspots" constitute an increased risk of violence and disease outbreaks. We hypothesize that the effects of poverty and associated air pollution-related stress on impaired cognitive skills are mediated by inflammatory cytokines. A research framework is proposed, encompassing (i) an epidemiological investigation of associations between poverty, high concentrations of air pollutants, violence and health, (ii) a longitudinal follow-up of working memory capacities and inflammatory markers, and (iii) intervention programs aiming to strengthen employability and decreased exposures to toxic air pollutants. PMID- 26005122 TI - [American Academy of Neurology, Washington, 18-25 April 2015]. AB - CEREBROVASCULAR DISEASES: The benefit of the thrombectomy using stents retrievers in the acute stroke phase is now demonstrated when there is a proximal occlusion of an intracranial artery, whatever its mechanism. The place of the anticoagulants in the management of cervical artery dissections remains uncertain, while the benefit of the blood pressure control in the secondary prevention of deep and lobar intracerebral hemorrhages is critical. The development of cardiac MRI, prolonged cardiac monitoring and transcranial doppler seems to improve the diagnosis of cardio-embolic sources of stroke. EPILEPSY: A specialized urgent-access single seizure clinic represents a model which reduces wait-times and improves patient access after a first fit. Co-locating a psychiatrist within outpatient epilepsy center leads to a reduction in psychiatric symptoms and people with psychogenic non-epileptic seizures. When neurologists around the world assess identical case scenarios for the diagnosis of epilepsy, concordance is between moderate and poor, showing that epilepsy diagnosis remains difficult. More than one third of elderly with new-onset epilepsy of unknown etiology exhibit temporal lobe atrophy on brain imaging. MOVEMENT DISORDERS: There is no major progress in the therapeutic approach of Parkinson's disease but the discovery of new genetic markers such as glucocerebrosidase mutations may greatly change our knowledge of the disease process and may induce new therapeutic strategies in the future. The natural history of the disease is also better understood from the prodromal phase to the post-mortem analysis of the brain and the classification of the processes based on abnormal protein deposits. DEMENTIA: The respective value of biomarkers (amyloid imaging versus CSF biomarkers) for in vivo diagnosis of Alzheimer's disease (AD) has been detailed. Therapeutic expectations mainly rely on anti Abeta immunization trials performed in preclinical (and no longer prodromal) stages of AD, with the aim of slowing the evolution of neuronal loss. Besides a lot of communications on dementia genetics or physiopathogeny, fascinating and promising results were presented on deep brain stimulation for depression resistant to medical treatment. PERIPHERAL NEUROPATHY: Ibudilast, administered with riluzole, is safe and tolerable in patients with amyotrophic lateral sclerosis (ALS), improves ALS function and delays progression. Patients with painful small fiber neuropathy have a high rate of mutations in the SCN9A gene, coding for Nav1.7 voltage-gated sodium-channels. Peripheral nerve lymphoma (NL) is a multifocal painful neuropathy that causes endoneurial inflammatory demyelination: primary NL is less severe than secondary NL, which occurs after remission, suggesting that nerve may be considered a "safe lymphoma haven". MULTIPLE SCLEROSIS (MS): Biotin in progressive forms of MS and daclizumab in relapsing-remitting forms appear to be promising treatments. In case of failure of current first-line and/or second-line therapeutics, alemtuzumab may be an interesting alternative treatment. Teriflunomide, dimethyl fumarate and fingolimod are oral treatments with confirmed efficacy and acceptable safety. Besides vitamin D insufficiency and smoking, which are confirmed risk factors for the disease, testosterone insufficiency (in males) and obesity are emerging risk factors, which could also be corrected. PMID- 26005123 TI - Dissociable roles of dopamine and serotonin transporter function in a rat model of negative urgency. AB - Negative urgency is a facet of impulsivity that reflects mood-based rash action and is associated with various maladaptive behaviors in humans. However, the underlying neural mechanisms of negative urgency are not fully understood. Several brain regions within the mesocorticolimbic pathway, as well as the neurotransmitters dopamine (DA) and serotonin (5-HT), have been implicated in impulsivity. Extracellular DA and 5-HT concentrations are regulated by DA transporters (DAT) and 5-HT transporters (SERT); thus, these transporters may be important molecular mechanisms underlying individual differences in negative urgency. The current study employed a reward omission task to model negative urgency in rats. During reward trials, a cue light signaled the non-contingent delivery of one sucrose pellet; immediately following the non-contingent reward, rats responded on a lever to earn sucrose pellets (operant phase). Omission trials were similar to reward trials, except that non-contingent sucrose was omitted following the cue light prior to the operant phase. As expected, contingent responding was higher following omission of expected reward than following delivery of expected reward, thus reflecting negative urgency. Upon completion of behavioral training, Vmax and Km were obtained from kinetic analysis of [(3)H]DA and [(3)H]5-HT uptake using synaptosomes prepared from nucleus accumbens (NAc), dorsal striatum (Str), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) isolated from individual rats. Vmax for DAT in NAc and for SERT in OFC were positively correlated with negative urgency scores. The current findings suggest that mood-based impulsivity (negative urgency) is associated with enhanced DAT function in NAc and SERT function in OFC. PMID- 26005124 TI - Drift diffusion model of reward and punishment learning in schizophrenia: Modeling and experimental data. AB - In this study, we tested reward- and punishment learning performance using a probabilistic classification learning task in patients with schizophrenia (n=37) and healthy controls (n=48). We also fit subjects' data using a Drift Diffusion Model (DDM) of simple decisions to investigate which components of the decision process differ between patients and controls. Modeling results show between-group differences in multiple components of the decision process. Specifically, patients had slower motor/encoding time, higher response caution (favoring accuracy over speed), and a deficit in classification learning for punishment, but not reward, trials. The results suggest that patients with schizophrenia adopt a compensatory strategy of favoring accuracy over speed to improve performance, yet still show signs of a deficit in learning based on negative feedback. Our data highlights the importance of applying fitting models (particularly drift diffusion models) to behavioral data. The implications of these findings are discussed relative to theories of schizophrenia and cognitive processing. PMID- 26005125 TI - Stress during pregnancy alters dendritic spine density and gene expression in the brain of new-born lambs. AB - Rodent studies show how prenatal stress (PS) can alter morphology in the cortico limbic structures that support emotional and cognitive functions. PS-induced alteration is less well described in species with a gyrencephalic brain and complex earlier fetal development, and never in sheep at birth to rule out postnatal environment effects or influences of maternal behavior. This study aimed to assess the consequences of a mild chronic stress in pregnant ewes on the neurobiological development of their lambs at birth. During the last third of gestation, 7 ewes were exposed daily to various unpredictable and negative routine management-based challenges (stressed group), while 7 other ewes were housed without any additional perturbation (control group). For each group, a newborn from each litter was sacrificed at birth to collect its brain and analyze its expression levels of genes involved in neuronal dendritic morphology (Dlg4, Rac1, RhoA, Doc2b), synaptic transmission (Nr1, Grin2A, Grin2B) and glucocorticoid receptor (Nr3C1) in hippocampus (HPC), prefrontal cortex (PFC) and amygdala (AMYG). Results revealed that lambs from stressed dam (PS lambs) showed under-expression of Rac1 and Nr1 in PFC and overexpression of Dlg4 in AMYG compared to controls. To assess the morphological consequences of gene dysregulations, the dendritic morphology of pyramidal neurons was explored by Golgi-Cox staining in HPC and PFC. PS lambs had higher dendritic spine density in both structures and more stubby-type spines in the CA1 area of HPC than controls. This is the first demonstration in sheep that PS alters fetal brain, possibly reflecting functional changes in synaptic transmission to cope with adversity experienced in fetal life. PMID- 26005126 TI - Post-training re-exposure to fear conditioned stimuli enhances memory consolidation and biases rats toward the use of dorsolateral striatum-dependent response learning. AB - In a dual-solution task that can be acquired using either hippocampus-dependent "place" or dorsolateral striatum-dependent "response" learning, emotional arousal induced by unconditioned stimuli (e.g. anxiogenic drug injections or predator odor exposure) biases rats toward response learning. In the present experiments emotionally-arousing conditioned stimuli were used to modulate the relative use of multiple memory systems. In Experiment 1, adult male Long-Evans rats initially received three standard fear-conditioning trials in which a tone (2 kHz, 75 dB) was paired with a brief electrical shock (1 mA, 2s). On day 2, the rats were trained in a dual-solution plus-maze task to swim from the same start arm (South) to a hidden escape platform always located in the same goal arm (East). Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli (i.e. tone and context) without shock. On day 3, the relative use of place or response learning was assessed on a probe trial in which rats were started from the opposite start arm (North). Post-training re-exposure to fear-conditioned stimuli produced preferential use of a response strategy. In Experiment 2, different rats received fear conditioning and were then trained in a single-solution task that required the use of response learning. Immediately following training, rats received post-training re-exposure to the fear conditioned stimuli without shock. Re-exposure to fear-conditioned stimuli enhanced memory consolidation in the response learning task. Thus, re-exposure to fear-conditioned stimuli biases rats toward the use of dorsolateral striatum dependent response learning and enhances memory consolidation of response learning. PMID- 26005127 TI - Music training improves speech-in-noise perception: Longitudinal evidence from a community-based music program. AB - Music training may strengthen auditory skills that help children not only in musical performance but in everyday communication. Comparisons of musicians and non-musicians across the lifespan have provided some evidence for a "musician advantage" in understanding speech in noise, although reports have been mixed. Controlled longitudinal studies are essential to disentangle effects of training from pre-existing differences, and to determine how much music training is necessary to confer benefits. We followed a cohort of elementary school children for 2 years, assessing their ability to perceive speech in noise before and after musical training. After the initial assessment, participants were randomly assigned to one of two groups: one group began music training right away and completed 2 years of training, while the second group waited a year and then received 1 year of music training. Outcomes provide the first longitudinal evidence that speech-in-noise perception improves after 2 years of group music training. The children were enrolled in an established and successful community based music program and followed the standard curriculum, therefore these findings provide an important link between laboratory-based research and real world assessment of the impact of music training on everyday communication skills. PMID- 26005129 TI - dcc Haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking. AB - Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence. PMID- 26005128 TI - Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice. AB - Human immunodeficiency virus (HIV) infection is associated with mood disorders and behavioral disinhibition. Impairments in sensorimotor gating and associated neurocognitive disorders are reported, but the HIV-proteins and mechanisms involved are not known. The regulatory HIV-1 protein, Tat, is neurotoxic and its expression in animal models increases anxiety-like behavior concurrent with neuroinflammation and structural changes in limbic and extra-limbic brain regions. We hypothesized that conditional expression of HIV-1 Tat1-86 in the GT tg bigenic mouse model would impair sensorimotor gating and increase microglial reactivity in limbic and extralimbic brain regions. Conditional Tat induction via doxycycline (Dox) treatment (0-125 mg/kg, i.p., for 1-14 days) significantly potentiated the acoustic startle reflex (ASR) of GT-tg mice and impaired prepulse inhibition (PPI) of this response in a dose-dependent manner when Dox (100mg/kg) was administered for brief (1 day) or prolonged (daily for 7 days) intervals. A greater proportion of active/reactive Iba1-labeled microglia was seen in the anterior cingulate cortex (ACC), dentate gyrus, and nucleus accumbens core when Tat protein was induced under either brief or prolonged expression conditions. Other subregions of the medial prefrontal cortex, amygdala, hippocampal formation, ventral tegmental area, and ventral pallidum also displayed Tat induced microglial activation, but only the activation observed in the ACC recapitulated the pattern of ASR and PPI behaviors. Tat exposure also increased frontal cortex GFAP. Pretreatment with indomethacin attenuated the behavioral effects of brief (but not prolonged) Tat-exposure. Overall, exposure to HIV-1 Tat protein induced sensorimotor deficits associated with acute and persistent neuroinflammation in limbic/extralimbic brain regions. PMID- 26005130 TI - Ehlers-Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. PMID- 26005131 TI - Presynaptically mediated effects of cholecystokinin-8 on the excitability of area postrema neurons in rat brain slices. AB - Cholecystokinin (CCK) is a well-known gut hormone that shows anorexigenic effects via action at peripheral and central receptors. CCK is also widely distributed throughout the mammalian brain and appears to function as a neurotransmitter and neuromodulator. The area postrema is one of the circumventricular organs, located on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle. Blood vessels in the area postrema lack a blood brain barrier, offering specific central neural elements unique access to circulating substances. Immunohistochemical studies show CCK-A receptors in the area postrema, and we reported CCK-sensitive area postrema neurons. However, the receptive mechanism of CCK in area postrema neurons still remains unexplained. We investigated the responses of area postrema neurons to agonists and antagonists of CCK receptors using whole cell and perforated patch-clamp recordings in rat brain slices. The application of CCK-8 elicited excitatory responses, such as increases in the frequency of mEPSCs (miniature excitatory postsynaptic currents), a shift toward larger amplitude mEPSCs, and increases in the frequency of action potentials. These changes were found mostly in cells not displaying the hyperpolarization-activated cation current (Ih), except for small excitatory changes in a minority of Ih-positive neurons. Tonic inward currents or an inhibitory response to CCK-8 were never seen. Analysis of the amplitude of mEPSCs before and after the administration of CCK-8 indicated the responses mediated via the presynaptic receptors. The effect of CCK-8 was abolished in the presence of CNQX (AMPA type glutamate receptor antagonist). In the presence of lorglumide (a selective CCK-A receptor antagonist), CCK-8-induced excitatory responses were inhibited. No cells responded to the administration of non-sulfated CCK-8 (CCK 8NS, a selective CCK-B receptor agonist). We conclude that CCK-8 exerts its action via presynaptic CCK-A receptors to facilitate glutamate release onto Ih negative area postrema cells. PMID- 26005132 TI - Clinical indicators of paraplegia underplay universal spinal cord neuronal injury from transient aortic occlusion. AB - Paraplegia following complex aortic intervention relies on crude evaluation of lower extremity strength such as whether the patient can lift their legs or flex the ankle. Little attention has been given to the possible long-term neurologic sequelae following these procedures in patients appearing functionally normal. We hypothesize that mice subjected to minimal ischemic time will have functional and histological changes despite the gross appearance of normal function. Male mice underwent 3 min of aortic occlusion (n=14) or sham surgery (n=4) via a median sternotomy. Neurologic function was graded by Basso Motor Score (BMS) preoperatively and at 24h intervals after reperfusion. Mice appearing functionally normal and sham mice were placed on a walking beam and recorded on high-definition, for single-frame motion analysis. After 96 hrs, spinal cords were removed for histological analysis. Following 3 min of ischemia, functional outcomes were split evenly with either mice displaying almost normal function n=7 or near complete paraplegia n=7. Additionally, single-frame motion analysis revealed significant changes in gait. Histologically, there was a significant stepwise reduction of neuronal viability, with even the normal function ischemic group demonstrating significant loss of neurons. Despite the appearance of normal function, temporary ischemia induced marked cyto-architectural changes and neuronal degeneration. Furthermore high-definition gait analysis revealed significant changes in gait and activity following thoracic aortic occlusion. These data suggest that all patients undergoing procedures, even with short ischemic times, may have spinal cord injury that is not evident clinically. PMID- 26005134 TI - The physical and degradation properties of starch-graft acrylonitrile/carboxylated nitrile butadiene rubber latex films. AB - Starch-graft-acrylonitrile (ANS) is compounded with carboxylated nitrile butadiene rubber (XNBR) latex. The control XNBR and the ANS/XNBR latex films were prepared through a coagulant dipping process. The films were subjected to ageing and soil burial procedures. For the biodegradation experiment, the surface of the film was assessed after the 2nd, 4th and 8th week of soil burial. The ANS, XNBR, and ANS/XNBR colloidal stability were determined with a Malvern Zetasizer. For the dipped latex films, the mechanical, morphological and thermal properties were analyzed. The addition of ANS into the XNBR latex increased the stability of the colloidal dispersions, decreased the latex film tensile strength, but increased the elongation at break due to the bipolar interaction of the ANS and XNBR particles. The ANS/XNBR latex films aged faster than the control films while the morphological analysis showed the existence of a starch crystal region and the formation of microbial colonies on the surfaces of the films. Based on the TGA DTA curves, a higher DeltaT was observed for the ANS/XNBR latex films signifying high thermal energy needed for the film to thermally degrade. PMID- 26005133 TI - Prognostic factors for the recurrence of sporadic desmoid-type fibromatosis after macroscopically complete resection: Analysis of 114 patients at a single institution. AB - AIMS: Desmoid-type fibromatoses (DFs) are rare soft-tissue neoplasms with frequent local recurrence. We sought to determine the prognostic factors that are predictive of recurrence-free survival (RFS) for these tumors. METHODS: One hundred and fourteen consecutive patients with sporadic DF who received macroscopically complete resection (R0/R1) at a single tertiary hospital between 1985 and 2014 were included. A total of 10 clinical and pathological parameters were analyzed. Histologic slides and the margin status were re-checked; close margins (<=1-mm clearance) were noted separately and were considered together with the R1 margin. RESULTS: The median follow-up interval was 72.5 months. Thirty-five (30.7%) patients had a local recurrence. The 2-, 5- and 10-year RFSs were 75.2%, 72.1% and 67.0%, respectively. In univariate analysis, age, tumor size, tumor site, margin status and presence of lesions at multiple sites had a significant impact on RFS. In multiple analysis, younger age (age<30 vs. age>=50 years: hazard ratio [HR] = 4.96; 95% confidence interval [95% CI], 1.50-16.4; p = 0.009); an extra-abdominal site (extra-abdominal site vs. other sites: HR = 4.08; 95% CI, 1.49-11.2; p = 0.006); larger tumor size (>=8 cm vs. <8 cm: HR = 2.43; 95% CI, 1.15-5.13; p = 0.021); and close or positive margin status (close margin/R1 vs. R0: HR = 2.64; 95% CI, 1.11-6.25; p = 0.027) were independent, unfavorable prognostic factors. CONCLUSIONS: Different prognostic subgroups were identified that allow for the better selection of favorable therapeutic strategies. The role of the margin status should be considered with caution and should be based on a more precise pathological result. PMID- 26005135 TI - Characterization, molecular dynamics, and encapsulation ability of beta cyclodextrin polymers crosslinked by polyethylene glycol. AB - A series of water-insoluble cyclodextrin polymers (CDP) was prepared by crosslinking beta-cyclodextrin (CD) with polyethylene glycol diglycidyl ether (PEGDE). Similarly, a reference CDP was prepared using ethylene glycol diglycidyl ether (EGDE). Increasing the feed ratio of PEGDE to CD in the reaction mixture led to high degrees of crosslinking. Relaxation measurements revealed structural homogeneity among the CDPs, which exhibited mobilities that strongly depended on the chain lengths of the crosslinking agents. In addition, all the CDPs displayed high encapsulation abilities toward bisphenol A (BPA) in aqueous media. In particular, the CDP sample with a low degree of crosslinking by PEGDE showed the highest encapsulation ability toward BPA. In contrast, the CDP crosslinked by EGDE exhibited low encapsulation ability because its highly dense structure, which results from the short chain lengths of the crosslinking agents, hinders the penetration of BPA molecules. PMID- 26005136 TI - Fabrication of TiO2/EP super-hydrophobic thin film on filter paper surface. AB - A composite filter paper with super-hydrophobicity was obtained by adhering micro/nano structure of amorphous titanium dioxide on the filter paper surface with modifying low surface energy material. By virtue of the coupling agent, which plays an important part in bonding amorphous titanium dioxide and epoxy resin, the structure of super-hydrophobic thin film on the filter paper surface is extremely stable. The microstructure of super-hydrophobic filter paper was characterized by scanning electron microscopy (SEM), the images showed that the as-prepared filter paper was covered with uniform amorphous titanium dioxide particles, generating a roughness structure on the filter paper surface. The super-hydrophobic performance of the filter paper was characterized by water contact angle measurements. The observations showed that the wettability of filter paper samples transformed from super-hydrophilicity to super hydrophobicity with the water contact angle of 153 +/- 1 degrees . Some experiments were also designed to test the effect of water-oil separation and UV resistant by the super-hydrophobic filter paper. The prepared super-hydrophobic filter paper worked efficiently and simply in water-oil separation as well as enduringly in anti-UV property after the experiments. This method offers an opportunity to the practical applications of the super-hydrophobic filter paper. PMID- 26005137 TI - Visualization of internal structure of banana starch granule through AFM. AB - Atomic force microscopy (AFM) is a high resolution technique for studying the external and internal structures of starch granules. For this purpose granules were isolated from bananas and embedded in a non-penetrating resin. To achieve image contrast of the ultrastructure, the face of the cut blocks were wetted in steam and force modulation mode imaging was used. Images of starch from green bananas showed large variation of height across the granule due to a locational specific absorption of water and swelling of amorphous regions; the data reveal that the center of the granules are structurally different and have different viscoelastic properties. Images of starches from ripe bananas showed an even greater different level of organization: absence of growth rings around the hilum; the central region of the granule is richer in amylose; very porous surface with round shaped dark structures; the size of blocklets are larger than the green fruits. PMID- 26005138 TI - Preparation and characterization of a bacterial cellulose/silk fibroin sponge scaffold for tissue regeneration. AB - Bacterial cellulose (BC) and silk fibroin (SF) are natural biopolymers successfully applied in tissue engineering and biomedical fields. In this work nanocomposites based on BC and SF were prepared and characterized by scanning electron microscopy (SEM), infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). In addition, the investigation of cytocompatibility was done by MTT, XTT and Trypan Blue dye technique. Cellular adhesion and proliferation were detected additionally. The evaluation of genotoxicity was realized by micronucleus assay. In vitro tests showed that the material is non-cytotoxic or genotoxic. SEM images revealed a greater number of cells attached at the BC/SF:50% scaffold surface than the pure BC one, suggesting that the presence of fibroin improved cell attachment. This could be related to the SF amino acid sequence that acts as cell receptors facilitating cell adhesion and growth. Consequently, BC/SF:50% scaffolds configured an excellent option in bioengineering depicting its potential for tissue regeneration and cultivation of cells on nanocomposites. PMID- 26005139 TI - Extraction optimization, characterization and antioxidant activity in vitro of polysaccharides from mulberry (Morus alba L.) leaves. AB - Extraction optimization, characterization and antioxidant activity in vitro of polysaccharides from mulberry leaves (MLP) were investigated in the present study. The optimal extraction conditions with an extraction yield of 10.0 +/- 0.5% for MLP were determined as follows: extraction temperature 92 degrees C, extraction time 3.5h and ratio (v/w, mL/g) of extraction solvent (water) to raw material 34. Two purified fractions, MLP-3a and MLP-3b with molecular weights of 80.99 and 3.64 kDa, respectively, were obtained from crude MLP by chromatography of DEAE-Cellulose 52 and Sephadex G-100. Fourier transform-infrared spectroscopy revealed that crude MLP, MLP-3a and MLP-3b were acidic polysaccharides. Furthermore, crude MLP and MLP-3a had more complicated monosaccharide compositions, while MLP-3b had a relatively higher content of uronic acid. Crude MLP, MLP-3a and MLP-3b exhibited potent Fe(2+) chelating power and scavenging activities on 1,1-diphenyl-2-picrylhydrazyl, hydroxyl, superoxide and 2,2' azinobis-(3-ethyl-benzothiazolin-6-sulfonic acid) radicals. The results suggested that MLP could be explored as natural antioxidant. PMID- 26005140 TI - Hyaluronic acid co-functionalized gold nanoparticle complex for the targeted delivery of metformin in the treatment of liver cancer (HepG2 cells). AB - In this study, green synthesis of gold nanoparticles (AuNPs) was achieved using the extract of eggplant as a reducing agent. Hyaluronic acid (HA) serves as a capping and targeting agent. Metformin (MET) was successfully loaded on HA capped AuNPs (H-AuNPs) and this formulation binds easily on the surface of the liver cancer cells. The synthesized nanoparticles were characterized by UV-Vis spectrophotometer, HR-TEM, particle size analyser and zeta potential measurement. Toxicity studies of H-AuNPs in zebra fish confirmed the in vivo safety of the AuNPs. The in vitro cytotoxicity results showed that the amount of MET-H-AuNPs enough to achieve 50% inhibition (IC50) was much lower than free MET. Flow cytometry analysis showed the significant reduction in G2/M phase after treatment with MET-H-AuNPs, and molecular level apoptosis were studied using western blotting. The novelty of this study is the successful synthesis of AuNPs with a higher MET loading and this formulation exhibited better targeted delivery as well as increased regression activity than free MET in HepG2 cells. PMID- 26005141 TI - Combining biomass wet disk milling and endoglucanase/beta-glucosidase hydrolysis for the production of cellulose nanocrystals. AB - Cellulose nanocrystals (CNCs), a biomaterial with high added value, were obtained from pure cellulose, Eucalyptus holocellulose, unbleached Kraft pulp, and sugarcane bagasse, by fibrillating these biomass substrates using wet disk milling (WDM) followed by enzymatic hydrolysis using endoglucanase/beta glucosidase. The hydrolysis experiments were conducted using the commercial enzyme OptimashBG or a blend of Pyrococcus horikoshii endoglucanase and Pyrococcus furiosus beta-glucosidase. The fibrillated materials and CNCs were analyzed by X-ray diffraction, atomic force microscopy, scanning electron microscopy, and the specific surface area (SSA) was measured. WDM resulted in the formation of long and twisted microfibers of 1000-5000 nm in length and 4-35 nm in diameter, which were hydrolyzed into shorter and straighter CNCs of 500-1500 nm in length and 4-12 nm in diameter, with high cellulose crystallinity. Therefore, the CNC's aspect ratio was successfully adjusted by endoglucanases under mild reaction conditions, relative to the reported acidic hydrolysis method. PMID- 26005142 TI - Novel hydrophilic carboxymethyl starch/montmorillonite nanocomposite films. AB - Preparation of novel carboxymethyl starch (CMS)-based biodegradable films with calcium montmorillonite has been described. The biocomposites were obtained by casting method, glycerol and citric acid were used as plasticizer and crosslinking agent, respectively. The effect of calcium montmorillonite (MMT-Ca) on hydrophilicity (moisture absorption, solubility in water as well as contact angle measurements) was evaluated. Moreover, thermomechanical and mechanical properties of nanocomposites were determined. For all the systems tested intercalated structure of MMT-Ca was revealed, however the most efficient clay platelets dispersion was noted for film containing 5 wt.% MMT-Ca. Such biodegradable CMS/MMT-Ca films exhibiting relatively good mechanical properties could find application in controlled delivery systems as well as in agriculture for seed tapes production where hydrophilicity of polymer carrier is strongly advantageous. PMID- 26005143 TI - Chemical characteristics and anti-proliferation activities of Ganoderma tsugae polysaccharides. AB - Polysaccharides were extracted by hot-water and hot-alkali from four forms of Ganoderma tsugae including mature and baby Ling chih, mycelium and filtrate. Different profiles of proximate composition and monosaccharide constituents, and element contents were found in the extracted polysaccharides from different extractions and different forms. The molecular weight distributions of polysaccharides were 2.8*10(4)-6.5*10(5)Da and their infrared spectra were comparable. The hot-alkali extracted polysaccharides exhibited better anti proliferation on IMR32 cells than the hot-water extracted polysaccharides, which were in turn more effective than the hot-water extracts. Besides, most hot-water extracts and both extracted polysaccharides exhibited an anti-proliferation effect on Hep G2 cells. However, the hot-water extracts showed less effective in anti-proliferation of IMR32 and Hep G2 cells. Based on the anti-tumor effects, both polysaccharides could be prepared for use in the formulation of nutraceuticals and functional foods. PMID- 26005144 TI - Correlating molar masses of nitrocelluloses with their intrinsic viscosities measured using capillary electrophoresis instrumentation. AB - Specific viscosities for a set of six nitrocellulose (NC) standards comprising three different mass-average molar masses (between 20,000 and 300,000 g mol(-1)) of two different nitrogen contents (11.2 and 12.1%) were measured at 20 degrees C in tetrahydrofuran, using capillary electrophoresis instrumentation as a bench top viscometer in frontal mode. Intrinsic viscosities were derived applying Huggins' and Kraemer's models, showing excellent convergence of both models at infinitely diluted polymer concentration. Good overall consistency was shown between viscosity data experimentally acquired by this new protocol and the mass average molar masses provided by the manufacturers. This simple protocol should be of interest for a better understanding of the solvent interaction given by this complex polymer, and beyond this, for tailoring NC solutions devoted to film deposition, and for the determination of mass-average molar masses of unknown NC samples. PMID- 26005145 TI - Homogeneous acylation of xylan with 3,5-dinitrobenzoyl in ionic liquid and the adsorption property. AB - A new xylan ester (xylan 3,5-dinitrobenzoate) as a creatinine adsorbent was prepared by the homogeneous acylation of xylan with 3,5-dinitrobenzoyl chloride in 1-butul-3-methylimidazolium chloride ionic liquid. The influences of reaction conditions on the degree of substitution values of xylan esters were discussed. Results indicated that xylan esters with the degree of substitution range from 1.34 to 1.77 were obtained under the given conditions. The FTIR and (13)C NMR spectroscopies provided the evidence of grafting 3,5-dinitrobenzoyl groups onto the backbone of xylan. Moreover, the adsorption properties of the xylan ester for creatinine were also investigated. Isotherm studies showed that the sorption capacities for creatinine were 2.45, 2.08 and 1.86 mg/g for 23, 30 and 37 degrees C, respectively. Thermodynamic studies performed indicated the sorption process mainly was controlled by the chemical adsorption. Therefore, xylan 3,5 dinitrobenzoate displayed the promising application in the treatment of chronic renal failure by the creatinine adsorption as the new oral adsorbent. PMID- 26005146 TI - Magnetic/pH-responsive beads based on caboxymethyl chitosan and kappa-carrageenan and controlled drug release. AB - This paper reports the synthesis of magnetic and pH-sensitive beads derived from kappa-carrageenan and carboxymethyl chitosan for drug delivery. The magnetic Fe3O4 nanoparticles were synthesized inside a mixture of biopolymers by in situ method. The structural properties of hydrogel beads were characterized by TEM, SEM, XRD, and VSM techniques. The swelling ratio of beads indicated pH-dependent properties with maximum water absorbing at pH 7.4. Introducing magnetic nanoparticles caused a decrease in swelling capacity from 16.4 to 10 g/g. Drug loading and release efficiency were investigated using diclofenac sodium as a model system. The in vitro drug release studies exhibited significant behaviors on the subject of physiological simulated pHs and external alternative magnetic fields. The maximum cumulative release was around 82% at pH 7.4. The presence of magnetite nanoparticles certainly influenced the drug release patterns. The response of beads to external stimulus makes them as good candidates for novel drug delivery systems. PMID- 26005147 TI - Biocomposites with tunable properties from poly(lactic acid)-based copolymers and carboxymethyl cellulose via ionic assembly. AB - Biocomposites with tunable properties were successfully prepared through ionic assembly between anionic carboxymethyl cellulose (CMC) and cationic copolymers (quaternized poly(l-lactide)-block-poly N,N-dimethylamino-2-ethyl methacrylate) (PLA-b-PDMAEMA). The quaternized PDMAEMA segment not only works as a compatibilizer between hydrophilic CMC and hydrophobic PLA, but also acts as a lubricant between these two rigid biopolymers. The (1)H NMR (nuclear magnetic resonance) spectra demonstrated successful synthesis of PLA-b-PDMAEMA with controlled molecular weight of PDMAEMA segment. The results from scanning electronic microscopy (SEM) and Fourier transform infrared spectrometry (FTIR) verified the interaction between quaternized copolymer micelles and anionic CMC networks. The resultant biocomposite could form a transparent and uniform film after casting. Both storage moduli and maximum degradation temperature of PLA/CMC composites were increased with the reduction of molecular weight of PDMAEMA segments. It suggests that the properties of biocomposite materials can be tailored by adjusting the chain length of inclusive PDMAEMA segment. PMID- 26005148 TI - Peptidoglycan diversity and anti-inflammatory capacity in Lactobacillus strains. AB - Lactobacillus species are potential probiotic bacteria for humans because of their capacity to improve certain biological functions in the host's immune system. In this study, we focused on three peptidoglycans (PGNs) derived from different Lactobacillus strains and investigated each PGN's anti-inflammatory capacity. Each PGN was analyzed using HPLC, MALDI-TOF/TOF MS and FTIR. All three PGNs displayed a beta-1,4-linked N-acetylmuramic acid (MurNAc) and N acetylglucosamine (GlcNAc) structure with some modifications in the polypeptides at the end of the MurNAc residue. In a new insight, we found that PGNs inhibit the release of inflammatory cytokines in LPS-induced RAW 264.7 cells; a capacity that may be related to the TLR-4 pathway. The goal for exploring PGN diversity in Lactobacillus strains is to better understand the potential use of Lactobacillus PGNs in food and pharmaceutical applications. PMID- 26005149 TI - Purification and characterization of a glucan from Bacillus Calmette Guerin and the antitumor activity of its sulfated derivative. AB - A water-soluble glucan, BCG-PASW, with a molecular weight of 2.10*10(4)Da, was separated from polysaccharide nucleic acid fraction of Bacillus Calmette Guerin (BCG-PSN) using DEAE-52 cellulose and Sephadex G-200 chromatography. Based on gas chromatography-mass spectrometry (GC-MS), fourier transform infrared (FT-IR) spectra, 1D and 2D nuclear magnetic resonance (NMR) spectroscopy techniques (COSY, HSQC and HMBC), BCG-PASW was found to be an alpha-d-glucan composed of alpha-d-(1->4)-linked glucopyranosyl residues, with branches at O-6 consisting of non-reducing terminal alpha-d-Glcp approximately every eight residues. In vitro antitumor activity by MTS method, its sulfated derivative with a substitution degree of 0.59, could inhibite C666-1 nasopharyngeal carcinoma cells growth significantly. The results indicated that the sulfate content play a decisive role in the bioactivities of the polysaccharides. PMID- 26005150 TI - Combined effects of raw materials and solvent systems on the preparation and properties of regenerated cellulose fibers. AB - To investigate the combined effects of materials and solvents on the preparation, structural and mechanical properties of regenerated cellulose fibers, four cellulosic materials (microcrystalline cellulose, cotton linter pulp, bamboo pulp and bleached softwood sulfite dissolving pulp) and six non-derivative solvents (NaOH/urea aqueous solution, N,N-dimethylacetamide/lithium chloride, N-methyl morpholine-N-oxide, 1-butyl-3-methylimidazolium chloride, 1-allyl-3 methylimidazolium chloride and 1-ethyl-3-methylimidazolium acetate) were used to prepare fibers with wet spinning method. The results showed that the dissolvability of solvent was the determining factor in cellulose dissolution, and the dissolving time was influenced by the raw materials' properties, such as molecular weight, exposed area and hemicellulose content. The crystallinity and elongation at break of the fibers were almost fixed and not affected by the materials and solvents. However, the tensile strength of the fibers was directly proportional to the molecular weight of the raw materials, and varied with the type of solvents through cellulose degradation. PMID- 26005151 TI - Susceptibility of glutinous rice starch to digestive enzymes. AB - To understand the susceptibility of glutinous rice starch to digestive enzymes and its potential impact on glycemic response, enzyme kinetics and in vitro digestibility of the native and gelatinized starches were investigated. The results showed that the Km values of the native and gelatinized starch were 10.35 mg/mL and 9.92 mg/mL, respectively. The digestion rate coefficients k values of the native and gelatinized starches were 2.0 * 10(-3)min(-1) and 1.1 * 10(-2)min( 1), respectively. The contents of rapid digestible starch (RDS), slowly digestible starch (SDS) and resistant starch (RS) in native glutinous rice starch were 8.92%, 21.52% and 69.56%, respectively. After gelatinization, the amounts of RDS, SDS and RS were 18.47%, 29.75% and 51.78%, respectively. The native and gelatinized glutinous rice starches were 10.34% and 14.07% for hydrolysis index (HI), as well as 43.14% and 45.92% for glycemic index (GI), respectively. During the in vitro digestion, the crystallinity of native glutinous rice starch was increased from 34.7% to 35.8% and 38.4% after 20 and 120 min, respectively. PMID- 26005152 TI - Conjugating an anticancer drug onto thiolated hyaluronic acid by acid liable hydrazone linkage for its gelation and dual stimuli-response release. AB - A prodrug gelation strategy was developed for the sustained and dual stimuli response release of doxorubicin hydrochloride (DOX.HCl), a commonly used anticancer drug. For this purpose, the chemical conjugation of DOX.HCl onto thiolated hyaluronic acid (HA) was carried out by an acid liable hydrazone linkage and verified by (1)H NMR analyses. When exposed to the air, such a polysaccharide conjugate showed unique self-gelation ability in aqueous solution. The gelation time and extent depended mainly on the content of thiol groups on thiolated HA. The resultant hydrogel exhibited a dominant elastic response and a thixotropic property. In particular, it could release sustainably conjugated DOX.HCl in dual pH- and reduction-responsive modes. The cumulative drug release was found to be significantly accelerated under the conditions mimicking the intracellular environments of cancer cells. The in vitro cytotoxicity assays for the human nasopharyngeal carcinoma CNE2 cells treated with various release media confirmed the effectiveness of this conjugate hydrogel for cancer cell inhibition. PMID- 26005153 TI - Efficient adsorption of 1-alkyl-3-methylimidazolium chloride ionic liquids onto modified cellulose microspheres. AB - A novel sulfonated cellulose microsphere adsorbent (CGS) was prepared by pre irradiation induced emulsion grafting of glycidyl methacrylate (GMA) onto the cellulose microsphere, followed by sulfonation. The resulting CGS exhibited superior adsorption ability toward 1-alkyl-3-methylimidazolium chloride ([CnMIM]Cl) ionic liquids (ILs). The adsorption equilibrium could be attained rapidly within 40 min for representative 1-butyl-3-methylimidazolium chloride ([C4MIM]Cl) using CGS with different amounts of SO3H group. The adsorption behavior of CGS toward [C4MIM]Cl was well described by the pseudo-second-order model and the Langmuir model. The maximum adsorption capacity toward [C4MIM]Cl was 1.08 mmol/g in the wide range of pH (4.8-10.1). In addition, the adsorption capacity of CGS toward [CnMIM]Cl increased with the alkyl length of cations of [CnMIM]Cl due to the hydrophobic interaction and cation exchange adsorption. Spent CGS could be easily regenerated by 0.1 mol/L HCl or NaCl. The results indicated that this new adsorbent is useful in removing ILs from wastewater. PMID- 26005154 TI - Carboxymethylated hyperbranched polysaccharide: Synthesis, solution properties, and fabrication of hydrogel. AB - The periphery of hyperbranched polysaccharides has many end groups that can be functioned and used as sites to interact with their surroundings. A water insoluble hyperbranched beta-d-glucan, coded as TM3a, extracted from sclerotia of an edible fungus (Pleurotus tuber-regium), was fractionated and modified chemically to obtain carboxymethylated derivatives (CTM3a). The solution properties of the carboxymethylated polysaccharides were studied systematically in phosphate buffer saline at 37 degrees C. The results indicated that the carboxymethylated glucans still kept hyperbranched structure after carboxymethylation, and existed as a swollen sphere-like chain conformation. The introduction of carboxymethylated groups permitted the formation of hydrogels through crosslinking CTM3a and silk fibroin with carbodiimide chemistry. The resultant hydrogels with porous and interconnected structure displayed good mechanical and swelling properties. This work provides some valuable and fundamental information of the natural hyperbranched polysaccharide from mushroom for further application in biomedical devices and tissue engineering. PMID- 26005155 TI - Fabrication of chitosan microspheres using vanillin/TPP dual crosslinkers for protein antigens encapsulation. AB - Microspheres were prepared from water soluble chitosan using dual vanillin/TPP crosslinkers. Placebo (C1), Bovine serum albumin (BSA) (C2), monovalent tetanus toxoid (TT) (C3) and divalent tetanus (TT) and diphtheria toxoids (DT) (C4) encapsulated microspheres were studied in terms of size (1-4 MUm), encapsulation efficiency (75-80%), swelling and mucoadhesion (56-68%). FT-IR, TGA, XRD and SEM characterization of microspheres suggested specific interaction, more thermal stability, amorphous nature and rough surfaces of encapsulated microspheres. EDS confirmed the co-crosslinking and ninhydrin tests were showing higher crosslinking density. Zeta potential was 47.7 to 66.2 +mV indicating the potential stability of the colloidal system. Equilibrium adsorption isotherms described encapsulated microspheres followed the Langmuir isotherm model, suggesting monolayer adsorption of the mucin on microspheres. In-vitro release studies up to four weeks indicated zero order kinetics and obeyed swelling controlled super case II transport release mechanism. Thus, the present study could be helpful in developing the multivalent oral vaccine. PMID- 26005156 TI - Partial and total C-6 oxidation of gelling carrageenans. Modulation of the antiviral activity with the anionic character. AB - The optimal conditions for the full C-6 oxidation of kappa- and iota-carrageenans using (2,2,6,6-tetramethylpiperidinyl)oxy (TEMPO) in the presence of sodium hypochlorite and sodium bromide were assessed. The fully oxidized products were characterized by NMR spectroscopy. Partially oxidized products were also obtained and analyzed by chemical and spectroscopical methods. The antiviral activity of carrageenans against herpes simplex virus HSV-1 and HSV-2 determined by plaque reduction assay, was not largely affected by full oxidation of the polysaccharides, but an increase in activity was detected by partial oxidation. A specific overoxidation on C-2 of the 3,6-anhydrogalactose moiety of kappa carrageenan was identified, solved experimentally and rationalized through the application of molecular modeling. PMID- 26005157 TI - Water soluble biocompatible vesicles based on polysaccharides and oligosaccharides inclusion complexes for carotenoid delivery. AB - Since carotenoids are highly hydrophobic, air- and light-sensitive hydrocarbon compounds, developing methods for increasing their bioavailability and stability towards irradiation and reactive oxygen species is an important goal. Application of inclusion complexes of "host-guest" type with polysaccharides and oligosaccharides such as arabinogalactan, cyclodextrins and glycyrrhizin minimizes the disadvantages of carotenoids when these compounds are used in food processing (colors and antioxidant capacity) as well as for production of therapeutic formulations. Cyclodextrin complexes which have been used demonstrated enhanced storage stability but suffered from poor solubility. Polysaccharide and oligosaccharide based inclusion complexes play an important role in pharmacology by providing increased solubility and stability of lipophilic drugs. In addition they are used as drug delivery systems to increase absorption rate and bioavailability of the drugs. In this review we summarize the existing data on preparation methods, analysis, and chemical reactivity of carotenoids in inclusion complexes with cyclodextrin, arabinogalactan and glycyrrhizin. It was demonstrated that incorporation of carotenoids into the "host" macromolecule results in significant changes in their physical and chemical properties. In particular, polysaccharide complexes show enhanced photostability of carotenoids in water solutions. A significant decrease in the reactivity towards metal ions and reactive oxygen species in solution was also detected. PMID- 26005158 TI - N-(furfural) chitosan hydrogels based on Diels-Alder cycloadditions and application as microspheres for controlled drug release. AB - In this study, chitosan was chemically modified by reductive amination in a two step process. The synthesis of N-(furfural) chitosan (FC) was confirmed by FT-IR and (1)H NMR analysis, and the degrees of substitution were estimated as 8.3 and 23.8%. The cross-linkable system of bismaleimide (BM) and FC shows that FC shared properties of furan-maleimide chemistry. This system produced non-reversible hydrogel networks by Diels-Alder cycloadditions at 85 degrees C. The system composed of BM and FC (23.8% substitution) generated stronger hydrogel networks than those of FC with an 8.3% degree of substitution. Moreover, the FC-BM system was able to produce hydrogel microspheres. Environmental scanning electron microscopy revealed the surface of the microspheres to be non-porous with small protuberances. In water, the microspheres swelled, increasing their volume by 30%. Finally, microspheres loaded with methylene blue were able to release the dye gradually, obeying second-order kinetics for times less than 600 min. This behavior suggests that diffusion is governed by the relaxation of polymer chains in the swelled state, thus facilitating drug release outside the microspheres. PMID- 26005159 TI - Gender-specific association between the cytoplasmic poly(A) binding protein 4 rs4660293 single nucleotide polymorphism and serum lipid levels. AB - Cytoplasmic poly(A) binding protein 4 (PABPC4) is an RNA-processing protein which has an important role in regulating gene expression. The association of the PABPC4 rs4660293 single nucleotide polymorphism (SNP) and serum lipid profiles has, to the best of our knowledge, not previously been studied in the Chinese population. The present study aimed to investigate the association between the PABPC4 rs4660293 SNP and several environmental factors with serum lipid levels in the Mulao and Han populations. A total of 727 individuals of Mulao nationality and 729 individuals of Han nationality were randomly selected from stratified randomized samples from a previous study by our group. Genotypes of the PABPC4 rs4660293 SNP were determined via polymerase chain reaction and restriction fragment length polymorphism analyses and subsequently confirmed by direct sequencing. Serum levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) B were higher in the Mulao group than those in the Han group (P<0.01 for each). The genotypic and allelic frequencies of the PABPC4 rs4660293 SNP were significantly different between males and females in the Mulao population (P<0.05 for each), while no significant difference was detected between those of males and females amongst the Han population. The frequency of the G allele was higher in Mulao males than in Mulao females (22.12 vs. 13.44%). The G allele carriers were found to have higher total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and ApoAI levels in Han females but not in Han males, and lower TC and HDL-C levels in Mulao females but not in Mulao males than those of the G allele non-carriers (P<0.05 for all). These associations were confirmed by multiple linear regression analysis (P<0.05 0.001). Serum lipid parameters were also correlated with multiple environmental factors (P<0.05-0.001). The PABPC4 rs4660293 SNP was associated with serum TC, HDL-C, LDL-C and ApoAI levels in these study populations; however, the association varied between the Mulao and Han populations. A gender-specific association was identified in the populations of the two ethnic groups. PMID- 26005160 TI - A call to restrict prescribing antibiotics for travellers' diarrhea--Travel medicine practitioners can play an active role in preventing the spread of antimicrobial resistance. PMID- 26005161 TI - Obtaining a reliable travel history from III returned travellers. PMID- 26005162 TI - Mapping chikungunya fever in municipalities of one coastal department of Colombia (Sucre) using geographic information system (GIS) during 2014 outbreak: Implications for travel advice. PMID- 26005163 TI - Evaluation of rabies immunogenicity and tolerability following a purified chick embryo cell rabies vaccine administered concomitantly with a Japanese encephalitis vaccine. AB - BACKGROUND: For individuals traveling at short notice to rabies and Japanese encephalitis (JE) endemic countries, concomitant administration of travel vaccines within a short period is often required. METHODS: The aim of this study was to determine whether an accelerated (one-week: Days 1-8) pre-exposure rabies (Rabipur((r)), Novartis Vaccines) vaccination regimen administered concomitantly with a Japanese encephalitis (JE) vaccination (Ixiaro((r)), Valneva) regimen, is non-inferior to the standard (four-week: Days 1, 8, 29) rabies regimen administered alone or concomitantly with the JE vaccine. Healthy adults (18 to <= 65 years) were randomized into Rabies + JE-Standard, Rabies + JE-Accelerated, Rabies-Standard and JE-Standard groups. Relative immunogenicity for rabies in each regimen was assessed using the rapid fluorescent focus inhibition test. Safety was evaluated up to and including Day 57. RESULTS: Non-inferior immunogenicity for rabies was established between the Rabies + JE-Accelerated group compared to both the Rabies-Standard and Rabies + JE-Standard groups; as well as between the Rabies + JE-Standard regimen and the Rabies-Standard regimen. By Day 57, adequate neutralizing levels were achieved by 97-100% of subjects across all groups. Adverse events (AEs) were comparable for all groups. CONCLUSIONS: An accelerated pre-exposure rabies and JE vaccination regimen is non inferior to the standard four-week rabies regimen and may thus provide a more convenient regimen for individuals traveling to endemic countries at short notice. NCT01662440. PMID- 26005164 TI - Clinical study of C3-C4 level surgical cases of cervical spondylosis. AB - OBJECTIVE: The purpose of this study was to elucidate the pathological characteristics of C3-C4 cervical spondylotic myelopathy (CSM). METHODS: Single level anterior cervical discectomy and fusion (ACDF) was performed at C3-C4 in 53 patients (38 men, 15 women). The mean duration of preoperative symptoms was 6.0 months. Fifty-three non C3-C4 ACDF patients of our random sample of ACDF patients were compared to the C3-C4 ACDF patients. Clinical outcomes were assessed according to the Japanese Orthopedic Association score (JOA score), the Neurosurgical Cervical Spine Scale (NCSS), and the Nurick scale. And radiological findings including C2-C7 lordosis, C3-C4 range of intervertebral motion (ROM), C2 C7 ROM, and C3-C4%ROM in the cervical spine were evaluated in both groups. RESULTS: The recovery rates of JOA score and the NCSS in C3-C4 ACDF patients were 62.5% and 62.1%, respectively. The radiological study of C3-C4 ACDF patients showed that they had significant cervical lordosis, and cervical motion was dependent on the C3-C4 segment, which accounted for 39.8% of C2-C7 ROM (total motion). CONCLUSION: In C3-C4 ACDF patients, not only static factors, but dynamic factors (instability) at the C3-C4 level contributed to the major causes of CSM. PMID- 26005165 TI - The bigger, the better? About the size of decompressive hemicraniectomies. AB - INTRODUCTION: Decompressive hemicraniectomy (DHC) is a treatment option in refractory ICP elevation and malignant infarction. A minimum diameter of 12 cm has been widely accepted as mandatory for effective decompression for ICP control. Complete hemispheric exposure is frequently advocated to further reduce the risk of parenchymal shear stress, hemorrhage and swelling. At the same time, superior efficacy and comparable risk profile of a more extensive decompression have yet to be established. MATERIAL AND METHODS: We reviewed 74 patients with comprehensive clinical data sets undergoing DHC from 2008 to 2013 at our institution. With a minimum threshold of 12 cm in AP diameter being observed in all cases, patients were grouped according to the absolute size of maximum AP diameter (<18 cm, >= 18 cm) and surface estimate (<180 cm(2), >= 180 cm(2)). Surgical technique, efficacy of ICP control, surgical complications and early clinical course were recorded. RESULTS: Baseline demographics were comparable in both groups. Surgery was effective in relieving or preventing intracranial hypertension in all patients, irrespective of craniectomy size. With smaller craniectomies, immediate surgical and secondary complications such as parenchymal herniation, hemorrhage, or swelling did not occur more frequently. CONCLUSION: Due to the heterogeneity of underlying disease, a conclusion as to effect of craniectomy size on long-term outcome cannot be made based on this study. However, if the obligatory lower threshold of 12 cm for DHC size and decompression to the temporal base are observed, a smaller craniectomy is equally effective in relieving intracranial hypertension. While not inadvertently associated with a more favorable surgical risk profile, it does not increase the risk for early secondary complications such as parenchymal shear stress, hemorrhage and swelling. PMID- 26005166 TI - Early neurologically-focused follow-up after cardiac arrest improves quality of life at one year: A randomised controlled trial. AB - BACKGROUND: Survivors of a cardiac arrest frequently have cognitive and emotional problems and their quality of life is at risk. We developed a brief nursing intervention to detect cognitive and emotional problems, provide information and support, promote self-management, and refer them to specialised care if necessary. This study examined its effectiveness. METHODS: Multicentre randomised controlled trial with measurements at two weeks, three months and twelve months after cardiac arrest. 185 adult cardiac arrest survivors and 155 caregivers participated. Primary outcome measures were societal participation and quality of life of the survivors at one year. Secondary outcomes were the patient's cognitive functioning, emotional state, extended daily activities and return to work, and the caregiver's well-being. Data were analysed using 'intention to treat' linear mixed model analyses. RESULTS: After one year, patients in the intervention group had a significantly better quality of life on SF-36 domains Role Emotional (estimated mean differences (EMD)=16.38, p=0.006), Mental Health (EMD=6.87, p=0.003) and General Health (EMD=8.07, p=0.010), but there was no significant difference with regard to societal participation. On the secondary outcome measures, survivors scored significantly better on overall emotional state (HADS total, EMD=-3.25, p=0.002) and anxiety (HADS anxiety, EMD=-1.79, p=0.001) at one year. Furthermore, at three months more people were back at work (50% versus 21%, p=0.006). No significant differences were found for caregiver outcomes. CONCLUSION: The outcomes of cardiac arrest survivors can be improved by an intervention focused on detecting and managing the cognitive and emotional consequences of a cardiac arrest. TRIAL REGISTRATION: Current controlled trials, ISRCTN74835019. PMID- 26005167 TI - Coronary vasospasm after dobutamine stress echocardiogram triggered by esmolol. PMID- 26005168 TI - Clinical impacts of high-sensitivity C-reactive protein reduction for secondary prevention in Asian patients with one-year survivor after acute myocardial infarction. PMID- 26005170 TI - Accessory pathway ablation in a patient with situs inversus totalis and Wolff Parkinson-White electrocardiographic pattern: Mirror approach. PMID- 26005169 TI - Stimulation of cardiomyogenesis from mouse embryonic stem cells by nuclear translocation of cardiotrophin-1. AB - BACKGROUND: Cardiotrophin-1 (CT-1) controls cardiomyogenesis of mouse embryonic stem (ES) cells. OBJECTIVES: To investigate the signaling pathway underlying the action of CT-1 on cardiac cell differentiation. METHODS: Protein expression was analyzed by western blot technique and cardiac areas by immunohistochemistry. Calcium, reactive oxygen species (ROS) and nitric oxide (NO) were assessed by microfluorometry using fluo-4, H2DCF, and DAF-2DA, respectively. Gene inactivation of CT-1 was achieved by siRNA technology. RESULTS: CT-1 as well as its receptor gp 130 were transiently upregulated during differentiation of ES cells. Exogenous CT-1 enhanced cardiomyogenesis, increased the cardiac transcription factors MEF2c, Nkx-2.5, TEAD3 and GATA4, the cardiac proteins alpha actinin, MLC2a, MYH7, MLC1a, MLC2v and HCN4 as well as vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), fibroblast growth factor-2 (FGF-2) and atrial natriuretic peptide (ANP). CT-1 downregulation by small interfering RNA (siRNA) inhibited cardiomyogenesis and decreased VEGF, PDGF-BB, FGF-2 and ANP expression. CT-1 raised intracellular calcium which was abolished by the intracellular calcium chelator BAPTA, AM and thapsigargin. Moreover, CT-1 treatment increased ROS, followed by NO generation and NOS3 activation. During ES cell differentiation CT-1 was translocated to the cell nucleus. Exogenous CT-1 induced nuclear translocation of endogenous CT-1, which was inhibited by BAPTA, the NOS inhibitor L-N(G)-Nitroarginine methyl ester (l NAME), the radical scavenger N-(2-mercaptopropionyl)-glycine (NMPG) as well as the janus kinase 2 (JAK2) inhibitor AG490 and the PI3 kinase (PI3K) inhibitor LY294002. CONCLUSIONS: Nuclear translocation of CT-1 regulates cardiomyogenesis of ES cells and involves calcium, NO, ROS as well as CT-1 regulated signaling pathways. PMID- 26005171 TI - Ventilatory inefficiency in patients with rheumatic mitral stenosis. PMID- 26005172 TI - Histamine induced coronary artery spasm, fish consumption and Kounis syndrome. PMID- 26005173 TI - Long-term processed and unprocessed red meat consumption and risk of heart failure: A prospective cohort study of women. AB - BACKGROUND: Epidemiologic studies of red meat consumption in relation to risk of heart failure (HF) are limited. We examined the associations between long-term unprocessed red meat and processed red meat consumption and incidence of HF in women. METHODS: The population-based prospective Swedish Mammography Cohort included 34,057 women, aged 48-83 years, with no history of HF or ischemic heart disease at baseline (in 1997). Meat consumption was assessed using a self administered food-frequency questionnaire (FFQ) in 1997 as well as FFQ administered in 1987-90. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During a mean follow-up of 13.2 years, 2806 women were diagnosed with HF. Consumption of processed meat (FFQ 1997) was statistically significant positively associated with HF incidence. Women who consumed >= 50 g/day processed red meat compared to those who consumed < 25 g/day had a 1.23 (95% CI: 1.09-1.39, P-trend=0.003) higher risk of HF. Long-term high consumption of processed red meat (average from 1987 to 1997) >= 50 g/day in comparison to < 25 g/day was associated with HR: 1.30 (95% CI: 1.05-1.60, P-trend=0.002). Women who consistently consumed (in both 1987 and 1997) >= 50 g/day vs. < 25 g/day had a 1.78 (95% CI: 1.00-3.16) higher risk of HF. Consumption of unprocessed meat was not associated with increased risk of HF incidence. CONCLUSIONS: Findings from this prospective study of women indicate that processed red meat, but not unprocessed red meat, consumption is associated with an increased risk of HF incidence. PMID- 26005174 TI - Giant right atrium due to rheumatic tricuspid valve stenosis. PMID- 26005175 TI - Aortic and right ventricular rupture in a patient after transcatheter aortic valve implantation; The direction of the calcification predicts aortic annulus rupture. PMID- 26005176 TI - Chamber-specific changes in calcium-handling proteins in the type 2 diabetic human heart with preserved ejection fraction. PMID- 26005177 TI - Loss of consciousness via oculocardiac reflex during deep breath-hold diving. A case report. PMID- 26005178 TI - Diastolic function, fasting plasma glucose and left ventricular mass index. PMID- 26005179 TI - Clinical determinants of acetylcholine-induced coronary artery spasm in Australian patients. PMID- 26005180 TI - Pericardial cyst hydatid rupture complicated by pericardial tamponade. PMID- 26005181 TI - Association of serum leptin with future left ventricular structure and function: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND/OBJECTIVES: Earlier studies differ on whether serum leptin is associated with adverse or beneficial cardiac structure. We determined the association between serum leptin with subsequent cardiac structure and function. METHODS: MESA is a multicenter longitudinal study of Black, White, Hispanic and Asian-American men and women. Cardiac MRI (CMR) was completed 6 to 8 years after leptin was measured. Left ventricular (LV) mass and volumes were indexed to body surface area. Multivariable linear regression models were constructed to assess the associations between leptin and risk factor adjusted (age, race, gender, systolic blood pressure, anti-hypertensive usage, LDL, HDL, hyperlipidemia medication usage, diabetes, diabetic medication usage, chronic kidney disease, alcohol and tobacco use, adiponectin and BMI) CMR variables. RESULTS: Relative to participants in the lowest quintile of leptin concentration, participants in the highest quintile had a lower risk factor adjusted LV mass (-14 g), LV mass index (-9 g/m(2)), LV end diastolic volume index (LVEDVi) (-7 ml/m(2)), LV end systolic volume index (LVESVi) (-3 ml/m(2)) and stroke volume (-5 ml) (all p<=0.05). On regression analysis, a doubling of leptin concentration was associated with lower LV mass (-2.5 g +/- 0.7 g), LV mass index (-1.7 +/- 0.3g/m(2)), LVEDVi (-1.5 +/- 0.4 ml/m(2)), LVESVi (-0.7 +/- 0.2 ml/m(2)) and stroke volume (-1.0 +/- 0.5 ml) (all p <= 0.05). CONCLUSIONS: Higher leptin was associated with more favorable subsequent cardiac structure. Further study is needed to assess the prognostic and therapeutic implications of these observations. PMID- 26005182 TI - Mechanisms of apoptosis inhibition in Chlamydia pneumoniae-infected neutrophils. AB - The obligatory intracellular bacterium Chlamydia pneumoniae (C. pneumoniae) can survive and multiply in neutrophil granulocytes. Since neutrophils are short living cells, inhibition of neutrophil apoptosis appears to play a major role in the productive infection of neutrophils by C. pneumoniae. In the present study, we have investigated which survival pathways and which events of the apoptotic process are modulated in C. pneumoniae-infected neutrophils. All infection experiments were carried out using primary human neutrophils in vitro. We show that infection with C. pneumoniae activates PI3K/Akt as well as the ERK1/2 and p38 MAP kinases and present evidence that activation of the PI3K/Akt and ERK1/2 pathways are essential to initiate the apoptosis delay in C. pneumoniae-infected neutrophils. Both the PI3K/Akt and ERK1/2 pathways are involved in the maintained expression of the anti-apoptotic protein Mcl-1. In addition, we also showed that the PI3K/Akt pathway leads to the activation of NF-kappaB-dependent release of IL 8 by infected neutrophils. Infection with C. pneumoniae activates the PI3K/Akt and ERK1/2 MAPK survival pathways in neutrophils, induces the NF-kappaB dependent release of IL-8 and leads to the maintenance of Mcl-1 expression in neutrophils. PMID- 26005183 TI - Catchment-scale distribution of radiocesium air dose rate in a mountainous deciduous forest and its relation to topography. AB - A large number of air dose rate measurements were collected by walking through a mountainous area with a small gamma-ray survey system, KURAMA-II. The data were used to map the air dose rate of a mountainous deciduous forest that received radiocesium from the Fukushima Dai-ichi Nuclear Power Plant accident. Measurements were conducted in a small stream catchment (0.6 km(2) in area) in August and September 2013, and the relationship between air dose rates and the mountainous topography was examined. Air dose rates increased with elevation, indicating that more radiocesium was deposited on ridges, and suggesting that it had remained there for 2.5 y with no significant downslope migration by soil erosion or water drainage. Orientation in relation to the dominant winds when the radioactive plume flowed to the catchment also strongly affected the air dose rates. Based on our continuous measurements using the KURAMA-II, we describe the variation in air dose rates in a mountainous forest area and suggest that it is important to consider topography when determining sampling points and resolution to assess the spatial variability of dose rates and contaminant deposition. PMID- 26005184 TI - The role of polyunsaturated fatty acids and GPR40 receptor in brain. AB - Polyunsaturated fatty acids (PUFAs) are found in abundance in the nervous system. They perform significant functions for example boosting synaptogenesis, neurogenesis, inducing antinociception, stimulating gene expression and neuronal activity, preventing apoptosis and neuroinflammation. G-protein-coupled receptor 40 (GPR40), also called free fatty acid receptor 1 (FFA1), is ubiquitously expressed in various regions of the human brain including the olfactory bulb, midbrain, medulla oblongata, hippocampus, hypothalamus, cerebral cortex, cerebellum and in the spinal cord. GPR40, when binding with polyunsaturated fatty acids (PUFAs) has shown promising therapeutic potential. This review presents current knowledge regarding the pharmacological properties of GPR40 and addresses its functions in brain, with a focus on neurodevelopment & neurogenesis. Furthermore, the demonstration of GPR40 involvement in several neuropathological conditions such as apoptosis, inflammatory pain, Alzheimer's disease and Parkinson's disease. Although the results are encouraging, further research is needed to clarify their role in the treatment of inflammatory pain, Alzheimer's disease and Parkinson's disease. This article is part of the Special Issue entitled 'Lipid Sensing G Protein-Coupled Receptors in the CNS'. PMID- 26005187 TI - Efficacy of intraoperative dexmedetomidine compared with placebo for surgery in adults: a meta-analysis of published studies. AB - Dexmedetomidine (Dex) demonstrates sedative and analgesic effects. We investigated the intraoperative and postoperative effects of intraoperative Dex administration during surgery in adult patients. A search for randomized placebo controlled trials was conducted in Pubmed and Embase databases to identify randomized controlled clinical trials using intraoperative Dex for surgery in adult population. Outcome assessed were: intraoperative and postoperative opioid consumption, time of recovery from anesthesia, postoperative pain, and postoperative nausea or vomiting (PONV) in the first 24 hours. Data from each trial were combined to calculate pooled odds ratios (OR), mean difference (MD) or standardized mean difference (SMD) and 95% confidence interval (95 % CI). Heterogeneity was measured using I2 statistics. Eighteen randomized controlled trials were analyzed. Dex was administered to 815 patients and 410 received placebo. Overall, Dex significantly decreased intraoperative opioid consumption (SMD=-1.58 [-2.98, -0.19], I2=95 %, P<0.00001), but did not decrease time of recovery from anesthesia (SMD=-0.13 [-1.60, 1.34] minutes, I2=95 %, P<0.00001). Dex significantly reduced postoperative opioid consumption (SMD=-1.58 [-2.98, 0.19], I2=95 %, P<0.00001), postoperative pain intensity (SMD=-0.73 [-1.19, 0.27], I2=62 %, P=0.03), and the prevalence of PONV (OR=0.43 [0.27, 0.69], I2=0 %, P=0.46). This meta-analysis shows that intraoperative Dex administration in adult patients reduces intra and postoperative opioid consumption, postoperative pain and PONV. Time of recovery is not affected. PMID- 26005188 TI - Treadmill gait training combined with functional electrical stimulation on hip abductor and ankle dorsiflexor muscles for chronic hemiparesis. AB - The purpose of this study was to investigate the effects of treadmill training (TT) with functional electrical stimulation (FES) applied to the gluteus medius (GM) and tibialis anterior (TA) muscles on gait and balance performance in individuals with chronic hemiparetic stroke. Thirty-six participants with chronic hemiparesis were recruited to this study and randomly distributed into three groups: TT with FES applied to the GM and TA muscles (TTFES-GM+TA group, 12 patients); TT with FES applied to the TA muscle (TTFES-TA group, 12 patients); and TT only (control group, 12 patients). All participants underwent 20 sessions of TT with a harness (30min five times per week for 4 weeks). They also received regular physical therapy for 1h five times per week for 4 weeks. All participants were assessed before and after training using digital muscle testing, the Medical Research Council (MRC) scale, the 6-min walk test (6MWT), and spatiotemporal parameters. After training, the TTFES-GM+TA group showed significant improvement in hip abductor strength, Berg Balance Scale score, 6MWT result, MRC scale score grade, gait velocity, and cadence compared to the TTFES-TA group and control group. These findings show that TT with FES applied to the GM and TA muscles increased lower limb muscle strength and improved balance and gait capacities. Therefore, TT with FES applied to the GM and TA could be a beneficial intervention in clinical settings for individuals with chronic hemiparetic stroke. PMID- 26005189 TI - Induction of apoptosis in oral squamous carcinoma cells by pyrrolo-1,5 benzoxazepines. AB - Oral cancer (OC) is a largely asymptomatic disease, resulting in one of the highest mortality rates of any cancer. OC is currently ranked as the sixth most common cancer in the world, according to a recent World Health Organization analysis, and its prevalence is increasing, both in western and developing regions. Depending on the stage of OC, treatment strategies include surgery, radiation therapy and chemotherapy, or a combination thereof. As with numerous other types of cancer, resistance to conventional chemotherapeutic drugs is increasing in oral squamous cell carcinoma (OSCC). The present study aimed to investigate the use of a novel group of compounds, the pyrrolo-1,5-benzoxazepines (PBOXs), as a therapeutic alternative for the treatment of OC. PBOXs are microtubule-targeting agents that are able to induce apoptosis in numerous cancer cell types, thereby preventing tumour cell proliferation. Ca9.22 gingival and TR146 buccal cell lines were used as models for OSSC. Cell viability and proliferation in the presence of two PBOXs: PBOX-6 and PBOX-15, was monitored using an AlamarBlueTM assay. Flow cytometric analysis of propidium iodide-stained cells was used to determine the DNA content, and therefore the percentage of cells in each phase of the cell cycle. Microtubule disruption was determined by indirect immunofluorescence staining. Changes in protein expression and degradation were determined by western blotting. The results of the present study indicated that both PBOX-6 and -15 were able to induce apoptotic cell death by disrupting the microtubule network in both cell lines. The EC50 values were subsequently calculated for both PBOX-6 and -15, and PBOX-15 was shown to possess a higher potency. Both compounds displayed anti-proliferative effects mediated through sustained G2/M arrest accompanied by tubulin disruption, and a decrease in DNA repair protein poly (ADP ribose) polymerase expression. These findings suggest that PBOXs may prove useful, either alone or in combination with other agents, in the treatment of chemotherapeutic resistant OSCC. PMID- 26005190 TI - Adsorption and transport of methane in biochars derived from waste wood. AB - Mitigation of landfill gas (LFG) is among the critical aspects considered in the design of a landfill cover in order to prevent atmospheric pollution and control global warming. In general, landfill cover soils can partially remove methane (CH4) through microbial oxidation carried out by methanotrophic bacteria present within them. The oxidizing capacity of these landfill cover soils may be improved by adding organic materials, such as biochar, which increase adsorption and promote subsequent or simultaneous oxidation of CH4. In this study, seven wood derived biochars and granular activated carbon (GAC) were characterized for their CH4 adsorption capacity by conducting batch and small-scale column studies. The effects of influential factors, such as exposed CH4 concentration, moisture content and temperature on CH4 adsorption onto biochars, were determined. The CH4 transport was modeled using a 1-D advection-dispersion equation that accounted for sorption. The effects of LFG inflow rates and moisture content on the combined adsorption and transport properties of biochars were determined. The maximum CH4 adsorption capacity of GAC (3.21mol/kg) was significantly higher than that of the biochars (0.05-0.9mol/kg). The CH4 gas dispersion coefficients for all of the biochars ranged from 1*10(-3) to 3*10(-3)m(2)s(-1). The presence of moisture significantly suppressed the extent of methane adsorption onto the biochars and caused the methane to break through within shorter periods of time. Overall, certain biochar types have a high potential to enhance CH4 adsorption and transport properties when used as a cover material in landfills. However, field-scale studies need to be conducted in order to evaluate the performance of biochar-based cover system under a more dynamic field condition that captures the effect of seasonal and temporal changes. PMID- 26005191 TI - Phenylhydrazine administration accelerates the development of experimental cerebral malaria. AB - Phenylhydrazine (PHZ) treatment is generally used to enhance parasitemia in infected mice models. Transient reticulocytosis is commonly observed in iron deficient anemic hosts after treatment with iron supplementation, and is also associated with short-term hemolysis caused by PHZ treatment. In this study, we investigated the relationship between reticulocytosis and cerebral malaria (CM) in a murine model induced by PHZ administration before Plasmodium berghei ANKA (PbA) infection. Mortality and parasitemia were checked daily. Pro-inflammatory cytokines and IL-10 were quantified by ELISA. The expression of CXCL9, CXCL10, CCL5, and CXCR3 mRNAs was determined by real-time PCR. Brain sequestration of CD4(+) and CD8(+) T cells and populations of splenic Th1 CD4(+) T cells, dendritic cells (DCs), CD11b(+) Gr1(+) cells, and regulatory T cells (Tregs) were assessed by FACS. PHZ administration dramatically increased parasitemia from day 3 to day 5 post infection (p.i.) compared with the untreated control infected mice group; also, CM developed at day 5 p.i., compared with day 7 p.i. in untreated control infected mice, as well as significantly decreased blood-brain barrier function (P < 0.001). PHZ administration during PbA infection significantly increased the expression of CXCL9 (P <0.05) and VCAM-1 (P <0.001) in the brain, increased the expression of CXCL10, CCL5 and CXCR3, and significantly increased the recruitment of CD4(+) and CD8(+) T cells (P <0.001 and P <0.01, respectively) as well as CD11b(+) Gr1(+) cells to the brain. In addition, PHZ administration significantly increased the numbers of IL-12 secreting DCs at days 3 and 5 p.i. compared to those of untreated control infected mice (P <0.001 and P <0.01, respectively). Consequently, the activation of CD4(+) T cells, especially the expansion of the Th1 subset (P <0.05), was significantly and dramatically enhanced and was accompanied by marked increases in the production of protein and/or mRNA of the Th1-type pro-inflammatory mediators, IFN-gamma and TNF-alpha (P <0.01 for both for protein; P <0.05 for TNF alpha mRNA). Our results suggest that, compared to healthy individuals, people suffering from reticulocytosis may be more susceptible to severe malaria infection in malaria endemic areas. This has implications for the most appropriate selection of treatment, which may also cause reticulocytosis in patients living in such areas. PMID- 26005192 TI - Caregiver distress and associated factors in dementia care in the community setting in China. AB - The aim of this study was to investigate caregiver distress in reacting to the care recipient's behavioral and psychological symptoms of dementia (BPSD) and factors contributing to caregiver distress in the community setting in China. One hundred and fifty-two family caregivers of people with dementia in community settings were assessed using the Chinese version of the Neuropsychiatric Inventory-Questionnaire and the Social Support Rating Scale. The prevalence of BPSD and caregiver distress in reacting to BPSD was higher in China than those reported in high income countries. The most common individual BPSD were apathy/indifference, depression/dysphoria and night-time behaviors. Delusions, hallucinations and apathy/indifference were rated as the most distressing to caregivers. BPSD contributed most to caregiver distress. The high level of caregiver distress identified in this study suggests that dementia services and caregiver support should be established in the public healthcare system to target the needs of people with dementia and their caregivers. PMID- 26005193 TI - Management of Chronic Hand Eczema. AB - Management of hand eczema is complex because of the broad range of different pathogeneses, courses, and prognoses. Furthermore, the efficacy of most available treatments is not well established and the more severe forms can have a major impact on the patient's quality of life. Patient education, preventive measures, and the use of emollients are the mainstays in the management of hand eczema. High-potency topical corticosteroids are the treatment of choice, with calcineurin inhibitors used for maintenance. Phototherapy or systemic treatments are indicated in patients who do not respond to topical treatments. Switching from topical treatments should not be delayed to avoid sensitizations, time off work, and a negative impact on quality of life. Alitretinoin is the only oral treatment approved for use in chronic hand eczema. PMID- 26005194 TI - Chronic treatment with resveratrol, a natural polyphenol found in grapes, alleviates oxidative stress and apoptotic cell death in ovariectomized female rats subjected to chronic cerebral hypoperfusion. AB - OBJECTIVES: Resveratrol appears to have neuroprotective potential in various animal models of brain disorders including cerebral ischemia and neurodegenerative diseases. Chronic cerebral hypoperfusion is a well-known pathological condition contributing to the neurodegenerative diseases such as vascular dementia. Purpose of the present study is to evaluate the possible therapeutic potential of resveratrol in a model of vascular dementia of ovariectomized female rats. Assessment of the potential was based on the determination of brain oxidative status, caspase-3 level, glial fibrillary acidic protein (GFAP), and neuronal damage on hippocampus and cerebral cortex. METHODS: For creating the model of chronic cerebral hypoperfusion, ovariectomized female Wistar rats were subjected to the modified two vessel occlusion method, with the right common carotid artery being occluded first and the left one a week later. RESULTS: At the 15th day following the ligation, neuronal damage was accompanied by the increased immunoreactivities of both GFAP and caspase-3, and significant neurodegeneration was evident in the hippocampus and cortex, all of which were significantly alleviated with resveratrol treatment (10 mg/kg). Biochemical analysis revealed that the resveratrol treatment decreased lipid peroxidation and restored reduced glutathione level as well. DISCUSSION: The collected data of the present study suggest that the administration of resveratrol may provide a remarkable therapeutic benefit for vascular dementia, which is most likely related to the prevention of both apoptotic cell death and oxidative stress. We believe that therapeutic efficacy of resveratrol deserves to be tested for potential clinical application in postmenopausal elderly women suffering from vascular dementia. PMID- 26005195 TI - Positive shift of Nav1.8 current inactivation curve in injured neurons causes neuropathic pain following chronic constriction injury. AB - Neuropathic pain is a global medical concern, characterized by spontaneous pain, heat hyperalgesia and mechanical allodynia. The condition has been associated with alterations in the voltage-gated sodium channels, Nav1.8 and Nav1.9, in nociceptive neurons termed nociceptors. However, an explanation for the contribution of these channels to the phenotype observed in neuropathic pain remains to be elucidated. The changes induced by chronic constriction injury (CCI) to Nav1.8 and Nav1.9 mRNA and protein levels, as well as electrical currents in injured and contralateral non-injured dorsal root ganglion (DRG) neurons are described in the present study. A marked downregulation was observed for each Nav isoform transcript and protein expressed in injured neurons with the exception of the Nav1.9 protein, which exhibited no change, while in contralateral non-injured neurons, the levels of protein and mRNA remained unchanged. Nav isoform functional analysis was then performed in L(4-6) DRG neurons 14 days after CCI. The Nav1.8 current density was markedly decreased in injured DRG neurons following CCI. The voltage-dependent activation of the Nav1.8 channel in these neurons was shifted to depolarized potentials by 5.3 mV, while it was shifted to hyperpolarized potentials by 10 mV for inactivation. The electrophysiological function of Nav1.9 was not affected by CCI. The present study demonstrated that ectopic discharge following CCI, which was likely induced by a positive shift in the Nav1.8 current inactivation curve in injured neurons, enhanced the excitability of the neurons by facilitating tetrodotoxin-resistant sodium channels into the fast inactivation state and did not occur as a result of a compensatory redistribution in the contralateral uninjured neurons. PMID- 26005196 TI - Novelty's effect on memory encoding. AB - It is often thought that novelty benefits memory formation. However, support for this idea mostly comes from paradigms that are open to alternative explanations. In the present study we manipulated novelty in a word-learning task through task irrelevant background images. These background images were either standard (presented repeatedly), or novel (presented only once). Two types of background images were used: Landscape pictures and fractals. EEG was also recorded during encoding. Contrary to the idea that novelty aids memory formation, memory performance was not affected by the novelty of the background. In the evoked response potentials, we found evidence of distracting effects of novelty: both the N1 and P3b components were smaller to words studied with novel backgrounds, and the amplitude of the N2b component correlated negatively with subsequent retrieval. We conclude that although evidence from other studies does suggest benefits on a longer time scale, novelty has no instantaneous benefits for learning. PMID- 26005198 TI - A Pilot Study of a Mindfulness Intervention for Adolescents and the Potential Role of Self-Compassion in Reducing Stress. AB - OBJECTIVE: In this pilot study, we sought to investigate the effects of a mindfulness intervention for adolescents on a community sample of teens. Specifically, we explored the effects of mindfulness training on emotional well being outcomes. Also, we examined the relationship between mindfulness and self compassion at baseline-predicted outcome measures. DESIGN: This design was a pre /post-pilot intervention study. Paired t-tests were conducted to examine change in outcome measures before and after the mindfulness intervention. Multiple regression was also conducted to investigate the influence of baseline mindfulness and self-compassion on outcome measures. SETTING: The study took place after school in a classroom at a local university. PARTICIPANTS: Overall 28 adolescents age 10-18 years from two different cohorts participated in this study. INTERVENTION: Learning to BREATHE, a mindfulness curriculum designed specifically for adolescents and taught in six 1.5h sessions, was implemented. MAIN OUTCOME MEASURES: The outcome measures, life satisfaction and perceived stress, were included in an online survey before and after the mindfulness intervention. RESULTS: Results indicated that mindfulness, self-compassion, perceived stress, and life satisfaction improved from pre-intervention to post intervention. Further, self-compassion (taught within the mindfulness intervention) was negatively related to perceived stress post-intervention while controlling for baseline stress. These findings suggest that mindfulness may be an effective intervention for improving indicators of emotional well-being among an adolescent population. Additionally, self-compassion may be a pathway through which youth can lower stress. Future research should examine self-compassion as a potential factor in promoting emotional well-being. PMID- 26005200 TI - Influence of sexual arousability on partner communication mediators of condom use among African American female adolescents. AB - Background Ample evidence shows that partner sexual communication is related to condom use. Although communication about safer sex may often occur when sexual arousal is high, no studies have examined arousability, one's propensity for sexual arousal and partner sexual communication. The purpose of this study was to examine associations between sexual arousability and partner-related mediators of condom use among African American female adolescents, who have disproportionate risk for HIV and sexually transmissible infections (STIs). METHODS: The study analysed self-reported baseline data from 701 African American females aged 14-20 years participating in a HIV/STI trial. Linear regression models examined associations between arousability and partner-related mediators of condom use (partner sexual communication self-efficacy, partner sexual communication frequency, sex refusal self-efficacy and condom use self-efficacy), controlling for age, impulsivity and relationship power. RESULTS: Greater arousability was significantly associated with reduced levels of each partner communication outcome assessed (partner sexual communication self-efficacy, partner sexual communication frequency and sex refusal self-efficacy) but was not associated with condom use self-efficacy. CONCLUSIONS: Arousal and other positive aspects of sex have largely been ignored by HIV/STI prevention efforts, which primarily focus on individual behaviour. A population-level sexual health approach focusing on sexual wellbeing may reduce stigma, facilitate partner sexual communication and be more effective at reducing HIV/STI rates than traditional approaches. PMID- 26005199 TI - Fibromyalgia Impact and Mindfulness Characteristics in 4986 People with Fibromyalgia. AB - CONTEXT AND OBJECTIVE: A growing body of literature suggests that mindfulness techniques may be beneficial in fibromyalgia. A recent systematic review and meta analysis of six trials indicated improvement in depressive symptoms and quality of life, calling for increased rigor and use of standardized measures in future trials. The purpose of the study was to examine the relationship between mindfulness [as measured by the Five Facet Mindfulness Questionnaire (FFMQ)] and fibromyalgia impact [as measured by the Revised Fibromyalgia Impact Questionnaire (FIQR)]. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey was conducted with adults diagnosed with fibromyalgia from a national fibromyalgia advocacy foundation e-mail list. RESULTS: A total of 4986 respondents represented all 50 states in the United States and 30 countries. FIQR scores demonstrated moderate to severe fibromyalgia with the majority of subjects (59%) scoring <=60. Scores on the FFMQ subscales ranged from 20.8 to 27.3, with highest scores for the observe subscale. All subscale correlations were small to moderate and indicated that more severe fibromyalgia impact was associated with less mindfulness except in the observe scale (r = .15, P > .000). No clinical or demographics explained as much variance in the FIQR total as any of the mindfulness subscales. CONCLUSIONS: Fibromyalgia patients experience symptoms that may be alleviated by mindfulness interventions. Baseline values for the observe subscale of the FFMQ were unexpectedly high. Further research is needed to know if this may be due to non-mindful observations and should be noted when the FFMQ is used in fibromyalgia clinical trials. PMID- 26005201 TI - Internet-based interpretation bias modification for social anxiety: A pilot study. AB - BACKGROUND AND OBJECTIVES: The biased interpretation of ambiguous social situations is considered a maintaining factor of Social Anxiety Disorder (SAD). Studies on the modification of interpretation bias have shown promising results in laboratory settings. The present study aims at pilot-testing an Internet-based training that targets interpretation and judgmental bias. METHOD: Thirty-nine individuals meeting diagnostic criteria for SAD participated in an 8-week, unguided program. Participants were presented with ambiguous social situations, were asked to choose between neutral, positive, and negative interpretations, and were required to evaluate costs of potential negative outcomes. Participants received elaborate automated feedback on their interpretations and judgments. RESULTS: There was a pre-to-post-reduction of the targeted cognitive processing biases (d = 0.57-0.77) and of social anxiety symptoms (d = 0.87). Furthermore, results showed changes in depression and general psychopathology (d = 0.47-0.75). Decreases in cognitive biases and symptom changes did not correlate. The results held stable accounting for drop-outs (26%) and over a 6-week follow-up period. Forty-five percent of the completer sample showed clinical significant change and almost half of the participants (48%) no longer met diagnostic criteria for SAD. LIMITATIONS: As the study lacks a control group, results lend only preliminary support to the efficacy of the intervention. Furthermore, the mechanism of change remained unclear. CONCLUSION: First results promise a beneficial effect of the program for SAD patients. The treatment proved to be feasible and acceptable. Future research should evaluate the intervention in a randomized-controlled setting. PMID- 26005197 TI - Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets. AB - Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions. PMID- 26005202 TI - Associations Between Fast-Food Consumption and Body Mass Index: A Cross-Sectional Study in Adult Twins. AB - Obesity is a substantial health problem in the United States, and is associated with many chronic diseases. Previous studies have linked poor dietary habits to obesity. This cross-sectional study aimed to identify the association between body mass index (BMI) and fast-food consumption among 669 same-sex adult twin pairs residing in the Puget Sound region around Seattle, Washington. We calculated twin-pair correlations for BMI and fast-food consumption. We next regressed BMI on fast-food consumption using generalized estimating equations (GEE), and finally estimated the within-pair difference in BMI associated with a difference in fast-food consumption, which controls for all potential genetic and environment characteristics shared between twins within a pair. Twin-pair correlations for fast-food consumption were similar for identical (monozygotic; MZ) and fraternal (dizygotic; DZ) twins, but were substantially higher in MZ than DZ twins for BMI. In the unadjusted GEE model, greater fast-food consumption was associated with larger BMI. For twin pairs overall, and for MZ twins, there was no association between within-pair differences in fast-food consumption and BMI in any model. In contrast, there was a significant association between within pair differences in fast-food consumption and BMI among DZ twins, suggesting that genetic factors play a role in the observed association. Thus, although variance in fast-food consumption itself is largely driven by environmental factors, the overall association between this specific eating behavior and BMI is largely due to genetic factors. PMID- 26005203 TI - Altered Functional Connectivity Strength in Abstinent Chronic Cocaine Smokers Compared to Healthy Controls. AB - Past research involving cocaine and resting-state functional connectivity (RSFC) has shown altered functional connectivity within the frontal and between the frontal and other cortical and subcortical brain regions in chronic users of cocaine. However, there have been discrepancies in literature regarding the relationship between RSFC between brain regions and cocaine use behavior. This study explored the RSFC between brain regions in cocaine smokers abstinent from cocaine use for 72 h and healthy controls. Also, the relationship between RSFC between brain regions and various cocaine use measures (cocaine use duration; frequency, and money spent on cocaine/week) was examined. Twenty chronic cocaine users and 17 controls completed a resting-state scan and an anatomical MPRAGE scan. Group independent component analysis performed on functional magnetic resonance imaging data identified 13 ICs pertaining to distinct resting-state networks, and group-level differences were examined. To examine inter-network functional connectivity between brain regions, these 13 ICs were divided into 61 distinct regions of interest (ROIs). Correlations were calculated between 61 ROI time series. For the ROI pairs that significantly differed from controls in connectivity strength, correlations were computed between connectivity strength and cocaine use measures. Results showed an enhanced RSFC within the sensory motor cortex and the left frontal-parietal network in cocaine users than controls. An increased inter-network RSFC between frontal-temporal and frontal parietal brain regions, and a decreased RSFC between parietal-parietal, occipital limbic, occipital-occipital, and occipital-parietal brain regions was found in cocaine users. This study demonstrated that intra-network connectivity strength of sensory motor cortex was negatively correlated with years of cocaine use. Inter-network connectivity strength between occipital-limbic brain regions was positively correlated with years of cocaine use, while connectivity strength within occipital brain regions was negatively related to cocaine use frequency and money spent on cocaine per week in abstinent cocaine users. PMID- 26005205 TI - Molecular characterization and expression analysis of five chitinases associated with molting in the Chinese mitten crab, Eriocheir sinensis. AB - Chitinases are crucial enzymes required for chitin degradation in crustaceans. Five chitinase genes, namely, EsCht1, EsCht2, EsCht3, EsCht4, and EsCht6, were identified in the Chinese mitten crab, Eriocheir sinensis. The open reading frames (ORF) of EsCht1, EsCht2, EsCht3, EsCht4 and EsCht6 ranged from 1182 bp to 1926 bp with encoding proteins between 393 and 641 amino acid residues. Domain analysis of the chitinase proteins showed that most EsChts contained the catalytic domain and the chitin-binding domain (CBD) connected with the serine/threonine (S/T)-rich linker region. Phylogenetic analyses revealed that EsChts with orthologs in crustaceans were divided into six groups. The tissue dependent, developmental stage-related and molting stage-related differential expression patterns of chitinase genes were determined using end-point polymerase chain reaction and real-time quantitative polymerase chain reaction. During the molting cycle, EsCht2 mRNA expression in the cuticle and EsCht4 and EsCht6 mRNA expression in the hepatopancreas were 108-fold (P<0.05), 19-fold (P<0.05) and 12 fold (P<0.05) higher in the premolt (D(0-1)) than in the intermolt stage, respectively. The results indicated that EsCht1 from group 1 might play a role in the digestion of chitin-containing food; EsCht2 from group 2 likely played a role in the degradation of chitinous cuticle during molting for growth and during the post-embryonic development; EsCh3 from group 3 potentially had a dual role in the digestion of chitin-containing food and defense against chitin-bearing pathogens. EsCht3, EsCht4, and EsCht6 were highly expressed in the reproductive system, indicating their potential roles in reproductive molting. Differential expression patterns of the chitinase genes suggested that they might have distinct biological functions in developmental stage- and physiological growth-related and reproductive molting processes, which are essential for metamorphosis, growth, and reproduction. The findings of this study might form a basis for further studies on the functions of chitinases in E. sinensis and other crustaceans. PMID- 26005204 TI - Characterization of carbonic anhydrase XIII in the erythrocytes of the Burmese python, Python molurus bivittatus. AB - Carbonic anhydrase (CA) is one of the most abundant proteins found in vertebrate erythrocytes with the majority of species expressing a low activity CA I and high activity CA II. However, several phylogenetic gaps remain in our understanding of the expansion of cytoplasmic CA in vertebrate erythrocytes. In particular, very little is known about isoforms from reptiles. The current study sought to characterize the erythrocyte isoforms from two squamate species, Python molurus and Nerodia rhombifer, which was combined with information from recent genome projects to address this important phylogenetic gap. Obtained sequences grouped closely with CA XIII in phylogenetic analyses. CA II mRNA transcripts were also found in erythrocytes, but found at less than half the levels of CA XIII. Structural analysis suggested similar biochemical activity as the respective mammalian isoforms, with CA XIII being a low activity isoform. Biochemical characterization verified that the majority of CA activity in the erythrocytes was due to a high activity CA II-like isoform; however, titration with copper supported the presence of two CA pools. The CA II-like pool accounted for 90 % of the total activity. To assess potential disparate roles of these isoforms a feeding stress was used to up-regulate CO2 excretion pathways. Significant up regulation of CA II and the anion exchanger was observed; CA XIII was strongly down-regulated. While these results do not provide insight into the role of CA XIII in the erythrocytes, they do suggest that the presence of two isoforms is not simply a case of physiological redundancy. PMID- 26005206 TI - Cyclothymia reloaded: A reappraisal of the most misconceived affective disorder. AB - Data emerging from both academic centers and from public and private outpatient facilities indicate that from 20% to 50% of all subjects that seek help for mood, anxiety, impulsive and addictive disorders turn out, after careful screening, to be affected by cyclothymia. The proportion of patients who can be classified as cyclothymic rises significantly if the diagnostic rules proposed by the DSM-5 are reconsidered and a broader approach is adopted. Unlike the DSM-5 definition based on the recurrence of low-grade hypomanic and depressive symptoms, cyclothymia is best identified as an exaggeration of cyclothymic temperament (basic mood and emotional instability) with early onset and extreme mood reactivity linked with interpersonal and separation sensitivity, frequent mixed features during depressive states, the dark side of hypomanic symptoms, multiple comorbidities, and a high risk of impulsive and suicidal behavior. Epidemiological and clinical research have shown the high prevalence of cyclothymia and the validity of the concept that it should be seen as a distinct form of bipolarity, not simply as a softer form. Misdiagnosis and consequent mistreatment are associated with a high risk of transforming cyclothymia into severe complex borderline-like bipolarity, especially with chronic and repetitive exposure to antidepressants and sedatives. The early detection and treatment of cyclothymia can guarantee a significant change in the long-term prognosis, when appropriate mood-stabilizing pharmacotherapy and specific psychological approaches and psychoeducation are adopted. The authors present and discuss clinical research in the field and their own expertise in the understanding and medical management of cyclothymia and its complex comorbidities. PMID- 26005207 TI - Recent trends in the incidence of anxiety and prescription of anxiolytics and hypnotics in children and young people: An e-cohort study. AB - BACKGROUND: Little is known regarding the recognition of anxiety in children and young people (CYP) in primary care. This study examined trends in the presentation, recognition and recording of anxiety and of anxiolytic and hypnotic prescriptions for CYP in primary care. METHOD: A population-based retrospective electronic cohort of individuals aged 6-18 years between 2003 and 2011 within the Secure Anonymised Information Linkage (SAIL) Databank primary care database was created. Incidence rates were calculated using person years at risk (PYAR) as a denominator accounting for deprivation, age and gender. RESULTS: We identified a cohort of 311,343 registered individuals providing a total of 1,546,489 person years of follow up. The incidence of anxiety symptoms more than tripled over the study period (Incidence Rate Ratio (IRR)=3.55, 95% CI 2.65-4.77) whilst that of diagnosis has remained stable. Anxiolytic/hypnotic prescriptions for the cohort as a whole did not change significantly over time; however there was a significant increase in anxiolytic prescriptions for the 15-18 year age group (IRR 1.62, 95% CI 1.30-2.02). LIMITATIONS: There was a lack of reliable information regarding other interventions available or received at a primary, secondary or tertiary level such as psychological treatments. CONCLUSIONS: There appears to be a preference over time for the recording of general symptoms over diagnosis for anxiety in CYP. The increase in anxiolytic prescriptions for 15-18 year olds is discrepant with current prescribing guidelines. Specific guidance is required for the assessment and management of CYP presenting with anxiety to primary care, particularly older adolescents. PMID- 26005208 TI - The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice. AB - The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis. PMID- 26005210 TI - The thrombogenic potential of contrast media and thrombotic complications after coronary angiography. PMID- 26005209 TI - Beneficial effects of the traditional medicine Igongsan and its constituent ergosterol on dextran sulfate sodium-induced colitis in mice. AB - Ulcerative colitis (UC) is a type of inflammatory bowel disease and is considered a chronic gastrointestinal disorder. Igongsan (IGS) is a Korean herbal medicine, which has been used to treat digestive disorders. However, the ameliorative effect and molecular mechanisms of IGS in intestinal inflammation have not yet been studied in detail. The present study aimed to investigate the protective effects of IGS and its constituent, ergosterol, in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Colitis was induced in mice by supplementing their drinking water with 5% (w/v) DSS for 7 days. The effects of IGS were then determined on DSS-induced clinical signs of colitis, including weight loss, colon shortening, diarrhea and obscure/gross bleeding. In addition, the effects of IGS were determined on the expression levels of inflammation associated genes in the colon tissue of DSS-treated mice. The results of the present study demonstrated that mice treated with DSS exhibited marked clinical symptoms, including weight loss and reduced colon length. Treatment with IGS attenuated these symptoms and also suppressed the expression levels of tumor necrosis factor-alpha and interleukin-6, as well as the expression of cyclooxygenase-2 in the colon tissue of DSS-treated mice. IGS also reduced the activation of the transcription factor nuclear factor-kappaB p65 in the colon tissue of DSS-treated mice. In addition, ergosterol was shown to attenuate the DSS-induced clinical symptoms of colitis in mice. In conclusion, the present study provided experimental evidence that IGS may be a useful therapeutic drug for patients with UC. PMID- 26005211 TI - The association of apolipoprotein E (APOE) gene polymorphisms with atherosclerosis susceptibility: a meta-analysis. AB - BACKGROUND: The aim of the present meta-analysis was to evaluate the association of apolipoprotein E (APOE) gene polymorphism with atherosclerosis risk. METHODS: Electronic databases (PubMed, Embase and Springer link) were used to search for relevant articles addressing on the association of APOE gene polymorphism with atherosclerosis. Meta-analysis was performed for 7 genotype models: epsilon2/epsilon2 vs. epsilon3/epsilon3, epsilon2/epsilon3 vs. epsilon3/epsilon3, epsilon2/epsilon4 vs. epsilon3/epsilon3, epsilon3/epsilon4 vs. epsilon3/epsilon3, epsilon4/epsilon4 vs. epsilon3/epsilon3, epsilon2 vs. epsilon3, and epsilon4 vs. epsilon3. The pooled odds ratios and 95% confidence intervals were used to assess relationship between alleles, as well as genotypes and susceptibility of atherosclerosis. Subgroup analysis was performed based on ethnicities and clinical phenotypes of atherosclerosis (clinical and subclinical atherosclerosis). Sensitivity analysis was performed to check the effects of one study on other studies. RESULTS: The overall analysis and subgroup analysis based on ethnicities showed no significant correlation between APOE polymorphisms and the susceptibility of atherosclerosis. However, subgroup analysis based on clinical phenotypes of atherosclerosis showed that, compared with APOE3 gene, APOE4 gene carriers were prone to clinical atherosclerosis incidence. Sensitive analysis did not change the overall effect in this study. CONCLUSIONS: This meta analysis demonstrates that there is no significant association between APOE polymorphism (APOE2, APOE3) and the susceptibility of atherosclerosis, while APOE4 gene may be a risk factor for the clinical atherosclerosis. However, further studies based on larger sample sizes are still needed. PMID- 26005212 TI - Management of cardiogenic shock in the setting of ST-elevation myocardial infarction: controversies and future directions. AB - The treatment of patients with ST-segment elevation myocardial infarction (STEMI) has changed dramatically since reperfusion therapy has been adopted more commonly, yet 5-10% of patients still develop cardiogenic shock and remain a therapeutic challenge in the setting of STEMI. In this review, we outline the available evidence from randomized controlled trials and registries, including risk factors, diagnostic tools, and various treatments. The main focus of this report is on the currently available treatment options (revascularization, intra aortic balloon counterpulsation), emerging treatment options (percutaneous hemodynamic support, extracorporeal membrane oxygenation), and ongoing efforts to design systems of care to more efficiently care for these patients. PMID- 26005213 TI - Friedrich Lenz (1922-2014). PMID- 26005214 TI - Cholestanol-loaded-cyclodextrin improves the quality of stallion spermatozoa after cryopreservation. AB - This study was to compare the effect of adding cholesterol or cholestanol loaded cyclodextrins in stallion sperm prior to cryopreservation to optimize sperm cryosurvival. Ejaculates from each of eight stallions were diluted to 120 million cells in a S-MEDIUM diluent. The diluted sperm were sub-divided into three treatments: no additive (control); 0.75mg of cyclodextrin pre-loaded with cholesterol (CLC)/120 million sperm (positive control); 1.5mg CLC/120 million sperm; 0.75mg of cyclodextrin pre-loaded with cholestanol (CnLC)/120 million sperm; and 1.5mg CnLC/120 million sperm. To set the experiments, the treated sperm were incubated for 15min at 22 degrees C to allow for the incorporation of cholesterol or cholestanol. In each experiment, treated sperm incubated for 15min at 22 degrees C to allow for incorporation of cholesterol or cholestanol. The samples were then diluted 1:5 (v/v) with Lactose-Egg Yolk diluent and cooled to 5 degrees C over a 2h period. Loaded into 0.25ml polyvinylchloride straws, frozen in liquid nitrogen vapor for 10min, and then plunged into liquid nitrogen until further use. Higher percentages of motile sperm and viable cells were achieved after thawing for stallion sperm treated with CLC and CnLC compared to control (P<0.05). Addition of CnLC also resulted in more number sperm binding to chicken egg perivitelline membrane (CEPM) after cryopreservation than cholestanol and control sperm (P<0.05). In conclusion, CnLC and CLC improved the percentage of post-thaw motility of equine sperm and CnLC provided greater binding efficiency. PMID- 26005216 TI - Against finality: Darwin, Mill and the end of essentialism. PMID- 26005215 TI - Participation of autophagy in the cytotoxicity against breast cancer cells by cisplatin. AB - Breast cancer is one of the most common cancers affecting women worldwide. Conventional chemotherapy is still one of the major approaches to the treatment of breast cancer. Autophagy, also termed as type II programmed cell death (PCD), exhibits either a protumorigenic or antitumorigenic function. In the present study, we investigated whether autophagy could be involved in the effect of chemotherapy against breast cancer. Epirubicin, docetaxel, methotrexate, cyclophosphamide, fluorouracil (5-FU) and cisplatin were applied in the present investigation. All of these chemotherapeutics presented cytotoxicity against breast cancer cells. DsRed-LC3 reporter assay revealed that only docetaxel and cisplatin induced autophagy. Autophagy inhibitor 3-methyladenine (3-MA) strengthened the cytotoxicity of docetaxel, yet impaired the cytotoxicity of cisplatin, suggesting that docetaxel stimulates protumorigenic autophagy, while cisplatin-induced autophagy could be antitumorigenic. Real-time PCR revealed that cisplatin upregulated multiple autophagy-related genes, including AMBRA1, ATG3, ATG4C, ATG4D, ATG5, ATG7, ATG13, ATG14, ATG16L2, Beclin1, DRAM1, GABARAP, GABARAPL1, GABARAPL2, HDAC6, IRGM, MAP1LC3B and ULK1, indicating that cisplatin induced autophagy through a multiple mechanism involved manner. PMID- 26005217 TI - Growth analysis and yield of two varieties of groundnut (Arachis hypogaea L.) as influenced by different weed control methods. AB - Field trials were carried out to evaluate the effects of seven weed management strategies on the growth and yield of two groundnut varieties (Samnut 10 and MK 373) for two successive seasons (2010-2011). The experimental layout was a split plot complete randomized block design with three replications. The two groundnut varieties showed identical pattern of results for leaf area index, dry matter accumulation, relative growth rate, net assimilation rate and crop growth rate as well as yield. All the weed control treatments significantly enhanced the growth and yield compared with the weedy check. The weed free check had the highest growth but the highest yield was recorded from rice straw mulch at 0.1 m depth + one hand weeding at 6 weeks after sowing (WAS) due to increase in number of matured pods per plant, seed weight per plant and 100-seed weight. The results showed that rice straw mulch at 0.1 m depth + one hand weeding at 6 WAS was better agronomical practice for enhancing growth and yield of groundnut. This enhancement could be as a result of its positive influence on physiological parameters such as leaf area index, dry matter accumulation, relative growth rate, net assimilation rate and crop growth rate. Its use is also ecofriendly as it limits the need for synthetic herbicide. PMID- 26005218 TI - Small worker bumble bees (Bombus impatiens) are hardier against starvation than their larger sisters. AB - In bumble bees (Bombus spp.), where workers within the same colony exhibit up to a tenfold difference in mass, labor is divided by body size. Current adaptive explanations for this important life history feature are unsatisfactory. Within the colony, what is the function of the smaller workers? Here, we report on the differential robustness to starvation of small and large worker bumble bees (Bombus impatiens); when nectar is scarce, small workers remain alive significantly longer than larger workers. The presence of small workers, and size variation in general, might act as insurance against times of nectar shortage. These data may provide a novel, adaptive explanation, independent of division of labor, for size polymorphism within the worker caste. PMID- 26005220 TI - Recognition errors by honey bee (Apis mellifera) guards demonstrate overlapping cues in conspecific recognition. AB - Honey bee (Apis mellifera) entrance guards discriminate nestmates from intruders. We tested the hypothesis that the recognition cues between nestmate bees and intruder bees overlap by comparing their acceptances with that of worker common wasps, Vespula vulgaris, by entrance guards. If recognition cues of nestmate and non-nestmate bees overlap, we would expect recognition errors. Conversely, we hypothesised that guards would not make errors in recognizing wasps because wasps and bees should have distinct, non-overlapping cues. We found both to be true. There was a negative correlation between errors in recognizing nestmates (error: reject nestmate) and nonnestmates (error: accept non-nestmate) bees such that when guards were likely to reject nestmates, they were less likely to accept a nonnestmate; conversely, when guards were likely to accept a non-nestmate, they were less likely to reject a nestmate. There was, however, no correlation between errors in the recognition of nestmate bees (error: reject nestmate) and wasps (error: accept wasp), demonstrating that guards were able to reject wasps categorically. Our results strongly support that overlapping cue distributions occur, resulting in errors and leading to adaptive shifts in guard acceptance thresholds. PMID- 26005219 TI - Multifunctional silk-tropoelastin biomaterial systems. AB - New multifunctional, degradable, polymeric biomaterial systems would provide versatile platforms to address cell and tissue needs in both in vitro and in vivo environments. While protein-based composites or alloys are the building blocks of biological organisms, similar systems have not been largely exploited to dates to generate ad hoc biomaterials able to control and direct biological functions, by recapitulating their inherent structural and mechanical complexities. Therefore, we have recently proposed silk-tropoelastin material platforms able to conjugate a mechanically robust and durable protein, silk, to a highly flexible and biologically active protein, tropoelastin. This review focuses on the elucidation of the interactions between silk and tropoelastin in order to control material structure, properties, and ultimately functions. In addition, an approach is provided for novel material designs to provide tools to control biological outcomes via surface roughness, elasticity, and net charge for neuronal and mesenchymal stem cell-based tissue engineering. PMID- 26005221 TI - Compensatory growth following transient intraguild predation risk in predatory mites. AB - Compensatory or catch-up growth following growth impairment caused by transient environmental stress, due to adverse abiotic factors or food, is widespread in animals. Such growth strategies commonly balance retarded development and reduced growth. They depend on the type of stressor but are unknown for predation risk, a prime selective force shaping life history. Anti-predator behaviours by immature prey typically come at the cost of reduced growth rates with potential negative consequences on age and size at maturity. Here, we investigated the hypothesis that transient intraguild predation (IGP) risk induces compensatory or catch-up growth in the plant-inhabiting predatory mite Phytoseiulus persimilis. Immature P. persimilis were exposed in the larval stage to no, low or high IGP risk, and kept under benign conditions in the next developmental stage, the protonymph. High but not low IGP risk prolonged development of P. persimilis larvae, which was compensated in the protonymphal stage by increased foraging activity and accelerated development, resulting in optimal age and size at maturity. Our study provides the first experimental evidence that prey may balance developmental costs accruing from anti-predator behaviour by compensatory growth. PMID- 26005222 TI - Ambient Air Temperature Does Not Predict whether Small or Large Workers Forage in Bumble Bees (Bombus impatiens). AB - Bumble bees are important pollinators of crops and other plants. However, many aspects of their basic biology remain relatively unexplored. For example, one important and unusual natural history feature in bumble bees is the massive size variation seen between workers of the same nest. This size polymorphism may be an adaptation for division of labor, colony economics, or be nonadaptive. It was also suggested that perhaps this variation allows for niche specialization in workers foraging at different temperatures: larger bees might be better suited to forage at cooler temperatures and smaller bees might be better suited to forage at warmer temperatures. This we tested here using a large, enclosed growth chamber, where we were able to regulate the ambient temperature. We found no significant effect of ambient or nest temperature on the average size of bees flying to and foraging from a suspended feeder. Instead, bees of all sizes successfully flew and foraged between 16 degrees C and 36 degrees C. Thus, large bees foraged even at very hot temperatures, which we thought might cause overheating. Size variation therefore could not be explained in terms of niche specialization for foragers at different temperatures. PMID- 26005223 TI - Regression Analysis for Differentially Misclassified Correlated Binary Outcomes. AB - In many epidemiological and clinical studies, misclassification may arise in one or several variables, resulting in potentially invalid analytic results (e.g., estimates of odds ratios of interest) when no correction is made. Here we consider the situation in which correlated binary response variables are subject to misclassification. Building upon prior work, we provide an approach to adjust for potentially complex differential misclassification via internal validation sampling applied at multiple study time points. We seek to estimate the parameters of a primary generalized linear mixed model (GLMM) that accounts for baseline and/or time-dependent covariates. The misclassification process is modeled via a second generalized linear model that captures variations in sensitivity and specificity parameters according to time and a set of subject specific covariates that may or may not overlap with those in the primary model. Simulation studies demonstrate the precision and validity of the proposed method. An application is presented based on longitudinal assessments of bacterial vaginosis conducted in the HIV Epidemiology Research (HER) Study. PMID- 26005224 TI - WHO IS PLACED INTO SPECIAL EDUCATION? AB - We use nationally representative data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-99 (ECLS-K) to identify variables measured in the fall of 1998 (when the sample's students were in kindergarten) that predict special education placement by the spring of 2004 (when those not retained were finishing fifth grade). Placement's strongest kindergarten predictor is a student's own level of academic achievement. Also important is the student's frequency of classroom task engagement. There is a "frog-pond" contextual effect - attending an elementary school with high levels of overall student academic ability and behavior increases a student's likelihood of special education placement. This is the case even after statistically controlling for a wide range of individual-, family-, and school-level characteristics. Social class background displayed a weak or statistically non-significant relation with special education placement. However, girls are placed less frequently than boys. African American, Hispanic, and Asian students are placed less frequently than non-Hispanic whites. The under- or equal-placement rates for racial/ethnic minorities are partially explained by their concentration in high-minority schools. PMID- 26005225 TI - The Importance of the Mining Subsidence Reservoirs Located Along the Trans Regional Highway in the Conservation of the Biodiversity of Freshwater Molluscs in Industrial Areas (Upper Silesia, Poland). AB - The objectives of the survey were to analyse the structure of the mollusc communities in the mining subsidence reservoirs that were created as a result of land subsidence over exploited hard coal seams and to determine the most predictive environmental factors that influence the distribution of mollusc species. The reservoirs are located in urbanised and industrialised areas along the Trans-Regional Highway, which has a high volume of vehicular traffic. They all have the same sources of supply but differ in the physical and chemical parameters of the water. In total, 15 mollusc species were recorded including four bivalve species. Among them Anodonta cygnea is classified as Endangered according to the Polish Red Data Book of Animals and also as Near Threatened according to the European Red List of Non-marine Molluscs. Eleven of the 15 mollusc species are included on the European Red List of Non-marine Molluscs as Least Concern. Conductivity, pH and the concentration of calcium were the parameters most associated with the distribution of mollusc species. Canonical correspondence analysis showed that Potamopyrgus antipodarum, Radix balthica, Physella acuta, Gyraulus crista and Pisidium casertanum were associated with higher conductivity and lower pH values. A. cygnea, Anodonta anatina and Ferrissia fragilis were negatively influenced by these parameters of the water. The results of this survey showed that the mining subsidence reservoirs located in urbanised and industrialised areas provide refuges for rare and legally protected species and that they play an essential role in the dispersal of alien species as well. PMID- 26005226 TI - Time use of youths by immigrant and native-born parents: ATUS results. AB - A study based on the American Time Use Survey finds that, although native-born and immigrant youths pass their days in similar ways, Latino and Asian immigrant youths spend more time studying and less time in paid employment than do native born youths; more time devoted to study may be a mechanism by which immigrants achieve educational mobility. PMID- 26005227 TI - The more g-loaded, the more heritable, evolvable, and phenotypically variable: Homology with humans in chimpanzee cognitive abilities. AB - Expanding on a recent study that identified a heritable general intelligence factor (g) among individual chimpanzees from a battery of cognitive tasks, we hypothesized that the cognitive abilities that are more g-loaded would be more heritable and would present more additive genetic variance, in addition to showing more phenotypic variability. This pattern was confirmed, and is comparable to that found in humans, indicating fundamental homology. Finally, tool use presented the highest heritability, the largest amount of additive genetic variance and of phenotypic variance, consistent with previous findings indicating that it is associated with high interspecies variance and evolutionary rates in comparative primate studies. PMID- 26005229 TI - Hydrological response to climate change in a glacierized catchment in the Himalayas. AB - The analysis of climate change impact on the hydrology of high altitude glacierized catchments in the Himalayas is complex due to the high variability in climate, lack of data, large uncertainties in climate change projection and uncertainty about the response of glaciers. Therefore a high resolution combined cryospheric hydrological model was developed and calibrated that explicitly simulates glacier evolution and all major hydrological processes. The model was used to assess the future development of the glaciers and the runoff using an ensemble of downscaled climate model data in the Langtang catchment in Nepal. The analysis shows that both temperature and precipitation are projected to increase which results in a steady decline of the glacier area. The river flow is projected to increase significantly due to the increased precipitation and ice melt and the transition towards a rain river. Rain runoff and base flow will increase at the expense of glacier runoff. However, as the melt water peak coincides with the monsoon peak, no shifts in the hydrograph are expected. PMID- 26005228 TI - Probabilistic Common Spatial Patterns for Multichannel EEG Analysis. AB - Common spatial patterns (CSP) is a well-known spatial filtering algorithm for multichannel electroencephalogram (EEG) analysis. In this paper, we cast the CSP algorithm in a probabilistic modeling setting. Specifically, probabilistic CSP (P CSP) is proposed as a generic EEG spatio-temporal modeling framework that subsumes the CSP and regularized CSP algorithms. The proposed framework enables us to resolve the overfitting issue of CSP in a principled manner. We derive statistical inference algorithms that can alleviate the issue of local optima. In particular, an efficient algorithm based on eigendecomposition is developed for maximum a posteriori (MAP) estimation in the case of isotropic noise. For more general cases, a variational algorithm is developed for group-wise sparse Bayesian learning for the P-CSP model and for automatically determining the model size. The two proposed algorithms are validated on a simulated data set. Their practical efficacy is also demonstrated by successful applications to single trial classifications of three motor imagery EEG data sets and by the spatio temporal pattern analysis of one EEG data set recorded in a Stroop color naming task. PMID- 26005230 TI - Authorship in IPCC AR5 and its implications for content: climate change and Indigenous populations in WGII. AB - This essay examines the extent to which we can expect Indigenous Knowledge, understanding, and voices on climate change ('Indigenous content') to be captured in WGII of the IPCC Fifth Assessment Report (AR5), based on an analysis of chapter authorship. Reviewing the publishing history of 309 chapter authors (CAs) to WGII, we document 9 (2.9%) to have published on climate change and Indigenous populations and involved as authors in 6/30 chapters. Drawing upon recent scholarship highlighting how authorship affect structure and content of assessment reports, we argue that, unaddressed, this will affect the extent to which Indigenous content is examined and assessed. While it is too late to alter the structure of AR5, there are opportunities to prioritize the recruitment of contributing authors and reviewers with expertise on Indigenous issues, raise awareness among CAs on the characteristics of impacts, adaptation, and vulnerability faced by Indigenous peoples, and highlight how Indigenous perspectives can help broaden our understanding of climate change and policy interventions. PMID- 26005231 TI - Climate change: impacts on electricity markets in Western Europe. AB - This paper studies some impacts of climate change on electricity markets, focusing on three climate effects. First, demand for electricity is affected because of changes in the temperature. Second, changes in precipitation and temperature have impact on supply of hydro electric production through a shift in the inflow of water. Third, plant efficiency for thermal generation will decrease because the temperature of water used to cool equipment increases. To find the magnitude of these partial effects, as well as the overall effects, on Western European energy markets, we use the multi-market equilibrium model LIBEMOD. We find that each of the three partial effects changes the average electricity producer price by less than 2%, while the net effect is an increase of only 1%. The partial effects on total electricity supply are small, and the net effect is a decrease of 4%. The greatest effects are found for Nordic countries with a large market share for reservoir hydro. In these countries, annual production of electricity increases by 8%, reflecting more inflow of water, while net exports doubles. In addition, because of lower inflow in summer and higher in winter, the reservoir filling needed to transfer water from summer to winter is drastically reduced in the Nordic countries. PMID- 26005232 TI - North American terrestrial CO2 uptake largely offset by CH4 and N2O emissions: toward a full accounting of the greenhouse gas budget. AB - The terrestrial ecosystems of North America have been identified as a sink of atmospheric CO2 though there is no consensus on the magnitude. However, the emissions of non-CO2 greenhouse gases (CH4 and N2O) may offset or even overturn the climate cooling effect induced by the CO2 sink. Using a coupled biogeochemical model, in this study, we have estimated the combined global warming potentials (GWP) of CO2, CH4 and N2O fluxes in North American terrestrial ecosystems and quantified the relative contributions of environmental factors to the GWP changes during 1979-2010. The uncertainty range for contemporary global warming potential has been quantified by synthesizing the existing estimates from inventory, forward modeling, and inverse modeling approaches. Our "best estimate" of net GWP for CO2, CH4 and N2O fluxes was -0.50 +/- 0.27 Pg CO2 eq/year (1 Pg = 1015 g) in North American terrestrial ecosystems during 2001-2010. The emissions of CH4 and N2O from terrestrial ecosystems had offset about two thirds (73 %+/-14 %) of the land CO2 sink in the North American continent, showing large differences across the three countries, with offset ratios of 57 % +/- 8 % in US, 83 % +/- 17 % in Canada and 329 % +/- 119 % in Mexico. Climate change and elevated tropospheric ozone concentration have contributed the most to GWP increase, while elevated atmospheric CO2 concentration have contributed the most to GWP reduction. Extreme drought events over certain periods could result in a positive GWP. By integrating the existing estimates, we have found a wide range of uncertainty for the combined GWP. From both climate change science and policy perspectives, it is necessary to integrate ground and satellite observations with models for a more accurate accounting of these three greenhouse gases in North America. PMID- 26005233 TI - Detection of point landmarks in multidimensional tensor data. AB - This paper describes a unified approach to the detection of point landmarks-whose neighborhoods convey discriminant information-including multidimensional scalar, vector, and higher-order tensor data. The method is based on the interpretation of generalized correlation matrices derived from the gradient of tensor functions, a probabilistic interpretation of point landmarks, and the application of tensor algebra. Results on both synthetic and real tensor data are presented. PMID- 26005234 TI - Educational Attainment and Timing to First Union across Three Generations of Mexican Women. AB - We use data from Wave 3 of the Mexican Family Life Survey (N = 7276) and discrete time regression analyses to evaluate changes in the association between educational attainment and timing to first union across three generations of women in Mexico, including a mature cohort (born between 1930 and 1949), a middle cohort (born between 1950 and 1969), and a young cohort (born between 1970 and 1979). Mirroring prior research, we find a curvilinear pattern between educational attainment and timing to first union for women born between 1930 and 1969, such that once we account for the delaying effect of school enrollment, those with the lowest (0-5 years) and highest levels of education (13+ years) are characterized by the earliest transition to a first union. For women born between 1970 and 1979, however, we find that the pattern between education and first union formation has changed. In contrast to their peers born in earlier cohorts, highly educated women in Mexico are now postponing first union formation relative to the least educated. We draw on competing theories of educational attainment and timing to first union to help clarify these patterns in the context of Mexico. PMID- 26005235 TI - PET/MRI assessment of the infarcted mouse heart. AB - Heart failure originating from myocardial infarction (MI) is a leading cause of death worldwide. Mouse models of ischaemia and reperfusion injury (I/R) are used to study the effects of novel treatment strategies targeting MI, however staging disease and treatment efficacy is a challenge. Damage and recovery can be assessed on the cellular, tissue or whole-organ scale but these are rarely measured in concert. Here, for the first time, we present data showing measures of injury in infarcted mice using complementary techniques for multi-modal characterisation of the heart. We use in vivo magnetic resonance imaging (MRI) to assess heart function with cine-MRI, hindered perfusion with late gadolinium enhancement imaging and muscular function with displacement encoded with stimulated echoes (DENSE) MRI. These measures are followed by positron emission tomography (PET) with 18-F-fluorodeoxyglucose to assess cellular metabolism. We demonstrate a protocol combining each of these measures for the same animal in the same imaging session and compare how the different markers can be used to quantify cardiac recovery on different scales following injury. PMID- 26005236 TI - Moving and sensing without input and output: early nervous systems and the origins of the animal sensorimotor organization. AB - It remains a standing problem how and why the first nervous systems evolved. Molecular and genomic information is now rapidly accumulating but the macroscopic organization and functioning of early nervous systems remains unclear. To explore potential evolutionary options, a coordination centered view is discussed that diverges from a standard input-output view on early nervous systems. The scenario involved, the skin brain thesis (SBT), stresses the need to coordinate muscle based motility at a very early stage. This paper addresses how this scenario with its focus on coordination also deals with sensory aspects. It will be argued that the neural structure required to coordinate extensive sheets of contractile tissue for motility provides the starting point for a new multicellular organized form of sensing. Moving a body by muscle contraction provides the basis for a multicellular organization that is sensitive to external surface structure at the scale of the animal body. Instead of thinking about early nervous systems as being connected to the environment merely through input and output, the implication developed here is that early nervous systems provide the foundation for a highly specific animal sensorimotor organization in which neural activity directly reflects bodily and environmental spatiotemporal structure. While the SBT diverges from the input-output view, it is closely linked to and supported by ongoing work on embodied approaches to intelligence to which it adds a new interpretation of animal embodiment and sensorimotor organization. PMID- 26005238 TI - Variations in Decision-Making Profiles by Age and Gender: A Cluster-Analytic Approach. AB - Using cluster-analysis, we investigated whether rational, intuitive, spontaneous, dependent, and avoidant styles of decision making (Scott & Bruce, 1995) combined to form distinct decision-making profiles that differed by age and gender. Self report survey data were collected from 1,075 members of RAND's American Life Panel (56.2% female, 18-93 years, Mage = 53.49). Three decision-making profiles were identified: affective/experiential, independent/self-controlled, and an interpersonally-oriented dependent profile. Older people were less likely to be in the affective/experiential profile and more likely to be in the independent/self-controlled profile. Women were less likely to be in the affective/experiential profile and more likely to be in the interpersonally oriented dependent profile. Interpersonally-oriented profiles are discussed as an overlooked but important dimension of how people make important decisions. PMID- 26005237 TI - Agent tracking: a psycho-historical theory of the identification of living and social agents. AB - To explain agent-identification behaviours, universalist theories in the biological and cognitive sciences have posited mental mechanisms thought to be universal to all humans, such as agent detection and face recognition mechanisms. These universalist theories have paid little attention to how particular sociocultural or historical contexts interact with the psychobiological processes of agent-identification. In contrast to universalist theories, contextualist theories appeal to particular historical and sociocultural contexts for explaining agent-identification. Contextualist theories tend to adopt idiographic methods aimed at recording the heterogeneity of human behaviours across history, space, and cultures. Defenders of the universalist approach tend to criticise idiographic methods because such methods can lead to relativism or may lack generality. To overcome explanatory limitations of proposals that adopt either universalist or contextualist approaches in isolation, I propose a philosophical model that integrates contributions from both traditions: the psycho-historical theory of agent-identification. This theory investigates how the tracking processes that humans use for identifying agents interact with the unique socio historical contexts that support agent-identification practices. In integrating hypotheses about the history of agents with psychological and epistemological principles regarding agent-identification, the theory can generate novel hypotheses regarding the distinction between recognition-based, heuristic-based, and explanation-based agent-identification. PMID- 26005239 TI - A Method for Assessing the Use of First Person Verb Forms by Preschool-Aged Children with SLI. AB - Children with specific language impairment (SLI) often have extraordinary difficulty in the use of tense and agreement morphemes. Because spontaneous speech samples may not provide a sufficient number of obligatory contexts for these morphemes, structured probe items are often employed. However, these usually emphasize actions that can be readily illustrated through drawings, which tend to have third person subjects. In this paper we describe a method that has been successful in creating obligatory contexts for a first person morpheme - auxiliary am - that heretofore has been assessed exclusively through spontaneous speech samples. Participants were 32 mainstream American English-speaking children comprising three diagnostic subgroups: children with SLI, typically developing age-matched peers, and younger typically developing peers matched for mean length of utterance (MLU). The children participated in a task in which they described their actions for an audience; these descriptions required the use of auxiliary am. The results revealed that the children with SLI used auxiliary am with significantly smaller percentages than both groups of typically developing children, a finding that is consistent with findings that employ other tense and agreement morphemes. Clinical applications of this method are discussed. PMID- 26005240 TI - Computational Insight Concerning Catalytic Decision Points of the Transition Metal Catalyzed [2 + 2 + 1] Cyclocarbonylation Reaction of Allenes. AB - Rhodium and molybdenum catalyzed allenic [2 + 2 + 1] cycloaddition reactions give 4-alkylidene and alpha-alkylidene cylopentenones, respectively. The selective reaction of one double bond of the allene over another is controlled by the transition metal and not the substrate structure. Calculations were performed to explain this unique control element using the B3LYP functional as implemented in Gaussian 03. The 6-31G(d) basis set was applied to all elements except rhodium, which is described with the LANL2 effective core potential and the LANL2DZ basis set. The product-determining step for both reaction pathways is oxidative addition of the metal to the alkynyl allene to form the corresponding metallocycles B and B'. The transition state calculations strongly suggest that geometry constraints imposed by the metal in the transition state are the key controlling factor of the double bond selectivity. The transition state structure of rhodium-catalyzed oxidative addition has a distorted square planar geometry that affords a lower transition state energy when coordinated to the distal double bond of the allene. In turn, the distorted trigonal bipyramidal geometry of molybdenum in the transition state structure imposes conformational constraints upon binding to the distal double on the allene and thus leads to the energetically preferred complexation and reaction with the proximal double bond. PMID- 26005241 TI - A fast heterogeneous algorithm for light fluence rate for prostate photodynamic therapy. AB - To accurately calculate light fluence rate distribution in prostate photodynamic therapy (PDT), optical heterogeneity has to be taken into account. Previous study has shown that a kernel based on analytic solution of the diffusion equation can perform the calculation with accuracy comparable to Finite-element method. An assumption is made that light fluence rate detected at a point in the medium is affected primarily by the optical properties of points (or elements) on the line between the source and the point. The exponential decay term of the light fluence rate is expressed as an integral of effective attenuation coefficient of each point along the line. The kernel method is first developed for a point source and then extended for a linear source. A linear source is considered being composed of multiple point sources and light fluence rate is summation of the fluence rates generated by the point sources. In this study, we have implemented a fast ray-trace algorithm to substantially speed up the calculation. The kernel calculation is compared with FEM calculation and is examined with light fluence rate measurements. The examination with clinical measurement data shows that calculated fluence rates present similar features in distribution as the measurement, with errors of 30%-70% for the peak fluence rates. We concluded that our heterogeneous algorithm is potentially valuable for light fluence rate optimization during interstitial PDT. PMID- 26005242 TI - A Treatment Planning System for Pleural PDT. AB - Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcome. However, common practice uses a point source to deliver light to the pleural cavity. To improve the uniformity of light fluence rate distribution, we have developed a treatment planning system using an infrared camera to track the movement of the point source. This study examines the light fluence (rate) delivered to chest phantom to simulate a patient undergoing pleural PDT. Fluence rate (mW/cm2) and cumulative fluence (J/cm2) was monitored at 7 different sites during the entire light treatment delivery. Isotropic detectors were used for in-vivo light dosimetry. Light fluence rate in the pleural cavity is also calculated using the diffusion approximation with a finite-element model. We have established a correlation between the light fluence rate distribution and the light fluence rate measured on the selected points based on a spherical cavity model. Integrating sphere theory is used to aid the calculation of light fluence rate on the surface of the sphere as well as inside tissue assuming uniform optical properties. The resulting treatment planning tool can be valuable as a clinical guideline for future pleural PDT treatment. PMID- 26005243 TI - In-vivo light dosimetry for HPPH-mediated pleural PDT. AB - This study examines the light fluence (rate) delivered to patients undergoing pleural PDT as a function of treatment time, treatment volume and surface area. The accuracy of treatment delivery is analyzed as a function of the calibration accuracies of each isotropic detector and the calibration integrating sphere. The patients studied here are enrolled in a Phase I clinical trial of HPPH-mediated PDT for the treatment of non-small cell lung cancer with pleural effusion. Patients are administered 4mg per kg body weight HPPH 24-48 hours before the surgery. Patients undergoing photodynamic therapy (PDT) are treated with light therapy with a fluence of 15-60 J/cm2 at 661nm. Fluence rate (mW/cm2) and cumulative fluence (J/cm2) is monitored at 7 different sites during the entire light treatment delivery. Isotropic detectors are used for in-vivo light dosimetry. The anisotropy of each isotropic detector was found to be within 15%. The mean fluence rate delivery and treatment time are recorded. A correlation between the treatment time and the treatment volume is established. The result can be used as a clinical guideline for future pleural PDT treatment. PMID- 26005244 TI - An IR navigation system for real-time treatment guidance of Pleural PDT. AB - Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcome. However, common practice uses a point source to deliver light to the pleural cavity with the light uniformity monitored by 7 detectors placed within the pleural cavity. To improve the uniformity of light fluence rate distribution, we have used a real-time infrared (IR) tracking camera to track the movement of the light point source. The same tracking device is used to determine the surface contour of the treatment area. This study examines the light fluence (rate) delivered between the measurement and calculation in phantom studies. Isotropic detectors were used for in-vivo light dosimetry. Light fluence rate in the pleural cavity is calculated and compared with the in-vivo calculation. Phantom studies show that the surface contour can be determined with an accuracy of 2 mm, with maximum deviation of 5 mm. We can successfully match the calculated light fluence rates with the in-vivo measurements. Preliminary results indicate that the light fluence rate can have up to 50% deviation compared to the prescription in phantom experiments. The IR camera has been used successfully in pleural PDT patient treatment to track the motion of light source in real-time. We concluded that it is feasible to develop an IR camera based system to guide the motion of the light source to improve the uniformity of light distribution. PMID- 26005245 TI - A real-time treatment guidance system for Pleural PDT. AB - Intrapleural photodynamic therapy (PDT) has been used as an adjuvant treatment with lung-sparing surgical treatment for mesothelioma. In the current intrapleural PDT protocol, a moving fiber-based point source is used to deliver the light and the light dose are monitored by 7 detectors placed in the pleural cavity. To improve the delivery of light dose uniformity, an infrared (IR) camera system is used to track the motion of the light sources. A treatment planning system uses feedback from the detectors as well as the IR camera to update light fluence distribution in real-time, which is used to guide the light source motion for uniform light dose distribution. We have reported previously the success of using IR camera to passively monitor the light fluence rate distribution. In this study, the real-time feedback has been implemented in the current system prototype, by transferring data from the IR camera to a computer at a rate of 20 Hz, and by calculation/displaying using Matlab. A dual-correction method is used in the feedback system, so that fluence calculation can match detector readings. Preliminary data from a phantom showed superior light uniformity using this method. Light fluence uniformity from patient treatments is also shown using the correction method dose model. PMID- 26005246 TI - Singlet oxygen dosimetry modeling for photodynamic therapy. AB - Photodynamic therapy (PDT) is an important treatment modality for cancer and other localized diseases. In addition to PDT dose, singlet oxygen (1O2) concentration is used as an explicit PDT dosimetry quantity, because 1O2 is the major cytotoxic agent in photodynamic therapy, and the reaction between 1O2 and tumor tissues/cells determines the treatment efficacy. 1O2 concentration can be obtained by the PDT model, which includes diffusion equation for the light transport in tissue and macroscopic kinetic equations for the generation of the singlet oxygen. This model was implemented using finite-element method (FEM) by COMSOL. In the kinetic equations, 5 photo-physiological parameters were determined explicitly to predict the generation of 1O2. The singlet oxygen concentration profile was calculated iteratively by comparing the model with the measurements based on mice experiments, to obtain the apparent reacted 1O2 concentration as an explicit PDT dosimetry quantity. Two photo sensitizers including Photofrin and BPD Verteporfin, were tested using this model to determine their photo-physiological parameters and the reacted 1O2 concentrations. PMID- 26005247 TI - Light dose verification for pleural PDT. AB - The ability to deliver uniform light dose in Photodynamic therapy (PDT) is critical to treatment efficacy. Current protocol in pleural photodynamic therapy uses 7 isotropic detectors placed at discrete locations within the pleural cavity to monitor light dose throughout treatment. While effort is made to place the detectors uniformly through the cavity, measurements do not provide an overall uniform measurement of delivered dose. A real-time infrared (IR) tracking camera is development to better deliver and monitor a more uniform light distribution during treatment. It has been shown previously that there is good agreement between fluence calculated using IR tracking data and isotropic detector measurements for direct light phantom experiments. This study presents the results of an extensive phantom study which uses variable, patient-like geometries and optical properties (both absorption and scattering). Position data of the treatment is collected from the IR navigation system while concurrently light distribution measurements are made using the aforementioned isotropic detectors. These measurements are compared to fluence calculations made using data from the IR navigation system to verify our light distribution theory is correct and applicable in patient-like settings. The verification of this treatment planning technique is an important step in bringing real-time fluence monitoring into the clinic for more effective treatment. PMID- 26005248 TI - Novel MRI-derived quantitative biomarker for cardiac function applied to classifying ischemic cardiomyopathy within a Bayesian rule learning framework. AB - Characterization of regional left ventricular (LV) function may have application in prognosticating timely response and informing choice therapy in patients with ischemic cardiomyopathy. The purpose of this study is to characterize LV function through a systematic analysis of 4D (3D + time) endocardial motion over the cardiac cycle in an effort to define objective, clinically useful metrics of pathological remodeling and declining cardiac performance, using standard cardiac MRI data for two distinct patient cohorts accessed from CardiacAtlas.org: a) MESA - a cohort of asymptomatic patients; and b) DETERMINE - a cohort of symptomatic patients with a history of ischemic heart disease (IHD) or myocardial infarction. The LV endocardium was segmented and a signed phase-to-phase Hausdorff distance (HD) was computed at 3D uniformly spaced points tracked on segmented endocardial surface contours, over the cardiac cycle. An LV-averaged index of phase-to-phase endocardial displacement (P2PD) time-histories was computed at each tracked point, using the HD computed between consecutive cardiac phases. Average and standard deviation in P2PD over the cardiac cycle was used to prepare characteristic curves for the asymptomatic and IHD cohort. A novel biomarker of RMS error between mean patient-specific characteristic P2PD over the cardiac cycle for each individual patient and the cumulative P2PD characteristic of a cohort of asymptomatic patients was established as the RMS-P2PD marker. The novel RMS-P2PD marker was tested as a cardiac function based feature for automatic patient classification using a Bayesian Rule Learning (BRL) framework. The RMS P2PD biomarker indices were significantly different for the symptomatic patient and asymptomatic control cohorts (p<0.001). BRL accurately classified 83.8% of patients correctly from the patient and control populations, with leave-one-out cross validation, using standard indices of LV ejection fraction (LV-EF) and LV end-systolic volume index (LV-ESVI). This improved to 91.9% with inclusion of the RMS-P2PD biomarker and was congruent with improvements in both sensitivity for classifying patients and specificity for identifying asymptomatic controls from 82.6% up to 95.7%. RMS-P2PD, when contrasted against a collective normal reference, is a promising biomarker to investigate further in its utility for identifying quantitative signs of pathological endocardial function which may boost standard image makers as precursors of declining cardiac performance. PMID- 26005249 TI - Live ultrasound volume reconstruction using scout scanning. AB - INTRODUCTION: Ultrasound-guided interventions often necessitate scanning of deep seated anatomical structures that may be hard to visualize. Visualization can be improved using reconstructed 3D ultrasound volumes. High-resolution 3D reconstruction of a large area during clinical interventions is challenging if the region of interest is unknown. We propose a two-stage scanning method allowing the user to perform quick low-resolution scouting followed by high resolution live volume reconstruction. METHODS: Scout scanning is accomplished by stacking 2D tracked ultrasound images into a low-resolution volume. Then, within a region of interest defined in the scout scan, live volume reconstruction can be performed by continuous scanning until sufficient image density is achieved. We implemented the workflow as a module of the open-source 3D Slicer application, within the SlicerIGT extension and building on the PLUS toolkit. RESULTS: Scout scanning is performed in a few seconds using 3 mm spacing to allow region of interest definition. Live reconstruction parameters are set to provide good image quality (0.5 mm spacing, hole filling enabled) and feedback is given during live scanning by regularly updated display of the reconstructed volume. DISCUSSION: Use of scout scanning may allow the physician to identify anatomical structures. Subsequent live volume reconstruction in a region of interest may assist in procedures such as targeting needle interventions or estimating brain shift during surgery. PMID- 26005251 TI - Frequency rate of atelectasis in patients following coronary artery bypass graft and its associated factors at mazandaran heart center in 2013-2014. AB - BACKGROUND AND AIM: As the most common postoperative pulmonary complication after cardiac surgery, atelectasis is one of the most important and serious early postoperative complications and one of the most important causes of prolonged hospitalization, increased costs, and mortality rise. Therefore, the present study was aimed at specifying the frequency of atelectasis in patients following coronary artery bypass graft and its associated factors in Mazandaran Heart Center in 2013-2014. MATERIALS AND METHODS: The present investigation was a descriptive cross-sectional study in which sequential sampling was used. It was conducted on 375 patients whose coronary artery bypass graft had been performed by the same surgeon and anesthesiologist. For data collection, first the patients' demographic variables and the information of their surgery were retrieved through their profiles, direct observation, patient inquiry, and the collected data were recorded in the data collection forms. Then, atelectasis was measured before the surgery and on the first and second days after it by taking CXR whose results were checked by two radiologists who were not aware of the previous observations. Data were analyzed through t-test, Pearson test, and Chi square test using SPSS 16.0. RESULTS: The results of the present study indicated that, 123 out of 375 patients (32.8%) were diagnosed with at least one type of tattletales during the first three days after the surgery. The mean age of the patients who were diagnosed with atelectasis was 62.9+/-9 and most of them were female. The results also showed that there was a significant relationship between postoperative frequency of atelectasis and the patients' pulmonary diseases and underlying diseases like diabetes and hyperlipidemia, smoking and alcohol use before the surgery, and transfusion of 4 units of packed red blood cells during the surgery (p<0.05). CONCLUSION: Atelectasis is the most common postoperative complication which emerges more in patients with pulmonary and underlying diseases than other patients. PMID- 26005250 TI - Perioperative results eversion carotid endarterectomy in bilateral symptomatic stenosis. AB - INTRODUCTION: Carotid endarterectomy (CEA) is a standard treatment for the prevention of stroke and death in patients with significant stenosis of the internal carotid artery. Eversion endarterectomy is warranted in patients with symptoms of cerebral ischemia and the degree of stenosis of 70-99%. The same is suitable for treating a symptomatic carotid artery stenosis with contralateral stenosis (50-70%). PURPOSE: The aim of this study was to evaluate perioperative complications (ICV, TIA, MI, mortality) in patients treated with carotid eversion endarterectomy with unilateral and bilateral symptomatic stenosis (with bilateral stenosis treated with ACI stenosis >=70%). PATIENTS AND METHODS: The study included 139 patients with symptomatic carotid artery stenosis at the Department of Vascular Surgery of the University Clinical Center of Sarajevo in the period from January 2012 to December 2014 year. Given the involvement of ACI stenosis patients were divided into two groups. Group A consisted of 74 patients with bilateral stenosis (surgically treated with ACI stenosis >=70%, while the degree of stenosis opposite ACI was from 50-70%), and group B of 65 patients with unilateral stenosis >=70%. RESULTS: Of the 139 patients included in the study, in the group A was 74, of which 46 male (62.2%) and 28 female (37.8%), while in group B were 42 male (64.6%) and 23 female (35.4%) (p = 0.90). The subjects in group A were slightly older 65.9 (+/- 7.8) compared to group B 64.2 (+/- 7.7) (p = 0.17). Analysis of risk factors indicating a higher number in Group A compared to group B, but the difference was not statistically significant: 34 smokers (45.9%) versus 36 (55.4%); p = 0:34), patients with hypertension (63 (85.1%) against the 52 (80.0%); p = 0.56), with statin therapy (62 (83.8%) versus 52 (80.0%); p = 0.72), diabetes (18 (24.3%) versus 18 (27.7%); p = 0.79) and with a heart disease (18 (24.3%) versus 7 (10.8%); p = 0.06). Analysis of the frequency of perioperative complications between the groups was not statistically significant: ICV (2/74 versus 3/65; p = 1.00), TIA (2/74 versus 3/65; p = 0.88), one death was recorded in group A, while myocardial infarction (MI) we had in either group. CONCLUSION: In this study, no statistically about significant differences in the number of perioperative complications (from 0 to 30 days) between the two groups. With this risk is acceptable to perform carotid endarterectomy in a patient in the opposite ACI stenosis of 50-70%. PMID- 26005252 TI - Renal Function Outcome Prognosis in Septic and Non-septic Acute Kidney Injury Patients. AB - AIM: The objective of this study was to evaluate prognostic impact of clinical factors on outcome of renal function in septic and non-septic acute kidney injury (AKI) patients. METHODS: The prospective, observational, clinical study was performed at Nephrology Clinic and Clinic for Infectious Diseases, University Clinical Centre Sarajevo. One hundred patients with diagnosis of AKI were enrolled in the study, and divided into two groups: septic and non-septic AKI patients. Clinical parameters included causes and type of AKI, pre-existing comorbidities and different treatment modalities. Patients were followed up until discharge or death. Renal function outcome was defined by creatinine clearance values at discharge. RESULTS: Septic AKI patients had significantly longer hospital stay (p=0.03), significantly worse renal function outcome (p<0.001), and higher burden of comorbidities (70.6% vs. 60.6%), compared to non-septic patients. Septic AKI patients were almost three times less likely to receive renal replacement therapy (8.8% vs. 24.4%) and they had significant delay in initiation of dialysis (p=0.03). By multivariate analysis, sepsis (95% CI 0.128 0.967, p=0.043) and hypertension (95% CI 0.114-0.788, p=0.015) were independent predictors of adverse renal function outcome in AKI patients. Postrenal type of AKI was independent predictor of renal function recovery in non-septic AKI patients (95% CI 1.174-92.264, p=0.035), while Failure, as third class of AKI, was independent predictor of non-recovered renal function only in septic AKI patients (95% CI 0.026 to 0.868, p=0.034). CONCLUSION: Septic AKI patients are clinically distinct compared to non-septic AKI patients with different prognostic factors and poorer renal function outcome. PMID- 26005253 TI - The Prevalence and Species Composition of Malassezia yeasts in Patients with Clinically Suspected Onychomycosis. AB - INTRODUCTION: There are limited numbers of studies which focused on the identification of Malassezia yeasts to a species level in onychomycosis. Therefore, the aim of our study was to determine the prevalence and species composition of Malassezia yeasts in patients with clinically suspected onychomycosis and to examine if the range of species varies with patient gender, age, site of involvement and clinical pattern of onychomycosis. METHODS: Specimens were taken from 785 patients presenting signs of onychomycosis and then incubated on Sabouraud dextrose agar and modified Dixon agar. The yeasts isolated were identified according to their macroscopic and microscopic features and physiological characteristics. RESULTS: Malassezia species were diagnosed both by microscopy and culture in fourteen (1.8%) patients. M. globosa was the predominant, if not only, species identified from nail samples. Mixed cultures were observed in five cases: in 4 cases Malassezia was co-isolated with Candida albicans and in one case with dermatophyte. Fingernails were affected more frequently than toenails (85.7%) and distolateral subungual onychomycosis was the most common clinical type (78.6%). CONCLUSION: No significant differences were found in the distribution of Malassezia species isolated according to demographic parameters. PMID- 26005254 TI - Psoriasis and metabolic syndrome. AB - INTRODUCTION: Psoriasis is a chronic skin ailment which can be connected with an increased occurrence of other illnesses, including the metabolic syndrome. EXAMINEES AND METHODS: A prospective study has been conducted which included 70 patients affected by psoriasis, both genders, older than 18 years. Average age being 47,14 (SD=+/-15,41) years, from that there were 36 men or 51,43 and 34 women or 48,57%. The average duration of psoriasis was 15,52 (SD= +/-12,54) years. For purposes of diagnosing the metabolic syndrome, the criteria of National Cholesterol Education Program Adult Treatment Panel III, (NCEP ATP III) were used. For purposes of detecting the severity and spread of psoriasis, Psoriasis Area and Severity Index (PASI) was used. RESULTS: The incidence of metabolic syndrome in patients with psoriasis was 38,57%. Average values of PASI score were 16,65. The increase in values of PASI score and metabolic syndrome were statistically highly connected. (r=0,3, p=0,0001). CONCLUSION: Psoriasis is connected with metabolic syndrome, there is a positive correlation between the severity of psoriasis and frequency of metabolic syndrome. PMID- 26005255 TI - Effect of two laparoscopic techniques for treatment of ovarian endometrioma on ovarian reserve. AB - INTRODUCTION: Operative laparoscopy is the most common used technique for treatment of patients with ovarian endometriomas, because of many positive effects in comparison with laparotomy. There are many laparoscopic techniques, but most used are cystectomy and puncture with endocoagulation (ablation) of the cyst's capsule. The aim of this study was to evaluate the effect of two laparoscopic techniques for treatment of ovarian endometriomas on ovarian reserve. We used two ultrasonographic markers for ovarian reserve: ovarian volume and antral follicle count (AFC). MATERIALS AND METHODS: Sixty patients in reproductive age (18-42 years) were treated for a chronic pelvic pain or infertility in a tertiary hospital (University Clinic for Gynecology and Obstetrics in Skopje, R. Macedonia). The study was prospective and two laparoscopic techniques were used. All patients were with confirmed ultrasound diagnosis for ovarian endometriomas with diameter between 3 and 8 cm. Complete cystectomy was done in 30 patients (group A) and puncture with endocoagulation was done in other 30 patients (group B). Ovarian reserve was analyzed before surgery and was controlled one and three months after laparoscopic surgery. RESULTS: In group A (operated with cystectomy) ovarian volume was 53.46+/-29.97 cm3 before surgery, which fell to 13.06+/-7.34 cm3 after one month, and 13.28+/ 7.17 cm3 after three months. Statistical analysis showed a significant reduction in ovarian volume one and three months after surgery (p<=0.01). In group B (operated with puncture and endocoagulation) the ovarian volume was 58.34+/-37.99 cm3 before surgery, which fell to 18.96+/-7.90 cm3 one month and 17.38+/-6.86 cm3 three months after surgery. In both groups there was a significant reduction in ovarian volume one and three months postoperatively (p<=0.01). In the first group AFC was 3.03+/-1.27 before surgery, 4.8+/-1.30 one month after surgery and 6.23+/ 1.57 after three months. Statistical analysis showed a significant increase in AFC after laparoscopic cystectomy (p<=0.01). In the second group AFC was 3.07+/ 1.05 before surgery, 5.33+/-1.60 after one month and 7.0+/-1.62 after three months. The comparison of AFC showed high statistically significant difference (p<=0.001), e.g. increase of AFC after one and three months in comparison with AFC before surgery. CONCLUSIONS: Ovarian reserve decreases after laparoscopic surgery using both laparoscopic techniques. But, this decrease was more frequent using cystectomy in comparison with ablation of the endometriotic cyst. PMID- 26005256 TI - Assessment of the tomographic values in keratoconic eyes after collagen crosslinking procedure. AB - GOAL: This study aimed to investigate the differences in values of K1 and K2 readings, the central corneal thickness (PAH) before the collagen crosslinking procedure (CXL) and 3, 6, 12 months later. METHODS: 64 eyes were evaluated in retrospective cross sectional study. The corneal biomechanical parameters were taken with WaveLight Allegro Oculyzer produced by Alcon before the CXL, 3,6, 12 months after the procedure. The curvature of K1 reading and K2 reading were taken and the central corneal thickness were considered due to the time after CXL. RESULTS: The value of K1 reading before the treatment was 48.8 diopters (D) (46.65-50.50) and was statistically significant lower comparing to the value of K1 3 months after the collagen CXL procedure 46.30 D (43.57-49.45) (p=0.0006), K1 reading one year post collagen CXL procedure was 47.20 D (44.35-50.07) (p=0.002). The value of K2 reading before the collagen CXL procedure was 52.65 D (47.55 54.72), 3 months after the procedure was 51.4 (45.05-54.0), 6 months later 48.55 D (47.20-50.62), 12 months later 51.30 D (47.22-54.77). There is statistically significant lower value of K2 reading 6 months after the treatment comparing to the values 3 months postoperatively (p=0.014). However there is significantly lower values of K2 reading 12 months postoperatively comparing to preoperative period (p=0.006). The value of central corneal thickness preoperative was 431.0 microns (398.0-446.25), 3 months after collagen CXL procedure was 373.50 microns (363.25-430.75), 6 months later 435.0 microns (360.0-464.75), 12 months after the CXL procedure was 429.50 microns (357.75-496.25). There is statistically significant lower values of central corneal thickness 3 months after collagen CXL treatment comparing to the central corneal thickness preoperative (p<0.005). There is statistically significant lower values of pachymetry 12 months after the CXL procedure comparing to the values 6 months later (p=0.036) and those preoperativelly (p=0.032). There is no statistically significant difference in the values of central corneal thickness in the period from 3 and 6 months postoperatively. CONCLUSION: After riboflavin-UVA CXL in eyes with keratokonus there was significant decrease in central corneal thickness 3 and 6 months after the procedure and the thickness is almost the same 12 months. However, K2 (Kmax) reading is significantly changed 3 and 6 months later and is followed by changing of K1 reading. PMID- 26005257 TI - Disorders of Accommodative Convergation and Accommodation (AC/A) Relations at Traumatic Brain Injury. AB - INTRODUCTION: Accommodative Convergence/Accommodation (AC/A) ratio is constant at one and the same person in the course of life, i.e. the same ratio accommodative convergence monitor any change in accommodation measured in diopters. Such a perfect relationship is possible if there are no refractive anomalies in both eyes and oculomotor imbalance of eye muscles. MATERIAL AND METHODS: We are examined 50 patients with close brain injury, and patients which had problems with near vision, accommodation and convergency were reducted, with loss motor fussion, and preserved stereoscopis vision, and showed us, that disturbances are clear motor and folowed with incapable of patient to hold of superposition view to watching object. RESULTS: The difference in average proximity distance vision and reading time with no fatigue after 6 months a statistically significant, the value of t-test, t = 1873 for p <0.01, r = 0. 718. The value of convergent fusion 6 months after treatment in 30% of the patients was from 0 to16 Pd, S. D. = 18. 6, and chi(2) = 7. 22. In 18% of the patients was from 0 to 10 Pd, S. D = 17. 61, and chi(2) = 5. 41, at 20% of patients 0 to 22 Pd, SD = 14. 18, chi(2) = 6. 84, in 16% of patients 0 to 4 Pd, SD = 16. 41, chi(2) t-test = 5. 13 and the remaining 16% of patients the value of convergent fusion is about 1 PD, S. D = 15. 01, chi(2) t = 5. 18. All patients showed significant improvement in near vision compared to the value of convergent fusion before treatment where chi(2) t test = 9.41, after 6 months of treatment, there is considerable significance p < 0 01, t-test 0. 914, correlation coefficient r = 0. 881. CONCLUSION: Disturbances of AC / A ratio should be evaluated only with regard to all symptoms and is only possible by proper rating interference in reading. PMID- 26005258 TI - Breast-feeding Continuation in South-Eastern of Iran: the Associated Factors. AB - BACKGROUND: Breast-feeding not only promotes health in an infancy period, but also leads to human vigor and safety at varied life periods viz. adolescence, youth, middle-age, or even adulthood. AIM: The present study was aimed to determine the factors affecting the breast-feeding continuation effectively for a selected region of Iran. METHODS: This cross-sectional study was performed on 523 women having less than two year old babies from the selected counties covered by the Zahedan University of Medical Sciences (Khash, Saravan, Sarbaz, Chabahar, Zahedan, Nikshahr, Iranshahr, and Konark) using the stratified sampling method. The Data was completed for the target group by using the check-list which included 3 parts: demographic data, case history of pregnancy, childbirth and mother's statue, and previous records of the newborn up to two years. The obtained data were fed into SPSS software, and all parametric and non-parametric statistical methods were used to analyze the data, especially appropriate to the data type. RESULTS: The results showed that the most important factors associated with breast-feeding discontinuation were infant's illness (only up to six months), mother's consciousness, parental support, practical breastfeeding training to the mother, mother's educational level, child's gender, place of birth, pregnancies' interval, mother's ethnicity and residence and the statue of taking (using) narcotics. The data also indicated that on maternal reasons the main factor which impelled most of the mothers to discontinue their breast feeding up to six months or even before two years was milk shortage in mother's breasts. Moreover, the main child- related factor that compelled most of the mothers for non-continuance of their breast-feeding up to six months or even before two years was child's crying and discomfort. CONCLUSIONS: It can be safely concluded that promotion of parental education, neglecting child's gender as far as cultural context and preference of a son is considered, observance of pregnancy interval for more than three years, non-smoking in nursing mothers, practical training of breast-feeding to mothers besides conductance of educative programs via maternity hospitals and health centers to educate parents about the importance of breast-feeding and benefits of spouse's support can be considered as the influential factors in continuation of breast-feeding. PMID- 26005259 TI - Comparative effectiveness of B and e vitamins with diclofenac in reducing pain due to osteoarthritis of the knee. AB - BACKGROUND: Knee osteoarthritis is one of the most prevalent chronic disorders. Several pharmacological and non pharmacological approaches are used to treat this disease. Today, the effect of B and E vitamins on rheumatology diseases is being discussed. In this study, the efficacy of B and E vitamins accompanied with diclofenac on pain relief in patients with knee osteoarthritis was investigated and compared. METHODS: In this double-blinded clinical trial, 120 patients with knee osteoarthritis referring training Rheumatology and Orthopedics Clinic of Shahrekord University of Medical sciences were investigated. Of these patients, 12 were excluded throughout the study. The patients underwent treatment in three groups (oral diclofenac + oral B vitamin, oral diclofenac + oral vitamin E, and oral diclofenac + placebo). Pain relief was assessed by visual analogue scale (VAS) questionnaire and morning stiffness and physical function were assessed by WOMAC standard questionnaire at three times; the first examination, two weeks, and three weeks after referring. RESULTS: The mean score of WOMAC questionnaire at VASs of knee pain, total pain severity, knee joint stiffness, and function of the last 48 hours decreased significantly in all three groups (diclofenac, E and B vitamins) from the first to third examination (P<0.001). Decrease in VAS of knee pain and function of the last 48 hours was higher in B vitamin group than the diclofenac and E vitamin group (P=0.008) and decrease in total pain severity was reported higher in B vitamin group than E vitamin and diclofenac group (P=0.019). Decrease in knee joint stiffness underwent a similar trend in the three groups. CONCLUSION: In view similar analgesic and anti-inflammatory properties, as well as very few, non prevalent complications of B and E vitamins, use of two or more drugs with a different mechanism of effect seems necessary to enhance their effect on osteoarthritis treatment. PMID- 26005260 TI - Comparison of tolerance of venlafaxine, paroxetine and amitriptyline in depression therapy. AB - INTRODUCTION: There are no controlled studies dedicated to research of side effects of antidepressants. It is a well known fact that antidepressants reciprocally differ according to their type, intensity and frequency of appearance of certain side effects. For example, cardiovascular and anticholinergic effects are essential feature of the tricyclics whereas gastrointestinal and sexual side effects are registered during the use of selective serotonin reuptake inhibitors. Interruptions of therapy or irregular use of drugs because of the appearance of side effects are not rare. Serious side effects of drugs are the fourth cause of death in the USA. AIM: The aim of this study is the evaluation of appearance of side effects comparing three different groups of antidepressants: venlafaxine, amitriptyline and paroxetine. MATERIAL AND METHODS: The study included 90 in-patients as well as outpatients of both sexes aged 18-65 who were treated for major depressive disorder at Psychiatric Clinic in Banjaluka. 30 patients were treated with amitriptyline 75-250 mg, 30 patients were treated with paroxetine 20-40 mg and 30 patients were treated with venlafaxine 75-300 mg. The selection of patients was done on the basis of diagnosis of major depressive disorder. RESULTS: Most patients did not have serious side effects. The study confirmed high efficiency of the mentioned drugs as well as the fact that paroxetine causes a bit more side effects in comparison with two other antidepressants. PMID- 26005261 TI - Static or dynamic intramedullary nailing of femur and tibia. AB - INTRODUCTION: The basic principle of non-surgical fracture treatment is to restore the original anatomical position of fractured fragments by different techniques, without direct access to the bone and without further traumatizing of tissues. Intramedullary nailing is synthesis and consolidation of fracture fragments with the main goal to gain strength and permanent placement of the implants. Two techniques of intramedullary osteosynthesis are used: with dynamic or with static intramedullary nail. Dynamization include conversion of static nail by removing screws from the longest fragment. AIM: The aim of this study is to determine whether there is a difference in the speed and quality of healing of the type A and B fractures of the femur and tibia treated by static or dynamic intramedullary nails and to compare the results. MATERIAL AND METHODS: The study was conducted at the Clinic for Orthopaedics and Traumatology, Clinical Center University Sarajevo from January 2004 to June 2009. The study was retrospective prospective, manipulative, controlled and it was conducted on a total of 129 patients with closed fractures of the diaphysis of the femur and tibia type A and type B, with different segments of bone, regardless of sex and age structure, with the exception of children under 14 years of age. RESULTS: Precisely there were 47 patients with femoral fractures and 82 patients with tibial fractures. The average number of weeks of healing femoral and tibial fractures was slightly in advantage of static intramedullary osteosynthesis, it was 17.08 weeks (SD=3.382). The average number of weeks of healing in 23 patients with fractures of the femur, treated by dynamic intramedullary osteosynthesis was 17.83 (SD=2.978). We can conclude that static intramedullary nailing osteosynthesis unable movements between fragments which directly stimulates bone formation and formation of minimal callus. CONCLUSION: Static intramedullary osteosynthesis resolve the problem of stabilizing the fracture, limb shortening and rotation of fragments. PMID- 26005262 TI - Low back pain and obesity. AB - INTRODUCTION: Low back pain poses a significant problem in clinics and public health. It presents one of the main problems with adults, since 70-80% of adults experience it at least once in their lifetime. Causes of the low back pain are numerous and often unknown. OBJECTIVES: The aim of the study is to find the most prevalent age group, pain localisation, and the frequency of physical therapy sessions in obese and non-obese subjects with LBP. MATERIALS AND METHODS: The study has been conducted by the Physical Rehabilitation Service of the Occupational Medicine Institute, during one year period. The total number of patients studied was 101 and all were Kosovo Energy Corporation (KEC) employees. The study was retrospective. RESULTS: Looking at the body weight index, out of 101 patients, 69.3% are classified as non-obese and 30.7% as obese. Using T-Test we have found a difference of high statistical significance between the average number of the physical therapy sessions applied in relation to the examined groups (T-Test=2.78, P=0.0065, so, P<0.01). CONCLUSION: Obesity and age have no direct influence in back pain, but they could prolong healing. Professional occupation and binding position are factors that affect back pain. Physical workload can cause the manifestation of sciatica; whereas psycho-social factors can prolong the overall healing process. PMID- 26005263 TI - Cortisol level and hemodynamic changes during tooth extraction at hypertensive and normotensive patients. AB - BACKGROUND: The patients that are subjects to oral-surgical interventions produce large amounts of steroids in comparison with healthy patients which are not a subject to any dental intervention. The aim of research was to determine the level of stress hormone cortisol in serum, arterial blood pressure and arterial pulse, and to compare the effectiveness of the usage of lidocaine with adrenalin in comparison with lidocaine without adrenalin during the tooth extraction. PATIENTS AND METHODS: This clinical research includes patients with indication of tooth extraction divided in hypertensive and normotensive patients. RESULTS: There is no important statistical distinction between groups, for the cortisol levels before, during and after tooth extraction regardless of the type of anesthetic used, while we registered higher values of systolic and diastolic values at hypertensive patients, regardless of the type of anesthetic. CONCLUSION: There is significant systolic and diastolic blood pressure rise in both groups of patients hypertensive and normotensive patients, (regardless of anesthetic used with or without vasoconstrictor), who underwent tooth extraction. The special emphasize is attributed to hypertensive patients where these changes are more significant. As per cortisol level and pulse rate, our results indicate no significant statistical difference in between groups. PMID- 26005264 TI - Physicians' perceptions about the quality of primary health care services in transitional Albania. AB - AIM: To date, the available information regarding the quality of primary health care services in Albania is scarce. The aim of our study was to assess the quality of primary health care services in Albania based on physicians' perceptions towards the quality of the services provided to the general population. METHODS: A cross-sectional study was conducted in January-March 2013 including a representative sample of 132 physicians (59 men aged 41.3+/-6.9 years and 73 women aged 43.7+/-4.8 years; overall response rate: 132/150=88%) providing primary health care services in several polyclinics (health centers) of Tirana, the Albanian capital city. A structured self-administered and anonymous questionnaire was applied including physicians' perceptions regarding different dimensions of the quality of primary health care. Binary logistic regression was used to assess the association of self-perceived quality of health care services with baseline characteristics of physicians. RESULTS: Self-perceived adequate quality of health care services was positively related to the age of physicians, their working experience, female gender, a lower population served, and specialization in family medicine. CONCLUSION: Our findings provide useful evidence on the self-perceived quality of health services from primary health care physicians' perspective in transitional Albania. Health authorities in Albania should implement suitable instruments to measure the quality of health care services at all levels. PMID- 26005265 TI - Cigarette smoking among students at the university of tuzla. AB - INTRODUCTION: Cigarette smoking among students is greatly widespread. Smoking prevalence ranges from 28% to 67% for students, respectively, from 19% to 34% for female students. AIM: The aim of this survey was to investigate the smoking habits of students, who are studying at three faculties at the University of Tuzla in academic Year 2012/2013 and to investigate whether there is a difference in smoking habits of students from different faculties and observed by gender. PATIENTS AND METHODS: The study included a total of 254 students, 170 females (66.93%) and 84 male patients (33.07%). A representative sample consisted of students of three faculties of the University of Tuzla. RESULTS: The conducted analyzes have shown that in this sample 22.8% of current smokers, and 7.8% are former smokers who now no longer smoke. Due to the adopted smoking habits, which some students began to adopt in the age of 13, in 47.5% part of students occasionally was observed some symptoms (cough, etc.) which are attributed to smoking. The analysis showed no statistically significant gender difference in smoking habits. Although the trend of smoking in the population students progression, one and the same quantity was well as male colleagues. We did not find any statistically significant difference in onset of adopting smoking habits. CONCLUSION: The analyzes have shown that in this sample 22.8% of current smokers, and 7.8% were former smokers who now no longer smoke. The analysis showed no statistically significant gender difference in smoking habits of all students. There were no statistically significant differences in the daily consumption of cigarettes between faculty. PMID- 26005266 TI - Pancreatic injury in blunt abdominal trauma. AB - INTRODUCTION: Pancreatic injuries are not common after blunt and penetrating trauma, but can be challenging to diagnose and manage. CASE REPORT: Twenty-three year old man, injured during a fall from a motorcycle two days earlier, was admitted to Department of Surgery, University Clinical Centre Tuzla because of suspicion of pancreatic trauma. Immediately after hospitalization, patient underwent laboratory and radiological tests that revealed the existence of pancreatic trauma, so we opted for urgent surgical treatment. Surgery and early postoperative course were normal and the patient was discharged on the ninth postoperative day. CONCLUSION: Proper diagnosis and well-selected surgical treatment significantly increases the chances for recovery of these patients. PMID- 26005267 TI - A new approach to the management of uninvestigated dyspepsia in primary care. AB - INTRODUCTION: The prevalence of dyspepsia in the general population worldwide is very high (20-40%). Upper abdominal complaints are one of the most common cause of patients' visits to primary care settings. Making an accurate etiological diagnosis of dyspepsia is difficult, but is an important challenge and goal for every doctor in primary care practice. Clinical guidelines have standards for gastroesophageal reflux disease, management of Helicobacter infection and indications for the use of endoscopy (empiric treatment, prompt endoscopy, "test and treat"). In spite of the application of those standards, many patients experience no improvement in their symptoms or often the recurrence of disease. AIM: This study presents a new approach to the diagnostic and therapeutic management of uninvestigated dyspepsia in primary care settings to provide long term effective control of symptoms for family doctors. MATERIAL AND METHODS: 3000 unselected consecutive dyspeptic patients underwent abdominal ultrasound, and 1000 dyspeptic patients from the same group upper endoscopy.. In this approach diagnostic evaluation of dyspepsia includes: abdominal ultrasonography as a first line obligatory routine method and the exact estimation of nutritional condition. RESULTS: Abdominal ultrasound, physical examination and BMI control have significant value in the diagnostic evaluation of dyspepsia. The therapeutic approach includes, besides general standards (acid suppressive drugs, eradication of H. pylori, prokinetic and antidepressant agents), life style modification and nutritional interventions as first-line treatments. In this approach the use of new drugs such as ursodeoxycholic acid (UDCA), pre and probiotics, and digestive enzymes supplements is recommended. CONCLUSION: Throug the combination of different diagnostic procedures as first line methods, including abdominal ultrasound and nutritional condition (BMI), a family doctor can manage successfully uninvestigated dyspepsia at the primary care level. PMID- 26005268 TI - Analysis of the influence of type of diabetes mellitus on the development and type of glaucoma. PMID- 26005269 TI - Combined use of cytogenetic and molecular methods in prenatal diagnostics of chromosomal abnormalities. AB - AIM: The aim of prenatal diagnostics is to provide information of the genetic abnormalities of the fetus early enough for the termination of pregnancy to be possible. Chromosomal abnormalities can be detected in an unborn child through the use of cytogenetic, molecular- cytogenetic and molecular methods. In between them, central spot is still occupied by cytogenetic methods. In cases where use of such methods is not informative enough, one or more molecular cytogenetic methods can be used for further clarification. Combined use of the mentioned methods improves the quality of the final findings in the diagnostics of chromosomal abnormalities, with classical cytogenetic methods still occupying the central spot. MATERIAL AND METHODS: Conducted research represent retrospective prospective study of a four year period, from 2008 through 2011. In the period stated, 1319 karyotyping from amniotic fluid were conducted, along with 146 FISH analysis. RESULTS: Karyotyping had detected 20 numerical and 18 structural aberrations in that period. Most common observed numerical aberration were Down syndrome (75%), Klinefelter syndrome (10%), Edwards syndrome, double Y syndrome and triploidy (5% each). Within observed structural aberrations more common were balanced chromosomal aberrations then non balanced ones. Most common balanced structural aberrations were as follows: reciprocal translocations (60%), Robertson translocations (13.3%), chromosomal inversions, duplications and balanced de novo chromosomal rearrangements (6.6% each). CONCLUSION: With non- balanced aberrations observed in the samples of amniotic fluid, non- balanced translocations, deletions and derived chromosomes were equally represented. Number of detected aneuploidies with FISH, prior to obtaining results with karyotyping, were 6. PMID- 26005270 TI - Ultrasound in detection of developmental hip dysplasia in premature born children. AB - INTRODUCTION: Developmental hip dysplasia represents the most common deformation of locomotor system in children. Developmental modulation of the hip is expressed during first year of life which is important for early diagnosis and treatment. Therefore, in the practice, it is very important to set a diagnosis early with application of simple and convenient methods (ultrasound) in order to achieve fast and efficient therapeutical effect and avoid permanent disability. AIM: The aim of this paper is to point out the increase of prematurely born infants and their survival thanks to the development of Unit for Intensive Neonatal Care at the Pediatric Clinics in Sarajevo. MATERIAL AND METHODS: Clinical investigation included 150 infants (77 girls and 73 boys) in whom the developmental hip dysplasia was diagnosed with clinical exam, ultrasound exam and x-ray of the hips. The exams were done in period of January 2012 to August 2014. RESULTS: Two groups of patients were formed. The first one consisted of premature infants, total number of 75 (34 girls and 41 boys), with developmental hip dysplasia that was diagnosed at the first exam at the Ultrasound unit of the Pediatric clinics and at the Intensive Neonatal Care Unit of the Pediatric Clinics in Sarajevo. Second (control) group consistsed of patients-on term infants who had diagnosed one of developmental hip dysplasia, total of 75 (43 girls and 32 boys) during first exam in the Ultrasound unit of the Pediatric clinics in Sarajevo. CONCLUSION: The frequency of premature birth is between 5 and 10% of all labors and demonstrates increasing trend. We suggest ultrasound examination of hips in each newborn, term or premature, at the age of 6 weeks after birth. PMID- 26005271 TI - Design and implementation of a software for teaching health related topics to deaf students: the first experience in iran. AB - INTRODUCTION: Deaf are not able to communicate with other community members due to hearing impaired. Providing health care for deaf is more complex because of their communication problems. Multimedia tools can provide multiple tangible concepts (movie, subtitles, and sign language) for the deaf and hard of hearing. In this study, identify the priority health needs of deaf students in primary schools and health education software has been created. METHOD: Priority health needs and software requirements were identified through interviews with teachers in primary schools in Tehran. After training videos recorded, videos edited and the required software has been created in stages. RESULTS: As a result, health care needs, including: health, dental, ear, nails, and hair care aids, washing hands and face, the corners of the bathroom. Expected Features of the software was including the use of sign language, lip reading, pictures, animations and simple and short subtitles. DISCUSSION: Based on the results of interviews and interest of educators and students to using of educational software for deaf health problems, we can use this software to help Teachers and student's families to education and promotion the health of deaf students for learn effectively. PMID- 26005272 TI - The ocular trauma score as a method for the prognostic assessment of visual acuity in patients with close eye injuries. AB - INTRODUCTION: Traumatic injuries of the eye are the most common cause of loss of visual function. In our study we performed Ocula Trauma Score (OTS). We compared with the values of visual acuity of injury and thus get an accurate model for determining the prognostic value of the final visual acuity before treatment of the patient. This model is a reliable test for both the ophthalmologist and the patient. AIM OF STUDY: The aim of this study was to show the socioepidemiological and demographic profile, as well as the most common mechanism in ophthalmic injuries, so to determine the final visual acuity and assessment and evaluation of sensitivity and specificity of ocular trauma score (OTS), and most importantly to determine the prognostic value final visual acuity after eye injuries. MATERIAL AND METHOD: We conducted a clinical-epidemiological, retrospective prospective study at the Department of Ophthalmology, Clinical Centre University in Sarajevo in the period 2009-2011. A sample of 124 patients with diagnosed closed of eye injuries were recruited. We applied Classifying Closed Globe Injury, performed Calculating the OTS and convert of total raw points into % chance of vision outcomes. RESULTS: Comparison of age groups by gender shows that there is no statistically significant (x(2) = 5.155; p = 0.2718). Of the total number of closed eye injuries (N = 124) at the admission from groups D and E with the worst vision were 29 patients (23.38%), in group C had low visual acuity of 20 (16.12%), in group B the mean visual acuity 33 (26.61%), and in group A well preserved visual acuity 42 (33.87%) patients. On the demission patients with well preserved visual function was 84 (67.74%), with a medium of visual function 10 (80.64%), while the poorer visual function was 4 (3.225%) and 7 (5.645%) patients had a sense of light and projections and 1 (0.8%) patient had lost visual acuity amaurosis. 18 (14:51%) patients did not take their eyesight due to a fresh post operative recovery. CONCLUSION: Data on each patient are based on the possibility of such characteristics of the mechanism of injuries presentation of vision at the beginning of disease, injury and zones relative afferent pupillary defect possibility assumptions what will be with the vision postoperatively. PMID- 26005273 TI - Comparison of specific ovarian tumor markers by elecsys analyzer 2010. AB - BACKGROUND: the most widely used tumor marker in ovarian cancer, often considered the 'gold standard' is CA125 but reliable clinical evidence demonstrates that human epididymis protein (HE4), used alone or in combination with CA125, substantially improves the accuracy of screening and/or disease monitoring. AIM: to evaluate the reliability of the determination a tumor marker HE4 in comparison with CA125 on the Elecsys analyzer 2010 in epithelial ovarian cancer, benign ovarian cyst and healthy controls. METHODS: we prospectively determined CA125 and HE4 serum levels in the Biochemical-Immunological-Haematological "Medical Laboratory" Ilidza, Sarajevo, B&H between June 1(st) and December 31(st) 2011. Electro-chemiluminescence immunoassay (ECLIA) methods for quantitative determination in vitro were performed on the Roche/Hitachi Elecsys 2010 Immunoassay Analyzer. Standard methods of descriptive statistics were performed for the data analysis. RESULTS: univariate statistical analyze of tumor marker control serum revealed a high reliability for both CA125 and HE4 determination (p>0.05). Levey-Jennings charts of quality control data show that the target and the obtained values of both markers control sera do not differ significantly in relation to the ideal value. In a total number of 60 patients compared values of tumor markers show a high correlation (r=0.85). This study confirmed higher sensitivity and specificity of HE4 tumor marker compared with CA125. ROC-AUC values show that the diagnostic performance of HE4 was significantly higher compared with CA125. CONCLUSION: We concluded that HE4 was better than CA125 as a single tumor marker. PMID- 26005274 TI - Selective Inhibition on RAGE-binding AGEs Required by Bioactive Peptide Alpha-S2 Case in Protein from Goat Ethawah Breed Milk: Study of Biological Modeling. AB - BACKGROUND: Advanced Glycation End Products (AGE) play a pivotal role in the development various degenerative diseases such as diabetes, cardiovascular disease, stroke, neuropathy, and nephropathy. Different studies have been done to employ AGEs as drug targets for the diseases therapy. In previous study, we have found bioactive peptide from Ethawah goat milk for anti-diabetic that may work through inhibition of AGE receptor function. However, the mechanism of bioactive peptides inhibits AGE- AGE receptor (RAGE) bonding still not clear yet. Therefore we investigated the inhibition mechanism by calculate the potential energy binding among the peptides, AGEs and RAGE using molecular docking system. METHODS: Modeling 3D-structure was predicted by SWISS-MODEL web server. The virtual interaction was analyzed by docking system using HEX 8.0, Pymol and Discovery Studio 4.0 software. RESULTS: this study showed that AGEs (Argypirimidine, Imidazole, Pentosidine and Pyrraline) bind to C-domain of RAGE. The total energy binding of RAGE with Argypirimidine, Imidazole, Pentosidine and Pyrraline were 378.35kJ/mol, -74.57kJ/mol, -301.25kJ/mol and -400.72kJ/mol, respectively. We have found three peptides among eight peptides from Ethawah goat milk, which are able bind to C-domain of RAGE, there are CSN1S2 f41-47, CSN1S2 f182-189, and CSN1S2 f214-221. The CSN1S22 f41-47 at arginine residue 47 interacts with proline162, leusine163 and leusine158 of RAGE. The total binding energy between CSN1S2 f41-47, CSN1S2 f182-189, and CSN1S2 f214-221 with RAGE were -378.35 kJ/mol, -359.97kJ/mol, -356.78 kJ/mol, respectively. Total binding energy and binding pattern indicated that RAGE more prefer bind with peptide and block AGE bind to functional site of RAGE. Further analysis showed that complex peptide RAGE shifted binding site of AGE on function domain RAGE. CONCLUSION: This study suggested that the peptides from Ethawah goat milk may act as an inhibitor of AGEs-RAGE interaction that impaired signal transduction cascade at the cellular level. PMID- 26005275 TI - Determining the Awareness and Attitude of Employees in Deputy of Health of Isfahan University of Medical Science toward Telemedicine and its Advantages. AB - INTRODUCTION: The useful capabilities of information and communication technologies for improving health services are becoming widely known. However many of the managers and policymakers of health systems are not yet familiar with these technologies, their dimensions and applications and the advantages of these new technologies for creating added value in health systems. Therefore the goal of this study is to determine the awareness and attitude of employees working for Deputy of Health of Isfahan University of Medical Science regarding telemedicine and its advantages. METHOD: This study uses a descriptive - analytical method with sectional information gathering. The investigated population consisted of all managers and experts employed by Deputy of health of Isfahan University of Medical Science. The sample size was determined based on inclusion criteria to be 60 people. The data gathering tool was a questionnaire designed by the researcher in order to determine the awareness and attitude of the subjects. In order to determine the validity and reliability of the questionnaire content validity method and Cronbach's alpha were used. The information was analyzed using descriptive (frequency, average) and analytical (Spearman correlation test and independent t-test) statistics with the help of SPSS19 software. FINDINGS: Research findings showed that the awareness and attitude of managers and experts toward telemedicine was mediocre. Spearman correlation test showed that there is a correlation between the educational degree and awareness of the subject, however the correlation coefficient was lower than 0.5 which shows a weak correlation (0.451). On the other hand, the calculated P-value of 0.008 showed that there is a meaningful relation between the education and awareness of managers regarding telemedicine. CONCLUSION: Due to importance of awareness and attitude in acceptance of new technologies, one can say that currently there is not enough readiness for planning and implementation of telemedicine projects in the Deputy of health. Therefore changes in the organizational culture, organizational structures and infrastructure, current plans and educating the employees in order to improve their awareness and attitude is of great importance. PMID- 26005276 TI - Electronic health records: critical success factors in implementation. AB - INTRODUCTION: EHR implementation results in the improved quality of care, customer-orientation and timely access to complete information. Despite the potential benefits of EHR, its implementation is a difficult and complex task whose success depends on many factors. The purpose of this research is indeed to identify the key success factors of EHR. METHOD AND MATERIALS: This is a cross sectional survey conducted with participation of 340 work forces from different types of job from Hospitals of TUMS in 2014. Data were collected using a self structured questionnaire which was estimated as both reliable and valid. The data were analyzed by SPSS software descriptive statistics and analytical statistics. RESULTS: 58.2% of respondents were female and their mean age and work experience were 37.7 and 11.2 years, respectively and most respondents (52.5%) was bachelor. In terms of job, the maximum rate was related to nursing (33 %) and physician (21 %). the main category of critical success factors in Implementation EHRs, the highest rate related to Project Management (4.62) and lowest related to Organizational factors (3.98). CONCLUSION: success in implementation EHRs requirement more centralization to project management and human factors. Therefore must be Creating to EHR roadmap implementation, establishment teamwork to participation of end-users and select prepare leadership, users obtains sufficient training to use of system and also prepare support from maintain and promotion system. PMID- 26005277 TI - Nurses readiness and electronic health records. AB - BACKGROUND: The importance of the electronic health records in health care well known to everybody, as well as, the role of nurses to provide clinical care; they have a valuable role in successful implementation of electronic systems. The aim of this paper is to assess the nurses' readiness for EHR implementation. METHODS AND MATERIALS: This was a descriptive cross sectional study, conducted in 2013. Using cluster sampling, 310 nurses selected from teaching hospitals at Tehran University of Medical Sciences (TUMS). A self-structured questionnaire was used for gathering data. Data management and analysis was performed using SPSS for windows by using descriptive statistics. RESULTS: 85.9% of nurses, participated in the study. The Microsoft Word (58.8%) was the higher level of skill according to ICDL. The mean of computer skills, knowledge and attitude of nurses towards EHR was 43.4%, 51.2% and 65.2%, respectively. In overall, the mean of readiness of nurses was 57.2%. Establish proper communication among providers and prevent duplications was the most positive attitude and complexity of service delivery was the most negative attitude toward EHR. CONCLUSION: The most obvious finding to emerge from this study is that it should be considered in the education, training and participation of nurses, it should be ensured the level of knowledge and attitude toward EHR and finally, some related courses in Health Information Systems suggested including the curriculum of nursing. PMID- 26005278 TI - Information technology - a tool for development of the teaching process at the faculty of medicine, university of sarajevo. AB - INTRODUCTION: Information Technologies, taking slow steps, have found its application in the teaching process of Faculty of Medicine, University of Sarajevo. Online availability of the teaching content is mainly intended for users of the Bologna process. AIM: The aim was to present the level of use of information technologies at the Faculty of Medicine, University of Sarajevo, comparing two systems, old system and the Bologna process, and to present new ways of improving the teaching process, using information technology. MATERIAL AND METHODS: The study included the period from 2012 to 2014, and included 365 students from the old system and the Bologna Process. Study had prospective character. RESULTS: Students of the old system are older than students of the Bologna process. In both systems higher number of female students is significantly present. All students have their own computers, usually using the Office software package and web browsers. Visits of social networks were the most common reason for which they used computers. On question if they know to work with databases, 14.6% of students of the old system responded positively and 26.2% of students of the Bologna process answered the same. Students feel that working with databases is necessary to work in primary health care. On the question of the degree of computerization at the university, there were significant differences between the two systems (p <0.05). When asked about the possibility of using computers at school, there were no significant differences between the two systems. There has been progress of that opportunity from year to year. Students of Bologna process were more interested in the introduction of information technology, than students of old system. 68.7% of students of the Bologna process of generation 2013-2014, and 71.3% of generation 2014-2015, believed that the subject of Medical Informatics, the same or similar name, should be included in the new reform teaching process of the Faculty of Medicine, University of Sarajevo. CONCLUSION: Information technologies can help the development of the teaching process, and represent attractive and accessible tool in the process of modernization and progress. PMID- 26005279 TI - Bathing epilepsy: report of three caucasian cases. AB - INTRODUCTION: Bathing epilepsy is a specific type of reflex epilepsy triggered by domestic bathing in water. It is a geographically specific epilepsy syndrome that is more prevalent in India Cases in Caucasian population are very rarely reported. These cases share many similar clinical features and a similar prognosis to the Indian cases. CASE REPORT: We describe three cases of bathing epilepsy in Albanian population; two cases with well controlled seizures and one with drug-resistant seizures. PMID- 26005280 TI - A rare case of biliary leakage after laparoscopic cholecystectomy-diagnostic evaluation and nonsurgical treatment: a case report. AB - Although laparoscopic cholecystectomy has become a gold standard in treatment of symptomatic cholelithiasis, it is associated with higher risk of intraoperative lesions and primarily lesions of biliary ducts. In small percentage of cases biliary fistulas occur, most commonly after leakage from cystic duct stump or accessory bile ducts - Luschka's duct. We report of a patient who had episodes of abdominal pain following routine laparoscopic cholecystectomy for acute calculous gallbladder. Results of conducted diagnostics verify the presence of biliary fistula caused by obstruction of bile pathways by stagnant pus and microcalculi of common bile duct, with development of biloma presumably caused by pressure injection of contrast material during ERCP procedure. Endoscopic sphincterectomy via ERCP enabled healing of formed biliary fistula, whilst continuous percutaneous ultrasound guided drainage of biloma was method of choice in later treatment of our patient. It is important to note that diagnostic evaluation of biliary fistula is very challenging and that timely nonsurgical treatment is of great benefit for patient. PMID- 26005281 TI - Is the Mean H-index of 38.5 Right for 40 Researchers? PMID- 26005282 TI - The most influential scientists in the development of medical informatics (5): charles edwin molnar. PMID- 26005283 TI - Miocene squat lobsters (Decapoda, Anomura, Galatheoidea) of the Central Paratethys - a review, with description of a new species of Munidopsis. AB - All squat lobsters of the families Galatheidae, Munididae and Munidopsidae from the Miocene of the Central Paratethys are reviewed taxonomically. Based on additional observations emended diagnoses are provided for Agononida cerovensis and Galathea weinfurteri, from the Lower and Middle Miocene, respectively. Munidopsis is represented by two species in the study area; additional data for M. lieskovensis from the Lower Miocene of Slovakia are presented and a new species, M. palmuelleri, from the Middle Miocene of Slovenia is erected. Implications for palaeoenvironmental reconstructions are briefly discussed for each taxon. PMID- 26005284 TI - Who would you like to be like? Family, village, and national role models among Black youth in rural South Africa. AB - In this paper, we examine how Black youth in rural South Africa construct role models and connect them to their own life aspirations. We pay particular attention to individual and group identity development in shaping these perceptions. Based on analysis of qualitative data from 99 Black male and female youth aged 14-22, we find that 1) the choice of role models reflects a balancing strategy to reconcile individual and group identity development; 2) while the reasons they give for choosing role models are aligned with dominant models of upward mobility in the new South Africa (and globally), our respondents are also attuned to the difficulty of attaining such success and 3) the choices underscore the continued importance of close and extended kin amidst an increasingly ego focused life strategy aimed at individual status attainment. These findings can contribute to strengthening the effectiveness of intervention programs aimed at strengthening positive influences in the lives of Black youth in South Africa. PMID- 26005285 TI - Quantifiers are incrementally interpreted in context, more than less. AB - Language interpretation is often assumed to be incremental. However, our studies of quantifier expressions in isolated sentences found N400 event-related brain potential (ERP) evidence for partial but not full immediate quantifier interpretation (Urbach & Kutas, 2010). Here we tested similar quantifier expressions in pragmatically supporting discourse contexts (Alex was an unusual toddler. Most/Few kids prefer sweets/vegetables...) while participants made plausibility judgments (Experiment 1) or read for comprehension (Experiment 2). Control Experiments 3A (plausibility) and 3B (comprehension) removed the discourse contexts. Quantifiers always modulated typical and/or atypical word N400 amplitudes. However, only the real-time N400 effects only in Experiment 2 mirrored offline quantifier and typicality crossover interaction effects for plausibility ratings and cloze probabilities. We conclude that quantifier expressions can be interpreted fully and immediately, though pragmatic and task variables appear to impact the speed and/or depth of quantifier interpretation. PMID- 26005286 TI - Preparing Emerging Doctoral Scholars for Transdisciplinary Research: A Developmental Approach. AB - Research models that bridge disciplinary, theoretical, and methodological boundaries are increasingly common as funders and the public push for timely, effective, collaborative responses to pressing social and environmental problems. Although social work is inherently an integrative discipline, there is growing recognition of the need to better prepare emerging scholars for sophisticated transdisciplinary and translational research environments. This paper outlines a developmental, competency-oriented approach to enhancing the readiness of doctoral students and emerging scholars in social work and allied disciplines for transdisciplinary research, describes an array of pedagogical tools applicable in doctoral course work and other program elements, and urges coordinated attention to enhancing the field's transdisciplinary training capacity. PMID- 26005287 TI - The Cultural Turn in Sociology: Can It Help Us Resolve an Age-Old Problem in Understanding Decision Making for Health Care? AB - Culture has long affected individuals' response to problems. A classic puzzle in the sociology of health and illness is discrepancy between theory and research regarding cultural beliefs and knowledge of medical care service use. "Utilization research," examining individuals' responses to the onset of health problems, has not consistently affected culture on the uptake of formal treatment. First, while ethnographic research often describes how culture shapes illness behaviors, survey-based studies rarely find significant beliefs or predispositions once "need" is controlled. Second, in quantitative studies, individuals report supportive treatment beliefs or predispositions to use services but low utilization levels, reinforcing claims about lack of utility of cultural ideologies in health-care decision making. We ask whether innovations in the sociology of culture and cognition provide theoretical scaffolding to conceptualize and measure culture in health service utilization. Rather than estimating effect of cultural beliefs on health-care decisionmaking, we question the measurement of cultural beliefs in understanding service use. Examining data from the General Social Survey, we focus on how approaches to culture might explain the paradox of high cultural predispositions and low actual use. Children with mental health problems provide a comparison between suggestions and endorsements. Suggestions, sources of care offered by individuals in response to a case description without any other social cues, align with new cultural approaches, and are measured by responses to open-ended questions about what should be done for the child described (with clinical criteria for ADHD, major depression, asthma, or "daily troubles"). Endorsements, requiring less cognitive work and cultural resistance, align with traditional conceptualizations of culture, and are measured by closed-ended questions that ask respondents to agree or disagree with seeking help from different treatment options placed later in the survey. Suggestions reveal cultural predispositions to use services corresponding closely to reported utilization levels; endorsements reveal high, unrealistic cultural predispositions to use services. Further, suggestions are associated with sociodemographics that proxy culture (e.g., race), while endorsements are associated only with perceived need. PMID- 26005288 TI - Behavioral Reversion and Dark-Light Choice Behavior in Workers of the Red Wood Ant Formica polyctena. AB - Social insect workers usually start adult life from intranidal tasks and then switch to extranidal activities, but this process may be reversed: foragers may switch again to intranidal brood care. The transition forager - reverted nurse is known as the behavioral reversion. Ant foragers are known to avoid illuminated zones less strongly than intranidal workers, but illumination responses of reverted nurses were so far never investigated. We compared dark-light choice behavior of three classes of workers of the red wood ant Formica polyctena: nurses, foragers and reverted nurses. Sets of ten ants belonging to the same class were tested in "double nests" made of two interconnected test tubes, one kept in darkness and the other exposed to light. The number of ants present in the illuminated zone of each nest (ni) was recorded on 10 sample points at 30 min intervals. The values of ni were lower in nurses than in foragers and reverted nurses and decreased as a function of time in all three groups. Nurses differed from foragers with respect to the dynamics of dark-light choice behavior, but reverted nurses did not differ in that respect either from nurses, or from foragers. Reverted nurses and foragers did not differ significantly from each other with respect to the overall level of avoidance of illuminated zone, nor with respect to the dynamics of dark-light choice behavior. This implies that behavioral reversion is not accompanied by the return of illumination responses of workers of F. polyctena to the state characteristic for nurses. PMID- 26005290 TI - A Universal Rig for Supporting Large Hammer Drills: Reduced Injury Risk and Improved Productivity. AB - Drilling holes into concrete with heavy hammer and rock drills is one of the most physically demanding tasks performed in commercial construction and poses risks for musculoskeletal disorders, noise induced hearing loss, hand arm vibration syndrome and silicosis. The aim of this study was to (1) use a participatory process to develop a rig to support pneumatic rock drills or large electric hammer drills in order to reduce the health risks and (2) evaluate the usability of the rig. Seven prototype rigs for supporting large hammer drills were developed and modified with feedback from commercial contractors and construction workers. The final design was evaluated by laborers and electricians (N=29) who performed their usual concrete drilling with the usual method and the new rig. Subjective regional fatigue was significantly less in the neck, shoulders, hands and arms, and lower back) when using the universal rig compared to the usual manual method. Usability ratings for the rig were significantly better than the usual method on stability, control, drilling, accuracy, and vibration. Drilling time was reduced by approximately 50% with the rig. Commercial construction contractors, laborers and electricians who use large hammer drills for drilling many holes should consider using such a rig to prevent musculoskeletal disorders, fatigue, and silicosis. PMID- 26005289 TI - What can measures of text comprehension tell us about creative text production? AB - Evidence is accumulating that the level of text comprehension is dependent on the situatedness and sensory richness of a child's mental representation formed during reading. This study investigated whether these factors involved in text comprehension also serve a functional role in writing a narrative. Direct influences of situatedness and sensory richness as well as indirect influences via the number of sensory and situational words on the creativity (i.e., originality/novelty) of a written narrative were examined in 165 primary school children through path analyses. Results showed that sensory richness and situatedness explained 35 % of the variance in creativity scores. Sensory richness influenced the originality/novelty of children's narrative writing directly, whereas situatedness had an indirect influence, through the number of sensory words, but both pathways influenced the outcomes to a comparable extent. Findings suggest that creative writing requires similar representational processes as reading comprehension, which may contribute to the development of instructional methods to help children in creative writing assignments. PMID- 26005291 TI - Maximizing overall liking results in a superior product to minimizing deviations from ideal ratings: an optimization case study with coffee-flavored milk. AB - In just-about-right (JAR) scaling and ideal scaling, attribute delta (i.e., "Too Little" or "Too Much") reflects a subject's dissatisfaction level for an attribute relative to their hypothetical ideal. Dissatisfaction (attribute delta) is a different construct from consumer acceptability, operationalized as liking. Therefore, we hypothesized minimizing dissatisfaction and maximizing liking would yield different optimal formulations. The objective of this research was to compare product optimization strategies, i.e. maximizing liking vis-a-vis minimizing dissatisfaction. Coffee-flavored dairy beverages (n = 20) were formulated using a fractional mixture design that constrained the proportions of coffee extract, milk, sucrose, and water. Participants (n = 388) were randomly assigned to one of three research conditions, where they evaluated 4 of the 20 samples using an incomplete block design. Samples were rated for overall liking and for intensity of the attributes sweetness, milk flavor, thickness and coffee flavor. Where appropriate, measures of overall product quality (Ideal_Delta and JAR_Delta) were calculated as the sum of the absolute values of the four attribute deltas. Optimal formulations were estimated by: a) maximizing liking; b) minimizing Ideal_Delta; or c) minimizing JAR_Delta. A validation study was conducted to evaluate product optimization models. Participants indicated a preference for a coffee-flavored dairy beverage with more coffee extract and less milk and sucrose in the dissatisfaction model compared to the formula obtained by maximizing liking. That is, when liking was optimized, participants generally liked a weaker, milkier and sweeter coffee-flavored dairy beverage. Predicted liking scores were validated in a subsequent experiment, and the optimal product formulated to maximize liking was significantly preferred to that formulated to minimize dissatisfaction by a paired preference test. These findings are consistent with the view that JAR and ideal scaling methods both suffer from attitudinal biases that are not present when liking is assessed. That is, consumers sincerely believe they want 'dark, rich, hearty' coffee when they do not. This paper also demonstrates the utility and efficiency of a lean experimental approach. PMID- 26005293 TI - Is dentistry becoming a carnival of rust? PMID- 26005292 TI - Effects of Parental Status on Male Body Mass in the Monogamous, Biparental California Mouse. AB - Studies of biparental mammals demonstrate that males may undergo systematic changes in body mass as a consequence of changes in reproductive status; however, these studies typically have not teased apart effects of specific social and reproductive factors, such as cohabitation with a female per se, cohabitation with a breeding female specifically, and engagement in paternal care. We aimed to determine whether California mouse (Peromyscus californicus) fathers undergo systematic changes in body mass and if so, which specific social/reproductive factor(s) might contribute to these changes. We compared mean weekly body masses over a 5-week period in 1) males housed with another male vs. males housed with a non-reproductive (tubally ligated) female; 2) males housed with a tubally ligated female vs. males housed with a female that was undergoing her first pregnancy; and 3) experienced fathers housed with vs. without pups during their mate's subsequent pregnancy. Body mass did not differ between males housed with another male and those housed with a non-reproductive female; however, males housed with a non-reproductive female were significantly heavier than those housed with a primiparous female. Among experienced fathers, those housed with pups from their previous litter underwent significant increases in body mass across their mates' pregnancy, whereas fathers housed without pups did not. These results suggest that male body mass is reduced by cohabitation with a breeding (pregnant) female, but not by cohabitation with a non-reproductive female, and that increases in body mass across the mate's pregnancy are associated with concurrent care of offspring rather than cohabitation with a pregnant female. Additional work is needed to determine the mechanisms and functional significance, if any, of these changes in male body mass with reproductive condition. PMID- 26005294 TI - Proposing national identification number on dental prostheses as universal personal identification code - A revolution in forensic odontology. AB - The proper identification of a decedent is not only important for humanitarian and emotional reasons, but also for legal and administrative purposes. During the reconstructive identification process, all necessary information is gathered from the unknown body of the victim and hence that an objective reconstructed profile can be established. Denture marking systems are being used in various situations, and a number of direct and indirect methods are reported. We propose that national identification numbers be incorporated in all removable and fixed prostheses, so as to adopt a single and definitive universal personal identification code with the aim of achieving a uniform, standardized, easy, and fast identification method worldwide for forensic identification. PMID- 26005295 TI - Determination of sexual dimorphism via maxillary first molar teeth in Himachali population. AB - CONTEXT: Sex determination of skeletal remains forms part of archaeological and medicolegal examinations. It is an aspect of forensic odontology. Forensic odontology primarily deals with identification, based on recognition of unique features present in an individual's dental structures. Correct sex determination limits the pool of missing persons to just one half of the population. AIM OF STUDY: Purpose of this study is to evaluate the existence of sexual dimorphism and variation in left and right maxillary first molars using bucco-lingual and mesio-distal dimensions in population of Sirmour District, H.P. MATERIALS AND METHODS: Base sample comprised 100 subjects (50 males and 50 females) of an age group ranging from 17 to 25 years. STATISTICAL ANALYSIS USED: Unpaired t-test. RESULTS: It was observed that the comparison of mean values of bucco-lingual and mesio-distal parameters showed highly statistically significant differences between males and females, measured both intraorally and on study casts. There were no significant differences between the mean values of both the parameters on the left side as compared to right side. CONCLUSION: The study concludes that sexual dimorphism is population specific. Among Himachali people, mesio-distal dimensions and bucco-lingual dimensions of first molar can aid in sex determination. PMID- 26005296 TI - Estimation of time elapsed since the death from identification of morphological and histological time-related changes in dental pulp: An observational study from porcine teeth. AB - AIM: Putrefaction of the human body with its rate and stages of the various changes occurring in this entire process have been explored widely by the forensic medicine experts to estimate the time elapsed since death. However, experimental data reported in literature pertaining to rates of putrefaction of the dental pulp retrieved from jaws of the dead is scarce. This study makes an attempt to find out the series of various changes which occur during the process of putrefaction of the dental pulp in a coastal environment like that of Southern India. An attempt has also been made to estimate the time elapsed since the death by assessing the duration for which dental pulp remains microscopically intact. MATERIALS AND METHODS: Three different study setups at different times, followed one by other were created. In each setup, 10 specimens of porcine jaws with teeth were buried in surface soil and 10 specimens in subsurface soil. Dental pulp was retrieved at an interval of every 24 h to see for the various changes. All the environmental parameters including average daily rainfall precipitation, temperature, soil humidity, soil temperature, and soil pH were recorded. RESULTS: A specific series of morphological changes in terms of changes in size, color, consistency, and odor; and a sequence of histological changes were observed from both surface and subsurface samples. CONCLUSION: Dental pulp buried in a coastal environment goes through a specific series of morphological and histological changes which can be interpreted up to 144 h from burial, after which pulp ceases to exist. PMID- 26005298 TI - Reliability of third molar development for age estimation in Gujarati population: A comparative study. AB - BACKGROUND: Age assessment may be a crucial step in postmortem profiling leading to confirmative identification. In children, Demirjian's method based on eight developmental stages was developed to determine maturity scores as a function of age and polynomial functions to determine age as a function of score. AIM: Of this study was to evaluate the reliability of age estimation using Demirjian's eight teeth method following the French maturity scores and Indian-specific formula from developmental stages of third molar with the help of orthopantomograms using the Demirjian method. MATERIALS AND METHODS: Dental panoramic tomograms from 30 subjects each of known chronological age and sex were collected and were evaluated according to Demirjian's criteria. Age calculations were performed using Demirjian's formula and Indian formula. Statistical analysis used was Chi-square test and ANOVA test and the P values obtained were statistically significant. RESULTS: There was an average underestimation of age with both Indian and Demirjian's formulas. The mean absolute error was lower using Indian formula hence it can be applied for age estimation in present Gujarati population. Also, females were ahead of achieving dental maturity than males thus completion of dental development is attained earlier in females. CONCLUSION: Greater accuracy can be obtained if population-specific formulas considering the ethnic and environmental variation are derived performing the regression analysis. PMID- 26005297 TI - Cheiloscopic patterns in Indian population and their efficacy in sex determination: A randomized cross-sectional study. AB - BACKGROUND: Cheiloscopy or the study of lip prints is an important tool in forensic dentistry which is gaining popularity in current times. Not only has it proven effective in identification of individuals, but its role in sex determination has also been investigated. There are six different types of cheiloscopic/lip print patterns according to Tsuchihashi. AIMS: The present study was conducted to find the prevalence of cheiloscopic/lip print pattern in 755 individuals and also to assess their efficacy in sex determination. MATERIALS AND METHODS: According to classification by Tsuchihashi, the lip prints were analysed. Sex determination using lip print was done by method given by Vahanwala et al. RESULTS: It was found that Type I was the most prevalent cheiloscopic pattern. Based on the method of sex determination using lip prints by Vahanwala et al., the percentage of individuals correctly identified was less. CONCLUSION: Although cheiloscopy holds promise as a supplementary tool along with other modes to recognize the sex of an individual, there is need for further studies using standardized methods to evaluate the same in larger population sizes. PMID- 26005299 TI - Cheiloscopy and dactyloscopy: Do they dictate personality patterns? AB - CONTEXT: Cheiloscopy and dactyloscopy, both are well-established forensic tools used in individual identification in any scenario be it a crime scene or civil cause. Like finger prints, lip prints are unique and distinguishable for every individual. But their relationship to personality types has not been established excepting the hypothesis stating that finger prints could explain these personality patterns. AIMS: The study was aimed to record and correlate the lip and finger prints with that of character/personality of a person. SETTINGS AND DESIGN: The lip and finger prints and character of a person were recorded and the data obtained was subjected for statistical analysis, especially for Pearson's Chi-square test and correlation/association between the groups was also studied. MATERIALS AND METHODS: The study sample comprised of 200 subjects, 100 males and 100 females, aged between 18 and 30 years. For recording lip prints, brown/pink colored lipstick was applied on the lips and the subjects were asked to spread uniformly over the lips. Lip prints were traced in the normal rest position on a plain white bond paper. For recording the finger prints, imprints of the fingers were taken on a plain white bond paper using ink pad. The collected prints were visualized using magnifying lens. To record the character of person, a pro forma manual for multivariable personality inventory by Dr. BC Muthayya was used. STATISTICAL ANALYSIS USED: Data obtained was subjected for statistical analysis, especially for Pearson's Chi-square test and correlation/association between the groups was also studied. RESULTS: In males, predominant lip pattern recorded was Type I with whorls-type finger pattern and the character being ego ideal, pessimism, introvert, and dogmatic; whereas in females, predominant lip pattern recorded was Type II with loops-type finger pattern and the character being neurotic, need achievers, and dominant. CONCLUSION: Many studies on lip pattern, finger pattern, palatal rugae, etc., for individual identification and gender determination exist, but correlative studies are scanty. This is the first study done on correlating patterns, that is, lip and finger pattern with the character of a person. With this study we conclude that this correlation can be used as an adjunct in the investigatory process in forensic sciences. PMID- 26005300 TI - Evaluation of skeletal and dental age using third molar calcification, condylar height and length of the mandibular body. AB - AIM: To identify the most reliable method for age estimation among three variables, that is, condylar height, length of mandibular body and third molar calcification by Demirjian's method. MATERIALS AND METHODS: Orthopantomograms and lateral cephalograms of 60 patients with equal gender ratio were included in the study, among each gender 15 subjects were below 18 years and 15 subjects were above 18 years. Lateral cephalograms were traced, height of condyle and mandibular body are measured manually on the tracing paper, OPG's were observed on radiographic illuminator and maturity score of third molar calcification was noted according to Demirjian's method. All the measurements were subjected to statistical analysis. RESULTS: The results obtained are of no significant difference between estimated age and actual age with all three parameters (P > 0.9780 condylar height, P > 0.9515 length of mandibular body, P > 0.8611 third molar calcification). Among these three, length of mandibular body shows least standard error test (i.e. 0.188). CONCLUSION: Although all three parameters can be used for age estimation, length of mandibular body is more reliable followed by height of condyle and third molar calcification. PMID- 26005301 TI - Diagonal tooth measurements in sex assessment: A study on North Indian population. AB - BACKGROUND: Sexual dimorphism has been of great interest to anthropologists and odontologists. Dental measurements are important in anthropology for the study of sexual dimorphism with most common being the traditional linear odontometric measurements. Apart from these, alternative dental measurements have been developed such as the crown and cervical diagonal diameters and mesiodistal and buccolingual cervical diameters of teeth. AIMS AND OBJECTIVE: The primary objective of the following study is to assess the degree of sexual dimorphism in teeth of a North Indian population using the crown diagonal diameters and secondary is to evaluate the applicability of diagonal measurements in sex determination by means of discriminant functional analysis. MATERIALS AND METHODS: The study sample comprised 200 individuals (100 males and 100 females) of an age group ranging from 18 to 57 years, in a North Indian population. The mesiobuccal-distolingual (MBDL) and distobuccal-mesiolingual (DBML) crown diameters of seven maxillary and seven mandibular teeth on the study models were measured using digital Vernier calipers. RESULTS: The most dimorphic teeth amongst all for crown diagonal diameters are the maxillary central incisors and the least dimorphic are the maxillary second premolars. The mean diagonal crown dimensions in all but one tooth (DBML of maxillary lateral incisor) of males exceeded that of females. The difference was statistically significant in MBDL dimensions of maxillary and mandibular central incisor, canine, first and second molar and DBML dimensions of maxillary central incisor and maxillary and mandibular canine, first molar and second molar (P < 0.05). The accuracy of determination of sex by MBDL crown dimension ranges from 55% to 75% in males and 47-84% in females, while by DBML crown dimension ranges from 55% to 80% in males and 65-80% in females with the overall accuracy of sex determination ranging from 51% to 80% respectively. CONCLUSION: MBDL and DBML crown dimensions are reliable indicators and can be used along with or/and instead of linear measurements in sex determination. In situations in which it is difficult to take correct measurements of linear dimensions of teeth, these alternative odontometric measurements can be used consistently to determine sex. PMID- 26005303 TI - Occlusal morphology of permanent mandibular first and second molars in Gujarati population. AB - BACKGROUND: Dental identification has been used since long time for disaster victim identification protocol. There is a difference of opinion regarding whether ethnicity influences dental morphology or not. Few studies have shown the associations between these dental features and crown traits in humans using quantitative methods. The present study is an attempt to find correlation of occlusal morphology of Gujarati population with forensic Odontology. AIM: To study different occlusal morphology of permanent mandibular first and second molars in Gujarati Population. MATERIALS AND METHODS: This study comprised of a total of 100 participants of Gujarati origin, selected by random sampling method. Total number of cusps and groove patterns of mandibular first and second molar were examined clinically and photographs of the same were taken. A descriptive statistics, Chi-square test and Student t-test were used for analysis of data. RESULTS: Mandibular first molar with 5 cusps in 71%, 4 cusps in 18% and 6 cusps in 11% were noted in the study. Mandibular first molars with "+" groove pattern in 39.5% and "Y" groove pattern in 60.5% were recorded. Mandibular second molar with 5 cusps in 6.5% and 4 cusps in 93.5% were recorded in the study. Mandibular second molars with "+" groove pattern in 93.5% and "Y" groove pattern in 6.5% were recorded. CONCLUSION: The most common occlusal morphology in permanent mandibular first molar is "5 cusp" and "Y" groove pattern in about 47% and for second molar is "4 cusp" and "+" groove pattern in 88.5% of Gujarati population. It may be concluded that variation in degree of expression and frequency of teeth in dentitions of different populations is different, which may help in forensic identification. PMID- 26005302 TI - Four odontometric parameters as a forensic tool in stature estimation. AB - OBJECTIVE: The study was conducted to investigate the possibility of predicting the height of an individual using selected odontometric parameters as a forensic tool. MATERIALS AND METHODS: The study sample consisted of 100 subjects (50 male and 50 female). Measurements of intercanine width (IC), interpremolar width (IP), mesiodistal dimension of six permanent maxillary anterior teeth (CW), and arch length (AL, canine to canine) were made directly on the subject. The data collected were subjected to statistical analysis and a linear regression formula was obtained against each odontometric parameter. RESULTS: Highly significant correlation was observed between height and intercanine width, interpremolar width (P < 0.0001), whereas correlation between height and the combined width of six anterior teeth and arch length was found to be not significant. The linear regression equation using formula y = c + mx was obtained for each odontometric parameter and also for combined parameters. CONCLUSION: Hence the study concludes that the two odontometric parameters such as intercanine width and interpremolar width can be used successfully to calculate the stature of an individual from fragmentary remains. PMID- 26005304 TI - A study of the palatal rugae pattern among male female and transgender population of Bhopal city. AB - CONTEXT: Transgenders are highly disadvantaged people, deprived of adequate opportunities of earning a respectable living. The forensic literature has emphasized on two genders, male and female, the existence of a third gender (Transgenders) is almost negligible in the literature, and this makes it compulsive to determine their identity through forensic approaches at the time of disasters. Previous studies have demonstrated that no two palatal rugae pattern are alike in their configuration and this unique feature has led us to undertake a study to establish individual identities using palatal rugae pattern. AIMS: The purpose of this study was to compare the palatal rugae pattern among male, female, and transgender population of the Bhopal city. SETTINGS AND DESIGN: This study was cross sectional in nature and conducted on a convenience sample of 148 subjects selected from Bhopal city, Madhya Pradesh. The study involved 49 males, 51 females, and 48 eunuchs in the age range of 17 to 35 years. MATERIALS AND METHODS: Maxillary impression using alginate impression material was made and the cast was prepared using die stone on palatal area and dental stone as a base. The palatal rugae pattern was assessed on the basis of number, length, shape, direction, and unification. STATISTICAL ANALYSIS USED: One way ANOVA was used for comparing the mean values between different genders. The multiple pairwise comparisons were done with the Bonferroni post hoc correction. The statistical significance was fixed at 0.05. RESULTS: The statistically significant difference with regard to some parameters like number of rugae, fragmentary rugae, wavy rugae, curve rugae, forwardly directed, and backwardly directed rugae between transgender and other gender groups were present. CONCLUSION: The difference in the parameters of the palatal rugae pattern among the transgender population and the other gender group is attributed to be the genetic makeup and sexual dimorphism. PMID- 26005305 TI - Effects of elevated temperatures on different restorative materials: An aid to forensic identification processes. AB - BACKGROUND: Heat-induced alterations to dental and restorative materials can be of great interest to forensic dentistry. Knowing the specific optical behavior of dental materials can be of high importance as recognition of changes induced by high temperatures can lead to the determination of material which was used in a dental restoration, facilitating identification of burned human remains. AIM: To observe the effects of predetermined temperatures (200 degrees C-400 degrees C 600 degrees C-800 degrees C-1000 degrees C) on unrestored teeth and different restorative materials macroscopically and then examine them under a stereomicroscope for the purpose of identification. MATERIALS AND METHODS: The study was conducted on 375 extracted teeth which were divided into five groups of 75 teeth each as follows: group 1- unrestored teeth, group 2- teeth restored with all-ceramic crowns, Group 3- with class I silver amalgam filling, group 4- with class I composite restoration, and group 5- with class I glass ionomer cement restoration. RESULTS: Unrestored and restored teeth display a series of specific macroscopic & stereomicroscopic structural changes for each range of temperature. CONCLUSION: Dental tissues and restorative materials undergo a series of changes which correlate well with the various temperatures to which they were exposed. These changes are a consequence of the nature of the materials and their physicochemical characteristics. PMID- 26005306 TI - Demirjian's method in the estimation of age: A study on human third molars. AB - AIM: The primary aim of the following study is to estimate the chronological age based on the stages of third molar development following the eight stages (A to H) method of Demirjian et al. (along with two modifications-Orhan) and secondary aim is to compare third molar development with sex and age. MATERIALS AND METHODS: The sample consisted of 115 orthopantomograms from South Indian subjects with known chronological age and gender. Multiple regression analysis was performed with chronological age as the dependable variable and third molar root development as independent variable. All the statistical analysis was performed using the SPSS 11.0 package (IBM (r) Corporation). RESULTS: Statistically no significant differences were found in third molar development between males and females. Depending on the available number of wisdom teeth in an individual, R (2) varied for males from 0.21 to 0.48 and for females from 0.16 to 0.38. New equations were derived for estimating the chronological age. CONCLUSION: The chronological age of a South Indian individual between 14 and 22 years may be estimated based on the regression formulae. However, additional studies with a larger study population must be conducted to meet the need for population-based information on third molar development. PMID- 26005307 TI - Age estimation using lower permanent first molars on a panoramic radiograph: A digital image analysis. AB - OBJECTIVE: A study was carried out to analyze the efficacy and practical application for age estimation using digital panoramic radiograph to exploit image analysis to obtain metric measurement of morphological parameters of permanent mandibular first molar on Sulaimani population. MATERIALS AND METHODS: In the present study a population of known age and sex was studied and subjected to digital panoramic radiographic examination. The correlation between the reduction of coronal pulp cavity and chronological age was examined in a sample of 96 individuals distributed into four age groups: 20-29 years (29 cases), 30-39 years (29 cases), 40-49 years (26 cases) and 50-59 years (12 cases). The height (mm) of the crown (CH = coronal height) and the height (mm) of coronal pulp cavity (CPCH = coronal pulp cavity height) of 96 of first molars from all subjects was measured. The tooth-coronal index (TCI) after Ikeda et al. was computed for each tooth and regressed on real age. RESULTS: ANOVA was used to show the strength of relation between the age and TCI (P = 0.0000). The correlation coefficient (r(2)) was 0.49, which mean there is strong negative linear regression between age and TCI with the r (2), regarding predicting age using TCI value, after the following equation calculated, Predicted age = 3.78 - (0.064 TCI) showed that there is no significant difference between real age and estimated age. CONCLUSION: There is a strong negative liner relationship between TCIs of mandibular first molars with chronological age of Sulaimani population, and age of individuals can therefore be estimated with a good degree of accuracy using regression equations. PMID- 26005308 TI - Sex determination using maxillary sinus. AB - BACKGROUND: Individual identification is a subtle concept and often one of the most important priorities in mass disasters, road accidents, air crashes, fires, and even in the investigation of criminal cases. Matching specific features detected on the cadaver with data recorded during the life of an individual is an important aspect in forensics, and can be performed by fingerprint analysis, deoxyribonucleic acid matching, anthropological methods, radiological methods and other techniques which can facilitate age and sex identification. Sinus radiography is one such method that has been used for determination of the sex of an individual. Hence, an attempt is being made to use the different dimensions of the maxillary sinus in the determination of sex using coronal and axial sections of plain computed tomography (CT) scan. MATERIALS AND METHODS: A total of 30 patients including 17 male and 13 female, visiting the Outpatient Department of the Mamata General Hospital were included as the study subjects. The dimensions of right and left maxillary sinuses of 30 subjects from plain CT were measured using SYNGO software and statistical analysis was done. RESULTS: Sex determination using height, length, width, and volume of the maxillary sinus on both sides showed statistically significant results with a higher percentage of sexual dimorphism in the case of volume. CONCLUSION: Volume of the right maxillary sinus can be used as accurate diagnostic parameter for sex determination. PMID- 26005309 TI - Histological appearance of postmortem pink teeth: Report of two cases. AB - This article presents images and histological changes in the dentin of two cases involving posmortem pink teeth. Postmortem pink teeth were noted among two deceased male individuals. Pink teeth were noted during autopsy examination after twelve days in one corpse, and eight days following death in the second case. During the examination decomposition and putrefaction of the body was noted. Cause of death was drowning in one case and haemorrhages and shock in another. A central incisor tooth was obtained from each body. Both teeth exhibited a pink appearance and the intensity was more pronounced in the cervical region. Although pink teeth can be noted in death due to asphyxia, carbon monoxide poisoning and so on, it is necessary to study the exact role behind the appearance of pink teeth and try to incorporate the finding medico legally. PMID- 26005310 TI - A High Level of Patient Activation Is Observed But Unrelated to Glycemic Control Among Adults With Type 2 Diabetes. AB - OBJECTIVE: To measure patient activation and its relationship to glycemic control among adults with type 2 diabetes who had not participated in a formal diabetes self-management education program as a baseline assessment for tailoring diabetes education in a primary care setting. RESEARCH DESIGN AND METHODS: Patient activation was assessed in a stratified, cross-sectional study of adults with controlled (n = 21) and uncontrolled (n = 27) type 2 diabetes, who were receiving primary care at a unique family practice center of Baylor Health Care System in Dallas, Tex. RESULTS: The mean patient activation was 66.0 (95% confidence interval [CI] 60.8-71.2) among patients with uncontrolled diabetes and 63.7 (55.9 71.5) among those with controlled diabetes (P = 0.607). A significant association was observed between the self-management behavior score and activation among patients whose glycemia was under control (rho = 0.73, P = 0.01) as well as among patients with uncontrolled glycemia (rho = 0.48, P < 0.001). CONCLUSIONS: Although activation is correlated with self-management and may be important in tailored patient-centered approaches to improving diabetes care outcomes, the highest stage of activation may be necessary to achieve glycemic control. These findings reinforce the importance of conducting prerequisite needs assessments so diabetes educators are able to tailor their educational interventions to individual patients' needs and readiness to take action. PMID- 26005311 TI - Reciprocal and Complementary Sibling Interactions: Relations with Socialization Outcomes in the Kindergarten Classroom. AB - RESEARCH FINDINGS: To examine associations between sibling interaction patterns and later social outcomes in single- and two-parent families, 113 kindergarteners took part in naturalistic observations at home with siblings, classmates participated in sociometric interviews, and teachers completed behavior ratings. Sibling interactions were coded using a newly-developed 39-item checklist, and proportions of complementary and reciprocal sibling interactions computed. Complementarity occurred more among dyads where kindergartners were with toddler or infant siblings than among kindergartners with older or near-age younger siblings. Higher levels of complementarity predicted lower levels of internalizing but were not related to externalizing problems. Kindergartners' sociometric status in the classroom differed as a function of sibling interaction patterns, with neglected and controversial children experiencing less complementarity/more reciprocity than popular, average, and rejected children. Finally, there was some evidence for differential associations of sibling interaction patterns with social outcomes for children in single- versus two parent families: regressions testing interaction effects show sibling reciprocity positively associated with kindergartners' social skills only in single-parent families, and complementary sibling interactions positively related to internalizing problems only in two-parent families. IMPLICATIONS FOR PRACTICE: Those working with divorcing or other single-parent families might consider sibling interactions as a potential target for social skill building. PMID- 26005312 TI - Shaping Social Activity by Incentivizing Users. AB - Events in an online social network can be categorized roughly into endogenous events, where users just respond to the actions of their neighbors within the network, or exogenous events, where users take actions due to drives external to the network. How much external drive should be provided to each user, such that the network activity can be steered towards a target state? In this paper, we model social events using multivariate Hawkes processes, which can capture both endogenous and exogenous event intensities, and derive a time dependent linear relation between the intensity of exogenous events and the overall network activity. Exploiting this connection, we develop a convex optimization framework for determining the required level of external drive in order for the network to reach a desired activity level. We experimented with event data gathered from Twitter, and show that our method can steer the activity of the network more accurately than alternatives. PMID- 26005313 TI - Silver Fractal-like Structures for Metal-Enhanced Fluorescence: Enhanced Fluorescence Intensities and Increased Probe Photostabilities. AB - Substantial increases in fluorescence emission from fluorophore-protein-coated fractal-like silver structures have been observed. We review two methods for silver fractal structure preparation, which have been employed and studied. The first, a roughened silver electrode, typically yielded a 100-fold increase in fluorophore emission, and the second, silver fractal-like structures grown on glass between two silver electrodes, produced a ~500-fold increase. In addition, significant increases in probe photostability were observed for probes coated on the silver fractal like structures. These results further serve to compliment our recent work on the effects of nobel metal particles with fluorophores, a relatively new phenomenon in fluorescence we have termed both "metal-enhanced fluorescence" [1] and "radiative decay engineering" [2,3]. These results are explained by the metallic surfaces modifying the radiative decay rate (Gamma) of the fluorescent labels. We believe that this new silver-surface preparation, which results in ultrabright and photostable fluorophores, offers a new generic technology platform for increased fluorescence signal levels, with widespread potential applications to the analytical sciences, imaging, and medical diagnostics. PMID- 26005314 TI - Interarticulatory Coordination of the Lips and Jaw in Childhood Apraxia of Speech. AB - Childhood apraxia of speech (CAS) is often characterized by an ability to produce phonemes in isolation, but not in more complex phonetic sequences. This has led to the hypothesis that articulator coordination is impaired in CAS, This study explored whether coordination between the lips and jaw during speech production is impaired in this group. We used two methods to investigate interarticulatory relationships. Cross-correlation analysis directly measures spatial-temporal coupling of articulator movements. The spatiotemporal index (STI; Smith, Goffman, Zelaznik, Ying, & MeGillem, 1995) measures repetition stability and has also been used as an indirect measure of interarticulatory coordination by providing an index of the coordinative consistency of the relationship between articulators within a pair (Smith & Zelaznik, 2004). Three groups of children were included: children with CAS; children with a speech sound disorder involving articulation, phonological errors, or both (the SD group); and typically developing (TD) children. A facial motion capture system was used to track upper lip, lower lip, and jaw movement during a naming task in which stimuli varied by word length. The CAS, SD, and TD children did not significantly differ in spatial-temporal coupling; however, coefficients of variation of the spatial and temporal coupling measures did differentiate the CAS and SD groups. Additionally, the CAS children were distinguished from the SD children by higher lip aperture STI values, indicating that the CAS group had more difficulty generating stable movement plans. PMID- 26005315 TI - GLO-STIX: Graph-Level Operations for Specifying Techniques and Interactive eXploration. AB - The field of graph visualization has produced a wealth of visualization techniques for accomplishing a variety of analysis tasks. Therefore analysts often rely on a suite of different techniques, and visual graph analysis application builders strive to provide this breadth of techniques. To provide a holistic model for specifying network visualization techniques (as opposed to considering each technique in isolation) we present the Graph-Level Operations (GLO) model. We describe a method for identifying GLOs and apply it to identify five classes of GLOs, which can be flexibly combined to re-create six canonical graph visualization techniques. We discuss advantages of the GLO model, including potentially discovering new, effective network visualization techniques and easing the engineering challenges of building multi-technique graph visualization applications. Finally, we implement the GLOs that we identified into the GLO-STIX prototype system that enables an analyst to interactively explore a graph by applying GLOs. PMID- 26005316 TI - Postoperative adhesion formation in a rabbit model: monopolar electrosurgery versus ultrasonic scalpel. AB - BACKGROUND AND OBJECTIVES: To determine if surgery using ultrasonic energy for dissection results in less adhesion formation than monopolar electrosurgical energy in the late (8 weeks) postoperative period. METHODS: Injuries were induced in rabbits by using ultrasonic energy on one uterine horn and the adjacent pelvic sidewall and using monopolar energy on the opposite side. Eight weeks postoperatively, the rabbits underwent autopsy and clinical and pathologic scoring of adhesions was performed by blinded investigators. RESULTS: There was no significant difference in clinical adhesion scores between the two modalities. The mean clinical score for monopolar cautery was 1.00 versus 0.88 for the Harmonic device (Ethicon Endo-Surgery, Cincinnati, Ohio) (P = .71). Furthermore, there was no significant difference found in the pathologic adhesion scores between the ultrasonic scalpel and monopolar energy. The mean pathologic score for monopolar electrosurgery was 4.35 versus 3.65 for the Harmonic scalpel (P = .30). CONCLUSION: Neither monopolar electrosurgery nor ultrasonic dissection is superior in the prevention of adhesion formation in the late postoperative period. PMID- 26005317 TI - Endometriosis in adolescents. AB - BACKGROUND AND OBJECTIVES: Women with endometriosis often report onset of symptoms during adolescence; however, the diagnosis of endometriosis is often delayed. The aim of this study was to describe the experience of adolescents who underwent laparoscopy for pelvic pain and were diagnosed with endometriosis: specifically, the symptoms, time from onset of symptoms to correct diagnosis, number and type of medical professionals seen, diagnosis, treatment, and postoperative outcomes. METHODS: We reviewed a series of 25 females <=21 years of age with endometriosis diagnosed during laparoscopy for pelvic pain over an 8 year period. These patients were followed up for 1 year after surgery. RESULTS: The mean age at the time of surgery was 17.2 (2.4) years (range, 10-21). The most common complaints were dysmenorrhea (64%), menorrhagia (44%), abnormal/irregular uterine bleeding (60%), >=1 gastrointestinal symptoms (56%), and >=1 genitourinary symptoms (52%). The mean time from the onset of symptoms until diagnosis was 22.8 (31.0) months (range, 1-132). The median number of physicians who evaluated their pain was 3 (2.3) (range, 1-12). The adolescents had stage I (68%), stage II (20%), and stage III (12%) disease. Atypical endometriosis lesions were most commonly observed during laparoscopy. At 1 year, 64% reported resolved pain, 16% improved pain, 12% continued pain, and 8% recurrent pain. CONCLUSIONS: Timely referral to a gynecologist experienced with laparoscopic diagnosis and treatment of endometriosis is critical to expedite care for adolescents with pelvic pain. Once the disease is diagnosed and treated, these patients have favorable outcomes with hormonal and nonhormonal therapy. PMID- 26005318 TI - Transvaginal morcellation. AB - BACKGROUND AND OBJECTIVES: Transvaginal uterine morcellation has been described in the literature for more than a century. Despite an extensive body of literature documenting its safety and feasibility, concerns about morcellating occult malignant entities have raised questions regarding this technique. In this study, we looked at a single teaching institution's experience with transvaginal morcellation for leiomyomatous uteri. In addition, we reviewed the published literature for outcomes associated with transvaginal morcellation techniques. METHODS: This study was a retrospective case series. Charts of women who underwent total laparoscopic hysterectomy, robot-assisted laparoscopic hysterectomy, and laparoscopic-assisted vaginal hysterectomy for leiomyoma from July 1, 2011, through December 31, 2013, were reviewed. Cases were included if transvaginal morcellation was performed. Morcellation was performed by bringing the uterus into the vagina and by performing a wedge resection technique to reduce the volume of the specimen. Baseline demographics and intra- and postoperative outcomes were abstracted from the charts. A PubMed search from January 1, 1970 to October 31, 2014 was performed to review the literature regarding transvaginal morcellation. RESULTS: Sixty-four women who underwent laparoscopy for leiomyomatous uteri with transvaginal morcellation were identified from July 1, 2011 through December 31, 2013. Mean operative time was 210 minutes (SD 75.5; range, 93-420). The mean blood loss was 153 mL (SD 165; range, 25-1000). The mean uterine size was 608 g (SD 367; range, 106-1834). There were no surgical complications directly attributed to morcellation. The literature search yielded 22 articles describing outcomes after transvaginal morcellation, with a total of 1953 morcellated specimens. CONCLUSIONS: Transvaginal uterine morcellation appears to be a safe alternative to laparotomy for the removal of large uterine specimens in select patients. PMID- 26005319 TI - Effectiveness of elective laparoscopic treatment for colonic diverticulitis. AB - BACKGROUND AND OBJECTIVES: To analyze the short- and long-term outcomes of laparoscopic sigmoid colectomy for the elective treatment of diverticular disease. METHODS: A consecutive unselected series of 94 patients undergoing elective laparoscopic sigmoid colectomy for diverticular disease from 2008 to 2012 was analyzed. We collected patients-, surgery- and hospital stay-related data, as well as the short- and long-term outcomes. Operative steps, instrumentation, and postoperative cares were standardized. Comorbidity was assessed by Charlson comorbidity index. Complications were classified using the Clavien-Dindo classification system. The qualitative long-term assessment was carried out by subjecting patients to the validated gastrointestinal quality of life index questionnaire before and after surgery. RESULTS: The mean age of our cohort was 61.3 +/- 11.0 years with a Charlson comorbidity index of 1.2 +/- 1.5. Mean operative time was 213.5 +/- 60.8 minutes and estimated blood loss was 67.2 +/- 94.3 mL. We had 3 cases (3.2%) of conversion to open laparotomy. The rates of postoperative complications were 35.1%, 6.3%, 2.1%, and 1.06%, respectively, for grades 1, 2, 3b, and 5 according to the Clavien-Dindo system. Length of hospital stay was 8.1 +/- 1.9 days, and we have not recorded readmissions in patients discharged within 60 days after surgery. Median follow-up was of 9.6 +/- 2.7 months. We observed no recurrence of diverticular disease, but there was evidence of 3 cases of incisional hernia (3.19%). The difference between preoperative and late gastrointestinal quality of life index score was statistically significant (97.1 +/- 5.8 vs 129.6 +/- 8.0). CONCLUSIONS: Elective laparoscopic treatment of colonic diverticular disease represents an effective option that produces adequate postoperative results and ensures a satisfactory functional outcome. PMID- 26005320 TI - Analysis of subcutaneous and visceral fat after gastric balloon treatment. AB - BACKGROUND AND OBJECTIVES: This project is a continuation of a larger project entitled "Treatment with intragastric balloon (IGB) in patients with overweight and obesity in Recife" developed by Professor Dr. Gustavo Lopes de Carvalho. It is a project studying the effectiveness of treatment with IGB evaluating the loss of weight and body mass index and its impact on blood pressure, blood glucose, triglycerides, total cholesterol and fractions. It also assesses the lifestyle of patients studying whether treatment with IGB interferes in smoking, alcohol consumption, eating habits and physical exercises performed by patients. The present study added a larger project, the separate evaluation of the different types of abdominal fat-visceral fat and subcutaneous cell tissue fat - and was conducted to discover which of the 2 types of fat undergoes the greater reduction after IGB treatment. To measure these 2 types of fat, we used the ultrasonography technique, because it has been shown to be accurate and noninvasive. METHODS: Twenty-five patients were evaluated before and after 6 months of IGB treatment. RESULTS: The patients' ages ranged from 20 to 61 years, with 60% being 40 years of age or older. The majority (72%) were women. All variables (weight, body mass index [BMI], VF, and SCTF) showed a significant reduction (P < .05) in mean values after treatment. The difference was highest in the SCTF (17.5%) and ranged from an 11.4% to an 11.6% reduction in all other variables. The average loss of SCTF was highest among the patients who had lost up to 10.0% of their initial weight (19.2% for the <=10.0% group vs 15.9% for the >10.0% group); however, the difference was not significant (P = .66). The average loss of VF was higher in the subgroup of patients who had lost >10.0% of their initial weight (16.2% vs 6.3%; P = .003). The Pearson correlation between the reductions in SCTF vs VF was negative, low, and nonsignificant (-0.17; P = .41). CONCLUSIONS: After 6 months of IGB treatment, there was no significant difference between the reduction in abdominal SCTF and VF, but the results signify a possible correlation between the percentage of body weight loss and the type of abdominal fat reduced, as the impact on the VF was higher when the patients lost >10.0% of their initial weight. PMID- 26005321 TI - A dual-valve system to minimize loss of pneumoperitoneum in laparoscopic surgery. AB - BACKGROUND AND OBJECTIVES: Loss of visualization of the surgical field due to pneumoperitoneum deflation when CO2 insufflator cylinders become empty can occur at key moments during laparoscopic surgery. The purpose of this study was to examine the incidence of intraoperative cylinder exhaustion in the United Kingdom, determine its impact on patient safety, and design and test a novel device to minimize the phenomenon. METHODS: We performed a national cross sectional survey of U.K. surgeons, inviting all members of the Association of Surgeons of Great Britain and Ireland (ASGBI) and the Association of Upper GI Surgeons (AUGIS) to participate. We designed and tested a novel dual-valve system to allow rapid intraoperative exchange of CO2 cylinders. RESULTS: Eighty-five percent of the U.K. surgeons surveyed reported loss of surgical visualization at critical times during laparoscopic surgery, caused by the decrease in pneumoperitoneum during CO2 cylinder exchange. Eighty-four percent said that the process contributed to the surgeon's stress, and 63% said that a device that maintains uninterrupted pneumoperitoneum would reduce the risk of intraoperative complications. In our locale, a timed cylinder exchange was, on average, 30 times quicker with the novel dual valve than by conventional cylinder exchange (mean conventional exchange time, 61.3 +/- 7.3 s vs. novel device, 2.0 +/- 0.2 s; P <= .0001) and could be performed just as rapidly by staff unfamiliar with the device (2.2 +/- 0.3 s vs. 1.9 +/- 0.4 s P = .1945). We suggest that this simple, low cost system could be developed for use in a clinical setting to enhance patient safety. PMID- 26005322 TI - BioMiner: Paving the Way for Personalized Medicine. AB - Personalized medicine is promising a revolution for medicine and human biology in the 21st century. The scientific foundation for this revolution is accomplished by analyzing biological high-throughput data sets from genomics, transcriptomics, proteomics, and metabolomics. Currently, access to these data has been limited to either rather simple Web-based tools, which do not grant much insight or analysis by trained specialists, without firsthand involvement of the physician. Here, we present the novel Web-based tool "BioMiner," which was developed within the scope of an international and interdisciplinary project (SYSTHER) and gives access to a variety of high-throughput data sets. It provides the user with convenient tools to analyze complex cross-omics data sets and grants enhanced visualization abilities. BioMiner incorporates transcriptomic and cross-omics high-throughput data sets, with a focus on cancer. A public instance of BioMiner along with the database is available at http://systherDB.microdiscovery.de/, login and password: "systher"; a tutorial detailing the usage of BioMiner can be found in the Supplementary File. PMID- 26005323 TI - Assessment of weighted quantile sum regression for modeling chemical mixtures and cancer risk. AB - In evaluation of cancer risk related to environmental chemical exposures, the effect of many chemicals on disease is ultimately of interest. However, because of potentially strong correlations among chemicals that occur together, traditional regression methods suffer from collinearity effects, including regression coefficient sign reversal and variance inflation. In addition, penalized regression methods designed to remediate collinearity may have limitations in selecting the truly bad actors among many correlated components. The recently proposed method of weighted quantile sum (WQS) regression attempts to overcome these problems by estimating a body burden index, which identifies important chemicals in a mixture of correlated environmental chemicals. Our focus was on assessing through simulation studies the accuracy of WQS regression in detecting subsets of chemicals associated with health outcomes (binary and continuous) in site-specific analyses and in non-site-specific analyses. We also evaluated the performance of the penalized regression methods of lasso, adaptive lasso, and elastic net in correctly classifying chemicals as bad actors or unrelated to the outcome. We based the simulation study on data from the National Cancer Institute Surveillance Epidemiology and End Results Program (NCI-SEER) case-control study of non-Hodgkin lymphoma (NHL) to achieve realistic exposure situations. Our results showed that WQS regression had good sensitivity and specificity across a variety of conditions considered in this study. The shrinkage methods had a tendency to incorrectly identify a large number of components, especially in the case of strong association with the outcome. PMID- 26005324 TI - Literature-based discovery of salivary biomarkers for type 2 diabetes mellitus. AB - The alarming increase in type 2 diabetes mellitus (T2DM) underscores the need for efficient screening and preventive strategies. Select protein biomarker profiles emerge over time during T2DM development. Periodic evaluation of these markers will increase the predictive ability of diabetes risk scores. Noninvasive methods for frequent measurements of biomarkers are increasingly being investigated. Application of salivary diagnostics has gained importance with the establishment of significant similarities between the salivary and serum proteomes. The objective of this study is to identify T2DM-specific salivary biomarkers by literature-based discovery. A serial interrogation of the PubMed database was performed using MeSH terms of specific T2DM pathological processes in primary and secondary iterations to compile cohorts of T2DM-specific serum markers. Subsequent search consisted of mining for the identified serum markers in human saliva. More than 60% of T2DM-associated serum proteins have been measured in saliva. Nearly half of these proteins have been reported in diabetic saliva. Measurements of salivary lipids and oxidative stress markers that can exhibit correlated saliva plasma ratio could constitute reliable factors for T2DM risk assessment. We conclude that a high percentage of T2DM-associated serum proteins can be measured in saliva, which offers an attractive and economical strategy for T2DM screening. PMID- 26005325 TI - The eye drop chart: a pilot study for improving administration of and compliance with topical treatments in glaucoma patients. AB - AIM: In order to improve patient education, compliance, and administration of eye drops prescribed for patients suffering with glaucoma within a UK ophthalmology department, an eye drop chart (EDC) was designed, developed, and piloted with patients attending the glaucoma clinic over 1 month. METHODS: A cross-sectional prospective pilot study of 25 patients using an administration aid and a self reported questionnaire. Chi-square tests were used to compare responses pre- and postintervention. RESULTS: Results demonstrated an impressive improvement in nine of eleven categories assessed regarding drop administration and compliance. Patients stating that they always wash their hands increased significantly from 64% (13 participants) to 92% (23 participants) (P=0.029), and those who always shake the bottle improved from 40% (10) to 84% (21) (P=0.001). Punctal occlusion techniques improved from 44% (11) to 72% (18) (P=0.015). Finally, patients who always discarded the bottle after 28 days of use rose from 68% to 92%, though the difference was not significant (P=0.09). Only the number of drops being administered to the eye and the length of time left between the application of drops remained relatively unchanged. Sixty-four percent reported finding EDC helpful or useful, 52% had positive responses when asked if they would continue using EDC, and 88% would recommend it to a friend. CONCLUSION: Although there are limitations to the data as they are subjective, descriptive, and limited to sample size of 25, the results of this pilot study have shown promise. The EDC appears to be a cost-effective way at improving patients' use of topical ocular medications. PMID- 26005326 TI - Efficacy and safety of fixed-combination travoprost 0.004%/timolol 0.5% in patients transitioning from bimatoprost 0.03%/timolol 0.5% combination therapy. AB - PURPOSE: To determine the efficacy and safety of fixed-combination travoprost 0.004%/timolol 0.5% preserved with polyquaternium-1 in patients with insufficient response to bimatoprost 0.03%/timolol 0.5% preserved with benzalkonium chloride. PATIENTS AND METHODS: In this open-label nonrandomized study conducted at 13 European sites, patients with primary open-angle glaucoma or ocular hypertension with insufficient intraocular pressure (IOP) reduction during bimatoprost/timolol therapy were transitioned to travoprost/timolol (DuoTrav((r))) administered every evening for 12 weeks. Change in IOP from baseline to week 12 was assessed in patients who transitioned from fixed-combination bimatoprost/timolol (n=57, primary endpoint). Secondary assessments included change in IOP at week 4, percentage of patients with IOP <=18 mmHg at weeks 4 and 12, change in Ocular Surface Disease Index and ocular hyperemia scores at week 12, and patient preference. Adverse events were also reported. RESULTS: IOP change (mean +/- SD) from baseline to week 12 was -3.8+/-1.9 mmHg (P<0.001); results were similar at week 4. Most patients had IOP <=18 mmHg at weeks 4 and 12 (78.6% and 85.5%, respectively). Mean Ocular Surface Disease Index score was significantly reduced (P<0.001); no significant change in ocular hyperemia score was observed (P=0.197). Treatment-related adverse events included dysgeusia, nausea, paresthesia, myalgia, headache, and eye irritation (n=1 each). Most patients (74.5%) preferred travoprost/timolol over bimatoprost/timolol. CONCLUSION: Transition to travoprost/timolol significantly reduced IOP and was well tolerated in patients who had elevated IOP despite bimatoprost/timolol therapy. Polyquaternium-1-preserved travoprost/timolol was preferred over prior treatment with benzalkonium chloride-preserved bimatoprost/timolol. PMID- 26005327 TI - Selective laser trabeculoplasty: current perspectives. AB - Selective laser trabeculoplasty (SLT) has been used in the treatment of glaucoma for just over a decade. Here, we review the current literature in terms of suggested mechanism, efficacy, method of treatment, predictors of success, adverse events, repeatability, and cost of SLT. The exact mechanism by which SLT lowers intraocular pressure (IOP) remains unknown although circumstantial evidence has come in many forms in relation to structural alteration; oxidative stress and inflammatory responses; tight junction integrity; proliferative responses; and microbubble formation. SLT is as effective as argon laser trabeculoplasty and medications in reducing IOP in glaucoma and ocular hypertension. The treatment is not uniformly effective in all eyes, and its IOP lowering effect decreases over time. High pretreatment IOP is the strongest predictor of success; however, significant pressure reduction has also been shown in normal-tension glaucoma and in patients already taking multiple antiglaucoma drops. Mild, transient adverse effects are common. Transient IOP spikes usually resolve quickly with or without antiglaucoma treatment but may be problematic in pigmented angles. The limited available evidence suggests SLT is repeatable and cost-effective for the treatment of glaucoma and ocular hypertension. PMID- 26005328 TI - Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats. AB - Streptozotocin (STZ) is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body's normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451-750 mg/dL), noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration-time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were altered when different initial blood glucose levels of STZ diabetic rats were selected for testing. Such findings emphasize the importance of selecting predefined and unified glucose levels when using STZ as a diabetogenic agent in experimental protocols evaluating new antidiabetic agents and insulin delivery systems. PMID- 26005329 TI - Efficacy and safety of different doses of a slow-release corticosteroid implant for macular edema: meta-analysis of randomized controlled trials. AB - BACKGROUND: The purpose of this meta-analysis was to assess the efficacy and safety of intravitreal corticosteroid implants for macular edema. METHODS: A total of 3,586 patients from previously reported randomized controlled trials were included. The meta-analysis was performed using RevMan 5.2. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, employing random effects or fixed-effects models according to between-study heterogeneity. The main outcome measures were the ORs for effects and safety of intravitreal corticosteroid implants. RESULTS: Four eligible studies were included. Compared with the sham group, the ORs for >=15 letter improvement of visual acuity in the high-dose and low-dose groups were 1.89 (95% CI 1.33-2.69, P=0.0004) and 1.62 (95% CI 1.10-2.41, P=0.02), respectively. The weight mean differences in central retinal thickness increases were -75.46 (95% CI -90.29, -60.63, P<0.0001) and 46.47 (95% CI -92.08, -0.86, P=0.05), respectively. However, the ORs for increased intraocular pressure in both intervention groups were higher than in the sham group, and were 11.50 (95% CI 7.24-18.28, P<0.00001) and 10.30 (95% CI 6.49-16.36, P<0.00001), respectively. The incidence of cataract was 7.25 (95% CI 5.68-9.25, P<0.00001) and 3.56 (95% CI 1.28-9.96, P=0.02) in the two intervention groups, respectively. There was no significant difference between the intervention groups except for the incidence of cataract in which the OR was 1.59 (95% CI 1.28-1.97, P<0.001). CONCLUSION: Intravitreal corticosteroid implants are effective in treating macular edema. However, the efficacy is not related to corticosteroid dose. PMID- 26005330 TI - A prospective treatment for sepsis. AB - The present paper proposes a prospective auxiliary treatment for sepsis. There exists no record in the published media on the subject. As an auxiliary therapy, efficacious extracorporeal removal of sepsis-causing bacterial antigens and their toxins (BATs) from the blood of septic patients is discussed. The principal component to this approach is a bacterial polyvalent antibody-column (BPVAC), which selectively traps wide spectrum of BATs from blood in an extracorporeal circuit, and detoxified blood returns back to the patient's body. BPVAC treatment would be a device of targeted medicine. Detoxification is performed under supervision of trained personnel using simple blood-circulating machines in which blood circulates from the patient to BPVAC and back to the patient aseptically. BPVACs' reactive sites consist of carbon nanotubes on which a vast spectra of polyvalent BATs-antibodies are bond to. The devise acts as a biological filter that selectively immobilizes harmful BATs from intoxicated blood; however, no dialysis is involved. For effective neutralization, BPVAC provides large contact surface area with blood. BPVAC approach would have advantages of: 1) urgent neutralization of notorious BATs from blood of septic patients; 2) applicability in parallel with conventional treatments; 3) potential to minimize side effects of the malady; 4) applicability for a vast range of BATs; 5) potential to eliminate contact of BATs with internal tissues and organs; 6) tolerability by patients sensitive to antiserum injections; 7) capability for universal application; 8) affectivity when antibiotic-resistant bacteria are involved and the physician has no or limited access to appropriate antibiotics; and 10) being a single-use, disposable, and stand-alone device. Before using it for clinical trials in human beings, it should pass animal evaluations accurately; however, research works should optimize its implementation in human beings. For optimization, it needs appropriate investments, collaboration of scientists in many fields of research, and development through several interdisciplinary sciences such as medical engineering, nanotechnology, immunology, biochemistry, emergency medicine, internal, and infectious diseases. PMID- 26005331 TI - Sonodynamic effect of hematoporphyrin monomethyl ether on ligature-induced periodontitis in rats. AB - OBJECTIVES: The aim of this study was to perform a histological evaluation of sonodynamic therapy (SDT) of hematoporphyrin monomethyl ether (HMME) on artificially induced periodontal disease in rats. METHODS: Submerging ligatures were placed at the subgingival region of the first maxillary molar in rats. Eighty rats were randomly assigned into four groups: group 1 received no treatment; group 2 was subjected to 50 MUg/mL HMME alone; group 3 was treated with low-intensity ultrasound alone (1 W/cm(2)); and group 4 was treated with 50 MUg/mL HMME plus ultrasound irradiation (1 MHz, 30 minutes). Ten rats in each group were euthanized at 7 and 15 days, and periodontal tissue samples were taken for histological examination. RESULTS: The animals treated by SDT showed less bone loss (P<0.05) at all experimental periods than the other three groups. No significant differences were found between the control and HMME groups (P>0.05). CONCLUSION: Our results suggest that HMME-mediated SDT can effectively alleviate the periodontal tissue destruction in artificially induced periodontitis in rats. Hence, SDT may have good clinic potential as a noninvasive treatment of periodontal diseases. PMID- 26005332 TI - The mazEF toxin-antitoxin system as an attractive target in clinical isolates of Enterococcus faecium and Enterococcus faecalis. AB - The toxin-antitoxin (TA) system is a regulatory system where two sets of genes encode the toxin and its corresponding antitoxin. In this study, the prevalence of TA systems in independently isolated clinical isolates of Enterococcus faecium and Enterococcus faecalis was determined, the dominant TA system was identified, different virulence genes in E. faecium and E. faecalis were surveyed, the level of expression of the virulence and TA genes in normal and stress conditions was determined, and finally their associations with the TA genes were defined. Remarkably, the analysis demonstrated higBA and mazEF in all clinical isolates, and their locations were on chromosomes and plasmids, respectively. On the other hand, a quantitative analysis of TA and virulence genes revealed that the expression level in both genes is different under normal and stress conditions. The results obtained by anti-mazF peptide nucleic acids demonstrated that the expression level of virulence genes had decreased. These findings demonstrate an association between TA systems and virulence factors. The mazEF on the plasmids and the higBA TA genes on the chromosomes of all E. faecium and E. faecalis strains were dominant. Additionally, there was a decrease in the expression of virulence genes in the presence of anti-mazF peptide nucleic acids. Therefore, it is suggested that mazEF TA systems are potent and sensitive targets in all E. faecium and E. faecalis strains. PMID- 26005334 TI - Update on the clinical utility of once-daily tacrolimus in the management of transplantation. PMID- 26005333 TI - Skin regeneration in deep second-degree scald injuries either by infusion pumping or topical application of recombinant human erythropoietin gel. AB - Large doses of recombinant growth factors formulated in solution form directly injected into the body is usual clinical practice in treating second-degree scald injuries, with promising results, but this approach creates side effects; furthermore, it may not allow appropriate levels of the factor to be sensed by the target injured tissue/organ in the specific time frame, owing to complications arising from regeneration. In this research, two delivery methods (infusion pumping and local topical application) were applied to deliver recombinant human erythropoietin (rHuEPO) for skin regeneration. First, rHuEPO was given in deep second-degree scald injury sites in mice by infusion pump. Vascularization was remarkably higher in the rHuEPO pumping group than in controls. Second, local topical application of rHuEPO gel was given in deep second-degree scald injury sites in rats. Histological analysis showed that epithelialization rate was significantly higher in the rHuEPO gel-treated group than in controls. Immunohistochemical studies showed that the rHuEPO gel-treated group showed remarkably higher expression of skin regeneration makers than the control group. An accurate method for visualization and quantification of blood vessel networks in target areas has still not been developed up to this point, because of technical difficulties in detecting such thin blood vessels. A method which utilizes a series of steps to enhance the image, removes noise from image background, and tracks the vessels edges for vessel segmentation and quantification has been used in this study. Using image analysis methods, we were able to detect the microvascular networks of newly formed blood vessels (less than 500 MUm thickness), which participate in the healing process, providing not only nutrition and oxygen to grow tissues but also necessary growth factors to grow tissue cells for complete skin regeneration. The rHuEPO-treated group showed higher expression of stem cell markers (CD 31, CD 90, CD 71, and nestin), which actively contribute to in-wound-healing processes for new hair follicle generation as well as skin regeneration. Collectively, both rHuEPO group pumping into the systemic circulation system, and injection into the local injury area, prompted mice and rats to form new blood vessel networks in scald injury sites, which significantly participate in the scald healing process. These results may lead to the development of novel treatments for scald wounds. PMID- 26005335 TI - Ferrous sulfate, but not iron polymaltose complex, aggravates local and systemic inflammation and oxidative stress in dextran sodium sulfate-induced colitis in rats. AB - BACKGROUND AND AIMS: Iron deficiency is common in inflammatory bowel disease, yet oral iron therapy may worsen the disease symptoms and increase systemic and local oxidative stress. The aim of this study was to compare the effects of oral ferrous sulfate and iron polymaltose complex on inflammatory and oxidative stress markers in colitic rats. METHODS: Animals were divided into four groups with ten animals each. Rats of three groups received dextran sodium sulfate to induce colitis and animals of two of these groups received 5 mg iron/kg of body weight a day, as ferrous sulfate or iron polymaltose complex, for 7 days. Gross colon anatomy, histology of colon and liver, stainings of L-ferritin, Prussian blue, hepcidin, tumor necrosis factor-alpha, and interleukin-6, as well serum levels of liver enzymes, inflammatory markers, and iron markers, were assessed. RESULTS: Body weight, gross anatomy, crypt injury and inflammation scores, inflammatory parameters in liver and colon, as well as serum and liver hepcidin levels were not significantly different between colitic animals without iron treatment and colitic animals treated with iron polymaltose complex. In contrast, ferrous sulfate treatment caused significant worsening of these parameters. As opposed to ferrous sulfate, iron polymaltose complex caused less or no additional oxidative stress in the colon and liver compared to colitic animals without iron treatment. CONCLUSION: Iron polymaltose complex had negligible effects on colonic tissue erosion, local or systemic oxidative stress, and local or systemic inflammation, even at high therapeutic doses, and may thus represent a valuable oral treatment of iron deficiency in inflammatory bowel disease. PMID- 26005336 TI - A quest to increase safety of anesthetics by advancements in anesthesia monitoring: scientometric analysis. AB - The aim of this study was to assess progress in the field of anesthesia monitoring over the past 40 years using scientometric analysis. The following scientometric indexes were used: popularity indexes (general and specific), representing the proportion of articles on either a topic relative to all articles in the field of anesthetics (general popularity index, GPI) or the subfield of anesthesia monitoring (specific popularity index, SPI); index of change (IC), representing the degree of growth in publications on a topic from one period to the next; and index of expectations (IE), representing the ratio of the number of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed. Publications on 33 anesthesia-monitoring topics were assessed. Our analysis showed that over the past 40 years, the rate of rise in the number of articles on anesthesia monitoring was exponential, with an increase of more than eleven-fold, from 296 articles over the 5-year period 1974-1978 to 3,394 articles for 2009-2013. This rise profoundly exceeded the rate of rise of the number of articles on general anesthetics. The difference was especially evident with the comparison of the related GPIs: stable growth of the GPI for anesthesia monitoring vs constant decline in the GPI for general anesthetics. By the 2009-2013 period, among specific monitoring topics introduced after 1980, the SPI index had a meaningful magnitude (>=1.5) in 9 of 24 topics: Bispectral Index (7.8), Transesophageal Echocardiography (4.2), Electromyography (2.8), Pulse Oximetry (2.4), Entropy (2.3), Train-of-four (2.3), Capnography (1.9), Pulse Contour (1.9), and Electrical Nerve Stimulation for neuromuscular monitoring (1.6). Only one of these topics (Pulse Contour) demonstrated (in 2009-2013) high values for both IC and IE indexes (76 and 16.9, respectively), indicating significant recent progress. We suggest that rapid growth in the field of anesthetic monitoring was one of the most important developments to compensate for the intrinsically low margins of safety of anesthetic agents. PMID- 26005337 TI - "I am active": effects of a program to promote active aging. AB - BACKGROUND: Active aging involves a general lifestyle strategy that allows preservation of both physical and mental health during the aging process. "I am Active" is a program designed to promote active aging by increased physical activity, healthy nutritional habits, and cognitive functioning. The purpose of this study was to assess the effectiveness of this program. METHODS: Sixty-four healthy adults aged 60 years or older were recruited from senior centers and randomly allocated to an experimental group (n=31) or a control group (n=33). Baseline, post-test, and 6-month follow-up assessments were performed after the theoretical-practical intervention. Effect sizes were calculated. RESULTS: At the conclusion of the program, the experimental group showed significant improvement compared with the control group in the following domains: physical activity (falls risk, balance, flexibility, self-efficacy), nutrition (self-efficacy and nutritional status), cognitive performance (processing speed and self-efficacy), and quality of life (general, health and functionality, social and economic status). Although some declines were reported, improvements at follow-up remained in self-efficacy for physical activity, self-efficacy for nutrition, and processing speed, and participants had better nutritional status and quality of life overall. CONCLUSION: Our findings show that this program promotes improvements in domains of active aging, mainly in self-efficacy beliefs as well as in quality of life in healthy elders. PMID- 26005339 TI - The role of perioperative oral nutritional supplementation in elderly patients after hip surgery. AB - BACKGROUND: The effect of perioperative oral nutritional supplementation (ONS) on elderly patients after hip surgery remains controversial. This study intended to ascertain whether perioperative ONS is beneficial for the rehabilitation of elderly patients after hip surgery. MATERIALS AND METHODS: We searched databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials for articles published up to May 2014. Randomized controlled trials of ONS for elderly patients after hip surgery were included. RESULTS: The combined trials showed that ONS had a positive effect on the serum total protein (P<0.00001) and led to a significantly decreased number of complications (P=0.0005). Furthermore, data from the infection subgroups showed significant decreases in wound infection (P=0.02), respiratory infection (P=0.04), and urinary tract infection (P=0.03). Clinical observation suggests that the intervention may improve the level of serum albumin, although the data did not reach statistical significance (P=0.48). Regarding mortality, there was no significant statistical difference between the intervention group and the control (P=0.93). CONCLUSION: Based on the evidence available, this meta-analysis is consistent with the hypothesis that perioperative ONS can help elderly patients recover after hip surgery and reduce complications. PMID- 26005338 TI - Association between functional performance and executive cognitive functions in an elderly population including patients with low ankle-brachial index. AB - INTRODUCTION: Peripheral arterial disease, as measured by the ankle-brachial index (ABI), is prevalent among the elderly, and is associated with functional performance, assessed by the 6-minute walk test (6MWT). Executive cognitive function (ECF) impairments are also prevalent in this population, but no existing study has investigated the association between ECF and functional performance in an elderly population including individuals with low ABI. AIM: To investigate the association between functional performance, as measured by the 6MWT, and loss in ECF, in an elderly sample including individuals with low ABI. METHOD: The ABI group was formed by 26 elderly individuals with low ABI (mean ABI: 0.63+/-0.19), and the control group was formed by 40 elderly individuals with normal ABI (mean ABI: 1.08+/-0.07). We analyzed functional performance using the 6MWT, global cognition using the Mini-Mental State Examination (MMSE), and ECF using the Digit Span for assessing attention span and working memory, the Stroop Color Word Test (SCWT) for assessing information processing speed and inhibitory control/impulsivity, and the Controlled Oral Word Association Test (COWAT) for assessing semantic verbal fluency and phonemic verbal fluency. We also used a factor analysis on all of the ECF tests (global ECF). RESULTS: Before adjustment, the ABI group performed worse on global cognition, attention span, working memory, inhibitory control/impulsivity, semantic verbal fluency, and phonemic verbal fluency. After adjustment, the ABI group performance remained worse for working memory and semantic verbal fluency. In a simple correlation analysis including all of the subjects, the 6MWT was associated with global cognition, attention span, working memory, information processing speed, inhibitory control/impulsivity, semantic verbal fluency, and global ECF. After adjustment, all the associations remained statistically significant. CONCLUSION: This study found an independent association between functional performance and ECF in an elderly population including low ABI individuals, showing that, in elderly populations with functional impairment, ECF may also be impaired. PMID- 26005340 TI - The association between combined non-cystic fibrosis bronchiectasis and lung cancer in patients with chronic obstructive lung disease. AB - BACKGROUND: Whereas the epidemiological association between lung cancer and chronic obstructive pulmonary disease (COPD), a chronic inflammatory respiratory disease, is well known, limited studies have examined the association between lung cancer and non-cystic fibrosis bronchiectasis, a representative chronic airway inflammatory disease. This study evaluated the association between bronchiectasis and lung cancer in patients with COPD. METHODS: A matched case control study was conducted in a referral hospital in South Korea. Among COPD patients with moderate to very severe airflow limitation (forced expiratory volume in one second/forced vital capacity <0.7 and forced expiratory volume in one second <=70% [% predicted]) who underwent chest computed tomography (CT) between January 1, 2010 and May 30, 2013, patients with lung cancer and controls matched for age, sex, and smoking history were selected. The risk of lung cancer was assessed according to the presence of underlying bronchiectasis confirmed by chest CT. RESULTS: The study enrolled 99 cases and 198 controls. Combined bronchiectasis on chest CT was inversely associated with the risk of lung cancer compared with controls (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.12 0.52, P<0.001). Significant associations were found in patients with squamous cell carcinoma (OR 0.11, 95% CI 0.03-0.49, P=0.001) and history of smoking (OR 0.27, 95% CI 0.12-0.57, P<0.001). However, the severity and location of bronchiectasis were not associated with the risk of lung cancer. CONCLUSION: Interestingly, the concomitant presence of bronchiectasis in COPD patients was associated with a lower risk of lung cancer. PMID- 26005341 TI - Patients with chronic obstructive pulmonary disease and chronically colonized with Haemophilus influenzae during stable disease phase have increased airway inflammation. AB - BACKGROUND: Some patients with chronic obstructive pulmonary disease (COPD) show increased airway inflammation and bacterial colonization during stable phase. The aim of this study was to follow COPD patients and investigate chronic colonization with pathogenic bacteria during stable disease phase, and relate these findings to clinical parameters, inflammatory pattern, lung function, and exacerbations. METHODS: Forty-three patients with COPD were included while in a stable state and followed up monthly until exacerbation or for a maximum of 6 months. The patients completed the Clinical COPD Questionnaire and Medical Research Council dyspnea scale questionnaires, and exhaled breath condensate was collected, followed by spirometry, impulse oscillometry, and sputum induction. RESULTS: Ten patients were chronically colonized (ie, colonized at all visits) with Haemophilus influenzae during stable phase. These patients had higher sputum levels of leukotriene B4 (P<0.001), 8-isoprostane (P=0.002), myeloperoxidase activity (P=0.028), and interleukin-8 (P=0.02) during stable phase when compared with other patients. In addition, they had lower forced vital capacity (P=0.035) and reactance at 5 Hz (P=0.034), but there was no difference in forced expiratory volume in 1 second (FEV1), FEV1 % predicted, forced vital capacity % predicted, exhaled breath condensate biomarkers, C-reactive protein, or Clinical COPD Questionnaire and Medical Research Council dyspnea scale results. Three patients had intermittent colonization (colonized at only some visits) of H. influenzae during stable phase, and had lower levels of inflammatory biomarkers in sputum when compared with the chronically colonized patients. The difference in airway inflammation seen during stable phase in patients chronically colonized with H. influenzae was not observed during exacerbations. CONCLUSION: Some COPD patients who were chronically colonized with H. influenzae during stable phase showed increased airway inflammation and reduced lung volumes when compared with non chronically colonized patients. PMID- 26005342 TI - Identification of a novel SERPINA-1 mutation causing alpha-1 antitrypsin deficiency in a patient with severe bronchiectasis and pulmonary embolism. AB - Deficiency in the serine protease inhibitor, alpha-1 antitrypsin (AAT), is known to cause emphysema and liver disease. Other manifestations, including airway disease or skin disorders, have also been described. A 44-year-old woman presented to our emergency department with dyspnea and respiratory insufficiency. She had never smoked, and had been diagnosed with COPD 9 years earlier. Three months previously, she had suffered a pulmonary embolism. Chest computed tomography scan revealed severe cystic bronchiectasis with destruction of the lung parenchyma. The sweat test was normal and there was no evidence of the cystic fibrosis transmembrane conductance regulator (CFTR) mutation. Capillary zone electrophoresis showed a decrease of alpha-1 globin band and AAT levels were below the quantification limit (<25 mg/dL). No S or Z mutation was identified, but sequencing analysis found a homozygous cytosine and adenine (CA) insertion in exon 2 of the SERPINA-1 gene, probably leading to a dysfunctional protein (PI Null/Null). This mutation has not been previously identified. The atypical presentation of the patient, with severe cystic bronchiectasis, highlights AAT deficiency as a differential diagnosis in bronchiectasis. Further, awareness should be raised regarding a possible increased risk of thromboembolism associated with AAT deficiency. PMID- 26005343 TI - Functionalized magnetic iron oxide/alginate core-shell nanoparticles for targeting hyperthermia. AB - Hyperthermia is one of the promising treatments for cancer therapy. However, the development of a magnetic fluid agent that can selectively target a tumor and efficiently elevate temperature while exhibiting excellent biocompatibility still remains challenging. Here a new core-shell nanostructure consisting of inorganic iron oxide (Fe3O4) nanoparticles as the core, organic alginate as the shell, and cell-targeting ligands (ie, D-galactosamine) decorated on the outer surface (denoted as Fe3O4@Alg-GA nanoparticles) was prepared using a combination of a pre gel method and coprecipitation in aqueous solution. After treatment with an AC magnetic field, the results indicate that Fe3O4@Alg-GA nanoparticles had excellent hyperthermic efficacy in a human hepatocellular carcinoma cell line (HepG2) owing to enhanced cellular uptake, and show great potential as therapeutic agents for future in vivo drug delivery systems. PMID- 26005344 TI - Sustained release of bactericidal concentrations of penicillin in the pleural space via an antibiotic-eluting pigtail catheter coated with electrospun nanofibers: results from in vivo and in vitro studies. AB - BACKGROUND: Inadequate intrapleural drug concentrations caused by poor penetration of systemic antibiotics into the pleural cavity is a major cause of treatment failure in empyema. Herein, we describe a novel antibiotic-eluting pigtail catheter coated with electrospun nanofibers used for the sustained release of bactericidal concentrations of penicillin in the pleural space. METHODS: Electrospun nanofibers prepared using polylactide-polyglycolide copolymer and penicillin G sodium dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol were used to coat the surface of an Fr6 pigtail catheter. The in vitro patterns of drug release were tested by placing the catheter in phosphate-buffered saline. In vivo studies were performed using rabbits treated with penicillin either intrapleurally (Group 1, 20 mg delivered through the catheter) or systemically (Group 2, intramuscular injection, 10 mg/kg). Penicillin concentrations in the serum and pleural fluid were then measured and compared. RESULTS: In vitro studies revealed a burst release of penicillin (10% of the total dose) occurring in the first 24 hours, followed by a sustained release in the subsequent 30 days. Intrapleural drug levels were significantly higher in Group 1 than in Group 2 (P<0.001). In the former, penicillin concentrations remained above the minimum inhibitory concentration breakpoint throughout the entire study period. In contrast, serum penicillin levels were significantly higher in Group 2 than in Group 1 (P<0.001). Notably, all Group 2 rabbits showed signs of systemic toxicity (paralytic ileus and weight loss). CONCLUSION: We conclude that our antibiotic eluting catheter may serve as a novel therapeutic option to treat empyema. PMID- 26005345 TI - Electrospun nanofibrous SF/P(LLA-CL) membrane: a potential substratum for endothelial keratoplasty. AB - BACKGROUND: Cornea transplant technology has progressed markedly in recent decades, allowing surgeons to replace diseased corneal endothelium by a thin lamellar structure. A thin, transparent, biocompatible, tissue-engineered substratum with corneal endothelial cells for endothelial keratoplasty is currently of interest. Electrospinning a nanofibrous structure can simulate the extracellular matrix and have beneficial effects for cell culture. Silk fibroin (SF) has good biocompatibility but poor mechanical properties, while poly(L lactic acid-co-epsilon-caprolactone) (P(LLA-CL)) has good mechanical properties but poor biocompatibility. Blending SF with P(LLA-CL) can maintain the advantages of both these materials and overcome their disadvantages. Blended electrospun nanofibrous membranes may be suitable for regeneration of the corneal endothelium. The aim of this study was to produce a tissue-engineered construct suitable for endothelial keratoplasty. METHODS: Five scaffolds containing different SF:P(LLA-CL) blended ratios (100:0, 75:25, 50:50, 25:75, 0:100) were manufactured. A human corneal endothelial (B4G12) cell line was cultured on the membranes. Light transmission, speed of cell adherence, cell viability (live-dead test), cell proliferation (Ki-67, BrdU staining), and cell monolayer formation were detected on membranes with the different blended ratios, and expression of some functional genes was also detected by real-time polymerase chain reaction. RESULTS: Different blended ratios of scaffolds had different light transmittance properties. The 25:75 blended ratio membrane had the best transmittance among these scaffolds. All electrospun nanofibrous membranes showed improved speed of cell adherence when compared with the control group, especially when the P(LLA CL) ratio increased. The 25:75 blended ratio membranes also had the highest cell proliferation. B4G12 cells could form a monolayer on all scaffolds, and most functional genes were also stably expressed on all scaffolds. Only two genes showed changes in expression. CONCLUSION: All blended ratios of SF:P(LLA-CL) scaffolds were evaluated and showed good biocompatibility for cell adherence and monolayer formation. Among them, the 25:75 blended ratio SF:P(LLA-CL) scaffold had the best transmittance and the highest cell proliferation. These attributes further the potential application of the SF:P(LLA-CL) scaffold for corneal endothelial transplantation. PMID- 26005346 TI - Selective inhibition of MG-63 osteosarcoma cell proliferation induced by curcumin loaded self-assembled arginine-rich-RGD nanospheres. AB - Osteosarcoma is the most frequent primary malignant form of bone cancer, comprising 30% of all bone cancer cases. The objective of this in vitro study was to develop a treatment against osteosarcoma with higher selectivity toward osteosarcoma cells and lower cytotoxicity toward normal healthy osteoblast cells. Curcumin (or diferuloylmethane) has been found to have antioxidant and anticancer effects by multiple cellular pathways. However, it has lower water solubility and a higher degradation rate in alkaline conditions. In this study, the amphiphilic peptide C18GR7RGDS was used as a curcumin carrier in aqueous solution. This peptide contains a hydrophobic aliphatic tail group leading to their self assembly by hydrophobic interactions, as well as a hydrophilic head group composed of an arginine-rich and an arginine-glycine-aspartic acid structure. Through characterization by transmission electron microscopy, self-assembled structures of spherical amphiphilic nanoparticles (APNPs) with diameters of 10-20 nm in water and phosphate-buffered saline were observed, but this structure dissociated when the pH value was reduced to 4. Using a method of codissolution with acetic acid and dialysis tubing, the solubility of curcumin was enhanced and a homogeneous solution was formed in the presence of APNPs. Successful encapsulation of curcumin in APNPs was then confirmed by Fourier transform infrared and X-ray diffraction analyses. The cytotoxicity and cellular uptake of the APNP/curcumin complexes on both osteosarcoma and normal osteoblast cell lines were also evaluated by methyl-thiazolyl-tetrazolium assays and confocal fluorescence microscopy. The results showed that the curcumin-loaded APNPs had significant selective cytotoxicity against MG-63 osteosarcoma cells when compared with normal osteoblasts. We have demonstrated for the first time that APNPs can encapsulate hydrophobic curcumin in their hydrophobic cores, and curcumin-loaded APNPs could be an innovative treatment for the selective inhibition of osteosarcoma cells. PMID- 26005347 TI - Photoactive TiO2 antibacterial coating on surgical external fixation pins for clinical application. AB - External fixation is a method of osteosynthesis currently used in traumatology and orthopedic surgery. Pin tract infection is a common problem in clinical practice. Infection occurs after bacterial colonization of the pin due to its contact with skin and the local environment. One way to prevent such local contamination is to create a specific coating that could be applied in the medical field. In this work, we developed a surface coating for external fixator pins based on the photocatalytic properties of titanium dioxide, producing a bactericidal effect with sufficient mechanical strength to be compatible with surgical use. The morphology and structure of the sol-gel coating layers were characterized using, respectively, scanning electron microscopy and X-ray diffraction. The resistance properties of the coating were investigated by mechanical testing. Photodegradation of acid orange 7 in aqueous solution was used as a probe to assess the photocatalytic activity of the titanium dioxide layers under ultraviolet irradiation. The bactericidal effect induced by the process was evaluated against two strains, ie, Staphylococcus aureus and multiresistant Staphylococcus epidermidis. The coated pins showed good mechanical strength and an efficient antibacterial effect after 1 hour of ultraviolet irradiation. PMID- 26005348 TI - Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading. AB - Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4 degrees C-55 degrees C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4 degrees C-25 degrees C and even after freeze-thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID- 26005349 TI - Anticancer activity of biostabilized selenium nanorods synthesized by Streptomyces bikiniensis strain Ess_amA-1. AB - Selenium is an important component of human diet and a number of studies have declared its chemopreventive and therapeutic properties against cancer. However, very limited studies have been conducted about the properties of selenium nanostructured materials in comparison to other well-studied selenospecies. Here, we have shown that the anticancer property of biostabilized selenium nanorods (SeNrs) synthesized by applying a novel strain Ess_amA-1 of Streptomyces bikiniensis. The strain was grown aerobically with selenium dioxide and produced stable SeNrs with average particle size of 17 nm. The optical, structural, morphological, elemental, and functional characterizations of the SeNrs were carried out using techniques such as UV-vis spectrophotometry, transmission electron microscopy, energy dispersive X-ray spectrometry, and Fourier transform infrared spectrophotometry, respectively. The MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay revealed that the biosynthesized SeNrs induces cell death of Hep-G2 and MCF-7 human cancer cells. The lethal dose (LD50%) of SeNrs on Hep-G2 and MCF-7 cells was recorded at 75.96 MUg/mL and 61.86 MUg/mL, respectively. It can be concluded that S. bikiniensis strain Ess_amA-1 could be used as renewable bioresources of biosynthesis of anticancer SeNrs. A hypothetical mechanism for anticancer activity of SeNrs is also proposed. PMID- 26005350 TI - Ataxia with Parkinsonism and dystonia after intentional inhalation of liquefied petroleum gas. AB - The practice of inhaling liquefied petroleum gas (LPG) to commit suicide is uncommon and almost exclusively a prerogative of the prison population. Numerous cases of sudden deaths caused by intentional propane and/or butane inhalation have been described, but these cases survived and a description of the consequences is very rare. We describe a prisoner who survived after voluntary inhalation of LPG, and who developed ataxia, Parkinsonism, and dystonia. Brain MRI showed bilateral hyperintensity in the basal ganglia and in the cerebellar hemispheres. The clinical evolution and the MRI abnormalities are similar to those described in cases of poisoning by CO where the mechanism of brain injury is related to histotoxic hypoxia. We believe that LPG, considered until now a mixture of gas with low neurotoxic power, may have caused direct toxic damage to the brain, mediated by a mechanism of hypoxia, such as in CO intoxication. PMID- 26005351 TI - Evaluation of costs accrued through inadvertent continuation of hospital initiated proton pump inhibitor therapy for stress ulcer prophylaxis beyond hospital discharge: a retrospective chart review. AB - BACKGROUND: Stress ulcers and related upper gastrointestinal bleeding are well known complications in intensive care unit (ICU) patients. Proton pump inhibitor (PPI)-based stress ulcer prophylaxis (SUP) has been widely prescribed in noncritically ill patients who are at low risk for clinically significant bleeding, which is then injudiciously continued after hospital discharge. This study aimed to evaluate the incidence of inappropriate prescribing of PPI-based preventative therapy in ICU versus non-ICU patients that subsequently continued postdischarge, and to estimate the costs incurred by the unwarranted outpatient continuation of PPI therapy. METHODS: A retrospective review of patient data at a major teaching hospital in Korea was performed. During the 4-year study period, adult patients who were newly initiated on PPI-based SUP during hospital admission and subsequently discharged on a PPI without a medical indication for such therapy were captured for data analysis. The incidence rates of inappropriate prescribing of PPIs were compared between ICU and non-ICU patients, and the costs associated with such therapy were also examined. RESULTS: A total of 4,410 patients, more than half of the inpatient-initiated PPI users, were deemed to have been inadvertently prescribed a PPI at discharge in the absence of a medical need for acid suppression. The incidence of inappropriate outpatient continuation of the prophylaxis was higher among ICU patients compared with non ICU patients (57.7% versus 52.2%, respectively; P=0.001). The total expenditure accrued through the continuation of nonindicated PPI therapy was approximately US$40,175. CONCLUSION: This study confirmed that excess usage of PPIs for SUP has spread to low-risk, non-ICU patients. The overuse of unwarranted PPI therapy can incur large health care expenditure, as well as clinical complications with minimal therapeutic benefits. Educating clinicians regarding SUP guidelines and the adverse effects of long-term use of acid suppression can improve the cost effectiveness of PPI therapy. PMID- 26005352 TI - Using Machine Learning to Estimate Global PM2.5 for Environmental Health Studies. AB - With the increasing awareness of health impacts of particulate matter, there is a growing need to comprehend the spatial and temporal variations of the global abundance of ground-level airborne particulate matter (PM2.5). Here we use a suite of remote sensing and meteorological data products together with ground based observations of PM2.5 from 8,329 measurement sites in 55 countries taken between 1997 and 2014 to train a machine learning algorithm to estimate the daily distributions of PM2.5 from 1997 to the present. We demonstrate that the new PM2.5 data product can reliably represent global observations of PM2.5 for epidemiological studies. An analysis of Baltimore schizophrenia emergency room admissions is presented in terms of the levels of ambient pollution. PM2.5 appears to have an impact on some aspects of mental health. PMID- 26005353 TI - Activated protein C modulates the proinflammatory activity of dendritic cells. AB - BACKGROUND: Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells. MATERIALS AND METHODS: Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells. RESULTS: Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naive CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C-treated ovalbumin pulsed dendritic cells had significantly less airway hyperresponsiveness, significantly decreased lung concentrations of Th1 and Th2 cytokines, and less plasma concentration of immunoglobulin E when compared to control mice. CONCLUSION: These results suggest that dendritic cells mediate the immunosuppressive effect of activated protein C during allergic inflammation. PMID- 26005354 TI - Antioxidant, anti-inflammatory, anti-apoptotic, and skin regenerative properties of an Aloe vera-based extract of Nerium oleander leaves (nae-8((r))). AB - OBJECTIVE: The goal for this study was to evaluate the effects of an Aloe vera based Nerium oleander extract (NAE-8((r))), compared to an extract of A. vera gel alone (ALOE), and to an aqueous extract of N. oleander (AQ-NOE) in bioassays pertaining to dermatologic potential with respect to antioxidant protection, anti inflammatory effects, and cytokine profiles in vitro. METHODS: Cellular antioxidant protection was evaluated in three separate bioassays: The cellular antioxidant protection of erythrocytes (CAP-e) assay, protection of cellular viability and prevention of apoptosis, and protection of intracellular reduced glutathione levels, where the last two assays were performed using human primary dermal fibroblasts. Reduction of intracellular formation of reactive oxygen species (ROS) was tested using polymorphonuclear cells in the absence and presence of oxidative stress. Changes to cytokine and chemokine profiles when whole blood cells and human primary dermal fibroblasts were exposed to test products were determined using a 40-plex Luminex array as a method for exploring the potential cross-talk between circulating and skin-resident cells. RESULTS: The NAE-8((r)) provided significantly better antioxidant protection in the CAP-e bioassay than AQ-NOE. NAE-8((r)) and AQ-NOE both protected cellular viability and intracellular reduced glutathione, and reduced the ROS formation significantly when compared to control cells, both under inflamed and neutral culture conditions. ALOE showed minimal effect in these bioassays. In contrast to the NAE 8((r)), the AQ-NOE showed induction of inflammation in the whole blood cultures, as evidenced by the high induction of CD69 expression and secretion of a number of inflammatory cytokines. The treatment of dermal fibroblasts with NAE-8((r)) resulted in selective secretion of cytokines involved in collagen and hyaluronan production as well as re-epithelialization during wound healing. CONCLUSION: NAE 8((r)), a novel component of a commercial cosmetic product, showed beneficial antioxidant protection in several cellular models, without the induction of leukocyte activation and secretion of inflammatory cytokines. The biological efficacy of NAE-8((r)) was unique from both ALOE and AQ-NOE. PMID- 26005355 TI - Nalfurafine hydrochloride to treat pruritus: a review. AB - Uremic pruritus has a great negative influence on quality of life in hemodialysis (HD) patients and, importantly, negatively affects mortality risk. Recently, nalfurafine hydrochloride, an opioid kappa-selective agonist, has been officially approved for resistant pruritus in HD patients on the basis of a well-evidenced clinical trial in Japan. From clinical observation, it has been suggested that the upper neuron system plays a role in its pathogenesis. According to previous experimental results, using mice injected with opioids, dynorphin suppresses itch through binding kappa-opioid receptors, suggesting that kappa-opioid opioid receptor agonists act as potential therapeutic reagents for pruritus in HD patients. In Japan, a large-scale placebo-controlled study was performed to examine the efficacy and safety of oral nalfurafine hydrochloride for intractable pruritus in 337 HD patients. Two daily doses of 2.5 or 5 MUg nalfurafine or placebo were orally administered for 2 weeks, and clinical responses were analyzed. The results showed that the mean decrease in the visual analog scale for pruritus from baseline was 22 mm in the 5 MUg nalfurafine hydrochloride group (n=114) and 23 mm in the 2.5 MUg group (n=112). These reductions were statistically significant compared with 13 mm, which is the mean decrease of visual analog scale in the placebo group (n=111), demonstrating that nalfurafine is an effective and safe drug for uremic pruritus in HD patients. Moreover, another open-label trial (n=145) examining the long-term effect of 5 MUg oral nalfurafine revealed the maintenance of the antipruritic effect of nalfurafine for 52 weeks. In addition, on the basis of recent data showing kappa-opioid receptor expression in the epidermis of atopic dermatitis and psoriasis, nalfurafine hydrochloride also can be potentially used for these two skin diseases. PMID- 26005356 TI - Web-based interventions for ulcerative colitis and Crohn's disease: systematic review and future directions. AB - Behavioral intervention technologies (BITs), the application of psychological and behavioral interventions through the use of technology, provide the opportunity for clinicians to deliver care through a means that overcomes a number of treatment barriers. Web-based interventions are a subset of BITs developing as promising alternatives to face-to-face delivery of treatments and monitoring for patients with ulcerative colitis (UC) and Crohn's disease (CD). A systematic review of literature resulted in five empirical studies of web-based interventions for UC and CD. Additionally, an informal search of a popular search engine yielded limited, currently available, web-based interventions for patients with UC and CD. Despite being an ideal population for the development and dissemination of online interventions, patients with UC and CD have far less treatment options compared to other behavioral health concerns. However, given the growing body of research involving web-based interventions for other conditions, researchers and clinicians targeting UC and CD management and treatment have the benefit of being able to utilize the BIT model, an existing conceptual framework for the development of web-based interventions for both conditions. The BIT model is presented and applied to the treatment of UC and CD, as well as a technology development program, Purple, and usability guidelines to guide clinical researchers in the future development, evaluation, and dissemination of BITs for patients with UC and CD. PMID- 26005357 TI - Prevalence and correlation of hypertension among adult population in Bahir Dar city, northwest Ethiopia: a community based cross-sectional study. AB - BACKGROUND: Hypertension is one of the most common causes of premature death and morbidity and has a major impact on health care costs. It is an important public health challenge to both developed and developing countries. The aim of this study was to determine the magnitude and correlates of hypertension. METHODS: A community-based cross-sectional study was conducted in June 2014 among 681 adult residents of Bahir Dar city using multistage sampling techniques. An interview administrated questionnaire and physical measurements such as blood pressure (BP), weight, height, and waist and hip circumferences were employed to collect the data. The data were coded, entered, and analyzed with SPSS version 16 software package. RESULTS: A total of 678 responses were included in the analysis resulting in a response rate of 99.6%. The findings declared that 17.6%, 19.8%, and 2.2% of respondents were prehypertension, hypertension stage I, and hypertension stage II, respectively, on screening test. The overall prevalence of hypertension (systolic BP >=140 mmHg, or diastolic BP >=90 mmHg, or known hypertensive patient taking medications) was 25.1%. According to the multivariate logistic regression analysis, age; having ever smoked cigarette; number of hours spent walking/cycling per day; number of hours spent watching TV per day; history of diabetes; adding salt to food in addition to the normal amount that is added to the food during cooking; and body mass index were statistically significant predictors of hypertension. CONCLUSION: One out of every four respondents of the study had hypertension, and more than one out of three cases of hypertension (38.8%) did not know that they had the hypertension; 17.6% of the respondents were in prehypertension stage, which adds to overall future risk of hypertension. Therefore, mass screening for hypertension, health education to prevent substance use, regular exercise, reducing salt consumption, and life style modifications are recommended. PMID- 26005358 TI - Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. AB - BACKGROUND: Intra-articular injection of hyaluronic acid is a common, yet controversial, therapeutic option for patients with knee osteoarthritis (OA). The purpose of this research was to determine the safety and efficacy of US-approved viscosupplements for symptomatic knee OA. METHODS: We searched MedLine and EMBase for randomized, sham-controlled trials evaluating safety and/or clinical efficacy of US-approved viscosupplements in patients with symptomatic knee OA. Knee pain severity and knee joint function were assessed at 4 to 13 weeks and 14 to 26 weeks. Safety outcomes included serious adverse events, treatment-related serious adverse events, patient withdrawal, and adverse event-related patient withdrawal occurring at any time during follow-up. RESULTS: A total of 29 studies representing 4,866 unique patients (active: 2,673, control: 2,193) were included. All sham-controlled trials used saline injections as a control. Viscosupplementation resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to preinjection values, with standardized mean difference values ranging from 1.07 to 1.37 (all P<0.001). Compared to controls, standardized mean difference with viscosupplementation ranged from 0.38 to 0.43 for knee pain and 0.32 to 0.34 for knee function (all P<0.001). There were no statistically significant differences between viscosupplementation and controls for any safety outcome, with absolute risk differences of 0.7% (95% confidence interval [CI]: -0.2 to 1.5%) for serious adverse events, 0% (95% CI: -0.4 to 0.4%) for treatment-related serious adverse events, 0% (95% CI: -1.6 to 1.6%) for patient withdrawal, and 0.2% (95% CI: -0.4 to 0.8%) for adverse event-related patient withdrawal. CONCLUSION: Intra articular injection of US-approved viscosupplements is safe and efficacious through 26 weeks in patients with symptomatic knee OA. PMID- 26005360 TI - Pharmacodynamics and Pharmacokinetics of oral factor Xa inhibitors. PMID- 26005359 TI - Clinical utilities of aromatase inhibitors in breast cancer. AB - Aromatase is an enzyme that converts testosterones to estrogens. Inhibition of this enzyme has been shown to have several clinical utilities in breast cancer. Currently, there are three aromatase inhibitors (AIs) in clinical use, namely anastrozole, letrozole, and exemestane. AIs have been used in various clinical settings for breast cancer, ranging from chemoprevention in breast cancer to treating breast cancer in both early stage in the adjuvant setting and metastatic disease. This article reviews mechanism of action, AI classification, and clinical utilities of AIs in various clinical settings in the context of breast cancer. PMID- 26005361 TI - Association of common variations on chromosome 4q25 and left atrial volume in patients with atrial fibrillation. AB - AIMS: Recent studies have shown that several genetic variants near the PITX2 locus on chromosome 4q25 are associated with atrial fibrillation (AF). However, the mechanism that mediates this association remains unclear. Basic murine studies suggest that reduced PITX2 expression is associated with left atrial dilatation. We sought to examine the association between single nucleotide polymorphisms (SNPs) near PITX2 and left atrial size in patients with AF. METHODS: We prospectively enrolled 96 consecutive patients (mean age 60 +/- 10 years, 72% male) with drug-resistant AF (57% paroxysmal, 38% persistent, and 5% long-standing persistent) who underwent catheter ablation. Following DNA extraction from blood obtained pre-operatively, SNPs rs10033464 and rs2200733 were genotyped using the Sequenom MassARRAY. Left atrial volume (LAV) was determined using three-dimensional imaging (CT or MRI prior to first ablation) and by investigators blinded to genotype results. RESULTS: The minor allele frequencies at SNPs rs10033464 and rs2200733 were 0.14 and 0.25, respectively. Using multivariable linear regression, homozygosity for the minor allele at rs10033464 (recessive model) was independently associated with larger LAV (P = 0.002) after adjustment for age, gender, BMI, height, type, and duration of AF, left ventricular ejection fraction, history of hypertension, valve disease, and antiarrhythmic drug use. The strength of the association was reconfirmed in a bootstrap study with 1000 resamplings. In contrast, no association was found between rs2200733 variant alleles and LAV. CONCLUSION: SNP rs10033464 near the PITX2 locus on 4q25 is associated with LAV. Left atrial dilatation may mediate the association of common variants at 4q25 with AF. PMID- 26005362 TI - How patients experience antral irrigation. AB - BACKGROUND: Antral irrigation earlier had an important role in the diagnosis and treatment of rhinosinusitis. Nowadays, it is often considered too unpleasant. However, the experience of patients of this procedure has been very seldom evaluated. Nor has the effect on pain in rhinosinusitis been evaluated. The aim of this study was to evaluate patients' experience of discomfort and pain during antral irrigation. We also assessed facial pain caused by rhinosinusitis before the procedure and pain soon after the procedure. METHODS: Doctors and 121 patients completed their questionnaires independently after antral irrigation in a university clinic, in a private hospital, and at a communal health center. RESULTS: Patients experienced mild pain during antral irrigation (mean and median visual analog scale score: <3). Their experience of pain during antral irrigation was closely comparable to pain during dental calculus scaling. Facial pain assessed before antral irrigation decreased quickly after the procedure. CONCLUSIONS: Antral irrigation was well tolerated as an outpatient procedure. The procedure seems to relieve facial pain caused by the disease quickly. The role of antral irrigation in the treatment of acute rhinosinusitis will need further investigation. PMID- 26005363 TI - Changes in the prevalence of diabetes mellitus in bulgaria (2006-2012). AB - AIM: The aim of this study was to compare two nationwide cross-sectional studies of diabetes prevalence in Bulgaria (2006 and 2012) and to assess its dynamics. MATERIAL AND METHODS: The two studies included 2396 and 2033 subjects, respectively. The International Diabetes Federation (IDF) diagnostic criteria were applied, and the data were weighed for type of settlement and age. RESULTS: Diabetes prevalence was found to be 7.9% in 2006 and 9.55% in 2012, P = 0.06, showing an increase of 20.9%. The absolute increase was 0.9% in the females and 2.3% in the males (P < 0.09). The increase was the largest in those aged 50-59: [9.4%, 2006 vs. 15.7%, 2012, P < 0.01]. Diabetes prevalence increased in the 20 60-year olds by 6.8% and decreased in the elderly by 6.1%. Obesity increased from 26.7 to 32.7%, P < 0.02. CONCLUSIONS: A significant increase in diabetes prevalence was found that necessitates healthcare measures and resources for community-based awareness and prevention programs. PMID- 26005364 TI - Is ESR Important for Predicting Post-ERCP Pancreatitis? AB - BACKGROUND: Pancreatitis remains the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), resulting in substantial morbidity and occasional mortality. There are notable controversies and conflicting reports about risk factors of post-ERCP pancreatitis (PEP). AIM: To evaluate the potential risk factors for PEP at a referral tertiary center, as a sample of the Iranian population. MATERIALS AND METHODS: Baseline characteristics and clinical as well as paraclinical information of 780 patients undergoing diagnostic and therapeutic ERCP at Taleghani hospital in Tehran between 2008 and 2012 were reviewed. Data were collected prior to the ERCP, at the time of the procedure, and 24-72 hours after discharge. PEP was diagnosed according to consensus criteria. RESULTS: Of the 780 patients who underwent diagnostic ERCP, pancreatitis developed in 26 patients (3.3%). In the multivariable risk model, significant risk factors with adjusted odds ratios (ORs) were age <65 years (OR = 10.647, P = 0.023) and erythrocyte sedimentation rate (ESR) >30 (OR = 6.414, P < 0.001). Female gender, history of recurrent pancreatitis, pre-ERCP hyperamylasemia, and difficult or failed cannulation could not predict PEP. There was no significant difference in the rate of PEP in wire-guided cannulation versus biliary cannulation using a sphincterotome and contrast injection as the conventional method. CONCLUSIONS: Performing ERCP may be safer in the elderly. Patients with high ESR may be at greater risk of PEP, which warrants close observation of these patients for signs of pancreatitis after ERCP. PMID- 26005365 TI - Profile of elotuzumab and its potential in the treatment of multiple myeloma. AB - Although the introduction of novel drugs has improved outcome significantly in multiple myeloma (MM), many patients still eventually relapse. Monoclonal antibodies (mAbs) targeting MM-related antigens can complement currently available therapies. CS1 (also known as CD2 subunit 1, SLAMF7, CD319, and CRACC), a cell surface glycoprotein receptor that is a member of the signaling lymphocytic activation molecule (SLAM) family, is highly and nearly uniformly expressed in myeloma cells at the gene and protein level, but not expressed in other tissues, including hematopoietic stem cells, making CS1 a compelling target for the design of immunotherapies directed at MM. Elotuzumab (formerly HuLuc63), which is a humanized IgG1 mAb recognizing the extracellular region of human CS1, has been shown to be effective in preclinical and early stage clinical investigations, and its efficacy and safety will be further validated in ongoing Phase III trials. Integration of elotuzumab into multidrug therapeutic paradigms seems logical, as elotuzumab is more effective when combined with other agents, such as immunomodulatory drugs or proteasome inhibitors. The functional role of CS1 in MM pathogenesis and the consequences of elotuzumab on normal immune cells should be further investigated. Identification of potential biomarkers and exploration of resistance mechanisms are important issues for elotuzumab-based therapies, as is determining the best clinical placement of elotuzumab, not only in the relapsed/refractory setting but also in upfront therapy for high-risk frank MM, smoldering MM at high-risk of progression, and in maintenance regimens. This review will cover the biological characteristics of CS1 in normal immune cells and MM cells, the efficacy profile and mechanisms of action of elotuzumab from preclinical and clinical investigations, and its potential impact on the treatment of MM. PMID- 26005366 TI - Surface induced dissociation yields substructure of Methanosarcina thermophila 20S proteasome complexes. AB - Native mass spectrometry (MS) and surface induced dissociation (SID) have been applied to study the stoichiometry and quaternary structure of non-covalent protein complexes. In this study, Methanosarcina thermophila 20S proteasome, which consists of four stacked heptameric rings (alpha7beta7beta7alpha7 symmetry), has been selected to explore the SID dissociation pattern of a complicated stacked ring protein complex. SID produces both alpha and beta subunits while collision induced dissociation (CID) produces only highly charged alpha subunit. In addition, the charge reduced 20S proteasome produces the alpha7beta7 fragment, reflecting the stacked ring topology of the complex. The combination of SID and charge reduction is shown to be a powerful tool for the study of protein complex structure. PMID- 26005367 TI - Serine effects on collision-induced dissociation and photodissociation of peptide cation radicals of the z+* -type. AB - The serine residue displays specific effects on the dissociations of peptide fragment cation-radicals of the z+* type which are produced by electron transfer dissociation. Energy-resolved collision-induced dissociation (ER-CID), time resolved infrared multiphoton dissociation (TR-IRMPD), and single-photon UV photodissociation at 355 nm revealed several competitive dissociation pathways consisting of loss of OH radical, water, and backbone cleavages occurring at N terminal and C-terminal positions relative to the serine residue. The activation modes using slow-heating and UV photon absorption resulted in different relative intensities of fragment ions. This indicated that the dissociations proceeded through several channels with different energy-dependent kinetics. The experimental data were interpreted with the help of electron structure calculations that provided fully optimized structures and relative energies for cis and trans amide isomers of the z4+* ions as well as isomerization, dissociation, and transition state energies. UV photon absorption by the z4+* ions was due to Calpha-radical amide groups created by ETD that provided a new chromophore absorbing at 355 nm. PMID- 26005368 TI - Lattice Universe: examples and problems. AB - We consider lattice Universes with spatial topologies [Formula: see text], [Formula: see text], and [Formula: see text]. In the Newtonian limit of General Relativity, we solve the Poisson equation for the gravitational potential in the enumerated models. In the case of point-like massive sources in the [Formula: see text] model, we demonstrate that the gravitational potential has no definite values on the straight lines joining identical masses in neighboring cells, i.e. at points where masses are absent. Clearly, this is a nonphysical result, since the dynamics of cosmic bodies is not determined in such a case. The only way to avoid this problem and get a regular solution at any point of the cell is the smearing of these masses over some region. Therefore, the smearing of gravitating bodies in [Formula: see text]-body simulations is not only a technical method but also a physically substantiated procedure. In the cases of [Formula: see text] and [Formula: see text] topologies, there is no way to get any physically reasonable and nontrivial solution. The only solutions we can get here are the ones which reduce these topologies to the [Formula: see text] one. PMID- 26005369 TI - Predictions for the [Formula: see text] decay. AB - We calculate the shape of the [Formula: see text] and [Formula: see text] invariant mass distributions in the [Formula: see text] and [Formula: see text] decays that are dominated by the [Formula: see text] resonance. The weak interaction part is the same for both processes and the hadronization into the different meson-baryon channels in the final state is given by symmetry arguments. The most important feature is the implementation of the meson-baryon final-state interaction using two chiral unitary models from different theoretical groups. Both approaches give a good description of antikaon-nucleon scattering data, the complex energy shift in kaonic hydrogen and the line shapes of [Formula: see text] in photoproduction, based on the two-pole scenario for the [Formula: see text]. We find that this reaction reflects more the higher mass pole and we make predictions of the line shapes and relative strength of the meson-baryon distributions in the final state. PMID- 26005370 TI - Association of vitamin D levels with type 2 diabetes in older working adults. AB - OBJECTIVES: Increasing evidence suggests that vitamin D plays a role in the development of chronic diseases including type 2 diabetes (DM). Aim of the study was to explore the association of vitamin D levels with prevalent DM in a sample of predominantly healthy working adults older than 45 years. METHODS: This cross sectional study (2009-2011) involved 1821 employees of a German engineering company (83.1% male, mean age 51.9 +/-5.6 years). Sociodemographics and medical history were assessed by self-report. Clinical characteristics were obtained including blood samples to determine vitamin D levels and diabetes status by fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c). Vitamin D was grouped into one of four categories (<10 ng/ml, 10-19.9 ng/ml, 20-29.9 ng/ml, >=30 ng/ml). Bivariate associations between vitamin D categories and a composite indicator for DM (FPG >=126 mg/dl or HbA1c >=6.5% or self-reported diagnosis) were calculated; multivariable models tested this association further, controlling for potential confounders. RESULTS: Severe vitamin D deficiency (<10 ng/ml) was associated with increasing FPG (beta 3.13; 95% CI: 0.78, 5.47; p<=0.01) and HbA1c (beta 0.15; 95% CI: 0.08, 0.23; p<=0.001) values in adjusted linear regression models. In multivariable models, severe vitamin D deficiency was associated with DM (OR 2.55; 95%CI 1.16, 5.62; p<=0.05) after controlling for potential confounders. CONCLUSIONS: Vitamin D deficiency is associated with prevalent DM in working older adults. The findings highlight that the workplace may be a unique location for conducting large-scale health screening to identify those at risk of DM using vitamin D. PMID- 26005372 TI - Reduction of QTD--A Novel Marker of Successful Reperfusion in NSTEMI. Pathophysiologic Insights by CMR. AB - BACKGROUND/OBJECTIVES: Non-ST segment elevation myocardial infarction (MI) poses similar detrimental long-term prognosis as ST-segment elevation MI. No marker on ECG is established to predict successful reperfusion in NSTEMI. QT dispersion is increased by myocardial ischemia and reduced by successful restoration of epicardial blood flow by PCI. Whether QT dispersion reduction translates to smaller infarcts and thus indicates successful reperfusion is unknown. We hypothesized that the relative reduction of QT dispersion (QTD-Rrel ) on a standard ECG in acutely reperfused NSTEMI is related to infarct size and infarct transmurality as assessed by delayed enhancement CMR (DE-CMR). METHODS AND RESULTS: 69 patients with a first acute NSTEMI were included. QTD-Rrel was stratified according to LV function and volumes, infarct transmurality and size as assessed by DE-CMR. Extensive myocardial infarction was defined as above median infarct size. LV function and end-systolic volume were only mildly related to QTD-Rrel . QTD-Rrel was inversely related to infarct size (r=-0.506,p=0.001) and infarct transmurality (r=-0.415, p=0.001). QTD-Rrel was associated with extensive myocardial infarction in univariate analysis (odds ratio (OR) 0.958, CI 0.935-0.982; p=0.001). Compared to clinical and angiographic data QTD-Rrel remained the only independent predictor of non-transmural infarcts (OR 1.110, CI 1.055-1.167; p=0.049). CONCLUSION: In patients with acute Non-ST-Segment Myocardial infarction QTd-Rrel calculated on a surface ECG prior and post PCI for restoration of epicardial blood flow detects small, non-transmural infarcts as assessed by delayed enhancement CMR. Thus, QTd-Rrel can indicate successful reperfusion therapy. PMID- 26005371 TI - The Association between Glomerular Hyperfiltration and Left Ventricular Structure and Function in Patients with Primary Aldosteronism. AB - BACKGROUND: Glomerular hyperfiltration has been recently noticed as an important issue in primary aldosteronism (PA) patients. However, its effect on the cardiovascular system remains unknown. METHODS: We prospectively analyzed 47 PA patients including 11 PA patients with estimated glomerular filtration rate (eGFR) > 130 ml/min per 1.73 m2 (group 1), and 36 PA patients with eGFR 90-110 ml/min per 1.73 m2 (group 2). Fourteen essential hypertension (EH) patients with eGFR 90-110 ml/min per 1.73 m2 were included as the control group (group 3). Echocardiography including left ventricular mass index (LVMI) measurement and tissue Doppler imaging (TDI) was performed. Predicted left ventricular mass (LVM) was calculated. Inappropriate LVM was defined as an excess of > 35% from the predicted value. RESULTS: The value of LVMI decreased significantly in order from groups 1 to 3 (group 1>2>3). While group 2 had a significantly higher percentage of inappropriate LVM than group 3, the percentage of inappropriate LVM were comparable in groups 1 and 2. Group 1 had a higher mitral E velocity, E/A ratio than that of group 2. In the TDI study, the E/E' ratio also decreased significantly in order from groups 1 to 3 (group 1>2>3). Group 2 had lower E' than that of group 3, although the E' of group 1 and 2 were comparable. CONCLUSIONS: Although PA patients with glomerular hyperfiltration were associated with higher LVMI, higher mitral E velocity, higher E/E' ratio, they had comparable E' with PA patients with normal GFR. This phenomenon may be explained by higher intravascular volume in this patient group. PMID- 26005373 TI - Major pathophysiological correlations of rosacea: a complete clinical appraisal. AB - BACKGROUND: Rosacea is a characteristic cutaneous disorder with a diverse clinical manifestations ranging from facial vascular hyper-reactivity to sebaceous gland hyperplasia. Many theories on pathophysiology of rosacea were proposed over the past decade, however the pathogenicity is poorly understood. AIM: To review the evidence on different pathophysiological correlations of rosacea. METHODS: A literature search was conducted for studies published between 1990 to March 2014. The inclusion criteria was pathophysiology, randomized controlled trials, controlled trials on rosacea. RESULTS: Out of 5141 articles, 14 high quality studies met all the selection criteria. Of 14 articles, 5 are randomized control trials (RCTs), 2 are controlled trial, 3 comparative trials, 2 observational trials, 1 prospective and 1 diagnostic trial. The studies were categorized into two groups: the trigger factors and sub-types & symptoms. Of 7 high quality studies, 4 provided strong evidence that immune responses causing disease triggered by external/internal factors such as sunlight, food and chemical agents, 3 trials provided significant evidence of microorganisms as causative agents. The remaining trials did not provide significant evidences on pathophysiology. CONCLUSION: Vasculature, chronic inflammatory responses, environmental triggers, food and chemicals ingested and microorganisms either alone or in combination are responsible for rosacea. Many promising drugs are under various phases of clinical trials and interestingly, probiotics could also possibly be used as one of the treatment option. PMID- 26005374 TI - Efficient Inhibition of Ovarian Cancer by Gelonin Toxin Gene Delivered by Biodegradable Cationic Heparin-polyethyleneimine Nanogels. AB - The use of toxins for cancer therapy has great promise. Gelonin, a potent plant toxin, causes cell death by inactivating the 60S ribosomal subunit. Recently, we developed a novel gene delivery system using biodegradable cationic heparin polyethyleneimine (HPEI) nanogels. In the current study, the antitumor activity of a recombinant plasmid expressing gelonin (pGelonin) on human ovarian cancer was assessed. The application of HPEI nanogels, was also evaluated. Gelonin-cDNA was cloned into the pVAX1 plasmid vector and transfected into SKOV3 human ovarian cancer cells using biodegradable cationic HPEI nanogels. The expression of gelonin in vitro and in vivo was confirmed using RT-PCR and western blot analysis. Cell viability and apoptosis were examined using an MTT assay and flow cytometric analysis. For the in vivo study, an SKOV3 intraperitoneal ovarian carcinomatosis model was established, and nude mice were randomly assigned into four groups receiving i.p. administration of pGelonin/HPEI complexes, pVAX/HPEI complexes, HPEI alone and 5% glucose solution. The tumor weight was monitored, and a TUNEL assay and Ki-67 immunohistochemistry were performed to evaluate apoptosis and cell proliferation in the tumor tissue sections, respectively. Gelonin was efficiently expressed in SKOV3 cancer cells in vitro and in vivo using pGelonin incorporated with HPEI nanogels. The pGelonin/HPEI complexes inhibited cell viability and induced apoptosis in the cell culture. Treatment for intraperitoneal carcinomatosis with pGelonin/HPEI complexes reduced the tumor weight by ~58.55% compared to the control groups (P<0.05). The antitumor effect was accompanied by increased apoptosis and reduced cell proliferation (P<0.05). No significant side effects were observed with i.p. administration of the pGelonin/HPEI complexes. Our data indicate that HPEI nanogel-delivered pGelonin may have promising applications against human ovarian cancer. PMID- 26005377 TI - Public health aspects of nephrology, dialysis and kidney transplantation in bosnia and herzegovina. PMID- 26005375 TI - Lentiviral Vectors Mediate Long-Term and High Efficiency Transgene Expression in HEK 293T cells. AB - OBJECTIVES: Lentiviral vectors have been used successfully to rapidly produce decigram quantities of active recombinant proteins in mammalian cell lines. To optimize the protein production platform, the roles of Ubiquitous Chromatin Opening Element (UCOE), an insulator, and selected promoters were evaluated based on efficiency and stability of foreign gene expression mediated by lentiviral vectors. METHODS: Five lentiviral vectors, pFIN-EF1alpha-GFP-2A-mCherH-WPRE containing EF1alpha promoter and HS4 insulator, p'HR.cppt.3'1.2kb-UCOE-SFFV-eGFP containing SFFV promoter and UCOE, pTYF-CMV(beta-globin intron)-eGFP containing CMV promoter and beta-globin intron, pTYF-CMV-eGFP containing CMV promoter, and pTYF-EF1alpha-eGFP with EF1alpha promoter were packaged, titered, and then transduced into 293T cells (1000 viral genomes per cell). The transduced cells were passaged once every three days at a ratio of 1:10. Expression level and stability of the foreign gene, green fluorescence protein (GFP), was evaluated using fluorescent microscopy and flow cytometry. Furthermore, we constructed a hepatitis C virus (HCV) E1 recombinant lentiviral vector, pLV-CMV-E1, driven by the CMV promoter. This vector was packaged and transduced into 293T cells, and the recombinant cell lines with stable expression of E1 protein were established by limiting dilution. RESULTS: GFP expression in 293T cells transduced with the five lentiviral vectors peaked between passages 3 and 5 and persisted for more than 5 weeks. The expression was prolonged in the cells transduced with TYF-CMV (beta-globin intron)-eGFP or TYF-CMV-eGFP, demonstrating less than a 50% decrease even at 9 weeks post transduction (p>0.05). The TYF-CMV-eGFP-transduced cells began with a higher level of GFP expression than other vectors did. The percentage of GFP positive cells for any of the five lentiviral vectors sustained over time. Moreover, the survival rates of all transfected cells exceeded 80% at both 5 and 9 weeks post transduction. Surprisingly, neither the HS4 insulator nor the UCOE sequence improved the GFP expression level or stability. Clonal cell lines with HCV E1 gene were generated from LV-CMV-E1 vector-infected 293T cells. A representative recombinant cell line maintained stable E1expression for at least 9 weeks without significant difference in morphology compared with untreated 293T cells. CONCLUSION: The results suggest that all five vectors can stably transduce 293T cells, producing long term transgene expression with different efficiencies. However, neither the insulator nor the UCOE improved the GFP expression. The vectors containing the promoter CMV or CMV (beta-globin intron) generated the highest gene expressions, manifesting as more favorable candidates for recombinant protein production in HEK293T cells. PMID- 26005376 TI - Delayed Reduction of Hepatitis B Viral Load and Dynamics of Adefovir-Resistant Variants during Adefovir plus Entecavir Combination Rescue Therapy. AB - OBJECTIVE: Entecavir (ETV) added to adefovir (ADV) is recommended in the consensus for management of patients with ADV resistance. However, little attention has been focused on the delayed reduction of HBV DNA and dynamics of ADV-resistant variants during ADV-ETV combination rescue therapy in the clinical setting. We characterized the dynamics of viral load and resistant variants in nucleos(t)ide analogues (NAs)-naive chronic hepatitis B (CHB) patients during antiviral treatment with ADV monotherapy followed by ADV-ETV combination therapy. METHODS: A cohort of 55 CHB patients was enrolled in this study. Three NAs-naive patients developed ADV-resistant variants during 24-33 months of ADV monotherapy, and then switched to ADV-ETV combination therapy. Thirty-five serial serum samples from these three patients were regularly collected during treatment. Ten mutants associated with commonly used antiviral drugs were detected by pyrosequencing. RESULTS: HBV DNA decreased to the lowest level during ADV monotherapy at 6-18 months, with a decrease of 0.95-5.51 log10 copies/mL, whereas rtA181V or rtN236T gradually increased with extended therapy. HBV DNA decreased to below the detectable level during ADV-ETV combination therapy at 21-24 months, with a decrease of 4.19-4.65 log10 copies/mL. Resistant rtA181V and rtN236T were undetectable after 21-24 months of combination therapy. Moreover, no LAM resistant rtM204I/V or ETV-resistant variants were detected during the 27-36 months of combination therapy. CONCLUSION: Although ADV-resistant variants were suppressed, viral load reduction was delayed during ADV-ETV combination rescue therapy in patients with ADV-resistant HBV. The quantification of resistant variants by pyrosequencing may facilitate monitoring of antiviral therapy. PMID- 26005378 TI - Clinical analysis of etiology, risk factors and outcome in patients with acute kidney injury. AB - INTRODUCTION: Acute kidney injury is characterized by a rapid loss of renal excretory function with the increase of nitrogen compounds in the blood and with different outcome. OBJECTIVE: Since descriptions of the risk factors and sequelae of acute kidney injury (AKI) remain relatively limited, the objective of this study was to determine etiology and clinical characteristics of AKI, as well as risk factors for adverse outcome of renal function and death in AKI patients. METHODS: We retrospectively studied a cohort of 84 adult AKI patients admitted to Nephrology Clinic in University Clinical Centre Sarajevo during period 2012-2014. Demographic, laboratory and clinical parameters were retrieved. The in-hospital and 6 months mortality were recorded. Renal function outcome was defined 3 months following discharge. RESULTS: Majority of patients were older (median age 73.5 years) with great severity of AKI (Stage III in 78.5% of cases) and high burden of comorbidities (mean Charlson comorbidity index, CCI score 6.4+/-3.05). The most common causes of AKI were acute interstitial nephritis (16.7%), heart failure (15.5%), gastroenterocolitis (13.1%), and sepsis (12%). Renal function recovery was recorded in 48.8% of patients, with prevalence of 10.7% of intrahospital mortality and 37.3% of 6 months mortality. Risk factors for poor outcome of renal function and mortality in AKI patients were increasing age and higher CCI score, while protective factor was higher diuresis. Sepsis proved to be risk factor for death. PMID- 26005379 TI - Serum cystatin C - marker of inflammation and cardiovascular morbidity in chronic kidney disease stages 1-4. AB - AIM: The aim of the research was to compare the relationship between inflammatory biomarkers and procoagulants with kidney function assessed by using cystatin C, serum creatinine, and eGFR and determine the sensitivity of cystatin C, serum creatinine and eGFR to total cardiovascular morbidity in patients with CKD stages 1-4. METHODS: The research included 120 patients older than 18 years with CKD stages 1-4 monitored over a period of 24 months. RESULTS: Serum cystatin C correlates with fibrinogen (p<0.01), serum albumin (p<0.01), D-dimer (p<0.05), antithrombin III (p<0.01) strongly in relation to the evaluation of kidney function based on serum creatinine and eGFR. By following cystatin C, creatinine and eGFR with comparison of ROC to total cardiovascular morbidity, the highest sensitivity in relation to the presence of cardiovascular morbidity shows cystatin C, then eGFR and the lowest, creatinine, with a significant difference between cystatin C and serum creatinine (p<0.05). CONCLUSION: Serum cystatin C is more strongly correlated with some biomarkers (fibrinogen, serum albumin, D dimer, antithrombin III), while simultaneously showing a stronger sensitivity in relation to total cardiovascular morbidity compared with the assessment of kidney function based on serum creatinine and eGFR. PMID- 26005380 TI - High prevalence of early chronic kidney disease in high risk outpatients. AB - INTRODUCTION: Chronic kidney disease (CKD) is a significant public health problem. The aim of this study was to determine the presence of early stages of renal disease in hypertensive and diabetic outpatients without previously diagnosed renal damages. METHODS: In this cross-sectional study we studied a random sample of outpatients with essential hypertension and/or diabetes mellitus type 2 in the general practice ambulance of city Sarajevo. Renal function was evaluated by using MDRD (Modification of Diet in Renal Disease) equation and with measurement of renal biomarkers. K/DOQI classification was used to define the stages of CKD. RESULTS: The study included 200 patients, of whom 75 (37.5%) were females, mean age of 54.81 +/- 6.1 years, and 125 (62.5%) male, mean age 52.46 +/ 8.2 years. More than half of respondents (54.0%) were hypertensive during the follow up period. Early CKD was detected in 52% respondents. Higher prevalence of early CKD was verified in the group of patients who had hypertension associated with diabetes mellitus type 2 (59.6% vs. 47.2% in hypertension group vs. 54,0% in diabetic group, p<0.05). Significant negative correlation was found between estimated glomerular filtration rate and presence of albuminuria (p<0.001), duration of hypertension (p=0.003), duration of type 2 diabetes mellitus (p=0.021), stages of hypertension (p=0.012), female gender (p<0.001) and older age of subjects (p=0.040). CONCLUSION: Our results confirmed high prevalence of CKD and the importance of early detection of CKD in high risk groups of patients in order to prevent the progression of the same. Prevention of chronic kidney disease in our country is still not carried out satisfactorily. Required is a much greater collaboration between primary care health givers and nephrologists. PMID- 26005381 TI - Analysis of Adequacy of 25-Hydroxi vitamin D3 Supplementation in Patients on Hemodialysis and Parathormone, Calcium and Phosphorus Level in the Blood of These Patients. AB - INTRODUCTION: Appropriate vitamin D turnover is essential for many physiological function. Knowledge of it's function was improved in last two decades with enlargement of scientific confirmation and understanding of overall importance. In addition to classical (skeletal) roles of vitamin D, many other function (no classical), out of bone and calcium-phosphate metabolism, are well defined today. AIM: To analyze vitamin D level in the blood in dialysis and pre dialysis patients and evaluate efficacy of supplementation therapy with vitamin D supplements. METHODS: Vitamin D3 level in form of 25-hydroxivitamin D3 was measured in dialysis and pre dialysis patients, using combination of enzyme immunoassay competition method with final fluorescent detection (ELFA). Parathormone was measured by ELISA method. Other parameters were measured by colorimetric methods. Statistical analysis was done by nonparametric methods, because of dispersion of results of Vitamin D and parathormone. RESULTS: In group of dialysis patients 38 were analyzed. Among them 35 (92%) presented vitamin D deficiency, whether they took supplementation or not. In only 3 patients vitamin D deficiency was not so severe. Vitamin D form were evaluated in 42 pre dialysis patients. Out of all 19 patients (45 %) have satisfied level, more than 30 ng/ml. Moderate deficiency have 16 patients (38%), 5 of all (12%) have severe deficiency, and two patients (5%) have very severe deficiency, less than 5 ng/ml. Parathormone was within normal range (9.5-75 pg/mL) in 13 patients (34 %), below normal range (2 %) in one subject, and in above normal range in 24 (63 %). CONCLUSION: Vitamin D3 deficiency was registered in most hemodialysis patients; nevertheless supplemental therapy was given regularly or not. It is to be considered more appropriate supplementation of Vitamin D3 for dialyzed patients as well as for pre dialysis ones. In pre dialysis patient moderate deficiency is shown in half of patients but sever in only two. PMID- 26005383 TI - Mortality in hemodialysis patients over 65 years of age. AB - INTRODUCTION: Based on the statistics the population in Bosnia and Herzegovina is getting older. In 2013 the average life span for women was 73.6 years and 68.1 for men. The chronic hemodialysis program is mainly reserved for elderly patients with high mortality risk. The most common cause of hemodialysis mortality relates to cardiovascular diseases (60.2%), regardless of frequent innovations and improvement of hemodialysis procedures. THE AIM OF THE STUDY: was to determine the mortality rate by age groups with comments on the presence of non-traditional predictors (anemia, hypoalbuminemia, CRP, vascular access and PTH) in dialysis patients in the follow-up period of 36 months. METHODS: The study included all patients undergoing chronic hemodialysis treatment at the Clinic of Hemodialysis of the Clinical Center University of Sarajevo (CCUS). RESULTS: Out of a total number of hemodialysis patients (n=232), the specific mortality rate in patients under 65 years of age was 16.8%, and 50.5% in patients over 65 years of age. According to the age groups the mortality rate in elderly patients is as follows: from 65 to 74 years (45.1%), from 75 to 84 years (55.0%), over >=85 years (75.0%). The most frequent vascular access in patients under and above 65 is arteriovenous fistula (79.6% and 62.1 %), temporary hemodialysis catheter (11.7% and 43.8 %) and long-term hemodialysis catheter (8.8% and 4.2 %). In the age group under 65 years of age the temporary hemodialysis catheter is significantly and more frequently used in diseased patients in respect to survivors (34.8% vs. 7.0%) [chi(2)(2)=15.769, p=0.001]. Diseased patients from the age group over 65 had a significantly lower mean value of haemoglobin in blood (M=100.9+/-17.5 g/L) in respect to survivors (M=109.2+/-17.1)[t(93)=2.339; p=0.021], lower mean value of albumin in blood (Me=32.0; IQR=29.0 do 35.0) in respect to survivors (Me=34.0; IQR=32.0 to 38.0) [U=762.5; p=0.006], and higher mean value of CRP in blood (Me=19.3 mg/L; IQR=6.6 to 52.0) in respect to survivors (Me=7.8; IQR=4.0 to 16.7) [U=773.5; p=0.008]. Diseased patients belonging to the age group over 65 had lower mean value of PTH, but without statistical significance (p>0.05). CONCLUSION: older age, temporary vascular access, anaemia and hypoalbuminemia are strong predictors of mortality in hemodialysis patients. Old age does not present contraindication for hemodialysis treatment, and treatment of terminal renal illness should not be abandoned. PMID- 26005382 TI - Correlation Between C-reactive Protein and Non-enzymatic Antioxidants (Albumin, Ferritin, Uric Acid and Bilirubin) in Hemodialysis Patients. AB - INTRODUCTION: Increased levels of C-Reactive Protein are found in 30-60% on hemodialysis patients and it is closely associated with the progression of atherosclerosis, cardiovascular morbidity and mortality. Non enzymatic antioxidants are antioxidants which primarily retain potentially dangerous ions of iron and copper in their inactive form and thereby prevent its participation in the production of free radicals. AIM: The aim of the study was to examine the relationship of CRP and non enzymatic antioxidants (albumin, ferritin, uric acid and bilirubin) i.e. examine the importance of CRP as a serum biomarker in assessing the condition of inflammation and its relationship to antioxidant protection in patients on hemodialysis. METHODS: The study was cross-sectional, clinical, comparative and descriptive. The study involved 100 patients (non diabetic) on chronic hemodialysis. The control group consisted of 50 subjects without subjective and objective indicators of chronic renal disease. In all patients, the concentration of CRP as well as concentrations of non enzymatic antioxidants were determined. RESULTS: In the group of hemodialysis patients 60% were men and 40% women. The average age of hemodialysis patients was 54.13 +/- 11.8 years and the average age of the control group 41.72 +/- 9.8 years. The average duration of hemodialysis treatment was 91.42 +/- 76.2 months. In the group of hemodialysis patients statistically significant, negative linear correlation was determined between the concentration of CRP in and albumin concentration (rho = -0.251, p = 0.012) as well as negative, statistics insignificant, linear correlation between serum CRP and the concentration of uric acid (r = -0.077, p = 0.448). Furthermore, the positive, linear correlation was determined between serum CRP and ferritin (r = 0.159, p = 0.114) and positive linear correlation between CRP and total serum bilirubin (r = 0.121, p = 0.230). In the control group was determined a statistically significant, positive, linear correlation between serum CRP and uric acid concentration (rho = 0.438, p = 0.001) and statistically significant, positive, linear correlation between serum CRP and total serum bilirubin (rho = 0.510, p = 0.0001) A statistically significant, negative linear correlation was determined between CRP and albumin concentration (rho= -0.393, p = 0.005) as well as statistically significant, negative linear correlation between serum CRP and ferritin control group (rho = 0.391, p = 0.005). CONCLUSION: Elevated CRP level is a strong and independent predictor of low levels of serum albumin, which indicates that the hypoalbuminemia in hemodialysis patients could be more due to inflammation than malnutrition. There was no statistically significant correlation between CRP and other non enzymatic antioxidants (uric acid, ferritin, bilirubin), which shows that indicators of antioxidant defense in hemodialysis patients must be individually measured to determine their actual stocks and activity. PMID- 26005384 TI - Homocystein as a risk factor for developing complications in chronic renal failure. AB - AIM: Cardiovascular diseases are leading cause of death in patients with chronic renal failure. The aim of our study was to establish connection between levels of homocysteine and traditional and nontraditional risk factors for developing cardiovascular diseases in dialysis and pre dialysis patients. METHODS: We included 33 pre dialysis (23 in stage three and 10 in stage four of chronic kidney disease) and 43 patients receiving hemodialysis longer than six months. Besides standard laboratory parameters, levels of homocysteine and blood pressure were measured in all patients. Glomerular filtration rate was measured in pre dialysis patients and dialysis quality parameters in dialysis patients. RESULTS: Homocysteine levels were elevated in all patients (19+/-5.42mmol/l). The connection between homocysteine levels and other cardiovascular diseases risk factors was not established in pre dialysis patients. In patients treated with hemodialysis we found negative correlation between homocysteine levels and patients' age (p<0.05) and positive correlation between homocysteine levels and length of dialysis (p<0.01) as well as between homocysteine and anemia parameters (erythrocytes, hemoglobin), (p<0.01). Homocysteine and LDL (and total cholesterol) were in negative correlation (p<0.01). CONCLUSION: Homocysteine, as one of nontraditional cardiovascular diseases risk factors, is elevated in all patients with chronic renal failure and it's positive correlation with some other risk factors was found. PMID- 26005385 TI - Elevated Serum Leptin Level Is Associated with Body Mass Index But Not with Serum C-reactive Protein and Erythrocyte Sedimentation Rate Values in Hemodialysis Patients. AB - OBJECTIVES: Aim of the present study was to investigate serum concentration of leptin and its association with values of body mass index (BMI), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) in hemodialysis (HD) patients. METHODS: This cross-sectional study included 60 HD patients (34 male, 26 female) and 30 age- and sex-matched (4 males, 26 females) apparently healthy subjects. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA). Serum CRP concentration was measured by means of particle-enhanced immunonephelometry. ESR value was determined by Western Green method. BMI was calculated as weight (kg) divided by height squared (m(2)). RESULTS: Results have shown that median serum leptin concentration (30.65 ng/mL; 12.48-86.40 ng/mL) was statistically significantly higher in HD patients compared to median serum leptin concentration (15.75 ng/mL; 9.15-30.65 ng/mL) in the control group of healthy subjects (p<0.05). Likewise, median serum CRP concentration (5.5 mg/L; 1.93-8.9 mg/L) and median ESR value (57.5 mm/h; 40.5 77.0 mm/h) were significantly higher in HD patients compared to median serum CRP concentration (0.8 mg/L; 0.38-1.43 mg/L) (p<0.001) and median ESR value (10.0 mm/h; 6.5-14.0 mm/h) (p<0.001) determined in the control group. Statistically significant positive correlation was found between BMI values and serum leptin concentration in HD patients (rho=0.434; p<0.001). Positive, although not significant, correlation was observed between serum CRP and leptin levels in HD patients (rho=0.171; p>0.05). Negative correlation between ESR values and serum leptin concentrations in HD patients was determined but it was not statistically significant (rho= -0.029; p>0.05). CONCLUSIONS: Increased serum concentration of leptin as pro-inflammatory cytokine as well as elevated serum values of CRP and ESR indicate presence of systemic micro inflammation in HD patients. Results of the present study point to possible use of serum leptin concentration as an indicator of nutritional status in HD patients based on observed significant positive correlation between serum leptin concentrations and BMI values. However, absence of significant association between serum leptin and CRP levels as well as between serum leptin concentrations and ESR values in HD patients requires further investigation and clarification. PMID- 26005386 TI - Role of Hypertension and Anaemia in Left Ventricular Remodelling in Patient with Renal Allograft in the First Post-transplant Year. AB - BACKGROUND: Hypertension (HT) and renal anaemia (RA) are well-established markers of cardiovascular risk in patients with chronic kidney disease (CKD). They appear to be the stimuli for left ventricular hypertrophy (LVH), who significantly participates in cardiac complications in uremic patients. Hypertension is extremely common after kidney transplantation (KTx) and it has been observed in up to 75% of patients. The prevalence of post-renal transplant anaemia (PTA) is variable (up to 30%) and several factors such as graft function contribute towards its pathophysiology. AIM: The aim of this study was to analyze the impact of blood pressure and anaemia on LV remodelling in first year after transplantation comparing echocardiographic findings before and twelve months after transplantation had done. METHODS: In five years retrospective-prospective study we followed up 30 patients with renal allograft in first post-transplant year. During the study values of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), blood hemoglobin (Hgb), serum creatinine and creatinine clearance were monitored monthly. RESULTS: Before transplantation (Tx) 86% of patients had HT, and RA was confirmed in all patients. Normal echocardiographic findings had 33% of patients and 67% of patients had echocardiographic sings of LVH. Before renal transplantation group with LVH had statistically higher the mean values of blood pressure (MBP) (p=0.053) compared to group with diastolic (LVDDF) (p=0.0047) and systolic diastolic dysfunction (LVSDDF) (p=0.0046). The values of SBP and DBP positively correlated with LV mass index (LVMI) in the group of patients with LVH (p=0.0007 and p=0.0142). The values of Hgb was statistically higher in group with normal LV mass index compared to LVH (p=0.019), with negative correlation between LVMI and values of Hgb in the patients group with LV hypertrophy (p=0.009). After the first year of transplantation, 63% of patients showed normal LV mass index and 37% remained with echocardiographic findings of the LVH. The values of SBP and values of Hgb in both groups, as well as values of DBP in group of LVH were statistically different in compare with data before transplantation (p<0.05). The positive echocardiographic remodelling of LV significantly correlated with the increase of Hgb values (p=0.05), but without significant correlation with the decrease of the mean SBP and DBP. CONCLUSION: These results confirmed that positive echocardiographic remodelling of left ventricle after successful renal transplantation is complex process depended on many risk factors and elimination of uremia- related factors is a priority. PMID- 26005387 TI - Incidence of subclinical hypothyroidism in renal transplant patients. AB - Thyroid disorders are common in chronic kidney disease. THE AIM: The purpose of this study was to compare thyroid gland disorders among healthy participants and renal transplant patients and to assess the duration of dialysis on thyroid disorders before transplantation. MATERIAL AND METHODS: Prospective study during 12 months period included 80 participants divided into two groups. Study group of 40 patients with transplanted kidney was divided in two subgroups, according to the time spent on dialysis (i.e. under and over 72 months). The control group included 40 healthy participants. The exclusion criteria was represented by the previous thyroid disorders and systemic illnesses and treatment with drugs that interfere with thyroid function (amiodarone, propranolol, lithium). The blood samples were taken for standard laboratory analysis, total thyroid hormone levels. Serum level of free thyroxine (T4) and free triiodothyronine (T3) were assayed by RIA using commercially available kits. Subclinical hypothyroidism is defined by the finding of elevated thyroid-stimulating hormone (TSH) > 4.4 mmol/L and normal values of T3 and T4. RESULTS: The relative distribution of the functional thyroid disorders is statistically significantly higher in the experimental group: the low T3 syndrome in 12.5% (n = 5) patients (p = 0.017); low T4 syndrome in 7.5% (n = 3) patients (p = 0.072) and subclinical hypothyroidism in 17.5% (n = 7) patients (p = 0.021). There is statistically significant difference in the relative representation (percentage) between respondents to 72 months and respondents over 72 months duration of hemodialysis, namely: low T3 syndrome, which is a higher percentage was recorded in patients up to 72 months duration of dialysis (19.23%), then subclinical hypothyroidism where a greater percentage recorded in subjects over 72 months duration of dialysis (35.71%) before transplantation. CONCLUSION: Considering that we are found in kidney transplant patients a significant link of subclinical hypothyroidism with decreased level of T3 and higher incidence of low T3 syndrome, which are associated with increased cardiovascular mortality and morbidity, and act as markers of survival patients after transplantation, it is necessary to conduct a periodically measuring levels of T3, T4 and TSH in these patients in order to assess the relationship between thyroid dysfunction and mortality risk in this population. PMID- 26005388 TI - Central venous catheter as vascular approach for hemodialysis - our experiences. AB - INTRODUCTION: Application of a central venous catheter (CVC), as a temporary or permanent vascular access for hemodialysis, has been continuous practice at the Sarajevo Pediatric Clinic, Department of Pediatric Intensive Care. The main goal of the article is to present our experiences with central venous catheters in the treatment of these patients. MATERIAL AND METHODS: In the period from January 2009 to December 2014 a total of 41 patients were treated and a total of 56 catheters were placed. RESULTS: The results show the prevalence of the femoral venous catheter (69,64%), with significantly smaller participation of jugular (28,57%) and symbolic participation of subclavian catheters (1,78%). Frequency of infections of 8,92% in our article is lower than the percentage contained in the data of the National Nosocomial Infections Surveillance System, which provided data related to 17% of catheter related infections. The most common agents of the catheter related infections in our patients are gram-negative bacteria from the Klebsiella pneumoniae group. CONCLUSION: The issue of the higher complication percentage during the treatment is linked with hemostasis related to bleeding into or around the catheters in 28,57% of patients, and to clotting disorder in terms of thrombosis in 10,71% of patients. PMID- 26005389 TI - The impact of Vascular Access on the Adequacy of Dialysis and the Outcome of the Dialysis Treatment: One Center Experience. AB - INTRODUCTION: Chronic kidney disease (CKD) is a gradually reduction in glomerular filtration rate (GFR) caused by destruction of a large number of nephrons. Kidney failure is the final stage of CKD with GFR <15ml/min/1.73m(2) or requiring dialysis. Patients must provide vascular access, which is also the "life line" and "Achilles heel" of hemodialysis treatment. AIM: The purpose of this research is to show the demographic structure of the hemodialysis center in Konjic, and also demonstrate the impact of vascular access to the adequacy and the outcome of dialysis treatment. METHODS: This cross-sectional study included 36 patients on hemodialysis in Center in Konjic from September 2010 to December 2014. The method of collecting data is performed through medical records and the quality of dialysis is taken to be Kt/V> 1.2. Statistical analysis was performed using SPSS software and Student T-test. RESULTS: The mortality of patients treated by dialysis is 37.8%. The ratio of male and female patients is 55.6% vs. 44.5%, with an average age of 52.91+/-14.36 years and an average duration of hemodialysis of five years. The highest percentage of patients dialyzed through arterio-venous fistula (AVF) on the forearm (72.2%). In that patients the most common complication is thrombosis with 30.5%, which require recanalization in 11% and replacement in 19.5% of patients. Of the other dialysis patients, 16.7% of patients are dialyzed via a temporary and 11.1% via a permanent catheter (the most common complication in that patients is infection in 83.3% cases) in v.subclavia. Although the AVF is more frequently, experience shows frequent implantation of a permanent catheter in elderly patients due to the less quality of their blood vessels. Although the Kt/V by patients who are dialyzed through temporary catheter is less than 1.2 and by the other two access is greater than 1.2, our results confirm that vascular access does not have an influence on quality of dialysis. Average Kt/V shows that the adequate dialysis dose is delivered in this Center, which means that despite the impact of vascular access in HD quality, other factors also can affect on dialysis treatment, which was noticed by patients and staff. CONCLUSION: Despite the largest mortality rate in patients with a permanent catheter and least in patients with AVF, the type of vascular access does not affect the outcome of dialysis treatment. PMID- 26005390 TI - Resistant hypertension and chronotherapy. AB - Resistant hypertension is defined as blood pressure that remains above 140/90 mmHg in spite of the continuous use of three antihypertensive agents in optimal dose, including diuretic, and lifestyle changes. According to data from United States of America and Europe, the prevalence ranges from 10 up to 30% in patients with hypertension. Numerous biological and lifestyle factors can contribute to the development of resistant hypertension: medications, volume overload, obesity, diabetes mellitus, older age, renal parenchymal and renovascular disease, primary aldosteronism, obstructive sleep apnea, pheochormocytoma, Cushing's syndrome, thyroid diseases, aortic coarctation. For diagnosing patient's history is important, assessing compliance, regular blood pressure measurement, physical examination, biochemical evaluation and noninvasive imaging. The evaluation including 24h ambulatory monitoring of blood pressure (ABPM) in the identification of "non-dipper" hypertension. Non-dipper has particular importance and the prevalence of abnormally high sleep blood pressure is very often in chronic kidney patients. Therapeutic restoration of normal physiologic blood pressure reduction during night-time sleep (circadial variation) is the most significant independent predictor of decreased risk and the basis for the chronotherapy. The resistant hypertension treatment is achieved with nonpharmacological and pharmacological approach, treating secondary hypertension causes and invasive procedures. PMID- 26005391 TI - Vitamin d in the patients with chronic kidney disease: when, to whom and in which form. AB - Alteration in vitamin D metabolism has a central role in the pathogenesis of secondary hyperparathyroidism (SHPT) and is also associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). For more than sixty years, vitamin D, nutritional vitamin D (ergocalciferol, cholecalciferol or calcifediol) and nonselective vitamin D receptor (VDR) activators (calcitriol, alfacalcidol) have been used in the prevention and treatment of SHPT. In the last twenty years, selective VDR activators (paricalcitol, maxacalcitol) have been used to target SHPT. However, there are many open questions regarding use of nutritional vitamin D or VDR activators. The K/DOQI and KDIGO guidelines recommended testing for vitamin D insufficiency and deficiency in patients with CKD, but there is no consensus on the definition of vitamin D insufficiency in CKD. There are a many open questions, for example, regarding the optimal nutritional vitamin D type and the dose and co-administration of nutritional vitamin and VDR activators. Therapy with VDRAs is required in the majority of patients with CKD, particularly in dialysis patients. However, when to start with VDRAs is not so apparent. Is PTH level the only indication of when to start therapy? Although VDRAs are very effective in lowering PTH levels and bone metabolism the effect of patients mortality is not so straightforward. Despite many unanswered questions, there is a large body of experimental and clinical data to support vitamin D use in patients with CKD. To obtain answers to the open questions, we need more randomized controlled trials. PMID- 26005392 TI - Recipe from the past for the future: public health intervention represent a process for century. AB - In the poor Bosnia, in the early 20(th) century endemic syphilis was widespread. Combating this disease entailed the necessity of etiology research, diagnosis and clinical nature of the disease, as well as the insight into the epidemiological image of this unresolved health problem. Thanks to the visionary, the enthusiasm and persistence of the expert team of doctors from that time in Croatia, School of Public Health and the Rockefeller Foundation as financial support, conditions were created to conduct population monitoring and research called "survey". The team of experts from Croatia and Bosnia led by Dr. Ante Vuletic began this important public health intervention in Central Bosnia underneath the mountain Vlasic 1934. In villages of mountain Vlasic people were living in very difficult social and unsanitary conditions. "Interviewers" worked in makeshift clinics in the rural schools Opare, Rankovici, Vitovlje Mehorica, Turbe, Bila and Gornji Vakuf. A hundred years later, a team of university professors from the School of Public Health "Andrija Stampar" led by Professor Silvije Viletic followed the footsteps of century "survey" on Vlasic in the summer of 2014. They determined that with the integrated approach to population monitoring and testing endemic syphilis in Bosnia was successfully suppressed. PMID- 26005393 TI - Parents' Emotion-Related Beliefs, Behaviors, and Skills Predict Children's Recognition of Emotion. AB - Children who are able to recognize others' emotions are successful in a variety of socioemotional domains, yet we know little about how school-aged children's abilities develop, particularly in the family context. We hypothesized that children develop emotion recognition skill as a function of parents' own emotion related beliefs, behaviors, and skills. We examined parents' beliefs about the value of emotion and guidance of children's emotion, parents' emotion labeling and teaching behaviors, and parents' skill in recognizing children's emotions in relation to their school-aged children's emotion recognition skills. Sixty-nine parent-child dyads completed questionnaires, participated in dyadic laboratory tasks, and identified their own emotions and emotions felt by the other participant from videotaped segments. Regression analyses indicate that parents' beliefs, behaviors, and skills together account for 37% of the variance in child emotion recognition ability, even after controlling for parent and child expressive clarity. The findings suggest the importance of the family milieu in the development of children's emotion recognition skill in middle childhood, and add to accumulating evidence suggesting important age-related shifts in the relation between parental emotion socialization and child emotional development. PMID- 26005394 TI - Self-compassionate young adults show lower salivary alpha-amylase responses to repeated psychosocial stress. AB - In this study we tested the hypothesis that participants higher in dispositional self-compassion would show lower stress-induced reactivity of salivary alpha amylase (sAA), a marker of sympathetic nervous system activation. Thirty-three healthy participants (18-34 years old) were exposed to a standardized laboratory stressor on two consecutive days. Self-compassion, self-esteem, and demographic factors were assessed by questionnaire and sAA was assessed at baseline and at 1, 10, 30, and 60 minutes following each stressor. Self-compassion was a significant negative predictor of sAA responses on both days. This relationship remained significant when controlling for self-esteem, subjective distress, age, gender, ethnicity, and Body Mass Index (BMI). These results suggest that self-compassion may serve as a protective factor against stress-induced physiological changes that have implications for health. PMID- 26005395 TI - Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir. AB - Ovarian cancer (OC) is most often contained within the peritoneal cavity, making it an ideal disease for adenoviral-delivered gene therapies. In effort to develop a safe and effective gene therapy for OC, we created a replication deficient adenovirus bearing the herpes simplex thymidine kinase (HSV-tk) gene under direction of the tumor specific promoter human epididymis protein 4 (HE4). The purpose of this study was to investigate the ability of our adenoviral construct to transduce OC cells in vitro and mediate transgene expression of HSV-tk, thereby sensitizing OC to the pro-drug ganciclovir. Cisplatin-sensitive (CS) and resistant (CR) A2780 OC cells, infected with virus for 6 hours at 100, 500, and 1000 multiplicity of infection followed by ganciclovir treatment every other day for 5 days, were assayed for cell viability. Adenoviral-mediated transgene expression increased with increasing amounts of virus and peaked at 48 hours after transduction in both A2780-CS and -CR. Unexpectedly, ganciclovir alone was slightly toxic to both A2780 cell lines (IC50 of 234.9 MUg/mL and 257.2 MUg/mL in A2780-CS and -CR, respectively). Transduction with ADV-HE4-HSV-tk followed by ganciclovir treatment increased (P<0.05) cell killing up to ten-fold, lowering the IC50 to 23.9 MUg/mL and 32.6 MUg/mL in A2780-CS and -CR, respectively, at 1000 multiplicity of infection. The results support the potential use of this approach as a gene therapy for OC, a disease that accounts for more deaths than any other cancer of the female reproductive system. PMID- 26005396 TI - Change in Trauma Narratives and Perceived Recall Ability over a Course of Cognitive Processing Therapy for PTSD. AB - This study sought to evaluate changes in written trauma narratives completed during a course of Cognitive Processing Therapy (CPT). Participants were 22 female survivors of interpersonal assault who represented a subset of participants from two larger CPT treatment trials. Participants completed two written trauma narratives over the course of treatment. We predicted that narratives would increase in length and peritraumatic detail, and that participants would perceive an increase in their recall ability for important aspects of the trauma. Although narrative length and amount of peritraumatic detail did not change significantly from first to final narrative, participants evidenced changes in the content of the peritraumatic details. Patients commonly omitted assaultive acts from one of their narratives. There was a greater degree of fluctuation within the reporting of sexual assaults, as compared to physical assaults, with 55% of participants reporting a forced sexual act in one narrative, but not the other. Participants did not report significant changes in perceived recall ability for the traumatic event after completing the narratives, but did report improvements in perceived recall from pre to posttreatment. Overall, findings indicate that clients included different details (but not more details) in their final narrative, and that perceived increases in recall ability may not be a typical experience for clients as they complete written narratives in the context of trauma treatment. PMID- 26005397 TI - A novel method for testing association of multiple genetic markers with a multinomial trait. AB - We developed a multinomial probit model with singular value decomposition for testing a large number of single nucleotide polymorphisms (SNPs) simultaneously, using maximum likelihood estimation and permutation. The method was validated by simulation. We simulated 1000 SNPs, including 9 associated with disease states, and 8 of the 9 were successfully identified. Applying the method to study 32 genes in our Mexican-American samples for association with prediabetes through either impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), we found 3 genes (SORCS1, AMPD1, PPAR) associated with both IGT and IFG, while 5 genes (AMPD2, PRKAA2, C5, TCF7L2, ITR) with the IGT mechanism only and 6 genes (CAPN10, IL4,NOS3, CD14, GCG, SORT1) with the IFG mechanism only. These data suggest that IGT and IFG may indicate different physiological mechanism to prediabetes, via different genetic determinants. PMID- 26005398 TI - Women's Perspectives of Personal Trainers: A Qualitative Study. AB - Personal trainers play an integral role in the day-to-day operation of the facilities in which they work. Research has identified a number of qualities and competencies necessary to be an effective exercise leader, but there is little scholarly work addressing clients' attitudes related to the performance of personal trainers. Utilizing focus group methodology, female clients of personal trainers were recruited to provide viewpoints related to the desirable qualities of personal trainers, as well as opinions regarding trainer certification and academic preparation. Responses of the participants were transcribed, coded, and analyzed for themes. Four global themes emerged: Selection Rationale, Personal Trainer Rationale, Loyalty Rationale and Negative Characteristics. Selection Rationale consisted of qualities that influence a client's decision to hire a particular trainer (e.g., physique, results observed in other clients, social skills). Personal Trainer Rationale referred to the clients' reasons (e.g., frustration with current fitness level) for hiring a specific trainer. Loyalty Rationale referred to the credentials of a personal trainer that solidify the client/trainer relationship and Negative Characteristics referred to qualities considered unethical or unprofessional. The results suggest that undergraduate exercise science programs should devote additional time toward the development of future fitness trainers' affective qualities and that clients' would benefit from information about the credentials of personal trainers. PMID- 26005399 TI - Mapping Moisture Sorption Through Carbohydrate Composite Glass with Fourier Transform Near-Infrared (FT-NIR) Hyperspectral Imaging. AB - Inherent changes in foods during storage are often caused by water sorption or desorption that often results in product matrix instability. Water sorption behavior differs depending on the matrix through which it moves. Often, concurrent phenomenon such as crystallization modifies water's movement. We describe a novel use of hyperspectral imaging combined with Fourier Transform Near Infrared (FT-NIR) spectroscopy to map where water molecules are in two dimensions while concurrently quantifying the crystallization motif as water sorbs into a carbohydrate matrix over a month's storage time. This methodology allows us to identify and quantify sucrose crystals formed within a carbohydrate matrix while also mapping water migration through this complex matrix. We compared corn syrup/sucrose blends where sucrose is supersaturated (high sucrose, HS), sucrose is below saturation (low sucrose, LS), sucrose below saturation with embedded sucrose crystals (LSS) and maltotriose is supersaturated within a corn syrup matrix (high maltotriose, LSM). This FT-NIR method was used to characterize water sorption through a carbohydrate matrix over time and measured both the propensity of the systems to form sucrose crystals and the influence sucrose crystals have on water sorption. We observed water diffusion was slower in lower sugar carbohydrate glasses, and the process of sorption was different. Amorphous systems supersaturated in sucrose allow crystallization when sufficient water is sorbed and thus, this concurrent action disrupts normal Fickian diffusion. The water front compresses to a narrow band as it sorbs through the matrix. The presence of embedded crystals in an amorphous matrix slows overall water penetration through the matrix by convoluting the path of moving water molecules. This did not appear to change the rate of diffusion. Experiments with maltotriose at supersaturation concentration showed the crystallization rate was slower than sucrose. Thus, pure maltotriose is not a practical solution as a potential replacement for sucrose to slow sorption in food systems. PMID- 26005401 TI - Biotransformation of acetophenone and its halogen derivatives by Yarrowia lipolytica strains. AB - The ability of 16 strains of Yarrowia lipolytica to biotransform acetophenone and its derivatives has been studied. Thirteen of these strains were derived from a wild-type strain Y. lipolytica A-101; six had the invertase gene (SUC2) from Saccharomyces cerevisiae integrated into their genome, as well as the damaged or undamaged gene encoding orotidine-5'-phosphate decarboxylase (URA3), three had integrated the damaged URA3 gene into their genome and three were UV acetate negative mutants, not able to growth on acetate as the sole carbon source. The other tested strains included two wild strains, A-101 and PMR-1, and an adenine auxotroph ATCC 32-338A. All strains were capable of reducing acetophenone to the R-alcohol in high enantiomeric excess (80-89 %). In all of the cultures tested, reversibility of the reduction was observed, which led to an increase in the enantiomeric excess. nantioselective reduction of the acetophenone halogen derivatives revealed that the nature and location of the halogen atom had a significant influence on the enantioselectivity of the reduction. In the culture of ATCC 32-338A, after a 3-day biotransformation of 2,4'-dibromoacetophenone the enantiopure R-alcohol was obtained at a rate of 100 % of substrate conversion. In conclusion, using these invertase-containing strains or uracyl auxotrophs provided no additional benefit in terms of biotransformation capacity over the parental strain. PMID- 26005400 TI - Strategies of Functional Foods Promote Sleep in Human Being. AB - Sleep is a vital segment of life, however, the mechanisms of diet promoting sleep are unclear and are the focus of research. Insomnia is a general sleep disorder and functional foods are known to play a key role in the prevention of insomnia. A number of studies have demonstrated that major insomnia risk factors in human being are less functional foods in dietary. There are higher functional components in functional foods promoting sleep, including tryptophan, GABA, calcium, potassium, melatonin, pyridoxine, L-ornithine and hexadecanoic acid; but wake-promoting neurochemical factors include serotonin, noradrenalin, acetylcholine, histamine, orexin and so on. The factors promoting sleep in human being are the functional foods include barley grass powder, whole grains, maca, panax, Lingzhi, asparagus powder, lettuce, cherry, kiwifruits, walnut, schisandra wine, and milk; Barley grass powder with higher GABA and calcium, as well as potassium is the most ideal functional food promoting sleep, however, the sleep duration for modern humans is associated with food structure of ancient humans. In this review, we put forward possible mechanisms of functional components in foods promoting sleep. Although there is clear relevance between sleep and diet, their molecular mechanisms need to be studied further. PMID- 26005402 TI - Evaluation of temperature sum models and timing of Quassia amara (Simaroubaceae) wood-chip extract to control apple sawfly (Hoplocampa testudinea Klug) in Sweden. AB - Apple sawfly (Hoplocampa testudinea Klug) is a serious pest in European organic apple production. They hatch during a short period only, making correct timing of control measures crucial. Swedish organic growers have requested a strategy for optimal timing of the Quassia amara (Simaroubaceae) extract against the apple sawfly. The aim of this study was, therefore, to develop methods to predict the timing of Q. amara control in Sweden. A temperature sum model for timely placement of monitoring or mass-trapping sticky traps was validated for Swedish conditions. The average emergence of sawflies occurred at 169 degree days (SD = 20) counted from March 15 (threshold temperature 4 degrees C). The difference in emergence from existing first flight model of average and maximum 9 and 39 degree days (1 and 9 calendar days) was found acceptable. Accumulated oviposition of 85 % at full bloom (BBCH 65) suggests that mass trapping and monitoring could stop at this time. This is supported by a tendency of decreased trap catches during that period. Three application times for Q. amara were compared: (A) at petal fall (BBCH 67), (B) at a date calculated using female trap catch numbers and temperature sums, and (C) prior to peak egg hatch observed in the field. All treatments resulted in significantly lower percentage of damaged apples compared to the unsprayed control, with significantly less damage (1.3 %) in plots treated according to method (B). The results provide information on adult phenology and methods that could be used to determine timing of mass trapping and insecticide application against the apple sawfly. PMID- 26005403 TI - Intracellular calcium dynamics in cortical microglia responding to focal laser injury in the PC::G5-tdT reporter mouse. AB - Microglia, the resident immune cells of the brain parenchyma, are highly responsive to tissue injury. Following cell damage, microglial processes redirect their motility from randomly scouting the extracellular space to specifically reaching toward the compromised tissue. While the cell morphology aspects of this defense mechanism have been characterized, the intracellular events underlying these responses remain largely unknown. Specifically, the role of intracellular Ca(2+) dynamics has not been systematically investigated in acutely activated microglia due to technical difficulty. Here we used live two-photon imaging of the mouse cortex ubiquitously expressing the genetically encoded Ca(2+) indicator GCaMP5G and fluorescent marker tdTomato in central nervous system microglia. We found that spontaneous Ca(2+) transients in microglial somas and processes were generally low (only 4% of all microglia showing transients within 20 min), but baseline activity increased about 8-fold when the animals were treated with LPS 12 h before imaging. When challenged with focal laser injury, an additional surge in Ca(2+) activity was observed in the somas and protruding processes. Notably, coherent and simultaneous Ca(2+) rises in multiple microglial cells were occasionally detected in LPS-treated animals. We show that Ca(2+) transients were pre-dominantly mediated via purinergic receptors. This work demonstrates the usefulness of genetically encoded Ca(2+) indicators for investigation of microglial physiology. PMID- 26005404 TI - Differential expression of sirtuins in the aging rat brain. AB - Although there are seven mammalian sirtuins (SIRT1-7), little is known about their expression in the aging brain. To characterize the change(s) in mRNA and protein expression of SIRT1-7 and their associated proteins in the brain of "physiologically" aged Wistar rats. We tested mRNA and protein expression levels of rat SIRT1-7, and the levels of associated proteins in the brain using RT-PCR and western blotting. Our data shows that SIRT1 expression increases with age, concurrently with increased acetylated p53 levels in all brain regions investigated. SIRT2 and FOXO3a protein levels increased only in the occipital lobe. SIRT3-5 expression declined significantly in the hippocampus and frontal lobe, associated with increases in superoxide and fatty acid oxidation levels, and acetylated CPS-1 protein expression, and a reduction in MnSOD level. While SIRT6 expression declines significantly with age acetylated H3K9 protein expression is increased throughout the brain. SIRT7 and Pol I protein expression increased in the frontal lobe. This study identifies previously unknown roles for sirtuins in regulating cellular homeostasis and healthy aging. PMID- 26005405 TI - Observation and manipulation of glial cell function by virtue of sufficient probe expression. AB - The development of gene-encoded indicators and actuators to observe and manipulate cellular functions is being advanced and investigated. Expressing these probe molecules in glial cells is expected to enable observation and manipulation of glial cell activity, leading to elucidate the behaviors and causal roles of glial cells. The first step toward understanding glial cell functions is to express the probes in sufficient amounts, and the Knockin mediated ENhanced Gene Expression (KENGE)-tet system provides a strategy for achieving this. In the present article, three examples of KENGE-tet system application are reviewed: depolarization of oligodendrocytes, intracellular acidification of astrocytes, and observation of intracellular calcium levels in the fine processes of astrocytes. PMID- 26005406 TI - Diversity and overlap of parvalbumin and somatostatin expressing interneurons in mouse presubiculum. AB - The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre, and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labeling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for parvalbumin (PV). Immunostaining for somatostatin (SOM) revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ~6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre, and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1). Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3). Another group (cluster 2) contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance. PMID- 26005408 TI - Identification of essential residues for binding and activation in the human 5 HT7(a) serotonin receptor by molecular modeling and site-directed mutagenesis. AB - The human 5-HT7 receptor is expressed in both the central nervous system and peripheral tissues and is a potential drug target in behavioral and psychiatric disorders. We examined molecular determinants of ligand binding and G protein activation by the human 5-HT7(a) receptor. The role of several key residues in the 7th transmembrane domain (TMD) and helix 8 were elucidated combining in silico and experimental mutagenesis. Several single and two double point mutations of the 5-HT7(a) wild type receptor were made (W7.33V, E7.35T, E7.35R, E7.35D, E7.35A, R7.36V, Y7.43A, Y7.43F, Y7.43T, R8.52D, D8.53K; E7.35T-R7.36V, R8.52D-D8.53K), and their effects upon ligand binding were assessed by radioligand binding using a potent agonist (5-CT) and a potent antagonist (SB269970). In addition, the ability of the mutated 5-HT7(a) receptors to activate G protein after 5-HT-stimulation was determined through activation of adenylyl cyclase. In silico investigation on mutated receptors substantiated the predicted importance of TM7 and showed critical roles of residues E7.35, W7.33, R7.36 and Y7.43 in agonist and antagonist binding and conformational changes of receptor structure affecting adenylyl cyclase activation. Experimental data showed that mutants E7.35T and E7.35R were incapable of ligand binding and adenylyl cyclase activation, consistent with a requirement for a negatively charged residue at this position. The mutant R8.52D was unable to activate adenylyl cyclase, despite unaffected ligand binding, consistent with the R8.52 residue playing an important role in the receptor-G protein interface. The mutants Y7.43A and Y7.43T displayed reduced agonist binding and AC agonist potency, not seen in Y7.43F, consistent with a requirement for an aromatic residue at this position. Knowledge of the molecular interactions important in h5 HT7 receptor ligand binding and G protein activation will aid the design of selective h5-HT7 receptor ligands for potential pharmacological use. PMID- 26005410 TI - Alterations in multidimensional motor unit number index of hand muscles after incomplete cervical spinal cord injury. AB - The objective of this study was to apply a novel multidimensional motor unit number index (MD-MUNIX) technique to examine hand muscles in patients with incomplete cervical spinal cord injury (SCI). The MD-MUNIX was estimated from the compound muscle action potential (CMAP) and different levels of surface interference pattern electromyogram (EMG) at multiple directions of voluntary isometric muscle contraction. The MD-MUNIX was applied in the first dorsal interosseous (FDI), thenar and hypothenar muscles of SCI (n = 12) and healthy control (n = 12) subjects. The results showed that the SCI subjects had significantly smaller CMAP and MD-MUNIX in all the three examined muscles, compared to those derived from the healthy control subjects. The multidimensional motor unit size index (MD-MUSIX) demonstrated significantly larger values for the FDI and hypothenar muscles in SCI subjects than those from healthy control subjects, whereas the MD-MUSIX enlargement was marginally significant for the thenar muscles. The findings from the MD-MUNIX analyses provide an evidence of motor unit loss in hand muscles of cervical SCI patients, contributing to hand function deterioration. PMID- 26005407 TI - Constructing the suprachiasmatic nucleus: a watchmaker's perspective on the central clockworks. AB - The circadian system constrains an organism's palette of behaviors to portions of the solar day appropriate to its ecological niche. The central light-entrained clock in the suprachiasmatic nucleus (SCN) of the mammalian circadian system has evolved a complex network of interdependent signaling mechanisms linking multiple distinct oscillators to serve this crucial function. However, studies of the mechanisms controlling SCN development have greatly lagged behind our understanding of its physiological functions. We review advances in the understanding of adult SCN function, what has been described about SCN development to date, and the potential of both current and future studies of SCN development to yield important insights into master clock function, dysfunction, and evolution. PMID- 26005409 TI - Neurophysiological and neurocognitive mechanisms underlying the effects of yoga based practices: towards a comprehensive theoretical framework. AB - During recent decades numerous yoga-based practices (YBP) have emerged in the West, with their aims ranging from fitness gains to therapeutic benefits and spiritual development. Yoga is also beginning to spark growing interest within the scientific community, and yoga-based interventions have been associated with measureable changes in physiological parameters, perceived emotional states, and cognitive functioning. YBP typically involve a combination of postures or movement sequences, conscious regulation of the breath, and various techniques to improve attentional focus. However, so far little if any research has attempted to deconstruct the role of these different component parts in order to better understand their respective contribution to the effects of YBP. A clear operational definition of yoga-based therapeutic interventions for scientific purposes, as well as a comprehensive theoretical framework from which testable hypotheses can be formulated, is therefore needed. Here we propose such a framework, and outline the bottom-up neurophysiological and top-down neurocognitive mechanisms hypothesized to be at play in YBP. PMID- 26005411 TI - Increase in short-term memory capacity induced by down-regulating individual theta frequency via transcranial alternating current stimulation. AB - Working memory (WM) and short-term memory (STM) supposedly rely on the phase amplitude coupling (PAC) of neural oscillations in the theta and gamma frequency ranges. The ratio between the individually dominant gamma and theta frequencies is believed to determine an individual's memory capacity. The aim of this study was to establish a causal relationship between the gamma/theta ratio and WM/STM capacity by means of transcranial alternating current stimulation (tACS). To achieve this, tACS was delivered at a frequency below the individual theta frequency. Thereby the individual ratio of gamma to theta frequencies was changed, resulting in an increase of STM capacity. Healthy human participants (N = 33) were allocated to two groups, one receiving verum tACS, the other underwent a sham control protocol. The electroencephalogram (EEG) was measured before stimulation and analyzed with regard to the properties of PAC between theta and gamma frequencies to determine individual stimulation frequencies. After stimulation, EEG was recorded again in order to find after-effects of tACS in the oscillatory features of the EEG. Measures of STM and WM were obtained before, during and after stimulation. Frequency spectra and behavioral data were compared between groups and different measurement phases. The tACS- but not the sham stimulated group showed an increase in STM capacity during stimulation. WM was not affected in either groups. An increase in task-related theta amplitude after stimulation was observed only for the tACS group. These augmented theta amplitudes indicated that the manipulation of individual theta frequencies was successful and caused the increase in STM capacity. PMID- 26005412 TI - Spindles in Svarog: framework and software for parametrization of EEG transients. AB - We present a complete framework for time-frequency parametrization of EEG transients, based upon matching pursuit (MP) decomposition, applied to the detection of sleep spindles. Ranges of spindles duration (>0.5 s) and frequency (11-16 Hz) are taken directly from their standard definitions. Minimal amplitude is computed from the distribution of the root mean square (RMS) amplitude of the signal within the frequency band of sleep spindles. Detection algorithm depends on the choice of just one free parameter, which is a percentile of this distribution. Performance of detection is assessed on the first cohort/second subset of the Montreal Archive of Sleep Studies (MASS-C1/SS2). Cross-validation performed on the 19 available overnight recordings returned the optimal percentile of the RMS distribution close to 97 in most cases, and the following overall performance measures: sensitivity 0.63 +/- 0.06, positive predictive value 0.47 +/- 0.08, and Matthews coefficient of correlation 0.51 +/- 0.04. These concordances are similar to the results achieved on this database by other automatic methods. Proposed detailed parametrization of sleep spindles within a universal framework, encompassing also other EEG transients, opens new possibilities of high resolution investigation of their relations and detailed characteristics. MP decomposition, selection of relevant structures, and simple creation of EEG profiles used previously for assessment of brain activity of patients in disorders of consciousness are implemented in a freely available software package Svarog (Signal Viewer, Analyzer and Recorder On GPL) with user friendly, mouse-driven interface for review and analysis of EEG. Svarog can be downloaded from http://braintech.pl/svarog. PMID- 26005414 TI - Corrigendum: Using Science and Psychology to improve the dissemination and evaluation of scientific work. AB - [This corrects the article on p. 82 in vol. 8, PMID: 25191261.]. PMID- 26005413 TI - Dimensionality of ICA in resting-state fMRI investigated by feature optimized classification of independent components with SVM. AB - Different machine learning algorithms have recently been used for assisting automated classification of independent component analysis (ICA) results from resting-state fMRI data. The success of this approach relies on identification of artifact components and meaningful functional networks. A limiting factor of ICA is the uncertainty of the number of independent components (NIC). We aim to develop a framework based on support vector machines (SVM) and optimized feature selection for automated classification of independent components (ICs) and use the framework to investigate the effects of input NIC on the ICA results. Seven different resting-state fMRI datasets were studied. 18 features were devised by mimicking the empirical criteria for manual evaluation. The five most significant (p < 0.01) features were identified by general linear modeling and used to generate a classification model for the framework. This feature-optimized classification of ICs with SVM (FOCIS) framework was used to classify both group and single subject ICA results. The classification results obtained using FOCIS and previously published FSL-FIX were compared against manually evaluated results. On average the false negative rate in identifying artifact contaminated ICs for FOCIS and FSL-FIX were 98.27 and 92.34%, respectively. The number of artifact and functional network components increased almost linearly with the input NIC. Through tracking, we demonstrate that incrementing NIC affects most ICs when NIC < 33, whereas only a few limited ICs are affected by direct splitting when NIC is incremented beyond NIC > 40. For a given IC, its changes with increasing NIC are individually specific irrespective whether the component is a potential resting-state functional network or an artifact component. Using FOCIS, we investigated experimentally the ICA dimensionality of resting-state fMRI datasets and found that the input NIC can critically affect the ICA results of resting-state fMRI data. PMID- 26005415 TI - Molecular quantum robotics: particle and wave solutions, illustrated by "leg-over leg" walking along microtubules. AB - Remarkable biological examples of molecular robots are the proteins kinesin-1 and dynein, which move and transport cargo down microtubule "highways," e.g., of the axon, to final nerve nodes or along dendrites. They convert the energy of ATP hydrolysis into mechanical forces and can thereby push them forwards or backwards step by step. Such mechano-chemical cycles that generate conformal changes are essential for transport on all different types of substrate lanes. The step length of an individual molecular robot is a matter of nanometers but the dynamics of each individual step cannot be predicted with certainty (as it is a random process). Hence, our proposal is to involve the methods of quantum field theory (QFT) to describe an overall reliable, multi-robot system that is composed of a huge set of unreliable, local elements. The methods of QFT deliver techniques that are also computationally demanding to synchronize the motion of these molecular robots on one substrate lane as well as across lanes. Three different challenging types of solutions are elaborated. The impact solution reflects the particle point of view; the two remaining solutions are wave based. The second solution outlines coherent robot motions on different lanes. The third solution describes running waves. Experimental investigations are needed to clarify under which biological conditions such different solutions occur. Moreover, such a nano-chemical system can be stimulated by external signals, and this opens a new, hybrid approach to analyze and control the combined system of robots and microtubules externally. Such a method offers the chance to detect mal functions of the biological system. PMID- 26005416 TI - Corrigendum: Transforming growth factor beta1 inhibition protects from noise induced hearing loss. PMID- 26005417 TI - Learning of bimanual motor sequences in normal aging. AB - While it is well accepted that motor performance declines with age, the ability to learn simple procedural motor tasks appears to remain intact to some extent in normal aging. Here we examined the impact of aging on the acquisition of a simple sequence of bimanual actions. We further asked whether such learning results from an overall decrease in response time or is also associated with improved coordination between the hands. Healthy young and old individuals performed a bimanual version of the classic serial reaction time task. We found no learning deficit in older adults and noted that older subjects were able to learn as much as young participants. We also observed that learning in both groups was associated with an overall decrease in response time, but switch cost, the increase in response time when a switch in hands was required during sequence execution, did not decrease with learning. Surprisingly however, overall switch cost was lower in the older group compared to the younger subjects. These findings are discussed in the context of interactions between procedural and declarative memory, reduced interhemispheric inhibition and more symmetric cortical activation during motor performance in normal aging. PMID- 26005418 TI - Corrigendum: Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance. AB - [This corrects the article on p. 57 in vol. 6, PMID: 25852559.]. PMID- 26005419 TI - Advancements in therapeutically targeting orphan GPCRs. AB - G-protein coupled receptors (GPCRs) are popular biological targets for drug discovery and development. To date there are more than 140 orphan GPCRs, i.e., receptors whose endogenous ligands are unknown. Traditionally orphan GPCRs have been difficult to study and the development of therapeutic compounds targeting these receptors has been extremely slow although these GPCRs are considered important targets based on their distribution and behavioral phenotype as revealed by animals lacking the receptor. Recent advances in several methods used to study orphan receptors, including protein crystallography and homology modeling are likely to be useful in the identification of therapeutics targeting these receptors. In the past 13 years, over a dozen different Class A GPCRs have been crystallized; this trend is exciting, since homology modeling of GPCRs has previously been limited by the availability of solved structures. As the number of solved GPCR structures continues to grow so does the number of templates that can be used to generate increasingly accurate models of phylogenetically related orphan GPCRs. The availability of solved structures along with the advances in using multiple templates to build models (in combination with molecular dynamics simulations that reveal structural information not provided by crystallographic data and methods for modeling hard-to-predict flexible loop regions) have improved the quality of GPCR homology models. This, in turn, has improved the success rates of virtual ligand screens that use homology models to identify potential receptor binding compounds. Experimental testing of the predicted hits and validation using traditional GPCR pharmacological approaches can be used to drive ligand-based efforts to probe orphan receptor biology as well as to define the chemotypes and chemical scaffolds important for binding. As a result of these advances, orphan GPCRs are emerging from relative obscurity as a new class of drug targets. PMID- 26005420 TI - Assessing the impact of dietary habits on health-related quality of life requires contextual measurement tools. AB - The increase of non-communicable diseases at all ages has fostered the general concern for sustaining population health worldwide. Unhealthy lifestyles and dietary habits impacting physical and psycho-social health are well known risk factors for developing life threatening diseases. Identifying the determinants of quality of life is an important task from a Public Health perspective. Consumer Reported Outcome measures of health-related quality of life (HRQoL) are becoming increasingly necessary and relevant in the field of nutrition. However, quality of life questionnaires are seldom used in the nutrition field. We conducted a scientific literature search to find out the questionnaires used to determine the association between dietary habits and quality of life. A total of 13 studies were eligible for inclusion. Across these studies the short form-36, a generic (non-disease specific) HRQoL measurement instrument was the most widely used. However, generic measures may have limited content validity in the context of dietary habits interventions. We recommend additional contextual diet-specific HRQoL measures are also needed for evaluating the impact of diet habits on daily life functioning and well-being. PMID- 26005422 TI - Structural determinants of criticality in biological networks. AB - Many adaptive evolutionary systems display spatial and temporal features, such as long-range correlations, typically associated with the critical point of a phase transition in statistical physics. Empirical and theoretical studies suggest that operating near criticality enhances the functionality of biological networks, such as brain and gene networks, in terms for instance of information processing, robustness, and evolvability. While previous studies have explained criticality with specific system features, we still lack a general theory of critical behavior in biological systems. Here we look at this problem from the complex systems perspective, since in principle all critical biological circuits have in common the fact that their internal organization can be described as a complex network. An important question is how self-similar structure influences self similar dynamics. Modularity and heterogeneity, for instance, affect the location of critical points and can be used to tune the system toward criticality. We review and discuss recent studies on the criticality of neuronal and genetic networks, and discuss the implications of network theory when assessing the evolutionary features of criticality. PMID- 26005421 TI - Multipotent stem cells of the heart-do they have therapeutic promise? AB - The last decade has brought a comprehensive change in our view of cardiac remodeling processes under both physiological and pathological conditions, and cardiac stem cells have become important new players in the general mainframe of cardiac homeostasis. Different types of cardiac stem cells show different capacities for differentiation into the three major cardiac lineages: myocytes, endothelial cells and smooth muscle cells. Physiologically, cardiac stem cells contribute to cardiac homeostasis through continual cellular turnover. Pathologically, these cells exhibit a high level of proliferative activity in an apparent attempt to repair acute cardiac injury, indicating that these cells possess (albeit limited) regenerative potential. In addition to cardiac stem cells, mesenchymal stem cells represent another multipotent cell population in the heart; these cells are located in regions near pericytes and exhibit regenerative, angiogenic, antiapoptotic, and immunosuppressive properties. The discovery of these resident cardiac stem cells was followed by a number of experimental studies in animal models of cardiomyopathies, in which cardiac stem cells were tested as a therapeutic option to overcome the limited transdifferentiating potential of hematopoietic or mesenchymal stem cells derived from bone marrow. The promising results of these studies prompted clinical studies of the role of these cells, which have demonstrated the safety and practicability of cellular therapies for the treatment of heart disease. However, questions remain regarding this new therapeutic approach. Thus, the aim of the present review was to discuss the multitude of different cardiac stem cells that have been identified, their possible functional roles in the cardiac regenerative process, and their potential therapeutic uses in treating cardiac diseases. PMID- 26005423 TI - Effectiveness of the workshop "adolescent depression: what can schools do?". AB - INTRODUCTION: Adolescent depression is associated with serious consequences. School staff is in a unique position to screen and refer adolescents with depression in a timely manner, and can collaborate with healthcare teams to assist in the proper management of the disease. The objective of this paper is to describe the results of a workshop that aims to improve the knowledge of adolescent depression among school staff. MATERIALS AND METHODS: This was a single-arm trial with a pre-post design. Six workshops were conducted in four cities in Chile. Each workshop lasted 4 h. Participatory methodology was used. A 26-item knowledge questionnaire about adolescent depression, with the alternatives "I agree," "I disagree," and "I don't know," was administered to the participants, before and after the workshop. RESULTS: A total of 152 people participated in the trial. Of these, 74.3% were female, and 44.7% were school psychologists, 25.0%, teachers, 17.8%, school counselors, and 5.3%, social workers. On average, there were 69.6% (SD 21.3) correct responses on the initial test, and 91.8% (SD 8.0) on the final test. All items had an increase of correct answers and a decrease of "don't know" answers. There were notable increases of correct responses on statements dealing with myths: "Antidepressants for the treatment of depression in adolescents must be avoided because they produce dependence" (59-96%), and "Depression in adolescence is better defined as a weakness of character than as a disease" (75-95%). School psychologists scored higher than the other participants on the questionnaire both before and after the workshop. CONCLUSION: The workshop: "Adolescent depression: What can schools do?" can improve school staff knowledge of this topic, especially aiding to dispel myths regarding the disease and its treatment. This can help bring about timely case detection and improved collaboration with health team for proper handling of adolescent depression. PMID- 26005425 TI - The affect of vision and compassion upon role factors in physician leadership. AB - The career path for many professionals is often into a leadership role, yet many professionals do not have the competencies or inclination to lead. This study explores physician leaders as a representative group of professionals. While there have been many efforts at understanding the characteristics of effective physician leaders, a greater understanding is needed on the nature of physician leadership. The largest healthcare organization for physician leaders in the United States was surveyed to gain a greater understanding of the nature of leadership. Partial Lease Squares (PLS) was used to analyze results from 677 online surveys to understand the causal relationship of role conflict and role endorsement to participation. The findings reveal the mediating influence that positivity exerts upon participation, and offers health care leaders an opportunity to increase understanding of the social identification process that leads a higher level of professional participation, which may increase effectiveness for physicians in leadership. PMID- 26005426 TI - An early sex difference in the relation between mental rotation and object preference. AB - Accumulating evidence suggests that males outperform females on mental rotation tasks as early as infancy. Sex differences in object preference have also been shown to emerge early in development and precede sex-typed play in childhood. Although research with adults and older children is suggestive of a relationship between play preferences and visuospatial abilities, including mental rotation, little is known about the developmental origins of this relationship. The present study compared mental rotation ability and object preference in 6- to 13-month old infants. We used a novel paradigm to examine individual differences in infants' mental rotation abilities as well as their differential preference for one of two sex-typed objects. A sex difference was found on both tasks, with boys showing an advantage in performance on the mental rotation task and exhibiting greater visual attention to the male-typed object (i.e., a toy truck) than to the female-typed object (i.e., a doll) in comparison to girls. Moreover, we found a relation between mental rotation and object preference that varied by sex. Greater visual interest in the male-typed object was related to greater mental rotation performance in boys, but not in girls. Possible explanations related to perceptual biases, prenatal androgen exposure, and experiential influences for this sex difference are discussed. PMID- 26005424 TI - Gene-environment interaction in major depression: focus on experience-dependent biological systems. AB - Major depressive disorder (MDD) is a multifactorial and polygenic disorder, where multiple and partially overlapping sets of susceptibility genes interact each other and with the environment, predisposing individuals to the development of the illness. Thus, MDD results from a complex interplay of vulnerability genes and environmental factors that act cumulatively throughout individual's lifetime. Among these environmental factors, stressful life experiences, especially those occurring early in life, have been suggested to exert a crucial impact on brain development, leading to permanent functional changes that may contribute to lifelong risk for mental health outcomes. In this review, we will discuss how genetic variants (polymorphisms, SNPs) within genes operating in neurobiological systems that mediate stress response and synaptic plasticity, can impact, by themselves, the vulnerability risk for MDD; we will also consider how this MDD risk can be further modulated when gene * environment interaction is taken into account. Finally, we will discuss the role of epigenetic mechanisms, and in particular of DNA methylation and miRNAs expression changes, in mediating the effect of the stress on the vulnerability risk to develop MDD. Taken together, we aim to underlie the role of genetic and epigenetic processes involved in stress- and neuroplasticity-related biological systems on the development of MDD after exposure to early life stress, thereby building the basis for future research and clinical interventions. PMID- 26005427 TI - An other-race effect for configural and featural processing of faces: upper and lower face regions play different roles. AB - We examined whether Asian individuals would show differential sensitivity to configural vs. featural changes to own- and other-race faces and whether such sensitivity would depend on whether the changes occurred in the upper vs. lower regions of the faces. We systematically varied the size of key facial features (eyes and mouth) of own-race Asian faces and other-race Caucasian faces, and the configuration (spacing) between the eyes and between the nose and mouth of the two types of faces. Results revealed that the other-race effect (ORE) is more pronounced when featural and configural spacing changes are in the upper region than in the lower region of the face. These findings reveal that information from the upper vs. lower region of the face contributes differentially to the ORE in face processing, and that processing of face race is influenced more by information location (i.e., upper vs. lower) than by information type (i.e., configural vs. featural). PMID- 26005428 TI - Juvenile zebra finches learn the underlying structural regularities of their fathers' song. AB - Natural behaviors, such as foraging, tool use, social interaction, birdsong, and language, exhibit branching sequential structure. Such structure should be learnable if it can be inferred from the statistics of early experience. We report that juvenile zebra finches learn such sequential structure in song. Song learning in finches has been extensively studied, and it is generally believed that young males acquire song by imitating tutors (Zann, 1996). Variability in the order of elements in an individual's mature song occurs, but the degree to which variation in a zebra finch's song follows statistical regularities has not been quantified, as it has typically been dismissed as production error (Sturdy et al., 1999). Allowing for the possibility that such variation in song is non random and learnable, we applied a novel analytical approach, based on graph structured finite-state grammars, to each individual's full corpus of renditions of songs. This method does not assume syllable-level correspondence between individuals. We find that song variation can be described by probabilistic finite state graph grammars that are individually distinct, and that the graphs of juveniles are more similar to those of their fathers than to those of other adult males. This grammatical learning is a new parallel between birdsong and language. Our method can be applied across species and contexts to analyze complex variable learned behaviors, as distinct as foraging, tool use, and language. PMID- 26005429 TI - Commentary: Short-term group schema therapy for mixed personality disorders: an introduction to the treatment protocol. PMID- 26005430 TI - Audiovisual integration of emotional signals from others' social interactions. AB - Audiovisual perception of emotions has been typically examined using displays of a solitary character (e.g., the face-voice and/or body-sound of one actor). However, in real life humans often face more complex multisensory social situations, involving more than one person. Here we ask if the audiovisual facilitation in emotion recognition previously found in simpler social situations extends to more complex and ecological situations. Stimuli consisting of the biological motion and voice of two interacting agents were used in two experiments. In Experiment 1, participants were presented with visual, auditory, auditory filtered/noisy, and audiovisual congruent and incongruent clips. We asked participants to judge whether the two agents were interacting happily or angrily. In Experiment 2, another group of participants repeated the same task, as in Experiment 1, while trying to ignore either the visual or the auditory information. The findings from both experiments indicate that when the reliability of the auditory cue was decreased participants weighted more the visual cue in their emotional judgments. This in turn translated in increased emotion recognition accuracy for the multisensory condition. Our findings thus point to a common mechanism of multisensory integration of emotional signals irrespective of social stimulus complexity. PMID- 26005431 TI - The future of health care: going to the dogs? PMID- 26005432 TI - Thrombolysis-related intracerebral hemorrhage and cerebral amyloid angiopathy: accumulating evidence. PMID- 26005433 TI - Shades of brown: a model for thermogenic fat. AB - Brown adipose tissue (BAT) is specialized to burn fuels to perform thermogenesis in defense of body temperature against cold. Recent discovery of metabolically active and relevant amounts of BAT in adult humans have made it a potentially attractive target for development of anti-obesity therapeutics. There are two types of brown adipocytes: classical brown adipocytes and brown adipocyte-like cells, so-called beige/brite cells, which arise in white adipose tissue in response to cold and hormonal stimuli. These cells may derive from distinct origins, and while functionally similar, have different gene signatures. Here, we highlight recent advances in the understanding of brown and beige/brite adipocytes as well as transcriptional regulation for development and function of murine brown and beige/brite adipocytes focusing on EBF2, IRF4, and ZFP516, in addition to PRDM16 as a coregulator. We also discuss hormonal regulation of brown and beige/brite adipocytes including several factors secreted from various tissues, including BMP7, FGF21, and irisin, as well as those from BAT itself, such as Nrg4 and adenosine. PMID- 26005434 TI - The anti-Candida activity by Ancillary Proteins of an Enterococcus faecium strain. AB - An antimycotic activity toward seven strains of Candida albicans was demonstrated erstwhile by a wild-type Enterococcus faecium isolated from a penguin rookery of the Antarctic region. In the present study the antimicrobial principle was purified by ion exchange and gel permeation chromatography and further was analyzed by LC-ESI-MS/MS. In the purification steps, the dialyzed concentrate and ion exchange fractions inhibited C. albicans MTCC 3958, 183, and SC 5314. However, the gel filtration purified fractions inhibited MTCC 3958 and 183. The data obtained from the LC-ESI-MS/MS indicate that the antimicrobial activity of the anti-Candida protein produced by E. faecium is facilitated by Sag A/Bb for the binding of the indicator organism's cell membrane. Partial N-terminal sequence revealed 12 N-terminal amino acid residues and its analysis shown that it belongs to the LysM motif. The nucleotide sequence of PCR-amplified product could detect 574 nucleotides of the LysM gene responsible for binding to chitin of the cell wall of Candida sp. PMID- 26005435 TI - Cropping systems modulate the rate and magnitude of soil microbial autotrophic CO2 fixation in soil. AB - The effect of different cropping systems on CO2 fixation by soil microorganisms was studied by comparing soils from three exemplary cropping systems after 10 years of agricultural practice. Studied cropping systems included: continuous cropping of paddy rice (rice-rice), rotation of paddy rice and rapeseed (rice rapeseed), and rotated cropping of rapeseed and corn (rapeseed-corn). Soils from different cropping systems were incubated with continuous (14)C-CO2 labeling for 110 days. The CO2-fixing bacterial communities were investigated by analyzing the cbbL gene encoding ribulose-1,5-bisphosphate carboxylase oxygenase (RubisCO). Abundance, diversity and activity of cbbL-carrying bacteria were analyzed by quantitative PCR, cbbL clone libraries and enzyme assays. After 110 days incubation, substantial amounts of (14)C-CO2 were incorporated into soil organic carbon ((14)C-SOC) and microbial biomass carbon ((14)C-MBC). Rice-rice rotated soil showed stronger incorporation rates when looking at (14)C-SOC and (14)C-MBC contents. These differences in incorporation rates were also reflected by determined RubisCO activities. (14)C-MBC, cbbL gene abundances and RubisCO activity were found to correlate significantly with (14)C-SOC, indicating cbbL carrying bacteria to be key players for CO2 fixation in these soils. The analysis of clone libraries revealed distinct cbbL-carrying bacterial communities for the individual soils analyzed. Most of the identified operational taxonomic units (OTU) were related to Nitrobacter hamburgensis, Methylibium petroleiphilum, Rhodoblastus acidophilus, Bradyrhizobium, Cupriavidus metallidurans, Rubrivivax, Burkholderia, Stappia, and Thiobacillus thiophilus. OTUs related to Rubrivivax gelatinosus were specific for rice-rice soil. OTUs linked to Methylibium petroleiphilum were exclusively found in rice-rapeseed soil. Observed differences could be linked to differences in soil parameters such as SOC. We conclude that the long-term application of cropping systems alters underlying soil parameters, which in turn selects for distinct autotrophic communities. PMID- 26005436 TI - Multidimensional metrics for estimating phage abundance, distribution, gene density, and sequence coverage in metagenomes. AB - Phages are the most abundant biological entities on Earth and play major ecological roles, yet the current sequenced phage genomes do not adequately represent their diversity, and little is known about the abundance and distribution of these sequenced genomes in nature. Although the study of phage ecology has benefited tremendously from the emergence of metagenomic sequencing, a systematic survey of phage genes and genomes in various ecosystems is still lacking, and fundamental questions about phage biology, lifestyle, and ecology remain unanswered. To address these questions and improve comparative analysis of phages in different metagenomes, we screened a core set of publicly available metagenomic samples for sequences related to completely sequenced phages using the web tool, Phage Eco-Locator. We then adopted and deployed an array of mathematical and statistical metrics for a multidimensional estimation of the abundance and distribution of phage genes and genomes in various ecosystems. Experiments using those metrics individually showed their usefulness in emphasizing the pervasive, yet uneven, distribution of known phage sequences in environmental metagenomes. Using these metrics in combination allowed us to resolve phage genomes into clusters that correlated with their genotypes and taxonomic classes as well as their ecological properties. We propose adding this set of metrics to current metaviromic analysis pipelines, where they can provide insight regarding phage mosaicism, habitat specificity, and evolution. PMID- 26005437 TI - Impact of metabolism and growth phase on the hydrogen isotopic composition of microbial fatty acids. AB - Microorganisms are involved in all elemental cycles and therefore it is important to study their metabolism in the natural environment. A recent technique to investigate this is the hydrogen isotopic composition of microbial fatty acids, i.e., heterotrophic microorganisms produce fatty acids enriched in deuterium (D) while photoautotrophic and chemoautotrophic microorganisms produce fatty acids depleted in D compared to the water in the culture medium (growth water). However, the impact of factors other than metabolism have not been investigated. Here, we evaluate the impact of growth phase compared to metabolism on the hydrogen isotopic composition of fatty acids of different environmentally relevant microorganisms with heterotrophic, photoautotrophic and chemoautotrophic metabolisms. Fatty acids produced by heterotrophs are enriched in D compared to growth water with epsilonlipid/water between 82 and 3590/00 when grown on glucose or acetate, respectively. Photoautotrophs (epsilonlipid/water between -149 and 2640/00) and chemoautotrophs (epsilonlipid/water between -217 and -2750/00) produce fatty acids depleted in D. Fatty acids become, in general, enriched by between 4 and 460/00 with growth phase which is minor compared to the influence of metabolisms. Therefore, the D/H ratio of fatty acids is a promising tool to investigate community metabolisms in nature. PMID- 26005438 TI - Dendritic cells as Achilles' heel and Trojan horse during varicella zoster virus infection. AB - Varicella zoster virus (VZV), a human alphaherpesvirus, causes varicella and subsequently establishes latency within sensory nerve ganglia. Later in life VZV can reactivate to cause herpes zoster. A reduced frequency of VZV-specific T cells is strongly associated with herpes zoster illustrating that these immune cells are central to control latency. Dendritic cells (DCs) are required for the generation of VZV-specific T cells. However, DCs can also be infected in vitro and in vivo allowing VZV to evade the antiviral immune response. Thus, DCs represent the immune systems' Achilles heel. Uniquely among the human herpesviruses, VZV infects both DCs and T cells, and exploits both as Trojan horses. During primary infection VZV-infected DCs traffic to the draining lymph nodes and tonsils, where the virus is transferred to T cells. VZV-infected T cells subsequently spread infection throughout the body to give the typical varicella skin rash. The delicate interplay between VZV and DCs and its consequences for viral immune evasion and viral dissemination will be discussed in this article. PMID- 26005439 TI - Diversity of acid stress resistant variants of Listeria monocytogenes and the potential role of ribosomal protein S21 encoded by rpsU. AB - The dynamic response of microorganisms to environmental conditions depends on the behavior of individual cells within the population. Adverse environments can select for stable stress resistant subpopulations. In this study, we aimed to get more insight in the diversity within Listeria monocytogenes LO28 populations, and the genetic basis for the increased resistance of stable resistant fractions isolated after acid exposure. Phenotypic cluster analysis of 23 variants resulted in three clusters and four individual variants and revealed multiple-stress resistance, with both unique and overlapping features related to stress resistance, growth, motility, biofilm formation, and virulence indicators. A higher glutamate decarboxylase activity correlated with increased acid resistance. Whole genome sequencing revealed mutations in rpsU, encoding ribosomal protein S21 in the largest phenotypic cluster, while mutations in ctsR, which were previously shown to be responsible for increased resistance of heat and high hydrostatic pressure resistant variants, were not found in the acid resistant variants. This underlined that large population diversity exists within one L. monocytogenes strain and that different adverse conditions drive selection for different variants. The finding that acid stress selects for rpsU variants provides potential insights in the mechanisms underlying population diversity of L. monocytogenes. PMID- 26005440 TI - The nucleoid as a smart polymer. PMID- 26005441 TI - Immune responses of ducks infected with duck Tembusu virus. AB - Duck Tembusu virus (DTMUV) can cause serious disease in ducks, characterized by reduced egg production. Although the virus has been isolated and detection methods developed, the host immune responses to DTMUV infection are unclear. Therefore, we systematically examined the expression of immune-related genes and the viral distribution in DTMUV-infected ducks, using quantitative real-time PCR. Our results show that DTMUV replicates quickly in many tissues early in infection, with the highest viral titers in the spleen 1 day after infection. Rig 1, Mda5, and Tlr3 are involved in the host immune response to DTMUV, and the expression of proinflammatory cytokines (Il-1beta, -2, -6, Cxcl8) and antiviral proteins (Mx, Oas, etc.) are also upregulated early in infection. The expression of Il-6 increased most significantly in the tissues tested. The upregulation of Mhc-I was observed in the brain and spleen, but the expression of Mhc-II was upregulated in the brain and downregulated in the spleen. The expression of the interferons was also upregulated to different degrees in the spleen but that of the brain was various. Our study suggests that DTMUV replicates rapidly in various tissues and that the host immune responses are activated early in infection. However, the overexpression of cytokines may damage the host. These results extend our understanding of the immune responses of ducks to DTMUV infection, and provide insight into the pathogenesis of DTMUV attributable to host factors. PMID- 26005442 TI - Prevalence and mechanism of triazole resistance in Aspergillus fumigatus in a referral chest hospital in Delhi, India and an update of the situation in Asia. AB - Aspergillus fumigatus causes varied clinical syndromes ranging from colonization to deep infections. The mainstay of therapy of Aspergillus diseases is triazoles but several studies globally highlighted variable prevalence of triazole resistance, which hampers the management of aspergillosis. We studied the prevalence of resistance in clinical A. fumigatus isolates during 4 years in a referral Chest Hospital in Delhi, India and reviewed the scenario in Asia and the Middle East. Aspergillus species (n = 2117) were screened with selective plates for azole resistance. The isolates included 45.4% A. flavus, followed by 32.4% A. fumigatus, 15.6% Aspergillus species and 6.6% A. terreus. Azole resistance was found in only 12 (1.7%) A. fumigatus isolates. These triazole resistant A. fumigatus (TRAF) isolates were subjected to (a) calmodulin and beta tubulin gene sequencing (b) in vitro antifungal susceptibility testing against triazoles using CLSI M38-A2 (c) sequencing of cyp51A gene and real-time PCR assay for detection of mutations and (d) microsatellite typing of the resistant isolates. TRAF harbored TR34/L98H mutation in 10 (83.3%) isolates with a pan-azole resistant phenotype. Among the remaining two TRAF isolates, one had G54E and the other had three non-synonymous point mutations. The majority of patients were diagnosed as invasive aspergillosis followed by allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. The Indian TR34/L98H isolates had a unique genotype and were distinct from the Chinese, Middle East, and European TR34/L98H strains. This resistance mechanism has been linked to the use of fungicide azoles in agricultural practices in Europe as it has been mainly reported from azole naive patients. Reports published from Asia demonstrate the same environmental resistance mechanism in A. fumigatus isolates from two highly populated countries in Asia, i.e., China and India and also from the neighboring Middle East. PMID- 26005443 TI - Structural constraints and dynamics of bacterial cell wall architecture. AB - The peptidoglycan wall (PG) is a unique structure which confers physical strength and defined shape to bacteria. It consists of a net-like macromolecule of peptide interlinked glycan chains overlying the cell membrane. The structure and layout of the PG dictates that the wall has to be continuously modified as bacteria go through division, morphological differentiation, and adaptive responses. The PG is poorly known in structural terms. However, to understand morphogenesis a precise knowledge of glycan strand arrangement and of local effects of the different kinds of subunits is essential. The scarcity of data led to a conception of the PG as a regular, highly ordered structure which strongly influenced growth models. Here, we review the structure of the PG to define a more realistic conceptual framework. We discuss the consequences of the plasticity of murein architecture in morphogenesis and try to define a set of minimal structural constraints that must be fulfilled by any model to be compatible with present day information. PMID- 26005444 TI - Deciphering Human Cell-Autonomous Anti-HSV-1 Immunity in the Central Nervous System. AB - Herpes simplex virus 1 (HSV-1) is a common virus that can rarely invade the human central nervous system (CNS), causing devastating encephalitis. The permissiveness to HSV-1 of the various relevant cell types of the CNS, neurons, astrocytes, oligodendrocytes, and microglia cells, as well as their response to viral infection, has been extensively studied in humans and other animals. Nevertheless, human CNS cell-based models of anti-HSV-1 immunity are of particular importance, as responses to any given neurotropic virus may differ between humans and other animals. Human CNS neuron cell lines as well as primary human CNS neurons, astrocytes, and microglia cells cultured/isolated from embryos or cadavers, have enabled the study of cell-autonomous anti-HSV-1 immunity in vitro. However, the paucity of biological samples and their lack of purity have hindered progress in the field, which furthermore suffers from the absence of testable primary human oligodendrocytes. Recently, the authors have established a human induced pluripotent stem cells (hiPSCs)-based model of anti-HSV-1 immunity in neurons, oligodendrocyte precursor cells, astrocytes, and neural stem cells, which has widened the scope of possible in vitro studies while permitting in depth explorations. This mini-review summarizes the available data on human primary and iPSC-derived CNS cells for anti-HSV-1 immunity. The hiPSC-mediated study of anti-viral immunity in both healthy individuals and patients with viral encephalitis will be a powerful tool in dissecting the disease pathogenesis of CNS infections with HSV-1 and other neurotropic viruses. PMID- 26005445 TI - Transport, ultrastructural localization, and distribution of chemical forms of lead in radish (Raphanus sativus L.). AB - Lead (Pb), a ubiquitous but highly toxic heavy metal (HM), is harmful to human health through various pathways including by ingestion of contaminated vegetables. Radish is a worldwide root vegetable crop with significant health and nutritional benefits. However, little is known about Pb translocation and distribution within radish plants after its uptake by the roots. In this study, Pb stress was induced using Pb(NO3)2 in hydroponic culture, aiming to characterize the transport, ultrastructural localization, and distribution of chemical forms of Pb in different tissues of radish. The results showed that the majority of Pb (85.76-98.72%) was retained in underground organs including lateral roots, root heads and taproot skins, while a small proportion of Pb was absorbed by root flesh (0.44-1.56%) or transported to the shoot (1.28-14.24%). A large proportion of Pb (74.11-99.30%) was integrated with undissolved Pb oxalate, protein and pectates forming Pb-phosphate complexes. Moreover, a low-Pb accumulating line of radish showed a higher proportion of Pb in water-soluble form compared with a high-Pb-accumulating line. Subcellular distribution analysis showed that a large proportion of Pb was bound to cell wall fraction in lateral roots (71.08-80.40%) and taproot skin (46.22-77.94%), while the leaves and roots had 28.36-39.37% and 27.35-46.51% of Pb stored in the soluble fraction, respectively. Furthermore, transmission electron microscopy (TEM) revealed Pb precipitates in intercellular space, cell wall, plasma lemma and vacuoles. Fractionation results also showed the accumulation of Pb on the cell wall, intercellular space and vacuole, and low uptake of undissolved Pb oxalate, protein, pectates and Pb-phosphate complexes, which might be due to low transport efficiency and Pb tolerance of radish. These findings would provide insight into molecular mechanism of Pb uptake and translocation in radish and facilitate development of low-Pb-content cultivars in root vegetable crops. PMID- 26005446 TI - Growth, physiological, and biochemical responses of Camptotheca acuminata seedlings to different light environments. AB - Light intensity critically affects plant growth. Camptotheca acuminata is a light demanding species, but its optimum light intensity is not known. To investigate the response of C. acuminata seedlings to different light intensities, specifically 100% irradiance (PAR, 1500 +/- 30 MUmol m(-2) s(-1)), 75% irradiance, 50% irradiance, and 25% irradiance, a pot experiment was conducted to analyze growth parameters, photosynthetic pigments, gas exchange, chlorophyll fluorescence, stomatal structure and density, chloroplast ultrastructure, ROS concentrations, and antioxidant activities. Plants grown under 75% irradiance had significantly higher total biomass, seedling height, ground diameter, photosynthetic capacity, photochemical efficiency, and photochemical quenching than those grown under 100%, 25%, and 50% irradiance. Malondialdehyde (MDA) content, relative electrolyte conductivity (REC), superoxide anion (O(.-) 2) production, and peroxide (H2O2) content were lower under 75% irradiance. The less pronounced plant growth under 100% and 25% irradiance was associated with a decline in photosynthetic capacity and photochemical efficiency, with increases in the activity of specific antioxidants (i.e., superoxidase dismutase, peroxidase, and catalase), and with increases in MDA content and REC. Lower levels of irradiance were associated with significantly higher concentrations of chlorophyll (Chl) a and b and lower Chla/b ratios. Stomatal development was most pronounced under 75% irradiance. Modification of chloroplast development was found to be an important mechanism of responding to different light intensities in C. acuminata. The results indicated that 75% irradiance is optimal for the growth of C. acuminata seedlings. The improvement in C. acuminata growth under 75% irradiance was attributable to increased photosynthesis, less accumulation of ROS, and the maintenance of the stomatal and chloroplast structure. PMID- 26005447 TI - Integrative analysis of functional genomic annotations and sequencing data to identify rare causal variants via hierarchical modeling. AB - Identifying the small number of rare causal variants contributing to disease has been a major focus of investigation in recent years, but represents a formidable statistical challenge due to the rare frequencies with which these variants are observed. In this commentary we draw attention to a formal statistical framework, namely hierarchical modeling, to combine functional genomic annotations with sequencing data with the objective of enhancing our ability to identify rare causal variants. Using simulations we show that in all configurations studied, the hierarchical modeling approach has superior discriminatory ability compared to a recently proposed aggregate measure of deleteriousness, the Combined Annotation-Dependent Depletion (CADD) score, supporting our premise that aggregate functional genomic measures can more accurately identify causal variants when used in conjunction with sequencing data through a hierarchical modeling approach. PMID- 26005448 TI - Antimicrobial effect of zataria multiflora extract in comparison with chlorhexidine mouthwash on experimentally contaminated orthodontic elastomeric ligatures. AB - OBJECTIVES: Long-term use of orthodontic appliances and fixation ligatures creates a favorable environment for the accumulation of oral normal microflora and increases the risk of enamel demineralization and periodontal disease. The aim of this study was to compare the antimicrobial effects of Zataria Multiflora extract and 0.2% chlorhexidine (CHX) mouthwash on experimentally contaminated orthodontic elastomeric ligatures. MATERIALS AND METHODS: In this lab trial study, Iranian and foreign-made elastomeric ligatures were experimentally contaminated in Streptococcus mutans, Enterococcus faecalis and Candida albicans suspensions. Ligatures were then decontaminated using 0.2% CHX as the control, 0.5 mg/ml Zataria multiflora extract mouthwashes as the test and phosphate buffered saline (PBS) as the negative control for one hour. Antimicrobial properties of both solutions were evaluated by comparing the mean viable bacterial cell count on both rings after decontamination, using SPSS version 15 software. RESULTS: The mean viable bacterial cell count on Iranian ligatures was greater than that on foreign-made ligatures before disinfection (P=0.001), however this difference for C. albicans was not statistically significant (P=0.061). Chlorhexidine mouthwash completely eliminated all tested microorganisms attached to both elastomeric rings, but Zataria extract was only capable of completely eliminating C. albicans from both ligatures. Statistically significant differences were found in viable bacterial counts on both ligatures before and after disinfection with Zataria extract (P=0.0001). CONCLUSION: Zataria multiflora extract has antimicrobial properties and can be used for disinfection of elastomeric ligatures. In vivo studies are required to evaluate the efficacy of the incorporation of this herbal extract in mouthwashes for orthodontic patients. PMID- 26005449 TI - Remineralizing Effect of Child Formula Dentifrices on Artificial Enamel Caries Using a pH Cycling Model. AB - OBJECTIVES: Although fluoridated toothpastes are among the most accessible fluoride sources for caries prevention, their remineralization potential remains questionable. This study sought to compare the effects of 5 different child formula dentifrices on remineralization of artificial primary enamel caries using a pH cycling model. MATERIALS AND METHODS: Twenty sound primary canine teeth were immersed in demineralizing solution for 96 hours to produce 100MUm-deep artificial caries. The teeth were then longitudinally sectioned into 100-150 MUm thick slices and randomly divided into 5 groups and treated as follows: group A. Calcium phosphate toothpaste, group B. Pooneh children's toothpaste, group C. Biotin toothpaste, group D. Crest children's toothpaste and group E. Darougar children's toothpaste. The specimens underwent a pH cycling model for 10 days. The degree of demineralization before and after treatment and its changes were evaluated under a polarized light microscope and a stereomicroscope and data were statistically analyzed using repeated measures ANOVA and post-hoc test. RESULTS: Stereomicroscopic analysis showed that only group C had a significant difference with other groups (P<0.001) and no significant differences were found between the remaining groups (P>0.05). Polarized light microscopic analysis revealed that in addition to group C, a significant difference was detected between groups A and B (P=0.02) and calcium phosphate toothpaste showed higher efficacy. CONCLUSION: All the understudy toothpastes had remineralizing effect but calcium phosphate children's toothpaste had the highest and biotin toothpaste had the lowest efficacy. PMID- 26005450 TI - Effect of tooth preparation on microleakage of stainless steel crowns placed on primary mandibular first molars with reduced mesiodistal dimension. AB - OBJECTIVES: Incomplete adaptation of stainless steel crown margins leads to microleakage. The aim of this study was to evaluate the effect of tooth preparation on microleakage of stainless steel crowns (SSCs) placed on mesiodistally reduced primary mandibular first molars. MATERIALS AND METHODS: In this In vitro study, 60 primary mandibular first molars with reduced mesiodistal dimension were selected. Pulp cavities were filled with amalgam and occlusal surfaces were reduced. The samples were randomly divided into two groups (groups P and BLP). Standard preparation was done in group P with only proximal reduction. In group BLP, after reducing the proximal undercuts, buccal and lingual surfaces were slightly reduced. Occlusal one-third of the buccal surfaces was beveled in both groups. Then, the SSCs of the primary maxillary and mandibular first molars were fitted and cemented in P and BLP groups, respectively. After immersing the samples into deionized water, thermo-cycling, and immersion in 2% basic fuchsin, the samples were sectioned buccolingually. The mesial halves were evaluated microscopically for microleakage in both buccal and lingual margins. Data were analyzed using Mann-Whitney U test in SPSS 19 at the significant level of 0.05. RESULTS: There was a significant difference in microleakage of the buccal margin (P=0.003); whereas, the difference observed in the lingual margin was not significant (P=0.54). CONCLUSION: We suggest reduction of buccal and lingual surfaces of mesiodistally reduced primary mandibular first molars and placing lower (mandibular) crowns. PMID- 26005451 TI - Effect of chloroform, eucalyptol and orange oil solvents on the microhardness of human root dentin. AB - OBJECTIVES: This study aimed to assess the effect of chloroform, eucalyptol and orange oil solvents on the microhardness of human root dentin. MATERIALS AND METHODS: Sixty-eight single-rooted single-canal extracted human premolar teeth were used. Tooth crowns were separated from the roots at the cementoenamel junction (CEJ). Roots were buccolingually sectioned into mesial and distal halves. Specimens were randomly divided into 5 groups, with 20 teeth in each solvent group and 4 teeth in each control group. Primary microhardness of specimens was measured using Vickers microhardness tester. Specimens were exposed to solvents for 15 minutes and were subjected to microhardness testing again. Data were recorded and analyzed using repeated measure ANOVA. RESULTS: No significant difference was found in dentin microhardness before and after exposure to solvents in any of the orange oil, eucalyptol, chloroform or saline groups (P=0.727). None of the experimental groups showed any significant difference in terms of dentin microhardness reduction (P=0.99) and had no significant difference with the negative control group. CONCLUSION: This study showed that chloroform, eucalyptol and orange oil as gutta percha solvents did not decrease the microhardness of root dentin. Thus, none of the mentioned solvents has any superiority over the others in terms of affecting dentin properties. PMID- 26005452 TI - Histologic evaluation of bone healing capacity following application of inorganic bovine bone and a new allograft material in rabbit calvaria. AB - OBJECTIVES: Considering the importance of bone augmentation prior to implant placement in order to obtain adequate bone quality and quantity, many studies have been conducted to evaluate different techniques and materials regarding new bone formation. In this study, we investigated the bone healing capacity of two different materials deproteinized bovine bone mineral (DBBM with the trade name of Bio-Oss) and demineralized freeze-dried bone allograft (DFDBA with the trade name of DynaGraft). MATERIALS AND METHODS: This randomized blinded prospective study was conducted on twelve New Zealand white rabbits. Three cranial defects with an equal diameter were created on their calvarium. Subsequently, they were distributed into three groups: 1. The control group without any treatment; 2. The Bio-Oss group; 3. The DynaGraft group. After 30 days, the animals were sacrificed for histologic and histomorphometric analysis. RESULTS: Substantial new bone formation was observed in both groups. DynaGraft: 56/1 % +/- 15/1 and Bio-Oss: 53/55 % +/- 13/5 compared to the control group: 28/6 % +/- 11/2. All groups showed slight inflammation and a small amount of residual biomaterial was observed. CONCLUSION: Considerable new bone formation was demonstrated in both DynaGraft and Bio-Oss groups in comparison with the control group. Both materials are considered biocompatible regarding the negligible foreign body reaction. PMID- 26005454 TI - Effect of fluoride on nickel-titanium and stainless steel orthodontic archwires: an in-vitro study. AB - OBJECTIVES: The commonly used Nickel-Titanium (NiTi) archwires in orthodontic treatment are often exposed to fluoride-containing mouthwashes. The aim of this in-vitro study was to evaluate and compare the corrosion resistance of three commercially available NiTi archwires exposed to 0.05 wt% and 0.2 wt% fluoride mouthwashes. MATERIALS AND METHODS: Three different types of NiTi archwires, 0.016" in diameter, from Dentaurum, Global, and GAC, and a stainless steel archwire from Dentaurum were examined to assess their corrosion resistance in Fusayama-Meyer artificial saliva and in two other artificial saliva containing 0.05 wt% and 0.2 wt% sodium fluoride (NaF). After the primary setup of wires, they were tested by potentiodynamic and potentiostatic polarization and corrosion potential/time analyses. Their surfaces were evaluated using a scanning electronic microscope (SEM). RESULTS: The results showed that all the wires were passive in artificial saliva. In contrast, by adding fluoride ions to the solution, the decrease in the archwires' corrosion resistance was in direct proportion to the increase in fluoride concentration. CONCLUSION: The NiTi wires experienced deterioration of their corrosion properties under the effect of fluoride but not as much as the stainless steel archwires. PMID- 26005453 TI - Effect of dietary ascorbic Acid on osteogenesis of expanding midpalatal suture in rats. AB - OBJECTIVES: After maxillary expansion, a long period of retention is necessary to prevent early relapse. Therefore, it is beneficial to accelerate bone formation in the expanding midpalatal suture to reduce relapse. This study was designed to evaluate the effect of dietary vitamin C on osteogenesis of rat midpalatal suture during expansion. MATERIALS AND METHODS: Fifty-four male Wistar rats were randomly divided into three groups, each with a control and an experimental subgroup. An open-loop spring was bonded to maxillary incisors of each animal to expand the premaxillary suture. Experimental groups received dietary vitamin C in their water. The rats in the three groups were sacrificed at three, nine or 17 day intervals after bonding the spring. Then, the premaxilla was dissected and sections were made and stained with hematoxylin and eosin and osteopontin marker. Osteoblasts and osteoclasts were counted in the suture. Two-way ANOVA and the Mann-Whitney-U test were used for analyzing the data. RESULTS: After three days, the number of osteoblasts was significantly higher in the vitamin C group but after nine days it was significantly higher in the control group and after seventeen days there were no significant differences between the groups. Osteoclast counts were not significantly different between vitamin C and control groups. CONCLUSION: Vitamin C had a positive effect on osteogenesis at the beginning of bone formation in the expanding suture, but after nine days it had a negative effect on suture osteogenesis in rats. PMID- 26005455 TI - Efficacy of a Newly Designed Cephalometric Analysis Software for McNamara Analysis in Comparison with Dolphin Software. AB - OBJECTIVES: Cephalometric norms of McNamara analysis have been studied in various populations due to their optimal efficiency. Dolphin cephalometric software greatly enhances the conduction of this analysis for orthodontic measurements. However, Dolphin is very expensive and cannot be afforded by many clinicians in developing countries. A suitable alternative software program in Farsi/English will greatly help Farsi speaking clinicians. The present study aimed to develop an affordable Iranian cephalometric analysis software program and compare it with Dolphin, the standard software available on the market for cephalometric analysis. MATERIALS AND METHODS: In this diagnostic, descriptive study, 150 lateral cephalograms of normal occlusion individuals were selected in Mashhad and Qazvin, two major cities of Iran mainly populated with Fars ethnicity, the main Iranian ethnic group. After tracing the cephalograms, the McNamara analysis standards were measured both with Dolphin and the new software. The cephalometric software was designed using Microsoft Visual C++ program in Windows XP. Measurements made with the new software were compared with those of Dolphin software on both series of cephalograms. The validity and reliability were tested using intra-class correlation coefficient. RESULTS: Calculations showed a very high correlation between the results of the Iranian cephalometric analysis software and Dolphin. This confirms the validity and optimal efficacy of the newly designed software (ICC 0.570-1.0). CONCLUSION: According to our results, the newly designed software has acceptable validity and reliability and can be used for orthodontic diagnosis, treatment planning and assessment of treatment outcome. PMID- 26005456 TI - Simple Method for Converting Conventional Face-bow to Postural Face-bow for Recording the Relationship of Maxilla Relative to the Temporomandibular Joint. AB - A fundamental assumption in prosthetic dentistry is that the axis-orbital plane will usually be parallel to the horizontal reference plane. Most articulator systems have incorporated this concept into their designs and use orbitale as the anterior reference point for transferring the vertical position of the maxilla to the articulator. Clinical observations of Cantonese patients suggest that in some individuals the Frankfort plane may not be horizontal, thus the orientation of the casts in the articulator is incorrect with respect to the horizontal plane. The purpose of this study was to introduce a simple method for converting the conventional face-bow to postural face-bow to reproduce the orientation of the occlusal plane relative to the true horizontal plane with the patient in Natural Head Posture (NHP). PMID- 26005457 TI - Calcifying epithelial odontogenic tumor: report of a recurrent destructive case with review of literature. AB - Calcifying epithelial odontogenic tumor (CEOT) is an uncommon odontogenic tumor with well-known histopathological features and a challenging treatment plan. Although some investigators advocate conservative approach as the treatment of choice, others believe in radical surgical excision to avoid recurrence or malignant transformation. The main objective of this case report is presenting an unusual destructive recurrence of CEOT after 8 years in a 34-year-old woman, and discussing an effective treatment plan for this tumor. PMID- 26005459 TI - Shear bond strength of one-step self-etch adhesives: pH influence. AB - BACKGROUND: The aim of this study was to compare the shear bond strength of four one-step self-etch adhesives with different pH values to enamel and dentin. MATERIALS AND METHODS: In this in vitro study, 200 bovine permanent mandibular incisors were used. Four one-step self-etch adhesives with different pH values were tested both on enamel and on dentin: AdperTM Easy Bond Self-Etch Adhesive (pH = 0.8-1), Futurabond NR (pH=2), G-aenial Bond (pH = 1.5), Clearfil S(3) Bond (pH = 2.7). After adhesive systems application, a nanohybrid composite resin was inserted into the bonded surface. The specimens were placed in a universal testing machine. The shear bond strength was performed at a cross-head speed of 1 mm/min until the sample rupture. The shear bond strength values (MPa) of the different groups were compared with analysis of variance after that Kolmogorov and Smirnov tests were applied to assess normality of distributions. P < 0.05 was considered as significant. RESULTS: In enamel shear bond strength, the highest shear bond strength values were reported with Futurabond NR (P < 0.01); however, no significant differences were found with Clearfil S(3) Bond. The others adhesive systems showed lower shear bond strength values with significant differences between them (P < 0.05). When comparing the dentin shear bond strength, the lowest shear bond strength values were reported with Clearfil S(3) Bond (P < 0.05), while there were no significant differences among the other three products (P > 0.05). CONCLUSION: The pH values of adhesive systems did not influence significantly their shear bond strength to enamel or dentin. PMID- 26005458 TI - Oral manifestations in transplant patients. AB - Organ transplantation is a widely undertaken procedure and has become an important alternative for the treatment of different end-stage organ diseases that previously had a poor prognosis. The field of organ transplant and hematopoietic stem cell transplant is developing rapidly. The increase in the number of transplant recipients also has an impact on oral and dental services. Most of the oral problems develop as a direct consequence of drug-induced immunosuppression or the procedure itself. These patients may present with oral complaints due to infections or mucosal lesions. Such lesions should be identified, diagnosed, and treated. New treatment strategies permit continuous adaptation of oral care regimens to the changing scope of oral complications. The aim of this review is to analyze those oral manifestations and to discuss the related literature. PMID- 26005461 TI - Marginal microleakage of a resin-modified glass-ionomer restoration: Interaction effect of delayed light activation and surface pretreatment. AB - BACKGROUND: Despite widespread clinical uses of resin-modified glass-ionomers (RMGIs), their sealing ability is still a concern. This study evaluated the effect of delayed light activation (DLA) of RMGI on marginal sealing in differently pretreated cavities. MATERIALS AND METHODS: In this in vitro study, two standardized Class V cavities were prepared on the buccal and lingual surfaces of 56 sound maxillary premolars at the cementoenamel junction. The cavities were randomly divided into eight equal groups. In groups 1-4 (immediate light activation [ILA]), no pretreatment (negative control [NC]) and three surface pretreatments were used, respectively as follows: Cavity conditioner, Vitremer primer, cavity conditioner plus and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP). Fuji II LC (GC, Japan) was prepared and placed in the cavities and immediately light-cured according to manufacturer's instructions. In groups 5-8 (DLA), the same pretreatments were applied, respectively. After placing Fuji II LC in the cavities, the restorations were light-cured after a 3-min delay. After finishing the restorations, the specimens were placed in water for 1-week and thermocycled. Microleakage scores were determined using the dye penetration technique. Kruskal-Wallis test and Mann Whitney U-test were used to analyze the obtained data (alpha = 0.05). RESULTS: At the dentin margins, DLA resulted in a lower microleakage for no treatment (NC), cavity conditioner and cavity conditioner plus ACP-CPP pretreatments groups (P <= 0.004); however, no difference was observed for Vitremer group (P > 0.05). At the enamel margins, no difference was observed between DLA and ILA for all groups (P > 0.05); only NC group exhibited a lower microleakage in case of DLA (P = 0.007). CONCLUSION: Delayed light activation of RMGI may lead to different effects on marginal sealing, depending on pretreatment procedures used in the cavity. It might improve dentin sealing when no treatment and conditioner alone or with CCP ACP is used. PMID- 26005460 TI - Comparative evaluation of low-level laser and systemic steroid therapy in adjuvant-enhanced arthritis of rat temporomandibular joint: A histological study. AB - BACKGROUND: Low-level laser therapy (LLLT) has shown a promising effect in ameliorating symptoms of rheumatoid arthritis (RA). The aim of this investigation was to compare the early and late anti-inflammatory effects of LLLT and betamethasone in RA. MATERIALS AND METHODS: In this animal experimental study, after inducing a model of RA in temporomandibular joint (TMJ) of 37 Wistar rats using adjuvant injection, they were randomly distributed into three experimental groups of 12 animals each: (1) LLLT group; (2) steroid group which received a single dose of betamethasone systemically; and (3) positive control group, which did not receive any treatment. One rat served as the negative control. Half of the animals in all the experimental groups were sacrificed on the 21(st) day after RA induction (early phase), and the other half were sacrificed 2 weeks later (late phase). Then, the severity of TMJ inflammation was assessed histologically in each group on a semi-quantitative scale. Kruskal-Wallis and Mann-Whitney tests were used to compare differences (alpha = 0.05). RESULTS: The LLLT and steroid groups showed significantly (P < 0.05) lower inflammation mean scores in both early (5.66 [+/-1.86] and 1.66 [+/-1.21], respectively) and late phases of evaluation (1.16 [+/-1.47] and 6.50 [+/-1.04], respectively) compared to positive control group in early and late stages of assessment (11.66 [+/-3.50] and 8.66 [+/-1.36], respectively). However, the best results (P < 0.005) were achieved in early phase of the steroid group as well as late phase of the LLLT group. CONCLUSION: Within limitations of this study, it may be concluded that LLLT method has a long-term promising effect on reducing inflammation severity of TMJ similar to betamethasone in earlier stages. PMID- 26005462 TI - The effects of aging process and preactivation on mechanical properties of nickel titanium closed coil springs. AB - BACKGROUND: The most favorable feature of nickel-titanium (Ni-Ti) alloys in orthodontics is producing constant forces in a wide deformation range. Ni-Ti closed coils produce compressive strength and can be used for several purposes such as space closure. The aim of this study was to evaluate the effects of the aging process (temperature changes and prolonged strain) on Ni-Ti closed coils and to assess the effects of preactivation on forces generated by these coils. MATERIALS AND METHODS: A total of 60 Ni-Ti closed coils (G&H Wire Co., Indiana, USA) were divided into four groups (n = 15). Two groups were kept in room temperature and two were incubated in 37 degrees C in normal saline for 45 days. All the samples were extended to 30% of their original length. One group of the incubated coils and one group of room temperature coils were preactivated the same amount of 30%. The incubated groups also received 1000 thermocycles on days 22 and 45. The unloading forces were measured by a universal testing machine on days 0, 22 and 45. The data were analyzed using SPSS. Significance was set at 0.05. RESULTS: The unloading forces of the Ni-Ti closed coils was not affected by prolonged heat and moisture either in preactivated groups (P = 0.8) or the nonpreactivated groups (P = 0.6). Furthermore, preactivation had no significant effect on the unloading forces of Ni-Ti closed coils (P = 0.7). CONCLUSION: Within the limitations of this study, both aging process and preactivation do not affect on mechanical properties of nickel-titanium closed coil springs. Preactivation had no effect on the forces generated by Ni-Ti closed coils. PMID- 26005463 TI - Estimation of malignant transformation rate in cases of oral epithelial dysplasia and lichen planus using immunohistochemical expression of Ki-67, p53, BCL-2, and BAX markers. AB - BACKGROUND: The issue of a possible malignant transformation in the lesions like epithelial dysplasia and oral lichen planus (OLP) is a matter of serious controversy. The purpose of this study was to suggest the malignant transformation rate in OLP and oral epithelial dysplasia (OED) by using immunohistochemical expression of the tumor markers Ki-67, p53, BCL-2, and BAX. MATERIALS AND METHODS: This was a cross-sectional study carried out among 70 samples, including 10 samples from normal healthy mucosa categorized into Group 1, Group 2 (30 OLP), and Group 3 (30 OED) samples. Five sections (4 MUm thick) were obtained and stained with monoclonal antibodies such as Ki-67, p53, BCL-2, and BAX and analyzed for number of positive cells and also for intensity of staining. Statistical analysis was done using Mann-Whitney U-test (P < 0.05). RESULTS: Significant results were found only for expressions of Ki-67, p53, BCL-2 markers in both study groups (P < 0.05). In these groups, the intensity of staining was mostly mild to moderate for all studied tumor markers. In this study, subjects with an average positive IHC expression of Ki-67, p53, BCL-2, and BAX markers in normal mucosa was about 22.5%, which was significantly lower when compared with OLP (54.9%) and OED (64.9%). CONCLUSION: The high propensity for malignant transformation in OED followed by OLP suggests that a wide range of inherent and extrinsic factors contribute to the disease progression and malignant transformation. PMID- 26005464 TI - The effect of multiple processing and re-use on orthodontic mini-screw torque values. AB - BACKGROUND: Reusing orthodontic mini-screws would reduce treatment cost and lead to more use of mini-screws and improvement of orthodontic treatments. This study has assessed the effects of reprocessing and reusing the titanium mini-screws on their maximum insertion, removal and fracture torque (FT). MATERIALS AND METHODS: In this experimental study, 20 titanium mini-screws (1.6-mm * 8-mm) were randomly divided into two equal groups. In the test group, the screws were first sterilized by autoclave and then their FT was assessed. In the control group, FT was assessed after 5 times of insertion, cleaning, processing (37% phosphoric acid for 10 min, 5.25% sodium hypochlorite for 30 min) and sterilizing with autoclave. The maximum insertion and removal torque values were compared using the repeated measure ANOVA and the FT data were analyzed by the t-test. The data were analyzed using the SPSS software (version 13.0) and the significance was set on 0.05. RESULTS: The paired t-test for maximum insertion torque (MIT) showed that MIT1 was significantly lower than other MIT values (P = 0.02) and also MIT2 was significantly higher than MIT5 (P = 0.01), but other MIT values had no significant differences. The paired t-test for maximum removal torque (MRT) showed that only MRT2 was significantly higher than other MRT values (except MRT1) (P = 0.046). Regarding FT, the t-test showed that there was no significant difference between FT0 and FT5 (P = 0.485). CONCLUSION: Within limitations of this study, five time insertion, cleaning, processing and steam sterilization had no significant negative effect on insertion, removal and FT of the mini-screws. PMID- 26005465 TI - The prevalence of dental anxiety and fear in patients referred to Isfahan Dental School, Iran. AB - BACKGROUND: Dental anxiety and fear are major complications for both patient and dental care provider. The purpose of this study was to assess the prevalence of dental anxiety and fear in patients who referred to Isfahan Dental School and their relation to their age, gender, educational level, past traumatic experiences and frequency of dental visits. MATERIALS AND METHODS: In this cross sectional study, 473 patients were provided with a questionnaire including three sections. First section contained questions concerning their age, gender, educational level, frequency of dental visits, reasons for irregular attendance and existence of past traumatic experiences. Second section comprised a Farsi version of Modified Dental Anxiety Scale (MDAS); and third included a Farsi version of dental fear survey (DFS). Data were analyzed by t-test, ANOVA, Pearson and Spearman correlation tests. RESULTS: The prevalence of dental anxiety among the study population was 58.8%. No correlation was found between age and MDAS (r = -0.08, P = 0.07) and DFS (r = -0.03, P = 0.53). Women demonstrated higher anxiety (P < 0.001) and fear (P = 0.003). Education had no significant effect on dental anxiety (r = -0.046, P = 0.32) and dental fear (r = -0.017, P = 0.79). Previous traumatic experiences were found to result in elevated anxiety and fear (P < 0.001). There was an inverse relationship between frequency of dental attendance and anxiety (r = -0.128, P = 0.008). CONCLUSIONS: Within the limitations of this study, anxiety associated with dental treatment was widespread in the study population. Dental fear and anxiety were not affected by age or education level. Dental fear and anxiety were higher in women. In addition, people who visited the dentist more regularly and individuals without previous traumatic dental experiences were less anxious. PMID- 26005466 TI - Effects of removing adhesive from tooth surfaces by Er:YAG laser and a composite bur on enamel surface roughnessand pulp chamber temperature. AB - BACKGROUND: At the end of fixed orthodontic treatment, the remnant of adhesive should be eliminated from the tooth surface. The purpose of this study was to compare the effect of three methods of removing adhesive on enamel surface roughness, dental pulp temperature, and also on the time spent. MATERIALS AND METHODS: The brackets on 90 extracted teeth were debonded using bracket removal pliers. A thermocouple sensor was fitted on the buccal wall of the pulp chamber through access cavity to measure thermal changes during adhesive removal. The residue of adhesive was eliminated from enamel surface of teeth by either tungsten carbide bur, erbium-doped yttrium aluminum garnet laser, or fiber reinforced composite bur. Scanning electron micrographs images were taken to assess the roughness of enamel surface. The time spent for adhesive removal was recorded as well. Chi-square test was used to evaluate the remnants of adhesive and enamel surface roughness; t-test and also repeated measurement analysis of variance were applied at P < 0.05 to compare the thermal changes of the pulp chamber and time spent between the methods of surface treatment. RESULTS: The results of surface roughness were significantly different (P < 0.001). The pulp temperature changed significantly (P < 0.001). Tungsten carbide bur increased the temperature by 5.5 degrees C significantly slower than reinforced composite bur (P = 0.004), however removed the adhesive residue faster than two other methods although not significantly (P = 0.069). CONCLUSION: Within the limitations of this study, fiber reinforced composite bur created the smoothest enamel surface while Er:YAG laser the roughest. Tungsten carbide and composite burs generated more heat compared to Er:YAG laser. In addition, tungsten carbide bur was the fastest and Er:YAG laser the slowest devices to remove adhesive residue. PMID- 26005467 TI - Evaluation of craniofacial proportions: A pilot study. AB - BACKGROUND: Regarding the need for determining the cephalometric norms for each population and the advantages of proportional analyses, we evaluated the variables of McNamara and Schwartz analyses and their relation in a pilot study on 6-17 years old Iranian students and provided formulas, which show these relations. MATERIALS AND METHODS: In this descriptive-analytical study, a tatal of cephalometric radiographs from the archive documents of Orthodontic Department of Isfahan Dental School was selected and traced. The variables of McNamara and Schwartz analyses were investigated. The data were analyzed by t-test and linear regression and Spearman correlation coefficient tests using SPSS 12 software, and the significance was set at 0.05. Then, a formula was suggested for predicting the relation between the jaws, cranium and face. RESULTS: The variables measured in this study were significantly different between the genders (P < 0.05), except for Co-Gn (P = 0.055), and they were higher in boys. All variables significantly increased (P < 0.05) with age from 6 to 17 years. The formulas presented in this study can be used for calculating the amount of PNS-APmax, Go-APmax and the Co Gn, anterior nasal spine-menton in the Iranian population. CONCLUSION: Within the limitation of this study, the formula presented in this study might be considered to predict the relation between jaw dimensions and cranial base and facial dimensions in the Iranian population. PMID- 26005468 TI - Shear bond strength of orthodontic color-change adhesives with different light curing times. AB - BACKGROUND: The purpose of this study was to evaluate the effect of light-curing time on the shear bond strength (SBS) of two orthodontic color-change adhesives (CCAs). MATERIALS AND METHODS: A total of 72 extracted premolars were randomly assigned into 6 groups of 12 teeth each. Subsequent to primer application, a metal bracket was bonded to the buccal surface using an orthodontic adhesive. Two CCAs (Greengloo and Transbond Plus) were tested and one conventional light-cured adhesive (Resilience) served as control. For each adhesive, the specimens were light-cured for two different times of 20 and 40 s. All the specimens underwent mechanical testing using a universal testing machine to measure the SBS. Adhesive remnant index (ARI) was used to assess the remnant adhesive material on the tooth surface. All statistical analyses were performed using SPSS software. The significance level for all statistical tests was set at P <= 0.05. RESULTS: The SBSs of the tested groups were in the range of 14.05-31.25 MPa. Greengloo adhesive showed the highest SBS values when light-cured for 40 s, and Transbond Plus adhesive showed the lowest values when light-cured for 20 s. ARI scores of Transbond Plus adhesive were significantly higher than those of controls, while other differences in ARI values were not significant. CONCLUSION: Within the limitations of his study, decreasing the light-curing time from 40 to 20 s decreased the SBS of the tested adhesives; however, this decline in SBS was statistically significant only in Transbond Plus adhesive. PMID- 26005469 TI - Accuracy and reliability of linear measurements using tangential projection and cone beam computed tomography. AB - BACKGROUND: Providing a cross-sectional image is essential for preimplant assessments. Computed tomography (CT) and cone beam CT (CBCT) images are very expensive and provide high radiation dose. Tangential projection is a very simple, available, and low-dose technique that can be used in the anterior portion of mandible. The purpose of this study was to evaluate the accuracy of tangential projection in preimplant measurements in comparison to CBCT. MATERIALS AND METHODS: Three dry edentulous human mandibles were examined in five points at intercanine region using tangential projection and CBCT. The height and width of the ridge were measured twice by two observers. The mandibles were then cut, and real measurements were obtained. The agreement between real measures and measurements obtained by either technique, and inter- and intra-observer reliability were tested. RESULTS: The measurement error was less than 0.12 for tangential technique and 0.06 for CBCT. The agreement between the real measures and measurements from radiographs were higher than 0.87. Tangential projection slightly overestimated the distances, while there was a slight underestimation in CBCT results. CONCLUSION: Considering the low cost, low radiation dose, simplicity and availability, tangenital projection would be adequate for preimplant assessment in edentulous patients when limited numbers of implants are required in the anterior mandible. PMID- 26005470 TI - Immunohistochemical analysis of COX-2 expression in dentigerous cyst, keratocystic odontogenic tumor and ameloblastoma: A comparative study. AB - BACKGROUND: Cyclo-oxygenase-2 (COX-2) is an early response gene that is induced by growth factors, oncogenes and carcinogens and its expression is increased in various tumors. Increased expression of COX-2 plays a significant role in the development and growth of tumors by interfering in biological processes such as cell division, cellular immunity, cell adhesion, apoptosis, and angiogenesis. This study aimed to investigate the immunohistochemical expression of COX-2 in keratocystic odontogenic tumor (KOT) in comparison with ameloblastoma and dentigerous cyst with regards to different clinical behavior and histopathological features of these lesions. MATERIALS AND METHODS: Paraffined blocks of 45 cases including 15 cases of dentigerous cyst, 15 cases of KOT and 15 cases of ameloblastoma were stained with immunohistochemical method for COX-2. Five high-power fields of each sample were evaluated to determine the percentage of stained cells and the intensity of staining. Degree of immunoreactivity was obtained from the sum of two. Statistical evaluation was performed by the Kruskal Wallis and ANOVA Mann-Whitney test (P < 0.05). RESULTS: Overexpression of COX-2 in ameloblastoma and KOT was observed compared with dentigerous cyst (P < 0.001). However, no significant difference was observed between the expression of COX-2 in ameloblastoma and KOT (P = 0.148). CONCLUSION: The COX-2 expression in odontogenic tumors such as ameloblastoma and cystic neoplasm with aggressive behavior such as KOT increases. However, it does not seem that COX-2 affects the development and growth of cysts with noninvasive behavior like dentigerous cyst. PMID- 26005471 TI - Guided bone regeneration: A novel approach in the treatment of pediatric dentoalveolar trauma. AB - Traumatic injuries in the primary dentition pose major challenges for management. This emergency treatment requires proper planning so as to achieve favorable results. Trauma causing severe dentoalveolar injuries, especially in children, needs an interdisciplinary approach so as to retain normal functional anatomy for that age. This article describes a clinical innovative technique, which utilizes a resorbable membrane in management of pediatric dentoalveolar trauma. The membrane was shaped to cover the multiple alveolar bone fracture, thereby favoring the healing of the bone defects. The use of this resorbable membrane maintained a secluded space for the bone growth and prevented overgrowth of the soft tissue in the region of the defect. This resulted in uneventful healing leading to well-maintained functional bone contour, which further favored the esthetic rehabilitation as well as protected the underlying permanent tooth buds. PMID- 26005472 TI - To irrigate or not to irrigate: Immediate postextraction socket irrigation and alveolar osteitis. PMID- 26005473 TI - Prevalence of Anxiety Disorders among Children and Adolescents in Iran: A Systematic Review. AB - OBJECTIVE: We aimed to conduct a review to investigate the prevalence of anxiety disorders among Iranian children and adolescents. METHOD: We systematically reviewed the literature up to June 2014. We searched three Persian databases (Magiran, IranMedex and SID) and three English databases: PubMed, Scopus and PsycINFO. All original studies that investigated the current prevalence of anxiety in a sample of Iranian children and adolescents were entered into the study. All studies conducted on special samples or in special settings were excluded. By searching English databases, we obtained 124 original studies. After removing duplicate papers, 120 articles remained. In the next step, we screened the articles based on their title. In sum, 95 Persian and English articles had relevant titles. After screening based on the abstract and full text, 26 studies remained. After screening based on the full text, all selected studies were qualitatively assessed by two evaluators separately. RESULT: Twenty five studies were eligible and reported different types of anxiety disorders (i.e., generalized anxiety, separation anxiety, obsessive-compulsive disorder, phobias and panic disorder). The samples varied from 81 to 2996 among studies and their age range was 5 to 18 years. These studies were conducted in different cities of Iran. SCL-90 is a frequently used questionnaire. All anxiety disorders were mostly investigated with the prevalence rates ranging from 6.8% in Saravan to 85% in Bandar Abbas. OCD was the second common study with prevalence rates ranging from 1% in Tabriz to 11.9% in Gorgan. CONCLUSION: Our findings revealed considerable amount of anxiety disorder among Iranian children and adolescents. Given the fact that anxiety disorder has negative effects on the well-being and function of individuals and can lead to severe problems, this disorder should be considered in mental health programs designed for children and adolescents. PMID- 26005474 TI - Characteristics of Alpha Band Frequency in Adolescents with Bipolar II Disorder: A Resting-State QEEG Study. AB - OBJECTIVE: The aim of this study was to compare the QEEG of adolescents affected by bipolar II disorder with age and gender matched healthy controls, and to extract the characteristics of the alpha frequency band to better understand this disorder. METHODS: Twenty one adolescents affected by acute episodes of bipolar II disorder (BMD II), both hypomanic and depressive episodes, were selected via convenience sampling based on DSM IV criteria and child and adolescent psychiatrist diagnosis. Eleven patients were going through a hypomanic episode and 10 patients were going through a depression episode. Of the participants, 18 who were matched with the patient group participated in this study as a normal group. Any major comorbidities and intellectual disabilities were excluded through applying K-SADS-PL and Raven's IQ test for all the patients and the healthy participants. Electroencephalogram signals were obtained according to 10 20 international system by 21 electrodes from participants in open and closed eyes in a resting state. We selected 40 seconds length segments from each recorded EEG signals that had minimal noise and artifacts. Power spectrum density (PSD) was estimated for each segment and extracted alpha band frequency. We used only referential (unipolar) montage for comparison. Eventually, data were analyzed by independent Mann-Whitney test and independent t test. RESULTS: We observed significant differences in the alpha frequency band in some brain regions. Alpha power increased in the fronto-central region and right parietal lobe in the patients (P < 0.05). In the patients with BMD II, entropy of alpha oscillations was larger than the normal participants in the central region and in the F3, F4 and P4 channels. Also, there were differences in the variance of alpha oscillations in these regions between the two groups (P < 0.05). In the occipital lobe, alpha wave had different skewness between the two groups (P < 0.05). CONCLUSION: Thalamus as a generator and modulator of at least a part of alpha oscillations may be involved in this disorder and hence this explains the major symptoms like distractibility and inattention in both hypomanic and depressive episodes of bipolar II disorder. PMID- 26005475 TI - Visual attention to emotional face in schizophrenia: an eye tracking study. AB - OBJECTIVE: Deficits in the processing of facial emotions have been reported extensively in patients with schizophrenia. To explore whether restricted attention is the cause of impaired emotion processing in these patients, we examined visual attention through tracking eye movements in response to emotional and neutral face stimuli in a group of patients with schizophrenia and healthy individuals. We also examined the correlation between visual attention allocation and symptoms severity in our patient group. METHOD: Thirty adult patients with schizophrenia and 30 matched healthy controls participated in this study. Visual attention data were recorded while participants passively viewed emotional neutral face pairs for 500 ms. The relationship between the visual attention and symptoms severity were assessed by the Positive and Negative Syndrome Scale (PANSS) in the schizophrenia group. Repeated Measures ANOVAs were used to compare the groups. RESULTS: Comparing the number of fixations made during face-pairs presentation, we found that patients with schizophrenia made fewer fixations on faces, regardless of the expression of the face. Analysis of the number of fixations on negative-neutral pairs also revealed that the patients made fewer fixations on both neutral and negative faces. Analysis of number of fixations on positive-neutral pairs only showed more fixations on positive relative to neutral expressions in both groups. We found no correlations between visual attention pattern to faces and symptom severity in schizophrenic patients. CONCLUSION: The results of this study suggest that the facial recognition deficit in schizophrenia is related to decreased attention to face stimuli. Finding of no difference in visual attention for positive-neutral face pairs between the groups is in line with studies that have shown increased ability to positive emotional perception in these patients. PMID- 26005476 TI - The efficacy of treatment reminders of life with emphasis on integrative reminiscence on self-esteem and anxiety in widowed old men. AB - OBJECTIVE: Loss of wife besides the phenomenon of aging could cause some psychological disorders and may shorten the duration of this stage of life. The aim of this study was to examine the efficacy of treatment reminders of life with emphasis on integrative reminiscence on self-esteem and anxiety in widowed old men. METHOD: This was a clinical trial with pre-test and post-test design with a control group. The study population included All 60 to 80 year old men living in Meshginshahr; among whom, 34 participants were selected using convenience sampling method. They were randomly allocated into two equal groups (experimental and control). The experimental group participated in therapy sessions and the control group did not receive any intervention. The research instruments were Rosenberg Self-Esteem Scale and the General Anxiety Questionnaire. Data were analyzed using multivariable covariance analysis in SSPS-19. Statistical significance was set at P<0.05. RESULTS: MANCOVA results showed that the treatment positively affected the variables of self-esteem and anxiety in old widowed men (p<0.001). CONCLUSION: The reminders of life therapy with emphasis on integrative reminiscence may enhance self-esteem and reduce anxiety in widowed old men. This treatment gives better results compared to the traditional treatments and it is recommended to be implemented in nursing homes. PMID- 26005477 TI - Validation and Psychometric Properties of Mobile Phone Problematic Use Scale (MPPUS) in University Students of Tehran. AB - OBJECTIVE: Despite the fact that the mobile phone has become a pervasive technology of our time, little research has been done on mobile dependency. Therefore, a valid and reliable instrument, conforming to Iranian culture seems essential. The aim of our study was to validate the Iranian version of MPPUS (Mobile Phone Problematic Use Scale). METHODS: This was a cross-sectional research, in which data were collected from 600 students studying at Tehran universities. Stratified sampling method was used to collect data. All participants completed Demographic Questionnaire, Cellular Phone Dependency Questionnaire (CPDQ) anonymously. Finally, a clinical interview (based on DSM-IV TR) was conducted with 100 participants. Data were analyzed using concurrent validity, factor analysis, internal consistency (Cronbach's'alpha), split half, test-retest and ROC Curve by SPSS18 Software. RESULTS: As a result of reliability analysis and factor analysis by principal component and Varimax rotation, we extracted three factors including preoccupation, withdrawal symptoms and overuse of mobile phones in both males and females. Internal consistency (Cronbach's alpha) of the MPPUS was .91; Cronbach's alpha of the factors was .87, .70, .82 respectively. The test-retest correlation of the MPPUS was .56. The best cut off point for this questionnaire (MPPUS) was 160. CONCLUSION: The MPPUS proved to be a reliable questionnaire with adequate factor models to assess the extent of problems caused by the "misuse" of mobile phones in the Iranian society; however, further studies are needed on this topic. PMID- 26005478 TI - Moral Distress among Iranian Nurses. AB - OBJECTIVE: The purpose of this study was to describe the moral distress among Iranian registered nurses. METHODS: This was a descriptive -analytic study, in which 264 out of 1000 nurses were randomly selected as a sample group and completed the questionnaire. The nurses' moral distress was assessed using Corley's 30-item Moral Distress Scale adapted for use in an Iranian population. The collected data were analyzed by SPSS version 19. RESULTS: In this study, no correlation was found between the level of moral distress and any of the demographic data. The mean moral distress score ranged from 3.56 to 5.83, indicating moderate to high levels of moral distress. The item with the highest mean score was "working with unsafe levels of nurse staffing". The item with the lowest mean score was "giving medication intravenously to a patient who has refused to take it". Nurses working in EMS and NICU units had the highest levels of moral distress. CONCLUSION: A higher degree of moral distress is observed among nurses who work in health care systems. The results of this study highly recommend practical and research-oriented evaluation of moral distress in the medical society in Iran. Our findings suggest that Iranian version of MDS is a reliable instrument to measure moral distress in nurses. PMID- 26005479 TI - Evaluation of some psychological factors in psoriatic patients. AB - BACKGROUND: Psoriasis is a disease which may have a direct impact on the psychological and social aspects of the patient, particularly due to its visibility. To date, we are unaware of any study showing a relationship between psoriasis and psychological parameters such as psychological vulnerability and coping strategies. OBJECTIVE: The aim of this study was to evaluate the effects of psoriasis on some psychological parameters in an Iranian population. METHODS: Patients having histopathologically confirmed psoriasis for at least 6 months attending the Dermatology Clinic of Razi Hospital were included if they agreed to participate in the study. Patients with history of schizophrenia, major depression or other psychological disorders were excluded. All patients were at least 18 years old. The patients were then referred to the researchers for filling out the appropriate questionnaires under the guidance of an involved psychologist. To evaluate skin involvement, Psoriasis Area Severity Index (PASI) score was calculated and used for all patients. All data were stored in files for further analysis. RESULTS: There were 101 females and 99 males with the mean age of 43.2(+/-16.32). The mean PASI Score was 6.58 +/- 6.04. Diffuse skin involvement was the commonest form of disease (133 patients, 66.5%). The highest score for Illness perception belonged to those with genitalia involvement (185.2, worst illness perception), and the lowest score for Illness perception belonged to those with nail involvement (168.2). Consistently, the lowest score of facing the problems (CISS: approach strategy to disease) belonged to those with hand involvement (50.5) whereas the highest score belonged to those with genitalia involvement (60.4). There was a significant correlation between psychological vulnerability vs. Illness perception score as well as psychological vulnerability vs. coping strategies score. Surprisingly, PASI score had an insignificant relationship with illness perception, coping strategies or psychological vulnerability score. CONCLUSION: PASI score as a representing factor of skin involvement has a limited role in predicting the effect of psoriasis on mental status and illness perception of psoriatic patients. Psychological vulnerability of the patients is the main predicting factor of illness perception and coping strategies (representing patients approach to their disease or their treatment beliefs). PMID- 26005480 TI - The effect of psychotherapy in improving physical and psychiatric symptoms in patients with functional dyspepsia. AB - OBJECTIVE: Functional Dyspepsia (FD) is a common symptom of upper gastrointestinal discomfort. Few data are available on the role of psychotherapy in the treatment of dyspeptic syndromes. This study assesses whether brief core conflictual relationship theme (CCRT) psychoanalytic psychotherapy improves gastrointestinal and psychiatric symptoms in patients with functional dyspepsia. METHODS: A randomized, controlled trial was planned in two educational hospitals in city of Babol. Forty-nine patients with FD were randomly assigned to receive standard medication treatment with CCRT psychotherapy (24 participants) or standard medication treatment alone (25 participants). The participants completed the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI SYM) and Symptom Checklist-90-Revised (SCL-90-R) questionnaires before the trial, after the treatment and at 1 and 12-month follow-ups. The mixed-effects (regression) model was used to analyze the data. RESULTS: The results showed that CCRT psychotherapy improved all of the FD symptoms (heartburn/regurgitation, nausea/vomiting, fullness, bloating, upper abdominal pain, and lower abdominal pain) and many of the psychiatric symptoms (depression, anxiety, somatization, interpersonal sensitivity and paranoid ideation) after the treatment and at 1 month and 12-month follow-ups. CONCLUSION: Brief CCRT psychoanalytic psychotherapy can serve as an effective intervention for promoting gastrointestinal and psychiatric symptoms in patients with functional dyspepsia. PMID- 26005481 TI - Predicting dimensions of psychological well being based on religious orientations and spirituality: an investigation into a causal model. AB - OBJECTIVE: The aim of this study was to investigate the possibility of predicting psychological well-being based on spirituality and religiousness. METHODS: A sample of 300 participants was selected from the whole entrants to Shiraz University of Medical Sciences and Shiraz University using a random cluster sampling. The tools of this study were the Spiritual Scale of Ironson, the Internal and External Orientations of Allport and Ross, Spiritual Religious Orientation of Betson and Showinerdand and the Psychological Well-Being Scale. To analyze the results of this study, we used the statistical method of Pearson correlation and we also performed the path analysis. Multiple regressions were used in a hierarchical simultaneous way in accordance with the stages of Barron and Kenny. RESULTS: The following results were obtained in this study: 1)Spirituality positively predicted two religious orientations (question and internal) among which the internal spirituality possessed a higher degree of predictability; 2)Through intra-religious orientation, and in a direct way, spirituality predicted psychological well-being; 3)The internal orientation was the only strong mediator in the relationship between spirituality and psychological well-being. CONCLUSION: Spirituality and religiosity were significant determinants of mental health, and they had more shares in psychological well-being, and made religious beliefs profound and internalized them. PMID- 26005482 TI - Trait mindfulness, reasons for living and general symptom severity as predictors of suicide probability in males with substance abuse or dependence. AB - OBJECTIVE: The aim of this study was to evaluate suicide probability in Iranian males with substance abuse or dependence disorder and to investigate the predictors of suicide probability based on trait mindfulness, reasons for living and severity of general psychiatric symptoms. METHOD: Participants were 324 individuals with substance abuse or dependence in an outpatient setting and prison. Reasons for living questionnaire, Mindfulness Attention Awareness Scale and Suicide probability Scale were used as instruments. Sample was selected based on convenience sampling method. Data were analyzed using SPSS and AMOS. RESULTS: The life-time prevalence of suicide attempt in the outpatient setting was35% and it was 42% in the prison setting. Suicide probability in the prison setting was significantly higher than in the outpatient setting (p<0.001). The severity of general symptom strongly correlated with suicide probability. Trait mindfulness, not reasons for living beliefs, had a mediating effect in the relationship between the severity of general symptoms and suicide probability. Fear of social disapproval, survival and coping beliefs and child-related concerns significantly predicted suicide probability (p<0.001). DISCUSSION: It could be suggested that trait mindfulness was more effective in preventing suicide probability than beliefs about reasons for living in individuals with substance abuse or dependence disorders. The severity of general symptom should be regarded as an important risk factor of suicide probability. PMID- 26005483 TI - Evaluating Reliability and Predictive Validity of the Persian Translation of Quantitative Checklist for Autism in Toddlers (Q-CHAT). AB - OBJECTIVE: Early screening of autism increases the chance of receiving timely intervention. Using the Parent Report Questionnaires is effective in screening autism. The Q-CHAT is a new instrument that has shown several advantages than other screening tools. Because there is no adequate tool for the early screening of autistic traits in Iranian children, we aimed to investigate the adequacy of the Persian translation of Q-CHAT. METHOD: At first, we prepared the Persian translation of the Quantitative Checklist for Autism in Toddlers (Q-CHAT). After that, an appropriate sample was selected and the check list was administered. Our sample included 100 children in two groups (typically developing and autistic children) who had been selected conveniently. Pearson's r was used to determine test-retest reliability, and Cronbach's alpha coefficient was used to explore the internal consistency of Q-CHAT. We used the receiver operating characteristics curve (ROC) to investigate whether Q-CHAT can adequately discriminate between typically developing and ASD children or not. Data analysis was carried out by SPSS 19. RESULT: The typically developing group consisted of 50 children with the mean age of 27.14 months, and the ASD group included50 children with the mean age of 29.62 months. The mean of the total score for the typically developing group was 22.4 (SD=6.26) on Q-CHAT and it was 50.94 (SD=12.35) for the ASD group, which was significantly different (p=0.00).The Cronbach's alpha coefficient of the checklist was 0.886, and test-retest reliability was calculated as 0.997 (p<0.01). The estimated area under the curve (AUC) was 0.971. It seems that the total score equal to 30 can be a good cut point to identify toddlers who are at risk of autism (sensitivity= 0.96 and specificity= 0.90). CONCLUSION: The Persian translation of Q-CHAT has good reliability and predictive validity and can be used as a screening tool to detect 18 to 24 months old children who are at risk of autism. PMID- 26005484 TI - Cardiovascular considerations in antidepressant therapy: an evidence-based review. AB - There is a definite correlation between cardiovascular diseases and depressive disorders. Nevertheless, many aspects of this association have yet to be fully elucidated. Up to half of coronary artery disease patients are liable to suffer from some depressive symptoms, with approximately 20% receiving a diagnosis of major depressive disorders. Pharmacotherapy is a key factor in the management of major depression, not least in patients with chronic diseases who are likely to fail to show proper compliance and response to non-pharmacological interventions. Antidepressants are not deemed completely safe. Indeed, numerous side effects have been reported with the administration of antidepressants, among which cardiovascular adverse events are of paramount importance owing to their disabling and life-threatening nature. We aimed to re-examine some of the salient issues in antidepressant therapy vis-a-vis cardiovascular considerations, which should be taken into account when prescribing such medications. PMID- 26005485 TI - Impact of Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers on mortality of coronary artery bypass grafting. AB - BACKGROUND: There is controversy over the potential benefits/harms of the usage of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as regards the postoperative mortality of coronary artery bypass grafting (CABG). This study investigates the correlation between the in-hospital mortality of CABG and the preoperative administration of ACEI/ARB. METHODS: Out of 10055 consecutive patients with isolated CABG from 2006 to 2009, 4664 (46.38%) patients received preoperative ACEI/ARB. Data were gathered from the Cardiac Surgery Registry of Tehran Heart Center. In-hospital mortality was defined as death within the same admission for surgery. Adjusted for confounders, multivariable logistic regression models were used to evaluate the impact of preoperative ACEI/ARB therapy on in-hospital death. RESULTS: The mean age of the patients was 60.04 +/- 9.51 years and 7364 (73.23%) were male. Eighty-seven (0.86%) patients expired within 30 days. Multivariate analysis revealed that the administration of ACEI/ARB significantly protected against in-hospital deaths inasmuch as there were 33 (0.70%) vs. 54 (1.0%) deaths in the ACEI/ARB positive and negative groups, respectively (OR: 0.628; p value = 0.09). Patients without ACEI/ARB were more likely to have a higher global ejection fraction. CONCLUSION: Preoperative ACEI usage in patients undergoing CABG can be associated with decreased in-hospital mortality. Large-scale randomized clinical trials are suggested. PMID- 26005486 TI - When Can We Release the Amplatzer Ductal Occluder (ADO) Safely? AB - BACKGROUND: The ductus arteriosus connects the main pulmonary trunk to the descending aorta. The incidence of isolated patent ductus arteriosus (PDA) in full-term infants is about 1 in 2000. The Amplatzer Ductal Occluder (ADO) is recommended for PDAs with sizes larger than 2 mm. In this procedure, we must confirm the ADO position in PDA by aortogram from the arterial line. The purpose of this study was to determine the optimal release time of the ADO in the PDA closure procedure, especially in the absence of an arterial line for post-PDA aortography. METHODS: This study recruited all patients scheduled to undergo PDA transcatheter closure with the ADO between September 2009 and September 2012 in our center. Age, weight, PDA diameter, systolic and diastolic pulmonic pressures, fluoroscopy time, and total angiographic time were studied. Major complications such as mortality and vascular complications were considered. RESULTS: We studied 237 patients in our investigation. We had 130 female and 107 male patients at a mean age of 34.3 +/- 40.6 months and mean weight of 14.2 +/-7.8 kg. PDA sizes ranged from 2.1 to 6.2 mm and its mean was 3.7 +/- 1.8 mm. Mean of fluoroscopy time was 11.4 +/- 9.7 min and mean of total angiographic time was 42.0 +/- 12.3 min. There were no significant complications. CONCLUSION: We herein describe a new sign, which proved extremely helpful during our PDA closure procedures with the ADO. By considering the angle between the ADO and the cable during the procedure, the operator can release the ADO safely. PMID- 26005487 TI - Advanced Cardiac Life Support Training by Problem-Based Method: Effect on the Trainee's Skills, Knowledge and Evaluation of Trainers. AB - BACKGROUND: Cardiopulmonary-cerebral resuscitation (CPCR) training is essential for all hospital workers, especially junior residents who might become the manager of the resuscitation team. In our center, the traditional CPCR knowledge training curriculum for junior residents up to 5 years ago was lecture-based and had some faults. This study aimed to evaluate the effect of a problem-based method on residents' CPCR knowledge and skills as well as their evaluation of their CPCR trainers. METHODS: This study, conducted at Tehran University of Medical Sciences, included 290 first-year residents in 2009-2010 - who were trained via a problem-based method (the problem-based group) - and 160 first-year residents in 2003-2004 - who were trained via a lecture-based method (the lecture based group). Other educational techniques and facilities were similar. The participants self-evaluated their own CPCR knowledge and skills pre and post workshop and also assessed their trainers' efficacy post workshop by completing special questionnaires. RESULTS: The problem-based group, trained via the problem based method, had higher self-assessment scores of CPCR knowledge and skills post workshop: the difference as regards the mean scores between the problem-based and lecture-based groups was 32.36 +/- 19.23 vs. 22.33 +/- 20.35 for knowledge (p value = 0.003) and 10.13 +/- 7.17 vs. 8.19 +/- 8.45 for skills (p value = 0.043). The residents' evaluation of their trainers was similar between the two study groups (p value = 0.193), with the mean scores being 15.90 +/- 2.59 and 15.46 +/- 2.90 in the problem-based and lecture-based groups - respectively. CONCLUSION: The problem-based method increased our residents' self-evaluation score of their own CPCR knowledge and skills. PMID- 26005488 TI - Transcatheter atrial septal defect closure using occlutech figulla device: a two center experience. AB - BACKGROUND: Despite several reports regarding the use of the Occlutech Figulla(r) Flex septal occluder (OFFSO) in adults, there are few reports on its use in children. We sought to study the result of the transcatheter closure of atrial septal defect (ASD) using the OFFSO in children <=12 years. METHODS: We enrolled 45 consecutive patients, ranging from 2.5 to 12 years of age, in two large pediatric cardiovascular centers. All the children underwent complete echocardiographic examination before the procedure. Defect/device ratio and device/weight ratio were measured. The device diameter to the cardiac diameter ratio (DD/CD ratio) in anteroposterior projection after device release and the DD/CD index were calculated by dividing the DD/CD ratio by the body surface area. RESULTS: Of the 45 enrolled patients, 25 (55%) were female. The range and mean +/ standard deviation (SD) of age were 2.5 to 12 years and 6.8 +/- 2.5 years, respectively. The range and mean +/- SD weight were 8.5 to 37.0 kg and 19.7 +/- 7.2 kg, respectively. Successful implantation was performed in all the patients. No major complications occurred in any of the subjects. We encountered one cobra head deformity in one patient. Neither residual shunt nor conduction abnormality was observed in any of the cases. CONCLUSION: Transcatheter ASD closure using the OFFSO was effective in our pediatric patients. Although this device needs relatively larger delivery sheaths, its use is safe while closing even large defects in children. PMID- 26005489 TI - Myxoma of the superior vena cava origin presented as a right atrial mass. AB - Myxomas are the most common benign cardiac tumors. Myxomas are more common in the left heart chamber than the right side chamber. An extracardiac origin presenting as a right atrial mass is very rare. We present a case of myxoma originating in the superior vena cava (SVC) in a 24-year-old man, who underwent surgical resection. Preoperative two-dimensional echocardiography demonstrated a mass in the right atrium. Intraoperatively, the tumor was found to have originated from the SVC orifice. The tumor was excised from the SVC by opening the one-third proximal portion of the SVC. Pathological examination revealed a myxoma, and one year follow-up showed no evidence of the recurrence of any tumors in the SVC. PMID- 26005490 TI - Congenital saccular aneurysm of coarctation of aorta: a case report. AB - True saccular aneurysm is exceptional in coarctation of aorta in children. A 6 year-old girl with headache and systemic arterial hypertension referred to our center for cardiovascular evaluation. Physical examination revealed high blood pressure and weak lower extremity pulses. Two-dimensional and Doppler echocardiography and angiography demonstrated a saccular aneurysm of the descending aorta, 5*4 cm in size, associated with aortic coarctation. Aneurysmectomy was performed without cardiopulmonary bypass. The section of the aorta containing the coarctation and the aneurysm was resected and replaced with a 15-mm woven polyester graft. Histological examination revealed a thin walled aneurysm with hyalinosis changes and decreased elastic fibers.One-year echocardiographic follow-up revealed no gradient across of Dacron tube and hypertension decreased to normal level. PMID- 26005491 TI - Unethical conduct of underpowered clinical trials. PMID- 26005492 TI - Thrombus-in-Transit Entrapped in a Partially Ligated Left Atrial Appendage. PMID- 26005493 TI - Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder. AB - OBJECTIVE: The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI) antidepressants. METHODS: A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), clinical laboratory tests, blood pressure (BP) and pulse, and electrocardiograms (ECGs). RESULTS: The analysis included 1260 patients treated with adjunctive edivoxetine and 806 treated with adjunctive placebo. Study completion rates were 85.2% and 84.5% (p=0.994), respectively. Discontinuations due to adverse events were 4.9% and 3.5% (p=0.07), respectively. Significantly more patients in the adjunctive edivoxetine group compared with adjunctive placebo group reported at least one TEAE (56.8 vs 43.7%, p<0.001). The most common TEAEs (occurred >=5% frequency) were hyperhidrosis, nausea, and tachycardia. Mean changes in sitting BP and pulse at the last visit were increased significantly in patients treated with adjunctive edivoxetine compared with adjunctive placebo (SBP: 2.7 vs 0.5 mm Hg, p<0.001; DBP: 4.1 vs 0.8 mm Hg, p<0.001; pulse: 8.8 vs -1.3 bpm, p<0.001). There were no clinically significant changes in laboratory measures. CONCLUSIONS: The tolerability and safety profile of edivoxetine as adjunctive treatment to SSRI antidepressants was consistent with its norepinephrine reuptake inhibitor mechanism of action, and was comparable with edivoxetine monotherapy treatment in patients with major depressive disorder. PMID- 26005494 TI - Synthesis and characterization of Se-adenosyl-L-selenohomocysteine selenoxide. AB - Selenium is an essential micronutrient in humans due to the important roles of the selenocysteine-containing selenoproteins. Organoselenium metabolites are generally found to be substrates for the biochemical pathways of their sulfur analogs, and the redox chemistry of selenomethionine and some other metabolites have been previously reported. We now report the first synthesis and characterization of Se-adenosylselenohomocysteine selenoxide (SeAHO) prepared via hydrogen peroxide oxidation of Se-adenosylselenohomocysteine (SeAH). The selenoxide SeAHO, in contrast to its corresponding sulfoxide S adenosylhomocysteine (SAHO), can form hydrate, has an electrostatic interaction between the alpha-amino acid moiety and the highly polar selenoxide functional group, and readily oxidizes glutathione (GSH) and cysteine thiols. PMID- 26005495 TI - Coulombic free energy and salt ion association per phosphate of all-atom models of DNA oligomer: dependence on oligomer size. AB - We investigate how the coulombic Gibbs free energy and salt ion association per phosphate charge of DNA oligomers vary with oligomer size (i.e. number of charged residues ?ZD?) at 0.15 M univalent salt by non-linear Poisson Boltzmann (NLPB) analysis of all-atom DNA models. Calculations of these quantities ([Formula: see text], [Formula: see text]) are performed for short and long double-stranded (ds) and single-stranded (ss) DNA oligomers, ranging from 4 to 118 phosphates (ds) and from 2 to 59 phosphates (ss). Behaviors of [Formula: see text] and [Formula: see text] as functions of ?ZD? provide a measure of the range of the coulombic end effect and determine the size of an oligomer at which an interior region with the properties (per charge) of the infinite-length polyelectrolyte first appears. This size (10-11 phosphates at each end for ds DNA and 6-9 for ss DNA at 0.15 M salt) is in close agreement with values obtained previously by Monte Carlo and NLPB calculations for cylindrical models of polyions, and by analysis of binding of oligocations to DNA oligomers. Differences in [Formula: see text] and in [Formula: see text] between ss and ds DNA are used to predict effects of oligomeric size and salt concentration on duplex stability in the vicinity of 0.15 M salt. Results of all-atom calculations are compared with results of less structurally detailed models and with experimental data. PMID- 26005496 TI - Lipoprotein effects of incretin analogs and dipeptidyl peptidase 4 inhibitors. AB - Elevated post-prandial lipoprotein levels are common in patients with type 2 diabetes. Post-prandial lipoprotein alterations in type 2 diabetics are widely believed to drive inflammation and are considered a major risk factor for cardiovascular disease in diabetic patients. The incretins glucagon like peptide 1 (GLP-1) and glucose insulinotropic peptide (GIP) modulate post-prandial lipoproteins through a multitude of pathways that are independent of insulin and weight loss. Evidence from both animal models and humans seems to suggest an important effect on triglyceride rich lipoproteins (Apo48 containing) with little to no effects on other lipoproteins at least in humans. Dipeptidyl peptidase-4 (DPP4) inhibitors also appear to share these effects suggesting an important role for incretins in these effects. In this review, we will summarize lipid modulating effects of incretin analogs and DPP-4 inhibitors in both animal models and human studies and provide an overview of mechanisms responsible for these effects. PMID- 26005497 TI - Concurrent DNA Preconcentration and Separation in Bipolar Electrode-Based Microfluidic Device. AB - This paper presents a bipolar electrode (BPE) device in a microfluidic dual channel design for concurrent preconcentration and separation of composite DNA containing samples. The novelty of the present effort relies on the combination of BPE-induced ion concentration polarization (ICP) and end-labeled free-solution electrophoresis (ELFSE). The ion concentration polarization effect arising from the faradaic reaction on the BPE is utilized to exert opposing electrophoretic and electroosmotic forces on the DNA samples. Meanwhile, end-labeled free solution electrophoresis alters the mass-charge ratio to enable simultaneous DNA separation in free solution. The microfluidic device was fabricated using standard and soft lithography techniques to form gold-on-glass electrode capped with a PDMS microfluidic channel. Experimental testing with various DNA samples was carried out over a range of applied electric field. Concentration ratios up to 285* within 5 minutes for a 102-mer DNA, and concurrent preconcentration and free-solution separation of binary mixture of free and bound 102-mer DNA within 6 minutes was demonstrated. The effect of applied electric field was also interrogated with respect to pertinent performance metrics of preconcentration and separation. PMID- 26005498 TI - Anticancer Camptothecin-N-Poly(lactic acid) Nanoconjugates with Facile Hydrolysable Linker. AB - We report a strategy of conjugating CPT to the terminal carboxylate group of polylactide (PLA) with a facile hydrolysable amino ester linker via a controlled polymerization method. The obtained CPT-N-PLA conjugates were able to self assemble into 50-100 nanometer-sized conjugates (NCs) with desired in vitro physicochemical properties and showed enhanced in vivo therapeutic efficacy against Lewis lung carcinoma (LLC) induced in C57BL/6 mice. PMID- 26005499 TI - A robust platform for functional microgels via thiol-ene achemistry with reactive polyether-based nanoparticles. AB - We herein report the development of crosslinked polyether particles as a reactive platform for the preparation of functional microgels. Thiol-ene crosslinking of poly(allyl glycidyl ether) in miniemulsion droplets - stabilized by a surface active, bio-compatible polyethylene glycol block copolymer - resulted in colloidal gels with a PEG corona and an inner polymeric network containing reactive allyl units. The stability of the allyl groups allows the microgels to be purified and stored before a second, subsequent thiol-ene functionalization step allows a wide variety of pH- and chemically-responsive groups to be introduced into the nanoparticles. The facile nature of this synthetic platform enables the preparation of microgel libraries that are responsive to different triggers but are characterized by the same size distribution, surface functionality, and crosslinking density. In addition, the utilization of a crosslinker containing cleavable ester groups renders the resulting hydrogel particles degradable at elevated pH or in the presence of esterase under physiological conditions. PMID- 26005500 TI - Trehalose hydrogels for stabilization of enzymes to heat. AB - Enzymes can catalyze various reactions with high selectivity and are involved in many important biological processes. However, the general instability of enzymes against high temperature often limits their application. To address this, we synthesized a trehalose-based hydrogel in two steps from commercial starting materials with minimal purification procedures. Mono- and multi-functional trehalose monomers were cross-linked by redox-initiated radical polymerization to form a hydrogel. Phytase, an important enzyme utilized in animal feedstock, was employed to study the effectiveness of the trehalose hydrogel to stabilize proteins against heat. Addition of the phytase solution to the hydrogel resulted in enzyme internalization as confirmed by confocal microscopy. The phytase in the hydrogel retained 100% activity upon heating at 90 degrees C compared to 39% when the hydrogel was absent. The enzyme could also be recovered from the hydrogel. The trehalose hydrogel synthesis reported herein should be readily scalable for thermal stabilization of a wide variety of enzymes. PMID- 26005502 TI - School- and Classroom-Based Supports for Children Following the 2013 Boston Marathon Attack and Manhunt. AB - School staff provide key mental health services following mass crisis events and teachers, in particular, can provide important supports within their classrooms. This study examines Boston-area teachers' perception of classroom-wide psychiatric distress and the types of supports that schools and teachers provided following the 2013 Boston Marathon bombing and subsequent manhunt. Boston-area K 12 teachers (N = 147) in communities with varying levels of exposure to the bombing and manhunt completed an anonymous web-based survey 2-5 months after the attack. Teachers reported on students' exposure to the bombings and manhunt, classroom-wide psychiatric distress, and the types of supports they and their schools provided students. Teacher reports of student exposure to the bombings and manhunt were significantly associated with their perceptions of greater classroom-wide psychiatric distress. Almost half indicated that their school had no formal policy for responding to the crisis, half reported no training to address events, and even the most common classroom-based support strategy reassuring students of their safety-was provided by only 76 % of teachers. Teacher perceptions of student exposure to the manhunt, but not the bombing, were significantly associated with greater provision of these supports. In the aftermath of the Boston Marathon bombings and manhunt, teachers and schools provided supports; however, the extent and types of supports varied considerably. Working with teachers to most effectively and consistently serve in this complex role has the potential to improve school-based crisis response plans, as well as student outcomes. PMID- 26005501 TI - Perspectives on the Potential Therapeutic Uses of Vesicles. AB - The role of extracellular vesicles as an important mediator of cell-to-cell communication has been well established by many studies that have shown their capability for exchanging proteins, bioactive lipids and nucleic acids. Extracellular vesicles have been implicated in several physiological and pathological processes according to the cell of origin. Identification of the innate properties of extracellular vesicles derived from stem cells and from immune cells has led to the possibility of their exploitation in regenerative medicine and immune therapies. As extracellular vesicles are able to cross biological barriers, express surface receptors and contain defined cargoes able to target specific cells/tissues, they may represent a biocompatible and effective tool for drug delivery. Herein, we review and discuss the perspectives related to the therapeutic opportunities of extracellular vesicles. PMID- 26005503 TI - Nanoscale protein domain motion and long-range allostery in signaling proteins- a view from neutron spin echo sprectroscopy. AB - Many cellular proteins are multi-domain proteins. Coupled domain-domain interactions in these multidomain proteins are important for the allosteric relay of signals in the cellular signaling networks. We have initiated the application of neutron spin echo spectroscopy to the study of nanoscale protein domain motions on submicrosecond time scales and on nanometer length scale. Our NSE experiments reveal the activation of protein domain motions over a long distance of over more than 100 A in a multidomain scaffolding protein NHERF1 upon binding to another protein Ezrin. Such activation of nanoscale protein domains motions is correlated with the allosteric assembly of multi-protein complexes by NHERF1 and Ezrin. Here, we summarize the theoretical framework that we have developed, which uses simple concepts from nonequilibrium statistical mechanics to interpret the NSE data, and employs a mobility tensor to describe nanoscale protein domain motion. Extracting nanoscale protein domain motion from the NSE does not require elaborate molecular dynamics simulations, or complex fits to rotational motion, or elastic network models. The approach is thus more robust than multiparameter techniques that require untestable assumptions. We also demonstrate that an experimental scheme of selective deuteration of a protein subunit in a complex can highlight and amplify specific domain dynamics from the abundant global translational and rotational motions in a protein. We expect NSE to provide a unique tool to determine nanoscale protein dynamics for the understanding of protein functions, such as how signals are propagated in a protein over a long distance to a distal domain. PMID- 26005504 TI - History of Mindfulness-Based Cognitive Therapy Is Associated with Increased Cognitive Reappraisal Ability. AB - Mindfulness-based cognitive therapy (MBCT) has been shown to be an effective treatment for mood and anxiety disorders. Little is known, however, about the specific psychological skills that may improve with MBCT. The present study investigated the relationship between history of MBCT and emotion regulation ability. Specifically, we examined cognitive reappraisal ability (CRA) in a sample of individuals with a history of MBCT compared with two control groups: a group without a history of any type of therapy and a group with a history of cognitive behavioral therapy (CBT). Groups were matched on key variables including age, sex, education, working memory, emotional reactivity, and life stress. CRA was measured using a standardized laboratory challenge. Results indicated that participants with a history of MBCT demonstrated higher CRA than both the no-therapy control group and the CBT control group. These results suggest that, by guiding people to accept thoughts and feelings without judgment and to focus on the present moment, MBCT may lay the foundation for increased CRA. PMID- 26005505 TI - A Review of the Diagnostic Scope of Biomarker Techniques, Genetic Screening and Virtual Scanning. AB - The purpose of this article is to compare and evaluate the advantages and benefits of the cognitive screening technique Virtual Scanning with contemporary diagnostic and screening techniques, in particular genetic screening and biomarkers. In the last 50 years biomarker techniques and more recently genetic screening have been developed to characterise the onset, progression and regression of pathologies. Nevertheless the scientific picture is not yet complete. It does not yet include an understanding of relationship between genotype and phenotype; the regulatory function of the autonomic nervous system; or the rate or level of the expressed protein, protein conformation, the rate at which proteins react, and the reaction conditions such as pH, levels of minerals and cofactors, and temperature. By contrast, Virtual Scanning is based upon the light absorbing and emitting properties of proteins and how this bioluminescence influences colour perception. It provides a measure of the level of expressed protein and the rate at which such expressed protein subsequently reacts with its reactive substrate. The article highlights the limitations of genetic screening and biomarkers and the perceived advantages which Virtual Scanning may have for routine mass screening e.g. of diabetes, cardiovascular disease, cancers, depression, migraine, etc. PMID- 26005506 TI - Review: Evidence-based Clinical Research of Anti-obesity Supplements in Japan. AB - BACKGROUND: The prevalence of obesity has increased dramatically throughout the world, and weight reduction through lifestyle management is urgently warranted. At present, numerous supplements advertised for their anti-overweight property are available in the Japanese market, but most of these lack proper evidence. Thus, we investigated dietary supplements that have been tested in clinical trials. SEARCH STRATEGY: We researched anti-obesity supplements in the Japanese market using the google search engine in Japanese with the key terms "anti obesity supplements," "diet supplements," and "weight reduction supplements." RESULTS: We listed 49 companies that supply anti-obesity supplements. Of these, 11 had published clinical evidence of the anti-obesity efficacy of their supplements. These products contain the following active ingredients: Angelica keiskei, bofu-tsusho-san, capsaishin, DHA/EPA, forskohlii, garcinia cambogia, lactoferrin, L-carnitine, oligonol, tea catechin, and yeast hydrolysate. CONCLUSION: We obtained 11 supplements for which clinical evidence was published in medical journals in English. We also found 10 products for which clinical or animal evidence was published in Japanese. We expect that many companies will produce evidence of the efficacy of their products in the near future, thereby validating the use of dietary anti-obesity supplements in Japan. PMID- 26005507 TI - Effects of Oral L-Citrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina. AB - BACKGROUND: Decreased nitric oxide (NO) bioavailability and increased lipid oxidation are associated with progressive endothelial dysfunction. L-Citrulline, the effective precursor of L-arginine which is essential as a substrate for endothelial NO synthase (eNOS), is effective in enhancing NO-dependent signaling. However, little is known about the efficacy of L-citrulline supplementation on lipoprotein oxidation and endothelial dysfunction. METHODS: Twenty-two patients (aged 41 - 64 years old) diagnosed with vasospastic angina with flow-mediated dilation (FMD) of the brachial artery (< 5.5 %) received 800 mg/day of L citrulline for 8 weeks. FMD (%), blood NOx, asymmetric dimethylarginine (ADMA), small dense LDL, oxidized lipids, amino acids concentrations were measured before and after supplementation. RESULTS: Compared with baseline values, FMD (%) was significantly improved at 4 and 8 weeks as well as at 4 weeks after the end of intake. L-Citrulline supplementation caused a significant lowering of plasma ADMA levels. Plasma L-arginine/ADMA ratio and NOx levels rose markedly throughout the study period. Moreover, significant reductions of serum oxidized LDL and lectin like oxidized LDL receptor 1 (LOX-1) ligand containing ApoB (LAB), an indicator of the biological activity of oxidized lipoprotein binding to LOX-1, were observed after L-citrulline intake. CONCLUSIONS: L-Citrulline supplementation improves endothelial dysfunction, probably due to potentiating NO-dependent reactions and decreasing the state of lipoprotein oxidation in humans. PMID- 26005508 TI - Therapeutic Angiogenesis by Gene Therapy for Critical Limb Ischemia: Choice of Biological Agent. AB - Peripheral artery disease (PAD) is caused by atherosclerosis, hardening and narrowing arteries over time due to buildup of fatty deposit in vascular bed called plaque. Severe blockage of an artery of the lower extremity markedly reduce blood flow, resulting in critical limb ischemia (CLI) manifested by a variety of clinical syndromes including rest pain in the feet or toes, ulcer and gangrene with infection. Despite significant advances in clinical care and interventions for revascularization, patients with CLI remain at high risk for amputation and cardiovascular death. To overcome this unmet need, therapeutic angiogenesis using angiogenic growth factors has evolved in an attempt to increase blood flow in ischemic limb. Initial animal studies and phase I clinical trials with vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) demonstrated promising results, inspiring scientists to progress forward. However, more rigorous phase II and III clinical trials have failed to demonstrate beneficial effects of these angiogenic growth factors to date. Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (phase III) and US (phase II) demonstrated that hepatocyte growth factor (HGF) gene therapy for CLI significant improved primary end points and tissue oxygenation up to two years in comparison to placebo. These clinical results implicate a distinct action of HGF on cellular processes involved in vascular remodeling under pathological condition. This review presents data from phase I III clinical trials of therapeutic angiogenesis by gene therapy in patients with PAD. Further, we discuss the potential explanation for the success or failure of clinical trials in the context of the biological mechanisms underlying angiogenesis and vascular remodeling, including cellular senescence, inflammation, and tissue fibrosis. PMID- 26005509 TI - Comparative Dynamics and Sequence Dependence of DNA and RNA Binding to Single Walled Carbon Nanotubes. AB - Noncovalent polymer-single walled carbon nanotube (SWCNT) conjugates have gained recent interest due to their prevalent use as electrochemical and optical sensors, SWCNT-based therapeutics, and for SWCNT separation. However, little is known about the effects of polymer-SWCNT molecular interactions on functional properties of these conjugates. In this work, we show that SWCNT complexed with related polynucleotide polymers (DNA, RNA) have dramatically different fluorescence stability. Surprisingly, we find a difference of nearly 2500-fold in fluorescence emission between the most fluorescently stable DNA-SWCNT complex, C30 DNA-SWCNT, compared to the least fluorescently stable complex, (AT)7A-(GU)7G DNA-RNA hybrid-SWCNT. We further reveal the existence of three regimes in which SWCNT fluorescence varies nonmonotonically with SWCNT concentration. We utilize molecular dynamics simulations to elucidate the conformation and atomic details of SWCNT-corona phase interactions. Our results show that variations in polynucleotide sequence or sugar backbone can lead to large changes in the conformational stability of the polymer SWCNT corona and the SWCNT optical response. Finally, we demonstrate the effect of the coronae on the response of a recently developed dopamine nanosensor, based on (GT)15 DNA- and (GU)15 RNA-SWCNT complexes. Our results clarify several features of the sequence dependence of corona phases produced by polynucleotides adsorbed to single walled carbon nanotubes, and the implications for molecular recognition in such phases. PMID- 26005510 TI - Measuring Physical Activity in Outdoor Community Recreational Environments: Implications for Research, Policy, and Practice. AB - Chronic diseases such as cardiovascular disease (CVD) are major contributors to escalating health care costs in the USA. Physical activity is an important protective factor against CVD, and the National Prevention Strategy recognizes active living (defined as a way of life that integrates physical activity into everyday routines) as a priority for improving the nation's health. This paper focuses on developing more inclusive measures of physical activity in outdoor community recreational environments, specifically parks and trails, to enhance their usability for at-risk populations such as persons with mobility limitations. We develop an integrated conceptual framework for measuring physical activity in outdoor community recreational environments, describe examples of evidence-based tools for measuring physical activity in these settings, and discuss strategies to improve measurement of physical activity for persons with mobility limitations. Addressing these measurement issues is critically important to making progress towards national CVD goals pertaining to active community environments. PMID- 26005513 TI - A silver anniversary of the internet. PMID- 26005512 TI - Interdisciplinarity as cognitive integration: auditory verbal hallucinations as a case study. AB - : In this article, we advocate a bottom-up direction for the methodological modeling of interdisciplinary research based on concrete interactions among individuals within interdisciplinary projects. Drawing on our experience in Hearing the Voice (a cross-disciplinary project on auditory verbal hallucinations running at Durham University), we focus on the dynamic if also problematic integration of cognitive science (neuroscience, cognitive psychology, and of mind), phenomenology, and humanistic disciplines (literature, narratology, history, and theology). We propose a new model for disciplinary integration which brings to the fore an under-investigated dynamic of interdisciplinary projects, namely their being processes of distributed cognition and cognitive integration. WIREs Cogn Sci 2014, 5:603-612. doi: 10.1002/wcs.1305 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. PMID- 26005511 TI - Effects of Exercise on Gene Expression of Inflammatory Markers in Human Peripheral Blood Cells: A Systematic Review. AB - Regular physical activity seems to be one of the most important contributors to prevent disease and promote health. Being physically active reduces the risk of developing chronic diseases such as cardiovascular disease, diabetes, and some types of cancers. The molecular mechanisms are however not fully elucidated. Depending on duration and intensity, exercise will cause disruption of muscle fibers triggering a temporary inflammatory response. This response may not only involve the muscle tissue, but also peripheral tissues such as white blood cells, which are important components of the immune system. The immune system plays a vital role in the development of atherosclerosis, thereby making white blood cells relevant to study when looking at molecular mechanisms induced by physical activity. In this review, we summarize the existing literature on exercise and gene expression in human white blood cells, and discuss these results in relation to inflammation and atherosclerosis. PMID- 26005514 TI - Cardiovascular-related healthcare resource utilization and costs in patients with hypertension switching from metoprolol to nebivolol. AB - BACKGROUND: The prevalence of hypertension is increasing in the United States and the associated costs are soaring. Despite the many treatment options, only approximately 50% of Americans with hypertension achieve optimal control. Patients receiving nebivolol, a third-generation beta-blocker, have fewer adverse events and better treatment persistence compared with patients receiving other antihypertensive agents. Little is known about the impact of switching from a second-generation beta-blocker, such as metoprolol, to nebivolol on healthcare resource utilization and costs. OBJECTIVE: To assess the impact of switching patients with hypertension from metoprolol to nebivolol on the associated healthcare resource utilization and cost. METHOD: This retrospective claims-based analysis included 765 adults aged >=18 years who were diagnosed with hypertension between January 1, 2008, and December 31, 2012. Data were extracted from the HealthCore Integrated Research Database; the study was conducted between July 1, 2007, and June 30, 2013. To be included in the study, patients had to receive metoprolol for >=6 months before switching from metoprolol to nebivolol (the preperiod), and continue to use nebivolol for an additional 6 months after switching (the postperiod). Patients with compelling indications for metoprolol but not for nebivolol were excluded from the study. The primary outcome measures were healthcare resource utilization and costs for cardiovascular (CV)-related events. The CV-related resource utilization was calculated based on 100 patients per month; the CV-related costs were calculated per patient per month (PPPM) in 2013 US dollars. RESULTS: A total of 765 patients were included in the analysis. Compared with the preperiod, patients switching to nebivolol had significantly fewer CV-related emergency department visits (0.2 [standard deviation (SD), 1.9] vs 0.04 [SD, 0.8], respectively; P = .012) and fewer CV-related outpatient visits (9.2 [SD, 19.9] vs 6.7 [SD, 17.5], respectively; P <.001). The numbers of inpatient visits in the preperiod and postperiod were similar (0.3 [SD, 2.4] vs 0.1 [SD, 1.5], respectively; P = .164). Patients switching to nebivolol also had significantly lower CV-related emergency department costs ($6 [SD, $78] vs $1 [SD, $27] PPPM, respectively; P = .028) and lower CV-related total medical costs ($94 [SD, $526] vs $54 [SD, $266] PPPM, respectively; P = .020). CONCLUSION: This analysis of real-world data suggests that patients with hypertension who switch from the second-generation antihypertensive metoprolol to the third-generation hypertensive nebivolol have significantly lower CV-related healthcare resource utilization (eg, emergency department and outpatient visits) and lower CV-related medical costs. PMID- 26005515 TI - The cost of unintended pregnancies for employer-sponsored health insurance plans. AB - BACKGROUND: Pregnancy is associated with a significant cost for employers providing health insurance benefits to their employees. The latest study on the topic was published in 2002, estimating the unintended pregnancy rate for women covered by employer-sponsored insurance benefits to be approximately 29%. OBJECTIVES: The primary objective of this study was to update the cost of unintended pregnancy to employer-sponsored health insurance plans with current data. The secondary objective was to develop a regression model to identify the factors and associated magnitude that contribute to unintended pregnancies in the employee benefits population. METHODS: We developed stepwise multinomial logistic regression models using data from a national survey on maternal attitudes about pregnancy before and shortly after giving birth. The survey was conducted by the Centers for Disease Control and Prevention through mail and via telephone interviews between 2009 and 2011 of women who had had a live birth. The regression models were then applied to a large commercial health claims database from the Truven Health MarketScan to retrospectively assign the probability of pregnancy intention to each delivery. RESULTS: Based on the MarketScan database, we estimate that among employer-sponsored health insurance plans, 28.8% of pregnancies are unintended, which is consistent with national findings of 29% in a survey by the Centers for Disease Control and Prevention. These unintended pregnancies account for 27.4% of the annual delivery costs to employers in the United States, or approximately 1% of the typical employer's health benefits spending for 1 year. Using these findings, we present a regression model that employers could apply to their claims data to identify the risk for unintended pregnancies in their health insurance population. CONCLUSION: The availability of coverage for contraception without employee cost-sharing, as was required by the Affordable Care Act in 2012, combined with the ability to identify women who are at high risk for an unintended pregnancy, can help employers address the costs of unintended pregnancies in their employee benefits population. This can also help to bring contraception efforts into the mainstream of other preventive and wellness programs, such as smoking cessation, obesity management, and diabetes control programs. PMID- 26005516 TI - Economic burden of opioid-induced constipation among long-term opioid users with noncancer pain. AB - BACKGROUND: Opioid-induced constipation (OIC) can be a debilitating side effect of opioid therapy and may result in increased medical costs. The published data on the economic burden of OIC among long-term opioid users are limited. OBJECTIVE: To assess the economic burden of OIC in patients with noncancer pain in a managed care population in the United States. METHODS: This retrospective study used 2007-2011 data from the Truven Health MarketScan Commercial and Medicare databases. The study included adults with >=12 months of insurance enrollment before and after starting long-term (>=90 days) use of opioids. Patients were excluded if they had cancer or a diagnosis of drug abuse or drug dependence during the study period, or if they had constipation or bowel obstruction within 90 days before starting opioid therapy during the study period. OIC was identified by International Classification of Diseases, Ninth Edition codes for constipation (564.0) or bowel obstruction (560.x) within 12 months of the initiation of an opioid. Patients with OIC were identified in the nonelderly, elderly (age >=65 years), and long-term care populations. Differences in costs and healthcare resource utilization were calculated using propensity scoring. RESULTS: A total of 13,808 nonelderly (age, 48.6 +/- 10.4 years; female, 50%) and 2958 elderly patients (age, 78.7 +/- 8.1 years; female, 70%) met the study inclusion criteria. Of 401 nonelderly and 194 elderly patients with OIC, 85 patients initiated opioid therapy in a long-term care facility (age, 80.7 +/- 11.6 years; female, 77%). After matching by key covariates, patients with OIC had significantly more hospital admissions than patients without OIC (nonelderly, 33% vs 22%, respectively; P <.001; elderly, 51% vs 31%, respectively; P <.001) and longer inpatient stays (nonelderly, 3.0 +/- 8.4 days vs 1.0 +/- 3.0 days, respectively; P <.001; elderly, 5.2 +/- 12.2 days vs 2.1 +/- 4.0 days, respectively; P <.001). The group with OIC had significantly higher total healthcare costs than the group without OIC in all 3 study cohorts (nonelderly, $23,631 +/- $67,209 vs $12,652 +/- $19,717, respectively; elderly, $16,923 +/- $38,191 vs $11,117 +/- $19,525, respectively; long-term care, $16,000 +/- $22,897 vs $14,437 +/- $25,690, respectively; all P <.05). CONCLUSION: To the best of our knowledge, this is the first study to analyze the economic impact of long-term use of opioids among patients with OIC, using real-world data. The findings underscore the significant economic burden associated with long-term opioid use for noncancer pain in a managed care population. Effective therapies for OIC may reduce the associated economic burden and improve quality of life for long-term opioid users. PMID- 26005517 TI - Lessons Learned from the Proteccion en Construccion Community Research Partnership. AB - PenC seeks to build community-university-labor partnership in order to design, implement and evaluate an intervention aimed at preventing falls and silica exposure among Latino construction workers. This study evaluated the PenC partnership process. Semi-structured partner interviews and surveys were used. Thematic, univariate and bivariate analyses were conducted; results were presented back to partners who then provided data context. Although all partners report increased capacity including new connections and knowledge, resident researchers, here promotores, are much more likely to share information with their neighbors and other local residents. Engaging residents can lead to deeper community penetration. PMID- 26005518 TI - Inhibitors of the PAR-2 Signaling Pathway May Treat Pain and Inflammation. PMID- 26005519 TI - Inhibitors of the PD-1/PD-L1 Pathway Can Mobilize the Immune System: An Innovative Potential Therapy for Cancer and Chronic Infections. PMID- 26005520 TI - EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. AB - Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology. PMID- 26005521 TI - Antagonism/Agonism modulation to build novel antihypertensives selectively triggering i1-imidazoline receptor activation. AB - Pharmacological studies have suggested that I1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I1-agonists, devoid of the side effects associated with the common hypotensive alpha2 adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I1 proteins. PMID- 26005522 TI - Discovery of Quinazoline-Based Fluorescent Probes to alpha1-Adrenergic Receptors. AB - alpha1-Adrenergic receptors (alpha1-ARs), as the essential members of G protein coupled receptors (GPCRs), can mediate numerous physiological responses in the sympathetic nervous system. In the current research, a series of quinazoline based small-molecule fluorescent probes to alpha1-ARs (1a-1e), including two parts, a pharmacophore for alpha1-AR recognition and a fluorophore for visualization, were well designed and synthesized. The biological evaluation results displayed that these probes held reasonable fluorescent properties, high affinity, accepted cell toxicity, and excellent subcellular localization imaging potential for alpha1-ARs. PMID- 26005523 TI - Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors. AB - A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c Met and warrants further investigation. PMID- 26005525 TI - Design and Validation of FRESH, a Drug Discovery Paradigm Resting on Robust Chemical Synthesis. AB - A method capable of identifying novel synthetic targets for small molecule lead optimization has been developed. The FRESH (FRagment-based Exploitation of modular Synthesis by vHTS) approach relies on a multistep synthetic route to a target series of compounds devised by a close collaboration between synthetic and computational chemists. It combines compound library generation, quantitative structure-acitvity relationship construction, fragment processing, virtual high throughput screening and display of results within the Pipeline Pilot framework. Outcomes enumerate tailored selection of novel synthetic targets with improved potency and optimized physical properties for an emerging compound series. To validate the application of FRESH, three retrospective case studies have been performed to pinpoint reported potent analogues. One prospective case study was performed to demonstrate that FRESH is able to capture additional potent analogues. PMID- 26005524 TI - Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes. AB - The imidazolyl-tetrahydro-beta-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1 ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro 1H-beta-carboline (17e, MK-1421). PMID- 26005527 TI - Simple Methods for Tracking Stem Cells with (64)Cu-Labeled DOTA-hexadecyl benzoate. AB - The purpose of this study was to evaluate (64)Cu-labeled hexadecyl-1,4,7,10 tetraazacyclododecane-tetraacetic acid-benzoate ((64)Cu-DOTA-HB) (1) as positron emission tomography (PET) radiotracer for stem cell imaging. Hexadecyl-DOTA benzoate (DOTA-HB) (2) was efficiently labeled with (64)Cu (>99%), and cell labeling efficiency with adipose-derived stem cells (ADSCs) was over 50%. Labeling with 1 did not compromise cell viability. In the PET imaging, intramuscularly transplanted 1-labeled ADSCs were monitored for 18 h in normal rat heart. These results indicate that 1 can be utilized as a promising radiotracer for monitoring of transplanted stem cells. PMID- 26005526 TI - Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors. AB - Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl) succinamides identified highly potent inhibitors of gamma-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation. PMID- 26005528 TI - Discovery of a Potent Class of PI3Kalpha Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT). AB - In the search of PI3K p110alpha wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110alpha protein. PMID- 26005529 TI - SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3. AB - A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-beta-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design. PMID- 26005530 TI - N-(3-Ethynyl-2,4-difluorophenyl)sulfonamide Derivatives as Selective Raf Inhibitors. AB - A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-Raf(V600E) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferation of a panel of human cancer cell lines and patient-derived melanoma cells with B Raf(V600E) mutation while being significantly less potent to the cells with B Raf(WT). The compounds also display favorable pharmacokinetic properties with a preferred example (3s) demonstrating significant in vivo antitumor efficacy in a xenograft mouse model of B-Raf(V600E) mutated Colo205 human colorectal cancer cells, supporting it as a promising lead compound for further anticancer drug discovery. PMID- 26005531 TI - Synthesis and Initial in Vivo Studies with [(11)C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3. AB - Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [(11)C]SB-216763, a high affinity inhibitor of GSK-3 (K i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [(11)C]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [(11)C]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [(11)C]SB-216763 in 1% noncorrected radiochemical yield (based upon [(11)C]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use. PMID- 26005532 TI - Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement. AB - Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1 ((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors. PMID- 26005533 TI - Monocarboxylate transporter 1 inhibitors as potential anticancer agents. AB - Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on alpha-cyano-4-hydroxycinnamic acid template. Structure-activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth. PMID- 26005534 TI - (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors. AB - Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs. PMID- 26005535 TI - Synthesis and Pharmacology of alpha/beta(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence. AB - The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of beta(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear alpha/beta(3)-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-beta(3)hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands. PMID- 26005537 TI - Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines. AB - As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2), we report here the synthesis and biological activities of a new series of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH2 (where Dmt = 2',6' dimethyltyrosine), incorporating fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine (2,4-F-Phe), or 4 trifluoromethylphenylalanine (4-CF3-Phe) instead of the Phe residue in position 3 or 4. Depending on the fluorinated amino acid residue and its position in the sequence, analogues were mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists, or selective KOP agonists. The in vitro potencies and efficacies of all novel analogues were assessed in calcium mobilization assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH2 and Dmt-c[d-Lys-Phe 2,4-F-Phe-Asp]NH2, were tested in vivo in the mouse hot-plate test. They produced strong antinociceptive effect not only after intracerebroventricular but also after intraperitoneal injection, indicating that they were able to cross the blood-brain barrier. PMID- 26005536 TI - Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys. AB - We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels. PMID- 26005538 TI - Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor. AB - Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report a 2-anilino-4-methylamino-5 chloropyrrolopyrimidine, JH-II-127 (18), as a potent and selective inhibitor of both wild-type and G2019S mutant LRRK2. Compound 18 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 MUM in a variety of cell types and is capable of inhibiting Ser935 phosphorylation in mouse brain following oral delivery of doses as low as 30 mg/kg. PMID- 26005539 TI - Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety. AB - Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 MUM. Dose-dependent efficacy (EC50 of 0.53 MUM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation. PMID- 26005540 TI - Design of Pyridopyrazine-1,6-dione gamma-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability. AB - Herein we describe the design and synthesis of a series of pyridopyrazine-1,6 dione gamma-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Abeta42 and Abeta40 were observed in a guinea pig time-course experiment. PMID- 26005541 TI - Design, Synthesis, and Pharmacological Evaluation of Fused beta-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused beta homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4. PMID- 26005542 TI - Design and Evaluation of 3-(Benzylthio)benzamide Derivatives as Potent and Selective SIRT2 Inhibitors. AB - Inhibitors of sirtuin-2 (SIRT2) deacetylase have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the 3 (benzylsulfonamido)benzamide scaffold and improving their metabolic stability. Molecular modeling and docking studies revealed an unfavorable role of the sulfonamide moiety for SIRT2 binding. This prompted us to replace the sulfonamide with thioether, sulfoxide, or sulfone groups. The thioether analogues were the most potent SIRT2 inhibitors with a two- to three-fold increase in potency relative to their corresponding sulfonamide analogues. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. Two thioether-derived compounds (17 and 18) increased alpha-tubulin acetylation in a dose-dependent manner in at least one neuronal cell line, and 18 was found to inhibit polyglutamine aggregation in PC12 cells. PMID- 26005543 TI - Bis-arylidene oxindole-betulinic Acid conjugate: a fluorescent cancer cell detector with potent anticancer activity. AB - Molecules offering simultaneous detection and killing of cancer cells are advantageous. Hybrid of cancer cell-selective, ROS generator betulinic acid and bis-arylidene oxindole with amino propyl-linker is developed. With intrinsic fluorescence, the molecule exhibited cancer cell-specific residence. Further, it generated ROS, triggered apoptosis, and exhibited potent cytotoxicity in cancer cells selectively. We demonstrate the first example and use of isatins as betulinic acid conjugate for selective detection of cancer and subsequent killing of cancer cells via apoptosis. PMID- 26005544 TI - Technology allows detection of target molecules and production of biologic agents for treatment of ocular inflammatory disorders. PMID- 26005545 TI - Measurement of Central Corneal Thickness Using Ultrasound Pachymetry and Orbscan II in Normal Eyes. AB - PURPOSE: To compare ultrasound pachymetry and Orbscan II for measurement of central corneal thickness (CCT) in normal eyes. METHODS: The current study was performed at Labbafinejad Medical Center (LMC), Tehran, Iran. Three hundred eyes from 150 healthy individuals referred for keratorefractive surgery were assessed first by Orbscan II and then by ultrasound pachymetry, and CCT values were recorded and compared. RESULTS: Overall, Orbscan II overestimated CCT as compared to ultrasound pachymetry by about 2.4% (mean values 547.6 +/- 34.7 versus 534.8 +/- 34.7, respectively, P < 0.001). The difference was more significant when CCT was less than 500 microns (mean values 493.2 +/- 16.9 versus 479.9 +/- 15.6, mean overestimation: 2.6%, P < 0.001). There was good linear correlation between the two methods (Pearson's correlation r = 0.968, P < 0.0001). CONCLUSION: Orbscan II has good correlation with ultrasound pachymetry for measurement of CCT in normal eyes; however Orbscan II should not be used to evaluate corneal thickness before keratorefractive surgeries, as it tends to overestimate corneal thickness and may result in undesirable, low residual stromal thickness. PMID- 26005546 TI - Sensitivity and specificity of posterior and anterior corneal elevation measured by orbscan in diagnosis of clinical and subclinical keratoconus. AB - PURPOSE: To determine the sensitivity and specificity of anterior and posterior corneal elevation parameters as determined by Orbscan II (Bausch and Lomb, Rochester, NY, USA) in discriminating between (sub) clinical keratoconus (KCN) and normal corneas. METHODS: This prospective case-control study included 28 eyes with subclinical KCN, 65 with clinical KCN and 141 normal corneas. Anterior and posterior corneal elevation was measured and compared in the central 5-mm corneal zone using Orbscan II. RESULTS: Receiver operating curves (ROC) curve analyses for posterior corneal elevation showed predictive accuracy in both KCN and subclinical KCN with an area under the curve (AUC) of 0.97 and 0.69, respectively while optimal cutoff points were 51 MUm for KCN and 35 MUm for subclinical KCN. These values were associated with sensitivity and specificity of 89.23% and 98.58%, respectively, for KCN; and 50.00% and 88.65% for subclinical KCN. ROC curve analyses for anterior corneal elevation showed predictive accuracy in both KCN and subclinical KCN with AUC of 0.97 and 0.69, respectively while optimal cutoff points were 19 MUm for KCN and 16 MUm for subclinical KCN. These values were associated with sensitivity and specificity of 93.85% and 97.16%, respectively, for KCN; and 60.71% and 87.94% for subclinical KCN. CONCLUSION: Anterior and posterior corneal elevation data obtained by Orbscan II can well discriminate between KCN and normal corneas, however the reliability of their indices is lower in differentiating subclinical KCN from normal cases. PMID- 26005547 TI - Corneal Collagen Cross-linking for Treatment of Non-healing Corneal Ulcers. AB - PURPOSE: To evaluate the efficacy of corneal collagen cross-linking (CXL) for treatment of corneal ulcers not responding to antimicrobial therapy. METHODS: Eight patients with corneal ulcers associated with corneal melting, not responding to conventional antibiotic therapy, were treated with CXL. The procedure was performed according to the standardized protocol for keratoconus. Preoperative medications were continued after CXL in all cases. Microbiological exams revealed Pseudomonas aeruginosa in 3 cases. Follow up continued from 1 to 10 months. RESULTS: In 6 of 8 eyes, progression of corneal melting was halted and complete epithelialization occurred. In one eye emergency keratoplasty was needed due to corneal perforation. A conjunctival flap was performed to treat severe localized corneal thinning in one of the patients a few days after CXL. Significant clinical improvement occurred in all cases of Pseudomonas aeruginosa keratitis. CONCLUSION: CXL can be considered as a promising new treatment in the management of refractory non-healing corneal ulcers, including Pseudomonas aeruginosa keratitis. PMID- 26005548 TI - Topical cyclosporine a for mustard gas induced ocular surface disorders. AB - PURPOSE: To evaluate the effectiveness of topical cyclosporine A 0.05% for treatment of mustard gas-induced ocular surface disorders with special attention to conjunctival goblet cell density in patients with severe dry eye. METHODS: This prospective clinical study included 20 eyes of 20 patients previously exposed to mustard gas with dry eye syndrome unresponsive to artificial tears. Before and after treatment with topical cyclosporine A 0.05% twice daily for 3 months, subjects were evaluated for improvement in symptoms using the ocular surface disease index (OSDI) and signs by tear breakup time (TBUT), Schirmer test and measurement of superior bulbar conjunctival goblet cell density. Limbal stem cell deficiency (LSCD) and the degree of corneal squamous cell metaplasia were also assessed before and after treatment. RESULTS: Before treatment, mean OSDI score, Schirmer test I value and mean TBUT were 42.8 +/- 6.1, 4.2 +/- 1.2 mm and 2.5 +/- 1.3 s, respectively. After 3 months of treatment with topical cyclosporine A, these scores reached 36.4 +/- 5.2, 5.8 +/- 1.6 mm and 4.9 +/- 2.1 s, respectively showing a statistically significant improvement (P < 0.001) in all parameters. Mean goblet cell density was 23.3 +/- 17.1/high power field (hpf) at baseline which was significantly increased to 47.7 +/- 16.1/hpf at the end of the study (P < 0.001). There was no improvement, however, in corneal conjunctivalization, LSCD and the degree of corneal squamous cell metaplasia based on impression cytology reports (P > 0.05). CONCLUSION: Treatment with topical cyclosporine A 0.05% in patients with severe dry eye due to mustard gas injury increases goblet cell density in the bulbar conjunctiva and improves symptoms of the disease. PMID- 26005549 TI - Ultra high resolution optical coherence tomography in Boston type I keratoprosthesis. AB - PURPOSE: To evaluate the anterior keratoprosthesis-cornea interface in eyes with Boston type I keratoprosthesis (Kpro). METHODS: In a prospective non interventional study, patients with Boston type I Kpro underwent ultra-high resolution optical coherence tomography (UHR-OCT) evaluation. The images were used to measure and describe characteristics of the anterior keratoprosthesis cornea interface, epithelial interaction at the keratoprosthesis edge and the keratoprosthesis-cornea interface gap. RESULTS: Ten patients including 4 male and 6 female subjects with different preoperative diagnoses, i.e. 8 multiple corneal graft failures and 2 immunological ocular surface diseases, were studied. Mean age was 62.1 +/- 20.0 (range, 33.0-83.0) years and mean interval between surgery and UHR-OCT evaluation was 15.2 +/- 11.09 months. In eight patients, 360 degrees epithelial growth over the peripheral edge of the Kpro was documented. We detected keratoprosthesis-cornea interface gap in three patients. One subject had developed postoperative endophthalmitis 8 months after surgery and the other two cases were among the high risk group according to the preoperative diagnosis. In one patient with severe ocular hypotony, the Kpro edge was inserted into the anterior stroma and covered with epithelium. CONCLUSION: UHR-OCT showed that corneal epithelium covers the Kpro edge and seals the potential space between the Kpro and cornea in 80% of cases. The presence of a gap in the interface and lack of epithelial sealing around the Kpro edge might be associated with endophthalmitis. PMID- 26005550 TI - Perioperative prophylaxis for endophthalmitis after cataract surgery in iran. AB - PURPOSE: To describe prophylactic patterns employed against endophthalmitis after cataract surgery in Iran. METHODS: This cross-sectional study included 486 ophthalmologists filling in a self-administered questionnaire during the 20(th) Annual Congress of the Iranian Society of Ophthalmology in December 2010, Tehran, working in both private and academic medical centers. Prophylactic measures used preoperatively, intraoperatively and postoperatively and self-reported rates of endophthalmitis were assessed as the main outcome measurements. RESULTS: In the preoperative phase, 75.5% of surgeons used povidone-iodine in the conjunctival sac and 71.4% of them did not use antibiotics. The rate of intraoperative prophylaxis was 61.9% either in the form of intracameral antibiotics or subconjunctival injection (mostly cephazolin or gentamicin). Only 7.8% of participants used intracameral cephalosporins. Postoperative antibiotics [mostly chloramphenicol (57%) and ciprofloxacin (28%)] were used by 94.2% of surgeons. On average, ten years of practice were required to observe one case of endophthalmitis. CONCLUSION: The surgeons in present setting used various prophylactic regimens against endophthalmitis after cataract surgery. Setting a local and evidence-based clinical practice guideline seems necessary. PMID- 26005551 TI - Neodymium-yttrium aluminium garnet laser capsulotomy energy levels for posterior capsule opacification. AB - PURPOSE: To study factors affecting laser energy levels required for neodymium: yttrium aluminium garnet (Nd: YAG) laser capsulotomy and to evaluate whether any correlation exists between applied laser energy levels and complications. METHODS: The present study examined 474 consecutive patients for a number of factors including age, type of posterior capsule opacification (PCO), material and fixation of intraocular lens (IOL) and complication rates, versus energy levels used for Nd: YAG laser capsulotomy. RESULTS: Mean patient age was 55.6 +/- 8.7 years and mean follow up period was 22.9 +/- 4.5 months. IOL biomaterial (KW ANOVA; P = 0.173) and patient's age (P = 0.246) did not significantly influence total laser energy requirement for capsulotomy. However, total laser energy levels were significantly higher (KW ANOVA; P < 0.001) with fibro-membranous and fibrous subtypes of PCO. Complications such as IOL pitting, intraocular pressure (IOP) elevation, uveitis, retinal detachment (RD) and cystoid macular edema (CME) were significantly more common when higher energy levels was used. The mean total energy in patients with RD was 77.7 +/- 17.7 mJ as compared to 43.4 +/- 26.9 mJ in the rest of the cohort. RD was more common in patients with higher axial length [n = 7 (63%)] (P < 0.001). CONCLUSION: Type of PCO significantly influenced laser energy levels required for capsulotomy, whereas IOL biomaterial and fixation did not. Complications such as IOL pitting, uveitis, IOP elevation, RD and CME was significantly more common when total laser energy was higher. It is recommended that the lowest possible single pulse laser energy be used for capsulotomy to minimize complications. PMID- 26005552 TI - Intraocular pressure measurement by three different tonometers in primary congenital glaucoma. AB - PURPOSE: To determine the agreement between intraocular pressure (IOP) measurements using an automated non-contact tonometer (NCT), Goldmann applanation tonometer (GAT), and the ocular response analyzer (ORA) in subjects with primary congenital glaucoma (PCG). METHODS: Twenty-nine eyes of 17 PCG patients underwent IOP measurements using NCT, GAT and ORA. Variables obtained by the ORA were corneal-compensated IOP (IOPcc), Goldmann-correlated IOP (IOPg), corneal hysteresis (CH), and corneal resistance factor (CRF). A difference more than 1.5 mmHg for IOP was considered as clinically relevant. RESULTS: Mean age of the patients was 12 years. Mean IOP (+/-standard deviation, SD) was 15.3 +/- 2.8 mmHg (GAT), 15.5 +/- 6.0 (NCT), 19.2 +/- 7.0 (IOPg), and 21.1 +/- 7.9 (IOPcc); (P = 0.001). Except for NCT vs. GAT (P = 1.0), the average IOP difference between each pair of measurements was clinically relevant. The 95% limits of agreements were - 10.2 to 10.3 mmHg (NCT vs. GAT), -7.8 to 15.3 (IOPg vs. GAT), and - 8.1 to 19.0 (IOPcc vs. GAT). The differences in IOP measurements increased significantly with higher average IOP values (r = 0.715, P = 0.001, for NCT vs. GAT; r = 0.802, P < 0.001, for IOPg vs. GAT; and r = 0.806, P < 0.001, for IOPcc vs. GAT). CH showed a significant association with differences in IOP measurements only for IOPcc vs. GAT (r = 0.830, P < 0.001). CONCLUSION: Mean IOP obtained by NCT was not significantly different from that of GAT, but ORA measured IOPs were significantly higher than both other devices. PMID- 26005553 TI - Aqueous Humor Levels of Different Interleukins 1-beta, 2, 6 and 10, Tumor Necrosis Factor-alpha and Vascular Endothelial Growth Factor in Uveitis Treated with Adalimumab. AB - PURPOSE: To assess changes in aqueous humor levels of different interleukins (IL), tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF) in patients with uveitis treated with adalimumab. METHODS: In this study, 24 aqueous humor samples including 12 pre- and post-treatment samples from 6 patients with uveitis treated with subcutaneous adalimumab and 12 samples from patients with cataracts (serving as controls) were evaluated. The levels of IL 1beta, IL-2, IL-6, IL-10, TNF-alpha and VEGF were measured using a Luminex((r)) 200TM flow cytometer (Merckmillipore, Merck KGaA, Darmstadt, Alemania) and a highly sensitive ELISA system. RESULTS: The levels of IL-1beta, IL-2, IL-6 and IL 10 in the aqueous humor before and after treatment with adalimumab did not show significant differences. Aqueous VEGF levels significantly reduced after treatment with adalimumab (P = 0.028). Aqueous TNF-alpha levels did not significantly change after treatment with adalimumab, however the post-treatment level was significantly higher in patients as compared to control subjects (P = 0.032). IL-2 showed significantly higher levels in uveitis patients before treatment as compared to controls (P = 0.024), while its post-treatment levels were almost normalized. CONCLUSION: Decrease in the aqueous humor levels of VEGF and IL-2 after treatment with systemic adalimumab indicates that anti-TNF-alpha therapy induces modifications of some inflammatory mediators involved in the pathogenesis of uveitis. Aqueous humor samples may be useful to assess the effect of adalimumab on intraocular inflammation through measurement of cytokines. PMID- 26005554 TI - Encircling Narrow Band versus Buckle for Retinal Detachments with Intrabasal or Unseen Retinal Breaks. AB - PURPOSE: To compare the results of narrow encircling band surgery with standard encircling scleral buckling for retinal detachments (RDs) with intrabasal or unseen breaks. METHODS: In a retrospective study, eyes with intrabasal or unseen breaks underwent narrow band implantation (group N) or standard encircling buckling plus wide tire placement (group W) and were followed for at least one year. RESULTS: A total of 112 eyes including 39 eyes in group N and 73 eyes in group W were studied. Preoperatively visual acuity of eyes in group N was significantly better (1.55 +/- 0.9 vs. 1.93 +/- 0.9 logMAR, P = 0.043). The two study groups (N and W) were comparable in terms of the extent of RD (2.8 +/- 0.96 vs. 2.8 +/- 0.93 quadrants), interval to surgery (88.3 +/- 176.4 vs. 71.9 +/- 135.4 days) and percentage of visible breaks (56.4% vs. 63%), respectively (all P values > 0.05). More atrophic holes were present in group W and more dialyses were reported in group N. The single operation success rate at 12 months was 69.2% in group N and 74% in group W (P = 0.1). The single operation success rate for eyes with unseen breaks was also comparable (66.7% vs. 85.7%, P = 0.157). Final corrected visual acuity was also similar (0.63 +/- 0.44 vs. 0.85 +/- 0.69 log MAR). The only factor influencing success rate was the type of retinal breaks (P = 0.04). Type of scleral buckling did not affect the single operation success rate (P = 0.460). CONCLUSION: Narrow encircling band surgery is a possible option with acceptable single operation success rate for RDs with intrabasal or unseen breaks. PMID- 26005555 TI - Cytochrome P450 1B1 and Primary Congenital Glaucoma. AB - Cytochrome P450 1B1 (Cyp1b1) belongs to the CYP450 superfamily of heme-binding mono-oxygenases which catalyze oxidation of various endogenous and exogenous substrates. The expression of Cyp1b1 plays an important role in the modulation of development and functions of the trabecular meshwork (TM). Mutations in Cyp1b1 have been reported in patients with primary congenital glaucoma (PCG). Mice lacking Cyp1b1 also exhibit developmental defects in the TM similar to those reported in congenital glaucoma patients. However, how Cyp1b1 deficiency contributes to TM dysgenesis remains unknown. In the present review, we will address the significance of Cyp1b1 expression and/or its function in anterior segment development. Cyp1b1-deficient (Cyp1b1 (-/-)) mice are discussed as a promising model for an oxidative stress-induced model of PCG, in which Cyp1b1 activity is revealed as an important modulator of oxidative homeostasis contributing to the development and structural function of the TM. This conclusion suggests a possible clinical intervention for individuals who are genetically at high risk of developing PCG. PMID- 26005556 TI - Glaucoma in iran and contributions of studies in iran to the understanding of the etiology of glaucoma. AB - Epidemiologic and genetic/molecular research on glaucoma in Iran started within the past decade. A population-based study on the epidemiology of glaucoma in Yazd, a city in central Iran, revealed that 4.4% of studied individuals were affected with glaucoma: 1.6% with high tension primary open angle glaucoma (POAG), 1.6% with normal tension POAG, and 0.4% each with primary angle closure glaucoma (PACG) and pseudoexfoliation glaucoma (PEXG), and other types of secondary glaucoma. Two notable observations were the relatively high frequency of normal tension glaucoma cases (1.6%) and the large fraction of glaucoma affected individuals (nearly 90%) who were unaware of their condition. The first and most subsequent genetic studies on glaucoma in Iran were focused on primary congenital glaucoma (PCG) showing that cytochrome P450 1B1 (CYP1B1) is the cause of PCG in the majority of Iranian patients, many different CYP1B1 mutations are present among Iranian patients but only four mutations constitute the vast majority, and the origins of most mutations in the Iranians are identical by descent (IBD) with the same mutations in other populations. Furthermore, most of the PCG patients are from the northern and northwestern provinces of Iran. A statistically significant male predominance of PCG was observed only among patients without CYP1B1 mutations. Clinical investigations on family members of PCG patients revealed that CYP1B1 mutations exhibit variable expressivity, but almost complete penetrance. A great number of individuals harboring CYP1B1 mutations become affected with juvenile onset POAG. Screening of JOAG patients showed that an approximately equal fraction of the patients harbor CYP1B1 and (myocilin) MYOC mutations; MYOC is a well-known adult onset glaucoma causing gene. Presence of CYP1B1 mutations in JOAG patients suggests that in some cases, the two conditions may share a common etiology. Further genetic analysis of Iranian PCG patients led to identification of Latent-transforming growth factor beta-binding protein 2 (LTBP2) as a causative gene for both PCG and several diseases which are often accompanied by glaucomatous presentations, such as Weill Marchesani syndrome 3 (WMS3). The findings on LTBP2 have contributed to recognize the importance of the extracellular matrix in pathways leading to glaucoma. PMID- 26005557 TI - PACK-CXL: Corneal Cross-linking for Treatment of Infectious Keratitis. AB - This article discusses corneal cross-linking (CXL) and how it transitioned from a modality for treating corneal ectatic disorders to an inventive means of treating infectious keratitis. Initially, CXL was successfully developed to halt the progression of ectatic diseases such as keratoconus, using the standard Dresden protocol. Later, indications were extended to treat iatrogenic ectasia developing after laser-assisted in situ keratomileusis (LASIK) and photo-refractive keratectomy (PRK). At the time, it had been postulated that the combination of ultraviolet light with riboflavin could not only biomechanically strengthen the cornea but also was capable of destroying living cells and organisms including keratocytes and pathogens. Thus a new and innovative concept of treatment for infectious keratitis emerged through the use of CXL technology. Initially only advanced infectious melting ulcers resisting standard microbicidal therapy were treated with CXL in addition to standard therapy. In subsequent studies CXL was also used to treat bacterial keratitis as first line therapy without the use of concomitant antibiotic therapy. With the increasing interest in CXL technology to treat infectious keratitis and to clearly separate its use from the treatment of ectatic disorders, a new term was adopted at the 9(th) CXL congress in Dublin for this specific indication: PACK-CXL (photoactivated chromophore for infectious keratitis). PACK-CXL has the potential to eventually become an interesting alternative to standard antibiotic therapy in treating infectious corneal disorders, and may help reduce the global burden of microbial resistance to antibiotics and other therapeutic agents. PMID- 26005558 TI - Complex Descemet's Membrane Tears and Detachment during Phacoemulsification. AB - PURPOSE: To report a case of complex Descemet's membrane detachment (DMD) and tears during phacoemulsification cataract surgery. CASE REPORT: A 64-year-old woman underwent phacoemulsification surgery in her right eye and developed tears and partial loss of Descemet's membrane (DM) while the aspiration port was inserted through the main incision. Massive corneal edema obscured the view and the anterior chamber was barely visible the following day. Scheimpflug imaging was used to complement slit lamp examination in the postoperative period. Frequent topical corticosteroid drops were initiated. After 5 days of treatment, multiple tears and detachment of DM were visible and the anterior chamber was filled with air. After 5 weeks, the cornea regained much of its clarity despite large DM tears and focal loss of DM. CONCLUSION: Despite partial loss of DM, the corneal edema mostly disappeared after 5 weeks of air bubble injection. Scheimpflug imaging was beneficial in the diagnosis and monitoring of DM tears and detachments. PMID- 26005559 TI - Resolution of primary acquired melanosis with atypia after treatment with topical mitomycin C and interferon alfa-2b. AB - PURPOSE: To report a case of primary acquired melanosis (PAM) successfully treated with combined topical mitomycin C and interferon-alpha2b. CASE REPORT: A 75-year-old man presented with an extensive unilateral pigmented lesion involving 360 degrees of the bulbar conjunctiva, extending to the fornices and palpebral conjunctiva. Map biopsy confirmed PAM with local atypia. Treatment was initiated with mitomycin C 0.04% eye drops for two courses. Although the lesion markedly responded to the treatment, residual lesions justified further therapy. To avoid ocular surface toxicity induced by excessive mitomycin C exposure, interferon alpha2b eye drops were started and continued for 6 months. The pigmented lesion almost completely disappeared and no significant complication or recurrence was observed for 24 months. CONCLUSION: Combination therapy using mitomycin C and interferon-alpha2b for PAM with atypia may be recommended as an effective treatment modality, avoiding the ocular surface toxicity due to excessive mitomycin C exposure. PMID- 26005560 TI - Use of a 24 gauge intravenous cannula for minimally invasive trabeculectomy. AB - We describe an innovative technique for performing standardized low cost glaucoma filtration surgery using a polytetrafluoroethylene (PTFE) intravenous cannula. The trocar of a 24 gauge (24G) PTFE intravenous cannula was used to create a trabeculectomy ostium and its tube was inserted under a partial thickness scleral flap in 2 patients with advanced glaucomatous optic neuropathy, in whom intraocular pressure (IOP) was not controlled on maximal tolerable hypotensive therapy. Postoperatively, IOP of the operated eyes at 3, 6 and 9 months' follow up ranged from 12 to 15 mmHg with a well formed anterior chamber and a diffuse bleb. PMID- 26005561 TI - Single block conjunctival limbal autograft for unilateral total limbal stem cell deficiency. PMID- 26005562 TI - Erratum: Amblyopia associated with prominent cilioretinal artery: Erratum. AB - [This corrects the article on p. 520 in vol. 9, PMID: 25709782.]. PMID- 26005563 TI - Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group. AB - Small molecules featuring a hydroxamic acid or a benzamide zinc binding group (ZBG) are the most thoroughly studied histone deacetylase (HDAC) inhibitors. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety and potential metabolic toxicity of the aniline portion of benzamide HDAC inhibitors have stimulated research efforts aimed at discovering alternative ZBGs. Here we report the 2-(oxazol-2-yl)phenol moiety as a novel ZBG that can be used to produce compounds that are potent HDAC inhibitors. A series of analogues with this novel ZBG have been synthesized, and these analogues exhibit selective inhibition against HDAC1 as well as the class IIb HDACs (HDAC6 and HDAC10). Compound 10 possesses an IC50 value of 7.5 MUM in the MV-4-11 leukemia cell line, and induces a comparable amount of acetylated histone 3 lysine 9 (H3K9) and p21Waf1/CIP1 as 0.5 MUM of SAHA. Modeling of compound 10 in the active site of HDAC2 demonstrates that the 2-(oxazol-2-yl)phenol moiety has a zinc-binding pattern similar to benzamide HDAC inhibitors. PMID- 26005564 TI - Evaluating a variety of text-mined features for automatic protein function prediction with GOstruct. AB - Most computational methods that predict protein function do not take advantage of the large amount of information contained in the biomedical literature. In this work we evaluate both ontology term co-mention and bag-of-words features mined from the biomedical literature and analyze their impact in the context of a structured output support vector machine model, GOstruct. We find that even simple literature based features are useful for predicting human protein function (F-max: Molecular Function =0.408, Biological Process =0.461, Cellular Component =0.608). One advantage of using literature features is their ability to offer easy verification of automated predictions. We find through manual inspection of misclassifications that some false positive predictions could be biologically valid predictions based upon support extracted from the literature. Additionally, we present a "medium-throughput" pipeline that was used to annotate a large subset of co-mentions; we suggest that this strategy could help to speed up the rate at which proteins are curated. PMID- 26005565 TI - Reaction of monocytes to polystyrene and silica nanoparticles in short-term and long-term exposures. AB - Nanoparticles (NPs) are increasingly used in industrial, health and consumer products. In addition to the intended effects, NPs may also cause cell damage. Typical cytotoxicity assays assess short-term effects in adherent cells but do not evaluate longer exposure times and do not focus on cells in suspension. Since NPs are not removed easily from the organism, non-biodegradable NPs may persist in the systemic circulation and affect monocyte function at low concentrations. To mimic this situation, THP-1 monocytes were exposed to low concentrations of plain polystyrene particles (PPP) in different sizes for short (24 h) and prolonged (16 d) time periods. CELLine CL350, a small two-chamber bioreactor, and sub-culturing in flasks were compared regarding prolonged cytotoxicity testing. Uptake rates of the particles, cytotoxicity screening assays, and interleukin secretion were used for the identification of adverse effects. After 24 h, 50 MUg ml-1 20 nm PPP did not affect cellular viability and interleukin secretion, while at higher concentrations the cytotoxicity of PPP (20 nm-500 nm) was correlated to surface area. After 16 d of exposure at 50 MUg ml-1 20 nm PPP, the decrease in cell number and the increase in interleukins were significant. 200 nm PPP, by contrast, caused only minimal effects. Due to lower reproducibility, CELLine proved to be less suitable for the assessment as compared to sub-culturing in flasks. After prolonged exposure, silica Aerosil OX50 particles also were more cytotoxic towards THP-1 monocytes. The data suggest that prolonged exposure to NPs leads to cytotoxicity at low doses and that induction of cell death may be involved in the observed pro-inflammatory action of NPs. PMID- 26005566 TI - Diagnoses and clinical features associated with high risk for unplanned readmission in vascular surgery. A cohort study. AB - BACKGROUND: Readmission rate is an established health quality indicator. Preventable readmissions bear an unnecessary, high cost on the healthcare system. An analysis performed by the National Centre for Health Outcomes Development (NCHOD) has demonstrated an increasing trend in emergency readmissions in the UK. Vascular surgery has been reported to have high readmission rates second only to congestive heart failure. This study aims to identify diagnoses and other clinical risk factors for high unplanned readmission rates. This may be the first step to sparing both the health care system and patients of unnecessary readmissions. RESULTS: The overall 30 day readmission rate for Leeds Vascular Institute was 8.8%. The two diagnoses with the highest readmission rates were lower limb ischaemia and diabetic foot sepsis. The readmission rate for medical reasons was overwhelmingly higher than for surgical reasons (6.5% and 2.3% respectively). The most common medical diagnoses were renal disease and COPD. The majority of the patients readmitted under the care of vascular surgery required further surgical treatment. CONCLUSION: Vascular units should focus on holistic and multidisciplinary treatment of lower limb ischaemia and diabetic foot sepsis, in order to prevent readmissions. Furthermore, the early involvement and input of physicians in the treatment of vascular patients with renal disease and COPD may be appropriate. PMID- 26005567 TI - Syndromic deafness-prevalence, distribution and hearing management protocol in Indian scenario. AB - BACKGROUND: The estimated prevalence of Sensory Neural Hearing Loss (SNHL) in patients less than 18 years of age is 6 per 1000. Roughly 50% of cases of congenital SNHL can be linked to a genetic cause, with approximately 30% being syndromic and the remaining 70% being non-syndromic. The term "syndromic" implies the presence of other distinctive clinical features in addition to hearing loss. The aim of our study was to find the distribution of various Syndromic associations in patients with profound deafness, presented at Madras ENT Research foundation, Chennai and to formulate a management protocol for these patients and to discuss in detail about the clinical features of commonly encountered syndromic deafness. MATERIALS AND METHODS: Our retrospective study was aimed at describing the various Syndromic associations seen in patients with congenital profound deafness. Information was collected from the medical records. At our centre all patients undergo a comprehensive evaluation. The distribution, etiological factors and management protocol for various syndromes are here presented. RESULTS: Out of 700 patients with congenital profound deafness all patients with Syndromic associations (n = 35) were studied. 5% of profoundly deaf candidates were found to be syndromic. Most common syndrome in our series was found to be congenital rubella syndrome followed by Jervell and Lange-Nielsen syndrome. CONCLUSION: Congenital deafness is an associated feature of many syndromes. Detailed history taking with comprehensive evaluation is mandatory to rule out the associated syndromes. Diagnosis must be confirm by a genetic study. Multidisciplinary approach is essential for appropriate diagnosis and management. PMID- 26005568 TI - A cross-sectional pilot study to investigate patient attitudes and perception regarding the use of real time digital recording of urological procedures for research and teaching purposes. AB - Little conclusive evidence exists regarding the best way to educate and evaluate skill acquisition of advanced surgical trainees, despite it being recognised as one of the most important aspects of training. Many laparoscopic trainers have been produced with complex engineering at great cost, but, there seems to be a reluctance to use the most precious entity available to us; the patient. We thus propose the use of real time digital recording of urological procedures for research and teaching purposes. This study was prompted by the lack of literature regarding such issues. A 19 question questionnaire was circulated at a single urology out-patient department (Essex, England) over a 6 month period to evaluate attitudes and perceptions of urological patients on potentially having their procedure digitally recorded for educational and research purposes. 11 patients declined, 187 questionnaires were included in the final analysis. Male patients are more willing to consent than female patients. Older patients resulted to have a higher propensity in being recorded for medical teaching. Greater than 50% believe being recorded is intrusive but the majority do not think privacy is an issue. Lastly, the vast majority require a formal debrief post operatively. Our results show that a percentage of the public are potentially willing to be digitally recorded but many financial and social barriers exist. We have also highlighted areas of possible future research, namely the reluctance behind young urology patients to consent and questions regarding how best to educate possible study participants to ensure proper informed consent is gained. PMID- 26005569 TI - Learning science and science education in a new era. AB - Today, it takes only a few months for the amount of knowledge to double. The volume of information available has grown so much that it cannot be fully encompassed by the human mind. For this reason, science, learning, and education have to change in the third millennium. The question is thus: what is it that needs to be done? The answer may be found through three basic stages. The first stage is persuading scientists of the necessity to change science education. The second stage is more difficult, in that scientists must be told that they should not place an exaggerated importance on their own academic field and that they should see their field as being on an equal basis with other fields. In the last stage, scientists need to condense the bulk of information on their hands to a manageable size. "Change" is the magic word of our time. Change brings about new rules, and this process happens very quickly in a global world. If we scientists do not rapidly change our scientific learning and education, we will find our students and ourselves caught up in an irreversibly destructive and fatal change that sets its own rules, just like the Arab spring. PMID- 26005571 TI - Arthroscopic treatment of synovial chondromatosis of the shoulder: A case report. AB - INTRODUCTION: Synovial chondromatosis is a mono-articular arthropathy rarely seen in diarthrodial joints. The classic treatment for synovial chondromatosis is open arthrotomy, synovectomy and complete removal of the free fragments. With recent advances in arthroscopic techniques and methods, the indications for arthroscopic treatment have been extended. PRESENTATION OF CASE: A 33-year old female presented with complaints of pain in the right shoulder. On the radiological examination, there were seen to be multiple calcified radio-opaque lesions filling all area of the glenohumeral joint. On computed tomography (CT) examination, again multiple radio-opaque free fragments were determined. Arthroscopy was applied to the right shoulder. The free fragments were completely removed. Approximately 33 free fragments, ranging in size from 0.5 to 1.3 cm, were removed. DISCUSSION: Cases of synovial chondromatosis in the shoulder have been rarely reported in literature. Generally the disease is self-limiting. Clinically, symptoms are generally not specific. Restrictions in the joint range of movement occur associated with the mechanical effect of the free fragments and in periods of active use, local pain and swelling may be seen in the shoulder. Simple removal of the free fragments, others have stated that removal with synovectomy is necessary to prevent recurrence of the cartilaginous metaplastic focus. Recurrence rates vary from 0 to 31%. CONCLUSION: Arthroscopic surgery can be successfully applied in the treatment of synovial chondromatosis. The advantages of the method include good visualisation during surgery, low morbidity and early healing. PMID- 26005570 TI - Complications and mortality after adult to adult living donor liver transplantation: A retrospective cohort study. AB - BACKGROUND AND AIMS: Living donor liver transplantation (LDLT) is widely performed for patients to resolve the critical shortage of organs from cadavers. Despite rapid implementation of the procedure, both complications and mortality of LDLT are annoying problems. The aim of this study was to analyze complications and mortality of patients after adult to adult LDLT (A-ALDLT) in a single center. METHODS: Between April 2003 and November 2013, 167 (A-ALDLT) recipients in National Liver Institute, Egypt were included. We retrospectively analyzed complications and mortality in them. RESULTS: The overall incidence of complications was 86.2% (n = 144) and classified as biliary 43.7% (n = 73), vascular 21.6% (n = 36), Small for size syndrome (SFSS) 12.6% (n = 21), Gastrointestinal tract (GIT) 19.8% (n = 33), wound 12.6% (n = 21), chest 19.8% (n = 33), neurological 26.3% (n = 44), renal 21% (n = 35), intra abdominal collection 21.6% (n = 36), recurrent hepatitis C virus (HCV) 16.8% (n = 28), recurrent hepatocellular carcinoma (HCC) 2.4% (n = 4), acute rejection 19.2% (n = 32). 65 (45.1%) of 144 complicated patients died, while 10 (43.5%) of 23 non complicated died. The incidence of whole, in hospital and late mortalities were 44.9%, 28.7% and 16.2% respectively. CONCLUSIONS: Mortality was higher among complicated cases where vascular complications and SFSS had significant effect on it so prevention and treatment of them is required for improving outcome. PMID- 26005572 TI - Enhanced Non-Viral Gene Delivery to Human Embryonic Stem Cells via Small Molecule Mediated Transient Alteration of Cell Structure. AB - Non-viral gene delivery into human embryonic stem cells (hESCs)is an important tool for controlling cell fate. However, the delivery efficiency remains low due in part to the tight colony structure of the cells which prevents effective exposure towards delivery vectors. We herein report a novel approach to enhance non-viral gene delivery to hESCs by transiently altering the cell and colony structure. (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y 27632), a small molecule that inhibits the rho-associated protein kinase pathway, is utilized to induce transient colony spreading which leads to increased transfection efficiency by 1.5 to 2 folds in a spectrum of non-viral transfection reagents including Lipofectamine 2000 and Fugene HD. After removal of Y-27632 post-transfection, cells can revert back to its normal state and do not show alteration of pluripotency. This approach provides a simple, effective tool to enhance non-viral gene delivery into adherent hESCs for genetic manipulation. PMID- 26005573 TI - The dumbest mistake I ever made. AB - Life as a Neurological Surgeon is a foreboding responsibility and a gratifying opportunity. Having the confidence and trust of individuals faced with a life or death situation requires extensive training and experience. Curiosity provides the motivation to continuously seek better understanding of complex disease problems, better technology, improved diagnostic capability, and surgical skills. Solution of these challenges has been a constant process for several decades and continues to pose opportunities for progress. Early observation of results provides important information, but in many circumstances it may require long term evaluation to fully document the benefit, or lack of benefit, for any treatment procedure. The focus of attention by the Neurological Surgeon must be on the proper immediate management of each given situation, but it is also important, and a responsibility to consider the long-term consequences or results. This presents a difficult challenge because patients move into distant places and Neurological Surgeons frequently move to accept new opportunities. It is expensive and cumbersome to retain records for many years. It is also unpredictable which patient's information will become particularly significant. It is an opportunity to describe experience with four patients to illustrate this dilemma. PMID- 26005574 TI - Lateral orbitotomy approach for removing hyperostosing en plaque sphenoid wing meningiomas. Description of surgical strategy and analysis of findings in a series of 88 patients with long-term follow up. AB - BACKGROUND: Sphenoid wing meningiomas extending to the orbit (ePMSW) are currently removed through several transcranial approaches. Presenting the largest surgical cohort of hyperostosing ePMSW with the longest follow up period, we will provide data supporting minilateral orbitotomy with excellent exposure for wide resection of all compartments of the tumor. METHODS: A retrospective survival analysis is made of the data cumulated prospectively during a period of 34 years, including 88 cases of ePMSW with a mean follow up period of 136.4 months. The impact of preoperative variables upon different outcome measures is evaluated. Standard pterional craniotomy was performed in 12 patients (C) while the other 76 cases underwent the proposed modified lateral miniorbitotomy (LO). RESULTS: There were 31 men and 57 women. The age range varied between 12 and 70 years. Patients presented with unilateral exophthalmos (Uex) ranging between 3 and 16 mm. Duration of proptosis before operation varied between 6 months and 16 years. The status of visual acuity (VA) prior to operation was: no light perception (NLP) in 16, light perception (LP) up to 0.2 in 3, 0.3-0.5 in 22, 0.6-0.9 in 24, and full vision in 23 patients. Postoperatively, acceptable cosmetic appearance of the eyes was seen in 38 cases and in 46 mild inequality of < 2 mm was detected. Four cases had mild enophthalmos (En). Among those who had the worst VA, two improved and one became almost blind after operation. The cases with VA in the range of 0.3-0.5 improved. Among those with good VA (0.5 to full vision), 2 became blind, vision diminished in 10, and improved or remained full in the other 35 cases. Tumor recurrence occurred in 33.3% of group C and 10.5% of group LO (P = 0.05). The major determinant of tumor regrowth was the technique of LO (P = 0.008). CONCLUSION: Using LO technique, the risky corners involved by the tumor is visualized from the latero-inferior side rather than from the latero-superior avenue. This is the crucial milestone to achieve aggressive removal of all the involved compartments of the lesion. Satisfactory cosmetic result is reported using mini LO technique after widely exposing and removing the hyperostotic bone down to the subtemporal fossa with only simple repair of the dura without cranioplasty. PMID- 26005575 TI - Complications corner: Anterior thoracic disc surgery with dural tear/CSF fistula and low-pressure pleural drain led to severe intracranial hypotension. AB - BACKGROUND: Thoracic disc surgery can lead to a life-threatening complication: intracranial hypotension due to a subarachnoid-pleural fistula. CASE DESCRIPTION: We report a 63-year-old male with paraparesis due to multiple herniated thoracic discs, with compressive myelopathy. The patient required a circumferential procedure including a laminectomy/fusion followed by an anterior thoracic decompression to address both diffuse idiopathic skeletal hyperostosis (DISH) anteriorly and posterior stenosis. The postoperative course was complicated by severe intracranial hypotension attributed to the erroneous placement of a low pressure drain placed in the pleural cavity instead of a lumbar drain; this resulted in subdural hematoma's necessitating subsequent surgery. CONCLUSION: Severe neurological deterioration occurring after thoracic decompressive surgery may rarely be attributed to intracranial hypotension due to a subarachnoid pleural fistula. Patients should be treated with external lumbar drainage of cerebrospinal fluid for 3-5 days rather than a low-pressure pleural drain to avoid the onset of intracranial hypotension leading to symptomatic subdural hematomas. PMID- 26005576 TI - Diagnosis and management of traumatic cervical central spinal cord injury: A review. AB - BACKGROUND: The classical clinical presentation, neuroradiographic features, and conservative vs. surgical management of traumatic cervical central spinal cord (CSS) injury remain controversial. METHODS: CSS injuries, occurring in approximately 9.2% of all cord injuries, are usually attributed to significant hyperextension trauma combined with congenital/acquired cervical stenosis/spondylosis. Patients typically present with greater motor deficits in the upper vs. lower extremities accompanied by patchy sensory loss. T2-weighted magnetic resonance (MR) scans usually show hyperintense T2 intramedullary signals reflecting acute edema along with ligamentous injury, while noncontrast computed tomography (CT) studies typically show no attendant bony pathology (e.g. no fracture, dislocation). RESULTS: CSS constitute only a small percentage of all traumatic spinal cord injuries. Aarabi et al. found CSS patients averaged 58.3 years of age, 83% were male and 52.4% involved accidents/falls in patients with narrowed spinal canals (average 5.6 mm); their average American Spinal Injury Association (ASIA) motor score was 63.8, and most pathology was at the C3-C4 and C4-C5 levels (71%). Surgery was performed within 24 h (9 patients), 24-48 h (10 patients), or after 48 h (23 patients). In the Brodell et al. study of 16,134 patients with CSS, 39.7% had surgery. In the Gu et al. series, those with CSS and stenosis/ossification of the posterior longitudinal ligament (OPLL) exhibited better outcomes following laminoplasty. CONCLUSIONS: Recognizing the unique features of CSS is critical, as the clinical, neuroradiological, and management strategies (e.g. conservative vs. surgical management: early vs. late) differ from those utilized for other spinal cord trauma. Increased T2-weighted MR images best document CSS, while CT studies confirm the absence of fracture/dislocation. PMID- 26005577 TI - C5 Nerve root palsies following cervical spine surgery: A review. AB - BACKGROUND: Cervical C5 nerve root palsies may occur in between 0% and 30% of routine anterior or posterior cervical spine operations. They are largely attributed to traction injuries/increased cord migration following anterior/posterior decompressions. Of interest, almost all studies cite spontaneous resolution of these deficits without surgery with 3-24 postoperative months. METHODS: Different studies cite various frequencies for C5 root palsies following anterior or posterior cervical spine surgery. In their combined anterior/posterior series involving C4-C5 level decompressions, Libelski et al. cited up to a 12% incidence of C5 palsies. In Gu et al. series, C5 root palsies occurred in 3.1% of double-door laminoplasty, 4.5% of open-door laminoplasty, and 11.3% of laminectomy. Miller et al. observed an intermediate 6.9% frequency of C5 palsies followed by posterior cervical decompressions and fusions (PCDF). RESULTS: Gu et al. also identified multiple risk factors for developing C5 palsies following posterior surgery; male gender, ossification of the posterior longitudinal ligament (OPLL), narrower foramina, laminectomy, and marked dorsal spinal cord drift. Miller et al. also identified an average $1918 increased cost for physical/occupational therapy for patients with C5 palsies. CONCLUSIONS: The incidence of C5 root deficits for anterior/posterior cervical surgery at C4-C5 was 12% in one series, and ranged up to 11.3% for laminectomies, while others cited 0-30%. Although identification of preoperative risk factors for C5 root deficits may help educate patients regarding these risks, there is no clear method for their avoidance at this time. PMID- 26005578 TI - Preliminary documentation of the comparable efficacy of vitoss versus NanOss bioactive as bone graft expanders for posterior cervical fusion. AB - BACKGROUND: Laminectomies with posterior cervical instrumented fusions often utilize bone graft expanders to supplement cervical lamina/iliac crest autograft/bone marrow aspirate (BMA). Here we compared posterior fusion rates utilizing two graft expanders; Vitoss (Orthovita, Malvern, PA, USA) vs. NanOss Bioactive (Regeneration Technologies Corporation [RTI: Alachua, FL, USA]). METHODS: Two successive prospective cohorts of patients underwent 1-3 level laminectomies with 5-9 level posterior cervical fusions to address cervical spondylotic myelopathy (CSM) and/or ossification of the posterior longitudinal ligament (OPLL). The first cohort of 72 patients received Vitoss, while the second cohort or 20 patients received NanOss. Fusions were performed utilizing the Vertex/Rod/Eyelet System (Medtronic, Memphis, TN, USA) with braided titanium cables through the base of intact spinous processes (not lateral mass screws) cephalad and caudad to laminectomy defects. Fusion was documented by an independent neuroradiologist blinded to the study design, utilizing dynamic X rays and two dimensional computed tomography (2D-CT) studies up to 6 months postoperatively, or until fusion or pseudarthrosis was confirmed at 1 year. RESULTS: Vitoss and NanOss resulted in comparable times to fusion: 5.65 vs. 5.35 months. Dynamic X-ray and CT-documented pseudarthrosis developed in 2 of 72 Vitoss patients at one postoperative year (e.g. bone graft resorbed secondary to early deep wound infections), while none occurred in the 20 patients receiving NanOss. CONCLUSION: In this preliminary study combining cervical laminectomy/fusions, the time to fusion (5.65 vs. 5.35 months), pseudarthrosis (2.7% vs. 0%), and infection rates (2.7% vs. 0%) were nearly comparable sequentially utilizing Vitoss (72 patients) vs. NanOss (20 patients) as bone graft expanders. PMID- 26005579 TI - Tisseel does not reduce postoperative drainage, length of stay, and transfusion requirements for lumbar laminectomy with noninstrumented fusion versus laminectomy alone. AB - BACKGROUND: Typically, fibrin sealants (FSs) and fibrin glues (FGs) are used to strengthen dural repairs during spinal surgery. In 2014, Epstein demonstrated that one FS/FG, Tisseel (Baxter International Inc., Westlake Village, CA, USA) equalized the average times to drain removal and length of stay (LOS) for patients with versus without excess bleeding (e.g. who did not receive Tisseel) undergoing multilevel laminectomies with 1-2 level noninstrumented fusions (LamF).[6]. METHODS: Here Tisseel was utilized to promote hemostasis for two populations; 39 patients undergoing average 4.4 level lumbar laminectomies with average 1.3 level noninstrumented fusions (LamF), and 48 patients undergoing average 4.0 level laminectomies alone (Lam). We compared the average operative time, estimated blood loss (EBL), postoperative drainage, LOS, and transfusion requirements for the LamF versus Lam groups. RESULTS: The average operative times, EBL, postoperative drainage, LOS, and transfusion requirements were all greater for LamF versus Lam patients; operative times (4.1 vs. 3.0 h), average EBL (192.3 vs. 147.9 cc), drainage (e.g. day 1; 199.6 vs. 167.4 cc; day 2; 172.9 vs. 63.9 cc), average LOS (4.6 vs. 2.5 days), and transfusion requirements (11 LamF patients; 18 Units [U] RBC versus 2 Lam patients; 3 U RBC). CONCLUSIONS: Utilizing Tisseel to facilitate hemostasis in LamF versus Lam still resulted in greater operative times, EBL, postoperative average drainage, LOS, and transfusion requirements for patients undergoing the noninstrumented fusions. Although Tisseel decreases back bleeding within the spinal canal, it does not reduce blood loss from LamF decorticated transverse processes. PMID- 26005580 TI - Resection of an Occipital-Cervical Junction Schwannoma through a modified minimally invasive approach: Technical Note. AB - BACKGROUND: Minimally invasive spine (MIS) techniques have been available for many years, but their application has been largely limited to degenerative spine diseases. There are few reports in the literature of using MIS techniques for removal of neoplasms. We report our experience using a modified MIS technique for removal of an occipital-cervical junction (OCJ) schwannoma with attention to technical aspects of this approach. CASE DESCRIPTION: A 64-year-old male presented with several months of neck pain radiating to the shoulder with bilateral hand numbness. The patient had evidence of early myelopathy on examination. Magnetic resonance imaging (MRI) demonstrated enhancing intradural lesion with significant mass effect on the spinal cord. The mass extended extradurally through the right C1 neural foramen. Imaging characteristics were suggestive of a schwannoma. The patient underwent a minimally invasive far lateral approach to the OCJ for resection of the lesion. A Depuy PipelineTM expandable retractor was used for visualization. Surgical resection was performed with microscopic visualization. Somatosensory evolved potentials (SSEP) monitoring was used. The patient tolerated the procedure well. Postoperative imaging demonstrated gross total resection. No intra- or postoperative complications were noted. The patient was discharged home on postoperative day 2. At 1-month follow-up, his preoperative symptoms were resolved and his wound healed excellently. CONCLUSION: In properly selected patients, minimally invasive approaches to the OCJ for resection of mass lesions are feasible, provide adequate visualization of tumor and surrounding structures, and may even be preferable given the lower morbidity of a smaller incision and minimal soft tissue dissection. PMID- 26005581 TI - Solid variant of aneurysmal bone cyst presenting as a giant cervical mass: A clinical, radiological, histopathological dilemma. AB - BACKGROUND: Typical aneurysmal bone cysts (ABCs) are osteolytic, multicystic lesions with parietal sclerosis and blood-filled cysts. In rare instances, the cystic components may be completely absent. Such solid variants in ABC (s-ABC) exhibit a solid architecture; making the clinical, radiological, and histological differentiation from other solid bone tumors like osteosarcoma (especially giant cell rich osteosarcoma) and giant cell tumor, a difficult task. CASE REPORT: We report the case of a 45-year-old male presenting with a giant solid cervical spine lesion. Histopathology revealed solid variant of ABC, even though the radiological and fine needle aspiration cytology studies pointed toward a giant cell tumor. CONCLUSION: We aim to discuss the clinical, radiological, and histological findings of solid ABC (a rare benign entity) vis-a-vis the common neoplastic entities of osteosarcoma and giant cell tumor. The histopathological nuisances in making the diagnosis of s-ABC are put forth, along with its impact on management of such giant bony spinal lesions. PMID- 26005582 TI - Operative costs, reasons for operative waste, and vendor credit replacement in spinal surgery. AB - BACKGROUND: In 2012, Epstein et al. documented that educating spinal surgeons reduced the cost of operative waste (explanted devices: placed but removed prior to closure) occurring during anterior cervical diskectomy/fusion from 20% to 5.8%.[5] This prompted the development of a two-pronged spine surgeon-education program (2012-2014) aimed at decreasing operative costs for waste, and reducing the nine reasons for operative waste. METHODS: The spine surgeon-education program involved posting the data for operative costs of waste and the nine reasons for operative waste over the neurosurgery/orthopedic scrub sinks every quarter. These data were compared for 2012 (latter 10 months), 2013 (12 months), and 2014 (first 9 months) (e.g. data were normalized). Savings from a 2013 Vendor Credit Replacement program were also calculated. RESULTS: From 2012 to 2013 and 2014, spinal operative costs for waste were, respectively reduced by 64.7% and 61% for orthopedics, and 49.4% and 45.2% for neurosurgery. Although reduced by the program, the major reason for operative waste for all 3 years remained surgeon-related factors (e.g. 159.6, to 67, and 96, respectively). Alternatively, the eight other reasons for operative waste were reduced from 68.4 (2012) to 12 (2013) and finally to zero by 2014. Additionally, the Vendor Replacement program for 2013 netted $78,564. CONCLUSIONS: The spine surgeon-education program reduced the costs/reasons for operative waste for 2012 to lower levels by 2013 and 2014. Although the major cost/reasons for operative waste were attributed to surgeon related factors, these declined while the other eight reasons for operative waste were reduced to zero by 2014. PMID- 26005583 TI - Clinical and surgical outcomes after lumbar laminectomy: An analysis of 500 patients. AB - BACKGROUND: The objective of this study is to determine the clinical and surgical outcomes following lumbar laminectomy. METHODS: We retrospectively reviewed medical records of neurosurgical patients who underwent first-time, bilateral, 1 3 level laminectomies for degenerative lumbar disease. Patients with discectomy, complete facetectomy, and fusion were excluded. RESULTS: Five hundred patients were followed for an average of 46.79 months. Following lumbar laminectomy, patients experienced statistically significant improvement in back pain, neurogenic claudication, radiculopathy, weakness, and sensory deficits. The rate of intraoperative durotomy was 10.00%; however, 1.60% experienced a postoperative cerebrospinal fluid leak. The risk of experiencing at least one postoperative complication with a lumbar laminectomy was 5.60%. Seventy-two patients (14.40%) required reoperations for progression of degenerative disease over a mean of 3.40 years. The most common symptoms prior to reoperation included back pain (54.17%), radiculopathy (47.22%), weakness (18.06%), sensory deficit (15.28%), and neurogenic claudication (19.44%). The relative risk of reoperation for patients with postoperative back pain was 6.14 times higher than those without postoperative back pain (P < 0.001). Of the 72 patients undergoing reoperations, 55.56% underwent decompression alone, while 44.44% underwent decompression and posterolateral fusions. When considering all-time reoperations, the lifetime risk of requiring a fusion after a lumbar laminectomy based on this study (average follow-up of 46.79 months) was 8.0%. CONCLUSION: Patients experienced statistically significant improvements in back pain, neurogenic claudication, radiculopathy, motor weakness, and sensory deficit following lumbar laminectomy. Incidental durotomy rate was 10.00%. Following a first-time laminectomy, the reoperation rate was 14.4% over a mean of 3.40 years. PMID- 26005585 TI - CT-based morphometric analysis of C1 laminar dimensions: C1 translaminar screw fixation is a feasible technique for salvage of atlantoaxial fusions. AB - BACKGROUND: Translaminar screw fixation has become an alternative in the fixation of the axial and subaxial cervical spine. We report utilization of this approach in the atlas as a salvage technique for atlantoaxial stabilization when C1 lateral mass screws are precluded. To assess the feasibility of translaminar fixation at the atlas, we have characterized the dimensions of the C1 lamina in the general adult population using computed tomography (CT)-based morphometry. METHODS: A 46-year-old male with symptomatic atlantoaxial instability secondary to os odontoideum underwent bilateral C1 and C2 translaminar screw/rod fixation as C1 lateral mass fixation was precluded by an anomalous vertebral artery. The follow-up evaluation 21/2 years postoperatively revealed an asymptomatic patient without recurrent neck/shoulder pain or clinical signs of instability. To better assess the feasibility of utilizing this approach in the general population, we retrospectively analyzed 502 consecutive cervical CT scans performed over a 3 month period in patients aged over 18 years at a single institution. Measurements of C1 bicortical diameter, bilateral laminar length, height, and angulation were performed. Laminar and screw dimensions were compared to assess instrumentation feasibility. RESULTS: Review of CT imaging found that 75.9% of C1 lamina had a sufficient bicortical diameter, and 63.7% of C1 lamina had sufficient height to accept bilateral translaminar screw placement. CONCLUSIONS: CT-based measurement of atlas morphology in the general population revealed that a majority of C1 lamina had sufficient dimensions to accept translaminar screw placement. Although these screws appear to be a feasible alternative when lateral mass screws are precluded, further research is required to determine if they provide comparable fixation strength versus traditional instrumentation methods. PMID- 26005586 TI - Does lumbar paraspinal muscle fatty degeneration correlate with aerobic index and Oswestry disability index? AB - BACKGROUND: We sought to analyze whether the amount of paraspinal fatty degeneration correlates with a patient's physical fitness, and to determine if these findings on lumbar magnetic resonance imaging (MRI) scans can help predict functional outcomes. METHODS: A retrospective review was performed on 172 patients. Inclusion criteria involved being seen by a spine surgeon for low back pain, having aerobic index (AI), body mass index (BMI), Oswestry disability index (ODI), and body fat percentage measured recently, and having had a recent lumbar MRI scan. The percentage of fatty muscle degeneration was graded by three reviewers using T2-weighted axial images at L3 and L5 using a newly proposed system that was validated independently. The system is graded as follows: Grade 1: 0-24%, Grade 2: 25-49%, Grade 3: 50-74%, and Grade 4: 75-100%. An independent t-test was used for comparisons. RESULTS: The average AI was 34.87, and the cohort was divided into two groups: above-average AI (89 patients) and below average AI (83 patients). For all paraspinal fat measurements and body fat percentage, the difference between the above- and below-average AI groups was statistically significant (P < 0.05), with the least amount of paraspinal fatty degeneration and body fat in the greater AI group. Weight alone and BMI were not found to be significantly different between those with above-average AI when compared to those with below-average AI (P = 0.491 and P = 0.122, respectively). There was a trend for lower ODI scores in the above-average AI group (41.9 vs 46.1), but this did not reach statistical significance between the two groups (P = 0.075). For all patients it was shown that there was significantly less paraspinal fat at the L3 level as compared to L5 (P < 0.001). CONCLUSIONS: We were able to show that patients with a higher AI have lower body fat percentages and lower amounts of fatty degeneration in their lumbar paraspinal musculature. The amount of paraspinal fatty degeneration, therefore, correlates with physical fitness. Patients with higher AI also showed a trend toward having a lower ODI score. PMID- 26005587 TI - Posterior atlantoaxial fixation: A cadaveric and fluoroscopic step-by-step technical guide. AB - BACKGROUND: Atlantoaxial surgical fixation is widely employed treatment strategy for a myriad of pathologies affecting the stability of the atlantoaxial joint. The most common technique used in adults, and in certain cases in children, involves a posterior construct with C1 lateral mass screws, and C2 pars or pedicle screws. This technical note aims to provide a step-by-step guide to this procedure using cadaveric and fluoroscopic images. METHODS: An embalmed, human, cadaveric, specimen was used for this study. The subject did not have obvious occipital-cervical pathology. Dissections and techniques were performed to mimic actual surgical technique. Photographs were taken during each step, and the critical aspects of each step were highlighted. Fluoroscopic images from a real patient undergoing C1/C2 fixation were also utilized to further highlight the anatomic-radiographic relationships. This study was performed without external or industry funding. RESULTS: Photographic and radiographic pictures and drawings are presented to illustrate the pertinent anatomy and technical aspects of this technique. The nuances of each step, including complication avoidance strategies are also highlighted. CONCLUSIONS: Given the widespread utilization of this technique, described step-by-step guide is timely for surgeons and trainees alike. PMID- 26005584 TI - Comparison of the efficacy of saline, local anesthetics, and steroids in epidural and facet joint injections for the management of spinal pain: A systematic review of randomized controlled trials. AB - BACKGROUND: The efficacy of epidural and facet joint injections has been assessed utilizing multiple solutions including saline, local anesthetic, steroids, and others. The responses to these various solutions have been variable and have not been systematically assessed with long-term follow-ups. METHODS: Randomized trials utilizing a true active control design were included. The primary outcome measure was pain relief and the secondary outcome measure was functional improvement. The quality of each individual article was assessed by Cochrane review criteria, as well as the criteria developed by the American Society of Interventional Pain Physicians (ASIPP) for assessing interventional techniques. An evidence analysis was conducted based on the qualitative level of evidence (Level I to IV). RESULTS: A total of 31 trials met the inclusion criteria. There was Level I evidence that local anesthetic with steroids was effective in managing chronic spinal pain based on multiple high-quality randomized controlled trials. The evidence also showed that local anesthetic with steroids and local anesthetic alone were equally effective except in disc herniation, where the superiority of local anesthetic with steroids was demonstrated over local anesthetic alone. CONCLUSION: This systematic review showed equal efficacy for local anesthetic with steroids and local anesthetic alone in multiple spinal conditions except for disc herniation where the superiority of local anesthetic with steroids was seen over local anesthetic alone. PMID- 26005588 TI - Radiosurgery for symptomatic cavernous malformations: A multi-institutional retrospective study in Japan. AB - BACKGROUND: A group study for symptomatic cavernous malformation (CM) treated with gamma knife (GK) surgery was performed. METHODS: A total of 298 cases collected from 23 GK centers across Japan were included. Hemorrhage was the most common manifestation, followed by seizures and neurological deficits. Most of the lesions were located in the brainstem and basal ganglia, followed by the cerebral or cerebellar hemispheres. The CMs, which had a mean diameter of 14.8 mm, were treated using GK surgery with a mean marginal dose of 14.6 Gy. RESULTS: In terms of hemorrhage-free survival (HFS), a marked dissociation was confirmed between the hemorrhage and seizure groups, while no obvious difference was noted between sexes. Superficial CMs located in cerebellum or lobar regions responded to the treatment better than deeply located CMs in the basal ganglia or brainstem. No significant difference of dose-dependent response was seen for three different ranges of marginal dose: Less than 15 Gy, between 15 and 20 Gy, and more than 20 Gy. Complications were more frequent after a marginal dose of over 15 Gy and in patients with lesions more than 15 mm in diameter. The rates of annual hemorrhage were estimated to be 7.4% during the first 2 years after radiosurgery and 2.8% thereafter. The overall hemorrhage rate after radiosurgery was 4.4%/year/patient. CONCLUSION: The risk of hemorrhage is considerably reduced after GK treatment. The HFS as well as annual hemorrhage rate after GK treatment was apparently superior to that after conservative treatment for symptomatic CMs. To optimize the success of GK treatment, it is important to reduce the incidence of complications. PMID- 26005589 TI - Antioxidant Therapy: Is it your Gateway to Improved Cardiovascular Health? AB - General use and popularity of over-the-counter supplemental antioxidants have rapidly spread all over the world and are believed to promote cardiovascular health and wellbeing. However, there is a paucity of information and lack of proof that physiological and above-physiological levels of oxidants do harm at the cellular and organismal levels. Instead, several reports demonstrated that reduction in Reactive Oxygen Species (ROS) did not improve vascular function. Interestingly, recent studies show that increased ROS levels play protective role in vascular endothelium and may improve coronary endothelial function. In the current review, we introduce the concept that increased ROS levels, often seen in association with cardiovascular disease, probably is an endothelial-way or 'oxidative response' to cope with vascular pathology. PMID- 26005591 TI - Involvement of Heparanase in Empyema: Implication for Novel Therapeutic Approaches. AB - Pleural empyema is an inflammatory condition that progresses from acute to chronic, life-threatening, phase. The incidence of empyema has been increasing both in children and adults worldwide in the past decades, mainly in healthy young adults and in older patients. Despite continued advances in the management of this condition, morbidity and mortality have essentially remained static over the past decade. Better understanding of the disease and the development of new therapeutic approaches are thus critically needed. Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. These macromolecules are most abounded in the sub-endothelial and sub-epithelial basement membranes and their cleavage by heparanase leads to disassembly of the extracellular matrix that becomes more susceptible to extravasation and dissemination of metastatic and immune cells. Here, we provide evidence that heparanase expression and activity are markedly increased in empyema and pleural fluids, associating with disease progression. Similarly, heparanase expression is increased in a mouse model of empyema initiated by intranasal inoculation of S. pneumonia. Applying this model we show that transgenic mice over expressing heparanase are more resistant to the infection and survive longer. PMID- 26005590 TI - Cardiovascular Disease-Risk Markers in HIV Patients. AB - OBJECTIVES: HIV-positive patients have an increased risk for CVD; however, the underlying mechanisms are not well understood. Our goal was to assess traditional and emerging CVD-risk factors in the CARE Study, a well-described cohort of HIV infected adults. METHODS: We analyzed demographic and clinical (viral load, CD4 count, ART regimen, cIMT) data including markers of lipid and glucose homeostasis in 176 HIV-positive subjects receiving regular care for HIV infection. RESULTS: No significant association between cIMT and LDL-C level was observed. HIV patients had significantly lower level of the large alpha-1 HDL particles and about 3-fold higher level of the small pre beta-1 HDL particles than the normal population, but these parameters were not significantly associated with cIMT. Components of the metabolic syndrome, high TG/low HDL-C, insulin resistance and high BMI, as well as viral load were significant but moderate contributors to increased cIMT. CONCLUSION: The major lipid disorder was low HDL-C and high TG level in this HIV-positive cohort. LDL-C was not elevated. These and previously published data indicate that HIV infection and HIV medications influence CVD risk by impairing cholesterol removal (efflux) via ABCA1 from macrophages. Decreasing CVD risk in HIV patients, with impaired cholesterol efflux from macrophages, may require a lower LDL-C goal than recommended for HIV-negative patients and also a better control of TG level. PMID- 26005592 TI - Free-Propagator Reweighting Integrator for Single-Particle Dynamics in Reaction Diffusion Models of Heterogeneous Protein-Protein Interaction Systems. AB - We present a new algorithm for simulating reaction-diffusion equations at single particle resolution. Our algorithm is designed to be both accurate and simple to implement, and to be applicable to large and heterogeneous systems, including those arising in systems biology applications. We combine the use of the exact Green's function for a pair of reacting particles with the approximate free diffusion propagator for position updates to particles. Trajectory reweighting in our free-propagator reweighting (FPR) method recovers the exact association rates for a pair of interacting particles at all times. FPR simulations of many-body systems accurately reproduce the theoretically known dynamic behavior for a variety of different reaction types. FPR does not suffer from the loss of efficiency common to other path-reweighting schemes, first, because corrections apply only in the immediate vicinity of reacting particles and, second, because by construction the average weight factor equals one upon leaving this reaction zone. FPR applications include the modeling of pathways and networks of protein driven processes where reaction rates can vary widely and thousands of proteins may participate in the formation of large assemblies. With a limited amount of bookkeeping necessary to ensure proper association rates for each reactant pair, FPR can account for changes to reaction rates or diffusion constants as a result of reaction events. Importantly, FPR can also be extended to physical descriptions of protein interactions with long-range forces, as we demonstrate here for Coulombic interactions. PMID- 26005594 TI - Evidence-Based Care of Acute Wounds: A Perspective. AB - Significance: Large variation and many controversies exist regarding the treatment of, and care for, acute wounds, especially regarding wound cleansing, pain relief, dressing choice, patient instructions, and organizational aspects. Recent Advances: A multidisciplinary team developed evidence-based guidelines for the Netherlands using the AGREE-II and GRADE instruments. A working group, consisting of 17 representatives from all professional societies involved in wound care, tackled five controversial issues in acute-wound care, as provided by any caregiver throughout the whole chain of care. Critical Issues: The guidelines contain 38 recommendations, based on best available evidence, additional expert considerations, and patient experiences. In summary, primarily closed wounds need no cleansing; acute open wounds are best cleansed with lukewarm (drinkable) water; apply the WHO pain ladder to choose analgesics against continuous wound pain; use lidocaine or prilocaine infiltration anesthesia for wound manipulations or closure; primarily closed wounds may not require coverage with a dressing; use simple dressings for open wounds; and give your patient clear instructions about how to handle the wound. Future Directions: These evidence-based guidelines on acute wound care may help achieve a more uniform policy to treat acute wounds in all settings and an improved effectiveness and quality of wound care. PMID- 26005593 TI - Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing. AB - Significance: Fibrinogen-related proteins (FRePs) comprise an intriguing collection of extracellular molecules, each containing a conserved fibrinogen like globe (FBG). This group includes the eponymous fibrinogen as well as the tenascin, angiopoietin, and ficolin families. Many of these proteins are upregulated during tissue repair and exhibit diverse roles during wound healing. Recent Advances: An increasing body of evidence highlights the specific expression of a number of FRePs following tissue injury and infection. Upon induction, each FReP uses its FBG domain to mediate quite distinct effects that contribute to different stages of tissue repair, such as driving coagulation, pathogen detection, inflammation, angiogenesis, and tissue remodeling. Critical Issues: Despite a high degree of homology among FRePs, each contains unique sequences that enable their diversification of function. Comparative analysis of the structure and function of FRePs and precise mapping of regions that interact with a variety of ligands has started to reveal the underlying molecular mechanisms by which these proteins play very different roles using their common domain. Future Directions: Fibrinogen has long been used in the clinic as a synthetic matrix serving as a scaffold or a delivery system to aid tissue repair. Novel therapeutic strategies are now emerging that harness the use of other FRePs to improve wound healing outcomes. As we learn more about the underlying mechanisms by which each FReP contributes to the repair response, specific blockade, or indeed potentiation, of their function offers real potential to enable regulation of distinct processes during pathological wound healing. PMID- 26005595 TI - Clinical Biofilms: A Challenging Frontier in Wound Care. AB - Significance: Biofilms have been implicated in a variety of wound complications. Recent Advances: Research has confirmed that biofilms form in wounds of patients experiencing delayed healing and may be a precursor to infection. Critical Issues: Research into the strength of this association is still in its infancy. Is biofilm formation a cause of these complications, a step toward them, or a signal that unresolved factors injuring tissue or delaying healing are setting the stage for biofilm formation, infection, and healing delay? To qualify biofilms for use in informing clinical practice decisions, biofilm characteristics supporting those decisions need standardized definitions and valid evidence that they predict or diagnose healing or infection outcomes. Literature searches of relevant terms reviewed biofilm definitions and validation of their role in predicting and diagnosing delayed wound healing or infection. Future Directions: Further research is needed to provide a rapid accurate technique to identify and characterize biofilms in ways that optimize their validity in diagnosing or screening patient risk of infection or delayed healing and to inform clinical decisions. This research will help validate biofilm's capacity to support wound care clinical practice decisions and establish their importance in guiding clinical practice. PMID- 26005596 TI - A Wireless Electroceutical Dressing Lowers Cost of Negative Pressure Wound Therapy. AB - Objective: To test whether the use of a wireless electroceutical dressing (WED) (Procellera(r)) in conjunction with a 5-day negative pressure wound therapy (NPWT) may reduce the number of dressing changes required per week with this therapy. Approach: At the Ohio State University Comprehensive Wound Center, chronic wound patients (n=30) undergoing NPWT were randomized into two arms following consent as approved by the institutional review board. The control arm received standard of care NPWT, where the dressing change was performed thrice a week. The test arm received the same care except that the WED was added as an interface layer and dressing change was limited to twice a week. Results: A reduced cost of care was achieved using the WED in conjunction with NPWT. Despite fewer dressing changes in wounds dressed with the WED, closure outcomes were comparable with no overt signs of any wound complication, including infection. The cost of NPWT care during the week was significantly lower (from $2918 to $2346) in the WED-treated group compared with patients in the control arm. Innovation: This work introduces a novel technology platform involving a WED, which may be used in conjunction with NPWT. If used as such, NPWT is effective in decreasing the frequency of dressing change and lowering the cost of care. Conclusion: This work points toward the benefit of using the WED combined with NPWT. A larger clinical trial investigating the cost-effectiveness of WED in wound care is warranted. PMID- 26005597 TI - A Bilayer Engineered Skin Substitute for Wound Repair in an Irradiation-Impeded Healing Model on Rat. AB - Objective: An engineered skin substitute is produced to accelerate wound healing by increasing the mechanical strength of the skin wound via high production of collagen bundles. During the remodeling stage of wound healing, collagen deposition is the most important event. The collagen deposition process may be altered by nutritional deficiency, diabetes mellitus, microbial infection, or radiation exposure, leading to impaired healing. This study describes the fabrication of an engineered bilayer skin substitute and evaluates its effectiveness for the production of collagen bundles in an impaired healing model. Approach: Rats were exposed to 10 Gy of radiation. Two months postirradiation, the wounds were excised and treated with one of three skin replacement products: bilayer engineered skin substitutes, chitosan skin templates, or duoderm(c). The collagen deposition was analyzed by hematoxylin and eosin staining. Results: On day 21 postwound, the irradiated wounds displayed increased collagen bundle deposition after treatment using bilayer engineered skin substitutes (3.4+/-0.25) and chitosan skin templates (3.2+/-0.58) compared with duoderm (2.0+/-0.63). Innovation: We provide the first report on the fabrication of bilayer engineered skin substitutes using high density human dermal fibroblasts cocultured with HFSCs on chitosan skin templates. Conclusion: The high density of fibroblasts significantly increases the penetration of cells into chitosan skin templates, contributing to the fabrication of bilayer engineered skin substitute. PMID- 26005598 TI - Intense Sweeteners, Appetite for the Sweet Taste, and Relationship to Weight Management. AB - High intensity, low-energy sweeteners (LES) are used by many consumers in order to limit energy intake and possibly facilitate body weight control. These beneficial effects are often questioned in the scientific and lay media. LES are frequently accused of stimulating and/or maintaining a liking for sweetness which in turn would be deleterious for adequate body weight control. Evidence for the specific effects of LES use on appetite for sweet products will be extracted from observational studies, experimental laboratory studies, randomized controlled trials, and finally brain imaging studies. While many of the existing studies cannot identify any causal links between use of LES and appetite for sweetness, randomized trials in children and adults suggest that use of LES tends to reduce rather than increase the intake of sugar-containing foods and to facilitate, rather than impair, weight loss. PMID- 26005599 TI - Mechanisms of Theta Plasmid Replication. AB - Plasmids are autonomously replicating pieces of DNA. This chapter discusses theta plasmid replication, which is class of circular plasmid replication that includes ColE1-like origins of replication popular with expression vectors. All modalities of theta plasmid replication initiate synthesis with the leading-strand at a pre determined site and complete replication through recruitment of the host's replisome, which extends the leading-strand continuously while synthesizing the lagging-strand discontinuously. There are clear differences between different modalities of theta plasmid replication in mechanisms of DNA duplex melting and in priming of leading- and lagging-strand synthesis. In some replicons duplex melting depends on transcription, while other replicons rely on plasmid-encoded trans-acting proteins (Reps); primers for leading-strand synthesis can be generated through processing of a transcript or in other replicons by the action of host- or plasmid-encoded primases. None of these processes require DNA breaks. The frequency of replication initiation is tightly regulated to facilitate establishment in permissive hosts and to achieve a steady state. The last section of the chapter reviews how plasmid copy number is sensed and how this feedback modulates the frequency of replication. PMID- 26005601 TI - The 29th CMAAO General Assembly and 50th Council Meeting: Manila, the Philippines, September 24-26, 2014. PMID- 26005602 TI - Inaugural address. PMID- 26005600 TI - Current Trends in Robot-Assisted Upper-Limb Stroke Rehabilitation: Promoting Patient Engagement in Therapy. AB - Stroke is one of the leading causes of long-term disability today; therefore, many research efforts are focused on designing maximally effective and efficient treatment methods. In particular, robotic stroke rehabilitation has received significant attention for upper-limb therapy due to its ability to provide high intensity repetitive movement therapy with less effort than would be required for traditional methods. Recent research has focused on increasing patient engagement in therapy, which has been shown to be important for inducing neural plasticity to facilitate recovery. Robotic therapy devices enable unique methods for promoting patient engagement by providing assistance only as needed and by detecting patient movement intent to drive to the device. Use of these methods has demonstrated improvements in functional outcomes, but careful comparisons between methods remain to be done. Future work should include controlled clinical trials and comparisons of effectiveness of different methods for patients with different abilities and needs in order to inform future development of patient specific therapeutic protocols. PMID- 26005603 TI - Building and sustaining a regional health research and innovation network in southeast Asia. PMID- 26005604 TI - The african health systems and the information society. PMID- 26005605 TI - Healthcare IT and Healthcare Databases. PMID- 26005606 TI - [Bangladesh]health databases in an information society-bangladesh perspective. PMID- 26005607 TI - [Hong Kong]health database in Hong Kong. PMID- 26005608 TI - [India]health database in an information society. PMID- 26005609 TI - [Indonesia]the health database in an information society. PMID- 26005610 TI - [Japan]health database in an information society. PMID- 26005611 TI - [Korea]ICT and Healthcare in Korea: Present and Prospect. PMID- 26005612 TI - [Malaysia]the health database. PMID- 26005613 TI - [Nepal]present progress of information technology in health care system of Nepal. PMID- 26005614 TI - [Philippines]health databases in the era of information technology: the philippine scene. PMID- 26005615 TI - [Singapore]Health Database in an IT Society. PMID- 26005616 TI - [Taiwan]the health database in an information society. PMID- 26005617 TI - [Thailand]health database in an information society. PMID- 26005618 TI - CMAAO Resolution on Ethical Frameworks for Health Databases and Human Genetic Databases: Adopted by the CMAAO General Assembly in Manila, the Philippines on September 24-26, 2014. PMID- 26005619 TI - Bangladesh Medical Association. PMID- 26005620 TI - Hong Kong Medical Association. PMID- 26005621 TI - Indian Medical Association. PMID- 26005622 TI - Indonesian Medical Association. PMID- 26005623 TI - Japan Medical Association. PMID- 26005624 TI - Korean Medical Association. PMID- 26005625 TI - Malaysian Medical Association. PMID- 26005626 TI - Myanmar Medical Association. PMID- 26005627 TI - Nepal Medical Association. PMID- 26005628 TI - Philippine Medical Association. PMID- 26005629 TI - Singapore Medical Association. PMID- 26005630 TI - Taiwan Medical Association. PMID- 26005631 TI - The Medical Association Of Thailand. PMID- 26005633 TI - DNA Methylation and Flavonoids in Genitourinary Cancers. AB - Malignancies of the genitourinary system have some of the highest cancer incidence and mortality rates. For example prostate cancer is the second most common cancer in men and ovarian cancer mortality and incidence are near equal. In addition to genetic changes modulation of the epigenome is critical to cancer development and progression. In this regard epigenetic changes in DNA methylation state and DNA hypermethylation in particular has garnered a great deal of attention. While hypomethylation occurs mostly in repeated sequence such as tandem and interspersed repeats and segment duplications, hypermethylation is associated with CpG islands. Hypomethylation leads to activation of cancer causing genes with global DNA hypomethylation being commonly associated with metastatic disease. Hypermethylation-mediated silencing of tumor suppressive genes is commonly associated with cancer development. Bioactive phytochemicals such as flavonoids present in fruits, vegetables, beverages etc. have the ability to modulate DNA methylation status and are therefore very valuable agents for cancer prevention. In this review we discuss several commonly methylated genes and flavonoids used to modulate DNA methylation in the prevention of genitourinary cancers. PMID- 26005632 TI - Management of gastrointestinal involvement in scleroderma. AB - Gastrointestinal tract (GIT) commonly affects patients with systemic sclerosis (SSc). The GI involvement is quite heterogeneous varying from asymptomatic disease to significant dysmotility causing complications like malabsorption, weight loss and severe malnutrition. This review focuses on the management of GI involvement in SSc and has been categorized based on the segment of GIT involved. A brief discussion on the role of patient reported outcome measures in SSc-GI involvement has also been incorporated. PMID- 26005634 TI - Inverse relationship between photon flux densities and nanotesla magnetic fields over cell aggregates: Quantitative evidence for energetic conservation. AB - The quantitative relationship between local changes in magnetic fields and photon emissions within ~2 mm of aggregates of 10(5)-10(6) cells was explored experimentally. The vertical component of the earth's magnetic field as measured by different magnetometers was ~15 nT higher when plates of cells removed from incubation were measured compared to plates containing only medium. Additional experiments indicated an inverse relationship over the first ~45 min between changes in photon counts (~10(-12) W.m(-2)) following removal from incubation and similar changes in magnetic field intensity. Calculations indicated that the energy within the aqueous volume containing the cells was equivalent for that associated with the flux densities of the magnetic fields and the photon emissions. For every approximately 1 nT increase in magnetic field intensity value there was a decrease of ~2 photons (equivalent of 10(-18) J). These results complement correlation studies and suggest there may be a conservation of energy between expression as magnetic fields that are subtracted or added to the adjacent geomagnetic field and reciprocal changes in photon emissions when aggregates of cells within a specific volume of medium (water) adapt to new environments. PMID- 26005635 TI - Exposure of vaccinated and naive cattle to natural challenge from buffalo-derived Theileria parva. AB - Integrative management of wildlife and livestock requires a clear understanding of the diseases transmitted between the two populations. The tick-borne protozoan parasite Theileria parva causes two distinct diseases in cattle, East Coast fever and Corridor disease, following infection with parasites derived from cattle or buffalo, respectively. In this study, cattle were immunized with a live sporozoite vaccine containing three T. parva isolates (the Muguga cocktail), which has been used extensively and successfully in the field to protect against cattle-derived T. parva infection. The cattle were exposed in a natural field challenge site containing buffalo but no other cattle. The vaccine had no effect on the survival outcome in vaccinated animals compared to unvaccinated controls: nine out of the 12 cattle in each group succumbed to T. parva infection. The vaccine also had no effect on the clinical course of the disease. A combination of clinical and post mortem observations and laboratory analyses confirmed that the animals died of Corridor disease. The results clearly indicate that the Muguga cocktail vaccine does not provide protection against buffalo-derived T. parva at this site and highlight the need to evaluate the impact of the composition of challenge T. parva populations on vaccine success in areas where buffalo and cattle are present. PMID- 26005636 TI - VNS terminating refractory nonconvulsive SE secondary to anti-NMDA encephalitis: A case report. AB - Anti-NMDA receptor encephalitis (ANRE) has been previously reported as a rare cause of nonconvulsive status epilepticus (NCSE). Vagus nerve stimulation (VNS) is generally considered as a palliative treatment for patients with drug resistant partial-onset epilepsy. Here, we report a case of refractory NCSE that was terminated after vagus nerve stimulator implantation. To our knowledge, similar cases have not been reported previously. PMID- 26005637 TI - Substantial and sustained seizure reduction with ketogenic diet in a patient with Ohtahara syndrome. AB - Ketogenic diet has been shown to be efficacious in some epileptic encephalopathies but rarely reported as being useful in children with Ohtahara syndrome. This could possibly be attributed to the rarity of the disease and associated short survival period. We report on a 5-year-old child with Ohtahara syndrome, whose seizures failed to improve with all known medications, continued to show persistent suppression-burst pattern on the electroencephalography (EEG) and had substantial reduction in seizure frequency for one year post-initiation of ketogenic diet. He has not had a single visit to the emergency room because of seizures in the last one year, and more importantly, there has been a clear improvement noted in his level of interaction and temperament. Patients with Ohtahara syndrome invariably have medically intractable seizures and catastrophic neurodevelopmental outcome. Ketogenic diet is a treatment modality that might be worth considering even in this group of patients. PMID- 26005638 TI - Enriched transcription factor signatures in triple negative breast cancer indicates possible targeted therapies with existing drugs. AB - PURPOSE: Triple negative (TN) breast cancers which lack expression of the estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors convey a poor prognosis due in part to a lack of targeted therapies. METHODS: To identify viable targets for the treatment of TN disease, we have conducted a gene set enrichment analysis (GSEA) on seven different breast cancer whole genome gene expression cohorts comparing TN vs. ER + HER2 - to identify consistently enriched genes that share a common promoter motif. The seven cohorts were profiled on three different genome expression platforms (Affymetrix, Illumina and RNAseq) consisting in total of 2088 samples with IHC metadata. RESULTS: GSEA identified enriched gene expression patterns in TN samples that share common promoter motifs associated with SOX9, E2F1, HIF1A, HMGA1, MYC BACH2, CEBPB, and GCNF/NR6A1. Unexpectedly, NR6A1 an orphan nuclear receptor normally expressed in germ cells of gonads is highly expressed in TN and ER + HER2 - samples making it an ideal drug target. CONCLUSION: With the increasing number of large sample size breast cancer cohorts, an exploratory analysis of genes that are consistently enriched in TN sharing common promoter motifs allows for the identification of possible therapeutic targets with extensive validation in patient derived data sets. PMID- 26005640 TI - Innovations and advancements in breast reconstruction. PMID- 26005639 TI - Association of interleukin-6 genetic polymorphisms with risk of OSCC in Indian population. AB - PURPOSE: Interleukin-6 (IL-6) encodes a cytokine protein, which causes inflammation, maintains immune homeostasis and plays an essential role in oral pathogenesis. The aim of this study was to evaluate the association between IL-6 (- 174 and - 572) G/C promoter gene polymorphisms and risk of OSCC among Indians. METHODS: Single nucleotide polymorphism in IL-6 genes was genotyped in OSCC patients and healthy controls by PCR-RFLP method. Genotype and allele frequencies were analyzed by chi-square test and strength of associations by odds ratio with 95% confidence intervals. RESULTS: Frequency distribution of IL-6 (- 174) G/C gene polymorphism was significantly associated with OSCC patients in comparison to healthy controls (OR: 0.541, CI: 0.356-0.822; p: 0.004. However, frequency of IL-6 (- 572) G/C gene polymorphism was not significantly associated with OSCC patients (p > 0.05). CONCLUSION: The genotype GC and allele C of IL-6 (- 174) G/C gene polymorphism play a significant role in OSCC susceptibility. PMID- 26005641 TI - Essential elements of the preoperative breast reconstruction evaluation. AB - A plethora of options exist for breast reconstruction and preoperative evaluation must be thorough to lead to a successful outcome. We review multiple components of the preoperative assessment including the patient's history, goals, imaging, and key elements of the physical exam. Consideration for tumor biology, staging, need or response to chemotherapy or radiation therapy is important in deciding on immediate versus delayed reconstruction. It is also important to consider the patient's anatomy, breast size and whether the reconstruction will be unilateral or bilateral. The reconstructive surgeon must accommodate all these factors to consider partial or complete mastectomy defects and guide the patient to the most appropriate reconstructive technique whether it be an oncoplastic reduction mammoplasty, expander-based reconstruction, immediate implant reconstruction, or immediate versus delayed autologous tissue reconstruction such as the deep inferior epigastric artery perforator (DIEP)/transverse rectus abdominis muscle (TRAM), latissimus, transverse upper gracilis (TUG)/profunda femoris artery perforator (PAP), or gluteal artery perforator (GAP) flaps. PMID- 26005643 TI - Current strategies with 1-stage prosthetic breast reconstruction. AB - BACKGROUND: 1-stage prosthetic breast reconstruction is gaining traction as a preferred method of breast reconstruction in select patients who undergo mastectomy for cancer or prevention. METHODS: Critical elements to the procedure including patient selection, technique, surgical judgment, and postoperative care were reviewed. RESULTS: Outcomes series reveal that in properly selected patients, direct-to-implant (DTI) reconstruction has similar low rates of complications and high rates of patient satisfaction compared to traditional 2 stage reconstruction. CONCLUSIONS: 1-stage prosthetic breast reconstruction may be the procedure of choice in select patients undergoing mastectomy. Advantages include the potential for the entire reconstructive process to be complete in one surgery, the quick return to normal activities, and lack of donor site morbidity. PMID- 26005642 TI - Evolution and update on current devices for prosthetic breast reconstruction. AB - Over the past decade, the leading breast reconstruction modality has shifted from autologous tissue to implants. This trend reversal is multi-factorial but includes increasing bilateral mastectomies and the more widespread acceptance of implants due to stringent quality and safety regulatory surveillance by the US Food and Drug Administration (FDA). Since 2012, the US FDA has approved several new implant styles, shapes and textures, increasing the choices for patients and surgeons. Predictable, superior aesthetic results after prosthetic breast reconstruction are attainable, but require thoughtful planning, precise surgical technique and appropriate device selection based on several different patient and surgeon parameters, such as patient desires, body mass index, breast shape, mastectomy flap quality and tissue based bio-dimensional assessment. This article briefly reviews historic devices used in prosthetic breast reconstruction beginning in the 1960s through the modern generation devices used today. We reflect on the rigorous hurdles endured over the last several decades leading to the approval of silicone gel devices, along with their well-established safety and efficacy. The various implant characteristics can affect feel and performance of the device. The many different styles and features of implants and expanders are described emphasizing surgical indications, advantages and disadvantages of each device. PMID- 26005644 TI - Anatomic and physiological fundamentals for autologous breast reconstruction. AB - The success of autologous tissue transfer is reliant on adequate blood supply and as we endeavour to tailor our reconstructive options through our flap choices and design. Autologous breast reconstruction has made substantial progress over the years and the evolution of refinements over the last 30 years has allowed flaps to be based on specific perforators. The ultimate goal of breast reconstruction following mastectomy is to match optimal tissue replacement with minimal donor site expenditure. In parallel surgeons will seek ways to ensure safe flap design and harvest while maintaining predictability and reliable tissue perfusion. Better understanding of the vascular anatomy and physiology of the cutaneous circulation of soft tissues, and that of patterns of blood flow from individual perforator has provided insight to advance perforator flap harvest and modifications in flap design. The aim of this article is to review the principles of blood supply and flap design exemplified through common flaps used in autologous breast reconstructive surgery, to better understand approaches for safe flap harvest and transfer of well perfused tissue. PMID- 26005645 TI - Achieving ideal breast aesthetics with autologous reconstruction. AB - Achieving ideal breast aesthetic has become a top priority for women considering breast reconstruction following mastectomy. The use of autologous tissue is generally regarded as providing the most natural results because donor tissues quality and consistency is similar to that of the native breast. There are several donor sites that are particularly useful for autologous reconstruction that include the abdomen, gluteal region, posterior thorax, and the thigh. Traditional and microsurgical techniques can be used. Shaping is a critical component and involves a basic understanding of the footprint, conus, and skin envelope. This manuscript will review many aspects of breast shaping in-order to achieve aesthetically pleasing results in a predictable manner. PMID- 26005646 TI - Achieving ideal donor site aesthetics with autologous breast reconstruction. AB - The appearance of the donor site following breast reconstruction with abdominal flaps has become an important topic for study. Given the variety of flaps that are derived from the abdomen, decisions are often based on how much muscle and fascia will be harvested. Comparisons between muscle sparing and non-muscle sparing techniques have been performed with outcomes related to function and contour. Closure techniques will vary and include primary fascial closure, mesh reinforcement and additional fascial plication all of which can produce natural and sometimes improved abdominal contours. Proper patient selection however is important. This manuscript will describe various techniques in order to achieve ideal abdominal contour following autologous reconstruction. PMID- 26005647 TI - Oncoplastic breast surgery: current strategies. AB - The surgical management of breast cancer has dramatically evolved over the past 20 years, with oncoplastic surgery gaining increased popularity. This field of breast surgery allows for complete resection of tumor, preservation of normal parenchyma tissue, and the use of local or regional tissue for immediate breast reconstruction at the time of partial mastectomy. These techniques extend the options for breast conservation surgery, improve aesthetic outcomes, have high patient satisfaction and result in better control of tumor margins. This article will detail the approach to evaluating and treating patients undergoing oncoplastic reconstruction. Different oncoplastic approaches will be described and applied to an oncoplastic reconstructive algorithm. Surgical complications, oncologic outcomes and aesthetic outcomes are reviewed. PMID- 26005649 TI - Immediate breast volume replacement using a free dermal fat graft after breast cancer surgery: multi-institutional joint research of short-term outcomes in 262 Japanese patients. AB - BACKGROUND: Immediate volume replacement using a free dermal fat graft (FDFG) has been proven safe with early postoperative benefits. The aims of the present study were to clarify adequate indications and risk factors associated with operative morbidity. PATIENTS AND METHODS: A multi-institutional analysis of partial mastectomy with immediate volume replacement with FDFG was undertaken in 14 hospitals specializing in breast cancer treatment. Clinical and oncological variables were analyzed to identify factors associated with postoperative complications. RESULTS: A total of 262 cases were analyzed. Considering the observation period and overlap of patients, 13 (5.4%) out of 242 patients had complications within 1 month of surgery while 7 (4.6%) out of 151 patients developed complications 1-12 months after surgery. Two hundred and eleven out of 242 patients were statistically examined using a multivariate analysis, which revealed that the weight of resected breast tissue, size of implanted FDFG (cranio-caudal length), and weight of implanted FDFG were associated with a higher likelihood of postoperative complications. CONCLUSIONS: Immediate breast volume replacement using a FDFG after breast cancer surgery should be done for selected patients with breast cancer to avoid postoperative complications. The prospective and larger investigations are warranted for the establishment of appropriate guidelines. PMID- 26005650 TI - Medical tourism: between entrepreneurship opportunities and bioethics boundaries: narrative review article. AB - Nowadays, medical tourism reports impressive growth in terms of number of persons, income and number of countries involved in cross-border flows. So this study was undertaken to clarify entrepreneurship opportunities and bio-ethics boundaries in medical tourism. For tourism entrepreneurs, these outgoing flows related to medical procedures and tourism become an opportunity that cannot be ignored, so a wide range of tourist services related to health care are provided on a private, entrepreneurial basis. However, social and economic boundaries are omnipresent (impaired health services in receiving (incoming) countries, the crisis of the health care systems in emitting (outgoing) countries, over consumption of medical and tourism services), and, not least, ethical considerations. Transforming medical care in a market tool, reducing human attributes to the status of commodity that can be bought, sold or negotiated, seriously challenges contemporary bioethics principles. It is a significant entering in the area (which is essentially un-ethic) of market transactions, where libertarianism and consumer-oriented attitudes dominates the spectrum of rational choice. So tourism comes to provide an organized and comfortable framework for all these choices, but many issues still re-main controversial and may worsen if national health systems and national and international regulations would not identify their problems and would continue to leave medical tourism to market mechanisms. Market will efficiently allocate the resources, but not always in an ethical manner. PMID- 26005648 TI - Comparative analysis of fluorescent angiography, computed tomographic angiography and magnetic resonance angiography for planning autologous breast reconstruction. AB - BACKGROUND: The high incidence of breast cancer and growing number of breast cancer patients undergoing mastectomy has led to breast reconstruction becoming an important part of holistic treatment for these patients. In planning autologous reconstructions, preoperative assessment of donor site microvascular anatomy with advanced imaging modalities has assisted in the appropriate selection of flap donor site, individual perforators, and lead to an overall improvement in flap outcomes. In this review, we compare the accuracy of fluorescent angiography, computed tomographic angiography (CTA), and magnetic resonance angiography (MRA) and their impact on clinical outcomes. METHODS: A review of the published English literature dating from 1950 to 2015 using databases, such as PubMed, Medline, Web of Science, and EMBASE was undertaken. RESULTS: Fluorescent angiography is technically limited by its inability to evaluate deep-lying perforators and hence, it has a minimal role in the preoperative setting. However, it may be useful intraoperatively in evaluating microvascular anastomotic patency and the mastectomy skin perfusion. CTA is currently widely considered the standard, due to its high accuracy and reliability. Multiple studies have demonstrated its ability to improve clinical outcomes, such as operative length and flap complications. However, concerns surrounding exposure to radiation and nephrotoxic contrast agents exist. MRA has been explored, however despite recent advances, the image quality of MRA is considered inferior to CTA. CONCLUSIONS: Preoperative imaging is an essential component in planning autologous breast reconstruction. Fluorescent angiography presents minimal role as a preoperative imaging modality, but may be a useful intraoperative adjunct to assess the anastomosis and the mastectomy skin perfusion. Currently, CTA is the gold standard preoperatively. MRA has a role, particularly for women of younger age, iodine allergy, and renal impairment. PMID- 26005651 TI - The Randomized Response Technique Application in the Survey of Homosexual Commercial Sex among Men in Beijing. AB - BACKGROUND: Traditional survey methods may cause refusals to respond or untruthful replies when encounter the sensitive questions. The Randomized Response Technique (RRT) is designed to decrease social desirability bias and obtain reliable estimates. This study aimed to apply these new methods on the sensitive questions survey. METHODS: Simmons model was applied in the survey of issues relevant to commercial sex among men who have sex with men (MSM) in Beijing, China. Stratified two-stage sampling and stratified random sampling were applied. RESULTS: During July to December 2010 in Beijing, the commercial sex proportion among MSM was 0.051(95% CI: 0.017, 0.085), its estimated variance was 3.01*10(-4). The last male condom use rate during commercial sex was 0.778(95% CI: 0.746, 0.810), its estimated variance was 2.6*10(-4). CONCLUSION: We have introduced new approaches for the sensitive question survey among MSM. The new approaches are proved to be reliable and valid. PMID- 26005652 TI - Detection of cell surface hydrophobicity, biofilm and fimbirae genes in salmonella isolated from tunisian clinical and poultry meat. AB - BACKGROUND: The aim of this study was to evaluate the ability of 15 serotypes of Salmonella to form biofilm on polystyrene, polyvinyl chloride (PVC) and glass surfaces. . METHODS: Initially slime production was assessed on CRA agar and hydrophobicity of 20 Salmonella strains isolated from poultry and human and two Salmonella enterica serovar Typhimurium references strains was achieved by microbial adhesion to n-hexadecane. In addition, biofilm formation on polystyrene, PVC and glass surfaces was also investigated by using MTT and XTT colorimetric assay. Further, distribution of Salmonella enterotoxin (stn), Salmonella Enteritidis fimbrial (sef) and plasmid encoded fimbrial (pef) genes among tested strains was achieved by PCR. RESULTS: Salmonella strains developed red and white colonies on CRA and they are considered as hydrophilic with affinity values to n-hexadecane ranged between 0.29% and 29.55%. Quantitative biofilm assays showed that bacteria are able to form biofilm on polystyrene with different degrees and 54.54% of strains produce a strong biofilm on glass. In addition, all the strains form only a moderate (54.54%) and weak (40.91%) biofilm on PVC. PCR detection showed that only S. Enteritidis harbour Sef gene, whereas Pef and stn genes were detected in S. Kentucky, S. Amsterdam, S. Hadar, S. Enteritidis and S. Typhimurium. CONCLUSION: Salmonella serotypes are able to form biofilm on hydrophobic and hydrophilic industrial surfaces. Biofilm formation of Salmonella on these surfaces has an increased potential to compromise food safety and potentiate public health risk. PMID- 26005653 TI - Predictive Power for Type 2 Diabetes Mellitus using Dynamic Change of Metabolic Syndrome, Dynamic Change of Fasting Plasma Glucose, Metabolic Syndrome and Fasting Plasma Glucose. AB - BACKGROUND: The aim was to compare the predictive power for Type 2 Diabetes mellitus (T2DM) using dynamic change (Difference) of metabolic syndrome (MS), Difference of fasting plasma glucose (FPG), baseline MS and FPG in cohort study. METHODS: Overall, 3461 subjects were recruited from Prevention of Multiple Metabolic disorders and MS in Jiangsu of China Study with 3.8 years follow-up. Cox proportional-hazards regression and receiver operating characteristic were used to evaluate the predictive power for T2DM using Difference MS, Difference of FPG, baseline MS and FPG. RESULTS: Adjusted relative risk (aRR 5.24, 95% CI 4.28 6.42) of Difference of FPG to T2DM was highest than other. Difference of FPG owns the largest AUC (0.89, P<0.05), the highest sensitivity (96.25%) and specificity (80.49%) demonstrating that Difference of FPG can provide strongest predictive information to T2DM, Difference of MS comes second. Between FPG related tools, sensitivity of Difference of FPG almost was twice than baseline FPG(96.25% vs. 54.38%) suggesting that using baseline FPG would missed found 46% T2DM patients. Among MS related indicators, sensitivity of Difference of MS almost was twice than baseline MS (sensitivity 66.25% vs. 39.38%) suggesting that using baseline would missed found 61% T2DM patients. CONCLUSION: Dynamic change of FPG had the highest predictive power for T2DM in Chinese than Dynamic Change of MS, baseline MS and FPG. PMID- 26005654 TI - Prevalence and Genetic Analysis of Bitter Taste Perception for Phenylthiocarbamide (PTC) Among Some Muslim Populations of Uttar Pradesh, India. AB - BACKGROUND: The ability to taste Phenylthiocarbamide (PTC), a bitter organic compound, described as a bimodal autosomal trait is widely used to know the heritable trait in both genetic and anthropological studies. The present study was carried out to analyze the prevalence of PTC taste sensitivity and to determine the gene frequencies among some Muslim populations of Uttar Pradesh, India. This study has some physiological relevance to highlight the adaptability of endogamous groups to behavioral traits in the same place. METHODS: Unrelated, healthy individuals of both sexes (Male-403, Female-418) belonging to different populations of Uttar Pradesh, India were randomly selected with the age range of 16-45 years observed for phenylthiocarbamide to taste sensitivity. PTC tasting ability was measured by using a serial dilution method of Harris and Kalmus. RESULTS: The phenotypic frequency of tasters was higher as compared to non tasters, and the same is statistically significant (chi(2)= 11.92, df = 5, P = 0.036). There were more females among tasters (67.94%) than males (64.76%). This observation was statistically significant (chi(2) = 14.79, df = 5, P = 0.011). CONCLUSION: The frequency of PTC tasters is greater than non-tasters and the females have lower non-taster pheno-types as compared to males. This type of study will provide background information about genetic structure of population and serves as useful interaction of genetics, food preferences and dietary patterns. PMID- 26005655 TI - The TP53 Codon 72 Polymorphism and Risk of Sporadic Prostate Cancer among Iranian Patients. AB - BACKGROUND: The TP53 gene is one of the most frequently mutated genes amongst human malignancies, particularly TP53 codon 72 polymorphism. Furthermore, an association between the TP53 codon 72 variants and prostate cancer has been reported in several studies. Although some studies have indicated an association between the TP53 Arg/Arg variant and an increased risk for prostate cancer, other studies have shown a positive correlation between the TP53 Pro/Pro genotype instead. Therefore, to clarify if this polymorphism is associated with an increased risk of prostate cancer in Iranian men, we conducted a case-control study of 40 sporadic prostate cancer patients and 80 benign prostate hyperplasia cases. METHODS: The TP53 codon 72 was genotyped using an allele specific PCR. RESULTS: A significant association between the TP53 codon 72 genotype and prostate cancer risk was found (OR = 6.8, 95% CI = [1.8-25.1], P = 0.005). However, the results of this study did not support an association between age, the Gleason score nor TP53 genotype at codon 72 in prostate cancer patients. CONCLUSIONS: TP53 codon 72 polymorphism may have a great impact in the development of prostate cancer. PMID- 26005656 TI - Natural airborne dust and heavy metals: a case study for kermanshah, Western iran (2005-2011). AB - BACKGROUND: Dust pollution has become a serious environmental problem especially in recent decades. The present study aim was the investigation of the levels of PM10 concentration in Kermanshah, western Iran and also measured five important heavy metals (Pb, Cd, As, Hg and Cr) in some samples during 2005 to 2011. METHODS: A total 2277 samples were collected from air pollution measurement station belonging to the Department of Environment in Kermanshah. Furthermore, four samples were collected during dusty days to determine the selected heavy metals concentration. The samples were analyzed statistically using the SPSS Ver.16. RESULTS: The highest seasonal average concentration in spring was recorded in 2008 with 216.63MUg/m(3), and the maximum values of 267.79 and 249.09MUg/m(3) were observed in summer and winter in 2009, respectively. The maximum concentration of 127.1MUg/m(3) was in autumn in 2010. The metals concentration (Pb, Cd, As, Hg and Cr) of samples were 42.32+/-5.40, 37.45+/-9.29, 3.51+/-2.07, 1.88+/-1.64 and 0MUg/g in July, 2009, respectively. CONCLUSION: According to National Ambient Air Quality of USEPA guidelines, the most days with non-standard, warning, emergency and critical conditions were related to 2009 (120 days) while the least polluted days were recorded in 2006 (16 days). There are concerns about the increasing frequency and intensity trend of dust storms in recent years as a result of special condition in neighboring Western countries which it could endanger public health and environment. All measured heavy metals except mercury was higher than the standard level of WHO and USEPA. PMID- 26005657 TI - Trend of HIV/AIDS Prevalence and Related Interventions Administered in Prisons of Iran -13 Years' Experience. AB - BACKGROUND: HIV/AIDS epidemic is concentrated among injecting drug users in Iran. Like many other countries with HIV/AIDS concentrated epidemic, prisons are high risk areas for spreading HIV/AIDS. The aim of this paper was to study the trend of HIV/AIDS prevalence and related interventions administered in prisons of Iran during a 13 years period. METHODS: This cross sectional study was conducted using the data collected from the sentinel sites in all prisons in the country and it also used the data about Harm Reduction interventions which has been implemented by Iran Prisons Organization. To evaluate the correlation between the prevalence and each of administered interventions in prisons the Correlation Coefficient Test was used for the second half of the mentioned time period. RESULTS: The prevalence of HIV/AIDS in prisons had increased rapidly in the early stages of epidemic, so that in 2002 the prevalence raised to 3.83%. Followed by the expansion of Methadone Maintenance Therapy and development of Triangular Clinics, HIV/AIDS prevalence in prisons declined. There was a relationship between interventions and the prevalence of HIV/AIDS. CONCLUSION: In regions and countries where the epidemic is highly prevalent among injecting drug users and prisoners, Methadone Maintenance Therapy and development of Triangular Clinics can be utilized to control HIV/AIDS epidemic quickly. PMID- 26005658 TI - Effect of mobile phone usage time on total antioxidant capacity of saliva and salivary immunoglobulin a. AB - BACKGROUND: Nowadays mobile phone is very popular, causing concern about the effect it has on people's health. Parotid salivary glands are in close contact to cell phone while talking with the phone and the possibility of being affected by them. Limited studies have evaluated the effect of cell phone use on the secretions of these glands; so this study was designed to investigate the effects of duration of mobile phone use on the total antioxidant capacity of saliva. METHODS: Unstimulated saliva from 105 volunteers without oral lesions collected. The volunteers based on daily usage of mobile phones were divided into three groups then total antioxidant capacity of saliva was measured by Ferric Reducing Ability of Plasma (FRAP) method. Data were analyzed by SPSS software version 19. ANOVA was used to compare 3 groups and post-hoc Tukey test to compare between two groups. RESULTS: Average total antioxidant capacities of saliva in 3 groups were 657.91 umol/lit, 726.77 um/lit and 560.17 umol/lit, respectively. The two groups had statistically significant different (P = 0.039). CONCLUSION: Over an hour talking with a cell phone decreases total antioxidant capacity of saliva in comparison with talking less than twenty minutes. PMID- 26005659 TI - Smoking and diet in healthy adults: a cross-sectional study in tehran, iran, 2010. AB - BACKGROUND: Smoking and unhealthy diet are two major risk factors for non communicable diseases. The aim of this study was to investigate the possible association between these two risk factors amongst healthy adults 30-60 years old in Tehran, Iran. METHODS: Overall, 2602 healthy adults 30 to 60 years old in Tehran were studied. The demographic characteristics, anthropometric and smoking status of the participants were questioned. The frequency of consumption of red meat, white meat, fruits and vegetables, dairy products, bread and cereals and fast food were questioned to be daily, weekly, monthly, once every 6 months or yearly and categorized as "healthy" or "unhealthy". RESULTS: Of the 2602 participants, 974 (37.4%) had smoked more than 100 cigarettes in their life time and continued daily or smoked occasionally. Smokers significantly consumed more fast food and white meat but less fruit and vegetables and dairy product (P<0.0001). Totally, 586 (22.5%) consumed "unhealthy" diet. A positive association between cigarette smoking and unhealthy diet (OR=1.68; 95% CI: 1.40 2.03) were found. After adjusting the analysis for the effect of age, education and gender, the odds ratio of consuming unhealthy diet for the smoker increased to 1.83 (1.50, 2.25) compared with non-smoker. CONCLUSION: Our study found a noticeable association between cigarette smoking and unhealthy diet. Smoking cessation and changing diet program for smokers is recommended. PMID- 26005660 TI - Heat Stress Level among Construction Workers. AB - BACKGROUND: The purpose of this study was to determine the level of heat stress to construction workers using Thermal Work Limit (TWL) and Wet Bulb Globe Temperature (WBGT) indices and by measuring Urine Specific Gravity (USG) among construction workers in Iran and comparing the appropriateness of these indices for measuring heat stress in Iran climate. METHODS: This comparative and experimental study was conducted during September 2012 in Baghe Ketabe Tehran, one of the large size construction sites in Tehran City, Iran. Sixty participants were randomly selected in two groups (exposed to sun and non-exposed) among the construction workers in a construction campus with similar work type, climate and diet. TWL and WBGT and USG were measured in two consequent days and at the beginning, mid and end of the work shift, for both groups. RESULTS: The mean WBGT index was 22.6 +/- 0.9 degrees C for control group and 27.5 +/- 1.2 degrees C for exposure group, the mean TWL index measure was 215.8 +/- 5.2 W/m(2) for control group and 144 +/- 9.8 W/m(2) for exposure group and the mean USG was 1.0213 +/- 0.0054 in control group and 1.026 +/- 0.005 in exposure group. There was a significant difference in TWL, WBGT and USG between exposed and non-exposed group (P<0.01). CONCLUSION: workers were at an allowed level of heat stress. TWL, WBGT and USG measures were significantly correlated; however as TWL level enabled classification based on required intervention, it had some merit over WBGT index. PMID- 26005661 TI - Risk factor of preterm labor in the west of iran: a case-control study. AB - BACKGROUND: Prematurity is the most common cause of neonatal death. Risk factors of premature birth can be related with ethnicity and genetic. There is no comprehensive high sample size study in Kurdish ethnicity to determine risk factors related to prematurity. This study evaluated risk factors of preterm labor in Kurdish ethnicity. METHODS: This case-control study was conducted in 200 preterm infants (case group) and 400 term infants (control group), in Besat Hospital, Sanandaj, Iran, in the year 2012. Data was analyzed using SPSS software and analysis was performed by Chi-square, Mann-Whitney and logistic regression tests. RESULTS: In univariate analysis, mother's own prematurity, history of previous preterm labor, prematurity in the first-degree family members, history of dead children, premature rupture of membranes, multiple pregnancies, overt diabetes, chronic hypertension, preeclampsia and eclampsia, infertility and cervical incompetence had significant relation-ship with preterm labor. However, multivariate analysis results showed that abnormal amniotic fluid, premature rupture of membranes, double and multiple pregnancies, chronic hypertension, family history of premature birth, mothers age over 35 years, and cervical incompetence (P<0.05) had significant relationship with the premature birth. CONCLUSION: Screening of newborns at risk of preterm labor could be achieved by these risk factors: family history of prematurity, mother's own history of prematurity and previous preterm labor, history of previous neonatal death, decreased amniotic fluid, multiple pregnancies, overt diabetes, hypertension, preeclampsia, infertility and cervical incompetence, however some of these factors are not the direct cause of prematurity. Our study suggests genetic' s role in preterm labor. PMID- 26005662 TI - Risk-based Analysis of Construction Accidents in Iran During 2007-2011-Meta Analyze Study. AB - BACKGROUND: The present study aimed to investigate the characteristics of occupational accidents and frequency and severity of work related accidents in the construction industry among Iranian insured workers during the years 20072011. METHODS: The Iranian Social Security Organization (ISSO) accident database containing 21,864 cases between the years 2007-2011 was applied in this study. In the next step, Total Accident Rate (TRA), Total Severity Index (TSI), and Risk Factor (RF) were defined. The core of this work is devoted to analyzing the data from different perspectives such as age of workers, occupation and construction phase, day of the week, time of the day, seasonal analysis, regional considerations, type of accident, and body parts affected. RESULTS: Workers between 15-19 years old (TAR=13.4%) are almost six times more exposed to risk of accident than the average of all ages (TAR=2.51%). Laborers and structural workers (TAR=66.6%) and those working at heights (TAR=47.2%) experience more accidents than other groups of workers. Moreover, older workers over 65 years old (TSI=1.97%> average TSI=1.60%), work supervisors (TSI=12.20% >average TSI=9.09%), and night shift workers (TSI=1.89% >average TSI=1.47%) are more prone to severe accidents. CONCLUSION: It is recommended that laborers, young workers, weekend and night shift workers be supervised more carefully in the workplace. Use of Personal Protective Equipment (PPE) should be compulsory in working environments, and special attention should be undertaken to people working outdoors and at heights. It is also suggested that policymakers pay more attention to the improvement of safety conditions in deprived and cold western regions. PMID- 26005663 TI - Psychological disorders in patients with retinitis pigmentosa in iran. AB - BACKGROUND: To identify mental disorders and their prevalence in patients with retinitis pigmentosa (RP). METHODS: This descriptive study was carried out between January 2009 and January 2010 on 417 patients with RP, who were members of Iran RP Center. The necessary data were collected using questionnaires consisting two parts: The background characteristics and questions assessing the mental health and screening personality and psychosocial disorders, which were designed based on the Minnesota Multiphasic Personality Inventory. Data were analyzed using SPSS software with Chi-square test to assess the relationship between background characteristics and each mental disorder. Scores in the range of 30 and 70 were considered normal. RESULTS: Patients with RP suffered from eight mental disorders with the following prevalence: Obsessive compulsive disorder (39.3%), schizophrenia (38.1%), antisocial personality (37.6%), paranoia (36.7%), hypochondrias (35.3%), depression (31.2%), hysteria (26.9%), and hypomania (23.7%). No one had all the eight mental disorders simultaneously. Statistical analysis showed no significant relationship between obsessive compulsive disorder, paranoia, depression, and hysteria and background characteristics. A significant association was found between schizophrenia and onset of RP (P = 0.047). Furthermore, a significant association was seen between hypochondrias and educational level (P = 0.026) as well as income (P = 0.037), and smoking (P = 0.009). There was also a significant association between hypomania and marital status (P = 0.027). CONCLUSION: The findings showed that RP might lead to various mental disorders, especially obsessive compulsive disorder. PMID- 26005664 TI - An Eagle's Eye on the Remuneration for Dentists Working in Primary and Community Health Centers in India. PMID- 26005665 TI - Conjecture about Hand-Foot Syndrome in CLASSIC Trial. PMID- 26005666 TI - Decay of free residual chlorine in drinking water at the point of use. PMID- 26005667 TI - Quality of work life and job satisfaction of nursing managers. PMID- 26005668 TI - IMPACT OF WEIGHT LOSS AND AEROBIC EXERCISE ON NUTRITION AND BONE MINERAL DENSITY IN AFRICAN AMERICAN AND CAUCASIAN POSTMENOPAUSAL WOMEN. AB - BACKGROUND: Weight loss is often recommended for obese women to reduce fat mass and the risk of developing chronic diseases, but may result in a reduction of bone mineral density (BMD). African Americans have greater BMD than Caucasians, but differences in the decrease in BMD between these races following weight reduction with and without exercise are unknown. OBJECTIVES: The purpose of this study was to investigate the hypothesis that Caucasian women would lose greater amounts of BMD than African American women after undergoing weight loss, but that the addition of aerobic exercise would attenuate the loss in both races. DESIGN: Longitudinal. PARTICIPANTS: African American (n=34) and Caucasian (n=63), overweight and obese postmenopausal (age 45-80 years). INTERVENTION: Six months of weight loss (250-350 kcal/days deficit) alone (WL) or in combination with aerobic exercise consisting of 3 days/week treadmill training at >85% of heart rate reserve for 45 min (AEX+WL). MEASUREMENTS: Femoral neck, total femur, and lumbar BMD, VO2max, urinary calcium, and dietary intake. RESULTS: African American women had a greater body weight, BMI, and BMD all sites and lower dietary protein and calcium intakes than Caucasian women (all P<0.05). Weight decreased 7.5% in both groups and VO2max increased only after AEX+WL (intervention effect, P<0.001). Both races lost ~1% of their femoral neck and total femur BMD following the interventions (P's<0.01). There were no race by intervention interactions. There was a trend for the women undergoing WL to lose greater femoral neck BMD than those in AEX+WL (P=0.07). There were no associations between changes in BMD and changes in VO2max, urinary calcium, or dietary intake. CONCLUSIONS: Our data indicate that despite beginning the interventions with greater BMD than Caucasian postmenopausal women, African Americans were not spared from losses of femoral neck and total femur BMD following six months of weight loss, but that addition of aerobic exercise to weight loss tends to attenuate the decreases in femoral neck BMD in both races. PMID- 26005670 TI - ADAPTIVE MULTILEVEL SPLITTING IN MOLECULAR DYNAMICS SIMULATIONS. AB - Adaptive Multilevel Splitting (AMS) is a replica-based rare event sampling method that has been used successfully in high-dimensional stochastic simulations to identify trajectories across a high potential barrier separating one metastable state from another, and to estimate the probability of observing such a trajectory. An attractive feature of AMS is that, in the limit of a large number of replicas, it remains valid regardless of the choice of reaction coordinate used to characterize the trajectories. Previous studies have shown AMS to be accurate in Monte Carlo simulations. In this study, we extend the application of AMS to molecular dynamics simulations and demonstrate its effectiveness using a simple test system. Our conclusion paves the way for useful applications, such as molecular dynamics calculations of the characteristic time of drug dissociation from a protein target. PMID- 26005669 TI - Quantitative measures of healthy aging and biological age. AB - Numerous genetic and non-genetic factors contribute to aging. To facilitate the study of these factors, various descriptors of biological aging, including 'successful aging' and 'frailty', have been put forth as integrative functional measures of aging. A separate but related quantitative approach is the 'frailty index', which has been operationalized and frequently used. Various frailty indices have been constructed. Although based on different numbers and types of health variables, frailty indices possess several common properties that make them useful across different studies. We have been using a frailty index termed FI34 based on 34 health variables. Like other frailty indices, FI34 increases non linearly with advancing age and is a better indicator of biological aging than chronological age. FI34 has a substantial genetic basis. Using FI34, we found elevated levels of resting metabolic rate linked to declining health in nonagenarians. Using FI34 as a quantitative phenotype, we have also found a genomic region on chromosome 12 that is associated with healthy aging and longevity. PMID- 26005671 TI - Corrigendum: Unveiling the potential of novel yeast protein extracts in white wines clarification and stabilization. AB - [This corrects the article on p. 20 in vol. 3, PMID: 25853122.]. PMID- 26005672 TI - SPECTRA: An Integrated Knowledge Base for Comparing Tissue and Tumor-Specific PPI Networks in Human. AB - Protein-protein interaction (PPI) networks available in public repositories usually represent relationships between proteins within the cell. They ignore the specific set of tissues or tumors where the interactions take place. Indeed, proteins can form tissue-selective complexes, while they remain inactive in other tissues. For these reasons, a great attention has been recently paid to tissue specific PPI networks, in which nodes are proteins of the global PPI network whose corresponding genes are preferentially expressed in specific tissues. In this paper, we present SPECTRA, a knowledge base to build and compare tissue or tumor-specific PPI networks. SPECTRA integrates gene expression and protein interaction data from the most authoritative online repositories. We also provide tools for visualizing and comparing such networks, in order to identify the expression and interaction changes of proteins across tissues, or between the normal and pathological states of the same tissue. SPECTRA is available as a web server at http://alpha.dmi.unict.it/spectra. PMID- 26005674 TI - Fatty liver disease and nutrient intervention. PMID- 26005673 TI - Prodromal Symptom Severity Predicts Accelerated Gray Matter Reduction and Third Ventricle Expansion Among Clinically High Risk Youth Developing Psychotic Disorders. AB - A recent prospective longitudinal neuroimaging study of 274 prodromal risk syndrome subjects revealed that those who later developed full-blown psychotic symptoms exhibited accelerated gray matter loss and third ventricle expansion around the time of onset of psychosis. Previous studies also indicate that higher levels of unusual thought content during prodromal states are a significant predictor of psychosis in clinically high-risk youth (CHR). However, the relationship between clinical symptoms and changes in neuroanatomical structure has not been previously examined in the North American Prodrome Longitudinal Study (NAPLS) sample at the atlas level. In this report, we investigated whether symptom severity as measured by the Scale of Prodromal Symptoms (SOPS) predicted the accelerated gray matter decline in 274 CHR cases, including 35 who converted to psychosis. Higher levels of unusual thought content (pre-delusional) symptoms at baseline were associated with a steeper rate of gray matter loss in the prefrontal cortex bilaterally among converters. In contrast, there was no association found among non-converters. Steeper gray matter loss seems to be unique to those (CHR) individuals with higher levels of sub-psychotic pre delusional symptoms that acutely worsen in the ramp-up to full-blown psychosis, and as such may reflect pathophysiological processes driving emergence of psychosis. PMID- 26005676 TI - Fatty liver disease in diabetes mellitus. AB - Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus (T2DM), likely reflecting the frequent occurrence of obesity and insulin resistance in T2DM. NAFLD also can occur in type 1 DM (T1DM), but must be distinguished from the more common glycogen hepatopathy as a cause of hepatomegaly and liver function abnormalities in T1DM. Weight reduction achieved by diet and exercise is effective in preventing and treating NAFLD in obese diabetic subjects. Bariatric surgery also has been shown to reverse NAFLD in T2DM, and recently approved weight loss medications should be evaluated for their impact on the development and progression of NAFLD. There is limited evidence suggesting that specific drugs used for blood glucose control in T2DM [thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors] and also statins may have a role in preventing or treating NAFLD in patients with diabetes. PMID- 26005675 TI - Sirtuin 1 signaling and alcoholic fatty liver disease. AB - Alcoholic fatty liver disease (AFLD) is one of the most prevalent forms of liver disease worldwide and can progress to inflammation (hepatitis), fibrosis/cirrhosis, and ultimately lead to end stage liver injury. The mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. Nevertheless, understanding its pathogenesis will facilitate the development of effective pharmacological or nutritional therapies for treating human AFLD. Chronic ethanol consumption causes steatosis and inflammation in rodents or humans by disturbing several important hepatic transcriptional regulators, including AMP-activated kinase (AMPK), lipin 1, sterol regulatory element binding protein 1 (SREBP-1), PPARgamma co-activator 1alpha (PGC-1alpha), and nuclear transcription factor-kappaB (NF-kappaB). Remarkably, the effects of ethanol on these regulators are mediated in whole or in part by inhibition of a central signaling molecule, sirtuin 1 (SIRT1), which is a nicotinamide adenine dinucleotide (NAD(+), NADH)-dependent class III protein deacetylase. In recent years, SIRT1 has emerged as a pivotal molecule controlling the pathways of hepatic lipid metabolism, inflammatory responses and in the development of AFLD in rodents and in humans. Ethanol-mediated SIRT1 inhibition suppresses or stimulates the activities of above described transcriptional regulators and co-regulators, thereby deregulating diverse lipid metabolism and inflammatory response pathways including lipogenesis, fatty acid beta-oxidation, lipoprotein uptake and secretion and expression of pro-inflammatory cytokines in the liver. This review aims to highlight our current understanding of SIRT1 regulatory mechanisms and its response to ethanol-induced toxicity, thus, affirming significant role of SIRT1 signaling in the development of AFLD. PMID- 26005677 TI - Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction. AB - Excessive accumulation of triglycerides (TG) in liver, in the absence of significant alcohol consumption is nonalcoholic fatty liver disease (NAFLD). NAFLD is a significant risk factor for developing cirrhosis and an independent predictor of cardiovascular disease. High fructose corn syrup (HFCS)-containing beverages were associated with metabolic abnormalities, and contributed to the development of NAFLD in human trials. Ingested carbohydrates are a major stimulus for hepatic de novo lipogenesis (DNL) and are more likely to directly contribute to NAFLD than dietary fat. Substrates used for the synthesis of newly made fatty acids by DNL are primarily glucose, fructose, and amino acids. Epidemiological studies linked HFCS consumption to the severity of fibrosis in patients with NAFLD. New animal studies provided additional evidence on the role of carbohydrate-induced DNL and the gut microbiome in NAFLD. The excessive consumption of HFCS-55 increased endoplasmic reticulum stress, activated the stress-related kinase, caused mitochondrial dysfunction, and increased apoptotic activity in the liver. A link between dietary fructose intake, increased hepatic glucose transporter type-5 (Glut5) (fructose transporter) gene expression and hepatic lipid peroxidation, MyD88, TNF-alpha levels, gut-derived endotoxemia, toll-like receptor-4, and NAFLD was reported. The lipogenic and proinflammatory effects of fructose appear to be due to transient ATP depletion by its rapid phosphorylation within the cell and from its ability to raise intracellular and serum uric acid levels. However, large prospective studies that evaluated the relationship between fructose and NAFLD were not performed yet. PMID- 26005678 TI - The generation of carcinogenic etheno-DNA adducts in the liver of patients with nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), in particular its more aggressive form nonalcoholic steatohepatitis (NASH) is increasingly observed as a cause of end stage liver disease and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) are an important factor in the pathogenesis of HCC. ROS can react with polyunsaturated fatty acids derived from membrane phospholipids resulting in the production of reactive aldehydes as lipid oxidation (LPO) byproducts, such as 4-hydroxynonenal (4 HNE). 4 HNE can react with DNA to form mutagenic exocyclic etheno-DNA adducts. ROS is induced by inflammatory processes, but also by induction of cytochrome P450 2E1 (CYP2E1), as seen with chronic alcohol consumption. METHODS: Immunohistochemical detection of CYP2E1, 4 HNE and hepatic exocyclic etheno-DNA adducts was performed on liver sections from 39 patients with NFLD. Spearman rank correlation was calculated to examine possible correlations. RESULTS: Exocyclic etheno-DNA adducts were detected and correlated significantly with 4 HNE, but not with CYP2E1. CONCLUSIONS: This is the first description of highly carcinogenic exocyclic etheno-DNA adducts in NAFLD patients. We could show that exocyclic etheno-DNA adducts significantly correlated with lipid peroxidation product 4 HNE, but not with CYP2E1, implying that in NAFLD ROS generation with consecutive DNA damage is rather inflammation driven through various cytokines than by induction of CYP2E1. PMID- 26005680 TI - Where will the China's organ transplantation move towards? PMID- 26005679 TI - Inhibition of diethylnitrosamine-initiated alcohol-promoted hepatic inflammation and precancerous lesions by flavonoid luteolin is associated with increased sirtuin 1 activity in mice. AB - BACKGROUND: Chronic and excessive alcohol consumption is an established risk for hepatic inflammation and carcinogenesis. Luteolin is one of the most common flavonoids present in plants and has potential beneficial effects against cancer. In this study, we examined the effect and potential mechanisms of luteolin supplementation in a carcinogen initiated alcohol-promoted pre-neoplastic liver lesion mouse model. METHODS: C57BL/6 mice were injected with diethylnitrosamine (DEN) [i.p. 25 mg/kg of body weight (BW)] at 14 days of age. At 8 weeks of age mice were group pair-fed with Lieber-DeCarli liquid control diet or alcoholic diet [ethanol (EtOH) diet, 27% total energy from ethanol] and supplemented with a dose of 30 mg luteolin/kg BW per day for 21 days. RESULTS: DEN-injected mice fed EtOH diet displayed a significant induction of pre-neoplastic lesions, a marker associated with presence of steatosis and inflammation. Dietary luteolin significantly reduced the severity and incidence of hepatic inflammatory foci and steatosis in DEN-injected mice fed EtOH diet, as well the presence of preneoplastic lesions. There was no difference on hepatic protein levels of sirtuin 1 (SIRT1) among all groups; however, luteolin supplementation significantly reversed alcohol-reduced SIRT1 activity assessed by the ratio of acetylated and total forkhead box protein O1 (FoXO1) and SIRT1 target proliferator-activated receptor gamma, coactivator 1 alpha (PGC1alpha). CONCLUSIONS: Dietary intake of luteolin prevents alcohol promoted pre-neoplastic lesions, potentially mediated by SIRT1 signaling pathway. PMID- 26005681 TI - China on the brink: there is hope for the end of their use of executed prisoner organs. PMID- 26005682 TI - Reforms in organ donation in China: still to be executed? PMID- 26005683 TI - Organ procurement from executed prisoners in China. PMID- 26005684 TI - Implementation of China's new policies on organ procurement: an important but challenging step forward. PMID- 26005685 TI - A dream comes true and a new journey begins. PMID- 26005686 TI - MicroRNAs and Malaria - A Dynamic Interaction Still Incompletely Understood. AB - Malaria is a mosquito-borne infectious disease caused by parasitic protozoa of the genus Plasmodium. It remains a major problem affecting humans today, especially children. However, the pathogenesis of malaria, especially severe malaria, remains incompletely understood, hindering our ability to treat this disease. Of recent interest is the role that small, non-coding RNAs play in the progression, pathogenesis of, and resistance to, malaria. Independent studies have now revealed the presence of microRNA (miRNA) in the malaria parasite, vector, and host, though these studies are relatively few. Here, we review these studies, focusing on the roles specific miRNA have in the disease, and how they may be harnessed for therapeutic purposes. PMID- 26005687 TI - Comparison of Abnormal Cervical Cytology from HIV Positive Women, Female Sex Workers and General Population. AB - BACKGROUND: Sex workers and HIV seropositive women are at high risk of abnormal cervical cytology. The objective of this study was to compare the cervical cytology among three groups of women: active sex workers, HIV-infected women, and general population in Iran. METHODS: This was a cross-sectional study performed in Hazrat Zeinab, Lavan clinics and drop in center (DIC) in Shiraz, Iran. This study was performed from October 2009 to October 2011. A total of 266 patients were assigned into three groups: sex-workers (85), HIV positive patients (100), and general population (81). Pap smear was performed for all participants from the exocervix and endocervix, using a plastic Ayres's spatula and cytobrush. The samples were sent to a pathology center, using a liquid-based media. RESULTS: The risk of cervical infection in sex workers and HIV positive women was greater than the general population (OR=5.47, 95% confidence interval [CI]:2.24, 13.40), (OR=3.71, 95% CI:1.52, 9.09), respectively. The frequency of abnormal cervical cytology in the HIV positive and sex worker groups was higher than the general population (OR=6. 76, 95% CI:2.25, 20.32), (OR=3. 80, 95% CI:1.19, 12.07), respectively. Low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) were associated with CD4 cell count<200I106/L, P=0.021 and P<0.001, respectively. CONCLUSION: Vaginal infections were seen more often in the sex worker group, and abnormal cervical cytology was greater in the HIV positive group. PMID- 26005688 TI - The factors associated with disease mismanagement in young patients with type 1 diabetes: a qualitative study. AB - BACKGROUND: The objective of this qualitative study on young adults with type 1 diabetes was to determine the factors associated with mismanagement of diabetes. METHODS: In this qualitative study, a descriptive phenomenological and psychological method was followed. Purposeful sampling method was used in this study. 28 young adults aged 18-25 with type 1 diabetes (16 females, 12 males) with HbA1c levels >6.5% were interviewed in-depth. Each interview lasted 40-45 minutes. The recorded interviews were transcribed verbatim, examined line-by-line and coded using open coding techniques and managed by QSR NVivo 7. During the research period, Guba ve Lincolln criteria were used to ensure the accuracy and precision of the study findings. RESULTS: The study identified seven themes which affect the diabetes management of the patients. These themes were negative emotions about the disease, difficulties arising from living condition, difficulties arising from the treatment treatment process, lack of social support, not solution oriented coping methods, concerns about the future and issues of developing knowledge and attitude regarding diabetes management. CONCLUSION: There are multiple factors affecting the management of diabetes in young adults with type 1 diabetes. Diabetes has a biopsychosocial impact on young adults' lives, developing a negative attitude toward their future and that of their family. PMID- 26005689 TI - Effects of continuous care model based non-pharmacological intervention on sleep quality in patients with type 2 diabetes mellitus: a randomized controlled clinical trial. AB - BACKGROUND: Sleep is an important aspect of healthy lifestyle. One of the prevalent Diabetes mellitus-related non-vascular complications is sleep problems. The aim of this study was to investigate the effects of a non-pharmacological care plan designed based on the Continuous Care Model (CCM) on sleep quality in patients with type II diabetes with two month follow up. METHODS: This randomized controlled clinical trial was conducted from May to November 2012 among 68 the patients with type II DM referring to the Diabetes Clinic of Gonabad University of Medical Sciences. The study instrument consisted of a self-report demographic questionnaire and the Pittsburgh Sleep Quality Index. The gathered data were analyzed via SPSS (V. 20) using t-test and Chi-square statistics. RESULTS: After the intervention, the study groups did not differ significantly in terms of sleep quality (0.628). However, the study findings revealed that the interventional group's sleep quality improved significantly after the intervention (P<0.001). CONCLUSION: Non-pharmacologic intervention according to CCM improved the sleep quality in the experimental group. Sleep care is a matter of great importance in diabetes mellitus, which deserves particular attention. The present study adds to the growing literature of the use of non-pharmaceutics intervention to improve sleep disorders of diabetic patients. TRIAL REGISTRATION NUMBER: IRCT201202269140N1. PMID- 26005690 TI - Women Empowerment through Health Information Seeking: A Qualitative Study. AB - BACKGROUND: Today, women empowering is an important issue. Several methods have been introduced to empower women. Health information seeking is one of the most important activities in this regard. A wide range of capabilities have been reported as outcomes of health information seeking in several studies. As health information seeking is developed within personal-social interactions and also the health system context, it seems that the qualitative paradigm is appropriate to use in studies in this regard. This study aimed to explore how women's empowerment through health information seeking is done. METHODS: In this qualitative content analysis study, data collection was done with regard to inclusion criteria, through purposive sampling by semi-structured interviews with 17 women and using documentation and field notes until data saturation. Qualitative data analysis was done constantly and simultaneous with data collection. RESULTS: Four central themes were emerged to explain women's empowerment through health information seeking that included: a) Health concerns management with three subcategories of Better coping, Stress management, Control of situation, b) Collaborative care with two subcategories of Effective interaction with health professions and Participation in health decision making c) Individual development d) Self-protection with four sub- categories of Life style modification, Preventive behaviors promoting, Self-care promoting, and medication adherence. CONCLUSION: The results of this study indicate the importance of women empowerment through foraging their health information seeking rights and comprehensive health information management. PMID- 26005691 TI - Prevalence of Dyslexia among Male Students in Primary Schools and Its Relationship with Obesity and Being Overweight in Ahvaz, Iran. AB - BACKGROUND: The most important process in childhood and adolescence is learning. The purpose of this study was to determine the prevalence of dyslexia among primary male school students and the relationship between dyslexia, obesity and overweight. METHODS: This is a cross-sectional study conducted on 1000 male students (first to fifth grade) in primary schools (20 schools) by using the multi-stage random sampling (50 students were selected randomly from each school). Data collection instruments were a weighting scale, a meter for evaluation of obesity and overweight and a reading inventory test for dyslexia. The height and weight were measured based on body mass index (BMI). Data were analyzed using SPSS17 by chi2 test. RESULTS: 17 and 28 percent of the students were obese and overweight in the first to fifth grades, respectively. On average, the percentage of dyslexia among the unhealthy students was 21 per cent; this rate was 3.5 per cent among the healthy students. In addition, chi2 test showed that there was a significant difference between dyslexic and healthy students (P=0.001). CONCLUSION: The prevalence of dyslexia among students with overweight and obesity in comparison to healthy students is high; then close monitoring will ensure that these problems are minimized. PMID- 26005692 TI - Challenges of applying continuing education in tehran hospital practice as viewed by nurses. AB - BACKGROUND: Although many planners of professional continuing education programs believe that this type of education positively affects the nurses' performance, the results obtained by conducted research do not confirm such a perspective. In fact, inadequate application of these trainings in clinical practice is among the most challenging areas in nursing practices. Hence, this study was conducted to describe the challenges nurses encounter in order to apply what they have learned during continuing education programs in clinical settings of TUMS hospitals. METHODS: This cross-sectional study was conducted on 400 medical-surgical nurses who worked in the hospitals of Tehran University of Medical sciences. For sampling, after listing all the general hospitals, their wards were selected in proportion to hospital. Nurses filled out a questionnaire about factors affecting the application of continuing education. The questionnaire contained 43 items and the dimensions were supportive-organizational, individual, professional, and educational program design factors. The analysis was carried out using parametric and non-parametric method using SPSS 16 package. RESULTS: The results showed while 48.5% and 53.8% of nurses mentioned organizational and professional factors, respectively as the most inhibiting factors; only 2.25% of the nurses believed that organizational factors are facilitating. CONCLUSION: The results obtained in this study are important regarding the fact that organizational and professional factors have a key role in applying or lack of application of learned materials. Thus, hospital authorities as well as nursing managers can provide the necessary condition in application of continuing education through promotion of facilitating factors and eliminating the hindering ones. PMID- 26005693 TI - The Effect of a Multi-Strategy Program on Developing Social Behaviors Based on Pender's Health Promotion Model to Prevent Loneliness of Old Women Referred to Gonabad Urban Health Centers. AB - BACKGROUND: Loneliness is one of the most significant problems during aging. This research has been done to determine the effect of a multi-strategy program based on Pender's Health Promotion model to prevent loneliness of elderly women by improving social relationships. METHODS: In this quasi-experimental study done in 2013 from January to November, 150 old women suffering medium loneliness referred to Gonabad urban Health Centers were enrolled. Data were gathered using Russell's UCLA loneliness questionnaire and the questionnaires based on Pender's Health Promotion Model about loneliness. The results were analyzed by descriptive statistics and Chi-square, T-pair, and independent-T tests through SPSS, version 20. RESULTS: Loneliness decreased significantly in the interventional group compared to the control group (P<0.00). In addition, mean scores related to variables of Health Promotion Model (received benefits and barriers, self efficacy, interpersonal effectives of loneliness) in both groups were significantly different before and after the study (P<0.05). CONCLUSION: Constructs of Pender's Health Promotion Model can be used as a framework for planning interventions in order to anticipate, improve and modify related behaviors related to loneliness in old women. PMID- 26005694 TI - Self-efficacy in foot-care and effect of training: a single-blinded randomized controlled clinical trial. AB - BACKGROUND: Diabetes mellitus (DM) is one of the most common metabolic and non communicable disorders worldwide and the mortality rates caused by the complications associated with the disease, such as diabetic foot ulcer, is increasing dramatically. Patient education is considered as an essential part of controlling DM. Therefore, we aimed to compare the effects of individual and group training methods on self-efficacy in foot care among the patients with DM. METHODS: In this single-blinded, randomized controlled clinical trial, we enrolled 150 patients with type 1 and 2 DM. The final participants were randomly assigned into two intervention groups (collective and individual training group) and a control group. Data were collected using foot-care self-efficacy questionnaire (Corrbet, 2003). A research assistant collected the data by interviewing the participants using the questionnaire once before and once one month after the intervention. The participants of the intervention groups attended a training program consisting of three sessions per week for one week. Statistical descriptive tests such as mean and standard deviation (SD) percentage were used to describe the features of the data inferential statistics test such as Chi-square, independent t-test and repeated measures analysis of variance and analysis co-variance (ANOVA, ANCOVA) tests were also used as appropriate. The significance level was set at <0.05. RESULTS: The results indicated that there was no significant difference between the three groups regarding the mean of self efficacy scores before foot-care training intervention (P=0.39). But, comparison of the scores before and after the intervention showed that both group and individual training interventions increased the patients' self-efficacy (P<=0/05). CONCLUSION: It can be concluded that both group and individual training approaches could increase foot care self-efficacy in the patients with DM. TRIAL REGISTRATION NUMBER: IRCT201203086918N6. PMID- 26005695 TI - The effect of yoga on the quality of life in the children and adolescents with haemophilia. AB - The problems caused by haemophilia lead to impairments of the quality of life in patients with haemophilia. This study aimed to investigate the effects of yoga on quality of life in the children and adolescents with haemophilia in Shiraz, Iran. This semi-experimental study with pre- and post-test design was performed on 27 boys between 8 and 16 years old who suffered from haemophilia. The patients were divided into two groups. The number of bleedings, absences from school, and referrals to the clinic was evaluated. The demographic data were collected through interviews and using the patients' records in the haemophilia center. Besides, the quality of life was assessed through the Haemo-QoL questionnaire. Then, the yoga intervention was performed for 14 weeks and the data were collected in three stages. The collected data were entered into the SPSS statistical software, version 18 and were analyzed using non-parametric Friedman test. After the intervention, significant differences were observed in the mean scores of quality of life dimensions and the number of bleedings, school absences, and referrals to the haemophilia clinic (P<0.001). Thus, yoga may improve the haemophilia children's and adolescents' perception of quality of life without the risk of injury. This intervention also seemed to be effective in reducing the number of bleedings, referrals to the haemophilia clinic, and absences from school. PMID- 26005696 TI - Factors Linked to Substance Use Disorder Counselors' (Non)Implementation Likelihood of Tobacco Cessation 5 A's, Counseling, and Pharmacotherapy. AB - STUDY BACKGROUND: Despite efforts to promote the use of tobacco cessation services (TCS), implementation extensiveness remains limited. This study investigated three factors (cognitive, behavioral, environmental) identified by social cognitive theory as predictors of substance use disorder counselors' likelihood of use versus non-use of tobacco cessation (TC) 5 A's (ask patients about tobacco use, advise to quit, assess willingness to quit, assist in quitting, arrange for follow-up contact), counseling, and pharmacotherapy with their patients who smoke cigarettes. METHODS: Data were collected in 2010 from 942 counselors working in 257 treatment programs that offered TCS. Cognitive factors included perceived job competence and TC attitudes. Behavioral factors encompassed TC-related skills and general training. External factors consisted of TC financial resource availability and coworker TC attitudes. Data were analyzed using logistic regression models with nested data. RESULTS: Approximately 86% of counselors used the 5 A's, 76% used counseling, and 53% used pharmacotherapy. When counselors had greater TC-related skills and greater general training they were more likely to implement the 5 A's. Implementation of counseling was more likely when counselors had more positive attitudes toward TC treatment, greater general training, greater financial resource availability, and when coworkers had more positive attitudes toward TC treatment. Implementation of pharmacotherapy was more likely when counselors had more positive attitudes toward TC treatment, greater general training, and greater financial resource availability. CONCLUSION: Findings indicate that interventions to promote TCS implementation should consider all three factors simultaneously as suggested by social cognitive theory. PMID- 26005697 TI - Does Your Result Checker Really Check? AB - A result checker is a program that checks the output of the computation of the observed program for correctness. Introduced originally by Blum, the result checking paradigm has provided a powerful platform assuring the reliability of software. However, constructing result checkers for most problems requires not only significant domain knowledge but also ingenuity and can be error prone. In this paper we present our experience in validating result checkers using formal methods. We have conducted several case studies in validating result checkers from the commercial LEDA system for combinatorial and geometric computing. In one of our case studies, we detected a logical error in a result checker for a program computing max flow of a graph. PMID- 26005698 TI - The pERK of being a target: Kinase regulation of the orphan nuclear receptor ERRgamma. AB - Estrogen-related receptors (ERRs) are orphan members of the nuclear receptor superfamily that are important regulators of mitochondrial metabolism with emerging roles in cancer. In the absence of an endogenous ligand, ERRs are reliant upon other regulatory mechanisms that include protein/protein interactions and post-translational modification, though the cellular and clinical significance of this latter mechanism is unclear. We recently published a study in which we establish estrogen-related receptor gamma (ERRgamma) as a target for extracellular signal-regulated kinase (ERK), and show that regulation of ERRgamma by ERK has important consequences for the function of this receptor in cellular models of estrogen receptor-positive (ER+) breast cancer. In this Research Highlight, we discuss the implications of these findings from a molecular and clinical perspective. PMID- 26005699 TI - Estrogen receptor-alpha signaling and localization regulates autophagy and unfolded protein response activation in ER+ breast cancer. AB - Antiestrogen therapy is commonly used to treat estrogen receptor (ER)+ breast cancers but acquired and de novo resistance limits their overall curative potential. An endoplasmic reticulum stress pathway, the unfolded protein response, and autophagy are both implicated in the development of antiestrogen therapy resistance in estrogen receptor-alpha (ER) positive breast cancer. Thus, we recently investigated how ERalpha can regulate autophagy and the unfolded protein response (Cook et al., FASEBJ, 2014). We showed that inhibiting ERalpha signaling stimulates autophagosome formation and flux. Moreover, we showed that ERalpha knockdown inhibited the unfolded protein response (UPR) signaling components. Here we support and extend this recent report showing additional data on ERalpha localization and provide a schematic of the overall signaling implicated by our results. Differential activation of UPR and autophagy highlight the pivotal role of ERalpha in regulating pro-survival signaling in breast cancer through UPR and autophagy. Furthermore, these data suggest new approaches to successful targeting ERalpha and preventing the regulation of key pro-survival signaling that confers resistance to endocrine therapies. PMID- 26005700 TI - Uncovering unique roles of LPA receptors in the tumor microenvironment. AB - The role of the lysophospholipase D autotaxin (ATX) and lysophosphatidic acid (LPA) in cancer is emerging and represents two key players in regulating cancer progression. In this brief review, we will discuss some of our recent findings, which highlight a central role that LPA and its receptor plays in orchestrating melanoma-stroma interactions in the establishment of lung metastases. In particular, we evaluated not only the function of LPA receptors on tumor cells but also their role on host tissues and how they can influence melanoma growth and metastasis. Using the syngeneic B16F10 murine melanoma model, we made three key observations. First, our in vitro findings demonstrate that LPA receptors, specifically LPA2 and LPA5 expressed in B16F10 cells appear to have opposing roles in cell invasion; the former seems to be responsible for the high basal invasion rate of B16F10 cells while the latter is anti-invasive upon exogenous LPA stimulation. Second, we observed a profound reduction in the incidence of pulmonary melanoma metastasis in LPA1- and LPA5-knockout (KO) mice, respectively, when compared to wild-type (WT) mice. Third, no differences in terms of subcutaneous tumor growth between LPA1KO, LPA5KO and WT mice were observed. These findings suggest that LPA receptors exert different functions in melanoma cells versus host tissues in terms of invasion and metastasis. PMID- 26005701 TI - Enhancement of osteoblastogenesis and suppression of osteoclastogenesis by inhibition of de-phosphorylation of eukaryotic translation initiation factor 2 alpha. AB - The phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) is activated in response to various stresses such as viral infection, nutrient deprivation, and stress to the endoplasmic reticulum. Severe stress to the endoplasmic reticulum, for instance, induces an apoptotic pathway, while mild stress, on the contrary, leads to a pro-survival pathway. Little has been known about the elaborate role of eIF2alpha phosphorylation in the development of bone forming osteoblasts and bone-resorbing osteoclasts. Using salubrinal and guanabenz as inhibitors of the de-phosphorylation of eIF2alpha, we have recently reported that the phosphorylation of eIF2alpha significantly alters fates of both osteoblasts and osteoclasts. Based on our recent findings, we review in this research highlight the potential mechanisms of the enhancement of osteoblastogenesis and the suppression of osteoclastogenesis through the elevated level of phosphorylated eIF2alpha. PMID- 26005702 TI - Implications of scavenger receptors in the safe development of nanotherapeutics. AB - Nanomaterials (NMs) are being utilized in a variety of biomedical applications including drug delivery, diagnostics, and therapeutic targeting. These applications are made possible due to the unique physicochemical properties that are exhibited at the nanoscale. To ensure safe development of NMs for clinical use, it is necessary to understand their interactions with cells and specifically cell surface receptors, which will facilitate either their toxicity and/or clinical function. Recently our research and others have investigated the role of scavenger receptors in mediating NM-cell interactions and responses. Scavenger receptors are expressed by a variety of cell types that are first to encounter NMs during clinical use such as macrophages and endothelial cells. Scavenger receptors are recognized to facilitate uptake of a wide variety of ligands ranging from foreign substances to endogenous lipids/proteins. While interaction of NMs with scavenger receptors may allow therapeutic targeting in some instances, it also presents a challenge for the stealth delivery of NMs and avoidance of the scavenging capability of this class of receptors. Due to their role in facilitating immune responses, scavenger receptor-mediated inflammation is also of concern following NM delivery. The research highlighted in this brief review intends to summarize our current understanding regarding the consequences of NM-scavenger receptor interactions. PMID- 26005703 TI - "Everybody Gotta Have a Dream": Rap-centered Aspirations among Young Black Males Involved in Rap Music Production - A Qualitative Study. AB - Youth express diverse desires for their educational and occupational futures. Sometimes these aspirations are directed towards somewhat unconventional careers such as rapping and other types of involvement in rap music production. Although many studies have examined traditional educational and occupational aspirations, less is known about the factors that give rise to rap-centered aspirations and how individuals pursue them, particularly as they transition to early adulthood. Drawing on 54 semi- and unstructured interviews with 29 black young men involved in rap music production, I find that rap-centered aspirations are shaped by a range of factors, most notably feedback regarding one's rap skills, access to recording and production equipment, and the financial means to maintain involvement in rap music production while also ensuring personal and family economic stability. The young men in the study attached different meanings to their aspirations and sometimes recast their motivations for participating in rap music production in response to various social and economic factors. PMID- 26005704 TI - Distinct phases of human prostate cancer initiation and progression can be driven by different cell-types. AB - The cells that initiate and propagate cancer are important therapeutic targets. However, the progression from cells of origin to tumor-propagating cells is poorly defined for most human cancers. Mouse models indicate that both basal and luminal cells can initiate prostate cancer, while studies with human prostate tissue have demonstrated a role for basal cells in transformation. Our recent study provides evidence that a common cell of origin can produce alternative variants of human epithelial cancer. Our findings also reveal that the cell of origin that initiates cancer is not continuously required to maintain and propagate the disease. Importantly, the cells responsible for initiating human prostate cancer can have a distinct cellular phenotype from the cells needed to maintain it. PMID- 26005705 TI - New insights into 4E-BP1-regulated translation in cancer progression and metastasis. AB - Remarkable progress has been made highlighting the importance of cap-dependent mRNA translation in cancer progression. 4E-BP1 is a translation initiation repressor by sequestering the mRNA cap-binding protein eIF4E and consequently inhibiting the translation of certain key oncogenic mRNAs encoding proteins for cell proliferation, survival, angiogenesis and malignancy. In most tumors, however, the repressive function of 4E-BP1 is compromised by reduction of its expression or phosphorylation mediated by oncogenic signaling pathways. We recently unveiled that 4E-BP1-regulated cap-dependent translation integrates oncogenic effects of the AKT and ERK signaling pathways on tumor growth and metastatic progression. Mechanistically, we demonstrate that AKT and ERK pathways selectively upregulate survivin expression at the level of translation by convergent activation of the mTORC1/4E-BP1/eIF4E signaling axis. In addition, loss of 4E-BP1 function induces epithelial-mesenchymal transition and increases metastatic capability of cancer cells by translational activation of Snail. Continuous translation of survivin and Snail is important for colorectal cancer progression to metastasis. Herein we discuss our findings concerning deregulation of translation in cancer progression and metastasis and highlight 4E-BP1 as a potential biomarker and therapeutic target. PMID- 26005706 TI - Role of caveolin-2 in subcutaneous tumor growth and angiogenesis associated with syngeneic mouse Lewis lung carcinoma and B16 melanoma models. AB - In addition to cancer cells, primary tumors are composed of a multitude of stromal cell types. Among others, the stromal cell types involved in tumor growth and progression include endothelial cells, fibroblasts, pericytes, stem cells and various cell types of immune origin. While the role of oncogenes or tumor suppressor proteins expressed in cancer cells has been extensively studied, far less is known about potential involvement of proteins expressed in stromal cell types present within the tumor microenvironment. Recent experimental evidence from our laboratory suggests that caveolin-2 (Cav-2) protein expressed in stromal cell types of the tumor microenvironment promotes subcutaneous tumor growth in two independent syngeneic mouse models, i.e., Lewis lung carcinoma (LLC) and B16 F10 melanoma. Mechanistically, the tumor growth promoting role of Cav-2 is associated with enhanced tumor induced neovascularization. At the molecular level, host-expressed Cav-2 appears to prevent excessive expression of anti angiogenic thrombospondin-1 (TSP-1) and promote phosphorylation of pro-angiogenic endothelial nitric oxide synthase (eNOS) at serine 1177. Taken together, our recent findings suggest that Cav-2 expressed within the tumor microenvironment could be a potential target for anti-cancer therapy. PMID- 26005707 TI - Regulating Tumor Myeloid-Derived Suppressor Cells by MicroRNAs. AB - Myeloid-derived suppressor cells (MDSCs) are one of the major cell components responsible for cancer immune evasion. Studying mechanisms associated with the regulation of MDSCs is becoming appreciated as another way to manipulate immune responses. MicroRNAs (miRNAs) have been recognized as substances which may interact with MDSCs, and eight miRNAs including miR-17-5p, miR-20a, miR-223, miR 21, miR-155, miR-494, miR-690 and miR-101 are of particular interest regarding MDSC accumulation and function. We have reviewed the data supporting this activity of these entities. PMID- 26005708 TI - Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy. AB - Combination therapy for the treatment of cancer is becoming increasingly essential as we gain improved understanding of the complexity of cancer progression and the mechanisms by which cancer cells become resistant to single agent therapy. Recent studies, both clinical and preclinical, have suggested that immunotherapy is a promising approach to the treatment of cancer; however, strategies to improve its clinical efficacy are still needed. A number of recent studies have indicated that antiangiogenic tyrosine kinase inhibitors (TKIs) target multiple components of the tumor microenvironment and are an ideal class of agents for synergizing with cancer immunotherapy. TKIs are well known to modulate tumor endothelial cells, leading to vascular normalization; however, these agents have also been recently shown to decrease tumor compactness and tight junctions, thereby reducing solid tumor pressure and allowing for improved perfusion of collapsed vessels and increased tumor oxygenation. In addition, some TKIs are capable of inducing immunogenic modulation, whereby tumor cells are sensitized to killing by T lymphocytes. Moreover, a number of TKIs have been shown to be involved in immune subset conditioning, increasing the frequency and function of effector immune elements, while decreasing the number and function of immune suppressor cells. The alteration of the immune landscape, direct modification of tumor cells, and improved vascular perfusion leads to improved antitumor efficacy when antiangiogenic TKIs are combined with immunotherapy. Collectively, the data presented in this review support the clinical combination of multi-targeted antiangiogenic TKIs, including but not limited to cabozantinib, sunitinib, and sorafenib, as well as to other antiangiogenic therapies, such as the anti-VEGF antibody bevacizumab, with cancer vaccines for improved treatment of solid tumors. PMID- 26005709 TI - Functional and speech outcomes of superiorly based flap pharyngoplasty combined with radical intravelar veloplasty. AB - OBJECTIVE: The aim of this study was to evaluate functional and speech outcomes of superiorly based pharyngeal flap (SBF) pharyngoplasty combined with radical intravelar veloplasty (RIVVP) for the management of velopharyngeal insufficiency (VPI) following surgically repaired cleft palate. DESIGN: A case series with chart review. The study was conducted in academic tertiary care medical centre. PATIENTS AND METHODS: Fifteen patients with VPIs following surgically repaired cleft palate were managed between May 2011 and August 2014, with SBF pharyngoplasty combined with RIVVP. RESULTS: We found that the speech defects improved by a success rate of 93.4%; the VP function became normal (circular pattern of closure) in 80% of patients and the postoperative overall success rate of VP competence grades was 93.4%. Moreover, we found that the overall incidence of complications were 33.3%. CONCLUSION: By doing SBF pharyngoplasty combined with RIVVP the surgical procedure was satisfactory in both functional and speech outcomes. PMID- 26005710 TI - Low eGFR is associated with dysexecutive and amnestic mild cognitive impairment. AB - BACKGROUND: Few studies have explored the association between renal function and major subtypes of mild cognitive impairment (MCI). METHODS: The sample was from the Einstein Aging Study. The estimated glomerular filtration rate (eGFR, calculated in mL/min/1.73m2 units) was classified into low (<45), moderate (45 59) and high (>=60). Separate binary logistic regression models were run to determine if eGFR is associated withamnestic MCI (aMCI) and dysexecutive MCI (dMCI). RESULTS: Out of 622 eligible participants 65 (10.5%) had low eGFR, 43 (7.1%) had aMCI, and 46 (7.6) had dMCI. Low eGFR was independently associated with dMCI and aMCI in fully adjusted models. CONCLUSION: At cross-section low eGFR is associated with a higher risk of both dMCI and aMCI. eGFR may contribute to the development of these cognitive states directly. Alternatively, low eGFR may be a marker for risk factors that influence both the kidney and the brain, such as coronary microvascular disease. PMID- 26005711 TI - Metabolic Signatures of Human Breast Cancer. AB - Metabolomics has emerged as a new discovery tool with the promise of identifying therapeutic targets in cancer. Recent discoveries described essential metabolomic pathways in breast cancer and characterized oncometabolites that drive tumor growth and progression. Oncogenes like MYC and tumor suppressor genes like TP53 prominently affect breast cancer biology through regulation of cell metabolism and mitochondrial biogenesis. These findings indicate that tumors with dominant mutations could be susceptible to inhibitors of disease metabolism. Moreover, various pre-clinical and clinical studies have linked tumor metabolism to therapeutic response and patient survival. Thus, recent advances suggest that metabolic profiling provides new opportunities to improve outcomes in breast cancer. In this review, we have summarized some of the identified roles of oncometabolites in breast cancer biology and highlight their clinical utility. PMID- 26005712 TI - MicroRNA-133alpha regulates neurotensin-associated colonic inflammation in colonic epithelial cells and experimental colitis. AB - Ulcerative colitis (UC) and Crohn's Disease (CD) are the two most common forms of Inflammatory Bowel Diseases (IBD) marked by chronic and persistent inflammation. Neurotensin (NT), together with its receptor, NT receptor 1 (NTR1), are important mediators in intestinal inflammation and their expression is upregulated in the intestine of experimental colitis models and UC colonic biopsies. MicroRNAs (miRNAs) are short, non-coding RNA molecules which act as transcription repressors. We have previously shown that NT exposure upregulates miR-133alpha expression in human colonocytes NCM460 cells overexpressing NTR1 (NCM460-NTR1). Recently, miR-133alpha was further examined forits role in NT-associated proinflammatory signaling cascades and acute colitis in vivo. Our study shows that NT-induced miR-133alpha upregulation modulates NF-kappaB phosphorylation and promotes proinflammatory cytokine production. In addition, intracolonicinjection of antisense-miR-133alpha before colitis induction improves histological scores and proinflammatory cytokine transcription. More importantly, dysregulation of miR-133alpha levels and aftiphilin (AFTPH), a newly-identified miR-133alpha downstream target, is found only in UC patients, but not in patients with CD. Taken together, we identified NTR1/miR-133alpha/aftiphilin as a novel regulatory axis involved in NT-associated colonic inflammation in human colonocytes, acute colitis mouse model and in colonic biopsies from UC patients. Our results also provide evidence that colonic levels of NTR1, miR-133alpha and aftiphilin may also serve as potential biomarkers in UC. PMID- 26005713 TI - Long-Term Function, Pain and Medication Use Outcomes of Radiofrequency Ablation for Lumbar Facet Syndrome. AB - OBJECTIVE: Radiofrequency ablation (RFA) of the medial branch nerves for facet mediated low back pain demonstrates clinical benefit for 6-12 months and possibly up to 2 years. This study investigated function, pain, and medication use outcomes of RFA for lumbar facet syndrome in a cohort with long-term follow-up. METHODS: Individuals evaluated in a tertiary academic pain practice between January, 2007-December, 2013, 18-60 years of age, with a clinical and radiologic diagnosis of lumbar facet syndrome, who underwent >=1set of diagnostic medial branch blocks with resultant >75% pain relief and subsequent RFA were included. Outcomes measured were the proportion of individuals who reported >=50% improvement in function, >=50% improvement in pain; change in median NRS pain score, daily morphine equivalent consumption (DME), Medication Quantification Scale III (MSQ III) score and procedure complications. RESULTS: Sixty-two consecutive individuals with a median age and 25%-75% interquartile range (IQR) of 34 years (35, 52) met inclusion criteria. Seven individuals were lost to follow-up. Duration of pain was <2 years in 42%, 2-5 years in 40%, >5 years in 18% of individuals. Median duration of follow-up was 39 months (16, 60). Function and pain improved by >=50% in 58% (CI 45%, 71%) and 53% (CI 40%, 66%) of individuals, respectively. The median reduction in MQS III score was 3.4 points (0, 8.8). No complications occurred in this cohort. CONCLUSIONS: This study demonstrates a durable treatment effect of RFA for lumbar facet syndrome at long term follow-up, as measured by improvement in function, pain, and analgesic use. PMID- 26005714 TI - Validation of 3D EM Reconstructions: The Phantom in the Noise. AB - Validation is a necessity to trust the structures solved by electron microscopy by single particle techniques. The impressive achievements in single particle reconstruction fuel its expansion beyond a small community of image processing experts. This poses the risk of inappropriate data processing with dubious results. Nowhere is it more clearly illustrated than in the recovery of a reference density map from pure noise aligned to that map-a phantom in the noise. Appropriate use of existing validating methods such as resolution-limited alignment and the processing of independent data sets ("gold standard") avoid this pitfall. However, these methods can be undermined by biases introduced in various subtle ways. How can we test that a map is a coherent structure present in the images selected from the micrographs? In stead of viewing the phantom emerging from noise as a cautionary tale, it should be used as a defining baseline. Any map is always recoverable from noise images, provided a sufficient number of images are aligned and used in reconstruction. However, with smaller numbers of images, the expected coherence in the real particle images should yield better reconstructions than equivalent numbers of noise or background images, even without masking or imposing resolution limits as potential biases. The validation test proposed is therefore a simple alignment of a limited number of micrograph and noise images against the final reconstruction as reference, demonstrating that the micrograph images yield a better reconstruction. I examine synthetic cases to relate the resolution of a reconstruction to the alignment error as a function of the signal-to-noise ratio. I also administered the test to real cases of publicly available data. Adopting such a test can aid the microscopist in assessing the usefulness of the micrographs taken before committing to lengthy processing with questionable outcomes. PMID- 26005716 TI - Cervical cytological abnormalities and HPV infection in perinatally HIV-infected adolescents. AB - BACKGROUND: Behaviourally HIV-infected adolescent females are at higher risk for abnormal cervical cytology and HPV infection compared to those who are uninfected, but data on perinatally HIV-infected adolescent females are lacking. METHODS: Cervical cytology, HPV infection and E6/E7 mRNA were assessed in sexually active 12-24-year-old adolescent females: perinatally HIV-infected (group 1, n = 40), behaviourally HIV-infected (group 2, n = 10), and HIV uninfected (group 3, n = 10). RESULTS: Median age was lower in group 1 (18 years) than in groups 2 (24 years) and 3 (20.5 years) (P < 0.001), and median time since sexual debut was shorter: 2 vs 5 vs 4 years (P < 0.001). More trial participants in group 1 than group 2 were on antiretrovirals (90% vs 70%; P <0.001). Abnormal cervical cytology (atypical squamous cells of undetermined significance and higher) was observed in 30% (group 1), 40% (group 2) and 30% (group 3) (P = 0.92), whereas high-risk HPV infection was observed in 45%, 45% and 40%, respectively (P = 1.00). Positive E6/E7 mRNA was found in 28% of group 1, but not in other groups. High-risk HPV infection predicted abnormal cytology in all groups [OR 6.77, 95% confidence interval (CI) 1.99-23.0; P = 0.001). Additionally, plasma HIV RNA >=50 copies/mL (OR 13.3, 95% CI 1.16-153.06; P = 0.04) predicted abnormal cytology in HIV-infected adolescent females. CONCLUSIONS: Despite the younger age and shorter time since sexual debut, cervical cytological abnormalities and HPV infection were as common in perinatally HIV-infected as in behaviourally infected and uninfected adolescents. HPV vaccination, pre-cancer screening and antiretroviral treatment in HIV infected female adolescents should be implemented to minimise the risk of cervical cancer. PMID- 26005717 TI - HIV self-testing among key populations: an implementation science approach to evaluating self-testing. AB - OBJECTIVES: To review methods for measuring HIV self-testing (HIVST) among key populations, including both conventional approaches and implementation science approaches. METHODS: We reviewed the literature on evaluating HIVST among key populations. RESULTS: Simple HIV self-tests have already entered markets in several regions, but metrics required to demonstrate the benefits and costs of HIVST remain simplistic. Conventional measurements of sensitivity, specificity, acceptability, and behavioural preferences must be supplemented with richer implementation science measurement tools and innovative research designs in order to capture data on the following components: how self-testing affects subsequent linkage to confirmatory testing, preventive services and onward steps in the HIV continuum of care; how self-testing can be marketed to reach untested subpopulations; and how self-testing can be sustained based on overarching organisational and financial models. We outline an implementation science research agenda that incorporates these components, drawing from evaluation study designs focused on HIVST and testing in general. CONCLUSION: HIVST holds great promise for key populations, but must be guided by implementation research to inform programmes and scale up. PMID- 26005715 TI - Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity. AB - INTRODUCTION: Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant. METHODS: We used case case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation. RESULTS: BMI 25-29.9kg/m2, and perhaps BMI>=30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI>=30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84). DISCUSSION: While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes. PMID- 26005718 TI - A Novel Network Model for Molecular Prognosis. AB - Network-based genome-wide association studies (NWAS) utilize the molecular interactions between genes and functional pathways in biomarker identification. This study presents a novel network-based methodology for identifying prognostic gene signatures to predict cancer recurrence. The methodology contains the following steps: 1) Constructing genome-wide coexpression networks for different disease states (metastatic vs. non-metastatic). Prediction logic is used to induct valid implication relations between each pair of gene expression profiles in terms of formal logic rules. 2) Identifying differential components associated with specific disease states from the genome-wide coexpression networks. 3) Dissecting network modules that are tightly connected with major disease signal hallmarks from the disease specific differential components. 4) Identifying most significant genes/probes associated with clinical outcome from the pathway connected network modules. Using this methodology, a 14-gene prognostic signature was identified for accurate patient stratification in early stage lung cancer. PMID- 26005720 TI - Spatial Confidence Regions for Quantifying and Visualizing Registration Uncertainty. AB - For image registration to be applicable in a clinical setting, it is important to know the degree of uncertainty in the returned point-correspondences. In this paper, we propose a data-driven method that allows one to visualize and quantify the registration uncertainty through spatially adaptive confidence regions. The method applies to various parametric deformation models and to any choice of the similarity criterion. We adopt the B-spline model and the negative sum of squared differences for concreteness. At the heart of the proposed method is a novel shrinkage-based estimate of the distribution on deformation parameters. We present some empirical evaluations of the method in 2-D using images of the lung and liver, and the method generalizes to 3-D. PMID- 26005721 TI - An Inter-Projection Interpolation (IPI) Approach with Geometric Model Restriction to Reduce Image Dose in Cone Beam CT (CBCT). AB - Cone beam computed tomography (CBCT) imaging is a key step in image guided radiation therapy (IGRT) to improve tumor targeting. The quality and imaging dose of CBCT are two important factors. However, X-ray scatter in the large cone beam field usually induces image artifacts and degrades the image quality for CBCT. A synchronized moving grid (SMOG) approach has recently been proposed to resolve this issue and shows great promise. However, the SMOG technique requires two projections in the same gantry angle to obtain full information due to signal blockage by the grid. This study aims to develop an inter-projection interpolation (IPI) method to estimate the blocked image information. This approach will require only one projection in each gantry angle, thus reducing the scan time and patient dose. IPI is also potentially suitable for sparse-view CBCT reconstruction to reduce the imaging dose. To be compared with other state-of-the art spatial interpolation (called inpainting) methods in terms of signal-to-noise ratio (SNR) on a Catphan and head phantoms, IPI increases SNR from 15.3dB and 12.7dB to 29.0dB and 28.1dB, respectively. The SNR of IPI on sparse-view CBCT reconstruction can achieve from 28dB to 17dB for undersample projection sets with gantry angle interval varying from 1 to 3 degrees for both phantoms. PMID- 26005724 TI - The difficulty of a fair comparison. PMID- 26005722 TI - Mutations in the opioid growth factor receptor in human cancers alter receptor function. AB - The opioid growth factor (OGF)-OGF receptor (OGFr) axis is present and tonically active in animal and human cancer cell lines and tumors. The OGF-OGFr pathway tonically mediates cell replication in cancer, with OGF serving as an autocrine produced inhibitory pentapeptide. The inhibitory effect of OGF on cancer cell replication requires the binding of OGF to OGFr and its trafficking into the nucleus, where it upregulates inhibitory kinase expression, thus suppressing the cell cycle. OGF has been reported to markedly inhibit the growth of human cancer cells transplanted into nude mice, and to enhance the therapeutic effects of agents, such as paclitaxel and gemcitabine. At the time that this study commenced, there were 13 missense mutations identified in OGFr that had been curated in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Little is known about any mutations identified in OGFr or how mutated OGFr may alter the inhibitory activity of OGF. In this study, two mutations identified in cancer samples, S378I and R444H, were characterized with respect to how they modified OGFr trafficking into the nucleus and changed the functional attributes of DNA synthesis. R444H demonstrated a significant decrease in the nuclear/cytoplasmic ratio, while S378I showed no change. Both mutations demonstrated a loss of response to OGF and the long-acting opioid antagonist, naltrexone (NTX), while only R444H showed a loss of inhibition in the 5-bromo-2'-deoxyuridine (BrdU) assay. These data demonstrate that an intact OGFr is required for a full response to biotherapy with OGF, and that it is important to characterize potential mutations in neoplasia which could affect therapeutic responsiveness. PMID- 26005725 TI - The author file: Richard Caprioli. PMID- 26005723 TI - Transforming growth factor-beta1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells. AB - Epithelial-mesenchymal transition (EMT), a process closely related to tumor development, is regulated by a variety of signaling pathways and growth factors, such as transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF). Hyaluronan (HA) has been shown to induce EMT through either TGF-beta1 or EGF signaling and to be a regulator of the crosstalk between these two pathways in fibroblasts. In this study, in order to clarify whether HA has the same effect in tumor cells, we utilized the lung cancer cell line, A549, and the breast cancer cell line, MCF-7, and found that the effects of stimulation with TGF-beta1 were more potent than those of EGF in regulating the expression of EMT-associated proteins and in enhancing cell migration and invasion. In addition, we observed that TGF-beta1 activated EGF receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we found that TGF-beta1 upregulated the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and promoted the expression of CD44, a cell surface receptor for HA, which interacts with EGFR, resulting in the activation of the downstream AKT and ERK pathways. Conversely, treatment with 4-methylumbelliferone (4-MU; an inhibitor of HAS) prior to stimulation with TGF-beta1, inhibited the expression of CD44 and EGFR, abolished the interaction between CD44 and EGFR. Furthermore, the use of shRNA targeting CD44 impaired the expression of EGFR, deactivated the AKT and ERK pathways, reversed EMT and decreased the migration and invasion ability of cells. In conclusion, our data demonstrate that TGF-beta1 induces EMT by the transactivation of EGF signaling through HA/CD44 in lung and breast cancer cells. PMID- 26005726 TI - Points of significance: Bayes' theorem. PMID- 26005727 TI - Sensors and probes: A snapshot of active neurons. PMID- 26005728 TI - Structural biology: Peering inside protein complexes with AFM. PMID- 26005729 TI - Sensors and probes: Site-specific RNA labeling in mammalian cells. PMID- 26005730 TI - Gene expression: Cellular diversity in a snapshot. PMID- 26005731 TI - Model organisms: Short-lived excitement. PMID- 26005733 TI - Abstract Book, 2014. PMID- 26005732 TI - Synthetic biology: RNA that activates transcription. PMID- 26005734 TI - Abstracts From the 6th Excellence in Pediatrics Annual Conference, December 4-6, 2014, Dubai, United Arab Emirates. PMID- 26005736 TI - Abstracts of the 104th USCAP (United States and Canadian Academy of Pathology) Annual Meeting, March 21-27, 2015, Boston, MA. PMID- 26005735 TI - Abstracts of the 104th Annual Meeting of the United States and Canadian Academy of Pathology, March 21-27, 2015, Boston, MA. PMID- 26005737 TI - Should we believe the Centers for Disease Control and Prevention's autism spectrum disorder prevalence estimates? PMID- 26005739 TI - Polyfluorinated substances in abiotic standard reference materials. AB - The National Institute of Standards and Technology (NIST) has a wide range of Standard Reference Materials (SRMs) which have values assigned for legacy organic pollutants and toxic elements. Existing SRMs serve as homogenous materials that can be used for method development, method validation, and measurement for contaminants that are now of concern. NIST and multiple groups have been measuring the mass fraction of a group of emerging contaminants, polyfluorinated substances (PFASs), in a variety of SRMs. Here we report levels determined in an interlaboratory comparison of up to 23 PFASs determined in five SRMs: sediment (SRMs 1941b and 1944), house dust (SRM 2585), soil (SRM 2586), and sludge (SRM 2781). Measurements presented show an array of PFASs, with perfluorooctane sulfonate being the most frequently detected. SRMs 1941b, 1944, and 2586 had relatively low concentrations of most PFASs measured while 23 PFASs were at detectable levels in SRM 2585 and most of the PFASs measured were at detectable levels in SRM 2781. The measurements made in this study were used to add values to the Certificates of Analysis for SRMs 2585 and 2781. PMID- 26005740 TI - Iodine and pregnancy - a UK cross-sectional survey of dietary intake, knowledge and awareness. AB - Iodine is a key component of the thyroid hormones, which are critical for healthy growth, development and metabolism. The UK population is now classified as mildly iodine-insufficient. Adequate levels of iodine during pregnancy are essential for fetal neurodevelopment, and mild iodine deficiency is linked to developmental impairments. In the absence of prophylaxis in the UK, awareness of nutritional recommendations during pregnancy would empower mothers to make the right dietary choices leading to adequate iodine intake. The present study aimed to: estimate mothers' dietary iodine intake in pregnancy (using a FFQ); assess awareness of the importance of iodine in pregnancy with an understanding of existing pregnancy dietary and lifestyle recommendations with relevance for iodine; examine the level of confidence in meeting adequate iodine intake. A cross-sectional survey was conducted and questionnaires were distributed between August 2011 and February 2012 on local (Glasgow) and national levels (online electronic questionnaire); 1026 women, UK-resident and pregnant or mother to a child aged up to 36 months participated in the study. While self-reported awareness about general nutritional recommendations during pregnancy was high (96 %), awareness of iodine-specific recommendations was very low (12 %), as well as the level of confidence of how to achieve adequate iodine intake (28 %). Median pregnancy iodine intake, without supplements, calculated from the FFQ, was 190 MUg/d (interquartile range 144-256MUg/d), which was lower than that of the WHO's recommended intake for pregnant women (250 MUg/d). Current dietary recommendations in pregnancy, and their dissemination, are found not to equip women to meet the requirements for iodine intake. PMID- 26005741 TI - Pre-protection re-haemorrhage following aneurysmal subarachnoid haemorrhage: Where are we now? AB - BACKGROUND: Re-haemorrhage is a negative, prognostic predictor of outcome in aneurysmal subarachnoid haemorrhage (aSAH). The process of aSAH care has changed however, and most reports on re-haemorrhage are from a time when aneurysms were treated predominantly by open microneurosurgery. The current frequency and impact of re-haemorrhage on outcome in the 'post-ISAT' era is therefore unknown. The aim of this study was to review current outcome, risk factors and causes for inpatient re-haemorrhage in aSAH patients. METHOD: The departmental aSAH database was reviewed between Jan 2008 and March 2014 (N = 1008) to identify cases of re haemorrhage. Re-haemorrhage was defined as inhospital deterioration in neurological status with CT confirmation of rebleeding. Binary logistic regression was used to (a) determine the impact of re-haemorrhage on outcome adjusted for age and injury severity and (b) to identify any independent predictors of its occurrence. RESULTS: Re-haemorrhage occurred in 55 (5.4%) of patients and most cases had occurred within 24h of ictus (32, 58.1%). Re haemorrhage was an independent predictor of death (AOR 10.0, p < 0.0005, 95%CI 4.9, 20.2) and unfavourable outcome (AOR 5.8 p < 0.0005, 95%CI 2.4, 14.0). Only WFNS grade on admission was an independent predictor (AOR 1.7, p < 0.0005, 95%CI 1.4, 1.9) of re-haemorrhage. Of the patients who re-bled, in 20 there was no intention to treat due to severe brain injury and in the remainder, the majority occurred early (<24h) (19/35, 54%), or had complicated aneurysm morphology (10/35, 31%) which necessitated a delayed treatment strategy. CONCLUSIONS: Re haemorrhage remains a poor prognostic predictor in aSAH and the grade of SAH is an independent risk factor. Earlier treatment of complex aneurysms could offer the most immediate improvements in its incidence. PMID- 26005742 TI - A video based run-off-road training program with practice and evaluation in a simulator. AB - A run-off-road (ROR) event occurs when one or more of a vehicle's wheels leaves the roadway and begins to travel on the surface or shoulder adjacent to the road. Despite various countermeasures, ROR crashes continue to yield a large number of fatalities and injuries. Infrastructure-based solutions do not directly address the critical factor of driver performance preceding and during an ROR event. In this study, a total of 75 individuals participated in a pre-post experiment to examine the effect of a training video on improving driver performance during a set of simulated ROR scenarios (e.g., on a high speed highway, a horizontal curve, and a residential rural road). In each scenario, the vehicle was unexpectedly forced into an ROR scenario for which the drivers were instructed to recover as safely as possible. The treatment group then watched a custom ROR training video while the control group viewed a placebo video. The participants then drove the same simulated ROR scenarios. The results suggest that the training video had a significant positive effect on drivers' steering response on all three roadway conditions as well as improvements in vehicle stability, subjectively rated demand on the driver, and self-evaluated performance in the highway scenario. Under the highway conditions, the treatment group reduced the frequency of spinouts from 70% in the pre-training events to 16% in the post training events (chi(2)(1)=23.32, p<0.001) with no significant improvement found for the control group. In the horizontal curve, spinouts were reduced for the treatment group from 50% in the pre-training events to 30% in the post-training events (chi(2)(1)=8.45, p=0.004) with the control group also not showing any significant improvement. The results of this study suggest that even a short video about recovering from ROR events can significantly influence a driver's ability to recover. It is possible that additional training may have further benefits in recovering from ROR events. PMID- 26005743 TI - Microwave-Assisted Extraction of Phenolic Compounds from Almond Skin Byproducts (Prunus amygdalus): A Multivariate Analysis Approach. AB - A microwave-assisted extraction (MAE) procedure to isolate phenolic compounds from almond skin byproducts was optimized. A three-level, three-factor Box Behnken design was used to evaluate the effect of almond skin weight, microwave power, and irradiation time on total phenolic content (TPC) and antioxidant activity (DPPH). Almond skin weight was the most important parameter in the studied responses. The best extraction was achieved using 4 g, 60 s, 100 W, and 60 mL of 70% (v/v) ethanol. TPC, antioxidant activity (DPPH, FRAP), and chemical composition (HPLC-DAD-ESI-MS/MS) were determined by using the optimized method from seven different almond cultivars. Successful discrimination was obtained for all cultivars by using multivariate linear discriminant analysis (LDA), suggesting the influence of cultivar type on polyphenol content and antioxidant activity. The results show the potential of almond skin as a natural source of phenolics and the effectiveness of MAE for the reutilization of these byproducts. PMID- 26005744 TI - Using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to characterize copper, zinc and mercury along grizzly bear hair providing estimate of diet. AB - We enhanced an existing technique, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), to function as a non-lethal tool in the temporal characterization of trace element exposure in wild mammals. Mercury (Hg), copper (Cu), cadmium (Cd), lead (Pb), iron (Fe) and zinc (Zn) were analyzed along the hair of captive and wild grizzly bears (Ursus arctos horribilis). Laser parameters were optimized (consecutive 2000 MUm line scans along the middle line of the hair at a speed of 50 MUm/s; spot size=30 MUm) for consistent ablation of the hair. A pressed pellet of reference material DOLT-2 and sulfur were used as external and internal standards, respectively. Our newly adapted method passed the quality control tests with strong correlations between trace element concentrations obtained using LA-ICP-MS and those obtained with regular solution ICP-MS (r(2)=0.92, 0.98, 0.63, 0.57, 0.99 and 0.90 for Hg, Fe, Cu, Zn, Cd and Pb, respectively). Cross-correlation analyses revealed good reproducibility between trace element patterns obtained from hair collected from the same bear. One exception was Cd for which external contamination was observed resulting in poor reproducibility. In order to validate the method, we used LA-ICP-MS on the hair of five captive grizzly bears fed known and varying amounts of cutthroat trout over a period of 33 days. Trace element patterns along the hair revealed strong Hg, Cu and Zn signals coinciding with fish consumption. Accordingly, significant correlations between Hg, Cu, and Zn in the hair and Hg, Cu, and Zn intake were evident and we were able to develop accumulation models for each of these elements. While the use of LA-ICP-MS for the monitoring of trace elements in wildlife is in its infancy, this study highlights the robustness and applicability of this newly adapted method. PMID- 26005745 TI - An evaluation of the water utilization and grain production of irrigated and rain fed croplands in China. AB - Irrigation plays a major role in Chinese agricultural production, as China is experiencing water and food scarcity. Assessing water use (WU) and water productivity (WP) will contribute to regional water management and grain production improvement. This paper quantifies the water use and productivity in grain production for 31 Chinese provinces, autonomous regions and municipalities (PAMs) by distinguishing between irrigated and rain-fed farmland. An indicator of marginal productivity of blue water (MWPb) is established and calculated to evaluate irrigation profits. National water use (WUt) for grain cultivation from 1998 to 2010 was approximately 689.04 Gm(3) (42.26% blue water and 57.74% green water). The productive water proportions for irrigated and total croplands were 65.57% and 76.85%, respectively. Water use compositions from both blue-green and productive-unproductive perspectives changed slightly over time. The water use productivity (WPU) and water consumption productivity (WPC) for integrated grain products of China during the study period were 0.747 and 0.972 kg/m(3), respectively. The spatial distribution patterns of irrigated WPs (WPUI, WPCI) were consistent with those for total cropland. China has achieved sufficient food supply without increasing water use. The national MWPb was estimated to be 0.673 kg/m(3), revealing a higher increase in crop yield on irrigated land compared to rain-fed land. The northeast provinces urgently need to improve irrigation efficiency, and the North China Plain PAMs should promote rain-fed crop yield to increase grain production and control water use in the future. PMID- 26005746 TI - Application of ICP-OES for evaluating energy extraction and production wastewater discharge impacts on surface waters in Western Pennsylvania. AB - Oil and gas extraction and coal-fired electrical power generating stations produce wastewaters that are treated and discharged to rivers in Western Pennsylvania with public drinking water system (PDWS) intakes. Inductively coupled plasma optical emission spectroscopy (ICP-OES) was used to quantify inorganic species in wastewater and river samples using a method based on EPA Method 200.7 rev4.4. A total of 53 emission lines from 30 elements (Al, As, B, Ba, Ca, Cd, Ce, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S, Sb, Se, Si, Sn, Sr, Ti, Tl, V, and Zn) were investigated. Samples were prepared by microwave assisted acid digestion using a mixture of 2% HNO3 and 0.5% HCl. Lower interferences and better detection characteristics resulted in selection of alternative wavelengths for Al, As, Sb, Mg, Mo, and Na. Radial view measurements offered accurate determinations of Al, Ba, K, Li, Na, and Sr in high-brine samples. Spike recovery studies and analyses of reference materials showed 80 105% recoveries for most analytes. This method was used to quantify species in samples with high to low brine concentrations with method detection limits a factor of 2 below the maximum contaminant limit concentrations of national drinking water standards. Elements B, Ca, K, Li, Mg, Na, and Sr were identified as potential tracers for the sources impacting PDWS intakes. Usability of the ICP OES derived data for factor analytic model applications was also demonstrated. PMID- 26005747 TI - Modeling the early-phase redistribution of radiocesium fallouts in an evergreen coniferous forest after Chernobyl and Fukushima accidents. AB - Following the Chernobyl accident, the scientific community gained numerous data on the transfer of radiocesium in European forest ecosystems, including information regarding the short-term redistribution of atmospheric fallout onto forest canopies. In the course of international programs, the French Institute for Radiological Protection and Nuclear Safety (IRSN) developed a forest model, named TREE4 (Transfer of Radionuclides and External Exposure in FORest systems), 15 years ago. Recently published papers on a Japanese evergreen coniferous forest contaminated by Fukushima radiocesium fallout provide interesting and quantitative data on radioactive mass fluxes measured within the forest in the months following the accident. The present study determined whether the approach adopted in the TREE4 model provides satisfactory results for Japanese forests or whether it requires adjustments. This study focused on the interception of airborne radiocesium by forest canopy, and the subsequent transfer to the forest floor through processes such as litterfall, throughfall, and stemflow, in the months following the accident. We demonstrated that TREE4 quite satisfactorily predicted the interception fraction (20%) and the canopy-to-soil transfer (70% of the total deposit in 5 months) in the Tochigi forest. This dynamics was similar to that observed in the Hoglwald spruce forest. However, the unexpectedly high contribution of litterfall (31% in 5 months) in the Tochigi forest could not be reproduced in our simulations (2.5%). Possible reasons for this discrepancy are discussed; and sensitivity of the results to uncertainty in deposition conditions was analyzed. PMID- 26005748 TI - Estimation and mitigation of N2O emission and nitrate leaching from intensive crop cultivation in the Haean catchment, South Korea. AB - Considering intensive agricultural management practices and environmental conditions, the LandscapeDNDC model was applied for simulation of yields, N2O emission and nitrate leaching from major upland crops and temperate deciduous forest of the Haean catchment, South Korea. Fertilization rates were high (up to 314 kg N ha(-1) year(-1)) and resulted in simulated direct N2O emissions from potato, radish, soybean and cabbage fields of 1.9 and 2.1 kg N ha(-1) year(-1) in 2009 and 2010, respectively. Nitrate leaching was identified as the dominant pathway of N losses in the Haean catchment with mean annual rates of 112.2 and 125.4 kg N ha(-1) year(-1), causing threats to water quality and leading to substantial indirect N2O emissions of 0.84 and 0.94 kg N ha(-1) year(-1) in 2009 and 2010 as estimates by applying the IPCC EF5. Simulated N2O emissions from temperate deciduous forest were low (approx. 0.50 kg N ha(-1) year(-1)) and predicted nitrate leaching rates were even negligible (<=0.01 kg N ha(-1) year( 1)). On catchment scale more than 50% of the total N2O emissions and up to 75% of nitrate leaching originated from fertilized upland fields, only covering 24% of the catchment area. Taking into account area coverage of simulated upland crops and other land uses these numbers agree well with nitrate loads calculated from discharge and concentration measurements at the catchment outlet. The change of current agricultural management practices showed a high potential of reducing N2O emission and nitrate leaching while maintaining current crop yields. Reducing (39%) and splitting N fertilizer application into 3 times was most effective and lead to about 54% and 77% reducing of N2O emission and nitrate leaching from the Haean catchment, the latter potentially contributing to improved water quality in the Soyang River Dam, which is the major source of drinking water for metropolitan residents. PMID- 26005749 TI - Stream primary producers relate positively to watershed natural gas measures in north-central Arkansas streams. AB - Construction of unconventional natural gas (UNG) infrastructure (e.g., well pads, pipelines) is an increasingly common anthropogenic stressor that increases potential sediment erosion. Increased sediment inputs into nearby streams may decrease autotrophic processes through burial and scour, or sediment bound nutrients could have a positive effect through alleviating potential nutrient limitations. Ten streams with varying catchment UNG well densities (0-3.6 wells/km(2)) were sampled during winter and spring of 2010 and 2011 to examine relationships between landscape scale disturbances associated with UNG activity and stream periphyton [chlorophyll a (Chl a)] and gross primary production (GPP). Local scale variables including light availability and water column physicochemical variables were measured for each study site. Correlation analyses examined the relationships of autotrophic processes and local scale variables with the landscape scale variables percent pasture land use and UNG metrics (well density and well pad inverse flow path length). Both GPP and Chl a were primarily positively associated with the UNG activity metrics during most sample periods; however, neither landscape variables nor response variables correlated well with local scale factors. These positive correlations do not confirm causation, but they do suggest that it is possible that UNG development can alleviate one or more limiting factors on autotrophic production within these streams. A secondary manipulative study was used to examine the link between nutrient limitation and algal growth across a gradient of streams impacted by natural gas activity. Nitrogen limitation was common among minimally impacted stream reaches and was alleviated in streams with high UNG activity. These data provide evidence that UNG may stimulate the primary production of Fayetteville shale streams via alleviation of N-limitation. Restricting UNG activities from the riparian zone along with better enforcement of best management practices should help reduce these possible impacts of UNG activities on stream autotrophic processes. PMID- 26005750 TI - Using PM(2.5) lanthanoid elements and nonparametric wind regression to track petroleum refinery FCC emissions. AB - A long term air quality study is being conducted in Roxana, Illinois, USA, at the fenceline of a petroleum refinery. Measurements include 1-in-6 day 24-hour integrated ambient fine particulate matter (PM2.5) speciation following the Chemical Speciation Network (CSN) sampling and analysis protocols. Lanthanoid elements, some of which are tracers of fluidized-bed catalytic cracker (FCC) emissions, are also measured by inductively coupled plasma-mass spectrometry (ICP MS) after extraction from PM2.5 using hot block-assisted acid digestion. Lanthanoid recoveries of 80-90% were obtained for two ambient particulate matter standard reference materials (NIST SRM 1648a and 2783). Ambient PM2.5 La patterns could be explained by a two-source model representing resuspended soil and FCC emissions with enhanced La/Ce ratios when impacted by the refinery. Nonparametric wind regression demonstrates that when the monitoring station was upwind of the refinery the mean La/Ce ratio is consistent with soil and when the monitoring station is downwind of the refinery the mean ratio is more than four times higher for bearings that corresponds to maximum impacts. Source apportionment modeling using EPA UNMIX and EPA PMF could not reliably apportion PM2.5 mass to the FCC emissions. However, the weight of evidence is that such contributions are small with no large episodes observed for the 164 samples analyzed. This study demonstrates the applicability of a hot block-assisted digestion protocol for the extraction of lanthanoid elements as well as insights obtained from long-term monitoring data including wind direction-based analyses. PMID- 26005751 TI - The effect of vegetation and soil texture on the nature of organics in runoff from a catchment supplying water for domestic consumption. AB - The influence of vegetation and soil texture on the concentration and character of dissolved organic matter (DOM) present in runoff from the surface and sub surface of zero order catchments of the Myponga Reservoir-catchment (South Australia) was investigated to determine the impacts of catchment characteristics and land management practices on the quality of waters used for domestic supply. Catchments selected have distinct vegetative cover (grass, native vegetation or pine) and contrasting texture of the surface soil horizon (sand or clay loam/clay). Water samples were collected from three slope positions (upper, middle, and lower) at soil depths of ~30 cm and ~60 cm in addition to overland flows. Filtered (0.45 MUm) water samples were analyzed for dissolved organic carbon (DOC) and UV-visible absorbance and by F-EEM and HPSEC with UV and fluorescence detection to characterize the DOM. Surface and sub-surface runoff from catchments with clay soils and native vegetation or grass had lower DOC concentrations and lower relative abundances of aromatic, humic-like and high molecular weight organics than runoff from sandy soils with these vegetative types. Sub-surface flows from two catchments with Pinus radiata had similar DOC concentrations and DOM character, regardless of marked variation in surface soil texture. Runoff from catchments under native vegetation and grass on clay soils resulted in lower DOC concentrations and hence would be expected to have lower coagulant demand in conventional treatment for potable water supply than runoff from corresponding sandy soil catchments. However, organics in runoff from clay catchments would be more difficult to remove by coagulation. Surface waters from the native vegetation and grass catchments were generally found to have higher relative abundance of organic compounds amenable to removal by coagulation compared with sub-surface waters. Biophysical and land management practices combine to have a marked influence on the quality of source water used for domestic supply. PMID- 26005752 TI - A comparison of forest and agricultural shallow groundwater chemical status a century after land use change. AB - Considering the increasing pace of global land use change and the importance of groundwater quality to humans and aquatic ecosystems, studies are needed that relate land use types to patterns of groundwater chemical composition. Piezometer grids were installed in a remnant bottomland hardwood forest (BHF) and a historic agricultural field (Ag) to compare groundwater chemical composition between sites with contrasting land use histories. Groundwater was sampled monthly from June 2011 to June 2013, and analyzed for 50 physiochemical metrics. Statistical tests indicated significant differences (p<0.05) between the study sites for 32 out of 50 parameters. Compared to the Ag site, BHF groundwater was characterized by significantly (p<0.05) lower pH, higher electrical conductivity, and higher concentrations of total dissolved solids and inorganic carbon. BHF groundwater contained significantly (p<0.05) higher concentrations of all nitrogen species except nitrate, which was higher in Ag groundwater. BHF groundwater contained significantly (p<0.05) higher concentrations of nutrients such as sulfur, potassium, magnesium, calcium, and sodium, relative to the Ag site. Ag groundwater was characterized by significantly (p<0.05) higher concentrations of trace elements such as arsenic, cadmium, cobalt, copper, molybdenum, nickel, and titanium. Comparison of shallow groundwater chemical composition with that of nearby receiving water suggests that subsurface concentration patterns are the result of contrasting site hydrology and vegetation. Results detail impacts of surface vegetation alteration on subsurface chemistry and groundwater quality, thereby illustrating land use impacts on the lithosphere and hydrosphere. This study is among the first to comprehensively characterize and compare shallow groundwater chemical composition at sites with contrasting land use histories. PMID- 26005753 TI - Rainwater harvesting systems for low demanding applications. AB - A rainwater harvesting system (RHS) was designed for a waste treatment facility located near the town of Mirandela (northern Portugal), to be used in the washing of vehicles and other equipment, the cleaning of outside concrete or asphalt floors, and the watering of green areas. Water tank volumes representing 100% efficiency (Vr) were calculated by the Ripple method with different results depending on two consumption scenarios adopted for irrigation. The RHS design was based on a precipitation record spanning a rather long period (3 decades). The calculated storage capacities fulfilled the water demand even when prolonged droughts occurred during that timeframe. However, because the drought events have been rather scarce the Vr values were considered oversized and replaced by optimal volumes. Notwithstanding the new volumes were solely half of the original Vr values, the projected RHS efficiency remained very high (around 90%) while the probability of system failure (efficiency<100%) stayed very low (in the order of 5%). In both scenarios, the economic savings related to the optimization of Vr were noteworthy, while the investment's return periods decreased substantially from the original to the optimized solutions. A high efficiency with a low storage capacity is typical of low demanding applications of rainwater harvesting, where water availability (Vw) largely exceeds water demand (Cw), that is to say where demand fractions (Cw/Vw) are very low. Based on the results of a literature review covering an ample geographic distribution and describing a very large number of demand fraction scenarios, a Cw/Vw=0.8 was defined as the threshold to generally distinguish the low from the high demanding RHS applications. PMID- 26005754 TI - Enhanced biological processes associated with alopecia in polar bears (Ursus maritimus). AB - Populations of wildlife species worldwide experience incidents of mass morbidity and mortality. Primary or secondary drivers of these events may escape classical detection methods for identifying microbial insults, toxin exposure, or additional stressors. In 2012, 28% of polar bears sampled in a study in the southern Beaufort Sea region of Alaska had varying degrees of alopecia that was concomitant with reduced body condition. Concurrently, elevated numbers of sick or dead ringed seals were detected in the southern Beaufort, Chukchi, and Bering seas in 2012, resulting in the declaration of an unusual mortality event (UME) by the National Oceanic and Atmospheric Administration (NOAA). The primary and possible ancillary causative stressors of these events are unknown, and related physiological changes within individual animals have been undetectable using classical diagnostic methods. Here we present an emerging technology as a potentially guiding investigative approach aimed at elucidating the circumstances responsible for the susceptibility of certain polar bears to observed conditions. Using transcriptomic analysis we identified enhanced biological processes including immune response, viral defense, and response to stress in polar bears with alopecia. Our results support an alternative mechanism of investigation into the causative agents that, when used proactively, could serve as an early indicator for populations and species at risk. We suggest that current or classical methods for investigation into events of unusual morbidity and mortality can be costly, sometimes unfocused, and often inconclusive. Advances in technology allow for implementation of a holistic system of surveillance and investigation that could provide early warning of health concerns in wildlife species important to humans. PMID- 26005755 TI - Occurrence, distribution and bioaccumulation of endocrine disrupting compounds in water, sediment and biota samples from a European river basin. AB - The occurrence, distribution and bioaccumulation of five endocrine disrupting compounds (4-tert-octylphenol, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol and bisphenol A) in water, sediment and biota (Corbicula fluminea) collected along the Minho River estuary (NW Iberian Peninsula) were examined. Samples were collected in two campaigns (May and November, 2012) and analyzed by different extraction procedures followed by liquid chromatography tandem mass spectrometry determination. The presence of linear isomers (4-n-octylphenol and 4-n nonylphenol) was scarcely observed whereas branched isomers (4-tert-octylphenol and nonylphenol) were measured in almost all samples. Wastewater treatment plant effluents and nautical, fishing and agricultural activities are considered the primary source of pollution of the river by alkylphenols. The presence of bisphenol A in the river could be mainly associated to punctual sources of contamination from industrial discharges. A decrease in the total concentration of phenolic compounds in water was observed from spring to autumn (from 0.888 MUg L(-1) in May to 0.05 MUg L(-1) in November), while similar values were shown in C. fluminea samples from the two campaigns (1388 and 1228 ng g(-1) dw in spring and autumn, respectively). In sediments, the total concentration of the target compounds varied between 13 and 4536 ng g(-1) dw (average of 1041 ng g(-1) dw). Sediment-water partition coefficient (Kd), bioaccumulation factor (BAF) and biota sediment accumulation factor (BSAF) were estimated and highest values were obtained for nonylphenol. Calculated risk quotients showed low and moderate risk for the aquatic environment from the presence of the target compounds at all sampling points. The estimation of the daily intake of the studied compounds via water and biota ingestion indicated no risk for human health. PMID- 26005756 TI - Linking groundwater dissolved organic matter to sedimentary organic matter from a fluvio-lacustrine aquifer at Jianghan Plain, China by EEM-PARAFAC and hydrochemical analyses. AB - The sources of dissolved organic matter (DOM) in groundwater are important to groundwater chemistry and quality. This study examined similarities in the nature of DOM and investigated the link between groundwater DOM (GDOM) and sedimentary organic matter (SOM) from a lacustrine-alluvial aquifer at Jianghan Plain. Sediment, groundwater and surface water samples were employed for SOM extraction, optical and/or chemical characterization, and subsequent fluorescence excitation emission matrix (EEM) and parallel factor analyses (PARAFAC). Spectroscopic properties of bulk DOM pools showed that indices indicative of GDOM (e.g., biological source properties, humification level, aromaticity and molecule mobility) varied within the ranges of those of two extracted end-members of SOM: humic-like materials and microbe-associated materials. The coexistence of PARAFAC compositions and the sustaining internal relationship between GDOM and extracted SOM indicate a similar source. The results from principal component analyses with selected spectroscopic indices showed that GDOM exhibited a transition trend regarding its nature: from refractory high-humification DOM to intermediate humification DOM and then to microbe-associated DOM, with decreasing molecular weight. Correlations of spectroscopic indices with physicochemical parameters of the groundwater suggested that GDOM was released from SOM and was modified by microbial diagenetic processes. The current study demonstrated the associations of GDOM with SOM from a spectroscopic viewpoint and provided new evidence supporting SOM as the source of GDOM. PMID- 26005757 TI - Significance of functional GRP78 polymorphisms in predicting the onset of type 2 diabetic peripheral neuropathy in Chinese population. AB - OBJECTIVE: The objective of this study is to investigate the significance of functional GRP78 polymorphisms in predicting the risk of type 2 diabetic peripheral neuropathy in Chinese population. METHODS: Between the years of 2006 and 2010, a total of 295 definitely diagnosed type 2 diabetes mellitus (T2DM) patients were included into our study cohort and followed for 3 years. At baseline and annual re-examinations, the patients underwent physical examinations, laboratory tests and evaluation of Michigan diabetic neuropathy score (MDNS). Age, gender, disease course, waist-hip circumference ratio (WHR), body mass index (BMI), triglycerine (TG), total cholesterol (Tch), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glycosylated haemoglobin (HbA1c), uric acid elimination rate (UAER) and uric acid (UA) were recorded and GRP78 polymorphisms were tested by direct sequencing. The prognostic significance of GRP78 polymorphisms were analysed using monovariate and multivariate logistic regression. RESULTS: Three years after baseline, 32.9% (97/295) of the T2DM patients had suffered the development of diabetic peripheral neuropathy and GRP78 rs391957 promoter polymorphism is a significant risk factor for the onset of type 2 diabetic peripheral neuropathy. In monovariate regression model, the OR values of GRP78 rs391957 promoter polymorphism were 2.233 (C/T) and 2.734 (T/T). As for the model calibrated with demographic and laboratory indexes, the OR values were, respectively, 2.124 (C/T) and 2.423 (T/T). CONCLUSION: Our study suggested that the GRP78 rs391957 promoter polymorphism is a potential risk factor for type 2 diabetic peripheral neuropathy. PMID- 26005758 TI - Heterogeneous Electrochemical Aptamer-Based Sensor Surfaces for Controlled Sensor Response. AB - Structure-switching sensors utilize recognition elements that undergo a conformation change upon target binding that is converted into a quantitative signal. Electrochemical, aptamer-based sensors achieve detection of analytes through a conformation change in an electrode-bound, oligonucleotide aptamer by measuring changes in electron transfer efficiencies. The analytical performance of these sensors is related to the magnitude of the conformation change of the aptamer. The goal of the present work is to develop a general method to predictably tune the analytical performance (sensitivity and linear range) of electrochemical, aptamer-based sensors by utilizing a mixture of rationally designed aptamer sequences that are specific for the same target but with different affinities on the same electrode surface. To demonstrate control over sensor performance, we developed heterogeneous sensors for two representative small molecule targets (adenosine triphosphate and tobramycin). We demonstrate that mixtures of modified sequences can be used to tune the affinity, dynamic range, and sensitivity of the resulting sensors predicted by a bi-Langmuir-type isotherm. PMID- 26005759 TI - Application of Europium Multiwalled Carbon Nanotubes as Novel Luminophores in an Electrochemiluminescent Aptasensor for Thrombin Using Multiple Amplification Strategies. AB - A novel electrochemiluminescent (ECL) aptasensor was proposed for the determination of thrombin (TB) using exonuclease-catalyzed target recycling and hybridization chain reaction (HCR) to amplify the signal. The capture probe was immobilized on an Au-GS-modified electrode through a Au-S bond. Subsequently, the hybrid between the capture probe and the complementary thrombin binding aptamer (TBA) was aimed at obtaining double-stranded DNA (dsDNA). The interaction between TB and its aptamer led to the dissociation of dsDNA because TB has a higher affinity to TBA than the complementary strands. In the presence of exonuclease, aptamer was selectively digested and TB could be released for target recycling. Extended dsDNA was formed through HCR of the capture probe and two hairpin DNA strands (NH2-DNA1 and NH2-DNA1). Then, numerous europium multiwalled carbon nanotubes (Eu-MWCNTs) could be introduced through amidation reaction between NH2 terminated DNA strands and carboxyl groups on the Eu-MWCNTs, resulting in an increased ECL signal. The multiple amplification strategies, including the amplification of analyte recycling and HCR, and high ECL efficiency of Eu-MWCNTs lead to a wide linear range (1.0*10(-12)-5.0*10(-9) mol/L) and a low detection limit (0.23 pmol/L). The method was applied to serum sample analysis with satisfactory results. PMID- 26005760 TI - Atherosclerotic disease in axial spondyloarthritis: increased frequency of carotid plaques. AB - OBJECTIVES: To establish whether subclinical atherosclerosis is increased in patients with axial spondyloarthritis (ax-SpA). METHODS: A set of 149 consecutive patients with no history of cardiovascular disease that fulfilled the Assessment of SpondyloArthritis International Society classification criteria for ax-SpA was studied by carotid ultrasonography. Carotid intima-media thickness (cIMT) and plaques were assessed. A series of 181 community-based controls with no cardiovascular disease were studied for comparison. To establish whether ax-SpA might have a direct effect on the risk of carotid plaques or an indirect effect via its putative influence on hypertension, dyslipidaemia or obesity, we obtained adjusted odds ratios (OR) for each clinical factor by the development of adjusted models. RESULTS: cIMT was increased in patients (0.621+/-0.123 mm) when compared to controls (0.607+/-0.117 mm) but the difference was not significant (p=0.30). Nevertheless, carotid plaques were more commonly observed in patients with ax-SpA than in controls (41.6% vs. 26.4%; p=0.003). Patients with plaques had longer duration of the disease than those without plaques (20.5+/-11.2 years vs. 12.0+/ 8.6 years; p<0.001). Plaques were more frequent in patients with hip involvement (crude odds ratio 3.15, 95% confidence interval [CI] 1.02-9.75; p=0.05), syndesmophytes (crude OR 4.94, 95% CI 2.14-11.4; p<0.001), in patients with higher functional limitation and mobility index measured by BASFI (crude OR 1.16, 95% CI 1.02-1.33; p=0.03) and BASMI (crude OR 1.45, 95% CI 1.19-1.77; p<0.001), and in those with psoriasis (crude OR 3.94, 95% CI 1.31-11.84; p=0.02. However, except for psoriasis that continued being a strong risk factor for plaques after adjustment, the relationship between other clinical features of ax-SpA and carotid plaques disappeared in the adjusted models. CONCLUSIONS: Our results confirm the presence of subclinical atherosclerosis in patients with ax-SpA. PMID- 26005761 TI - Taxes on tobacco, alcohol and sugar sweetened beverages: Linkages and lessons learned. AB - Increased consumption of sugar-sweetened beverages (SSBs) has been linked to increases in obesity in both high-income and low- and middle-income countries. Tobacco and alcohol taxes have proven to be effective tools to reduce tobacco and alcohol use. Many public health advocates propose using similar taxes to reduce consumption of SSBs. South Africa is a middle-income country that is considered a leader in the area of tobacco tax policy. A case study of tobacco and alcohol taxes is used to better understand optimal tax structures for SSBs. The case study tracks aggregate data over time on taxes, prices, consumption, tax revenues, and marketing expenditures at the brand level. Tobacco and alcohol taxes are shown to be effective in reducing the demand for tobacco. Additionally, taxes on the dose of alcohol rather than the volume of the beverage may incentivize producers to reduce the volume of alcohol in beverages through the supply side. While specific taxes based on the volume of beverages are likely to reduce the demand for SSBs, policy makers should also consider taxes on alcohol and SSBs that tax the dose of the alcohol and calories in order to create supply side incentives for producers to lower alcohol and calorie levels in existing products or promote products with lower levels of alcohol and calories. PMID- 26005762 TI - pH triggered in vivo photothermal therapy and fluorescence nanoplatform of cancer based on responsive polymer-indocyanine green integrated reduced graphene oxide. AB - We have synthesized a pH-dependent, NIR-sensitive, reduced graphene oxide (rGO) hybrid nano-composite via electrostatic interaction with indocyanine green (ICG) which is designed not only to destroy localized cancer cells but also be minimally invasive to surrounding normal cells. The near-infrared (NIR) irradiated hybrid nano-composites showed pH dependent photo-thermal heat generation capability from pH 5.0 to 7.4 due to the pH response relief and quenching effects of poly(2-dimethyl amino ethyl methacrylate) [poly(PDMAEMA)] with ICG on a single rGO sheet. This pH-triggered relief and quenching mechanism regulated in vitro photo-thermolysis as the pH changed from 5.0 to 7.4. The in vitro cellular uptake and confocal laser scan microscopic (CLSM) images at different pH values show promise for environment sensitive bio-imaging. The NIR absorbing hybrid nanomaterials showed a remarkably improved in vitro cancer cell targeted photothermal destruction compared to free ICG. Upon local NIR irradiation, these hybrid nano-composites-treated tumors showed necrotic, shrunken, ablation of malignant cells and totally healed after 18 days treatment. Our finding regarding the acidic pH stimulus of cancer cellular environment has proven to be a wining platform for the fight against cancer. PMID- 26005763 TI - Dynamic control and quantification of bacterial population dynamics in droplets. AB - Culturing and measuring bacterial population dynamics are critical to develop insights into gene regulation or bacterial physiology. Traditional methods, based on bulk culture to obtain such quantification, have the limitations of higher cost/volume of reagents, non-amendable to small size of population and more laborious manipulation. To this end, droplet-based microfluidics represents a promising alternative that is cost-effective and high-throughput. However, difficulties in manipulating the droplet environment and monitoring encapsulated bacterial population for long-term experiments limit its utilization. To overcome these limitations, we used an electrode-free injection technology to modulate the chemical environment in droplets. This ability is critical for precise control of bacterial dynamics in droplets. Moreover, we developed a trapping device for long term monitoring of population dynamics in individual droplets for at least 240 h. We demonstrated the utility of this new microfluidic system by quantifying population dynamics of natural and engineered bacteria. Our approach can further improve the analysis for systems and synthetic biology in terms of manipulability and high temporal resolution. PMID- 26005765 TI - Balancing the effect of corona on therapeutic efficacy and macrophage uptake of lipid nanocapsules. AB - Several studies have shown the potential of biocompatible lipid nanocapsules as hydrophobic drug delivery systems. Understanding the factors that determine the interactions of these oil-in-water nanoemulsions with cells is a necessary step to guide the design of the most effective formulations. The aim of this study was to probe the ability of two surfactants with a markedly different nature, a non ionic poloxamer, and a charged phospholipid, to prepare formulations with shells of different composition and different surface properties. Thus we determined their effects on the interaction with biological environments. In particular, we investigated how the shell formulation affected the adsorption of biomolecules from the surrounding biological fluids on the nanocapsule surface (corona formation). A complete physicochemical characterization including an isothermal titration calorimetry (ITC) study revealed that the use of poloxamer led to nanocapsules with a marked reduction in the number of protein-binding sites. Surface hydrophilicity and changes in corona formation strongly correlated to changes in uptake by cancer cells and by macrophages. Our results indicate that the nature and concentration of surfactants in the nanocapsules can be easily manipulated to effectively modulate their surface architecture with the aim of controlling the environmental interactions, thus optimizing functionality for in vivo applications. In particular, addition of surfactants that reduce protein binding can modulate nanoparticle clearance by the immune system, but also screens the desired interactions with cells, leading to lower uptake, thus lower therapeutic efficacy. The two effects need to be balanced in order to obtain successful formulations. PMID- 26005764 TI - A defined synthetic substrate for serum-free culture of human stem cell derived cardiomyocytes with improved functional maturity identified using combinatorial materials microarrays. AB - Cardiomyocytes from human stem cells have applications in regenerative medicine and can provide models for heart disease and toxicity screening. Soluble components of the culture system such as growth factors within serum and insoluble components such as the substrate on which cells adhere to are important variables controlling the biological activity of cells. Using a combinatorial materials approach we develop a synthetic, chemically defined cellular niche for the support of functional cardiomyocytes derived from human embryonic stem cells (hESC-CMs) in a serum-free fully defined culture system. Almost 700 polymers were synthesized and evaluated for their utility as growth substrates. From this group, 20 polymers were identified that supported cardiomyocyte adhesion and spreading. The most promising 3 polymers were scaled up for extended culture of hESC-CMs for 15 days and were characterized using patch clamp electrophysiology and myofibril analysis to find that functional and structural phenotype was maintained on these synthetic substrates without the need for coating with extracellular matrix protein. In addition, we found that hESC-CMs cultured on a co-polymer of isobornyl methacrylate and tert-butylamino-ethyl methacrylate exhibited significantly longer sarcomeres relative to gelatin control. The potential utility of increased structural integrity was demonstrated in an in vitro toxicity assay that found an increase in detection sensitivity of myofibril disruption by the anti-cancer drug doxorubicin at a concentration of 0.05 MUM in cardiomyocytes cultured on the co-polymer compared to 0.5 MUM on gelatin. The chemical moieties identified in this large-scale screen provide chemically defined conditions for the culture and manipulation of hESC-CMs, as well as a framework for the rational design of superior biomaterials. PMID- 26005766 TI - Acellular human heart matrix: A critical step toward whole heart grafts. AB - The best definitive treatment option for end-stage heart failure currently is transplantation, which is limited by donor availability and immunorejection. Generating an autologous bioartificial heart could overcome these limitations. Here, we have decellularized a human heart, preserving its 3-dimensional architecture and vascularity, and recellularized the decellularized extracellular matrix (dECM). We decellularized 39 human hearts with sodium-dodecyl-sulfate for 4-8 days. Cell removal and architectural integrity were determined anatomically, functionally, and histologically. To assess cytocompatibility, we cultured human cardiac-progenitor cells (hCPC), bone-marrow mesenchymal cells (hMSCs), human endothelial cells (HUVECs), and H9c1 and HL-1 cardiomyocytes in vitro on dECM ventricles up to 21 days. Cell survival, gene expression, organization and/or electrical coupling were analyzed and compared to conventional 2-dimensional cultures. Decellularization removed cells but preserved the 3-dimensional cardiac macro and microstructure and the native vascular network in a perfusable state. Cell survival was observed on dECM for 21 days. hCPCs and hMSCs expressed cardiocyte genes but did not adopt cardiocyte morphology or organization; HUVECs formed a lining of endocardium and vasculature; differentiated cardiomyocytes organized into nascent muscle bundles and displayed mature calcium dynamics and electrical coupling in recellularized dECM. In summary, decellularization of human hearts provides a biocompatible scaffold that retains 3-dimensional architecture and vascularity and that can be recellularized with parenchymal and vascular cells. dECM promotes cardiocyte gene expression in stem cells and organizes existing cardiomyocytes into nascent muscle showing electrical coupling. These findings represent a first step toward manufacturing human heart grafts or matrix components for treating cardiovascular disease. PMID- 26005767 TI - Preoperative immunosuppressive therapy reduces paravalvular leakage after aortic valve surgery in patients with aortic regurgitation attributable to Behcet's disease. AB - OBJECTIVES: Severe aortic regurgitation (AR) attributable to Behcet's disease (BD) is a rare but challenging problem in light of the surgical treatment notoriously complicated with paravalvular leakage (PVL) and high mortality. This study aims to test whether immunosuppressive therapy is effective in reducing the complication of the operation and improve the prognosis. METHODS: In a retrospective cohort of 644 hospitalised BD patients who were diagnosed and followed up between January 1998 and September 2014, 18 patients (2.8%) with severe AR due to BD were identified and their medical records were analysed. RESULTS: Among the 18 patients, 15 patients underwent the valve surgery and PVL developed in 7 (47%) at a median interval of 3.5 months. In the median follow-up of 32.5 months from first operations, patients with PVL had a significantly higher incidence of repeat surgery and death (71% vs. 0%, p=0.007). They less likely received preoperative immunotherapy (14% vs. 100%, p=0.001), had a lower cumulative dosage of cyclophosphamide before first operations (2.1+/-5.7g vs. 13.0+/-6.4g, p=0.004) and a higher preoperative erythrocyte sedimentation rate (44.4+/-20.7mm/first hour vs. 25.0+/-12.1mm/first hour, p=0.04) compared with those without developing PVL. Multivariate analysis showed preoperative immuno suppressive therapy (hazard ratio 18.58; 95% confidence interval, 2.134-161.81; p=0.008) was an independent factor associated with the absence of PVL. The 5-year PVL-free survival rates were significantly higher in patients receiving preoperative immunotherapy (p=0.0004). CONCLUSIONS: In patients with severe AR due to BD, preoperative immunosuppressive therapy, especially cyclophosphamide in conjunction with glucocorticoid, could reduce PVL after the corrective surgery and improve the outcomes. PMID- 26005768 TI - Ability in daily activities after early supported discharge models of stroke rehabilitation. AB - More knowledge is needed about how different rehabilitation models in the municipality influence stroke survivors' ability in activities of daily living (ADL). OBJECTIVES: To compare three models of outpatient rehabilitation; early supported discharge (ESD) in a day unit, ESD at home and traditional treatment in the municipality (control group), regarding change in ADL ability during the first three months after stroke. METHODS: A group comparison study was designed within a randomized controlled trial. Included participants were tested with the Assessment of Motor and Process Skills (AMPS) at baseline and discharged directly home. Primary and secondary outcomes were the AMPS and the modified Rankin Scale (mRS). RESULTS AND CONCLUSIONS: Included were 154 participants (57% men, median age 73 years), and 103 participants completed the study. There were no significant group differences in pre-post changed ADL ability measured by the AMPS. To find the best rehabilitation model to improve the quality of stroke survivors' motor and process skills needs further research. Patients participating in the ESD rehabilitation models were, compared with traditional treatment, significantly associated with improved ADL ability measured by the mRS when controlling for confounding factors, indicating that patients with social needs and physical impairment after stroke may benefit from ESD rehabilitation models. PMID- 26005769 TI - Are patients with truncal type of Stiff Person Syndrome hidden in a heterogenous group of non-radiographic axial spondyloarthritis? PMID- 26005770 TI - Equilibration Time of Solid Contact Ion-Selective Electrodes. AB - Papers published on ion-selective electrodes (ISEs) generally report on the performance characteristics of these devices after long, extensive conditioning. Conditioning refers to the equilibration of the ion-selective electrode in an aqueous solution before the measurement of the sample. The requirement for long and repeated conditioning is a significant burden in a variety of applications, for example, single-use sensors aimed for in vivo or field applications and solid contact (SC) ISEs, which were developed to provide simple, mass-produced sensors that have the potential to be implemented without calibration and extensive conditioning. In this study we recorded the potential of SC K(+), Na(+), and H(+) ISEs as a function of time following their first contact with an aqueous electrolyte solution and used these transients to determine their equilibration times. The SC electrodes were built on Au, Pt, and glassy carbon (GC) substrates using galvanostatically deposited conductive polymer (PEDOT(PSS(-)), poly(3,4 ethylenedioxythiophene) polystyrenesulfonate) as ion-to-electron transducer (solid internal contact) between the ion-selective membrane and the substrate. The SC electrodes built on GC and Au had significantly shorter equilibration times (between 5 and 13 min) than the SC electrodes built on Pt substrates (>60 min). Such significant differences in the equilibration times of SC ISEs built on different substrate electrodes are reported here for the first time. These unexpected findings suggest that the interface between the conductive polymer and the electron-conducting substrate (EC) has significant influence on the long-term dynamic behavior of SC ISEs. PMID- 26005771 TI - Pre-assessment of dose rates of (134)Cs, (137)Cs, and (60)Co for marine biota from discharge of Haiyang Nuclear Power Plant, China. AB - Haiyang Nuclear Power Plant to be built in China was selected as a case for the dose pre-assessment for marine biota in this study. The concentrations of Cs and Co in organisms (turbot, yellow croaker, swimming crab, abalone, sea cucumber, and sea lettuce), seawater, and bottom sediment sampled on-site were measured by neutron activation analysis, and the site-specific transfer parameters (concentration ratios and distribution coefficients) of Cs and Co were calculated. (134)Cs, (137)Cs, and (60)Co activity concentrations in the organisms and the sediment at the site were calculated with the site-specific transfer parameters and the anticipated activity concentrations in the liquid effluent of the nuclear power plant. The ERICA tool was used to estimate the dose rates of (134)Cs, (137)Cs, and (60)Co to the selected organisms based on the biological models developed. The total dose rates of (134)Cs, (137)Cs, and (60)Co to the six organisms were all <0.001 MUGy h(-1). PMID- 26005772 TI - Time series study of a 17-year record of (7)Be and (210)Pb fluxes in northern Taiwan using ensemble empirical mode decomposition. AB - Using the ensemble empirical mode decomposition (EEMD) and a significance test method, we have analyzed time series data on the fluxes of (7)Be and (210)Pb collected over a span of 17 y in Northern Taiwan. Among nine intrinsic mode functions (IMFs) extracted from the method five (IMF4-8) are non-trivial for (210)Pb and have adequate S/N with significant power in localized windows around the periodicities of 0.5 y, 1 y, 2 y, 5 y, and 11 y, respectively. For (7)Be, IMF5 and IMF8 with periods around 1 y and 11 y, respectively, have adequate S/N. The semi-annual and annual cycles represented by IMF4 and IMF5, respectively, are dominated by East Asian monsoon. The sum of IMF6 and IMF7 reveals an inter-annual cycle where both (7)Be and (210)Pb fluxes are well-correlated with the East Asian winter monsoon index (EAWMI). The close tracking of the (210)Pb and (7)Be in IMF8 cases may reflect an 11 y cycle; implying that it is caused by common climatologic factors, likely related to solar cycle, rather than their distinct production modes. PMID- 26005774 TI - Continuous Microfluidic Particle Separation via Elasto-Inertial Pinched Flow Fractionation. AB - Many of the fluids encountered in chemical and biomedical applications exhibit non-Newtonian behavior. However, the majority of current particle separation methods have been demonstrated in Newtonian fluids only. This work presents an experimental study of continuous particle separation in viscoelastic solutions via a combined action of elastic and inertial lift forces, which we term elasto inertial pinched flow fractionation (eiPFF). The parametric effects on eiPFF are systematically investigated in terms of dimensionless numbers. It is found that eiPFF offers much higher particle throughput and separation resolution than the traditional steric effects-based PFF. Moreover, eiPFF works most efficiently when the Reynolds number, Re, is of order 1 and hence fills perfectly into the gap of our recently proposed inertia-enhanced PFF (iPFF) technique (Anal. Chem. 2015, 87, 4560-4565) that favors Re of the order 10 or more. However, the particle separation via eiPFF does not increase monotonically with the elasticity number at higher polymer concentrations and is strongly affected by the aspect ratio of channel width to height, both of which have not been previously reported. More surprisingly, the elasto-inertial deflection of small particles can be even greater than that of large particles in a high-aspect-ratio channel for Re less than 1. PMID- 26005773 TI - Serum levels, tissue expression and cellular secretion of macrophage migration inhibitory factor in limited and diffuse systemic sclerosis. AB - OBJECTIVES: To investigate serum levels, tissue/cellular expression of macrophage migration inhibitory factor (MIF) in patients with limited (lSSc) and diffuse (dSSc) systemic sclerosis. METHODS: 10 lSSc-patients, 10 dSSc-patients and 10 controls were enrolled. MIF serum levels were assayed by ELISA. MIF and its receptors CD74/CD44 were evaluated by immunohistochemistry on skin biopsies from patients with dSSc, lSSc (affected and not-affected skin) and controls. MIF levels were assessed (ELISA) in supernatants of healthy dermal microvascular endothelial cells (MVECs) and in control (CTR), non-affected SSc (NA) and affected (SSc) fibroblasts treated for 48 h with 10% control serum and 10% SSc serum. MIF supernatant (ELISA) and mRNA (quantitative real-time PCR) levels were determined in SSc dermal fibroblasts and in control dermal fibroblasts untreated or stimulated at 6 h-24 h-48 h with bleomycin (50 mU/ml). RESULTS: Serum MIF was significantly higher in dSSc (18.7+/-4.1 ng/ml, p<0.001) and in lSSc (10.4+/-4.4 ng/ml, p<0.001) patients respect to controls (2.6+/-1.4 ng/ml). Enhanced MIF immunoreactivity was found in keratinocytes, fibroblasts, endothelium, sebaceous/sweat glands from lSSc/dSSc affected skin. Faint MIF immunoreactivity was found in control skin and not-affected skin of lSSc patients. No differences were found in CD74/CD44 receptors' analysis among control and dSSc/lSSc affected and non-affected skin. MVECs and fibroblasts (CTR, NA and SSc) produced significantly more MIF, when stimulated with SSc serum respect to control-serum (p<0.001). Finally, MIF mRNA levels significantly increased at 6h (p<0.001) and decreased at 48 h (p<0.001) in control fibroblasts treated with bleomycin compared to control untreated. Simultaneously, MIF supernatant protein levels increased after 48 h (p<0.01) in bleomycin-treated fibroblasts respect to untreated ones. CONCLUSIONS: These results suggest that MIF could be implicated in the pathogenesis of SSc, probably acting as protective factor against the SSc stressful conditions. PMID- 26005775 TI - An investigation of neighborhood-level social, economic and physical factors for railway suicide in Victoria, Australia. AB - BACKGROUND: This study investigates the associations between railway suicide and neighborhood social, economic, and physical determinants using postcode-level data. It also examines whether the associations are influenced by having high concentration of high-risk individuals in a neighborhood area. METHODS: Railway suicide cases from Victoria, Australia for the period of 2001-2012, their age, sex, year of death, usual residential address and suicide location were obtained from the National Coronial Information System. Univariate negative binomial regression models were used to estimate the association between railway suicide and neighborhood-level social, economic and physical factors. Variables which were significant in these univariate models were then assessed in a multivariate model, controlling for age and sex of the deceased and other known confounders. RESULTS: Findings from the multivariate analysis indicate that an elevated rate of railway suicide was strongly associated with neighborhood exposure of higher number of railway stations (IRR=1.30 95% CI=1.16-1.46). Other significant neighborhood risk factors included patronage volume (IRR=1.06, 95% CI=1.02-1.11) and train frequency (IRR=1.02, 95% CI=1.01-1.04). An increased number of video surveillance systems at railway stations and carparks was significantly associated with a modest reduction in railway suicide risk (IRR=0.93, 95% CI=0.88 0.98). These associations were independent of concentration of high-risk individuals. LIMITATIONS: Railway suicide may be under-reported in Australia. CONCLUSIONS: Interventions to prevent railway suicide should target vulnerable individuals residing in areas characterized by high station density, patronage volume and train frequency. PMID- 26005776 TI - Simvastatin versus atorvastatin for improving mild to moderate depression in post coronary artery bypass graft patients: A double-blind, placebo-controlled, randomized trial. AB - BACKGROUND: A decreased risk of developing depression has been reported among statin users. Aside from their lipid-lowering effects, statins are considered immunomodulatory agents and have protective effects against oxidative stress and inflammation which are well known for their association with depression. The aim of the present study was to compare the probable antidepressant effects of simvastatin and atorvastatin among post-coronary artery bypass graft (CABG) surgery patients with high and low potentials for blood-brain-barrier penetration, respectively. METHOD: Forty-six outpatients who had undergone CABG in the last 6 months and suffered from mild to moderate depression participated in a parallel, double-blind, placebo-controlled trial, and were randomized to undergo 6 weeks of treatment with either simvastatin (20mg/day) or atorvastatin (20mg/day). Participants were evaluated using Hamilton depression rating scale (HDRS) at baseline and weeks 3 and 6. The primary outcome was to evaluate the efficacy of simvastatin in improving the depressive symptoms. RESULT: General linear model repeated measures demonstrated significant effect for time*treatment interaction on the HDRS scores [F (1.62, 71.06)=3.41, P=0.048]. There was no significant difference between the treatment groups regarding the adverse events. No one experienced serious adverse event. LIMITATION: The limitations of the present study were its small sample size and the short-term follow-up period. CONCLUSION: Treatment with simvastatin seems to be well tolerated with superior antidepressant effects compared to atorvastatin in post-CABG patients. Long-term outcomes of this practice and its probable influence on other psychological aspects are yet to be investigated in future studies. TRIAL REGISTRATION: Iranian registry of clinical trials (http://www.irct.ir): IRCT201410271556N68. PMID- 26005777 TI - Polymorphism in the promoter of the gene for the serotonin transporter affects the age of onset of major depressive disorder in the Japanese population. AB - OBJECTIVE: Recent research has suggested that a functional polymorphism in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region, 5HTTLPR) may be implicated in gene-environment interactions leading to major depressive disorder (MDD). METHODS: Our study examined the association between 5HTTLPR and clinical variables of MDD in the Japanese population. We genotyped 5HTTLPR in 216 patients with MDD and 213 age- and sex matched controls. RESULTS: The genotype distributions and allele frequencies were similar in the patients and controls. When the relationships between the polymorphism and several clinical variables (i.e., age of onset, number of episodes, presence of psychotic features, suicidal behavior, and family history) were examined, the dose of the long (l) allele had significant effects on the age of onset. CONCLUSION: These results suggest that 5HTTLPR may not be entirely related to the development of MDD but may be related to the age of onset of MDD, which may be due to gene-environment interactions in the Japanese population. LIMITATIONS: Because of the low frequencies of psychotic features and suicidal behavior, our results must be treated with caution until they are replicated in larger numbers of Japanese samples. MDD patients did not undergo a structured interview. Clinical information from the medical records may have not been complete. PMID- 26005778 TI - Lithium is associated with decrease in all-cause and suicide mortality in high risk bipolar patients: A nationwide registry-based prospective cohort study. AB - BACKGROUND: Mortality rates, in particular due to suicide, are especially high in bipolar patients. This nationwide, registry-based study analyses the associations of medication use with hospitalization due to attempted suicides, deaths from suicide, and overall mortality across different psychotropic agents in bipolar patients. METHOD: Altogether 826 bipolar patients hospitalized in Finland between 1996-2003 because of a suicide attempt were followed-up for a mean of 3.5 years. The relative risk of suicide attempts leading to hospitalization, completed suicide, and overall mortality during lithium vs. no-lithium, antipsychotic vs. no-antipsychotic, valproic acid vs. no-valproic acid, antidepressant vs. no antidepressant and benzodiazepine vs. no-benzodiazepine treatment was measured. RESULTS: The use of valproic acid (RR=1.53, 95% CI: 1.26-1.85, p<0.001), antidepressants (RR=1.49, 95% CI: 1.23-1.8, p<0.001) and benzodiazepines (RR=1.49, 95% CI: 1.23-1.80, p<0.001) was associated with increased risk of attempted suicide. Lithium was associated with a (non-significantly) lower risk of suicide attempts, and with significantly decreased suicide mortality in univariate (RR=0.39, 95% CI: 0.17-0.93, p=0.03), Cox (HR=0.37, 95% CI: 0.16-0.88, p=0.02) and marginal structural models (HR=0.31, 95% CI: 0.12-0.79, p=0.02). Moreover, lithium was related to decreased all-cause mortality by 49% (marginal structural models). LIMITATIONS: Only high-risk bipolar patients hospitalized after a suicide attempt were studied. Diagnosis was not based on standardized diagnostic interviews; treatment regimens were uncontrolled. CONCLUSIONS: Maintenance therapy with lithium, but not with other medications, is linked to decreased suicide and all-cause mortality in high-risk bipolar patients. Lithium should be considered for suicide prevention in high-risk bipolar patients. PMID- 26005779 TI - Microbiological analysis of pre-packed sweet basil (Ocimum basilicum) and coriander (Coriandrum sativum) leaves for the presence of Salmonella spp. and Shiga toxin-producing E. coli. AB - Enteric pathogens, such as Salmonella spp. and pathogenic Escherichia coli, have been detected and associated with food borne outbreaks from (imported) fresh leafy herbs. Screening on imported herbs from South East Asian countries has been described. However, limited information on prevalence of these pathogens is available from other sourcing regions. Therefore, fresh pre-packed basil and coriander leaves from a Belgian trading company were investigated for the presence of Salmonella spp., Shiga toxin-producing E. coli (STEC), generic E. coli and coliforms. In total 592 samples were collected originating from Belgium, Israel and Cyprus during 2013-2014. Multiplex PCR followed by further culture confirmation was used for the detection of Salmonella spp. and STEC, whereas the Petrifilm Select E. coli and VRBL-agar were used, respectively, for the enumeration of E. coli and coliforms. Salmonella was detected in 10 out of 592 samples (25g) (1.7%; 5 from basil and 5 from coriander), of which two samples were sourced from Israel and eight from Cyprus. The presence of STEC was suspected in 11 out of 592 samples (25g) (1.9%; 3 basil and 8 coriander), due to the detection of stx and eae genes, of which one sample originated from Belgium, four from Israel and six from Cyprus. No STEC was isolated by culture techniques, but in three samples a serotype (O26, O103 or O111) with its most likely associated eae-variant (beta or theta) was detected by PCR. Generic E. coli was enumerated in 108 out of 592 samples, whereby 55, 32 and 13 samples respectively between 10-100, 100-1000 and 1000-10,000cfu/g and 8 samples exceeding 10,000cfu/g. Coliforms were enumerated in all herb samples at variable levels ranging from 1.6 to 7.5logcfu/g. Further statistics indicate that the E. coli class (categorized by level) was significantly correlated with the presence of Salmonella (p<0.001) or STEC (p=0.019), while coliform counts were significant correlated with Salmonella (p<0.001), but not with STEC (p=0.405). Generic E. coli class is a better indicator for the presence of enteric pathogens than coliforms on fresh herbs, but the relationship between E. coli and Salmonella or STEC was not strong enough to provide a threshold value for E. coli to assure food safety (i.e. no pathogens present). Results indicate that fresh leafy herbs like basil and coriander sourced from different cultivation regions, may contain enteric pathogens and potentially pose a risk for human health. PMID- 26005780 TI - Discovery of 3-phenylquinolinylchalcone derivatives as potent and selective anticancer agents against breast cancers. AB - A number of 3-phenylquinolinylchalcone derivatives were synthesized and evaluated in vitro for their antiproliferative activities against three breast cancer cell lines (MCF-7, MDA-MB-231, and SKBR-3), and a non-cancer normal epithelial cell line (H184B5F5/M10). Among them, (E)-3-[3-(4-methoxyphenyl)quinolin-2-yl]-1 (3,4,5-trimethoxyphenyl)prop-2-en-1-one (7) was active against the growth of MCF 7, MDA-MB-231, and SKBR-3 with IC50 values of 1.05, 0.75, and 0.78 MUM respectively without significant cytotoxicity to the normal H184B5F5/M10 cell line and therefore, was selected as a new lead for further mechanism studies. Results indicated that compound 7 inhibited the polymerization of tubulins, induced G2/M cell cycle arrest via modulation of the cyclin B1, cdk1 and CDC25. Compound 7 ultimately induced cell apoptosis by the increase of apoptotic protein Bax and the decrease of anti-apoptotic protein Bcl-2. In addition, PARP was cleaved while caspase-3 and -8 activities were induced after the treatment of compound 7 for 24 h in a concentration-dependent manner. Thus, compound 7 induces cell cycle arrest at G2/M phase via cleavage of PARP, induces caspase-3 and -8 activities and consequently to cause the cell death. Further study on the structure optimization of 7 is ongoing. PMID- 26005782 TI - High Speed Size Sorting of Subcellular Organelles by Flow Field-Flow Fractionation. AB - Separation/isolation of subcellular species, such as mitochondria, lysosomes, peroxisomes, Golgi apparatus, and others, from cells is important for gaining an understanding of the cellular functions performed by specific organelles. This study introduces a high speed, semipreparative scale, biocompatible size sorting method for the isolation of subcellular organelle species from homogenate mixtures of HEK 293T cells using flow field-flow fractionation (FlFFF). Separation of organelles was achieved using asymmetrical FlFFF (AF4) channel system at the steric/hyperlayer mode in which nuclei, lysosomes, mitochondria, and peroxisomes were separated in a decreasing order of hydrodynamic diameter without complicated preprocessing steps. Fractions in which organelles were not clearly separated were reinjected to AF4 for a finer separation using the normal mode, in which smaller sized species can be well fractionated by an increasing order of diameter. The subcellular species contained in collected AF4 fractions were examined with scanning electron microscopy to evaluate their size and morphology, Western blot analysis using organelle specific markers was used for organelle confirmation, and proteomic analysis was performed with nanoflow liquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS). Since FlFFF operates with biocompatible buffer solutions, it offers great flexibility in handling subcellular components without relying on a high concentration sucrose solution for centrifugation or affinity- or fluorescence tag-based sorting methods. Consequently, the current study provides an alternative, competitive method for the isolation/purification of subcellular organelle species in their intact states. PMID- 26005781 TI - Probing allosteric mechanisms using native mass spectrometry. AB - Native mass spectrometry (MS) and ion mobility MS provide a way to discriminate between various allosteric mechanisms that cannot be distinguished using ensemble measurements of ligand binding in bulk protein solutions. Native MS, which yields mass measurements of intact assemblies, can be used to determine the values of ligand binding constants of multimeric allosteric proteins, thereby providing a way to distinguish, for example, between concerted and sequential allosteric models. Native MS can also be employed to study cooperativity owing to ligand modulated protein oligomerization. The rotationally averaged cross-section areas of complexes obtained by ion mobility MS can be used to distinguish between induced fit and conformational selection. Native MS and its allied techniques are, therefore, becoming increasingly powerful tools for dissecting allosteric mechanisms. PMID- 26005783 TI - Biogenic acids produced on epoxy linings installed in sewer crown and tidal zones. AB - In this study the biogenic acids generated by microbes on the surface of Bisphenol A epoxy mortar coupons were investigated for up to 30 months. The epoxy coupons were installed in six sewers in three city locations, Sydney, Melbourne and Perth. Coupons were installed in both the crown and the tidal zones of the sewers to capture the effect of location within the pipe on acid production. The coupons were retrieved approximately every 6 months to provide a dynamic analysis of the biogenic acid production. Our results reveal the colonisation of epoxy mortar by the more aggressive acidophilic bacteria occurred within six months to two years of their installation in the sewer pipes. Biogenic acid generation appear to occur homogeneously from the tidal zone to the crown of the sewer pipes. The reduction in the surface pH of the epoxy lining was supported by the successive growth of microbes beginning with fungi followed be neutrophilic and heterotrophic bacteria and finally by the acidophilic bacteria and the corresponding accumulation of organic and sulphuric acids attributed to these organisms. This study also revealed the potential inhibiting effects on the microbes induced by the accumulation of metabolic products on the epoxy surface. The accumulation of organic acids and H2S coincided with the growth and metabolism inhibition of fungi and acidophilic bacteria. These results provide insights into the microbial interaction and biogenic acids production that contribute to lining degradation and corrosion of concrete in sewer pipes. PMID- 26005784 TI - Isomeric specific partitioning behaviors of perfluoroalkyl substances in water dissolved phase, suspended particulate matters and sediments in Liao River Basin and Taihu Lake, China. AB - The occurrence and distribution of eleven perfluoroalkyl substances (PFASs) and the isomers of perfluorooctanoate (PFOA), perfluorooctanesulfonate (PFOS) and perfluorooctane sulfonamide (PFOSA) were investigated in water dissolved phase, sediment and suspended particulate matter (SPM) in two typical watersheds in China: Liao River Basin and Taihu Lake. The total concentrations of the PFASs in the dissolved phase were 44.4-781 ng/L in Liao River with high contribution of perfluorobutane sulfonate (PFBS) (75.7%) and PFOA (9.86%). The ?PFASs in the dissolved phase in Taihu Lake was 17.2-94.4 ng/L with PFOA (39.8%), perfluorohexanoate (PFHxA) (30.1%) and PFOS (16.8%) as the dominant PFASs. The log Koc values of the PFASs in both SPM and sediment increased with increasing the perfluorinated carbon chain length. In Liao River Basin, the long chain perfluorocarboxylates (C10-12) bound with SPM contributed >30% to the total amount in water, suggesting that SPM could not be ignored when the environmental load of long chain PFASs in water was assessed. For the isomers of PFOA, PFOS and PFOSA, the linear isomers always displayed higher partition coefficients on particulate phases than the branched ones. An established isomer-profiling technique was applied to assess the relative contributions of various industrial origins for PFOA. In Liao River, when SPM was included in the water samples, there were contributions of PFOA from electrochemical fluorination (ECF) (~55%), linear telomer (~41%) and isopropyl telomer (~4%) sources. While, the results based on the dissolved phase alone indicated more contribution of ECF (~70%) source and lower contribution from linear telomer (~26%) source. The discrepancy suggests that omitting SPM from water samples might lead to misunderstanding on the industrial origins of PFOA. In Taihu Lake, the isomer profile of PFOA was influenced mainly by ECF (~88%) and partially by linear-telomer (~12%) sources. PMID- 26005785 TI - High methylmercury production under ferruginous conditions in sediments impacted by sewage treatment plant discharges. AB - Sewage treatment plants (STPs) are important point sources of mercury (Hg) to the environment. STPs are also significant sources of iron when hydrated ferric oxide (HFO) is used as a dephosphatation agent during water purification. In this study, we combined geochemical and microbiological characterization with Hg speciation and sediment amendments to evaluate the impact of STP's effluents on monomethylmercury (MMHg) production. The highest in-situ Hg methylation was found close to the discharge pipe in subsurface sediments enriched with Hg, organic matter, and iron. There, ferruginous conditions were prevailing with high concentrations of dissolved Fe(2+) and virtually no free sulfide in the porewater. Sediment incubations demonstrated that the high MMHg production close to the discharge was controlled by low demethylation yields. Inhibition of dissimilatory sulfate reduction with molybdate led to increased iron reduction rates and Hg-methylation, suggesting that sulfate-reducing bacteria (SRB) may not have been the main Hg methylators under these conditions. However, Hg methylation in sediments amended with amorphous Fe(III)-oxides was only slightly higher than control conditions. Thus, in addition to iron-reducing bacteria, other non-SRB most likely contributed to Hg methylation. Overall, this study highlights that sediments impacted by STP discharges can become local hot-spots for Hg methylation due to the combined inputs of i) Hg, ii) organic matter, which fuels bacterial activities and iii) iron, which keeps porewater sulfide concentration low and hence Hg bioavailable. PMID- 26005786 TI - Fast formation of aerobic granules by combining strong hydraulic selection pressure with overstressed organic loading rate. AB - The combined strong hydraulic selection pressure (HSP) with overstressed organic loading rate (OLR) as a fast granulation strategy was used to enhance aerobic granulation. To investigate the wide applicability of this strategy to different scenarios and its relevant mechanism, different settling times, different inoculums, different exchange ratios, different reactor configurations, and different shear force were used in this study. It was found that clear granules were formed within 24 h and steady state reached within three days when the fast granulation strategy was used in a lab-scale reactor seeded with well settled activated sludge (Reactor 2). However, granules appeared after 2-week operation and reached steady state after one month at the traditional step-wise decreased settling time from 20 to 2 min with OLR of 6 g COD/L.d (Reactor 1). With the fast granulation strategy, granules appeared within 24 h even with bulking sludge as seed to start up Reactor 3, but 6-day lag phase was observed compared with Reactor 2. Both Reactor 2 and Reactor 3 experienced sigmoidal growth curve in terms of biomass accumulation and granule size increase after granulation. In addition, the reproducible results in pilot-scale reactors (Reactor 5 and Reactor 6) with diameter of 20 cm and height/diameter ratio (H/D) of 4 further proved that reactor configuration and fluid flow pattern had no effect on the aerobic granulation when the fast granulation strategy was employed, but biomass accumulation experienced a short lag phase too in Reactor 5 and Reactor 6. Although overstressed OLR was favorable for fast granulation, it also led to the fluffy granules after around two-week operation. However, the stable 6-month operation of Reactor 3 demonstrated that the rapidly formed granules were able to maintain long-term stability by reducing OLR from 12 g COD/L.d to 6 g COD/L.d. A mechanism of fast granulation with the strategy of combined strong HSP and OLR was proposed to explain results and guide the operation with this fast strategy. PMID- 26005787 TI - Performance and life cycle environmental benefits of recycling spent ion exchange brines by catalytic treatment of nitrate. AB - Salt used to make brines for regeneration of ion exchange (IX) resins is the dominant economic and environmental liability of IX treatment systems for nitrate contaminated drinking water sources. To reduce salt usage, the applicability and environmental benefits of using a catalytic reduction technology to treat nitrate in spent IX brines and enable their reuse for IX resin regeneration were evaluated. Hybrid IX/catalyst systems were designed and life cycle assessment of process consumables are used to set performance targets for the catalyst reactor. Nitrate reduction was measured in a typical spent brine (i.e., 5000 mg/L NO3(-) and 70,000 mg/L NaCl) using bimetallic Pd-In hydrogenation catalysts with variable Pd (0.2-2.5 wt%) and In (0.0125-0.25 wt%) loadings on pelletized activated carbon support (Pd-In/C). The highest activity of 50 mgNO3(-)/(min - g(Pd)) was obtained with a 0.5 wt%Pd-0.1 wt%In/C catalyst. Catalyst longevity was demonstrated by observing no decrease in catalyst activity over more than 60 days in a packed-bed reactor. Based on catalyst activity measured in batch and packed bed reactors, environmental impacts of hybrid IX/catalyst systems were evaluated for both sequencing-batch and continuous-flow packed-bed reactor designs and environmental impacts of the sequencing-batch hybrid system were found to be 38 81% of those of conventional IX. Major environmental impact contributors other than salt consumption include Pd metal, hydrogen (electron donor), and carbon dioxide (pH buffer). Sensitivity of environmental impacts of the sequencing-batch hybrid reactor system to sulfate and bicarbonate anions indicate the hybrid system is more sustainable than conventional IX when influent water contains <80 mg/L sulfate (at any bicarbonate level up to 100 mg/L) or <20 mg/L bicarbonate (at any sulfate level up to 100 mg/L) assuming 15 brine reuse cycles. The study showed that hybrid IX/catalyst reactor systems have potential to reduce resource consumption and improve environmental impacts associated with treating nitrate contaminated water sources. PMID- 26005788 TI - Impact of FeCl3 dosing on AnMBR treatment of municipal wastewater. AB - The long-term (90 days) impact of dosing FeCl3 on bioprocess performance and membrane performance in a pilot AnMBR fed with authentic sewage was evaluated. The addition of 26 mg/L of FeCl3 enhanced the performance of the AnMBR with respect to removal efficiencies of COD and BOD5, but did not have a significant influence on the removal efficiencies of TKN and TP and the methane yield. The membrane was operated at a constant flux of 17 LMH and its performance was significantly improved by dosing FeCl3. This was demonstrated by a reduction in the fouling that withstood scouring stresses to values lower than 5 kPa and negligible reversible fouling for the first 75 days. The superior membrane performance was consistent with the shift of particle size distribution to the particulate fraction and the reduced colloidal and soluble substances in the sludge, especially the soluble protein, carbohydrate, Ca and S. CLSM tests showed that the addition of FeCl3 resulted in a thicker foulant layer and the deposition of protein and carbohydrate on the membrane surface was significantly reduced. Therefore a more porous foulant layer was formed and this prevented the development of a strongly-attached cake layer and pore blocking. A recovery cleaning study indicated FeCl3 dosing enhanced the efficiency of the recovery cleaning protocol. The foulants formed with the Fe-dosed sludge had greater inorganic content, as 75% of the foulant resistance was removed by citric acid. The superior membrane performance during the operation combined with enhanced cleaning efficiency by FeCl3 dosing would significantly improve the sustainability of AnMBR in municipal wastewater treatment. PMID- 26005789 TI - Evaluation of poly (aspartic acid sodium salt) as a draw solute for forward osmosis. AB - Poly (aspartic acid sodium salt) (PAspNa) was evaluated for its potential as a novel draw solute in forward osmosis (FO). The inherent advantages of PAspNa, such as good water solubility, high osmotic pressure, and nontoxicity, were first examined through a series of physicochemical analyses and atomic-scale molecular dynamics simulations. Then, lab-scale FO tests were performed to evaluate its suitability in practical processes. Compared to other conventional inorganic solutes, PAspNa showed comparable water flux but significantly lower reverse solute flux, demonstrating its suitability as a draw solute. Moreover, fouling experiments using synthetic wastewater as a feed solution demonstrated that PAspNa reversely flowed to the feed side reduced inorganic scaling on the membrane active layer. The recyclability of PAspNa was studied using both nanofiltration (NF) and membrane distillation (MD) processes, and the results exhibited its ease of recovery. This research reported the feasibility and applicability of FO-NF or FO-MD processes using PAspNa for wastewater reclamation and brackish water desalination. PMID- 26005790 TI - Accuracy of latent-variable estimation in Bayesian semi-supervised learning. AB - Hierarchical probabilistic models, such as Gaussian mixture models, are widely used for unsupervised learning tasks. These models consist of observable and latent variables, which represent the observable data and the underlying data generation process, respectively. Unsupervised learning tasks, such as cluster analysis, are regarded as estimations of latent variables based on the observable ones. The estimation of latent variables in semi-supervised learning, where some labels are observed, will be more precise than that in unsupervised, and one of the concerns is to clarify the effect of the labeled data. However, there has not been sufficient theoretical analysis of the accuracy of the estimation of latent variables. In a previous study, a distribution-based error function was formulated, and its asymptotic form was calculated for unsupervised learning with generative models. It has been shown that, for the estimation of latent variables, the Bayes method is more accurate than the maximum-likelihood method. The present paper reveals the asymptotic forms of the error function in Bayesian semi-supervised learning for both discriminative and generative models. The results show that the generative model, which uses all of the given data, performs better when the model is well specified. PMID- 26005791 TI - The role of carbonic anhydrase in the pathogenesis of vascular calcification in humans. AB - Carbonic anhydrases are a group of isoenzymes that catalyze the reversible conversion of carbon dioxide into bicarbonate. They participate in a constellation of physiological processes in humans, including respiration, bone metabolism, and the formation of body fluids, including urine, bile, pancreatic juice, gastric secretion, saliva, aqueous humor, cerebrospinal fluid, and sweat. In addition, carbonic anhydrase may provide carbon dioxide/bicarbonate to carboxylation reactions that incorporate carbon dioxide to substrates. Several isoforms of carbonic anhydrase have been identified in humans, but their precise physiological role and the consequences of their dysfunction are mostly unknown. Carbonic anhydrase isoenzymes are involved in calcification processes in a number of biological systems, including the formation of calcareous spicules from sponges, the formation of shell in some animals, and the precipitation of calcium salts induced by several microorganisms, particularly urease-producing bacteria. In human tissues, carbonic anhydrase is implicated in calcification processes either directly by facilitating calcium carbonate deposition which in turn serves to facilitate calcium phosphate mineralization, or indirectly via its action upon gamma-glutamyl-carboxylase, a carboxylase that enables the biological activation of proteins involved in calcification, such as matrix Gla protein, bone Gla protein, and Gla-rich protein. Carbonic anhydrase is implicated in calcification of human tissues, including bone and soft-tissue calcification in rheumatological disorders such as ankylosing spondylitis and dermatomyositis. Carbonic anhydrase may be also involved in bile and kidney stone formation and carcinoma-associated microcalcifications. The aim of this review is to evaluate the possible association between carbonic anhydrase isoenzymes and vascular calcification in humans. PMID- 26005792 TI - Joining of Silver Nanomaterials at Low Temperatures: Processes, Properties, and Applications. AB - A review is provided, which first considers low-temperature diffusion bonding with silver nanomaterials as filler materials via thermal sintering for microelectronic applications, and then other recent innovations in low temperature joining are discussed. The theoretical background and transition of applications from micro to nanoparticle (NP) pastes based on joining using silver filler materials and nanojoining mechanisms are elucidated. The mechanical and electrical properties of sintered silver nanomaterial joints at low temperatures are discussed in terms of the key influencing factors, such as porosity and coverage of substrates, parameters for the sintering processes, and the size and shape of nanomaterials. Further, the use of sintered silver nanomaterials for printable electronics and as robust surface-enhanced Raman spectroscopy substrates by exploiting their optical properties is also considered. Other low temperature nanojoining strategies such as optical welding of silver nanowires (NWs) through a plasmonic heating effect by visible light irradiation, ultrafast laser nanojoining, and ion-activated joining of silver NPs using ionic solvents are also summarized. In addition, pressure-driven joining of silver NWs with large plastic deformation and self-joining of gold or silver NWs via oriented attachment of clean and activated surfaces are summarized. Finally, at the end of this review, the future outlook for joining applications with silver nanomaterials is explored. PMID- 26005793 TI - First review on psoriasis severity risk stratification: An engineering perspective. AB - Computer-aided diagnosis (CAD) systems have been used for characterization of several dermatologic diseases in the last few years. Psoriasis is a potentially life-threatening skin disease which affects 125 million people worldwide. The paper presents the first state-of-the-art review of technology solicitation in psoriasis along with its current practices, challenges and assessment techniques. The paper also conducts in-depth examination of the existing literature for all clinical parameters of Psoriasis Area and Severity Index (PASI) i.e., area, erythema, scaliness and thickness. We suggest a role of risk assessment using a decision support system for stratification of psoriasis in large populations. A balanced insight has been presented in all the components of the design, namely: feature extraction, feature selection, disease stratification and overall CAD performance evaluation. We conclude that CAD systems are promising for risk stratification and assessment of psoriasis. PMID- 26005794 TI - UV-Induced Proton Transfer between DNA Strands. AB - UV radiation creates excited states in DNA that lead to mutagenic photoproducts. Photoexcitation of single-stranded DNA can transfer an electron between stacked bases, but the fate of excited states in the double helix has been intensely debated. Here, photoinduced interstrand proton transfer (PT) triggered by intrastrand electron transfer (ET) is detected for the first time by time resolved vibrational spectroscopy and quantum mechanical calculations. Long-lived excited states are shown to be oppositely charged base pair radical ions. In two of the duplexes, the base pair radical anions are present as tautomers formed by interstrand PT. Charge recombination occurs on the picosecond time scale preventing the accumulation of damaging radicals or mutagenic tautomers. PMID- 26005795 TI - Detecting reactive drug metabolites for reducing the potential for drug toxicity. AB - INTRODUCTION: A number of withdrawn drugs are known to undergo bioactivation by a range of drug metabolizing enzymes to chemically reactive metabolites that bind covalently to protein and DNA resulting in organ toxicity and carcinogenesis, respectively. An important goal in drug discovery is to identify structural sites of bioactivation within discovery molecules for providing strategic modifications that eliminate or minimize reactive metabolite formation, while maintaining target potency, selectivity and desired pharmacokinetic properties leading to the development of efficacious and nontoxic drugs. AREAS COVERED: This review covers experimental techniques currently used to detect reactive drug metabolites and provides recent examples where information from mechanistic in vitro studies was successfully used to redesign candidate drugs leading to blocked or minimized bioactivation. Reviewed techniques include in vitro radiolabeled drug covalent binding to protein and reactive metabolite trapping with reagents such as glutathione, cyanide, semicarbazide and DNA bases. Case studies regarding reactive metabolite detection using a combination of varied techniques, including liquid chromatography-tandem mass spectrometry and NMR analyses and subsequent structural modification are discussed. EXPERT OPINION: Information derived from state-of-art mechanistic drug metabolism studies can be used successfully to direct medicinal chemistry towards the synthesis of candidate drugs devoid of bioactivation liabilities, while maintaining desired pharmacology and pharmacokinetic properties. PMID- 26005796 TI - Pd-Catalyzed Regioselective Alkoxycarbonylation of 1-Alkenes Using a Lewis Acid [SnCl2 or Ti(O(i)Pr)4] and a Phosphine. AB - The phosphine ligand mediated palladium catalyzed alkoxycarbonylation of alkenes was investigated with the objective of attaining good linear selectivity for the ester. The effect of various parameters such as solvents, additives, palladium precursors, CO pressures, and alkenes of various structural complexities were examined. The results revealed the importance of using a Lewis acid such as SnCl2 or Ti(O(i)Pr)4 in combination with a monodentate ligand such CYTOP 292 or P(p anisyl)3 to enhance the regioselectivity for the linear isomers in the range of 70-96%. PMID- 26005797 TI - Controlling nanoparticles dispersion in ionic liquids by tuning the pH. AB - HYPOTHESIS: Getting colloidally stable dispersions of nanoparticles in ionic liquids is a challenging task. Indeed, long-range electrostatic repulsions often involved in molecular solvents are screened in ionic liquids and cannot counterbalance the interparticle attractions. Using a polyelectrolyte coating should provide a good stabilisation of the nanoparticles. Investigating the role of the polyelectrolyte charge on the dispersion state should yield to a better comprehension of the stabilisation mechanisms. EXPERIMENTS: Polyacrylate coated maghemite nanoparticles were transferred from water to ethylammonium nitrate, a protic ionic liquid, for various polymer chain length and nanoparticles size. Titrations of coated nanoparticles and of free polymer chains were performed in water and in ethylammonium nitrate. The dispersion state of the nanoparticles was monitored at different pH by small-angle X-ray scattering. FINDINGS: Polyacrylate coating stabilised the nanoparticles in ethylammonium nitrate. However, reversible aggregation with the pH was observed. Surprisingly, this control was not directly related to the surface charge like in water but to the solvent quality for the polyelectrolyte. This study is the first report on the use of the pH to tune the dispersion state of nanoparticles in an ionic liquid. It provides a better understanding of the mechanisms responsible for colloidal stability in ionic liquids. PMID- 26005798 TI - Adsorption of cadmium(II) on waste biomaterial. AB - Significant increase of the adsorption ability of the eggshell biomaterial toward cadmium was observed upon milling, as is evidenced by the value of maximum monolayer adsorption capacity of 329mgg(-1), which is markedly higher than in the case of most "green" sorbents. The main driving force of the adsorption was proven to be the presence of aragonite phase as a consequence of phase transformation from calcite occurring during milling. Cadmium is adsorbed in a non-reversible way, as documented by different techniques (desorption tests, XRD and EDX measurements). The optimum pH for cadmium adsorption was 7. The adsorption process was accompanied by the increase of the value of specific surface area. The course of adsorption has been described by Langmuir, Freundlich and Dubinin-Radushkevich isotherms. The adsorption kinetics was evaluated using three models, among which the best correlation coefficients and the best normalized standard deviation values were achieved for the pseudo-second order model and the intraparticle diffusion model, respectively. PMID- 26005799 TI - Spinel type CoFe oxide porous nanosheets as magnetic adsorbents with fast removal ability and facile separation. AB - Adsorption is often time consuming due to slow diffusion kinetic. Sizing he adsorbent down might help to accelerate adsorption. For CoFe spinel oxide, a magnetically separable adsorbent, the preparation of nanosheets faces many challenges including phase separation, grain growth and difficulty in preparing two-dimensional materials. In this work, we prepared porous CoFe oxide nanosheet with chemical formula of Co2.698Fe0.302O4 through topochemical transformation of a CoFe precursor, which has a layered double hydroxide (LDH) analogue structure and a large interlayer spacing. The LDH precursor was synthesized from a cheap deep eutectic solvent (DES) system. The calcined Co2.698Fe0.302O4 has small grain size (10-20nm), nanosheet morphology, and porous structure, which contribute to a large specific surface area of 79.5m(2)g(-1). The Co2.698Fe0.302O4 nanosheets show fast removal ability and good adsorption capacity for both organic waste (305mgg(-1) in 5min for Congo red) and toxic heavy metal ion (5.27mgg(-1) in 30min for Cr (VI)). Furthermore, the Co2.698Fe0.302O4 can be separated magnetically. Considering the precursor can be prepared through a fast, simple, surfactant-free and high-yield synthetic strategy, this work should have practical significance in fabricating adsorbents. PMID- 26005801 TI - Erratum to: Highest Impact Articles in Microsurgery: A Citation Analysis. PMID- 26005800 TI - Prognostic significance of quantitative assessment of focal myocardial fibrosis in patients with heart failure with preserved ejection fraction. AB - BACKGROUND: The aim of this study was to investigate the prognostic value of myocardial focal fibrosis quantified by late gadolinium enhanced (LGE) magnetic resonance imaging (MRI) in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: One-hundred eleven HFpEF patients (mean age: 70 +/- 14 years, 55 (50%) female) were enrolled. We excluded patients with previous history of coronary artery disease and/or ischemic pattern of hyper enhancement on LGE MRI. Myocardial enhancement was defined using signal intensity >2SD above the mean signal intensity of a remote myocardium. Major adverse cardiovascular events were defined as cardiovascular death and heart failure requiring hospitalization. RESULTS: During a mean follow up period of 851 +/- 609 days, 10 events (2 cardiovascular death, 8 hospitalization for heart failure decompensation) were observed. Area under the receiver operating characteristics curve of LGE% for the detection of future events was 0.721 (95% CI: 0.628-0.802). Multivariate Cox proportional hazard analysis showed that LGE% is an independent predictor of future events after the adjustment with prognostic 5 factors - age, diabetes mellitus, New York Heart Association classification, history of heart failure hospitalization and left ventricular ejection fraction - which were identified in the I-PRESERVE study (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (hazard ratio=7.913, 95% CI: 1.603-39.05, P=0.012). CONCLUSIONS: Larger size of LGE was significantly associated with high rate of future cardiovascular death and heart failure hospitalization, suggesting that the quantification of myocardial focal fibrosis by LGE MRI could be useful for the risk stratification in HFpEF patients. PMID- 26005802 TI - Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome. AB - BACKGROUND: Patients with Marfan syndrome (MFS) have a highly variable occurrence of aortic complications. Aortic tortuosity is often present in MFS and may help to identify patients at risk for aortic complications. METHODS: 3D-visualization of the total aorta by MR imaging was performed in 211 adult MFS patients (28% with prior aortic root replacement) and 20 controls. A method to assess aortic tortuosity (aortic tortuosity index: ATI) was developed and reproducibility was tested. The relation between ATI and age, and body size and aortic dimensions at baseline was investigated. Relations between ATI at baseline and the occurrence of a clinical endpoint (aortic dissection, and/or aortic surgery) and aortic dilatation rate during 3 years of follow-up were investigated. RESULTS: ATI intra and interobserver agreements were excellent (ICC: 0.968 and 0.955, respectively). Mean ATI was higher in 28 age-matched MFS patients than in the controls (1.92 +/- 0.2 vs. 1.82 +/- 0.1, p=0.048). In the total MFS cohort, mean ATI was 1.87 +/- 0.20, and correlated with age (r=0.281, p<0.001), aortic root diameter (r=0.223, p=0.006), and aortic volume expansion rate (r=0.177, p=0.026). After 49.3 +/- 8.8 months follow-up, 33 patients met the combined clinical endpoint (7 dissections) with a significantly higher ATI at baseline than patients without endpoint (1.98 +/- 0.2 vs. 1.86 +/- 0.2, p=0.002). Patients with an ATI>1.95 had a 12.8 times higher probability of meeting the combined endpoint (log rank-test, p<0.001) and a 12.1 times higher probability of developing an aortic dissection (log rank-test, p=0.003) compared to patients with an ATI<1.95. CONCLUSIONS: Increased ATI is associated with a more severe aortic phenotype in MFS patients. PMID- 26005803 TI - Lower cardiovascular mortality with atorvastatin and rosuvastatin vs simvastatin: Data from "moderate-intensity" statin users in an observational registry on chronic heart failure (Daunia Heart Failure Registry). PMID- 26005804 TI - Usefulness of 3D SPECT/CT fusion image in CTEPH. PMID- 26005805 TI - Imaging of myocardial inflammation with somatostatin receptor based PET/CT - A comparison to cardiac MRI. AB - BACKGROUND: Acute myocarditis as well as post-ischemic myocardial inflammation are generally associated with a profound activation of the immune system. Current established imaging techniques such as cardiac MRI reliably demonstrate signs of acute myocardial injury. However, detection of mediating cells such as macrophages is currently limited to experimental settings. We aimed to investigate the feasibility of somatostatin receptor (SSTR) based positron emission tomography/computed tomography (PET/CT) for detecting inflammatory lesions in patients after acute myocardial infarction or acute peri-/myocarditis. METHODS: 12 patients with active peri-/myocarditis (n=6) or sub-acute myocardial infarction (n=6) underwent SSTR-PET/CT and cardiac MRI within 3-10 days after onset of symptoms. The AHA 17-segment model of the left myocardium was used for visual localization of inflamed myocardium for both imaging modalities. Tracer uptake of infarcted/inflamed myocardium was assessed as mean and maximum standardized uptake value (SUVmean and SUVmax) and compared with both remote myocardium and left ventricular (LV) cavity. RESULTS: SSTR-PET/CT revealed areas with increased cardiac tracer uptake in all patients. In the 17-segment model, PET/CT yielded 55 and MRI 47 positive segments. Overall, concordance of the 2 modalities was 85.3% (174/204 segments analyzed). In 9.3% (19/204), more positive segments were identified by PET/CT, whereas in 5.4% (11/204), MRI detected more positive segments. CONCLUSIONS: The imaging patterns of SSTR-directed radiotracers and MRI in vivo show a close spatial relation of macrophage concentration and structural changes. This suggests the possibility of a new potential biomarker that predicts cardiac remodeling and, hence, progression towards heart failure. Prospective trials are warranted. PMID- 26005806 TI - The cardiomyopathy in Friedreich's ataxia - New biomarker for staging cardiac involvement. AB - BACKGROUND: Patients with autosomal-recessively inherited Friedreich's ataxia (FA) may develop a hypertrophic cardiomyopathy (CM), which potentially progresses towards a life-limiting problem. The typical features of this CM and the sequence of progression are widely unknown. METHODS: Thirty-two consecutive patients with genetically confirmed FA were included. All patients received resting electrocardiogram (ECG), 24-hour Holter-ECG, echocardiography with speckle tracking imaging, cardiac magnetic resonance imaging (cMRI) with late enhancement imaging (for replacement fibrosis), and measurement of high-sensitive troponin-T (hsTNT). In addition, morphological parameters were retrospectively compared to data obtained five years before. RESULTS: Based on criteria comprising ejection fraction (<55%), left ventricular end-diastolic posterior wall thickness (LVPWT >= 11 mm), fibrosis on cMRI, hsTNT >= 14 ng/ml, or T-wave-inversion, in all but two patients a CM could be detected (94%). Using these criteria we propose the following staging: a) mild CM (n=5, 16%; T-wave-inversion only); b) intermediate CM (n=4, 13%; T-wave-inversion with hypertrophy but no fibrosis); c) severe CM (n=13, 41%; fibrosis with raised hsTNT); and d) end-stage CM (n=8; 25%; ejection fraction<55%). All patients with end-stage CM also showed fibrosis on cMRI, T wave-inversion, marked elevation in hsTNT, and a decrease in LVPWT during the last five years (from 10.7 +/- 1.2mm to 9.5 +/- 1.3mm, p=0.025). In addition, 38% suffered from supraventricular tachycardia on Holter-ECG. CONCLUSIONS: A comprehensive cardiac assessment will unravel established CM in almost all patients with FA with electrocardiographic abnormalities as earliest signs. Advanced stages can be characterized by elevated hsTNT and replacement fibrosis leading to recession of hypertrophy, reduction of global myocardial function, and electrical instability. PMID- 26005807 TI - Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. PMID- 26005808 TI - Association between weekend admission and in-hospital mortality for pulmonary embolism: An observational study and meta-analysis. PMID- 26005809 TI - Active Tracing and Monitoring of Contacts Associated With the First Cluster of Ebola in the United States. AB - BACKGROUND: Following hospitalization of the first patient with Ebola virus disease diagnosed in the United States on 28 September 2014, contact tracing methods for Ebola were implemented. OBJECTIVE: To identify, risk-stratify, and monitor contacts of patients with Ebola. DESIGN: Descriptive investigation. SETTING: Dallas County, Texas, September to November 2014. PARTICIPANTS: Contacts of symptomatic patients with Ebola. MEASUREMENTS: Contact identification, exposure risk classification, symptom development, and Ebola. RESULTS: The investigation identified 179 contacts, 139 of whom were contacts of the index patient. Of 112 health care personnel (HCP) contacts of the index case, 22 (20%) had known unprotected exposures and 37 (30%) did not have known unprotected exposures but interacted with a patient or contaminated environment on multiple days. Transmission was confirmed in 2 HCP who had substantial interaction with the patient while wearing personal protective equipment. These HCP had 40 additional contacts. Of 20 community contacts of the index patient or the 2 HCP, 4 had high-risk exposures. Movement restrictions were extended to all 179 contacts; 7 contacts were quarantined. Seven percent (14 of 179) of contacts (1 community contact and 13 health care contacts) were evaluated for Ebola during the monitoring period. LIMITATION: Data cannot be used to infer whether in-person direct active monitoring is superior to active monitoring alone for early detection of symptomatic contacts. CONCLUSION: Contact tracing and monitoring approaches for Ebola were adapted to account for the evolving understanding of risks for unrecognized HCP transmission. HCP contacts in the United States without known unprotected exposures should be considered as having a low (but not zero) risk for Ebola and should be actively monitored for symptoms. Core challenges of contact tracing for high-consequence communicable diseases included rapid comprehensive contact identification, large-scale direct active monitoring of contacts, large-scale application of movement restrictions, and necessity of humanitarian support services to meet nonclinical needs of contacts. PRIMARY FUNDING SOURCE: None. PMID- 26005810 TI - Predicting the reaction rate constants of micropollutants with hydroxyl radicals in water using QSPR modeling. AB - Quantitative structure-property relationship (QSPR) models which predict hydroxyl radical rate constants (kOH) for a wide range of emerging micropollutants are a cost effective approach to assess the susceptibility of these contaminants to advanced oxidation processes (AOPs). A QSPR model for the prediction of kOH of emerging micropollutants from their physico-chemical properties was developed with special attention to model validation, applicability domain and mechanistic interpretation. In this study, 118 emerging micropollutants including those experimentally determined by the author and data collected from the literature, were randomly divided into the training set (n=89) and validation set (n=29). 951 DRAGON molecular descriptors were calculated for model development. The QSPR model was calibrated by applying forward multiple linear regression to the training set. As a result, 7 DRAGON descriptors were found to be important in predicting the kOH values which related to the electronegativity, polarizability, and double bonds, etc. of the compounds. With outliers identified and removed, the final model fits the training set very well and shows good robustness and internal predictivity. The model was then externally validated with the validation set showing good predictive power. The applicability domain of the model was also assessed using the Williams plot approach. Overall, the developed QSPR model provides a valuable tool for an initial assessment of the susceptibility of micropollutants to AOPs. PMID- 26005813 TI - [Totally laparoscopic gastrectomy for the treatment of gastric tumors]. AB - BACKGROUND: The laparoscopic approach for the treatment of gastric tumors has many advantages. AIM: To evaluate the results of a laparoscopic gastrectomy program developed in a public hospital. PATIENTS AND METHODS: Retrospective review of epidemiological, perioperative and follow-up data of patients who were treated with a laparoscopic gastrectomy due to gastric tumors between 2006 and 2013. A totally laparoscopic technique was used for all cases. Complications were evaluated according to the Clavien-Dindo classification. RESULTS: Fifty one patients, aged 65 (36-85) years, underwent a laparoscopic gastrectomy. In 22 patients a total gastrectomy was performed. Conversion rate to open surgery was 8%. Operative time was 330 (90-500) min and bleeding was 200 (20-500) ml. Median hospital stay was 7 (3-37) days. Postoperative morbidity was present in 17 (33%) patients, 3 (6%) patients had complications grade 3 or higher and one patient died (1.9%). Tumor pathology was adenocarcinoma in 39 patients. A complete resection was achieved in 97%. Twenty nine patients (74%) with gastric adenocarcinoma had early gastric cancer and 84% of patients were in stage one. Median lymph node count was 24. Median follow-up was 26 (1-91) months. There was no cancer related mortality among patients subjected to a curative resection. Overall survival for patients with adenocarcinoma was 92% at 3 years. CONCLUSIONS: This study supports the feasibility and safety of a laparoscopic gastrectomy program in a public hospital; with low morbidity, adequate lymph node dissection and long-term survival. This approach must be considered an option for selected patients with gastric cancer. PMID- 26005812 TI - Dexterous robotic manipulation of alert adult Drosophila for high-content experimentation. AB - We present a robot that enables high-content studies of alert adult Drosophila by combining operations including gentle picking; translations and rotations; characterizations of fly phenotypes and behaviors; microdissection; or release. To illustrate, we assessed fly morphology, tracked odor-evoked locomotion, sorted flies by sex, and dissected the cuticle to image neural activity. The robot's tireless capacity for precise manipulations enables a scalable platform for screening flies' complex attributes and behavioral patterns. PMID- 26005811 TI - Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. AB - The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex-like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro. PMID- 26005814 TI - [Resistance exercise improves serum lipids in adult women]. AB - BACKGROUND: Sedentariness is one of the main cardiovascular risk factors. Aerobic exercise can reduce the risk; however, resistance training seems to be more effective in reducing cardiovascular risk. AIM: To determine the metabolic effects of a 12 weeks resistance training program of high intensity and low volume in two groups of sedentary adult women. MATERIAL AND METHODS: Forty women aged between 30 and 60 years were randomly assigned to an experimental group and a control group. Four kinds of strength exercises, using their own body weight were chosen. Plasma lipid profile and body composition were measured at baseline and at the end of the intervention. RESULTS: A reduction in total cholesterol and triacylglycerol and an increase in HDL cholesterol was observed in the experimental group after the training program. CONCLUSIONS: The high intensity and low volume training improved plasma lipid profile in this group of women. PMID- 26005815 TI - [Age of onset of puberty in Chilean boys according to testicular volume and Tanner stage]. AB - BACKGROUND: A secular trend towards a younger age of puberty onset has been reported in Chilean girls. AIM: To evaluate the age of onset of puberty and prevalence of early puberty in Chilean boys. MATERIAL AND METHODS: A pediatric endocrinologist examined 319 children attending schools in central Santiago. Pubertal development was assessed by testicular volume (TV) and genital inspection (GI) using Tanner graduation. Precocious and early puberty development was diagnosed if TV >= 4 ml or GI > stage 2 occurred in boys younger than 9 years and at 9-10 years of age, respectively. RESULTS: Pubertal onset occurred at 10.2 +/- 1.5 years according to TV and at 11.1 +/- 1.6 years according to GI (p < 0.01). Before the age of nine, 15.2% of children had a VT >= 4 ml, 3% had genital changes in GI and only 3% had both changes simultaneously. Early puberty was observed in 23.8% of children according to TV and 9.5% according to GI. However, no child of less than 11 years old had a TV >= 4 ml, genital changes and pubic hair simultaneously. Late pubertal stages occurred at the same age according to both criteria used. Body mass index z score was not associated with the age of pubertal onset. CONCLUSIONS: Testicular enlargement occurs one year earlier than changes in genitalia according to inspection. Testicular growth, but not late stages of puberty, are occurring one year earlier than previously reported in Chile 10 years ago. PMID- 26005816 TI - [Facioscapulohumeral muscular dystrophy: Report of seven patients]. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy is the third most common muscular dystrophy with an estimated prevalence of 1 per 20.000 and a normal life expectancy in the majority of patients. However, approximately 15% of patients become wheelchair bound in the course of their life. It is a hereditary autosomal dominant disease with high (95%) penetrance by the age of 20, but with variable degree of phenotypic expression even in the same family group. Symptoms frequently start in the second decade of life, with facial and scapular weakness. AIM: To report the clinical features of seven patients with the disease, seen at a public hospital. MATERIAL AND METHODS: Analysis of seven patients with genetic study seen in a public Hospital in Santiago. RESULTS: The age of patients fluctuated from 18 to 61 years and four were females. The mean age at onset of symptoms was 29 years and four had a family history of the disease. The usual presenting complaint was arm or shoulder asymmetric weakness. Four patients had bone pain. Facial involvement was present in four. A genetic study was done in five patients, the other two patients were relatives, confirming the contraction or lower number of repetitions in D4Z4 region. After 12 years of follow up only 2 patients older than 60 years cannot work and one female patients is in a semi dependent state at the age of 30. CONCLUSIONS: The clinical workup in the diagnosis and the timely indication of genetic studies are highlighted, to avoid unnecessary and invasive procedures. The variability in the phenotypic expression in a similar genetic defect is discussed and the genetic or epigenetic mechanisms of this muscular dystrophy are described. PMID- 26005817 TI - [Molecular analysis of sporadic colon cancer]. AB - BACKGROUND: In Chile, colorectal cancer (CRC) is often diagnosed in late stages. Thus, surgical treatment must be complemented with chemotherapy. KRAS mutations and microsatellite instability have been detected in these tumors. However, the response to treatment in patients without KRAS mutations varies and requires a better understanding. AIM: To determine the frequency and distribution of somatic point mutations in KRAS, BRAF and PIK3CA genes and microsatellite instability status (MSI) in patients with colon cancer (CC). MATERIAL AND METHODS: A prospective observational study of patients undergoing surgery for colon cancer. Tumor-derived DNA was analyzed by polymerase chain reaction (PCR) for the most frequent mutations of KRAS, BRAF and PIK3CA. PCR was also used to analyze MSI. RESULTS: Fifty-eight patients with sporadic CC were analyzed, 16 showed KRAS mutations (G12R, G12D, G12V, G13D) and out of the 42 patients that did not show any mutation, 10 had mutations in BRAF (V600E) and PIK3CA (E542K, E545D, E545K, Q546E, H1047R). BRAF mutations alone or in combination with PIK3CA mutations were observed in 27% of high MSI tumors and in 2% of tumors without instability (p < 0.049). A higher percentage of high MSI tumors were located in the right colon (p < 0.001), and showed BRAF mutation (p < 0.020). CONCLUSIONS: The highest percentage of high MSI and BRAF mutations was observed in the right colon. Therefore, this study suggests the presence of different molecular features between right and left colon tumors that should be considered when defining the therapeutic management. PMID- 26005819 TI - [Assessment for learning: experience in an undergraduate medical theoretical course]. AB - BACKGROUND: Assessment for learning is a paradigm that is taking shape in the field of medical education. This approach aims to embed the assessment process within the educational and learning process. AIM: To evaluate the impact of curricular changes, from a focus of assessment of learning to one of assessment for learning, in the perception of undergraduate students of medicine and their final grades obtained in a theoretical course (TCG). MATERIAL AND METHODS: In the year 2011 lectures were reduced and intermediate assessments followed by a feedback session were introduced. The activities of each program course, surveys about student perceptions of the course and the final grades of students (assessments with multiple choice questions) were compared between the periods prior and after curricular changes (2005-2010 and 2011-2013). RESULTS: As a consequence of curricular changes, time for lectures was reduced by 19.5%, time for summative assessments was increased by 8.5%, and feedback activity, occupying 7.3% of the course time was added. There were significant improvements in student is perceptions in all areas assessed by surveys, emphasizing feedback and assessments. The overall grade assigned to the course dictated after implementing the changes increased from 6.18 to 6.59 (p < 0.001, 1-7 scale). The grades of students also improved from an average of 5.78 to 6.43 (p < 0.001, 1-7 scale). CONCLUSIONS: Assessment for learning achieved the desired educational impact without increasing the assigned curricular time. Programmatic assessment is favorably perceived by students. PMID- 26005818 TI - [Suicide attempts among Chilean adolescents]. AB - BACKGROUND: Suicide mortality rates are increasing among teenagers. AIM: To study the prevalence and predictive factors of suicide attempts among Chilean adolescents. MATERIAL AND METHODS: A random sample of 195 teenagers aged 16 +/- 1 years (53% males) answered an anonymous survey about their demographic features, substance abuse, the Osaka suicidal ideation questionnaire, Smilksten familial Apgar. Beck hopelessness scale, Beck depression scale and Coppersmith self-esteem inventory. RESULTS: Twenty five percent of respondents had attempted suicide at least in one occasion during their lives. These attempts were significantly associated with female gender, absent parents, family dysfunction, drug abuse, smoking, low self-esteem, hopelessness, depression and recent suicidal ideation. A logistic regression analysis accepted female gender, smoking and recent suicidal ideation as significant independent predictors of suicide attempt. CONCLUSIONS: Suicide attempted is common among teenagers and its predictors are female sex, smoking and previous suicidal ideation. PMID- 26005820 TI - [Health and humanization Diploma: the value of reflection and face to face learning]. AB - BACKGROUND: In a rapidly changing culture like ours, with emphasis on productivity, there is a strong need to find the meaning of health care work using learning instances that privilege reflection and face to face contact with others. The Diploma in Health and Humanization (DSH), was developed as an interdisciplinary space for training on issues related to humanization. AIM: To analyze the experience of DSH aiming to identify the elements that students considered key factors for the success of the program. MATERIAL AND METHODS: We conducted a focus group with DSH graduates, identifying factors associated with satisfaction. Transcripts were coded and analyzed by two independent reviewers. RESULTS: DSH graduates valued a safe space, personal interaction, dialogue and respect as learning tools of the DSH. They also appreciates the opportunity to have emotional interactions among students and between them and the teacher as well as the opportunity to share personal stories and their own search for meaning. DISCUSSION: DSH is a learning experience in which their graduates value the ability to think about their vocation and the affective interaction with peers and teachers. We hope to contribute to the development of face to face courses in the area of humanization. Face to face methodology is an excellent teaching technique for contents related to the meaning of work, and more specifically, to a group of learners that require affective communication and a personal connection of their work with their own values and beliefs. PMID- 26005821 TI - [Professional liability claims against dentists]. AB - BACKGROUND: The frequency and features of malpractice lawsuits against dentists in Chile are not well known. AIM: To determine the magnitude and frequency of professional liability claims against dentists. MATERIAL AND METHODS: A retrospective analysis of the Medical Liability Unit of the Legal Medical Service of Chile database. This public organization deals with most professional liability claims in Chile. RESULTS: Between 2007 and 2012, 3,990 expert opinions about liability of health care professionals were requested. Odontology was the fifth specialty most commonly sued and dentists, the second most frequently sued professionals. Sixty nine percent of cases originated in private clinics, which is coincident with a higher frequency of dentists working in private practice. Most petitioners were adult women and most claims originated from surgical interventions and infections. In 35% of claims against dentists, a violation of Lex Artis was confirmed, compared with 9% of all expert opinions that generated in the unit. CONCLUSIONS: Claims against dentists are more common than previously thought and these professionals should adopt preventive measures to avoid them. PMID- 26005822 TI - [Clinical implications of the "war against cancer"]. AB - This article discusses the origin and implications of the "war on cancer" metaphor. Commonly present in mass media, the "war on cancer" notion circulates also among patients, their loved ones, their support networks, and oncological multidisciplinary teams. In our view when cancer is uprooted of its illness status, and conceptualized as an "enemy", myths about disease and those who suffer it (especially the idea of psychogenesis) are strengthened. Two topics in which the war metaphor is particularly problematic in the clinical context, are analyzed in depth. The first one is the relationship between the oncologic patient and his or her loved ones and support networks. When patients are insistently prompted to fight the disease and think positive, the expression of emotions associated to the adaptive process of receiving a diagnosis of cancer may be inhibited. Secondly, the war metaphor promotes an authoritarian view among the health teams and on the physician-patient relationship, undermining the patent's autonomy in the decision-making process, which may affect his global quality of life. Also, it encourages emotional isolation, concealment of psychiatric symptoms and conspiracies of silence. It is concluded that public policies to avoid the "war on" notion are required. Instead, education of the general population about wrong beliefs about cancer should be encouraged. PMID- 26005823 TI - [Some current threats to confidentiality in medicine]. AB - Social, technical and legal conditions of the current practice of medicine make it necessary to insist on certain actions and circumstances that may jeopardize the confidentiality of information, offered by patients to their health providers. Therefore, some effects of the current Chilean law are analyzed in this respect, regarding access to data from the clinical record of a patient. Also, the risks of putting certain data on social networking sites are analyzed, as well as some of its effects on clinical practice. The reasons because of mandatory reporting of diseases, meaning danger to public health, is allowed, are mentioned. We also discuss the difficulties involved in managing the results of preventative health screenings and its knowledge by third parties, as well as some possible violations of personal privacy, regarding dissemination of some people health information and its further mention or figuration in mass media. We conclude that it is a must for both physicians and other health team members, to safeguard confidentiality of data to which they have had access, as well as the need to know the relevant law, in order to respect human dignity of patients, each one as a person. We address the attention to the possibility that, practicing in a different way, it could endanger the reliability of clinical records, also impairing the quality of people's health care. PMID- 26005824 TI - [Association between non-nutritive sweeteners and obesity risk among university students in Latin America]. AB - BACKGROUND: The association between non-nutritive sweeteners and obesity is controversial. AIM: To determine whether the consumption of non-nutritive sweeteners is related to higher risk for overweight or obesity among university students in Chile, Panama, Guatemala and Peru. MATERIAL AND METHODS: A total of 1,224 (472 from Chile, 300 from Panama, 248 from Guatemala and 204 from Peru) male and female university students aged between 18 and 26 years participated in the study. Each student reported their food intake (frequency of weekly consumption) in a survey that contained photos of foods containing non-nutritive sweeteners adapted for each country. Anthropometry was also measured. RESULTS: More than 80% of students consumed at least one product containing non-nutritive sweeteners. Females who ate acesulfame potassium and sucralose had a lower risk of overweight or obesity with an odds ratio (OR) of 0.5 (confidence intervals (CI) = 0.3-0.9; p = 0.003) and OR = 0.4 (IC = 0.2-0.8; p = 0.01), respectively. CONCLUSIONS: In this sample of Latinamerican university students, consumption of non-nutritive sweeteners was associated with lower risk of overweight only in females. PMID- 26005825 TI - [Factors associated with self-directed learning among medical students]. AB - BACKGROUND: Self-directed learning is a skill that must be taught and evaluated in future physicians. AIM: To analyze the association between self-directed learning, self-esteem, self-efficacy, time management and academic commitment among medical students. MATERIAL AND METHODS: The self-directed learning, Rosemberg self-esteem, general self- efficacy, time management and Utrecht work engagement scales were applied to 297 first year medical students. RESULTS: A multiple regression analysis showed a significant association between self efficacy, time management and academic commitment with self-directed learning. Self-esteem and satisfaction with studies did not enter in the model. CONCLUSIONS: self-esteem, academic commitment and a good time management were associated with self-directed learning in these students. PMID- 26005826 TI - Ivemark syndrome-a rare entity with specific anatomical features. AB - Ivemark syndrome (IS) is a rare embryological disorder which results from failure of development of the left-right asymmetry of organs. It is often associated with cardiac and other organ abnormalities, which are the usual causes of death in early neonatal life. We report a 3 months old girl with IS with dextrocardia, transposition of the great vessels, atrio-ventricular connection, total anomalous pulmonary venous drainage, a right atrial and right pulmonary isomerism, a midline liver, a midline gallbladder, asplenia, intestinal malrotation and vena cava anomalies. To our knowledge, complete right heterotaxia syndrome has been rarely described in literature. Lateralization defects such as situs inversus, asplenia or polysplenia due to defective left-right axis development are considered as defects of the primary developmental field. Therefore, additional malformations in IS can be synchronic defects in the primary developmental field rather than causally independent malformations. PMID- 26005827 TI - [Emphysematous cystitis: Report of one case]. AB - Emphysematous cystitis is found in diabetic patients and in individuals with urinary stasis and immunosuppression. We report a 58-year-old male with hypertension, type 2 Diabetes on insulin treatment and central nervous system vasculitis on immunosuppressive therapy. He was admitted with weight loss and gait instability. A PET-CT showed a circumscribed image of air in the bladder contour without involving the upper urinary tract, suggesting emphysematous cystitis. Re-interrogated, the patient referred pneumaturia, dysuria and febrile sensation one week before admission. Urine culture showed Enterobacter aerogenes. He was treated with a urinary catheter, metabolic control and parenteral antimicrobials. The patient was discharged without symptoms 21 days after admission, with the bladder catheter. PMID- 26005828 TI - [Non-fatal hyperkalemia in lactic acidosis due to metformin overdose. Report of one case]. AB - We report a 74-year-old man with diabetes mellitus type 2 and hypertension, who recently underwent coronary bypass surgery due to severe triple vessel disease receiving cardiological and combined antidiabetic therapy, including metformin 4 g/day. He was admitted with abdominal pain, nausea, vomiting, diarrhea and loss of consciousness. At admission, he was disoriented and agitated with signs of poor perfusion. His blood pressure was 80/70 mmHg, pulse rate 40 beats/min, respiratory rate 20-breaths/min, and axillary temperature 35 degrees C. Biochemical profile revealed an extreme hyperkalemia of 15.4 mEq/L (double checked), elevated creatinine, uremia and brain natriuretic peptide; hypoglycemia (blood glucose 68 mg/dl) and normal C Reactive Protein. Arterial blood gases revealed severe lactic acidemia. The electrocardiogram showed sinus bradycardia, simple AV block, widened QRS with prominent T wave and prolonged QT. He was admitted to the Intensive Care Unit (ICU) with the suspicion of lactic acidosis associated with metformin, receiving fluid management, intravenous hypertonic glucose plus insulin and sodium bicarbonate, mechanical ventilation, vasopressor therapy, a temporary pacemaker lead, in addition to continuous venovenous hemodiafiltration. Two days later, the patient experienced a significant clinical improvement with normalization of the acid-base status, plasma lactate and potassium levels. On day 9, diuresis was recovered, creatinine and uremia returned to normal levels and the patient was discharged from the ICU. PMID- 26005829 TI - [Cervical macroadenoma causing hyperparathyroidism: Report of one case]. AB - We report a 59-year-old man with a history of hypertension, recurrent renal stones and a severe hypercalcemia of 14.9 mg/dl with a serum phosphorus of 2.4 mg/dl and a serum albumin of 3.6 g/dl. Physical examination showed a 4 cm left cervical nodule, consistent with the diagnosis of thyroid nodule. Parathyroid hormone (PTH) levels were 844 pg/mL (normal 15-65 pg/ml) and a cervical ultrasound examination disclosed a solid nodule in the lower left lobe of 40 x 30 x 25 mm, adjacent to the thyroid parenchyma. Abdominal ultrasound revealed bilateral renal stones. Parathyroid scintigraphy showed a high uptake of the left lower parathyroid mass and a bone densitometry showed bone density t scores of 1.2 in the spine, -2.0 in the right femoral neck and -3.5 in the distal radius. A review of his medical record revealed the presence of hypercalcemia for at least 4 years. He was admitted for hydration and administration of 4 mg zoledronic acid iv. At 24 hours, serum calcium dropped to 11.0 mg/dl, and a left thyroid lobectomy was performed including the lower left parathyroid gland. The pathology report showed a 22.6 g parathyroid adenoma. Intraoperatory PTH descended > 50%, consistent with successful parathyroidectomy. At 7 days after surgery serum calcium was 8.8 mg/dl, phosphorus 2.1 mg/dl, alkaline phosphatase 166 U/L, albumin 3.9 g/dL, PTH 230 pg/ml and 25-OH vitamin D 12.4 ng/ml. This finding was interpreted as secondary hyperparathyroidism due to vitamin D deficiency and "hungry bone", being less likely the presence of residual or metastatic parathyroid tissue. A cholecalciferol load was administered, with significant descent of PTH. PMID- 26005830 TI - [Cultural Competence in health: an urgent need for health workers]. PMID- 26005831 TI - [Ninety years after the foundation of the first School of Social Work in Chile and Latin America by Alejandro del Rio M.D]. PMID- 26005832 TI - [Cutaneous lupus erythematosus in a dog: reflections on human-animal evolutionary connections]. PMID- 26005833 TI - [Correction]. PMID- 26005834 TI - Haemocytes control stem cell activity in the Drosophila intestine. AB - Coordination of stem cell activity with inflammatory responses is critical for regeneration and homeostasis of barrier epithelia. The temporal sequence of cell interactions during injury-induced regeneration is only beginning to be understood. Here we show that intestinal stem cells (ISCs) are regulated by macrophage-like haemocytes during the early phase of regenerative responses of the Drosophila intestinal epithelium. On tissue damage, haemocytes are recruited to the intestine and secrete the BMP homologue DPP, inducing ISC proliferation by activating the type I receptor Saxophone and the Smad homologue SMOX. Activated ISCs then switch their response to DPP by inducing expression of Thickveins, a second type I receptor that has previously been shown to re-establish ISC quiescence by activating MAD. The interaction between haemocytes and ISCs promotes infection resistance, but also contributes to the development of intestinal dysplasia in ageing flies. We propose that similar interactions influence pathologies such as inflammatory bowel disease and colorectal cancer in humans. PMID- 26005836 TI - Alan Hall 1952-2015. PMID- 26005835 TI - RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth. AB - The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR-SOS1 Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras-ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR-RasGRP1 and EGFR-SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma. PMID- 26005837 TI - Metacognitions, worry and sleep in everyday life: Studying bidirectional pathways using Ecological Momentary Assessment in GAD patients. AB - BACKGROUND: The metacognitive model of generalized anxiety disorder proposes that negative metacognitive beliefs are crucial in the maintenance of excessive worry. Furthermore, according to the cognitive model of insomnia, worry leads to problems falling or staying asleep and poor sleep quality. In order to test the assumed causal relationships, the present study examined the time-dependent course of negative metacognition and worry as well as worry and sleep quality, using Ecological Momentary Assessment (EMA). METHOD: Negative metacognitions, worry and sleep were assessed by self-report questionnaires as well as EMA in 56 GAD patients who carried a portable device for 1 week and logged sleep quality, negative metacognition and worry processes four times a day. RESULTS: Metacognitions, worry and sleep were significantly correlated. Structural equation modeling using multilevel analyses showed a unidirectional relationship of negative metacognitions leading to prolonged worry processes and a bidirectional relationship of worry and sleep quality. CONCLUSIONS: These findings support the theoretically derived assumptions on the relationship between negative metacognitions, worry and sleep. Implications for further research as well as clinical implications are discussed. PMID- 26005838 TI - Anxiety sensitivity and the anticipation of predictable and unpredictable threat: Evidence from the startle response and event-related potentials. AB - There is growing evidence that heightened sensitivity to unpredictable threat is a core mechanism of dysfunction in anxiety disorders. However, it is unclear whether anxiety sensitivity is also associated with sensitivity to unpredictable threat. In the present study, 131 participants completed the Anxiety Sensitivity Index-3, which includes physical concerns (PC), social concerns (SC), and cognitive concerns (CC) subscales, and a predictable vs. unpredictable threat-of shock task. Startle eyeblink and ERP responses (N100, P300) to the acoustic startle probes were measured during the task. PC and CC were associated with heightened and attenuated, respectively, startle for the unpredictable (but not predictable) condition. CC were also associated with attenuated probe N100 for the unpredictable condition only, and PC were associated with increased P300 suppression across the predictable and unpredictable conditions. This study provides novel evidence that the different anxiety sensitivity dimensions demonstrate unique relationships with the RDoC domains "acute" and "potential" threat. PMID- 26005841 TI - Autism and behavior in adult patients with Dravet syndrome (DS). AB - INTRODUCTION: Autism and behavioral characteristics in adults with Dravet syndrome (DS) have rarely been systematically studied. METHOD: Three scales were used to assess the outcomes of DS in adulthood in terms of autism and behavior. All the adult patients with DS, nine male and four female, aged between 18 and 60 years, living at the Epilepsy Center Kempenhaeghe in The Netherlands were included in the study. In addition, the past medical history of each patient was systematically screened for diagnoses like autism, Pervasive Development Disorder Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD), hyperactivity, Attention Deficit Hyperactivity Disorder (ADHD), and self-mutilation. Information concerning past and current use of psychoactive drugs was also evaluated. RESULTS: Eight patients (61.5%) were classified as having autism spectrum disorder (ASD) according to the AVZ-R or according to the medical record. Self mutilation was seen in four patients (30.8%), hyperactivity in none. Three patients (23.1%) currently used psychoactive drugs. CONCLUSION: Autism spectrum disorders persist in adult patients with DS, while certain characteristics associated with behavioral problems, such as hyperactivity or use of psychoactive medication, seem to be less prominent than in childhood. PMID- 26005840 TI - S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction. AB - Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration appears critical for S100A1's cyclic adenosine monophosphate independent inotropic effects but raises concerns about potential diastolic SR Ca(2+) leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca(2+)- and beta-adrenergic receptor-triggered proarrhythmogenic SR Ca(2+) leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca(2+) leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca(2+) leak in HF, combining antiarrhythmic potency with chronic inotropic actions. PMID- 26005842 TI - Quantification of material slippage in the iliotibial tract when applying the partial plastination clamping technique. AB - The objective of this study was to evaluate the potential of the partial plastination technique in minimizing material slippage and to discuss the effects on the tensile properties of thin dense connective tissue. The ends of twelve iliotibial tract samples were primed with polyurethane resin and covered by plastic plates to provide sufficient grip between the clamps. The central part of the samples remained in an anatomically unfixed condition. Strain data of twelve partially plastinated samples and ten samples in a completely anatomically unfixed state were obtained using uniaxial crosshead displacement and an optical image tracking technique. Testing of agreement between the strain data revealed ongoing but markedly reduced material slippage in partially plastinated samples compared to the unfixed samples. The mean measurement error introduced by material slippage was up to 18.0% in partially plastinated samples. These findings might complement existing data on measurement errors during material testing and highlight the importance of individual quantitative evaluation of errors that come along with self-made clamping techniques. PMID- 26005839 TI - Cognitive-behavioral therapy for late-life anxiety: Similarities and differences between Veteran and community participants. AB - Cognitive-behavioral therapy (CBT) is an evidence-based treatment for anxiety; however, a growing body of research suggests that CBT effect sizes are smaller in Veteran samples. The aim of this study was to perform secondary data analyses of a randomized controlled trial of CBT for late-life generalized anxiety disorder compared with treatment as usual (TAU) in a Veteran (n = 101) and community-based (n = 122) sample. Veterans had lower income and less education than community participants, greater severity on baseline measures of anxiety and depression, poorer physical health, and higher rates of psychiatric comorbidity. Treatment effects were statistically significant in the community sample (all ps < 0.01), but not in Veterans (all ps > 0.05). Further analyses in Veterans revealed that poorer perceived social support significantly predicted poorer outcomes (all ps < 0.05). Our results underscore the complexity of treating Veterans with anxiety, and suggest that additional work is needed to improve the efficacy of CBT for Veterans, with particular attention to social support. PMID- 26005843 TI - Mechanical and hyperthermic properties of magnetic nanocomposites for biomedical applications. AB - An understanding of the properties of multifunctional materials is important for the design of devices for biomedical applications. In this paper, a combination of experiments and models was used to study the mechanical and hyperthermic properties of magnetic nanoparticles (MNP)-filled PDMS composites for biomedical applications. These are studied as a function of the weight of MNP, gamma-Fe2O3. The results showed the effects on mechanical behavior, and specific losses in a magnetic field. The measured Young's moduli are in good agreement with the moduli predicted from the Bergstrom-Boybce model. Specific losses calculated from magnetic measurements are used to predict the thermal dose under in-vivo conditions. The implications of the results were discussed for potential applications in biomedical devices. PMID- 26005844 TI - Sintering and the mechanical properties of the tricalcium phosphate-titania composites. AB - The sintering of the tricalcium phosphate with different percentages of titania was investigated. The samples were characterized by differential thermal analysis, dilatometry analysis, X-Ray diffraction, infrared spectroscopy, magic angle scanning nuclear magnetic resonance and scanning electronic microscopy measurements. The samples were examined by using the mechanical properties such as rupture strength, Vickers hardness and elastic modulus. The sintering of the tricalcium phosphate-titania composites indicates the evolution of the microstructure, the densification and the mechanical properties. The performances of the composites increase with both the sintering temperature and the addition of the titania. The highest values of the composites of rupture strength (33 MPa), Vickers hardness (270 Hv), Young's modulus (33.1GPa) and shear modulus (15.7 GPa) were obtained after the sintering process with 40 wt% titania at 1200 degrees C. The increase of these performances is due to the formation of the liquid-phase which helps to fill the pores in the microstructure. Above 40 wt% TiO2, the mechanical properties of the composites are hindered by the exaggerated grain growth formation. PMID- 26005845 TI - Metagenomics meets time series analysis: unraveling microbial community dynamics. AB - The recent increase in the number of microbial time series studies offers new insights into the stability and dynamics of microbial communities, from the world's oceans to human microbiota. Dedicated time series analysis tools allow taking full advantage of these data. Such tools can reveal periodic patterns, help to build predictive models or, on the contrary, quantify irregularities that make community behavior unpredictable. Microbial communities can change abruptly in response to small perturbations, linked to changing conditions or the presence of multiple stable states. With sufficient samples or time points, such alternative states can be detected. In addition, temporal variation of microbial interactions can be captured with time-varying networks. Here, we apply these techniques on multiple longitudinal datasets to illustrate their potential for microbiome research. PMID- 26005846 TI - A combined experimental and theoretical study of the tautomeric and conformational properties of (5-phenyl-tetrazol-2-yl)-acetic acid methyl ester. AB - The tautomeric and conformational properties of a new tetrazole derivative are studied in a combined approach that includes the analysis of the experimental vibrational data together with theoretical calculation methods, especially in terms of natural bond orbital (NBO) population analysis. Moreover, the molecular and crystal structure was determined by single crystal X-ray diffraction. The compound crystallized as the 2-tautomeric form, monoclinic space group P21/c with Z=4, a=10.0630(14), b=8.2879(11), c=12.8375(18) A, beta=105.546(3) degrees , V=1031.5(2) A(3). The tetrazole and phenyl rings are coplanar with the acetate group oriented perpendicular to the plane. The NBO analysis showed that delocalizing interactions of the lpp(N2) lone pair orbital contributes to a strong resonance interactions with both adjacent pi(*)(N3N4) and pi(*)(N1C5) antibonding orbitals of the tetrazole group. PMID- 26005847 TI - Glucose encapsulating liposome for signal amplification for quantitative detection of biomarkers with glucometer readout. AB - A new technology was developed to quantitatively detect a broad range of disease biomarkers and proven to be portable, economical, and conveniently accessible. Measurements were performed based on releasing encapsulated glucose from antibody tagged liposomes and subsequently detecting the released glucose using a commercial personal glucose meter (GM). The innovative aspect of this approach lies in the quantification of target biomarkers through the detection of glucose, thus expanding the applicability of the GM by broadening the range of target biomarkers instead of detecting only one analyte, glucose. Because of the bilayer membrane of liposomes, which can accommodate tens of thousands of glucose molecules, the sensitivity was greatly enhanced by using glucose encapsulating liposomes as a signal output and an amplifier. Here, the model analyte, protein 53 phosphorylated on Serine 15 (phospho-p53(15)), was captured by primary antibodies bound on magnetic Fe3O4 nanoparticles and then recognized by reporting antibodies conjugated to glucose encapsulating liposomes. Finally, the target phospho-p53(15) was detected by lysing the bound liposomes to release the encapsulated glucose (4 * 10(5) glucose molecules per liposome), which is detected with the GM. This approach was demonstrated to be a universal technology that can be easily produced to quantify a wide variety of biomarkers in medical diagnostics, food safety, public health, and environmental monitoring. In the near future, it is expected that these sensors, in combination with a portable GM, can be used in many fields such as physicians' laboratories, hospitals and the common household. PMID- 26005848 TI - Experience-dependent DNA methylation regulates plasticity in the developing visual cortex. AB - DNA methylation is an epigenetic repressor mark for transcription dynamically regulated in neurons. We analyzed visual experience regulation of DNA methylation in mice and its involvement in ocular dominance plasticity of the developing visual cortex. Monocular deprivation modulated the expression of factors controlling DNA methylation and exerted opposite effects on DNA methylation and hydroxymethylation in specific plasticity genes. Inhibition of DNA methyltrasferase (DNMT) blocked molecular and functional effects of monocular deprivation, partially reversing the monocular deprivation transcriptional program. PMID- 26005849 TI - The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration. AB - Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor gamma2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy associated mutant gamma2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases. PMID- 26005850 TI - Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. AB - PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-beta (Abeta) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Abeta clearance across the murine blood brain barrier (BBB) and accelerated Abeta pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Abeta bound to the low density lipoprotein receptor related protein-1, a key Abeta clearance receptor, and guided Abeta trafficking to Rab5 and Rab11, leading to Abeta endothelial transcytosis and clearance. PICALM levels and Abeta clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Abeta clearance. Thus, PICALM regulates Abeta BBB transcytosis and clearance, which has implications for Abeta brain homeostasis and clearance therapy. PMID- 26005851 TI - mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress. AB - Resilience to aversive events has a central role in determining whether stress leads to the development of depression. mGluR5 has been implicated in the pathophysiology of depression, but the effect of mGluR5 activity on stress resilience remains unexplored. We found that mGluR5(-/-) (also known as Grm5(-/ )) mice displayed more depression-like behaviors (for example, learned helplessness, social withdrawal and anhedonia) than control mice following exposure to various stressful stimuli. Lentiviral 'rescue' of mGluR5 in the nucleus accumbens (NAc) decreased these depression-like behaviors in mGluR5(-/-) mice. In the NAc, DeltaFosB, whose induction promotes stress resilience, failed to be upregulated by stress in mGluR5(-/-) mice. Notably, targeted pharmacological activation of mGluR5 in the NAc increased DeltaFosB expression. Our findings point to an essential role for mGluR5 in promoting stress resilience and suggest that a defect in mGluR5-mediated signaling in the NAc may represent an endophenotype for stress-induced depression. PMID- 26005852 TI - The schizophrenia risk gene product miR-137 alters presynaptic plasticity. AB - Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele-carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), Nsf and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus. PMID- 26005853 TI - Mitochondria and chloroplasts shared in animal and plant tissues: significance of communication. AB - Mitochondria have long been recognized as the main source of energy production for the eukaryotic cell. Recent studies have found that the mitochondria have a variety of dynamic functions aside from the production of energy. It communicates bidirectionally with other organelles in order to modulate its energy balance efficiently, as well as maintain homeostasis, ultimately prolonging its own and the cell's longevity. The mitochondria achieves this level of regulation via specific and common bidirectional chemical messengers, especially involving the endoplasmic/sarcoplasmic reticulum (ER/SR), deoxyribonucleoside triphosphates (dNTP's), ATP and the generation of reactive oxygen species (ROS). Its communication network is also involved in stress associated events. In this regard, the activation of the Bax family proteins and the release of cytochrome c occurs during cellular stress. The communication can also promote apoptosis of the cell. When mitochondrial abnormalities cannot be dealt with, there is an increased chance that major illnesses like type 2 diabetes, Alzheimer's disease, and cancer may occur. Importantly, functioning chloroplasts can be found in animals, suggesting conserved chemical messengers during its evolutionary path. The dynamic capacity of mitochondria is also noted by their ability to function anaerobically. Indeed, this latter phenomenon may represent a return to an earlier developmental stage of mitochondria, suggesting certain disorders result from its untimely appearance. PMID- 26005854 TI - The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells. AB - B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt-beta-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies. PMID- 26005856 TI - Hymenal lesions and legal outcome in sexually abused girls with a history of vaginal penetration. AB - PURPOSE: In many cultures, it is commonly accepted that the hymen remains unchanged throughout childhood, until it is torn at the first episode of sexual intercourse. Therefore, the definition of virginity is directly linked to a normal hymen. However, most girls referred for medical forensic colposcopic examination have normal or nonspecific findings, the prevalence of abnormal findings in girls with a history of genital penetration being only 4-6%. The aim of this study was to investigate the relation between hymenal findings seen at the colposcopic examination and the legal outcome: prosecution in court and conviction in court. RESULTS: During the 80-month period of our study, 426 girls with a median age of 9 years (range 0-15 years) were included. A history of at least one vaginal penetration was given in 226 of the girls with a median age of 12 years (range 2-14 years). The hymenal findings were described as normal in 125 of the 226 cases (55%). In 50 cases (22%), hymenal clefts were found, 17 (34%) of which were complete and 33 (66%) incomplete. The finding of hymenal clefts increased with age. Of the 226 cases of girls being sexually assaulted with vaginal penetration, 119 cases (53%) were prosecuted in court, 102 of which (86%) resulted in conviction. Thirty-five (70%) of the cases with hymenal clefts and 100 (57%) of the cases without hymenal clefts were prosecuted in court, showing a correlation between hymenal clefts and conviction; however, the correlation was not significant (chi(2) test=2.1 and P=0.14). In total, 29 (58%) of the cases with hymenal clefts and 88 (50%) of the cases without hymenal clefts were convicted in court, which shows no significance (chi(2) test=1.0 and P=0.33). CONCLUSIONS: The single most important feature for conviction in court is the child's testimony and not hymenal findings seen at the colposcopic examination. Especially the testimony of the older children leads to conviction, raising the question whether the videotaped testimonies are aimed at the court proceedings, or whether hearing the child's testimony directly in court has a more powerful effect. Overall, it is crucial that the videotaped police questioning of the younger children is performed by specialized personnel, with the aim of presenting the testimony in a detailed and credible manner in court, giving children of all ages a fair trial. PMID- 26005855 TI - Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1 alpha. AB - Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1alpha (HIF1-alpha) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-alpha controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-alpha degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-alpha and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-alpha and AHR integrate immunological, metabolic and environmental signals to regulate the immune response. PMID- 26005857 TI - 4F-PBP (4'-fluoro-alpha-pyrrolidinobutyrophenone), a new substance of abuse: Structural characterization and purity NMR profiling. AB - The rapidly growing problem of new psychoactive substances (NPS) makes the time management for international control a real challenge, with the traditional detection methods becoming increasingly inadequate. NPS screening technologies, such as NMR, which allows multiple substances to be detected, characterized and quantified simultaneously from a single sample, offers a rapid solution to this problem. This study describes the application of NMR to the simultaneous detection, characterization and quantification of samples of white powders seized by the Portuguese Police. 4F-PBP (4'-fluoro-alpha-pyrolidinobutyrophenone) a new synthetic psychoactive cathinone cut with myo-inositol was found in two seized products. The structural characterization of 4F-PBP was elucidated in the mixture, and confirmed after isolation from the matrix by (1)H, (13)C, (19)F NMR and MS. Myo-inositol was found for the first time as a cutting agent of cathinones. Furthermore another seized product was characterized as being MDPBP, with a high degree of purity, and its spectroscopic elucidation enabled the correction of (13)C NMR literature assignments. PMID- 26005858 TI - Class-conditional feature modeling for ignitable liquid classification with substantial substrate contribution in fire debris analysis. AB - Forensic chemical analysis of fire debris addresses the question of whether ignitable liquid residue is present in a sample and, if so, what type. Evidence evaluation regarding this question is complicated by interference from pyrolysis products of the substrate materials present in a fire. A method is developed to derive a set of class-conditional features for the evaluation of such complex samples. The use of a forensic reference collection allows characterization of the variation in complex mixtures of substrate materials and ignitable liquids even when the dominant feature is not specific to an ignitable liquid. Making use of a novel method for data imputation under complex mixing conditions, a distribution is modeled for the variation between pairs of samples containing similar ignitable liquid residues. Examining the covariance of variables within the different classes allows different weights to be placed on features more important in discerning the presence of a particular ignitable liquid residue. Performance of the method is evaluated using a database of total ion spectrum (TIS) measurements of ignitable liquid and fire debris samples. These measurements include 119 nominal masses measured by GC-MS and averaged across a chromatographic profile. Ignitable liquids are labeled using the American Society for Testing and Materials (ASTM) E1618 standard class definitions. Statistical analysis is performed in the class-conditional feature space wherein new forensic traces are represented based on their likeness to known samples contained in a forensic reference collection. The demonstrated method uses forensic reference data as the basis of probabilistic statements concerning the likelihood of the obtained analytical results given the presence of ignitable liquid residue of each of the ASTM classes (including a substrate only class). When prior probabilities of these classes can be assumed, these likelihoods can be connected to class probabilities. In order to compare the performance of this method to previous work, a uniform prior was assumed, resulting in an 81% accuracy for an independent test of 129 real burn samples. PMID- 26005859 TI - Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo. AB - Loss of Ras association domain family protein 1 isoform A (RASSF1A) expression is associated with the development of a variety of human cancers and the expression of carcinoembryonic antigen (CEA) frequently occurs in gastric cancer. This study investigated the effects of RASSF1A expression restoration using a hypoxia inducible CEA promoter-driven vector on xenograft tumor growth in nude mice and on the in-vitro regulation of gastric cancer cell viability, cell cycle distribution, apoptosis, colony formation and invasion capacity. The data showed that the level of CEA mRNA and protein was much higher in gastric cancer SGC7901 cells than in a second gastric cancer cell line, MKN28, or in the MCF-10A normal epithelial breast cell line. RASSF1A expression was restored in SGC7901 cells compared with the negative control virus-infected SGC7910 cells. RASSF1A expression restoration significantly inhibited gastric cancer cell viability, colony formation and invasion capacity, but induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. At the gene level, restoration of RASSF1A expression under hypoxic culture conditions significantly suppressed matrix metalloproteinase-2 expression and prevented cyclinD1 expression. A nude mouse xenograft assay showed that the restoration of RASSF1A expression reduced gastric cancer xenograft formation and growth. In conclusion, the restoration of RASSF1A expression using a hypoxia-inducible and CEA promoter-driven vector suppressed aggressive phenotypes of gastric cancer cells in vitro and in vivo. These results suggest that LV-5HRE-CEAp-RASSF1A gene therapy may be a promising novel approach to treat advanced gastric cancer. PMID- 26005860 TI - Cyclodextrin mediated delivery of NF-kappaB and SRF siRNA reduces the invasion potential of prostate cancer cells in vitro. AB - Prostate cancer is the most common cancer in men of the western world. To date, no effective treatment exists for metastatic prostate cancer and consequently, there is an urgent need to develop new and improved therapeutics. In recent years, the therapeutic potential of RNA interference (RNAi) has been extensively explored in a wide range of diseases including prostate cancer using numerous gene delivery vectors. The aims of this study were to investigate the ability of a non-viral modified cyclodextrin (CD) vector to deliver siRNA to the highly metastatic PC-3 prostate cancer cell line, to quantify the resulting knockdown of the two target genes (RelA and SRF) and to study the effects of the silencing on metastasis. Data from a Matrigel in vitro invasion assay indicated that the silencing of the target genes achieved by the CD vector resulted in significant reductions (P=0.0001) in the metastatic potential of these cells. As the silencing of these target genes was shown not to have a negative impact on cell viability, we hypothesise that the mechanism of invasion inhibition is due, in part, to the significant reduction observed (P?0.0001) in the level of pro inflammatory cytokine, MMP9, which is known to be implicated in the metastasis of prostate cancer. PMID- 26005861 TI - Viral vector-based improvement of optic nerve regeneration: characterization of individual axons' growth patterns and synaptogenesis in a visual target. AB - Lack of axon growth ability in the central nervous system poses a major barrier to achieving functional connectivity after injury. Thus, a non-transgenic regenerative approach to reinnervating targets has important implications in clinical and research settings. Previous studies using knockout (KO) mice have demonstrated long-distance axon regeneration. Using an optic nerve injury model, here we evaluate the efficacy of viral, RNA interference (RNAi) and pharmacological approaches that target the phosphatase and tensin homolog (PTEN) and signal transducer and activator of transcription-3 pathways to improve long distance axon regeneration in wild-type mice. Our data show that adeno-associated virus (AAV) expressing short hairpin RNA (shRNA) against PTEN (shPTEN) enhances retinal ganglion cell axon regeneration after crush injury. However, compared with the previous data in PTEN KO mice, AAV-shRNA results in a lesser degree of regeneration, likely due to incomplete gene silencing inherent to RNAi. In comparison, an extensive enhancement in regeneration is seen when AAV-shPTEN is coupled to AAV encoding ciliary neurotrophic factor (CNTF) and to a cyclic adenosine monophosphate (cAMP) analog, allowing axons to travel long distances and reach their target. We apply whole-tissue imaging that facilitates three dimensional visualization of single regenerating axons and document heterogeneous terminal patterns in the targets. This shows that some axonal populations generate extensive arbors and make synapses with the target neurons. Collectively, we show a combinatorial viral RNAi and pharmacological strategy that improves long-distance regeneration in wild-type animals and provide single fiber projection data that indicates a degree of preservation of target recognition. PMID- 26005862 TI - Natural soil mineral nanoparticles are novel sorbents for pentachlorophenol and phenanthrene removal. AB - Natural soil montmorillonite and kaolinite nanoparticles (NPs) were tested as efficient sorbents for organic contaminant (OC) removal through mimicking their natural environmental dispersive states. Sorption of both mineral NPs decreased with increasing pH with ionizable pentachlorophenol (PCP), but increased with pH with non-ionizable phenanthrene (PHE), within the pH range of 4-10. In contrast, sorption decreased consistently for both PCP and PHE, as a function of increasing ion concentration (0.001-0.1 mol L(-1)). Sorption differences were likely caused by the electrolytic conditions dependent upon surface chemistry of OCs and mineral NPs. The results confirmed that the highly dispersive soil mineral NPs would prevail over both engineered NPs and their regular MUm-sized colloids for OC removal, due to their ecological advantages and higher sorption properties. This finding provided a realistic assessment of the environmental function of soil natural minerals in water once they are released from soil into OC polluted aqueous systems. PMID- 26005863 TI - Assessing levels and seasonal variations of current-use pesticides (CUPs) in the Tuscan atmosphere, Italy, using polyurethane foam disks (PUF) passive air samplers. AB - Polyurethane foam disks (PUF) passive air samplers (PAS) were deployed over 4 sampling periods of 3-5-months (>= 1 year) at ten urban and rural locations throughout the Tuscany Region. The purpose was to assess the occurrence and seasonal variations of ten current-use pesticides (CUPs). PUF disk extracts were analyzed using GC-MS. The organophosphates insecticides; chlorpyrifos (3-580 pg m(-3)) and chlorpyrifos-methyl (below detection limit - to 570 pg m(-3)) presented the highest levels in air, and showed seasonal fluctuation coinciding with the growing seasons. The relative proportion urban/(urban + rural) ranged from 0.4 to 0.7 showing no differences between urban and rural concentrations. Air back trajectories analysis showed air masses passing over agricultural fields and potentially enhancing the drift of pesticides into the urban sites. This study represents the first information regarding CUPs in the atmosphere of Tuscany region using PAS-PUF disk. PMID- 26005864 TI - An ancient protein-DNA interaction underlying metazoan sex determination. AB - DMRT transcription factors are deeply conserved regulators of metazoan sexual development. They share the DM DNA-binding domain, a unique intertwined double zinc-binding module followed by a C-terminal recognition helix, which binds a pseudopalindromic target DNA. Here we show that DMRT proteins use a unique binding interaction, inserting two adjacent antiparallel recognition helices into a widened DNA major groove to make base-specific contacts. Versatility in how specific base contacts are made allows human DMRT1 to use multiple DNA binding modes (tetramer, trimer and dimer). Chromatin immunoprecipitation with exonuclease treatment (ChIP-exo) indicates that multiple DNA binding modes also are used in vivo. We show that mutations affecting residues crucial for DNA recognition are associated with an intersex phenotype in flies and with male-to female sex reversal in humans. Our results illuminate an ancient molecular interaction underlying much of metazoan sexual development. PMID- 26005865 TI - A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. AB - The major pathway by which the brain obtains essential omega-3 fatty acids from the circulation is through a sodium-dependent lysophosphatidylcholine (LPC) transporter (MFSD2A), expressed in the endothelium of the blood-brain barrier. Here we show that a homozygous mutation affecting a highly conserved MFSD2A residue (p.Ser339Leu) is associated with a progressive microcephaly syndrome characterized by intellectual disability, spasticity and absent speech. We show that the p.Ser339Leu alteration does not affect protein or cell surface expression but rather significantly reduces, although not completely abolishes, transporter activity. Notably, affected individuals displayed significantly increased plasma concentrations of LPCs containing mono- and polyunsaturated fatty acyl chains, indicative of reduced brain uptake, confirming the specificity of MFSD2A for LPCs having mono- and polyunsaturated fatty acyl chains. Together, these findings indicate an essential role for LPCs in human brain development and function and provide the first description of disease associated with aberrant brain LPC transport in humans. PMID- 26005866 TI - Spatial genomic heterogeneity within localized, multifocal prostate cancer. AB - Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis. PMID- 26005867 TI - Transcriptional regulator PRDM12 is essential for human pain perception. AB - Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics. PMID- 26005870 TI - [Hyperuricemia and cardiovascular diseases: from phylogenesys to patogenetic mechanisms]. AB - During human evolution, the accumulation of loss of function mutations of the uricase gene led progressively to the lack of the ability to metabolize uric acid into further end-products. Consequently, serum uric acid levels progressively increased over time along with the dietary availability of purine-rich foods. At first, the increase in uricemia contributed positively to primate development by increasing the antioxidant power of the organism, favouring an increase in blood pressure and lipid metabolism. However, later, these positive effects have been overcome by more dangerous consequences. In fact, in the recent period of human being history, the impact of dietary changes on uricemia was so significant that pathological consequences such as gout or renal stones appeared. Furthermore, it has been proved that abnormal uric acid level induces endothelial dysfunction and renal fibrosis. The shift between positive and negative consequences secondary to uric acid is clearly in accordance with the J curve shaped relation that describes the correlation between mortality and serum uric acid level. PMID- 26005868 TI - Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. AB - Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans. PMID- 26005871 TI - [Renal handling of uric acid]. AB - Uric acid is the end product of purine catabolism in humans. The plasma concentration is the result of an intricate and partially known process that regulates its synthesis and excretion. Plasma levels range from 3 to 7 mg/dl, and are influenced by diet rich in purines, cell turnover and reduced renal excretion. The kidney plays a pivotal role in acid uric homeostasis, and the pathogenesis of hyperuricemia often correlates with a reduction in the amount of renal excretion, as happens in chronic kidney failure or as a result of certain drugs. Physiologically, uric acid is freely filtered by glomerulus; along the proximal tubule it is reabsorbed and secreted, with a fractional excretion equal to 6-12%. During the last decades many efforts have led to a better understanding of the molecular basis of renal urate handling. The present study analyzes the most recent evidences that demonstrate the role of several proteins involved in urate transport. Understanding this physiological mechanisms had a great impact in clinical practice, providing advances in our knowledge of drug action and genetic associations in hyperuricemic patients; contextually it opened new avenues for drug development. PMID- 26005869 TI - A cascade of arabinosyltransferases controls shoot meristem size in tomato. AB - Shoot meristems of plants are composed of stem cells that are continuously replenished through a classical feedback circuit involving the homeobox WUSCHEL (WUS) gene and the CLAVATA (CLV) gene signaling pathway. In CLV signaling, the CLV1 receptor complex is bound by CLV3, a secreted peptide modified with sugars. However, the pathway responsible for modifying CLV3 and its relevance for CLV signaling are unknown. Here we show that tomato inflorescence branching mutants with extra flower and fruit organs due to enlarged meristems are defective in arabinosyltransferase genes. The most extreme mutant is disrupted in a hydroxyproline O-arabinosyltransferase and can be rescued with arabinosylated CLV3. Weaker mutants are defective in arabinosyltransferases that extend arabinose chains, indicating that CLV3 must be fully arabinosylated to maintain meristem size. Finally, we show that a mutation in CLV3 increased fruit size during domestication. Our findings uncover a new layer of complexity in the control of plant stem cell proliferation. PMID- 26005872 TI - [Uric acid, the kidney and cardiovascular mortality]. AB - Hyperuricemia is one of the many metabolic changes that occur during the course of chronic kidney disease (CKD). Even though it is clear its genesis of high uric acid levels (decreased renal clearance, overproduction, summation of both factors), we do not know the significance with regard to its effects on the cardiovascular (CV) system. On the other hand, the exact role of hyperuricemia in the general population it is not even established . In the general population, many studies have shown a strong correlation between uric acid levels and CV morbidity and mortality. However there are many researches that suggest a role of innocent bystander of uric acid, even in presence of elevated serum levels. Recently, there is an accumulation of evidence that emphasize a close link between uric acid and CV disease, at least in the field of CKD. In the patient population participating to the PIRP project (Prevention of Progressive Renal Failure of the Emilia-Romagna Region), we have seen, even with multivariate analysis, an independent role of high levels of uric acid concerning both, the occurrence of CV events and CV mortality. PMID- 26005873 TI - [Hyperuricemia and renal risk]. AB - Recent studies have revealed an association between elevated levels of uric acid and conditions correlated to chronic kidney diseases such as hypertension, cardiovascular and cerebral disease, insulin resistance. Several pathogenetic mechanisms at cellular and tissue levels could justify a direct correlation between serum uric acid levels and renal damage. Growing evidence indicating a correlation between urate lowering therapy and renal morbidity could encourage the use of urate lowering therapy in primary or secondary prevention in chronic kidney disease. PMID- 26005874 TI - [Gout and chronic kidney disease: specific diagnostic and therapeutic features]. AB - In the last decades, the increase in life expectancy, changes in diet and lifestyle have resulted in raising of incidence and prevalence of gout in all countries. The phenotype of patients with gout has changed a lot over the years: more and more frequently they have several co-morbidities such as hypertension, cardiovascular disease, diabetes, obesity, chronic kidney disease (CKD) and metabolic syndrome that influence the progression and challenge the therapeutic management. The management of gout in CKD patients demands more attention and specific features in diagnosis and therapeutic approach. This article summarizes the most recent published evidences on how to best diagnose and treat the gouty patients with CKD, how to better manage medications for the treatment of acute gouty flares and for the chronic hyperuricemia management. PMID- 26005875 TI - [Uric acid nephrolithiasis]. AB - Nephrolithiasis is a common condition in the general population. About 5-10% of all kidney stones is composed of uric acid, however the prevalence of uric acid stones significantly increases among patients with obesity, diabetes or metabolic syndrome. A key role in the pathogenesis of uric acid nephrolithiasis is played by excessive urinary acidification, which increases the risk of precipitation of uric acid salts in the urine. An excessive presence of uric acid in the urine, due to increased circulating levels or tubular defects, might contribute to the pathogenesis. The cornerstones of prevention of recurrences of uric acid stones include interventions aimed at expanding urine volume and alkalinizing the urine. PMID- 26005876 TI - [Treatment of hyperuricemia in CKD]. AB - Numerous epidemiological studies conducted in the general population indicate that hyperuricemia is associated with an increased risk of developing renal failure. Moreover, among those subjects who are already suffering from chronic kidney disease (CKD), hyperuricemia is associated with a more rapid progression of disease besides with an increased risk of mortality and cardiovascular events. However, to date, the causal role of hyperuricaemia in determining the onset and progression of cardiovascular and renal damage is not yet fully established. Therefore the indications for pharmacological treatment of hyperuricemia (and particulary of asymptomatic hyperuricemia) in patients with CKD are still assigned to the personal orientation of the physician. In order to produce an evidence-based clinical appraisal on this topic, we performed a comparative analysis that included all the prospective studies that have evaluated the impact of treatment with xanthine oxidase inhibithors (XOI) with respect to the onset and progression of CKD. Moreover, since in the past the treatment with XOI was associated with a high risk of toxicity in patients with impaired renal function, we analyzed the toxicity of these drugs for various degrees of renal function impairment summarizing indications, contraindications and recommended doses in patients affected by CKD. In the end, as conclusion of our analysis, we propose an algorithm aimed at guiding the clinical decisions about the treatment of hyperuricemia in patients with CKD. PMID- 26005877 TI - [Hyperuricemia, diabetes and hypertension]. AB - Hyperuricemia is frequently found in association with several condition predisposing to cardiovascular events such as arterial hypertension and diabetes mellitus. This has led researchers to investigate possible pathogenetic mechanisms underlying this association. Several experimental studies and some indirect clinical evidence support a causal link between mild hyperuricemia and the developement of hypertension as well as new onset diabetes. At the tissue level, chronic exposure to increased uric acid has been shown to promote vascular changes leading to renal ischemia as well as stimulation of the renin angiotensin system. Furthermore, uric acid has been shown to promote the development of insulin resistance, hypertrglyceridemia and haepatic steatosis through pro oxidative mechanisms. These experimental pathophysiological changes may be partly preventable by hypouricemic treatments. Whether clinical implications of these findings are confirmed by solid clinical intervention trials, mild hyperuricemia may soon change its status from risk predictor to treatment target for patients at high cardiovascular and renal risk. PMID- 26005878 TI - An external pilot study to test the feasibility of a randomised controlled trial comparing eye muscle surgery against active monitoring for childhood intermittent exotropia [X(T)]. AB - INTRODUCTION: The evidence base for the treatment of strabismus (squint) is poor. Our main aim is to improve this evidence base for the treatment of a common type of childhood squint {intermittent exotropia, [X(T)]}. We conducted an external pilot study in order to inform the design and conduct of a future full randomised controlled trial (RCT). METHODS: Children of between 6 months and 16 years with a recent diagnosis of X(T) were eligible for recruitment. Participants were recruited from secondary care at the ophthalmology departments at four UK NHS foundation trusts. Participants were randomised to either active monitoring or surgery. This report describes the findings of the Pilot Rehearsal Trial and Qualitative Study, and assesses the success against the objectives proposed. RECRUITMENT AND RETENTION: The experience gained during the Pilot Rehearsal Trial demonstrates the ability to recruit and retain sites that are willing to randomise children to both trial arms, and for parents to agree to randomisation of their children to such a study. One child declined the group allocation. A total of 231 children were screened (expected 240), of whom 138 (60%) were eligible (expected 228: 95%) and 49 (35% of eligible) children were recruited (expected 144: 63% of eligible). Strategies that improved recruitment over the course of the trial are discussed, together with the reasons why fewer children were eligible for recruitment than initially anticipated. Attrition was low. Outcome data were obtained for 47 of 49 randomised children. TRIAL PROCESSES AND DATA COLLECTION: The Trial Management processes proved effective. There were high levels of completion on all of the data collection forms. However, the feedback from the treatment orthoptists revealed that some modifications should be made to the length and frequency of the health service assessment and travel assessment questionnaires, thus reducing the burden on participants in the main trial. Modifications to the wording of the questions also need to be made. MONITORING OF BIAS: Children who recruited to the trial were older and had more severe strabismus than those children eligible but declining participation. Strategies to account for this in a full trial are proposed. REASONS FOR PARTICIPATION OR DECLINING STUDY: These were identified using qualitative interviews. The principal reasons for declining entry into the study were strong preferences for and against surgical treatment. HARMS: There were no serious unexpected adverse events. Two children had overcorrection of their X(T) with reduction in binocular vision following surgery, which is in line with previous studies. No children in the active monitoring arm developed a constant strabismus although two showed some reduction in control. CONCLUSIONS: The SamExo study has demonstrated that it is possible to recruit and retain participants to a randomised trial of surgery compared with active monitoring for X(T). For longer-term full RCTs, in order to maximise the generalisability of future studies, consideration needs to be given to planning more time and clinic appointments to assess eligibility and to allow consideration of participation; the greater use of research nurses for recruitment; and accommodating the strong preferences of some parents both for and against surgical intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44114892. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 39. See the NIHR Journals Library website for further project information. PMID- 26005879 TI - Clinical profile and direct medical cost of care of adults presenting with systemic lupus erythematosus in Italy. AB - OBJECTIVES: To determine the clinical profile and estimate the annual direct medical cost of care of adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) in Italy. METHODS: A two-year, retrospective, multicentre, observational study was conducted from January to May 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (e.g. medications, etc.) were evaluated. Medical costs were assessed from the Italian National Health Insurance perspective. RESULTS: Four centres enrolled 96 eligible patients, including 85.4% women. Patients were equally stratified per disease severity (severe SLE: 51%). The mean (SD) age was 42.9 (13.8) years. At baseline, SLE duration was 12.6 (7.2) years. The mean (SD) SELENA-SLEDAI score was higher in severe than in non-severe patients 9.2 (6.4) vs. 3.3 (3.1) (p<0.001). The mean (SD) SLICC/ACR index score was similar in the two subgroups: 0.4 (0.8) vs. 0.3 (0.8). Over the study period, severe patients experienced on average 0.73 (0.56) flares/year and non-severe patients 0.57 (0.63). The annual medical cost was 1.6 times higher in severe than in non-severe patients (?2,101 vs. ?1,320; p=0.031). The cost of medications was also 2.5 times higher in severe patients (?1101 vs. ?445, p=0.007). Low C3/C4 complement levels and each severe flare incremented the annual cost of ?550 (p=0.011) and ?465 (p=0.02), respectively. CONCLUSIONS: The medical cost of SLE in Italy is related to disease severity and flares. Medications identified as the main cost drivers, and low C3/C4 complement levels and severe flares as the main cost predictors, increased significantly the cost of SLE management. PMID- 26005880 TI - The antifibrotic role of hepatocyte growth factor in dermal fibroblasts of systemic sclerosis. PMID- 26005881 TI - Familial Mediterranean fever with a single MEFV mutation: comparison of rare and common mutations in a Turkish paediatric cohort. AB - OBJECTIVES: Presence of common MEFV gene mutations strengthened the diagnosis of FMF in addition to the typical clinical characteristics of FMF. However, there are also rare mutations. P369S, A744S, R761H, K695R, F479L are the main rare mutations in Turkish population. We aimed to evaluate FMF patients with a single allele MEFV mutation and to compare patients with common and rare mutations. METHODS: We retrospectively reviewed the medical records of FMF patients with a single allele mutation who were followed up between 2008 and 2013 in six centres. We compared the patients with rare and common mutations for disease severity score, frequent exacerbations ( >1 attack per month), long attack period (>3 day), symptoms, age at the onset of symptoms, gender, consanguinity, and family history. RESULTS: Two hundred and seventeen patients (M/F=101/116) with the diagnosis of FMF and single mutation were included. Heterozygote mutations were defined as common (M694V, V726A, M68OI) and rare mutations (A744S, P369S, K695R, R761H, F479L). Sixty-seven patients (27 males, 40 females) had one single rare mutation and 150 (74 males, 76 females) had one single common mutation. No difference was found between the rare and common mutations with respect to the disease severity score. There was no significant difference between common and rare heterozygote form of mutations in terms of disease severity. CONCLUSIONS: Patients with typical characteristics of FMF, with some rare mutations (A744S, P369S) should be treated in the same manner as patients with a common mutation. PMID- 26005882 TI - Telangiectasia as a potential clinical marker of microvascular lesions in systemic sclerosis patients from EUSTAR data in China. AB - OBJECTIVES: To investigate the prevalence and clinical relevance of telangiectasia in Chinese patients with systemic sclerosis (SSc). METHODS: Data from 230 SSc EUSTAR patients from Peking Union Medical College Hospital (2009 2011) that fulfilled the 1980 American College of Rheumatology SSc classification criteria were prospectively collected. Demographic, clinical, and laboratory data were calculated between groups with and without telangiectasia, and a six-minute walk test, pulmonary function test (PFT), transthoracic echocardiography (TTE), right heart catheterisation (RHC) and modified Rodnan skin score (mRSS) were performed. RESULTS: 96 patients (41.7%) were diagnosed with telangiectasia. There were no significant differences between patients with and without telangiectasia based on gender, age at onset, Raynaud's phenomenon (RP) duration, or SSc classification. Disease duration both from RP onset of patients and from first non-RP manifestation of patients with telangiectasia was significantly longer than patients without (p<0.05). RP (97.9% vs. 90.3%), finger/toe sclerosis (96.9% vs. 88.1%), facial sclerosis (68.8% vs. 53.7%), digital ulcers (DUs; 40.6% vs. 23.1%), digital pitting (49.0% vs. 33.8%), joint contracture (20.8% vs. 10.4%) and erythrocyte sedimentation rate elevation (26.7% vs. 14.8%) were significantly greater in telangiectasia patients (p<0.05). There were no differences in autoantibody development between patients with and without telangiectasia (p>0.05). PFT showed that forced vital capacity (77.0+/-17.26 vs. 83.05+/-16.53, p=0.005) and diffusion capacity for CO of the lung (58.9+/-19.4 vs. 65.7+/-19.7, p=0.030) were lower, while forced expiratory volume ratio (87.02+/-7.8 vs. 84.33+/-7.1, p=0.029) was higher in SSc with telangiectasia. Pulmonary artery hypertension (PAH) prevalence (25.0% vs. 14.2%) was significantly greater in patients with telangiectasia. CONCLUSIONS: Telangiectasia are common in Chinese SSc patients and usually associated with DUs, RP, and PAH. Telangiectasia could be a clinical marker of microvascular disease in SSc. PMID- 26005883 TI - Lack of association of TNFAIP3 and JAK1 with Behcet's disease in the European population. AB - OBJECTIVES: Behcet's disease (BD) is an immune-mediated and complex disease which has been associated with HLA class I molecules although other genes such as IL23R and IL10 have also been involved in the susceptibility to BD. Recently, an association of variants of the JAK1 and TNFAIP3 genes with the disease has been reported in the Chinese Han population. The aim of the present work was to asses whether the association described in Asian populations is replicated in Europeans. METHODS: This study includes a total of 1155 Spanish subjects of European origin (372 BD and 783 unrelated healthy individuals). Patients were recruited from different hospitals and controls were collected in the same geographic regions and they matched with patients in age and gender. A total of five SNPs, two in the JAK1 gene: rs2780815 and rs310241 and the other three in the TNFAIP3: rs10499194, rs9494885 and rs610604, were included in this study. The genotyping of these SNPs was performed using a real time PCR system (TaqMan(r) SNP Genotyping Assays). RESULTS: No statistically significant differences were found when the patient and control groups were compared. The distribution of the risk alleles was similar in patients with and without eye manifestations and in patients with and without HLA-B*51. CONCLUSIONS: The association of variants of the genes JAK1 and the TNFAIP3 with BD which has been described in the Chinese population was not replicated in Europeans. PMID- 26005884 TI - On scene injury severity prediction (OSISP) algorithm for car occupants. AB - Many victims in traffic accidents do not receive optimal care due to the fact that the severity of their injuries is not realized early on. Triage protocols are based on physiological and anatomical criteria and subsequently on mechanisms of injury in order to reduce undertriage. In this study the value of accident characteristics for field triage is evaluated by developing an on scene injury severity prediction (OSISP) algorithm using only accident characteristics that are feasible to assess at the scene of accident. A multivariate logistic regression model is constructed to assess the probability of a car occupant being severely injured following a crash, based on the Swedish Traffic Accident Data Acquisition (STRADA) database. Accidents involving adult occupants for calendar years 2003-2013 included in both police and hospital records, with no missing data for any of the model variables, were included. The total number of subjects was 29128, who were involved in 22607 accidents. Partition between severe and non severe injury was done using the Injury Severity Score (ISS) with two thresholds: ISS>8 and ISS>15. The model variables are: belt use, airbag deployment, posted speed limit, type of accident, location of accident, elderly occupant (>55 years old), sex and occupant seat position. The area under the receiver operator characteristic curve (AUC) is 0.78 and 0.83 for ISS>8 and ISS>15, respectively, as estimated by 10-fold cross-validation. Belt use is the strongest predictor followed by type of accident. Posted speed limit, age and accident location contribute substantially to increase model accuracy, whereas sex and airbag deployment contribute to a smaller extent and seat position is of limited value. These findings can be used to refine triage protocols used in Sweden and possibly other countries with similar traffic environments. PMID- 26005886 TI - [Biosimilars: old debates, new arguments]. PMID- 26005885 TI - Attenuation of lead neurotoxicity by supplementation of polyunsaturated fatty acid in Wistar rats. AB - BACKGROUND: Among various types of polyunsaturated fatty acid (PUFA), omega-3 fatty acids play a crucial role in development and function of the brain. This study was undertaken to investigate the possible neuroprotective efficacy of omega-3 fatty acid on lead-induced neurotoxicity in rats. MATERIAL AND METHODS: The experiment was carried out on 32 male Wistar rats divided into four groups. The first group (control) was treated with distilled water and second group with lead acetate at the doses of 3 mg/kg b.wt. (body weight)/oral, whereas third and fourth groups were simultaneously treated with lead acetate (3 mg/kg b.wt.) plus omega-3 fatty acid (300 mg/kg b.wt./oral) and lead acetate (3 mg/kg b.wt.) plus vitamin E (100 mg/kg b.wt./oral), respectively, for a period of 90 days. Their biochemical and histopathological investigations have been carried out. RESULTS: The level of lead was markedly elevated in brain (4.71-fold) and blood (5.65 fold), also increased levels of ROS, GSH, LPO with concomitant reduction in the activities of delta-ALAD, CAT, SOD, and GPx. In addition, lead-induced brain damage was indicated by histopathological changes. Omega-3 fatty acid resulted in marked improvement in most of the biochemical parameters as well as histopathological changes in rats. The results obtained were compared with vitamin E as the standard antioxidant agents. DISCUSSION: Omega-3 fatty acid significantly (P < 0.05) decreased the effect of lead-induced brain damage as well as biochemical changes similar to that of standard drug, vitamin E. So, our result suggested that omega-3 fatty acid may play a protective role in lead induced neurotoxicity and associated human health risk. PMID- 26005887 TI - [Methods to obtain platelet-rich plasma and osteoinductive therapeutic use]. AB - INTRODUCTION: Platelet-Rich Plasma (PRP) is autologous plasma with higher concentration of platelet than basal level, because of an extracting and concentration process. PRP therapeutical use, as osteinductor role, is a controversial issue, due to there are no clinical studies with rigorous design and no firm conclusions can be drawn regarding its uses. Propose: To provide information about methods to obtain PRP, legal considerations about its extraction and use, molecular mechanism of action, as well as available evidence about security and tolerance. RESULTS: PRP can be obtained by manual procedures (opened technique) or disposable kits (closed technique), the latter being medical devices classified as type IIa. AEMPS considers PRP as a drug, establishing some minimum requirements to guarantee safety, traceability, pharmacovigilance and information. PRP provides ideal qualities to play a powerful osteoinductor role to speed up fracture healing or to produce an efficiently and quickly osseointegration of different bone implants, due to the high growth factors content. Infiltration tolerance is generally good, however, it has to be taken into account its great angiogenical potential. CONCLUSIONS: In view of its production and application characteristics, PRP is considered as a drug on restricted medical prescription by the AEMPS, so pharmacy department must, at least, supervise its management and handling. PMID- 26005888 TI - [Implementation of a robot for the preparation of antineoplastic drugs in the Pharmacy Service]. AB - OBJECTIVE: To describe the implementation of a robot for the preparation of antineoplastic drugs in the Pharmacy Service and to be able to analyze the added value to pharmacotherapy. METHODS: The implementation was carried out in June 2012 at a tertiary level Hospital, taking place in two periods: 1- test period with the installation of the robot, with technical configuration of the equipment and validation of 29 active ingredients and the integration of electronic prescribing software with the robot application (9 months). 2- Usage period (22 months). On the other hand, training was given to pharmacists and nurses. The robot uses image recognition, barcode identification and gravimetric controls for proper operation. These checks provide information about the error ratio in the preparation, with a margin of +/- 10%, which after a pilot study was restricted to a range of +/-4%. The robot was programmed to recognize bags, infusion pumps, syringes and vials. The added value was assessed for 31 months by identifying preparation's errors. RESULTS: 11,865 preparations were made by the robot, which meant approximately 40% of all antineoplastic prepared from 29 different active ingredients. 1.12% (n=133) of the errors were identified by the robot and therefore didn't reach the patient (negative desviation - 4%). These errors were corrected manually. CONCLUSION: The implementation of a robot in the preparation of antineoplastic drugs allows to identify errors therefore preventing them to arrive to the patient. This promotes safety and quality of the process, reducing the exposure to cytotoxic drugs from the manipulator. PMID- 26005889 TI - [Etanercept on steroid-refractary acute graft-versus-host disease]. AB - Objetive: To describe etanercept use and effectiveness on steroid- refractary acute graft-versus-host disease after hematopoietic cell transplantation. METHOD: Patients treated with etanercept as off label use for steroid-refractary acute graft-versus-host disease were selected and each patient's medical history was reviewed to assess the clinical response. RESULTS: The study included five patients: four presented with digestive manifestations and one presented pulmonary and liver manifestations. 80% of patients showed a clinical response: 60% a partial response and 20% a total response. In four cases etanercept 25mg was administered twice a week with variable duration of treatment, achieving no response in 1 case (3 weeks), partial response in two 2 cases (4 weeks and 8 weeks) and a complete response in 1 case (8 week period). Only one case was treated with etanercept 50mg administered twice a week for 5 weeks with a partial treatment response. CONCLUSIONS: The clinical response rate is consistent with the previously published data. This updates the scarce bibliographic information about etanecept use in steroid-refractary acute graft-versus-host disease. Due to clinical design limitations and the small patient population, future clinical studies should be conducted to assess the efficacy and security of etanercept in these patients. PMID- 26005890 TI - [Design and validation of a satisfaction survey with pharmaceutical care received in hospital pharmacyconsultation]. AB - OBJECT: To design and to validate a questionnaire to assess satisfaction with pharmaceutical care (PC) received at the hospital pharmacy. METHODS: Multicentric study in five andalusian hospital in January 2013. A bibliography search was performed in PUBMED; MESH term; pharmaceutical services, patients satisfaction and questionnaire. Next, the questionnaire was produced by Delphi methodology with ten items and with the following variables; demographics, socials, pharrmacologicals and clinics which the patient was asked for the consequences of the PC in his treatment and illness and for the acceptance with the received service. The patient could answer between one= very insufficient and five= excellent. Before the validation phase questionnaire, a pilot phase was carried out. Descriptive analysis, Cronbach's alpha coefficient and intraclass correlation coefficient (ICC) were performed in both phases. Data analysis was conducted using the SPSS statistical software package release 20.0. RESULTS: In the pilot phase were included 21 questionnaires and 154 of them in validation phase (response index of 100%). In the last phase, 62% (N=96) of patients were men. More than 50% of patients answered "excelent" in all items of questionnaire in both phases. The Cronbach's alpha coefficient and ICC were 0.921 and 0.915 (95%IC: 0.847-0.961) and 0.916 and 0,910 (95%IC: 0.886-0.931) in pilot and validation phases, respectively. CONCLUSIONS: A high reliability instrument was designed and validated to evaluate the patient satisfaction with PC received at hospital pharmacy. PMID- 26005891 TI - [Experience of off-label use of Eltrombopag in the treatment of thrombocytopenia associated with solid tumors]. AB - PURPOSE: To describe the results of the off-label use of eltrombopag in patients with solid tumors and thrombocytopenia that limits chemotherapy. METHODS: Retrospective observational study including all patients with solid tumors who were treated with eltrombopag for thrombocytopenia during the chemotherapy treatment between January 2012 and December 2014. RESULTS: Six patients, with solid tumors and thrombocytopenia that limits chemotherapy treatment, received eltrombopag during the study and it was observed a decrease in the delay of chemotherapy cycles (4.83 +/- 4.79 delayed cycles before starting eltrombopag vs 2.50 +/- 4.32 delayed cycles during the treatment with eltrombopag, p=0.492) and an increase in the percentage of administrated dosage (89.29 +/- 13.36% vs 91.43 +/- 10.69%, p=0.682). Also, there was an increase in platelet nadir (55.29 +/- 16.45x109/L vs 76.14 +/- 36.38x109/L, p=0.248) without platelet transfusion support in any patient during treatment with eltrombopag. CONCLUSIONS: eltrombopag has resulted to be an alternative in the treatment of patients with thrombocytopenia that limits chemotherapy, clinical trials with more number or patients are needed to confirm these results. PMID- 26005892 TI - [Cost-effectiveness analysis of Belimumab in patients with systemic lupus erythematosus in Spain]. AB - OBJECTIVE: To estimate the cost-effectiveness of belimumab in patients with systemic lupus erythematosus (SLE) presenting positive biomarkers and active disease despite standard treatment (ST), from the Spanish social perspective. METHODS: A microsimulation model was used to estimate the cost-effectiveness of belimumab plus ST versus ST alone. A treatment duration of two years with a life time horizon were considered. Efficacy data were obtained from belimumab clinical trials and the evolution of the disease was simulated from John Hopkins ' patient cohort data in the United States. Utility data were obtained from literature review. Direct and indirect costs were calculated based on Spanish published data (?, 2014), applying a discount rate (DR) of 3% to both costs and effects. Results were expressed as incremental cost-effectiveness ratio (ICER) in terms of gained life years (LY) and quality of life adjusted life years (QALYs). Probabilistic (PSA) and deterministic sensitivity analyses (DR of 0% and 5%, 5-years treatment duration and excluding indirect costs) were performed to determine the robustness of the model. RESULTS: The incremental cost-effectiveness ratio (ICER) was 16,647? per life year gained, with an incremental cost-utility ratio (ICUR) of 23,158? per additional QALY gained. In 68% of the scenarios simulated in the PSA, belimumab was found to be a cost-effective alternative, considering a threshold of 30,000?/ QALY. CONCLUSION: Belimumab can be regarded as a cost-effective alternative from the Spanish social perspective. PMID- 26005893 TI - Trastuzumab emtansine in locally advanced or metastatic HER2 positive breast cancer; GENESIS-SEFH drug evaluation report. AB - Trastuzumab emtansina (T-DM1) is an antibody-drug conjugate directed against the HER2 for the treatment of HER2+ mestastatic breast cancer (MBC), who has previously received trastuzumab plus a taxane. According to the results of the EMILIA trial versus lapatinib plus capecitabine T-DM1 shows an improvement in progression-free survival (PFS) and the overall survival (OS). It has a favorable profile reducing the incidence of grade 3-4 adverse reactions such as hand-foot syndrome and diarrhea. On the contrary increases significantly severe thrombocytopenia; bleeding risk and liver function should also be monitored. With the current import price T-DM1 has a cost per QALY of over 120,000 ?. The price of the drug for the Spanish NHS has not yet been established. Drug cost would be the key factor in the sensitivity analysis and a 50% reduction in the price of the drug would place it close to the threshold of cost-effectiveness usually considered in our midst. According to the budget impact model used, a maximum of 1,218 patients / year and the budgetary impact throughout the Spanish state would be at ? 70,490,850. In the initial analysis no advantage was found for T-DM1 in those patients without visceral involvement. Although a subsequent re-analysis of the results of PFS in which the definition of visceral involvement was specified a significant benefit was shown in this subgroup. We believe that this approach introduces a high degree of uncertainty, which does not guarantee the benefit achieved for this subgroup of patients. PMID- 26005894 TI - Off-label and unlicensed utilization of drugs in a Brazilian pediatric hospital. AB - AIM: To describe the off-label and unlicensed utilization patterns of drugs in a Brazilian pediatric hospital. METHODS: The research consisted of a descriptive, prospective and cross-sectional study. RESULTS: A total of 1,158 medicines were prescribed for 320 patients, accounting for 65 different drugs. Regarding the classification of drug utilization, the majority of the drugs were prescribed as in-label (57.2%), followed by off-label (36.4%) and by unlicensed (6.3%). The prevalences of unlicensed and off-label utilization of drugs in the studied population were 20.9 and 77.8%, respectively. Polypharmacy was highly associated to both off-label and unlicensed regimen (OR 12.9; 95% CI 3.07-54.2 and OR 3.68; 95% CI 2.02-6.69, respectively) whereas preschool children were less prone to unlicensed prescription (OR 0.39; 95% CI 0.19-0.79). Sex and length of hospitalization were not related to these outcomes. CONCLUSIONS: Further studies are necessary to verify the impact of this pattern on the occurrence of adverse drug events. PMID- 26005895 TI - [Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: experience of use]. AB - OBJECTIVE: To evaluate the results obtained with the combined use of nab paclitaxel and gemcitabine in the treatment of patients with metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Retrospective observational study. Patients treated with nab-paclitaxel and gemcitabine between January of 2013 and January of 2014 were selected. Demographical and clinical data were gathered. RESULTS: 15 patients (mean age 59,4 +/- 10,3 years) were included. All patients received the combination of nab-paclitaxel and gemcitabine in first-line metastatic disease. Nine received adjuvant treatment before the disease was metastatic. The median progression-free survival rate with combined nab paclitaxel and gemcitabine was 5,6 months (95% CI: 4,44 - 8,03). In two patients the treatment was stopped due to toxicity. CONCLUSIONS: The treatment with nab paclitaxel and gemcitabine in our patients resulted in progression-free survival rates similar to those published in clinical trials with good treatment tolerability. PMID- 26005896 TI - [Fatal Outcome for subcutaneous administration of Pegylated IFN alpha 2b in a man with Chronic C hepatitis under treatment with traditional bitherapy]. PMID- 26005897 TI - Quantitative Assessment of Destruxins from Strawberry and Maize in the Lower Parts per Billion Range: Combination of a QuEChERS-Based Extraction Protocol with a Fast and Selective UHPLC-QTOF-MS Assay. AB - The entomopathogenic fungus Metarhizium brunneum is widely applied as a biological pest control agent. Consequently, its use has to be accompanied by a risk management approach, which includes the need to monitor the fate of its bioactive metabolites in the environment, for example, in treated crops. A fast and selective UHPLC-QTOF-MS method was developed to monitor the presence of secreted destruxins in two model food plants for the application of this fungal biocontrol agent, namely, strawberry and maize. The liquid chromatography-mass spectrometric assay for destruxin trace analysis is combined with a novel QuEChERS-based extraction protocol. The whole assay was optimized for the application in these crops, and it allows quantitative analysis of the major M. brunneum metabolites destruxin A, 1, destruxin B, 2, and destruxin E, 3, down to the parts per billion range. In strawberry, limits of quantitation (LOQs) were found to be <2.0 ppb for all analytes; in maize LOQs were found to be <3.2 ppb for destruxin A and destruxin B. Destruxin E showed a distinctive loss of recovery in maize and was excluded from further quantitative analysis in this crop. For both crops assay linearities ranged from the LOQs to 100 ppb, interassay repeatabilities (RSD) were found to be better than 16.4%, and accuracies ranged from 83.5 to 105.3% (assessed at four spiking levels between 5 and 75 ppb). PMID- 26005898 TI - Analysis of Total Human Urinary Glycosaminoglycan Disaccharides by Liquid Chromatography-Tandem Mass Spectrometry. AB - The determination of complex analytes, present at low concentrations, in biological fluids poses a difficult challenge. This study relies on an optimized method of recovery, enzymatic treatment, and disaccharide analysis by liquid chromatography-tandem mass spectrometry to rapidly determine low concentrations of glycosaminoglycans in human urine. The approach utilizes multiple reaction monitoring (MRM) of glycosaminoglycan disaccharides obtained from treating urine samples with recombinant heparin lyases and chondroitin lyase. This rapid and sensitive method allows the analysis of glycosaminoglycan content and disaccharide composition in urine samples having concentrations 10- to 100-fold lower than those typically analyzed from patients with metabolic diseases, such as mucopolysaccharidosis. The current method facilitates the analysis low (ng/mL) levels of urinary glycosaminoglycans present in healthy individuals and in patients with pathological conditions, such as inflammation and cancers, that can subtly alter glycosaminoglycan content and composition. PMID- 26005899 TI - Construction of Fe3O4/Vancomycin/PEG Magnetic Nanocarrier for Highly Efficient Pathogen Enrichment and Gene Sensing. AB - Infectious diseases, especially pathogenic bacterial infections, pose a growing threat to public health worldwide. As pathogenic bacteria usually exist in complex experimental matrixes at very low concentrations, developing a technology for rapid and biocompatible sample enrichment is essential for sensitive diagnosis. In this study, an Fe3O4/Vancomycin/PEG magnetic nanocarrier was constructed for efficient sample enrichment and in situ nucleic acid preparation of pathogenic bacteria for subsequent gene sensing. We attached Vancomycin, a well-known broad-spectrum antibiotic, to the surface of Fe3O4 nanoparticles as a universal molecular probe to target bacterial cells. Polyethylene glycol (PEG) was introduced to enhance the nanocarrier's water solubility and biocompatibility. Results show that the proposed nanocarrier achieved a 90% capture efficiency even if at a Listeria monocytogenes concentration of 1*10(2) cfu/mL. Contributing to the good water solubility achieved by the employment of modified PEG, highly efficient enrichment (enrichment factor 10 times higher than PEG-free nanocarrier) can be completed in 30 min. Moreover, PEG would also develop the nanoparticles' biocompatibility by passivating the positively charged unreacted amines on the magnetic nanoparticles, thus helping to release the negatively charged bacterial genome from the nanocarrier/bacteria complexes when an in situ nucleic acids extraction step was executed. The outstanding bacterial capture capability and biocompatibility of this nanocarrier enabled the implementation of a highly sensitive gene-sensing strategy of pathogens. By employing an electrochemiluminescence-based gene-sensing assay, L. monocytogenes can be rapidly detected with a limit of detection of 10 cfu/mL, which shows great potential for clinical applications. PMID- 26005900 TI - Oxidoreductase-Facilitated Visualization and Detection of Human Cancer Cells. AB - Achieving highly selective and sensitive detection/visualization of intracellular biological events through the use of cell-penetrable, bioanalyte-activatable, turn-on probes is dependent on the presence of specific event-linked cellular biomarkers, if and only if there exist activatable probes that appropriately respond to the biomarker analyte. Here is described the evaluation of, and use in cellular imaging studies, a previously undisclosed naphthalimide probe QMeNN, whose fluorescence is deactivated by photoinduced electron transfer (PeT) quenching that results from the presence of a covalently linked biomarker specific quinone trigger group. Highly selective and rapid activation of the quinone group by the human cancer tumor-linked NAD(P)H: quinone oxido-reductase isozyme 1 (hNQO1) results in fast trigger group removal to yield a highly fluorescent green-energy-range reporter that possesses a high molar absorptivity; there is a 136-fold increase in brightness for the enzymatically produced reporter versus probe precursor, a value 4 times greater than previously reported for the hNQO1 analyte. The novel probe is taken up and activated rapidly within only hNQO1-positive human cancer cells; addition of an hNQO1 inhibitor prevents the selective activation of the probe. Comparison of cytosolic fluorescence intensity in positive cells versus background in negative cells yields a quantitative metric (positive-to-negative ratio, PNR) for judging hNQO1 activity. We show it is possible to determine hNQO1 presence in previously studied colorectal cancer cells and the unexplored ovarian cancer cell line NIH:OVCAR-3, with respective PNR values of 926 and 34 being obtained. Even with 10 min probe incubation, ready discrimination of positive cells from negative cells is achieved. Cell viability is unaffected by probe presence, thereby highlighting the practicality of probe use in live-cell imaging applications. PMID- 26005901 TI - Photo Induced Membrane Separation for Water Purification and Desalination Using Azobenzene Modified Anodized Alumina Membranes. AB - Water purification and desalination to produce end-use water are important agendas in 21st century, because the global water shortage is becoming increasingly serious. Those processes using light energy, especially solar energy, without the consumption of fossil fuels are desired for creating sustainable society. For these earth-friendly water treatments, nanoporous materials and membranes are expected to provide new technologies. We have reported before that the repetitive photo isomerization of azobenzene groups between the trans and cis isomers induced by the simultaneous irradiation of UV and visible lights accelerates the molecular movement of nearby molecules in nanoporous materials. After further studies, we recently found that the permeation of water through azobenzene modified anodized alumina membranes as a photo responsive nanoporous membrane was achieved by the simultaneous irradiation of UV and visible lights, while no water penetration occurred under no light, only single UV or visible light. The photo induced permeation of water was promoted by the vaporization of water with the repetitive photo isomerization of azobenzene. This membrane permeation achieved the purification of water solutions, because dye molecules and a protein dissolved in aqueous solutions were not involved in the photo induced penetrated water. When 3.5% of sodium chloride solution as model seawater was employed for this membrane separation, the salt content of the permeated water was less than 0.01% to accomplish the complete desalination of seawater. PMID- 26005902 TI - Quantitative Characterization of Gold Nanoparticles by Coupling Thin Layer Chromatography with Laser Ablation Inductively Coupled Plasma Mass Spectrometry. AB - Metal nanoparticles (NPs) determination has recently attracted considerable attention because of the continuing boom of nanotechnology. In this study, a novel method for separation and quantitative characterization of NPs in aqueous suspension was established by coupling thin layer chromatography (TLC) with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Gold nanoparticles (AuNPs) of various sizes were used as the model system. It was demonstrated that TLC not only allowed separation of gold nanoparticles from ionic gold species by using acetyl acetone/butyl alcohol/triethylamine (6:3:1, v/v) as the mobile phase, but it also achieved the separation of differently sized gold nanoparticles (13, 34, and 47 nm) by using phosphate buffer (0.2 M, pH = 6.8), Triton X-114 (0.4%, w/v), and EDTA (10 mM) as the mobile phase. Various experimental parameters that affecting TLC separation of AuNPs, such as the pH of the phosphate buffer, the coating of AuNPs, the concentrations of EDTA and Triton X-114, were investigated and optimized. It was found that separations of AuNPs by TLC displayed size dependent retention behavior with good reproducibility, and the retardation factors (R(f) value) increased linearly with decreasing nanoparticle size. The analytical performance of the present method was evaluated under optimized conditions. The limits of detection were in the tens of pg range, and repeatability (RSD, n = 7) was 6.3%, 5.9%, and 8.3% for 30 ng of 13 nm AuNPs, 34 nm AuNPs, and 47 nm AuNPs, respectively. The developed TLC-LA-ICP-MS method has also been applied to the analysis of spiked AuNPs in lake water, river water, and tap water samples. PMID- 26005903 TI - Photoinduced Four-State Three-Step Ordering Transformation of Photochromic Terthiophene at a Liquid/Solid Interface Based on Two Principles: Photochromism and Polymorphism. AB - We have investigated photoinduced ordering transformation of a photochromic terthiophene derivative by scanning tunneling microscopy (STM) at the trichlorobenzene (TCB)/highly oriented pyrolytic graphite (HOPG) interface. The open-ring and annulated isomers of the terthiophene formed two-dimensional molecular orderings with different patterns while the closed-ring isomer did not form any ordering. The ordering of the open-ring isomer exhibited polymorphism depending on the concentration of supernatant solution. Upon UV light irradiation to a solution of the open-ring isomer or the closed-ring isomer, ordering composed of the annulated isomer was irreversibly formed. Upon visible light irradiation or thermal stimulus to the closed-ring isomer, the two kinds of polymorph composed of the open-ring isomer were formed due to the polymorphism. By controlling photochromism and polymorphism among four states made of three photochemical isomers, four-state three-step transformation was achieved by in situ photoirradiation from a solution of the closed-ring isomer (no ordering) into the ordering composed of the open-ring isomer (ordering alpha and beta) followed by the orderings composed of the annulated isomer (ordering gamma). PMID- 26005904 TI - Solar Hydrogen Production by Amorphous Silicon Photocathodes Coated with a Magnetron Sputter Deposited Mo2C Catalyst. AB - Coupling of Earth-abundant hydrogen evolution catalysts to photoabsorbers is crucial for the production of hydrogen fuel using sunlight. In this work, we demonstrate the use of magnetron sputtering to deposit Mo2C as an efficient hydrogen evolution reaction catalyst onto surface-protected amorphous silicon (a Si) photoabsorbers. The a-Si/Mo2C photocathode evolves hydrogen under simulated solar illumination in strongly acidic and alkaline electrolytes. Onsets of photocurrents are observed at potentials as positive as 0.85 V vs RHE. Under AM 1.5G (1 sun) illumination, the photocathodes reach current densities of -11.2 mA cm(-2) at the reversible hydrogen potential in 0.1 M H2SO4 and 1.0 M KOH. The high photovoltage and low-cost of the Mo2C/a-Si assembly make it a promising photocathode for solar hydrogen production. PMID- 26005907 TI - The Grand Experiment changing peer review and the granting structure at Canada's largest funder of medical research. PMID- 26005908 TI - Benefits of "Best for Groin" Strategy Leading to a Transapical TAVI Dominance. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a recognized therapeutic option for high-risk and inoperable patients with aortic valve stenosis. The choice of access route is a matter of debate. We are presenting our 5-year experience of transapical TAVI dominance. PATIENTS: This single-center study includes 575 patients. Two groups were compared: transapical (TA) and transfemoral (TF) with 454 and 121 patients, respectively. Individual access route decision was made by our heart team following a clinical and computed tomography (CT) data based nonbiased strategy. The same team performed all procedures. The mean logistic EuroSCORE was significantly higher in the TA group, however, without difference in STS score. The number of patients with coronary artery disease, previous cardiac surgery, and low left ventricular ejection fraction was higher in the TA group. There were no significant differences in age and presence of other comorbidities. RESULTS: Procedural success in both TA and TF groups was high (97.9% and 97.6%). No patient died during the procedure. Patient survival (30 days: TF, 97.5% vs. TA, 95.7%; 1 year: TF, 94.6% vs. TA, 81.8%; 2 years: TF, 84.7% vs. TA, 76.7%; 3 years: TF, 59.9% vs. TA, 67.8%) and a low TF vascular complication rate (1.6%) are encouraging compared with other registry data. CONCLUSION: A "no competition" team approach strategy along with an experienced hybrid team leads to fewer vascular complications and better outcomes for both TA and TF TAVI patients. PMID- 26005909 TI - Longer- Versus Shorter-Duration Dual-Antiplatelet Therapy After Drug-Eluting Stent Placement: A Systematic Review and Meta-analysis. AB - BACKGROUND: The appropriate duration of dual-antiplatelet therapy (DAPT) after drug-eluting stent (DES) placement remains controversial. PURPOSE: To summarize data on clinical outcomes with longer- versus shorter-duration DAPT after DES placement in adults with coronary artery disease. DATA SOURCES: Ovid MEDLINE and EMBASE, 1996 to 27 March 2015, and manual screening of references. STUDY SELECTION: Randomized, controlled trials comparing longer- versus shorter duration DAPT after DES placement. DATA EXTRACTION: Two reviewers screened potentially eligible articles; extracted data on populations, interventions, and outcomes; assessed risk of bias; and used the Grading of Recommendations Assessment, Development and Evaluation guidelines to rate overall confidence in effect estimates. DATA SYNTHESIS: Among 1010 articles identified, 9 trials including 29,531 patients were eligible; data were complete for 28,808 patients. Moderate-quality evidence showed that longer-duration DAPT decreased risk for myocardial infarction (risk ratio [RR], 0.73 [95% CI, 0.58 to 0.92]) and increased mortality (RR, 1.19 [CI, 1.04 to 1.36]). High-quality evidence showed that DAPT increased risk for major bleeding (RR, 1.63 [CI, 1.34 to 1.99]). LIMITATION: Confidence in estimates were decreased owing to imprecision for most outcomes (particularly myocardial infarction), risk of bias from limited blinding in 7 of 9 studies, indirectness due to variability in use of first- and second generation stents, and off-protocol use of DAPT in some studies. CONCLUSION: Extended DAPT is associated with approximately 8 fewer myocardial infarctions per 1000 treated patients per year but 6 more major bleeding events than shorter duration DAPT. Because absolute effects are very small and closely balanced, decisions regarding the duration of DAPT therapy must take into account patients' values and preference. PRIMARY FUNDING SOURCE: None. PMID- 26005910 TI - Involvement of endoplasmic reticulum stress in angiotensin II-induced NLRP3 inflammasome activation in human renal proximal tubular cells in vitro. AB - AIM: NLRP3 inflammasome plays an important role in renal injury and may be a therapeutic target in the treatment of patients with progressive chronic kidney disease. In this study we investigated whether angiotensin II (Ang II)-induced NLRP3 inflammasome activation was linked to endoplasmic reticulum stress (ERS) in human renal proximal tubular cells in vitro. METHODS: Human kidney proximal epithelial cells (HK-2) were pretreated with telmisartan or 4-PBA, and then treated with Ang II. The expression levels of mRNAs and proteins related to NLRP3 inflammasomes and ERS was examined by real-time PCR, Western blot and immunofluorescence. RESULTS: Treatment with Ang II (10, 100, and 1000 nmol/L) increased the expression of the inflammasome markers NLRP3 and ASC, as well as caspase-1, IL-1beta, and IL-18 in dose- and time-dependent manners with peak levels detected at 100 nmol/L and 12 h. Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1beta, and IL-18 were significantly reduced by pretreatment with telmisartan (1 MUmol/L). Immunofluorescence studies showed that Ang II increased the expression of NLRP3 and ASC, which was inhibited by telmisartan. Furthermore, Ang II treatment increased the expression of ERS markers GRP78 and p-eIF2alpha in dose- and time-dependent manners, which was significantly reduced by telmisartan. Moreover, Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1beta, and IL-18 were significantly inhibited by pretreatment with the ERS inhibitor 4-PBA (5 mmol/L). CONCLUSION: Ang II treatment induces NLRP3 inflammasome activation in HK-2 cells in vitro and ER stress is involved in this process, which may represent a new mechanism for the renal rennin-angiotensin system to induce tubulointerstitial inflammation. PMID- 26005911 TI - Omega-3 fatty acids induce Ca(2+) mobilization responses in human colon epithelial cell lines endogenously expressing FFA4. AB - AIM: Free fatty acid receptor 4 (FFA4; formerly known as GPR120) is the G protein coupled receptor (GPCR) for omega-3 polyunsaturated fatty acids. FFA4 has been found to express in the small intestines and colons of mice and humans. In this study we investigate the effects of omega-3 polyunsaturated fatty acids on FFA4 in human colon epithelial cells in vitro. METHODS: HCT116 and HT-29 human colon epithelial cell lines endogenously expressing FFA4 were used. Intracellular Ca(2+) concentration ([Ca(2+)]i) was measured in fura 2-AM-loaded cells with fluorescence spectrophotometry. RT-PCR and immunohistochemistry were used to detect FFA4. RESULTS: Ten to 100 MUmol/L of omega-3 polyunsaturated fatty acids alpha-linolenic acid (alphaLA) or eicosapentaenoic acid (EPA) induced dose dependent [Ca(2+)]i increase in HCT116 and HT-29 cells, whereas docosahexaenoic acid (DHA) had no effect. In addition, the omega-6 fatty acids linoleic acid and gamma-linoleic acid also dose-dependently increase [Ca(2+)]i, but the mono unsaturated fatty acid oleic acid and saturated fatty acids such as stearic acid and palmitic acid had no effect. In HCT116 and HT-29 cells, the alphaLA-induced [Ca(2+)]i increase was partially inhibited by pretreatment with EGTA, phospholipase C inhibitor edelfosine, cADPR inhibitors 8-bro-cADPR or DAB, and abolished by pretreatment with Ca(2+)ATPase inhibitor thapsigargin, but was not affected by Gi/o protein inhibitor PTX or IP3R inhibitor 2-APB. CONCLUSION: Omega 3 and omega-6 long-chain polyunsaturated fatty acids (C18-20) induce Ca(2+) mobilization responses in human colonic epithelial cells in vitro through activation of FFA4 and PTX-insensitive Gi/o protein, followed by Ca(2+) release from thapsigargin-sensitive Ca(2+) stores and Ca(2+) influx across the plasma membrane. PMID- 26005912 TI - Dietary vitamin A restriction affects adipocyte differentiation and fatty acid composition of intramuscular fat in Iberian pigs. AB - The aim of this study was to investigate whether dietary vitamin A level is associated with differences in adipocyte differentiation or lipid accumulation in Iberian pigs at early growing (35.8kg live weight) and at finishing (158kg live weight). Iberian pigs of 16.3kg live weight were allocated to two feeding groups, one group received 10,000IU of vitamin A/kg diet (control); the other group received a diet with 0IU of vitamin A (var) for the whole experimental period. The dietary vitamin A level had no effect on growth performance and carcass traits. The early suppression of vitamin A increased the preadipocyte number in Longissimus thoracis (LT) muscle in the early growth period (P<0.001) and the neutral lipid content and composition (higher MUFA and lower SFA content) at the end of the finishing period (P<0.05). Vitamin A restriction in young pigs increases their lipogenic potential without affecting carcass traits. PMID- 26005913 TI - Release of copper from embedded solid copper bullets into muscle and fat tissues of fallow deer (Dama dama), roe deer (Capreolus capreolus), and wild boar (Sus scrofa) and effect of copper content on oxidative stability of heat-processed meat. AB - When venison with embedded copper bullets was subjected to different culinary processing procedures, the amount of copper released from the embedded bullet was affected more by the retention period of the bullet in the meat during cool storage, than by the different heating protocols. The presence of copper fragments had no significant effect on levels of thiobarbituric acid reactive substances (TBARS). Conversely, TBARS in lean meat (fallow deer, wild boar, roe deer) were significantly affected by culinary treatment (higher TBARS in boiled and boiled-stored meat than in meat barbecued or boiled in brine). In pork-beef patties doped with up to 28mg/kg Cu, TBARS increased after dry-heating and subsequently storing the meat patties. The amount of copper doping had no effect on TBARS for 0 and 7days of storage, but a significant effect at day 14 (fat oxidation retarded at higher Cu doses). Evidence is presented that wild boar meat may be more sensitive to fat oxidation than pork-beef. PMID- 26005914 TI - Ironic effects as reflexive responses: Evidence from word frequency effects on involuntary subvocalizations. AB - In ironic processing, one is more likely to think about something (e.g., white bears) when instructed to not think about that thing. To further investigate this phenomenon involving cognitive control, in the Reflexive Imagery Task (RIT), participants are instructed to not subvocalize the names of visual objects. On the majority of the trials, participants fail to suppress such subvocalizations. This finding supports theorizing that conscious thoughts can be triggered by external stimuli in a manner that is nontrivial, involuntary, and, importantly, reflex-like. These conclusions challenge intuitions that consciousness is unpredictable, whimsical, and somewhat insulated from external control. Perhaps these thoughts arise, not in a reflex-like manner, but from experimental demand or other high-level, strategic processes. This prevalent criticism would be inconsistent with the observation that the RIT effect is influenced by a stimulus parameter such as word frequency. Regarding demand characteristics, such an artifact would require participants to have a theory regarding how word frequency should influence responses. We introduce evidence that stimuli associated with high frequency names are more likely to yield involuntary subvocalizations than stimuli associated with low frequency names. These theoretically-relevant data suggest that ironic effects in paradigms such as the RIT resemble reflex-like processes. PMID- 26005915 TI - Mapping the emotional landscape: The role of specific emotions in conceptual categorization. AB - Although researchers generally subscribe to the opinion that emotions play a critical role in cognition, very few (see Niedenthal, Halberstadt, & Innes-Ker, 1999) have examined the specific interaction between the emotional state of the perceiver and the emotional meaning of stimuli in conceptual categorization - an important aspect of "higher-level" cognition. Niedenthal et al. (1999) advanced a fine-grained theory of emotional response categorization, arguing that emotional states increase the tendency to categorize concepts into a predictable set of emotional response categories characterized by the common, distinct emotional responses elicited by the concepts. Based on the pioneering work of Niedenthal et al., we further argued that (1) the specific emotion experienced by the individual should selectively facilitate the categorization of concepts associated with the same emotion, (2) both in terms of category inclusion and category exclusion, and (3) this facilitation effect should not be contingent on the awareness of the emotional state. In three experiments, participants were induced to experience different emotional states through movies or a facial feedback manipulation. They judged whether or not a target concept belonged to the same category as the two comparison concepts. Some of the concept triads shared emotional associations, while others didn't. Results showed that emotive participants had a greater tendency than those in a neutral mood to group concepts according to their emotional associations, and to distinguish concepts with different emotional associations. They were also more efficient in categorizing concepts that had specific emotional meaning corresponding to their own emotional state than to other emotional concepts. Furthermore, participants posing a disgust expression without their knowledge showed higher tendency to categorize concepts according to their relevance to disgust. Implications and potential applications of the findings were discussed. PMID- 26005916 TI - Palladium(II) complexes of OS donor N-(di(butyl/phenyl)carbamothioyl)benzamide and their antiamoebic activity. AB - Two promising palladium(II) compounds of general formula, cis-[Pd(L-O,S)2] [where HL-O,S = N-(di(butyl/phenyl)carbamothioyl)benzamide] as metal based antiamoebic drug candidates, have been synthesized. Both complexes are characterized in the solid state by FT-IR spectroscopy, TGA and single crystal X-ray study, as well as in solution by other spectroscopic techniques such as (1)H and (13)C NMR, and UV visible. All these studies confirm the coordination of ligands through oxygen and sulphur atoms upon thioenolization induced delocalization. Complexes adopt cis configuration in the solid state. Both the complexes and their respective ligands were screened in vitro for antiamoebic activity against HM1:1MSS strain of Entamoeba histolytica by microdilution method and cell viability in response to drugs was checked by using MTT assay. The IC50 values in the range 0.30-0.80 MUM for ligands as well as complexes compared to 1.40 for metronidazole along with their similar inhibitory effect on cell viability of HEK293 cells like metronidazole make them promising future antiamoebic drugs. PMID- 26005917 TI - Anti-cancer chalcones: Structural and molecular target perspectives. AB - Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold remained a fascination among researchers in the 21st century due to its simple chemistry, ease of synthesis and a wide variety of promising biological activities. Several natural and (semi) synthetic chalcones have shown anti-cancer activity due to their inhibitory potential against various targets namely ABCG2/P-gp/BCRP, 5alpha reductase, aromatase, 17-beta-hydroxysteroid dehydrogenase, HDAC/Situin-1, proteasome, VEGF, VEGFR-2 kinase, MMP-2/9, JAK/STAT signaling pathways, CDC25B, tubulin, cathepsin-K, topoisomerase-II, Wnt, NF-kappaB, B-Raf and mTOR etc. In this review, a comprehensive study on molecular targets/pathways involved in carcinogenesis, mechanism of actions (MOAs), structure activity relationships (SARs) and patents granted have been highlighted. With the knowledge of molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective anti-cancer chalcones. PMID- 26005918 TI - Synthesis, antimalarial and antitubercular activities of meridianin derivatives. AB - Meridianins are marine-derived indole alkaloids, known to possess kinase inhibitory and antimalarial activities. A series of N-aryl and heteroaryl sulfonamide derivatives of meridianins were prepared and screened for antimalarial activity against D6 and W2 strains of Plasmodium falciparum. 2-Nitro 4-trifluoromethyl sulfonamide derivative 14v displayed promising antiplasmodial activity against both strains with IC50 values of 2.56 and 3.41 MUM, respectively. These compounds were not cytotoxic to mammalian cell lines including VERO (monkey kidney fibroblasts), LLC-PK1 (pig kidney epithelial cells) and four cancer cell lines; SK-MEL (human malignant, melanoma), KB (human epidermal carcinoma), BT-549 (ductal carcinoma), SK-OV-3 (human ovary carcinoma) up to 25 MUg/ml. Furthermore, all sulfonamide derivatives along with acyl, alkyl and C-ring modified derivatives of meridianins were screened for antitubercular activity against a sensitive strain (H37Rv) of Mycobacterium tuberculosis (Mtb), wherein several compounds showed MIC values in the range of 5.2-304.8 MUM. Meridianin C (3) and meridianin G (7) showed anti-tubercular activity with MIC values of 111.1 and 304.8 MUM, respectively. The C-ring modified analog 12 exhibited potent anti-tubercular activity against H37Rv strain of Mtb with MIC of 5.2 MUM. Furthermore, the most potent analogs 11b and 12 were screened against two clinical isolates of M. tuberculosis INH(R) and MDR and one laboratory generated mutant strain Rif(R). These two analogs 11b and 12 displayed promising activity against these resistant strains with MIC values in the range of 5.2 187.7 MUM. This is the first report on the anti-tubercular activity of this scaffold. PMID- 26005919 TI - Histopatological alterations and oxidative stress in liver and kidney of Leuciscus cephalus following exposure to heavy metals in the Tur River, North Western Romania. AB - Pollution of the aquatic environment by heavy metals is a great concern worldwide. Freshwater fish ingests various metals through gills, skin or diet. Our aim was to investigate the oxidative stress and histopathological injuries induced by Fe, Cu, Zn, Pb, Cd in the liver and kidney of Leuciscus cephalus. Fish samples were collected from two sites in the Tur River, NW Romania, in upstream and downstream of a pollution source. Metals were differently distributed in the liver and kidney of fish. The highest concentrations of Fe, Cu and Pb were found in liver, whereas Zn and Cd concentrations were the highest in kidney in specimens collected from the downstream site. The histopathological changes were associated with metal bioaccumulation, being more severe in kidney than liver. Malondialdehyde (MDA) and advanced oxidation protein products (AOPP) increased significantly in the liver and kidney of fish from downstream site compared to upstream one, whereas reduced glutathione (GSH) decreased. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) increased significantly in livers, whereas SOD increased in kidney. Our study revealed that liver has a higher capacity and adaptability to counteract ROS compared to kidney. The more pronounced increase of hepatic SOD, CAT and GST activities is related milder structural changes observed in liver compared to kidney, where lesions were not reduced by antioxidant defense system. PMID- 26005920 TI - Effects of crude oil exposure and elevated temperature on the liver transcriptome of polar cod (Boreogadus saida). AB - Petroleum-related activities in the Arctic have raised concerns about the adverse effects of potential oil spill on the environment and living organisms. Polar cod plays a key role in the Arctic marine ecosystem and is an important species for monitoring oil pollution in this region. We examined potential interactions of oil pollution and global warming by analysing liver transcriptome changes in polar cod exposed to crude oil at elevated temperature. Adult males and females were kept at high (11 degrees C) or normal (4 degrees C) temperature for 5 days before exposure to mechanically dispersed crude oil for 2 days followed by recovery in clean sea water for 11 days at the two temperatures. Genome-wide microarray analysis of liver samples revealed numerous differentially expressed genes induced by uptake of oil as confirmed by increased levels of bile polycyclic aromatic hydrocarbon (PAH) metabolites. The hepatic response included genes playing important roles in xenobiotic detoxification and closely related biochemical processes, but also of importance for protein stress response, cell repair and immunity. Though magnitude of transcriptome responses was similar at both temperatures, the upregulated expression of cyp1a1 and several chaperone genes was much stronger at 11 degrees C. Most gene expression changes returned to basal levels after recovery. The microarray results were validated by qPCR measurement of eleven selected genes representing both known and novel biomarkers to assess exposure to anthropogenic threats on polar cod. Strong upregulation of the gene encoding fibroblast growth factor 7 is proposed to protect the liver of polar fish with aglomerular kidneys from the toxic effect of accumulated biliary compounds. The highly altered liver transcriptome patterns after acute oil exposure and recovery suggests rapid responses in polar cod to oil pollutants and the ability to cope with toxicity in relatively short time. PMID- 26005921 TI - Comparison of the acute effects of benzo-a-pyrene on adult zebrafish (Danio rerio) cardiorespiratory function following intraperitoneal injection versus aqueous exposure. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants. PAH exposure causes developmental toxicity in multiple fish species, while acute adult fish toxicity is thought to be minimal. The literature increasingly suggests sublethal PAH effects may occur, but differences in exposure route may confound conclusions. We hypothesized that acute PAH exposure in adult fish will cause cardiorespiratory impairment that will not differ with exposure route. In order to investigate this hypothesis, adult zebrafish (Danio rerio) were injected intraperitoneal (i.p.) twice with increasing concentrations of the prototypical PAH, benzo-a-pyrene (BaP; 0.1, 10, and 1000MUg/kg) or exposed aqueously (static, renewal at 24h; 16.2 and 162MUg/L) for 48h and compared to corresponding dimethylsulfoxide controls. No mortalities or significant effects on weight of the fish were noted at any exposure concentration or route. At 48h, fish were subjected to swimming tests with concurrent oxygen consumption measurement (n=10 fish/treatment) or echocardiography (n=12 fish/treatment). Oxygen consumption (MO2) was increased at three swimming speeds in BaP-injected groups compared to control (p<0.01 in Fisher's LSD tests after two-way ANOVA). In contrast, aqueously BaP-exposed fish showed increased MO2 under only basal conditions. Despite increased oxygen demand, ventricular heart rate was significantly decreased in BaP-exposed fish, both injected and aqueously-exposed. Analysis of BaP body burdens in fish tissue allowed for identification of an overlapping dose group between exposure routes, through which comparisons of cardiorespiratory toxicity were then made. This comparison revealed most effects were similar between the two exposures routes, although minor differences were noted. At similar BaP body burdens, injected fish suffered from more severe bradycardia than aqueously exposed fish and had greater levels of increases in cytochrome P4501A (CYP1A) mRNA levels in liver and heart tissue compared to aqueous exposed fish. In conclusion, acute BaP exposure in adult zebrafish had negative effects on cardiorespiratory function. Differences in effect between exposure routes were attributed primarily to differences in bioavailability, since overall, similar effects were noted between the two exposure routes when similar BaP body burdens were achieved. PMID- 26005922 TI - Towards the design of organocatalysts for nerve agents remediation: The case of the active hydrolysis of DCNP (a Tabun mimic) catalyzed by simple amine containing derivatives. AB - We report herein a study of the hydrolysis of Tabun mimic DCNP in the presence of different amines, aminoalcohols and glycols as potential suitable organocatalysts for DCNP degradation. Experiments were performed in CD3CN in the presence of 5% D2O, which is a suitable solvent mixture to follow the DCNP hydrolysis. These studies allowed the definition of different DCNP depletion paths, resulting in the formation of diethylphosphoric acid, tetraethylpyrophosphate and phosphoramide species as final products. Without organocatalysts, DCNP hydrolysis occurred mainly via an autocatalysis path. Addition of tertiary amines in sub stoichiometric amounts largely enhanced DCNP depletion whereas non-tertiary polyamines reacted even faster. Glycols induced very slight increment in the DCNP hydrolysis, whereas DCNP hydrolysis increased sharply in the presence of certain aminoalcohols especially, 2-(2-aminoethylamino)ethanol. For the latter compound, DCNP depletion occurred ca. 80-fold faster than in the absence of organocatalysts. The kinetic studies revealed that DCNP hydrolysis in the presence of 2-(2-aminoethylamino)ethanol occurred via a catalytic process, in which the aminoalcohol was involved. DCNP hydrolysis generally depended strongly on the structure of the amine, and it was found that the presence of the OHCH2CH2N moiety in the organocatalyst structure seems important to induce a fast degradation of DCNP. PMID- 26005923 TI - Genotypic responses of bacterial community structure to a mixture of wastewater borne PAHs and PBDEs in constructed mangrove microcosms. AB - Mangrove microcosms capable of removing polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenyl ethers (PBDEs) from wastewater were established under everyday tidal and non-tidal flooding regimes, along with two different mangrove species. Defining how bacterial communities change with pollutants or across treatments will contribute to understanding the microbial ecology of in situ bioremediation systems. A semi-nested PCR-DGGE (denaturing gradient gel electrophoresis) approach was employed, with known genus/species-specific primers targeting the 16S rRNA genes of Sphingomonas and Mycobacterium (related to PAH degradation) and Dehalococcoides (related to PBDE degradation). Results showed that the composition of Mycobacterium- and Dehalococcoides-like populations was critically determined by tidal regime during a medium-term (4-8 months) exposure, while that of Sphingomonas-like population, along with total bacterial community, was more dependent on sediment layer and became prominently affected by tidal regime till the end of 8-month treatment. The effect of plant species was relatively small. Canonical correspondence analysis (CCA) further revealed that Sphingomonas- and Mycobacterium-like populations were significantly associated with phenanthrene and benzo(a)pyrene, respectively, while Dehalococcoides-like population was the only group significantly related to the highest PBDE congener (BDE-209) in the mangrove microcosms. PMID- 26005924 TI - Understanding the lateral movement of particles adsorbed at a solid-liquid interface. AB - In this paper we study the phenomenon of lateral movement of particles that are electrostatically adsorbed at a solid-liquid interface. The experimental system involves negatively charged silica particles of two different sizes (65 nm and 90 nm) that are exposed to the positively charged solid surface (silane coated silicon wafer) in sequential steps. The particle-adsorbed wafers are analyzed under a scanning electron microscope and the images are processed to determine the pair-correlation function for the particles adsorbed in the first step. From the pair correlation data and the particle surface coverage data we show that the adsorbed particles are mobile at the solid-liquid interface. In specific, we show that the adsorbed particles are mobile at the solid-liquid interface when there is a driving force for the adsorbed particles to move. The driving force in the scheme of experiments discussed in this paper is the reduction in the free energy of the system. PMID- 26005925 TI - Effects of inherent alkali and alkaline earth metallic species on biomass pyrolysis at different temperatures. AB - This work aimed to investigate effects of inherent alkali and alkaline earth metallic species (AAEMs) on biomass pyrolysis at different temperatures. The yield of CO, H2 and C2H4 was increased and that of CO2 was suppressed with increasing temperature. Increasing temperature could also promote depolymerization and aromatization reactions of active tars, forming heavier polycyclic aromatic hydrocarbons, leading to decrease of tar yields and species diversity. Diverse performance of inherent AAEMs at different temperatures significantly affected the distribution of pyrolysis products. The presence of inherent AAEMs promoted water-gas shift reaction, and enhanced the yield of H2 and CO2. Additionally, inherent AAEMs not only promoted breakage and decarboxylation/decarbonylation reaction of thermally labile hetero atoms of the tar but also enhanced thermal decomposing of heavier aromatics. Inherent AAEMs could also significantly enhance the decomposition of levoglucosan, and alkaline earth metals showed greater effect than alkali metals. PMID- 26005926 TI - Deep eutectic solvent pretreatment and subsequent saccharification of corncob. AB - Ionic liquid (ILs) pretreatment of lignocellulosic biomass has attracted broad scientific interest, despite high costs, possible toxicity and energy intensive recycling. An alternative group of ionic solvents with similar physicochemical properties are deep eutectic solvents (DESs). Corncob residues were pretreated with three different DES systems: choline chloride and glycerol, choline chloride and imidazole, choline chloride and urea. The pretreated biomass was characterised in terms of lignin content, sugars concentration, enzymatic digestibility and crystallinity index. A reduction of lignin and hemicellulose content resulted in increased crystallinity of the pretreated biomass while the crystallinity of the cellulose fraction could be reduced, depending on DES system and operating conditions. The subsequent enzymatic saccharification was enhanced in terms of rate and extent. A total of 41 g fermentable sugars (27 g glucose and 14 g xylose) could be recovered from 100g corncob, representing 76% (86% and 63%) of the initially available carbohydrates. PMID- 26005927 TI - Microbial diversity and the implications of sulfide levels in an anaerobic reactor used to remove an anionic surfactant from laundry wastewater. AB - The objective of this study was to evaluate the removal of linear alkylbenzene sulfonate (LAS) from commercial laundry wastewater using an expanded granular sludge bed (EGSB) reactor with two specific LAS loading rates (SLLRs), 1.0 and 2.7 mg LAS gVS(-1)d (-1). The biomass was characterized using denaturing gradient gel electrophoresis (DGGE) and 16S Ion Tag sequencing. Higher LAS removal (92.9%) was observed in association with an SLLR of 1.0 mg LAS gVS(-1) d(-1) than with an SLLR of 2.7 mg LAS gVS(-1) d(-1) (58.6%). A relationship between the S(-2) concentration in the effluent and the surfactant removal efficiency was observed. This result is indicative of the inhibition of LAS-removing microbiota at S(-2) concentrations greater than 20 mg SL(-1). By using DGGE, microbial stratification was observed in the reactor in association with granule size, even though the reactor is considered to be a completely mixed regime. The RDP-classifier identified 175 genera, 33 of which were related to LAS degradation. PMID- 26005928 TI - The method of integrated kinetics and its applicability to the exo-glycosidase catalyzed hydrolysis of p-nitrophenyl glycosides. AB - In the present work we suggest an efficient method, using the whole time course of the reaction, whereby parameters kcat, Km and product KI for the hydrolysis of a p-nitrophenyl glycoside by an exo-acting glycoside hydrolase can be estimated in a single experiment. Its applicability was demonstrated for three retaining exo-glycoside hydrolases, beta-xylosidase from Aspergillus awamori, beta galactosidase from Penicillium sp. and alpha-galactosidase from Thermotoga maritima (TmGalA). During the analysis of the reaction course catalyzed by the TmGalA enzyme we had observed that a non-enzymatic process, mutarotation of the liberated alpha-d-galactose, affected the reaction significantly. PMID- 26005929 TI - Natures balancing act: examining biosynthesis de novo, recycling and processing damaged vitamin B metabolites. AB - Plants use B vitamin compounds as cofactors for metabolism. Biosynthesis de novo of these metabolites in plants is almost fully elucidated. However, salvaging of precursors as well as cofactor derivatives is only being unraveled. Furthermore, processing of these compounds when damaged by cellular activities to prevent deleterious effects on metabolism is emerging. Recent investigations indicate that the role of B vitamins goes beyond metabolism and are being linked with epigenetic traits, specific developmental cues, the circadian clock, as well as abiotic and biotic stress responses. More in depth investigations on the regulation of the provision of these compounds through biosynthesis de novo, salvage and transport is suggesting that plants may share the cost of this load by division of labor. PMID- 26005930 TI - Impact of pH on molecular structure and surface properties of lentil legumin-like protein and its application as foam stabilizer. AB - The capacity of a protein to form and stabilize foams and emulsions depends on its structural characteristics and its physicochemical properties. The structural properties of lentil legumin-like protein including molecular weight, hydrodynamic size, surface charge and hydrophobicity, and conformation were studied in relation to its air-water interfacial behaviors. Kinetics study suggested that the foaming stability was closely related to the surface conformation of the protein that strongly affected adsorption and re-organization of the protein layer at the air-water interface. Foams prepared at neutral pH showed dense and strong networks at the interface, where combination of the alpha helix secondary structure, medium hydrodynamic molecular size, and balance between solubility/hydrophobicity all contributed to the formation of such strong protein network at the interface. At pH 5.0, the protein formed a dense and thick network composed of randomly aggregated protein particles at the air-water interface. Whereas at pH 3.0, the unordered structure increased intra-protein flexibility producing a less compact and relaxed interface that reduces elasticity modulus with time and reduced foam resistance against collapse. This research revealed that lentil legumin-like protein could form long-life foams at mild acidic and neutral pH. The potential for use of lentil protein as a novel foaming plant-based stabilizer is demonstrated in food and non-food applications where stable, long-life foams are required. PMID- 26005931 TI - Amphiphilic copolymers with pendent carboxyl groups for high-efficiency loading and controlled release of doxorubicin. AB - In this paper, biodegradable amphiphilic block copolymer based on methoxy poly(ethylene glycol)-b-poly(5-allyloxy-1,3-dioxan-2-one) (mPEG-b-PATMC) was successfully synthesized in bulk using immobilized porcine pancreas lipase (IPPL) as the catalyst. After thiol-ene "click" reactions occur between thiol group of thioglycolic acid and carbon-carbon double bonds of PATMC segments, the pendent carboxyl-modified copolymer mPEG-b-PATMC-g-SCH2COOH was obtained for high efficiency loading and controlled release of doxorubicin (DOX) to cancer cells. Both the carboxyl-modified and unmodified copolymers could self-assemble to form nano-sized micelles in aqueous solution, while transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano size before and after DOX loading. Compared with the unmodified copolymer, the pendent carboxyl-modified structure in mPEG-b-PATMC-g-SCH2COOH could markedly enhance the drug-loading capacity and entrapment efficiency via the electrostatic interaction. The in vitro release studies showed more sustained drug release behavior of mPEG-b-PATMC-g-SCH2COOH without an initial burst, which could be further adjusted by the conditions of ionic strength and pH. Confocal laser scanning microscopy (CLSM) indicated efficient cellular uptake of DOX delivered by mPEG-b-PATMC-g-SCH2COOH, while MTT assays also demonstrated potent cytotoxic activity against HeLa cells. PMID- 26005932 TI - PEGylated ofloxacin nanoparticles render strong antibacterial activity against many clinically important human pathogens. AB - The rise of bacterial resistance against important drugs threatens their clinical utility. Fluoroquinones, one of the most important classes of contemporary antibiotics has also reported to suffer bacterial resistance. Since the general mechanism of bacterial resistance against fluoroquinone antibiotics (e.g. ofloxacin) consists of target mutations resulting in reduced membrane permeability and increased efflux by the bacteria, strategies that could increase bacterial uptake and reduce efflux of the drug would provide effective treatment. In the present study, we have compared the efficiencies of ofloxacin delivered in the form of free drug (OFX) and as nanoparticles on bacterial uptake and antibacterial activity. Although both poly(lactic-co-glycolic acid) (OFX-PLGA) and methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (OFX-mPEG-PLGA) nanoformulations presented improved bacterial uptake and antibacterial activity against all the tested human bacterial pathogens, namely, Escherichia coli, Proteus vulgaris, Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus, OFX-mPEG-PLGA showed significantly higher bacterial uptake and antibacterial activity compared to OFX-PLGA. We have also found that mPEG-PLGA nanoencapsulation could significantly inhibit Bacillus subtilis resistance development against OFX. PMID- 26005933 TI - Tuning in to teens: Improving parental responses to anger and reducing youth externalizing behavior problems. AB - Parent emotion socialization plays an important role in shaping emotional and behavioral development during adolescence. The Tuning in to Teens (TINT) program aims to improve parents' responses to young people's emotions with a focus on teaching emotion coaching. This study examined the efficacy of the TINT program in improving emotion socialization practices in parents and whether this reduced family conflict and youth externalizing difficulties. Schools were randomized into intervention and control conditions and 225 primary caregiving parents and 224 youth took part in the study. Self-report data was collected from parents and youth during the young person's final year of elementary school and again in their first year of secondary school. Multilevel analyses showed significant improvements in parent's impulse control difficulties and emotion socialization, as well as significant reductions in family conflict and youth externalizing difficulties. This study provides support for the TINT program in reducing youth externalizing behavior problems. PMID- 26005934 TI - [Marketing research in health service]. AB - Marketing research is the systematic and objective search for, and analysis of, information relevant to the identification and solution of any problem in the field of marketing. The key words in this definition are: systematic, objective and analysis. Marketing research seeks to set about its task in a systematic and objective fashion. This means that a detailed and carefully designed research plan is developed in which each stage of the research is specified. Such a research plan is only considered adequate if it specifies: the research problem in concise and precise terms, the information necessary to address the problem, the methods to be employed in gathering the information and the analytical techniques to be used to interpret it. Maintaining objectivity in marketing research is essential if marketing management is to have sufficient confidence in its results to be prepared to take risky decisions based upon those results. To this end, as far as possible, marketing researchers employ the scientific method. The characteristics of the scientific method are that it translates personal prejudices, notions and opinions into explicit propositions (or hypotheses). These are tested empirically. At the same time alternative explanations of the event or phenomena of interest are given equal consideration. PMID- 26005935 TI - [Oral communication: short history and some rules]. AB - The verbal communication represents the first human communication, that even more used and one most immediate. History and the development of communication is divided into historical periods, is complex and is bound to the period contingencies and to the social reference community. The oral communication is never isolated but is always taken by the not verbal one, including the silences, the position and the spaces (c.d. proxemics). The good communicator stimulates the cooperation through the conversation rule respect (qualities, amounts, way and relation) and reduces the possible asymmetry between broadcaster and receiver fitting its code to that of the interlocutor. PMID- 26005936 TI - [What if it is not an acute pyelonephritis? A monocentric experience of renal infarcts]. AB - BACKGROUND: Often the reduced contrast enhancement on CT renal imaging is radiologically interpreted as acute pyelonephritis (PNA), but it is the task of the clinician to assess a possible differential diagnosis such as a renal infarct and look for a cause. METHODS: In our experience (2010-2013), we hospitalized 51 patients with radiological imaging consistent with acute pyelonephritis in native kidneys. However, three of these cases result, after a second look, to be ischemic lesions, only sometimes complicated by over-infections (Tabella 1). RESULTS: FIRST CASE: a woman hospitalized for fever and flank pain with blood culture positive for Klebsiella Pneumoniae. Antibiotic therapy allowed a clinical laboratory improvement, but after 45 days persisted a focal wedge to the CT scan. The labs showed a anemia due to a sickle cell disease (SLC). The overview was finally interpreted as a renal infarct secondary to a sickle cell anemia, initially complicated by over-infection. SECOND CASE: a men hospitalized for a acute flank pain. The CT scan showed a left renal infarct and a partial renal artery thrombosis, resulting in abuse of cannabinoids and LAC positivity.Third case: a woman hospitalized for flank pain and slight movement of inflammatory markers. CT showed a cuneiform area in the right kidney not vascularized, that did not resolved after prolonged antibiotic therapy. The labs evidence a heterozygous mutation of prothrombin and MTHFR causing the renal infarction. CONCLUSIONS: 6% of radiographic imaging consistent with acute pyelonephritis concealed an underlying infarct, due to a unknown state of thrombophilia. The presence of hypovascular imaging to the TC scan, therefore, requires a differential diagnosis between PNA and infarct, especially in the case of atypical development. PMID- 26005937 TI - [Strongyloidiasis in nephrologic patients]. AB - Strongyloides stercoralis is a nematode causing strongyloidiasis, more frequent in immigrants and in travelers coming from tropical and subtropical areas. Infection is usually asymptomatic, frequently associated with eosinophilia. Immunocompromised patients are at high risk of developing hyperinfection syndrome (HI) or dissemination (SD), life threatening complications. Diagnosis of strongyloidiasis is firstly based on larvae isolation in stool samples; specific therapy involves the use of ivermectin as first choice and albendazole as second choice. We describe two cases of strongyloidiasis. The first one is a disseminated strongyloidiasis occurred in an Ecuadorian male on corticosteroid therapy for nephrotic syndrome due to focal segmental glomerulosclerosis, successfully treated with ivermectin; the second one involves another Ecuadorian male affected by acute kidney failure and nephrotic syndrome in IgA nephropathy with a diagnosis of chronic strongyloidiasis performed before starting the immunosuppressive treatment. The timing of treatment with ivermectin has allowed the complete eradication of the parasite before starting steroid and mycophenolate mofetil therapy, preventing the occurrence of a disseminated infection. Epidemiological data show us how strongyloidiasis is rising at our latitude because of increased number of migrants and travelers coming from endemic areas. So we must always exclude asymptomatic strongyloidiasis before prescribing a steroid or immunosuppressive therapy, in order to avoid developement of disseminated and often fatal disease. PMID- 26005938 TI - [Pharmacogenetics of immunosuppressants]. AB - Individualized drug therapy with immunosuppressants is an hot topic in transplantation. Therapeutic drug monitoring (TDM) is currently utilized to guide therapy, but toxic or subtherapeutic concentrations can only be identified after the drug is administered. Pharmacogenetics, by studying the relationship between a human genetic difference and drug response, holds great promises in optimizing immunosuppressive drug prescribing for solid organ transplantation.Nevertheless, a complete translation in the clinic has lagged behind,due to the overall complexity of the genetic approach, and the lack of sound evidence of identified genetic polymorphisms in ultimately explaining drug exposure. However, for tacrolimus it is likely that a genotype-based drug dosage can benefit patient outcome, while for cyclosporine data appear less convincing. Mycophenolic acid undergoes a complex metabolic pathway and various genes affecting drug disposition are under investigations, with promising results for some of them of being of value in aiding clinicians in decision making. Finally, for sirolimus and everolimus the lack of data and the absence of large prospective studies do not allow to draw any conclusion. PMID- 26005939 TI - [Immuknow and long term kidney graft]. AB - INTRODUCTION: The survival of transplanted kidneys has improved over time, but there is an increased risk of neoplastic disease. In the long time follow up, non melanoma skin cancers (NMSC) are the most frequent diseases and at the time of the occurrence of a NMSC we should evaluate a reduction or a change of IS. From a clinical point of view, the evaluation of immunosuppression is still a problem. The Immuknow assay may be of help in evaluating the immune response of transplanted patients. Here, by means of the ImmKnow assay, we tried to evaluate if long term renal transplant patients with NMSC are more immunosuppressed than patients without NMSC. METHODS: 33 long term kidney transplant patients, 16 with NMSC and 17 without NMSC, were recruited and blood samples were drawn at baseline, 4 months, 8 months and 12 months to check renal function, blood levels of cni and to perform immuknow assay. RESULTS: most values of T CD4+ reactivity were comprised between (atp) 225 and 525 ng/ml as for an moderate immunosuppression. No major differences have been observed between the two groups. No correlation with blood level of CNI was detected. T CD4+ activity changed over time for both the groups. 3 patients of the group without NMSC had levels of CD4+ reactivity constantly under (ATP) 225 ng/ml, classified as low per manifacturers definition. CONCLUSION: in our limited experience the measure of cell-mediated immunity by immuknow assay years after transplantation, has not evidenced any significant difference between patients positive for NMSC and negative patients. We observed variation of the CD4 reactivity with time, no correlation with the level of CNI and the useful identification of some cases of low levels of cell reactivity. PMID- 26005940 TI - [It's not always a cyst]. AB - Congenital arteriovenous renal fistulas are rare malformations due to abnormal communications between arterial and the venous systems. There are two types of congenital arteriovenous malformations: crisoid or, as in the present study, aneurysmal. Hematuria is the major and most common symptom, along with other clinical manifestations, such as hypertension, left ventricular hypertrophy, cardiac failure, and abdominal pain, but the congenital aneurysmatic arteriovenous renal fistulas can be also asymptomatic. Diagnosis can arise from a focused survey, suggested by a medical case or to be occasional, as in the present case of study. Ultrasonography with color duplex studies is the first line of imaging studies used in the diagnosis of renal arteriovenous malformations, The differential diagnosis must be made with other anechoic lesion: abscesses, tumors, hydronephrosis or, as in this case, a renal cyst. Angiography is the gold standard in the diagnosis of arteriovenous malformations, especially in those cases where the diagnostic -therapeutic treatment requires the endovascular treatment of the vessel, as in the case of a 46 years old man submitted in our clinic to the ultrasonography follow-up for a renal cyst. PMID- 26005941 TI - [Kidney Transplantation and inborn errors of metabolism]. AB - Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100 000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients. PMID- 26005942 TI - [The refusal and on the suspension (but, perhaps, not even on the beginning) hemodialysis replacement]. AB - The possibilities offered by scientific progress and technology are, more and more pressing questions about the limits of care:not in the perspective indicated by the policies of cost containment as a promotional support of the defense of fundamental rights of the human person. The Author explores the circumstances in which we must ask yourself some questions before or discontinuation of dialysis replacement. Discusses the scientific evidence and the recommendations contained in international documents, formulating a draft operational perspective advance care planning with 10 statements from which to draft a consensus document professional Italian. PMID- 26005943 TI - [Lupus Nephritis and Enteritis, a dual simultaneous involvement with Arteriolar Thrombosis]. AB - Arteriolar thrombosis is a complication that may occur during systemic lupus erithematosus. The pathophysiology could be related to abnormal endothelial function secondary to immune dysregulation. In particular renal and intestinal vessels may be target of thrombosis. We report a simultaneous appearance of lupus nephritis and enteritis in a young female who presented with renal failure and proteinuria. The presence of renal arteriolar thrombosis together with intestinal ischemia lead us to speculate a possible common pathways. PMID- 26005944 TI - [Insurance for the doctors: the news]. AB - The Italian Legislation considers the physician-patient relationship of "contractual" nature: such vision has determined both the taking of conscience of the personal rights from the patients and an important increase of the physician legal contentiouses. It is born the necessity for the Medical Doctors ones to protect him through the lighting of a' fit policy assicurativa that allows to adequately answer in case of physician-legal problem list. to the responsibilities that the Italian legislation imposes. Here they are exposed the last consequent legislative novelties that they aim to answer to the demands of guardianship both of the the patients/clients that of the medical professionals. PMID- 26005945 TI - [Characteristics of patients with chronic kidney disease referred to a nephrology outpatient clinic: results of Nefrodata study]. AB - Chronic kidney disease is acknowledged as one of the most relevant disease for public health. Knowledge of epidemiology of CKD may allow public health interventions both for prevention and treatment in order to limit burden and management costs. Nefrodata is a multicentric, prospective, and observational study conducted in Italy, including patients with CKD followed in a specialist setting. The study uses a web-based data setting; it includes 1263 subjects with an estimate glomerular filtration rate (eGFR) less than 60 ml/min *1,73 sqm, followed in outpatient clinics in Italy. Patients' characteristics analysis evidences that old subjects (mean age of 70.3 13.4 years, 55% of them older than 70 years), with cardiovascular morbidity (50,6%) and diabetics (37%) have a high prevalence. With the reduction of residual renal function, prevalence of hyperphospatemia, metabolic acidosis, use of erythropoiesis-stimulating agents, Vitamin D, and diuretics increases. Also allopurinol and gastric-protective drugs are widely used. Fifty-four and eight % of patients with CKD stage 4 and 65.9% of patients with CKD stage 5 received indication on nutritional therapy. PMID- 26005946 TI - [Rhabdomyolysis from gabapentin: a case report]. AB - Gabapentin (GBP) is a drug with different indications.Is not metabolized and is excreted by the kidney. The common side effects are: arthralgia, myalgia, fatigue, dizziness and ataxia. Rhabdomyolysis is an extremely rare side effect. This latter, that can be caused by trauma, strenuous exercise, infections, drugs and toxins, is a syndrome characterized by loss of skeletal muscle resulting in the release of myocyte components in the circulation. Following a case of rhabdomyolysis caused by GBP in patient with chronic renal failure (CRF). A 65 year-old diabetic men, in peritoneal dialysis (PD), affected by ischemic and hypokinetic cardiomyopathy, sensorimotor neuropathy. The patient reported: weakness, diffuse myalgias, hypotension. He had been taking GBP for three days, after the failure of therapies with tricyclic antidepressants, opioids and NSAIDs. Laboratory tests confirmed the increase of the indices of muscle necrosis.The immediate withdrawal of the drug in association with CAPD dialysis treatment, led to improvement of the clinical and biochemical parameters. During the last 10 years, 3 cases of rhabdomyolysis referred to the assumption of GBP have been reported. The use of PD for treatment of acute renal failure, has been significantly reduced over the years. The effectiveness of the purification method is much lower than the one with the continuous extracorporeal treatments. In conclusion, GBP may be associated with rhabdomyolysis. Since GBP toxicity in CRF patients is often overlooked, a better awareness of this phenomenon and a thorough follow-up of laboratory tests to detect any possible early adverse reaction is suggested. PMID- 26005947 TI - [Biologic drug-induced nephropathies]. AB - Frequency of autoimmune diseases secondary to biologic drugs used in rheumatic disorders (bio-DMARDS) is increasing. Reports of renal diseases is also increasing. The literature reports small series and many case reports of association between the use of a biologic drug and glomerular, vascular or interstitial nephropathies elapsing several months to more than 3 years from the beginning of treatment. Some of the reported glomerular diseases are already known to be possibly associated to the rheumatic disease. Prevention consists in careful clinical, immunologic and renal evaluation before giving bioDMARDS and in careful monitoring. These nephropathies and autoimmune diseases may go into remission just by drug discontinuation, which is mandatory in case of renal, nervous and pulmonary involvement. Corticosteroids or immunsuppressive drugs may be necessary. PMID- 26005948 TI - [What I read today?]. PMID- 26005949 TI - Control of alphavirus-based gene expression using engineered riboswitches. AB - Alphavirus-based replicons are a promising nucleic acid vaccine platform characterized by robust gene expression and immune responses. To further explore their use in vaccination, replicons were engineered to allow conditional control over their gene expression. Riboswitches, comprising a ribozyme actuator and RNA aptamer sensor, were engineered into the replicon 3' UTR. Binding of ligand to aptamer modulates ribozyme activity and, therefore, gene expression. Expression from DNA-launched and VRP-packaged replicons containing riboswitches was successfully regulated, achieving a 47-fold change in expression and modulation of the resulting type I interferon response. Moreover, we developed a novel control architecture where riboswitches were integrated into the 3' and 5' UTR of the subgenomic RNA region of the TC-83 virus, leading to an 1160-fold regulation of viral replication. Our studies demonstrate that the use of riboswitches for control of RNA replicon expression and viral replication holds promise for development of novel and safer vaccination strategies. PMID- 26005950 TI - Estimating magnetic fields of homes near transmission lines in the California Power Line Study. AB - The California Power Line Study is a case-control study investigating the relation between residences near transmission lines and risk of childhood leukemia. It includes 5788 childhood leukemia cases and 5788 matched primary controls born between 1986 and 2007. We describe the methodology for estimating magnetic fields at study residences as well as for characterizing sources of uncertainty in these estimates. Birth residences of study subjects were geocoded and their distances to transmission lines were ascertained. 302 residences were deemed sufficiently close to transmission lines to have non-zero magnetic fields attributable to the lines. These residences were visited and detailed data, describing the physical configuration and dimensions of the lines contributing to the magnetic field at the residence, were collected. Phasing, loading, and directional load flow data for years of birth and diagnosis for each subject as well as for the day of site visit were obtained from utilities when available; when yearly average load for a particular year was not available, extrapolated values based on expert knowledge and prediction models were obtained. These data were used to estimate the magnetic fields at the center, closest and farthest point of each residence. We found good correlation between calculated fields and spot measurements of fields taken on site during visits. Our modeling strategies yielded similar calculated field estimates, and they were in high agreement with utility extrapolations. Phasing was known for over 90% of the lines. Important sources of uncertainty included a lack of information on the precise location of residences located within apartment buildings or other complexes. Our findings suggest that we were able to achieve high specificity in exposure assessment, which is essential for examining the association between distance to or magnetic fields from power lines and childhood leukemia risk. PMID- 26005951 TI - Quantifying the influence of ambient temperature on dairy and beef cattle mortality in France from a time-series analysis. AB - In the context of climate change, the frequency and severity of extreme weather events are expected to increase in temperate regions, and potentially have a severe impact on farmed cattle through production losses or deaths. In this study, we used distributed lag non-linear models to describe and quantify the relationship between a temperature-humidity index (THI) and cattle mortality in 12 areas in France. THI incorporates the effects of both temperature and relative humidity and was already used to quantify the degree of heat stress on dairy cattle because it does reflect physical stress deriving from extreme conditions better than air temperature alone. Relationships between daily THI and mortality were modeled separately for dairy and beef cattle during the 2003-2006 period. Our general approach was to first determine the shape of the THI-mortality relationship in each area by modeling THI with natural cubic splines. We then modeled each relationship assuming a three-piecewise linear function, to estimate the critical cold and heat THI thresholds, for each area, delimiting the thermoneutral zone (i.e. where the risk of death is at its minimum), and the cold and heat effects below and above these thresholds, respectively. Area-specific estimates of the cold or heat effects were then combined in a hierarchical Bayesian model to compute the pooled effects of THI increase or decrease on dairy and beef cattle mortality. A U-shaped relationship, indicating a mortality increase below the cold threshold and above the heat threshold was found in most of the study areas for dairy and beef cattle. The pooled estimate of the mortality risk associated with a 1 degrees C decrease in THI below the cold threshold was 5.0% for dairy cattle [95% posterior interval: 4.4, 5.5] and 4.4% for beef cattle [2.0, 6.5]. The pooled mortality risk associated with a 1 degrees C increase above the hot threshold was estimated to be 5.6% [5.0, 6.2] for dairy and 4.6% [0.9, 8.7] for beef cattle. Knowing the thermoneutral zone and temperature effects outside this zone is of primary interest for farmers because it can help determine when to implement appropriate preventive and mitigation measures. PMID- 26005952 TI - Place of work and residential exposure to ambient air pollution and birth outcomes in Scotland, using geographically fine pollution climate mapping estimates. AB - OBJECTIVES: A relationship between ambient air pollution and adverse birth outcomes has been found in a large number of studies that have mainly used a nearest monitor methodology. Recent research has suggested that the effect size may have been underestimated in these studies. This paper examines associations between birth outcomes and ambient levels of residential and workplace sulphur dioxide, particulates and Nitrogen Dioxide estimated using an alternative method pollution climate mapping. METHODS: Risk of low birthweight and mean birthweight (for n=21,843 term births) and risk of preterm birth (for n=23,086 births) were modelled against small area annual mean ambient air pollution concentrations at work and residence location adjusting for potential confounding factors for singleton live births (1994-2008) across Scotland. RESULTS: Odds ratios of low birthweight of 1.02 (95% CI, 1.01-1.03) and 1.07 (95% CI, 1.01-1.12) with concentration increases of 1 ug/m(3) for NO2 and PM10 respectively. Raised but insignificant risks of very preterm birth were found with PM10 (relative risk ratio=1.08; 95% CI, 1.00 to 1.17 per 1 ug/m(3)) and NO2 (relative risk ratio=1.01; 95% CI, 1.00 to 1.03 per 1 ug/m(3)). An inverse association between mean birthweight and mean annual NO2(-1.24 g; 95% CI, -2.02 to -0.46 per 1 ug/m(3)) and PM10 (-5.67 g; 95% CI, -9.47 to -1.87 per 1 ug/m(3)). SO2 showed no significant associations. CONCLUSIONS: This study highlights the association between air pollution exposure and reduced newborn size at birth. Together with other recent work it also suggests that exposure estimation based on the nearest monitor method may have led to an under-estimation of the effect size of pollutants on birth outcomes. PMID- 26005953 TI - Newly developed apolipoprotein A-I mimetic peptide promotes macrophage reverse cholesterol transport in vivo. AB - BACKGROUND: We elucidated the effect of newly developed Fukuoka Apolipoprotein A I Mimetic Peptide (FAMP) on in vivo macrophage reverse cholesterol transport (RCT) and the underlying mechanisms. METHODS AND RESULTS: Cholesteryl ester transfer protein transgenic mice were divided into FAMP, and placebo control groups, and injected with FAMP or phosphate buffer saline intraperitoneally for 5 days. The FAMP group showed a significant decrease in plasma high-density lipoprotein cholesterol (HDL-C), and plasma from the FAMP group had an increased ability to promote ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from bone marrow macrophages ex vivo. Furthermore, mice were injected intraperitoneally with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of (3)H-tracer. The amount of (3)H tracer excreted into feces over 48h in the FAMP group was significantly higher than that in the control group. (3)H-cholesterol ester (CE)-HDL was injected intravenously and (3)H-cholesterol in blood was counted. In the FAMP group, plasma (3)H-CE-HDL decreased rapidly, and treatment with FAMP markedly increased the fractional catabolic rate. CONCLUSIONS: The administration of FAMP promoted ABCA1-dependent efflux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo despite reduced plasma HDL-C levels. FAMP might have atheroprotective potential. PMID- 26005954 TI - Secondary and subsequent DNA transfer during criminal investigation. AB - With the introduction of new multiplex PCR kits and instrumentation such as the Applied Biosystems 3500xl, there has recently been a rapid change in technology that has greatly increased sensitivity of detection so that a DNA profile can routinely be obtained from only a few cells. Research to evaluate the risks of passive transfer has not kept pace with this development; hence the risk of innocent DNA transfer at the crime-scene is currently not properly understood. The purpose of this study was to investigate the possibility of investigator mediated transfer of DNA traces with disposable nitrile-gloves used during crime scene examinations. We investigated the primary transfer of freshly deposited DNA from touched plastic, wood or metal substrates and secondary and tertiary transfer by a person wearing disposable nitrile-gloves and onto a third object. We show that with use of the new highly sensitive technologies available in forensic DNA analysis there is an enhanced probability to obtain a DNA-profile which has not been directly deposited on the object but is an outcome of one or more transfer events. The nitrile-gloves used by investigators during exhibit examination can act as a vector for DNA transfer from one item to another. We have shown that the amount of DNA deposited on an object affects the probability of transfer. Secondly, the type of substrate material that DNA is deposited onto has an impact on transfer rates. PMID- 26005955 TI - Taxonomic studies on seven species of Dysteria (Ciliophora, Cyrtophoria), including a description of Dysteria paraprocera sp. n. AB - The living morphology and infraciliature of seven Dysteria species isolated from the seas around China were investigated by observation of both living cells and specimens after protargol impregnation. Dysteria paraprocera sp. n. is characterized as follows: cell size 110-150*30-40MUm in vivo; body elongate rectangular and slender; a yellow-brown to dark red coloured pigment spot located at anterior end of body; three right kineties, with rightmost two extending apically to dorsal margin and innermost one starting at level of cytostome; eight or nine short left kineties at equatorial area. Dysteria nabia, D. proraefrons, D. brasiliensis, D. cristata, D. derouxi and D. crassipes basically correspond well with previous studies and therefore only brief descriptions are presented. Discussions of these species are helpful, however, in understanding the circumscription of Dysteria morphotypes. After careful comparison, Dysteria procera sensu Liu et al. (2008, Acta Hydrobiol. Sin. 32 (suppl.), 84-89 (in Chinese with English abstract)) was verified as a new species, D. subtropica sp. n., mainly because the innermost right kinety starts at mid-body. Small-subunit (SSU) rRNA genes were sequenced for four species of Dysteria, namely, D. paraprocera sp. n., D. subtropica sp. n., D. proraefrons and D. nabia. Sequence comparisons and phylogenetic analyses indicate that these species are well outlined and cluster with their congeners. PMID- 26005956 TI - Synthesis of oxadiazole-morpholine derivatives and manifestation of the repressed CD31 Microvessel Density (MVD) as tumoral angiogenic parameters in Dalton's Lymphoma. AB - A series of oxadiazole derivatives possessing morpholine 6a-l were synthesized by nucleophilic substitution reaction of key intermediates [1,3,4]-oxadiazole-2 thiol derivatives 5a-l with 4-(2-chloroethyl) morpholine. Compounds 6a-l were evaluated for their in vitro and in vivo antitumor potential in Dalton's Lymphoma Ascites (DLA) tumor cells. Among 6a-l series, compound 6a with concentration ~8.5MUM have shown extensive cytotoxicity in vitro and 85% reduction in tumor volume in vivo, attributing an excellent anti-proliferative capability towards the cancer cells. Compound 6a has extensively inhibited the Microvessel Density (MVD) or tumoral neovasculature which was evident from the CD31 immuno staining and peritoneal H&E staining. The major reason for the antiproliferative activity of compound 6a was due to the repression of tumor vasculature. PMID- 26005957 TI - Editorial in this issue--The importance of Renal Anatomy in Endourologic Procedures. PMID- 26005958 TI - Editor's Comment--How Dangerous is Testosterone Supplementation? PMID- 26005959 TI - Difference of opinion--In the era of flexible ureteroscopy is there still a place for Shock-wave lithotripsy? Opinion: YES. PMID- 26005960 TI - Difference of opinion--In the era of flexible ureteroscopy is there still a place for Shock-wave lithotripsy? Opinion: NO. PMID- 26005961 TI - OnabotulinumtoxinA for neurogenic detrusor overactivity and dose differences: a systematic review. AB - PURPOSE: To evaluate the efficacy and safety of onabotulinumtoxinA for patients with neurogenic detrusor overactivity (NDO). MATERIALS AND METHODS: We searched the Cochrane Library, PUBMED, EMBASE, Chinese Bio-medicine database, China Journal Full-text Database, VIP database, Wanfang database for randomized controlled trials (from inception to September 2012). Two authors independently selected studies, extracted data and assessed the methodological and evidence quality using the Cochrane Risk of Bias Table and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) respectively. Data analysis was performed by RevMan 5.1 and descriptive analysis was employed if necessary. RESULTS: Eight studies were selected (n=1879 participants). OnabotulinumtoxinA was more related to urinary tract infection (UTI) (200 U: OR 1.72, CI: 1.18-2.52; 300 U: OR 1.88, CI: 1.31-2.69) versus placebo. Also, OnabotulinumtoxinA was superior to placebo in improving maximum cystometric capacity (MCC) (200 U: OR 138.80, CI: 112.45-165.15; 300 U: OR 152.09, CI: 125.25 178.93) and decreasing maximum detrusor pressure (MDP) (200 U: MD -29.61, CI: 36.52--22.69; 300 U: MD-28.92, CI: -39.59--18.25). However, there were no statistical differences between 200 U and 300 U onabotulinumtoxinA in UTI (OR 0.84, CI: 0.58-1.22), MCC (OR-12.72, CI: -43.36-17.92) and MDP (MD 2.21, CI: 6.80-11.22). CONCLUSIONS: OnabotulinumtoxinA may provide superior clinical and urodynamic benefit for populations with NDO. High-quality studies are required for evaluating the optimal dose, long-term application and when to perform repeated injections. PMID- 26005962 TI - Comparison between the retropubic and transobturator approaches in the treatment of female stress urinary incontinence: a systematic review and meta-analysis of effectiveness and complications. AB - OBJECTIVE: This study aimed to compare the effectiveness and complications between the retropubic and transobturator approaches for the treatment of female stress urinary incontinence (SUI) by conducting a systematic review. MATERIALS AND METHODS: We selected all randomized controlled trials (RCTs) that compared retropubic and transobturator sling placements for treatment of SUI. We estimated pooled odds ratios and 95% confidence intervals for intraoperative and postoperative outcomes and complications. RESULTS: Six hundred twelve studies that compared retropubic and transobturator approaches to midurethral sling placement were identified, of which 16 were included in our research. Our study was based on results from 2646 women. We performed a subgroup analysis to compare outcomes and complications between the two approaches. The evidence to support the superior approach that leads to better objective/subjective cure rate was insufficient. The transobturator approach was associated with lower risks of bladder perforation (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.09 0.32), retropubic/vaginal hematoma (OR 0.32, 95% CI 0.16-0.63), and long-term voiding dysfunction (OR 0.32, 95% CI 0.17-0.61). However, the risk of thigh/groin pain seemed higher in the transobturator group (OR 2.53, 95% CI 1.72-3.72). We found no statistically significant differences in the risks of other complications between the two approaches. CONCLUSIONS: This meta-analysis shows analogical objective and subjective cure rates between the retropubic and transobturator approaches to midurethral sling placement. The transobturator approach was associated with lower risks of several complications. However, good quality studies with long-term follow-ups are warranted for further research. PMID- 26005963 TI - The effect of adjuvant vitamin C after varicocele surgery on sperm quality and quantity in infertile men: a double blind placebo controlled clinical trial. AB - Varicocele is one of the most common causes of male infertility and spontaneous pregnancy rate after varicocelectomy is only about 30%. The most important seminal antioxidant is vitamin C but recent studies about the effects of vitamin C on spermatogenesis are controversial; therefore, we decided to evaluate its role after varicocelectomy. In a double blind randomized controlled clinical trial, 115 men with infertility and clinical varicocele with abnormal semen analyses were recruited. After surgery, the intervention group received vitamin C (250 mg bid) and the control group received placebo for three months. Mean sperm count, motility, and morphology index of two semen analyses (before and after surgery) were compared between the two groups. Univariate general linear model and stepwise linear regression were used in analysis. The mean age (+/- SD) of participants was 27.6 +/- 5.3 years. Vitamin C group had statistically significant better normal motility (20.8 vs. 12.6, P=0.041) and morphology (23.2 vs. 10.5, P<0.001) than placebo group. Considering the values prior to surgery as covariate, vitamin C was not effective on sperm count (P=0.091); but it improved sperm motility (P=0.016) and morphology (P<0.001) even after excluding the confounding effect of age (P=0.044 and P=0.001, respectively). Vitamin C was also an independent factor in predicting motility and normal morphology after surgery. Ascorbic acid can play a role as adjuvant treatment after varicocelectomy in infertile men. PMID- 26005964 TI - Outcome of transurethral plasmakinetic vaporization for benign prostatic hyperplasia. AB - PURPOSE: To assess the outcome of transurethral plasmakinetic vaporization (PKVP) in the management of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: From August 2010 to May 2012, 60 patients with obstructive LUTS due to BPH were included in the study. All patients were evaluated by International Prostate Symptom Score (IPSS), general examination, digital rectal examination, PSA, routine laboratory examinations, pelvi-abdominal ultrasound, trans-rectal ultrasound, and uroflowmetry. Patients with Qmax of <10 mL/sec., an IPSS of >8 and a prostate volume of >40 mL underwent transurethral PKVP. RESULTS: Mean age of the patients was 66.8 +/- 4.5 years. The mean times of the operation, post operative bladder irrigation, and post-operative catheterization were 63.8 +/- 13.9 minutes, 15.2 +/- 5.7 hours, and 23.9 +/- 5.2 hours, respectively. At 3 months of follow-up, there were significant reductions in the mean IPSS from 23.4 +/- 3.5 to 9.2 +/- 3.7 (P=0.4), mean PSA from 3.03 +/- 2.2 ng/mL to 1.2 +/- 1.04 ng/mL (P value=0.02), mean post voiding residual urine from 149.8 +/- 59.5 mL to 46.9 +/- 24.1 mL (P value <0.01), and mean prostate volume from 72.8 +/- 10.3 mL to 22.7 +/- 6.1 mL (P value <0.01). Also, there was a statistically significant increase in the mean Q max. from 8.7 +/- 2.4 mL/s to 19.5 +/- 3.5 mL/s (P value <0.01). CONCLUSION: PKVP is an effective and safe treatment option in the management of symptomatic BPH. PMID- 26005965 TI - Intrarenal Surgery vs Percutaneous Nephrolithotomy in the Management of Lower Pole Stones Greater than 2 cm. AB - PURPOSE: To compare the efficacy of RIRS and PNL in lower pole stones >= 2 cm. Materials and and Methods: A total of 109 patients who underwent PNL or RIRS for solitary lower pole stone between April 2009 and December 2012, were retrospectively analyzed. Lower pole stone was diagnosed with CT scan. Stone size was assessed as the longest axis of the stone. All patients were informed about the advantages, disadvantages and probable complications of both PNL and RIRS before the selection of the procedure. Patients decided the surgery type by themselves without being under any influences and written informed consent was obtained from all patients prior to the surgery. Patients were divided into two groups according to the patients' preference of surgery type. Group 1 consisted of 77 patients who underwent PNL and Group 2 consisted of 32 patients treated with RIRS. Stone free statuses, postoperative complications, operative time and hospitalization time were compared in both groups. RESULTS: There was no statistical significance between the two groups in mean age, stone size, stone laterality, mean follow-up periods and mean operative times. In PNL group, stone free rate was 96.1% at first session and 100% after the additional procedure. In Group 2, stone-free rate was 90.6% at the first procedure and 100% after the additional procedure. The final stone-free rates and operative times were similar in both groups. CONCLUSIONS: RIRS should be an effective treatment alternative to PNL in lower pole stones larger than 2 cm, especially in selected patients. PMID- 26005966 TI - Prostate-Specific Antigen fluctuation: what does it mean in diagnosis of prostate cancer? AB - OBJECTIVE: To investigate whether prostate-specific antigen (PSA) fluctuation correlates with a prostate cancer and to assess whether PSA fluctuation could be used for diagnosis of prostate cancer. MATERIALS AND METHODS: Our study included 229 patients who were performed a prostate biopsy (non-cancer group, 177; prostate cancer group, 52). Enrolled patients were provided twice PSA tests within 6 months. PSA fluctuation (%/month) was defined as a change rate of PSA per a month. Independent t test was used to compare between two groups. Receiver operator characteristic curve was used to assess the availability as a differential diagnostic tool and the correlation. Simple linear regression was performed to analyze a correlation between PSA fluctuation and other factors such as age, PSA, PSA density, and prostate volume. RESULTS: There were significant differences in PSA, PSA density, percentage of free PSA, and PSA fluctuation between two groups. PSA fluctuation was significantly greater in non-cancer group than prostate cancer group (19.95 +/- 23.34%/month vs 9.63 +/- 8.57%/ month, P=0.004). The most optimal cut-off value of PSA fluctuation was defined as 8.48%/month (sensitivity, 61.6%; specificity, 59.6%; AUC, 0.633; P=0.004). In a simple linear regression model, only PSA level was significantly correlated with PSA fluctuation. CONCLUSION: Patients with wide PSA fluctuations, although baseline PSA levels are high, might have a low risk of diagnosis with prostate cancer. Thus, serial PSA measurements could be an option in patients with an elevated PSA level. PMID- 26005967 TI - Preoperative erectile function and the pathologic features of prostate cancer. AB - PURPOSE: We evaluated whether preoperative erectile function is associated with pathologic features in the patients who underwent radical prostatectomy (RP). MATERIALS AND METHODS: We reviewed medical records of 1,743 men who underwent RP from November 2003 through May 2012. Of these, 50 patients who had prior hormone therapy and 272 patients who had lacking data of International Index of Erectile Function-5 (IIEF-5) were excluded. Men whose IIEF-5 was in the lower 25 percentile were assigned as Low Erectile Function group and the others were assigned as Control group. We compared pathologic features using univariable and multivariable logistic regression analysis between two groups. RESULTS: A total of 1,421 patients were included in the analysis. Patients' age was 65.8 +/- 6.7 years and prostate-specific antigen (PSA) was 12.8 +/- 16.1 ng/mL. Median and low 25 percentile of IIEF-5 were 14 and 8, respectively. Low Erectile Function group (IIEF-5 < 8) had higher risk to have high Gleason score (>= 7(4+3), odds ratio (OR) 1.642, p < 0.001) and large tumor volume (>= 5 mL, OR 1.292, p=0.042). Even after adjusting age, year of surgery, body mass index, Charlson comorbidity index, PSA, clinical stage and biopsy Gleason score, Low Erectile Function group still had higher risk of high Gleason score (OR 1.910, p < 0.001) and large tumor volume (OR 1.390, p=0.04) by multivariable logistic regressions. CONCLUSIONS: Lower erectile function before RP was associated with higher Gleason's score and larger tumor volume in final pathology. Thus, erectile function could be a surrogate barometer for prostate cancer aggressiveness. PMID- 26005968 TI - Incidence of retrorenal colon during percutaneous nephrolithotomy. AB - OBJECTIVE: The aim of this study was to investigate retrorenal colon incidence in percutaneous nephrolithotomy (PNL) interventions made in our clinic. MATERIALS AND METHODS: Clinical data of 804 PNL patients, accumulated over a 7 year period (2006-2012), was surveyed. The patient files were reviewed retrospectively, and only those who had abdominal computed tomography (CT) images before PNL intervention were included in the study. In the CT images, the position of both the ascending and descending colon in relation to the right and left kidneys were evaluated. RESULTS: According to our hospital reports, 394 patients with CT images were included in the present study 27 patients (6.9%) had retrorenal colon, of which 18 (4.6%) were on the left side, 4 (1.0%) on the right side and 5 (1.3%) had bilateral retrorenal colons. Colonic perforation complication was seen only in two patients and the colonic perforation rate was 0.3%. These two cases had no CT images. CONCLUSIONS: PNL, in the process of becoming the standard treatment modality, is a safe and reliable technique for renal stone treatment. Colonic injury should be taken into consideration during PNL interventions of the lower pole of the kidney (especially on the left side) due to the location of retrorenal colon. PMID- 26005969 TI - Beneficial effects montelukast, cysteinyl-leukotriene receptor antagonist, on renal damage after unilateral ureteral obstruction in rats. AB - INTRODUCTION: Ureteral obstruction is a common pathology and caused kidney fibrosis and dysfunction at late period. In this present, we investigated the antifibrotic and antiinflammatory effects of montelukast which is cysteinyl leukotriene receptor antagonist, on kidney damage after unilateral ureteral obstruction(UUO) in rats. MATERIALS AND METHODS: 32 rats divided four groups. Group 1 was control, group 2 was sham, group 3 was rats with UUO and group 4 was rats with UUO which were given montelukast sodium (oral 10 mg/kg/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. Tubular necrosis, mononuclear cell infiltration and interstitial fibrosis scoring were determined histopathologically in a part of kidneys; nitric oxide(NO), malondialdehyde(MDA) and reduced glutathione(GSH) levels were determined in the other part of kidneys. Urea-creatinine levels were investigated at blood analysis. Statistical analyses were made by the Chi-square test and one way analysis of variance (ANOVA). RESULTS: There was no difference significantly for urea-creatinine levels between groups. Pathologically, there was serious tubular necrosis and fibrosis in group 3 and there was significantly decreasing for tubular necrosis and fibrosis in group 4(p<0.005). Also, there was significantly increasing for NO and MDA levels; decreasing for GSH levels in group 3 compared the other groups(p<0.005). CONCLUSION: We can say that montelukast prevent kidney damage with antioxidant effect, independently of NO. PMID- 26005970 TI - Assessment of survival of patients with metastatic clear cell renal cell carcinoma after radical cytoreductive nephrectomy versus no surgery: a seer analysis. AB - PURPOSES: To examine the factors related to the choice of cytoreductive nephrectomy (CN) for patients with metastatic clear cell renal cell carcinoma (mCCRCC), and compare the population-based survival rates of patients treated with or without surgery in the modern targeted therapy era. MATERIALS AND METHODS: From 2006 to 2009, patients with mCCRCC were identified from SEER database. The factors that affected patients to be submitted to CN were examined and propensity scores for each patient were calculated. Then patients were matched based upon propensity scores. Univariable and multivariable cox regression models were used to compare survival rates of patients treated with or without surgery. Finally, sensitivity analysis for the cox model on a hazard ratio scale was performed. RESULTS: Age, race, tumor size, T stage and N stage were associated with nephrectomy univariablely. After the match based upon propensity scores, the 1-, 2-, and 3-year cancer-specific survival rate estimates were 45.1%, 27.9%, and 21.7% for the no-surgery group vs 70.6%, 52.2%, and 41.7% for the surgery group, respectively (hazard ratio 0.42, 95%CI: 0.35-0.52, log rank P<0.001). In multivariable Cox proportional hazard regression model, race, T stage, N stage and median household income were significantly associated with survival. Sensitivity analysis on a hazard ratio scale indicated that the hazard ratio might be above 1.00 only when the unknown factor had an opposite effect on survival which was 3-fold than CN. CONCLUSION: The results of our study showed that CN significantly improves the survival of patients with metastatic CCRCC even in the targeted therapy era. PMID- 26005971 TI - Retroperitoneal Laparoscopic Nephroureterectomy for Tuberculous Nonfunctioning Kidneys: a single-center experience. AB - PURPOSE: To present our surgical techniques and experiences of retroperitoneal laparoscopic nephroureterectomy for the treatment of tuberculous nonfunctioning kidneys. MATERIALS AND METHODS: From March 2005 to March 2013, a total of 51 patients with tuberculous nonfunctioning kidney underwent retroperitoneal laparoscopic nephroureterectomy at our medical center. The techniques included early control of renal vessels and dissection of the diseased kidney along the underlying layer outside the Gerato's fascia. The distal ureter was dissected through a Gibson incision and the entire specimen was removed en bloc from the incision. Patient demographics, perioperative characteristics and laboratory parameters as well as postoperative outcome were retrospectively reviewed. RESULTS: Retroperitoneal laparoscopic nephroureterectomy was successfully performed in 50 patients, whereas one case required conversion to open surgery due to non-progression of dissection. The mean operating time was 123.0 minutes (107-160 minutes) and the mean estimated blood loss was 134 mL (80-650 mL).The mean postoperative hospital stay was 3.6 days (3-5 days) and the mean return to normal activity was 11.6 days (10-14 days). Most intra-operative and post operative complications were minor complications and can be managed conservatively. After 68 months (12-96 months) follow-up, the outcome was satisfactory, and ureteral stump syndrome did not occur. CONCLUSIONS: Retroperitoneal laparoscopic nephroureterectomy as a minimally invasive treatment option is feasible for treatment of tuberculous nonfunctioning kidneys. PMID- 26005972 TI - High-grade Primary Renal Leiomyosarcoma. AB - OBJECTIVE: To investigate the clinical characteristics, prognosis, survival and diagnosis of high-grade primary renal leiomyosarcoma. MATERIALS AND METHODS: From January 2003 to April 2013, 10 cases of high-grade primary renal leiomyosarcoma were retrospectively reviewed. We analyzed clinical manifestations, treatment and prognosis of our group and correlated to the literature. RESULTS: Ten cases (five male and five female patients; age range 43-77 years, mean = 57 +/- std d:12.3 ) were enrolled. The mean diameter of the tumor masses was 9.35 +/- 4.5 cm (range 3 18 cm). 40% of the patients were asymptomatic while the major symptom of 60% patients was lumbar pain. Nephrectomy was performed in 90% of patients. Partial nephrectomy surgery was preferred for only one patient. Pleomorphism and necrosis with high-grade, pink spindle cell cytoplasm were viewed in all patients. All patients were high-grade, pink spindle cell cytoplasm and pleomorfism and necrosis were observed in all. In an immunohistochemical examination, vimentin was seen in 100%, desmin in 90% and smooth muscle actin in 80% of the patients. CD117 was negative in all patients. All of the cases were followed-up, and the time of survival varied from 6 to 68 months (mean 23.9 +/- std d:20.1). No patient received adjuvant CTx and/or RTx. CONCLUSION: High-grade primary renal leiomyosarcomas (LMSs) are rare and highly malignant and the prognosis is poor. Early diagnosis and radical nephrectomy can prolong the patient's life. Surgery is the main treatment modality for renal (leiomyosarcoma) LMS. PMID- 26005973 TI - Adjustable perineal male sling using tissue expander as an effective treatment of post-prostatectomy urinary incontinence. AB - PURPOSE: To report our intermediate experience in treating patients with severe incontinence using an adjustable perineal male sling with a tissue expander. MATERIALS AND METHODS: An adjustable male sling procedure was performed on 21 patients with severe incontinence. The underlying etiology of urinary incontinence was radical prostatectomy in 13 patients, open prostatectomy in 5 patients and transurethral prostate resection in 3 patients. The difference between the classical and the adjustable sling is that in the latter there is a 25 mL tissue expander between the two layers of polypropylene mesh with an injection port. Adjustment of the sling was performed with saline via an inflation port, in case of recurrence or persistence of incontinence. RESULTS: The mean age of the patients was 66.2 +/- 7.3 (50-79) years and mean pad usage was 6.4 +/- 0.6 per day. The mean follow-up time was 40.1 +/- 23.2 (6-74) months. The balloon was postoperatively inflated on average with 11.6 +/- 5.7 (5-25) mL. After the mean 40.1 months of follow-up, 16 of the 21 patients (76.2%) were dry (11 patients, 0 pads; 5 patients using safety pads), 3 patients (14%) had mild and 2 (9.8%) had moderate degree post-prostatectomy urinary incontinence (PPI). The average maximum urine flow rate of the patients was 15.6 +/- 4.7 (10-31) mL/s. No residual urine was found. In 2 patients, all parts of the device were removed due to infection and discomfort, and in 3 patients only the inflation component was removed due to local scrotal infection. CONCLUSIONS: Our results show that using an adjustable perineal male sling with a tissue expander seems to be an efficient, and safe surgical treatment option in patients with PPI. PMID- 26005974 TI - Factors associated with intraoperative conversion during robotic sacrocolpopexy. AB - OBJECTIVE: To evaluate for potential predictors of intraoperative conversion from robotic sacrocolpopexy (RSC) to open abdominal sacrocolpopexy. PATIENTS AND METHODS: We identified 83 consecutive patients from 2002-2012 with symptomatic high-grade post-hysterectomy vaginal vault prolapse that underwent RSC. Multiple clinical variables including patient age, comorbidities (body-mass index [BMI], hypertension, diabetes mellitus, tobacco use), prior intra-abdominal surgery and year of surgery were evaluated for potential association with conversion. RESULTS: Overall, 14/83 cases (17%) required conversion to an open sacrocolpopexy. Patients requiring conversion were found to have a significantly higher BMI compared to those who did not (median 30.2 kg/m(2) versus 25.8 kg/m(2); p=0.003). Other medical and surgical factors evaluated were similar between the cohorts. When stratified by increasing BMI, conversion remained associated with an increased BMI. That is, conversion occurred in 3.8% (1/26) of patients with BMI <= 25 kg/m(2), 14.7% (5/34) with BMI 25-29.9 kg/m(2) and 34.7% (8/23) with BMI >= 30 kg/m(2) (p=0.004). When evaluated as a continuous variable, BMI was also associated with a significantly increased risk of conversion to an open procedure (OR 1.18, p=0.004). CONCLUSIONS: Higher BMI was the only clinical factor associated with a significantly increased risk of intra-operative conversion during robotic sacrocolpopexy. Recognition of this may aid in pre operative counseling and surgical patient selection. PMID- 26005975 TI - The value of magnetic resonance imaging in the diagnosis of penile fracture. AB - PURPOSE: We studied the use of magnetic resonance imaging in the diagnosis of penile fracture. MATERIALS AND METHODS: Between 1997 and 2012, fifteen patients (age range 17-48 years, mean age 37 years) with suspected penile fracture underwent MRI examinations. Ten patients were injured during sexual intercourse, whereas four patients were traumatized by non-physiological bending of the penis during self manupilation, one patient was traumatized falling from the bed. Investigations were performed with 1.5 T MR unit. With the patient in the supine position, the penis was taped against the abdominal wall and surface coil was placed on the penis. All patients were studied with axial, coronal, sagittal precontrast and postcontrast T1-weighted TSE(TR/TE:538/13 msn) and T2-weighted TSE(5290/110 msn) sequences. All patient underwent surgical exploration. The follow-up ranged from 3 months to 72 months. Clinically all patients showed normal healing process without complications. In 11 patients a shortening and thickening of tunica albuginea was observed. Three patients have post traumatic erectile disfunction. RESULTS: In all patient corpus cavernosum fractures were clearly depicted on a discontinuity of the low signal intensity of tunica albuginea. These findings were most evident on T1WI and also depicted on T2W sequences. Images obtained shortly after contrast medium administration showed considerable enhancement only in rupture site. Subcutaneous extratunical haematoma in all patients were also recognizable on T2 WI. MRI findings were confirmed at surgery. CONCLUSIONS: Magnetic resonance imaging is of great value for the diagnosis of penile fracture. Furthermore this method is well suited for visualising the post-operative healing process. PMID- 26005976 TI - Does PSA reduction after antibiotic therapy permits postpone prostate biopsy in asymptomatic men with PSA levels between 4 and 10 ng/mL? AB - PURPOSE: We investigated the effect of antibiotics on PSA in asymptomatic patients with mild PSA elevation. MATERIALS AND METHODS: We prospectively evaluated, in a non-randomized design, 106 asymptomatic patients with PSA of 4-10 ng/mL, with a negative digital rectal examination and with no urinary tract infection evidence for 2 years. Patients were divided into two groups: those treated with antibiotics for 3 weeks (G1) and those who were not treated (G2). PSA was taken six weeks after and prostate biopsy was performed in all patients. RESULTS: PCa was diagnosed in 25 of 106 patients (23.6%): 16 (25.0%) in G1 and 9 (21.4%) in G2 (p>0.05). PSA normalization was experienced in 24.5%. In G1, PSA returned to <4 ng/mL in 15 (23.4%) patients compared to 11 (26%) patients in G2. In the patients with a positive biopsy, no significant variation was noted in PSA, fPSA, %fPSA and DPSA after antibiotic treatment. A significantly lower cancer detection rate was noted with decreased PSA, fPSA, and DPSA after antibiotic use. A PSA reduction rate of >= 10% occurred in 58.5%, and this was similar in both G1 and G2 groups. The sensibility, specificity and accuracy of PSA reduction of >= 10% were 31%, 23% and 25%, respectively. CONCLUSION: Empirical antibiotic therapy in asymptomatic male patients is not related to PSA reduction. The greater than 10% PSA reduction after antibiotic in this population cannot postpone prostate biopsy. PMID- 26005977 TI - Effect on hemostasis of an absorbable hemostatic gelatin sponge after transrectal prostate needle biopsy. AB - OBJECTIVES: To examine the usefulness of an absorbable hemostatic gelatin sponge for hemostasis after transrectal prostate needle biopsy. SUBJECTS AND METHODS: The subjects comprised 278 participants who underwent transrectal prostate needle biopsy. They were randomly allocated to the gelatin sponge insertion group (group A: 148 participants) and to the non-insertion group (group B: 130 participants). In group A, the gelatin sponge was inserted into the rectum immediately after biopsy. A biopsy-induced hemorrhage was defined as a case in which a subject complained of bleeding from the rectum, and excretion of blood clots was confirmed. A blood test was performed before and after biopsy, and a questionnaire survey was given after the biopsy. RESULTS: Significantly fewer participants in group A required hemostasis after biopsy compared to group B (3 (2.0%) vs. 11 (8.5%), P=0.029). The results of the blood tests and the responses from the questionnaire did not differ significantly between the two groups. In multivariate analysis, only "insertion of a gelatin sponge into the rectum" emerged as a significant predictor of hemostasis. CONCLUSION: Insertion of a gelatin sponge into the rectum after transrectal prostate needle biopsy significantly increases hemostasis without increasing patient symptoms, such as pain and a sense of discomfort. PMID- 26005978 TI - Unraveling Brazilian Indian population prostate good health: clinical, anthropometric and genetic features. AB - PURPOSE: To compare dietary, lifestyle, clinical, anthropometric, genetic and prostatic features of Brazilian Indians and non-Indians (Amazon). METHODS: 315 men, 228 Indians and 89 non-Indians, >= 40 years old were submitted to digital rectal examination, serum prostate specific antigen (PSA), testosterone, TP53 and GSTP1 genotyping, anthropometric, lifestyle, dietary, personal and familial medical history. Prostatic symptoms were evaluated with the International Prostate Symptom Score (IPSS). RESULTS: Macuxis and Yanomamis represented 43.6% and 14.5% of Indians respectively who spontaneously referred no prostate symptoms. Mean IPSS was 7, range 3-19, with only 15% of moderate symptoms (score 8-19); Mean age was 54.7 years, waist circumference 86.6 cm, BMI 23.9 kg/m(2). Yanomamis presented both lower BMI (21.4 versus 24.8 and 23.3, p=0,001) and prostate volume than Macuxis and "other ethnic groups" (15 versus 20, p=0.001). Testosterone (414 versus 502 and 512, p=0.207) and PSA (0.48 versus 0.6 and 0.41, p=0.349) were similar with progressive PSA increase with aging. Val/Val correlated with lower PSA (p=0.0361). Indians compared to control population presented: - TP53 super representation of Arg/Arg haplotype, 74.5% versus 42.5%, p<0.0001. -GSTP1 Ile/Ile 35.3% versus 60.9%; Ile/Val 45.9% versus 28.7%; Val/Val 18.8% versus 10.3%; p=0.0003. CONCLUSIONS: Observed specific dietary, lifestyle, anthropometric and genetic profile for TP53 and GSTP1 may contribute to Brazilian Indian population prostate good health. PMID- 26005979 TI - Analysis of monotherapy prostate brachytherapy in patients with prostate cancer. Initial PSA and Gleason are important for recurrence? AB - PURPOSE: To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with 125-I permanent brachytherapy at the Sao Jose Hospital--CHLC, Lisbon. MATERIALS AND METHODS: A retrospective analysis was carried out on 429 patients with low and intermediate-risk of prostate adenocarcinoma, according to the recommendations of the EORTC, who underwent 125I brachytherapies in intraoperative dosimetry "real-time" system between September 2003 and September 2013. RESULTS: The mean follow-up was 71.98 months. Biochemical relapse of disease by rising PSA (Phoenix criterion) was observed in 18 patients (4.2%). Through the application of Kaplan-Meier survival curves in this sample, the rate of survival at 6 years without biochemical relapse was higher than 95%. By Iog rank test comparing biochemical relapse with initial PSA (15-10 and <10) and Gleason values (7 and <7), there was no statistical difference (P=0.830) of the initial PSA in the probability of developing biochemical relapse. In relation to Gleason score, it was noted a statistical difference (P <0.05), demonstrating that patients with Gleason 7 are more likely to develop biochemical relapse. CONCLUSIONS: Brachytherapy as monotherapy is at present an effective choice in the treatment of localized prostate adenocarcinoma. Biochemical relapses are minimal. The initial PSA showed no statistically difference in the rate of relapses, unlike the value Gleason, where it was demonstrated that patients with Gleason 7 have a higher probability of biochemical relapse. Cases with PSA bounce should be controlled before starting a salvage treatment. PMID- 26005980 TI - Heterogeneous methodology of racial/ethnic classification may be responsible for the different risk assessments for prostate cancer between Black and White men in Brazil. AB - OBJECTIVES: To evaluate if the different results of prostate cancer risk between black and white Brazilian men may be associated with the varying methodology used to define participants as either Blacks or Whites. PATIENTS AND METHODS: We evaluated median PSA values, rate of PSA level >= 4.0 ng/ mL, indications for prostate biopsy, prostate cancer detection rate, biopsy/cancer rate, cancer/biopsy rate, and the relative risk of cancer between blacks versus whites, blacks versus non-blacks (browns and whites), non-whites (browns and blacks) versus whites, African versus non-African descendants, and African descendants or blacks versus non-African descendants and non-blacks. RESULTS: From 1544 participants, there were 51.4% whites, 37.2% browns, 11.4% blacks, and 5.4% African descendants. Median PSA level was 0.9 ng/mL in whites, browns, and non African descendants, compared to 1.2 ng/mL in blacks, and African descendants or blacks, and 1.3 ng/mL in African descendants. Indications for prostate biopsy were present in 16.9% for African descendants, 15.9% of black, 12.3% of white, 11.4% for non-African descendants, and 9.9% of brown participants. Prostate cancer was diagnosed in 30.3% of performed biopsies: 6.2% of African descendants, 5.1% of blacks, 3.3% of whites, 3.0% of non-African descendants, and 2.6% of browns. CONCLUSIONS: Median PSA values were higher for Blacks versus Whites in all classification systems, except for non-white versus white men. The rate of prostate biopsy, prostate cancer detection rate, and relative risk for cancer was increased in African descendants, and African descendants or blacks, compared to non-African descendants, and non-African descendants and non-blacks, respectively. PMID- 26005981 TI - Predictive criteria of insignificant prostate cancer: what is the correspondence of linear extent to percentage of cancer in a single core? AB - OBJECTIVE: The aim of active surveillance of early prostate cancer is to individualize therapy by selecting for curative treatment only patients with significant cancer. Epstein's criteria for prediction of clinically insignificant cancer in surgical specimens are widely used. Epstein's criterion "no single core with >50% cancer has no correspondence in linear extent. The aim of this study is to find a possible correspondence. MATERIALS AND METHODS: From a total of 401 consecutive patients submitted to radical prostatectomy, 17 (4.2%) met criteria for insignificant cancer in the surgical specimen. The clinicopathologic findings in the correspondent biopsies were compared with Epstein's criteria for insignificant cancer. Cancer in a single core was evaluated in percentage as well as linear extent in mm. RESULTS: Comparing the clinicopathologic findings with Epstein's criteria predictive of insignificant cancer, there was 100% concordance for clinical stage T1c, no Gleason pattern 4 or 5, <= 2 cores with cancer, and no single core with >50% cancer. However, only 25% had density <= 0.15. The mean, median and range of the maximum length of cancer in a single core in mm were 1.19, 1, and 0.5-2.5, respectively. Additionally, the mean, median, and range of length of cancer in all cores in mm were 1.47, 1.5, and 0.5-3, respectively. CONCLUSION: To pathologists that use Epstein's criteria predictive of insignificant cancer and measure linear extent in mm, our study favors that "no single core with >50% cancer" may correspond to >2.5 mm in linear extent. PMID- 26005982 TI - An inexpensive yet realistic model for teaching vasectomy. AB - PURPOSE: Teaching the no-scalpel vasectomy is important, since vasectomy is a safe, simple, and cost-effective method of contraception. This minimally invasive vasectomy technique involves delivering the vas through the skin with specialized tools. This technique is associated with fewer complications than the traditional incisional vasectomy (1). One of the most challenging steps is the delivery of the vas through a small puncture in the scrotal skin, and there is a need for a realistic and inexpensive scrotal model for beginning learners to practice this step. MATERIALS AND METHODS: After careful observation using several scrotal models while teaching residents and senior trainees, we developed a simplified scrotal model that uses only three components-bicycle inner tube, latex tubing, and a Penrose drain. RESULTS: This model is remarkably realistic and allows learners to practice a challenging step in the no-scalpel vasectomy. The low cost and simple construction of the model allows wide dissemination of training in this important technique. CONCLUSIONS: We propose a simple, inexpensive model that will enable learners to master the hand movements involved in delivering the vas through the skin while mitigating the risks of learning on patients. PMID- 26005983 TI - Migration of endotacker into the bladder 7 years after laparoscopic retroperitoneal Burch application. AB - Laparoscopy began to be used widely since the second half of 1990s as an alternative to laparotomy or vaginal approaches in incontinence and pelvic diseases in women, based on its claimed better success rates. Injuries were reported in the bladder, gastrointestinal system and the entry of the Verress cannula in early and late laparoscopic applications. De-novo urging, voiding dysfunctions, marked recurrences and surgical inefficiencies were observed in 5 year follow-ups after laparoscopic incontinence surgery. Although tension-free midurethral sling operations replaced open laparoscopic colposuspensions nowadays, laparoscopic colposuspension is still preferred in cases where simultaneous laparoscopic paravaginal repair or sacrocolpopexy is considered or where synthetic graft implantation is contraindicated. Moreover, meshes and endotackers are still frequently used in many laparoscopic applications in various clinics. The migration of the tacker used in mesh fixation in a patient where retroperitoneal laparoscopic Burch was performed 7 years ago due to stress urinary incontinence and the extraction of the ossified tacker from the bladder will be presented. PMID- 26005984 TI - Bilateral isolated Epididymal Agenesis in a 32 year old man. AB - Epididymal agenesis is defined as the absence of the epididymis totally or segmentally, unilateral or bilateral, which is secondary to the Wolffian duct malformation (1). Rete testis, epididymis, vas deferens and seminal vesicle are believed to develop from Wolffian ducts. PMID- 26005985 TI - A comparative study of ascending urethrogram and sono-urethrogram in the evaluation of stricture urethra. AB - To compare the efficacy of sono-urethrogram and ascending urethrogram in the evaluation of stricture urethra. MATERIALS AND METHODS: In this prospective study 40 patients with obstructive lower urinary tract symptoms and suspected to be having stricture urethra were subjected to ascending urethrogram and sonourethrogram. The radiologist was blinded to the findings of ascending urethrogram. All the sonourethrograms were done by the same radiologist. The findings of sonourethrogram & ascending urethrogram were compared with the findings of cystoscopy and intra-operative findings. The specificity, sensitivity,positive predictive value and negative predictive value of each modality in the diagnosis of various urethral anomalies were estimated. RESULTS: The sonourethrogram identified stricture disease in all the patients who had abnormal ascending urethrogram. In addition, other abnormalities like spongiofibrosis, diverticula and stones which were not picked up in ascending urethrogram were diagnosed by sonourethrogram. The cystoscopic and intra operative findings with respect to stricture length, diameter and spongiofibrosis correlated well with sono-urethrogram findings. 5 patients who had stricture in the ascending urethrogram were found to be having the normal urethra in sonourethrogram and confirmed by cystoscopy. CONCLUSION: sonourethrogram is an effective alternative to ascending urethrogram in the evaluation of stricture urethra. It is more sensitive in the diagnosis of anterior urethral strictures than posterior urethral strictures. It is superior to ascending urethrogram in the identification of spongiofibrosis, diameter and length of the stricture. The complications were lower in sonourethrogram group compared to ascending urethrogram. PMID- 26005986 TI - 18F-FDG PET/CT with unusual bone and CNS metastases from testicular seminoma. PMID- 26005987 TI - Single port varicocelectomy using SILSTM multiple access port. AB - PURPOSE: Several surgical approaches have been used for varicocelectomy. We report single port varicocelectomy using SILSTM (Covidien, Norwalk, CT) multiple access port. CASE: The greade III varicocele patient was 23 years old and placed in supine position. About 2 cm vertical skin incision was made in a crease just lateral to the umbilicus and SILSTM port was placed with three 5-mm trocars. Incision to posterior peritoneum from the point 3 cm superior to the internal inguinal was made by needle holder with a broken 15th blade tip. The testicular vessels were exposed. The lymphatic vessels and testicular artery were identified and separated from the testicular vein with flexible laparoscopic instruments and conventional rigid instruments. Three testicular veins were clipped with hemoclips (EndoClip , Autosuture, Norwalk, CT). Posterior peritoneum was repaired with 4-0 vicryl with one side of 5 mm Hem-o-lok clip (Weck Research,Triangle Park, NC). Than the distal end of suture site was also closed with Hem-o-lok. RESULTS: The whole procedure was completed with no complication. The operative time was 85 minutes, and blood loss was minimal. The patient was discharged 2 days after the operation. Left scrotal pain and vein engorgement was disappeared. CONCLUSIONS: Our single port varicocelectomy method is a safe and effective alternative to conventional method. This will provide minimally invasive surgical option for varicocele and we can expect more potential cosmetic benefit and less morbid. PMID- 26005988 TI - Reduction corporoplasty. AB - OBJECTIVE: Here we present the first video demonstration of reduction corporoplasty in the management of phallic disfigurement in a 17 year old man with a history sickle cell disease and priapism. INTRODUCTION: Surgical management of aneurysmal dilation of the corpora has yet to be defined in the literature. MATERIALS AND METHODS: We preformed bilateral elliptical incisions over the lateral corpora as management of aneurysmal dilation of the corpora to correct phallic disfigurement. RESULTS: The patient tolerated the procedure well and has resolution of his corporal disfigurement. CONCLUSIONS: Reduction corporoplasty using bilateral lateral elliptical incisions in the management of aneurysmal dilation of the corpora is a safe an feasible operation in the management of phallic disfigurement. PMID- 26005989 TI - Use of biological Glue (Bioglue(r)) in laparoscopic partial nephrectomy: a study in pigs. AB - INTRODUCTION: Partial nephrectomy is the standard of care for localized renal tumors. However, bleeding and warm ischemia time are still controversial when laparoscopic surgeries are carried out. Herein, we aim to compare the outcomes from laparoscopic partial nephrectomy with and without the use of biological glue with purified bovine albumin and glutaraldehyde (BioGlue (r)). MATERIALS AND METHODS: Twenty-four kidneys of 12 pigs were used in this study. A pre-determined lower pole segment was resected (3 cm x 1 cm) and one of two different hemostatic techniques was performed. In one kidney, hemostatic " U suture " (poliglecaprone 3.0) was performed and in the contra-lateral kidney, only the biological glue was applied. Data recorded was comprised of warm ischemia time (seconds) and estimated blood loss (mL) for each procedure. In cases of bleeding after glue administration, a complementary suture was done. RESULTS: Mean warm ischemia time was 492.9 +/- 113.1 (351-665) seconds and 746 +/- 185.3 (409-1125) seconds for biological glue and suture groups, respectively. There was a positive significant difference in terms of warm ischemia favoring the biological glue group over the suture group (p<0.001). Mean blood loss was 39.4 (0-115) mL for the biological glue group and 39.1 (5-120) mL for the suture group (p=0.62). CONCLUSION: Biological glue is an important tool for laparoscopic partial nephrectomies. It is effective for hemostatic control in selected cases, and it can be used in combination with the traditional suture techniques. PMID- 26005990 TI - Spectrofluorimetric and micelle-enhanced spectrofluorimetric methods for determination of Felodipine and Nimodipine in pharmaceutical preparations and human plasma. AB - Rapid, simple and sensitive two spectrofluorimetric methods have been developed for determination of Felodipine (FLD) and Nimodipine (NDP). The first method is based on measuring the native fluorescence of either Felodipine or Nimodipine at 426 nm after excitation at 385 nm. The fluorescence intensity-concentration plots of Felodipine and Nimodipine were rectilinear over the concentration ranges (0.2 3.0) and (0.5-4.0) MUg ml(-1), respectively. The second method is based on measuring the fluorescence intensity of the studied drugs in micellar media (0.3% Tween-80) at lambdaex=385 nm and lambdaem=423 nm. In the presence of 0.3% Tween 80, about 1.6-fold and 2.1-fold enhancement can be achieved in the relative fluorescence intensity (RFI) of Felodipine and Nimodipine, respectively. The fluorescence intensity-concentration plots of Felodipine and Nimodipine with Tween-80 were rectilinear over the concentration ranges (0.05-4.0) and (0.1-4.0) MUg ml(-1), respectively with determination coefficients (r(2)) of 0.9981 and 0.9990, and limit of quantitation of 0.05 and 0.027MUg ml(-1) for FLD and NDP, respectively. The proposed methods were validated according to ICH guidelines and have been successfully applied to the analysis of these drugs in their commercial tablets with high accuracy (97.6-98.8+/-0.50-1.42%, n=5). The high sensitivity of micellar method permits its application for determination of the cited drugs in spiked human plasma with % recovery (91.9-106.6+/-0.66-1.7%, n=6). PMID- 26005991 TI - An investigation on optical characteristics of nanocrystalline ZnS:Ni thin films prepared by chemical deposition method. AB - Nanocrystalline nickel doped ZnS (ZnS:Ni) thin films were deposited by chemical bath deposition method. The effect of Ni doping on structural, photoluminescence, and optical properties of the ZnS:Ni films was studied. Structural analysis using X-ray diffraction revealed that the films are polycrystalline in nature with a cubic structure. The fluorescence (FL) spectra of the ZnS:Ni films showed two characteristic bands, one broad band centered at 430 and another narrow band at 523 nm. UV-vis transmission data showed that the films were transparent in the visible region. Also, using these data, the absorption coefficients, the optical band gap, the extinction coefficients, the refractive index, the real and imaginary parts of the dielectric constants, and the dissipation factor were calculated. PMID- 26005992 TI - Adsorption and sub-nanomolar sensing of thioflavin T on colloidal gold nanoparticles, silver nanoparticles and silver-coated films studied using surface enhanced Raman scattering. AB - Raman and surface-enhanced Raman scattering (SERS) studies of thioflavin T (ThT) in solid, solution, gold nanoparticles (GNPs), silver nanoparticles (SNPs) and silver-coated films (SCFs) were investigated. Concentration-dependent SERS spectrum of ThT in GNPs and SNPs indicated the existence of two possible structures, one with the torsional angle (phi) between benzothiazole and dimethylaminobenzene rings being 37 degrees and the other with phi=90 degrees . The SERS spectrum of ThT in SCFs were similar to the Raman spectrum of solid and solution that suggests phi=37 degrees . In this paper, the high sensitivity of the SERS technique was employed for sub-nanomolar (picomolar) sensing of ThT. PMID- 26005993 TI - The comparison of C-proteasome activity in the plasma of children after burn injury, mild head injury and blunt abdominal trauma. AB - PURPOSE: We aimed to evaluate and compare the changes in circulating 20S proteasome activity in the plasma of children suffering from blunt abdominal trauma, thermal injury and mild head injury. PATIENTS AND METHODS: The study population comprised 40 patients with burns, 35 children admitted due to mild head injury, and 30 children suffering from blunt abdominal trauma, who were admitted to Pediatric Surgery Department of Medical University of Bialystok Poland, between 2010 and 2014, and their parents gave informed consent, were included into the study. Patients were aged 9 months to 17 years (median=5.73+/ 1.91y). The girls to boys ratio was nearly 1:2 (34 girls and 106 boys). Plasma proteasome activity was assessed using Suc-Leu-Leu-Val-Tyr-AMC peptide substrate, 2-6h, 12-16h, and 48h after the injury. 20 healthy children admitted for planned inguinal hernia repair served as controls. RESULTS: In our series of patients, the C-proteasome activity was much higher 12-16h after burns, than after mild head injuries, or blunt abdominal injuries, and the difference was statistically significant (p<0.05). CONCLUSIONS: Circulating 20S proteasome is probably released from damaged tissues in response to the injury and is a biomarker of tissue damage - more severe in the group of burnt patients in comparison to the patients with mild head injury and blunt abdominal trauma. Therefore detection of 20S proteasome may represent a novel marker of immunological activity and cellular degradation in trauma patients. PMID- 26005994 TI - Columnar-integrated aerosol optical properties and classification of different aerosol types over the semi-arid region, Anantapur, Andhra Pradesh. AB - This study presents a characterization of aerosol columnar properties measured at a semi-arid station Anantapur in the southern part of India during the period from October 2012 to September 2013. Aerosol optical depth (AOD) and Angstrom exponent (alpha) have been retrieved from Microtops II Sunphotometer over the observation site. The results show that a pronounced spectral and monthly variability in the optical properties of aerosols is mainly due to anthropogenic sources. The results show that the spectral curvature can effectively be used as a tool for aerosol type discrimination, since the fine-mode aerosols exhibit negative curvature, while the coarse-mode particles are positive. The classification of aerosols is also proposed by using the values of AOD at 500 nm and Angstrom exponent values (alpha(380-870)) by applying threshold values obtained from the frequency distribution of AOD. The results of the analysis were identified by four individual components (anthropogenic/biomass burning, coarse/dust, coarse/marine, clean continental) of different origin and compositions. The most frequent situations observed over the site are that due to the anthropogenic/biomass burning situations which account for about 45.37%, followed by coarse/dust (43.64%), clean continental (7.2%) and coarse/marine (3.82%) during summer. The identification of the aerosol source type and the modification processes are analyzed by using the Gobbi et al. (2007) classification scheme based on the measured scattering properties (alpha, dalpha) derived from the Microtops II Sunphotometer. PMID- 26005995 TI - Factors affecting fluoride and natural organic matter (NOM) removal from natural waters in Tanzania by nanofiltration/reverse osmosis. AB - This study examined the feasibility of nanofiltration (NF) and reverse osmosis (RO) in treating challenging natural tropical waters containing high fluoride and natural organic matter (NOM). A total of 166 water samples were collected from 120 sources within northern Tanzania over a period of 16 months. Chemical analysis showed that 81% of the samples have fluoride levels exceeding the WHO drinking guideline of 1.5mg/L. The highest fluoride levels were detected in waters characterized by high ionic strength, high inorganic carbon and on some occasions high total organic carbon (TOC) concentrations. Bench-scale experiments with 22 representative waters (selected based on fluoride concentration, salinity, origin and in some instances organic matter) and 6 NF/RO membranes revealed that ionic strength and recovery affected fluoride retention and permeate flux. This is predominantly due to osmotic pressure and hence the variation of diffusion/convection contributes to fluoride transport. Different membranes had distinct fluoride removal capacities, showing different raw water concentration treatability limits regarding the WHO guideline compliance. BW30, BW30-LE and NF90 membranes had a feed concentration limit of 30-40 mg/L at 50% recovery. NOM retention was independent of water matrices but is governed predominantly by size exclusion. NOM was observed to have a positive impact on fluoride removal. Several mechanisms could contribute but further studies are required before a conclusion could be drawn. In summary, NF/RO membranes were proved to remove both fluoride and NOM reliably even from the most challenging Tanzanian waters, increasing the available drinking water sources. PMID- 26005996 TI - Advances in quantum simulations of ATPase catalysis in the myosin motor. AB - During its contraction cycle, the myosin motor catalyzes the hydrolysis of ATP. Several combined quantum/classical mechanics (QM/MM) studies of this step have been published, which substantially contributed to our thinking about the catalytic mechanism. The methodological difficulties encountered over the years in the simulation of this complex reaction are now understood: (a) Polarization of the protein peptide groups surrounding the highly charged ATP(4-) cannot be neglected. (b) Some unsuspected protein groups need to be treated QM. (c) Interactions with the gamma-phosphate versus the beta-phosphate favor a concurrent versus a sequential mechanism, respectively. Thus, these practical aspects strongly influence the computed mechanism, and should be considered when studying other catalyzed phosphor-ester hydrolysis reactions, such as in ATPases or GTPases. PMID- 26005997 TI - Electrical detection of coherent spin precession using the ballistic intrinsic spin Hall effect. AB - The spin-orbit interaction in two-dimensional electron systems provides an exceptionally rich area of research. Coherent spin precession in a Rashba effective magnetic field in the channel of a spin field-effect transistor and the spin Hall effect are the two most compelling topics in this area. Here, we combine these effects to provide a direct demonstration of the ballistic intrinsic spin Hall effect and to demonstrate a technique for an all-electric measurement of the Datta-Das conductance oscillation, that is, the oscillation in the source-drain conductance due to spin precession. Our hybrid device has a ferromagnet electrode as a spin injector and a spin Hall detector. Results from multiple devices with different channel lengths map out two full wavelengths of the Datta-Das oscillation. We also use the original Datta-Das technique with a single device of fixed length and measure the channel conductance as the gate voltage is varied. Our experiments show that the ballistic spin Hall effect can be used for efficient injection or detection of spin polarized electrons, thereby enabling the development of an integrated spin transistor. PMID- 26005998 TI - Single-molecule diodes with high rectification ratios through environmental control. AB - Molecular electronics aims to miniaturize electronic devices by using subnanometre-scale active components. A single-molecule diode, a circuit element that directs current flow, was first proposed more than 40 years ago and consisted of an asymmetric molecule comprising a donor-bridge-acceptor architecture to mimic a semiconductor p-n junction. Several single-molecule diodes have since been realized in junctions featuring asymmetric molecular backbones, molecule-electrode linkers or electrode materials. Despite these advances, molecular diodes have had limited potential for applications due to their low conductance, low rectification ratios, extreme sensitivity to the junction structure and high operating voltages. Here, we demonstrate a powerful approach to induce current rectification in symmetric single-molecule junctions using two electrodes of the same metal, but breaking symmetry by exposing considerably different electrode areas to an ionic solution. This allows us to control the junction's electrostatic environment in an asymmetric fashion by simply changing the bias polarity. With this method, we reliably and reproducibly achieve rectification ratios in excess of 200 at voltages as low as 370 mV using a symmetric oligomer of thiophene-1,1-dioxide. By taking advantage of the changes in the junction environment induced by the presence of an ionic solution, this method provides a general route for tuning nonlinear nanoscale device phenomena, which could potentially be applied in systems beyond single-molecule junctions. PMID- 26006000 TI - Single-molecule diodes: The environment does the trick. PMID- 26005999 TI - Prescribed nanoparticle cluster architectures and low-dimensional arrays built using octahedral DNA origami frames. AB - Three-dimensional mesoscale clusters that are formed from nanoparticles spatially arranged in pre-determined positions can be thought of as mesoscale analogues of molecules. These nanoparticle architectures could offer tailored properties due to collective effects, but developing a general platform for fabricating such clusters is a significant challenge. Here, we report a strategy for assembling three-dimensional nanoparticle clusters that uses a molecular frame designed with encoded vertices for particle placement. The frame is a DNA origami octahedron and can be used to fabricate clusters with various symmetries and particle compositions. Cryo-electron microscopy is used to uncover the structure of the DNA frame and to reveal that the nanoparticles are spatially coordinated in the prescribed manner. We show that the DNA frame and one set of nanoparticles can be used to create nanoclusters with different chiroptical activities. We also show that the octahedra can serve as programmable interparticle linkers, allowing one- and two-dimensional arrays to be assembled with designed particle arrangements. PMID- 26006001 TI - Frictional transition from superlubric islands to pinned monolayers. AB - The inertial sliding of physisorbed submonolayer islands on crystal surfaces contains unexpected information on the exceptionally smooth sliding state associated with incommensurate superlubricity and on the mechanisms of its disappearance. Here, in a joint quartz crystal microbalance and molecular dynamics simulation case study of Xe on Cu(111), we show how superlubricity emerges in the large size limit of naturally incommensurate Xe islands. As coverage approaches a full monolayer, theory also predicts an abrupt adhesion driven two-dimensional density compression on the order of several per cent, implying a hysteretic jump from superlubric free islands to a pressurized commensurate immobile monolayer. This scenario is fully supported by the quartz crystal microbalance data, which show remarkably large slip times with increasing submonolayer coverage, signalling superlubricity, followed by a dramatic drop to zero for the dense commensurate monolayer. Careful analysis of this variety of island sliding phenomena will be essential in future applications of friction at crystal/adsorbate interfaces. PMID- 26006002 TI - Anisotropic nanoparticle complementarity in DNA-mediated co-crystallization. AB - Whether two species will co-crystallize depends on the chemical, physical and structural complementarity of the interacting components. Here, by using DNA as a surface ligand, we selectively co-crystallize mixtures of two different anisotropic nanoparticles and systematically investigate the effects of nanoparticle size and shape complementarity on the resultant crystal symmetry, microstrain, and effective 'DNA bond' length and strength. We then use these results to understand a more complicated system where both size and shape complementarity change, and where one nanoparticle can participate in multiple types of directional interactions. Our findings offer improved control of non spherical nanoparticles as building blocks for the assembly of sophisticated macroscopic materials, and provide a framework to understand complementarity and directional interactions in DNA-mediated nanoparticle crystallization. PMID- 26006003 TI - Selective transformations between nanoparticle superlattices via the reprogramming of DNA-mediated interactions. AB - The rapid development of self-assembly approaches has enabled the creation of materials with desired organization of nanoscale components. However, achieving dynamic control, wherein the system can be transformed on demand into multiple entirely different states, is typically absent in atomic and molecular systems and has remained elusive in designed nanoparticle systems. Here, we demonstrate with in situ small-angle X-ray scattering that, by using DNA strands as inputs, the structure of a three-dimensional lattice of DNA-coated nanoparticles can be switched from an initial 'mother' phase into one of multiple 'daughter' phases. The introduction of different types of reprogramming DNA strands modifies the DNA shells of the nanoparticles within the superlattice, thereby shifting interparticle interactions to drive the transformation into a particular daughter phase. Moreover, we mapped quantitatively with free-energy calculations the selective reprogramming of interactions onto the observed daughter phases. PMID- 26006004 TI - Photooxidation and quantum confinement effects in exfoliated black phosphorus. AB - Thin layers of black phosphorus have recently raised interest owing to their two dimensional (2D) semiconducting properties, such as tunable direct bandgap and high carrier mobilities. This lamellar crystal of phosphorus atoms can be exfoliated down to monolayer 2D-phosphane (also called phosphorene) using procedures similar to those used for graphene. Probing the properties has, however, been challenged by a fast degradation of the thinnest layers on exposure to ambient conditions. Herein, we investigate this chemistry using in situ Raman and transmission electron spectroscopies. The results highlight a thickness dependent photoassisted oxidation reaction with oxygen dissolved in adsorbed water. The oxidation kinetics is consistent with a phenomenological model involving electron transfer and quantum confinement as key parameters. A procedure carried out in a glove box is used to prepare mono-, bi- and multilayer 2D-phosphane in their pristine states for further studies on the effect of layer thickness on the Raman modes. Controlled experiments in ambient conditions are shown to lower the A(g)(1)/A(g)(2) intensity ratio for ultrathin layers, a signature of oxidation. PMID- 26006005 TI - Symmetry of charge order in cuprates. AB - Charge-ordered ground states permeate the phenomenology of 3d-based transition metal oxides, and more generally represent a distinctive hallmark of strongly correlated states of matter. The recent discovery of charge order in various cuprate families has fuelled new interest into the role played by this incipient broken symmetry within the complex phase diagram of high-T(c) superconductors. Here, we use resonant X-ray scattering to resolve the main characteristics of the charge-modulated state in two cuprate families: Bi2Sr(2-x)La(x)CuO(6+delta) (Bi2201) and YBa2Cu3O(6+y) (YBCO). We detect no signatures of spatial modulations along the nodal direction in Bi2201, thus clarifying the inter-unit-cell momentum structure of charge order. We also resolve the intra-unit-cell symmetry of the charge-ordered state, which is revealed to be best represented by a bond order with modulated charges on the O-2p orbitals and a prominent d-wave character. These results provide insights into the origin and microscopic description of charge order in cuprates, and its interplay with superconductivity. PMID- 26006006 TI - De novo assembly of a haplotype-resolved human genome. AB - The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine. PMID- 26006007 TI - Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting. AB - Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening. PMID- 26006008 TI - COMPASS identifies T-cell subsets correlated with clinical outcomes. AB - Advances in flow cytometry and other single-cell technologies have enabled high dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software. PMID- 26006009 TI - Assembling large genomes with single-molecule sequencing and locality-sensitive hashing. AB - Long-read, single-molecule real-time (SMRT) sequencing is routinely used to finish microbial genomes, but available assembly methods have not scaled well to larger genomes. We introduce the MinHash Alignment Process (MHAP) for overlapping noisy, long reads using probabilistic, locality-sensitive hashing. Integrating MHAP with the Celera Assembler enabled reference-grade de novo assemblies of Saccharomyces cerevisiae, Arabidopsis thaliana, Drosophila melanogaster and a human hydatidiform mole cell line (CHM1) from SMRT sequencing. The resulting assemblies are highly continuous, include fully resolved chromosome arms and close persistent gaps in these reference genomes. Our assembly of D. melanogaster revealed previously unknown heterochromatic and telomeric transition sequences, and we assembled low-complexity sequences from CHM1 that fill gaps in the human GRCh38 reference. Using MHAP and the Celera Assembler, single-molecule sequencing can produce de novo near-complete eukaryotic assemblies that are 99.99% accurate when compared with available reference genomes. PMID- 26006010 TI - Prolonged and tunable residence time using reversible covalent kinase inhibitors. AB - Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo. PMID- 26006012 TI - Drug-target interactions: Stay tuned. PMID- 26006011 TI - Convergence of biological nitration and nitrosation via symmetrical nitrous anhydride. AB - The current perspective holds that the generation of secondary signaling mediators from nitrite (NO2(-)) requires acidification to nitrous acid (HNO2) or metal catalysis. Herein, the use of stable isotope-labeled NO2(-) and LC-MS/MS analysis of products reveals that NO2(-) also participates in fatty acid nitration and thiol S-nitrosation at neutral pH. These reactions occur in the absence of metal centers and are stimulated by autoxidation of nitric oxide ((*)NO) via the formation of symmetrical dinitrogen trioxide (nitrous anhydride, symN2O3). Although theoretical models have predicted physiological symN2O3 formation, its generation is now demonstrated in aqueous reaction systems, cell models and in vivo, with the concerted reactions of (*)NO and NO2(-) shown to be critical for symN2O3 formation. These results reveal new mechanisms underlying the NO2(-) propagation of (*)NO signaling and the regulation of both biomolecule function and signaling network activity via NO2(-)-dependent nitrosation and nitration reactions. PMID- 26006014 TI - Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. AB - Acute systemic lupus erythematosus (SLE) courses with surges of antibody secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies. PMID- 26006013 TI - Interferon-lambda and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. AB - The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-lambda (IFN-lambda), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-lambda, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons. PMID- 26006015 TI - The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. AB - Aire is a transcriptional regulator that induces the promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. Studies have offered molecular insights into how Aire operates, but more comprehensive understanding of this process still remains elusive. Here we found abundant expression of the protein deacetylase Sirtuin-1 (Sirt1) in mature Aire(+) mTECs, wherein it was required for the expression of Aire-dependent TRA encoding genes and the subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and identifies a unique function for Sirt1 in preventing organ-specific autoimmunity. PMID- 26006016 TI - Role of alpha1 and alpha2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts. AB - Early fibrotic lesions are thought to be the initial findings of fibrogenesis in idiopathic interstitial pneumonias, but little is known about their properties. Type IV collagen comprises six gene products, alpha1-alpha6, and although it is known as a major basement membrane component, its abnormal deposition is seen in fibrotic lesions of certain organs. We studied the expression of type I and III collagen and all alpha chains of type IV collagen in lung specimens from patients with usual interstitial pneumonia (UIP) or organizing pneumonia (OP) via immunohistochemistry. With cultured lung fibroblasts, we analyzed the expression and function of all alpha chains of type IV collagen via immunohistochemistry, western blotting, real-time quantitative PCR, and a Boyden chamber migration assay after the knockdown of alpha1 and alpha2 chains. Although we observed type I and III collagens in early fibrotic lesions of both UIP and OP, we found type IV collagen, especially alpha1 and alpha2 chains, in early fibrotic lesions of UIP but not OP. Fibroblasts enhanced the expression of alpha1 and alpha2 chains of type IV collagen after transforming growth factor-beta1 stimulation. Small interfering RNA against alpha1 and alpha2 chains increased fibroblast migration, with upregulated phosphorylation of focal adhesion kinase (FAK), and adding medium containing fibroblast-produced alpha1 and alpha2 chains reduced the increased levels of fibroblast migration and phosphorylation of FAK. Fibroblasts in OP were positive for phosphorylated FAK but fibroblasts in UIP were not. These results suggest that fibroblasts in UIP with type IV collagen deposition, especially alpha1 and alpha2 chains, have less ability to migrate from early fibrotic lesions than fibroblasts in OP without type IV collagen deposition. Thus, type IV collagen deposition in early fibrotic lesions of UIP may be implicated in refractory pathophysiology including migration of lesion fibroblasts via a FAK pathway. PMID- 26006017 TI - TGFbeta1 exacerbates blood-brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5. AB - Recent studies have found that vasogenic brain edema is present during hepatic encephalopathy following acute liver failure and is dependent on increased matrix metalloproteinase 9 (MMP9) activity and downregulation of tight junction proteins. Furthermore, circulating transforming growth factor beta1 (TGFbeta1) is increased following liver damage and may promote endothelial cell permeability. This study aimed to assess whether increased circulating TGFbeta1 drives changes in tight junction protein expression and MMP9 activity following acute liver failure. Blood-brain barrier permeability was assessed in azoxymethane (AOM) treated mice at 6, 12, and 18 h post-injection via Evan's blue extravasation. Monolayers of immortalized mouse brain endothelial cells (bEnd.3) were treated with recombinant TGFbeta1 (rTGFbeta1) and permeability to fluorescein isothiocyanate-dextran (FITC-dextran), MMP9 and claudin-5 expression was assessed. Antagonism of TGFbeta1 signaling was performed in vivo to determine its role in blood-brain barrier permeability. Blood-brain barrier permeability was increased in mice at 18 h following AOM injection. Treatment of bEnd.3 cells with rTGFbeta1 led to a dose-dependent increase of MMP9 expression as well as a suppression of claudin-5 expression. These effects of rTGFbeta1 on MMP9 and claudin-5 expression could be reversed following treatment with a SMAD3 inhibitor. AOM-treated mice injected with neutralizing antibodies against TGFbeta demonstrated significantly reduced blood-brain barrier permeability. Blood-brain barrier permeability is induced in AOM mice via a mechanism involving the TGFbeta1-driven SMAD3-dependent upregulation of MMP9 expression and decrease of claudin-5 expression. Therefore, treatment modalities aimed at reducing TGFbeta1 levels or SMAD3 activity may be beneficial in promoting blood-brain barrier integrity following liver failure. PMID- 26006018 TI - Epstein-Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage. AB - Epstein-Barr virus (EBV) infection is closely associated with several human malignancies including nasopharyngeal carcinoma (NPC). The EBV immediate-early protein BZLF1 is the key mediator that switches EBV infection from latent to lytic forms. The lytic form of EBV infection has been implicated in human carcinogenesis but its molecular mechanisms remain unclear. BZLF1 has been shown to be a binding partner of several DNA damage response (DDR) proteins. Its functions in host DDR remain unknown. Thus, we explore the effects of BZLF1 on cellular response to DNA damage in NPC cells. We found that expression of BZLF1 impaired the binding between RNF8 and MDC1 (mediator of DNA damage checkpoint 1), which in turn interfered with the localization of RNF8 and 53BP1 to the DNA damage sites. The RNF8-53BP1 pathway is important for repair of DNA double-strand breaks and DNA damage-induced G2/M checkpoint activation. Our results showed that, by impairing DNA damage repair as well as abrogating G2/M checkpoint, BZLF1 induced genomic instability and rendered cells more sensitive to ionizing radiation. Moreover, the blockage of 53BP1 and RNF8 foci formation was recapitulated in EBV-infected cells. Taken together, our study raises the possibility that, by causing mis-localization of important DDR proteins, BZLF1 may function as a link between lytic EBV infection and impaired DNA damage repair, thus contributing to the carcinogenesis of EBV-associated human epithelial malignancies. PMID- 26006020 TI - Fibrin supports human fetal islet-epithelial cell differentiation via p70(s6k) and promotes vascular formation during transplantation. AB - The human fetal pancreas expresses a variety of extracellular matrix (ECM) binding receptors known as integrins. A provisional ECM protein found in blood clots that can bind to integrin receptors and promote beta cell function and survival is fibrin. However, its role in support of human fetal pancreatic cells is unknown. We investigated how fibrin promotes human fetal pancreatic cell differentiation in vitro and in vivo. Human fetal pancreata were collected from 15 to 21 weeks of gestation and collagenase digested. Cells were then plated on tissue-culture polystyrene, or with 2D or 3D fibrin gels up to 2 weeks, or subcutaneously transplanted in 3D fibrin gels. The human fetal pancreas contained rich ECM proteins and expressed integrin alphaVbeta3. Fibrin-cultured human fetal pancreatic cells had significantly increased expression of PDX-1, glucagon, insulin, and VEGF-A, along with increased integrin alphaVbeta3 and phosphorylated FAK and p70(s6k). Fibrin-cultured cells treated with rapamycin, the mTOR pathway inhibitor, had significantly decreased phospho-p70(s6k) and PDX-1 expression. Transplanting fibrin-mixed cells into nude mice improved vascularization compared with collagen controls. These results suggest that fibrin supports islet cell differentiation via p70(s6k) and promotes vascularization in human fetal islet epithelial clusters in vivo. PMID- 26006019 TI - Bronchial lesions of mouse model of asthma are preceded by immune complex vasculitis and induced bronchial associated lymphoid tissue (iBALT). AB - We systematically examined by immune histology the lungs of some widely used mouse models of asthma. These models include sensitization by multiple intraperitoneal injections of soluble ovalbumin (OVA) or of OVA with alum, followed by three intranasal or aerosol challenges 3 days apart. Within 24 h after a single challenge there is fibrinoid necrosis of arterial walls with deposition of immunoglobulin (Ig) and OVA and infiltration of eosinophilic polymorphonuclear cells that lasts for about 3 days followed by peribronchial B cell infiltration and slight reversible goblet cell hypertrophy (GCHT). After two challenges, severe eosinophilic vasculitis is present at 6 h, increases by 72 h, and then declines; B-cell proliferation and significant GCHT and hyperplasia (GCHTH) and bronchial smooth muscle hypertrophy recur more prominently. After three challenges, there is significantly increased induced bronchus-associated lymphoid tissue (iBALT) formation, GCHTH, and smooth muscle hypertrophy. Elevated levels of Th2 cytokines, IL-4, IL-5, and IL-13, are present in bronchial lavage fluids. Sensitized mice have precipitating antibody and positive Arthus skin reactions but also develop significant levels of IgE antibody to OVA but only 1 week after challenge. We conclude that the asthma like lung lesions induced in these models is preceded by immune complex-mediated eosinophilic vasculitis and iBALT formation. There are elevations of Th2 cytokines that most likely produce bronchial lesions that resemble human asthma. However, it is unlikely that mast cell-activated atopic mechanisms are responsible as we found only a few presumed mast cells by toluidine blue and metachromatic staining limited to the most proximal part of the main stem bronchus, and none in the remaining main stem bronchus or in the lung periphery. PMID- 26006021 TI - Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts. AB - Although the phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway is essential for conferring cardioprotection in response to ischemic preconditioning (IP), the role of PI3K/Akt signaling in the infarcted heart for mediating the anti arrhythmic effects in response to IP remains unclear. We explored the involvement of PI3K/Akt in the IP-like effect of connexin 43 and proangiogenic factors with particular regard to its role in protecting against ischemia-induced arrhythmia, heart failure, and myocardial remodeling. Groups of pigs were administered phosphate-buffered saline (PBS) or LY294002 solution. Before induction of myocardial infarction (MI), pigs were grouped according to whether or not they underwent IP. Next, all animals underwent MI induction by ligation of the left anterior descending (LAD) coronary artery. Myocardial tissues from the pig hearts at 7 days after MI were used to assess myocardium myeloperoxidase and reaction oxygen species, infarct size, collagen content, blood vascular density, expression of Akt, connexin 43, and proangiogenic growth factors, using spectrophotometer, histology, immunohistochemistry, real-time RT-PCR, and western blot. At 7 days after MI, IP significantly reduced animal mortality and malignant ventricular arrhythmia, myocardial inflammation, infarct size, and collagen content, and improved cardiac function and remodeling; use of the PI3K inhibitor LY294002 diminished these effects. In parallel with a decline in Akt expression and phosphorylation by MI, LY294002 injection resulted in significant suppression of connexin 43 and proangiogenic factor expression, and a reduction of angiogenesis and collateral circulation. These findings demonstrate that the cardioprotective effects of IP on antiventricular arrhythmia and myocardial repair occur through upregulation of PI3K/Akt-mediated connexin 43 and growth factor signaling. PMID- 26006022 TI - Estrogen suppresses hepatocellular carcinoma cells through ERbeta-mediated upregulation of the NLRP3 inflammasome. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The incidence of HCC is strikingly higher in males than in females. The remarkable gender disparity suggests an important role for sex hormones in HCC pathogenesis. Recently, estrogen has emerged as a protective factor in the development and progression of HCC, but whether it prevents and attenuates HCC, and the mechanism of protection, have not been elucidated. The present study shows that expression of estrogen receptor (ER) beta was significantly downregulated in HCC tissue compared with normal liver tissue; moreover, its expression level showed a significant negative correlation with disease progression and a positive correlation with the expression level of NLRP3 inflammasome components. In a previous study, we showed that loss of NLRP3 inflammasome in HCC tissue contributed to tumor progression, whereas the mechanism of its deregulation was not elucidated. In this study, we investigated the potential link between NLRP3 inflammasome and estrogen. Our data reveal that treatment with 17beta-estradiol (E2) significantly inhibited the malignant behavior of HCC cells through E2/ERbeta/MAPK pathway-mediated upregulation of the NLRP3 inflammasome. This study shows a novel link between ERbeta and the NLRP3 inflammasome in HCC progression, which provides a potentially valuable therapeutic strategy for treatment of HCC patients. PMID- 26006024 TI - AORN position statement on care of the older adult in perioperative settings. PMID- 26006023 TI - The hepatocyte growth factor receptor as a potential therapeutic target for dedifferentiated liposarcoma. AB - Dedifferentiated liposarcomas (DDLPS) are highly resistant to conventional chemo- and radiotherapies, with surgical resection remaining the classic treatment strategy; therefore, there is a pressing need for novel anti-DDLPS-targeted chemotherapeutics. Hepatocyte growth factor receptor (Met) expression is elevated in DDLPS, but the functional role of Met signaling in this disease is not known. We found that the in vitro stimulation of DDLPS cells with hepatocyte growth factor (HGF) elevated the degree of PI3K/AKT and MAPK pathway signaling, and that pro-tumorigenic phenotypes such as cell proliferation, invasion, and migration were significantly enhanced. Conversely, Met knockdown using shRNA-mediated interference decreased HGF-induced Met signaling, the invasive and migratory nature of DDLPS cells in vitro, and the tumorigenicity of DDLPS cells in vivo. These data strongly support the role for Met as a DDLPS therapeutic target. To that end, using EMD1214063, an ATP-competitive kinase inhibitor that targets Met more specifically than other kinases, inhibited Met-dependent signaling, reduced the oncogenicity of DDLPS cells in vitro, and significantly increased the survival of nude mice bearing subcutaneous DDLPS xenografts. These findings support further investigations of HGF-induced Met signaling inhibition in DDLPS, as a potential strategy to enhance clinical outcomes for this disease. PMID- 26006026 TI - The methodology flaws in Hinman's acupuncture clinical trial, Part II: Zelen design and effectiveness dilutions. PMID- 26006027 TI - Early reports of bone repair techniques and bone xenograft in Persian traditional medicine. PMID- 26006025 TI - Risk factors for bronchiolitis hospitalization during the first year of life in a multicenter Italian birth cohort. AB - BACKGROUND: Respiratory Syncytial Virus (RSV) is one of the main causes of respiratory infections during the first year of life. Very premature infants may contract more severe diseases and 'late preterm infants' may also be more susceptible to the infection. The aim of this study is to evaluate the risk factors for hospitalization during the first year of life in children born at different gestational ages in Italy. METHODS: A cohort of 33-34 weeks gestational age (wGA) newborns matched by sex and age with two cohort of newborns born at 35 37 wGA and > 37 wGA were enrolled in this study for a three-year period (2009 2012). Hospitalization for bronchiolitis (ICD-9 code 466.1) during the first year of life was assessed through phone interview at the end of the RSV season (November-March) and at the completion of the first year of life. RESULTS: The study enrolled 2314 newborns, of which 2210 (95.5 %) had a one year follow-up and were included in the analysis; 120 (5.4 %) were hospitalized during the first year of life for bronchiolitis. Children born at 33-34 wGA had a higher hospitalization rate compared to the two other groups. The multivariate analysis carried out on the entire population associated the following factors with higher rates for bronchiolitis hospitalization: male gender; prenatal treatment with corticosteroids; prenatal exposure to maternal smoking; singleton delivery; respiratory diseases in neonatal period; surfactant therapy; lack of breastfeeding; siblings <10 years old; living in crowded conditions and/or in unhealthy households and early exposure to the epidemic RSV season. When analysis was restricted to preterms born at 33-34 wGA the following variables were associated to higher rates of bronchiolitis hospitalization: male gender, prenatal exposure to maternal smoking, neonatal surfactant therapy, having siblings <10 years old, living in crowded conditions and being exposed to epidemic season during the first three months of life. CONCLUSION: Our study identified some prenatal, perinatal and postnatal conditions proving to be relevant and independent risk factors for hospitalization for bronchiolitis during the first year of life. The combination of these factors may lead to consider palivizumab prophylaxis in Italy. PMID- 26006028 TI - Chinese medicines for prevention and treatment of human hepatocellular carcinoma: current progress on pharmacological actions and mechanisms. AB - Hepatocellular carcinoma (HCC) is one of leading causes of death in the world. Although various treatments have been developed, the therapeutic side effects are far from desirable. Chinese medicines (CMs, including plants, animal parts and minerals) have drawn a great deal of attention in recent years for their potential in the treatment of HCC. Most studies have shown that CMs may be able to retard HCC progression with multiple actions, either alone or in combination with other conventional therapies to improve quality of life in HCC patients. Additionally, CMs are used for preventing HCC occurrence. The aim of this study is to review the potential prophylactic and curative effects of CMs on human HCC and the possible mechanisms that underlie these pharmacological actions. Publications were collected and reviewed from PubMed and China National Knowledge Infrastructure from 2000 to 2014. Keywords for literature searches include "Chinese medicine", "Chinese herb", "traditional Chinese Medicine", "hepatocellular carcinoma" and "liver cancer". CMs in forms of pure compounds, isolated fractions, and composite formulas are included. Combination therapies are also considered. Both in vitro and in vivo efficacies of CMs are being discussed and the translational potential to bedside is to be discussed with clinical cases, which show the actions of CMs on HCC may include tumor growth inhibition, antimetastatic activities, anti-inflammation, anti-liver cancer stem cells, reversal on multi-drug resistance and induction/reduction of oxidative stress. Multiple types of molecules are found to contribute in the above actions. The review paper indicated that CMs might have potential to both prevent HCC occurrence and retard HCC progression with several molecular targets involved. PMID- 26006029 TI - Effects of Ayurvedic Rasayana botanicals on CYP3A4 isoenzyme system. AB - OBJECTIVE: Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic (PK-PD) herb-drug interactions (HDI). The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals. METHODS: The aqueous extracts of Asparagus racemosus (ARE) and Gymnema sylvester (GSE) were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography (HPLC). Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC & mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite (6-beta hydroxy testosterone) were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration (IC50) was used to predict plausible HDI. RESULTS: ARE and GSE showed no inhibition with IC50 values >1 000 MUg/mL while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 MUg/mL and IC50 was found to be 0.036 MUg/mL. CONCLUSION: ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance. PMID- 26006030 TI - Qualitative phytochemical screening and evaluation of anti-inflammatory, analgesic and antipyretic activities of Microcos paniculata barks and fruits. AB - OBJECTIVE: The main objectives of this study were to qualitatively evaluate the profile of phytochemical constituents present in methanolic extract of Microcos paniculata bark (BME) and fruit (FME), as well as to evaluate their anti inflammatory, analgesic and antipyretic activities. METHODS: Phytochemical constituents of BME and FME were determined by different qualitative tests such as Molisch's test, Fehling's test, alkaloid test, frothing test, FeCl3 test, alkali test, Salkowski's test and Baljet test. The anti-inflammatory, analgesic and antipyretic activities of the extracts were evaluated through proteinase inhibitory assay, xylene-induced ear edema test, cotton pellet-induced granuloma formation in mice, formalin test, acetic acid-induced writhing test, tail immersion test and Brewer's yeast-induced pyrexia in mice. RESULTS: M. paniculata extracts revealed the presence of carbohydrates, alkaloids, saponins, tannins, flavonoids and triterpenoids. All of the extracts showed significant (P<0.05, vs aspirin group) proteinase-inhibitory activity, whereas the highest effect elicited by plant extracts was exhibited by the BME (75.94% proteinase inhibition activity) with a half-maximal inhibitory concentration (IC50) of 61.31 MUg/mL. Each extract at the doses of 200 and 400 mg/kg body weight showed significant (P<0.05, vs control) percentage inhibition of ear edema and granuloma formation. These extracts significantly (P<0.05, vs control) reduced the paw licking and abdominal writhing of mice. In addition, BME 400 mg/kg, and FME at 200 and 400 mg/kg showed significant (P<0.05, vs control) analgesic activities at 60 min in the tail immersion test. Again, the significant (P<0.05, vs control) post treatment antipyretic activities were found by BME 200 and 400 mg/kg and FME 400 mg/kg respectively. CONCLUSION: Study results indicate that M. paniculata may provide a source of plant compounds with anti-inflammatory, analgesic and antipyretic activities. PMID- 26006031 TI - Antioxidant, antiangiogenic and antiproliferative activities of root methanol extract of Calliandra portoricensis in human prostate cancer cells. AB - OBJECTIVE: Prostate cancer (PCa) is a major health concern. Calliandra portoricensis (CP) is traditionally known for its analgesic, anti-ulcerogenic and anticonvulsant properties. However, its antiproliferative properties for PCa still need to be investigated. METHODS: Antioxidant activities of CP were determined by 1,1-diphenyl-2-picryhydrazyl (DPPH) and hydroxyl (OH(-)) radicals scavenging methods. PC-3 and LNCaP (androgen-refractory and androgen-dependent PCa-derived cell lines) were cultured and treated with CP (10, 50 and 100 MUg/mL). Effects of CP on cells were determined by cytotoxicity assay (lactate dehydrogenase, LDH) and viability assay (sodium 3'-[1-(phenylaminocarbonyl)-3,4 tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate, XTT). DNA fragmentation was detected by cell death detection enzyme-linked immunosorbent assay plus kit. CP was tested as an inhibitor of angiogenesis using chicken chorioallantoic membrane (CAM) assay. RESULTS: CP showed significant scavenging of DPPH and OH(-) radicals. CP significantly (P<0.05) inhibited lipid peroxidation in a dose-dependent manner. Precisely, CP (10, 50 and 100 MUg/mL) inhibited PC-3 and LNCaP growth by 7%, 74% and 92%, and 27%, 73%, and 85% respectively at 48 h. CP had low toxicity in vitro at its half inhibitory concentration dose. Detection of cell death induced by CP at 50 MUg/mL showed higher enrichment factors in LNCaP (7.38+/-0.95) than PC-3 (3.48+/-0.55). Also, treatment with CP (50 MUg/mL) significantly reduced network of vessels in CAM, suggesting its antiangiogenic potential. CONCLUSION: Calliandra portoricensis elicited antioxidant, antiangiogenic and antiproliferative effects in PCa cells. PMID- 26006032 TI - Alpha-adrenoceptor antagonism by Crassostrea gigas oyster extract inhibits noradrenaline-induced vascular contraction in Wistar rats. AB - OBJECTIVE: Crassostrea gigas oyster extract has been reported to have antioxidant, antihypertensive and lipid-lowering properties that may be useful for treating cardiovascular diseases. This study aimed to evaluate the effect of C. gigas oyster extract on cardiovascular function in tissues from healthy rats. METHODS: Single-cell microelectrode and isolated thoracic aortic organ bath studies were performed on tissues from 8-week-old healthy Wistar rats, using varying concentrations of C. gigas oyster extract. To elucidate a mechanism of action for the oyster's vasoactive properties, concentration response curves were carried out in the presence of a calcium channel inhibitior (verapamil), a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methyl ester), a potassium channel inhibitor (4-aminopyridine), in addition to the alpha-adrenoceptor inhibitor prazosin. RESULTS: Oyster solution at 7 500 mg/mL inhibited noradrenaline-induced contraction in isolated aortic rings. Cardiac electrophysiology results showed that neither concentration of oyster solution was able to significantly reduce action potential duration at all phases of repolarisation in left ventricular papillary muscles from healthy animals. CONCLUSION: When administered to healthy vascular tissue, C. gigas oyster extract inhibits contraction induced by noradrenaline. This effect is likely to be mediated through alpha-adrenoceptor inhibition, and to a lesser extent, calcium modulating activity. PMID- 26006033 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: Diseases of Paediatrics (Part 3). PMID- 26006034 TI - On English translation of infant Tuina points in traditional Chinese medicine. PMID- 26006035 TI - Anti-tumor activity of staurosporine in the tumor microenvironment of cervical cancer: An in vitro study. AB - AIM: The fundamental events for cancer progression and metastases include loss of cell adhesion, cell proliferation, anchorage-independent cell growth (evading anoikis), cell migration and cell invasion. All these events leading to cancer progression happen in a favorable nurturing tumor microenvironment. This study was designed to explore the anti-tumor activity of staurosporine (a nonspecific protein kinase inhibitor) in the tumor microenvironment of cervical cancer. MAIN METHODS: The anti-tumor activity of staurosporine was investigated by cell adhesion assay, colony formation assay, apoptosis assay and quantitative real time polymerase chain reaction (PCR) in cervical cancer cell lines. KEY FINDINGS: The cell adhesion assay showed that staurosporine induces adhesion of cervical cancer cells to the extracellular matrix (ECM) protein fibronectin. The soft agar colony formation assay showed that staurosporine inhibits both the number and size of colony formation in a dose dependent manner and also induces adherent tendency in the cancer cells. Staurosporine also induces prominent apoptosis in single cell suspensions compared to adherent cells. Stroma cell induced transcription of matrix metalloprotease 1 (MMP1) and matrix metalloprotease 2 (MMP2) in cervical cancer cells was inhibited by staurosporine. SIGNIFICANCE: Our results indicate that staurosporine induces anti-tumor response in the cervical tumor microenvironment by inhibiting the fundamental events for cancer progression and metastases. The present study represents an attractive area for further research and opens up new avenues towards the understanding of cervical cancer therapeutics. PMID- 26006036 TI - The glutathione mimic ebselen inhibits oxidative stress but not endoplasmic reticulum stress in endothelial cells. AB - AIMS: Reactive oxygen species are associated with cardiovascular disease, diabetes, and atherosclerosis, yet the use of antioxidants in clinical trials has been ineffective at improving outcomes. In endothelial cells, high-dextrose induced oxidative stress and endoplasmic reticulum stress promote endothelial dysfunction leading to the recruitment and activation of peripheral blood lymphocytes and the breakdown of barrier function. Ebselen, a glutathione peroxidase 1 (GPX1) mimic, has been shown to improve beta-cell function in diabetes and prevent atherosclerosis. MAIN METHODS: To determine if ebselen inhibits both oxidative stress and endoplasmic reticulum (ER) stress in endothelial cells, we examined its effects in human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC) with and without high-dextrose. Oxidative stress and ER stress were measured by 2-methyl-6 (4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride chemiluminescence and ER stress alkaline phosphatase assays, respectively. GPX1 over-expression and knockdown were performed by transfecting cells with a GPX1 expression construct or a GPX1-specific siRNA, respectively. KEY FINDINGS: Ebselen inhibited dextrose-induced oxidative stress but not ER stress in both HUVEC and HCAEC. Ebselen also had no effect on tunicamycin-induced ER stress in HCAEC. Furthermore, augmentation of GPX1 activity directly by sodium selenite supplementation or transfection of a GPX1 expression plasmid decreased dextrose induced oxidative stress but not ER stress, while GPX1 knockout enhanced oxidative stress but had no effect on ER stress. SIGNIFICANCE: These results suggest that ebselen targets only oxidative stress but not ER stress. PMID- 26006037 TI - Tissue distribution of CysAP activity and its relationship to blood pressure and water balance. AB - AIMS: To better understand the functional role of soluble (Sol) and membrane bound (MB) cystinyl-aminopeptidase (CysAP) activities, we studied differentially their organ distribution in adult male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR)with or without treatment with captopril.We searched for a possible tissue-specific association of CysAP with water balance and blood pressure. MAIN METHODS: We used twenty WKY rats distributed in ten controls and ten captopril-treated, and sixteen SHR divided in eight controls and eight captopril-treated. Captopril (100 mg/kg/day) was administered in drinking water for 4 weeks. Systolic blood pressure, water intake and diuresis were measured individually. CysAP was assayed fluorometrically using L-cystine-di-beta naphthylamide as substrate. KEY FINDINGS: Sol or MB activities were generally higher in SHR compared to WKY notably in hypothalamus and kidney than in the other tissues. Captopril mainly decreased CysAP in SHR whereas it increased in WKY. The distribution of Sol CysAP was more homogeneous among tissues ofWKY than SHR. In contrast, the distribution of MB CysAP was more heterogeneous than Sol CysAP in both WKY and SHR. This suggests that MB CysAP activity acts in a more tissue-specific manner than Sol CysAP. The majority of the significant correlations between tissue activities and the measured physiological parameters were observed mostly in renal medulla and hypothalamus. SIGNIFICANCE: Sol and MB CysAP activities, acting separately or in concert and mainly in renal medulla, regulate the function of their susceptible endogenous substrates, and may participate meaningfully in the control of blood pressure and fluid balance. PMID- 26006038 TI - The long-term administration of calcineurin inhibitors decreases antioxidant enzyme activity in the rat parotid and submandibular salivary glands. AB - AIMS: Calcineurin inhibitors are widely used for prevention of graft rejection and treatment of autoimmune disorders, which result in increased longevity and enhanced quality of life for patients. Unfortunately, the toxic side effects of these drugs (mainly renal, hepatic and cardiac) limit their use. In this work, we studied the effects of long-term treatment of rats with the immunosuppressant cyclosporin (CsA) or tacrolimus (Tac) on salivation, saliva composition and on the major salivary glands (parotid and submandibular) in terms of histological alterations and oxidative stress, evaluated as lipoperoxidation (thiobarbituric acid reactive species--TBARS) and antioxidant enzyme activity contents (superoxide dismutase--SOD, catalase--CAT and glutathione peroxidase--GPx). MAIN METHODS: Male adult rats were treated with either CsA (10 mg/kg/day) or Tac (1 mg/kg/day) subcutaneously for 30 or 60 days. At the end of the experimental periods, pilocarpine-stimulated salivary flow rate was measured, saliva samples were collected and the salivary glands were dissected for morphological and biochemical analyses. KEY FINDINGS: After a 60-day treatment with any of the immunosuppressants, the total protein, Ca(2+) and Na(+) saliva concentrations were decreased but salivary flow rates were unaffected. In addition, both parotid and submandibular glands showed decreased SOD, CAT and GPx activities, increased TBARS contents and histomorphological alterations involving the epithelium and acini. SIGNIFICANCE: Based on these results, we suggest that the systemic long term administration of the calcineurin inhibitor CsA or Tac induces an impairment of the antioxidant enzymatic defense in the rat major salivary glands, which may, in turn, lead to altered saliva composition. PMID- 26006039 TI - Origin of endogenous nitric oxide released in the nucleus accumbens under real time in vivo conditions. AB - AIMS: Nitric oxide (NO), is a simple but multifarious molecule. It is implicated in physiological and pathological processes within the striatum, mainly in the nucleus accumbens (NAc). The aim of the present study was to determine the origin of NO in the NAc of anaesthetized rats by applying various compounds known to modulate the release of NO when applied either systemically or locally. MAIN METHODS: Real-time monitoring of NO was carried out by introducing an amperometric NO sensor into the outer tubing of a push-pull cannula. For local application of substances, the push-pull superfusion technique was used. KEY FINDINGS: An overdose of urethane (i.p.) or superfusion of the NAc with tetrodotoxin (TTX) led to a fall of NO release in the NAc. The NO synthase (NOS) inhibitors 7-nitroindazolmonosodiumsalt (7-NINA, neuronal NOS selective) and N nitro-L-arginine (L-NNA, NOS selective) decreased release of NO when applied i.p. or locally. Superfusion of the NAc with N-methyl-D-aspartate (NMDA) elicited a dose dependent increase of NO release. SIGNIFICANCE: Combination of an amperometric NO sensor for real-time monitoring of NO release with the push-pull superfusion technique showed that NO released in the NAc is, at least to a great extent, of neuronal origin. The enhanced release of NO elicited by locally applied NMDA demonstrates that activation of NMDA receptors facilitates NO synthesis, thus underlining the functionality of NO targets within the NAc. PMID- 26006040 TI - Extracellular superoxide dismutase ameliorates streptozotocin-induced rat diabetic nephropathy via inhibiting the ROS/ERK1/2 signaling. AB - AIM: Diabetic nephropathy is the leading cause of end stage renal disease in developed countries throughout the world. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system is the main problem that is responsible for the progression of diabetic kidney disease. In this study, we investigated whether human extracellular superoxide dismutase (hEC SOD) can prevent diabetic nephropathy in the rat model. MAIN METHODS: Diabetic nephropathy symptoms were induced by intraperitoneal injection with 60 mg/kg streptozotocin (STZ) in male Sprague-Dawley (SD) rats. After daily supplement of rhEC-SOD (3200 U/kg/day) for 4 weeks, the serum or urine biochemical markers (glucose, creatinine, blood urea nitrogen, triglyceride, hemoglobin A1c, and microalbuminuria), histological changes, gene expressions (phox47, opn, and gapdh), and protein levels (TGF-beta, AT1-R, phospho-p42/p44 MAPK, and p42/p44 MAPK) were determined. KEY FINDINGS: Results showed that rhEC-SOD administration could reverse SOD activity measured in kidney and diabetic-associated changes, including the fibrosis change, expression of collagen I, transforming growth factor-beta (TGF-beta) and angiotensin II type I receptor (AT1-R), as well as the activation of the intracellular mitogen-activated protein kinase (MAPK) signaling pathway, associating with its inhibition of p42(MAPK)/p44(MAPK) (ERK1/2) phosphorylation. Additionally, diabetic nephropathy up-regulated the expression of the phox47 and opn genes, and these changes could also be suppressed. Though the proteinuria did not significantly reduce. Treatment with rhEC-SOD ameliorates STZ-induced diabetic nephropathy, leading to reduced death rates, kidney weight/body weight ratio, fibrosis change, and TGF-beta1 expression through the down-regulation of ROS/ERK1/2 signaling pathway. SIGNIFICANCE: We conclude that rhEC-SOD can act as a therapeutic agent to protect the progression of diabetic nephropathy. PMID- 26006042 TI - Flavonoids and mitochondrial pharmacology: A new paradigm for cardioprotection. AB - Acute myocardial ischemia is one of the major causes of illness and of deaths in Western society; therefore the definition of the signaling pathways involved in the cardioprotection represents a challenging goal in order to discover novel pharmacological approaches. In this regard, a number of epidemiologic studies demonstrate a relationship between intake of flavonoid-rich foods and reduction of cardiovascular risk factors and mortality. Moreover, numerous experimental studies have examined flavonoid-induced cardioprotective effects on several animal models of myocardial ischemia/reperfusion. As concerns the mechanisms of action, although the antioxidant effect of flavonoids has been long thought to be a crucial factor accounting for cardioprotection, mitochondrial pathways (ion channels, protein kinases, etc.) are presently emerging as specific pharmacological targets more relevantly involved in the anti-ischemic effects of some flavonoids. Since these pharmacodynamic features seem to be poorly considered, this review examines the mitochondrial role in the cardioprotective mechanisms of some members of this phytochemical class, by describing the biological pathways and reporting an overview of the most important experimental evidence in this field. PMID- 26006041 TI - Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia reperfusion-induced hepatic injury in rats. AB - AIM: Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. MATERIALS AND METHODS: Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-alpha) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. KEY FINDINGS: Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-alpha, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. SIGNIFICANCE: The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors. PMID- 26006043 TI - Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N acetylcysteine in U-87MG human astrocytoma cells. AB - AIMS: The aim of this study was to clarify the involvement of oxidative stress in methylmercury (MeHg)-induced pro-inflammatory cytokine expressions and the suppressive effects of N-acetylcysteine (NAC) in MeHg-induced cytokine expression. MATERIALS AND METHODS: Using U-87-MG human astrocytoma cell line, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 expressions induced by 4 MUM MeHg were measured at mRNA and protein levels. Hydrogen peroxide (H2O2) and superoxide anion (O2(-)) were quantified by flow-cytometry analysis. To examine the suppressive effects of NAC on the cytokine expressions among different timing of NAC treatment, cells were treated with 0.5 or 5mM NAC before, simultaneously, or after MeHg administration. KEY FINDINGS: MeHg exposure at 4 MUM, a non-cytotoxic concentration, significantly induced MCP-1 and IL-6 expressions at both mRNA and protein levels. A significant increase of H2O2 production but not O2(-) was observed. MeHg-induced expression of MCP-1 and IL-6 mRNA was reduced by 10-20% in the presence of 5mM NAC (co-treatment experiment) compared to cells treated with MeHg only. Pre-treatment of cells with 0.5 or 5mM NAC at 0.5 or 1h and its subsequent washout before MeHg addition suppressed MCP-1 and IL-6 cytokine expressions. Post-treatment of cells with NAC after MeHg addition also suppressed the cytokine induction, but the magnitude of suppression was evidently lower than in co-treated cells even though the H2O2 generation was almost completely suppressed by NAC. SIGNIFICANCE: NAC may effectively suppress the MeHg-induced cytokine production through both, inhibition of reactive oxygen species as well as extracellular chelation of MeHg in astrocytes. PMID- 26006044 TI - Resveratrol and sildenafil synergistically improve diabetes-associated erectile dysfunction in streptozotocin-induced diabetic rats. AB - AIMS: Despite effective control of blood glucose levels in diabetic patients, complaints of diabetes-associated erectile dysfunction (ED) persist. Resveratrol has been indicated to possess anti-diabetic effects and therapeutic potential for ED. This study was conducted to observe the effect of resveratrol alone or in combination with sildenafil on ED in streptozotocin (STZ)-induced diabetic rats. MAIN METHOD: Among 58 adult male STZ-induced (60 mg/kg) diabetic Sprague-Dawley rats, 48 STZ-induced diabetic rats were randomized equally to four groups: untreated diabetic rats, resveratrol (25mg/kg), sildenafil (5mg/kg) or resveratrol (25mg/kg) plus sildenafil (5mg/kg) through oral gavage for 8 weeks. Additionally, 12 age-matched rats were chosen as controls. Intracavernous pressure (ICP) and mean arterial blood pressure (MAP) were used to measure erectile function. The cavernous level of cyclic guanosine monophosphate (cGMP), protein and mRNA of endothelial NO synthase (eNOS), neuronal NOS (nNOS), and phosphodiesterase-5 (PDE5) was measured. KEY FINDINGS: Treatment with either resveratrol or sildenafil improved ICP/MAP compared to the untreated diabetic rats (P<0.05). Treatment with resveratrol increased nNOS and eNOS expression, inhibited PDE5 expression, and increased the cavernous cGMP level compared to the untreated diabetic rats. Resveratrol significantly decreased superoxide anion and ROS production. Two-way ANOVA indicated that resveratrol in combination with sildenafil therapy had a significant synergistic effect in improving ICP/MAP and cavernous cGMP levels. SIGNIFICANCE: Resveratrol improves diabetes-associated ED in rats. Combination therapies with resveratrol and sildenafil have a synergistic effect in improving ED. The mechanisms might be attributed to its anti-oxidative properties and NO-cGMP signaling pathway upregulation. PMID- 26006045 TI - Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells. AB - BACKGROUND: Mechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury. METHODS: Expression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively. RESULTS: TRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4. CONCLUSION: These studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells. PMID- 26006046 TI - Evaluation of Outpatient Parenteral Antimicrobial Therapy at a Veterans Affairs Hospital. AB - We reviewed outpatient parenteral antimicrobial therapy at a Veterans Affairs Medical Center to identify opportunities for antimicrobial stewardship intervention. A definite or possible modification would have been recommended in 60% of courses. Forty-one percent of outpatient parenteral antimicrobial therapy courses were potentially avoidable, including 22% involving infectious diseases consultation. PMID- 26006047 TI - Facile Removal of Leader Peptides from Lanthipeptides by Incorporation of a Hydroxy Acid. AB - The biosynthesis of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products typically involves a precursor peptide which contains a leader peptide that is important for the modification process, and that is removed in the final step by a protease. Genome mining efforts for new RiPPs are often hampered by the lack of a general method to remove the leader peptides. We describe here the incorporation of hydroxy acids into the precursor peptides in E. coli which results in connection of the leader peptide via an ester linkage that is readily cleaved by simple hydrolysis. We demonstrate the method for two lantibiotics, lacticin 481 and nukacin ISK-1. PMID- 26006048 TI - Popliteal vein repair may not impact amputation rates in combined popliteal artery and vein injury. AB - INTRODUCTION: This study aimed to determine the incidence, management, and outcomes of popliteal artery injury, popliteal vein injury, and concomitant popliteal artery injury and vein injury. METHODS: A retrospective analysis was completed using the 2000-2010 Nationwide Inpatient Sample utilizing International Classification of Diseases-9 codes to select patients with isolated popliteal artery injury (904.41), isolated popliteal vein injury (904.42), and isolated concomitant popliteal artery and vein injury (958.92). Variables included demographics, procedure type, and outcome during hospital course. Statistical analysis was with chi-square, Fisher exact test, and multivariate analysis. RESULTS: A total of 2216 patients presented with injury to the popliteal system; 71% (1568) presented with isolated popliteal artery injury, 14% (306) with isolated popliteal vein injury, and 15% (342) with concomitant popliteal artery and vein injury. Amputation was significantly increased in popliteal artery injury and concomitant popliteal artery and vein injury (P < 0.001) as compared to popliteal vein injury. Ligation of the vein was more common in concomitant popliteal artery and vein injury when compared to popliteal vein injury (P < 0.05). The rate of amputation was 9.8% for popliteal artery injury, significantly greater than for popliteal vein injury (0.7%, P < 0.001) but not different than for concomitant popliteal artery and vein injury (8.2%, P = NS). CONCLUSION: Evidence-based management of popliteal vasculature may increase rates of limb salvage. Within the limitations of the data set used, conclusions appear to be that patients with popliteal vein injury or concomitant popliteal artery and vein injury may be managed with vein ligation without increased amputation rates as compared to popliteal artery injury. PMID- 26006049 TI - European Union funded project on the development of a whole complement deficiency screening ELISA-A story of success and an exceptional manager: Mohamed R. Daha. AB - A whole complement ELISA-based assay kit, primarily designed to screen for deficiencies in components of the complement system was developed during a European Union grant involving more than a dozen European scientists and a small medium enterprise company (Wieslab, which later merged into Eurodiagnostica). The consortium was led by Prof. Mohamed R. Daha who had already guided a preceding European grant which prepared the ground for this endeavor to create a novel and sophisticated complement measurement tool. The final result of the grant was a scientific publication (Seelen et al., 2005, J. Immunol. Methods 296, 187-198) and a commercially available complement deficiency screening kit, WIESLAB((r)) Complement system Screen. Thereafter, the group decided to carry on with a grant, located at Innsbruck Medical University, and supported by royalties and unrestricted educational grants from Eurodiagnostica, Malmo, entitled "Search for Applications for WIESLAB((r)) Complement system Screen (SAW)" with the aim to look for further applications of this assay. During the latter project the group organized several scientific meetings aimed at evaluating the use of the assay as well as developing further branches of its platform. A look back over almost two decades reveals a great story of excellent research which was also commercially successful, fulfilling the aims of European Union grants. It is also a story of ageless friendship, only possible due to the vision and guidance of an exceptional manager: Moh Daha. PMID- 26006050 TI - Proteolytic enzymes involved in MHC class I antigen processing: A guerrilla army that partners with the proteasome. AB - Major histocompatibility complex class I proteins (MHC-I) load short peptides derived from proteolytic cleavage of endogenous proteins in any cell of the body, in a process termed antigen processing and presentation. When the source proteins are altered self or encoded by a pathogen, recognition of peptide/MHC-I complexes at the plasma membrane leads to CD8(+) T-lymphocyte responses that clear infections and probably underlie tumor immune surveillance. On the other hand, presentation of self peptides may cause some types of autoimmunity. The peptides that are presented determine the specificity and efficiency of pathogen clearance or, conversely, of immunopathology. In this review we highlight the growing number of peptidases which, as a by-product of their regular activity, can generate peptide epitopes for immune surveillance. These ~20 peptidases collectively behave as a guerrilla army partnering with the regular proteasome army in generating a variety of peptides for presentation by MHC-I and thus optimally signaling infection. PMID- 26006051 TI - Systematic Review: Psychosocial Interventions for Children and Young People With Visible Differences Resulting From Appearance Altering Conditions, Injury, or Treatment Effects. AB - OBJECTIVE: Evaluate critically the evidence of the effectiveness of psychosocial interventions for children/young people (<18 years old) with visible differences in improving self-esteem, social experiences, psychological well-being, and behavioral outcomes. METHODS: Studies were systematically identified using electronic databases, appraised according to eligibility criteria and evaluated for risk of bias. Findings were reported using the PRISMA checklist. RESULTS: Studies were identified that evaluated residential social camps, exercise with counseling, social skills training (SIST), behavioral therapy (BT), and cognitive behavioral therapy (CBT). Risk of bias within studies was high. Camp studies and exercise with counseling showed little or no effect postintervention on self esteem, social experiences, and psychological well-being. The five studies evaluating SIST, CBT, and BT provided limited support for their effectiveness. CONCLUSIONS: Evidence base is inconclusive. Further rigorous research using appropriate outcome measures to evaluate the effectiveness of interventions for young people with visible differences is required. PMID- 26006052 TI - Human health risk assessment from arsenic exposures in Bangladesh. AB - High arsenic exposures, prevalent through dietary and non-dietary sources in Bangladesh, present a major health risk to the public. A quantitative human health risk assessment is described as a result of arsenic exposure through food and water intake, tea intake, accidental soil ingestion, and chewing of betel quid, while people meet their desirable dietary intake requirements throughout their lifetime. In evaluating the contribution of each intake pathway to average daily arsenic intake, the results show that food and water intake combined, makes up approximately 98% of the daily arsenic intake with the balance contributed to by intake pathways such as tea consumption, soil ingestion, and quid consumption. Under an exposure scenario where arsenic concentration in water is at the WHO guideline (0.01 mg/L), food intake is the major arsenic intake pathway ranging from 67% to 80% of the average daily arsenic intake. However, the contribution from food drops to a range of 29% to 45% for an exposure scenario where arsenic in water is at the Bangladesh standard (0.05 mg/L). The lifetime excess risk of cancer occurrence from chronic arsenic exposure, considering a population of 160 million people, based on an exposure scenario with 85 million people at the WHO guideline value and 75 million people at the Bangladesh standard, and assuming that 35 million people are associated with a heavy activity level, is estimated as 1.15 million cases. PMID- 26006053 TI - Electron efficiency of nZVI does not change with variation of environmental parameters. AB - Nanoscale zero-valent iron particles (nZVI) are already applied for in-situ dechlorination of halogenated organic contaminants in the field. We performed batch experiments whereby trichloroethene (TCE) was dehalogenated by nZVI under different environmental conditions that are relevant in practice. The tested conditions include different ionic strengths, addition of polyelectrolytes (carboxymethylcellulose and ligninsulphonate), lowered temperature, dissolved oxygen and different particle contents. Particle properties were determined by Mossbauer spectroscopy, XRD, TEM, SEM, AAS and laser obscuration time measurements. TCE dehalogenation and H2 evolution were decelerated by reduced ionic strength, addition of polyelectrolytes, temperature reduction, the presence of dissolved oxygen and reduced particle content. The partitioning of released electrons between reactions with the contaminant vs. with water (selectivity) was low, independent of the tested conditions. Basically out of hundred electrons that were released via nZVI oxidation only 3.1+/-1.4 were used for TCE dehalogenation. Even lower selectivities were observed at TCE concentrations below 3.5 mg l(-1), hence particle modifications and/or combination of nZVI with other remediation technologies seem to be necessary to reach target concentrations for remediation. Our results suggest that selectivity is particle intrinsic and not as much condition dependent, hence particle synthesis and potential particle modifications of nZVI particles may be more important for optimization of the pollutant degradation rate, than tested environmental conditions. PMID- 26006054 TI - Adipokines as potential prognostic biomarkers in patients with acute knee injury. AB - This review considers adipokines as predictive biomarkers for early onset post traumatic knee osteoarthritis (KOA). Serum concentrations of leptin and resistin can predict radiographic changes and are elevated in early KOA, with higher leptin concentrations independently associated with more severe knee changes. Plasma concentrations of resistin are chronically elevated after injury. Leptin, resistin, chemerin and vistfatin induce catabolic enzymes associated with cartilage degeneration. Available literature on adipokines in post-traumatic KOA pathogenesis suggests that they could contribute to risk prediction of early onset post-traumatic KOA. Further research is needed to further understand the association between adipokines, synovitis and long-term outcomes in this population. PMID- 26006056 TI - Differentiation of benign and malignant thyroid nodules based on the proportion of sponge-like areas on ultrasonography: imaging-pathologic correlation. AB - PURPOSE: The purpose of this study was to determine whether it is possible to differentiate benign from malignant thyroid nodules according to the proportion of sponge-like appearance within the nodules. METHODS: A total of 201 thyroid nodules containing sponge-like appearance from 195 patients (157 women and 38 men) were included this study. Each thyroid nodule was classified into one of three grades by real-time ultrasonography (US) based on the areas with a sponge like appearance within nodule: grade I had sponge-like areas occupying <50%; grade II, between 50% and 75%; and grade III, >75%. We evaluated whether a correlation existed between these grades and cytopathologic diagnoses. RESULTS: Of the 201 nodules, 196 were benign and five were malignant, and according to the US classification, 101 nodules were grade I, 45 were grade II, and 55 were grade III. Of the five malignant nodules, four were grade I, and one was grade II. No statistically significant difference was found in the rate of malignancy between grade III and grades I and II, due to insufficient statistical power. A sponge like appearance was correlated with follicles filled with colloid and cholesterol granules in benign nodules and with papillary fronds around the dilated cystic spaces in malignant nodules. CONCLUSION: No malignancies were found in thyroid nodules with >75% sponge-like appearance. Due to the overall low incidence of malignancy and the limited number of patients, a statistically significant difference could not be found in the prevalence of malignancy depending on the proportion of sponge-like areas within the nodule. PMID- 26006057 TI - Synergistically enhanced oxygen reduction activity of MnO(x)-CeO2/Ketjenblack composites. AB - Here we report a hybrid of MnOx-CeO2/Ketjenblack as a novel catalyst for oxygen reduction reaction (ORR) by a facile strategy. This hybrid exhibits comparable activity and better stability towards ORR than the commercial 20 wt% Pt/C due to the synergistic effect. PMID- 26006055 TI - Alcohol-induced dysregulation of stress-related circuitry: The search for novel targets and implications for interventions across the sexes. AB - While the ability to process fermented fruits and alcohols was once an adaptive trait that improved nutrition and quality of life, the availability and prevalence of high potency alcoholic drinks has contributed to alcohol abuse disorders in a vulnerable portion of the population. Although the neural reward systems take part in the initial response to alcohol, negative reinforcement and stress, which are normally adaptive responses, can intersect to promote continued alcohol use at all stages of the addiction cycle. Eventually a point is reached where these once adaptive responses become dysregulated resulting in uncontrolled intake that constitutes a clinically important condition termed alcohol use disorder (AUD). Current research is targeted at both the behavioral and molecular adaptations in AUDs in an effort to better develop novel approaches to intervention. In this review, historical context is provided demonstrating the societal burden of alcohol use and abuse disorders. The importance of gender in the mechanism of action of alcohol is discussed. Finally, the impact of alcohol on stress-related circuitry, uncovered by preclinical research, is outlined to provide insight into potential novel pharmacological approaches to the treatment of AUD. PMID- 26006058 TI - Transcranial focal electrical stimulation reduces the convulsive expression and amino acid release in the hippocampus during pilocarpine-induced status epilepticus in rats. AB - The aim of the present study was to evaluate the effects of transcranial focal electrical stimulation (TFS) on gamma-aminobutyric acid (GABA) and glutamate release in the hippocampus under basal conditions and during pilocarpine-induced status epilepticus (SE). Animals were previously implanted with a guide cannula attached to a bipolar electrode into the right ventral hippocampus and a concentric ring electrode placed on the skull surface. The first microdialysis experiment was designed to determine, under basal conditions, the effects of TFS (300 Hz, 200 MUs biphasic square pulses, for 30 min) on afterdischarge threshold (ADT) and the release of GABA and glutamate in the hippocampus. The results obtained indicate that at low current intensities (<2800 MUA), TFS enhances and decreases the basal extracellular levels of GABA and glutamate, respectively. However, TFS did not modify the ADT. During the second microdialysis experiment, a group of animals was subjected to SE induced by pilocarpine administration (300 mg/kg, i.p.; SE group). The SE was associated with a significant rise of GABA and glutamate release (up to 120 and 182% respectively, 5h after pilocarpine injection) and the prevalence of high-voltage rhythmic spikes and increased spectral potency of delta, gamma, and theta bands. A group of animals (SE-TFS group) received TFS continuously during 2h at 100 MUA, 5 min after the establishment of SE. This group showed a significant decrease in the expression of the convulsive activity and spectral potency in gamma and theta bands. The extracellular levels of GABA and glutamate in the hippocampus remained at basal conditions. These results suggest that TFS induces anticonvulsant effects when applied during the SE, an effect associated with lower amino acid release. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26006059 TI - Response to: 'is chondroitin sulfate plus glucosamine superior to placebo in the treatment of knee osteoarthritis?' by Zeng et al. PMID- 26006061 TI - The subperitoneal space and peritoneal cavity: basic concepts. AB - The subperitoneal space and peritoneal cavity are two mutually exclusive spaces that are separated by the peritoneum. Each is a single continuous space with interconnected regions. Disease can spread either within the subperitoneal space or within the peritoneal cavity to distant sites in the abdomen and pelvis via these interconnecting pathways. Disease can also cross the peritoneum to spread from the subperitoneal space to the peritoneal cavity or vice versa. PMID- 26006060 TI - Orbitofrontal lesions eliminate signalling of biological significance in cue responsive ventral striatal neurons. AB - The ventral striatum has long been proposed as an integrator of biologically significant associative information to drive actions. Although inputs from the amygdala and hippocampus have been much studied, the role of prominent inputs from orbitofrontal cortex (OFC) are less well understood. Here, we recorded single-unit activity from ventral striatum core in rats with sham or ipsilateral neurotoxic lesions of lateral OFC, as they performed an odour-guided spatial choice task. Consistent with prior reports, we found that spiking activity recorded in sham rats during cue sampling was related to both reward magnitude and reward identity, with higher firing rates observed for cues that predicted more reward. Lesioned rats also showed differential activity to the cues, but this activity was unbiased towards larger rewards. These data support a role for OFC in shaping activity in the ventral striatum to represent the biological significance of associative information in the environment. PMID- 26006062 TI - Phylogeography of the subgenus Transphlebotomus Artemiev with description of two new species, Phlebotomus anatolicus n. sp. and Phlebotomus killicki n. sp. AB - The subgenus Transphlebotomus comprises sand fly species with distribution markedly restricted to the Mediterranean basin and suspected of Leishmania transmission. Only three species, Phlebotomus mascittii, Phlebotomus canaaniticus and Phlebotomus economidesi, have been described up to the present. Due to their similar morphology, proper identification remains difficult and relies mainly on molecular markers. We studied sand fly species of this subgenus from Crete and south-western coast of Anatolia. Based on the sequencing analysis of mitochondrial genes (cytochrome b, NADH dehydrogenase subunit 4, cytochrome oxidase I), two new Transphlebotomus species were identified and subsequently distinguished also by morphological characters: Phlebotomus anatolicus n. sp. and Phlebotomus killicki n. sp. Moreover, Ph. economidesi, previously only recorded from Cyprus, was found in Turkey sympatrically with these two new species. Based on the divergence time estimates, the first split has occurred in the subgenus Transphlebotomus ~10 million years ago and the paleogeographic events took place around the Aegean and Mediterranean regions were suggested as the main drivers of the diversification of the subgenus. Our findings indicate that for Transphlebotomus species, morphological identification should be confirmed by molecular approaches, especially for investigations concerning their possible vectorial role in Leishmania transmission. PMID- 26006063 TI - A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects. AB - BACKGROUND: When chemical health hazards have been identified, probabilistic dose response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. OBJECTIVES: We developed a unified framework for probabilistic dose-response assessment. METHODS: We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. RESULTS: Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects >= M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences >= M = 1%-10% effect sizes. CONCLUSIONS: Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better informed risk management decisions. PMID- 26006065 TI - Olefin polymerisation catalysts: when perfection is not enough. AB - Despite decades of thorough mechanistic investigations, it is still hard to predict the activity of a novel olefin polymerisation catalyst, even when the precursor is a well-defined molecular entity. In the present study, we highlight the crucial importance of activation entropy on the polymerisation rate and how weak interactions of the catalytic species with electron donating species in the reaction pool can ultimately lower the activation free energy. PMID- 26006066 TI - Structural analysis of sigma E interactions with core RNA polymerase and its cognate P-hsp20 promoter of Mycobacterium tuberculosis. AB - Alternate sigma factor plays an important role for the survival of Mycobacterium tuberculosis in adverse environmental condition. Stress-induced sigma factors are major cause for expression of genes involved in pathogenesis, dormancy and various unusual environmental conditions. In the present work, an attempt has been made to characterize one of such M. tuberculosis (Mtb) sigma factor, SigE. The structures of Mtb-SigE and Mtb-beta have been predicted using comparative modelling techniques and validated. Effort has also been implied to understand the nature of interaction of SigE with the core RNA polymerase subunits which have well identified the amino acid residues in the binding interface and prompted the fact that Mtb-beta' and Mtb-beta interact with domain 2 and domain 4 of Mtb-SigE, respectively. Furthermore, intermolecular docking study predicted the interface between the Mtb-SigE and its putative promoter P-hsp20. The report confers the probable amino acid residues and the nitrogenous bases involved in the recognition of P-hsp20 by the sigma factor to initiate the transcription process. PMID- 26006067 TI - Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). AB - The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population. PMID- 26006068 TI - Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes. AB - The prognostic significance of tumor-infiltrating lymphocytes and immune signals has been described previously in triple-negative breast cancer (TNBC). Furthermore, recent studies have shown that immunologic parameters are relevant for the response to neoadjuvant chemotherapy (NAC) in breast cancer as well as for outcomes after adjuvant chemotherapy. However, immune signals are variable, and which signals are important is largely unknown. We, therefore, evaluated the expression of immune-related genes in TNBC treated with NAC. We retrospectively evaluated biopsy tissue from 55 patients with primary TNBC treated with NAC (anthracycline, cyclophosphamide, and docetaxel) against the NanoString nCounter GX Human Immunology Panel (579 immune-related genes). Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, cytokines related to T helper cell type 1 (Th1), and B cell markers was associated with a pathologic complete response (pCR). Higher expression of NFKB1, MAPK1, TRAF1, CXCL13, GZMK, and IL7R was significantly associated with pCR, higher Miller-Payne grade, and lower residual cancer burden class. Expression of NFKB1, TRAF1, and CXCL13genes, in particular, was significantly correlated with a longer disease free survival rate. Conversely, patients those who failed to achieve a pCR showed increased expression of genes related to neutrophils. Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, Th1-related cytokines, and B cell markers is correlated with pCR and survival in TNBC patients treated with NAC. Our results suggest that the activation status of neutrophils may provide additional predictive information for TNBC patients treated with NAC. PMID- 26006069 TI - Morphology, ultrastructure and mineral uptake is affected by copper toxicity in young plants of Inga subnuda subs. luschnathiana (Benth.) T.D. Penn. AB - Toxic effects of copper (Cu) were analyzed in young plants of Inga subnuda subs. luschnathiana, a species that is highly tolerant to flooding and found in Brazil in wetlands contaminated with Cu. Plants were cultivated in fully nutritive solution, containing different concentrations of Cu (from 0.08 MUmol to 0.47 mmol L(-1)). Symptoms of Cu toxicity were observed in both leaves and roots of plants cultivated from 0.16 mmol Cu L(-1). In the leaves, Cu clearly induced alterations in the thickness of the epidermis, mesophyll, palisade parenchyma, and intercellular space of the lacunose parenchyma. Also, this metal induced disorganization in thylakoid membranes, internal and external membrane rupture in chloroplasts, mitochondrial alterations, and electrodense material deposition in vacuoles of the parenchyma and cell walls. The starch grains disappeared; however, an increase of plastoglobule numbers was observed according to Cu toxicity. In the roots, destruction of the epidermis, reduction of the intercellular space, and modifications in the format of initial cells of the external cortex were evident. Cell walls and endoderm had been broken, invaginations of tonoplast and vacuole retractions were found, and, again, electrodense material was observed in these sites. Mineral nutrient analysis revealed higher Cu accumulation in the roots and greater macro- and micronutrients accumulation into shoots. Thus, root morphological and ultrastructural changes induced differential nutrients uptake and their translocations from root toward shoots, and this was related to membrane and endoderm ruptures caused by Cu toxicity. PMID- 26006070 TI - Optimization of photocatalytic degradation of meloxicam using titanium dioxide nanoparticles: application to pharmaceutical wastewater analysis, treatment, and cleaning validation. AB - Meloxicam is a commonly prescribed nonsteroidal anti-inflammatory drug with analgesic and fever-reducing effects. In this study, photocatalytic degradation of meloxicam in the presence of TiO2 nanoparticles (TiO2NP) was optimized and applied for pharmaceutical wastewater treatment. A validated stability-indicating orthogonal testing protocol (reversed-phase (RP)-HPLC and capillary zone electrophoresis) was developed and validated for monitoring of meloxicam concentration in the presence of its photodegradation products. Fractional factorial design was employed in order to investigate the effects of pH, irradiation time, UV light intensity, TiO2NP loading, and initial meloxicam concentration on the efficiency of the process. The light intensity was found as the most significant parameter followed by irradiation time and concentration, respectively. The most influencing interactions were noted between irradiation time-concentration and irradiation time-light intensity. The kinetics of meloxicam degradation was investigated at the optimum set of experimental conditions. The protocol was successfully applied for treatment of incurred water samples collected during various cleaning validation cycles. A percentage degradation of 77.34 +/- 0.02 % was achieved upon irradiation of samples containing 64.57 +/- 0.09 MUg/mL with UV light (1012 MUW/cm(2), 8 h) in the presence of 0.4 mg/mL TiO2NP at pH 9.0 +/- 0.05. Treatment of wastewaters collected during the cleaning validation of each product separately rather than the combined waste should result in a significant improvement in the economics of pharmaceutical wastewater treatment. This could be attributed to the relatively small waste volumes and the ability to tailor the experimental conditions to achieve maximum efficiency. PMID- 26006071 TI - Regulatory effects of dioxin-like and non-dioxin-like PCBs and other AhR ligands on the antioxidant enzymes paraoxonase 1/2/3. AB - Paraoxonase 1 (PON1), an antioxidant enzyme, is believed to play a critical role in many diseases, including cancer. PCBs are widespread environmental contaminants known to induce oxidative stress and cancer and to produce changes in gene expression of various pro-oxidant and antioxidant enzymes. Thus, it appeared of interest to explore whether PCBs may modulate the activity and/or gene expression of PON1 as well. In this study, we compared the effects of dioxin like and non-dioxin-like PCBs and of various aryl hydrocarbon receptor (AhR) ligands on PON1 regulation and activity in male and female Sprague-Dawley rats. Our results demonstrate that (i) the non-dioxin-like PCB154, PCB155, and PCB184 significantly reduced liver and serum PON1 activities, but only in male rats; (ii) the non-dioxin-like PCB153, the most abundant PCB in many matrices, did not affect PON1 messenger RNA (mRNA) level in the liver but significantly decreased serum PON1 activity in male rats; (iii) PCB126, an AhR ligand and dioxin-like PCB, increased both PON1 activities and gene expression; and (iv) even though three tested AhR ligands induced CYP1A in several tissues to a similar extent, they displayed differential effects on the three PONs and AhR, i.e., PCB126 was an efficacious inducer of PON1, PON2, PON3, and AhR in the liver, while 3 methylcholantrene induced liver AhR and lung PON3, and 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD), the most potent AhR agonist, increased only PON3 in the lung, at the doses and exposure times used in these studies. These results show that PCBs may have an effect on the antioxidant protection by paraoxonases in exposed populations and that regulation of gene expression through AhR is highly diverse. PMID- 26006072 TI - Effect of Rht alleles on wheat grain yield and quality under high temperature and drought stress during booting and anthesis. AB - The present study examined the effects of gibberellin semi-sensitive reduced height (Rht) alleles on wheat grain yield and quality under high temperature and drought stress during booting and anthesis stages. Near-isogenic lines (NILs) of winter wheat (Rht (tall), Rht-B1b, Rht-D1b, Rht-B1c, Rht-8c, Rht-D1c, Rht-12) having background of Mercia and Maris Widgeon cultivars were compared under variable temperatures (day/night: 20/12, 27/19, 30/22, 33/25, 36/28, and 39/31 degrees C) and irrigation regimes. Pots were transferred to controlled thermal conditions (Saxcil growth chamber) during booting and anthesis stages and were maintained at field capacity (FC) or had water withheld. High temperature (>30 degrees C) and drought stress for seven consecutive days during booting and anthesis stages reduced the grain yield, while increased nitrogen (N) and sulphur (S) concentrations. A 50 % reduction in grain yield was fitted to have occurred at 37.4 degrees C for well-watered plants and at 31.4 degrees C for drought stressed plants. The N and S concentrations were higher for severe dwarfs, whereas no significant differences were observed between tall and semi-dwarfs in Mercia. In the taller background (Maris Widgeon), N and S concentrations were significantly higher compared with that in Mercia. In Mercia, the severe dwarf Rht-D1c had higher Hagberg falling number (HFN) and sodium dodecyl sulphate (SDS) sedimentation volume. In both backgrounds, semi-dwarfs and severe dwarfs had higher HFN. Moreover, the SDS sedimentation volumes in Maris Widgeon were also higher than that in Mercia. Greater adaptability and improved grain quality traits suggested that severe dwarf Rht alleles are better able to enhance tolerance to high temperature and drought stress in wheat. PMID- 26006074 TI - Performance of different assessment methods to evaluate contaminant sources and fate in a coastal aquifer. AB - The present study deals with the application of different monitoring techniques and numerical models to characterize coastal aquifers affected by multiple sources of contamination. Specifically, equivalent freshwater heads in 243 monitoring wells were used to reconstruct the piezometric map of the studied aquifer; flow meter tests were carried out to infer vertical groundwater fluxes at selected wells; deuterium and oxygen isotopes were used to identify the groundwater origin, and tritium was analyzed to estimate the residence time; compound-specific isotope analyses and microbial analyses were employed to track different sources of contamination and their degradation; numerical modelling was used to estimate and verify groundwater flow direction and magnitude throughout the aquifer. The comparison of the information level for each technique allowed determining which of the applied approaches showed the best results to locate the possible sources and better understanding of the fate of the contaminants. This study reports a detailed site characterization process and outcomes for a coastal industrial site, where a comprehensive conceptual model of pollution and seawater intrusion has been built using different assessment methods. Information and results from this study encourages combining different methods for the design and implementation of the monitoring activities in real-life coastal contaminated sites in order to develop an appropriate strategy for control and remediation of the contamination. PMID- 26006073 TI - The role of authigenic sulfides in immobilization of potentially toxic metals in the Bagno Bory wetland, southern Poland. AB - The supply of Cd, Cu, Fe, Pb, Zn, and Tl into a wetland in the industrial area of Upper Silesia, southern Poland via atmospheric precipitation and dust deposition has been counterbalanced by the biogenic metal sulfide crystallization in microsites of the thin (<30 cm) peat layer, despite the overall oxidative conditions in the wetland. Disequilibrium of the redox reactions in the peat pore water (pH 5.4-6.2) caused by sulfate-reducing microorganisms has resulted in the localized decrease in Eh and subsequent precipitation of micron- and submicron sized framboidal pyrite, spheroidal ZnS and (Zn,Cd)S, and galena as revealed by high-resolution scanning electron microscopy (SEM)/energy dispersive spectrometer (EDS). Saturation index for each sulfide is at a maximum within the calculated Eh range of -80 and -146 mV. Lead was also immobilized in galena deposited in fungal filaments, possibly at a higher Eh. Thallium (up to 3 mg kg(-1)) in the peat strongly correlates with Zn, whereas Cu (up to 55 mg kg(-1)) co-precipitated with Pb. The metal sulfides occur within microbial exudates, which protect them from oxidation and mechanical displacement. Vertical distribution of toxic metals in the peat layer reflects differences in pollution loads from atmospheric deposition, which has been much reduced recently. PMID- 26006075 TI - Analysis of phenolic compounds in the dissolved and suspended phases of Lake Balaton water by gas chromatography-tandem mass spectrometry. AB - As a novel approach to characterize the phenolic pollutants of Lake Balaton (Central Europe, western Hungary), 26 endocrine disrupting phenols (chlorophenols, nitrophenols, alkylphenols, triclosan, bisphenol-A) were quantified in dissolved and suspended particulate matter (SPM) phases, alike. Sample collection was performed in the western and eastern basins, at 20 sites in April and October 2014. Solid-phase and ultrasound-assisted extractions to withdraw target phenols from dissolved and suspended phases were employed. Compounds were derivatized with hexamethyldisilazane and trifluoroacetic acid for their quantification as trimethylsilyl derivatives by gas chromatography-tandem mass spectrometry. In Lake Balaton's dissolved phase, 2-chlorophenol (103-164 ng/L), 4-chlorophenol (407-888 ng/L), 2,4-dichlorophenol (20.2-72.0 ng/L), 2,4,6 trichlorophenol (10.4-38.1 ng/L), 2-nitrophenol (31.0-66.5 ng/L), 4-nitrophenol (31.5-94.1 ng/L), and bisphenol-A (20.6-112 ng/L), while in its SPM, 4 chlorophenol (1.57) to evaluate their main effect and the interaction effect of FPR and the week of study on OS using linear mixed models with cow identification being a random factor. Cows with ovulatory oestrous cycles (n=20) presented significantly greater SOD levels than cows that did not ovulate ((n=10; P<0.05). On the other hand, LPO, GSH-Px and GSH concentrations were lower in ovulated cows compared to the an-ovulated cows (P<0.05). The highest level of LPO and AOPP were noted at prooestrus phase while beta-carotene presented the lowest value at that phase of oestrous cycle. It could be postulated that the elevated level of milk SOD and the observed lower level of LPO, GSH-Px and GSH in ovulating cows may be an essential event preceding the ovulatory response. PMID- 26006095 TI - New Evidences of Key Factors Involved in "Silent Stones" Etiopathogenesis and Trace Elements: Microscopic, Spectroscopic, and Biochemical Approach. AB - The knowledge of the key factors involved in etiopathogenesis of the gallstone disease requires chemical, structural, and elemental composition analysis. The application of different complementary analytical techniques, both microscopic and spectroscopic, are aimed to provide a more comprehensive determination of the gallbladder calculi ultrastructure and trace element identification. High sensitivity techniques such as electron microscopy (SEM), Fourier transform infrared (FTIR), electron paramagnetic resonance (EPR) spectroscopy, and X-ray diffraction (XRD) along with biochemical analysis are used in a new attempt to investigate various factors which play a regulatory role in the pathogenesis of gallstones. The microstructure of different types of gallbladder stones has specific characteristics which are related to the elemental composition. The binding of metal ions with bile salts and bilirubin plays important roles in gallstone formation as revealed by FTIR spectrum of calcium bilirubinate complex in pigment gallstones. The EPR results demonstrated the generation of bilirubin free radicals and variation of its electronic structure and conjugation system in the skeleton of bilirubin molecule during complex formation. EPR spectra of pigment gallstones demonstrate the coexistence of four paramagnetic centers including stable bilirubin free radical, Mn2+, Cu2+, and Fe3+ with distinct magnetic parameters and well-resolved hyperfine structure in the case of Mn2+ ions. The result confirms a macromolecular network structure with proteins and the formation of bilirubin-coordinated polymer. Bilirubin and bilirubinate free radical complexes may play an important role in pigment gallstone formation. PMID- 26006096 TI - Surface Ultrastructural Changes in the Gill and Liver Tissue of Asian Sea Bass Lates calcarifer (Bloch) Exposed to Copper. AB - Surface ultrastructure of the gill and liver of 3-month-old Asian sea bass, Lates calcarifer, after copper exposure, was investigated by scanning electron microscopy (SEM). Fish samples were exposed to copper concentrations of 6.83 and 13.66 ppm (sublethal) for 28 days with parallel untreated control. These structures showed structural modifications in both low and high concentrations of copper exposure. Oedema, hyperplasia, desquamation, necrosis, epithelial lifting, lamellar fusion, collapsed secondary lamellae, curling of secondary lamellae and aneurism in the secondary lamellae were observed in gill tissues exposed to copper. Hepatic lesions related to cloudy swelling of hepatocytes, congestion, vacuolar degeneration, dilation of sinusoids and nuclear hypertrophy were evident in the exposed sea bass liver tissue. PMID- 26006097 TI - Lyse or not to lyse: Clinical significance of red blood cell autoantibodies. AB - Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease characterized by a hemolytic anemia caused by autoantibodies against red blood cells (RBCs). These autoantibodies are routinely detected via the direct antiglobulin test (DAT). As expected, the DAT score correlates with the presence of clinical symptoms, but this correlation is far from perfect. Regularly, strongly positive DAT scores are encountered with no sign of hemolysis, while severe hemolysis can be seen even in patients with a negative DAT score. Apparently, the mere amount of antibody is not the sole predictor of disease. In this paper, we review the current literature on aspects of both the autoantibodies and the patients' clearance system that together determine the clinical significance of an anti-RBC autoantibody, ranging from antibody isotype to antibody Fc-glycosylation to alternative clearance mechanisms. From this, the ensemble of tests is inferred that in our view best assesses the main determinants for pathogenicity of autoantibodies. PMID- 26006098 TI - Evaluation of IDH1 status in diffusely infiltrating gliomas by immunohistochemistry using anti-mutant and wild type IDH1 antibodies. AB - Glioma cells with the isocitrate dehydrogenase (IDH) 1 G395A mutation are strongly immunopositive for mIDH1(R132H), an antibody against mutant IDH1(R132H) (clone H09). However, we encountered some gliomas which were ambiguously positive for mIDH1(R132H) despite having the IDH1 G395A mutation. The aim of this study was to establish an evaluation procedure of IDH1 status by immunohistochemistry. Forty-three diffusely infiltrating gliomas were studied, and four of eight anaplastic oligoastrocytomas with the IDH1 G395A mutation were modestly or weakly positive for both the mIDH1(R132H) and an antibody against wild type IDH1, RcMab 1. Based on our staining results, the IDH1 expression of both wild and mutated types seemed to be codominant and also to be evenly suppressed under a certain condition. We propose a procedure for determining IDH1 status. If a glioma is weakly positive for mIDH1(R132H), immunohistochemistry for RcMab-1 should be performed. If the tumor cells are strongly positive for RcMab-1, the IDH1 G395A mutation is judged to be absent on the grounds that IDH1 expression is not suppressed. If the tumor cells are weakly positive for both mIDH1(R132H) and RcMab-1, then a conclusion should be made after DNA sequencing. This procedure is useful for practical evaluation of IDH1 status. PMID- 26006099 TI - Determination of Glucose and Cholesterol Using a Novel Optimized Luminol- CuO Nanoparticles-H2O 2 Chemiluminescence Method by Box-Behnken Design. AB - In this study, a simple, rapid and sensitive luminol-CuO nanoparticles-H2O2 chemiluminescence (CL) method has been proposed for determination of glucose and cholesterol in plasma. Response surface methodology (RSM) based on Box-Behnken design (BBD) was used to optimize the most important operating variables (solution pH effect and the CL reagents concentration) of luminol CL system. In optimum conditions, it was found that CuO nanoparticles (NPs) could enhance the CL intensity and the method sensitivity towards evaluation of trace amount of glucose and cholesterol. Under the optimal conditions, there is a good linear relationship between the luminol-CuO NPs - H2O2 relative CL intensity and the concentration over the range of 1.2 * 10(-6)-1.0 * 10(-3) M (R (2) = 0.9991) for glucose and 2.5 * 10(-5)-CuO NPs7.17 * 10(-3) M (R (2) = 0.9968) for cholesterol and with a 3sigma detection limit of 7.1 * 10(-7) and 6.4 * 10(-6) M, respectively. The relative standard deviations (RSD) < 3.3% were obtained. PMID- 26006100 TI - Molecular Interactions of Flavonoids to Hyaluronidase: Insights from Spectroscopic and Molecular Modeling Studies. AB - In the work described on this paper, the interactions between eight flavonoids and hyaluronidase (HAase), an important enzyme involved in a promoting inflammation pathway, were investigated by spectroscopic and molecular modeling methods. The results revealed that all flavonoids could interact with HAase to form flavonoid-HAase complexes. The binding parameters obtained from the data at different temperatures indicated that flavonoids could spontaneously bind with HAase mainly through electrostatic forces and hydrophobic interactions with one binding site. According to synchronous and three-dimensional fluorescence spectra and the molecular docking results, all flavonoids bound directly into the enzyme cavity site and the binding of flavonoid into the enzyme cavity influenced the microenvironment of the HAase activity site which led to the reduced enzyme activity. The present study provides direct evidence at a molecular level to understand the mechanism of inhibitory effect of flavonoid against HAase and explain the anti-inflammatory mechanism of the Traditional Chinese Medicines as anti-inflammatory drugs. PMID- 26006102 TI - Vertical ultrathin MoS2 nanosheets on a flexible substrate as an efficient counter electrode for dye-sensitized solar cells. AB - Vertical MoS2 nanosheets with both large specific surface areas and sharp, active edges are strongly desirable due to their potential applications as catalysts, sensors and field emitters. Nevertheless, the growth of vertical MoS2 nanosheets is still a challenge and has rarely been reported. In this contribution, vertical ultrathin MoS2 nanosheets were grown on diverse substrates via a facile chemical vapor deposition method using CS2 as the sulfur precursor. To the best of our knowledge, it is the first time that CS2 has been applied as the sulfur source for the CVD growth of MoS2. In comparison with sulfur powder, the conventional sulfur source, CS2, can be imported in the growth chamber by a carrying gas, which provides considerable convenience for controlling growth parameters. Vertical MoS2 nanosheets presented a comparable catalytic activity to Pt on triiodide reduction and were used as efficient counter electrodes in dye sensitized solar cells. PMID- 26006101 TI - Cost-utility of first-line actinic keratosis treatments in Finland. AB - INTRODUCTION: Cost-utility assessment of first-line actinic keratosis (AK) treatments for max 25 cm2 AK field. METHODS: A probabilistic, 2-year decision tree model was used to assess costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratio (ICER), cost-effectiveness efficiency frontier, cost-effectiveness acceptability frontier (CEAF), and expected value of perfect information (EVPI) of AK treatments from the Finnish health care payer perspective with 3% discounting per annum. In the model, the first-line AK treatment resulted in complete clearance (CC) or non-CC with or without local skin responses (LSR), or AK recurrence. Non-CC AK was treated with methyl aminolevulinate+photodynamic therapy (MAL+PDT), and AK recurrence was retreated with the previous effective treatment. Costs included primary and secondary health care, outpatient drugs, and LSR management. QALYs were assessed with the EuroQol (EQ-5D-3L). Result robustness was assessed with sensitivity analyses. RESULTS: The mean simulated per patient QALYs (costs) were 1.526 (?982) for MAL+PDT, 1.524 (?794) for ingenol mebutate gel (IngMeb) 0.015% (3 days), 1.522 (?869) for IngMeb 0.05% (2 days), 1.520 (?1062) for diclofenac 3% (12 weeks), 1.518 (?885) for imiquimod 3.75% (6 weeks), 1.517 (?781) for imiquimod 5% (4/8 weeks), and 1.514 (?1114) for cryosurgery when treating AK affecting any body part. IngMeb 0.015% was less costly and more effective (dominating) than other AK treatments indicated for face and scalp area with the exception of imiquimod 5% for which the ICER was estimated at ?1933/QALY gained and MAL+PDT, which had an ICER of ?82,607/QALY gained against IngMeb 0.015%. With willingness-to-pay ?2526 18,809/QALY gained, IngMeb 0.015% had >50% probability for cost-effectiveness on the CEAF. IngMeb 0.05% dominated AK treatments indicated for trunk and extremities. EVPIs for face and scalp (trunk and extremities) analyses were ?26 (?0), ?86 (?58), and ?250 (?169) per patient with the willingness-to-pay of ?0, ?15,000, and ?30,000 per QALY gained, respectively. CONCLUSION: IngMebs were cost effective AK treatments in Finland. FUNDING: LEO Pharma. PMID- 26006103 TI - Nitrosative stress induces a novel intra-S checkpoint pathway in Schizosaccharomyces pombe involving phosphorylation of Cdc2 by Wee1. AB - Excess production of nitric oxide and reactive nitrogen intermediates causes nitrosative stress on cells. Schizosaccharomyces pombe was used as a model to study the cell cycle regulation under nitrosative stress response. We discovered a novel intra-S-phase checkpoint that is activated in S. pombe under nitrosative stress. The mechanism for this intra-S-phase checkpoint activation is distinctly different than previously reported for genotoxic stress in S. pombe by methyl methane sulfonate. Our flow cytometry data established the fact that Wee1 phosphorylates Cdc2 Tyr15 which leads to replication slowdown in the fission yeast under nitrosative stress. We checked the roles of Rad3, Rad17, Rad26, Swi1, Swi3, Cds1, and Chk1 under nitrosative stress but those were not involved in the activation of the DNA replication checkpoint. Rad24 was found to be involved in intra-S-phase checkpoint activation in S. pombe under nitrosative stress but that was independent of Cdc25. PMID- 26006104 TI - Oxidation of calprotectin by hypochlorous acid prevents chelation of essential metal ions and allows bacterial growth: Relevance to infections in cystic fibrosis. AB - Calprotectin provides nutritional immunity by sequestering manganese and zinc ions. It is abundant in the lungs of patients with cystic fibrosis but fails to prevent their recurrent infections. Calprotectin is a major protein of neutrophils and composed of two monomers, S100A8 and S100A9. We show that the ability of calprotectin to limit growth of Staphylococcus aureus and Pseudomonas aeruginosa is exquisitely sensitive to oxidation by hypochlorous acid. The N terminal cysteine residue on S100A9 was highly susceptible to oxidation which resulted in cross-linking of the protein monomers. The N-terminal methionine of S100A8 was also readily oxidized by hypochlorous acid, forming both the methionine sulfoxide and the unique product dehydromethionine. Isolated human neutrophils formed these modifications on calprotectin when their myeloperoxidase generated hypochlorous acid. Up to 90% of the N-terminal amine on S100A8 in bronchoalveolar lavage fluid from young children with cystic fibrosis was oxidized. Oxidized calprotectin was higher in children with cystic fibrosis compared to disease controls, and further elevated in those patients with infections. Our data suggest that oxidative stress associated with inflammation in cystic fibrosis will stop metal sequestration by calprotectin. Consequently, strategies aimed at blocking extracellular myeloperoxidase activity should enable calprotectin to provide nutritional immunity within the airways. PMID- 26006106 TI - Role of extracellular Hydrogen peroxide in regulation of iron homeostasis genes in neuronal cells: Implication in iron accumulation. AB - Iron accumulation and oxidative stress are associated with neurodegenerative disease. Labile iron is known to catalyze free radical generation and subsequent neuronal damage, whereas the role of oxidative stress in neuronal iron accumulation is less well understood. Here, we examined the effect of hydrogen peroxide (H2O2) treatment on cellular iron-uptake, -storage, and -release proteins in the neuroblastoma cell line SH-SY5Y. We found no detectable change in the iron-uptake proteins transferrin receptor-1 and divalent metal ion transporter. In contrast, H2O2 treatment resulted in significant degradation of the iron-exporter ferroportin (Fpn). A decrease in Fpn is expected to increase the labile iron pool (LIP), reducing the iron-regulatory protein (IRP)-iron responsive element interaction and increasing the expression of ferritin-H (Ft-H) for iron storage. Instead, we detected IRP1 activation, presumably due to oxidative stress, and a decrease in Ft-H translation. A reduction in Ft-H mRNA was also observed, probably dependent on an antioxidant-response element present in the Ft-H enhancer. The decrease in Fpn and Ft-H upon H2O2 treatment led to a time-dependent increase in the cellular LIP. Our study reveals a complex regulation of neuronal iron-release and iron-storage components in response to H2O2 that may explain iron accumulation detected in neurodegenerative diseases associated with oxidative stress. PMID- 26006105 TI - Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder. AB - CDKL5 mutation is associated with an atypical Rett syndrome (RTT) variant. Recently, cholesterol homeostasis perturbation and oxidative-mediated loss of the high-density lipoprotein receptor SRB1 in typical RTT have been suggested. Here, we demonstrate an altered lipid serum profile also in CDKL5 patients with decreased levels of SRB1 and impaired activation of the defensive system Nrf2. In addition, CDKL5 fibroblasts showed an increase in 4-hydroxy-2-nonenal- and nitrotyrosine-SRB1 adducts that lead to its ubiquitination and probable degradation. This study highlights a possible common denominator between two different RTT variants (MECP2 and CDKL5) and a possible common future therapeutic target. PMID- 26006107 TI - Feasibility of using 'lung density' values estimated from EIT images for clinical diagnosis of lung abnormalities in mechanically ventilated ICU patients. AB - This paper reports on the results of a study which compares lung density values obtained from electrical impedance tomography (EIT), clinical diagnosis and CT values (HU) within a region of interest in the lung. The purpose was to assess the clinical use of lung density estimation using EIT data. In 11 patients supported by a mechanical ventilator, the consistency of regional lung density measurements as estimated by EIT was validated to assess the feasibility of its use in intensive care medicine. There were significant differences in regional lung densities recorded in the supine position between normal lungs and diseased lungs associated with pneumonia, atelectasis and pleural effusion (normal; 240 +/ 71.7 kg m(-3), pneumonia; 306 +/- 38.6 kg m(-3), atelectasis; 497 +/- 130 kg m( 3), pleural effusion; 467 +/- 113 kg m(-3): Steel-Dwass test, p < 0.05). In addition, in order to compare lung density with CT image pixels, the image resolution of CT images, which was originally 512 * 512 pixels, was changed to 16 * 16 pixels to match that of the EIT images. The results of CT and EIT images from five patients in an intensive care unit showed a correlation coefficient of 0.66 +/- 0.13 between the CT values (HU) and the lung density values (kg m(-3)) obtained from EIT. These results indicate that it may be possible to obtain a quantitative value for regional lung density using EIT. PMID- 26006108 TI - Endurance training upregulates the nitric oxide/soluble guanylyl cyclase/cyclic guanosine 3',5'-monophosphate pathway in the striatum, midbrain and cerebellum of male rats. AB - The nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate (NO/sGC/cGMP) brain pathway plays an important role in motor control. We studied the effects of 6-week endurance training (running) of moderate intensity on this pathway by comparing, between sedentary and endurance-trained young adult male Wistar rats, the expression of endothelial (eNOS) and neuronal (nNOS) NO synthases and of alpha1, alpha2 and beta1 GC subunits, as well as cGMP levels, in the brain cortex, hippocampus, striatum, midbrain and cerebellum. Additionally, we compared the respective regional expressions of BDNF and the BDNF receptor TrkB. Twenty-four hours after the last training session, the endurance-trained rats showed 3-fold higher spontaneous locomotor activity than their sedentary counterparts in an open-field test. Forty-eight hours after the completion of the training, the trained rats showed significantly elevated BDNF and TrKB mRNAs in the hippocampus, midbrain and striatum, and significantly increased BDNF levels in the hippocampus and striatum. Simultaneously, significant increases were found in mRNA and protein levels and activities of nNOS and eNOS as well as in mRNA and protein levels of GCalpha2 and GCbeta1, but not GCalpha1, in the striatum, midbrain and cerebellum; no change in these variables was found in the cortex and hippocampus except for marked elevations in cortical GCbeta1 mRNA and protein. Changes in regional cGMP levels paralleled those in eNOS, nNOS and GCalpha2 expression and NOSs' activities. These results suggest that favorable extrapyramidal motor effects of physical training are related to the enhanced activity of the NO/sGC/cGMP pathway in certain motor control-related subcortical brain regions. PMID- 26006109 TI - Intrauterine growth restriction increases the preference for palatable foods and affects sensitivity to food rewards in male and female adult rats. AB - Clinical evidence suggests that intrauterine growth restriction (IUGR) can cause persistent changes in the preference for palatable foods. In this study, we compared food preferences, the response to food rewards, and the role of the mesolimbic dopaminergic system in feeding behavior, between IUGR and control rats. Time-mated pregnant Sprague-Dawley rats were randomly allocated to a control group (standard chow ad libitum) or a 50% food restriction (FR) group, which received 50% of the control dams' habitual intake. These diets were provided from gestation day 10 to the 21st day of lactation. Within 24h of birth, pups were cross-fostered and divided into four groups: Adlib/Adlib, FR/Adlib, FR/FR, Adlib/FR. Standard chow consumption was compared between all groups. Food preferences, conditioned place preference to a palatable diet, and the levels of tyrosine hydroxylase (TH) phosphorylation and D2 receptors in the nucleus accumbens were analyzed and compared between the two groups of interest: Adlib/Adlib (control) and FR/Adlib (exposed to growth restriction during the fetal period only). IUGR adult rats had a stronger preference for palatable foods, but showed less conditioned place preference to a palatable diet than controls. D2 receptors levels were lower in IUGR rats. At baseline, TH and pTH levels were higher in FR/Adlib than control males. Measurements taken after exposure to sweet foods revealed higher levels of TH and pTH in FR/Adlib than control females. These data showed that IUGR rats exhibited a preference for palatable foods, potentially due to alterations in their mesolimbic reward pathway. Additionally, the changes observed in the mesolimbic dopaminergic system of IUGR rats proved to be sex-specific. This article is part of a Special Issue entitled 1618. PMID- 26006110 TI - Construction and Deciphering of Human Phosphorylation-Mediated Signaling Transduction Networks. AB - Protein phosphorylation is the most abundant reversible covalent modification. Human protein kinases participate in almost all biological pathways, and approximately half of the kinases are associated with disease. PhoSigNet was designed to store and display human phosphorylation-mediated signal transduction networks, with additional information related to cancer. It contains 11 976 experimentally validated directed edges and 216 871 phosphorylation sites. Moreover, 3491 differentially expressed proteins in human cancer from dbDEPC, 18 907 human cancer variation sites from CanProVar, and 388 hyperphosphorylation sites from PhosphoSitePlus were collected as annotation information. Compared with other phosphorylation-related databases, PhoSigNet not only takes the kinase substrate regulatory relationship pairs into account, but also extends regulatory relationships up- and downstream (e.g., from ligand to receptor, from G protein to kinase, and from transcription factor to targets). Furthermore, PhoSigNet allows the user to investigate the impact of phosphorylation modifications on cancer. By using one set of in-house time series phosphoproteomics data, the reconstruction of a conditional and dynamic phosphorylation-mediated signaling network was exemplified. We expect PhoSigNet to be a useful database and analysis platform benefiting both proteomics and cancer studies. PMID- 26006111 TI - The grid-based fast multipole method--a massively parallel numerical scheme for calculating two-electron interaction energies. AB - Algorithms and working expressions for a grid-based fast multipole method (GB FMM) have been developed and implemented. The computational domain is divided into cubic subdomains, organized in a hierarchical tree. The contribution to the electrostatic interaction energies from pairs of neighboring subdomains is computed using numerical integration, whereas the contributions from further apart subdomains are obtained using multipole expansions. The multipole moments of the subdomains are obtained by numerical integration. Linear scaling is achieved by translating and summing the multipoles according to the tree structure, such that each subdomain interacts with a number of subdomains that are almost independent of the size of the system. To compute electrostatic interaction energies of neighboring subdomains, we employ an algorithm which performs efficiently on general purpose graphics processing units (GPGPU). Calculations using one CPU for the FMM part and 20 GPGPUs consisting of tens of thousands of execution threads for the numerical integration algorithm show the scalability and parallel performance of the scheme. For calculations on systems consisting of Gaussian functions (alpha = 1) distributed as fullerenes from C20 to C720, the total computation time and relative accuracy (ppb) are independent of the system size. PMID- 26006112 TI - Enantioselective N-heterocyclic carbene-catalyzed synthesis of indenopyrones. AB - The chiral N-heterocyclic carbene-catalyzed [4 + 2] cyclization of alpha chloroaldehydes and arylidene indanediones was developed, giving the corresponding indenopyrones in good yields with high diastereoselectivities and enantioselectivities. PMID- 26006113 TI - Influence of heart motion on cardiac output estimation by means of electrical impedance tomography: a case study. AB - Electrical impedance tomography (EIT) is a non-invasive imaging technique that can measure cardiac-related intra-thoracic impedance changes. EIT-based cardiac output estimation relies on the assumption that the amplitude of the impedance change in the ventricular region is representative of stroke volume (SV). However, other factors such as heart motion can significantly affect this ventricular impedance change. In the present case study, a magnetic resonance imaging-based dynamic bio-impedance model fitting the morphology of a single male subject was built. Simulations were performed to evaluate the contribution of heart motion and its influence on EIT-based SV estimation. Myocardial deformation was found to be the main contributor to the ventricular impedance change (56%). However, motion-induced impedance changes showed a strong correlation (r = 0.978) with left ventricular volume. We explained this by the quasi-incompressibility of blood and myocardium. As a result, EIT achieved excellent accuracy in estimating a wide range of simulated SV values (error distribution of 0.57 +/- 2.19 ml (1.02 +/- 2.62%) and correlation of r = 0.996 after a two-point calibration was applied to convert impedance values to millilitres). As the model was based on one single subject, the strong correlation found between motion-induced changes and ventricular volume remains to be verified in larger datasets. PMID- 26006114 TI - Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease. AB - OBJECTIVE: Increased fasting blood ethanol levels, suggested to stem from an increased endogenous ethanol synthesis in the GI tract, are discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to further delineate the mechanisms involved in the elevated blood ethanol levels found in patients with NAFLD. DESIGN: In 20 nutritionally and metabolically screened children displaying early signs of NAFLD and 29 controls (aged 5-8 years), ethanol plasma levels were assessed. Ethanol levels along the GI tract, in vena cava and portal vein, intestinal and faecal microbiota, and activity of alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) were measured in wild-type, ob/ob and anti-TNFalpha antibody (aT) treated ob/ob mice. RESULTS: Despite not differing in dietary pattern or prevalence of intestinal overgrowth, fasting ethanol levels being positively associated with measures of insulin resistance were significantly higher in children with NAFLD than in controls. Ethanol levels were similar in portal vein and chyme obtained from different parts of the GI tract between groups while ethanol levels in vena cava plasma were significantly higher in ob/ob mice. ADH activity was significantly lower in liver tissue obtained from ob/ob mice in comparison to wild-type controls and ob/ob mice treated with aT. CONCLUSIONS: Taken together, our data of animal experiments suggest that increased blood ethanol levels in patients with NAFLD may result from insulin-dependent impairments of ADH activity in liver tissue rather than from an increased endogenous ethanol synthesis. TRIAL REGISTRATION NUMBER: NCT01306396. PMID- 26006115 TI - Prediction of oesophageal variceal bleeding by measuring spleen stiffness in patients with liver cirrhosis. PMID- 26006116 TI - The role of noninvasive positive pressure ventilation in community-acquired pneumonia. PMID- 26006117 TI - Chinese Pediatrician Attitudes and Practices Regarding Child Exposure to Secondhand Smoke (SHS) and Clinical Efforts against SHS Exposure. AB - BACKGROUND: Secondhand Smoke (SHS) exposure is a leading cause of childhood illness and premature death. Pediatricians play an important role in helping parents to quit smoking and reducing children's SHS exposure. This study examined Chinese pediatricians' attitudes and practices regarding children's exposure to SHS and clinical efforts against SHS exposure. METHODS: A cross-sectional survey of pediatricians was conducted in thirteen conveniently selected hospitals in southern China, during September to December 2013. Five hundred and four pediatricians completed self-administered questionnaires with a response rate of 92%. chi2 tests were used to compare categorical variables differences between smokers and non-smokers and other categorical variables. RESULTS: Pediatricians thought that the key barriers to encouraging parents to quit smoking were: lack of professional training (94%), lack of time (84%), resistance to discussions about smoking (77%). 94% of the pediatricians agreed that smoking in enclosed public places should be prohibited and more than 70% agreed that smoking should not be allowed in any indoor places and in cars. Most of the pediatricians thought that their current knowledge on helping people to quit smoking and SHS exposure reduction counseling was insufficient. CONCLUSIONS: Many Chinese pediatricians did not have adequate knowledge about smoking and SHS, and many lacked confidence about giving cessation or SHS exposure reduction counseling to smoking parents. Lack of professional training and time were the most important barriers to help parents quit smoking among the Chinese pediatricians. Intensified efforts are called for to provide the necessary professional training and increase pediatricians' participation in the training. PMID- 26006119 TI - Comparative Cytotoxicity Study of Silver Nanoparticles (AgNPs) in a Variety of Rainbow Trout Cell Lines (RTL-W1, RTH-149, RTG-2) and Primary Hepatocytes. AB - Among all classes of nanomaterials, silver nanoparticles (AgNPs) have potentially an important ecotoxicological impact, especially in freshwater environments. Fish are particularly susceptible to the toxic effects of silver ions and, with knowledge gaps regarding the contribution of dissolution and unique particle effects to AgNP toxicity, they represent a group of vulnerable organisms. Using cell lines (RTL-W1, RTH-149, RTG-2) and primary hepatocytes of rainbow trout (Oncorhynchus mykiss) as in vitro test systems, we assessed the cytotoxicity of the representative AgNP, NM-300K, and AgNO3 as an Ag+ ion source. Lack of AgNP interference with the cytotoxicity assays (AlamarBlue, CFDA-AM, NRU assay) and their simultaneous application point to the compatibility and usefulness of such a battery of assays. The RTH-149 and RTL-W1 liver cell lines exhibited similar sensitivity as primary hepatocytes towards AgNP toxicity. Leibovitz's L-15 culture medium composition (high amino acid content) had an important influence on the behaviour and toxicity of AgNPs towards the RTL-W1 cell line. The obtained results demonstrate that, with careful consideration, such an in vitro approach can provide valuable toxicological data to be used in an integrated testing strategy for NM-300K risk assessment. PMID- 26006118 TI - Highly Pathogenic Avian Influenza H5N1 in Mainland China. AB - Highly pathogenic avian influenza (HPAI) H5N1 has posed a significant threat to both humans and birds, and it has spanned large geographic areas and various ecological systems throughout Asia, Europe and Africa, but especially in mainland China. Great efforts in control and prevention of the disease, including universal vaccination campaigns in poultry and active serological and virological surveillance, have been undertaken in mainland China since the beginning of 2006. In this study, we aim to characterize the spatial and temporal patterns of HPAI H5N1, and identify influencing factors favoring the occurrence of HPAI H5N1 outbreaks in poultry in mainland China. Our study shows that HPAI H5N1 outbreaks took place sporadically after vaccination campaigns in poultry, and mostly occurred in the cold season. The positive tests in routine virological surveillance of HPAI H5N1 virus in chicken, duck, goose as well as environmental samples were mapped to display the potential risk distribution of the virus. Southern China had a higher positive rate than northern China, and positive samples were mostly detected from chickens in the north, while the majority were from duck in the south, and a negative correlation with monthly vaccination rates in domestic poultry was found (R = -0.19, p value = 0.005). Multivariate panel logistic regression identified vaccination rate, interaction between distance to the nearest city and national highway, interaction between distance to the nearest lake and wetland, and density of human population, as well as the autoregressive term in space and time as independent risk factors in the occurrence of HPAI H5N1 outbreaks, based on which a predicted risk map of the disease was derived. Our findings could provide new understanding of the distribution and transmission of HPAI H5N1 in mainland China and could be used to inform targeted surveillance and control efforts in both human and poultry populations to reduce the risk of future infections. PMID- 26006120 TI - Estimating the dietary intake of breastfeeding preterm infants. AB - AIM: To determine how accurately the daily prescribed feed volume (mL/day) estimates the actual intake of breastfeeding preterm infants and to characterise the volume taken during a breastfeed at differing gestational and postmenstrual ages. METHODS: A cross sectional study was conducted on preterm infants born <37 weeks gestation from two Australian neonatal units. To determine the volume taken in a 24-h period infants were weighed before and after each breastfeed. This volume was added to the charted intake to determine the total intake and then compared to the prescribed feed volume. Bland Altman analyses were used to assess the level of agreement between the two methods. RESULTS: Fifty six infants were studied on 206 breastfeeding occasions. There was a small bias (27 mLs/day) but large 95% limits of agreement (-76 to 130 mL/day). The volume taken during a single breastfeed ranged from 0 to 101 mL (median 23 mL, IQR 9 to 31 mL) and was greater in more mature infants. CONCLUSIONS: Using the prescribed feed volume to estimate total intake has limited clinical utility for the individual infant, however the relatively small bias means that it may be useful within a population or for comparison between groups in which population means are compared. There was a large variation in volume taken during a breastfeed across all gestational and postmenstrual ages. PMID- 26006121 TI - Spatial-Temporal Variations of Chlorophyll-a in the Adjacent Sea Area of the Yangtze River Estuary Influenced by Yangtze River Discharge. AB - Carrying abundant nutrition, terrigenous freshwater has a great impact on the spatial and temporal heterogeneity of phytoplankton in coastal waters. The present study analyzed the spatial-temporal variations of Chlorophyll-a (Chl-a) concentration under the influence of discharge from the Yangtze River, based on remotely sensed Chl-a concentrations. The study area was initially zoned to quantitatively investigate the spatial variation patterns of Chl-a. Then, the temporal variation of Chl-a in each zone was simulated by a sinusoidal curve model. The results showed that in the inshore waters, the terrigenous discharge was the predominant driving force determining the pattern of Chl-a, which brings the risk of red tide disasters; while in the open sea areas, Chl-a was mainly affected by meteorological factors. Furthermore, a diversity of spatial and temporal variations of Chl-a existed based on the degree of influences from discharge. The diluted water extended from inshore to the east of Jeju Island. This process affected the Chl-a concentration flowing through the area, and had a potential impact on the marine environment. The Chl-a from September to November showed an obvious response to the discharge from July to September with a lag of 1 to 2 months. PMID- 26006122 TI - Gateway Effects: Why the Cited Evidence Does Not Support Their Existence for Low Risk Tobacco Products (and What Evidence Would). AB - It is often claimed that low-risk drugs still create harm because of "gateway effects", in which they cause the use of a high-risk alternative. Such claims are popular among opponents of tobacco harm reduction, claiming that low-risk tobacco products (e.g., e-cigarettes, smokeless tobacco) cause people to start smoking, sometimes backed by empirical studies that ostensibly support the claim. However, these studies consistently ignore the obvious alternative causal pathways, particularly that observed associations might represent causation in the opposite direction (smoking causes people to seek low-risk alternatives) or confounding (the same individual characteristics increase the chance of using any tobacco product). Due to these complications, any useful analysis must deal with simultaneity and confounding by common cause. In practice, existing analyses seem almost as if they were designed to provide teaching examples about drawing simplistic and unsupported causal conclusions from observed associations. The present analysis examines what evidence and research strategies would be needed to empirically detect such a gateway effect, if there were one, explaining key methodological concepts including causation and confounding, examining the logic of the claim, identifying potentially useful data, and debunking common fallacies on both sides of the argument, as well as presenting an extended example of proper empirical testing. The analysis demonstrates that none of the empirical studies to date that are purported to show a gateway effect from tobacco harm reduction products actually does so. The observations and approaches can be generalized to other cases where observed association of individual characteristics in cross-sectional data could result from any of several causal relationships. PMID- 26006123 TI - Introducing Simple Detection of Bioavailable Arsenic at Rafaela (Santa Fe Province, Argentina) Using the ARSOlux Biosensor. AB - Numerous articles have reported the occurrence of arsenic in drinking water in Argentina, and the resulting health effects in severely affected regions of the country. Arsenic in drinking water in Argentina is largely naturally occurring due to elevated background content of the metalloid in volcanic sediments, although, in some regions, mining can contribute. While the origin of arsenic release has been discussed extensively, the problem of drinking water contamination has not yet been solved. One key step in progress towards mitigation of problems related with the consumption of As-containing water is the availability of simple detection tools. A chemical test kit and the ARSOlux biosensor were evaluated as simple analytical tools for field measurements of arsenic in the groundwater of Rafaela (Santa Fe, Argentina), and the results were compared with ICP-MS and HPLC-ICP-MS measurements. A survey of the groundwater chemistry was performed to evaluate possible interferences with the field tests. The results showed that the ARSOlux biosensor performed better than the chemical field test, that the predominant species of arsenic in the study area was arsenate and that arsenic concentration in the studied samples had a positive correlation with fluoride and vanadium, and a negative one with calcium and iron. PMID- 26006124 TI - Molecular tools for the selective detection of nine diatom species biomarkers of various water quality levels. AB - Our understanding of the composition of diatom communities and their response to environmental changes is currently limited by laborious taxonomic identification procedures. Advances in molecular technologies are expected to contribute more efficient, robust and sensitive tools for the detection of these ecologically relevant microorganisms. There is a need to explore and test phylogenetic markers as an alternative to the use of rRNA genes, whose limited sequence divergence does not allow the accurate discrimination of diatoms at the species level. In this work, nine diatom species belonging to eight genera, isolated from epylithic environmental samples collected in central Italy, were chosen to implement a panel of diatoms covering the full range of ecological status of freshwaters. The procedure described in this work relies on the PCR amplification of specific regions in two conserved diatom genes, elongation factor 1-a (eEF1-a) and silicic acid transporter (SIT), as a first step to narrow down the complexity of the targets, followed by microarray hybridization experiments. Oligonucleotide probes with the potential to discriminate closely related species were designed taking into account the genetic polymorphisms found in target genes. These probes were tested, refined and validated on a small-scale prototype DNA chip. Overall, we obtained 17 highly specific probes targeting eEF1-a and SIT, along with 19 probes having lower discriminatory power recognizing at the same time two or three species. This basic array was validated in a laboratory setting and is ready for tests with crude environmental samples eventually to be scaled-up to include a larger panel of diatoms. Its possible use for the simultaneous detection of diatoms selected from the classes of water quality identified by the European Water Framework Directive is discussed. PMID- 26006125 TI - Detection of emerging and re-emerging pathogens in surface waters close to an urban area. AB - Current knowledge about the spread of pathogens in aquatic environments is scarce probably because bacteria, viruses, algae and their toxins tend to occur at low concentrations in water, making them very difficult to measure directly. The purpose of this study was the development and validation of tools to detect pathogens in freshwater systems close to an urban area. In order to evaluate anthropogenic impacts on water microbiological quality, a phylogenetic microarray was developed in the context of the EU project uAQUA to detect simultaneously numerous pathogens and applied to samples from two different locations close to an urban area located upstream and downstream of Rome in the Tiber River. Furthermore, human enteric viruses were also detected. Fifty liters of water were collected and concentrated using a hollow-fiber ultrafiltration approach. The resultant concentrate was further size-fractionated through a series of decreasing pore size filters. RNA was extracted from pooled filters and hybridized to the newly designed microarray to detect pathogenic bacteria, protozoa and toxic cyanobacteria. Diatoms as indicators of the water quality status, were also included in the microarray to evaluate water quality. The microarray results gave positive signals for bacteria, diatoms, cyanobacteria and protozoa. Cross validation of the microarray was performed using standard microbiological methods for the bacteria. The presence of oral-fecal transmitted human enteric-viruses were detected using q-PCR. Significant concentrations of Salmonella, Clostridium, Campylobacter and Staphylococcus as well as Hepatitis E Virus (HEV), noroviruses GI (NoGGI) and GII (NoGII) and human adenovirus 41 (ADV 41) were found in the Mezzocammino site, whereas lower concentrations of other bacteria and only the ADV41 virus was recovered at the Castel Giubileo site. This study revealed that the pollution level in the Tiber River was considerably higher downstream rather than upstream of Rome and the downstream location was contaminated by emerging and re-emerging pathogens. PMID- 26006126 TI - The physical activity levels and sedentary behaviors of Latino children in London (Ontario, Canada). AB - OBJECTIVE: To assess the physical activity and sedentary behaviors of a sample of Latino children in London, Ontario, Canada. METHODS: Seventy-four Latino children (54.1% male; mean age = 11.4) completed self-report questionnaires related to physical activity and sedentary behaviors. A subset of children (n = 64) wore Actical (Mini Mitter, Respironics) accelerometers for a maximum of four days. RESULTS: Latino children self-reported moderate levels of physical activity (i.e., mean score of 2.8 on 5-point scale). Accelerometer data revealed that children spent an average of 50.0 min in moderate-to-vigorous physical activity (MVPA; 59.2 min on weekdays and 50.6 min on weekend days) and were sedentary for an average of 8.4 h (508.0 min) per day (533.5 min on weekdays and 497.7 min on weekend days). Children reported spending an average of 3.8 h (228 min) daily in front of screens--1.7 h (102 min) watching television, 1.2 h (72 min) on the computer, and 0.9 h (54 min) playing video games. CONCLUSIONS: This feasibility project provided a preliminary account of objectively measured daily physical activity and sedentary time among a sample of Latino children in Canada, as well as insight into the challenge of measuring these behaviors. Sedentary behavior reduction techniques should be explored and implemented in this young population, along with strategies to promote adherence to accelerometer protocols. PMID- 26006127 TI - The Impact of Hurricane Katrina on Students' Behavioral Disorder: A Difference-in Difference Analysis. AB - OBJECTIVE: The objective of this paper is to examine the impact of Hurricane Katrina on displaced students' behavioral disorder. METHODS: First, we determine displaced students' likelihood of discipline infraction each year relative to non evacuees using all K12 student records of the U.S. state of Louisiana during the period of 2000-2008. Second, we investigate the impact of hurricane on evacuee students' in-school behavior in a difference-in-difference framework. The quasi experimental nature of the hurricane makes this framework appropriate with the advantage that the problem of endogeneity is of least concern and the causal effect of interest can be reasonably identified. RESULTS: Preliminary analysis demonstrates a sharp increase in displaced students' relative likelihood of discipline infraction around 2005 when the hurricane occurred. Further, formal difference-in-difference analysis confirms the results. To be specific, post Katrina, displaced students' relative likelihood of any discipline infraction has increased by 7.3% whereas the increase in the relative likelihood for status offense, offense against person, offense against property and serious crime is 4%, 1.5%, 3.8% and 2.1%, respectively. CONCLUSION: When disasters occur, as was the case with Hurricane Katrina, in addition to assistance for adult evacuees, governments, in cooperation with schools, should also provide aid and assistance to displaced children to support their mental health and in-school behavior. PMID- 26006128 TI - Do neighborhood characteristics in Amsterdam influence adiposity at preschool age? AB - BACKGROUND: Neighborhood characteristics may contribute to adiposity in young children, but results in the current literature are inconsistent. This study aimed to investigate whether objective (socioeconomic status (SES)) and subjective (perceived safety, satisfaction with green spaces and perceived physical disorder) neighborhood characteristics directly influence child adiposity (as measured by BMI, percent body fat (%BF) and waist-to-height ratio (WHtR)). METHODS: Data on child BMI, %BF and WHtR were obtained from the Amsterdam Born Children and their Development cohort at 5-6 years of age. Three thousand four hundred and sixty nine (3469) children were included in the analyses. Mixed models, using random intercepts for postal code area to account for neighborhood clustering effects, were used to analyze the relationships of interest. RESULTS: Associations were observed for both perceived safety and neighborhood SES with %BF after adjustment for maternal education and ethnicity. All relationships were eliminated with the inclusion of individual covariates and parental BMI into the models. CONCLUSIONS: In general, child adiposity at age 5-6 years was not independently associated with neighborhood characteristics, although a small relationship between child %BF and both neighborhood SES and perceived safety cannot be ruled out. At this young age, familial and individual factors probably play a more important role in influencing child adiposity than neighborhood characteristics. PMID- 26006129 TI - Modeling flows and concentrations of nine engineered nanomaterials in the Danish environment. AB - Predictions of environmental concentrations of engineered nanomaterials (ENM) are needed for their environmental risk assessment. Because analytical data on ENM concentrations in the environment are not yet available, exposure modeling represents the only source of information on ENM exposure in the environment. This work provides material flow data and environmental concentrations of nine ENM in Denmark. It represents the first study that distinguishes between photostable TiO2 (as used in sunscreens) and photocatalytic TiO2 (as used in self cleaning surfaces). It also provides first exposure estimates for quantum dots, carbon black and CuCO3. Other ENM that are covered are ZnO, Ag, CNT and CeO2. The modeling is based for all ENM on probability distributions of production, use, environmental release and transfer between compartments, always considering the complete life-cycle of products containing the ENM. The magnitude of flows and concentrations of the various ENM depends on the one hand on the production volume but also on the type of products they are used in and the life-cycles of these products and their potential for release. The results reveal that in aquatic systems the highest concentrations are expected for carbon black and photostable TiO2, followed by CuCO3 (under the assumption that the use as wood preservative becomes important). In sludge-treated soil highest concentrations are expected for CeO2 and TiO2. Transformation during water treatments results in extremely low concentrations of ZnO and Ag in the environment. The results of this study provide valuable environmental exposure information for future risk assessments of these ENM. PMID- 26006130 TI - Season of birth, sex and sleep timing preferences. AB - OBJECTIVE: To evaluate whether the season of birth and sex are associated with preferences for bedtime among Chinese adults. METHODS: A national population based study on sleep preferences was conducted among Chinese in 2008. A questionnaire was used to collect information on the sleep time of Chinese adults. Analysis of covariance was used to examine the relationship between season of birth and preferences for bedtime. Two sets of potential confounders were used in the adjusted models. Model 1 adjusted for age. Model 2 additionally adjusted for area, occupation, education level, smoking, and drinking. PARTICIPANTS AND MEASUREMENTS: The questionnaire was administered to a sample of 3959 Chinese adults. RESULTS: Men had a higher delayed mean sleep onset and offset time (22:38 and 6:32) than women (22:18 and 6:25). Men also slept for a shorter duration compared to women (7 h 54 min vs. 8 h 7 min). Women born in fall had the latest sleep onset time sleep offset time (22:23/6:30), compared to their counterparts born in winter. These associations were attenuated by additional adjustments of more confounders. CONCLUSIONS: There were significant differences in sleep timing preferences between men and women. Season of birth was not associated with sleep timing in Chinese adults. PMID- 26006131 TI - Estimation of arsenic intake from drinking water and food (raw and cooked) in a rural village of northern Chile. Urine as a biomarker of recent exposure. AB - The aim of this study was to estimate both the contribution of drinking water and food (raw and cooked) to the total (t-As) and inorganic (i-As) arsenic intake and the exposure of inhabitants of Socaire, a rural village in Chile's Antofagasta Region, by using urine as biomarker. The i-As intake from food and water was estimated using samples collected between November 2008 and September 2009. A 24 hour dietary recall questionnaire was given to 20 participants. Drinking water, food (raw and cooked) and urine samples were collected directly from the homes where the interviewees lived. The percentage of i-As/t-As in the drinking water that contributed to the total intake was variable (26.8-92.9). Cereals and vegetables are the food groups that contain higher concentrations of i-As. All of the participants interviewed exceeded the reference intake FAO/OMS (149.8 ug?i As.day-1) by approximately nine times. The concentration of t-As in urine in each individual ranged from 78 to 459 ng.mL-1. Estimated As intake from drinking water and food was not associated with total urinary As concentration. The results show that both drinking water and food substantially contribute to i-As intake and an increased exposure risk to adult residents in contaminated areas. PMID- 26006132 TI - Development of an RF-EMF Exposure Surrogate for Epidemiologic Research. AB - Exposure assessment is a crucial part in studying potential effects of RF-EMF. Using data from the HERMES study on adolescents, we developed an integrative exposure surrogate combining near-field and far-field RF-EMF exposure in a single brain and whole-body exposure measure. Contributions from far-field sources were modelled by propagation modelling and multivariable regression modelling using personal measurements. Contributions from near-field sources were assessed from both, questionnaires and mobile phone operator records. Mean cumulative brain and whole-body doses were 1559.7 mJ/kg and 339.9 mJ/kg per day, respectively. 98.4% of the brain dose originated from near-field sources, mainly from GSM mobile phone calls (93.1%) and from DECT phone calls (4.8%). Main contributors to the whole-body dose were GSM mobile phone calls (69.0%), use of computer, laptop and tablet connected to WLAN (12.2%) and data traffic on the mobile phone via WLAN (6.5%). The exposure from mobile phone base stations contributed 1.8% to the whole-body dose, while uplink exposure from other people's mobile phones contributed 3.6%. In conclusion, the proposed approach is considered useful to combine near-field and far-field exposure to an integrative exposure surrogate for exposure assessment in epidemiologic studies. However, substantial uncertainties remain about exposure contributions from various near-field and far field sources. PMID- 26006134 TI - Development of a LC-MS-MS Method for Quantification of Valtrate and Its Application to Pharmacokinetic Study. AB - A simple and selective liquid chromatography-tandem mass spectrometric method for determination of valtrate in rat plasma was developed in this study. Chromatographic separation was achieved on a Thermo BDS HYPERSIL C18 column using acetonitrile-water-formic acid (75 : 25 : 0.1, v/v/v) as mobile phase in an isocratic mode of elution at a flow rate of 300 uL/min. MS-MS detection was performed in a positive ion electrospray ionization mode with the ion transitions 445.2 -> 219.2 for valtrate and 355.2 -> 135.1 for internal standard (sesamin). The developed method exhibited a linear dynamic range over 5.65-1695 ng/mL for valtrate in rat plasma. The overall extraction recovery of valtrate from plasma was 86.13-88.32%. The intra- and inter-day accuracy and precision were within the pre-defined limits of <=15% at all concentrations. The method was successfully applied to pharmacokinetic studies of valtrate in rats. PMID- 26006135 TI - New Salting Out Stability-Indicating and Kinetic Thin Layer Chromatographic Method for Determination of Glimepiride and Metformin HCl Binary Mixture. AB - A simple, selective salting out and stability-indicating thin layer chromatographic (SOTLC) technique was developed for determination of two antidiabetic drugs; glimepiride and metformin HCl in pure and in tablets as a binary mixture. Separation was performed on silica gel 60 F254 plates using aqueous ammonium sulfate and acetonitrile (7:3, v/v) as a mobile phase. The Rf values were 0.26 +/- 0.02 and 0.73 +/- 0.02 for glimepiride and metformin HCl, respectively. The separated bands were scanned at lambda 237 nm using CAMAG TLC scanner III. The proposed method focusing on study of all the factors that play important role in the mechanism of salting out process. The proposed method was validated according to ICH guidelines and complied with USP31-NF26 validation guidelines. The correlation coefficients of calibration curves were 0.996 and 0.997 for glimepiride and metformin HCl, respectively, in the concentration range of 60-1,400 ng/band for both drugs. The investigated drugs were also subjected to acidic, basic, oxidative and photo-degradation and kinetic study was carried out. PMID- 26006133 TI - Triclosan: current status, occurrence, environmental risks and bioaccumulation potential. AB - Triclosan (TCS) is a multi-purpose antimicrobial agent used as a common ingredient in everyday household personal care and consumer products. The expanded use of TCS provides a number of pathways for the compound to enter the environment and it has been detected in sewage treatment plant effluents; surface; ground and drinking water. The physico-chemical properties indicate the bioaccumulation and persistence potential of TCS in the environment. Hence, there is an increasing concern about the presence of TCS in the environment and its potential negative effects on human and animal health. Nevertheless, scarce monitoring data could be one reason for not prioritizing TCS as emerging contaminant. Conventional water and wastewater treatment processes are unable to completely remove the TCS and even form toxic intermediates. Considering the worldwide application of personal care products containing TCS and inefficient removal and its toxic effects on aquatic organisms, the compound should be considered on the priority list of emerging contaminants and its utilization in all products should be regulated. PMID- 26006136 TI - Clinical and electrophysiological evaluation of pediatric Wolff-Parkinson-White patients. AB - OBJECTIVE: Wolff-Parkinson-White (WPW) syndrome presents with paroxysmal supraventricular tachycardia and is characterized by electrocardiographic (ECG) findings of a short PR interval and a delta wave. The objective of this study was to evaluate the electrophysiological properties of children with WPW syndrome and to develop an algorithm for the management of these patients with limited access to electrophysiological study. METHODS: A retrospective review of all pediatric patients who underwent electrophysiological evaluation for WPW syndrome was performed. RESULTS: One hundred nine patients underwent electrophysiological evaluation at a single tertiary center between 1997 and 2011. The median age of the patients was 11 years (0.1-18). Of the 109 patients, 82 presented with tachycardia (median age 11 (0.1-18) years), and 14 presented with syncope (median age 12 (6-16) years); 13 were asymptomatic (median age 10 (2-13) years). Induced AF degenerated to ventricular fibrillation (VF) in 2 patients. Of the 2 patients with VF, 1 was asymptomatic and the other had syncope; the accessory pathway effective refractory period was <=180 ms in both. An intracardiac electrophysiological study was performed in 92 patients, and ablation was not attempted for risk of atrioventricular block in 8 (8.6%). The success and recurrence rate of ablation were 90.5% and 23.8% respectively. CONCLUSION: The induction of VF in 2 of 109 patients in our study suggests that the prognosis of WPW in children is not as benign as once thought. All patients with a WPW pattern on the ECG should be assessed electrophysiologically and risk-stratified. Ablation of patients with risk factors can prevent sudden death in this population. PMID- 26006138 TI - Coronary slow flow: Electrophysiologic evidence of ischemia? PMID- 26006137 TI - Efficiency of postoperative statin treatment for preventing new-onset postoperative atrial fibrillation in patients undergoing isolated coronary artery bypass grafting: A prospective randomized study. AB - OBJECTIVE: Recent studies have demonstrated that preoperative statin therapy reduces the incidence of postoperative atrial fibrillation (AF). The objective of this study was to assess the efficacy of statin therapy started in the early postoperative period for the prevention from new-onset AF after isolated coronary artery bypass grafting (CABG). METHODS: This prospective and randomized study consisted of 60 consecutive patients who underwent elective isolated CABG. Patients were divided into two groups to examine the influence of statins: those with postoperative statin therapy (statin group, n=30) and those without it (non statin group, n=30). Patient data were collected and analyzed prospectively. In the statin group, each extubated patient was given 40 mg of atorvastatin per day, starting from an average of 6 hours after the operation. RESULTS: The overall incidence of postoperative AF was 30%. Postoperative AF occurred in 5 patients (16.7%) in the statin group. This was significantly lower compared with 13 patients (43.3%) in the non-statin group (p=0.049). According to the multivariate analysis, postoperative atorvastatin reduced the risk of postoperative AF by 49% [odds ratio (OR) 0.512, 95% confidence interval (CI) 0.005 to 0.517, p=0.012]. Also, age was an independent predictor of postoperative AF (OR 1.299, 95% CI 1.115 to 1.514, p=0.001). CONCLUSION: Postoperative statin therapy seems to reduce new-onset AF after isolated CABG in our study. PMID- 26006140 TI - Hybrid approach of percutaneous mitral valve repair with the MitraClip followed by off-pump coronary artery bypass grafting. PMID- 26006139 TI - A rare association: concomitant presence of mitral valve blood cyst with atrial septal aneurysm and cor triatriatum dexter. PMID- 26006141 TI - Treatment of left main shock syndrome with percutaneous coronary intervention in the absence of an advanced left ventricular assist device or ECMO. PMID- 26006142 TI - Possible renoprotective effects of dabigatran. PMID- 26006143 TI - The possibility of using spectral indices of heart rate variability to improve the diagnostic value of cardiovascular autonomic function tests in rheumatoid arthritis patients. PMID- 26006144 TI - Restless leg syndrome and slow coronary flow. Is it inflammation or autonomic nervous system? PMID- 26006145 TI - Ultrasound-assisted catheter-directed thrombolysis for pulmonary embolism. PMID- 26006146 TI - Electrical storm in an adolescent with arrhythmogenic right ventricle cardiomyopathy treated with cardiac transplantation. PMID- 26006147 TI - Long term follow-up in a patient with acute type A aortic dissection complicated with cardiac tamponade without surgery. PMID- 26006148 TI - Percutaneous transcatheter closure of giant coronary artery fistulazing to left ventricular cavity. PMID- 26006149 TI - Giant coronary sinus of Valsalva aneurysm. PMID- 26006150 TI - Rapidly growing fungus ball on prosthetic valve: Candida albicans endocarditis. PMID- 26006151 TI - A rare cause of embolism in the popliteal artery of an adolescent: ruptured cardiac hydatid cyst. PMID- 26006152 TI - Where is the culprit? Acute occlusion of the anomalous branch of the circumflex coronary artery (CX). PMID- 26006153 TI - Excess Length of Stay Attributable to Clostridium difficile Infection (CDI) in the Acute Care Setting: A Multistate Model. AB - BACKGROUND: Standard estimates of the impact of Clostridium difficile infections (CDI) on inpatient lengths of stay (LOS) may overstate inpatient care costs attributable to CDI. In this study, we used multistate modeling (MSM) of CDI timing to reduce bias in estimates of excess LOS. METHODS: A retrospective cohort study of all hospitalizations at any of 120 acute care facilities within the US Department of Veterans Affairs (VA) between 2005 and 2012 was conducted. We estimated the excess LOS attributable to CDI using an MSM to address time dependent bias. Bootstrapping was used to generate 95% confidence intervals (CI). These estimates were compared to unadjusted differences in mean LOS for hospitalizations with and without CDI. RESULTS: During the study period, there were 3.96 million hospitalizations and 43,540 CDIs. A comparison of unadjusted means suggested an excess LOS of 14.0 days (19.4 vs 5.4 days). In contrast, the MSM estimated an attributable LOS of only 2.27 days (95% CI, 2.14-2.40). The excess LOS for mild-to-moderate CDI was 0.75 days (95% CI, 0.59-0.89), and for severe CDI, it was 4.11 days (95% CI, 3.90-4.32). Substantial variation across the Veteran Integrated Services Networks (VISN) was observed. CONCLUSIONS: CDI significantly contributes to LOS, but the magnitude of its estimated impact is smaller when methods are used that account for the time-varying nature of infection. The greatest impact on LOS occurred among patients with severe CDI. Significant geographic variability was observed. MSM is a useful tool for obtaining more accurate estimates of the inpatient care costs of CDI. PMID- 26006155 TI - Percutaneous tracheostomy in animal models: it's the year of the sheep! PMID- 26006154 TI - Moderate-degree acidosis is an independent determinant of postoperative bleeding in cardiac surgery. AB - BACKGROUND: Acidosis is a well-known factor leading to coagulopathy. It has been widely explored as a risk factor for severe bleeding in trauma patients. However, no information with respect to acidosis as a determinant of postoperative bleeding in cardiac surgery patients exists. The aim of this study was to investigate the role of acidosis and hyperlactatemia (HL) in determining postoperative bleeding and need for surgical revision in cardiac surgery patients. METHODS: We carried out a retrospective analysis on 4521 patients receiving cardiac operations in two institutions. For each patient the preoperative data and operative profile was available. Arterial blood gas analysis data at the arrival in the intensive care unit were analyzed to investigate the association between acidosis (pH<7.35), HL (>4.0 mMol/L) and postoperative bleeding and surgical revision rate. RESULTS: After correction for the potential confounders, both acidosis (P=0.001) and HL (P=0.001) were significantly associated with the amount of postoperative bleeding. HL was an independent risk factor for postoperative bleeding even in absence of acidosis. Overall, surgical revision rate was 5.6% in patients with HL and no acidosis; 7.7% in patients with acidosis and HL, and 7.2% in patients with acidosis and no HL. All these values are significantly (P=0.001) higher than the ones in patients without acidosis/HL (2%). CONCLUSIONS: Even a moderate degree of postoperative acidosis is associated with a greater postoperative bleeding and surgical revision rate in cardiac surgery patients. Correction of acidosis with bicarbonate does not lead to an improvement of the postoperative bleeding asset. PMID- 26006156 TI - Dual-Mode SERS-Fluorescence Immunoassay Using Graphene Quantum Dot Labeling on One-Dimensional Aligned Magnetoplasmonic Nanoparticles. AB - A novel dual-mode immunoassay based on surface-enhanced Raman scattering (SERS) and fluorescence was designed using graphene quantum dot (GQD) labels to detect a tuberculosis (TB) antigen, CFP-10, via a newly developed sensing platform of linearly aligned magnetoplasmonic (MagPlas) nanoparticles (NPs). The GQDs were excellent bilabeling materials for simultaneous Raman scattering and photoluminescence (PL). The one-dimensional (1D) alignment of MagPlas NPs simplified the immunoassay process and enabled fast, enhanced signal transduction. With a sandwich-type immunoassay using dual-mode nanoprobes, both SERS signals and fluorescence images were recognized in a highly sensitive and selective manner with a detection limit of 0.0511 pg mL(-1). PMID- 26006157 TI - Azathioprine plus corticosteroid treatment in Chinese patients with neuromyelitis optica. AB - We investigated the efficacy of azathioprine (AZA) plus long-term low dose corticosteroids in Chinese patients with neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) at the Center for Demyelinating Diseases, South China. We prospectively enrolled patients between June 2010 and June 2014. Annualized relapse rate (ARR), expanded disability status scale (EDSS) score and modified Rankin Scale (mRS) were analyzed retrospectively. Of 77 patients with NMO/NMOSD (four males, 73 females; age range: 4-69 years), median disease duration before initiation of AZA was 32.0 months (range: 2.0-197.0). Median post-treatment follow-up was 23 months (range: 6-58) and 44 patients (57.1%) were relapse-free at median follow-up 19 months (range: 6-51). Pre treatment ARR was 0.923, and post-treatment ARR was 0 (p < 0.0001). Survival analysis indicated a significantly lower risk of relapse (hazard ratio 0.522; 95% confidence interval 0.377-0.722; p < 0.0001). Significant improvements were shown in the EDSS (3.0 versus 1.0; p < 0.0001) and mRS (2.0 versus 1.0; p < 0.0001). Our study provides evidence supporting the use of AZA plus a low dose corticosteroid as an effective and safe strategy which is associated with a reduction in the risk of relapse in Chinese patients with NMO. PMID- 26006158 TI - Point-of-Care Platelet Function Testing in Cardiac Surgery: A Bundle of Measures Create Adequate Hemostatic Algorithm. PMID- 26006159 TI - Indigo Carmine-Induced Hypotension in a Parturient With Idiopathic Pulmonary Artery Hypertension, Hypertrophic Cardiomyopathy, and LAD Myocardial Bridging. PMID- 26006160 TI - Interatrial Block Is Not a Predictor of Post-CABG Atrial Fibrillation. PMID- 26006161 TI - Control of Cardiopulmonary Bypass Flow Rate Using Transfontanellar Ultrasonography and Cerebral Oximetry During Selective Antegrade Cerebral Perfusion. PMID- 26006162 TI - Quantitative Imaging of Single Unstained Magnetotactic Bacteria by Coherent X-ray Diffraction Microscopy. AB - Novel coherent diffraction microscopy provides a powerful lensless imaging method to obtain a better understanding of the microorganism at the nanoscale. Here we demonstrated quantitative imaging of intact unstained magnetotactic bacteria using coherent X-ray diffraction microscopy combined with an iterative phase retrieval algorithm. Although the signal-to-noise ratio of the X-ray diffraction pattern from single magnetotactic bacterium is weak due to low-scattering ability of biomaterials, an 18.6 nm half-period resolution of reconstructed image was achieved by using a hybrid input-output phase retrieval algorithm. On the basis of the quantitative reconstructed images, the morphology and some intracellular structures, such as nucleoid, polybeta-hydroxybutyrate granules, and magnetosomes, were identified, which were also confirmed by scanning electron microscopy and energy dispersive spectroscopy. With the benefit from the quantifiability of coherent diffraction imaging, for the first time to our knowledge, an average density of magnetotactic bacteria was calculated to be ~1.19 g/cm(3). This technique has a wide range of applications, especially in quantitative imaging of low-scattering biomaterials and multicomponent materials at nanoscale resolution. Combined with the cryogenic technique or X-ray free electron lasers, the method could image cells in a hydrated condition, which helps to maintain their natural structure. PMID- 26006163 TI - Metal Complex Pigment Involved in the Blue Sepal Color Development of Hydrangea. AB - Anthocyanins exhibit various vivid colors from red through purple to blue and are potential sources of food colorants. However, their usage is restricted because of their instability, especially as a blue colorant. The blue sepal color of Hydrangea macrophylla is due to a metal complex named "hydrangea-blue complex" composed of delphinidin 3-O-glucoside, 1, 5-O-caffeoylquinic acid, 2, and/or 5-O p-coumaroylquinic acid, 3, as copigments, and Al(3+) in aqueous solution at approximately pH 4.0. However, the ratio of each component ins not stoichiometric, but is fluctuates within a certain range. The hydrangea-blue complex exists only in aqueous solution, exhibiting a stable blue color, but attempts at crystallization have failed; therefore, the structure remains obscure. To clarify the basis of the character of the hydrangea-blue pigment and to obtain its structural information, we studied the mixing conditions to reconstruct the same blue color as observed in the sepals. In highly concentrated sodium acetate buffer (6 M, pH 4.0) we could measure (1)H NMR of both the hydrangea-blue complex composed of 1 (5 mM), 2 (10 mM), and Al(3+) (10 mM) and a simple 1-Al(3+) complex. We also recorded the spectra of complexes composed with structurally different anthocyanins and copigments. Comparison of those signals indicated that in the hydrangea-blue complex 1 might be under equilibrium between chelating and nonchelating structures having an interaction with 2. PMID- 26006164 TI - Microemulsion-loaded hydrogel formulation of butenafine hydrochloride for improved topical delivery. AB - Topical microemulsion systems for the antifungal drug, butenafine hydrochloride (BTF) were designed and developed to overcome the problems associated with the cutaneous delivery due to poor water solubility. The solubility of BTF in oils, surfactants and co-surfactants was evaluated to screen the components of the microemulsion. Isopropyl palmitate was used as the oil phase, aerosol OT as the surfactant and sorbitan monooleate as co-surfactant. The pseudoternary diagrams were constructed to identify the area of microemulsion existence and optimum systems were designed. The systems were assessed for drug-loading efficiency and characterized for pH, robustness to dilution, globule size, drug content and stability. Viscosity analysis, spreadability, drug content assay, ex vivo skin permeation study and antifungal activity assay were performed for the optimized microemulsion-loaded hydrogel. The optimized BTF microemulsion had a small and uniform globule size. The incorporation of microemulsion system into Carbopol 940 gel was found to be better as compared to sodium alginate or hydroxyl propyl methyl cellulose (HPMC K4 M) gel. The developed gel has shown better ex vivo skin permeation and antifungal activity when compared to marketed BTF cream. Thus, the results provide a basis for the successful delivery of BTF from microemulsion loaded hydrogel formulation, which resulted in improved penetration of drug and antifungal activity in comparison with commercial formulation of BTF. PMID- 26006165 TI - Design and synthesis of digitally encoded polymers that can be decoded and erased. AB - Biopolymers such as DNA store information in their chains using controlled sequences of monomers. Here we describe a non-natural information-containing macromolecule that can store and retrieve digital information. Monodisperse sequence-encoded poly(alkoxyamine amide)s were synthesized using an iterative strategy employing two chemoselective steps: the reaction of a primary amine with an acid anhydride and the radical coupling of a carbon-centred radical with a nitroxide. A binary code was implemented in the polymer chains using three monomers: one nitroxide spacer and two interchangeable anhydrides defined as 0 bit and 1-bit. This methodology allows encryption of any desired sequence in the chains. Moreover, the formed sequences are easy to decode using tandem mass spectrometry. Indeed, these polymers follow predictable fragmentation pathways that can be easily deciphered. Moreover, poly(alkoxyamine amide)s are thermolabile. Thus, the digital information encrypted in the chains can be erased by heating the polymers in the solid state or in solution. PMID- 26006166 TI - Physical Functioning, Emotional, and Behavioral Problems in Children With ADHD and Comorbid ASD: A Cross-Sectional Study. AB - OBJECTIVE: To examine (a) physical and daily functioning in children with ADHD and autism spectrum disorder (ASD) compared with ADHD alone and (b) whether decreased physical quality of life (QoL) is associated with increased emotional and behavioral problems in children with ADHD-ASD. METHOD: Cross-sectional study comprising 392 children with confirmed ADHD (ADHD-ASD, n = 93; ADHD alone, n = 299) recruited from 21 pediatric practices in Victoria, Australia. Data were collected via parent and teacher surveys. Key measures included the Strengths and Difficulties Questionnaire (SDQ) and Pediatric Quality of Life Inventory (PedsQL). RESULTS: Children with ADHD-ASD had poorer QoL across both psychosocial and physical health domains, and also had greater parent-reported behavioral, emotional, and peer problems, compared with children with ADHD alone. Poorer physical QoL partially mediated the relationship between comorbid ASD status and poorer emotional and behavioral functioning. CONCLUSION: The comorbid overlay of ASD in ADHD appears to influence not only problems in physical functioning but also the severity of problems relating to areas of emotional and behavioral functioning. PMID- 26006167 TI - The Specificity and Independent Contribution of Inhibition, Working Memory, and Reaction Time Variability in Relation to Symptoms of ADHD and ASD. AB - OBJECTIVE: The aim of the present study was to investigate the specificity of inhibition, working memory (WM), and reaction time variability (RTV) in relation to symptoms of ADHD and autism spectrum disorder (ASD). METHOD: A community-based sample of schoolchildren aged 7 to 9 years (N = 200) completed tasks designed to measure inhibition, WM, and RTV. RESULTS: All neuropsychological functions were related to symptoms of both ADHD and ASD. The results from regression analyses showed that inhibition and RTV were related specifically to ADHD symptoms when controlling for symptoms of ASD. Regarding WM, no specific association with either symptom domain was evident after controlling for the other. Furthermore, independent contributions of inhibition and RTV were found in relation to ADHD symptoms after controlling for ASD symptoms. CONCLUSION: The present study underscores the relevance of controlling for ADHD symptoms when examining ASD symptoms in relation to neuropsychological functions. PMID- 26006168 TI - Comorbidity and Factors Affecting Treatment Non-Persistence in ADHD. AB - OBJECTIVE: The aim of the study was to identify factors for treatment non persistence in patients with ADHD. METHOD: Data for 100 patients with ADHD aged 5 to 16 who completed the Kiddie-Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version-Korean Version (K-SADS-PL-K) and Korean Wechsler Intelligence Scale for Children (K-WISC) were obtained between 2008 and 2013. Patients were classified as treatment-persistent and treatment-non-persistent based on 6-month follow-up. Sociodemographic data, comorbidities, intelligence quotient (IQ), severity, and social/school functioning were compared. RESULTS: Adolescence and poor parental spousal relationships significantly predicted treatment non-persistence. Although comorbid major depressive disorder and absence of transient tic disorder were associated with treatment non-persistence, there was no difference in overall psychiatric comorbidity. No differences existed for IQ, Clinical Global Impressions-Severity (CGI-S) score, peer relationships, and academic achievement. CONCLUSION: Lower treatment persistence was associated with adolescence, comorbid depression, absence of tics, and poor parental spousal relationships, but not with symptom severity or impairment of the disorder. PMID- 26006169 TI - Footedness Is Associated With ADHD Symptoms in the Adult General Population. AB - OBJECTIVE: Mixed-handedness among children has recently been proposed as a marker of neurodevelopmental disorder and ADHD. This study expanded this initial evidence to the questions of whether mixed-handedness as well as mixed-footedness are similarly associated with ADHD among adults. METHOD: Self-reported ADHD symptoms, handedness, footedness, and current depression and anxiety were assessed in a large, heterogeneous general population sample ( N = 2,592). Latent variable analysis was used to investigate the structure and measurement properties of ADHD symptoms, the dimensionality of footedness, and the classification of lateral preferences. RESULTS: Mixed-footedness was associated with probable ADHD (odds ratio [OR] = 1.76 [1.07, 2.89], p = .026). Left- and mixed-footedness were associated with higher inattention and impulsivity scores. CONCLUSION: Developmental continuities of the associations of mixed lateral preferences with ADHD from child to adult age seem to exist. In particular, mixed footedness, rather than mixed-handedness, appears to be an ADHD marker among adults. PMID- 26006171 TI - In vivo bioimpedance measurement of healthy and ischaemic rat brain: implications for stroke imaging using electrical impedance tomography. AB - In order to facilitate the imaging of haemorrhagic and ischaemic stroke using frequency difference electrical impedance tomography (EIT), impedance measurements of normal and ischaemic brain, and clotted blood during haemorrhage, were gathered using a four-terminal technique in an in vivo animal model, a first for ischaemic measurements. Differences of 5-10% in impedance were seen between the frequency spectrums of healthy and ischaemic brain, over the frequency range 0-3 kHz, while the spectrum of blood was predominately uniform. The implications of imaging blood/ischaemia in the brain using electrical impedance tomography are discussed, supporting the notion that it will be possible to differentiate stroke from haemorrhage. PMID- 26006170 TI - WHO Better Outcomes in Labour Difficulty (BOLD) project: innovating to improve quality of care around the time of childbirth. AB - As most pregnancy-related deaths and morbidities are clustered around the time of childbirth, quality of care during this period is critical to the survival of pregnant women and their babies. Despite the wide acceptance of partograph as the central tool to optimize labour outcomes for over 40 years, its use has not successfully improved outcomes in many settings for several reasons. There are also increasing questions about the validity and applicability of its central feature - "the alert line" - to all women regardless of their labour characteristics. Apart from the known deficiencies in labour care, attempts to improve quality of care in low resource settings have also failed to address and integrate women's birth experience into quality improvement processes. It was against this background that the World Health Organization (WHO) embarked on the Better Outcomes in Labour Difficulty (BOLD) project to improve the quality of intrapartum care in low- and middle-income countries. The main goal of the BOLD project is to reduce intrapartum-related stillbirths, maternal and newborn mortalities and morbidities by addressing the critical barriers to the process of good quality intrapartum care and enhancing the connection between health systems and communities. The project seeks to achieve this goal by (1) developing an evidence-based, easy to use, labour monitoring-to-action decision-support tool (currently termed Simplified, Effective, Labour Monitoring-to-Action - SELMA); and (2) by developing innovative service prototypes/tools, co-designed with users of health services (women, their families and communities) and health providers, to promote access to respectful, dignified and emotionally supportive care for pregnant women and their companions at the time of birth ("Passport to Safer Birth"). This two-pronged approach is expected to positively impact on important domains of quality of care relating to both provision and experience of care. In this paper, we briefly describe the rationale for innovative thinking in relation to improving quality of care around the time of childbirth and introduce WHO current plans to improve care through research, design and implementation of innovative tools and services in the post-2015 era.Please see related articles ' http://dx.doi.org/10.1186/s12978-015-0029-4 ' and ' http://dx.doi.org/10.1186/s12978-015-0028-5 '. PMID- 26006172 TI - Urinary tract infection of mice to model human disease: Practicalities, implications and limitations. AB - Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Murine models of human UTI are vital experimental tools that have helped to elucidate UTI pathogenesis and advance knowledge of potential treatment and infection prevention strategies. Fundamentally, several variables are inherent in different murine models, and understanding the limitations of these variables provides an opportunity to understand how models may be best applied to research aimed at mimicking human disease. In this review, we discuss variables inherent in murine UTI model studies and how these affect model usage, data analysis and data interpretation. We examine recent studies that have elucidated UTI host pathogen interactions from the perspective of gene expression, and review new studies of biofilm and UTI preventative approaches. We also consider potential standards for variables inherent in murine UTI models and discuss how these might expand the utility of models for mimicking human disease and uncovering new aspects of pathogenesis. PMID- 26006173 TI - Surgical outcomes of the endoscopic transsphenoidal route to pituitary tumours in paediatric patients >10 years of age: 5 years of experience at a single institute. AB - OBJECTIVE: To evaluate the safety and effectiveness of the endoscopic endonasal transsphenoidal approach (EETA) for the management of pituitary adenomas in paediatric patients >10 years of age. METHODS: A retrospective chart review was performed to identify 56 paediatric patients between 10 and 18 years of age who underwent an endonasal endoscopic transsphenoidal approach for the resection of a pituitary adenoma during the last 5 years. The age, sex, symptoms, tumour size, extent of tumour resection, clinical outcome and surgical complications of patients were reviewed. RESULTS: Total resection was achieved in 49 (87.5%) cases, subtotal resection was achieved in 7 (12.5%) cases and no patient had a partial or insufficient resection. Of the 35 patients who experienced preoperative deterioration of vision, 33 (94.2%) achieved visual remission with rates of 34.2% and 60% for normalisation and improvement, respectively. Endocrinological normalisation was achieved in 13 (31.7%) of 41 patients who had preoperative hyperhormonal levels; hormone levels decreased in 25 (61.0%) patients, and 3 (7.3%) patients had no change in hormone level. Two (3.5%) patients incurred postoperative cerebrospinal fluid leakage, which was resolved after lumbar drainage. Four (7.1%) patients developed hypopituitarism, which required hormone therapy. Post-surgery, five (8.9%) patients incurred transient diabetes insipidus (DI), of which one (1.7%) patient developed persistent DI and was administered Minirin. Meningitis occurred in one (1.7%) patient who was cured by the administration of a third-generation antibiotic. There were no cases of intracranial haematoma, reoperation or death. CONCLUSIONS: EETA allows neurosurgeons to safely and effectively remove paediatric pituitary adenomas with low morbidity and mortality. PMID- 26006174 TI - Cognitive-behavioural treatment for subacute and chronic neck pain. AB - BACKGROUND: Although research on non-surgical treatments for neck pain (NP) is progressing, there remains uncertainty about the efficacy of cognitive behavioural therapy (CBT) for this population. Addressing cognitive and behavioural factors might reduce the clinical burden and the costs of NP in society. OBJECTIVES: To assess the effects of CBT among individuals with subacute and chronic NP. Specifically, the following comparisons were investigated: (1) cognitive-behavioural therapy versus placebo, no treatment, or waiting list controls; (2) cognitive-behavioural therapy versus other types of interventions; (3) cognitive-behavioural therapy in addition to another intervention (e.g. physiotherapy) versus the other intervention alone. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, SCOPUS, Web of Science, and PubMed, as well as ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2014. Reference lists and citations of identified trials and relevant systematic reviews were screened. SELECTION CRITERIA: We included randomised controlled trials that assessed the use of CBT in adults with subacute and chronic NP. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias in each study and extracted the data. If sufficient homogeneity existed among studies in the pre defined comparisons, a meta-analysis was performed. We determined the quality of the evidence for each comparison with the GRADE approach. MAIN RESULTS: We included 10 randomised trials (836 participants) in this review. Four trials (40%) had low risk of bias, the remaining 60% of trials had a high risk of bias.The quality of the evidence for the effects of CBT on patients with chronic NP was from very low to moderate. There was low quality evidence that CBT was better than no treatment for improving pain (standard mean difference (SMD) 0.58, 95% confidence interval (CI) -1.01 to -0.16), disability (SMD -0.61, 95% CI -1.21 to -0.01), and quality of life (SMD -0.93, 95% CI -1.54 to -0.31) at short term follow-up, while there was from very low to low quality evidence of no effect on various psychological indicators at short-term follow-up. Both at short and intermediate-term follow-up, CBT did not affect pain (SMD -0.06, 95% CI 0.33 to 0.21, low quality, at short-term follow-up; MD -0.89, 95% CI -2.73 to 0.94, low quality, at intermediate-term follow-up) or disability (SMD -0.10, 95% CI -0.40 to 0.20, moderate quality, at short-term follow-up; SMD -0.24, 95% CI 0.54 to 0.07, moderate quality, at intermediate-term follow-up) compared to other types of interventions. There was moderate quality evidence that CBT was better than other interventions for improving kinesiophobia at intermediate-term follow up (SMD -0.39, 95% CI -0.69 to -0.08, I(2) = 0%). Finally, there was very low quality evidence that CBT in addition to another intervention did not differ from the other intervention alone in terms of effect on pain (SMD -0.36, 95% CI -0.73 to 0.02) and disability (SMD -0.10, 95% CI -0.56 to 0.36) at short-term follow up.For patients with subacute NP, there was low quality evidence that CBT was better than other interventions at reducing pain at short-term follow-up (SMD 0.24, 95% CI -0.48 to 0.00), while no difference was found in terms of effect on disability (SMD -0.12, 95% CI -0.36 to 0.12) and kinesiophobia.None of the included studies reported on adverse effects. AUTHORS' CONCLUSIONS: With regard to chronic neck pain, CBT was found to be statistically significantly more effective for short-term pain reduction only when compared to no treatment, but these effects could not be considered clinically meaningful. When comparing both CBT to other types of interventions and CBT in addition to another intervention to the other intervention alone, no differences were found. For patients with subacute NP, CBT was significantly better than other types of interventions at reducing pain at short-term follow-up, while no difference was found for disability and kinesiophobia. Further research is recommended to investigate the long-term benefits and risks of CBT including for the different subgroups of subjects with NP. PMID- 26006175 TI - Improvement of Cd(2+) uptake ability of SmtA protein by Lys/Cys mutation; experimental and theoretical studies. AB - The improved Cd(2+) surface affinity characteristics of a mutated cyanobacterial metallothionein SmtA (K45C) were investigated via experimental and theoretical methods. Molecular dynamics simulations were carried out using a model of Cd(2+) and other ions enclosed in a fully hydrated simulation box with the wild-type or mutated SmtA protein. The theoretical results suggested that mutated SmtA was more powerful in absorption of Cd(2+) than the wild-type protein. Then, the mutated smtA gene (from Synechococcus PCC 7942) was synthesized by simplified gene synthesis method and expressed on isopropyl-beta-d-thiogalactopyranoside induction. The protein expression was investigated by SDS-PAGE and verified by Western blotting. Finally, cadmium uptake ratio of mutant protein toward wild type was analyzed by atomic absorption. This study is the first example of cytoplasmic expression of a mutant protein. Experimental results also verified that the mutation intensifies uptake of Cd(2+) ions. PMID- 26006177 TI - Ligand field influence on the electronic and magnetic properties of quasi-linear two-coordinate iron(II) complexes. AB - The 2 to 300 K magnetic susceptibilities of Fe{N(SiMe2Ph)2}2, 1, Fe{N(SiMePh2)2}2, 2, and the diaryl complex Fe(Ar(Pr(i)4))2, 3, where Ar(Pr(i)4) is C6H3-2,6(C6H3-2,6-Pr(i)2)2 have been measured. Initial fits of these properties in the absence of an independent knowledge of their ligand field splitting have proven problematic. Ab initio calculations of the CASSCF/RASSI/SINGLE-ANISO type have indicated that the orbital energies of the complexes, as well as those of Fe(Ar(Me6))2, 4, where Ar(Me6) is C6H3-2,6(C6H2 2,4,6-Me3)2), are in the order d(xy)~ d(x(2)-y(2)) < d(xz) ~ d(yz) < d(z(2)), and the iron(II) complexes in this ligand field have the (d(xy), d(x(2) y(2)))(3)(d(xz), d(yz))(2)(d(z(2)))(1) ground electronic configuration with a substantial orbital contribution to their effective magnetic moments. An ab initio-derived ligand field and spin-orbit model is found to yield an excellent simulation of the observed magnetic properties of 1-3. The calculated ligand field strengths of these ligands are placed in the broader context of common coordination ligands in hypothetical two-coordinate linear iron(ii) complexes. This yields the ordering I(-) < H(-) < Br(-)~ PMe3 < CH3(-) < Cl(-)~ C(SiMe3)3(-) < CN(-)~ SAr(Pr(i)6-) < Ar(Pr(i)4-) < Ar(Me6-)~ N3(-) < NCS(-)~ NCSe(-)~ NCBH3( )~ MeCN ~ H2O ~ NH3 < NO3(-)~ THF ~ CO ~ N(SiMe2Ph)2(-)~ N(SiMePh2)2(-) < F(-)~ N(H)Ar(Pr(i)6-)~ N(SiMe3)Dipp(-) < OAr(Pr(i)4-). The magnetic susceptibility of the bridged dimer, [Fe{N(SiMe3)2}2]2, 5, has also been measured between 2 and 300 K and a fit of chiMT with the isotropic Heisenberg Hamiltonian, H = -2JS1.S2 yields an antiferromagnetic exchange coupling constant, J, of -131(2) cm(-1). PMID- 26006178 TI - Solution-based fabrication of a highly catalytically active 3D network constructed from 1D metal-organic framework-coated polymeric worm-like micelles. AB - A 3D network constructed from metal-organic framework composite nanowires with a uniform width and a loose (swollen) structure has been prepared. It contained micro-, meso- and macro-pores, which make the 3D network ideal for use as a catalyst, as evidenced by its high catalytic activity in the Knoevenagel reaction. PMID- 26006179 TI - A systematic approach to diverse, lead-like scaffolds from alpha,alpha disubstituted amino acids. AB - A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four alpha-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, each individual scaffold has the ability to specifically target lead-like chemical space. PMID- 26006180 TI - Controllable poly-crystalline bilayered and multilayered graphene film growth by reciprocal chemical vapor deposition. AB - We report the selective growth of large-area bilayered graphene film and multilayered graphene film on copper. This growth was achieved by introducing a reciprocal chemical vapor deposition (CVD) process that took advantage of an intermediate h-BN layer as a sacrificial template for graphene growth. A thin h BN film, initially grown on the copper substrate using CVD methods, was locally etched away during the subsequent graphene growth under residual H2 and CH4 gas flows. Etching of the h-BN layer formed a channel that permitted the growth of additional graphene adlayers below the existing graphene layer. Bilayered graphene typically covers an entire Cu foil with domain sizes of 10-50 MUm, whereas multilayered graphene can be epitaxially grown to form islands a few hundreds of microns in size. This new mechanism, in which graphene growth proceeded simultaneously with h-BN etching, suggests a potential approach to control graphene layers for engineering the band structures of large-area graphene for electronic device applications. PMID- 26006181 TI - A comparison framework for temporal image reconstructions in electrical impedance tomography. AB - Electrical impedance tomography (EIT) provides low-resolution images of internal conductivity distributions, but is able to achieve relatively high temporal resolutions. Most EIT image reconstruction algorithms do not explicitly account for the temporal constraints on the measurements or physiological processes under investigation. Instead, algorithms typically assume both that the conductivity distribution does not change during the acquisition of each EIT data frame, and that frames can be reconstructed independently, without consideration of the correlation between images. A failure to account for these temporal effects will result in aliasing-related artefacts in images. Several methods have been proposed to compensate for these effects, including interpolation of raw data, and reconstruction algorithms using Kalman and temporal filtering. However, no systematic work has been performed to understand the severity of the temporal artefacts nor the extent to which algorithms can account for them. We seek to address this need by developing a temporal comparison framework and figures of merit to assess the ability of reconstruction algorithms to account for temporal effects. Using this approach, we compare combinations of three reconstruction algorithms using three EIT data frame types: perfect, realistic and interpolated. The results show that, without accounting for temporal effects, artefacts are present in images for dynamic conductivity contrasts at frequencies 10-20 times slower than the frame rate. The proposed methods show some improvements in reducing these artefacts. PMID- 26006183 TI - Tuning of electron transfer reactions in pluronic-surfactant supramolecular assemblies. AB - Photoinduced electron transfer (ET) reaction between an anionic acceptor, coumarin-343 (C343), and a neutral donor, N,N-dimethylaniline (DMAN), has been investigated in composite supramolecular assemblies (mixed micelles) comprised of a pluronic copolymer (P123: EO20-PO70-EO20 or F88: EO103-PO39-EO103 where EO: ethylene oxide and PO: propylene oxide) and a cationic surfactant (CTAC: cetyltrimethylammonium chloride), following fluorescence quenching studies. Systematic increase in the quenching rates for the studied donor-acceptor system with the increasing CTAC to pluronic molar ratio in the mixed micelles demonstrates a large modulation in the ET rates. The mixed micellar systems in the present cases are formed through the incorporation of the hydrocarbon chains of CTAC into the poly-PO core of the pluronic micelles whereby the cationic head groups of CTAC are placed at the periphery of the micellar core, protruded into the hydrated poly-EO corona region, leading to the formation of a positively charged layer deep inside these mixed micelles. Thus, the anionic C343 dye, initially dissolved at the micelle-water interface, experiences a gradually increasing electrostatic attraction and is therefore systematically dragged deeper inside the micellar corona, as the CTAC composition is increased in the mixed micellar systems. Consequently, the ET rate of the C343-DMAN pair undergoes a large enhancement in the studied mixed micellar systems with the increasing CTAC to pluronic molar ratio. The present strategy of modulating ET reactions using such composite supramolecular assemblies can find applications in areas where bimolecular ET is an integral reaction step. PMID- 26006182 TI - Mixed amlodipine/valsartan overdose treated by the molecular adsorbent recirculating system (MARSTM). AB - CASE REPORT: We describe the case of a 58-year-old woman who developed a severe distributive shock following the intentional ingestion of a large overdose of amlodipine (480 mg) combined with valsartan (3680 mg). Extreme vasoplegia remained refractory to maximal standard therapy including fluid resuscitation, intravenous calcium, vasopressors at very high doses, hyperinsulinemia-euglycemia therapy, lipid emulsion, and methylene blue administration. Besides, the patient exhibited hyperglycemia refractory to very high doses of insulin. Due to its theoretical ability to effectively remove protein-bound drugs such as amlodipine from the circulation, albumin dialysis with the molecular adsorbent recirculating system (MARSTM) was performed during two consecutive sessions. Blood was drawn for toxicokinetic calculations. Amlodipine elimination half-life during the first MARSTM session was calculated at 7.6 h. In addition, there was a rapid fall in blood glucose, requiring the introduction of a continuous infusion of glucose in order to achieve euglycemia. Moreover, a few hours after the initiation of the MARSTM therapy, the hemodynamic status was not significantly modified but a significant tapering of epinephrine infusion was possible, together with a progressive decrease of blood lactate level. However, the need for vasopressors in decreasing doses was present until day 5 post-ingestion. Eventually, the patient fully recovered and was discharged home 8 days after admission. DISCUSSION: The role of the MARSTM in the treatment of severe poisoning of calcium channel blockers is still to be defined. We were able to demonstrate a relatively short elimination half-life of amlodipine. A decreased insulin resistance and a reduction of epinephrine infusion were also observed. PMID- 26006184 TI - Mitochondrially targeted redox probe reveals the variations in oxidative capacity of the haematopoietic cells. AB - Both oxidative stress and mitochondrial dysfunction play roles in a myriad of pathological conditions. There is therefore a need for tools that possess the ability to measure the dynamics of oxidative capacity within the mitochondria, particularly those that can measure reversible changes. Here, we report a mitochondrially-targeted fluorescent redox sensor NpFR2, which can reversibly measure changes in the mitochondrial redox environment. The probe has been used to report on variations in oxidative capacity of the haematopoietic cells in bone marrow, thymus and spleen. PMID- 26006185 TI - Phylogeny and classification of the East Asian Amitostigma alliance (Orchidaceae: Orchideae) based on six DNA markers. AB - BACKGROUND: Tribe Orchideae dominates the orchid flora of the temperate Northern Hemisphere but its representatives in East Asia had been subject to less intensive phylogenetic study than those in Eurasia and North America. Although this situation was improved recently by the molecular phylogenetic study of Jin et al., comparatively few species were analyzed from the species-rich and taxonomically controversial East Asian Amitostigma alliance. Here, we present a framework nrITS tree of 235 accessions of Orchideae plus an in-depth analysis of 110 representative accessions, encompassing most widely recognized species within the alliance, to elucidate their relationships. RESULTS: We used parsimony, likelihood and Bayesian approaches to generate trees from data for two nuclear (nrITS, low-copy Xdh) and four chloroplast (matK, psbA-trnH, trnL-F, trnS-trnG) markers. Nuclear and plastid data were analyzed separately due to a few hard incongruences that most likely reflect chloroplast capture. Our results suggest key phylogenetic placements for Sirindhornia and Brachycorythis, and confirm previous assertions that the Amitostigma alliance is monophyletic and sister to the Eurasian plus European clades of subtribe Orchidinae. Seven robust clades are evident within the alliance, but none corresponds precisely with any of the traditional genera; the smaller and more morphologically distinct genera Tsaiorchis, Hemipilia, Neottianthe and Hemipiliopsis are monophyletic but each is nested within a polyphyletic plexus of species attributed to either Ponerorchis or the most plesiomorphic genus, Amitostigma. Two early-divergent clades that escaped analysis by Jin et al. undermine their attempt to circumscribe an expanded monophyletic genus Ponerorchis. CONCLUSIONS: We provide a new framework on the complex phylogenetic relationships between Amitostigma and other genera traditionally included in its alliance; based on which, we combine the entire Amitostigma alliance into a morphologically and molecularly circumscribed Amitostigma sensu latissimo that also contains seven molecularly circumscribed sections. Our molecular trees imply unusually high levels of morphological homoplasy, but these will need to be quantified via a future group-wide review of the alliance based on living plants if morphology is to be fully integrated into our classification. PMID- 26006186 TI - Health insurance for people with citizenship problems in Thailand: a case study of policy implementation. AB - In 2002, Thailand achieved universal health coverage through the introduction of the Universal Coverage Scheme (UCS). However, people with citizenship problems, so-called 'stateless people', were left uninsured. Consequently, the 'Health Insurance for People with Citizenship Problems' (HIS-PCP) policy was adopted in 2010 with features emulating the UCS. This study sought to examine the operational constraints faced by health providers in implementing the HIS-PCP policy. Qualitative methods were used, and a case study was conducted to explore the implementation of the HIS-PCP in Ranong and Tak provinces. Individual in depth interviews and group interviews were conducted with a total of 33 key informants. Interview data were analysed by a thematic approach. The study found that the HIS-PCP faced several operational challenges. Inadequate communication and unclear service guidelines contributed to ineffectiveness in budget spend and service provision. Other problems included the legal instruments that permitted stateless people to live only in certain areas, when such people were in fact highly mobile. Some providers adapted their practices to cope with on-the-job difficulties, including establishing a mutual agreement with neighbouring hospitals to allow stateless patients to bypass primary care gatekeepers. The challenges were aggravated by the delays in nationality verification procedures and insufficient collaboration between the Ministry of Public Health (MOPH) and the Ministry of Interior. Policy recommendations are suggested. In the short term, collaboration with relevant authorities both within and outside the MOPH should be improved. Guidelines concerning budgeting and scope of service provision should be fine-tuned. In the long run, the nationality verification process for stateless people should be expedited. The MOPH should develop clear and practical guidelines to assist health personnel to support patients to resolve their citizenship problems. PMID- 26006187 TI - Enabling low amounts of YAG:Ce(3+) to convert blue into white light with plasmonic Au nanoparticles. AB - We report a new strategy to directly attach Au nanoparticles onto YAG:Ce(3+) phosphor via a chemical preparation method, which yields efficient and quality conversion of blue to yellow light in the presence of a low amount of phosphor. Photoluminescent intensity and quantum yield of YAG:Ce(3+) phosphor are significantly enhanced after Au nanoparticle modification, which can be attributed to the strongly enhanced local surface electromagnetic field of Au nanoparticles on the phosphor particle surface. The CIE color coordinates shifted from the blue light (0.23, 0.23) to the white light region (0.30, 0.33) with a CCT value of 6601 K and a good white light CRI value of 78, which indicates that Au nanoparticles greatly improve the conversion efficiency of low amounts of YAG:Ce(3+) in WLEDs. PMID- 26006189 TI - Phylodynamic Inference with Kernel ABC and Its Application to HIV Epidemiology. AB - The shapes of phylogenetic trees relating virus populations are determined by the adaptation of viruses within each host, and by the transmission of viruses among hosts. Phylodynamic inference attempts to reverse this flow of information, estimating parameters of these processes from the shape of a virus phylogeny reconstructed from a sample of genetic sequences from the epidemic. A key challenge to phylodynamic inference is quantifying the similarity between two trees in an efficient and comprehensive way. In this study, I demonstrate that a new distance measure, based on a subset tree kernel function from computational linguistics, confers a significant improvement over previous measures of tree shape for classifying trees generated under different epidemiological scenarios. Next, I incorporate this kernel-based distance measure into an approximate Bayesian computation (ABC) framework for phylodynamic inference. ABC bypasses the need for an analytical solution of model likelihood, as it only requires the ability to simulate data from the model. I validate this "kernel-ABC" method for phylodynamic inference by estimating parameters from data simulated under a simple epidemiological model. Results indicate that kernel-ABC attained greater accuracy for parameters associated with virus transmission than leading software on the same data sets. Finally, I apply the kernel-ABC framework to study a recent outbreak of a recombinant HIV subtype in China. Kernel-ABC provides a versatile framework for phylodynamic inference because it can fit a broader range of models than methods that rely on the computation of exact likelihoods. PMID- 26006190 TI - Procalcitonin Is Not Useful to Discriminate Between Infectious and Noninfectious CRP Elevation in Patients with Non-Small Cell Lung Cancer. PMID- 26006188 TI - Mechanisms Underlying Mammalian Hybrid Sterility in Two Feline Interspecies Models. AB - The phenomenon of male sterility in interspecies hybrids has been observed for over a century, however, few genes influencing this recurrent phenotype have been identified. Genetic investigations have been primarily limited to a small number of model organisms, thus limiting our understanding of the underlying molecular basis of this well-documented "rule of speciation." We utilized two interspecies hybrid cat breeds in a genome-wide association study employing the Illumina 63 K single-nucleotide polymorphism array. Collectively, we identified eight autosomal genes/gene regions underlying associations with hybrid male sterility (HMS) involved in the function of the blood-testis barrier, gamete structural development, and transcriptional regulation. We also identified several candidate hybrid sterility regions on the X chromosome, with most residing in close proximity to complex duplicated regions. Differential gene expression analyses revealed significant chromosome-wide upregulation of X chromosome transcripts in testes of sterile hybrids, which were enriched for genes involved in chromatin regulation of gene expression. Our expression results parallel those reported in Mus hybrids, supporting the "Large X-Effect" in mammalian HMS and the potential epigenetic basis for this phenomenon. These results support the value of the interspecies feline model as a powerful tool for comparison to rodent models of HMS, demonstrating unique aspects and potential commonalities that underpin mammalian reproductive isolation. PMID- 26006191 TI - How to interpret liver function tests in heart failure patients? AB - Cardiac hepatopathy has generally been used to describe any liver damage caused by cardiac disorders in the absence of other possible causes of liver damage. Although there is no consensus on the terminology used, cardiac hepatopathy can be examined as congestive hepatopathy (CH) and acute cardiogenic liver injury (ACLI). CH is caused by passive venous congestion of the liver that generally occurs in the setting of chronic cardiac conditions such as chronic HF, constrictive pericarditis, tricuspid regurgitation, or right-sided heart failure (HF) of any cause, and ACLI is most commonly associated with acute cardiocirculatory failure resulting from acute myocardial infarction, acute decompensated HF, or myocarditis. Histologically, CH is characterized by sinusoidal dilation, replacement of hepatocytes with red blood cells extravasating from the sinusoids, and necrosis/apoptosis of zone 3 of the Rappaport acinus, and it could progress to cirrhosis in advanced cases. In ACLI, however, massive necrosis of zone 3 is the main histological finding. Primary laboratory findings of CH are elevated serum cholestasis markers including bilirubin, alkaline phosphatase, and gamma-glutamyl-transpeptidase levels, whereas those of ACLI are a striking elevation in transaminase and lactate dehydrogenase levels. Both CH and ACLI have a prognostic value for identifying cardiovascular events and mortality and have some special implications in the management of patients undergoing ventricular assist device implantation or cardiac transplantation. There is no specific treatment for CH or ACLI other than treatment of the underlying cardiac disorder. PMID- 26006192 TI - New modalities in the treatment of HCV in pre and post - transplantation setting. AB - End-stage liver disease and hepatocellular carcinoma (HCC) secondary to hepatitis C virus (HCV) infection are the leading indications for liver transplantation (LT) in developed countries. Recurrence of HCV following LT is universal if the recipient has detectable serum HCV RNA at the time of LT. Recurrent HCV has an accelerated course and is associated with poor long term patient and graft survival. Interferon (IFN)-based regimens have achieved low Sustained Virological Rates (SVR) in this setting and are associated with a high rate of adverse events, resulting in treatment discontinuation. With advances in understanding the HCV life cycle, drugs targeting specific steps, particularly inhibiting the NS3/4A protease, NS5B RNA dependent RNA polymerase and the NS5A protein, have been developed. Sofosbuvir (SOF), a nucleotide analogue inhibitor of NS5B polymerase was the first compound to enter the market. Combinations of SOF with new HCV antivirals from other classes have allowed for IFN-free regimens with low rates of adverse events and SVR rates >90%. With the availability of newer agents, the approach to the treatment of HCV infection during the pre-and post liver transplantation period has changed. We will hereby review the current status of HCV treatment and discuss the potential future therapies in the transplant setting. PMID- 26006193 TI - Prevalence of Barrett's esophagus in Lebanon. AB - BACKGROUND/AIMS: To determine the prevalence of Barrett's Esophagus (BE) in a tertiary care center in Lebanon and to compare IT with regional and global data. MATERIALS AND METHODS: All esophagogastroduodenoscopies (EGDs) performed between January 2003 and October 2013 at the American University of Beirut Medical Center (AUBMC) were reviewed, and cases of endoscopically suspected esophageal metaplasia (ESEM) were identified. Definite BE was considered only if histologically proven intestinal metaplasia was present. RESULTS: Totally, 16,787 patients underwent EGD; 219 patients (1.3%) were labeled as having ESEM. Only 41 patients had biopsyproven BE (18.7% of ESEM and 0.24% of total patients). The mean age of the patients with BE was 58.1 years [Standard deviation (SD) =13.7] and 78% were men. Of the 41 patients, 14 (34.1%) had long-segment BE (LSBE) (>3 cm) while 27 had short segment Barrett's Esophagus (SSBE) (<=3 cm). Hiatal hernia was identified in 54% of the patients, more commonly in those with LSBE. Only four patients had low-grade dysplasia, and none had high-grade dysplasia. CONCLUSION: The prevalence of BE in Lebanon is much lower than that in Western countries. The reasons for this East-West divide are unknown and require further investigation. PMID- 26006194 TI - The last innovation in achalasia treatment; per-oral endoscopic myotomy. AB - BACKGROUND/AIMS: Per-oral endoscopic myotomy (POEM) is a minimally invasive endoscopic treatment option for patients with achalasia and has been performed since 2010. It is less invasive than Heller myotomy and its use is spreading rapidly worldwide. We present our results of POEM that, to the best of our knowledge, are the first cases in Turkey. MATERIALS AND METHODS: We enrolled patients between May 2014 and September 2014; 8 patients with achalasia whose complaints recurred after pneumatic balloon dilatation underwent POEM. The procedure was performed under general anesthesia at the endoscopy unit of the gastroenterology clinic. Demographic data was recorded before the procedure, and the results of the procedure were recorded prospectively. RESULTS: The median age of the patients was 42.5 (30-72) years. Preoperative and postoperative median Eckardt scores were 10 (8-12) and 1 (0-2), respectively. The median total duration of the procedure was 101 (71-158) min, and the median myotomy length was 13.5 (10-16) cm. Postoperative oral intake started on median day 1 (1-2) and the length of hospital stay was 4 (3-6) days. In 2 patients, capnoperitoneum developed during the procedure and was treated with a Veress needle. CONCLUSION: POEM is a safe endoscopic treatment modality for patients with achalasia in centers that are experienced in advanced endoscopic techniques. PMID- 26006195 TI - Lidocaine versus lidocaine plus benzydamine as a topical anesthesia regimen for unsedated upper gastrointestinal endoscopy: A comparison study. AB - BACKGROUND/AIMS: The aim was to assess the efficacy of adding benzydamine (B) spray to standard treatment with a lidocaine (L) spray before upper gastrointestinal endoscopy (UGE) as a topical anaesthetic regimen. MATERIALS AND METHODS: A total of 118 adult patients undergoing outpatient UGE were randomly assigned to receive L (n=44), LB (n=38) or B (n=36) before the procedure. The primary outcome was the patient tolerance score, which represents a summative evaluation of the taste of the anesthetic agent, the intensity of pharyngeal numbness, the amount of coughing or gagging and the degree of discomfort during oesophageal intubation. RESULTS: The median (min-max) patient tolerance scores were comparable between groups LB (10.5; range 5-12) and L (10; range 4-13) (p=0.235) and significantly lower in group B (7.5; range 3-12) (p<0.01). LB improved several secondary outcomes. Oesophageal intubation was less difficult (5 [range 2-10] vs 3 [range 0-8], p<0.001), and a lower proportion of patients developed postprocedural sore throat (4 [10.5%] vs 15 [34.1%], p=0.011) in LB compared to L. CONCLUSION: LB is not superior to L in terms of overall patient tolerance, but LB may be preferred over L in cases with difficult oesophageal intubation or a previous history of postprocedural sore throat. PMID- 26006196 TI - The importance of upper gastrointestinal endoscopy in morbidly obese patients. AB - BACKGROUND/AIMS: Obesity is an epidemic and its prevalence and number of patients underwent bariatric surgery continue to increase worldwide. This study aimed to evaluate endoscopic findings and co-morbidities, to investigate the prevalence of Helicobacter pylori (H. pylori) infection and the relationship between body mass index (BMI) and gastroesophageal sphincter incompetency in obese patients. MATERIALS AND METHODS: An upper gastrointestinal system endoscopy and mucosal sampling were performed in all patients hospitalized for bariatric surgery. Age, gender, BMI, co-morbidities and endoscopic findings were recorded. Gastroesophageal sphincter incompetency was classified according to Hill classification. The patients were divided into two groups: group I, endoscopically normal and group II, endoscopically abnormal. RESULTS: Total 127 patients were enrolled into prospective study. Of these, 93 (%73.2) were female and the mean age was 38.9+/-12.5 years (range: 16-68). Abnormal endoscopic findings and H. pylori were detected in 80.4% and 44.9% of patients, respectively. In group II, patients were older, BMI higher and H. pylori more prevalent (all statistically significant). Diabetes mellitus, hypertension and dyslipidemia were the most frequent common co-morbidities. Rate of multiple co morbidities were more common in group II. Gastroesophageal sphincter incompetency in total group was observed in a rate of 46.5% and was weakly correlated with BMI. CONCLUSION: Four-fifths of obese patients have at least one endoscopic abnormal finding, three fourth at least one co-morbidity and half H. pylori positivity. Upper gastrointestinal system endoscopy should be performed routinely in all patients to predict and prevent complications following bariatric surgery. PMID- 26006197 TI - Comparison of one and two-day bowel preparation with polyethylene glycol in pediatric colonoscopy. AB - BACKGROUND/AIMS: Proper colon preparation in children has been a challenge for many years. Different regimens have been used for this purpose, but the best regimen is not determined. The aim of this study was to evaluate successful colon preparation before colonoscopy in children who were treated with one- or two-day regimen with polyethylene glycol (PEG) plus bisacodyl and clear liquids. MATERIALS AND METHODS: In this randomized clinical trial, 100 children (2-14 years old) who were candidates for colonoscopy were enrolled and divided into two groups. The children in group one were started on 2 g/kg PEG powder (17 g in 240 mL water or another beverage) and 5 mg bisacodyl suppository (BD) the day before colonoscopy, whereas those in the other group were started on 1.5 g/kg PEG with fruit juices for two days and 5 mg bisacodyl suppository (BD) for two days before colonoscopy. RESULTS: Compliance rates, regimens, adverse effects, and complete colonoscopy were not significantly different between the two groups. The Boston score was excellent and good in 70% of group one and 72% of group two children, respectively. Compliance rate, adverse effects, and need for enema were similar in both groups. The rate of compliance and non-requirement of enema were significantly higher in children with satisfactory colon preparation. CONCLUSION: The one-day PEG plus bisacodyl regimen for bowel preparation is as effective as the two-day regimen in children; furthermore, it is well tolerated and has low adverse effects. PMID- 26006199 TI - Genotype-phenotype relationship in Iranian patients with cystic fibrosis. AB - BACKGROUND/AIMS: Cystic fibrosis (CF), the most common hereditary, life threatening disease, is caused by a mutation in the CFTR gene. Because different mutations can affect clinical manifestations of patients, this study was conducted to investigate the possible genotype-phenotype relationship in a group of Iranian patients with CF. MATERIALS AND METHODS: This case-series study was conducted in 30 patients with CF who were referred to a tertiary pediatric hospital in Tehran. In this study, the DNA of the patients was evaluated for delta F508 mutation, whereas some parameters such as the age at diagnosis, the sweat chloride level, and clinical manifestations related to pancreatic insufficiency and pulmonary involvement were also assessed. RESULTS: Among all the studied patients, 16.6% had a delta F508 mutation, either homozygote or heterozygote. The mean age at diagnosis was lower in patients with the delta F508 mutation, but the sweat chloride level tended to be higher in these patients. All the patients with the delta F508 mutation had exocrine pancreatic insufficiency, which tended to be higher than 84% in those without this mutation. In addition, all of these patients had pulmonary involvement, which tended to be higher than 64% in those with negative delta F508 mutation. CONCLUSION: According to the results of this study, the frequency of delta F508 mutations in Iranian patients appears to be much lower than what is seen in American and the European patients. In those with the delta F508 mutation, pulmonary involvement and pancreatic insufficiency are more common; the sweat chloride level tended to be higher, but the age at diagnosis was lower, all of which resemble a more severe form of disease. PMID- 26006198 TI - Rectal indomethacin for the prevention of post-ERCP pancreatitis: A meta-analysis of randomized controlled trials. AB - BACKGROUND/AIMS: This meta-analysis was undertaken to evaluate the effect of rectal indomethacin in the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. MATERIALS AND METHODS: Major databases including Embase, Medline, Science Citation Index Expanded, Pubmed and the Cochrane Central Register of Controlled Trials, were searched to identify all relevant studies from January 1960 to July 2013. Randomized controlled trials (RCTs) comparing prophylactic use of rectal indomethacin versus placebo were included. Risk ratio (RR) with 95% confidence interval (CI) was calculated using fixed- or random-effect models. RESULTS: Three studies met the inclusion criteria and were included in the final analyses. The overall incidence of post-ERCP pancreatitis (PEP) was significantly decreased by prophylactic rectal indomethacin compared with the placebo (RR=0.51; 95% CI=0.37-0.70). The pooled incidence of moderate to severe pancreatitis was also decreased by rectal indomethacin prophylaxis (RR=0.43; 95% CI=0.23-0.80). CONCLUSION: Rectal indomethacin can reduce the overall incidence and the severity of PEP. PMID- 26006200 TI - Efficacy of autologous mesenchymal stem cell transplantation in patients with liver cirrhosis. AB - BACKGROUND/AIMS: Because of several limitations and complications of liver transplantation, new alternative treatment modalities are required for patients with liver cirrhosis. Many study results encourage the use of autologous bone marrow-derived mesenchymal stem cells for liver diseases. In this study, we assessed the impact of autologous mesenchymal stem cell transplantation on liver tissue and liver chemistry. MATERIALS AND METHODS: Twenty-five patients with biopsy-proven liver cirrhosis were enrolled in the study. Patients received 1*106 autologous mesenchymal stem cells/kg via a peripheral vein. Biochemical parameters were checked monthly. Periodical radiological screening and liver biopsies before mesenchymal stem cell transplantation were performed after 6 months. Liver specimens were assessed by a pathologist. RESULTS: No side effect was observed and the mesenchymal stem cell transplantation procedure was well tolerated. Twelve patients completed the study. In 8 patients, improvements in Model for End-Stage Liver Disease (MELD) scores were observed. Serum albumin levels markedly increased in the third month. In patients with non-responder hepatitis C, HCV RNA levels both became negative after mesenchymal stem cell transplantation. Histopathological examinations of liver tissues before and at 6 months after transplantation revealed no change in liver tissue regeneration or fibrosis. However, in 5 patients, hepatitis activity index scores decreased. CONCLUSION: Autologous mesenchymal stem cell transplantation via peripheral vein is safe and feasible. Consecutive liver biopsy examinations suggested that mesenchymal stem cells could not reach the liver in a sufficient amount. Improvement in patients and clearance of HCV RNA may have occurred through immunomodulatory mediators secreted by transplanted mesenchymal stem cells, namely the "endocrine" effect. PMID- 26006201 TI - Low incidence of alpha-1-antitrypsin deficiency in Iranian patients with neonatal cholestasis. AB - BACKGROUND/AIMS: There is little data concerning the incidence of alpha-1 antitrypsin"(AAT) deficiency, the most common genetic cause of liver disease, among children with neonatal cholestasis in Iran. Thus, this study was performed to analyze AAT deficiency in this group of patients. MATERIALS AND METHODS: DNA samples from patients with neonatal cholestasis were investigated for Pi S and Pi Z alleles, using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Thirty patients with neonatal cholestasis were enrolled. Among those who underwent biopsies, the results revealed neonatal hepatitis in 19, bile duct paucity in 1, steatohepatitis in 1, bile duct proliferation in 1, cirrhosis in 2, fibrosis in 2, and extrahepatic biliary atresia in 1 patient. No mutant allele was found in any patient. CONCLUSION: The incidence of AAT deficiency is very low in Iran; therefore, screening for AAT is not recommended for patients with neonatal cholestasis in Iran. PMID- 26006202 TI - Autonomic neuropathy and gallbladder motility in patients with liver cirrhosis. AB - BACKGROUND/AIMS: Impaired gallbladder motility has been suggested as a contributor to increased incidence of gallstones in patients with liver cirrhosis. The purpose of this study was to determine gallbladder function and its relation with autonomic neuropathy in liver cirrhosis. MATERIALS AND METHODS: Gallbladder function was measured using ultrasonography in 48 patients with liver cirrhosis and in 31 controls. Autonomic neuropathy tests were applied in patients with liver cirrhosis. Patients with liver cirrhosis were analyzed in subgroups according to the severity of disease using the Child-Pugh classification. RESULTS: Fasting gallbladder volume was 16.2 mL (range: 2.1 mL-71.9 mL) in patients and 17.6 mL (range: 4.9 mL-76.6 mL) in controls. There were no differences in fasting gallbladder volume among the study groups (p>0.05). Gallbladder ejection fraction was significantly higher in patients compared with controls (84% vs. 65%) (p<0.001). No correlation was found between gallbladder ejection fraction and autonomic neuropathy (p>0.05). CONCLUSION: Our results indicate that liver cirrhosis does not impair gallbladder emptying, and that there is no association between gallbladder motility and autonomic neuropathy. Further investigations are required to explain increased gallbladder motility in liver cirrhosis. PMID- 26006203 TI - Seroprevalence of human fascioliasis in Van province, Turkey. AB - BACKGROUND/AIMS: Fasciola hepatica is a rare zoonotic parasite that infects the liver of many mammals including humans. The aim of this study was to determine the seroprevalence of fascioliasis in Van province by ELISA (antibody detection) on the assumption that not all cases could be detected by stool examination alone. MATERIALS AND METHODS: A total of randomly selected 1,600 patients, directed from affiliated outpatient clinics to Yuzuncu Yil University Medical Faculty Parasitology Laboratory, were enrolled in the study. Their mean age was 44.44+/-19.00 years. Blood samples were collected from all the patients, and their stool samples were examined. For the stool examination, native-lugol and sedimentation (in formalin-ethyl acetate) methods were employed. ELISA for F. hepatica was performed on the blood samples from all patients. Seropositive patients were treated with triclabendazole. RESULTS: F. hepatica was detected by ELISA in 89 (5.6%) of the 1,600 patients, but eggs were identified on the stool examination in only 29 (1.8%) patients. The prevalence of F. hepatica was higher in females (7.2%) than in males (4.2%) and was higher in the >=36-year age group (6.7%) than in the <=35-year age group (4.4%). Abdominal pain (93.3%), fatigue (88.8%), and weight loss (69.7%) were the most common symptoms. Eosinophilia was present in 89.9% of the patients. All seropositive patients had a history of eating raw aquatic plants. CONCLUSION: Stool examination alone is not sufficient to diagnose F. hepatica. Serological tests such as ELISA must be used together with stool examination. PMID- 26006204 TI - A comparative analysis of colonoscopy findings in a Chinese and American tertiary hospital. AB - BACKGROUND/AIMS: To compare the colonoscopy findings of a tertiary Chinese hospital with those of an American tertiary hospital. MATERIALS AND METHODS: Hundred consecutive colonoscopies performed in August 2008 at the First Affiliated Hospital of Nanchang University in China and at the Emory University Hospital, United States of America, were investigated. The endoscopic findings and the histopathology results were statistically compared. RESULTS: The average age of Chinese patients who underwent colonoscopy in this study was 45.23+/-15.38 years, whereas that of American patients was 55.38+/-12.11 years; no difference in sex ratio was observed (p=0.202) between the two populations. Screening colonoscopy accounted for 38% of patients in the American group and zero patients in the Chinese group. Polyps and diverticula were the most common findings in both groups. Abnormal findings in the American patients were three times higher than those in the Chinese patients. Proximal colon polyps were more common in the American group. Conversely, proximal colon diverticula were more common in the Chinese group. The prevalence of non-neoplasm lesions was not different between the two groups (p=0.232); the prevalence of adenomas significantly increased in patients who were more than 50 years old in both groups and was higher in the American group (p=0.038). CONCLUSION: The prevalence of bowel diseases in American patients was higher than that in Chinese patients. Polyps and diverticula were the main bowel abnormalities in both groups. Chinese patients lacked awareness of colonoscopy screening and should be enhanced aged 50 years old or older, because the prevalence of advanced neoplasia was increased in this age group in both groups. PMID- 26006205 TI - Intrapancreatic pseudoaneurysm causing massive gastrointestinal hemorrhage and chronic pancreatitis. AB - Pseudoaneurysms of the splenic artery is a well-known complication of pancreatitis. However, to the best of our knowledge, a subcentimetric intrapancreatic pseudoaneurysm (without an associated pseudocyst) causing massive gastrointestinal bleeding and distal main pancreatic duct obstruction is a rare clinical phenomenon. Herein, we present such a unique complication with computed tomography images and subsequent successful endovascular treatment. PMID- 26006206 TI - Effectiveness of extracorporeal shock wave lithotripsy on intrahepatic biliary calculi developing after choledochal cyst surgery: A case report. AB - The development of intra- and extrahepatic bile duct stones has been reported as one of the most serious complications after choledochal cyst excision with biliary-enteric reconstruction through Roux-en-Y hepaticojejunostomy (HJ). Here, we report our experience with extracorporeal shock wave lithotripsy (ESWL) in a case of giant intrahepatic stones developing after choledochal cyst surgery. ESWL is an excellent therapeutic modality for large intrahepatic biliary calculi, and after dilating the HJ anastomosis percutaneously, it can be offered as first-line therapy to these patients. PMID- 26006207 TI - A rare case of a heavily calcified gastrointestinal stromal tumors with an intraluminal growth pattern. PMID- 26006208 TI - Crohn's disease presenting as multiple pulmonary nodules in FDG PET/CT scan. PMID- 26006209 TI - Cecocolic intussusception in a patient with a cecal duplication cyst. PMID- 26006210 TI - Development of hypocalcemia with telaprevir-based triple treatment in a case of genotype 1 chronic hepatitis C. PMID- 26006211 TI - Biliopleural fistula of a large retroperitoneal hydatid cyst. PMID- 26006212 TI - Eosinophilic gastroenteritis as an unusual manifestation of multiple mesenteric lymph node enlargements and recurrent diarrheas. PMID- 26006213 TI - EGJ outflow obstruction must be excluded in patients with high IRP and weak peristalsis. PMID- 26006214 TI - Olanzapine-induced acute pancreatitis. PMID- 26006215 TI - Retraction: Fatty liver disease might increase the risk of abdominal operation in patients with fatty liver and the prevalence of cancer in first degree relatives. AB - [This corrects the article DOI: 10.5152/tjg.2014.7674.]. PMID- 26006217 TI - Current controversies over bioresorbable scaffolds. AB - The field of coronary intervention has made great strides since the first balloon angioplasty performed by Andreas Gruentzig in Zurich in 1977.1 Starting with that case, coronary interventional data has been rigorously generated through single center and multicenter registries and randomized trials, allowing for remarkably broad-sweeping, evidence-based, leapfrog improvements in technology and outcomes in just a few decades. In this paper we outline the natural evolution from "plain old balloon angioplasty" (POBA) to bioresorbable scaffolds (BRS) and other novel therapies, and discuss the emerging data regarding the promise of BRS as well as controversies and residual concerns regarding this technology. PMID- 26006216 TI - High intensity focused ultrasound ablation for atrial fibrillation: results from the National Spanish Registry. AB - BACKGROUND: A National Spanish Registry to compile all patients treated with high intensity focused ultrasound (HIFU) energy for atrial fibrillation (AF) was created to evaluate the safety and efficacy of AF surgical ablation. METHODS: A national Spanish registry was created, and ten hospitals using HIFU to ablate AF joined it. A total of 412 patients undergoing cardiac surgery between 2006 and February 2013 were included. AF was divided between paroxysmal AF (33%) and persistent AF (67%) with a mean AF duration of 29.3+/-108.2 months. Mean left atrial diameter was 51.2+/-6.5 mm. Mean underlying heart disease were aortic valve disease (49.3%), ischemic disease (25.2%) and mitral disease (33.2%) Clinical follow-up of patients and a 6 months postoperative echocardiogram were performed in all patients. RESULTS: A pacemaker implantation was needed in 4.9% of patients with a perioperative stroke in 2.5%. Rhythm at discharge from hospital was sinus rhythm in 58%, AF in 35.9% and atrial flutter in 0.8% of patients. Sinus rhythm restoration at 6, 12, 24 and 36 months follow-up was achieved in 66.1%, 63.8%, 63.9% and 45.9% of patients respectively. Multivariate analysis showed paroxysmal AF and sinus rhythm restoration in the operating theatre as factors related to sinus rhythm long term restoration. CONCLUSIONS: The Spanish national registry showed an efficacy of AF ablation with the HIFU Epicor system of 66.1%, 63.8%, 63.9% and 45.9% at 6, 12, 24 and 36 months follow up. There were no device-related complications. PMID- 26006218 TI - Prospective multicenter cohort study of estrogen and insulin-like growth factor system in BRCA mutation carriers. AB - PURPOSE: Major clinical characteristics of BRCA1/2-related cancers include association with estrogen and metabolic consequences. We aimed to evaluate serum estradiol (E2) and insulin-like growth factor 1 (IGF-1) levels as a marker of insulin resistance in BRCA1/2 mutation carriers and high-risk, BRCA-negative controls. METHODS: Eligible cancer-free women (age 18-42 with regular menstrual cycles) who had been screened for BRCA1/2 mutations between 2005 and 2013 completed a questionnaire and underwent a single blood draw. E2 was measured with radioimmunoassay, and IGF-1 was measured with enzyme-linked immunosorbent assay. RESULTS: Eighty-six women participated (44 carriers and 42 non-carriers) in this study. BRCA mutation carriers were significantly younger than non-carriers (p = 0.0002). Age-adjusted basal (menstrual cycle days 2-5) serum E2 level was not significantly different between BRCA mutation carriers and non-carriers (30.4 vs. 24.7 pg/mL, p = 0.07). BRCA mutation carriers have significantly lower age adjusted serum IGF-1 levels compared to non-carriers (89.7 vs. 112.6 ng/mL, p < 0.001). In women with BRCA mutations, the risk of having low serum IGF-1 level (IGF-1: <=85 ng/mL) was 10.7 times as great as that of women without BRCA mutations (95 % CI 2.5, 46.2). There was a significant inverse association between basal E2 and IGF-1 levels in BRCA mutation carriers after adjusting age and BMI (p = 0.03). CONCLUSIONS: IGF-1 level is significantly lower in cancer free BRCA mutation carriers versus BRCA-negative controls, and there is a potential association between E2 and IGF-1 in cancer-free BRCA mutation carriers. Our findings may instigate future studies evaluating the role of both E2 and IGF 1 in BRCA mutation carriers. PMID- 26006219 TI - Withaferin A Analogs That Target the AAA+ Chaperone p97. AB - Understanding the mode of action (MOA) of many natural products can be puzzling with mechanistic clues that seem to lack a common thread. One such puzzle lies in the evaluation of the antitumor properties of the natural product withaferin A (WFA). A variety of seemingly unrelated pathways have been identified to explain its activity, suggesting a lack of selectivity. We now show that WFA acts as an inhibitor of the chaperone, p97, both in vitro and in cell models in addition to inhibiting the proteasome in vitro. Through medicinal chemistry, we have refined the activity of WFA toward p97 and away from the proteasome. Subsequent studies indicated that these WFA analogs retained p97 activity and cytostatic activity in cell models, suggesting that the modes of action reported for WFA could be connected by proteostasis modulation. Through this endeavor, we highlight how the parallel integration of medicinal chemistry with chemical biology offers a potent solution to one of natures' intriguing molecular puzzles. PMID- 26006221 TI - Resprout and Survival of Willow (Salix) Cuttings on Bioengineering Structures in Actively Eroding Gullies in Marls in a Mountainous Mediterranean Climate: A Large Scale Experiment in the Francon Catchment (Southern Alps, France). AB - Improving the understanding of the role of vegetation and bioengineering structures on erosion and sedimentation control, especially in torrent-prone catchments in a mountainous Mediterranean climate, has become a key issue today for the scientific community working in ecological engineering and restoration ecology. The objective of this study was to evaluate the performance of willow (Salix) cuttings in resprouting and survival on bioengineering structures in actively eroding gullies in marls and to identify the factors influencing this performance. Measurements were taken from 2008 to 2011 on 336 bioengineering structures, namely brush layers on wooden sills (BL) and brush layers with brush mats on wooden sills (BLM), using 8890 cuttings of Salix purpurea and Salix incana. These structures were built in 18 gullies of the Francon Catchment in marls (73 ha) in the Southern French Alps. After four growing seasons, the results revealed a total cutting survival rate of 45%. They also demonstrated that in BLM, brush mats provided better survival (56%) than brush layers (37%). In BL, brush layers alone showed 51% cutting survival. Cutting resprout and survival were observed for all structure aspects. They were positively related to increasing gully size and vegetation cover on gully sides. The results of this large-scale experiment clarified previous data obtained on a limited sample of bioengineering structures, providing further detail and showing that it is possible to use such structures made of willow cuttings to revegetate actively eroding gullies in marls within a mountainous Mediterranean climate. PMID- 26006220 TI - Biogeochemical Research Priorities for Sustainable Biofuel and Bioenergy Feedstock Production in the Americas. AB - Rapid expansion in biomass production for biofuels and bioenergy in the Americas is increasing demand on the ecosystem resources required to sustain soil and site productivity. We review the current state of knowledge and highlight gaps in research on biogeochemical processes and ecosystem sustainability related to biomass production. Biomass production systems incrementally remove greater quantities of organic matter, which in turn affects soil organic matter and associated carbon and nutrient storage (and hence long-term soil productivity) and off-site impacts. While these consequences have been extensively studied for some crops and sites, the ongoing and impending impacts of biomass removal require management strategies for ensuring that soil properties and functions are sustained for all combinations of crops, soils, sites, climates, and management systems, and that impacts of biomass management (including off-site impacts) are environmentally acceptable. In a changing global environment, knowledge of cumulative impacts will also become increasingly important. Long-term experiments are essential for key crops, soils, and management systems because short-term results do not necessarily reflect long-term impacts, although improved modeling capability may help to predict these impacts. Identification and validation of soil sustainability indicators for both site prescriptions and spatial applications would better inform commercial and policy decisions. In an increasingly inter-related but constrained global context, researchers should engage across inter-disciplinary, inter-agency, and international lines to better ensure the long-term soil productivity across a range of scales, from site to landscape. PMID- 26006222 TI - Effect of mini-dose epidural dexmedetomidine in elective cesarean section using combined spinal-epidural anesthesia: a randomized double-blinded controlled study. AB - BACKGROUND: Combined spinal-epidural anesthesia is commonly used for elective cesarean section. Our study aimed to evaluate the effect of adding dexmedetomidine to epidural bupivacaine and fentanyl in patients undergoing elective cesarean section using combined spinal-epidural anesthesia. METHODS: Eighty healthy women at term were randomly assigned to two groups: a control group (n = 40; "Bup/Fen group") received combined spinal-epidural anesthesia with intrathecal hyperbaric bupivacaine 5 mg and an epidural mixture of 10 mL plain bupivacaine 0.25 % and fentanyl 50 MUg, whereas the study group (n = 40; "Dex/Bup/Fen group") received 1 mL epidural dexmedetomidine 0.5 ug/kg in addition. The primary outcome measure was the difference between the groups in the supplementary fentanyl analgesic required. The quality of surgical anesthesia, incidences of hypotension and bradycardia, APGAR scores, intraoperative pain assessment, and onset of postoperative pain, sedation score, and side effects were recorded. RESULTS: There was no statistically significant difference between the groups regarding block characteristics. Significantly less intraoperative and postoperative fentanyl were required by the Dex/Bup/Fen group (P = 0.015 and P = 0.0011, respectively). There was no statistically significant difference between the groups regarding sedation score or the incidences of hypotension, nausea and vomiting, dizziness, and pruritus. CONCLUSIONS: The addition of mini-dose epidural dexmedetomidine 0.5 ug/kg as a single injection to bupivacaine fentanyl in women undergoing elective cesarean section with combined spinal-epidural anesthesia improved intraoperative conditions and the quality of postoperative analgesia. PMID- 26006223 TI - Manadodioxans A-E: polyketide endoperoxides from the marine sponge Plakortis bergquistae. AB - Five new polyketide endoperoxides, manadodioxans A-E, were isolated from the marine sponge Plakortis bergquistae. Manadodioxan E showed antimicrobial activity against Escherichia coli at 10 MUg/disk, while its oxo congener, manadodioxan D, was inactive. PMID- 26006224 TI - Chitosan Oligosaccharides Inhibit/Disaggregate Fibrils and Attenuate Amyloid beta Mediated Neurotoxicity. AB - Alzheimer's disease (AD) is characterized by a large number of amyloid-beta (Abeta) deposits in the brain. Therefore, inhibiting Abeta aggregation or destabilizing preformed aggregates could be a promising therapeutic target for halting/slowing the progression of AD. Chitosan oligosaccharides (COS) have previously been reported to exhibit antioxidant and neuroprotective effects. Recent study shows that COS could markedly decrease oligomeric Abeta-induced neurotoxicity and oxidative stress in rat hippocampal neurons. However, the potential mechanism that COS reduce Abeta-mediated neurotoxicity remains unclear. In the present study, our findings from circular dichroism spectroscopy, transmission electron microscope and thioflavin T fluorescence assay suggested that COS act as an inhibitor of Abeta aggregation and this effect shows dose dependency. Moreover, data from thioflavin T assay indicated that COS could significantly inhibit fibrils formation and disrupt preformed fibrils in a dose dependent manner. Furthermore, the addition of COS attenuated Abeta1-42-induced neurotoxicity in rat cortical neurons. Taken together, our results demonstrated for the first time that COS could inhibit Abeta1-42 fibrils formation and disaggregate preformed fibrils, suggesting that COS may have anti-Abeta fibrillogenesis and fibril-destabilizing properties. These findings highlight the potential role of COS as novel therapeutic agents for the prevention and treatment of AD. PMID- 26006225 TI - Cyanobacterial hydrogenases and hydrogen metabolism revisited: recent progress and future prospects. AB - Cyanobacteria have garnered interest as potential cell factories for hydrogen production. In conjunction with photosynthesis, these organisms can utilize inexpensive inorganic substrates and solar energy for simultaneous biosynthesis and hydrogen evolution. However, the hydrogen yield associated with these organisms remains far too low to compete with the existing chemical processes. Our limited understanding of the cellular hydrogen production pathway is a primary setback in the potential scale-up of this process. In this regard, the present review discusses the recent insight around ferredoxin/flavodoxin as the likely electron donor to the bidirectional Hox hydrogenase instead of the generally accepted NAD(P)H. This may have far reaching implications in powering solar driven hydrogen production. However, it is evident that a successful hydrogen-producing candidate would likely integrate enzymatic traits from different species. Engineering the [NiFe] hydrogenases for optimal catalytic efficiency or expression of a high turnover [FeFe] hydrogenase in these photo autotrophs may facilitate the development of strains to reach target levels of biohydrogen production in cyanobacteria. The fundamental advancements achieved in these fields are also summarized in this review. PMID- 26006226 TI - Removal of toxic mercury from petroleum oil by newly synthesized molecularly imprinted polymer. AB - In recent years, molecularly-imprinted polymers (MIPs) have attracted the attention of several researchers due to their capability for molecular recognition, easiness of preparation, stability and cost-effective production. By taking advantage of these facts, Hg(II) imprinted and non-imprinted copolymers were prepared by polymerizing mercury nitrate stock solution (or without it) with methacrylic acid (MAA), 2-hydroxyl ethyl methacrylate (HEMA), methanol and ethylene glycol dimethacrylate (EGDMA) as the monomer, co-monomer solvent (porogen) and cross-linker, respectively. Thus, the formed Hg(II) imprinted polymer was characterized by using Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscopy (FESEM), Brunauer, Emmett and Teller (BET) and thermal gravimetric analysis (TGA). The separation and preconcentration characteristics of Hg(II) imprinted polymer were investigated by solid phase extraction (SPE) procedures, and an optimal pH of 7 was investigated as ideal. The specific surface area of the Hg(II) imprinted polymer was found to be 19.45 m2/g with a size range from 100 to 140 um in diameter. The maximum adsorption capacity was observed to be 1.11 mg/g of Hg(II) imprinted beads with 87.54% removal of Hg(II) ions within the first 5 min. The results of the study therefore confirm that the Hg(II) imprinted polymer can be used multiple times without significantly losing its adsorption capacity. PMID- 26006227 TI - Encapsulated cellular implants for recombinant protein delivery and therapeutic modulation of the immune system. AB - Ex vivo gene therapy using retrievable encapsulated cellular implants is an effective strategy for the local and/or chronic delivery of therapeutic proteins. In particular, it is considered an innovative approach to modulate the activity of the immune system. Two recently proposed therapeutic schemes using genetically engineered encapsulated cells are discussed here: the chronic administration of monoclonal antibodies for passive immunization against neurodegenerative diseases and the local delivery of a cytokine as an adjuvant for anti-cancer vaccines. PMID- 26006228 TI - Calculated third order rate constants for interpreting the mechanisms of hydrolyses of chloroformates, carboxylic Acid halides, sulfonyl chlorides and phosphorochloridates. AB - Hydrolyses of acid derivatives (e.g., carboxylic acid chlorides and fluorides, fluoro- and chloroformates, sulfonyl chlorides, phosphorochloridates, anhydrides) exhibit pseudo-first order kinetics. Reaction mechanisms vary from those involving a cationic intermediate (SN1) to concerted SN2 processes, and further to third order reactions, in which one solvent molecule acts as the attacking nucleophile and a second molecule acts as a general base catalyst. A unified framework is discussed, in which there are two reaction channels-an SN1-SN2 spectrum and an SN2-SN3 spectrum. Third order rate constants (k3) are calculated for solvolytic reactions in a wide range of compositions of acetone-water mixtures, and are shown to be either approximately constant or correlated with the Grunwald-Winstein Y parameter. These data and kinetic solvent isotope effects, provide the experimental evidence for the SN2-SN3 spectrum (e.g., for chloro- and fluoroformates, chloroacetyl chloride, p-nitrobenzoyl p toluenesulfonate, sulfonyl chlorides). Deviations from linearity lead to U- or V shaped plots, which assist in the identification of the point at which the reaction channel changes from SN2-SN3 to SN1-SN2 (e.g., for benzoyl chloride). PMID- 26006229 TI - Potential role of thymosin Beta 4 in liver fibrosis. AB - Liver fibrosis, the main characteristic of chronic liver diseases, is strongly associated with the activation of hepatic stellate cells (HSCs), which are responsible for extracellular matrix production. As such, investigating the effective regulators controlling HSC activation provides important clues for developing therapeutics to inhibit liver fibrosis. Thymosin beta 4 (Tbeta4), a major actin-sequestering protein, is known to be involved in various cellular responses. A growing body of evidence suggests that Tbeta4 has a potential role in the pathogenesis of liver fibrosis and that it is especially associated with the activation of HSCs. However, it remains unclear whether Tbeta4 promotes or suppresses the activation of HSCs. Herein, we review the potential role of Tbeta4 in liver fibrosis by describing the effects of exogenous and endogenous Tbeta4, and we discuss the possible signaling pathway regulated by Tbeta4. Exogenous Tbeta4 reduces liver fibrosis by inhibiting the proliferation and migration of HSCs. Tbeta4 is expressed endogenously in the activated HSCs, but this endogenous Tbeta4 displays opposite effects in HSC activation, either as an activator or an inhibitor. Although the role of Tbeta4 has not been established, it is apparent that Tbeta4 influences HSC activation, suggesting that Tbeta4 is a potential therapeutic target for treating liver diseases. PMID- 26006230 TI - MicroRNA-27a-3p Inhibits Melanogenesis in Mouse Skin Melanocytes by Targeting Wnt3a. AB - MicroRNAs (miRNAs) play an essential role in the regulation of almost all the biological processes, including melanogenesis. MiR-27a-3p is nearly six times higher in white alpaca skin compared to brown skin, which indicates that miR-27a 3p may be a candidate regulator for melanogenesis. Wnt3a plays an important role in promoting melanoblasts to differentiate into melanocytes and melanogenesis. To confirm the function of miR-27a-3p to melanogenesis in mammals, miR-27a-3p mimic, inhibitor and their negative control were transfected into mouse melanocytes. As a result, miR-27a-3p inhibits melanogenesis by repressing Wnt3a at post transcriptional level. A significant decrease in Wnt3a luciferase activity was observed in 293T cells co-transfected with the matched luciferase reporter vector and pre-miR-27a. Furthermore, the presence of exogenous miR-27a-3p significantly decreased Wnt3a protein expression rather than mRNA and reduced beta-catenin mRNA levels in melanocytes. The over-expression of miR-27a-3p significantly increased the melanin content of melanocytes. However, miR-27a-3p inhibitor performs an opposite effect on melanogenesis. Wnt3a is one target of miR-27a-3p. MiR-27a-3p could inhibit Wnt3a protein amount by post-transcriptional regulation and melanogenesis in mouse melanocytes. Previous studies reported that Wnt3a promoted melanogenensis in mouse melanocytes. Thus, miR-27-3p inhibits melanogenesis by repressing Wnt3a protein expression. PMID- 26006231 TI - Characterization and evaluation of neuronal trans-differentiation with electrophysiological properties of mesenchymal stem cells isolated from porcine endometrium. AB - Endometrial stromal cells (EMSCs) obtained from porcine uterus (n = 6) were positive for mesenchymal stem cell markers (CD29, CD44 and CD90), and negative for epithelial marker CD9 and hematopoietic markers CD34, CD45 analyzed by flow cytometry. Further the cells were positive for expression of mesenchymal markers, CD105, CD140b, and CD144 by PCR. Pluripotent markers OCT4, SOX2, and NANOG were positively expressed in EMSCs analyzed by Western blotting and PCR. Further, differentiation into adipocytes and osteocytes was confirmed by cytochemical staining and lineage specific gene expression by quantitative realtime-PCR. Adipocyte (FABP, LPL, AP2) and osteocyte specific genes (ON, BG, RUNX2) in differentiated EMSCs showed significant (p < 0.05) increase in expression compared to undifferentiated control cells. Neurogenic transdifferentiation of EMSCs exhibited distinctive dendritic morphology with axon projections and neuronal specific genes, NFM, NGF, MBP, NES, B3T and MAP2 and proteins, B3T, NFM, NGF, and TRKA were positively expressed in neuronal differentiated cells. Functional analysis of neuronal differentiated EMSCs displayed voltage-dependence and kinetics for transient outward K+ currents (Ito), at holding potential of -80 mV, Na+ currents and during current clamp, neuronal differentiated EMSCs was more negative than that of control EMSCs. Porcine EMSCs is a suitable model for studying molecular mechanism of transdifferentiation, assessment of electrophysiological properties and their efficiency during in vivo transplantation. PMID- 26006232 TI - Mass spectrometry-based proteomics for pre-eclampsia and preterm birth. AB - Pregnancy-related complications such as pre-eclampsia and preterm birth now represent a notable burden of adverse health. Pre-eclampsia is a hypertensive disorder unique to pregnancy. It is an important cause of maternal death worldwide and a leading cause of fetal growth restriction and iatrogenic prematurity. Fifteen million infants are born preterm each year globally, but more than one million of those do not survive their first month of life. Currently there are no predictive tests available for diagnosis of these pregnancy-related complications and the biological mechanisms of the diseases have not been fully elucidated. Mass spectrometry-based proteomics have all the necessary attributes to provide the needed breakthrough in understanding the pathophysiology of complex human diseases thorough the discovery of biomarkers. The mass spectrometry methodologies employed in the studies for pregnancy-related complications are evaluated in this article. Top-down proteomic and peptidomic profiling by laser mass spectrometry, liquid chromatography or capillary electrophoresis coupled to mass spectrometry, and bottom-up quantitative proteomics and targeted proteomics by liquid chromatography mass spectrometry have been applied to elucidate protein biomarkers and biological mechanism of pregnancy-related complications. The proteomes of serum, urine, amniotic fluid, cervical-vaginal fluid, placental tissue, and cytotrophoblastic cells have all been investigated. Numerous biomarkers or biomarker candidates that could distinguish complicated pregnancies from healthy controls have been proposed. Nevertheless, questions as to the clinically utility and the capacity to elucidate the pathogenesis of the pre-eclampsia and preterm birth remain to be answered. PMID- 26006233 TI - Prenatal exposure to lipopolysaccharide results in myocardial fibrosis in rat offspring. AB - The epigenetic plasticity hypothesis indicates that exposure during pregnancy may cause adult-onset disorders, including hypertension, myocardial infarction and heart failure. Moreover, myocardial fibrosis coincides with hypertension, myocardial infarction and heart failure. This study was designed to investigate the effects of prenatal exposure to lipopolysaccharide (LPS) on myocardial fibrosis. The result showed that at six and 16 weeks of age, the LPS-treated offspring exhibited increased collagen synthesis, an elevated cardiac index (CI), higher mRNA levels of TIMP-2 and TGFbeta and a reduced mRNA level of MMP2. The protein levels corresponded to the mRNA levels. The offspring that were prenatally treated with pyrrolidine dithiocarbamic acid (PDTC), an inhibitor of NF-kappaB, displayed improvements in the CI and in collagen synthesis. Moreover, PDTC ameliorated the expression of cytokines and proteins associated with myocardial fibrosis. The results showed that maternal inflammation can induce myocardial fibrosis in offspring during aging accompanied by an imbalance of TIMP 2/MMP2 and TGFbeta expression. PMID- 26006234 TI - Optimal Scanning Protocols for Dual-Energy CT Angiography in Peripheral Arterial Stents: An in Vitro Phantom Study. AB - OBJECTIVE: To identify the optimal dual-energy computed tomography (DECT) scanning protocol for peripheral arterial stents while achieving a low radiation dose, while still maintaining diagnostic image quality, as determined by an in vitro phantom study. METHODS: Dual-energy scans in monochromatic spectral imaging mode were performed on a peripheral arterial phantom with use of three gemstone spectral imaging (GSI) protocols, three pitch values, and four kiloelectron volts (keV) ranges. A total of 15 stents of different sizes, materials, and designs were deployed in the phantom. Image noise, the signal-to-noise ratio (SNR), different levels of adaptive statistical iterative reconstruction (ASIR), and the four levels of monochromatic energy for DECT imaging of peripheral arterial stents were measured and compared to determine the optimal protocols. RESULTS: A total of 36 scans with 180 datasets were reconstructed from a combination of different protocols. There was a significant reduction of image noise with a higher SNR from monochromatic energy images between 65 and 70 keV in all investigated preset GSI protocols (p < 0.05). In addition, significant effects were found from the main effect analysis for these factors: GSI, pitch, and keV (p = 0.001). In contrast, there was significant interaction on the unstented area between GSI and ASIR (p = 0.015) and a very high significant difference between keV and ASIR (p < 0.001). A radiation dose reduction of 50% was achieved. CONCLUSIONS: The optimal scanning protocol and energy level in the phantom study were GSI-48, pitch value 0.984, and 65 keV, which resulted in lower image noise and a lower radiation dose, but with acceptable diagnostic images. PMID- 26006235 TI - De Novo Assembly and Characterization of the Transcriptome of the Chinese Medicinal Herb, Gentiana rigescens. AB - Gentiana rigescens is an important medicinal herb in China. The main validated medicinal component gentiopicroside is synthesized in shoots, but is mainly found in the plant's roots. The gentiopicroside biosynthetic pathway and its regulatory control remain to be elucidated. Genome resources of gentian are limited. Next generation sequencing (NGS) technologies can aid in supplying global gene expression profiles. In this study we present sequence and transcript abundance data for the root and leaf transcriptome of G. rigescens, obtained using the Illumina Hiseq2000. Over fifty million clean reads were obtained from leaf and root libraries. This yields 76,717 unigenes with an average length of 753 bp. Among these, 33,855 unigenes were identified as putative homologs of annotated sequences in public protein and nucleotide databases. Digital abundance analysis identified 3306 unigenes differentially enriched between leaf and root. Unigenes found in both tissues were categorized according to their putative functional categories. Of the differentially expressed genes, over 130 were annotated as related to terpenoid biosynthesis. This work is the first study of global transcriptome analyses in gentian. These sequences and putative functional data comprise a resource for future investigation of terpenoid biosynthesis in Gentianaceae species and annotation of the gentiopicroside biosynthetic pathway and its regulatory mechanisms. PMID- 26006237 TI - Spontaneous gammaH2AX Foci in Human Solid Tumor-Derived Cell Lines in Relation to p21WAF1 and WIP1 Expression. AB - Phosphorylation of H2AX on Ser139 (gammaH2AX) after exposure to ionizing radiation produces nuclear foci that are detectable by immunofluorescence microscopy. These so-called gammaH2AX foci have been adopted as quantitative markers for DNA double-strand breaks. High numbers of spontaneous gammaH2AX foci have also been reported for some human solid tumor-derived cell lines, but the molecular mechanism(s) for this response remains elusive. Here we show that cancer cells (e.g., HCT116; MCF7) that constitutively express detectable levels of p21WAF1 (p21) exhibit low numbers of gammaH2AX foci (<3/nucleus), whereas p21 knockout cells (HCT116p21-/-) and constitutively low p21-expressing cells (e.g., MDA-MB-231) exhibit high numbers of foci (e.g., >50/nucleus), and that these foci are not associated with apoptosis. The majority (>95%) of cells within HCT116p21 /- and MDA-MB-231 cultures contain high levels of phosphorylated p53, which is localized in the nucleus. We further show an inverse relationship between gammaH2AX foci and nuclear accumulation of WIP1, an oncogenic phosphatase. Our studies suggest that: (i) p21 deficiency might provide a selective pressure for the emergence of apoptosis-resistant progeny exhibiting genomic instability, manifested as spontaneous gammaH2AX foci coupled with phosphorylation and nuclear accumulation of p53; and (ii) p21 might contribute to positive regulation of WIP1, resulting in dephosphorylation of gammaH2AX. PMID- 26006238 TI - Optimization of NaOH Molarity, LUSI Mud/Alkaline Activator, and Na2SiO3/NaOH Ratio to Produce Lightweight Aggregate-Based Geopolymer. AB - This paper presents the mechanical function and characterization of an artificial lightweight geopolymer aggregate (ALGA) using LUSI (Sidoarjo mud) and alkaline activator as source materials. LUSI stands for LU-Lumpur and SI-Sidoarjo, meaning mud from Sidoarjo which erupted near the Banjarpanji-1 exploration well in Sidoarjo, East Java, Indonesia on 27 May 2006. The effect of NaOH molarity, LUSI mud/Alkaline activator (LM/AA) ratio, and Na2SiO3/NaOH ratio to the ALGA are investigated at a sintering temperature of 950 degrees C. The results show that the optimum NaOH molarity found in this study is 12 M due to the highest strength (lowest AIV value) of 15.79% with lower water absorption and specific gravity. The optimum LUSI mud/Alkaline activator (LM/AA) ratio of 1.7 and the Na2SiO3/NaOH ratio of 0.4 gives the highest strength with AIV value of 15.42% with specific gravity of 1.10 g/cm3 and water absorption of 4.7%. The major synthesized crystalline phases were identified as sodalite, quartz and albite. Scanning Electron Microscope (SEM) image showed more complete geopolymer matrix which contributes to highest strength of ALGA produced. PMID- 26006236 TI - Vasa vasorum in atherosclerosis and clinical significance. AB - Atherosclerosis is a chronic inflammatory disease that leads to several acute cardiovascular complications with poor prognosis. For decades, the role of the adventitial vasa vasorum (VV) in the initiation and progression of atherosclerosis has received broad attention. The presence of VV neovascularization precedes the apparent symptoms of clinical atherosclerosis. VV also mediates inflammatory cell infiltration, intimal thickening, intraplaque hemorrhage, and subsequent atherothrombosis that results in stroke or myocardial infarction. Intraplaque neovessels originating from VV can be immature and hence susceptible to leakage, and are thus regarded as the leading cause of intraplaque hemorrhage. Evidence supports VV as a new surrogate target of atherosclerosis evaluation and treatment. This review provides an overview into the relationship between VV and atherosclerosis, including the anatomy and function of VV, the stimuli of VV neovascularization, and the available underlying mechanisms that lead to poor prognosis. We also summarize translational researches on VV imaging modalities and potential therapies that target VV neovascularization or its stimuli. PMID- 26006240 TI - Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy. AB - A k-nearest neighbor (k-NN) classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS)) database chemicals, employing two acute toxicity (LD50)-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL). We have successfully predicted the LOELs of 54 of 70 training set chemicals (77%) and 14 of 19 test set chemicals (74%) to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k NN model predicts LD50 classes correctly for a certain chemical, then the k analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity. PMID- 26006239 TI - The Influence of PSCA Gene Variation on Its Expression and Gastric Adenocarcinoma Susceptibility in the Northwest Chinese Population. AB - Gastric adenocarcinoma (GAC) imposes a considerable health burden around the world. Gene variation in prostate stem cell antigen gene (PSCA) has been identified to be associated with GAC risk, while the results showed regional variation. To explore the influence of PSCA gene variation on its expression and GAC risk in the Northwest Chinese population, four single nucleotide polymorphisms (SNPs) of PSCA were genotyped in 476 GAC cases and 481 controls using MassARRAY system. Two SNPs of rs2294008 (C>T) and rs2976392 (G>A) were identified to be associated with GAC risk. rs2294008, rs2976392 and rs10216533 made up two statistically significant haplotypes (Hap-CGG and Hap-TAG). Additionally, PSCA expression was analyzed by quantitative real time PCR, immunohistochemistry and tissue microarray. The results showed that PSCA expression was decreased in GAC tissues compared with adjacent normal tissues. For normal tissues, PSCA expression was higher with Hap-TA than that with Hap-CG. For GAC tissues, the differentiation degree of Hap-TA was higher than that of Hap CG. The expression distribution of PSCA in multiple human organs showed disparity. These results suggest that PSCA gene variation has a potential effect on its expression and GAC risk in the Northwest Chinese population. PMID- 26006241 TI - Genetic Variant rs10757278 on Chromosome 9p21 Contributes to Myocardial Infarction Susceptibility. AB - Large-scale genome-wide association studies (GWAS) have revealed that rs10757278 polymorphism (or its proxy rs1333049) on chromosome 9p21 is associated with myocardial infarction (MI) susceptibility in individuals of Caucasian ancestry. Following studies in other populations investigated this association. However, some of these studies reported weak or no significant association. Here, we reevaluated this association using large-scale samples by searching PubMed and Google Scholar databases. Our results showed significant association between rs10757278 polymorphism and MI with p = 6.09 * 10-22, odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.22-1.36 in pooled population. We further performed a subgroup analysis, and found significant association between rs10757278 polymorphism and MI in Asian and Caucasian populations. We identified that the association between rs10757278 polymorphism and MI did not vary substantially by excluding any one study. However, the heterogeneity among the selected studies varies substantially by excluding the study from the Pakistan population. We found even more significant association between rs10757278 polymorphism and MI in pooled population, p = 3.55 * 10-53, after excluding the study from the Pakistan population. In summary, previous studies reported weak or no significant association between rs10757278 polymorphism and MI. Interestingly, our analysis suggests that rs10757278 polymorphism is significantly associated with MI susceptibility by analyzing large-scale samples. PMID- 26006242 TI - Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats. AB - Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding) on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66) were grouped into normal diet (n = 30) and high-fat diet (n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL), malondialdehyde (MDA), 4-hydroxynonenal (HNE), the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats. PMID- 26006243 TI - MicroRNA-24 Regulates Osteogenic Differentiation via Targeting T-Cell Factor-1. AB - MicroRNAs (miRNAs) have been reported to have diverse biological roles in regulating many biological processes, including osteogenic differentiation. In the present study, we identified that miR-24 was a critical regulator during osteogenic differentiation. We found that overexpression of miR-24 significantly inhibited osteogenic differentiation, which decreased alkaline phosphatase activity, matrix mineralization and the expression of osteogenic differentiation markers. In contrast, inhibition of miR-24 exhibited an opposite effect. Furthermore, we delineated that miR-24 regulates post-transcriptionals of T-cell factor-1 (Tcf-1) via targeting the 3'-untranslated region (UTR) of Tcf-1 mRNA. MiR-24 was further found to regulate the protein expression of Tcf-1 in the murine osteoprogenitors cells and bone mesenchymal stem cells. Additionally, the positive effect of miR-24 suppression on osteoblast differentiation was apparently abrogated by Tcf-1 silencing. Taken together, our data suggest that miR-24 participates in osteogenic differentiation by targeting and regulating Tcf 1 expression in osteoblastic cells. PMID- 26006244 TI - Intravital FRET: Probing Cellular and Tissue Function in Vivo. AB - The development of intravital Forster Resonance Energy Transfer (FRET) is required to probe cellular and tissue function in the natural context: the living organism. Only in this way can biomedicine truly comprehend pathogenesis and develop effective therapeutic strategies. Here we demonstrate and discuss the advantages and pitfalls of two strategies to quantify FRET in vivo ratiometrically and time-resolved by fluorescence lifetime imaging-and show their concrete application in the context of neuroinflammation in adult mice. PMID- 26006246 TI - Aminomethylphosphonic acid and methoxyacetic acid induce apoptosis in prostate cancer cells. AB - Aminomethylphosphonic acid (AMPA) and its parent compound herbicide glyphosate are analogs to glycine, which have been reported to inhibit proliferation and promote apoptosis of cancer cells, but not normal cells. Methoxyacetic acid (MAA) is the active metabolite of ester phthalates widely used in industry as gelling, viscosity and stabilizer; its exposure is associated with developmental and reproductive toxicities in both rodents and humans. MAA has been reported to suppress prostate cancer cell growth by inducing growth arrest and apoptosis. However, it is unknown whether AMPA and MAA can inhibit cancer cell growth. In this study, we found that AMPA and MAA inhibited cell growth in prostate cancer cell lines (LNCaP, C4-2B, PC-3 and DU-145) through induction of apoptosis and cell cycle arrest at the G1 phase. Importantly, the AMPA-induced apoptosis was potentiated with the addition of MAA, which was due to downregulation of the anti apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2), leading to activation of caspases 7 and 3. These results demonstrate that the combination of AMPA and MAA can promote the apoptosis of prostate cancer cells, suggesting that they can be used as potential therapeutic drugs in the treatment of prostate cancer. PMID- 26006245 TI - Soy and breast cancer: focus on angiogenesis. AB - Epidemiological studies have revealed that high consumption of soy products is associated with low incidences of hormone-dependent cancers, including breast and prostate cancer. Soybeans contain large amounts of isoflavones, such as the genistein and daidzain. Previously, it has been demonstrated that genistein, one of the predominant soy isoflavones, can inhibit several steps involved in carcinogenesis. It is suggested that genistein possesses pleiotropic molecular mechanisms of action including inhibition of tyrosine kinases, DNA topoisomerase II, 5alpha-reductase, galectin-induced G2/M arrest, protein histidine kinase, and cyclin-dependent kinases, modulation of different signaling pathways associated with the growth of cancer cells (e.g., NF-kappaB, Akt, MAPK), etc. Moreover, genistein is also a potent inhibitor of angiogenesis. Uncontrolled angiogenesis is considered as a key step in cancer growth, invasion, and metastasis. Genistein was found to inhibit angiogenesis through regulation of multiple pathways, such as regulation of VEGF, MMPs, EGFR expressions and NF-kappaB, PI3-K/Akt, ERK1/2 signaling pathways, thereby causing strong antiangiogenic effects. This review focuses on the antiangiogenic properties of soy isoflavonoids and examines their possible underlying mechanisms. PMID- 26006247 TI - Supramolecular phase-selective gelation by peptides bearing side-chain azobenzenes: effect of ultrasound and potential for dye removal and oil spill remediation. AB - Phase selective gelation (PSG) of organic phases from their non-miscible mixtures with water was achieved using tetrapeptides bearing a side-chain azobenzene moiety. The presence of the chromophore allowed PSG at the same concentration as the minimum gelation concentration (MGC) necessary to obtain the gels in pure organic phases. Remarkably, the presence of the water phase during PSG did not impact the thermal, mechanical, and morphological properties of the corresponding organogels. In the case of miscible oil/water mixtures, the entire mixture was gelled, resulting in the formation of quasi-hydrogels. Importantly, PSG could be triggered at room temperature by ultrasound treatment of the mixture or by adding ultrasound-aided concentrated solution of the peptide in an oil-phase to a mixture of the same oil and water. Moreover, the PSG was not affected by the presence of salts or impurities existing in water from natural sources. The process could be scaled-up, and the oil phases (e.g., aromatic solvents, gasoline, diesel fuel) recovered almost quantitatively after a simple distillation process, which also allowed the recovery and reuse of the gelator. Finally, these peptidic gelators could be used to quantitatively remove toxic dyes from aqueous solutions. PMID- 26006248 TI - Biomedical application of low molecular weight heparin/protamine nano/micro particles as cell- and growth factor-carriers and coating matrix. AB - Low molecular weight heparin (LMWH)/protamine (P) nano/micro particles (N/MPs) (LMWH/P N/MPs) were applied as carriers for heparin-binding growth factors (GFs) and for adhesive cells including adipose-derived stromal cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BMSCs). A mixture of LMWH and P yields a dispersion of N/MPs (100 nm-3 MUm in diameter). LMWH/P N/MPs can be immobilized onto cell surfaces or extracellular matrix, control the release, activate GFs and protect various GFs. Furthermore, LMWH/P N/MPs can also bind to adhesive cell surfaces, inducing cells and LMWH/P N/MPs-aggregate formation. Those aggregates substantially promoted cellular viability, and induced vascularization and fibrous tissue formation in vivo. The LMWH/P N/MPs, in combination with ADSCs or BMSCs, are effective cell-carriers and are potential promising novel therapeutic agents for inducing vascularization and fibrous tissue formation in ischemic disease by transplantation of the ADSCs and LMWH/P N/MPs-aggregates. LMWH/P N/MPs can also bind to tissue culture plates and adsorb exogenous GFs or GFs from those cells. The LMWH/P N/MPs-coated matrix in the presence of GFs may provide novel biomaterials that can control cellular activity such as growth and differentiation. Furthermore, three-dimensional (3D) cultures of cells including ADSCs and BMSCs using plasma-medium gel with LMWH/P N/MPs exhibited efficient cell proliferation. Thus, LMWH/P N/MPs are an adequate carrier both for GFs and for stromal cells such as ADSCs and BMSCs, and are a functional coating matrix for their cultures. PMID- 26006250 TI - Incorporation of stochastic variability in mechanistic population pharmacokinetic models: handling the physiological constraints using normal transformations. AB - The utilisation of physiologically-based pharmacokinetic models for the analysis of population data is an approach with progressively increasing impact. However, as we move from empirical to complex mechanistic model structures, incorporation of stochastic variability in model parameters can be challenging due to the physiological constraints that may arise. Here, we investigated the most common types of constraints faced in mechanistic pharmacokinetic modelling and explored techniques for handling them during a population data analysis. An efficient way to impose stochastic variability on the parameters of interest without neglecting the underlying physiological constraints is through the assumption that they follow a distribution with support and properties matching the underlying physiology. It was found that two distributions that arise through transformations of the normal, the logit-normal generalisation and the logistic normal, are excellent for such an application as not only they can satisfy the physiological constraints but also offer high flexibility during characterisation of the parameters' distribution. The statistical properties and practical advantages/disadvantages of these distributions for such an application were clearly displayed in the context of different modelling examples. Finally, a simulation study clearly illustrated the practical gains of the utilisation of the described techniques, as omission of population variability in physiological systems parameters leads to a biased/misplaced stochastic model with mechanistically incorrect variance structure. The current methodological work aims to facilitate the use of mechanistic/physiologically-based models for the analysis of population pharmacokinetic clinical data. PMID- 26006249 TI - Small-nucleic-acid-based therapeutic strategy targeting the transcription factors regulating the vascular inflammation, remodeling and fibrosis in atherosclerosis. AB - Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis. PMID- 26006251 TI - Molecular Investigation on the Presence of Hepatitis E Virus (HEV) in Wild Game in North-Western Italy. AB - Meat products from HEV-infected reservoir animal species are capable of transmitting HEV to humans and represent a public health concern. Human HEV cases have been linked to the consumption of raw or undercooked pig liver sausages, pork, and game meats, such as wild boars and deer worldwide. Direct exposure to swine or wild game species might also represent a source of HEV transmission especially for veterinarians, hunters, or butchers. A limited amount of data is available on HEV prevalence in wild boars in Italy and no data are available for other wild game species intended for human consumption. In this study, the circulation of HEV in four different animal species hunted in north-western Italy was evaluated to gain insight into the infection levels and the genetic diversity of the virus in such animal populations. Liver samples of 372 wild boars, 30 roe deer, 47 European hares and 38 coypus were analyzed for HEV RNA by real-time RT PCR; positive samples were then sequenced and submitted to phylogenetic analysis. HEV RNA was detected in the livers of 7/372 (1.9%) wild boars tested, while no sample was positive for roe deer, European hare, and coypu. Phylogenetic analysis showed that wild boar HEV sequences belonged to HEV subtypes 3e, 3c, and 3f. Our results indicate that HEV is circulating only in wild boar among the considered game species in north-western Italy and suggest a potential zoonotic risk related to handling and/or consumption of raw or undercooked meat and products made of the liver from this species. PMID- 26006252 TI - Sequential and Simultaneous Applications of UV and Chlorine for Adenovirus Inactivation. AB - Adenoviruses are water-borne human pathogens with high resistance to UV disinfection. Combination of UV treatment and chlorination could be an effective approach to deal with adenoviruses. In this study, human adenovirus 5 (HAdV-5) was challenged in a bench-scale experiment by separate applications of UV or chlorine and by combined applications of UV and chlorine in either a sequential or simultaneous manner. The treated samples were then propagated in human lung carcinoma epithelial cells to quantify the log inactivation of HAdV-5. When the processes were separate, a fluence of 100 mJ/cm(2) and a CT value of 0.02 mg min/L were required to achieve 2 log inactivation of HAdV-5 by UV disinfection and chlorination, respectively. Interestingly, synergistic effects on the HAdV-5 inactivation rates were found in the sequential process of chlorine followed by UV (Cl2-UV) (p < 0.05, ANCOVA) in comparison to the separate processes or the simultaneous application of UV/Cl2. This implies that a pretreatment with chlorine may increase the sensitivity of the virus to the subsequent UV disinfection. In conclusion, this study suggests that the combined application of UV and chlorine could be an effective measure against adenoviruses as a multi barrier approach in water disinfection. PMID- 26006253 TI - Psychosocial sequelae of cannabis use and implications for policy: findings from the Christchurch Health and Development Study. AB - BACKGROUND: The Christchurch Health and Development Study is a longitudinal study of a birth cohort of 1265 children who were born in Christchurch, New Zealand, in 1977. This cohort has now been studied from birth to the age of 35. SCOPE OF THIS REVIEW: This article examines a series of findings from the CHDS that address a range of issues relating to the use of cannabis amongst the cohort. These issues include: (a) patterns of cannabis use and cannabis dependence; (b) linkages between cannabis use and adverse educational and economic outcomes; (c) cannabis and other illicit drug use; (d) cannabis and psychotic symptoms; (e) other CHDS findings related to cannabis; and (f) the consequences of cannabis use for adults using cannabis regularly. FINDINGS: In general, the findings of the CHDS suggest that individuals who use cannabis regularly, or who begin using cannabis at earlier ages, are at increased risk of a range of adverse outcomes, including: lower levels of educational attainment; welfare dependence and unemployment; using other, more dangerous illicit drugs; and psychotic symptomatology. It should also be noted, however, that there is a substantial proportion of regular adult users who do not experience harmful consequences as a result of cannabis use. CONCLUSIONS: Collectively, these findings suggest that cannabis policy needs to be further developed and evaluated in order to find the best way to regulate a widely-used, and increasingly legal substance. PMID- 26006254 TI - Is it necessary to strictly diagnose fibromyalgia syndrome in patients with chronic widespread pain? AB - The applicability of the American College of Rheumatology (ACR) 1990 and 2010 criteria for the diagnosis of fibromyalgia syndrome (FMS) was determined in 284 patients with chronic widespread pain (CWP) including those with regional and systemic painful disorders. On the basis of initial evaluation, patients were classified into three groups. Group 1, those without any comorbid disease (N = 105), group 2, those having regional non-inflammatory painful disorders (N = 104), and group 3, those with a diagnosis of an inflammatory rheumatic disease (N = 75). Overall, 65 % of the patients fulfilled the 1990 criteria, while 94 % of them fulfilled the 2010 criteria. Almost all of the patients (97 %) with CWP did meet at least one of the criteria set, regardless of whether they have accompanying painful disorders. Widespread pain index (WPI), symptom severity scale (SS), and fibromyalgia impact questionnaire (FIQ) scores were found to be significantly higher in the patients who satisfied the 1990 criteria than those who did not (P < 0.001). Tender point counts were found to be significantly correlated with WPI, SS, FIQ, and Beck depression inventory (BDI) scores (P < 0.001). The findings of the study support the suggestion that FMS is just a continuum of CWP, rather than a distinct diagnostic entity. As treatment of FMS is usually identical with that of CWP, strict diagnosis of FMS will provide little or no significance from the viewpoint of clinical practice. We suggest that future research should be directed toward classification of CWP to provide guidance to clinicians in selecting effective therapies. PMID- 26006255 TI - Peripartum changes of the sacroiliac joints on MRI: increasing mechanical load correlating with signs of edema and inflammation kindling spondyloarthropathy in the genetically prone. AB - The purpose of this study is to characterize the MRI changes of the sacroiliac joints (SIJs) during pregnancy and following labor and to correlate them with clinical symptoms. Ninety-three pelvic and hip MRIs of pregnant and <=6 months postpartum women were retrospectively evaluated (Berlin method), for the presence of acute and structural SIJ changes. A telephone questionnaire focusing on pain characterization, co-morbidities, and clinical outcome was conducted with 52 subjects. Findings were correlated with pregnancy week/postpartum time and clinical parameters. SIJ-bone marrow edema (BME) and subchondral sclerosis were a prevalent peripartum finding (46/26 % subjects, respectively), and their frequency increased with pregnancy age. Also, BME, joint fluid, capsulitis, and enthesitis total score were correlated with pregnancy age/postpartum time (r = 0.2-0.31, P = 0.013-0.036). Significant correlation was noted between BME and subchondral sclerosis scores (r = 0.485, P < 0.0001). A sizable proportion of women showed diffuse SIJ BME (7.6 %) and this correlated with slower resolution of symptoms. Indeed, in half of the cases in which MRI was performed due to pregnancy-induced low-back pain (LBP) and diffuse BME was found spondyloarthropathy ensued. In conclusion, pregnancy and puerperium are associated with a host of acute findings in and around the SIJ, including BME, capsulitis, and enthesitis, reflecting most probably, mechanical load and hormonal changes. While the vast majority of symptoms abate within weeks to several months postpartum, 3.8 % of women go on to develop spondyloarthropathy. Diffuse SIJ BME and the presence of risk factors for spondyloarthropathy are predictive of a chronic course. PMID- 26006256 TI - Dual-task costs in aging are predicted by formal education. AB - The capacity to manage different concurrent tasks at the same time decays in older adults. There is however a considerable amount of inter-individual variability in this capacity even in healthy aging. The purpose of this empirical study is to investigate which factors help explaining this variability. A dual task paradigm was administered to 64 older adults and 31 younger controls. In this paradigm, a primary simple response time task had to be carried out either by itself (single-task condition) or while concurrently performing a secondary subtraction task (dual-task condition). Dual-task costs were operationalized by comparing dual-task and single-task conditions. Older adults showed higher dual task interference than younger controls. Within the older group, the influence of age, general cognitive abilities, performance on the secondary task, and years of formal education was assessed with a multiple regression analysis. The results showed that years of formal education in older adults were the best predictor that significantly explained a portion of the variance in dual-task performance. These findings extend previous literature by showing that formal education provides an important dose of cognitive reserve, which is useful to successfully implement cognitive dual-task management despite aging. PMID- 26006257 TI - Synthesis and Herbicidal Activity of Triketone-Quinoline Hybrids as Novel 4 Hydroxyphenylpyruvate Dioxygenase Inhibitors. AB - 4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is one of the most important targets for herbicide discovery. In the search for new HPPD inhibitors with novel scaffolds, triketone-quinoline hybrids were designed and subsequently optimized on the basis of the structure-activity relationship (SAR) studies. Most of the synthesized compounds displayed potent inhibition of Arabidopsis thaliana HPPD (AtHPPD), and some of them exhibited broad-spectrum and promising herbicidal activity at the rate of 150 g ai/ha by postemergence application. Most promisingly, compound III-l, 3-hydroxy-2-(2-methoxy-7-(methylthio)quinoline-3 carbonyl)cyclohex-2-enone (Ki = 0.009 MUM, AtHPPD), had broader spectrum of weed control than mesotrione. Furthermore, compound III-l was much safer to maize at the rate of 150 g ai/ha than mesotrione, demonstrating its great potential as herbicide for weed control in maize fields. Therefore, triketone-quinoline hybrids may serve as new lead structures for novel herbicide discovery. PMID- 26006258 TI - In-office transvaginal hydrolaparoscopy: a step-by-step, intraoperative pain evaluation. AB - PURPOSE: Transvaginal hydrolaparoscopy (THL) is a mini-invasive technique, which allows exploration of the posterior pelvis. THL can be carried out as an office procedure and may replace hysterosalpingography and laparoscopy for the diagnosis of infertility. The aim of this study was to assess pain level during each step of THL. METHODS: Forty infertile women underwent office THL with local anesthesia and had to score pain on a Likert scale (0-no pain, 5-maximum pain) during five stages of THL: stage 1, introduction of the intrauterine catheter; stage 2, introduction of the Veress needle in the Douglas pouch; stage 3, introduction of the trocar in the pelvis; stage 4, exploration of pelvic organs; stage 5, chromosalpingoscopy. At the end of the study, patients scored their overall satisfaction on a VAS scale (0-not satisfied at all; 10-completely satisfied). RESULTS: Stage 5 was associated with the highest pain score in comparison with stages 1-4 (p < 0.001), while pain score during stage 4 was significantly higher in comparison with stages 1-3 (p = 0.001). CONCLUSIONS: Office THL seems to be well tolerated by patients. Chromosalpingoscopy was the least tolerated stage but it does not adversely impact on the procedure, which can be adequately accomplished by performing proper counseling. PMID- 26006259 TI - Risk factors for treatment failure following cold coagulation cervical treatment for CIN pathology: a cohort-based study. AB - PURPOSE: To determine any risk factors for cytology recurrence in women after cold coagulation ablative treatment for cervical intraepithelial neoplasia (CIN). METHODS: This was a retrospective observational study of a cohort of women having had cold coagulation between 2001 and 2011 in the colposcopy unit of an NHS hospital. We retrospectively collected data from our colposcopy unit database. Women with previous cervical treatment were excluded. RESULTS: 559 eligible women were identified with a mean age of 28.7 +/- 6.2 years. Nulliparous women were 66.3 % with smokers involving 35.3 %. Referral cytology, pretreatment cervical punch biopsies and colposcopy were high grade in 51.9, 71.9 and 45.8 % of women. Endocervical crypt involvement (ECI) on pretreatment cervical punch biopsy involved 9.7 % of women. Mean follow-up was 3.1 +/- 2.4 years. Overall cytology recurrence (mild/moderate/severe dyskaryosis) at 6 and 12 months follow-up was 7.4 and 5 %. High-grade cytology recurrence (moderate/severe dyskaryosis) involved 2.7 % of women over the entire follow-up period. Multiple regression analysis showed that ECI on pretreatment cervical punch biopsy was a risk factor for high-grade cytology recurrence (HR 3.72; 95 %CI 1.18-11.71; p = 0.024). There were no risk factors identified for overall cytology recurrence. However, when cytology tests with borderline nuclear changes at follow-up were pooled with mild/moderate/severe dyskaryosis cytology tests, then parity >=2 was a risk factor for abnormal cytology (HR 1.71; 95 %CI 1.08-2.69; p = 0.022). CONCLUSIONS: Endocervical crypt involvement on pretreatment cervical punch biopsy and multiparity >=2 are risk factors that increase the likelihood of abnormal cytology following cold coagulation. These two risk factors should be taken in consideration when performing cold coagulation cervical treatment for CIN pathology. PMID- 26006261 TI - Living With Schizophrenia. PMID- 26006260 TI - Malaria preventive therapy in pregnancy and its potential impact on immunity to malaria in an area of declining transmission. AB - BACKGROUND: Regular anti-malarial therapy in pregnancy, a pillar of malaria control, may affect malaria immunity, with therapeutic implications in regions of reducing transmission. METHODS: Plasma antibodies to leading vaccine candidate merozoite antigens and opsonizing antibodies to endothelial-binding and placental binding infected erythrocytes were quantified in pregnant Melanesian women receiving sulfadoxine-pyrimethamine (SP) with chloroquine taken once, or three courses of SP with azithromycin. RESULTS: Malaria prevalence was low. Between enrolment and delivery, antibodies to recombinant antigens declined in both groups (p<0.0001). In contrast, median levels of opsonizing antibodies did not change, although levels for some individuals changed significantly. In multivariate analysis, the malaria prevention regimen did not influence antibody levels. CONCLUSION: Different preventive anti-malarial chemotherapy regimens used during pregnancy had limited impact on malarial-immunity in a low-transmission region of Papua New Guinea. TRIAL REGISTRATIONS: NCT01136850. PMID- 26006262 TI - Reward System Dysfunction as a Neural Substrate of Symptom Expression Across the General Population and Patients With Schizophrenia. AB - Dysfunctional patterns of activation in brain reward networks have been suggested as a core element in the pathophysiology of schizophrenia. However, it remains unclear whether this dysfunction is specific to schizophrenia or can be continuously observed across persons with different levels of nonclinical and clinical symptom expression. Therefore, we sought to investigate whether the pattern of reward system dysfunction is consistent with a dimensional or categorical model of psychosis-like symptom expression. 23 patients with schizophrenia and 37 healthy control participants with varying levels of psychosis-like symptoms, separated into 3 groups of low, medium, and high symptom expression underwent event-related functional magnetic resonance imaging while performing a Cued Reinforcement Reaction Time task. We observed lower activation in the ventral striatum during the expectation of high vs no reward to be associated with higher symptom expression across all participants. No significant difference between patients with schizophrenia and healthy participants with high symptom expression was found. However, connectivity between the ventral striatum and the medial orbitofrontal cortex was specifically reduced in patients with schizophrenia. Dysfunctional local activation of the ventral striatum depends less on diagnostic category than on the degree of symptom expression, therefore showing a pattern consistent with a psychosis continuum. In contrast, aberrant connectivity in the reward system is specific to patients with schizophrenia, thereby supporting a categorical view. Thus, the results of the present study provide evidence for both continuous and discontinuous neural substrates of symptom expression across patients with schizophrenia and the general population. PMID- 26006263 TI - Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans. AB - Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.0 * 10(-8) in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated "out of Africa" and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution. PMID- 26006266 TI - Real-time intermembrane force measurements and imaging of lipid domain morphology during hemifusion. AB - Membrane fusion is the core process in membrane trafficking and is essential for cellular transport of proteins and other biomacromolecules. During protein mediated membrane fusion, membrane proteins are often excluded from the membrane membrane contact, indicating that local structural transformations in lipid domains play a major role. However, the rearrangements of lipid domains during fusion have not been thoroughly examined. Here using a newly developed Fluorescence Surface Forces Apparatus (FL-SFA), migration of liquid-disordered clusters and depletion of liquid-ordered domains at the membrane-membrane contact are imaged in real time during hemifusion of model lipid membranes, together with simultaneous force-distance and lipid membrane thickness measurements. The load and contact time-dependent hemifusion results show that the domain rearrangements decrease the energy barrier to fusion, illustrating the significance of dynamic domain transformations in membrane fusion processes. Importantly, the FL-SFA can unambiguously correlate interaction forces and in situ imaging in many dynamic interfacial systems. PMID- 26006264 TI - A Multisite, Randomized Controlled Clinical Trial of Computerized Cognitive Remediation Therapy for Schizophrenia. AB - The effectiveness of cognitive remediation therapy (CRT) for the neuropsychological deficits seen in schizophrenia is supported by meta-analysis. However, a recent methodologically rigorous trial had negative findings. In this study, 130 chronic schizophrenic patients were randomly assigned to computerized CRT, an active computerized control condition (CC) or treatment as usual (TAU). Primary outcome measures were 2 ecologically valid batteries of executive function and memory, rated under blind conditions; other executive and memory tests and a measure of overall cognitive function were also employed. Carer ratings of executive and memory failures in daily life were obtained before and after treatment. Computerized CRT was found to produce improvement on the training tasks, but this did not transfer to gains on the primary outcome measures and most other neuropsychological tests in comparison to either CC or TAU conditions. Nor did the intervention result in benefits on carer ratings of daily life cognitive failures. According to this study, computerized CRT is not effective in schizophrenia. The use of both active and passive CCs suggests that nature of the control group is not an important factor influencing results. PMID- 26006267 TI - Intracellular signalling and intercellular coupling coordinate heterogeneous contractile events to facilitate tissue folding. AB - Cellular forces generated in the apical domain of epithelial cells reshape tissues. Recent studies highlighted an important role for dynamic actomyosin contractions, called pulses, that change cell and tissue shape. Net cell shape change depends on whether cell shape is stabilized, or ratcheted, between pulses. Whether there are different classes of contractile pulses in wild-type embryos and how pulses are spatiotemporally coordinated is unknown. Here we develop a computational framework to identify and classify pulses and determine how pulses are coordinated during invagination of the Drosophila ventral furrow. We demonstrate biased transitions in pulse behaviour, where weak or unratcheted pulses transition to ratcheted pulses. The transcription factor Twist directs this transition, with cells in Twist-depleted embryos exhibiting abnormal reversed transitions in pulse behaviour. We demonstrate that ratcheted pulses have higher probability of having neighbouring contractions, and that ratcheting of pulses prevents competition between neighbouring contractions, allowing collective behaviour. PMID- 26006268 TI - Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model. AB - Parkinson's disease (PD) is characterized by a steady loss of dopamine neurons through apoptotic, inflammatory and oxidative stress processes. In that line of view, the pituitary adenylate cyclase-activating polypeptide (PACAP), with its ability to cross the blood-brain barrier and its anti-apoptotic, anti inflammatory and anti-oxidative properties, has proven to offer potent neuroprotection in various PD models. Nonetheless, its peripheral actions, paired with low metabolic stability, hampered its clinical use. We have developed Ac [Phe(pI)(6), Nle(17)]PACAP(1-27) as an improved PACAP-derived neuroprotective compound. In vitro, this analog stimulated cAMP production, maintained mitochondrial potential and protected SH-SY5Y neuroblastoma cells from 1-methyl-4 phenylpyridinium (MPP(+)) toxicity, as potently as PACAP. Furthermore, contrasting with PACAP, it is stable in human plasma and against dipeptidyl peptidase IV activity. When injected intravenously to 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated mice, PACAP and Ac-[Phe(pI)(6), Nle(17)]PACAP(1 27) restored tyrosine hydoxylase expression into the substantia nigra and modulated the inflammatory response. Albeit falls of mean arterial pressure (MAP) were observed with both PACAP- and Ac-[Phe(pI)(6), Nle(17)]PACAP(1-27)-treated mice, the intensity of the decrease as well as its duration were significantly less marked after iv injections of the analog than after those of the native polypeptide. Moreover, no significant changes in heart rate were measured with the animals for both compounds. Thus, Ac-[Phe(pI)(6), Nle(17)]PACAP(1-27) appears as a promising lead molecule for the development of PACAP-derived drugs potentially useful for the treatment of PD or other neurodegenerative diseases. PMID- 26006269 TI - The 5alpha-reductase inhibitor Dutasteride but not Finasteride protects dopamine neurons in the MPTP mouse model of Parkinson's disease. AB - Finasteride and Dutasteride are 5alpha-reductase inhibitors used in the clinic to treat endocrine conditions and were recently found to modulate brain dopamine (DA) neurotransmission and motor behavior. We investigated if Finasteride and Dutasteride have a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) male mice as a model of Parkinson's disease (PD). Experimental groups included saline treated controls and mice treated with saline, Finasteride (5 and 12.5 mg/kg) or Dutasteride (5 and 12.5 mg/kg) for 5 days before and 5 days after MPTP administration (4 MPTP injections, 6.5 mg/kg on day 5 inducing a moderate DA depletion) and then they were euthanized. MPTP administration decreased striatal DA contents measured by HPLC while serotonin contents remained unchanged. MPTP mice treated with Dutasteride 5 and 12.5 mg/kg had higher striatal DA and metabolites (DOPAC and HVA) contents with a decrease of metabolites/DA ratios compared to saline-treated MPTP mice. Finasteride had no protective effect on striatal DA contents. Tyrosine hydroxylase (TH) mRNA levels measured by in situ hybridization in the substantia nigra pars compacta were unchanged. Dutasteride at 12.5 mg/kg reduced the effect of MPTP on specific binding to striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) measured by autoradiography. MPTP reduced compared to controls plasma testosterone (T) and dihydrotestosterone (DHT) concentrations measured by liquid chromatography-tandem mass spectrometry; Dutasteride and Finasteride increased plasma T levels while DHT levels remained low. In summary, our results showed that a 5alpha-reductase inhibitor, Dutasteride has neuroprotective activity preventing in male mice the MPTP-induced loss of several dopaminergic markers. PMID- 26006270 TI - [Procalcitonin and early-onset seizures: When do we offer a higher diagnostic yield?]. PMID- 26006271 TI - [Is azithromycin really a therapeutic option in intestinal salmonellosis?]. PMID- 26006272 TI - [Scab ulcers in the scalp]. PMID- 26006273 TI - [Systematic review of the validity of urine cultures collected by sterile perineal bags]. AB - INTRODUCTION: The perineal adhesive bag is the most used method in our country for urine culture collection in infants, despite having a high risk of contamination and false-positive results. We aim to quantify both types of risks through a systematic review. METHODS: Search updated in May 2014 in PUBMED, SCOPUS (includes EMBASE), IBECS; CINAHL, LILACS AND CUIDEN, without language or time limits. Percentages of contaminated urines, false positives, sensitivity and specificity (with respect to catheterization or bladder puncture) were recorded. RESULTS: A total of 21 studies of medium quality (7,659 samples) were selected. The pooled percentage of contaminated urines was 46.6% (15 studies; 6856 samples; 95% confidence interval [95% CI]: 35.6 to 57.8%; I(2): 97.3%). The pooled percentage of false positives was 61.1% (12 studies; 575 samples; 95% CI: 37.9 to 82.2%; I(2): 96.2%). Sensitivity (88%; 95% CI: 81-93%; I(2): 55.2%), and specificity (82%; 95% CI: 75-89%; I(2): 41.3%) were estimated in five studies, but without including contaminated urines. CONCLUSION: The perineal adhesive bag is not a valid enough method for urine culture collection, because almost half are contaminated and, if they are positive, two out of three are false. Although these estimates are imprecise, because of their great heterogeneity, they should be considered when choosing the method of urine collection. The estimates of sensitivity and specificity are not applicable because they do not take into account the risk of contamination. PMID- 26006274 TI - [Review of patients studied for coagulopathy in a Hematology/Oncology unit]. AB - INTRODUCTION: Symptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. PATIENTS AND METHODS: Retrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. RESULTS: A total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor xii deficiency (19.1%), factor xi deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor x (2.1%), and factor ix deficiency (2.1%). CONCLUSIONS: A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor xii deficiency. PMID- 26006275 TI - [Vaginal reflux: A common cause of urinary incontinence]. PMID- 26006276 TI - [Contribution of serial neurophysiological studies in atypical Guillain-Barre syndrome]. PMID- 26006277 TI - [When and to whom is the method of conception of interest in assisted reproduction techniques?]. PMID- 26006278 TI - [Propionic acidemia and long QT syndrome: A potentially serious combination]. PMID- 26006281 TI - The complete mitochondrial genome of Eurasian water shrew (Neomys fodiens). AB - The complete mitogenome sequence of Eurasian water shrew (Neomys fodiens) was determined using long PCR. The genome was 17,260 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 control region. The overall base composition of the heavy strand is A (33.0%), C (23.2%), T (30.9%) and G (12.9%). The base compositions present clearly the A-T skew, which is most obviously in the control region and protein-coding genes. The extended termination-associated sequence domain, the central conserved domain and the conserved sequence block domain are defined in the mitochondrial genome control region of Eurasian water shrew. Mitochondrial genomes analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees. Neomys elegans, Soriculus fumidus, and N. fodiens formed a monophyletic group with the high bootstrap value (100%) in all examinations. This clade with the Anourosorex squamipes as the sister taxon to Sorex. PMID- 26006279 TI - Estimating a regional ventilation-perfusion index. AB - This is a methods paper, where an approximation to the local ventilation perfusion ratio is derived. This approximation, called the ventilation-perfusion index since it is not exactly the physiological ventilation-perfusion ratio, is calculated using conductivity reconstructions obtained using electrical impedance tomography. Since computation of the ventilation-perfusion index only requires knowledge of the internal conductivity, any conductivity reconstruction method may be used. The method is explained and results are presented using conductivities obtained from two EIT systems, one using an iterative method and the other a linearization method. PMID- 26006282 TI - Comparative mtDNA analyses of three sympatric macropodids from a conservation area on the Huon Peninsula, Papua New Guinea. AB - Matschie's tree kangaroo (Dendrolagus matschiei), New Guinea pademelon (Thylogale browni), and small dorcopsis (Dorcopsulus vanheurni) are sympatric macropodid taxa, of conservation concern, that inhabit the Yopno-Urawa-Som (YUS) Conservation Area on the Huon Peninsula, Papua New Guinea. We sequenced three partial mitochondrial DNA (mtDNA) genes from the three taxa to (i) investigate network structure; and (ii) identify conservation units within the YUS Conservation Area. All three taxa displayed a similar pattern in the spatial distribution of their mtDNA haplotypes and the Urawa and Som rivers on the Huon may have acted as a barrier to maternal gene flow. Matschie's tree kangaroo and New Guinea pademelon within the YUS Conservation Area should be managed as single conservation units because mtDNA nucleotides were not fixed for a given geographic area. However, two distinct conservation units were identified for small dorcopsis from the two different mountain ranges within the YUS Conservation Area. PMID- 26006284 TI - The whole mitochondrial genome of the Lesser Kestrel (Falco naumanni). AB - Falconiformes include most of the predatory birds, they play crucial role in maintaining the balance of ecology system. To further illustrate the phylogenetic status for the species of Falconiformes, the entire mitochondrial DNA (mtDNA) genome of Falco naumanni was amplified and sequenced, further phylogenetic analysis was performed by incorporating with other 8 entire mtDNA genomes representing 8 species of predatory birds by taking the Apus apus and Haematopus ater as out-groups. Our results indicated that the mtDNA genome of F. naumanni includes 17,370 base pairs in length, which has the similar organization and gene order with other mtDNA genomes of the species belonging to Falconiformes. Further phylogenetic analyses supported that the F. naumanni clustered with other species of Falconidae, which formed the sister group of Accipitridae, Cathartes aura located at the basal position with Haematopus ater. In addition, Pandion haliaetus was clustered with other species of Accipitridae, which was conflict with the traditional classification system by taking P. haliaetus as an independent Familia of Falconidae. PMID- 26006283 TI - The complete mitochondrial genome of Amur bitterling (Rhodeus sericeus) from China. AB - The complete mitogenome sequence of Amur bitterling (Rhodeus sericeus) was determined using long PCR. The genome was 16,581 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, 1 origin of L strand replication and 1 control region. The overall base composition of the heavy strand was A (28.9%), C (27.2%), T (26.6%), and G (17.3%). The control region was 925 bp in length and the A + T content of the region was 63.5%. The extended termination-associated sequence domain, the central conserved domain and the conserved sequence block domain are defined in the mitochondrial genome control region of Amur bitterling. Mitochondrial genome analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity to the 13 Cyprinidae species. It appeared that no less than three major phyletic lineages were present in Cyprinidae. A clade (Rhodeus and Tanakia) with the R. lighti and R. Sinensis as the sister taxon to Acheilognathus was supported by bootstrap values of 100%. The close relationship of Amur bitterling to other Rhodeus species, especially R. pseudosericeus, is consistent with the results confirmed using morphology analysis. PMID- 26006285 TI - Phylogenetic analysis of the complete mitochondrial genome of the Korean field mouse Apodemus peninsulae (Rodentia, Murinae) from China. AB - We sequenced and characterized a complete mitogenome (KP671850) of the Chinese Apodemus peninsulae and compared it with a previously published mitogenome of the Korean A. peninsulae (NC016060). The total length of the Chinese A. peninsulae mitogenome is 16,457 bp. The mitogenome consists of 13 protein-coding genes (PCGs), two rRNA (12S rRNA and 16S rRNA) genes, 22 tRNA genes, and one D-loop region. The most common start codon was ATG, used in the nine PCGs for initiation. The mitogenomes of Chinese and Korean A. peninsulae showed 98.9% sequence similarity. The intra-/interspecific phylogeny of the Chinese A. peninsulae revealed that the Chinese A. peninsulae was well grouped with the Korean A. peninsulae. The clade of A. peninsulae was sister to that of Apodemus agrarius, Apodemus chejuensis, and Apodemus chevrieri. PMID- 26006286 TI - The complete mitochondrial genome of Gloydius intermedius (Squamata: Viperidae: Crotalinae) from China. AB - The mitochondrial genome sequence of Gloydius intermedius is analyzed and presented for the first time. The genome was 17, 226 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 2 control region. The overall base composition was A (32.4%), C (28.8%), T (25.9%), and G (12.9%). The base compositions clearly presented the A-C skew, which was most obvious in the protein-coding genes. The extended termination-associated sequence domain, the central conserved domain and the conserved sequence block domain are defined in the mitochondrial genome control region of G. intermedius. Mitochondrial genome analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the 13 Crotalinae species. It appeared that no less than two major phyletic lineages were present in Crotalinae. The main clades within the Crotalinae supported are: A clade including the Protobothrops. A clade (G. brevicaudus, G. ussuriensis, G. intermedius, G. saxatilis) with the Ovophis appeared as the sister taxon to Protobothrops and was supported by bootstrap values of 88%. The four Gloydius species formed a paraphyletic group with the high bootstrap value (100 %) in all examinations. PMID- 26006287 TI - Complete mitochondrial genome of the Trichogaster leeri (Anabantoidei: Osphronemidae). AB - The complete mitochondrial genome of Trichogaster leeri is determined in this study. It is 16,454 bp in length and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a non-coding control region (D-loop). The overall base composition of the heavy-strand (H-strand) of the T. trichopterus mitochondrial genome is A: 29.18%, T: 28.07%, C: 27.20% and G: 15.55%. The total length of the 13 protein-coding genes was 11,435 bp. Phylogenetic analysis showed that the species of Trichogaster (T. trichopterus, T. lalius and T. leeri) formed a monophyletic group and represented close relationship with the species of Anabantoidei. This study provides an important data set for phylogenetic and taxonomic analyses of the species of genus Trichogaster. PMID- 26006288 TI - The complete mitochondrial genome of the Aluterus monoceros. AB - The complete mitochondrial genome of Aluterus monoceros (A. monoceros) has been sequenced. The mitochondrial genome of A. monoceros is 16,429 bp in length, consisting of 22 tRNA genes, 2 rRNA genes, 13 protein-coding genes and a D-loop region (Gen Bank accession number KP637022). The base A + T of the mitochondrial genome is 63.25%, including 33.16% of A, 30.09% of T and 20.74% of C. Twelve protein-coding genes start with a standard ATG as the initiation codon, expect for the COXI, which begins with GTG. Some of the termination codons are incomplete T or TA, except for the ND1, COXI, ATP8, ND4L1, ND5 and ND6, which stop with TAA. Construction of phylogenetic trees based on the entire mitochondrial genome sequence of 14 Tetrodontiformes species constructed has suggested that A. monoceros has closer relationship with Acreichthys tomentosus and Monacanthus chinensis, and they constitute a sister group. PMID- 26006289 TI - Complete mitochondrial genome sequence of Heliocidaris crassispina (Camarodonta, Echinometridae). AB - The whole mitochondrial genome sequence of sea urchin Heliocidaris crassispina of the family Echinometridae is determined for the first time in this study. The circular mitogenome (15,702 bp) consists of typical Camarodonta gene order and its components including 2 rRNA, 22 tRNA, 13 protein-coding genes and a control region. Phylogenetic analysis based on the 13 concatenated protein-coding gene sequences shows that H. crassispina is closer to the species of Strongylocentrotidae than Parechinidae, but the separation between H. crassispina and the Strongylocentrotid species occurred early in their evolution. The complete mitochondrial genome presented in this study is useful for inferring the phylogenetic relationship among the families of Echinidea sea urchins. PMID- 26006290 TI - The complete mitochondrial genome of Colias erate (Lepidoptera: pieridae). AB - The complete mitochondrial genome of Colias erate was investigated and analyzed. The mitochondrial genome is a circular molecule of 15,184 bp, containing 13 protein-coding genes (PCGs), two rRNA genes, 22 tRNA genes, and an A + T-rich region. The nucleotide composition of the C. erate mitogenome is strongly biased toward A + T nucleotides (81.34%). Nine protein-coding genes and 14 tRNA genes are encoded on the H strand, and the other four protein-coding genes and eight tRNA genes are encoded on the L strand. The arrangement of genes is identical to all know the Pieridae species. Finally, the phylogenetic relationships of 12 Pieridae species were reconstructed based on the nucleotide sequences of 13 mitochondrial PCGs using the Bayesian inference method. These molecular-based phylogenies support the traditional morphologically based view of relationships within the Pieridae. PMID- 26006291 TI - Acute phase proteins in intraperitoneal drain fluid: to drain or not to drain. PMID- 26006292 TI - A combined process of adsorption and Fenton-like oxidation for furfural removal using zero-valent iron residue. AB - In this study, the feasibility of using a combined adsorption and Fenton-like oxidation process (with zero-valent iron (ZVI) residue from heat wraps as an absorbent and catalyst) to remove furfural in the solution was evaluated. The influencing parameters (e.g. pH, H2O2 concentration, initial furfural concentration) and the reusability of ZVI residue (to replace the iron powder) were estimated. The ZVI residue was found to have much better adsorption effect on furfural at pH 2.0 compared with pH 6.7. For Fenton-like reaction alone with ZVI residue, the highest furfural removal of 97.5% was observed at the concentration of 0.176 mol/L H2O2, and all of the samples had >80% removal efficiency at different initial furfural concentrations of 2, 10, 20, 30 and 40 mmol/L. However, with a combined adsorption and Fenton-like oxidation, the removal efficiency of furfural was nearly 100% for all treatments. The ZVI residue used for furfural removal was much better than that of iron powder in the Fenton-like reaction at a seven-cycle experiment. This study suggests the combined process of adsorption and Fenton-like oxidation using ZVI residue is effective for the treatment of furfural in the liquid. PMID- 26006293 TI - Biomarkers for Paediatric Respiratory Diseases. PMID- 26006294 TI - The 5'-proximal region of Potato virus X RNA involves the potential cap-dependent "conformational element" for encapsidation. AB - Filamentous helical Potato virus X (PVX) can be regarded as one of the well studied viruses. Nevertheless, some aspects of the PVX assembly remained obscure. Previously, we have shown that the presence of a cap structure at the 5' end of PVX RNA is indispensable for assembly of viral ribonucleoprotein (vRNP) particles varying in length. Here, most significantly, removal of the cap structure from previously capped PVX RNA did not affect the efficiency of decapped RNA molecules to be assembled into vRNP. This result provided evidence that the cap structure by itself does not act as a signal for initiation of vRNP assembly. These observations allowed to presume that the capping triggers some spatial changes in the 5'-proximal site of PVX RNA creating a "conformational encapsidation signal for vRNP assembly", which is capable of triggering vRNP assembly in the absence of cap structure. Apparently, during capping the 5'-proximal segment of PVX RNA acquires a unique conformation which is stable to be retained even after cap removal. PMID- 26006295 TI - Characterization of the growth-related transcriptome in California red abalone (Haliotis rufescens) through RNA-Seq analysis. AB - One of the largest detriments in the abalone aquaculture industry is the inherently low growth rate of this marine gastropod. In order to confront this issue, greater molecular knowledge is needed on growth traits. Therefore, transcriptome analyses were performed using RNA-Seq for groups of California red abalones (Haliotis rufescens) cultured under the same conditions, but with high growth rates (HGR) or low growth rates (LGR). De novo assembly generated 44312 contigs used as references for RNA-Seq analysis. Results showed a total of 1437 differentially expressed contigs, among which, 435 were up-regulated in the HGR group and 1002 in LGR individuals. Overall, LGR abalones evidenced a greater number of exclusive transcripts and differentially transcribed genes. These results provide a valuable resource of novel transcripts in this species and further understandings of the molecular bases regulating growth traits in H. rufescens. PMID- 26006296 TI - Noninvasive monitoring of peripheral microcirculatory hemodynamics under varying degrees of hypoxia. AB - The effect of hypoxia on skin blood flow was examined in anesthetized rabbits during induction of various levels of hypoxia. Peripheral perfusion and oxygenation were monitoring using a combined system (LPT) composed of a laser Doppler flowmeter (LDF), a photoplatysmograph (PPG), and a transcutaneous oxygen tension monitor (tc-PO2). Central blood parameters (PaO2, HCO3(-), SaO2, pH, and lactate) were measured concomitantly throughout the experiment. A continuous decline was found in both peripheral and central values, depending on the severity of the hypoxia. The results clearly indicate that monitoring peripheral indices with the LPT system enables monitoring changes of vital blood parameters during hypoxia. The system has clinical potential for sensitive and noninvasive monitoring of vital variables during medical procedures in clinics, as well as for homecare for patients with respiratory diseases. Minimizing the system may be useful in various conditions of exposure to low oxygen levels, such as during mountain climbing. PMID- 26006297 TI - Is winter worse for stressed fish? The consequences of exogenous cortisol manipulation on over-winter survival and condition of juvenile largemouth bass. AB - Over-winter mortality is an important selective force for warm-water fish (e.g., centrarchids) that live in temperate habitats. Inherent challenges faced by fish during winter may be compounded by additional stressors that activate the hypothalamic-pituitary-interrenal axis, either before or during winter, leading to negative sub-lethal impacts on fish health and condition, and possibly reducing chance of survival. We used experimental cortisol manipulation to test the hypothesis that juvenile largemouth bass (Micropterus salmoides) exposed to semi-chronic elevation in cortisol prior to winter would experience higher levels of over-winter mortality, physiological alterations and impaired immune status relative to control and sham-treated bass. Over-winter survival in experimental ponds was high, averaging 83%, and did not differ among treatment groups. Over the study period, bass exhibited an average increase in mass of 19.4%, as well as a slight increase in Fulton's condition factor, but neither measure differed among groups. Hepatosomatic index in cortisol-treated bass was 23% lower than in control fish, suggesting lower energy status, but white muscle lipid content was similar across all groups. Lastly, there was no difference in spleen somatic index or parasite load among treatment groups, indicating no long-term immune impairment related to our cortisol manipulation. The current study adds to a growing body of literature on glucocorticoid manipulations where field-based findings are not consistent with laboratory-based conceptual understanding of multiple stressors. This suggests that field conditions may provide fish with opportunities to mitigate negative effects of some stressors. PMID- 26006298 TI - Physiological condition of bank voles (Myodes glareolus) during the increase and decline phases of the population cycle. AB - The dynamics of animal populations are greatly influenced by interactions with their natural enemies and food resources. However, quantifying the relative effects of these factors on demographic rates remains a perpetual challenge for animal population ecology. Food scarcity is assumed to limit the growth and to initiate the decline of cyclic herbivore populations, but this has not been verified with physiological health indices. We hypothesized that individuals in declining populations would exhibit signs of malnutrition-induced deterioration of physiological condition. We evaluated the association of body condition with population cycle phase in bank voles (Myodes glareolus) during the increase and decline phases of a population cycle. The bank voles had lower body masses, condition indices and absolute masses of particular organs during the decline. Simultaneously, they had lower femoral masses, mineral contents and densities. Hemoglobin and hematocrit values and several parameters known to respond to food deprivation were unaffected by the population phase. There were no signs of lymphopenia, eosinophilia, granulocytosis or monocytosis. Erythrocyte counts were higher and plasma total protein levels and tissue proportions of essential polyunsaturated fatty acids lower in the population decline. Ectoparasite load was lower and adrenal gland masses or catecholamine concentrations did not suggest higher stress levels. Food availability seems to limit the size of voles during the decline but they can adapt to the prevailing conditions without clear deleterious health effects. This highlights the importance of quantifying individual health state when evaluating the effects of complex trophic interactions on the dynamics of wild animal populations. PMID- 26006299 TI - Control of cardiorespiratory function in response to hypoxia in an air-breathing fish, the African sharptooth catfish, Clarias gariepinus. AB - We evaluated the role of the first pair of gill arches in the control of cardiorespiratory responses to normoxia and hypoxia in the air-breathing catfish, Clarias gariepinus. An intact group (IG) and an experimental group (EG, bilateral excision of first gill arch) were submitted to graded hypoxia, with and without access to air. The first pair of gill arches ablations reduced respiratory surface area and removed innervation by cranial nerve IX. In graded hypoxia without access to air, both groups displayed bradycardia and increased ventilatory stroke volume (VT), and the IG showed a significant increase in breathing frequency (fR). The EG exhibited very high fR in normoxia that did not increase further in hypoxia, this was linked to reduced O2 extraction from the ventilatory current (EO2) and a significantly higher critical O2 tension (PcO2) than the IG. In hypoxia with access to air, only the IG showed increased air breathing, indicating that the first pair of gill arches excision severely attenuated air-breathing responses. Both groups exhibited bradycardia before and tachycardia after air-breaths. The fH and gill ventilation amplitude (VAMP) in the EG were overall higher than the IG. External and internal NaCN injections revealed that O2 chemoreceptors mediating ventilatory hypoxic responses (fR and VT) are internally oriented. The NaCN injections indicated that fR responses were mediated by receptors predominantly in the first pair of gill arches but VT responses by receptors on all gill arches. Receptors eliciting cardiac responses were both internally and externally oriented and distributed on all gill arches or extra-branchially. Air-breathing responses were predominantly mediated by receptors in the first pair of gill arches. In conclusion, the role of the first pair of gill arches is related to: (a) an elevated EO2 providing an adequate O2 uptake to maintain the aerobic metabolism during normoxia; (b) a significant bradycardia and increased fAB elicited by externally oriented O2 chemoreceptors; (c) increase in the ventilatory variables (fR and VAMP) stimulated by internally oriented O2 chemoreceptors. PMID- 26006300 TI - Molecular characterization of 7 patients affected by dys- or hypo dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation. AB - Fibrinogen is a hexameric glycoprotein consisting of two sets of three polypeptides (the Aalpha, Bbeta, and gamma chains, encoded by the three genes FGA, FGB, and FGG). It is involved in the final phase of the coagulation process, being the precursor of the fibrin monomers necessary for the formation of the hemostatic plug. Rare inherited fibrinogen disorders can manifest as quantitative deficiencies, qualitative defects, or both. In particular, dysfibrinogenemia and hypo-dysfibrinogenemia are characterized by reduced functional activity associated with normal or reduced antigen levels, and are usually determined by heterozygous mutations affecting any of the three fibrinogen genes. In this study, we investigated the genetic basis of dys- and hypo-dysfibrinogenemia in seven unrelated patients. Mutational screening disclosed six different variants, two of which novel (FGB-p.Asp185Asn and FGG-p.Asn230Lys). The molecular characterization of the FGG-p.Asn230Lys mutation, performed by transient expression experiments of the recombinant mutant protein, demonstrated that it induces an almost complete impairment in fibrinogen secretion, according to a molecular mechanism often associated with quantitative fibrinogen disorders. Conversely, the FGB-p.Asp185Asn variant was demonstrated to be a gain-of glycosylation mutation leading to a hyperglycosylation of the Bbeta chain, not affecting fibrinogen assembly and secretion. To our knowledge, this is the second gain-of-glycosylation mutation involving the FGB gene. PMID- 26006301 TI - Gynecardiology: Distinct patterns of ischemic heart disease in middle-aged women. AB - The past 25 years have revealed that distinct patterns of ischemic heart disease exist in women that are importantly different from the male standard. Premenopausal women have a lower risk factor profile resulting in fewer cardiovascular events at younger age, which reverses at older age. First signs of vascular ageing appear in middle-aged women, with a predominance of functional coronary abnormalities over anatomical obstructions. Over 50% of symptomatic middle-aged women have coronary microvascular dysfunction that is often poorly recognized and treated. This microvascular syndrome has different symptomatic characteristics compared to the classic pattern of angina pectoris related with obstructive coronary disease. Vascular dysfunction is also an important contributor to the occurrence of acute coronary syndromes in relatively young women. Female-specific signs and symptoms related to various stages of life are increasingly helpful tools in identifying women at increased risk. This evolving knowledge in 'gynecardiology' is an important challenge for more interaction between gynecologists and cardiologists to further improve accurate prevention in those women at highest need. PMID- 26006302 TI - The management of urinary tract infections in octogenarian women. AB - Urinary Tract Infections are common in women of all ages and the incidence increases with age. Whilst they are a common cause of lower urinary tract symptoms in all women they may be associated with increased morbidity in the elderly. Appropriate investigation and treatment in primary and secondary care are essential to effectively manage urinary tract infection and decrease morbidity and hospitalisation rates. Loss of endogenous oestrogen at the time of the menopause is associated with the urogenital atrophy and an increased incidence of urinary tract infection. Consequently vaginal oestrogen therapy may offer a rationale for treatment and prevent of urinary tract infection. The aim of this paper is to review the clinical management of elderly women presenting with primary and recurrent urinary tract infection. PMID- 26006303 TI - [Primary surgery for cleft palate and short hospital stay (48 h): Are they compatible?]. AB - The aim of this study was to evaluate our practices by studying the duration of hospitalization and the parental real-life experience after a primary surgery of a cleft palate. MATERIALS AND METHODS: Monocentric retrospective study by analysis of the patients files and phone interview of the parents whose children were operated for a primary surgery of a cleft palate isolated, or associated with a labial cleft, or included in a syndromic form. RESULTS: Forty-nine patients (25 B-24 G) were performed by 44 Wardill and five Furlow procedures (average age: 11 months 1/2) between 2010 and 2012. The average duration of the post-operative stay was 1.5 days. Thirty-three parents were contacted (67%). The return was "very well" or "well done" in 82% of the cases. The pain at home was estimated by the parents as "worthless" or "little intense" in 73% of the cases. For 16% of the parents, the child seemed "uncomfortable". The prescription of analgesic was followed only in 70% of the cases. The duration of hospitalization was considered by the families as "good one" in 70% of the cases, "too long" for 12% and "too short" for 18% in particular because of difficulty in eating or parental anxiety. CONCLUSION: Even if palatine surgery is considered to be painful, anaesthetic techniques and current analgesic protocols allow to envisage very simple and fast consequences, authorizing an early return of the children at home. PMID- 26006304 TI - [Median congenital fistula of the upper lip associated with Goldenhar syndrome: Report of a case]. AB - AIM OF THE STUDY: We present the case of a patient with Goldenhar syndrome associated with congenital fistula in the middle of philtrum at the upper lip. PATIENTS AND METHODS: The patient was supported from birth for Goldenhar syndrome. Several procedures were performed in childhood to correct a macrostomia and mandibular hypoplasia right. At 14 years old, she has a rhinoplasty to correct a complex nasal malformation. During the procedure, a hole in the upper central incisor inter-space is found. It is extended by a fistula which runs through the front palate towards the vomer rail at the base of the partition. This fistula is blind behind the vomer and can be completely resected. Pathological examination of the resection reveals a squamous lining. RESULTS: The median fistula of the upper lip are extremely rare : less than 30 cases reported in the literature. The unusual run of the fistula and the recent appearance of a pituitary syndrome in this patient makes us look for a continuity between it and Rathke's pocket by computed tomography imaging type. CONCLUSION: The association of Goldenhar syndrome and median congenital fistula of the upper lip was never yet described in the literature. The association with hypopituitarism was suspected with the posterior extension of the malformation, not confirmed by the scanner, but strongly suspected jointly by the neurosurgical and plastic surgery team. PMID- 26006305 TI - Enlargement of the flexor pulleys by an omega plasty: A study comparing the release of one or both sides of the A2 and/or A4 pulley. AB - PURPOSE: The omega plasty on one side of the A2 and/or A4 pulley improves the gliding of repaired flexor tendons in zone II. The purpose of this study was whether or not the enlargement of the digital channel was better after the release of one or both sides of each pulley. METHODS: In fresh cadavers, the technique was to first disinsert the ulnar attachments of the A2 and A4 pulleys and then the radial insertions. An ultrasound was used to measure the large axis, the circumference, and the cross-sectional surface of each of A2 and A4 pulleys before release, after ulnar release and after radial release. RESULTS: The release of the A2 pulley reduces the risk of conflict in the sutured flexor tendons in the digital channel. The release of the A4 pulley seems less effective than that of A2. The release of the two pulleys reduces the risk of conflict in one sutured zone of the flexor tendons in the digital channel. CONCLUSION: In all, if there is a conflict between the flexor tendons sutured opposite A2, we recommend an omega plasty on the two sides of the pulley. If the conflict appears opposite A4, we recommend the plasty of the two sides of A4 and A2. PMID- 26006306 TI - The use of captisol (SBE7-beta-CD) in oral solubility-enabling formulations: Comparison to HPbetaCD and the solubility-permeability interplay. AB - The aim of this research was to study the interaction of sulfobutyl ether7 beta cyclodextrin (captisol) and 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) with the poorly soluble antiarrhythmic drug amiodarone, and to investigate the consequent solubility-permeability interplay. Phase-solubility studies of amiodarone with the two cyclodextrins, followed by PAMPA and rat intestinal permeability experiments, were carried out, and the solubility-permeability interplay was then illustrated as a function of increasing cyclodextrin content. Equimolar levels of captisol allowed ~10-fold higher amiodarone solubility than HPbetaCD, as well as binding constant. With both captisol and HPbetaCD, decreased in vitro and in vivo amiodarone apparent permeability was evident with increasing CD levels and increased apparent solubility. A theoretical model assuming direct proportionality between the apparent solubility increase allowed by the CD and permeability decrease was able to accurately predict the solubility-permeability tradeoff as a function of CD levels. In conclusion, the addition of ionic interactions (e.g. amiodarone-captisol) to hydrophobic interactions of the inclusion complex formation may result in synergic effect on solubilization; however, it is not merely the solubility that should be examined when formulating an oral poorly soluble compound, but the solubility-permeability balance, in order to maximize the overall drug exposure. PMID- 26006307 TI - Qualitative and quantitative methods to determine miscibility in amorphous drug polymer systems. AB - Amorphous drug-polymer systems or amorphous solid dispersions are commonly used in pharmaceutical industry to enhance the solubility of compounds with poor aqueous solubility. The degree of miscibility between drug and polymer is important both for solubility enhancement as well as for the formation of a physically stable amorphous system. Calculation of solubility parameters, Computational data mining, Tg measurements by DSC and Raman mapping are established traditional methods used to qualitatively detect the drug-polymer miscibility. Calculation of Flory-Huggins interaction parameter, computational analysis of X-Ray Diffraction (XRD) data, solid state Nuclear Magnetic Resonance (NMR) spectroscopy and Atomic Forced Microscopy (AFM) have been recently developed to quantitatively determine the miscibility in amorphous drug-polymer systems. This brief review introduces and compiles these qualitative and quantitative methods employed in the evaluation of drug-polymer miscibility. Combination of these techniques can provide deeper insights into the true miscibility of the drug-polymer systems. PMID- 26006308 TI - Passive stiffness of hindlimb muscles in anurans with distinct locomotor specializations. AB - Anurans (frogs and toads) have been shown to have relatively compliant skeletal muscles. Using a meta-analysis of published data we have found that muscle stiffness is negatively correlated with joint range of motion when examined across mammalian, anuran and bird species. Given this trend across a broad phylogenetic sample, we examined whether the relationship held true within anurans. We identified four species that differ in preferred locomotor mode and hence joint range of motion (Lithobates catesbeianus, Rhinella marina, Xenopus laevis and Kassina senegalensis) and hypothesized that smaller in vivo angles (more flexed) at the knee and ankle joint would be associated with more compliant extensor muscles. We measured passive muscle tension during cyclical stretching (20%) around L0 (sarcomere lengths of 2.2 MUm) in fiber bundles extracted from cruralis and plantaris muscles. We found no relationship between muscle stiffness and range of motion for either muscle-joint complex. There were no differences in the passive properties of the cruralis muscle among the four species, but the plantaris muscles of the Xenopus and Kassina were significantly stiffer than those of the other two species. Our results suggest that in anurans the stiffness of muscle fibers is a relatively minor contributor to stiffness at the level of joints and that variation in other anatomical properties including muscle-tendon architecture and joint mechanics as well as active control likely contribute more significantly to range of motion during locomotion. PMID- 26006309 TI - Bridging-type enzyme-linked immunoassay for zinc transporter 8 autoantibody measurements in adult patients with diabetes mellitus. AB - AIMS: A bridging-type ELISA for measuring autoantibodies to zinc transporter 8 (ZnT8A) was assessed using samples from different forms of diabetes mellitus. METHODS: ZnT8A were measured using an ELISA in patients with type 1 diabetes mellitus (T1DM; n=94), latent autoimmune diabetes of adulthood (LADA; n=51), type 2 diabetes mellitus (T2DM; n=59) and healthy blood donors (HBD; n=200). ZnT8A in ELISA and immunoprecipitation assays (IPA) using ZnT8 dimer (W325/R325) and monomers (W325, R325 and Q325) were compared. RESULTS: Inter- and intra-assay coefficients of variation (CV) were 7.1% and 1.7%, respectively (medium ZnT8A) and 8.5% and 2.7%, respectively (high ZnT8A). In the ELISA 51/94 (54.3%) T1DM, 16/51 (31.4%) LADA and 1/59 (1.7%) T2DM sera were ZnT8A positive. ROC analysis of T1DM and HBD for the ELISA showed 54% sensitivity and 99% specificity (cutoff 15u/mL) and AUC 0.80 (95% CI, 0.74-0.86). ELISA and IPA measurements were in very good agreement (r=0.856, k=0.889, n=204). Measurement of ZnT8A in addition to autoantibodies for GAD, IA-2 and insulin increased antibody positivity in T1DM by 4.3%, from 80.9% to 85.1%. CONCLUSIONS: The bridging-type ELISA is a convenient and reproducible method for determination of ZnT8A in serum. Measurement of ZnT8A increased autoantibody positivity in adult T1DM. PMID- 26006310 TI - [Allergic dermatopathology or a rare disease?]. PMID- 26006312 TI - [When did we lose our heads?]. PMID- 26006311 TI - [Cost-effectiveness analysis of celecoxib versus non-selective non-steroidal anti inflammatory drug therapy for the treatment of osteoarthritis in Spain: A current perspective]. AB - OBJECTIVE: To assess the cost-effectiveness of celecoxib and non-selective non steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. METHODS: A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed "GI-Reasons" trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. RESULTS: Compared with non-selective non steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs ?201 and ?157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (p<.001), with mean incremental cost effectiveness ratio of ?13,286 per QALY gained and ?4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. CONCLUSION: Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS. PMID- 26006313 TI - [Low blood pressure in type 2 diabetes. A systematic review and meta-analysis]. PMID- 26006314 TI - [Out-of-hospital births]. AB - Childbirth is a physiological process and, as such, there should be limited assistance for the woman to ensure that it follows its natural process, avoiding any possible complication and, if they do appear, attempting to resolve them. Health personnel should try to achieve a balance between safety and the least possible outside assistance. The out-of-hospital delivery is considered an emergency as it happens unexpectedly, that is, without being previously planned. Given that it has to be treated outside the ideal conditions of a maternity ward, it is considered as an emergency. PMID- 26006316 TI - [Purple urine in the bag]. PMID- 26006315 TI - [When the common stops being trite]. PMID- 26006318 TI - Thumbprint Sign in the Colon: A Diagnostic Finding of Necrotizing Enterocolitis in Premature Infants. PMID- 26006317 TI - Effects of metal exposure on motor neuron development, neuromasts and the escape response of zebrafish embryos. AB - Low level metal contaminations are a prevalent issue with often unknown consequences for health and the environment. Effect-based, multifactorial test systems with zebrafish embryos to assess in particular developmental toxicity are beneficial but rarely used in this context. We therefore exposed wild-type embryos to the metals copper (CuSO4), cadmium (CdCl2) and cobalt (CoSO4) for 72 h to determine lethal as well as sublethal morphological effects. Motor neuron damage was investigated by immunofluorescence staining of primary motor neurons (PMNs) and secondary motor neurons (SMNs). In vivo stainings using the vital dye DASPEI were used to quantify neuromast development and damage. The consequences of metal toxicity were also assessed functionally, by testing fish behavior following tactile stimulation. The median effective concentration (EC50) values for morphological effects 72 h post fertilization (hpf) were 14.6 mg/L for cadmium and 0.018 mg/L for copper, whereas embryos exposed up to 45.8 mg/L cobalt showed no morphological effects. All three metals caused a concentration dependent reduction in the numbers of normal PMNs and SMNs, and in the fluorescence intensity of neuromasts. The results for motor neuron damage and behavior were coincident for all three metals. Even the lowest metal concentrations (cadmium 2mg/L, copper 0.01 mg/L and cobalt 0.8 mg/L) resulted in neuromast damage. The results demonstrate that the neuromast cells were more sensitive to metal exposure than morphological traits or the response to tactile stimulation and motor neuron damage. PMID- 26006319 TI - Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety. AB - A downward trend in preoperative autologous donation (PAD) continues in Europe and the Americas, with many jurisdictions only funding medically necessary collections at present. This is the result of decreasing real and perceived residual risks of allogeneic transfusion-transmitted disease and the declining need for transfusion due to patient blood management, which have also led to escalating logistical and cost constraints for PAD programs. We outline collection trends in North America, Europe, and Latin America and review the benefits, risks, effectiveness, and safety of PAD. Important elements of informed consent follow from these points. Evidence-based medical criteria for PAD and autologous transfusion are discussed as are methods to optimize autologous collection timing to regenerate donated red cells. Recommendations for identification of patients whose risk-to-benefit ratio suggests substantial benefit compared with other autologous blood salvage and anemia management alternatives conclude the review. PMID- 26006321 TI - Cationic dinuclear platinum and palladium complexes with bridging hydrogermylene and hydrido ligands. AB - Hydride-abstraction reactions of hydrido(dihydrogermyl) complexes [MH(GeH2Trip)(dcpe)] [M = Pt, Pd, Trip = 9-triptycyl, dcpe = 1,2 bis(dicyclohexylphosphino)ethane] with B(C6F5)3 led to the unexpected formation of new cationic (MU-germyl)(MU-hydrido) dinuclear platinum and palladium complexes, [{M(dcpe)}2(MU-GeHTrip)(MU-H)](+). PMID- 26006320 TI - Formative research and development of innovative tools for "Better Outcomes in Labour Difficulty" (BOLD): study protocol. AB - BACKGROUND: Most complications during labour and childbirth could be averted with timely interventions by skilled healthcare providers. Yet, the quality and outcomes of childbirth care remains suboptimal in many health facilities in low resource settings. To accelerate the reduction of childbirth-related maternal, fetal and newborn mortality and morbidity, the World Health Organization has initiated the "Better Outcomes in Labour Difficulty" (BOLD) project to address weaknesses in labour care processes and better connect health systems and communities. The project seeks to develop a "Simplified, Effective, Labour Monitoring-to-Action" tool (SELMA) to assist healthcare providers to monitor labour and take decisive actions more efficiently; and by developing an innovative set of service prototypes and/or tools termed "Passport to Safer Birth", designed with communities and healthcare providers, to promote access to quality care for women during childbirth. This protocol describes the formative research activities to support the development of these tools. METHODS/DESIGN: We will employ qualitative research and service design methodologies in eight health facilities and their catchment communities in Nigeria and Uganda. In the health facilities, focus group discussions (FGD) and in-depth interviews (IDI) will be conducted among different cadres of healthcare providers and facility administrators. In the communities, FGDs and IDIs will be conducted among women who have delivered in a health facility. We will use service design methods to explore women's journey to access and receive childbirth care in order to innovate and design services around the needs and expectations of women, within the context of the health system. DISCUSSION: This formative research will serve several roles. First, it will provide an in-depth understanding of healthcare providers and health system issues to be accounted for in the final design and implementation of SELMA. Second, it will help to identify key moments ("touch points") where women's experiences of childbirth care are shaped, and where the overall experience of quality care could be improved. The synthesis of findings from the qualitative and service design activities will help identify potential areas for behaviour change related to the provision and experience of childbirth care, and serve as the basis for the development of Passport to Safer Birth. Please see related articles 'http://dx.doi.org/ 10.1186/s12978-015-0027-6 ' and 'http://dx.doi.org/ 10.1186/s12978-015-0029-4 '. PMID- 26006322 TI - Infrared nonlinear optical properties of lithium-containing diamond-like semiconductors Li2ZnGeSe4 and Li2ZnSnSe4. AB - Two new lithium-containing diamond-like semiconductors, Li2ZnGeSe4 and Li2ZnSnSe4, have been prepared by high-temperature, solid-state synthesis. Single crystal X-ray diffraction reveals that both compounds adopt the wurtz-kesterite structure type, crystallizing in the noncentrosymmetric space group Pn. X-ray powder diffraction coupled with Rietveld refinement indicates the high degree of phase purity in which the materials are prepared. Both compounds display optical bandgaps around 1.8 eV, wide optical transparency windows from 0.7 to 25 MUm and type-I phase matched second harmonic generation starting at 2500 nm and persisting deeper into the infrared. Using the Kurtz powder method, the second order nonlinear optical coefficient, chi((2)), was estimated to be 19 and 23 pm V(-1) for Li2ZnGeSe4 and Li2ZnSnSe4, respectively. Using a 1064 nm incident laser beam with a pulse width (tau) of 30 ps both compounds exhibit a laser damage threshold of 0.3 GW cm(-2), which is higher than that of the AgGaSe2 reference material measured under identical conditions. Differential thermal analysis shows that the title compounds are stable up to 684 and 736 degrees C, respectively. These properties collectively demonstrate that Li2ZnGeSe4 and Li2ZnSnSe4 have great potential for applications in tunable laser systems, especially in the infrared and even up to the terahertz regime. Electronic structure calculations using a plane-wave pseudopotential method within density functional theory provide insight regarding the nature of the bandgap and bonding. PMID- 26006323 TI - Quinone-Bodipy H-bonding interaction over pi-stacking in toluene. AB - Quinone type compounds (o-chloranil, p-chloranil and DDQ) demonstrate excellent H bonding interactions with a meso-phenol Bodipy dye (1) in both ground and excited state in a non-polar toluene medium. The spectroscopic detection of isosbestic absorption occurs with both quinones and fullerenes, but only quinones form isoemissive complexes with dye 1. (1)H NMR study and Monte Carlo global minima searching justified the above mentioned results with efficiency. PMID- 26006324 TI - The magic of the sugar code. PMID- 26006325 TI - Regioselectivity switch in chiral amine-catalysed asymmetric addition of aldehydes to reactive enals. AB - In this communication, we present a regioselectivity switch for the chiral amine catalysed asymmetric addition of aldehydes to reactive enals to afford either aldol adducts or conjugate adducts in a stereoselective fashion. The unprecedented asymmetric aldol reaction of aldehydes with enals was realized by the use of a diarylprolinol catalyst, giving synthetically useful and important chiral allylic alcohols. PMID- 26006326 TI - Correction: Preparation of Nd-Fe-B by nitrate-citrate auto-combustion followed by the reduction-diffusion process. PMID- 26006327 TI - Positioning of electrode plane systematically influences EIT imaging. AB - Up to now, the impact of electrode positioning on electrical impedance tomography (EIT) had not been systematically analyzed due to the lack of a reference method. The aim of the study was to determine the impact of electrode positioning on EIT imaging in spontaneously breathing subjects at different ventilation levels with our novel lung function measurement setup combining EIT and body plethysmography. EIT measurements were conducted in three transverse planes between the 3rd and 4th intercostal space (ICS), at the 5th ICS and between the 6th and 7th ICS (named as cranial, middle and caudal) on 12 healthy subjects. Pulmonary function tests were performed simultaneously by body plethysmography to determine functional residual capacity (FRC), vital capacity (VC), tidal volume (VT), expiratory reserve volume (ERV), and inspiratory reserve volume (IRV). Ratios of impedance changes and body plethysmographic volumes were calculated for every thorax plane (DeltaIERV/ERV, DeltaIVT/VT and DeltaIIRV/IRV). In all measurements of a subject, FRC values and VC values differed <=5%, which confirmed that subjects were breathing at comparable end-expiratory levels and with similar efforts. In the cranial thorax plane the normalized DeltaIERV/ERV ratio in all subjects was significantly higher than the normalized DeltaIIRV/IRV ratio whereas the opposite was found in the caudal chest plane. No significant difference between the two normalized ratios was found in the middle thoracic plane. Depending on electrode positioning, impedance to volume ratios may either increase or decrease in the same lung condition, which may lead to opposite clinical decisions. PMID- 26006328 TI - Nanosponge-based pediatric-controlled release dry suspension of Gabapentin for reconstitution. AB - CONTEXT: Gabapentin was selected to formulate oral controlled release dry suspension because of short biological half life of 5-7 h and low bioavailability (60%). Gabapentin is a bitter drug so an attempt was made to mask its taste. OBJECTIVE: To formulate and evaluate controlled release dry suspension for reconstitution to increase the bioavailability and to control bitter taste of drug. MATERIALS AND METHODS: Cyclodextrin based nanosponges were synthesized by previously reported melt method. The nanosponge-drug complexes were characterized by FTIR, DSC and PXRD as well as evaluated for taste and saturation solubility. The complexes were coated on Espheres by a suspension layering technique followed by coating with ethyl cellulose and Eudragit RS-100. A dry powder suspension for reconstitution of the microspheres was formulated and evaluated for taste, redispersibility, in vitro dissolution, sedimentation volume, leaching and pharmacokinetics. RESULTS AND DISCUSSION: The complexes showed partial entrapment of drug nanocavities. Significant decrease in solubility (25%) was observed in the complexes than pure drug in different media. The microspheres of nanosponge complexes showed desired controlled release profile for 12 h. Insignificant drug leaching was observed in reconstituted suspension during storage for 7 days at 45 degrees C/75% RH. Nanosponges effectively masked the taste of Gabapentin and the coating polymers provided controlled release of the drug and enhanced taste masking. The results of in vivo studies showed increase in bioavailability of controlled release suspension by 24.09% as compared to pure drug. CONCLUSION: The dry powder suspension loaded with microspheres of nanosponges complexes can be proposed as a suitable controlled release drug delivery for Gabapentin. PMID- 26006329 TI - Development and evaluation of chitosan and chitosan derivative nanoparticles containing insulin for oral administration. AB - Chitosan and chitosan derivative-based nanoparticles loaded with insulin were prepared by self-assembly, via electrostatic interactions between the negatively charged drug and the positively charged polymers. In the investigated chitosan derivatives, the amine groups were substituted to different extents (33, 52 or 99%) by 2-hydroxypropyl-3-trimethyl ammonium groups, rendering the polymers permanently positively charged, irrespective of the pH. This is an important property for this type of advanced drug delivery system, since the pH value changes throughout the gastrointestinal tract and electrostatic interactions are of crucial importance for the stability of the nanoparticles. Permanent positive charges are also in favor of mucoadhesion. In contrast, the electric charges of chitosan molecules depend on the pH of the surrounding medium. Since the solubility of the chitosan derivatives increased due to the introduction of quaternary ammonium groups, sodium tripolyphosphate (TPP) was added to the systems to create supplementary cross-links and stabilize the nanoparticles. The presence of TPP influenced both the dissolution of the polymer matrix as well as the resulting release kinetics. The underlying drug release mechanisms were found to be more complex than simple diffusion under constant conditions, likely involving also ionic interactions and matrix dissolution. The most promising formulation was based on a chitosan derivative with 33% substitution degree and characterized by a Z-average of 142 +/- 10 nm, a zeta potential of 29 +/- 1 mV, an encapsulation efficacy of 52 +/- 3% and, most importantly, the release of insulin was sustained for more than 210 min. PMID- 26006330 TI - Multipronged, strategic delivery of paclitaxel-topotecan using engineered liposomes to ovarian cancer. AB - CONTEXT: Synergistically active combinations have been used to enhance therapeutic efficacy for ovarian cancer chemotherapy. OBJECTIVE: The synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) were loaded into folate-anchored PEGylated liposomes (FPL-Pac-Top) for safe and effective treatment of ovarian cancer. MATERIALS AND METHODS: Coupling reactions were carried out using carbodiimide chemistry and confirmed by infrared spectral analysis. These liposomes were studied for shape and physical interaction (and integrity), in vitro drug release kinetics, hemolytic toxicity, ex vivo pharmacodynamics in OVCAR-3 cell lines, and pharmacokinetics in ovarian tumor bearing mice. RESULTS: The differential scanning calorimeter studies exhibited melting of liposomes (~150 nm) at ~41 degrees C. The drug(s) release from liposomes followed Fickian diffusion model. The hematological studies revealed insignificant toxicity to blood cells. In vivo studies showed long circulatory behavior (increased AUC0-t and AUMC0-t and MRT) and selective accumulation of FPL Pac-Top in the ovaries. FPL-Pac-Top showed less necrosis and more apoptosis in flow cytometry. Kaplan-Meier survival analysis revealed the doubling of the survival time with FPL-Pac-Top in comparison to Pac-Top solution. DISCUSSION AND CONCLUSION: Potentiated anti-cancer activity of FPL-Pac-Top was attributed to multiple features viz. thermosensitivity, long circulatory nature and targetability. Such approach could be a paradigm chemotherapeutic approach for safe and effective targeting of cancer. PMID- 26006331 TI - Enteric-coated epichlorohydrin crosslinked dextran microspheres for site-specific delivery to colon. AB - Enteric-coated epichlorohydrin crosslinked dextran microspheres containing 5 Fluorouracil (5-FU) for colon drug delivery was prepared by emulsification crosslinking method. The formulation variables studied includes different molecular weights of dextran, volume of crosslinking agent, stirring speed, time and temperature. Dextran microspheres showed mean entrapment efficiencies ranging between 77 and 87% and mean particle size ranging between 10 and 25 um. About 90% of drug was released from uncoated dextran microspheres within 8 h, suggesting the fast release and indicated the drug loaded in uncoated microspheres, released before they reached colon. Enteric coating (Eudragit-S-100 and Eudragit-L-100) of dextran microspheres was performed by oil-in-oil solvent evaporation method. The release study of 5-FU from coated dextran microspheres was complete retardation in simulated gastric fluid (pH 1.2) and once the coating layer of enteric polymer was dissolved at higher pH (7.4 and 6.8), a controlled release of the drug from the microspheres was observed. Further, the release of drug was found to be higher in the presence of dextranase and rat caecal contents, indicating the susceptibility of dextran microspheres to colonic enzymes. Organ distribution and pharmacokinetic study in albino rats was performed to establish the targeting potential of optimized formulation in the colon. PMID- 26006332 TI - Inhaled PYY(3-36) dry-powder formulation for appetite suppression. AB - OBJECTIVE: Peptide YY3-36 [PYY(3-36)] has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3-36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study. METHODS: Dry powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3-36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3-36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data. RESULTS: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2 * higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65 mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4 h, which is similar to IP and subcutaneous delivery routes. CONCLUSIONS: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3-36). Additionally, engineered PYY(3-36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression. PMID- 26006333 TI - Stability of 10 mg/mL cefuroxime solution for intracameral injection in commonly used polypropylene syringes and new ready-to-use cyclic olefin copolymer sterile vials using the LC-UV stability-indicating method. AB - CONTEXT: Injecting intracameral cefuroxime has been found beneficial in reducing the risk of postoperative endophthalmitis but its use has been limited through a lack of approved marketing and of ready-to-use single-units as well as the problem of aseptic compounding. OBJECTIVE: Our aim was to assess a new automated primary packaging system which should ensure a higher level of sterility, thanks to its closed, sterile, ready-to-use polymer vial called "Crystal(r) vial". The chemical stability of a 10 mg/mL cefuroxime solution was compared in 1 mL Crystal(r) vials and 1 mL Luer-lock polypropylene syringes (actual reference) to eliminate any potential and specific interactions with its cyclic olefin copolymer (COC) body and elastomer stopper. METHODS: Cefuroxime solution was introduced into vials and syringes and stored at -20 degrees C, +5 degrees C and +25 degrees C/60% Relative Humidity. Cefuroxime concentration and the relative amount of the main degradation product (descarbamoyl-cefuroxime) were both determined by an HPLC/UV method indicating stability. Solutions were considered steady if the concentration remained at over 90% of the initial value. In the adapted storage conditions, the evolution of osmolality, pH and sterility was assessed. RESULTS: Stability profiles were identical between vials and syringes in all storage and temperature conditions. The solution was stable (cefuroxime concentration, pH and osmolality) and still sterile for 365 days at 20 degrees C. The concentration fell below 90% after 21 days at +5 degrees C and after 16 h at +25 degrees C/60%s relative humidity. CONCLUSIONS: The COC and thermoplastic elastomer of the vials had no impact on the degradation process confirming its possible use for a ready-to-use cefuroxime solution single-unit dose. PMID- 26006334 TI - Topical delivery of leflunomide for rheumatoid arthritis treatment: evaluation of local tissue deposition of teriflunomide and its anti-inflammatory effects in an arthritis rat model. AB - OBJECTIVE: We investigated whether leflunomide can be delivered topically and metabolized into teriflunomide through the skin, and evaluated the therapeutic effect of topical leflunomide. METHODS: Permeation of leflunomide across and formation of its active metabolite within the skin was examined ex vivo. Deposition of teriflunomide in micropig knee joints after applying topical and transdermal patches containing leflunomide was investigated by determining the plasma and joint tissue concentrations. Finally, the anti-inflammatory effects and inhibition of skin sensitization by topical leflunomide were evaluated in a rat adjuvant arthritis model and mice with delayed-type induced hypersensitivity. RESULTS: We found that after topical application of leflunomide on freshly excised mouse, rat and guinea pig skin, ~24% of the permeated drug existed as teriflunomide. In micropigs treated topically with leflunomide on the knee joint, significantly lower teriflunomide concentrations were found in plasma, but its concentrations in the knee joint were 3.4-fold to 54.6-fold higher than those after oral administration. In a rat arthritis model, the plasma concentration of teriflunomide after treatment with 10% leflunomide topical solution was 7.54-fold lower than that after 10 mg/kg oral leflunomide. However, topical leflunomide was nearly as effective as oral in inhibiting paw edema (37% versus 56%, respectively). The values for hypersensitized mouse ear weight after treatment with topical leflunomide decreased significantly by 26% compared to vehicle. CONCLUSION: These results demonstrate that topically applied leflunomide can be delivered effectively and deposited as teriflunomide in an arthritic joint, possibly allowing better compliance in rheumatoid arthritis patients by avoiding leflunomide's side effects. PMID- 26006335 TI - Selective GaSb radial growth on crystal phase engineered InAs nanowires. AB - In this work we have developed InAs nanowire templates, with designed zinc blende and wurtzite segments, for selective growth of radial GaSb heterostructures using metal organic vapor phase epitaxy. We find that the radial growth rate of GaSb is determined by the crystal phase of InAs, and that growth is suppressed on InAs segments with a pure wurtzite crystal phase. The morphology and the thickness of the grown shell can be tuned with full control by the growth conditions. We demonstrate that multiple distinct core-shell segments can be designed and realized with precise control over their length and axial position. Electrical measurements confirm that suppression of shell growth is possible on segments with wurtzite structures. This growth method enables new functionalities in structures formed by using bottom-up techniques, with complexity beyond that attainable by using top-down techniques. PMID- 26006336 TI - In vitro steroid-induced meiosis in Rhinella arenarum oocytes: role of pre-MPF activation. AB - In this work we showed the relationship between seasonal periods and the response of R. arenarum follicles and oocytes to different steroids. Using in vitro germinal vesicle breakdown (GVBD) assays, we demonstrated that P4 is the main steroid capable of inducing maturation in R. arenarum oocytes and follicles. In the second part of this work we showed that androgens can activate pre-maturation promoting factors (pre-MPFs) such as P4, by cytoplasm microinjection experiments. The results indicated that the steroids assayed induced oocyte and follicle maturation in a dose- and time-dependent manner. In oocytes, P4 was the most efficient steroid as a maturation inducer (EC50 of the reproductive period, 6 nM, EC50 of the non-reproductive period ? 30 nM). Androgens (DHEA, dehydroepiandrosterone; T, testosterone; and AD, androstenedione) were less efficient maturation inducers than P4 (EC50 reproductive period ? 50, 120 and 600 nM respectively). Similar results were obtained with intact follicles in both seasonal periods. Although the response of follicles to the different androgens was variable, in no case was it above the above the response induced by P4. Independently of the season, oocytes and follicles incubated in P4, P5 and T underwent GVBD after 6-10 h while oocytes and follicles incubated in DHEA and AD matured more slowly. Furthermore, we demonstrated that microinjection of mature cytoplasm from androgen-treated oocytes is sufficient to promote GVBD in immature recipient oocytes (DHEA, 57 +/- 12%; AD, 60 +/- 8%; T, 56 +/- 13%). Thus, androgens such as DHEA, T and AD are as competent as P4 to activate pre-MPF. PMID- 26006337 TI - Phonon-assisted energy back transfer-induced multicolor upconversion emission of Gd2O3:Yb(3+)/Er(3+) nanoparticles under near-infrared excitation. AB - Manipulation of upconversion (UC) emission is of particular importance for multiplexed bioimaging. Here, we precisely manipulate the UC color output by utilizing the phonon-assisted energy back transfer (EBT) process in ultra-small (sub-10 nm) Gd2O3:Yb(3+)/Er(3+) UC nanoparticles (UCNPs). We synthesized the Gd2O3:Yb(3+)/Er(3+) UCNPs by adopting the laser ablation in liquid (LAL) technique. The synthesized Gd2O3:Yb(3+)/Er(3+) UCNPs are small spherical and monoclinic structures. Continuous color-tunable (from green to red) UC fluorescence emission is achieved by increasing the concentration of Yb(3+) ions from 0 to 15 mol%. A phonon-assisted energy back transfer (EBT) process from Er(3+) ((4)S3/2 -> (4)I13/2) to nearby Yb(3+) ((2)F7/2 -> (2)F5/2), which can significantly enhance red emission at 672 nm and decrease green emission, is responsible for the color-tunable UC emission by increasing the Yb(3+) concentration in Gd2O3:Yb(3+)/Er(3+) UC nanoparticles. PMID- 26006338 TI - Socioeconomic Status Across the Life Course and Cognitive Function Among Older Adults: An Examination of the Latency, Pathways, and Accumulation Hypotheses. AB - OBJECTIVE: This study investigated the relationship between life course socioeconomic status (SES) and cognitive function among older adults in the United States over a 12-year observation period. The mediation of adult SES on the association between childhood SES and cognition was examined, along with the relationship between cumulative SES and cognition. METHOD: Using a nationally representative sample from the Health and Retirement Study, cognitive status and change in cognition from 1998 to 2010 were examined using growth curve models. RESULTS: The results showed that cognitive function varied within-persons and between-persons. SES disadvantage in childhood was associated with lower cognitive function at baseline. Adult SES mediated the relationship between childhood SES and cognitive function. Persons with higher cumulative SES demonstrated an advantage in cognitive function. DISCUSSION: Childhood SES and adult SES both had relationships with cognitive status and, to a lesser degree, change in cognition in later life. PMID- 26006698 TI - NanoBRET--A Novel BRET Platform for the Analysis of Protein-Protein Interactions. AB - Dynamic interactions between proteins comprise a key mechanism for temporal control of cellular function and thus hold promise for development of novel drug therapies. It remains technically challenging, however, to quantitatively characterize these interactions within the biologically relevant context of living cells. Although, bioluminescence resonance energy transfer (BRET) has often been used for this purpose, its general applicability has been hindered by limited sensitivity and dynamic range. We have addressed this by combining an extremely bright luciferase (Nanoluc) with a means for tagging intracellular proteins with a long-wavelength fluorophore (HaloTag). The small size (19 kDa), high emission intensity, and relatively narrow spectrum (460 nm peak intensity) make Nanoluc luciferase well suited as an energy donor. By selecting an efficient red-emitting fluorophore (635 nm peak intensity) for attachment onto the HaloTag, an overall spectral separation exceeding 175 nm was achieved. This combination of greater light intensity with improved spectral resolution results in substantially increased detection sensitivity and dynamic range over current BRET technologies. Enhanced performance is demonstrated using several established model systems, as well as the ability to image BRET in individual cells. The capabilities are further exhibited in a novel assay developed for analyzing the interactions of bromodomain proteins with chromatin in living cells. PMID- 26006699 TI - Obesity: single house for many evils. AB - World Health Organization (WHO) considers obesity as one of the fastest growing metabolic disorders other than diabetes. It is a complex interplay of lifestyle and associated genes. Obesity has been considered as a disease with multiple targets and very often compared in this sense with its sibling disease type 2 diabetes. The disease is pathology of the adipocytes and develops as a result of hypertrophy and hyperplasia of these cells, former being the major concern but its effects could be seen on various organs in the form of cardio-vascular disease, stroke, cancer, diabetes, sexual dysfunction, respiratory problems and many more. An increase in the lipid content of the adipocytes changes the physiology of these cells towards more inflammatory phenotype. The array of molecules or adipokines secreted by these cells varies in concentration and type among healthy and obese subjects. On one hand where adiponectin concentration decreases, the resistin concentration increases resulting in insulin resistance among many other adipokine related effects. Specifically, an obese person develops hyperlipidemia, insulin resistance, vascular blockage, sleep apnoea, cancer etc. This review is an attempt to focus, in detail, about obesity related complications. PMID- 26006697 TI - Women veterans' experience with a web-based diabetes prevention program: a qualitative study to inform future practice. AB - BACKGROUND: Diabetes prevention is a national goal and particularly important in the Veterans Health Administration (VHA) where 1 in 4 veterans has diabetes. There is growing evidence to support the use of Web-based diabetes prevention program (DPP) interventions, shown to be as effective and often more feasible than in-person interventions. OBJECTIVE: Our primary objective was to qualitatively explore women veterans' early experiences with a Web-based DPP intervention. Our secondary objective was to estimate weight loss, participation, and engagement to provide context for our qualitative findings. METHODS: We conducted and analyzed semistructured interviews and collected data on weight change, participation, and engagement. A total of 17 women veterans with prediabetes from a Midwest VA Women's Health Clinic were eligible to participate; 15 completed interviews. RESULTS: Participants perceived the DPP program as an appealing way of initiating lifestyle changes and made them feel accountable in achieving their daily goals. The online program was convenient because it could be accessed at any time, and many found that it integrated well into daily life. However, some did not like the logging aspect and some found it to be too impersonal. Participants logged in a mean 76 times, posted a mean 46 group messages, and sent a mean 20.5 private messages to the health coach over 16 weeks. Participants lost 5.24% of baseline weight, and 82% (14/17) of participants completed at least 9 of 16 core modules. CONCLUSIONS: Women veterans' early experiences with a Web-based DPP intervention were generally positive. Accountability and convenience were key enabling factors for participation and engagement. A Web-based DPP intervention appears to be a promising means of translating the DPP for women veterans with prediabetes. PMID- 26006700 TI - The relationship between phthalates and obesity: serum and urine concentrations of phthalates. AB - BACKGROUND: A limited number of human and animal studies suggest that a relationship exists between phthalates and obesity, although this is not supported by all research. The purpose of this study was to investigate the relationship between Body Mass Index (BMI) and the levels of phthalates in human blood and urine samples. METHODS: Sixty-four overweight or 132 obese individuals (total=196) of different ages (min-max, 17-62; mean +/- SD, 42.07+/-11.3) and genders (F:M 97:99) enrolled in the study. BMI and waist circumference were measured to diagnose obesity. Venous blood samples were taken after overnight fasting. To compare the urine phthalates among participants, single spot urine (at least 10 mL) was collected from the subject after blood samples were taken. Urine and blood phthalate concentrations were measured using gas chromatography. RESULTS: Total blood/urinary phthalate levels significantly increased in proportion to the degree of obesity. There was a high correlation between the level of total phthalates in serum and BMI (rho=0.697, P<0.001), and between total urinary phthalate levels and BMI (rho=0.707, P<0.001). CONCLUSIONS: This is the first study to have shown that both blood and urinary phthalates increased in proportion to BMI. The results show a strong association between obesity and phthalates. PMID- 26006701 TI - Gender-Related Differences in Atherosclerosis. AB - Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. Considerable research has been done over the last several decades to understand the pathophysiology of atherosclerosis. It is widely believed that estrogen is responsible for the protection of women from CVD in the premenopausal age group. However, hormone replacement therapy has failed to decrease CVD events in clinical studies which points to the complexity of the relationship between vascular biology and estrogen hormones. Interestingly, preponderance of vascular and connective tissue disorders in women also points to an inherent role of hormones and tissue factors in maintenance of vascular endothelial function. The differential effect of GPER, lipoprotein A, TLRs, leucocyte-platelet aggregate markers in men and women also suggests inherent gender-related differences in the pathophysiology of atherosclerosis. A better understanding of the pathophysiology is likely to open ways to improve evidence based treatment of CVD in women. PMID- 26006702 TI - A single-dose PK study of onapristone including the effect of food on absorption. AB - PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean +/- SD) was 4.36 +/- 0.81 h for the fasted state and 3.76 +/- 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-infinity of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23 day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food. PMID- 26006703 TI - Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma. AB - PURPOSE: Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine's effect on cardiac repolarization in treatment-naive adults with advanced indolent NHL/mantle cell lymphoma (MCL). METHODS: In this multicenter, open-label, phase 3 study, patients received 6-8 28-day cycles of bendamustine (90 mg/m(2), days 1 and 2) and rituximab (375 mg/m(2), day 1). Exclusions included a history of cardiac conditions with potential for QT prolongation. The primary endpoint was change in Fridericia-corrected QT (QTcF; 3 electrocardiograms per time point) on day 2 of cycle 1, from just before infusion to end of infusion (immediately postinfusion, coinciding with maximum plasma concentration of bendamustine). Change 1 h postinfusion was also measured. Exploratory assessments included specific QTcF outlier analyses (new QTcF >500 ms, change >60 ms) and morphological changes. RESULTS: Of the 54 enrolled patients (mean age, 62.9 years), 53 received >=1 dose; 49 completed >=6 cycles. Mean QTcF change from baseline was 6.7 ms at end of infusion; no mean changes >20 ms were detected <=1 h postinfusion. No patients met specific outlier criteria at end of infusion or 1 h postinfusion. No morphological changes were detected. CONCLUSIONS: In this small treatment-naive population with advanced NHL/MCL, bendamustine did not produce a clinically relevant increase in mean QTcF on the second infusion day. The potential for delayed effects on QT interval after 1 h was not evaluated. PMID- 26006704 TI - One-stage posterior-only lumbosacral hemivertebra resection with short segmental fusion: a more than 2-year follow-up. AB - INTRODUCTION: Lumbosacral hemivertebra poses a unique problem because it can cause gross imbalance and progressive compensatory thoracolumbar deformity. Previous studies have reported lumbosacral hemivertebra resection through a combined anterior and posterior approach, but there have been no reports on the results and complications of hemivertebra resection via a posterior-only procedure and short fusion with large series of patients. MATERIALS AND METHODS: This retrospective study of a prospective collected database comprises a consecutive series of 14 congenital scoliosis due to lumbosacral hemivertebra treated by 1-stage posterior hemivertebra resection with short segmental fusion, with at least a 2-year follow-up period (24-144 months). Surgical reports and patient charts were reviewed. Radiographic evaluation included measured changes in segmental scoliosis and lordosis, compensatory scoliosis, thoracic kyphosis, lumbar lordosis, and trunk shift. Quality of life data from Scoliosis Research Society (SRS)-22 questionnaires were also collected. RESULTS: Our results showed that the mean follow-up period was 38.4 months. The mean fusion level was 3.2 segments. Mean operation time was 207.8 min with the average blood loss of 235.7 ml. The mean segmental scoliosis was 30 degrees preoperatively, 5 degrees postoperatively (83 % correction rate), and 4 degrees (87 %) at the latest follow-up. The compensatory coronal curve of 30 degrees was spontaneously corrected to 13 degrees at most recent follow-up. Trunk shift was significantly improved on both coronal (63 %) and sagittal plane (58 %) after the surgery, and kept stable during the follow-up. The total SRS-22 score, the self-image domain score and the satisfaction domain score demonstrated significant improvement compared with preoperative status. Only one intra-operative complication was observed, a pedicle fracture. CONCLUSIONS: In summary, our results showed that one-stage HV resection and short segment fusion by a posterior approach can offer excellent scoliosis correction and trunk shift improvement without neurological complications, while saving motion segments as much as possible. This strategy is not only corrective of the deformity but also preventive of compensatory curve progression, thus avoiding long lumbar fusion. PMID- 26006705 TI - Prevalence of gluteus medius weakness in people with chronic low back pain compared to healthy controls. AB - PURPOSE: Clinical observation suggests that hip abductor weakness is common in patients with low back pain (LBP). The purpose of this study is to describe and compare the prevalence of hip abductor weakness in a clinical population with chronic non-specific LBP and a matched sample without LBP. METHODS: One hundred fifty subjects with chronic non-specific LBP and a matched cohort of 75 control subjects were recruited. A standardized back and hip physical exam was performed. Specifically tensor fascia lata, gluteus medius, and gluteus maximus strength were assessed with manual muscle testing. Functional assessment of the hip abductors was performed with assessment for the presence of the Trendelenburg sign. Palpation examination of the back, gluteal and hip region was performed to try and reproduce the subject's pain complaint. Friedman's test or Cochran's Q with post hoc comparisons adjusted for multiple comparisons was used to compare differences between healthy controls and people with chronic low back pain for both the affected and unaffected sides. Mann-Whitney U was used to compare differences in prevalence between groups. Hierarchical linear regression was used to identify predictors of LBP in this sample. RESULTS: Gluteus medius is weaker in people with LBP compared to controls or the unaffected side (Friedman's test, p < 0.001). The Trendelenburg sign is more prevalent in subjects with LBP than controls (Cochran's Q, p < 0.001). There is more palpation tenderness over the gluteals, greater trochanter, and paraspinals in people with low back pain compared to controls (Cochran's Q, p < 0.001). Hierarchical linear regression, with BMI as a covariate, demonstrated that gluteus medius weakness, low back regional tenderness, and male sex were predictive of LBP in this sample. CONCLUSION: Gluteus medius weakness and gluteal muscle tenderness are common symptoms in people with chronic non-specific LBP. Future investigations should validate these findings with quantitative measures as well as investigate the effect of gluteus medius strengthening in people with LBP. PMID- 26006707 TI - Evaluation of blood volume by use of blood oxygen level-dependent magnetic resonance imaging in a cuff-compression model: usefulness of calculated echo time image. AB - PURPOSE: Separate assessment of changes in blood oxygenation and blood volume is required in blood oxygen level-dependent (BOLD) imaging. We developed a calculated echo time (TE) imaging technique designed to minimize effects of blood oxygenation and to evaluate blood volume specifically. MATERIALS AND METHODS: Dynamic 3T multi-echo BOLD images of calf muscle were acquired from six healthy volunteers by use of a cuff-compression model. Calculated TE images at TE = 0 ms (cTE0) and T2* map (T2*) were calculated from acquired multi-echo images. The time courses of the mean value for the entire calf muscles in cTE0, in acquired BOLD images at TE = 45.2 ms (aTE45), and in T2* were obtained. The Euclidean distances between the two pairs of time courses were calculated: distance between aTE45 and T2* (D at), and that between cTE0 and T2* (D ct). The difference between D at and D ct was tested by use of the Wilcoxon signed rank test. RESULTS: D at was significantly different from D ct (P = 0.031), indicating that the time course of cTE0 was significantly different from that of blood oxygenation-weighted images (T2* and aTE45). CONCLUSION: The effect of blood oxygenation could be minimized using cTE0. Thus, signal intensity changes of cTE0 reflected changes in blood volume more specifically. PMID- 26006706 TI - Characteristics of lumbar spondylolysis in elementary school age children. AB - PURPOSE: Lumbar spondylolysis, a stress fracture of the pars interarticularis in the lumbar spine, is often precipitated by trauma, but there may be a congenital predisposition to this condition. There have been few studies on spondylolysis in young children, despite their suitability for studies on congenital defects. The aim of this study was to identify the clinical features of lumbar spondylolysis in elementary school age children in order to elucidate its pathogenesis. METHODS: Thirty lumbar spondylolysis patients (23 boys, 7 girls, including a pair of twins; mean age 9.5 years, age range 5-12 years) were studied. Patient data on history of athletic activity, symptoms at first consultation, and radiological findings such as spinal level, stage of the stress fracture, and skeletal age were collected. RESULTS: Among the 30 patients, 27 (21 boys, 6 girls) had L5 spondylolysis (90.0 %). Only 2 patients had no history of athletic activity at the first consultation. All patients, except for 2 whose diagnosis was incidental, complained of low back pain. In the 27 patients with L5 spondylolysis, 17 (63.0 %) had terminal-stage fracture and 25 (92.6 %) had spina bifida occulta (SBO) involving the S1 lamina. Sixteen of the 27 (59.3 %) had SBO involving the affected lamina (L5) and S1 lamina. In contrast, the 3 patients with L3 or L4 spondylolysis had no evidence of SBO. With respect to skeletal age, 23 of the 27 L5 spondylolysis patients (85.2 %) were in the cartilaginous stage while the remaining 4 patients were in the apophyseal stage. CONCLUSION: Lumbar spondylolysis in elementary school age children was commonly a terminal-stage bone defect at L5, which was not necessarily related to history of athletic activity and was sometimes asymptomatic. It was often associated with SBO, indicating a possible congenital predisposition. These findings may provide further insight into the pathogenesis of lumbar spondylolysis. PMID- 26006708 TI - Externalizing Problem Behavior in Adolescence: Dopaminergic Genes in Interaction with Peer Acceptance and Rejection. AB - Molecular gene-by-environment studies primarily have focuses on the parent-child relationship as an environmental factor, whereas studies including peer relationships as environmental factor are rare. However, the effects of the peer context may not be the same for all adolescents due to biological characteristics. This study examined whether the effects of peer rejection and acceptance on externalizing behavior depend upon adolescents' genotype for the dopamine transporter (DAT1) or receptor D4 (DRD4) gene. In a sample of 563 adolescents (52% girls; Mage = 13.81), saliva samples, within-classroom peer nominations, and multi-informant behavior ratings were collected. Peer rejection, but not acceptance, was associated with externalizing problems. One out of eight models tested for rule-breaking behavior showed genetic moderation. According to the Roisman criteria, there was evidence for the differential susceptibility hypothesis. DAT1 10R carriers showed more rule-breaking behavior according to parents when experiencing high peer rejection, but less rule-breaking behavior when experiencing low peer rejection. The long DRD4 variant was associated with less aggression, but no moderation effects were found. The results are discussed in light of the differential susceptibility hypothesis and the reward sensitivity mechanism. PMID- 26006709 TI - Genetic Influences on Peer and Family Relationships Across Adolescent Development: Introduction to the Special Issue. AB - Nearly all aspects of human development are influenced by genetic and environmental factors, which conjointly shape development through several gene environment interplay mechanisms. More recently, researchers have begun to examine the influence of genetic factors on peer and family relationships across the pre-adolescent and adolescent time periods. This article introduces the special issue by providing a critical overview of behavior genetic methodology and existing research demonstrating gene-environment processes operating on the link between peer and family relationships and adolescent adjustment. The overview is followed by a summary of new research studies, which use genetically informed samples to examine how peer and family environment work together with genetic factors to influence behavioral outcomes across adolescence. The studies in this special issue provide further evidence of gene-environment interplay through innovative behavior genetic methodological approaches across international samples. Results from the quantitative models indicate environmental moderation of genetic risk for coercive adolescent-parent relationships and deviant peer affiliation. The molecular genetics studies provide support for a gene-environment interaction differential susceptibility model for dopamine regulation genes across positive and negative peer and family environments. Overall, the findings from the studies in this special issue demonstrate the importance of considering how genes and environments work in concert to shape developmental outcomes during adolescence. PMID- 26006710 TI - lambda-Carrageenan Suppresses Tomato Chlorotic Dwarf Viroid (TCDVd) Replication and Symptom Expression in Tomatoes. AB - The effect of carrageenans on tomato chlorotic dwarf viroid (TCDVd) replication and symptom expression was studied. Three-week-old tomato plants were spray treated with iota(iota)-, lambda(lambda)-, and kappa(kappa)-carrageenan at 1 g.L 1 and inoculated with TCDVd after 48 h. The lambda-carrageenan significantly suppressed viroid symptom expression after eight weeks of inoculation, only 28% plants showed distinctive bunchy-top symptoms as compared to the 82% in the control group. Viroid concentration was reduced in the infected shoot cuttings incubated in lambda-carrageenan amended growth medium. Proteome analysis revealed that 16 tomato proteins were differentially expressed in the lambda-carrageenan treated plants. Jasmonic acid related genes, allene oxide synthase (AOS) and lipoxygenase (LOX), were up-regulated in lambda-carrageenan treatment during viroid infection. Taken together, our results suggest that lambda-carrageenan induced tomato defense against TCDVd, which was partly jasmonic acid (JA) dependent, and that it could be explored in plant protection against viroid infection. PMID- 26006711 TI - Design of Chitosan-Grafted Carbon Nanotubes: Evaluation of How the -OH Functional Group Affects Cs+ Adsorption. AB - In order to explore the effect of -OH functional groups in Cs+ adsorption, we herein used the low temperature plasma-induced grafting method to graft chitosan onto carbon nanotubes (denoted as CTS-g-CNTs), as raw-CNTs have few functional groups and chitosan has a large number of -OH functional groups. The synthesized CTS-g-CNT composites were characterized using different techniques. The effect of -OH functional groups in the Cs+ adsorption process was evaluated by comparison of the adsorption properties of raw-CNTs with and without grafting chitosan. The variation of environmental conditions such as pH and contact time was investigated. A comparison of contaminated seawater and simulated groundwater was also evaluated. The results indicated that: (1) the adsorption of Cs+ ions was strongly dependent on pH and the competitive cations; (2) for CNT-based material, the -OH functional groups have a positive effect on Cs+ removal; (3) simulated contaminated groundwater can be used to model contaminated seawater to evaluate the adsorption property of CNTs-based material. These results showed direct observational evidence on the effect of -OH functional groups for Cs+ adsorption. Our findings are important in providing future directions to design and to choose effective material to remedy the removal of radioactive cesium from contaminated groundwater and seawater, crucial for public health and the human social environment. PMID- 26006712 TI - Tackling the Cytotoxic Effect of a Marine Polycyclic Quinone-Type Metabolite: Halenaquinone Induces Molt 4 Cells Apoptosis via Oxidative Stress Combined with the Inhibition of HDAC and Topoisomerase Activities. AB - A marine polycyclic quinone-type metabolite, halenaquinone (HQ), was found to inhibit the proliferation of Molt 4, K562, MDA-MB-231 and DLD-1 cancer cell lines, with IC50 of 0.48, 0.18, 8.0 and 6.76 MUg/mL, respectively. It exhibited the most potent activity against leukemia Molt 4 cells. Accumulating evidence showed that HQ may act as a potent protein kinase inhibitor in cancer therapy. To fully understand the mechanism of HQ, we further explored the precise molecular targets in leukemia Molt 4 cells. We found that the use of HQ increased apoptosis by 26.23%-70.27% and caused disruption of mitochondrial membrane potential (MMP) by 17.15%-53.25% in a dose-dependent manner, as demonstrated by Annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of Molt 4 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by HQ, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of HQ. The results of a cell-free system assay indicated that HQ could act as an HDAC and topoisomerase catalytic inhibitor through the inhibition of pan-HDAC and topoisomerase IIalpha expression, respectively. On the protein level, the expression of the anti-apoptotic proteins p-Akt, NFkappaB, HDAC and Bcl-2, as well as hexokinase II was inhibited by the use of HQ. On the other hand, the expression of the pro-apoptotic protein Bax, PARP cleavage, caspase activation and cytochrome c release were increased after HQ treatment. Taken together, our results suggested that the antileukemic effect of HQ is ROS-mediated mitochondrial apoptosis combined with the inhibitory effect on HDAC and topoisomerase activities. PMID- 26006713 TI - Molecular architecture and biomedical leads of terpenes from red sea marine invertebrates. AB - Marine invertebrates including sponges, soft coral, tunicates, mollusks and bryozoan have proved to be a prolific source of bioactive natural products. Among marine-derived metabolites, terpenoids have provided a vast array of molecular architectures. These isoprenoid-derived metabolites also exhibit highly specialized biological activities ranging from nerve regeneration to blood-sugar regulation. As a result, intense research activity has been devoted to characterizing invertebrate terpenes from both a chemical and biological standpoint. This review focuses on the chemistry and biology of terpene metabolites isolated from the Red Sea ecosystem, a unique marine biome with one of the highest levels of biodiversity and specifically rich in invertebrate species. PMID- 26006715 TI - Determination of the chemical structures of tandyukisins B-D, isolated from a marine sponge-derived fungus. AB - Tandyukisins B-D (1-3), novel decalin derivatives, have been isolated from a strain of Trichoderma harzianum OUPS-111D-4 originally derived from the marine sponge Halichondria okadai, and their structures have been elucidated on the basis of spectroscopic analyses using 1D and 2D NMR techniques. In addition, their chemical structures were established by chemical transformation. They exhibited weak cytotoxicity, but selective growth inhibition on panel screening using 39 human cancer cell lines. PMID- 26006714 TI - Alternative and efficient extraction methods for marine-derived compounds. AB - Marine ecosystems cover more than 70% of the globe's surface. These habitats are occupied by a great diversity of marine organisms that produce highly structural diverse metabolites as a defense mechanism. In the last decades, these metabolites have been extracted and isolated in order to test them in different bioassays and assess their potential to fight human diseases. Since traditional extraction techniques are both solvent- and time-consuming, this review emphasizes alternative extraction techniques, such as supercritical fluid extraction, pressurized solvent extraction, microwave-assisted extraction, ultrasound-assisted extraction, pulsed electric field-assisted extraction, enzyme assisted extraction, and extraction with switchable solvents and ionic liquids, applied in the search for marine compounds. Only studies published in the 21st century are considered. PMID- 26006716 TI - Enhanced Control of Bladder-Associated Tumors Using Shrimp Anti Lipopolysaccharide Factor (SALF) Antimicrobial Peptide as a Cancer Vaccine Adjuvant in Mice. AB - Shrimp anti-lipopolysaccharide factor (SALF) is an antimicrobial peptide with reported anticancer activities, such as suppression of tumor progression. In this study, we prepared a potential cancer vaccine comprised of SALF in conjunction with the cell lysate of inactivated murine bladder carcinoma cells (MBT-2), and evaluated its efficacy in a mouse tumor model. Our study shows that SALF added to cell culture media inhibits growth progression of MBT-2, and that SALF together with inactivated MBT-2 lysate elevates the level of inflammasome activity, and modulates the levels of IL-1beta, MCP-1, IL-6, IL-12, and TNF-alpha in mouse macrophages. Immunization of 7, 14, and 21 day-old mice with the vaccine prevented growth of MBT-2 cell-mediated tumors. The vaccine was found to enhance expression of T-cell, cytotoxic T cells, and NK cells in the immunized mice groups. Recruitment of macrophages, T-helper cells, and NK cells was enhanced, but levels of VEGF were decreased in immunized mice. This report provides empirical evidence that our SALF as vaccine adjuvant enhances antitumor immunity in mice. PMID- 26006717 TI - Prognostic significance of ultrasound-assessed jugular vein distensibility in heart failure. AB - AIMS: Jugular venous distension is a classical sign of heart failure (HF) but it can be difficult to assess clinically. METHODS AND RESULTS: Outpatients with HF and control subjects were assessed. Internal jugular vein diameter (JVD) was measured using a linear high-frequency ultrasound probe (10 MHz) at rest, after a Valsalva manoeuvre and during deep inspiration. JVD ratio was calculated as the maximum diameter during Valsalva to that measured at rest. 311 patients (mean age 71 years, mean left ventricular EF 42%, median (IQR) amino-terminal pro-brain natriuretic peptide 979 (441-2007) ng/L) and 66 controls were included. JVD (median and IQR range) at rest was smaller in controls (0.16 (0.14-0.20) cm) than in patients with HF (0.23 (0.17-0.33) cm; p<0.001) but similar during Valsalva (1.03 (0.90-1.16) cm vs 1.08 (0.90-1.25) cm; p=0.28). Consequently, JVD ratio was greater in controls (6.3 (4.9-7.6)) than in patients (4.5 (2.9-6.1); p<0.001). During a median follow-up of 516 (IQR 335-622) days, 48 patients (15%) with HF died or were hospitalised for HF. In multivariable models, among clinical, echocardiographic or biochemical variables, only increasing NT-proBNP and ultrasound assessment of internal jugular vein were independently associated with prognosis. Comparing top and bottom tertiles of JVD ratio (2.3 (IQR 1.7-2.9) versus 6.8 (6.1-7.7)), the tertile with lower values had a 10-fold greater risk of an adverse event (HR 10.05, 95% CI 3.07 to 32.93). CONCLUSIONS: Ultrasound assessment of the internal jugular vein identifies outpatients with HF who have a higher risk of an adverse outcome. CLINICAL TRIAL REGISTRATION: NCT01872299. PMID- 26006719 TI - Heavy Metals in Sediment from Bei Shan River: Distribution, Relationship with Soil Characteristics and Multivariate Assessment of Contamination Sources. AB - The concentrations and correlation between some heavy metals (Mn, Cd, Cr, Cu, Ni, Zn and Pb) measured in sediments in part of Bei shan River near uranium mill tailings were studied. The mean concentration of Cr (57.7 mg/g) was more than the mean values established for uncultivated areas worldwide (46.3 mg/g). Negative correlations with pH and positive correlations with organic matter have been observed for most of elements analyzed in this study. Correlation analysis showed that all metals except Cr are highly correlated (p <= 0.01, p <= 0.05). This may indicate the different origin or controlling factors of Cr in analyzed sediments. Cluster analysis highlighted the lithogenic origin of heavy metals (Mn, Cd, Cu, Ni, Zn and Pb) and pointed out the primary input of Cr from anthropogenic sources. PMID- 26006720 TI - Molecular Characterization of QDPR Gene in Iranian Families with BH4 Deficiency: Reporting Novel and Recurrent Mutations. AB - Newborn screening for PKU has been in practice in Iran since 2007. Some hyperphenylalaninemia cases have tetrahydrobiopterin (BH4) biosynthesis deficiency/disorder. Several genes including QDPR (encodes DHPR enzyme, the necessary cofactor for PAH activity) have been associated with the BH4. Mutations have been previously described in the QDPR gene. The incidence of BH4 deficiency is expected to be higher in Iran due to high rate of consanguineous marriages.We identified a total of 93 BH4-deficient families. A multiplex set of STR markers linked to 4 genes responsible for the BH4 deficiency (i.e., GCH1, PCBD1, PTS, and QDPR genes) was used to quickly determine which gene may be responsible to cause the disease. Mutation analysis of QDPR gene revealed some known and novel mutations. Our findings show that no common mutation predominates, and they are scattered in the gene in our population. PMID- 26006718 TI - Eosinophilic Drug Allergy. AB - While peripheral or tissue eosinophilia may certainly characterize drug eruptions, this feature is hardly pathognomonic for a medication-induced etiology. While delayed drug hypersensitivity reactions with prominent eosinophilic recruitment have been typically classified as type IVb reactions, their pathophysiology is now known to be more complex. Eosinophilic drug reactions have a diversity of presentations and may be benign and self-limited to severe and life-threatening. The extent of clinical involvement is also heterogeneous, ranging from isolated peripheral eosinophilia or single organ involvement (most often the skin and lung) to systemic disease affecting multiple organs, classically exemplified by drug-reaction with eosinophilia and systemic symptoms (DRESS). The spectrum of implicated medications in the causation of DRESS is ever expanding, and multiple factors including drug metabolites, specific HLA alleles, herpes viruses, and immune system activation have been implicated in pathogenesis. Due to this complex interplay of various factors, diagnostic workup in terms of skin and laboratory testing has not been validated. Similarly, the lack of controlled trials limits treatment options. This review also describes other localized as well as systemic manifestations of eosinophilic disease induced by various medication classes, including their individual pathophysiology, diagnosis, and management. Given the multitude of clinical patterns associated with eosinophilic drug allergy, the diagnosis can be challenging. Considerable deficits in our knowledge of these presentations remain, but the potential for severe reactions should be borne in mind in order to facilitate diagnosis and institute appropriate management. PMID- 26006721 TI - CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency. AB - Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease. PMID- 26006722 TI - Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency. AB - Sepiapterin reductase (SR) deficiency is a rare autosomal recessively inherited error of tetrahydrobiopterin (BH4) biosynthesis, resulting in disturbed dopaminergic and serotonergic neurotransmission. The clinical phenotype is characterized by dopa-responsive movement disorders including muscular hypotonia, dystonia, and parkinsonism. Due to the rarity of the disease, the phenotype of SR deficiency is far from being completely understood. Here, we report a 7-year-old boy, who was referred for diagnostic evaluation of combined psychomotor retardation, spastic tetraplegia, extrapyramidal symptoms, and short stature. Due to discrepancy between motor status and mental condition, analyses of biogenic amines and pterins in CSF were performed, leading to the diagnosis of SR deficiency. The diagnosis was confirmed by a novel homozygous mutation c.530G>C; p.(Arg177Pro) in exon 2 of the SPR gene. Because of persistent short stature, systematic endocrinological investigations were initiated. Insufficient growth hormone release in a severe hypoglycemic episode after overnight fasting confirmed growth-hormone deficiency as a cause of short stature. In addition, central hypothyroidism was present. A general hypothalamic affection could be excluded. Since dopamine is known to regulate growth-hormone excretion, IGF-1, IGF-BP3, and peripheral thyroid hormone levels were monitored under L dopa/carbidopa supplementation. Both growth-hormone-dependent factors and thyroid function normalized under treatment. This is the first report describing growth hormone deficiency and central hypothyroidism in SR deficiency. It extends the phenotypic spectrum of the disease and identifies dopamine depletion as cause for the endocrinological disturbances. PMID- 26006723 TI - The learning of action sequences through social transmission. AB - Previous empirical work on animal social learning has found that many species lack the ability to learn entire action sequences solely through reliance on social information. Conversely, acquiring action sequences through asocial learning can be difficult due to the large number of potential sequences arising from even a small number of base actions. In spite of this, several studies report that some primates use action sequences in the wild. We investigate how social information can be integrated with asocial learning to facilitate the learning of action sequences. We formalize this problem by examining how learners using temporal difference learning, a widely applicable model of reinforcement learning, can combine social cues with their own experiences to acquire action sequences. The learning problem is modeled as a Markov decision process. The learning of nettle processing by mountain gorillas serves as a focal example. Through simulations, we find that the social facilitation of component actions can combine with individual learning to facilitate the acquisition of action sequences. Our analysis illustrates that how even simple forms of social learning, combined with asocial learning, generate substantially faster learning of action sequences compared to asocial processes alone, and that the benefits of social information increase with the length of the action sequence and the number of base actions. PMID- 26006724 TI - One stage combined endoscopic and per-oral buccal fat pad approach for large oro antral-fistula closure with secondary chronic maxillary sinusitis. AB - There are numerous surgical approaches for oro-antral-fistula (OAF) closure. Secondary sinus disease is still considered by many experts a relative contra indication for primary closure. To describe a single-stage combined endoscopic sinus surgery and per-oral buccal fat pad (BFP) flap approach for large OAF causing chronic maxillary sinusitis. The records of all the patients with OAF and chronic manifestations of secondary rhinosinusitis that were treated between 2010 and 2013 in our tertiary care medical center were reviewed. The exclusion criteria were: OAF <= 5 mm, resolved sino-nasal disease, OAF secondary to malignancy, recurrent fistula, medical history that included radiotherapy to the maxillary bone and age <18 years. Each procedure was performed by a team consisting of a rhinologist and a maxillofacial surgeon. The surgical approach included an endoscopic middle antrostomy with maxillary sinus drainage, and a per oral BFP regional flap for OAF closure. Total OAF closure, complications and need for revision surgeries. Forty-five patients that underwent OAF closure together with sinus surgery using a combined endoscopic sinus surgery (ESS) and BFP flap approach met the inclusion criteria. There were 28 males and 17 females with a mean +/- SD age of 53.5 +/- 14.9 years (range 22-80 years). The presenting signs and symptoms included purulent rhinorrhea (n = 22, 48.9 %), foreign body in sinus (n = 10, 22.2 %) nasal congestion (n = 7, 15.5 %), halitosis (n = 6, 13.3 %) and pain (n = 5, 12.2 %). Surgical complications included local pain (n = 2, 4.4 %), persistent rhinitis (n = 2, 4.4 %) and synechia (n = 1, 2.2 %). One patient required revision surgery due to an unresolved OAF. The OAF of all the other 44 patients (97.8 %) was closed after the first procedure and the paranasal sinuses on the treated side were completely recovered. The mean follow-up time for the group was 7.6 +/- 4.3 months (7-21 months), and no untoward sequelae or recurrence were reported. Combined, one step, endoscopic Maxillary sinus drainage together with per-oral BFP flap approach is an efficacious surgical approach for safe closure of OAFs that are complicated with secondary chronic maxillary sinusitis. PMID- 26006725 TI - Importance of Postoperative Hydration and Lower Extremity Elevation in Preventing Deep Venous Thrombosis in Full Abdominoplasty: A Report on 450 Consecutive Cases Over a 37-Year Period. AB - BACKGROUND: Abdominoplasty is a common plastic surgery procedure and has a higher rate of postoperative deep venous thrombosis (DVT) than any other such surgery. DVT prevention remains an important topic in the plastic surgery community. Many surgeons avoid DVT chemoprophylaxis, because they are concerned about the risk of postoperative bleeding. OBJECTIVE: This study was performed in order to evaluate postoperative hydration and lower extremity elevation as two alternative methods of aiding DVT prevention after abdominoplasty. METHODS: Preoperative, intraoperative, and postoperative measures were taken to monitor patient hydration via urine output and to ensure adequate hydration by providing intravenous fluids. In addition, measures were taken throughout these three phases to ensure adequate lower extremity elevation. RESULTS: In a group of 450 consecutive full abdominoplasties from 1976 to 2013, the overall rate of patient DVT at 30 days following surgery was 0.22%. CONCLUSIONS: Hydration and lower extremity elevation are innocuous and risk-free adjuncts that improve venous return from the legs and lessen the chance of postoperative DVT. PMID- 26006726 TI - Isolation and differentiation potential of human mesenchymal stem cells from adipose tissue harvested by water jet-assisted liposuction. AB - BACKGROUND: In recent years the therapeutic application of extracted adipose tissue for autologous fat grafting and the application of adipose tissue-derived mesenchymal stem cells (adMSC) isolated thereof has progressed. Water-jet assisted liposuction (WAL) is 1 procedure for harvesting adipose tissue and provides a favorable aesthetic outcome combined with high tissue protection. Tissue aspirated by WAL has been successfully applied in grafting procedures. OBJECTIVES: The aims of this study were to confirm the tissue viability and to understand the abundance and mesenchymal differentiation capacity of stem cells within the tissue. METHODS: We analyzed tissue integrity of WAL tissue particles via fluorescence microscopy. The adMSC content was determined by isolating the cells from the tissue. The mesenchymal differentiation capacity was confirmed with cytochemical staining methods. RESULTS: The stromal vascular fraction of WAL tissue showed high viability and contained an average of 2.6 * 105 CD34-positive cells per milliliter of tissue. Thus WAL tissue contains a high number of stem cells. Furthermore adMSC isolated from WAL tissue showed typical mesenchymal differentiation potential. CONCLUSIONS: WAL of adipose tissue is well suited for autologous fat grafting because it retains tissue viability. Furthermore it is a valid source for the subsequent isolation of adMSC with multipotent differentiation potential. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 26006727 TI - Yield, Quality, and Nutrient Concentrations of Strawberry (Fragaria *ananassa Duch. cv. 'Sonata') Grown with Different Organic Fertilizer Strategies. AB - Four combinations of two solid organic fertilizers (Monterra Malt and chicken manure) applied before planting and two liquid organic fertilizers (broad bean and Pioner Hi-Fruit/K-Max) given through drip irrigation (fertigation) were compared with inorganic fertilization regarding growth, yield, nutrient concentration, and fruit quality of strawberries. Broad bean fertigation combined with Monterra Malt resulted in a similar fruit yield as inorganic fertilizer and a higher yield than Monterra Malt combined with Pioner; however, total soluble solids, firmness, and titratable acid were improved with Pioner fertigation, although these parameters were more affected by harvest time than the applied fertilizers. The concentrations of most nutrients in fruits and leaves were higher in inorganically fertigated plants. The reductions in fruit yield in three of four treatments and fruit weight in all organic treatments may be due to a combination of the following conditions in the root zone: (1) high pH and high NH4(+)/NO3(-) ratio; (2) high EC and/or high NaCl concentration; (3) cation imbalance; and (4) nutrient deficiency. PMID- 26006728 TI - Unexpected edge conduction in mercury telluride quantum wells under broken time reversal symmetry. AB - The realization of quantum spin Hall effect in HgTe quantum wells is considered a milestone in the discovery of topological insulators. Quantum spin Hall states are predicted to allow current flow at the edges of an insulating bulk, as demonstrated in various experiments. A key prediction yet to be experimentally verified is the breakdown of the edge conduction under broken time-reversal symmetry. Here we first establish a systematic framework for the magnetic field dependence of electrostatically gated quantum spin Hall devices. We then study edge conduction of an inverted quantum well device under broken time-reversal symmetry using microwave impedance microscopy, and compare our findings to a non inverted device. At zero magnetic field, only the inverted device shows clear edge conduction in its local conductivity profile, consistent with theory. Surprisingly, the edge conduction persists up to 9 T with little change. This indicates physics beyond simple quantum spin Hall model, including material specific properties and possibly many-body effects. PMID- 26006729 TI - Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells. AB - Developmental toxicity testing has traditionally relied on animal models which are costly, time consuming, and require the sacrifice of large numbers of animals. In addition, there are significant disparities between human beings and animals in their responses to chemicals. Thalidomide is a species-specific developmental toxicant that causes severe limb malformations in humans but not in mice. Here, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on differentiation of mouse embryonic stem cells (mESCs). C57BL/6 mESCs were allowed to differentiate spontaneously and RNA was collected at 24, 48, and 72h after exposure to 0.25mM thalidomide. Global gene expression analysis using microarrays revealed hundreds of differentially expressed genes upon thalidomide exposure that were enriched in gene ontology (GO) terms and canonical pathways associated with embryonic development and differentiation. In addition, many genes were found to be involved in small GTPases-mediated signal transduction, heart development, and inflammatory responses, which coincide with clinical evidences and may represent critical embryotoxicities of thalidomide. These results demonstrate that transcriptomics in combination with mouse embryonic stem cell differentiation is a promising alternative model for developmental toxicity assessment. PMID- 26006730 TI - Requirement of ERalpha and basal activities of EGFR and Src kinase in Cd-induced activation of MAPK/ERK pathway in human breast cancer MCF-7 cells. AB - Cadmium (Cd) is a common environmental toxicant and an established carcinogen. Epidemiological studies implicate Cd with human breast cancer. Low micromolar concentrations of Cd promote proliferation of human breast cancer cells in vitro. The growth promotion of breast cancer cells is associated with the activation of MAPK/ERK pathway. This study explores the mechanism of Cd-induced activation of MAPK/ERK pathway. Specifically, the role of cell surface receptors ERalpha, EGFR, and Src kinase was evaluated in human breast cancer MCF-7 cells treated with 1 3MUM Cd. The activation of ERK was studied using a serum response element (SRE) luciferase reporter assay. Receptor phosphorylation was detected by Western blot analyses. Cd treatment increased both the SRE reporter activity and ERK1/2 phosphorylation in a concentration-dependent manner. Cd treatment had no effect on reactive oxygen species (ROS) generation. Also, blocking the entry of Cd into the cells with manganese did not diminish Cd-induced activation of MAPK/ERK. These results suggest that the effect of Cd was likely not caused by intracellular ROS generation, but through interaction with the membrane receptors. While Cd did not appear to activate either EGFR or Src kinase, their inhibition completely blocked the Cd-induced activation of ERK as well as cell proliferation. Similarly, silencing ERalpha with siRNA or use of ERalpha antagonist blocked the effects of Cd. Based on these results, it is concluded that not only ERalpha, but also basal activities of EGFR and Src kinase are essential for Cd-induced signal transduction and activation of MAPK/ERK pathway for breast cancer cell proliferation. PMID- 26006731 TI - High-performance green flexible electronics based on biodegradable cellulose nanofibril paper. AB - Today's consumer electronics, such as cell phones, tablets and other portable electronic devices, are typically made of non-renewable, non-biodegradable, and sometimes potentially toxic (for example, gallium arsenide) materials. These consumer electronics are frequently upgraded or discarded, leading to serious environmental contamination. Thus, electronic systems consisting of renewable and biodegradable materials and minimal amount of potentially toxic materials are desirable. Here we report high-performance flexible microwave and digital electronics that consume the smallest amount of potentially toxic materials on biobased, biodegradable and flexible cellulose nanofibril papers. Furthermore, we demonstrate gallium arsenide microwave devices, the consumer wireless workhorse, in a transferrable thin-film form. Successful fabrication of key electrical components on the flexible cellulose nanofibril paper with comparable performance to their rigid counterparts and clear demonstration of fungal biodegradation of the cellulose-nanofibril-based electronics suggest that it is feasible to fabricate high-performance flexible electronics using ecofriendly materials. PMID- 26006732 TI - Changes in endothelial progenitor cell subsets in normal pregnancy compared with preeclampsia. AB - BACKGROUND: The results of studies measuring the number of endothelial progenitor cells (EPCs) in normal pregnancies and in preeclampsia have been highly controversial or even contradictory because of cross-sectional designs and different methodologies enumerating three distinct subsets of EPCs: circulating angiogenic cells (CAC), colony-forming unit endothelial cell (CFU-ECs), and endothelial colony forming cells (ECFCs). To provide a clear explanation for these underlying controversies, we designed a prospective study to compare the number of all EPC subsets between three trimesters of normal gestation and a case control study to compare these values as preeclampsia occurs with those from gestational age (GA) matched normal pregnancy. METHODS: Samples from peripheral blood of nine women were taken during their three consecutive trimesters of normal pregnancy, and from eight women with preeclampsia. To cover most of the reported phenotypes for CACs and ECFCs in the literature, we enumerated 13 cell populations by quantitative flow cytometry using various combinations of the markers CD34, CD133, CD309, and CD45. We used routine culturing techniques to enumerate CFU-ECs. RESULTS: The numbers of CACs and ECFCs were higher in women with preeclampsia (p = 0.014). By contrast, preeclampsia was associated with a reduced number of CFU-ECs (p = 0.039). The CAC number rose with the increase in GA (p = 0.016) during normal pregnancy, while the number of CFU-ECs and ECFCs did not differ during the trimesters. CONCLUSION: Although we did demonstrate an increase in absolute counts of CACs and ECFCs in preeclampsia, fewer colony formation capacities indicated a loss in their functional capabilities. By contrast, the number of CACs increased without alterations in colony formation ability in normal pregnancy with the growth of the fetus. Here, by comparing different methodologies to calculate the number of EPC subsets, we could imitate the existing controversy in the literature for such calculations, which may help to elucidate clearer explanations. PMID- 26006733 TI - Intensified food production and correlated risks to human health in the Greater Mekong Subregion: a systematic review. AB - BACKGROUND: Intensified food production, i.e. agricultural intensification and industrialized livestock operations may have adverse effects on human health and promote disease emergence via numerous mechanisms resulting in either direct impacts on humans or indirect impacts related to animal and environmental health. For example, while biodiversity is intentionally decreased in intensive food production systems, the consequential decrease in resilience in these systems may in turn bear increased health risks. However, quantifying these risks remains challenging, even if individual intensification measures are examined separately. Yet, this is an urgent task, especially in rapidly developing areas of the world with few regulations on intensification measures, such as in the Greater Mekong Subregion (GMS). METHODS: We systematically searched the databases PubMed and Scopus for recent studies conducted on the association between agricultural (irrigation, fertilization, pesticide application) and livestock (feed additives, animal crowding) intensification measures and human health risks in the GMS. The search terms used were iteratively modified to maximize the number of retrieved studies with relevant quantitative data. RESULTS: We found that alarmingly little research has been done in this regard, considering the level of environmental contamination with pesticides, livestock infection with antibiotic resistant pathogens and disease vector proliferation in irrigated agroecosystems reported in the retrieved studies. In addition, each of the studies identified focused on specific aspects of intensified food production and there have been no efforts to consolidate the health risks from the simultaneous exposures to the range of hazardous chemicals utilized. CONCLUSIONS: While some of the studies identified already reported environmental contamination bearing considerable health risks for local people, at the current state of research the actual consolidated risk from regional intensification measures cannot be estimated. Efforts in this area of research need to be rapidly and considerably scaled up, keeping pace with the current level of regional intensification and the speed of pesticide and drug distribution to facilitate the development of agriculture related policies for regional health promotion. PMID- 26006734 TI - Cost and efficacy comparison of in vitro fertilization and tubal anastomosis for women after tubal ligation. AB - OBJECTIVE: To compare cost and efficacy of tubal anastomosis to in vitro fertilization (IVF) in women who desired fertility after a tubal ligation. DESIGN: Cost-effectiveness analysis. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cost per ongoing pregnancy. RESULT(S): Cost per ongoing pregnancy for women after tubal anastomosis ranged from $16,446 to $223,482 (2014 USD), whereas IVF ranged from $32,902 to $111,679 (2014 USD). Across maternal age groups <35 and 35-40, years tubal anastomosis was more cost effective than IVF for ongoing pregnancy. Sensitivity analyses validated these findings across a wide range of ongoing pregnancy probabilities as well as costs per procedure. CONCLUSION(S): Tubal anastomosis was the most cost-effective approach for most women less than 41 years of age, whereas IVF was the most cost-effective approach for women aged >=41 years who desired fertility after tubal ligation. A model was created that can be modified based on cost and success rates in individual clinics for improved patient counseling. PMID- 26006735 TI - Infertility as a proxy of general male health: results of a cross-sectional survey. AB - OBJECTIVE: To evaluate the prevalence, and clinical and seminal impact of comorbidities in white European men presenting for couple infertility. DESIGN: Cross-sectional study. SETTING: Academic reproductive medicine outpatient clinic. PATIENT(S): Cohort of 2,100 consecutive infertile men (noninterracial infertile couples). INTERVENTION(S): Obtaining complete demographic, clinical, and laboratory data from 2,100 consecutive infertile men with health-significant comorbidities scored via the Charlson comorbidity index (CCI; categorized 0 vs. 1 vs. >=2) and semen analysis values assessed based on 2010 World Health Organization reference criteria. MAIN OUTCOME MEASURE(S): Assessment of the rate of comorbidities by means of CCI scores and possible associations between CCI, semen and hormonal parameters. RESULT(S): Descriptive statistics and regression models tested the associations among semen parameters, clinical characteristics, and CCI. When assessing general comorbidity prevalence, CCI 0, CCI 1, and CCI >=2 was found in 1,921 (91.5%), 102 (4.9%), and 77 (3.6%) patients, respectively. Patient age and follicle-stimulating hormone levels increased as the general health status decreased. Conversely, the total testosterone levels and sperm concentration decreased as CCI scores increased. A higher rate of oligozoospermia and nonobstructive azoospermia was observed in patients with CCI >=1. No differences were observed among the considered comorbidity groups in terms of testicular volume or further hormonal or seminal parameters. Both continuously coded and categorized sperm concentrations were independent predictors of CCI >=1. Patients with sperm concentration <45.6 million/mL (most informative cutoff value) had a 2.74-fold increased risk of having a CCI >=1. CONCLUSION(S): Decreased general health status appears to be associated with impaired male reproductive health, including lower sperm concentration, lower total testosterone levels, and higher follicle-stimulating hormone values. PMID- 26006736 TI - Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms. AB - OBJECTIVE: To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patient's age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. DESIGN: Cross sectional study. SETTING: Referral center. PATIENT(S): Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. RESULT(S): The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (beta = 0.363) and the number of myomas (beta = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. CONCLUSION(S): The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma. PMID- 26006737 TI - Blastocoel fluid from differentiated blastocysts harbors embryonic genomic material capable of a whole-genome deoxyribonucleic acid amplification and comprehensive chromosome microarray analysis. AB - OBJECTIVE: To obtain embryonic molecular karyotypes from genomic DNA (deoxyribonucleic acid) isolated from blastocoel fluid (BF) and to compare these karyotypes with the karyotypes from the remaining inner cell mass (ICM) and trophectoderm (TE) of the blastocyst. DESIGN: Prospective cohort study. SETTING: Academic center and preimplantation genetics laboratory. PATIENT(S): Ninety-six donated cryopreserved embryos. INTERVENTION(S): Embryo biopsy, BF aspiration, DNA analysis using a comparative genomic hybridization microarray (aCGH). MAIN OUTCOME MEASURE(S): The aCGH of a single blastomere, BF-DNA, and ICM-TE. RESULT(S): The BF-DNA samples resulted in a successful aCGH in 63% of cases. Discordance in karyotypes was found between the BF-DNA and the ICM-TE in 52% of cases. A total of 70% of aneusomic (mosaicism), cleavage-stage embryos differentiated into euploid blastocysts. Probabilities for diagnostic accuracy were calculated and demonstrated the following: sensitivity of 0.88 (95% confidence interval [CI]: 0.62-0.98); specificity of 0.55 (95% CI: 0.39-0.70); positive predictive value of 0.41 (95% CI: 0.25-0.60); negative predictive value of 0.92 (95% CI: 0.75-0.99). CONCLUSION(S): Genomic DNA from the BF can be amplified and characterized by comprehensive chromosome microarrays. The results demonstrated that aneusomic cleavage-stage embryos differentiated into euploid blastocysts, possibly using a mechanism that marginalizes aneuploid nuclei into the blastocoel cavity. In addition, owing to the high discordance between the karyotypes obtained from the BF-DNA and the ICM-TE, using BF-DNA for preimplantation genetic testing is not yet advised. PMID- 26006738 TI - Evaluation of a hospital-based day-structuring exercise programme on exacerbated behavioural and psychological symptoms in dementia--the exercise carrousel: study protocol for a randomised controlled trial. AB - BACKGROUND: Conceptual reviews and observational studies describe a link between physical inactivity and behavioural disturbances in people with dementia. Consequently, treatment of these symptoms requires physical activation and pharmacological or physical immobilization should be avoided. The few trials that have been conducted in inpatient dementia care to investigate the effects of exercise on behavioural and psychological symptoms revealed inconsistent results. Due to a lack of evidence, there is a paucity of recommendations for physical activation in this stage of care. Therefore, this trial seeks to investigate the effects of a day-structuring exercise programme on behavioural and psychological symptoms as well as on circadian rhythms of patients with dementia, hospitalized because of their behavioural and psychological disturbances. METHODS/DESIGN: A single-centre randomised controlled trial will be conducted in three special dementia care units of an old age psychiatry hospital. Enrolled patients will receive either a 2-week exercise programme, or a 2-week social stimulation programme in addition to usual care. Due to the provision of four day-structuring exercise-sessions in the course of an intervention day, the exercise programme for the study group is called exercise-carrousel. Baseline and post-intervention assessment for the primary outcome variable - the overall effects on behavioural and psychological symptoms--will be measured by the Alzheimer's disease Cooperative Study-Clinical Global Impression of Change. The following objectives are set up as secondary outcomes: dimensions of the behavioural and psychological symptoms of dementia (BPSD) and caregiver burden, routine and on-demand psychotropic medication, patients' motor behaviour, diurnal cortisol-levels from saliva probes and brain-derived neurotrophic factor-levels from blood serum. DISCUSSION: In order to be regarded as an important treatment option for behavioural and psychological symptoms, physical activation in inpatient hospital dementia care requires more evidence and appropriate recommendations. Respecting hospital routines and the intra-daily variability of the patients' motivation and behavioural disturbances in the provision of exercise sessions could lead to higher exercise adherence and better effects on patients' behavioural and psychological symptoms than former trials have presented. The concealment of allocation throughout the trial and the rating of individual exercise exertion present the key challenges and main limitations of this trial. TRIAL REGISTRATION: DRKS00006740 (German Clinical Trial Register, date of registration: 28 October 2014). PMID- 26006739 TI - Perfusion redistribution after a pulmonary-embolism-like event with contrast enhanced EIT. AB - Recent studies showed that regional pulmonary perfusion can be reliably estimated using electrical impedance tomography (EIT) with the aid of hypertonic saline based contrast enhancement. Building on these successful studies, we studied contrast EIT for pulmonary perfusion defect caused by an artificially induced pulmonary embolism (PE) in a large ovine model (N = 8, 78 +/- 7.8 kg). Furthermore, the efficacy of a less invasive contrast bolus of 0.77 ml kg(-1) of NaCl 3% was compared with a more concentrated bolus of 0.13 ml kg(-1) of NaCl 20%. Prior to the injection of each contrast bolus injection, ventilation was turned off to provide a total of 40 to 45 s of apnoea. Each bolus of impedance contrast was injected through a catheter into the right atrium. Pulmonary embolisation was performed by balloon occlusion of part of the right branch of the pulmonary trunk. Four parameters representing the kinetics of the contrast dilution in the lung were evaluated for statistical differences between baseline and PE, including peak value, maximum uptake, maximum washout and area under the curve of the averaged contrast dilution curve in each lung. Furthermore, the right lung to left lung (R2L) ratio of each the aforementioned parameters were assessed. While all of the R2L ratios yielded significantly different means between baseline and PE, it can be concluded that the R2L ratios of area under the curve and peak value of the averaged contrast dilution curve are the most promising and reliable in assessing PE. It was also found that the efficacy of the two types of impedance contrasts were not significantly different in distinguishing PE from baseline in our model. PMID- 26006740 TI - Temperature-controlled polymorphism of chiral Cu(II)-Ln(III) dinuclear complexes exhibiting slow magnetic relaxation. AB - A new family of 3d-4f dinuclear complexes derived from a chiral Schiff-base ligand, (R,R)-N,N'-bis(3-methoxysalicylidene)cyclohexane-1,2-diamine (H2L), has been synthesized and structurally characterized, namely, [Cu(L)Ln(NO3)3(H2O)] (Ln = Ce (1) and Nd (2)), [Cu(L)Sm(NO3)3].2CH3CN (3) and [Cu(L)Ln(NO3)3] (Ln = Eu (4), Gd (5 and 5'), Tb (6 and 6'), Dy (7 and 7'), Ho (8), Er (9) and Yb (10)). Structural determination revealed that these complexes are composed of two diphenoxo-bridged Cu(II)-Ln(III) dinuclear clusters with slight structural differences. Complexes 1, 2 and 4-7 crystallize in the chiral space group P1, and the space group of 3 is P21, while the other six complexes (5'-7' and 8-10) are isomorphous and each of them contains two slightly different Cu(II)-Ln(III) dinuclear clusters in the asymmetric unit with the chiral space group P21. Magnetic investigations showed that ferromagnetic couplings between the Cu(II) and Ln(III) ions exist in 5-7 and 5'-7'. Moreover, the alternating current (ac) magnetic susceptibilities of 6, 6', 7 and 7' showed that both the in-phase (chi') and out-of-phase (chi'') are frequency- and temperature-dependent with a series of frequency-dependent peaks for the chi'', which being typical features of field induced slow magnetic relaxation phenomena. For 8, a frequency dependent chi' with peaks but chi'' without peaks appeared; however, the compound displays field induced slow magnetic relaxation behavior. Furthermore, no obvious frequency dependent ac signal was observed in 9 owing to the absence of the easy-axis anisotropy. More significantly, we observed the temperature-controlled reversible conversion from one chiral single-crystal (5-7) to another chiral single-crystal (5'-7') exhibiting slow magnetic relaxation. PMID- 26006741 TI - Effect of wall material on the antioxidant activity and physicochemical properties of Rubus fruticosus juice microcapsules. AB - Blackberry (Rubus fruticosus) juice possesses compounds with antioxidant activity, which can be protected by different biopolymers used in the microencapsulation. Therefore, the effects of cell wall material including maltodextrin (MD), Arabic gum (GA) and whey protein concentrate (WPC) were evaluated on the physicochemical and antioxidant properties of encapsulated blackberries using a spray-drying technique. Anthocyanin concentration, polymeric colour, total polyphenols, radical scavenging activity of the 1,1-diphenyl-2 picrilhydrazil radical, reducing power and the stability at different storage conditions were evaluated. GA and MD conferred a similar protection to the antioxidant compounds when the microcapsules were stored at low water activities (aw < 0.515) in contrast to at a high moisture content (aw > 0.902), whereas WPC presented a high protection. Therefore, the selection of the best wall material for blackberry juice encapsulation depends of the conditions of storage of the powder. PMID- 26006742 TI - Surfactant-modified montmorillonite as a nanosized adsorbent for removal of an insecticide: kinetic and isotherm studies. AB - Surfactant-modified montmorillonites (MMT) were prepared using trimethyloctylammonium bromide (TMOAB) and employed as a nanosized adsorbent to remove diazinon from aqueous solutions. The prepared adsorbent was characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX). The dependence of removal efficiency on initial diazinon concentration, amount of adsorbent, pH of the solution and ionic strength was investigated. The affinity sequence for ion adsorption on TMOAB/MMT was in the order: without anion> sodium carbonate> sodium bicarbonate> sodium sulphate> sodium chloride. The adsorption kinetic and isotherm were best fit by a pseudo-second-order kinetic and Langmuir isotherm models, respectively. PMID- 26006743 TI - Endotracheal intubation versus supraglottic airway placement in out-of-hospital cardiac arrest: A meta-analysis. AB - OBJECTIVE: Overall survival from out-of-hospital cardiac arrest (OHCA) is less than 10%. After initial bag-valve mask ventilation, 80% of patients receive an advanced airway, either by endotracheal intubation (ETI) or placement of a supraglottic airway (SGA). The objective of this meta-analysis was to compare patient outcomes for these two advanced airway methods in OHCA patients treated by Emergency Medical Services (EMS). METHODS: A dual-reviewer search was conducted in PubMed, Scopus, and the Cochrane Database to identify all relevant peer-reviewed articles for inclusion in the meta-analysis. Exclusion criteria were traumatic arrests, pediatric patients, physician/nurse intubators, rapid sequence intubation, video devices, and older airway devices. Outcomes were (1) return of spontaneous circulation (ROSC), (2) survival to hospital admission, (3) survival to hospital discharge, and (4) neurologically intact survival to hospital discharge. Results were adjusted for covariates when available and combined using the random effects model. RESULTS: From 3,454 titles, 10 observational studies fulfilled all criteria, representing 34,533 ETI patients and 41,116 SGA patients. Important covariates were similar between groups. Patients who received ETI had statistically significant higher odds of ROSC (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.05-1.55), survival to hospital admission (OR 1.34, CI 1.03-1.75), and neurologically intact survival (OR 1.33, CI 1.09-1.61) compared to SGA. Survival to hospital discharge was not statistically different (OR 1.15, CI 0.97-1.37). CONCLUSIONS: Patients with OHCA who receive ETI by EMS are more likely to obtain ROSC, survive to hospital admission, and survive neurologically intact when compared to SGA. PMID- 26006744 TI - The impact of nonphysician providers on diagnostic and interventional radiology practices: regulatory, billing, and compliance perspectives. AB - The numbers of nurse practitioners and physician assistants are increasing throughout the entire health care enterprise, and a similar expansion continues within radiology. Some practices have instead embraced radiologist assistants. The increased volume of services rendered by this growing nonphysician provider subset of the health care workforce within and outside of radiology departments warrants closer review. The authors evaluate the recent literature and offer recommendations to radiology practices regarding both regulatory and scope-of practice issues related to these professionals. Additionally, billing and compliance issues for care provided by nurse practitioners, physician assistants, and radiologist assistants are detailed. An analysis of the integration of these professionals into interventional and diagnostic radiology practices, as well as potential implications for medical education, is provided in the second part of this series. PMID- 26006745 TI - Human- Versus System-Level Factors and Their Effect on Electronic Work List Variation: Challenging Radiology's Fundamental Attribution Error. AB - PURPOSE: The aim of this study was to analyze sources of variation influencing the unread volume on an electronic abdominopelvic CT work list and to compare those results with blinded radiologist perception. METHODS: The requirement for institutional review board approval was waived for this HIPAA-compliant quality improvement effort. Data pertaining to an electronic abdominopelvic CT work list were analyzed retrospectively from July 1, 2013, to June 30, 2014, and modeled with respect to the unread case total at 6 pm (Monday through Friday, excluding holidays). Eighteen system-level factors outside individual control (eg, number of workers, workload) and 7 human-level factors within individual control (eg, individual productivity) were studied. Attending radiologist perception was assessed with a blinded anonymous survey (n = 12 of 15 surveys completed). RESULTS: The mean daily unread total was 24 (range, 3-72). The upper control limit (48 CT studies [3 SDs above the mean]) was exceeded 10 times. Multivariate analysis revealed that the rate of unread CT studies was affected principally by system-level factors, including the number of experienced trainees on service (postgraduate year 5 residents [odds ratio, 0.83; 95% confidence interval, 0.74 0.92; P = .0008] and fellows [odds ratio, 0.84; 95% confidence interval, 0.74 0.95; P = .005]) and the daily workload (P = .02 to P < .0001). Individual faculty productivity had a weak effect (Spearman rho = 0.13, P = .03; adequacy: 3% of variance explained). The majority (67%) of radiologists (8 of 12) completing the survey believed that variation in faculty effort was the most important influence on the daily unread total. CONCLUSIONS: System-level factors best predict the variation in unread CT examinations, but blinded faculty radiologists believe that it relates most strongly to variable individual effort. PMID- 26006746 TI - Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing. AB - The advent of high-throughput technologies has provided exceptional assistance for lung scientists to discover novel genetic variants underlying the development and progression of complex lung diseases. However, the discovered variants thus far do not explain much of the estimated heritability of complex lung diseases. Here, we review the literature of successfully used genome-wide association studies (GWASs) and identified the polymorphisms that reproducibly underpin the susceptibility to various noncancerous complex lung diseases or affect therapeutic responses. We also discuss the inherent limitations of GWAS approaches and how the use of next-generation sequencing technologies has furthered our understanding about the genetic determinants of these diseases. Next, we describe the contribution of the metagenomics to understand the interactions of the airways microbiome with lung diseases. We then highlight the urgent need for new integrative genomics-phenomics methods to more effectively interrogate and understand multiple downstream "omics" (eg, chromatin modification patterns). Finally, we address the scarcity of genetic studies addressing under-represented populations such as African Americans and Hispanics. PMID- 26006747 TI - In silico analysis of family GH77 with focus on amylomaltases from borreliae and disproportionating enzymes DPE2 from plants and bacteria. AB - The CAZy glycoside hydrolase (GH) family GH77 is a monospecific family containing 4-alpha-glucanotransferases that if from prokaryotes are known as amylomaltases and if from plants including algae are known as disproportionating enzymes (DPE). The family GH77 is a member of the alpha-amylase clan GH-H. The main difference discriminating a GH77 4-alpha-glucanotransferase from the main GH13 alpha-amylase family members is the lack of domain C succeeding the catalytic (beta/alpha)8 barrel. Of more than 2400 GH77 members, bacterial amylomaltases clearly dominate with more than 2300 sequences; the rest being approximately equally represented by Archaea and Eucarya. The main goal of the present study was to deliver a detailed bioinformatics study of family GH77 (416 collected sequences) focused on amylomaltases from borreliae (containing unique sequence substitutions in functionally important positions) and plant DPE2 representatives (possessing an insert of ~140 residues between catalytic nucleophile and proton donor). The in silico analysis reveals that within the genus of Borrelia a gradual evolutionary transition from typical bacterial Thermus-like amylomaltases may exist to family GH77 amylomaltase versions that currently possess progressively mutated the most important and otherwise invariantly conserved positions. With regard to plant DPE2, a large group of bacterial amylomaltases represented by the amylomaltase from Escherichia coli with a longer N-terminus was identified as a probable intermediary connection between Thermus-like and DPE2-like (existing also among bacteria) family GH77 members. The presented results concerning both groups, i.e. amylomaltases from borreliae and plant DPE2 representatives (with their bacterial counterpart), may thus indicate the direction for future experimental studies. PMID- 26006748 TI - CDK8 kinase--An emerging target in targeted cancer therapy. AB - Cyclin-dependent kinase (CDK) inhibitors have been developed as potential anticancer therapeutics and several nonselective compounds are currently in advanced clinical trials. This review is focused on the key biological roles of CDK8 kinase, which provide a proof-of-principle for continued efforts toward effective cancer treatment, targeting activity of this CDK family member. Among currently identified kinase inhibitors, several displayed significant selectivity for CDK8 and notably the effectiveness in targeting cancer specific gene expression programs. Structural features of CDK8 and available ligands were discussed from a perspective of the rational drug design process. Current state of the art confirms that further development of CDK8 inhibitors will translate into targeted therapies in oncology. This article is part of a Special Issue entitled:Inhibitors of Protein Kinases. PMID- 26006749 TI - The other prey-capture silk: Fibres made by glow-worms (Diptera: Keroplatidae) comprise cross-beta-sheet crystallites in an abundant amorphous fraction. AB - Glow-worms (larvae of dipteran genus Arachnocampa) are restricted to moist habitats where they capture flying prey using snares composed of highly extensible silk fibres and sticky mucus droplets. Little is known about the composition or structure of glow-worm snares, or the extent of possible convergence between glow-worm and arachnid capture silks. We characterised Arachnocampa richardsae silk and mucus using X-ray scattering, Fourier transform infrared spectroscopy and amino acid analysis. Silk but not mucus contained crystallites of the cross-beta-sheet type, which occur in unrelated insect silks but have not been reported previously in fibres used for prey capture. Mucus proteins were rich in Gly (28.5%) and existed in predominantly a random coil structure, typical of many adhesive proteins. In contrast, the silk fibres were unusually rich in charged and polar residues, particularly Lys (18.1%), which we propose is related to their use in a highly hydrated state. Comparison of X-ray scattering, infrared spectroscopy and amino acid analysis data suggests that silk fibres contain a high fraction of disordered protein. We suggest that in the native hydrated state, silk fibres are capable of extension via deformation of both disordered regions and cross-beta-sheet crystallites, and that high extensibility is an adaptation promoting successful prey capture. This study illustrates the rich variety of protein motifs that are available for recruitment into biopolymers, and how convergently evolved materials can nevertheless be based on fundamentally different protein structures. PMID- 26006750 TI - Congenital neurogenic muscular atrophy in megaconial myopathy due to a mutation in CHKB gene. AB - Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(*)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern). PMID- 26006751 TI - Childhood Sjogren syndrome presenting as acute brainstem encephalitis. AB - Sjogren syndrome is an autoimmune disease characterized by dry mouth and eyes, known as sicca symptoms. The exact spectrum of neurological involvement, especially of the central nervous system, in childhood Sjogren syndrome has not been well defined. We report a girl who presented with acute febrile brainstem encephalitis. In retrospect, she had exhibited a preceding history of recurrent conjunctivitis and strong halitosis that could be considered as sicca symptoms. The histopathology results of a minor salivary biopsy, the presence of anti SSA/Ro antibody, and keratoconjunctivitis confirmed the diagnosis of Sjogren syndrome. Commonly observed features in previously reported patients with childhood Sjogren syndrome and central nervous system complications have included fever at the time of neurologic presentation, cerebrospinal fluid pleocytosis, abnormal neuroimaging, and positivity for several specific antibodies. In children presenting with unknown acute febrile encephalopathy, Sjogren syndrome should be included in the differential diagnosis, especially when sicca symptoms are present. PMID- 26006752 TI - The Epidemiology of Mandibular Fractures in the United States, Part 1: A Review of 13,142 Cases from the US National Trauma Data Bank. AB - PURPOSE: To date, no studies have analyzed the national demographics of mandibular fractures in the United States. This report is part 1 of a 2-part series characterizing the modern demographics, epidemiology, and outcomes of mandibular fractures in the United States. The purpose of this study was to characterize mandibular fractures in relation to age, gender, mechanism of injury, and anatomic location of fracture. MATERIAL AND METHODS: A retrospective cohort study was conducted using the National Trauma Data Bank (NTDB). The sample was derived from the population of hospitalized patients enrolled in the NTDB from 2001 to 2005 using mandibular fracture (International Classification of Diseases, Ninth Revision codes 802.21 through 802.39) as an inclusion criterion. Patient- and injury-related variables, including age, gender, anatomic location of fracture, and mechanism of injury, were analyzed by Fisher exact and chi(2) testing. RESULTS: A total of 13,142 patients with mandibular fractures from participating trauma centers were included in the study. Eighty percent of patients were male. Fracture distribution by age was roughly bell-shaped, with fractures occurring most frequently at 18 to 54 years of age. Mechanism of injury differed by gender, with men most often sustaining mandibular fracture from assault (49.1%), followed by motor vehicle accidents (MVAs; 25.4%) and falls (12.8%). Women most commonly sustained mandibular fracture from MVAs (53.7%), followed by assault (14.5%) and falls (23.7%). Falls were a significantly more common mechanism in patients who were at least 65 years old (P < .001). CONCLUSION: This study sought to characterize the largest, modern, population based sample of mandibular fractures in the United States. Overall, men had a 4 fold higher incidence, but this distribution varied by age. Similarly, mechanism of injury varied across gender and age range. A better understanding of the influence of age and gender on mechanism of injury and anatomic site is of great clinical importance in the assessment, diagnosis, and treatment of traumatic mandibular fractures. PMID- 26006753 TI - Body mass index, respiratory conditions, asthma, and chronic obstructive pulmonary disease. AB - BACKGROUND: This study aims to assess the relationship of body mass index (BMI) status with respiratory conditions, asthma, and chronic obstructive pulmonary disease (COPD) in a state population. METHODS: Self-reported data from 11,868 adults aged >=18 years in the 2012 South Carolina Behavioral Risk Factor Surveillance System telephone survey were analyzed using multivariable logistic regression that accounted for the complex sampling design and adjusted for sex, age, race/ethnicity, education, smoking status, physical inactivity, and cancer history. RESULTS: The distribution of BMI (kg/m(2)) was 1.5% for underweight (<18.5), 32.3% for normal weight (18.5-24.9), 34.6% for overweight (25.0-29.9), 26.5% for obese (30.0-39.9), and 5.1% for morbidly obese (>=40.0). Among respondents, 10.0% had frequent productive cough, 4.3% had frequent shortness of breath (SOB), 7.3% strongly agreed that SOB affected physical activity, 8.4% had current asthma, and 7.4% had COPD. Adults at extremes of body weight were more likely to report having asthma or COPD, and to report respiratory conditions. Age adjusted U-shaped relationships of BMI categories with current asthma and strongly agreeing that SOB affected physical activity, but not U-shaped relationship with COPD, persisted after controlling for the covariates (p < 0.001). Morbidly obese but not underweight or obese respondents were significantly more likely to have frequent productive cough and frequent SOB than normal weight adults after adjustment. CONCLUSION: Our data confirm that both underweight and obesity are associated with current asthma and obesity with COPD. Increased emphasis on exercise and nutrition may improve respiratory conditions. PMID- 26006754 TI - Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. AB - BACKGROUND: Umeclidinium (UMEC; long-acting muscarinic antagonist [LAMA])/vilanterol (VI; long-acting beta2-agonist [LABA]) and fluticasone propionate/salmeterol (FP/SAL) (inhaled corticosteroid/LABA) are approved maintenance therapies for chronic obstructive pulmonary disease (COPD). Two studies compared efficacy and safety of UMEC/VI with FP/SAL in patients with moderate-to-severe COPD with no exacerbations in the previous year. METHODS: In these 12-week, multicenter, double-blind, parallel-group, double-dummy trials, randomized (1:1) patients received once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 250/50 mcg (DB2114930 n = 353 and 353; DB2114951 n = 349 and 348, respectively; intent-to-treat). Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, dyspnea, quality of life (QoL) and safety. RESULTS: UMEC/VI demonstrated statistically significant, clinically meaningful improvements in lung function measures versus FP/SAL. For 0-24 h wmFEV1 (Day 84), improvements with UMEC/VI versus FP/SAL were 74 mL (95% confidence interval [CI]: 38-110; DB2114930) and 101 mL (63-139; DB2114951) (both p < 0.001). Trough FEV1 improvements were 82 mL (45-119) and 98 mL (59-137) (both p < 0.001) for UMEC/VI versus FP/SAL, respectively. Both treatments demonstrated similar, clinically meaningful improvements from baseline in dyspnea (Transition Dyspnea Index focal score >1 unit) and QoL (St George's Respiratory Questionnaire Total score >4-unit decrease) in both studies with no statistical differences between treatments. Adverse event rates were similar: 26 and 30% UMEC/VI; 27 and 31% FP/SAL. CONCLUSIONS: Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in statistically significant, clinically meaningful improvements in lung function versus twice-daily FP/SAL 250/50 mcg in patients with moderate-to-severe COPD with infrequent exacerbations. Both treatments improved dyspnea and QoL. CLINICAL TRIAL REGISTRATION: DB2114930/NCT01817764; DB2114951/NCT01879410. PMID- 26006755 TI - Sudden sensorineural hearing loss after non-otologic surgery. AB - Sudden sensorineural hearing loss following non-otologic surgery is a rare event described in the medical literature. Cardiopulmonary bypass surgery is most commonly associated with this type of hearing loss. Our case report and review of the literature describe two cases with postoperative hearing loss - neither of which are cardiac surgeries - making them exceedingly rare in the medical literature. Regardless of the rarity of this unfortunate event, the possibility for permanent hearing loss is a potentially devastating unanticipated complication and one that all surgeons should be aware. PMID- 26006756 TI - Body fluid matrix evaluation on a Roche cobas 8000 system. AB - OBJECTIVES: Chemical analysis of body fluids is commonly requested by physicians. Because most commercial FDA-cleared clinical laboratory assays are not validated by diagnostic manufacturers for "non-serum" and "non-plasma" specimens, laboratories may need to complete additional validation studies to comply with regulatory requirements regarding body fluid testing. The objective of this report is to perform recovery studies to evaluate potential body fluid matrix interferences for commonly requested chemistry analytes. DESIGN AND METHODS: Using an IRB-approved protocol, previously collected clinical body fluid specimens (biliary/hepatic, cerebrospinal, dialysate, drain, pancreatic, pericardial, peritoneal, pleural, synovial, and vitreous) were de-identified and frozen (-20 degrees C) until experiments were performed. Recovery studies (spiking with high concentration serum, control, and/or calibrator) were conducted using 10% spiking solution by volume; n=5 specimens per analyte/body fluid investigated. Specimens were tested on a Roche cobas 8000 system (c502, c702, e602, and ISE modules). RESULTS: In all 80 analyte/body fluid combinations investigated (including amylase, total bilirubin, urea nitrogen, carbohydrate antigen 19-9, carcinoembryonic antigen, cholesterol, chloride, creatinine, glucose, potassium, lactate dehydrogenase, lipase, rheumatoid factor, sodium, total protein, triglycerides, and uric acid), the average percent recovery was within predefined acceptable limits (less than +/-10% from the calculated ideal recovery). CONCLUSIONS: The present study provides evidence against the presence of any systematic matrix interference in the analyte/body fluid combinations investigated on the Roche cobas 8000 system. Such findings support the utility of ongoing body fluid validation initiatives conducted to maintain compliance with regulatory requirements. PMID- 26006757 TI - Adiponectin predicts cardiovascular events in diabetes dialysis patients. AB - OBJECTIVES: Adiponectin is an insulin-sensitizing, anti-inflammatory adipokine with anti-atherogenic actions in the general population. In dialysis patients it is unclear whether adiponectin conserves its protective value or is, on the contrary, associated to worse prognosis. We assessed the predictive value of adiponectin for atherosclerosis related cardiovascular events in type 2 diabetic dialysis patients. DESIGN AND METHODS: Prevalent diabetic dialysis patients from three dialysis units (n=77) were enrolled in a 3years' prospective observational study. Serum adiponectin, clinical and laboratory parameters were determined at baseline; new occurrence of atherosclerosis related events (coronary events, atherosclerosis obliterans, and stroke) was recorded. RESULTS: Baseline adiponectin was 17.25(9.53-31.97) MUg/mL and significantly correlated to HDL cholesterol (r=0.29, p=0.01), triglycerides (r=-0.40, p=0.0004), ferritin (r= 0.29, p=0.02), transferrin (r=-0.28, p=0.02), and uric acid (r=-0.24, p=0.04). In multivariate analysis association to triglycerides (p=0.001), HDL cholesterol (p=0.01) and ferritin (p=0.04) remained significant. 36 new fatal and non-fatal new cardiovascular events occurred, 29 patient died. Cox proportional regression analysis showed that adiponectin below or above a ROC-derived cut-off of 27.33MUg/mL significantly influenced event-free survival: hazard ratio (HR) 2.48, 95% confidence interval (CI) (1.09-5.66), p=0.031 along with fasting glucose HR 1.01, 95%CI(1.00-1.02), p=0.01 and history of cardiovascular events at inclusion HR 3.16, 95%CI(1.36-7.32), p=0.007. In multivariate analysis baseline adiponectin HR 5.02, 95%CI(0.98-25.06), p=0.05 and glycemia HR 1.01, 95%CI(1.00-1.02), p=0.01 influenced event-free survival. Adiponectin also predicted cardiovascular events in patients without cardiovascular disease at inclusion but was not associated to overall mortality. CONCLUSIONS: In diabetes dialysis patients low adiponectin favors occurrence of atherosclerosis related cardiovascular events. PMID- 26006759 TI - Molecular docking and QSAR analyses for understanding the antimalarial activity of some 7-substituted-4-aminoquinoline derivatives. AB - The quinoline moiety is one of the widely studied scaffolds for generating derivatives with various pharmacophoric groups due to its potential antimalarial activities. In the present study, a series of 7-substituted-4-aminoquinoline derivatives were selected to understand their antimalarial properties computationally by molecular modeling techniques including 2D QSAR, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and molecular docking. The 2D-QSAR model built with four descriptors selected by genetic algorithm technique and CoMFA model showed satisfactory statistical results (Q(2)=0.540, R(2)ncv=0.881, F value=157.09). A reliable CoMSIA model out of the fourteen different combinations has a Q(2) value of 0.638. The molecular docking studies of the compounds for 1CET as the protein target revealed that ten compounds showed maximum interactions with the binding site of the protein. The present study highlights the unique binding signatures of the ligands within the active site groove of the target and it explains the subtle differences in their EC50 values and their mechanism of inhibition. PMID- 26006758 TI - The development of a Simplified, Effective, Labour Monitoring-to-Action (SELMA) tool for Better Outcomes in Labour Difficulty (BOLD): study protocol. AB - BACKGROUND: The partograph is currently the main tool available to support decision-making of health professionals during labour. However, the rate of appropriate use of the partograph is disappointingly low. Apart from limitations that are associated with partograph use, evidence of positive impact on labour related health outcomes is lacking. The main goal of this study is to develop a Simplified, Effective, Labour Monitoring-to-Action (SELMA) tool. The primary objectives are: to identify the essential elements of intrapartum monitoring that trigger the decision to use interventions aimed at preventing poor labour outcomes; to develop a simplified, monitoring-to-action algorithm for labour management; and to compare the diagnostic performance of SELMA and partograph algorithms as tools to identify women who are likely to develop poor labour related outcomes. METHODS/DESIGN: A prospective cohort study will be conducted in eight health facilities in Nigeria and Uganda (four facilities from each country). All women admitted for vaginal birth will comprise the study population (estimated sample size: 7,812 women). Data will be collected on maternal characteristics on admission, labour events and pregnancy outcomes by trained research assistants at the participating health facilities. Prediction models will be developed to identify women at risk of intrapartum-related perinatal death or morbidity (primary outcomes) throughout the course of labour. These predictions models will be used to assemble a decision-support tool that will be able to suggest the best course of action to avert adverse outcomes during the course of labour. To develop this set of prediction models, we will use up-to date techniques of prognostic research, including identification of important predictors, assigning of relative weights to each predictor, estimation of the predictive performance of the model through calibration and discrimination, and determination of its potential for application using internal validation techniques. DISCUSSION: This research offers an opportunity to revisit the theoretical basis of the partograph. It is envisioned that the final product would help providers overcome the challenging tasks of promptly interpreting complex labour information and deriving appropriate clinical actions, and thus increase efficiency of the care process, enhance providers' competence and ultimately improve labour outcomes. Please see related articles ' http://dx.doi.org/10.1186/s12978-015-0027-6 ' and ' http://dx.doi.org/10.1186/s12978-015-0028-5 '. PMID- 26006760 TI - Polyacrylonitrile-derived polyconjugated ladder structures for high performance all-organic dielectric materials. AB - A novel all-organic polyconjugated ladder structures-polyimide (PcLS-PI) composite was successfully synthesized, in which PcLS were derived from polyacrylonitrile (PAN). The PcLS-PI composite not only presents high dielectric performances of high dielectric permittivity, low dielectric loss, high electrical breakdown strength and high energy density, but also has excellent mechanical and thermal properties. PMID- 26006761 TI - [Regional treatment for axillary lymph node micrometastases of breast cancer]. AB - In patients with breast cancer, axillary lymph node micrometastasis detection has been more frequent with a better definition since the introduction of the sentinel node procedure. In this review, we focus on pN1mi micrometastasis and review the literature in order to determine factors involved in making the decision of a regional treatment. PMID- 26006762 TI - [Is there a rationale for regional node irradiation in pN1mi and pN0(i+) breast tumours?]. AB - The advent of sentinel lymph node technique has led to a shift in lymph node staging, due to the emergence of new entities, namely micrometastases and isolated tumour cells. In addition, the therapeutic role of axillary lymph node dissection is more and more questioned and radiotherapy has been shown to be equivalent to complementary axillary lymph node dissection in patients without clinical node involvement. This article looks at the literature in favour of performing axillary irradiation in patients with pN1mi stage breast cancer who have undergone a mastectomy without a complementary axillary lymph node dissection, and in favour of abstention of any further treatment of the axilla in patients with pN0(i+) or pN1mi tumours who have undergone breast conserving surgery and a sentinel lymph node procedure followed by systemic treatment. The impact of regional lymph nodes irradiation in case of axillary involvement 2mm or less is also discussed. PMID- 26006763 TI - [Irradiation of internal mammary nodes: State of the art]. AB - In the adjuvant breast cancer treatment, postoperative radiotherapy plays a principal part with an action against the microscopic residual disease in the lymph nodes after mastectomy as well as after breast conserving surgery. This positive effect is observed also in the case of small inner lesions in patients without lymph node involvement. At the same time, there is a recognized risk of cardiac toxicity directly related to the irradiation of internal mammary nodes. This paper is a report on the current available techniques to irradiate the internal mammary nodes, including promising new technology that may help limiting the risk of cardiac toxicity. PMID- 26006764 TI - [Radiosensitivity settings in breast cancer]. AB - Breast cancers are highly radiosensitive since the risk of recurrences and of mortality after adjuvant radiotherapy following breast-conserving surgery is decreased by 15.7% and 3.8%, respectively at 10 years. The total dose if irradiation also significantly increases local control: a boost of 16 Gy to the tumour bed after breast-conserving surgery reduces the absolute risk of recurrence by 4% at 10 years. Breast cancers are sensitive to the dose per fraction, as shown by the results from four randomized trials which compared standard irradiation (50 Gy/25 fractions) with a hypofractionated scheme: no statistical difference was observed in locoregional recurrence and overall survival at 10 years. The alpha/beta ratio, which reflects the dose per fraction and is theoretically over 10 Gy for tumour tissues, has been estimated between 2.2 and 4.4 Gy for breast cancers. Molecular abnormalities, such as overexpression of HER1 (especially in triple negative breast cancer) and HER2, induce a higher radioresistance. In vitro studies showed that targeted therapies, which block these receptors, increase breast cancer radiosensitivity. Tumour stem cells have been identified in breast cancers and are characterized by a higher radioresistance. This radioresistance could be related to a better repair of radiation-induced DNA damages and a decrease of reactive oxygen species (ROS), which are involved in their occurrence. In the future, a better understanding of genetics tumour abnormalities will allow to identify new radiosensitivity settings in breast cancers. PMID- 26006765 TI - Nickel-catalyzed synthesis of diarylsulfides and sulfones via C-H bond functionalization of arylamides. AB - The direct sulfenylation and sulfonylation of (sp(2))C-H bonds of benzamide derivatives were achieved using a Ni catalyst with the aid of an 8-aminoquinoline moiety as a bidentate directing group. These protocols represent a convenient route for the formation of valuable diaryl sulfides and sulfones in moderate to excellent yields. PMID- 26006766 TI - Improving the fracture toughness and the strength of epoxy using nanomaterials--a review of the current status. AB - The incorporation of nanomaterials in the polymer matrix is considered to be a highly effective technique to improve the mechanical properties of resins. In this paper the effects of the addition of different nanoparticles such as single walled CNT (SWCNT), double-walled CNT (DWCNT), multi-walled CNT (MWCNT), graphene, nanoclay and nanosilica on fracture toughness, strength and stiffness of the epoxy matrix have been reviewed. The Young's modulus (E), ultimate tensile strength (UTS), mode I (GIC) and mode II (GIIC) fracture toughness of the various nanocomposites at different nanoparticle loadings are compared. The review shows that, depending on the type of nanoparticles, the integration of the nanoparticles has a substantial effect on mode I and mode II fracture toughness, strength and stiffness. The critical factors such as maintaining a homogeneous dispersion and good adhesion between the matrix and the nanoparticles are highlighted. The effect of surface functionalization, its relevancy and toughening mechanism are also scrutinized and discussed. A large variety of data comprised of the mechanical properties of nanomaterial toughened composites reported to date has thus been compiled to facilitate the evolution of this emerging field, and the results are presented in maps showing the effect of nanoparticle loading on mode I fracture toughness, stiffness and strength. PMID- 26006767 TI - Three-dimensional culture of mouse pancreatic islet on a liver-derived perfusion decellularized bioscaffold for potential clinical application. AB - The cutting-edge technology of three-dimensional liver decellularized bioscaffold has a potential to provide a microenvironment that is suitable for the resident cells and even develop a new functional organ. Liver decellularized bioscaffold preserved the native extracellular matrix and three-dimensional architecture in support of the cell culture. The goal of this study was to discover if three dimensional extracellular matrix derived from mouse liver could facilitate the growth and maintenance of physiological functions of mouse isolated islets. We generated a whole organ liver decellularized bioscaffold which could successfully preserve extracellular matrix proteins and the native vascular channels using 1% Triton X-100/0.1% ammonium protocol. To evaluate the potential of decellularized liver as a scaffold for islets transplantation, the liver decellularized bioscaffold was infused with mouse primary pancreatic islets which were obtained through Collagenase P digestion protocol. Its yield, morphology, and quality were estimated by microscopic analysis, dithizone staining, insulin immunofluorescence and glucose stimulation experiments. Comparing the three-dimensional culture in liver decellularized bioscaffold with the orthodoxy two-dimensional plate culture, hematoxylin-eosin staining, immunohistochemistry, and insulin gene expression were tested. Our results demonstrated that the liver decellularized bioscaffold could support cellular culture and maintenance of cell functions. In contrast with the conventional two-dimensional culture, three-dimensional culture system could give rise to an up-regulated insulin gene expression. These findings demonstrated that the liver bioscaffold by a perfusion-decellularized technique could serve as a platform to support the survival and function of the pancreatic islets in vitro. Meanwhile three-dimensional culture system had a superior role in contrast with the two-dimensional culture. This study advanced the field of regenerative medicine towards the development of a liver decellularized bioscaffold capable of forming a neo-organ and could be used as potential clinical application. PMID- 26006768 TI - Investigation of the colon-targeting, improvement on the side-effects and therapy on the experimental colitis in mouse of a resin microcapsule loading dexamethasone sodium phosphate. AB - CONTEXT: Dexamethasone is the major drug in the treatment of ulcerative colitis (UC). However, the extensive or long-time use of dexamethasone causes many toxic side-effects. Ion exchange resins react with external-ions through their own functional groups and Eudragit S occurs degradation when pH > 7. These features make them suitable for oral delivery system. OBJECTIVE: Resin microcapsule (DRM) composed by 717 anion exchange resin and Eudragit S100 was used to target dexamethasone to the colon to improve its treatment effect on UC and reduce its toxic side-effects. RESULTS: Dexamethasone sodium phosphate (DXSP) was sequentially encapsulated in 717 anion-exchange resin and Eudragit S100 to prepare the DXSP-loaded resin microcapsule (DXSP-DRM). The in vitro release study and in vivo study of pharmacokinetics and the intestinal drug residues in rat demonstrated the good colon-targeting of DXSP-DRM. Moreover, the DXSP-DRM can reduce the toxic side-effects induced by DXSP and have good therapeutic effects on colitis mouse induced by 2,4,6-trinitrobenzenesulfonic acid. DISCUSSION: Dexamethasone can be targeted to the colon by DRM, thereby enhancing its treatment effect and reducing its toxic side effects. CONCLUSION: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeted preparations. PMID- 26006769 TI - Therapeutic effects of nanogel containing triterpenoids isolated from Ganoderma lucidum (GLT) using therapeutic ultrasound (TUS) for frostbite in rats. AB - OBJECTIVE: The aim of this study was to evaluate the effect of therapeutic ultrasound (TUS) on dermal delivery and therapeutic effect for frostbite of nanogel containing triterpenoids isolated from Ganoderma lucidum (GLT). METHODS: GLT nanosuspension (GLT-NS) was prepared by high pressure homogenization and then suitably gelled to obtain GLT nanogel. The effects of TUS on GLT releasing from GLT nanogel and GLT permeation through the excised rat abdominal skin were evaluated. Moreover, a comparative study was also undertaken between different treatments of frostbite in rats: topical application of GLT nanogel (alone), TUS (alone) and GLT nanogel + TUS (plus). RESULTS: In the in vitro release study, TUS has no influence on drug release from the nanogel. Results of the in vitro transdermal study indicated that TUS significantly increased the cumulative amount of GLT permeating across and into the skin and reduced the lag time in comparison with passive diffusion (without TUS). As evidenced by the significant increase of wound healing area and the improvement in frostbite, TUS applied with simultaneous treatment method could improve the therapeutic effect of the GLT nanogel for frostbite. CONCLUSION: The present study revealed that the TUS can be effectively used to actively enhance topical delivery of GLT from nanogel and improve the therapeutic effect for frostbite in rats. PMID- 26006770 TI - Calculation of external knee adduction moments: a comparison of an inverse dynamics approach and a simplified lever-arm approach. AB - BACKGROUND: The external knee adduction moment (EKAM) is often studied in knee osteoarthritis research. This study compared EKAMs between two methods of calculation: a method that only requires ground reaction force and knee position data (i.e. lever-arm), and an inverse dynamics link-segment method. METHODS: Sixteen participants walked while wearing a control shoe with and without a six millimeter lateral wedge insole. Peak EKAMs between the lever-arm and inverse dynamics methods were compared for the control condition, and the %change in moment induced by the lateral wedge was compared between methods. RESULTS: When comparing EKAMs between methods, no correlation was found (r=0.24, p=0.36); peak EKAMs with the lever-arm method (26.0Nm) were significantly lower than EKAMs with the inverse dynamics method (40.2Nm, pb0.001); and Bland-Altman plots showed poor agreement between methods. When assessing the %change in moment with a lateral wedge, a moderate correlation was found (r=0.55, p=0.03) between methods; Bland Altman plots showed moderate agreement between methods; and the lever-arm method (-6.4%) was not significantly different from the inverse dynamics method (-11.4%, p=0.09); however, the two methods produced opposite results 31% of the time. CONCLUSION: The lever-arm method cannot estimate peak EKAMs, and can only approximate the %change in moment induced by a lateral wedge; however, the error rate was 31%. Therefore, the lever-arm method is not recommended for use in its current form. CLINICAL RELEVANCE: This study may help guide the development of a fast and simple method for determining EKAMs for individuals with knee osteoarthritis. PMID- 26006771 TI - Effect of unstable meniscal injury on three-dimensional knee kinematics during gait in anterior cruciate ligament-deficient patients. AB - BACKGROUND: Our purpose was to clarify the differences of three-dimensional knee kinematics in anterior cruciate ligament (ACL)-deficient patients between with and without meniscal injury using gait analysis. METHODS: A total of 72 knees in 36 young athletes with primary and unilateral ACL injury, with a mean age of 22 years, participated. Gait analysis was done before surgery. According to the arthroscopic findings, patients were divided into two groups. The patients with an unstable meniscal tear were allocated to the meniscal injury group (ACL+M group), and the patients without a meniscal tear were allocated to the no meniscal injury group (ACL group). In the gait analysis, three-dimensional knee kinematics was evaluated and compared. RESULTS: The patients in both groups exhibited lower sagittal plane knee excursions and peak knee extension angles on the affected limb than on the unaffected limb during the mid-stance. In terms of the axial plane, a rotation angle was significantly smaller in the affected knees than in the unaffected knees in the ACL group. On the other hand, an opposite phenomenon was observed in the ACL+M group. Moreover, a significantly larger rotation angle in the affected knees during the stance phase and the whole gait cycle was observed in the ACL+M group than in the ACL group. CONCLUSION: Increased rotational motion during the gait was observed in the ACL-deficient knees combined with unstable meniscal injuries. Meniscal condition may be a key factor for compensatory gait mechanics to prevent rotatory instability in ACL deficient patients patients. LEVEL OF EVIDENCE: III. PMID- 26006772 TI - The cost of adverse events from knee surgery in the United Kingdom: an in-depth review of the National Health Service Litigation Authority database. AB - BACKGROUND: There has been a significant rise in the number and value of claims against the National Health Service (NHS), with limited studies on litigation in orthopaedic surgery and none in knee surgery alone. We aimed to examine claims against the NHS involving all aspects of knee surgery with respect to costs and trends. CLINICAL RELEVANCE: To raise awareness of the reasons for litigation in knee surgery, thus potentially improve patient care and reduce future claims. METHODS: We analysed the NHS litigation authority (NHSLA) database for all orthopaedic surgery claims reported to the NHSLA between 2005 and 2010, with calculation of litigation success rates and odds ratios for those relating to knee surgery. RESULTS: There were 515 cases identified from the 4609 orthopaedic cases in the NHSLA database (11.2%): 298 (58%) involving total knee replacements (TKRs), 11 (2%) involving unicondylar knee replacements, and 90 cases (30%) remaining open. The total pay out for closed cases was L10.45 million and amputation following TKR resulted in the highest single pay out. Litigation success rates for claimants were highest for retained drains (100%), incorrect prosthesis/prosthesis size (78%), renal failure (75%), poor outcome requiring further surgery (74%) and malalignment (71%). There were also 60 cases of delayed diagnosis which resulted in pay outs totalling L2.90 million. Based on these data, projected future pay out costs for the open TKR cases were estimated to be L2.71 million. CONCLUSION: Litigation success rates for TKR were highest following technical errors such as malalignment compared to events less under the surgeon's control, such as infection. The number of claims involving incorrect prosthesis/size continues to be of concern. Despite the increased availability of imaging modalities, missed diagnosis also resulted in substantial pay outs. PMID- 26006773 TI - Temporal gene expression profiling of the rat knee joint capsule during immobilization-induced joint contractures. AB - BACKGROUND: Contractures of the knee joint cause disability and handicap. Recovering range of motion is recognized by arthritic patients as their preference for improved health outcome secondary only to pain management. Clinical and experimental studies provide evidence that the posterior knee capsule prevents the knee from achieving full extension. This study was undertaken to investigate the dynamic changes of the joint capsule transcriptome during the progression of knee joint contractures induced by immobilization. We performed a microarray analysis of genes expressed in the posterior knee joint capsule following induction of a flexion contracture by rigidly immobilizing the rat knee joint over a time-course of 16 weeks. Fold changes of expression values were measured and co-expressed genes were identified by clustering based on time series analysis. Genes associated with immobilization were further analyzed to reveal pathways and biological significance and validated by immunohistochemistry on sagittal sections of knee joints. RESULTS: Changes in expression with a minimum of 1.5 fold changes were dominated by a decrease in expression for 7732 probe sets occurring at week 8 while the expression of 2251 probe sets increased. Clusters of genes with similar profiles of expression included a total of 162 genes displaying at least a 2 fold change compared to week 1. Functional analysis revealed ontology categories corresponding to triglyceride metabolism, extracellular matrix and muscle contraction. The altered expression of selected genes involved in the triglyceride biosynthesis pathway; AGPAT-9, and of the genes P4HB and HSP47, both involved in collagen synthesis, was confirmed by immunohistochemistry. CONCLUSIONS: Gene expression in the knee joint capsule was sensitive to joint immobility and provided insights into molecular mechanisms relevant to the pathophysiology of knee flexion contractures. Capsule responses to immobilization was dynamic and characterized by modulation of at least three reaction pathways; down regulation of triglyceride biosynthesis, alteration of extracellular matrix degradation and muscle contraction gene expression. The posterior knee capsule may deploy tissue-specific patterns of mRNA regulatory responses to immobilization. The identification of altered expression of genes and biochemical pathways in the joint capsule provides potential targets for the therapy of knee flexion contractures. PMID- 26006774 TI - Energy-drink consumption and its relationship with substance use and sensation seeking among 10th grade students in Istanbul. AB - Aim of this study was to determine the prevalence and correlates of energy-drink (ED) consumption among 10th grade students in Istanbul/Turkey. Cross-sectional online self-report survey conducted in 45 schools from the 15 districts in Istanbul. The questionnaire included sections about demographic data, self destructive behavior and use of substances including tobacco, alcohol and drugs. Also Psychological Screening Test for Adolescents (PSTA) was used. The analyses were conducted based on the 4957 subjects. Rate of those reported a ED consumption once within last year was 62.0% (n=3072), whereas rate of those reported ED consumption at least once in a month was 31.1%. There were consistent, statistically significant associations between genders, lifetime substance use (tobacco, alcohol and drug use), measures of sensation seeking, psychological problems (depression, anxiety, anger, impulsivity) and self destructive behavior (self-harming behavior and suicidal thoughts) with ED consumption. In logistic regression models male gender, sensation seeking, life time tobacco, alcohol and drug use predicted all frequencies of ED consumption. In addition to these predictors, anger and self-harming behavior also predicted ED consumption at least once in a month. There were no interactions between the associations of lifetime tobacco, alcohol and drug use with ED consumption. The findings suggest that the ED consumption of male students is related with three clusters of substances (tobacco, alcohol and drug) through sensation seeking and these relationships do not interact with each other. PMID- 26006775 TI - Bayesian inference-based environmental decision support systems for oil spill response strategy selection. AB - Contingency plans are essential in guiding the response to marine oil spills. However, they are written before the pollution event occurs so must contain some degree of assumption and prediction and hence may be unsuitable for a real incident when it occurs. The use of Bayesian networks in ecology, environmental management, oil spill contingency planning and post-incident analysis is reviewed and analysed to establish their suitability for use as real-time environmental decision support systems during an oil spill response. It is demonstrated that Bayesian networks are appropriate for facilitating the re-assessment and re validation of contingency plans following pollutant release, thus helping ensure that the optimum response strategy is adopted. This can minimise the possibility of sub-optimal response strategies causing additional environmental and socioeconomic damage beyond the original pollution event. PMID- 26006776 TI - Biodegradation of HDPE by Aspergillus spp. from marine ecosystem of Gulf of Mannar, India. AB - High density polyethylene (HDPE) is the most commonly found non-degradable solid waste among the polyethylene. In this present study, HDPE degrading various fungal strains were isolated from the polyethylene waste dumped marine coastal area and screened under in vitro condition. Based on weight loss and FT-IR Spectrophotometric analysis, two fungal strains designated as VRKPT1 and VRKPT2 were found to be efficient in HDPE degradation. Through the sequence analysis of ITS region homology, the isolated fungi were identified as Aspergillus tubingensis VRKPT1 and Aspergillus flavus VRKPT2. The biofilm formation observed under epifluorescent microscope had shown the viability of fungal strains even after one month of incubation. The biodegradation of HDPE film nature was further investigated through SEM analysis. HDPE poses severe environmental threats and hence the ability of fungal isolates was proved to utilize virgin polyethylene as the carbon source without any pre-treatment and pro-oxidant additives. PMID- 26006777 TI - Metal triflate-mediated coupling of allylgermanes with thiols: a facile route to thiogermanes. AB - A novel coupling reaction of thiols with (2-methylallyl)germanes catalyzed by metal triflates has been developed. This reaction provides a direct and efficient method to afford thiogermanes and opens a valuable and general synthetic route for the Ge-S cross-coupling with the elimination of isobutylene as a single by product. Scandium(iii) triflate demonstrates the highest catalytic activity among the tested triflates. All reactions were carried out under extremely mild conditions to give thiogermanes in excellent yields. This Ge-S coupling reaction shows high generality for the variety of thiols. PMID- 26006778 TI - Effect of sodium salicylate and sodium deoxycholate on fibrillation of bovine serum albumin: comparison of fluorescence, SANS and DLS techniques. AB - The impact of biocompatible additives on the fibrillation and defibrillation of proteins provides valuable insight into the development of suitable formulations for the treatment of protein-related diseases or the storage of proteins in the laboratory. We have studied the effects of the addition of sodium deoxycholate (NaDC) and sodium salicylate (NaSal) on the fibrillation of bovine serum albumin (BSA) using fluorescence, circular dichroism, dynamic light scattering (DLS) and small angle neutron scattering (SANS). Spectroscopic studies indicate that the additives are adsorbed on the surfaces of proteins and change their secondary structures, irrespective of the sequence of addition. DLS and SANS studies show that the addition of either NaSal or NaDC to native proteins slows down or arrests the formation of fibrils. However, the additives do not defibrillate preformed fibrils when added after fibril formation. Thus, NaSal and NaDC can act as potential adjuvants for the prevention of fibril formation in BSA solutions. PMID- 26006780 TI - The reemergence of chemistry for post-graphene two-dimensional nanomaterials. PMID- 26006781 TI - Comment on "Interfacial carbon nanoplatelet formation by ion irradiation of graphene on iridium(111)". PMID- 26006779 TI - Celiac disease, non-celiac gluten sensitivity and inflammatory bowel disease. AB - Celiac disease (CD) and inflammatory bowel disease (IBD), such as Crohn's disease (CrD) and ulcerative colitis (UC), are chronic inflammatory condition of the gastro-intestinal tract. The prevalence of IBD in celiac patients has been reported as 5-10 times higher than in the general population. The possibility of the presence of CD in IBD should be considered in IBD patients with long-term iron deficiency anemia (IDA) not responsive to iron supplementation. Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra intestinal symptoms due to the ingestion of gluten-containing food in subject without CD and/or wheat allergy. Patients with Crohn's disease and SR-NCGS were more significantly affected by joint pains compared to UC patients (50% versus 11.1%). In Crohn's patients, a higher percentage of fatigue (50% versus 38.9%) and headache (27.3% versus 22.2%) was evident. For the association between NCGS and IBD new studies are warranted and, at this moment, a gluten free diet (GFD) may be useful more in CrD than in UC. PMID- 26006783 TI - Graphene edges and beyond: temperature-driven structures and electromagnetic properties. AB - The atomic configuration of graphene edges significantly influences the various properties of graphene nanostructures, and realistic device fabrication requires precise engineering of graphene edges. However, the imaging and analysis of the intrinsic nature of graphene edges can be illusive due to contamination problems and measurement-induced structural changes to graphene edges. In this issue of ACS Nano, He et al. report an in situ heating experiment in aberration-corrected transmission electron microscopy to elucidate the temperature dependence of graphene edge termination at the atomic scale. They revealed that graphene edges predominantly have zigzag terminations below 400 degrees C, while above 600 degrees C, the edges are dominated by armchair and reconstructed zigzag edges. This report brings us one step closer to the true nature of graphene edges. In this Perspective, we outline the present understanding, issues, and future challenges faced in the field of graphene-edge-based nanodevices. PMID- 26006784 TI - Perceptions relating to body size, weight loss and weight-loss interventions in black South African women: a qualitative study. AB - OBJECTIVE: A higher tolerance for a larger body size has been associated with obesity in black South African (SA) women. The aim of the present study was to explore perceptions regarding body size and weight loss in a sample of black women from a low-income community in Cape Town, SA. DESIGN: Qualitative pilot study including five focus groups. Data were analysed using thematic analysis. SETTING: Khayelitsha, Cape Town, SA. SUBJECTS: Twenty-one black SA women. RESULTS: The majority of participants had positive perceptions of overweight/obesity, which were influenced by community and cultural perceptions, but some inconsistencies were observed as overweight/obesity was also associated with ill health. Participants identified many benefits to weight loss, but due to the association with sickness, they were concerned about being stigmatised in their community. Although participants had knowledge about healthy eating, the main barrier to eating healthily included the perceived higher cost of healthier food and food insecurity. All participants saw exercise as a strategy to lose weight and improve health, and were interested in participating in a community based exercise intervention, but negative community perceptions and conflicting views regarding who should lead the intervention were identified as barriers. CONCLUSIONS: These findings highlight the complexities surrounding participants' perceptions regarding body size, weight loss and weight-loss interventions, and emphasise low socio-economic status as a barrier to change. The study also highlights the strong influence of cultural ideals and community perceptions on personal perceptions. These findings underscore the necessity for culturally appropriate weight-loss interventions in low-income, transitioning communities. PMID- 26006785 TI - Non-injected illicit drug use and infectious disease risk of donor tissue: a single institution retrospective review. AB - This study assessed the relationship of non-injected illicit drug use and infectious disease seropositivity for human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), hepatitis C virus (HCV), and Syphilis. In a retrospective review of 986 donor charts recovered from 2009 to 2011 at a single tissue bank, the absence of reported non-injected illicit drug use corresponded with seropositivity in 6.61 %, of recovered donors while reported illicit drug use in the medical and social history corresponded with seropositivity in 11.25 %, representing a 70 % increased risk. There was no significant difference noted for overall seropositivity rates between types on noninjected illicit drugs, although donors that used cocaine had a higher incidence of HIV, while marijuana use was associated with a higher rate of HBV, HCV, and syphilis positivity. Toxicology screening results were not an accurate predictor of seropositivity (PPV = 3.77 %; NPV = 91.56 %). Further, the degree of relationship between the donor and the next of kin had no bearing on the veracity of actual drug use when comparing the response of the medical-social history and the toxicology screen. PMID- 26006786 TI - All-polyethylene tibial components are not inferior to metal-backed tibial components in long-term follow-up of knee arthroplasties. AB - BACKGROUND: All-polyethylene tibias (APT) are under-utilized in most of the Western countries, due to a shift from the original all-polyethylene design to metal-backed tibia (MBT) components. Only few total knee prostheses allow direct comparison between APT and MBT components, due to different geometric designs in many systems. The Depuy PFC Sigma prostheses have a similar geometric design in both the MBT and the APT, and with the same corresponding femoral component, thus allowing an assessment and comparison between APT and MBT components. METHODS: This is a retrospective analysis of a consecutive series of osteoarthritic patients who underwent total knee arthroplasties with at least 10-year follow-up comparing a modern congruent APT component to a modular MBT component of the same design. RESULTS: Seventy-three patients (81 knees, mean age 73 years) were available for assessment. Among the cohort, three patients had revision surgery (one from the APT group). In total, 73 patients were available for follow-up (59 MBT prostheses and 22 APT prostheses). There were no differences in knee function (Knee Society score, range of motion, stability) or radiographic parameters between the groups. Of the three revisions due to tibial tray loosening, only one was performed in the APT group and two were performed in the MBT group; another revision in the MBT group was due to loosening of both components; none of the revisions were due to septic complications. Ten-year survivorship of both designs was 92 %. CONCLUSIONS: While function of both designs appears similar, the APT design shows a trend toward requiring fewer revisions and is more cost-effective. PMID- 26006787 TI - A new redox strategy for low-temperature formation of strong basicity on mesoporous silica. AB - A redox strategy was designed to generate strong basicity on mesoporous silica by using the redox interaction of a precursor with methanol vapor. The formation of strongly basic sites was realized at 400 degrees C, which breaks the tradition of thermally induced decomposition that usually requires much higher temperatures (>600 degrees C). PMID- 26006789 TI - Development of the Knowledge of Dementia Competencies Self-Assessment Tool. AB - Competent dementia care requires caregivers with specialized knowledge and skills. The Knowledge of Dementia Competencies Self-Assessment Tool was developed to help direct care workers (DCWs) assess their knowledge of 7 dementia competencies identified by the Michigan Dementia Coalition. Item selection was guided by literature review and expert panel consultation. It was given to 159 DCWs and readministered to 57 DCWs in a range of long-term care settings and revised based on qualitative feedback and statistical item analyses, resulting in 82 items demonstrating good internal consistency and test-retest reliability. Performance on items assessing competencies rated as most important was significantly related to training in these competencies. The DCWs in day care obtained higher scores than those in home care settings, and their sites reported a greater number of hours of dementia training. Validation in a more diverse group of DCWs and assessing its relationship to other measures of knowledge and skill is needed. PMID- 26006788 TI - Characteristics of men who have sex with men in southern Africa who seek sex online: a cross-sectional study. AB - BACKGROUND: Use of the Internet for finding sexual partners is increasing, particularly among men who have sex with men (MSM). In particular, MSM who seek sex online are an important group to target for human immunodeficiency virus (HIV)/sexually transmitted infection (STI) interventions because they tend to have elevated levels of sexual risk behavior and because the Internet itself may serve as a promising intervention delivery mechanism. However, few studies have examined the correlates of online sexual partner seeking among MSM in sub-Saharan Africa. OBJECTIVE: These analyses aim to describe the prevalence of using the Internet to find new male sexual partners among MSM in two southern African countries. In addition, these analyses examine the sociodemographic characteristics, experiences of discrimination and stigma, mental health and substance use characteristics, and HIV-related knowledge, attitudes, and behaviors among MSM associated with meeting sex partners online. METHODS: MSM were enrolled into a cross-sectional study across two sites in Lesotho (N=530), and one in Swaziland (N=322) using respondent-driven sampling. Participants completed a survey and HIV testing. Data were analyzed using bivariate and multivariable logistic regression models to determine which factors were associated with using the Internet to meet sex partners among MSM. RESULTS: The prevalence of online sex-seeking was high, with 39.4% (209/530) of MSM in Lesotho and 43.8% (141/322) of MSM in Swaziland reporting meeting a new male sexual partner online. In the multivariable analysis, younger age (adjusted odds ratio [aOR] 0.37, 95% confidence interval [CI] 0.27-0.50 per 5 years in Lesotho; aOR 0.68, 95% CI 0.49-0.93 in Swaziland), having more than a high school education (aOR 18.2, 95% CI 7.09-46.62 in Lesotho; aOR 4.23, 95% CI 2.07-8.63 in Swaziland), feeling scared to walk around in public places (aOR 1.89, 95% CI 1.00 3.56 in Lesotho; aOR 2.06, 95% CI 1.23-3.46 in Swaziland), and higher numbers of male anal sex partners within the past 12 months (aOR 1.27, 95% CI 1.01-1.59 per 5 partners in Lesotho; aOR 2.98, 95% CI 1.51-5.89 in Swaziland) were significantly associated with meeting sex partners online in both countries. Additional country-specific associations included increasing knowledge about HIV transmission, feeling afraid to seek health care services, thinking that family members gossiped, and having a prevalent HIV infection among MSM in Lesotho. CONCLUSIONS: Overall, a high proportion of MSM in Lesotho and Swaziland reported meeting male sex partners online, as in other parts of the world. The information in this study can be used to tailor interventions or to suggest modes of delivery of HIV prevention messaging to these MSM, who represent a young and highly stigmatized group. These data suggest that further research assessing the feasibility and acceptability of online interventions will be increasingly critical to addressing the HIV epidemic among MSM across sub-Saharan Africa. PMID- 26006790 TI - Dementia With Lew Body: Impacts of Surgery. AB - Patients who have dementia with Lewy bodies (DLB) and undergo surgery may develop aggravated postoperative cognitive dysfunction or postoperative delirium. Many patients with DLB respond poorly to surgery and anesthesia, and their conditions may worsen if they have other medical complications along with dementia. They may also face high risk of prolonged hospital stay, increased medical problems and/or mortality, causing significant physical, psychosocial, and financial burdens on individuals, family members, and society. Anesthesia, pain medications, old age, and surgery-related stresses are usually held responsible for the complications; however, the exact causes are still not fully understood. Literature on surgery related complications for patients with DLB appears to be inadequate, and hence the topic merits detailed and systematic research. This article reviews postoperative complications and various surgery-related risk factors for DLB in light of other dementias such as Alzheimer's disease, as their neuropathologic features overlap with those of DLB. PMID- 26006793 TI - Blood Pressure and the Risk of Alzheimer's Disease: Is There a Link? AB - Alzheimer disease is one of the most common neurodegenerative disorder, and the incidence is increasing. Many epidemiologic studies have considered the association between blood pressure and Alzheimer disease, yet the relationship is still controversial. The objective of this study was to validate whether or not blood pressure is indeed associated with AD. We compared different prospective studies and ultimately found that it is also a controversial issue. Large prospective double-blinded and placebo-controlled studies conducted with the use of standardized outcome measures in different levels are necessary to assess the association of blood pressure and Alzheimer disease. PMID- 26006792 TI - Severe Impairment Rating Scale: A Useful and Brief Cognitive Assessment Tool for Advanced Dementia for Nursing Home Residents. AB - To investigate the utility of the Severe Impairment Rating Scale (SIRS) as a cognitive assessment tool among nursing home residents with advanced dementia, we conducted a cross-sectional study of 96 residents in 3 nursing homes with Functional Assessment Staging Test (FAST) stage 6a and above. We compared the discriminatory ability of SIRS with the Chinese version of Mini-Mental State Examination, Abbreviated Mental Test, and Clock Drawing Test. Among the cognitive tests, SIRS showed the least "floor" effect and had the best capacity to distinguish very severe (FAST stages 7d-f) dementia (area under the curve 0.80 vs 0.46-0.76 for the other tools). The SIRS had the best correlation with FAST staging (r = -.59, P < .01) and, unlike the other 3 tools, exhibited only minimal change in correlation when adjusted for education and ethnicity. Our results support the utility of SIRS as a brief cognitive assessment tool for advanced dementia in the nursing home setting. PMID- 26006791 TI - Glucose Dysregulation Interacts With APOE-?4 to Potentiate Temporoparietal Cortical Thinning. AB - We examined the interactive effects of apolipoprotein ?4 (APOE-?4), a risk factor for Alzheimer's disease (AD), and diabetes risk on cortical thickness among 107 healthy elderly participants; in particular, participants included 27 APOE-?4+ and 80 APOE-?4- controls using T1-weighted structural magnetic resonance imaging. Regions of interests included select frontal, temporal, and parietal cortical regions. Among APOE-?4, glucose abnormalities independently predicted reduced cortical thickness among temporoparietal regions but failed to predict changes for noncarriers. However, among noncarriers, age independently predicted reduced cortical thickness among temporoparietal and frontal regions. Diabetes risk is particularly important for the integrity of cortical gray matter in APOE-?4 and demonstrates a pattern of thinning that is expected in preclinical AD. However, in the absence of this genetic factor, age confers risk for reduced cortical thickness among regions of expected compromise. This study supports aggressive management of cerebrovascular factors and earlier preclinical detection of AD among individuals presenting with genetic and metabolic risks. PMID- 26007149 TI - Brain activation in response to overt and covert fear and happy faces in women with borderline personality disorder. AB - Borderline personality disorder (BPD) is a serious condition involving emotion dysregulation. Past research has identified BPD-associated differences within fronto-limbic circuitry during conditions of processing negative emotion. Functional magnetic resonance imaging (fMRI) paradigms that incorporate overt and covert (masked) presentations of emotional stimuli can provide complementary information about neural systems underlying emotion processing (e.g., both slow [overt] and fast [covert; automatic] processing pathways). This study examined brain activation during processing of overt and covert presentations of emotional faces in 12 women with BPD and 12 age-matched healthy controls. To assess a range of emotional valence and arousal, we examined responses to fear, happy and neutral expressions. All participants underwent an fMRI scanning session in which participants passively viewed emotional faces. Scanning sessions consisted of 5 runs including: (1) Overt Fear (OF) versus Neutral (N), (2) Covert Fear (CF) versus Covert Neutral (CN), (3) Overt Happy (OH) versus N, (4) Covert Happy (CH) versus CN, and (5) N versus fixation. We compared whole-brain activation between groups for each run. In response to overt fear, BPD patients showed greater activation both in left amygdala and in several frontal cortical regions. There were no significant differences in brain activation in response to overt happy faces. In response to covert fear and covert happy stimuli, the BPD group also showed greater activation than controls in several regions including frontal and temporal cortical regions, as well as cerebellum and thalamus. These findings add to prior reports suggesting increased amygdala activation in BPD, but we found this only in the overt fear versus fixation condition. In this sample, BPD patients showed hyper-activation, rather than hypo-activation, of cortical regulatory regions during overt fear. Enhanced cortical recruitment in response to covert fear and happy faces in BPD could reflect a more extended response system in which stimuli that typically only activate automatic pathways are additionally tapping into cortical regulatory systems. The observation of this pattern both in response to fear and in response to happy presentations suggests that the effect of arousal may be as or more impactful than the effect of emotional valence. PMID- 26007150 TI - Tracking boundary movement and exterior shape modelling in lung EIT imaging. AB - Electrical impedance tomography (EIT) has shown significant promise for lung imaging. One key challenge for EIT in this application is the movement of electrodes during breathing, which introduces artefacts in reconstructed images. Various approaches have been proposed to compensate for electrode movement, but no comparison of these approaches is available. This paper analyses boundary model mismatch and electrode movement in lung EIT. The aim is to evaluate the extent to which various algorithms tolerate movement, and to determine if a patient specific model is required for EIT lung imaging. Movement data are simulated from a CT-based model, and image analysis is performed using quantitative figures of merit. The electrode movement is modelled based on expected values of chest movement and an extended Jacobian method is proposed to make use of exterior boundary tracking. Results show that a dynamical boundary tracking is the most robust method against any movement, but is computationally more expensive. Simultaneous electrode movement and conductivity reconstruction algorithms show increased robustness compared to only conductivity reconstruction. The results of this comparative study can help develop a better understanding of the impact of shape model mismatch and electrode movement in lung EIT. PMID- 26007151 TI - Influence of rheumatoid arthritis-related morning stiffness on productivity at work: results from a survey in 11 European countries. AB - The objective of this study was to evaluate the influence of morning stiffness on productivity at work and to estimate the work-related economic consequences of morning stiffness among patients with RA-related morning stiffness in 11 European countries. The original sample comprised 1061 RA patients from 11 European countries (Belgium, Denmark, Finland, France, Germany, Italy, Norway, Poland, Spain, Sweden and UK). They had been diagnosed with RA and experience morning stiffness three or more times per week. Data were collected by interviews. Women comprised 77.9 % of the sample, the average age was 50.4 years, and 84.3 % had RA diagnosed for more than 2 years. Overall costs of RA-related morning stiffness was calculated to be 27,712? per patient per year, varying from 4965? in Spain to 66,706? in Norway. On average, 96 % of the overall production losses were attributed to early retirement, with a markedly lower level (77 %) in Italy than in other countries (p < 0.0001). The proportion of patients who reported retirement due to morning stiffness and productivity losses due to late work arrivals and working while sick showed considerable variation across the countries represented in the study. Overall, the average annual cost of late arrivals (0.8 % of the total costs) was approximately half of the costs attributed to sick leave (1.7 %) and working while sick (1.5 %). Morning stiffness due to RA causes significant production losses and is a significant cost burden throughout Europe. There seem to be notable differences in the impact of morning stiffness on productivity between European countries. PMID- 26007153 TI - Serum sclerostin is decreased following vitamin D treatment in young vitamin D deficient female adults. AB - Sclerostin is produced almost exclusively by osteocytes, which also express receptors for 1,25 dihydroxyvitamin D3. The aim of this study was to investigate the effects of vitamin D3 treatment on serum sclerostin levels in young adult females with severe vitamin D deficiency. A total of 26 subjects were treated orally with calcium (1.200 mg/day for 2 months) and vitamin D3 (300.000 IU/week for 1 month). Serum 25-hydroxyvitamin D (25(OH)D) and sclerostin levels were measured before and after treatment. Baseline serum 25(OH)D and sclerostin levels were at 5.7 +/- 2.4 ng/mL and 39.1 +/- 14.4 pg/mL, respectively. Serum 25(OH)D was significantly increased, to 62.4 +/- 18.7 ng/mL, following treatment; serum sclerostin was significantly decreased, to 29.3 +/- 8.8 pg/mL. We conclude that serum sclerostin level is decreased following vitamin D3 treatment in patients with vitamin D deficiency. PMID- 26007152 TI - Polymorphism of VEGF gene in susceptibility to chronic immune-mediated inflammatory diseases: a meta-analysis. AB - Background Vascular endothelial growth factor (VEGF) is an important angiogenic factor and may be connected with chronic immune-mediated inflammatory diseases (IMIDs) to some extent. However, previous researches about the relationship between the +405G>C (dbSNP: rs2010963) polymorphism in VEGF gene and the risk of IMIDs are controversial and inconsistent. So we conducted this meta-analysis to assess whether the relationship between the +405G>C polymorphism in the 5'-UTR region of VEGF gene and IMID susceptibility exists. Methods Our literature search was conducted on the PubMed, Embase, Web of science, Chinese National Knowledge Infrastructure, and Chinese Biomedical databases to retrieve for eligible studies. Odds ratios as well as their 95 % confidence intervals were utilized to deduce the possible relationship. Results A total number of 5175 patients with IMIDs and 7069 healthy controls from 27 case-control studies were included. For the overall eligible data collected in our meta-analysis, there was no marked relationship between +405G>C polymorphism and the risk of IMIDs. However, subgroup analysis by ethnicity suggested that +405C allele could be a protective factor for IMIDs in Asians, whereas an opposite conclusion was drawn in Caucasians. Conclusion Thus, we may come to the conclusion that the VEGF +405G>C polymorphism could be associated with IMIDs, and the correlation might vary with ethnic groups. PMID- 26007154 TI - Structural bases for mechano-responsive properties in molecular gels of (R)-12 hydroxy-N-(omega-hydroxyalkyl)octadecanamides. Rates of formation and responses to destructive strain. AB - The self-assembly and gelation behavior of a series of (R)-12-hydroxy-N-(omega hydroxyalkyl)octadecanamides (HS-n-OH, where n = 2, 3, 4 and 5 is the length of the alkyl chain on nitrogen), as well as those of two 'model' compounds, N-(3 hydroxypropyl)octadecanamide (S-3-OH) and (R)-12-hydroxy-N-propyloctadecanamide (HS-3), have been investigated in a wide range of liquids. A unique aspect of some of the HS-n-OH gels is the degree and velocity of their recovery of viscoelasticity after the cessation of destructive shear. The recovery times vary from less than one second to hundreds of seconds, depending on the length of the omega-hydroxyalkyl group on nitrogen. The data indicate that the modes and dynamics of aggregation of the gelator molecules from incubation of a sol phase below the gel melting temperature, as analyzed by Avrami and fractal equations, cannot be used to explain the degree and dynamics of the thixotropy: sol-to-gel transformations involve assembly of 0-dimensional objects (i.e., individual gelator molecules) into 1-dimensional fibrils and then into 3-dimensional networks; recovery after mechano-destruction of gels requires only 1-dimensional to 3-dimensional re-assembly or re-association of 3-dimensional spherulitic objects. A model to understand the extreme sensitivity of the thixotropy on the length of the omega-hydroxyalkyl group in the HS-n-OH (which is based upon detailed comparisons among the dynamic properties of the gels, the morphologies of the neat gelators, and the fibrillar networks of the gels) invokes the importance of the cleavage and reformation of H-bonds between fibers at 'junction zones' or between spherulitic objects. PMID- 26007155 TI - Sphingomonas flavus sp. nov. isolated from road soil. AB - A yellow-colored, Gram-negative, strictly aerobic, non-motile, rod-shaped bacterium, designated THG-MM5(T), was isolated from road soil in Yongin-si, Gyeonggi-do, Republic of Korea. Based on 16S rRNA gene sequence, strain THG MM5(T) was moderately related to Sphingomonas sediminicola KACC 15039(T) (96.1%), Sphingomonas ginsengisoli KACC 16858(T) (96.1%) and Sphingomonas jaspsi KACC 13230(T) (96.0%). Chemotaxonomic data revealed that strain THG-MM5(T) possesses ubiquinone-10 as the only respiratory quinone, sym-homospermidine as the major polyamine and summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), C18:1 omega7c and C16:0 as the major fatty acids. The polar lipid profile included sphingoglycolipid. The DNA G + C content was 60.7 mol%. These data, together with phenotypic characterization, corroborated the affiliation of strain THG-MM5(T) to the genus Sphingomonas. Thus, the isolate represents a novel species, for which the name Sphingomonas flavus sp. nov. is proposed, with THG-MM5(T) as the type strain (=KACC 18277(T) = CCTCC AB 2014320(T)). PMID- 26007156 TI - Driver Gene Mutations in Primary Carcinoids of the Lung: Who Are the Best Candidates for Genetic "Next-Generation Sequencing"? PMID- 26007158 TI - Application of X-rays to dental age estimation in medico-legal practice. AB - AIM OF THE STUDY: The paper addresses the use of dental age assessment methods based on radiographs in medico-legal practice. Different cases of practical application of the methods are presented including identification of human remains, dental age assessment in a living person and one archaeological case. MATERIAL AND METHODS: The study material consisted of cases involving dental age assessment performed in the Department of Forensic Medicine, Poznan University of Medical Sciences in Poznan. Depending on the preliminary assessment of age, the Liversidge or the Kvaal et al. methods were applied. Dental age was estimated on the basis of available pantomograms. In the case of the living person, it was a radiograph supplied for expert evaluation. In the other cases, dental computed tomography was performed. RESULTS: Dental age was successfully estimated in all of the cases. Various methods based on the analysis of X-ray images were applied. Dental age was shown to be correlated with skeletal age. CONCLUSIONS: The methods based on radiographs were demonstrated to be useful, and the results they yield are fully correlated with results of anthropological analyses. PMID- 26007157 TI - The Relationship of HLA-DQ Alleles with Tuberculosis Risk: A Meta-analysis. AB - BACKGROUND: The human leukocyte antigen (HLA) system plays an important role in regulating immune response because it takes part in the defense against pathogens. Some individual research studies have demonstrated that HLA class II genes play an important role in tuberculosis (TB) in several populations. However, the results were controversial. A meta-analysis was performed to examine the associations between HLA alleles and TB risk. METHODS: Relevant studies on the association of HLA-DQA1 and DQB1 alleles with TB were included in the analyses. We examined papers published in the PubMed and EMBASE databases up to June 10, 2014. The odds ratios (ORs) and 95 % confidence intervals (CI) were analyzed from fixed-effects or random-effects models. Subgroup analyses were conducted by ethnicity. RESULTS: This meta-analysis included 12 studies with DQB1 (1290 TB patients and 1471 controls) and 6 studies with DQA1 (453 TB patients and 648 controls). Only DQB1*0601 was found to have a significant association with an increased risk for TB [OR (95 % CI) = 1.68 (1.32-2.14), P = 0.000]. No significant association with TB risk was found in any HLA-DQA1 allele or in other HLA-DQB1 alleles. DQB1*0601 was significantly related to an increased risk of TB in Asian group, whereas no evidence was found in the non-Asian group. CONCLUSION: Our meta-analysis supports the hypothesis that the specific HLA-DQB1 may be regarded as a marker of real worth for predicting the risk of developing TB. The same result was shown in Asian population. PMID- 26007159 TI - The search for mass graves of the soldiers of the National Armed Forces murdered in September 1946 in the Opole region of Poland - results of forensic medical examination. AB - The aim of the study is the identification and forensic-medical and anthropological evaluation of the remains of soldiers of the National Armed Forces murdered by the secret police in September 1946 in the Opole region. The remains were located during the search for mass graves of victims of the Communist regime carried out by the Institute of National Remembrance (IPN). MATERIAL AND METHODS: In June 2012 and April 2013, in the area of the Hubertus clearing between the villages of Barut and Dabrowka, 41 human bone fragments were revealed in the course of archaeological works carried with use of the open pit method at the probable site of the liquidation of one of the groups of soldiers from the unit of Captain Henryk Flame, aka "Bartek". In the vicinity of the ruins of the former Scharfenberg manor, in a forest of the Lambinowice commune, a mass grave was discovered containing the remains of at least 25 individuals, mostly young men. The grave was damaged and bore traces of subsequent interference. The forensic-medical-anthropological examination procedures were carried out, the biological profile of the victims evaluated, the minimum number of individuals (MNI) determined and the injuries interpreted. RESULTS: A portion of the remains discovered near the village of Barut bore traces of trauma associated with a great force. On the remains from the mass grave in the Lambinowice commune, numerous traces of injuries of the perimortem trauma nature were disclosed, including gunshot damage, both within the skulls and in post-cranial skeletons. CONCLUSIONS: The activity of the Institute of National Remembrance led to the confirmation of archival data regarding the site of liquidation of one of the partisan groups of the National Armed Forces in the vicinity of the village of Barut in the Opole region. The research did not allow unambiguous determination of the origin of remains discovered in the mass grave in the Lambinowice commune. The archival data indicate that the remains may be those of victims of Communist terror. PMID- 26007160 TI - Suicidal asphyxiation by using helium - two case reports. AB - Helium is one of inert gases causing physical asphyxiation, whose excess content in the breathing atmosphere reduces the partial pressure of oxygen and may be fatal after short-term exposure. When breathing a mixture of an inert gas (helium, nitrogen, argon) with a small amount of oxygen, with the possibility of exhaling carbon dioxide, no warning signs characteristic of suffocation are perceived by the subject. Freedom from discomfort and pain, effectiveness, rapid effect and relatively easy availability of required accessories have resulted in the use of inert gases for suicidal purposes. The paper reports two cases of suicide committed by using a special kit consisting of the so-called "suicide bag" (or "exit bag") filled with helium supplied through a plastic tube. In both cases, examination of the sites where the corpses were found and analysis of collected material allowed to establish that before their death the subjects had searched the Internet for instructions on how to commit suicide using helium. Due to the advanced putrefaction process, the autopsies failed to determine the causes of their death unequivocally. However, the circumstances surrounding the deaths suggested rapid asphyxiation as a result of oxygen deficiency in the breathing mixture. Since in cases of the type discussed here the cause of death cannot generally be established by autopsy, knowledge of the circumstances of disclosure of the corpse, as well as examination of the cadaver and the death scene is of utmost importance. PMID- 26007161 TI - "Surgically created" excision of the back mimicking homicide: report of an unusual case. AB - Fatalities due to sharp force trauma, with respect to manner of death, may be homicidal, self-inflicted, or accidental in nature. This article presents a case of an unusual sharp force injury inflicted under very specific and seemingly obscured circumstances, initially suggestive of homicidal origin. A 69-year-old, socially isolated male was found dead with a strange, heavily blood-stained excision-like lesion on the right subscapular area. The autopsy confirmed that the wound led to fatal external blood loss. Toxicological analysis of the blood and urine revealed severe alcohol intoxication. The police investigation turned up that the man had suffered from a painful skin furuncle of the right upper back. As he was worried about receiving medical treatment, he voluntarily asked his two acquaintances for "surgical" assistance to remove the skin affection. Based on the circumstances surrounding death and findings at autopsy, it was concluded that the injury was inflicted without the intent to harm or cause death, as a result of simple negligence. Consequently, the manner of death was ultimately certified as an involuntary manslaughter. Our case has clearly illustrated that even highly suspicious and atypically shaped wounds created by sharp-edged instruments with localization in non-accessible body areas does not exclusively indicate homicidal activity, hence, the accidental, suicidal or even iatrogenic origin of the wounding mechanism must be taken into consideration. PMID- 26007162 TI - Post-mortem diagnostics in cases of sepsis. Part 2. Biochemical and morphological examinations. AB - Contemporary post-mortem diagnostics of sepsis makes it possible to obtain multiple evidence verifying the cause of death which is valuable for forensic medicine. There are a number of reports indicating the usefulness of tests of inflammatory markers (chiefly C-reactive protein and procalcitonin) that are employed in clinical medicine. During medico-legal autopsy, it becomes necessary to perform a careful search of pathological symptoms and inflammatory foci - both during external and internal examinations. Although sepsis lacks pathognomonic lesions that can be identified by histopathological examination, it represents an intrinsic element of post-mortem diagnostics. In order to be able to interpret the findings and establish the cause of death, the evaluation must concurrently take into account the circumstances of death, clinical symptoms, results of microbiological and biochemical tests, autopsy findings and histopathological examination results. PMID- 26007163 TI - Upfront chemotherapy and subsequent resection for molecularly defined gliomas. AB - Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB 1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy. PMID- 26007164 TI - Can lateral ventricle contact predict the ontogeny and prognosis of glioblastoma? AB - Lateral ventricle contact (LVC) by glioblastomas has been proposed to reveal their origin and may have prognostic value; however, results from previous studies have been controversial. This study explored the association between LVC and tumor origin and prognosis in glioblastoma patients. Magnetic resonance imaging and clinical data from 115 glioma patients were retrospectively reviewed, and Kaplan-Meier analysis and Cox proportional hazards models were used to assess the occurrence of LVC as a function of survival in 43 glioblastoma patients. The mRNA expression profiles were compared by microarray analysis in LV-contacting and non-LV-contacting glioblastomas (LVCGs and NLVCGs, respectively). The sphere forming and invasive capabilities of LVCG- and NLVCG-derived stem cells were compared in primary glioma stem cell cultures with tumorsphere formation and Matrigel assays, respectively. LVC was more frequently detected in high-grade gliomas which, along with LVCGs, were significantly larger than low-grade gliomas and NLVCGs. LVC parameters were not independent predictors of glioblastoma patient prognosis; the expression profiles (including stemness genes expression) were similar between LVCGs and NLVCGs, and no significant differences were observed in tumorsphere-forming capacity and invasiveness between stem cells derived from the two glioblastoma types. Our results suggest that the origin of glioblastomas cannot be simply estimated by radiographic LVC, and after standard therapy the prognostic value of LVC needs to be carefully interpreted. PMID- 26007165 TI - Special issue: single molecule techniques. AB - Technological advances in the detection and manipulation of single molecules have enabled new insights into the function, structure and interactions of biomolecules. This Special Issue was launched to account for the rapid progress in the field of "Single Molecule Techniques". Four original research articles and seven review articles provide an introduction, as well as an in-depth discussion, of technical developments that are indispensable for the characterization of individual biomolecules. Fluorescence microscopy takes center stage in this Special Issue because it is one of the most sensitive and flexible techniques, which has been adapted in many variations to the specific demands of single molecule analysis. Two additional articles are dedicated to single molecule detection based on atomic force microscopy. PMID- 26007166 TI - Special issue: practical applications of metal complexes. AB - In 1913 Alfred Werner received the Nobel Prize in Chemistry for his work that was of great importance for the development of coordination chemistry. In the years that followed numerous complexes consisting of metal ions and organic ligands were isolated, thus building a strong connection between inorganic and organic chemistry. Coordination compounds have many interesting properties which find diverse applications in numerous aspects of human life. Fourteeen contributions were received for this Special Issue covering very different aspects of metal complexes and their practical applications. The highest number of manuscripts deals with the biological activity of complexes which might potentially be used in the clinical practice. Authors have tested their cytotoxicity, antibacterial activity and enzyme inhibition. Their optical properties were studied in view of their potential use in photodynamic therapy. Moreover, optical properties could also be used for bioanalysis. It is also known that metal complexes are useful catalysts and a few such examples are also described herein. Many other interesting properties and facts about the isolated and described complexes are also reported (radioactivity, design of metal-organic frameworks, etc.). PMID- 26007167 TI - Culture Conditions Affect Expression of DUX4 in FSHD Myoblasts. AB - Facioscapulohumeral muscular dystrophy (FSHD) is believed to be caused by aberrant expression of double homeobox 4 (DUX4) due to epigenetic changes of the D4Z4 region at chromosome 4q35. Detecting DUX4 is challenging due to its stochastic expression pattern and low transcription level. In this study, we examined different cDNA synthesis strategies and the sensitivity for DUX4 detection. In addition, we investigated the effects of dexamethasone and knockout serum replacement (KOSR) on DUX4 expression in culture. Our data showed that DUX4 was consistently detected in cDNA samples synthesized using Superscript III. The sensitivity of DUX4 detection was higher in the samples synthesized using oligo(dT) primers compared to random hexamers. Adding dexamethasone to the culture media significantly suppressed DUX4 expression in immortalized (1.3 fold, p < 0.01) and primary (4.7 fold, p < 0.01) FSHD myoblasts, respectively. Culture medium with KOSR increased DUX4 expression and the response is concentration dependent. The findings suggest that detection strategies and culture conditions should be carefully considered when studying DUX4 in cultured cells. PMID- 26007169 TI - Classification of Sparkling Wine Style and Quality by MIR Spectroscopy. AB - In this study, the suitability of attenuated total reflection (ATR) mid-infrared (MIR) spectroscopy, combined with principal component analysis (PCA) and partial least squares (PLS) regression, was evaluated as a rapid analytical technique for the classification of sparkling wine style and quality. Australian sparkling wines (n = 139) comprising a range of styles (i.e., white, rose, red, Prosecco and Moscato) were analyzed by ATR-MIR spectroscopy combined with multivariate data analysis. The MIR spectra of 50 sparkling white wines, produced according to four different production methods (i.e., Carbonation, Charmat, Transfer and Methode Traditionelle) were also evaluated against: (i) quality ratings determined by an expert panel; and (ii) sensory attributes rated by a trained sensory panel. Wine pH, titratable acidity (TA), residual sugar (RS), alcohol and total phenolic content were also determined. The sparkling wine styles were separated on the PCA score plot based on their MIR spectral data; while the sparkling white wines showed separation based on production method, which strongly influenced the style and sensory properties of wine (i.e., the intensity of fruit versus yeast-derived characters). PLS calibrations of 0.73, 0.77, 0.82 and 0.86 were obtained for sweetness, tropical fruit, confectionary and toasty characters (on the palate), respectively. PMID- 26007168 TI - Structure Based Modeling of Small Molecules Binding to the TLR7 by Atomistic Level Simulations. AB - Toll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of Toll-Like Receptor 7 (TLR7)-targeting drugs, the mechanism of interaction between the TLR7 and two important classes of agonists (imidazoquinoline and adenine derivatives) was investigated through docking and Molecular Dynamics simulations. To perform the computational analysis, a new model for the dimeric form of the receptors was necessary and therefore created. Qualitative and quantitative differences between agonists and inactive compounds were determined. The in silico results were compared with previous experimental observations and employed to define the ligand binding mechanism of TLR7. PMID- 26007170 TI - A Survey of Recent Synthetic Applications of 2,3-Dideoxy-Hex-2-enopyranosides. AB - Unsaturated carbohydrate derivatives are useful intermediates in synthetic transformations leading to a variety of compounds. The aim of this review is to highlight the rich chemistry of ?-2,3 unsaturated pyranosides, emphasizing the variety of transformations that have been carried out in these substrates during the last decade. PMID- 26007171 TI - Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3 (Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid Amides. AB - A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH. PMID- 26007173 TI - Synthesis, antiproliferative and antifungal activities of 1,2,3-triazole substituted carnosic Acid and carnosol derivatives. AB - Abietane diterpenes exhibit an array of interesting biological activities, which have generated significant interest among the pharmacological community. Starting from the abietane diterpenes carnosic acid and carnosol, twenty four new triazole derivatives were synthesized using click chemistry. The compounds differ in the length of the linker and the substituent on the triazole moiety. The compounds were assessed as antiproliferative and antifungal agents. The antiproliferative activity was determined on normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells while the antifungal activity was assessed against Candida albicans ATCC 10231 and Cryptococcus neoformans ATCC 32264. The carnosic acid gamma-lactone derivatives 1-3 were the most active antiproliferative compounds of the series, with IC50 values in the range of 43.4-46.9 MUM and 39.2-48.9 MUM for MRC-5 and AGS cells, respectively. Regarding antifungal activity, C. neoformans was the most sensitive fungus, with nine compounds inhibiting more than 50% of its fungal growth at concentrations <=250 ug?mL-1. Compound 22, possessing a p-Br-benzyl substituent on the triazole ring, showed the best activity (91% growth inhibition) at 250 ug?mL-1 In turn, six compounds inhibited 50% C. albicans growth at concentrations lower than 250 ug?mL-1. PMID- 26007172 TI - Synthesis of a Functionalized Benzofuran as a Synthon for Salvianolic Acid C Analogues as Potential LDL Antioxidants. AB - A palladium mediated synthesis of a common synthon for the syntheses of antioxidant analogues of naturally occurring salvianolic acids is presented. The synthetic route may be used to obtain analogues with a balanced lipophilicity/hydrophilicity which may result in potentially interesting LDL antioxidants for the prevention of cardiovascular diseases. PMID- 26007174 TI - Synthesis and Biological Evaluation of N-Alkyl-3-(alkylamino)-pyrazine-2 carboxamides. AB - A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3 chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3 (octylamino)-N-methyl-pyrazine-2-carboxamides 14-16, was 25 MUg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains. PMID- 26007175 TI - Synthesis, in-vitro antibacterial, antifungal, and molecular modeling of potent anti-microbial agents with a combined pyrazole and thiophene pharmacophore. AB - Ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate (2) and there derivatives 3a-c, 4, 6a-c and 9a-f were synthesized. The structure of compound 2 was deduced by 1H-NMR, 13C-NMR, FT-IR, MS, microanalysis, and single-crystal X ray crystallography. The compound crystallized in the monoclinic system, with space group P21/c and cell coordinates a = 8.5752(16) A, b = 21.046(4) A, c = 8.2941(12) A, beta = 101.131(6) degrees , V = 1468.7(4) A3, and Z = 4. Compounds 2, 3a-c, 4, 5a-c and 9a-f were subjected into in vitro antimicrobial activity tests. Compounds 3a and 3c were more potent than standard drug amphotericin B, showing MIC values of 23.8 +/- 0.42 and 24.3 +/- 0.68, respectively, against Aspergillus fumigatus while the standard drug MIC was 23.7 +/- 0.1. Compound 3c was also more potent (MIC 24.8 +/- 0.64) than the standard drug amphotericin B (MIC 19.7 +/- 0.2) against Syncephalastrum racemosum. Compounds 4 and 9f also showed promising anti-microbial activity. Molecular modeling was performed for the most active compounds. PMID- 26007176 TI - Characterization of Melanogenesis Inhibitory Constituents of Morus alba Leaves and Optimization of Extraction Conditions Using Response Surface Methodology. AB - Melanin is a natural pigment that plays an important role in the protection of skin, however, hyperpigmentation cause by excessive levels of melatonin is associated with several problems. Therefore, melanogenesis inhibitory natural products have been developed by the cosmetic industry as skin medications. The leaves of Morus alba (Moraceae) have been reported to inhibit melanogenesis, therefore, characterization of the melanogenesis inhibitory constituents of M. alba leaves was attempted in this study. Twenty compounds including eight benzofurans, 10 flavonoids, one stilbenoid and one chalcone were isolated from M. alba leaves and these phenolic constituents were shown to significantly inhibit tyrosinase activity and melanin content in B6F10 melanoma cells. To maximize the melanogenesis inhibitory activity and active phenolic contents, optimized M. alba leave extraction conditions were predicted using response surface methodology as a methanol concentration of 85.2%; an extraction temperature of 53.2 degrees C and an extraction time of 2 h. The tyrosinase inhibition and total phenolic content under optimal conditions were found to be 74.8% inhibition and 24.8 MUg GAE/mg extract, which were well-matched with the predicted values of 75.0% inhibition and 23.8 MUg GAE/mg extract. These results shall provide useful information about melanogenesis inhibitory constituents and optimized extracts from M. alba leaves as cosmetic therapeutics to reduce skin hyperpigmentation. PMID- 26007177 TI - Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1). AB - Reactive oxygen species (ROS) are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions. This review focuses on the antioxidant system's roles in maintaining redox homeostasis. Especially, glutathione (GSH) is the most important thiol-containing molecule, as it functions as a redox buffer, antioxidant, and enzyme cofactor against oxidative stress. In the brain, dysfunction of GSH synthesis leading to GSH depletion exacerbates oxidative stress, which is linked to a pathogenesis of aging-related neurodegenerative diseases. Excitatory amino acid carrier 1 (EAAC1) plays a pivotal role in neuronal GSH synthesis. The regulatory mechanism of EAAC1 is also discussed. PMID- 26007178 TI - Predicting the composition of red wine blends using an array of multicomponent Peptide-based sensors. AB - Differential sensing using synthetic receptors as mimics of the mammalian senses of taste and smell is a powerful approach for the analysis of complex mixtures. Herein, we report on the effectiveness of a cross-reactive, supramolecular, peptide-based sensing array in differentiating and predicting the composition of red wine blends. Fifteen blends of Cabernet Sauvignon, Merlot and Cabernet Franc, in addition to the mono varietals, were used in this investigation. Linear Discriminant Analysis (LDA) showed a clear differentiation of blends based on tannin concentration and composition where certain mono varietals like Cabernet Sauvignon seemed to contribute less to the overall characteristics of the blend. Partial Least Squares (PLS) Regression and cross validation were used to build a predictive model for the responses of the receptors to eleven binary blends and the three mono varietals. The optimized model was later used to predict the percentage of each mono varietal in an independent test set composted of four tri blends with a 15% average error. A partial least square regression model using the mouth-feel and taste descriptive sensory attributes of the wine blends revealed a strong correlation of the receptors to perceived astringency, which is indicative of selective binding to polyphenols in wine. PMID- 26007179 TI - Curcumin, inflammation, and chronic diseases: how are they linked? AB - It is extensively verified that continued oxidative stress and oxidative damage may lead to chronic inflammation, which in turn can mediate most chronic diseases including cancer, diabetes, cardiovascular, neurological, inflammatory bowel disease and pulmonary diseases. Curcumin, a yellow coloring agent extracted from turmeric, shows strong anti-oxidative and anti-inflammatory activities when used as a remedy for the prevention and treatment of chronic diseases. How oxidative stress activates inflammatory pathways leading to the progression of chronic diseases is the focus of this review. Thus, research to date suggests that chronic inflammation, oxidative stress, and most chronic diseases are closely linked, and the antioxidant properties of curcumin can play a key role in the prevention and treatment of chronic inflammation diseases. PMID- 26007180 TI - Aromatic Amino Acids-Guanidinium Complexes through Cation-pi Interactions. AB - Continuing with our interest in the guanidinium group and the different interactions than can establish, we have carried out a theoretical study of the complexes formed by this cation and the aromatic amino acids (phenylalanine, histidine, tryptophan and tyrosine) using DFT methods and PCM-water solvation. Both hydrogen bonds and cation-pi interactions have been found upon complexation. These interactions have been characterized by means of the analysis of the molecular electron density using the Atoms-in-Molecules approach as well as the orbital interactions using the Natural Bond Orbital methodology. Finally, the effect that the cation-pi and hydrogen bond interactions exert on the aromaticity of the corresponding amino acids has been evaluated by calculating the theoretical NICS values, finding that the aromatic character was not heavily modified upon complexation. PMID- 26007181 TI - Synthesis and biological evaluation of hydrazone derivatives as antifungal agents. AB - Emerging yeasts are among the most prevalent causes of systemic infections with high mortality rates and there is an urgent need to develop specific, effective and non-toxic antifungal agents to respond to this issue. In this study 35 aldehydes, hydrazones and hydrazines were obtained and their antifungal activity was evaluated against Candida species (C. parapsilosis, C. tropicalis, C. krusei, C. albicans, C. glabrata and C. lusitaneae) and Trichosporon asahii, in an in vitro screening. The minimum inhibitory concentrations (MICs) of the active compounds in the screening was determined against 10 clinical isolates of C. parapsilosis and 10 of T. asahii. The compounds 4-pyridin-2-ylbenzaldehyde] (13a) and tert-butyl-(2Z)-2-(3,4,5-trihydroxybenzylidine)hydrazine carboxylate (7b) showed the most promising MIC values in the range of 16-32 MUg/mL and 8-16 MUg/mL, respectively. The compounds' action on the stability of the cell membrane and cell wall was evaluated, which suggested the action of the compounds on the fungal cell membrane. Cell viability of leukocytes and an alkaline comet assay were performed to evaluate the cytotoxicity. Compound 13a was not cytotoxic at the active concentrations. These results support the discovery of promising candidates for the development of new antifungal agents. PMID- 26007182 TI - Caffeic Acid phenethyl ester and ethanol extract of propolis induce the complementary cytotoxic effect on triple-negative breast cancer cell lines. AB - Chemotherapy of breast cancer could be improved by bioactive natural substances, which may potentially sensitize the carcinoma cells' susceptibility to drugs. Numerous phytochemicals, including propolis, have been reported to interfere with the viability of carcinoma cells. We evaluated the in vitro cytotoxic activity of ethanol extract of propolis (EEP) and its derivative caffeic acid phenethyl ester (CAPE) towards two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and Hs578T, by implementation of the MTT and lactate dehydrogenase (LDH) assays. The morphological changes of breast carcinoma cells were observed following exposure to EEP and CAPE. The IC50 of EEP was 48.35 ug?mL-1 for MDA-MB-23 cells and 33.68 ug?mL-1 for Hs578T cells, whereas the CAPE IC50 was 14.08 uM and 8.01 uM for the MDA-MB-231 and Hs578T cell line, respectively. Here, we report that propolis and CAPE inhibited the growth of the MDA-MB-231 and Hs578T lines in a dose-dependent and exposure time-dependent manner. EEP showed less cytotoxic activity against both types of TNBC cells. EEP and, particularly, CAPE may markedly affect the viability of breast cancer cells, suggesting the potential role of bioactive compounds in chemoprevention/chemotherapy by potentiating the action of standard anti-cancer drugs. PMID- 26007183 TI - Recent advances in click chemistry applied to dendrimer synthesis. AB - Dendrimers are monodisperse polymers grown in a fractal manner from a central point. They are poised to become the cornerstone of nanoscale devices in several fields, ranging from biomedicine to light-harvesting. Technical difficulties in obtaining these molecules has slowed their transfer from academia to industry. In 2001, the arrival of the "click chemistry" concept gave the field a major boost. The flagship reaction, a modified Huisgen cycloaddition, allowed researchers greater freedom in designing and building dendrimers. In the last five years, advances in click chemistry saw a wider use of other click reactions and a notable increase in the complexity of the reported structures. This review covers key developments in the click chemistry field applied to dendrimer synthesis from 2010 to 2015. Even though this is an expert review, basic notions and references have been included to help newcomers to the field. PMID- 26007184 TI - Comparisons of the pharmacokinetic profile of four bioactive components after oral administration of gan-sui-ban-xia decoction plus-minus gansui and gancao drug combination in normal rats. AB - Gan-Sui-Ban-Xia Decoction (GSBXD) was first presented by Zhang Zhongjing in the book Synopsis of Golden Chamber during the Han Dynasty period. The formula was then used for the treatment of persistent fluid retention with floating pulse in Traditional Chinese Medicine (TCM), which in modern medicine is known as malignant ascites. Here, a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the determination of glycyrrhizinic acid, liquiritin, paeoniflorin, albiflorin after oral administration of GSBXD plus-minus Gansui and Gancao anti-drug combination to investigate the possible pharmacokinetic profile differences of different prescriptions with GSBXD in normal rats. The differences of pharmacokinetic parameters among groups were tested by the Student's t-test with p < 0.05 as the level of significance. Significant differences were found between the Gansui and Gancao anti-drug combination and other herbs in GSBXD on pharmacokinetic profile of glycyrrhizinic acid, liquiritin, paeoniflorin and albiflorin. The obtained knowledge might contribute to the rationality of the clinic use of GSBXD and also reveal the compatibility conditions of the Gansui and Gancao anti-drug combination. PMID- 26007185 TI - Synthesis, Structural Characterization and Biological Activity of Novel Cyclohexane-1,3-dione Ligands and Their Metal Complexes. AB - Some new Zn(II) and Cu(II) complexes [Cu(L1)(OAc)2]?H2O, [Cu(L1)(NO3)H2O]?NO3?3.5H2O, [Zn(L1)(NO3)2]?4.5H2O, [Zn(L1)(OAc)2(H2O)2]?3H2O, [Cu2(L2)(OAc)4]?2H2O?2DMF, [Cu(L2)2]?2NO3?1.5DMF?H2O, [Zn(L2)2(NO3)2]?DMF and [Zn2(L2)(OAc)4(H2O)4]?5H2O; L1 = 2-[2-(2-methoxyphenyl)hydrazono]cyclohexane-1,3 dione and L2 = 2-[2-(3-nitrophenyl)hydrazono]cyclohexane-1,3-dione were synthesized and characterized by IR, 1H-NMR,13C-NMR and ultraviolet (UV-Vis.) spectroscopy, elemental analysis, magnetic susceptibility, mass spectrometry and thermogravimetry-differential thermal analysis (TGA-DTA). The synthesized ligands and their complexes were tested for antibacterial activity against Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, and Salmonella typhimurium CCM 583. Some of complexes showed medium-level antibacterial activity against the test bacteria compared with ampicillin. PMID- 26007186 TI - Complex Interplay of Hormonal Signals during Grape Berry Ripening. AB - Grape and wine production and quality is extremely dependent on the fruit ripening process. Sensory and nutritional characteristics are important aspects for consumers and their development during fruit ripening involves complex hormonal control. In this review, we explored data already published on grape ripening and compared it with the hormonal regulation of ripening of other climacteric and non-climacteric fruits. The roles of abscisic acid, ethylene, and brassinosteroids as promoters of ripening are discussed, as well as the role of auxins, cytokinins, gibberellins, jasmonates, and polyamines as inhibitors of ripening. In particular, the recently described role of polyamine catabolism in grape ripening is discussed, together with its putative interaction with other hormones. Furthermore, other recent examples of cross-talk among the different hormones are presented, revealing a complex interplay of signals during grape development and ripening. PMID- 26007187 TI - Essential Oil from Berries of Lebanese Juniperus excelsa M. Bieb Displays Similar Antibacterial Activity to Chlorhexidine but Higher Cytocompatibility with Human Oral Primary Cells. AB - Chlorhexidine (CHX), one of the most effective drugs administered for periodontal treatment, presents collateral effects including toxicity when used for prolonged periods; here, we have evaluated the bactericidal potency and the cytocompatibility of Juniperus excelsa M. Bieb essential oil (EO) in comparison with 0.05% CHX. The EO was extracted from berries by hydrodistillation and components identified by gas chromatography and mass spectrometry. Bacterial inhibition halo analysis, quantitative cell viability 2,3-bis(2-methoxy-4-nitro-5 sulphophenyl)-5-[(phenyl amino) carbonyl]-2H-tetrazolium hydroxide assay (XTT), and colony forming unit (CFU) count were evaluated against the two biofilm formers Aggregatibacter actinomycetemcomitans and Streptococcus mutans. Finally, cytocompatibility was assessed with human primary gingival fibroblasts (HGF) and mucosal keratinocytes (HK). The resulting EO was mainly composed of monoterpene hydrocarbons and oxygenated monoterpenes. An inhibition halo test demonstrated that both bacteria were sensitive to the EO; XTT analysis and CFU counts confirmed that 10-fold-diluted EO determined a statistically significant (p < 0.05) reduction in bacteria count and viability towards both biofilm and planktonic forms in a comparable manner to those obtained with CHX. Moreover, EO displayed higher cytocompatibility than CHX (p < 0.05). In conclusion, EO exhibited bactericidal activity similar to CHX, but a superior cytocompatibility, making it a promising antiseptic alternative to CHX. PMID- 26007188 TI - Green polymer chemistry: enzyme catalysis for polymer functionalization. AB - Enzyme catalyzed reactions are green alternative approaches to functionalize polymers compared to conventional methods. This technique is especially advantageous due to the high selectivity, high efficiency, milder reaction conditions, and recyclability of enzymes. Selected reactions can be conducted under solventless conditions without the application of metal catalysts. Hence this process is becoming more recognized in the arena of biomedical applications, as the toxicity created by solvents and metal catalyst residues can be completely avoided. In this review we will discuss fundamental aspects of chemical reactions biocatalyzed by Candida antarctica lipase B, and their application to create new functionalized polymers, including the regio- and chemoselectivity of the reactions. PMID- 26007189 TI - Chemical composition and antioxidant activity of essential oil of six pinus taxa native to China. AB - The essential oils obtained by steam distillation from needles of six China endemic Pinus taxa (P. tabulaeformis, P. tabulaeformis f. shekanensis, P. tabulaeformis var. mukdensis, P. tabulaeformis var. umbraculifera, P. henryi and P. massoniana) were analysed by GC/MS. A total of 72 components were separated and identified by GC/MS from the six taxa. The major constituents of the essential oils were: alpha-pinene (6.78%-20.55%), bornyl acetale (3.32%-12.71%), beta-caryophellene (18.26%-26.31%), alpha-guaiene (1.23%-8.19%), and germacrene D (1.26%-9.93%). Moreover, the essential oils were evaluated for antioxidant potential by three assays (DPPH, FRAP and ABTS) and tested for their total phenolic content. The results showed that all essential oils exhibited acceptable antioxidant activities and these strongly suggest that these pine needles may serve as a potential source of natural antioxidants for food and medical purposes. PMID- 26007190 TI - Synthesis and Biological Evaluation of Novel Water-Soluble Poly-(ethylene glycol) 10-hydroxycamptothecin Conjugates. AB - In order to improve the antitumor activity and water solubility of 10 hydroxycamptothecin (HCPT), a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG) to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of these synthesized compounds was determined in pH 7.4 buffer at 37 degrees C, and the results showed that they released HCPT at different rates. All the compounds demonstrated significant antitumor activity in vitro against K562, HepG2 and HT-29 cells. Among them, compounds, 4a, 4d, 4e and 4f, exhibited 2-5 times higher potency than HCPT. The stability and antitumor activity of these conjugates were found to be closely related to the length of PEG and the linker type, conjugates with a relatively short PEG chain and carbamate linkages (compounds 4a and 4f) exhibited controlled release of HCPT and excellent antitumor in vitro activity. PMID- 26007191 TI - Cellular Structural Changes in Candida albicans Caused by the Hydroalcoholic Extract from Sapindus saponaria L. AB - Vulvovaginal candidiasis (VVC) is a disease caused by the abnormal growth of yeast-like fungi in the mucosa of the female genital tract. Candida albicans is the principal etiological agent involved in VVC, but reports have shown an increase in the prevalence of Candida non-C. albicans (CNCA) cases, which complicates VVC treatment because CNCA does not respond well to antifungal therapy. Our group has reported the in vitro antifungal activity of extracts from Sapindus saponaria L. The present study used scanning electron microscopy and transmission electron microscopy to further evaluate the antifungal activity of hydroalcoholic extract from S. saponaria (HE) against yeast obtained from VVC and structural changes induced by HE. We observed the antifungal activity of HE against 125 vaginal yeasts that belonged to four different species of the Candida genus and S. cerevisae. The results suggest that saponins that are present in HE act on the cell wall or membrane of yeast at the first moments after contact, causing damage to these structures and cell lysis. PMID- 26007192 TI - Palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides. AB - Synthetic modification of nucleoside structures provides access to molecules of interest as pharmaceuticals, biochemical probes, and models to study diseases. Covalent modification of the purine and pyrimidine bases is an important strategy for the synthesis of these adducts. Palladium-catalyzed cross-coupling is a powerful method to attach groups to the base heterocycles through the formation of new carbon-carbon and carbon-heteroatom bonds. In this review, approaches to palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides are reviewed. Polar reaction media, such as water or polar aprotic solvents, allow reactions to be performed directly on the hydrophilic nucleosides and nucleotides without the need to use protecting groups. Homogeneous aqueous-phase coupling reactions catalyzed by palladium complexes of water-soluble ligands provide a general approach to the synthesis of modified nucleosides, nucleotides, and oligonucleotides. PMID- 26007194 TI - Protein-Carbohydrate Interaction between Sperm and the Egg-Coating Envelope and Its Regulation by Dicalcin, a Xenopus laevis Zona Pellucida Protein-Associated Protein. AB - Protein-carbohydrate interaction regulates multiple important processes during fertilization, an essential biological event where individual gametes undergo intercellular recognition to fuse and generate a zygote. In the mammalian female reproductive tract, sperm temporarily adhere to the oviductal epithelium via the complementary interaction between carbohydrate-binding proteins on the sperm membrane and carbohydrates on the oviductal cells. After detachment from the oviductal epithelium at the appropriate time point following ovulation, sperm migrate and occasionally bind to the extracellular matrix, called the zona pellucida (ZP), which surrounds the egg, thereafter undergoing the exocytotic acrosomal reaction to penetrate the envelope and to reach the egg plasma membrane. This sperm-ZP interaction also involves the direct interaction between sperm carbohydrate-binding proteins and carbohydrates within the ZP, most of which have been conserved across divergent species from mammals to amphibians and echinoderms. This review focuses on the carbohydrate-mediated interaction of sperm with the female reproductive tract, mainly the interaction between sperm and the ZP, and introduces the fertilization-suppressive action of dicalcin, a Xenopus laevis ZP protein-associated protein. The action of dicalcin correlates significantly with a dicalcin-dependent change in the lectin-staining pattern within the ZP, suggesting a unique role of dicalcin as an inherent protein that is capable of regulating the affinity between the lectin and oligosaccharides attached on its target glycoprotein. PMID- 26007193 TI - Relationship between High-Performance Liquid Chromatography Fingerprints and Uric Acid-Lowering Activities of Cichorium intybus L. AB - This study aimed to explore the spectrum-effect relationships between high performance liquid chromatography fingerprints and the uric acid-lowering activities of chicory. Chemical fingerprints of chicory samples from ten different sources were determined by high-performance liquid chromatography, and then investigated by similarity analysis and hierarchical clustering analysis. Pharmacodynamics experiments were conducted in animals to obtain the uric acid lowering activity information of each chicory sample. The spectrum-effect relationships between chemical fingerprints and the uric acid-lowering activities of chicory were established by canonical correlation analysis. The structures of potential effective peaks were identified by liquid chromatography with tandem mass spectrometry. The results showed that a close correlation existed between the spectrum and effect of chicory. Aesculin, chlorogenic acid, chicoric acid, isochlorogenic acid A/B/C and 13,14-seco-stigma5(6),14(15)-diene-3alpha-ol might be the main effective constituents. This work provides a general model of the combination of high-performance liquid chromatography and uric acid-lowering activities to study the spectrum-effect relationships of chicory, which can be used to discover the principle components responsible for the bioactivity. PMID- 26007195 TI - Opsoclonus associated with autoantibodies to glutamate receptors delta2. PMID- 26007196 TI - Postharvest Exogenous Application of Abscisic Acid Reduces Internal Browning in Pineapple. AB - Internal browning (IB) is a postharvest physiological disorder causing economic losses in pineapple, but there is no effective control measure. In this study, postharvest application of 380 MUM abscisic acid (ABA) reduced IB incidence by 23.4-86.3% and maintained quality in pineapple fruit. ABA reduced phenolic contents and polyphenol oxidase and phenylalanine ammonia lyase activities; increased catalase and peroxidase activities; and decreased O2(.-), H2O2, and malondialdehyde levels. This suggests ABA could control IB through inhibiting phenolics biosynthesis and oxidation and enhancing antioxidant capability. Furthermore, the efficacy of IB control by ABA was not obviously affected by tungstate, ABA biosynthesis inhibitor, nor by diphenylene iodonium, NADPH oxidase inhibitor, nor by lanthanum chloride, calcium channel blocker, suggesting that ABA is sufficient for controlling IB. This process might not involve H2O2 generation, but could involve the Ca(2+) channels activation. These results provide potential for developing effective measures for controlling IB in pineapple. PMID- 26007197 TI - Rectal varices in extrahepatic portal vein obstruction. PMID- 26007198 TI - Association between periodontal disease and oral and gastric Helicobacter pylori infection. PMID- 26007199 TI - Clinical, Molecular, and Functional Characterization of CLCN1 Mutations in Three Families with Recessive Myotonia Congenita. AB - Myotonia congenita (MC) is an inherited muscle disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. Both recessive (Becker's disease) or dominant (Thomsen's disease) MC are caused by mutations in the CLCN1 gene encoding the voltage-dependent chloride ClC-1 channel, which is quite exclusively expressed in skeletal muscle. More than 200 CLCN1 mutations have been associated with MC. We provide herein a detailed clinical, molecular, and functional evaluation of four patients with recessive MC belonging to three different families. Four CLCN1 variants were identified, three of which have never been characterized. The c.244A>G (p.T82A) and c.1357C>T (p.R453W) variants were each associated in compound heterozygosity with c.568GG>TC (p.G190S), for which pathogenicity is already known. The new c.809G>T (p.G270V) variant was found in the homozygous state. Patch-clamp studies of ClC-1 mutants expressed in tsA201 cells confirmed the pathogenicity of p.G270V, which greatly shifts the voltage dependence of channel activation toward positive potentials. Conversely, the mechanisms by which p.T82A and p.R453W cause the disease remained elusive, as the mutated channels behave similarly to WT. The results also suggest that p.G190S does not exert dominant-negative effects on other mutated ClC-1 subunits. Moreover, we performed a RT-PCR quantification of selected ion channels transcripts in muscle biopsies of two patients. The results suggest gene expression alteration of sodium and potassium channel subunits in myotonic muscles; if confirmed, such analysis may pave the way toward a better understanding of disease phenotype and a possible identification of new therapeutic options. PMID- 26007201 TI - A feasibility study of a rotary planar electrode array for electrical impedance mammography using a digital breast phantom. AB - A feasibility study of an electrical impedance mammography (EIM) system with a rotary planar electrode array, named RPEIM, is presented. The RPEIM system is an evolution of the Sussex MK4 system, which is a prototype instrument for breast cancer detection. Comparing it with the other planar electrode EIM systems, the rotation feature enables a dramatic increase in the number of independent measurements. To assist impedance evaluation exploiting electrode array rotation, a synchronous mesh method is proposed. Using the synchronous mesh method, the RPEIM system is shown to have superior performance in image accuracy, spatial resolution and noise tolerance over the MK4 system. To validate the study, we report simulations based on a close-to-realistic 3D digital breast phantom, which comprises of: skin, nipple, ducts, acinus, fat and tumor. A digital breast phantom of a real patient is constructed, whose tumor was detected using the MK4 system. The reconstructed conductivity image of the breast phantom indicates that the breast phantom is a close replica of the patient's real breast as assessed by the MK4 system in a clinical trial. A comparison between the RPEIM system and the MK4 system is made based on this phantom to assess the advantages of the RPEIM system. PMID- 26007202 TI - Combination of music with lifestyle modification versus lifestyle modification alone on blood pressure reduction - A randomized controlled trial. AB - OBJECTIVE: To evaluate the change in blood pressure (BP) after 3 months of music intervention combined with lifestyle modifications, in comparison with conventional lifestyle modifications. METHODS: A Prospective randomized control trial was conducted on hundred prehypertensives or stage I hypertensives who were randomly divided into two groups (n = 50 each). Both the groups were given lifestyle modifications while one had added music intervention (raga bhimpalas) for 3 months. Main outcome measures were 24 h ambulatory BP monitoring, stress levels, and biomarkers of hypertension. RESULTS: Mean (SD) of diastolic BP (DBP) pre and post intervention were overall = 85.1(6.8) and 83(8.7){P = 0.004}, awake = 87.7(7.6) and 85.9(9.2){P = 0.021}. Regression analysis showed association between diastolic BP change and post-intervention stress score in the music intervention group. Significant change in BP was seen among those who were prehypertensives prior to intervention. CONCLUSION: Music decreased DBP and when used as an adjunct benefitted subjects with initial BP in prehypertension range. PMID- 26007203 TI - Translational regulation shapes the molecular landscape of complex disease phenotypes. AB - The extent of translational control of gene expression in mammalian tissues remains largely unknown. Here we perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. Remarkably, we observe hundreds of strain-specific differences in translation, almost doubling the number of differentially expressed genes. The integration of genetic, transcriptional and translational data sets reveals distinct signatures in 3'UTR variation, RNA-binding protein motifs and miRNA expression associated with translational regulation of gene expression. We show that a large number of genes associated with heart and liver traits in human genome-wide association studies are primarily translationally regulated. Capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes. PMID- 26007200 TI - Structure, Distribution, and Function of Neuronal/Synaptic Spinules and Related Invaginating Projections. AB - Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These "invaginating projections" can occur in almost any combination of postsynaptic, presynaptic, and glial processes. Invaginating projections provide a precise mechanism for one neuron to communicate or exchange material exclusively at a highly localized site on another neuron, e.g., to regulate synaptic plasticity. The best-known types are postsynaptic projections called "spinules" that invaginate into presynaptic terminals. Spinules seem to be most prevalent at large very active synapses. Here, we present a comprehensive review of all kinds of invaginating projections associated with both neurons in general and more specifically with synapses; we describe them in all animals including simple, basal metazoans. These structures may have evolved into more elaborate structures in some higher animal groups exhibiting greater synaptic plasticity. In addition to classic spinules and filopodial invaginations, we describe a variety of lesser-known structures such as amphid microvilli, spinules in giant mossy terminals and en marron/brush synapses, the highly specialized fish retinal spinules, the trophospongium, capitate projections, and fly gnarls, as well as examples in which the entire presynaptic or postsynaptic process is invaginated. These various invaginating projections have evolved to modify the function of a particular synapse, or to channel an effect to one specific synapse or neuron, without affecting those nearby. We discuss how they function in membrane recycling, nourishment, and cell signaling and explore how they might change in aging and disease. PMID- 26007204 TI - Para-aortic lymph node metastases in locally advanced cervical cancer: Comparison between surgical staging and imaging. AB - OBJECTIVE: Compare surgical staging with imaging (PET-CT, PET or CT) of the para aortic lymph nodes (PAOLN) in locally advanced cervical cancer (LACC). METHODS: Monocentric retrospective study of 336 patients with cervical cancer FIGO stage IB2-IVA. All patients underwent staging of the PAOLN using imaging by PET-CT, PET or CT. Two hundred and four patients with normal or not overtly malignant PAOLN on imaging underwent surgical PAOLN staging up to the inferior mesenteric artery (189 endoscopy and 15 laparotomy). RESULTS: The patients were divided into 4 groups: 16 with positive surgical staging and negative PAOLN imaging (sPAOLN+), 172 negative surgical staging (sPAOLN-), 20 positive imaging without surgical staging (iPAOLN+) and 128 negative imaging without surgical staging (iPAOLN-). Median operative time of staging was 70 (40-160) min and median number of removed PAOLN was 5 (0-24). Operative complications were 10 peroperative bleedings, 2 ureteral traumas, 1 carbon dioxide retention and 1 retroperitoneal abscess. The median follow-up was 31 (1-218) months. Overall survival at 2 years was for sPAOLN+, sPAOLN-, iPAOLN+, and iPAOLN- 40%, 83%, 58%, and 69%, respectively (p<0.001 for sPAOLN+ and iPAOLN+ versus sPAOLN- and iPAOLN-). The most frequent site of recurrence was distant LN metastases (outside the pelvic and PAO area) (36%) for sPAOLN+. For sPAOLN-, iPAOLN+, and iPAOLN- the most frequent site of recurrence was the cervix (27%, 66% and 26%, respectively). CONCLUSION: Despite negative imaging, PAOLN metastases were present in 8% at surgical staging. Overall survival is significantly influenced by the presence of PAOLN metastases. PMID- 26007205 TI - Benchmark Outcomes for Pulmonary Valve Replacement Using The Society of Thoracic Surgeons Databases. AB - BACKGROUND: As less invasive alternatives to surgical pulmonary valve replacement (PVR) are being refined and evaluated, there is a need for benchmark data concerning outcomes from surgical PVR. METHODS: We examined in-hospital outcomes from surgical PVR in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) and Adult Cardiac Surgery Database (STS-ACSD) between 2007 and 2013, with a focus on patients likely to be eligible for transcatheter PVR (ie, >= 5 years age and >= 30 kg). Patient characteristics, morbidity, and mortality were described. RESULTS: The STS-CHSD included 6,431 eligible patients with a median age of 17 years (interquartile range [IQR], 14-25 years). Preoperative comorbidities were uncommon: arrhythmia (1.7%), renal failure (0.1%), endocarditis (0.3%), neurologic deficit (0.8%), and diabetes (0.5%). In hospital mortality was 0.9%. A major complication occurred in 2.2%. The STS-ACSD included 3,352 eligible patients; the median age was 41 years (IQR, 30-55 years). Preoperative comorbidities were more common: arrhythmia (24.3%), renal failure (3.8%), endocarditis (12.2%), cerebrovascular disease (7.9%), and diabetes (10.9%). In-hospital mortality was 4.1%. A major complication occurred in 20.9%. CONCLUSIONS: Contemporary outcomes from surgical PVR include a low risk of in hospital death or major complications. Patients in the STS-ACSD are older and have an increased prevalence of preoperative factors, which may contribute to higher morbidity and mortality. PMID- 26007206 TI - Bilobectomy Versus Lobectomy for Non-Small Cell Lung Cancer: A Comparative Study of Outcomes, Long-Term Survival, and Quality of Life. AB - BACKGROUND: We aimed to compare long-term survival and quality of life (QOL) outcomes after bilobectomy and lobectomy for non-small cell lung cancer patients. METHODS: A cohort of 951 consecutive patients was identified from a single treatment institution, of whom 128 underwent bilobectomy and 823, lobectomy. Propensity score matching (1:3) was applied to balance known confounders between the two surgical groups and resulted in 512 patients (matched cohort). Unmatched and matched analyses were performed to compare clinical outcomes between the two groups, including operative mortality rate, morbidity rate, long-term survival, overall QOL, and specific symptoms. RESULTS: Operative mortality was higher in the bilobectomy group than in the lobectomy group (2.3% versus 0.5%, p = 0.022). Morbidity rates did not differ significantly between the two groups in either unmatched or matched cohort. In the unmatched analysis, the overall survival (OS [p = 0.003]) and disease-free survival (DFS [p = 0.003]) were significantly lower in the bilobectomy group; whereas in the matched analysis, no significant difference was found in either OS (p = 0.473) or DFS (p = 0.387). Using multivariate analysis, the operation type was not found to be a significant factor for either OS (hazard ratio 1.18; 95% confidence interval: 0.91 to 1.52; p = 0.22) or DFS (hazard ratio 1.22; 95% confidence interval: 0.95 to 1.58; p = 0.13). Patients who underwent bilobectomy appeared to have similar measures of QOL as lobectomy patients, except for coughing and dyspnea. CONCLUSIONS: Our findings indicate that patients with non-small cell lung cancer treated with bilobectomy had similar morbidity, OS, DFS, and overall QOL as patients treated with lobectomy, but had higher mortality by matched analysis. PMID- 26007207 TI - Emotion dysregulation mediates the influence of relationship difficulties on non suicidal self-injury behavior in young adults. AB - This study examined associations between relationship difficulties with parents and peers and non-suicidal self-injury (NSSI). Particular emphasis was placed on examining mediating pathways through emotion dysregulation, as per commonly accepted theory. Participants were 1153 university students (905 females; Mage=19.35 years, S.D.=1.49); 79 of these participants had engaged in NSSI during the previous 6 months (63 females, Mage=19.35 years, S.D.=1.51). Participants completed questionnaires assessing NSSI, quality of relationships with parents and peers, and emotion dysregulation. Hierarchical logistic regressions suggest that the quality of parent-child relationships has a greater impact on the prediction of NSSI engagement than the quality of peer relationships. Results of a structural equation model showed that feelings of alienation in both parent and peer relationships had indirect effects on NSSI through deficits in emotion regulation (ER). Results suggest the importance of examining emotion dysregulation in association with NSSI, and that both parent and peer relationships are implicated in NSSI engagement through emotion regulation deficits. Important clinical implications regarding the need to acknowledge both emotion dysregulation and interpersonal difficulties when treating NSSI in young adults are discussed. PMID- 26007208 TI - Once upon a spine: setting striatal dopamine. PMID- 26007209 TI - Hunger logic. PMID- 26007210 TI - Social nudges: utility conferred from others. PMID- 26007211 TI - Lysosomes to combat Parkinson's disease. PMID- 26007214 TI - Corrigendum: Anchoring the neural compass: coding of local spatial reference frames in human medial parietal lobe. PMID- 26007212 TI - The case for rejecting the amyloid cascade hypothesis. AB - Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-beta, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis. PMID- 26007215 TI - Erratum: A region-specific neurogenesis mode requires migratory progenitors in the Drosophila visual system. PMID- 26007216 TI - Corrigendum: Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. PMID- 26007213 TI - Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. AB - The amyloid hypothesis, which has been the predominant framework for research in Alzheimer's disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that amyloid-beta peptide (Abeta) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Abeta causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that Abeta likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Abeta acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. Abeta appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process. PMID- 26007217 TI - Erratum: Visual recognition memory, manifested as long-term habituation, requires synaptic plasticity in V1. PMID- 26007218 TI - Prevalence and clinical impact of magnesium disorders in end-stage renal disease: a protocol for a systematic review. AB - BACKGROUND: Magnesium plays a key role in maintaining internal homeostasis through actions in the musculoskeletal, nervous, endocrine and cellular messenger systems. Renal excretion is the major route of magnesium elimination from the body. A positive magnesium balance would be expected in renal failure. However, a compensatory decrease in tubular reabsorption is expected to operate to maintain adequate urinary magnesium excretion even when glomerular filtration rate is very low. Patients with end-stage renal disease and those on dialysis have impaired regulatory mechanisms, predisposing them to disturbances in magnesium levels. The effects of high or low magnesium can have deleterious health outcomes, which impact on the co-morbidities and outcomes of chronic renal disease. This systematic review aims to determine the prevalence and clinical outcomes of magnesium disorders in end-stage renal disease. METHODS/DESIGN: We will undertake a comprehensive search of various databases, MEDLINE, PubMED, EMBASE, Cochrane Library, Cochrane Collaboration, CIHNAL (Ebsco), Web of Science and Google Scholar, for observational studies and clinical trials on magnesium disorders in end-stage renal disease using key terms to identify papers for inclusion. Paper selection and data extraction (where appropriate) will be performed in duplicate on socio-demographic characteristics of participants, diagnosis of end-stage renal disease, magnesium levels, prevalence and clinical outcomes. An assessment of quality will be performed using a modified Newcastle-Ottawa Scale (NOS), including identification of any bias, which may influence findings. Data will be pooled together according to whether the studies were on pre-dialysis, hemodialysis or peritoneal dialysis participants. References from individual papers will also be screened as appropriate. Paper organisation and data extraction and analysis will take place using Microsoft Excel(r) and Stata version 13(r). DISCUSSION: This systematic review will represent a significant effort at pooling together information on prevalence and outcomes of magnesium disturbances amongst end-stage renal disease patients, which may guide further research and management of the disorders. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42014014354. PMID- 26007219 TI - A heterobimetallic [Mn5(II)Cu5(II)] nanowheel modulated by a flexible bis-oxamate type ligand. AB - The synthesis, crystal structure and preliminary magnetic characterization of a new heterobimetallic [Mn5(II)Cu5(II)] wheel containing a flexible bis-oxamate type ligand are described. This decanuclear compound exhibits a relatively strong intra-wheel antiferromagnetic interaction leading to a ground spin state S = 10. PMID- 26007220 TI - Pyogenic granuloma of the transverse colon. PMID- 26007221 TI - Impact of a simulation training curriculum on technical and nontechnical skills in colonoscopy: a randomized trial. AB - BACKGROUND: GI endoscopy simulation-based training augments early clinical performance; however, the optimal manner by which to deliver training is unknown. OBJECTIVE: We aimed to validate a simulation-based structured comprehensive curriculum (SCC) designed to teach technical, cognitive, and integrative competencies in colonoscopy. DESIGN: Single-blinded, randomized, controlled trial. SETTING: Endoscopic simulation course at an academic hospital. PARTICIPANTS AND INTERVENTIONS: Thirty-three novice endoscopists were allocated to an SCC group or self-regulated learning (SRL) group. The SCC group received a curriculum consisting of 6 hours of didactic lectures and 8 hours of virtual reality simulation-based training with expert feedback. The SRL group was provided a list of desired objectives and was instructed to practice on the simulator for an equivalent time (8 hours). MAIN OUTCOME MEASUREMENTS: Clinical transfer was assessed during 2 patient colonoscopies using the Joint Advisory Group Direct Observation of Procedural Skills (JAG DOPS) scale. Secondary outcome measures included differences in procedural knowledge, immediate post-training simulation performance, and delayed post-training (4-6 weeks) performance during an integrated scenario test on the JAG DOPS communication and integrated scenario global rating scales. RESULTS: There was no significant difference in baseline or post-training performance on the simulator task. The SCC group performed superiorly during their first and second clinical colonoscopies. Additionally, the SCC group demonstrated significantly better knowledge and colonoscopy specific performance, communication, and global performance during the integrated scenario. LIMITATIONS: We were unable to measure SRL participants' effort outside of mandatory training. In addition, feedback metrics and number of available simulation cases are limited. CONCLUSIONS: These results support integration of endoscopy simulation into a structured curriculum incorporating instructional feedback and complementary didactic knowledge as a means to augment technical, cognitive, and integrative skills acquisition, as compared with SRL on virtual reality simulators. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01991522.) PMID- 26007222 TI - Knowledge and predictors of dysplasia surveillance performance in inflammatory bowel diseases in Australia. AB - BACKGROUND: Dysplasia surveillance is recognized as an integral component in the management of inflammatory bowel diseases (IBDs). The adherence to surveillance guidelines is variable, and understanding of quality indicators and predictors of behavior is currently limited. OBJECTIVE: To perform a nationwide evaluation of the quality of IBD surveillance practiced by Australian endoscopists and to determine the predictors of quality practice. DESIGN: Cross-sectional nationwide survey. SETTING: Survey distributed through the gastroenterology and colorectal surgery societies covering knowledge and practice of IBD surveillance. MAIN OUTCOME MEASUREMENTS: Adherence to indicators of high-quality surveillance and median score of IBD surveillance guideline knowledge. RESULTS: A total of 264 responses were received, comprising 240 respondents who perform surveillance screening (218 gastroenterologists, 46 colorectal surgeons). Gastroenterologists were significantly more likely to undertake surveillance (P < .001), adhere to guidelines (P = .02), use advanced imaging modalities (P = .04), and have greater surveillance knowledge than colorectal surgeons (P < .001). Knowledge score and gastroenterologists were independent predictors of dysplasia screening (odds ratio [OR] 1.66; 95% confidence interval [CI], 1.41-1.96 and OR 11.2; 95% CI, 4.53-27.87), guideline adherence (OR 1.15; 95% CI, 1.01-1.31 and OR 2.42; 95% CI, 1.11-5.30), and advanced endoscopic imaging technique use (OR 1.19; 95% CI, 1.05 1.35 and OR 2.2; 95% CI, 1.02-4.74). LIMITATIONS: Potential responder bias results appear, however, aligned with those of previous studies. CONCLUSIONS: IBD dysplasia surveillance in Australia is being performed at a high standard. Gastroenterology specialization and knowledge score have been demonstrated to be strong predictors of high-quality surveillance practice. This is the first study to determine predictors of screening behavior and quantify surveillance quality. These results further emphasize that gastroenterologists should play a key role in IBD surveillance. PMID- 26007224 TI - Tailoring and visualizing the pore architecture of hierarchical zeolites. AB - Recently the concept of hierarchical zeolites invoked more explicit attention to enhanced accessibility of zeolites. By realizing additional meso-/macroporosity with the intrinsic microporosity of zeolites, a hierarchical pore system arises which facilitates mass transport while maintaining the zeolite shape selectivity. A great number of synthesis strategies have been developed for tailoring the pore architecture of hierarchical zeolites. In this review, we give a general overview of different synthesis methods for introduction of additional porosity. Advantages and limitations of these different synthesis approaches are addressed. The assessment of pore structure is essential to build the link between the zeolite pore structure and its functionality. A variety of 2D and 3D microscopy techniques are crucial to visualize the hierarchical pore structure, providing unique and comprehensive information that, however, should be linked to the results of bulk characterization techniques as much as possible. The microscopy techniques are classified and discussed according to the different probes used, such as optical light, X-rays and electrons. Representative work is reviewed to elucidate the capability of each technique and their drawbacks. PMID- 26007223 TI - A comprehensive assay for nine major cytochrome P450 enzymes activities with 16 probe reactions on human liver microsomes by a single LC/MS/MS run to support reliable in vitro inhibitory drug-drug interaction evaluation. AB - 1. A comprehensive method for the simultaneous characterization of xenobiotic compound inhibition of nine major CYP enzymes in human liver microsomes was established by using 16 CYP-catalyzed reactions of 14 probe substrates with three cocktail incubation sets and a single LC/MS/MS analysis. 2. The three cocktail subgroups were developed to minimize the effects of organic solvents, polyunsaturated fatty acids and mutual substrate interactions: Group I was composed of tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), testosterone (CYP3A4), dextromethorphan (CYP2D6); Group II was composed of nifedipine (CYP3A4), midazolam (CYP3A4), coumarin (CYP2A6), bupropion (CYP2B6), diclofenac (CYP2C9); Group III was composed of phenacetin (CYP1A2), chlorzoxazone (CYP2E1), omeprazole (CYP2C19 and CYP3A4), paclitaxel (CYP2C8), (+)-bufuralol (CYP2D6). In the case of CYP2C9, CYP2C19, CYP2D6 and CYP3A4, multiple probe substrates were used due to the phenomenon of multiple substrate-binding pockets and substrate-dependent inhibition. All probe metabolites were simultaneously analyzed with a polarity switching mode in a single LC/MS/MS run. 3. This method was validated against the single probe substrate assay using 12 well-characterized CYP inhibitors and two new entities (GT0918, MDV3100). The IC50 values of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values reported in previous literatures. PMID- 26007225 TI - Quantitative transformation for implementation of adder circuits in physical systems. AB - Computing devices are composed of spatial arrangements of simple fundamental logic gates. These gates may be combined to form more complex adding circuits and, ultimately, complete computer systems. Implementing classical adding circuits using unconventional, or even living substrates such as slime mould Physarum polycephalum, is made difficult and often impractical by the challenges of branching fan-out of inputs and regions where circuit lines must cross without interference. In this report we explore whether it is possible to avoid spatial propagation, branching and crossing completely in the design of adding circuits. We analyse the input and output patterns of a single-bit full adder circuit. A simple quantitative transformation of the input patterns which considers the total number of bits in the input string allows us to map the respective input combinations to the correct outputs patterns of the full adder circuit, reducing the circuit combinations from a 2:1 mapping to a 1:1 mapping. The mapping of inputs to outputs also shows an incremental linear progression, suggesting its implementation in a range of physical systems. We demonstrate an example implementation, first in simulation, inspired by self-oscillatory dynamics of the acellular slime mould P. polycephalum. We then assess the potential implementation using plasmodium of slime mould itself. This simple transformation may enrich the potential for using unconventional computing substrates to implement digital circuits. PMID- 26007226 TI - IgSimulator: a versatile immunosequencing simulator. AB - MOTIVATION: The recent introduction of next-generation sequencing technologies to antibody studies have resulted in a growing number of immunoinformatics tools for antibody repertoire analysis. However, benchmarking these newly emerging tools remains problematic since the gold standard datasets that are needed to validate these tools are typically not available. RESULTS: Since simulating antibody repertoires is often the only feasible way to benchmark new immunoinformatics tools, we developed the IgSimulator tool that addresses various complications in generating realistic antibody repertoires. IgSimulator's code has modular structure and can be easily adapted to new requirements to simulation. AVAILABILITY AND IMPLEMENTATION: IgSimulator is open source and freely available as a C++ and Python program running on all Unix-compatible platforms. The source code is available from yana-safonova.github.io/ig_simulator. CONTACT: safonova.yana@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26007227 TI - Epigenomic k-mer dictionaries: shedding light on how sequence composition influences in vivo nucleosome positioning. AB - MOTIVATION: Information-theoretic and compositional analysis of biological sequences, in terms of k-mer dictionaries, has a well established role in genomic and proteomic studies. Much less so in epigenomics, although the role of k-mers in chromatin organization and nucleosome positioning is particularly relevant. Fundamental questions concerning the informational content and compositional structure of nucleosome favouring and disfavoring sequences with respect to their basic building blocks still remain open. RESULTS: We present the first analysis on the role of k-mers in the composition of nucleosome enriched and depleted genomic regions (NER and NDR for short) that is: (i) exhaustive and within the bounds dictated by the information-theoretic content of the sample sets we use and (ii) informative for comparative epigenomics. We analize four different organisms and we propose a paradigmatic formalization of k-mer dictionaries, providing two different and complementary views of the k-mers involved in NER and NDR. The first extends well known studies in this area, its comparative nature being its major merit. The second, very novel, brings to light the rich variety of k-mers involved in influencing nucleosome positioning, for which an initial classification in terms of clusters is also provided. Although such a classification offers many insights, the following deserves to be singled-out: short poly(dA:dT) tracts are reported in the literature as fundamental for nucleosome depletion, however a global quantitative look reveals that their role is much less prominent than one would expect based on previous studies. AVAILABILITY AND IMPLEMENTATION: Dictionaries, clusters and Supplementary Material are available online at http://math.unipa.it/rombo/epigenomics/. CONTACT: simona.rombo@unipa.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26007228 TI - Defining a safe player run-off zone around rugby union playing areas. AB - OBJECTIVES: To identify the circumstances in which international rugby players exit the playing area during match activities and to define a safe run-off distance around the playing area. METHOD: An observational study using video recordings of 102 matches associated with the Rugby World Cup (2011), Rugby Championship (2013, 2014) and Six Nations Championship (2013, 2014) were used to analyse every event in which one or more players exited the playing area during normal match activities. The circumstances in which a player exited the playing area were categorised using a range of parameters: playing position, location, out-of-play region, match activity, distance travelled over the touchline, contacts made with pitchside fixtures and fittings. RESULTS: Ninety-five per cent of player-excursions took place within 5.2 m of the touchline. Players exiting the playing area were nearly three times more likely to be a back than a forward (p<0.001) and the event was more likely to take place when a team was defending than attacking (p<0.001). Being forced out of play during a contact event (70%) was the major reason for players exiting the playing area. Most players (88%) exiting the playing area only made contact with the perimeter area surface; a small proportion of players contacted touchline flags (6.1%), advertising boards (2.3%) and TV cameras/equipment (1.0%). CONCLUSIONS: A minimum hazard-free distance of 5 m around a Rugby pitch is proposed based on the 95% percentile frequency distribution of player-excursion events into the areas contiguous with the playing area. PMID- 26007229 TI - Challenging conventional wisdom. PMID- 26007230 TI - Automated speed enforcement systems to reduce traffic-related injuries: closing the policy implementation gap. PMID- 26007232 TI - Prevalence of malnutrition among HIV-infected children in Central and West African HIV-care programmes supported by the Growing Up Programme in 2011: a cross-sectional study. AB - BACKGROUND: The burden of malnutrition among HIV-infected children is not well described in sub-Saharan Africa, even though it is an important problem to take into account to guarantee appropriate healthcare for these children. We assessed the prevalence of malnutrition and its associated factors among HIV-infected children in HIV care programmes in Central and West-Africa. METHODS: A cross sectional study was conducted from September to December 2011 among the active files of HIV-infected children aged 2-19 years old, enrolled in HIV-care programmes supported by the Sidaction Growing Up Programme in Benin, Burundi, Cameroon, Cote d'Ivoire, Mali, Chad and Togo. Socio-demographics characteristics, anthropometric, clinical data, and nutritional support were collected. Anthropometric indicators, expressed in Z-scores, were used to define malnutrition: Height-for-age (HAZ), Weight-for-Height (WHZ) for children < 5 years and BMI-for-age (BAZ) for children >=5 years. Three types of malnutrition were defined: acute malnutrition (WHZ/BAZ < -2 SD and HAZ >= -2 SD), chronic malnutrition (HAZ < -2 SD and WHZ/BAZ >= -2 SD) and mixed malnutrition (WHZ/BAZ < -2 SD and HAZ < -2 SD). A multinomial logistic regression model explored associated factors with each type of malnutrition. RESULTS: Overall, 1350 HIV infected children were included; their median age was 10 years (interquartile range [IQR]: 7-13 years), 49 % were girls. 80 % were on antiretroviral treatment (ART), for a median time of 36 months. The prevalence of malnutrition was 42 % (95 % confidence interval [95% CI]: 40-44 %) with acute, chronic and mixed malnutrition at 9 % (95% CI: 6-12 %), 26 % (95% CI: 23-28 %), and 7 % (95% CI: 5 10 %), respectively. Among those malnourished, more than half of children didn't receive any nutritional support at the time of the survey. Acute malnutrition was associated with male gender, severe immunodeficiency, and the absence of ART; chronic malnutrition with male gender and age (<5 years); and mixed malnutrition with male gender, age (<5 years), severe immunodeficiency and recent ART initiation (<6 months). Orphanhood and Cotrimoxazole prophylaxis were not associated with any type of malnutrition. CONCLUSIONS: The prevalence of malnutrition in HIV-infected children even on ART remains high in HIV care programmes. Anthropometric measurements and appropriate nutritional care of malnourished HIV-infected children remain insufficient and a priority to improve health care of HIV-infected children in Africa. PMID- 26007233 TI - Effect of Hematologic Parameters on Microvascular Reperfusion in Patients With ST Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention. AB - OBJECTIVES: Despite the significant role of certain hematologic parameters in reperfusion injury, their relationship with microvascular reperfusion remains not well understood. Therefore, our objective was to evaluate the relationship between hematologic parameters at admission and microvascular reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (primary PCI). METHODS: A total of 213patients (mean age: 57.5 +/- 11 years) with STEMI were included. Blood samples were obtained from all patients prior to primary PCI. Electrocardiographic recordings were made for the evaluation of ST-segment resolution (STR) before and after primary PCI. Angiographic assessment in the infarct-related artery was performed using the myocardial blush grade (MBG) and thrombolysis in myocardial infarction (TIMI) flow. Patients were categorized into 2 groups as those with impaired microvascular reperfusion (STR <70%, TIMI: 0-1, and MBG: 0-1) and those with normal microvascular reperfusion (STR >70%, TIMI: 2-3, and MBG: 2-3). RESULTS: Of the overall study group, 139, 105, and 69 patients had an STR of <70%, MBG of 0-1, and TIMI of 0-1, respectively. Demographic parameters in both groups are shown in the tables. Patients with impaired microvascular reperfusion were found to have higher white blood cell (WBC) count, neutrophil count, lymphocyte count, and mean platelet volume (MPV). Neutrophil-lymphocyte ratio and platelet count were similar between the 2 groups. Correlation analysis showed a negative correlation between lymphocyte count and STR (r: -.195, P: .004), lymphocyte count and TIMI flow(r: -.09, P: .14), and lymphocyte count and MBG (r: -.211, P: .002). CONCLUSION: Our results suggest that higher WBC count and MPV at admission are independent predictors of impaired microvascular perfusion in patients with STEMI. On the other hand, a negative correlation was found between lymphocyte count and impaired microvascular perfusion. Specifically, elevated lymphocyte count seemed to indicate the presence of impaired microvascular reperfusion in patients with STEMI. PMID- 26007235 TI - Galphas proteins activate p72(Syk) and p60-c-Src tyrosine kinases to mediate sickle red blood cell adhesion to endothelium via LW-alphavbeta3 and CD44-CD44 interactions. AB - G protein-coupled receptors (GPCRs) have been suggested as new drug targets to treat a variety of diseases. In sickle cell disease (SCD), the LW erythrocyte adhesion receptor can be activated by stimulation of beta2 adrenergic receptors (beta2ARs), to mediate sickle erythrocyte (SSRBC) adhesion to endothelium. However, the involvement of tyrosine protein kinases in beta2AR signaling to activate SSRBC adhesion to endothelium has not been thoroughly elucidated. Either direct activation with Cholera toxin of Galphas protein, which acts downstream of beta2ARs, or inhibition with Pertussis toxin of Galphai, mediating suppression of adenylyl cyclase, increased SSRBC adhesion to endothelium over baseline adhesion. This effect involved the non-receptor tyrosine kinases, p72(Syk) and p60-c-Src, which were more abundant in SSRBCs than in normal erythrocytes. In contrast, Pertussis toxin and Cholera toxin failed to increase adhesion of normal erythrocytes. SSRBC Galphai inhibition also increased phosphorylation of p72(Syk) and p60-c-Src. Further, we investigated the relevance of activation of p72(Syk) and p60-c-Src, and identified LW (ICAM-4, CD242) and CD44 as the erythroid adhesion molecules both physically interacting with activated p60-c-Src. As a result, SSRBC LW underwent increased tyrosine phosphorylation, leading to SSRBC LW and CD44 binding to endothelial alphavbeta3 integrin and CD44, respectively. These data provide in vitro mechanistic evidence that p60-c-Src, which could act downstream of Galphas/p72(Syk), associates with LW and CD44 on SSRBCs leading to their interactions with endothelial alphavbeta3 and CD44, respectively. Thus, increased activation of these signaling mechanisms in SSRBCs could initiate or exacerbate vascular occlusion, the hallmark of SCD. PMID- 26007234 TI - Apoptosis of cholangiocytes modulated by thioredoxin of carcinogenic liver fluke. AB - Chronic infection with the food-borne liver fluke, Opisthorchis viverrini, frequently induces cancer of the bile ducts, cholangiocarcinoma. Opisthorchiasis is endemic in Thailand, Lao PDR, Cambodia and Vietnam, where eating undercooked freshwater fish carrying the juvenile stage of this pathogen leads to human infection. Because inhibition of apoptosis facilitates carcinogenesis, this study investigated modulation by thioredoxin from O. viverrini of apoptosis of bile duct epithelial cells, cholangiocytes. Cells of a cholangiocyte line were incubated with the parasite enzyme after which they were exposed hydrogen peroxide. Oxidative stress-induced apoptosis was monitored using flow cytometry, growth in real time and imaging of living cells using laser confocal microscopy. Immunolocalization revealed liver fluke thioredoxin within cholangiocytes. Cells exposed to thioredoxin downregulated apoptotic genes in the mitogen activated protein kinases pathway and upregulated anti-apoptosis-related genes including apoptosis signaling kinase 1, caspase 9, caspase 8, caspase 3, survivin and others. Western blots of immunoprecipitates of cell lysates revealed binding of thioredoxin to apoptosis signaling kinase 1. Together the findings indicated that thioredoxin from O. viverrini inhibited oxidative stress-induced apoptosis of bile duct epithelial cells, which supports a role for this liver fluke oxidoreductase in opisthorchiasis-induced cholangiocarcinogenesis. PMID- 26007236 TI - Reductive carboxylation and 2-hydroxyglutarate formation by wild-type IDH2 in breast carcinoma cells. AB - Mitochondrial NADPH-dependent isocitrate dehydrogenase, IDH2, and cytosolic IDH1, catalyze reductive carboxylation of 2-oxoglutarate. Both idh2 and idh1 monoallelic mutations are harbored in grade 2/3 gliomas, secondary glioblastomas and acute myeloid leukemia. Mutant IDH1/IDH2 enzymes were reported to form an oncometabolite r-2-hydroxyglutarate (2HG), further strengthening malignancy. We quantified CO2-dependent reductive carboxylation glutaminolysis (RCG) and CO2 independent 2HG production in HTB-126 and MDA-MB-231 breast carcinoma cells by measuring (13)C incorporation from 1-(13)C-glutamine into citrate, malate, and 2HG. For HTB-126 cells, (13)C-citrate, (13)C-malate, and (13)C-2-hydroxyglutarate were enriched by 2-, 5-, and 15-fold at 5mM glucose (2-, 2.5-, and 13-fold at 25 mM glucose), respectively, after 6 h. Such enrichment decreased by 6% with IDH1 silencing, but by 30-50% upon IDH2 silencing while cell respiration and ATP levels rose up to 150%. Unlike 2HG production RCG declined at decreasing CO2. At hypoxia (5% O2), IDH2-related and unrelated (13)C-accumulation into citrate and malate increased 1.5-2.5-fold with unchanged IDH2 expression; whereas hypoxic 2HG formation did not. (13)C-2HG originated by ~50% from other than IDH2 or IDH1 reactions, substantiating remaining activity in IDH1&2-silenced cells. Relatively high basal (12)C-2HG levels existed (5-fold higher vs. non-tumor HTB-125 cells) and (13)C-2HG was formed despite the absence of any idh2 and idh1 mutations in HTB-126 cells. Since RCG is enhanced at hypoxia (frequent in solid tumors) and 2HG can be formed without idh1/2 mutations, we suggest 2HG as an analytic marker (in serum, urine, or biopsies) predicting malignancy of breast cancer in all patients. PMID- 26007237 TI - Comprehensive evaluation of electronic medical record system use and user satisfaction at five low-resource setting hospitals in ethiopia. AB - BACKGROUND: Electronic medical record (EMR) systems are increasingly being implemented in hospitals of developing countries to improve patient care and clinical service. However, only limited evaluation studies are available concerning the level of adoption and determinant factors of success in those settings. OBJECTIVE: The objective of this study was to assess the usage pattern, user satisfaction level, and determinants of health professional's satisfaction towards a comprehensive EMR system implemented in Ethiopia where parallel documentation using the EMR and the paper-based medical records is in practice. METHODS: A quantitative, cross-sectional study design was used to assess the usage pattern, user satisfaction level, and determinant factors of an EMR system implemented in Ethiopia based on the DeLone and McLean model of information system success. Descriptive statistical methods were applied to analyze the data and a binary logistic regression model was used to identify determinant factors. RESULTS: Health professionals (N=422) from five hospitals were approached and 406 responded to the survey (96.2% response rate). Out of the respondents, 76.1% (309/406) started to use the system immediately after implementation and user training, but only 31.7% (98/309) of the professionals reported using the EMR during the study (after 3 years of implementation). Of the 12 core EMR functions, 3 were never used by most respondents, and they were also unaware of 4 of the core EMR functions. It was found that 61.4% (190/309) of the health professionals reported over all dissatisfaction with the EMR (median=4, interquartile range (IQR)=1) on a 5-level Likert scale. Physicians were more dissatisfied (median=5, IQR=1) when compared to nurses (median=4, IQR=1) and the health management information system (HMIS) staff (median=2, IQR=1). Of all the participants, 64.4% (199/309) believed that the EMR had no positive impact on the quality of care. The participants indicated an agreement with the system and information quality (median=2, IQR=0.5) but strongly disagreed with the service quality (median=5, IQR=1). The logistic regression showed a strong correlation between system use and dissatisfaction (OR 7.99, 95% CI 5.62-9.10) and service quality and satisfaction (OR 8.23, 95% CI 3.23-17.01). CONCLUSIONS: Health professionals' use of the EMR is low and they are generally dissatisfied with the service of the implemented system. The results of this study show that this dissatisfaction is caused mainly and strongly by the poor service quality, the current practice of double documentation (EMR and paper-based), and partial departmental use of the system in the hospitals. Thus, future interventions to improve the current use or future deployment projects should focus on improving the service quality such as power infrastructure, user support, trainings, and more computers in the wards. After service quality improvement, other departments (especially inter-dependent departments) should be motivated and supported to use the EMR to avoid the dependency deadlock. PMID- 26007239 TI - Half-dosage and bolus injection photodynamic therapy for symptomatic circumscribed choroidal hemangioma: a case report. PMID- 26007238 TI - Genome-wide identification and characterization of cystatin family genes in rice (Oryza sativa L.). AB - KEY MESSEAGE: 11 Cystatin genes in rice were identified, and their expression patterns were comprehensively analyzed, which reveals multiple roles in both seed development and plant response to environmental variations. Cystatin is a group of small proteins and known to inhibit the activities of cysteine proteases in the papain C1A and legumain C13 peptidase families in plants. Cystatin family genes have only been well characterized recently in a few plant species such as Hordeum vulgare and Nicotiana tabacum, which show their critical roles in programmed cell death and responses to biotic stresses. Up to now, little is known about cystatin family genes and their roles in Oryza sativa, a model plant for cereal biology study. Here, we identified 11 cystatin genes in rice genome. Comprehensive expression profile analysis reveals that cystatin family genes in rice display diverse expression pattern. They are temporally regulated at different developmental stages during the process of seed production and germination. Our experiments also reveal that the majority of cystatin genes are responsive to plant hormones and different environmental cues including cold, drought and other abiotic stresses, while some others are very stable under different stresses, indicating their fundamental roles in normal plant development. In addition, their distribution in rice chromosomes and their evolutionary relation to the members of Cystatin family in A. thaliana and N. tabacum have also been analyzed. These works suggest multiple roles of cystatin family genes in both seed development and plant response to environmental variations. PMID- 26007240 TI - Investigation of anti-inflammatory and anti-proliferative activities promoted by photoactivated cationic porphyrin. AB - BACKGROUND: Photodynamic therapy (PDT) is a technique that uses light and a photosensitizer, converting local molecular oxygen into singlet oxygen, which eliminates a target unhealthy tissue. It has been increasingly used for the treatment of several diseases including skin disorders. Psoriasis is a chronic inflammatory skin disease expressing immune and hyperproliferative features. OBJECTIVE: This study aimed to evaluate the effect of the photosensitizer 5,10 diphenyl-15,20-di(N-methylpyridinium-4-yl)porphyrin (Di-cis-Py+) in in vivo models whereby some psoriasis-like parameters could be investigated. METHODS: The antiinflammation and antiproliferative activities of Di-cis-Py+ photoactivated was measured by myeloperoxidase (MPO) and N-acetyl-beta-d-glucosaminidase (NAG) enzyme activity assay, measurement of IL-6, IL-1beta and TNF-alpha levels, evaluation of proliferating cell nuclear antigen (PCNA) levels by immunohistochemistry and by Western blot. RESULTS: Treatment involving PDT and Di cis-Py+ resulted in reduction of edema, cellular infiltration, proinflammatory cytokines, as well as reduced hyperproliferation of the epidermis. All the evaluated parameters were promoted by topical application of phlogistic agents and are similar to that observed in lesions of psoriatic skin. CONCLUSION: The results shows the advantage of topical application, do not cause apparently photosensitivity and have effects comparable to dexamethasone, a first-line drug for the treatment of the disease. PMID- 26007241 TI - A real-time follow-up of photodynamic therapy during PET imaging. AB - PURPOSE: To monitor a real-time follow-up of tumor response to photodynamic therapy (PDT) by dynamic 2-deoxy-2-[(18)F]fluoro-d-glucose ((18)FDG) and positron emission tomography (PET) using two photosensitizing drugs in vivo, and to assess their mechanisms of action. METHODS: Two types of photosensitizers with different action mechanisms were used in rats implanted with two tumors: AlPcS4 mainly affecting the tumor vascular system, and ZnPcS2 largely inducing direct cell kill. Twenty-four hours after administration of either photosensitizer, one tumor served as control while the other was treated with red light during 30min within the 2h PET imaging by infusion of (18)FDG. The usual two-tissue compartment kinetic model was modified to take into account the perturbation of the treatment during imaging. RESULTS: The illumination of the tumors during PET imaging provoked a net decrease of (18)FDG uptake in tumors treated with AlPcS4 and a near total absence of (18)FDG uptake in tumors treated with ZnPcS2. After the end of illumination, the tumors regained (18)FDG uptake with a more pronounced uptake in the tumors treated with ZnPcS2. The rate constant values of the new (18)FDG kinetic model reflected the response of the tumors to the treatment in both photosensitizers. CONCLUSIONS: Dynamic PET imaging can be used to quantitatively assess in vivo and in real-time the response of tumors to treatments. It is demonstrated that the 30min of treatment was not sufficient to reduce the activity of the tumors. The technique could be extended to directly monitor the effects of drugs in vivo. PMID- 26007243 TI - Cryostructuring of polymer systems. Proteinaceous wide-pore cryogels generated by the action of denaturant/reductant mixtures on bovine serum albumin in moderately frozen aqueous media. AB - Freeze-thaw processing of bovine serum albumin (BSA) aqueous solutions, which contain also the additives of denaturants (urea in this case) and thiol-bearing reductants [cysteine (Cys) in this case] leads to the formation of wide-pore cryogels. The properties and porous morphology of these spongy gel matrices were demonstrated to depend on the initial concentration of all precursors and on the freezing/frozen storage temperature. The optimum conditions for preparing such BSA-based cryogels were found to be as follows: [BSA] = 3-5 g dL(-1), [urea] = 0.5-2.0 mol L(-1), [Cys] = 0.01 mol L(-1), and freezing temperatures in the range of -15 to -20 degrees C. The size of gross pores in thus prepared cryogels is ~50-150 MUm. The spatial network of BSA-cryogels was shown to be cross-linked chemically via interchain disulfide bridges. The significant role of hydrophobic interactions in the stabilization of 3D networks of these cryogels is inferred, as well as the supposition about the relay-race sequence mechanism of the intermolecular disulfide cross-link formation is made. PMID- 26007242 TI - The efficacy of photodynamic therapy and sodium hypochlorite in root canal disinfection by a single-file instrumentation technique. AB - AIM: The aim of this in vitro study was to evaluate the efficacy of photodynamic therapy (PDT) and sodium hypochlorite (NaOCl) in root canal disinfection by a single-file instrumentation technique. MATERIAL AND METHODS: Seventy human single rooted mandibular premolars were infected with Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, and divided into seven groups (n=10) according to the protocol of disinfection used. Group 1: 1% NaOCl; Group 2: 5.25% NaOCl; Group 3: saline+PDT; Group 4: 1% NaOCl+PDT; Group 5: 5.25% NaOCl+PDT; Group 6: positive control; Group 7: negative control. For PDT, methylene blue (15MUg/mL) remained in the root canal for 2min, followed by irradiation with diode laser. Samples were collected before and after instrumentation and plated in specific media cultures, to assess the presence or absence of microbial growth and determine the average reduction of viable microorganisms. RESULTS: 5.25% NaOCl+PDT resulted in the highest number of specimens with no microbial growth. Also, 1% NaOCl and 1% NaOCl+PDT exhibited similar antimicrobial effects. Saline+PDT was not able to eliminate all microorganisms. There was statistical significant differences between the groups and the microorganisms. CONCLUSION: The association of 5.25% NaOCl with PDT was the most effective treatment against microorganisms from endodontic infection in root canals instrumented by a single-file instrumentation technique. This result shows that PDT can be useful to improve the root canal disinfection. PMID- 26007244 TI - A Simple Metric for Determining Resolution in Optical, Ion, and Electron Microscope Images. AB - A resolution metric intended for resolution analysis of arbitrary spatially calibrated images is presented. By fitting a simple sigmoidal function to pixel intensities across slices of an image taken perpendicular to light-dark edges, the mean distance over which the light-dark transition occurs can be determined. A fixed multiple of this characteristic distance is then reported as the image resolution. The prefactor is determined by analysis of scanning transmission electron microscope high-angle annular dark field images of Si. This metric has been applied to optical, scanning electron microscope, and helium ion microscope images. This method provides quantitative feedback about image resolution, independent of the tool on which the data were collected. In addition, our analysis provides a nonarbitrary and self-consistent framework that any end user can utilize to evaluate the resolution of multiple microscopes from any vendor using the same metric. PMID- 26007245 TI - Increased Cell Proliferations and Neurogenesis in the Hippocampal Dentate Gyrus of Ahnak Deficient Mice. AB - Expression of the giant protein Ahnak has been reported in endothelial cells of the blood brain barrier and in non-neuronal cells including myelinating Schwann cells. However, the function of Ahnak in neurogenesis has not been determined. In the present study, we report for the first time the effects of Ahnak on adult hippocampal neurogenesis using Ahnak(-/-) mice. Proliferating cells were labeled with BrdU for a 30-day period before sacrifice. In Ahnak(-/-) mice, the incorporation of BrdU with NeuN (Neuronal Nuclei) increased significantly in both the subgranular zone and the granular cell layer of the dentate gyrus. In addition, Ahnak(-/-) mice displayed increased Doublecortin-immunoreactive neuroblasts compared with wild-type controls. Taken together, Ahnak deficiency plays a positive role for hippocampal neurogenesis in adult mice because proliferating cells were increased in Ahnak(-/-) mice and advanced to mature neurons. These findings suggest that Ahnak might be involved in modulating the differentiation of newly generated cells into neuronal or non-neuronal cells. PMID- 26007247 TI - Experience of Exchange Transfusion in a Newly Established SCANU at a Tertiary Care Hospital in Bangladesh. AB - Hyperbilirubinemia is common in neonates. The value of exchange transfusion (ET) is recognized. The procedure has some risks and complications. This descriptive observational cross sectional study was done in the Neonatology department during the period of January 2013 to December 2013. Total 62 patients were studied. ET was done in 47 patients. Among 47 patients, 29(61.7%) were male and 18(38.3%) were female. The most common cause of ET was Rh incompatibility (46.8%). In order of frequency, major findings were ABO incompatibility (25.5%), unidentified (14.9%), Sepsis (6.4%), minor blood group incompatibility (4.3%) and others (2.1%) respectively. Mean Serum bilirubin level was 22+/-5.1mg/dl. Most common complications following ET were anemia (12.7%), Sepsis (10.6%), and omphalitis (6.4%). The overall mortality observed was 6.4%. The majority of the adverse events associated with ET were treatable. PMID- 26007246 TI - In vitro assessment of antibacterial effect of garlic (allium sativum) extracts on pseudomonas aeruginosa. AB - The study was aimed to determine the antibacterial effect of crude and aqueous extract of garlic (Allium stivum) against standard strain of Pseudomonas aeruginosa ATCC 27853. An interventional study was conducted in Department of Pharmacology and Therapeutics in collaboration with Department of Microbiology, Mymensingh Medical College, Mymensingh. The minimum inhibitory concentration (MIC) of aqueous garlic extract (AGE) and antibiotic Imipenem were also determined with the help of broth dilution method. Inhibitory effect of crude garlic extract (CGE) was determined by inoculation of bacteria in CGE incorporated nutrient agar (NA) media and for AGE antibacterial effect was determined by disc diffusion method. All experiments except disc diffusion procedure were reconfirmed by subculture in pure NA media. In case of CGE the growth inhibition of test organism was observed in 30% CGE incorporated NA media. On the other hand sensitivity of AGE also determined in disc diffusion and the zone of inhibition (ZOI) was 7 mm, 12 mm and 20 mm at 25 MUg/10 MUl, 50 MUg/10 MUl and 100 MUg/10 MUl concentrations respectively. The MICs of AGE and Imipenem were 600 MUg/ml and 1MUg/ml. The MIC of imipenen was far less in comparison with the MIC of AGE. From the findings it is clearly determined that both the extracts have definite antibacterial effect upon Pseudomonas aeruginosa. Further studies are required to detect and isolate the active ingredients present in the Garlic extract responsible for antibacterial effect. Then their effects against the studied organism should be studied in vivo separately and its toxicity profile should also be taken into account. Only then the Garlic extracts fulfilled the criteria for its therapeutic use. Still then external application advised for burn and superficial skin infections and may be used in food poisoning, and respiratory tract infection along with conventional antibiotics which are used in those conditions. PMID- 26007248 TI - Correlation between Clinical Diagnosis and Colonoscopic Findings of Patients Presented with Lower Gastrointestinal Bleeding. AB - Lower gastrointestinal bleeding is a frequently encountered problem in general medical practice. This bleeding comes from a site distal to ligament of Treitz. But it may also come from upper gastrointestinal tract when it is massive and pass through the stool. This study was intended to explore the causes of lower gastrointestinal bleeding and correlating them with their colonoscopic findings. This study was cross-sectional prospective. Sample was taken purposively. Out of 200 patients which were selected for the study, 122(61%) were male and 78(39%) were female with a male to female ratio of 5:3. The ages of the patients were ranging from 5 to 80 years with the mean age of 41.9+/-15.0 years; maximum 38(19%) patients were in 51 to 60 years. All patients were presented with per rectal bleeding & underwent colonoscopy & maximum 57(28.5%) patients were diagnosed as hemorrhoids, followed by colorectal cancer in 55(27.5%) cases. In 10(5%) cases of haemorrhoids 2nd pathology was found associated with it. In 32(16%) cases colonoscopic findings were normal. It was concluded that the most common cause of lower gastrointestinal bleeding was hemorrhoids followed by colorectal cancer. But several cases of colon cancer were misdiagnosed clinically as colitis. So clinical diagnosis should be correlated & confirmed by colonoscopy and biopsy. PMID- 26007249 TI - Association of hypoglycemia, hypocalcemia and hypomagnesemia in neonates with perinatal asphyxia. AB - The clinical evidence of neurological menifestations associated with asphyxia is described as hypoxic ischaemic encephalopathy (HIE). A variety of metabolic problems are present in asphyxiated newborns including hypoglycemia, hypocalcemia, hypomagnesemia and others metabolic abnormalities. Some of these biochemical disturbances may trigger seizure or potentiate further brain damage. This cross sectional case-control study was done in Mymensingh Medical College Hospital, to identify the association of hypoglycemia, hypocalcemia, hypomagnesemia in neonates with perinatal asphyxia. Study period was six months. Sample size was 60. Among total sample 30 term asphyxiated newborns of <24 hours age were case and equal number term healthy newborns <24 hours age were control. The main clinical presentations were delayed cry after birth along with respiratory distress, convulsion and absence of cry in asphyxiated newborns. Major physical findings were cyanosis, convulsion and tachypnoea in asphyxiated group. The mean value of serum calcium level was significantly lower in asphyxiated newborns (7.37 +/- 0.10mg/dl) than control value (8.04+/-0.09mg/dl). Hypocalcemia was found among 23.33% babies in case group. On the contrary, hypocalcemia was found in single baby among control group. The mean value of serum magnesium was significantly lower in asphyxiated newborns (1.83 +/- 0.04mg/dl) than control value (1.96 +/- 0.05mg/dl). Hypomagnesemia was found among 3(10%) newborns but none was found among control group. Hypoglycemia was found in 7(23.33%) cases though the mean value of blood glucose was higher in case group (5.72 +/- 0.62mmol/l) than control group (4.87 +/- 0.15mmol/l) difference was not statistically significant. Combined hypoglycemia, hypocalcemia and hypomagnesemia were found in 1(3.33%) case; combined hypoglycemia and hypocalcemia were found in 2(6.67%) cases; and combined hypocalcemia and hypomagnesemia were found in 1(3.33%) case. During the study period, 3(10.0%) cases were expired but no death occurred among control group. This study shows isolated or combined hypoglycemia, hypocalcemia, hypomagnesemia are frequently found in newborns with perinatal asphyxia. So, it is necessary to monitor blood glucose, serum calcium and also serum magnesium among asphyxiated newborns for proper management. PMID- 26007250 TI - Epidemiological Aspect and common Bacterial and Fungal isolates from Suppurative Corneal Ulcer in Mymensingh Region. AB - This prospective study was done to find out the epidemiological factors of suppurative corneal ulcer and the common causative bacterial and fungal isolates from the, patients with suppurative corneal ulcer in secondary and tertiary level hospital at Mymensingh region. A total 100 samples of corneal scrapings were collected purposively from clinically diagnosed suppurative corneal ulcer patients from March 18, 2012 to March 17, 2013. Out of the total 100 samples, bacterial species were 29(29%) cases and the fungal spacies were 71(71%) identified by the culture in blood agar, chocolate agar and sabouraud's agar media and also by microscopic examination. The bacterial species were streptococcus pneumonae 12 cases (12%), Staphylococcus aureus 9 cases (9%), pseudomonas in 6 cases (6%), and Streptococcus pyoganes 2 cases (2%). Fungal species were aspergillus fumigatus 61 cases (61%), aspergillus niger 10 cases (10%). Out of the study populations, most of the populations were from the age group of 41 to 60 years (39 %), followed 21 to 40 years (34%) age group. Considering the sex, male were 67%, female were 33%. The majority of patients came from the rural area of Mymensingh region; occupationally they were farmers (44%). Ocular trauma due to agricultural materials was the most common associated factor (71%). The etiological and epidemiological pattern of suppurative corneal ulcer varies significantly with geographical region, patient population and health of the cornea. The present study was carried out to explore the epidemiological pattern, causative bacterial and fungal specie by laboratory procedure from corneal scraping and to invent a prospective guide line for the management of corneal ulcer in the community. PMID- 26007251 TI - Measurement of Apolipoprotein B May Predict Acute Coronary Syndrome in Hyper triglyceridemic Young Population. AB - The purpose of this study is to measure apolipoprotein B (ApoB) in hyper triglyceridemic (HTG) young people of Bangladesh for predicting risk of acute coronary syndrome. This case-control study was carried out in Department of Cardiology, of Mymensingh Medical College Hospital within the period from June 2009 to May 2010. A total 50 case of 18-45 years of age with first attack of acute coronary syndrome admitted in coronary care unit and 50 healthy controls of same age and sex distribution were studied. Twenty (40%) of the studied case and 21(42%) of controls had hyper hyper-triglyceridemia, of those 18(90%) of HTG cases and 12(57.1%) of HTG controls had hyper-ApoB condition. The present study shows significant association of apolipoprotein B as an independent determinant and estimation of ApoB may be an alternative tool for predicting risk of development of acute coronary syndrome in hyper-triglyceridemic young people. PMID- 26007252 TI - Smear Positive Tuberculosis amongst Suspects Reported to DOTS Corner of Mymensingh Medical College Hospital, Bangladesh. AB - Sputum microscopy still remains the primary tool for the laboratory diagnosis of tuberculosis. A retrospective study was conducted in the directly observed treatment, short-course (DOTS) corner of Mymensingh Medical College Hospital (MMCH), in Bangladesh from May 2013 to May 2014. The study was designed to evaluate the extent of smear positive microscopy including multi-drug resistance (MDR) amongst tuberculosis suspected cases. A total of 2,361 Pulmonary Tuberculosis (PTB) suspects were noticed to DOTS corner during this period, with the mean age of 43 years. The male female ratio was 2.02:1 and the smear positivity rate was about 10%. Study found majority of the suspects were in the economically productive year of life 20-70 years. Smear negative suspects were not re-evaluated further, though smear negativity does not rule out absence of tuberculosis. Extra pulmonary or non tuberculous mycobacteria were not evaluated in this study. Twenty two patients 0.9% of total 2361 were identified as MDR during the study period where 61 clinically highly suspected cases were sent for GeneXpert that seems to be much lesser than the national rate (3.6% in new cases and 19% in retreated cases). The smear positivity rate of all three (1st, 2nd and 3rd) smear was 94.5%, all the second smear was 100% positive and the third were 95.47% positive. It is evident from this study that two smear microscopy was found sufficiently reliable to diagnose TB. However, further in depth prospective study might be undertaken to ascertain the scenario of this chronic diseases. PMID- 26007253 TI - Knowledge and practices of mothers on childhood diarrhoea and its management attended at a tertiary hospital in bangladesh. AB - This descriptive cross sectional study was conducted in Pediatric out Patient Department (OPD) of Mymensingh Medical College Hospital (MMCH) from March 2014 to August 2014 to assess the knowledge and practices of the mothers in acute diarrhoeal diseases in children under-five years of age regarding use of oral rehydration solution (ORS), zinc, other drugs and feeding practices. Four hundred children under-five years of age having acute diarrhoea were included in the study by systematic random sampling. A structured, pretested, interviewer administered questionnaire was used to collect data from mothers of children having diarrhoeal diseases. ORS was offered by 360(90.00%) of the mothers. Out of which 279(77.50%) used it by their own knowledge. One hundred and ninety-one (53.06%) mothers prepared it correctly, while 169(46.94%) prepared it incorrectly. Of 169, 129(35.83%) mothers used less amount of water, while 40(11.11%) mothers used much amount of water to prepare ORS. Of 360 mothers, 89(24.72%) mixed part of the content of ORS sachet at a time. Of 360 mothers, only 55(15.28%) offered correct amount of ORS after each purging. Zinc was offered in 142(35.50%) children. Of 400, only 13(3.25%) mothers used recommended home-based fluid, while 70(17.50%) mothers offered increased amount of fluid to their child. Drugs other than zinc and ORS were used in 247(61.75%) children. Among drugs, other than zinc and ORS, antibiotics was used in 109(44.13%) cases, whereas antiprotozoal in 97(39.27%) cases. Amount of liquid given was more than usual in 70(17.50%) children, same as usual in 57(14.25%) children and less than usual in 273(68.25%) children. Amount of food given was same as usual in 59(14.75%) children, while less than usual in 341(85.25%) children. Control of diarrhoeal diseases programme is successful in introducing ORS at mass level. Great emphasis is needed to educate mothers about preparation and quantity of ORS to be given to children with diarrhoeal diseases. PMID- 26007254 TI - Rapid Immuno-Chromatographic Assay for the Detection of Antibodies to HIV Compare with Elisa among Voluntary and Replacement Blood Donor of Mymensingh Medical College Hospital. AB - Suitable algorithms based on a combination of two or more simple rapid HIV assays have been shown to have a diagnostic accuracy comparable to double enzyme-linked immunosorbent assay (ELISA) or double ELISA with Western Blot strategies. The aims of this study were to evaluate the performance of five simple rapid HIV assays using whole blood samples from voluntary and replacement blood donors & HIV-infected patients (positive samples from BSMMU, Dhaka). Five rapid HIV assays: DetermineTM HIV-1/2 (Inverness Medical), SD Bioline HIV 1/2 3.0 (Standard Diagnostics Inc.), First Response HIV Card 1-2.0 (PMC Medical India Pvt Ltd.), HIV1/2 Stat-Pak Dipstick (Chembio Diagnostic System, Inc) and Uni-GoldTM HIV-1/2 (Biotech) were evaluated between 1st February to 30th June, 2013 using 400 whole blood samples from voluntary and replacement blood donors. All samples that were reactive on all or any of the five rapid assays and 10% of non-reactive samples were tested on a confirmatory Inno-Lia HIV I/II immunoblot assay (Immunogenetics). Only 01 sample including ten positive samples from BSMMU were confirmed HIV-1 antibody positive, while 399 were HIV negative. The sensitivity at initial testing of Determine, SD Bioline and Uni-GoldTM was 100% (95% CI; 99.1 100) while First Response and Stat-Pak had sensitivity of 99.5% (95% CI; 98.2 99.9) and 97.7% (95% CI; 95.7-98.9) respectively, which increased to 100% (95% CI; 99.1-100) on repeat testing. The initial specificity of the Uni-GoldTM assay was 100% (95% CI; 99.6-100) while specificities were 99.6% (95% CI; 99-99.9), 99.4% (95% CI; 98.8-99.7), 99.6% (95% CI; 99-99.9) and 99.8% (95% CI; 99.3-99.9) for Determine, SD Bioline, First Response and Stat-Pak assays, respectively. There was no any sample which was concordantly false positive in Uni-GoldTM, Determine and SD Bioline assays. An alternative confirmatory HIV testing strategy based on initial testing on either SD Bioline or Determine assays followed by testing of reactive samples on the Determine or SD Bioline gave 100% sensitivity (95% CI; 99.1-100) and 100% specificity (95% CI; 96-99.1) with Uni-GoldTM as tiebreaker for discordant results. PMID- 26007255 TI - Otitis media with effusion in children admitted for adenoidectomy. AB - This cross-sectional prospective study was done in the Department of Otolaryngology Head & Neck Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka during the period of January 2008 to December 2009 with the aim to find out the frequency of otitis media with effusion in patients with enlarged adenoid admitted for Adenoidectomy, To see the frequency of otitis media with effusion in different age group, To find out the degree of hearing loss in enlarged Adenoid patients. A total number of 60 patients who were admitted for adenoidectomy with or without tonsillectomy were purposively collected. Male female ratio was 1.6:1. Majority of patients (61.67%) came from lower socioeconomic group. Amongst the patients with enlarged adenoids, OME was found in 32(53.33%) cases. Out of 25 grossly enlarged adenoid cases, OME was found in 19(76%) cases. In 35 cases of moderately enlarge adenoid, OME was found in 13(37.14%) cases. Out of 28 enlarged adenoid cases in age group 0-5 years, OME was present in 19(67.86%) cases and out of 32 enlarge adenoid cases in age group 6-15 years; OME was present in 13(40.62%) cases. Most of the patients presented with multiple clinical features, the commonest was mouth breathing (80%), other features were snoring (58.33%), nasal discharge (56.67%) and hearing impairment (53.33%). In tympanometry, flat curve without peak was found in 25 cases and negative middle ear pressure was seen in 7 cases. Regarding hearing status of patients, 25 cases had a mild to moderate degree of hearing loss and PTA was not done in 7 cases due to lower age group (below 4 years). PMID- 26007256 TI - Comparative study of early and conventional catheter removal following buccal mucosal graft urethroplasty. AB - The duration of catheterization period following urethroplasty is a great controversy. For buccal mucosal graft urethroplasty recommended catheterization period ranges from 2-4 weeks. In recent years, early catheter removal has been advocated for several reasons. Early catheter removal improves both patient comfort, mobility and reduces catheter related complications and shortens post operative hospital stay. This prospective observational study was done from January 2007 and December 2008, 50 patients underwent dorsal onlay buccal mucosal graft urethroplasty for stricture urethra. Among them 25 cases were selected for early catheter removal on 7th postoperative day and 25 cases for conventional catheter removal at 3 weeks. Three patients (12%) of early catheter removal group and 2 patients (8%) of conventional catheter removal group exhibited periurethral leakage. One patient (4%) and three patients (12%) developed wound infection in early and conventional catheter removal group respectively. No significant difference was observed in urinary flow (p=0.089). In these two groups the mean postoperative hospital stay was significant (p<0.001). Early catheter removal on 7th postoperative day is safe and has better impact on patient comfort with minimum catheter related complications and shortens hospital stay. PMID- 26007257 TI - Functional constipation - prevalence and life style factors in a district of bangladesh. AB - Constipation is a common problem throughout the world and is particularly prevalent in women, children and older adults producing considerable health care expenditure. Data on functional constipation is limited especially in Asian countries. This cross-sectional survey assessed prevalence and association of functional constipation or chronic constipation (FC) with a number of socio demographic and lifestyle factors. Data were collected from 3000 apparently healthy subjects by personal interview in a home setting with a questionnaire based on Rome III criteria for FC. Persons were selected by cluster sampling method from the population of Sylhet district. Among the 3000 subjects 148 subjects fulfilled the criteria for FC (Male=67, Female=81) giving a prevalence of 4.9%. Functional constipation was more prevalent in elderly (50-60 years, 10.1%, p=0.000), married persons (and widow/widowers, separated) (5.6-9.1%, p=0.000), city dwellers (6.2%), farmers (10.5%, p=0.000), house wives 6.1%, subjects taking vegetable (7.35%) and spices (6.0%) less frequently. The highest prevalent symptoms were feeling of incomplete evacuation (96.6%) and sensation of ano-rectal blockage (93.9%). No significant difference was found in the symptom pattern of FC among men and women. Older age (OR 2.755), female sex (OR 1.249), low intake of vegetable (OR 2.350) and spice (OR 2.050) appeared as important associated factor for FC. BMI and smoking had no significant association with FC. Functional constipation is a less prevalent disorder than IBS in our community. Female gender, old age and low intake of vegetable and spice were important associated factors for FC. PMID- 26007258 TI - Association of heart rate response with scan and left ventricular function on adenosine stress myocardial perfusion imaging. AB - To evaluate the association of heart rate (HR) response with abnormal scan and/or left ventricular (LV) function in patients undergoing adenosine myocardial perfusion imaging, we prospectively studied 164 consecutive patients who underwent a standard adenosine stress test (without exercise) and myocardial perfusion imaging (MPI) using technetium-99m sestamibi radioisotope. Change in HR was calculated by subtracting HR at rest from peak HR. The percentage change in HR was calculated. All patients underwent stress and resting single photon emission computed tomography (SPECT) imaging. Left ventricular ejection fraction (EF) was calculated using gated SPECT. Mean age was 54 +/- 11.7 years and 126 of the patients (72%) were men. We divided the patients into 2 groups: group 1(42 patients, 25%) had normal scans and group 2(122 patients, 74.3%) had abnormal scans; abnormal scans were defined as presence of either fixed defects, reversible defects, or both. Average HR increased by 35 beats/min in the normal scan group compared with 23 beats/min in the abnormal scan group (p=0.002). Sixty four (64) patients (39%) had reduced EF (<45%). This group had an average HR and percentage HR increase of 23 beats/min (27%) compared with an increase of 35 beats/min (38%) in patients with normal EF (p=0.002 and p=0.02, respectively). Thus, a diminished HR response had a significant association with both an abnormal scan and reduced EF on adenosine MPI. PMID- 26007259 TI - Clinical and Biochemical Characteristics of Polycystic Ovarian Syndrome among Women in Bangladesh. AB - Clinical and Biochemical characteristics age, central obesity, Glucose intolerance, lipid abnormality, thyroid function, prolactin level, clinical signs & symptoms and ultrasonographic ovarian feature of 70 women were studied and prevalence of hyper-prolactinemia, hypothyroidism and Metabolic syndrome were calculated in the Endocrine OPD of BIRDEM during November 2010 to May 2011.Age of the PCOS population was 23.02+/-7.04 year, central obesity in 81.4%, abnormal glucose tolerance in 47.1%, dyslipidemia in 45.7%, hypertension in 24.3%, hirsutism in 88.6%, acanthosis nigricans in 50%, polycystic ovaries by ultrasound (87%) cases. One third of the PCOS cases i.e.; 33% were without hyperprolactinemia or hypothyroidism or Metabolic Syndrome. And the rest 47 cases had one, two or all the 3 with them. The distribution was PCOS with hyperprolactinemia 18.6%, PCOS with hypothyroidism 11.4%, PCOS with Metabolic Syndrome 15.3%, PCOS with hyperprolactinemia with MS 8.6%, PCOS with hypothyrodism with MS 5.6%, PCOS with hypothyrodism with hyperprolactinemia 4.3% and rest 4.3% had all the 4 in combination. Blood glucose levels during OGTT and TSH levels of the group without Hypothyrid, hyperprolactinoma or Metabolic Syndrome were significantly lower (p<=0.008). Significant proportion of Bangladeshi women with PCOS has hypothyroidsm with or without high prolactin and also have higher incidence of metabolic syndrome. So, all PCOS patients should also be screened for hypothyroidsm and hyperprolactinemia. PMID- 26007260 TI - Pylorus Preserving Pancreaticoduodenectomy vs. Standard Whipple's Procedure in Case of Carcinoma head of the Pancreas and Periampullary Carcinoma. AB - Pancreatic carcinoma is a life threatening condition. Surgical resection is the only hope of cure. Advances in surgical technique have reduced the mortality rate. Nevertheless, operative complications related with morbidity still remains high. Two operation techniques in the treatment of periampullary and pancreatic head cancer: the Standard Whipple operation (SW) and Pylorus Preserving Pancreaticoduodenectomy (PPPD) are performed predominantly. This study was performed to compare the results of Pylorus Preserving Pancreaticoduodenectomy (PPPD) with that of the Standard Whipple's (SW) procedure. This prospective study was carried out in the Department of General Surgery, BSMMU in two years duration. All admitted patient's with periampullary carcinoma and carcinoma of the head of the pancreas were included and randomized for a SW or a PPPD resection. Data regarding patients demographics, preoperative assessment, intraoperative and postoperative findings were collected and analyzed. Less blood loss (2.67+/-0.65 units in Group I and 2.88+/-0.64 units in Group II), fewer need of blood transfusions and shorter hospital stay in the PPPD group were observed. Gastrointestinal leakage was similar in both groups of patients (1:1). One pancreatic fistula (8.3% in Group I) was observed in PPPD group and one intra abdominal abscess developed in Standard Whipple's procedure (00.0% in Group I and 12.5% in Group II). Bile leakage was higher in standard Whipple procedure (8.3% in Group I and 37.5% in Group II). Morbidity was more or less similar in both groups (58.0% in Group I and 50.0% in Group II) but one patient (12.5% in Group II) died in standard Whipple's resection. PPPD procedure is more effective treatment for periampullary carcinoma and cancer of the pancreatic head region than the standard Whipple's operation. PMID- 26007261 TI - A regulatory approach on serum bilirubin level in subjects with impaired glucose tolerance. AB - The present study was undertaken to find the role of dietary intervention and physical exercise on serum bilirubin level in IGT subjects. Thirty three newly detected otherwise healthy subjects with IGT, aged 35-63 years, were randomly selected to participate in a 12 weeks diet and exercise program. Nine participants were within 35-40 years while majority fifteen participants aged 41 50 years and rest six participants were above 50 (51-63) years. A male preponderance was observed among the study participants where 53.3% of the total participants were male (n=16) and 46.7% were female (n=14). Mean bilirubin (mg/dl) level was recorded 0.68 +/- 0.29 at base line and with follow-up, the value was 0.66 +/- 0.26 mg/dl. For men (n=16), serum bilirubin were 0.77 +/- 0.39 and 0.75 +/- 0.36 mg/dl at base line and follow-up while for women (n=14), the values were 0.67 +/- 0.33 and 0.59 +/- 0.28 mg respectively. The 35-40 years group (n=9) showed bilirubin from 0.66 +/- 0.23 at base line to 0.73 +/- 0.19 mg/dl at follow-up while 41-50 years group (n=15) had 0.70 +/- 0.34 and 0.58 +/- 0.26 mg/dl and for 51-63 years group (n=6), the values were 0.65 +/- 0.29 and 0.73 +/- 0.33 mg/dl respectively. Participants with BMI 20-25 had bilirubin 0.62 +/- 0.29 mg/dl at base line and 0.71 +/- 0.21 mg/dl at follow-up while with BMI >25 (n=20) had 0.71 +/- 0.30 and 0.63 +/- 0.2 8 mg/dl respectively. No significant changes in serum bilirubin were observed among the groups and therefore, the dietary intervention and physical exercise during the period did not have a significant role in this respect. PMID- 26007262 TI - Serum LDH and CA-125: Markers for Diagnosis of Ovarian Malignancy. AB - This prospective multi-centre study was carried out in the Department of obstetrics and gynaecology of Bangabandhu Sheikh Mujib Medical University, Dhaka Medical College Hospital and Bangladesh Medical College Hospital, Shaheed Suhrawardy Medical College Hospital, Dhaka, Bangladesh, during the period of January 2008 to December 2009, to establish the raised level of serum LDH and serum CA-125 in pre-operative discrimination of benign and malignant ovarian cancer to be used as a diagnostic marker and its validity by determining sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPP). A total number of 141 consecutive suspected subjects of ovarian tumour admitted in the above mentioned hospitals and enrolled for surgical management were included in this study. Serum LDH was done in all these subjects and they were followed up from the admission upto the postoperative tissue diagnosis of live tumor in respective pathology departments for histopathological correlation. The patients who were diagnosed as malignant placed in Group I and diagnosed benign ovarian tumor placed in Group II. Serous cystadenoma and mucinous cyst adenoma were more common in benign tumors, which were 38.9% and 20.4% respectively. However, more than a half (57.1%) had serous cyst adenocarcinoma in malignant tumors. In LDH for evaluation of malignancy, true positive 16 and false positive 18, false negative 12 and true negative 95 cases. LDH and serum CA-125 level (combined, i.e. both positive) for evaluation of malignancy, true positive 14 and false positive 0, false negative 14 and true negative 113 cases. LDH/serum CA-125 level (anyone positive) for evaluation of malignancy, true positive 25 and false positive 37, false negative 3 and true negative 76 cases. The validity of LDH were sensitivity 57.1%, specificity 84.1%, accuracy 78.7%, positive predictive values 47.1% and negative predictive values 88.8% for malignancy of ovarian tumour. The validity of CA-125 were sensitivity 78.6%, specificity 82.3%, accuracy 81.6%, positive predictive values 52.4% and negative predictive values 93.9% for malignancy of ovarian tumour. The validity of LDH and serum CA-125 level (combined, i.e. both positive) for malignant ovarian tumour it was found that sensitivity 50.0%, specificity 100.0%, accuracy 90.1%, positive predictive values 100.0% and negative predictive values 89.0%. PMID- 26007263 TI - Surgical Decompression of Resistant Cases of DeQuervain's Disease. AB - DeQuervain's disease of the first dorsal compartment of the wrist, is a common wrist pathology, pain results from resisted gliding of the abductor pollicis longus and the extensor pollicis brevis tendon in the fibroosseous canal. Management of resistant cases of DeQuervain's disease with failed conservative treatment treated by surgical decompression yield satisfactory outcomes. A large number of patients being dissatisfied with the medical treatment, still present with persistent pain and positive clinical finding. Surgical decompression is an effective method for the treatment of resistant cases of DeQuervain's disease. Outcome variables were measured by Scheller, Forget and Macey evaluation criteria. Most of our patients were female 28(93.3%), housewife 17(56.7%) with mean age of 41.57 years, ranging from 25-60 years. Right sided involvement was 20(66.7%) and Left sided involvement was 10(33.3%). Restricted movement of thumb in 30(100%) were the predominant symptoms. One (3.3%) patient develop chronic tenosynovitis, 1(3.3%) patient develop hypertrophic scar. There was no wound infection in the follow-up period of 3-18 months. Satisfactory results were found in 29(96.7%). PMID- 26007264 TI - Isosorbide Mononitrate versus Misoprostol for Cervical Ripening and Induction of Labour at Term. AB - To assess the efficacy and safety of isosorbide mononitrate (IMN) compared with misoprostol for cervical ripening and labour induction at term. In this comparative study two hundred term pregnant women with indication for induction of labour were randomly divided to receive either 40 mg IMN tablet vaginally (n=100) or 50 MUg misoprostol tablet vaginally (n=100) every 6 hours interval for a maximum of 4 doses. Progress & outcome of cervical ripening, labour induction and adverse effects were assessed. Change in cervical score was higher in misoprostol group than IMN group. Time from start of medication to vaginal delivery in IMN group was significantly longer, 28.66 +/- 5.283 hours, than in misoprostol group, 16.12 +/- 5.581 hours. Vaginal delivery occurred in 77% in IMN group and 69% in misoprostol group. There were no tachysystole or uterine hyper stimulation in the IMN group while in misoprostol group it was 17% and 11% respectively. Maternal satisfaction was higher in IMN group. Cervical ripening is satisfactory with IMN. Though misoprostol is singly more effective than IMN but IMN with oxytocin results in more vaginal delivery. Fetal and maternal side effects are less in IMN group. PMID- 26007265 TI - Urinary tract anomalies in patients with anorectal malformation. AB - Urinary tract anomalies are common associated anomalies in anorectal malformation (ARM) and major contributory factor for high morbidity and mortality in ARM. In this study, urinary tract anomalies were evaluated in 72 patients of ARM (43 high varieties & 29 low varieties) that were admitted in Dhaka Medical College & Hospital (DMCH) during the period of January 2007 to April 2008. In all cases, evaluation was done by ultrasonogram (USG) and voiding cysto-urethrography (VCUG). Intravenous urography (IVU) was done in selected cases. Urinary tract anomalies were found in 20(27.85%) cases of ARM patients. These anomalies were significantly higher 16(37.2%) in high variety of ARM than 4(13.8%) those with low variety of ARM. The pattern of urological anomalies were vesicoureteral reflux (VUR - 35%), hydronephrosis due to PUJ obstruction (25%), posterior urethral valve (PUV - 15%), renal agenesis (10%), duplex ureter (10%) and bladder diverticulum (5%). Before definite management of ARM urological evaluation is essential to prevent renal damage and to reduce the morbidity and mortality. PMID- 26007266 TI - Digital Subtraction Angiography is Superior to Magnetic Resonance Angiography in Diagnosis of Cerebral Arteriovenous Malformation. AB - This study was carried out to compare MRA and DSA in diagnosis of cerebral AVM. It was a retrospective observational study conducted in the Department of Neurology Dhaka Medical College Hospital (DMCH), Dhaka during the period of January 2010 to December 2010. Thirty patients with haemorrhagic stroke age ranging from 13 to 65 years were selected on the basis of inclusion and exclusion criteria as the study sample. MRA and DSA were done in all the selected patients. The mean age of the patients of haemorrhagic stroke was 30.3 +/- 14.3 years and male female ratio was 2.7:1. Regarding the venous drainage of AVM 13 and 12 were superficial and deep respectively, and evaluated 100% by MRA. In the diagnosis of cerebral AVM nidus size S1: <3 and S2: 3-6 cm sensitivity was 100% but accuracy was 100% and 73.3% respectively. DSA was 100% sensitive in the diagnosis of superficial and deep venous drainage AVM. Regarding the eloquence of brain area 15 had no eloquence by both MRA and DSA and identification of eloquence of brain area sensitivity was 73.3% and accuracy was 86.7%. The main feeding vessels was found (22, 73.3%) in both DSA and MRA findings. Distal vessels was seen (8, 26.7%) in DSA but not seen in MRA findings. Intranidal aneurysm and Angiopathic AVM were seen in 3(10.0%) and 4(13.3%) respectively in DSA. This study was carried out to diagnose the patients presented with cerebral AVM by MRA and DSA. MRA could not be evaluated flow status of AVM, distal feeding arteries, intranidal aneurysm and angiopathic AVM which could be detected by DSA. So, DSA is superior to MRA in diagnosis of cerebral AVM. PMID- 26007267 TI - Maternal and foetal outcome of 206 high risk pregnancy cases in border guard hospital, dhaka. AB - This observational study was carried out to identify the various types of high risk pregnancy and to determine the maternal and foetal outcome. The study was carried out on 206 pregnant high risk women in the Gynecology and Obstetrics department of Border Guard Hospital, Dhaka from January 2012 to December 2012. During mentioned period among 598 pregnant women 206 high risk pregnancy cases were randomly selected. Pregnant women (gestational age from 34 weeks upto 40 weeks) having medical condition and pregnancy related high risk factors were included and uncomplicated pregnancy, pregnancy before 37 weeks, post dated pregnancy were excluded from this study. Data was collected from semi structured history sheet and data analysis done by percentage. High risk pregnant women were grouped into three. Group A and Group B includes pregnant women having medical condition before and during pregnancy respectively. Group C consists of pregnant women had pregnancy related high risk issues. Among 206 high risk pregnancy cases majority 47.57% women had medical condition during pregnancy, 31.55% patient had medical condition before pregnancy. Among them majority 30.58% of the patient suffered from pregnancy induced hypertension, 15.04% patients suffered from gestational Diabetes Mellitus and premature rupture of membranes were 12.13%. In this study majority 43.68% of high risk pregnant patients were in age group of 30 35 years, 19.90% pregnant women were in age group of >35 years and 19.40% were in age group of upto 20 years. Among study groups maximum 65.04% of the patients were multiparous. Among 206 study population 60.19% high risk pregnant women were at term at the time of delivery and 39.8% women delivered their babies preterm. Caesarean section was done in 69.41% of high risk pregnant women. After delivery majority 77.66% women had no complication, only 10.19%, 8.25%, 2.91% and 0.97% high risk pregnant women suffered from fever, UTI, abdominal wound infection and post partum hemorrhage respectively. In this study, among 206 pregnancy cases 91.31% of the neonates had Apgar score >7 and 8.61% neonates had Apgar score <7%, 33.49% neonates had low birth weight and premature 39.80%. During the study period no maternal and neonatal death were observed. PMID- 26007268 TI - Is malnutrition a risk factor of stroke? AB - Obesity is an established risk factor of stroke. Malnutrition in post-stroke period is common and can influence outcome. But malnutrition, though predicted, has not yet been established as a risk factor of stroke. This descriptive study was carried out in the Department of Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka and Department of Neurology, Dhaka Medical College (DMC), from January 2009 to December 2010 to explore whether malnutrition is an independent risk factor of stroke. Nutritional status of 100 stroke patients and 100 healthy controls were assessed in this study. Anthropometric measurements including Body Mass Index (BMI), Triceps skin fold (TSF), Mid-arm circumference (MAC) and Arm-muscle circumference (AMC) were measured within 7 days of stroke. Haemoglobin and haematocrit percentage, serum iron and serum albumin were measured at the same time. No significant difference was observed regarding TSF thickness, MAC, AMC, mean Hb and mean albumin level between the stroke patients and the control group, although iron level was significantly lower in stroke group. Multiple logistic regressions analysis showed that increase in age, smoking and decreased serum iron level has a positive association with stroke. Malnutrition is, according to this study, not a significant risk factor of stroke and triceps skin fold (TSF) thickness, mid-arm circumference (MAC), arm-muscle circumference (AMC), hemoglobin and serum albumin are not appropriate predictor of stroke. PMID- 26007269 TI - Effect of Sub Clinical Hypothyroidism on C-reactive Protein and Ischemia Modified Albumin. AB - Thyroid disorders are associated with imbalance in redox status throughout the body along with a pro-inflammatory state. Aim of our present study was to evaluate any potential role of ischemia modified albumin (IMA) in both sub clinical and established hypothyroidism and to explore its potential relationship with the hsCRP. Serum TSH, fT4, IMA and hsCRP were measured in 30 cases and 40 age and sex matched controls by ELISA and standard photometric techniques. IMA value was compared between the sub clinical and clinical hypothyroid patients. Strength of association between the IMA and hsCRP was assessed also to analyze the prevalence of pro-inflammatory condition in hypothyroid patients. Serum values (mean +/- SD) of hsCRP (07.49 +/- 2.73), TSH (22.18 +/- 12.9) and IMA (128.31 +/- 16.96) were significantly higher in the case group. Bivariate correlation study indicated that TSH and fT4 showed direct and inverse relationship respectively with the hsCRP and IMA. IMA itself exhibited direct correlation with the pro-inflammatory marker hsCRP showing a positive correlation with IMA. Results of the general linear model analysis showed that only TSH had a significant positive predictive value on IMA while fT4 itself as a continuous covariate, or in the fraction of its normal or subnormal range, did not show any significant predictive value on IMA values. We suggest in conclusion that a pro inflammatory status and derangement of the redox balance towards an overall ischemic state start at an early stage of sub clinical hypothyroidism. Early detection of these parameters may help in provision of necessary preventive measures against complications of hypothyroidism. PMID- 26007270 TI - A matched case control study of risk indicators of breast cancer in assam, India. AB - Breast cancer is the leading cause of cancer death among women worldwide especially in a developing country like India. It also occupies the highest place with relative proportion 17.5% in the Hospital Based Cancer Registry in progress in the Dr. B. Borooah Cancer Research Institute. Dr. B. Borooah Cancer Research Institute is the Regional Cancer Care Center for entire North East region of India. With this background a matched case control study of 100 cases of breast cancer and 100 controls was carried out to investigate the role of different Socio economic, Female Reproductive and Life style related factors and to understand the etiology of breast cancer in Assam. Controls are matched to the cases by age at diagnosis (+/-5 years), family income and place of residence with matching ratio 1:1. Data were collected using questionnaire and then conditional logistic regression analysis is used to estimate the odd ratios for several factors. Study revealed that breast cancer occurrence has statistical association with the factors chewing habits (p=0.003), number of children (p=0.080), age at marriage (p=0.014), age at first child birth (p=0.007), age at menarche (p=0.010). PMID- 26007271 TI - Retrobulbar abscess in a child. AB - A 14 months old male child was admitted into Mymensingh Medical College Hospital (MMCH), Bangladesh, with fever, watering, swelling, redness of right eye and running nose. On initial examination, patient was febrile, toxic, right-sided severe proptosis, restricted ocular movement, conjunctival chemosis and exposure keratitis of right eye. A sluggish pupillary light reaction was present in the right eye. Visual acuity was not recordable. CT scan of Brain and Orbit revealed, retrobulbar abscess of right orbit. The left eye was normal. The abscess was drained through a wide bore needle. The extraocular motility improved and pupil became brisk with a reduction in the temperature and toxic signs within 48 hours following surgery. Proptosis at the time of discharge from the hospital was absent in the right eye with no other complication. Post operative 8 months follow up period was excellent. PMID- 26007272 TI - Primary extramedullary esophageal plasmacytoma - a case report. AB - Extramedullary plasmacytomas are very uncommon tumors, may occur commonly in the upper respiratory passages. These are rarely seen in the middle and lower gastrointestinal system and exceptional to originate in the esophagus. We present a novel case of a 65-year old man who presented with dysphagia and weight loss. After taking detailed clinical history and physical examination endoscopy was performed that showed an ulcero-proliferative lesion involving the lower third of esophagus. Histopathological examination revealed sheets of malignant plasma cells, some with prominent nucleoli. Immuno-histochemistry could not be done due to unavailability. A bone marrow biopsy was performed which was negative for involvement. This is a rare case of esophageal plasmacytoma diagnosed on endoscopy in a patient presenting with dysphagia. PMID- 26007273 TI - Orthodontic management of a young girl with class I malocclusion and severe crowding: a case report. AB - We describe the treatment of a young girl age, 16 years, with Class I malocclusion. Both upper and lower anterior segment of jaws were crowded with buccally placed canines. Treatment consisted mainly of premolars extractions, canine retraction, labeling and alignment with Edgewise fixed appliances by multiloop technique. The patient did not show good cooperation, hence treatment time was prolonged. However the treatment resulted in Class I molar occlusion with proper alignment of both upper and lower anterior segment, an ideal overjet, overbite and incisor angulation. PMID- 26007275 TI - Treatment of a recurrent parotid fistula and sialocele by controlled internal fistula: a case report. AB - A 17 years old male patient presented with continuous flow of clear watery discharge from his right cheek for 14 years following trauma. He had previous history of two surgical interventions but result was not satisfactory. The diagnosis was parotid fistula & sialocele based on clinical examination & investigation. To repair this fistula we entered the sialocele cavity where saliva was accumulated between the superficial fascia & parotid fascia, then one end of feeding tube (5Fr) was placed at the bottom of the cavity and another end was fixed intra-orally to create a controlled fistula. After four weeks the feeding tube removed and a channel was made through which the salivary flow comes out, up to one year follow up resulting a satisfactory outcome. PMID- 26007274 TI - A 42-year-old man with huge abdominal mass. AB - Patients presenting with abdominal lump is a common clinical finding in our medical practice. Most of the cases can be diagnosed without much difficulty. But sometimes it can be difficult to diagnose the cause of the lump. Here we are presenting a 42-year-old man who visited his physician in Bangabandhu Sheikh Mujib Medical University with huge abdominal lump. Initially it was diagnosed as hepatocellular carcinoma (HCC). Later it turned out to be case of adrenocortical carcinoma (ACC). Problems related to diagnosis and management is also discussed. PMID- 26007276 TI - Gitelman's Syndrome Presenting with Hypocalcaemia - A Case Report. AB - Gitelman's syndrome is an autosomal recessive renal tubular disorder characterized by severe hypomagnesaemia, hypokalaemia, metabolic alkalosis and hypocalcaemia. It is caused by defective NaCl transport in the Distal Convoluted Tubule and presents in adolescence or adulthood, with a distinctly more benign course than Bartter's Syndrome. The dominant clinical features are muscle weakness, fatigue, carpopedal spasm, cramps and tetany. We report the case of a 26 year old male who presented with flaccid quadriparesis and carpopedal spasms, hypokalaemia, hypomagnesaemia, hypocalcaemia and severe urinary magnesium wasting. He was treated with potassium and magnesium supplementation and regained full function of all limbs. PMID- 26007277 TI - A male person of 55 years with hypothyroidism, ascites and heart failure. AB - Primary hypothyroidism is a common clinical condition but ascites caused by hypothyroidism is rare. Concurrent exudative ascites with heart failure even rarer. So its diagnosis is often delayed and patients frequently receive unnecessary procedures such as liver biopsies and exploratory laparotomies. We report a male person of 55 years with hypothyroidism with ascites and heart failure who responded well with thyroid hormone replacement therapy with complete resolution of ascites. Analyses of ascites from patients in this condition usually shows exudative ascites with high protein (>2.5gm/dl) and SAAG <1.1gm/dl. High index of suspicion is required to reach at such diagnosis. Though it is a rare but prognosis is excellent with replacement therapy. PMID- 26007278 TI - A case of acute intermittent porphyria. AB - Acute intermittent porphyria (AIP) is a rare autosomal dominant hereditary metabolic disorder having protean manifestations. The clinical presentations of abdominal pain, peripheral neuropathy and changes in mental status are the classic triad of an acute attack. A 15-year old girl was admitted in the medicine department of Sylhet MAG Osmani Medical College with the complaints of recurrent abdominal pain, convulsions and weakness of lower limbs. She presented with a combination of medical and neuropsychiatric symptoms suggestive of a case of AIP. The clinical presentation and the presence of porphyrins in urine confirmed the diagnosis of AIP. AIP can be life-threatening, so an accurate diagnosis and proper management are highly important. PMID- 26007279 TI - Atypical post operative discharging sinus - a case report. AB - Surgical site infections (SSIs) are the second most common health care associated infection reported to the National Health Safety Network of the centre of disease control and prevention. SSIs by Mycobacterium tuberculosis are uncommon and diagnosis can be missed. Our patient had primary tuberculosis at surgical site without any evidence of tuberculosis at initial investigation. She presented with repeated discharging sinus at the wound of elective lower uterine caesarean section (LUCS). The case was diagnosed by histo-pathological evidence of chronic granulomatous lesion suggestive of tuberculosis from the excised tissue from wound and detection of acid fast bacilli (AFB) from swab by Ziehl Neelsen staining. After proper diagnosis the patient was treated with anti-tubercular drugs regiment for six months as per schedule of national guidelines for management of tuberculosis of Bangladesh Government. Then the patient was cured from unusual long sufferings. PMID- 26007280 TI - Recent Trends in the Presentation of Neuroanatomy in Contemporary Neuroanatomy Books as Revealed in Their 'Preface's: A Review. AB - Many changes have been made in the field of Neuroanatomy teaching and assessment. One important way to know the changes in other country is by analyzing the Neuroanatomy text books and we can compare their reflections in our curriculum by analyzing the assessment system. To analyze the 'Preface's of contemporary Neuroanatomy text books, qualitatively, for noting the approaches taken and means applied in dealing with Neuroanatomy in the text books. This review was done in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from July 2008 and June 2009. The 'Preface's of ten contemporary text books dealing with Neuroanatomy, published since 1993, was analyzed. Among them, the two that are most commonly recommended to the medical postgraduates in Bangladesh were selected for analyzing their presentation of text and illustrations. The 'Preface's of ten books were analyzed qualitatively to identify the information and explanations provided and comments made by their author(s)/editor(s) on the approaches taken and the means applied in the books in selecting and presenting topics, text and illustrations. The observations were organized into specific 'theme's. Twelve 'theme's were identified from the analyses of the 'Preface's of ten contemporary Neuroanatomy text books. These include special emphasis in the books on incorporation of new information, on practical application of Neuroanatomical facts. Addition and improvement regarding illustrations are also highlighted. By incorporating the findings of the present study with the present day ideas and trends in Neuroanatomy in the developed world as evident from the available literature, suggestions could be formulated on improving the methods of teaching and assessment of Neuroanatomy in Bangladesh. PMID- 26007281 TI - Resistant hypertension - an update. AB - Patients with hypertension are increasing in Bangladesh. Among these patients a growing number of patients are having resistant hypertension faced by both primary care physicians and specialists. There is no data regarding prevalence of resistant hypertension in Bangladesh, but clinical trials abroad suggests that it is not rare, involving perhaps 20% to 30% of study participants. Cardiovascular risk is undoubtedly increased in such patients and the condition is often complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multi drug regimens. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; presence of multiple disease processes and their associated medical therapies, which confound interpretation of study results. Therefore we should concentrate on expanding our knowledge of the causes of resistant hypertension which will allow for more effective prevention and/or treatment which is essential to improve long-term clinical management of this condition. PMID- 26007283 TI - Recent advancement in discovery and development of natural product combretastatin inspired anticancer agents. AB - The natural stilbenoids combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent antitubulin agents demonstrating antimitotic activity as well as tumor vascular disruption property. Due to structural simplicity and potent cytotoxicity of CA4 and CA1, they are considered as promising leads for the development of potent anticancer agents. In fact, scientific fraternity is motivated to synthesize several derivatives of CA4 and CA1 as novel therapeutic agents. In the literature, several studies have been carried out to evaluate the medicinal chemistry, pharmacology and structure-activity relationships (SAR) of a variety of modified combretastatin derivatives. The present report aimed at comprehensively revising the recent advancements (2006-2014) in the medicinal chemistry and SAR of diversified combretastatin analogues. The published data concerning new combretastatin A-4 analogues as antimitotic anticancer agents are presented and SAR is reviewed and discussed. PMID- 26007282 TI - An incompressible state of a photo-excited electron gas. AB - Two-dimensional electrons in a magnetic field can form new states of matter characterized by topological properties and strong electronic correlations as displayed in the integer and fractional quantum Hall states. In these states, the electron liquid displays several spectacular characteristics, which manifest themselves in transport experiments with the quantization of the Hall resistance and a vanishing longitudinal conductivity or in thermodynamic equilibrium when the electron fluid becomes incompressible. Several experiments have reported that dissipationless transport can be achieved even at weak, non-quantizing magnetic fields when the electrons absorb photons at specific energies related to their cyclotron frequency. Here we perform compressibility measurements on electrons on liquid helium demonstrating the formation of an incompressible electronic state under these resonant excitation conditions. This new state provides a striking example of irradiation-induced self-organization in a quantum system. PMID- 26007284 TI - Work-related musculoskeletal disorders among physical therapists: an online survey. AB - PURPOSE: To evaluate the rates and characteristics of musculoskeletal disorders (MSDs) in physical therapists (PTs) according to their specialty and setting. METHOD: Participants completed an online questionnaire including 15 demographic questions, 7 work-related and 8 injury-related questions for 9 different body parts. RESULTS: Complete responses were obtained from 121 PTs; 96% reported MSD symptoms during the previous 12 months, 64% affecting at least 3 body parts. The body parts with the highest prevalence of symptoms were the low back (66%) and the neck (61%). For PTs specialized in acute care, geriatrics and pediatrics, the body part most commonly affected was the low back, while for PTs specialized in orthopedics and neurology, the body part most commonly affected was the neck. Regarding work settings, the low back was the most commonly affected for PTs working in skilled nursing facilities, outpatient clinics and hospitals, and the neck in PTs working in academic and home health settings. CONCLUSIONS: MSDs are common among PTs; the body parts most often affected were the low back and neck. The prevalence and body parts affected varied by practice setting and specialty area. The findings can help informing the design of evidence-based rehabilitation, prevention, training and educational programs. IMPLICATIONS FOR REHABILITATION: Rehabilitation of injured physical therapists needs to address the symptoms of the multiple body parts that are usually affected (e.g. back, wrists and hands). Rehabilitation of injured physical therapists needs to take into consideration their job demands, practice setting and specialty area. The findings can inform the design of rehabilitation, prevention, training and educational programs for physical therapists. PMID- 26007285 TI - Influence of Cladophora-Quagga Mussel Assemblages on Nearshore Methylmercury Production in Lake Michigan. AB - Recent spread of invasive mussels in Lake Michigan has altered primary productivity in the nearshore zone, resulting in proliferation of filamentous benthic green algae (Cladophora glomerata). In areas of dense Cladophora and quagga mussel (Dreissena bugensis) assemblages, as well as in regions where sloughed Cladophora accumulates, methylmercury (MeHg) production is enhanced. A shoreline transect from a river mouth through waters overlying Cladophora/quagga rich zones showed that aqueous MeHg concentrations increased, despite river dilution. Cladophora, as primary producers, ranged from 0.6 to 7.5 ng g(-1) MeHg [4-47% of total mercury (Hg) as MeHg], and were higher than MeHg concentrations in offshore-collected seston. Concentrations of MeHg in decaying Cladophora accumulated onshore ranged from 2.6 to 18.0 ng g(-1) MeHg (18-41% as MeHg) and from 0.1 to 3.0 ng g(-1) MeHg (2-21% as MeHg) in deposits of recently sloughed and accumulated Cladophora in a nearshore topographical depression. Relative to offshore open waters, interstitial waters within decaying Cladophora from onshore and nearshore deposits were elevated in MeHg concentration, 1000- and 10-fold, respectively. Percent Hg as MeHg was also elevated (65-75% and 9-19%, respectively for onshore interstitial water and nearshore interstitial water, compared to 0.2-3.3% as MeHg for open water). Quagga mussels collected within growing Cladophora beds in the nearshore zone were significantly higher in MeHg than offshore counterparts. Our combined results suggest that recent changes in nearshore primary production contributes to MeHg production and bioaccumulation in Lake Michigan. PMID- 26007286 TI - Activation of hepatic CREBH and Insig signaling in the anti-hypertriglyceridemic mechanism of R-alpha-lipoic acid. AB - The activation of sterol regulatory element binding proteins (SREBPs) is regulated by insulin-induced genes 1 and 2 (Insig-1 and Insig-2) and SCAP. We previously reported that feeding R-alpha-lipoic acid (LA) to Zucker diabetic fatty (ZDF) rats improves severe hypertriglyceridemia. In this study, we investigated the role of cyclic AMP-responsive element binding protein H (CREBH) in the lipid-lowering mechanism of LA and its involvement in the SREBP-1c and Insig pathway. Incubation of McA cells with LA (0.2 mM) or glucose (6 mM) stimulated activation of CREBH. LA treatment further induced mRNA expression of Insig-1 and Insig-2a, but not Insig-2b, in glucose-treated cells. In vivo, feeding LA to obesity-induced hyperlipidemic ZDF rats activated hepatic CREBH and stimulated transcription and translation of Insig-1 and Insig-2a. Activation of CREBH and Insigs induced by LA suppressed processing of SREBP-1c precursor into nuclear SREBP-1c, which subsequently inhibited expression of genes involved in fatty acid synthesis, including FASN, ACC and SCD-1, and reduced triglyceride (TG) contents in both glucose-treated cells and ZDF rat livers. Additionally, LA treatment also decreased abundances of very low density lipoprotein (VLDL) associated apolipoproteins, apoB100 and apoE, in glucose-treated cells and livers of ZDF rats, leading to decreased secretion of VLDL and improvement of hypertriglyceridemia. This study unveils a novel molecular mechanism whereby LA lowers TG via activation of hepatic CREBH and increased expression of Insig-1 and Insig-2a to inhibit de novo lipogenesis and VLDL secretion. These findings provide novel insight into the therapeutic potential of LA as an anti hypertriglyceridemia dietary molecule. PMID- 26007287 TI - DHA at nutritional doses restores insulin sensitivity in skeletal muscle by preventing lipotoxicity and inflammation. AB - Skeletal muscle plays a major role in the control of whole body glucose disposal in response to insulin stimulus. Excessive supply of fatty acids to this tissue triggers cellular and molecular disturbances leading to lipotoxicity, inflammation, mitochondrial dysfunctions, impaired insulin response and decreased glucose uptake. This study was conducted to analyze the preventive effect of docosahexaenoic acid (DHA), a long-chain polyunsaturated n-3 fatty acid, against insulin resistance, lipotoxicity and inflammation in skeletal muscle at doses compatible with nutritional supplementation. DHA (30 MUM) prevented insulin resistance in C2C12 myotubes exposed to palmitate (500 MUM) by decreasing protein kinase C (PKC)-theta activation and restoring cellular acylcarnitine profile, insulin-dependent AKT phosphorylation and glucose uptake. Furthermore, DHA protected C2C12 myotubes from palmitate- or lipopolysaccharide-induced increase in Ptgs2, interleukin 6 and tumor necrosis factor-alpha mRNA level, probably through the inhibition of p38 MAP kinase and c-Jun amino-terminal kinase. In LDLR -/- mice fed a high-cholesterol-high-sucrose diet, supplementation with DHA reaching up to 2% of daily energy intake enhanced the insulin-dependent AKT phosphorylation and reduced the PKC-theta activation in skeletal muscle. Therefore, DHA used at physiological doses participates in the regulation of muscle lipid and glucose metabolisms by preventing lipotoxicity and inflammation. PMID- 26007288 TI - Grape seed procyanidins administered at physiological doses to rats during pregnancy and lactation promote lipid oxidation and up-regulate AMPK in the muscle of male offspring in adulthood. AB - The aim of the present study was to test whether the administration of a grape seed procyanidin extract (GSPE) during pregnancy and lactation, at doses extrapolated to human consumption, programs male offspring toward improved metabolism in adulthood. For this purpose, female rats were fed a normal-fat diet (NFD) and treated with either GSPE (25 mg kg(-1) of body weight/day) or vehicle during gestation and lactation. The metabolic programming effects of GSPE were evaluated in the male offspring fed NFD from 30 to 170 days of life. No changes were observed in body weight, adiposity, circulating lipid profile and insulin sensitivity between the offspring of dams treated with GSPE (STD-GSPE group) and their counterparts (STD-veh). However, the STD-GSPE offspring had lower circulating levels of C-reactive protein and lower respiratory quotient values, shifting whole-body energy catabolism from carbohydrate to fat oxidation. Furthermore, the STD-GSPE animals also exhibited increased levels of total and phosphorylated AMP-activated protein kinase (AMPK) and an over-expression of the mRNA levels of key genes related to fatty acid uptake (Fatp1 and CD36) and beta oxidation (pparalpha and had) in skeletal muscle. Our results indicate that GSPE programs healthy male offspring towards a better circulating inflammatory profile and greater lipid utilisation in adulthood. The metabolic programming effects of GSPE that are related to the enhancement of fatty acid oxidation in skeletal muscle seem to be mediated, at least in part, by AMPK. These findings could be of relevance in the prevention of pathologies associated to lifestyle and aging, such as obesity and insulin resistance. PMID- 26007289 TI - The Latin American School of Human and Medical Genetics: promoting education and collaboration in genetics and ethics applied to health sciences across the continent. AB - The Latin American Network of Human Genetics (RELAGH) created the Latin American School of Human and Medical Genetics (ELAG) to prepare young researchers and professionals of Latin America to deal with the growing challenge of the genomic medicine. ELAG promotes an annually course since 2005, which received 838 students from 17 Latin American countries over these 10 years. ELAG plays an important role to provide education in genetics applied to health sciences to fellows who live in countries with a less favorable economic situation. Influenced, among others, by the humanitarian perspective of Jose Maria Cantu, one of its founders, ELAG has always favored the discussion of ethical and social issues related to genetics in Latin America. Few initiatives in Latin America lasted 10 consecutive years. One of the factors responsible for the ELAG's success has been its group of faculty members, who contribute to a friendly environment prone to facilitating the exchange of their own experiences with young researchers. PMID- 26007290 TI - Relationship between surface concentration of L-leucine and bulk powder properties in spray dried formulations. AB - The amino acid L-leucine has been demonstrated to act as a lubricant and improve the dispersibility of otherwise cohesive fine particles. It was hypothesized that optimum surface L-leucine concentration is necessary to achieve optimal surface and bulk powder properties. Polyvinylpyrrolidone was spray dried with different concentration of L-leucine and the change in surface composition of the formulations was determined using X-ray photoelectron spectroscopy (XPS) and time of flight-secondary ion mass spectrometry (ToF-SIMS). The formulations were also subjected to powder X-ray diffraction analysis in order to understand the relationship between surface concentration and solid-state properties of L leucine. In addition, the morphology, surface energy and bulk cohesion of spray dried formulations were also assessed to understand the relation between surface L-leucine concentration and surface and bulk properties. The surface concentration of L-leucine increased with higher feed concentrations and plateaued at about 10% L-leucine. Higher surface L-leucine concentration also resulted in the formation of larger L-leucine crystals and not much change in crystal size was noted above 10% L-leucine. A change in surface morphology of particles from spherical to increasingly corrugated was also observed with increasing surface l-leucine concentration. Specific collapsed/folded over particles were only seen in formulations with 10% or higher l-leucine feed concentration suggesting a change in particle surface formation process. In addition, bulk cohesion also reduced and approached a minimum with 10% L-leucine concentration. Thus, the surface concentration of L-leucine governs particle formation and optimum surface L-leucine concentration results in optimum surface and bulk powder properties. PMID- 26007291 TI - Hormonal contraceptives and HIV: hazards of pronouncing "negative" studies with low power. PMID- 26007292 TI - Effect of an atraumatic vulsellum versus a single-tooth tenaculum on pain perception during intrauterine device insertion: a randomized controlled trial. AB - INTRODUCTION: Intrauterine devices (IUDs) are used by only 5.6% of contraceptive users in the United States. One barrier to IUD uptake is fear of pain during insertion, particularly among nulliparous women. Many interventions to reduce pain during IUD insertion have proven unsuccessful. Comparisons of different tenaculae have not been previously reported. METHODS: This was a single-blinded, randomized control trial of 80 women randomized to the use of a vulsellum or a single-tooth tenaculum during IUD insertion. The primary outcome was reported pain on a 100-mm visual analog scale at the time of vulsellum placement. Secondary outcomes included pain at other intervals during IUD insertion and bleeding from the tenaculum site. Pain scores were analyzed with a Mann-Whitney test because they were not normally distributed. RESULTS: Pain scores at the time of single-tooth tenaculum (33.3 mm) and vulsellum (35.0 mm) placement were the same in both groups (p=0.58). It took longer to control bleeding in the single tooth tenaculum versus the vulsellum group (1.1 vs. 0.4 min, p=0.001), although there was no statistically significant difference in the number of maneuvers required to control bleeding at the tenaculum site between the two groups. Preprocedure anxiety appeared to correlate with more pain during IUD insertion. CONCLUSION: This is the first randomized trial comparing tenaculae. There was no difference in reported pain, but the vulsellum may be associated with less bleeding than a single-tooth tenaculum. Women with higher preprocedure anxiety may experience more pain during IUD insertion. Future research could investigate an anxiolytic's effect on pain during IUD insertion. PMID- 26007294 TI - Influence of tidal volume on ventilation inhomogeneity assessed by electrical impedance tomography during controlled mechanical ventilation. AB - The global inhomogeneity (GI) index is a parameter of ventilation inhomogeneity that can be calculated from images of tidal ventilation distribution obtained by electrical impedance tomography (EIT). It has been suggested that the GI index may be useful for individual adjustment of positive end-expiratory pressure (PEEP) and for guidance of ventilator therapy. The aim of the present work was to assess the influence of tidal volume (VT) on the GI index values. EIT data from 9 patients with acute respiratory distress syndrome ventilated with a low and a high VT of 5 +/- 1 (mean +/- SD) and 9 +/- 1 ml kg(-1) predicted body weight at a high and a low level of PEEP (PEEPhigh, PEEPlow) were analyzed. PEEPhigh and PEEPlow were set 2 cmH2O above and 5 cmH2O below the lower inflection point of a quasi-static pressure volume loop, respectively. The lower inflection point was identified at 8.1 +/- 1.4 (mean +/- SD) cmH2O, resulting in a PEEPhigh of 10.1 +/- 1.4 and a PEEPlow of 3.1 +/- 1.4 cmH2O. At PEEPhigh, we found no significant trend in GI index with low VT when compared to high VT (0.49 +/- 0.15 versus 0.44 +/- 0.09, p = 0.13). At PEEPlow, we found a significantly higher GI index with low VT compared to high VT (0.66 +/- 0.19 versus 0.59 +/- 0.17, p = 0.01). When comparing the PEEP levels, we found a significantly lower GI index at PEEPhigh both for high and low VT. We conclude that high VT may lead to a lower GI index, especially at low PEEP settings. This should be taken into account when using the GI index for individual adjustment of ventilator settings. PMID- 26007293 TI - MiR-9 and miR-21 as prognostic biomarkers for recurrence in papillary thyroid cancer. AB - Despite low mortality rates, nodal recurrence in papillary thyroid carcinoma occurs in up to 20 % of patients. Emerging evidences indicate that dysregulated microRNAs are implicated in the process of metastasis. In the present study, we investigated whether miR-9, miR-10b, miR-21 and miR-146b levels are predictive of papillary thyroid carcinoma recurrence. Using macro-dissection followed by quantitative real-time PCR, we measured miR-9, miR-10b, miR-21 and miR-146b expression levels in formalin-fixed, paraffin-embedded samples of 66 patients with papillary thyroid carcinoma categorized into two groups: the recurrent group (n = 19) and the non-recurrent group (n = 47). All patients underwent total thyroidectomy and were followed for at least 120 months after surgery to be considered recurrence-free. Univariate and multivariate analysis were performed using the Cox proportional hazard model in order to identify associations between multiple clinical variables and microRNA expression levels and papillary thyroid carcinoma recurrence. MiR-9 and miR-21 expression levels were found to be significant prognostic factors for recurrence in patients with papillary thyroid carcinoma (HR = 1.48; 95 % CI 1.24-1.77, p < 0.001; and HR = 1.52; 95 % CI 1.18 1.94, p = 0.001; respectively). Multivariate analysis involving the expression level of miR-9 and miR-21 and various clinical parameters identified the expression of these microRNAs as independent prognostic factors for papillary thyroid cancer patients. In conclusion, our results support the potential clinical value of miR-9 and miR-21 as prognostic biomarkers for recurrence in papillary thyroid carcinoma. PMID- 26007295 TI - The association of C-reactive protein and physical activity among a church-based population of African Americans. AB - OBJECTIVE: Regular physical activity can reduce systemic inflammation and, thereby, the burden of chronic inflammatory-related conditions. This study examined whether regular physical activity, measured subjectively (Rapid Assessment of Physical Activity [RAPA]) and objectively (Bodymedia's SenseWear(r) activity monitor [SWA]), is associated with inflammatory or glycemic control markers. METHODS: Subjects were 345 participants of the Healthy Eating and Active Living in the Spirit (HEALS) lifestyle intervention among African American (AA) churches in South Carolina from 2009 to 2012. Linear regression analyses were performed to assess the relationship between both subjectively and objectively measured physical activity and inflammatory markers including high sensitivity C reactive protein (CRP), interleukin-6 (IL-6), and glycosylated hemoglobin (HbA1c). RESULTS: Those who participated in regular physical activity (from RAPA) had lower CRP values compared to those who were sedentary (2.3 vs. 3.8mg/L, p<0.01). Lower levels of CRP or IL-6 were observed among those in the highest quartile of active energy expenditure (CRP: 2.0 vs. 3.6 mg/L, p=0.01) or moderate vigorous physical activity minutes (CRP=1.7 vs. 4.5mg/L, p<0.01; IL-6=1.5 vs. 2.1pg/mL, p=0.01) compared to their lowest respective quartiles as measured by the SWA. CONCLUSION: Physical activity may improve chronic inflammation, which is a primary pathophysiological mechanism for numerous chronic disorders, especially among minority populations. PMID- 26007297 TI - Neighborhood walkability: Differential associations with self-reported transport walking and leisure-time physical activity in Canadian towns and cities of all sizes. AB - OBJECTIVE: To estimate associations between walkability and physical activity during transportation and leisure in a national-level population. METHODS: Walkability was measured by Walk Score(r) (2012-2014) and physical activity by the Canadian Community Health Survey (2007-2012) for urban participants who worked or attended school. Multiple linear regression was done on the total study population, four age subgroups (12-17, 18-29, 30-64, 65+) and three population center subgroups (1000-29,999, 30,000-99,999, 100,000+). RESULTS: 151,318 respondents were examined. Comparing highest to lowest Walk Score(r) quintiles, covariate-adjusted energy expenditure on transport walking [95% confidence interval] was 0.17 [0.15, 0.18] kcal/kg/day higher in the total study population, and significantly higher in all age and population center subgroups. Leisure physical activity was lower in the age 18-29 subgroup (-0.28 [-0.43, -0.12]) and population centers 100,000+ subgroup (-0.10 [-0.18, -0.03]), but higher in the population centers 1000-29,999 subgroup (0.30 [0.12, 0.48]). Total physical activity was higher in the following subgroups: age 30-64 (0.19 [0.12, 0.26]), population centers 100,000+ (0.12 [0.04, 0.19]) and population centers 1000 29,999 (0.40 [0.20, 0.59]). CONCLUSIONS: Walkability is associated with transport walking in all age groups and towns and cities of all sizes. Walkability's inverse associations with leisure physical activity among young adults and in large population centers may offset energy expenditure gains, while positive associations with leisure physical activity in small centers may add to energy expenditure. PMID- 26007296 TI - Food insecurity and dyslipidemia in a representative population-based sample in the US. AB - OBJECTIVE: The association of food insecurity with dyslipidemia has not been firmly established. The main objective of this study was to assess whether food insecurity was associated with dyslipidemia. METHOD: A population-based sample of 1,663 adults from the 2008-2011 Survey of the Health of Wisconsin was used. Food insecurity was defined as an affirmative response to either of the questions: (1) "In the last 12months, have you been concerned about having enough food for you or your family?" (2) "In the last 12months, have your food choices been limited because there wasn't enough money?" High total cholesterol was defined as total cholesterol (TC) >240mg/dL or taking prescribed lipid-lowering medication. Low high-density lipoprotein cholesterol (HDL-C) was defined as <40mg/dL in men and <50mg/dL in women. RESULTS: Food insecurity was not associated with high TC either among men or women. Food insecurity was associated with a higher likelihood of low HDL-C among women (adjusted odds ratio [AOR]: 2.31 {95% confidence interval [CI]: 1.42, 3.76}), but not among men. Obesity appears to be a partial mediator of the association among women (P from the Sobel test=0.01). CONCLUSION: These findings suggest that food insecurity may contribute to an increased risk of low HDL-C in women. PMID- 26007298 TI - Dietary patterns in relation to quality-adjusted life years in the EPIC-NL cohort. AB - BACKGROUND: Dietary patterns have been associated with the incidence or mortality of individual non-communicable diseases, but their association with disease burden has received little attention. OBJECTIVE: The aim of our study was to relate dietary patterns to health expectancy using quality-adjusted life years (QALYs) as outcome parameter. METHODS: Data from the EPIC-NL study were used, a prospective cohort study of 33,066 healthy men and women aged 20-70 years at recruitment. A lifestyle questionnaire and a validated food frequency questionnaire were administered at study entry (1993-1997). Five dietary patterns were studied: three a priori patterns (the modified Mediterranean Diet Score (mMDS), the WHO-based Healthy Diet Indicator (HDI) and the Dutch Healthy Diet index (DHD-index)) and two a posteriori data-based patterns. QALYs were used as a summary health measure for healthy life expectancy, combining a person's life expectancy with a weight reflecting loss of quality of life associated with having chronic diseases. RESULTS: The mean QALYs of the participants were 74.9 (standard deviation 4.4). A higher mMDS and HDI were associated with a longer life in good health. Participants who had a high mMDS score (6-9) had 0.17 [95% CI, 0.05; 0.30] more QALYs than participants with a low score (0-3), equivalent to two months longer life in good health. Participants with a high HDI score also had more QALYs (0.15 [95% CI, 0.03; 0.27]) than participants with a low HDI score. CONCLUSION: A Mediterranean-type diet and the Healthy Diet Indicator were associated with approximately 2months longer life in good health. PMID- 26007299 TI - Low statin use in adults hospitalized with acute coronary syndrome. AB - OBJECTIVE: To assess recommended and actual use of statins in primary prevention of cardiovascular disease (CVD) based on clinical prediction scores in adults who develop their first acute coronary syndrome (ACS). METHOD: Cross-sectional study of 3172 adults without previous CVD hospitalized with ACS at 4 university centers in Switzerland. The number of participants eligible for statins before hospitalization was estimated based on the European Society of Cardiology (ESC) guidelines and compared to the observed number of participants on statins at hospital entry. RESULTS: Overall, 1171 (37%) participants were classified as high risk (10-year risk of cardiovascular mortality >=5% or diabetes); 1025 (32%) as intermediate risk (10-year risk <5% but >=1%); and 976 (31%) as low risk (10-year risk <1%). Before hospitalization, 516 (16%) were on statins; among high-risk participants, only 236 of 1171 (20%) were on statins. If ESC primary prevention guidelines had been fully implemented, an additional 845 high-risk adults (27% of the whole sample) would have been eligible for statins before hospitalization. CONCLUSION: Although statins are recommended for primary prevention in high-risk adults, only one-fifth of them are on statins when hospitalized for a first ACS. PMID- 26007300 TI - Released lipids regulate transient receptor potential channel (TRP)-dependent oral cancer pain. AB - BACKGROUND: Pain in the head neck area is an early symptom in oral cancer, supporting the hypothesis that cancer cells control the activities of surrounding nociceptors at the site of the tumor. Several reports implicate TRPV1 and TRPA1 in cancer pain, although there is a large gap in knowledge since the mechanisms for tumor-induced activation of these TRP receptors are unknown. Interestingly, TRP-active lipids such as linoleic acid, arachidonic acid, hydroxyoctadecadienoic acid and hydroxyeicosatetraenoic acid are significantly elevated in the saliva of oral cancer patients compared to normal patients, supporting a possible linkage between these lipids and oral cancer pain. We therefore hypothesize that oral squamous cell carcinomas release certain lipids that activate TRPV1 and/or TRPA1 on sensory neurons, contributing to the development of oral cancer pain. METHODS: Lipid extracts were made from conditioned media of three human oral squamous cell carcinoma (OSCC) cell lines as well as one normal human oral keratinocytes cell line. These were then injected intraplantarly into rat hindpaws to measure spontaneous nocifensive behavior, as well as thermal and mechanical allodynia. For interventional experiments, the animals were pretreated with AMG517 (TRPV1 antagonist) or HC030031 (TRPA1 antagonist) prior to extract injection. RESULTS: These studies demonstrate that lipids released from the three OSCC cell lines, but not the normal cell line, were capable of producing significant spontaneous nocifensive behaviors, as well as thermal and mechanical allodynia. Notably each of the cell lines produced a different magnitude of response for each of three behavioral assays. Importantly, pre-treatment with a TRPVI antagonist blocked lipid-mediated nocifensive and thermal hypersensitivity, but not mechanical hypersensitivity. In addition, pre-treatment with a TRPA1 antagonist only reversed thermal hypersensitivity without affecting lipid-induced nocifensive behavior or mechanical allodynia. CONCLUSIONS: These data reveal a novel mechanism for cancer pain and provide strong direction for future studies evaluating the cellular mechanism regulating the TRP-active lipids by OSCC tumors. PMID- 26007301 TI - The reductive P-P coupling of primary and secondary phosphines mediated by N heterocyclic carbenes. AB - The dehydrogenative coupling of primary and secondary phosphines with the N heterocyclic carbene iPr2Im (1,3-di-isopropyl-imidazolin-2-ylidene) has been reported. The dehydrogenation of R2PH affords diphosphines R2P-PR2. The reaction of iPr2Im with ArPH2 leads to the formation of NHC phosphinidene adducts iPr2Im[double bond, length as m-dash]PAr and cyclic oligophosphines P4Ar4, P5Ar5 and P6Ar6, depending on the stoichiometry used. The NHC acts in these reactions as a phosphine activator and hydrogen acceptor. PMID- 26007302 TI - New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies. AB - Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (Kis >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII. PMID- 26007303 TI - Simple structural modifications confer cytotoxicity to allobetulin. AB - A variety of allobetulin derivatives was synthesized from allobetulin or allobetulone. These compounds were screened for their cytotoxic activity using a photometric SRB assay employing six different human tumor cell lines. In summary, opening of ring A of allobetulin in general lowers the cytotoxicity, but the 2,3 seco diethyl ester was highly cytotoxic and remarkable selective for A549 lung carcinoma cells while being significantly less cytotoxic for non-malignant mouse fibroblasts. The introduction of an amino group at position C-3 in the allobetulin skeleton enhances cytotoxicity and furnishes highly cytotoxic compounds. Their selectivity to distinguish between cancer cell and non-malignant cell depends on the configuration at position C-3. PMID- 26007304 TI - Reversible deformation-formation of a multistimuli responsive vesicle by a supramolecular peptide amphiphile. AB - A systematic study of the ternary complex formation process for aromatic amino acids using ucurbit[8]uril (CB[8]) and a viologen amphiphile shows that the affinity of the amino acid needs to be higher or in a comparable range to that of CB[8] for the amphiphile in order to form the ternary complex. Based on these observations, a supramolecular peptide amphiphile and its corresponding vesicle are prepared using a peptide containing an azobenzene moiety. The azobenzene group at the N-terminus of the peptide served as the second guest for CB[8]. The vesicles obtained from this peptide amphiphile show response to a number of external triggers. The trans-cis isomerization of the azobenzene group upon irradiation with UV-light of 365 nm leads to the breakdown of the ternary complex and eventually to the disruption of the vesicle. The deformation-reformation of the vesicle can be controlled by illuminating the disrupted solution with light of 420 nm as it facilitates the cis-trans isomerization. Thus, the vesicle showed a controlled and reversible response to UV-light with the ability for manipulation of the formation-deformation of the vesicle by the choice of an appropriate wavelength. The vesicle showed response to a stronger guest (1 adamantylamine) for CB[8], which displaces both the guests from the CB[8] cavity and consequently ruptures the vesicle structure. 2,6-Dihydroxynaphthalene acts as a competitive guest and thereby behaves as another external trigger for replacing the peptide from the CB[8] cavity by self-inclusion to form the ternary complex. Henceforth, it allows retaining the vesicle structure and results in the release of the peptide from the vesicle. PMID- 26007305 TI - Electrochromic polyoxometalate material as a sensor of bacterial activity. AB - Lactobacillus fermentum, a bacterium of human microbiota, acts as an electron donor for the electrochromic [P2Mo(VI)18O62](6-). Since the reductive capacity of L. fermentum correlates with its metabolic activity, the reaction with [P2Mo(VI)18O62](6-) affords a means of evaluating its activity. Following this logic, we have concluded that vancomycin severely affects the activity of L. fermentum whereas omeprazole does not. PMID- 26007307 TI - Low-temperature VUV photoluminescence and thermoluminescence of UV excited afterglow phosphor Sr3AlxSi1-xO5:Ce(3+),Ln(3+) (Ln = Er, Nd, Sm, Dy and Tm). AB - Low-temperature (10 K) photoluminescence excitation and emission spectra of undoped Sr3SiO5 as well as Ce(3+) and Eu(3+) single doped Sr3SiO5 have been investigated. They show the host exciton band and the O(2-) to Eu(3+) charge transfer band at 5.98 eV (207 nm) and 3.87 eV (320 nm) respectively. Low temperature thermoluminescence measurements are reported for Ce(3+) and lanthanide (Er, Nd, Sm, Dy, Er and Tm) co-doped Sr3AlxSi1-xO5. The results show that Ce(3+) is the recombination centre and Nd, Sm, Dy and Tm work as electron traps with trap depths of 0.95 eV, 1.89 eV, 1.02 eV, and 1.19 eV, respectively. Thermoluminescence excitation spectra of Sr2.98Al0.02Si0.98O5:0.01Ce(3+),0.01Dy(3+) show that the traps can be charged by 260 nm UV excitation. PMID- 26007306 TI - Indicators of microbial-rich environments and the development of papillary thyroid cancer in the California Teachers Study. AB - BACKGROUND: Little epidemiologic research has focused on the role of immune function in papillary thyroid cancer risk despite scattered observations suggesting it may be important (e.g., hygiene hypothesis). Here we investigate papillary thyroid cancer risk associated with self-reported living environments across the lifespan reflecting immunologically relevant exposures to microbial rich environments. METHODS: Among 61,803 eligible participants in the California Teachers Study cohort, 100 were diagnosed with invasive papillary thyroid cancer between 2005 and 2012. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Living in a rural area during early childhood was associated with significantly reduced risk of developing papillary thyroid cancer as an adult (HR=0.51, 95% CI: 0.28 0.94). Specifically, reduced risks were observed for living within a half mile of hoofed animals (HR=0.47, 95% CI: 0.26-0.84), as was having an indoor dog or cat (HR=0.51, 95% CI: 0.32-0.80). Neither sharing a bedroom or living in a rented home as a child nor attending daycare or kindergarten was associated with reduced risk. CONCLUSIONS: Early childhood exposures to hoofed animals or indoor furry pets were associated with reduced risk of subsequently developing papillary thyroid cancer. IMPACT: Our findings point to immunologically relevant, early life exposures to microbial-rich environments as potentially important in reducing thyroid cancer risk, consistent with the hygiene hypothesis and suggesting that certain, possibly animal-derived, microbial exposures may be important to immune calibration or priming. PMID- 26007309 TI - Parents' Prenatal, Onward, and Postdischarge Experiences in Case of Extreme Prematurity: When to Set the Course for a Trusting Relationship between Parents and Medical Staff. AB - OBJECTIVES: This article aims to investigate the impact of prenatal counseling on subsequent parents' experiences during in-patient care of their infant(s) and whether feelings of parents with deceased infants are different in principle. STUDY DESIGN: A questionnaire was sent to 99 families with a child born less than 26 weeks' gestational age at Medical School Hanover 2000-2008. Statistical analysis was performed using Fisher exact t test and chi-square tests in IBM SPSS Statistics for Windows, Version 20.0. RESULTS: Response rate was 73%. Parents with solely surviving children significantly more often answered the questionnaire (p < 0.001). Regardless of the infants' outcome, parents who felt well involved in prenatal decision making significantly more often also felt adequately involved in postnatal treatment of their child (p = 0.006) and would again decide on life-sustaining treatment of an extremely premature infant (p = 0.007). Furthermore, they were significantly less dubious about the treatment of their baby (p = 0.013) than parents not feeling sufficiently involved. Significantly fewer parents with only surviving child(ren) decided to have another baby later than parents with at least one deceased child (p = 0.004). CONCLUSION: This study stresses the impact of prenatal counseling and shows that, regardless of outcome, the course of a trusting relationship between parents and health care team is already set before birth. PMID- 26007308 TI - Proton-induced direct and indirect damage of plasmid DNA. AB - Clustered DNA damage induced by 10, 20 and 30 MeV protons in pBR322 plasmid DNA was investigated. Besides determination of strand breaks, additional lesions were detected using base excision repair enzymes. The plasmid was irradiated in dry form, where indirect radiation effects were almost fully suppressed, and in water solution containing only minimal residual radical scavenger. Simultaneous irradiation of the plasmid DNA in the dry form and in the solution demonstrated the contribution of the indirect effect as prevalent. The damage composition slightly differed when comparing the results for liquid and dry samples. The obtained data were also subjected to analysis concerning different methodological approaches, particularly the influence of irradiation geometry, models used for calculation of strand break yields and interpretation of the strand breaks detected with the enzymes. It was shown that these parameters strongly affect the results. PMID- 26007310 TI - Accuracy of Estimated Blood Loss in Predicting Need for Transfusion after Delivery. AB - OBJECTIVE: The definition of postpartum hemorrhage (PPH) was developed more than 50 years ago. Since then, the obstetric population has changed dramatically. We sought to determine how well we estimated blood loss (EBL) and find thresholds predicting need for transfusion. STUDY DESIGN: We performed a prospective cohort study from 2010 to 2012, comparing those who needed transfusion postpartum and those who did not. EBL, calculated EBL (cEBL), and change in hematocrit were calculated for patients who did not receive transfusion, and EBL was calculated for those who did receive transfusion, stratified by delivery type. Receiver operator curves were created and optimal thresholds of EBL to predict transfusion were estimated. RESULTS: Among 4,804 patients, transfusion was required for 0.65% of vaginal and 8.7% of cesarean deliveries. Median EBL was higher in women requiring transfusion. A weak correlation was noted between EBL and cEBL for all deliveries. Thresholds of 500 mL blood loss for vaginal delivery and 1,000 mL for cesarean had the best predictive ability for transfusion. CONCLUSION: In this modern obstetric, cohort EBL is weakly correlated with cEBL, suggesting that accuracy of clinical estimates of blood loss is modest. However, EBL predicts need for transfusion, with optimal thresholds of 500 mL for a vaginal delivery and 1,000 mL in a cesarean. This validates the traditional definitions of PPH in our modern population. PMID- 26007312 TI - Angiogenic and Antiangiogenic Factors in Preterm Neonates Born to Mothers with and without Preeclampsia. AB - BACKGROUND: Angiogenic and antiangiogenic factors are altered in pregnant women with preeclampsia (PE), but the pattern of expression of these factors in their newborns remains unknown. OBJECTIVE: This study aims to measure vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) levels in preterm neonates born to mothers with PE. METHODS: Neonates with birth weight<2,000 g and gestational age<=34 weeks were included and divided into the following two groups: born to mothers with PE and without PE. Blood was collected from neonates within the first 72 hours of life. VEGF and sFlt-1 levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: A total of 88 neonates were included (37 born to mothers with PE and 51 born to mothers without PE), with a mean gestational age of 29.12+/-2.96 weeks and birth weight of 1,223.80+/-417.48 g. In the multivariate analysis, VEGF was 80% lower and sFlt 1 was 13.48 times higher in the group with PE. sFlt-1 concentration was higher in neonates small for gestational age (SGA) than in those appropriate for gestational age. CONCLUSION: Higher sFlt-1 and lower VEGF levels in the group with PE, as well as higher sFlt-1 levels in SGA neonates, reflect a predominance of antiangiogenic mechanisms in PE and growth restriction. PMID- 26007313 TI - Regional Brain Biometrics at Term-Equivalent Age and Developmental Outcome in Extremely Low-Birth-Weight Infants. AB - OBJECTIVE: This study aims to evaluate individual regional brain biometrics and their association with developmental outcome in extremely low-birth-weight (ELBW) infants. STUDY DESIGN: This is a retrospective study evaluating term-equivalent magnetic resonance imaging (TE-MRI) from 27 ELBW infants with known developmental outcomes beyond 12 months corrected age. Regional biometric measurements were performed by a pediatric neuroradiologist blinded to outcome data. Measures included biparietal width, transcerebellar diameter (TCD), deep gray matter area (DGMA), ventricular dilatation, corpus callosum, and interhemispheric distance. The relationship between regional biometrics and Bayley-II developmental scores were evaluated with linear regression models. RESULTS: The study cohort had an average+/-standard deviation birth weight of 684+/-150 g, gestational age of 24.6+/-2 weeks and 48% males. DGMA was significantly associated with both cognitive and motor outcomes. Significant associations were also observed between TCD and corpus callosum splenium with cognitive and motor outcomes, respectively. Other biometric measures were not associated with outcome (p>0.05). DGMA<10.26 cm2 was highly specific for poor motor and cognitive outcome. CONCLUSION: TE-MRI biometrics reflecting impaired deep gray matter, callosal, and cerebellar size is associated with worse early childhood cognitive and motor outcomes. DGMA may be the most robust single biometric measure to predict adverse developmental outcome in preterm survivors. PMID- 26007311 TI - Skin-to-Skin Care and the Development of the Preterm Infant Oral Microbiome. AB - OBJECTIVE: The oral cavity represents an initial entry way for oral and gut indigenous colonization. Skin-to-skin (STS) care, in which the mother holds the diaper clad naked preterm (PT) infant between her breasts, is associated with improved digestive function, decreased stress, and improved survival. This study evaluated the development of oral microbial colonization repertoires and health characteristics in PT infants with or without STS exposure. METHODS: Saliva from 42 PT infants (<32 weeks of gestation at birth) was collected prospectively at 1 month and/or at discharge. High-throughput 16S rRNA sequencing identified microbial diversity and prevalence of bacterial signatures correlated with clinical STS or non-STS care. RESULTS: Corrected for gestational age (CGA) at sampling, bacterial taxa demonstrated increased Streptococcus as a signature of oral repertoire maturation. STS was associated with increased Streptococcus (p < 0.024), while non-STS was associated with greater Corynebacterium (p < 0.023) and Pseudomonas (p < 0.019) in infants <= 32 weeks CGA. In infants > 32 weeks CGA, Neisseria and Acinetobacter were more prevalent, 50 vs. 16.7% and 40 vs. 0%, respectively. STS care was associated with shorter hospitalization (p < 0.039). CONCLUSION: STS care during earlier gestation was associated with a distinct microbial pattern and an accelerated pace of oral microbial repertoire maturity. PMID- 26007314 TI - The Effect of Oral High-dose Ibuprofen on Patent Ductus Arteriosus Closure in Preterm Infants. AB - OBJECTIVE: The aim of this study is to compare the efficacy and possible adverse effects of the oral high-dose ibuprofen regimen to that of standard regimen in closing patent ductus arteriosus (PDA). STUDY DESIGN: This clinical trial study was performed from April 2012 to May 2013 on preterm infants with gestational age<37 weeks and postnatal age 3 to 7 days with echocardiographic diagnosis of hemodynamically significant PDA. These neonates were randomly assigned to two treatment groups that respectively received high dose (20-10-10 mg/kg/d) and standard dose (10-5-5 mg/kg/d) oral ibuprofen regimen for 3 days. Effect of ibuprofen therapy was evaluated by echocardiography and neonates were followed for renal dysfunction, gastrointestinal complication, bleeding, and hyperbilirubinemia. RESULTS: From a total of 60 enrolled infants, 30 cases received the high dose of ibuprofen and the remaining 30 received the standard dose. Complete ductal closure was observed in 20 (70%) infants treated with high dose regimen in comparison with 11 (36.7%) in the standard-dose regimen group (p=0.010). No gastrointestinal, renal, or hematological adverse effects were reported. CONCLUSION: The high-dose oral ibuprofen seems to be more effective than the current standard dose regimen for PDA closure in premature neonates without increasing the adverse effects. PMID- 26007315 TI - Increased Incidence of Late-Onset Circulatory Collapse after Changing Clinical Practice: A Retrospective Investigation of Causative Factors. AB - OBJECTIVE: Acute primary profound circulatory failure responsive to glucocorticoid therapy after the first week of age in preterm infants is termed late-onset circulatory collapse (LCC). This study was performed to identify factors that notably increased the incidence of LCC after various management practices were changed. STUDY DESIGN: We retrospectively studied the clinical characteristics of infants (<29 weeks' gestation) before (n=26) and after (n=35) implementing the following practice changes: stress reduction, conservative replacement of thyroid hormone, positive antenatal glucocorticoid administration, sedation with fentanyl (<7 days after birth), and hydrocortisone therapy for hypotension. RESULTS: After the aforementioned changes, the incidence of LCC increased from 4 to 43%, and that of intraventricular hemorrhage decreased from 42 to 9%. Antenatal glucocorticoids (75 vs. 20%), fentanyl (94 vs. 53%), and hydrocortisone (63 vs. 31%) (<2 weeks of age) were given to infants with LCC and non-LCC. After the practice changes, infants with LCC had lower serum sodium levels than did infants without LCC at 7 to 14 days of age. CONCLUSION: Relative hyponatremia was an early sign of imminent LCC. In addition to adrenal prematurity, the antenatal administration of glucocorticoids and fentanyl, which influence adrenal function, might increase the incidence of LCC. PMID- 26007316 TI - Adnexal mass during pregnancy: a review. AB - OBJECTIVE: The purpose of this review was to determine the likelihood of malignancy or complications with ultrasonographic diagnosis of adnexal masses in pregnancy and to evaluate the obstetrical outcomes. Materials and METHODS: A review of literature was performed using keywords "adnexal mass and pregnancy" or "ovarian mass and pregnancy." RESULTS: Out of the 340 abstracts reviewed, 313 were excluded. The incidence of adnexal mass in pregnancy varied from 0.1 to 2.4%, with an average of 0.02%. Regarding the likelihood of malignancy, in seven publications, there were 557 women with 563 adnexal masses. Of these 563 masses, 48% were classified as simple and 52% as complex. Among the simple masses, 1% were malignant. Among the complex masses, 9% were malignant. When comparing laparoscopy and laparotomy, the rate of preterm contractions was found to be higher in patients undergoing laparotomy and this was statistically significant. Other measures, such as spontaneous abortion, vaginal bleeding, < 37 week delivery, and intrauterine fetal demise, were not found to have a significant difference. CONCLUSION: Adnexal masses in pregnancy occur infrequently and depending on whether the surgery was performed emergently or electively, via laparoscopy or laparotomy, the outcomes will vary. PMID- 26007317 TI - Usefulness of two clinical chorioamnionitis definitions in predicting neonatal infectious outcomes: a systematic review. AB - OBJECTIVE: To assess the usefulness of two definitions of acute clinical chorioamnionitis (ACCA) in predicting risk of neonatal infectious outcomes (NIO) and mortality, the first definition requiring maternal fever alone (Fever), and the second requiring >= 1 Gibbs criterion besides fever (Fever + 1). STUDY DESIGN: PubMed, Web of Science, and the Cochrane Database of Systematic Reviews were searched from January 1, 1979 to April 9, 2013. Twelve studies were reviewed (of 316 articles identified): three studies with term patients, four with preterm premature rupture of membranes (PPROM) patients, and five mixed studies with mixed gestational ages and/or membrane status (intact and/or ruptured). RESULTS: Both definitions demonstrated an increased NIO risk for ACCA versus non-ACCA patients, with an odds ratio increase for the Fever + 1 definition that was about twofold larger than the Fever definition. CONCLUSION: As the Fever definition demonstrated increased NIO risk for ACCA versus non-ACCA patients, the Fever alone ACCA definition should be used to trigger future clinical treatment in many clinical situations. PMID- 26007319 TI - Stabilization of fullerene-like boron cages by transition metal encapsulation. AB - The stabilization of fullerene-like boron (B) cages in the free-standing form has been long sought after and a challenging problem. Studies that have been carried out for more than a decade have confirmed that the planar or quasi-planar polymorphs are energetically favored ground states over a wide range of small and medium-sized B clusters. Recently, the breakthroughs represented by Nat. Chem., 2014, 6, 727 established that the transition from planar/quasi-planar to cage like Bn clusters occurs around n = ~38-40, paving the way for understanding the intriguing chemistry of B-fullerene. We herein demonstrate that the transition demarcation, n, can be significantly reduced with the help of transition metal encapsulation. We explore via extensive first-principles swarm-intelligence based structure searches the free energy landscapes of B24 clusters doped by a series of transition metals and find that the low-lying energy regime is generally dominated by cage-like isomers. This is in sharp contrast to that of bare B24 clusters, where the quasi-planar and rather irregular polyhedrons are prevalent. Most strikingly, a highly symmetric B cage with D3h symmetry is discovered in the case of Mo or W encapsulation. The endohedral D3h cages exhibit robust thermodynamic, dynamic and chemical stabilities, which can be rationalized in terms of their unique electronic structure of an 18-electron closed-shell configuration. Our results indicate that transition metal encapsulation is a feasible route for stabilizing medium-sized B cages, offering a useful roadmap for the discovery of more B fullerene analogues as building blocks of nanomaterials. PMID- 26007318 TI - Fusarium spp. is able to grow and invade healthy human nails as a single source of nutrients. AB - Onychomycosis caused by Fusarium spp. is emerging, but some factors associated with its development remain unclear, such as whether this genus is keratinolytic. The main aim of the present study was to evaluate the ability of Fusarium to use the human nail as a single source of nutrients. We also performed an epidemiological study and antifungal susceptibility testing of Fusarium spp. that were isolated from patients with onychomycosis. The epidemiological study showed that Fusarium species accounted for 12.4 % of onychomycosis cases, and it was the most common among nondermatophyte molds. The most frequent species identified were F. oxysporum (36.5 %), F. solani (31.8 %), and F. subglutinans (8.3 %). Fluconazole was not active against Fusarium spp., and the response to terbinafine varied according to species. Fusarium was able to grow in vitro without the addition of nutrients and invade healthy nails. Thus, we found that Fusarium uses keratin as a single source of nutrients, and the model proposed herein may be useful for future studies on the pathogenesis of onychomycosis. PMID- 26007320 TI - Comparative effects of red and white grapes on oxidative markers and lipidemic parameters in adult hypercholesterolemic humans. AB - The present study compared the effects of consuming red versus white whole grapes on oxidative and lipidemic indices in people with hypercholesterolemia. Sixty nine patients were randomized into three groups. The two treatment groups consumed 500 g of either Condori red grapes or Shahroodi white grapes daily for 8 weeks, and the third group served as a control. Plasma glucose, triacylglycerol (TG), cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were determined by colorimetric methods at baseline and at the end of the study. In addition, the polyphenol and fiber content of the two grape varieties was measured. TBARS was reduced in both study groups compared to the control group, and the reduction was greater in the group that consumed red grapes compared to the white grapes. TAC was increased significantly in both red and white grape consuming groups compared to the control group. Total cholesterol and LDL-C were decreased in the red grape group compared to the control group. No significant changes in fasting blood glucose, TG or HDL-C were observed among the groups. The results of this study suggest that consumption of the whole fruit of red grapes has more potent anti-oxidative and hypolipidemic effects compared to the white grapes in hyperlipidemic adult humans. Hence, the whole fruit of red grapes may be an excellent fruit choice not only to prevent oxidative stress related metabolic disorders but also cholesterol related cardiovascular diseases, particularly in hyperlipidemic adult humans. PMID- 26007321 TI - Direct Derivatization vs Aqueous Extraction Methods of Fecal Free Fatty Acids for GC-MS Analysis. AB - A comprehensive and accurate determination of free fatty acids (FFA) is required for fecal metabolomic investigations. The present study compares three aqueous extraction methods (1) ULTRA-TURRAX((r)), (2) whirl mixing and (3) basic ULTRA TURRAX extraction of fecal FFA with a direct derivatization approach using ethyl chloroformate as the derivatization reagent before determination by gas chromatography-mass spectrometry. The direct derivatization method resulted in significantly higher estimations (P < 0.01) of short- and long-chain fatty acids than was the case when applying the aqueous extraction methods using ULTRA TURRAX, whirl mixing, or basic ULTRA-TURRAX extraction before the derivatization step. Thus, avoiding an aqueous extraction before derivatization reduces the loss of volatile short-chain FFA and the less water-soluble long-chain FFA. PMID- 26007322 TI - Simultaneous resection for colorectal cancer and synchronous liver metastases. AB - PURPOSES: The correct timing of hepatectomy in patients with synchronous colorectal liver metastases is unclear. The aim of this study was to assess the clinical value of simultaneous resection (SR) for patients with colorectal cancer and synchronous liver metastases. METHODS: Between January 2006 and December 2013, 158 patients underwent resection of primary colorectal cancer and liver metastases. Sixty-three patients possessed synchronous colorectal liver metastases. Of those with synchronous colorectal liver metastases, 41 patients (65 %) underwent SR, and 22 (35 %) underwent delayed resection (DR). The clinicopathologic and operative data and the surgical outcomes of the patients in the SR and DR groups were retrospectively analyzed. RESULTS: The type of primary/liver resection, liver resection time, total blood loss volume, R0 resection rate, and morbidity rate were similar between the two groups. The SR group was associated with a shorter total postoperative hospital stay (21 vs 32 days, p < 0.001). However, the overall survival rate was similar between the two groups (3-year survival, 65.6 % in the SR group versus 66.8 % in the DR group, p = 0.054). CONCLUSION: Simultaneous resection of colorectal cancer and synchronous liver metastases is associated with a comparable morbidity rate and shorter hospital stay, even when following rectal resection and major hepatectomy. PMID- 26007323 TI - Oleanane-type saponins from Glochidion glomerulatum and their cytotoxic activities. AB - Eight oleanane-type saponins, glomerulosides A-H, were isolated from leaves of Glochidion glomerulatum. All isolated compounds were evaluated for cytotoxic activity on four human cancer cell lines, A-549, HT-29, OVCAR, and MCF-7. Glomerulosides C and E, which contain a benzoyloxy group at C-22, showed significant cytotoxic activities against the A-549, HT-29, and OVCAR cancer cell lines with IC50 values ranging from 5.9 to 9.8MUM. Glomeruloside A showed cytotoxicity on HT-29 and OVCAR cell lines with IC50 values of 7.3 and 6.6MUM, respectively. Moreover, glomeruloside B exhibited significant activity on A-549 and HT-29 cancer cell lines with IC50 values of 9.7 and 7.5MUM. In contrast, glomerulosides F-H, lacking a benzoyloxy group, showed only moderate cytotoxic activity. PMID- 26007325 TI - Palladium-catalyzed chemoselective synthesis of indane-1,3-dione derivatives via tert-butyl isocyanide insertion. AB - A simple and efficient strategy for the synthesis of indane-1,3-dione derivatives through a palladium(0)-catalyzed reaction incorporating tert-butyl isocyanide has been developed. In addition, by applying this protocol as the key step, indenopyrazole derivatives can be easily synthesized in high yields in a one-pot procedure. This methodology is tolerant of a wide range of substrates and applicable to library synthesis. PMID- 26007324 TI - The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study. AB - RATIONALE: Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. OBJECTIVES: The objectives of the study were to test the effects of systemic and intra-OFC 5 HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. METHODS: In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 MUg/side) on performance in this task. RESULTS: In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). CONCLUSION: Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders. PMID- 26007327 TI - Orbicularis-levator-tarsus composite suture technique in double-eyelid operation. AB - OBJECTIVE: Fold loss and suture extrusion are fairly common in double-eyelid surgeries. We hereby explore a new composite suture technique that aims to reduce such complications and to improve the long-term aesthetic outcome. METHODS: Based on the conventional external incision procedure, the suture procedure in our technique involves three stitches that fixate the orbicularis oculi, the levator aponeurosis, and the tarsal plate. This modified upper-eyelid blepharoplasty was performed in 98 patients (91 female and seven male, 196 eyes) with either congenital absence of the upper-eyelid folds (n = 84) or loss of fold from previous procedures (n = 14). The patients were followed up for 6-30 months. The complications were documented, and the overall outcomes of upper-eyelid folds were evaluated by both surgeons and patients as excellent, good, fair, or poor. RESULTS: Among 98 patients, 89 (91%) had excellent results and nine (9%) had good results; no patient had fair or poor results. Four patients had scar formation at postoperative week 2, all resolved without particular treatments at 6 months. The buried sutures could not be seen or felt through the skin. In addition, no suture extrusion was noted. There was no case of faded or disappeared folds during the follow-up. All patients were satisfied with the outcome. CONCLUSIONS: The composite suture technique ensures a firmer fixation and improves the aesthetic outcomes. It is a highly applicable and reliable approach for upper-eyelid blepharoplasty. PMID- 26007326 TI - Cyclic phosphatidic acid inhibits the secretion of vascular endothelial growth factor from diabetic human coronary artery endothelial cells through peroxisome proliferator-activated receptor gamma. AB - Atherosclerosis is a disease characterized by building up plaques formation and leads to a potentially serious condition in which arteries are clogged by fatty substances such as cholesterol. Increasing evidence suggests that atherosclerosis is accelerated in type 2 diabetes. Recent study reported that high level of alkyl glycerophosphate (AGP) was accumulated in atherosclerotic lesions. The presence of this phospholipid in mildly oxidized low-density lipoprotein (LDL) is likely to be involved in atherogenesis. It has been reported that the activation of peroxisome proliferator-activated receptor gamma plays a key role in developing atherosclerosis. Our previous result indicates that cyclic phosphatidic acid (cPA), one of bioactive lipids, potently suppresses neointima formation by inhibiting the activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, the detailed mechanism is still unclear. In this study, to elucidate the mechanism of the cPA-PPARgamma axis in the coronary artery endothelium, especially in patients with type 2 diabetes, we investigated the proliferation, migration, and secretion of VEGF in human coronary artery endothelial cells from diabetes patients (D-HCAECs). AGP induced cell growth and migration; however, cPA suppressed the AGP-elicited growth and migration in D HCAECs. Moreover, AGP increased VEGF secretion from D-HCAECs, and this event was attenuated by cPA. Taken together, these results suggest that cPA suppresses VEGF stimulated growth and migration in D-HCAECs. These findings could be important for regulatory roles of PPARgamma and VEGF in the vascular processes associated with diabetes and atherosclerosis. PMID- 26007328 TI - Photoluminescence Blinking and Reversible Electron Trapping in Copper-Doped CdSe Nanocrystals. AB - Single-particle photoluminescence blinking is observed in the copper-centered deep-trap luminescence of copper-doped CdSe (Cu(+):CdSe) nanocrystals. Blinking dynamics for Cu(+):CdSe and undoped CdSe nanocrystals are analyzed to identify the effect of Cu(+), which selectively traps photogenerated holes. Analysis of the blinking data reveals that the Cu(+):CdSe and CdSe nanocrystal "off"-state dynamics are statistically identical, but the Cu(+):CdSe nanocrystal "on" state is shorter lived. Additionally, a new and pronounced temperature-dependent delayed luminescence is observed in the Cu(+):CdSe nanocrystals that persists long beyond the radiative lifetime of the luminescent excited state. This delayed luminescence is analogous to the well-known donor-acceptor pair luminescence of bulk copper-doped phosphors and is interpreted as revealing metastable charge separated excited states formed by reversible electron trapping at the nanocrystal surfaces. A mechanistic link between this delayed luminescence and the luminescence blinking is proposed. Collectively, these data suggest that electron (rather than hole) trapping/detrapping is responsible for photoluminescence intermittency in these nanocrystals. PMID- 26007329 TI - On the application of frequency selective common mode feedback for multifrequency EIT. AB - Common mode voltages are frequently a problem in electrical impedance tomography (EIT) and other bioimpedance applications. To reduce their amplitude common mode feedback is employed. Formalised analyses of both current and voltage feedback is presented in this paper for current drives. Common mode effects due to imbalances caused by the current drives, the electrode connections to the body load and the introduction of the body impedance to ground are considered. Frequency selective narrowband common mode feedback previously proposed to provide feedback stability is examined. As a step towards multifrequency applications the use of narrowband feedback is experimentally demonstrated for two simultaneous current drives. Measured results using standard available components show a reduction of 62 dB for current feedback and 31 dB for voltage feedback. Frequencies ranged from 50 kHz to 1 MHz. PMID- 26007330 TI - Combining Bone Marrow Stromal Cells with Green Tea Polyphenols Attenuates the Blood-Spinal Cord Barrier Permeability in Rats with Compression Spinal Cord Injury. AB - This study was performed to investigate the effect of bone marrow stromal cells (BMSCs) combined with green tea polyphenols (GTPs) on the blood-spinal cord barrier (BSCB) permeability after spinal cord injury (SCI) in the rat model. In the model of SCI rats, we found that the water content and the BSCB permeability were decreased by BMSCs and GTPs treatment, and their combination had a synergistic effect. Further, the motor function of rats was also greatly improved by BMSCs and GTPs administration. After treated by the combination of BMSCs and GTPs, SCI rats showed the up-regulated expression of tight junction (TJ) associated proteins claudin-5, occludin and ZO-1 by Western blot, which was more remarkable than that in the single treatment. The increased expression levels of claudin-5, occludin, and ZO-1 were the most obvious in the spinal cord microvessels using immunohistochemistry assay. This led to the conclusion that the combination of BMSCs and GTPs could decrease the BSCB permeability by up regulating protein expression levels of claudin-5, occludin, and ZO-1. In addition, after BMSCs and GTPs administration, the results of Western blot and enzyme-linked immunosorbent assay (ELISA) revealed a significant decrease in protein expression level and the activation of nuclear factor-kB (NF-kB) p65. Our results indicated that combination of BMSCs and GTPs could improve motor function after SCI, which might be correlated with improvements in BSCB integrity, and that NF-kB might be involved in the modulating process. PMID- 26007331 TI - Schizophrenia and Depression: A systematic Review of the Effectiveness and the Working Mechanisms Behind Acupuncture. AB - OBJECTIVE: This systematic review assessed clinical evidence for the use of acupuncture as an add-on treatment in patients with depression and schizophrenia and for its underlying working mechanisms. DATA SOURCES: Four databases (Medline, Scopus, ERIC, and the Cochrane Library) were searched with a cutoff date of March 31, 2014. STUDY SELECTION: Systematic reviews and meta-analyses of acupuncture treatment for depression and schizophrenia were considered for inclusion. The scarcity of acupuncture research involving schizophrenia led to the inclusion of randomized controlled trials and case studies. DATA EXTRACTION: The primary and secondary aims of this study were to evaluate the effects of acupuncture in treating patients with depression or schizophrenia and the possible working mechanisms underlying acupuncture through a systematic literature review. DATA SYNTHESIS: The overall clinical results on using acupuncture to treat depression are promising, but only limited evidence for its effectiveness in treating schizophrenia was found. Acupuncture improves the quality of life, particularly that of sleep, in psychiatric patients. Brain research has revealed that acupuncture has a modulating and normalizing effect on the limbic-paralimbic neocortical network (LPNN), including the default mode network. Because the LPNN is related to sleep and emotions, this might explain the improved qualities of life and sleep after acupuncture. CONCLUSIONS: From the evidence found in this study, acupuncture seems to be an effective add-on treatment in patients with depression and, to a lesser degree, in patients with schizophrenia, but large well-designed studies are needed to confirm that evidence. PMID- 26007332 TI - Low folate and selenium in the mouse maternal diet alters liver gene expression patterns in the offspring after weaning. AB - During pregnancy, selenium (Se) and folate requirements increase, with deficiencies linked to neural tube defects (folate) and DNA oxidation (Se). This study investigated the effect of a high-fat diet either supplemented with (diet H), or marginally deficient in (diet L), Se and folate. Pregnant female mice and their male offspring were assigned to one of four treatments: diet H during gestation, lactation and post-weaning; diet L during gestation, lactation and post-weaning; diet H during gestation and lactation but diet L fed to offspring post-weaning; or diet L during gestation and lactation followed by diet H fed to offspring post-weaning. Microarray and pathway analyses were performed using RNA from colon and liver of 12-week-old male offspring. Gene set enrichment analysis of liver gene expression showed that diet L affected several pathways including regulation of translation (protein biosynthesis), methyl group metabolism, and fatty acid metabolism; this effect was stronger when the diet was fed to mothers, rather than to offspring. No significant differences in individual gene expression were observed in colon but there were significant differences in cell cycle control pathways. In conclusion, a maternal low Se/folate diet during gestation and lactation has more effects on gene expression in offspring than the same diet fed to offspring post-weaning; low Se and folate in utero and during lactation thus has persistent metabolic effects in the offspring. PMID- 26007333 TI - Leucine Promotes Proliferation and Differentiation of Primary Preterm Rat Satellite Cells in Part through mTORC1 Signaling Pathway. AB - Signaling through the mammalian target of rapamycin (mTOR) in response to leucine modulates many cellular and developmental processes. However, in the context of satellite cell proliferation and differentiation, the role of leucine and mTORC1 is less known. This study investigates the role of leucine in the process of proliferation and differentiation of primary preterm rat satellite cells, and the relationship with mammalian target of rapamycin complex 1 (mTORC1) activation. Dissociation of primary satellite cells occurred with type I collagenase and trypsin, and purification, via different speed adherence methods. Satellite cells with positive expression of Desmin were treated with leucine and rapamycin. We observed that leucine promoted proliferation and differentiation of primary satellite cells and increased the phosphorylation of mTOR. Rapamycin inhibited proliferation and differentiation, as well as decreased the phosphorylation level of mTOR. Furthermore, leucine increased the expression of MyoD and myogenin while the protein level of MyoD decreased due to rapamycin. However, myogenin expressed no affect by rapamycin. In conclusion, leucine may up-regulate the activation of mTORC1 to promote proliferation and differentiation of primary preterm rat satellite cells. We have shown that leucine promoted the differentiation of myotubes in part through the mTORC1-MyoD signal pathway. PMID- 26007334 TI - Vitamin D and Graves' disease: a meta-analysis update. AB - The association between vitamin D levels and Graves' disease is not well studied. This update review aims to further analyze the relationship in order to provide an actual view of estimating the risk. We searched for the publications on vitamin D and Graves' disease in English or Chinese on PubMed, EMBASE, Chinese National Knowledge Infrastructure, China Biology Medical and Wanfang databases. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for the vitamin D levels. Pooled odds ratio (OR) and 95% CI were calculated for vitamin D deficiency. We also performed sensitivity analysis and meta-regression. Combining effect sizes from 26 studies for Graves' disease as an outcome found a pooled effect of SMD = -0.77 (95% CI: -1.12, -0.42; p < 0.001) favoring the low vitamin D level by the random effect analysis. The meta regression found assay method had the definite influence on heterogeneity (p = 0.048). The patients with Graves' disease were more likely to be deficient in vitamin D compared to the controls (OR = 2.24, 95% CI: 1.31, 3.81) with a high heterogeneity (I2 = 84.1%, p < 0.001). We further confirmed that low vitamin D status may increase the risk of Graves' disease. PMID- 26007335 TI - Preliminary Finnish measures of eating competence suggest association with health promoting eating patterns and related psychobehavioral factors in 10-17 year old adolescents. AB - Eating competence is an attitudinal and behavioral concept, based on The Satter Eating Competence Model. In adults, it has been shown to be associated with a higher quality of diet. Eating competence or its association with the quality of diet has not been studied in adolescents. The aim of the current study was to explore the utility of using a preliminary Finnish translation of the ecSI 2.0 for evaluating presumed eating competence and its association with food selection, meal patterns and related psychobehavioral factors in 10-17 year old adolescents. Altogether 976 10-17 years old Finnish adolescents filled in the study questionnaire. When exploring the construct validity of ecSI 2.0, the confirmatory factor analysis (CFA) indicated acceptable model fit and all four components of the ecSI 2.0 (eating attitudes, food acceptance, internal regulation of food intake, management of eating context) correlated with each other and were internally consistent. Over half (58%) of the adolescents scored 32 or higher and were thus classified as presumably eating competent (pEC). Eating competence was associated with greater meal frequency, more frequent consumption of vegetables and fruits, and more health-promoting family eating patterns. In addition the pEC, adolescents more often perceived their body size as appropriate, had less often tried to lose weight and had a higher self-esteem and a stronger sense of coherence than the not pEC ones. Family eating patterns and self-esteem were the main underlying factors of eating competence. In conclusion, this preliminary study suggests eating competence could be a useful concept to characterize eating patterns and related behaviors and attitudes in adolescents. However, these preliminary findings need to be confirmed in further studies with an instrument fully validated for this age group. PMID- 26007336 TI - Multiple-Micronutrient Fortified Non-Dairy Beverage Interventions Reduce the Risk of Anemia and Iron Deficiency in School-Aged Children in Low-Middle Income Countries: A Systematic Review and Meta-Analysis (i-iv). AB - Multiple-micronutrient (MMN) fortification of beverages may be an effective option to deliver micronutrients to vulnerable populations. The aim of the present systematic review and meta-analysis is to evaluate the nutritional impacts of MMN fortified beverages in the context of low-middle income countries. A systematic search of published literature yielded 1022 citations, of which 10 randomized controlled trials (nine in school-aged children and one in pregnant women) met inclusion criteria. Results of school-aged children were included in the meta-analysis. Compared to iso-caloric controls, children who received MMN fortified beverages for 8 weeks to 6 months showed significant improvements in hemoglobin (+2.76 g/L, 95% CI [1.19, 4.33], p = 0.004; 8 studies) and serum ferritin (+15.42 pmol/L, [5.73, 25.12], p = 0.007; 8 studies); and reduced risk of anemia (RR 0.58 [0.29, 0.88], p = 0.005; 6 studies), iron deficiency (RR 0.34 [0.21, 0.55], p = 0.002; 7 studies), and iron deficiency anemia (RR 0.17 [0.06, 0.53], p = 0.02; 3 studies). MMN fortified beverage interventions could have major programmatic implications for reducing the burden of anemia and iron deficiency in school-aged children in low-middle income countries. Additional research is needed to investigate effects on other biochemical outcomes and population subgroups. PMID- 26007337 TI - Fructose:glucose ratios--a study of sugar self-administration and associated neural and physiological responses in the rat. AB - This study explored whether different ratios of fructose (F) and glucose (G) in sugar can engender significant differences in self-administration and associated neurobiological and physiological responses in male Sprague-Dawley rats. In Experiment 1, animals self-administered pellets containing 55% F + 45% G or 30% F + 70% G, and Fos immunoreactivity was assessed in hypothalamic regions regulating food intake and reward. In Experiment 2, rats self-administered solutions of 55% F + 42% G (high fructose corn syrup (HFCS)), 50% F + 50% G (sucrose) or saccharin, and mRNA of the dopamine 2 (D2R) and mu-opioid (MOR) receptor genes were assessed in striatal regions involved in addictive behaviors. Finally, in Experiment 3, rats self-administered HFCS and sucrose in their home cages, and hepatic fatty acids were quantified. It was found that higher fructose ratios engendered lower self-administration, lower Fos expression in the lateral hypothalamus/arcuate nucleus, reduced D2R and increased MOR mRNA in the dorsal striatum and nucleus accumbens core, respectively, as well as elevated omega-6 polyunsaturated fatty acids in the liver. These data indicate that a higher ratio of fructose may enhance the reinforcing effects of sugar and possibly lead to neurobiological and physiological alterations associated with addictive and metabolic disorders. PMID- 26007338 TI - The role of gangliosides in neurodevelopment. AB - Gangliosides are important components of neuronal cell membranes and it is widely accepted that they play a critical role in neuronal and brain development. They are functionally involved in neurotransmission and are thought to support the formation and stabilization of functional synapses and neural circuits required as the structural basis of memory and learning. Available evidence, as reviewed herein, suggests that dietary gangliosides may impact positively on cognitive functions, particularly in the early postnatal period when the brain is still growing. Further, new evidence suggests that the mechanism of action may be through an effect on the neuroplasticity of the brain, mediated through enhanced synaptic plasticity in the hippocampus and nigro-striatal dopaminergic pathway. PMID- 26007339 TI - Reviewing the Effects of L-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. AB - Leucine is a well-known activator of the mammalian target of rapamycin (mTOR). Because mTOR signaling regulates several aspects of metabolism, the potential of leucine as a dietary supplement for treating obesity and diabetes mellitus has been investigated. The objective of the present review was to summarize and discuss the available evidence regarding the mechanisms and the effects of leucine supplementation on the regulation of food intake, energy balance, and glucose homeostasis. Based on the available evidence, we conclude that although central leucine injection decreases food intake, this effect is not well reproduced when leucine is provided as a dietary supplement. Consequently, no robust evidence indicates that oral leucine supplementation significantly affects food intake, although several studies have shown that leucine supplementation may help to decrease body adiposity in specific conditions. However, more studies are necessary to assess the effects of leucine supplementation in already-obese subjects. Finally, although several studies have found that leucine supplementation improves glucose homeostasis, the underlying mechanisms involved in these potential beneficial effects remain unknown and may be partially dependent on weight loss. PMID- 26007604 TI - Flow-synthesis of carboxylate and phosphonate based metal-organic frameworks under non-solvothermal reaction conditions. AB - A continuous flow reactor was developed for the synthesis of porous metal-organic frameworks (MOFs) under mild reaction conditions. Commodity hardware was used to assemble the device, giving it a great degree of flexibility in its configuration. The use of paraffin to encapsulate reactions and also ultrasonic treatment were employed to prevent clogging of the reactor. Reactor design was optimised through studies of the synthesis of zirconium carboxylate framework UiO 66. Synthesis of the aluminium carboxylate CAU-13 was also performed, to demonstrate the versatility of the device. Finally the reactor was used to synthesise a new cadmium phosphonate framework, bearing the STA-12 network. PMID- 26007340 TI - The subcellular location of selenoproteins and the impact on their function. AB - Most human selenium containing proteins contain selenium in the form of the amino acid selenocysteine, which is encoded in the corresponding mRNA as a UGA codon. Only a few non-selenocysteine containing selenoproteins are present and the nature of the association with selenium is not well understood. This review focuses on two selenocysteine-containing proteins that are members of the glutathione peroxidase family, GPx-1 and GPx-4, and the selenium-associated protein referred to as Selenium Binding Protein 1. Each of these proteins have been described to reside in two or more cellular compartments, and in the case of GPx-1 and SBP1, interact with each other. The enzymatic activity of GPx-1 and GPx 4 have been well described, but it is less clear how their cellular location impacts the health related phenotypes associated with activities, while no catalytic function is assigned to SBP1. The distribution of these proteins is presented as is the possible consequences of that compartmentalization. PMID- 26007603 TI - Stepwise stent deployment technique for tandem intracranial aneurysms: a review of 21 cases. AB - OBJECTIVES: We performed this study to report our experience using a stepwise stent deployment technique for the treatment of tandem intracranial aneurysms. METHODS: Patients with intracranial tandem aneurysms that were treated with a stepwise stent deployment technique between May 2009 and June 2013 were retrospectively reviewed. RESULTS: Twenty-one patients with 42 tandem aneurysms were identified (11 men, 10 women), with a mean age of 53.7 years (range, 17-82 years). Subarachnoid haemorrhage was confirmed in 12 patients using computed tomography at onset. Complete occlusion was achieved in 20 of the aneurysms (47.6%) after the procedure, neck remnant in 9 (21.4%), and aneurysm remnant in 13 (31.0%). The perioperative complications included in-stent thrombosis in one case and vasospasm in two cases, none of which left a permanent neurological deficit. The modified Rankin Scale (mRS) score at discharge was 0-2 in 20 cases and 3 in one case. The follow-up angiograms available for 17 patients showed complete occlusion in 26 aneurysms, improved in 4, and stable in 4. All of the patients had mRS scores of 0-1 during the clinical follow-up period. CONCLUSIONS: The stepwise stent deployment technique is feasible and helpful in the treatment of intracranial tandem aneurysms. KEY POINTS: * Treating wide-necked intracranial aneurysms with stent-assisted coiling is preferable. * Tandem wide-necked intracranial aneurysms can be treated with a single stent. * Stepwise stent deployment is technically feasible for embolizing tandem intracranial aneurysms. PMID- 26007605 TI - Metal nanoparticles: a theranostic nanotool against cancer. AB - Cancer remains one of the most deadly diseases worldwide, but conventional anticancer therapies come with several drawbacks. Therefore, there is a need to develop new anticancer strategies. Theranostics is a strategy that combines treatment with diagnosis and monitoring. Metal nanoparticles are proposed as one of the most promising theranostic agents for the treatment of cancer. Thus, metals including iron, gold (Au), silver (Ag), zinc (Zn), and titanium, have potential as anticancer agents, either inherently or as a result of surface modifications. As a functional component of theranostic tools, metal nanoparticles have crucial dual roles as a diagnostic and active therapeutic agent for the treatment of cancer. PMID- 26007607 TI - Studying RNAP-promoter interactions using atomic force microscopy. AB - The most fundamental step in gene expression is transcription, during which DNA is transcribed to a corresponding RNA strand by the action of RNA polymerases (RNAPs). Over the past two decades, atomic force microscopy (AFM) has been used as one of the key tools in the investigation of transcriptional events at the single-molecule level. AFM studies have provided significant insights into the structure-function relationships of RNAP-DNA complexes in different stages of transcription. Here, we begin by illustrating the basic setup of AFM, followed by an introduction of the applications of AFM techniques, including high-speed AFM (HS-AFM) imaging, to investigate RNAP-DNA interactions with a special focus on promoter-search processes and open promoter formations. The combination of AFM with a newly developed experimental technique, DNA origami nanotechnology, will also be described. PMID- 26007606 TI - ESI-IMS-MS: A method for rapid analysis of protein aggregation and its inhibition by small molecules. AB - Electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) is a powerful method for the study of conformational changes in protein complexes, including oligomeric species populated during protein self-aggregation into amyloid fibrils. Information on the mass, stability, cross-sectional area and ligand binding capability of each transiently populated intermediate, present in the heterogeneous mixture of assembling species, can be determined individually in a single experiment in real-time. Determining the structural characterisation of oligomeric species and alterations in self-assembly pathways observed in the presence of small molecule inhibitors is of great importance, given the urgent demand for effective therapeutics. Recent studies have demonstrated the capability of ESI-IMS-MS to identify small molecule modulators of amyloid assembly and to determine the mechanism by which they interact (positive, negative, non-specific binding, or colloidal) in a high-throughput format. Here, we demonstrate these advances using self-assembly of Abeta40 as an example, and reveal two new inhibitors of Abeta40 fibrillation. PMID- 26007608 TI - Yucca schidigera extract can promote rabbit fecundity and ovarian progesterone release. AB - The aim of the present in vivo study was to determine the effects of yucca powder extract added to the rabbit females feed mixtures on kindling and conception rate. Rabbit does of the experimental groups were fed with the standard diet enriched with supplement of yucca dry extract at doses of 5 g/100 kg feed (E1 group) or 20 g/100 kg feed (E2 group) for 50 days. In our preliminary in vivo results, we shown that conception rate was significantly higher in both experimental E1 and E2 groups (82.4% and 100.0%, respectively) than in the control group (47.1%). The kindling rate was also significantly higher in the experimental groups (70.6% and 100.0%, respectively) than in the control group (41.2%). The differences between control and yucca-treated groups in the number of liveborn, stillborn, and weaned pups per doe were not statistically significant. To understand possible endocrine mechanisms of yucca action on fertility rate, we have examined the influence of yucca extract additions on the release of steroid hormones by isolated and cultured rabbit ovarian fragments. Yucca additions promoted release of progesterone (at dose of 1 MUg/mL, but not at doses of 10 and 100 MUg/mL). Yucca addition at these doses did not affect testosterone or estradiol release. Our observations show the stimulatory effect of yucca consumption on rabbit fecundity, which can be due to its direct stimulatory influence on ovarian progesterone but not on testosterone or estradiol output. PMID- 26007609 TI - Endothelin 1 in healthy foals and in foals affected by neonatal diseases. AB - In newborn babies, endothelin 1 (ET-1), a potent vasoconstrictor, increases during septicemia and severe respiratory syndromes. Because equine neonatal sepsis (ENS) and perinatal asphyxia syndrome (PAS) are major causes of morbidity and mortality in newborn foals and because no information on the concentration of ET-1 in healthy and sick foals has been reported yet, the aims of this study were (1) to define the serum concentration of Big ET-1 in healthy neonatal foals during the first week of age; (2) to preliminarily explore the diagnostic and prognostic role of Big ET-1 during ENS and PAS. Six healthy and 23 sick foals affected by ENS and/or PAS were enrolled in the study. In healthy foals, Big ET-1 concentration increased in the first hours of life until 24 hours after birth, and it remained constant during the first 3 days, then gradually decreased becoming significantly lower from Day 4 onward (P < 0.05). In sick foals, only 26.1% of animals showed higher values of Big ET-1 than controls at admission, and no difference between surviving and nonsurviving foals was found. Because in nonsurviving foals, Big ET-1 remained over the maximum value recorded in clinically healthy horses or, when normal at admission, increased over time; this study suggested that repeated measurement of Big ET-1 during hospitalization may be helpful in monitoring the course of the disease. In conclusion, possible prognostic information may be obtained by repeated analysis of Big ET-1 during hospitalization, but further studies are needed. PMID- 26007610 TI - Embryo vitrification in rabbits: Consequences for progeny growth. AB - The objective of this research is to examine if there are any effects of the rederivation procedures on rabbit growth pattern and on weight of different organ in adults. For this purpose, three experiments were conducted on two different groups of animals (control group and vitrified-transferred group) to evaluate the possible effect of embryo manipulation (vitrification and transfer procedures) on future growth traits. The first experiment studies body weight from 1 to 9 weeks of age from the two groups. The second experiment describes the growth curve of progeny from experimental groups and analyzes their Gompertz curve parameters, including the estimation of adult body weight. The third experiment has been developed to study if there are any differences in different organ weight in adult males from the two experimental groups. In general, the results indicate that rederivation procedures had effect on the phenotypic expression of growth traits. The results showed that rabbit produced by vitrification and embryo transfer had higher body weight in the first four weeks of age than control progeny. Results from body weight (a parameter) and b parameter estimated by fitting the Gompertz growth curve did not show any difference between experimental groups. However, differences related with growth velocity (k parameter of the Gompertz curve) were observed among them, showing that the control group had higher growth velocity than the vitrified-transferred group. In addition, we found that liver weight at 40th week of age exhibits significant differences between the experimental groups. The liver weight was higher in the control males than in the VF males. Although the present results indicate that vitrification and transfer procedures might affect some traits related with growth in rabbits, further research is needed to assess the mechanisms involved in the appearance of these phenotypes and if these phenotypes could be transferred to the future progeny. PMID- 26007612 TI - Reproductive endocrinology: Epigenetics in pregnancy. PMID- 26007611 TI - Factors affecting pregnancy length and phases of parturition in Martina Franca jennies. AB - The knowledge of normal pregnancy length, duration of parturition stages, and neonatal early adaptation is mandatory for a rationale management of birth, especially in monotocous species with long gestations. This study reports data obtained from a large number of Martina Franca jennies with normal healthy pregnancies and spontaneous eutocic delivery of a mature, healthy, and viable donkey foal. Pregnancy lasts, on average, 371 days, and only the fetal gender significantly determines pregnancy length, with longer gestations observed in jennies bearing male fetuses. Other factors such as the year of foaling, month of ovulation, month of parturition, birth weight of the foal, and age of the jenny did not influence pregnancy length. The first stage of foaling lasted on average 65 minutes, the second stage 19 minutes, and the third stage 58 minutes. The umbilical cord ruptured on average within 16 minutes after birth; the foal stood up in 61 minutes and suckled the colostrum for the first time within 10 minutes after birth and again after 143 minutes of birth; meconium passage occurred, on average, 86 minutes after birth. Although times reported for the process of foaling are similar to data reported for the horse, the times for early neonatal donkey foal adaptation are longer as compared to the horse foal. PMID- 26007615 TI - Treatment of verb anomia in aphasia: efficacy of self-administered therapy using a smart tablet. AB - Aphasia is a chronic condition that usually requires long-term rehabilitation. However, even if many effective treatments can be offered to patients and families, speech therapy services for individuals with aphasia often remain limited because of logistical and financial considerations, especially more than 6 months after stroke. Therefore, the need to develop tools to maximize rehabilitation potential is unquestionable. The aim of this study was to test the efficacy of a self-administered treatment delivered with a smart tablet to improve written verb naming skills in CP, a 63-year-old woman with chronic aphasia. An ABA multiple baseline design was used to compare CP's performance in verb naming on three equivalent lists of stimuli trained with a hierarchy of cues, trained with no cues, and not trained. Results suggest that graphemic cueing therapy, done four times a week for 3 weeks, led to better written verb naming compared to baseline and to the untrained list. Moreover, generalization of the effects of treatment was observed in verb production, assessed with a noun to-verb production task. Results of this study suggest that self-administered training with a smart tablet is effective in improving naming skills in chronic aphasia. Future studies are needed to confirm the effectiveness of new technologies in self-administered treatment of acquired language deficits. PMID- 26007613 TI - Perimenopause as a neurological transition state. AB - Perimenopause is a midlife transition state experienced by women that occurs in the context of a fully functioning neurological system and results in reproductive senescence. Although primarily viewed as a reproductive transition, the symptoms of perimenopause are largely neurological in nature. Neurological symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms and sensory processing) and affect multiple domains of cognitive function. Estrogen is a master regulator that functions through a network of estrogen receptors to ensure that the brain effectively responds at rapid, intermediate and long timescales to regulate energy metabolism in the brain via coordinated signalling and transcriptional pathways. The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction can develop. For some women, this hypometabolic state might increase the risk of developing neurodegenerative diseases later in life. The perimenopausal transition might also represent a window of opportunity to prevent age-related neurological diseases. This Review considers the importance of neurological symptoms in perimenopause in the context of their relationship to the network of estrogen receptors that control metabolism in the brain. PMID- 26007614 TI - Subspeciation of Bifidobacterium longum by multilocus approaches and amplified fragment length polymorphism: Description of B. longum subsp. suillum subsp. nov., isolated from the faeces of piglets. AB - The species Bifidobacterium longum is currently divided into three subspecies, B. longum subsp. longum, B. longum subsp. infantis and B. longum subsp. suis. This classification was based on an assessment of accumulated information on the species' phenotypic and genotypic features. The three subspecies of B. longum were investigated using genotypic identification [amplified-fragment length polymorphism (AFLP), multilocus sequence analysis (MLSA) and multilocus sequence typing (MLST)]. By using the AFLP and the MLSA methods, we allocated 25 strains of B. longum into three major clusters corresponding to the three subspecies; the cluster comprising the strains of B. longum subsp. suis was further divided into two subclusters differentiable by the ability to produce urease. By using the MLST method, the 25 strains of B. longum were divided into eight groups: four major groups corresponding to the results obtained by AFLP and MLSA, plus four minor disparate groups. The results of AFLP, MLSA and MLST analyses were consistent and revealed a novel subspeciation of B. longum, which comprised three known subspecies and a novel subspecies of urease-negative B. longum, for which the name B. longum subsp. suillum subsp. nov. is proposed, with type strain Su 851(T)=DSM 28597(T)=JCM 19995(T). PMID- 26007616 TI - Local antibiotic therapy strategies in orthopaedic trauma: Practical tips and tricks and review of the literature. AB - The use of local antibiotics for the prevention of infection in the setting of open fractures and as part of the treatment of osteomyelitis is well established. Antibiotics are most commonly incorporated into polymethylmethacrylate (PMMA) cement, which can then be formed into beads, moulded to fit a bone defect or used to coat a guide wire or IM nail. Newer delivery vehicles and techniques are being evaluated to improve upon these methods. Many factors influence how local antibiotics are applied. Treatment strategies are challenging to standardise due to the variability of clinical presentations. The presence of hardware, upper versus lower extremity, healed versus non-healed fracture and quality of soft tissues overlying the affected bone, as well as patients' comorbidities all need to be considered. Despite the accepted use of local antibiotic therapy in orthopaedic trauma, high-quality evidence regarding the use of local antibiotics is lacking. Indications, techniques, dosages, types of antibiotics, elution properties and pharmacokinetics are poorly defined in the clinical setting. The purpose of our manuscript is to review current strategies and provide practical tips for local application of antibiotics in orthopaedic trauma. We focus on delivery vehicles, types of antibiotics, dosage recommendations when mixed with PMMA and indications. PMID- 26007618 TI - [Foreword]. PMID- 26007617 TI - A posterior reversed L-shaped approach for the tibial plateau fractures-A prospective study of complications (95 cases). AB - PURPOSE: This study was aiming to investigate intraoperative and postoperative complications and outcomes of a posterior reversed L-shaped approach (PRLA) in the treatment of the tibial plateau fractures. METHODS: Inclusion criterion was tibial plateau fractures treated through the PRLA either separated or combined with other approaches. Main exclusion criterion was poly-trauma patients. Ninety five patients with tibial plateau fractures from a prospectively collected database were included and followed in this study. The intraoperative and postoperative complications consisted of vascular and nerve injury, wound infection, dehiscence, haematoma, nonunion, skin necrosis and skin paresthesia. Hospital for Special Surgery Knee Score (HSS) was adopted to evaluate patients' knee function while Short Form 36 Health Survey (SF-36) was used to investigate the patients' general health status. RESULTS: Patients' average age was 46.2 years old (range, 22.0-89.0). The fractures were mainly from high energy injuries involving posterior (and medial) column. 78 of 95 cases were combined with an additional anterolateral approach due to the lateral column involvement. The average follow-up was 52.0 months (range, 12.4-102.6). The total complications rate was 4.2% (4/95). Intraoperative complications occurred in two patients (2.1%). One suffered a popliteal artery injury resulted from an antero posteriorly drilled K-wire. The patient had a loss of 7 degrees knee extension at one year's follow-up. The other endured an injury of nutrient vessel within the medial head of gastrocnemius. Postoperative skin paresthesia occurred in two patients (2.1%). The other complications associated with the PRLA were not observed. The mean HSS score was 96.1 (range, 80-100). The mean SF-36 score was 94.2 (range, 80-100). CONCLUSIONS: The posterior reversed L-shaped approach allows satisfied visualization of the medial and posterior tibial plateau and has promising clinical results with low complication occurrence. It can be recommended as a routine approach for the treatment of the tibial plateau fractures involving the posterior column. PMID- 26007619 TI - [French guidelines for the management of adult sickle cell disease: 2015 update]. AB - Sickle cell disease is a systemic genetic disorder, causing many functional and tissular modifications. As the prevalence of patients with sickle cell disease increases gradually in France, every physician can be potentially involved in the care of these patients. Complications of sickle cell disease can be acute and chronic. Pain is the main symptom and should be treated quickly and aggressively. In order to reduce the fatality rate associated with acute chest syndrome, it must be detected and treated early. Chronic complications are one of the main concerns in adults and should be identified as early as possible in order to prevent end organ damage. Many organs can be involved, including bones, kidneys, eyes, lungs, etc. The indications for a specific treatment (blood transfusion or hydroxyurea) should be regularly discussed. Coordinated health care should be carefully organized to allow a regular follow-up near the living place and access to specialized departments. We present in this article the French guidelines for the sickle cell disease management in adulthood. PMID- 26007620 TI - A new hereditary congenital facial palsy case supports arg5 in HOX-DNA binding domain as possible hot spot for mutations. AB - Moebius syndrome (MBS) is a rare congenital disorder characterized by rhombencephalic mal development, mainly presenting with facial palsy with limited gaze abduction. Most cases are sporadic, possibly caused by a combination of environmental and genetic factors; however, no proven specific associations have been yet established. Hereditary congenital facial palsy (HCFP) is an autosomal dominant congenital dysinnervation syndrome, recognizable by the isolated dysfunction of the seventh cranial nerve. Mutant mice for Hoxb1 were reported to present with facial weakness, resembling MBS. Recently a homozygous mutation altering arg5 residue of HOXB1 homeodomain into cys5 was identified in two families with HCFP. We screened 95 sporadic patients diagnosed as MBS or HCFP for mutations in HOXB1. A novel homozygous alteration was identified in one HCFP case, affecting the same residue, resulting to his5. In silico protein analysis predicted stronger HOXB1-DNA binding properties for his5 than cys5 that resulted to milder phenotype. It should be noted that, inclusive of the previous report, only two mutations revealed in HOXB1 associated with HCFP involved the same amino acid arg5 in HOXB1 residing in HOXB1-DNA-PBX1 ternary complex. PMID- 26007621 TI - Normothermic versus hypothermic cardiopulmonary bypass in children undergoing open heart surgery (thermic-2): study protocol for a randomized controlled trial. AB - BACKGROUND: During open heart surgery, patients are connected to a heart-lung bypass machine that pumps blood around the body ("perfusion") while the heart is stopped. Typically the blood is cooled during this procedure ("hypothermia") and warmed to normal body temperature once the operation has been completed. The main rationale for "whole body cooling" is to protect organs such as the brain, kidneys, lungs, and heart from injury during bypass by reducing the body's metabolic rate and decreasing oxygen consumption. However, hypothermic perfusion also has disadvantages that can contribute toward an extended postoperative hospital stay. Research in adults and small randomized controlled trials in children suggest some benefits to keeping the blood at normal body temperature throughout surgery ("normothermia"). However, the two techniques have not been extensively compared in children. OBJECTIVE: The Thermic-2 study will test the hypothesis that the whole body inflammatory response to the nonphysiological bypass and its detrimental effects on different organ functions may be attenuated by maintaining the body at 35 degrees C-37 degrees C (normothermic) rather than 28 degrees C (hypothermic) during pediatric complex open heart surgery. METHODS: This is a single-center, randomized controlled trial comparing the effectiveness and acceptability of normothermic versus hypothermic bypass in 141 children with congenital heart disease undergoing open heart surgery. Children having scheduled surgery to repair a heart defect not requiring deep hypothermic circulatory arrest represent the target study population. The co-primary clinical outcomes are duration of inotropic support, intubation time, and postoperative hospital stay. Secondary outcomes are in-hospital mortality and morbidity, blood loss and transfusion requirements, pre- and post-operative echocardiographic findings, routine blood gas and blood test results, renal function, cerebral function, regional oxygen saturation of blood in the cerebral cortex, assessment of genomic expression changes in cardiac tissue biopsies, and neuropsychological development. RESULTS: A total of 141 patients have been successfully randomized over 2 years and 10 months and are now being followed-up for 1 year. Results will be published in 2015. CONCLUSIONS: We believe this to be the first large pragmatic study comparing clinical outcomes during normothermic versus hypothermic bypass in complex open heart surgery in children. It is expected that this work will provide important information to improve strategies of cardiopulmonary bypass perfusion and therefore decrease the inevitable organ damage that occurs during nonphysiological body perfusion. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN93129502, http://www.isrctn.com/ISRCTN93129502 (Archived by WebCitation at http://www.webcitation.org/6Yf5VSyyG). PMID- 26007622 TI - OnabotulinumtoxinA in overactive bladder: Evidence-based consensus recommendations. AB - OBJECTIVE: To offer a set of useful recommendations for urologists who are starting to provide treatment of overactive bladders with onabotulinumtoxinA. METHODS: A literature search to December 2013 was conducted, as well as a subsequent critical reading of the selected publications. The coordinators prepared a document that was submitted for review by the members of the Spanish Group for the use of Botulinum Toxin in Urology. RESULTS: The expert group considered that onabotulinumtoxinA may be used for overactive bladder syndrome with urinary urge incontinence secondary to neurogenic or idiopathic detrusor overactivity for patients for whom conservative treatment and first-line medical treatment has failed, is not tolerated or is contraindicated. Treatment in most cases was performed with local intravesical anesthesia, although it can also be performed under epidural or general anesthesia. Patients must be informed of the possibility of requiring self-catheterization or temporary catheterization. Clinicians should ensure that the patients are capable of performing this catheterization before the treatment is conducted. Patients must also be informed of the need for antibiotic prophylaxis to reduce the risk of urinary tract infections. At least 2 follow-up visits are recommended: the first at days 7-14 after the injection and the second at 2-3 months. Reinjection is indicated when the effect of the treatment decreases. CONCLUSION: These guidelines can help clinicians in their daily decisions and limit the potential risks associated with the incorrect use of the drug. PMID- 26007623 TI - Are we moving towards the end of the prostate specific antigen era? PMID- 26007624 TI - Holmium laser enucleation of the prostate and retropubic prostatic adenomectomy: morbidity analysis and anesthesia considerations. AB - OBJECTIVE: Holmium laser enucleation of the prostate (HoLEP) is an alternative to prostatic adenomectomy for the surgical treatment of benign prostatic hypertrophy. We analyzed our learning curve for this technique, and we compared it in a secondary manner with prostatic adenomectomy. MATERIALS AND METHODS: A retrospective comparative study was conducted that included the first 100 cases of HoLEP performed in our center and the latest 50 cases of retropubic adenomectomy. We collected data on the patients, the surgery, the anesthesia, the perioperative variables, the anesthesia complications and the postoperative variables, with a 6-month follow-up. We analyzed the learning curve without mentors for HoLEP and compared the characteristics of HoLEP in 2 separate phases (learning and stabilization phases) with the latest retropubic prostatic adenomectomies performed. RESULTS: Intradural anesthesia was the most common technique. The transfusion needs, length of stay (P<.01) and postoperative morbidity were lower for HoLEP than for adenomectomy. However, the retropubic adenomectomy group had larger initial prostate volumes (P<.001) and shorter surgical times (P<.001). Better surgical performance (P<.001) and a lower incidence of complications were observed in the HoLEP-B group (once the learning curve had been overcome) compared with the HoLEP-A group. CONCLUSION: In our center, HoLEP was introduced as a valid alternative to open retropubic adenomectomy, with excellent results in terms of morbidity and reduced hospital stay. In terms of the learning curve, we consider that approximately 50 patients (without mentor) is an appropriate cutoff. Local anesthesia is a good choice for the anesthesia technique. PMID- 26007626 TI - Acute Mediastinitis as a Complication of Epstein-Barr Virus. AB - Acute mediastinitis is a rare, potentially life-threatening condition that is most commonly seen as a complication of esophageal perforations or cardiac surgery. The term "descending necrotizing mediastinitis" (DNM) is used to describe oropharyngeal infections that spread to the mediastinum, most commonly following odontogenic infections, peritonsillar or retropharyngeal abscesses, cervical lymphadenitis, trauma, or endotracheal intubation. Infectious mononucleosis is another rare cause of DNM. The mortality of acute mediastinitis is high, while the mortality for DNM is even higher. Major determinants of mortality are delayed diagnosis and/or treatment. While DNM is seen infrequently, its severe nature makes it essential that emergency physicians consider the diagnosis in patients presenting with upper respiratory infections, chest pain, and systemic symptoms, and also in patients with a recent diagnosis of EBV, in order to mitigate a high rate of morbidity and mortality. PMID- 26007627 TI - Endoscopic Plantar Fasciotomy Improves Early Postoperative Results: A Retrospective Comparison of Outcomes After Endoscopic Versus Open Plantar Fasciotomy. AB - Plantar fasciotomy is offered to patients with recalcitrant plantar fasciitis. Few studies have characterized the functional outcomes over time for the endoscopic approach compared with the open approach. We hypothesized that patients undergoing endoscopic surgery will have better postoperative functional outcomes early in the postoperative period but equivalent long-term outcomes compared with patients undergoing open surgery. We analyzed the prospectively collected data of all patients undergoing plantar fasciotomy at our institution from December 2007 to August 2014. A total of 42 feet of 38 patients were included in the analysis. The clinical data were collected preoperatively and at 3 and 6 months and 1 year. The functional outcomes analyzed included the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scale, the Medical Outcomes Study, Short-Form, 36-item Health Survey, and patient satisfaction and expectations. Patients undergoing endoscopic surgery had significantly greater American Orthopaedic Foot and Ankle Society Ankle-Hindfoot and SF-36 Health Survey scores and lower pain scores at the 3-month period. They were also significantly more likely to be satisfied with and have had their expectations met by surgery. Compared with the open approach, the patients who had undergone endoscopic plantar fasciotomy experienced significantly greater improvements in the subjective and objective functional outcomes, with less pain and greater satisfaction, and had had their expectations met earlier in the recovery period, with equivalent long-term outcomes, compared with the patients who had undergone open plantar fasciotomy. PMID- 26007625 TI - Applications of two-dimensional infrared spectroscopy. AB - Two-dimensional infrared (2D IR) spectroscopy has recently emerged as a powerful tool with applications in many areas of scientific research. The inherent high time resolution coupled with bond-specific spatial resolution of IR spectroscopy enable direct characterization of rapidly interconverting species and fast processes, even in complex systems found in chemistry and biology. In this minireview, we briefly outline the fundamental principles and experimental procedures of 2D IR spectroscopy. Using illustrative example studies, we explain the important features of 2D IR spectra and their capability to elucidate molecular structure and dynamics. Primarily, this minireview aims to convey the scope and potential of 2D IR spectroscopy by highlighting select examples of recent applications including the use of innate or introduced vibrational probes for the study of nucleic acids, peptides/proteins, and materials. PMID- 26007628 TI - Short-Term Clinical Outcome of Hemiarthroplasty Versus Arthrodesis for End-Stage Hallux Rigidus. AB - Few data are available to compare the outcomes of first metatarsophalangeal joint (MTPJ) hemiarthroplasty and arthrodesis. We included 46 patients who had undergone BioPro((r)) first MTPJ hemiarthroplasty and 132 who had undergone arthrodesis, with a minimum follow-up duration of 12 months. The primary outcome was patient satisfaction, which was determined using binominal questions. The Foot and Ankle Outcome Score, Foot Function Index, and Numerical Rating Scale for pain and limitations questionnaires were also used. The secondary outcome was treatment failure. No differences were found in the satisfaction rate (p = .54) after a median period of 38.4 (range 12 to 96) months and 39.8 (range 12 to 96) months in the hemiarthroplasty and arthrodesis patients, respectively. Furthermore, no differences were found in the failure rates (p = .93) or the interval to failure (p = .32).The results of the present study showed no significant differences in the short-term clinical outcomes and failure rates for BioPro((r)) first MTPJ hemiarthroplasty and arthrodesis. Prospective comparative studies are required to determine whether BioPro((r)) first MTPJ hemiarthroplasty is a good alternative for first MTPJ arthrodesis in the long term. PMID- 26007629 TI - Early Research on the Localization of the Primary Gustatory Cortex. PMID- 26007631 TI - Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: A literature review. AB - OBJECTIVE: Since its introduction 50 years ago, the contraceptive pill has continuously evolved to decrease the risk of venous thromboembolism (VTE) associated with its use. An increased risk of VTE still remains, however. Other concerns, such as effects on lipid and carbohydrate metabolism, have also been reported. In this study we compared two reference combined oral contraceptives (COCs) containing ethinylestradiol (EE)/levonorgestrel (LNG) and EE/drospirenone (DRSP) with COCs containing estradiol (E2) (estradiol valerate [E2V]/dienogest [DNG] and E2/nomegestrol acetate [NOMAC]). They were evaluated according to their influence on recognised haemostatic and metabolic markers. METHODS: A literature search of the MEDLINE/PubMed database was conducted for head-to-head studies. EE/LNG was chosen as the comparator pill. RESULTS: The haemostatic impact of E2 pills and EE/LNG has been extensively compared, in contrast to that of EE/DRSP and EE/LNG. Changes in haemostatic and metabolic marker levels between EE/LNG and E2V/DNG were generally not statistically significant. E2/NOMAC showed statistically significantly favourable results on haemostatic markers and had a neutral effect on carbohydrate and lipid metabolism when compared with EE/LNG. CONCLUSION: E2/NOMAC exhibits less haemostatic and metabolic impact than EE/LNG and other COCs, suggesting that it may be a promising candidate to reduce residual VTE risk associated with COC use. Confirmation from a well-powered prospective clinical trial is, however, needed. PMID- 26007630 TI - Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma. AB - Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 * 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 * 10(-9) and P=6.4 * 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024). PMID- 26007633 TI - "Control-alt-delete": rebooting solutions for the E-waste problem. AB - A number of efforts have been launched to solve the global electronic waste (e waste) problem. The efficiency of e-waste recycling is subject to variable national legislation, technical capacity, consumer participation, and even detoxification. E-waste management activities result in procedural irregularities and risk disparities across national boundaries. We review these variables to reveal opportunities for research and policy to reduce the risks from accumulating e-waste and ineffective recycling. Full regulation and consumer participation should be controlled and reinforced to improve local e-waste system. Aiming at standardizing best practice, we alter and identify modular recycling process and infrastructure in eco-industrial parks that will be expectantly effective in countries and regions to handle the similar e-waste stream. Toxicity can be deleted through material substitution and detoxification during the life cycle of electronics. Based on the idea of "Control-Alt-Delete", four patterns of the way forward for global e-waste recycling are proposed to meet a variety of local situations. PMID- 26007632 TI - Fish consumption and resilience to depression in Japanese company workers: a cross-sectional study. AB - BACKGROUND: Depression is a common disorder that is influenced by psychosocial factors in the workplace. Increasing resilience, the ability to cope with stress in the face of adversity, is considered an important strategy to prevent depression. It has been suggested that consumption of fish, which is a major source of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA), may prevent depression. However, associations between depression, resilience, and fish consumption have not been documented. The aim of the study is to investigate the association between fish consumption and resilience to depression. METHODS: Participants were 527 Japanese employees at three worksites of a large company. The Center for Epidemiologic Studies Depression (CES-D) Scale was administered to assess depressive symptoms, and the 14-item Resilience Scale (RS-14) was administered to assess resilience. A self-report questionnaire extracted from the Food Frequency Questionnaire was used to measure fish consumption frequency. Regression analyses were conducted to assess a mediation model based on a statistical analysis framework defined by Baron and Kenny. The indirect association of resilience was calculated with the bootstrapping method. Each analysis was adjusted by age, sex, marital status, work position, and educational background. RESULTS: The association between fish consumption frequency and total CES-D score was significant (B=-0.94; p=0.011). The association between fish consumption frequency and total RS-14 score was significant (B=1.4; p=0.010), as was association total RS-14 score and the total CES-D score (B=-0.34; p<0.001). When controlling for total RS-14 score, there was no longer a significant association between fish consumption frequency and total CES-D score. The bootstrapping results revealed that significant indirect association though fish consumption frequency and total CES-D score (bias corrected and accelerated confidence interval=-0.83 to -0.13; 95% confidence interval) through total RS-14 score. CONCLUSIONS: Fish consumption might be associated with resilience to depression. Further studies are needed, particularly double blind randomized placebo controlled intervention trials on the potential preventative effect of LC n-3 PUFA on resilience to depression. PMID- 26007634 TI - Systematic review with meta-analysis: HIF-1alpha attenuates liver ischemia reperfusion injury. AB - Ischemia-reperfusion injury (IRI) induces inevitable complications in liver transplantation. Many studies have demonstrated that hypoxia-inducible factor 1alpha (HIF-1alpha) plays an important role in IRI. However, the mechanism of its pleiotropic effect remains unclear. This systematic review provides a comprehensive evaluation of all available evidence concerning the function of HIF 1alpha in transplant-induced hepatic IRI. Data were obtained through a search of Medline (PubMed), Embase, and the Cochrane Library literature review on the effect of HIF-1alpha in IRI (from inception to 12/2014). RevMan was used to calculate standardized mean difference (SMD) and 95% confidence intervals (CIs). Forty articles met inclusion criteria with 2 clinical and 38 basic studies. Two clinical trials (n = 68) revealed ischemic preconditioning (IPC) aroused protection after hepatic IRI based on the higher level of HIF-1alpha in IPC group compared with control group. In vitro studies confirmed the salutary effect of IPC disappearance in the inhabitation of stabilized HIF-1alpha. In vivo animal studies showed different HIF-1alpha expression and distribution patterns in the ischemia and reperfusion stage due to distinctive partial oxygen pressure gradient intra-liver, and 5 animal studies (n=66) showed that stabilized HIF 1alpha treatment was associated with lower alanine aminotransferase (ALT) (SMD = 1.58; 95% CI =- 2.65, -0.52) when compared with unstabilized HIF-1alpha group. Not only decreased liver IR injury, stabilized HIF-1alpha during the acute phase of IR could also promote graft regeneration capacity leading to better initial function and survival rate. More rigorous studies are needed to gauge the effectiveness due to insufficient sample size and possible publication bias. PMID- 26007635 TI - Opinions of Romanian Dental Students Toward Tobacco Use Interventions in the Dental Setting. AB - The aim of the present study was to assess smoking habits as well as attitudes toward smoking cessation counseling among Romanian dental students in order to build an evidence base for further undergraduate curriculum development. A 38 item self-administered questionnaire was delivered to first to sixth dental students enrolled at the University "Lucian Blaga" Sibiu. The questionnaire covered sociodemographics, smoking habits, knowledge concerning health effects, attitudes, and confidence toward smoking cessation counseling. Smoking was reported by 37 % of participants and was more prevalent among clinical (48.98 %) than preclinical (29.58 %) and basic science students (35.93 %). Students' knowledge that tobacco affects general and oral/dental health and knowledge of dental students regarding the smoking and alcohol behavior taken during medical history varied according to academic year and smoking status, but not according to gender. Only 51.1 % of all students agreed or strongly agreed that they were adequately trained to provide tobacco cessation education. 58.6 %, respectively 52.9 %, strongly agreed that is part of their role as a dentist to assist their patients to stop smoking and to prevent patients from starting to use tobacco products, while only 35.8 % believed that smoking cessation counseling provided by a dentist can be effective in helping patients stop smoking. The main determinants of student's attitudes toward smoking cessation counseling were academic year, clinical experience in the dental settings, and knowledge of smoking adverse effects. Dental school should offer adequate training in tobacco dependence and available continuing education in tobacco intervention in aim to encourage oral health care practitioners to have up-to-date information in aim to play their role effectively in the overall smoking cessation and prevention activities. PMID- 26007636 TI - "Everybody Knows Everybody Else's Business"-Privacy in Rural Communities. AB - Patients have a right to privacy in a health care setting. This involves conversational discretion, security of medical records and physical privacy of remaining unnoticed or unidentified when using health care services other than by those who need to know or whom the patient wishes to know. However, the privacy of cancer patients who live in rural areas is more difficult to protect due to the characteristics of rural communities. The purpose of this article is to reflect on concerns relating to the lack of privacy experienced by cancer patients and health care professionals in the rural health care setting. In addition, this article suggests future research directions to provide much needed evidence for educating health care providers and guiding health care policies that can lead to better protection of privacy among cancer patients living in rural communities. PMID- 26007637 TI - A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels. AB - Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE). It has been proposed that the disease severity rests on the inhibitory impact of mutations on M current density. Here, we have analyzed the phenotype of 7 patients carrying the p.A294V mutation located on the S6 segment of the Kv7.2 pore domain (Kv7.2(A294V)). We investigated the functional and subcellular consequences of this mutation and compared it to another mutation (Kv7.2(A294G)) associated with a benign epilepsy and affecting the same residue. We report that all the patients carrying the p.A294V mutation presented the clinical and EEG characteristics of EOEE. In CHO cells, the total expression of Kv7.2(A294V) alone, assessed by western blotting, was only 20% compared to wild type. No measurable current was recorded in CHO cells expressing Kv7.2(A294V) channel alone. Although the total Kv7.2(A294V) expression was rescued to wild type levels in cells co-expressing the Kv7.3 subunit, the global current density was still reduced by 83% compared to wild-type heteromeric channel. In a configuration mimicking the patients' heterozygous genotype i.e., Kv7.2(A294V)/Kv7.2/Kv7.3, the global current density was reduced by 30%. In contrast to Kv7.2(A294V), the current density of homomeric Kv7.2(A294G) was not significantly changed compared to wild-type Kv7.2. However, the current density of Kv7.2(A294G)/Kv7.2/Kv7.3 and Kv7.2(A294G)/Kv7.3 channels were reduced by 30% and 50% respectively, compared to wild-type Kv7.2/Kv7.3. In neurons, the p.A294V mutation induced a mislocalization of heteromeric mutant channels to the somato dendritic compartment, while the p.A294G mutation did not affect the localization of the heteromeric channels to the axon initial segment. We conclude that this position is a hotspot of mutation that can give rise to a severe or a benign epilepsy. The p.A294V mutation does not exert a dominant-negative effect on wild type subunits but alters the preferential axonal targeting of heteromeric Kv7 channels. Our data suggest that the disease severity is not necessarily a consequence of a strong inhibition of M current and that additional mechanisms such as abnormal subcellular distribution of Kv7 channels could be determinant. PMID- 26007638 TI - The deubiquitinase ataxin-3 requires Rad23 and DnaJ-1 for its neuroprotective role in Drosophila melanogaster. AB - Ataxin-3 is a deubiquitinase and polyglutamine (polyQ) disease protein with a protective role in Drosophila melanogaster models of neurodegeneration. In the fruit fly, wild-type ataxin-3 suppresses toxicity from several polyQ disease proteins, including a pathogenic version of itself that causes spinocerebellar ataxia type 3 and pathogenic huntingtin, which causes Huntington's disease. The molecular partners of ataxin-3 in this protective function are unclear. Here, we report that ataxin-3 requires its direct interaction with the ubiquitin-binding and proteasome-associated protein, Rad23 (known as hHR23A/B in mammals) in order to suppress toxicity from polyQ species in Drosophila. According to additional studies, ataxin-3 does not rely on autophagy or the proteasome to suppress polyQ dependent toxicity in fly eyes. Instead this deubiquitinase, through its interaction with Rad23, leads to increased protein levels of the co-chaperone DnaJ-1 and depends on it to protect against degeneration. Through DnaJ-1, our data connect ataxin-3 and Rad23 to protective processes involved with protein folding rather than increased turnover of toxic polyQ species. PMID- 26007640 TI - Re: Craig Rogers, Ravi Barod, Scott Schwartz, Mani Menon. Endovascular extraction of caval tumor thrombus to facilitate minimally invasive cytoreductive nephrectomy for metastatic kidney cancer. Eur Urol 2015;68:167-8. PMID- 26007639 TI - Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect. AB - BACKGROUND: Numerous studies have focused on the association between endocrine disrupting chemicals (EDCs) and hypospadias. Phenotype variability, the absence of representative comparison groups and concomitant genetic testing prevent any definitive conclusions. OBJECTIVE: To identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias. DESIGN, SETTING, AND PARTICIPANTS: A total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009-2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs. Environmental exposure was estimated using the zip code, the type of surrounding hazards, and distance from these hazards. Multivariate analysis was performed. RESULTS: Fetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias (40.00% vs 17.55%, odds ratio 3.13, 95% confidence interval 2.11-4.65). The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys (19.73% vs 10.26%, p=0.0019), especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias (40.13% vs 27.48%, p=0.02). Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys (13.29% vs. 6.64%, p<0.00005). Association of occupational and environmental exposures increases this risk. CONCLUSIONS: This multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk. PATIENT SUMMARY: Our multi-institutional study showed that parental professional, occupational, and environmental exposures to chemical products increase the risk of hypospadias in children. PMID- 26007641 TI - Apelin receptors: From signaling to antidiabetic strategy. AB - The G protein-coupled receptor APJ and its cognate ligand, apelin, are widely expressed throughout human body. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, fluid homeostasis and energy metabolism regulation. On the other hand, this couple ligand-receptor is also involved in the development and progression of different pathologies including diabetes, obesity, cardiovascular disease and cancer. Recently, a new endogenous peptidic ligand of APJ, named Elabela/Toddler, has been identified and shown to play a crucial role in embryonic development. Whereas nothing is yet known regarding Elabela/Toddler functions in adulthood, apelin has been extensively described as a beneficial adipokine regarding to glucose and lipid metabolism and is endowed with anti-diabetic and anti-obesity properties. Indeed, there is a growing body of evidence supporting apelin signaling as a novel promising therapeutic target for metabolic disorders (obesity, type 2 diabetes). In this review, we provide an overview of the pharmacological properties of APJ and its endogenous ligands. We also report the activity of peptidic and non-peptidic agonists and antagonists targeting APJ described in the literature. Finally, we highlight the important role of this signaling pathway in the control of energy metabolism at the peripheral level and in the central nervous system in both physiological conditions and during obesity or diabetes. PMID- 26007642 TI - Role of thymol on hyperglycemia and hyperlipidemia in high fat diet-induced type 2 diabetic C57BL/6J mice. AB - Thymol is a monoterpene phenol with many pharmacological activities, but their anti- hyperglycemic and anti-hyperlipidemic activities are not yet explored. This study evaluates the beneficial effects of thymol on plasma, hepatic lipids and hyperglycaemic effects in high-fat diet (HFD) induced type 2 diabetes in C57BL/6J mice. These mice were fed continuously with high fat diet (fat- 35.8%) for 10 weeks and subjected to intragastric administration of various doses (10mg, 20mg and 40mg/kg body weight (BW)) of thymol daily for the subsequent 5 weeks. Body weight (BW), food intake, plasma glucose, insulin, insulin resistance, HbA1c, leptin and adiponectin were significantly decreased and there was an increase in food efficacy ratio. Thymol supplementation were significantly lowered the concentration of plasma triglyceride (TG), total cholesterol (TC), free fatty acids (FFAs), low density lipoprotein (LDL) and increased high density lipoprotein (HDL) cholesterol as compared to the HFD induced diabetic group due to lipid enzymatic activity. Also, the hepatic lipid contents such as triglycerides, total cholesterol, free fatty acid and phospholipids (PL) were significantly lowered in the thymol supplemented groups. As compared to other two tested doses of 10mg and 20mg, thymol (40mg/kg BW) were showed significant protective effect on the parameters studied. Thus, indicate thymol protects C57BL/6J mice against HFD due to its anti-hyperglycaemic and anti-hyperlipidemic activity. The above outcome concludes that thymol may exhibit promising anti diabetic activity. PMID- 26007643 TI - Apigenin, a natural flavonoid, inhibits glutamate release in the rat hippocampus. AB - The purpose of this study was to examine the effect and mechanism of apigenin, a natural flavonoid, on glutamate release in the rat hippocampus. In rat hippocampal nerve terminals (synaptosomes), apigenin inhibited glutamate release and the elevation of the cytosolic free Ca(2+) concentration evoked by 4 aminopyridine, whereas it had no effect on 4-aminopyridine-mediated depolarization and Na(+) influx. The apigenin-mediated inhibition of evoked glutamate release was prevented by chelating the extracellular Ca(2+) ions and blocking Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel activity. Furthermore, we determined that gamma-aminobutyric acid type A (GABAA) receptors are present in the hippocampal nerve terminals because they are colocalized with the presynaptic marker synaptophysin. However, the effect of apigenin on 4-aminopyridine-evoked glutamate release from synaptosomes was unaffected by the GABAA receptor antagonists SR95531 and bicuculline. Furthermore, in slice preparations, whole cell patch-clamp experiments showed that apigenin reduced the frequency of spontaneous excitatory postsynaptic currents without affecting their amplitude, suggesting a presynaptic mechanism. On the basis of these results, we suggested that apigenin exerts its presynaptic inhibition probably by reducing Ca(2+) entry mediated by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, thereby inhibiting glutamate release from the rat hippocampal nerve terminals. PMID- 26007644 TI - Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins. AB - CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10mg/kg), simvastatin (30mg/kg), atorvastatin (30mg/kg), simvastatin+CoQ10 or atorvastatin+CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10. PMID- 26007646 TI - Trans-arterial chemoembolization and external beam radiation therapy for treatment of hepatocellular carcinoma with a tumor thrombus in the inferior vena cava and right atrium. AB - BACKGROUND: Hepatocellular carcinoma (HCC) with a tumor thrombus in the inferior vena cava (IVC) and right atrium (RA) rarely occurs and is usually associated with extremely poor prognosis, we carried out this study to evaluate the efficacy and safety of a combination of trans-arterial chemoembolization (TACE) and external beam radiation therapy (EBRT) in the treatment of HCC with a tumor thrombus in the IVC and RA. METHODS: From September 2005 to September 2008, 11 cases of HCC with a tumor thrombus in the IVC and RA were treated with a combination of TACE and EBRT. Clinical adverse events, laboratory toxicity, and survival were retrospectively studied. RESULTS: Thirty-one interventional procedures were conducted and EBRT was performed 11 times. All treatments were successful and without significant complications. No severe adverse effects were observed. The median survival time of the 11 cases was 21.0 months. One patient was monitored for 97 months and no recurrence was observed. CONCLUSION: The combination of TACE and EBRT can be safely performed and may improve the prognosis of the HCC cases with a tumor thrombus in the IVC and RA. PMID- 26007645 TI - The opioid antagonist, beta-funaltrexamine, inhibits NF-kappaB signaling and chemokine expression in human astrocytes and in mice. AB - Opioid-immune crosstalk occurs when opioid drugs alter the activity of the immune system. In this study, the opioid antagonist beta-funaltrexamine (beta-FNA) decreases the expression and release of an inflammatory chemokine, interferon gamma inducible protein-10 (CXCL10) from normal human astrocytes stimulated by interleukin 1beta (IL-1beta). beta-FNA decreased CXCL10 by an unknown action that did not involve the mu opioid receptor (MOR). As IL-1beta acts through its receptor to activate NF-kappaB/MAPK signaling pathways which leads to CXCL10 expression and release, key steps in the IL-1beta signaling pathways were examined following beta-FNA treatment. IL-1beta-induced activation of p38 mitogen activated protein kinases (p38 MAPK) was inhibited by beta-FNA as shown by decreased p38 MAPK phosphorylation in treated cells. beta-FNA also decreased the levels of activated subunits of NF-kappaB (p50 and p65) in treated astrocytes. The impact of beta-FNA was also observed in proteins that act to negatively regulate NF-kappaB signaling. IL-1beta upregulated the expression of A20, a ubiquitin (Ub)-editing enzyme that dampens NF-kappaB signaling by altering ubiquination patterns on IL-1 receptor second messengers, and the increase in A20 was significantly inhibited by beta-FNA treatment. Inhibition of the Ub activating enzyme E1 by the inhibitor PYR41 also decreased CXCL10 release, like beta-FNA, and concurrent treatment with both PYR41 and beta-FNA inhibited CXCL10 more than did either agent alone. In mice, lipopolysaccharide-induced CXCL10 expression in the brain was inhibited by treatment with beta-FNA. These findings suggest that beta-FNA exerts an anti-inflammatory action in vitro and in vivo that is MOR-independent and possibly due to the alkylating ability of beta-FNA. PMID- 26007647 TI - Indo-Canadian Collaboration for Suicide Prevention: Training Needs Assessment for Healthcare Professionals in India. AB - The main purpose of the study was to conduct a comprehensive needs assessment of primary healthcare professionals in order to develop a training program aimed at enhancing competencies in suicide risk assessment and management. A total of 144 primary healthcare professionals (physicians = 46; primary care workers = 98) completed the needs assessment questionnaire. The majority of healthcare professionals rated their level of comfort and competence in assessing, treating, and referring suicidal patients as medium or high. However, their knowledge about suicide, risk factors for suicide, asking about suicidal behaviour, and helping a suicidal patient was rated low or medium. Overall, the scarcity of qualified healthcare professionals and the existing gaps in core competencies for suicide risk assessment and management was identified. Development of innovative and effective competencies-based suicide specific training for primary care providers in India is urgently required. PMID- 26007648 TI - Focus on Exercise: Client and Clinician Perspectives on Exercise in Individuals with Serious Mental Illness. AB - The health benefits of exercise are well established, yet individuals with serious mental illness (SMI) have a shorter life expectancy due in large part to physical health complications associated with poor diet and lack of exercise. There is a paucity of research examining exercise in this population with the majority of studies having examined interventions with limited feasibility and sustainability. Before developing an intervention, a thorough exploration of client and clinician perspectives on exercise and its associated barriers is warranted. Twelve clients and fourteen clinicians participated in focus groups aimed at examining exercise, barriers, incentives, and attitudes about walking groups. Results indicated that clients and clinicians identified walking as the primary form of exercise, yet barriers impeded consistent participation. Distinct themes arose between groups; however, both clients and clinicians reported interest in a combination group/pedometer based walking program for individuals with SMI. Future research should consider examining walking programs for this population. PMID- 26007649 TI - Gene target specificity of the Super Elongation Complex (SEC) family: how HIV-1 Tat employs selected SEC members to activate viral transcription. AB - The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes. Although they can dimerize, it is unclear whether the dimers exist and function within a SEC in vivo. Furthermore, it is unknown whether AFF1 and AFF4 function similarly in mediating SEC-dependent activation of diverse genes. Providing answers to these questions, our current study shows that AFF1 and AFF4 reside in separate SECs that display largely distinct gene target specificities. While the AFF1-SEC is more potent in supporting HIV-1 transactivation by the viral Tat protein, the AFF4-SEC is more important for HSP70 induction upon heat shock. The functional difference between AFF1 and AFF4 in Tat-transactivation has been traced to a single amino acid variation between the two proteins, which causes them to enhance the affinity of Tat for P-TEFb, a key SEC component, with different efficiency. Finally, genome-wide analysis confirms that the genes regulated by AFF1-SEC and AFF4-SEC are largely non overlapping and perform distinct functions. Thus, the SEC represents a family of related complexes that exist to increase the regulatory diversity and gene control options during transactivation of diverse cellular and viral genes. PMID- 26007650 TI - LYRA, a webserver for lymphocyte receptor structural modeling. AB - The accurate structural modeling of B- and T-cell receptors is fundamental to gain a detailed insight in the mechanisms underlying immunity and in developing new drugs and therapies. The LYRA (LYmphocyte Receptor Automated modeling) web server (http://www.cbs.dtu.dk/services/LYRA/) implements a complete and automated method for building of B- and T-cell receptor structural models starting from their amino acid sequence alone. The webserver is freely available and easy to use for non-specialists. Upon submission, LYRA automatically generates alignments using ad hoc profiles, predicts the structural class of each hypervariable loop, selects the best templates in an automatic fashion, and provides within minutes a complete 3D model that can be downloaded or inspected online. Experienced users can manually select or exclude template structures according to case specific information. LYRA is based on the canonical structure method, that in the last 30 years has been successfully used to generate antibody models of high accuracy, and in our benchmarks this approach proves to achieve similarly good results on TCR modeling, with a benchmarked average RMSD accuracy of 1.29 and 1.48 A for B- and T-cell receptors, respectively. To the best of our knowledge, LYRA is the first automated server for the prediction of TCR structure. PMID- 26007651 TI - Disturbance-free rapid solution exchange for magnetic tweezers single-molecule studies. AB - Single-molecule manipulation technologies have been extensively applied to studies of the structures and interactions of DNA and proteins. An important aspect of such studies is to obtain the dynamics of interactions; however the initial binding is often difficult to obtain due to large mechanical perturbation during solution introduction. Here, we report a simple disturbance-free rapid solution exchange method for magnetic tweezers single-molecule manipulation experiments, which is achieved by tethering the molecules inside microwells (typical dimensions-diameter (D): 40-50 MUm, height (H): 100 MUm; H:D~2:1). Our simulations and experiments show that the flow speed can be reduced by several orders of magnitude near the bottom of the microwells from that in the flow chamber, effectively eliminating the flow disturbance to molecules tethered in the microwells. We demonstrate a wide scope of applications of this method by measuring the force dependent DNA structural transitions in response to solution condition change, and polymerization dynamics of RecA on ssDNA/SSB-coated ssDNA/dsDNA of various tether lengths under constant forces, as well as the dynamics of vinculin binding to alpha-catenin at a constant force (< 5 pN) applied to the alpha-catenin protein. PMID- 26007652 TI - Tailor: a computational framework for detecting non-templated tailing of small silencing RNAs. AB - Small silencing RNAs, including microRNAs, endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs), have been shown to play important roles in fine-tuning gene expression, defending virus and controlling transposons. Loss of small silencing RNAs or components in their pathways often leads to severe developmental defects, including lethality and sterility. Recently, non-templated addition of nucleotides to the 3' end, namely tailing, was found to associate with the processing and stability of small silencing RNAs. Next Generation Sequencing has made it possible to detect such modifications at nucleotide resolution in an unprecedented throughput. Unfortunately, detecting such events from millions of short reads confounded by sequencing errors and RNA editing is still a tricky problem. Here, we developed a computational framework, Tailor, driven by an efficient and accurate aligner specifically designed for capturing the tailing events directly from the alignments without extensive post processing. The performance of Tailor was fully tested and compared favorably with other general-purpose aligners using both simulated and real datasets for tailing analysis. Moreover, to show the broad utility of Tailor, we used Tailor to reanalyze published datasets and revealed novel findings worth further experimental validation. The source code and the executable binaries are freely available at https://github.com/jhhung/Tailor. PMID- 26007653 TI - StemChecker: a web-based tool to discover and explore stemness signatures in gene sets. AB - Stem cells present unique regenerative abilities, offering great potential for treatment of prevalent pathologies such as diabetes, neurodegenerative and heart diseases. Various research groups dedicated significant effort to identify sets of genes-so-called stemness signatures-considered essential to define stem cells. However, their usage has been hindered by the lack of comprehensive resources and easy-to-use tools. For this we developed StemChecker, a novel stemness analysis tool, based on the curation of nearly fifty published stemness signatures defined by gene expression, RNAi screens, Transcription Factor (TF) binding sites, literature reviews and computational approaches. StemChecker allows researchers to explore the presence of stemness signatures in user-defined gene sets, without carrying-out lengthy literature curation or data processing. To assist in exploring underlying regulatory mechanisms, we collected over 80 target gene sets of TFs associated with pluri- or multipotency. StemChecker presents an intuitive graphical display, as well as detailed statistical results in table format, which helps revealing transcriptionally regulatory programs, indicating the putative involvement of stemness-associated processes in diseases like cancer. Overall, StemChecker substantially expands the available repertoire of online tools, designed to assist the stem cell biology, developmental biology, regenerative medicine and human disease research community. StemChecker is freely accessible at http://stemchecker.sysbiolab.eu. PMID- 26007654 TI - Regulation of the Type I-F CRISPR-Cas system by CRP-cAMP and GalM controls spacer acquisition and interference. AB - The CRISPR-Cas prokaryotic 'adaptive immune systems' represent a sophisticated defence strategy providing bacteria and archaea with protection from invading genetic elements, such as bacteriophages or plasmids. Despite intensive research into their mechanism and application, how CRISPR-Cas systems are regulated is less clear, and nothing is known about the regulation of Type I-F systems. We used Pectobacterium atrosepticum, a Gram-negative phytopathogen, to study CRISPR Cas regulation, since it contains a single Type I-F system. The CRP-cAMP complex activated the cas operon, increasing the expression of the adaptation genes cas1 and cas2-3 in addition to the genes encoding the Csy surveillance complex. Mutation of crp or cyaA (encoding adenylate cyclase) resulted in reductions in both primed spacer acquisition and interference. Furthermore, we identified a galactose mutarotase, GalM, which reduced cas operon expression in a CRP- and CyaA-dependent manner. We propose that the Type I-F system senses metabolic changes, such as sugar availability, and regulates cas genes to initiate an appropriate defence response. Indeed, elevated glucose levels reduced cas expression in a CRP- and CyaA-dependent manner. Taken together, these findings highlight that a metabolite-sensing regulatory pathway controls expression of the Type I-F CRISPR-Cas system to modulate levels of adaptation and interference. PMID- 26007655 TI - Destruction of a distal hypoxia response element abolishes trans-activation of the PAG1 gene mediated by HIF-independent chromatin looping. AB - A crucial step in the cellular adaptation to oxygen deficiency is the binding of hypoxia-inducible factors (HIFs) to hypoxia response elements (HREs) of oxygen regulated genes. Genome-wide HIF-1alpha/2alpha/beta DNA-binding studies revealed that the majority of HREs reside distant to the promoter regions, but the function of these distal HREs has only been marginally studied in the genomic context. We used chromatin immunoprecipitation (ChIP), gene editing (TALEN) and chromosome conformation capture (3C) to localize and functionally characterize a 82 kb upstream HRE that solely drives oxygen-regulated expression of the newly identified HIF target gene PAG1. PAG1, a transmembrane adaptor protein involved in Src signalling, was hypoxically induced in various cell lines and mouse tissues. ChIP and reporter gene assays demonstrated that the -82 kb HRE regulates PAG1, but not an equally distant gene further upstream, by direct interaction with HIF. Ablation of the consensus HRE motif abolished the hypoxic induction of PAG1 but not general oxygen signalling. 3C assays revealed that the -82 kb HRE physically associates with the PAG1 promoter region, independent of HIF-DNA interaction. These results demonstrate a constitutive interaction between the -82 kb HRE and the PAG1 promoter, suggesting a physiologically important rapid response to hypoxia. PMID- 26007657 TI - Two mechanisms coordinate replication termination by the Escherichia coli Tus-Ter complex. AB - The Escherichia coli replication terminator protein (Tus) binds to Ter sequences to block replication forks approaching from one direction. Here, we used single molecule and transient state kinetics to study responses of the heterologous phage T7 replisome to the Tus-Ter complex. The T7 replisome was arrested at the non-permissive end of Tus-Ter in a manner that is explained by a composite mousetrap and dynamic clamp model. An unpaired C(6) that forms a lock by binding into the cytosine binding pocket of Tus was most effective in arresting the replisome and mutation of C(6) removed the barrier. Isolated helicase was also blocked at the non-permissive end, but unexpectedly the isolated polymerase was not, unless C(6) was unpaired. Instead, the polymerase was blocked at the permissive end. This indicates that the Tus-Ter mechanism is sensitive to the translocation polarity of the DNA motor. The polymerase tracking along the template strand traps the C(6) to prevent lock formation; the helicase tracking along the other strand traps the complementary G(6) to aid lock formation. Our results are consistent with the model where strand separation by the helicase unpairs the GC(6) base pair and triggers lock formation immediately before the polymerase can sequester the C(6) base. PMID- 26007656 TI - Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells. AB - DNA methylation is thought to induce transcriptional silencing through the combination of two mechanisms: the repulsion of transcriptional activators unable to bind their target sites when methylated, and the recruitment of transcriptional repressors with specific affinity for methylated DNA. The Methyl CpG Binding Domain proteins MeCP2, MBD1 and MBD2 belong to the latter category. Here, we present MBD2 ChIPseq data obtained from the endogenous MBD2 in an isogenic cellular model of oncogenic transformation of human mammary cells. In immortalized (HMEC-hTERT) or transformed (HMLER) cells, MBD2 was found in a large proportion of methylated regions and associated with transcriptional silencing. A redistribution of MBD2 on methylated DNA occurred during oncogenic transformation, frequently independently of local DNA methylation changes. Genes downregulated during HMEC-hTERT transformation preferentially gained MBD2 on their promoter. Furthermore, depletion of MBD2 induced an upregulation of MBD2 bound genes methylated at their promoter regions, in HMLER cells. Among the 3,160 genes downregulated in transformed cells, 380 genes were methylated at their promoter regions in both cell lines, specifically associated by MBD2 in HMLER cells, and upregulated upon MBD2 depletion in HMLER. The transcriptional MBD2 dependent downregulation occurring during oncogenic transformation was also observed in two additional models of mammary cell transformation. Thus, the dynamics of MBD2 deposition across methylated DNA regions was associated with the oncogenic transformation of human mammary cells. PMID- 26007659 TI - Spring loading a pre-cleavage intermediate for hairpin telomere formation. AB - The Borrelia telomere resolvase, ResT, forms the unusual hairpin telomeres of the linear Borrelia replicons in a process referred to as telomere resolution. Telomere resolution is a DNA cleavage and rejoining reaction that proceeds from a replicated telomere intermediate in a reaction with mechanistic similarities to that catalyzed by type IB topoisomerases. Previous reports have implicated the hairpin-binding module, at the end of the N-terminal domain of ResT, in distorting the DNA between the scissile phosphates so as to promote DNA cleavage and hairpin formation by the catalytic domain. We report that unwinding the DNA between the scissile phosphates, prior to DNA cleavage, is a key cold-sensitive step in telomere resolution. Through the analysis of ResT mutants, rescued by substrate modifications that mimic DNA unwinding between the cleavage sites, we show that formation and/or stabilization of an underwound pre-cleavage intermediate depends upon cooperation of the hairpin-binding module and catalytic domain. The phenotype of the mutants argues that the pre-cleavage intermediate promotes strand ejection to favor the forward reaction and that subsequent hairpin capture is a reversible reaction step. These reaction features are proposed to promote hairpin formation over strand resealing while allowing reversal back to substrate of aborted reactions. PMID- 26007658 TI - A modular open platform for systematic functional studies under physiological conditions. AB - Any profound comprehension of gene function requires detailed information about the subcellular localization, molecular interactions and spatio-temporal dynamics of gene products. We developed a multifunctional integrase (MIN) tag for rapid and versatile genome engineering that serves not only as a genetic entry site for the Bxb1 integrase but also as a novel epitope tag for standardized detection and precipitation. For the systematic study of epigenetic factors, including Dnmt1, Dnmt3a, Dnmt3b, Tet1, Tet2, Tet3 and Uhrf1, we generated MIN-tagged embryonic stem cell lines and created a toolbox of prefabricated modules that can be integrated via Bxb1-mediated recombination. We used these functional modules to study protein interactions and their spatio-temporal dynamics as well as gene expression and specific mutations during cellular differentiation and in response to external stimuli. Our genome engineering strategy provides a versatile open platform for efficient generation of multiple isogenic cell lines to study gene function under physiological conditions. PMID- 26007660 TI - DNA3'pp5'G de-capping activity of aprataxin: effect of cap nucleoside analogs and structural basis for guanosine recognition. AB - DNA3'pp5'G caps synthesized by the 3'-PO4/5'-OH ligase RtcB have a strong impact on enzymatic reactions at DNA 3'-OH ends. Aprataxin, an enzyme that repairs A5'pp5'DNA ends formed during abortive ligation by classic 3'-OH/5'-PO4 ligases, is also a DNA 3' de-capping enzyme, converting DNAppG to DNA3'p and GMP. By taking advantage of RtcB's ability to utilize certain GTP analogs to synthesize DNAppN caps, we show that aprataxin hydrolyzes inosine and 6-O-methylguanosine caps, but is not adept at removing a deoxyguanosine cap. We report a 1.5 A crystal structure of aprataxin in a complex with GMP, which reveals that: (i) GMP binds at the same position and in the same anti nucleoside conformation as AMP; and (ii) aprataxin makes more extensive nucleobase contacts with guanine than with adenine, via a hydrogen bonding network to the guanine O6, N1, N2 base edge. Alanine mutations of catalytic residues His147 and His149 abolish DNAppG de capping activity, suggesting that the 3' de-guanylylation and 5' de-adenylylation reactions follow the same pathway of nucleotidyl transfer through a covalent aprataxin-(His147)-NMP intermediate. Alanine mutation of Asp63, which coordinates the guanosine ribose hydroxyls, impairs DNAppG de-capping. PMID- 26007661 TI - Identifying high-affinity aptamer ligands with defined cross-reactivity using high-throughput guided systematic evolution of ligands by exponential enrichment. AB - Oligonucleotide aptamers represent a novel platform for creating ligands with desired specificity, and they offer many potentially significant advantages over monoclonal antibodies in terms of feasibility, cost, and clinical applicability. However, the isolation of high-affinity aptamer ligands from random oligonucleotide pools has been challenging. Although high-throughput sequencing (HTS) promises to significantly facilitate systematic evolution of ligands by exponential enrichment (SELEX) analysis, the enormous datasets generated in the process pose new challenges for identifying those rare, high-affinity aptamers present in a given pool. We show that emulsion PCR preserves library diversity, preventing the loss of rare high-affinity aptamers that are difficult to amplify. We also demonstrate the importance of using reference targets to eliminate binding candidates with reduced specificity. Using a combination of bioinformatics and functional analyses, we show that the rate of amplification is more predictive than prevalence with respect to binding affinity and that the mutational landscape within a cluster of related aptamers can guide the identification of high-affinity aptamer ligands. Finally, we demonstrate the power of this selection process for identifying cross-species aptamers that can bind human receptors and cross-react with their murine orthologs. PMID- 26007662 TI - Aortic blood pressure measured via EIT: investigation of different measurement settings. AB - Electrical impedance tomography (EIT) allows the measurement of intra-thoracic impedance changes related to cardiovascular activity. As a safe and low-cost imaging modality, EIT is an appealing candidate for non-invasive and continuous haemodynamic monitoring. EIT has recently been shown to allow the assessment of aortic blood pressure via the estimation of the aortic pulse arrival time (PAT). However, finding the aortic signal within EIT image sequences is a challenging task: the signal has a small amplitude and is difficult to locate due to the small size of the aorta and the inherent low spatial resolution of EIT. In order to most reliably detect the aortic signal, our objective was to understand the effect of EIT measurement settings (electrode belt placement, reconstruction algorithm). This paper investigates the influence of three transversal belt placements and two commonly-used difference reconstruction algorithms (Gauss Newton and GREIT) on the measurement of aortic signals in view of aortic blood pressure estimation via EIT. A magnetic resonance imaging based three-dimensional finite element model of the haemodynamic bio-impedance properties of the human thorax was created. Two simulation experiments were performed with the aim to (1) evaluate the timing error in aortic PAT estimation and (2) quantify the strength of the aortic signal in each pixel of the EIT image sequences. Both experiments reveal better performance for images reconstructed with Gauss-Newton (with a noise figure of 0.5 or above) and a belt placement at the height of the heart or higher. According to the noise-free scenarios simulated, the uncertainty in the analysis of the aortic EIT signal is expected to induce blood pressure errors of at least +/- 1.4 mmHg. PMID- 26007663 TI - Screening of polysaccharides from tamarind, fenugreek and jackfruit seeds as pharmaceutical excipients. AB - The paper describes the isolation and screening of plant polysaccharides namely tamarind seed polysaccharide (TSP), fenugreek seed mucilage (FSM) and jackfruit seed starch (JFSS) from tamarind (Tamarindus indica L.) seeds, fenugreek (Trigonella foenum-graecum L.) seeds and jackfruit (Artocarpus heterophyllus L.) seeds, respectively. The yields of isolated dried TSP, FSM and JFSS were 47.00%, 17.36% and 18.86%, respectively. Various physicochemical properties like colour, odour, taste, solubility in water, pH and viscosity of these isolated plant polysaccharides were assessed. Isolated polysaccharide samples were subjected to some phytochemical identification tests. FTIR and (1)H NMR analyses of isolated polysaccharides were performed, which suggest the presence of sugar residues. Isolated TSP, FSM and JFSS can be used as pharmaceutical excipients in various pharmaceutical formulations. PMID- 26007665 TI - Facile preparation of smooth perovskite films for efficient meso/planar hybrid structured perovskite solar cells. AB - Smooth organolead halide perovskite films for meso/planar hybrid structured perovskite solar cells were prepared by a simple compressed air blow-drying method under ambient conditions. The resultant perovskite films show high surface coverage, leading to a device power conversion efficiency of over 10% with an open circuit voltage up to 1.003 V merely using pristine poly(3-hexylthiophene) (P3HT) as a hole transporter. PMID- 26007664 TI - Regulation of proliferation and apoptosis in human osteoblastic cells by microRNA 15b. AB - MicroRNAs (miRNAs) play an important role in proliferation and differentiation of osteoblasts. We recently reported that miR-15b acts as a positive regulator of osteoblast differentiation, whereas its functional role in osteoblastic proliferation remains not known. In this study, we found that there was increased proliferation of human osteoblastic cells (MG63) when they were transiently transfected with miR-15b inhibitor. A significant level of cell population was found to be decreased at G0/G1 phase, and increased at S and G2/M phase by miR 15b inhibitor treatment. Cyclin E1 was found to be one of the putative target genes of miR-15b, and miR-15b mimic and miR-15b inhibitor treatments in cells decreased and increased cyclin E1 expression, respectively. We further identified that the cyclin E1 3'UTR is directly targeted by miR-15b using the luciferase reporter gene system. No significant effect was found on apoptosis of MG63 cells with miR-15b inhibitor. Thus, these findings provide new insights in understanding the role of miR-15b expression as negative regulator of osteoblast proliferation. PMID- 26007666 TI - Effects of CAP-regimen Chemotherapy on Blood Redox Status in Patients with Ovarian Cancer. AB - BACKGROUND: Ovarian cancer (OC) is the most lethal of gynecologic tumors because women generally present with advanced stage disease. Platinum-based chemotherapy play a pivotal role in OC treatment. The aim of the study was to assess the effects of CAP-regimen chemotherapy on blood redox status in patients with ovarian cancer. MATERIALS AND METHODS: Patients were 132 women with primary OC with FIGO stage III-IV. Patients were examined before treatment, 3 and 14 days after the first and 3 and 14 days after the second course of CAP-regimen chemotherapy. The activity of antioxidant enzymes, the intensity of lipid peroxidation, the level of oxidative modification of proteins (OMP) were evaluated. RESULTS: We have found elevated levels of OMP products in plasma and erythrocytes of patients with ovarian cancer in comparison with donors. Our results suggest activation of lipid peroxidation in plasma and erythrocytes of ovarian cancer patients in comparison with healthy women. Sensitive and specific indicators of oxidative stress are levels of glutathione-S-transferase (sensitivity 80%, specificity 89%), diene conjugates (sensitivity 85,71%, specificity 72,73%) and OMP 430 nm (sensitivity 80%, specificity 90%) in blood plasma and the activity of catalase in erythrocytes (sensitivity 100%, specificity 89%). CONCLUSION: CAP chemotherapy in patients with ovarian cancer with FIGO stage III-IV induces radical formation and changes the homeostasis of the patient. The lipid peroxidation and antioxidant system in plasma move to a higher level of functioning, and the erythrocytes develop oxidative stress. PMID- 26007667 TI - A simulation study on the self-assembly of rod-coil-rod triblock copolymers within nanoslits. AB - Self-assembly of rod-coil-rod R4C12R4 triblock copolymers within a nanoslit is investigated by using dissipative particle dynamics simulations. Perpendicular lamellae (L?) in nonselective or weak selective slits and parallel lamellae (L?) in coil-selective slits are observed, and both are almost independent of the slit thickness. However, in the rod-selective slits, the assembled structures are strongly dependent on the slit thickness. With an increase in the slit thickness, we sequentially observe hexagonally packed cylinders (HC) of rod blocks perpendicular to surfaces in thin slits, parallel wavy lamellae, orderly packed alternating cylinders in moderate slits, a mixture structure of HC near surfaces and L? in the interior region, and finally L? in wide slits. Our simulation results reveal that the rod block and surface properties play an important role in the assembly of confined rod-coil-rod triblock copolymers. Results also illustrate the competition between the slit thickness and the length scale of lamellae in bulk for the confined copolymers in nanoslits. PMID- 26007668 TI - Organ-specific Neurodegeneration in Triple A syndrome-related Achalasia. PMID- 26007669 TI - An unusual thyroid mass. PMID- 26007670 TI - Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers. AB - BACKGROUND: The association between occupational exposure and autoimmune disease is well recognized for silica, and suspected for other inhalants. We used a large cohort to estimate the risks of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and dermatomyositis associated with silica and other occupational exposures. METHODS: We analyzed data for male Swedish construction industry employees. Exposure was defined by a job-exposure matrix for silica and for other inorganic dusts; those with other job-exposure matrix exposures but not to either of the 2 inorganic dust categories were excluded. National hospital treatment data were linked for International Classification of Diseases, 10(th) Revision-coded diagnoses of rheumatoid arthritis (seronegative and positive), systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. The 2 occupational exposures were tested as independent predictors of prospective hospital-based treatment for these diagnoses using age adjusted Poisson multivariable regression analyses to calculate relative risk (RR). RESULTS: We analyzed hospital-based treatment data (1997 through 2010) for 240,983 men aged 30 to 84 years. There were 713 incident cases of rheumatoid arthritis (467 seropositive, 195 seronegative, 51 not classified) and 128 cases combined for systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Adjusted for smoking and age, the 2 occupational exposures (silica and other inorganic dusts) were each associated with increased risk of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and dermatomyositis combined: RR 1.39 (95% confidence interval [CI], 1.17-1.64) and RR 1.31 (95% CI, 1.11-1.53), respectively. Among ever smokers, both silica and other inorganic dust exposure were associated with increased risk of rheumatoid arthritis (RRs 1.36; 95% CI, 1.11-1.68 and 1.42; 95% CI, 1.17-1.73, respectively), while among never smokers, neither exposure was associated with statistically significant increased risk of rheumatoid arthritis. CONCLUSION: This analysis reaffirms the link between occupational silica and a range of autoimmune diseases, while also suggesting that other inorganic dusts may also impart excess risk of such disease. PMID- 26007671 TI - Acute Cholecystitis at Initial Presentation of Microscopic Polyangiitis. PMID- 26007672 TI - Characteristics of contemporary patients discharged from the hospital after an acute coronary syndrome. AB - BACKGROUND: Limited contemporary data compare the clinical and psychosocial characteristics and acute management of patients hospitalized with an initial vs a recurrent episode of acute coronary disease. We describe these factors in a cohort of patients recruited from 6 hospitals in Massachusetts and Georgia after an acute coronary syndrome. MATERIALS AND METHODS: We performed structured baseline in-person interviews and medical record abstractions for 2174 eligible and consenting patients surviving hospitalization for an acute coronary syndrome between April 2011 and May 2013. RESULTS: The average patient age was 61 years, 64% were men, and 47% had a high school education or less; 29% had a low general quality of life, and 1 in 5 were cognitively impaired. Patients with a recurrent coronary episode had a greater burden of previously diagnosed comorbidities. Overall, psychosocial burden was high, and more so in those with a recurrent vs those with an initial episode. Patients with an initial coronary episode were as likely to have been treated with all 4 effective cardiac medications (51.6%) as patients with a recurrent episode (52.3%), but were significantly more likely to have undergone cardiac catheterization (97.9% vs 92.9%) and a percutaneous coronary intervention (73.7% vs 60.9%) (P < .001) during their index hospitalization. CONCLUSIONS: Patients with a first episode of acute coronary artery disease have a more favorable psychosocial profile, less comorbidity, and receive more invasive procedures but similar medical management, than patients with previously diagnosed coronary disease. Implications of the high psychosocial burden on various patient-related outcomes require investigation. PMID- 26007673 TI - Rewriting History: Fever of Unknown Origin. PMID- 26007674 TI - Approach to the patient with dysphagia. AB - Dysphagia is a fascinating symptom. It is ostensibly simple when defined by trouble swallowing, yet its subtleties in deciphering and its variations in pathophysiology almost mandate a thorough knowledge of medicine itself. With patience and careful questioning, a multitude of various disorders may be suggested before an objective test is performed. Indeed, the ability to diligently and comprehensively explore the symptom of dysphagia is not only rewarding but also a real test for a physician who prides himself or herself on good history taking. PMID- 26007675 TI - Not Simply Sinus Tachycardia. PMID- 26007677 TI - A detachable ester bond enables perfect Z-alkylations of olefins for the synthesis of tri- and tetrasubstituted alkenes. AB - 2-Vinyl-substituted phenol and an alpha-bromoester undergo a tandem esterification-alkylation reaction in the presence of a Cu-amine catalyst system to produce benzene-fused lactone. Z-Alkylated styrene is obtained after hydrolysis of the lactone with perfect selectivity. The simple protocol developed in this work opens a new avenue in the multi-substitution chemistry of alkenes. PMID- 26007676 TI - Under-pressure: Right Ventricular Infarction. PMID- 26007678 TI - New Generation CoreValve EvolutTM R 23mm Aortic Valve Prosthesis: Initial Experience. PMID- 26007679 TI - Selective Pinacol Coupling on Regeneratable Supported Acids in Sole Water. AB - Efficient pinacol coupling was developed in sole water, using a reusable heterogeneous supported acid source and zinc as cheap available metal source. This medium can be easily regenerated up to 10-fold without loss of activity. Moreover, supported acids enhance the selectivity of the pinacol coupling reaction compared with homogeneous acids. PMID- 26007681 TI - Infrared multiple photon dissociation spectrum of protonated bis(2-methoxyethyl) ether obtained with a tunable CO2 laser. AB - A moderate-resolution infrared multiple photon dissociation (IRMPD) spectrum of protonated bis(2-methoxyethyl) ether (diglyme) was obtained using a grating-tuned CO2 laser. The experimental spectrum compares well with one calculated theoretically at the MP2 level and exhibits defined peaks over the span of the CO2 laser output lines as opposed to a relatively featureless spectrum over this wavelength range obtained using free electron laser infrared radiation. The lowest energy structure corresponding to the calculated vibrational spectrum is consistent with structures previously calculated at the same level of theory. Alternative structures were calculated at lower levels of theory for comparison and investigation of the energetics of proton-heteroatom interactions. Broadening of the IRMPD action spectrum due to energetic phenomena characteristic of proton bridges was not observed and thus did not obscure the correlation between theoretical calculations and experimentally determined spectra as it may have in previous studies. PMID- 26007680 TI - Effect of nonsurgical periodontal treatment in conjunction with either systemic administration of amoxicillin and metronidazole or additional photodynamic therapy on the concentration of matrix metalloproteinases 8 and 9 in gingival crevicular fluid in patients with aggressive periodontitis. AB - BACKGROUND: To evaluate in patients with aggressive periodontitis (AgP) the effect of nonsurgical periodontal treatment in conjunction with either additional administration of systemic antibiotics (AB) or application of photodynamic therapy (PDT) on the gingival crevicular fluid (GCF) concentration of matrix metalloproteinases 8 and 9 (MMP-8 and -9). METHODS: Thirty-six patients with AgP were included in the study. Patients were randomly assigned to treatment with either scaling and root planing (SRP) followed by systemic administration of AB (e.g. Amoxicillin + Metronidazole) or SRP + PDT. The analysis of MMP-8 and -9 GCF concentrations was performed at baseline and at 3 and 6 months after treatment. Nonparametric U-Mann-Whitney test was used for comparison between groups. Changes from baseline to 3 and 6 months were analyzed with the Friedman's ANOVA test with Kendall's index of consistency. RESULTS: In the AB group, patients showed a statistically significant (p = 0.01) decrease of MMP-8 GCF level at both 3 and 6 months post treatment. In the PDT group, the change of MMP-8 GCF level was not statistically significant. Both groups showed at 3 and 6 months a decrease in MMP 9 levels. However, this change did not reach statistical significance. CONCLUSIONS: Within the limits of the present study, it may be suggested that in patients with AgP, nonsurgical periodontal therapy in conjunction with adjunctive systemic administration of amoxicilin and metronidazole is more effective in reducing GCF MMP-8 levels compared to the adjunctive use of PDT. PMID- 26007682 TI - Economic evaluation of Community Level Interventions for Pre-eclampsia (CLIP) in South Asian and African countries: a study protocol. AB - BACKGROUND: Globally, hypertensive disorders of pregnancy, particularly pre eclampsia and eclampsia, are the leading cause of maternal and neonatal mortality, and impose substantial burdens on the families of pregnant women, their communities, and healthcare systems. The Community Level Interventions for Pre-eclampsia (CLIP) Trial evaluates a package of care applied at both community and primary health centres to reduce maternal and perinatal disabilities and deaths resulting from the failure to identify and manage pre-eclampsia at the community level. Economic evaluation of health interventions can play a pivotal role in priority setting and inform policy decisions for scale-up. At present, there is a paucity of published literature on the methodology of economic evaluation of large, multi-country, community-based interventions in the area of maternal and perinatal health. This study protocol describes the application of methodology for economic evaluation of the CLIP in South Asia and Africa. METHODS: A mixed-design approach i.e. cost-effectiveness analysis (CEA) and qualitative thematic analysis will be used alongside the trial to prospectively evaluate the economic impact of CLIP from a societal perspective. Data on health resource utilization, costs, and pregnancy outcomes will be collected through structured questionnaires embedded into the pregnancy surveillance, cross sectional survey and budgetary reviews. Qualitative data will be collected through focus groups (FGs) with pregnant women, household male-decision makers, care providers, and district level health decision makers. The incremental cost effectiveness ratio will be calculated for healthcare system and societal perspectives, taking into account the country-specific model inputs (costs and outcome) from the CLIP Trial. Emerging themes from FGs will inform the design of the model, and help to interpret findings of the CEA. DISCUSSION: The World Health Organization (WHO) strongly recommends cost-effective interventions as a key aspect of achieving Millennium Development Goal (MDG)-5 (i.e. 75 % reduction in maternal mortality from 1990 levels by 2015). To date, most cost-effectiveness studies in this field have focused specifically on the diagnostic and clinical management of pre-eclampsia, yet rarely on community-based interventions in low and-middle-income countries (LMICs). This study protocol will be of interest to public health scientists and health economists undertaking community-based trials in the area of maternal and perinatal health, particularly in LMICs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01911494. PMID- 26007683 TI - Autophagy plays an important role in triptolide-induced apoptosis in cardiomyocytes. AB - Triptolide (TP), a major bioactive component isolated from the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), has been shown to exert various pharmacological effects. However, the severe toxicity of TP prevents wide clinical use. In a previous study, we reported that TP-induced mitochondria dependent apoptosis in cardiomyocytes is mediated by reactive oxygen species (ROS). Autophagy is a cellular self-digestion process and is one of the first lines of defense against oxidative stress. Additionally, recent evidence suggests that autophagy can selectively eliminate damaged mitochondria. This study investigated the role of autophagy in TP-induced cardiotoxicity. We investigated the effects of autophagy in combination with TP on apoptosis, ROS and mitochondrial function. Rat cardiomyocytes were pre-treated with chloroquine or rapamycin followed by TP. The augmentation of autophagy with rapamycin in the presence of TP substantially ameliorated the detrimental effects induced by TP, while suppression of autophagy by chloroquine accelerates TP-induced cellular damage. In addition, pre-treated with rapamycin before TP administration also attenuated TP-induced damage in Balb/c mice heart tissues. Taken together, these results suggest that TP-induced cell death can be modified by autophagy. Furthermore, induction of autophagy by rapamycin may be a potential cardioprotective role against TP-induced cardiotoxicity by facilitating removal of dysfunctional mitochondria. PMID- 26007684 TI - Spontaneous mutations of the UDP-glucose:flavonoid 3-O-glucosyltransferase gene confers pale- and dull-colored flowers in the Japanese and common morning glories. AB - MAIN CONCLUSION: UDP-glucose:flavonoid 3- O -glucosyltransferase is essential for maintaining proper production quantity, acylation, and glucosylation of anthocyanin, and defects cause pale and dull flower pigmentation in morning glories. The Japanese (Ipomoea nil) and the common (I. purpurea) morning glory display bright blue and dark purple flowers, respectively. These flowers contain acylated and glucosylated anthocyanin pigments, and a number of flower color mutants have been isolated in I. nil. Of these, the duskish mutants of I. nil produce pale- and dull-colored flowers. We found that the Duskish gene encodes UDP-glucose:flavonoid 3-O-glucosyltransferase (3GT). The duskish-1 mutation is a frameshift mutation caused by a 4-bp insertion, and duskish-2 is an insertion of a DNA transposon, Tpn10, at 1.3 kb upstream of the 3GT start codon. In the duskish-2 mutant, excision of Tpn10 is responsible for restoration of the expression of the 3GT gene. The recombinant 3GT protein displays expected 3GT enzymatic activities to catalyze 3-O-glucosylation of anthocyanidins in vitro. Anthocyanin analysis of a duskish-2 mutant and its germinal revertant showing pale and normal pigmented flowers, respectively, revealed that the mutation caused around 80 % reduction of anthocyanin accumulation. We further characterized two I. purpurea mutants showing pale brownish-red flowers, and found that they carry the same frameshift mutation in the 3GT gene. Most of the flower anthocyanins in the mutants were previously found to be anthocyanidin 3-O glucosides lacking several caffeic acid and glucose moieties that are attached to the anthocyanins in the wild-type plants. These results indicated that 3GT is essential not only for production, but also for proper acylation and glucosylation, of anthocyanin in the morning glories. PMID- 26007685 TI - Misexpression of the Niemann-Pick disease type C1 (NPC1)-like protein in Arabidopsis causes sphingolipid accumulation and reproductive defects. AB - MAIN CONCLUSION: Misexpression of the AtNPC1 - 1 and AtNPC1 - 2 genes leads to altered sphingolipid metabolism, growth impairment, and male reproductive defects in a hemizygous Arabidopsis thaliana (L.) double-mutant population. Abolishing the expression of both gene copies has lethal effects. Niemann-Pick disease type C1 is a lysosomal storage disorder caused by mutations in the NPC1 gene. At the cellular level, the disorder is characterized by the accumulation of storage lipids and lipid trafficking defects. The Arabidopsis thaliana genome contains two genes (At1g42470 and At4g38350) with weak homology to mammalian NPC1. The corresponding proteins have 11 predicted membrane-spanning regions and contain a putative sterol-sensing domain. The At1g42470 protein is localized to the plasma membrane, while At4g38350 protein has a dual localization in the plasma and tonoplast membranes. A phenotypic analysis of T-DNA insertion mutants indicated that At1g42470 and At4g38350 (designated AtNPC1-1 and AtNPC1-2, respectively) have partially redundant functions and are essential for plant reproductive viability and development. Homozygous plants impaired in the expression of both genes were not recoverable. Plants of a hemizygous AtNPC1-1/atnpc1-1/atnpc1 2/atnpc1-2 population were severely dwarfed and exhibited male gametophytic defects. These gene disruptions did not have an effect on sterol concentrations; however, hemizygous AtNPC1-1/atnpc1-1/atnpc1-2/atnpc1-2 mutants had increased fatty acid amounts. Among these, fatty acid alpha-hydroxytetracosanoic acid (h24:0) occurs in plant sphingolipids. Follow-up analyses confirmed the accumulation of significantly increased levels of sphingolipids (assayed as hydrolyzed sphingoid base component) in the hemizygous double-mutant population. Certain effects of NPC1 misexpression may be common across divergent lineages of eukaryotes (sphingolipid accumulation), while other defects (sterol accumulation) may occur only in certain groups of eukaryotic organisms. PMID- 26007686 TI - Identification and functional characterization of grapevine transporters that mediate glucose-6-phosphate uptake into plastids. AB - MAIN CONCLUSION: Two grapevine glucose-6-Pi plastidial transporters differently expressed in plant organs and in response to environmental and hormonal signals are characterized. They are involved in starch accumulation in berries and canes. In grapevine, starch accumulation in the trunk is important for winter storage of carbon and in the flower for reproductive development. Berries also accumulate starch in their plastids, which are also involved in the synthesis of aroma compounds important for fruit quality. The present work characterizes two glucose phosphate translocators (VvGPT1, VvGPT2) that control the accumulation of starch in grape amyloplasts. Three different splicing variants identified for VvGPT2 (VvGPT2alpha, VvGPT2beta and VvGPT2Omega) were more expressed in the leaves than in other organs. In contrast, VvGPT1 transcripts were more abundant in mature berries, canes and flowers than in the leaves. Expression of 35S-VvGPT1-GFP and 35S-VvGPT2Omega-GFP in tobacco leaf epidermal cells showed that the fusion proteins localized at the plastidial envelope. Complementation of the Arabidopsis pgi1-1 mutant impaired in leaf starch synthesis restored its ability to synthesize starch, demonstrating that VvGPT1 and VvGPT2Omega mediate the transport of glucose-6-Pi across the plastidial envelope. In grape cell suspensions, ABA, light and galactinol, together with sucrose and fructose, significantly increased the transcript abundance of VvGPT1, whereas VvGPT2Omega expression was affected only by sucrose. In addition, elicitation with methyl jasmonate strongly upregulated VvGPT1, VvGPT2Omega and VvPAL1, suggesting a role for GPTs in the production of secondary compounds in grapevine. Moreover, in grapevines cultivated in field conditions, VvGPT1 expression was higher in berries more exposed to the sun and subjected to higher temperatures. Although both VvGPT1 and VvGPT2 mediate the same function at the molecular level, they exhibit different expression levels and regulation in plant organs and in response to environmental and hormonal signals. PMID- 26007687 TI - Exploring natural variation of photosynthetic, primary metabolism and growth parameters in a large panel of Capsicum chinense accessions. AB - MAIN CONCLUSION: Collectively, the results presented improve upon the utility of an important genetic resource and attest to a complex genetic basis for differences in both leaf metabolism and fruit morphology between natural populations. Diversity of accessions within the same species provides an alternative method to identify physiological and metabolic traits that have large effects on growth regulation, biomass and fruit production. Here, we investigated physiological and metabolic traits as well as parameters related to plant growth and fruit production of 49 phenotypically diverse pepper accessions of Capsicum chinense grown ex situ under controlled conditions. Although single-trait analysis identified up to seven distinct groups of accessions, working with the whole data set by multivariate analyses allowed the separation of the 49 accessions in three clusters. Using all 23 measured parameters and data from the geographic origin for these accessions, positive correlations between the combined phenotypes and geographic origin were observed, supporting a robust pattern of isolation-by-distance. In addition, we found that fruit set was positively correlated with photosynthesis-related parameters, which, however, do not explain alone the differences in accession susceptibility to fruit abortion. Our results demonstrated that, although the accessions belong to the same species, they exhibit considerable natural intraspecific variation with respect to physiological and metabolic parameters, presenting diverse adaptation mechanisms and being a highly interesting source of information for plant breeders. This study also represents the first study combining photosynthetic, primary metabolism and growth parameters for Capsicum to date. PMID- 26007688 TI - Silicon in vascular plants: uptake, transport and its influence on mineral stress under acidic conditions. AB - MAIN CONCLUSION: So far, considerable advances have been achieved in understanding the mechanisms of Si uptake and transport in vascular plants. This review presents a comprehensive update about this issue, but also provides the new insights into the role of Si against mineral stresses that occur in acid soils. Such information could be helpful to understand both the differential Si uptake ability as well as the benefits of this mineral element on plants grown under acidic conditions. Silicon (Si) has been widely recognized as a beneficial element for many plant species, especially under stress conditions. In the last few years, great efforts have been made to elucidate the mechanisms involved in uptake and transport of Si by vascular plants and recently, different Si transporters have been identified. Several researches indicate that Si can alleviate various mineral stresses in plants growing under acidic conditions, including aluminium (Al) and manganese (Mn) toxicities as well as phosphorus (P) deficiency all of which are highly detrimental to crop production. This review presents recent findings concerning the influence of uptake and transport of Si on mineral stress under acidic conditions because a knowledge of this interaction provides the basis for understanding the role of Si in mitigating mineral stress in acid soils. Currently, only four Si transporters have been identified and there is little information concerning the response of Si transporters under stress conditions. More investigations are therefore needed to establish whether there is a relationship between Si transporters and the benefits of Si to plants subjected to mineral stress. Evidence presented suggests that Si supply and its subsequent accumulation in plant tissues could be exploited as a strategy to improve crop productivity on acid soils. PMID- 26007689 TI - Psychological impact of breast cancer screening in Japan. AB - OBJECTIVE: The purpose of this study was to evaluate the psychological impact of breast cancer screening by use of mammography and/or ultrasound, and to reveal factors related to psychological distress. METHODS: Three hundred and twenty women were recalled to our hospital because of suspicious malignant findings from breast cancer screening between March and November 2012. They were asked to complete three questionnaires: the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression, the Brief Coping Orientations to Problems Experienced scale (Brief COPE) for coping styles, and an original questionnaire for personal information. RESULTS: Complete data were available for 312 of 320 women (97.5 %). The median age was 45 years (range 23-73). The HADS revealed borderline or clinically significant anxiety for 70 % of the women. Family history of breast cancer, area of residence, number of times screened, number of recalls, and the period before the first visit were significantly related to psychological distress (p < 0.05). Brief COPE scores showed that self-blame, behavioral disengagement, self-distraction, use of emotional support, venting, denial, and less acceptance were related to increased anxiety. CONCLUSION: Seventy percent of women who were recalled after breast cancer screening experienced psychological distress. Thus, negative psychological impact should be regarded as an adverse effect of breast cancer screening. PMID- 26007690 TI - Sequential chemotherapy using gemcitabine + carboplatin followed by gemcitabine + carboplatin + docetaxel for advanced upper-tract urothelial cancer. AB - BACKGROUND: Retrospective evaluation of the effectiveness and adverse events (AEs) of a sequential chemotherapy regimen using gemcitabine + carboplatin (GCarbo) followed by GCarbo + docetaxel (GCarboD) for advanced upper-tract urothelial carcinoma (UTUC). METHODS: We treated 56 patients with advanced UTUC. Mean patient age was 68.9 years, creatinine clearance was 51.2 mL/min, and the observation period was 20 months. Patients received two courses of GCarbo comprising 800 mg/m(2) gemcitabine on days 1, 8, and 15, and carboplatin at an area under the curve of four on day 2. If this regimen was effective, we administered two more courses of GCarbo; if the regimen was ineffective, we switched to two courses of GCarboD (70 mg/m(2)). RESULTS: Complete (n = 3) and partial response (PR; n = 25) were achieved after GCarbo. Mean response duration was 9.7 months. Two of 17 cases achieved PR after GCarboD treatment (mean duration, 31.5 months). Median survival was 14.0 months with the GCarbo/GCarboD regimen. Responders to GCarbo therapy survived significantly longer. AEs with the GCarbo regimen included 31 instances of G3/4 blood toxicity and 8 instances of G3/4 urticaria; however, there were only 6 instances of G3/4 gastrointestinal complications. AEs with the GCarboD regimen included 16 instances of blood toxicity and 8 instances of gastrointestinal complications. Neither regimen resulted in G3/4 renal toxicity. CONCLUSIONS: GCarbo and GCarboD chemotherapy may be administered safely to patients with advanced UTUC, with or without renal dysfunction. Response to GCarbo was high (50.0 %) whereas GCarboD was of limited effectiveness for non-responders to GCarbo. PMID- 26007691 TI - Interleukin-23 Increases Intestinal Epithelial Cell Permeability In Vitro. AB - Background Breast milk has a heterogeneous composition that differs between mothers and changes throughout the first weeks after birth. The proinflammatory cytokine IL-23 has a highly variable expression in human breast milk. We hypothesize that IL-23 found in human breast milk is biologically active and promotes epithelial barrier dysfunction. Methods The immature rat small intestinal epithelial cell line, IEC-18, was grown on cell inserts or standard cell culture plates. Confluent cultures were exposed to human breast milk with high or low levels of IL-23 and barrier function was measured using a flux of fluorescein isothiocyanate-dextran (FD-70). In addition, protein and mRNA expression of occludin and ZO-1 were measured and immunofluorescence used to stain occludin and ZO-1. Results Exposure to breast milk with high levels of IL 23 caused an increase flux of FD-70 compared with both controls and breast milk with low levels of IL-23. The protein expression of ZO-1 but not occludin was decreased by exposure to high levels of IL-23. These results correlate with immunofluorescent staining of ZO-1 and occludin which show decreased staining of occludin in both the groups exposed to breast milk with high and low IL-23. Conversely, cells exposed to high IL-23 breast milk had little peripheral staining of ZO-1 compared with controls and low IL-23 breast milk. Conclusion IL 23 in human breast milk is biologically active and negatively affects the barrier function of intestinal epithelial cells through the degradation of tight junction proteins. PMID- 26007692 TI - Stability and immunogenicity of hypoallergenic peanut protein-polyphenol complexes during in vitro pepsin digestion. AB - Allergenic peanut proteins are relatively resistant to digestion, and if digested, metabolized peptides tend to remain large and immunoreactive, triggering allergic reactions in sensitive individuals. In this study, the stability of hypoallergenic peanut protein-polyphenol complexes was evaluated during simulated in vitro gastric digestion. When digested with pepsin, the basic subunit of the peanut allergen Ara h 3 was more rapidly hydrolyzed in peanut protein-cranberry or green tea polyphenol complexes compared to uncomplexed peanut flour. Ara h 2 was also hydrolyzed more quickly in the peanut protein cranberry polyphenol complex than in uncomplexed peanut flour. Peptides from peanut protein-cranberry polyphenol complexes and peanut protein-green tea polyphenol complexes were substantially less immunoreactive (based on their capacity to bind to peanut-specific IgE from patient plasma) compared to peptides from uncomplexed peanut flour. These results suggest that peanut protein polyphenol complexes may be less immunoreactive passing through the digestive tract in vivo, contributing to their attenuated allergenicity. PMID- 26007693 TI - Nanoscale structure and superhydrophobicity of sp(2)-bonded boron nitride aerogels. AB - Aerogels have much potential in both research and industrial applications due to their high surface area, low density, and fine pore size distribution. Here we report a thorough structural study of three-dimensional aerogels composed of highly crystalline sp(2)-bonded boron nitride (BN) layers synthesized by a carbothermic reduction process. The structure, crystallinity and bonding of the as-prepared BN aerogels are elucidated by X-ray diffraction, (11)B nuclear magnetic resonance, transmission electron microscopy, and resonant soft X-ray scattering. The macroscopic roughness of the aerogel's surface causes it to be superhydrophobic with a contact angle of ~155 degrees and exhibit high oil uptake capacity (up to 1500 wt%). The oil can be removed from the BN aerogel by oxidizing in air without damaging the crystalline porous structure of the aerogel or diminishing its oil absorption capacity. PMID- 26007694 TI - Routinely obtained chest X-rays after elective video-assisted thoracoscopic surgery can be omitted in most patients; a retrospective, observational study. AB - OBJECTIVE: To investigate whether the use of routinely obtained chest X-rays is necessary after elective VATS. METHODS: We retrospectively reviewed 1097 chest X rays obtained routinely after elective VATS, performed in patients aged over 15 years during an 18-month period. VATS procedures were divided into three groups according to the degree of pulmonary resection. The chest X-rays (obtained anterior-posterior in one plane with the patient in the supine position) were categorized as abnormal if showing pneumothorax >5 cm, possible intra-thoracic bleeding and/or a displaced chest tube. Medical charts were reviewed for all patients with abnormal chest X-rays to see if an intervention was made based on the X-ray. In case of an intervention, detailed clinical data were collected. RESULTS: 44 of 1097 chest X-rays (4.0 %) were abnormal and 10 of these X-rays (0.9 %) led to a clinical intervention. Proportions of abnormal chest X-rays were unequally distributed between groups (p < 0.001), whereas the number of interventions was not (p = 0.43). Of the ten chests X-rays that led to an intervention, three showed possible intra-thoracic bleeding, six showed pneumothorax >5 cm and one showed a kinked chest tube. All the patients with possible intra-thoracic bleeding were re-explored in the operating theatre the same day. CONCLUSIONS: Only 10 of 1097 chest X-rays (0.9 %) obtained routinely after elective VATS procedures led to a clinical intervention, supporting the abandon of routine chest X rays in favour of a more individualised approach, based on clinical observations. PMID- 26007695 TI - Involvement in Child Rearing and Firm Control Parenting by Male Cohabiting Partners in Black Low-Income Stepfamilies: Forecasting Adolescent Problem Behaviors. AB - Cohabitation is a family structure that is rapidly increasing in the United States. The current longitudinal study examined the interplay of involvement in a youth's daily activities and firm control parenting by male cohabiting partners (MCPs) on change in adolescents' internalizing and externalizing problems. In a sample of 111 inner-city African American families, adolescents reported on involvement and parenting by MCPs at Wave 1 and biological mothers reported on adolescent problem behaviors at Waves 1 and 2. A significant interaction indicated that low involvement and low firm control by MCPs at Wave 1 were associated with the highest level of internalizing problems at Wave 2. An interaction did not emerge when externalizing problems served as the outcome. The findings indicate that male partners play an important role in parenting adolescents in cohabiting families and should be considered potential participants in prevention and intervention programs. PMID- 26007696 TI - Patient characteristics support unfavorable psychiatric outcome after treatment of unruptured intracranial aneurysms. AB - INTRODUCTION: Previous studies demonstrated an unfavorable psychological outcome after treatment of unruptured intracranial aneurysms despite an objectively favorable clinical and radiological outcome. The current study was therefore designed to analyze the psychiatric vulnerability of this specific patient collective. MATERIALS AND METHODS: Patients treated for a WHO grade I meningioma and incidental intracranial aneurysms in two German neurosurgical centers between 2007 and 2013 were screened for exclusion criteria including malignant/chronic diseases, recurrence of the tumor/aneurysm after more than 12 months and focal neurological deficits, among others. Seventy-five meningioma patients (M) and 56 incidental aneurysm patients (iA) met the inclusion criteria. The past medical psychiatric history, post-morbid personality characters and coping strategies were determined by questionnaires mailed to the patients in a printed version (Brief COPE, Big Five Personality Test). RESULTS: Fifty-eight M and 45 iA patients returned the questionnaires. Patients with iA demonstrated significantly higher pre-interventional rates of depressive episodes (p = 0.002) and psychological supervision (p = 0.038). These findings were especially aggravated in iA patients who received their cranial imaging for unspecific symptoms such as dizziness, headaches or tinnitus (n = 33, history of depressions: 39.4%; previous psychological supervision: 33.3%). Furthermore, the analysis of the Big Five personality traits revealed remarkably elevated neuroticism scores in the iA collective. CONCLUSION: The current study demonstrates an increased rate of positive pre-interventional psychiatric histories in the iA collective. Although those patients represent only a small subgroup, they still may play an important role concerning the overall outcome after iA treatment. Early detection and psychological support in this subgroup might help to improve the overall outcome. Further studies are needed to evaluate the influence of this new aspect on the multifactorial etiology of unfavorable psychiatric outcome after treatment of iA. PMID- 26007697 TI - MSI.R scripts reveal volatile and semi-volatile features in low-temperature plasma mass spectrometry imaging (LTP-MSI) of chilli (Capsicum annuum). AB - In cartography, the combination of colour and contour lines is used to express a three-dimensional landscape on a two-dimensional map. We transferred this concept to the analysis of mass spectrometry imaging (MSI) data and developed a collection of R scripts for the efficient evaluation of .imzML archives in a four step strategy: (1) calculation of the density distribution of mass-to-charge ratio (m/z) signals in the .imzML file and assembling of a pseudo-master spectrum with peak list, (2) automated generation of mass images for a defined scan range and subsequent visual inspection, (3) visualisation of individual ion distributions and export of relevant .mzML spectra and (4) creation of overlay graphics of ion images and photographies. The use of a Hue-Chroma-Luminance (HCL) colour model in MSI graphics takes into account the human perception for colours and supports the correct evaluation of signal intensities. Further, readers with colour blindness are supported. Contour maps promote the visual recognition of patterns in MSI data, which is particularly useful for noisy data sets. We demonstrate the scalability of MSI.R scripts by running them on different systems: on a personal computer, on Amazon Web Services (AWS) instances and on an institutional cluster. By implementing a parallel computing strategy, the execution speed for .imzML data scanning with image generation could be improved by more than an order of magnitude. Applying our MSI.R scripts ( http://www.bioprocess.org/MSI.R ) to low-temperature plasma (LTP)-MSI data shows the localisation of volatile and semi-volatile compounds in the cross-cut of a chilli (Capsicum annuum) fruit. The subsequent identification of compounds by gas and liquid chromatography coupled to mass spectrometry (GC-MS, LC-MS) proves that LTP-MSI enables the direct measurement of volatile organic compound (VOC) distributions from biological tissues. PMID- 26007698 TI - Automatic in-syringe dispersive liquid-liquid microextraction of 99Tc from biological samples and hospital residues prior to liquid scintillation counting. AB - A new approach exploiting in-syringe dispersive liquid-liquid microextraction (DLLME) for (99)Tc extraction and preconcentration from biological samples, i.e., urine and saliva, and liquid residues from treated patients is presented. (99)Tc is a beta emitter with a long half-life (2.111 * 10(5) years) and mobility in the different environmental compartments. One of the sources of this radionuclide is through the use of its father (99m)Tc in medical diagnosis. For the first time a critical comparison between extractants and disperser solvents for (99)Tc DLLME is presented, e.g., tributyl phosphate (TBP), trioctylmethylammonium chloride (Aliquat(r)336), triisooctylamine (TiOA), as extractants in apolar solvents such as xylene and dodecane, and disperser solvents such as acetone, acetonitrile, ethanol, methanol, 1-propanol, and 2-propanol. The system was optimized by experimental design, and 22.5% of Aliquat(r)336 in acetone was selected as extractant and disperser, respectively. Off-line detection was performed using a liquid scintillation counter. The present method has a (99)Tc minimum detectable activity (MDA) of 0.075 Bq with a high extraction/preconcentration frequency (8 h(-1)). Urine, saliva, and hospital residues were satisfactorily analyzed with recoveries of 82-119%. Thus, the proposed system is an automatic powerful tool to monitor the entry of (99)Tc into the environment. Graphical Abstract (99m)Tc is widely used in Nuclear Medicine for diagnosis. Its daugther (99)Tc is automatically monitored in biological samples from treated patients by in-syringe dispersive liquid-liquid microextraction. PMID- 26007699 TI - CuX(2)-mediated oxybromination/aminochlorination of unsaturated amides: synthesis of iminolactones and lactams. AB - We report herein a CuX2-mediated halocyclization of gamma,delta-unsaturated amides for the synthesis of functionalized iminolactones and lactams respectively under mild reaction conditions. Mechanism studies indicated that N-attack cyclization was via a radical route while oxycyclization was via a nucleophilic attack on the activated C=C bond. PMID- 26007700 TI - Microglial ROS production in an electrical rat post-status epilepticus model of epileptogenesis. AB - Reactive oxygen species and inflammatory signaling have been identified as pivotal pathophysiological factors contributing to epileptogenesis. Considering the development of combined anti-inflammatory and antioxidant treatment strategies with antiepileptogenic potential, a characterization of the time course of microglial reactive oxygen species generation during epileptogenesis is of major interest. Thus, we isolated microglia cells and analyzed the generation of reactive oxygen species by flow cytometric analysis in an electrical rat post status epilepticus model. Two days post status epilepticus, a large-sized cell cluster exhibited a pronounced response with excessive production of reactive oxygen species upon stimulation with phorbol-myristate-acetate. Neither in the latency phase nor in the chronic phase with spontaneous seizures a comparable cell population with induction of reactive oxygen species was identified. We were able to demonstrate in the electrical rat post-status-epilepticus model, that microglial ROS generation reaches a peak after the initial insult, is only marginally increased in the latency phase, and returns to control levels during the chronic epileptic phase. The data suggest that a combination of anti inflammatory and radical scavenging approaches might only be beneficial during a short time window after an epileptogenic brain insult. PMID- 26007701 TI - Isovaline attenuates generalized epileptiform activity in hippocampal and primary sensory cortices and seizure behavior in pilocarpine treated rats. AB - Anti-seizure drugs are the most commonly employed treatment option for epilepsy and these generally provide effective management of seizures. However, 30% of patients with epilepsy are not adequately treated with anti-seizure medications and are considered intractable. Recently we reported that isovaline, a unique amino acid, could attenuate seizure like events (SLEs) in two in vitro hippocampal seizure models by selectively increasing the activity of interneurons, but not pyramidal neurons. Isovaline also attenuated hippocampal epileptiform activity and behavioral seizures in vivo in rats administered 4 aminopyridine (4AP). Here, we investigate whether isovaline is efficacious in attenuating secondarily generalized epileptiform activity and behavioral seizures in rats administered pilocarpine. We found that 150 mg/kg isovaline administered intravenously abolished pilocarpine-induced epileptiform activity in the primary sensory cortex and hippocampus and attenuated generalized forebrain behavioral seizures. We are the first to demonstrate that isovaline may be a plausible anti seizure drug for secondarily generalized seizures and this could potentially lead to the development of a novel class of anti-seizure drugs focused around the unique mechanism(s) of isovaline. PMID- 26007702 TI - Phobos: A novel software for recording rodents' behavior during the thigmotaxis and the elevated plus-maze test. AB - Evaluation of fear and anxiety levels offers valuable insight on the impact of experimental conditions. The elevated plus-maze and the open field (thigmotactic responce) tests are two well-established behavioral procedures for the quantification of anxiety in rodents. In this study, Phobos, a novel, effective and simple application developed for recording rodents' behavior during the elevated plus-maze and the open-field test, is being presented. Phobos is able to generate all basic locomotor-related behavioral results at once, immediately after a simple manual record of the rodent's position, along with simultaneous analysis of the experiment in 5-min periods. The efficiency of Phobos is demonstrated by presenting results from the two behavioral tests showing that animal's behavior unfolds differently in each one. Phobos manages to ease the experimenter from laborious work by providing self-explanatory characteristics and a convenient way to record the behavior of the animal, while it quickly calculates all basic locomotor-related parameters, easing behavioral studies. Phobos is freely accessible at https://sourceforge.net/projects/phobosapplication/. PMID- 26007703 TI - Effective synaptome analysis of itch-mediating neurons in the spinal cord: A novel immunohistochemical methodology using high-voltage electron microscopy. AB - Transmission electron microscopy (TEM) is used for three-dimensional (3-D) analysis of synaptic connections in neuroscience research. However, 3-D reconstruction of the synapses using serial ultrathin sections is a powerful but tedious approach requiring advanced technical skills. High-voltage electron microscopy (HVEM) allows examination of thicker sections of biological specimens due to the increased penetration of the more accelerated electrons, which is useful to analyze the 3-D structure of biological specimens. However, it is still difficult to visualize the neural networks and synaptic connections in 3-D using HVEM because of insufficient and non uniform heavy metal staining in the membranous structures in semi-thin sections. Here, we present the successful chemical 3-D neuroanatomy of the rat spinal dorsal horn at the ultrastructural level as a first step for effective synaptome analysis by applying a high contrast en bloc staining method to immune-HVEM tomography. Our new approach made it possible to examine many itch-mediating synaptic connections and neural networks in the spinal cord simultaneously using HVEM tomography. This novel 3-D electron microscopy is very useful for the analysis of synaptic structure and the chemical neuroanatomy at the 3-D ultrastructural level. PMID- 26007704 TI - Antidepressant action via the nitric oxide system: A pilot study in an acute depressive model induced by arginin. AB - Nitric oxide (NO) may be a neurotransmitter related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7 nitroindazole, induces dose-dependent antidepressant-like effects. However, its role in MDD is not yet known. The purpose of our study was to determine if antidepressants improve depression via the NO pathway using an acute depressive rat model induced by L-arginine (AR). Three types of antidepressants were examined, fluoxetine (FLX, 10 mg/kg), milnacipran (MIL, 30 mg/kg), and mirtazapine (MIR, 10 mg/kg), in a depressive model that used AR (750 mg/kg) pretreatment. mRNA expression levels of three NOS subtypes were analyzed by real time PCR, as well as serum NO levels. Significant increases in iNOS mRNA expression levels were found in brain regions after AR treatment, although the eNOS gene tended to decrease with AR injection. After antidepressant treatment, there were no mRNA expression changes in either nNOS or iNOS. However, eNOS mRNA expression significantly increased with FLX (cerebellum, P=0.011; hippocampus, P=0.011; midbrain, P=0.011; pons, P=0.013; striatum, P=0.011; and thalamus, P<0.001). There was a statistically significant increase in serum NO levels with MIL treatment (P=0.011). We conclude that changes in eNOS mRNA levels in the brain with FLX treatment, and amount of serum NO with MIL treatment may be related to antidepressant effects of both agents, but further experiments are needed to confirm involvement of the NO system in MDD. PMID- 26007705 TI - Metabolic changes in de novo Parkinson's disease after dopaminergic therapy: A proton magnetic resonance spectroscopy study. AB - The aim of this study was to assess metabolic changes in the motor cortex in de novo Parkinson's disease (PD) patients before and after therapy with ropinirole. Twenty de novo drug-naive PD patients and 15 healthy controls underwent conventional magnetic resonance imaging and proton magnetic resonance spectroscopy imaging ((1)H-MRSI). The resonance intensities of N-acetylaspartate (NAA) and choline (Cho) were normalized for the resonance intensities of creatine (Cr). At baseline, lower NAA/Cr and NAA/Cho ratios and higher Cho/Cr ratios were found in the motor cortex of PD patients compared with controls (p<0.001). Ten months after ropinirole treatment, PD patients showed a significant clinical improvement in the UPDRS motor sub-scores (p<0.001) and an increase of NAA/Cr and NAA/Cho ratios (p<0.006 and p=0.01, respectively). A highly significant correlation between NAA/Cr and NAA/Cho ratios and UPDRS motor sub-scores was observed (r=-0.981 and r=-0.983, respectively). We could argue that the ropinirole efficacy to improve the motor performances is the result of partial restoration of neuronal functions, due to the increase of NAA in motor cortex. PMID- 26007706 TI - Deep seroma after incisional hernia repair. Case reports and review of the literature. AB - AIM: Wound-related complications are common after incisional hernia repair with mesh; seroma formation is the most frequent problem. The formation of a deep seroma has been rarely reported in the literature. MATERIAL OF STUDY: In one year, September 2012-2013, 136 patients underwent surgery for incisional hernia repair, both elective and urgent. RESULTS: The following complications were observed: one dislocation of polypropylene prosthesis, a massive relapsed seroma and two deep seromas described in this article. A 63- years-old female underwent open incisional hernia repair with an intraperitoneal PTFE patch. She developed recurrent seroma under the mesh drained percutaneously, and finally the prosthesis was removed. A 72- years-old male underwent open incisional hernia repair with an intraperitoneal PTFE patch. After several months the patient had seroma infection. The prosthesis was then removed. CONCLUSIONS: Seroma is a wellknown complication of postoperative ventral hernia repair, especially where prosthetic mesh is used. The formation of a deep seroma is rare. Only few works mention this complication in literature. In the development of these chronic seromas a role may be played by a long-term inflammatory reaction, more pronounced with polypropylene and polyester meshes than with ePTFE. A conservative follow up of the seromas is recommended because drainage can introduce infection. In cases where the seroma causes discomfort or is infected then drainage is necessary. From experience at our institution we suggest that patients with the deep subtype of mesh-associated seromas may require closer clinical follow up. When possible, we recommend attempting the drainage of the liquid, eventually followed by microbiological examination. PMID- 26007707 TI - Identification of Giant Mott Phase Transition of Single Electric Nanodomain in Manganite Nanowall Wire. AB - In the scaling down of electronic devices, functional oxides with strongly correlated electron system provide advantages to conventional semiconductors, namely, huge switching owing to their phase transition and high carrier density, which guarantee their rich functionalities even at the 10 nm scale. However, understanding how their functionalities behave at a scale of 10 nm order is still a challenging issue. Here, we report the construction of the well-defined (La,Pr,Ca)MnO3 epitaxial oxide nanowall wire by combination of nanolithography and subsequent thin-film growth, which allows the direct investigation of its insulator-metal transition (IMT) at the single domain scale. We show that the width of a (La,Pr,Ca)MnO3 nanowall sample can be reduced to 50 nm, which is smaller than the observed 70-200 nm-size electronic domains, and that a single electronic nanodomain in (La,Pr,Ca)MnO3 exhibited an intrinsic first-order IMT with an unusually steep single-step change in its magnetoresistance and temperature-induced resistance due to the domains arrangement in series. A simple model of the first-order transition for single electric domains satisfactorily illustrates the IMT behavior from macroscale down to the nanoscale. PMID- 26007708 TI - Hypoxia and Prostate Cancer Aggressiveness: A Tale With Many Endings. AB - Angiogenesis, increased glycolysis, and cellular adaptation to hypoxic microenvironment are characteristic of solid tumors, including prostate cancer. These representative features are the cornerstone of cancer biology, which are well correlated with invasion, metastasis, and lethality, as well as likely with the success of prostate cancer treatment (eg, tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy). It is well established that prostate cancer cells also metabolically depend on enhanced glucose transport and glycolysis for expansion, whereas growth is contingent with neovascularization to permit diffusion of oxygen and glucose. While hypoxia inducible factor 1 alpha (HIF-1alpha) remains the central player, the succeeding activated molecules and pathways track distinct branches, all positively correlated with the degree of intratumoral hypoxia. Among these, the vascular endothelial growth factor axis as well as the lysyl oxidase and carbonic anhydrase IX activities are notable in prostate cancer and merit further study. Here, we demonstrate their linkage with HIF-1alpha as a tentative explanatory mechanism of prostate cancer aggressiveness. Hypoxia drives a tale where HIF-1alpha-dependent effects lead to many influences in distinct key cancer biology features, rendering targeted therapies toward targets at the endings less efficient. The most appropriate approach will be to inhibit the upstream common driver (HIF-1alpha) activity. Additional translational and clinical research initiatives in prostate cancer are required to prove its usefulness. PMID- 26007709 TI - Pulmonary Metastasectomy Could Prolong Overall Survival in Select Cases of Metastatic Urinary Tract Cancer. AB - BACKGROUND: The purpose of the study was to evaluate the efficacy of metastasectomy for urinary tract carcinoma (UTC) and to determine prognostic factors that affect survival. PATIENTS AND METHODS: Data from a total of 30 patients with metastatic UTC who underwent a metastasectomy between February 2000 and July 2014 were analyzed retrospectively. Time to disease progression (TTP) and overall survival (OS) from metastasectomy, and potential prognostic factors were evaluated. RESULTS: The lung was the most frequent site of metastasectomy (n = 24) followed by the liver (n = 3) and lymph nodes (n = 3). With a median follow up duration of 54.2 months, the median TTP was 15.2 months and the median OS was 30.0 months (95% confidence interval, 15.1-42.9) with a 3-year survival rate of 41%. In multivariate analysis, initial stage IV disease (P = .047), pure urothelial pathology (P = .034), and nonpulmonary metastasectomy (P = .040) were independent prognostic factors for a shorter TTP. Nonpulmonary metastasectomy was an independent factor affecting OS (P = .001). CONCLUSION: A metastasectomy has the potential to contribute to better oncologic outcome in select patients with metastatic UTC, especially those with a single rather than multiple and pulmonary rather than nonpulmonary metastases due to recurrent rather than initially metastatic urinary tract cancer. PMID- 26007710 TI - Effect of pimobendan on the incidence of arrhythmias in small breed dogs with myxomatous mitral valve degeneration. AB - OBJECTIVE: To determine if pimobendan, a phosphodiesterase III inhibitor and calcium sensitizer with positive survival benefits, has an effect on incidence of arrhythmias compared to placebo in small breed dogs with congestive heart failure (CHF) due to myxomatous mitral valve degeneration (MMVD). ANIMALS: Eight client owned small breed dogs (<15 kg) with CHF due to MMVD. METHODS: A prospective double-blind randomized placebo-controlled crossover study design was used. Data were recorded at baseline and 2 weeks post-administration of placebo or pimobendan. Average heart rate and incidence of arrhythmia were determined from 24 h Holter analysis. Owners completed a quality of life (QOL) questionnaire at each time point and recorded sleeping respiratory rates (SRR). Mixed effects analysis of variance, with dog as the random variable was used to compare values obtained between baseline, placebo, and pimobendan. RESULTS: Compared to baseline, QOL scores were significantly improved following administration of either placebo or pimobendan (p = 0.021 and p < 0.001, respectively). No significant differences in type or incidence of supraventricular or ventricular arrhythmia were identified. Average heart rate with pimobendan was significantly lower than baseline (p < 0.001). Compared to baseline, SRR was significantly lower with pimobendan (p = 0.004), and significantly different from placebo (p = 0.045). CONCLUSIONS: No significant difference between pimobendan and placebo was found on incidence of supraventricular or ventricular arrhythmia. The decrease in average heart rate and SRR may be reflective of superior heart failure control achieved with pimobendan therapy. PMID- 26007711 TI - Weighing the impact (factor) of publishing in veterinary journals. AB - The journal in which you publish your research can have a major influence on the perceived value of your work and on your ability to reach certain audiences. The impact factor, a widely used metric of journal quality and prestige, has evolved into a benchmark of quality for institutions and graduate programs and, inappropriately, as a proxy for the quality of individual authors and articles, affecting tenure, promotion, and funding decisions. As a result, despite its many limitations, publishing decisions by authors often are based solely on a journal's impact factor. This can disadvantage journals in small disciplines, such as veterinary medicine, and limit the ability of authors to reach key audiences. In this article, factors that can influence the impact factor of a journal and its applicability, including precision, citation practices, article type, editorial policies, and size of the research community will be reviewed. The value and importance of veterinary journals such as the Journal of Veterinary Cardiology for reaching relevant audiences and for helping shape disciplinary specialties and influence clinical practice will also be discussed. Lastly, the efforts underway to develop alternative measures to assess the scientific quality of individual authors and articles, such as article-level metrics, as well as institutional measures of the economic and social impact of biomedical research will be considered. Judicious use of the impact factor and the implementation of new metrics for assessing the quality and societal relevance of veterinary research articles will benefit both authors and journals. PMID- 26007712 TI - Resource-efficient fusion with pre-compensated transmissions for cooperative spectrum sensing. AB - Recently, a novel fusion scheme for cooperative spectrum sensing was proposed for saving resources in the control channel. Secondary users (SUs) simultaneously report their decisions using binary modulations with the same carrier frequencies. The transmitted symbols add incoherently at the fusion centre (FC), leading to a larger set of symbols in which a subset is associated with the presence of the primary user (PU) signal, and another subset is associated with the absence of such a signal. The decision criterion applied for discriminating these subsets works under the assumption that the channel gains are known at the FC. In this paper, we propose a new simultaneous transmission and decision scheme in which the task of channel estimation is shifted from the FC to the SUs, without the need for feeding-back of the estimates to the FC. The estimates are used at the SUs to pre-compensate for the reporting channel phase rotations and to partially compensate for the channel gains. This partial compensation is the result of signal clipping for peak-to-average power ratio (PAPR) control. We show, analytically and with simulations, that this new scheme can produce large performance improvements, yet reduces the implementation complexity when compared with the original one. PMID- 26007713 TI - Electrical impedance spectroscopy-based defect sensing technique in estimating cracks. AB - A defect sensing method based on electrical impedance spectroscopy is proposed to image cracks and reinforcing bars in concrete structures. The method utilizes the frequency-dependent behavior of thin insulating cracks: low-frequency electrical currents are blocked by insulating cracks, whereas high-frequency currents can pass through thin cracks to probe the conducting bars. From various frequency dependent electrical impedance tomography (EIT) images, we can show its advantage in terms of detecting both thin cracks with their thickness and bars. We perform numerical simulations and phantom experiments to support the feasibility of the proposed method. PMID- 26007714 TI - Multi-scale pixel-based image fusion using multivariate empirical mode decomposition. AB - A novel scheme to perform the fusion of multiple images using the multivariate empirical mode decomposition (MEMD) algorithm is proposed. Standard multi-scale fusion techniques make a priori assumptions regarding input data, whereas standard univariate empirical mode decomposition (EMD)-based fusion techniques suffer from inherent mode mixing and mode misalignment issues, characterized respectively by either a single intrinsic mode function (IMF) containing multiple scales or the same indexed IMFs corresponding to multiple input images carrying different frequency information. We show that MEMD overcomes these problems by being fully data adaptive and by aligning common frequency scales from multiple channels, thus enabling their comparison at a pixel level and subsequent fusion at multiple data scales. We then demonstrate the potential of the proposed scheme on a large dataset of real-world multi-exposure and multi-focus images and compare the results against those obtained from standard fusion algorithms, including the principal component analysis (PCA), discrete wavelet transform (DWT) and non-subsampled contourlet transform (NCT). A variety of image fusion quality measures are employed for the objective evaluation of the proposed method. We also report the results of a hypothesis testing approach on our large image dataset to identify statistically-significant performance differences. PMID- 26007715 TI - On the deployment of a connected sensor network for confident information coverage. AB - Coverage and connectivity are two important performance metrics in wireless sensor networks. In this paper, we study the sensor placement problem to achieve both coverage and connectivity. Instead of using the simplistic disk coverage model, we use our recently proposed confident information coverage model as the sensor coverage model. The grid approach is applied to discretize the sensing field, and our objective is to place the minimum number of sensors to form a connected network and to provide confident information coverage for all of the grid points. We first formulate the sensor placement problem as a constrained optimization problem. Then, two heuristic algorithms, namely the connected cover formation (CCF) algorithm and the cover formation and relay placement with redundancy removal (CFRP-RR) algorithm, are proposed to find the approximate solutions for the sensor placement problem. The simulation results validate their effectiveness, and the CCF algorithm performs slightly better than the CFRP-RR algorithm. PMID- 26007716 TI - Heart Rate Variability Monitoring during Sleep Based on Capacitively Coupled Textile Electrodes on a Bed. AB - In this study, we developed and tested a capacitively coupled electrocardiogram (ECG) measurement system using conductive textiles on a bed, for long-term healthcare monitoring. The system, which was designed to measure ECG in a bed with no constraints of sleep position and posture, included a foam layer to increase the contact region with the curvature of the body and a cover to ensure durability and easy installation. Nine healthy subjects participated in the experiment during polysomnography (PSG), and the heart rate (HR) coverage and heart rate variability (HRV) parameters were analyzed to evaluate the system. The experimental results showed that the mean of R-peak coverage was 98.0% (95.5% 99.7%), and the normalized errors of HRV time and spectral measures between the Ag/AgCl system and our system ranged from 0.15% to 4.20%. The root mean square errors for inter-beat (RR) intervals and HR were 1.36 ms and 0.09 bpm, respectively. We also showed the potential of our developed system for rapid eye movement (REM) sleep and wake detection as well as for recording of abnormal states. PMID- 26007717 TI - The Elderly's Independent Living in Smart Homes: A Characterization of Activities and Sensing Infrastructure Survey to Facilitate Services Development. AB - Human activity detection within smart homes is one of the basis of unobtrusive wellness monitoring of a rapidly aging population in developed countries. Most works in this area use the concept of "activity" as the building block with which to construct applications such as healthcare monitoring or ambient assisted living. The process of identifying a specific activity encompasses the selection of the appropriate set of sensors, the correct preprocessing of their provided raw data and the learning/reasoning using this information. If the selection of the sensors and the data processing methods are wrongly performed, the whole activity detection process may fail, leading to the consequent failure of the whole application. Related to this, the main contributions of this review are the following: first, we propose a classification of the main activities considered in smart home scenarios which are targeted to older people's independent living, as well as their characterization and formalized context representation; second, we perform a classification of sensors and data processing methods that are suitable for the detection of the aforementioned activities. Our aim is to help researchers and developers in these lower-level technical aspects that are nevertheless fundamental for the success of the complete application. PMID- 26007718 TI - Measuring kinematic variables in front crawl swimming using accelerometers: a validation study. AB - Objective data on swimming performance is needed to meet the demands of the swimming coach and athlete. The purpose of this study is to use a multiple inertial measurement units to calculate Lap Time, Velocity, Stroke Count, Stroke Duration, Stroke Rate and Phases of the Stroke (Entry, Pull, Push, Recovery) in front crawl swimming. Using multiple units on the body, an algorithm was developed to calculate the phases of the stroke based on the relative position of the body roll. Twelve swimmers, equipped with these devices on the body, performed fatiguing trials. The calculated factors were compared to the same data derived to video data showing strong positive results for all factors. Four swimmers required individual adaptation to the stroke phase calculation method. The developed algorithm was developed using a search window relative to the body roll (peak/trough). This customization requirement demonstrates that single based devices will not be able to determine these phases of the stroke with sufficient accuracy. PMID- 26007719 TI - A wavelet-based approach to fall detection. AB - Falls among older people are a widely documented public health problem. Automatic fall detection has recently gained huge importance because it could allow for the immediate communication of falls to medical assistance. The aim of this work is to present a novel wavelet-based approach to fall detection, focusing on the impact phase and using a dataset of real-world falls. Since recorded falls result in a non-stationary signal, a wavelet transform was chosen to examine fall patterns. The idea is to consider the average fall pattern as the "prototype fall".In order to detect falls, every acceleration signal can be compared to this prototype through wavelet analysis. The similarity of the recorded signal with the prototype fall is a feature that can be used in order to determine the difference between falls and daily activities. The discriminative ability of this feature is evaluated on real-world data. It outperforms other features that are commonly used in fall detection studies, with an Area Under the Curve of 0.918. This result suggests that the proposed wavelet-based feature is promising and future studies could use this feature (in combination with others considering different fall phases) in order to improve the performance of fall detection algorithms. PMID- 26007720 TI - Mapping the salinity gradient in a microfluidic device with schlieren imaging. AB - This work presents the use of the schlieren imaging to quantify the salinity gradients in a microfluidic device. By partially blocking the back focal plane of the objective lens, the schlieren microscope produces an image with patterns that correspond to spatial derivative of refractive index in the specimen. Since salinity variation leads to change in refractive index, the fluid mixing of an aqueous salt solution of a known concentration and water in a T-microchannel is used to establish the relation between salinity gradients and grayscale readouts. This relation is then employed to map the salinity gradients in the target microfluidic device from the grayscale readouts of the corresponding micro schlieren image. For saline solution with salinity close to that of the seawater, the grayscale readouts vary linearly with the salinity gradient, and the regression line is independent of the flow condition and the salinity of the injected solution. It is shown that the schlieren technique is well suited to quantify the salinity gradients in microfluidic devices, for it provides a spatially resolved, non-invasive, full-field measurement. PMID- 26007721 TI - A Negative Index Metamaterial-Inspired UWB Antenna with an Integration of Complementary SRR and CLS Unit Cells for Microwave Imaging Sensor Applications. AB - This paper presents a negative index metamaterial incorporated UWB antenna with an integration of complementary SRR (split-ring resonator) and CLS (capacitive loaded strip) unit cells for microwave imaging sensor applications. This metamaterial UWB antenna sensor consists of four unit cells along one axis, where each unit cell incorporates a complementary SRR and CLS pair. This integration enables a design layout that allows both a negative value of permittivity and a negative value of permeability simultaneous, resulting in a durable negative index to enhance the antenna sensor performance for microwave imaging sensor applications. The proposed MTM antenna sensor was designed and fabricated on an FR4 substrate having a thickness of 1.6 mm and a dielectric constant of 4.6. The electrical dimensions of this antenna sensor are 0.20 lambda * 0.29 lambda at a lower frequency of 3.1 GHz. This antenna sensor achieves a 131.5% bandwidth (VSWR < 2) covering the frequency bands from 3.1 GHz to more than 15 GHz with a maximum gain of 6.57 dBi. High fidelity factor and gain, smooth surface-current distribution and nearly omni-directional radiation patterns with low cross polarization confirm that the proposed negative index UWB antenna is a promising entrant in the field of microwave imaging sensors. PMID- 26007722 TI - An energy-efficient transmission scheme for real-time data in wireless sensor networks. AB - The Internet of things (IoT) is a novel paradigm where all things or objects in daily life can communicate with other devices and provide services over the Internet. Things or objects need identifying, sensing, networking and processing capabilities to make the IoT paradigm a reality. The IEEE 802.15.4 standard is one of the main communication protocols proposed for the IoT. The IEEE 802.15.4 standard provides the guaranteed time slot (GTS) mechanism that supports the quality of service (QoS) for the real-time data transmission. In spite of some QoS features in IEEE 802.15.4 standard, the problem of end-to-end delay still remains. In order to solve this problem, we propose a cooperative medium access scheme (MAC) protocol for real-time data transmission. We also evaluate the performance of the proposed scheme through simulation. The simulation results demonstrate that the proposed scheme can improve the network performance. PMID- 26007724 TI - Classifying Sources Influencing Indoor Air Quality (IAQ) Using Artificial Neural Network (ANN). AB - Monitoring indoor air quality (IAQ) is deemed important nowadays. A sophisticated IAQ monitoring system which could classify the source influencing the IAQ is definitely going to be very helpful to the users. Therefore, in this paper, an IAQ monitoring system has been proposed with a newly added feature which enables the system to identify the sources influencing the level of IAQ. In order to achieve this, the data collected has been trained with artificial neural network or ANN--a proven method for pattern recognition. Basically, the proposed system consists of sensor module cloud (SMC), base station and service-oriented client. The SMC contain collections of sensor modules that measure the air quality data and transmit the captured data to base station through wireless network. The IAQ monitoring system is also equipped with IAQ Index and thermal comfort index which could tell the users about the room's conditions. The results showed that the system is able to measure the level of air quality and successfully classify the sources influencing IAQ in various environments like ambient air, chemical presence, fragrance presence, foods and beverages and human activity. PMID- 26007723 TI - Medically relevant assays with a simple smartphone and tablet based fluorescence detection system. AB - Cell phones and smart phones can be reconfigured as biomedical sensor devices but this requires specialized add-ons. In this paper we present a simple cell phone based portable bioassay platform, which can be used with fluorescent assays in solution. The system consists of a tablet, a polarizer, a smart phone (camera) and a box that provides dark readout conditions. The assay in a well plate is placed on the tablet screen acting as an excitation source. A polarizer on top of the well plate separates excitation light from assay fluorescence emission enabling assay readout with a smartphone camera. The assay result is obtained by analysing the intensity of image pixels in an appropriate colour channel. With this device we carried out two assays, for collagenase and trypsin using fluorescein as the detected fluorophore. The results of collagenase assay with the lowest measured concentration of 3.75 ug/mL and 0.938 ug in total in the sample were comparable to those obtained by a microplate reader. The lowest measured amount of trypsin was 930 pg, which is comparable to the low detection limit of 400 pg for this assay obtained in a microplate reader. The device is sensitive enough to be used in point-of-care medical diagnostics of clinically relevant conditions, including arthritis, cystic fibrosis and acute pancreatitis. PMID- 26007725 TI - Optimal Self-Tuning PID Controller Based on Low Power Consumption for a Server Fan Cooling System. AB - Recently, saving the cooling power in servers by controlling the fan speed has attracted considerable attention because of the increasing demand for high density servers. This paper presents an optimal self-tuning proportional-integral derivative (PID) controller, combining a PID neural network (PIDNN) with fan power-based optimization in the transient-state temperature response in the time domain, for a server fan cooling system. Because the thermal model of the cooling system is nonlinear and complex, a server mockup system simulating a 1U rack server was constructed and a fan power model was created using a third-order nonlinear curve fit to determine the cooling power consumption by the fan speed control. PIDNN with a time domain criterion is used to tune all online and optimized PID gains. The proposed controller was validated through experiments of step response when the server operated from the low to high power state. The results show that up to 14% of a server's fan cooling power can be saved if the fan control permits a slight temperature response overshoot in the electronic components, which may provide a time-saving strategy for tuning the PID controller to control the server fan speed during low fan power consumption. PMID- 26007726 TI - Entropy-Based TOA Estimation and SVM-Based Ranging Error Mitigation in UWB Ranging Systems. AB - The major challenges for Ultra-wide Band (UWB) indoor ranging systems are the dense multipath and non-line-of-sight (NLOS) problems of the indoor environment. To precisely estimate the time of arrival (TOA) of the first path (FP) in such a poor environment, a novel approach of entropy-based TOA estimation and support vector machine (SVM) regression-based ranging error mitigation is proposed in this paper. The proposed method can estimate the TOA precisely by measuring the randomness of the received signals and mitigate the ranging error without the recognition of the channel conditions. The entropy is used to measure the randomness of the received signals and the FP can be determined by the decision of the sample which is followed by a great entropy decrease. The SVM regression is employed to perform the ranging-error mitigation by the modeling of the regressor between the characteristics of received signals and the ranging error. The presented numerical simulation results show that the proposed approach achieves significant performance improvements in the CM1 to CM4 channels of the IEEE 802.15.4a standard, as compared to conventional approaches. PMID- 26007727 TI - Evaluation of Three State-of-the-Art Classifiers for Recognition of Activities of Daily Living from Smart Home Ambient Data. AB - Smart homes for the aging population have recently started attracting the attention of the research community. The "health state" of smart homes is comprised of many different levels; starting with the physical health of citizens, it also includes longer-term health norms and outcomes, as well as the arena of positive behavior changes. One of the problems of interest is to monitor the activities of daily living (ADL) of the elderly, aiming at their protection and well-being. For this purpose, we installed passive infrared (PIR) sensors to detect motion in a specific area inside a smart apartment and used them to collect a set of ADL. In a novel approach, we describe a technology that allows the ground truth collected in one smart home to train activity recognition systems for other smart homes. We asked the users to label all instances of all ADL only once and subsequently applied data mining techniques to cluster in-home sensor firings. Each cluster would therefore represent the instances of the same activity. Once the clusters were associated to their corresponding activities, our system was able to recognize future activities. To improve the activity recognition accuracy, our system preprocessed raw sensor data by identifying overlapping activities. To evaluate the recognition performance from a 200-day dataset, we implemented three different active learning classification algorithms and compared their performance: naive Bayesian (NB), support vector machine (SVM) and random forest (RF). Based on our results, the RF classifier recognized activities with an average specificity of 96.53%, a sensitivity of 68.49%, a precision of 74.41% and an F-measure of 71.33%, outperforming both the NB and SVM classifiers. Further clustering markedly improved the results of the RF classifier. An activity recognition system based on PIR sensors in conjunction with a clustering classification approach was able to detect ADL from datasets collected from different homes. Thus, our PIR-based smart home technology could improve care and provide valuable information to better understand the functioning of our societies, as well as to inform both individual and collective action in a smart city scenario. PMID- 26007728 TI - An ultra-low power wireless sensor network for bicycle torque performance measurements. AB - In this paper, we propose an energy-efficient transmission technique known as the sleep/wake algorithm for a bicycle torque sensor node. This paper aims to highlight the trade-off between energy efficiency and the communication range between the cyclist and coach. Two experiments were conducted. The first experiment utilised the Zigbee protocol (XBee S2), and the second experiment used the Advanced and Adaptive Network Technology (ANT) protocol based on the Nordic nRF24L01 radio transceiver chip. The current consumption of ANT was measured, simulated and compared with a torque sensor node that uses the XBee S2 protocol. In addition, an analytical model was derived to correlate the sensor node average current consumption with a crank arm cadence. The sensor node achieved 98% power savings for ANT relative to ZigBee when they were compared alone, and the power savings amounted to 30% when all components of the sensor node are considered. The achievable communication range was 65 and 50 m for ZigBee and ANT, respectively, during measurement on an outdoor cycling track (i.e., velodrome). The conclusions indicate that the ANT protocol is more suitable for use in a torque sensor node when power consumption is a crucial demand, whereas the ZigBee protocol is more convenient in ensuring data communication between cyclist and coach. PMID- 26007729 TI - Building keypoint mappings on multispectral images by a cascade of classifiers with a resurrection mechanism. AB - Inspired by the boosting technique for detecting objects, this paper proposes a cascade structure with a resurrection mechanism to establish keypoint mappings on multispectral images. The cascade structure is composed of four steps by utilizing best bin first (BBF), color and intensity distribution of segment (CIDS), global information and the RANSAC process to remove outlier keypoint matchings. Initial keypoint mappings are built with the descriptors associated with keypoints; then, at each step, only a small number of keypoint mappings of a high confidence are classified to be incorrect. The unclassified keypoint mappings will be passed on to subsequent steps for determining whether they are correct. Due to the drawback of a classification rule, some correct keypoint mappings may be misclassified as incorrect at a step. Observing this, we design a resurrection mechanism, so that they will be reconsidered and evaluated by the rules utilized in subsequent steps. Experimental results show that the proposed cascade structure combined with the resurrection mechanism can effectively build more reliable keypoint mappings on multispectral images than existing methods. PMID- 26007730 TI - ZnO Nanostructure-Based Intracellular Sensor. AB - Recently ZnO has attracted much interest because of its usefulness for intracellular measurements of biochemical species by using its semiconducting, electrochemical, catalytic properties and for being biosafe and biocompatible. ZnO thus has a wide range of applications in optoelectronics, intracellular nanosensors, transducers, energy conversion and medical sciences. This review relates specifically to intracellular electrochemical (glucose and free metal ion) biosensors based on functionalized zinc oxide nanowires/nanorods. For intracellular measurements, the ZnO nanowires/nanorods were grown on the tip of a borosilicate glass capillary (0.7 um in diameter) and functionalized with membranes or enzymes to produce intracellular selective metal ion or glucose sensors. Successful intracellular measurements were carried out using ZnO nanowires/nanorods grown on small tips for glucose and free metal ions using two types of cells, human fat cells and frog oocytes. The sensors in this study were used to detect real-time changes of metal ions and glucose across human fat cells and frog cells using changes in the electrochemical potential at the interface of the intracellular micro-environment. Such devices are helpful in explaining various intracellular processes involving ions and glucose. PMID- 26007731 TI - Modeling of acoustic emission signal propagation in waveguides. AB - Acoustic emission (AE) testing is a widely used nondestructive testing (NDT) method to investigate material failure. When environmental conditions are harmful for the operation of the sensors, waveguides are typically mounted in between the inspected structure and the sensor. Such waveguides can be built from different materials or have different designs in accordance with the experimental needs. All these variations can cause changes in the acoustic emission signals in terms of modal conversion, additional attenuation or shift in frequency content. A finite element method (FEM) was used to model acoustic emission signal propagation in an aluminum plate with an attached waveguide and was validated against experimental data. The geometry of the waveguide is systematically changed by varying the radius and height to investigate the influence on the detected signals. Different waveguide materials were implemented and change of material properties as function of temperature were taken into account. Development of the option of modeling different waveguide options replaces the time consuming and expensive trial and error alternative of experiments. Thus, the aim of this research has important implications for those who use waveguides for AE testing. PMID- 26007732 TI - Highly stable liquid metal-based pressure sensor integrated with a microfluidic channel. AB - Pressure measurement is considered one of the key parameters in microfluidic systems. It has been widely used in various fields, such as in biology and biomedical fields. The electrical measurement method is the most widely investigated; however, it is unsuitable for microfluidic systems because of a complicated fabrication process and difficult integration. Moreover, it is generally damaged by large deflection. This paper proposes a thin-film-based pressure sensor that is free from these limitations, using a liquid metal called galinstan. The proposed pressure sensor is easily integrated into a microfluidic system using soft lithography because galinstan exists in a liquid phase at room temperature. We investigated the characteristics of the proposed pressure sensor by calibrating for a pressure range from 0 to 230 kPa (R2 > 0.98) using deionized water. Furthermore, the viscosity of various fluid samples was measured for a shear-rate range of 30-1000 s(-1). The results of Newtonian and non-Newtonian fluids were evaluated using a commercial viscometer and normalized difference was found to be less than 5.1% and 7.0%, respectively. The galinstan-based pressure sensor can be used in various microfluidic systems for long-term monitoring with high linearity, repeatability, and long-term stability. PMID- 26007733 TI - Electronic Properties of DNA-Based Schottky Barrier Diodes in Response to Alpha Particles. AB - Detection of nuclear radiation such as alpha particles has become an important field of research in recent history due to nuclear threats and accidents. In this context; deoxyribonucleic acid (DNA) acting as an organic semiconducting material could be utilized in a metal/semiconductor Schottky junction for detecting alpha particles. In this work we demonstrate for the first time the effect of alpha irradiation on an Al/DNA/p-Si/Al Schottky diode by investigating its current voltage characteristics. The diodes were exposed for different periods (0-20 min) of irradiation. Various diode parameters such as ideality factor, barrier height, series resistance, Richardson constant and saturation current were then determined using conventional, Cheung and Cheung's and Norde methods. Generally, ideality factor or n values were observed to be greater than unity, which indicates the influence of some other current transport mechanism besides thermionic processes. Results indicated ideality factor variation between 9.97 and 9.57 for irradiation times between the ranges 0 to 20 min. Increase in the series resistance with increase in irradiation time was also observed when calculated using conventional and Cheung and Cheung's methods. These responses demonstrate that changes in the electrical characteristics of the metal semiconductor-metal diode could be further utilized as sensing elements to detect alpha particles. PMID- 26007734 TI - Branch-based centralized data collection for smart grids using wireless sensor networks. AB - A smart grid is one of the most important applications in smart cities. In a smart grid, a smart meter acts as a sensor node in a sensor network, and a central device collects power usage from every smart meter. This paper focuses on a centralized data collection problem of how to collect every power usage from every meter without collisions in an environment in which the time synchronization among smart meters is not guaranteed. To solve the problem, we divide a tree that a sensor network constructs into several branches. A conflict free query schedule is generated based on the branches. Each power usage is collected according to the schedule. The proposed method has important features: shortening query processing time and avoiding collisions between a query and query responses. We evaluate this method using the ns-2 simulator. The experimental results show that this method can achieve both collision avoidance and fast query processing at the same time. The success rate of data collection at a sink node executing this method is 100%. Its running time is about 35 percent faster than that of the round-robin method, and its memory size is reduced to about 10% of that of the depth-first search method. PMID- 26007735 TI - Surface Acoustic Wave (SAW) Resonators for Monitoring Conditioning Film Formation. AB - We propose surface acoustic wave (SAW) resonators as a complementary tool for conditioning film monitoring. Conditioning films are formed by adsorption of inorganic and organic substances on a substrate the moment this substrate comes into contact with a liquid phase. In the case of implant insertion, for instance, initial protein adsorption is required to start wound healing, but it will also trigger immune reactions leading to inflammatory responses. The control of the initial protein adsorption would allow to promote the healing process and to suppress adverse immune reactions. Methods to investigate these adsorption processes are available, but it remains difficult to translate measurement results into actual protein binding events. Biosensor transducers allow user friendly investigation of protein adsorption on different surfaces. The combination of several transduction principles leads to complementary results, allowing a more comprehensive characterization of the adsorbing layer. We introduce SAW resonators as a novel complementary tool for time-resolved conditioning film monitoring. SAW resonators were coated with polymers. The adsorption of the plasma proteins human serum albumin (HSA) and fibrinogen onto the polymer-coated surfaces were monitored. Frequency results were compared with quartz crystal microbalance (QCM) sensor measurements, which confirmed the suitability of the SAW resonators for this application. PMID- 26007736 TI - Fruit quality evaluation using spectroscopy technology: a review. AB - An overview is presented with regard to applications of visible and near infrared (Vis/NIR) spectroscopy, multispectral imaging and hyperspectral imaging techniques for quality attributes measurement and variety discrimination of various fruit species, i.e., apple, orange, kiwifruit, peach, grape, strawberry, grape, jujube, banana, mango and others. Some commonly utilized chemometrics including pretreatment methods, variable selection methods, discriminant methods and calibration methods are briefly introduced. The comprehensive review of applications, which concentrates primarily on Vis/NIR spectroscopy, are arranged according to fruit species. Most of the applications are focused on variety discrimination or the measurement of soluble solids content (SSC), acidity and firmness, but also some measurements involving dry matter, vitamin C, polyphenols and pigments have been reported. The feasibility of different spectral modes, i.e., reflectance, interactance and transmittance, are discussed. Optimal variable selection methods and calibration methods for measuring different attributes of different fruit species are addressed. Special attention is paid to sample preparation and the influence of the environment. Areas where further investigation is needed and problems concerning model robustness and model transfer are identified. PMID- 26007737 TI - A Lightweight White-Box Symmetric Encryption Algorithm against Node Capture for WSNs. AB - Wireless Sensor Networks (WSNs) are often deployed in hostile environments and, thus, nodes can be potentially captured by an adversary. This is a typical white box attack context, i.e., the adversary may have total visibility of the implementation of the build-in cryptosystem and full control over its execution platform. Handling white-box attacks in a WSN scenario is a challenging task. Existing encryption algorithms for white-box attack contexts require large memory footprint and, hence, are not applicable for wireless sensor networks scenarios. As a countermeasure against the threat in this context, in this paper, we propose a class of lightweight secure implementations of the symmetric encryption algorithm SMS4. The basic idea of our approach is to merge several steps of the round function of SMS4 into table lookups, blended by randomly generated mixing bijections. Therefore, the size of the implementations are significantly reduced while keeping the same security efficiency. The security and efficiency of the proposed solutions are theoretically analyzed. Evaluation shows our solutions satisfy the requirement of sensor nodes in terms of limited memory size and low computational costs. PMID- 26007738 TI - User Activity Recognition in Smart Homes Using Pattern Clustering Applied to Temporal ANN Algorithm. AB - This paper discusses the possibility of recognizing and predicting user activities in the IoT (Internet of Things) based smart environment. The activity recognition is usually done through two steps: activity pattern clustering and activity type decision. Although many related works have been suggested, they had some limited performance because they focused only on one part between the two steps. This paper tries to find the best combination of a pattern clustering method and an activity decision algorithm among various existing works. For the first step, in order to classify so varied and complex user activities, we use a relevant and efficient unsupervised learning method called the K-pattern clustering algorithm. In the second step, the training of smart environment for recognizing and predicting user activities inside his/her personal space is done by utilizing the artificial neural network based on the Allen's temporal relations. The experimental results show that our combined method provides the higher recognition accuracy for various activities, as compared with other data mining classification algorithms. Furthermore, it is more appropriate for a dynamic environment like an IoT based smart home. PMID- 26007739 TI - A Highly Sensitive Porous Silicon (P-Si)-Based Human Kallikrein 2 (hK2) Immunoassay Platform toward Accurate Diagnosis of Prostate Cancer. AB - Levels of total human kallikrein 2 (hK2), a protein involved the pathology of prostate cancer (PCa), could be used as a biomarker to aid in the diagnosis of this disease. In this study, we report on a porous silicon antibody immunoassay platform for the detection of serum levels of total hK2. The surface of porous silicon has a 3-dimensional macro- and nanoporous structure, which offers a large binding capacity for capturing probe molecules. The tailored pore size of the porous silicon also allows efficient immobilization of antibodies by surface adsorption, and does not require chemical immobilization. Monoclonal hK2 capture antibody (6B7) was dispensed onto P-Si chip using a piezoelectric dispenser. In total 13 * 13 arrays (169 spots) were spotted on the chip with its single spot volume of 300 pL. For an optimization of capture antibody condition, we firstly performed an immunoassay of the P-Si microarray under a titration series of hK2 in pure buffer (PBS) at three different antibody densities (75, 100 and 145 ug/mL). The best performance of the microarray platform was seen at 100 ug/mL of the capture antibody concentration (LOD was 100 fg/mL). The platform then was subsequently evaluated for a titration series of serum-spiked hK2 samples. The developed platform utilizes only 15 uL of serum per test and the total assay time is about 3 h, including immobilization of the capture antibody. The detection limit of the hK2 assay was 100 fg/mL in PBS buffer and 1 pg/mL in serum with a dynamic range of 106 (10(-4) to 10(2) ng/mL). PMID- 26007740 TI - Revision of J3Gen and Validity of the Attacks by Peinado et al. AB - This letter is the reply to: Remarks on Peinado et al.'s Analysis of J3Gen by J. Garcia-Alfaro, J. Herrera-Joancomarti and J. Melia-Segui published in Sensors 2015, 15, 6217-6220. Peinado et al. cryptanalyzed the pseudorandom number generator proposed by Melia-Segui et al., describing two possible attacks. Later, Garcia-Alfaro claimed that one of this attack did not hold in practice because the assumptions made by Peinado et al. were not correct. This letter reviews those remarks, showing that J3Gen is anyway flawed and that, without further information, the interpretation made by Peinado et al. seems to be correct. PMID- 26007741 TI - Survey of WBSNs for Pre-Hospital Assistance: Trends to Maximize the Network Lifetime and Video Transmission Techniques. AB - This survey aims to encourage the multidisciplinary communities to join forces for innovation in the mobile health monitoring area. Specifically, multidisciplinary innovations in medical emergency scenarios can have a significant impact on the effectiveness and quality of the procedures and practices in the delivery of medical care. Wireless body sensor networks (WBSNs) are a promising technology capable of improving the existing practices in condition assessment and care delivery for a patient in a medical emergency. This technology can also facilitate the early interventions of a specialist physician during the pre-hospital period. WBSNs make possible these early interventions by establishing remote communication links with video/audio support and by providing medical information such as vital signs, electrocardiograms, etc. in real time. This survey focuses on relevant issues needed to understand how to setup a WBSN for medical emergencies. These issues are: monitoring vital signs and video transmission, energy efficient protocols, scheduling, optimization and energy consumption on a WBSN. PMID- 26007742 TI - Gated silicon drift detector fabricated from a low-cost silicon wafer. AB - Inexpensive high-resolution silicon (Si) X-ray detectors are required for on-site surveys of traces of hazardous elements in food and soil by measuring the energies and counts of X-ray fluorescence photons radially emitted from these elements. Gated silicon drift detectors (GSDDs) are much cheaper to fabricate than commercial silicon drift detectors (SDDs). However, previous GSDDs were fabricated from 10-kOmega.cm Si wafers, which are more expensive than 2-kOmega.cm Si wafers used in commercial SDDs. To fabricate cheaper portable X-ray fluorescence instruments, we investigate GSDDs formed from 2-kOmega.cm Si wafers. The thicknesses of commercial SDDs are up to 0.5 mm, which can detect photons with energies up to 27 keV, whereas we describe GSDDs that can detect photons with energies of up to 35 keV. We simulate the electric potential distributions in GSDDs with Si thicknesses of 0.5 and 1 mm at a single high reverse bias. GSDDs with one gate pattern using any resistivity Si wafer can work well for changing the reverse bias that is inversely proportional to the resistivity of the Si wafer. PMID- 26007743 TI - Highly sensitive bacteria quantification using immunomagnetic separation and electrochemical detection of guanine-labeled secondary beads. AB - In this paper, we report the ultra-sensitive indirect electrochemical detection of E. coli O157:H7 using antibody functionalized primary (magnetic) beads for capture and polyguanine (polyG) oligonucleotide functionalized secondary (polystyrene) beads as an electrochemical tag. Vacuum filtration in combination with E. coli O157:H7 specific antibody modified magnetic beads were used for extraction of E. coli O157:H7 from 100 mL samples. The magnetic bead conjugated E. coli O157:H7 cells were then attached to polyG functionalized secondary beads to form a sandwich complex (magnetic bead/E. coli secondary bead). While the use of magnetic beads for immuno-based capture is well characterized, the use of oligonucleotide functionalized secondary beads helps combine amplification and potential multiplexing into the system. The antibody functionalized secondary beads can be easily modified with a different antibody to detect other pathogens from the same sample and enable potential multiplexing. The polyGs on the secondary beads enable signal amplification up to 108 guanine tags per secondary bead (7.5 x 106 biotin-FITC per secondary bead, 20 guanines per oligonucleotide) bound to the target (E. coli). A single-stranded DNA probe functionalized reduced graphene oxide modified glassy carbon electrode was used to bind the polyGs on the secondary beads. Fluorescent imaging was performed to confirm the hybridization of the complex to the electrode surface. Differential pulse voltammetry (DPV) was used to quantify the amount of polyG involved in the hybridization event with tris(2,2'-bipyridine)ruthenium(II) (Ru(bpy)3(2+)) as the mediator. The amount of polyG signal can be correlated to the amount of E. coli O157:H7 in the sample. The method was able to detect concentrations of E. coli O157:H7 down to 3 CFU/100 mL, which is 67 times lower than the most sensitive technique reported in literature. The signal to noise ratio for this work was 3. We also demonstrate the use of the protocol for detection of E. coli O157:H7 seeded in waste water effluent samples. PMID- 26007744 TI - Multisensor Super Resolution Using Directionally-Adaptive Regularization for UAV Images. AB - In various unmanned aerial vehicle (UAV) imaging applications, the multisensor super-resolution (SR) technique has become a chronic problem and attracted increasing attention. Multisensor SR algorithms utilize multispectral low resolution (LR) images to make a higher resolution (HR) image to improve the performance of the UAV imaging system. The primary objective of the paper is to develop a multisensor SR method based on the existing multispectral imaging framework instead of using additional sensors. In order to restore image details without noise amplification or unnatural post-processing artifacts, this paper presents an improved regularized SR algorithm by combining the directionally adaptive constraints and multiscale non-local means (NLM) filter. As a result, the proposed method can overcome the physical limitation of multispectral sensors by estimating the color HR image from a set of multispectral LR images using intensity-hue-saturation (IHS) image fusion. Experimental results show that the proposed method provides better SR results than existing state-of-the-art SR methods in the sense of objective measures. PMID- 26007745 TI - Iterative Precise Conductivity Measurement with IDEs. AB - The paper presents a new approach in the field of precise electrolytic conductivity measurements with planar thin- and thick-film electrodes. This novel measuring method was developed for measurement with comb-like electrodes called interdigitated electrodes (IDEs). Correction characteristics over a wide range of specific conductivities were determined from an interface impedance characterization of the thick-film IDEs. The local maximum of the capacitive part of the interface impedance is used for corrections to get linear responses. The measuring frequency was determined at a wide range of measured conductivity. An iteration mode of measurements was suggested to precisely measure the conductivity at the right frequency in order to achieve a highly accurate response. The method takes precise conductivity measurements in concentration ranges from 10(-6) to 1 M without electrode cell replacement. PMID- 26007746 TI - LED-Absorption-QEPAS Sensor for Biogas Plants. AB - A new sensor for methane and carbon dioxide concentration measurements in biogas plants is presented. LEDs in the mid infrared spectral region are implemented as low cost light source. The combination of quartz-enhanced photoacoustic spectroscopy with an absorption path leads to a sensor setup suitable for the harsh application environment. The sensor system contains an electronics unit and the two gas sensors; it was designed to work as standalone device and was tested in a biogas plant for several weeks. Gas concentration dependent measurements show a precision better than 1% in a range between 40% and 60% target gas concentration for both sensors. Concentration dependent measurements with different background gases show a considerable decrease in cross sensitivity against the major components of biogas in direct comparison to common absorption based sensors. PMID- 26008113 TI - A Case of SAPHO Syndrome with Endodontic Implications and Treatment with Biologic Drugs. AB - SAPHO syndrome (SS) is an autoinflammatory disease characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. Among the sites affected by the osteoarticular manifestations of SS are the anterior chest wall and the mandible. The etiology of SS is still unknown; theories advocate a genetic predisposition and an infectious cause in association with disorders of the immune system. We report a case of SS in which there was the involvement of the mandible with a lesion of endodontic origin. A 44-year-old white woman diagnosed with SS at the university hospital was referred to the Department of Conservative Dentistry and Endodontics for a consultation. She reported spontaneous pain localized to the periapical area of tooth #19 with a history of multiple restorative and endodontic treatments. It was diagnosed as a previously treated tooth with symptomatic apical periodontitis (AP) at the time of the endodontic evaluation. A second retreatment was then performed in 1 appointment under local anesthesia. During retreatment, a separated instrument and a ledge were found in the mesiobuccal canal, and attempts to bypass it were not successful; the canal was then obturated to the reachable length. Within the same month, the patient was also administered an anti-tumor necrosis factor alpha biologic medication in association with a disease-modifying antirheumatic drugs for the treatment of SS. Within 3 months, the overall therapy had led to a marked improvement of the systemic and mandibular symptoms, and a periapical radiograph showed almost complete healing of the lesion. Medical examinations have shown a total remission of signs and symptoms starting 6 months after the initiation of treatment. After 5 years, the disease is under control, and tooth #19 is symptom free and shows absence of AP. The endodontists need to be aware of the existence of SS and the possible effects of the use of disease-modifying antirheumatic drugs and biologic medications on the treatment of persistent AP. PMID- 26008114 TI - Influence of Irrigation Sequence on the Adhesion of Root Canal Sealers to Dentin: A Fourier Transform Infrared Spectroscopy and Push-out Bond Strength Analysis. AB - INTRODUCTION: There is a lack of evidence on the chemical interaction between sealers and dentin. The influence of irrigation on the chemical interaction between root canal sealers and dentin was analyzed by using Fourier transform infrared spectroscopy (FTIRS) and measurement of dislocation resistance. METHODS: Single-rooted teeth (n = 120) were instrumented with 3% NaOCl as the irrigant and divided into 4 groups (n = 30) on the basis of irrigation protocol: group 1, 3% NaOCl, 17% EDTA, water; group 2, 17% EDTA, 3% NaOCl, water; group 3, 3% NaOCl, QMix, water; group 4, 3% NaOCl, water. Each group was divided into 3 subgroups (n = 10) on the basis of the root canal sealer: A, epoxy resin (AH Plus); B, silicone (RoekoSeal); C, calcium hydroxide (Sealapex). The dislocation resistance was assessed by using push-out bond strength test. The data were statistically analyzed by three-way analysis of variance and Holm-Sidak tests (P = .05). Dentin powder treated as per the conditioning protocols mentioned was mixed with the sealers and analyzed by FTIRS. RESULTS: A significant interaction was observed between irrigation protocol, type of sealer, and root segment (P < .001) for AH Plus but not for RoekoSeal and Sealapex (P > .05). AH Plus showed the highest bond strength (P < .05). FTIRS showed chemical bonding between AH Plus and dentinal collagen. In groups 2 and 4, no chemical bonding was observed. CONCLUSIONS: Bond strength of sealers is differentially affected by the irrigation protocol. The epoxy resin sealer AH Plus chemically bonds to dentinal collagen. This interaction is influenced by the irrigation protocols. PMID- 26008115 TI - Organ-specific matrix self-assembled by mesenchymal cells improves the normal urothelial differentiation in vitro. AB - PURPOSE: Enterocystoplasty is the gold standard to perform bladder reconstruction. Since this technique has a high morbidity rate, several matrix scaffolds have been proposed to support the urothelial maturation. Unfortunately, epithelial cells failed to fully integrate the cell-matrix interactions and therefore appropriate signalling pathways of normal differentiation. Based on these observations, we proposed to culture bladder urothelial cells (BUC) onto a matrix self-assembled by bladder mesenchymal cells (BMC), to form a vesical model (VM). METHODS: Different serum proportions were assessed to obtain a manipulable matrix deposited by BMC. The BUC were then seeded onto the BMC's matrix to evolve in a three-dimensional culture. Haematoxylin-eosin staining, immunolabeling, scanning electron microscopy, western blot and matrix metalloproteinases analysis were performed for the VM characterization. RESULTS: We were able to obtain an original matrix made of collagen-I and presenting specific organization. Matrix remodelling was observed and led to a cellular compartmentalization. The reconstructed urothelium developed in a pseudostratified arrangement, displaying an adequate cellular polarity and apical membrane remodelling of superficial cells. Like native bladder, cytokeratin 14 immunolabeling was not observed in our VM, which indicate the conformity of the development sequence taken by BUC under the influence of the BMC's matrix. CONCLUSION: Thus, it was possible to elaborate a VM without the use of exogenous matrices. The particular characteristics of the BMC's matrix permitted the development of an urothelium that shared the phenotype of native tissue. The autologous character of our VM, and its appropriate urothelial maturation, could potentially promote a better integration after grafting. PMID- 26008116 TI - Gracilis muscle interposition flap repair of urinary fistulae: pelvic radiation is associated with persistent urinary incontinence and decreased quality of life. AB - PURPOSE: The primary goal of urinary fistulae repair is to improve continence and quality of life. Irradiated patients are predisposed to development of bladder outlet dysfunction (BOD), defined as bladder neck contracture or stress urinary incontinence. Here, we review our experience with gracilis flap repairs for rectourinary fistulae (RUF) and urinary cutaneous fistulae (UCF) in patients who underwent pelvic radiation. METHODS: Twenty-seven patients underwent repair of a RUF/UCF with gracilis flap between 2003 and 2013. Patients were assessed for postoperative fistula closure and BOD, and quality of life was assessed with the Expanded Prostate Index Composite (EPIC) questionnaire administered via telephone at the time of final follow-up. RESULTS: Mean age was 60 years (50-73) with median follow-up of 28.7 months (1.0-128). Flap failure was noted in 5/20 radiated patients versus 3/7 non-radiated patients (p = 0.63). Of the 8 flap failures, 7 underwent secondary repair: repeat gracilis flap (2), coloanal pull through (2), rectal advancement flap (1), sliding flap (1), and omental flap (1). Median time to revision was 7.2 months (3.5-24.9). In irradiated patients, 18/20 (90 %) developed BOD compared with 1/7 (14 %) who were not radiated (p = 0.0006). Radiation was associated with worse scores on the urinary incontinence domain of the EPIC questionnaire compared with non-radiated patients (p = 0.0458). CONCLUSIONS: Urinary fistula repairs in radiated patients should be undertaken with caution. Even if the fistula is successfully repaired, patients may still have bladder outlet dysfunction and decreased quality of life. Consequently, patients should be counseled about all possible procedures, including permanent urinary diversion as primary therapy. PMID- 26008117 TI - Advancing Rhodobacter sphaeroides as a platform for expression of functional membrane proteins. AB - Membrane protein overexpression is often hindered by toxic effects on the expression host, limiting achievable volumetric productivity. Moreover, protein structure and function may be impaired due to inclusion body formation and proteolytic degradation. To address these challenges, we employed the photosynthetic bacterium, Rhodobacter sphaeroides for expression of challenging membrane proteins including human aquaporin 9 (hAQP9), human tight junction protein occludin (Occ), Escherichia coli toxin peptide GhoT, cellulose synthase enzyme complex (BcsAB) of R. sphaeroides and cytochrome-cy (Cyt-cy) from Rhodobacter capsulatus. Titers of 47 mg/L for Cyt-cy, 7.5 mg/L for Occ, 1.5 mg/L for BcsAB and 0.5 mg/L for hAQP9 were achieved from affinity purification. While purification of GhoT was not successful, transformants displayed a distinct growth phenotype that correlated with GhoT expression. We also evaluated the functionality of these proteins by performing water transport studies for hAQP9, peroxidase activity for cytochrome-cy, and in vitro cellulose synthesis activity assay for BcsAB. While previous studies with Rhodobacter have utilized oxygen limited semi-aerobic growth for membrane protein expression, substantial titer improvements are achieved as a result of a 3-fold increase in biomass yield using the anaerobic photoheterotrophic growth regime, which utilizes the strong native puc promoter. This versatile platform is shown to enable recovery of a wide variety of difficult-to-express membrane proteins in functional form. PMID- 26008118 TI - Preparation of holo- and malonyl-[acyl-carrier-protein] in a manner suitable for analog development. AB - The fatty acid biosynthetic pathway generates highly reduced carbon based molecules. For this reason fatty acid synthesis is a target of pathway engineering to produce novel specialty or commodity chemicals using renewable techniques to supplant molecules currently derived from petroleum. Malonyl-[acyl carrier protein] (malonyl-ACP) is a key metabolite in the fatty acid pathway and donates two carbon units to the growing fatty acid chain during each step of biosynthesis. Attempts to test engineered fatty acid biosynthesis enzymes in vitro will require malonyl-ACP or malonyl-ACP analogs. Malonyl-ACP is challenging to prepare due to the instability of the carboxylate leaving group and the multiple steps of post-translational modification required to activate ACP. Here we report the expression and purification of holo- and malonyl-ACP from Escherichia coli with high yields (>15 mg per L of expression). The malonyl-ACP is efficiently recognized by the E. coli keto-acyl synthase enzyme, FabH. A FabH assay using malonyl-ACP and a coumarin-based fluorescent reagent is described that provides a high throughput alternative to reported radioactive assays. PMID- 26008120 TI - Host specificity and seasonality of helminth component communities in central European grebes (Podicipediformes) and loons (Gaviiformes). AB - Structure and pattern of helminth component communities parasitizing grebes and loons are poorly understood. Here we analyze the prevalence, intensity and diversity of helminths in 505 Czech grebes (Podiceps cristatus, Podiceps nigricollis, Tachybaptus ruficollis) and loons (Gavia arctica, Gavia stellata) collected between 1962 and 2014. The species richness of helminth component communities ranged from 31+/-8 (P. cristatus) to 50+/-4 (G. stellata) species, with helminth load similar in all five host species, but with strong differences in prevalence and intensity of infection at a helminth species-specific level. The dominance was low, ranging from 0.11 (P. cristatus and G. stellata) to 0.21 (P. nigricollis). Dominant species (>25% prevalence) in P. cristatus were Confluaria sp., Tylodelphys clavata, Echinochasmus coaxatus, Petasiger neocomense and Ligula colymbi; in P. nigricollis and T. ruficollis: Confluaria sp. and Tatria sp.; in G. arctica and G. stellata: Tetrabothrius microcephalus, Stephanoprora denticulata, Cryptocotyle concava, Diplostomum gavium and Ichthyocotylurus erraticus; in G. stellata only: Echinochasmus (Monilifer) spinulosus. Four (12%) of the grebe digenean species were not locally acquired (with non-sympatric intermediate hosts) despite the fact that they represented 25% of digenean individuals found. In loons, five (28%) of digenean species and striking 38% of individuals found used the non-sympatric intermediate host species. Component communities of grebes were similar to each other (Sorensen similarity index 0.47-0.65) but differed strongly from those hosted by loons (0.00-0.20). We present the first systematically collected evidence of intra annual changes of helminth component communities in grebes, and provide 20 new host records. PMID- 26008121 TI - Filtering the muddied waters of brain edema. PMID- 26008119 TI - Pregnancy intendedness and the association with physical, sexual and emotional abuse - a European multi-country cross-sectional study. AB - BACKGROUND: Unintended pregnancies are common and when not resulting in a termination of pregnancy may lead to unintended childbirth. Unintended pregnancies are associated with increased health risks, also for women for whom pregnancy continues to childbirth. Our objective was to present the prevalence of unintended pregnancy in six European countries among pregnant women attending routine antenatal care, and to investigate the association with a history of physical, sexual and emotional abuse. METHODS: A prospective cross-sectional study, of 7102 pregnant women who filled out a questionnaire during pregnancy as part of a multi-country cohort study (Bidens) with the participating countries: Belgium, Iceland, Denmark, Estonia, Norway and Sweden. A validated instrument, the Norvold Abuse Questionnaire (NorAq) consisting of 10 descriptive questions measured abuse. Pregnancy intendedness was assessed using a single question asking women if this pregnancy was planned. Cross-tabulation, Chi-square tests and binary logistic regression analysis were used. RESULTS: Approximately one fifth (19.2 %) of all women reported their current pregnancy to be unintended. Women with an unintended pregnancy were significantly younger, had less education, suffered economic hardship, had a different ethnic background from the regional majority and more frequently were not living with their partner. The prevalence of an unintended pregnancy among women reporting any lifetime abuse was 24.5 %, and 38.5 % among women reporting recent abuse. Women with a history of any lifetime abuse had significantly higher odds of unintended pregnancy, also after adjusting for confounding factors, AOR for any lifetime abuse 1.41 (95 % CI 1.23-1.60) and for recent abuse AOR 2.03 (95 % CI 1.54-2.68). CONCLUSION: Women who have experienced any lifetime abuse are significantly more likely to have an unintended pregnancy. This is particularly true for women reporting recent abuse, suggesting that women living in a violent relationship have less control over their fertility. PMID- 26008122 TI - A large scale clinical evaluation of the AmpliVue and Illumigene molecular tests for the identification of Clostridium difficile-associated diarrhea in adult and pediatric patients. AB - The AmpliVue (Quidel, San Diego, CA, USA) and Illumigene (Meridian Biosciences, Cincinnati, OH, USA) molecular tests were compared for the detection of C. difficile toxin in fresh fecal samples from adult and pediatric patients. A total of 758 samples were collected, in 3 clinical sites: Nationwide Children's (Columbus, OH, USA), Penn State Hershey (Hershey, PA, USA), Primary Children's (Salt Lake City, UT, USA). Each site tested the fecal specimens using both assays. Any discordant results were resolved by performing toxigenic culture. There were 16 discordant samples among the 3 sites. Following discordant resolution, the combined performance for all 3 sites for sensitivity, specificity, PPV, and NPV for AmpliVue was 96.1%, 99.2%, 96.1%, and 99.2%, respectively, while for Illumigene was 96.1%, 99.8%, 99.2%, and 99.2%, respectively. The AmpliVue and Illumigene methods are both relatively rapid and simple to use, sensitive, and specific for detection of C. difficile toxin and demonstrate similar performance. PMID- 26008123 TI - Assay for estimating total bacterial load: relative qPCR normalisation of bacterial load with associated clinical implications. AB - Relative microorganism abundance is a parameter describing biodiversity, referring to how common a bacterial species is within the total bacterial flora. Anal, rectal, skin, mucal, and respiratory swabs are typical clinical samples where knowledge of relative bacterial abundance might make distinction between asymptomatic carriers and symptomatic cases. Assays trying to measure total bacterial load are usually based on the amplification of universal segments of 16S rRNA genes. Previous assays were not adoptable to "direct" PCR protocols, and/or they were not compatible with hydrolysis-based detection. Using the latest summary of universal 16S sequence motifs present in literature and testing our design with 500 liquid and 50 formed stool samples, we illustrate the performance characteristics of a new 16S quantitative PCR (qPCR) assay, which addresses well known technical problems, including a) positive priming reaction in the absence of intended target due to self-priming and/or mispriming of unintended targets; b) amplification bias due to nonoptimal primer/probe coverage; and c) too large amplicons for clinical qPCR. Stool swabs ranked into bins of different bacterial loads show significant correlation with threshold cycle values of our new assay. To the best of our knowledge, this is the first description of qPCR assay measuring individual differences of total bacterial load present in human stool. PMID- 26008124 TI - Frequency of biocide-resistant genes and susceptibility to chlorhexidine in high level mupirocin-resistant, methicillin-resistant Staphylococcus aureus (MuH MRSA). AB - The aim of this study was to determine the prevalence of biocide-resistant determinants and the susceptibility to chlorhexidine in high-level mupirocin resistant, methicillin-resistant Staphylococcus aureus (MuH MRSA). Fifty-three MuH MRSA isolates were analyzed for plasmid-borne genes (qacA/B, smr, qacG, qacH, and qacJ) by polymerase chain reaction (PCR); for chromosome-mediated genes (norA, norB, norC, mepA, mdeA, sepA, and sdrM) by PCR and quantitative reverse transcription-PCR (qRT-PCR); and for susceptibility to chlorhexidine by MIC and minimum bactericidal concentration (MBC). Furthermore, disinfectant efficacy was tested in the presence of 3.0% bovine serum albumin (BSA) in MBC detection. The plasmid-borne genes qacA/B (83.0%) and smr (77.4%) and overexpressions of chromosome-mediated genes norA (49.0%) and norB (28.8%) were predominantly found in isolates studied, and 90.6% of the isolates revealed tolerance to chlorhexidine. In the presence of BSA, the average MBC of chlorhexidine for these isolates rose to 256 MUg/mL. Altogether, our results suggest that surveillance of sensitivity to biocides among MuH MRSA isolates is essential for hospital infection control. PMID- 26008125 TI - Hybrid uranyl-vanadium nano-wheels. AB - Hybrid uranyl-vanadium oxide clusters intermediate between transition metal polyoxometalates and uranyl peroxide cage clusters were obtained by dissolving uranyl nitrate in the ionic liquid 3-ethyl-1-methylimidazolium ethyl sulfate mixed with an aqueous solution containing vanadium. Where sulfate was present, wheel-shaped {U20V20} crystallized and contains ten sulfate tetrahedra, and in the absence of added sulfate, {U2V16}, a derivative of {V18}, was obtained. PMID- 26008126 TI - Architectural proteins, transcription, and the three-dimensional organization of the genome. AB - Architectural proteins mediate interactions between distant sequences in the genome. Two well-characterized functions of architectural protein interactions include the tethering of enhancers to promoters and bringing together Polycomb containing sites to facilitate silencing. The nature of which sequences interact genome-wide appears to be determined by the orientation of the architectural protein binding sites as well as the number and identity of architectural proteins present. Ultimately, long range chromatin interactions result in the formation of loops within the chromatin fiber. In this review, we discuss data suggesting that architectural proteins mediate long range chromatin interactions that both facilitate and hinder neighboring interactions, compartmentalizing the genome into regions of highly interacting chromatin domains. PMID- 26008127 TI - A systematic review identifies shortcomings in the reporting of crossover trials in chronic painful conditions. AB - OBJECTIVES: To investigate the reporting of study features of interest in abstracts and full texts of journal publications of crossover trials in chronic painful conditions. STUDY DESIGN AND SETTING: Systematic review based on a MEDLINE (PubMed) search (January 1990-August 2014). RESULTS: Ninety-eight publications on crossover studies with 3,513 study participants were eligible for inclusion. Double-blind status and randomized allocation to treatment groups are commonly reported in both abstracts and full texts (90 of 98 publications and 82 of 98 publications, respectively). Adverse events are reported in both abstract and full text in 49 of 98 publications and in the full text only in 44 of 98. A breakdown of results by treatment period is provided only in 23 of 98 publications, and if so, is reported only in the full text, never in the abstract. There is a time trend for the reporting of randomization in abstracts; it is more likely to be reported in recent studies (P = 0.0094). No time trends are detected in the reporting of double-blind status (P = 0.1087) and adverse events (P = 0.6084). CONCLUSION: The reporting of adverse events in the abstract and the reporting of results specified by crossover period in the full texts of journal publications on crossover pain trials should be improved. PMID- 26008128 TI - Gut microbiota: Commensal bacteria and intestinal surgery complications. PMID- 26008130 TI - Biliary tract: Newly identified biliatresone causes biliary atresia. PMID- 26008131 TI - Hepatitis: Myeloid-derived suppressor cells in HBV infection. PMID- 26008132 TI - Preparation of CdS nanoparticle loaded flower-like Bi2O2CO3 heterojunction photocatalysts with enhanced visible light photocatalytic activity. AB - In this work, a series of novel flower-like Bi2O2CO3/CdS heterojunctions were prepared by a simple and feasible two-step process. The phase structures of as prepared samples were examined by X-ray diffraction (XRD). Scanning electron microscopy (SEM), Transmission Electron Microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM) were used to confirm the flower-like heterostructures of the Bi2O2CO3/CdS composites. The Brunauer-Emmett-Teller (BET) specific surface area (SBET) of samples were analyzed by N2 adsorption-desorption isotherms. UV-vis diffuse reflectance spectrometry (DRS) revealed that Bi2O2CO3/CdS heterojunctions exhibited better light absorptive properties than pure Bi2O2CO3. The photocatalytic activity was investigated by the degradation of MB under visible light irradiation. The results showed that the as-prepared Bi2O2CO3/CdS heterojunctions exhibited much higher activity than pure Bi2O2CO3. The photoluminescence (PL) spectra and photocurrent studies indicated that the recombination of photogenerated electron-hole pairs was decreased effectively due to the formation of heterojunctions between flower-like Bi2O2CO3 and CdS nanoparticles. Trapping experiments indicated that O(2-) radicals were the main reactive species for MB degradation in the present photocatalytic system. Furthermore, the cycling experiments revealed the good stability of Bi2O2CO3-CdS composites. PMID- 26008129 TI - Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. AB - Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease. PMID- 26008133 TI - Ventilation heterogeneity in ex-smokers without airflow limitation. AB - RATIONALE AND OBJECTIVES: Hyperpolarized (3)He magnetic resonance imaging (MRI) ventilation abnormalities are visible in ex-smokers without airflow limitation, but the clinical relevance of this is not well-understood. Our objective was to phenotype healthy ex-smokers with normal and abnormally elevated ventilation defect percent (VDP). MATERIALS AND METHODS: Sixty ex-smokers without airflow limitation provided written informed consent to (3)He MRI, computed tomography (CT), and pulmonary function tests in a single visit. (3)He MRI VDP and apparent diffusion coefficients (ADCs) were measured for whole-lung and each lung lobe as were CT measurements of emphysema (relative area [RA] with attenuation <=-950 HU, RA950) and airway morphology (wall area percent [WA%], lumen area [LA] and LA normalized to body surface area [LA/BSA]). RESULTS: In 42 ex-smokers, there was abnormally elevated VDP and no significant differences for pulmonary function, RA950, or airway measurements compared to 18 ex-smokers with normal VDP. Ex smokers with abnormally elevated VDP reported significantly greater (3)He ADC in the apical lung (right upper lobe [RUL], P = .02; right middle lobe [RML], P = .04; and left upper lobe [LUL], P = .009). Whole lung (r = 0.40, P = .001) and lobar VDP (RUL, r = 0.32, P = .01; RML, r = 0.46, P = .002; right lower lobe [RLL], r = 0.38, P = .003; LUL, r = 0.35, P = .006; and left lower lobe, r = 0.37, P = .004) correlated with regional (3)He ADC. Although whole-lung VDP and CT airway morphology measurements were not correlated, regional VDP was correlated with RUL LA (r = -0.37, P = .004), LA/BSA (r = -0.42, P = .0008), RLL WA% (r = 0.28, P = .03), LA (r = -0.28, P = .03), and LA/BSA (r = -0.37, P = .004). CONCLUSIONS: Abnormally elevated VDP in ex-smokers without airflow limitation was coincident with very mild emphysema detected using MRI and regional airway remodeling detected using CT representing a subclinical obstructive lung disease phenotype. PMID- 26008134 TI - Depressive symptoms, pain, and sexual dysfunction over the first year following vaginal or cesarean delivery: A prospective longitudinal study. AB - BACKGROUND: Childbirth has a significant impact on maternal health, and the high rate of cesarean delivery is a global health concern. Few studies have used validated measures to explore depression, pain, and sexual dysfunction following vaginal or cesarean delivery over a prolonged time period. OBJECTIVE: We examined the associations between vaginal and cesarean delivery and depressive symptoms, pain, and sexual function during the 1-year postpartum period. DESIGN: A prospective, five-time-point longitudinal study. SETTING: Maternity unit at a medical center. PARTICIPANTS: A total of 351 of 736 women completed a questionnaire that described demographic characteristics, depressive symptoms, and pain levels at 3-5 days postpartum, and updated personal data, depressive symptoms, pain levels, and sexual function at 4-6 weeks and at 3, 6, and 12 months after delivery. METHODS: Differences between the vaginal and cesarean groups in depressive symptoms, pain, and sexual function and trends of changes in these factors over the first postpartum year were examined. RESULTS: Compared with the vaginal birth group, the cesarean birth group had a significantly higher prevalence of depressive symptoms at 3 months (p=0.03); higher scores for non localized pain at 3-5 days (p<0.001), 4-6 weeks (p=0.03), and 3 months (p=0.046); higher scores for abdominal pain at 3-5 days (p<0.001), 4-6 weeks (p<0.001), and 6 months (p=0.01); lower perineal pain scores at 3-5 days (p <0.001); and higher sexual desire scores (p=0.04) but lower sexual satisfaction scores (p=0.02) at 4 6 weeks. Differences between the vaginal and cesarean groups were significant (p=0.01, p=0.049, respectively) in terms of the decrease in non-localized pain from 3-5 days to 4-6 weeks postpartum and the increase in sexual desire from 4-6 weeks to 3 months postpartum. CONCLUSIONS: Cesarean delivery was associated with an increased prevalence of depressive symptoms at 3 months and higher pain levels that persisted at 6 months postpartum in Taiwan. We found no difference in sexual function between vaginal and cesarean delivery after 6 weeks postpartum, and no differences in the trends related to depressive symptoms or in sexual functioning (except for desire) within 1 year postpartum. PMID- 26008135 TI - The role of noise in clinical environments with particular reference to mental health care: A narrative review. AB - BACKGROUND: There is a large literature suggesting that noise can be detrimental to health and numerous policy documents have promoted noise abatement in clinical settings. OBJECTIVES: This paper documents the role of noise in clinical environments and its deleterious effects with a particular focus on mental health care. Our intention however, is to go beyond the notion that noise is simply undesirable and examine the extent to which researchers have explored the meaning of sound in hospital settings and identify new opportunities for research and practice. DATA SOURCES AND REVIEW METHODS: This is a narrative review which has grouped the literature and issues in the field into themes concerning the general issues of noise in health care; sleep noise and hospital environments; noise in intensive care units; implications for service users and staff; and suggestions for new ways of conceptualising and researching clinical soundscapes. Data sources comprised relevant UK policy documents and the results of a literature search of Pubmed, Scopus and Web of Knowledge using terms such as noise, health, hospital, soundscape and relevant additional terms derived from the papers retrieved. In addition the references of retrieved articles were scanned for additional relevant material and historical items significant in shaping the field. RESULTS: Excess unwanted noise can clearly be detrimental to health and impede recovery, and this is clearly recognised by policymakers especially in the UK context. We use the literature surveyed to argue that it is important also to see the noise in clinical environments in terms of the meaning it conveys and rather than merely containing unwanted sound, clinical environments have a 'soundscape'. This comprises noises which convey meaning, for example about the activities of other people, the rhythms of the day and the nature of the auditory community of the hospital. Unwanted sound may have unwanted effects, especially on those who are most vulnerable, yet this does not necessarily mean that silence is the better option. Therefore it is our contention that it is important to begin thinking about the social functions of sound in the mental health environment. CONCLUSIONS: Whilst it can be stressful, sound can also be soothing, reassuring and a rich source of information about the environment as well. It may be used to secure a degree of privacy for oneself, to exclude others or as a source of solidarity among friends and colleagues. The challenge then is to understand the work that sound does in its ecological context in health care settings. PMID- 26008136 TI - Delivery of Mental Health Care in a Large Disaster Shelter. AB - Large numbers of evacuees arrived in Dallas, Texas, from Hurricanes Katrina and Rita just 3 weeks apart in 2005 and from Hurricanes Gustav and Ike just 3 weeks apart again in 2008. The Dallas community needed to locate, organize, and manage the response to provide shelter and health care with locally available resources. With each successive hurricane, disaster response leaders applied many lessons learned from prior operations to become more efficient and effective in the provision of services. Mental health services proved to be an essential component. From these experiences, a set of operating guidelines for large evacuee shelter mental health services in Dallas was developed, with involvement of key stakeholders. A generic description of the processes and procedures used in Dallas that highlights the important concepts, key considerations, and organizational steps was then created for potential adaptation by other communities. PMID- 26008137 TI - Growth trajectories in early childhood, their relationship with antenatal and postnatal factors, and development of obesity by age 9 years: results from an Australian birth cohort study. AB - BACKGROUND: In an era where around one in four children in the United Kingdom, the United States, and Australia are overweight or obese, the development of obesity in early life needs to be better understood. We aimed to identify groups of children with distinct trajectories of growth in infancy and early childhood, to examine any association between these trajectories and body size at age 9, and to assess the relative influence of antenatal and postnatal exposures on growth trajectories. DESIGN: Prospective Australian birth cohort study. SUBJECTS AND METHODS: In total, 557 children with serial height and weight measurements from birth to 9 years were included in the study. Latent class growth models were used to derive distinct groups of growth trajectories from birth to age 31/2 years. Multivariable logistic regression models were used to explore antenatal and postnatal predictors of growth trajectory groups, and multivariable linear and logistic regression models were used to examine the relationships between growth trajectory groups and body size at age 9 years. RESULTS: We identified four discrete growth trajectories from birth to age 31/2 years, characterised as low, intermediate, high, or accelerating growth. Relative to the intermediate growth group, the low group had reduced z-body mass index (BMI) (-0.75 s.d.; 95% confidence interval (CI) -1.02, -0.47), and the high and accelerating groups were associated with increased body size at age 9 years (high: z-BMI 0.70 s.d.; 95% CI 0.49, 0.62; accelerating: z-BMI 1.64 s.d.; 95% CI 1.16, 2.11). Of the antenatal and postnatal exposures considered, the most important differentiating factor was maternal obesity in early pregnancy, associated with a near quadrupling of risk of membership of the accelerating growth trajectory group compared with the intermediate growth group (odds ratio (OR) 3.72; 95% CI 1.15, 12.05). CONCLUSIONS: Efforts to prevent childhood obesity may need to be embedded within population-wide strategies that also pay attention to healthy weight for women in their reproductive years. PMID- 26008138 TI - Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis -A randomised placebo-controlled pilot trial. AB - An overwhelming inflammatory process is the hallmark of severe sepsis and septic shock. Matrix metalloproteinases (MMPs)-8 and -9 are released from neutrophils and activated in sepsis to participate in inflammation in several ways. High levels of MMP-8 may associate with increased ICU mortality. The activity of MMP-8 and -9 is regulated by a natural inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Moreover, MMPs are chemically inhibited by tetracycline-group antibiotics, such as doxycycline. We therefore aimed to study plasma concentration and MMP inhibition after intravenous doxycycline in critically ill patients with severe sepsis and septic shock in a prospective, randomised, placebo-controlled double-blinded pilot trial. Twenty-four patients with severe sepsis or septic shock were randomised in 3 groups. Group 1 received 200, 100 and 100mg, group 2 100, 50 and 50mg of intravenous doxycycline and group 3 placebo on three consecutive days. We measured doxycycline concentrations from baseline up to day 5. MMPs and TIMP-1 concentrations were measured from baseline up to day 10 of study and we compared their changes over time from baseline to 72 h and from baseline to 120 h. Data from 23 patients were analysed. At 72 h all patients in group 1 showed doxycycline concentrations >1 mg/l, whereas none in group 2 did. No serious adverse effects of the drug were recorded. We observed no differences over time up to 72 or up to 120 h in the concentrations or activities of MMP-8, -9 or TIMP-1 in any of the groups. We found intravenous doxycycline 100, 50 and 50mg to be adequate to achieve a sub-antimicrobial concentration in patients with severe sepsis or septic shock but having no impact on MMP-8, -9 or TIMP-1 concentrations or activities. PMID- 26008139 TI - Comprehensive survey of condition-specific reproductive isolation reveals genetic incompatibility in yeast. AB - Genetic variation within a species could cause negative epistasis leading to reduced hybrid fitness and post-zygotic reproductive isolation. Recent studies in yeasts revealed chromosomal rearrangements as a major mechanism dampening intraspecific hybrid fertility on rich media. Here, by analysing a large number of Saccharomyces cerevisiae crosses on different culture conditions, we show environment-specific genetic incompatibility segregates readily within yeast and contributes to reproductive isolation. Over 24% (117 out of 481) of cases tested show potential epistasis, among which 6.7% (32 out of 481) are severe, with at least 20% of progeny loss on tested conditions. Based on the segregation patterns, we further characterize a two-locus Dobzhansky-Muller incompatibility case leading to offspring respiratory deficiency caused by nonsense mutation in a nuclear-encoding mitochondrial gene and tRNA suppressor. We provide evidence that this precise configuration could be adaptive in fluctuating environments, highlighting the role of ecological selection in the onset of genetic incompatibility and reproductive isolation in yeast. PMID- 26008140 TI - Medically-Derived (131)I as a Tool for Investigating the Fate of Wastewater Nitrogen in Aquatic Environments. AB - Medically derived (131)I (t1/2 = 8.04 d) is discharged from water pollution control plants (WPCPs) in sewage effluent. Iodine's nutrient-like behavior and the source-specificity of (131)I make this radionuclide a potentially valuable tracer in wastewater nitrogen studies. Iodine-131 was measured in Potomac River water and sediments in the vicinity of the Blue Plains WPCP, Washington, DC, USA. Dissolved (131)I showed a strong, positive correlation with delta(15)N values of nitrate (delta(15)NO3(-)) in the river, the latter being a traditional indicator of nutrient inputs and recycling. Surface water delta(15)NO3(-) values ranged from 8.7 to 33.40/00; NO3(-) + NO2(-) concentrations were 0.39-2.79 mg N L(-1) (26-186 MUM). Sediment profiles of particulate (131)I and delta(15)N indicate rapid mixing or sedimentation and in many cases remineralization of a heavy nitrogen source consistent with wastewater nitrogen. Values of delta(15)N in sediments ranged from 4.7 to 9.30/00. This work introduces (131)I as a tool to investigate the short-term fate of wastewater nitrogen in the Potomac River and demonstrates the general utility of (131)I in aquatic research. PMID- 26008141 TI - Complications Following Stereotactic Needle Biopsy of Intracranial Tumors. AB - BACKGROUND: Data from single-institution studies suggest that perioperative complication rates after stereotactic needle brain biopsies range from 6% to 12%, with permanent morbidity and mortality ranging from 3.1% to 6.4% and 0% to 1.7%, respectively. However, no population-level data are available. We conducted a population-based analysis to study complications after needle brain biopsy. METHODS: We analyzed patients recorded in the Nationwide Inpatient Sample who underwent stereotactic needle brain biopsy for neoplastic lesions between 2006 and 2012. A multivariate logistic model was used to identify factors associated with complications. RESULTS: We identified 7514 patients who underwent biopsy for various intracranial pathologies, including primary malignant neoplasm (52.3%), unspecified neoplasm (17.9%), metastasis (9.7%), meningioma (1.5%), radiation necrosis (0.8%), lymphoma (0.5%), and pineal region neoplasm (0.3%). Intracranial hemorrhage was the most frequent complication (5.8%). Other complications, including operative infection (0.1%) and wound breakdown (0.2%), were rare. Multivariate logistic regression analysis revealed that hemorrhage is associated with older age (reference <40 years; 40-59 years, odds ratio [OR] 2.26, 95% confidence interval [CI] 1.51-3.38; >=60 years, OR 1.90, 95% CI 1.22-2.97), hydrocephalus (OR 3.02, 95% CI 2.20-4.14), and cerebral edema (OR 2.16, 95% CI 1.72-2.72). Hemorrhage is less likely when taking a biopsy from a primary malignant neoplasm (OR 0.73, 95% CI 0.59-0.90). Overall inpatient mortality after biopsy was 2.8%. Patients with intracranial hemorrhage were significantly more likely than patients without hemorrhage to die in the hospital (12.8% vs. 2.2%, P < 0.001) or be discharged to a rehabilitation/nursing facility (45.2% vs. 23.1%, P < 0.001). CONCLUSIONS: Intracranial hemorrhage is the most frequent complication associated with needle brain biopsy and is associated with inpatient mortality and hospital disposition. Other complications are rare. PMID- 26008142 TI - The Expanding Spectrum of Disease Treated by the Transnasal, Transsphenoidal Microscopic and Endoscopic Anterior Skull Base Approach: A Single-Center Experience 2008-2015. AB - INTRODUCTION: The transsphenoidal approach was initially developed in neurosurgical practice as an operative approach to the pituitary gland. The introduction of the operating endoscope has improved the versatility of the transsphenoidal approach, broadening the spectrum of lesions that can be treated effectively with this operative strategy. METHODS: We performed a retrospective review of all patients who underwent transnasal, transsphenoidal operations at Brigham and Women's Hospital from April 2008 to February 2015 and categorized each case by pathologic diagnosis. RESULTS: A total of 792 transnasal, transsphenoidal operations (512 endoscopic) were performed by 9 neurosurgeons for 33 pathologies over a 7-year period. Pituitary adenomas (535, 67.55%) were the most common impetus for a transsphenoidal operation. Others included Rathke cleft cysts (86, 10.86%), craniopharyngiomas (25, 3.16%), lympocytic hypophysitis/pituitary inflammation (21, 2.65%), arachnoid cysts (8, 1.01%), spindle cell oncocytoma (4, 0.51%), colloid cysts (4, 0.51%), and pituicytoma (2, 0.25%). Pituitary hyperplasia was treated in 9 cases (1.14%) and pituitary apoplexy in 7 (0.88%). Nineteen operations were undertaken for postoperative repairs (2.40%) and 3 for abscesses (0.38%). Other diseases treated transsphenoidally included chordomas (12, 1.52%), metastases (9, 1.14%), meningiomas (5, 0.63%), clival lesions (4, 0.51%), germinomas (3, 0.38%), granulomas (2, 0.25%), dermoid tumors (2, 0.25%), and 1 (0.13%) each of esthesioneuroblastoma, granular cell tumor, Wegener granulomatosis, olfactory neuroblastoma, glioneuronal tumor, chondromyxoid fibroma, epidermoid, meningoencephalocele, aneurysm, neuroendocrine carcinoma, chondrosarcoma, and lymphoma. CONCLUSIONS: Although initially devised in neurosurgical practice for tumors of the pituitary gland, developments in technology now make the transsphenoidal approach an effective operative strategy for a wide range of anterior skull base lesions. PMID- 26008143 TI - Pathogenesis, Surgical Treatment, and Cure for SUNCT Syndrome. AB - BACKGROUND: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are characterized by attacks of moderate to severe stabbing pain, strictly unilateral, with periorbital or temporal distribution, associated with cranial autonomic symptoms, such as lacrimation and redness of the ipsilateral eye. METHODS: To obtain mechanistic insights into the pathogenesis of SUNCT syndrome, more than 800 cases treated in our institution during the last 7 years were retrospectively reviewed. Two patients showed typical autonomic symptoms of SUNCT. RESULTS: Magnetic resonance imaging suggested potential compression of the trigeminal nerve by the intracranial artery in these cases and complete remission was achieved by microvascular decompression. CONCLUSIONS: Microvascular decompression provides an appropriate therapeutic choice if vascular compression of the trigeminal nerve is identified. From our 2 cases, we propose that, in some cases of SUNCT diagnosed previously, characteristic symptoms were induced by compression of the side surface of the first branch of the trigeminal nerve at the root exit zone by the intracranial artery. PMID- 26008144 TI - Preparation of Xenopus laevis retinal cryosections for electron microscopy. AB - Transmission electron microscopy is the gold standard for examination of photoreceptor outer segment morphology and photoreceptor outer segment abnormalities in transgenic animal models of retinal disease. Small vertebrates such as zebrafish and Xenopus laevis tadpoles have been used to generate retinal disease models and to study outer segment processes such as protein trafficking, and their breeding capabilities facilitate experiments involving large numbers of animals and conditions. However, electron microscopy processing and analysis of these very small eyes can be challenging. Here we present a methodology that facilitates processing of X. laevis tadpole eyes for electron microscopy by introducing an intermediate cryosectioning step. This method reproducibly provides a well-oriented tissue block that can be sectioned with minimal effort by a non-expert, and also allows retroactive analysis of samples collected on slides for light microscopy. PMID- 26008145 TI - Recycling of ladle slag in cement composites: Environmental impacts. AB - In the present work compact and ground cement composites in which 30% of cement by mass was replaced by ladle slag were investigated for their chemical and physico-mechanical properties. To evaluate long-term environmental impacts, leachability test based on diffusion, which combined both, diffusion and dissolution of contaminants, was performed in water and saline water. Total element concentrations and Cr(VI) were determined in leachates over a time period of 180days. At the end of the experiment, the mineralogical composition and the physico-mechanical stability of cement composites was also assessed. The results revealed that Cr(III) and Cr(VI) were immobilized by the hydration products formed in the cement composites with the addition of ladle slag. Cr(VI) content originating from the cement was also appreciably reduced by Fe(II) from minerals present in the added ladle slag, which thus had significant positive environmental effects. Among metals, only Mo and Ba were leached in elevated concentrations, but solely in ground cement composites with the addition of ladle slag. Lower V concentrations were observed in leachates of ground than compact composite. It was demonstrated that the presence of ladle slag in cement composites can even contribute to improved mortar resistance. The investigated ladle slag can be successfully implemented in cement composites as supplementary cementitious material. PMID- 26008146 TI - EBP1 suppresses growth, migration, and invasion of thyroid cancer cells through upregulating RASAL expression. AB - Ebp1, a protein identified by its interactions with the ErbB3 receptor, has been characterized as a negative regulator of cancers. RAS GTPase-activating protein (RasGAP), RASAL1, was recently identified as a major tumor suppressor in thyroid cancer. In this study, we examined EBP1 expression in papillary and follicular thyroid cancer cells. We found that compared with normal thyroid cells, TPC1, WRO, and FTC133 thyroid tumor cells exhibited lower EBP1 expression at messenger RNA (mRNA) and protein levels. We then investigated the effects of forced EBP1 expression on growth, migration, and invasiveness of thyroid tumor cells. By using MTT and Boyden chamber assays, we showed that EBP1 overexpression dramatically reduced growth rate, migration, and invasiveness of K1 and FTC133 thyroid tumor cells. Furthermore, we explored the molecular mechanism underlying the effects of EBP1 on the cells by disclosing the correlation of EBP1 and RASAL1 expression. RASAL expression was elevated in thyroid tumor cells overexpressing EBP1. Knockdown RASAL by transduction of RASAL1 shRNA lentiviral particles markedly reduced RASAL levels with restoration of EBP1, and RASAL1 knockdown abrogated the effects of forced EBP1 expression on cell growth, migration, and invasiveness of thyroid tumor cells. These findings suggest that Ebp1 suppressed thyroid cancer cell lines by upregulating RASRAL expression. PMID- 26008148 TI - FACTORS INFLUENCING MISTIMED AND UNWANTED PREGNANCIES AMONG NEPALI WOMEN. AB - This paper assesses the factors influencing mistimed and unwanted pregnancies in Nepal separately using data from the 2011 Nepal Demographic and Health Survey. Women who had given birth within the five years before the survey were interviewed about the intendedness of their last pregnancy. The data were analysed with a chi-squared test, followed by multiple logistic regression analysis. Among the total 5391 participants, 11.29% and 13.13% reported their last pregnancy as mistimed and unwanted respectively. Logistic regression analysis showed that women from the hill region were more likely to report mistimed pregnancy, while women from the Western and Far-Western development regions were less likely to report mistimed pregnancy. Education status was positively correlated with the reporting of mistimed pregnancy. Women involved in agriculture, with full autonomy on household decision, with some exposure to mass media, belonging to higher age group and having third or higher parity were less likely to report mistimed pregnancy. Similarly, women from the Western development region had relatively higher odds of reporting unwanted pregnancy. Women with husbands involved in a paid job had lower odds of unwanted pregnancy. Women's autonomy was also positively correlated with unwanted pregnancy. Women with the intention to use contraceptive had lower odds of unwanted pregnancy. Interventions targeting the factors identified by this study could be useful in reduction of mistimed and unwanted pregnancies among Nepali women. PMID- 26008147 TI - Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia. AB - Telomeric dysfunction has been proposed as an emerging prognostic factor in chronic lymphocytic leukemia (CLL). We have explored the relationship between telomere length (TL) and chromosome alterations studied by fluorescence in situ hybridization (FISH) and conventional cytogenetics in 107 newly diagnosed CLL patients; 61 normal controls were also evaluated. Results were correlated with clinical parameters and outcome. Absolute TL measurement was carried out on DNA samples by real-time quantitative PCR. A significant telomere shortening in patients compared to controls was observed (p = 0.0001). The analysis taking into account FISH risk groups showed shorter TLs in cases with del11q/17p compared to patients with 13q14 deletion as a single alteration (p = 0.0037), no alterations (NA) (p = 0.028), and cases with abnormal karyotypes (p = 0.014). In addition, a significant TL reduction in cases with two or more anomalies with respect to those with NA (p = 0.033) and with one alteration (p = 0.045), and no differences compared to cases with deletions 11q/17p were observed. Patients with only one anomaly did not show statistical differences with respect to controls; meanwhile, a significant TL reduction in cases with two or more aberrations was observed (p = 0.025). The shortest telomeres were associated to 11q/17p deletion with significant differences compared to the remaining groups (p <= 0.045). Significantly shorter treatment free survival in patients with two or more alterations compared to those with NA plus one abnormality was observed (p = 0.0006). Our findings support the association between short TL and chromosome alterations in CLL and indicate the importance of telomere dysfunction in driving genomic instability in this pathology. PMID- 26008149 TI - Both BMP4 and serum have significant roles in differentiation of embryonic stem cells to primitive and definitive endoderm. AB - Differentiation of embryonic stem (ES) cells is a heterogeneous process which is influenced by different parameters, including growth and differentiation factors. The aim of the present study was to investigate the effect of bone morphogenetic protein-4 (BMP4) signaling on differentiation of mouse ES cells to endodermal lineages. For this purpose, differentiation of the ES cells was induced by embryoid body (EB) formation through hanging drop method. During the suspension stage, EBs were treated with BMP4 in a medium containing either fetal bovine serum (FBS) or knockout serum replacement (KoSR). After plating, EBs showed differentiation to a heterogeneous population of specialized cell types. Two weeks after plating, all the experimental groups expressed three germ layer markers and some primitive and definitive endoderm-specific genes. Quantitative real-time PCR analysis showed higher expression levels of Sox17, Pdx1, Cdx2 and Villin mRNAs in the KoSR plus BMP4 condition and higher Gata4 and Afp expression levels in the FBS plus BMP4 condition. Formation of visceral endoderm and derivatives of definitive endoderm was detected in the BMP4 treated EBs. In conclusion, we demonstrated that both BMP4 signaling and serum composition have significant roles in differentiation of mouse ES cells towards endodermal lineages. PMID- 26008150 TI - A shape-based quality evaluation and reconstruction method for electrical impedance tomography. AB - Linear methods of reconstruction play an important role in medical electrical impedance tomography (EIT) and there is a wide variety of algorithms based on several assumptions. With the Graz consensus reconstruction algorithm for EIT (GREIT), a novel linear reconstruction algorithm as well as a standardized framework for evaluating and comparing methods of reconstruction were introduced that found widespread acceptance in the community. In this paper, we propose a two-sided extension of this concept by first introducing a novel method of evaluation. Instead of being based on point-shaped resistivity distributions, we use 2759 pairs of real lung shapes for evaluation that were automatically segmented from human CT data. Necessarily, the figures of merit defined in GREIT were adjusted. Second, a linear method of reconstruction that uses orthonormal eigenimages as training data and a tunable desired point spread function are proposed. Using our novel method of evaluation, this approach is compared to the classical point-shaped approach. Results show that most figures of merit improve with the use of eigenimages as training data. Moreover, the possibility of tuning the reconstruction by modifying the desired point spread function is shown. Finally, the reconstruction of real EIT data shows that higher contrasts and fewer artifacts can be achieved in ventilation- and perfusion-related images. PMID- 26008151 TI - Peptide GE11-Polyethylene Glycol-Polyethylenimine for targeted gene delivery in laryngeal cancer. AB - The objective of this study was to evaluate the possibility of using GE11 polyethylene glycol-polyethylenimine (GE11-PEG-PEI) for targeted gene delivery to treat epidermal growth factor receptor (EGFR)-overexpressing laryngeal cancer. This study described the design, characterization, and in vitro and in vivo study of the nanocarrier GE11-PEG-PEI for gene delivery to treat laryngeal cancer. Analysis of the sizes and zeta potentials indicated that the formation of PEGylated complexes was dependent on the N/P ratio, and these complexes were capable of binding plasmid DNA and condensing DNA into small positively charged nanoparticles. The results also revealed that GE11-PEG-PEI had a weaker effect on cell survival in vitro. Gene transfection was performed on human laryngeal cancer Hep-2 cells in vitro and in vivo. Both the in vitro and in vivo results demonstrated that GE11-PEG-PEI had greater transfection efficiency than mPEG-PEI. Compared with mPEG-PEI/pORF-hTRAIL and saline, GE11-PEG-PEI/pORFh-TRAIL significantly (p < 0.05) reduced tumor growth in nude mice with laryngeal cancer. Moreover, the GE11-PEG-PEI/pORF-hTRAIL-treated groups showed more apoptosis than the mPEG-PEI/pORF-hTRAIL-treated groups. Therefore, our results showed that the peptide GE11 conjugated to PEG-PEI delivered significantly more genes to EGFR overexpressing laryngeal cancer cells in vivo, indicating that GE11-PEG-PEI may be a suitable gene vector for treating EGFR-overexpressing laryngeal cancer. PMID- 26008152 TI - Knockdown of eIF3d inhibits cell proliferation through G2/M phase arrest in non small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related death worldwide. Eukaryotic translation initiation factor 3, subunit d (eIF3d) has been recognized recently in several human cancers. In this paper, we attempt to evaluate the functional role of eIF3d in NSCLC cells. Lentivirus-mediated RNA interference (RNAi) was applied to silence eIF3d in the human NSCLC cell lines A549 and 95D. Cell viability was measured by MTT. Cell colony-forming ability was measured by colony formation. Cell cycle progression was determined by propidium iodide staining and flow cytometry. Intracellular signaling molecules were detected using a PathScan((r)) intracellular signaling array kit. In this study, we firstly proved that lentivirus-mediated RNAi specifically suppressed the expression of eIF3d both at the mRNA and protein levels in A549 and 95D cell lines. Further investigations revealed that eIF3d knockdown significantly inhibited cell proliferation and colony formation. Moreover, the cell cycle of A549 cells was arrested at G2/M phase after eIF3d knockdown. Furthermore, the activations of AKT, HSP27 and SAPK/JNK were suppressed by eIF3d knockdown. This study highlights the crucial role of eIF3d in promoting NSCLC cell proliferation, and provides a foundation for further study into the clinical potential of lentiviral-mediated delivery of eIF3d RNAi therapy for treatment of NSCLC. PMID- 26008154 TI - Intracellular and cell-to-apoplast compartmentation of carbohydrate metabolism. AB - In most plants, carbohydrates represent the major energy store as well as providing the building blocks for essential structural polymers. Although the major pathways for carbohydrate biosynthesis, degradation, and transport are well characterized, several key steps have only recently been discovered. In addition, several novel minor metabolic routes have been uncovered in the past few years. Here we review current studies of plant carbohydrate metabolism detailing the expanding compendium of functionally characterized transport proteins as well as our deeper comprehension of more minor and conditionally activated metabolic pathways. We additionally explore the pertinent questions that will allow us to enhance our understanding of the response of both major and minor carbohydrate fluxes to changing cellular circumstances. PMID- 26008153 TI - Lymphatic-targeted therapy following neoadjuvant chemotherapy: a promising strategy for lymph node-positive breast cancer treatment. AB - Neoadjuvant chemotherapy has been increasingly used to downstage breast cancer prior to surgery recently. However, in some cases, it was observed that despite sufficient regression of primary tumors, the metastatic lymph nodes remained nonresponsive. In this study, we applied lymphatic-targeted strategy to evaluate its efficacy and safety for patients presenting refractory nodes following systemic chemotherapy. A total of 318 breast cancer patients were demonstrated with lymph node metastasis by needle biopsy and given neoadjuvant chemotherapy. Two cycles later, 72 patients were observed with responsive tumors but stable nodes, 42 of which received a subcutaneous injection of lymphatic-targeted pegylated liposomal doxorubicin during the third cycle, while the remaining 30 patients were continued with former neoadjuvant therapeutic pattern and regarded as the control. Lymphatic-targeted treatment substantially increased both clinical and pathological node response rate [62 % (26/42) vs. 13 % (4/30) and 12 % (5/42) vs. 0 (0/30), respectively], and induced a higher apoptosis level of metastatic cells (median, 41 vs. 6 %), compared with the control. Moreover, a higher disease-free survival was observed after a median follow-up of 4 years (69 vs. 56 %). Inflammatory reaction surrounding injection sites was the most common side effect. Lymphatic chemotherapy has reliable efficacy and well-tolerated toxicity for breast cancer patients presenting refractory lymph nodes following neoadjuvant chemotherapy. PMID- 26008155 TI - Differential expression of CART in feeding and reward circuits in binge eating rat model. AB - Binge eating (BE) disrupts feeding and subverts reward mechanism. Since cocaine- and amphetamine-regulated transcript peptide (CART) mediates satiety as well as reward, its role in BE justifies investigation. To induce BE, rats were provided restricted access to high fat sweet palatable diet (HFSPD) for a period of 4 weeks. Immunoreactivity profile of the CART elements, and accompanying neuroplastic changes were studied in satiety- and reward-regulating brain nuclei. Further, we investigated the effects of CART, CART-antibody or rimonabant on the intake of normal chow or HFSPD. Rats fed on HFSPD showed development of BE-like phenotype as reflected by significant consumption of HFSPD in short time frame, suggestive of dysregulated satiety mechanisms. At the mid-point during BE, CART immunoreactivity was significantly increased in hypothalamic arcuate (ARC), lateral (LH), nucleus accumbens shell (AcbSh) and paraventricular nucleus of thalamus (PVT). However, for next 22-h post-binge time-period, the animals showed no interest in food, and low CART expression. Pre-binge treatment with rimonabant, a drug recommended for the treatment of BE, produced anorexia, increased CART expression in ARC and LH, but not in AcbSh and PVT. Higher dose of CART was required to produce anorexia in binged rats. While neuronal tracing studies confirmed CART fiber connectivity from ARC and LH to AcbSh, increase in CART and synaptophysin immunostaining in this pathway in BE rats suggested strengthening of the CART connectivity. We conclude that CART bearing ARC-LH-PVT AcbSh reward circuit may override the satiety signaling in ARC-PVN pathway in BE rats. PMID- 26008156 TI - Nicotine-induced place conditioning and locomotor activity in an adolescent animal model of attention deficit/hyperactivity disorder (ADHD). AB - Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.0, 0.1, 0.3 and 0.6 mg/kg). Prior to conditioning, SHRs were more active and less biased toward one side of the CPP chamber than WKY rats. Following conditioning, SHRs developed CPP to the highest dose of nicotine (0.6 mg/kg), whereas WKYs did not develop CPP to any nicotine dose tested. During conditioning, SHRs displayed greater locomotor activity in the nicotine-paired compartment than in the saline-paired compartment across conditioning trials. SHRs that received nicotine (0.1, 0.3, 0.6 mg/kg) in the nicotine-paired compartment showed an increase in locomotor activity between conditioning trials. Nicotine did not significantly affect WKY locomotor activity. These findings suggest that the SHR strain is a suitable model for studying ADHD-related nicotine use and dependence, but highlights potential limitations of the WKY control strain and the CPP procedure for modeling ADHD related nicotine reward. PMID- 26008157 TI - Differential protein expression in the nucleus accumbens of high and low active mice. AB - Physical inactivity is associated with the development of a variety of chronic illnesses. Literature has shown that physical activity is genetically regulated; however there is limited information on the mechanisms that influence this process with existing studies primarily focused on genomic and/or transcription association studies. There have been no studies to determine differential protein expression in the nucleus accumbens, the brain site thought to be involved in activity regulation, between high and low active animals. We compared the global nucleus accumbens proteome signature from known high- and low-active mice and identified seven differentially expressed proteins. Low active mice generally over expressed proteins associated with neural stress (Stress 70 protein and V type proton ATPase catalytic subunit A), and the high-active mice over expressed proteins associated with metabolism (creatine kinase B, succinyl-CoA ligase). Previously suggested mechanisms associated with activity regulation in the nucleus accumbens have centered on dopamine receptor 1 and endocannabinoid receptor 1. However, these proteins and the associated pathways were not differentially expressed between high and low active mice. In conclusion, protein expression must be determined as part of the effort to identify involved mechanisms in regulating activity and there appears to be separate nucleus accumbens proteome signatures associated with high- and low-active mice. PMID- 26008158 TI - Repeated administration of estradiol promotes mechanisms of sexual excitation and inhibition: Glutamate signaling in the ventromedial hypothalamus attenuates excitation. AB - Repeated administration of 10 MUg of estradiol benzoate (EB) every 4 days to the ovariectomized (OVX) rat induces a behavioral sensitization of sexual behaviors. Repeated copulation or the receipt of vaginocervical stimulation (VCS) attenuates the sensitization of appetitive sexual behaviors, suggesting that VCS acts in opposition to the mechanisms that induce the sensitization. It is known that VCS accelerates the onset of estrous termination (characterized by a decrease in appetitive sexual behaviors, and an increase in defensive behaviors prior to the decline in lordosis), and glutamate transmission in the ventromedial hypothalamus (VMH), particularly via AMPA receptor signaling, is an important regulator of this effect. Thus, the current studies examined whether mechanisms of estrous termination are involved in the attenuated sensitization to EB that occurs with repeated copulation. In the first study, OVX rats received infusions of AMPA to the VMH on tests 2-4, and sexual behavior was measured on tests 1 and 5. Appetitive sexual behaviors were lower in females that received AMPA infusions in place of copulation compared to saline, suggesting that AMPA receptor activation by VCS may be playing a role in the attenuation of sensitization. In the second study, females that were not given the opportunity to copulate on tests 2-4 fell out of behavioral estrus faster than those that did, suggesting that both excitatory and inhibitory mechanisms of sexual behavior become sensitized with repeated administration of EB. Together these findings extend our hypothesis that repeated episodes of heat sensitize the activation of sexual behaviors to increase the probability of eventual fertilization. PMID- 26008168 TI - New patient access for pediatric specialties: some tools and challenges. PMID- 26008169 TI - New challenges in the diagnosis and management of cystic fibrosis. PMID- 26008170 TI - 50 Years Ago in The Journal of Pediatrics: Treatment of Hydrocephalus with Acetazolamide: Results in 15 Cases. PMID- 26008171 TI - 50 Years Ago in The Journal of Pediatrics: Cerebrospinal Fluid Protein Values of Premature Infants. PMID- 26008172 TI - 50 Years Ago in The Journal of Pediatrics: Acquired Disaccharide Intolerance in Malnutrition. PMID- 26008173 TI - A multicenter study on childhood constipation and fecal incontinence: effects on quality of life. AB - OBJECTIVE: To describe the effects of childhood functional constipation compared with functional constipation plus fecal incontinence on quality of life, evaluating effects on physical, psychosocial, and family functioning. STUDY DESIGN: This prospective, multicenter study collected data from 5 regional children's hospitals. Children meeting Rome III criteria for functional constipation were included. Parents completed the following 5 instruments: Pediatric Quality of Life Inventory (PedsQL), PedsQL-Family Impact Module, Functional Disability Inventory-Parent Version, Pediatric Inventory for Parents (PIP), and Pediatric Symptom Checklist-Parent Report. RESULTS: Families of 410 children aged 2-18 years (mean [SD], 7.8 [3.5] years; 52% male) were included. Children with functional constipation+fecal incontinence had worse quality of life than children with functional constipation alone (PedsQL Total Score, P <= .03). Older children with functional constipation + fecal incontinence had lower quality of life than their younger counterparts (PedsQL Total Score, P <= .047). Children with functional constipation+fecal incontinence had worse family functioning (PedsQL-Family Impact Module Total Score, P <= .012), greater parental stress (PIP-F Total Score, P <= .016; PIP-D Total Score, P <= .013), and poorer psychosocial functioning (Pediatric Symptom Checklist Total Score, P <= .003). There were no statistically significant between-group differences in physical functioning based on the functional Disability Inventory. CONCLUSION: Fecal incontinence significantly decreases quality of life compared with functional constipation alone in children. Older children with functional constipation+fecal incontinence may be at particular risk. Strategies for early identification and treatment of constipation along with diagnosis and treatment of related adjustment difficulties may mitigate the negative impact of this highly prevalent condition. PMID- 26008174 TI - Reversible two-photon fluorescent probe for imaging of hypochlorous acid in live cells and in vivo. AB - Herein, we have developed a novel reversible two-photon fluorescent probe that is well suited for monitoring HOCl levels selectively and instantaneously. Results showed the reversible and instantaneous responses of the probe towards intracellular HOCl. Moreover, the probe was successfully applied to the imaging of the HOCl levels in zebrafish and mice via two-photon imaging. PMID- 26008175 TI - Factors associated with triage assignment of emergency department patients ultimately diagnosed with acute myocardial infarction. AB - BACKGROUND: The objective of this study was to explore factors associated with the triage category assigned by the triage nurse for patients ultimately diagnosed with acute myocardial infarction. METHODS: This was a retrospective analysis of 12 months of data, on adult emergency department patients ultimately diagnosed with acute myocardial infarction. Data were obtained from hospital databases and included patient demographics, patient clinical characteristics and nurses' experience. RESULTS: Of the 153 patients, 20% (95% CI: 14-27%) were given a lower urgency triage category than recommended by international guidelines. Compared to patients who were triaged Australasian Triage Category 1 or 2, patients with an Australasian Triage Category 3-5 were older (mean age 76 versus 68 years), more likely to be female (63% versus 32%), more likely to present without chest pain (93% versus 35%) and less likely to have a cardiac history (3.3% versus 17.9%). A slightly higher proportion of patients Australasian Triage Category 3-5 were triaged by an experienced nurse (50%) compared to patients categorised Australasian Triage Category 1-2 (35.2%) but this finding did not reach statistical significance. CONCLUSIONS: One in five presentations was given a lower urgency triage category than recommended by international guidelines, potentially leading to delays in medical treatment. The absence of chest pain was the defining characteristic in this group of patients, along with other factors identified by previous research such as being of female sex and elderly. PMID- 26008176 TI - Three-dimensional clustering of Janus cylinders by convex curvature and hydrophobic interactions. AB - The three-dimensional (3D) clustering of Janus cylinders is controlled by simply tuning the cylinder geometry and hydrophobic interactions. Janus cylinders were prepared by combining two approaches: micromolding and initiated chemical vapor deposition (iCVD). Hydrophilic cylinders with a flat- or convex-top curvature were prepared by micromolding based on surface tension-induced flow. The iCVD process then provides a hydrophobic domain through the simple and precise deposition of a polymer film on the top surface, forming monodisperse Janus microcylinders. We use these Janus cylinders as building blocks to form 2D or 3D clusters via hydrophobic interactions in methanol. We investigate how cylinder geometry or degree of hydrophobic interaction affects the resulting cluster geometries. The convex-top Janus cylinders lead to 3D clustering through tip-to tip interactions, and the flat-top Janus cylinders lead to 2D clustering through face-to-face attraction. The number of Janus cylinders in 3D clusters is tuned by controlling the degree of hydrophobic (or hydrophilic) interaction. PMID- 26008177 TI - Fetal MRI detects early alterations of brain development in Tetralogy of Fallot. AB - OBJECTIVE: Prenatal imaging has identified alterations of brain growth in fetuses with congenital heart disease. However, little is known about the timing of altered brain development and its occurrence in specific congenital heart disease subgroups. This magnetic resonance imaging study aimed to identify early (median, 25 gestational weeks [GW]) changes in fetal total brain (TBV), gray matter (GMV), and subcortical brain (SBV) volumes in Tetralogy of Fallot (TOF) cases in utero. STUDY DESIGN: Fetal magnetic resonance imaging (1.5 Tesla) was performed in 24 fetuses who were diagnosed with TOF and 24 normal age-matched control fetuses (20 34 GW). TBV, GMV, SBV, intracranial cavity, cerebellar, ventricular, and external cerebrospinal fluid volumes were quantified by manual segmentation based on coronal T2-weighted sequences. Mixed model analyses of variance and t-tests were conducted to compare cases and control fetuses. RESULTS: TBV was significantly lower (P < .001) in early (<25 GW) and late TOF cases. Both GMV (P = .003) and SBV (P = .001) were affected. The GMV-to-SBV ratio declined in fetuses with TOF (P = .026). Compared with normal fetuses, ventricular volume was increased (P = .0048). External cerebrospinal fluid was enlarged in relation to head size (P < .001). Intracranial cavity volume (P = .314) and cerebellar volume (P = .074) were not significantly reduced in fetuses with TOF. CONCLUSION: TOF is associated with smaller volumes of gray and white matter and enlarged cerebrospinal fluid spaces. These changes are present at <=25 GW and indicate altered fetal brain growth in this pathophysiologic entity during early stages of human brain development. PMID- 26008178 TI - Should pregnant women be included in phase IV clinical drug trials? AB - Relatively few drugs, especially those recently approved by the US Food and Drug Administration, have published human pregnancy experience. Although all drugs contain animal reproduction data, these are usually not predictive of human risk. Clinical trials in pregnant women are rarely conducted because of ethical and legal concerns, and it may be many years before sufficient observational data are collected to guide clinical treatment decisions. Because many of these drugs will be used in pregnancy, human data are needed shortly after the drugs come to the market. Lack of human data leads to uncertainty over whether a drug can be safely prescribed for a pregnant patient. Unless there are compelling scientific and ethical reasons to exclude them, pregnant women should be included in phase IV clinical trials (postmarketing studies to obtain additional information, including the risks, benefits, and optimal use of a drug). This paper examines how physicians currently counsel pregnant women when there are no human data and proposes an alternative method in which knowledge regarding risks associated with the use of drugs during pregnancy can be enhanced in a clinical trial setting. PMID- 26008179 TI - Maternal metabolic syndrome, preeclampsia, and small for gestational age infancy. AB - OBJECTIVE: We sought to explore to what extent the presence of cardiometabolic and cardiovascular risk constitutions differ between pregnancies complicated by small-for-gestational-age (SGA) infancy, preeclampsia (PE), or a combination of both. STUDY DESIGN: We conducted a cohort study in women after pregnancies complicated by placental syndrome with fetal manifestations (SGA infancy [n = 113]), maternal manifestations (PE [n = 729]), or both (n = 461). Independent sample t test was used to compare cardiometabolic and cardiovascular risk factors between groups. Logistic regression was used to calculate odds ratios and adjusted odds ratios of the prevalence of the metabolic syndrome and its constituents between groups. Adjustments were made for maternal age, parity, smoking, interval between delivery and measurements, and intrauterine fetal demise. RESULTS: The metabolic syndrome was present in 7.5% of women who delivered SGA infants, 15.6% of former PE women, and 19.8% of women after pregnancy complicated by both SGA and PE. Hypertension was observed in 25% of former PE women and 15% of women with solely SGA. Women who delivered a SGA infant had lower global vascular compliance compared to former PE women without SGA. CONCLUSION: Cardiometabolic risk factors consistent with metabolic syndrome relate to the maternal rather than to the fetal presentation of placental syndrome. Nonetheless, highest incidence of metabolic syndrome was observed in women with both PE and SGA. PE relates to chronic hypertension, whereas increased arterial stiffness seems to be associated with women who deliver a SGA infant. PMID- 26008181 TI - A novel strategy for reversible hydrogen storage in Ca(BH4)2. AB - We report that decomposition pathway of Ca(BH4)2 can be efficiently controlled by reaction temperature. That is, it decomposes into CaB6 at a lower temperature range of 320 to 350 degrees C, but into amorphous boron at 400 to 450 degrees C. We identified the formation of CaB2H6 as the crucial intermediate step on the way to CaB6 that only forms at 320 to 350 degrees C. PMID- 26008180 TI - A model to predict vaginal delivery in nulliparous women based on maternal characteristics and intrapartum ultrasound. AB - OBJECTIVE: Accurate prediction of whether a nulliparous woman will have a vaginal delivery would be a major advance in obstetrics. The objective of the study was to develop such a model based on maternal characteristics and the results of intrapartum ultrasound. STUDY DESIGN: One hundred twenty-two nulliparous women in the first stage of labor were included in a prospective observational 2-centre study. Labor was classified as prolonged according to the respective countries' national guidelines. Fetal head position was assessed with transabdominal ultrasound and cervical dilatation by digital examination, and transperineal ultrasound was used to determine head-perineum distance and the presence of caput succedaneum. The subjects were divided into a testing set (n = 61) and a validation set (n = 61) and a risk score derived using multivariable logistic regression with vaginal birth as the outcome, which was dichotomized into no/cesarean delivery and yes/vaginal birth. Covariates included head-perineum distance, caput succedaneum, and occiput posterior position, which were dichotomized respectively into the following: <=40 mm, >40 mm, <10 mm, >=10 mm, and no, yes. Maternal age, gestational age, and maternal body mass index were included as continuous covariates. RESULTS: Dichotomized score is significantly associated with vaginal delivery (P = .03). Women with a score above the median had greater than 10 times the odds of having a vaginal delivery as compared with those with a score below the median. The receiver-operating characteristic curve showed an area under the curve of 0.853 (95% confidence interval, 0.678-1.000). CONCLUSION: A risk score based on maternal characteristics and intrapartum findings can predict vaginal delivery in nulliparous women in the first stage of labor. PMID- 26008182 TI - Conjugated polymer P3HT-Au hybrid nanostructures for enhancing photocatalytic activity. AB - Metal-semiconductor nanostructures have been the subject of great interest, mainly due to their interesting optical properties and their potential applications in light harvesting, photocatalysis and photovoltaic devices. Here, we have designed raspberry type organic-inorganic hybrid nanostructures of the poly-3-hexylthiophene (P3HT)-Au nanoparticle (NP) composite by a simple solution based synthetic method. The electronic interaction of semiconducting P3HT polymer nanoparticles with Au nanoparticles exhibits a bathochromic shift of absorption bands and significant photoluminescence quenching of P3HT nanoparticles in this organic-inorganic hybrid system. The photocatalytic activity of this raspberry type hybrid nanostructure is demonstrated under the visible light irradiation and the degradation efficiency is found to be 90.6%. Such organic-inorganic hybrid nanostructures made of a semiconducting polymer and plasmonic nanoparticles could pave the way for designing new optical based materials for applications in photocatalytic and light harvesting systems. PMID- 26008185 TI - Structure-Based Design of Mucor pusillus Pepsin for the Improved Ratio of Clotting Activity/Proteolytic Activity in Cheese Manufacture. AB - Previous theoretical studies have determined the intermolecular interactions between Mucor pusillus pepsin (MPP) and the key domain of kappa-casein, with the aim to understand the mechanism of milk clotting in the specific hydrolysis of kappa-casein by MPP for cheese making. Here, we combined the docking model with site-directed mutagenesis to further investigate the functional roles of amino acid residues in the active site of MPP. T218S replacement caused a low thermostability and moderate increase in the clotting activity. Mutations of three amino acid residues, T218A and T218S in S2 region and L287G in S4 region, led to a significant decrease in proteolytic activity. For T218S and L287G, an increase in the ratio of clotting activity to proteolytic activity (C/P) was observed, in particular 3.34-fold increase was found for T218S mutants. Structural analysis of the binding mode of MPP and chymosin splitting domain (CSD) of kappa-casein indicated that T218S plays a critical role in forming a hydrogen bond with the hydroxyl group of Ser(104) around the MPP-sensitive Phe(105)-Met(106) peptide bond of kappa- casein and L287G is partially responsible for CSD accommodation in a suitable hydrophobic environment. These data suggested that T218S mutant could serve as a promising milk coagulant that contributes to an optimal flavor development in mature cheese. PMID- 26008186 TI - Rifampicin Induced Aggregation of Ovalbumin: Malicious Behaviour of Antibiotics. AB - Molecular modeling deciphered the site of interaction of rifampicin in the structure of ovalbumin at a site which is surrounded by residues Glu-214, Asp-98, Pro-85, Asp-91 and Asp-47. Isothermal calorimetric analysis determined the thermodynamic parameters i.e. DeltaH and DeltaS which came out be -8.086 cal/mol and -131 cal/mol/deg. respectively. Ovalbumin is a secretory protein of hen oviduct, present in the human blood serum and interacts with the drug rifampicin in vivo, when administered. Simulating these conditions in vitro revealed that rifampicin induced the aggregated state at 6 uM concentration which was featured by a decrease in the ANS fluorescence intensity relative to the native state while as the pre-molten and molten globule state were obtained at 3 uM and 5 uM concentration of rifampicin respectively displaying a hike in the ANS fluorescence intensity. Far-UV CD analysis suggested beta-sheet rich structure with negative ellipticity peak at 217 nm for native ovalbumin incubated with 6 uM rifampicin. Increase in absorbance at 450 nm, red shift of 50 nm in the congo red binding assay and a hike of 10 fold in the ThT fluorescence intensity compared to the native state further confirmed aggregate formation. Moreover, TEM images displayed aggregates to be spherical morphologically. Aggregates formed at 6 uM rifampicin concentration were found to be cytotoxic as there was a reduction of cell viability to 28%. Thus, protein-drug interaction primarily facilitates a structural alteration in the native structure of proteins leading to their aggregation which were proved to be cytotoxic in nature. PMID- 26008187 TI - Stability of Asp(B28) Insulin Exposed to Modified and Unmodified Polypropylene. AB - Polypropylene (PP) plates have been modified with two different hydrophilic polymeric materials, poly(N,N-dimethylacrylamide) (poly(DMAAm)) and poly(poly(ethylene glycol)methacrylate) (poly(PEGMA)) in order to reduce insulin adsorption when the plates were exposed to insulin aspart (Asp(B28) insulin). The influence of surface modification on the chemical and physical stability of Asp(B28) insulin was evaluated by two chromatographic methods, size exclusion chromatography (SEC) and reverse phase high pressure liquid chromatography (RP HPLC) and the Thioflavin T assay. A clear difference in the stability of Asp(B28) insulin was observed between the three tested surfaces. PP coated with poly(DMAAm) resulted in a poor chemical stability and a significantly improved physical stability compared with unmodified PP. In addition to this a lower phenol concentration was observed for the poly(DMAAm) coating. The results from the poly(PEGMA) coating looked very promising with respect to the stability of Asp(B28) insulin in comparison with the data from unmodified PP and the poly(DMAAm) coating. Two hydrophilic coatings have been tested and surprisingly a difference in Asp(B28) insulin stability was observed. Therefore, Asp(B28) insulin adsorption and stability will be influenced by more than the hydrophilicity of the surface. PMID- 26008189 TI - Synthesis and Biological Evaluation of Quinazoline Derivatives as Potential Anticancer Agents (II). AB - Under the guidance of our previous work, we synthesized 21 new structures of quinazolines (3a~3u) and evaluated their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines using the MTT method. Most compounds showed good to excellent anticancer activity. In particular, 3o (regarded as erlotinib analogues) has marked anticancer activity against A549, HCT116 and MCF-7 cell lines (IC50s: 4.26, 3.92 and 0.14 MUM, respectively) as compared with the standard anticancer drug gefitinib (IC50s: 17.9, 21.55 and 20.68 MUM, respectively), and which can be regarded as the best candidate for development of anticancer drugs. PMID- 26008184 TI - Contributions of nonhematopoietic cells and mediators to immune responses: implications for immunotoxicology. AB - Immunotoxicology assessments have historically focused on the effects that xenobiotics exhibit directly on immune cells. These studies are invaluable as they identify immune cell targets and help characterize mechanisms and/or adverse outcome pathways of xenobiotics within the immune system. However, leukocytes can receive environmental cues by cell-cell contact or via released mediators from cells of organs outside of the immune system. These organs include, but are not limited to, the mucosal areas such as the lung and the gut, the liver, and the central nervous system. Homeostatic perturbation in these organs induced directly by toxicants can initiate and alter the outcome of local and systemic immunity. This review will highlight some of the identified nonimmune influences on immune homeostasis and provide summaries of how immunotoxic mechanisms of selected xenobiotics involve nonimmune cells or mediators. Thus, this review will identify data gaps and provide possible alternative mechanisms by which xenobiotics alter immune function that could be considered during immunotoxicology safety assessment. PMID- 26008188 TI - Epigenetic priming of non-small cell lung cancer cell lines to the antiproliferative and differentiating effects of all-trans retinoic acid. AB - PURPOSE: The retinoic acid signaling pathway, crucial for differentiation, is silenced by epigenetic mechanisms in many cancers. Epigenetically active, chromatin-modifying agents offer a novel treatment approach, by reactivating aberrantly silenced genes in tumor cells and by sensitizing them to subsequent treatments. We hypothesized that the treatment of non-small cell lung cancer (NSCLC) cells with a histone deacetylase (HDAC) inhibitor may prime them to the antiproliferative and differentiating activity of all-trans retinoic acid. METHODS: The NSCLC cell lines A549, NCI-H460 and HCC827 were treated with ATRA (2 uM) and the pan-HDAC inhibitor panobinostat (LBH589; 10-35 nM). RESULTS: While treatment with ATRA alone showed only very modest effects, panobinostat reduced cellular proliferation by at least 50 %. Notably, the combination of panobinostat and ATRA had additive and synergistic effects, respectively, on growth inhibition and differentiation, with almost no cytotoxicity. Effects were strongest in A549, followed by the EGFR-mutant HCC827, and least pronounced in NCI-H460. Global histone H3 acetylation was strongly induced by panobinostat; interestingly, ATRA alone had also an effect on histone acetylation, which was synergistically enhanced when the HDAC inhibitor was added. The combination of the two drugs additively decreased expression of phospho-ERK and phospho-AKT, whereas p53 and p21(CIP1/WAF1) proteins were both induced. CONCLUSION: Panobinostat sensitized, to varying degrees, all three cell lines to the antiproliferative and differentiating effects of ATRA, with synergistic histone H3 acetylation. Combination therapy with an epigenetic drug and ATRA may offer an alternative to aggressive chemotherapy even in primary ATRA-insensitive tumors, such as adenocarcinomas of the lung. PMID- 26008190 TI - Regulation of length and density of Arabidopsis root hairs by ammonium and nitrate. AB - Root hairs expand the effective root surface to increase the uptake of nutrients and water from the soil. Here the local effects of the two major nitrogen sources, ammonium and nitrate, on root hairs were investigated using split plates. In three contrasting accessions of A. thaliana, namely Col-0, Tsu-0 and Sha, root hairs were differentially affected by the nitrogen forms and their concentration. Root hairs in Sha were short in the absence of nitrate. In Col-0, hair length was moderately decreased with increasing nitrate or ammonium. In all accessions, the root hair density was insensitive to 1,000-fold changes in the ammonium concentrations, when supplied locally as the exclusive nitrogen form. In contrast, the root hair density generally increased with nitrate as the exclusive local nitrogen source. The nitrate sensitivity was reduced at mM concentrations in a loss-of-function mutant of the nitrate transporter and sensor gene NRT1;1 (NPF6.3). Little differences with respect to ammonium were found in a mutant lacking four high affinity AMT-type ammonium transporters, but interestingly, the response to high nitrate was reduced and may indicate a general defect in nitrogen signaling in that mutant. Genetic diversity and the presence of the nitrogen transceptor NRT1;1 explain heterogeneity in the responses of root hairs to different nitrogen forms in Arabidopsis accessions. PMID- 26008191 TI - The next generation of smart gold nanobeacons: nanotheranostics is ready for prime time. PMID- 26008192 TI - Functionalization of mesoporous silica nanoparticles with a cell-penetrating peptide to target mammalian sperm in vitro. AB - AIM: This study aimed to investigate the effects of actively targeting mesoporous silica nanoparticles (MSNPs) toward mammalian sperm with a cell-penetrating peptide (C105Y), with subsequent analysis of binding rates and nano-safety profiles. MATERIALS & METHODS: Boar sperm were exposed in vitro to C105Y functionalized MSNPs or free C105Y, in a series of increasing doses for up to 2 h, followed by the evaluation of sperm motility, kinematic parameters, acrosome morphology, MSNP-sperm binding and cell fluorescence levels. RESULTS: C105Y functionalized MSNPs preserved their biocompatibility with sperm, and exhibited an approximately fourfold increase in affinity toward gametes, compared with unmodified MSNPs, during the early stages of incubation. CONCLUSION: Our findings support the application of MSNPs and active targeting to sperm as valuable tools for reproductive biology. PMID- 26008193 TI - Metabolic and structural integrity of magnetic nanoparticle-loaded primary endothelial cells for targeted cell therapy. AB - AIM: To successfully translate magnetically mediated cell targeting from bench to bedside, there is a need to systematically assess the potential adverse effects of magnetic nanoparticles (MNPs) interacting with 'therapeutic' cells. Here, we examined in detail the effects of internalized polymeric MNPs on primary rat endothelial cells' structural intactness, metabolic integrity and proliferation potential. MATERIALS & METHODS: The intactness of cytoskeleton and organelles was studied by fluorescent confocal microscopy, flow cytometry and high-resolution respirometry. RESULTS: MNP-loaded primary endothelial cells preserve intact cytoskeleton and organelles, maintain normal rate of proliferation, calcium signaling and mitochondria energy metabolism. CONCLUSION: This study provides supportive evidence that MNPs at doses necessary for targeting did not induce significant adverse effects on structural integrity and functionality of primary endothelial cells - potential cell therapy vectors. PMID- 26008194 TI - Oral insulin delivery using deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles. AB - AIM: To develop insulin loaded deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles and carry out in vitro and in vivo testing of enteric coated granules comprising these nanoparticles. MATERIALS & METHODS: Insulin loaded nanoparticles were prepared and characterized in vitro. Cellular uptake was studied using hyperspectral and live cell confocal microscopy. Enteric coated granules of nanoparticles were fed orally to diabetic rats and the pharmacokinetic and pharmacodynamic parameters were evaluated. RESULTS: Ultra small (~10 nm) nanoparticles with polydispersity index of 0.299 were obtained. The enteric coated granules showed a negligible insulin release in acidic pH, but released insulin in alkaline environment. High cellular uptake was observed and nanoparticles were able to maintain the blood glucose levels up to 24 h. CONCLUSION: These enteric-coated nanoparticle granules sustained the release of insulin and showed enhanced insulin bioavailability. Hence, these may serve as a platform device for oral insulin delivery with extended release. PMID- 26008195 TI - Biodegradable chitosan nanoparticles in drug delivery for infectious disease. AB - Increasing rates of antimicrobial resistance have left a significant gap in the standard antimicrobial armament. Nanotechnology holds promise as a new approach to combating resistant microbes. Chitosan, a form of deacetylated chitin, has been used extensively in medicine, agriculture and industry due to its ease of production, biocompatibility and antimicrobial activity. Chitosan has been studied extensively as a main structural component and additive for nanomaterials. Specifically, numerous studies have demonstrated its potent microbicidal activity and its efficacy as an adjuvant to vaccines, including mucosally administered vaccines. In this review, we present fundamental information about chitosan and chitosan nanoparticles as well as the most recent data about their antimicrobial mechanism and efficacy as a nanotechnology-based drug delivery system. PMID- 26008196 TI - Cyclodextrin complexes for treatment improvement in infectious diseases. AB - Infectious diseases are a heterogeneous group of maladies that represent a serious burden to healthcare systems worldwide. Most of the available antimicrobial drugs display poor biopharmaceutical properties that compromise their effectiveness. Cyclodextrins (CDs) are cyclic oligosaccharides of glucopyranose formed by a variable number of repeating units that combine a hydrophilic surface with a hydrophobic cavity. The production of drug/CD complexes has become one of the most extensively investigated technology approaches to improve the stability, solubility, dissolution rate and bioavailability of drugs. The present work overviews the applications of CDs for the formulation of anti-infective agents along with the most relevant administration routes. Finally, an update on the complexes with CDs available on the market to treat infectious diseases is presented. PMID- 26008197 TI - Next-generation nanoantibacterial tools developed from peptides. AB - Bacteria resistant against various antimicrobial compounds have emerged in many countries, and the age of resistance has just started. Among the more promising novel antimicrobial compounds on which current research is focusing are the antimicrobial peptides (AMPs). These are often less susceptible to bacterial resistance since multiple modifications in the cellular membranes, cell wall and metabolism are required to reduce their effectiveness. Most likely, the use of pure AMPs will be insufficient for controlling pathogenic bacteria, and innovative approaches are required to employ AMPs in new antibiotic treatments. Therefore, here we review novel bionanotechnological approaches, including nanofibers, nanoparticles and magnetic particles for effectively using AMPs in fighting infectious diseases. PMID- 26008198 TI - Exploiting the novel properties of protein coronas: emerging applications in nanomedicine. AB - Protein coronas have been the focus of a great deal of study recently due to their inevitable formation and their impact on the biological consequences of nanomaterials. Although the field is still far from completely and definitively understanding protein coronas, we now have a good understanding of their behavior and their key characteristics. Protein corona composition changes with the environment and time, and also the physical properties of the underlying nanoparticle. More importantly, the protein corona has significant biological impact. Because we have a basic understanding of coronas, we can now move forward to exploiting their unique properties. Here, we discuss some emerging ways in which the protein corona is explicitly utilized for different applications in biology and medicine. PMID- 26008199 TI - Corrigendum. AB - Following publication of the Research Article by Rutika A Kokate, Sanjay I Thamake, Pankaj Chaudhary, Brittney Mott, Sangram Raut, Jamboor K Vishwanatha and Harlan P Jones, titled 'Enhancement of anti-tumor effect of particulate vaccine delivery system by 'Bacteriomimetic' CpG functionalization of poly-lactic-co glycolic acid nanoparticles', which appeared in the March 2015 issue of Nanomedicine (Nanomedicine [Lond.]) 10[6], 915-929 [2015]), it has been brought to our attention that Figure 1 was presented incorrectly.The correct presentation is shown above.The authors and editors of Nanomedicine would like to sincerely apologize for any inconvenience or confusion this may have caused our readers. PMID- 26008200 TI - Sonoran propolis and some of its chemical constituents inhibit in vitro growth of Giardia lamblia trophozoites. AB - Propolis is a cereus resin with a complex chemical composition that possesses a wide range of biological activities. The aim of this study was to evaluate the in vitro anti-Giardia lamblia activity of Sonoran propolis collected from three different areas of Sonoran Desert in northwestern Mexico (Caborca, Pueblo de Alamos, and Ures) and some of its chemical constituents. Additionally, we also analyzed the seasonal effect on the anti-G. lamblia activity of propolis. G. lamblia trophozoite cultures were treated with different concentrations of Sonoran propolis or chemical compounds during 48 h cell proliferation and cell viability were determined. Ures propolis showed the highest inhibitory activity against G. lamblia (IC50 63.8 +/- 7.1 ug/mL) in a dose-dependent manner (Ures > Pueblo de Alamos > Caborca). Season had a significant effect on the in vitro anti G. lamblia activity of Ures propolis. Summer propolis showed the highest inhibitory effect on the G. lamblia trophozoite growth (IC50 23.8 +/- 2.3 ug/mL), followed by propolis collected during winter (IC50 59.2 +/- 34.7 ug/mL), spring (IC50 102.5 +/- 15.3 ug/mL), and autumn (IC50 125.0 +/- 3.1 ug/mL). Caffeic acid phenethyl ester, an Ures propolis exclusive constituent, had the highest growth inhibitory activity towards G. lamblia [IC50 63.1 +/- 0.9 ug/mL (222.1 +/- 3.2 uM)]. To our knowledge, this is the first study showing that caffeic acid phenethyl ester possesses antiparasitic activity against G. lamblia. Naringenin [IC50 125.7 +/- 20.7 ug/mL (461.8 +/- 76.3 uM)], hesperetin [IC50 149.6 +/- 24.8 ug/mL (494.9 +/- 82.2 uM)], and pinocembrin [IC50 174.4 +/- 26.0 ug/mL (680.6 +/- 101.7 uM)] showed weak anti-G. lamblia activity. On the other hand, chrysin and rutin did not show significant antiparasitic activity. In conclusion, our results suggest that Sonoran propolis and some of its chemical constituents had inhibitory effects on the in vitro growth of G. lamblia trophozoites. PMID- 26008201 TI - Sulforaphane protected the injury of human vascular endothelial cell induced by LPC through up-regulating endogenous antioxidants and phase II enzymes. AB - Sulforaphane (SFN), which is an isothiocyanate (ITC) that is found in cruciferous vegetables, has received considerable attention because of its beneficial effects. In this study, the protection by SFN in the lysophosphatidylcholine (LPC)-induced injury of human vascular endothelial EA.hy.926 cells was investigated. ROS intensity was obtained by fluorescence microscopic imaging. Levels of MDA, GSH and the activity of SOD were determined spectrophotometrically. Expressions of GST, GSH-Px, TrxR and Nrf-2 proteins were measured by western blotting analysis. SFN largely decreased ROS production, similar to vitamin E. The MDA level was decreased by SFN to a level that was comparable to the negative group. Incubation with 0.5, 1.25, 2.5 MUmol L(-1) SFN for 24 h restored the activity of SOD by 58%, 64%, and 123%, respectively. SOD activities were individually increased by 53%, 97%, 103% after treatment with 2.5 MUmol L(-1) SFN for 12 h, 24 h, and 48 h, respectively. SFN restored and up regulated the expressions of GST, GSH-Px and TrxR both in dose- and time dependent ways. Although VE presents comparable induction of phase 2 enzymes as 1.25 MUmol L(-1) SFN, it cannot induce the translocation of Nrf-2 to the nucleus. SFN protected the injury of vascular endothelial cell by LPC by enhancing anti oxidative capabilities mediated by Nrf-2 translocation. PMID- 26008202 TI - Protocol for the evaluation of a social franchising model to improve maternal health in Uttar Pradesh, India. AB - BACKGROUND: Social franchising is the fastest growing market-based approach to organising and improving the quality of care in the private sector of low- and middle-income countries, but there is limited evidence on its impact and cost effectiveness. The "Sky" social franchise model was introduced in the Indian state of Uttar Pradesh in late 2013. METHODS/DESIGN: Difference-in-difference methods will be used to estimate the impact of the social franchise programme on the quality and coverage of health services along the continuum of care for reproductive, maternal and newborn health. Comparison clusters will be selected to be as similar as possible to intervention clusters using nearest neighbour matching methods. Two rounds of data will be collected from a household survey of 3600 women with a birth in the last 2 years and a survey of 450 health providers in the same localities. To capture the full range of effects, 59 study outcomes have been specified and then grouped into conceptually similar domains. Methods to account for multiple inferences will be used based on the pre-specified grouping of outcomes. A process evaluation will seek to understand the scale of the social franchise network, the extent to which various components of the programme are implemented and how impacts are achieved. An economic evaluation will measure the costs of setting up, maintaining and running the social franchise as well as the cost-effectiveness and financial sustainability of the programme. DISCUSSION: There is a dearth of evidence demonstrating whether market based approaches such as social franchising can improve care in the private sector. This evaluation will provide rigorous evidence on whether an innovative model of social franchising can contribute to better population health in a low income setting. PMID- 26008203 TI - Green synthesis of Pt-doped TiO2 nanocrystals with exposed (001) facets and mesoscopic void space for photo-splitting of water under solar irradiation. AB - We report a non-trivial facile chemical approach using ionic liquid ([bmim][Cl]) as a porogen for the synthesis of (001) faceted TiO2 nanocrystals having mesoscopic void space. This faceted TiO2 nanomaterial has been doped with Pt nanoclusters through chemical impregnation. The resulting Pt-doped TiO2 nanomaterials are thoroughly characterized by powder X-ray diffraction (PXRD), Raman spectroscopy, field emission scanning electron microscopy (FE-SEM), ultra high resolution transmission electron microscopy (UHR-TEM), energy dispersive X ray spectrometry (EDX), UV-vis diffuse reflection spectroscopy (DRS) and N2 sorption studies. These Pt/TiO2 nanocrystals with (001) exposed facets are employed as efficient and benign catalysts for hydrogen production from pure water and methanol-water systems under one AM 1.5G sunlight illumination. The effect of platinum loading and methanol-water ratio on the photocatalytic activity of the faceted TiO2 nanocrystals are investigated and it is found that hydrogen evolution rates have been enhanced significantly upon Pt loading. Under optimized reaction conditions the highest photocatalytic activity of 11.2 mmol h( 1) g(-1) has been achieved over ca. 1.0 wt% Pt loaded Pt/TiO2 nanocrystals with (001) exposed facets, which is one of the highest hydrogen evolution rates over the noble metal/TiO2 system reported to date in the literature. PMID- 26008204 TI - Association of SNPs in miR-146a, miR-196a2, and miR-499 with the risk of endometrial/ovarian cancer. PMID- 26008205 TI - d(GC)n repeats form Z-DNA within promoter region and repress the promoter activity in Escherichia coli. PMID- 26008206 TI - Parkin-induced ubiquitination of Mff promotes its association with p62/SQSTM1 during mitochondrial depolarization. AB - The ubiquitin ligase Parkin and autophagic adapter protein p62 are known to function in a common pathway controlling mitochondrial autophagy (mitophagy). However, the evidence supporting that p62 is directly recruited by ubiquitinated proteins remains undetermined. Here, we demonstrate that mitochondrial fission factor (Mff) associates with Parkin and carbonyl cyanide m-chlorophenyl hydrazone treatment significantly increases the affinity of Parkin with Mff. After recruitment to depolarized mitochondria, Parkin mediates poly-ubiquitination of Mff at lysine 251. Replacement of lysine 251 by arginine (K251R) totally abrogates Parkin-stimulated ubiquitination of Mff. Subsequently, the ubiquitinated Mff promotes its association with p62. Mff knockout interferes with p62 translocation to damaged mitochondria. Only re-transfection of Mff WT, but not K251R mutant, rescues this phenotype. Furthermore, loss of Mff results in failure of Parkin translocation and final clearance of damaged mitochondria. Thus, our data reveal functional links among Mff, p62, and the selective autophagy of mitochondria, which are implicated in the pathogenesis of neurodegeneration diseases. PMID- 26008207 TI - Physical inactivity and risk of poor quality of life among elderly cancer survivors compared to women without cancer: the Iowa Women's Health Study. AB - PURPOSE: Few studies have examined lifestyle factors and quality of life (QOL) in cancer survivors compared to a cancer-free group. Compared to active cancer-free women, we examined the association between physical inactivity and QOL in elderly cancer survivors and similar-aged women without cancer. METHODS: Participants included 1776 cancer survivors and 12,599 cancer-free women enrolled in the Iowa Women's Health Study in 1986 who completed the SF36 QOL assessment in 2004 (ages 73-88 years). The odds of poor QOL were computed for each SF36 subscale (>0.5 SD below mean score of cancer-free women) associated with physical inactivity (moderate-vigorous activity =5ug/mL), significantly decreased forward scatter (>=2.5ug/mL), significantly increased ROS abundance (10 ug/mL), and significantly increased [Ca2+]i (>=5 ug/mL). The up regulation of annexin-V-binding following nelfinavir treatment was significantly blunted, but not abolished by either addition of the antioxidant N-acetylcysteine (1 mM) or removal of extracellular Ca2+. In conclusion, exposure of erythrocytes to nelfinavir induces oxidative stress and Ca2+ entry, thus leading to suicidal erythrocyte death characterized by erythrocyte shrinkage and erythrocyte membrane scrambling. PMID- 26008230 TI - A method for simultaneous determination of 20 Fusarium toxins in cereals by high resolution liquid chromatography-Orbitrap mass spectrometry with a pentafluorophenyl column. AB - A high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS) method was developed for simultaneous determination of 20 Fusarium toxins (nivalenol, fusarenon-X, deoxynivalenol, 3-acetyl deoxynivalenol, 15-acetyl deoxynivalenol, HT-2 toxin, T-2 toxin, neosolaniol, diacetoxyscirpenol, fumonisin B1, fumonisin B2, fumonisin B3, fumonisin A1, fumonisin A2, fumonisin A3, zearalenone, alpha-zearalenol, beta-zearalenol, alpha-zearalanol, and beta zearalanol) in cereals. The separation of 20 Fusarium toxins with good peak shapes was achieved using a pentafluorophenyl column, and Orbitrap MS was able to detect accurately from cereal matrix components within +/-0.77 ppm. The samples were prepared using a QuEChERS kit for extraction and a multifunctional cartridge for purification. The linearity, repeatability, and recovery of the method were >0.9964, 0.8%-14.7%, and 71%-106%, respectively. Using this method, an analysis of 34 commercially available cereals detected the presence of deoxynivalenol, 15 acetyl deoxynivalenol, fumonisin B1, fumonisin B2, fumonisin B3, fumonisn A1, fumonisin A2, fumonisin A3, and zearalenone in corn samples with high concentration and frequency. Trichothecenes was detected from wheat samples with high frequency; in particular, the concentration of deoxynivalenol was high. Conversely, alpha-zearalenol, beta-zearalenol, alpha-zearalanol, and beta zearalanol were not detected in any of the samples. PMID- 26008231 TI - Natural compounds interacting with nicotinic acetylcholine receptors: from low molecular weight ones to peptides and proteins. AB - Nicotinic acetylcholine receptors (nAChRs) fulfill a variety of functions making identification and analysis of nAChR subtypes a challenging task. Traditional instruments for nAChR research are d-tubocurarine, snake venom protein alpha bungarotoxin (alpha-Bgt), and alpha-conotoxins, neurotoxic peptides from Conus snails. Various new compounds of different structural classes also interacting with nAChRs have been recently identified. Among the low-molecular weight compounds are alkaloids pibocin, varacin and makaluvamines C and G. 6 Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human alpha7 nAChR. To get more selective alpha-conotoxins, computer modeling of their complexes with acetylcholine-binding proteins and distinct nAChRs was used. Several novel three finger neurotoxins targeting nAChRs were described and alpha-Bgt inhibition of GABA-A receptors was discovered. Information on the mechanisms of nAChR interactions with the three-finger proteins of the Ly6 family was found. Snake venom phospholipases A2 were recently found to inhibit different nAChR subtypes. Blocking of nAChRs in Lymnaea stagnalis neurons was shown for venom C-type lectin like proteins, appearing to be the largest molecules capable to interact with the receptor. A huge nAChR molecule sensible to conformational rearrangements accommodates diverse binding sites recognizable by structurally very different compounds. PMID- 26008228 TI - Ribosome-inactivating and related proteins. AB - Ribosome-inactivating proteins (RIPs) are toxins that act as N-glycosidases (EC 3.2.2.22). They are mainly produced by plants and classified as type 1 RIPs and type 2 RIPs. There are also RIPs and RIP related proteins that cannot be grouped into the classical type 1 and type 2 RIPs because of their different sizes, structures or functions. In addition, there is still not a uniform nomenclature or classification existing for RIPs. In this review, we give the current status of all known plant RIPs and we make a suggestion about how to unify those RIPs and RIP related proteins that cannot be classified as type 1 or type 2 RIPs. PMID- 26008233 TI - Effect of PKC-beta Signaling Pathway on Expression of MCP-1 and VCAM-1 in Different Cell Models in Response to Advanced Glycation End Products (AGEs). AB - Advanced glycation end products (AGEs) are compounds classified as uremic toxins in patients with chronic kidney disease that have several pro-inflammatory effects and are implicated in the development of cardiovascular diseases. To explore the mechanisms of AGEs-endothelium interactions through the receptor for AGEs (RAGE) in the PKC-beta pathway, we evaluated the production of MCP-1 and VCAM-1 in human endothelial cells (HUVECs), monocytes, and a coculture of both. AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. The effect of AGEs on cell viability was assessed with an MTT assay. The cells were also treated with AGEs with and without a PKC-beta inhibitor. MCP-1 and VCAM-1 in the cell supernatants were estimated by ELISA, and RAGE was evaluated by immunocytochemistry. AGEs exposure did not affect cell viability, but AGEs induced RAGE, MCP-1, and VCAM-1 expression in HUVECs. When HUVECs or monocytes were incubated with AGEs and a PKC-beta inhibitor, MCP-1 and VCAM-1 expression significantly decreased. However, in the coculture, exposure to AGEs and a PKC-beta inhibitor produced no significant effect. This study demonstrates, in vitro, the regulatory mechanisms involved in MCP-1 production in three cellular models and VCAM-1 production in HUVECs, and thus mimics the endothelial dysfunction caused by AGEs in early atherosclerosis. Such mechanisms could serve as therapeutic targets to reduce the harmful effects of AGEs in patients with chronic kidney disease. PMID- 26008232 TI - Perfringolysin O: The Underrated Clostridium perfringens Toxin? AB - The anaerobic bacterium Clostridium perfringens expresses multiple toxins that promote disease development in both humans and animals. One such toxin is perfringolysin O (PFO, classically referred to as theta toxin), a pore-forming cholesterol-dependent cytolysin (CDC). PFO is secreted as a water-soluble monomer that recognizes and binds membranes via cholesterol. Membrane-bound monomers undergo structural changes that culminate in the formation of an oligomerized prepore complex on the membrane surface. The prepore then undergoes conversion into the bilayer-spanning pore measuring approximately 250-300 A in diameter. PFO is expressed in nearly all identified C. perfringens strains and harbors interesting traits that suggest a potential undefined role for PFO in disease development. Research has demonstrated a role for PFO in gas gangrene progression and bovine necrohemorrhagic enteritis, but there is limited data available to determine if PFO also functions in additional disease presentations caused by C. perfringens. This review summarizes the known structural and functional characteristics of PFO, while highlighting recent insights into the potential contributions of PFO to disease pathogenesis. PMID- 26008234 TI - First Detection of Tetrodotoxin in Greek Shellfish by UPLC-MS/MS Potentially Linked to the Presence of the Dinoflagellate Prorocentrum minimum. AB - During official shellfish control for the presence of marine biotoxins in Greece in year 2012, a series of unexplained positive mouse bioassays (MBA) for lipophilic toxins with nervous symptomatology prior to mice death was observed in mussels from Vistonikos Bay-Lagos, Rodopi. This atypical toxicity coincided with (a) absence or low levels of regulated and some non-regulated toxins in mussels and (b) the simultaneous presence of the potentially toxic microalgal species Prorocentrum minimum at levels up to 1.89 * 103 cells/L in the area's seawater. Further analyses by different MBA protocols indicated that the unknown toxin was hydrophilic, whereas UPLC-MS/MS analyses revealed the presence of tetrodotoxins (TTXs) at levels up to 222.9 MUg/kg. Reviewing of official control data from previous years (2006-2012) identified a number of sample cases with atypical positive to asymptomatic negative MBAs for lipophilic toxins in different Greek production areas, coinciding with periods of P. minimum blooms. UPLC-MS/MS analysis of retained sub-samples from these cases revealed that TTXs were already present in Greek shellfish since 2006, in concentrations ranging between 61.0 and 194.7 MUg/kg. To our knowledge, this is the earliest reported detection of TTXs in European bivalve shellfish, while it is also the first work to indicate a possible link between presence of the toxic dinoflagellate P. minimum in seawater and that of TTXs in bivalves. Confirmed presence of TTX, a very heat-stable toxin, in filter-feeding mollusks of the Mediterranean Sea, even at lower levels to those inducing symptomatology to humans, indicates that this emerging risk should be seriously taken into account by the EU to protect the health of shellfish consumers. PMID- 26008235 TI - Influence of honeybee sting on peptidome profile in human serum. AB - The aim of this study was to explore the serum peptide profiles from honeybee stung and non-stung individuals. Two groups of serum samples obtained from 27 beekeepers were included in our study. The first group of samples was collected within 3 h after a bee sting (stung beekeepers), and the samples were collected from the same person a second time after at least six weeks after the last bee sting (non-stung beekeepers). Peptide profile spectra were determined using MALDI TOF mass spectrometry combined with Omix, ZipTips and magnetic beads based on weak-cation exchange (MB-WCX) enrichment strategies in the mass range of 1-10 kDa. The samples were classified, and discriminative models were established by using the quick classifier, genetic algorithm and supervised neural network algorithms. All of the statistical algorithms used in this study allow distinguishing analyzed groups with high statistical significance, which confirms the influence of honeybee sting on the serum peptidome profile. The results of this study may broaden the understanding of the human organism's response to honeybee venom. Due to the fact that our pilot study was carried out on relatively small datasets, it is necessary to conduct further proteomic research of the response to honeybee sting on a larger group of samples. PMID- 26008236 TI - Superantigens Modulate Bacterial Density during Staphylococcus aureus Nasal Colonization. AB - Superantigens (SAgs) are potent microbial toxins that function to activate large numbers of T cells in a T cell receptor (TCR) Vbeta-specific manner, resulting in excessive immune system activation. Staphylococcus aureus possesses a large repertoire of distinct SAgs, and in the context of host-pathogen interactions, staphylococcal SAg research has focused primarily on the role of these toxins in severe and invasive diseases. However, the contribution of SAgs to colonization by S. aureus remains unclear. We developed a two-week nasal colonization model using SAg-sensitive transgenic mice expressing HLA-DR4, and evaluated the role of SAgs using two well-studied stains of S. aureus. S. aureus Newman produces relatively low levels of staphylococcal enterotoxin A (SEA), and although we did not detect significant TCR-Vbeta specific changes during wild-type S. aureus Newman colonization, S. aureus Newman Deltasea established transiently higher bacterial loads in the nose. S. aureus COL produces relatively high levels of staphylococcal enterotoxin B (SEB), and colonization with wild-type S. aureus COL resulted in clear Vbeta8-specific T cell skewing responses. S. aureus COL Deltaseb established consistently higher bacterial loads in the nose. These data suggest that staphylococcal SAgs may be involved in regulating bacterial densities during nasal colonization. PMID- 26008237 TI - Honeybee (Apis mellifera) Venom Reinforces Viral Clearance during the Early Stage of Infection with Porcine Reproductive and Respiratory Syndrome Virus through the Up-Regulation of Th1-Specific Immune Responses. AB - Porcine reproductive and respiratory syndrome (PRRS) is a chronic and immunosuppressive viral disease that is responsible for substantial economic losses for the swine industry. Honeybee venom (HBV) is known to possess several beneficial biological properties, particularly, immunomodulatory effects. Therefore, this study aimed at evaluating the effects of HBV on the immune response and viral clearance during the early stage of infection with porcine reproductive and respiratory syndrome virus (PRRSV) in pigs. HBV was administered via three routes of nasal, neck, and rectal and then the pigs were inoculated with PRRSV intranasally. The CD4+/CD8+ cell ratio and levels of interferon (IFN) gamma and interleukin (IL)-12 were significantly increased in the HBV administered healthy pigs via nasal and rectal administration. In experimentally PRRSV-challenged pigs with virus, the viral genome load in the serum, lung, bronchial lymph nodes and tonsil was significantly decreased, as was the severity of interstitial pneumonia, in the nasal and rectal administration group. Furthermore, the levels of Th1 cytokines (IFN-gamma and IL-12) were significantly increased, along with up-regulation of pro-inflammatory cytokines (TNF-alpha and IL-1beta) with HBV administration. Thus, HBV administration-especially via the nasal or rectal route-could be a suitable strategy for immune enhancement and prevention of PRRSV infection in pigs. PMID- 26008238 TI - Effect of repeated firings on flexural strength of veneered zirconia. AB - OBJECTIVE: Chipping and/or delamination represent a clinical failure of porcelain fused to zirconia (PFZ) prostheses. Causes and solutions have not been completely clarified. The present study was aimed at evaluating the effects of number of firings on the flexural strength of PFZ specimen. METHODS: Forty-five zirconia specimens in shape of bars were cut, sintered and divided in 3 groups (n=15). Group 1: veneering ceramic was layered "in bulk" and fired. Group 2: veneering ceramic was layered in three layers, individually fired. Group 3: veneering ceramic was layered in five layers, individually fired. Each layer thickness was controlled by the use of calibrated molds. The total veneering ceramic thickness for all the specimens was 1.2mm, and the total thickness of the specimen of 2.0mm. Three-point bending test was performed. Fracture load was recorded in Newton and MPa value was calculated taking into account the bi-layered nature of the specimen. Data were statistically analyzed. RESULTS: Specimens obtained with on single firing cycle obtained a statistically significant (p<0.001) lower flexural strength (54.61+/-8.98MPa) than specimens veneered with 3 or 5 firing cycles. The last two obtained very similar results (77.63+/-13.17MPa and 73.62+/ 12.38MPa respectively) and the differences was not statistically significant. SIGNIFICANCE: In bi-layered PFZ specimen, three to five layers and firings determine higher flexural resistance when compared to a single firing. Thus, a 3 layers veneering procedure is recommended to increase flexural resistance. If a 5 layer procedure is necessary to improve esthetics, it does not decrease flexural resistance. PMID- 26008574 TI - Spontaneous hemorrhages in pediatric supratentorial pilocytic astrocytomas. Malignant presentation of a benign entity. AB - BACKGROUND: Hemorrhage as a presenting feature in pilocytic astrocytoma is an extremely rare phenomenon. When seen in children, most of such tumors exist in the cerebellum. Rarely, a supratentorial pilocytic astrocytoma can present with bleeding. RESULTS: We present similar two cases and discuss the pathophysiology of such hemorrhage and histopathological changes in thinned hyalinised vessels of this tumor. CONCLUSION: The presence of calcifications in the peri-hemorrhagic areas and the presence of mass effect disproportionate to the size of the bleeding are harbingers of the presence of a benign neoplasm that may have bled. PMID- 26008575 TI - Reply to Dr. Ijichi's group letter. PMID- 26008576 TI - A case of relapsing spinal atypical teratoid/rhabdoid tumor (AT/RT) responding to vinorelbine, cyclophosphamide, and celecoxib. AB - INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a highly aggressive neoplasm which prevalently affects children and is characterized by a severe prognosis. CASE PRESENTATION: The authors describe an extremely rare case of a primary spinal AT/RT that occurred in a young girl. The patient underwent a wide surgical resection of a lumbar mass, followed by aggressive chemotherapy, myeloablative treatment, and local radiotherapy. After 7 months from the end of the treatment, the patient experienced local recurrence and was treated with surgery and second-line chemotherapy with antiangiogenic purposes, consisting of oral vinorelbine, cyclophosphamide, and celecoxib. Treatment was well tolerated, and patient was still alive 36 months after diagnosis. CONCLUSION: The peculiarity of this case report is the clinical radiological response to a metronomic therapy in a case of early-relapsing spinal AT/RT despite previous maximal surgery, chemotherapy, and radiotherapy. PMID- 26008577 TI - Pathogen group specific risk factors for clinical mastitis, intramammary infection and blind quarters at the herd, cow and quarter level in smallholder dairy farms in Jimma, Ethiopia. AB - A cross-sectional study on clinical mastitis, intramammary infection (IMI) and blind quarters was conducted on 50 smallholder dairy farms in Jimma, Ethiopia. A questionnaire was performed, and quarters of 211 cows were sampled and bacteriologically cultured. Risk factors at the herd, cow, and quarter level for clinical mastitis and (pathogen-specific) intramammary infection were studied using multilevel modeling. As well, factors associated with quarters being blind were studied. Eleven percent of the cows and 4% of the quarters had clinical mastitis whereas 85% of the cows and 51% of the quarters were infected. Eighteen percent of the cows had one or more blind quarter(s), whereas 6% of the quarters was blind. Non-aureus staphylococci were the most frequently isolated pathogens in both clinical mastitis cases and IMI. The odds of clinical mastitis was lower in herds where heifers were purchased in the last year [odds ratio (OR) with 95% confidence interval: 0.11 (0.01-0.90)], old cows (>4 years) [OR: 0.45 (0.18 1.14)], and quarters not showing teat injury [OR: 0.23 (0.07-0.77)]. The odds of IMI caused by any pathogen was higher in herds not practicing teat drying before milking (opposed to drying teats with 1 towel per cow) [OR: 1.68 (1.05-2.69)], cows in later lactation (>180 DIM opposed to <=90 DIM) [OR: 1.81 (1.14-2.88)], cows with a high (>3) body condition score (BCS) [OR: 1.57 (1.06-2.31)], right quarters (opposed to a left quarter position) [OR: 1.47 (1.10-1.98)], and quarters showing teat injury [OR: 2.30 (0.97-5.43)]. Quarters of cows in herds practicing bucket-fed calf feeding (opposed to suckling) had higher odds of IMI caused by Staphylococcus aureus [OR: 6.05 (1.31-27.90)]. Except for BCS, IMI caused by non-aureus staphylococci was associated with the same risk factors as IMI caused by any pathogen. No access to feed and water immediately after milking [OR: 2.41 (1.26-4.60)], higher parity [OR: 3.60 (1.20-10.82)] and tick infestation [OR: 2.42 (1.02-5.71)] were risk factors for quarters being blind. In conclusion, replacement of old cows, prevention of teat injuries/lesions, drying teats with 1 towel per cow before milking, improving fertility in order to shorten the lactation period, allowing (restricted) suckling, access to feed and water immediately after milking, and improving tick control could improve udder health in Jimma. PMID- 26008580 TI - Magnetic fields and intrathecal pump malfunction. AB - Medical technology has impacted the overall life expectancy. Many conditions traditionally considered fatal are now curable. Surviving chronic diseases and aging of the population have increased the number of people with chronic pain. Many devices are also available to manage severe refractory pain. As such, implantable drug-delivery system (IDDS) is a small battery-powered, programmable pump implanted under the subcutaneous tissue of the abdomen and connected to a small catheter tunneled into the spine. Implantable drug-delivery system is used for the administration of morphine, ziconotide, baclofen, or their mixtures into the cerebrospinal fluid. Like many medical devices, IDDS has technical glitch which limits its performance under certain conditions. Implantable drug-delivery system is susceptible to magnetic field such as a magnetic resonance imaging (MRI) which can temporarily stall the rotor of the pump motor and suspend drug delivery. We encountered a patient from out of town seen at emergency department with increased pain and symptoms of opiates withdrawal after intermittent IDDS malfunction. He denied any exposure to magnetic fields or MRI. However, the pump interrogation showed multiple motor stall events in the event log. After a detailed inquiry, the most likely cause of pump malfunction appears to be frequent placement of a laptop computer on his abdomen close to the pump. The magnets in the laptop speakers may have caused the rotor of the pump motor to stall during the computer use, and frequent stall has caused symptoms of withdrawal. No other mechanical failures were found. The patient was discharged home after the symptoms resolved, and the pump was reprogrammed. PMID- 26008579 TI - Stereospecific biosynthesis of (9S,13S)-10-oxo-phytoenoic acid in young maize roots. AB - Profiling of oxylipins from young maize roots revealed complex patterns of products mainly originating from the combined actions of 9- and 13-lipoxygenases and allene oxide synthase (AOS). A distinctive feature was the high content of the cyclopentenone 10-oxo-11-phytoenoic acid (10-oxo-PEA). Incubations with [1 14C]linoleic acid led to the formation of the alpha-ketols 13-hydroxy-12-oxo-9 octadecenoic acid and 9-hydroxy-10-oxo-12-octadecenoic acid as well as the cyclopentenones 12-oxo-10-phytoenoic acid (12-oxo-PEA) and 10-oxo-PEA in a ratio of 10:2:1:3. Chiral phase radio-HPLC showed that the labeled 10-oxo-PEA was mainly (93%) due to the 9S,13S-enantiomer, whereas 12-oxo-PEA was racemic. Recombinant maize AOS CYP74A19 (ZmAOS2) converted linoleic acid 9(S) hydroperoxide (9-HPOD) into an allene oxide, 9,10-epoxy-10,12-octadecadienoic acid (9,10-EOD), which did not undergo cyclization but was solely hydrolyzed into the alpha-ketol. A cyclase activity promoting the conversion of 9,10-EOD into (9S,13S)-10-oxo-PEA was detected in the 10(5)*g supernatant prepared by differential centrifugation of the maize root homogenate. The data obtained suggested the existence of a new type of allene oxide cyclase, which is active towards an allene oxide formed from a 9-lipoxygenase-derived hydroperoxide. PMID- 26008578 TI - Yeast Coq9 controls deamination of coenzyme Q intermediates that derive from para aminobenzoic acid. AB - Coq9 is a polypeptide subunit in a mitochondrial multi-subunit complex, termed the CoQ-synthome, required for biosynthesis of coenzyme Q (ubiquinone or Q). Deletion of COQ9 results in dissociation of the CoQ-synthome, but over-expression of Coq8 putative kinase stabilizes the CoQ-synthome in the coq9 null mutant and leads to the accumulation of two nitrogen-containing Q intermediates, imino demethoxy-Q6 (IDMQ6) and 3-hexaprenyl-4-aminophenol (4-AP) when para-aminobenzoic acid (pABA) is provided as a ring precursor. To investigate whether Coq9 is responsible for deamination steps in Q biosynthesis, we utilized the yeast coq5-5 point mutant. The yeast coq5-5 point mutant is defective in the C methyltransferase step of Q biosynthesis but retains normal steady-state levels of the Coq5 polypeptide. Here, we show that when high amounts of 13C6-pABA are provided, the coq5-5 mutant accumulates both 13C6-imino-demethyl-demethoxy-Q6 (13C6-IDDMQ6) and 13C6-demethyl-demethoxy-Q6 (13C6-DDMQ6). Deletion of COQ9 in the yeast coq5-5 mutant along with Coq8 over-expression and 13C6- pABA labeling leads to the absence of 13C6-DDMQ6, and the nitrogen-containing intermediates 13C6-4-AP and 13C6-IDDMQ6 persist. We describe a coq9 temperature-sensitive mutant and show that at the non-permissive temperature, steady-state polypeptide levels of Coq9-ts19 increased, while Coq4, Coq5, Coq6, and Coq7 decreased. The coq9-ts19 mutant had decreased Q6 content and increased levels of nitrogen containing intermediates. These findings identify Coq9 as a multi-functional protein that is required for the function of Coq6 and Coq7 hydroxylases, for removal of the nitrogen substituent from pABA-derived Q intermediates, and is an essential component of the CoQ synthome. PMID- 26008581 TI - Tips and Troubleshooting for Use of the GlideScope Video Laryngoscope for Emergency Endotracheal Intubation. AB - Video laryngoscopy (VL) is still a relatively novel advancement in airway management that offers many potential benefits over direct laryngoscopy. These advantages include decreased time to intubation in difficulty airways, unique opportunities in teaching as the video screen allows for real time teaching points, increased first pass success, particularly with novice operators, and decreased cervical spine motion during intubation. Despite the advantages, the intubation procedure itself has some subtle but significant differences from direct laryngoscopy that change the expected motion as well as troubleshooting techniques, which might discourage the use of the GlideScope by practitioners less familiar with the product. With the hope of generating confidence in the video laryngoscopy procedure, we have compiled some basic tips that we have found helpful when intubating with the GlideScope. These tips include inserting the blade to the left of midline to improve space allowed for the endotracheal tube itself, backing the scope up a small amount to improve the view, holding the tube close to the connector to improve maneuverability, and withdrawing the tube with your thumb to improve advancement through the cords. We hope that, with these tips, in conjunction with ample practice, clinicians can gain comfort and experience with all the tools at our disposal in an effort to provide the best possible care for our patients. PMID- 26008582 TI - Opportunities for earlier HIV diagnosis in a pediatric ED. AB - OBJECTIVES: Emergency department (ED) HIV screening is recommended but challenging to implement and of uncertain effectiveness in pediatric EDs (PEDs). We sought to determine whether there were opportunities for earlier HIV diagnosis in the PED for a cohort of young adults diagnosed with HIV. METHODS: This retrospective cohort study reviewed PED records of a group of young adults receiving HIV care in an urban hospital setting. Pediatric ED visits were selected for review if they took place after the patient's estimated time of HIV acquisition and before their eventual diagnosis. Charts were reviewed to determine whether HIV infection was suspected and whether testing was offered. RESULTS: Among a cohort of HIV-positive young adults, only 3 (3.6%; 95% confidence interval, 0.9-10.8) of 84 were seen in the PED during the time they were undiagnosed but likely to be infected with HIV. Among these subjects, there was no documentation that HIV testing was offered or refused nor was there documented suspicion of HIV. CONCLUSIONS: There are opportunities for earlier diagnosis of HIV in PEDs, affirming the importance of HIV screening implementation in these settings. However, PEDs are unlikely to have the same frequency of contact with undiagnosed individuals as do adult EDs. Alternative methods of accessing at-risk adolescent populations must be identified. PMID- 26008583 TI - Ventricular tachycardia cardiac arrest during central line placement. AB - Central venous catheterization is often necessary for the safe administration of medications that are caustic to peripheral veins, to place temporary transvenous pacemakers and to provide invasive hemodynamic monitoring in the critically ill. While a wide range of complications are known to occur with insertion of these catheters, there is a paucity of cases associated with cardiac arrest during the catheters placement. We describe an unusual case of sustained ventricular tachycardia and subsequent cardiac arrest that occurred during an ultrasound guided central venous catheter placement for a patient in septic shock. This case serves as a reminder of the rare, but potentially fatal complication of central venous access placement. PMID- 26008584 TI - A healthy young woman with massive hemorrhagic ascites. AB - Retrograde menstruation is the backward movement of menstrual fluids. The underlying mechanisms remain unknown. The converse current itself is benign, but the result can be abdominal pain caused by peritoneal irritation and, eventually, endometriosis. The case was of a 25-year-old woman with lower abdominal pain accompanied by significant hemoperitoneum. Physical examination and inspection using abdominal ultrasonography and computed tomography failed to reveal a differential diagnosis. Detailed history taking revealed sexual activities during her menstrual period, which allowed for a diagnosis of retrograde menstruation. These findings emphasize the importance of extensive history taking. PMID- 26008585 TI - Unveiling epimerization effects: a rotational study of alpha-D-galactose. AB - By studying its C4 epimer alpha-D-galactose, the effects of epimerization on the conformational behaviour of alpha-D-glucose have been unveiled. Using laser ablation of crystalline samples, four conformers of alpha-D-galactopyranose have been observed, for the first time, in a supersonic expansion by analyzing the Fourier transform rotational spectrum. PMID- 26008586 TI - T cell memory: New insight on old-timers. PMID- 26008588 TI - T cells: LEM keeps the wheels turning. PMID- 26008592 TI - Carbon bridged triphenolate lanthanide complexes: synthesis, characterization, DFT studies and catalytic activities for isoprene polymerization. AB - The dinuclear lanthanide complexes [Ln2(L)2(THF)n] (Ln = Nd (1) n = 4, Gd (2) n = 3, Lu (3) n = 2) supported by carbon bridged triphenolate ligands [LH3 = tris(3,5 di-tert-butyl-2-hydroxyphenyl)methane] were synthesized via a salt metathesis reaction between lanthanide trichlorides and LNa3 in THF. All complexes were characterized by elemental analysis and X-ray crystallography, and complex 3 was characterized by (1)H and (13)C NMR spectroscopy. Agostic interactions were found in these complexes and were further substantiated by DFT calculations of complex 3. These lanthanide complexes in combination with aluminum alkyls and [Ph3C](+)[B(C6F5)4](-) generated efficient homogeneous catalysts for the cis-1,4 polymerization of isoprene, with complex 1 having the best catalytic activity. PMID- 26008594 TI - Fiber-based solid phase microextraction using fused silica lined bottles to collect, store, and stabilize a multianalyte headspace gas sample for offline analyses. AB - We have developed a solid phase microextraction (SPME) sampling method using fused silica lined bottles (400 ml) to collect, store, and stabilize a headspace subsample from the source for subsequent offline, repetitive analyses of the gas using fiber-based SPME. The method enables long-term stability for repeated offline analysis of the organic species collected from the source headspace and retains all the advantages of fiber SPME sampling (e.g. rapid extraction, solvent free, simple and inexpensive) while providing additional advantages. Typically, the analytes collected on the SPME fiber must be desorbed and analyzed immediately to mitigate analyte loss or contamination. The new SPME sampling method, conducted offline using carboxen/polydimethylsiloxane (carboxen/PDMS - 85 MUm) coated fibers, has been shown to be identical to in situ SPME sampling of a headspace acquired from an 80 component organic matrix with reproducibility demonstrated to be less than %RSD=7.0% for replicate samples measured over a 30 day period. In addition, repetitive samplings from one headspace aliquot are possible using one or more fibers and fiber types as well as quantitative options such as internal standard addition as demonstrated in a feasibility study using a benzene/toluene/xylene (BTX; 1 ppmv) certified gas standard, in which the SPME measurement precision (%RSD) was improved by a factor of 1.5-1.9 compared to the use of an external standard. PMID- 26008595 TI - Separation and characterization of phenolic compounds and triterpenoid saponins in licorice (Glycyrrhiza uralensis) using mobile phase-dependent reversed phase*reversed-phase comprehensive two-dimensional liquid chromatography coupled with mass spectrometry. AB - Licorice is one of the most popular herbal medicines worldwide. It contains a big array of phenolic compounds (flavonoids, coumarins, and diphenylethanones). Due to high structural diversity, low abundance, and co-elution with licorice saponins, these phenolic compounds are difficult to be separated by conventional chromatography. In this study, a mobile phase-dependent reversed-phase*reversed phase comprehensive two-dimensional liquid chromatography (RP*RP 2DLC) method was established to separate phenolic compounds in licorice (the roots of Glycyrrhiza uralensis). Organic solvents in the mobile phase were optimized to improve orthogonality of the first and second dimensions, and a synchronized gradient mode was used to improve chromatographic resolution. Finally, licorice extracts were eluted with methanol/water/formic acid in the first dimension (Acquity CSH C18 column), and acetonitrile/water/formic acid in the second dimension (Poroshell Phenyl-Hexyl column). By using this 2DLC system, a total of 311 compounds were detected within 40min. The practical and effective peak capacity was 1329 and 524, respectively, and the orthogonality was 79.8%. The structures of 21 selected unknown compounds were tentatively characterized by mass spectrometry, and 8 of them were discovered from G. uralensis for the first time. The mobile phase-dependent 2DLC/MS system could benefit the separation and characterization of natural products in complicated herbal extracts. PMID- 26008593 TI - Clinical utility of a novel urine-based gene fusion TTTY15-USP9Y in predicting prostate biopsy outcome. AB - OBJECTIVE: In recent years, great effort has been made to explore new biomarkers for early detection of prostate cancer. Our previous study has demonstrated the high prevalence of TTTY15-USP9Y in prostate cancer samples from a Chinese population. Our aim was to evaluate the clinical utility of TTTY15-USP9Y in predicting the prostate biopsy outcome. MATERIALS AND METHODS: We retrospectively examined the expression of TTTY15-USP9Y in 226 qualified urine sediment samples. Total RNA was extracted from the urine sediment by using TRIzol reagent, and complementary DNA was synthesized using TransPlex Complete Whole Transcriptome Amplification Kit (WTA2). Real-time quantitative polymerase chain reaction was performed to evaluate the expression of TTTY15-USP9Y and the prostate cancer specific antigen (PSA) level. The TTTY15-USP9Y score was calculated as 2(Ct(PSA) Ct(TTTY15-USP9Y))* 1,000. RESULTS: The TTTY15-USP9Y score was statistically significantly higher in men with positive biopsy outcome than in men with negative biopsy outcome (P<0.001). The area under the curve was 0.828 for the TTTY15-USP9Y score in the entire patient cohort. The TTTY15-USP9Y score's cutoff of 90.28 provided the optimal balance between sensitivity (84.0%) and specificity (77.5%). The combination of PSA level and the TTTY15-USP9Y score significantly improved the diagnostic performance of PSA level (P = 0.001). The TTTY15-USP9Y score alone was superior to PSA level, percent free PSA, and PSA density (serum PSA/prostate volume) in the subgroup of clinical interest (PSA level: 4-10ng/ml, gray zone). Univariable and multivariable logistic analyses indicated that TTTY15 USP9Y score, PSA level, age, and prostate volume were independent predictors of PCa. Adding the TTTY15-USP9Y score in the clinical base model (PSA level, age, and prostate volume) could bring a higher net benefit and reduce more unnecessary biopsies in the defined range of interest (10%-40% threshold probability). CONCLUSION: In conclusion, our study explored the potential utility of measuring the TTTY15-USP9Y score in post-digital rectal examination urine samples to predict biopsy outcome and provided the basis for the utility of this novel gene fusion in multicenter and large cohort studies. PMID- 26008591 TI - Regulation of tumour necrosis factor signalling: live or let die. AB - Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that has important roles in mammalian immunity and cellular homeostasis. Deregulation of TNF receptor (TNFR) signalling is associated with many inflammatory disorders, including various types of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases. This Review focuses on the recent advances that have been made in understanding TNFR signalling and the consequences of its deregulation for cellular survival, apoptosis and regulated necrosis. We discuss how TNF-induced survival signals are distinguished from those that lead to cell death. Finally, we provide a brief overview of the role of TNF in inflammatory and autoimmune diseases, and we discuss up-to-date and future treatment strategies for these disorders. PMID- 26008596 TI - Electrophoretic concentration and sweeping-micellar electrokinetic chromatography analysis of cationic drugs in water samples. AB - Sample preparation by electrophoretic concentration, followed by analysis using sweeping-micellar electrokinetic chromatography, was studied as a green and simple analytical strategy for the trace analysis of cationic drugs in water samples. Electrophoretic concentration was conducted using 50 mmol/L ammonium acetate at pH 5 as acceptor electrolyte. Electrophoretic concentration was performed at 1.0 kV for 50 min and 0.5 kV and 15 min for purified and 10-fold diluted waste water samples, respectively. Sweeping-micellar electrokinetic chromatography was with 100 mmol/L sodium phosphate at pH 2, 100 mmol/L sodium dodecyl sulfate and 27.5%-v/v acetonitrile as separation electrolyte. The separation voltage was -20 kV, UV-detection was at 200 nm, and the acidified concentrate was injected for 36 s at 1 bar (or 72% of the total capillary length, 60 cm). Both purified water and 10-fold diluted waste water exhibited a linear range of two orders of concentration magnitude. The coefficient of determination, and intra- and interday repeatability were 0.991-0.997, 2.5-6.2, and 4.4-9.7%RSD (n=6), respectively, for purified water. The values were 0.991-0.997, 3.4-7.1, and 8.7-9.8%RSD (n=6), correspondingly, for 10-fold diluted waste water. The method detection limit was in the range from 0.04-0.09 to 1.20-6.97 ng/mL for purified and undiluted waste water, respectively. PMID- 26008597 TI - Liquid chromatography-mass spectrometry coupled with multivariate analysis for the characterization and discrimination of extractable and nonextractable polyphenols and glucosinolates from red cabbage and Brussels sprout waste streams. AB - Nonextractable polyphenol (NEP) fractions are usually ignored because conventional extraction methods do not release them from the plant matrix. In this study, we optimized the conditions for sonicated alkaline hydrolysis to the residues left after conventional polyphenol extraction of Brussels sprouts top (80 degrees C, 4M NaOH, 30min) and stalks (60 degrees C, 4M NaOH, 30min), and red cabbage waste streams (80 degrees C, 4M NaOH, 45min) to release and characterize the NEP fraction. The NEP fractions of Brussels sprouts top (4.8+/-1.2mg gallic acid equivalents [GAE]/g dry waste) and stalks (3.3+/-0.2mg GAE/g dry waste), and red cabbage (11.5mg GAE/g dry waste) waste have significantly higher total polyphenol contents compared to their respective extractable polyphenol (EP) fractions (1.5+/-0.0, 2.0+/-0.0 and 3.7+/-0.0mg GAE/g dry waste, respectively). An LC-MS method combined with principal components analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to tentatively identify and discriminate the polyphenol and glucosinolate composition of the EP and NEP fractions. Results revealed that phenolic profiles of the EP and NEP fractions are different and some compounds are only found in either fraction in all of the plant matrices. This suggests the need to account both fractions when analyzing the polyphenol and glucosinolate profiles of plant matrices to attain a global view of their composition. This is the first report on the discrimination of the phenolic and glucosinolate profiles of the EP and NEP fractions using metabolomics techniques. PMID- 26008598 TI - Ammonium fluoride as a mobile phase additive in aqueous normal phase chromatography. AB - The use of ammonium fluoride as a mobile phase additive in aqueous normal phase chromatography with silica hydride-based stationary phases and mass spectrometry detection is evaluated. Retention times, peak shape, efficiency and peak intensity are compared to the more standard additives formic acid and ammonium formate. The test solutes were NAD, 3-hydroxyglutaric acid, alpha-ketoglutaric acid, p-aminohippuric acid, AMP, ATP, aconitic acid, threonine, N-acetyl carnitine, and 3-methyladipic acid. The column parameters are assessed in both the positive and negative ion detection modes. Ammonium fluoride is potentially an aggressive mobile phase additive that could have detrimental effects on column lifetime. Column reproducibility is measured and the effects of switching between different additives are also tested. PMID- 26008600 TI - Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease. PMID- 26008599 TI - Long-term effects of maternal undernutrition on offspring carotid artery remodeling: role of miR-29c. AB - The purpose of this study was to examine the hypothesis that excess maternal glucocorticoids in response to maternal undernutrition programs the expression of extracellular matrix (ECM) components potentially by miR-29c. We measured the expression of mRNA (qRT-PCR) and protein (Western blot) for collagen 3A1, collagen 4A5 and matrix metalloproteinase 2 (MMP2) in offspring carotid arteries from three groups of dams: 50% food-restricted in latter half of gestation [maternal undernutrition (MUN)], MUN dams who received metyrapone (MET) (500 mg/ml ) in drinking water from day 10 of gestation to term, and control dams fed an ad libitum diet. The expression of miR-29c was significantly decreased at 3 weeks, 3 months and 9 months in MUN carotid arteries, and these decreases in expression were partially blocked by treatment of dams with MET. The expression pattern of ECM genes that are targets of miR-29c correlated with miR-29c expression. Expression of mRNA was increased for elastin (ELN) and MMP2 mRNA in 3 week MUN carotids; in 9-month carotids there were also significant increases in expression of Col3A1 and Col4A5. These changes in mRNA expression of ECM genes at 3 weeks and 9 months were blocked by MET treatment. Similarly, the expression of ELN and MMP2 proteins at 3 weeks were increased in MUN carotids, and by 9 months there were also increases in expression of Col3A1 and Col4A5, which were blocked by MET in MUN carotids. Overall, the results demonstrate a close correlation between expression of miR-29c and the ECM proteins that are its targets thus supporting our central hypothesis. PMID- 26008602 TI - Serum salusins levels are increased and correlated positively with cyst size in ovarian endometrioma. AB - OBJECTIVES: The objective of this study is to evaluate plasma concentrations of salusin-alpha and salusin-beta levels in women with endometrioma and non endometriotic benign ovarian cysts. METHOD: Endometrioma patients (n = 14), non endometriotic ovarian cysts (n = 14), and age-matched normal healthy fertile subjects (n = 14) participated in this study. Plasma salusin-alpha and salusin beta levels at the time of mid-luteal phase before and 3 months after L/S cystectomy were measured using ELISA and EIA tests, and their relation with demographic parameters was also assessed. RESULTS: The mean salusin-alpha and salusin-beta levels were significantly higher in women with endometrioma before the removal of cyst compared with cases with non-endometriotic cyst and fertile cases. Surgical removal of the endometrioma decreased the mean salusin-alpha and salusin-beta levels to the level of those with non-endometriotic cyst before and after the cystectomy and fertile women, in both unilateral and bilateral endometrioma cases. Plasma salusin-beta concentrations were found to be positively correlated with age, size of cyst, bilaterality, and salusin-alpha levels. Salusin-beta values showed no correlations to BMI and size of the ovarian cysts. CONCLUSIONS: Plasma salusin-alpha and salusin-beta levels are increased in endometrioma patients and positively correlated with endometrioma size. Laparoscopic removal of the endometrioma by stripping technique decreases the salusin levels to a similar level of fertile women. PMID- 26008601 TI - Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth. AB - Beclin 1, a protein essential for autophagy, regulates autophagy by interacting with Vps34 and other cofactors to form the Beclin 1 complex. Modifications of Beclin 1 may lead to the induction, inhibition or fine-tuning of the autophagic response under a variety of conditions. Here we show that Beclin 1 is acetylated by p300 and deacetylated by SIRT1 at lysine residues 430 and 437. In addition, the phosphorylation of Beclin 1 at S409 by CK1 is required for the subsequent p300 binding and Beclin 1 acetylation. Beclin 1 acetylation inhibits autophagosome maturation and endocytic trafficking by promoting the recruitment of Rubicon. In tumour xenografts, the expression of 2KR mutant Beclin 1 (substitution of K430 and K437 to arginines) leads to enhanced autophagosome maturation and tumour growth suppression. Therefore, our study identifies an acetylation-dependent regulatory mechanism governing Beclin 1 function in autophagosome maturation and tumour growth. PMID- 26008603 TI - Descriptive epidemiology of World Health Organization grades II and III intracranial meningiomas in the United States. AB - BACKGROUND: Because World Health Organization (WHO) grades II and III meningiomas are relatively uncommon, there is limited literature on the descriptive epidemiology of these tumors, and the existing literature predates the 2000 WHO classification revisions. Our purpose was to provide a modern, population-based study of the descriptive epidemiology of WHO II and III meningiomas in the United States. METHODS: The Central Brain Tumor Registry of the United States (CBTRUS) was queried for intracranial meningiomas categorized by WHO grade for the 2004- 2010 study period. Age-adjusted incidence (95% confidence interval in parentheses) per 100,000 population was calculated by age, sex, race, and ethnicity. Annual percent change (APC) was calculated using Joinpoint. RESULTS: From 2004 to 2010, the incidence of WHO II intracranial meningiomas increased from 0.28 (95% CI, 0.27--0.29) to 0.30 (95% CI, 0.28-0.32), representing an APC of 3.6% (95%CI, 0.8%-6.5%). Conversely, from 2000-2010, the incidence of WHO III meningiomas decreased from 0.13 (95% CI, 0.11-0.14) to 0.06 (95%CI, 0.06-0.07), representing an APC of -5.4% (95% CI, -6.8% to -4.0%). From 2004 to 2010, the overall proportion of WHO I, II, and III intracranial meningiomas was 94.6%, 4.2%, and 1.2%, respectively. For WHO II/III meningiomas, females in the 35-64 year age group had a higher incidence than males in the same age group, whereas males in the >= 75 year age group >= had a higher incidence. Black and Asian Pacific Islander races were both associated with the highest incidence of WHO II/III meningiomas. Hispanic ethnicity was not associated with any difference in incidence. CONCLUSION: This study presents the most comprehensive evaluation of the modern descriptive epidemiology of WHO II and III meningiomas. Temporal trends likely reflect the 2000 WHO histological criteria revisions. PMID- 26008604 TI - A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. AB - BACKGROUND: Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor. METHODS: This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers. RESULTS: Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1alpha, and cerebral blood flow increased. CONCLUSIONS: The combination of cediranib with cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination. PMID- 26008605 TI - CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models. AB - BACKGROUND: The prognosis of glioblastoma (GBM) remains poor; therefore, effective therapeutic strategies need to be developed. CD40 is a costimulatory molecule whose agonistic antibody has been shown to activate antitumor effects. Recently, CD40 has been extensively targeted for immunotherapeutic purposes. METHODS: Expressions of CD40/CD40L mRNAs were examined in 86 cases of World Health Organization grade IV GBM and 36 cases of grade III gliomas and correlated with outcomes. CD40 signaling was employed to augment the efficacy of immunotherapy against gliomas. The efficacy of FGK45, an agonistic antibody for CD40, was examined by adding it to a tumor lysate-based subcutaneous vaccination against a GL261 glioma model and an NSCL61 glioma-initiating cell-like cell tumor model. RESULTS: We demonstrated for the first time using quantitative PCR that grade III gliomas express higher levels of CD40/CD40L than does grade IV GBM. The higher expression of CD40/CD40L was associated with good prognoses in patients with GBM. Addition of FGK45 to the subcutaneous tumor cell lysate-based vaccination significantly prolonged survival in both tumor models. However, the efficacy was modest in NSCL61-model mice. Therefore, we established combination immunotherapeutic strategies using FGK45 and OX86, an agonistic antibody for OX40. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis increased and proliferation decreased in tumors treated with combination immunotherapy. CONCLUSIONS: The high expression of CD40/CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells. PMID- 26008607 TI - Sulfonated graphene nanosheets as a superb adsorbent for various environmental pollutants in water. AB - Graphene nanosheets, as a novel nanoadsorbent, can be further modified to optimize the adsorption capability for various pollutants. To overcome the structural limits of graphene (aggregation) and graphene oxide (hydrophilic surface) in water, sulfonated graphene (GS) was prepared by diazotization reaction using sulfanilic acid. It was demonstrated that GS not only recovered a relatively complete sp(2)-hybridized plane with high affinity for aromatic pollutants but also had sulfonic acid groups and partial original oxygen containing groups that powerfully attracted positively charged pollutants. The saturated adsorption capacities of GS were 400 mg/g for phenanthrene, 906 mg/g for methylene blue and 58 mg/g for Cd(2+), which were much higher than the corresponding values for reduced graphene oxide and graphene oxide. GS as a graphene-based adsorbent exhibits fast adsorption kinetic rate and superior adsorption capacity toward various pollutants, which mainly thanks to the multiple adsorption sites in GS including the conjugate pi region sites and the functional group sites. Moreover, the sulfonic acid groups endow GS with the good dispersibility and single or few nanosheets which guarantee the adsorption processes. It is great potential to expose the adsorption sites of graphene nanosheets for pollutants in water by regulating their microstructures, surface properties and water dispersion. PMID- 26008606 TI - The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. AB - BACKGROUND: We evaluated the diagnostic value of static and dynamic O-(2 [(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) PET parameters in patients with progressive or recurrent glioma. METHODS: We retrospectively analyzed 132 dynamic (18)F-FET PET and conventional MRI scans of 124 glioma patients (primary World Health Organization grade II, n = 55; grade III, n = 19; grade IV, n = 50; mean age, 52 +/- 14 y). Patients had been referred for PET assessment with clinical signs and/or MRI findings suggestive of tumor progression or recurrence based on Response Assessment in Neuro-Oncology criteria. Maximum and mean tumor/brain ratios of (18)F-FET uptake were determined (20-40 min post-injection) as well as tracer uptake kinetics (ie, time to peak and patterns of the time-activity curves). Diagnoses were confirmed histologically (95%) or by clinical follow-up (5%). Diagnostic accuracies of PET and MR parameters for the detection of tumor progression or recurrence were evaluated by receiver operating characteristic analyses/chi-square test. RESULTS: Tumor progression or recurrence could be diagnosed in 121 of 132 cases (92%). MRI and (18)F-FET PET findings were concordant in 84% and discordant in 16%. Compared with the diagnostic accuracy of conventional MRI to diagnose tumor progression or recurrence (85%), a higher accuracy (93%) was achieved by (18)F-FET PET when a mean tumor/brain ratio >=2.0 or time to peak <45 min was present (sensitivity, 93%; specificity, 100%; accuracy, 93%; positive predictive value, 100%; P < .001). CONCLUSION: Static and dynamic (18)F-FET PET parameters differentiate progressive or recurrent glioma from treatment-related nonneoplastic changes with higher accuracy than conventional MRI. PMID- 26008608 TI - Osteoclast fusion is initiated by a small subset of RANKL-stimulated monocyte progenitors, which can fuse to RANKL-unstimulated progenitors. AB - Osteoclasts are multinucleated, bone-resorbing cells formed via fusion of monocyte progenitors, a process triggered by prolonged stimulation with RANKL, the osteoclast master regulator cytokine. Monocyte fusion into osteoclasts has been shown to play a key role in bone remodeling and homeostasis; therefore, aberrant fusion may be involved in a variety of bone diseases. Indeed, research in the last decade has led to the discovery of genes regulating osteoclast fusion; yet the basic cellular regulatory mechanism underlying the fusion process is poorly understood. Here, we applied a novel approach for tracking the fusion processes, using live-cell imaging of RANKL-stimulated and non-stimulated progenitor monocytes differentially expressing dsRED or GFP, respectively. We show that osteoclast fusion is initiated by a small (~2.4%) subset of precursors, termed "fusion founders", capable of fusing either with other founders or with non-stimulated progenitors (fusion followers), which alone, are unable to initiate fusion. Careful examination indicates that the fusion between a founder and a follower cell consists of two distinct phases: an initial pairing of the two cells, typically lasting 5-35 min, during which the cells nevertheless maintain their initial morphology; and the fusion event itself. Interestingly, during the initial pre-fusion phase, a transfer of the fluorescent reporter proteins from nucleus to nucleus was noticed, suggesting crosstalk between the founder and follower progenitors via the cytoplasm that might directly affect the fusion process, as well as overall transcriptional regulation in the developing heterokaryon. PMID- 26008610 TI - Oral dependent-dose toxoplasmic infection model induced by oocysts in rats: Myenteric plexus and jejunal wall changes. AB - Toxoplasmosis is a widely distributed disease caused by the protozoan Toxoplasma gondii that is mainly transmitted orally. Once ingested, the parasite crosses the intestinal barrier to reach the blood and lymph systems to migrate to other regions of the host. The objective of this study was to evaluate the changes in the myenteric plexus and the jejunal wall of Wistar rats caused by oral infection with T. gondii oocysts (ME-49 strain). Inocula of 10, 100, 500 and 5000 oocysts were used. The total population of myenteric neurons and the most metabolically active subpopulation (NADH-diaphorase positive - NADH-dp) exhibited a decrease proportional to the dose of T. gondii. There was also a quantitative increase in the subpopulation of NADPH-diaphorase-positive (NADPH-dp) myenteric neurons, indicating greater expression of the NOS enzyme. Neuronal atrophy was observed, and morphological and morphometric alterations such as jejunal atrophy were found in the infected groups. Hypertrophy of the external muscle with the presence of inflammatory foci was observed in the group infected with 5000 oocysts. The changes observed in the infected groups were proportional to the number of oocysts inoculated. PMID- 26008609 TI - Fatigue-induced microdamage in cancellous bone occurs distant from resorption cavities and trabecular surfaces. AB - Impaired bone toughness is increasingly recognized as a contributor to fragility fractures. At the tissue level, toughness is related to the ability of bone tissue to resist the development of microscopic cracks or other tissue damage. While most of our understanding of microdamage is derived from studies of cortical bone, the majority of fragility fractures occur in regions of the skeleton dominated by cancellous bone. The development of tissue microdamage in cancellous bone may differ from that in cortical bone due to differences in microstructure and tissue ultrastructure. To gain insight into how microdamage accumulates in cancellous bone we determined the changes in number, size and location of microdamage sites following different amounts of cyclic compressive loading. Human vertebral cancellous bone specimens (n=32, 10 male donors, 6 female donors, age 76 +/- 8.8, mean +/- SD) were subjected to sub-failure cyclic compressive loading and microdamage was evaluated in three-dimensions. Only a few large microdamage sites (the largest 10%) accounted for 70% of all microdamage caused by cyclic loading. The number of large microdamage sites was a better predictor of reductions in Young's modulus caused by cyclic loading than overall damage volume fraction (DV/BV). The majority of microdamage volume (69.12 +/- 7.04%) was located more than 30 MUm (the average erosion depth) from trabecular surfaces, suggesting that microdamage occurs primarily within interstitial regions of cancellous bone. Additionally, microdamage was less likely to be near resorption cavities than other bone surfaces (p<0.05), challenging the idea that stress risers caused by resorption cavities influence fatigue failure of cancellous bone. Together, these findings suggest that reductions in apparent level mechanical performance during fatigue loading are the result of only a few large microdamage sites and that microdamage accumulation in fatigue is likely dominated by heterogeneity in tissue material properties rather than stress concentrations caused by micro-scale geometry. PMID- 26008611 TI - Efficacy of chimeric DNA vaccines encoding Eimeria tenella 5401 and chicken IFN gamma or IL-2 against coccidiosis in chickens. AB - Chimeric DNA vaccines encoding Eimeria tenella (E. tenella) surface antigen 5401 were constructed and their efficacies against E. tenella challenge were studied. The open reading frame (ORF) of 5401 was cloned into the prokaryotic expression vector pGEX-4T2 to express the recombinant protein and the expressed recombinant protein was identified by Western blot. The ORF of 5401 and chicken cytokine gene IFN-gamma or IL-2 were cloned into the eukaryotic expression vector pVAX1 consecutively to construct DNA vaccines pVAX-5401-IFN-gamma, pVAX-5401-IL-2 and pVAX-5401. The expression of aim genes in vivo was detected by reverse transcription-polymerase chain reaction and Western blot. Fourteen-day-old chickens were inoculated twice at an interval of 7 days with 100 ug of plasmids pVAX-5401, pVAX-5401-IFN-gamma and pVAX-5401-IL-2 or 200 ug of recombinant 5401 protein by leg intramuscular injection, respectively. Seven days after the second inoculation, all chickens except the unchallenged control group were challenged orally with 5 * 10(4) sporulated oocysts of E. tenella. Seven days after challenge, all chickens were weighted and slaughtered to determine the effects of immunization. The results showed the recombinant protein was about 90 kDa and reacted with antiserum against soluble sporozoites. The animal experiment showed that all the DNA vaccines pVAX-5401, pVAX-5401-IFN-gamma or pVAX-5401-IL-2 and the recombinant 5401 protein could obviously alleviate body weight loss and cecal lesions as compared with non-vaccinated challenged control and empty vector pVAX1control. Furthermore, pVAX-5401-IFN-gamma or pVAX-5401-IL-2 induced anti coccidial index (ACI) of 180.01 or 177.24 which were significantly higher than that of pVAX-5401. The results suggested that 5401 was an effective candidate antigen for vaccine. This finding also suggested that chicken IFN-gamma or IL-2 could effectively improve the efficacies of DNA vaccines against avian coccidiosis. PMID- 26008613 TI - Economic impact of syndesmosis hardware removal. AB - Ankle syndesmosis injuries are commonly seen with 5-10% of sprains and 10% of ankle fractures involving injury to the ankle syndesmosis. Anatomic reduction has been shown to be the most important predictor of clinical outcomes. Optimal surgical management has been a subject of debate in the literature. The method of fixation, number of screws, screw size, and number of cortices are all controversial. Postoperative hardware removal has also been widely debated in the literature. Some surgeons advocate for elective hardware removal prior to resuming full weightbearing. Returning to the operating room for elective hardware removal results in increased cost to the patient, potential for infection or complication(s), and missed work days for the patient. Suture button devices and bioabsorbable screw fixation present other options, but cortical screw fixation remains the gold standard. This retrospective review was designed to evaluate the economic impact of a second operative procedure for elective removal of 3.5mm cortical syndesmosis screws. Two hundred and two patients with ICD-9 code for "open treatment of distal tibiofibular joint (syndesmosis) disruption" were identified. The medical records were reviewed for those who underwent elective syndesmosis hardware removal. The primary outcome measurements included total hospital billing charges and total hospital billing collection. Secondary outcome measurements included average individual patient operative costs and average operating room time. Fifty-six patients were included in the study. Our institution billed a total of $188,271 (USD) and collected $106,284 (55%). The average individual patient operating room cost was $3579. The average operating room time was 67.9 min. To the best of our knowledge, no study has previously provided cost associated with syndesmosis hardware removal. Our study shows elective syndesmosis hardware removal places substantial economic burden on both the patient and the healthcare system. PMID- 26008614 TI - Potential use of a polycarbonate-urethane matrix reinforced with polyethylene fibers for shock-absorbing dental implants. AB - The absence of a shock-absorbing mechanism in commercial dental implants is a likely factor in the resulting bone loss and possible implant failure. The aim of the current study is to generate a shock-absorbing dental implant that resembles the periodontal ligament, which naturally absorbs occlusal overloading forces. To achieve this, a polycarbonate-urethane composite reinforced with polyethylene fibers will be constructed. Tests based on finite element analysis and mechanical testing are proposed to further examine this novel implant type. PMID- 26008612 TI - Protein phosphorylation during Plasmodium berghei gametogenesis. AB - Plasmodium gametogenesis within the mosquito midgut is a complex differentiation process involving signaling mediated by phosphorylation, which modulate metabolic routes and protein synthesis required to complete this development. However, the mechanisms leading to gametogenesis activation are poorly understood. We analyzed protein phosphorylation during Plasmodium berghei gametogenesis in vitro in serum free medium using bidimensional electrophoresis (2-DE) combined with immunoblotting (IB) and antibodies specific to phosphorylated serine, threonine and tyrosine. Approximately 75 protein exhibited phosphorylation changes, of which 23 were identified by mass spectrometry. These included components of the cytoskeleton, heat shock proteins, and proteins involved in DNA synthesis and signaling pathways among others. Novel phosphorylation events support a role for these proteins during gametogenesis. The phosphorylation sites of six of the identified proteins, HSP70, WD40 repeat protein msi1, enolase, actin-1 and two isoforms of large subunit of ribonucleoside reductase were investigated using TiO2 phosphopeptides enrichment and tandem mass spectrometry. In addition, transient exposure to hydroxyurea, an inhibitor of ribonucleoside reductase, impaired male gametocytes exflagellation in a dose-dependent manner, and provides a resource for functional studies. PMID- 26008615 TI - Communal visual histories to detect environmental change in northern areas: Examples of emerging North American and Eurasian practices. AB - This article explores the pioneering potential of communal visual-optic histories which are recorded, painted, documented, or otherwise expressed. These materials provide collective meanings of an image or visual material within a specific cultural group. They potentially provide a new method for monitoring and documenting changes to ecosystem health and species distribution, which can effectively inform society and decision makers of Arctic change. These visual histories can be positioned in a continuum that extends from rock art to digital photography. They find their expressions in forms ranging from images to the oral recording of knowledge and operate on a given cultural context. For monitoring efforts in the changing boreal zone and Arctic, a respectful engagement with visual histories can reveal emerging aspects of change. The examples from North America and case studies from Eurasia in this article include Inuit sea ice observations, Yu'pik visual traditions of masks, fish die-offs in a sub-boreal catchment area, permafrost melt in the Siberian tundra and early, first detection of a scarabaeid beetle outbreak, a Southern species in the Skolt Sami area. The pros and cons of using these histories and their reliability are reviewed. PMID- 26008616 TI - Low Yield of Methicillin-Resistant Staphylococcus aureus Screening in Hemodialysis Patients: 10 Years' Experience. AB - OBJECTIVE: To determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in hemodialysis patients and to analyze the cost effectiveness of our screening approach compared with an alternative strategy. DESIGN Screening study and cost-effectiveness analysis. METHODS: Analysis of twice-yearly MRSA prevalence studies conducted in the hemodialysis unit of a 950 bed tertiary care hospital from January 1, 2004, through December 31, 2013. For this purpose, nasal swab samples were cultured on MRSA screening agar (mannitol oxacillin biplate). RESULTS: There were 20 mass screenings during the 10-year study period. We identified 415 patients participating in at least 1 screening, with an average of 4.5 screenings per patient. Of 415 screened patients, 15 (3.6%) were found to be MRSA carriers. The first mass screening in 2004 yielded the highest percentage of MRSA (6/101 [6%]). Only 7 subsequent screenings revealed new MRSA carriers, whereas 4 screenings confirmed previously known carriers, and 8 remained negative. None of the carriers developed MRSA bacteremia during the study period. The total cost of our screening approach, that is, screening and isolation costs, was US $93,930. The total cost of an alternative strategy (ie, no mass screening administered) would be equivalent to costs of isolation of index cases and contact tracing was estimated to be US $5,382 (difference, US $88,548). CONCLUSIONS: In an area of low MRSA endemicity (<5%), regular nasal screenings of a high-risk population yielded a low rate of MRSA carriers. Twice-yearly MRSA screening of dialysis patients is unlikely to be cost effective if MRSA prevalence is low. PMID- 26008617 TI - Cyclophilin A Enhances Cell Proliferation and Xenografted Tumor Growth of Early Gastric Cancer. AB - BACKGROUND: Recently Cyclophilin A (CypA) was identified as a candidate target protein in gastric carcinoma. However, the role of CypA in gastric cancer (GC) has not been investigated extensively so far. AIM: The purpose of this study was to determine the expression pattern of CypA in human GC, and to explore the effects of suppressed CypA expression on cell proliferation and xenografted tumor growth of gastric cancer. METHODS: In the present study, we detected the expression pattern of CypA in human GC by immunohistochemistry analysis. Further, the RNAi method was used to silence CypA, and colony formation assay, growth curves, cell cycle and mouse xenograft were analysed. RESULTS: An elevated expression of CypA in GC tissues compared with normal gastric mucosa was observed, especially in TNM stage-I and intestinal type of tumor. CypA was overexpressed in most GC cell lines and endogenous expression of CypA correlated with cell growth phenotypes. Transient suppression of CypA reduced the proliferation of BGC-823 and SGC-7901 GC cell lines. Exogenous CypA promoted the proliferation of NCI-N87 GC cells in a concentration dependent manner. Further study revealed that stable CypA silencing inhibited the proliferation, prevented cell cycle and reduced autophagy of BGC-823 GC cells in vitro through suppressing the ERK1/2 signal pathway. Stable CypA silencing also inhibited the growth of xenografted tumor of BGC-823 GC cell in nude mice. CONCLUSIONS: These results indicate a special function mode for CypA of playing more important roles in the early stage of gastric tumorigenesis and suggest CypA as a new molecular target of diagnosis and treatment for GC patients. PMID- 26008619 TI - Detection of admittivity anomaly on high-contrast heterogeneous backgrounds using frequency difference EIT. AB - This paper describes a multiple background subtraction method in frequency difference electrical impedance tomography (fdEIT) to detect an admittivity anomaly from a high-contrast background conductivity distribution. The proposed method expands the use of the conventional weighted frequency difference EIT method, which has been used limitedly to detect admittivity anomalies in a roughly homogeneous background. The proposed method can be viewed as multiple weighted difference imaging in fdEIT. Although the spatial resolutions of the output images by fdEIT are very low due to the inherent ill-posedness, numerical simulations and phantom experiments of the proposed method demonstrate its feasibility to detect anomalies. It has potential application in stroke detection in a head model, which is highly heterogeneous due to the skull. PMID- 26008618 TI - Hepatitis C Infection in the Elderly. AB - Hepatitis C virus (HCV) infection in the elderly population is a global medical burden and healthcare utilization concern. The majority of patients with hepatitis C in the USA are "baby boomers," who were born between 1945 and 1965. Consistently worldwide, HCV infection in elderly population is overrepresented and poses public health concerns. These individuals have been infected now for over two decades and are presenting with advanced liver disease. Traditionally, the use of pegylated interferon-based therapy has been limited in the elderly because of its adverse effects. The sustained virologic responses have also tended to be lower in the elderly than in younger adults. The emergence of non interferon-based therapy with direct acting antiviral agents has expanded the pool of patients eligible for treatment. These agents have been found to be effective, tolerable, and safe in the elderly population. PMID- 26008621 TI - Thiacremonone Potentiates Anti-Oxidant Effects to Improve Memory Dysfunction in an APP/PS1 Transgenic Mice Model. AB - Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Abeta) peptide. Evidence suggests that amyloid accumulation can be caused by oxidative stress and inflammatory responses. In this study, we examined neuroprotective effects of thiacremonone, an anti-oxidant and anti-inflammatory compound isolated from garlic. Treatment of thiacremonone significantly attenuated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) double-mutant transgenic mice. In addition, activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and extracellular signal-regulated kinase (ERK) pathways in the brain was potently inhibited by thiacremonone. We also observed that thiacremonone significantly inhibited activation of NF-kappaB and ERK pathways induced by H2O2 and Abeta1-42 in embryonic neuronal cells. Furthermore, thiacremonone augmented peroxiredoxin 6 (PRDX6) expression in vivo and in vitro associated with reduced oxidative stress of macromolecules such as protein and lipids. This study indicates that thiacremonone might exert memory improvement via stimulating anti-oxidant system. These multiple properties could attenuate Abeta accumulation and oxidative stress in Alzheimer's brains. Thus, these results suggest that thiacremonone might be useful to intervene development or progression of neurodegeneration in AD. PMID- 26008620 TI - LSD1 is Required for Hair Cell Regeneration in Zebrafish. AB - Lysine-specific demethylase 1 (LSD1/KDM1A) plays an important role in complex cellular processes such as differentiation, proliferation, apoptosis, and cell cycle progression. It has recently been demonstrated that during development, downregulation of LSD1 inhibits cell proliferation, modulates the expression of cell cycle regulators, and reduces hair cell formation in the zebrafish lateral line, which suggests that LSD1-mediated epigenetic regulation plays a key role in the development of hair cells. However, the role of LSD1 in hair cell regeneration after hair cell loss remains poorly understood. Here, we demonstrate the effect of LSD1 on hair cell regeneration following neomycin-induced hair cell loss. We show that the LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA) significantly decreases the regeneration of hair cells in zebrafish after neomycin damage. In addition, immunofluorescent staining demonstrates that 2-PCPA administration suppresses supporting cell proliferation and alters cell cycle progression. Finally, in situ hybridization shows that 2-PCPA significantly downregulates the expression of genes related to Wnt/beta-catenin and Fgf activation. Altogether, our data suggest that downregulation of LSD1 significantly decreases hair cell regeneration after neomycin-induced hair cell loss through inactivation of the Wnt/beta-catenin and Fgf signaling pathways. Thus, LSD1 plays a critical role in hair cell regeneration and might represent a novel biomarker and potential therapeutic approach for the treatment of hearing loss. PMID- 26008622 TI - Production of optically pure L-phenyllactic acid by using engineered Escherichia coli coexpressing L-lactate dehydrogenase and formate dehydrogenase. AB - L-Phenyllactic acid (L-PLA) is a novel antiseptic agent with broad and effective antimicrobial activity. In addition, L-PLA has been used for synthesis of poly(phenyllactic acid)s, which exhibits better mechanical properties than poly(lactic acid)s. However, the concentration and optical purity of L-PLA produced by native microbes was rather low. An NAD-dependent L-lactate dehydrogenase (L-nLDH) from Bacillus coagulans NL01 was confirmed to have a good ability to produce L-PLA from phenylpyruvic acid (PPA). In the present study, l nLDH gene and formate dehydrogenase gene were heterologously coexpressed in Escherichia coli. Through two coupled reactions, 79.6mM l-PLA was produced from 82.8mM PPA in 40min and the enantiomeric excess value of L-PLA was high (>99%). Therefore, this process suggested a promising alternative for the production of chiral l-PLA. PMID- 26008623 TI - Complete genome sequence of Spirosoma radiotolerans, a gamma-radiation-resistant bacterium isolated from rice field in South Korea. AB - Spirosoma radiotolerans is a Gram-negative, short rod-shaped and gamma-radiation resistant bacterium isolated from rice field in South Korea (GPS; 37 degrees 34'30"N, 127 degrees 00'30"E). The complete genome of S. radiotolerans consists of a chromosome (7,029,352bp). From the genome sequence database, we have identified the cluster of genes responsible for DNA recovery from ionizing radiation. The key enzymes for the nucleotide excision repair (NER) were investigated and were identified, suggesting that S. radiotolerans DG5A use (NER) pathways for efficient removal of pyrimidine dimers which are the most abundant type of UV-induced damage. Complete genome information enables further studies on the DNA repair mechanisms during the ionizing radiation. PMID- 26008624 TI - Job and life satisfaction and preference of future practice locations of physicians on remote islands in Japan. AB - BACKGROUND: The objective of this research is to investigate job and life satisfaction and preference of future practice locations of physicians in rural and remote islands in Japan. METHODS: A cross-sectional study was conducted for physicians who reside or resided on the Oki islands: isolated islands situated in the Sea of Japan between the Eurasian continent and the mainland of Japan. A questionnaire was sent to physicians on the Oki islands to evaluate physician satisfaction regarding job environment, career development, living conditions, salary, and support by local government. RESULTS: Data was analysed for 49 physicians; 47 were male and 2 were female, and the mean +/- SD age was 44.3 +/- 10.9 years. Among the variables related to physicians' satisfaction, most of the physicians (>90%) were satisfied with "team work" and "salary". On the other hand, the majority of physicians (approximately 70%) were not satisfied with the "opportunity to continue professional development". Age >= 50 years, graduates of medical schools other than Jichi Medical University (established in 1972 with the aim to produce rural physicians), self-selected the Oki islands as a practice location, and satisfaction in "work as a doctor", "opportunity to consult with peers about patients", "relationship with people in the community", and "acceptance by community" were found to be significant factors influencing the choice of the Oki islands as a future practice location. Factors influencing future practice locations on the remote islands were included in a self-reported questionnaire which illustrated the importance of factors that impact both the spouses and children of physicians. CONCLUSIONS: Improving work satisfaction, providing outreach support programmes for career development and professional support in rural practice, and building appropriate relationships between physicians and people in the community, which can in turn improve work satisfaction, may contribute to physicians' choices of practising medicine on rural and remote islands in Japan. Addressing family issues is also crucial in encouraging the choice of a rural medical practice location. PMID- 26008625 TI - Object processing in the infant: lessons from neuroscience. AB - Object identification is a fundamental cognitive capacity that forms the basis for complex thought and behavior. The adult cortex is organized into functionally distinct visual object-processing pathways that mediate this ability. Insights into the origin of these pathways have begun to emerge through the use of neuroimaging techniques with infant populations. The outcome of this work supports the view that, from the early days of life, object-processing pathways are organized in a way that resembles that of the adult. At the same time, theoretically important changes in patterns of cortical activation are observed during the first year. These findings lead to a new understanding of the cognitive and neural architecture in infants that supports their emerging object processing capacities. PMID- 26008627 TI - Confronting the complexity of CNT materials. AB - The morphology of commercially available carbon nanotube materials is often much more complex than the term "carbon nanotube" (CNT) would imply. Commercial CNT materials are typically composed of roughly spherical CNT domains having a highly ramified internal structure and a size on the order of microns. Clearly, such structures cannot reasonably be modeled as "rods". To address this problem, we first perform molecular dynamics simulations (MD) to generate structures similar to those measured experimentally, based on the presumptions that CNT domains are composed of worm-like cylinders having observed persistence lengths and that these CNTs are confined to spherical domains having the observed average domain size. This simple model generates structures remarkably similar to those observed experimentally. We then consider numerical path-integral computations to calculate the self-capacitance C and intrinsic conductivity [sigma]infinity of these CNT rich domains. This information is then incorporated in a generalized effective medium theory to estimate the conductivity of bulk composite materials composed of these complex-shaped "particles". We term these CNT structures "tumbleweeds", given their evident morphological similarity to this naturally occurring growth form. Based on this model, we find that the conductivity percolation threshold of the tumbleweeds can be quite low, despite their quasi spherical average shape. We also examine the structure factor S(q) of the CNT rich domains as function of the number N of CNTs within them, to aid in the structural characterization of CNT nanocomposites. The structure factor S(q) of our model tumbleweed is found to resemble that of hyperbranched, star and dendrimer polymers, and also domain structures observed in polyelectrolytes. Commercial CNT materials at high loading should then have physical features in common with suspension of "soft" colloidal particles by virtue of their deformability and roughly spherical shape. PMID- 26008628 TI - Blue-emitting pyrene-based aggregates. AB - The supramolecular polymerization of pyrene imidazoles 1 and 2, governed by H bonding and C-H...pi interactions, yields aggregates showing the characteristic bluish emission pattern of pyrene-based monomers. PMID- 26008626 TI - Current Protocols of Corneal Collagen Cross-Linking: Visual, Refractive, and Tomographic Outcomes. AB - PURPOSE: To study the effect of different protocols of collagen cross-linking on visual, refractive, and tomographic parameters in patients with progressive keratoconus. DESIGN: Prospective randomized interventional study. METHODS: In this study, 138 eyes of 138 patients with progressive keratoconus underwent corneal collagen cross-linking (CXL). Following detailed preoperative examination, Group I underwent conventional cross-linking (36 patients, 3 mW/cm(2) for 30 min); Group II (36 patients, 9 mW/cm(2) for 10 min), Group III (33 patients, 18 mW/cm(2) for 5 min), and Group IV (33 patients, 30 mW/cm(2) for 3 min) underwent accelerated cross-linking. Changes in corrected distance visual acuity (CDVA), spherical equivalent (SE), flat keratometry, steep keratometry, thinnest pachymetry, specular microscopy, and demarcation line were studied at 6 and 12 months. RESULTS: Improvement in the mean CDVA and SE were statistically significant in all groups except Group IV (P = .15 at 6 months, P = .17 at 12 months), with Group III (P = .01 at 6 and 12 months) showing the best results. Flattening of steep and flat keratometry was significant in Groups I (P = .01) and II (P = .01) as compared to the other groups. There was no significant difference in the pachymetry or specular microscopy in any of the groups. Groups I and II demonstrated a good demarcation line when compared to other groups. CONCLUSION: Conventional CXL (Group I) and accelerated CXL with irradiations of 9 mW/cm(2) (Group II) and 18 mW/cm(2) (Group III) showed better visual, refractive, and tomographic improvements at the end of 12 months. PMID- 26008629 TI - [The carcinogenic effects of low doses of ionizing radiation: Always questions]. PMID- 26008630 TI - [Nab-paclitaxel]. AB - Paclitaxel is conventionally used in a wide range of oncology indications. Nab paclitaxel is synthesized by a process of high pressure homogenization of paclitaxel in the presence of human albumin and it was originally developed to reduce the toxicity usually associated with cremophor in soluble paclitaxel and to increase its penetration in tumor tissues. After the trials that led to its approval in first-line treatment of metastatic pancreatic carcinomas and in second line therapy for metastatic breast cancer, nab-paclitaxel is being tested for many other situations in oncology due to its profile of security and its good tolerance. Different lines of research are being developed about the possible biomarkers that could predict the effect of nab-paclitaxel. This review summarizes the results of trials that led to the approval of the nab-paclitaxel in advanced breast cancer and pancreatic cancer, and also resumes the lines of research to the future development of the drug. PMID- 26008631 TI - Construction of a reusable multi-enzyme supramolecular device via disulfide bond locking. AB - A strategy for constructing a reusable multi-enzyme supramolecular device was developed by reprogramming protein-protein interactions and disulfide bond locking. The resultant multi-enzyme supramolecular device demonstrated good reusability, and approximately 80% of its initial catalytic activity was retained even after eight cycles of reuse. PMID- 26008632 TI - Retrospective study of cumulative diagnostic radiation exposure during childhood in patients with spina bifida. AB - BACKGROUND: The Biological Effects of Ionizing Radiation Committee of the National Academy of Sciences in 2005 and other expert panels have warned that risk of cancer increases with higher doses of radiation. Children with spina bifida and hydrocephalus have far greater exposure to radiation than the average person, starting almost directly after birth and continuing throughout their lifetimes. OBJECTIVE: The purpose of this study was to estimate the amount of ionizing radiation that patients with spina bifida and hydrocephalus are exposed to during childhood from diagnostic imaging. METHODS: Thirty patients, ages 18 years or older, with spina bifida and hydrocephalus were randomly selected from a spina bifida clinic and their radiology records were reviewed. Descriptive analyses were conducted. The total radiation exposure was then calculated for the study group, and the mean effective dose per patient was determined. RESULTS: In the study group, during their first 18 years, each patient had a mean of 55.1 studies and a median of 45 radiologic studies, a mean of 9.6 brain CT scans, and a mean cumulative effective dose of 81.9 mSv (2.6 mSv/patient/year over 18 years) and a median cumulative effective dose of 77.2 mSV of accumulated radiation exposure (4.5 mSv/patient/year over 18 years). CONCLUSIONS: Clinicians should recognize that increased radiation exposure puts patients with spina bifida and hydrocephalus at higher risk for cancer. The population of children and adults with spina bifida and hydrocephalus should be surveyed for incidence of cancer. PMID- 26008633 TI - What is the primary mover of water dynamics? AB - Even today, the H-bonded cluster structure of water still stands as a major point of debate in the science of liquids. Much of this discussion is devoted to understand its dynamic nature. This has a direct impact on deciphering the many anomalies of water such as its exceptional heat capacity. Of these properties, dielectric permittivity and relaxation are of particular interest. The argument rages over whether the almost Debye-like character of the dispersion is the result of the reorientation of an apparent dipole moment of the water cluster or simply the cumulative effect of single water molecule reorientation. Furthermore, like many glass formers, it has a high frequency excess wing that does not fit into the accepted models of a single relaxation time of the main peak. Herein, we present evidence that the microscopic origins of both the excess wing and the main relaxation process of pure water are the same. The origin of these two features is explored and we suggest a new paradigm for water relaxation based on the concept of a proton cascade leading to a cluster reorientation. PMID- 26008634 TI - beta-Alanine Supplementation Does Not Augment the Skeletal Muscle Adaptive Response to 6 Weeks of Sprint Interval Training. AB - Sprint interval training (SIT), repeated bouts of high-intensity exercise, improves skeletal muscle oxidative capacity and exercise performance. beta alanine (beta-ALA) supplementation has been shown to enhance exercise performance, which led us to hypothesize that chronic beta-ALA supplementation would augment work capacity during SIT and augment training-induced adaptations in skeletal muscle and performance. Twenty-four active but untrained men (23 +/- 2 yr; VO2peak = 50 +/- 6 mL . kg(-1) . min(-1)) ingested 3.2 g/day of beta-ALA or a placebo (PLA) for a total of 10 weeks (n = 12 per group). Following 4 weeks of baseline supplementation, participants completed a 6-week SIT intervention. Each of 3 weekly sessions consisted of 4-6 Wingate tests, i.e., 30-s bouts of maximal cycling, interspersed with 4 min of recovery. Before and after the 6-week SIT program, participants completed a 250-kJ time trial and a repeated sprint test. Biopsies (v. lateralis) revealed that skeletal muscle carnosine content increased by 33% and 52%, respectively, after 4 and 10 weeks of beta-ALA supplementation, but was unchanged in PLA. Total work performed during each training session was similar across treatments. SIT increased markers of mitochondrial content, including cytochome c oxidase (40%) and beta-hydroxyacyl-CoA dehydrogenase maximal activities (19%), as well as VO2peak (9%), repeated-sprint capacity (5%), and 250-kJ time trial performance (13%), but there were no differences between treatments for any measure (p < .01, main effects for time; p > .05, interaction effects). The training stimulus may have overwhelmed any potential influence of beta-ALA, or the supplementation protocol was insufficient to alter the variables to a detectable extent. PMID- 26008635 TI - In vitro hatching of Trichuris suis eggs. AB - Eggs of the pig whipworm, Trichuris suis ova (TSO), are currently tested in human clinical trials for their potential immunomodulatory capacity. The biological potency of TSO (egg viability and infectivity) is traditionally assessed in Gottingen minipigs as the establishment of intestinal larvae after inoculation with a known number of eggs. To minimize testing in animal models, development of an in vitro egg hatching assay is proposed as a reliable, cost-effective, and a faster alternative to test the egg viability. The present study aimed to investigate the influence of different chemical, physical, and biological factors on egg hatching. Thus, in a series of experiments and in different combinations, the eggs were stimulated with glass beads, artificial gastric juice, bile salt and trypsin solution, fermentation gut medium, or stimulated with mucosal scrapings from the ileum and the large intestine of the infected and uninfected Gottingen minipig. Mechanical stimulation with glass beads presented a simple and reproducible method for egg hatching. However, incubation of eggs with mucosal scrapings from the ileum, caecum, and colon for 24 h at 38 degrees C significantly increased hatching. PMID- 26008636 TI - Prognosis of patients with diabetic macular edema before Japanese approval of anti-vascular endothelial growth factor. AB - PURPOSE: To examine the prognosis of patients with diabetic macular edema (DME) before Japanese approval of antivascular endothelial growth factor (VEGF). METHODS: This retrospective study included 135 eyes of 115 patients who received treatments (photocoagulation, pharmacological treatments, vitrectomy) for DME between January 2003 and August 2012. The best-corrected visual acuity (BCVA) before and 1, 3, 6, 12, and 24 months after treatment was examined. BCVA was classified based on the decimal value of BCVA before treatment as good (BCVA > 0.7, BCVA = 0.7), moderate (BCVA > 0.7 but <0.2), or poor (BCVA < 0.2, BCVA = 0.2), and each prognosis of BCVA was investigated. RESULTS: Thirty-five (25.9%) patients were classified with good BCVA, while 69 (51.1%) had moderate and 31 (23.0%) poor BCVA. Following 24 months of treatment, the averaged good BCVA maintained its value (0.0513 +/- 0.0954 to 0.0773 +/- 0.258). Similarly, the averaged moderate BCVA maintained its value (0.449 +/- 0.169 to 0.441 +/- 0.431), whereas the averaged poor BCVA significantly improved (1.070 +/- 0.291 to 0.879 +/- 0.361: p < 0.001). Specifically, the averaged BCVA of patients who initially received vitrectomy increased 0.380 logMAR after 24 months (0.859 +/- 0.414 to 0.479 +/- 0.549). CONCLUSION: DME patients with good BCVA at the time of initial treatment generally maintained the averaged BCVA at 24 months, while patients with moderate BCVA did not significantly improve without a standard regimen of anti-VEGF therapy. However, the results indicate that early vitrectomy is a potential treatment option for DME patients with poor BCVA. PMID- 26008637 TI - Processing negative valence of word pairs that include a positive word. AB - Previous research has suggested that cognitive performance is interrupted by negative relative to neutral or positive stimuli. We examined whether negative valence affects performance at the word or phrase level. Participants performed a semantic decision task on word pairs that included either a negative or a positive target word. In Experiment 1, the valence of the target word was congruent with the overall valence conveyed by the word pair (e.g., fat kid). As expected, response times were slower in the negative condition relative to the positive condition. Experiment 2 included target words that were incongruent with the overall valence of the word pair (e.g., fat salary). Response times were longer for word pairs whose overall valence was negative relative to positive, even though these word pairs included a positive word. Our findings support the Cognitive Primacy Hypothesis, according to which emotional valence is extracted after conceptual processing is complete. PMID- 26008638 TI - Discovery and Biochemical Characterization of UDP-Glucose Dehydrogenase from Granulibacter bethesdensis. AB - UDP-glucose dehydrogenases (EC 1.1.1.22) are responsible for the conversion of UDP-glucose to UDP-glucuronic acid, a key precursor in the biosynthesis of glycoconjugates. Herein we report the discovery and characterization of a UDPglucose dehydrogenase (GbUGD) from Granulibacter bethesdensis, a bacterium originally isolated from the lymph nodes of patients with chronic granulomatous disease (CGD). The recombinant form of the protein was expressed in high yield and the purified enzyme showed highest activity at 37 degrees C/pH 9.0 and was strongly inhibited by Zn(2+) ions, sodium dodecyl sulfate (SDS) and urea. UDP xylose, an allosteric feedback inhibitor, reduced significantly the activity of the enzyme. High activities were observed using the co-substrates UDP-glucose and NAD+, whereas no activity could be detected using other nucleotide sugars or NADP(+) as potential alternative substrates. The high activity combined with the simple purification procedure used make GbUGD a valuable new alternative biocatalyst for the synthesis of UDP-glucuronic acid or the development of NAD+ regeneration systems. PMID- 26008639 TI - The Interactions Between Diabetes Mellitus and Myelodysplastic Syndromes: Current State of Evidence and Future Directions. AB - Diabetes mellitus (DM) and cancer are disorders of global importance. Multiple epidemiologic studies show that diabetic patients have an increased risk of developing cancer of different types. Myelodysplastic syndromes (MDS) are among the most common hematologic malignancies and include a heterogeneous group of hematopoietic neoplasms characterized by dysplastic changes, low blood counts, and an increased risk of progression to acute myeloid leukemia. Potential epigenetic and metabolic interferences between DM and MDS have been reported but are poorly understood. DM and MDS share some predisposing risk factors such as obesity. Patients with MDS and DM can experience worsening of diabetic control due to multiple factors that exacerbate hyperglycemia and insulin resistance such as stress, infections, adjunct drugs (e.g. steroids to control nausea), and others. In addition, accurate assessment of glucose control in diabetic patients who have MDS can be complicated. Alternatively, DM when associated with end-organ damage can complicate management of MDS, increase risks of complications, and limit the applicability of intensive therapeutic interventions. Here we review the current knowledge of the interactions between DM and MDS at the pathogenetic, clinical and epidemiologic levels, discuss how this knowledge could be used therapeutically to improve the outcome of patients affected by both conditions, and delineate important unmet needs that should be addressed in future research. PMID- 26008640 TI - Origin and function of myofibroblasts in the liver. PMID- 26008642 TI - Pesticide Residues in Bovine Milk in Punjab, India: Spatial Variation and Risk Assessment to Human Health. AB - In the present study, gas chromatographic analysis of pesticide residues in bovine milk (n = 312) from Punjab, India, showed chlorpyrifos, DDT, and gamma-HCH as the predominant contaminants. In addition, the presence of beta-endosulfan, endosulfan suphate, cypermethrin, cyhalothrin, fenvalerate, deltamethrin, malathion, profenofos, and ethion was reported in milk samples. In this study, it was observed that 12 milk samples exceeded the maximum residue limits (MRLs) for gamma-HCH (lindane), 18 for DDT and chlorpyrifos, and 1 sample each for endosulfan, cypermethrin, and profenophos. In India, DDT is still permitted for a malaria control program, which may be the plausible reason for its occurrence in milk samples. The spatial variation for presence of pesticide residues in milk indicated greater levels in cotton-growing areas of Punjab. At current levels of pesticide residues in bovine milk, the human health risk assessment in terms of noncancer and cancer hazard was calculated based on both lower-bound [LB (mean residue levels)] and upper-bound [UP (95th percentile level)] limits. It was noticed that cancer and noncancer risk were within United States Environmental Protection Agency prescribed limits for both adults and children at the LB, but children were being exposed to greater risk for DDT and HCH at the 95th percentile UB level. PMID- 26008641 TI - A gold nanohole array based surface-enhanced Raman scattering biosensor for detection of silver(I) and mercury(II) in human saliva. AB - A surface-enhanced Raman scattering (SERS) biosensor has been developed by incorporating a gold nanohole array with a SERS probe (a gold nanostar@Raman reporter@silica sandwich structure) into a single detection platform via DNA hybridization, which circumvents the nanoparticle aggregation and the inefficient Raman scattering issues. Strong plasmonic coupling between the Au nanostar and the Au nanohole array results in a large enhancement of the electromagnetic field, leading to amplification of the SERS signal. The SERS sensor has been used to detect Ag(I) and Hg(II) ions in human saliva because both the metal ions could be released from dental amalgam fillings. The developed SERS sensor can be adapted as a general detection platform for non-invasive measurements of a wide range of analytes such as metal ions, small molecules, DNA and proteins in body fluids. PMID- 26008643 TI - High-throughput, motility-based sorter for microswimmers such as C. elegans. AB - Animal motility varies with genotype, disease, aging, and environmental conditions. In many studies, it is desirable to carry out high throughput motility-based sorting to isolate rare animals for, among other things, forward genetic screens to identify genetic pathways that regulate phenotypes of interest. Many commonly used screening processes are labor-intensive, lack sensitivity, and require extensive investigator training. Here, we describe a sensitive, high throughput, automated, motility-based method for sorting nematodes. Our method is implemented in a simple microfluidic device capable of sorting thousands of animals per hour per module, and is amenable to parallelism. The device successfully enriches for known C. elegans motility mutants. Furthermore, using this device, we isolate low-abundance mutants capable of suppressing the somnogenic effects of the flp-13 gene, which regulates C. elegans sleep. By performing genetic complementation tests, we demonstrate that our motility-based sorting device efficiently isolates mutants for the same gene identified by tedious visual inspection of behavior on an agar surface. Therefore, our motility-based sorter is capable of performing high throughput gene discovery approaches to investigate fundamental biological processes. PMID- 26008644 TI - Supporting young people living with cancer to tell their stories in ways that make them stronger: The Beads of Life approach. AB - This article describes the 'Beads of Life' approach--a five-part methodology informed by narrative therapy to enable children and young people to make sense of their cancer journey in ways that make them stronger. Young people are invited to use beads as prompts to tell preferred stories of their identity to create a safe place to stand from which to story their cancer journey. The approach positions young people as experts in their lives. It aims to change their relationship with cancer to reduce its negative impact on life by lessening isolation. By enabling medical staff to get to know the young person apart from the cancer, this approach aims to create hope for the future and improve quality of care. PMID- 26008645 TI - Chronic adverse effects of long-term exposure of children to dichlorodiphenyltrichloroethane (DDT) through indoor residual spraying: A systematic review. AB - INTRODUCTION: Malaria remains a significant public health problem in endemic regions of the world, most especially in sub-Saharan Africa. As part of the global efforts to control malaria, dichlorodiphenyltrichloroethane (DDT), a cheap and effective chemical, was endorsed by the World Health Organization for use in indoor residual spraying (IRS). However, in the light of evidence on the acute toxicity of DDT, concerns have grown about the safety or the possible chronic health effects from the continued use of this persistent chemical, generating much debate and research efforts over the years. The purpose of this study was to identify, appraise and synthesise evidence about the chronic adverse effects of long-term exposure to DDT in children, 0-18 years, in zones where IRS is practised, in order to contribute to informing policy decisions. METHODS: Twenty seven electronic databases were systematically searched using pre-defined inclusion/exclusion criteria. Two were trial registers while 25 others indexed studies of various designs. Other complementary methods were also employed in searching for both published and grey literature. Eligible studies were critically appraised using amended versions of available validated guidelines (and in a case, an improvised guideline) and a narrative synthesis was undertaken. RESULTS: Only nine studies met the inclusion/exclusion criteria out of 3281 hits generated. Five of the studies are of high quality while four are of moderate quality. For the three studies on neurodevelopment, evidence suggestive of negative impact of DDT was found. For the three studies on endocrine/congenital disorders, ambivalent evidence existed. In the case of the immunity-related outcome, there was growing but insufficient evidence of negative effect. The only study on survival outcome was inconclusive. CONCLUSIONS: Empirically, insufficient evidence exists with regard to the chronic adverse effects of long-term exposure of children to DDT through IRS. Considering the dearth of studies and the fact that many adverse effects might take much longer time to manifest, inferences drawn are weak. It would therefore require a series of well-coordinated observational studies done in the context of IRS to adequately address this evidence gap in the future. PMID- 26008646 TI - Eating and rumination activity in 10 cows over 10 days. AB - Eating and rumination activities were evaluated in 10 Brown Swiss cows over 10 days, and the coefficients of variation (CV) were calculated for the investigated variables. A pressure sensor integrated into the noseband of a halter recorded jaw movements during chewing, which allowed the recording of eating and rumination times and the number of regurgitated boluses. The mean CVs ranged from 5.9 to 12.7% and were smaller for rumination (chewing cycles per bolus, 5.9%; daily number of cuds, 8.4%; rumination time, 9.1%) than for eating (eating time, 12.0%; chewing cycles related to eating, 12.7%). We concluded that of eating and rumination variables examined, the number of chewing cycles per regurgitated bolus is the most robust with little variation in individual cows. PMID- 26008648 TI - Glycosmisines A and B: isolation of two new carbazole-indole-type dimeric alkaloids from Glycosmis pentaphylla and an evaluation of their antiproliferative activities. AB - Two unique carbazole-indole-type dimeric alkaloids, glycosmisines A (1) and B (2), have been isolated from the stems of Glycosmis pentaphylla and their structures are elucidated by 1D and 2D NMR analyses, and their cytotoxicity against the growth of three cancer cell lines (A549, HepG-2 and Huh-7 cells) in culture was investigated using an MTT assay. Compounds 1 and 2 exhibited significant levels of cytotoxicity against three human cancer cell lines, and these two compounds also induced apoptosis in the same cell lines, as evidenced by changes in the morphological features of cells treated with these compounds and their dose-dependent accumulation of a sub-G1 population. PMID- 26008647 TI - Whole finger iontophoresis of sodium nitroprusside to increase blood flow in patients with systemic sclerosis: Influence of concentration. AB - Iontophoresis of sodium nitroprusside increases finger blood flow in patients with systemic sclerosis, a multisystem connective tissue disease. Our aim was to examine the influence of dose, as a first step in exploring a possible new therapeutic approach. Ten patients with SSc and nine healthy controls were recruited. Blood flow in a single finger was assessed using laser Doppler imaging following iontophoresis of sodium nitroprusside at 'doses' of 2, 1, 0.5 and 0%. Graphs of perfusion over time (30 min) were produced for each dose and from these curves, summary measures of response were calculated (area under curve/baseline and maximum perfusion/baseline. These measures were subject to regression analysis to investigate the effect of dose on response and to consider whether response differed between patients and healthy controls. Individual responses to altering the dose of iontophoresed sodium nitroprusside were highly variable but there was evidence to suggest increased response at doses of 0.5 and 1% (but not at 2%) compared to 0% for both area under curve/baseline (p=0.028 and p=0.011 respectively) and maximum perfusion/baseline (p=0.001 and p=0.002 respectively). There was no evidence that responses differed between patients and controls. Therefore the optimal dose for sodium nitroprusside iontophoresis is likely to be around 1%. PMID- 26008649 TI - Detection of Waterborne Viruses Using High Affinity Molecularly Imprinted Polymers. AB - Molecularly imprinted polymers (MIPs) are artificial receptor ligands which can recognize and specifically bind to a target molecule. They are more resistant to chemical and biological damage and inactivation than antibodies. Therefore, target specific-MIP nanoparticles are aimed to develop and implemented to biosensors for the detection of biological toxic agents such as viruses, bacteria, and fungi toxins that cause many diseases and death due to the environmental contamination. For the first time, a molecularly imprinted polymer (MIP) targeting the bacteriophage MS2 as the template was investigated using a novel solid-phase synthesis method to obtain the artificial affinity ligand for the detection and removal of waterborne viruses through optical-based sensors. A high affinity between the artificial ligand and the target was found, and a regenerative MIP-based virus detection assay was successfully developed using a new surface plasmon resonance (SPR)-biosensor which provides an alternative technology for the specific detection and removal of waterborne viruses that lead to high disease and death rates all over the world. PMID- 26008652 TI - Issue of open access and predatory journals. PMID- 26008650 TI - Fruit ripening mutants reveal cell metabolism and redox state during ripening. AB - Ripening which leads to fruit senescence is an inimitable process characterized by vivid changes in color, texture, flavor, and aroma of the fleshy fruits. Our understanding of the mechanisms underlying the regulation of fruit ripening and senescence is far from complete. Molecular and biochemical studies on tomato (Solanum lycopersicum) ripening mutants such as ripening inhibitor (rin), nonripening (nor), and never ripe (Nr) have been useful in our understanding of fruit development and ripening. The MADS-box transcription factor RIN, a global regulator of fruit ripening, is vital for the broad aspects of ripening, in both ethylene-dependent and independent manners. Here, we have carried out microarray analysis to study the expression profiles of tomato genes during ripening of wild type and rin mutant fruits. Analysis of the differentially expressed genes revealed the role of RIN in regulation of several molecular and biochemical events during fruit ripening including fruit specialized metabolism and cellular redox state. The role of reactive oxygen species (ROS) during fruit ripening and senescence was further examined by determining the changes in ROS level during ripening of wild type and mutant fruits and by analyzing expression profiles of the genes involved in maintaining cellular redox state. Taken together, our findings suggest an important role of ROS during fruit ripening and senescence, and therefore, modulation of ROS level during ripening could be useful in achieving desired fruit quality. PMID- 26008651 TI - Cellular and molecular changes associated with competence acquisition during passion fruit somatic embryogenesis: ultrastructural characterization and analysis of SERK gene expression. AB - The integration of cellular and molecular data is essential for understanding the mechanisms involved in the acquisition of competence by plant somatic cells and the cytological changes that underlie this process. In the present study, we investigated the dynamics and fate of Passiflora edulis Sims cotyledon explants that were committed to somatic embryogenesis by characterizing the associated ultrastructural events and analysing the expression of a putative P. edulis ortholog of the Somatic Embryogenesis Receptor-like Kinase (SERK) gene. Embryogenic calli were obtained from zygotic embryo explants cultured on Murashige and Skoog medium supplemented with 2,4-dichlorophenoxyacetic acid and 6 benzyladenine. Callus formation was initiated by the division of cells derived from the protodermal and subprotodermal cells on the abaxial side of the cotyledons. The isodiametric protodermal cells of the cotyledon explants adopted a columnar shape and became meristematic at the onset of PeSERK expression, which was not initially detected in explant cells. Therefore, we propose that these changes represent the first observable steps towards the acquisition of a competent state within this regeneration system. PeSERK expression was limited to the early stages of somatic embryogenesis; the expression of this gene was confined to proembryogenic zones and was absent in the embryos after the globular stage. Our data also demonstrated that the dynamics of the mobilization of reserve compounds correlated with the differentiation of the embryogenic callus. PMID- 26008653 TI - Ultrasound guided internal jugular venous cannulation: comparison with land-mark technique. AB - OBJECTIVE: To compare real-time ultrasonography-guided technique versus the traditional land-mark technique for internal Jugular venous cannulation. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Anaesthesia, Combined Military Hospital, Rawalpindi, from September 2013 to July 2014. METHODOLOGY: A total of 200 patients who required internal jugular vein cannulation were randomly assigned using either real-time ultrasound-guided technique or land-mark technique. Access time, number of attempts until successful cannulation, complications and the demographics of each patient were recorded. RESULTS: Access time was significantly less in real-time ultrasound group (34.95 +/- 11.47 vs. 146.59 +/- 40.20 seconds, p < 0.001). Cannulation was performed in first attempt in 99% of patients in ultrasound group as compared to 89% of landmark group. Complication rate was significantly higher in the land mark group than in the ultrasound-guided group. Carotid artery puncture rate (9% vs. 1%) and haematoma formation (7% vs. 0%) were more frequent in the land-mark group than in the ultrasound-guided group. Brachial plexus irritation was also more in land-mark group (6% vs. 0%). CONCLUSION: Access time, failure rate and procedure related complications are reduced when real-time ultrasonography is used to cannulate internal Jugular vein. PMID- 26008654 TI - Comparison of the Effect of Pre-operative Single Oral Dose of Tramadol and Famotidine on Gastric Secretions pH and Volume in Patients Scheduled for Laparoscopic Cholecystectomy. AB - OBJECTIVE: To evaluate and compare the effects of pre-operative single oral dose of tramadol and famotidine on gastric secretions pH and volume in patients electively scheduled for laparoscopic cholecystectomy. STUDY DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Department of Anaesthesia, King Saud University Riyadh, Saudi Arabia, from August 2011 to June 2013. METHODOLOGY: Ninety adult, ASA-I and II patients scheduled for laparoscopic cholecystectomy were included in the study. Patients were randomly assigned to receive pre operatively either placebo (Group-C, n=30), oral tramadol 100 mg (Group-T, n=30) or famotidine 40 mg (Group-F, n=30). After induction of general anaesthesia, gastric fluid was aspirated through orogastric tube. The gastric secretions volume and pH was measured using pH meter. RESULTS: There was no statistically difference between groups in age, weight and gender. The gastric secretions mean pH was 2.06 +/- 0.22,2.04 +/- 0.20, 5.79 +/- 0.77 and volume was 0.59 +/- 0.17, 0.59 +/- 0.14 and 0.28 +/- 0.16 ml/kg in Group-C, Group-T and Group-F respectively. There was a significant statistical difference in the mean pH values between Group-C vs. Group-F (p < 0.001) and Group-T vs. Group-F (p < 0.001). Statistically significant difference was also found in the mean gastric secretions volume between Group - C vs. Group-F (p < 0.001) and Group-T vs. Group F (p < 0.001). There was no significant difference in the mean gastric fluid pH values (p=0.99) and mean gastric secretions volume (p=0.99) between Group-T and Group-C. CONCLUSION: As compared to famotidine, pre-operative single oral dose of tramadol was unable to elevate the desired level of gastric fluid pH (> 2.5) and decrease in gastric secretions volume (< 0.4 ml/kg). PMID- 26008655 TI - Dyslipidemia and Psoriasis: A Case Control Study. AB - OBJECTIVE: To compare the mean values of lipid profile in psoriatic patients and healthy controls. STUDY DESIGN: Case control study. PLACE AND DURATION OF STUDY: Department of Dermatology, PNS Shifa, Karachi, from November 2012 to April 2013. METHODOLOGY: Patients with psoriasis fulfilling the inclusion and exclusion criteria were selected from Dermatology Outpatient Department (OPD) of PNS Shifa, Karachi. After fasting for 14 hours, 5 ml of venous blood was drawn in sterile syringe and submitted to the Hospital Laboratory for lipid profile, by enzymatic method on Hitachi (Roshe((r))) using reagents by the same firm. The mean values lipid profile in psoriatic patients versus healthy controls were recorded and compared. RESULTS: Atotal of 256 patients (128 in each group) were enrolled. Mean lipid profile in both groups revealed cholesterol (mg/dl) value of 203.43 +/-1 1.43 in cases and 173.64 +/- 13.65 in controls. Triglyceride (mg/dl) was 178.87 +/- 43.60 and in cases 144.23 +/- 34.01 in controls, HDL-C (mg/dl) was 37.81 +/- 10.78 in cases and 41.41 +/- 9.72 in controls while LDL-C (mg/dl) was 139.52 +/- 13.71 in cases and 109.44 +/- 13.80 in controls. Each parameters had p-value < 0.05 which was significant. CONCLUSION: Dyslipidemia was found in a high percentage of psoriatic patients than healthy controls. Psoriatic patients require thorough lipid and cardiovascular examinations as they should be considered as individuals with increased risk of cardiovascular diseases. PMID- 26008656 TI - Comparison of BISAP Score with Ranson's Score in Determining the Severity of Acute Pancreatitis. AB - OBJECTIVE: To determine the accuracy of BISAP score in finding out the frequency of severity and mortality in patients with acute pancreatitis by comparing it with Ranson's score. STUDY DESIGN: Crosse-sectional study. PLACE AND DURATION OF STUDY: Department of Surgery, Pakistan Institute of Medical Sciences, Islamabad, from April to December 2010. METHODOLOGY: Atotal of 80 patients who presented in emergency with acute pancreatitis were included by consecutive non probability sampling technique. Cases of acute pancreatitis were classified as mild or severe based on the organ failure criteria and/or local complications according to the Atlanta Symposium. All patients were scored according to both Ranson's score and BISAP score. RESULTS: Out of 80 patients, 35 (44%) were males and 45 (56%) were females. The mean age was 46.89 +/- 15.75 years. Twenty five patients (31.25%) were classified as severe acute pancreatitis and 3 patients (3.75%) had evidence of pancreatic necrosis on CT scan. The duration of hospital stay was 1 - 54 days with a mean of 13.12 +/- 12.83 days and mortality rate was 5%. The number of patients with a BISAP score of >= 3 was 15 and Ranson's score >= 3 was 25. The observed incidence of severe disease stratified by the BISAP score has (p < 0.001) and by Ranson's score has (p < 0.001). In regards to mortality, patients having BISAP score >= 3 has p=0.003, while patients having Ranson's score >= 3 has p=0.002, both are statistically significant. CONCLUSION: The newly proposed BISAP score is a simple and accurate tool for severity stratification and is equally effective in finding out frequency of severity and in turns mortality in patients with acute pancreatitis as Ranson's score. PMID- 26008657 TI - Histological features of antiphospholipid nephropathy in patients with Systemic Lupus Erythematosus. AB - OBJECTIVE: To determine the histological features of renal biopsies of Systemic Lupus Erythematosus (SLE) patients with and without antiphospholipid antibodies in Saudi population. STUDY DESIGN: Cross-sectional, comparative study. PLACE AND DURATION OF STUDY: King Khalid University Hospital, Riyadh, Saudi Arabia, from January to December 2013. METHODOLOGY: Consecutive SLE patients admitted to King Khalid University Hospital, Riyadh for renal biopsy for evaluation of proteinuria or deterioration of renal function were recruited. SLE patients with renal involvement were divided in two groups. Group one included patients with positive APS antibodies and group two included patients with negative APS antibodies. The histological features of renal biopsies of the two patients groups were compared. Data was analyzed using simple statistical analysis. RESULTS: The mean age of APS antibodies-positive patients was 30.37 +/- 10.714 years while mean age of APS negative patients was 33.62 +/- 11.717 years (p=0.224). Twenty five (83.33%) patients were females and 5 (16.67%) patients were males in APS positive patients while 42 (89.36%) were females and 5 (10.63%) were males in group two. Acute lesions like thrombotic microangiopathy were in 2 (6.7%) of APS positive patients while chronic lesions like focal cortical atrophy was found in 6 (20%) and fibrous intimal hyperplasia was found in 9 (30%). Other significant histological findings in APS antibodies positive group were glomerular basement membrane wrinkling in 12 (40%), glomerular double wall contour in 17 (56.7%), fibrous adhesions in 11 (36.7%) patients with APS antibodies. CONCLUSION: Systemic Lupus Erythematosus (SLE) patients with positive APS antibodies has specific histological findings suggesting an important role of APS antibodies in the pathogenesis of APS nephropathy. PMID- 26008658 TI - Extensively and pre-extensively drug resistant tuberculosis in clinical isolates of multi-drug resistant tuberculosis using classical second line drugs (levofloxacin and amikacin). AB - OBJECTIVE: To find out the frequency of Extensively Drug Resistant (XDR) and pre XDR tuberculosis in clinical isolates of Multi-Drug Resistant (MDR) Tuberculosis (TB) by determining the susceptibilities against Levofloxacin and Amikacin (classical second line antituberculosis drugs). STUDY DESIGN: Adescriptive cross sectional study. PLACE AND DURATION OF STUDY: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. METHODOLOGY: Amikacin (AK) and Levofloxacin (LEVO) were obtained in chemically pure form from Sigma (Taufkirchen, Germany). The breakpoint concentration used for AK was 1.0 ug/ml and for LEVO 2.0 ug/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. RESULTS: A total of 3 MDR-TB isolates (3%) turned out to be XDR-TB based upon simultaneous resistance to injectable second line antituberculosis drug AK and one of the fluoro-quinolones (LEVO). A total of 24 MDR-TB isolates (24%) were found to be pre-XDR based upon resistance to LEVO alone. Treatment status record of patients with XDR and pre-XDRTB isolates revealed that majority of patients had received fluoroquinolones (FQs) during the course of treatment. CONCLUSION: XDR-TB has started to emerge in MDR-TB isolates in our set up. The worrying sign is the high frequency of pre-XDR tuberculosis. Urgent steps need to be taken to stem the tide of pre-XDR-TB in our population. It is thus recommended to develop facilities to carry out drug susceptibility testing to monitor the status of pre-XDR and XDR-TB in our population. PMID- 26008659 TI - In vitro Efficacy of Meropenem, Colistin and Tigecycline Against the Extended Spectrum Beta-Lactamase Producing Gram Negative Bacilli. AB - OBJECTIVE: To compare the in vitro efficacy of meropenem, colistin and tigecycline against extended spectrum Betalactamase producing Gram negative bacilli by minimal inhibitory concentration. STUDY DESIGN: Cross-sectional descriptive study. PLACE AND DURATION OF STUDY: Department of Microbiology, Army Medical College, National University of Sciences and Technology, Rawalpindi, from June to December 2010. METHODOLOGY: Routine clinical specimens were subjected to standard microbiological procedures and the isolates were identified to species level. Extended spectrum beta-lactamase producing Gram negative bacilli were detected by Jarlier disc synergy method and confirmed by ceftazidime and ceftazidime-clavulanate Etest. Minimum Inhibitory Concentration (MIC(90)) of meropenem, colistin and tigecycline was determined by Etest (AB BIOMERIUX) and the results were interpreted according to the manufacturer's instructions and Clinical and Laboratory Standards Institute guidelines and Food and Drug Authority recommendations. Results were analyzed by using Statistical Package for the Social Sciences version 20. RESULTS: A total of 52 non-duplicate extended spectrum Beta-lactamase-producing Gram negative bacilli were included in the study. The MIC(90) of tigecycline (0.75 ug/ml) was lowest as compared to the meropenem (2 ug/ml) and colistin (3 ug/ml). CONCLUSION: Tigecycline is superior in efficacy against the extended spectrum Beta-lactamase producing Gram negative bacilli as compared to colistin and meropenem. PMID- 26008660 TI - Frequency and antimicrobial susceptibility pattern of acinetobacter species isolated from pus and pus swab specimens. AB - OBJECTIVE: To evaluate the frequency and antimicrobial susceptibility pattern of Acinetobacter species isolated from pus and pus swab specimens at a tertiary care setting. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from July 2008 to July 2012. METHODOLOGY: Data regarding positive culture and antimicrobial sensitivity pattern was retrieved from the pus and pus swab culture records of the Microbiology Department, AFIP, Rawalpindi. Only those pus and pus swab specimens which yielded the growth of Acinetobacterspecies were included in the study. RESULTS: Out of 2781, 1848 were of pure pus while 933 were pus swab specimens. Out of 2538 culture positive isolates, 276 (10.9%) were identified as Acinetobacterspecies. Among 276 Acinetobacterspp., 245 (88.8%) were Acinetobacter baumannii and 31 (11.2%) were Acinetobacterjohnsonii. Male/female ratio of the affected patients was 5.6:1. Doxycycline was the most sensitive antibiotic to which 45% of the tested isolates were sensitive. Sensitivity to all other antimicrobials was 15% or less. CONCLUSION: About 11% of soft tissue and wound infections are caused by Acinetobacterspecies in our set up particularly in male. Doxycycline was the most sensitive antibiotic. Sensitivity to all other antimicrobials was 15% or less. In vitro sensitivity to carbapenems is very low. PMID- 26008661 TI - Concurrent oxytocin in women needing second dinoprostone. AB - OBJECTIVE: To reduce average induction delivery internal in patients with poor Bishop score without compromising fetomaternal outcome (in terms of birth weight, NICU admission, maternal complications and mode of delivery). STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynaecology, Pakistan Atomic Energy Commission (PAEC) General Hospital, Islamabad, from February to December 2009. METHODOLOGY: All patients needing 2nd dinoprostone pessary for induction of labour were included in the study. Patients with gestation below 37 weeks, those with intra-uterine growth restriction, bad obstetric history, previous uterine scar and patients in whom Bishop score improved for amniotomy after 1st dinoprostone pessary, were excluded. Data was collected on a special proforma where all variables were defined. RESULTS: Out of 90 patients, 44 (48.8%) had spontaneous vertex deliveries and 12 (13.3%) had instrumental deliveries so a total vaginal deliveries occurred in 56 (62.2%) patients. Thirty four patients (37.8%) had emergency caesarean sections. Main indication for cesarean was failure to progress in 1st stage of labour followed by fetal distress. There were 3 failed inductions. Only 2 patients had hyperstimulation. NICU admission were 8 and all babies were discharged healthy from nursery with no case of early neonatal death. CONCLUSION: Concurrent oxytocin with 2nd dinoprostone in patients with poor Bishop scores (initial scores 2 and 3) resulted in more vaginal birth and comparatively shorter induction delivery time with almost negligible fetomaternal complications. PMID- 26008662 TI - Use of N-acetylcysteine in children with fulminant hepatic failure caused by acute viral hepatitis. AB - OBJECTIVE: To determine the efficacy of N-acetylcysteine (NAC) in children aged > 1 month to 16 years admitted with Fulminant Hepatic Failure (FHF) secondary to Acute Viral Hepatitis (AVH) in a tertiary care center of a developing country. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: Department of Paediatrics, The Aga Khan University Hospital, Karachi, Pakistan, from January 2007 to December 2011. METHODOLOGY: Medical records of children (> 1 month - 16 years) with FHF admitted with AVH of known etiology who received NAC were reviewed retrospectively. Liver function tests (mean +/- SD) at baseline, 24 hours after NAC and before or at the time of discharge/death were recorded and compared via using repeated measures ANOVA(r-ANOVA). Efficacy of NAC is defined in improvement in biochemical markers, liver function test and discharge disposition (survived or died). Mortality associated risk factors were identified by using logistic regression analysis. P-value and 95% confidence interval were recorded. RESULTS: Forty children (mean age was 80 +/- 40 months) with FHF secondary to AVH received NAC. Majority were males (n=25; 63%). Vomiting (75%) and jaundice (65%) were the main presenting symptoms, one-third had hypoglycemic, while 40% had altered sensorium at the time of admission. There was significant statistical difference in liver enzymes and prothrombin time on admission comparing at discharge in children received NAC (p < 0.001). Fifteen (38%) children died. Severe vomiting {Odds Ratio (OR) 0.22, 95% Confidence Interval (CI) 0.05 - 0.8}, jaundice (OR 9.3, CI 1.1 - 82.6), inotropic support (OR 20.6, CI 3.5 - 118.3) and mechanical ventilation (OR 4.3, CI 1.1 - 16.6) at the time of admission are associated with risk factors for mortality in children with FHF secondary to AVH. CONCLUSION: NAC used in children with FHF secondary to AVH is associated with markedly improved liver function tests and recovery. FHF with complications is high risk for mortality. PMID- 26008663 TI - Therapeutic bronchoalveolar lavage with conventional treatment in allergic bronchopulmonary aspergillosis. AB - OBJECTIVE: To establish the role of therapeutic bronchoalveolar lavage in addition to conventional treatment among two groups, with allergic bronchopulmonary aspergillosis, in terms of regression in serum IgE levels and clinical recurrence at 3 and 6 months of follow-up. STUDY DESIGN: Aquasi experimental study. PLACE AND DURATION OF STUDY: Department of Pulmonology, Fauji Foundation Hospital, Rawalpindi, from July 2010 to December 2013. METHODOLOGY: The study was carried out on 132 patients who fulfilled the Greenberger and Patterson criteria and underwent a chest X-ray, an HRCT chest and classified radiologically as with Central Bronchiectasis (CB), High Attenuation Mucus (HAM) or Other Radiological Features (ORF). Baseline serum IgE levels were noted. All patients were given treatment including prednisolone and antifungal agent itraconazole for 4 months. Patients with ORF on HRCTchest and just received the medical treatment were labeled as conventional group. Those patients who had CB or HAM radiological features also underwent bronchoscopy with therapeutic Bronchoalveolar Lavage (BAL), labeled as BALgroup. Clinical recurrence and serum IgE levels were noted at 3 and 6 months. Values were compared using chi-square and Mann-Whitney tests respectively. RESULTS: Around 78 (59.1%) of patients underwent bronchoscopy with therapeutic bronchoalveolar lavage to remove the mucus plugs. The mean serum IgE levels at baseline were 3312.04 +/- 2526.217 and 3486.15 +/- 2528.324 IU/ml in the BAL and conventional groups respectively. There was a statistically significant reduction in the mean serum IgE levels at 3 (p < 0.00) and 6 months (p < 0.001) of follow-up in BALas compared to conventional group. There was no significant difference in the clinical recurrence rate in both the groups (p=0.078 at 3 and 0.343 at 6 months respectively). CONCLUSION: Therapeutic bronchoalveolar lavage may be a useful adjunct to treatment in patients with allergic bronchopulmonary aspergillosis, serum in terms of IgE level reduction. PMID- 26008664 TI - The pattern of peripheral nerve injuries among Pakistani soldiers in the war against terror. AB - OBJECTIVE: To determine the pattern of peripheral nerve injuries in Pakistani soldiers in the War against terror. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Electrodiagnosis at Armed Forces Institute of Rehabilitation Medicine (AFIRM), Rawalpindi, Pakistan, from June 2008 to June 2011. METHODOLOGY: All new cases of war wounded soldiers with peripheral nerve injuries were consecutively enrolled. Physical examination and electrodiagnostic study was carried out by experienced physiatrists. Data was entered in pretested especially designed questionnaire which was analysed using SPSS version 17.0. Seddon's classification system was used to assess the severity of injury. RESULTS: There were 418 cases of peripheral nerve injuries with 504 different nerve segments. Mean age was 29.41 +/-8 years. Blast was the main cause of nerve injury in 244 (48.5%) cases followed by gunshot in 215 (42.7%) and 45 (8.9%) cases had nerve injuries secondary to fall, burial under debris and motor vehicle accidents. Eighty six (17%) cases had multiple nerve injuries. Most commonly injured nerve was ulnar (20.6%) followed by sciatic (16.7%), median (16.5%), radial (16.3%), peroneal (8.7%), brachial plexus (8.5%), axillary (4.8%), tibial (2%), femoral (1.8%), long thoracic (0.4%) and others (3.8%). Axonotmesis was seen in 459 (91.1%) cases, 44 (8.7%) cases revealed neurotmesis and 1 (0.2%) case had neuropraxia. CONCLUSION: Peripheral nerve injuries are a major component of war related injuries mainly involving the upper limbs. Electrodiagnostic studies help in assessing severity and determining prognosis. Precise documentation of severity of nerve injuries is important to estimate the burden on our resources and to extend rehabilitation services. PMID- 26008665 TI - Diagnosis and management of retained foreign objects. AB - Retained surgical foreign objects (RFO) include surgical sponges, instruments, tools or devices that are left behind following a surgical procedure unintentionally. It can cause serious morbidity as well as even mortality. It is frequently misdiagnosed. It should be considered in the differential diagnosis of any postoperative case with unresolved or unusual problems. Risk factors for RFOs include emergency procedures, unplanned change in operation, and body mass index and are clarified as being more frequent approximately 1 in 700 emergent cases. Although human errors cannot be completely prevented, medical training and consistency to rules seem to reduce the incidence to a minimum. It is a legal issue and potentially dangerous medical error. The definition, types, incidence, risk factors, complications and prevention strategies from RFOs are reviewed, from the comprehensive series until the year 2014. PMID- 26008666 TI - Primary amenorrhea with bilateral endometriotic cysts. AB - Primary amenorrhea is a common problem. Diagnosis is usually by going through systematic approach of history, examination and investigations. This case had bilateral large endometriotic cysts in the adnexal region. Uterus was normal sized with well-formed endometrium. She underwent laparotomy followed by drainage of endometriotic cysts, stripping and reconstruction of ovaries was performed. Patient was given a trial of combined oral contraceptive pills for two consecutive cycles to observe withdrawal bleeding, but it failed. Till now we are unable to find out such case in literature. Exact case of primary amenorrhea could not be found. PMID- 26008667 TI - Isolated cardiac hydatid cyst. AB - Hydatid cyst disease is common in our part of the world. Cardiac hydatid cyst is its rare manifestation. We report this case of 48-year male having isolated cardiac hydatid cyst, incidentally found on computed tomography. This patient presented in medical OPD of Combined Military Hospital, Lahore with one month history of mild retrosternal discomfort. His general physical and systemic examinations as well as ECG were unremarkable. Chest X-ray showed an enlarged cardiac shadow with mildly irregular left heart border. Contrast enhanced CT scan of the chest showed a large well defined multiloculated non-enhancing cystic lesion with multiple daughter cysts involving wall of left ventricle and overlying pericardium. Serology for echinococcus confirmed the diagnosis of hydatid cyst. Patient was offered the surgical treatment but he opted for medical treatment only. Albendezol was prescribed. His follow-up echocardiography after one month showed no significant decrease in size of the cyst. PMID- 26008668 TI - An unusual case of neonatal stridor. AB - A25-day baby neonate presented with fever and stridor. He had severe respiratory distress at admission. The systemic examination was unremarkable. The roentgenogram of soft tissues of neck revealed widening of superior mediastinum. Computed tomography of neck and upper chest revealed multiple abscesses in the retropharyngeal space, parapharyngeal space, and superior mediastinum. The child improved on aggressive antibiotic treatment protocol. It raises awareness among paediatricians to consider this diagnosis when confronting neonate with fever and stridor. An early diagnosis and aggressive appropriate management will reduce mortality and morbidity associated with this life-threatening condition. A thorough search for a primary source of infection should be done. Neonate should be screened for primary and secondary immunodeficiency disorders before discharge. PMID- 26008669 TI - Accidental phosphine gas poisoning with fatal myocardial dysfunction in two families. AB - Aluminum phosphide is commonly used as a rodenticide and insecticide and is one of the most fatal poisons. The active ingredient is Phosphine gas which inhibits cytochrome oxidase and cellular oxygen utilization. The clinical symptoms are due to multiorgan involvement including cardiac toxicity which is the most common cause of mortality. Severity of clinical manifestations depends upon the amount of the gas to which a person is exposed. There is no specific antidote available. High index of suspicion and early aggressive treatment is the key to success. We report 2 cases of aluminum phosphide toxicity in 2 families due to incidental exposure after fumigation. PMID- 26008670 TI - Effect of Clopidogrel on Platelet CD Markers in Normal Individuals and in Patients with Untreated Type 2 Diabetes Mellitus. AB - The objective of this study was to evaluate the effect of clopidogrel response in patients with untreated type 2 diabetes mellitus as compared with normal individuals. One hundred and seven subjects i.e. 32 normal and 75 patients with untreated type 2 diabetes mellitus were enrolled in this study. In the first step, normal subjects as well as diabetic patients were selected and tested for various laboratory parameters and platelets flow cytometry. In the second step, an antiplatelet drug (clopidogrel) was administered for 10 days to each individual enrolled in the study. After 10 days blood samples were collected for platelets flow cytometry. CD41 and CD61 did not show any change after the administration of clopidogrel in resting and activated platelets. CD63 and CD62p positivity was increased in normal and in diabetic patients' platelets after activation with ADP before clopidogrel. It was decreased in normal resting and ADP stimulated platelets after clopidogrel treatment. CD63 and CD62p positivity in resting and ADP stimulated patients' platelets was also decreased after clopidogrel treatment. The change was, however, not as marked as in normal subjects. PMID- 26008671 TI - Congenital constriction ring of limbs in subjects with history of maternal substance use. AB - Congenital Constriction Ring (CCR) is a rare malformation which manifests itself in the form of ring-like constrictive bands. Due to its heterogeneous nature, its etiology remains unclear. Here, we present a series of seven independent individuals afflicted with CCR, which primarily involved the digits. The phenotypic manifestations included terminal phalangeal reduction, anonychia, digit hypoplasia, and acrosyndactyly. Mesoaxial digits in hands and preaxial digits in feet were most frequently affected. Camptodactyly and clubfoot were witnessed in four and one subject, respectively. Curiously, mothers of six of these subjects revealed that they consumed copious amounts of Multani mitti(Fuller's clay) and/or Naswar(nonsmoke-tobacco), during their respective pregnancies. Maternal substance use during pregnancy is not an unusual practice, however, its relationship with CCR as pregnancy outcome remains unexplored. Case control studies are warranted to elucidate the relationship between the exposure to these substances and the etiology of CCR and/or other limb defects in the offspring. PMID- 26008673 TI - Quality of Life of ICU Survivors and their Loved Ones - A Pilot Asian Perspective. PMID- 26008672 TI - Profile of psychiatric patients presenting to a tertiary care emergency department of Karachi. AB - This study reviewed the presentations of psychiatric patients admitted through the Emergency Department (ED), The Aga Khan University Hospital, Karachi. Psychiatric patients admitted through the ED to the psychiatry ward were compared to those admitted through the same units other than the psychiatry ward, from 2006 to 2010 using medical records. Psychiatric patients were defined as those in whom psychiatry consult was generated and 1127 cases were included in study. There were 550 (48.8%) female patients. Most common presentations in the ED were sleep-related problems (n=205, 15.9%) followed by aggressive behavior (n=191, 14.8%). Depression was the most common diagnosis made in the ED (n=331, 29.3%) and at the time of discharge from the hospital (n=354, 29.5%). Psychiatric patients presenting to the ED had signs and symptoms which one generally disregards. However, these minor indicators can lead to major events in a patient's life. PMID- 26008674 TI - A Case of Bacteremia by Brevundimonas vesicularisin a Hospitalized Patient. PMID- 26008675 TI - Complications associated with End Stage Renal Disease. PMID- 26008676 TI - Effect of an acute bout of aerobic exercise on chemerin levels in obese adults. AB - AIMS: Serum chemerin concentrations are elevated in obese individuals and may play a role in type 2 diabetes. Exercise improves insulin sensitivity, which may be related to changes in chemerin. This study explored how an acute bout of aerobic exercise affected chemerin levels in non-diabetic obese adults. METHODS: Blood samples from 11 obese adults were obtained during two separate conditions: sedentary (SED) and exercise (EX; 60-65% VO2peak). Samples were drawn at baseline, immediately following exercise and hourly for an additional 2h. ANOVA was used to test for differences in chemerin between conditions. RESULTS: Unadjusted analysis showed no difference in overall change (baseline to 2h post) in chemerin between conditions. During the 2-h post-exercise period, chemerin decreased to 12% below baseline, compared to a 2.5% increase above baseline during that time period on the sedentary day (p=0.06, difference in post-to-2h change between conditions). Controlling for homeostatic model assessment of insulin resistance (HOMA-IR), a significant difference existed between EX and SED in the change in chemerin from baseline to 2-h post (p=0.02). Stratified analyses showed a consistent exercise-induced decrease in chemerin among non-insulin resistant subjects, while chemerin increased during exercise among insulin resistant subjects, and then decreased post-exercise. CONCLUSION: An acute bout of exercise in obese individuals may elicit a drop in chemerin levels during the post-exercise period, and this response may vary based on insulin resistance. PMID- 26008678 TI - Acute proximal junctional failure in patients with preoperative sagittal imbalance. AB - BACKGROUND CONTEXT: Proximal junctional failure (PJF) is a recognized complication of spinal deformity surgery. Acute PJF (APJF) has recently been demonstrated to be 5.6% in the adult spinal deformity (ASD) population. The incidence and rate of return to the operating room for APJF have not been specifically investigated in individuals with sagittal imbalance. PURPOSE: The purpose of this study was to report the incidence of APJF in patients with preoperative sagittal imbalance and the rate of return to the operating room for APJF. STUDY DESIGN/SETTING: This study is based on a retrospective review of prospectively collected database of ASD patients. PATIENT SAMPLE: One hundred seventy-three consecutive patients were included with preoperative sagittal imbalance according to one of the following common parameters: sagittal vertical axis (SVA) greater than 50 mm, global sagittal alignment greater than 45 degrees , or pelvic incidence minus lumbar lordosis greater than 10 degrees . OUTCOME MEASURES: Outcome measure was presence and/or absence of APJF defined as fracture at the upper instrumented vertebra (UIV) or UIV+1, failure of UIV fixation, 15 degrees or more proximal junctional kyphosis, or need for extension of instrumentation within 6 months of surgery. METHODS: We performed radiographic measurements on X-rays at preoperative, immediate postoperative, and 6-month follow-up visits. The APJF rate was reported for the entire patient population with preoperative sagittal imbalance. Acute PJF incidence was calculated postoperatively for each of the accepted sagittal balance parameters and/or formulas. Patients with persistent postoperative sagittal imbalance were compared with the sagittally balanced group. We also assessed for threshold values. RESULTS: Acute PJF was observed in 60 of 173 patients (35%) and was least common in fusions with the UIV in the upper thoracic (UT) spine (p=.035). Of those who developed APJF, 21.7% required surgery. Proximal junctional kyphosis 15 degrees or more was the most common form of APJF in fusions to the UT spine but least likely to need revision (p=.014). The most common mode of failure in lower thoracic (LT) or lumbar (L) fusions was UIV fracture. Postoperative SVA less than 50 mm was a significant risk factor for APJF (p=.009). CONCLUSIONS: Acute PJF is more common in patients with preoperative sagittal imbalance (35%) than the general adult deformity patient population, and 37% of those with APJF require revision. It is least common when the UIV is in the UT spine, compared with the LT or L spine. Sagittal balance correction to an SVA 50 mm or less was a significant risk factor in patients with preoperative sagittal imbalance. PMID- 26008677 TI - Overexpression of ZmMAPK1 enhances drought and heat stress in transgenic Arabidopsis thaliana. AB - Mitogen-activated protein kinase (MAPK) signal transduction cascades play a crucial role in the response to extracellular stimuli in eukaryotes. A number of MAPK family genes have been isolated in plants, but the maize MAPK genes have been little studied. Here, we studied the role of maize MAP kinase 1 (ZmMAPK1) using gene expression, protein subcellular localization, transformation in Arabidopsis, expression patterns of the stress-responsive genes and physiological parameter analysis. Our physiological parameter analysis suggested that over expression ZmMAPK1 can increase proline content and decrease malondialdehyde content under drought, and prevent chlorophyll loss and the production of scavenger reactive oxygen species under heat stress. The resistance characteristics of the over-expression of ZmMAPK1 were associated with a significant increase in survival rate. These results suggest that ZmMAPK1 plays a positive role in response to drought and heat stress in Arabidopsis, and provide new insights into the mechanisms of action of MAPK in response to abiotic stress in plants. PMID- 26008679 TI - Is lateral stabilization enough in thoracolumbar burst fracture reconstruction? A biomechanical investigation. AB - BACKGROUND CONTEXT: Traditional reconstruction for burst fractures involves columnar support with posterior fixation at one or two levels cephalad/caudad; however, some surgeons choose to only stabilize the vertebral column. PURPOSE: The aim was to distinguish biomechanical differences in stability between a burst fracture stabilized through a lateral approach using corpectomy spacers of different end plate sizes with and without integrated screws and with and without posterior fixation. STUDY DESIGN/SETTING: This was an in vitro biomechanical study assessing thoracolumbar burst fracture stabilization. METHODS: Six human spines (T11-L3) were tested on a six-degrees-of-freedom simulator enabling unconstrained range of motion (ROM) at +/-6 N.m in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) after a simulated burst fracture at L1. Expandable corpectomy spacers with/without integrated screws (Fi/F; FORTIFY Integrated/FORTIFY; Globus Medical, Inc., Audubon, PA, USA) were tested with different end plate sizes (21*23 mm, 22*40-50 mm). Posterior instrumentation (PI) via bilateral pedicle screws and rods was used one level above and one level below the burst fracture. Lateral plate (LP) fixation was tested. Devices were tested in the following order: intact; Fi21*23; Fi21*23+PI; F21*23+PI+LP; F21*23+LP; F22*40-50+LP; F22*40-50+PI+LP; Fi22*40-50+PI; Fi22*40-50. RESULTS: In FE and AR, constructs without PI showed no significant difference (p<.05) in stability compared with intact. In LB, F22*40-50+LP showed a significant increase in stability relative to intact, but no other construct without PI reached significance. In FE and LB, circumferential constructs were significantly more stable than intact. In AR, no construct showed significant differences in motion when compared with the intact condition. CONCLUSIONS: Constructs without posterior fixation were the least stable of all tested constructs. Circumferential fixation provided greater stability in FE and LB than lateral fixation and intact. Axial rotation showed no significant differences in any construct compared with the intact state. PMID- 26008680 TI - Redundant nerve root syndrome of the cauda equina: the benefits of 3D CISS MRI sequence. PMID- 26008681 TI - Tuberculosis of lower cervical spine (C4-C5) with severe angulation. PMID- 26008682 TI - Diastematomyelia with the owl sign (Type I split cord malformation). PMID- 26008683 TI - Costotransverse screw fixation in a severe cervicothoracic deformity because of a type 1 neurofibromatosis: case report. AB - BACKGROUND CONTEXT: Spinal implant placement may be challenging in cases of severe cervicothoracic spinal deformities and anatomical anomalies as in Type 1 neurofibromatosis. Intralaminar screwing of the thoracic spine has been described in few cases in which pedicles were hypoplasic. The costovertebral joints have never been used before as an anchorage point for screws. PURPOSE: The purpose of the study was to describe a new thoracic fixation technique to be used in severe deformities whenever the posterior arch (laminae and pedicles) is not available because of anatomic abnormalities. STUDY DESIGN: This is a case report. METHODS: An 18-year-old woman with progressive tetraparesis caused by increasing deformity of cervicothoracic spine underwent evaluation and surgical treatment: procedure and techniques were described. The clinical features, the radiological findings, and the outcomes were assessed. Complications and local recurrences were also recorded. RESULTS: Costotransverse joint screwing was successfully used in one case of severe cervicothoracic spine deformity with major hypoplasia of the pedicles. The posterior arch of one thoracic vertebra became mobile soon after periosteal stripping probably because of iatrogenic fracture of the only existent pedicle. The four-cortical trajectory of the screws resulted in a good bone purchase allowing the surgeon to complete the procedure. No local or general complications were recorded during 2 years of follow-up. CONCLUSIONS: The procedure was used as a salvage technique during a difficult surgery where a local complication forced a change of strategy. Although the implant remained stable long enough to achieve fusion, it still consists of placing a screw through a joint that remains slightly mobile. This could possibly result in a screw loosening in the long period if fusion is not achieved. We suggest the use of this technique when all the other options have been explored and excluded for anatomical reasons. PMID- 26008684 TI - Radiologic and clinical characteristics of vertebral fractures in multiple myeloma. AB - BACKGROUND CONTEXT: Nearly 80% of patients with newly diagnosed multiple myeloma (MM) have bony lesions on magnetic resonance imaging (MRI). These lesions may progress to debilitating vertebral fractures. No studies have quantitatively characterized these fractures or identified predictors of fracture burden and severity. PURPOSE: The purpose of this study was to characterize the clinical and radiologic features of these fractures and to identify independent predictors of fracture burden and severity. STUDY DESIGN/SETTING: A consecutive retrospective chart review was conducted from January 2007 to December 2013 at a single tertiary-care institution. PATIENT SAMPLE: Patients with diagnoses of both MM and vertebral fracture were included in this study. Those with a history of non-MM vertebral fracture were excluded. OUTCOME MEASURES: The primary outcome measure was height loss of the fractured vertebral body, whereas secondary outcome measures included number of fractures and morphology. METHODS: Data were collected at fracture presentation. Radiologic data were obtained from T1 weighted MRI. Anterior, middle, and posterior vertebral body height losses were recorded, and a Genant grading was made. Multivariable Poisson and logistic regression were performed to identify predictors of fracture burden and severity. RESULTS: Among 50 patients presenting with vertebral fracture, 124 fractures were observed. The majority (76%) of these patients did not have a previous MM diagnosis. The most common presenting symptom was back pain (84%), followed by neurologic (54%) and constitutional (50%) symptoms. The mean anterior, middle, and posterior height losses of the fractured vertebral body were 30%, 37%, and 16%, respectively. Twenty percent of fractures were Genant Grade 1 (mild), whereas 32% and 48% were grades 2 (moderate) and 3 (severe). Fifty-five percent of fractures were biconcave, whereas 32% and 13% were wedge and crush fractures. Lower body mass index and albumin and increased myeloma protein, light chains, and creatinine predicted an increased number of fractures at presentation. Increased beta2-microglobulin and creatinine predicted more severe vertebral fractures. CONCLUSIONS: In the present study, 124 fractures were observed among 50 patients. These fractures were generally severe, biconcave, and in the thoracic spine. Laboratory signs of advanced MM predict greater fracture burden and severity. In the future, monitoring of these predictors may raise suspicion for an MM-associated vertebral fracture. PMID- 26008685 TI - The management of severe rigid tuberculous kyphosis of the lumbar spine with multilevel vertebral column resection. PMID- 26008686 TI - The early and late stages of crowned dens syndrome: two case reports. AB - BACKGROUND CONTEXT: Crowned dens syndrome (CDS) is a rare form of calcium phosphate crystal depositions and often presents with recurrent neck pain, stiffness of neck, increased erythrocyte sedimentation rate, and episodes of fever. PURPOSE: The goal of this report is to identify the early and late stages of CDS and its consequences as the result of repeated attacks of CDS at cervical spine in its late stage. STUDY DESIGN: This is a case report. METHODS: We reported one case of early-stage CDS and one late-stage CDS. RESULTS: The two patients shared some common clinical features of acute attack of CDS, such as increased erythrocyte sedimentation rate, C-reactive protein, episode of fever, and increased white blood cells along with high blood glucose levels. The first case showed early phase of CDS with computed tomography (CT) scan that only showed mild calcification around the dens. The second case had appearance of late stage of CDS with more severe chronic degenerative changes of cervical spine. CONCLUSIONS: Early stage of CDS can be difficult to identify because of mild clinical symptoms, but CT scan is a preferable method to demonstrate densities surrounding the top and sides of the odontoid process. In the late stage of CDS, radiolographic features often include diffuse periodontoid calcifications, diffuse destructive discopathies, and apophyseal joint destruction, and patient might have severe neurological symptoms. PMID- 26008687 TI - Research teaching in learning disability nursing: Exploring the views of student and registered learning disability nurses. AB - BACKGROUND: Whilst there is a need to develop the research base within learning disability nursing it is also significant that currently there is little published data as to how research is taught to this group of nurses. OBJECTIVES: To increase understanding of how research is currently taught to learning disability nurses within the UK. DESIGN: A survey design was used. SETTING: The research was undertaken at a conference held in the UK in March 2014. PARTICIPANTS: 310 learning disability nurses attending the conference of which 212 completed the free text question. This comprised student nurses (n=158), registered nurses working in practice settings (n=25) and registered nurses working in educational institutions (n=24). Five participants did not specify their background. METHODS: Participants were invited to complete a questionnaire that included a free text question regarding the teaching of research to learning disability nurses: it is the responses to this question that are reported in this paper. Responses were transcribed and thematically analysed. FINDINGS: Eight themes emerged: Teaching approach--the good and the bad; finding the right level; right from the start; we need more time; generic versus specialist; there's not enough; getting research into practice; and what should we focus on? CONCLUSIONS: Variations exist in terms of the timing of research education, the teaching approaches used, and hence the quality of student experience. Of particular concern is the apparent gap between research teaching and the use of research in practice, and the reported lack of support for research within practice settings. However, enthusiasm for research is evident and hence recommendations are made both to enhance teaching and to strengthen links with practice. PMID- 26008689 TI - Ebola vaccine trial in Guinea. PMID- 26008688 TI - Development of an assessment instrument to evaluate performance of the skill of decontamination. AB - BACKGROUND AND PURPOSE: Nurses must competently demonstrate psychomotor skills. Few reliable and valid instruments are available for psychomotor evaluation for disaster skills, including the skill of decontamination. OBJECTIVES: The purpose of this study was to develop and refine an instrument to measure the skill of decontamination. DESIGN: A seven step instrument development design was implemented that included content validity and reliability as well as inter-rater reliability analysis. SETTING AND PARTICIPANTS: A convenience sample of approximately 140 participants was drawn from two colleges of nursing at two large academic universities. The sample included senior nursing students in either their community or final practicum nursing course. METHODS: Based on a sample of 140 students who participated in a decontamination training experience using virtual reality simulation, a seven step established process for assessment of reliability and validity was implemented to develop a checklist for the skill of decontamination. RESULTS: The final instrument statistics: Content Validity Index for the overall instrument score was 0.94, Internal consistency coefficient=0.607(KR-20) and Inter-rater reliability=0.9114. CONCLUSIONS: This instrument provides a reliable and valid assessment of nurses' competency in performing the skill of decontamination offering a template for educators to develop similar tools. PMID- 26008690 TI - DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy. AB - BACKGROUND: Acute myeloid leukemia (AML) is predominantly a disease of older patients with a poor long-term survival. Approval of decitabine (DAC) in the European Union (EU) in 2012 for the treatment of patients with AML >=65 years marks the potential for hypomethylating agents in elderly AML. Nevertheless the situation is dissatisfactory and the quest for novel treatment approaches, including combination epigenetic therapy is actively ongoing. The given randomized trial should be helpful in investigating the question whether combinations of DAC with the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and/or all-trans retinoic acid (ATRA), which in vitro show a very promising synergism, are superior to the DAC monotherapy. The accompanying translational research project will contribute to find surrogate molecular end points for drug efficacy and better tailor epigenetic therapy. An additional aim of the study is to investigate the prognostic value of geriatric assessments for elderly AML patients treated non-intensively. METHODS/DESIGN: DECIDER is a prospective, randomized, observer blind, parallel group, multicenter, Phase II study with a 2x2 factorial design. The primary endpoint is objective best overall response (complete remission (CR) and partial remission (PR)). The target population is AML patients aged 60 years or older and unfit for standard induction chemotherapy. Patients are randomized to one of the four treatment groups: DAC alone or in combination with VPA or ATRA or with both add-on drugs. One interim safety analysis was planned and carried out with the objective to stop early one or more of the treatment arms in case of an unacceptable death rate. This analysis showed that in all treatment arms the critical stopping rule was not reached. No important safety issues were observed. The Data Monitoring Committee (DMC) recommended continuing the study as planned. The first patient was included in December 2011. A total of 189 out of 200 planned patients were randomized since then (status 31.12.2014). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00867672 (registration date 23.03.2009); German clinical trials registry number: DRKS00000733 (registration date 19.04.2011). PMID- 26008694 TI - Genomic Analysis of 15 Human Coronaviruses OC43 (HCoV-OC43s) Circulating in France from 2001 to 2013 Reveals a High Intra-Specific Diversity with New Recombinant Genotypes. AB - Human coronavirus OC43 (HCoV-OC43) is one of five currently circulating human coronaviruses responsible for respiratory infections. Like all coronaviruses, it is characterized by its genome's high plasticity. The objectives of the current study were to detect genetically distinct genotypes and eventually recombinant genotypes in samples collected in Lower Normandy between 2001 and 2013. To this end, we sequenced complete nsp12, S, and N genes of 15 molecular isolates of HCoV OC43 from clinical samples and compared them to available data from the USA, Belgium, and Hong-Kong. A new cluster E was invariably detected from nsp12, S, and N data while the analysis of nsp12 and N genes revealed the existence of new F and G clusters respectively. The association of these different clusters of genes in our specimens led to the description of thirteen genetically distinct genotypes, among which eight recombinant viruses were discovered. Identification of these recombinant viruses, together with temporal analysis and tMRCA estimation, provides important information for understanding the dynamics of the evolution of these epidemic coronaviruses. PMID- 26008695 TI - The Role of the DNA Damage Response throughout the Papillomavirus Life Cycle. AB - The DNA damage response (DDR) maintains genomic integrity through an elaborate network of signaling pathways that sense DNA damage and recruit effector factors to repair damaged DNA. DDR signaling pathways are usurped and manipulated by the replication programs of many viruses. Here, we review the papillomavirus (PV) life cycle, highlighting current knowledge of how PVs recruit and engage the DDR to facilitate productive infection. PMID- 26008696 TI - Molecular Characterization of a Novel Positive-Sense, Single-Stranded RNA Mycovirus Infecting the Plant Pathogenic Fungus Sclerotinia sclerotiorum. AB - Recent studies have demonstrated that a diverse array of mycoviruses infect the plant pathogenic fungus Sclerotinia sclerotiorum. Here, we report the molecular characterization of a newly identified mycovirus, Sclerotinia sclerotiorum fusarivirus 1 (SsFV1), which was isolated from a sclerotia-defective strain JMTJ14 of S. sclerotiorum. Excluding a poly (A) tail, the genome of SsFV1 comprises 7754 nucleotides (nts) in length with 83 and 418 nts for 5'- and 3' untranslated regions, respectively. SsFV1 has four non-overlapping open reading frames (ORFs): ORF1 encodes a 191 kDa polyprotein (1664 amino acid residues in length) containing conserved RNA-dependent RNA polymerase (RdRp) and helicase domains; the other three ORFs encode three putative hypothetical proteins of unknown function. Phylogenetic analysis, based on RdRp and Helicase domains, indicated that SsFV1 is phylogenetically related to Rosellinia necatrix fusarivirus 1 (RnFV1), Fusarium graminearum virus-DK21 (FgV1), and Penicillium roqueforti RNA mycovirus 1 (PrRV1), a cluster of an independent group belonging to a newly proposed family Fusarividae. However, SsFV1 is markedly different from FgV1 and RnFV1 in genome organization and nucleotide sequence. SsFV1 was transmitted successfully to two vegetatively incompatible virus-free strains. SsFV1 is not responsible for the abnormal phenotype of strain JMTJ14. PMID- 26008698 TI - IPNV Antigen Uptake and Distribution in Atlantic Salmon Following Oral Administration. AB - One impediment to the successful oral vaccination in fish is the hostile stomach environment that antigens must cross. Furthermore, uptake of antigens from the gut to systemic distribution is required for induction of systemic immunity, the dynamics of which are poorly understood. In the present study, groups of Atlantic salmon parr were intubated with live or inactivated infectious pancreatic necrosis virus (IPNV), either orally or anally. At 1, 24 and 72 h post infection (p.i.), the fish were sacrificed. Serum was used for assessing IPNV by ELISA, while formalin-fixed head-kidney, spleen, liver and intestine tissues were used for the demonstration of antigens by immunohistochemistry. Both live and inactivated IPNV antigens were observed in enterocytes of the intestines and in immune cells of the head-kidneys and spleens of all groups. In the liver, no antigens were observed in any of the groups. Significantly higher serum antigen OD values (p < 0.04) were observed in orally- compared to anally-intubated fish. By contrast, no difference (p = 0.05) was observed in tissue antigens between these groups by immunohistochemistry. No significant difference (p = 0.05) in serum antigens was observed between groups intubated with live and inactivated IPNV, while in tissues, significantly more antigens (p < 0.03) were observe in the latter compared to the former. These findings demonstrate that both live and inactivated IPNV are taken up by enterocytes in the intestines of Atlantic salmon, likely by receptor-mediated mechanisms. Higher IPNV uptake by the oral compared to anal route suggests that both the anterior and posterior intestines are important for the uptake of the virus and that IPNV is resistant to gastric degradation of the Atlantic salmon stomach. PMID- 26008697 TI - High-risk human papillomavirus targets crossroads in immune signaling. AB - Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review. PMID- 26008699 TI - Recessive Resistance Derived from Tomato cv. Tyking-Limits Drastically the Spread of Tomato Yellow Leaf Curl Virus. AB - The tomato yellow leaf curl disease (TYLCD) causes severe damage to tomato (Solanum lycopersicum L.) crops throughout tropical and subtropical regions of the world. TYLCD is associated with a complex of single-stranded circular DNA plant viruses of the genus Begomovirus (family Geminiviridae) transmitted by the whitefy Bemisia tabaci Gennadius (Hemiptera: Aleyrodidae). The tomato inbred line TX 468-RG is a source of monogenic recessive resistance to begomoviruses derived from the hybrid cv. Tyking F1. A detailed analysis of this germplasm source against tomato yellow leaf curl virus-Israel (TYLCV-IL), a widespread TYLCD associated virus, showed a significant restriction to systemic virus accumulation even under continuous virus supply. The resistance was effective in limiting the onset of TYLCV-IL in tomato, as significantly lower primary spread of the virus occurred in resistant plants. Also, even if a limited number of resistant plants could result infected, they were less efficient virus sources for secondary spread owing to the impaired TYLCV-IL accumulation. Therefore, the incorporation of this resistance into breeding programs might help TYLCD management by drastically limiting TYLCV-IL spread. PMID- 26008700 TI - A Taxonomic Review of Clostridium difficile Phages and Proposal of a Novel Genus, "Phimmp04likevirus". AB - Currently, only three phages that infect the medically important bacterium Clostridium difficile have been discussed by the International Committee of Viral Taxonomy (ICTV). They are all myoviruses, and have been assigned to the genus "phicd119likevirus". An additional nine phages have since been described in the literature with their genome data available. The Phicd119likevirus is named after the type species: the myovirus PhiCD119 which was the first C. difficile phage to be sequenced. The two additional myoviruses, phiCD27 and phiC2, also fall into this genus based on the similarity of their genome and morphological characteristics. The other nine phages have not been assigned to this genus, and four of them do not fit the criteria for the current taxonomic grouping. We have applied protein clustering analysis to determine their phylogenetic relationships. From these results we propose an additional myoviridae genus, that we term "phiMMP04likevirus". PMID- 26008703 TI - Insights into Human Astrocyte Response to H5N1 Infection by Microarray Analysis. AB - Influenza virus infects not only the respiratory system but also the central nervous system (CNS), leading to influenza-associated encephalopathy and encephalitis. Astrocytes are essential for brain homeostasis and neuronal function. These cells can also be infected by influenza virus. However, genome wide changes in response to influenza viral infection in astrocytes have not been defined. In this study, we performed gene profiling of human astrocytes in response to H5N1. Innate immune and pro-inflammatory responses were strongly activated at 24 h post-infection (hpi). Antiviral genes, as well as several cytokines and chemokines, including CXCL9, CXCL10, and CXCL11, were robustly induced. Phosphorylation of p65 and p38 can be activated by viral infection, suggesting their potential critical roles in H5N1-induced pro-inflammatory response. Moreover, H5N1 infection significantly upregulated the gene expressions related to the neuroactive ligand-receptor interaction pathway at 24 hpi, such as MC2R, CHRNG, P2RY13, GABRA1, and HRH2, which participant in synaptic transmission and may take part in CNS disorders induced by H5N1 infection. Targeting key components of innate immune response and the neuroactive ligand-receptor interaction pathway may provide a strategy to control H5N1-induced encephalopathy and encephalitis. This research can contribute to the understanding of H5N1 pathogenesis in astrocytes. PMID- 26008704 TI - The Agrobacterium tumefaciens Ti Plasmid Virulence Gene virE2 Reduces Sri Lankan Cassava Mosaic Virus Infection in Transgenic Nicotiana benthamiana Plants. AB - Cassava mosaic disease is a major constraint to cassava cultivation worldwide. In India, the disease is caused by Indian cassava mosaic virus (ICMV) and Sri Lankan cassava mosaic virus (SLCMV). The Agrobacterium Ti plasmid virulence gene virE2, encoding a nuclear-localized, single-stranded DNA binding protein, was introduced into Nicotiana benthamiana to develop tolerance against SLCMV. Leaf discs of transgenic N. benthamiana plants, harboring the virE2 gene, complemented a virE2 mutation in A. tumefaciens and produced tumours. Three tested virE2 transgenic plants displayed reduction in disease symptoms upon agroinoculation with SLCMV DNA A and DNA B partial dimers. A pronounced reduction in viral DNA accumulation was observed in all three virE2 transgenic plants. Thus, virE2 is an effective candidate gene to develop tolerance against the cassava mosaic disease and possibly other DNA virus diseases. PMID- 26008701 TI - Modulation of DNA damage and repair pathways by human tumour viruses. AB - With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved in the development of specific malignancies. It has long been known that the introduction of chromosomal aberrations is a common feature of viral infections. Intensive research over the past two decades has subsequently revealed that viruses specifically interact with cellular mechanisms responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). These interactions can involve activation and deactivation of individual DDR pathways as well as the recruitment of specific proteins to sites of viral replication. Since the DDR has evolved to protect the genome from the accumulation of deleterious mutations, deregulation is inevitably associated with an increased risk of tumour formation. This review summarises the current literature regarding the complex relationship between known human tumour viruses and the DDR and aims to shed light on how these interactions can contribute to genomic instability and ultimately the development of human cancers. PMID- 26008702 TI - Interaction of human tumor viruses with host cell surface receptors and cell entry. AB - Currently, seven viruses, namely Epstein-Barr virus (EBV), Kaposi's sarcoma associated herpes virus (KSHV), high-risk human papillomaviruses (HPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T cell lymphotropic virus type 1 (HTLV-1), have been described to be consistently associated with different types of human cancer. These oncogenic viruses belong to distinct viral families, display diverse cell tropism and cause different malignancies. A key to their pathogenicity is attachment to the host cell and entry in order to replicate and complete their life cycle. Interaction with the host cell during viral entry is characterized by a sequence of events, involving viral envelope and/or capsid molecules as well as cellular entry factors that are critical in target cell recognition, thereby determining cell tropism. Most oncogenic viruses initially attach to cell surface heparan sulfate proteoglycans, followed by conformational change and transfer of the viral particle to secondary high-affinity cell- and virus-specific receptors. This review summarizes the current knowledge of the host cell surface factors and molecular mechanisms underlying oncogenic virus binding and uptake by their cognate host cell(s) with the aim to provide a concise overview of potential target molecules for prevention and/or treatment of oncogenic virus infection. PMID- 26008705 TI - Dynamics of Apis mellifera Filamentous Virus (AmFV) Infections in Honey Bees and Relationships with Other Parasites. AB - Apis mellifera filamentous virus (AmFV) is a large double stranded DNA virus of honey bees, but its relationship with other parasites and prevalence are poorly known. We analyzed individual honey bees from three colonies at different times post emergence in order to monitor the dynamics of the AmFV gut colonization under natural conditions. Prevalence and loads of microsporidia and trypanosomes were also recorded, as well as five common honey bee RNA viruses. The results show that a high proportion of bees get infected with AmFV during the first week post-emergence (75%) and that AmFV DNA levels remained constant. A similar pattern was observed for microsporidia while trypanosomes seem to require more time to colonize the gut. No significant associations between these three infections were found, but significant positive correlations were observed between AmFV and RNA viruses. In parallel, the prevalence of AmFV in France and Sweden was assessed from pooled honey bee workers. The data indicate that AmFV is almost ubiquitous, and does not seem to follow seasonal patterns, although higher viral loads were significantly detected in spring. A high prevalence of AmFV was also found in winter bees, without obvious impact on overwintering of the colonies. PMID- 26008707 TI - The use of convalescent sera in immune-electron microscopy to detect non suspected/new viral agents. AB - Negative staining electron microscopy methods can be employed for the diagnosis of viral particles in animal samples. In fact, negative staining electron microscopy methods are used to identify viruses, especially in minor species and wild animals, when no other methods are available and in cases of rare, emerging or re-emerging infections. In particular, immune-electron-microscopy with convalescent sera is employed to detect etiological agents when there are undiagnosed clinical outbreaks, when alternative diagnostic methods fail due to the lack of immunological reagents and primers, and when there is no indicative clinical suspect. An overview of immune-electron-microscopy with convalescent sera's use in the diagnosis of new and unsuspected viruses in animals of domestic and wild species is provided through the descriptions of the following four diagnostic veterinary cases: (I) enteric viruses of pigs: Porcine Rotavirus, Porcine Epidemic Diarrhea Virus, Porcine Circovirus and Porcine Torovirus; (II) Rotavirus and astrovirus in young turkeys with enteritis; (III) Parvovirus-like particles in pheasants; and (IV) Lagoviruses: Rabbit Hemorrhagic Disease Virus and European Brown Hare Syndrome Virus. PMID- 26008706 TI - Nucleocytoplasmic shuttling of influenza A virus proteins. AB - Influenza viruses transcribe and replicate their genomes in the nuclei of infected host cells. The viral ribonucleoprotein (vRNP) complex of influenza virus is the essential genetic unit of the virus. The viral proteins play important roles in multiple processes, including virus structural maintenance, mediating nucleocytoplasmic shuttling of the vRNP complex, virus particle assembly, and budding. Nucleocytoplasmic shuttling of viral proteins occurs throughout the entire virus life cycle. This review mainly focuses on matrix protein (M1), nucleoprotein (NP), nonstructural protein (NS1), and nuclear export protein (NEP), summarizing the mechanisms of their nucleocytoplasmic shuttling and the regulation of virus replication through their phosphorylation to further understand the regulation of nucleocytoplasmic shuttling in host adaptation of the viruses. PMID- 26008708 TI - Hepatitis E virus genotype 3 diversity: phylogenetic analysis and presence of subtype 3b in wild boar in Europe. AB - An increasing number of indigenous cases of hepatitis E caused by genotype 3 viruses (HEV-3) have been diagnosed all around the word, particularly in industrialized countries. Hepatitis E is a zoonotic disease and accumulating evidence indicates that domestic pigs and wild boars are the main reservoirs of HEV-3. A detailed analysis of HEV-3 subtypes could help to determine the interplay of human activity, the role of animals as reservoirs and cross species transmission. Although complete genome sequences are most appropriate for HEV subtype determination, in most cases only partial genomic sequences are available. We therefore carried out a subtype classification analysis, which uses regions from all three open reading frames of the genome. Using this approach, more than 1000 published HEV-3 isolates were subtyped. Newly recovered HEV partial sequences from hunted German wild boars were also included in this study. These sequences were assigned to genotype 3 and clustered within subtype 3a, 3i and, unexpectedly, one of them within the subtype 3b, a first non-human report of this subtype in Europe. PMID- 26008709 TI - Characterization of novel transcripts in pseudorabies virus. AB - In this study we identified two 3'-coterminal RNA molecules in the pseudorabies virus. The highly abundant short transcript (CTO-S) proved to be encoded between the ul21 and ul22 genes in close vicinity of the replication origin (OriL) of the virus. The less abundant long RNA molecule (CTO-L) is a transcriptional readthrough product of the ul21 gene and overlaps OriL. These polyadenylated RNAs were characterized by ascertaining their nucleotide sequences with the Illumina HiScanSQ and Pacific Biosciences Real-Time (PacBio RSII) sequencing platforms and by analyzing their transcription kinetics through use of multi-time-point Real Time RT-PCR and the PacBio RSII system. It emerged that transcription of the CTOs is fully dependent on the viral transactivator protein IE180 and CTO-S is not a microRNA precursor. We propose an interaction between the transcription and replication machineries at this genomic location, which might play an important role in the regulation of DNA synthesis. PMID- 26008710 TI - Membrane tension controls the assembly of curvature-generating proteins. AB - Proteins containing a Bin/Amphiphysin/Rvs (BAR) domain regulate membrane curvature in the cell. Recent simulations have revealed that BAR proteins assemble into linear aggregates, strongly affecting membrane curvature and its in plane stress profile. Here, we explore the opposite question: do mechanical properties of the membrane impact protein association? By using coarse-grained molecular dynamics simulations, we show that increased surface tension significantly impacts the dynamics of protein assembly. While tensionless membranes promote a rapid formation of long-living linear aggregates of N-BAR proteins, increase in tension alters the geometry of protein association. At high tension, protein interactions are strongly inhibited. Increasing surface density of proteins leads to a wider range of protein association geometries, promoting the formation of meshes, which can be broken apart with membrane tension. Our work indicates that surface tension may play a key role in recruiting proteins to membrane-remodelling sites in the cell. PMID- 26008711 TI - Role of interfacial protein membrane in oxidative stability of vegetable oil substitution emulsions applicable to nutritionally modified sausage. AB - The potential health risk associated with excessive dietary intake of fat and cholesterol has led to a renewed interest in replacing animal fat with nutritionally-balanced unsaturated oil in processed meats. However, as oils are more fluid and unsaturated than fats, one must overcome the challenge of maintaining both physical and chemical (oxidative) stabilities of prepared emulsions. Apart from physical entrapments, an emulsion droplet to be incorporated into a meat protein gel matrix (batter) should be equipped with an interactive protein membrane rather than a small surfactant, and the classical DLVO stabilization theory becomes less applicable. This review paper describes the steric effects along with chemical roles (radical scavenging and metal ion chelation) of proteins and their structurally modified derivatives as potential interface-building materials for oxidatively stable meat emulsions. PMID- 26008712 TI - Winter Polycyclic Aromatic Hydrocarbon-Bound Particulate Matter from Peri-urban North China Promotes Lung Cancer Cell Metastasis. AB - On the basis of the close relationship between human exposure to high concentrations of small particulate matter (PM) and increased lung cancer mortality, PM was recently designated as a Group I carcinogen. Considering that PM is highly heterogeneous, the potential health risks of PM promoting tumor metastasis in lung cancer, as well as its chemical characteristics, remain elusive. In the present study, we collected PM2.5 and PM10 in a peri-urban residential site of Taiyuan and determined the concentration and source of polycyclic aromatic hydrocarbons (PAHs). The results indicated that 18 PAHs, ranging from 38.21 to 269.69 ng/m(3) (for PM2.5) and from 44.34 to 340.78 ng/m(3) (for PM10), exhibited seasonal variations, and the PAHs in winter PM mainly originated from coal combustion. We calculated the benzo(a)pyrene-equivalent (BaPeq) and found that the PAH-bound PM in winter exhibited higher carcinogenic risks for humans. Following this result, in vitro bioassays demonstrated that PM2.5 and PM10 induced A549 cell migration and invasion, and the mechanism involved reactive oxygen species (ROS)-mediated epithelial-to-mesenchymal transition (EMT) activation and extracellular matrix (ECM) degradation. Our data indicate the potential risk for winter PAH-bound PM from peri-urban North China promoting lung cancer cell metastasis and reveal a mechanistic basis for treating, ameliorating, or preventing outcomes in polluted environments. PMID- 26008714 TI - Polycystic kidney disease: Macrophage migration inhibitory factor regulates cyst growth in ADPKD. PMID- 26008715 TI - Nephrotic syndrome: The KANK family in podocyte function. PMID- 26008713 TI - The affective dimension of pain as a risk factor for drug and alcohol addiction. AB - Addiction, or substance use disorder (SUD), is a devastating psychiatric disease composed of multiple elemental features. As a biobehavioral disorder, escalation of drug and/or alcohol intake is both a cause and consequence of molecular neuroadaptations in central brain reinforcement circuitry. Multiple mesolimbic areas mediate a host of negative affective and motivational symptoms that appear to be central to the addiction process. Brain stress- and reinforcement-related regions such as the central amygdala (CeA), prefrontal cortex (PFC), and nucleus accumbens (NAc) also serve as central processors of ascending nociceptive input. We hypothesize that a sensitization of brain mechanisms underlying the processing of persistent and maladaptive pain contributes to a composite negative affective state to drive the enduring, relapsing nature of addiction, particularly in the case of alcohol and opioid use disorder. At the neurochemical level, pain activates central stress-related neuropeptide signaling, including the dynorphin and corticotropin-releasing factor (CRF) systems, and by this process may facilitate negative affect and escalated drug and alcohol use over time. Importantly, the widespread prevalence of unresolved pain and associated affective dysregulation in clinical populations highlights the need for more effective analgesic medications with reduced potential for tolerance and dependence. The burgeoning epidemic of prescription opioid abuse also demands a closer investigation into the neurobiological mechanisms of how pain treatment could potentially represent a significant risk factor for addiction in vulnerable populations. Finally, the continuing convergence of sensory and affective neuroscience fields is expected to generate insight into the critical balance between pain relief and addiction liability, as well as provide more effective therapeutic strategies for chronic pain and addiction. PMID- 26008716 TI - Metallacrowns as products of the aqueous medium self-assembly of histidinehydroxamic acid-containing polypeptides. AB - Self-assembly is a widely studied, spontaneous, and reversible phenomenon leading to the formation of the ordered structures by non-covalent specific interactions among starting molecules. In this work, a new template for the self-assembly of polypeptides based on peptides containing the C-terminal histidinehydroxamic acid moiety and Cu(2+) ions is characterized. Two peptide (tripeptide and pentadecapeptide) hydroxamic acid systems were synthesized and their interactions with Cu(2+) ions were investigated, revealing a high stability of the supramolecular assemblies formed. The supramolecular metallacrown-based L4Cu5 complexes exist at physiological pH in the presence of Cu(2+) ions as is evidenced from the spectroscopic methods, ESI mass spectrometry, and physicochemical techniques. PMID- 26008717 TI - Influence of polyphenols from lingonberry, cranberry, and red grape on in vitro digestibility of rice. AB - Dietary polyphenols are abundant antioxidants in the human diet and are associated with lower rates of diabetes and cardiovascular disease. This study aims to determine the effects of cooking white rice (WR) added with lingonberry (WRLB), cranberry (WRCB), and red grape (WRRG) on in vitro digestibility. There was significantly lower level of glucose release for WRRG compared with WR (p < 0.05). WRLB and WRCB showed no effect on glucose release compared with WR (p > 0.05). Increasing concentrations of red grape polyphenol decreased digestibility of white rice (p < 0.05). A positive correlation between the red grape phenolic content and the resistant starch was observed (R = 0.9854). Red grape polyphenol had the greatest impact on reducing in vitro digestibility of white rice. The addition of polyphenols in carbohydrate-rich foods may be a practical means to reduce the high glycemic response of rice eaten around the world. PMID- 26008718 TI - Study of Stevia rebaudiana Bertoni antioxidant activities and cellular properties. AB - The aim of our study was to determine the antioxidant activities, cytotoxicity and proliferative properties in Stevia rebaudiana leaves and stems. Leaves extracts exhibited a higher antioxidant activity than stems extract, through oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays. Stevioside and rebaudioside A, the main sweetening metabolites in stevia leaves, exhibited a low ORAC value in comparison with plant extracts, while did not elicit any CAA. Stevia rebaudiana did not exhibit toxicity against HepG2 (hepatocellular carcinoma) human cells. No proliferative nor catalase modulations were observed in cells treated with such extracts. Our findings support the promising role of stevia that, apart from its sweetness, can act as a source of antioxidants, even at the intracellular level. This activity makes S. rebaudiana crude extract an interesting resource of natural sweetness with antioxidant properties which may find numerous applications in foods and nutritional supplements industries. PMID- 26008719 TI - Differences in chewing behaviors between healthy fully dentate young and older adults assessed by electromyographic recordings. AB - To characterize changes in chewing behaviors associated with healthy aging, 10 young and 10 older fully dentate healthy participants were enrolled in this study. They chewed carrot samples that differed in hardness until their normal swallowing threshold. Their chewing behaviors were assessed using an electromyographic recording device. Adjusting for gender and body mass index, older adults had a higher number of chewing cycles (p = 0.020), a longer chewing duration (p < 0.001), a slower chewing rate (p = 0.002), a greater maximal electromyographic voltage (p = 0.003) and a greater muscle activity (p = 0.002) before they could comfortably swallow the food bolus. A statistically significant main effect of food hardness on the number of chewing cycles, chewing duration, chewing rate and muscle activity was also observed (p < 0.001 for all). These results suggest that reduced mastication efficiency is associated with healthy aging in fully dentate adults. This ingestive behavior may contribute to aging related reduction in appetite in older adults. PMID- 26008720 TI - Super-paramagnetic nano-Fe3O4/graphene for visible-light-driven hydrogen evolution. AB - A super-paramagnetic nano-architecture, which could be separated and re-dispersed easily for reuse, was designed for effective dye-sensitized H2 evolution. By the enhancement of electron-transfer and surface-repair ability of graphene, the visible-light-driven hydrogen evolution rate over the exposed Pt(111) facet loaded Fe3O4/GO catalyst was remarkably enhanced. PMID- 26008721 TI - Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: A review of the literature. AB - AIMS: Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus. A systematic literature review was conducted to provide an overview of published literature in the last 10-years on the epidemiology, humanistic burden and economic burden of PDPN in Europe. METHODS: A search was performed according to pre-defined strategy and review criteria in Embase, Pubmed, and conference proceedings databases from 2003 till December 2012. In total, 30 publications written in English covering the relevant patient population and topics of interest. RESULTS: European prevalence ranges from 6% to 34% in diabetes mellitus patients. PDPN has a significant humanistic and economic impact. Patients are limited in their general functioning and their ability to sleep and often experience anxiety and depression. Not surprisingly, PDPN is associated with reduced Health-Related-Quality-of-Life (HRQoL). PDPN patients incur high health care costs due to hospitalizations and outpatient visits. In addition, the painful symptoms cause impaired work productivity. Studies suggest both humanistic and economic burden increase with higher pain severity. CONCLUSIONS: The burden from PDPN appears to be higher with increasing pain severity. More severe pain leads to a higher impairment in daily functioning, sleep and HRQoL. Higher pain intensity also leads to increasing healthcare costs and work productivity losses. PMID- 26008722 TI - Insulin sensitivity and secretion in youth onset type 2 diabetes with and without visceral adiposity. AB - AIM: To investigate insulin sensitivity and insulin secretion patterns among Asian Indian youth without and with type 2 diabetes (T2DM-y defined as onset of diabetes at or below 25 years) with normal and high visceral fat (VF) levels. METHODS: We recruited 74 T2DM-y individuals, within 18 months of diagnosis and compared them to 77 age-matched controls with normal glucose tolerance (NGT). Using L4/L5 abdominal CT images, VF levels were categorized as normal or high according to their median values. Oral glucose tolerance tests (glucose and insulin measures) were used to derive Matsuda index, insulin resistance (HOMA-IR) and oral disposition index (DIo). Relationships between measures of insulin sensitivity and secretion and T2DM-y by VF level were assessed using standardized multinomial regression models. RESULTS: Participants were categorized into four groups: NGT-normal VF; NGT-high VF; T2DM-normal VF, and T2DM-high VF. Among NGTs, those with high VF had significantly lower insulin sensitivity (0.013 vs.0.019 pM(-1)) and Matsuda index (10.2 vs.13.8), than normal VF. When compared, T2DM high VF had lowest insulin sensitivity (0.009 vs.0.019, 0.013, 0.012 pM-1; p<0.001), Matsuda index (6.4 vs. 13.8, 10.2, 8.6; p<0.001), OGIS120 (305 vs. 396, 382, 316; p<0.001) and DIo (0.48 vs. 3.75, 3.20, 0.55 mmol/L; p<0.001). At every category of 2 h PG values, NGT-high VF had lower DIo than NGT-normal VF participants. In standardized multinomial models, that included DIo and Matsuda index adjusted for age, gender, BMI, and leptin, DIo (Odds ratio: 0.001; 95%Confidence interval: 0.000-0.020), matsuda index (0.26; 0.07-0.93), age (2.92; 1.18-7.19) and leptin (3.17; 1.12-8.99) were associated with high VF among T2DM. CONCLUSION: Lower DIo and Matsuda index, younger age and higher leptin were independently associated with high visceral fat among T2DM participants. Also, lower DIo was seen with increasing 2 h PG values even among normal glucose tolerant individuals. PMID- 26008723 TI - Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. AB - AIMS: Although sulfonylureas increase the risk of hypoglycemia which may lead to fall-associated fractures, studies quantifying the association between sulfonylureas and falls and/or fractures are sparse and existing studies have yielded inconsistent results. Our objective is to evaluate the extent to which sulfonylurea use was associated with fractures and falls among nursing home residents with type 2 diabetes mellitus. METHODS: We performed a propensity matched retrospective new user cohort study of 12,327 Medicare Parts A/B/D eligible long-stay NH residents. Medicare Part D data provided information on sulfonylurea and biguanide use initiated as monotherapy (nsulfonylurea=5807 and nbiguanide=6151) after NH entry. Medicare hospitalizations were used to identify hypoglycemic events (ICD-9-CM codes 250.8, 251.1, 251.2) and fall-associated fractures (ICD-9-CM codes 800, 804, 812-817, 820, 823, 824). Minimum Data Set 2.0 (2008-2010) provided information on falls and potential confounders. Cox models conducted on propensity-matched samples provided adjusted hazard ratio (aHR) estimates and 95% confidence intervals (CI). RESULTS: Falls were common (37.4 per 100 person-years). Fractures were not associated with initiation of sulfonylureas. Sulfonylurea initiation was associated with an excess risk of falls among residents with moderate activities of daily living limitations (aHR: 1.13; 95% CI: 1.00-1.26), but not among those with minimal limitations or dependence in activities of daily living. CONCLUSIONS: Nursing home residents with moderate limitations in activities of daily living are at increased risk of falls upon initiation of sulfonylureas. Initiating sulfonylurea use in NH residents must be done with caution. PMID- 26008725 TI - Compression of the medulla oblongata due to an elongated vertebral artery is a common incidental finding on MRI of the brain. PMID- 26008724 TI - Diabetes retinopathy is a poor predictor for renal and cardiovascular outcomes in comparison with hypertensive retinopathy in patients with chronic kidney disease. AB - AIMS: Chronic kidney disease (CKD) and retinopathy share the common pathophysiology of microvascular dysfunction. It is unclear whether the clinical significance of diabetic retinopathy (DMR) and hypertensive retinopathy (HTNR) differs in CKD patients. METHODS: We included 684 nondialysis-dependent CKD stage 3-5 patients with diabetes or hypertension: 501 patients with diabetes and 183 with hypertension. The clinical significance of DMR and HTNR was evaluated in terms of the rate of renal function decline and composite of any cardiovascular event or death. RESULTS: DMR was observed in 261 (52.1%) CKD patients with diabetes, and HTNR in 44 (24.0%) CKD patients with hypertension. In the diabetes group, the renal function decline rate was significantly steeper in patients with than in those without DMR (-7.4 +/- 9.8mL/min/1.73m(2)/yr vs. -2.4 +/- 7.6mL/min/1.73m(2)/yr; P<0.001). In multivariate analysis, DMR were independently associated with a rapid decline in renal function (beta=-2.44; P=0.20). However, HTNR did not affect the renal function decline in CKD patients. The composite event-free survival rate was lower in patients with diabetes and DMR than in those without DMR (P=0.043). Patients with diabetes and DMR were independently associated with a 2.13-fold increased risk for composite events (P=0.010). HTNR was not associated with higher risk for composite events in CKD patients. CONCLUSION: Coexistence of diabetes and DMR were independently associated with CKD progression and composite cardiovascular event/death, but the clinical significance of HTNR is less clear in CKD patients. PMID- 26008726 TI - Increased serum level of IL-37 in patients with multiple sclerosis and neuromyelitis optica. AB - Multiple sclerosis (MS) is a common autoimmune disease of central nervous system in which neurodegenerative and inflammatory mechanisms cause alternate neurological impairments. Many inflammatory and anti-inflammatory cytokines were suggested as contributor in MS pathogenesis, and the balance between these opposing cytokines can regulate MS severity. IL-37, an anti-inflammatory cytokine, is the most recently identified member of IL-1 family, which acts as a natural inhibitor of innate immunity. However, the role of IL-37 in MS has not investigated so far. Therefore, in this study, we aimed to measure serum level of IL-37 in patients with relapsing remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO). In a case-control study, plasma was collected from healthy controls (n = 49) and also patients with RRMS (n = 122) and NMO (n = 31). Serum level measurement of IL-37 was performed using enzyme-linked immunoassay (ELISA) method. The serum levels of IL-37 were 247.46 +/- 74.02 and 312.00 +/- 86.72 and 114.63 +/- 20.58 in RRMS and NMO patients and healthy controls, respectively, showing statistically significant difference between them (P = 0.00). Furthermore, we found a positive correlation between the serum levels of IL-37 and EDSS of patients (r = +0.31 and P = 0.00). In summary, the serum level of IL-37 was found to be significantly increased in MS patients compared to healthy controls. Furthermore, the mean serum level of IL-37 was correlated with disease severity. This suggests that IL-37 may be part of a feed-back loop to control underlying inflammation in MS pathogenesis. However, further studies will be required to indicate exact role of IL-37 in the MS pathomechanisms. PMID- 26008727 TI - Transmission of Methicillin-Resistant Staphylococcus aureus (MRSA) to Healthcare Worker Gowns and Gloves During Care of Nursing Home Residents. AB - OBJECTIVE: To estimate the frequency of methicillin-resistant Staphylococcus aureus (MRSA) transmission to gowns and gloves worn by healthcare workers (HCWs) interacting with nursing home residents to better inform infection prevention policies in this setting DESIGN: Observational study SETTING: Participants were recruited from 13 community-based nursing homes in Maryland and Michigan PARTICIPANTS: Residents and HCWs from these nursing homes METHODS: Residents were cultured for MRSA at the anterior nares and perianal or perineal skin. HCWs wore gowns and gloves during usual care activities. At the end of each activity, a research coordinator swabbed the HCW's gown and gloves. RESULTS: A total of 403 residents were enrolled; 113 were MRSA colonized. Glove contamination was higher than gown contamination (24% vs 14% of 954 interactions; P1.0; P<.05). We also identified low-risk care activities: giving medications and performing glucose monitoring (OR<1.0; P<.05). Residents with chronic skin breakdown had significantly higher rates of gown and glove contamination. CONCLUSIONS: MRSA transmission from MRSA-positive residents to HCW gown and gloves is substantial; high-contact activities of daily living confer the highest risk. These activities do not involve overt contact with body fluids, skin breakdown, or mucous membranes, which suggests the need to modify current standards of care involving the use of gowns and gloves in the nursing home setting. PMID- 26008728 TI - A systematic review and meta-analysis to reappraise the role of adjuvant hepatic arterial infusion for colorectal cancer liver metastases. AB - OBJECTIVE: The potential benefit of adjuvant hepatic arterial infusion remains unknown for patients with colorectal liver metastases after radical hepatic resection. The principle aim of this study was to investigate the long-term outcome of adjuvant hepatic arterial infusion. METHODS: Eligible trials were identified from Embase, PubMed, the Web of Science, and the Cochrane library since their inception to June 1, 2014. Patients with colorectal liver metastases, who underwent radical hepatic resection and received adjuvant hepatic arterial infusion, were enrolled. The study outcomes included 5-year disease-free and overall survival rate, respectively. Hazard ratio with a 95 % confidence interval was used to measure the pooled effect according to a random effects model or fixed effects model, depending on the heterogeneity between the included studies. The statistical heterogeneity between trials was detected by I (2) test. Sensitivity analyses were also carried out. RESULTS: A total of nine studies containing 1057 patients were included. The comparison indicated that the overall pooled hazard ratio for 5-year overall survival was 0.75 (95 % CI: 0.56-0.99, p = 0.048). The hazard ratio for 5-year disease-free survival rate was 0.61 (95 % CI: 0.48-0.79, p = 0.001). When compared with systemic chemotherapy alone, adjuvant hepatic arterial infusion plus systemic chemotherapy also improved the long-term survival. CONCLUSIONS: Adjuvant hepatic arterial infusion improved the 5-year disease-free and overall survival rate, respectively. It should be recommended for patients with a high risk of recurrence, but these findings require prospective confirmation. PMID- 26008729 TI - CD93 gene polymorphism is associated with disseminated colorectal cancer. AB - PURPOSE: Cluster of differentiation 93 (CD93) is involved in apoptosis and inflammation and has a suggested role in angiogenesis, and all of which are involved in the development and dissemination of cancer. We evaluated the expression of CD93 and the association with two single nucleotide polymorphisms (SNPs), rs2749812 and rs2749817, as possible biomarkers in colorectal cancer (CRC). METHODS: Tissue levels and plasma levels of CD93 were measured using an enzyme-linked immunosorbent assay (ELISA). Expression of CD93 was determined by immunohistochemistry, western blot and gene expression analysis. Genotype frequencies were established for the SNPs by real-time polymerase chain reaction (PCR), and the association with tumour stage and survival was analysed. RESULTS: Total CD93 levels were 82% higher (P < 0.001) in tumours compared to matched normal tissues. Mean levels of soluble CD93 in plasma were 30% lower (P < 0.001) in the patients compared to the controls. The T/T genotype of SNP rs2749817 was more common in stage IV patients, with consequently higher risk of CRC death (T/T vs. C/C and C/T; hazard ratio (HR) = 1.73, 95% confidence interval (CI) = 1.11 2.67, P = 0.014), and was associated with a higher risk of CRC recurrence after radical operation (T/T vs. C/C and C/T; HR = 2.07, CI = 1.22-3.51, P = 0.007). CONCLUSIONS: We showed that the T/T genotype of SNP rs2749817 is associated with disseminated cancer at diagnosis and an increased recurrence rate after radical operation. Patients with this genotype may benefit from early identification. PMID- 26008730 TI - Circular anastomotic experimental fibrin sealant protection in deep colorectal anastomosis in pigs in a randomized 9-day survival study. AB - PURPOSE: The reported rate of clinically apparent anastomotic leakage (AL) in a low anterior resection of the rectum (LAR) (<=7 cm from the anal verge) using a circular double-stapled anastomosis (CDSA) without defunctioning stoma is up to 37.5 %. Since AL may result in life-threatening peritonitis, sepsis, and multiple organ failure, LAR and CDSA are regularly combined with defunctioning stoma. Accordingly, we now evaluated whether LAR and CDSA without defunctioning stoma but with extraluminal anastomotic application of an experimental fibrin sealant reduce the AL rate. This might prevent humans from defunctioning stoma increasing quality of life and decreasing surgical costs. METHODS: Forty 8-week-old pigs underwent LAR and CDSA in an end-to-end technique (descendo-rectostomy). Animals were randomized into a therapy and control group (gr.). The therapy gr. (n = 20) received an additional extraluminal circular application of an experimental fibrin sealant to the anastomosis. The objective was to assess the incidence of clinically apparent and non-clinically apparent leakage through the ninth postoperative day. Double-contrast barium CT radiographs of the colorectal region were performed on the ninth postoperative day or earlier, in case there were clinical signs of AL. All remaining animals were sacrificed on the ninth postoperative day and the anastomotic region was histopathologically analyzed. In case of earlier diagnosed AL, animals were sacrificed immediately. Blood samples were taken for complete blood count, chemistry, and coagulation profile prior to surgery and on the first, third, fifth, seventh, and ninth postoperative day. RESULTS: A circular extraluminal anastomotic application of an experimental fibrin protection decreased the rate of clinically and non-clinically apparent AL from 20 % (n = 4) in the control group to 5 % (n = 1) in the treatment group. Ulcerations were also observed in both gr. (control gr.-5 animals, therapy gr. -3 animals). All animals with AL showed necrosis surrounding the hole at the anastomoses. Three additional animals had a full wall defect at the anastomotic region that was blocked by the experimental fibrin sealant. The fibrin sealant was present at necropsy in all treated animals. CONCLUSION: Circular anastomotic protection with the experimental fibrin sealant blocked anastomotic full wall defects, preventing peritonitis and significantly reducing the AL rate from 25 to 5 %. PMID- 26008731 TI - Early peri-implant bone loss: a prospective cohort study. AB - The aim of this study was to measure the early peri-implant bone level changes before the completion of an implant-abutment connection and to evaluate the influence of demographic, biologically relevant, anatomical, and implant-specific variables on these changes. A prospective cohort study design was used. STROBE guidelines were followed. The sample comprised 493 implants placed using a two stage surgical procedure. Random allocation was used to determine the implant placement depth. Peri-apical radiographs taken at implant insertion and at the second surgery 2 months later were matched. Kappa statistics were used to compute intra- and inter-examiner reliability. The statistical analysis was performed at the implant level. Two-way analysis of variance (ANOVA) with the Bonferroni adjusted post hoc test was used to evaluate the influence of variables. One-way ANOVA with Tukey's range test and unpaired Student t-tests were used to analyze significant variables. Early marginal bone remodelling was -0.86 mm. The timing of implant placement (P=0.00) and the depth of implant placement (P<=0.05) significantly influenced early bone remodelling. Relevant radiographic early bone loss was found, but implants initially positioned below the alveolar crest and inserted >=3 months after tooth extraction showed statistically significant higher marginal bone loss during the healing phase. PMID- 26008732 TI - Clinical utility of three-dimensional SPECT/CT imaging as a guide for the resection of medication-related osteonecrosis of the jaw. AB - In recent years, proactive surgical treatment has been reported to be effective for medication-related osteonecrosis of the jaw (MRONJ). However, an uncertain resection entails the risk of recurrence, whereas an extensive surgical procedure may lead to a marked reduction in quality of life as a result of reduced masticatory function and poor cosmesis. Therefore, radiological assessment can be helpful to accurately localize MRONJ before surgery. The integrated single-photon emission computed tomography and computed tomography system (SPECT/CT) allows oral and maxillofacial surgeons to identify an area of MRONJ, especially when three-dimensional (3D) SPECT and CT fusion images are offered. A patient for whom 3D SPECT and CT image fusion (as developed in the radiology department of the study institution) contributed to determining the extent of the lesion, thereby leading to a favourable patient prognosis, is reported herein. There was exact correlation between the histological and radiological results. PMID- 26008733 TI - Temporomandibular joint ankylosis caused by condylar fractures: a retrospective analysis of cases at an urban teaching hospital in Nigeria. AB - Mandibular condylar fractures are common presentations to hospitals across the globe and remain the most important cause of temporomandibular joint (TMJ) ankylosis. This study aimed to analyze cases of mandibular condylar fracture complicated by TMJ ankylosis after treatment. A 16-year retrospective analysis was performed at the dental and maxillofacial surgery clinic of the study institution; patient data were collected from the hospital records and entered into a pro-forma questionnaire. It was found that 56/3596 (1.6%) fractures resulted in TMJ ankylosis. The age of patients with ankylosis ranged from 12 to 47 years. The age (P=0.03) and gender (P=0.01) distributions were significant, with most cases of ankylosis occurring in those aged 11-30 years (n=43/56, 76.8%). Fractures complicated by ankylosis were intracapsular (n=22/56, 39.3%) and extracapsular (n=34/56, 60.7%). Ankylosis increased significantly with the increase in time lag between injury and fracture treatment (P=0.001). Ankylosis was associated with concomitant mandibular (85.7%) and middle third (66.1%) fractures. Treatment methods were not significantly related to ankylosis (P=0.32). All cases of ankylosis were unilateral, and complete (n=36, 64.3%) and incomplete ankylosis (n=20, 35.7%) were diagnosed clinically. The incorporation of computed tomography scans and rigid internal fixation in the management of condylar fractures will reduce ankylosis. PMID- 26008734 TI - " . . . I Should Maintain a Healthy Life Now and Not Just Live as I Please . . . ": Men's Health and Fatherhood in Rural South Africa. AB - This study examines the social context of men's health and health behaviors in rural KwaZulu-Natal, South Africa, particularly in relationship to fathering and fatherhood. Individual interviews and focus groups were conducted with 51 Zulu speaking men. Three themes related to men's health emerged from the analysis of transcripts: (a) the interweaving of health status and health behaviors in descriptions of "good" and "bad" fathers, (b) the dominance of positive accounts of health and health status in men's own accounts, and (c) fathers' narratives of transformations and positive reinforcement in health behaviors. The study reveals the pervasiveness of an ideal of healthy fathers, one in which the health of men has practical and symbolic importance not only for men themselves but also for others in the family and community. The study also suggests that men hold in esteem fathers who manage to be involved with their biological children who are not coresident or who are playing a fathering role for nonbiological children (social fathers). In South Africa, men's health interventions have predominantly focused on issues related to HIV and sexual health. The new insights obtained from the perspective of men indicate that there is likely to be a positive response to health interventions that incorporate acknowledgment of, and support for, men's aspirations and lived experiences of social and biological fatherhood. Furthermore, the findings indicate the value of data on men's involvement in families for men's health research in sub-Saharan Africa. PMID- 26008735 TI - Socioeconomic Determinants of Inequality in Smoking Stages: A Distributive Analysis on a Sample of Male High School Students. AB - The effect of socioeconomic status on adolescent smoking behaviors is unclear, and sparse studies are available about the potential association. The present study aimed to measure and explain socioeconomic inequality in smoking behavior among a sample of Iranian adolescents. In a cross-sectional survey, a multistage sample of adolescents ( n = 1,064) was recruited from high school students in Zanjan city, northwest of Iran. Principal component analysis was used to measure economic status of adolescents. Concentration index was used to measure socioeconomic inequality in smoking behavior, and then it was decomposed to reveal inequality contributors. Concentration index and its 95% confidence interval for never, experimental, and regular smoking behaviors were 0.004 [ 0.03, 0.04], 0.05 [0.02, 0.11], and -0.10 [-0.04, -0.19], respectively. The contribution of economic status to measured inequality in experimental and regular smoking was 80.0% and 68.8%, respectively. Household economic status could be targeted as one of the relevant factors in the unequal distribution of smoking behavior among adolescents. PMID- 26008736 TI - Gene expression in major depressive disorder. AB - The search for genetic variants underlying major depressive disorder (MDD) has not yet provided firm leads to its underlying molecular biology. A complementary approach is to study gene expression in relation to MDD. We measured gene expression in peripheral blood from 1848 subjects from The Netherlands Study of Depression and Anxiety. Subjects were divided into current MDD (N=882), remitted MDD (N=635) and control (N=331) groups. MDD status and gene expression were measured again 2 years later in 414 subjects. The strongest gene expression differences were between the current MDD and control groups (129 genes at false discovery rate, FDR<0.1). Gene expression differences across MDD status were largely unrelated to antidepressant use, inflammatory status and blood cell counts. Genes associated with MDD were enriched for interleukin-6 (IL-6) signaling and natural killer (NK) cell pathways. We identified 13 gene expression clusters with specific clusters enriched for genes involved in NK cell activation (downregulated in current MDD, FDR=5.8 * 10(-5)) and IL-6 pathways (upregulated in current MDD, FDR=3.2 * 10(-3)). Longitudinal analyses largely confirmed results observed in the cross-sectional data. Comparisons of gene expression results to the Psychiatric Genomics Consortium (PGC) MDD genome-wide association study results revealed overlap with DVL3. In conclusion, multiple gene expression associations with MDD were identified and suggest a measurable impact of current MDD state on gene expression. Identified genes and gene clusters are enriched with immune pathways previously associated with the etiology of MDD, in line with the immune suppression and immune activation hypothesis of MDD. PMID- 26008738 TI - Specific Direct Small Molecule p300/beta-Catenin Antagonists Maintain Stem Cell Potency. AB - Despite their high degree of identity and even higher homology, the two Kat3 transcriptional coactivators, CBP and p300, have distinct functions, particularly within the Wnt/beta-catenin signaling cascade. ICG-001, by directly binding to CBP but not p300, inhibits CBP/beta-catenin transcription and has served as an invaluable chemical genomic tool to dissect the Wnt signaling cascade and the divergent roles of these two coactivators. However, to date no direct antagonist of the p300/beta-catenin interaction has been reported. We now report the identification and validation of the first highly specific, direct p300/beta catenin antagonists, YH249/250 and their ability to maintain pluripotency in ESC. PMID- 26008739 TI - Eva Nogales: See how they run. PMID- 26008737 TI - Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice. AB - NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists. PMID- 26008740 TI - VEGF tips its hand in angiogenesis. PMID- 26008741 TI - The expanding implications of polyploidy. AB - Polyploid cells, which contain more than two genome copies, occur throughout nature. Beyond well-established roles in increasing cell size/metabolic output, polyploidy can also promote nonuniform genome, transcriptome, and metabolome alterations. Polyploidy also frequently confers resistance to environmental stresses not tolerated by diploid cells. Recent progress has begun to unravel how this fascinating phenomenon contributes to normal physiology and disease. PMID- 26008743 TI - Nesprin provides elastic properties to muscle nuclei by cooperating with spectraplakin and EB1. AB - Muscle nuclei are exposed to variable cytoplasmic strain produced by muscle contraction and relaxation, but their morphology remains stable. Still, the mechanism responsible for maintaining myonuclear architecture, and its importance, is currently elusive. Herein, we uncovered a unique myonuclear scaffold in Drosophila melanogaster larval muscles, exhibiting both elastic features contributed by the stretching capacity of MSP300 (nesprin) and rigidity provided by a perinuclear network of microtubules stabilized by Shot (spectraplakin) and EB1. Together, they form a flexible perinuclear shield that protects myonuclei from intrinsic or extrinsic forces. The loss of this scaffold resulted in significantly aberrant nuclear morphology and subsequently reduced levels of essential nuclear factors such as lamin A/C, lamin B, and HP1. Overall, we propose a novel mechanism for maintaining myonuclear morphology and reveal its critical link to correct levels of nuclear factors in differentiated muscle fibers. These findings may shed light on the underlying mechanism of various muscular dystrophies. PMID- 26008742 TI - Brain barriers: Crosstalk between complex tight junctions and adherens junctions. AB - Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the endothelial blood-brain barrier (BBB) and the epithelial blood cerebrospinal fluid barrier (BCSFB), respectively. These barriers inhibit paracellular diffusion, thereby protecting the CNS from fluctuations in the blood. Studies of brain barrier integrity during development, normal physiology, and disease have focused on BBB and BCSFB tight junctions but not the corresponding endothelial and epithelial adherens junctions. The crosstalk between adherens junctions and tight junctions in maintaining barrier integrity is an understudied area that may represent a promising target for influencing brain barrier function. PMID- 26008744 TI - BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery. AB - Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS models to place BLOC-2 within a cargo transport pathway from recycling endosomal domains to maturing melanosomes. In BLOC-2-deficient melanocytes, the melanosomal protein TYRP1 was largely depleted from pigment granules and underwent accelerated recycling from endosomes to the plasma membrane and to the Golgi. By live-cell imaging, recycling endosomal tubules of wild-type melanocytes made frequent and prolonged contacts with maturing melanosomes; in contrast, tubules from BLOC-2-deficient cells were shorter in length and made fewer, more transient contacts with melanosomes. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation. PMID- 26008745 TI - Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling. AB - Type I interferons (IFNs) activate differential cellular responses through a shared cell surface receptor composed of the two subunits, IFNAR1 and IFNAR2. We propose here a mechanistic model for how IFN receptor plasticity is regulated on the level of receptor dimerization. Quantitative single-molecule imaging of receptor assembly in the plasma membrane of living cells clearly identified IFN induced dimerization of IFNAR1 and IFNAR2. The negative feedback regulator ubiquitin-specific protease 18 (USP18) potently interferes with the recruitment of IFNAR1 into the ternary complex, probably by impeding complex stabilization related to the associated Janus kinases. Thus, the responsiveness to IFNalpha2 is potently down-regulated after the first wave of gene induction, while IFNbeta, due to its ~100-fold higher binding affinity, is still able to efficiently recruit IFNAR1. Consistent with functional data, this novel regulatory mechanism at the level of receptor assembly explains how signaling by IFNbeta is maintained over longer times compared with IFNalpha2 as a temporally encoded cause of functional receptor plasticity. PMID- 26008746 TI - Wnt ligands regulate Tkv expression to constrain Dpp activity in the Drosophila ovarian stem cell niche. AB - Stem cell self-renewal versus differentiation is regulated by the niche, which provides localized molecules that favor self-renewal. In the Drosophila melanogaster female germline stem cell (GSC) niche, Decapentaplegic (Dpp), a fly transforming growth factor beta molecule and well-established long-range morphogen, acts over one cell diameter to maintain the GSCs. Here, we show that Thickveins (Tkv; a type I receptor of Dpp) is highly expressed in stromal cells next to Dpp-producing cells and functions to remove excess Dpp outside the niche, thereby spatially restricting its activity. Interestingly, Tkv expression in these stromal cells is regulated by multiple Wnt ligands that are produced by the niche. Our data demonstrate a self-restraining mechanism by which the Drosophila ovarian GSC niche acts to define its own boundary. PMID- 26008747 TI - Nuclear accessibility of beta-actin mRNA is measured by 3D single-molecule real time tracking. AB - Imaging single proteins or RNAs allows direct visualization of the inner workings of the cell. Typically, three-dimensional (3D) images are acquired by sequentially capturing a series of 2D sections. The time required to step through the sample often impedes imaging of large numbers of rapidly moving molecules. Here we applied multifocus microscopy (MFM) to instantaneously capture 3D single molecule real-time images in live cells, visualizing cell nuclei at 10 volumes per second. We developed image analysis techniques to analyze messenger RNA (mRNA) diffusion in the entire volume of the nucleus. Combining MFM with precise registration between fluorescently labeled mRNA, nuclear pore complexes, and chromatin, we obtained globally optimal image alignment within 80-nm precision using transformation models. We show that beta-actin mRNAs freely access the entire nucleus and fewer than 60% of mRNAs are more than 0.5 um away from a nuclear pore, and we do so for the first time accounting for spatial inhomogeneity of nuclear organization. PMID- 26008748 TI - Population mixing and the risk of childhood leukaemia in Switzerland: a census based cohort study. AB - Childhood leukaemia (CL) may have an infectious cause and population mixing may therefore increase the risk of CL. We aimed to determine whether CL was associated with population mixing in Switzerland. We followed children aged <16 years in the Swiss National Cohort 1990-2008 and linked CL cases from the Swiss Childhood Cancer Registry to the cohort. We calculated adjusted hazard ratios (HRs) for all CL, CL at age <5 years and acute lymphoblastic leukaemia (ALL) for three measures of population mixing (population growth, in-migration and diversity of origin), stratified by degree of urbanisation. Measures of population mixing were calculated for all municipalities for the 5-year period preceding the 1990 and 2000 censuses. Analyses were based on 2,128,012 children of whom 536 developed CL. HRs comparing highest with lowest quintile of population growth were 1.11 [95 % confidence interval (CI) 0.65-1.89] in rural and 0.59 (95 % CI 0.43-0.81) in urban municipalities (interaction: p = 0.271). Results were similar for ALL and for CL at age <5 years. For level of in migration there was evidence of a negative association with ALL. HRs comparing highest with lowest quintile were 0.60 (95 % CI 0.41-0.87) in urban and 0.61 (95 % CI 0.30-1.21) in rural settings. There was little evidence of an association with diversity of origin. This nationwide cohort study of the association between CL and population growth, in-migration and diversity of origin provides little support for the population mixing hypothesis. PMID- 26008749 TI - Prolonged second stage of labor is associated with low Apgar score. AB - There is no consensus on the effects of a prolonged second stage of labor on neonatal outcomes. In this large Swedish population-based cohort study, our objective was to investigate prolonged second stage and risk of low Apgar score at 5 min. All nulliparous women (n = 32,796) delivering a live born singleton infant in cephalic presentation at >=37 completed weeks after spontaneous onset of labor between 2008 and 2012 in the counties of Stockholm and Gotland were included. Data were obtained from computerized records. Exposure was time from fully retracted cervix until delivery. Logistic regression analyses were used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Adjustments were made for maternal age, height, BMI, smoking, sex, gestational age, sex-specific birth weight for gestational age and head circumference. Epidural analgesia was included in a second model. The primary outcome measure was Apgar score at 5 min <7 and <4. We found that the overall rates of 5 min Apgar score <7 and <4 were 7.0 and 1.3 per 1000 births, respectively. Compared to women with <1 h from retracted cervix to birth, adjusted ORs of Apgar score <7 at 5 min generally increased with length of second stage of labor: 1 to <2 h: OR 1.78 (95% CI 1.19-2.66); 2 to <3 h: OR 1.66 (1.05 2.62); 3 to <4 h: OR 2.08 (1.29-3.35); and >=4 h: OR 2.71 (1.67-4.40). We conclude that prolonged second stage of labor is associated with an increased risk of low 5 min Apgar score. PMID- 26008750 TI - Risk of Guillain-Barre syndrome after exposure to pandemic influenza A(H1N1)pdm09 vaccination or infection: a Norwegian population-based cohort study. AB - Vaccinations and infections are possible triggers of Guillain-Barre syndrome (GBS). However, studies on GBS after vaccinations during the influenza A(H1N1)pmd09 pandemic in 2009, show inconsistent results. Only few studies have addressed the role of influenza infection. We used information from national health data-bases with information on the total Norwegian population (N = 4,832,211). Cox regression analyses with time-varying covariates and self controlled case series was applied. The risk of being hospitalized with GBS during the pandemic period, within 42 days after an influenza diagnosis or pandemic vaccination was estimated. There were 490 GBS cases during 2009-2012 of which 410 cases occurred after October 1, 2009 of which 46 new cases occurred during the peak period of the influenza pandemic. An influenza diagnosis was registered for 2.47% of the population and the vaccination coverage was 39.25%. The incidence rate ratio of GBS during the pandemic peak relative to other periods was 1.46 [95% confidence interval (CI) 1.08-1.98]. The adjusted hazard ratio (HR) of GBS within 42 days after a diagnosis of pandemic influenza was 4.89 (95% CI 1.17-20.36). After pandemic vaccination the adjusted HR was 1.11 (95% CI 0.51-2.43). Our results indicated that there was a significantly increased risk of GBS during the pandemic season and after pandemic influenza infection. However, vaccination did not increase the risk of GBS. The small number of GBS cases in this study warrants caution in the interpretation of the findings. PMID- 26008751 TI - Lauq: A Sustained-Release Dosage Form for Respiratory Disorders in Traditional Persian Medicine. AB - Lauq is a pharmaceutical dosage form that had been mainly used for the treatment of various respiratory disorders in traditional Persian medicine. It is important from 2 aspects: a dosage form with efficient and optimum delivery of drugs to the respiratory tract and biological effects of its ingredients. Natural medicine in lauq has been demonstrated to act in respiratory disorders by their antitussive, antiallergic, anti-inflammatory, antioxidant, spasmolytic, and antibacterial activities. Some of these natural remedies act by most of the mentioned mechanisms such as Cydonia oblonga, Glycyrrhiza glabra, Crocus sativus, Hyssopus officinalis, Foeniculum vulgare, and honey. However, the evidence is limited including Cassia fistula, Papaver somniferum, and Drimia maritima. According to positive pharmacokinetic and pharmacodynamic aspects of lauqs, they may be considered as efficient dosage forms for delivery of drugs to the respiratory tract. For better compatibility of patients, it could be substituted lauqs with newer drug delivery systems like lozenges. PMID- 26008752 TI - Immunoliposome-mediated drug delivery to Plasmodium-infected and non-infected red blood cells as a dual therapeutic/prophylactic antimalarial strategy. AB - One of the most important factors behind resistance evolution in malaria is the failure to deliver sufficiently high amounts of drugs to early stages of Plasmodium-infected red blood cells (pRBCs). Despite having been considered for decades as a promising approach, the delivery of antimalarials encapsulated in immunoliposomes targeted to pRBCs has not progressed towards clinical applications, whereas in vitro assays rarely reach drug efficacy improvements above 10-fold. Here we show that encapsulation efficiencies reaching >96% are achieved for the weak basic drugs chloroquine (CQ) and primaquine using the pH gradient loading method in liposomes containing neutral saturated phospholipids. Targeting antibodies are best conjugated through their primary amino groups, adjusting chemical crosslinker concentration to retain significant antigen recognition. Antigens from non-parasitized RBCs have also been considered as targets for the delivery to the cell of drugs not affecting the erythrocytic metabolism. Using this strategy, we have achieved unprecedented complete nanocarrier targeting to early intraerythrocytic stages of the malaria parasite for which there is a lack of specific extracellular molecular tags. Immunoliposomes studded with monoclonal antibodies raised against the erythrocyte surface protein glycophorin A were capable of targeting 100% RBCs and pRBCs at the low concentration of 0.5MUM total lipid in the culture, with >95% of added liposomes retained on cell surfaces. When exposed for only 15min to Plasmodium falciparum in vitro cultures of early stages, free CQ had no significant effect on the viability of the parasite up to 200nM, whereas immunoliposomal 50nM CQ completely arrested its growth. In vivo assays in mice showed that immunoliposomes cleared the pathogen below detectable levels at a CQ dose of 0.5mg/kg, whereas free CQ administered at 1.75mg/kg was, at most, 40-fold less efficient. Our data suggest that this significant improvement is in part due to a prophylactic effect of CQ found by the pathogen in its host cell right at the very moment of invasion. PMID- 26008753 TI - Prognostic value of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and meta-analysis. AB - PURPOSE: The objective of this systematic review is to provide an unprecedented summary of the prognostic impact of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma. METHODS: Studies evaluating PAX3/7-FOXO1 fusion gene or its variants as a prognostic marker were systematically searched and comparative meta analysis of overall survival was carried out. RESULTS: A total of 7 studies comprising 993 patients with rhabdomyosarcoma were included. Three eligible studies showed no significant difference of survival between fusion positive and negative alveolar rhabdomyosarcoma. Four eligible studies showed that PAX3-FOXO1 fusion variant may indicate a lower survival probability than PAX7-FOXO1, although the effect did not reach a level of statistical significance (pooled hazard ratios, 1.66; 95% CI, 0.95-2.89; p=0.07). CONCLUSIONS: There was no significant difference in the overall survival between patients with the positive and negative fusion gene, but there were indications of PAX3-FOXO1 being an unfavorable prognostic factor. PMID- 26008754 TI - Cardiorespiratory fitness, C-reactive protein and lung cancer risk: A prospective population-based cohort study. AB - BACKGROUND: Little is known about the joint impact of C-reactive protein (CRP) and cardiorespiratory fitness (CRF) in lung cancer risk. The aim of this study is to examine the joint impact of CRF and CRP in predicting lung cancer risk. METHODS: A population-based cohort study of 2276 men with no history of cancer was carried out. Baseline measures of CRP and CRF were divided into median values and categorised. During an average follow-up of 21-years, 73 cases of lung cancer occurred. RESULTS: In a multivariate model, men with the combination of high CRP (>50% 1.24 mg/l) and low CRF (maximal oxygen uptake (VO2max) < 50% 30.08 ml/kg/min) had a fourfold (relative risk (RR) 4.19 95% confidence interval (CI) 1.66-10.57, p < 0.01) risk of lung cancer as compared to the reference group of low CRP (<50% 1.24 mg/l) and high CRF (VO2max>50% 30.08 ml/kg/min). Furthermore, men categorised in high CRP and combined with either low/high CRF, had an increased risk for lung cancer as compared to reference group. In further separate independent analysis for CRP and CRF, lung cancer risk was threefold for high CRP (RR 3.22, 95% CI 1.44-7.20, p < 0.01) and low CRF (RR 3.15, 95% CI 1.27 7.78, p = 0.01) as compared to reference CRP (>2.38 mg/l) and CRF (>35.15 ml/kg/min). CONCLUSIONS: In this study, the joint impact of CRP and CRF is a strong risk marker for lung cancer. Furthermore, men with an increase in CRP were at higher risk for lung cancer than men with low CRP and high CRF may reduce the risk. PMID- 26008755 TI - [Return to Work after Fractures of the Pelvis and the Acetabulum]. AB - BACKGROUND AND INTRODUCTION: Pelvic and acetabular fractures are severe injuries with serious consequences that mainly happen to young people. Therefore it is highly interesting to find out to what extent affected patients succeed in returning to work, which is an important factor concerning quality of live. Thus, the objective of this study was to estimate the "return to work" in a two-year follow-up after rehabilitative treatment of patients with pelvic and acetabular fractures and to identify influencing factors. METHODS: A retrospective cohort study was conducted using population-based administrative data of the Baden Wurttemberg statutory pension fund. All patients (age 18 to 63 years) who had participated in a rehabilitation programme between 2004 and 2009 due to a pelvic or acetabular fracture were included. Return to work was modelled using multivariate logistic regression analysis. Rehabilitants were classified as "returned" if they have paid at least one monthly contribution due to employment during 13 to 24 months after rehabilitation. Age, gender, diagnostic group, type of rehabilitation programme, fractures of the spine, nerve injuries of the lumbosacral area and/or the lower limb and employment status before the fractures were considered as prognostic covariates. RESULTS: Two-thirds of the 249 researched patients returned to work. This corresponds to a reduction of employment amounting to 16.6 % for patients with a pelvic fracture and 20.8 % for patients with an acetabular fracture. Main predictor for a return to work was the employment status before the fracture. Younger patients had a better chance to return to work than older ones. Patients with fractures of the spine or nerve injuries of the lumbosacral area and/or the lower limb had a 73 % or, respectively, 78 % higher risk of not returning to work. CONCLUSION: Fractures of the pelvis and the acetabulum currently lead in one of five patients to loss of employment. Thereby the trauma threatens the social security of the young patients. Follow-up care should be intensified to increase recovery rates and reduce the burden of long-term work disability. PMID- 26008756 TI - [Sensorimotor Deficits in Functional Ankle Instability]. AB - Lateral ankle sprains are among the most common sports injuries, with a prevalence of 25 to 30 % of all injuries. At least one-third of individuals develop long-term complaints and chronic instabilities at the ankle, which in many cases cannot be attributed to mechanical insufficiencies of the joint. This condition is referred to as functional ankle instability (FAI). Impairments of the sensorimotor control system, such as disturbed proprioception and postural control, as well as reduced muscle strength and reflex activity, have been suggested to contribute to the aetiology of FAI. This review summarises the current body of literature regarding sensorimotor control in individuals with FAI. We discuss the results in the context of current neurophysiological models of the development of functional joint instabilities. PMID- 26008757 TI - Transient Adverse Side Effects During Neurofeedback Training: A Randomized, Sham Controlled, Double Blind Study. AB - The benefits of clinical neurofeedback training are well known, however, its adverse side-effects are less studied. This research focuses on the transient adverse side effects of neurofeedback training via a double-blind, sham/controlled methodology. Thirty healthy undergraduate students volunteers were randomly divided into three treatment groups: increasing a modified Sensory Motor Rhythm, increasing Upper Alpha, and Sham/control group who receive a random reward. The training sessions were administered for a total of ten sessions. Questionnaires of transient adverse side effects were completed by all volunteers before each session. The results suggest that similar to most medical treatments, neurofeedback can cause transient adverse side effects. Moreover, most participants reported experiencing some side effects. The side effects can be divided into non-specific side effect, associated with the neurofeedback training in general and specific ones associated with the particular protocol. Sensory Motor Rhythm protocol seems to be the most sensitive to side effects. PMID- 26008758 TI - Comparison of Umbilical Cord Milking and Delayed Cord Clamping on Cerebral Blood Flow in Term Neonates. AB - OBJECTIVE: To compare the effect of umbilical cord milking (UCM) and delayed cord clamping (DCC) on cerebral blood flow in term neonates. METHODS: This randomized controlled trial was conducted at a teaching hospital in India during 2012 to 2013. Two hundred newborns (>36wk) were randomized to UCM and DCC groups. UCM was done on 25cm of cord length. In DCC group, clamping was delayed by 60 to 90s. Resistive Index (RI), Pulsatility Index (PI) and cerebral blood flow velocities of middle cerebral artery (MCA) were measured at 24 to 48h of life. RESULTS: Baseline characteristics and hemodynamic parameters were comparable. Mean PI [1.18 (0.26)] and RI [0.65 (0.08)] in UCM group was comparable to mean PI [1.18 (0.25)] and RI [0.65 (0.08)] in DCC group. The peak systolic velocity and end diastolic velocity (cm/s) of blood flow in MCA for UCM group were 34.94 (11.82) and 11.71 (4.75) respectively, while in DCC group they were 37.24 (12.63) and 13.07 (4.78) (p 0.23 and 0.07) respectively. Indices among growth retarded babies were not different. CONCLUSIONS: DCC and UCM had similar effect on cerebral blood flow velocities and Doppler indices in MCA, in term neonates. PMID- 26008759 TI - Bovine gamma delta T cells and the function of gamma delta T cell specific WC1 co receptors. AB - The study of gammadelta T cells in ruminants dates to the discovery of the gammadelta TCR in humans and mice. It is important since cattle offer an alternative model to the mouse for evaluating the role of gammadelta T cells in zoonotic disease research and for control of disease reservoirs in non-human animals. In addition, maintaining the health of cattle and other members of the order Artiodactyla is critical to meet the global human need for animal-source protein. In this review, we examine the bovine gammadelta T cell responses to Mycobacteria, which infects a third of the human population, and bovine gamma and delta TCR diversity and the relationship to the TCR of human mycobacteria responsive gammadelta T cells. We review the utilization of the gammadelta T cell specific scavenger receptor cysteine-rich (SRCR) glycoproteins known as WC1, and that are part of the CD163 family, which function as both gammadelta T cell activating co-receptors and pattern recognition receptors (PRR) for bovine gammadelta T cells and highlight the presence and evolution of this multigenic array, with potential for the same function, in birds, reptiles, jawless and bony fishes, and prototherian and eutherian mammals. PMID- 26008760 TI - Transition state theory for enzyme kinetics. AB - This article is an essay that discusses the concepts underlying the application of modern transition state theory to reactions in enzymes. Issues covered include the potential of mean force, the quantization of vibrations, the free energy of activation, and transmission coefficients to account for nonequilibrium effect, recrossing, and tunneling. PMID- 26008761 TI - Three-dimensional reconstruction methods in Single Particle Analysis from transmission electron microscopy data. AB - The Transmission Electron Microscope provides two-dimensional (2D) images of the specimens under study. However, the architecture of these specimens is defined in a three-dimensional (3D) coordinate space, in volumetric terms, making the direct microscope output somehow "short" in terms of dimensionality. This situation has prompted the development of methods to quantitatively estimate 3D volumes from sets of 2D images, which are usually referred to as "three-dimensional reconstruction methods". These 3D reconstruction methods build on four considerations: (1) The relationship between the 2D images and the 3D volume must be of a particularly simple type, (2) many 2D images are needed to gain 3D volumetric information, (3) the 2D images and the 3D volume have to be in the same coordinate reference frame and (4), in practical terms, the reconstructed 3D volume will only be an approximation to the original 3D volume which gave raise to the 2D projections. In this work we will adopt a quite general view, trying to address a large community of interested readers, although some sections will be particularly devoted to the 3D analysis of isolated macromolecular complexes in the application area normally referred to as Single Particle Analysis (SPA). PMID- 26008762 TI - Comparing Retesting Rates Between Different Screening Methods for Critical Congenital Heart Disease: A Case from Northeast Brazil. PMID- 26008763 TI - Surgical Results of Anomalous Origin of One Pulmonary Artery Branch from the Ascending Aorta. AB - We reviewed our surgical experience with anomalous origin of one pulmonary artery from the ascending aorta (AOPA). From 1989 to 2012, 12 children (five neonates) aged 3-734 days (mean 152 +/- 222) with AOPA underwent operations. Eight patients had right AOPA, and four patients had left AOPA. The majority of the patients had elevated right ventricular pressure, with 58 % (7 of 12) demonstrating suprasystemic right ventricular pressure. Surgery was performed by direct anastomosis (group 1) in seven patients and by employing an autologous patch (group 2) in five patients. There were two postoperative mortalities caused by heart failure and pulmonary hypertensive crisis. The mean follow-up duration was 12.6 +/- 8 years. Catheterization showed that the right ventricle-to-systemic pressure ratio decreased following operation (preoperative vs. postoperative; 1.13 +/- 0.19 vs. 0.48 +/- 0.03, p = 0.043). There was no difference in the perfusion of the affected lung as measured by the final lung perfusion scan, between the two groups (group 1 vs. group 2; 50.0 +/- 10.3 vs. 42.7 +/- 28.7 %, p = 0.158). Two patients required reoperations for pulmonary regurgitation and pulmonary artery stenosis. There were two catheter-based interventions. At 20 years, survival by the Kaplan-Meier was 91.7 +/- 8.0 %, freedom from reoperation was 80.0 +/- 17.9 %, and freedom from catheter intervention was 80.8 +/- 12.2 %. Early repair of AOPA improves right ventricular pressure and overall hemodynamics with excellent survival and low risk of reintervention. The type of surgical repair did not significantly affect the long-term outcomes (measured via lung perfusion scan). PMID- 26008765 TI - Editorial. PMID- 26008764 TI - Fetal Ventricular Hypertrabeculation/Noncompaction: Clinical Presentation, Genetics, Associated Cardiac and Extracardiac Abnormalities and Outcome. AB - Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology. Aim of the review was to summarize the current knowledge about fetal LVHT, including clinical presentation, associated cardiac and extracardiac abnormalities and outcome. In 88 cases, LVHT was diagnosed by fetal echocardiography. In 36 %, no additional cardiac abnormalities were reported; in the remaining 64 %, one or more cardiac abnormalities were reported. Eight cases died prenatally, 17 were electively terminated, and 24 patients died after birth. Six patients were lost to follow-up, and 33 patients are alive at a mean age of 26 months. Surviving cases presented less frequently with fetal hydrops (13 vs. 62 %, p = 0.0004), complete heart block (27 vs. 78 %, p = 0.0076), more than three associated cardiac abnormalities (9 vs. 47 %, p = 0.0008) and more frequently with isolated LVHT (52 vs. 19 %, p = 0.009) than cases who died. Of the surviving patients, 16 received pharmacotherapy, three received pacemakers, eight underwent surgical procedures and four underwent heart transplantation. Postnatal regression of left ventricular hypertrophy and development of LVHT was found in four cases, improvement in cardiac function in two, and regression of right VHT in two. At autopsy, endocardial fibrosis was the most frequent abnormality in 92 %. Thirty-eight percentage of cases with fetal LVHT survived. Fetal and postnatal echocardiographic findings challenge the "embryonic pathogenetic" hypothesis of LVHT. Furthermore, fetal pathoanatomic findings like endocardial fibrosis might play a role in clarifying the still unsolved pathogenesis of LVHT. PMID- 26008766 TI - E3 SUMO ligase AtSIZ1 positively regulates SLY1-mediated GA signalling and plant development. AB - Gibberellins affect various plant development processes including germination, cell division and elongation, and flowering. A large number of studies have been carried out to address the molecular mechanisms that mediate gibberellin signalling effects on plant growth. However, such studies have been limited to DELLA protein degradation; the regulatory mechanisms controlling how the stability and function of SLEEPY1 (SLY1), a protein that interacts with target DELLA proteins as components of the Skp, Cullin, F-box (SCF)(SLY1) complex, are modulated at the post-translational level have not been addressed. In the present study, we show that the E3 SUMO (small ubiquitin-related modifier) ligase AtSIZ1 regulates gibberellic acid signalling in Arabidopsis species by sumoylating SLY1. SLY1 was less abundant in siz1-2 mutants than in wild-type plants, but the DELLA protein repressor of ga1-3 (RGA) was more abundant in siz1-2 mutants than in wild type plants. SLY1 also accumulated to a high level in the SUMO protease mutant esd4. Transgenic sly1-13 mutants over-expressing SLY1 were phenotypically similar to wild-type plants; however, sly1-13 plants over-expressing a mutated mSLY1 protein (K122R, a mutation at the sumoylation site) retained the mutant dwarfing phenotype. Over-expression of SLY1 in sly1-13 mutants resulted in a return of RGA levels to wild-type levels, but RGA accumulated to high levels in mutants over expressing mSLY1. RGA was clearly detected in Arabidopsis co-expressing AtSIZ1 and mSLY1, but not in plants co-expressing AtSIZ1 and SLY1. In addition, sumoylated SLY1 interacted with RGA and SLY1 sumoylation was significantly increased by GA. Taken together, our results indicate that, in Arabidopsis, AtSIZ1 positively controls GA signalling through SLY1 sumoylation. PMID- 26008767 TI - A catalytic asymmetric carbonyl-ene reaction of beta,gamma-unsaturated alpha ketoesters with 5-methyleneoxazolines. AB - A catalytic asymmetric carbonyl-ene reaction of beta,gamma-unsaturated alpha ketoesters with 5-methyleneoxazolines was accomplished. The process was based on the utilization of a chiral N,N'-dioxide/Mg(II) catalyst, providing the desired products with excellent outcomes (up to 99% yield, >99% ee) under mild reaction conditions. Based on the experimental investigations and previous reports, a possible transition state was proposed. PMID- 26008768 TI - Comparison of total variation algorithms for electrical impedance tomography. AB - The applications of total variation (TV) algorithms for electrical impedance tomography (EIT) have been investigated. The use of the TV regularisation technique helps to preserve discontinuities in reconstruction, such as the boundaries of perturbations and sharp changes in conductivity, which are unintentionally smoothed by traditional l2 norm regularisation. However, the non differentiability of TV regularisation has led to the use of different algorithms. Recent advances in TV algorithms such as the primal dual interior point method (PDIPM), the linearised alternating direction method of multipliers (LADMM) and the spilt Bregman (SB) method have all been demonstrated successful EIT applications, but no direct comparison of the techniques has been made. Their noise performance, spatial resolution and convergence rate applied to time difference EIT were studied in simulations on 2D cylindrical meshes with different noise levels, 2D cylindrical tank and 3D anatomically head-shaped phantoms containing vegetable material with complex conductivity. LADMM had the fastest calculation speed but worst resolution due to the exclusion of the second derivative; PDIPM reconstructed the sharpest change in conductivity but with lower contrast than SB; SB had a faster convergence rate than PDIPM and the lowest image errors. PMID- 26008769 TI - Lung abscesses in children--twenty four years of experience. PMID- 26008770 TI - Inhaled steroids in COPD: reasons for a debate. PMID- 26008771 TI - Development of a screening program to assess motor function in the adult population: a cross-sectional observational study. AB - BACKGROUND: Motor dysfunction is a major reason why the elderly lose their independence in their daily lives. The concept of locomotive syndrome has been proposed to describe the risk of mobility dependence caused by various locomotive organ disorders. The preservation of locomotive organs is now socially important in the middle-aged and geriatric population. Therefore, it is important to establish a screening program to evaluate motor function and related quality of life in a wide range of ages. METHODS: We propose a new set of pre-existing scales (the Two-Step test, Stand-Up test, and 25-question Geriatric Locomotive Function Scale) as screening tools to identify the population at high risk for locomotive syndrome. We performed a preliminary survey on 777 subjects who had no apparent disorders related to motor function. We also examined the reliability of the Two-Step test and Stand-Up test. RESULTS: We found that each scale did not show ceiling or floor effects in various age groups. Because the correlations between the three scales were significant but weak, we assume that each scale covers different aspects of mobility. The test-retest reliability was found to be satisfactory for the Two-Step test and the Stand-Up test. CONCLUSION: Our results suggest that our "Short Test Battery for Locomotive syndrome" is a feasible and reliable tool for screening the adult population as a preventative strategy for locomotive syndrome in a super-aged society. PMID- 26008772 TI - Diffuse large B-cell lymphoma with microsatellite instability developing in the setting of Muir-Torre variant hereditary non-polyposis colon cancer. PMID- 26008773 TI - Team members' emotional displays as indicators of team functioning. AB - Emotions are inherent to team life, yet it is unclear how observers use team members' emotional expressions to make sense of team processes. Drawing on Emotions as Social Information theory, we propose that observers use team members' emotional displays as a source of information to predict the team's trajectory. We argue and show that displays of sadness elicit more pessimistic inferences regarding team dynamics (e.g., trust, satisfaction, team effectiveness, conflict) compared to displays of happiness. Moreover, we find that this effect is strengthened when the future interaction between the team members is more ambiguous (i.e., under ethnic dissimilarity; Study 1) and when emotional displays can be clearly linked to the team members' collective experience (Study 2). These studies shed light on when and how people use others' emotional expressions to form impressions of teams. PMID- 26008774 TI - Intractable diarrhoea despite immune reconstitution in an HIV positive man. PMID- 26008775 TI - Effects of environmental hypercapnia and metal (Cd and Cu) exposure on acid-base and metal homeostasis of marine bivalves. AB - Elevated CO2 levels reduce seawater pH and may affect bioavailability of trace metals in estuaries. We studied the interactive effects of common metal pollutants (50 MUg l(-1) Cd or Cu) and PCO2 (~395, 800 and 2000 MUatm) on metal levels, intracellular pH, expression of metal binding proteins and stress biomarkers in estuarine bivalves Crassostrea virginica (oysters) and Mercenaria mercenaria (hard clams). Cd (but not Cu or hypercapnia) exposure affected the acid-base balance of hemocytes resulting in elevated intracellular pH. Cd and Cu exposure led to the increase in the tissue metal burdens, and metal accumulation was reduced by elevated PCO2 in the mantle but not hemocytes. No change was found in the intracellular free Cd(2+), Cu(2+) or Fe(2+) during Cu or Cd exposure indicating that these metals are bound to intracellular ligands. Free Zn(2+) content in oyster hemocytes was suppressed by Cd and Cu exposure and below the detection limits in clam hemocytes, which went hand-in-hand with the elevated mRNA expression of metallothioneins and ferritin in Cd- and Cu-exposed bivalves, enhanced by hypercapnia. The metal-binding and antioxidant mechanisms of oysters and clams were sufficient to effectively maintain intracellular redox status, even though metal exposure combined with moderate hypercapnia (~800 MUatm PCO2) led to the elevated production of reactive oxygen species in hemocytes. Overall, while hypercapnia modulates metal accumulation, binding capacity and oxidative stress in estuarine bivalves, the physiological effects of elevated CO2 are mild compared to the effects of other common stressors. PMID- 26008776 TI - Primary renal myxofibrosarcoma. AB - Kidney sarcomas are rare, representing only 1% of malignant renal tumors. We herein report the case of a 70-year-old woman that was admitted for an episode of confusion in relation to hypertensive encephalopathy. Imaging investigations revealed a large mass in the right kidney with extension to the renal hilum. The patient underwent right open radical nephrectomy. The histopathologic study disclosed a 15-cm, myxoid and cellular, pleomorphic tumor with elongated, curvilinear, thin-walled vessels, and focal necrosis that involved the upper and middle segments of the kidney. Immunohistochemically, the tumor cells showed strong positivity for vimentin, bcl2 protein (nuclear staining pattern), CD34, CD99, and alpha-methylacyl coenzyme A racemase. The tumor was diagnosed as myxofibrosarcoma (MFS) grade 2 according to the FNCLCC system. To the best of our knowledge, this is the first report of an MFS arising from the kidney. Thus, MFS is an uncommon soft tissue tumor that can exceptionally arise from the kidney. The differential diagnosis with other myxoid tumors is of vital importance because it includes lesions with subtle differences and extremely variable biological behavior. Radical surgery is the treatment of choice. Long-term follow up is recommended because of the tumor's capability for local recurrence and distant metastasis. PMID- 26008777 TI - Ectopic expression of gastrokine 1 in gastric cancer cells up-regulates tight and adherens junction proteins network. AB - Gastrokine 1 (GKN1) is a stomach-specific protein important in the replenishment of the surface lumen epithelial cell layer and in maintaining mucosal integrity. A role in cell proliferation and differentiation has also been hypothesized. Despite these findings, the function(s) as well as the cellular localization of GKN1 in the cellular machinery are currently not clarified. The investigation of subcellular localization of GKN1 in gastric cancer cells can provide insights into its potential cellular roles. Subcellular fractions of gastric cancer cells (AGS) transfected with full-length GKN1 (flGKN1) or incubated with recombinant GKN1 (rGKN1) lacking the first 20 amino acids at N-terminal were analyzed by Western blot and confocal microscopy and compared with those from normal gastric tissue. Wild type GKN1 (wtGKN1) and flGKN1 were revealed in the cytoplasm and in the membrane fractions of gastric cells, whereas rGKN1 was revealed in the cytoplasmic fractions, but a high amount was detected in the membrane pellet of the AGS lysate. The cellular distribution of GKN1 was also confirmed by confocal microscopy. The purified protein was also used to highlight its possible association with actin through confocal microscopy, pelleting assay, and size exclusion chromatography. GKN1 co-localizes with actin in normal gastric tissue, but no direct interaction was observed between the two proteins in vitro. Most likely, GKN1 indirectly participates in actin stabilization since its overexpression in gastric cancer cells strongly increases the expression of tight and adherens junction proteins. PMID- 26008778 TI - Malignancies arising in allograft kidneys, with a first reported translocation RCC post-transplantation: A case series. AB - BACKGROUND: The increased risk of malignancy in the post-renal transplant population has been well documented. Renal carcinoma is more common in this population, usually arising in native kidneys. Rarely, tumors arise in the transplanted kidney. Our case series reports four cases of malignancy in allograft kidneys, one of which is a first reported case of translocation RCC in a transplanted kidney. METHODS: The renal transplantation database (1584 patients) at St. Michael's Hospital was reviewed for malignancies arising in allograft kidneys: reports and pathology slides were reviewed. RESULTS: Four cases of malignancies arising in the allograft kidney were identified among our kidney transplant population. One patient developed a high grade urothelial carcinoma in the donor kidney post BK virus infection. The other 3 cases were renal cell carcinomas: one clear cell renal cell carcinoma, one translocation renal cell carcinoma, and one papillary renal cell carcinoma. The translocation renal cell cancer had confirmed TFE3 protein over-expression by immunohistochemistry. Molecular testing of the tumors in all 4 cases identified two separate genetic profiles, favored to represent tumors arising from donor tissues along with infiltrating recipient lymphocytes. DISCUSSION: Previous reports suggested that epithelial malignancies in allograft kidneys are rare. We identified 4 such tumors in 1584 transplant patients. Further, we identified the first reported case of translocation RCC in an allograft kidney. While the rate of malignancy in allograft kidneys is low, screening of the donor kidneys by ultrasound and/or urine cytology may be of use in detecting these lesions. PMID- 26008779 TI - Rectal blue nevus: Case report of a rare entity and literature review. AB - Blue nevus, a pigmented skin lesion, affects the dermal melanocytes that are rich in melanin. Its occurrence on skin has been well described in literature. Less commonly, involvement of mucosal surfaces especially genitourinary tract has also been noticed. Here we present a rare case of a blue nevus involving the rectum. So far there has been only one prior description of the blue nevus involving the gastrointestinal mucosa. Differentiation of this lesion from melanoma is the key. Simple excision of the blue nevus with a biopsy forceps during the colonoscopy is an effective management. PMID- 26008780 TI - Effects and mechanism of recombinant human erythropoietin on the growth of human breast cancer MDA-MB-231 cells in nude mice. AB - This study aimed to explore the effects of recombinant human erythropoietin (rhEPO) on the growth of human breast cancer MDA-MB-231 cells in nude mice, and investigate its functions in regulating tumor growth, angiogenesis and apoptosis. A tumor-bearing nude mice model was established by subcutaneous injection of human breast cancer MDA-MB-231 cells. Two weeks later, the mice were randomly divided into four groups (n=6 for each group): negative control group, rhEPO group, EPO antibody group and EPO+EPO antibody group. Drugs were administered to the corresponding mice once every 3 days for five times. The size and weight of tumors were measured after the mice were sacrificed by cervical dislocation. The expression levels of EPO/EPOR, TNF-alpha, IL-10, and Bcl-2 in the tumor tissues were determined using RT-PCR and Western blot. The microvessel density (MVD) and expression of VEGF in the tumors were detected using immunohistochemistry. TUNEL assay was used to determine apoptosis in tumors. Results show that rhEPO significantly promoted the growth of MDA-MB-231 cells in nude mice (P<0.05). Compared with the negative control group, the expression levels of EPO, EPOR, TNF alpha, IL-10, and VEGF, as well as the MVD values, were significantly elevated in the rhEPO group. However, the apoptotic index was significantly reduced (P<0.05). The ability of rhEPO to promote tumor growth may be associated with its functions in promoting microvessel formation and inhibiting tumor cell apoptosis. PMID- 26008781 TI - Nur77 is involved in graft infiltrating T lymphocyte apoptosis in rat cardiac transplantation model. AB - Acute allograft rejection is initiated by a large number of recipient T cells that recognize donor alloantigens. Apoptotic signals trigger Nur77 production. Nur77 translocates from the nucleus to the mitochondria to induce a loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators, including HtrA2/Omi. In this study, we investigated the relationship between Nur77, HtrA2/Omi, and T lymphocyte apoptosis during acute allograft rejection in a rat cardiac transplantation model. The median survival time of the isograft group was longer than that of the allograft group. The cardiac grafts in isogenic (Lewis to Lewis) and allogenic (Wistar to Lewis) models were subjected to HE stain, showing that no rejection occurred in the isografts and that the rejection level was increased in allografts. Compared with the rare expression in syngeneic Lewis rat hearts by western blot analysis, Nur77 protein level in allograft increased from day 1, peaked at day 5 after transplantation, and maintained the highest level until day 7. Double immunofluorescence staining on allograft tissues at day 5 showed Nur77 immunocompetence in most CD3(+) cells, and Nur77 positive T cells also showed HtrA2/Omi-positive signal. Meanwhile, active caspase-3 was apparent in these HtrA2/Omi-positive T cells. Immunohistochemical results suggested that both Nur77 and active caspase-3 were expressed in increasing infiltrating lymphocytes. Our results demonstrated that upregulated Nur77 may promote graft-infiltrating T lymphocyte apoptosis by translocating and inducing HtrA2/Omi release from mitochondria in acute rejection after cardiac transplantation. PMID- 26008782 TI - Glucocorticoid receptor is involved in the breed-dependent transcriptional regulation of 3beta-hydroxysteroid dehydrogenase in the liver of preweaning piglets. AB - BACKGROUND: Hepatic 3beta-hydroxysteroid dehydrogenase (3beta-HSD) plays an important role in steroid inactivation and catabolism. Serum concentrations of steroid hormones differ significantly between breeds in pigs, however the molecular mechanism regulating hepatic 3beta-HSD expression in different breeds of pigs is poorly understood. In the present study, we used preweaning purebred male Large White (LW) and Erhualian (EHL) piglets as model to investigate the breed difference in the expression and regulation of 3beta-HSD gene in porcine liver. RESULTS: The hepatic expression of 3beta-HSD mRNA was significantly lower (P < 0.01) in EHL piglets compared to that in LW piglets. Significant breed differences were detected for the hepatic expression of transcription factors such as androgen receptor (AR), glucocorticoid receptor (GR), and CCAAT/enhancer binding protein beta (C/EBPbeta). The nucleoprotein contents of AR (P < 0.05), GR (P < 0.01) and phospho-Ser(211)GR (P < 0.01) were significantly higher in the liver of EHL piglets. Chromatin immunoprecipitation (ChIP) assay demonstrated significantly lower binding of GR, but not AR or C/EBPbeta, to 3beta-HSD gene promoter in EHL piglets (P < 0.05). GR was not detected to interact with C/EBPbeta or AR in the co-immunoprecipitation analysis. CONCLUSIONS: These results indicate that GR binding to 3beta-HSD promoter is involved in the breed dependent 3beta-HSD expression in the liver of piglets. PMID- 26008784 TI - New insights into the organization of plasma membrane and its role in signal transduction. AB - Plasma membranes have heterogeneous structures for efficient signal transduction, required to perform cell functions. Recent evidence indicates that the heterogeneous structures are produced by (1) compartmentalization by actin-based membrane skeleton, (2) raft domains, (3) receptor-receptor interactions, and (4) the binding of receptors to cytoskeletal proteins. This chapter provides an overview of recent studies on diffusion, clustering, raft association, actin binding, and signal transduction of membrane receptors, especially glycosylphosphatidylinositol (GPI)-anchored receptors. Studies on diffusion of GPI-anchored receptors suggest that rafts may be small and/or short-lived in plasma membranes. In steady state conditions, GPI-anchored receptors form transient homodimers, which may represent the "standby state" for the stable homodimers and oligomers upon ligation. Furthermore, It is proposed that upon ligation, the binding of GPI-anchored receptor clusters to cytoskeletal actin filaments produces a platform for downstream signaling, and that the pulse-like signaling easily maintains the stability of the overall signaling activity. PMID- 26008785 TI - Regulators of G-protein-signaling proteins: negative modulators of G-protein coupled receptor signaling. AB - Regulators of G-protein-signaling (RGS) proteins are a category of intracellular proteins that have an inhibitory effect on the intracellular signaling produced by G-protein-coupled receptors (GPCRs). RGS along with RGS-like proteins switch on through direct contact G-alpha subunits providing a variety of intracellular functions through intracellular signaling. RGS proteins have a common RGS domain that binds to G alpha. RGS proteins accelerate GTPase and thus enhance guanosine triphosphate hydrolysis through the alpha subunit of heterotrimeric G proteins. As a result, they inactivate the G protein and quickly turn off GPCR signaling thus terminating the resulting downstream signals. Activity and subcellular localization of RGS proteins can be changed through covalent molecular changes to the enzyme, differential gene splicing, and processing of the protein. Other roles of RGS proteins have shown them to not be solely committed to being inhibitors but behave more as modulators and integrators of signaling. RGS proteins modulate the duration and kinetics of slow calcium oscillations and rapid phototransduction and ion signaling events. In other cases, RGS proteins integrate G proteins with signaling pathways linked to such diverse cellular responses as cell growth and differentiation, cell motility, and intracellular trafficking. Human and animal studies have revealed that RGS proteins play a vital role in physiology and can be ideal targets for diseases such as those related to addiction where receptor signaling seems continuously switched on. PMID- 26008786 TI - New insights into the role of podoplanin in epithelial-mesenchymal transition. AB - Podoplanin is a small mucin-like transmembrane protein expressed in several adult tissues and with an important role during embryogenesis. It is needed for the proper development of kidneys and lungs as well as accurate formation of the lymphatic vascular system. In addition, it is involved in the physiology of the immune system. A wide variety of tumors express podoplanin, both in the malignant cells and in the stroma. Although there are exceptions, the presence of podoplanin results in poor prognosis. The main consequence of forced podoplanin expression in established and tumor-derived cell lines is an increase in cell migration and, eventually, the triggering of an epithelial-mesenchymal transition, whereby cells acquire a fibroblastoid phenotype and increased motility. We will examine the current status of the role of podoplanin in the induction of epithelial-mesenchymal transition as well as the different interactions that lead to this program. PMID- 26008787 TI - Microtubule-depolymerizing kinesins in the regulation of assembly, disassembly, and length of cilia and flagella. AB - Defects in ciliary assembly, maintenance, and signaling are associated with various human diseases and developmental disorders, termed ciliopathies. Eukaryotic flagella and cilia (interchangeable terms) are microtubule-based organelles. Thus, microtubule dynamics and microtubule-dependent transport are predicted to affect the structural integrity and functionality of cilia profoundly. Kinesin-2 is well known for its role in intraflagellar transport to transport ciliary precursors and signaling molecules. Recently, microtubule depolymerizing kinesins found in kinesin-8, -13, and -14A families have emerged as regulators of cilia. We first discuss ciliary kinesins identified in the flagellar or ciliary proteome, and then focus on the function and regulation of microtubule-depolymerizing kinesins. Lastly, we review the recent advances of microtubule-depolymerizing kinesins in controlling ciliary assembly, disassembly, and length. PMID- 26008788 TI - Nuclear envelope and chromatin, lock and key of genome integrity. AB - More than as an inert separation between the inside and outside of the nucleus, the nuclear envelope (NE) constitutes an active toll, which controls the import and export of molecules, and also a hub for a diversity of genomic processes, such as transcription, DNA repair, and chromatin dynamics. Proteins localized at the inner surface of the NE (such as lamins, nuclear pore proteins, lamin associated proteins) interact with chromatin in a dynamic manner, contributing to the establishment of topological domains. In this review, we address the complex interplay between chromatin and NE. We discuss the divergence of this cross talk during evolution and comment both on the current established models and the most recent findings. In particular, we focus our attention on how the NE cooperates with chromatin in protecting the genome integrity. PMID- 26008789 TI - Role of Ocrl1 in primary cilia assembly. AB - Lowe syndrome is a lethal X-linked genetic disorder characterized by congenital cataracts, mental retardation, and kidney dysfunction. It is caused by mutations in the OCRL1 (oculocerebrorenal syndrome of Lowe) gene that encodes a phosphatidylinositol 5-phosphatase (EC 3.1.3.36). The gene product Ocrl1 has been linked to a multitude of functions due to the central role played by phosphoinositides in signaling. Moreover, this protein also has the ability to bind Rho GTPases, the master regulators of the actin cytoskeleton, and to interact with elements of the vesicle trafficking machinery. It is currently under investigation how deficiencies in Ocrl1 affect these different processes and contribute to patient symptoms. This chapter outlines the known physiological roles of Ocrl1 which might be relevant to the mechanism underlying Lowe syndrome. PMID- 26008783 TI - Oxidative stress, unfolded protein response, and apoptosis in developmental toxicity. AB - Physiological development requires precise spatiotemporal regulation of cellular and molecular processes. Disruption of these key events can generate developmental toxicity in the form of teratogenesis or mortality. The mechanism behind many developmental toxicants remains unknown. While recent work has focused on the unfolded protein response (UPR), oxidative stress, and apoptosis in the pathogenesis of disease, few studies have addressed their relationship in developmental toxicity. Redox regulation, UPR, and apoptosis are essential for physiological development and can be disturbed by a variety of endogenous and exogenous toxicants to generate lethality and diverse malformations. This review examines the current knowledge of the role of oxidative stress, UPR, and apoptosis in physiological development as well as in developmental toxicity, focusing on studies and advances in vertebrates model systems. PMID- 26008790 TI - Editorial: the activity of products from Cnidaria: a therapeutic tool in neurological diseases - part 1. PMID- 26008791 TI - Large conformational fluctuations of the multi-domain xylanase Z of Clostridium thermocellum. AB - The cellulosome is a multi-enzyme machinery which efficiently degrades plant cell wall polysaccharides. The multiple domains of the cellulosome complexes are often tethered to one another by intrinsically disordered regions. The properties and functions of these disordered linkers are unknown to a large extent. In this work, we study the conformational variability of one component of the cellulosome - the multi-domain xylanase Z (XynZ) of Clostridium thermocellum. We use a coarse grained protein model to efficiently simulate conformations of the enzyme. Our simulation results are in excellent agreement with data from small angle X-ray scattering experiments, which validates the simulation outcome. Both in the presence and absence of the cohesin domain, the XynZ enzyme appears to be flexible in the sense that it takes various compact and extended conformations. The physical interactions between the individual domains are rather weak and transient, and the XynZ enzyme is held together mainly by the flexible linkers connecting the domains. The end-to-end distance distributions for the flexible linkers can be rationalized by the excluded volume effect. Taken together, our results provide a detailed picture of the conformational ensemble of the XynZ enzyme in solution. PMID- 26008792 TI - Evolutionary analysis of RB/Rpi-blb1 locus in the Solanaceae family. AB - Late blight caused by the oomycete Phytophthora infestans is one of the most severe threats to potato production worldwide. Numerous studies suggest that the most effective protective strategy against the disease would be to provide potato cultivars with durable resistance (R) genes. However, little is known about the origin and evolutional history of these durable R-genes in potato. Addressing this might foster better understanding of the dynamics of these genes in nature and provide clues for identifying potential candidate R-genes. Here, a systematic survey was executed at RB/Rpi-blb1 locus, an exclusive broad-spectrum R-gene locus in potato. As indicated by synteny analysis, RB/Rpi-blb1 homologs were identified in all tested genomes, including potato, tomato, pepper, and Nicotiana, suggesting that the RB/Rpi-blb1 locus has an ancient origin. Two evolutionary patterns, similar to those reported on RGC2 in Lactuca, and Pi2/9 in rice, were detected at this locus. Type I RB/Rpi-blb1 homologs have frequent copy number variations and sequence exchanges, obscured orthologous relationships, considerable nucleotide divergence, and high non-synonymous to synonymous substitutions (Ka/Ks) between or within species, suggesting rapid diversification and balancing selection in response to rapid changes in the oomycete pathogen genomes. These characteristics may serve as signatures for cloning of late blight resistance genes. PMID- 26008793 TI - Cardiovascular disease risk factor clustering among rural adult population in West Bengal, India. AB - OBJECTIVE: This study aimed to find out the prevalence of cardiovascular disease (CVD) risk factor clustering in a rural adult population of West Bengal, India. METHODS: This cross-sectional study was carried out among 1007 participants (645 males and 362 females) aged >=20 years in a rural community. All participants were grouped: Group I (20-39 years); Group II (40-59 years); Group III (>=60 years). Anthropometric measures were collected using standard techniques. Metabolic profiles and blood pressure were also measured. RESULTS: Mean of minimum waist circumference (MWC), waist-hip ratio (WHR), trunk-extremity ratio (TER), fat free mass (FFM), basal metabolic rate (BMR), intra-abdominal visceral fat (IVF) and arm muscle area (AMA) was found to be higher among males in comparison to females, whereas, the mean of body mass index (BMI), maximum hip circumference (MHC), waist-height ratio (WHtR), sum of four skinfolds (?SF4), percentage of body fat (%BF), fat mass (FM), insulin, HOMA-IR and arm fat area (AFA) was higher in females. 37% of individuals (males 25% and females 49%) with high triglyceride (TG) also had low high density lipoprotein (HDL), whereas, 25% individuals (males 25% and females 24%) with overweight also had high fasting blood glucose (FBG). The prevalence of high systolic blood pressure (SBP) among individuals having high %BF was higher in the age groups of 40-59 years for both sexes. CONCLUSION: The study showed that prevalence of CVD risk factor clustering is high in the study population and warranted early intervention to safeguard the cardiovascular health of the nation. PMID- 26008794 TI - Hydrogen peroxide generation and antioxidant enzyme activities in the leaves and roots of wheat cultivars subjected to long-term soil drought stress. AB - The dynamics of the activity of catalase, ascorbate peroxidase, guaiacol peroxidase, and benzidine peroxidase, as well as the level of hydrogen peroxide in the vegetative organs of durum wheat (Triticum durum Desf.) cultivars was studied under long-term soil drought conditions. It was established that hydrogen peroxide generation occurred at early stages of stress in the tolerant variety Barakatli-95, whereas in the susceptible variety Garagylchyg-2 its significant amounts were accumulated only at later stages. Garagylchyg-2 shows a larger reduction of photochemical activity of PS II in both genotypes at all stages of ontogenesis under drought stress than Barakatli-95. The highest activity of catalase which plays a leading role in the neutralization of hydrogen peroxide was observed in the leaves and roots of the drought-tolerant variety Barakatli 95. Despite the fact that the protection system also includes peroxidases, the activity of these enzymes even after synthesis of their new portions is substantially lower compared with catalase. Native PAGE electrophoresis revealed the presence of one isoform of CAT, seven isoforms of APX, three isoforms of GPO, and three isoforms of BPO in the leaves, and also three isoforms of CAT, four isoforms of APX, two isoforms of GPO, and six isoforms of BPO in the roots of wheat. One isoform of CAT was found in the roots when water supply was normal and three isoforms were observed under drought conditions. Stress associated with long-term soil drought in the roots of wheat has led to an increase in the heterogeneity due to the formation of two new sedentary forms of catalase: CAT2 and CAT3. PMID- 26008796 TI - Assessing silver nanoparticles behaviour in artificial seawater by mean of AF4 and spICP-MS. AB - The use of nanotechnology-based products is constantly increasing and there are concerns about the fate and effect on the aquatic environment of antimicrobial products such as silver nanoparticles. By combining different characterization techniques (asymmetric flow field-flow fractionation, single particle ICP-MS, UV Vis) we show that it is possible to assess in detail the agglomeration process of silver nanoparticles in artificial seawater. In particular we show that the presence of alginate or humic acid differentially affects the kinetic of the agglomeration process. This study provides an experimental methodology for the in depth analysis of the fate and behaviour of silver nanoparticles in the aquatic environment. PMID- 26008797 TI - Scaling of anomalous Hall effects in facing-target reactively sputtered Fe4N films. AB - The anomalous Hall effect (AHE) in the reactively sputtered epitaxial and polycrystalline gamma'-Fe4N films is investigated systematically. The Hall resistivity is positive over the entire temperature range. The magnetization, carrier density and grain boundary scattering have a major impact on the AHE scaling law. The scaling exponent gamma in the conventional scaling of rhoAH ? rho(gamma)(xx) is larger than 2 in both the epitaxial and polycrystalline gamma' Fe4N films. Although gamma > 2 has been found in heterogeneous systems due to the effects of the surface and interface scattering on AHE, gamma > 2 is not expected in homogenous epitaxial systems. We demonstrated that gamma > 2 results from residual resistivity (rhoxx0) in gamma'-Fe4N films. Furthermore, the side-jump and intrinsic mechanisms are dominant in both epitaxial and polycrystalline samples according to the proper scaling relation. PMID- 26008795 TI - Dysfunctional chloroplasts up-regulate the expression of mitochondrial genes in Arabidopsis seedlings. AB - Chloroplasts and mitochondria play important roles in maintaining metabolic and energy homeostasis in the plant cell. The interactions between these two organelles, especially photosynthesis and respiration, have been intensively studied. Still, little is known about the regulation of mitochondrial gene expression by chloroplasts and vice versa. The gene expression machineries in chloroplasts and mitochondria rely heavily on the nuclear genome. Thus, the interactions between nucleus and these organelles, including anterograde and retrograde regulation, have been actively investigated in the last two decades. Norflurazon (NF) and lincomycin (Lin) are two commonly used inhibitors to study chloroplast-to-nucleus retrograde signaling in plants. We used NF and Lin to block the development and functions of chloroplasts and examined their effects on mitochondrial gene expression, RNA editing and splicing. The editing of most mitochondrial transcripts was not affected, but the editing extents of nad4-107, nad6-103, and ccmFc-1172 decreased slightly in NF- and Lin-treated seedlings. While the splicing of mitochondrial transcripts was not significantly affected, steady-state mRNA levels of several mitochondrial genes increased significantly in NF- and Lin-treated seedlings. Moreover, Lin seemed to have more profound effects than NF on the expression of mitochondrial genes, indicating that signals derived from these two inhibitors might be distinct. NF and Lin also significantly induced the expression of nuclear genes encoding subunits of mitochondrial electron transport chain complexes. Thus, dysfunctional chloroplasts may coordinately up-regulate the expression of nuclear and mitochondrial genes encoding subunits of respiratory complexes. PMID- 26008798 TI - Composite silica coated gold nanosphere and quantum dots nanoparticles for X-ray CT and fluorescence bimodal imaging. AB - In this study, silica coated Au nanospheres (Au@SiO2) were prepared by a reverse microemulsion method; subsequently, a layer of fluorescent quantum dots (QDs) were adsorbed onto it and then it was coated with silica again. After modifying with PVP, the composite silica coated gold nanosphere and quantum dots nanoparticle (Au@SiO2-QDs/SiO2-PVP) was obtained. This composite structure contained Au and QDs, and it could be used for contrast-enhanced X-ray CT imaging and fluorescence imaging. Characterization showed that the composite nanoparticle had good dispersity, a high fluorescence intensity and a good effect of X-ray absorption, and it was suitable for using as a bimodal imaging probe. PMID- 26008799 TI - Expression and localisation of c-kit and KITL in the adult human ovary. AB - BACKGROUND: The c-kit/kit ligand (KITL) signalling axis is an essential component of ovarian folliculogenesis in mammals, but little is known about expression and localisation of its key components in the ovaries of reproductive age women. This study aimed to characterise mRNA expression of c-kit and KITL isoforms and the localisation of c-kit and KITL proteins in adult human premenopausal ovaries. METHODS: This study utilised granulosa cells obtained from the preovulatory follicles of women undergoing assisted reproduction, pieces of ovarian tissue obtained from premenopausal women undergoing gynaecological surgeries and archival paraffin-embedded premenopausal ovarian tissues. Methodology included PCR for gene expression and Western blot or immunohistochemistry for protein expression. RESULTS: Both c-kit mRNA isoforms, known as GNNK+ and GNNK-, were detected in human ovarian cortex, while KITL protein isoforms (KITL1 and KITL2) were present in ovarian cortex and human granulosa cells. Immunohistochemistry showed expression of KITL and c-kit protein in multiple cell types within follicles throughout development, from primordial follicles to large antral follicles, in addition to atretic follicles. Oocytes of all follicle stages expressed c-kit protein exclusively. Interestingly, unlike animal models, expression of both proteins displayed a less cell-type specific distribution with immunostaining present in granulosa, theca and stromal cells, suggesting that autocrine signalling occurs within the human ovary. CONCLUSION: The results of this study indicate that c-kit/KITL signalling also occurs in the human ovary, as established in various animal models, and may involve previously unknown autocrine signalling. PMID- 26008801 TI - Effect of Two- Versus Three-Way Split Resistance Training Routines on Body Composition and Muscular Strength in Bodybuilders: A Pilot Study. AB - The purpose of this study was to compare different split resistance training routines on body composition and muscular strength in elite bodybuilders. Ten male bodybuilders (26.7 +/- 2.7 years, 85.3 +/- 10.4 kg) were randomly assigned into one of two resistance training groups: 4 and 6 times per week (G4* and G6*, respectively), in which the individuals trained for 4 weeks, 4 sets for each exercise performing 6-12 repetitions maximum (RM) in a pyramid fashion. Body composition was assessed by dual energy X-ray absorptiometry, muscle strength was evaluated by 1RM bench-press testing. The food intake was planned by nutritionists and offered individually throughout the duration of the experiment. Significant increases (p < .05) in fat-free mass (G4* = +4.2%, G6* = +3.5%) and muscular strength (G4* = +8.4%, G6* = +11.4%) with no group by time interaction were observed. We conclude that 4 and 6 weekly sessions frequencies of resistance training promote similar increases in fat-free mass and muscular strength in elite bodybuilders. PMID- 26008800 TI - Vehicular Traffic-Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP). AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure. OBJECTIVES: Our study aim was to evaluate the association between residential exposure to vehicular traffic and breast cancer incidence. METHODS: Residential histories of 1,508 participants with breast cancer (case participants) and 1,556 particpants with no breast cancer (control participants) were assessed in a population-based investigation conducted in 1996-1997. Traffic exposure estimates of benzo[a]pyrene (B[a]P), as a proxy for traffic-related PAHs, for the years 1960-1995 were reconstructed using a model previously shown to generate estimates consistent with measured soil PAHs, PAH-DNA adducts, and CO readings. Associations between vehicular traffic exposure estimates and breast cancer incidence were evaluated using unconditional logistic regression. RESULTS: The odds ratio (95% CI) was modestly elevated by 1.44 (0.78, 2.68) for the association between breast cancer and long-term 1960-1990 vehicular traffic estimates in the top 5%, compared with below the median. The association with recent 1995 traffic exposure was elevated by 1.14 (0.80, 1.64) for the top 5%, compared with below the median, which was stronger among women with low fruit/vegetable intake [1.46 (0.89, 2.40)], but not among those with high fruit/vegetable intake [0.92 (0.53, 1.60)]. Among the subset of women with information regarding traffic exposure and tumor hormone receptor subtype, the traffic-breast cancer association was higher for those with estrogen/progesterone negative tumors [1.67 (0.91, 3.05) relative to control participants], but lower among all other tumor subtypes [0.80 (0.50, 1.27) compared with control participants]. CONCLUSIONS: In our population-based study, we observed positive associations between vehicular traffic-related B[a]P exposure and breast cancer incidence among women with comparatively high long-term traffic B[a]P exposures, although effect estimates were imprecise. CITATION: Mordukhovich I, Beyea J, Herring AH, Hatch M, Stellman SD, Teitelbaum SL, Richardson DB, Millikan RC, Engel LS, Shantakumar S, Steck SE, Neugut AI, Rossner P Jr., Santella RM, Gammon MD. 2016. Vehicular traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence: the Long Island Breast Cancer Study Project (LIBCSP). Environ Health Perspect 124:30-38; http://dx.doi.org/10.1289/ehp.1307736. PMID- 26008802 TI - Rapid electrochemical phenotypic profiling of antibiotic-resistant bacteria. AB - Rapid phenotyping of bacteria to identify drug-resistant strains is an important capability for the treatment and management of infectious disease. At present, the rapid determination of antibiotic susceptibility is hindered by the requirement that, in existing devices, bacteria must be pre-cultured for 2-3 days to reach detectable levels. Here we report a novel electrochemical approach that achieves rapid readout of the antibiotic susceptibility profile of a bacterial infection within one hour. The electrochemical reduction of a redox-active molecule is monitored that reports on levels of metabolically-active bacteria. Bacteria are captured in miniaturized wells, incubated with antimicrobials and monitored for resistance. This electrochemical phenotyping approach is effective with clinically-relevant levels of bacteria, and provides results comparable to culture-based analysis. Results, however, are delivered on a much faster timescale, with resistance profiles available after a one hour incubation period. PMID- 26008803 TI - Non-alcoholic fatty liver disease associated with increased arterial stiffness in subjects with normal glucose tolerance, but not pre-diabetes and diabetes. AB - AIM: To evaluate the association between non-alcoholic fatty liver disease and arterial stiffness in adults with normal glucose tolerance, pre-diabetes and newly diagnosed diabetes after excluding known diabetes. METHODS: A total of 4860 subjects were divided into normal glucose tolerance, pre-diabetes and newly diagnosed diabetes groups according to the American Diabetes Association 2011 diagnostic criteria. The severity of non-alcoholic fatty liver disease was divided into mild and moderate to severe. Increased arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) ? 1400 cm/s. RESULTS: There was a significant difference in the prevalence of mild and moderate to severe non alcoholic fatty liver disease between subjects with and without increased arterial stiffness. Mild (odds ratio (OR) = 2.02, 95% confidence interval (CI) = 1.43-2.84) and moderate to severe (OR = 2.15, 95% CI = 1.33-3.46) non-alcoholic fatty liver disease were independently associated with increased arterial stiffness in the normal glucose tolerance group. In the pre-diabetes and diabetes groups, neither mild nor moderate to severe non-alcoholic fatty liver disease was associated with increased arterial stiffness. CONCLUSION: The effect of non alcoholic fatty liver disease on arterial stiffness is apparent in subjects with normal glucose tolerance, but not in diabetes and pre-diabetes. PMID- 26008804 TI - Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. AB - The effect of dapagliflozin on blood pressure was evaluated in non-hypertensive (<140 mm Hg) and hypertensive (?140 mm Hg) patients with type 2 diabetes mellitus. Data were pooled from 13 placebo-controlled studies. Patients received dapagliflozin 10 mg/day (n = 2360) or placebo (n = 2295) for up to 24 weeks. Dapagliflozin was associated with placebo-subtracted changes from baseline in systolic and diastolic blood pressures of -3.6 and -1.2 mm Hg, respectively, in hypertensive patients and -2.6 and -1.2 mm Hg, respectively, in non-hypertensive patients. At 24 weeks, a similar proportion of patients experienced measured orthostatic reactions with dapagliflozin versus placebo in hypertensive (6.1% and 6.6%, respectively) and non-hypertensive (4.0% and 4.2%) patients. No clinically relevant difference was observed between dapagliflozin and placebo in heart rate. In conclusion, dapagliflozin 10 mg induces a modest reduction in blood pressure compared with placebo in patients with diabetes with a low risk of orthostatic reactions, regardless of baseline blood pressure. PMID- 26008805 TI - The opposite gating behaviors of solid-state nanochannels modified with long and short polymer chains. AB - The influence of long and short polymer chains on the gating properties of nanochannel systems modified with a NIPAAm-co-PBA copolymer have been explored. We not only discovered the negative temperature gating behavior of the NIPAAm modified nanochannel systems for the first time, but also achieve these two fully opposite gating behaviors (negative/positive) on the same platform. PMID- 26008806 TI - Retraction: N, S co-doped graphene quantum dots from a single source precursor used for photodynamic cancer therapy under two-photon excitation. PMID- 26008808 TI - The neurology of solid organ transplantation. AB - Transplantation is the rescue treatment for end-stage organ failure with more than 110,000 solid organs transplantations performed worldwide annually. Recent advances in transplantation procedures and posttransplantation management have improved long-term survival and quality of life of transplant recipients, shifting the focus from acute perioperative critical care needs toward long-term chronic medical problems. Neurologic complications affect up to 30-60 % of solid organ transplant recipients. Common etiologies include opportunistic infections and toxicities of antirejection medications, and wide spectrum of toxic and metabolic disturbances. Most complications are common to all allograft types, but some are relatively specific for individual allograft types (e.g., central pontine myelinolysis in liver transplant recipients). Close collaboration between neurologists and other transplant team members is essential for effective management. Early recognition of complications and accurate diagnosis leading to timely treatment is essential to reduce the morbidity and improve the overall transplant outcome. PMID- 26008807 TI - The genetics of the epilepsies. AB - While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling. PMID- 26008809 TI - Retinal Vascular Changes are a Marker for Cerebral Vascular Diseases. AB - The retinal circulation is a potential marker of cerebral vascular disease because it shares origin and drainage with the intracranial circulation and because it can be directly visualized using ophthalmoscopy. Cross-sectional and cohort studies have demonstrated associations between chronic retinal and cerebral vascular disease, acute retinal and cerebral vascular disease, and chronic retinal vascular disease and acute cerebral vascular disease. In particular, certain qualitative features of retinopathy, retinal artery occlusion, and increased retinal vein caliber are associated with concurrent and future cerebrovascular events. These associations persist after accounting for confounding variables known to be disease-causing in both circulations, which supports the potential use of retinal vasculature findings to stratify individuals with regards to cerebral vascular disease risk. PMID- 26008810 TI - The relationship between atrophy and hypometabolism: is it regionally dependent in dementias? AB - Neuronal failure leading to dementia in neurodegenerative diseases is evidenced in vivo by functional and structural changes in the brain such as reductions of glucose consumption and volume of grey matter. The earliest phase of cognitive decline and presymptomatic stages of these diseases are heralded by specific patterns of hypometabolism, even in the absence of atrophy, which are currently considered as diagnostic biomarkers. Atrophy is less consistently found as an initial marker of these diseases and is invariably present in moderate to severe stages with a disease-related topography. The relationship between these two markers is not uniform, but in the two diseases in which they have been directly compared, Alzheimer's and Parkinson's disease, altered hypometabolism precedes and exceeds atrophy in most regions. This suggests a two-step degenerative process. In contrast to these findings, the hippocampus skips this pattern and is more structurally than functionally affected, thereby suggesting a different pathological mechanism in this particular area. More studies are needed to disentangle the mechanisms underlying both markers and their relationship in neurodegenerative diseases. PMID- 26008811 TI - Treatment of chronic inflammatory demyelinating polyneuropathy. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is one of the acquired demyelinating neuropathies and is considered to be immune mediated. Diagnosis is typically based on clinical history, neurologic examination, electrophysiologic studies, CSF studies, and pathologic examination. Early diagnosis and treatment is important to prevent irreversible axonal loss and optimize improvement in function. The first-line agents for treatment are intravenous immunoglobulin (IVIg), corticosteroids, and plasmapheresis, which have all been demonstrated to be effective in controlled studies. Studies have not shown a significant difference between these three treatments, and the initial choice of therapy is often based on availability, cost, ease of administration, and side effect profile. If patients do not respond to one of these agents, they may respond to one of the others and sometimes in combination. If the first-line agents are not effective, chemotherapeutic or immunosuppressive agents may be considered. There are limited controlled studies of these modalities, and they are often used in conjunction with a first-line treatment. The majority of patients require long term therapy to maintain a response and to prevent relapse. PMID- 26008812 TI - LRRK2 Pathways Leading to Neurodegeneration. AB - Mutations in LRRK2 are associated with inherited Parkinson's disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the pathophysiology of PD. PMID- 26008813 TI - Neuromuscular issues in systemic disease. AB - The neuromuscular system can be involved in several systemic conditions. Clinical manifestations can appear at onset or throughout the course of the disease process. New investigational methods, including imaging of peripheral nerves, new laboratory tests, and antibodies, are available. In addition to symptomatic therapies, specific treatment options, such as for familial amyloid neuropathy and Fabry's disease, are becoming increasingly available. Pathomechanisms vary depending on the underlying disease process. In addition to metabolic, hormonal, immune, and antibody-mediated mechanisms, in some generalized diseases, genetic causes need to be considered. This review focuses on different aspects of the peripheral nervous system including the nerve roots, plexuses, mononeuropathies and generalized neuropathies, neuromuscular junction disorders, muscle, and autonomic nervous system. PMID- 26008814 TI - Developments in the role of transcranial sonography for the differential diagnosis of parkinsonism. AB - In the last two decades transcranial sonography (TCS) has developed as a valuable, supplementary tool in the diagnosis and differential diagnosis of movement disorders. In this review, we highlight recent evidence supporting TCS as a reliable method in the differential diagnosis of parkinsonism, combining substantia nigra (SN), basal ganglia and ventricular system findings. Moreover, several studies support SN hyperechogenicity as one of most important risk factors for Parkinson's disease (PD). The advantages of TCS include short investigation time, low cost and lack of radiation. Principal limitations are still the dependency on the bone window and operator experience. New automated algorithms may reduce the role of investigator skill in the assessment and interpretation, increasing TCS diagnostic reliability. Based on the convincing evidence available, the EFNS accredited the method of TCS a level A recommendation for supporting the diagnosis of PD and its differential diagnosis from secondary and atypical parkinsonism. An increasing number of training programmes is extending the use of this technique in clinical practice. PMID- 26008815 TI - Psychotic symptoms in frontotemporal dementia. AB - Although psychotic features have long been recognized in association with frontotemporal dementia (FTD), recent genetic discoveries enabling further subtyping of FTD have revealed that psychotic symptoms are frequent in some forms of FTD. Hallucinations and delusions can even precede onset of other cognitive or behavioural symptoms in patients with FTD. In this review, we explore the frequency and types of psychotic symptoms reported in patients with FTD, as well as in other neuropsychiatric disorders, to aid practitioners' consideration of these features in the diagnosis of FTD and related disorders. PMID- 26008816 TI - Neuroscience of aphasia recovery: the concept of neural multifunctionality. AB - Aphasia therapy, while demonstrably successful, has been limited by its primary focus on language, with relatively less attention paid to nonlinguistic factors (cognitive, affective, praxic) that play a major role in recovery from aphasia. Neuroscientific studies of the past 15-20 years have opened a breach in the wall of traditional clinico-anatomical teachings on aphasia. It is not an exaggeration to talk of a paradigm shift. The term "neural multifunctionality" denotes a complex web of neural networks supporting both linguistic and nonlinguistic functions in constant and dynamic interaction, creating language as we know it and contributing to recovery from aphasia following brain damage. This paper reviews scientific underpinnings of neural multifunctionality and suggests ways in which this new approach to understanding the neural basis of language can lead to meaningful, practical steps for improvements in aphasia therapy. PMID- 26008818 TI - Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. AB - Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes. Autosomal recessive HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP; complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations. In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders. PMID- 26008819 TI - Clinical implications of neuropharmacogenetics. AB - INTRODUCTION: Pharmacogenetics aims to identify the underlying genetic factors participating in the variability of drug response. Indeed, genetic variability at the DNA or RNA levels can directly or indirectly modify the pharmacokinetic or the pharmacodynamic parameters of a drug. The ultimate aim of pharmacogenetics is to move towards a personalised medicine by predicting responders and non responders, adjusting the dose of the treatment, and identifying individuals at risk of adverse drug effects. METHODS: A literature research was performed in which we reviewed all pharmacogenetic studies in neurological disorders including neurodegenerative diseases, multiple sclerosis, stroke and epilepsy. RESULTS: Several pharmacogenetic studies have been performed in neurology, bringing insights into the inter-individual drug response variability and in the pathophysiology of neurological diseases. The principal implications of these studies for the management of patients in clinical practice are discussed. CONCLUSION/DISCUSSION: Although several genetic factors have been identified in the modification of drug response in neurological disorders, most of them have a marginal predictive effect at the single gene level, suggesting mutagenic interactions as well as other factors related to drug interaction and disease subtypes. Most pharmacogenetic studies deserve further replication in independent populations and, ideally, in pharmacogenetic clinical trials to demonstrate their relevance in clinical practice. PMID- 26008817 TI - What does imaging reveal about the pathology of amyotrophic lateral sclerosis? AB - Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre symptomatic landscape. PMID- 26008821 TI - Correction to "Improving Paclitaxel Delivery: In Vitro and In Vivo Characterization of PEGylated Polyphosphoester-Based Nanocarriers". PMID- 26008820 TI - Fast-digestive protein supplement for ten days overcomes muscle anabolic resistance in healthy elderly men. AB - BACKGROUND/OBJECTIVE: Adequate protein intake is crucial to maintain muscle protein content in elderly subjects, but quality of dietary proteins should be considered. The aim was to determine whether soluble milk protein offers an original strategy to increase muscle anabolism in elderly subjects via a synergistic effect of fast-digesting proteins together with a unique essential AA content. DESIGN: We investigated the effect of a 10-day adequate-protein (AP) or high-protein (HP) diet together with the protein source as caseins (CAS) or soluble milk proteins (PRO) on specific muscle protein fractional synthesis rates (FSRs) in healthy elderly men (71.8 +/- 2.4 yr, n = 31). The isotopic study consisted of two periods of 4 h each: a post-absorptive and a postprandial period. The fed state was defined by consumption of either 15 g or 30 g of PRO or CAS, given fractionally every 20 min for 4 h. Soluble milk proteins are produced using a membrane process directly from pasteurized milk. MEASUREMENTS: Specific muscle protein FSRs were measured during both postabsorptive and postprandial period using a continuous infusion of l-[1-(13)C]leucine. RESULTS: FSR of sarcoplasmic muscle proteins and actin did not increase significantly in the postprandial state compared to postabsorptive state, whereas myosin FSR rate was increased by feeding whatever the protein source in HP groups (0.024 +/- 0.005 vs 0.053 +/- 0.011% h(-1), P < 0.05 and 0.026 +/- 0.004 vs 0.050 +/- 0.005% h(-1), P < 0.004 for PRO HP and CAS HP) but only with the PRO meal in the AP groups (0.031 +/- 0.003 vs 0.062 +/- 0.009% h(-1), P < 0.03 for PRO AP). Mitochondrial muscle protein FSR was also increased by feeding, irrespective of the protein quantity, but only in PRO meal groups (P < 0.02). CONCLUSION: Fast-digesting soluble milk proteins improved postprandial muscle protein synthesis, especially mitochondrial muscle proteins and myosin fractional synthesis rates, in elderly subjects. PMID- 26008822 TI - Nrf2 inducer and cncC overexpression attenuates neurodegeneration due to alpha synuclein in Drosophila. AB - The study of the genes that are related to the pathogenesis of Parkinson's disease (PD) will improve our understanding of the mechanisms that underlie the development of PD. alpha-Synuclein is a major protein component of Lewy bodies, which are characteristic structures of PD pathology. Mutations in alpha-synuclein are closely related to the early onset of autosomal dominant PD. Transgenic flies with mutant alpha-synuclein (A53T) display neurodegenerative changes that include movement dysfunctions and a loss of dopaminergic neurons in the brain. In the present study, we measured reactive oxygen species (ROS) levels in alpha synuclein transgenic flies by monitoring the fluorescence levels of redox sensitive indicators based on GFP (roGFP) in flies co-expressing roGFP and mutant alpha-synuclein. We found that the ROS levels were significantly increased in the mutant alpha-synuclein flies. The elevations in ROS levels were also proportionate to the behavioral disorders and the losses of dopaminergic neurons. We also found that CDDO-Me inhibited the increases in ROS levels in the A53T flies and improved the neurodegenerative changes by activating the Nrf2/antioxidant response element signaling pathway. Selective expression of the Nrf2 homologous gene cncC in the dopaminergic neurons effectively protected against the neurodegenerative phenotype of the A53T alpha-synuclein flies, compared to the flies that expressed cncC in all neurons. These results indicate that the reductions in oxidative stress that are mediated by the activation of the antioxidant signaling pathway can effectively attenuate the neurotoxicity caused by mutations in alpha-synuclein. PMID- 26008823 TI - The Ebola endgame, and what comes after. PMID- 26008824 TI - From the big three to the big four. PMID- 26008825 TI - Approaches to demonstration of Ebola virus vaccine efficacy. PMID- 26008826 TI - Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. PMID- 26008827 TI - Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. PMID- 26008828 TI - Ebola: the real lessons from HIV scale-up. PMID- 26008829 TI - Ebola: the real lessons from HIV scale-up. PMID- 26008830 TI - Global extent of chloroquine-resistant Plasmodium vivax. PMID- 26008831 TI - Global extent of chloroquine-resistant Plasmodium vivax. PMID- 26008832 TI - Global extent of chloroquine-resistant Plasmodium vivax - Authors' reply. PMID- 26008833 TI - Infectious causes of stroke. PMID- 26008834 TI - Infectious causes of stroke. PMID- 26008835 TI - Hepatitis A outbreaks. PMID- 26008836 TI - Ethics of HIV research in children. PMID- 26008837 TI - Hepatitis A outbreaks. PMID- 26008838 TI - HIV/AIDS registration in Pakistan. PMID- 26008839 TI - India's budget reduction and AIDS initiatives. PMID- 26008840 TI - India tackles vaccine preventable diseases. PMID- 26008841 TI - Highlights from the 25th ECCMID. PMID- 26008842 TI - Re-emergence of neglected tropical diseases in Venezuela. PMID- 26008845 TI - Bilateral conjunctival swelling after dental extraction. PMID- 26008847 TI - Recent developments and applications of the Cadiot-Chodkiewicz reaction. AB - The classical heterocoupling of a 1-haloalkyne with a terminal alkyne catalyzed by copper salts in the presence of a base for the synthesis of unsymmetrical diynes is termed the Cadiot-Chodkiewicz coupling reaction. The diynes are of great importance due to their biological, optical and electronic properties. A number of modifications have been developed recently to improve the efficiency of Cadiot-Chodkiewicz coupling reactions in terms of selectivity and yield. This is the first review on the Cadiot-Chodkiewicz cross-coupling reaction which highlights the modern approaches and protocols developed for the synthesis and applications of unsymmetrical 1,3-diynes. PMID- 26008846 TI - Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems. AB - BACKGROUND: Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized. METHODS: In this study, we use publically available ChIP-Seq data on regulatory factor binding in order to link transcription factors to gene signatures defining molecular subtypes of urothelial carcinoma. RESULTS: We identify PPARG and STAT3, as well as ADIRF, a novel regulator of fatty acid metabolism, as putative mediators of the SCC-like phenotype. We link the PLK1-FOXM1 axis to the rapidly proliferating Genomically Unstable and SCC-like subtypes and show that differentiation programs involving PPARG/RXRA, FOXA1/GATA3 and HOXA/HOXB are differentially expressed in UC molecular subtypes. We show that gene signatures and regulatory systems defined in urothelial carcinoma operate in breast cancer in a subtype specific manner, suggesting similarities at the gene regulatory level of these two tumor types. CONCLUSIONS: At the gene regulatory level Urobasal, Genomically Unstable and SCC like tumors represents three fundamentally different tumor types. Urobasal tumors maintain an apparent urothelial differentiation axis composed of PPARG/RXRA, FOXA1/GATA3 and anterior HOXA and HOXB genes. Genomically Unstable and SCC-like tumors differ from Urobasal tumors by a strong increase of proliferative activity through the PLK1-FOXM1 axis operating in both subtypes. However, whereas SCC-like tumors evade urothelial differentiation by a block in differentiation through strong downregulation of PPARG/RXRA, FOXA1/GATA3, our data indicates that Genomically Unstable tumors evade differentiation in a more dynamic manner. PMID- 26008848 TI - Nurses' adherence to ethical codes: The viewpoints of patients, nurses, and managers. AB - BACKGROUND: Ethical codes are guidelines that orient nurses and ensure that their decisions are in accordance with the values of the professional system. These codes show that there is a connection among values, patients' rights, and nurses' duties. OBJECTIVES: This study aimed to compare the viewpoints of patients, nurses, and nurse managers regarding the extent to which clinical ethical codes are observed. RESEARCH DESIGN: In this descriptive-comparative study, data were collected using three questionnaires based on Iranian nurses' ethical codes with a focus on clinical care. The reliability of the questionnaire was verified by test-retest method (r = 0.9). The patients were interviewed by the researcher, but nurses and managers completed the questionnaires themselves. After all, the data were analyzed using the SPSS statistical software (v 15). PARTICIPANTS AND RESEARCH CONTEXT: In all, 100 patients, 100 nurses, and 30 managers from internal and surgical wards of two major hospitals in Shiraz, Iran, participated in 2014. ETHICAL CONSIDERATIONS: This research was approved by the Ethics Committee of Shiraz University of Medical Sciences. All the participants signed written informed consents. FINDINGS: According to the results, 70% of the patients, 86% of the nurses, and 53.3% of the nurse managers rated nurses' adherence to ethical codes as satisfactory. The mean scores (standard deviation) of the level of adherence to ethical codes were 38.44 (6.91) in the patients, 41.08 (4.82) in the nurses, and 37.83 (6.98) in the nurse managers. The results of analysis of variance revealed a significant difference between the attitudes of the nurses and the other two groups (p = 0.001). DISCUSSION: Nurses' adherence to ethical codes was satisfactory in all three groups. Accordingly, our findings agree with the results of some national and international studies, although there are still controversies in this regard. CONCLUSION: Although the nurses rated their performance in certain fields more satisfactory compared to the patients and managers, all the three groups agreed that clinical ethical codes were properly observed in the internal and surgical wards. Nurses can improve the quality of care by considering the viewpoints of patients and managers about their ethical performance. PMID- 26008849 TI - Educating for ethical leadership through web-based coaching. AB - BACKGROUND: Ethical leadership is important for developing ethical healthcare practice. However, there is little research-based knowledge on how to stimulate and educate for ethical leadership. OBJECTIVES: The aim was to develop and investigate the feasibility of a 6-week web-based, ethical leadership educational programme and learn from participants' experience. Training programme and research design: A training programme was developed consisting of (1) a practice part, where the participating middle managers developed and ran an ethics project in their own departments aiming at enhancing the ethical mindfulness of the organizational culture, and (2) a web-based reflection part, including online reflections and coaching while executing the ethics project. Focus group interviews were used to explore the participants' experiences with and the feasibility of the training. Participants and research context: Nine middle managers were recruited from a part-time master's programme in leadership in Oslo, Norway. The research context was the participating leaders' work situation during the 6 weeks of training. Ethical considerations: Participation was voluntary, data anonymized and the confidentiality of the participating leaders/students and their institutions maintained. No patient or medical information was involved. FINDINGS: Eight of the nine recruited leaders completed the programme. They evaluated the training programme as efficient and supportive, with the written, situational feedback/coaching as the most important element, enhancing reflection and motivation, counteracting a feeling of loneliness and promoting the execution of change. DISCUSSION: The findings seem consistent with the basic assumptions behind the educational design, based partly on e-health research, feedback studies and organizational ethics methodology, partly on theories on workplace learning, reflection, recognition and motivation. CONCLUSION: The training programme seems feasible. It should be adjusted according to participants' proposals and tested further in a large-scale study. PMID- 26008850 TI - Ultrasensitive and Fast Voltammetric Determination of Iron in Seawater by Atmospheric Oxygen Catalysis in 500 MUL Samples. AB - A new method based on adsorptive cathodic stripping voltammetry with catalytic enhancement for the determination of total dissolved iron in seawater is reported. It was demonstrated that iron detection at the ultratrace level (0.1 nM) may be achieved in small samples (500 MUL) with high sensitivity, no need for purging, no added oxidant, and a limit of detection of 5 pM. The proposed method is based on the adsorption of the complex Fe/2,3-dihydroxynaphthalene (DHN) exploiting the catalytic effect of atmospheric oxygen. As opposite to the original method (Obata, H.; van den Berg, C. M. Anal. Chem. 2001, 73, 2522-2528), atmospheric oxygen dissolved in solution replaced bromate ions in the oxidation of the iron complex: removing bromate reduces the blank level and avoids the use of a carcinogenic species. Moreover, the new method is based on a recently introduced hardware that enables the determinations to be performed in 500 MUL samples. The analyses were carried out on buffered samples (pH 8.15, HEPPS 0.01 M), 10 MUM DHN and iron quantified by the standard addition method. The sensitivity is 49 nA nM(-1) min(-1) with 30 s deposition time and the LOD is equal to 5 pM. As a result, the whole procedure for the quantification of iron in one sample requires around 7.5 min. The new method was validated via analysis on two reference samples (SAFe S and SAFe D2) with low iron content collected in the North Pacific Ocean. PMID- 26008851 TI - Fabrication and photoelectric properties of La-doped p-type ZnO nanofibers and crossed p-n homojunctions by electrospinning. AB - La-doped p-type ZnO nanofibers were successfully synthesized by electrospinning, followed by calcination. The microstructure and morphology of the La-doped ZnO nanofibers were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy. The field effect curve of individual nanofibers confirms that the resulting La doped ZnO fibers are p-type semiconductors. The doping mechanism is discussed. Furthermore, crossed p-n homojunction nanofibers were also prepared based on electrospun La-doped p-type ZnO and n-type pure ZnO fibers. The current-voltage curve shows the typical rectifying characteristic of a p-n homojunction device. The turn-on voltage appears at about 2.5 V under the forward bias and the reverse current is impassable. PMID- 26008853 TI - Head morphology of ram spermatozoa is associated with their ability to migrate in vitro and correlates with fertility. AB - Fertility is a highly complex biological function that depends on several properties of spermatozoa that are necessary for them to overcome various barriers in the female reproductive tract to reach the fertilisation site. This ability has been evaluated in vitro using cervical mucus migration tests. Head morphology has been widely studied, and various studies have reported correlations between head morphology and motility, fertility and DNA fragmentation. In the present study, we first evaluated the relationship between the ability of ram spermatozoa to overcome the mucus surrogate barrier in an in vitro migration test and sperm head morphology. Sperm motility (determined by computer-aided sperm analysis) and the acrosomal status, viability and mitochondrial status (determined by flow cytometry) of control and migrating spermatozoa were assessed. Principal component analysis and clustering analysis of the values for the morphometric parameters assessed defined three cell subpopulations. One of these subpopulations, namely spermatozoa with a short and wide head, was absent from samples collected after conclusion of the migration test. Second, we evaluated relationships among head morphology characteristics, the ability to penetrate the artificial mucus and fertility. We did not find any correlation between fertility and the number of spermatozoa that migrated, whereas there was a negative correlation between the proportion of spermatozoa with a short and wide head in the fresh sperm sample and fertility. In conclusion, the head morphology of spermatozoa was associated with their ability to overcome a mucus barrier in a migration test, and the relative size of the non migrating subpopulation was negatively related to male fertility. PMID- 26008852 TI - Chemical synthesis of a two-photon-activatable chemokine and photon-guided lymphocyte migration in vivo. AB - Chemokine-guided lymphocyte positioning in tissues is crucial for normal operation of the immune system. Direct, real-time manipulation and measurement of single-cell responses to chemokines is highly desired for investigating the cell biology of lymphocyte migration in vivo. Here we report the development of the first two-photon-activatable chemokine CCL5 through efficient one-pot total chemical synthesis in milligram scale. By spatiotemporally controlled photoactivation, we show at the single-cell level that T cells perceive the directional cue without relying on PI3K activities, which are nonetheless required for persistent migration over an extended period of time. By intravital imaging, we demonstrate artificial T-cell positioning in cutaneous tissues and lymph nodes. This work establishes a general strategy to develop high-quality photo-activatable protein agents through tailor-designed caging of multiple residues and highlights the potential of photo-activatable chemokines for understanding and potential therapeutic manipulation of cell positioning and position-controlled cell behaviours in vivo. PMID- 26008854 TI - Strongyloides stercoralis hyperinfection syndrome: a case series and a review of the literature. AB - BACKGROUND: Strongyloides stercoralis may lead to overwhelming infestation [Strongyloides hyperinfection syndrome (SHS)]. We aimed at describing a case series of patients admitted in intensive care unit (ICU) with SHS and report a literature review of such cases. PATIENTS AND METHODS: Retrospective multicenter study of 11 patients admitted to the ICU of tertiary hospitals with SHS between 2000 and 2013. Literature review with Pubmed retrieved 122 cases. Logistic regression analysis was performed to identify predictive factors of ICU mortality and shock occurrence. RESULTS: 133 patients [median age 53 (39, 64), 72.2 % males] were included. Underlying immunosuppression was present in 127 patients, mostly long-term corticosteroid treatment in 111 (83.5 %) patients. Fever (80.8 %), respiratory (88.6 %), and gastrointestinal (71.2 %) symptoms were common clinical manifestations. Shock occurred in 75 (57.3 %) patients and mechanical ventilation was required in 89 (67.9 %) patients. Hypereosinophilia and a concomitant bacterial infection were observed in 34 (34.3 %) and 51 (38.4 %) patients, respectively. The in-ICU mortality rate was 60.3 %. Predictive factors of ICU mortality were shock occurrence [Odds ratio (OR) 18.1, 95 % confidence interval (95 % CI) 3.03-107.6, p < 0.01] and mechanical ventilation (OR 28.1, 95 % CI 3.6-217, p < 0.01). Hypereosinophilia (OR 0.21, 95 % CI 0.06-0.7, p = 0.01) and a concomitant bacterial infection (OR 4.68, 95 % CI 1.3-16.8, p = 0.02) were independent predictors of shock occurrence. CONCLUSION: SHS remains associated with a poor outcome, especially when associated with shock and mechanical ventilation. Deterioration to shock is often related to concomitant bacterial infection. The poor outcome of established SHS pleads for a large application of antiparasitic primary prophylaxis in at-risk patients. PMID- 26008855 TI - Normobaric Intermittent Hypoxia over 8 Months Does Not Reduce Body Weight and Metabolic Risk Factors--a Randomized, Single Blind, Placebo-Controlled Study in Normobaric Hypoxia and Normobaric Sham Hypoxia. AB - OBJECTIVE: Both a 1- to 4-week continuous or intermittent stay and moderate exercise in hypoxia versus normoxia can lead to weight loss. We examined the reproducibility and durability of added hypoxic exposure in a feasible health program of several months. METHODS: 32 obese persons, randomly assigned to either a hypoxia (age 50.3 +/- 10.3 years, BMI 37.9 +/- 8.1 kg/m(2)) or a normoxia (age 52.4 +/- 7.9 years, BMI 36.3 +/- 4.0 kg/m(2)) group, completed 52 exercise sessions within 8 months. Participants exercised for 90 min (65-70% HR(peak)) either at a simulated altitude of 3,500 m or in normoxia, and rested for further 90 min at 4,500 m or normoxia. Before, after 5 weeks, after 3 months, and after the intervention, body composition and exercise capacity were determined. Risk markers (e.g., blood pressure, cholesterol) were measured before, after 3 months, and after the intervention period. RESULTS: Body weight, BMI, waist and hip circumference, P(peak) and BP(sys) improved over time (p < 0.05) but without group difference. Fat mass reductions correlated with HDL changes (r = -0.427; p < 0.05) in the entire group. CONCLUSION: Long-term, moderate intensity exercise and rest in hypoxia does not lead to higher reductions in body weight than normoxia alone. Therefore, for weight loss and metabolic markers hypoxic exposure does not add effects at least when stimuli (i.e., hypoxia dose, exercise intensity/duration) are unaltered throughout the intervention. PMID- 26008856 TI - Concordance of positron emission tomography and computed tomography in patients with locally advanced gastric and esophageal cancer. AB - BACKGROUND: PET-CT is important for evaluating the cancer stage preoperatively. In patients with locally advanced disease, who are candidates for curative treatment modalities following computed tomography (CT) and ultrasonography evaluation, PET-CT can show distant metastases and spare patients unnecessary surgical interventions. We aimed to evaluate the contribution of PET-CT scans compared to conventional imaging studies on the change of treatment plan in patients with locally advanced esophagogastric cancer from neoadjuvant to palliative setting. MATERIALS AND METHODS: In this study, 91 patients with histopathologically proven diagnosis of esophageal or gastric cancer in our clinic between the years 2010-2014 were included. Prior to PET-CT evaluation, all of the patients were evaluated with thorax and abdomen computed tomography. Seventy-six of these patients were further evaluated by PET-CT due to ambiguous findings on computed tomography and 15 of them for staging purposes. The patients, who were shown to have distant metastases on conventional radiological imaging, were excluded from the study population. RESULTS: Ninety-one patients were included in the study. Their median age was 57 (range 30-80) years and three quarters of the patients were male. Most of the patients were evaluated by PET-CT due to suspicion of distant metastasis (83.5%). Primary sites of the tumors on PET-CT were: esophagus 38.5% and stomach 61.5%. Between CT and PET-CT tumor stage and pathological lymphadenopathy concordance rates were 75.8, and 69.2%, respectively. On PET-CT evaluation 47.3% of patients had distant metastasis. New metastases were detected in 34.1% of patients by PET-CT despite entering to scanning field of tomography. Following the PET-CT evaluation due to detected metastasis, 47.3% of patients' treatment plan was changed from neoadjuvant to palliative therapy. CONCLUSION: In the current study, 47.3% (n = 43) of patients had distant metastasis that were not detected by CT evaluation. These patients were spared unnecessary surgical interventions. Evaluating the locally advanced gastric and esophageal cancer patients for PET-CT new metastasis could be indicated when the treatment plan of these patients would be changed from curative to palliative. PMID- 26008857 TI - Primary hepatic angiosarcoma. AB - Primary hepatic angiosarcoma is a rare, aggressive tumor; composed of spindle or pleomorphic cells that line, or grow into, the lumina of pre-existing vascular spaces like sinusoids and terminal hepatic venules; with only about 200 cases diagnosed annually worldwide but it is the most common primary malignant mesenchymal tumor of the liver in adults and accounts for 2% of all primary hepatic malignancies. HAS occurs in association with known chemical carcinogens, but 75% of the tumors have no known etiology. Patients present with vague symptoms like abdominal pain, weight loss, fatigue or an abdominal mass. Hepatic angiosarcoma is usually multicentric and involves both lobes, entire liver may also found to be involved. CD31 is the most reliable marker. These tumors lack specific features on imaging, so, pathological diagnosis is necessary. There are no established treatment guidelines because of low frequency and aggressive nature of tumor, chemotherapy is only palliative, liver resection is indicated for solitary mass and liver transplant is contraindicated. The aim of this article is to comprehensively review all the available literature and to present detailed information and an update on primary hepatic angiosarcoma. PMID- 26008858 TI - Commentary: Intravenous Immunoglobulin (IVIG) Therapy for Patients with Langerhans Cell Histiocytosis (LCH)-Related Neurodegenerative Diseases of the CNS. PMID- 26008859 TI - Gaps in Knowledge and Research Priorities for Alcoholic Hepatitis. PMID- 26008860 TI - Obesity and Hepatocellular Carcinoma: A Complex Relationship. PMID- 26008861 TI - Adjunctive Molecular Analysis of Pancreatic Cyst Fluid to Determine Malignant Potential. PMID- 26008862 TI - Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome. AB - BACKGROUND: Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts. METHODS: Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database. RESULTS: Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy. CONCLUSION: We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene. PMID- 26008864 TI - Corrigendum. PMID- 26008863 TI - Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review. AB - BACKGROUND: Pyruvate dehydrogenase (PDH) deficiency is a disorder of energy metabolism with variable clinical presentations, ranging from severe infantile lactic acidosis to milder chronic neurological disorders. The spectrum of clinical manifestations is continuously expanding. METHODS AND RESULTS: We report on a 19-year-old intelligent female with PDH deficiency caused by a Leu216Ser mutation in PDHA1. She presented with recurrent hemidystonic attacks, triggered by prolonged walking or running, as the unique clinical manifestation that manifested since childhood. Laboratory workup and neuroimages were initially normal but bilateral globus pallidum involvement appeared later on brain MRI. Dystonia completely remitted after high doses of thiamine, remaining free of symptoms after 3 years of follow up. We reviewed the literature for similar observations. CONCLUSIONS: Dystonia precipitated by exercise may be the only symptom of a PDH deficiency, and the hallmark of the disease as high serum lactate or bilateral striatal necrosis at neuroimaging may be absent. A high index of suspicion and follow up is necessary for diagnosis. The clinical presentation of this patient meets the criteria for a Paroxysmal Exercise induced Dystonia, leading us to add this entity as another potential etiology for this type of paroxysmal dyskinesia, which is besides a treatable condition that responds to thiamine supplementation. PMID- 26008865 TI - Coronary slow flow accompanying exertional blurred vision and effects of corticosteroids. AB - Background Various pathophysiological mechanisms such as microvascular and endothelial dysfunction, small vessel disease, diffuse atherosclerosis, and inflammation have been held responsible in the etiology of coronary slow flow. It is also thought to be a reflection of a systemic slow-flow phenomenon in the coronary arterial tree. Case Report A 44-year-old man presented with chest pain causing fatigue, together with blurred vision for the last 2 years, which disappeared after resting. He had used corticosteroid therapy for facial paralysis 1 month ago. Coronary slow flow was detected in all 3 major coronary arteries on coronary angiography. TIMI measurements for the left anterior descending artery, circumflex, and right coronary artery were 64, 72, and 55, respectively. In fundus fluorescein angiography, retinal vascularity was normal, the arm-to-retina circulation time was 21.8 s, and the arteriovenous transit time was 4.3 s. In the early arteriovenous phase, choroidal filling was long, with physiological patchy type. Diltiazem 90 mg/day and acetylsalicylic acid 100 mg/day were given. His chest pain and visual symptoms disappeared after medical treatment. Conclusions Physicians should be aware that glucocorticoids might cause an increase in the symptoms of coronary slow flow and some circulation problems, which might lead to systematic symptoms. PMID- 26008866 TI - Ultrathin carbon layer coated MoO2 nanoparticles for high-performance near infrared photothermal cancer therapy. AB - Carbon layer-coated molybdenum dioxide nanoparticles exhibit strong photo absorption in the near infrared (NIR) region with good photostability. The in vitro and in vivo experiments reveal that an excellent photothermal ablation induced from the nanoparticle agents under NIR irradiation can kill tumor cells not only at the cellular level but also in living organs. PMID- 26008867 TI - Ethnomedicinal plants of Shankaracharya Hill, Srinagar, J&K, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Primitive human societies have always relied on plants and plant products for various remedies. In certain areas, these folk medical prescriptions are endemic and have survived through ages from one generation to the next through word of mouth. They do not exist as written knowledge. The present study was undertaken with an objective of documenting the ethnobotanical information of medicinal plants of Shankaracharya Hill by taking the help of local herbalists, elderly and knowledgeable people. MATERIAL AND METHODS: The data was quantitatively analysed using use-value (UV), informant consensus factor (ICF) and fidelity level (Fl%) indices. RESULTS: Total 130 plant species from 57 families and 111 genera were ethno-medicinally utilized by the 103 informants interviewed in the present study. The most used families were Asteraceae, Rosaceae, Lamiaceae, Fabaceae and Brassicaceae. The medicinal plants were mainly herbs (79.2%). Leaves were the most used (27.6%) plant part followed by whole plant (14.8%), root (11.4%) and seed (10.5%). The most important species on the basis of UV were Viola odorata, Taraxacum campylodes, Aesculus hippocastanum, Artemisia absinthium, Daucus carota, Thymus serphyllum, Ephedra gerardiana and Salvia moorcroftiana. The values ICF ranged between 0.93 and 0.76. Only Epilobium hirsutum recorded 100% Fl. Some of the most important medicinal plants with high Fl values were Tribulus terrestris, Asparagus officinalis, Trifolium repens, Anemone biflora, Melia azedarach, A. absinthium, Lonicera quinquelocularis, Rosa webbiana, D. carota, Oxalis corniculata and Potentilla reptans. CONCLUSION: The contribution of plant parts collected through destructive methods was 29.5%. Harvesting of roots, rhizomes, bulbs and corm kills the parent plant and could be a severe threat for survival of the often rare and slowly reproducing medicinal plants, and therefore need sustainable utilization and conservation strategies. Ethnomedicinal species like A. absinthium, A. hippocastanum, D. carota, M. azedarach, T. campylodes, T. serphyllum, T. terrestris having high number of citations, UV and FL should be analyzed for phytochemicals and pharmacology. PMID- 26008868 TI - 5'-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling. AB - The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection. The biological activity of the 16 resulting compounds together with that of 14 previously reported compounds I, lacking the 5' methylene group, was evaluated on the MraY transferase activity. Out of the 30 tested compounds, 18 compounds revealed MraY inhibition with IC50 ranging from 15 to 150 MUM. A molecular modeling study was performed to rationalize the observed structure-activity relationships (SAR), which allowed us to correlate the activity of the most potent compounds with an interaction involving Leu191 of MraYAA. The antibacterial activity was also evaluated and seven compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 MUg mL(-1), including the methicillin resistant Staphylococcus aureus (MRSA). PMID- 26008869 TI - Synthesis and structural characterization of BINOL-modified chiral polyoxometalates. AB - Chiral ligand-modified polyoxometalates (POMs) were successfully synthesized by the introduction of BINOL into the dititanium-substituted POM in an organic medium and characterized by X-ray crystallography, spectroscopy, and elemental analyses. These BINOL-modified POMs were stable in the solution state and showed catalytic activity for asymmetric oxidation of thioanisole. PMID- 26008870 TI - Retrospective comparison of gradient recalled echo R2* and spin-echo R2 magnetic resonance analysis methods for estimating liver iron content in children and adolescents. AB - BACKGROUND: Serial surveillance of liver iron concentration (LIC) provides guidance for chelation therapy in patients with iron overload. The diagnosis of iron overload traditionally relies on core liver biopsy, which is limited by invasiveness, sampling error, cost and general poor acceptance by pediatric patients and parents. Thus noninvasive diagnostic methods such as MRI are highly attractive for quantification of liver iron concentration. OBJECTIVE: To compare two MRI-based methods for liver iron quantification in children. MATERIALS AND METHODS: 64 studies on 48 children and young adults (age range 4-21 years) were examined by gradient recalled echo (GRE) R2* and spin-echo R2 MRI at 1.5T to evaluate liver iron concentration. Scatter plots and Bland-Altman difference plots were generated to display and assess the relationship between the methods. RESULTS: With the protocols used in this investigation, Bland-Altman agreement between the methods is best when LIC is <20 mg/g dry tissue. Scatter plots show that all values with LIC <20 mg/g dry tissue fall within the 95% prediction limits. CONCLUSION: Liver iron concentration as determined by the R2* and R2 MR methods is statistically comparable, with no statistical difference between these methods for LIC <20 mg/g. PMID- 26008871 TI - Cinegraphic versus Combined Static and Cinegraphic Imaging for Initial Cranial Ultrasound Screening in Premature Infants. AB - BACKGROUND: Cranial ultrasound is an essential screening and diagnostic tool in the care of neonates and is especially useful in the premature population for evaluation of potential germinal matrix/intraventricular hemorrhage (GM/IVH). There are typically two screening examinations, with the initial cranial sonography performed between 3 days and 14 days after birth, usually consisting of a series of static images plus several cinegraphic sweeps. OBJECTIVE: Our primary goal was to assess whether cinegraphic sweeps alone are as accurate for diagnosing neurological abnormalities as combined static and cinegraphic imaging in the initial cranial US evaluation of premature infants. Our secondary goal was to establish the difference in time required to perform these two examinations. MATERIALS AND METHODS: We retrospectively obtained 140 consecutive initial cranial US screening studies of premature infants. Three pediatric radiologists blinded to patient data read cinegraphic images alone and also combined (dual) imaging sets for a subset of subjects, recording findings for seven disease processes: germinal matrix/intraventricular hemorrhage (GM/IVH), right or left side; periventricular leukomalacia (PVL); choroid plexus cyst; subependymal cyst; cerebral and cerebellar infarction or hemorrhage; posterior fossa hemorrhage or infarction, and extra-axial hemorrhage. Separately, we compared retrospective dual imaging acquisition time against prospectively collected cinegraphic imaging time for premature infants undergoing initial cranial US evaluation. RESULTS: Equivalence testing demonstrated no difference in equivalency between initial cranial US screening using cinegraphic evaluation alone and dual imaging for GM/IVH, cerebral and cerebellar infarct or hemorrhage, and subependymal cyst (all P < 0.05). For PVL and choroid plexus cyst, cinegraphic imaging and dual imaging did not demonstrate equivalence (P > 0.05). Cinegraphic images were obtained in less than one-third of the time required for dual imaging. CONCLUSION: For the diagnoses that are critical to establish at initial screening (GM/IVH, cerebral and cerebellar infarct or hemorrhage) initial cranial US screening using cinegraphic sweeps was equivalent to dual imaging. Cinegraphic imaging required significantly less time to perform than dual imaging. We suggest that performance of cranial US screening using cinegraphic imaging alone is a potentially advantageous option in the initial evaluation of the premature neonate. PMID- 26008872 TI - Tenosynovial chondromatosis of the flexor hallucis longus in a 17-year-old girl. AB - Tenosynovial chondromatosis is a benign chondrogenic metaplasia of extra articular synovial tissue. The most common locations for tenosynovial chondromatosis to develop are the hands and feet. The condition has rarely been reported in children. We present a case of tenosynovial chondromatosis of the flexor hallucis longus in a 17-year-old girl. The presentation was unusual not only due to the location and young age of the patient but also the absence of any palpable mass on physical exam and complete lack of calcification of the cartilage bodies. Initial diagnosis was made by MRI. The patient underwent tenosynovectomy with an excellent postoperative recovery at 6-month follow-up. Histopathology confirmed the diagnosis of tenosynovial chondromatosis. PMID- 26008873 TI - Partial Body Weight-Supported Treadmill Training in Patients With Parkinson Disease: Impact on Gait and Clinical Manifestation. AB - OBJECTIVE: To evaluate the effect of conventional gait training (CGT) and partial weight-supported treadmill training (PWSTT) on gait and clinical manifestation. DESIGN: Prospective experimental research design. SETTING: Hospital. PARTICIPANTS: Patients with idiopathic Parkinson disease (PD) (N=60; mean age, 58.15+/-8.7y) on stable dosage of dopaminomimetic drugs were randomly assigned into the 3 following groups (20 patients in each group): (1) nonexercising PD group, (2) CGT group, and (3) PWSTT group. INTERVENTIONS: The interventions included in the study were CGT and PWSTT. The sessions of the CGT and PWSTT groups were given in patient's self-reported best on status after regular medications. The interventions were given for 30min/d, 4d/wk, for 4 weeks (16 sessions). MAIN OUTCOME MEASURES: Clinical severity was measured by the Unified Parkinson Disease Rating Scale (UPDRS) and its subscores. Gait was measured by 2 minutes of treadmill walking and the 10-m walk test. Outcome measures were evaluated in their best on status at baseline and after the second and fourth weeks. RESULTS: Four weeks of CGT and PWSTT gait training showed significant improvements of UPDRS scores, its subscores, and gait performance measures. Moreover, the effects of PWSTT were significantly better than CGT on most measures. CONCLUSIONS: PWSTT is a promising intervention tool to improve the clinical and gait outcome measures in patients with PD. PMID- 26008874 TI - Photoacoustic imaging of human lymph nodes with endogenous lipid and hemoglobin contrast. AB - Lymph nodes play a central role in metastatic cancer spread and are a key clinical assessment target. Abnormal node vascularization, morphology, and size may be indicative of disease but can be difficult to visualize with sufficient accuracy using existing clinical imaging modalities. To explore the potential utility of photoacoustic imaging for the assessment of lymph nodes, images of ex vivo samples were obtained at multiple wavelengths using a high-resolution three dimensional photoacoustic scanner. These images showed that hemoglobin based contrast reveals nodal vasculature and lipid-based contrast reveals the exterior node size, shape, and boundary integrity. These two sources of complementary contrast may allow indirect observation of cancer, suggesting a future role for photoacoustic imaging as a tool for the clinical assessment of lymph nodes. PMID- 26008875 TI - The effects of short-term jump training on bone metabolism in females using oral contraceptives. AB - The purpose of this study was to determine the effect of oral contraceptive use on bone serum markers following a 3-week jumping protocol. Twenty-three females (18-25 years) were grouped as oral contraceptive users (OC+) or non-users (OC-). Following a 3-week observation period, participants completed a 3-week (15-day) jump protocol. Jump sessions consisting of ten 42 cm drop jumps with a 30 s rest interval between jumps were completed each day, 5 days per week. Peak vertical ground reaction force and loading rate were measured and the osteogenic index was calculated. Serum markers for bone formation, bone alkaline phosphatase (BAP) and bone resorption, C-terminal telopeptides of type I collagen (CTX) were measured at three time points (pre-, mid-, post-jump). BAP and CTX increased significantly (P = 0.0017, 0.0488) in both groups post-jump; however, bone metabolic markers were not different between the OC+ and OC- groups. Osteogenic index, ground reaction force and vertical jump height were similar between groups. Correlations between markers of bone metabolism and participants' age at menarche, weight, loading rate and years on OC were not significant. A 3-week jumping protocol was found to be effective in stimulating bone metabolism in both OC+ and OC- groups. PMID- 26008876 TI - Seasonal Variation of Common Surgical Site Infections: Does Season Matter? AB - OBJECTIVE: To evaluate seasonal variation in the rate of surgical site infections (SSI) following commonly performed surgical procedures. DESIGN: Retrospective cohort study. METHODS: We analyzed 6 years (January 1, 2007, through December 31, 2012) of data from the 15 most commonly performed procedures in 20 hospitals in the Duke Infection Control Outreach Network. We defined summer as July through September. First, we performed 3 separate Poisson regression analyses (unadjusted, multivariable, and polynomial) to estimate prevalence rates and prevalence rate ratios of SSI following procedures performed in summer versus nonsummer months. Then, we stratified our results to obtain estimates based on procedure type and organism type. Finally, we performed a sensitivity analysis to test the robustness of our findings. RESULTS: We identified 4,543 SSI following 441,428 surgical procedures (overall prevalence rate, 1.03/100 procedures). The rate of SSI was significantly higher during the summer compared with the remainder of the year (1.11/100 procedures vs 1.00/100 procedures; prevalence rate ratio, 1.11 [95% CI, 1.04-1.19]; P=.002). Stratum-specific SSI calculations revealed higher SSI rates during the summer for both spinal (P=.03) and nonspinal (P=.004) procedures and revealed higher rates during the summer for SSI due to either gram-positive cocci (P=.006) or gram-negative bacilli (P=.004). Multivariable regression analysis and sensitivity analyses confirmed our findings. CONCLUSIONS: The rate of SSI following commonly performed surgical procedures was higher during the summer compared with the remainder of the year. Summer SSI rates remained elevated after stratification by organism and spinal versus nonspinal surgery, and rates did not change after controlling for other known SSI risk factors. PMID- 26008877 TI - A weighted rule based method for predicting malignancy of pulmonary nodules by nodule characteristics. AB - Predicting malignancy of solitary pulmonary nodules from computer tomography scans is a difficult and important problem in the diagnosis of lung cancer. This paper investigates the contribution of nodule characteristics in the prediction of malignancy. Using data from Lung Image Database Consortium (LIDC) database, we propose a weighted rule based classification approach for predicting malignancy of pulmonary nodules. LIDC database contains CT scans of nodules and information about nodule characteristics evaluated by multiple annotators. In the first step of our method, votes for nodule characteristics are obtained from ensemble classifiers by using image features. In the second step, votes and rules obtained from radiologist evaluations are used by a weighted rule based method to predict malignancy. The rule based method is constructed by using radiologist evaluations on previous cases. Correlations between malignancy and other nodule characteristics and agreement ratio of radiologists are considered in rule evaluation. To handle the unbalanced nature of LIDC, ensemble classifiers and data balancing methods are used. The proposed approach is compared with the classification methods trained on image features. Classification accuracy, specificity and sensitivity of classifiers are measured. The experimental results show that using nodule characteristics for malignancy prediction can improve classification results. PMID- 26008878 TI - Circulating irisin detection: Does it really work? AB - The recent discovery of irisin has generated considerable interest in the scientific community. However, many studies on the biochemistry and biology of this intriguing hormone yielded controversial results in humans, which were mostly attributable to a number of drawbacks in the methods used for its detection and measurement. PMID- 26008879 TI - Regional differences in perivascular adipose tissue impacting vascular homeostasis. AB - Perivascular adipose tissue (PVAT) releases several important vasoactive factors with physiological and pathophysiological paracrine effects. A large body of evidence suggests regional phenotypic and functional differences among PVAT depots, depending on the specific vascular bed or different regions in the vascular bed where the PVAT is located. These non-uniform and separate PVATs exert various paracrine effects on vascular structure and function that largely impact disease states, such as endothelial dysfunction, atherosclerosis, or insulin resistance. This emerging view of PVAT function requires considering heterogeneous PVAT as a specialized organ that can differentially regulate vascular function depending on its anatomical location. In this context, the adipose-vascular axis may represent a novel target for pharmacological intervention in vasculopathy in cardiometabolic disorders. PMID- 26008880 TI - Intraoperative peripheral nerve injury in colorectal surgery. An update. AB - Intraoperative peripheral nerve injury during colorectal surgery procedures is a potentially serious complication that is often underestimated. The Trendelenburg position, use of inappropriately padded armboards and excessive shoulder abduction may encourage the development of brachial plexopathy during laparoscopic procedures. In open colorectal surgery, nerve injuries are less common. It usually involves the femoral plexus associated with lithotomy position and self-retaining retractor systems. Although in most cases the recovery is mostly complete, treatment consists of physical therapy to prevent muscular atrophy, protection of hypoesthesic skin areas and analgesics for neuropathic pain. The aim of the present study is to review the incidence, prevention and management of intraoperative peripheral nerve injury. PMID- 26008881 TI - Classifying pairs with trees for supervised biological network inference. AB - Networks are ubiquitous in biology, and computational approaches have been largely investigated for their inference. In particular, supervised machine learning methods can be used to complete a partially known network by integrating various measurements. Two main supervised frameworks have been proposed: the local approach, which trains a separate model for each network node, and the global approach, which trains a single model over pairs of nodes. Here, we systematically investigate, theoretically and empirically, the exploitation of tree-based ensemble methods in the context of these two approaches for biological network inference. We first formalize the problem of network inference as a classification of pairs, unifying in the process homogeneous and bipartite graphs and discussing two main sampling schemes. We then present the global and the local approaches, extending the latter for the prediction of interactions between two unseen network nodes, and discuss their specializations to tree-based ensemble methods, highlighting their interpretability and drawing links with clustering techniques. Extensive computational experiments are carried out with these methods on various biological networks that clearly highlight that these methods are competitive with existing methods. PMID- 26008882 TI - Motivated to do well: an examination of the relationships between motivation, effort, and cognitive performance in schizophrenia. AB - The uncertain relationship between negative symptoms, and specifically motivational deficits, with cognitive dysfunction in schizophrenia is in need of further elucidation as it pertains to the interpretation of cognitive test results. Findings to date have suggested a possible mediating role of motivational deficits on cognitive test measures, although findings from formal examinations of effort using performance validity measures have been inconsistent. The aim of this study was to examine the relationships between motivation, effort exerted during cognitive testing, and cognitive performance in schizophrenia. Sixty-nine outpatients with schizophrenia or schizoaffective disorder were evaluated for psychopathology, severity of motivational deficits, effort exerted during cognitive testing, and cognitive performance. Motivation and degree of effort exerted during cognitive testing were significantly related to cognitive performance, specifically verbal fluency, verbal and working memory, attention and processing speed, and reasoning and problem solving. Further, effort accounted for 15% of the variance in cognitive performance, and partially mediated the relationship between motivation and cognitive performance. Examining cognitive performance profiles for individuals exerting normal or reduced effort revealed significant differences in global cognition, as well as attention/processing speed and reasoning and problem solving. These findings suggest that cognitive domains may be differentially affected by impairments in motivation and effort, and highlight the importance of understanding the interplay between motivation and cognitive performance deficits, which may guide the appropriate selection of symptom targets for promoting recovery in patients. PMID- 26008883 TI - Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Non-response to an initial antipsychotic trial emerges frequently in the pharmacological management of schizophrenia. Increasing the dose (high-dose treatment, dose escalation) is an often applied strategy in this regard, but there are currently no meta-analytic data available to ascertain the evidence of this treatment option. METHODS: We systematically searched for all randomized controlled trials (RCTs) that compared a dose increase directly to the continuation of standard-dose medication in patients with initial non-response to a prospective standard-dose pharmacotherapy with the same antipsychotic compound. Primary outcome was mean change in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) total score. Secondary outcomes were positive and negative symptoms, response rates, and attrition rates. Hedges's g and risks ratios were calculated as effect sizes and the influence of the amount of the dose increase was examined by meta-regressions. RESULTS: Altogether, five trials with 348 patients investigating dose escalation with quetiapine, ziprasidone, haloperidol, and fluphenazine could be included. We did not find any significant difference for the mean PANSS/BPRS score change between the dose-increase and control group, neither for the pooled antipsychotic group nor for the individual antipsychotic drugs. Moreover, there were no between-group differences in positive and negative symptoms, response rates, and drop-out rates. The meta-regressions indicate no significant influence of the different amounts of dose increments on effect sizes. CONCLUSIONS: This meta-analysis suggests no evidence for a dose-escalation of the investigated antipsychotic drugs fluphenazine, haloperidol, quetiapine, and ziprasidone in case of initial non-response to standard-dose pharmacotherapy. PMID- 26008885 TI - Dynamic causal modelling of brain-behaviour relationships. AB - In this work, we expose a mathematical treatment of brain-behaviour relationships, which we coin behavioural Dynamic Causal Modelling or bDCM. This approach aims at decomposing the brain's transformation of stimuli into behavioural outcomes, in terms of the relative contribution of brain regions and their connections. In brief, bDCM places the brain at the interplay between stimulus and behaviour: behavioural outcomes arise from coordinated activity in (hidden) neural networks, whose dynamics are driven by experimental inputs. Estimating neural parameters that control network connectivity and plasticity effectively performs a neurobiologically-constrained approximation to the brain's input-outcome transform. In other words, neuroimaging data essentially serves to enforce the realism of bDCM's decomposition of input-output relationships. In addition, post-hoc artificial lesions analyses allow us to predict induced behavioural deficits and quantify the importance of network features for funnelling input-output relationships. This is important, because this enables one to bridge the gap with neuropsychological studies of brain-damaged patients. We demonstrate the face validity of the approach using Monte-Carlo simulations, and its predictive validity using empirical fMRI/behavioural data from an inhibitory control task. Lastly, we discuss promising applications of this work, including the assessment of functional degeneracy (in the healthy brain) and the prediction of functional recovery after lesions (in neurological patients). PMID- 26008884 TI - Working memory impairment in probands with schizoaffective disorder and first degree relatives of schizophrenia probands extend beyond deficits predicted by generalized neuropsychological impairment. AB - OBJECTIVE: Working memory impairment is well established in psychotic disorders. However, the relative magnitude, diagnostic specificity, familiality pattern, and degree of independence from generalized cognitive deficits across psychotic disorders remain unclear. METHOD: Participants from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study included probands with schizophrenia (N=289), psychotic bipolar disorder (N=227), schizoaffective disorder (N=165), their first-degree relatives (N=315, N=259, N=193, respectively), and healthy controls (N=289). All were administered the WMS-III Spatial Span working memory test and the Brief Assessment of Cognition in Schizophrenia (BACS) battery. RESULTS: All proband groups displayed significant deficits for both forward and backward span compared to controls. However, after covarying for generalized cognitive impairments (BACS composite), all proband groups showed a 74% or greater effect size reduction with only schizoaffective probands showing residual backward span deficits compared to controls. Significant familiality was seen in schizophrenia and bipolar pedigrees. In relatives, both forward and backward span deficits were again attenuated after covarying BACS scores and residual backward span deficits were seen in relatives of schizophrenia patients. CONCLUSIONS: Overall, both probands and relatives showed a similar pattern of robust working memory deficits that were largely attenuated when controlling for generalized cognitive deficits. PMID- 26008886 TI - Individual differences in local gray matter density are associated with differences in affective and cognitive empathy. AB - The understanding of empathy from a neuroscientific perspective has recently developed quickly, with numerous functional MRI studies associating different brain regions with different components of empathy. A recent meta-analysis across 40 fMRI studies revealed that affective empathy is most often associated with increased activity in the insula, whereas cognitive empathy is most often associated with activity in the midcingulate cortex and adjacent dorsomedial prefrontal cortex (MCC/dmPFC). To date, however, it remains unclear whether individual differences in brain morphometry in these regions underlie different dispositions in affective and cognitive empathy. In order to test this hypothesis, voxel-based morphometry (VBM) was used to examine the extent to which gray matter density predicts scores from an established empathy measure (Questionnaire of Cognitive and Affective Empathy; QCAE). One hundred and seventy six participants completed the QCAE and underwent MRI in order to acquire a high resolution, three-dimensional T1-weighted structural scans. A factor analysis of the questionnaire scores revealed two distinct factors of empathy, affective and cognitive, which confirmed the validity of the QCAE. VBM results revealed gray matter density differences associated with the distinct components of empathy. Higher scores on affective empathy were associated with greater gray matter density in the insula cortex and higher scores of cognitive empathy were associated with greater gray matter density in the MCC/dmPFC. Taken together, these results provide validation for empathy being a multi-component construct, suggesting that affective and cognitive empathy are differentially represented in brain morphometry as well as providing convergent evidence for empathy being represented by different neural and structural correlates. PMID- 26008888 TI - Numerical investigation of the hydrodynamic parameters of blood flow through stenotic descending aorta. AB - In this study, the blood flow passing through a three-dimensional geometrically realistic stenosis is investigated both experimentally and numerically. Although the blood flow in stenotic arteries has been extensively studied in the past few decades, not much work has been focused on irregularity of stenosis. Thus, a model of an irregular stenotic descending aorta is used in this work. Due to the irregularity of stenosis model, the governing differential equations for continuity and momentum are solved numerically using finite-volume/finite difference techniques in the generalized body-fitted coordinates. In order to verify the numerical results, the experimental measured pressure drops are compared with the numerical result. In addition, an improved method for nearly orthogonal grid generation is presented in numerical study. The grid generating system is based on the solution of a set of partial differential equations with finite difference discretization. Numerical calculations are performed to examine the effect of 55% (ratio between cross-sectional area at upstream and stenosis) irregular stenosis on the hemodynamic characteristics such as flow separation zone, wall shear stress and pressure drop. The maximum calculated wall shear stress is related to the maximum velocity gradient due to minimum cross-sectional area at the neck of stenosis. In addition, the pressure is shown as an important characteristic that is effecting on the resistance against the flow in the artery. Based on our results, the 55% irregular constriction is considered critical unlike the studies that have believed the reduction, which is greater than 75% become significant. PMID- 26008887 TI - Enamel matrix derivative and bone grafts for periodontal regeneration of intrabony defects. A systematic review and meta-analysis. AB - OBJECTIVE: The aim of the present systematic review and meta-analysis was to assess the clinical efficacy of regenerative periodontal surgery of intrabony defects using a combination of enamel matrix derivative (EMD) and bone graft compared with that of EMD alone. MATERIALS AND METHODS: The Cochrane Oral Health Group specialist trials, MEDLINE, and EMBASE databases were searched for entries up to February 2014. The primary outcome was gain of clinical attachment (CAL). Weighted means and forest plots were calculated for CAL gain, probing depth (PD), and gingival recession (REC). RESULTS: Twelve studies reporting on 434 patients and 548 intrabony defects were selected for the analysis. Mean CAL gain amounted to 3.76 +/- 1.07 mm (median 3.63 95 % CI 3.51-3.75) following treatment with a combination of EMD and bone graft and to 3.32 +/- 1.04 mm (median 3.40; 95 % CI 3.28-3.52) following treatment with EMD alone. Mean PD reduction measured 4.22 +/ 1.20 mm (median 4.10; 95 % CI 3.96-4.24) at sites treated with EMD and bone graft and yielded 4.12 +/- 1.07 mm (median 4.00; 95 % CI 3.88-4.12) at sites treated with EMD alone. Mean REC increase amounted to 0.76 +/- 0.42 mm (median 0.63; 95 % CI 0.58-0.68) at sites treated with EMD and bone graft and to 0.91 +/- 0.26 mm (median 0.90; 95 % CI 0.87-0.93) at sites treated with EMD alone. CONCLUSIONS: Within their limits, the present results indicate that the combination of EMD and bone grafts may result in additional clinical improvements in terms of CAL gain and PD reduction compared with those obtained with EMD alone. The potential influence of the chosen graft material or of the surgical procedure (i.e., flap design) on the clinical outcomes is unclear. CLINICAL RELEVANCE: The present findings support the use of EMD and bone grafts for the treatment of intrabony periodontal defects. PMID- 26008889 TI - A novel approach for preparation of modified-biochar derived from marine macroalgae: Dual purpose electro-modification for improvement of surface area and metal impregnation. AB - In the present study, an aluminum electrode-based electrochemical process was newly adopted as a modification method for fabricating physically and chemically modified biochar derived from marine macroalgae. Specifically, a current density of 93.96 mA cm(-2) was applied for 5 min at pH 3.0. Subsequently, the mixture was stirred continuously for 30 min without electric field, and the dried sample was then pyrolyzed at 450 degrees C under a N2 environment for 2 h. SEM-EDS and XRD analyses clearly indicated that nano-sized aluminum crystals (beohemite, AlOOH) were uniformly present on the EM-biochar surface. Adsorption equilibrium tests showed that the phosphate adsorption onto EM-biochar agreed well with the Langmuir-Freundlich adsorption isotherm model, with a maximum adsorption capacity of 31.28 mg-P g(-1). These findings suggest that this novel and simple electro modification method is a reasonable and effective option for simultaneously upgrading both the surface area and chemical properties of biochar. PMID- 26008890 TI - Preventing postoperative delirium. AB - BACKGROUND: Delirium is a common complication in elderly hospitalized patients. It prolongs the length of hospital stay, raises costs, increases the workload of the nursing staff, and may necessitate transfer of the patient to a nursing home. The risk of postoperative delirium is particularly high in elderly patients with pre-existing cognitive deficits. METHODS: In an open study, we systematically assessed the frequency of postoperative delirium in patients over age 70 on two surgical wards of a general hospital. In a six-month "prevalence phase," from March to August 2011, we counted the number of patients with postoperative delirium, but did not initiate any intervention. Thereafter, in a ten-month "intervention phase" from September 2011 to June 2012, a nurse with special training in the management of delirium carried out an intervention involving component measures of the Hospital Elder Life Program (HELP) on one of the two wards, with the aim of preventing postoperative delirium. The patients on the other ward served as a control group. RESULTS: In the prevalence phase, 20.2% of all patients developed postoperative delirium (95% confidence interval [CI], 14.6 26.4). In the intervention phase, postoperative delirium arose in 20.8% (95% CI, 11.3-32.1) of the patients on the ward with no specific interventions, but in only 4.9% (95% CI, 0.0-11.5) of those on the ward where the intervention was carried out. The difference was presumably due to the measures initiated by the specially trained nurse, including validation, improvement of sleep, cognitive activation, early mobilization, improved sensory stimulation, and improved nutritional and fluid intake. Important predictors of postoperative delirium included a low score on the Mini-Mental State Examination, advanced age, and preoperative infection. CONCLUSION: The frequency of postoperative delirium in elderly patients with cognitive deficits can be lowered with nursing measures carried out by a specially trained nurse, close postoperative supervision, and cognitive activation. PMID- 26008891 TI - Increased quality of life. PMID- 26008892 TI - In reply. PMID- 26008893 TI - De novo acute heart failure and acutely decompensated chronic heart failure. AB - BACKGROUND: Heart failure is one of the most common diseases of adults in Europe, with an overall prevalence of 1-2%. Among persons aged 60 and above, its prevalence is above 10% in men and 8% in women. Acute heart failure has a poor prognosis; it is associated with a high rate of rehospitalization and a 1-year mortality of 20-30%. METHODS: This review is based on pertinent literature, including guidelines, retrieved by a selective search in PubMed. RESULTS: There are different types of acute heart failure; the basic diagnostic assessment is performed at once and consists of ECG, echocardiography, and the measurement of N terminal pro-brain natriuretic peptide (NTproBNP) and troponin levels. The most common causes of decompensation are arrhythmia, valvular dysfunction, and acute cardiac ischemia, each of which accounts for 30% of cases. The potential indication for immediate revascularization should be carefully considered in cases where acute heart failure is due to coronary heart disease. The basic treatment of acute heart failure is symptomatic, with the administration of oxygen, diuretics, and vasodilators. Ino-tropic agents, vasopressors, and temporary mechanical support for the circulatory system are only used to treat cardiogenic shock. CONCLUSION: The treatment of acute heart failure is markedly less evidence-based than that of chronic heart failure. Newer treatment approaches that are intended to improve outcomes still need to be tested in multicenter trials. PMID- 26008894 TI - Incidence of stroke and seizure in Alzheimer's disease dementia. AB - BACKGROUND: the objective of the study was to estimate and compare the incidence rates of ischaemic and haemorrhagic stroke and seizure among cohorts with and without Alzheimer's disease (AD) dementia. METHODS: we conducted a retrospective cohort study using electronic medical records (EMRs) from primary care practices that participated in The Health Improvement Network (THIN) in the United Kingdom from 1 January 1990 to 31 July 2009. For each AD-dementia patient, we selected one general population control patient without AD-dementia matched to one AD dementia patient on year of birth, sex and physician practice. FINDINGS: the AD dementia cohorts were 68% female and averaged 80 years of age at the start of follow-up. Populations for analysis included 19,902 AD-dementia and matched non AD-dementia patients with no history of stroke at baseline in which 790 incident cases of stroke occurred, and similarly, 22,084 AD-dementia and matched patients with no history of seizure at baseline in which 286 cases of seizure occurred. After adjusting for risk factors for each outcome, hazard ratios comparing AD dementia with non-AD-dementia patients indicated higher rates among AD-dementia patients for stroke (HR = 1.29, 95% CI 1.11, 1.50) and seizure (HR = 5.31, 95% CI 3.97, 7.10). For stroke and seizure, the incidence rate ratios comparing AD dementia patients with non-AD-dementia controls were greatest for the younger age groups. AD-dementia was observed to be a risk factor for both haemorrhagic stroke and seizures. Increasing age was associated with a decrease in relative risk and an increase in absolute risk. PMID- 26008895 TI - Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis. AB - BACKGROUND: Risk stratification in patients with suspected myocarditis is pivotal for optimizing therapy. Stromal cell-derived factor 1 (SDF-1) is an inflammatory chemokine expressed in the inflamed and failing myocardium. Therefore, we aimed to investigate whether endomyocardial expression of SDF-1 identifies high-risk patients with suspected myocarditis. METHODS AND RESULTS: We prospectively enrolled 174 patients with non-ischemic HF who underwent endomyocardial biopsy for suspected myocarditis. Biopsies were analyzed using established histopathological and immunohistological criteria together with SDF-1 staining. SDF-1 was significantly enhanced in patients with inflammatory cardiomyopathy (65.4 % positive biopsies) as compared to patients with non-inflammatory cardiomyopathy (19.1 %, p < 0.001). SDF-1 expression levels correlated significantly with the degree of myocardial fibrosis (correlation coefficient r = 0.196; p = 0.010) since patients with severe myocardial fibrosis displayed high myocardial SDF-1 expression. During a mean follow-up of 27.5 months, 20 patients (11.5 %) died. The 4-year mortality rate was 26.0 % among the 92 SDF-1-positive patients vs. 9.5 % among the 82 SDF-1-negative patients (p = 0.001). On multivariable analysis which considered clinical (NYHA functional class, left ventricular ejection fraction), laboratory (brain natriuretic peptide, troponin I) and biopsy staining, SDF-1 was the strongest independent predictor of mortality (hazard ratio 6.1; 95 % confidence interval 1.4-27.5; p = 0.018). Subgroup analysis revealed SDF-1 as a predictor of mortality in both patients with inflammatory and non-inflammatory cardiomyopathy. CONCLUSIONS: Endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy, positively correlates with myocardial fibrosis and identifies high-risk patients with suspected myocarditis. PMID- 26008896 TI - Neuropeptide Y as an indicator of successful alterations in sympathetic nervous activity after renal sympathetic denervation. AB - BACKGROUND: Renal sympathetic denervation (RSD) represents a safe and effective treatment option for certain patients with resistant hypertension and has been shown to decrease sympathetic activity. Neuropeptide Y (NPY) is a neurotransmitter that is co-released with norepinephrine and is up-regulated during increased sympathetic activity. The aim of the present study was to examine the effect of RSD on NPY and to analyze the association between changes in NPY levels and blood pressure reduction after RSD. METHODS: A total of 150 consecutive patients (age 64.9 +/- 10.2 years) from three clinical centers undergoing RSD were included in this study. Response to RSD was defined as an office systolic blood pressure (SBP) reduction of >10 mmHg 6 months after RSD. Venous blood samples for measurement of NPY were collected prior to and 6 months after RSD. RESULTS: BP and NPY levels were significantly reduced by 23/9 mmHg (p = 0.001/0.001) and 0.24 mg/dL (p < 0.01) 6 months after RSD. There was a significant correlation between baseline SBP- and RSD-related systolic BP reduction (r = -0.43; p < 0.001) and between serum NPY baseline values and NPY level changes (r = -0.52; p < 0.001) at the 6-month follow-up. The BP response to RSD (>10 mmHg) was associated with a significantly greater reduction in NPY level when compared with BP non-responders (p = 0.001). CONCLUSION: This study demonstrates an effect of RSD on serum NPY levels, a specific marker for sympathetic activity. The association between RSD-related changes in SBP and NPY levels provides further evidence of the effect of RSD on the sympathetic nervous system. PMID- 26008897 TI - DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3. AB - Pre-B and pre-T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells' proliferation, but little is known about its posttranslational regulation at this stage. Here, we show that the dual specificity tyrosine regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition in mice, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a nonphosphorylatable Cyclin D3 T283A mutant recapitulated these defects, whereas inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition or loss. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development. PMID- 26008900 TI - OH-stretch overtone of methanol: empirical assignment using a two temperature technique in a supersonic jet. AB - This paper describes a novel approach for empirical lower state assignments in complex high resolution ro-vibrational overtone spectra of molecules with low rotational constants and complex intramolecular dynamics. Methanol, CH3OH, was chosen as a representative of such molecules - it is an asymmetric top with two non-hydrogen nuclei and hindered internal rotation leading to dense and disordered rotational structure of vibrational overtone bands. We report the first rotationally resolved methanol spectra of the OH-stretch overtone 2nu1 band using sub-Doppler diode laser spectroscopy in a supersonic jet, and describe how the combination of two temperature analysis (TTA) and analysis by ground state combination differences (GSCDs) is used to reliably identify spectral lines that originate from lowest rotational states. In the first step of the analysis, the TTA was utilized to obtain a set of possible rotational assignments for each spectral line using the line intensity variation between two different temperatures in the supersonic jet (13, and 56 K respectively). Thereafter, the GSCDs were used to confirm specific lower state assignment for those spectral lines that have been identified to have low rotational ground states by the TTA. We show that the TTA pre-selection leads to fast and reliable confirmation by GSCDs and avoids false assignments due to accidental GSCD matches. The procedure yields an important subset of reliably assigned spectral lines in the complex ro vibrational structure that provides a convenient starting point for subsequent application of traditional spectral analysis techniques. PMID- 26008898 TI - Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta. AB - Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL 1beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease. PMID- 26008901 TI - Evaluation of Improvement in Externalizing Behaviors and Callous-Unemotional Traits in Children with Disruptive Behavior Disorder: A 1-Year Follow Up Clinic Based Study. AB - Multi-component interventions based on cognitive behavioral principles and practices have been found effective in reducing behavioral problems in children with disruptive behavior disorders (oppositional defiant disorder and conduct disorder). However, it is still unclear if these interventions can affect children's callous-unemotional traits, which are predictive of subsequent antisocial behavior. Furthermore, it could be important to identify empirically supported treatment protocols for specific disorders addressed by child mental health services. The present study aimed to test the following two hypotheses: first, the Coping Power (CP) treatment program is able to reduce externalizing behaviors in children with disruptive behavior disorders treated in a mental health care unit; second, the CP program can reduce children's callous unemotional traits. The sample included 98 Italian children, 33 treated with the CP program; 37 with a less focused multi-component intervention, and 28 with child psychotherapy. The results showed that the CP program was more effective than the other two treatments in reducing aggressive behaviors. Furthermore, only the CP program was associated with a decrease in children's callous unemotional traits. The CP program was also associated with lower rate of referrals to mental health services at one-year follow-up. These findings support the importance of disseminating manualized and focused intervention programs in mental health services. PMID- 26008902 TI - Expected Impact of Health Care Reform on the Organization and Service Delivery of Publicly Funded Addiction Health Services. AB - Little is known about how the Affordable Care Act (ACA) will be implemented in publicly funded addiction health services (AHS) organizations. Guided by a conceptual model of implementation of new practices in health care systems, this study relied on qualitative data collected in 2013 from 30 AHS clinical supervisors in Los Angeles County, California. Interviews were transcribed, coded, and analyzed using a constructivist grounded theory approach with ATLAS.ti software. Supervisors expected several potential effects of ACA implementation, including increased use of AHS services, shifts in the duration and intensity of AHS services, and workforce professionalization. However, supervisors were not prepared for actions to align their programs' strategic change plans with policy expectations. Findings point to the need for health care policy interventions to help treatment providers effectively respond to ACA principles of improving standards of care and reducing disparities. PMID- 26008899 TI - Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. AB - Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC. The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex. Linear ubiquitination and NF kappaB activation are impaired in the patient's fibroblasts stimulated by IL 1beta or TNF. In contrast, the patient's monocytes respond to IL-1beta more vigorously than control monocytes. However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement. These cellular and clinical phenotypes largely overlap those of HOIL-1-deficient patients. Clinical differences between HOIL-1- and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our findings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells. PMID- 26008904 TI - Half-metallicity induced by boron adsorption on an Fe3O4(100) surface. AB - The spin polarization of magnetite Fe3O4 is significantly reduced at its surfaces, which is unfavorable for the development of spintronic devices based on this material. In order to enhance the surface spin polarization, the Fe3O4(100) surface is modified here through the adsorption of boron (B) atoms and investigated using density functional theory (DFT) calculations. We find for the bulk-terminated and cation-redistributed surfaces that a band gap is opened in the spin-up electronic states due to the formation of a strong bond between the B atom and a surface oxygen atom, i.e., B adsorption induces half-metallicity at the Fe3O4(100) surface. Besides the surface Fe and O atoms, the adsorbed B atoms have a considerable density of -100% spin-polarized electronic states at the Fermi level, which might provide a means of improving the efficiency of spin injection into spintronic devices. PMID- 26008903 TI - Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK). AB - BACKGROUND: Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight. OBJECTIVES: We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS-birth weight association observed in epidemiologic studies might be attributable to GFR. METHODS: We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta analysis of epidemiologic data. RESULTS: The reduction in birth weight for each 1 ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: -3.40, -2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: -8.46, -5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR-birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: -21.66, -7.78) and 14.72 g (95% CI: -8.92, -1.09) reductions in birth weight, respectively. CONCLUSION: Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy. PMID- 26008906 TI - Quantitative Analysis of Hydration Using Nitrogen-14 Nuclear Quadrupole Resonance. AB - Hydration is a quite common process in pharmaceutical solids. Sometimes it is desirable, as it stabilizes the crystal structure; in other cases it is unwanted, as it changes the physical and chemical properties of drugs. We here use (14)N NQR spectroscopy to quantitatively analyze hydration of a model compound, 5 aminotetrazole. (14)N NQR has some great advantages compared to other routinely used techniques to study hydration, like a very simple spectrum, single point calibration, and no need for special sample preparation, but the method's great disadvantage is a rather small sensitivity. Nevertheless, here we demonstrate that (14)N NQR, although being significantly less sensitive than XRD, NIR, and also (35)Cl NQR, is still capable of providing excellent quantitative accuracies. We can achieve errors <1% of the total amount, provided good temperature stabilization is implemented, which then allows long experimental times. We also present results obtained with a SLSE pulse sequence, which is a less robust approach but allows the use of much shorter measuring times (~200*) and could be used for quantitative real time monitoring of hydration or dehydration. PMID- 26008905 TI - A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency. AB - Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be recessively inherited through segregation studies. The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma. By introducing both mutations into Saccharomyces cerevisiae, we were able to confirm that the p.(Asp92Gly) mutation causes a more severe oxidative growth phenotype than the p.(Asp92Tyr) mutant, and provides functional evidence to support the pathogenicity of the patient's SDHD mutation. This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency. PMID- 26008907 TI - Two Pioneer 19th-Century Women Who Breached Ophthalmology's Glass Ceiling. PMID- 26008908 TI - The posterior cornea: hiding in plain sight. PMID- 26008909 TI - Author reply: To PMID 24907059. PMID- 26008910 TI - Re: Tang et al.: Bilateral lacrimal gland disease: clinical features of 97 cases (Ophthalmology 2014;121:2040-6). PMID- 26008911 TI - Re: Kessel et al.: Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops (Ophthalmology 2014;121:1915 24). PMID- 26008912 TI - Author reply: To PMID 24935281. PMID- 26008913 TI - Author reply: To PMID 24939513. PMID- 26008914 TI - Re: Aptel et al.: Long-term reproducibility of diurnal intraocular pressure patterns in patients with glaucoma (Ophthalmology 2014;121:1998-2003). PMID- 26008915 TI - Re: Korobelnik et al.: Intravitreal aflibercept for diabetic macular edema (Ophthalmology 2014;121:2247-54). PMID- 26008916 TI - Author reply: To PMID 25012934. PMID- 26008917 TI - History of the medical licensing examination (uieop) in Korea's Goryeo Dynasty (918-1392). AB - This article aims to describe the training and medical licensing system (uieop) for becoming a physician officer (uigwan) during Korea's Goryeo Dynasty (918 1392). In the Goryeo Dynasty, although no license was necessary to provide medical services to the common people, there was a licensing examination to become a physician officer. No other national licensing system for healthcare professionals existed in Korea at that time. The medical licensing examination was administered beginning in 958. Physician officers who passed the medical licensing examination worked in two main healthcare institutions: the Government Hospital (Taeuigam) and Pharmacy for the King (Sangyakguk). The promotion and expansion of medical education differed depending on the historical period. Until the reign of King Munjong (1046-1083), medical education as a path to licensure was encouraged in order to increase the number of physician officers qualifying for licensure by examination; thus, the number of applicants sitting for the examination increased. However, in the late Goryeo Dynasty, after the officer class of the local authorities (hyangri) showed a tendency to monopolize the examination, the Goryeo government limited the examination applications by this group. The medical licensing examination was divided into two parts: medicine and 'feeling the pulse and acupuncture' (jugeumeop). The Goryeo Dynasty followed the Chinese Dang Dynasty's medical system while also taking a strong interest in the Chinese Song Dynasty's ideas about medicine. PMID- 26008919 TI - Bilateral serous retinal detachments associated with IgA nephropathy. AB - CASE REPORT: A 41-year-old woman with a bilateral loss of visual acuity and a history of IgA nephropathy. The ophthalmic examination revealed bilateral neurosensory detachments that resolved completely after four months of peritoneal dialysis. DISCUSSION: Bilateral serous retinal detachments are a rare manifestation of IgA nephropathy, in which the etiology is probably multifactorial and their resolution depends on the underlying disease. PMID- 26008920 TI - Dexamethasone intravitreal implants for diabetic macular edema refractory to ranibizumab monotherapy or combination therapy. AB - OBJECTIVE: To determine the effectiveness and local safety of dexamethasone intravitreal implants as a treatment in diabetic macular edema (DME) refractory to intravitreal injections of ranibizumab monotherapy or combination therapy. METHODS: A retrospective study conducted on patients with DME refractory to ranibizumab monotherapy or combined with other treatments treated with dexamethasone intravitreal implants. The parameters analyzed were visual acuity (VA) by ETDRS (Early Treatment Diabetic Retinopathy Study) charts and foveal thickness by spectral-domain optical coherence tomography (SD-OCT) before the treatment, 2 months after treatment, and at the end of the follow-up. RESULTS: A total of 14 eyes of 14 patients were included, with a mean age of 64 years (SD: 9.5; range 41-78) and a mean follow-up of 7.6 months. The mean VA improved from 53 letters to 59 letters at 2 months (P=.03), and 57 at the end of the follow-up period (P=.3). The mean foveal thickness decreased from 502 MU to 304 MU at 2 months (P=.001), and 376 MU at the end of the follow-up period (P=.009). Further treatment with intravitreal dexamethasone was required in 43% of the patients, and 21% had increased intraocular pressure, which was controlled with topical medication. CONCLUSIONS: Intravitreal dexamethasone implant is an effective and locally safe treatment for the management of DME refractory to ranibizumab monotherapy or combined with other treatments. PMID- 26008918 TI - Optimizing the use of neoadjuvant endocrine therapy. AB - Nowadays, neoadjuvant endocrine therapy is a clinically acceptable (and sometimes preferred) strategy in patients with operable estrogen receptor-positive (ER+) breast cancer. Despite the overall effectiveness of endocrine therapy in breast cancer in all settings, de novo (primary) and acquired (secondary) endocrine therapy resistance remains a major clinical problem. Neoadjuvant endocrine therapy trials for breast cancer are not only a great opportunity to determine which ER+ breast cancers can be treated without chemotherapy, but also a great strategy to develop insights into the biologic basis for the efficacy of estrogen receptor-targeting agents, alone or in combination, in an effort to counteract resistance to endocrine therapy and discover actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in ER+ breast cancers. PMID- 26008921 TI - Which scale should we choose to assess activity and severity in Graves orbitopathy? PMID- 26008922 TI - "Dry Lake" technique for the treatment of hypertrophic bleb following XEN((r)) Gel Stent placement. AB - CASE REPORT: The case of a patient with previous uncomplicated XEN((r)) drainage glaucoma surgery is described, who presented with hypertrophic bleb and mechanical ectropion. Treatment consisted of the "Dry Lake" procedure to drain the hypertrophic bleb following blockage with viscoelastic of the ab-interno stent and bleb sealing with a tissue adhesive. DISCUSSION: Proposals for the management of this type of bleb include therapeutic strategies, sutures or even autologous blood. The use of Tissucol((r)), already described in glaucoma surgery, may be appropriate to treat this complication of XEN((r)) placement. PMID- 26008923 TI - Reproducibility of the water drinking test. AB - OBJECTIVES: To investigate the reproducibility of the water drinking test in determining intraocular pressure peaks and fluctuation. It has been suggested that there is limited agreement between the water drinking test and diurnal tension curve. This may be because it has only been compared with a 10-hour modified diurnal tension curve, missing 70% of IOP peaks that occurred during night. METHODS: This was a prospective, analytical and comparative study that assesses the correlation, agreement, sensitivity and specificity of the water drinking test. RESULTS: The correlation between the water drinking test and diurnal tension curve was significant and strong (r=0.93, Confidence interval 95% between 0.79 and 0.96, p<01). A moderate agreement was observed between these measurements (pc=0.93, Confidence interval 95% between 0.87 and 0.95, p<.01). The agreement was within+/-2mmHg in 89% of the tests. DISCUSSION: Our study found a moderate agreement between the water drinking test and diurnal tension curve, in contrast with the poor agreement found in other studies, possibly due to the absence of nocturnal IOP peaks. CONCLUSIONS: These findings suggest that the water drinking test could be used to determine IOP peaks, as well as for determining baseline IOP. PMID- 26008924 TI - Interleukin-6 concentrations in the vitreous body of patients with retinal detachment. AB - OBJECTIVE: To measure interleuquin-6 (IL-6) levels in the vitreous body of patients with retinal detachment (RD). PATIENTS AND METHODS: Undiluted vitreous samples were obtained from 40 patients with no history of prior vitreous or intraocular surgery. Patients were divided into two groups: A (n=20) patients with RD and B (n=20) patients with pre-retinal macular membranes and macular holes. IL-6 was determined using radioimmunoassay. RESULTS: IL-6 vitreous concentration in group A was 122.4+-16pg/mL (range 91.5-620) and in group B was 46+/-23pg/mL (range 3-150) (p <.001). CONCLUSIONS: These results show that the concentration of IL-6 in the vitreous body was significantly higher in patients with RD than in the control group. PMID- 26008925 TI - Morphological characteristics of the optic nerve evaluated by confocal laser tomography (HRT3) and laser polarimetry (GDx-VCC) in a normal population from the city of Barcelona. AB - OBJECTIVE: To evaluate morphological parameters of optic disc and retinal nerve fiber layer (RNFL) examined with confocal laser tomography (HRT3) and laser polarimetry (GDx-VCC) in a normal population, and analyze correlations of these parameters with demographic variables. PATIENTS AND METHODS: Cross-sectional study in the context of a glaucoma screening campaign in the primary care center of Barcelona. The individuals selected were non-hypertensive Mediterranean Caucasians with risk for glaucoma development (individuals>=60 years old or>=40 years old with family history of glaucoma or intraocular pressure or myopia>3diopter). All subjects underwent a complete ophthalmic examination, confocal laser tomography (HRT3) and scanning laser polarimetry (GDX-VCC), subjects with results within normal limits only being included. Structural parameters were analyzed along with age, refraction, and pachymetry based on the Spearman rank correlation test. RESULTS: A total of 224 subjects included, with a mean age of 63.4+/-11.1 years. Disc areas, excavation and ring area were 2.14+/ 0.52mm(2), 0.44+/-0.34mm (2) and 1.69+/-0.38mm(2), respectively. The mean RNFL (GDX) was 55.9+/-6.9MUm. Age was correlated with lower ring volume, highest rate of cup shape measure, largest mean and maximum cup depth, lower nerve fiber index (NFI) and RNFL (all p-values below .05). CONCLUSION: The mean values and distribution of several parameters of the papilla and the RNFL in normal Mediterranean Caucasians population are presented. A loss of thickness of the RNFL, ring thinning, and enlarged cup was observed with increased age. PMID- 26008926 TI - Stenotrophomonas maltophilia keratitis treated with trimethoprim sulfamethoxazole. AB - CASE REPORT: An 84 year-old woman with persistent epithelial defect and a dense stromal infiltrate post-corneal transplantation. According to the microbiological results, it was due to a Stenotrophomonas maltophilia (S. maltophilia) resistant to all antibiotics except trimethoprim-sulfamethoxazole (TMP/SMX). Healing was achieved after three weeks of treatment with oral and topical TMP/SMX. DISCUSSION: S. maltophilia is an opportunistic microorganism rarely described in ophthalmology. It is associated with conjunctivitis, keratitis, scleritis, dacryrocystitis, cellulitis, and endophthalmitis with significant morbidity. Treatment is complicated because of its resistances to broad-spectrum antibiotics. TMP/SMX monotherapy can be considered an option of treatment for this type of keratitis. PMID- 26008927 TI - Effect of Muller cells on the survival and neuritogenesis in retinal ganglion cells. AB - OBJECTIVE: Retinal ganglion cells (RGCs) are the first affected cells in neuropathies like glaucoma, for that reason it is very important to explore new methods to neuroprotect these neurons. Muller cells are glial cells that provide the neurons with trophic factors and scaffold. The purpose of this study was to analyze the effect of Muller cells on survival and neurite formation in RGCs. METHOD: Rat Muller cells were grown until a confluent culture on which rat RGCs were added, using pure culture of rat RGCs as controls. RGCs were labeled with betaIII-tubulin, and Muller cells with glutamine synthetase antibodies. In addition, nuclei were stained with DAPI. The number of RGCs and number and neurite length were measured. RESULTS: No differences were found in the number of RGCs between control and cells grown on the substrate of Muller cells. The proportion of RGCs with neurites increased when they grew on Muller (RGCs with 1 3 neurites increased from 19% to 43%. The length of neurites also increased in RGCs grown on Muller cells, with the number of RGCs with neurites from 50 to 200MUm increasing from 21% to 41%, and with neurites of more than 200MUm the increase was from 6% to 20%. CONCLUSIONS: Muller cells support the survival of RGCs and induced an increase in the number and length of neurites of RGCs. PMID- 26008928 TI - Pigment dispersion syndrome associated with optic nerve melanocytoma. AB - CASE REPORT: A 60-year old patient was referred for cataract surgery. The examination showed retrokeratic pigment in the left eye, which had an intraocular pressure of 24 mm Hg. The funduscopy showed a brown lesion on the left optic disk, with adjacent vitreous seeding of pigment. The patient was thus diagnosed with secondary pigment dispersion syndrome due to optic disk melanocytoma. DISCUSSION: Although melanocytoma is most commonly a benign, stationary tumor, it may present with major complications leading to significant visual loss. A patient with melanocytoma of the optic disk should be examined periodically. PMID- 26008929 TI - Alternative treatment for retinoblastoma: Intra-arterial chemotherapy with melphalan. AB - CASE REPORT: A 10-month old infant was referred for the study of a leukocoria of the left eye of one month onset. On examination, a retinoblastoma occupying the macular area was detected. Treatment with intra-arterial chemotherapy (melphalan 6 mg) was performed, with no further intervention required for disease control. DISCUSSION: Melphalan is an effective chemotherapeutic agent. However, its use is limited by the systemic toxicity that may occur. Intra-arterial chemotherapy allows the selective release of melphalan into the ophthalmic artery, thus limiting its systemic toxicity. This combination of efficiency, safety and accuracy makes it an attractive therapeutic alternative for the management of retinoblastoma. PMID- 26008930 TI - [Deep layers of the cornea and basic research in Spain]. PMID- 26008931 TI - When all else fails: Tectonic keratoplasty with silica gel re-dried cornea in a patient with high risk of corneal perforation. PMID- 26008932 TI - Editors' welcome. PMID- 26008933 TI - On the origin of Neurostatus. PMID- 26008934 TI - Further to the origin of EDSS (Response to: L. Kappos et al: "On the origin of Neurostatus" Multiple Sclerosis and Related Disorders 2015; 4: 186). PMID- 26008935 TI - Smoke and mirrors: Limited value of relative risk reductions for assessing the benefits of disease-modifying therapies for multiple sclerosis. AB - A reduction in relapse rate is the main primary outcome in most clinical trials in patients with multiple sclerosis (MS), with the effect of a treatment commonly expressed as relative risk reduction for this outcome. Physicians often assume that a drug with a higher relative risk reduction demonstrated in one trial is more effective than a drug with a lower relative risk reduction in another, and may pass this idea on to younger physicians and to patients. The use of the relative risk reduction as a measure of drug efficacy can be misleading, as it depends on the nature of the population studied: a treatment effect characterized by a lower relative risk reduction may be more clinically meaningful than one with a higher relative risk reduction. This concept is especially important with regard to clinical trials in patients with MS, where relapse rates in placebo groups have been declining in recent decades. Direct, head-to-head comparisons are the only way to compare the efficacy of the different treatments for MS. PMID- 26008936 TI - Functional clinical outcomes in multiple sclerosis: Current status and future prospects. AB - For decades, the Expanded Disability Status Scale (EDSS) has been the principal measure of disability in clinical trials in patients with multiple sclerosis (MS) and in clinical practice. However, this test is dominated by effects on ambulation. Composite endpoints may provide a more sensitive measure of MS related disability through the measurement of additional neurological functions. The MS Functional Composite (MSFC) includes a walking test (25-ft walk) plus tests of upper extremity dexterity (9-hole peg test) and cognitive function (Paced Auditory serial Addition test [PASAT]). Replacing PASAT with the Symbol Digit Modality test, a more sensitive test preferred by patients, may improve the clinical utility of the MSFC. In addition, disease-specific measures of QoL may be used alongside the MSFC (which does not include measurement of QoL). Clinical data suggest that disease-modifying therapies may delay or prevent relapse, and better composite measures will be valuable in the assessment of disease activity free status in people with MS. PMID- 26008937 TI - Achieving patient engagement in multiple sclerosis: A perspective from the multiple sclerosis in the 21st Century Steering Group. AB - While advances in medicine, technology and healthcare services offer promises of longevity and improved quality of life (QoL), there is also increasing reliance on a patient's skills and motivation to optimize all the benefits available. Patient engagement in their own healthcare has been described as the 'blockbuster drug of the century'. In multiple sclerosis (MS), patient engagement is vital if outcomes for the patient, society and healthcare systems are to be optimized. The MS in the 21st Century Steering Group devised a set of themes that require action with regard to patient engagement in MS, namely: 1) setting and facilitating engagement by education and confidence-building; 2) increasing the importance placed on QoL and patient concerns through patient-reported outcomes (PROs); 3) providing credible sources of accurate information; 4) encouraging treatment adherence through engagement; and 5) empowering through a sense of responsibility. Group members independently researched and contributed examples of patient engagement strategies from several countries and examined interventions that have worked well in areas of patient engagement in MS, and other chronic illnesses. The group presents their perspective on these programs, discusses the barriers to achieving patient engagement, and suggests practical strategies for overcoming these barriers. With an understanding of the issues that influence patient engagement in MS, we can start to investigate ways to enhance engagement and subsequent health outcomes. Engaging patients involves a broad, multidisciplinary approach. PMID- 26008939 TI - Disease modifying therapies use associated with comorbid autoimmune diseases in multiple sclerosis patients. AB - BACKGROUND: The relation between the use of disease modifying therapies (DMT's) and the occurrence of comorbid autoimmune diseases (AID's) in multiple sclerosis (MS) patients is still unclear. OBJECTIVE: To investigate the difference in duration from MS symptom onset to first reported AID in subjects using DMT's vs. DMT naive. Type and prevalence of comorbid AID's was also investigated. METHODS: Data was extracted from the New York State MS Consortium (NYSMSC) registry and comprised of MS patients with a minimum of 5 years follow-up. After exclusion, 1792 patients were enrolled in the study, 1478 had no AID, and 314 patients had comorbid AID's that developed after the initial enrollment. Patients who had an AID were divided into two groups: those with an AID after DMT initiation (n=281) and patients with an AID who were DMT naive (n=33). Logistic regression analysis was used to test differences in duration between MS symptom onset and the development of AID between the two groups while adjusting for confounders RESULTS: DMT use did not change the frequency of self-reported AID (17.2 vs. 20.4%). However, the duration between first MS symptom onset and the initial reported occurrence of a comorbid AID was significantly shorter in the DMT user group (192 months+/-115) compared to the DMT naive group (262 months+/-107, p=.002). CONCLUSION: There were no group differences between DMT users vs. DMT naive subjects with regards to AID frequency. The DMT user group reported the development of an AID earlier than the DMT naive group. Further studies that can identify patients with higher risk for developing AID's is warranted. PMID- 26008938 TI - Systematic review of efficacy of TENS for management of central pain in people with multiple sclerosis. AB - BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a non pharmacological therapy that can be used for central pain (CP) management without the side effects of pharmacological interventions. Currently, the efficacy of TENS for management of CP in people living with multiple sclerosis (MS) is considered questionable. METHODS: Relevant electronic databases were searched from their inception to November 2014 using appropriate terms for case-control (CC) studies or randomized controlled trials (RCTs) utilizing TENS for management of CP in MS. Included studies were combined in a meta-analysis. A standardized mean difference (SMD) expressed as Hedges' g and 95% confidence interval (CI) of efficacy of TENS intervention were computed using a random effects model. The resulting evidence was graded in accordance to the GRADE system. RESULTS: A total of 11 effect sizes were extracted from four studies. High and low frequency TENS was utilized in separate subgroup of participants in three studies and conventional TENS in one study. These seven effect sizes were combined for the final analysis (one effect size for each subgroup of participants). Two studies measured pain using visual analog scale and McGill Pain Questionnaire. The findings of this study demonstrate a medium sized statistically significant effect of TENS for management of CP in people with MS [Hedges' g=0.35; p=0.009]. The frequency of TENS or outcome used to measure pain had no effect on our study results. These findings are consistent with GRADE 2 level of evidence. CONCLUSION: TENS is a safe and effective non-pharmacological alternative in the management of central pain in people living with MS. TENS intervention to address CP is desirable. PMID- 26008940 TI - Impact of multiple sclerosis relapse: The NARCOMS participant perspective. AB - Acute relapses continue to be a significant aspect of multiple sclerosis (MS) on both the epidemiologic level and the individual patient level. Past work demonstrates residual disability from relapses as well as high patient-reported rates of ineffective relapse treatment. To better characterize the impact of MS relapses on the patient, a relapse-specific survey was administered through the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry to 1000 registry participants who had reported at least one relapse in the past 12 months. Thirty percent of respondents confirmed lack of relapse treatment efficacy at one month and at three months. Relapses also impacted socioeconomic measures; for individuals still going to school or working, more than half missed days and their average loss of school or work was 12.7 days. An impact on household tasks was reported by 68% of respondents. A healthcare facility such as a hospital, emergency room or urgent care center was utilized by 20.4% of respondents. The most common relapse symptoms were fatigue, weakness of the lower extremity, sensory symptoms, problems walking, and weakness of the upper extremity. Of the respondents who reported receiving corticosteroid treatment (53.3%), over half reported an adverse event. However, this was not a significant factor in dictating whether or not respondents would seek a different treatment on their next relapse, although 31% would choose a different treatment for their next relapse. Relapses continue to be an impactful experience that requires continued clinical attention. Improved follow-up from relapses and relapse treatment might be beneficial. PMID- 26008941 TI - Risk tolerance to MS therapies: Survey results from the NARCOMS registry. AB - BACKGROUND: There is little information about risk acceptance of multiple sclerosis (MS) patients to various MS therapies. OBJECTIVE: To determine MS patients' tolerance to risky therapies and identify associated characteristics. METHODS: MS patients from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry's online cohort were invited to complete questionnaires on decision making and risk tolerance (RT) to two therapeutic scenarios: a theoretical cure for MS [CureMS], with permanent reversal of all MS symptoms but a risk of immediate painless death; and natalizumab [NAT], a real life scenario with benefits and risks as defined by Phase III trial results. RESULTS: The median RT for both scenarios was 1:10,000; 15-23% of respondents were not willing to take any risk for their MS therapy. Participants with greater disability or not taking any MS therapy showed a greater RT, while females and those caring for dependents had a lower RT. Females and older age were predictors of lower RT, while increasing disability and greater blunting attitude with respect to information seeking behavior were predictors of higher RT. CONCLUSION: MS patients displayed a wide range of RT for MS therapies. Our study identified gender, age, disability and information seeking behavior to be associated with RT. PMID- 26008942 TI - Multiple sclerosis in India: An institutional study. AB - BACKGROUND: Few population based studies on multiple sclerosis have been published from India. There is an increasing demand to establish a nationwide MS registry in India especially in view of the percieved increased incidence and prevalence. OBJECTIVES: To create a registry data base for all MS patients presenting at our institute and understand the disease characteristics in our population and compare them with the published reports from the west. METHODS: MS was diagnosed on the basis of clinical and imaging features (Revised McDonald's criteria 2010). Demographics, clinical data, treatment details and disease behavior were recorded over a follow up of one year. Descriptive analyses was performed. RESULTS: 101 patients (61 females) were recruited in the study period from June 2011 to December 2012. Mean age of the patients at the time of presentation was 33.3+/-9.2 years and mean duration of illness was 5.98+/-4.95. 68.4% patients had RRMS, 16.8% had SPMS whereas 14.8% patients had PPMS. Site(s) involved in first relapse was spinal cord in 43.7% patients followed by brainstem 25.3% and optic nerve in 24.1% patients. Mean number of relapses were 3.26+/ 2.026. Mean EDSS at the time of presentation was 3.20+/-2.11. Overall, 55.44% patients took DMT at some point during their course of disease. No significant differences were observed between our patient characteristics when compared to publications from west. CONCLUSION: Demographic data in the present study are comparable to those reported in population-based epidemiological studies from west. A nationwide registry network will help establish stronger data on incidence, prevalence and disease profile of MS in India. PMID- 26008943 TI - Autonomic symptom burden is associated with MS-related fatigue and quality of life. AB - BACKGROUND: Nonspecific symptoms such as fatigue and dizziness are common in multiple sclerosis (MS), even in patients with normal exams. Little is known about the relationship of autonomic dysfunction with these symptoms and quality of life. OBJECTIVE: Assess the association of autonomic symptom burden with fatigue, clinical status and quality of life. METHODS: Subjects completed an autonomic symptom (COMPASS-31), quality of life (MSQOL-54) and fatigue (FSS) questionnaire at their routine MS clinic follow-up. Demographic and clinical data were collected from the medical record. Pearson correlations were assessed between autonomic symptoms and fatigue, quality of life, disability and disease duration. RESULTS: One-hundred subjects completed the study (mean age 48 years; 78% female; 84% relapsing-remitting), mean disease duration was 14.7 years and mean EDSS 2.5. MSQOL-54 composite scores were 58 physical and 65 mental. COMPASS 31 correlated with MSQOL-54 (Physical R= -0.60; Mental -0.54; p<0.001) and FSS (R=0.51; p<0.001). There was no relationship between COMPASS-31 and EDSS (R=0, p=0.97) or disease duration (R= -0.02, p=0.84). CONCLUSIONS: Autonomic symptom burden is correlated with decreased quality of life and increased fatigue. Autonomic symptoms are present early in the disease and at low disability and may reflect aspects of disease burden that are not well-captured by current disability measures. PMID- 26008944 TI - Cervical cord area is associated with infratentorial grey and white matter volume predominantly in relapsing-remitting multiple sclerosis: A study using semi automated cord volumetry and voxel-based morphometry. AB - BACKGROUND AND PURPOSE: Atrophy of the brain and the upper cervical cord, which both have major impact on the severity of clinical symptoms in multiple sclerosis (MS), may be interrelated by neuraxonal degeneration. Aiming to identify possible spatially remote effects of neuraxonal brain damage on spinal cord atrophy, we studied regional and global brain volumes and the upper cervical cord area (UCCA) in a large group of MS patients and a healthy control group. METHODS: In a group of 132 MS patients (71 relapsing-remitting MS; 61 secondary progressive MS; median [range] of EDSS: 5 [0-7], respectively 6 [2-8.5] and mean+/-standard deviation of age/disease duration: 37+/-11 years/6.7+/-6.3 years; respectively: 49+/-8 years/14.5+/-8.0 years) and 45 healthy subjects UCCA, regional and global brain volumes, and brain lesion load were assessed. Associations between MRI results and clinical parameters in the entire cohort and differentiated according to MS-subtype were investigated using t-tests, partial correlation analyses, voxel-based morphometry and statistical parametric mapping. RESULTS: Exclusively in RRMS, a significant positive correlation of UCCA with cerebellar cortical grey matter (GM) in the vermis and with regional white matter volume in the entire brainstem, corresponding to the corticospinal tracts, was detected. Although SPMS patients were considerably more affected by disability and decrease of UCCA (RRMS:75.2+/-10.4 mm(2); SPMS: 66.0+/-11.8 mm(2),controls: 84.5+/-8.7mm(2)), brain grey matter (RRMS:585.8+/-53.6 ml; SPMS: 528.2+/-61.5 ml, controls: 608.7+/ 48.1 ml) and total brain volume (RRMS:1162.9+/-41.8 ml; SPMS: 1117.9+/-51.2 ml, controls: 1194.1+/-19.5 ml) than RRMS patients, significant positive associations in this group were found only between UCCA and a cluster of white matter in the medulla, but not in grey matter. CONCLUSION: Cervical cord and brain atrophy were present in both, RRMS and even more severe in SPMS. Still, spatial associations between cervical cord area and remote cerebellar and brainstem volume, possibly driven by neuraxonal degeneration, were detected mostly in RRMS patients with predominantly short disease durations. Future longitudinal studies may elucidate the interplay between affection of spinal cord and infratentorial structures in MS, and contribute to the understanding of the conversion processes from relapsing-remitting to secondary progressive MS. PMID- 26008946 TI - Transverse myelitis presenting in a patient with Hughes-Stovin syndrome. PMID- 26008945 TI - Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors. AB - Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya((r)), Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6 h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6 h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5 mg, -7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod 0.5 mg, -6.6 bpm; placebo, 0.3 bpm). In patients treated with fingolimod 0.5 mg, the mean change in corrected QT interval from baseline to 6 h after treatment initiation was under 10 ms, and few patients had absolute corrected QT intervals of over 450 ms (men) or 470 ms (women), calculated according to Bazett's or Fridericia's correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83-86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation. PMID- 26008947 TI - Interferon beta related pulmonary arterial hypertension; an emerging worrying entity? PMID- 26008948 TI - Different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast of the human placenta. AB - INTRODUCTION: The syncytiotrophoblast (STB) epithelial covering of the villous tree in the human placenta is a multi-nucleated syncytium that is sustained by continuous incorporation of differentiating cytotrophoblast (CTB) cells. STB nuclei display a variety of morphologies, but are generally more condensed in comparison to CTB nuclei. Here, we consider whether this condensation is a feature of epigenetic regulation of chromatin structure. METHODS: Semi quantitative immunohistochemical investigations of a panel of histone modifications were performed to determine the relative proportions in CTB and STB nuclear populations. We also investigated the patterns of DNA methylation and distribution of DNA methyltransferases enzymes in these populations. RESULTS: Unexpectedly DNA methylation, and H3K9me3 and H3K27me3, which are modifications associated with heterochromatin, are present at lower levels in STB nuclei compared to CTB, despite the intensive condensation in the former nuclear population and the progenitor state of the latter. By contrast, STB nuclei are enriched for H4K20me3, which is also associated with repressive states. 5'hydroxymethylcytosine immunoreactivity is higher in STB, with intense staining observed in the highly condensed nuclei within syncytial knots. DISCUSSION: Cell type specific epigenetic states exist within the trophoblast populations potentially regulating their different functions and developmental properties and suggesting non-canonical epigenetic states associated with the properties of these cells. PMID- 26008949 TI - Regioselective direct oxidative C-H cyanation of quinoline and its derivatives catalyzed by vanadium-containing heteropoly acids. AB - A direct oxidative C-H cyanation of quinoline and its derivatives using trimethylsilyl cyanide as the cyano source and molecular oxygen as the terminal oxidant has been developed. In the presence of catalytic amounts of vanadium containing heteropoly acids, e.g., H7PV4Mo8O40, cyanation of various quinoline and its derivatives preferentially took place at the 4-position, affording the corresponding substituted 4-cyanoquinolines as the major products. PMID- 26008950 TI - Design of novel fluorescent mitochondria-targeted peptides with iron-selective sensing activity. AB - Mitochondrial labile iron (LI) plays a crucial role in oxidative injuries and pathologies. At present, there is no organelle-specific sensitive iron sensor which can reside exclusively in the mitochondria and reliably monitor levels of LI in this organelle. In the present study, we describe the development of novel fluorescent and highly specific mitochondria iron sensors, using the family of mitochondria-homing 'SS-peptides' (short cell-permeant signal peptides mimicking mitochondrial import sequence) as carriers of highly specific iron chelators for sensitive evaluation of the mitochondrial LI. Microscopic analysis of subcellular localization of a small library of fluorescently labelled SS-like peptides identified dansyl (DNS) as the lead fluorophore for the subsequent synthesis of chimaeric iron chelator-peptides of either catechol (compounds 10 and 11) or hydroxypyridinone (compounds 13 and 14) type. The iron-sensing ability of these chimaeric compounds was confirmed by fluorescent quenching and dequenching studies both in solution and in cells, with compound 13 exhibiting the highest sensitivity towards iron modulation. The intramolecular fluorophore-chelator distance and the iron affinity both influence probe sensitivity towards iron. These probes represent the first example of highly sensitive mitochondria directed fluorescent iron chelators with potential to monitor mitochondrial LI levels. PMID- 26008951 TI - High Tibial Osteotomy in Combination With Chondrogenesis After Stem Cell Therapy: A Histologic Report of 8 Cases. AB - PURPOSE: To histologically evaluate the quality of articular cartilage regeneration from the medial compartment after arthroscopic subchondral drilling followed by postoperative intra-articular injections of autologous peripheral blood stem cells (PBSCs) and hyaluronic acid with concomitant medial open-wedge high tibial osteotomy (HTO) in patients with varus deformity of the knee joint. METHODS: Eight patients with varus deformity of the knee joint underwent arthroscopic subchondral drilling of International Cartilage Repair Society (ICRS) grade 4 bone-on-bone lesions of the medial compartment with concomitant HTO. These patients were part of a larger pilot study in which 18 patients underwent the same procedure. PBSCs were harvested and cryopreserved preoperatively. At 1 week after surgery, 8 mL of PBSCs was mixed with 2 mL of hyaluronic acid and injected intra-articularly into the knee joint; this was repeated once a week for 5 consecutive weeks. Three additional intra-articular injections were administered weekly at intervals of 6, 12, and 18 months postoperatively. Informed consent was obtained at the time of hardware removal for opportunistic second-look arthroscopy and chondral biopsy. Biopsy specimens were stained with H&E, safranin O, and immunohistochemical staining for type I and II collagen. Specimens were graded using the 14 components of the ICRS Visual Assessment Scale II, and a total score was obtained. RESULTS: Second-look arthroscopy showed satisfactory healing of the regenerated cartilage. Histologic analysis showed significant amounts of proteoglycan and type II collagen. The total ICRS Visual Assessment Scale II histologic scores comparing the regenerated articular cartilage (mean, 1,274) with normal articular cartilage (mean, 1,340) indicated that the repair cartilage score approached 95% of the normal articular cartilage score. There were no infections, delayed unions, or nonunions. CONCLUSIONS: Chondrogenesis with stem cells in combination with medial open-wedge HTO for varus deformity correction of the knee joint regenerates cartilage that closely resembles the native articular cartilage. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26008952 TI - Outcome After Arthroscopic Reconstruction of the Coracoclavicular Ligaments Using a Double-Bundle Coracoid Cerclage Technique. AB - PURPOSE: We report the outcome of an arthroscopic technique for coracoclavicular ligament reconstruction using an anatomic coracoid cerclage. METHODS: Between March 2011 and September 2012, 12 consecutive patients with symptomatic chronic (>4 weeks from injury) type V acromioclavicular separation for which nonoperative treatment failed were treated with arthroscopic double-bundle reconstruction of the coracoclavicular ligaments using tendon allograft by the first author. The clinical records, operative reports, and preoperative and follow-up radiographs were reviewed. The visual analog scale score, Subjective Shoulder Value, Simple Shoulder Test score, and Constant-Murley score were evaluated preoperatively and at each follow-up appointment. RESULTS: The study included 12 shoulders in 12 young active-duty soldiers with symptomatic high-grade acromioclavicular separation who were treated with a technique for arthroscopic reconstruction of the coracoclavicular ligaments. The mean age was 25 years (range, 20 to 35 years). The injury occurred during sports activity in 11 patients. One patient was injured in a motorcycle accident. The mean time from injury to surgery was 17.8 months (range, 1.5 to 72 months). The minimum length of follow-up was 24 months (mean, 30.4 months; range, 24 to 42 months). The mean preoperative and postoperative outcome scores were significantly different (P < .0001) for all subjective outcome measures. The mean Constant-Murley score improved from 58.4 (range, 51 to 76) to 96 (range, 88 to 100). The mean visual analog scale score improved from 8.1 (range, 7 to 10) to 0.58 (range, 0 to 2). The mean Subjective Shoulder Value improved from 32.9% (range, 10% to 70%) to 95% (range, 80% to 100%). The mean Simple Shoulder Test score improved from 6 (range, 5 to 8) to 11.83 (range, 11 to 12). All patients returned to their normal preinjury level of activity by 6 months. Radiographs at last follow-up showed no loss of reduction with maintenance of the coracoclavicular interval. There was 1 complication (8.5%), a postoperative superficial wound infection, that was treated accordingly. CONCLUSIONS: We present an arthroscopic technique for double-bundle tendon graft reconstruction of the coracoclavicular ligaments using the coracoid cerclage technique. This method showed good outcomes and maintenance of radiographic reduction with high patient satisfaction and a low complication rate. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26008953 TI - Long-Term Outcome of Endonasal Transsphenoidal Approach for the Treatment of Pontine Cavernous Malformation: Case Report with 11 Years of Follow-Up. AB - Ventromedial localized cavernous malformations in the pons pose a difficult problem because of their surgical access and the high risk of deleterious consequences due to damage of the surrounding tissues. We report an endonasal transsphenoidal approach for the treatment of ventromedial pontine cavernomas that also follows principles of optimal access known as the "two-point method" for the resection of cavernous malformations. A 31-year-old woman presented with sudden left hemiparesis, nausea, and headache. Radiologic findings demonstrated a ventral pontine cavernous malformation in the midline slightly extending to the right, together with signs of acute hemorrhage. Surgical intervention was performed, and the cavernoma was completely resected via a transnasal transsphenoidal approach. Cerebrospinal fluid (CSF) rhinorrhea that ensued postoperatively needed an additional reconstructive surgery using the same approach. No further CSF leakage was evident, and an 11-year follow-up examination revealed neither signs of neurologic deficit nor recurrence of the resected pontine cavernoma. The long-term outcome proves the effectiveness and safety of this novel surgical route in the treatment of ventromedial cavernous malformations in the pons. PMID- 26008954 TI - Endoscopic Approaches to Intraventricular Lesions. AB - BACKGROUND: Endoscopy is becoming increasingly popular for the neurosurgical management of intraventricular lesions and has recently been accepted as an effective alternative approach to open surgery. The deep location of intraventricular lesions makes the microsurgical approach difficult. Moreover, many intraventricular tumors do not require aggressive neurosurgical treatment. Some of these lesions are even associated with hydrocephalus or an enlarged ventricular system. METHODS: We collected the data of 32 patients affected by purely intraventricular lesions in the lateral or third ventricles who underwent 33 endoscopic intraventricular procedures from 2006 to 2011. We classified the lesions according to their location within the ventricles so as to plan the best endoscopic trajectory. We approached the lesions using rigid and flexible endoscopes through precoronal or supraorbital trajectories according to their localization and the presence of hydrocephalus. In many procedures we used neuronavigation. RESULTS: Thirty-three endoscopic intraventricular procedures were performed in 32 patients; 27 procedures were performed via the precoronal, and 6 procedures via the supraorbital frontopolar approach. A complete excision of the lesion was obtained in only three cases. In all other cases, a biopsy was taken. CONCLUSIONS: Our series shows that an endoscopic approach to intraventricular lesions should be tailored according to localization of the lesion and ventricular size. The complete excision of intraventricular lesions is often impossible with the endoscope, but biopsies allow diagnoses to be obtained in almost all cases. PMID- 26008955 TI - Spinal Extradural Arachnoid Cysts: A Series of 10 Cases. AB - BACKGROUND AND OBJECTIVE: Spinal arachnoid cysts are rare lesions, accounting for only 1% of all primary spinal mass lesions. They can occur in extradural, intradural, or intramedullary locations. The extradural cysts are thought to arise from defects in the dura mater through which the arachnoid herniates. This report presents 10 cases of spinal extradural arachnoid cysts and discusses our diagnostic and therapeutic approach to this rare clinical entity. PATIENTS: The archive records of 10 patients with extradural arachnoid cysts who were treated between 2002 and 2009 were evaluated retrospectively. The study included four male and six female patients. In nine cases, the lesion was symptomatic; in only one case was the cyst diagnosed incidentally. Surgical treatment was performed in the nine symptomatic cases. RESULTS: In nine of these cases, the extradural cysts were solitary; in one case, multiple extradural cysts were observed. In most of the cases, the lesion was located in the thoracic region. Total excision of the cyst was achieved for all of the cases treated surgically except the case with multiple extradural arachnoid cysts. On follow-up examination, neurologic improvement was observed in all of the surgically treated patients. CONCLUSION: Spinal extradural arachnoid cysts are rare pathologies, and treatment options should be considered carefully. In symptomatic cases, total excision of the cyst should be considered the gold standard of treatment. We believe that the closure of the dural defect should be the main surgical goal to prevent recurrence. We propose laminoplasty for the treatment of extradural arachnoid cysts that involve multiple segments to prevent postoperative kyphosis. PMID- 26008956 TI - Modified Anterior Temporal Lobectomy: Anatomical Landmarks and Operative Technique. AB - There is great controversy about which surgical approach is the most selective and efficient for resection of mesial structures of the temporal lobe for treatment of mesial temporal lobe epilepsy. Selective approaches have been described in an attempt to preserve the neocortex and the temporal stem. Nonselective approaches, such as anterior temporal lobectomy (ATL), result in injuries in these structures. We describe a modified selective technique for resection of the amygdala and hippocampus with resection of the temporal pole performed through the Sylvian fissure based on anatomical landmarks and diligent microsurgical techniques. Briefly, after opening the Sylvian fissure, the temporal pole is resected and the temporal horn is directly accessed through the uncus, in an anteroposterior direction, preserving the temporal stem and the neocortex of the temporal lobe. The surgical technique used by our group is described in detail with illustrations. Precise microsurgical techniques associated with knowledge of microsurgical anatomy are of paramount importance for temporal lobe epilepsy surgery. According to our analysis, the modified ATL approach to the temporal mesial structures is a feasible selective technique that can be used as an alternative to traditional surgical procedures. PMID- 26008957 TI - Hyperbranched polyphosphates: synthesis, functionalization and biomedical applications. AB - Hyperbranched polyphosphates (HBPPs) are newly emerged polymeric biomaterials with repeating phosphate bonds in a highly branched framework over the past 5 years. Due to the integration of the advantages of both hyperbranched polymers and polyphosphates, HBPPs are versatile in chemical structure, flexible in physicochemical properties, water soluble, biocompatible and biodegradable in biological features. On the basis of their excellent water solubility, biocompatibility, biodegradability and potential functionalization as well as their simple preparation in one-pot synthesis, HBPPs have fascinating biomedical applications, especially for drug delivery. In this tutorial review, the recent advances of HBPPs are summarized. HBPPs with different topological structures and various functionalities were synthesized via adjusting the side group of cyclic phosphate monomers, which have shown promising biomedical applications, for example, using as a macromolecular anticancer agent and constructing advanced drug delivery systems, including site-specific delivery systems, self-delivery systems, and stimuli-responsive delivery systems. Such progress may promote the further development of interdisciplinary research between polymer chemistry, material science and biomedicine. PMID- 26008958 TI - New avenues to prevent sudden unexpected death in nocturnal frontal lobe epilepsy: follow the route established by omega-3 polyunsaturated fatty acids. PMID- 26008959 TI - Emotional memory processing is influenced by sleep quality. AB - OBJECTIVE: The recall of emotional memory is enhanced after sleep and is hindered by sleep deprivation. We used an emotional memory task to assess whether poor sleep quality, as well as sleep deprivation, may influence the accuracy of memory recognition, but also the affective tone associated with the memory. METHODS: Seventy-five subjects, divided into poor sleeper (PS), good sleeper (GS), and sleep deprivation (SD) groups, completed two recall (R) sessions: R1, 1 h after the encoding phase; and R2, after one night of sleep for PS and GS groups and after one night of sleep deprivation for the SD group. During the encoding phase, the participants rated valence and arousal of 90 pictures. During R1 and R2, the participants first made a yes/no memory judgment of the 45 target pictures intermingled with 30 non-target pictures, then rated valence and arousal of each picture. RESULTS: Recognition accuracy was higher for the PS and GS groups compared to the SD group for all pictures. Emotional valence of the remembered pictures was more negative after sleep deprivation and poor quality sleep, while it was preserved after a good sleep. CONCLUSIONS: These results provide the first evidence that poor sleep quality negatively affects emotional valence of memories, within the context of preserved emotional memory consolidation. It is suggested that low sleep quality and lack of sleep may impose a more negative affective tone to memories. The reported effects are not to be ascribed to depressive mood, but to a specific influence of poor sleep quality. PMID- 26008960 TI - Is a diverting ostomy needed in mid-high rectal cancer patients undergoing a low anterior resection after neoadjuvant chemoradiation? An NSQIP analysis. AB - INTRODUCTION: A diverting stoma is often performed at the time of low anterior resection (LAR) for rectal cancer after neoadjuvant chemoradiation (nCRT) to protect the anastomosis. The aim of this study was to compare surgical outcomes in large cohorts of mid-high rectal cancer patients undergoing LAR after nCRT with and without a diverting stoma. METHODS: Patients undergoing LAR for rectal cancer (ICD-9 diagnosis code 154.1) after nCRT were identified from the American College of Surgeons National Surgical Quality Improvement Program database records from 2005 to 2012. Using Current Procedural Terminology (CPT) codes for LAR for mid-high rectal tumors, patients were stratified into diverting stoma (CPT: 44146, 44208) or no diverting stoma (CPT: 44145, 44207) cohorts. Emergency resection, stage IV disease, and permanent end colostomy patients were excluded. RESULTS: We included 1,406 patients in the analysis. All patients received nCRT; 607 (43%) received a diverting stoma and 799 (57%) were not diverted. The diverted group was more likely to have a higher body mass index (28.3 vs 27.4 kg/m(2); P = .02) and hypertension (46% vs 39%; P = .002). Otherwise, the group demographics and comorbidities were comparable. Overall morbidity was 28% for the entire cohort with no differences in deep organ space infection, sepsis and septic shock, unplanned reoperation, duration of stay, or overall mortality between the groups. CONCLUSION: Diverting stoma does not decrease mortality or infectious complications in mid-high rectal cancer patients undergoing LAR after nCRT. The decision to construct a protective stoma should not be driven solely on the receipt of nCRT. PMID- 26008961 TI - Influence of body mass index on outcomes after major resection for cancer. AB - BACKGROUND: Evidence supporting worse outcomes among obese patients is inconsistent. This study examined associations between body mass index (BMI) and outcomes after major resection for cancer. METHODS: Data from the 2005-2012 ACS NSQIP were used to identify cancer patients (>=18 years) undergoing 1 of 6 major resections: lung surgery, esophagectomy, hepatectomy, gastrectomy, colectomy, or pancreatectomy. We used crude and multivariable regression to compare differences in 30-day mortality, serious and overall morbidity, duration of stay, and operative time among 3 BMI cohorts defined by the World Health Organization: normal versus underweight, overweight-obese I, and obese II-III. Propensity scored secondary assessment and resection type-specific stratified analyses corroborated results. RESULTS: A total of 529,955 patients met inclusion criteria; 32.06% had normal BMI, 3.45% were underweight, 32.52% overweight, and 17.76%, 7.51%, and 4.94% obese I-III, respectively. Risk-adjusted outcomes for underweight patients consistently were worse. Overweight-obese I fared similarly to patients with normal BMI but had greater odds of isolated complications. Obese II-III patients experienced only marginally increased odds of morbidity. Analyses among propensity-scored cohorts and stratified by cancer-resection type reported similar trends. Worse outcomes were observed among morbidly obese hepatectomy and pancreatectomy patients. CONCLUSION: Evidence-based assessment of outcomes after major resection for cancer suggests that obese patients should be treated with the aim for optimal oncologic standards without being hindered by a misleading perception of prohibitively increased perioperative risk. Underweight and certain types of morbidly obese patients require targeted provision of appropriate care. PMID- 26008962 TI - Development of an endoluminal intestinal lengthening device using a geometric intestinal attachment approach. AB - BACKGROUND: Distraction enterogenesis may provide a novel therapy for short bowel syndrome. Previously described methods have relied on isolated intestinal segments or transmural fixation because of ineffective endoluminal attachment. We hypothesized that a novel approach of geometric coupling between a tapering device and the mesenteric curvature would allow trans-stomal distraction enterogenesis. METHODS: A catheter device was designed with tapering stiffness, consisting of a stiff catheter with a taper to a flexible latex tip to prevent perforation. Yorkshire pigs underwent creation of a jejunal Roux limb with device placed via jejunostomy. Intestinal attachment was achieved without a substantial decrease in bowel perfusion as measured by laser Doppler. An external clamp was secured at the stoma to provide external fixation of the device. The catheter was advanced 1 cm/day for either 7 or 14 days before explant. RESULTS: After 7 days, the distracted segment achieved a mean +/- SD increase in length of 37 +/- 6% versus fed, nondistracted bowel, corresponding to an absolute gain of 10.6 +/- 1.7 cm (1.5 cm/day). After 14 days, the Roux limb achieved an 80 +/- 2% increase in length versus fed control bowel, corresponding to an absolute gain of 16.8 +/- 3.0 cm (1.2 cm/day). No perforation or stoma-related complication occurred. CONCLUSION: We describe a novel catheter device with tapering stiffness allowing for endoluminal distraction enterogenesis via geometric coupling. This approach may allow development of clinically applicable technology for the treatment of patients with short bowel syndrome. PMID- 26008963 TI - Neoparamoeba perurans loses virulence during clonal culture. AB - Amoebic Gill Disease affects farmed salmonids and is caused by Neoparamoeba perurans. Clonal cultures of this amoeba have been used for challenge experiments, however the effect of long-term culture on virulence has not been investigated. Here we show, using in vitro and in vivo methods, that a clone of N. perurans which was virulent 70 days after clonal culture lost virulence after 3 years in clonal culture. We propose that this is related either to the lack of attachment to the gills or the absence of an extracellular product, as shown by the lack of cytopathic effect on Chinook salmon embryo cells. The avirulent clonal culture of N. perurans allowed us to propose two potential virulence mechanisms/factors involved in Amoebic Gill Disease and is an invaluable tool for host-pathogen studies of Amoebic Gill Disease. PMID- 26008964 TI - Correlation between alveolar ventilation and electrical properties of lung parenchyma. AB - One key problem in modern medical imaging is linking measured data and actual physiological quantities. In this article we derive such a link between the electrical bioimpedance of lung parenchyma, which can be measured by electrical impedance tomography (EIT), and the magnitude of regional ventilation, a key to understanding lung mechanics and developing novel protective ventilation strategies. Two rat-derived three-dimensional alveolar microstructures obtained from synchrotron-based x-ray tomography are each exposed to a constant potential difference for different states of ventilation in a finite element simulation. While the alveolar wall volume remains constant during stretch, the enclosed air volume varies, similar to the lung volume during ventilation. The enclosed air, serving as insulator in the alveolar ensemble, determines the resulting current and accordingly local tissue bioimpedance. From this we can derive a relationship between lung tissue bioimpedance and regional alveolar ventilation. The derived relationship shows a linear dependence between air content and tissue impedance and matches clinical data determined from a ventilated patient at the bedside. PMID- 26008965 TI - Bioremediation of soils contaminated with polycyclic aromatic hydrocarbons, petroleum, pesticides, chlorophenols and heavy metals by composting: Applications, microbes and future research needs. AB - Increasing soil pollution problems have caused world-wide concerns. Large numbers of contaminants such as polycyclic aromatic hydrocarbons (PAHs), petroleum and related products, pesticides, chlorophenols and heavy metals enter the soil, posing a huge threat to human health and natural ecosystem. Chemical and physical technologies for soil remediation are either incompetent or too costly. Composting or compost addition can simultaneously increase soil organic matter content and soil fertility besides bioremediation, and thus is believed to be one of the most cost-effective methods for soil remediation. This paper reviews the application of composting/compost for soil bioremediation, and further provides a critical view on the effects of this technology on microbial aspects in contaminated soils. This review also discusses the future research needs for contaminated soils. PMID- 26008966 TI - Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells. AB - Herein we show that a majority of human brain tumor samples and cell lines over expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-beta1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction. PMID- 26008967 TI - MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8 MMP3 interaction. AB - Interferon regulatory factor-8 (IRF8), originally identified as a leukemic tumor suppressor, can also exert anti-neoplastic activities in solid tumors. We previously showed that IRF8-loss enhanced tumor growth, which was accompanied by reduced tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on tumor growth could not be explained solely by its effects on regulating apoptotic response. Exploratory gene expression profiling further revealed an inverse relationship between IRF8 and MMP3 expression, implying additional intrinsic mechanisms by which IRF8 modulated neoplastic behavior. Although MMP3 expression was originally linked to tumor initiation, the role of MMP3 beyond this stage has remained unclear. Therefore, we hypothesized that MMP3 governed later stages of disease, including progression to metastasis, and did so through a novel IRF8-MMP3 axis. Altogether, we showed an inverse mechanistic relationship between IRF8 and MMP3 expression in tumor progression. Importantly, the growth advantage due to IRF8-loss was significantly compromised after silencing MMP3 expression. Moreover, MMP3-loss reduced spontaneous lung metastasis in an orthotopic mouse model of mammary carcinoma. MMP3 acted, in part, in a cell-intrinsic manner and served as a direct transcriptional target of IRF8. Thus, we identified a novel role of an IRF8-MMP3 axis in tumor progression, which unveils new therapeutic opportunities. PMID- 26008968 TI - Lemur Tyrosine Kinase 2, a novel target in prostate cancer therapy. AB - Progression from early forms of prostate cancer to castration-resistant disease is associated with an increase in signal transduction activity. The majority of castration-resistance cancers persist in the expression of the androgen receptor (AR), as well as androgen-dependent genes. The AR is regulated not only by it associated steroid hormone, but also by manifold regulatory and signaling molecules, including several kinases. We undertook evaluation of the role of Lemur Tyrosine Kinase 2 (LMTK2) in modulating AR activity, as several Genome Wide Association Studies (GWAS) have shown a marked association of LMTK2 activity with the development of prostate cancer. We confirm that not only is LMTK2 mRNA reduced in prostate cancer tissue, but also LMTK2 protein levels are markedly diminished. Knockdown of LMTK2 protein in prostate cell lines greatly increased the transcription of androgen-responsive genes. In addition, LMTK2 knockdown led to an increase in prostate cancer stem cell populations in LNCaP cells, indicative of increased tumorogenicity. Using multiple approaches, we also demonstrate that LMTK2 interacts with the AR, thus putting LMTK2 as a component of a signaling complex modulating AR activity. Our finding that LMTK2 is a negative regulator of AR activity defines a novel cellular pathway for activation of AR-responsive genes in castrate resistant-prostate cancer. Moreover, pharmacologic manipulation of LMTK2 activity will provide a novel therapeutic target for more effective treatments for patients with castrate-resistant prostate cancer. PMID- 26008969 TI - Short-term expansion of breast circulating cancer cells predicts response to anti cancer therapy. AB - Circulating tumor cells (CTCs) are considered as surrogate markers for prognosticating and evaluating patient treatment responses. Here, 226 blood samples from 92 patients with breast cancer, including patients with newly diagnosed or metastatic refractory cancer, and 16 blood samples from healthy subjects were cultured in laser-ablated microwells. Clusters containing an increasing number of cytokeratin-positive (CK+) cells appeared after 2 weeks, while most blood cells disappeared with time. Cultures were heterogeneous and exhibited two distinct sub-populations of cells: 'Small' (<= 25 MUm; high nuclear/cytoplasmic ratio; CD45-) cells, comprising CTCs, and 'Large' (> 25 MUm; low nuclear/cytoplasmic ratio; CD68+ or CD56+) cells, corresponding to macrophage and natural killer-like cells. The Small cell fraction also showed copy number increases in six target genes (FGFR1, Myc, CCND1, HER2, TOP2A and ZNF217) associated with breast cancer. These expanded CTCs exhibited different proportions of epithelial-mesenchymal phenotypes and were transferable for further expansion as spheroids in serum-free suspension or 3D cultures. Cluster formation was affected by the presence and duration of systemic therapy, and its persistence may reflect therapeutic resistance. This novel and advanced method estimates CTC clonal heterogeneity and can predict, within a relatively short time frame, patient responses to therapy. PMID- 26008970 TI - A small-molecule inhibitor suppresses the tumor-associated mitochondrial NAD(P)+ dependent malic enzyme (ME2) and induces cellular senescence. AB - Here, we found a natural compound, embonic acid (EA), that can specifically inhibit the enzymatic activity of mitochondrial NAD(P)+-dependent malic enzyme (m NAD(P)-ME, ME2) either in vitro or in vivo. The in vitro IC50 value of EA for m NAD(P)-ME was 1.4 +/- 0.4 MUM. Mutagenesis and binding studies revealed that the putative binding site of EA on m-NAD(P)-ME is located at the fumarate binding site or at the dimer interface near the site. Inhibition studies reveal that EA displayed a non-competitive inhibition pattern, which demonstrated that the binding site of EA was distinct from the active site of the enzyme. Therefore, EA is thought to be an allosteric inhibitor of m-NAD(P)-ME. Both EA treatment and knockdown of m-NAD(P)-ME by shRNA inhibited the growth of H1299 cancer cells. The protein expression and mRNA synthesis of m-NAD(P)-ME in H1299 cells were not influenced by EA, suggesting that the EA-inhibited H1299 cell growth occurs through the suppression of in vivo m-NAD(P)-ME activity EA treatment further induced the cellular senescence of H1299 cells. However, down-regulation of the enzyme-induced cellular senescence was not through p53. Therefore, the EA-evoked senescence of H1299 cells may occur directly through the inhibition of ME2 or a p53-independent pathway. PMID- 26008971 TI - Essential role for cyclic-AMP responsive element binding protein 1 (CREB) in the survival of acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) relapse remains a leading cause of cancer related death in children, therefore, new therapeutic options are needed. Recently, we showed that a peptide derived from Cyclic-AMP Responsive Element Binding Protein (CREB) was highly phosphorylated in pediatric leukemias. In this study, we determined CREB phosphorylation and mRNA levels showing that CREB expression was significantly higher in ALL compared to normal bone marrow (phosphorylation: P < 0.0001, mRNA: P = 0.004). High CREB and phospho-CREB expression was correlated with a lower median overall survival in a cohort of 140 adult ALL patients. ShRNA mediated knockdown of CREB in ALL cell lines blocked leukemic cell growth by inducing cell cycle arrest and apoptosis. Gene expression array analysis showed downregulation of CREB target genes regulating cell proliferation and glucose metabolism and upregulation of apoptosis inducing genes. Similar to CREB knockdown, the CREB inhibitor KG-501 decreased leukemic cell viability and induced apoptosis in ALL cell lines, as well as primary T-ALL samples, with cases showing high phospho-CREB levels being more sensitive than those with lower phospho-CREB levels. Together, these in vitro findings support an important role for CREB in the survival of ALL cells and identify this transcription factor as a potential target for treatment. PMID- 26008972 TI - Acetylation at lysine 71 inactivates superoxide dismutase 1 and sensitizes cancer cells to genotoxic agents. AB - Cancer cells are characterized by a high dependency on antioxidant enzymes to cope with the elevated rates of reactive oxygen species (ROS). Impairing antioxidant capacity in cancer cells disturbs the ROS homeostasis and exposes cancer cells to massive oxidative stress. In this study, we have discovered that superoxide dismutase 1 (SOD1), a major player in maintaining the cellular redox status, was acetylated at lysine 71. This acetylation, which was primarily deacetylated by Sirtuin 1 (SIRT1), suppressed the enzymatic activity of SOD1 via disrupting its association with copper chaperone for SOD1 (CCS). More importantly, genotoxic agents, such as camptothecin (CPT), induced SOD1 acetylation by disrupting its binding with SIRT1. CPT-induced SOD1 acetylation was stimulated by its provoked ROS, suggesting a positive feedback loop, in which ROS per se impairs the antioxidative defence of cancer cells and reinforces oxidative stress stimulated by anticancer agents. The intrinsic abundance of SOD1 acetylation varied among cancer cells, and high level of SOD1 acetylation was correlated with elevated sensitivity to CPT. Together, our findings gained mechanistic insights into how cytotoxic agents fine tune the intracellular ROS homeostasis to strengthen their anticancer effects, and suggested SOD1 acetylation as a candidate biomarker for predicting response to CPT-based chemotherapy. PMID- 26008973 TI - Tumor promotion by gamma and suppression by beta non-muscle actin isoforms. AB - Here we have shown that beta-cytoplasmic actin acts as a tumor suppressor, inhibiting cell growth and invasion in vitro and tumor growth in vivo. In contrast, gamma-cytoplasmic actin increases the oncogenic potential via ERK1/2, p34-Arc, WAVE2, cofilin1, PP1 and other regulatory proteins. There is a positive feedback loop between gamma-actin expression and ERK1/2 activation. We conclude that non-muscle actin isoforms should not be considered as merely housekeeping proteins and the beta/gamma-actins ratio can be used as an oncogenic marker at least for lung and colon carcinomas. Agents that increase beta- and/or decrease gamma-actin expression may be useful for anticancer therapy. PMID- 26008974 TI - Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis. AB - BACKGROUND: Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. MATERIALS AND METHODS: Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. RESULTS: ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. CONCLUSION: Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC. PMID- 26008975 TI - Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo. AB - Despite great efforts taken to advance therapeutic measures for patients with glioblastoma, the clinical prognosis remains grim. The antiapoptotic Bcl-2 family protein Mcl-1 is overexpressed in glioblastoma and represents an important resistance factor to the BH-3 mimetic ABT263. In this study, we show that combined treatment with ABT263 and GX15-070 overcomes apoptotic resistance in established glioblastoma cell lines, glioma stem-like cells and primary cultures. Moreover, this treatment regimen also proves to be advantageous in vivo. On the molecular level, GX15-070 enhanced apoptosis by posttranslational down-regulation of the deubiquitinase, Usp9X, and the chaperone Bag3, leading to a sustained depletion of Mcl-1 protein levels. Moreover, knock-down of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2/Bcl-xL inhibition. In conclusion, combined treatment with ABT263 and GX15 070 results in a significantly enhanced anti-cancer activity in vitro as well as in vivo in the setting of glioblastoma. Both drugs, ABT263 and GX15-070 have been evaluated in clinical studies which facilitates the translational aspect of taking this combinatorial approach to the clinical setting. Furthermore we present a novel mechanism by which GX15-070 counteracts Mcl-1 expression which may lay a foundation for a novel target in cancer therapy. PMID- 26008976 TI - Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo. AB - Extracellular circulating microRNAs (miRNAs) have been suggested to be biomarkers for disease monitoring but data are inconsistent, one reason being that blood miRNA is of heterogeneous origin. Here, we sampled extracellular microRNAs locally in situ using microdialysis. Three different cohorts of women were included; postmenopausal women with ongoing breast cancer investigated within the cancer and in normal adjacent breast tissue, postmenopausal women investigated in their normal healthy breast and subcutaneous fat before and after six weeks of tamoxifen therapy, premenopausal women during the menstrual cycle. Samples were initially screened using TaqMan array cards with subsequently absolute quantification. 124 miRNA were expressed in microdialysates. After absolute quantifications extracellular miRNA-21 was found to be significantly increased in breast cancer. In addition, the levels were significantly higher in pre menopausal breast tissue compared with postmenopausal. In breast tissue of pre menopausal women miRNA-21 exhibited a cyclic variation during the menstrual cycle and in postmenopausal women six weeks of tamoxifen treatment decreased miRNA-21 suggesting that this miRNA may be important for breast carcinogenesis. None of these changes were found in plasma or microdialysates from subcutaneous fat. Our data revealed tissue specific changes of extracellular circulating miRNAs that would be otherwise unraveled using blood samples. PMID- 26008977 TI - Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c Abelson-positive leukemia cells. AB - The potency of Abelson (ABL) tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML) has been demonstrated. However, ABL TKI resistance can develop. In this study, we investigated the efficacy of a combination therapy including rigosertib (ON 01910.Na), a polo-like kinase (PLK) and phosphoinositide 3-kinase (PI3K) inhibitor, and ABL TKIs. A 72-h rigosertib treatment was found to inhibit cell growth, induce apoptosis, reduce phosphorylation of the breakpoint cluster region-c (BCR)-ABL and its substrate Crk-L, and increase the activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). This combination therapy also exerted a synergistic inhibitory effect on Philadelphia chromosome (Ph) positive cell proliferation and reduced the phosphorylation of BCR-ABL and Crk-L while increasing that of cleaved PARP and the H2A.X histone. Rigosertib also potently inhibited the growth of ABL TKI-resistant cells, and cotreatment with ABL TKIs and rigosertib induced higher cytotoxicity. These results indicate that rigosertib treatment may be a powerful strategy against ABL TKI-resistant cells and could enhance the cytotoxic effects of ABL TKIs. PMID- 26008978 TI - RAB7 counteracts PI3K-driven macropinocytosis activated at early stages of melanoma development. AB - Derailed endolysosomal trafficking is emerging as a widespread feature of aggressive neoplasms. However, the oncogenic signals that alter membrane homeostasis and their specific contribution to cancer progression remain unclear. Understanding the upstream drivers and downstream regulators of aberrant vesicular trafficking is distinctly important in melanoma. This disease is notorious for its inter- and intra-tumoral heterogeneity. Nevertheless, melanomas uniformly overexpress a cluster of endolysosomal genes, being particularly addicted to the membrane traffic regulator RAB7. Still, the underlying mechanisms and temporal determinants of this dependency have yet to be defined. Here we addressed these questions by combining electron microscopy, real time imaging and mechanistic analyses of vesicular trafficking in normal and malignant human melanocytic cells. This strategy revealed Class I PI3K as the key trigger of a hyperactive influx of macropinosomes that melanoma cells counteract via RAB7 mediated lysosomal degradation. In addition, gain- and loss-of-function in vitro studies followed by histopathological validation in clinical biopsies and genetically-engineered mouse models, traced back the requirement of RAB7 to the suppression of premature cellular senescence traits elicited in melanocytes by PI3K-inducing oncogenes. Together, these results provide new insight into the regulators and modes of action of RAB7, broadening the impact of endosomal fitness on melanoma development. PMID- 26008979 TI - Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of beta-catenin activity. AB - The Ron receptor is upregulated in human breast cancers and correlates with enhanced metastasis and reduced patient survival. Ron overexpression drives mammary tumorigenesis through direct beta-catenin activation and augmented tumor cell proliferation, migration and invasion. Ron and beta-catenin are also coordinately elevated in breast cancers. The vitamin D receptor (VDR) antagonizes beta-catenin signaling. Herein, we examined mammary tumor onset and progression using a Ron-driven murine model of breast tumorigenesis crossed with VDR deficient mice. VDR ablation accelerated mammary tumor onset and led to tumors that exhibited a desmoplastic phenotype and enhanced metastases. Tumor levels of active beta-catenin were markedly increased in the absence of VDR. In vitro, VDR activation in breast cancer cells reduced beta-catenin activation and transcriptional activity leading to elevated expression of the extracellular Wnt inhibitor dickkopf-related protein 1, and a reduction in the interaction of beta catenin with the cyclin D1 promoter. Expression of a stabilized form or beta catenin ablated the protective effects of VDR activation.Collectively, these studies delineate a protective role for VDR signaling in Ron-induced mammary tumorigenesis through disruption of beta-catenin activation. PMID- 26008980 TI - Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas. AB - Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has become the main treatment modality in malignant gliomas. However unlike glioblastomas, there are inconsistent result about fluorescence status in WHO grade III gliomas. Here, we show that mutational status of IDH1 is linked to 5-ALA fluorescence. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) IDH1, we demonstrated a lag in 5-ALA metabolism and accumulation of protoporphyrin IX (PpIX) in U87MG-IDH1R132Hcells. Next, we used liquid chromatography-mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes caused by 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. High levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporarily enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. In conclusion, we have discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Low levels of NADPH in tumors with mutated IDH1 is responsible for the enhanced fluorescence. PMID- 26008981 TI - Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer. AB - T-cell exhaustion represents a progressive loss of T-cell function. The inhibitory receptor PD-1 is known to negatively regulate CD8+ T cell responses directed against tumor antigen, but the blockades of PD-1 pathway didn't show the objective responses in patients with colorectal cancer (CRC). Thus, further exploring the molecular mechanism responsible for inducing T-cell dysfunction in CRC patients may reveal effective strategies for immune therapy. This study aims to characterize co-inhibitory receptors on T cells in CRC patients to identify novel targets for immunotherapy. In this study, peripheral blood samples from 20 healthy controls and 54 consented CRC patients, and tumor and matched paraneoplastic tissues from 7 patients with advanced CRC, subjected to multicolor flow cytometric analysis of the expression of PD-1 and Tim-3 receptors on CD8+ T cells. It was found that CRC patients presented with significantly higher levels of circulating Tim-3+PD-1+CD8+ T cells compared to the healthy controls (medians of 3.12% and 1.99%, respectively, p = 0.0403). A similar increase of Tim-3+PD 1+CD8+ T cells was also observed in the tumor tissues compared to paraneoplastic tussues. Tim-3+PD-1+CD8+ T cells in tumor tissues produced even less cytokine than that in paraneoplastic tissues. Functional ex vivo experiments showed that Tim-3+PD-1+CD8+ T cells produced significantly less IFN-gamma than Tim-3-PD-1 CD8+ T cells, followed by Tim-3+PD-1-CD8+ T cells, and Tim-3-PD-1+CD8+ T cells, indicating a stronger inhibition of IFN-gamma production of Tim-3+CD8+ T cells . It is also found in this study that Tim-3+PD-1+CD8+ T cell increase in circulation was correlated with clinical cancer stage but not histologic grade and serum concentrations of cancer biomarker CEA. Our results indicate that upregulation of the inhibitory receptor Tim-3 may restrict T cell responses in CRC patients, and therefore blockage of Tim-3 and thus restoring T cell responses may be a potential therapeutic approach for CRC patients. PMID- 26008982 TI - Prognostic value of HPV-mRNA in sentinel lymph nodes of cervical cancer patients with pN0-status. AB - Up to 15% of patients with cervical cancer and pN0-status develop recurrent disease. This may be due to occult metastatic spread of tumor cells. We evaluated the use of human-papillomavirus-(HPV)-mRNA as a molecular marker for disseminated tumor cells to predict the risk of recurrence. For this prospective, multi-center prognostic study, 189 patients free of lymphnode metastases by conventional histopathology could be analyzed. All patients underwent complete lymphadenectomy. Of each sentinel node (SLN) a biopsy was taken for the detection of HPV-E6-E7-mRNA. Median follow-up time after surgery was 8.1 years. HPV-mRNA could be detected in SLN of 52 patients (27.5%). Recurrence was observed in 22 patients. Recurrence-free-survival was significantly longer for patients with HPV negative SLN (log rank p = 0.002). By Cox regression analysis the hazard ratio (95%CI) for disease-recurrence was 3.8 (1.5 - 9.3, p = 0.004) for HPV-mRNA positive compared to HPV-mRNA-negative patients. After adjustment for tumor size as the most influential covariate the HR was still 2.8 (1.1 - 7.0, p = 0.030). In patients with cervical cancer and tumor-free lymph nodes by conventional histopathology HPV-mRNA-positive SLN were of prognostic value independent of tumor size. Particularly, patients with tumors larger than 20mm diameter could possibly benefit from further risk stratification using HPV-mRNA as a molecular marker. PMID- 26008983 TI - Monocytes and macrophages, implications for breast cancer migration and stem cell like activity and treatment. AB - Macrophages are a major cellular constituent of the tumour stroma and contribute to breast cancer prognosis. The precise role and treatment strategies to target macrophages remain elusive. As macrophage infiltration is associated with poor prognosis and high grade tumours we used the THP-1 cell line to model monocyte macrophage differentiation in co-culture with four breast cancer cell lines (MCF7, T47D, MDA-MB-231, MDA-MB-468) to model in vivo cellular interactions. Polarisation into M1 and M2 subtypes was confirmed by specific cell marker expression of ROS and HLA-DR, respectively. Co-culture with all types of macrophage increased migration of ER-positive breast cancer cell lines, while M2 macrophages increased mammosphere formation, compared to M1-macrophages, in all breast cancer cells lines. Treatment of cells with Zoledronate in co-culture reduced the "pro-tumourigenic" effects (increased mammospheres/migration) exerted by macrophages. Direct treatment of breast cancer cells in homotypic culture was unable to reduce migration or mammosphere formation.Macrophages promote "pro tumourigenic" cellular characteristics of breast cancer cell migration and stem cell activity. Zoledronate targets macrophages within the microenvironment which in turn, reduces the "pro-tumourigenic" characteristics of breast cancer cells. Zoledronate offers an exciting new treatment strategy for both primary and metastatic breast cancer. PMID- 26008984 TI - Zinc finger factor 521 enhances adipogenic differentiation of mouse multipotent cells and human bone marrow mesenchymal stem cells. AB - Previously, we found that ZNF521 expression was up-regulated with advancing age in human bone marrow mesenchymal stem cells (bmMSCs). Here, we investigated the regulatory role of ZNF521 in the differentiation of mouse C3H10T1/2 cells and human bmMSCs. Our data show that ZNF521 overexpression repressed osteoblastic differentiation of C3H10T1/2 cells, accompanied by a decrease in Runx2 expression and an increase in PPARgamma2 expression. In contrast, ZNF521 overexpression enhanced adipogenic differentiation of C3H10T1/2 cells, concomitant with increased expression of PPARgamma2, aP2, adiponectin and C/EBPdelta. Chromatin immunoprecipitation followed by quantitative PCR analyses and luciferase reporter assays suggested that ZNF521 overexpression enhances PPARgamma2 expression at the transcriptional level. The enhancing effect of ZNF521 overexpression on the adipogenic differentiation of C3H10T1/2 cells was also observed ex vivo. Finally, similar to those noted in C3H10T1/2 cells, ZNF521 overexpression in human bmMSCs was found to promote adipogenic differentiation in vitro and ex vivo, but repressed osteoblastic differentiation in vitro. ZNF521 knockdown significantly repressed adipogenic differentiation in vitro and ex vivo, but promoted osteoblastic differentiation in vitro. We propose that ZNF521 can function as a repressor of osteoblastic differentiation of bmMSCs while promoting adipogenesis, and that elevated ZNF521 expression might play a role in the age-related bone loss. PMID- 26008985 TI - Effects of DRG-based hospital payment in Poland on treatment of patients with stroke. AB - A prospective payment system based on Diagnosis Related Groups (DRGs) presents strong financial incentives to healthcare providers. These incentives may have intended as well as unintended consequences for the healthcare system. In this paper we use administrative data on stroke admissions to Polish hospitals in order to demonstrate the response of hospitals to the incentives embedded in the design of stroke-related groups in Poland. The design was intended to motivate hospitals for the development of specialized stroke units by paying significantly higher tariffs for treatment of patients in these units. As a result, an extensive network of stroke units has emerged. However, as it is shown in the paper, there is no evidence that outcomes in hospitals with stroke units are significantly different from outcomes in hospitals without stroke units. It is also demonstrated that the reliance on the length of stay as a major grouping variable provides incentives for regrouping patients into more expensive groups by extending their length of stay in stroke units. The results of the study are limited by the incompleteness of the casemix data. There is a need to develop information and audit systems which would further inform a revision of the DRG system aimed to reduce the risk of regrouping and up-coding. PMID- 26008986 TI - Adverse Drug Reactions and Clinical Outcomes in Patients Initiated on Antiretroviral Therapy: A Prospective Cohort Study From Ethiopia. AB - INTRODUCTION: In Ethiopia, the use of antiretroviral therapy (ART) has been scaled up for HIV/AIDS over the past decade. Adverse drug reactions (ADRs) associated with ART pose a unique challenge in the treatment of the infection in this resource-limited setting. OBJECTIVES: The aims of this study were to examine the incidence and nature of ADRs, identify the risk factors associated with the development of ADRs, and assess their impact on treatment outcomes. METHODS: A prospective cohort study was conducted in adult patients (>=18 years of age) with HIV/AIDS who commenced ART. All ADRs in the first 12 months of therapy were recorded, and the severity, causality, and preventability assessed. The impact of severe ADRs on self-reported adherence, immunological, and body mass index (BMI) outcomes were assessed. RESULTS: Of the 211 patients included in the analysis, 181 (85.7 %) experienced at least one ADR and 66 (31.3 %) experienced at least one severe ADR within 12 months of commencing ART (incidence rates for any ADR and severe ADR of 14.8 and 3.2 per 100 person-months, respectively). Logistic regression analysis indicated that taking zidovudine-containing regimens (odds ratio [OR] 4.2, 95 % confidence interval [CI] 2.1-8.4) or being unemployed (OR 2.2, 95 % CI 1.1-4.3) were independent predictors of experiencing severe ADRs. Patients who experienced a severe ADR were less likely (OR 0.4, 95 % CI 0.2-0.9) to be >=90 % adherent to ART. The mean gain in BMI was significantly lower in patients with severe ADRs after 3 and 12 months of therapy. CONCLUSIONS: ADRs were common within the first 3 months in patients initiated on ART. Severe ADRs were negatively associated with self-reported adherence and gain in BMI. Measures need to be implemented to routinely monitor for severe ADRs to improve ART adherence and treatment outcomes. PMID- 26008988 TI - CeO2 nanorod/g-C3N4/N-rGO composite: enhanced visible-light-driven photocatalytic performance and the role of N-rGO as electronic transfer media. AB - A novel CeO2 nanorod/g-C3N4/N-rGO ternary composite was synthesized using a simple ultrasonic-heat treatment method for application in the photocatalytic degradation of organic pollutants under the irradiation of visible light. This material shows superior photocatalytic activity compared with pure g-C3N4 and CeO2 nanorods, and the photodegradation rate of RhB is up to 2.1-fold higher than that of the g-C3N4/N-rGO (at the optimum content of 0.25 wt% N-rGO) catalyst when the content of CeO2 nanorods was 2 wt%. The enhancement of photocatalytic activity could be attributed to the synergistic effect among CeO2, g-C3N4 and N rGO (serves as a conductive network), which was found to lead to more efficient separation of photogenerated electron-hole pairs, resulting in the effective photodegradation of organic pollutants. In addition, superoxide radical anions (O2(-)) and holes (h(+)) were considered as the main reactive species during the photodegradation process, and the ternary composite also exhibited preferable stability for the decomposition of RhB. This work provides an in-depth perspective for understanding the N-doped graphene-involved photocatalytic mechanism. PMID- 26008987 TI - Update on Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on QT Interval, Left Ventricular Dysfunction and Overall Risk/Benefit. AB - We previously reviewed the cardiovascular safety of 16 tyrosine kinase inhibitors (TKIs), approved for use in oncology as of 30 September 2012. Since then, the indications for some of them have been widened and an additional nine TKIs have also been approved as of 30 April 2015. Eight of these nine are indicated for use in oncology and one (nintedanib) for idiopathic pulmonary fibrosis. This report is an update on the cardiovascular safety of those 16 TKIs, including the post marketing data concerning their pro-arrhythmic effects, and reviews the cardiovascular safety of the nine new TKIs approved since (afatinib, cabozantinib, ceritinib, dabrafenib, ibrutinib, lenvatinib, nintedanib, ponatinib, and trametinib). As before, we focus on specific aspects of cardiovascular safety, namely their potential to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension but now also summarise the risks of arterial thromboembolic events (ATEs) associated with these agents. Of the newer TKIs, cabozantinib and ceritinib have been shown to induce a mild to moderate degree of QTc interval prolongation while cardiac dysfunction has been reported with the use of afatinib, dabrafenib, lenvatinib, ponatinib and trametinib. The label for axitinib was revised to include a new association with cardiac dysfunction. Hypertension is associated with cabozantinib, lenvatinib, nintedanib, ponatinib and trametinib. Ponatinib, within 10 months of its approval in December 2012, required voluntary (temporary) suspension of its marketing until significant safety revisions (restricted indication, additional warnings and precautions about the risk of arterial occlusion and thromboembolic events and amended dose) were made to its label. Compared with the previous 16 TKIs, more of the recently introduced TKIs are associated with the risk of LV dysfunction, and fewer with QT prolongation. Available data on morbidity and mortality associated with TKIs, together with post-marketing experience with lapatinib and ponatinib, emphasise the need for effective pharmacovigilance and ongoing re-assessment of their risk/benefit after approval of these novel agents. If not adequately managed, these cardiovascular effects significantly decrease the quality of life and increase the morbidity and mortality in a population already at high risk. Evidence accumulated over the last decade suggests that their clinical benefit, although worthwhile, is modest and extends only to progression-free survival and complete response without any effect on overall survival. During uncontrolled use in routine clinical practice, their risk/benefit is likely to be inferior to that perceived from highly controlled clinical trials. PMID- 26008990 TI - Pterostilbene, an Active Constituent of Blueberries, Stimulates Nitric Oxide Production via Activation of Endothelial Nitric Oxide Synthase in Human Umbilical Vein Endothelial Cells. AB - Endothelial dysfunction, a key process in development of cardiovascular diseases, is largely due to reduced nitric oxide (NO) derived from endothelial NO synthase (eNOS). Resveratrol has been reported to stimulate NO production via estrogen receptor alpha (ERalpha) activation in endothelial cells. Here, we investigated whether two natural methylated analogs of resveratrol, pterostilbene (Pts) and trans-3,5,4'-trimethoxystilbene (TMS), similarly to resveratrol, could influence endothelial NO release in human umbilical vein endothelial cells (HUVECs). In HUVECs exposed to Pts or TMS, NO production and phosphorylation of eNOS, protein kinase B (Akt), and ERalpha were measured by using a fluorimetric NO assay kit and Western blot analysis, respectively. Dimethylated Pts, but not trimethylated TMS, stimulated dose-dependent NO production via eNOS phosphorylation. Pts also stimulated dose-dependent phosphorylation of Akt, but not of ERalpha. NO production and eNOS phosphorylation in response to Pts were significantly abolished by the phosphoinositide 3-kinase (PI3K)/Akt inhibitor LY294002, but not by the ERalpha antagonist ICI182780. Our results suggest that Pts, but not TMS, is capable of inducing eNOS phosphorylation and the subsequent NO release, presumably, by activating PI3K/Akt pathway. The potential efficacy of Pts, an active constituent of blueberries, may aid in the prevention of cardiovascular diseases characterized by endothelial dysfunction. PMID- 26008989 TI - Piezo1 ion channel pore properties are dictated by C-terminal region. AB - Piezo1 and Piezo2 encode mechanically activated cation channels that function as mechanotransducers involved in vascular system development and touch sensing, respectively. Structural features of Piezos remain unknown. Mouse Piezo1 is bioinformatically predicted to have 30-40 transmembrane (TM) domains. Here, we find that nine of the putative inter-transmembrane regions are accessible from the extracellular side. We use chimeras between mPiezo1 and dPiezo to show that ion-permeation properties are conferred by C-terminal region. We further identify a glutamate residue within a conserved region adjacent to the last two putative TM domains of the protein, that when mutated, affects unitary conductance and ion selectivity, and modulates pore block. We propose that this amino acid is either in the pore or closely associates with the pore. Our results describe important structural motifs of this channel family and lay the groundwork for a mechanistic understanding of how Piezos are mechanically gated and conduct ions. PMID- 26008991 TI - Uncovering a law of corresponding states for electron tunneling in molecular junctions. AB - Laws of corresponding states known so far demonstrate that certain macroscopic systems can be described in a universal manner in terms of reduced quantities, which eliminate specific substance properties. To quantitatively describe real systems, all these laws of corresponding states contain numerical factors adjusted empirically. Here, we report a law of corresponding states deduced analytically for charge transport via tunneling in molecular junctions, which we validate against current-voltage measurements for conducting probe atomic force microscope junctions based on benchmark molecular series (oligophenylenedithiols and alkanedithiols) and electrodes (silver, gold, and platinum), as well as against transport data for scanning tunneling microscope junctions. Two salient features distinguish the present law of corresponding states from all those known previously. First, it is expressed by a universal curve free of empirical parameters. Second, it demonstrates that a universal behavior is not necessarily affected by strong stochastic fluctuations often observed in molecular electronics. An important and encouraging message of this finding is that transport behavior across different molecular platforms can be similar and extraordinarily reproducible. PMID- 26008995 TI - Neurodegenerative disease: Tau is linked to cognitive decline in Huntington disease. PMID- 26009001 TI - Traumatic brain injury: Structural changes can progress for months after brain injury. PMID- 26009003 TI - The effectiveness of a high-intensity games intervention on improving indices of health in young children. AB - This study assessed the effectiveness of a 6-week, high-intensity, games-based intervention on physiological and anthropometric indices of health, in normal weight (n = 26; 32.5 +/- 8.9 kg) and obese (n = 29; 49.3 +/- 8.9 kg) children (n = 32 boys, 23 girls), aged 8-10 years. Children were randomised into an exercise or control group. The exercise group participated in a twice-weekly, 40 min active games intervention, alongside their usual school physical education classes. The control group did not take part in the intervention. Before and after the intervention, participants completed both a maximal and submaximal graded exercise test. The submaximal exercise test comprised of a 6 min, moderate and 6 min heavy-intensity bout, interspersed with a 5 min recovery. The exercise group demonstrated improvements in maximal oxygen uptake (51.4 +/- 8.5 vs 54.3 +/ 9.6 ml . kg(-1) . min(-1)) and peak running speed (11.3 +/- 1.6 vs 11.9 +/- 1.6 km . h(-1)), and a reduction in the oxygen cost of submaximal exercise between assessments (P < .05). A decrease in waist circumference and increase in muscle mass were observed between assessments for the obese participants randomised to the intervention (both P < .05). This study demonstrates that a short-term, high intensity games intervention may elicit positive changes in physiological and anthropometric indices of health in normal weight and obese children. PMID- 26009002 TI - Spinal cord MRI in multiple sclerosis--diagnostic, prognostic and clinical value. AB - Multiple sclerosis (MS) is an inflammatory disorder of the CNS that affects both the brain and the spinal cord. MRI studies in MS focus more often on the brain than on the spinal cord, owing to the technical challenges in imaging this smaller, mobile structure. However, spinal cord abnormalities at disease onset have important implications for diagnosis and prognosis. Furthermore, later in the disease course, in progressive MS, myelopathy becomes the primary characteristic of the clinical presentation, and extensive spinal cord pathology- including atrophy, diffuse abnormalities and numerous focal lesions--is common. Recent spinal cord imaging studies have employed increasingly sophisticated techniques to improve detection and quantification of spinal cord lesions, and to elucidate their relationship with physical disability. Quantitative MRI measures of cord size and tissue integrity could be more sensitive to the axonal loss and other pathological processes in the spinal cord than is conventional MRI, putting quantitative MRI in a key role to elucidate the association between disability and spinal cord abnormalities seen in people with MS. In this Review, we summarize the most recent MS spinal cord imaging studies and discuss the new insights they have provided into the mechanisms of neurological impairment. Finally, we suggest directions for further and future research. PMID- 26009004 TI - D-Galactosamine Intoxication in Experimental Animals: Is it Only an Experimental Model of Acute Liver Failure? AB - BACKGROUND: Short-term administration of Galactosamine to experimental animals causes liver damage and acute liver failure (ALF), as well as acute renal failure in some cases. The aim of our study was to describe kidney disorders that developed in the course of galactosamine-induced liver failure. MATERIAL AND METHODS: Sprague-Dawley rats were randomly divided into 2 groups: a study group administered galactosamine intraperitoneally and a control group administered saline. RESULTS: All the animals in the study group developed liver damage and failure within 48 h, with significant increase of alanine (p<0.001), aspartate aminotransferases (p<0.0001), bilirubin (p<0.004), and ammonia (p<0.005) and decrease of albumin (p<0.001) concentrations. Acute renal failure was observed in all test animals, with a significant increase in creatinine (p<0.001) and urea (p<0.001) concentrations and a decrease in creatinine clearance (p<0.0012). Moreover, osmotic clearance (p<0.001), daily natriuresis (p<0.003), and fractional sodium excretion (p<0.016) decreased significantly in this group of animals. The ratio of urine osmolality to serum osmolality did not change. Histopathology of the liver revealed massive necrosis of hepatocytes, whereas renal histopathology showed no changes. CONCLUSIONS: Acute renal failure that developed in the course of galactosamine-induced ALF was of a functional nature, with the kidneys retaining the ability to concentrate urine and retain sodium, and there were no renal changes in the histopathological examination. It seems that the experimental model of ALF induced by galactosamine can be viewed as a model of hepatorenal syndrome that occurs in the course of acute damage and liver failure. PMID- 26009005 TI - Investigation of vitamin B6 inadequacy, induced by exposure to the anti-B6 factor 1-amino D-proline, on plasma lipophilic metabolites of rats: a metabolomics approach. AB - PURPOSE: Vitamin B6 status in the body is affected by several factors including dietary supply of the antivitamin B6 factor, 1-amino D-proline (1ADP), which is present in flaxseed. Owing to the prevalence of moderate B6 deficiency in the general population, a co-occurrence of 1ADP may lead to a further deterioration of B6 status. To this end, we applied a nontargeted metabolomics approach to identify potential plasma lipophilic biomarkers of deleterious effect of 1ADP on moderately vitamin B6-deficient rats using a high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. METHODS: Twenty-four rats were fed with a semi-purified diet containing pyridoxine.HCl (PN.HCl) either 7 mg/kg diet (optimal B6) or 0.7 mg/kg diet (moderate B6). The rats were divided into four treatments (n = 6), and one treatment in each B6 diet group was also fed ad libitum with 10 mg/kg diet of synthetic 1ADP. After 5 weeks of study, plasma was collected from the rats and lipophilic metabolites were extracted using acetonitrile as a solvent for analysis. RESULTS: Ten potential plasma lipophilic biomarkers were identified out of >2500 detected entities, which showed significant differences between the treatments. Plasma glycocholic acid, glycoursodeoxycholic acid, murocholic acid, N-docosahexaenoyl GABA, N arachidonoyl GABA, lumula, nandrolone and orthothymotinic acid concentrations were significantly elevated, while plasma cystamine and 3-methyleneoxindole concentrations were significantly reduced as a result of either low B6 status or 1ADP or their interaction. CONCLUSION: Changes in these metabolites revealed a potential defect in pathways linked with the biosynthesis and metabolism of bile acid components, N-acyl amino acids, analgesic androgens, anti-inflammatory and neuroprotective molecules. We also noted that the changes in these biomarkers can be alleviated by the application of adequate vitamin B6. PMID- 26009006 TI - Do bread-crust-derived Maillard reaction products affect the retention and tissue distribution of trace elements? AB - PURPOSE: To investigate the effects of the consumption of Maillard reaction products (MRPs) from bread crust (BC) on iron, copper and zinc body retention and tissue distribution, determining whether these effects are related to the molecular weight of browning products. METHODS: During an 88-day study period, rats were fed a Control diet or diets containing BC as source of MRPs, its soluble high or low molecular weight fractions (BC, LMW or HMW diets). A mineral balance was conducted throughout the experiment to determine iron, copper and zinc retention. At day 88, animals were killed, blood was drawn for haemoglobin determination and some organs removed to analyse minerals. RESULTS: Copper and zinc balances were unchanged, and scant modification detected in their body delivery. However, the Fe retention rate from the diet increased (13, 22 and 32 % for BC, LMW and HMW diets), and a parallel higher Fe body concentration was observed (13-18 % higher than the Control group). Incoming iron accumulated particularly in the liver, femur and small intestine, but functional iron tended to decrease, as reflected by haemoglobin levels. CONCLUSIONS: The long-term intake of BC or derivatives did not produce a notable effect on copper or zinc balances, although slightly increased iron retention rate and the body concentration of this mineral were observed. Iron accumulated in some organs, but the production of haemoglobin was not improved. In view of the differences observed between the effects of BC and its derivatives, our results underline the importance of working with real food matrices, where the joint presence of different components modulates the in vivo final effects. PMID- 26009007 TI - 4-(Dimethylamino)pyridine-catalysed iodolactonisation of gamma,delta-unsaturated carboxylic acids. AB - 4-(Dimethylamino)pyridine functioned as an excellent catalyst for iodolactonisation reactions of gamma,delta-unsaturated carboxylic acids, affording gamma-lactones, delta-lactones, or both under neutral conditions at room temperature. The effects of substrate structures on the iodolactonisation were investigated, and a catalytic mechanism is proposed. PMID- 26009008 TI - A miniaturized readout strategy for endogenous histone deacetylase activity. AB - Histone deacetylases are important drug targets, which are difficult to characterize due to their poor accessibility. We have developed a miniaturized assay for the multi-site readout of deacetylase activity and profiled the substrate selectivity of HDACs for acetylation sites on histone H4 and tumor suppressor protein p53. PMID- 26009009 TI - A current review of non-vascularized bone grafting in osteonecrosis of the femoral head. AB - Over the past three decades, non-vascularized bone grafts have been demonstrated to be viable treatments for pre- and early post-collapse osteonecrosis of the femoral head; however, there are limited reviews on this topic. Therefore, the purposes of this review are to (1) provide a summary of the different surgical techniques and their respective clinical outcomes and (2) evaluate new adjunct therapies. Originally, non-vascularized bone grafting was performed using the Phemister technique with varying results. More recently, newer techniques such as the lightbulb and trapdoor are used to place non-vascularized bone grafts with excellent results. The addition of various biological agents has demonstrated positive results; however, further studies are needed to confirm the best appropriate indications and to elucidate long-term results. PMID- 26009010 TI - Cell-intrinsic adaptation of lipid composition to local crowding drives social behaviour. AB - Cells sense the context in which they grow to adapt their phenotype and allow multicellular patterning by mechanisms of autocrine and paracrine signalling. However, patterns also form in cell populations exposed to the same signalling molecules and substratum, which often correlate with specific features of the population context of single cells, such as local cell crowding. Here we reveal a cell-intrinsic molecular mechanism that allows multicellular patterning without requiring specific communication between cells. It acts by sensing the local crowding of a single cell through its ability to spread and activate focal adhesion kinase (FAK, also known as PTK2), resulting in adaptation of genes controlling membrane homeostasis. In cells experiencing low crowding, FAK suppresses transcription of the ABC transporter A1 (ABCA1) by inhibiting FOXO3 and TAL1. Agent-based computational modelling and experimental confirmation identified membrane-based signalling and feedback control as crucial for the emergence of population patterns of ABCA1 expression, which adapts membrane lipid composition to cell crowding and affects multiple signalling activities, including the suppression of ABCA1 expression itself. The simple design of this cell-intrinsic system and its broad impact on the signalling state of mammalian single cells suggests a fundamental role for a tunable membrane lipid composition in collective cell behaviour. PMID- 26009012 TI - Thinking Outside the Box: Treating Acute Heart Failure Outside the Hospital to Improve Care and Reduce Admissions. AB - The management of acute heart failure is shifting toward treatment approaches outside of a traditional hospital setting. Many heart failure providers are now treating patients in less familiar health care settings, such as acute care clinics, emergency departments, and skilled nursing facilities. In this review we describe the current pressures driving change in the delivery of acute heart failure and summarize the evidence regarding treatments for acute heart failure outside of the inpatient setting. We also provide considerations for the design of future treatment strategies to be implemented in alternative care settings. PMID- 26009013 TI - How does an amorphous surface influence molecular binding?--ovocleidin-17 and amorphous calcium carbonate. AB - Atomistic molecular dynamics simulations of dehydrated amorphous calcium carbonate interacting with the protein ovocleidin-17 are presented. These simulations demonstrate that the amorphisation of the calcium carbonate surface removes water structure from the surface. This reduction of structure allows the protein to bind with many residues, unlike on crystalline surfaces where binding is strongest when only a few residues are attached to the surface. Basic residues are observed to dominate the binding interactions. The implications for protein control over crystallisation are discussed. PMID- 26009011 TI - Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. AB - Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain of-functions activities. Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization. We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele) and H/H (R172H allele) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target. PMID- 26009014 TI - Novel MHC class I full-length allele and haplotype characterization in sooty mangabeys. AB - Sooty mangabeys (Cercocebus atys) are natural SIV hosts and the presumed source of HIV-2 and SIVmac, which makes them a valuable model for HIV/SIV research. However, like other African primates, little is known about their major histocompatibility complex (MHC) genetics. In this study, we used Roche/454 and Illumina MiSeq deep sequencing in order to determine the MHC class I transcripts in a cohort of 165 sooty mangabeys from the Yerkes National Primate Research Center (YNPRC). We have characterized 121 functionally full-length classical (Ceat-A and Ceat-B) and non-classical (Ceat-F and Ceat-I) alleles and have also identified 22 Ceat-A/Ceat-B haplotype chromosomal combinations. We correlated these Ceat-A/Ceat-B haplotype combinations to recently described microsatellite haplotypes from the YNPRC colony. These newly identified alleles and haplotypes establish a resource for studying cellular immunity in sooty mangabeys and provide a framework for rapidly cataloging MHC class I sequences in an understudied, yet important, nonhuman primate species. PMID- 26009016 TI - The cytochrome ba3 oxidase from Thermus thermophilus does not generate a tryptophan radical during turnover: Implications for the mechanism of proton pumping. AB - Oxygen reduction by cytochrome ba3 oxidase from Thermus thermophilus was studied by stopped-flow and microsecond freeze-hyperquenching analyzed with UV-Vis and EPR spectroscopy. In the initial phase, the low-spin heme b560 is rapidly and almost completely oxidized (kobs>33,000s(-1)) whereas CuA remains nearly fully reduced. The internal equilibrium between CuA and heme b560 with forward and reverse rate constants of 4621s(-1) and 3466s(-1), respectively, indicates a ~7.5mV lower midpoint potential for CuA compared to heme b560. The formation of the oxidized enzyme is relatively slow (693s(-1)). In contrast to the Paracoccus denitrificans cytochrome aa3 oxidase, where in the last phase of the oxidative half cycle a radical from the strictly conserved Trp272 is formed, no radical is formed in the cytochrome ba3 oxidase. Mutation of the Trp229, the cytochrome ba3 oxidase homologue to the Trp272, did not abolish the activity, again in contrast to the Paracoccus cytochrome aa3 oxidase. Differences in the proton pumping mechanisms of Type A and Type B oxidases are discussed in view of the proposed role of the strictly conserved tryptophan residue in the mechanism of redox linked proton pumping in Type A oxidases. In spite of the differences between the Type A and Type B oxidases, we conclude that protonation of the proton-loading site constitutes the major rate-limiting step in both catalytic cycles. PMID- 26009015 TI - Effect of monovalent cations on the kinetics of hypoxic conformational change of mitochondrial complex I. AB - Mitochondrial complex I is a large, membrane-bound enzyme central to energy metabolism, and its dysfunction is implicated in cardiovascular and neurodegenerative diseases. An interesting feature of mammalian complex I is the so-called A/D transition, when the idle enzyme spontaneously converts from the active (A) to the de-active, dormant (D) form. The A/D transition plays an important role in tissue response to ischemia and rate of the conversion can be a crucial factor determining outcome of ischemia/reperfusion. Here, we describe the effects of alkali cations on the rate of the D-to-A transition to define whether A/D conversion may be regulated by sodium. At neutral pH (7-7.5) sodium resulted in a clear increase of rates of activation (D-to-A conversion) while other cations had minor effects. The stimulating effect of sodium in this pH range was not caused by an increase in ionic strength. EIPA, an inhibitor of Na(+)/H(+) antiporters, decreased the rate of D-to-A conversion and sodium partially eliminated this effect of EIPA. At higher pH (>8.0), acceleration of the D-to-A conversion by sodium was abolished, and all tested cations decreased the rate of activation, probably due to the effect of ionic strength. The implications of this finding for the mechanism of complex I energy transduction and possible physiological importance of sodium stimulation of the D-to-A conversion at pathophysiological conditions in vivo are discussed. PMID- 26009017 TI - Immune Abnormalities in Fontan Protein-Losing Enteropathy: A Case-Control Study. AB - OBJECTIVE: To comprehensively characterize the immunologic characteristics of patients with protein-losing enteropathy (PLE) post-Fontan and compare them with patients without PLE post-Fontan. STUDY DESIGN: Patients with PLE post-Fontan and age-matched controls post-Fontan were prospectively studied with laboratory markers of immune function. Infectious history was obtained by interview and chart review. The groups' demographics, cardiac history, immune characteristics, and infection history were compared using appropriate 2-group statistics. RESULTS: A total of 16 patients enrolled (8 patients with PLE and 8 controls). All patients with PLE had lymphopenia compared with 25% of controls (P = .01). All patients with PLE had markedly depressed CD4 T cell counts (median 58 cells/MUL) compared with controls (median 450 cells/MUL, P = .0002); CD4% was also low in the PLE group (12.3%) and normal in control (36.9%, P = .004). Both groups had mildly depressed CD8 T cells and normal to slightly elevated natural killer and B-cell subsets. A majority of patients with PLE (62.5%) had negative titers to measles, mumps, and rubella vaccination, compared with no control Fontan with a negative titer (P = .03). Despite profoundly low CD4 counts, the frequency of infection was not different between groups with no reported opportunistic infections. CONCLUSIONS: Patients with Fontan-associated PLE have extensive quantitative immune abnormalities, particularly CD4 deficiency. These immune abnormalities are similar to those found in non-Fontan patients with PLE caused by intestinal lymphangiectasia. PMID- 26009018 TI - Distinguishing Benign Mediastinal Masses from Malignancy in a Histoplasmosis Endemic Region. AB - OBJECTIVE: To describe the characteristics of benign and malignant mediastinal masses, which may predict their etiology and facilitate the safe and timely management of patients, especially those residing in histoplasmosis-endemic regions. STUDY DESIGN: We conducted a retrospective review of the health records of 131 patients aged <19 years who were referred to 2 tertiary care children's hospitals between 2005 and 2010 for evaluation of mediastinal masses. RESULTS: Most patients (79%) had benign masses, including 98 with confirmed or suspected histoplasmosis. Overall, compared with patients with malignant masses, patients with benign masses were younger and more likely to be African American, to complain of cough, and to have pulmonary nodules by chest computed tomography. In addition, patients with malignant disease were more likely to complain of malaise and to have neck swelling, abnormal extrathoracic lymphadenopathy, lymphopenia, anterior mediastinal involvement, and/or pleural effusion. Positive histoplasmosis serologic tests were specific but insensitive for a benign etiology. No single clinical, laboratory, or radiologic feature was sufficiently sensitive and specific for distinguishing between benign and malignant masses; however, the presence of lymphopenia, anterior mediastinal involvement, or enlarged cervical lymph nodes on computed tomography had a sensitivity of 93%, specificity of 95%, positive predictive value of 86%, and negative predictive value of 97% for cancer. Sixty-four patients (49%) underwent invasive testing, including 37 (36%) of those with benign masses. CONCLUSION: Patients in this series who had involvement of the anterior mediastinum, lymphopenia, or enlarged cervical lymph nodes had a high likelihood of cancer. Expectant management of patients lacking these characteristics may be safe and reduce unnecessary invasive testing. PMID- 26009019 TI - Preliminary report: nephroscope-assisted "pulling-thread" technique for placement of peritoneal dialysis catheter. AB - BACKGROUND: Several catheter placement procedures have been described for initiation of peritoneal dialysis, including percutaneous insertion, open surgery, and laparoscopic surgery. However, the optimal approach to catheter placement for peritoneal dialysis remains controversial, because each procedure has specific advantages and disadvantages. PATIENTS AND METHODS: From June 2010 to October 2014, we performed a nephroscope-assisted "pulling-thread" technique for placement of peritoneal dialysis catheters in 46 patients with end-stage renal disease at our medical center. We retrospectively reviewed the operation related data, early catheter-related complications during the first month after placement, and longterm technical catheter survival. RESULTS: Catheters in all 46 patients were placed precisely in a single step during surgery. The mean operative time was 63.0+/-18.2 minutes, and no intra-operative complications occurred in any patient. Early catheter-related complications included only exit site infection (n=2; 4.3%) and catheter obstruction (n=2; 4.3%). There was a mean follow-up period of 18.3+/-12.7 months. The probability of catheter survival at 1 year was 97.1% and at 2 years was 80.1%. CONCLUSION: Our technique has the advantages of simplicity, safety, minimal equipment, low early catheter- related complication rate, and favorable long-term catheter outcome, making it ideal for patients with end-stage renal disease. PMID- 26009020 TI - Chemical and biological metal nanoparticles as antimycobacterial agents: A comparative study. AB - Resistance among mycobacteria leading to multidrug-resistant and extensively drug resistant tuberculosis is a major threat. However, nanotechnology has provided new insights in drug delivery and medicine development. This is the first comparative report to determine the activity of chemically and biologically synthesised silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) against mycobacteria. Screening data revealed the high mycobactericidal efficiency of AgNPs, with minimum inhibitory concentrations (MICs) of <3MUg/mL, whereas no such activity was exhibited by AuNPs at concentrations up to 100MUg/mL. Moreover, in vitro and ex vivo THP-1 infection model assays showed greater efficacy of chemical AgNPs compared with biogenic AgNPs to inhibit active and dormant stage mycobacterial growth. Up to 40% cytotoxicity against human cell lines was observed at a AgNP concentration of 10* MIC (30MUg/mL) after 48h. AgNPs were shown to have more specificity towards mycobacteria than towards other Gram negative and Gram-positive pathogenic bacteria. The selectivity index was found to be in the range of 11-23, indicating the potential of these nanoparticles for use in developing new therapeutics for tuberculosis. PMID- 26009021 TI - IL-18 contributes to susceptibility to Leishmania amazonensis infection by macrophage-independent mechanisms. AB - We evaluated the role of IL-18 during Leishmania amazonensis infection in C57BL/6 mice, using IL-18KO mice. We showed that IL-18 is involved in susceptibility to L. amazonensis, since IL-18KO mice presented reduced lesions and parasite loads. Because macrophages are the host cells of the parasite, we investigated if macrophages were involved in IL-18-mediated susceptibility to L. amazonensis. We showed that macrophages obtained from WT or IL-18KO responded similarly to L. amazonensis infection. Moreover, we showed that C57BL/6 macrophages do not respond to IL-18, since they do not express IL-18R. Therefore, macrophages are not involved in IL-18-mediated susceptibility to L. amazonensis. PMID- 26009022 TI - Mucinous spindle and tubular renal cell carcinoma: analysis of chromosomal aberration pattern of low-grade, high-grade, and overlapping morphologic variant with papillary renal cell carcinoma. AB - The chromosomal numerical aberration pattern in mucinous tubular and spindle renal cell carcinoma (MTSRCC) is referred to as variable with frequent gains and losses. The objectives of this study are to map the spectrum of chromosomal aberrations (extent and location) in a large cohort of the cases and relate these findings to the morphologic variants of MTSRCC. Fifty-four MTSRCCs with uniform morphologic pattern were selected (of 133 MTSRCCs available in our registry) and divided into 3 groups: classic low-grade MTSRCC (Fuhrman nucleolar International Society of Urological Pathology grade 2), high-grade MTSRCC (grade 3), and overlapping MTSRCC with papillary renal cell carcinoma (RCC) morphology. Array comparative genomic hybridization analysis was applied to 16 cases in which DNA was well preserved. Four analyzable classic low-grade MTSRCCs showed multiple losses affecting chromosomes 1, 4, 8, 9, 14, 15, and 22. No chromosomal gains were found. Four analyzable cases of MTSRCC showing overlapping morphology with PRCC displayed a more variable pattern including normal chromosomal status; losses of chromosomes 1, 6, 8, 9, 14, 15, and 22; and gains of 3, 7, 16, and 17. The group of 4 high-grade MTSRCCs exhibited a more uniform chromosomal aberration pattern with losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22 and without any gains detected. (1) MTSRCC, both low-grade and high-grade, shows chromosomal losses (including 1, 4, 6, 8, 9, 13, 14, 15, and 22) in all analyzable cases; this seems to be the most frequent chromosomal numerical aberration in this type of RCC. (2) Cases with overlapping morphologic features (MTSRCC and PRCC) showed a more variable pattern with multiple losses and gains, including gains of chromosomes 7 and 17 (2 cases). This result is in line with previously published morphologic and immunohistochemical studies that describe the broad morphologic spectrum of MTSRCC, with changes resembling papillary RCC. (3) The diagnosis of MTSRCC in tumors with overlapping morphology (MTSRCC and PRCC) showing gains of both chromosomes 7 and 17 remains questionable. Based on our findings, we recommend that such tumors should not be classified as MTSRCC but rather as PRCC. PMID- 26009023 TI - Motivational tools to improve probationer treatment outcomes. AB - BACKGROUND: Motivational interviewing (MI) is a promising practice to increase motivation, treatment retention, and reducing recidivism among offender populations. Computer-delivered interventions have grown in popularity as a way to change behaviors associated with drug and alcohol use. METHODS/DESIGN: Motivational Assistance Program to Initiate Treatment (MAPIT) is a three arm, multisite, randomized controlled trial, which examines the impact of Motivational interviewing (MI), a motivational computer program (MC), and supervision as usual (SAU) on addiction treatment initiation, engagement, and retention. Secondary outcomes include drug/alcohol use, probation progress, recidivism (i.e., criminal behavior) and HIV/AIDS testing and treatment among probationers. Participant characteristics are measured at baseline, 2, and 6 months after assignment. The entire study will include 600 offenders, with each site recruiting 300 offenders (Baltimore City, Maryland and Dallas, Texas). All participants will go through standard intake procedures for probation and participate in probation requirements as usual. After standard intake, participants will be recruited and screened for eligibility. DISCUSSION: The results of this clinical trial will fill a gap in knowledge about ways to motivate probationers to participate in addiction treatment and HIV care. This randomized clinical trial is innovative in the way it examines the use of in-person vs. technological approaches to improve probationer success. TRIAL REGISTRATION: NCT01891656. PMID- 26009024 TI - Safety of discontinuing cotrimoxazole prophylaxis among HIV infected adults on anti-retroviral therapy in Uganda (COSTOP trial): Design. AB - INTRODUCTION: Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organisation for HIV infected persons. However, once HIV infected patients have commenced ART in resource limited settings, the benefits of continued CTX prophylaxis are not known. The few studies that investigated the safety of discontinuing CTX prophylaxis in these settings had limitations due to their design. MATERIALS AND METHODS: COSTOP is a randomised double blind placebo controlled non-inferiority trial among HIV infected Ugandan adults stabilised on anti-retroviral treatment (ART). Participants with CD4 count of 250 or more cells/mm(3) are randomised to two arms: the intervention arm in which CTX is discontinued and the control arm in which CTX prophylaxis is continued. The study aims to assess whether the intervention regimen is not inferior, with respect to the incidence of pre-defined CTX-preventable events, to the control regimen and superior with respect to the incidence of haematological adverse events. DISCUSSION: Studies that have previously evaluated the safety of discontinuing CTX prophylaxis among HIV infected adults in resource limited settings have provided moderate to low quality evidence owing in part to methodological limitations. COSTOP is designed and conducted with sufficient rigour to answer this question. The results of the trial will assist in guiding policy recommendations. CONCLUSION: This paper describes the design and methodological considerations important for the conduct of CTX cessation studies. PMID- 26009025 TI - Angiogenin and apoptosis in hypertension in pregnancy. AB - Hypertension is a common medical condition that complicates pregnancy, and has significant adverse effects on pregnancy outcomes, including maternal and perinatal morbidity and mortality. In seeking the aetiology of pregnancy-related hypertension there has been a shift in focus from the foeto-placental axis to the maternal vasculature, and two possibly related pathophysiological mechanisms have been introduced - angiogenesis and apoptosis. Both processes have been extensively studied as possible pathophysiological mechanisms underlying a variety of diseases, including cardiovascular diseases such as hypertension, myocardial infarction, as well as conditions such as malignancy states, and there is a slowly developing body of knowledge justifying hypothesis of roles in pregnancy. This review presents the data regarding this position and explores the role of angiogenesis and apoptosis in the pathogenesis of hypertension in pregnancy and their effects on pregnancy outcomes. PMID- 26009026 TI - Severe pre-eclampsia and HELLP syndrome after massive fetomaternal hemorrhage following blunt abdominal trauma. AB - Severe pre-eclampsia and HELLP syndrome developed within 24h after a 31year old nulliparous woman suffered a blunt abdominal trauma with massive fetomaternal hemorrhage and fetal intracranial bleeding. This is the first case reported of fulminating pre-eclampsia and HELLP syndrome following maternal exposure to a large amount of fetal cells and/or fetal cell debris as DNA or microparticles. PMID- 26009027 TI - Increase of high molecular weight adiponectin in hypertensive pregnancy was correlated with brain-type natriuretic peptide stimulation on adipocyte. AB - BACKGROUND: High-molecular weight (HMW)-adiponectin is an active multimer for insulin sensitivity and anti-inflammatory reactions. We compared the ratio of serum total and HMW-adiponectin with brain-type natriuretic peptide (BNP) and other adipocytokines in normal pregnancy and pregnancy-induced hypertension (PIH). Effect of BNP on the secretion of adiponectin from cultured adipocytes was also examined. METHODS: The three study groups consisted of 44 non-pregnant women, 40 normal (healthy) pregnant women over 28weeks gestation and 29 patients with severe PIH. Adiponectin (protease-pretreated for HMW), BNP-N-terminal, leptin, and monocyte chemoattractant protein (MCP)-1 were measured with ELISA. Pre-adipocytes were differentiated to matured adipocytes and cultured with recombinant-BNP addition. RESULTS: HMW-to-total adiponectin ratio (HMW-ratio) was lower in normal pregnancy than in non-pregnant, and significantly higher in PIH than normal pregnancies. BNP-N-terminal showed positive correlation with HMW adiponectin and HMW-ratio. Leptin and MCP-1 showed positive correlation with HMW adiponectin, but not with HMW-ratio. Adiponectin in the supernatant of adipocyte cultures and intracellular cyclic-GMP was increased in dose-dependent manner in response to BNP. CONCLUSION: The observed increase in the HMW-adponectin ratio in subjects with PIH may reflect a functional increase of adiponectin in the pathophysiology of PIH. Additionally, this increase seemed to be related to BNP via stimulation of adipocytes. PMID- 26009028 TI - Interleukin-18 concentrations in pregnancies complicated by preeclampsia with and without IUGR: A comparison with normotensive pregnant women with isolated IUGR and healthy pregnant women. AB - OBJECTIVE: The aim of present study was to assess the maternal serum levels and clinical significance of interleukin-18 (IL-18) in pregnancies complicated by preeclampsia and/or intrauterine growth restriction (IUGR). PATIENTS AND METHODS: The study was carried out on 30 patients with pregnancy complicated by severe preeclampsia (15 patients with IUGR and 15 with appropriate-for-gestational-age weight fetuses), 11 normotensive pregnant patients with pregnancy complicated by isolated IUGR and 32 healthy normotensive women with uncomplicated pregnancies. The interleukin-18 levels were determined using an ELISA assay. RESULTS: Decreased levels of maternal serum IL-18 in preeclamptic patients with and without IUGR were observed. Contrary to the preeclamptic women, no difference was found in the maternal serum levels of IL-18 in normotensive patients with pregnancies complicated by isolated fetal growth restriction. These levels were the same as observed in the healthy controls. The mean values of maternal serum IL-18 were 219.118+/-180.079pg/mL in the PRE group, 438.170+/-229.657pg/mL in the group of women with isolated IUGR, and 457.053+/-528.142pg/mL in the control group. The levels of maternal serum IL-18 were similar in both study preeclamptic subgroups. The mean values of IL-18 were 204.823+/-188.171pg/mL in the group PI and 233.414+/-176.995pg/mL in the P group. CONCLUSIONS: Our findings suggest that decreased levels of IL-18 in maternal serum play a significant role in etiology and pathogenesis of preeclampsia. But normotensive pregnancies complicated by isolated IUGR are not associated with the altered interleukin 18 levels in maternal serum. PMID- 26009029 TI - Selenium and preeclampsia: A global perspective. AB - Preeclampsia is a complex multisystem disorder of pregnancy where oxidative stress plays an important aetiological role. The role of selenium in the synthesis of endogenous antioxidants is well documented, and a significant reduction in selenium has been reported in preeclamptic women. The objective of this study was to map global selenium status and preeclampsia incidence. This study identified peer reviewed journal articles reporting national preeclampsia incidence (%) and matched these with reported values of selenium intake and plasma/serum selenium concentrations (MUg/L). Matched data were obtained for 45 regions, reporting 6456,570 births, spanning Europe, Asia, Australasia, Africa, North and South America. Increasing plasma selenium concentration was found to be correlated with a reduction in preeclampsia incidence (Pearson's r=-0.604, P<0.0001). Countries with a reported serum/plasma selenium level of ?95MUg/L were considered selenium sufficient and a significant reduction in preeclampsia incidence for countries above this value (P=0.0007) was noted. Significant reductions in preeclampsia incidence were found to coincide with increases in plasma/serum selenium concentration in the New Zealand (P=0.0003) and Finland (0.0028) populations following Government intervention. This study supports the hypothesis that selenium supplementation may be beneficial in reducing oxidative stress in women at risk of preeclampsia. PMID- 26009030 TI - Does a patient information sheet lead to better understanding of pre-eclampsia? A randomised controlled trial. AB - OBJECTIVE: To investigate whether a structured patient information sheet would improve women's satisfaction and understanding of pre-eclampsia, its management and risks. STUDY DESIGN: A randomised, controlled trial conducted in a referral centre in South Africa. Seventy-four women with early pre-eclampsia, who qualified for expectant management, were enroled. They all completed an anonymous, structured, and self-administered questionnaire before randomisation. Cases (n=37) received a patient information sheet addressing key features of pre eclampsia; controls (n=37) received a welcome note. Within 5-7days, but still before delivery, they completed the same questionnaire again. MAIN OUTCOME MEASURES: Primarily assessing their general understanding and knowledge of pre eclampsia, secondarily to assess their satisfaction and the impact of the information received. RESULTS: The patient information sheet improved their understanding of the immediate and long-term risks (p<0.01) and the chance of recurrence (p<0.01). Controls had good levels of understanding and appreciation. Most women in both groups felt well informed but levels of concern remained high. CONCLUSIONS: The structured information sheet improved patients' understanding and knowledge in a limited way but did not alleviate their anxiety. Although women appear to be generally well counselled in the study unit, measures to alleviate associated anxiety should be investigated. PMID- 26009031 TI - Different effects of different phosphodiesterase type-5 inhibitors in pre eclampsia. AB - OBJECTIVES: We aimed to determine the effects of sildenafil and vardenafil in human umbilical artery preparation taken from pre-eclamptic or normal pregnant women, and also to investigate the underlying mechanisms in these effects. STUDY DESIGN: Fifteen pregnant women with pre-eclampsia and 15 healthy pregnant women were involved. Relaxation responses of sildenafil and vardenafil in the presence and absence of nitric oxide synthase inhibitor, N-[omega]-nitro-l-arginine methyl ester (l-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one (ODQ), were compared between the pre-eclampsia group and the control group. RESULTS: Sildenafil induced relaxation responses were significantly attenuated in the presence of pre-eclampsia, l-NAME and QDO. Similarly, pre-eclampsia, l-NAME or ODQ incubation also shifted vardenafil induced relaxation responses rightward. However, in all set of experiments a maximal relaxation response was achieved by vardenafil unlike sildenafil. In conclusion vardenafil seems to relax human umbilical artery stronger than sildenafil in both pre-eclamptic and normal pregnancies. CONCLUSION: These data indicate that vardenafil might affect vascular responsiveness of human umbilical artery through the involvement of NO/cGMP-dependent and independent pathways while sildenafil-induced responses were seemed to be completely NO/cGMP dependent. Further investigations are needed to clarify the mechanisms. PMID- 26009032 TI - L1. Imitators of severe preeclampsia. PMID- 26009033 TI - L2. Clinical utility of placental growth factor - Pathological insights from commercial assays. PMID- 26009034 TI - L3. Trophoblast invasion and spiral artery transformation in pre-eclampsia and fetal growth restriction. PMID- 26009035 TI - L4. Placental inflammatory factors and preeclampsia. PMID- 26009036 TI - L5. Genetic aspects of preeclampsia. PMID- 26009037 TI - L6. Placental oxygenation and respiration in preeclampsia. PMID- 26009038 TI - L7. Evaluation of different model for the prediction of late preeclampsia at the 1st trimester of pregnancy. PMID- 26009039 TI - L8. First trimester screening for pre-eclampsia. PMID- 26009040 TI - L9. NGAL, an early marker of endothelial dysfunction in preeclampsia. PMID- 26009041 TI - L10. Prediction and prevention of preeclampsia in autoimmune disease. PMID- 26009042 TI - L11. Using biochemical markers of cardiac function to predict preeclampsia. PMID- 26009043 TI - L12. The role of heparin in the prevention of preeclampsia. PMID- 26009044 TI - L13. The routine measurement of the sFlt1/PlGF ratio allows differential diagnosis of hypertensive pregnancy disorders and has prognostic potential in preeclamptic patients. PMID- 26009045 TI - L14. Hyperglycemia and adverse pregnancy outcome (HAPO) study: Preeclampsia. PMID- 26009046 TI - L15. Biological aspects of inositol phosphoglycans in human pregnancy and preeclampsia. PMID- 26009047 TI - L16. The role of glycemic control in the development of preeclampsia in type 1 diabetic women. PMID- 26009048 TI - L17. The role of aldosterone in normal and preeclamptic pregnancies. PMID- 26009049 TI - L18. Total Vascular Resistance in complicated pregnancies. PMID- 26009050 TI - L19. Maternal cardiac function in preeclampsia. PMID- 26009051 TI - L20. Differences in the hemodynamic profile between pre-eclampsia and other forms of hypertension in pregnancy. PMID- 26009052 TI - L21. Maternal cardiac function in normal and complicated twin pregnancy: A longitudinal study. PMID- 26009053 TI - L22. How we might do without vitamins. PMID- 26009054 TI - L23. Short and long term neurological consequences of (pre) eclampsia. PMID- 26009055 TI - L24. The meaning of proteinuria in preeclampsia. PMID- 26009056 TI - L25. Renal disease and preeclampsia. PMID- 26009057 TI - L26. Severe preeclampsia: When to deliver? PMID- 26009058 TI - L27. Management of non severe gestational hypertension through the modulation of total vascular resistance. PMID- 26009059 TI - L28. Calcium antagonists in hypertensive disorders of pregnancy. PMID- 26009060 TI - L29. Pathophysiology and treatment of hypertension in women in the different phases of life. PMID- 26009061 TI - L30. Echocardiographic markers of cardiovascular risk after pregnancy complications and cardiovascular outcome after a 4 years follow up. PMID- 26009062 TI - L31. Preeclampsia: Not only a disease of pregnancy. PMID- 26009063 TI - O1. Dramatic upregulation of HIF-1alpha in the endovascular and extravillous trophoblasts at the maternal-fetal interface in preeclamptic pregnancies. PMID- 26009064 TI - O2. Serum concentrations of angiogenic factors as predictors of severity of preeclampsia, in Colombian population. PMID- 26009065 TI - O3. The predominante of Th17 lymphocytes and decreased number and function of Treg cells are present in preeclampsia. PMID- 26009066 TI - O4. Predisposing factors for early- and late-onset preclampsia. PMID- 26009067 TI - O5. Low-dose aspirin therapy in pregnant women with chronic hypertension. PMID- 26009068 TI - O6. Uterine artery Doppler in a risk population: What's its role in the prediction of small for gestational age fetuses? PMID- 26009069 TI - O7. Prospective evaluation of ultrasound and biochemical-based multivariable models for the prediction of late preeclampsia. PMID- 26009070 TI - O8. Comparison of two placental growth factor immunoassays as an aid in the diagnosis of preterm preeclampsia. PMID- 26009071 TI - O9. Evaluating fetal cord blood lipids and oxidized LDL status in intrauterine growth restriction and preeclampsia. PMID- 26009072 TI - O10. An obesity-related FTO variant and the risk of pre-eclampsia in a Finnish study population. PMID- 26009073 TI - O11. Myo-inositol may prevent metabolic and hypertensive disorders in PCOS pregnant women. PMID- 26009074 TI - O12. Pre-pregnancy to early pregnancy changes in maternal cardiovascular physiology. PMID- 26009075 TI - O13. Microvascular and macrovascular hemodynamic effects of nicardipine in the treatment of severe pre-eclampsia. PMID- 26009076 TI - O14. Impaired mid-gestational maternal cardiac function and left ventricular remodelling in women who subsequently develop preterm but not term preeclampsia. PMID- 26009077 TI - O15. Non-invasive assessment of hemodynamics in early pregnancy. PMID- 26009078 TI - O16. Placental folate receptor alpha (FR-alpha) and proton coupled folate transporter (PCFT) mRNA and protein expression are decreased in pre-eclampsia. PMID- 26009079 TI - O17. Hypertension in pregnancy and endothelial dysfunction: An emerging risk factor for cardiovascular disease. PMID- 26009080 TI - O18. Endothelial function and glucose metabolism in overweight and obese nondiabetic woman: A possible role of l-Arginine/Nitric Oxide pathway. PMID- 26009081 TI - O19. Kidney transplantation and pregnancy: Maternal and fetal outcome. PMID- 26009082 TI - O20. Body liquids sectors of puerperal women with preeclampsia and their diagnostic role. PMID- 26009083 TI - O21. Total vascular resistance and multigate spectral doppler analysis (MSDA) as a screening tool for preeclampsia: A pilot study. PMID- 26009084 TI - O22. Secondary preventive interventions of cardiovascular risk in women who had hypertension during pregnancy after 36 weeks gestation. PMID- 26009085 TI - O23. Effects of S-nitrosoglutathione (GSNO) on arterial stiffness in severe early onset preeclampsia. PMID- 26009086 TI - O24. Is there any cardiovascular effect of carbetocin utilization that might prevent its use in preeclampsia? A TVR and CO study. PMID- 26009087 TI - O25. Preeclampsia is associated to persistent long-term postpartum left ventricular myocardial injury. PMID- 26009088 TI - O26. Decreased vision-related quality of life following eclampsia. PMID- 26009089 TI - O28. Cardiovascular biomarkers during and after preeclamptic pregnancy. PMID- 26009090 TI - O27. Hypertensive disorders in pregnancy and risk of severe mental disorders in the offspring in adulthood: The Helsinki Birth Cohort study. PMID- 26009091 TI - P1. Targeted gene arrays across the severely-discordant growth monochorionic twin placenta: Implications for angiogenesis and metabolic programming. PMID- 26009092 TI - P2. The effects of statins and antihypertensives on placental secretion of angiogenic proteins in term pre-eclampsia. PMID- 26009093 TI - P3. Placental effects of antihypertensives on activin A and inhibin A in pre eclampsia. PMID- 26009094 TI - P4. Uteroplacental arterio-venosus difference in sFlt, but not in endoglin concentrations in preeclampsia. PMID- 26009095 TI - P5. Bioinformatic analysis of protein-protein interaction network in preeclampsia. PMID- 26009096 TI - P6. Active and inactivated hemopexin in pregnancy and preeclampsia: Do they activate monocytes and endothelial cells? PMID- 26009097 TI - P7. Role of EGF-like domain 7 (Egfl7) in placental development and implantation. PMID- 26009098 TI - P8. Circulating ficolins in normal pregnancy and preeclampsia. PMID- 26009099 TI - P9. The elecsys assay for PlGF, sFlt1 and their ratio (sFlt1/PlGF) as an aid in differential diagnosis of pregnancy-related hypertensive disorders. PMID- 26009100 TI - P10. Placental expression of haemostatic and angiogenic markers in preeclampsia. PMID- 26009101 TI - P11. Differentially expressed micro-RNAs in microparticles from haemoglobin perfused placentas. PMID- 26009102 TI - P13. Alterations in placental expression of Caveolin-1, Cavin-1 and eNOS in women with pre-eclampsia. PMID- 26009103 TI - P12. Placental gene expression analysis at the end of the first trimester of pregnancy in patients at high risk of subsequent development of preeclampsia. PMID- 26009104 TI - P14. The number and location of vessels with decidual vasculopathy correlate with disease severity in preeclampsia. PMID- 26009105 TI - Are components of the Renin Angiotensin System (RAS) associated with oxidative stress in normotensive (NT) and pre-eclamptic (PE) placentae? PMID- 26009106 TI - P15. The influence of maternal Lewis, Secretor and ABO(H) blood groups on pre eclampsia and fetal growth restriction. PMID- 26009107 TI - P16. Uterine artery Doppler ultrasonography and pre-eclampsia. PMID- 26009108 TI - P17. Significance of uteroplacental Doppler at midtrimester in low risk parous women. PMID- 26009109 TI - P19. Comparing the pregnancy outcome in nuliparas both with and without microalbuminuria at the end of the second trimester of pregnancy. PMID- 26009110 TI - P18. Angiogenic factors for the prediction of early- and late onset preeclampsia in a high risk cohort. PMID- 26009111 TI - P20. Prediction of preterm preeclampsia by combining histidine-rich glycoprotein and uterine artery Doppler in early pregnancy. PMID- 26009112 TI - P22. Evaluation of a new, simple and rapid placental growth factor test for the evaluation of hypertensive disorders in pregnancy. PMID- 26009113 TI - P23. Prediction of preeclampsia during early pregnancy in primiparas with soluble fms-like tyrosine kinase-1 and placental growth factor. PMID- 26009114 TI - P21. Role of uterine artery doppler in pregnant women with chronic hypertension. PMID- 26009115 TI - P24. Study of C677T methylene tetrahydrofolate reductase (MTHFR) polymorphism in preeclampsia. PMID- 26009116 TI - P25. Increased inhibin A in severed preeclampsia/eclampsia. PMID- 26009117 TI - P28. Predictive value of the sFlt-1/PlGF ratio in pregnancies at risk for hypertensive disorders. PMID- 26009118 TI - P27. Clinical utility of uric acid in the detection of preeclampsia in hypertensive pregnancy - Preliminary results. PMID- 26009119 TI - P26. Comparison serum inhibin A level, placenta inhibin A level and placenta inhibin A expression in severe preeclampsia/eclampsia and normal pregnant women. PMID- 26009120 TI - P30. Angiogenic factors combined with clinical risk factors to predict preterm preeclampsia in nulliparous women. PMID- 26009121 TI - P29. Vascular reactivity in preeclampsia assessed using finger tip hyperemia in a rural African setting. PMID- 26009122 TI - P31. Risk factors for Pre-eclampsia, study in Iran. PMID- 26009123 TI - P32. Did calcium management prevent preeclampsia? PMID- 26009124 TI - P33. Uterine artery Doppler and biochemical markers (PAPP-A, PlGF, sFlt-1, P Selectin, NGAL) at 11+0 to 13+6weeks in the prediction of late (>34weeks) preeclampsia. PMID- 26009125 TI - P35. Hypertensive disorders in pregnant women affected by type 1 diabetes. PMID- 26009126 TI - P34. Prepregnancy body mass index, weight gain and hypertensive disorders in pregnancy. PMID- 26009127 TI - P37. Non-invasive haemodynamic monitoring using transthoracic echocardiography in pregnancy: Validation against cardiac catheterisation. PMID- 26009128 TI - P36. Association of aortic stiffness with uterine artery Doppler pulsatility index and risk of preeclampsia. PMID- 26009129 TI - Association of augmentation index with uterine artery Doppler and risk of preeclampsia. PMID- 26009130 TI - P39. Comparison of amino terminal pro brain natriuretic peptide levels in hypertensional gestational syndrome and normotensive pregnancy. PMID- 26009131 TI - Pre-pregnancy cardiovascular risk in women with previous preeclampsia (PET)/intrauterine growth restriction (IUGR). PMID- 26009132 TI - P42. Hypertensive disorders in pregnancy and risk of severe mental disorders in the offspring in adulthood: The Helsinki Birth Cohort Study. PMID- 26009133 TI - P41. Long term objective higher visual functioning and vision-realted quality of life following eclampsia. PMID- 26009134 TI - P40. HELLP syndrome - statistic of the department. PMID- 26009135 TI - P43. Fathers with PTSD and depression in pregnancies complicated by preeclampsia or PPROM. PMID- 26009136 TI - P44. The effect of hypertensive disorders in pregnancy on quality of life post partum. PMID- 26009137 TI - Increased maternal growth-differentiation factor-15 in preeclampsia does not predict endothelial function 5-8 years postpartum. PMID- 26009138 TI - P45. Improving the quality of care using evidence-based approaches in hypertension in pregnancy: The role of audit to optimisze clinical effectiveness. PMID- 26009139 TI - P46. TOTEM study (temporise or terminate pregnancy in women with severe preeclampsia at 28-34 weeks): A study protocol. PMID- 26009140 TI - P47. The application of the electrolyte balanced hydroxyethylstarch solution - Tetraspan in complex infusion therapy of preeclampsia in perioperative care. PMID- 26009142 TI - P50. Infant growth following a hypertensived pregnancy. PMID- 26009141 TI - P48. Brain injury on pregnancy. PMID- 26009143 TI - P49. Do circulating angiogenic factors in pregnancies complicated by diabetes mellitus predict angiogenic factors and endothelial function postpartum? PMID- 26009144 TI - P51. Pregnancy stimulates cerebellar hemangioblastoma growth in von Hippel-Lindau disease. PMID- 26009145 TI - P53. Association between trombophilia and preeclampsia. PMID- 26009146 TI - P52. Age and parity as a risk factor for preeclampsia. PMID- 26009147 TI - P54. Normotensive-hypertensive pregnancy patterns among pregnant women of abstract child bearing ages: A Chinese study. PMID- 26009148 TI - Design and use of an instrument for video-assisted surgical treatment of unstable fractures of the zygomatic arch: the Z instrument. PMID- 26009149 TI - Opening up animal research and science-society relations? A thematic analysis of transparency discourses in the United Kingdom. AB - The use of animals in scientific research represents an interesting case to consider in the context of the contemporary preoccupation with transparency and openness in science and governance. In the United Kingdom, organisations critical of animal research have long called for more openness. More recently, organisations involved in animal research also seem to be embracing transparency discourses. This article provides a detailed analysis of publically available documents from animal protection groups, the animal research community and government/research funders. Our aim is to explore the similarities and differences in the way transparency is constructed and to identify what more openness is expected to achieve. In contrast to the existing literature, we conclude that the slipperiness of transparency discourses may ultimately have transformative implications for the relationship between science and society and that contemporary openness initiatives might be sowing the seeds for change to the status quo. PMID- 26009150 TI - Eight-year incidence of psychiatric disorders and service use from adolescence to early adulthood: longitudinal follow-up of the Mexican Adolescent Mental Health Survey. AB - Half of mental disorders have their first onset before adulthood when the presence of a disorder may be particularly disruptive to developmental milestones. Retrospective prevalence estimates have been shown to underestimate the burden of mental illness and scarce data are available on the incidence of disorders throughout the adolescent period, especially in developing countries. Thus, the objective was to determine the incidence of mental disorders in an 8 year period from adolescence to young adulthood, onset of service use and their predictors in a Mexican cohort. 1071 respondents from a representative two-wave panel sample participated in the Mexican Adolescent Mental Health Survey in 2005 and in the follow-up survey in 2013. Disorders were evaluated with the World Mental Health Composite International Diagnostic Interview. 37.9% experienced the onset of a psychiatric disorder and 28.4% sought services for the first time. Substance use disorders had the greatest incidence, followed by mood and behavior disorders, anxiety disorders and lastly eating disorders. Sex, age, school dropout, childhood adversities and prior mental disorders predicted the onset of new disorders. Being female, having more educated parents and most classes of disorder predicted first time service use. These findings contribute to a paradigm shift in conceptions of mental disorder similar to how we think of common physical afflictions as near universal experiences across the life course, but less frequent at any given moment. Adolescents are particularly vulnerable. Therefore, public health policy should focus on early universal promotion of positive mental health and structural determinants of mental health. PMID- 26009151 TI - Sample-to-Answer Isolation and mRNA Profiling of Circulating Tumor Cells. AB - The isolation and rapid molecular characterization of circulating tumor cells (CTCs) from a liquid biopsy could enable the convenient and effective characterization of the state and aggressiveness of cancerous tumors. Existing technologies enumerate CTCs using immunostaining; however, these approaches are slow, labor-intensive, and often fail to enable further genetic characterization of CTCs. Here, we report on an integrated circuit that combines the capture of CTCs with the profiling of their gene expression signatures. Specifically, we use a velocity valley chip to efficiently capture magnetic nanoparticle-bound CTCs, which are then directly analyzed for their gene expression profiles using nanostructured microelectrode biosensors. CTCs are captured with 97% efficiency from 2 mL of whole blood, yielding a 500-fold concentration within 1 h. We show efficient capture of as few as 2 cancer cells/(mL of blood) and demonstrate that the gene expression module accurately profiles the expression of prostate specific genes in CTCs captured from whole blood. This advance provides the first sample-to-answer solution for gene-based testing of CTCs. The approach was successfully validated using samples collected from prostate cancer patients: both CTCs and prostate-specific antigen (PSA) mRNA sequences were detected in all cancer patient samples and not in the healthy controls. PMID- 26009152 TI - Purification of proteins from solutions containing residual host cell proteins via preparative crystallization. AB - OBJECTIVES: To investigate quantitatively and reproducibly a scalable, preparative crystallization method in novel stirred tanks using three different protein solutions containing residual microbial host cell proteins (HCP). RESULTS: Lysozyme from solutions being spiked with up to 15% host cell proteins (HCP) (corresponding to 176,500 ppm) was crystallized within a 2.4-4.6 h at 93.7% yield using NaCl and glycerol. Lipase was crystallized under comparable conditions using NaCl and a mixture of two polyethylene glycols (PEG). Enhanced green fluorescent protein (eGFP) was overexpressed in E. coli yielding a solution containing 23% target protein. Residual HCP content after pre-treatment was 7 16%. eGFP was crystallized from these solutions within 1.75-4 h at 88.7% step yield using ethanol and the same mixture of two PEG as in the case of lipase. HCP contained in the solvent channels of the protein crystals could be removed by diffusive washing yielding final purities at or above 99%. CONCLUSION: Preparative crystallization can be carried out with fast kinetics and high yields from solutions containing residual impurities and may represent an attractive alternative purification method compared to preparative chromatography, especially at large production scales. PMID- 26009153 TI - Mechanical Overloading Increases Maximal Force and Reduces Fragility in Hind Limb Skeletal Muscle from Mdx Mouse. AB - There is fear that mechanical overloading (OVL; ie, high-force contractions) accelerates Duchenne muscular dystrophy. Herein, we determined whether short-term OVL combined with wheel running, short-term OVL combined with irradiation, and long-term OVL are detrimental for hind limb mdx mouse muscle, a murine model of Duchene muscular dystrophy exhibiting milder dystrophic features. OVL was induced by the surgical ablation of the synergic muscles of the plantaris muscle, a fast muscle susceptible to contraction-induced muscle damage in mdx mice. We found that short-term OVL combined with wheel and long-term OVL did not worsen the deficit in specific maximal force (ie, absolute maximal force normalized to muscle size) and histological markers of muscle damage (percentage of regenerating fibers and fibrosis) in mdx mice. Moreover, long-term OVL did not increase the alteration in calcium homeostasis and did not deplete muscle cell progenitors expressing Pax 7 in mdx mice. Irradiation before short-term OVL, which is believed to inhibit muscle regeneration, was not more detrimental to mdx than control mice. Interestingly, short-term OVL combined with wheel and long term OVL markedly improved the susceptibility to contraction-induced damage, increased absolute maximal force, induced hypertrophy, and promoted a slower, more oxidative phenotype. Together, these findings indicate that OVL is beneficial to mdx muscle, and muscle regeneration does not mask the potentially detrimental effect of OVL. PMID- 26009154 TI - Embracing open access and offering greater choice for authors. PMID- 26009156 TI - Influence of donor age in allogeneic stem cell transplant outcome in acute myeloid leukemia and myelodisplastic syndrome. AB - The impact of donor age in patients with acute myeloid leukemia and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplant (HSCT) remains unclear. In the current study, we evaluate 179 consecutive patients who received an HSCT, from January 2000 to January 2013, in our Institution. Most of the HSCT (91%) were HLA-matched. Patient and donor median age were 51 years (18-69) and 47 years (12-75) respectively, and 81 donors (45%) were older than 50 years. The median follow-up was 38 months (range 1-138), Kaplan-Meier estimated 3-year overall survival (OS) was 63% and disease free survival (DFS) was 56%. Interestingly, patients who received an HSCT from a donor older age (>50 y) showed a poorer OS (51% vs 73%; p=0.01), as well as a higher TRM (20% vs 8%; p=0.038) and higher relapse rate (28% vs 39%; p=0.03). In a stratified subanalysis, 3-year estimated OS was significantly lower among patients undergoing an HSCT from >50 years sibling donors compared to those receiving an HSCT from <50 years unrelated donor (54% vs 72%; p<0.001). In summary, we can conclude that receiving an HSCT from a donor over 50 years old is associated with poorer outcome in patients diagnosed with MDS and AML, and this information may be incorporated into the complex process of donor selection. PMID- 26009157 TI - Comparison of different static methods for assessment of AMD generation potential in mining waste dumps in the Muteh Gold Mines, Iran. AB - Acid mine drainage (AMD) gives rise to several problems in sulfide-bearing mineral deposits whether in an ore body or in the mining wastes and tailings. Hence, several methods and parameters have been proposed to evaluate the acid producing and acid-neutralizing potential of a material. This research compares common static methods for evaluation of acid-production potential of mining wastes in the Muteh gold mines by using 62 samples taken from six waste dumps around Senjedeh and Chah-Khatoun mines. According to a detailed mineralogical study, the waste materials are composed of mica-schist and quartz veins with a high amount of pyrite and are supposed to be susceptible to acid production, and upon a rainfall, they release acid drainage. All parameters introduced in different methods were calculated and compared in this research in order to predict the acid-generating and neutralization potential, including APP, NNP, MPA, NPR, and NAGpH. Based on the analytical results and calculation of different parameters, all methods are in a general consensus that DWS-02 and DWS-03 waste dumps are acid-forming which is clearly attributed to high content of pyrite in samples. DWS-04 is considered as non-acid forming in all methods except method 8 which is uncertain about its acid-forming potential and method 7 which considers a low potential for it. DWC-01 is acid-forming based on all methods except 8, 9, 10, and 11 which are also uncertain about its potential. The methods used are not reached to a compromise on DWS-01 and DWC-02 waste dumps. It is supposed that method 7 gives the conservationist results in all cases. Method 8 is unable to decide on some cases. It is recommended to use and rely on results provided by methods 1, 2, 3, and 12 for taking decisions for further studies. Therefore, according to the static tests used, the aforementioned criteria in selected methods can be used with much confidence as a rule of thumb estimation. PMID- 26009158 TI - Design of sampling locations for river water quality monitoring considering seasonal variation of point and diffuse pollution loads. AB - The design of a water quality monitoring network (WQMN) is a complicated decision making process because each sampling involves high installation, operational, and maintenance costs. Therefore, data with the highest information content should be collected. The effect of seasonal variation in point and diffuse pollution loadings on river water quality may have a significant impact on the optimal selection of sampling locations, but this possible effect has never been addressed in the evaluation and design of monitoring networks. The present study proposes a systematic approach for siting an optimal number and location of river water quality sampling stations based on seasonal or monsoonal variations in both point and diffuse pollution loadings. The proposed approach conceptualizes water quality monitoring as a two-stage process; the first stage of which is to consider all potential water quality sampling sites, selected based on the existing guidelines or frameworks, and the locations of both point and diffuse pollution sources. The monitoring at all sampling sites thus identified should be continued for an adequate period of time to account for the effect of the monsoon season. In the second stage, the monitoring network is then designed separately for monsoon and non-monsoon periods by optimizing the number and locations of sampling sites, using a modified Sanders approach. The impacts of human interventions on the design of the sampling net are quantified geospatially by estimating diffuse pollution loads and verified with land use map. To demonstrate the proposed methodology, the Kali River basin in the western Uttar Pradesh state of India was selected as a study area. The final design suggests consequential pre- and post-monsoonal changes in the location and priority of water quality monitoring stations based on the seasonal variation of point and diffuse pollution loadings. PMID- 26009159 TI - Field monitoring of a LID-BMP treatment train system in China. AB - In order to assess the urban runoff control effectiveness of a low-impact development best management practice (LID-BMP) treatment train system, a field test of selected LID-BMPs was conducted in China. The LID-BMPs selected include three grassed swales, a buffer strip, a bioretention cell, two infiltration pits, and a constructed wetland. The test site is in a campus in southern China. The LID-BMPs, connected in a series, received stormwater runoff from four tennis courts with an area of 2808 m(2) and eight basketball courts with an area of 4864 m(2). Construction of the LID-BMPs was completed in early spring of 2012, and the sampling was conducted during May of 2012 to September of 2013. During the sampling effort, besides the performance evaluations of grassed swales and the bioretention cell in controlling runoff quantity as well as quality, the emphasis was also on determining the performance of the LID-BMP treatment train system. A total of 19 storm events were monitored, with nine producing no runoff and ten producing runoff. Data collected from the ten storm events were analyzed for estimating runoff quantity (peak flow rate and total runoff volume) and quality reduction by the LID-BMPs. The sum of loads (SOL) method was used for calculating the water quality performance of LID-BMPs. Results indicated that, for peak flow rate, a bioretention cell reduction of 50-84 % was obtained, and grassed swale reduction was 17-79 %, with a runoff volume reduction of 47-80 and 9-74 %, respectively. For water quality, the bioretention cell in general showed good removal for zinc (nearly 100 %), copper (69 %), NH3-N (ammonia nitrogen) (51 %), and total nitrogen (TN) (49 %); fair removal for chemical oxygen demand (COD) (18 %); and poor removal for total suspended solids (TSS) (-11 %) and total phosphorus (TP) (-21 %). And its performance effectiveness for pollutant removal increased in the second year after 1 year of stabilizing. When considering the aggregated effect of the LID-BMP treatment train system, it showed excellent removal for NH3-N (73 %), TN (74 %), and TP (95 %) and fair removal for COD (19 %) and TSS (35 %). The assessment results of the LID-BMP treatment train system provide valuable information on how to link the different types of LID-BMP facilities and maximize the integrated effectiveness on urban runoff control. PMID- 26009160 TI - Fiber optic light sensor. AB - We describe a low-cost fiber optic sensor for measuring photosynthetically active radiation (PAR) in turbulent flow. Existing technology was combined in a novel way for probe development addressing the need for a small but durable instrument for use in flowing water. Optical components including fiber optics and a wide spectrum light detector were used to separate light collection from electronic detection so that measurements could be completed in either the field or laboratory, in air or underwater. Connection of the detector to Arduino open source electronics and a portable personal computer (PC) enabled signal processing and allowed data to be stored in a spreadsheet for ease of analysis. Calibration to a commercial cosine-corrected instrument showed suitable agreement with the added benefit that the small sensor face allowed measurements in tight spaces such as close to the streambed or within leafy or filamentous plant growth. Subsequently, we applied the probe in a separate study where over 35 experiments were successfully completed to characterize downward light attenuation in filamentous algae in turbulent flow. PMID- 26009161 TI - Presence of aflatoxin M1 in raw, reconstituted, and powdered milk samples collected in Algeria. AB - Aflatoxins are potent toxic metabolites produced by Aspergillus spp. Aflatoxin M1 (AFM1) is a metabolite of aflatoxin B1 that can be present in milk, and it is a public health concern. There is scarce information on the incidence of aflatoxin M1 contamination in milk consumed in Algeria. The presence of AFM1 was investigated in raw milk samples collected between February and October 2011 from 11 dairy farms representative of Algerian production conditions and that were located around Constantine city. Reconstituted and powdered milk samples were purchased from local supermarkets. The analysis was performed by liquid chromatography-fluorescence detection after immunoaffinity purification. AFM1 was detected in 5 out of 47 samples (11 %) at levels ranging from 9 to 103 ng/L, with one sample exceeding the limit of 50 ng/L set by European regulations. Traces of AFM1 (less than 8 ng/L) were also found in 11 other samples. The incidence of AFM1 contamination was higher in imported powdered milk (29 %) than in raw milk (5 %). Although the concentration of AFM1 in contaminated samples was low, the relatively considerable prevalence found in this exploratory study justifies more detailed and continuous monitoring to reduce consumers' exposure to AFM1. PMID- 26009162 TI - Gastroprotective activity of ent-beyerene derivatives in mice: Effects on gastric secretion, endogenous prostaglandins and non-protein sulfhydryls. AB - Seventeen compounds (2-18) synthetized from the diterpenoid ent-beyer-15-en-18-ol (1) isolated from aerial part of Baccharis tola were tested for their gastroprotective activity on the model of HCl/EtOH-induced gastric lesions in mice. Furthermore cytotoxicity test toward fibroblasts and AGS cells were performed. The results showed that compound 1 (ED50=50 mg/kg), 2, 6 and 13 were the most active regarding gastroprotective activity. Compounds 8-10 and 17-18 showed the lowest cytotoxicity toward fibroblasts and AGS cells. Regarding to mode of gastroprotective action, the effect elicited by 6 (50 mg/kg) was reversed by Indomethacin but not by N-ethylmaleimide, N(G)-nitro-L-arginine methyl ester or ruthenium red, which suggests that prostaglandins are involved in the mode of gastroprotective action of 6. PMID- 26009163 TI - A new class of ghrelin O-acyltransferase inhibitors incorporating triazole-linked lipid mimetic groups. AB - Inhibitors of ghrelin O-acyltransferase (GOAT) have untapped potential as therapeutics targeting obesity and diabetes. We report the first examples of GOAT inhibitors incorporating a triazole linkage as a biostable isosteric replacement for the ester bond in ghrelin and amide bonds in previously reported GOAT inhibitors. These triazole-containing inhibitors exhibit sub-micromolar inhibition of the human isoform of GOAT (hGOAT), and provide a foundation for rapid future chemical diversification and optimization of hGOAT inhibitors. PMID- 26009164 TI - Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo[2,3 b]pyridin-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides. AB - We report herein the design and synthesis of a series of novel 5-halogenated-7 azaindolin-2-one derivatives containing a 2,4-dimethylpyrrole moiety. Nine target compounds with ?70% inhibition against MCF-7 at 30 MUM were further evaluated for their in vitro antitumor activity against seven human cancer cell lines by SRB assay. Results reveal that some compounds have potent antitumor activity, and the most active 13c7 (IC50s: 4.49-15.39 MUM) was found to be more active than Sunitinib (IC50s: 4.70->30 MUM) against all of the tested cancer cell lines. PMID- 26009165 TI - Michael acceptor in gambogic acid--Its role and application for potent antitumor agents. AB - Gambogic acid (GA), a natural product with unique structure, was reported to have broad antiproliferation activities against cancer cell lines. As a reactive Michael acceptor, the 10-position of GA is susceptible to nucleophiles, thus limiting its clinical application as an anticancer agent. Moreover, the 6-OH forms an intramolecular hydrogen bond with 8-CO, which can make the 9, 10 double bond more reactive to nucleophiles. In this essay, two strategies (A and B) were applied to solve the above-mentioned problems. Strategy A was to increase the steric hindrance of C-10 to reduce the activity of GA towards nucleophiles. Strategy B was to replace the hydroxyl of C-6 with other substituents based on the assumption that the intra-molecular hydrogen bond could increase the electrophilicity of C-10. Results showed the electrophilicity of C-10 disappeared as well as the antiproliferation activity against cancer cell lines by introducing a methyl group at C-10. Strategy B showed that the electrophilicity of C-10 was reduced dramatically while maintained the activity by replacement of the hydroxyl of C-6 with neutral or basic groups. PMID- 26009166 TI - Validation of the Spot Urine in Evaluating 24-Hour Sodium Excretion in Chinese Hypertension Patients. AB - BACKGROUND: The spot urine method as an alternative approach in estimating daily urine sodium excretion has been proposed for many years. Kawasaki has created an equation to predict daily urinary sodium excretion using second morning urine (SMU) samples which was obtained before breakfast after initial voiding upon arising. Tanaka has developed another equation by examining spot urine samples submitted at random times during the day. A newly published study proposed that the "PM sample," collected in the late afternoon or early evening before dinner, showed a stronger relationship with actual sodium excretion. We aimed to verify the effectiveness of these methods in evaluating 24-hour urinary sodium in Chinese hypertensive patients. METHODS: A total of 334 hypertensive participants were eligible to participate in this study. A total of 222 patients provided qualified SMU samples, Post Meridiem (PM) samples, and complete 24-hour urine collections. RESULTS: Biases using the Kawasaki formula were 2.1 mmol/day for the SMU specimens; for the Tanaka equation, biases of SMU and PM samples were 21.1 and 30.1 mmol/day, respectively. The highest intraclass correlation coefficient (ICC) was 0.64 when the Kawasaki formula was used in PM specimens, with the lowest ICC 0.17 when it is used in SMUs. CONCLUSIONS: Spot urine method is acceptable for estimating 24-hour urinary sodium excretion in hypertensive individuals. Kawasaki's formula is useful for estimating population mean levels of sodium excretion from SMU, although it is not suitable for estimating individual sodium excretion. PMID- 26009167 TI - Measuring Sodium Intake in Populations: Simple Is Best? PMID- 26009168 TI - Determining the geometry of oligomers of the human epidermal growth factor family on cells with <10 nm resolution. AB - There is a limited range of methods available to characterize macromolecular organization in cells on length scales from 5-50 nm. We review methods currently available and show the latest results from a new single-molecule localization based method, fluorophore localization imaging with photobleaching (FLImP), using the epidermal growth factor (EGF) receptor (EGFR) as an example system. Our measurements show that FLImP is capable of achieving spatial resolution in the order of 6 nm. PMID- 26009169 TI - Protein clustering and spatial organization in T-cells. AB - T-cell protein microclusters have until recently been investigable only as microscale entities with their composition and structure being discerned by biochemistry or diffraction-limited light microscopy. With the advent of super resolution microscopy comes the ability to interrogate the structure and function of these clusters at the single molecule level by producing highly accurate pointillist maps of single molecule locations at ~20nm resolution. Analysis tools have also been developed to provide rich descriptors of the pointillist data, allowing us to pose questions about the nanoscale organization which governs the local and cell wide responses required of a migratory T-cell. PMID- 26009170 TI - Post-transcriptional regulation of gene expression by Unr. AB - Unr (upstream of N-ras) is a eukaryotic RNA-binding protein that has a number of roles in the post-transcriptional regulation of gene expression. Originally identified as an activator of internal initiation of picornavirus translation, it has since been shown to act as an activator and inhibitor of cellular translation and as a positive and negative regulator of mRNA stability, regulating cellular processes such as mitosis and apoptosis. The different post-transcriptional functions of Unr depend on the identity of its mRNA and protein partners and can vary with cell type and changing cellular conditions. Recent high-throughput analyses of RNA-protein interactions indicate that Unr binds to a large subset of cellular mRNAs, suggesting that Unr may play a wider role in translational responses to cellular signals than previously thought. PMID- 26009171 TI - Regulation and roles of elongation factor 2 kinase. AB - Eukaryotic elongation factor 2 kinase (eEF2K) belongs to the small family of atypical protein kinases termed alpha-kinases, and is the only calcium/calmodulin (Ca/CaM)-dependent member of that group. It phosphorylates and inactivates eEF2, to slow down the rate of elongation, the stage in mRNA translation that consumes almost all the energy and amino acids consumed by protein synthesis. In addition to activation by Ca/CaM, eEF2K is also regulated by an array of other regulatory inputs, which include inhibition by the nutrient- and growth-factor activated signalling pathways. Recent evidence shows that eEF2K plays an important role in learning and memory, processes that require the synthesis of new proteins and involve Ca-mediated signalling. eEF2K is activated under conditions of nutrient and energy depletion. In cancer cells, or certain tumours, eEF2K exerts cytoprotective effects, which probably reflect its ability to inhibit protein synthesis, and nutrient consumption, under starvation conditions. eEF2K is being evaluated as a potential therapeutic target in cancer. PMID- 26009172 TI - Control of translation in the cold: implications for therapeutic hypothermia. AB - Controlled whole-body cooling has been used since the 1950s to protect the brain from injury where cerebral blood flow is reduced. Therapeutic hypothermia has been used successfully during heart surgery, following cardiac arrest and with varied success in other instances of reduced blood flow to the brain. However, why reduced temperature is beneficial is largely unknown. Here we review the use of therapeutic hypothermia with a view to understanding the underlying biology contributing to the phenomenon. Interestingly, the benefits of cooling have recently been extended to treatment of chronic neurodegenerative diseases in two mouse models. Concurrently studies have demonstrated the importance of the regulation of protein synthesis, translation, to the cooling response, which is also emerging as a targetable process in neurodegeneration. Through these studies the potential importance of the rewarming process following cooling is also beginning to emerge. Altogether, these lines of research present new opportunities to manipulate cooling pathways for therapeutic gain. PMID- 26009173 TI - G-quadruplexes mediate local translation in neurons. AB - There has recently been a huge increase in interest in the formation of stable G quadruplex structures in mRNAs and their functional significance. In neurons, local translation of mRNA is essential for normal neuronal behaviour. It has been discovered that local translation of specific mRNAs encoding some of the best known synaptic proteins is dependent on the presence of a G-quadruplex. The recognition of G-quadruplexes in mRNAs, their transport as repressed complexes and the control of their translation at their subcellular destinations involves a diversity of proteins, including those associated with disease pathologies. This is an exciting field, with rapid improvements to our knowledge and understanding. Here, we discuss some of the recent work on how G-quadruplexes mediate local translation in neurons. PMID- 26009174 TI - Selective mRNA translation in erythropoiesis. AB - The daily production of up to 1011 erythrocytes is tightly controlled to maintain the number of erythrocytes in peripheral blood between narrow boundaries. Availability of growth factors and nutrients, particularly iron, control the proliferation and survival of precursor cells partly through control of mRNA translation. General translation initiation mechanisms can selectively control translation of transcripts that carry specific structures in the UTRs. This selective mRNA translation is an important layer of gene expression regulation in erythropoiesis. Ribosome profiling is a recently developed high throughput sequencing technique for global mapping of translation initiation sites across the transcriptome. Here we describe what is known about control of mRNA translation in erythropoiesis and how ribosome profiling will help to further our knowledge. Ribosome footprinting will give insight in transcript-specific translation at codon resolution, which is of great value to understand many cellular processes during erythropoiesis. It will be of particular interest to understand responses to iron availability and reactive oxygen species (ROS), which affects translation initiation of transcripts harbouring upstream ORFs (uORF) and potential alternative downstream ORFs (aORF). PMID- 26009175 TI - Vitamin D: a custodian of cell signalling stability in health and disease. AB - There is increasing evidence that a deficiency in vitamin D contributes to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. The ability of vitamin D to maintain healthy cells seems to depend on its role as a guardian of phenotypic stability particularly with regard to the reactive oxygen species (ROS) and Ca2+ signalling systems. Vitamin D maintains the expression of those signalling components responsible for stabilizing the low-resting state of these two signalling pathways. This vitamin D signalling stability hypothesis proposes that vitamin D, working in conjunction with klotho and Nrf2 (nuclear factor erythroid-2-related factor 2), acts as a custodian to maintain the normal function of the ROS and Ca2+ signalling pathways. A decline in vitamin D levels will lead to an erosion of this signalling stability and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca2+ signalling. PMID- 26009176 TI - Examining a new role for zinc in regulating calcium release in cardiac muscle. AB - It is well established that mammalian cells contain a small but measurable pool of free or labile zinc in the cytosol that is buffered in the high picomolar range. Recent attention has focused on the fact that this pool of free zinc has signalling effects that can be evoked through extracellular stimuli posing the question as to whether zinc should be regarded as a second messenger. Our knowledge of the targets, the biological significance and the molecular mechanisms of zinc signalling is limited but recent evidence suggests that zinc homoeostasis may be intimately linked to intracellular calcium signalling. In this review, we discuss the role of zinc as an intracellular signalling molecule with an emphasis on the potential role of zinc in shaping calcium-dynamics in cardiac muscle. We also consider the evidence that the cardiac ryanodine receptor (RyR2) is a potential zinc signalling target. PMID- 26009177 TI - Using concatenated subunits to investigate the functional consequences of heterotetrameric inositol 1,4,5-trisphosphate receptors. AB - Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of ubiquitous, ER localized, tetrameric Ca2+ release channels. There are three subtypes of the IP3Rs (R1, R2, R3), encoded by three distinct genes, that share ~60-70% sequence identity. The diversity of Ca2+ signals generated by IP3Rs is thought to be largely the result of differential tissue expression, intracellular localization and subtype-specific regulation of the three subtypes by various cellular factors, most significantly InsP3, Ca2+ and ATP. However, largely unexplored is the notion of additional signal diversity arising from the assembly of both homo and heterotetrameric InsP3Rs. In the present article, we review the biochemical and functional evidence supporting the existence of homo and heterotetrameric populations of InsP3Rs. In addition, we consider a strategy that utilizes genetically concatenated InsP3Rs to study the functional characteristics of heterotetramers with unequivocally defined composition. This approach reveals that the overall properties of IP3R are not necessarily simply a blend of the constituent monomers but that specific subtypes appear to dominate the overall characteristics of the tetramer. It is envisioned that the ability to generate tetramers with defined wild type and mutant subunits will be useful in probing fundamental questions relating to IP3R structure and function. PMID- 26009178 TI - Novel signalling mechanism and clinical applications of sperm-specific PLCzeta. AB - Egg activation is the first step of embryonic development and in mammals is triggered by a series of cytoplasmic calcium (Ca2+) oscillations. Sperm-egg fusion initiates these Ca2+ oscillations by introducing a sperm-specific protein factor into the egg cytoplasm. Substantial evidence indicates that this protein is a sperm-specific phospholipase C (PLC), termed PLC-zeta (PLCzeta). PLCzeta stimulates cytoplasmic Ca2+ oscillations matching those at fertilization triggering early embryonic development in several mammalian species. Structurally, PLCzeta is comprised of four EF-hands, a C2 domain, and X and Y catalytic domains. PLCzeta is an unusual PLC since it lacks a pleckstrin homology (PH) domain. It is also distinctive in that its X-Y linker is not involved in auto-inhibition of catalytic activity, but instead binds to phosphatidylinositol 4,5-bisphosphate (PIP2). Moreover, relative to other PLC isoforms, PLCzeta possesses unique potency in stimulating Ca2+ oscillations in eggs, although it does not appear to bind to plasma membrane PIP2. In contrast, PLCzeta appears to interact with intracellular vesicles in eggs that contain PIP2. I discuss the recent advances in our knowledge of the intriguing biochemical and physiological properties of sperm PLCzeta and postulate potential roles for PLCzeta in terms of clinical diagnosis and therapy for certain forms of male infertility. PMID- 26009179 TI - Structural and functional interactions within ryanodine receptor. AB - The ryanodine receptor/Ca2+ release channel plays a pivotal role in skeletal and cardiac muscle excitation-contraction coupling. Defective regulation leads to neuromuscular disorders and arrhythmogenic cardiac disease. This mini-review focuses on channel regulation through structural intra- and inter-subunit interactions and their implications in ryanodine receptor pathophysiology. PMID- 26009180 TI - TPC: the NAADP discovery channel? AB - The Ca2+-mobilizing second messenger, NAADP (nicotinic acid adenine dinucleotide phosphate), has been with us for nearly 20 years and yet we still cannot fully agree on the identity of its target Ca2+-release channel. In spite of some recent robust challenges to the idea that two-pore channels (TPCs) represent the elusive "NAADP receptor", evidence continues to accumulate that TPCs are important for NAADP-mediated responses. This article will briefly outline the background and review more recent work pertaining to the TPC story. PMID- 26009181 TI - Alterations in late endocytic trafficking related to the pathobiology of LRRK2 linked Parkinson's disease. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene comprise the most common cause of familial Parkinson's disease (PD), and variants increase the risk for sporadic PD. LRRK2 displays kinase and GTPase activity, and altered catalytic activity correlates with neurotoxicity, making LRRK2 a promising therapeutic target. Despite the importance of LRRK2 for disease pathogenesis, its normal cellular function, and the mechanism(s) by which pathogenic mutations cause neurodegeneration remain unclear. LRRK2 seems to regulate a variety of intracellular vesicular trafficking events to and from the late endosome in a manner dependent on various Rab proteins. At least some of those events are further regulated by LRRK2 in a manner dependent on two-pore channels (TPCs). TPCs are ionic channels localized to distinct endosomal structures and can cause localized calcium release from those acidic stores, with downstream effects on vesicular trafficking. Here, we review current knowledge about the link between LRRK2, TPC- and Rab-mediated vesicular trafficking to and from the late endosome, highlighting a possible cross-talk between endolysosomal calcium stores and Rab proteins underlying pathomechanism(s) in LRRK2-related PD. PMID- 26009182 TI - Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein-protein interactions for channel regulation. AB - The 12- and 12.6-kDa FK506-binding proteins, FKBP12 (12-kDa FK506-binding protein) and FKBP12.6 (12.6-kDa FK506-binding protein), have been implicated in the binding to and the regulation of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs), both tetrameric intracellular Ca2+-release channels. Whereas the amino acid sequences responsible for FKBP12 binding to RyRs are conserved in IP3Rs, FKBP12 binding to IP3Rs has been questioned and could not be observed in various experimental models. Nevertheless, conservation of these residues in the different IP3R isoforms and during evolution suggested that they could harbour an important regulatory site critical for IP3R-channel function. Recently, it has become clear that in IP3Rs, this site was targeted by B-cell lymphoma 2 (Bcl-2) via its Bcl-2 homology (BH)4 domain, thereby dampening IP3R mediated Ca2+ flux and preventing pro-apoptotic Ca2+ signalling. Furthermore, vice versa, the presence of the corresponding site in RyRs implied that Bcl-2 proteins could associate with and regulate RyR channels. Recently, the existence of endogenous RyR-Bcl-2 complexes has been identified in primary hippocampal neurons. Like for IP3Rs, binding of Bcl-2 to RyRs also involved its BH4 domain and suppressed RyR-mediated Ca2+ release. We therefore propose that the originally identified FKBP12-binding site in IP3Rs is a region critical for controlling IP3R-mediated Ca2+ flux by recruiting Bcl-2 rather than FKBP12. Although we hypothesize that anti-apoptotic Bcl-2 proteins, but not FKBP12, are the main physiological inhibitors of IP3Rs, we cannot exclude that Bcl-2 could help engaging FKBP12 (or other FKBP isoforms) to the IP3R, potentially via calcineurin. PMID- 26009183 TI - Metabotropic glutamate receptor-mediated cyclic ADP ribose signalling. AB - Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as specific membrane currents and neurotransmitter release linked to their ability to mobilize calcium from intracellular calcium stores. As such, most I-mGluR research to date has focused on the coupling of these receptors to phospholipase C (PLC)-dependent and inositol (1,4,5) trisphosphate (IP3)-mediated calcium release via activation of IP3 receptors located upon the sarco/endoplasmic reticulum. However, there are now numerous examples of PLC- and IP3-independent I-mGluR-evoked signals, which may instead be mediated by activation of ryanodine receptors (RyRs). A prime candidate for mediating this coupling between I-mGluR activation and RyR opening is cyclic ADP ribose (cADPR) and, indeed, several of these PLC-/IP3-independent I-mGluR-evoked calcium signals have now been shown to be mediated wholly or partly by cADPR-evoked activation of RyRs. The contribution of cADPR signalling to I-mGluR-mediated responses is relatively complex, dependent as it is on factors such as cell type, excitation state of the cell and location of I-mGluRs on the cell. However, these factors notwithstanding, I-mGluR-mediated cADPR signalling remains poorly characterized, with several key aspects yet to be fully elucidated such as (1) the range of stimuli which evoke cADPR production, (2) the specific molecular mechanism(s) coupling cADPR to RyR activation and (3) the contribution of cADPR-mediated responses to downstream outputs such as synaptic plasticity. Furthermore, it is possible that the cADPR pathway may play a role in diseases underpinned by dysregulated calcium homoeostasis such as Alzheimer's disease (AD). PMID- 26009184 TI - Pulmonary vein sleeve cell excitation-contraction-coupling becomes dysynchronized by spontaneous calcium transients. AB - Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia. Substantial evidence indicates that cardiomyocytes located in the pulmonary veins [pulmonary vein sleeve cells (PVCs)] cause AF by generating ectopic electrical activity. Electrical ablation, isolating PVCs from their left atrial junctions, is a major treatment for AF. In small rodents, the sleeve of PVCs extends deep inside the lungs and is present in lung slices. Here we present data, using the lung slice preparation, characterizing how spontaneous Ca2+ transients in PVCs affect their capability to respond to electrical pacing. Immediately after a spontaneous Ca2+ transient the cell is in a refractory period and it cannot respond to electrical stimulation. Consequently, we observe that the higher the level of spontaneous activity in an individual PVC, the less likely it is that this PVC responds to electrical field stimulation. The spontaneous activity of neighbouring PVCs can be different from each other. Heterogeneity in the Ca2+ signalling of cells and in their responsiveness to electrical stimuli are known pro-arrhythmic events. The tendency of PVCs to show spontaneous Ca2+ transients and spontaneous action potentials (APs) underlies their potential to cause AF. PMID- 26009185 TI - Designer small molecules to target calcium signalling. AB - Synthetic compounds open up new avenues to interrogate and manipulate intracellular Ca2+ signalling pathways. They may ultimately lead to drug-like analogues to intervene in disease. Recent advances in chemical biology tools available to probe Ca2+ signalling are described, with a particular focus on those synthetic analogues from our group that have enhanced biological understanding or represent a step towards more drug-like molecules. Adenophostin (AdA) is the most potent known agonist at the inositol 1,4,5-trisphosphate receptor (IP3R) and synthetic analogues provide a binding model for receptor activation and channel opening. 2-O-Modified inositol 1,4,5-trisphosphate (IP3) derivatives that are partial agonists at the IP3R reveal key conformational changes of the receptor upon ligand binding. Biphenyl polyphosphates illustrate that simple non-inositol surrogates can be engineered to give prototype IP3R agonists or antagonists and act as templates for protein co-crystallization. Cyclic adenosine 5'-diphosphoribose (cADPR) can be selectively modified using total synthesis, generating chemically and biologically stable tools to investigate Ca2+ release via the ryanodine receptor (RyR) and to interfere with cADPR synthesis and degradation. The first neutral analogues with a synthetic pyrophosphate bioisostere surprisingly retain the ability to release Ca2+, suggesting a new route to membrane-permeant tools. Adenosine 5'-diphosphoribose (ADPR) activates the Ca2+-, Na+- and K+-permeable transient receptor potential melastatin 2 (TRPM2) cation channel. Synthetic ADPR analogues provide the first structure-activity relationship (SAR) for this emerging messenger and the first functional antagonists. An analogue based on the nicotinic acid motif of nicotinic acid adenine dinucleotide phosphate (NAADP) antagonizes NAADP-mediated Ca2+ release in vitro and is effective in vivo against induced heart arrhythmia and autoimmune disease, illustrating the therapeutic potential of targeted small molecules. PMID- 26009186 TI - The ryanodine receptor provides high throughput Ca2+-release but is precisely regulated by networks of associated proteins: a focus on proteins relevant to phosphorylation. AB - Once opened, ryanodine receptors (RyR) are efficient pathways for the release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR). The precise nature of the Ca2+-release event, however, requires fine-tuning for the specific process and type of cell involved. For example, the spatial organization of RyRs, the luminal [Ca2+] and the influence of soluble regulators that fluctuate under physiological and pathophysiological control mechanisms, all affect the amplitude and duration of RyR Ca2+ fluxes. Various proteins are docked tightly to the huge bulky structure of RyR and there is growing evidence that, together, they provide a sophisticated and integrated system for regulating RyR channel gating. This review focuses on those proteins that are relevant to phosphorylation of RyR channels with particular reference to the cardiac isoform of RyR (RyR2). How phosphorylation of RyR affects channel activity and whether proteins such as the FK-506 binding proteins (FKBP12 and FKBP12.6) are involved, have been highly controversial subjects for more than a decade. But that is expected given the large number of participating proteins, the relevance of phosphorylation in heart failure and inherited arrhythmic diseases, and the frustrations of predicting relationships between structure and function before the advent of a high resolution structure of RyR. PMID- 26009188 TI - Regulation of TRPML1 function. AB - TRPML1 is a ubiquitously expressed cation channel found on lysosomes and late endosomes. Mutations in TRPML1 cause mucolipidosis type IV and it has been implicated in Alzheimer's disease and HIV. However, the mechanisms by which TRPML1 activity is regulated are not well understood. This review summarizes the current understanding of TRPML1 activation and regulation. PMID- 26009189 TI - Overview of the 8th UK Gap Junction meeting - 5th December 2014. AB - The 8th UK Gap Junction meeting was held in Glasgow Caledonian University (GCU) on 5th December 2014. Emeritus Professor Howard Evans presented an overview of 50 years of gap junction research whereas Dr Brant Isakson, University of Virginia, discussed the intriguing role of recently identified pannexin proteins in endothelial function. Forty-five delegates from across the U.K. and the Europe attended the day with 12 talks from young researchers and five posters. This issue of biochemical transactions provides an overview of the highlights of the work discussed throughout the day. PMID- 26009187 TI - Two-pore channels at the intersection of endolysosomal membrane traffic. AB - Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that localize to acidic organelles such as lysosomes. The TPC complex is the proposed target of the Ca2+-mobilizing messenger NAADP, which releases Ca2+ from these acidic Ca2+ stores. Whereas details of TPC activation and native ion permeation remain unclear, a consensus has emerged around their function in regulating endolysosomal trafficking. This role is supported by recent proteomic data showing that TPCs interact with proteins controlling membrane organization and dynamics, including Rab GTPases and components of the fusion apparatus. Regulation of TPCs by PtdIns(3,5)P2 and/or NAADP (nicotinic acid adenine dinucleotide phosphate) together with their functional and physical association with Rab proteins provides a mechanism for coupling phosphoinositide and trafficking protein cues to local ion fluxes. Therefore, TPCs work at the regulatory cross-roads of (patho)physiological cues to co-ordinate and potentially deregulate traffic flow through the endolysosomal network. This review focuses on the native role of TPCs in trafficking and their emerging contributions to endolysosomal trafficking dysfunction. PMID- 26009190 TI - Cell communication across gap junctions: a historical perspective and current developments. AB - Collaborative communication lies at the centre of multicellular life. Gap junctions (GJs) are surface membrane structures that allow direct communication between cells. They were discovered in the 1960s following the convergence of the detection of low-resistance electrical interactions between cells and anatomical studies of intercellular contact points. GJs purified from liver plasma membranes contained a 27 kDa protein constituent; it was later named Cx32 (connexin 32) after its full sequence was determined by recombinant technology. Identification of Cx43 in heart and later by a further GJ protein, Cx26 followed. Cxs have a tetraspan organization in the membrane and oligomerize during intracellular transit to the plasma membrane; these were shown to be hexameric hemichannels (connexons) that could interact end-to-end to generate GJs at areas of cell-to cell contact. The structure of the GJ was confirmed and refined by a combination of biochemical and structural approaches. Progress continues towards obtaining higher atomic 3D resolution of the GJ channel. Today, there are 20 and 21 highly conserved members of the Cx family in the human and mouse genomes respectively. Model organisms such as Xenopus oocytes and zebra fish are increasingly used to relate structure to function. Proteins that form similar large pore membrane channels in cells called pannexins have also been identified in chordates. Innexins form GJs in prechordates; these two other proteins, although functionally similar, are very different in amino acid sequence to the Cxs. A time line tracing the historical progression of wide ranging research in GJ biology over 60 years is mapped out. The molecular basis of channel dysfunctions in disease is becoming evident and progress towards addressing Cx channel dependent pathologies, especially in ischaemia and tissue repair, continues. PMID- 26009191 TI - CO2 carbamylation of proteins as a mechanism in physiology. AB - Carbamate bonds occur following the nucleophilic attack of CO2 on to an amine. In proteins, this can occur at lysine side chains or at the N-terminus. For CO2 binding to occur an amine must be present in the NH2 form and consequently carbamates represent a site-specific post-translational modification, occurring only in environments of reduced hydration. Due to the specific nature of these interactions, coupled with the inability of these bonds to survive protein preparation methods, carbamate reactions appear rare. However, more biologically important examples continue to emerge that use carbamates as key parts of their mechanisms. In this review, we discuss specific examples of carbamate bond formation and their biological consequences with an aim to highlight this important, and often forgotten, biochemical group. PMID- 26009192 TI - Post-transcriptional regulation of connexins. AB - Gap junctions allow intercellular communication. Their structural subunits are four-transmembrane proteins named connexins (Cxs), which can be post transcriptionally regulated by developmental and cellular signalling cues. Cx translation and mRNA stability is regulated by miRNAs and RNA-binding proteins (RBPs) such as human antigen R (HuR). In addition, several Cxs have also been suggested to contain 5' internal ribosome entry site (IRES) elements that are thought to allow cap-independent translation in situations such as mitosis, stress and senescence. Furthermore, several recent reports have documented internal translation of Cx mRNAs that result in N-terminally truncated protein isoforms that may have unique gap junction-independent functions [Ul-Hussain et al. (2008) BMC Mol. Biol. 9, 52; Smyth and Shaw (2013) Cell Rep. 5, 611-618; Salat-Canela et al. (2014) Cell Commun. Signal. 12, 31; Ul-Hussain et al. (2014) J. Biol. Chem. 289, 20979-20990]. This review covers the emerging field of the post-transcriptional regulation of Cxs, with particular focus on the translational control of Cx 43 and its possible functional consequences. PMID- 26009193 TI - Connexin 43 ubiquitination determines the fate of gap junctions: restrict to survive. AB - Connexins (Cxs) are transmembrane proteins that form channels which allow direct intercellular communication (IC) between neighbouring cells via gap junctions. Mechanisms that modulate the amount of channels at the plasma membrane have emerged as important regulators of IC and their de-regulation has been associated with various diseases. Although Cx-mediated IC can be modulated by different mechanisms, ubiquitination has been described as one of the major post translational modifications involved in Cx regulation and consequently IC. In this review, we focus on the role of ubiquitin and its effect on gap junction intercellular communication. PMID- 26009194 TI - To beat or not to beat: degradation of Cx43 imposes the heart rhythm. AB - The main function of the heart is to pump blood to the different parts of the organism, a task that is efficiently accomplished through proper electric and metabolic coupling between cardiac cells, ensured by gap junctions (GJ). Cardiomyocytes are the major cell population in the heart, and as cells with low mitotic activity, are highly dependent upon mechanisms of protein degradation. In the heart, both the ubiquitin-proteasome system (UPS) and autophagy participate in the fine-tune regulation of cardiac remodelling and function, either in physiological or pathological conditions. Indeed, besides controlling cardiac signalling pathways, UPS and autophagy have been implicated in the turnover of several myocardial proteins. Degradation of Cx43, the major ventricular GJ protein, has been associated to up-regulation of autophagy at the onset of heart ischemia and ischemia/reperfusion (I/R), which can have profound implications upon cardiac function. In this review, we present recent studies devoted to the involvement of autophagy and UPS in heart homoeostasis, with a particular focus on GJ. PMID- 26009195 TI - Connexin43 plays diverse roles in co-ordinating cell migration and wound closure events. AB - Chronic wounds are not only debilitating to patients, but also impose a huge financial burden on healthcare providers, as current treatments are not particularly effective. Wound healing is a highly co-ordinated process involving a vast array of signalling molecules and different cell types, therefore a substantial amount of research has been carried out in the quest to develop new therapies. The gap junction (GJ) protein connexin43 (Cx43) is one of the many molecules whose expression has been found to be up-regulated in chronic wounds and as a result targeting it may have therapeutic potential. Two different approaches have been adopted to investigate this: knockdown of Cx43 using antisense oligonucleotides and connexin mimetic peptides (CMPs) which inhibit the function of Cx43 without affecting gene expression. These peptides are targeted to the C-terminal domain or the extracellular loops of Cx43 and thus are likely to function by different means. However, both block channel function and have been shown to enhance cell migration rates. In recent years, non-channel functions have emerged for Cx43, many of which are linked to cytoskeletal dynamics and the extracellular matrix (ECM), showing that Cx43 plays diverse roles in co-ordinating wound closure events. It is clear that both CMPs and antisense oligonucleotides hold therapeutic potential, however maintaining Cx43 expression may be beneficial to the cell by preserving other non-channel functions of Cx43. Recent data in the field will be discussed in this article. PMID- 26009196 TI - Gap junctions and connexin hemichannels in the regulation of haemostasis and thrombosis. AB - Platelets are involved in the maintenance of haemostasis but their inappropriate activation leads to thrombosis, a principal trigger for heart attack and ischaemic stroke. Although platelets circulate in isolation, upon activation they accumulate or aggregate together to form a thrombus, where they function in a co ordinated manner to prevent loss of blood and control wound repair. Previous report (1) indicates that the stability and functions of a thrombus are maintained through sustained, contact-dependent signalling between platelets. Given the role of gap junctions in the co-ordination of tissue responses, it was hypothesized that gap junctions may be present within a thrombus and mediate intercellular communication between platelets. Therefore studies were performed to explore the presence and functions of connexins in platelets. In this brief review, the roles of hemichannels and gap junctions in the control of thrombosis and haemostasis and the future directions for this research will be discussed. PMID- 26009198 TI - Regulation of Pannexin-1 channel activity. AB - Pannexin-1 (Panx1) forms anion-selective channels with a permeability up to 1 kDa and represents a pathway for the release of cytosolic ATP. Several structurally similar connexin (Cx) proteins have been identified in platelets and shown to play roles in haemostasis and thrombosis. More recently, functional Panx1 channels have been demonstrated on the surface of human platelets [Taylor et al. (2014) J. Thromb. Haemost. 12, 987-998]. Since their identification in the year 2000, several mechanisms have been reported to activate Panx1 channels, including mechanical stimulation, oxygen-glucose deprivation, a rise of [Ca2+]i, caspase cleavage and phosphorylation. Within this review, the regulation of Panx1 channels is discussed, with a focus on how they may contribute to platelet function. PMID- 26009197 TI - Emerging concepts regarding pannexin 1 in the vasculature. AB - Pannexin channels are newly discovered ATP release channels expressed throughout the body. Pannexin 1 (Panx1) channels have become of great interest as they appear to participate in a multitude of signalling cascades, including regulation of vascular function. Although numerous Panx1 pharmacological inhibitors have been discovered, these inhibitors are not specific for Panx1 and have additional effects on other proteins. Therefore, molecular tools, such as RNA interference and knockout animals, are needed to demonstrate the role of pannexins in various cellular functions. This review focuses on the known roles of Panx1 related to purinergic signalling in the vasculature focusing on post-translational modifications and channel gating mechanisms that may participate in the regulated release of ATP. PMID- 26009200 TI - Electrical consequences of cardiac myocyte: fibroblast coupling. AB - Gap junctions are channels which allow electrical signals to propagate through the heart from the sinoatrial node and through the atria, conduction system and onwards to the ventricles, and hence are essential for co-ordinated cardiac contraction. Twelve connexin (Cx) proteins make up one gap junction channel, of which there are three main subtypes in the heart; Cx40, Cx43 and Cx45. In the cardiac myocyte, gap junctions are present mainly at the intercalated discs between neighbouring myocytes, and assist in rapid electrical conduction throughout the ventricular myocardium. Fibroblasts provide the structural skeleton of the myocardium and fibroblast numbers significantly increase in heart disease. Fibroblasts also express connexins and this may facilitate heterocellular electrical coupling between myocytes and fibroblasts in the setting of cardiac disease. Interestingly, cardiac fibroblasts have been demonstrated to increase Cx43 expression in experimental models of myocardial infarction and functional gap junctions between myocytes and fibroblasts have been reported. Therefore, in the setting of heart disease enhanced cardiac myocyte: fibroblast coupling may influence the electrical activity of the myocyte and contribute to arrhythmias. PMID- 26009199 TI - Gap junctions - guards of excitability. AB - Cardiomyocytes are connected by mechanical and electrical junctions located at the intercalated discs (IDs). Although these structures have long been known, it is becoming increasingly clear that their components interact. This review describes the involvement of the ID in electrical disturbances of the heart and focuses on the role of the gap junctional protein connexin 43 (Cx43). Current evidence shows that Cx43 plays a crucial role in organizing microtubules at the intercalated disc and thereby regulating the trafficking of the cardiac sodium channel NaV1.5 to the membrane. PMID- 26009201 TI - Protein kinase C-dependent regulation of connexin43 gap junctions and hemichannels. AB - Connexin43 (Cx43) generates intercellular gap junction channels involved in, among others, cardiac and brain function. Gap junctions are formed by the docking of two hemichannels from neighbouring cells. Undocked Cx43 hemichannels can upon different stimuli open towards the extracellular matrix and allow transport of molecules such as fluorescent dyes and ATP. A range of phosphorylated amino acids have been detected in the C-terminus of Cx43 and their physiological role has been intensively studied both in the gap junctional form of Cx43 and in its hemichannel configuration. We present the current knowledge of protein kinase C (PKC)-dependent regulation of Cx43 and discuss the divergent results. PMID- 26009202 TI - Connexin-mediated regulation of the pulmonary vasculature. AB - Pulmonary arterial hypertension (PAH) is a complex, multi-factorial disorder characterized by both constriction and remodelling of the distal pulmonary vasculature. This leads to increased pulmonary pressures and eventually right heart failure. Current drugs, which primarily target the vasoconstriction, serve only to prolong life and novel therapies targeting both the vasoconstriction and the remodelling are required. Aberrant signalling between cells of the pulmonary vasculature has been associated with the development of PAH. In particular, endothelial dysfunction can lead to hyperplasia of the underlying medial layer. Connexins are a family of transmembrane proteins which can form intercellular communication channels known as gap junctions. This review will discuss recent evidence which shows that connexins play a role in regulation of the pulmonary vasculature and that dysregulation of connexins may contribute to PAH pathogenesis. Interaction of connexins with signalling pathways relevant to the pathogenesis of PAH, such as bone morphogenetic protein (BMP), serotonin and oestrogen are discussed. PMID- 26009203 TI - Examining women's perceptions of their mother's and romantic partner's interpersonal styles for a better understanding of their eating regulation and intuitive eating. AB - Intuitive eating is a positive approach to weight and eating management characterized by a strong reliance on internal physiological hunger and satiety cues rather than emotional and external cues (e.g., Tylka, 2006). Using a Self Determination Theory framework (Deci & Ryan, 1985), the main purpose of this research was to examine the role played by both the mother and the romantic partner in predicting women's intuitive eating. Participants were 272 women (mean age: 29.9 years) currently involved in a heterosexual romantic relationship. Mothers and romantic partners were both found to have a role to play in predicting women's intuitive eating via their influence on women's motivation for regulating eating behaviors. Specifically, both the mother's and partner's controlling styles were found to predict women's controlled eating regulation, which was negatively related to their intuitive eating. In addition, autonomy support from the partner (but not from the mother) was found to positively predict intuitive eating, and this relationship was mediated by women's more autonomous regulation toward eating. These results were uncovered while controlling for women's body mass index, which is likely to affect women's eating attitudes and behaviors. Overall, these results attest to the importance of considering women's social environment (i.e., mother and romantic partner) for a better understanding of their eating regulation and ability to eat intuitively. PMID- 26009204 TI - Higher weight status of only and last-born children. Maternal feeding and child eating behaviors as underlying processes among 4-8 year olds. AB - Birth order has been associated with childhood obesity. The objective of this cross-sectional study was to examine maternal feeding and child eating behaviors as underlying processes for increased weight status of only children and youngest siblings. Participants included 274 low-income 4-8 year old children and their mothers. The dyads completed a videotaped laboratory mealtime observation. Mothers completed the Caregiver's Feeding Styles Questionnaire and the Children's Eating Behavior Questionnaire. Child weight and height were measured using standardized procedures. Path analysis was used to examine associations of birth order, maternal feeding behavior, child eating behavior, and child overweight/obese status. The association between only child status and greater likelihood of overweight/obesity was fully mediated by higher maternal Verbal Discouragement to eat and lower maternal Praise (all p values < 0.05). The association between youngest sibling status and greater likelihood of overweight/obesity was partially mediated by lower maternal Praise and lower child Food Fussiness (all p values < 0.05). Results provide support for our hypothesis that maternal control and support and child food acceptance are underlying pathways for the association between birth order and weight status. Future findings can help inform family-based programs by guiding family counseling and tailoring of recommendations for family mealtime interactions. PMID- 26009205 TI - The role of television viewing and direct experience in predicting adolescents' beliefs about the health risks of fast-food consumption. AB - BACKGROUND: Fast-food advertising abounds on television (TV), and programs targeting youth often display fast-food consumption but rarely with any negative consequences. Cultivation research maintains that cumulative exposure to TV influences audiences' views of and beliefs about the real world. Thus, the amount of TV adolescents watch is likely to bias their views of the consequences of eating fast food. This research posits that this relationship varies as a function of adolescents' actual experience with fast food. METHOD: Two cross sectional surveys conducted in the cultivation research tradition assess the relationship between the amount of adolescents' regular exposure to TV and their beliefs about the risks and benefits of eating fast food. Teenage children of members of online panels reported hours of TV viewing, beliefs about the consequences of eating fast food, and their frequency of fast-food consumption. RESULTS: In both studies, beliefs about health risks of fast-food consumption vary as a function of the amount of TV watched. Heavy TV viewers have less negative and more positive beliefs about the consequences of fast-food consumption than light viewers. As direct experience with fast food increases, the relationship between TV viewing and risk perceptions weakens, but the relationship between TV viewing and positive perceptions strengthens. These moderated relationships remain when we control for physical activity (Study 1) and the density of fast-food restaurants in respondents' geographical area (Study 2). CONCLUSION: Given the role of TV viewing in biasing perceptions of the consequences of eating fast food, public health researchers and practitioners should carefully monitor and perhaps regulate the amount of fast-food advertising on TV and the content of TV programs. PMID- 26009206 TI - Dissociation from beloved unhealthy brands decreases preference for and consumption of vegetables. AB - Many people form strong bonds with brands, including those for unhealthy foods. Thus, prompting people to dissociate from beloved but unhealthy food brands is an intuitively appealing means to shift consumption away from unhealthy options and toward healthy options. Contrary to this position, we demonstrate that dissociating from unhealthy but beloved brands diminishes people's interest in consuming vegetables because the dissociation depletes self-regulatory resources. Across three experimental studies, we manipulate dissociation from two beloved brands both implicitly (studies 1-2) and explicitly (study 3) and observe effects on both preference for vegetables (studies 2-3) and actual vegetable consumption (study 1). In study 1, participants consumed fewer vegetables following dissociation from (vs. association with) a beloved candy brand. Study 2 demonstrates that the effect of depletion on preference for vegetables is more pronounced for those who strongly identify with the brand, as these individuals are most depleted by the dissociation attempt. Finally, study 3 illustrates that the difficulty experienced when trying to dissociate from beloved brands drives the observed effects on vegetable preference and consumption for those who strongly (vs. weakly) identify with the brand. PMID- 26009208 TI - A triazine-based covalent organic polymer for efficient CO2 adsorption. AB - A new triazine functionalized hexagonally ordered covalent organic polymer (TRITER-1) has been synthesized via the Schiff-base condensation reaction between a tailor made triamine 1,3,5-tris-(4-aminophenyl)triazine (TAPT) and terephthaldehyde. This ordered porous polymer showed a high BET surface area (716 m(2) g(-1)) and an excellent CO2 uptake capacity of 58.9 wt% at 273 K under 5 bar pressure. PMID- 26009207 TI - Emolabeling increases healthy food choices among grade school children in a structured grocery aisle setting. AB - Health literacy, the ability to acquire health-related knowledge and make appropriate health-related decisions, is regarded as a key barrier to meaningfully convey health information to children and can impact food choice. Emolabeling is an image-based labeling strategy aimed at addressing this problem by conveying health information using emotional correlates of health using emoticons (happy = healthy; sad = not healthy). To test the utility of such a method to promote healthy food choices among children, 64 children (59% girls, <5% non-White, mean BMI = 52nd percentile) in kindergarten through 5th grade were first given a brief 5-min lesson on how to use the emoticons, then asked to choose any 4 foods in each of 2 aisles structured to mimic a grocery aisle - there were 12 identical foods placed in the same location in each aisle with half being low calorie and half high calorie snacks. Foods were emolabeled in one aisle; no emolabels were used in the other aisle; the order that children were brought in each aisle was counterbalanced. Results showed that adding emolabels increased the number (M +/- SD) of healthy foods chosen (3.6 +/- 0.7 with vs. 2.3 +/- 1.1 without emolabels present [95% CI 1.0, 1.5], R(2) = .67) and reduced the total calories (M +/- SD) of foods chosen (193.5 +/- 88.5 Cal with vs. 374.3 +/- 152.6 Cal without emolabels present [95% CI -212.6, -149.0], R(2) = .70). Hence, adding emolabels was associated with healthier food choices among children, thereby demonstrating one possible strategy to effectively overcome health literacy barriers at these ages. PMID- 26009210 TI - Strengthening clinical research in children and young people. PMID- 26009211 TI - The next era of disaster risk reduction. PMID- 26009209 TI - Temporal variability and sources of triclosan exposure in pregnancy. AB - BACKGROUND: Triclosan (TCS) is an antibacterial agent commonly added to personal care products. Some animal research studies have associated TCS exposure with androgenic and thyroid effects, as well as endocrine disruption, contact dermatitis and skin irritation. Limited Canadian data exist on exposure levels, temporal variability and sources of exposure to TCS, especially among pregnant women. METHODS: Single and serial spot urine samples (n=1249), as well as consumer product use information were collected over 5 study visits across pregnancy and post-partum from 80 healthy pregnant women in Ottawa, Canada. Urine samples were analyzed for TCS by GC-MS-MS. Summary statistics, linear mixed effects models, and surrogate category analysis were used to describe the results. RESULTS: Triclosan was detected in 87% of maternal urine samples (LOD=3.0MUg/L). The geometric mean TCS concentration of all urine samples was 21.6MUg/L (95% CI 18.2-25.7). Triclosan concentrations were significantly higher when the urine was collected before 16:00, in the autumn, and more than 90min since last void, and in nulliparous women with household incomes greater than $100,000. A significant correlation was observed between maternal urinary TCS concentrations and number of reported uses of TCS-containing products. The ability of a single spot urine sample collected at any time during or post pregnancy to predict an individual's geometric mean urinary TCS level corresponding to low, medium, or high exposure was 86.7%. Intraclass correlation coefficients indicated high reproducibility within a week-day (0.77) and week-end day (0.79) and moderate reproducibility across the study period (0.50). CONCLUSIONS: This study provided the first data on temporal variability of urinary TCS concentrations and predictors of exposure in Canadian pregnant women. These results can inform exposure assessments in pregnant women and justify collection of single spot urine samples in epidemiologic studies, especially for women with higher exposures. PMID- 26009212 TI - Adolescents with diabetes. PMID- 26009213 TI - Spondyloarthropathy: interleukin 23 and disease modification. PMID- 26009214 TI - Dual RAAS blockade for kidney failure: hope for the future. PMID- 26009215 TI - An alternative combination therapy for type 2 diabetes? PMID- 26009217 TI - India's BJP Government and health: 1 year on. PMID- 26009218 TI - Russia's gaps in diabetes control. PMID- 26009219 TI - Fergus Cameron: getting the big picture in childhood diabetes. PMID- 26009220 TI - The marathon of diabetes. PMID- 26009221 TI - Rising food insecurity in Europe. PMID- 26009222 TI - Sex and relationship education should be statutory. PMID- 26009223 TI - Bivalirudin versus heparin use for patients undergoing PPCI. PMID- 26009224 TI - Bivalirudin versus heparin use for patients undergoing PPCI. PMID- 26009225 TI - Bivalirudin versus heparin use for patients undergoing PPCI. PMID- 26009226 TI - Bivalirudin versus heparin use for patients undergoing PPCI - Authors' reply. PMID- 26009227 TI - Bivalirudin versus heparin use for patients undergoing PPCI. PMID- 26009228 TI - Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. AB - BACKGROUND: The comparative efficacy and safety of pharmacological agents to lower blood pressure in adults with diabetes and kidney disease remains controversial. We aimed to investigate the benefits and harms of blood pressure lowering drugs in this population of patients. METHODS: We did a network meta analysis of randomised trials from around the world comparing blood pressure lowering agents in adults with diabetic kidney disease. Electronic databases (the Cochrane Collaboration, Medline, and Embase) were searched systematically up to January, 2014, for trials in adults with diabetes and kidney disease comparing orally administered blood pressure-lowering drugs. Primary outcomes were all cause mortality and end-stage kidney disease. We also assessed secondary safety and cardiovascular outcomes. We did random-effects network meta-analysis to obtain estimates for primary and secondary outcomes and we presented these estimates as odds ratios or standardised mean differences with 95% CIs. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities. FINDINGS: 157 studies comprising 43,256 participants, mostly with type 2 diabetes and chronic kidney disease, were included in the network meta-analysis. No drug regimen was more effective than placebo for reducing all-cause mortality. However, compared with placebo, end stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor (odds ratio 0.62, 95% CI 0.43-0.90) and after ARB monotherapy (0.77, 0.65-0.92). No regimen significantly increased hyperkalaemia or acute kidney injury, although combined ACE inhibitor and ARB treatment had the lowest rank among all interventions because of borderline increases in estimated risks of these harms (odds ratio 2.69, 95% CI 0.97-7.47 for hyperkalaemia; 2.69, 0.98-7.38 for acute kidney injury). INTERPRETATION: No blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease. ACE inhibitors and ARBs, alone or in combination, were the most effective strategies against end stage kidney disease. Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalaemia and acute kidney injury. FUNDING: Canterbury Medical Research Foundation, Italian Medicines Agency. PMID- 26009229 TI - Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. AB - BACKGROUND: For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. METHODS: We did this 52 week, randomised, open-label, phase 3, non inferiority trial at 105 study sites in 15 countries. Patients (aged >=18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1.5 mg, dulaglutide 0.75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0.4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268. FINDINGS: Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1.5 mg (n=295), dulaglutide 0.75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1.5 mg (-1.64% [95% CI -1.78 to -1.50], -17.93 mmol/mol [-19.44 to -16.42]) and dulaglutide 0.75 mg (-1.59% [-1.73 to 1.45], -17.38 mmol/mol [-18.89 to -15.87]) than in those receiving glargine ( 1.41% [-1.55 to -1.27], -15.41 mmol/mol [-16.92 to -13.90]). The adjusted mean difference versus glargine was -0.22% (95% CI -0.38 to -0.07, -2.40 mmol/mol [ 4.15 to -0.77]; p=0.005) for dulaglutide 1.5 mg and -0.17% (-0.33 to -0.02, -1.86 mmol/mol [-3.61 to -0.22]; p=0.015) for dulaglutide 0.75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1.5 mg group); pneumonia (n=1 in the dulaglutide 0.75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1.5 mg group, 44 (15%) patients in the dulaglutide 0.75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. INTERPRETATION: Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment. FUNDING: Eli Lilly and Company. PMID- 26009230 TI - Care of diabetes in children and adolescents: controversies, changes, and consensus. AB - Diabetes is one of the most common chronic medical disorders in children. The management of diabetes remains a substantial burden on children with diabetes and their families, despite improvements in treatment and rates of morbidity and mortality. Although most children with diabetes have type 1 diabetes, the increasing recognition of type 2 diabetes and genetic forms of diabetes in the paediatric population has important treatment implications. Diabetes therapy focuses strongly on targets for good metabolic control to reduce the risk of long term complications. A parallel goal is to minimise short-term complications of hypoglycaemia and diabetic ketoacidosis. Technology offers opportunity for improvement in care, but has not yet fully lived up to its potential. New insights into the pathogenesis of diabetes and the development of new therapies have led to clinical trials aimed at the prevention of diabetes. PMID- 26009232 TI - Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and recurrent intrauterine fetal death. PMID- 26009231 TI - Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. AB - Individuals with diabetes are not only at high risk of developing heart failure but are also at increased risk of dying from it. Fortunately, antiheart failure therapies such as angiotensin-converting-enzyme inhibitors, beta blockers and mineralocorticoid-receptor antagonists work similarly well in individuals with diabetes as in individuals without the disease. Response to intensive glycaemic control and the various classes of antihyperglycaemic agent therapy is substantially less well understood. Insulin, for example, induces sodium retention and thiazolidinediones increase the risk of heart failure. The need for new glucose-lowering drugs to show cardiovascular safety has led to the unexpected finding of an increase in the risk of admission to hospital for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. Here we review the relation between glycaemic control and heart failure risk, focusing on the state of knowledge for the various types of antihyperglycaemic drugs that are used at present. PMID- 26009233 TI - Oxygen electroreduction promoted by quasi oxygen vacancies in metal oxide nanoparticles prepared by photoinduced chlorine doping. AB - Quasi oxygen-deficient indium tin oxide nanoparticles (ITO NPs) were prepared by photoinduced chlorine doping, and exhibited much enhanced electrocatalytic activity for oxygen reduction reaction (ORR) in alkaline media, as compared with pristine ITO. PMID- 26009235 TI - Gliolectin positively regulates Notch signalling during wing-vein specification in Drosophila. AB - Notch signalling is essential for animal development. It integrates multiple pathways controlling cell fate and specification. Here we report the genetic characterization of Gliolectin, presumably a lectin, a cytoplasmic protein, significantly enriched in Golgi bodies. Its expression overlaps with regions where Notch is activated. Loss of gliolectin function results in ectopic veins, while gain of its function causes loss of wing veins. It positively regulates Enhancer of split mβ, a target of Notch signalling. These observations suggest that it is a positive regulator of Notch signalling during wing development in Drosophila. PMID- 26009234 TI - Dual roles of voltage-gated sodium channels in development and cancer. AB - Voltage-gated Na(+) channels (VGSCs) are heteromeric protein complexes containing pore-forming alpha subunits together with non-pore-forming beta subunits. There are nine alpha subunits, Nav1.1-Nav1.9, and four beta subunits, beta1-beta4. The beta subunits are multifunctional, modulating channel activity, cell surface expression, and are members of the immunoglobulin superfamily of cell adhesion molecules. VGSCs are classically responsible for action potential initiation and conduction in electrically excitable cells, including neurons and muscle cells. In addition, through the beta1 subunit, VGSCs regulate neurite outgrowth and pathfinding in the developing central nervous system. Reciprocal signalling through Nav1.6 and beta1 collectively regulates Na(+) current, electrical excitability and neurite outgrowth in cerebellar granule neurons. Thus, alpha and beta subunits may have diverse interacting roles dependent on cell/tissue type. VGSCs are also expressed in non-excitable cells, including cells derived from a number of types of cancer. In cancer cells, VGSC alpha and beta subunits regulate cellular morphology, migration, invasion and metastasis. VGSC expression associates with poor prognosis in several studies. It is hypothesised that VGSCs are up-regulated in metastatic tumours, favouring an invasive phenotype. Thus, VGSCs may have utility as prognostic markers, and/or as novel therapeutic targets for reducing/preventing metastatic disease burden. VGSCs appear to regulate a number of key cellular processes, both during normal postnatal development of the CNS and during cancer metastasis, by a combination of conducting (i.e. via Na(+) current) and non-conducting mechanisms. PMID- 26009236 TI - Identification of distal enhancers for Six2 expression in pronephros. AB - The embryonic nephric mesenchyme contains pluripotent progenitor cells. Six2, a homeodomain transcription factor, is expressed in a subset of the nephric mesenchyme, and it functions to maintain a progenitor state by suppressing nephrogenesis. Despite the functional significance of Six2 in nephric development, its regulatory mechanisms remain unclear. To identify the cis regulatory elements for Six2, we focused on the evolutionarily conserved sequences known as conserved noncoding sequences (CNSs) associated with the Six2 locus. Transgenic experiments using Xenopus laevis embryos revealed that three of the eight CNSs located within a 317-kb segment of the Six2 genomic locus were nephric enhancers. Motif analysis of transcription factors combined with phylogenetic footprinting revealed the enrichment of putative T-cell factor (Tcf) , Hox-, and SWI/SNF complex helicase-like transcription factor (Hltf)- and AT rich interactive domain 3A (Arid3a)-binding motif sequences in these enhancers. PMID- 26009237 TI - Comparative expression analysis of pfdn6a and tcp1alpha during Xenopus development. AB - We recently identified pfdn6a and tcp1alpha (also known as cct-alpha) as genes coregulated by the transcription factor Rx1. The proteins encoded by these genes belong to two interacting complexes (Prefoldin and "chaperonin containing t complex polypeptide 1"), which promote the folding of actin and tubulin and have more recently been reported to be involved in a variety of additional functions including cell cycle control and transcription regulation. However, little is known about the expression and function of these two genes during vertebrate development. To assess whether pfdn6a and tcp1alpha display a general coordinated expression during Xenopus development, we determined, by RT-PCR and in situ hybridization, the spatio-temporal expression pattern of pfnd6a, which was not previously described, and compared it to that of tcp1alpha, extending the analysis to stages not previously investigated for this gene. We detected maternal transcripts of pfnd6a in the animal hemisphere at early blastula stage. During gastrulation, pfdn6a was expressed in the involuting mesoderm and subsequently in the anterior and dorsal neural plate. At tailbud and tadpole stages, pfdn6a RNA was mainly detected in the forebrain, midbrain, eye vesicle, otic vesicle, branchial arches, and developing pronephros. The pfnd6a expression pattern largely overlaps with that of tcp1alpha indicating a spatio-temporal transcriptional coregulation of these genes in the majority of their expression sites, which is suggestive of a possible involvement in the same developmental events. PMID- 26009238 TI - Regulated cell death in diagnostic histopathology. AB - Regulated cell death (RCD) is a controlled cellular process, essential for normal development, tissue integrity and homeostasis, and its dysregulation has been implicated in the pathogenesis of various conditions including developmental and immunological disorders, neurodegenerative diseases, and cancer. In this review, we briefly discuss the historical perspective and conceptual development of RCD, we overview recent classifications and some of the key players in RCD; finally we focus on current applications of RCD in diagnostic histopathology. PMID- 26009240 TI - Combinatorial cancer immunotherapy strategies with proapoptotic small-molecule IAP antagonists. AB - Members of the inhibitor of apoptosis (IAP) family control several critical aspects of innate immunity, cell death, and tumorigenesis. Small molecule antagonists that target specific IAP oncoproteins, primarily cIAP1 and cIAP2, but potentially also XIAP and Livin, modulate distinct immune signal transduction pathways that can lead to an increased sensitivity of tumors cells to cytokine mediated apoptosis. These antagonists are based on the structure of an endogenous cellular IAP inhibitor called Smac. Smac is normally sequestered within the mitochondria and is released into the cytoplasm upon cell death stimuli, thereby overcoming the anti-apoptotic action of the IAPs. The therapeutic usefulness of recombinant tumoricidal cytokines to treat cancer patients is principally limited due to their unacceptable adverse side effects. Therefore, investigators have sought to develop alternative regimens that do not rely on exogenously delivered death ligands. These approaches include the stimulation of the immune system with oncolytic virus-based agents or Toll-like receptor agonists in combination with Smac mimetics. Similarly, preclinical combination immunotherapy studies reveal that recombinant interferon synergizes with Smac mimetics to kill cancer. This strategy opens up new therapeutic avenues for anti-cancer therapy by modulating specific immune-mediated death pathways employing unique dual-pronged combinatorial approaches. PMID- 26009239 TI - Direct regulation of siamois by VegT is required for axis formation in Xenopus embryo. AB - The homeobox gene siamois is one of the earliest genes expressed in the Spemann organizer and plays a critical role in the formation of the dorsoventral axis. It is directly regulated by maternal Wnt signalling and functions as an essential zygotic intermediary between maternal factors and the formation of the Spemann organizer. The maternal T domain transcription factor VegT interacts with Wnt signalling and is also involved in the formation of the Spemann organizer. However, the molecular mechanism of this functional interaction is not fully understood. Here we show that VegT is required for siamois expression through direct binding to the T-box binding sites in the siamois promoter. Mutational analysis of each of the five consensus T-box binding sites suggests that the proximal site close to the transcription start site is essential for activation of siamois promoter by VegT, while individual mutation of the four distal sites has no effect. VegT and Wnt signalling also functionally interact and are mutually required for siamois expression. In particular, VegT synergizes with Tcf1, but not Tcf3 and Tcf4, to induce siamois expression, and this is independent of Tcf/Lef-binding sites or the proximal T-box binding site in the siamois promoter. We further extend previous observations by showing that VegT cooperates with maternal Wnt signalling in the formation of the dorsoventral axis. These results demonstrate that maternal VegT directly regulates siamois gene transcription in the formation of the Spemann organizer, and provide further insight into the mechanism underlying the functional interaction between VegT and Wnt signalling during development. PMID- 26009241 TI - [Car driving, cognitive aging and Alzheimer disease]. AB - Older drivers are more numerous on the roads. They are expert drivers, but with increasing age certain physiological changes can interfere with driving, which is a complex activity of daily living. Older drivers are involved in fewer accidents than younger drivers, but they have a higher accident rate per kilometer driven. The elderly are heavily represented in the balance sheet of road deaths, being motorists or pedestrians. This high mortality is largely explained by their physical frailty. In the presence of deficits, self-regulation of driving habits, changes/reductions or stopping in driving activity occur in the elderly. But cognitive deficits are associated with an increased risk of accidents. Among drivers with Alzheimer's disease, there is a heterogeneity of driving ability, making difficult the advisory role of a physician for driving. A protocol for physicians was developed to assess cognitive impairments that may affect driving in an elderly patient. The car plays an important role in the autonomy of the elderly and patient advice on stopping driving should take into account the risk/benefit ratio. PMID- 26009242 TI - Risks of treatments and long-term outcomes of systemic ANCA-associated vasculitis. AB - Patients with ANCA-associated vasculitis (AAV) have an increased risk of premature death and organ failure. Treatment strategies with immune-suppressive drugs need to balance disease control and prevention of relapse against the risk of side effects in particular infection and malignancy. The longer-term outcome of patients with AAV who participated in several randomised controlled trials has been published in recent years. The results of these and other newer studies will be the focus of this review. PMID- 26009243 TI - Clonal integration in homogeneous environments increases performance of Alternanthera philoxeroides. AB - Physiological integration between connected ramets can increase the performance of clonal plants when ramets experience contrasting levels of resource availabilities in heterogeneous environments. It has generally been shown or assumed that clonal integration has little effect on clonal performance in homogeneous environments. However, a conceptual model suggests that integration could increase performance in a homogeneous environment when connected ramets differ in uptake ability and external resource supply is high. We tested this hypothesis in a greenhouse experiment with the amphibious plant Alternanthera philoxeroides. Ramets in clonal fragments containing three rooted and two unrooted ramets were either left connected or divided into a basal part with two rooted ramets and an apical part with the other ramets. To simulate realistic, homogeneous environments of the species with different levels of resource supply, plants were grown at 0, 20, or 40 cm of water depth. Water depth had a positive effect on most measures of growth, indicating that resource supply increased with depth. Connection had negative to neutral effects on total growth of fragments at a water depth of 0 cm, and neutral to positive effects at 20- and 40-cm depths; effects on the apical part were generally positive and larger at greater depth; effects on the basal part were generally negative and smaller at greater depth. Results largely supported the hypothesis and further suggest that clonal integration of allocation and reproduction may modify benefits of resource sharing in homogeneous environments. PMID- 26009244 TI - Asynchronous vegetation phenology enhances winter body condition of a large mobile herbivore. AB - Understanding how spatial and temporal heterogeneity influence ecological processes forms a central challenge in ecology. Individual responses to heterogeneity shape population dynamics, therefore understanding these responses is central to sustainable population management. Emerging evidence has shown that herbivores track heterogeneity in nutritional quality of vegetation by responding to phenological differences in plants. We quantified the benefits mule deer (Odocoileus hemionus) accrue from accessing habitats with asynchronous plant phenology in northwest Colorado over 3 years. Our analysis examined both the direct physiological and indirect environmental effects of weather and vegetation phenology on mule deer winter body condition. We identified several important effects of annual weather patterns and topographical variables on vegetation phenology in the home ranges of mule deer. Crucially, temporal patterns of vegetation phenology were linked with differences in body condition, with deer tending to show poorer body condition in areas with less asynchronous vegetation green-up and later vegetation onset. The direct physiological effect of previous winter precipitation on mule deer body condition was much less important than the indirect effect mediated by vegetation phenology. Additionally, the influence of vegetation phenology on body fat was much stronger than that of overall vegetation productivity. In summary, changing annual weather patterns, particularly in relation to seasonal precipitation, have the potential to alter body condition of this important ungulate species during the critical winter period. This finding highlights the importance of maintaining large contiguous areas of spatially and temporally variable resources to allow animals to compensate behaviourally for changing climate-driven resource patterns. PMID- 26009245 TI - Contrasting effects of plant species traits and moisture on the decomposition of multiple litter fractions. AB - Environmental variation in moisture directly influences plant litter decomposition through effects on microbial activity, and indirectly via plant species traits. Whether the effects of moisture and plant species traits are mutually reinforcing or counteracting during decomposition are unknown. To disentangle the effects of moisture from the effects of species traits that vary with moisture, we decomposed leaf litter from 12 plant species in the willow family (Salicaceae) with different native habitat moisture preferences in paired mesic and wetland plots. We fit litter mass loss data to an exponential decomposition model and estimated the decay rate of the rapidly cycling litter fraction and size of the remaining fraction that decays at a rate approaching zero. Litter traits that covaried with moisture in the species' native habitat significantly influenced the decomposition rate of the rapidly cycling litter fraction, but moisture in the decomposition environment did not. In contrast, for the slowly cycling litter fraction, litter traits that did not covary with moisture in the species' native habitat and moisture in the decomposition environment were significant. Overall, the effects of moisture and plant species traits on litter decomposition were somewhat reinforcing along a hydrologic gradient that spanned mesic upland to wetland (but not permanently surface saturated) plots. In this system, plant trait and moisture effects may lead to greater in situ decomposition rates of wetland species compared to upland species; however, plant traits that do not covary with moisture will also influence decomposition of the slowest cycling litter fraction. PMID- 26009246 TI - Communication between lymphatic and venous systems in mice. AB - The lymphatic system in mice consists of lymphatic vessels and 22 types of lymph nodes. Metastatic tumor cells in the lymphatic system spread to distant organs through the venous system. However, the communication routes between the lymphatic and venous systems have not been fully elucidated. Here, we identify the communication routes between the lymphatic and venous systems in the axillary and subiliac regions of MXH10/Mo-lpr/lpr inbred mice, which develop systemic swelling of lymph nodes up to 10mm in diameter, allowing investigation of the topography of the lymph nodes and lymphatic vessels. Using a gross anatomy dissection approach, the efferent lymphatic vessels of the proper axillary lymph node were shown to communicate with the subclavian vein. Furthermore, we found that the thoracoepigastric vein, which connects the subclavian vein and inferior vena cava, runs adjacent to the subiliac and proper axillary lymph nodes, and receives venous blood from these lymph nodes routed through small branches. The direction of blood flow in the thoracoepigastric vein occurred in two directions in the intermediate region between the proper axillary lymph node and subiliac lymph node; one to the subclavian vein, the other to the inferior vena cava. This paper reveals the anatomy of the communication between the lymphatic and venous systems in the axillary and subiliac regions of the mouse, and provides new insights relevant to the investigation of the mechanisms of lymph node metastasis and cancer immunology, and the development of diagnostic and treatment methods for lymph node metastasis, including drug delivery systems. PMID- 26009247 TI - A novel immunoassay to measure total serum lymphotoxin-alpha levels in the presence of an anti-LTalpha therapeutic antibody. AB - During drug development, measurement of suitable pharmacodynamic biomarkers is key to establishing in vivo drug activity. Binding of monoclonal antibody (mAb) therapeutics to soluble target proteins often results in elevated serum levels of their target antigen, and measuring total (free and bound) concentration of the target antigen can be an important means of demonstrating that the mAb has reached its specific target. However, accurately measuring soluble circulating antigen in preclinical or clinical samples in the presence of a therapeutic mAb presents a bioanalytical challenge. Particularly in the case of low molecular weight and/or multimeric targets, epitopes for capture and detection of the target by reagent antibodies can be obscured by bound therapeutic mAb. Lymphotoxin-alpha (LTalpha) is a cytokine in the TNF superfamily that has been implicated in the pathophysiology of autoimmune disease, and is a therapeutic target for neutralizing mAb. During preclinical safety studies in cynomolgus macaques, we encountered difficulties in measuring total LTalpha in serum of dosed animals. When serum LTalpha trimer was saturated with the anti-LTalpha mAb, binding of two reagent antibodies, as required for a classic sandwich ELISA, was not feasible, and dissociation methods were also found to be unsuitable. We therefore developed an approach in which excess anti-LTalpha mAb was added to the in vitro assay system to fully saturate all binding sites, and an anti-idiotypic antibody was used to detect bound therapeutic antibody. Using this method, total LTalpha could be accurately measured in cynomolgus macaque serum, and was observed to increase with increasing anti-LTalpha therapeutic mAb dose. Additional in vitro studies demonstrated that the method worked equally well in human serum. This assay strategy will be useful for quantifying total concentrations of other small and/or multimeric target proteins in the presence of a therapeutic antibody. PMID- 26009249 TI - Potential Signal Transduction Regulation by HDL of the beta2-Adrenergic Receptor Pathway. Implications in Selected Pathological Situations. AB - The main atheroprotective mechanism of high-density lipoprotein (HDL) has been regarded as reverse cholesterol transport, whereby cholesterol from peripheral tissues is removed and transported to the liver for elimination. Although numerous additional atheroprotective mechanisms have been suggested, the role of HDL in modulating signal transduction of cell membrane-bound receptors has received little attention to date. This potential was recently highlighted following the identification of a polymorphism in the adenylyl cyclase 9 gene (ADCY9) that was shown to be a determining factor in the risk of cardiovascular (CV) events in patients treated with the HDL-raising compound dalcetrapib. Indeed, ADCY9 is part of the signaling pathway of the beta2-adrenergic receptor (beta2-AR) and both are membrane-bound proteins affected by changes in membrane rich cholesterol plasma membrane domains (caveolae). Numerous G-protein-coupled receptors (GPCRs) and ion channels are affected by caveolae, with caveolae composition acting as a 'signalosome'. Polymorphisms in the genes encoding ADCY9 and beta2-AR are associated with response to beta2-agonist drugs in patients with asthma, malaria and with sickle cell disease. Crystallization of the beta2-AR has found cholesterol tightly bound to transmembrane structures of the receptor. Cholesterol has also been shown to modulate the activity of this receptor. Apolipoprotein A1 (ApoA1), the major protein component of HDL, destabilizes and removes cholesterol from caveolae with high affinity through interaction with ATP binding cassette transporter. Furthermore, beta2-AR activity may be affected by ApoA1/HDL-targeted therapies. Taken together, these observations suggest a common pathway that potentially links a primary HDL function to the regulation of signal transduction. PMID- 26009248 TI - Therapeutic Plasma Exchange in Multiple Sclerosis Patients with Abolished Interferon-beta Bioavailability. AB - BACKGROUND: Neutralizing antibodies (NAb) to interferon-beta (IFN-beta) are associated with reduced bioactivity and efficacy of IFN-beta in multiple sclerosis (MS). The myxovirus resistance protein A (MxA) gene expression is one of the most appropriate markers of biological activity of exogenous IFN-beta. We hypothesized that therapeutic plasma exchange (TPE) can restore the ability of IFN-beta to induce the MxA mRNA expression and that maintenance plasmapheresis can sustain the bioavailability of IFN-beta. MATERIAL AND METHODS: Eligible patients underwent 4 primary separate plasma exchange sessions. After the induction TPE sessions, they were transferred to maintenance plasmapheresis. Bioactivity of IFN-beta was expressed as in vivo MxA mRNA induction in whole blood using RT-qPCR. RESULTS: Six patients with low IFN-beta bioavailability detected by the MxA mRNA response were included. Four patients became biological responders after induction plasmapheresis. In 2 patients an increase of MxA mRNA expression was found, but the values persisted below the cut-off and the patients remained as "poor biological responders". The effect of maintenance plasmapheresis was transient: MxA mRNA expression values reverted to the baseline levels after 1-2 months. CONCLUSIONS: Therapeutic plasma exchange is able to restore the bioavailability of IFN-beta in the majority of studied patients, but the effect of TPE on the IFN-beta bioavailability was transient. PMID- 26009250 TI - Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis. AB - Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-a-vis the coronary arteries favoring the local inflammation and the atheroma calcification. PMID- 26009254 TI - Maintenance of protein synthesis reading frame by EF-P and m(1)G37-tRNA. AB - Maintaining the translational reading frame poses difficulty for the ribosome. Slippery mRNA sequences such as CC[C/U]-[C/U], read by isoacceptors of tRNA(Pro), are highly prone to +1 frameshift (+1FS) errors. Here we show that +1FS errors occur by two mechanisms, a slow mechanism when tRNA(Pro) is stalled in the P-site next to an empty A-site and a fast mechanism during translocation of tRNA(Pro) into the P-site. Suppression of +1FS errors requires the m(1)G37 methylation of tRNA(Pro) on the 3' side of the anticodon and the translation factor EF-P. Importantly, both m(1)G37 and EF-P show the strongest suppression effect when CC[C/U]-[C/U] are placed at the second codon of a reading frame. This work demonstrates that maintaining the reading frame immediately after the initiation of translation by the ribosome is an essential aspect of protein synthesis. PMID- 26009255 TI - Treatment of patella fracture by claw-like shape memory alloy. AB - INTRODUCTION: Titanium-nickel shape memory alloy (Ti-Ni SMA) is characterized by shape-memory effect, super-elasticity, excellent fatigue behavior, corrosion resistance, acceptable biocompatibility and high damping capacity. MATERIALS AND METHODS: Claw-like Ti-Ni SMA fixator (SMA-claw) has been used to treat transverse fracture of patella. 29 patients (19 males, 10 females) aged from 21 to 71 years old (averaged 43.0 years old) have been received open reduction and internal fixation with SMA-claw from January 2011 to December 2011. After operation, patients have been received gradual knee function exercises, followed by radiographic analysis and Lysholm Knee Score at 1, 2, 3, 6, 9 and 12 months postoperation. RESULTS: The mean follow-up time was 11.48 months (25 patients finished, 1 lost after 6 months and 3 lost after 9 months). Radiographic bone union occurred at 2 months (7 patients) or 3 months (22 patients). Satisfied range of motion for the knee joint has been observed with 1.90/141.72 degrees (hyperextension/flexion) at 3 months, 4.83/143.97 degrees at 6 months, 4.82/144.82 degrees at 9 months and 5.2/145 degrees at 12 months postsurgery. CONCLUSION: The Ti-Ni SMA-claw fixator produced good osteosynthesis effect by continuous recovery stress with relatively simple and minimally invasive handling process, which can be introduced as an alternative to traditional tension band technique for treatment of patellar transverse fracture. PMID- 26009253 TI - Prepubertal Serum Concentrations of Organochlorine Pesticides and Age at Sexual Maturity in Russian Boys. AB - BACKGROUND: Few human studies have evaluated the impact of childhood exposure to organochlorine pesticides (OCP) on pubertal development. OBJECTIVE: We evaluated associations of serum OCP concentrations [hexachlorobenzene (HCB), beta hexachlorocyclohexane (betaHCH), and p,p-dichlorodiphenyldichloroethylene (p,p' DDE)] with age at attainment of sexual maturity among boys. METHODS: From 2003 through 2005, 350 8- to 9-year-old boys from Chapaevsk, Russia, with measured OCPs were enrolled and followed annually for 8 years. We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with three physician-assessed measures of sexual maturity: Tanner stage 5 for genitalia growth, Tanner stage 5 for pubic hair growth, or testicular volume (TV) >= 20 mL in either testis. RESULTS: In adjusted models, boys with higher HCB concentrations achieved sexual maturity reflected by TV >= 20 mL a mean of 3.1 months (95% CI: -1.7, 7.8), 5.3 months (95% CI: 0.6, 10.1), and 5.0 months (95% CI: 0.2, 9.8) later for quartiles Q2, Q3, and Q4, respectively, compared with Q1 (p trend = 0.04). Tanner stage 5 for genitalia growth was attained a mean of 2.2 months (95% CI: -3.1, 7.5), 5.7 months (95% CI: 0.4, 11.0), and 3.7 months (95% CI: -1.7, 9.1) later for quartiles Q2, Q3, and Q4, respectively, of betaHCH compared with Q1 (p trend = 0.09). Tanner stage 5 for pubic hair growth occurred 6-9 months later on average for boys in the highest versus lowest quartile for HCB (p trend < 0.001), betaHCH (trend p = 0.01), and p,p'-DDE (p trend = 0.04). No associations were observed between p,p'-DDE and Tanner stage 5 for genitalia growth or TV >= 20 mL. CONCLUSIONS AND RELEVANCE: Higher prepubertal serum HCB and betaHCH concentrations were associated with a later age at attainment of sexual maturity. Only the highest quartile of serum p,p'-DDE was associated with later pubic hair maturation. CITATION: Lam T, Williams PL, Lee MM, Korrick SA, Birnbaum LS, Burns JS, Sergeyev O, Revich B, Altshul LM, Patterson DG Jr, Hauser R. 2015. Prepubertal serum concentrations of organochlorine pesticides and age at sexual maturity in Russian boys. Environ Health Perspect 123:1216-1221; http://dx.doi.org/10.1289/ehp.1409022. PMID- 26009257 TI - Surfactant-assisted fabrication of 3D Prussian blue-reduced graphene oxide hydrogel as a self-propelling motor for water treatment. AB - Three-dimensional Prussian blue-reduced graphene oxide hydrogel was synthesized with the assistance of sodium dodecyl sulfate (SDS) through a facile hydrothermal method. The hydrogel exhibited strong mechanical properties and was successfully applied as a self-propelling motor for water treatment. During the self propelling degradation process, SDS facilitated the rapid liberation of oxygen bubbles from the motor and the oxygen bubbles assisted the rapid diffusion of hydroxyl radicals. In addition, the well-defined structure increased the number of reaction sites and the synergy between reduced graphene oxide and Prussian blue, which accelerated the degradation efficiency. The self-propelling motor had an average velocity of 0.026 +/- 0.013 cm s(-1) in 7.5% H2O2 and 0.069 +/- 0.032 cm s(-1) in 22.5% H2O2. Moreover, the self-propelling motor maintained high degradation efficiency even after cycling for 9 times. These excellent properties make the self-propelling motor an ideal candidate for water treatment. PMID- 26009251 TI - Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein. AB - Although reducing low-density lipoprotein-cholesterol (LDL-C) levels with lipid lowering agents (statins) decreases cardiovascular disease (CVD) risk, a substantial residual risk (up to 70% of baseline) remains after treatment in most patient populations. High-density lipoprotein (HDL) is a potential contributor to residual risk, and low HDL-cholesterol (HDL-C) is an established risk factor for CVD. However, in contrast to conventional lipid-lowering therapies, recent studies show that pharmacologic increases in HDL-C levels do not bring about clinical benefits. These observations have given rise to the concept of dysfunctional HDL where increases in serum HDL-C may not be beneficial because HDL loss of function is not corrected by or even intensified by the therapy. Chronic kidney disease (CKD) increases CVD risk, and patients whose CKD progresses to end-stage renal disease (ESRD) requiring dialysis are at the highest CVD risk of any patient type studied. The ESRD population is also unique in its lack of significant benefit from standard lipid-lowering interventions. Recent studies indicate that HDL-C levels do not predict CVD in the CKD population. Moreover, CKD profoundly alters metabolism and composition of HDL particles and impairs their protective effects on functions such as cellular cholesterol efflux, endothelial protection, and control of inflammation and oxidation. Thus, CKD-induced perturbations in HDL may contribute to the excess CVD in CKD patients. Understanding the mechanisms of vascular protection in renal disease can present new therapeutic targets for intervention in this population. PMID- 26009256 TI - Mitochondrial DNA heteroplasmy in the emerging field of massively parallel sequencing. AB - Long an important and useful tool in forensic genetic investigations, mitochondrial DNA (mtDNA) typing continues to mature. Research in the last few years has demonstrated both that data from the entire molecule will have practical benefits in forensic DNA casework, and that massively parallel sequencing (MPS) methods will make full mitochondrial genome (mtGenome) sequencing of forensic specimens feasible and cost-effective. A spate of recent studies has employed these new technologies to assess intraindividual mtDNA variation. However, in several instances, contamination and other sources of mixed mtDNA data have been erroneously identified as heteroplasmy. Well vetted mtGenome datasets based on both Sanger and MPS sequences have found authentic point heteroplasmy in approximately 25% of individuals when minor component detection thresholds are in the range of 10-20%, along with positional distribution patterns in the coding region that differ from patterns of point heteroplasmy in the well-studied control region. A few recent studies that examined very low-level heteroplasmy are concordant with these observations when the data are examined at a common level of resolution. In this review we provide an overview of considerations related to the use of MPS technologies to detect mtDNA heteroplasmy. In addition, we examine published reports on point heteroplasmy to characterize features of the data that will assist in the evaluation of future mtGenome data developed by any typing method. PMID- 26009258 TI - What is Proof of Concept Research and how does it Generate Epistemic and Ethical Categories for Future Scientific Practice? AB - "Proof of concept" is a phrase frequently used in descriptions of research sought in program announcements, in experimental studies, and in the marketing of new technologies. It is often coupled with either a short definition or none at all, its meaning assumed to be fully understood. This is problematic. As a phrase with potential implications for research and technology, its assumed meaning requires some analysis to avoid it becoming a descriptive category that refers to all things scientifically exciting. I provide a short analysis of proof of concept research and offer an example of it within synthetic biology. I suggest that not only are there activities that circumscribe new epistemological categories but there are also associated normative ethical categories or principles linked to the research. I examine these and provide an outline for an alternative ethical account to describe these activities that I refer to as "extended agency ethics". This view is used to explain how the type of research described as proof of concept also provides an attendant proof of principle that is the result of decision-making that extends across practitioners, their tools, techniques, and the problem solving activities of other research groups. PMID- 26009259 TI - Impact of body mass on recurrence and progression in Chinese patients with Ta, T1 urothelial bladder cancer. AB - OBJECTIVE: To evaluate the impact of body mass on recurrence and progression in patients with Ta, T1 urothelial bladder cancer. METHODS: Data from 469 patients with Ta, T1 bladder cancer who were treated with transurethral resection of bladder tumor at our center during 2006-2014 were retrospectively studied. According to body mass index (BMI), patients were divided into three groups: normal weight (BMI < 24 kg/m(2)), overweight (24 kg/m(2) <= BMI < 28 kg/m(2)) and obesity (BMI >= 28 kg/m(2)). Clinicopathologic features were compared across groups. Kaplan-Meier curves and Cox proportional hazards regression analyses were employed to assess the association between body mass and oncologic outcomes. RESULTS: Compared with patients with normal weight, overweight and obese counterparts showed significantly shorter recurrence-free or progression-free survival. In multivariate analyses, being overweight was an independent factor for recurrence and obesity was for both recurrence and progression. The presence of diabetes mellitus (DM) was not a strong risk factor for the entire cohort, while it became a significant predictor for both recurrence and progression in the subgroup of overweight and obese patients. CONCLUSION: Excessive body mass seems to act as independent risk factors for worse oncologic outcomes of Ta, T1 bladder cancer. Further studies should be carried out to elucidate the exact impact of obesity, DM or even other metabolic disorders. PMID- 26009260 TI - Prediction across sensory modalities: A neurocomputational model of the McGurk effect. AB - The McGurk effect is a textbook illustration of the automaticity with which the human brain integrates audio-visual speech. It shows that even incongruent audiovisual (AV) speech stimuli can be combined into percepts that correspond neither to the auditory nor to the visual input, but to a mix of both. Typically, when presented with, e.g., visual /aga/ and acoustic /aba/ we perceive an illusory /ada/. In the inverse situation, however, when acoustic /aga/ is paired with visual /aba/, we perceive a combination of both stimuli, i.e., /abga/ or /agba/. Here we assessed the role of dynamic cross-modal predictions in the outcome of AV speech integration using a computational model that processes continuous audiovisual speech sensory inputs in a predictive coding framework. The model involves three processing levels: sensory units, units that encode the dynamics of stimuli, and multimodal recognition/identity units. The model exhibits a dynamic prediction behavior because evidence about speech tokens can be asynchronous across sensory modality, allowing for updating the activity of the recognition units from one modality while sending top-down predictions to the other modality. We explored the model's response to congruent and incongruent AV stimuli and found that, in the two-dimensional feature space spanned by the speech second formant and lip aperture, fusion stimuli are located in the neighborhood of congruent /ada/, which therefore provides a valid match. Conversely, stimuli that lead to combination percepts do not have a unique valid neighbor. In that case, acoustic and visual cues are both highly salient and generate conflicting predictions in the other modality that cannot be fused, forcing the elaboration of a combinatorial solution. We propose that dynamic predictive mechanisms play a decisive role in the dichotomous perception of incongruent audiovisual inputs. PMID- 26009262 TI - Automated robust test framework for electrical impedance tomography. AB - An automated test system and procedure is proposed, designed to enable systematic testing of electrical impedance tomography (EIT) devices. The system is designed to calculate reliable, repeatable and accurate performance figures of merit of an EIT system using a saline phantom and an industrial robot arm. Applications of the test system are to compare EIT devices against requirements, or to help optimize a device for its operating parameters. A test methodology and sample test results are presented to illustrate its use. The system is used to compare image quality and contrast detection for a range of stimulation and measurement patterns, and results show the best images when the pair of current injection electrodes is spaced between 45 and 170 degrees on a tank. Finally, we propose a classification of the object detection errors, which can facilitate comparison of EIT instrument specifications. PMID- 26009261 TI - Phase II Trial of Tandem High-Dose Chemotherapy with Autologous Stem Cell Transplantation Followed by Reduced-Intensity Allogeneic Stem Cell Transplantation for Patients with High-Risk Lymphoma. AB - Many patients with lymphoma relapse after autologous stem cell transplantation (AutoSCT). These patients are often considered for allogeneic stem cell transplantation (AlloSCT) if remission can be achieved. If a tandem approach was organized, some cases of relapse might be prevented. We conducted a phase II trial of tandem AutoSCT followed by reduced-intensity conditioning (RIC) AlloSCT for patients with high-risk lymphoma. High-dose chemotherapy was given with busulfan, cyclophosphamide, and etoposide. AlloSCT was composed of RIC with busulfan/fludarabine and tacrolimus, sirolimus, and methotrexate as graft-versus host disease (GVHD) prophylaxis. Donors were fully matched related or unrelated donors. AlloSCT was performed any time between 40 days and 6 months after AutoSCT. Forty-two patients were enrolled, and all patients underwent AutoSCT. RIC AlloSCT was performed in 29 patients. In the 29 patients who underwent tandem transplant, median time from AutoSCT to AlloSCT was 96 days (range, 48 to 169). The 6-month cumulative incidence of grades II to IV acute GVHD was 13.8% (90% confidence interval [CI], 5.3% to 26.3%). Cumulative incidence of chronic GVHD at 1 year was 37.9% (90% CI, 23.1% to 52.7%). Nonrelapse mortality at 2 years after AlloSCT was 11.1% (90% CI, 3.5% to 23.6%). At a median follow-up of 30 months (range, 17.1 to 51.5) for the entire group, the 2-year progression-free survival rate was 64% (90% CI, 50% to 75%) and the 2-year overall survival rate was 69% (90% CI, 43% to 85%). For the 29 patients who underwent tandem SCT, the 2-year progression-free survival rate was 72% (90% CI, 55% to 83%) and the 2-year OS rate was 89% (90% CI, 74% to 96%). Tandem AutoSCT-RIC AlloSCT appears to be safe and effective in patients with high-risk lymphoma. Prospective trials using such an approach in specific lymphoma subtypes are warranted. PMID- 26009263 TI - Acute myeloid leukemia cells MOLM-13 and SKM-1 established for resistance by azacytidine are crossresistant to P-glycoprotein substrates. AB - Establishment of the acute myeloid leukemia cells SKM-1 and MOLM-13 for resistance by azacytidine (AzaC) resulted in SKM-1/AzaC and MOLM-13/AzaC cell variants with reduced sensitivity to AzaC. Despite the fact that AzaC is not substrate of P-glycoprotein (P-gp), the adaptation procedure resulted in an induction in P-gp expression/efflux activity that confers crossresistance to P-gp substrates in both resistant cell variants. While the resistance to P-gp substrates in SKM-1/AzaC and MOLM-13/AzaC cells could be reversed by the P-gp inhibitors, resistance to AzaC was insensitive to these inhibitors in both resistant cell variants. In addition, NF-kappaB and the antiapoptotic protein Bcl 2 were downregulated and the proapoptotic proteins Bax and p53 were upregulated in both resistant cell variants when compared with their sensitive counterparts. Moreover, at least five times the elevation in overall glutathione S-transferase activity was measured with 1-chloro-2, 5-dinitrobenzene as a substrate in the resistant variant of both cell lines. Taken together, the findings of the present study indicate that the treatment of AML cells with AzaC might lead to a drug resistance phenotype that may be associated with cross resistance to P-gp substrates and substrates of glutathione S-transferases. PMID- 26009264 TI - Toward the practical utility of systems mapping: Reply to comments on "Mapping complex traits as a dynamic system". PMID- 26009265 TI - Effect of electrolytes on proteins physisorption on ordered mesoporous silica materials. AB - This short review highlights the effect of electrolytes on the performance of proteins-mesoporous silica conjugates which can open interesting perspectives in biotechnological fields, particularly nanomedicine and biocatalysis. Indeed therapeutic proteins and peptides represent a challenging innovation for several kinds of diseases, but since their self-life in biological fluids is very short, they need a stealth protective carrier. Similarly, enzymes need a solid support to improve thermal stability and to allow for recycling. Ordered mesoporous silica materials represent a valid choice as widely demonstrated. Both proteins and silica mesoporous materials possess charged surfaces, and here, the crucial role of pH, buffer, ionic strength and electrolyte type is posed in relation with loading/release of proteins onto/from the silica support through the analysis of adsorption and release processes. A delicate interplay of electrostatic and van der Waals interactions arises from considering electrolytes' effects on the two different charged surfaces. Clear outcomes concern the effect of pH and ionic strength. Protein loading onto the silica matrix is favored by an adsorbing solution having a pH close to the protein pI, and by a high ionic strength that reduces the Debye length. Release is instead favored by an adsorbing solution characterized by an intermediate ionic strength, close to the physiological values. Significant specific ions effects are shown to affect both proteins and silica matrices, as well as protein adsorption onto silica matrices. Further work is needed to quantify specific ion effects on the preservation of the biological activity, and on the release performance. PMID- 26009266 TI - Assessment of driver stopping prediction models before and after the onset of yellow using two driving simulator datasets. AB - Accurate modeling of driver decisions in dilemma zones (DZ), where drivers are not sure whether to stop or go at the onset of yellow, can be used to increase safety at signalized intersections. This study utilized data obtained from two different driving simulator studies (VT-SCORES and NADS datasets) to investigate the possibility of developing accurate driver-decision prediction/classification models in DZ. Canonical discriminant analysis was used to construct the prediction models, and two timeframes were considered. The first timeframe used data collected during green immediately before the onset of yellow, and the second timeframe used data collected during the first three seconds after the onset of yellow. Signal protection algorithms could use the results of the prediction model during the first timeframe to decide the best time for ending the green signal, and could use the results of the prediction model during the first three seconds of yellow to extend the clearance interval. It was found that the discriminant model using data collected during the first three seconds of yellow was the most accurate, at 99% accuracy. It was also found that data collection should focus on variables that are related to speed, acceleration, time, and distance to intersection, as opposed to secondary variables, such as pavement conditions, since secondary variables did not significantly change the accuracy of the prediction models. The results reveal a promising possibility for incorporating the developed models in traffic-signal controllers to improve DZ protection strategies. PMID- 26009267 TI - Cultural Expressions of Intergenerational Trauma and Mental Health Nursing Implications for U.S. Health Care Delivery Following Refugee Resettlement: An Integrative Review of the Literature. AB - PURPOSE: The purpose of this integrative review of the literature is to examine cultural expressions of intergenerational trauma among refugees following resettlement, and to determine culturally sensitive mental health care practice implications for health care practitioners working in U.S. health care delivery. METHODOLOGY: Data were collected utilizing a comprehensive computer-assisted search in CINAHL and PsychARTICLES/ProQuest from 2003 to 2013 of full text, peer reviewed, scholarly journal articles, published in English. Eight articles met selection criteria and were analyzed using Gadamer's philosophical interpretation of play, symbolism, and festival in The Relevance of the Beautiful RESULTS: Six recurrent themes were identified important to refugee health care delivery: silence, communication, adaptation, relationship, remembering, and national redress. IMPLICATIONS FOR PRACTICE: Practitioners need to consider cultural influences of intergenerational trauma in processing grief related to loss and how artistic modes of expression are experienced, both individually and communally, in refugee health care delivery. PMID- 26009268 TI - Conventional versus virtual radiographs of the injured pelvis and acetabulum. AB - BACKGROUND: Evaluation of the fractured pelvis or acetabulum requires both standard radiographic evaluation as well as computed tomography (CT) imaging. The standard anterior-posterior (AP), Judet, and inlet and outlet views can now be simulated using data acquired during CT, decreasing patient discomfort, radiation exposure, and cost to the healthcare system. The purpose of this study is to compare the image quality of conventional radiographic views of the traumatized pelvis to virtual radiographs created from pelvic CT scans. METHODS: Five patients with acetabular fractures and ten patients with pelvic ring injuries were identified using the orthopedic trauma database at our institution. These fractures were evaluated with both conventional radiographs as well as virtual radiographs generated from a CT scan. A web-based survey was created to query overall image quality and visibility of relevant anatomic structures. This survey was then administered to members of the Orthopaedic Trauma Association (OTA). RESULTS: Ninety-seven surgeons completed the acetabular fracture survey and 87 completed the pelvic fracture survey. Overall image quality was judged to be statistically superior for the virtual as compared to conventional images for acetabular fractures (3.15 vs. 2.98, p = 0.02), as well as pelvic ring injuries (2.21 vs. 1.45, p = 0.0001). Visibility ratings for each anatomic landmark were statistically superior with virtual images as well. DISCUSSION: Virtual radiographs of pelvic and acetabular fractures offer superior image quality, improved comfort, decreased radiation exposure, and a more cost-effective alternative to conventional radiographs. PMID- 26009269 TI - A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies. AB - OBJECTIVES: Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy. MATERIALS AND METHODS: Patients with unresectable thymic malignancy were treated with saracatinib 175mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%. RESULTS: 21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated. CONCLUSION: Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population (NCT00718809). PMID- 26009270 TI - New insights into the molecular mechanisms of biomembrane structural changes and interactions by optical biosensor technology. AB - Biomolecular-membrane interactions play a critical role in the regulation of many important biological processes such as protein trafficking, cellular signalling and ion channel formation. Peptide/protein-membrane interactions can also destabilise and damage the membrane which can lead to cell death. Characterisation of the molecular details of these binding-mediated membrane destabilisation processes is therefore central to understanding cellular events such as antimicrobial action, membrane-mediated amyloid aggregation, and apoptotic protein induced mitochondrial membrane permeabilisation. Optical biosensors have provided a unique approach to characterising membrane interactions allowing quantitation of binding events and new insight into the kinetic mechanism of these interactions. One of the most commonly used optical biosensor technologies is surface plasmon resonance (SPR) and there have been an increasing number of studies reporting the use of this technique for investigating biophysical analysis of membrane-mediated events. More recently, a number of new optical biosensors based on waveguide techniques have been developed, allowing membrane structure changes to be measured simultaneously with mass binding measurements. These techniques include dual polarisation interferometry (DPI), plasmon waveguide resonance spectroscopy (PWR) and optical waveguide light mode spectroscopy (OWLS). These techniques have expanded the application of optical biosensors to allow the analysis of membrane structure changes during peptide and protein binding. This review provides a theoretical and practical overview of the application of biosensor technology with a specific focus on DPI, PWR and OWLS to study biomembrane-mediated events and the mechanism of biomembrane disruption. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 26009271 TI - Protein kinase C affects the internalization and recycling of organic anion transporting polypeptide 1B1. AB - Organic anion-transporting polypeptides are members of the solute carrier (SLC) family and key determinants for the transmembrane transport of a wide variety of compounds. OATP1B1 is predominantly expressed at the basolateral membrane of human hepatocytes and play an important role in drug clearance from the body. It has been demonstrated to be responsible for the hepatic uptake of various drugs. Computer-based hydropathy analysis predicted several putative phosphorylation sites at the amino and carboxyl termini and at intracellular loop 3 of OATP family members. Therefore, their transport functions may be regulated by phosphorylation. Previous studies have demonstrated that uptake function of OATP2B1 and OATP1A2 is regulated by protein kinase C (PKC). In the present study, we treated HEK293 cells stably expressing OATP1B1 with different PKC modulators and measured their transport activity for prototypic substrate estrone-3-sulfate. It was found that OATP1B1 uptake function was reduced upon PKC activation. Further studies indicated that PKC may affect OATP1B1 activity through regulation of the cell surface protein level. Moreover, we found out that PKC activator phorbol 12-myristate 13-acetate (PMA) not only affects the internalization of OATP1B1 but its recycling as well. Immunocytochemistry analysis revealed that internalized OATP1B1 co-localized with early and recycling endosomal markers and the co-localization of OATP1B1 with recycling endosome is dependent on PKC activation. Taken together, our present study demonstrated that PKC regulates the function of OATP1B1 by affecting internalization and recycling of the transporter protein. PMID- 26009272 TI - Formulation and antifungal performance of natamycin-loaded liposomal suspensions: the benefits of sterol-enrichment. AB - The aim of this study is to develop and evaluate food-grade liposomal delivery systems for the antifungal compound natamycin. Liposomes made of various soybean lecithins are prepared by solvent injection, leading to small unilamellar vesicles (<130 nm) with controlled polydispersity, able to encapsulate natamycin without significant modification of their size characteristics. Presence of charged phospholipids and reduced content of phosphatidylcholine in the lecithin mixture are found to be beneficial for natamycin encapsulation, indicating electrostatic interactions of the preservative with the polar head of the phospholipids. The chemical instability of natamycin upon storage in these formulations is however significant and proves that uncontrolled leakage out of the liposomes occurs. Efficient prevention of natamycin degradation is obtained by incorporation of sterols (cholesterol, ergosterol) in the lipid mixture and is linked to higher entrapment levels and reduced permeability of the phospholipid membrane provided by the ordering effect of sterols. Comparable action of ergosterol is observed at concentrations 2.5-fold lower than cholesterol and attributed to a preferential interaction of natamycin-ergosterol as well as a higher control of membrane permeability. Fine-tuning of sterol concentration allows preparation of liposomal suspensions presenting modulated in vitro release kinetics rates and enhanced antifungal activity against the model yeast Saccharomyces cerevisiae. PMID- 26009273 TI - Untethered magnetic millirobot for targeted drug delivery. AB - This paper reports the design and development of a novel millimeter-sized robotic system for targeted therapy. The proposed medical robot is conceived to perform therapy in relatively small diameter body canals (spine, urinary system, ovary, etc.), and to release several kinds of therapeutics, depending on the pathology to be treated. The robot is a nearly-buoyant bi-component system consisting of a carrier, in which the therapeutic agent is embedded, and a piston. The piston, by exploiting magnetic effects, docks with the carrier and compresses a drug-loaded hydrogel, thus activating the release mechanism. External magnetic fields are exploited to propel the robot towards the target region, while intermagnetic forces are exploited to trigger drug release. After designing and fabricating the robot, the system has been tested in vitro with an anticancer drug (doxorubicin) embedded in the carrier. The efficiency of the drug release mechanism has been demonstrated by both quantifying the amount of drug released and by assessing the efficacy of this therapeutic procedure on human bladder cancer cells. PMID- 26009274 TI - Separation and assisted patterning of hippocampal neurons from glial cells using positive dielectrophoresis. AB - In this work, we describe the separation of embryonic mouse hippocampal neurons from glial cells using a positive dielectrophoresis (DEP) process. Here, we have implemented a cell trapping-favorable, cell suspension solution with low conductivity. It enables positive dielectrophoresis for hippocampal neurons (thereby attracting them to the electrodes), while resulting in negative dielectrophoresis for glial cells (repelling them from the electrodes). We have systematically performed a mathematical simulation and analysis to anticipate the DEP frequency at which hippocampal neurons and glial cells are separated. Simulated DEP crossover frequencies have been experimentally verified, and new, refined glial dielectric and physical properties are suggested that better reflect the experimental results obtained. DEP movements of neurons and glial cells in targeted separation media were experimentally analyzed, under the specified electric signal. Additionally, we have confirmed our modeling results by selectively trapping neurons over electrodes on a custom-made, multi-electrode array (MEA), resulting in active recruitment of neurons over the stimulation and recording sites. This technique is a valuable addition to the toolbox for creating more functional and versatile multi-electrode arrays. PMID- 26009275 TI - A microneedle-based method for the characterization of diffusion in skin tissue using doxorubicin as a model drug. AB - Hollow microneedles can overcome the stratum corneum (SC) barrier and deposit a compound directly into the viable epidermis or the dermis, unlike adhesive patches that rely on drug diffusion across the SC. The traditional one dimensional methods used to study the diffusivity of drugs across the skin layers are not very accurate for hollow microneedles, since the ejection of compounds out of microneedle lumens resembles a point-source spreading in all directions and is highly dependent on injection depth. This paper presents a technique that is useful for studying drug injection using hollow microneedles at various depths below the SC. This technique uses confocal microscopy to image the distribution of a fluorescent compound in the skin after injection. The fluorescence distribution in the skin is observed over time and applied to a spherical Gaussian diffusion model for limited source diffusion to determine the diffusion coefficient of the compound in the skin. Applied to freshly excised pig skin, the diffusion coefficient for the anti-cancer drug doxorubicin was measured as 4.61 * 10(-9) cm(2)/s, while the diffusion coefficient in previously refrigerated or frozen pig skin was 1.31 * 10(-8) cm(2)/s and 4.21 * 10(-8) cm(2)/s, respectively. Our data suggests that skin storage conditions can substantially alter the diffusion of drugs. The use of refrigerated and, even more so, previously frozen skin should be avoided for quantitative transdermal drug delivery studies. PMID- 26009276 TI - Adolescent Endometriosis. PMID- 26009277 TI - Robotic-assisted Laparoscopic Management of Chemoresistant Myoinvasive Complete Molar Pregnancy. AB - Postmolar malignant conditions are rare after evacuation of a complete molar pregnancy. Both medical and surgical management have a role in the treatment of persistent gestational trophoblastic neoplasia. Treatment decisions must account for the natural history of the disease, previous therapies, site of disease, and the patient's desire for uterine preservation. We report on a woman who presented with chemotherapy-refractory persistent gestational trophoblastic disease (GTD). She was found to have isolated, persistent trophoblastic tissue within the uterine myometrium. She underwent a robotic-assisted laparoscopic hysterectomy with curative results. Minimally invasive surgical management may be an option for treatment of women with isolated myoinvasive GTD. PMID- 26009278 TI - Total Vaginal NOTES Hysterectomy: A New Approach to Hysterectomy. AB - The aim of this study was to demonstrate the feasibility of a total hysterectomy performed entirely by transvaginal natural orifice transluminal endoscopic surgery (vNOTES). Conventional, reusable laparoscopic instruments were used, inserted through an inexpensive, self-constructed single-port device. Ten total vaginal NOTES hysterectomies (TVNHs) were performed by a single surgeon. The self constructed single-port device was made by assembling a surgical glove, a wound protector or modified laryngeal mask airway, 1 reusable 10-mm trocar, and 4 reusable 5-mm trocars. This gloveport was inserted into the vagina to create a pneumovagina. The conventional steps of a vaginal hysterectomy were followed, but performed endoscopically with standard reusable endoscopic instruments. The patient and perioperative data were analyzed. No conversion to standard laparoscopy or laparotomy was necessary in any of the 10 patients who underwent a TVNH. Mean operation time was 97 min (range: 60-120); mean drop in hemoglobin level was 1.5 g/dL (range: 0.5-2.4). There were no operative complications, and postoperative pain scores were very low. This first report on a small number of patients demonstrates that TVNH is possible. By incorporating the advantages of endoscopic surgery, TVNH broadens the indications for vaginal hysterectomy and helps overcome its limitations. At the same time, the NOTES approach avoids abdominal wall wounds and trocar-related complications. TVNH is feasible, even when performed with reusable, conventional laparoscopic instruments. This frugally innovative technique also enables surgeons to perform hysterectomies by vNOTES in low resource settings. PMID- 26009279 TI - A high pressure study of the eigenvectors of the infra-red active vibrational modes of crystalline adenosine. AB - High-pressure infrared spectroscopy has been used to study the eigenvectors and eigenvalues of the vibrational modes of crystalline adenosine at 298 K by evaluating the logarithmic derivative of the vibrational frequency with respect to pressure: [Formula: see text]. Crystalline samples of molecular materials such as adenosine have vibrational modes that are localized within a molecular unit ("internal" modes) as well as modes in which the molecular units vibrate against each other ("external" modes). The value of the logarithmic derivative is that it is a diagnostic probe of the nature of the eigenvector of these vibrational modes. Stretching modes, which are predominantly internal to the molecule, have low logarithmic derivatives while external modes have higher logarithmic derivatives. Particular attention is paid to modes in the 800-1000 cm(-1) range since modes in that region of the vibrational spectrum are found to be sensitive to the conformation of double-helical DNA. Since the sugar pucker is different for the various conformations of DNA, this fact suggests that these modes involve the motion of atoms in the sugar group. The vibrations of the hydrogen atoms are also of interest to study since the vibrational frequency of hydrogen atoms involved in hydrogen bonds has a negative pressure derivative. Such behavior clearly shows which hydrogen atoms are involved in hydrogen bonding. PMID- 26009280 TI - The Chaperone Activity of the Developmental Small Heat Shock Protein Sip1 Is Regulated by pH-Dependent Conformational Changes. AB - Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the aggregation of unfolding proteins during proteotoxic stress. In Caenorhabditis elegans, Sip1 is the only sHsp exclusively expressed in oocytes and embryos. Here, we demonstrate that Sip1 is essential for heat shock survival of reproducing adults and embryos. X-ray crystallography and electron microscopy revealed that Sip1 exists in a range of well-defined globular assemblies consisting of two half-spheres, each made of dimeric "spokes." Strikingly, the oligomeric distribution of Sip1 as well as its chaperone activity depend on pH, with a trend toward smaller species and higher activity at acidic conditions such as present in nematode eggs. The analysis of the interactome shows that Sip1 has a specific substrate spectrum including proteins that are essential for embryo development. PMID- 26009281 TI - Gene expression profiling of diffuse large B-Cell lymphomas supervised by CD5 expression. AB - CD5-positive (CD5(+)) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5(+) DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5(+) DLBCL and 57 CD5-negative (CD5(-)) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B cell-like (GCB) DLBCLs. All cases of CD5(+) DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. Enriched GO categories in the CD5(+) ABC DLBCL signature gene set included multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. The present study, which includes the largest reported number of patients with CD5(+) DLBCL, confirmed that most CD5(+) DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5(+) DLBCL. Our CD5(+) ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5(+) DLBCL. PMID- 26009282 TI - High frequency of autonomous T-cell proliferation compatible with T-cell large granular lymphocytic leukemia in patients with cytopenia of unknown etiology. AB - Large granular lymphocytic leukemia/lymphoproliferative disorder (LGL-L/LPD) is a heterogeneous neoplastic disease of large granular lymphocytes and is a well known cause of cytopenias. We aimed to reveal the incidence of LGL-L/LPD in patients with cytopenia(s) of unknown etiology (CUE). Twenty-eight patients with CUE were investigated for LGL-L/LPD. T-cell LGL leukemia (LGL-L) was diagnosed in 12 (42.9 %) patients. The frequencies of LGL-L in patients who had anemia, neutropenia, and thrombocytopenia were 9/14 (64.2 %), 11/23 (47.8 %), and 3/10 (30 %), respectively. Seventeen of the 28 patients met the criteria of idiopathic cytopenia of undetermined significance (ICUS), and LGL-L was found in six (35.3 %) of them. We conclude that LGL-L is a rather common disease in patients with CUE and ICUS. It should be considered in this patient group and investigated thoroughly. PMID- 26009283 TI - Real-time investigation of cytochrome c release profiles in living neuronal cells undergoing amyloid beta oligomer-induced apoptosis. AB - Intracellular Cyt c release profiles in living human neuroblastoma undergoing amyloid beta oligomer (AbetaO)-induced apoptosis, as a model Alzheimer's disease associated pathogenic molecule, were analysed in a real-time manner using plasmon resonance energy transfer (PRET)-based spectroscopy. PMID- 26009284 TI - Balancing early extubation and rates of reintubation in cardiac surgical patients: where does the fulcrum lie? PMID- 26009285 TI - In-hospital mortality in cardiac surgery patients after readmission to the intensive care unit: a single-center experience with 10,992 patients. AB - OBJECTIVES: Determine if readmission to the intensive care unit (ICU) after cardiac surgery procedures is associated with increased mortality. DESIGN: This was a retrospective non-randomized study to evaluate the cause of readmission and mortality rate in patients readmitted to the ICU after cardiac surgery and to compare the clinical variables of patients readmitted to the ICU who died and those who survived. SETTING: The study was performed in a single university hospital. PARTICIPANTS: This was an analysis of 10,992 consecutive adult patients. Readmission rate to the ICU, mortality rate, the reason for readmission to the ICU, type of surgery, length of stay, cause of mortality, and day of the week of ICU readmission were analyzed. INTERVENTIONS: All patients underwent cardiac surgery at a single center and were discharged after primary stay from the ICU. MEASUREMENTS AND MAIN RESULTS: A total of 197 (1,8%) of 10,992 patients were readmitted to the ICU. In-hospital mortality rate for patients readmitted and not readmitted to the ICU was 23.9% and 4.7%, respectively. The main causes of ICU readmission were cardiac (40%) and respiratory (37%) complications. The mortality rate in readmitted patients who underwent coronary artery bypass graft (CABG) or valve surgery was 26% and 19%, respectively. CONCLUSIONS: Patient readmission to the ICU following cardiac surgery was associated with a 5-fold increase in hospital mortality rate compared to non-readmitted patients. The highest mortality rate was observed among readmitted patients who underwent CABG. Older age, previous myocardial infarction, and initial long length of stay in the post-operative ward were independent risk factors for death after readmission to the ICU. PMID- 26009286 TI - Percutaneous Coronary Sinus Catheterization With the ProPlege Catheter Under Transesophageal Echocardiography and Pressure Guidance. AB - OBJECTIVES: Percutaneous catheterization of the coronary sinus (CS) to enable the administration of retrograde cardioplegia may play an important role in minimally invasive cardiac surgery. A new specially designed device (ProPlege; Edwards Lifesciences, Irvine, CA) is described that can be placed under transesophageal echocardiography (TEE) and pressure guidance with a high rate of success and low rate of complications. DESIGN: Case series. SETTING: A university-affiliated private hospital. PARTICIPANTS: Patients undergoing minimally invasive cardiac surgery. INTERVENTIONS: The ProPlege device was placed under TEE and pressure guidance only. MEASUREMENTS AND MAIN RESULTS: Records of 70 patients managed with ProPlege were reviewed and analyzed. Successful placement was attained in 69 patients (98.6%) as confirmed by the ventricularization of the CS pressure curve and TEE images. Direct imaging of the ProPlege tip was possible in 34 patients (49.2%). The capacity to generate a CS pressure>30 mmHg during retrograde cardioplegia administration at a flow>150 mL/min was obtained in 64 patients; ProPlege displacement occurred in 5 cases (7.2%). Successful retrograde cardioplegia was delivered in 91.4% of cases. No CS perforation or other injuries to the right heart were noted at intraoperative TEE or direct surgical inspection. CONCLUSIONS: Percutaneous CS catheterization with ProPlege was performed with a high rate of success for positioning and low complication rate using TEE and pressure guidance only. Further studies are needed to more accurately determine complication rates and to establish the possible complementary role of fluoroscopy. PMID- 26009288 TI - Management of direct oral anticoagulants in the perioperative setting. PMID- 26009287 TI - Genetic Variants Associated With Atrial Fibrillation and PR Interval Following Cardiac Surgery. AB - OBJECTIVE: The authors hypothesized that genetic association between atrial fibrillation (AF)-associated and PR-associated genetic loci was biologically mediated through slower conduction velocities for some or all of these loci. DESIGN: Prospectively collected cohort study. SETTING: Single tertiary care university hospital. PARTICIPANTS: A total of 1227 Caucasian patients who underwent coronary artery bypass grafting (CABG). INTERVENTIONS: A total of 677 single nucleotide polymorphisms previously associated with ambulatory AF or PR interval were tested for association with postoperative atrial fibrillation (poAF) and preoperative PR interval, maximum PR interval, maximum change in PR interval, and maximum change in PR interval from preoperative PR interval. MEASUREMENTS AND MAIN RESULTS: The incidence of new-onset poAF was 31%. All of the PR interval variables were longer in the poAF cohort. Two variants on 1q21 and 12 on 4q25 were associated with poAF after adjustment for false discovery rate (FDR), but no variants were associated with PR interval variables after adjustment for FDR. Several variants were associated with both poAF and PR interval variables at p<0.05, but none of them remained significant after adjusting for FDR. CONCLUSION: It was found that patients with poAF have significantly longer PR interval. Genetic variants in both the 1q21 and 4q25 regions associate with poAF after CABG surgery, but the authors were unable to find association between these variants and PR interval after adjusting for FDR. PMID- 26009289 TI - Thresholds for Perioperative Administration of Hemostatic Blood Components and Coagulation Factor Concentrates: An Unmet Medical Need. PMID- 26009290 TI - Expanding the role of mobile devices in the operating room: direct wireless connection to the anesthesia monitor. PMID- 26009291 TI - Atrial fibrillation after cardiac surgery: clinical update on mechanisms and prophylactic strategies. PMID- 26009292 TI - Coronary sinus: a new imaging frontier. PMID- 26009293 TI - Autoimmunity: Altered antibody response to vaccination in patients with SLE. PMID- 26009294 TI - Rheumatoid arthritis: Clues to the HLA-RA connection from T-cell crossreactivity to vinculin and microorganisms. PMID- 26009295 TI - Association between maternal nutritional extremes and offspring mortality: A population-based cross-sectional study, Brazil, Demographic Health Survey 2006. AB - OBJECTIVE: to estimate the association between maternal nutritional extremes and offspring mortality in the Brazilian population. METHODS: this cross-sectional study used secondary data from Brazilian women of reproductive age obtained from the National Demographic and Health Survey 2006. Maternal anthropometric indices were used: height, body mass index (BMI), and waist circumference. Logistic regression modelling was used to evaluate the relationship between obesity and offspring mortality. The data analysis was appropriate for the complex sample design. RESULTS: children of mothers of short stature were at greater risk of death in the postnatal period than children of mothers of normal height, even after adjusting for sociodemographic characteristics [odds ratio (OR) 4.54, 95% confidence interval (CI) 1.31-15.77]. Maternal obesity was associated with mortality, and children whose mothers were abdominally obese were at greater risk of dying in the neonatal period (OR 3.19, 95% CI 1.23-8.27). Children of mothers who were overweight or obese (BMI>=25kg/m(2)) were at greater risk of dying in the neonatal period (OR 2.41, 95% CI 1.12-5.16), and children of malnourished mothers (BMI<18.5kg/m(2)) were at greater risk of dying during the postneonatal period (OR 9.47, 95% CI 2.07-43.41). CONCLUSION: maternal obesity is a risk factor for neonatal death, maternal malnutrition is a risk factor for postneonatal death, and maternal short stature is a risk factor for mortality among Brazilian children. PMID- 26009296 TI - Why water makes 2-aminopurine fluorescent? AB - 2-Aminopurine (2AP) is often chosen as a fluorescent replacement for purine bases and used as a probe in nucleic acid research. The luminescence of this molecule is strongly dependent on the environment. Through computational simulations of isolated 2AP and a series of 2AP-water clusters, we show that the experimentally observed dependence of the excited-state lifetime of 2AP on the number and location of water molecules is controlled by a barrier for internal conversion between the S1 minimum and a conical intersection. Other possible competing pathways (proton transfer, intersystem crossing, and internal conversion at other intersections) were also investigated but discarded. The tuning of the luminescence of 2AP by water is related to the order of the npi* and pipi* states. When a water molecule interacts with the amino group, the pathway from the S1 minimum to the conical intersection requires a nonadiabatic change, thus increasing the energy barrier for internal conversion. As a consequence, a single water molecule hydrogen-bonded to the amino group is sufficient to make 2AP fluorescent. PMID- 26009297 TI - Opening mechanism of adenylate kinase can vary according to selected molecular dynamics force field. AB - Adenylate kinase is a widely used test case for many conformational transition studies. It performs a large conformational transition between closed and open conformations while performing its catalytic function. To understand conformational transition mechanism and impact of force field choice on E. Coli adenylate kinase, we performed all-atom explicit solvent classical molecular dynamics simulations starting from the closed conformation with four commonly used force fields, namely, Amber99, Charmm27, Gromos53a6, Opls-aa. We carried out 40 simulations, each one 200 ns. We analyzed completely 12 of them that show full conformational transition from the closed state to the open one. Our study shows that different force fields can have a bias toward different transition pathways. Transition time scales, frequency of conformational transitions, order of domain motions and free energy landscapes of each force field may also vary. In general, Amber99 and Charmm27 behave similarly while Gromos53a6 results have a resemblance to the Opls-aa force field results. PMID- 26009298 TI - Marital status and work-related health limitation: a longitudinal study of young adult and middle-aged Americans. AB - OBJECTIVES: The literature establishes clearly the health benefit of marriage. Much less clear from published data is whether work-related health (dis)advantages accruing to marital transitions persist over time or are limited to the short term. Informed by the marital resources and marital crisis perspectives, this study sought links between marital status measured via three approaches and work-related health limitation, exploring these relationships across genders. METHODS: The study employed data from eight recent waves (1996 2010) of the National Longitudinal Survey of Youth. It applied generalized estimating equations to estimate the impacts, on work-related health limitation, of current marital status; of marital transition 2 years in the past; and of marital transition 8 years in the past. RESULTS: Our gender-specific results indicated that lower likelihood of work-related health limitation was associated with a married status, a stable married status, and an entry into marriage. CONCLUSIONS: Results are consistent overall with the marital resources perspective. The use of three different approaches to evaluate the relationship of marital status to work-related health limitation may explain the gender specific results. PMID- 26009299 TI - Does escitalopram reduce neurotoxicity in major depression? AB - A pro-inflammatory state and a dysregulation in the tryptophan/kynurenine pathway have been documented in depression. This study examined whether treatment with the SSRI, escitalopram (ESC), could suppress inflammation and favorably shift metabolites of the kynurenine pathway in patients with major depressive disorder (MDD) within the utilized treatment period. Twenty seven healthy control subjects were included for comparison. Thirty patients were enrolled after completing baseline assessments. They received a 12-week ESC monotherapy. Twenty subjects were completers. Clinical assessments were carried out at each visit using the HAM-D, HAM-A, CGI and BDI rating scales. Blood samples were collected at each assessment and stored until analyzed. Cytokines were analyzed with Randox multiplex assay and tryptophan and kynurenine metabolites were analyzed using HPLC/GCMS. Baseline plasma concentrations of hsCRP, TNFalpha, IL6 and MCP-1 were significantly higher in patients compared to healthy controls. IL10 trended toward an increase. Baseline plasma IL1beta correlated significantly with IL1alpha, and IL4. Patients showed significant improvement in all outcome measures with a high remission rate. Significant correlations were obtained between specific symptoms and certain biomarkers at baseline but these correlations must be viewed as very preliminary. During ESC treatment concentrations of inflammatory biomarkers did not change except for TNFalpha that trended lower. Metabolites and ratios of the tryptophan/kynurenine pathway showed reductions of the neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, 3-hydroxykynurenine/kynurenine, quinolinic acid/tryptophan, kynurenic acid/quinolinic acid and quinolinic acid/3-hydroxykynurenine. The results indicate that ESC may exert its antidepressant effect in part through inhibition of synthesis of certain neurotoxic kynurenine metabolites and possibly also through reduction of the inflammatory response, although there was no concordance in the time course of changes between antidepressant efficacy and reversal of the pro-inflammatory status. PMID- 26009301 TI - Surface-Enhanced Electrochemiluminescence of Ru@SiO2 for Ultrasensitive Detection of Carcinoembryonic Antigen. AB - Carcinoembryonic antigen (CEA) is recognized as a disease biomarker to reflect the existence of various cancers and tumors in the human body. Sensitive detection of CEA in body fluid is valuable for clinical diagnosis and treatment assessment of cancers. Herein, we present a new approach for ultrasensitive determination of CEA in human serum based on localized surface plasmon resonance (LSPR) enhanced electrochemiluminescence (ECL) of Ru(bpy)3(2+). In this surface enhanced ECL (SEECL) sensing scheme, Ru(bpy)3(2+)-doped SiO2 nanoparticles (Ru@SiO2) act as ECL luminophores, and AuNPs are used as LSPR source to enhance the ECL signal. Two different kinds of aptamers specific to CEA are modified on the surface of Ru@SiO2 and AuNPs, respectively. In the presence of CEA, a multilayer of Ru@SiO2-AuNPs nanoarchitectures would be formed. Our investigation reveals that the ECL signal of Ru@SiO2 can be effectively enhanced by AuNPs. One layer of Ru@SiO2-AuNPs nanoarchitectures would generate about 3-fold ECL enhancement compared with the ECL of the nanoarchitectures without the presence of AuNPs. As much as 30-fold ECL enhancement could be obtained by a multilayer of Ru@SiO2-AuNPs nanoarchitectures. Under the optimal conditions, a detection limit of 1.52 * 10(-6) ng/mL of CEA in human serum was achieved. To the best of our knowledge, CEA assays with such a low LOD have never been reported for an ECL sensor. PMID- 26009300 TI - Boosting in Elite Athletes with Spinal Cord Injury: A Critical Review of Physiology and Testing Procedures. AB - Many individuals with spinal cord injury (SCI) experience autonomic dysfunction, which can have major implications on heart rate and blood pressure responses to exercise, and consequently athletic performance. Athletic performance may be improved by the induction of autonomic dysreflexia ('boosting'), a dangerous and sometimes life-threatening condition. Here, we review the autonomic response to exercise in individuals with SCI and the current testing methods for boosting, and examine the potential for autonomic testing to be used in the classification of SCI athletes. Given the difficulties associated with researching the effects of boosting, only three studies have compared the physiological performance of elite athletes in the boosted and unboosted state. These studies found athletes had an improved performance of ~7 to 10% in the boosted state. Blood pressure, heart rate, oxygen consumption, and circulating catecholamines were also higher in the boosted state. Although 27.1% of athletes believe that boosting was common in their sport, no athlete has ever tested positive for boosting at an event sanctioned by the International Paralympic Committee. Athletes with SCI competing in sports that have a high cardiovascular demand/aerobic component may experience the greatest benefit of boosting. Boosting improves athletic performance even at blood pressure levels well below the current threshold for disqualification set by the International Paralympic Committee, a level at which individuals with SCI are putting their health and lives at serious risk. PMID- 26009302 TI - Methicillin-resistant Staphylococcus aureus (MRSA) is associated with low within herd prevalence of intra-mammary infections in dairy cows: Genotyping of isolates. AB - Staphylococcus aureus is one of the most common mastitis-causing pathogens worldwide. In the last decade, livestock-associated methicillin-resistant S. aureus (LA-MRSA) infections have been described in several species, included the bovines. Hence, this paper investigates the diffusion of MRSA within Italian dairy herds; the strains were further characterized using a DNA microarray, which detects 330 different sequences, including the methicillin-resistance genes mecA and mecC and SCCmec typing. The analysis of overall patterns allows the assignment to Clonal Complexes (CC). Overall 163 S. aureus isolates, collected from quarter milk samples in 61 herds, were tested. MRSA strains were further processed using spa typing. Fifteen strains (9.2%), isolated in 9 herds (14.75%), carried mecA, but none harboured mecC. MRSA detection was significantly associated (P<0.011) with a within-herd prevalence of S. aureus intra-mammary infections (IMI) <=5%. Ten MRSA strains were assigned to CC398, the remaining ones to CC97 (n=2), CC1 (n=2) or CC8 (n=1). In 3 herds, MRSA and MSSA co-existed: CC97-MRSA with CC398-MSSA, CC1-MRSA with CC8-MSSA and CC398-MRSA with CC126-MSSA. The results of spa typing showed an overall similar profile of the strains belonging to the same CC: t127-CC1, t1730-CC97, t899 in 8 out of 10 CC398. In the remaining 2 isolates a new spa type, t14644, was identified. The single CC8 was a t3092. The SCCmec cassettes were classified as type IV, type V or type IV/V composite. All or most strains harboured the genes encoding the beta-lactamase operon and the tetracycline resistance. Streptogramin resistance gene was related to CC398. Enterotoxin and leukocidin genes were carried only by CC1, CC8 and CC97 MRSA. The persistence of MRSA clones characterized by broader host range, in epidemiologically unrelated areas and in dairy herds with low prevalence of S. aureus IMI, might enhance the risk for adaptation to human species. PMID- 26009303 TI - Vaccine breaks: Outbreaks of myxomatosis on Spanish commercial rabbit farms. AB - Despite the success of vaccination against myxoma virus, myxomatosis remains a problem on rabbit farms throughout Spain and Europe. In this study we set out to evaluate possible causes of myxoma virus (MYXV) vaccine failures addressing key issues with regard to pathogen, vaccine and vaccination strategies. This was done by genetically characterising MYXV field isolates from farm outbreaks, selecting a representative strain for which to assay its virulence and measuring the protective capability of a commercial vaccine against this strain. Finally, we compare methods (route) of vaccine administration under farm conditions and evaluate immune response in vaccinated rabbits. The data presented here show that the vaccine tested is capable of eliciting protection in rabbits that show high levels of seroconversion. However, the number of animals failing to seroconvert following subcutaneous vaccination may leave a large number of rabbits unprotected following vaccine administration. Successful vaccination requires the strict implication of workable, planned, on farm programs. Following this, analysis to confirm seroconversion rates may be advisable. Factors such as the wild rabbit reservoir, control of biting insects and good hygienic practices must be taken into consideration to prevent vaccine failures from occurring. PMID- 26009304 TI - Truce-Smiles rearrangement of substituted phenyl ethers. AB - The requirement of aryl ring activation by strong-electron withdrawing substituents in substrates for the intramolecular nucleophilic aromatic substitution reaction known as the Truce-Smiles rearrangement was examined. Preliminary mechanistic experiments support the SNAr mechanism, including (1)H and (13)C NMR spectra of a Meisenheimer intermediate formed in situ. The rearrangement was generally observed to be successful for substrates with strong electron withdrawing substituents, such as nitro-, cyano-, and benzoyl- functional groups, but also for those with multiple, weakly electron withdrawing substituents, such as chloro- and bromo-functional groups. These results lend further clarification to the effect of aryl substituents in this type of SNAr reaction. Additionally, the survey revealed several tandem cyclization and/or elimination reactions accessed by certain substrates. PMID- 26009307 TI - How to compare the oncological safety of oncoplastic breast conservation surgery To wide local excision or mastectomy? AB - BACKGROUND: Comparative studies suggest that patients treated with oncoplastic breast conservation surgery (OBCS) have similar pathology to patients treated with wide local excision (WLE). However, patients treated with OBCS have never been compared to patients treated with mastectomy. The aim of this study was to identify which control group was comparable to patients undergoing OBCS. METHODS: Commonly reported histopathological variables of patients treated with OBCS, WLE or mastectomy +/- immediate reconstruction (Ms +/- IR) were compared using Fisher Exact or Chi squared tests. RESULTS: 1000 patients' data were analysed (OBCS: n = 119; WLE: n = 600; Ms +/- IR: n = 281). Tumour size was significantly bigger after OBCS than WLE (p < 0.001), but similar to Ms +/- IR (p = 0.138). Tumour grade was higher after OBCS than WLE (p < 0.001), but similar to Ms +/- IR (p = 0.497). More axillary nodes were involved in patients with OBCS than WLE (p < 0.001), but comparable to Ms +/- IR (p = 0.175). ER and PR expressions were lower after OBCS compared to WLE (p = 0.007, p = 0.009), but identical to Ms +/- IR (p = 1, p = 0.904 respectively). Differences in application of systemic (neo)adjuvant therapy followed the above trend. CONCLUSION: Striking similarities found between OBCS and mastectomy patients' histopathological results are in sharp contrast with previously published data. This study suggests that oncological outcomes following OBCS should be compared to mastectomy besides WLE. PMID- 26009308 TI - Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is immunohistochemically characterised by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). TNBC is known for its poor prognosis and high recurrence probability. There is no effective targeted treatment for TNBC, but only adjuvant chemotherapies. There are two TNBC subtypes, basal-like and non-basal-like, which are defined based on positive cytokeratin (CK) 5/6 and/or epidermal growth factor receptor (EGFR) expression. In particular, CK5/6 expression is reported to correlate with TNBC recurrence. TNBC lacks ER-alpha expression, but some TNBCs are known to express the androgen receptor (AR). Moreover, although p53 accumulation is detected in various malignant tumors, its influence on adjuvant chemotherapy for patients with TNBC remains unclear. The aim of this study was to assess the combined immunohistochemical expression of CK 5/6, AR, and p53 as a potential prognostic marker of adjuvant chemotherapy for patients with TNBC. The expression of CK5/6, AR, and p53 in formalin-fixed and paraffin-embedded (FFPE) surgical sections from 52 patients with TNBC was analysed by immunohistochemistry (IHC) and the co expression patterns in individual cells were investigated by immunofluorescent (IF) staining. Low AR expression was correlated with high clinical stage (P < 0.05) and low nuclear grade (P < 0.05). The expression of CK5/6 and p53 did not correlate with clinicopathological features. Patients who needed adjuvant chemotherapy presented the worst prognosis. In particular, when the IHC expression pattern was CK5/6 (-), AR (-), and p53 (+), the disease free survival (DFS) and overall survival (OS) were the worst. On the other hand, patients with AR (+) and p53 (-) TNBC presented a good prognosis. The analysis of the co expression status of these three markers showed that no cells presented both AR and CK5/6 expression. Furthermore, TP53 mRNA expression was higher in patients with AR-negative TNBC (P < 0.05) and in patients with the worst prognosis (P < 0.05) than in the other patients. These results suggested that, in patients with CK5/6-negative TNBC, AR expression correlated with good prognosis, but p53 accumulation correlated with poor prognosis. The present IHC markers allowed us to predict the post-surgery prognosis of patients with TNBC. In conclusion, TNBCs are heterogeneous. Patients with the CK5/6 (-), AR (-), and p53 (+) TNBC subtype, evaluated by IHC, presented the worst prognosis. These IHC markers will be helpful to follow patients with TNBC. PMID- 26009309 TI - Elevated expression of the retinoic acid-metabolizing enzyme CYP26C1 in primary breast carcinomas. AB - Retinoic acid (RA)-metabolizing enzyme CYP26A1 has been shown to have increased expression levels in breast cancers and to effectively promote the survival of breast carcinoma cells, implying a potential oncogenic function. However, the expression of CYP26C1, another CYP26 family member, in primary breast carcinoma remains to be clarified. In the present study, we examined the expression of CYP26C1 by immunohistochemistry, using three different types of microarray, and observed strong cytoplasmic staining of CYP26C1 in 73 of the 219 (33.3 %) breast carcinomas. In contrast, CYP26C1 was not expressed in normal ductal and lobular cells in non-neoplastic tissue. Interestingly, increased expression of CYP26C1 was significantly associated with a high Ki-67 labeling index and a grade of tumor. However, CYP26C1 immunoreactivity was not associated with clinicopathological variables, including primary tumor status, lymph node involvement, distant metastasis, and tumor stage. In addition, CYP26C1 positivity was independent of the expression status of the hormone receptors and immunohistochemical surrogates for the intrinsic subtypes of breast cancer. This report is the first to demonstrate elevated expression of CYP26C1 in primary breast carcinomas. Based on the RA-catabolizing activity of CYP26C1, our data suggest that CYP26C1 expression may contribute to neoplasia in the breast. PMID- 26009310 TI - Children who are exposed to intimate partner violence: Interviewing mothers to understand its impact on children. AB - Children's victimization related to intimate partner violence (IPV) has damaging effects on their well-being and development. The purpose of this research was to assess the impact of IPV on children's emotional and behavioral problems through their mothers' narratives. A total of 30 Spanish mothers (mean age=41.57 years, SD=8.54 years) were individually interviewed. The results showed that many of the children directly suffered from aggression, and most of them witnessed IPV. As a result of their exposure to violence, children often develop psychological, social, and school problems. Their learning of aggressive behaviors is especially remarkable, and these behaviors are sometimes directed towards their mothers. Thus, women can suffer a twofold victimization: by their partner and by their children. These additional problems contribute to hindering the recovery process of victims. Fortunately, not all children develop problems as a result of exposure to IPV; some of them are capable of mature responses. PMID- 26009311 TI - Assessing anxiety and depression with respect to the quality of life in cancer inpatients receiving palliative care. AB - PURPOSE: The study aimed at assessing the presence of anxiety and depression in cancer inpatients receiving palliative care at an oncology department using the Hospital Anxiety and Depression Scale (HADS) and determining whether anxiety and depression contribute to a lower quality of life controlled for pain and illness severity. METHOD: This cross-sectional study comprised 225 advanced cancer inpatients (a mean age of 65.1 years). Data were collected with the HADS, EORTC QLQ-C30 and Karnofsky Performance Status scale. RESULTS: Anxiety (HADS-a >=8) was found in 33.9% and depression (HADS-d >=8) in 47.6% of patients. Higher anxiety scores were observed in patients living with a partner (p = 0.042) and non religious patients (p = 0.045). Correlations were found between anxiety, depression and all quality of life dimensions (r = 0.31-0.63). Multiple regression analysis showed that anxiety and depression contribute to lower physical and emotional functioning. Patients with anxiety (HADS-a >=8) and depression (HADS-d >=8) reported a lower total quality of life (p < 0.01). CONCLUSION: Management of anxiety and depression in cancer patients receiving palliative care may contribute to improvement in certain quality of life dimensions. PMID- 26009313 TI - Hydrophobic monolayered nanoflakes of tungsten oxide: coupled exfoliation and fracture in a nonpolar organic medium. AB - Coupled exfoliation and fracture induced formation of hydrophobic monolayered nanoflakes in a nonpolar organic medium. The hydrophobic monolayered nanoflakes 5 20 nm in lateral size consisted of a tungstate layer with surface modification by stearylammonium ions (C18H37NH3)0.397 H0.603Cs3W11O35.xH2O (x < 0.625). PMID- 26009312 TI - Is the link between posttraumatic growth and anxious symptoms mediated by marital intimacy in breast cancer patients? AB - PURPOSE: This study aimed to determine whether marital intimacy mediates the association between posttraumatic growth (PTG) and anxious symptoms in women who had recently completed breast cancer treatments and breast cancer survivors. METHODS: Forty-eight patients who had completed their treatment six months prior to the study and 46 disease-free survivors who had completed their treatments at least one year prior to the study completed the Posttraumatic Growth Inventory, the Personal Assessment of Intimacy Scale, and the Hospital Anxiety and Depression Scale. RESULTS: Recently off-treatment patients reported higher levels of intimacy than survivors did. Path analyses showed that higher levels of the Appreciation of Life dimension of PTG were associated with less anxious symptoms through higher levels of marital intimacy. The type of group did not moderate these associations. CONCLUSION: Regardless of the disease phase, the experience of positive changes after breast cancer in terms of an enhanced appreciation of life seems to be associated with an increased perception of intimacy in the context of a dyadic relationship, which, in turn, is associated with less anxiety. PMID- 26009314 TI - Evaluation of Human Exposure to metals from some popular brands of underarm cosmetics in Nigeria. AB - The concentrations of metals (Cd, Pb, Ni, Cr, Cu, Co, Fe, Mn, Zn and Al) were determined in thirty brands of popular of underarm cosmetics in Nigeria with a view to providing information on the levels of metals and the risk of exposure to metals by humans through long time usage of these products. The concentrations of metals in these samples of underarm cosmetics were measured by using atomic absorption spectrometry after acid digestion. The concentrations of metals in these types of underarm cosmetics studied ranged from <0.15 to 1.2 MUg g(-1)Cd, <0.02 to 11.2 MUg g(-1)Pb, <0.03 to 4.9 MUg g(-1)Ni, <0.1 to 25.0 MUg g(-1), <0.02 to 2.8 MUg g(-1)Co, 2.0 to 6.4 MUg g(-1)Cu, 4.7 to 91.2 MUg g(-1)Fe, <0.05 to 14.1 MUg g(-1)Mn, 77.9 to 132 MUg g(-1) and 69.2 to 83,500 MUg g(-1)Al. The results of this study indicate that Cd, Pb, Ni, Cr and Co were presents in these types of underarm cosmetics at concentrations below the regulatory control limits for metal impurities in color additives for cosmetics and suggested limits following good manufacturing practice. The estimated margin of safety (MoS) indicated that the concentrations of the examined metals in these underarm cosmetic products present no potential risk to the users. The continuous use of these brands of underarm cosmetics represents a potential source of human exposure to metals such as aluminum in the local area of the breast, particularly to the upper outer quadrant. PMID- 26009315 TI - Using Annual Data to Estimate the Public Health Impact of Extreme Temperatures. AB - Short-term associations between both hot and cold ambient temperatures and higher mortality have been found worldwide. Few studies have examined these associations on longer time scales. Age-standardized mortality rates (ASMRs) were calculated for 1976-2012 for Hong Kong SAR, People's Republic of China, defining "annual" time periods in 2 ways: from May through April of the following year and from November through October. Annual frequency and severity of extreme temperatures were summarized by using a degree-days approach with extreme heat expressed as annual degree-days >29.3 degrees C and cold as annual degree-days <27.5 degrees C. For example, a day with a mean temperature of 25.0 degrees C contributes 2.5 cold degree-days to the annual total. Generalized additive models were used to estimate the association between annual hot and cold degree-days and the ASMR, with adjustment for long-term trends. Increases of 10 hot or 200 cold degree-days in an annual period, the approximate interquartile ranges for these variables, were significantly (all P's <= 0.011) associated with 1.9% or 3.1% increases, respectively, in the annual ASMR for the May-April analyses and with 2.2% or 2.8% increases, respectively, in the November-October analyses. Associations were stronger for noncancer and elderly mortality. Mortality increases associated with extreme temperature are not simply due to short-term forward displacement of deaths that would have occurred anyway within a few weeks. PMID- 26009468 TI - Hospital Length of Stay following Primary Total Knee Arthroplasty: Data from the Nationwide Inpatient Sample Database. AB - Demand and cost of total knee arthroplasty (TKA) has increased significantly over the past decade resulting in decreased hospital length of stay (LOS) to counterbalance increasing cost of health care. The purpose of this study was to determine the factors that influence LOS following primary TKA. Discharge data from the 2009-2011 Nationwide Inpatient Sample were used. Patients included underwent primary TKA and were grouped based on LOS; 3 days or less, and 4 days or more. Majority of patients had a hospital LOS of 3 or less (74.8%). The most significant predictors of increased hospital LOS (>= 4 days) were age >= 80 years, Hispanic race, Medicaid payer status, lower median household income, weekend admission, rural non-teaching hospital, discharge to another facility and any complication. PMID- 26009470 TI - A Case-Control Study of Prenatal Thallium Exposure and Low Birth Weight in China. AB - BACKGROUND: Thallium (Tl) is a highly toxic heavy metal widely present in the environment. Case reports have suggested that maternal exposure to high levels of Tl during pregnancy is associated with low birth weight (LBW), but epidemiological data are limited. OBJECTIVES: This study was designed to evaluate whether prenatal Tl exposure is associated with an increased risk of LBW. METHODS: This case-control study involving 816 study participants (204 LBW cases and 612 matched controls) was conducted in Hubei Province, China, in 2012-2014. Tl concentrations were measured in maternal urine collected at delivery, and associations with LBW were evaluated using conditional logistic regression. RESULTS: Higher maternal urinary Tl levels were significantly associated with increased risk of LBW [crude odds ratio (OR) = 1.52; 95% CI: 1.00, 2.30 for the highest vs. lowest tertile], and the association was similarly elevated after adjustment for potential confounders (adjusted OR = 1.90; 95% CI: 1.01, 3.58 for the highest vs. lowest tertile). Stratified analyses showed slightly higher risk estimates for LBW associated with higher Tl levels for mothers < 28 years old and for mothers with lower household income; however, there was no statistical evidence of heterogeneity in risk according to maternal age (p for heterogeneity = 0.18) or household income (p for heterogeneity = 0.28). CONCLUSION: To our knowledge, ours is the first case-control study to investigate the association between prenatal Tl exposure and LBW. The results suggest that prenatal exposure to high levels of Tl may be associated with an increased risk of LBW. CITATION: Xia W, Du X, Zheng T, Zhang B, Li Y, Bassig BA, Zhou A, Wang Y, Xiong C, Li Z, Yao Y, Hu J, Zhou Y, Liu J, Xue W, Ma Y, Pan X, Peng Y, Xu S. 2016. A case control study of prenatal thallium exposure and low birth weight in China. Environ Health Perspect 124:164-169; http://dx.doi.org/10.1289/ehp.1409202. PMID- 26009471 TI - Enhancing Cryptosporidium parvum recovery rates for improved water monitoring. AB - Water monitoring is essential to ensure safe drinking water for consumers. However existing methods have several drawbacks, particularly with regard to the poor recovery of Cryptosporidium due to the inability to efficiently elute Cryptosporidium oocysts during the established detection process used by water utilities. Thus the development of new inexpensive materials that could be incorporated into the concentration and release stage that would control Cryptosporidium oocysts adhesion would be beneficial. Here we describe improved filter performance following dip-coating of the filters with a "bioactive" polyacrylate. Specifically 69% more oocysts were eluted from the filter which had been coated with a polymer than on the naked filter alone. PMID- 26009469 TI - Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti Apoptotic Bcl-2 Proteins. AB - Viral homologs of the anti-apoptotic Bcl-2 proteins are highly diverged from their mammalian counterparts, yet they perform overlapping functions by binding and inhibiting BH3 (Bcl-2 homology 3)-motif-containing proteins. We investigated the BH3 binding properties of the herpesvirus Bcl-2 homologs KSBcl-2, BHRF1, and M11, as they relate to those of the human Bcl-2 homologs Mcl-1, Bfl-1, Bcl-w, Bcl xL, and Bcl-2. Analysis of the sequence and structure of the BH3 binding grooves showed that, despite low sequence identity, M11 has structural similarities to Bcl-xL, Bcl-2, and Bcl-w. BHRF1 and KSBcl-2 are more structurally similar to Mcl 1 than to the other human proteins. Binding to human BH3-like peptides showed that KSBcl-2 has similar specificity to Mcl-1, and BHRF1 has a restricted binding profile; M11 binding preferences are distinct from those of Bcl-xL, Bcl-2, and Bcl-w. Because KSBcl-2 and BHRF1 are from human herpesviruses associated with malignancies, we screened computationally designed BH3 peptide libraries using bacterial surface display to identify selective binders of KSBcl-2 or BHRF1. The resulting peptides bound to KSBcl-2 and BHRF1 in preference to Bfl-1, Bcl-w, Bcl xL, and Bcl-2 but showed only modest specificity over Mcl-1. Rational mutagenesis increased specificity against Mcl-1, resulting in a peptide with a dissociation constant of 2.9nM for binding to KSBcl-2 and >1000-fold specificity over other Bcl-2 proteins, as well as a peptide with >70-fold specificity for BHRF1. In addition to providing new insights into viral Bcl-2 binding specificity, this study will inform future work analyzing the interaction properties of homologous binding domains and designing specific protein interaction partners. PMID- 26009472 TI - Ozone production efficiency of a ship-plume: ITCT 2K2 case study. AB - Ozone production efficiency (OPE) of ship plume was first evaluated in this study, based on ship-plume photochemical/dynamic model simulations and the ship plume composition data measured during the ITCT 2K2 (Intercontinental Transport and Chemical Transformation 2002) aircraft campaign. The averaged instantaneous OPEs (OPE(i)?) estimated via the ship-plume photochemical/dynamic modeling for the ITCT 2K2 ship-plume ranged between 4.61 and 18.92, showing that the values vary with the extent of chemical evolution (or chemical stage) of the ship plume and the stability classes of the marine boundary layer (MBL). Together with OPE(i)?, the equivalent OPEs (OPE(e)?) for the entire ITCT 2K2 ship-plume were also estimated. The OPE(e)? values varied between 9.73 (for the stable MBL) and 12.73 (for the moderately stable MBL), which agreed well with the OPE(e)? of 12.85 estimated based on the ITCT 2K2 ship-plume observations. It was also found that both the model-simulated and observation-based OPE(e)? inside the ship-plume were 0.29-0.38 times smaller than the OPE(e)? calculated/measured outside the ITCT 2K2 ship-plume. Such low OPEs insides the ship plume were due to the high levels of NO and non-liner ship-plume photochemistry. Possible implications of this ship-plume OPE study in the global chemistry-transport modeling are also discussed. PMID- 26009473 TI - Hardwood biochar and manure co-application to a calcareous soil. AB - Biochar may affect the mineralization rate of labile organic C sources such as manures via microbial community shifts, and subsequently affect nutrient release. In order to ascertain the positive or negative priming effect of biochar on manure, dairy manure (2% by wt.) and a hardwood-based, fast pyrolysis biochar were applied (0%, 1%, 2%, and 10% by wt.) to a calcareous soil. Destructive sampling occurred at 1, 2, 3, 4, 6 and 12 months to monitor for changes in soil chemistry, water content, microbial respiration, bacterial populations, and microbial community structure. Overall results showed that increasing biochar application rate improved the soil water content, which may be beneficial in limited irrigation or rainfall areas. Biochar application increased soil organic C content and plant-available Fe and Mn, while a synergistic biochar-manure effect increased plant-available Zn. Compared to the other rates, the 10% biochar application lowered concentrations of NO3-N; effects appeared masked at lower biochar rates due to manure application. Over time, soil NO3-N increased likely due to manure N mineralization, yet soil NO3-N in the 10% biochar rate remained lower as compared to other treatments. In the presence of manure, only the 10% biochar application caused subtle microbial community structure shifts by increasing the relative amounts of two fatty acids associated with Gram-negative bacteria and decreasing Gram-positive bacterial fatty acids, each by ~1%. Our previous findings with biochar alone suggested an overall negative priming effect with increasing biochar application rates, yet when co-applied with manure the negative priming effect was eliminated. PMID- 26009474 TI - Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus. AB - Hepatitis C virus (HCV) infection is a disease that affects approximately 3% of the global population and requires new therapeutic agents without the inconvenience associated with current anti-HCV treatment. This paper reports on a study of a virtual screening and a molecular dynamics simulation of compounds derived from natural products from the Amazon region that are potentially effective against the NS3-4A enzyme of HCV, which plays an important role in the replication process of this virus. According to the results of the molecular docking calculations and subsequent consensual analysis, the best scored compounds showed interactions between hydrogen and residues of the catalytic triad as well as interactions with residues that guide ligands to the active site of the enzyme. They also showed stability in the molecular dynamics simulation, as the structures preserved important interactions at the active site of the enzyme. The root mean square deviation (RMSD) values were stabilized at the end of the simulation time. Such compounds are considered promising as novel therapies against HCV. PMID- 26009475 TI - Surgical treatment of popliteal venous aneurysms. AB - BACKGROUND: Popliteal venous aneurysms (PVAs) are rare; however, they can lead to pulmonary emboli (PEs) and death. The purpose of this study was to review our institutional management of PVA. METHODS: All patients with PVA undergoing intervention in our institution were identified over a 15-year period (1998 2013). A retrospective review including clinical presentation, modality of diagnosis, surgical treatment, 30-day morbidity and mortality, and follow-up are reported. RESULTS: Five male and 3 female patients with PVA were identified. Mean age was 38.6 years (range, 14-65). Five patients presented with PE; 1 developed PE while on anticoagulation. Two presented with lower extremity pain. Two patients had PVA found incidentally. Diagnosis of PVA was made by duplex ultrasound (US) in 6 patients, physical examination confirmed with duplex US in 1 patient, and magnetic resonance imaging in 1 patient. Mean aneurysm size was 26 mm (range, 20-37). Four were saccular and 4 fusiform. Three PVAs contained thrombus, including 2 patients presenting with PE and 1 with calf pain. Five patients underwent aneurysmectomy with lateral venorrhaphy, and 3 patients had resection of the aneurysm with interposition vein graft. There were no operative or 30-day mortalities. Two patients with vein grafts had early postoperative complications; one developed a hematoma that required operative evacuation and one had thrombosis of the vein graft requiring thrombolysis. Mean follow-up was 26 months with 87.5% primary patency, 100% secondary patency, and no recurrences. CONCLUSIONS: PVAs are rare, but can lead to significant morbidity and death. Based on this small group, aneurysmectomy with lateral venorrhaphy appears to have fewer complications compared with those treated with vein grafts. Overall, operative repair of PVA is safe and recommended in select patients with PVA. PMID- 26009476 TI - Re: mycotic abdominal aortic aneurysm caused by campylobacter fetus: a case report and literature review. PMID- 26009477 TI - Secondary interventions after endovascular repair of aortic dissections. AB - BACKGROUND: Review the literature on secondary interventions performed for patients who underwent endovascular repair of their type B aortic dissection. Endovascular repair for type B aortic dissection (TBAD) has been proven to be both technically feasible and beneficial in some patients. However, the information regarding secondary interventions is not cohesive. To date, there are little data to help guide physicians on the indications and benefits of secondary interventions in the setting of previous endovascular repair for TBAD. METHODS: PubMed database was queried for publications using the following combination of keywords; "aortic dissection," "type B," "secondary intervention," "false lumen thrombosis," "stent graft," "aortic remodeling," and endovascular repair. Sixteen articles were selected and reviewed for secondary interventions, indications for procedure, and effects on false lumen thrombosis. Data were collected, and a composite database of patients was created. RESULTS: Literature review demonstrated 161 of 862 patients required secondary interventions for entry tears, retrograde type A dissection, false lumen degeneration with aortic expansion, graft malfunction, and various access complications. The complete false lumen thrombosis rate was 33%, and overall mortality was 18.2%. CONCLUSIONS: Secondary interventions provide a useful adjunct to failing endovascular repair of aortic dissections. A variety of treatment options are available for aneurysmal degeneration after thoracic endovascular aneurysm repair. This review also shows that these secondary interventions, in combination with proper surveillance and optimal medical management, are feasible but carry a high all-cause mortality. PMID- 26009478 TI - Impact of duplex ultrasound surveillance program on patency of prosthetic arteriovenous graft for hemodialysis: a single-center experience. AB - BACKGROUND: Arteriovenous prosthetic graft (AVG) is an alternative hemodialysis vascular access choice; however, its performance is limited by a high rate of thrombosis. The aim of the study was to compare the long-term secondary patency of AVG in patients undergoing a surveillance program and the long-term secondary patency of AVG in patients with clinical assessment of AVG malfunction. METHODS: From 2009 to 2012, all patients with AVG entered in a duplex ultrasound (DUS) surveillance program (at 3 months and then every 6 months postoperatively) to assess AVG malfunction and/or stenosis (stenosis >50% and blood flow decrease [<600 mL/min]) and eventually treated by endovascular revascularization. AVG long term patency in the surveillance group was compared with that obtained in a historical control group in which the malfunction was clinically detected. As secondary end point, the central vein catheter (CVC) placement after AVG thrombosis was compared in the 2 groups. RESULTS: Sixty patients were included in the study, 33 (55%) in the surveillance program and 27 (45%) in the historical group. The 2 groups had similar clinical characteristics and follow-up (59, interquartile range [IQR]: 45 vs. 56 [IQR, 40 months], P = 0.32). Fifteen (45%) AVG malfunctions were detected in the surveillance group and successfully treated (10 [66.6%] angioplasty and 5 [33.4%] angioplasty stenting). No malfunction was detected in the historical control group. By Kaplan-Meier analysis, the 5-year secondary patency was significantly higher in the surveillance group compared with the historical group: 42 +/- 13% vs. 9 +/- 7%, P = 0.03. By Cox analysis, the DUS surveillance was a significantly protective factor for AVG thrombosis, otherwise the use of CVC before the AVG and diabetes mellitus were AVG thrombosis risk factors. The CVC placement was significantly lower in the surveillance group compared with the historical group (14.0% vs. 42.2%, P = 0.02). CONCLUSIONS: The DUS surveillance allows a greater secondary patency compared with a clinical evaluation and reduces CVC placement rate. PMID- 26009479 TI - The efficacy of autologous femoropopliteal vein reconstruction for primary aortic and aortic graft infection. AB - BACKGROUND: The objective of our study was to analyze the efficacy of autologous superficial femoropopliteal vein reconstruction for primary aortic or aortic graft infection. METHODS: We performed a retrospective analysis of 14 patients treated for an infected aortic prosthesis or primary infected aorta between 2012 and 2014. Three patients had a primary mycotic aneurysm caused by a Salmonella or Coxiella burnetti infection. Seven patients were treated previously for aortic aneurysms with a conventional Dacron vascular prosthesis and 4 with an endovascular prosthesis. All infected prostheses were explanted via median laparotomy with subsequent debridement of the aortic aneurysm wall. Aortic reconstruction was performed with 1 or 2 superficial femoropopliteal veins, interpositioning the greater omentum when possible. The primary outcome measure was 30-day mortality. Secondary outcome measures were reoperation, operating time, amputation rate, length of intensive care unit (ICU) and hospital stay, reinfection rate, and limb edema requiring compression therapy. RESULTS: The 30 day mortality was 28%. Two patients died of an abdominal sepsis, one patient of a cerebrovascular accident and another of a hypovolemic shock. One patient died at home 2 years after surgery of unknown cause. Four patients required a reoperation. The median intraoperative blood loss was 1,500 mL (500-8000). Median operating time was 364 min (264-524). Median length of ICU stay was 3.5 days (1 47), and median hospital stay was 20 days (10-47). There were no limb amputations. Mild edema of the donor leg was documented in 2 patients. Compression stockings were not worn by any patients. Postoperative antibiotic treatment was administered for at least 6 weeks. No recurrent infections were diagnosed. CONCLUSIONS: Autologous venous reconstruction of the aorta offers advantages over other therapeutic approaches and deserves a prominent place in the treatment of the primary infected aorta or an infected aortic prosthetic graft. PMID- 26009481 TI - Clinical Neuropathology teaching case 4-2015: Heterogenous brain pathologies temporally and spatially coinciding in limbic regions. PMID- 26009480 TI - Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. AB - Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons) were detected in 28% of invasive ductal carcinomas as compared to only 12% of invasive lobular carcinomas and 8% of ductal carcinomas in situ (p = 0.0003). In invasive breast cancers, the presence of nerve fibers was observed in 15% of lymph node negative tumors and 28% of lymph node positive tumors (p = 0.0031), indicating a relationship with the metastatic potential. In addition, there was an association between the presence of nerve fibers and the expression of nerve growth factor (NGF) in cancer cells (p = 0.0001). In vitro, breast cancer cells were able to induce neurite outgrowth in PC12 cells, and this neurotrophic activity was partially inhibited by anti-NGF blocking antibodies. In conclusion, infiltration by nerve fibers is a feature of the tumor microenvironment that is associated with aggressiveness and involves NGF production by cancer cells. The potential participation of nerve fibers in breast cancer progression needs to be further considered. PMID- 26009482 TI - Anti-aquaporin 4 related paraneoplastic neuromyelitis optica in the presence of adenocarcinoma of the lung. PMID- 26009483 TI - Blood homocysteine level in patients with oral lichen planus. PMID- 26009484 TI - Low-normal serum potassium is associated with an increased risk of cardiovascular and all-cause death in community-based elderly. AB - BACKGROUND/PURPOSE: Several studies have already reported that serum potassium (SK) correlated inversely with adverse events among patients with preexisting cardiovascular disease and impaired renal function; less is known about the prognostic value of SK at the normal range in community-based elderly individuals. This study aimed to examine whether low normal SK value was associated with cardiovascular and all-cause mortalities in elderly people. METHODS: A prospective study was conducted using two independent elderly Taiwanese community cohorts that included 2065 individuals with relatively normal SK values (2.8-5.6 mmol/L). The participants were grouped as follows: low (2.8 3.4 mmol/L), low-normal SK (3.5-3.8 mmol/L), normal (3.9-4.4 mmol/L), and high normal SK (4.5-5.6 mmol/L). Proportional hazards model was applied to compare the association between SK concentration groups and mortality. RESULTS: The relationship between baseline SK and all-cause and cardiovascular mortality was U shaped, with the lowest mortality rates observed in patients with SK levels of 3.9-4.4 mmol/L. The low-normal SK group had significantly higher risks of all cause (hazard ratio, 1.3; 95% confidence interval, 1.0-1.6) and cardiovascular mortality (hazard ratio, 1.6; 95% confidence interval, 1.1-2.3) than the normal SK group. The high-normal SK group had higher but nonsignificant risk compared to the normal group. CONCLUSION: Our findings suggest that low-normal SK may be used as a marker of poor survival for elderly outpatient cares. PMID- 26009485 TI - Affordable health technology assessment in Taiwan: A model for middle-income countries. PMID- 26009486 TI - Investigation of potential artefactual changes in measurements of impedance changes during evoked activity: implications to electrical impedance tomography of brain function. AB - Electrical impedance tomography (EIT) could provide images of fast neural activity in the adult human brain with a resolution of 1 ms and 1 mm by imaging impedance changes which occur as ion channels open during neuronal depolarization. The largest changes occur at dc and decrease rapidly over 100 Hz. Evoked potentials occur in this bandwidth and may cause artefactual apparent impedance changes if altered by the impedance measuring current. These were characterized during the compound action potential in the walking leg nerves of Cancer pagurus, placed on Ag/AgCl hook electrodes, to identify how to avoid artefactual changes during brain EIT. Artefact-free impedance changes (deltaZ) decreased with frequency from -0.045 +/- 0.01% at 225 Hz to -0.02 +/- 0.01% at 1025 Hz (mean +/- 1 SD, n = 24 in 12 nerves) which matched changes predicted by a finite element model. Artefactual deltaZ reached c.300% and 50% of the genuine membrane impedance change at 225 Hz and 600 Hz respectively but decreased with frequency of the applied current and was negligible above 1 kHz. The proportional amplitude (deltaZ (%)) of the artefact did not vary significantly with the amplitude of injected current of 5-20 uA pp. but decreased significantly from 0.09 +/- 0.024 to -0.03 +/- 0.023% with phase of 0 to 45 degrees . For fast neural EIT of evoked activity in the brain, artefacts may arise with applied current of >10 uA. Independence of deltaZ with respect to phase but not the amplitude of applied current controls for them; they can be minimized by randomizing the phase of the applied measuring current and excluded by recording at >1 kHz. PMID- 26009487 TI - Effects of interleukin-6 on the bio-electric activity of rat atrial tissue under normal conditions and during gradual stretching. AB - Using the micro-electrode technique we studied the effects of interleukin-6 on bio-electric activity of rat atrial tissue under normal conditions and after gradual stretching. It was shown that IL-6 caused increasing of the duration of the action potential at the levels of 25, 50, and 90% re-polarization. The hump like depolarization at APD90 appeared 7-10 min after initial stretching and transformed into single extra-potentials after tension removing. Perfusion with IL-6 for more than 20 min led to the appearance of atrial fibrillation even with the application of slight tension. Close observation of the IL-6 induced mechanisms and stretch induced APD alteration, confirmed the existence of a tight link between examined cytokine and stretch induced mechanisms. PMID- 26009488 TI - Clnk plays a role in TNF-alpha-induced cell death in murine fibrosarcoma cell line L929. AB - Clnk, as a third member of the Blnk/SLP-76 adapter family, is involved in the positive regulation of immunoreceptor signaling. Here we provide findings that Clnk may be is required for TNF induced cell death, it functions downstream of RIP3 and promotes TNF- induced ROS generation and MLKL tetramer formation and subsequent necrosis of L929 cells. Therefore, Clnk, as an adaptor protein, may take part in the other cellular processes. PMID- 26009489 TI - [Diagnostic test scale SI5: Assessment of sacroiliac joint dysfunction]. AB - OBJECTIVE: Sacroiliac joint dysfunction is a known cause of low back pain. We think that a diagnostic score scale (SI5) may be performed to assess diagnostic utility of clinical signs of sacroiliac joint dysfunction. The primary aim of the present study was to conduct the pilot study of our new diagnostic score scale, the SI5, for sacroiliac joint syndrome. MATERIAL AND METHODS: We reviewed the literature on clinical characteristics, diagnostic tests and imaging most commonly used in diagnosing sacroiliac joint dysfunction. Our group evaluated the diagnostic utility of these aspects and we used those considered most representative to develop the SI5 diagnostic scale. The SI5 scale was applied to 22 patients with low back pain; afterwards, the standard test for diagnosing this pathology (selective blockage of the SI joint) was also performed on these patients. The sensitivity and specificity for each sign were also assessed and the diagnostic scale called SI5 was then proposed, based on these data. RESULTS: The most sensitive clinical tests for diagnosing SI joint dysfunction were 2 patient-reported clinical characteristics, the Laguerre Test, sacroiliac rocking test and Yeomans test (greater than 80% sensitivity). The tests with greatest diagnostic specificity (>80%) were the Lewitt test, Piedallu test and Gillet test. The proposed SI5 test score scale showed sensitivity of 73% and specificity of 71%. CONCLUSIONS: Sacroiliac joint syndrome has been shown to produce low back pain frequently; however, the diagnostic value of examination tests for sacroiliac joint pain has been questioned by other authors. The pilot study on the SI5 diagnostic score scale showed good sensitivity and specificity. However, the process of statistical validation of the SI5 needs to be continued. PMID- 26009490 TI - Signal-to-noise ratio and parallel imaging performance of commercially available phased array coils in 3.0 T brain magnetic resonance imaging. AB - The signal-to-noise ratio (SNR) and parallel imaging (PI) performance of two commercial phased-array coils (PACs) were examined in magnetic resonance imaging (MRI) of the brain. All measurements were performed on a 3.0 T MRI instrument. The SNR and PI performance were evaluated with 32-channel and 15-channel PACs. A gradient echo sequence was used for obtaining images of a phantom. SNR and geometry factor (g-factor) maps were calculated from two images with identical parameters. Horizontal and vertical profiles were taken through the SNR maps in the axial plane. The average g-factor was measured in a circular region of interest in the g-factor maps for the axial plane. The SNR map of the 32-channel coil showed a higher SNR than that of the 15-channel coil at the phantom's posterior and lateral surfaces. The SNR profiles for the 32-channel coil also showed a 1.3-fold increase at the phantom's center. The average g-factor of the 32-channel coil was lower than that of the 15-channel coil at the same acceleration factor. These results indicate that the 32-channel coil can provide a higher spatial resolution and/or a faster imaging speed. Horizontal and vertical profiles are useful for evaluation of the performance of commercially available PACs. PMID- 26009491 TI - IL-derived N, S co-doped ordered mesoporous carbon for high-performance oxygen reduction. AB - A highly efficient N, S co-doped porous carbon ORR catalyst was simply designed in our report from ordered mesoporous carbon (OMC) and trace ionic liquids (ILs). The microstructure OMC was chosen as the template for improving the specific area, confining the ILs in the mesopores, and promoting the formation of the planar N and S doping. The resulting IL/OMC (IOMC) nanostructure exhibits comparable ORR activity and better stability than the commercial Pt/C catalyst in 0.10 M KOH solution, which makes it one of the best-performing metal-free carbon ORR catalysts. We deduced that the excellent ORR activity is attributed to the synergistic effect of N, S, and the ordered mesoporous structure. Interestingly, the ORR activity can be further boosted in both basic and acidic solutions after Fe doping into the IOMC nanostructures which clearly emphasizes that transition metal Fe is important for the construction of ORR active functional sites especially in acidic solution. PMID- 26009493 TI - Early hematologic changes during prostate cancer radiotherapy predictive for late urinary and bowel toxicity. AB - BACKGROUND: The primary objective of the study was to identify early hematologic changes predictive for radiotherapy (RT)-associated genitourinary and gastrointestinal toxicity. METHODS: In a group of 91 prostate cancer patients presenting for primary (n = 51) or postoperative (n = 40) curative RT, blood samples (blood count, acute phase proteins, and cytokines) were analyzed before (T1), three times during (T2-T4), and 6-8 weeks after (T5) radiotherapy. Before RT (baseline), on the last day (acute toxicity), a median of 2 months and 16 months (late toxicity) after RT, patients responded to a validated questionnaire (Expanded Prostate Cancer Index Composite). Acute score changes > 20 points and late changes > 10 points were considered clinically relevant. RESULTS: Radiotherapy resulted in significant changes of hematologic parameters, with the largest effect on lymphocytes (mean decrease of 31-45 %) and significant dependence on target volume. C-reactive protein (CRP) elevation > 5 mg/l and hemoglobin level decrease >= 5 G/1 at T2 were found to be independently predictive for acute urinary toxicity (p < 0.01, respectively). CRP elevation was predominantly detected in primary prostate RT (p = 0.02). Early lymphocyte level elevation >= 0.3G/l at T2 was protective against late urinary and bowel toxicity (p = 0.02, respectively). Other significant predictive factors for late bowel toxicity were decreasing hemoglobin levels (cut-off >= 5 G/l) at T2 (p = 0.04); changes of TNF-alpha (tumor necrosis factor; p = 0.03) and ferritin levels (p = 0.02) at T5. All patients with late bowel toxicity had interleukin (IL)-6 levels < 1.5 ng/l at T2 (63 % without; p = 0.01). CONCLUSION: Early hematologic changes during prostate cancer radiotherapy are predictive for late urinary and bowel toxicity. PMID- 26009492 TI - Biomechanical evaluation of a novel suturing scheme for grafting load-bearing collagen scaffolds for rotator cuff repair. AB - BACKGROUND: Currently, there are no well-established suture protocols to attach fully load-bearing scaffolds which span tendon defects between bone and muscle for repair of critical sized tendon tears. Methods to attach load-bearing tissue repair scaffolds could enable functional repair of tendon injuries. METHODS: Sixteen rabbit shoulders were dissected (New Zealand white rabbits, 1yr. old, female) to isolate the humeral-infraspinatus muscle complex. A unique suture technique was developed to allow for a 5mm segmental defect in infraspinatus tendon to be replaced with a mechanically strong bioscaffold woven from pure collagen threads. The suturing pattern resulted in a fully load-bearing scaffold. The tensile stiffness and strength of scaffold repair were compared with intact infraspinatus and regular direct repair. FINDINGS: The failure load and displacement at failure of the scaffold repair group were 59.9N (standard deviation, SD=10.7) and 10.3mm (SD=2.9), respectively and matched those obtained by direct repair group which were 57.5N (SD=15.3) and 8.6mm (SD=1.5), (p>0.05). Failure load, displacement at failure and stiffness of both of the repair groups were half of the intact infraspinatus shoulder group. INTERPRETATION: With the developed suture technique, scaffold repair showed similar failure load, displacement at failure and stiffness to the direct repair. This novel suturing pattern and the mechanical robustness of the scaffold at time zero indicates that the proposed model is mechanically viable for future in vivo studies which has a higher potential to translate into clinical uses. PMID- 26009494 TI - Development of a metastatic murine colon cancer model. AB - BACKGROUND: It has now become clear that the complex interplay of cancer and the immune responses against it plays a critical role in the tumor microenvironment during cancer progression. As new targets for cancer treatment are being discovered and investigated, murine models used for preclinical studies need to include intact immune responses to provide a closer correlation with human cancer. We have recently developed a modified syngeneic orthotopic murine colon cancer model that mimics human colon cancer progression with consistent results. MATERIALS AND METHODS: Tumors were created using the murine colon adenocarcinoma cell line, CT26, modified to overexpress the firefly luciferase gene (CT26-luc1), which allowed real-time in vivo monitoring of tumor burden when the substrate, D luciferin, was injected intraperitoneally using the In Vivo Imaging System. Mice are Balb/c (Harlan), syngeneic with the CT26-luc1 cells. Cells are injected submucosally, suspended in Matrigel, into the cecum wall under direct visualization. RESULTS: The model has demonstrated consistent implantation in the cecum. In vivo bioluminescence allowed real-time monitoring of total tumor burden. Perioperative preparation had a significant impact on reproducibility of the model. Finally, total tumor burden quantified with bioluminescence enabled estimation of lymph node metastasis ex vivo. CONCLUSIONS: This method maintains an intact immune response and closely approximates the clinical tumor microenvironment. It is expected to provide an invaluable murine metastatic colon cancer model particularly in preclinical studies for drug development targeting those mechanisms. PMID- 26009495 TI - Scatter Reduction and Correction for Dual-Source Cone-Beam CT Using Prepatient Grids. AB - PURPOSE: Scatter significantly limits the application of the dual-source cone beam computed tomography by inducing scatter artifacts and degrading contrast-to noise ratio, Hounsfield-unit accuracy, and image uniformity. Although our previously developed interleaved acquisition mode addressed the cross scatter between the 2 X-ray sources, it doubles the scanning time and doesn't address the forward scatter issue. This study aims to develop a prepatient grid system to address both forward scatter and cross scatter in the dual-source cone-beam computed tomography. METHODS: Grids attached to both X-ray sources provide physical scatter reduction during the image acquisition. Image data were measured in the unblocked region, while both forward scatter and cross scatter were measured in the blocked region of the projection for postscan scatter correction. Complementary projections were acquired with grids at complementary locations and were merged to form complete projections for reconstruction. Experiments were conducted with different phantom sizes, grid blocking ratios, image acquisition modes, and reconstruction algorithms to investigate their effects on the scatter reduction and correction. The image quality improvement by the prepatient grids was evaluated both qualitatively through the artifact reduction and quantitatively through contrast-to-noise ratio, Hounsfield-unit accuracy, and uniformity using a CATphan 504 phantom. RESULTS: Scatter artifacts were reduced by scatter reduction and were removed by scatter correction method. Contrast-to noise ratio, Hounsfield-unit accuracy, and image uniformity were improved substantially. The simultaneous acquisition mode achieved comparable contrast-to noise ratio as the interleaved and sequential modes after scatter reduction and correction. Higher grid blocking ratio and smaller phantom size led to higher contrast-to-noise ratio for the simultaneous mode. The iterative reconstruction with total variation regularization was more effective than the Feldkamp, Davis, and Kress method in reducing noise caused by the scatter correction to enhance contrast-to-noise ratio. CONCLUSION: The prepatient grid system is effective in removing the scatter effects in the simultaneous acquisition mode of the dual source cone-beam computed tomography, which is useful for scanning time reduction or dual energy imaging. PMID- 26009496 TI - Effects of Oxymatrine on the Proliferation and Apoptosis of Human Hepatoma Carcinoma Cells. AB - Oxymatrine, one of the main active components of extracts from the dry roots of Sophora flavescens, has been reported to possess anticancer activities in vitro and in vivo However, the precise mechanism involved remains largely unknown. The present study is conducted to investigate the anticancer activity and the underlying mechanisms of oxymatrine in human hepatoma cells (Hep-G2 and SMMC 7721) in vitro and in vivo Hep-G2 and SMMC-7721 cells were treated by oxymatrine and subjected to methyl thiazolyl tetrazolium analysis, Hoechst 33342 staining, annexin V/propidium iodide double staining, reverse transcription polymerase chain reaction, and Western blot analysis. In addition, SMMC-7721 xenograft tumors were established in male nude BALB/c mice, and oxymatrine was intravenously administered to evaluate the anticancer capacity in vivo Our results showed that oxymatrine inhibited the proliferation and induced apoptosis of Hep-G2 and SMMC-7721 cells in a dose-dependent manner in vitro Furthermore, the RNA and protein expression of Bax and caspase 3 levels were significantly upregulated, whereas the expression of Bcl-2 was downregulated. These protein interactions may play a pivotal role in the regulation of proliferation and apoptosis. More importantly, our in vivo studies showed that administration of oxymatrine decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated an increase of Bax and caspase 3 and a decrease of Bcl-2 in tumor tissues following oxymatrine treatment which are consistent with the in vitro results. Taken together, our findings indicated that oxymatrine can inhibit cell proliferation and induce apoptosis of human hepatoma Hep-G2 and SMMC-7721 cells and might offer a therapeutic potential advantage for human hepatoma chemoprevention or chemotherapy. PMID- 26009497 TI - H2O2 Detection at Carbon Nanotubes and Nitrogen-Doped Carbon Nanotubes: Oxidation, Reduction, or Disproportionation? AB - The electrochemical behavior of hydrogen peroxide (H2O2) at carbon nanotubes (CNTs) and nitrogen-doped carbon nanotubes (N-CNTs) was investigated over a wide potential window. At CNTs, H2O2 will be oxidized or reduced at large overpotentials, with a large potential region between these two processes where electrochemical activity is negligible. At N-CNTs, the overpotential for both H2O2 oxidation and reduction is significantly reduced; however, the reduction current from H2O2, especially at low overpotentials, is attributed to increased oxygen reduction rather than the direct reduction of H2O2, due to a fast chemical disproportionation of H2O2 at the N-CNT surface. Additionally, N-CNTs do not display separation between observable oxidation and reduction currents from H2O2. Overall, the analytical sensitivity of N-CNTs to H2O2, either by oxidation or reduction, is considerably higher than CNTs, and obtained at significantly lower overpotentials. N-CNTs display an anodic sensitivity and limit of detection of 830 mA M(-1) cm(-2) and 0.5 MUM at 0.05 V, and a cathodic sensitivity and limit of detection of 270 mA M(-1) cm(-2) and 10 MUM at -0.25 V (V vs Hg/Hg2SO4). N CNTs are also a superior platform for the creation of bioelectrodes from the spontaneous adsorption of enzyme, compared to CNTs. Glucose oxidase (GOx) was allowed to adsorb onto N-CNTs, producing a bioelectrode with a sensitivity and limit of detection to glucose of 80 mA M(-1) cm(-2) and 7 MUM after only 30 s of adsorption time from a 81.3 MUM GOx solution. PMID- 26009498 TI - Low Serum Vitamin D Is Independently Associated with Larger Lesion Volumes after Ischemic Stroke. AB - BACKGROUND: Despite its high prevalence, known association with vascular disease and stroke incidence and fatality, little is known about the contribution of vitamin D status to a worse outcome after ischemic stroke. Therefore, we sought to assess whether low serum 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, is predictive of the ischemic infarct volume and whether it relates to a worse outcome. METHODS: We retrospectively analyzed prospective, consecutive acute ischemic stroke patients evaluated from January 2013 to January 2014 at a tertiary referral center. All patients (n = 96) had a magnetic resonance imaging proven acute ischemic stroke. Multivariable linear and logistic regression analyses were used to test whether vitamin D represents an independent predictor of infarct volume and poor 90-day outcome (modified Rankin Scale score of >2). RESULTS: In univariable analyses, lacunar infarct etiology, lower admission National Institutes of Health Stroke Scale, and higher serum 25(OH)D concentration were associated with smaller infarct volumes (P < .05). The association of 25(OH)D with ischemic infarct volume was independent of other known predictors of the infarct extent (P = .001). Multivariable analyses showed that the risk for a poor 90-day outcome doubled with each 10-ng/mL decrease in serum 25(OH)D. CONCLUSIONS: Low serum 25(OH)D was independently associated with larger ischemic infarct volume, which may partially explain observed worse outcomes in ischemic stroke patients with poor vitamin D status. Although causality remains to be proven, our results provide the rationale to further explore vitamin D as a promising marker for cerebral ischemic vulnerability and to identify stroke patients at high risk for poor outcome. PMID- 26009499 TI - Ruptured Cerebral Microaneurysm Diagnosed by 3-Dimensional Fast Spin-Echo T1 Imaging with Variable Flip Angles. AB - Cerebral microaneurysms, which are 2 mm or small in size, are a rare cause of subarachnoid hemorrhage (SAH). The authors present 2 cases with ruptured microaneurysms, in which 3-dimensional (3D) fast spin-echo T1 imaging with variable flip angles (CUBE T1) using gadolinium-diethylenetriaminepentaacetic acid (Gd) enhancement was useful in diagnosing the microaneurysms as the source of bleeding. Case 1 was a 61-year-old woman who had an SAH localized to the left Sylvian fissure. A small bulge (1.4 mm) at the bifurcation of left middle cerebral artery (MCA), which was detected by 3D angiography, was well enhanced by CUBE T1 with Gd enhancement. The patient was successfully treated by trapping of the lower division of the left M2 segment with superficial temporal artery-M3 bypass. The intraoperative findings indicated that the microaneurysm at the bifurcation of the left MCA was the ruptured site. Case 2 was a 41-year-old man who had a diffuse SAH. A small bulge (1.5 mm) at the inferolateral wall of the left internal carotid artery (ICA), which was detected by 3D angiography, was well enhanced by CUBE T1 with Gd enhancement. The patient was treated by trapping of the left ICA with external carotid artery-saphenous vein graft-M2 bypass without complications. The intraoperative findings indicated that the microaneurysm at the inferolateral wall of the left ICA was the ruptured site. CUBE T1 with Gd enhancement was useful as an adjunctive tool for the diagnosis of ruptured cerebral microaneurysms. This sequence might enable neurosurgeons to perform curative surgery with certainty for ruptured microaneurysms. PMID- 26009500 TI - Reliability and concurrent validity of the Microsoft Xbox One Kinect for assessment of standing balance and postural control. AB - The Microsoft Kinect V2 for Windows, also known as the Xbox One Kinect, includes new and potentially far improved depth and image sensors which may increase its accuracy for assessing postural control and balance. The aim of this study was to assess the concurrent validity and reliability of kinematic data recorded using a marker-based three dimensional motion analysis (3DMA) system and the Kinect V2 during a variety of static and dynamic balance assessments. Thirty healthy adults performed two sessions, separated by one week, consisting of static standing balance tests under different visual (eyes open vs. closed) and supportive (single limb vs. double limb) conditions, and dynamic balance tests consisting of forward and lateral reach and an assessment of limits of stability. Marker coordinate and joint angle data were concurrently recorded using the Kinect V2 skeletal tracking algorithm and the 3DMA system. Task-specific outcome measures from each system on Day 1 and 2 were compared. Concurrent validity of trunk angle data during the dynamic tasks and anterior-posterior range and path length in the static balance tasks was excellent (Pearson's r>0.75). In contrast, concurrent validity for medial-lateral range and path length was poor to modest for all trials except single leg eyes closed balance. Within device test-retest reliability was variable; however, the results were generally comparable between devices. In conclusion, the Kinect V2 has the potential to be used as a reliable and valid tool for the assessment of some aspects of balance performance. PMID- 26009501 TI - Intracellular expression of purinoceptors. PMID- 26009502 TI - Laparoscopic percutaneous inguinal hernia repair in children: review of technique and comparison with open surgery. AB - INTRODUCTION: Minimally-invasive approaches for inguinal hernia repair have evolved from conventional laparoscopy requiring placement of three ports and intracorporeal suturing to simple, one and two port extraperitoneal closure techniques. We utilize a single port laparoscopic percutaneous repair (LPHR) technique for selected children requiring operative intervention for inguinal hernia. We suspect that compared to open surgery, LPHR offers shorter operative duration with comparable safety and efficacy. Our objectives are to (1) illustrate this technique and (2) compare operative times and surgical outcomes in patients undergoing LPHR versus traditional open repair. METHODS: We reviewed operative times, complications, and recurrence rates in 38 patients (49 hernias) who underwent LPHR at our institution between January 2010 and September 2013. These data were compared with an age-, gender-, weight-, and laterality-matched cohort undergoing open repair during the same 3 year period. All cases were performed by a pediatric urologist or pediatric surgeon. RESULTS: Thirty-eight patients with a median age of 21.5 months underwent LPHR, and 38 patients with a median age of 23 months underwent open repair. In both groups, 27/38 patients (71%) had unilateral repairs, and 11/38 patients (29%) had bilateral repairs. For unilateral procedures, average operative duration was 25 min for LPHR and 59 min for OHR (p < 0.001). For bilateral procedures, average operative duration was 31 min for LPHR and 79 min for OHR (p < 0.001). There were no intraabdominal injuries in either group. In the LPHR group, there were no vascular or cord structure injuries and no conversions to open technique. Median follow-up was 51 days for the LPHR group and 47 days for the OHR group (p = 0.346). No hernia recurrence was observed in either group. CONCLUSIONS: In select patients, LPHR is an efficient, safe, and effective minimally invasive alternative to OHR, with reduced operative times but without increased rates of complications or recurrences. The technique has a short learning curve and is a practical alternative to OHR for pediatric urologists who infrequently utilize pure laparoscopic technique. PMID- 26009503 TI - Words and meanings. PMID- 26009504 TI - Patient co-payment for general practice services: slippery slope or a survival imperative for the NHS? PMID- 26009505 TI - A new Hundred Years' War? The Affordable Care Act. PMID- 26009506 TI - Online access to medical records: finding ways to minimise harms. PMID- 26009507 TI - Mandatory reporting of female genital mutilation by healthcare professionals. PMID- 26009510 TI - Physician associates. PMID- 26009508 TI - Scanning the human genome and the horizon: the potential and pitfalls of pharmacogenetics and stratified medicine. PMID- 26009511 TI - Hold the bunting on PAs! PMID- 26009512 TI - Physician associates in primary care. PMID- 26009513 TI - Self-monitoring of blood glucose in type 2 diabetes. PMID- 26009514 TI - Authors' response. PMID- 26009515 TI - Correction. PMID- 26009516 TI - 'Doctor, Doctor, have you elicited my expectations?'. PMID- 26009517 TI - General practice: a better way forward? PMID- 26009518 TI - Discretion is the better part of general practice. PMID- 26009519 TI - Dannie Abse: Wales' finest literary doctor. PMID- 26009520 TI - International primary care snapshots: Armenia and South Africa. PMID- 26009521 TI - Burping, fear of childbirth, cancer diagnosis, and corner shops. PMID- 26009524 TI - Myth-based medicine. PMID- 26009525 TI - Should general practice give up the independent contractor status? PMID- 26009526 TI - Sexual orientation monitoring and documentation: intrusive or important for patient care? PMID- 26009527 TI - Solutions to problematic polypharmacy: learning from the expertise of patients. PMID- 26009528 TI - Peripheral arterial disease: diagnostic challenges and how photoplethysmography may help. PMID- 26009529 TI - Randomised controlled trial of a brief intervention targeting predominantly non verbal communication in general practice consultations. AB - BACKGROUND: The impact of changing non-verbal consultation behaviours is unknown. AIM: To assess brief physician training on improving predominantly non-verbal communication. DESIGN AND SETTING: Cluster randomised parallel group trial among adults aged >=16 years attending general practices close to the study coordinating centres in Southampton. METHOD: Sixteen GPs were randomised to no training, or training consisting of a brief presentation of behaviours identified from a prior study (acronym KEPe Warm: demonstrating Knowledge of the patient; Encouraging [back-channelling by saying 'hmm', for example]; Physically engaging [touch, gestures, slight lean]; Warm-up: cool/professional initially, warming up, avoiding distancing or non-verbal cut-offs at the end of the consultation); and encouragement to reflect on videos of their consultation. Outcomes were the Medical Interview Satisfaction Scale (MISS) mean item score (1-7) and patients' perceptions of other domains of communication. RESULTS: Intervention participants scored higher MISS overall (0.23, 95% confidence interval [CI] = 0.06 to 0.41), with the largest changes in the distress-relief and perceived relationship subscales. Significant improvement occurred in perceived communication/partnership (0.29, 95% CI = 0.09 to 0.49) and health promotion (0.26, 95% CI = 0.05 to 0.46). Non-significant improvements occurred in perceptions of a personal relationship, a positive approach, and understanding the effects of the illness on life. CONCLUSION: Brief training of GPs in predominantly non-verbal communication in the consultation and reflection on consultation videotapes improves patients' perceptions of satisfaction, distress, a partnership approach, and health promotion. PMID- 26009530 TI - Verbal and non-verbal behaviour and patient perception of communication in primary care: an observational study. AB - BACKGROUND: Few studies have assessed the importance of a broad range of verbal and non-verbal consultation behaviours. AIM: To explore the relationship of observer ratings of behaviours of videotaped consultations with patients' perceptions. DESIGN AND SETTING: Observational study in general practices close to Southampton, Southern England. METHOD: Verbal and non-verbal behaviour was rated by independent observers blind to outcome. Patients competed the Medical Interview Satisfaction Scale (MISS; primary outcome) and questionnaires addressing other communication domains. RESULTS: In total, 275/360 consultations from 25 GPs had useable videotapes. Higher MISS scores were associated with slight forward lean (an 0.02 increase for each degree of lean, 95% confidence interval [CI] = 0.002 to 0.03), the number of gestures (0.08, 95% CI = 0.01 to 0.15), 'back-channelling' (for example, saying 'mmm') (0.11, 95% CI = 0.02 to 0.2), and social talk (0.29, 95% CI = 0.4 to 0.54). Starting the consultation with professional coolness ('aloof') was helpful and optimism unhelpful. Finishing with non-verbal 'cut-offs' (for example, looking away), being professionally cool ('aloof'), or patronising, ('infantilising') resulted in poorer ratings. Physical contact was also important, but not traditional verbal communication. CONCLUSION: These exploratory results require confirmation, but suggest that patients may be responding to several non-verbal behaviours and non specific verbal behaviours, such as social talk and back-channelling, more than traditional verbal behaviours. A changing consultation dynamic may also help, from professional 'coolness' at the beginning of the consultation to becoming warmer and avoiding non-verbal cut-offs at the end. PMID- 26009531 TI - Assessing the appropriateness of information on childhood fever in thermometer package leaflets: a systematic audit of thermometers available in the UK. AB - BACKGROUND: Thermometers are found in most parents' homes, but little is known about the quality and accuracy of the information they provide, nor its consistency with current guidelines for managing fever. AIM: To compare information included with commonly available thermometers with National Institute for Health and Care Excellence (NICE) guidance for management of feverish illness in children. DESIGN AND SETTING: Systematic thermometer sampling from UK retailers between February 2013 and May 2013. METHOD: Information was extracted from device packaging and leaflets on details and type of thermometer, instructions for use, normal ranges, and fever thresholds cited. This was compared with key parental recommendations from the 2013 NICE guidance on feverish illness in children. Associations were explored between cost of device and level of information. RESULTS: There were 123 thermometers identified (ranging from L0.99 to L69.99), none of which made explicit reference to NICE guidance. Most (n = 81, 65.9%) recommended use at a body site consistent with NICE guidance, but only 17 (13.8%) defined fever using the correct threshold (>=38.0 degrees C), and few (n = 12, 9.8%) included advice on fever management, of which four suggested actions not advised by NICE. There was no association between thermometer cost and provision of information consistent with NICE guidance. CONCLUSION: Parents and caregivers have access to a large number of thermometers, yet they lack evidence-based information about fever detection and management, and in some cases contain misleading information. This represents a missed opportunity to disseminate best practices from guidelines for management of fever in children, and thermometer manufacturers are urged to include information consistent with current guidance. PMID- 26009532 TI - GPs' approaches to documenting stigmatising information: a qualitative study. AB - BACKGROUND: Complete medical documentation is essential for continuity of care, but the competing need to protect patient confidentiality presents an ethical dilemma. This is particularly poignant for GPs because of their central role in facilitating continuity. AIM: To examine how GPs manage medical documentation of stigmatising mental health (MH) and non-MH information. DESIGN AND SETTING: A qualitative sub-study of a factorial experiment with GPs practising in Massachusetts, US. METHOD: Semi-structured interviews (n = 128) were audiorecorded and transcribed verbatim. Transcripts were coded and analysed for themes. RESULTS: GPs expressed difficulties with and inconsistent strategies for documenting stigmatising information. Without being asked directly about stigmatising information, 44 GPs (34%) expressed difficulties documenting it: whether to include clinically relevant but sensitive information, how to word it, and explaining to patients the importance of including it. Additionally, 75 GPs (59%) discussed strategies for managing documentation of stigmatising information. GPs reported four strategies that varied by type of information: to exclude stigmatising information to respect patient confidentiality (MH: 26%, non MH: 43%); to include but restrict access to information (MH: 13%, non-MH: 25%); to include but neutralise information to minimise potential stigma (MH: 26%, non MH: 29%); and to include stigmatising information given the potential impact on care (MH: 68%, non-MH: 32%). CONCLUSION: Lack of consistency undermines the potential of medical documentation to efficiently facilitate continuous, coordinated health care because providers cannot be certain how to interpret what is or is not in the chart. A proactive consensus process within the field of primary care would provide much needed guidance for GPs and, ultimately, could enhance quality of care. PMID- 26009533 TI - A mismatch between population health literacy and the complexity of health information: an observational study. AB - BACKGROUND: Low health literacy is associated with poorer health and higher mortality. Complex health materials are a barrier to health. AIM: To assess the literacy and numeracy skills required to understand and use commonly used English health information materials, and to describe population skills in relation to these. DESIGN AND SETTING: An English observational study comparing health materials with national working-age population skills. METHOD: Health materials were sampled using a health literacy framework. Competency thresholds to understand and use the materials were identified. The proportion of the population above and below these thresholds, and the sociodemographic variables associated with a greater risk of being below the thresholds, were described. RESULTS: Sixty-four health materials were sampled. Two competency thresholds were identified: text (literacy) only, and text + numeracy; 2515/5795 participants (43%) were below the text-only threshold, while 2905/4767 (61%) were below the text + numeracy threshold. Univariable analyses of social determinants of health showed that those groups more at risk of socioeconomic deprivation had higher odds of being below the health literacy competency threshold than those at lower risk of deprivation. Multivariable analysis resulted in some variables becoming non-significant or reduced in effect. CONCLUSION: Levels of low health literacy mirror those found in other industrialised countries, with a mismatch between the complexity of health materials and the skills of the English adult working-age population. Those most in need of health information have the least access to it. Efficacious strategies are building population skills, improving health professionals' communication, and improving written health information. PMID- 26009534 TI - Does mindfulness improve outcomes in patients with chronic pain? Systematic review and meta-analysis. AB - BACKGROUND: Chronic pain and its associated distress and disability are common reasons for seeking medical help. Patients with chronic pain use primary healthcare services five times more than the rest of the population. Mindfulness has become an increasingly popular self-management technique. AIM: To assess the effectiveness of mindfulness-based interventions for patients with chronic pain. DESIGN AND SETTING: Systematic review and meta-analysis including randomised controlled trials of mindfulness-based interventions for chronic pain. There was no restriction to study site or setting. METHOD: The databases MEDLINE((r)), Embase, AMED, CINAHL, PsycINFO, and Index to Theses were searched. Titles, abstracts, and full texts were screened iteratively against inclusion criteria of: randomised controlled trials of mindfulness-based intervention; patients with non-malignant chronic pain; and economic, clinical, or humanistic outcome reported. Included studies were assessed with the Yates Quality Rating Scale. Meta-analysis was conducted. RESULTS: Eleven studies were included. Chronic pain conditions included: fibromyalgia, rheumatoid arthritis, chronic musculoskeletal pain, failed back surgery syndrome, and mixed aetiology. Papers were of mixed methodological quality. Main outcomes reported were pain intensity, depression, physical functioning, quality of life, pain acceptance, and mindfulness. Economic outcomes were rarely reported. Meta-analysis effect sizes for clinical outcomes ranged from 0.12 (95% confidence interval [CI] = -0.05 to 0.30) (depression) to 1.32 (95% CI = -1.19 to 3.82) (sleep quality), and for humanistic outcomes 0.03 (95% CI = -0.66 to 0.72) (mindfulness) to 1.58 (95% CI = -0.57 to 3.74) (pain acceptance). Studies with active, compared with inactive, control groups showed smaller effects. CONCLUSION: There is limited evidence for effectiveness of mindfulness-based interventions for patients with chronic pain. Better-quality studies are required. PMID- 26009535 TI - Understanding depression associated with chronic physical illness: a Q methodology study in primary care. AB - BACKGROUND: Detection of depression can be difficult in primary care, particularly when associated with chronic illness. Patient beliefs may affect detection and subsequent engagement with management. Q-methodology can help to identify viewpoints that are likely to influence either clinical practice or policy intervention. AIM: To identify socially shared viewpoints of comorbid depression, and characterise key overlaps and discrepancies. DESIGN AND SETTING: A Q-methodology study of patients registered with general practices or community clinics in Leeds, UK. METHOD: Patients with coronary heart disease or diabetes and depression from three practices and community clinics were invited to participate. Participants ranked 57 statements about comorbid depression. Factor analyses were undertaken to identify independent accounts, and additional interview data were used to support interpretation. RESULTS: Thirty-one patients participated; 13 (42%) had current symptoms of depression. Five accounts towards comorbid depression were identified: overwhelmed resources; something medical or within me; a shameful weakness; part of who I am; and recovery-orientated. The main differences in attitudes related to the cause of depression and its relationship with the patient's chronic illness, experience of shame, and whether medical interventions would help recovery. CONCLUSION: There are groups of patients who do not perceive a relationship between their depression and chronic illness; they may not understand the intention behind policy initiatives to identify depression during chronic illness reviews. Tailoring detection strategies for depression to take account of different clusters of attitudes and beliefs could help improve identification and personalise management. PMID- 26009536 TI - Provision of medical student teaching in UK general practices: a cross-sectional questionnaire study. AB - BACKGROUND: Health care is increasingly provided in general practice. To meet this demand, the English Department of Health recommends that 50% of all medical students should train for general practice after qualification. Currently 19% of medical students express general practice as their first career choice. Undergraduate exposure to general practice positively influences future career choice. Appropriate undergraduate exposure to general practice is therefore highly relevant to workforce planning AIM: This study seeks to quantify current exposure of medical students to general practice and compare it with past provision and also with postgraduate provision. DESIGN AND SETTING: A cross sectional questionnaire in the UK. METHOD: A questionnaire regarding provision of undergraduate teaching was sent to the general practice teaching leads in all UK medical schools. Information was gathered on the amount of undergraduate teaching, how this was supported financially, and whether there was an integrated department of general practice. The data were then compared with results from previous studies of teaching provision. The provision of postgraduate teaching in general practice was also examined. RESULTS: General practice teaching for medical students increased from <1.0% of clinical teaching in 1968 to 13.0% by 2008; since then, the percentage has plateaued. The total amount of general practice teaching per student has fallen by 2 weeks since 2002. Medical schools providing financial data delivered 14.6% of the clinical curriculum and received 7.1% of clinical teaching funding. The number of departments of general practice has halved since 2002. Provision of postgraduate teaching has tripled since 2000. CONCLUSION: Current levels of undergraduate teaching in general practice are too low to fulfil future workforce requirements and may be falling. Financial support for current teaching is disproportionately low and the mechanism counterproductive. Central intervention may be required to solve this. PMID- 26009537 TI - Itch and liver: management in primary care. PMID- 26009538 TI - Dose specification for 192Ir high dose rate brachytherapy in terms of dose-to water-in-medium and dose-to-medium-in-medium. AB - Dose calculation in high dose rate brachytherapy with (192)Ir is usually based on the TG-43U1 protocol where all media are considered to be water. Several dose calculation algorithms have been developed that are capable of handling heterogeneities with two possibilities to report dose: dose-to-medium-in-medium (Dm,m) and dose-to-water-in-medium (Dw,m). The relation between Dm,m and Dw,m for (192)Ir is the main goal of this study, in particular the dependence of Dw,m on the dose calculation approach using either large cavity theory (LCT) or small cavity theory (SCT). A head and neck case was selected due to the presence of media with a large range of atomic numbers relevant to tissues and mass densities such as air, soft tissues and bone interfaces. This case was simulated using a Monte Carlo (MC) code to score: Dm,m, Dw,m (LCT), mean photon energy and photon fluence. Dw,m (SCT) was derived from MC simulations using the ratio between the unrestricted collisional stopping power of the actual medium and water. Differences between Dm,m and Dw,m (SCT or LCT) can be negligible (<1%) for some tissues e.g. muscle and significant for other tissues with differences of up to 14% for bone. Using SCT or LCT approaches leads to differences between Dw,m (SCT) and Dw,m (LCT) up to 29% for bone and 36% for teeth. The mean photon energy distribution ranges from 222 keV up to 356 keV. However, results obtained using mean photon energies are not equivalent to the ones obtained using the full, local photon spectrum. This work concludes that it is essential that brachytherapy studies clearly report the dose quantity. It further shows that while differences between Dm,m and Dw,m (SCT) mainly depend on tissue type, differences between Dm,m and Dw,m (LCT) are, in addition, significantly dependent on the local photon energy fluence spectrum which varies with distance to implanted sources. PMID- 26009539 TI - Granular cell tumors overexpress TFE3 without corollary gene rearrangement. PMID- 26009540 TI - Of BK regulation, painful connections, and versatile neuropeptide signaling. PMID- 26009542 TI - Rational strategy to stop arrhythmias: Early afterdepolarizations and L-type Ca2+ current. PMID- 26009543 TI - Orchestrating Ca2+ influx through Ca(V)1.2 and Ca(V)3.x channels in human cerebral arteries. PMID- 26009541 TI - The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle. AB - A novel category of diseases of striated muscle is proposed, the couplonopathies, as those that affect components of the couplon and thereby alter its operation. Couplons are the functional units of intracellular calcium release in excitation contraction coupling. They comprise dihydropyridine receptors, ryanodine receptors (Ca2+ release channels), and a growing list of ancillary proteins whose alteration may lead to disease. Within a generally similar plan, the couplons of skeletal and cardiac muscle show, in a few places, marked structural divergence associated with critical differences in the mechanisms whereby they fulfill their signaling role. Most important among these are the presence of a mechanical or allosteric communication between voltage sensors and Ca2+ release channels, exclusive to the skeletal couplon, and the smaller capacity of the Ca stores in cardiac muscle, which results in greater swings of store concentration during physiological function. Consideration of these structural and functional differences affords insights into the pathogenesis of several couplonopathies. The exclusive mechanical connection of the skeletal couplon explains differences in pathogenesis between malignant hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia (CPVT), conditions most commonly caused by mutations in homologous regions of the skeletal and cardiac Ca(2+) release channels. Based on mechanistic considerations applicable to both couplons, we identify the plasmalemma as a site of secondary modifications, typically an increase in store-operated calcium entry, that are relevant in MH pathogenesis. Similar considerations help explain the different consequences that mutations in triadin and calsequestrin have in these two tissues. As more information is gathered on the composition of cardiac and skeletal couplons, this comparative and mechanistic approach to couplonopathies should be useful to understand pathogenesis, clarify diagnosis, and propose tissue-specific drug development. PMID- 26009545 TI - Molecular basis for differential modulation of BK channel voltage-dependent gating by auxiliary gamma subunits. AB - Large conductance Ca(2+)- and voltage-activated potassium (BK) channels are comprised of pore-forming alpha subunits and various regulatory auxiliary subunits. The BK channel auxiliary gamma (BKgamma) subunits are a newly identified class of proteins containing an extracellular leucine-rich repeat domain (LRRD), a single transmembrane (TM) segment, and a short cytoplasmic C terminal tail (C-tail). Although each of the four BKgamma proteins shifts the voltage dependence of BK channel activation in a hyperpolarizing direction, they show markedly different efficacies, mediating shifts over a range of 15-145 mV. Analyses of chimeric BKgamma subunits created by swapping individual structural elements, and of BKgamma deletion and substitution mutants, revealed that differential modulation of BK gating by the four BKgamma subunits depends on a small region consisting of the TM segment and the adjacent intracellular cluster of positively charged amino acids. The gamma1 and gamma2 TM segments contributed approximately -100 mV, and the gamma1 and gamma3 C-tails contributed approximately -40 mV, to shifting the voltage dependence of BK channel activation, whereas the gamma3 and gamma4 TM segments and the gamma2 and gamma4 C tails contributed much less. The large extracellular LRRDs were mainly functionally interchangeable, although the gamma1 LRRD was slightly less effective at enhancing (or slightly more effective at attenuating) the shift in BK channel voltage-dependent gating toward hyperpolarizing potentials than those of the other BKgamma subunits. Analysis of mutated BKgamma subunits revealed that juxta-membrane clusters of positively charged amino acids determine the functions of the gamma1 and gamma3 C-tails. Therefore, the modulatory functions of BKgamma subunits are coarse- and fine-tuned, respectively, through variations in their TM segments and in the adjacent intracellular positively charged regions. Our results suggest that BK channel modulation by auxiliary gamma subunits depends on intra- and/or juxta-membrane mechanisms. PMID- 26009546 TI - Beyond non-integer Hill coefficients: A novel approach to analyzing binding data, applied to Na+-driven transporters. AB - Prokaryotic and eukaryotic Na(+)-driven transporters couple the movement of one or more Na(+) ions down their electrochemical gradient to the active transport of a variety of solutes. When more than one Na(+) is involved, Na(+)-binding data are usually analyzed using the Hill equation with a non-integer exponent n. The results of this analysis are an overall Kd-like constant equal to the concentration of ligand that produces half saturation and n, a measure of cooperativity. This information is usually insufficient to provide the basis for mechanistic models. In the case of transport using two Na(+) ions, an n < 2 indicates that molecules with only one of the two sites occupied are present at low saturation. Here, we propose a new way of analyzing Na(+)-binding data for the case of two Na(+) ions that, by taking into account binding to individual sites, provides far more information than can be obtained by using the Hill equation with a non-integer coefficient: it yields pairs of possible values for the Na(+) affinities of the individual sites that can only vary within narrowly bounded ranges. To illustrate the advantages of the method, we present experimental scintillation proximity assay (SPA) data on binding of Na(+) to the Na(+)/I(-) symporter (NIS). SPA is a method widely used to study the binding of Na(+) to Na(+)-driven transporters. NIS is the key plasma membrane protein that mediates active I(-) transport in the thyroid gland, the first step in the biosynthesis of the thyroid hormones, of which iodine is an essential constituent. NIS activity is electrogenic, with a 2:1 Na(+)/I(-) transport stoichiometry. The formalism proposed here is general and can be used to analyze data on other proteins with two binding sites for the same substrate. PMID- 26009544 TI - Ryanodine receptor gating controls generation of diastolic calcium waves in cardiac myocytes. AB - The role of cardiac ryanodine receptor (RyR) gating in the initiation and propagation of calcium waves was investigated using a mathematical model comprising a stochastic description of RyR gating and a deterministic description of calcium diffusion and sequestration. We used a one-dimensional array of equidistantly spaced RyR clusters, representing the confocal scanning line, to simulate the formation of calcium sparks. Our model provided an excellent description of the calcium dependence of the frequency of diastolic calcium sparks and of the increased tendency for the production of calcium waves after a decrease in cytosolic calcium buffering. We developed a hypothesis relating changes in the propensity to form calcium waves to changes of RyR gating and tested it by simulation. With a realistic RyR gating model, increased ability of RyR to be activated by Ca2+ strongly increased the propensity for generation of calcium waves at low (0.05-0.1-uM) calcium concentrations but only slightly at high (0.2-0.4-uM) calcium concentrations. Changes in RyR gating altered calcium wave formation by changing the calcium sensitivity of spontaneous calcium spark activation and/or the average number of open RyRs in spontaneous calcium sparks. Gating changes that did not affect RyR activation by Ca2+ had only a weak effect on the propensity to form calcium waves, even if they strongly increased calcium spark frequency. Calcium waves induced by modulating the properties of the RyR activation site could be suppressed by inhibiting the spontaneous opening of the RyR. These data can explain the increased tendency for production of calcium waves under conditions when RyR gating is altered in cardiac diseases. PMID- 26009547 TI - The Hill analysis and co-ion-driven transporter kinetics. AB - Interaction of multiple ligands with a protein or protein complex is a widespread phenomenon that allows for cooperativity. Here, we review the use of the Hill equation, which is commonly used to analyze binding or kinetic data, to analyze the kinetics of ion-coupled transporters and show how the mechanism of transport affects the Hill coefficient. Importantly, the Hill analysis of ion-coupled transporters can provide the exact number of transported co-ions, regardless of the extent of the cooperativity in ion binding. PMID- 26009548 TI - Examining Determinants of Radiotherapy Access: Do Cost and Radiotherapy Inconvenience Affect Uptake of Breast-conserving Treatment for Early Breast Cancer? AB - AIMS: Radiotherapy utilisation is likely affected by multiple factors pertaining to radiotherapy access. Radiotherapy is an integral component of breast conserving treatment (BCT) for early breast cancer. We aimed to determine if stepwise improvements in radiotherapy access in regional Australia affected the uptake of BCT and thus radiotherapy. MATERIALS AND METHODS: Breast cancer operations in the Central Coast of New South Wales between January 2010 and March 2014 for T1-2N0-1M0 invasive or in situ (<=5 cm) disease in female patients eligible for BCT were examined. BCT uptake was calculated for three 1 year periods: period 1 (local radiotherapy available at cost to user or out of area radiotherapy with travel cost and inconvenience); period 2 (as per period 1 + publicly funded transport and radiotherapy at out of area facilities at no cost to user); period 3 (as per period 1 + publicly funded local radiotherapy at no cost to user). RESULTS: In total, 574 cases met eligibility criteria. BCT declined with increasing distance to publicly funded radiotherapy (P = 0.035). BCT rates for periods 1, 2 and 3 were 63% (113/180), 61% (105/173) and 71% (156/221). There were no statistically significant differences in BCT between periods 1 and 2 in the whole cohort or within age, histology or tumour size subgroups. Overall, there was a 9% increase in BCT in the whole cohort in period 3 compared with periods 1 and 2 (P = 0.031). This increase was statistically significant for women over 70 years (19% increase, P = 0.034), for women with ductal carcinoma in situ (25% increase, P = 0.013) and for women with primary tumours that were <=10 mm (21% increase, P = 0.016). CONCLUSIONS: Improving the affordability of radiotherapy through publicly funded transport and radiotherapy at out of area facilities did not improve BCT uptake in a region where radiotherapy was locally available, albeit at cost to the user. Improving both affordability and convenience through the provision of local publicly funded radiotherapy increased BCT uptake. Service availability and affordability have long been recognised as important determinants of radiotherapy access. Our findings suggest that inconvenience may also influence radiotherapy utilisation. PMID- 26009549 TI - Merkel Cell Carcinoma: Current Management and Controversies. AB - Merkel cell carcinoma is a rare skin tumour with a poor outcome and high rates of both local and distant recurrence despite radical management. We review the management of local and locoregional disease, and the role of sentinel lymph node biopsy in staging. This overview aims to highlight some of the controversies regarding the current treatment of this disease, which seems to be on the increase. Data are conflicting as to whether there is any survival benefit from adjuvant primary site or regional nodal irradiation, partly due to the lack of prospective clinical trials. We also review the evolving role of primary radiotherapy and suggest areas where ongoing research is urgently required. PMID- 26009551 TI - A cutaneous clue to a systemic illness. PMID- 26009552 TI - Dual adaptive statistical approach for quantitative noise reduction in photon counting medical imaging: application to nuclear medicine images. AB - Noise reduction in photon-counting images remains challenging, especially at low count levels. We have developed an original procedure which associates two complementary filters using a Wiener-derived approach. This approach combines two statistically adaptive filters into a dual-weighted (DW) filter. The first one, a statistically weighted adaptive (SWA) filter, replaces the central pixel of a sliding window with a statistically weighted sum of its neighbors. The second one, a statistical and heuristic noise extraction (extended) (SHINE-Ext) filter, performs a discrete cosine transformation (DCT) using sliding blocks. Each block is reconstructed using its significant components which are selected using tests derived from multiple linear regression (MLR). The two filters are weighted according to Wiener theory. This approach has been validated using a numerical phantom and a real planar Jaszczak phantom. It has also been illustrated using planar bone scintigraphy and myocardial single-photon emission computed tomography (SPECT) data. Performances of filters have been tested using mean normalized absolute error (MNAE) between the filtered images and the reference noiseless or high-count images.Results show that the proposed filters quantitatively decrease the MNAE in the images and then increase the signal-to noise Ratio (SNR). This allows one to work with lower count images. The SHINE-Ext filter is well suited to high-size images and low-variance areas. DW filtering is efficient for low-size images and in high-variance areas. The relative proportion of eliminated noise generally decreases when count level increases. In practice, SHINE filtering alone is recommended when pixel spacing is less than one-quarter of the effective resolution of the system and/or the size of the objects of interest. It can also be used when the practical interest of high frequencies is low. In any case, DW filtering will be preferable.The proposed filters have been applied to nuclear medicine images but can also be used for any other kind of photon-counting images, such as x-ray and fluorescence images. PMID- 26009553 TI - Why is EIT so hard, and what are we doing about it? PMID- 26009555 TI - The Lawrence W. Green paper of the year award. PMID- 26009554 TI - Risk factors for injury in sport climbing and bouldering: a systematic review of the literature. AB - BACKGROUND: Rock climbing is an increasingly popular sport worldwide, as a recreational activity and a competitive sport. Several disciplines including sport climbing and bouldering have developed, each employing specific movements and techniques, leading to specific injuries. OBJECTIVE: To examine risk factors and prevention measures for injury in sport climbing and bouldering, and to assess the methodological quality of existing studies. METHODS: 12 electronic databases and several other sources were searched systematically using predetermined inclusion and exclusion criteria. Eligible articles were peer reviewed, based on primary research using original data; outcome measures included injury, morbidity or mortality in rock climbing, and included one or more potential risk factor or injury prevention strategy. Two independent reviewers assessed the methodology of research in each study using the Downs and Black Quality Index. The data extracted is summarised, and appraisals of the articles are presented with respect to the quality of evidence presented. RESULTS: 19 studies met the inclusion criteria, and introduced 35 possible risk factors or injury prevention measures in climbing. Age, increasing years of climbing experience, highest climbing grade achieved (skill level), high climbing intensity score (CIS) and participating in lead climbing are potential risk factors. Results regarding injury prevention measures remain inconclusive. DISCUSSION: This field is relatively new and, as such, the data are not as robust as for more established sports with a larger research foundation. The key need is establishing modifiable risk factors using prospective studies and high quality methodology, such that injury prevention strategies can be developed. The CIS may be a useful measure in this field of research. PMID- 26009556 TI - Preteen-parent experiences with PREP-T1 feasibility intervention. AB - PURPOSE: The purpose of this article is to report the focus group perspectives of preteens' and parents' experiences with a feasibility intervention entitled PREP T1 (Preteen Re-Education with Parents-Type 1 Diabetes), an interactive education and peer mentoring intervention. METHODS: The parent and preteen focus groups were conducted by the principal investigator, coinvestigator, and note takers at 2 sites. The preteen-parent groups were conducted concurrently with a total of 11 preteens and 11 parents. Note-based qualitative content analysis was used, resulting in preteen-parent perspectives on reeducation and strategies for families to work more effectively in managing type 1 diabetes (T1DM). RESULTS: The findings suggest that the preteens enjoyed learning about their diabetes management from a teen educator mentor in conjunction with a human patient simulator. They reported this type of peer support would benefit other preteens with T1DM. Parents were overwhelmingly positive about their interactions with the parent educator mentor in conjunction with the psychologist and about focusing on how to better collaborate with their preteens on diabetes management decision making. Further recommendations about the timing and intervention dose were also discussed. CONCLUSIONS: Moderated peer mentoring with technology has potential as a means for teaching preteens and their parents shared diabetes management. These data will be used to inform the PREP-T1 fully powered intervention study. PMID- 26009557 TI - Assessing the effectiveness of pharmacist-directed medication therapy management in improving diabetes outcomes in patients with poorly controlled diabetes. AB - PURPOSE: The purpose of this study was to compare medication adherence rates and type 2 diabetes mellitus (T2DM) health outcomes in a sample of underserved patients with suboptimally controlled T2DM (A1C >7%) who had received pharmacist directed medication therapy management (MTM) to those who had not received MTM. METHODS: A retrospective review of 100 patient records was conducted. For the MTM group, a pharmacist engaged patients in patient-centered services to optimize therapeutic outcomes. Non-MTM patients received usual care. Outcomes were A1C, medication adherence, blood pressure, lipids, and creatinine. Group comparisons on clinical outcomes were analyzed before and after matching MTM and non-MTM patients on demographic characteristics. RESULTS: Before matching, the MTM group had a higher rate of medication adherence than the non-MTM group. The A1C levels were lower in the MTM group compared to the non-MTM group. Similarly, low-density lipoprotein (LDL) cholesterol was lower in the MTM group compared to the non-MTM group. After matching, medication adherence rate remained higher in the MTM group than the non-MTM group. Similarly, A1C levels remained lower in the MTM group than the non-MTM group. CONCLUSIONS: There is a paucity of research focused on behavioral interventions for improving health outcomes in underserved communities. Our results advance the existing literature by demonstrating a positive association between pharmacist-directed MTM, medication adherence, and glycemic control in a sample of underserved patients with suboptimally controlled T2DM. A prospective pharmacy intervention and examination of long-term effects of MTM on medication adherence and T2DM health outcomes in this population is warranted. PMID- 26009558 TI - Kentucky Teen Institute: Results of a 1-Year, Health Advocacy Training Intervention for Youth. AB - The Kentucky Teen Institute trains youth throughout the state to advocate for policies that promote health in their communities. By evaluating two program summits held at universities, regularly scheduled community meetings, ongoing technical support, and an advocacy day at the state Capitol, the aims of this study were to assess the impact of the intervention on correlates of youths' advocacy intentions and behaviors and to assess youth participants' and other key stakeholders' perceptions of the intervention. An ecological model approach and the theory of planned behavior served as theoretical frameworks from which pre post, one-group survey and qualitative data were collected (June 2013-June 2014). An equal number of low-income and non-low-income youth representing five counties participated in the Summer Summit pretest (n = 24) and Children's Advocacy Day at the Capitol posttest (n = 14). Survey data revealed that youths' attitude toward advocacy, intentions to advocate, and advocacy behaviors all improved over the intervention. Observations, interviews, a focus group, and other written evaluations identified that the youths', as well as their mentors' and advocacy coaches', confidence, communities' capacity, and mutually beneficial mentorship strengthened. Stronger public speaking skills, communication among the teams, and other recommendations for future advocacy interventions are described. PMID- 26009559 TI - Stroke and the noncommunicable diseases: A global burden in need of global advocacy. PMID- 26009560 TI - Progressive outer retinal necrosis in a multiple sclerosis patient on natalizumab. PMID- 26009561 TI - Sensitivity and specificity of diagnostic ultrasound in the diagnosis of phrenic neuropathy. PMID- 26009562 TI - Pearls & Oy-sters: CSF analysis and the therapeutic paradox in tuberculous meningitis. PMID- 26009563 TI - A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. PMID- 26009564 TI - Mystery Case: A 21-year-old man with visual loss following marijuana use. PMID- 26009565 TI - Clinical Reasoning: A case of unilateral facial pain. PMID- 26009566 TI - Clinical Reasoning: Partial Horner syndrome and upper right limb symptoms following chiropractic manipulation. PMID- 26009567 TI - Cost of disease-modifying therapies for multiple sclerosis. PMID- 26009569 TI - Why people in Benin are reluctant to undergo amputations? A systematic inventory of motives. AB - We made an inventory of the reasons for inhabitants of Benin are reluctant to undergo the amputation of a limb. A robust six-factor structure of motives was found: Change in Appearance, Lack of Information, Fear of Hospitals and Medical Staff, Loss of Others' Consideration and Affection, Denial of Necessity, and Spiritual and Religious Concerns. The first three motives were the most strongly endorsed. To improve people's timely acceptance, it is important to attack the main emotional-motivational barriers by using artificial limbs imitating real ones, by providing complete information on post-operative care and rehabilitation, and by strengthening family support. PMID- 26009568 TI - The Proximal Effects of Acute Alcohol Consumption on Male-to-Female Aggression: A Meta-Analytic Review of the Experimental Literature. AB - The current meta-analytic review examined the experimental literature to quantify the causal effect of acute alcohol consumption on self-reported and observed indicators of male-to-female general, sexual, and intimate partner aggression. Database and reference list searches yielded 22 studies conducted between 1981 and 2014 that met all criteria for inclusion and that were subjected to full text coding for analysis. Results detected a significant overall effect (d = .36), indicating that male participants who consumed alcohol evidenced greater aggressive behavior toward females while completing a subsequent laboratory aggression paradigm than male participants who received no alcohol. We found homogeneity across all categories of potential moderator variables. Results further indicated that alcohol resulted in comparable increases of male-to-female sexual (d = .32) and intimate partner (d = .45) aggression. Further research is required to draw meaningful conclusions about individual and situational factors that may interact with acute alcohol consumption to produce the highest levels of risk. PMID- 26009570 TI - alpha-Fetoprotein-Producing Hepatoid Gastric Adenocarcinoma With Osteoclast-Like Giant Cells and Neuroendocrine Differentiation: A Case Study With Molecular Profiling. AB - Here we present the case of a 73-year-old woman with an ulcerated, advanced, hepatoid, and alpha-fetoprotein-producing poorly differentiated (G3) primary gastric adenocarcinoma pT3 N3a M1 with multinucleated cells and evident neuroendocrine component. This tumor was consistent with giant cell tumor type gastric carcinoma with osteoclast-like giant cells (OGCs). The cancer was HER2 and E-cadherin negative, chromogranin A dispersedly and moderately positive, and strongly alpha-fetoprotein-positive with evident CK AE1/AE3 immunoreactivity, while OGCs expressed CD68. To provide an insight into the molecular background of this peculiar neoplasm, next-generation sequencing (NGS) was performed to analyze the 50 most frequently mutated oncogenes and tumor suppressors. We detected mutations in the primary tumor in the following genes: KIT, EGFR, PTEN, ATM, and RB1. In the liver metastasis, we revealed mutations in 3 genes: PIK3CA, KIT, and CDKN2A. PMID- 26009571 TI - Radiation-Associated Low-Grade Extraskeletal Osteosarcoma of the Neck Following Treatment for Thyroid Cancer. AB - Low-grade extraskeletal osteosarcoma is a rare tumor that may arise de novo or following radiation therapy. Because of the low-grade histology, it may be misdiagnosed as a benign lesion. We present a case of a 59-year-old man with a past history of radiotherapy for papillary carcinoma of the thyroid, presenting 16 years later with a low-grade extraskeletal osteosarcoma of the neck. The patient was treated with surgical excision and is disease free after 12 months of follow-up. The prognosis for patients with low-grade extraskeletal osteosarcoma is relatively good when compared with high-grade sarcomas. While there is a report of a low-grade extraskeletal osteosarcoma arising following radiotherapy for a benign condition, to the best of our knowledge this is the first reported case of a low-grade extraskeletal osteosarcoma occurring following radiotherapy for thyroid cancer, and the only case reported in the soft tissue of the head and neck region. PMID- 26009572 TI - Between compliance and resistance: exploring discourses on family planning in Community Health Committees in Mozambique. AB - OBJECTIVES: Although the Mozambican government has implemented a community-based approach to family planning (FP), little is known about the appropriateness of this process. We explore how members of Community Health Committees (CHCs) address and act regarding FP. METHODS/SETTINGS: An in-depth qualitative study of CHCs was conducted at two sites in Maputo province--Ndlavela and Boane--using focus group discussions (n=6), informal conversations (n=4) and observation. The analysis followed a phenomenological approach. RESULTS: CHCs in Ndlavela appeared to transfer more of the expected information than those in Boane. However, in the CHCs at both study sites, we found heterogeneity in CHCs' perspectives leading to conflicting views among committee members (CMs). Arising issues included contraceptive type, target groups, the desirable number of children per family as well as the way FP was to be represented. Moreover, weak communication between CMs and health workers, and lack of payment for CMs' activities influenced promotion of FP. CONCLUSIONS: The two CHCs framed FP in different ways leading to inconsistent participation of CHC members in promoting FP. Policymakers should consider the diversity of discourses and aspirations of these committees when delivering information to them. PMID- 26009573 TI - Risk factors influencing the prescription of tiotropium Respimat formulation: a population-based cohort study. AB - OBJECTIVES: The study aims at investigating the influence of several factors on the probability of receiving one of the two tiotropium formulations (Respimat or Handihaler). DESIGN: Drug utilisation study. SETTING: All residents in the Region Umbria, Italy, aged >=45 years, who received prescriptions of tiotropium during 2011-2012. PARTICIPANTS: Two groups of patients were studied: (1) incident users of the two tiotropium formulations (ie, without tiotropium prescriptions in the previous 6 months); (2) switchers from Handihaler to Respimat. Users of the two formulations were compared with regard to baseline characteristics and medical history. The adjusted OR of receiving Respimat was estimated for several factors. RESULTS: Incident users of the two formulations (4390 participants) had similar characteristics. They were older and with more comorbidities than patients included in randomised control trials (RCTs). Among prevalent users of Handihaler, the probability of switching to Respimat was greater in patients with severe respiratory disease (users of >=4 respiratory drugs: adjusted OR=4.62; 95% CI 2.46 to 8.69) and among beta-blocker users (adjusted OR=1.76; 95% CI 1.13 to 2.75). Age above 75 years and lipid-lowering drug use reduced the probability of switching. A positive association was also found between neurological conditions and the use of Respimat. CONCLUSIONS: When starting tiotropium treatment, the choice between the two formulations is weakly affected by comorbidities and chronic obstructive pulmonary disease severity. Instead, these characteristics influence the likelihood of switching from Handihaler to Respimat. Since tiotropium users in clinical practice are more severe than those included in RCTs, further aetiological studies are needed to compare the safety profile of the two formulations in routine care. PMID- 26009574 TI - Surgical care for the aged: a retrospective cross-sectional study of a national surgical mortality audit. AB - OBJECTIVES: It is assumed that increased age signifies increased surgical care. Few surgical studies describe the differences in care provided to older patients compared with younger patients. We aimed to examine the relationships between increasing age, preoperative factors and markers of postoperative care in adults who died in-hospital after surgery in Australia. DESIGN: This retrospective cross sectional study extracted data from a national surgical mortality audit--an independent, peer-reviewed process. SETTING: From January 2009 to December 2012, 111 public and 61 private Australian hospitals notified the audit of in-hospital deaths after general anaesthetic surgery or if the patient was admitted under a surgeon. PARTICIPANTS: Notified deaths totalled 19,723. We excluded deaths if patients were brain dead, younger than 17 years or never had an operation (n=11,376). From this baseline population, we divided 11,201 deaths into three patient age groups: youngest (17-64 years), medium (65-79 years) and oldest (>=80 years). OUTCOME MEASURES: Univariable and multivariable logistic regression analyses determined the relationships between increasing age and the measured preoperative factors and postoperative variables. RESULTS: The baseline population's median age was 78 years (IQR 66-85), 43.7% (4892/11,201) were 80 years or older and 83.4% (9319/11,173) had emergency admissions. The oldest group had increased trauma and emergency admissions than the medium and youngest age groups. Seven of the eight measured markers of postoperative care demonstrate strong and significant relationships with increasing age. The oldest group compared with the medium group had decreased rates of: unplanned returns to theatre (11.2% (526/4709) vs 20.2% (726/3586)), unplanned intensive care admissions (16.3% (545/3350) vs 24.0% (601/2504)) and treatment in intensive care units (59.7% (2689/4507) vs 76.7% (2754/3590)). CONCLUSIONS: The oldest patients received lower levels of care than the medium and youngest age groups. PMID- 26009575 TI - Acute myocardial infarction or acute myocarditis? Discharge registry-based study of likelihood and associated features in hospitalised patients. AB - OBJECTIVE: To evaluate the likelihood of and patient features associated with acute myocardial infarction (AMI) versus acute myocarditis in different population segments. DESIGN: Nationwide, multihospital observational retrospective registry study of 9.6 years in Finland. PARTICIPANTS: All consecutive patients aged >=18 years hospitalised with a primary diagnosis of AMI (n=89 399) or acute myocarditis (n=2131) in 22 hospitals with a coronary catheterisation laboratory. PRIMARY OUTCOME MEASURES: Likelihood of AMI versus acute myocarditis and associated patient features. RESULTS: Men were over represented in patients with AMI (59.8%) and in patients with acute myocarditis (76.1%). Age distributions of AMI and acute myocarditis were opposite as a majority of patients with myocarditis were aged 18-29 years, while the number of patients with AMI increased gradually up to 80 years of age. Patients aged 18-29 years were more likely to have acute myocarditis as the cause of hospitalisation (relative risk (RR)=11.4; 95% CI 7.6 to 16.1 for myocarditis, p<0.0001), but after 30 years of age the likelihood of infarction was higher with exponentially increasing RR for AMI. In youngest patients (18-29 years), the likelihood of AMI was higher in women, but men had higher odds for AMI after 40 years of age. Overall, men had OR of 1.97 (95% CI 1.74 to 2.23, p<0.0001) for AMI versus myocarditis when compared with women. Hypercholesterolaemia, chronic coronary artery disease, diabetes and hypertension predicted AMI in multivariate analysis. Odds for myocarditis were significantly higher if the patient had an otolaryngeal infection (OR 18.13; 95% CI 8.96 to 36.67, p<0.0001). CONCLUSIONS: Acute myocarditis is more common than AMI in hospitalised patients aged 18-29 years, but the risk of AMI increases exponentially thereafter. Hypercholesterolaemia, diabetes and hypertension predict AMI regardless of age and gender. PMID- 26009576 TI - Extra Physiotherapy in Critical Care (EPICC) Trial Protocol: a randomised controlled trial of intensive versus standard physical rehabilitation therapy in the critically ill. AB - INTRODUCTION: Patients discharged from Critical Care suffer from excessive longer term morbidity and mortality. Physical and mental health measures of quality of life show a marked and immediate fall after admission to Critical Care with some recovery over time. However, physical function is still significantly reduced at 6 months. The National Institute for Health and Care Excellence clinical guideline on rehabilitation after critical illness, identified the need for high quality randomised controlled trials to determine the most effective rehabilitation strategy for critically ill patients at risk of critical illness associated physical morbidity. In response to this, we will conduct a randomised controlled trial, comparing physiotherapy aimed at early and intensive patient mobilisation with routine care. We hypothesise that this intervention will improve physical outcomes and the mental health and functional well-being of survivors of critical illness. METHODS AND ANALYSIS: 308 adult patients who have received more than 48 h of non-invasive or invasive ventilation in Critical Care will be recruited to a patient-randomised, parallel group, controlled trial, comparing two intensities of physiotherapy. Participants will be randomised to receive either standard or intensive physiotherapy for the duration of their Critical Care admission. Outcomes will be recorded on Critical Care discharge, at 3 and 6 months following initial recruitment to the study. The primary outcome measure is physical health at 6 months, as measured by the SF-36 Physical Component Summary. Secondary outcomes include assessment of mental health, activities of daily living, delirium and ventilator-free days. We will also include a health economic analysis. ETHICS AND DISSEMINATION: The trial has ethical approval from Newcastle and North Tyneside 2 Research Ethics Committee (11/NE/0206). There is a Trial Oversight Committee including an independent chair. The results of the study will be submitted for publication in peer reviewed journals and presented at national and international scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN20436833. PMID- 26009578 TI - Differences in Tobacco Product Use Among Past Month Adult Marijuana Users and Nonusers: Findings From the 2003-2012 National Survey on Drug Use and Health. AB - INTRODUCTION: This study assessed differences in individual tobacco product use between past month marijuana users and nonusers, and trends in overall tobacco use and use of specific tobacco products among marijuana users. METHODS: Data were obtained from 378 459 adults participating in the 2003-2012 National Survey on Drug Use and Health, a cross-sectional, household interview survey conducted annually. Data from the most recent 2 years (2011-2012) were used to assess differences in the prevalence of various tobacco products by past month marijuana status. Data from all years were used to assess historical trends in overall tobacco use, and use of cigarettes, cigars, and blunts among marijuana users; trend significance was assessed using orthogonal polynomials. RESULTS: From 2011 2012, the prevalence of any past month tobacco use among the 9727 past month marijuana users was 68.6% excluding blunts, and 78.3% including blunts (vs. 25.3% for nonusers, P < .0001); 77.3% of past month marijuana users reported past month combusted tobacco use (vs. 23.4% of non-MJ users, P < .0001). By product, 60.1% of past month marijuana users reported past month cigarette use, 42.0% reported past month blunt use, and 20.6% reported past month cigar use. Overall, adjusted trends in past month cigarette use decreased, while trends in past month blunt use increased; cigar use did not change. DISCUSSION: Tobacco use is highly prevalent among adult marijuana users and represents an important potential comorbidity of marijuana use. In light of increasing policies legalizing marijuana, it is critical to monitor changes in overall and specific tobacco product use. PMID- 26009577 TI - Protocol for a multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin versus standard therapy for the treatment of transverse myelitis in adults and children (STRIVE). AB - INTRODUCTION: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord which causes motor and sensory disturbance and limited recovery in 50% of patients. Standard treatment is steroids, and patients with more severe disease appear to respond to plasma exchange (PLEX). Intravenous immunoglobulin (IVIG) has also been used as an adjunct to steroids, but evidence is lacking. We propose the first randomised control trial in adults and children, to determine the benefit of additional treatment with IVIG. METHODS AND ANALYSIS: 170 adults and children aged over 1 year with acute first episode TM or neuromyelitis optica (with myelitis) will be recruited over a 2.5-year period and followed up for 12 months. Participants randomised to the control arm will receive standard therapy of intravenous methylprednisolone (IVMP). The intervention arm will receive the above standard therapy, plus additional IVIG. Primary outcome will be a 2-point improvement on the American Spinal Injury Association (ASIA) Impairment scale at 6 months postrandomisation by blinded assessors. Additional secondary and tertiary outcome measures will be collected: ASIA motor and sensory scales, Kurtzke expanded disability status scale, International Spinal Cord Injury (SCI) Bladder/Bowel Data Set, Client Services Receipt Index, Pediatric Quality of Life Inventory, EQ-5D, SCI Pain and SCI Quality of Life Data Sets. Biological samples will be biobanked for future studies. After 6-months' follow-up of the first 52 recruited patients futility analysis will be carried out. Health economics analysis will be performed to calculate cost-effectiveness. After 6 months' recruitment futility analysis will be performed. ETHICS AND DISSEMINATION: Research Ethics Committee Approval was obtained: 14/SC/1329. Current protocol: v3.0 (15/01/2015). Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: This study is registered with EudraCT (REF: 2014 002335-34), Clinicaltrials.gov (REF: NCT02398994) and ISRCTN (REF: 12127581). PMID- 26009580 TI - Going gently. PMID- 26009579 TI - Exposure to traffic noise and markers of obesity. AB - OBJECTIVES: Limited evidence suggests adverse effects of traffic noise exposure on the metabolic system. This study investigates the association between road traffic noise and obesity markers as well as the role of combined exposure to multiple sources of traffic noise. METHODS: In a cross-sectional study performed in 2002-2006, we assessed exposure to noise from road traffic, railways and aircraft at the residences of 5075 Swedish men and women, primarily from suburban and semirural areas of Stockholm County. A detailed questionnaire and medical examination provided information on markers of obesity and potential confounders. Multiple linear and logistic regression models were used to assess associations between traffic noise and body mass index (BMI), waist circumference and waist hip ratio using WHO definitions of obesity. RESULTS: Road traffic noise was significantly related to waist circumference with a 0.21 cm (95% CI 0.01 to 0.41) increase per 5 dB(A) rise in L(den). The OR for central obesity among those exposed to road traffic noise >= 45 dB(A) was 1.18 (95% CI 1.03 to 1.34) in comparison to those exposed below this level. Similar results were seen for waist hip ratio (OR 1.29; 95% CI 1.14 to 1.45) but not for BMI (OR 0.89; 95% CI 0.76 to 1.04). Central obesity was also associated with exposure to railway and aircraft noise, and a particularly high risk was seen for combined exposure to all three sources of traffic noise (OR 1.95; 95% CI 1.24 to 3.05). CONCLUSIONS: Our results suggest that traffic noise exposure can increase the risk of central obesity. Combined exposure to different sources of traffic noise may convey a particularly high risk. PMID- 26009581 TI - Dr. David Sackett, a giant among giants (1934-2015). PMID- 26009582 TI - Health researchers highlighted in online project. PMID- 26009584 TI - E-cigarette data don't end debate. PMID- 26009583 TI - Association between frailty and 30-day outcomes after discharge from hospital. AB - BACKGROUND: Readmissions after hospital discharge are common and costly, but prediction models are poor at identifying patients at high risk of readmission. We evaluated the impact of frailty on readmission or death within 30 days after discharge from general internal medicine wards. METHODS: We prospectively enrolled patients discharged from 7 medical wards at 2 teaching hospitals in Edmonton. Frailty was defined by means of the previously validated Clinical Frailty Scale. The primary outcome was the composite of readmission or death within 30 days after discharge. RESULTS: Of the 495 patients included in the study, 162 (33%) met the definition of frailty: 91 (18%) had mild, 60 (12%) had moderate, and 11 (2%) had severe frailty. Frail patients were older, had more comorbidities, lower quality of life, and higher LACE scores at discharge than those who were not frail. The composite of 30-day readmission or death was higher among frail than among nonfrail patients (39 [24.1%] v. 46 [13.8%]). Although frailty added additional prognostic information to predictive models that included age, sex and LACE score, only moderate to severe frailty (31.0% event rate) was an independent risk factor for readmission or death (adjusted odds ratio 2.19, 95% confidence interval 1.12-4.24). INTERPRETATION: Frailty was common and associated with a substantially increased risk of early readmission or death after discharge from medical wards. The Clinical Frailty Scale could be useful in identifying high-risk patients being discharged from general internal medicine wards. PMID- 26009586 TI - Eyelid ptosis. PMID- 26009585 TI - Multifocal strokes in a 56-year-old man with HIV infection. PMID- 26009588 TI - Diagnosis and management of developmental coordination disorder. PMID- 26009589 TI - Will Quebec influence Ontario's IVF plans? PMID- 26009591 TI - Tomato Glutamate Decarboxylase Genes SlGAD2 and SlGAD3 Play Key Roles in Regulating gamma-Aminobutyric Acid Levels in Tomato (Solanum lycopersicum). AB - Tomato (Solanum lycopersicum) can accumulate relatively high levels of gamma aminobutyric acid (GABA) during fruit development. However, the molecular mechanism underlying GABA accumulation and its physiological function in tomato fruits remain elusive. We previously identified three tomato genes (SlGAD1, SlGAD2 and SlGAD3) encoding glutamate decarboxylase (GAD), likely the key enzyme for GABA biosynthesis in tomato fruits. In this study, we generated transgenic tomato plants in which each SlGAD was suppressed and those in which all three SlGADs were simultaneously suppressed. A significant decrease in GABA levels, i.e. 50-81% compared with wild-type (WT) levels, was observed in mature green (MG) fruits of the SlGAD2-suppressed lines, while a more drastic reduction (up to <10% of WT levels) was observed in the SlGAD3- and triple SlGAD-suppressed lines. These findings suggest that both SlGAD2 and SlGAD3 expression are crucial for GABA biosynthesis in tomato fruits. The importance of SlGAD3 expression was also confirmed by generating transgenic tomato plants that over-expressed SlGAD3. The MG and red fruits of the over-expressing transgenic lines contained higher levels of GABA (2.7- to 5.2-fold) than those of the WT. We also determined that strong down-regulation of the SlGADs had little effect on overall plant growth, fruit development or primary fruit metabolism under normal growth conditions. PMID- 26009590 TI - Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism. AB - AIMS: To define the molecular mechanisms of cardiotoxicity induced by Sunitinib and to identify the role of biological sex in modulating toxicity. METHODS AND RESULTS: Exposure of isolated cardiomyocytes to plasma-relevant concentrations of Sunitinib and other tyrosine kinase inhibitors produces a broad spectrum of abnormalities and cell death via apoptosis downstream of sexually dimorphic kinase inhibition. Phosphorylation of protein kinase C and phospholipase gamma abrogates these effects for most tyrosine kinase inhibitors tested. Female sex and estradiol cause increased cardiotoxicity, which is mediated by reduced expression of a drug efflux transporter and a metabolic enzyme. Female but not male mice exposed to a 28-day course of oral Sunitinib exhibit similar abnormalities as well as functional deficits and their hearts exhibit differential expression of genes responsible for transport and metabolism of Sunitinib. CONCLUSION: We identify the specific pathways affected by tyrosine kinase inhibitors in mammalian cardiomyocytes, interactions with biological sex, and a role for oestrogen in modulating drug efflux and metabolism. These findings represent a critical step toward reducing the incidence of cardiotoxicity with tyrosine kinase inhibitor chemotherapeutics. PMID- 26009592 TI - RNA-seq Transcriptional Profiling of an Arbuscular Mycorrhiza Provides Insights into Regulated and Coordinated Gene Expression in Lotus japonicus and Rhizophagus irregularis. AB - Gene expression during arbuscular mycorrhizal development is highly orchestrated in both plants and arbuscular mycorrhizal fungi. To elucidate the gene expression profiles of the symbiotic association, we performed a digital gene expression analysis of Lotus japonicus and Rhizophagus irregularis using a HiSeq 2000 next generation sequencer with a Cufflinks assembly and de novo transcriptome assembly. There were 3,641 genes differentially expressed during arbuscular mycorrhizal development in L. japonicus, approximately 80% of which were up regulated. The up-regulated genes included secreted proteins, transporters, proteins involved in lipid and amino acid metabolism, ribosomes and histones. We also detected many genes that were differentially expressed in small-secreted peptides and transcription factors, which may be involved in signal transduction or transcription regulation during symbiosis. Co-regulated genes between arbuscular mycorrhizal and root nodule symbiosis were not particularly abundant, but transcripts encoding for membrane traffic-related proteins, transporters and iron transport-related proteins were found to be highly co-up-regulated. In transcripts of arbuscular mycorrhizal fungi, expansion of cytochrome P450 was observed, which may contribute to various metabolic pathways required to accommodate roots and soil. The comprehensive gene expression data of both plants and arbuscular mycorrhizal fungi provide a powerful platform for investigating the functional and molecular mechanisms underlying arbuscular mycorrhizal symbiosis. PMID- 26009593 TI - Sulfite-stress induced functional and structural changes in the complexes of photosystems I and II in a cyanobacterium, Synechococcus elongatus PCC 7942. AB - Excess sulfite is well known to have toxic effects on photosynthetic activities and growth in plants, however, so far, the behavior of the photosynthetic apparatus during sulfite-stress has not been characterized as to the responsible proteins or genes. Here, the effects of sulfite on photosystem complexes were investigated in a cyanobacterium, Synechococcus elongatus PCC 7942, a possible model organism of chloroplasts. Culturing of the cells for 24 h in the presence of 10 mM sulfite retarded cell growth of the wild type, concomitantly with synthesis of Chl and phycobilisome repressed. The excess sulfite simultaneously repressed photosynthesis by more than 90%, owing largely to structural destabilization and resultant inactivation of the PSII complex, which seemed to consequently retard the cell growth. Notably, the PsbO protein, one of the subunits that construct the water-splitting system of PSII, was retained at a considerable level, and disruption of the psbO gene led to higher sensitivity of photosynthesis and growth to sulfite. Meanwhile, the PSI complex showed monomerization of its trimeric configuration with little effect on the activity. The structural alterations of these PS complexes depended on light. Our data provide evidence for quantitative decreases in the photosystem complex(es) including their antenna(e), structural alterations of the PSI and PSII complexes that would modulate their functions, and a crucial role of psbO in PSII protection, in Synechococcus cells during sulfite-stress. We suggest that the reconstruction of the photosystem complexes is beneficial to cell survival. PMID- 26009594 TI - Drug-coated balloon treatment for lower extremity vascular disease intervention: an international positioning document. PMID- 26009595 TI - The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the EchoCRT trial. AB - AIMS: In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT is recommended in patients with a QRS duration of >=120 ms. However, there is some ambiguity from clinical trial data regarding the benefit of patients with a QRS duration of 120-130 ms. METHODS AND RESULTS: The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared data for CRT-ON vs. -OFF in patients with QRS < 120 (n = 661) and QRS 120-130 ms (n = 139). On uni- and multivariable analyses, no significant interaction was observed between the two groups and randomized treatment for the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was observed in patients with a QRS duration of 120-130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18, 95% CI 1.02-4.65; P = 0.044). However, no statistically significant interaction, compared with patients with QRS < 120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction = 0.160). CONCLUSIONS: In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of 120-130 ms. These data further question the usefulness of CRT in this patient population. PMID- 26009597 TI - Congenital left atrial appendage herniation. PMID- 26009598 TI - Amniotic membrane graft to reconstruct divided nevi of eyelids. AB - Two patients with congenital divided nevi of the eyelids presented with chief symptoms of cosmetic blemish (n=2) and epiphora (n=1). All the lesions were surgically excised with histological free margins and amniotic membrane graft (AMG) was used to cover the mucosal and eyelid marginal defects. Caruncular and punctal involvement was managed with complete excision and monocanalicular stent insertion to prevent punctal stenosis. AMG provided an adequate scaffold for conjunctival regenesis and anatomic continuity was found within 6 weeks in both patients. None of them had any residual pigmentation or disease recurrence after a follow-up of more than 2.5 years. Local absence of eyelashes was the only drawback which patients masked with modern artificial eyelashes or make-up. This novel utility of AMG illustrates effective conjunctival regenesis and maintenance of mucocutaneous junction functionality. PMID- 26009599 TI - Malignant systemic hypertension, encephalopathy and bradycardia following splenectomy for hereditary spherocytosis. AB - An 8-year-old girl suffering from hereditary spherocytosis underwent splenectomy for chronic severe anaemia. Surgery was uneventful and the patient had a good early postoperative recovery. On the third postoperative day, however, she developed severe headache with associated abnormal movements of upper limbs and nystagmus. She had a heart rate of 50 bpm and a blood pressure of 180/110 mm Hg. She was managed with triple antihypertensives, antiepileptics and sedatives. She recovered slowly over 2 weeks and is fine at 5 months follow-up. PMID- 26009600 TI - Acute liver failure in dengue haemorrhagic fever. AB - While dengue virus infection leads to a mild to moderate elevation of liver transaminases in almost all cases, hepatic failure rarely dominates the clinical picture in adults. We present a case of dengue haemorrhagic fever in a young adult, leading to the rare complication of acute liver failure. He was managed with supportive care and discharged after 5 days. At follow-up after 1 week, he had complete recovery and no residual symptoms. PMID- 26009601 TI - Carcinoma of the cervix complicating a genital prolapse. AB - Although uterine prolapse and carcinoma of the uterine cervix are not rare events, their association is very uncommon. The treatment of cervical cancer has been protocolled, but the management of uterovaginal prolapse associated with carcinoma of the cervix is not standardised and therapy strategies vary considerably among authors. Our case reports a 74-year-old patient, admitted to the emergency department with an ulcerated prolapsed uterus. Biopsy of the cervical lesion confirmed a squamous-cell carcinoma. The patient underwent vaginal hysterectomy plus open bilateral iliopelvic lymphadenectomy complemented with radiotherapy with quimiosensibilisation. With this aggressive treatment approach, there was progression of the disease. The authors believe that this case typiaddition to the few published reports. PMID- 26009602 TI - Electroconvulsive therapy: a life course approach for recurrent depressive disorder. AB - We describe the case of an 89-year-old woman (deceased) with a 60-year history of recurrent depressive disorder treated with electroconvulsive therapy (ECT). It is estimated that she received up to 400 ECTs over her life course as her symptoms would not respond to oral medication. Despite extensive exposure to ECT, there was only minimal cognitive impairment and an excellent safety record, even in later life, as she became increasingly frail from multiple comorbidities. Over the years, there has been a drive to reduce the frequency of ECT administration. However, this case illustrates how in some patients ECT may be vital for acute episodes of severe depression as well as for maintenance therapy. This case report adds to observational evidence that maintenance ECT may be an underused treatment for recurrent depression and also recommends that greater emphasis be given to incorporating carers' views when planning individualised treatment approaches. PMID- 26009596 TI - Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. AB - Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C >=5 mmol/L (190 mg/dL), or an LDL-C >=4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is >=3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH. PMID- 26009603 TI - Glucocorticoid-induced myopathy in the intensive care unit. AB - Glucocorticoids (GC) are used for intensive care unit (ICU) patients on several indications. We present a patient who was admitted to the ICU due to severe respiratory failure caused by bronchospasm requiring mechanical ventilation and treated with methylprednisolone 240 mg/day in addition to antibiotics and bronchiolytics. When the sedation was lifted on day 10, the patient was awake but quadriplegic. Blood samples revealed elevated muscle enzymes, electromyography showed myopathy, and a muscle biopsy was performed. Glucocorticoid-induced myopathy was suspected, GC treatment was tapered, and muscle strength gradually returned. The patient made full recovery from the quadriplegia a few months later. PMID- 26009604 TI - When treatment can be worse than the disease: nicorandil-induced colitis. AB - A 75-year-old woman presented with severe abdominal pain and diarrhoea. Symptoms started 10 years earlier but multiple investigations failed to offer a clear diagnosis. On recent admission, blood tests, endoscopies and CT scans indicated chronic colonic inflammation. Treatment strategies for bowel inflammation were unsuccessful and the patient was subsequently discussed at a multidisciplinary team meeting with surgeons for consideration of colectomy. A drug review highlighted that the patient was taking an antiangina drug, nicorandil, thought to cause bowel ulceration. This was discontinued, which dramatically improved symptoms and avoided surgery and the patient was discharged within days. Follow up colonoscopy showed much improved colitis, and the diarrhoea had resolved. It is important that clinicians are aware of the link between pharmacotherapy, specifically nicorandil and gastrointestinal ulceration and inflammation causing severe diarrhoea. Drug cessation is the only necessary and immediately effective treatment. Awareness of this will become more clinically relevant as nicorandil use increases. PMID- 26009605 TI - Molecular detection of Schizophyllum commune in a case of allergic fungal rhinosinusitis. AB - We present a rare case of Schizophyllum commune causing allergic fungal rhinosinusitis (AFRS) in a 56-year-old immunocompetent woman. In our case, diagnosis of AFRS was based on the history of illness, CT scan findings, culture and PCR. The PCR product was further analysed by sequencing to confirm S. commune. The patient was treated by functional endoscopic sinus surgery (FESS) and antiallergic drugs. PMID- 26009606 TI - Simplified technique for retrieval of large trichobezoars in children. AB - Trichobezoars are concentrations of indigestible hair or hair-like fibres within the proximal intestinal tract. In children, delayed presentation with large bezoar masses is not unusual as bezoar formation is an indolent process that takes many months or years before becoming symptomatic. Surgical management is challenging and becomes inevitable once a trichobezoar becomes more established. The standard approach involves a sizeable transverse or midline laparotomy. We describe a less invasive technique for extraction of large gastric trichobezoars via a mini-laparotomy. The key aspect to this technique involves insertion of an Alexis O Wound Protector/Retractor (Applied Medical, Rancho Santa Margarita, California, USA) into the stomach following creation of a secure temporary gastrostomy by hitching gastrotomy edges to the abdominal wall. This simplified approach has advantages of (1) secure and excellent direct intragastric access, (2) shorter operating time and (3) reliable protection of both the wound edges and peritoneal cavity from bezoar contamination. PMID- 26009607 TI - Golden ring in the eyes: Weill-Marchesani syndrome. PMID- 26009608 TI - 2025 Saito et al [j infect dis 2015; 211:452-61]. PMID- 26009610 TI - A review of data quality of an electronic tuberculosis surveillance system for case-based reporting in Kenya. AB - BACKGROUND: Kenya recently transitioned from a paper to an electronic system for recording and reporting of tuberculosis (TB) data. METHODS: During September October 2013, the data quality of the new system was evaluated through an audit of data in paper source documents and in the national electronic system, and an analysis of all 99 281 cases reported in 2012. RESULTS: While the new electronic system overall is robust, this assessment demonstrated limitations in the concordance and completeness of data reaching the national level. CONCLUSIONS: Additional oversight and training in data entry are needed to strengthen TB surveillance data quality in Kenya. PMID- 26009611 TI - Obesity and the potential reduction of social inequalities in mortality: evidence from 21 European populations. AB - BACKGROUND: Obesity contributes considerably to the problem of health inequalities in many countries, but quantitative estimates of this contribution and to what extent it is modifiable are scarce. We identify the potential for reducing educational inequalities in all-cause and obesity-related mortality in 21 European populations, by modifying educational differences in obesity and overweight. METHODS: Prevalence data and mortality data come from 21 European populations. Mortality rate ratios come from literature reviews. We use the population attributable fraction (PAF) to estimate the impact of scenario-based changes in the social distribution of obesity on educational inequalities in mortality. RESULTS: An elimination of differences in obesity between educational groups would decrease relative inequality in all-cause mortality between those with high and low education by up to 12% for men and 42% for women. About half of the relative inequality in mortality could be reduced for some causes of death in several countries, often in southern Europe. Absolute inequalities in all-cause mortality would be reduced by up to 69 (men) and 67 (women) deaths per 100,000 person-years. CONCLUSION: The potential reduction of health inequality by an elimination of social inequalities in obesity might be substantial. The reductions differ by country, cause of death and gender, suggesting that the priority given to obesity as an entry-point for tackling health inequalities should differ between countries and gender. PMID- 26009612 TI - Occipital MEG Activity in the Early Time Range (<300 ms) Predicts Graded Changes in Perceptual Consciousness. AB - Two electrophysiological components have been extensively investigated as candidate neural correlates of perceptual consciousness: An early, occipitally realized component occurring 130-320 ms after stimulus onset and a late, frontally realized component occurring 320-510 ms after stimulus onset. Recent studies have suggested that the late component may not be uniquely related to perceptual consciousness, but also to sensory expectations, task associations, and selective attention. We conducted a magnetoencephalographic study; using multivariate analysis, we compared classification accuracies when decoding perceptual consciousness from the 2 components using sources from occipital and frontal lobes. We found that occipital sources during the early time range were significantly more accurate in decoding perceptual consciousness than frontal sources during both the early and late time ranges. These results are the first of its kind where the predictive values of the 2 components are quantitatively compared, and they provide further evidence for the primary importance of occipital sources in realizing perceptual consciousness. The results have important consequences for current theories of perceptual consciousness, especially theories emphasizing the role of frontal sources. PMID- 26009614 TI - Drug metabolism and drug interactions: potential application to antituberculosis drugs. AB - Drug-drug interaction is an important element of modern drug development. In the case of antituberculosis drugs, which are frequently administered as combinations of multiple therapeutic agents, the potential for interactions between coadministered drugs and between new and existing drugs should be considered during the development of new antituberculosis drugs and combination regimens. The current understanding of drug-drug interactions involving the first-line antituberculosis drugs is reviewed in this article, along with the approaches that are used to prospectively delineate potential interactions during development of new therapies. In addition, current knowledge gaps are identified, and future directions for enhancing the understanding of drug-drug interactions that will further facilitate the development of novel antituberculosis therapies are discussed. PMID- 26009613 TI - Thalamo-Cortical Disruption Contributes to Short-Term Memory Deficits in Patients with Medial Temporal Lobe Damage. AB - Short-term (STM) and long-term memory (LTM) have largely been considered as separate brain systems reflecting fronto-parietal and medial temporal lobe (MTL) functions, respectively. This functional dichotomy has been called into question by evidence of deficits on aspects of working memory in patients with MTL damage, suggesting a potentially direct hippocampal contribution to STM. As the hippocampus has direct anatomical connections with the thalamus, we tested the hypothesis that damage to thalamic nuclei regulating cortico-cortical interactions may contribute to STM deficits in patients with hippocampal dysfunction. We used diffusion-weighted magnetic resonance imaging-based tractography to identify anatomical subdivisions in patients with MTL epilepsy. From these, we measured resting-state functional connectivity with detailed cortical divisions of the frontal, temporal, and parietal lobes. Whereas thalamo temporal functional connectivity reflected LTM performance, thalamo-prefrontal functional connectivity specifically predicted STM performance. Notably, patients with hippocampal volume loss showed thalamic volume loss, most prominent in the pulvinar region, not detected in patients with normal hippocampal volumes. Aberrant thalamo-cortical connectivity in the epileptic hemisphere was mirrored in a loss of behavioral association with STM performance specifically in patients with hippocampal atrophy. These findings identify thalamo-cortical disruption as a potential mechanism contributing to STM deficits in the context of MTL damage. PMID- 26009616 TI - Assessing the landscape of tools and approaches for novel tuberculosis regimen development. PMID- 26009617 TI - Nonclinical models for antituberculosis drug development: a landscape analysis. AB - BACKGROUND: Several nonclinical drug-development tools (DDTs) have been used for antituberculosis drug development over several decades. The role of the DDTs used for evaluating the efficacy of antituberculosis drug combinations and the gaps in the evidence base for which new tools or approaches are needed are as yet undefined. METHODS: We performed a landscape analysis based on a comprehensive literature review to create evidence based guidelines. RESULTS: There are 3 important questions that a DDT should answer with regard to antituberculosis drugs: What combination(s) of drugs will be most effective? What dose(s) and schedule(s) of each drug should be administered? and What duration(s) of treatment will be efficacious? Four DDTs were identified as having a track record to answer these questions: in vitro susceptibility tests, the hollow fiber system model of tuberculosis, mice, and guinea pigs. No single nonclinical in vitro or animal model recapitulates all aspects of human tuberculosis. Therefore, a combination of models is recommended for drug development. Gaps identified include the need for standardization of nonclinical model experiments, evaluation of animal models with pathology more similar to that in humans, and identification of experimental quantitative output in the DDTs that correlates with sterilizing effect in humans. CONCLUSIONS: There is a need for formal quantitative analyses of how well DDTs forecast clinical outcomes. PMID- 26009615 TI - Special populations and pharmacogenetic issues in tuberculosis drug development and clinical research. AB - Special populations, including children and pregnant women, have been neglected in tuberculosis drug development. Patients in developing countries are inadequately represented in pharmacology research, and postmarketing pharmacovigilance activities tend to be rudimentary in these settings. There is an ethical imperative to generate evidence at an early stage to support optimal treatment in these populations and in populations with common comorbid conditions, such as diabetes and human immunodeficiency virus (HIV) infection. This article highlights the research needed to support equitable access to new antituberculosis regimens. Efficient and opportunistic pharmacokinetic study designs, typically using sparse sampling and population analysis methods, can facilitate optimal dose selection for children and pregnant women. Formulations suitable for children should be developed early and used in pharmacokinetic studies to guide dose selection. Drug-drug interactions between commonly coprescribed medications also need to be evaluated, and when these are significant, alternative approaches should be sought. A potent rifamycin-sparing regimen could revolutionize the treatment of adults and children requiring a protease inhibitor as part of antiretroviral treatment regimens for HIV infection. A sufficiently wide formulary of drugs should be developed for those with contraindications to the standard approaches. Because genetic variations may influence an individual's response to tuberculosis treatment, depending on the population being treated, it is important that samples be collected and stored for pharmacogenetic study in future clinical trials. PMID- 26009618 TI - Pharmacokinetic-pharmacodynamic and dose-response relationships of antituberculosis drugs: recommendations and standards for industry and academia. AB - BACKGROUND: Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science is vital to early antibiotic drug development to enable more efficient dose-effect study designs, identification of doses that may suppress drug resistance and choice of susceptibility breakpoints. Proper conduct of such studies is essential in the field of tuberculosis. METHODS: We conducted an exhaustive review of literature on the hollow fiber system (HFS) model, murine model, and guinea pig model of tuberculosis as well as clinical studies to identify PK/PD studies that have been applied to antituberculosis therapy. Lessons learned are presented as recommendations and standards for both industry and academia in the field of antituberculosis drug development. RESULTS: PK/PD studies have been performed for both first-line and experimental antituberculosis agents. When properly designed exposure-effect and dose-fractionation studies have been performed in preclinical models, optimal drug exposures, and PK/PD parameters identified in these models have been found to be similar to clinical studies. Susceptibility breakpoints identified using these methods differed from previous concentrations in the literature but were found to be similar to those in prospective clinical studies. CONCLUSIONS: Preclinical PK/PD studies are essential value added in the development of antituberculosis agents. We provide 8 recommendations and standards for the proper conduct of such studies. PMID- 26009619 TI - Ophthalmic abnormalities and reading impairment. AB - OBJECTIVES: To explore associations between specific learning disorder with impairment in reading (dyslexia) and ophthalmic abnormalities in children aged 7 to 9 years. METHODS: Cross-sectional analysis was performed on cohort study data from the Avon Longitudinal Study of Parents and Children. Reading impairment was defined according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Children who achieved >2 SD below the mean in the Neale Analysis of Reading Ability Scale II and level <4 in nonmathematical national key stage 2 tests were defined as having severe reading impairment (SRI). Children with blindness or IQ <70 were excluded. RESULTS: Data were available for 5822 children, of whom 172 (3%) met the criteria for SRI. No association was found between SRI and strabismus, motor fusion, sensory fusion at a distance, refractive error, amblyopia, convergence, accommodation, or contrast sensitivity. Abnormalities in sensory fusion at near were mildly higher in children with SRI compared with their peers (1 in 6 vs 1 in 10, P = .08), as were children with stereoacuity worse than 60 seconds/arc (1 in 6 vs 1 in 10, P = .001). CONCLUSIONS: Four of every 5 children with SRI had normal ophthalmic function in each test used. A small minority of children displayed minor anomalies in stereoacuity or fusion of near targets. The slight excess of these children among those with SRI may be a result of their reading impairment or may be unrelated. We found no evidence that vision-based treatments would be useful to help children with SRI. PMID- 26009620 TI - Tumor-induced rickets in a child with a central giant cell granuloma: a case report. AB - Tumor-induced osteomalacia/rickets is a rare paraneoplastic disorder associated with a tumor-producing fibroblast growth factor 23 (FGF23). We present a child with symptoms of rickets as the first clinical sign of a central giant cell granuloma (CGCG) with high serum levels of FGF23, a hormone associated with decreased phosphate resorption. A 3-year-old boy presented with a limp and 6 months later with painless growth of the jaw. On examination gingival hypertrophy and genu varum were observed. Investigations revealed hypophosphatemia, normal 1,25 and 25 (OH) vitamin D, and high alkaline phosphatase. An MRI showed an osteolytic lesion of the maxilla. Radiographs revealed typical rachitic findings. Incisional biopsy of the tumor revealed a CGCG with mesenchymal matrix. The CGCG was initially treated with calcitonin, but the lesions continued to grow, making it necessary to perform tracheostomy and gastrostomy. One year after onset the hyperphosphaturia worsened, necessitating increasing oral phosphate supplements up to 100 mg/kg per day of elemental phosphorus. FGF23 levels were extremely high. Total removal of the tumor was impossible, and partial reduction was achieved after percutaneous computed tomography-guided radiofrequency, local instillation of triamcinolone, and oral propranolol. Compassionate use of cinacalcet was unsuccessful in preventing phosphaturia. The tumor slowly regressed after the third year of disease; phosphaturia improved, allowing the tapering of phosphate supplements, and FGF23 levels normalized. Tumor-induced osteomalacia/rickets is uncommon in children and is challenging for physicians to diagnose. It should be suspected in patients with intractable osteomalacia or rickets. A tumor should be ruled out if FGF23 levels are high. PMID- 26009621 TI - Sudden infant death syndrome and residential altitude. AB - BACKGROUND: Theories of sudden infant death syndrome (SIDS) suggest hypoxia is a common pathway. Infants living at altitude have evidence of hypoxia; however, the association between SIDS incidence and infant residential altitude has not been well studied. METHODS: We performed a retrospective cohort study by using data from the Colorado birth and death registries from 2007 to 2012. Infant residential altitude was determined by geocoding maternal residential address. Logistic regression was used to determine adjusted association between residential altitude and SIDS. We evaluated the impact of the Back to Sleep campaign across various altitudes in an extended cohort from 1990 to 2012 to assess for interaction between sleep position and altitude. RESULTS: A total of 393 216 infants born between 2007 and 2012 were included in the primary cohort (51.4% boys; mean birth weight 3194 +/- 558 g). Overall, 79.6% infants resided at altitude <6000 feet, 18.5% at 6000 to 8000 feet, and 1.9% at >8000 feet. There were no meaningful differences in maternal characteristics across altitude groups. Compared with residence <6000 feet, residence at high altitude (>8000 feet), was associated with an adjusted increased risk of SIDS (odds ratio 2.30; 95% confidence interval 1.01-5.24). Before the Back to Sleep campaign, the incidence of SIDS in Colorado was 1.99/1000 live births and dropped to 0.57/1000 live births after its implementation. The Back to Sleep campaign had similar effect across different altitudes (P = .45). CONCLUSIONS: Residence at high altitude was significantly associated with an increased adjusted risk for SIDS. Impact of the Back to Sleep campaign was similar across various altitudes. PMID- 26009625 TI - Congenital adrenal hyperplasia: a case report with premature teeth exfoliation and bone resorption. AB - Congenital adrenal hyperplasia (CAH) is an inherited autosomal recessive disorder characterized by insufficient production of cortisol. The aim of this case report was to present a child with CAH, premature exfoliation of primary teeth and accelerated eruption of his permanent teeth related to bone resorption. A 4.5 year-old Caucasian boy with CAH and long-term administration of glucocorticoids was referred for dental restoration. Clinical examination revealed primary molars with worn stainless steel crowns, severe attrition of the upper canines, and absence of the upper incisors. Before the completion of treatment, abnormal mobility of the first upper primary molars and the lower incisors was detected, and a few days later the teeth exfoliated prematurely. Histologic examination revealed normal tooth structure. Alkaline phosphatase and blood cells values were normal. Eruption of the permanent dentition was also accelerated. Tooth mobility was noticed in the permanent teeth as soon as they erupted, along with bone destruction. Examination revealed an elevated level of receptor activator of nuclear factor-kappaB ligand and lower-than-normal osteoprotegerin and vitamin D levels. The patient was treated with vitamin D supplements, and his teeth have been stable ever since. CAH is a serious chronic disorder appearing in children with accelerated dental development and possibly premature loss of primary teeth. PMID- 26009624 TI - A pediatrician's practical guide to diagnosing and treating hereditary spherocytosis in neonates. AB - Newborn infants who have hereditary spherocytosis (HS) can develop anemia and hyperbilirubinemia. Bilirubin-induced neurologic dysfunction is less likely in these neonates if the diagnosis of HS is recognized and appropriate treatment provided. Among neonates listed in the USA Kernicterus Registry, HS was the third most common underlying hemolytic condition after glucose-6-phosphate dehydrogenase deficiency and ABO hemolytic disease. HS is the leading cause of direct antiglobulin test (direct Coombs) negative hemolytic anemia requiring erythrocyte transfusion in the first months of life. We anticipate that as physicians become more familiar with diagnosing HS in the newborn period, fewer neonates with HS will develop hazardous hyperbilirubinemia or present to emergency departments with unanticipated symptomatic anemia. We predict that early suspicion, prompt diagnosis and treatment, and anticipatory guidance will prevent adverse outcomes in neonates with HS. The purpose of this article was to review the neonatal presentation of HS and to provide practical and up-to-date means of diagnosing and treating HS in neonates. PMID- 26009626 TI - The need to build capability and capacity in quality improvement and patient safety. PMID- 26009628 TI - Diagnostic accuracy of the urinalysis for urinary tract infection in infants <3 months of age. AB - BACKGROUND: The 2011 American Academy of Pediatrics urinary tract infection (UTI) guideline suggests incorporation of a positive urinalysis (UA) into the definition of UTI. However, concerns linger over UA sensitivity in young infants. Infants with the same pathogenic organism in the blood and urine (bacteremic UTI) have true infections and represent a desirable population for examination of UA sensitivity. METHODS: We collected UA results on a cross-sectional sample of 276 infants <3 months of age with bacteremic UTI from 11 hospital systems. Sensitivity was calculated on infants who had at least a partial UA performed and had >=50 000 colony-forming units per milliliter from the urine culture. Specificity was determined by using a random sample of infants from the central study site with negative urine cultures. RESULTS: The final sample included 245 infants with bacteremic UTI and 115 infants with negative urine cultures. The sensitivity of leukocyte esterase was 97.6% (95% confidence interval [CI] 94.5% 99.2%) and of pyuria (>3 white blood cells/high-power field) was 96% (95% CI 92.5%-98.1%). Only 1 infant with bacteremic UTI (Group B Streptococcus) and a complete UA had an entirely negative UA. In infants with negative urine cultures, leukocyte esterase specificity was 93.9% (95% CI 87.9 - 97.5) and of pyuria was 91.3% (84.6%-95.6%). CONCLUSIONS: In young infants with bacteremic UTI, UA sensitivity is higher than previous reports in infants with UTI in general. This finding can be explained by spectrum bias or by inclusion of faulty gold standards (contaminants or asymptomatic bacteriuria) in previous studies. PMID- 26009629 TI - The diagnosis of UTI: liquid gold and the problem of gold standards. PMID- 26009631 TI - Trends of US hospitals distributing infant formula packs to breastfeeding mothers, 2007 to 2013. AB - OBJECTIVE: To examine trends in the prevalence of hospitals and birth centers (hereafter, hospitals) distributing infant formula discharge packs to breastfeeding mothers in the United States from 2007 to 2013. METHODS: The Maternity Practices in Infant Nutrition and Care survey is administered every 2 years to all hospitals with registered maternity beds in the United States. A Web or paper-based questionnaire was distributed and completed by the people most knowledgeable about breastfeeding-related hospital practices. We examined the distribution of infant formula discharge packs to breastfeeding mothers from 2007 to 2013 by state and hospital characteristics. RESULTS: The percentage of hospitals distributing infant formula discharge packs to breastfeeding mothers was 72.6% in 2007 and 31.6% in 2013, a decrease of 41 percentage points. In 2007, there was only 1 state (Rhode Island) in which <25% of hospitals distributed infant formula discharge packs to breastfeeding mothers, whereas in 2013 there were 24 such states and territories. Distribution declined across all hospital characteristics examined, including facility type, teaching versus nonteaching, and size (annual number of births). CONCLUSIONS: The distribution of infant formula discharge packs to breastfeeding mothers declined markedly from 2007 to 2013. Discontinuing the practice of distributing infant formula discharge packs is a part of optimal, evidence-based maternity care to support mothers who want to breastfeed. PMID- 26009632 TI - Population Seasonality: Will They Stay or Will They Go? A Case Study of the Sogatella furcifera (Hemiptera: Delphacidae). AB - The whitebacked planthopper Sogatella furcifera (Horvath) (Hemiptera: Delphacidae) is one of the most destructive pests of rice in East and Southeast Asia. It is also a long-distance migratory insect and population size fluctuates frequently in these rice regions along the middle and lower Yangtze River. We analyzed the population seasonality of S. furcifera based on field surveys, light trap catching, and meteorological factors. We found that many S. furcifera were retained in local late rice in 2012, due to continuous rain and slightly windy weather conditions during the migration period. These results suggest that a new pattern of population fluctuation may occur where resident S. furcifera are dispersed into a single medium rice during harvest period, then rebound and thrive in late rice when there are suitable temperatures in September. Although the residency of S. furcifera in late rice fields in 2012 seems to be a special case, our findings suggest that S. furcifera exhibit a type of facultative migration. Our research also illuminates studies of the migration events of S. furcifera and benefits our understanding of the dynamics of S. furcifera in Hunan Province. PMID- 26009634 TI - Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats. AB - Mild hyperhomocysteinemia (HHcy, clinically defined as less than 30 MUmol/L) is an independent cardiovascular disease (CVD) risk factor, and is associated with many complications during pregnancy, such as preeclampsia (PE). The aim of this study was to assess the effect of long-term mild HHcy on cardiac metabolic function of multiparous rats. Female rats were mated 3 to 4 times and were fed with methionine in drinking water to increase plasma Hcy (2.9 +/- 0.3 to 10.5 +/- 2.3 MUmol/L) until termination. This caused significant increase of heart weight/body weight (0.24 +/- 0.01 to 0.27 +/- 0.01 g/100 g) and left ventricle weight (0.69 +/- 0.03 to 0.78 +/- 0.01 g). Superoxide production was increased by 2.5-fold in HHcy hearts using lucigenin chemiluminescence. The ability of bradykinin and carbachol to regulate myocardial oxygen consumption (MVO2) in vitro was impaired by 59% and 66% in HHcy heart, and it was restored by ascorbic acid (AA), tempol, or apocynin (Apo). Protein expression of p22(phox) subunit of NAD(P)H oxidase was increased by 2.6-fold, but there were no changes in other NAD(P)H oxidase subunits, NOSs or SODs. Microarray revealed 1518 genes to be differentially regulated (P < 0.05). The mRNA level of NAD(P)H oxidase subunits, NOSs or SODs remained unchanged. In conclusion, long-term mild HHcy increases cardiac superoxide mainly through regulation of p22(phox) component of the NAD(P)H oxidase and impairs the ability of NO to regulate MVO2 in heart of multiparous mothers. PMID- 26009635 TI - Reduced glomerular size selectivity in late streptozotocin-induced diabetes in rats: application of a distributed two-pore model. AB - Microalbuminuria is an early manifestation of diabetic nephropathy. Potential contributors to this condition are reduced glomerular filtration barrier (GFB) size- and charge selectivity, and impaired tubular reabsorption of filtered proteins. However, it was recently reported that no significant alterations in charge selectivity of the GFB occur in early experimental diabetic nephropathy. We here aimed at investigating the functional changes in the GFB in long-term type-1 diabetes in rats, applying a novel distributed two-pore model. We examined glomerular permeability in 15 male Wistar rats with at least 3 months of streptozotocin (STZ)-induced diabetes (blood glucose ~20 mmol/L) and in age matched control rats. The changes in glomerular permeability were assessed by determining the glomerular sieving coefficients (theta) for FITC-Ficoll (molecular radius 20-90 A) using size exclusion HPLC. The values of theta for FITC-Ficoll of radius >50 A were significantly increased in STZ-diabetic rats compared to age-matched controls (theta for 50-69 A = 0.001 vs. 0.0002, and theta for 70-90 A = 0.0007 vs. 0.00006, P < 0.001), while theta for FITC-Ficoll <50 A tended to be lower in diabetic rats than in controls (theta for 36-49 A = 0.013 vs. 0.016, ns). According to the distributed two-pore model, there was primarily an increase in macromolecular transport through large pores in the glomerular filter of diabetic rats associated with a loss of small-pore area. Deterioration in the glomerular size selectivity due to an increase in the number and size spread of large pores, with no changes in the permeability of the small-pore system, represent the major functional changes observed after 3 months of induced experimental diabetes. PMID- 26009633 TI - PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity. AB - Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a case-control study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A final stepwise regression considering both nongenetic and genetic variables identified the combination of covariates that explained maximal PLTPa variance. PLTPa was significantly associated with CAAD (7.90 * 10(-9)), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 * 10(-5)), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 * 10(-7)), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD. PMID- 26009636 TI - Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats. AB - Ketogenic diets are low-carbohydrate, sufficient protein, high-fat diets with anticonvulsant activity used primarily as a treatment for pediatric epilepsy. The anticonvulsant mechanism is thought to involve elevating inhibition and/or otherwise limiting excitability in the brain. Such a mechanism, however, might also significantly affect normal brain activity and limit synaptic plasticity, effects that would be important to consider in the developing brain. To assess ketogenic diet effects on synaptic transmission and plasticity, electrophysiological recordings were performed at the perforant path/dentate gyrus synapse in awake, freely-behaving juvenile male rats. Electrodes were implanted 1 week prior to recording. Animals were fed regular chow or a ketogenic diet ad libitum for 3 weeks before recording. Although the ketogenic diet did not significantly alter baseline excitability (assessed by input-output curves) or short-term plasticity (using the paired-pulse ratio), it did reduce the magnitude of long-term potentiation at all poststimulation timepoints out to the last time measured (48 h). The results suggest an effect of ketogenic diet-feeding on the induction magnitude but not the maintenance of long-term potentiation. The lack of effect of the diet on baseline transmission and the paired-pulse ratio suggests a mechanism that limits excitation preferentially in conditions of strong stimulation, consonant with clinical reports in which the ketogenic diet alleviates seizures without a major impact on normal brain activity. Limiting plasticity in a seizure-susceptible network may limit seizure-induced epileptogenesis which may subserve the ongoing benefit of the ketogenic diet in epilepsy. PMID- 26009637 TI - Influence of prior anterograde shear rate exposure on exercise-induced brachial artery dilation. AB - Shear rate can elicit substantial adaptations to vascular endothelial function. Recent studies indicate that prior exposure to anterograde flow and shear increases endothelium-dependent flow-mediated dilation at rest and that anterograde shear can create an anti-atherosclerotic and provasodilatory state. The primary aim of the present study was therefore to determine the effects of prior exposure to anterograde shear on exercise-induced brachial artery dilation, total forearm blood flow (FBF), and vascular conductance (FVC) during dynamic handgrip exercise. Eight men completed a constant-load exercise test corresponding to 10% maximal voluntary contraction, prior to (baseline) and following a 40 min shear rate intervention (post-SRI) achieved via unilateral forearm heating, which has previously been shown to increase anterograde shear rate in the brachial artery. During the SRI, anterograde shear rate increased 60.9 +/- 29.2 sec(-1) above baseline (P < 0.05). Post-SRI, the exercise-induced brachial artery vasodilation was significantly increased compared to baseline (4.1 +/- 0.7 vs. 4.3 +/- 0.6 mm, P < 0.05). Post-SRI FBF mean response time (33.2 +/- 16.0 vs. 23.0 +/- 11.8 sec, P < 0.05) and FVC mean response time (31.1 +/- 12.8 20.2 +/- 10.7 sec, P < 0.05) at exercise onset were accelerated compared to baseline. These findings demonstrate that prior exposure to anterograde shear rate increases the vascular responses to exercise and supports the possible beneficial effects of anterograde shear rate in vivo. PMID- 26009638 TI - Influence of Connexin40 on the renal myogenic response in murine afferent arterioles. AB - Renal autoregulation consists of two main mechanisms; the myogenic response and the tubuloglomerular feedback mechanism (TGF). Increases in renal perfusion pressure activate both mechanisms causing a reduction in diameter of the afferent arteriole (AA) resulting in stabilization of the glomerular pressure. It has previously been shown that connexin-40 (Cx40) is essential in the renal autoregulation and mediates the TGF mechanism. The aim of this study was to characterize the myogenic properties of the AA in wild-type and connexin-40 knockout (Cx40KO) mice using both in situ diameter measurements and modeling. We hypothesized that absence of Cx40 would not per se affect myogenic properties as Cx40 is expressed primarily in the endothelium and as the myogenic response is known to be present also in isolated, endothelium-denuded vessels. Methods used were the isolated perfused juxtamedullary nephron preparation to allow diameter measurements of the AA. A simple mathematical model of the myogenic response based on experimental parameters was implemented. Our findings show that the myogenic response is completely preserved in the AA of the Cx40KO and if anything, the stress sensitivity of the smooth muscle cell in the vascular wall is increased rather than reduced as compared to the WT. These findings are compatible with the view of the myogenic response being primarily a local response to the local transmural pressure. PMID- 26009639 TI - Editorial: RNA in bacteria: biogenesis, regulatory mechanisms and functions. PMID- 26009640 TI - Small RNAs, 5' UTR elements and RNA-binding proteins in intracellular bacteria: impact on metabolism and virulence. AB - Sequencing-based studies have illuminated increased transcriptional complexity within the genome structure of bacteria and have resulted in the identification of many small regulatory RNAs (sRNA) and a large amount of antisense transcription. It remains an open question whether these sRNAs all indeed play regulatory roles, but their identification led to an exponential increase in studies searching for their function. This allowed to show that sRNAs may modulate virulence gene expression, cellular differentiation, metabolic functions, adaptation to environmental conditions and pathogenesis. In this review we will provide mechanistic insights into how sRNAs bind mRNAs and/or proteins. Furthermore, the important roles of the RNA chaperone Hfq, the CsrA system and the CRISPR RNA will be discussed. We will then focus on sRNAs and 5(') untranslated region (UTR) elements of intracellular bacteria like Chlamydia, Listeria, Legionella, or Salmonella, and place emphasis on those that are expressed during replication in host cells and are implicated in virulence and metabolism. In addition, sRNAs that regulate motility, iron homeostasis, and differentiation or stress responses will be highlighted. Taken together sRNAs constitute key elements in many major regulatory networks governing the intracellular life and virulence of pathogenic bacteria. PMID- 26009641 TI - Longitudinal Relationships Between Cognitive Decline and Gait Slowing: The Tasmanian Study of Cognition and Gait. AB - BACKGROUND: Gait slowing and cognitive decline are both common in older people. Although cross-sectionally related, the longitudinal associations between specific cognitive functions and gait speed are less well understood. We aimed to determine whether decline in specific cognitive domains are associated with change in gait speed. METHODS: Participants aged 60-85, randomly selected from the electoral roll, were assessed twice over 3 years. Gait speed was obtained using the GAITRite walkway. Raw scores from a cognitive battery were subjected to principal component analyses deriving summary domains of executive function, processing speed, memory, and visuospatial ability. Multivariable linear regression was used to examine the associations between change in each cognitive domain and change in gait speed, adjusting for covariates and stratifying for the presence of baseline cognitive impairment. RESULTS: Mean age at baseline was 71.1 years (SD = 6.7) and 56% (159/284) were men. Mean follow-up was 2.55 (0.47) years. Decline in executive function, but not other cognitive domains (p > .05), was associated with decline in gait speed, cm/s (beta = -3.55, 95% CI = -5.49, 1.61; p < .001), both in the presence and absence of baseline cognitive impairment. Stronger associations were seen for those with baseline multiple domain cognitive impairment (beta = -6.38, 95% CI = -12.49, -0.27) and nonamnestic single-domain cognitive impairment (beta = -7.74, 95% CI = -14.76, 0.72). CONCLUSION: Decline in nonamnestic function (specifically executive function) was associated with decline in gait speed irrespective of the presence of baseline cognitive impairment. Strategies to improve or maintain executive function may prevent gait slowing. PMID- 26009642 TI - Heterogeneity in stabilization phenomena in FLT PET images of canines. AB - 3'-((18)F)fluoro-3'-deoxy-L-thymidine (FLT) is a PET marker of cellular proliferation. Its tissue uptake rate is often quantified with a Standardized Uptake Value (SUV), although kinetic analysis provides a more accurate quantification. The purpose of this study is to investigate the heterogeneity in FLT stabilization phenomena. The study was done on 15 canines with spontaneously occurring sinonasal tumours. They were imaged dynamically for 90 min with FLT PET/CT twice; before and during the radiotherapy. Images were analyzed for kinetics on a voxel basis through compartmental analysis. Stabilization curves were calculated as a time-dependant correlation between the time-dependant SUV and the kinetic parameters (voxel values within the tumour were correlated). Stabilization curves were analyzed for stabilization speed, maximal correlation and correlation decrease following the maximal correlation. These stabilization parameters were correlated with the region-averaged kinetic parameters. The FLT SUV was highly correlated with vasculature fraction immediately post-injection, followed by maximum in correlation with the perfusion/permeability. At later times post-injection the FLT SUV was highly correlated (Pearson correlation coefficient above 0.95) with the FLT influx parameter for cases with tumour averaged SUV(30-50 min) above 2, while others were indeterminate (correlation coefficients from 0.1 to 0.97). All cases with highly correlated SUV and FLT influx parameter had correlation coefficient within 0.5% of its maximum in the period of 30-50 min post-injection. Stabilization time was inversely proportional to the FLT influx rate. Correlation between the FLT SUV and FLT influx parameter dropped at later times post-injection with drop being proportional to the dephosphorylation rate. The FLT was found to be metabolically stable in canines. FLT PET imaging protocol should define minimal and maximal FLT uptake period, which would be 30-50 min for our patients. Additionally, kinetic analysis should be used when low FLT avidity is expected. Low SUVs should be treated with great caution. PMID- 26009643 TI - D-002 (beeswax alcohols): concurrent joint health benefits and gastroprotection. AB - Nonsteroidal antiinflammatory drugs include the traditional drugs and more selective COX-2 inhibitors. Traditional nonsteroidal antiinflammatory drug use is hampered by their gastrotoxicity, while COX-2-inhibitors increase the cardiovascular risk. The search of safer substances for managing inflammatory conditions is updated, a challenge wherein dual COX/5-LOX inhibitors have a place. This review summarizes the benefits of D-002, a mixture of higher aliphatic beeswax alcohols, on joint health and gastric mucosa. D-002 elicits gastroprotection through a multiple mechanism that involves the increased secretion and improved quality of the gastric mucus, the reduction of hydroxyl radical, lipid peroxidation, protein oxidation, neutrophil infiltration and the increase of antioxidant enzymes on the gastric mucosa. Consistently, D-002 inhibits NSAIDs, ethanol, pylorus-ligation and acetic acid-induced gastric ulceration in rats, and has reduced gastrointestinal symptoms in clinical studies. Early results found that D-002 was effective in the cotton pellet induced granuloma and carrageenan-induced pleurisy model in rats, lowering pleural leukotriene B4 levels without causing gastrointestinal ulceration. However, D-002 effects on inflammation received little attention for years. Recent data have shown that D-002 inhibited both COX and 5-LOX activities with a greater affinity for 5-LOX and could act as a dual COX/5-LOX inhibitor. This mechanism might explain efficacy in experimental inflammatory and osteoarthritic models as well as clinical efficacy in osteoarthritic patients while supporting the lack of D-002 gastrotoxicity, but not the gastroprotective effects, which appear to be due to multiple mechanisms. In summary oral D-002 intake could help manage inflammatory conditions that impair joint health, while offering gastroprotection. PMID- 26009644 TI - Pharmacogenetics, pharmacogenomics and ayurgenomics for personalized medicine: a paradigm shift. AB - The value of health care can be increased tremendously through individualized medicine. With the promise of individualized medicine, healthcare professionals will be able to better predict disease risk, prevent development of disease and manage treatments more efficiently thereby allowing people to be healthier and active longer. The developments in the area of pharmacogenetics/pharmacogenomics can help the physicians achieve the target of personalized medicine. Personalized medicine will come to mean not just the right drug for the right individual, but the right drug for the specific disease affecting a specific individual. The use of personalized medicine will make clinical trials more efficient by lowering the costs that would arise due to adverse drug effects and prescription of drugs that have been proven ineffective in certain genotypes. The genotypic experiments have laid valuable insights into genetic underpinnings of diseases. However it is being realized that identification of sub-groups within normal controls corresponding to contrasting disease susceptibility could lead to more effective discovery of predictive markers for diseases. However there are no modern methods available to look at the inter-individual differences within ethnically matched healthy populations. Ayurveda, an exquisitely elaborate system of predictive medicine which has been practiced for over 3500 years in India, can help in bridging this gap. In contrast to the contemporary system of medicine, the therapeutic regimen in Ayurveda is implicated on tridoshas and prakriti. According to this system, every individual is born with his or her own basic constitution, which to a great extent regulates inter-individual variability in susceptibility to diseases and response to external environment, diet and drugs. Thus the researchers in India have demonstrated that integration of this stratified approach of Ayurveda into genomics i.e. Ayurgenomics could complement personalized medicine. PMID- 26009645 TI - Comparative Study to Predict Dipeptidyl Peptidase IV Inhibitory Activity of beta Amino Amide Scaffold. AB - Comparative study was performed on 34 beta-amino amide derivatives as dipeptidyl peptidase IV inhibitors in order to determine their structural requirement to enhance the antidiabetic activities. Hologram quantitative structure activity relationships models utilized specialized fragment fingerprints (hologram length 353) which showed good predictivity with cross-validated q(2) and conventional r(2) values of 0.971 and 0.971, respectively. Models were validated and optimized by a test set of eight compounds and gave satisfactory predictive ability. Hologram quantitative structure activity relationships maps were helpful in prediction of the structural features of the ligands to account for the activity in terms of positively and negatively contributing towards activity. The information obtained from maps could be effectively use as a guiding tool for further structure modifications and synthesis of new potent antidiabetic agents. PMID- 26009646 TI - Combating drug resistant pathogenic bacteria isolated from clinical infections, with silver oxide nanoparticles. AB - The antibiogram study of methicillin resistant Staphylococcus aureus isolates revealed 100% resistance to vancomycin, bacitracin, erythromycin, ciprofloxacin and nalidixic acid. Eight isolates (53.3%) showed resistance to co-trimoxazole and one isolate to rifampicin, which was the drug of choice. An effort was made to evaluate the antimethicillin resistant Staphylococcus aureus activity of silver oxide (Ag2O) nanoparticles synthesized from Aspergillus terreus VIT 2013. Production of Ag2O nanoparticles was confirmed by color change of fungal filtrate and UV light absorption at 450 nm. X-ray diffraction pattern showed 2theta values at 27, 32, 38 and 57 degrees , which corresponded to the cubic structure of Ag2O nanocrystals. Fourier transform infrared spectroscopy indicated the presence of primary amine, carbonyl group, NO2 and silver, revealing protein mediated nanoparticle production. The scanning electron microscope image showed freely dispersed Ag2O nanoparticles. The nanoparticles were active against all methicillin resistant isolates and hence can be used as antibacterial agents against drug resistant bacteria. PMID- 26009647 TI - Influence of Triazine Herbicide Exposure on Guppies (Poecilia sphenops) Aromatase Activities, Altered Sex Steroid Concentration and Vitellogenin Induction. AB - Atrazine, a herbicide is one the most toxic and sustaining pollutants in aquatic environment. It is detectable in surface water and in underground sources of drinking water. Many studies indicate that atrazine might be a potent endocrine disrupting xenobiotic. There are limited studies have revealed that the effects of atrazine on sex steroids hormones, vitellogenin and induction of aromatase, gonadosomatic index and hepatosomatic index. In this study, juvenile Poecilia sphenops fish was exposed to three different (0.83, 1.25 and 2.5 ppm) concentration of atrazine for 100 d. Changes in plasma and gonadal content and concentrations of sex steroids and vitellogenin protein in poecilia sphenops under laboratory conditions were assessed. The low level of the atrazine show estrogenic effect in males, as determined by a shortage of testosterone induction. Present study suggests that low induction of plasma vitellogenin and aromatase in male fish become suitable biomarkers of exposure to estrogenic chemicals. PMID- 26009648 TI - Protective Effect of Total Phenolic Compounds from Inula helenium on Hydrogen Peroxide-induced Oxidative Stress in SH-SY5Y Cells. AB - Inula helenium has been reported to contain a large amount of phenolic compounds, which have shown promise in scavenging free radicals and prevention of neurodegenerative diseases. This study is to investigate the neuroprotective effects of total phenolic compounds from I. helenium on hydrogen peroxide-induced oxidative damage in human SH-SY5Y cells. Antioxidant capacity of total phenolic compounds was determined by radical scavenging activity, the level of intracellular reactive oxygen species and superoxide dismutase activity. The cytotoxicity of total phenolic compounds was determined using a cell counting kit 8 assay. The effect of total phenolic compounds on cell apoptosis due to hydrogen peroxide-induced oxidative damage was detected by Hoechst 33258 and Annexin-V/PI staining using fluorescence microscope and flow cytometry, respectively. Mitochondrial function was evaluated using the mitochondrial membrane potential and mitochondrial ATP synthesis by JC-1 dye and high performance liquid chromatography, respectively. It was shown that hydrogen peroxide significantly induced the loss of cell viability, increment of apoptosis, formation of reactive oxygen species, reduction of superoxide dismutase activity, decrease in mitochondrial membrane potential and a decrease in adenosine triphosphate production. On the other hand, total phenolic compounds dose-dependently reversed these effects. This study suggests that total phenolic compounds exert neuroprotective effects against hydrogen peroxide-induced oxidative damage via blocking reactive oxygen species production and improving mitochondrial function. The potential of total phenolic compounds and its neuroprotective mechanisms in attenuating hydrogen peroxide-induced oxidative stress-related cytotoxicity is worth further exploration. PMID- 26009649 TI - In vitro Antioxidant and Pharmacognostic Studies of Leaf Extracts of Cajanus cajan (L.) Millsp. AB - Cajanus cajan (L.) Millsp is one of the second most dietary legume crops. The leaf extracts may be used as a potential source of natural antioxidant. The ash values, extractive values, total phenolic and flavonoid content, in vitro antioxidant activity of various leaf extracts as well as anatomical investigation of Cajanus cajan were carried out. Physicochemical parameters such as total, acid insoluble and water-soluble ash values and moisture content of the leaf powder of C. cajan were found to be 9.50%, 1.40 g/100 g, 4.15 g/100 g drug and 6.72%, respectively. Percent yield of acetone, aqueous, ethanol, ethyl acetate and chloroform leaf extracts were 9.0, 10.6, 13.75, 8.7 and 5.8 g/100 g, respectively. Significant amount of phenolic and flavonoid content were observed. The results of the antioxidant activity were found to be concentration-dependent. The IC50 values for DPPH assay determined for aqueous and ethanol extracts were 0.69 and 0.79 mg/ml, respectively. Reducing power is increased with increasing amount of concentration in both aqueous and ethanol leaf extracts. The highest hydroxyl radical scavenging activity reached up to 83.67% in aqueous and 78.75% in ethanol extracts and in phosphomolybdenum assay the aqueous extract showed strong antioxidant capacity up to 55.97 nM gallic acid equivalents/g. It was found that the aqueous extract possessed highest antioxidant activity in all the assays tested. The antioxidant characteristics of leaf extracts are possibly because of the presence of polyphenols. Microscopic study showed the presence of collenchyma, fibres, xylem, phloem, epidermis, trichomes, palisade tissue, basal sheath, pith and cortex in leaf, petiole and pulvinus. PMID- 26009650 TI - Self Medication Practices among Medical Students of a Private Institute. AB - The study was undertaken to evaluate various aspects of self-medication in medical students. A prospective, cross-sectional, questionnaire-based study was carried out among 488 medical students selected by simple random sampling from January 2013 to June 2013. Data was collected and analyzed for counts and percentage. Students reported self-medication in the preceding one year was 71.7 % and the prevalence was more in final year students. Fever and headache were the most frequently reported illnesses, commonly used drugs were antipyretics and analgesics, obtained information through reading material, and reasons quoted were minor ailments and quick relief. Majority students agreed that medical knowledge is necessary for administration of medicine by self. Self-medication is highly prevalent in medical students, which is quite alarming. PMID- 26009651 TI - Evaluation of antioxidant producing potential of halophilic bacterial bionts from marine invertebrates. AB - Marine invertebrates exposed to high levels of reactive oxygen species in the oceans have been reported to produce antioxidants as a major defense against free radical mediated toxicity; protecting their tissues from the damage associated with the oxidative stress. In view of this, the present study was carried out to determine the antioxidant activity of 100 bacterial bionts isolated from marine sponges, corals and a single bivalve. Methanol extract of biont GUVFCFM-3 produced 67.83% scavenging of 2,2-diphenyl-2-picrylhydrazyl free radicals and 65.87% scavenging of superoxide free radicals. Preliminary tests leading to the identification of the extracellular antioxidant factor produced by GUVFCFM-3 revealed that it is a peptide. We report that the genera Chromohalobacter sp. primarily known for its unique salt tolerating abilities by virtue of the production of osmolytes is an excellent scavenger of free radicals. PMID- 26009652 TI - Human bioequivalence evaluation of two losartan potassium tablets under fasting conditions. AB - The bioequivalence of two different tablet formulations containing losartan potassium 100 mg was determined in healthy volunteers after a single oral dose in a randomized crossover study. Test and reference products were administered to 60 volunteers with 240 ml water after overnight fasting. Plasma concentrations of losartan and its active carboxylic acid metabolite were monitored over a period of 36 h after drug administration by validated LC/MS/MS analytical method. The pharmacokinetic parameters Cmax, AUC0-t, AUC0-infinity, AUC0-t/AUC0-infinity, tmax, Kel and t1/2 were determined from plasma concentration time profile of both formulations for losartan and its active metabolite losartan carboxylic acid and were found to be in good agreement. The carboxylic acid metabolite was considered for profiling purpose only. The analysis of variance did not show any significant difference between the two formulations and 90% confidence intervals for the ratio of Cmax (84.89-104.09%), AUC0-t (95.84-102.84%) and AUC0-infinity (96.43 103.25%) values for losartan between the test and reference products were within the 80-125% interval, satisfying the bioequivalence criteria of the US FDA guidelines. These results indicate that the test and the reference products of losartan potassium are bioequivalent and, thus, may be prescribed interchangeably. PMID- 26009653 TI - Synthesis and antimicrobial activity of 9-o-substituted palmatine derivatives. AB - A series of new palmatine derivatives with alkyl or alkyl with N-heterocyclic structures were designed and synthesized at C-9-O according to the principle of association. These compounds were characterised by (1)H NMR, (13)C NMR, ESI-MS and elemental analysis, and tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. The results indicated that 9-O substituted palmatine derivatives exhibit varying degrees of antimicrobial activity. Antibacterial activities of compounds (3a-f) against Gram +ve bacteria increased 2- to 64-fold than that of palmatine. The compounds (3a-f) possessed relatively weaker inhibitory effects against Gram -ve bacteria and fungi than that against Gram +ve bacteria. Antimicrobial activities of compounds (5a-e) are lower than that of compounds (3a-f). Compound 3d showed the highest antimicrobial activity of all the compounds. The LD50 values of compounds (3a-f) decreased as the alkyl side chain was elongated. Compound 3f showed least toxicity. PMID- 26009654 TI - Synthesis and in vitro Screening of 29, 30-Dibromo-28-oxoallobetulin against Parasitic Protozoans, Leishmania donovani and Leishmania Major. AB - A simple synthesis and in vitro antileishmanial activity of 29,30-dibromo-28 oxoallobetulin against the parasitic protozoans, Leishmania donovani and Leishmania major is described. The structure of the compound is established on the basis of spectral data (IR, NMR, MS). Both the antiproliferative effect and the cell cycle progression were studied. PMID- 26009655 TI - Antimelanoma Potential of Eruca sativa Seed Oil and its Bioactive Principles. AB - The present communication reports the comparison of in vivo antioxidant, antimelanoma and antimutagenic activities of Eruca sativa seed oil and its bio principles (allyl isothiocyanate, phenylethyl isothiocyanate and sulphoraphane) against B16F10 melanoma cells induced in C57BL/6 mice model. Among the various treatments considered for the study, isothiocyanates combination (allyl isothiocyanate, phenylethyl isothiocyanate and sulphoraphane; 1:1:1; 10 uM) exhibited optimum antioxidant activity, 51.95+/-1.14 uM glutathione per mg protein compared to seed oil 25.91+/-1.26 uM. Lipid peroxidation value was 9.97+/ 1.72 uM malondialdehyde per mg wet weight for isothiocyanates combination against seed oil, 28.45+/-1.87 uM and rendered significant protection against oxidative stress induced by melanoma in liver tissue. Isothiocyanates combination significantly suppressed various parameters, such as tumor growth, isothiocyanates combination by 36.36% while the seed oil by 15.23%; tumor weight, isothiocyanates combination by 45.9% and seed oil by 19.6%; tumor volume, isothiocyanates combination by 41.7% while the seed oil by 32.3%, measured for antimelanoma activity at a concentration of 10 uM. Isothiocyanates combination has been found to be more cytotoxic bioagent against B16F10 melanoma cells induced in C57BL/6 mice compared to naturally occurring Eruca sativa seed oil. PMID- 26009656 TI - Essential oil composition of valeriana jatamansi jones from himalayan regions of India. AB - Valeriana jatamansi Jones germplasm collected from sub-temperate Himalayan region of Uttarakhand and North-East state of Meghalaya, India was evaluated under identical conditions at National Bureau of Plant Genetic Resources, Bhowali, India, to study germplasm diversity based on essential oil composition. Twenty one compounds were identified in V. jatamansi root oil by GC and GC-MS. The major compounds identified were patchouli alcohol (0.4-63.7%), maaliol (2.9-53.8%), seychellene (4.1-27.4%), calarene/beta-gurjunene (3.0-20.8%), alpha-santalene (0.6-12.0%). Other compounds present were bornyl acetate (0.6-1.5%), alpha guaiene (0.7-2.3%), alpha-bulnesene/delta-guaiene (0.7-6.3%), 7-epi-alpha selinene (0.4-1.4%), kessane (2.1-3.3%), spathulenol (0.7-3.4%), viridiflorol (0.9-7.1%), alpha-patchoulene (0.8-6.6%), beta-patchoulene (0.4-0.8%). Two superior chemotypes identified in V. jatamansi oil from Uttarakhand were: patchouli alcohol rich (IC573221, 63.7%) and maaliol rich (IC573222, 53.8%; IC589096, 51.7%), while accession from north-east was patchouli alcohol rich chemotype (IC574522, 57.2%). These superior chemotypes with higher amounts of patchouli alcohol and maaliol could be used for promoting cultivation as well as for meeting need of pharmaceutical industries. PMID- 26009657 TI - Inhibitory effect of curcumin on the contractility of isolated caprine detrusor muscle. AB - Curcumin is a naturally occurring compound which has been used in traditional medicine in India for a long time. This study investigated the ability of curcumin to inhibit the contractility of isolated caprine (goat) detrusor muscle. The ability of three concentrations of curcumin (30, 100 and 300 uM) to inhibit the 100 uM acetylcholine-induced contractility of the isolated caprine urinary bladder detrusor muscle was investigated. The effect of raising the concentration of acetylcholine from 100, 200 and 400 uM to overcome the curcumin-induced inhibition of detrusor contractility and the effects of the reversal agents tetraethylammonium, a potassium channel blocker (100 uM), glibenclamide, an ATP sensitive potassium channel blocker (10 uM), and propranolol, a beta adrenergic receptor blocker (1 uM), on the inhibitory effect of detrusor contractility was also studied. Curcumin caused a concentration-dependent inhibition of acetylcholine-induced contractility of the isolated detrusor muscle which was statistically significant at all three concentrations of curcumin used. This inhibition was partially overcome by raising the concentration of ACh to 200 and 400 uM. The inhibition was overcome by the concurrent administration of tetraethylammonium. Glibenclamide reversed the inhibitory effect of 100 uM curcumin, but not that of 300 uM curcumin. Propranolol reversed the inhibitory effect of 100 uM curcumin but not that of 300 uM curcumin. These results suggest that curcumin inhibited the contractions of the isolated detrusor muscle. The results further suggest that the inhibitory effect is mediated by various mechanisms: stimulation of beta adrenergic receptors; an anticholinergic effect; and the opening of ATP-sensitive potassium channels. PMID- 26009658 TI - Total Phenolic Content and Antioxidant Activity of Morinda tinctoria Leaves. AB - The antioxidant activity and total phenolic content of Morinda tinctoria leaves was evaluated. The successively extracted leaves of Morinda tinctoria using various solvents was analyzed for their total phenolic content. The extracts were subjected to column chromatography for the isolation of bioactive molecules. In vitro antioxidant activity was evaluated by employing different assays, including 2,2-diphenyl-1-picrylhydrazyl, nitric oxide scavenging assay and phosphomolybdenum reducing power assay. The 2,2-diphenyl-1-picrylhydrazyl radical scavenging efficacy of hexane extract is significant at higher concentration (500 MUg/ml-91.2+/-0.05%) and the efficacy at lower concentration is more significant for ethyl acetate extract (100 MUg/ml - 65.1+/-0.05%). The total phenolic content was highest in methanol extract (5.30+/-0.011 MUg/mg). Cynarin, a hydroxy cinnamic acid was isolated from chloroform extract; oleuropein, a polyphenolic iridoid was isolated from methanol extract. The results obtained suggeted that Morinda tinctoria leaf extracts possessed antioxidant properties and might offer protection from free radicals. Two compounds, cynarin and oleuropein were reported for the first time from Morinda tinctoria leaves. PMID- 26009659 TI - Synthesis and biological activities of some benzimidazolone derivatives. AB - The reaction of 5-nitrobenzimidazolone with phenoxyethyl bromide in presence of potassium carbonate in dimethyl formamide obtained 6-nitro-1,3-bis(2 phenoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one. It was reduced using stannous chloride to get 6-amino -1,3-bis(2-phenoxyethyl)-1, 3-dihydro-2H-benzimidazol -2 one, which was further treated with aromatic sulphonyl chloride to obtain benzimidazolone derivatives, 6a-k. These compounds were tested for antibacterial, antituberculosis and antifungal activity. Most of them have shown very good activity against some gram positive and gram negative microorganisms and fungal strains. Some of them have shown moderate activity against Mycobacterium tuberculosis. PMID- 26009660 TI - Hypoglycemic Effect of the Methanol flower Extract of Piper Claussenianum and the Major Constituent 2',6'-dihydroxy-4'-methoxychalcone in Streptozotocin Diabetic Rats. AB - Piper claussenianum inflorescences crude methanol extract was tested for hypoglycemic effect in streptozotocin-induced diabetic rats. The blood glucose levels of rats treated with methanol extract were reduced from 318.4+/-28.1 mg/dl before treatment to 174.2+/-38.3 mg/dl after 12 days of treatment (P<0.05). Phytochemical studies were carried out on inflorescences methanol crude extract in order to investigate the possible metabolites responsible for the pharmacological properties of the extract. After chromatographic procedures, three flavonoids were isolated and characterized. The major compound 2',6' dihydroxy-4'-methoxychalcone was also tested. Rats that received the chalcone content also displayed a reduction in blood glucose levels from 277.4+/-7.7 mg/dl before treatment to 158.8+/-9.2 mg/dl after 12 days of treatment (P<0.05). The results suggest this chalcone is one of the metabolite responsible for the blood glucose levels reduction in rats with streptozotocin-induced diabetes. The inflorescence crude extract of P. claussenianum was found to be composed mainly by flavonoids and may be a potential natural source of compounds with hypoglycemic properties. PMID- 26009661 TI - Evaluation of Ethanol and Aqueous extracts of Cinnamomum verum Leaf Galls for Potential Antioxidant and Analgesic activity. AB - In the present study, ethanol and aqueous extracts of leaf galls of Cinnamomum verum were prepared to evaluate the antioxidant activity using 2,2-diphenyl-1 picrylhydrazyl free radical scavenging assay and superoxide radical scavenging assay with ascorbic acid as a standard, and analgesic activity by tail immersion test and acetic acid-induced writhing test methods using diclofenac sodium as the reference drug. Swiss albino mice maintained under standard laboratory conditions were used for analgesic tests. In the 2,2-diphenyl-1-picrylhydrazyl assay it was found that the aqueous and the ethanol extract possessed almost equal capacity to inhibit free radicals (IC50=13.3 and 13.53 ug/ml) but found less than ascorbic acid (IC50=9.96 ug/ml). And in superoxide assay the ethanol extract was found to be more potent in scavenging super oxide radicals when compared to ascorbic acid and the aqueous extract (IC50=237.1 and 197.8 ug/ml) with the IC50=119.7 ug/ml. For analgesic activity, ethanol extract showed the maximum time required for response against thermal stimuli (6.75+/-0.47 s) and maximum % of writhing inhibition (44.57%) when compared to aqueous extract (5.25+/-0.48 s and 32.61%), whereas diclofenac showed response in 7.25+/-0.25 s 67.39% inhibition in tail immersion and writhing tests, respectively. These results demonstrate that the ethanol extracts of leaf galls possessed high antioxidant and analgesic activity. PMID- 26009662 TI - Live forever, for the moment. PMID- 26009663 TI - Indian Association of Palliative Care Conference: February 13-15(th) 2015, Hyderabad. PMID- 26009664 TI - Utility and potential of bedside ultrasound in palliative care. AB - Bedside ultrasound is an important tool in modern palliative care practice. It can be utilized for rapid diagnostic evaluation or as an image guidance to perform invasive therapeutic procedures. With advent of portable ultrasound machines, it can also be used in community or home care settings, apart from palliative care wards. Major applications of bedside ultrasound include drainage of malignant pleural effusions and ascites, nerve blocks, venous access, evaluation of urinary obstruction, deep vein thrombosis and abscesses. Bedside ultrasound leads to better clinical decision-making as well as more accurate and faster invasive therapeutic procedures. It also enhances patient comfort and reduces cost burden. However, use of bedside ultrasound is still not widespread among palliative care givers, owing to initial cost, lack of basic training in ultrasound and apprehensions about its use. A team approach involving radiologists is important to develop integration of bedside ultrasound in palliative care. PMID- 26009666 TI - The prevalence of severe pain, its etiopathological characteristics and treatment profile of patients referred to a tertiary cancer care pain clinic. AB - Pain is the most feared symptom in cancer. About 52-77% patients suffer pain despite World Health Organization (WHO) recommendations. Out of total, one-third patients suffer moderate to severe pain. This study was undertaken to determine the prevalence, etiopathogenesis and characteristics of severe pain and treatment response among pain clinic referrals in a busy tertiary care cancer center. This study found a high prevalence (31.5%) of severe pain. A total of 251 patients who had complete pain data were analyzed for etiopathological characteristics and treatment response. Head and neck cancer contributed the highest prevalence among all regions. Oncologists prescribed non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol with or without mild opioids to 14% patients and pain clinic physicians prescribed opioids and overall 63.7% patients had a better response after pain clinic referral, even then, morphine was not prescribed to many deserving patients. Doctors need pain education about opioids to remove any fear of prescribing opioids in presence of severe pain. PMID- 26009665 TI - Evidence-based Clinical Practice Guidelines for Interventional Pain Management in Cancer Pain. AB - Intractable cancer pain not amenable to standard oral or parenteral analgesics is a horrifying truth in 10-15% of patients. Interventional pain management techniques are an indispensable arsenal in pain physician's armamentarium for severe, intractable pain and can be broadly classified into neuroablative and neuromodulation techniques. An array of neurolytic techniques (chemical, thermal, or surgical) can be employed for ablation of individual nerve fibers, plexuses, or intrathecalneurolysis in patients with resistant pain and short life expectancy. Neuraxial administration of drugs and spinal cord stimulation to modulate or alter the pain perception constitutes the most frequently employed neuromodulation techniques. Lately, there is a rising call for early introduction of interventional techniques in carefully selected patients simultaneously or even before starting strong opioids. After decades of empirical use, it is the need of the hour to head towards professionalism and standardization in order to secure credibility of specialization and those practicing it. Even though the interventional management has found a definite place in cancer pain, there is a dearth of evidence-based practice guidelines for interventional therapies in cancer pain. This may be because of paucity of good quality randomized controlled trials (RCTs) evaluating their safety and efficacy in cancer pain. Laying standardized guidelines based on existing and emerging evidence will act as a foundation step towards strengthening, credentialing, and dissemination of the specialty of interventional cancer pain management. This will also ensure an improved decision-making and quality of life (QoL) of the suffering patients. PMID- 26009667 TI - Burden and outcomes of pressure ulcers in cancer patients receiving the kerala model of home based palliative care in India: results from a prospective observational study. AB - AIM: To report the prevalence and outcomes of pressure ulcers (PU) seen in a cohort of cancer patients requiring home-based palliative care. MATERIALS AND METHODS: All patients referred for home care were eligible for this prospective observational study, provided they were living within a distance of 35 km from the institute and gave informed consent. During each visit, caregivers were trained and educated for providing nursing care for the patient. Dressing material for PU care was provided to all patients free of cost and care methods were demonstrated. Factors influencing the occurrence and healing of PUs were analyzed using logistic regression. Duration for healing of PU was calculated using the Kaplan Meier method. P < 0.05 are taken as significant. RESULTS: Twenty one of 108 (19.4%) enrolled patients had PU at the start of homecare services. None of the patients developed new PU during the course of home care. Complete healing of PU was seen in 9 (42.9%) patients. The median duration for healing of PU was found to be 56 days. Median expenditure incurred in patients with PU was Rs. 2323.40 with a median daily expenditure of Rs. 77.56. CONCLUSIONS: The present model of homecare service delivery was found to be effective in the prevention and management of PUs. The high prevalence of PU in this cohort indicates a need for greater awareness for this complication. CLINICAL TRIAL REGISTRY NUMBER: CTRI/2014/03/004477. PMID- 26009668 TI - Continuing professional development for volunteers working in palliative care in a tertiary care cancer institute in India: a cross-sectional observational study of educational needs. AB - CONTEXT: Training programs for volunteers prior to their working in palliative care are well-established in India. However, few studies report on continuing professional development programs for this group. AIMS: To conduct a preliminary assessment of educational needs of volunteers working in palliative care for developing a structured formal continuing professional development program for this group. SETTINGS AND DESIGN: Cross-sectional observational study conducted in the Department of Palliative Medicine of a tertiary care cancer institute in India. MATERIALS AND METHODS: Participant volunteers completed a questionnaire, noting previous training, years of experience, and a comprehensive list of topics for inclusion in this program, rated in order of importance according to them. STATISTICAL ANALYSIS USED: Descriptive statistics for overall data and Chi-square tests for categorical variables for group comparisons were applied using Statistical Package for Social Sciences version 18. RESULTS: Fourteen out of 17 volunteers completed the questionnaire, seven having 5-10-years experience in working in palliative care. A need for continuing professional development program was felt by all participants. Communication skills, more for children and elderly specific issues were given highest priority. Spiritual-existential aspects and self-care were rated lower in importance than psychological, physical, and social aspects in palliative care. More experienced volunteers (>5 years of experience) felt the need for self-care as a topic in the program than those with less (<5-years experience) (P < 0.05). CONCLUSIONS: Understanding palliative care volunteers' educational needs is essential for developing a structured formal continuing professional development program and should include self-care as a significant component. PMID- 26009669 TI - Audiometric patterns in ototoxicity after radiotherapy and chemotherapy in patients of head and neck cancers. AB - INTRODUCTION: Inspite of various strategies adopted to protect the sensitive structures during organ preservation strategies, radiation damage can occur from the pharyngotympanic tube to the brain stem auditory pathway causing hearing loss. The purpose of this study is to evaluate the audiometric abnormalities and characterize them among the patients of head and neck cancers who have undergone radiotherapy (RT) and chemoradiation therapy (CT+RT). MATERIALS AND METHODS: Sixty-six histopathologically proven head and neck cancer patients receiving RT and 34 patients receiving concomitant CT + RT underwent evaluation for audiometric abnormalities from 1(st) September 2010 to 31(st) August 2012. RESULTS: Hearing losses were predominately of sensorineural type and mild. Patients who received concomitant CT+RT experienced greater sensorineural hearing loss compared with patients treated with RT alone. A paired sample t-test was conducted to compare the hearing losses before therapy and 6 and 12 months after therapy and was found to be significant (P < 0.05). It was found that hearing loss was persistent. Significant difference was found in the proportion of hearing loss after RT and RT+CT (P < 0.05) after 1 month. In addition, mixed hearing loss occurred due to damage to the middle ear contents and can be improved if intervened appropriately. PMID- 26009670 TI - Analysis of patterns of palliative radiotherapy in north west India: a regional cancer center experience. AB - BACKGROUND: Palliative radiotherapy (PRT) is the eventual requirement in 30-50% of all cancer patients. PRT is primarily aimed to relieve pain and prevent/treat collapse or fracture in case of bone metastasis, to reduce edema in patients with cranial metastasis, and to control distressing symptoms of rapid primary growth. An audit of PRT planned in a busy cancer center can help in the characterization of the requirements of the patients and the formulation of institutional policies. MATERIALS AND METHODS: In total, 516 patients who received PRT in our regional cancer center from January 2012 to December 2012 and whose complete records were available for analysis were selected for this retrospective study. Medical records and radiotherapy files were analyzed to obtain data such as sociodemographic parameters, prescription of PRT, and follow up. Descriptive statistics were evaluated in terms of frequencies and percentages to allow comparisons. RESULTS: Of the 516 patients, 73% patients were male; the median age of the patients receiving PRT was 62 years (range 13-83 years). About 48% (n = 248) patients received PRT at the primary site while rest (52%) were given PRT at the metastatic site. The most common indication of PRT was pain (56.8% cases), followed by cytostatic PRT (19.8%) and raised ICT (12.4%). The median dose prescribed was 30 Gy (range 8-36 Gy) delivered in 1-12 fractions over the duration of 1-18 days. The overall response rate was about 43% at 2 weeks of completion of PRT; the median follow-up of the patients was 154 days (range 9-256 days). The long-term symptom relief at median follow up was 8%. CONCLUSIONS: Good clinical judgment and expertise is required in prescribing correct fractionation schedule to achieve effective symptom palliation with lowest possible cost and inconvenience to the patients and relatives. Hypofractionated radiotherapy is a feasible treatment option in patients with advanced incurable disease to achieve effective palliation. PMID- 26009671 TI - Effects of an integrated Yoga Program on Self-reported Depression Scores in Breast Cancer Patients Undergoing Conventional Treatment: A Randomized Controlled Trial. AB - AIM: To compare the effects of yoga program with supportive therapy on self reported symptoms of depression in breast cancer patients undergoing conventional treatment. PATIENTS AND METHODS: Ninety-eight breast cancer patients with stage II and III disease from a cancer center were randomly assigned to receive yoga (n = 45) and supportive therapy (n = 53) over a 24-week period during which they underwent surgery followed by adjuvant radiotherapy (RT) or chemotherapy (CT) or both. The study stoppage criteria was progressive disease rendering the patient bedridden or any physical musculoskeletal injury resulting from intervention or less than 60% attendance to yoga intervention. Subjects underwent yoga intervention for 60 min daily with control group undergoing supportive therapy during their hospital visits. Beck's Depression Inventory (BDI) and symptom checklist were assessed at baseline, after surgery, before, during, and after RT and six cycles of CT. We used analysis of covariance (intent-to-treat) to study the effects of intervention on depression scores and Pearson correlation analyses to evaluate the bivariate relationships. RESULTS: A total of 69 participants contributed data to the current analysis (yoga, n = 33, and controls, n = 36). There was 29% attrition in this study. The results suggest an overall decrease in self-reported depression with time in both the groups. There was a significant decrease in depression scores in the yoga group as compared to controls following surgery, RT, and CT (P < 0.01). There was a positive correlation (P < 0.001) between depression scores with symptom severity and distress during surgery, RT, and CT. CONCLUSION: The results suggest possible antidepressant effects with yoga intervention in breast cancer patients undergoing conventional treatment. PMID- 26009672 TI - Preserving self-concept in the burn survivors: a qualitative study. AB - BACKGROUND: Burn injury is a devastating experience affecting all aspects of a person's essence, including his/her identity and perception. These patients require complex cognitive efforts to redefine their identity to deal with difficult condition after burn injury and preserve self-concept. The experience of life after burn injury is generally a solitary one, closely related to the patients' cultural and religious context. Therefore, this study was conducted aiming at investigating burn patients' experiences regarding how to preserve self concept in life after burn injury in Iran. MATERIALS AND METHODS: This qualitative study was carried out using qualitative content analysis and in-depth unstructured interviews with 17 surviving burn subjects. RESULTS: During the qualitative content analysis process, the concept of "locating" as the essence of the participants' experience was extracted as follows: (A) self-exploration (exploring the changes in one's life), (B) others' exploration (exploring the changes in the life of family members and the relationship between self and others), (C) position evaluation (self-position analysis), and (D) self-concept preservation. CONCLUSION: The present study has developed new understandings of mental experiences of burn patients' self-concept by describing the concept of "self-locating". It helps us in classifying and understanding the concepts described in comprehensive theories developed in this area. They do this by focusing on what burn patients experience for choosing self-preservation strategies and having a meaningful life. The finding can be used as a conceptual framework for palliative care program in Iran. PMID- 26009673 TI - Caring for dying patients: attitude of nursing students and effects of education. AB - BACKGROUND: Education about caring for dying patients could be effective in changing nursing students' attitude toward caring for dying patients. AIM: The aim of the present study was to examine the nursing students' attitude toward caring for dying patients and effects of education on their attitude. MATERIALS AND METHODS: The present study enjoys a quasi-experimental method with using one group pre-test/post-test design conducted in Bam in southeast of Iran. The attitude of nursing students was measured using Frommelt Attitude Toward Care of the Dying (FATCOD) scale before and after an educational intervention. Data were analyzed using non-parametric tests in Statistical Package for the Social Sciences (SPSS) 18 software. RESULTS: Of 32 students, 30 participated in this study (response rate of 94%). Only 20% of the students reported previous experience of dying patients in their clinical courses. Students showed moderately negative to neutral attitudes toward caring for dying patients. Education has improved students' attitude significantly (mean score of FATCOD before study were 3.5 +/- 0.43 and after intervention were 4.7 +/- 0.33) (P < 0.001). CONCLUSION: Educational programs about death and caring for dying patients should be added to undergraduate nursing curricula. Further research recommended examining nursing students' knowledge about caring for dying patients and the effect of education on their knowledge. PMID- 26009674 TI - The Relationship between Body Esteem and Hope and Mental Health in Breast Cancer Patients after Mastectomy. AB - BACKGROUND: Breast cancer and its treatment, including mastectomy, can cause feelings of mutilation, depreciation in the value of the body, reduction in attractiveness, and lead to mental disorders and hopelessness. OBJECTIVE: The present study aimed to determine the relationship between appreciating the body, hope and mental health in women with breast cancer after mastectomy. MATERIALS AND METHODS: This study was a descriptive study of 100 breast cancer patients who had undergone mastectomy and referred to the Sayed Al-Shohada Medical Center in Isfahan, Iran. The subjects were selected by convenient sampling. Data gathering tools were the Body Esteem Scale (BES), Herth Hope Index (HHI), and Symptom Checklist 25 (SCL-25) mental health questionnaire. Data analysis was performed using SPSS software. RESULTS: Most of the patients had low body esteem. There was a significant direct linear relationship between body esteem and hope and mental health. This relationship was stronger between valuing the body and hope. CONCLUSION: Body esteem has a significant linear relationship with hope and mental health. PMID- 26009675 TI - Impact of medical intervention on stress and quality of life in patients with cancer. AB - CONTEXT: Many studies have explored stress and quality of life in (QOL) patients with cancer, under several phases of disease and treatment. However, the impact of medical intervention on psychological parameters, such as stress and quality of life focusing on psychological intervention has been sparsely studied. AIMS: The main aim of the study was to examine the impact of medical intervention on the level of stress and quality of life of patients with lung, breast, and head and neck cancers. SETTINGS AND DESIGN: The study was carried out in hospital settings by following a one-group pre-test-post-test pre-experimental design. STATISTICAL ANALYSIS USED: The quantitative data were analysed by means of descriptive statistics, paired t-tests, Cohen's d, and bar graphs accordingly. RESULTS: The effect of medical intervention was medium in case of reduction of overall stress in participants. So far as the components are concerned, the effect was high in case of psychosomatic complaints, medium in case of fear and information deficit, and low in case of everyday life restrictions. The effect of medical intervention in respect of the quality of life was found to be high in case of symptom scale (pain) and additional symptoms (constipation); medium in case of functional scale (emotional functioning, cognitive functioning) and symptoms scale (nausea, vomiting). In additional symptoms scale the effect of medical intervention was found to be medium in dyspnoea and appetite loss. CONCLUSIONS: The findings revealed that though the medical intervention reduced stress and improved the quality of life, it was not instrumental in bringing down the stress to minimal level and enhancing the quality of life to optimum level. Therefore, the findings point to the need of inclusion of psychological intervention along with the medical intervention for minimizing stress and optimizing the quality of life of patients with cancer. PMID- 26009676 TI - Attitudes and Knowledge of Iranian Nurses about Hospice Care. AB - CONTEXT: Due to expansion of chronic diseases and increase of health care costs, there is a need for planning and delivering hospice care for patients in their final stages of life in Iran. The aim of the present study is to investigate the knowledge and attitudes of nurses about delivering hospice care for End of Life (EOL) patients. MATERIALS AND METHODS: This cross-sectional study was conducted in 2012 with a sample size of 200 nurses that were selected by convenient (available) sampling. The data collection instrument was a self-administered questionnaire whose validity was approved by experts' opinions and its reliability was approved by test-retest method. RESULTS: Among all participants of this study, 87% were female. The mean age of nurses was 32.00 +/- 6.72. From all respondents 62% stated that they have no knowledge about hospice care and 80% declared that need for hospice care is increasing. Most of the participants felt that, appropriate services are not presented to patients in the final stages of their lives. About 80% believed that hospice care leads to reduction of health care costs, improvement of physical, mental and social health of patients and finally improvement of the quality of health care services. There was a significant relationship between age, employment history and level of education of nurses and their attitude and knowledge about how this service is provided. CONCLUSION: In view of the increase in chronic illnesses and the costs of caring, the need for provision of hospice care is felt more and more every day. However the awareness level of nurses about these services is low. Therefore the need for including these issues in nursing curriculum and holding scientific courses and seminars in this field is needed. PMID- 26009677 TI - Effective factors in providing holistic care: a qualitative study. AB - BACKGROUND: Holistic care is a comprehensive model of caring. Previous studies have shown that most nurses do not apply this method. Examining the effective factors in nurses' provision of holistic care can help with enhancing it. Studying these factors from the point of view of nurses will generate real and meaningful concepts and can help to extend this method of caring. MATERIALS AND METHODS: A qualitative study was used to identify effective factors in holistic care provision. Data gathered by interviewing 14 nurses from university hospitals in Iran were analyzed with a conventional qualitative content analysis method and by using MAXQDA (professional software for qualitative and mixed methods data analysis) software. RESULTS: Analysis of data revealed three main themes as effective factors in providing holistic care: The structure of educational system, professional environment, and personality traits. CONCLUSION: Establishing appropriate educational, management systems, and promoting religiousness and encouragement will induce nurses to provide holistic care and ultimately improve the quality of their caring. PMID- 26009678 TI - Nurses' Knowledge and Education about Oral Care of Cancer Patients Undergoing Chemotherapy and Radiation Therapy. AB - CONTEXT: Oral health awareness and oral care are crucial aspects of oncology nursing practice. However very few studies concentrate on the oral care of cancer patients undergoing cancer treatment and nursing practice in the Indian subcontinent. Most of the published studies have been conducted in the Western and European countries. AIM: This study aimed to determine the nurses' knowledge and education about oral care in cancer patient undergoing chemotherapy and radiation therapy. SETTING AND DESIGN: A cross sectional descriptive survey was conducted among 158 staff nurses working in oncology related areas from 4 different hospitals of Dakshina Kannada district and Udupi district of Karnataka state, India. STATISTICAL ANALYSIS: descriptive and inferential statistics was used by using SPSS 16 version. RESULTS: Majority 81 (51.3%) of the staff nurses had poor knowledge of oral care in cancer patients whereas 87 (55.1%) reported that knowledge acquired through basic education in oral care is not sufficient. Most of the staff nurses 115 (72.8%) did not receive basic education in oral care of cancer patients. There was significant association between knowledge and variables such as designation (.005), years of work experience (.040) and years of experience in cancer wards (.000) at 0.05 levels. CONCLUSION: Lack of knowledge suggest the need to develop and implement continuing nursing education programs on oral care specifically for patients receiving cancer treatments, for improving knowledge of staff nurses' in order to render comprehensive care to the patients. This study also recommends the importance of inclusion of cancer patient specific oral care in the curriculum which can enhance competency of the qualified nurses in cancer wards. PMID- 26009679 TI - The correlation between perceived social support and illness uncertainty in people with human immunodeficiency virus/acquired immune deficiency syndrome in iran. AB - BACKGROUND: Illness uncertainty is a source of a chronic and pervasive psychological stress for people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (PLWH), and largely affects their quality of life and the ability to cope with the disease. Based on the uncertainty in illness theory, the social support is one of the illness uncertainty antecedents, and influences the level of uncertainty perceived by patients. AIM: To examine uncertainty in PLWH and its correlation with social support in Iran. MATERIALS AND METHODS: This cross-sectional correlational study was conducted with 80 PLWH presenting to AIDS Research Center, Tehran, Iran in 2013. The data collected using illness uncertainty and social support inventories were analyzed through Pearson's correlation coefficient, Spearman's correlation coefficient, and regression analysis. RESULTS: The results showed a high level of illness uncertainty in PLWH and a negative significant correlation between perceived social support and illness uncertainty (P = 0.01, r = -0.29). CONCLUSION: Uncertainty is a serious aspect of illness experience in Iranian PLWH. Providing adequate, structured information to patients as well as opportunities to discuss their concerns with other PLWH and receive emotional support from their health care providers may be worthwhile. PMID- 26009680 TI - Treating Palliative Care Patients with Pain with the Body Tambura: A Prospective Case Study at St. Joseph's Hospice for Dying destitute in Dindigul South India. AB - BACKGROUND: The Body Tambura is a recently invented stringed instrument that is used for receptive music therapy designed to be placed and attached on the human body. The aim of this study was to record perceived effects of a treatment with the Body Tambura on palliative care patients with special reference to pain. MATERIALS AND METHODS: A prospective case study was carried out with patients of St. Joseph's Hospice for Dying Destitute in Dindigul/South India. Patients were treated with a treatment after baseline assessment and also on the next day. Outcomes were measured quantitatively by using a numeric rating scale (0-10, 10 maximum intensity of pain felt) at baseline, directly after treatment, and the day after the treatment to determine the intensity of the pain. RESULTS: Ten patients (five women and five men) participated in the study. The majority described the therapy as a pleasant experience. The pain intensity at baseline was reduced from 8.3 +/- standard deviation (SD) 1.16 to 4.6 +/- 1.52 at day 1 and from 4.6 +/- 2.07 to 2.4 +/- 1.58 at day 2. CONCLUSION: A clinically relevant pain reduction was described as short time outcome; the therapy was received and perceived well. Forthcoming research should include a control group, randomization, a larger number of participants, and a longer period of treatment. PMID- 26009681 TI - Metastatic Adenocarcinoma of Prostate in a 28-Year-Old Male: The outcome is poor in young patients? AB - Prostate cancer is common in older patients. Rarity in younger population limits the study of natural history and prognosis in this population. Most of the published data has reported poor outcome in younger patients with metastatic prostate cancer. Here, we report a case of prostate cancer in 28-year-old male who presented with bone metastasis. After bilateral inguinal orchidectomy, he was started on anti-androgen therapy and received palliative radiotherapy for bone metastasis. There was only a slight decrease in prostate-specific antigen (PSA) level and pelvic disease post treatment. Subsequently, he was started on opioid analgesics (by World Health Organization, WHO, step ladder) in view of persistent pain. The index case is being presented for its rarity and probable poor outcome in young patients and to stress on the fact that the possibility of primary prostatic adenocarcinoma should be investigated in a male presenting with bone metastasis irrespective of the age. PMID- 26009682 TI - Metronomic chemotherapy in anaplastic thyroid carcinoma: a potentially feasible alternative to therapeutic nihilism. AB - Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC. PMID- 26009683 TI - Palliative Home Care: A Designer's Perspective. AB - The purpose for this observational research was to understand how Can Support provides palliative care at home and analyze its strengths and weaknesses in various socioeconomic scenarios for future development. In the period of 2 weeks, patients and their caregivers were silently observed in their natural surroundings during home care visits in order to listen their problems, identify the pattern of questions for the home care team, their natural way of storytelling, organizational techniques for medicines and medical reports, care givers lives, patient journey, etc. Such observations have enabled the understanding of the phenomena of home palliative care and have led to the identification of certain influential variables of the practice. PMID- 26009684 TI - Caregivers' Perspective on Home-based Care of Operated Neurosurgery Patients Discharged From PGIMER, Chandigarh, India. PMID- 26009685 TI - Nicotine replacement therapy for the palliation of nicotine abstinence syndrome: boon more than bane. PMID- 26009686 TI - Sweetgum: An ancient source of beneficial compounds with modern benefits. AB - Sweetgum trees are large, deciduous trees found in Asia and North America. Sweetgum trees are important resources for medicinal and other beneficial compounds. Many of the medicinal properties of sweetgum are derived from the resinous sap that exudes when the outer bark of the tree has been damaged. The sap, known as storax, has been used for centuries to treat common ailments such as skin problems, coughs, and ulcers. More recently, storax has proven to be a strong antimicrobial agent even against multidrug resistant bacteria such as methicillin-resistant Staphylococcus aureus. In addition to the sap, the leaves, bark, and seeds of sweetgum also possess beneficial compounds such as shikimic acid, a precursor to the production of oseltamivir phosphate, the active ingredient in Tamiflu(r)-an antiviral drug effective against several influenza viruses. Other extracts derived from sweetgum trees have shown potential as antioxidants, anti-inflammatory agents, and chemopreventive agents. The compounds found in the extracts derived from sweetgum sap suppress hypertension in mice. Extracts from sweetgum seeds have anticonvulsant effects, which may make them suitable in the treatment of epilepsy. In addition to the potential medicinal uses of sweetgum extracts, the extracts of the sap possess antifungal activity against various phytopathogenic fungi and have been effective treatments for reducing nematodes and the yellow mosquito, Aedes aegypti, populations thus highlighting the potential of these extracts as environment-friendly pesticides and antifungal agents. The list of value-added products derived from sweetgum trees can be increased by continued research of this abundantly occurring tree. PMID- 26009687 TI - Cucurbitacins - An insight into medicinal leads from nature. AB - Cucurbitacins which are structurally diverse triterpenes found in the members of Cucurbitaceae and several other plant families possess immense pharmacological potential. This diverse group of compounds may prove to be important lead molecules for future research. Research focused on these unattended medicinal leads from the nature can prove to be of immense significance in generating scientifically validated data with regard to their efficacy and possible role in various diseases. This review is aimed to provide an insight into the chemical nature and medicinal potential of these compounds exploring their proposed mode of action, probable molecular targets and to have an outlook on future directions of their use as medicinal agents. PMID- 26009688 TI - Occurrence of taraxerol and taraxasterol in medicinal plants. AB - Indian soil germinates thousands of medicinal drugs that are cultivated with a purpose to obtain a novel drug. As it is a well-established fact that the structural analogs with greater pharmacological activity and fewer side-effects may be generated by the molecular modification of the functional groups of such lead compounds. This review throws light on two natural triterpenes - Taraxerol and Taraxasterol which have many important pharmacological actions including anti cancer activity, their chemistry, biosynthesis aspects, and possible use of these compounds as drugs in treatment of cancer. A silent crisis persists in cancer treatment in developing countries, and it is intensifying every year. Although at least 50-60% of cancer victims can benefit from radiotherapy that destroys cancerous tumors, but search for the paramount therapy which will prove to be inexpensive with minimal side effects still persists. Various treatment modalities have been prescribed, along with conventional and non-conventional medicine but due to their adverse effects and dissatisfaction among users, these treatments are not satisfactory enough to give relief to patients. Hence, this review sparks the occurrence of Taraxerol (VI) and Taraxasterol (VII) in nature, so that the natural godowns may be harvested to obtain these potent compounds for novel drug development as well as discusses limitations of these lead compounds progressing clinical trials. PMID- 26009689 TI - Biosynthesis and regulation of terpenoid indole alkaloids in Catharanthus roseus. AB - Catharanthus roseus produces a wide range of terpenoid indole alkaloids (TIA). Many of them, such as vinblastine and vincristine, have significant bioactivity. They are valuable chemotherapy drugs used in combination with other drugs to treat lymphoma and leukemia. The TIA biosynthetic pathway has been investigated for many years, for scientific interest and for their potential in manufacturing applications, to fulfill the market demand. In this review, the progress and perspective of C. roseus TIA biosynthesis and its regulating enzymes are described. In addition, the culture condition, hormones, signaling molecules, precursor feeding on the accumulation of TIA, and gene expression are also evaluated and discussed. PMID- 26009690 TI - Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus: A brief review. AB - Infections caused by Staphylococcus aureus strains with Methicillin resistance are associated with increased mortality and morbidity, aggressive course, multiple drug resistance and hospital outbreaks. Several first and second line antibiotics are rapidly becoming ineffective for treatment due to emergence of resistance. Extracts of medicinal plants are rich source of unique phytochemicals. Plants used in traditional medicine have been reported to have significant anti-MRSA activity. The objective of this review is to provide a brief overview of antibiotics as well as anti-MRSA natural products and their future prospect. PMID- 26009691 TI - Hepcidin - A novel biomarker with changing trends. AB - Hepcidin is a novel peptide hormone of hepatic origin. It has a crucial role in iron metabolism. The causative association of this peptide in anemia and iron overloading states has been well established. Current research has expanded the diagnostic implications of hepcidin in other medical conditions. Increased serum hepcidin has been reported in neoplastic diseases, inflammation, and sepsis. However, the clinical use of hepcidin as a biomarker is limited owing to nonavailability of an appropriate diagnostic test. Assays for serum and urine hepcidin estimation have been developed recently, which are likely to facilitate the use of hepcidin in research as well as in patient care in the near future. PMID- 26009692 TI - Azadirachta indica: A herbal panacea in dentistry - An update. AB - Azadirachta indica commonly known as Neem, is an evergreen tree. Since time immemorial it has been used by Indian people for treatment of various diseases due to its medicinal properties. It possesses anti-bacterial, anti-cariogenic, anti-helminthic, anti-diabetic, anti-oxidant, astringent, anti-viral, cytotoxic, and anti-inflammatory activity. Nimbidin, Azadirachtin and nimbinin are active compounds present in Neem which are responsible for antibacterial activity. Neem bark is used as an active ingredient in a number of toothpastes and toothpowders. Neem bark has anti-bacterial properties, it is quite useful in dentistry for curing gingival problems and maintaining oral health in a natural way. Neem twigs are used as oral deodorant, toothache reliever and for cleaning of teeth. The objective of this article is to focus on the various aspects of Azadirachta indica in dentistry in order to provide a tool for future research. PMID- 26009694 TI - Alpinia calcarata Roscoe: A potential phytopharmacological source of natural medicine. AB - Alpinia calcarata Roscoe (Family: Zingiberaceae), is a rhizomatous perennial herb, which is commonly used in the traditional medicinal systems in Sri Lanka. Alpinia calcarata is cultivated in tropical countries, including Sri Lanka, India, and Malaysia. Experimentally, rhizomes of Alpinia calcarata are shown to possess antibacterial, antifungal, anthelmintic, antinociceptive, anti inflammatory, antioxidant, aphrodisiac, gastroprotective, and antidiabetic activities. Phytochemical screening revealed the presence of polyphenols, tannins, flavonoids, steroid glycosides and alkaloids in the extract and essential oil of this plant. Essential oil and extracts from this plant have been found to possess wide range of pharmacological and biological activities. This article provides a comprehensive review of its ethnomedical uses, chemical constituents and the pharmacological profile as a medicinal plant. Particular attention has been given to the pharmacological effects of the essential oil of Alpinia calcarata in this review so that the potential use of this plant either in pharmaceutics or as an agricultural resource can be evaluated. PMID- 26009693 TI - Phytochemical profile of sugarcane and its potential health aspects. AB - Sugarcane (Saccharum officinarum Linn.) is an important perennial grass of Poaceae family, indigenous to tropical South Asia and Southeast Asia. It is cultivated worldwide due to the economical and medicinal value of its high yielding products. Sugarcane juice is well known as a raw material for the production of refined sugar and its wax is considered as a potential substitute for the expensive carnauba wax, which is of cosmetic and pharmaceutical interest. Refined sugar is the primary product of sugarcane juice, but during its processing, various other valuable products are also obtained in an unrefined form, such as, brown sugar, molasses, and jaggery. Sugarcane juice is widely used in India in the treatment of jaundice, hemorrhage, dysuria, anuria, and other urinary diseases. Herein, we have summarized the different phytoconstituents and health benefits of sugarcane and its valuable products. The phytochemistry of sugarcane wax (obtained from the leaves and stalks of sugarcane), leaves, juice, and its products has revealed the presence of various fatty acid, alcohol, phytosterols, higher terpenoids, flavonoids, -O- and -C-glycosides, and phenolic acids. The future prospective of some of the sugarcane products has been discussed, which needs a phytopharmacological study and has a great potential to be a valuable medicinal product. PMID- 26009695 TI - Echinacea purpurea: Pharmacology, phytochemistry and analysis methods. AB - Echinacea purpurea (Asteraceae) is a perennial medicinal herb with important immunostimulatory and anti-inflammatory properties, especially the alleviation of cold symptoms. The plant also attracted scientists' attention to assess other aspects of its beneficial effects. For instance, antianxiety, antidepression, cytotoxicity, and antimutagenicity as induced by the plant have been revealed in various studies. The findings of the clinical trials are controversial in terms of side effects. While some studies revealed the beneficial effects of the plant on the patients and no severe adverse effects, some others have reported serious side effects including abdominal pain, angioedema, dyspnea, nausea, pruritus, rash, erythema, and urticaria. Other biological activities of the plant such as antioxidant, antibacterial, antiviral, and larvicidal activities have been reported in previous experimental studies. Different classes of secondary metabolites of the plant such as alkamides, caffeic acid derivatives, polysaccharides, and glycoproteins are believed to be biologically and pharmacologically active. Actually, concurrent determination and single analysis of cichoric acid and alkamides have been successfully developed mainly by using high-performance liquid chromatography (HPLC) coupled with different detectors including UV spectrophotometric, coulometric electrochemical, and electrospray ionization mass spectrometric detectors. The results of the studies which were controversial revealed that in spite of major experiments successfully accomplished using E. purpurea, many questions remain unanswered and future investigations may aim for complete recognition of the plant's mechanism of action using new, complementary methods. PMID- 26009696 TI - Phytochemistry, pharmacology, toxicology, and clinical trial of Ficus racemosa. AB - Ficus racemosa is an important medicinal plant, found in India, Australia, and Southeast Asia. It is popularly known as 'gular.' It reduces blood glucose concentration due to the presence of beta-sitosterol. Many active constituents that have been isolated from various parts of this plant possess useful pharmacological activities. The literature survey proposed that it has multiple pharmacological actions that include antidiabetic, antioxidant, antidiarrhoeal, anti-inflammatory, antipyretic, antifungal, antibacterial, hypolipidemic, antifilarial, and hepatoprotection. This review article elaborately describes the traditional uses, phytochemistry, pharmacology, and toxicology of this plant. We also provide useful structures of the secondary metabolites along with their nuclear magnetic resonance (NMR) data. Some clinical trial data have also been provided in this review. This review would assist researchers to gather scientific information in future. PMID- 26009697 TI - Pharmaceutical scope of a phytochemically unexplored medicinal plant, Sarcochlamys pulcherrima (Roxb.) Gaud.: A review. AB - Sarcochlamys pulcherrima (Roxb.) Gaud. is widely used as traditional medicine and food by different tribes and communities of Assam in India and in neighboring countries. Recent studies conducted in our laboratory showed the broad-spectrum antimicrobial and antioxidant activities of its crude extract and different solvent fractions and detected the presence of phenolics, flavonoids, saponin, and acidic compounds. This review gives a bird's eye view of the traditional uses of S. pulcherrima as food and medicine based on the information gathered by personal interaction with the people of different places of Assam as well as the investigations made on its ethno-botanical claims, biological activities, and other aspects by various workers since years till date and highlight the prospects of future research. PMID- 26009698 TI - Misleading "non-rasayanas". PMID- 26009699 TI - Understanding Associations among Family Support, Friend Support, and Psychological Distress. AB - Emotional support from family and friends is associated with lower psychological distress. This study examined whether genetic and environmental influences explain associations among family support, friend support, and psychological distress. Data were drawn from the Midlife Development in the United States (MIDUS) study and included 947 pairs of MZ, same-sex DZ, and opposite-sex DZ twins. Results showed that a genetic factor explains the relationship between friend support and psychological distress, independent of family support. Alternatively, a nonshared environmental factor accounts for an association among family support, friend support, and psychological distress. Thus, heritable factors shape a distinct relationship between friend support and psychological distress, but unique experiences contribute to a link among family support, friend support, and psychological distress. PMID- 26009701 TI - Animal venom studies: Current benefits and future developments. AB - Poisonous organisms are represented in many taxa, including kingdom Animalia. During evolution, animals have developed special organs for production and injection of venoms. Animal venoms are complex mixtures, compositions of which depend on species producing venom. The most known and studied poisonous terrestrial animals are snakes, scorpions and spiders. Among marine animals, these are jellyfishes, anemones and cone snails. The toxic substances in the venom of these animals are mainly of protein and peptide origin. Recent studies have indicated that the single venom may contain up to several hundred different components producing diverse physiological effects. Bites or stings by certain poisonous species result in severe envenomations leading in some cases to death. This raises the problem of bite treatment. The most effective treatment so far is the application of antivenoms. To enhance the effectiveness of such treatments, the knowledge of venom composition is needed. On the other hand, venoms contain substances with unique biological properties, which can be used both in basic science and in clinical applications. The best example of toxin application in basic science is alpha-bungarotoxin the discovery of which made a big impact on the studies of nicotinic acetylcholine receptor. Today compositions of venom from many species have already been examined. Based on these data, one can conclude that venoms contain a large number of individual components belonging to a limited number of structural types. Often minor changes in the amino acid sequence give rise to new biological properties. Change in the living conditions of poisonous animals lead to alterations in the composition of venoms resulting in appearance of new toxins. At the same time introduction of new methods of proteomics and genomics lead to discoveries of new compounds, which may serve as research tools or as templates for the development of novel drugs. The application of these sensitive and comprehensive methods allows studying either of venoms available in tiny amounts or of low abundant components in already known venoms. PMID- 26009700 TI - Promise and challenges on the horizon of MET-targeted cancer therapeutics. AB - MET (MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor (HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, and metastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of MET-targeted cancer drugs and discuss the challenges in such development. PMID- 26009702 TI - MicroRNAs as mediators of cardiovascular disease: Targets to be manipulated. AB - Cardiovascular disease has been the leading cause of death worldwide for the last few decades. Even with the rapid progression of the biomedical field, conquering/managing cardiovascular disease is not an easy task because it is multifactorial disease. One of the key players of the development and progression of numerous diseases is microRNA (miRNA). These small, non-coding RNAs bind to target mRNAs to inhibit translations of and/or degrade the target mRNAs, thus acting as negative regulators of gene expressions. Accumulating evidence indicates that non-physiological expressions of miRNAs contribute to both development and progression of cardiovascular diseases. Since even a single miRNA can have multiple targets, dysregulation of miRNAs can lead to catastrophic changes of proteins that may be important for maintaining physiologic conditions of cells, tissues, and organs. Current knowledge on the role of miRNAs in cardiovascular disease is mostly based on the observational data such as microarray of miRNAs in animal disease models, thus relatively lacking insight of how such dysregulation of miRNAs is initiated and regulated. Consequently, future research should aim to elucidate the more comprehensive mechanisms of miRNA dysregulation during pathogenesis of the cardiovascular system so that appropriate counter-measures to prevent/manage cardiovascular disease can be developed. PMID- 26009704 TI - Nontraumatic aneurysm rupture following an endoscopic third ventriculostomy and ventricular drainage: Case report of a rare complication. AB - BACKGROUND: Although endoscopic third ventriculostomy is a safe procedure, the authors report a case of aneurysmal subarachnoid hemorrhage as an unusual and serious complication of an endoscopic third ventriculostomy and ventricular drainage. CASE DESCRIPTION: A 60-year-old male presented with obstructive hydrocephalus caused by midbrain tumors was admitted to our hospital. Endoscopic third ventriculostomy and external ventricular drainage were successfully performed. Two days after the operation, he became comatose, and a computed tomography (CT) scan revealed a diffuse subarachnoid hemorrhage. Emergency cerebral angiogram showed an aneurysm of the left internal carotid artery. Endovascular coil embolization of the ruptured aneurysm was then performed. CONCLUSION: The rupture of the aneurysm may have been induced by excessive cerebrospinal fluid drainage after the endoscopic third ventriculostomy. Planning for intracranial endoscopic procedures should consider that rupture of an unknown previously unruptured aneurysm is a possible complication. PMID- 26009703 TI - Adipocyte activation of cancer stem cell signaling in breast cancer. AB - Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment, have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6 (IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activator of transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte breast cancer cell signaling via targeting the IL-6 or leptin pathways. PMID- 26009705 TI - Minimally invasive tubular access for posterior cervical foraminotomy. AB - BACKGROUND: Minimally invasive tubular access for posterior cervical foraminotomy can be an effective and safe technique for decompression of the nerve root utilizing minimally invasive muscle splitting with routine outpatient discharge. This technique has come under scrutiny calling into question the associated learning curve, a subjective limited exposure provided, and an argument that the risks and complications are largely unknown. In response to previously published critiques, this study aims to describe the outcomes and complications associated with this technique in a large patient series. METHODS: A retrospective chart review was performed from 1999 to 2013 capturing a single surgeon's experience with the minimally invasive tubular access for posterior cervical foraminotomy technique from a single institution, encompassing 463 patients. Surgical outcome documented at follow-up and complications were obtained from this patient series. Additional variables analyzed include: Hospital length of stay, number of levels operated, targeted root for decompression, side operated, length of surgery, and estimated blood loss. RESULTS: Outpatient discharge was achieved in 91.6% of cases. There were 10 complications (2.2%) among the 463 patients undergoing this technique from 1999 to 2013. Patients were followed for an average of 1 year and 2 months postoperatively. Improvement from the preoperative condition was observed in 98.2% of patients and excellent outcomes with patients reporting complete relief of symptoms with no or mild residual discomfort was seen in 92.2%. CONCLUSIONS: Compared with open techniques, minimally invasive tubular access for posterior cervical foraminotomy demonstrates comparable, if not superior, complication rates, and patient outcomes. PMID- 26009708 TI - Clinical photography in dermatology using smartphones: An overview. AB - The smartphone is one of the biggest revolutions in the era of information technology. Its built in camera offers several advantages. Dermatologists, who handle a specialty that is inherently visual, are most benefited by this handy technology. Here in this article, we attempt to provide an overview of smartphone photography in clinical dermatology in order to help the dermatologist to get the best out of the available camera for clinical imaging and storage. PMID- 26009709 TI - Dermoscopic evaluation of idiopathic guttate hypomelanosis: A preliminary observation. AB - BACKGROUND: Depigmented skin lesions are of great concern in the society, especially in the Indian subcontinent. These comprise many infective and inflammatory conditions that cause apprehension and anxiety among patients due to the social stigma attached to these conditions. Idiopathic guttate hypomelanosis (IGH) appears similar to many depigmented lesions and differentiation of IGH from these conditions is difficult clinically as well as histopathologically. METHODS: Clinically suspected IGH were included in the study. All IGH lesions were confirmed by histopathology. Clinical data and dermoscopic patterns were analyzed and presented in proportions and percentages. RESULTS: Thirty patients were included in the study with 16 females and 14 males. Dermoscopy showed amoeboid, feathery, petaloid and nebuloid patterns in 12, 7, 6 and 1 patients respectively. Four patients had combination of these patterns. CONCLUSION: Dermoscopy of IGH revealed consistent patterns. Hence, we propose these patterns were specific to IGH and help clinician to differentiate many depigmented skin lesions from IGH in clinical practice. However, histopathology must be done for confirmation of diagnosis. Further studies on dermoscopy of IGH with histopathology correlation are proposed. PMID- 26009706 TI - Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction. AB - Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence. PMID- 26009710 TI - A study of cutaneous adverse drug reactions at a tertiary center in Jammu, India. AB - AIM: The aim was to study various morphological patterns of cutaneous adverse drug reactions (CADRs) and identify the culprit drug or drugs by establishing a causal link using Naranjo adverse drug reaction probability scale. MATERIALS AND METHODS: The study was carried out between November 2010 and November 2011 at the Department of Dermatology, Government Medical College, Jammu. A total of 150 patients with CADR reporting to the dermatology department or referred from other departments were evaluated. Detailed history, clinical examination, hematological, and biochemical investigations were recorded. The venereal disease research laboratory test, HIV (ELISA), and histopathological examination were done wherever indicated. RESULTS: A total of 150 patients were evaluated after applying the inclusion and exclusion criteria. The mean age of the patients with CADRs was 33.26 years. A majority of patients (30.6%) were in the age group of 21 30 years. The male to female ratio was 1.7:1.2. The most common CADRs were fixed drug eruption in 33.3% of patients followed by urticaria in 17.3%, and maculopapular rash in 13.3%. The most common classes of drugs implicated were antimicrobials in 40% of patients followed by nonsteroidal antiinflammatory drugs in 35.3%. The Naranjo adverse drug reaction probability scale indicated probable association of 77.3%, highly probable association of 12.6%, and 1% possible association with the implicated drugs. CONCLUSION: The pattern of CADRs and the drugs causing them is remarkably different in our population. Knowledge of these drug reactions, their causative drugs, and prognostic indicators is essential for the clinician. PMID- 26009707 TI - Light-based therapies in acne treatment. AB - The use of light and laser in the treatment of acne is increasing as these modalities are safe, effective, and associated with no or minimal complications when used appropriately. These light and laser sources are also being used in combination with pharmacological and/or physical measures to synergize their effects and optimize the therapeutic outcome. This review focuses on optical devices used in treating acne and serves to delineate the current application of various methods, including their utility and efficacy. PMID- 26009711 TI - Role of direct immunofluorescence in dermatological disorders. AB - BACKGROUND: Direct immunofluorescence (DIF) test for tissue-bound autoantibodies, has been found to be of value in the diagnosis of several dermatological disorders. The location and pattern of deposition of immunoreactants helps in classifying various immune-mediated diseases. AIMS AND OBJECTIVES: The aim of this study was to analyze the concordance between the clinical, histopathological and DIF diagnosis in bullous and nonbullous lesions of the skin, and thus determine the impact of immunofluorescence on diagnosis. MATERIALS AND METHODS: A total of 215 skin biopsies performed in suspected immune-mediated vesiculobullous disease, vasculitis or dermatosis, were studied. Histopathological examination was done along with DIF study for deposits of immunoglobulin G(IgG), IgA, IgM, and C3. RESULTS: Direct immunofluorescence was positive in 103/215 cases. There was very good concordance between the clinical, histological and DIF results (observed agreement = 93.4%, kappa =0.90, with 95% confidence interval = 0.86 0.94). The overall sensitivity of DIF in immune-mediated skin disorders was 98.0%. DIF was positive in 52/53 cases (98.1%) in the pemphigus group and 24/25 (96.0%) bullous pemphigoid cases. None of the clinically suspected cases of dermatitis herpetiformis showed DIF positivity. A positive lupus band test was seen in 9/9 (100%) cases of lupus erythematosus. DIF was positive in 10/10 (100%) clinically suspected cases of Henoch-Schonlein purpura. In 110 cases, negative DIF results helped to rule out immune-mediated vesiculobullous disorders, lupus erythematosus and vasculitis, and the final diagnosis was made on the basis of the clinical features and/or histopathology. CONCLUSION: Direct immunofluorescence is a useful supplement for the accurate diagnosis of immune mediated dermatological disorders, and helps to classify various autoimmune bullous disorders. When the clinical features/histopathology are inconclusive, the diagnosis often can be made on the basis of the DIF findings alone. A combination of the clinical features, histopathology and DIF usually gives the best results. PMID- 26009712 TI - Acyclovir in pityriasis rosea: An observer-blind, randomized controlled trial of effectiveness, safety and tolerability. AB - BACKGROUND: Pityriasis rosea (PR) is an acute inflammatory dermatosis. The association of human herpes virus 6 and 7 suggests the utility of use of antiviral agents in this disease. AIMS AND OBJECTIVES: To evaluate the effectiveness and safety of acyclovir in the treatment of PR. METHODS: An observer-blind, randomized (1:1), parallel group, add-on trial was conducted on 24 adult patients with PR. Subjects of both Group A and B received the standard of care in the form of cetirizine 10 mg OD and calamine. Group A in addition received acyclovir 400 mg tablets thrice daily for 7 days. Both groups were followed up for four consecutive weeks for assessment of effectiveness and adverse events. RESULTS: Group A complained of significantly fewer new lesions than Group B (P = 0.046). A complete response was obtained in all patients of Group A and 83% patients of Group B at the end of the follow up period. There was significant reduction in both lesional score and pruritus at second week follow up in Group A and third week follow-up in Group B (P < 0.05). Minor adverse effects were observed in both treatment arms. CONCLUSION: Acyclovir offered rapid resolution of clinical severity of PR from second week onwards without significantly increased adverse events as compared to supportive therapy alone. PMID- 26009713 TI - Azathioprine in autologous serum skin test positive chronic urticaria: A case control study in a tertiary care hospital of eastern India. AB - CONTEXT: Urticaria, also referred to as hives or wheals is a common and distinctive reaction pattern characterized by spontaneous eruption of wheals. About 30-50% of patients categorized as idiopathic urticaria have autoimmune urticaria, needing immunosuppressive agents. Immunosuppressive agents are either too costly or have serious side effects. Azathioprine seems to address both these issues, being less costly. AIMS: The aim was to evaluate the role of azathioprine in autologous serum skin test (ASST) positive chronic urticaria (CU). SETTINGS AND DESIGN: A single-blind randomized control trial of ASST positive patients of CU. MATERIALS AND METHODS: Patients with positive ASST were allotted into two treatment groups, named group A and group B. Patients in group A were administered azathioprine (50 mg/day) for a period of 8 weeks and followed up till 36 weeks, while patients in group B were given placebo pills. All patients were directed to take levocetirizine (5 mg) on as and when basis, in addition. Urticaria was assessed by total severity score. STATISTICAL ANALYSIS USED: MedCalc statistical software (v 12.5 for Windows) to calculate P values in independent samples by t-test, Mann-Whitney test, Friedmann test, and ANOVA. RESULTS: Administration of azathioprine in group A resulted in a significant diminution of the intensity of the disease as well as in the requirement of rescue antihistamine (positive primary and secondary outcome). CONCLUSION: Azathioprine not only had immunomodulatory properties during the treatment period, but also had lasting therapeutic effect as well. There were some gastrointestinal side effects in the initial stages but no incidence of hematological or biochemical disturbances. PMID- 26009714 TI - Rhinocerebrocutaneous mucormycosis caused by Mucor species: A rare causation. AB - Rhinocerebral mucormycosis is the most common form of mucormycosis occurring commonly in patients of diabetic ketoacidosis. Fungi of the order Mucorales belong to six families, among whom Rhizopus is the most common, while Mucor is a rare cause. We report a 45-year-old female with uncontrolled diabetes mellitus diagnosed to have rhinocerebrocutaneous mucormycosis caused by Mucor species. The diagnosis was confirmed on histology and culture. A high-index of suspicion is required for early diagnosis and timely initiation of therapy to optimize the outcome. Our patient succumbed to her infection. PMID- 26009715 TI - Subcutaneous leiomyosarcoma of scrotum presenting as an exophytic mass: An unusual presentation. AB - Paratesticular leiomyosarcoma originates from testicular tunica (48%), spermatic cord (48%), epididymis (2%) and dartos muscle, as well as subcutaneous tissue of the scrotum (2%). Leiomyosarcomas of the scrotum, not involving the testis, epididymis or spermatic cord, are rare, and belong to the group of subcutaneous superficial leiomyosarcomas. To the knowledge of the authors, less than 10 cases of leiomyosarcoma of the scrotum have so far been reported from India. The tumor usually presents as a painless, slow-growing scrotal mass in middle-aged or elderly men. The current approach is wide local excision, often with adjuvant therapy. The prognosis is usually good following complete excision, though a local recurrence rate of 40% has been reported. Long term follow-up is, therefore, necessary to monitor for recurrence. Herein we present the case of 35 year-old male who presented with an exophytic scrotal mass. Histopathological and immunohistochemical findings of the mass were consistent with leiomyosarcoma. PMID- 26009716 TI - Lupus vulgaris leading to perforation of nasal septum in a child. AB - Lupus vulgaris (LV) is a common form of cutaneous tuberculosis in India, mostly involving the lower half of the body. Facial involvement is uncommon. Untreated disease may lead to significant morbidity due to atrophic scarring, mutilation, and deformity. We report a case of multi-focal LV in a 10-year-old boy affecting the nose and cheek that resulted in perforation of the nasal septum, a rarely reported complication. PMID- 26009717 TI - Asymptomatic papules over central and pericentral areas of the face. AB - We report the case of a 24-year-old college girl, presenting with numerous acneiform papular eruptions over the central part of the face. PMID- 26009718 TI - Giant cell tumor of the tendon sheath mimicking a plexiform neurofibroma. AB - Giant-cell tumor of the tendon sheath (GCTTS) is a benign soft tissue tumor of the limbs arising from the complex of the tendon sheath and periarticular soft tissues of small joints. It is the second most common benign space occupying lesion in the hand and usually presents as a painless soft tissue mass, which grows slowly in size for many years. We present an interesting case of an enormous GCTTS presenting as a slowly growing mass over left sole of a 52-year old woman. The duration of GCTTS may range from a few weeks to 30 years but in our case the duration of tumor was almost 48 years, which could be the longest reported duration of GCTTS. PMID- 26009719 TI - Diffuse leprosy with "deck-chair" sign. AB - A 55-year-old male presented with asymptomatic extensive skin lesions since one year. He was found to have diffuse lesions involving the face, trunk, arms, and thighs along with symmetric peripheral nerve thickening. Bacteriological and histopathological examination confirmed lepromatous leprosy. There was a conspicuous sparing of the abdominal creases and axillae from the infiltrative lesions suggesting a positive "deck-chair" sign. This sign has been described in the past with papulo-erythroderma of Ofuji and certain other disorders. Leprosy may be now included among the causes of "deck-chair" sign. PMID- 26009720 TI - Ineffectiveness of tumor necrosis factor-alpha blockers and ustekinumab in a case of type IV pityriasis rubra pilaris. AB - Treatment of pityriasis rubra pilaris (PRP) may be difficult since no standardized therapeutic approach has been established. Recently, tumor necrosis factor-alpha (TNF-alpha) blockers have been demonstrated to be favorable in the management of recalcitrant PRP. The authors report a case of a patient who presented a type IV PRP or circumscribed, juvenile type. Such a condition follows an unpredictable course, presenting with diffuse, palmoplantar keratoderma and sharply-demarcated areas of follicular hyperkeratosis on the elbows and knees. Treatment with all available TNF-alpha inhibitors and ustekinumab did not prove to be helpful. The authors suggest that circumscribed variants of PRP could respond to therapy in ways different from classical PRP. PMID- 26009721 TI - Acropigmentation of Kitamura with immigration delay disease: A rare entity. AB - Reticulate acropigmentation of Kitamura (RAK) is a rare, autosomal dominant disorder first described in Japan characterised by a reticulate pattern of slightly atrophic, angulated, hyperpigmented macules affecting the acral areas of the body. We hereby report a case of RAK in a young Indian male with adermatoglyphia that has not been previously reported in the literature. PMID- 26009722 TI - Cutaneous metastasis in anorectal adenocarcinoma. AB - Cutaneous metastasis in anorectal adenocarcinoma is a rare entity. Here, we report the case of a 40-year-old female who presented with yellowish-brown, irregular, solid, elevated rashes over the pubis with a recent history off palliative colostomy for anorectal adenocarcinoma. Clinically, we suspected metastasis that was proved on biopsy. We report this case due to the rare presenting site (i.e., perineum) of a metastatic adenocarcinoma. PMID- 26009723 TI - Tumor with the features of both squamous cell carcinoma and melanoma (melanocarcinoma). AB - Combined tumors of malignant melanoma (MM) and squamous cell carcinoma (SCC) are extremely rare and have unknown biological potential. Different theories of their development, including collision and dual/divergent differentiation, are proposed. Although some observations suggest an indolent course for such tumors, a case of MM metastasis was reported in a patient who initially presented with a combined MM-SCC tumor. Re-excisions of such tumors may show MM in situ and should be treated accordingly. Herein we present another case of a combined MM-SCC tumor in a 78 male patient with lentigo maligna seen after complete re-excision of the tumor. PMID- 26009724 TI - Newly described signs in dermatology. AB - Authors have attempted to discuss recently described "signs" in the field of dermatology. PMID- 26009725 TI - "Reversed pigmentary network pattern" in evolving lesions of vitiligo. PMID- 26009726 TI - Pheohyphomycotic cyst. PMID- 26009727 TI - Malignant peripheral nerve sheath tumour in a patient with a plexiform neurofibromatosis. PMID- 26009728 TI - Adrenocorticotropic hormone test and estimation of a safe dose for high potency steroids in vitiligo. PMID- 26009729 TI - SkIndia Quiz 18: Multiple erythematous nodules in a 30-year-old woman. PMID- 26009730 TI - Brownish macule on the palm. PMID- 26009731 TI - Acute methotrexate toxicity presenting as ulcers in plaques of psoriasis vulgaris. PMID- 26009732 TI - Acral freckling with palmar pits. PMID- 26009733 TI - Bilateral asymmetrical herpes zoster. PMID- 26009734 TI - Dermoscopic patterns in lichen sclerosus: A report of three cases. PMID- 26009735 TI - Don't be so quick to write off frenotomy. PMID- 26009736 TI - Chest pain . shortness of breath . fever and nausea . Dx? PMID- 26009737 TI - RADIOLOGY REPORT: An imaging guide to abdominal pain. AB - When patients present with acute nontraumatic abdominal pain, knowing what disorders and which imaging modalities to consider is essential. Let this article and handy table be your guide. PMID- 26009738 TI - RADIOLOGY REPORT: Two radiologists offer 6 tips of the trade. PMID- 26009739 TI - RADIOLOGY REPORT: 2 cases to test your skills. PMID- 26009740 TI - Clinical Inquiry: What's the best test for underlying osteomyelitis in patients with diabetic foot ulcers? AB - Magnetic resonance imaging (MRI) has a higher sensitivity and specificity (90% and 79%) than plain radiography (54% and 68%) for diagnosing diabetic foot osteomyelitis. MRI performs somewhat better than any of several common tests- probe to bone (PTB), erythrocyte sedimentation rate (ESR) >70 mm/hr, C-reactive protein (CRP) >14 mg/L, procalcitonin >0.3 ng/mL, and ulcer size >2 cm2--although PTB has the highest specificity of any test and is commonly used together with MRI. No studies have directly compared MRI with a combination of these tests, which may assist in diagnosis. PMID- 26009741 TI - Is nonoperative therapy as effective as surgery for meniscal injuries? PMID- 26009742 TI - What is the most effective topical treatment for allergic conjunctivitis? PMID- 26009743 TI - Prepping for the Boards? We can help. PMID- 26009744 TI - Liquid soap to remove that tick? PMID- 26009745 TI - Accidental scratch--or a sign of self-cutting? AB - Having a high index of suspicion is key to identifying adolescents who cut themselves. The approach described here can help you properly evaluate these patients and get them the help they need. PMID- 26009746 TI - Catching up on the latest USPSTF recommendations. AB - Screening is now encouraged for hepatitis B in those at high risk and for gestational diabetes at 24 weeks gestation. Low-dose aspirin is also advised for pregnant women at risk for preeclampsia. PMID- 26009747 TI - Another good reason to recommend low-dose aspirin. AB - Evidence shows that daily low-dose aspirin during pregnancy can safely lower the risk of preeclampsia and other adverse outcomes. PMID- 26009748 TI - Pleuritic chest pain and globus pharyngeus. PMID- 26009749 TI - Rash and fever in a 14-month-old girl. PMID- 26009750 TI - Bacillus amyloliquefaciens supplementation alleviates immunological stress in lipopolysaccharide-challenged broilers at early age. AB - This study was conducted to investigate the effect of Bacillus amyloliquefaciens ( BA: ) on the immune function of broilers challenged with lipopolysaccharide ( LPS: ). 192 one-day-old male Arbor Acre broiler chickens were randomly distributed into four treatments: 1) broilers fed a basal diet; 2) broilers fed a basal diet supplemented with BA; 3) LPS-challenged broilers fed a basal diet; and 4) LPS-challenged broilers fed a basal diet supplemented with BA. Each treatment consisted of six replicates with eight broilers per replicate. Broilers were intraperitoneally injected with either 500 MUg LPS per kg body weight or sterile saline at 16, 18 and 20 d of age. LPS decreased the average daily gain ( ADG: , P = 0.001) and average daily feed intake (P = 0.001). The decreased ADG (P = 0.009) and increased feed conversion ratio (P = 0.047) in LPS-challenged broilers were alleviated by BA. LPS increased the relative spleen weight (P = 0.001). Relative spleen (P = 0.014) and bursa (P = 0.024) weights in the LPS-challenged broilers were reduced by BA. LPS increased white blood cell ( WBC: ) numbers (P = 0.001). However, the WBC numbers (P = 0.042) and the ratio of lymphocytes to WBC (P = 0.020) in LPS-challenged broilers were decreased with BA treatment. LPS decreased plasma lysozyme activity (P = 0.001), but increased concentrations of plasma corticosterone (P = 0.012) and IL-2 (P = 0.020). In contrast, BA increased lysozyme activity in plasma (P = 0.040). LPS increased mRNA abundances of splenic toll-like receptor 4 (P = 0.046), interferon gamma (P = 0.008), IL-1beta (P = 0.045) and IL-6, (P = 0.006). IL-2 (P = 0.014) and IL-6 (P = 0.074) mRNA abundances in LPS-challenged broilers were reduced by BA, although BA had an opposite effect for IL-10 mRNA expression in those broilers (P = 0.004). In conclusion, BA supplementation could partially alleviate the compromised growth performance and immune status of broilers under immune stress induced by LPS challenge at early age. PMID- 26009751 TI - Genetic parameters of feed efficiency traits in laying period of chickens. AB - Laying records on 1,534 F2 hens, derived from a reciprocal cross between White Leghorns and Dongxiang blue-shelled chickens, were used to estimate genetic parameters for residual feed intake (RFI), feed conversion ratio (FCR), daily feed intake (FI), metabolic BW (MBW), BW gain (BWG), and daily egg mass (EM) at 37 to 40 (T1) and 57 to 60 wk age (T2), respectively. Genetic analysis was subsequently conducted with the AI-REML method using an animal model. Estimates for heritability of RFI, FCR, and FI were 0.21, 0.19, and 0.20 in T1, and 0.29, 0.13, and 0.26 in T2, respectively. In T1 and T2, RFI showed high and positive genetic correlations with FCR (0.51, 0.43) and FI (0.72, 0.84), whereas the genetic correlation between FI and FCR was very low (-0.09, 0.11). Genetically, negative correlations were found between RFI and its component traits (-0.01 to 0.47). In addition, high genetic correlations, from 0.76 to 0.94, were observed between T1 and T2 for RFI, FCR, and FI, suggesting that feed efficiency traits in the 2 stages had a similar genetic background. The results indicate that selection for low RFI could reduce FI without significant changes in EM, while selection on FCR will increase EM. The present study lays the foundation for genetic improvement of feed efficiency during the laying period of chickens. PMID- 26009753 TI - Effect of light-emitting diode vs. fluorescent lighting on laying hens in aviary hen houses: Part 1 - Operational characteristics of lights and production traits of hens. AB - Light-emitting diode (LED) lights are becoming more affordable for agricultural applications. Despite many lab-scale studies concerning impact of LED on poultry, little research has been documented under field production conditions, especially for laying hens. This 15-month field study was carried out to evaluate the effects of LED vs. fluorescent (FL) lights on laying hens (Dekalb white breed) using 4 (2 pairs) aviary hen houses each at a nominal capacity of 50,000 hens. The evaluation was done regarding operational characteristics of the lights and hen production traits. The results show that spatial distribution of the LED light was less uniform than that of the FL light. Light intensity of the LED light decreased by 27% after 3,360 h use but remained quite steady from 3,360 to 5,760 h use. Eleven out of 762 (1.44%) LED lamps (new at onset of the study) in the 2 houses failed during the 15-month experiment period. The neck area of the LED lamp was hottest, presumably the primary reason for the lamp failure as cracks were noticed in the neck region of all failed LED lamps. No differences were observed in egg weight, hen-day egg production, feed use, and mortality rate between LED and FL regimens. However, hens under the FL had higher eggs per hen housed and better feed conversion than those under the LED during 20 to 70 wk production (P < 0.05). Hens under the LED tended to have less feather uniformity and insulation than those under the FL (P < 0.05). Moreover, hens under the LED showed a larger median avoidance distance than those under the FL at 36 wk age (P < 0.05), indicating that hens under the LED were more alert; but no difference at 60 wk age. More comparative research to quantify behavioral and production responses of different breeds of hens to LED vs. FL lighting seems warranted. PMID- 26009752 TI - Review of rearing-related factors affecting the welfare of laying hens. AB - Laying hens may face a number of welfare problems including: acute and chronic pain caused by beak trimming; exaggerated fearfulness that may cause stress and suffocation; difficulties in locating resources, resulting potentially in emaciation and dehydration; frustration and boredom, caused by an environment that is barren; feather pecking; cannibalism; foot lesions; and bone fractures. In Europe, a greater proportion of laying hens are housed in non-cage systems compared to the rest of the world. The extent of the different welfare problems may therefore vary between countries as the type of housing system influences the risk of suffering. More generally, many of these welfare problems are influenced by the rearing environment of the pullets. This article therefore focuses on welfare problems in laying hens that can be traced back to rearing. Factors that have been studied in relation to their effects on bird welfare include beak trimming, housing type, furnishing, enrichment, feeding, stocking density, flock size, sound and light levels, concentration of gasses, age at transfer from rearing to production facilities, similarity between rearing and production facilities, competence of staff, and interactions between bird strain and environment. The present review aims to summarize rearing-related risk factors of poor welfare in adult laying hens housed according to European Union legislation. It aims to identify gaps in current knowledge, and suggests strategies for improving bird welfare by improving rearing conditions. Two main conclusions of this work are that attempts should be made to use appropriate genetic material and that beak trimming should be limited where possible. In addition to this, the rearing system should provide constant access to appropriate substrates, perches, and mashed feed, and should be as similar as possible to the housing system used for the adult birds. Finally, young birds (pullets) should be moved to the production facilities before 16 weeks of age. The measures outlined in this review may be useful for improving the welfare of pullets and adult laying hens. PMID- 26009754 TI - Housing systems interacting with sex and genetic line affect broiler growth and carcass traits. AB - Housing systems used in the production of poultry meat vary worldwide dependent on climate, land availability, and other resources essential for production. Reported here are comparisons between pen and cage rearing (the housing system, denoted HS: ), line crosses LC: ), two native Chinese lines (EM males were mated to Y1 and Y2 and their offspring denoted as EMY1 and EMY2), and sex in determining broiler traits. At hatch, 320 males and 320 females from each LC (giving a total of 1,280 chicks) were randomly assigned within each subgroup to 16 battery pens. There were 4 replicates for each combination of LC by sex. On d 28, half of the chicks were transferred to indoor floor pens, and the others were raised in single cages from d 29 to 91. Weekly body weights, livability, and feed conversion ratios ( FCR: ) were obtained to d 91, the age at which the broilers were slaughtered for carcass measurements. The caged males and females were heavier (P < 0.05) than their penned counterparts (2,292 vs 2,219 g). Except for females from line EMY1 (94.9%), the livability for each unit from 1 to 28 d, and 29 to 91 d was greater than 95%. Penned EMY2 broilers had the highest FCR (3.02), whereas penned EMY1 broilers had the lowest FCR (2.96) among the housing systems by LC combinations (P < 0.05). Caged chickens had thicker subcutaneous fat (7.24 mm), a higher percentages of abdominal fat (5.01%) and liver mass (3.13%) , but lower eviscerated carcass (60.63%) and breast muscle weights (pectoralis major and minor, 17.10%). Males were heavier and had higher percentages of leg muscle (boneless drum plus thigh, 24.22%) and heart muscle (1.08%) than the females (P < 0.05). However, the females had thicker subcutaneous fat (7.19 mm) and higher percentages of carcass weight (87.28%), breast muscle (18.11%), abdominal fat (6.54%), and liver mass (3.15%) than males. Penned females had the highest percentage of breast muscle (18.94%), and caged females had the highest percentage of liver mass (3.72%). Females of EMY1 had the highest percentage of breast muscle (18.40%). Generally, the housing system employed and the sex of the broilers greatly affect the carcass traits. PMID- 26009755 TI - Effect of the presence of hens on roosters sperm variables. AB - This study examines the effect of the presence of hens on sperm variables in Black Barred Andaluza roosters (which respond well to the massage technique). Between 8 and 22 weeks of age, roosters (n = 60) were housed separate from hens in straw litter pens (4 birds/m(2)). Two groups of roosters were then formed to study the effect of hen presence on sperm variables at 36 weeks of age. The first group (n = 11 roosters) was housed with hens (n = 55; sex ratio 1:5), while the second (n = 27 roosters) was again housed separate from hens. Twenty four sperm pools were obtained over 12 weeks (12 pools from each group, each pool produced by mixing semen from 11 males) for analysis. Compared to the no-female-contact group, the roosters living with hens showed significantly (P < 0.05) reduced percentages of non-progressive motile sperm and slow sperm, and significantly increased VCL and VSL values; they also showed trends (P < 0.1) towards increased progressive motility and a higher percentage of rapid sperm. The presence of hens had no significant effect on the number of spermatozoa per ejaculate or sperm concentration. Positive correlations were recorded between VSL and VCL, and between both of these and progressive motility, and the percentage of rapid sperm. In addition, both VSL and VCL correlated negatively with non-progressive motility and the percentage of slow sperm. These results indicate that rooster sperm quality, but not quantity, improves in the presence of hens. PMID- 26009756 TI - Response of layer and broiler strain chickens to parenteral administration of a live Salmonella Typhimurium vaccine. AB - Responses to the parenteral administration of a live aroA deletion Salmonella serovar Typhimurium vaccine given to three brown egg layer strains and two broiler strains were studied. Twenty-five birds of each strain were reared together in floor pens to 6 weeks of age and then moved as individual strains to new floor pens and injected with 10(8) colony forming units (CFU) per bird of the vaccine bacteria intramuscularly or subcutaneously, 10(6) CFU per bird subcutaneously, or phosphate buffered saline (PBS) subcutaneously as a vaccination control. Three birds of one layer strain were injected intramuscularly with 0.5mg/ bird S. Typhimurium lipopolysaccharide (LPS) to evaluate whether response was similar for vaccine and endotoxin. Birds were weighed, and rectal temperatures recorded at the time of injection, then observed over 24 hours. Rectal temperatures were measured and blood samples collected for serum IL-6 assay at 3 hours post injection (PI). At 12 hours PI blood samples were drawn for analyses for plasma phosphorus (P), glucose (Glu), cholesterol (Cho), aspartate transaminase (AST), total protein (Ptn) and creatinine kinase (CK). Blood was sampled 14 days PI and tested for serum antibody to S. Typhimurium. Vaccination resulted in significant seroconversion by 14 days PI in all strains compared to the controls. The three layer strains exhibited a clinical malaise, evident within 90 minutes of injection, lasting for 12 hours, with complete recovery by 24 hours PI. Only the 10(8) CFU dose given subcutaneously produced an increase in rectal temperature 3 hours PI. Vaccination had no effect on IL-6 or Ptn. All vaccine doses increased P and the higher dose by either route decreased Cho in all bird strains. The 10(8) vaccine dose increased Glu and intramuscular injection markedly elevated CK only in the layer strains. The response was not completely congruous with that to LPS alone. The results highlight the need for consideration of differences in response of bird strain when consideration is given to the parenteral administration of live Salmonella vaccines. PMID- 26009757 TI - Relationship between water-holding capacity and protein denaturation in broiler breast meat. AB - The objective of this study was to determine the relationship between water holding capacity (WHC) attributes and protein denaturation in broiler breast meat. Boneless skinless breast fillets (n = 72) were collected from a commercial processing plant at 2 h postmortem and segregated into low-WHC and high-WHC groups based on muscle pH and color (L*a*b*). At 6 and 24 h postmortem, brine uptake (%), cooking loss (%), and protein solubility (sarcoplasmic and myofibrillar) were measured and protein fractions were analyzed using SDS-PAGE. Drip loss accumulation (%) was measured after storage for 2 and 7 days postmortem. High-WHC fillets exhibited lower L*-lightness values and greater pH values at 2 and 24 h postmortem than low-WHC fillets. High-WHC fillets had greater brine uptake and less cooking loss at both 6 and 24 h postmortem compared to low-WHC fillets. Aging from 6 to 24 h postmortem increased brine uptake in high-WHC fillets, but did not affect cooking loss in either low-WHC or high-WHC fillets. Drip loss accumulation was greater in low-WHC fillets at both 2 and 7 days postmortem. Myofibrillar protein solubility decreased with postmortem time but was not different between low-WHC and high-WHC fillets. Sarcoplasmic protein solubility increased with postmortem time and was greater in high-WHC fillets. SDS-PAGE analysis indicated that low-WHC fillets exhibited more glycogen phosphorylase denaturation than high-WHC fillets as evidenced by a more extensive shift of the protein from the sarcoplasmic to the myofibrillar protein fraction. Correlation analysis revealed that overall protein solubility measurements were not related to WHC attributes but that the degree of glycogen phosphorylase denaturation was significantly correlated (|r| = 0.52 to 0.80) to measures of WHC. Data indicated that WHC differences in broiler breast fillets were not due to differences in myofibrillar protein denaturation and suggested that the denaturation of sarcoplasmic proteins onto myofibrils may influence WHC in breast meat. PMID- 26009758 TI - Efficacy of fumigation with Trans-cinnamaldehyde and eugenol in reducing Salmonella enterica serovar Enteritidis on embryonated egg shells. AB - This study investigated the efficacy of two GRAS (generally regarded as safe) status, plant-derived antimicrobials (PDAs), namely trans-cinnamaldehyde (TC) and eugenol (EUG) applied as a fumigation treatment in reducing SE on embryonated egg shells. Egg shells of day-old embryonated eggs were spot inoculated with a 4 strain mixture of SE (~6.5 log CFU/egg) and subjected to fumigation with the aforementioned PDAs (0 or 1% concentration) for 20 minutes in a hatching incubator. SE on the shell and embryo was enumerated on days 1, 3, 6, 9, 13, 16 and 18. On day 13, the eggs were re-inoculated, followed by fumigation treatment for 20 minutes. Since the two PDAs were dissolved in ethanol (final concentration 0.04%), eggs fumigated with ethanol were included as a control.Approximately 6 log CFU/egg of SE were recovered from the shell of untreated, inoculated eggs on days 1 and 13. The fumigation of embryonated egg shells with the two PDAs was more effective in reducing SE on the shell and embryo compared to controls (P < 0.05). On day 18, the eggs fumigated with ethanol were SE positive on the shell, whereas no pathogen was detected on eggs subjected to fumigation with TC and EUG. Similarly, although the embryos of eggs subjected to fumigation with ethanol yielded 1 log CFU/egg of SE on day 18, the embryos of TC and EUG treated eggs were devoid of the pathogen. This study demonstrated that TC and EUG dissolved in 0.04% ethanol could potentially be used as a fumigation treatment for reducing SE on embryonated egg shell, however, quality traits of eggs, including the hatchability need to be ascertained. PMID- 26009759 TI - Efficacy of various protein-based coating on enhancing the shelf life of fresh eggs during storage. AB - The effectiveness of various coatings (whey protein isolate [WPI], whey protein concentrate [WPC], zein, and shellac) on functional properties, interior quality, and eggshell breaking strength of fresh eggs were evaluated during storage at 24 degrees : C for 6 weeks. Coatings and storage time had significant effects on Haugh unit, yolk index, albumen pH, dry matter (DMA), relative whipping capacity (RWC), and albumen viscosity. Uncoated eggs had higher albumen pH (9.56) and weight loss, and lower albumen viscosity (5.73), Haugh unit (HU), and yolk index (YI) during storage. Among the coated eggs, the shellac and zein coated eggs had the highest value of albumen viscosity (27.26 to 26.90), HU (74.10 to 73.61), and YI (44.84 to 44.63) after storage. Shellac (1.44%) was more effective in preventing weight loss than WPC (4.59%), WPI (4.60%), and zein (2.13%) coatings. Uncoated eggs had the higest value (6.71%) of weight lost. All coatings increased shell strength (5.18 to 5.73 for top and 3.58 to 4.71 for bottom) significantly (P < 0.05) compared to the uncoated eggs (4.70 for top and 3.15 for bottom). The functional properties such as albumen DMA (14.50 to 16.66 and 18.97 for uncoated) and albumen RWC (841 to 891 and 475 for uncoated) of fresh eggs can be preserved during storage when they are coated. The shellac and zein coatings were more effective for maintaining the internal quality of fresh eggs during storage. Fourier transform near infrared (FT-NIR) in the 800 to 2500 nm reflection spectra were used to quantify the contents of the fresh eggs at the end of storage. Eggs coated with shellac or zein displayed a higher absorbance at 970 and 1,197 nm respectively (OH vibration of water) compared with those coated with WPI or WPC and the uncoated group at the end of storage. The coatings improved functional properties and also shell strength and could be a viable alternative technology for maintaining the internal quality of eggs during long-term storage. This study highlights the promising use of various coatings to both enhance the functional properties and to reduce the breakage of eggs. PMID- 26009760 TI - Release of chemical transmitters from cell bodies and dendrites of nerve cells. AB - Papers in this issue concern extrasynaptic transmission, namely release of signalling molecules by exocytosis or diffusion from neuronal cell bodies, dendrites, axons and glia. Problems discussed concern the molecules, their secretion and importance for normal function and disease. Molecules secreted extrasynaptically include transmitters, peptides, hormones and nitric oxide. For extrasynaptic secretion, trains of action potentials are required, and the time course of release is slower than at synapses. Questions arise concerning the mechanism of extrasynaptic secretion: how does it differ from the release observed at synaptic terminals and gland cells? What kinds of vesicles take part? Is release accomplished through calcium entry, SNAP and SNARE proteins? A clear difference is in the role of molecules released synaptically and extrasynaptically. After extrasynaptic release, molecules reach distant as well as nearby cells, and thereby produce long-lasting changes over large volumes of brain. Such changes can affect circuits for motor performance and mood states. An example with clinical relevance is dyskinesia of patients treated with l-DOPA for Parkinson's disease. Extrasynaptically released transmitters also evoke responses in glial cells, which in turn release molecules that cause local vasodilatation and enhanced circulation in regions of the brain that are active. PMID- 26009761 TI - Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin. AB - The mammalian hypothalamic magnocellular neurons of the supraoptic and paraventricular nuclei are among the best understood of all peptidergic neurons. Through their anatomical features, vasopressin- and oxytocin-containing neurons have revealed many important aspects of dendritic functions. Here, we review our understanding of the mechanisms of somato-dendritic peptide release, and the effects of autocrine, paracrine and hormone-like signalling on neuronal networks and behaviour. PMID- 26009762 TI - The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural-glial networks. AB - Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma-dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non coding regulatory microRNAs. At the soma-dendritic membrane, sets of dynamic postsynaptic heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the heteroreceptor complexes in the postsynaptic membrane. PMID- 26009763 TI - Levodopa-induced plasticity: a double-edged sword in Parkinson's disease? AB - The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients. PMID- 26009765 TI - Extrasynaptic release of GABA and dopamine by retinal dopaminergic neurons. AB - In the mouse retina, dopaminergic amacrine (DA) cells synthesize both dopamine and GABA. Both transmitters are released extrasynaptically and act on neighbouring and distant retinal neurons by volume transmission. In simultaneous recordings of dopamine and GABA release from isolated perikarya of DA cells, a proportion of the events of dopamine and GABA exocytosis were simultaneous, suggesting co-release. In addition, DA cells establish GABAergic synapses onto AII amacrine cells, the neurons that transfer rod bipolar signals to cone bipolars. GABAA but not dopamine receptors are clustered in the postsynaptic membrane. Therefore, dopamine, irrespective of its site of release-synaptic or extrasynaptic-exclusively acts by volume transmission. Dopamine is released upon illumination and sets the gain of retinal neurons for vision in bright light. The GABA released at DA cells' synapses probably prevents signals from the saturated rods from entering the cone pathway when the dark-adapted retina is exposed to bright illumination. The GABA released extrasynaptically by DA and other amacrine cells may set a 'GABAergic tone' in the inner plexiform layer and thus counteract the effects of a spillover of glutamate released at the bipolar cell synapses of adjacent OFF and ON strata, thus preserving segregation of signals between ON and OFF pathways. PMID- 26009764 TI - Somatodendritic dopamine release: recent mechanistic insights. AB - Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K(+) channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca(2+) dependence of release and the potential role of exocytotic proteins. PMID- 26009766 TI - Effect of amyloids on the vesicular machinery: implications for somatic neurotransmission. AB - Certain neurodegenerative diseases are thought to be initiated by the aggregation of amyloidogenic proteins. However, the mechanism underlying toxicity remains obscure. Most of the suggested mechanisms are generic in nature and do not directly explain the neuron-type specific lesions observed in many of these diseases. Some recent reports suggest that the toxic aggregates impair the synaptic vesicular machinery. This may lead to an understanding of the neuron type specificity observed in these diseases. A disruption of the vesicular machinery can also be deleterious for extra-synaptic, especially somatic, neurotransmission (common in serotonergic and dopaminergic systems which are specifically affected in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively), though this relationship has remained unexplored. In this review, we discuss amyloid-induced damage to the neurotransmitter vesicular machinery, with an eye on the possible implications for somatic exocytosis. We argue that the larger size of the system, and the availability of multi-photon microscopy techniques for directly visualizing monoamines, make the somatic exocytosis machinery a more tractable model for understanding the effect of amyloids on all types of vesicular neurotransmission. Indeed, exploring this neglected connection may not just be important, it may be a more fruitful route for understanding AD and PD. PMID- 26009767 TI - Muscarinic inhibition of nicotinic transmission in rat sympathetic neurons and adrenal chromaffin cells. AB - Little is known about the interactions between nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs). Here we report that methacholine (MCh), a selective agonist of mAChRs, inhibited up to 80% of nicotine-induced nAChR currents in sympathetic superior cervical ganglion neurons and adrenal chromaffin cells. The muscarine-induced inhibition (MiI) substantially reduced ACh-induced membrane currents through nAChRs and quantal neurotransmitter release. The MiI was time- and temperature-dependent. The slow recovery of nAChR current after washout of MCh, as well as the high value of Q10 (3.2), suggested, instead of a direct open-channel blockade, an intracellular metabotropic process. The effects of GTP-gamma-S, GDP-beta-S and pertussis toxin suggested that MiI was mediated by G-protein signalling. Inhibitors of protein kinase C (bisindolymaleimide-Bis), protein kinase A (H89) and PIP2 depletion attenuated the MiI, indicating that a second messenger pathway is involved in this process. Taken together, these data suggest that mAChRs negatively modulated nAChRs via a G-protein-mediated second messenger pathway. The time dependence suggests that MiI may provide a novel mechanism for post-synaptic adaptation in all cells/neurons and synapses expressing both types of AChRs. PMID- 26009768 TI - The structure and function of 'active zone material' at synapses. AB - The docking of synaptic vesicles on the presynaptic membrane and their priming for fusion with it to mediate synaptic transmission of nerve impulses typically occur at structurally specialized regions on the membrane called active zones. Stable components of active zones include aggregates of macromolecules, 'active zone material' (AZM), attached to the presynaptic membrane, and aggregates of Ca(2+)-channels in the membrane, through which Ca(2+) enters the cytosol to trigger impulse-evoked vesicle fusion with the presynaptic membrane by interacting with Ca(2+)-sensors on the vesicles. This laboratory has used electron tomography to study, at macromolecular spatial resolution, the structure and function of AZM at the simply arranged active zones of axon terminals at frog neuromuscular junctions. The results support the conclusion that AZM directs the docking and priming of synaptic vesicles and essential positioning of Ca(2+) channels relative to the vesicles' Ca(2+)-sensors. Here we review the findings and comment on their applicability to understanding mechanisms of docking, priming and Ca(2+)-triggering at other synapses, where the arrangement of active zone components differs. PMID- 26009771 TI - Exocytosis from chromaffin cells: hydrostatic pressure slows vesicle fusion. AB - Pressure affects reaction kinetics because chemical transitions involve changes in volume, and therefore pressure is a standard thermodynamic parameter to measure these volume changes. Many organisms live in environments at external pressures other than one atmosphere (0.1 MPa). Marine animals have adapted to live at depths of over 7000 m (at pressures over 70 MPa), and microorganisms living in trenches at over 110 MPa have been retrieved. Here, kinetic changes in secretion from chromaffin cells, measured as capacitance changes using the patch clamp technique at pressures of up to 20 MPa are presented. It is known that these high pressures drastically slow down physiological functions. High hydrostatic pressure also affects the kinetics of ion channel gating and the amount of current carried by them, and it drastically slows down synaptic transmission. The results presented here indicate a similar change in volume (activation volume) of 390 +/- 57 A(3) for large dense-core vesicles undergoing fusion in chromaffin cells and for degranulation of mast cells. It is significantly larger than activation volumes of voltage-gated ion channels in chromaffin cells. This information will be useful in finding possible protein conformational changes during the reactions involved in vesicle fusion and in testing possible molecular dynamic models of secretory processes. PMID- 26009770 TI - ATP release through pannexon channels. AB - Extracellular adenosine triphosphate (ATP) serves as a signal for diverse physiological functions, including spread of calcium waves between astrocytes, control of vascular oxygen supply and control of ciliary beat in the airways. ATP can be released from cells by various mechanisms. This review focuses on channel mediated ATP release and its main enabler, Pannexin1 (Panx1). Six subunits of Panx1 form a plasma membrane channel termed 'pannexon'. Depending on the mode of stimulation, the pannexon has large conductance (500 pS) and unselective permeability to molecules less than 1.5 kD or is a small (50 pS), chloride selective channel. Most physiological and pathological stimuli induce the large channel conformation, whereas the small conformation so far has only been observed with exclusive voltage activation of the channel. The interaction between pannexons and ATP is intimate. The pannexon is not only the conduit for ATP, permitting ATP efflux from cells down its concentration gradient, but the pannexon is also modulated by ATP. The channel can be activated by ATP through both ionotropic P2X as well as metabotropic P2Y purinergic receptors. In the absence of a control mechanism, this positive feedback loop would lead to cell death owing to the linkage of purinergic receptors with apoptotic processes. A control mechanism preventing excessive activation of the purinergic receptors is provided by ATP binding (with low affinity) to the Panx1 protein and gating the channel shut. PMID- 26009769 TI - Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced by L-DOPA? AB - Inflammatory mechanisms are proposed to play a role in L-DOPA-induced dyskinesia. Cyclooxygenase-2 (COX2) contributes to inflammation pathways in the periphery and is constitutively expressed in the central nervous system. Considering that inhibition of nitric oxide (NO) formation attenuates L-DOPA-induced dyskinesia, this study aimed at investigating if a NO synthase (NOS) inhibitor would change COX2 brain expression in animals with L-DOPA-induced dyskinesia. To this aim, male Wistar rats received unilateral 6-hydroxydopamine microinjection into the medial forebrain bundle were treated daily with L-DOPA (21 days) combined with 7 nitroindazole or vehicle. All hemi-Parkinsonian rats receiving l-DOPA showed dyskinesia. They also presented increased neuronal COX2 immunoreactivity in the dopamine-depleted dorsal striatum that was directly correlated with dyskinesia severity. Striatal COX2 co-localized with choline-acetyltransferase, calbindin and DARPP-32 (dopamine-cAMP-regulated phosphoprotein-32), neuronal markers of GABAergic neurons. NOS inhibition prevented L-DOPA-induced dyskinesia and COX2 increased expression in the dorsal striatum. These results suggest that increased COX2 expression after L-DOPA long-term treatment in Parkinsonian-like rats could contribute to the development of dyskinesia. PMID- 26009772 TI - Contribution of extrasynaptic N-methyl-D-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials. AB - Thin basal dendrites can strongly influence neuronal output via generation of dendritic spikes. It was recently postulated that glial processes actively support dendritic spikes by either ceasing glutamate uptake or by actively releasing glutamate and adenosine triphosphate (ATP). We used calcium imaging to study the role of NR2C/D-containing N-methyl-d-aspartate (NMDA) receptors and adenosine A1 receptors in the generation of dendritic NMDA spikes and plateau potentials in basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. We found that NR2C/D glutamate receptor subunits contribute to the amplitude of synaptically evoked NMDA spikes. Dendritic calcium signals associated with glutamate-evoked dendritic plateau potentials were significantly shortened upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D receptors prolong the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, adenosine A1 receptors act to abbreviate dendritic and somatic signals via the activation of dendritic K(+) current. This current is characterized as a slow-activating outward-rectifying voltage- and adenosine-gated current, insensitive to 4-aminopyridine but sensitive to TEA. Our data support the hypothesis that the release of glutamate and ATP from neurons or glia contribute to initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials. PMID- 26009773 TI - Regulation of neuronal excitability by release of proteins from glial cells. AB - Effects of glial cells on electrical isolation and shaping of synaptic transmission between neurons have been extensively studied. Here we present evidence that the release of proteins from astrocytes as well as microglia may regulate voltage-activated Na(+) currents in neurons, thereby increasing excitability and speed of transmission in neurons kept at distance from each other by specialized glial cells. As a first example, we show that basic fibroblast growth factor and neurotrophin-3, which are released from astrocytes by exposure to thyroid hormone, influence each other to enhance Na(+) current density in cultured hippocampal neurons. As a second example, we show that the presence of microglia in hippocampal cultures can upregulate Na(+) current density. The effect can be boosted by lipopolysaccharides, bacterial membrane derived stimulators of microglial activation. Comparable effects are induced by the exposure of neuron-enriched hippocampal cultures to tumour necrosis factor alpha, which is released from stimulated microglia. Taken together, our findings suggest that release of proteins from various types of glial cells can alter neuronal excitability over a time course of several days. This explains changes in neuronal excitability occurring in states of thyroid hormone imbalance and possibly also in seizures triggered by infectious diseases. PMID- 26009774 TI - Glial cell regulation of neuronal activity and blood flow in the retina by release of gliotransmitters. AB - Astrocytes in the brain release transmitters that actively modulate neuronal excitability and synaptic efficacy. Astrocytes also release vasoactive agents that contribute to neurovascular coupling. As reviewed in this article, Muller cells, the principal retinal glial cells, modulate neuronal activity and blood flow in the retina. Stimulated Muller cells release ATP which, following its conversion to adenosine by ectoenzymes, hyperpolarizes retinal ganglion cells by activation of A1 adenosine receptors. This results in the opening of G protein coupled inwardly rectifying potassium (GIRK) channels and small conductance Ca(2+)-activated K(+) (SK) channels. Tonic release of ATP also contributes to the generation of tone in the retinal vasculature by activation of P2X receptors on vascular smooth muscle cells. Vascular tone is lost when glial cells are poisoned with the gliotoxin fluorocitrate. The glial release of vasoactive metabolites of arachidonic acid, including prostaglandin E2 (PGE2) and epoxyeicosatrienoic acids (EETs), contributes to neurovascular coupling in the retina. Neurovascular coupling is reduced when neuronal stimulation of glial cells is interrupted and when the synthesis of arachidonic acid metabolites is blocked. Neurovascular coupling is compromised in diabetic retinopathy owing to the loss of glial mediated vasodilation. This loss can be reversed by inhibiting inducible nitric oxide synthase. It is likely that future research will reveal additional important functions of the release of transmitters from glial cells. PMID- 26009776 TI - John Montgomery Gorman MDS, FDS, FFD(12th October 1929-18th November 2014). PMID- 26009775 TI - Serotonin release from the neuronal cell body and its long-lasting effects on the nervous system. AB - Serotonin, a modulator of multiple functions in the nervous system, is released predominantly extrasynaptically from neuronal cell bodies, axons and dendrites. This paper describes how serotonin is released from cell bodies of Retzius neurons in the central nervous system (CNS) of the leech, and how it affects neighbouring glia and neurons. The large Retzius neurons contain serotonin packed in electrodense vesicles. Electrical stimulation with 10 impulses at 1 Hz fails to evoke exocytosis from the cell body, but the same number of impulses at 20 Hz promotes exocytosis via a multistep process. Calcium entry into the neuron triggers calcium-induced calcium release, which activates the transport of vesicle clusters to the plasma membrane. Exocytosis occurs there for several minutes. Serotonin that has been released activates autoreceptors that induce an inositol trisphosphate-dependent calcium increase, which produces further exocytosis. This positive feedback loop subsides when the last vesicles in the cluster fuse and calcium returns to basal levels. Serotonin released from the cell body is taken up by glia and released elsewhere in the CNS. Synchronous bursts of neuronal electrical activity appear minutes later and continue for hours. In this way, a brief train of impulses is translated into a long-term modulation in the nervous system. PMID- 26009777 TI - Incidence and risk of hand-foot skin reaction with cabozantinib, a novel multikinase inhibitor: a meta-analysis. AB - BACKGROUND: Cabozantinib is approved in the treatment of progressive, metastatic medullary thyroid cancer (MTC). It is a small molecule inhibitor, which targets multiple receptors, including vascular endothelial growth factor receptor, tyrosine kinase with Ig and epidermal growth factor homology domains-2 and the proto-oncogenes MET (mesenchymal-epithelial transition factor) and RET (rearranged during transfection). The drug is currently in phase I/II/III clinical trials for a number of other solid tumours and haematological malignancies. The adverse event (AE) profile is similar to that of other newer angiogenesis inhibitors. Hand-foot skin reaction (HFSR) is an important dose limiting dermatological adverse event of this class of drugs. AIM: To ascertain the incidence and risk of HFSR in patients with cancer during treatment with cabozantinib. METHODS: Electronic databases (PubMed, Web of Science) and the American Society of Clinical Oncology Meeting Library were queried from inception to July 2014. Only phase II/III studies investigating cabozantinib for the treatment of cancer were shortlisted. The incidence, relative risk (RR) and 95% CI were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. RESULTS: We included 831 patients treated with cabozantinib for various solid malignancies in the analysis. The overall incidence was 35.3% (95% CI 27.9-43.6%) for all-grade and 9.5% (95% CI 7.6-11.7%) for high-grade HFSR. The RR of all-grade and high-grade HFSR with cabozantinib, compared with controls, was increased for both all-grade (27.3; 95% CI 6.9-108.3; P < 0.001) and high-grade (28.1; 95% CI 1.7-457; P < 0.02) HFSR, respectively. CONCLUSIONS: The incidence and risk of developing HFSR with cabozantinib are high. Timely recognition of this dose-limiting AE is critical to direct supportive care efforts including patient counselling, and to institute preventative and/or treatment interventions. PMID- 26009778 TI - The meaning of social support for persons with serious mental illness. AB - OBJECTIVE: This study sought to better understand the population-specific types of social support relevant to adults living with serious mental illness (SMI). Our study was exploratory and used a qualitative approach that centered on uncovering the types of social support meaningful and relevant to persons with SMI. METHOD: The sample comprised of 52 adults receiving county mental health services in the San Francisco Bay Area. Data was gathered from 6 focus groups and analyzed using NVivo10 and Consensual Qualitative Research (CQR; Hill et al., 2005; Hill et al., 1997). RESULTS: Six qualitative domains were identified: (a) supportive conditions, (b) day-to-day living, (c) illness management, (d) resources and information, (e) guidance and advice, and (f) community participation support. DISCUSSION: While the 6 support domains share some broad based conceptual underpinnings with traditional models of emotional and instrumental support, the domains emerging from our study represent supports uniquely tied to the stressors associated with living with SMI, and therefore hold conceptual distinction from traditional types of support. CONCLUSIONS/IMPLICATIONS: Findings from this study offer a conceptual framework for understanding social support for persons living with SMI and lay the groundwork for the development of a SMI-specific measure of social support. In addition, our research permits future researchers to investigate the conditions under which social support buffers the impact of SMI stressors, assisting service providers in more effective identification of individual support needs for clinical intervention. PMID- 26009779 TI - Resilience in family caregivers of persons with acquired brain injury. AB - PURPOSE/OBJECTIVE: The authors' purpose was to develop the Questionnaire of Resilience in Caregivers of Acquired Brain Injury (QRC-ABI) and explore its psychometric properties The QRC-ABI was developed to measure the process of resilience, including resilient factors that, according to the literature, are the most relevant for caregivers. RESEARCH METHOD/DESIGN: This is a cross sectional study of Spanish primary caregivers of individuals with ABI. It included 237 caregivers (77.6% women and 21.1% men) who completed the QRC-ABI, the Posttraumatic Growth Inventory (Weiss & Berger, 2006), the World Health Organization Quality of Life-BREF (Skevington, Lotfy, O'Connell, & the WHOQOL Group, 2004) assessment, and the Positive Aspects of Caregiving (Tarlow et al., 2004) assessment. RESULTS: An item pool of 36 items was developed, from which 17 were finally selected based on a consensus among researchers and adequate symmetry indexes and kurtoses. Confirmatory factor analysis of the QRC-ABI confirmed a hierarchical solution in which 4 resilience dimensions were explained by a broader general resilience factor. The internal consistency of each scale was >.80. Convergent validity was supported through positive correlations of the QRC-ABI with quality of life, positive aspects of caregiving, and posttraumatic growth, and a negative correlation with perceived burden. CONCLUSION/IMPLICATIONS: The new QRC-ABI showed good reliability and validity. Our results are consistent with previous studies that have argued that resilient qualities are important for a healthy and positive adaptation to the challenging adversities faced by caregivers of individuals with ABI. Future interventions based on resilience should promote these factors in caregivers. PMID- 26009780 TI - Effectiveness of Internet-based cognitive-behavior therapy for social anxiety disorder in clinical psychiatry. AB - OBJECTIVE: Internet-based cognitive-behavioral therapy (ICBT) has received increased attention as an innovative approach to improve access to evidence-based psychological treatments. Although the efficacy of ICBT for social anxiety disorder has been established in several studies, there is limited knowledge of its effectiveness and application in clinical psychiatric care. The purpose of this study was to evaluate the effectiveness of ICBT in the treatment of social anxiety disorder and to determine the significance of patient adherence and the clinic's years of experience in delivering ICBT. METHOD: A longitudinal cohort study was conducted using latent growth curve modeling of patients (N = 654) treated with ICBT at an outpatient psychiatric clinic between 2009 and 2013. The primary outcome measure was the Liebowitz Social Anxiety Scale-Self-Rated. RESULTS: Significant reductions in symptoms of social anxiety were observed after treatment (effect size d = 0.86, 99% CI [0.74, 0.98]). Improvements were sustained at 6-month follow-up (d = 1.15, 99% CI [0.99, 1.32]). Patient adherence had a positive effect on the rate of improvement. A positive association between the clinic's years of experience with ICBT and treatment outcome was also observed. CONCLUSIONS: This study suggests that ICBT for social anxiety disorder is effective when delivered within the context of a unit specialized in Internet based psychiatric care and may be considered as a treatment alternative for implementation within the mental health care system. PMID- 26009781 TI - Toward a dynamic model of psychological assessment: Implications for personalized care. AB - OBJECTIVE: The present article proposes a general framework and a set of specific methodological steps for conducting person-specific dynamic assessments, which yield information about syndrome structures and states that can be used to provide actionable information for the formulation of personalized interventions. It is proposed that researchers should (a) determine the relevant constituent inputs for a diagnostic system; (b) measure these inputs with as much detail as possible; (c) assess the correlational structure of system inputs via factor analytic methods within individuals; and (d) subject the individual-level, latent dimension time series to dynamic analyses such as the dynamic factor model (Molenaar, 1985) to discern the time-dependent, dynamic relationships within and between system components. METHOD: An exemplar is provided wherein 10 individuals with clinically diagnosed generalized anxiety disorder completed surveys related to generalized anxiety disorder symptomatology for at least 60 consecutive days. These data were then subjected to person-specific exploratory and confirmatory factor analyses for the identification of latent symptom dimensions. Finally, dynamic factor models were used to model the dynamic interrelationships within and between symptom domains on a person-by-person basis. RESULTS: Person-specific factor analyses returned models with 3 (n = 8) or 4 (n = 2) latent factors, all with excellent fit. Dynamic factor modeling successfully revealed the contemporaneous correlations and time-lagged predictive relationships between factors, providing prescriptive information for the formulation of targeted interventions. CONCLUSIONS: The proposed approach has the potential to inform the construction and implementation of personalized treatments by delineating the idiosyncratic structure of psychopathology on a person-by-person basis. PMID- 26009782 TI - Motivational enhancement mitigates the effects of problematic alcohol use on treatment compliance among partner violent offenders: Results of a randomized clinical trial. AB - OBJECTIVE: Treatment programs for intimate partner violence (IPV) evidence high rates of noncompliance, which is associated with repeat offending. Problematic alcohol use is reported in approximately half of all partner violent offenders and represents a strong risk factor for treatment noncompliance. However, previous research with IPV offenders mandated to treatment has not evaluated methods to mitigate the effects of alcohol misuse on treatment compliance. METHOD: In the current study, 60 male IPV offenders (25 binge drinkers) were randomly assigned to a single-session brief motivational interview (BMI) or control intervention prior to treatment commencement. Treatment compliance data were collected 6 months later. RESULTS: Findings indicated that binge drinkers had lower treatment compliance than non-binge-drinking participants, and that binge-drinking BMI participants attended more treatment sessions and evidenced lower dropout rates than binge-drinking control participants. CONCLUSIONS: Findings highlight the importance of individualized treatment planning for IPV offenders in order to maximize available resources while accommodating the needs of males at greatest risk for noncompliance and continued violence. PMID- 26009784 TI - A national evaluation of parenting programs in Sweden: The short-term effects using an RCT effectiveness design. AB - OBJECTIVE: We evaluated the effectiveness of 4 parent-training programs for children with externalizing problems. We tested the effectiveness of 3 behavioral programs (Comet, Cope, and Incredible Years) and 1 nonbehavioral program (Connect) in reducing child behavior problems and attention-deficit/hyperactivity disorder (ADHD) symptoms, in improving positive parenting and parenting competence, and in decreasing negative parenting and parents' stress and depressive symptoms. METHOD: This national study was designed as a randomized controlled effectiveness trial (RCT). The treatments were carried out in 30 clinical and community-based practices. Parents of 908 children (ages 3-12 years) were randomly assigned to 1 of 2 parent training programs available at each practice, or to a wait-list condition, where parents had sought help from regular services. Before and after treatment, parents rated child behavior problems and parenting strategies. RESULTS: At posttreatment, children whose parents had received interventions showed a strong decrease in child conduct problems and a moderate to strong decrease in ADHD symptoms. About half of parents whose children scored over the 95th percentile on the behavior measures (Eyberg Child Behavior Inventory, Swanson, Nolan, and Pelham Rating Scale), a clinically meaningful cutoff, reported that their children were no longer above the cutoff after the intervention. Parents showed considerably less negative behaviors toward their children at posttest compared with pretest; they increased in parental competence, and decreased in both stress and depressive symptoms. Overall, the behavioral programs were more effective than the nonbehavioral program. CONCLUSIONS: The results support the general efficacy of parent training in a short-term perspective. PMID- 26009783 TI - Augmenting serotonin reuptake inhibitors in obsessive-compulsive disorder: What moderates improvement? AB - OBJECTIVE: Patients with obsessive-compulsive disorder (OCD) often only partially respond to serotonin reuptake inhibitors (SRIs). In such cases, American Psychiatric Association practice guidelines suggest augmenting SRIs with cognitive-behavioral therapy consisting of exposure and ritual prevention (EX/RP) or antipsychotic medication (i.e., risperidone). We examined moderators and predictors of these 2 augmentation strategies. METHOD: Data came from a randomized controlled trial that compared adding EX/RP or risperidone to SRIs in adults with OCD. Patients entered the study on a stable SRI dosage and were randomized to EX/RP (N = 40), risperidone (N = 40), or placebo (N = 20). Data were analyzed using multilevel modeling. RESULTS: Pretreatment OCD severity, age, and depression were significant moderators. Although OCD severity was unrelated to EX/RP response, individuals with more severe OCD had poorer outcomes and slower improvement with risperidone. Increasing age predicted better response to risperidone, but not EX/RP. Increased depression predicted poorer response to placebo, but not EX/RP or risperidone. Poorer functioning predicted worse outcome across all 3 conditions. Together, these moderators and predictor accounted for 33% of the variance in outcomes, above and beyond the 30.8% accounted for by treatment condition. CONCLUSIONS: SRI augmentation with EX/RP was more effective than risperidone across all of the demographic and clinical variables tested. EX/RP's superiority over risperidone increased with baseline OCD severity and with younger age. These data indicate that EX/RP should be the recommended SRI augmentation strategy, even for severe OCD. What determines the degree of EX/RP response in individual patients deserves further study. PMID- 26009785 TI - Efficacy of personalized normative feedback as a brief intervention for college student gambling: a randomized controlled trial. AB - OBJECTIVE: Social influences on gambling among adolescents and adults have been well documented and may be particularly evident among college students, who have higher rates of problem and pathological gambling relative to the general population. Personalized normative feedback (PNF) is a brief intervention designed to correct misperceptions regarding the prevalence of problematic behavior by showing individuals engaging in such behaviors that their own behavior is atypical with respect to actual norms. The current randomized controlled trial evaluated a computer-delivered PNF intervention for problem gambling college students. METHOD: Following a baseline assessment, 252 college student gamblers scoring 2+ on the South Oaks Gambling Screen (SOGS) were randomly assigned to receive PNF or attention-control feedback. Follow-up assessments were completed 3 and 6 months postintervention. RESULTS: Results indicated significant intervention effects in reducing perceived norms for quantities lost and won, and in reducing actual quantity lost and gambling problems at the 3-month follow-up. All intervention effects except reduced gambling problems remained at the 6-month follow-up. Mediation results indicated that changes in perceived norms at 3 months mediated the intervention effects. Further, the intervention effects were moderated by self-identification with other student gamblers, suggesting that PNF worked better at reducing gambling for those who more strongly identified with other student gamblers. CONCLUSIONS: Results support the use of PNF as a stand-alone brief intervention for at-risk gambling students. Extending this approach more broadly may provide an accessible, empirically supported gambling prevention option for universities and related institutions. PMID- 26009787 TI - Mechanisms of symptom reduction in a combined treatment for comorbid posttraumatic stress disorder and alcohol dependence. AB - OBJECTIVE: To examine the mechanisms of prolonged exposure (PE) and naltrexone (NAL) that underlie symptom reduction among individuals with comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). We hypothesized that (a) reduction in negative cognitions mediates PTSD improvement during PE; (b) reduction in alcohol craving mediates reduction in drinking frequency during NAL treatment; and (c) PTSD improvement mediates reduction in craving and alcohol use during PE. METHOD: Participants were 159 individuals meeting the DSM-IV diagnosis of PTSD and AD randomly assigned to 1 of 4 conditions: PE + NAL, PE + placebo (PBO), supportive counseling (SC) + NAL; and SC + PBO. All participants received supportive counseling. RESULTS: Lagged multilevel mediational analyses indicated that (a) a reciprocal relationship between cognitive change and PTSD improvement was observed in PE + NAL, PE + PBO, and SC + NAL, but not in SC + PBO; (b) reduction in craving significantly mediated subsequent decrease in alcohol use in PE + NAL and SC + PBO, but not in PE + PBO and SC + NAL; and (c) PTSD improvement significantly mediated subsequent reduction of craving in PE + PBO, and mediated decrease in alcohol use in PE + NAL. CONCLUSIONS: The efficacy of combining PE and NAL for reducing alcohol use among those with comorbid PTSD/AD seems to be through reduction in both PTSD symptoms and craving. These findings shed light on the mechanism of PE and highlight the central role of PTSD in the maintenance of alcohol craving and use in patients with comorbid PTSD/AD. PMID- 26009786 TI - Efficacy and moderators of a family group cognitive-behavioral preventive intervention for children of parents with depression. AB - OBJECTIVE: Building on an earlier study (Compas, Forehand, Thigpen, et al., 2011), tests of main effects and potential moderators of a family group cognitive behavioral (FGCB) preventive intervention for children of parents with a history of depression are reported. METHOD: Assessed a sample of 180 families (242 children ages 9-15 years) in a randomized controlled trial assessed at 2, 6, 12, 18 and 24 months after baseline. RESULTS: Significant effects favoring the FGCB intervention over a written information comparison condition were found on measures of children's symptoms of depression, mixed anxiety/depression, internalizing problems, and externalizing problems, with multiple effects maintained at 18 and 24 months, and on incidence of child episodes of major depressive disorder over the 24 months. Effects were stronger for child self reports than for parent reports. Minimal evidence was found for child age, child gender, parental education, parental depressive symptoms, or presence of a current parental depressive episode at baseline as moderators of the FGCB intervention. CONCLUSIONS: The findings provide support for sustained and robust effects of this preventive intervention. PMID- 26009789 TI - Identification of the Binding Position of Amilorides in the Quinone Binding Pocket of Mitochondrial Complex I. AB - We previously demonstrated that amilorides bind to the quinone binding pocket of bovine mitochondrial complex I, not to the hitherto suspected Na+/H+ antiporter like subunits (ND2, ND4, and ND5) [Murai, M., et al. (2015) Biochemistry 54, 2739 2746]. To characterize the binding position of amilorides within the pocket in more detail, we conducted specific chemical labeling [alkynylation (-C=CH)] of complex I via ligand-directed tosyl (LDT) chemistry using a newly synthesized amide-type amiloride AAT as a LDT chemistry reagent. The inhibitory potency of AAT, in terms of its IC50 value, was markedly higher (~1000-fold) than that of prototypical guanidine-type amilorides such as commercially available EIPA and benzamil. Detailed proteomic analyses in combination with click chemistry revealed that the chemical labeling occurred at Asp160 of the 49 kDa subunit (49 kDa Asp160). This labeling was significantly suppressed in the presence of an excess amount of other amilorides or ordinary inhibitors such as quinazoline and acetogenin. Taking into consideration the fact that 49 kDa Asp160 was also specifically labeled by LDT chemistry reagents derived from acetogenin [Masuya, T., et al. (2014) Biochemistry 53, 2307-2317, 7816-7823], we found this aspartic acid to elicit very strong nucleophilicity in the local protein environment. The structural features of the quinone binding pocket in bovine complex I are discussed on the basis of this finding. PMID- 26009788 TI - Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice. AB - BACKGROUND: Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. METHODS: Wild-type or cytokine-deficient (IL-13(-/-) or IL-4(-/-) ) eosinophils treated with cytokines (GM-CSF, IL-4, IL 33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. RESULTS: In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLN. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4(+) T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4, and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4(+) T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13, whereas IL-4 expression by eosinophils had no significant role. CONCLUSION: The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID- 26009790 TI - Multiple inductive effects of carbamazepine on combined therapy with paliperidone and amlodipine. AB - WHAT IS KNOWN AND OBJECTIVE: Carbamazepine is a potent inducer of cytochrome P450 3A and P-glycoprotein. However, there are no reports of the effects of carbamazepine on more than one co-administered drug. CASE SUMMARY: A 53-year-old female patient with schizophrenia and hypertension was on paliperidone 12 mg/day and amlodipine 5 mg/day. When carbamazepine was added to this prescription, the plasma concentrations of both drugs decreased dramatically in a dose-dependent manner. Although the patient's psychotic symptoms did not change, as a result, her mean blood pressure increased to 160.1/103.6 mmHg from 138.4/91.4 mmHg at a carbamazepine dose of 600 mg/day. WHAT IS NEW AND CONCLUSION: Theses cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together. PMID- 26009792 TI - Quantitative clinical pharmacology for size and age scaling in pediatric drug development: A systematic review. AB - The establishment of drug dosing in children is often hindered by the lack of actual pediatric efficacy and safety data. To overcome this limitation, scaling approaches are frequently employed to leverage adult clinical information for informing pediatric dosing. The objective of this review is to provide a comprehensive overview of the different scaling approaches used in pediatric pharmacotherapy as well as their proper implementation in drug development and clinical use. We will start out with a brief overview of the current regulatory requirements in pediatric drug development, followed by a review of the most commonly employed scaling approaches in increasing order of complexity ranging from simple body weight-based dosing to physiologically-based pharmacokinetic (PBPK) modeling approaches. Each of the presented approaches has advantages and limitations, which will be highlighted throughout the course of the review by the use of clinically-relevant examples. The choice of the approach employed consequently depends on the clinical question at hand and the availability of sufficient clinical data. The main effort while establishing and qualifying these scaling approaches should be directed towards the development of safe and effective dosing regimens in children rather than identifying the best model, ie models should be fit for purpose. PMID- 26009791 TI - Initial validation of a web-based self-administered neuropsychological test battery for older adults and seniors. AB - INTRODUCTION: Computerized neuropsychological tests are effective in assessing different cognitive domains, but are often limited by the need of proprietary hardware and technical staff. Web-based tests can be more accessible and flexible. We aimed to investigate validity, effects of computer familiarity, education, and age, and the feasibility of a new web-based self-administered neuropsychological test battery (Memoro) in older adults and seniors. METHOD: A total of 62 (37 female) participants (mean age 60.7 years) completed the Memoro web-based neuropsychological test battery and a traditional battery composed of similar tests intended to measure the same cognitive constructs. Participants were assessed on computer familiarity and how they experienced the two batteries. To properly test the factor structure of Memoro, an additional factor analysis in 218 individuals from the HUNT population was performed. RESULTS: Comparing Memoro to traditional tests, we observed good concurrent validity (r = .49-.63). The performance on the traditional and Memoro test battery was consistent, but differences in raw scores were observed with higher scores on verbal memory and lower in spatial memory in Memoro. Factor analysis indicated two factors: verbal and spatial memory. There were no correlations between test performance and computer familiarity after adjustment for age or age and education. Subjects reported that they preferred web-based testing as it allowed them to set their own pace, and they did not feel scrutinized by an administrator. CONCLUSIONS: Memoro showed good concurrent validity compared to neuropsychological tests measuring similar cognitive constructs. Based on the current results, Memoro appears to be a tool that can be used to assess cognitive function in older and senior adults. Further work is necessary to ascertain its validity and reliability. PMID- 26009794 TI - MSLT-I: it's all about the lymph nodes...: reply from the authors. PMID- 26009795 TI - One-Dimensional Au-ZnO Heteronanostructures for Ultraviolet Light Detectors by a Two-Step Dielectrophoretic Assembly Method. AB - One-dimensional ZnO decorated with metal nanoparticles has received much attention in the field of ultraviolet light detection because of its high photosensitivity and fast response, while how to form effective metal-ZnO heterostructures cost efficiently is still in development. We report an efficient and well-controlled method to form Au-ZnO heterostructures by two-step dielectrophoretic assembly. First, ZnO nanowires dispersed in deionized water were assembled dielectrophoretically in a planar microelectrode system. To control the number and position of assembled ZnO nanowires, a planar triangle shaped microelectrode pair was imposed with a high-frequency ac voltage signal in this assembly process. Then a droplet of Au nanoparticle suspension was applied to decorate the preformed ZnO nanowire by another dielectrophoretic assembly process. The near-field dielectrophoretic force induced by the existence of ZnO nanowire spanning the electrode gap attracts Au nanoparticles onto the surface of ZnO nanowires and forms effective Au-ZnO heterostructures. After the adsorption of Au nanoparticles, the performances of Au-ZnO heteronanostructures in UV detection were studied. Experimental results indicate that the ratio of the photo to-dark current of the Au-ZnO heteronanostucture-based detector was improved significantly, and the photoresponse was accelerated considerably. This kind of enhancement in performance can be attributed to the localized Schottky junctions on the surface of ZnO nanowire which improves the surface band bending. PMID- 26009793 TI - Glucose-6-phosphate dehydrogenase and alternative oxidase are involved in the cross tolerance of highland barley to salt stress and UV-B radiation. AB - In this study, a new mechanism involving glucose-6-phosphate dehydrogenase (G6PDH) and alternative pathways (AP) in salt pretreatment-induced tolerance of highland barley to UV-B radiation was investigated. When highland barley was exposed to UV-B radiation, the G6PDH activity decreased but the AP capacity increased. In contrast, under UV-B+NaCl treatment, the G6PDH activity was restored to the control level and the maximal AP capacity and antioxidant enzyme activities were reached. Glucosamine (Glucm, an inhibitor of G6PDH) obviously inhibited the G6PDH activity in highland barley under UV-B + NaCl treatment and a similar pattern was observed in reduced glutathione (GSH) and ascorbic acid (Asc) contents. Similarly, salicylhydroxamic acid (SHAM, an inhibitor of AOX) significantly reduced the AP capacity in highland barley under UV-B + NaCl treatment. The UV-B-induced hydrogen peroxide (H2O2) accumulation was also followed. Further studies indicated that non-functioning of G6PDH or AP under UV B+NaCl + Glucm or UV-B + NaCl + SHAM treatment also caused damages in photosynthesis and stomatal movement. Western blot analysis confirmed that the alternative oxidase (AOX) and G6PDH were dependent each other in cross tolerance to UV-B and salt. The inhibition of AP or G6PDH activity resulted in a significant accumulation or reduction of NADPH content, respectively, under UV B+NaCl treatment in highland barley leaves. Taken together, our results indicate that AP and G6PDH mutually regulate and maintain photosynthesis and stomata movement in the cross adaptation of highland barley seedlings to UV-B and salt by modulating redox homeostasis and NADPH content. PMID- 26009797 TI - Scarred communities - psychosocial impact of man-made and natural disasters on Sri Lankan society. PMID- 26009796 TI - Hypertension in children after renal transplantation. AB - BACKGROUND: Hypertension (HT) is a common and serious complication following renal transplantation in children, and an important risk factor for cardiovascular morbidity and mortality. This study evaluated the clinical characteristics of HT in children after renal transplantation. METHODS: Twenty four children who were followed up at least 6 months after renal transplantation were enrolled in the study. From the clinical records, demographic and laboratory data, casual blood pressure (BP) measurement, ambulatory BP monitoring (ABPM), medication, and left ventricular mass index (LVMI) at echocardiogram were documented. RESULTS: Mean age at time of transplantation was 12.6 +/- 3.0 years and mean follow-up period was 19.6 +/- 15.8 months. HT was detected in 21 children (87.5%) after renal transplantation. Twelve patients (50%) had HT both before and after transplantation and nine (38%) had HT only after transplantation. HT developed in 67% within the first week and in 95% within the first month. All hypertensive children had night-time HT and no child had isolated daytime HT. The efficacy of HT control was 42%. Median LVMI in patients with HT after renal transplantation was 42.3 g/m(2.7). CONCLUSIONS: Severe HT, an important complication, was frequently seen in the early period after renal transplantation. Predominance of nocturnal HT and the lack of isolated daytime HT after transplantation underline the importance of ABPM. ABPM should be performed regularly in the first year after transplantation, not only for diagnosis but also for evaluation of HT control. PMID- 26009798 TI - Dubowitz syndrome and the increased risk of developing malignancies. PMID- 26009799 TI - Fentanyl Buccal Tablet: A New Breakthrough Pain Medication in Early Management of Severe Vaso-Occlusive Crisis in Sickle Cell Disease. AB - BACKGROUND: Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder. The principal clinical manifestations of SCD are the chronic hemolytic anemia and the acute vaso-occlusive crisis (VOCs), which are mainly characterized by ischemic/reperfusion tissue injury. Pain is the main symptom of VOCs, and its management is still a challenge for hematologists, requiring a multidisciplinary approach. METHODS: We carried out a crossover study on adult SCD patients, who received two different types of multimodal analgesia during two separate severe VOCs with time interval between VOCs of at least 6 months. The first VOC episode was treated with ketorolac (0.86 mg/kg/day) and tramadol (7.2 mg/kg/day) (TK treatment). In the second VOC episode, fentanyl buccal tablet (FBT; 100 MUg) was introduced in a single dose after three hours from the beginning of TK analgesia (TKF treatment). We focused on the first 24 hours of acute pain management. The primary efficacy measure was the time-weighted-sum of pain intensity differences (SPID24). The secondary efficacy measures included the pain intensity difference (PID), the total pain relief (TOTPAR), and the time wighted sum of anxiety (SAID24). RESULTS: SPID24 was significantly higher in TKF than in TK treatment. All the secondary measures were significantly ameliorated in TKF compared to TK treatment, without major opioid side effects. Patients satisfaction was higher with TKF treatment than with TK one. CONCLUSIONS: We propose that VOCs might require breakthrough pain drug strategy as vaso-occlusive phenomena and enhanced vasoconstriction promoting acute ischemic pain component exacerbate the continuous pain of VOCs. FBT might be a powerful and feasible tool in early management of acute pain during VOCs in emergency departments. PMID- 26009800 TI - Rice responds to endophytic colonization which is independent of the common symbiotic signaling pathway. AB - As molecular interactions of plants with N2 -fixing endophytes are largely uncharacterized, we investigated whether the common signaling pathway (CSP) shared by root nodule symbioses (RNS) and arbuscular mycorrhizal (AM) symbioses may have been recruited for the endophytic Azoarcus sp.-rice (Oryza sativa) interaction, and combined this investigation with global approaches to characterize rice root responses to endophytic colonization. Putative homologs of genes required for the CSP were analyzed for their putative role in endophytic colonization. Proteomic and suppressive subtractive hybridization (SSH) approaches were also applied, and a comparison of defense-related processes was carried out by setting up a pathosystem for flooded roots with Xanthomonas oryzae pv. oryzae strain PXO99 (Xoo). All tested genes were expressed in rice roots seedlings but not induced upon Azoarcus sp. inoculation, and the oscyclops and oscastor mutants were not impaired in endophytic colonization. Global approaches highlighted changes in rice metabolic activity and Ca(2+) -dependent signaling in roots colonized by endophytes, including some stress proteins. Marker genes for defense responses were induced to a lesser extent by the endophytes than by the pathogen, indicating a more compatible interaction. Our results thus suggest that rice roots respond to endophytic colonization by inducing metabolic shifts and signaling events, for which the CSP is not essential. PMID- 26009801 TI - Properties of Cationic Pnicogen-Bonded Complexes F(4-n)H(n)P(+):N-Base with F P...N Linear and n = 0-3. AB - Ab initio MP2/aug'-cc-pVTZ calculations were performed to investigate the pnicogen-bonded complexes F(4-n)H(n)P(+):N-base, for n = 0-3, each with a linear or nearly linear F-P...N alignment. The nitrogen bases include the sp(3) bases NH3, NClH2, NFH2, NCl2H, NCl3, NFCl2, NF2H, NF2Cl, and NF3 and the sp bases NCNH2, NCCH3, NP, NCOH, NCCl, NCH, NCF, NCCN, and N2. The binding energies vary between -20 and -180 kJ.mol(-1), while the P-N distances vary from 1.89 to 3.01 A. In each series of complexes, binding energies decrease exponentially as the P N distance increases, provided that complexes with sp(3) and sp hybridized bases are treated separately. Different patterns are observed for the change in the binding energies of complexes with a particular base as the number of F atoms in the acid changes. Thus, the particular acid-base pair is a factor in determining the binding energies of these complexes. Three different charge-transfer interactions stabilize these complexes. These arise from the nitrogen lone pair to the sigma*P-F(ax), sigma*P-F(eq), and sigma*P-H(eq) orbitals. The dominant single charge-transfer energy in all complexes is N(lp) -> sigma*P-F(ax). However, since there are three N(lp) -> sigma*P-F(eq) charge-transfer interactions in complexes with F4P(+) and two in complexes with F3HP(+), the sum of the N(lp) -> sigma*P-F(eq) charge-transfer energies is greater than the N(lp) > sigma*P-F(ax) charge-transfer energies in the former complexes, and similar to the N(lp) -> sigma*P-F(ax) energies in the latter. The total charge-transfer energies of all complexes decrease exponentially as the P-N distance increases. Coupling constants (1p)J(P-N) across the pnicogen bond vary with the P-N distance, but different patterns are observed for complexes with F4P(+) and complexes of the sp(3) bases with F3HP(+). These initially increase as the P-N distance decreases, reach a maximum, and then decrease with decreasing P-N distance as the P...N bond acquires increased covalent character. For the remaining complexes, (1p)J(P-N) increases with decreasing P-N distance. Complexation increases the P-F(ax) distance and (1)J(P-F(ax)) relative to the corresponding isolated ion. (1)J(P-F(ax)) correlates quadratically with the P-N distance. PMID- 26009803 TI - Ultrasonographic evaluation of gastrointestinal graft-versus-host disease after hematopoietic stem cell transplantation. AB - Gastrointestinal graft-versus-host disease (GI-GVHD) is a major and life threatening complication of hematopoietic stem cell transplantation (HSCT). This study evaluated the efficacy of ultrasonography (US) for assessing and monitoring GI-GVHD. GI tract was evaluated by US in 81 patients. US findings were positive in 43 patients, including 11 false positive, and negative in 38 patients. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of US for the diagnosis of GI-GVHD were 100%, 78%, 74%, 100%, and 86%, respectively. Diffuse wall thickening of the ileum was the most frequent finding in patients with GI-GVHD. Severity of GI-GVHD was correlated with the thickness of internal low echoic layer of the wall, the echogenicity of mesenteric fat tissue, and the intensity of Doppler signaling. We classified US findings of GI-GVHD into four US grades. There was a significant correlation between clinical stage of GI-GVHD and the US grade. These ultrasonographic abnormalities were improved with clinical improvement of GI-GVHD upon treatment. Thus, US is an effective and efficient non-invasive means of identifying the extent and severity of GI-GVHD and monitoring response to treatment. PMID- 26009805 TI - Masaya Segawa, MD, PhD, 1936-2014. PMID- 26009804 TI - Benign multiple sclerosis: physical and cognitive impairment follow distinct evolutions. AB - BACKGROUND: Benign multiple sclerosis (BMS) definitions rely on physical disability level but do not account sufficiently for cognitive impairment which, however, is not rare. OBJECTIVE: To study the evolution of physical disability and cognitive performance of a group of patients with BMS followed at an University Hospital Multiple Sclerosis Center. METHODS: A consecutive sample of 24 BMS cases (diagnosis according to 2005 McDonald's criteria, relapsing remitting course, disease duration >= 10 years, and expanded disability status scale [EDSS] score <= 2.0) and 13 sex- and age-matched non-BMS patients differing from BMS cases for having EDSS score 2.5-5.5 were included. Main outcome measures were as follows: (i) baseline and 5-year follow-up cognitive impairment defined as failure of at least two tests of the administered neuropsychological battery; (ii) EDSS score worsening defined as confirmed increase >= 1 point (or 0.5 point if baseline EDSS score = 5.5). RESULTS: At inclusion, BMS subjects were 41 +/- 8 years old and had median EDSS score 1.5 (range 0-2), while non-BMS patients were 46 +/- 8 years old and had median EDSS score 3.0 (2.5-5.5). At baseline 16% of patients in both groups were cognitively impaired. After 5 years, EDSS score worsened in 8% of BMS and 46% of non-BMS patients (P = 0.008), while the proportion of cognitively impaired subjects increased to 25% in both groups. CONCLUSIONS: Patients with BMS had better physical disability outcome at 5 years compared to non-BMS cases. However, cognitive impairment frequency and decline over time appeared similar. Neuropsychological assessment is essential in patients with BMS given the distinct pathways followed by disease progression in cognitive and physical domains. PMID- 26009806 TI - Scale development study: The Fluid Control in Hemodialysis Patients. AB - AIM: The aim of this study was to develop a valid and reliable measurement instrument to identify knowledge, behaviors, and attitudes of hemodialysis (HD) patients about fluid control as these patients are inadequate in ensuring and sustaining fluid control. METHODS: The sample of this methodological study consisted of 276 HD patients who are being treated in two public and two private hemodialysis centers. The validity of the scale was assessed through content validity, construct validity, and similar scale validity, and its reliability through item analysis, internal consistency coefficient and test-retest. For the content validity of the scale, expert views were assessed, and opinions of a Turkish language specialist were obtained. RESULTS: According to the exploratory factor analysis, the scale had 24 items and three subdimensions, namely, knowledge, behavior, and attitude. The total variance explained was found to be 51.15%. Cronbach's alpha reliability coefficient of the Fluid Control in Hemodialysis Patients Scale (FCHPS) turned out to be 0.88 and Cronbach's alpha for its subdimensions were 0.92, 0.80, and 0.67, respectively. The correlation value between test and retest was 0.94 (P < 0.001). A moderate significant correlation (r = 0.58, P < 0.001) was found between the scale scores and the scores of the Dialysis Diet and Fluid Restrictions Non-adherence Questionnaire. CONCLUSION: The FCHPS that was developed has good validity and reliability. This scale can be used to measure knowledge, behavior, and attitude of hemodialysis patients about fluid restriction. PMID- 26009802 TI - Is a multivalent hand, foot, and mouth disease vaccine feasible? AB - Enterovirus A infections are the primary cause of hand, foot and mouth disease (HFMD) in infants and young children. Although enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are the predominant causes of HFMD epidemics worldwide, EV-A71 has emerged as a major neurovirulent virus responsible for severe neurological complications and fatal outcomes. HFMD is a serious health threat and economic burden across the Asia-Pacific region. Inactivated EV-A71 vaccines have elicited protection against EV-A71 but not against CV-A16 infections in large efficacy trials. The current development of a bivalent inactivated EV-A71/CV-A16 vaccine is the next step toward that of multivalent HFMD vaccines. These vaccines should ultimately include other prevalent pathogenic coxsackieviruses A (CV-A6 and CV-A10), coxsackieviruses B (B3 and B5) and echovirus 30 that often co-circulate during HFMD epidemics and can cause severe HFMD, aseptic meningitis and acute viral myocarditis. The prospect and challenges for the development of such multivalent vaccines are discussed. PMID- 26009808 TI - Dynamics of suspended and attached aerobic toluene degraders in small-scale flow through sediment systems under growth and starvation conditions. AB - The microbially mediated reactions, that are responsible for field-scale natural attenuation of organic pollutants, are governed by the concurrent presence of a degrading microbial community, suitable energy and carbon sources, electron acceptors, as well as nutrients. The temporal lack of one of these essential components for microbial activity, arising from transient environmental conditions, might potentially impair in situ biodegradation. This study presents results of small scale flow-through experiments aimed at ascertaining the effects of substrate-starvation periods on the aerobic degradation of toluene by Pseudomonas putida F1. During the course of the experiments, concentrations of attached and mobile bacteria, as well as toluene and oxygen were monitored. Results from a fitted reactive-transport model, along with the observed profiles, show the ability of attached cells to survive substrate-starvation periods of up to four months and suggest a highly dynamic exchange between attached and mobile cells under growth conditions and negligible cell detachment under substrate starvation conditions. Upon reinstatement of toluene, it was readily degraded without a significant lag period, even after a starvation period of 130 days. Our experimental and modeling results strongly suggest that aerobic biodegradation of BTEX-hydrocarbons at contaminated field sites is not hampered by intermittent starvation periods of up to four months. PMID- 26009807 TI - The moderating role of cognitive capacities in the association between social norms and drinking behaviors. AB - BACKGROUND: The literature documents 2 related yet distinct social normative influences on adolescent drinking. Descriptive norms refer to perceptions of how much others engage in a particular behavior, whereas injunctive norms refer to the extent to which others approve of a particular behavior. Theoretical formulations suggest that whether descriptive or injunctive norms guide drinking behavior depends on cognitive factors related to executive functioning. Cognitive capacities, specifically inhibitory control (IC) and preplanning, were tested as moderators of the association between social norms and alcohol use using a longitudinal design and community sample of adolescents. METHODS: This longitudinal study included 387 adolescents and 3 annual waves of data. Behavioral tasks assessed IC (Stop Signal Task) and preplanning (Tower of London) and social norms and drinking were assessed using self-report measures. RESULTS: Significant interactions were found for descriptive and injunctive norms with preplanning and descriptive norms with IC. As hypothesized, descriptive norms were stronger prospective predictors of alcohol use at low levels of cognitive preplanning, whereas injunctive norms were stronger prospective predictors at high levels of cognitive preplanning. Descriptive norms prospectively predicted alcohol use at high, but not at low levels of IC. CONCLUSIONS: These findings highlight the complexity of normative influences and suggest that descriptive and injunctive norms have differential effects on future drinking for individuals with different cognitive capacities. PMID- 26009809 TI - Relaxed predation results in reduced phenotypic integration in a suite of dragonflies. AB - Although changes in magnitude of single traits responding to selective agents have been studied intensively, little is known about selection shaping networks of traits and their patterns of covariation. However, this is central for our understanding of phenotypic evolution as traits are embedded in a multivariate environment with selection affecting a multitude of traits simultaneously rather than individually. Here, we investigate inter- and intraspecific patterns of trait integration (trait correlations) in the larval abdomen of dragonflies as a response to a change in predator selection. Species of the dragonfly genus Leucorrhinia underwent a larval habitat shift from predatory fish to predatory dragonfly-dominated lakes with an associated relaxation in selection pressure from fish predation. Our results indicate that the habitat-shift-induced relaxed selection pressure caused phenotypic integration of abdominal traits to be reduced. Intraspecific findings matched patterns comparing species from both habitats with higher abdominal integration in response to predatory fish. This higher integration is probably a result of faster burst swimming speed. The abdomen holds the necessary morphological machinery to successfully evade predatory fish via burst swimming. Hence, abdominal traits have to function in a tight coordinated manner, as maladaptive variation and consequently nonoptimal burst swimming would cause increased mortality. In predatory dragonfly-dominated lakes, no such strong link between burst swimming and mortality is present. Our findings highlight the importance of studying multivariate trait relationships as a response to selection for understanding patterns of phenotypic diversification. PMID- 26009810 TI - Existential crises in two religious patients: Vicissitudes of faith and the emergence of the true self. AB - The authors present two clinical cases involving an existential crisis which led the patients to lose what had been the foundation in their lives, their faith. Although the therapeutic settings differ--the first patient had a few psychotherapy sessions following a psychotic episode with a mystical background, while the second was in the final stage of analytic treatment - the authors highlight how in both clinical cases a loss of faith becomes a total and urgent crisis of the Self. The fracture which ensues seems to generate an intense engagement of the body which, paradoxically during a loss of faith, induces an experience of ecstasy of the kind that has traditionally been reported. In the first case the experience of ecstasy was lived first-hand by the patient who thereafter redefined the psychotic breakdown as a "moment of truth"; whereas the second patient, through a deep projective identification, induces an eerie countertransferential feeling of 'metaphysical' shortfall in the agnostic psychoanalyst, triggering bewilderment, physical discomfort and awe in him. In both cases the authors believe that the notable somatic involvement may be correlated to a potentially profound and unprecedented contact with the True Self. PMID- 26009811 TI - Fate and stereoselective behavior of benalaxyl in a water-sediment microcosm. AB - The environmental behavior and stereoselectivity of the chiral fungicide benalaxyl and its chiral metabolite benalaxyl acid in water, sediment, and water sediment microcosms were studied. The microcosms were incubated at 25 degrees C with light or under darkness. The influencing factors such as light and microorganism were investigated. The results showed that benalaxyl had half-lives of >21 days in the microcosm system and that the metabolite benalaxyl acid could exist in the microcosm for >70 days. Benalaxyl was mainly transformed through microbial degradation, and thus sediment microorganisms played a major role in the dissipation of benalaxyl in the aquatic microcosm. The stereoselective behavior of benalaxyl and benalaxyl acid was also investigated. (-)-Benalaxyl was preferentially degraded in the microcosm, resulting in an enrichment of the more toxic enantiomer (+)-benalaxyl, which may cause higher risk to the aquatic system. Moreover, (-)-benalaxyl acid was preferentially formed in the microcosm. The enantioselectivity of the enantiomers in the microcosm should be taken into consideration for an accurate risk assessment. PMID- 26009812 TI - RIP1-Dependent Programmed Necrosis is Negatively Regulated by Caspases During Hepatic Ischemia-Reperfusion. AB - Programmed necrosis (necroptosis), a newly discovered form of cell death, is mediated by receptor-interacting protein 1 (RIP1) and plays a pivotal role after myocardial, renal, and cerebral ischemia-reperfusion (I/R). The relevance of necroptosis in the postischemic liver remains, however, unclear. The aim of this study was to analyze the role of programed necrosis during hepatic I/R. C57BL6 mice were subjected to warm hepatic I/R (90 min/240 min). The animals were pretreated with either the RIP1 inhibitor necrostatin-1 (Nec-1, 3.5 MUg kg) or vehicle (Nec-1inactive, 3.5 MUg kg) administered systemically before ischemia. Sham-operated animals served as controls (n = 6 each group). The inflammatory response was evaluated by intravital microscopy. The hepatic transaminases alanine aminotransferase/aspartate aminotransferase in plasma as well as the activity of caspase-3 in tissue were determined as markers of hepatocellular injury. Leukocyte recruitment to the liver, sinusoidal perfusion failure, as well as the transaminase activities were strongly increased on I/R as compared with the sham-operated mice. Inhibition of the RIP1-dependent pathway with Nec-1, however, did not attenuate I/R-induced leukocyte migration, perfusion failure, and hepatocellular injury. Western blot analysis showed a baseline RIP1 expression in livers from sham-operated mice, whereas RIP1 expression was not detectable in both Nec-1-treated and vehicle-treated I/R group. Caspase-3 activity was significantly elevated after I/R in both postischemic groups. Our in vivo data show that RIP1-mediated necroptosis is not present in the postischemic liver and that I/R-induced caspase activation is associated with loss of RIP1 expression. Because caspases are able to cleave RIP1, we hypothesize that I/R triggered caspase activation negatively regulates necroptosis and, thereby, determines apoptosis as a preferred route of cell death after hepatic I/R. PMID- 26009813 TI - Burn-Evoked Reactive Oxygen Species Immediately After Injury are Crucial to Restore the Neutrophil Function Against Postburn Infection in Mice. AB - Although reactive oxygen species (ROS) basically play beneficial roles to maintain host homeostasis against external disturbance/stress including infection, excessive ROS generation by activated neutrophils can sometimes cause organ damage. We investigated the role of burn-induced ROS generation in the injured hosts, focusing on postburn infection. C57BL/6 mice received a 20% full thickness burn injury. In these mice, the burn-induced ROS generation was inhibited during and immediately after injury by pretreatment with superoxide dismutase (at 1 h before and immediately before injury), or the subsequent ROS production was inhibited posttreatment with superoxide dismutase (at 1 and 2 h after injury), which could not scavenge the ROS produced immediately after injury. As expected, inhibition of ROS production during/immediately after injury reduced the burn-induced pulmonary damage at 6 h, whereas inhibition of the subsequent ROS production did not lead to any improvements. Burn injury rendered the mice susceptible to bacterial infection at 5 days after injury and impaired bactericidal activity of neutrophils. Nevertheless, inhibition of the ROS production during/immediately after injury did not improve the burn-induced susceptibility to infection or the neutrophil dysfunction. Interestingly, inhibition of the subsequent ROS production potently restored the neutrophil functions and hematopoietic function of the bone marrow myelocytes, thereby improving the postburn infection. Thus, although the inhibition of burn-evoked ROS generation is effective against burn-induced organ injury, it may be ineffective against postburn infection. Preservation of the immediate burn-evoked ROS production, but the inhibition of subsequent ROS production, may be crucial to protect against postburn infection. PMID- 26009815 TI - Physical Effort Affects Heatstroke Thermoregulatory Response and Mortality in Rats. AB - Animals suffering from heatstroke (HS) after physical effort may have different heat-related core temperature (Tc) responses compared with passive HS. In the present study, conscious and unrestrained rats were exposed to ambient temperature (Ta) of 39.5 degrees C +/- 0.2 degrees C with or without running (run heated or rest-heated, respectively) until HS onset, which was defined as the systolic blood pressure starting to drop. In comparison with rest-heated rats, run-heated rats had a significantly shorter latency of HS onset. Physical effort did not have significant influence on hyperthermia severity (43.3 degrees C +/- 0.2 degrees C at rest-heated, and 43.4 degrees C +/- 0.2 degrees C at run heated), but it could significantly decrease the thermal load to develop HS (315.1 degrees C +/- 37.3 degrees C.min for rest-heated, and 133.5 +/- 21.4 degrees C.min for run-heated). Working component during heat exposure may contribute to a decreased survival rate of HS (46.9% at rest-heated and 31.3% at run-heated). Impaired heat dissipation during recovery may be responsible for relative poor survival of run-heated rats. In both groups, survival was affected by Tc at HS onset and thermal area. Hypothermia (Tc <35 degrees C) developed after HS onset, with no significant difference in Tc,min between the rest-heated and run-heated groups. These thermoregulatory responses to HS after physical effort may provide insight into HS pathophysiology. PMID- 26009814 TI - Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases. AB - Hypertonic saline (HS) resuscitation has been studied as a possible strategy to reduce polymorphonuclear neutrophil (PMN) activation and tissue damage in trauma patients. Hypertonic saline blocks PMNs by adenosine triphosphate (ATP) release and stimulation of A2a adenosine receptors. Here, we studied the underlying mechanisms in search of possible reasons for the inconsistent results of recent clinical trials with HS resuscitation. Purified human PMNs or PMNs in whole blood were treated with HS to simulate hypertonicity levels found after HS resuscitation (40 mmol/L beyond isotonic levels). Adenosine triphosphate release was measured with a luciferase assay. Polymorphonuclear neutrophil activation was assessed by measuring oxidative burst. The pannexin-1 (panx1) inhibitor panx1 and the gap junction inhibitor carbenoxolone (CBX) blocked ATP release from PMNs in purified and whole blood preparations, indicating that HS releases ATP via panx1 and gap junction channels. Hypertonic saline blocked N-formyl-Met-Leu-Phe-induced PMN activation by 40% in purified PMN preparations and by 60% in whole blood. These inhibitory effects were abolished by panx1 but only partially reduced by CBX, which indicates that panx1 has a central role in the immunomodulatory effects of HS. Inhibition of the ectonucleotidases CD39 and CD73 abolished the suppressive effect of HS on purified PMN cultures but only partially reduced the effect of HS in whole blood. These findings suggest redundant mechanisms in whole blood that may strengthen the immunomodulatory effect of HS in vivo. We conclude that HS resuscitation exerts anti-inflammatory effects that involve panx1, CD39, CD73, and other ectonucleotidases, which produce the adenosine that blocks PMNs by stimulating their A2a receptors. Our findings shed new light on the immunomodulatory mechanisms of HS and suggest possible new strategies to improve the clinical efficacy of hypertonic resuscitation. PMID- 26009816 TI - Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome. AB - Primed neutrophils that are capable of releasing matrix metalloproteinases (MMPs) into the circulation are thought to play a significant role in the pathophysiology of acute respiratory distress syndrome (ARDS). We hypothesized that direct measurement of plasma MMP-9 activity may be a predictor of incipient tissue damage and subsequent lung injury, which was investigated in both an animal model of ARDS and a small cohort of 38 critically ill human patients. In a mouse model of ARDS involving instillation of intratracheal lipopolysaccharide (LPS) to induce lung inflammation, we measured neutrophil-mediated inflammation, along with MMP-9 activity in the airways and lung tissue and MMP-9 expression in the plasma. Neutrophil recruitment, inflammation, and MMP-9 activity in the airways and lung tissue increased throughout the 72 h after LPS instillation, whereas plasma MMP-9 expression was greatest at 12 to 24 h after LPS instillation. The results suggest that the peak in plasma MMP-9 activity may precede the peak of neutrophil inflammation in the airways and lung tissue in the setting of ARDS. Based on this animal study, a retrospective observational cohort study involving 38 patients admitted to a surgical intensive care unit at a tertiary care university hospital with acute respiratory failure requiring intubation and mechanical ventilation was conducted. Plasma samples were collected daily, and MMP-9 activity was compared with lung function as determined by the PaO2/FiO2 ratio. In patients who developed ARDS, a notable increase in plasma MMP-9 activity on a particular day correlated with a decrease in the PaO2/FiO2 ratio on the following day (r = -0.503, P < 0.006). Taken together, these results suggest that plasma MMP-9 activity changes, as a surrogate for primed neutrophils may have predictive value for the development of ARDS in a selected subset of critically ill patients. PMID- 26009818 TI - The Impact of Intramedullary Nailing of Tibia Fractures on the Innate Immune System. AB - INTRODUCTION: Inflammation after trauma is thought to be aggravated by intramedullary nailing (IMN) and predisposes to acute respiratory distress syndrome. Polymorphonuclear granulocytes (PMNs) are the main effector cells in this process. However, in patients with a femur fracture, the injury severity was the decisive factor for the PMN phenotype. A tibia fracture is often caused by a more moderate injury and might allow for a window to assess the innate immune response caused by IMN. METHODS: A consecutive series of patients with a tibia fracture were included. The innate immune response was measured before and after IMN by plasma interleukin 6, PMN Mac1, and active FcgammaRII (FcgammaRII*) expression both before and after fMLF (N-formylmethionyl-leucyl-phenylalanine) stimulation. Furthermore, HLA-DR on monocytes was analyzed. RESULTS: Twenty-five consecutive patients were included. Polymorphonuclear granulocyte fMLF-induced Mac1 and FcgammaRII* were decreased. In concordance, HLA-DR expression on monocytes was decreased in patients compared with control subjects. Intramedullary nailing was associated with a further decrease of HLA-DR-positive monocytes, whereas no changes in PMN phenotype or plasma interleukin 6 levels were observed. CONCLUSION: Intramedullary nailing of a tibial fracture did not affect the PMN phenotype. The impact from injury determined the PMN phenotype. In contrast, the monocyte phenotype changed after the additional insult by IMN in patients with an isolated tibial fracture. PMID- 26009817 TI - Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy: Implications for Sepsis Metabolomics. AB - Serum is a common sample of convenience for metabolomics studies. Its processing time can be lengthy and may result in the loss of metabolites including those of red blood cells (RBCs). Unlike serum, whole blood (WB) is quickly processed, minimizing the influence of variable hemolysis while including RBC metabolites. To determine differences between serum and WB metabolomes, both sample types, collected from healthy volunteers, were assayed by H-NMR (proton nuclear magnetic resonance) spectroscopy. A total of 34 and 50 aqueous metabolites were quantified from serum and WB, respectively. Free hemoglobin (Hgb) levels in serum were measured, and the correlation between Hgb and metabolite concentrations was determined. Most metabolites detected in serum were at higher concentrations in WB with the exception of acetoacetate and propylene glycol. The 18 unique metabolites of WB included adenosine, AMP, ADP, and ATP, which are associated with RBC metabolism. The use of serum results in the underrepresentation of a number of metabolic pathways including branched-chain amino acid degradation and glycolysis and gluconeogenesis. The range of free Hgb in serum was 0.03 to 0.01 g/dL, and eight metabolites were associated (P <= 0.05) with free Hgb. The range of free Hgb in serum samples from 18 sepsis patients was 0.02 to 0.46 g/dL. Whole blood and serum have unique aqueous metabolite profiles, but the use of serum may introduce potential pathway bias. Use of WB for metabolomics may be particularly important for studies in diseases such as sepsis in which RBC metabolism is altered, and mechanical and sepsis-induced hemolysis contributes to variance in the metabolome. PMID- 26009819 TI - Impact of Injury Severity on Dynamic Inflammation Networks Following Blunt Trauma. AB - INTRODUCTION: Clinical outcomes following trauma depend on the extent of injury and the host's response to injury, along with medical care. We hypothesized that dynamic networks of systemic inflammation manifest differently as a function of injury severity in human blunt trauma. STUDY DESIGN: From a cohort of 472 blunt trauma survivors studied following institutional review board approval, three Injury Severity Score (ISS) subcohorts were derived after matching for age and sex: mild ISS (49 patients [33 males and 16 females, aged 42 +/- 1.9 years; ISS 9.5 +/- 0.4]); moderate ISS (49 patients [33 males and 16 females, aged 42 +/- 1.9; ISS 19.9 +/- 0.4]), and severe ISS (49 patients [33 males and 16 females, aged 42 +/- 2.5 years; ISS 33 +/- 1.1]). Multiple inflammatory mediators were assessed in serial blood samples. Dynamic Bayesian Network inference was utilized to infer causal relationships based on probabilistic measures. RESULTS: Intensive care unit length of stay, total length of stay, days on mechanical ventilation, Marshall Multiple Organ Dysfunction score, prevalence of prehospital hypotension and nosocomial infection, and admission lactate and base deficit were elevated as a function of ISS. Multiple circulating inflammatory mediators were significantly elevated in severe ISS versus moderate or mild ISS over both the first 24 h and out to 7 days after injury. Dynamic Bayesian Network suggested that interleukin 6 production in severe ISS was affected by monocyte chemotactic protein 1/CCL2, monokine inducible by interferon gamma (MIG)/CXCL9, and IP-10/CXCL10; by monocyte chemotactic protein 1/CCL2 and MIG/CXCL9 in moderate ISS; and by MIG/CXCL9 alone in mild ISS over 7 days after injury. CONCLUSIONS: Injury Severity Score correlates linearly with morbidity, prevalence of infection, and early systemic inflammatory connectivity of chemokines to interleukin 6. PMID- 26009820 TI - Delayed but not Early Treatment with DNase Reduces Organ Damage and Improves Outcome in a Murine Model of Sepsis. AB - Sepsis is characterized by systemic activation of coagulation and inflammation in response to microbial infection. Although cell-free DNA (cfDNA) released from activated neutrophils has antimicrobial properties, it may also exert harmful effects by activating coagulation and inflammation. The authors aimed to determine whether deoxyribonuclease (DNase) administration reduces cfDNA levels, attenuates coagulation and inflammation, suppresses organ damage, and improves outcome in a cecal ligation and puncture (CLP) model of polymicrobial sepsis. Healthy C57Bl/6 mice were subjected to CLP, a surgical procedure involving two punctures of the ligated cecum, or sham surgery (no ligation/puncture). Mice were given DNase or saline by intraperitoneal injection 2, 4, or 6 h after surgery. Two hours after treatment, organs were harvested and plasma levels of cfDNA, interleukin-6 (IL-6), IL-10, thrombin-antithrombin complexes, lung myeloperoxidase, creatinine, alanine transaminase, and bacterial load were quantified. Survival studies were also performed. The CLP-operated mice had rapid time-dependent elevations in cfDNA that correlated with elevations in IL-6, IL 10, and thrombin-antithrombin complexes and had organ damage in the lungs and kidneys. Administration of DNase at 2 h after CLP resulted in increased IL-6 and IL-10 levels and organ damage in the lungs and kidneys. In contrast, DNase administration at 4 or 6 h after CLP resulted in reduced cfDNA and IL-6 levels, increased IL-10, and suppressed organ damage and bacterial dissemination. Deoxyribonuclease administration every 6 h after CLP also rescued mice from death. Our studies are the first to demonstrate that delayed but not early administration of DNase may be protective in experimental sepsis. PMID- 26009821 TI - Methane Attenuates Hepatic Ischemia/Reperfusion Injury in Rats Through Antiapoptotic, Anti-Inflammatory, and Antioxidative Actions. AB - Hepatic ischemia/reperfusion (I/R) injury, which occurs in various diseases, introduces severe tissue damage and liver dysfunction. However, no promising therapies for such a significant condition currently exist. Methane has been suggested to exert a protective effect against intestinal I/R injury. In this study, we introduced methane to treat hepatic I/R injury to show its promising protective effect. Also, intraperitoneal injection with methane-rich saline, which could have potential clinical applications, was applied as a new method. Partial liver warm ischemia was applied in Sprague-Dawley rats for 60 min followed by succedent reperfusion. In the test for effective dosage, methane-rich saline was administrated intraperitoneally to the rats at doses of 1, 5, 20, or 40 mL/kg at onset of reperfusion. In the test for protective effect, rats received methane-rich saline intraperitoneally at a dose of 10 mL/kg before the initiation of reperfusion. We found that methane-rich saline significantly decreased serum alanine aminotransferase, aspartate aminotransferase activity, and the occurrence of necrosis. Moreover, methane-rich saline reduced the amount of caspase-3 and the number of apoptotic cells. In addition, methane-rich saline increased the level of superoxide dismutase and decreased the level of malondialdehyde and 8-hydroxyguanosine. Furthermore, research indicated that methane-rich saline markedly decreased gene expression and content of tumor necrosis factor-alpha and interleukin-6. Also, reduced CD68-positive cells showed decreased inflammatory cells in the liver. Our results suggest that methane protects the liver against I/R injury through antiapoptotic, antioxidative, and anti-inflammatory actions. PMID- 26009822 TI - Interrater Reliability and Diagnostic Performance of Subjective Evaluation of Sublingual Microcirculation Images by Physicians and Nurses: A Multicenter Observational Study. AB - INTRODUCTION: This was a cross-sectional multicenter study to investigate the ability of physicians and nurses from three different countries to subjectively evaluate sublingual microcirculation images and thereby discriminate normal from abnormal sublingual microcirculation based on flow and density abnormalities. METHODS: Forty-five physicians and 61 nurses (mean age, 36 +/- 10 years; 44 males) from three different centers in The Netherlands (n = 61), Uruguay (n = 12), and Japan (n = 33) were asked to subjectively evaluate a sample of 15 microcirculation videos randomly selected from an experimental model of endotoxic shock in pigs. All videos were first analyzed offline using the A.V.A. software by an independent, experienced investigator and were categorized as good, bad, or very bad microcirculation based on the microvascular flow index, perfused capillary density, and proportion of perfused capillaries. Then, the videos were randomly assigned to the examiners, who were instructed to subjectively categorize each image as good, bad, or very bad. An interrater analysis was performed, and sensitivity and specificity tests were calculated to evaluate the proportion of A.V.A. score abnormalities that the examiners correctly identified. RESULTS: The kappa statistics indicated moderate agreement in the evaluation of microcirculation abnormalities using three categories, i.e., good, bad, or very bad (kappa = 0.48), and substantial agreement using two categories, i.e., normal (good) and abnormal (bad or very bad) (kappa = 0.66). There was no significant difference between the kappa three and kappa two statistics. We found that the examiner's subjective evaluations had good diagnostic performance and were highly sensitive (84%; 95% confidence interval, 81%-86%) and specific (87%; 95% confidence interval, 84%-90%) for sublingual microcirculatory abnormalities as assessed using the A.V.A. software. CONCLUSIONS: The subjective evaluations of sublingual microcirculation by physicians and nurses agreed well with a conventional offline analysis and were highly sensitive and specific for sublingual microcirculatory abnormalities. PMID- 26009823 TI - Neuropathological Correlates of Hyperglycemia During Prolonged Polymicrobial Sepsis in Mice. AB - Glucose toxicity may play a crucial role in evoking neurologic complications of critical illness. We studied whether the neuropathological alterations in fatal human critical illness observed under hyperglycemia are present and can be attenuated by maintaining normoglycemia in a mouse model of prolonged sepsis induced by cecal ligation and puncture. Mice were randomized to moderate hyperglycemia (>8.3 mmol/L, n = 8) or normoglycemia (4.4-6.7 mmol/L, n = 8). After 5 days, hippocampus and frontal cortex from septic mice were compared with those from healthy controls (n = 8). Blood glucose was 7.8 +/- 1.3 mmol/L in hyperglycemic and 6.1 +/- 0.7 mmol/L in normoglycemic critically ill mice (P = 0.007). The percentage of damaged neurons was twofold higher in frontal cortex (P = 0.01) and hippocampus (P = 0.06) of hyperglycemic ill mice than that of healthy mice. In frontal cortex, neuronal damage was attenuated under normoglycemia (P = 0.04). Critical illness reduced astrocyte density and activation status fourfold in hippocampus (P <= 0.02), but not in frontal cortex, irrespective of glycemic control. Microglia were twofold to fourfold more abundant in both brain areas of hyperglycemic critically ill mice (P <= 0.002), but only in frontal cortex were they reduced in number with normoglycemia (P = 0.0008). The density of apoptotic cells and abundance of carbonylated proteins were significantly higher than normal in frontal cortex of hyperglycemic ill mice only (P = 0.05). In a mouse model of prolonged polymicrobial sepsis, remarkable neuropathological changes develop with neuronal damage, impaired astrocyte activation, increased microglia, apoptosis, and accumulation of carbonylated proteins. These changes were partially prevented or attenuated when hyperglycemia was prevented with insulin. Frontal cortex appeared more vulnerable to hyperglycemic insults than hippocampus. PMID- 26009824 TI - Severe Burn Injury Induces Thermogenically Functional Mitochondria in Murine White Adipose Tissue. AB - Chronic cold exposure induces functionally thermogenic mitochondria in the inguinal white adipose tissue (iWAT) of mice. Whether this response occurs in pathophysiological states remains unclear. The purpose of this study was to determine the impact of severe burn trauma on iWAT mitochondrial function in mice. Male BALB/c mice (10-12 weeks) received full-thickness scald burns to ~30% of the body surface area. Inguinal white adipose tissue was harvested from mice at 1, 4, 10, 20, and 40 days postinjury. Total and uncoupling protein 1 (UCP1) dependent mitochondrial thermogenesis were determined in iWAT. Citrate synthase activity was determined as a proxy of mitochondrial abundance. Immunohistochemistry was performed to assess iWAT morphology and UCP1 expression. Uncoupling protein 1-dependent respiration was significantly greater at 4 and 10 days after burn compared with sham, peaking at 20 days after burn (P < 0.001). Citrate synthase activity was threefold greater at 4, 10, 20, and 40 days after burn versus sham (P < 0.05). Per mitochondrion, UCP1 function increased after burn trauma (P < 0.05). After burn trauma, iWAT exhibited numerous multilocular lipid droplets that stained positive for UCP1. The current findings demonstrate the induction of thermogenically competent mitochondria within rodent iWAT in a model of severe burn trauma. These data identify a specific pathology that induces the browning of white adipose tissue in vivo and may offer a mechanistic explanation for the chronic hypermetabolism observed in burn victims. PMID- 26009825 TI - Increased Neutrophil Gelatinase-Associated Lipocalin is Associated with Mortality and Multiple Organ Dysfunction Syndrome in Severe Sepsis and Septic Shock. AB - BACKGROUND: This study examines the clinical utility of increased neutrophil gelatinase-associated lipocalin (NGAL) as an indicator of mortality and multiple organ dysfunction syndrome (MODS) in severe sepsis and septic shock. METHODS: We designed a prospective cohort study in an intensive care unit, and 123 patients with severe sepsis or septic shock were included. Data were used to determine a relationship between NGAL and the development of MODS and mortality. These associations were determined by the Mann-Whitney U test, log-rank test, Cox proportional hazards regression analyses, and plotting the receiver operating characteristic curve. RESULTS: Patients with high NGAL (75th percentile) had increased risk of mortality and MODS compared with patients with low NGAL (log rank test, P < 0.05). There were 39 patients (32%) with mortality during follow up at 12 months, 10 patients (8%) with MODS on day 1, and 37 patients (30%) on day 7. The area under the receiver operating characteristic curve showed that high NGAL could predict mortality (0.6385) during intensive care unit stay. After adjustment for confounding risk factors chosen by backward elimination by Cox regression analysis, high NGAL remained an independent predictor of mortality and MODS (hazard ratios, 2.128 [95% confidence interval, 1.078-4.203; P = 0.030] and 1.896 [95% confidence interval, 1.012-3.552; P = 0.046], respectively). CONCLUSIONS: High plasma NGAL independently predicts mortality and MODS in severe sepsis and septic shock. PMID- 26009826 TI - The Utility of Inflammatory and Endothelial Markers to Identify Infection in Emergency Department Patients. AB - BACKGROUND: Identifying infection in emergency department (ED) patients can be challenging. This study assesses the value that inflammatory and endothelial biomarkers add to clinical data when predicting infectious etiologies of abnormal vital signs (AVSs) in ED patients. METHODS: This study was a prospective, observational cohort study of ED patients with AVSs at an urban, academic tertiary-care hospital, identified from March 1, 2013, to April 15, 2013. Collected blood samples were assayed for soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule 1, vascular cell adhesion molecule 1, plasminogen activator inhibitor 1, interleukin 6, sFlt-1, and procalcitonin. History and physical examination were abstracted from the ED documentation. The primary outcome, infectious etiology, was adjudicated by review of the hospital documentation. Three multivariate logistic regression models predicting infection were created using clinical data, biomarkers, and combined clinical data and biomarker assessments. Integrated discrimination improvement tested the discriminate value of the biomarker and combined models compared with the clinical data model. RESULTS: We enrolled 115 patients: 49 determined to have an infection (43%) and 66 without (57%). All biomarkers were significantly associated with infection in univariate analysis. The best clinical model (area under the curve [AUC] = 0.76) included initial temperature (odds ratio [OR], 1.6; confidence interval [CI], 1.1-2.2) and history of fever (OR, 5.0; CI, 1.4-14). The best biomarker model (AUC, 0.82) predicting infection included sE-selectin (OR, 11.0; 95% CI, 1.6-74) and interleukin 6 (OR, 5.1; CI, 2.3-11.6). The combined clinical and biomarker model had an AUC of 0.88, with integrated discrimination improvement = 0.21, compared with the clinical model alone. CONCLUSION: Inflammatory and endothelial markers can improve the clinical identification of infection in ED patients with AVSs. PMID- 26009827 TI - Sirtuin 1 Agonist Minimizes Injury and Improves the Immune Response Following Traumatic Shock. AB - Survival from traumatic injury requires a coordinated and controlled inflammatory and immune response. Mitochondrial and metabolic responses to stress have been shown to play a role in these inflammatory and immune responses. We hypothesized that increases in mitochondrial biogenesis via a sirtuin 1 agonist would decrease tissue injury and partially ameliorate the immunosuppression seen following trauma. C57Bl/6 mice were subjected to a multiple trauma model. Mice were pretreated with either 100 mg/kg per day of the sirtuin 1 agonist, Srt1720, via oral gavage for 2 days prior to trauma and extended until the day the animals were killed, or they were pretreated with peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) siRNA via hydrodynamic tail vein injection 48 h prior to trauma. Markers for mitochondrial function and biogenesis were measured in addition to splenocyte proliferative capacity and bacterial clearance. Srt1720 was noted to improve mitochondrial biogenesis, mitochondrial function, and complex IV activity following traumatic injury (P < 0.05), whereas knockdown of PGC1alpha resulted in exacerbation of mitochondrial dysfunction (P < 0.05). These changes in mitochondrial function were associated with altered severity of hepatic injury with significant reductions in serum alanine aminotransferase levels seen in mice treated with srt1720. Splenocyte proliferative capacity and intraperitoneal bacterial clearance were evaluated as markers for overall immune function following trauma-hemorrhage. Treatment with Srt1720 minimized the trauma-induced decreases in splenocyte proliferation (P < 0.05), whereas treatment with PGC1alpha siRNA led to diminished bacterial clearance. The PGC1alpha signaling pathway is an important regulator of mitochondrial function and biogenesis, which can potentially be harnessed to protect against hepatic injury and minimize the immunosuppression that is seen following trauma-hemorrhage. PMID- 26009828 TI - Geriatric Syndromes in Older HIV-Infected Adults. AB - BACKGROUND: Geriatric syndromes such as falls, frailty, and functional impairment are multifactorial conditions used to identify vulnerable older adults. Limited data exist on these conditions in older HIV-infected adults, and no studies have comprehensively examined these conditions. METHODS: Geriatric syndromes including falls, urinary incontinence, functional impairment, frailty, sensory impairment, depression, and cognitive impairment were measured in a cross-sectional study of HIV-infected adults aged 50 years and older who had an undetectable viral load on antiretroviral therapy. We examined both HIV and non-HIV-related predictors of geriatric syndromes including sociodemographics, number of comorbidities and nonantiretroviral medications, and HIV-specific variables in multivariate analyses. RESULTS: We studied 155 participants with a median age of 57 (interquartile range: 54-62) and 94% were men. Prefrailty (56%), difficulty with instrumental activities of daily living (46%), and cognitive impairment (47%) were the most frequent geriatric syndromes. Lower CD4 nadir incidence rate ratio [IRR: 1.16, 95% (confidence interval) CI: 1.06 to 1.26], non-white race (IRR: 1.38, 95% CI: 1.10 to 1.74), and increasing number of comorbidities (IRR: 1.09, 95% CI: 1.03 to 1.15) were associated with increased risk of having more geriatric syndromes. CONCLUSIONS: Geriatric syndromes are common in older HIV infected adults. Treatment of comorbidities and early initiation of antiretroviral therapy may help to prevent development of these age-related complications. Clinical care of older HIV-infected adults should consider incorporation of geriatric principles. PMID- 26009829 TI - Reductions in Plasma Cystatin C After Initiation of Antiretroviral Therapy Are Associated With Reductions in Inflammation: ACTG A5224s. AB - BACKGROUND: Among patients with HIV infection, changes in the kidney filtration marker cystatin C after initiation of antiretroviral therapy (ART) may be related to changes in body composition or biomarkers of inflammation. METHODS: ACTG A5224s was a substudy of A5202, which randomly assigned ART-naive HIV-infected subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or ritonavir-boosted atazanavir. This analysis explored changes in cystatin C from 0 to 96 weeks. RESULTS: Of the 269 subjects, 85% were male and 66% white non-Hispanics; baseline mean CD4 count was 236 cells per cubic millimeter and cystatin C was 0.89 mg/L. Cystatin C decreased significantly within each arm; however, ritonavir-boosted atazanavir attenuated the beneficial effects of ART on cystatin C compared to EFV. Compared to ABC/3TC, TDF/FTC led to a marginally significant attenuation for percent change analyses only. Higher baseline body mass index and HIV RNA were associated with larger reductions in cystatin C in multivariable models. At baseline, cystatin C was positively correlated with high-sensitivity C-reactive protein (Spearman r = 0.25), interleukin 6 (r = 0.34), soluble intercellular adhesion molecule (r = 0.36), soluble vascular cell adhesion molecule (r = 0.54), tumor necrosis factor alpha (r = 0.57), and soluble TNF-alpha receptor I (r = 0.70, all P < 0.001). Reductions in cystatin C from 0 to 96 weeks correlated with reductions in all inflammatory biomarkers (r = 0.39-0.58, P < 0.001) except for high-sensitivity C reactive protein (r = 0.01, P = 0.89) and IL-6 (r = 0.08, P = 0.24). CONCLUSIONS: The beneficial effect of ART on cystatin C concentrations is attenuated by boosted ATV when compared to EFV. Reductions in cystatin C after ART are associated with reductions in systemic inflammation. PMID- 26009830 TI - Meconium Atazanavir Concentrations and Early Language Outcomes in HIV-Exposed Uninfected Infants With Prenatal Atazanavir Exposure. AB - OBJECTIVE: To investigate whether prenatal atazanavir (ATV) exposure, assessed by meconium antiretroviral (ARV) quantification, predicts early child language outcomes. Prenatal ATV exposure previously was associated with poorer language development in 1-year olds. METHODS: Pregnant women with HIV and their uninfected infants enrolled in the Surveillance Monitoring of Antiretroviral Therapy Toxicities study. Meconium ARV concentrations were quantified by liquid chromatography-tandem mass spectrometry. Language development at 1 year was assessed with MacArthur-Bates Communicative Development Inventory (CDI) and Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Late language emergence was defined as >= 1 of 4 CDI scores <= 10th percentile for age. Associations between fetal ATV exposure timing and duration, meconium ATV concentration, and language outcomes were evaluated, adjusting for potential confounders. RESULTS: Through 2013, meconium samples were available from 175 of 432 infants with prenatal ATV exposure. Valid Bayley-III (n = 93) and CDI (n = 106) assessments also were available. After adjustment for potential confounders, higher ATV meconium concentrations were associated with lower late language emergence risk (P = 0.04) and cumulative ATV exposure duration also was associated with higher Bayley-III Language scores (P = 0.03). Maternal ATV duration and initiation week correlated with ATV meconium concentrations (positively and negatively, respectively). CONCLUSIONS: Higher meconium ATV concentrations were protective against developmental language delays at 1 year, suggesting the importance of fetal ATV detoxification into meconium. This information supports ATV exposure safety for infant language development. ATV is a preferred ARV for pregnant women with HIV, suggesting the importance of ATV safety investigations. Additionally, further pursuit of the influences on language development in HIV-exposed uninfected infants is required. PMID- 26009831 TI - Long-term Prescription of Opioids and/or Benzodiazepines and Mortality Among HIV Infected and Uninfected Patients. AB - BACKGROUND: Increased long-term prescription of opioids and/or benzodiazepines necessitates evaluating risks associated with their receipt. We sought to evaluate the association between long-term opioids and/or benzodiazepines and mortality in HIV-infected patients receiving antiretroviral therapy and uninfected patients. METHODS: Prospective analysis of all-cause mortality using multivariable methods and propensity score matching among HIV-infected patients receiving antiretroviral therapy and uninfected patients. RESULTS: Of 64,602 available patients (16,989 HIV-infected and 47,613 uninfected), 27,128 (exposed and unexposed to long-term opioids and/or benzodiazepines) were 1:1 matched by propensity score. The hazard ratio for death was 1.40 [95% confidence interval (CI): 1.22 to 1.61] for long-term opioid receipt, 1.26 (95% CI: 1.08 to 1.48) for long-term benzodiazepine receipt, and 1.56 (95% CI: 1.26 to 1.92) for long-term opioid and benzodiazepine receipt. There was an interaction (P = 0.01) between long-term opioid receipt and HIV status with mortality. For long-term opioid receipt, the hazard ratio was 1.46 (95% CI: 1.15 to 1.87) among HIV-infected patients, and 1.25 (95% CI: 1.05 to 1.49) among uninfected patients. Mortality risk was increased for patients receiving both long-term opioids and benzodiazepines when opioid doses were >= 20 mg morphine-equivalent daily dose and for patients receiving long-term opioids alone when doses were >= 50 mg morphine-equivalent daily dose. CONCLUSIONS: Long-term opioid receipt was associated with an increased risk of death; especially with long-term benzodiazepine receipt, higher opioid doses, and among HIV-infected patients. Long-term benzodiazepine receipt was associated with an increased risk of death regardless of opioid receipt. Strategies to mitigate risks associated with these medications, and caution when they are coprescribed, are needed particularly in HIV-infected populations. PMID- 26009832 TI - Adherence to Early Antiretroviral Therapy: Results From HPTN 052, a Phase III, Multinational Randomized Trial of ART to Prevent HIV-1 Sexual Transmission in Serodiscordant Couples. AB - BACKGROUND: Combination antiretroviral therapy (ART) for HIV-1-infected individuals prevents sexual transmission if viral load is suppressed. METHODS: Participants were HIV-1-infected partners randomized to early ART (CD4 350-550) in HPTN052 (n = 886, median follow-up = 2.1 years), a clinical trial of early ART to prevent sexual transmission of HIV-1 in serodiscordant couples at 13 sites in 9 countries. Adherence was assessed through pill count (dichotomized at <95%) and through self-report items. Predictors of adherence were mental health and general health perceptions, substance use, binge drinking, social support, sexual behaviors, and demographics. Viral suppression was defined as HIV plasma viral load <400 copies per milliliter. Adherence counseling and couples' counseling about safer sex were provided. Logistic and linear regression models using generalized estimating equation for repeated measurements were used. FINDINGS: Through pill count, 82% of participants were adherent at 1 month and 83.3% at 1 year. Mental health was the only psychosocial variable associated with adherence [pill count, odds ratios (OR) = 1.05, 95% confidence intervals (CIs): 1.00 to 1.11; self-report parameter estimate, OR = 0.02, 95% CI: 0.01 to 0.04], although regional differences emerged. Pill count (OR = 1.19, 95% CI: 1.10 to 1.30) and self-report (OR = 1.42, 95% CI: 1.14 to 1.77) adherence were associated with viral suppression. INTERPRETATION: Although adherence was high among individuals in stable relationships taking ART for prevention, mental health and adherence covaried. Assessing and intervening on mental health in the context of promoting adherence to ART as prevention should be explored. Adherence and couples' counseling, feedback about viral suppression, and/or altruism may also help explain the magnitude of adherence observed. PMID- 26009834 TI - Brief Report: Relationship and Demographic Factors Associated With Willingness to Use an In-Home Rapid HIV Test to Screen Potential Sex Partners Among a US Sample of HIV-Negative and HIV-Discordant Male Couples. AB - With dyadic data from a US Internet sample of 275 HIV-negative and 58 discordant male couples, we assessed HIV-negative partnered men's attitudes toward using an in-home rapid HIV test (HT) to screen potential new sex partners and associated factors by multivariate multilevel modeling. HIV-negative partnered men were "likely" to use an HT for screening purposes. More positive attitudes were associated with being in a mixed/nonwhite relationship; having an open sexual agreement. Less positive attitudes were associated with both partners being well educated. These findings may highlight how to make the most of HTs as risk reduction screening tool among at-risk male couples. PMID- 26009833 TI - Antiretroviral Therapy Availability and HIV Disclosure to Spouse in Rakai, Uganda: A Longitudinal Population-Based Study. AB - BACKGROUND: A decade after the rollout of antiretroviral therapy (ART) in sub Saharan Africa, the effects of this structural change on social aspects of HIV, such as rates of HIV disclosure to partners, remain largely unmeasured. We evaluated whether the introduction of ART was associated with disclosure of HIV diagnosis to spouses in Rakai, Uganda, using longitudinal, population-based data. METHODS: We identified individuals in marital/cohabitating unions who were newly diagnosed with HIV in Rakai Community Cohort Study surveys between 2000 and 2008, where ART was introduced in mid-2004. Using discrete-time survival analysis, we assessed the hazard of self-reported HIV disclosure to spouse after diagnosis pre ART and post-ART rollout, adjusting for individual and union characteristics. Disclosure in the ART period was further stratified by ART initiation. RESULTS: The analysis included 557 married adults, 264 of whom were diagnosed with HIV before ART was available (2000-2004), and 293 diagnosed after ART was introduced (2005-2008). The cumulative incidence of self-reported disclosure was 75.2% in the post-ART period, compared with 58.3% before ART availability [P < 0.001, adjusted hazard ratio: 1.46 (95% confidence interval: 1.16 to 1.83)]. In the post ART period, observed disclosure rates were 39% (72 of 184) among those not in HIV care, 65% (82 of 126) among those in pre-ART care, and 85% (64 of 75) among persons on ART (P < 0.001). CONCLUSIONS: Treatment availability and use, especially ART initiation, was associated with increased self-disclosure of HIV diagnosis to partners. ART access may facilitate the prevention of transmission to uninfected partners and linkage to treatment for infected couples. PMID- 26009835 TI - Implementation and Operational Research: Linkage to Care Among Methadone Clients Living With HIV in Dar es Salaam, Tanzania. AB - BACKGROUND: The first methadone maintenance treatment clinic in Tanzania was launched in February 2011 to address an emerging HIV epidemic among people who inject drugs. We conducted a retrospective cohort study to understand factors associated with linkage to HIV care and explore how a methadone maintenance treatment clinic can serve as a platform for integrated HIV care and treatment. METHODS: This study used routine programmatic and clinical data on clients enrolled in methadone at Muhimbili National Hospital from February 2011 to January 2013. Multivariable proportional hazards regression model was used to examine time to initial CD4 count. RESULTS: Final analyses included 148 HIV positive clients, contributing 31.7 person-years. At 30, 60, and 90 days, the probability of CD4 screening was 40% [95% confidence interval (CI): 32% to 48%], 55% (95% CI: 47% to 63%), and 63% (95% CI: 55% to 71%), respectively. Clients receiving high methadone doses (>= 85 mg/d) [adjusted hazard ratio (aHR): 1.68, 95% CI: 1.03 to 2.74] had higher likelihood of CD4 screening than those receiving low doses (<85 mg/d). Clients with primary education or lower (aHR: 1.62, 95% CI: 1.05 to 2.51) and self-reported poor health (aHR: 1.96, 95% CI: 1.09 to 3.51) were also more likely to obtain CD4 counts. Clients with criminal arrest history (aHR: 0.56, 95% CI: 0.37 to 0.85]) were less likely to be linked to care. Among 17 antiretroviral therapy eligible clients (CD4 <= 200), 12 (71%) initiated treatment, of which 7 (41%) initiated within 90 days. CONCLUSIONS: Levels of CD4 screening and antiretroviral therapy initiation were similar to Sub-Saharan programs caring primarily for people who do not inject drugs. Adequate methadone dosing is important in retaining clients to maximize HIV treatment benefits and allow for successful linkage to services. PMID- 26009837 TI - Implementation and Operational Research: Scaling Up the Provision of the PMTCT Services, Using the Linked Response Approach in Cambodia From 2008 to 2012. AB - INTRODUCTION: In Cambodia, the Linked Response (LR) approach for strengthening linkages between HIV and reproductive health services, especially for the prevention of mother-to-child transmission of HIV (PMTCT), was scaled up in 2009. This article describes the LR scale-up and the concomitant evolution of key PMTCT indicators at the national level. METHODS: A descriptive analysis of routine LR, PMTCT programme data, and national laboratory data from 2008 to 2012 was conducted. RESULTS: LR data show that between 2008 and 2012, the number of LR/PMTCT sites increased from 67 to 956 (of 1004) public health facilities to cover 74 (of 77) operational districts. In LR operational districts, the number of pregnant women (PW) tested for HIV increased from 41,800 in 2009 to 269,935 [of whom 375 (0.14%) were newly tested positive for HIV] in 2012; the number of PW living with HIV and exposed infants receiving antiretrovirals increased from 49 and 44 in 2009 to 720 and 551 in 2012, respectively. Concomitantly, national PMTCT programme data showed that the percent of PW tested for HIV increased from 34.4% (117,832 of 342,929 estimated PW) in 2008 to 86.1% (324,996 of 377,340) in 2012. In 2012, 65.3% (862 of 1321) of estimated HIV-positive PW and 72.7% (960 of 1321) of exposed infants received antiretrovirals. By 6-8 weeks postpartum, 7.4% (8 of 108) and 1.5% (6 of 409) of DNA-polymerase chain reaction tested positive in 2008 and in 2012, respectively. CONCLUSIONS: The LR approach provided a model, which catalyzed increased access of PW to HIV testing and treatment, thereby contributing to the scale-up of PMTCT service provision and improved coverage in Cambodia. PMID- 26009836 TI - Implementation and Operational Research: Correlates of Adherence and Treatment Failure Among Kenyan Patients on Long-term Highly Active Antiretroviral Therapy. AB - BACKGROUND: Universal access to highly active antiretroviral therapy (HAART) is still elusive in most developing nations. We asked whether peer support influenced adherence and treatment outcome and if a single viral load (VL) could define treatment failure in a resource-limited setting. METHODS: A multicenter longitudinal and cross-sectional survey of VL, CD4 T cells, and adherence in 546 patients receiving HAART for up to 228 months. VL and CD4 counts were determined using m2000 Abbott RealTime HIV-1 assay and FACS counters, respectively. Adherence was assessed based on pill count and on self-report. RESULTS: Of the patients, 55.8%, 22.2%, and 22% had good, fair, and poor adherence, respectively. Adherence, peer support, and regimen, but not HIV disclosure, age, or gender, independently correlated with VL and durability of treatment in a multivariate analysis (P < 0.001). Treatment failure was 35.9% using sequential VL but ranged between 27% and 35% using alternate single VL cross-sectional definitions. More patients failed stavudine (41.2%) than zidovudine (37.4%) or tenofovir (28.8%, P = 0.043) treatment arms. Peer support correlated positively with adherence (chi(2), P < 0.001), with nonadherence being highest in the stavudine arm. VL before the time of regimen switch was comparable between patients switching and not switching treatment. Moreover, 36% of those switching still failed the second line regimen. CONCLUSION: Weak adherence support and inaccessible VL testing threaten to compromise the success of HAART scale-up in Kenya. To hasten antiretroviral therapy monitoring and decision making, we suggest strengthening patient-focused adherence programs, optimizing and aligning regimen to WHO standards, and a single point-of-care VL testing when multiple tests are unavailable. PMID- 26009838 TI - Implementation and Operational Research: Uptake of Services and Behaviors in the Prevention of Mother-to-Child HIV Transmission Cascade in Zimbabwe. AB - OBJECTIVE: To examine the uptake of services and behaviors in the prevention of mother-to-child HIV transmission (PMTCT) cascade in Zimbabwe and to determine factors associated with MTCT and maternal antiretroviral therapy (ART) or antiretroviral (ARV) prophylaxis. DESIGN: Analysis of cross-sectional data from mother-infant pairs. METHODS: We analyzed baseline data collected in 2012 as part of the impact evaluation of Zimbabwe's Accelerated National PMTCT Program. Using multistage cluster sampling, eligible mother-infant pairs were randomly sampled from the catchment areas of 157 facilities in 5 provinces, tested for HIV infection, and interviewed about PMTCT service utilization. RESULTS: Of 8800 women, 94% attended >= 1 antenatal care visit, 92% knew their HIV serostatus during pregnancy, 77% delivered in a health facility, and 92% attended the 6-8 week postnatal visit. Among 1075 (12%) HIV-infected women, 59% reported ART/ARV prophylaxis and 63% of their HIV-exposed infants received ARV prophylaxis. Among HIV-exposed infants, maternal receipt of ART/ARV prophylaxis was protective against MTCT [adjusted prevalence ratio (PR(a)): 0.41, 95% confidence interval (CI): 0.23 to 0.74]. Factors associated with receipt of maternal ART/ARV prophylaxis included >= 4 antenatal care visits (PR(a): 1.18, 95% CI: 1.01 to 1.38), institutional delivery (PR(a): 1.31, 95% CI: 1.13 to 1.52), and disclosure of serostatus (PRa: 1.30, 95% CI: 1.12 to 1.49). CONCLUSIONS: These data from women in the community indicate gaps in the PMTCT cascade before the accelerated program, which may have been missed by examination of health facility data alone. These gaps were especially noteworthy for services targeted specifically to HIV infected women and their infants, such as maternal and infant ART/ARV prophylaxis. PMID- 26009839 TI - Screening of anthocyanins in single red grapes using a non-destructive method based on the near infrared hyperspectral technology and chemometrics. AB - BACKGROUND: Anthocyanins are the main compounds responsible for the colour of red wines and therefore it may be important to evaluate the content of the aforesaid secondary metabolites during grape ripening due to the crucial importance to determine wine colour. Nowadays, there is a growing demand of rapid and non destructive analytical tools for analysing grapes, such as the emerging hyperspectral analysis. RESULTS: The hyperspectral images of intact grapes (Vitis vinifera L. cv. Tempranillo, Graciano, Garnacha and Mazuelo red grape from vineyards located in the D.O.Ca. Rioja at two different developmental stages) were recorded using a near infrared hyperspectral imaging device (900-1700 nm). Reference values of anthocyanins were obtained by HPLC-DAD. Calibrations were performed by modified partial least squares regression and present a good potential (coefficient of determination of 0.72 and standard error of cross validation values of 0.78 and 0.70 mg per grape for total and non-acylated anthocyanins respectively). CONCLUSION: The procedure reported here presents a good potential for a fast and reasonably inexpensive screening of these compounds in intact single berries. Moreover, the heterogeneity of anthocyanins within the same ripeness stage could be evaluated using this non-detructive tool. PMID- 26009840 TI - Cetacean response to summer maritime traffic in the Western Mediterranean Sea. AB - Maritime traffic is one of many anthropogenic pressures threatening the marine environment. This study was specifically designed to investigate the relationship between vessels presence and cetacean sightings in the high sea areas of the Western Mediterranean Sea region. We recorded and compared the total number of vessels in the presence and absence of cetacean sightings using data gathered during the summer season (2009-2013) along six fixed transects repeatedly surveyed. In locations with cetacean sightings (N = 2667), nautical traffic was significantly lower, by 20%, compared to random locations where no sightings occurred (N = 1226): all cetacean species, except bottlenose dolphin, were generally observed in locations with lower vessel abundance. In different areas the species showed variable results likely influenced by a combination of biological and local environmental factors. The approach of this research helped create, for the first time, a wide vision of the different responses of animals towards a common pressure. PMID- 26009841 TI - Colony-specific investigations reveal highly variable responses among individual corals to ocean acidification and warming. AB - As anthropogenic climate change is an ongoing concern, scientific investigations on its impacts on coral reefs are increasing. Although impacts of combined ocean acidification (OA) and temperature stress (T) on reef-building scleractinian corals have been studied at the genus, species and population levels, there are little data available on how individual corals respond to combined OA and anomalous temperatures. In this study, we exposed individual colonies of Acropora digitifera, Montipora digitata and Porites cylindrica to four pCO2-temperature treatments including 400 MUatm-28 degrees C, 400 MUatm-31 degrees C, 1000 MUatm 28 degrees C and 1000 MUatm-31 degrees C for 26 days. Physiological parameters including calcification, protein content, maximum photosynthetic efficiency, Symbiodinium density, and chlorophyll content along with Symbiodinium type of each colony were examined. Along with intercolonial responses, responses of individual colonies versus pooled data to the treatments were investigated. The main results were: 1) responses to either OA or T or their combination were different between individual colonies when considering physiological functions; 2) tolerance to either OA or T was not synonymous with tolerance to the other parameter; 3) tolerance to both OA and T did not necessarily lead to tolerance of OA and T combined (OAT) at the same time; 4) OAT had negative, positive or no impacts on physiological functions of coral colonies; and 5) pooled data were not representative of responses of all individual colonies. Indeed, the pooled data obscured actual responses of individual colonies or presented a response that was not observed in any individual. From the results of this study we recommend improving experimental designs of studies investigating physiological responses of corals to climate change by complementing them with colony-specific examinations. PMID- 26009842 TI - Platelet-rich plasma increases proliferation of tendon cells by modulating Stat3 and p27 to up-regulate expression of cyclins and cyclin-dependent kinases. AB - OBJECTIVES: To investigate effects of platelet-rich plasma on tendon cell proliferation and the underlying molecular mechanisms. MATERIALS AND METHODS: Platelet-rich plasma was prepared manually by two-step centrifugation. Proliferation was evaluated in cultured rat tendon cells by the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Cell cycle progression was assessed by flow cytometry. Messenger RNA expression of proliferating cell nuclear antigen (PCNA), cyclin E1, A2 and B1, and cyclin dependent kinases (Cdks) 1 and 2 was assessed by real-time polymerase chain reaction. Protein expression of the above cyclins and Cdks and of signal transducer and activator of transcription (Stat) 3 and p27 was evaluated by western blotting. RESULTS: Platelet-rich plasma used in the present study had concentrations of platelets, TGF-beta1 and PDGF over 3-fold higher than normal whole blood. Platelet-rich plasma enhanced tendon cell proliferation (P = 0.008) by promoting G1 /S phase transition in the cell cycle, and increased expression of PCNA, cyclin E1, A2 and B1, Cdks1 and 2, and phosphorylated Stat3, while inhibiting p27 expression. CONCLUSIONS: Platelet-rich plasma contains high concentrations of TGF-beta1 and PDGF that increase tendon cell proliferation by modulating Stat3/p27(Kip1), which enhances expression of cyclin-Cdk complexes that promote cell cycle progression. These results provide molecular evidence for positive effects of platelet-rich plasma on tendon cell proliferation, which can be useful in clinical applications of tendon injury. PMID- 26009843 TI - Design and implementation of a combined influenza immunization and tuberculosis screening campaign with simulation modelling. AB - RATIONALE, AIMS AND OBJECTIVES: Design and implement a concurrent campaign of influenza immunization and tuberculosis (TB) screening for health care workers (HCWs) that can reduce the number of clinic visits for each HCW. METHOD: A discrete-event simulation model was developed to support issues of resource allocation decisions in planning and operations phases. RESULTS: The campaign was compressed to100 days in 2010 and further compressed to 75 days in 2012 and 2013. With more than 5000 HCW arrivals in 2011, 2012 and 2013, the 14-day goal of TB results was achieved for each year and reduced to about 4 days in 2012 and 2013. CONCLUSION: Implementing a concurrent campaign allows less number of visiting clinics and the compressing of campaign length allows earlier immunization. The support of simulation modelling can provide useful evaluations of different configurations. PMID- 26009844 TI - Domain position prediction based on sequence information by using fuzzy mean operator. AB - The prediction of protein domain region is an advantageous process on the study of protein structure and function. In this study, we proposed a new method, which is composed of fuzzy mean operator and region division, to predict the particular positions of domains in a target protein based on its sequence. The whole sequence is aligned and scored by using fuzzy mean operator, and the final determination of domain region position is realized by region division. A published benchmark is used for the comparison with previous researches. In addition, we generate two extra datasets to examine the stability of this method. Finally, the prediction accuracy of independent test dataset achieved by our method was up to 84.13%. We wish that this method could be useful for related researches. PMID- 26009845 TI - How do I figure out what I want to do if I don't know who I am supposed to be? PMID- 26009846 TI - Additional suggestions for facilitating professional identity formation. PMID- 26009847 TI - In reply to Weissman. PMID- 26009848 TI - Towards robust validity evidence for learning environment assessment tools. PMID- 26009849 TI - Towards robust validity evidence for learning environment assessment tools. PMID- 26009850 TI - In reply to Roff and McAleer and to Loo and Byrne. PMID- 26009851 TI - How do U.S. and Canadian medical schools teach about the role of physicians in the Holocaust? PMID- 26009852 TI - All the small things. PMID- 26009853 TI - Keeping my humanity. PMID- 26009854 TI - Artists' statement: inner light. PMID- 26009856 TI - Medicine and the arts. "The needle and the damage done" by Neil Young. Commentary. PMID- 26009857 TI - Prostate contours delineation using interactive directional active contours model and parametric shape prior model. AB - Prostate contours delineation on Magnetic Resonance (MR) images is a challenging and important task in medical imaging with applications of guiding biopsy, surgery and therapy. While a fully automated method is highly desired for this application, it can be a very difficult task due to the structure and surrounding tissues of the prostate gland. Traditional active contours-based delineation algorithms are typically quite successful for piecewise constant images. Nevertheless, when MR images have diffuse edges or multiple similar objects (e.g. bladder close to prostate) within close proximity, such approaches have proven to be unsuccessful. In order to mitigate these problems, we proposed a new framework for bi-stage contours delineation algorithm based on directional active contours (DAC) incorporating prior knowledge of the prostate shape. We first explicitly addressed the prostate contour delineation problem based on fast globally DAC that incorporates both statistical and parametric shape prior model. In doing so, we were able to exploit the global aspects of contour delineation problem by incorporating a user feedback in contours delineation process where it is shown that only a small amount of user input can sometimes resolve ambiguous scenarios raised by DAC. In addition, once the prostate contours have been delineated, a cost functional is designed to incorporate both user feedback interaction and the parametric shape prior model. Using data from publicly available prostate MR datasets, which includes several challenging clinical datasets, we highlighted the effectiveness and the capability of the proposed algorithm. Besides, the algorithm has been compared with several state-of-the-art methods. PMID- 26009858 TI - Editorial Comment from Dr Mearini to Postoperative prostate-specific antigen monitoring interval for radical prostatectomy patients with low recurrence risk. PMID- 26009860 TI - Regenerative nano-hybrid coating tailored for autonomous corrosion protection. AB - A novel bilayer coating system for autonomous corrosion-triggered self-healing is demonstrated. The storage of the encapsulated monomer and the catalyst is separated in two different layers. The encapsulated catalyst is stored inside a metallic coating, which ensures its activity even for an extended exposure time. The release from the capsules is triggered by corrosion and the correlated pH increase. PMID- 26009859 TI - Association Between Hospice Use and Depressive Symptoms in Surviving Spouses. AB - IMPORTANCE: Family caregivers of individuals with serious illness are at risk for depressive symptoms and depression. Hospice includes the provision of support services for family caregivers, yet evidence is limited regarding the effect of hospice use on depressive symptoms among surviving caregivers. OBJECTIVE: To determine the association between hospice use and depressive symptoms in surviving spouses. DESIGN, SETTING, AND PARTICIPANTS: We linked data from the Health and Retirement Study, a nationally representative longitudinal survey of community-dwelling US adults 50 years or older, to Medicare claims. Participants included a propensity score-matched sample of 1016 Health and Retirement Study decedents with at least 1 serious illness and their surviving spouses interviewed between August 2002 and May 2011. We compared the spouses of individuals enrolled in hospice with the spouses of individuals who did not use hospice, performing our analysis between January 30, 2014, and January 16, 2015. EXPOSURES: Hospice enrollment for at least 3 days in the year before death. MAIN OUTCOMES AND MEASURES: Spousal depressive symptom scores measured 0 to 2 years after death with the Center for Epidemiologic Studies Depression Scale, which is scored from 0 (no symptoms) to 8 (severe symptoms). RESULTS: Of the 1016 decedents in the matched sample, 305 patients (30.0%) used hospice services for 3 or more days in the year before death. Of the 1016 spouses, 51.9% had more depressive symptoms over time (mean [SD] change, 2.56 [1.65]), with no significant difference related to hospice use. A minority (28.2%) of spouses of hospice users had improved Center for Epidemiologic Studies Depression Scale scores compared with 21.7% of spouses of decedents who did not use hospice, although the difference was not statistically significant (P = .06). Among the 662 spouses who were the primary caregivers, 27.3% of spouses of hospice users had improved Center for Epidemiologic Studies Depression Scale scores compared with 20.7% of spouses of decedents who did not use hospice; the difference was not statistically significant (P = .10). In multivariate analysis, the odds ratio for the association of hospice enrollment with improved depressive symptoms after the spouse's death was 1.63 (95% CI, 1.00-2.65). CONCLUSIONS AND RELEVANCE: After bereavement, depression symptoms increased overall for surviving spouses regardless of hospice use. A modest reduction in depressive symptoms was more likely among spouses of hospice users than among spouses of nonhospice users. PMID- 26009861 TI - Injection therapies for Achilles tendinopathy. AB - BACKGROUND: Achilles tendinopathy is a common condition, often with significant functional consequences. As a wide range of injection treatments are available, a review of randomised trials evaluating injection therapies to help inform treatment decisions is warranted. OBJECTIVES: To assess the effects (benefits and harms) of injection therapies for people with Achilles tendinopathy. SEARCH METHODS: We searched the following databases up to 20 April 2015: the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, CINAHL and SPORTDiscus. We also searched trial registers (29 May 2014) and reference lists of articles to identify additional studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials evaluating injection therapies in adults with an investigator-reported diagnosis of Achilles tendinopathy. We accepted comparison arms of placebo (sham) or no injection control, or other active treatment (such as physiotherapy, pharmaceuticals or surgery). Our primary outcomes were function, using measures such as the VISA-A (Victorian Institute of Sport Assessment-Achilles questionnaire), and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included studies. We assessed treatment effects using mean differences (MDs) and 95% confidence intervals (CIs) for continuous variables and risk ratios (RRs) and 95% CIs for dichotomous variables. For follow-up data, we defined short-term as up to six weeks, medium-term as up to three months and longer-term as data beyond three months. We performed meta-analysis where appropriate. MAIN RESULTS: We included 18 studies (732 participants). Seven trials exclusively studied athletic populations. The mean ages of the participants in the individual trials ranged from 20 years to 50 years. Fifteen trials compared an injection therapy with a placebo injection or no injection control, four trials compared an injection therapy with active treatment, and one compared two different concentrations of the same injection. Thus no trials compared different injection therapies. Two studies had three trial arms and we included them twice in two different categories. Within these categories, we further subdivided injection therapies by mode of action (injury-causing versus direct repair agents).The risk of bias was unclear (due to poor reporting) or high in six trials published between 1987 and 1994. Improved methodology and reporting for the subsequent trials published between 2004 and 2013 meant that these were at less risk of bias.Given the very low quality evidence available from each of four small trials comparing different combinations of injection therapy versus active treatment and the single trial comparing two doses of one injection therapy, only the results of the first comparison (injection therapy versus control) are presented.There is low quality evidence of a lack of significant or clinically important differences in VISA-A scores (0 to 100: best function) between injection therapy and control groups at six weeks (MD 0.79, 95% CI -4.56 to 6.14; 200 participants, five trials), three months (MD -0.94, 95% CI -6.34 to 4.46; 189 participants, five trials) or between six and 12 months (MD 0.14, 95% CI -6.54 to 6.82; 132 participants, three trials). Very low quality evidence from 13 trials showed little difference between the two groups in adverse events (14/243 versus 12/206; RR 0.97, 95% CI 0.50 to 1.89), most of which were minor and short-lasting. The only major adverse event in the injection therapy group was an Achilles tendon rupture, which happened in a trial testing corticosteroid injections. There was very low quality evidence in favour of the injection therapy group in short-term (under three months) pain (219 participants, seven trials) and in the return to sports (335 participants, seven trials). There was very low quality evidence indicating little difference between groups in patient satisfaction with treatment (152 participants, four trials). There was insufficient evidence to conclude on subgroup differences based on mode of action given that only two trials tested injury-causing agents and the clear heterogeneity of the other 13 trials, which tested seven different therapies that act directly on the repair pathway. AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised controlled trials to draw conclusions on the use, or to support the routine use, of injection therapies for treating Achilles tendinopathy. This review has highlighted a need for definitive research in the area of injection therapies for Achilles tendinopathy, including in older non-athletic populations. This review has shown that there is a consensus in the literature that placebo-controlled trials are considered the most appropriate trial design. PMID- 26009864 TI - Risk of renal failure with the non-vitamin K antagonist oral anticoagulants: systematic review and meta-analysis. AB - PURPOSE: Vitamin K antagonists (VKA)-related nephropathy is a novel entity characterized by acute kidney injury related to International Normalized Ratio supratherapeutic levels. Non-vitamin K antagonists oral anticoagulants (NOACs) have a predictable dose-response relationship and an improved safety profile. We hypothesized that these drugs do not have an increased risk of incident renal failure, which may be detrimental for the use of NOACs. METHODS: Systematic review and meta-analysis of phase III randomized controlled trials (RCTs). Trials were searched through Medline, Cochrane Library and public assessment reports in August 2014. Primary outcome was renal failure. NOACs were evaluated against any comparator. Random-effects meta-analysis was performed by default, and pooled estimates were expressed as Risk Ratio (RR) and 95%CI. Heterogeneity was evaluated with I(2) test. RESULTS: Ten RCTs fulfilled inclusion criteria (one apixaban RCT, three dabigatran RCTs, and six rivaroxaban RCTs), enrolling 75 100 patients. Overall NOACs did not increase the risk of renal failure with an RR 0.96, 95%CI 0.88-1.05 compared with VKA or Low-molecular weight heparin (LMWH), without significant statistical heterogeneity (I(2) = 3.5%). Compared with VKA, NOACs did not increase the risk of renal failure (RR 0.96, 95%CI 0.87-1.07; I(2) = 17.8%; six RCTs). Rivaroxaban did not show differences in the incidence of renal failure compared with LMWH (RR 1.20, 95%CI 0.37-3.94; four trials), but there was an increased risk of creatinine elevation RR 1.25, 95%CI 1.08-1.45; I(2) = 0%. CONCLUSIONS: NOACs had a similar risk of renal failure compared with VKA/LMWH in phase III RCTs. Post-marketing surveillance should be warranted. PMID- 26009865 TI - Length of Stay at Inpatient Rehabilitation Facility and Stroke Patient Outcomes. AB - PURPOSE: To examine the association of inpatient rehabilitation facility (IRF) length of stay (LOS) with stroke patient outcomes. DESIGN: A secondary data analysis of the Uniform Data System for Medical Rehabilitation database. METHODS: Stroke patients discharged from IRFs in the United States between 2009 and 2011 were identified and divided into mild (n = 639), moderate (n = 2,065), and severely (n = 2,077) impaired groups. Study outcomes included cognition and motor functional gains measured by the Functional Independence Measure (FIM) instrument and discharge to the community. FINDINGS: The average LOS was 8.9, 13.9, and 22.2 days for mild, moderate, and severely impaired stroke patients, respectively. After controlling for FIM admission and other important covariates, a longer LOS was associated with a modest increase in cognition gain (beta = 0.038, p = .0045) for the moderately impaired patients, and a modest increase in cognition (beta = 0.13, p < .0001) and motor gains (beta = 0.25, p < .0001) as well as a tendency for discharge to the community (OR = 1.01, 95% CI = 1.00-1.02) among the severely impaired patients. However, a longer LOS showed a negative association with functional gains among the mildly impaired patients as well as discharge to community for both mild and moderately impaired patients. CONCLUSION: The association of IRF LOS and patient outcomes varied by stroke impairment severity, positively for more severely impaired patients and negatively for mildly impaired patients. CLINICAL RELEVANCE: The study provides evidence for the care of stroke patients at the IRF setting. PMID- 26009866 TI - AC electric field for rapid assembly of nanostructured polyaniline onto microsized gap for sensor devices. AB - Interconnected network of nanostructured polyaniline (PANI) is giving strong potential for enhancing device performances than bulk PANI counterparts. For nanostructured device processing, the main challenge is to get prototypes on large area by requiring precision, low cost and high rate assembly. Among processes meeting these requests, the alternate current electric fields are often used for nanostructure assembling. For the first time, we show the assembly of nanostructured PANI onto large electrode gaps (30-60 MUm width) by applying alternate current electric fields, at low frequencies, to PANI particles dispersed in acetonitrile (ACN). An important advantage is the short assembly time, limited to 5-10 s, although electrode gaps are microsized. That encouraging result is due to a combination of forces, such as dielectrophoresis (DEP), induced-charge electrokinetic (ICEK) flow and alternate current electroosmotic (ACEO) flow, which speed up the assembly process when low frequencies and large electrode gaps are used. The main achievement of the present study is the development of ammonia sensors created by direct assembling of nanostructured PANI onto electrodes. Sensors exhibit high sensitivity to low gas concentrations as well as excellent reversibility at room temperature, even after storage in air. PMID- 26009868 TI - The Integration of Family-Based Treatment and Dialectical Behavior Therapy for Adolescent Bulimia Nervosa: Philosophical and Practical Considerations. AB - Dialectical behavior therapy (DBT) and family-based treatment (FBT) are two evidence-based interventions that have been applied in the treatment of bulimia nervosa (BN) in adolescents. While DBT focuses on providing skills for coping with emotion dysregulation that often co-occurs with BN, FBT targets the normalization of eating patterns. The purpose of the current article is to introduce an integration of both treatments to provide a more comprehensive approach that targets the full scope of the disorder. We provide a review of the conceptual similarities and differences between FBT-BN and DBT along with strategies to guide a blended treatment approach. Given the strengths and limitations of either independent treatment, DBT and FBT-BN complement one another and together can address the range of symptoms and behaviors typically seen in adolescent BN. PMID- 26009867 TI - "Sub is a weird drug:" A web-based study of lay attitudes about use of buprenorphine to self-treat opioid withdrawal symptoms. AB - BACKGROUND: Illicit use of buprenorphine has increased in the U.S., but our understanding of its use remains limited. This study aims to explore Web-forum discussions about the use of buprenorphine to self-treat opioid withdrawal symptoms. METHODS: PREDOSE, a novel Semantic Web platform, was used to extract relevant posts from a Web-forum that allows free discussions on illicit drugs. First, we extract information about the total number of buprenorphine-related posts per year between 2005 and 2013. Second, PREDOSE was used to identify all posts that potentially contained discussions about buprenorphine and opioid withdrawal. A total number of 1,217 posts that contained these terms were extracted and entered into NVivo data base. A random sample of 404 (33%) posts was selected and content analyzed. RESULTS: Buprenorphine-related posts increased over time, peaking in 2011. The posts were about equally divided between those that expressed positive and negative views about the effectiveness of buprenorphine in relieving withdrawal symptoms. Web-forum participants emphasized that buprenorphine's effectiveness may become compromised because of the "size of a person habit," and/or when users repeatedly switch back and forth between buprenorphine and other illicit opioids. Most posts reported use of significantly lower amounts of buprenorphine (<=2 mg) than doses used in standard treatment. Concomitant use of other psychoactive substances was also commonly reported, which may present significant health risks. CONCLUSIONS: Our findings highlight the usefulness of Web-based data in drug abuse research and add new information about lay beliefs about buprenorphine that may help inform prevention and policy measures. PMID- 26009869 TI - Esophageal cancer-derived microvesicles induce regulatory B cells. AB - The role of B cells in the generation of cancer-immune tolerance is unclear. This study aims to investigate the role of cancer-derived microvesicles (Mvcs) in the generation of transforming growth factor (TGF)-beta(+) B cells. In this study, esophageal cancer (Eca) cells were isolated from surgically removed cancer tissue. Mvcs were purified from the culture supernatant and characterized by Western blotting. The immune suppression assay was carried out with a cell culture model and flow cytometry. The results showed that Eca-derived Mvcs were LAMP1 positive and carried MMP9. Exposure to the Mvcs induces naive B cells to differentiate into TGF-beta-producing regulatory B cells; the latter show immune suppressor functions on CD8(+) T-cell proliferation. In conclusion, Eca-derived Mvc can induce TGF-beta(+) B cells; the latter suppress CD8(+) T-cell activities. The MMP9-laden Mvcs may be a new therapeutic target in the treatment of Eca. PMID- 26009870 TI - Glycyrrhizic acid (GA) inhibits reactive oxygen Species mediated photodamage by blocking ER stress and MAPK pathway in UV-B irradiated human skin fibroblasts. AB - BACKGROUND: Previously we have reported that generation of reactive oxygen species is the prime event responsible for calcium mediated activation of PERK eIF2alpha-CHOP pathway and apoptosis in UV-B irradiated human skin fibroblasts (Hs68). We have also reported that glycyrrhizic acid (GA) mediates potent photoprotective activity against UV-B - irradiation-induced photodamage in human skin fibroblast. OBJECTIVE: In the present study, we aimed to investigate the role of GA in preventing oxidative stress mediated unfolded protein response (UPR) and mitogen activated protein kinases (MAPK) pathway. METHODS: Human skin fibroblast (Hs68) cells were exposed to UV-B radiations in lab conditions. Different parameters of UVB induced cellular and molecular changes were analysed using western-blotting, microscopy and flow cytometry. RESULTS: Our results show that GA has strong photoprotective action against UV-B induced cellular damage. It was observed that: (a) Oxidative disturbances and intracellular Ca(2+) imbalance induced by UV-B irradiation was significantly restored by GA treatment; (b) activation of PERK-eIF2alpha-CHOP and MAPK pathway induced by UV-B was significantly blocked by GA; (c) Loss of mitochondrial membrane potential and apoptosis induced by UV-B were reduced by GA treatment. CONCLUSION: Based on the above findings we conclude GA has a highly significant ROS quenching activity, thereby blocking the cascade of events including release of calcium from ER and subsequent ER stress, MAPK pathway and cellular demise. GA offers highly potent anti photodamage effect and can be exploited for cosmetic or therapeutic purposes. PMID- 26009871 TI - The influence of physical strain on esophageal motility in healthy volunteers studied with gas-perfusion manometry. AB - BACKGROUND: The influence of physical strain on the esophageal motility has already been examined in a number of studies. It was found that high physical strain compromises the sufficient contractility of the esophagus. However, it needs more examinations to verify these findings. METHODS: To validate these results healthy volunteers were examined using gas-perfusion manometrie. Bicycle ergometry was performed to generate an exactly defined physical exercise. After a pilot study, the changing of the contraction amplitude was determined as the main variable to evaluate the esophageal motility, and the sample size was calculated. Eight subjects without esophageal diseases or symptoms were examined by simultaneous gas-perfusion esophageal manometry and bicycle ergometry. KEY RESULTS: The results showed that high physical strain during bicycle ergometry can induce a significant decrease of the contraction amplitude (alpha = 5%, beta = 10%). The 95% confidence interval of the quotient of contraction amplitude at rest and under physical strain is (1.074; 1.576). This effect is more pronounced in liquid acts of swallowing than in dry and is also more obvious at the middle measuring point (7.8 cm above the lower esophageal sphincter) than at the distal and proximal point (2.8 and 12.8 cm). Furthermore, a decreasing tendency of the contraction duration could be found. CONCLUSIONS & INTERFERENCES: Gas-perfusion manometry is an inexpensive examination method, which enables the evaluation of the esophageal motility in moving test subjects under conditions of physical strain. It could be proved that physical strain negatively influences the esophageal motility by a decrease of the contraction amplitude. PMID- 26009872 TI - The Role of Intentionally Introduced Defects on Electrode Materials for Alkali Ion Batteries. AB - Simple defect modification is a powerful means to improve material intercalation capabilities. It has received considerable interest lately as it can directly alter both the chemical and structural characteristics; techniques of note include cationic disordering, amorphization, doping, partial cation reduction, and manipulation of intrinsic defects. Defects can reduce the stress and the electrostatic repulsion between adjacent oxygen layers, which can directly alter the migration energy and diffusion barriers the alkali ion must overcome during intercalation. Complementary to experimental observations, theoretical predictions are paramount to developing a detailed understanding of material defect chemistry. This focus review aims to demonstrate that the optimized design of stable intercalation compounds could lead to substantial improvements in energy-storage applications by overcoming intrinsic limitations. PMID- 26009873 TI - HX-MS2 for high performance conformational analysis of complex protein states. AB - Water-mediated hydrogen exchange (HX) processes involving the protein main chain are sensitive to structural dynamics and molecular interactions. Measuring deuterium uptake in amide bonds provides information on conformational states, structural transitions and binding events. Increasingly, deuterium levels are measured by mass spectrometry (MS) from proteolytically generated peptide fragments of large molecular systems. However, this bottom-up method has limited spectral capacity and requires a burdensome manual validation exercise, both of which restrict analysis of protein systems to generally less than 150 kDa. In this study, we present a bottom-up HX-MS(2) method that improves peptide identification rates, localizes high-quality HX data and simplifies validation. The method combines a new peptide scoring algorithm (WUF, weighted unique fragment) with data-independent acquisition of peptide fragmentation data. Scoring incorporates the validation process and emphasizes identification accuracy. The HX-MS(2) method is illustrated using data from a conformational analysis of microtubules treated with dimeric kinesin MCAK. When compared to a conventional Mascot-driven HX-MS method, HX-MS(2) produces two-fold higher alpha/beta-tubulin sequence depth at a peptide utilization rate of 74%. A Mascot approach delivers a utilization rate of 44%. The WUF score can be constrained by false utilization rate (FUR) calculations to return utilization values exceeding 90% without serious data loss, indicating that automated validation should be possible. The HX-MS(2) data confirm that N-terminal MCAK domains anchor kinesin force generation in kinesin-mediated depolymerization, while the C-terminal tails regulate MCAK-tubulin interactions. PMID- 26009874 TI - Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. AB - Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1 dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC. PMID- 26009875 TI - Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP). AB - Hypoxic stress drives cancer progression by causing a transcriptional reprogramming. Recently, KIAA1199 was discovered to be a cell-migration inducing protein (renamed CEMIP) that is upregulated in human cancers. However, the mechanism of induction of CEMIP in cancer was hitherto unknown. Here we demonstrate that hypoxia induces CEMIP expression leading to enhanced cell migration. Immunohistochemistry of human colon cancer tissues revealed that CEMIP is upregulated in cancer cells located at the invasive front or in the submucosa. CEMIP localization inversely correlated with E-cadherin expression, which is characteristic of the epithelial-to-mesenchymal transition. Mechanistically, hypoxia-inducible-factor-2alpha (HIF-2alpha), but not HIF-1alpha binds directly to the hypoxia response element within the CEMIP promoter region resulting in increased CEMIP expression. Functional characterization reveals that CEMIP is a downstream effector of HIF-2alpha-mediated cell migration. Expression of CEMIP was demonstrated to negatively correlate with the expression of Jarid1A, a histone demethylase that removes methyl groups from H3K4me3 (an activation marker for transcription), resulting in altered gene repression. Low oxygen tension inhibits the function of Jarid1A, leading to increased presence of H3K4me3 within the CEMIP promoter. These results provide insight into the upregulation of CEMIP within cancer and can lead to novel treatment strategies targeting this cancer cell migration-promoting gene. PMID- 26009876 TI - Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression. AB - Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC. PMID- 26009877 TI - Quality control of processed Crataegi Fructus and its medicinal parts by ultra high performance liquid chromatography with electrospray ionization tandem mass spectrometry. AB - Crataegi Fructus, an edible food, has been used as a traditional medicine to treat diseases for many years. There is substantial evidence that multiple constituents are responsible for the beneficial effects of Crataegi Fructus. To effectively control the quality of this herbal medicine, we developed an ultra high performance liquid chromatography with electrospray ionization tandem mass spectrometry protocol to simultaneously quantify ten compounds (chlorogenic acid, procyanidin B2, l-epicatechin, glucosylvitexin, vitexin-2-O-rhamnoside, vitexin, rutin, hyperoside, isoquercitrin, and quercetin) in Crataegi Fructus. Multiple reaction monitoring was used for the quantification in the negative mode for 8 min. This proposed method is simple, reliable, sensitive, and specific. Further, the quantification parameters, including linearity, limit of detection, limit of quantification, precision, reproducibility, stability, and accuracy were optimized. The quality of the processed samples of Crataegi Fructus was evaluated using this method. Additionally, the method was successfully used to distinguish the medicinal components, including peel, kernel, and flesh. The data described in this study offer valuable information for the quality control and proper use of Crataegi Fructus. PMID- 26009878 TI - Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide. AB - Muscle aging is associated with changes in myeloid cell phenotype that may influence age-related changes in muscle structure. We tested whether preventing age-related reductions in muscle neuronal nitric oxide synthase (nNOS) would obviate age-related changes in myeloid cells in muscle. Our findings show that muscle aging is associated with elevations of anti-inflammatory M2a macrophages that can increase muscle fibrosis. Expression of a muscle-specific nNOS transgene in mice prevented age-related increases in M2a macrophages. Transgene expression also reduced expression of collagens and decreased muscle fibrosis. The nNOS transgene prevented age-related increases in arginase-1 but did not influence TGFbeta expression, indicating that the transgene may prevent age-related muscle fibrosis by inhibiting the arginase-dependent profibrotic pathway. Although aged satellite cells or fibro-adipogenic precursor (FAPs) cells also promote fibrosis, transgene expression had no effect on the expression of key signaling molecules that regulate fibrogenic activity of those cells. Finally, we tested whether increases in M2a macrophages and the associated increase in fibrosis were attributable to aging of myeloid lineage cells. Young bone marrow cells (BMCs) were transplanted into young or old mice, and muscles were collected 8 months later. Muscles of young mice receiving young BMCs showed no effect on M2a macrophage number or collagen accumulation compared to age-matched, nontransplanted controls. However, muscles of old mice receiving young BMCs showed fewer M2a macrophages and less accumulation of collagen. Thus, the age related increase in M2a macrophages in aging muscle and the associated muscle fibrosis are determined in part by the age of bone marrow cells. PMID- 26009879 TI - Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer. AB - The deletion of 16q23-q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow-up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p < 0.0001 each) and positive surgical margin (p = 0.0004). 16q Deletion was more frequent in ERG fusion-positive (27%) as compared to ERG fusion-negative cancers (16%, p < 0.0001), and was linked to other ERG-associated deletions including phosphatase and tensin homolog (PTEN) (p < 0.0001) and 3p13 (p = 0.0303). In univariate analysis, the deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p < 0.0001). Tumors with codeletions of 16q and PTEN had a worse prognosis (p = 0.0199) than those with PTEN or the deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low- and intermediated grade prostate cancers. PMID- 26009880 TI - The challenges of water governance in Ho Chi Minh City. AB - Population growth, urbanization, pollution, and climate change pose urgent water challenges in cities. In this study, the sustainability of integrated water resources management in Ho Chi Minh City (HCMC) was evaluated using the City Blueprint approach. The City Blueprint is a set of 24 dedicated indicators divided over 8 categories (i.e., water security, water quality, drinking water, sanitation, infrastructure, climate robustness, biodiversity and attractiveness, and governance including public participation). The analysis showed that the rapid increase of water use for urban, industrial, and agricultural activities in HCMC has resulted in depletion of groundwater and severe pollution of both groundwater and surface water. Surface water quality, groundwater quality, biodiversity, and the sanitation of domestic and industrial wastewater are matters that need serious improvement. Current and future water supply in HCMC is at risk. HCMC can cope with it, but the 7 governance gaps as described by the Organisation for Economic Co-operation and Development (OECD) are major obstacles for HCMC. Rainwater harvesting, pollution reduction, as well as wastewater reuse are among the practical options. Wastewater reuse could lower the water stress index to 10%. The window to do this is narrow and rapidly closing as a result of the unprecedented urbanization and economic growth of this region. PMID- 26009881 TI - A water-soluble fluorescent pH probe based on perylene dyes and its application to cell imaging. AB - A fluorescent pH probe, N,N'-bi( l-phenylalanine amine)-perylene-3,4;9,10 dicarboxylic diimide (PDCDA) was synthesized and used for pH sensing in living cells. A significant fluorescence intensity change was observed over a pH range from 7.0 to 4.0. Electrostatic potential maps (MEP) suggested that the electronic repulsion between PDCDAs was increased by the high negative electrostatic potential which resulted in a high water solubility of PDCDA. PDCDA was successfully applied as a high-performance fluorochrome for living HeLa cell imaging. The results demonstrate that the probe PDCDA is a good candidate for monitoring pH fluctuations in living cells with good water solubility, low cytotoxicity, high fluorescence quantum yield and photostability. PMID- 26009882 TI - Solving the Puzzle of Recruitment and Retention-Strategies for Building a Robust Clinical and Translational Research Workforce. AB - This paper is the first in a five-part series on the clinical and translational science educational pipeline and presents strategies to support recruitment and retention to create diverse pathways into clinical and translational research (CTR). The strategies address multiple levels or contexts of persistence decisions and include: (1) creating a seamless pipeline by forming strategic partnerships to achieve continuity of support for scholars and collective impact; (2) providing meaningful research opportunities to support identity formation as a scientist and sustain motivation to pursue and persist in CTR careers; (3) fostering an environment for effective mentorship and peer support to promote academic and social integration; (4) advocating for institutional policies to alleviate environmental pull factors; and, (5) supporting program evaluation particularly, the examination of longitudinal outcomes. By combining institutional policies that promote a culture and climate for diversity with quality, evidence-based programs and integrated networks of support, we can create the environment necessary for diverse scholars to progress successfully and efficiently through the pipeline to achieve National Institutes of Health's vision of a robust CTR workforce. PMID- 26009884 TI - Estimating Urban Traffic Patterns through Probabilistic Interconnectivity of Road Network Junctions. AB - The emergence of large, fine-grained mobility datasets offers significant opportunities for the development and application of new methodologies for transportation analysis. In this paper, the link between routing behaviour and traffic patterns in urban areas is examined, introducing a method to derive estimates of traffic patterns from a large collection of fine-grained routing data. Using this dataset, the interconnectivity between road network junctions is extracted in the form of a Markov chain. This representation encodes the probability of the successive usage of adjacent road junctions, encoding routes as flows between decision points rather than flows along road segments. This network of functional interactions is then integrated within a modified Markov chain Monte Carlo (MCMC) framework, adapted for the estimation of urban traffic patterns. As part of this approach, the data-derived links between major junctions influence the movement of directed random walks executed across the network to model origin-destination journeys. The simulation process yields estimates of traffic distribution across the road network. The paper presents an implementation of the modified MCMC approach for London, United Kingdom, building an MCMC model based on a dataset of nearly 700000 minicab routes. Validation of the approach clarifies how each element of the MCMC framework contributes to junction prediction performance, and finds promising results in relation to the estimation of junction choice and minicab traffic distribution. The paper concludes by summarising the potential for the development and extension of this approach to the wider urban modelling domain. PMID- 26009883 TI - Examination of the Relationship between Oral Health and Arterial Sclerosis without Genetic Confounding through the Study of Older Japanese Twins. AB - OBJECTIVE: Although researchers have recently demonstrated a relationship between oral health and arterial sclerosis, the genetic contribution to this relationship has been ignored even though genetic factors are expected to have some effect on various diseases. The aim of this study was to evaluate oral health as a significant risk factor related to arterial sclerosis after eliminating genetic confounding through study of older Japanese twins. SUBJECTS AND METHODS: Medical and dental surveys were conducted individually for 106 Japanese twin pairs over the age of 50 years. Maximal carotid intima-media thickness (IMT-Cmax) was measured as a surrogate marker of arterial sclerosis. IMT-Cmax > 1.0 mm was diagnosed as arterial sclerosis. All of the twins were examined for the number of remaining teeth, masticatory performance, and periodontal status. We evaluated each measurement related with IMT-Cmax and arterial sclerosis using generalized estimating equations analysis adjusted for potential risk factors. For non smoking monozygotic twins, a regression analysis using a "between within" model was conducted to evaluate the relationship between IMT-Cmax and the number of teeth as the environmental factor controlling genetic and familial confounding. RESULTS: We examined 91 monozygotic and 15 dizygotic twin pairs (males: 42, females: 64) with a mean (+/- standard deviation) age of 67.4 +/- 10.0 years. Out of all of the oral health-related measurements collected, only the number of teeth was significantly related to arterial sclerosis (odds ratio: 0.72, 95% confidence interval: 0.52-0.99 per five teeth). Regression analysis showed a significant association between the IMT-Cmax and the number of teeth as an environmental factor (p = 0.037). CONCLUSIONS: Analysis of monozygotic twins older than 50 years of age showed that having fewer teeth could be a significant environmental factor related to arterial sclerosis, even after controlling for genetic and familial confounding. PMID- 26009885 TI - Efficacy of thermotherapy to treat cutaneous leishmaniasis: a meta-analysis of controlled clinical trials. AB - INTRODUCTION: The efficacy of thermotherapy for the treatment of cutaneous leishmaniasis presents diverse results with low statistical power. OBJECTIVE: To evaluate the efficacy of thermotherapy to treat cutaneous leishmaniasis. METHODS: A meta-analysis of controlled clinical trials in 12 databases based on the implementation of a research protocol with inclusion and exclusion criteria and an assessment of methodological quality. The reproducibility and completeness were guaranteed in the information search and extraction. Heterogeneity, sensitivity and publication bias were assessed by graphical methods (Galbraith, L'Abble, funnel plot, Egger plot, and influence plot) and analytical methods (DerSimonian-Laird, Begg and Egger). Random-effects forest plots were constructed, and a cumulative meta-analysis was performed. RESULTS: Eight studies were included with 622 patients who underwent thermotherapy, with an efficacy of 73.2% (95% confidence interval (CI) = 69.6-76.7%), and with 667 patients who underwent systemic treatment, with an efficacy of 70.6% (95% CI=67.1-74.1%). Heterogeneity between studies, good sensitivity for the combined measure, and no publication bias were observed. The relative risk for comparison of the efficacy of treatment was 1.02 (95%CI=0.91, 1.15), showing that the effectiveness of thermotherapy is equal to that of pentavalent antimonial drugs. CONCLUSION: Due to its efficacy, greater safety and lower cost, thermotherapy should be the first treatment option for cutaneous leishmaniasis in areas where the prevalence of the mucocutaneous form is low and in patients with contraindications to systemic treatment, such as kidney, liver and heart diseases, as well as in pregnant women, infants, and patients with human immunodeficiency virus infection/acquired immune deficiency syndrome. PMID- 26009887 TI - Thermodynamic and ultrasonic properties of ascorbic Acid in aqueous protic ionic liquid solutions. AB - In this work, we report the thermodynamic and ultrasonic properties of ascorbic acid (vitamin C) in water and in presence of newly synthesized ammonium based protic ionic liquid (diethylethanolammonium propionate) as a function of concentration and temperature. Apparent molar volume and apparent molar isentropic compression, which characterize the solvation state of ascorbic acid (AA) in presence of protic ionic liquid (PIL) has been determined from precise density and speed of sound measurements at temperatures (293.15 to 328.15) K with 5 K interval. The strength of molecular interactions prevailing in ternary solutions has been discussed on the basis of infinite dilution partial molar volume and partial molar isentropic compression, corresponding volume of transfer and interaction coefficients. Result has been discussed in terms of solute-solute and solute-solvent interactions occurring between ascorbic acid and PIL in ternary solutions (AA + water + PIL). PMID- 26009886 TI - CRMP1 Inhibits Proliferation of Medulloblastoma and Is Regulated by HMGA1. AB - Many facets of the tumor biology of medulloblastoma (MB) have not been fully elucidated. Collapsin response mediator protein 1 (CRMP1) is a member of cytoplasmic family of proteins that regulate the development of central nervous system. Recent studies demonstrated that CRMP1 could function as an invasion suppressor. We reported previously that high mobility group AT-hook 1 (HMGA1) contributed to development of MB and regulated its growth and migration/invasion. Transcriptional profiling and quantitative RT-PCR revealed increased expression of CRMP1 in HMGA1-depleted cells, suggesting that CRMP1 may be a downstream target of HMGA1 in MB. In this study, we showed HMGA1 can bind CRMP1 promoter by chromatin immunoprecipitation (ChIP) assay. Luciferase assay demonstrated a marked enhancement of CRMP1 transcription activity in HMGA1-depleted cells. Furthermore, quantitative RT-PCR revealed a negative correlation between HMGA1 and CRMP1 in 32 MB samples. To investigate the biological roles of CRMP1 in MB pathogenesis, we established MB clones stably expressing CRMP1. Functional analysis revealed that expression of CRMP1 significantly inhibited proliferation, migration, invasion and formation of filopodia and intense stress fiber of MB cells. Our data suggest that HMGA1 regulates CRMP1 expression and CRMP1 is implicated in MB pathogenesis. PMID- 26009888 TI - Evaluation of voice disorders in patients with active laryngeal tuberculosis. AB - INTRODUCTION: Laryngeal tuberculosis (LTB) is the most frequent larynx granulomatous disease. In general there is lung involvement, but in an important proportion of cases you can find LTB without pulmonary disease. The lesions observed in LTB, such as ulceration and fibrosis, can interfere in the process of voice production. The involvement of the mucous lining of the vocal folds can change their flexibility and, consequently, change voice quality, and the main symptom is dysphonia present in almost 90% of cases. OBJECTIVE: To describe the anatomical characteristics and voice quality in LTB patients. MATERIAL AND METHOD: A descriptive cross-sectional study was conducted with 24 patients. RESULT: The most frequently affected sites were vocal folds in 87.5% patients, vestibular folds in 66.7%, epiglottis in 41.7%, arytenoid in 50%, aryepiglottic folds in 33.3%, and interarytenoid region in 33.3% patients. We found 95.8% cases of dysphonia. The voice acoustic analysis showed 58.3% cases of Jitter alterations, 83.3% of Shimmer and 70.8% of GNE. CONCLUSION: Voice disorders found in active laryngeal tuberculosis are similar to those reported after clinical healing of the disease, suggesting that sequelae and vocal adjustments may install during the active phase of the disease, negatively impacting the process of vocal quality reestablishment. PMID- 26009890 TI - A 9,000 Year History of Seal Hunting on Lake Baikal, Siberia: The Zooarchaeology of Sagan-Zaba II. AB - Sagan-Zaba II, a habitation site on the shore of Siberia's Lake Baikal, contains a record of seal hunting that spans much of the Holocene, making it one of the longest histories of seal use in North Asia. Zooarchaeological analyses of the 16,000 Baikal seal remains from this well-dated site clearly show that sealing began here at least 9000 calendar years ago. The use of these animals at Sagan Zaba appears to have peaked in the Middle Holocene, when foragers used the site as a spring hunting and processing location for yearling and juvenile seals taken on the lake ice. After 4800 years ago, seal use declined at the site, while the relative importance of ungulate hunting and fishing increased. Pastoralists began occupying Sagan-Zaba at some point during the Late Holocene, and these groups too utilized the lake's seals. Domesticated animals are increasingly common after about 2000 years ago, a pattern seen elsewhere in the region, but spring and some summer hunting of seals was still occurring. This use of seals by prehistoric herders mirrors patterns of seal use among the region's historic and modern groups. Overall, the data presented in the paper demonstrate that Lake Baikal witnessed thousands of years of human use of aquatic resources. PMID- 26009889 TI - Manganese-Enhanced MRI Reflects Both Activity-Independent and Activity-Dependent Uptake within the Rat Habenulomesencephalic Pathway. AB - Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful technique for assessing the functional connectivity of neurons within the central nervous system. Despite the widely held proposition that MEMRI signal is dependent on neuronal activity, few studies have directly tested this implicit hypothesis. In the present series of experiments, MnCl2 was injected into the habenula of urethane-anesthetized rats alone or in combination with drugs known to alter neuronal activity by modulating specific voltage- and/or ligand-gated ion channels. Continuous quantitative T1 mapping was used to measure Mn2+ accumulation in the interpeduncular nucleus, a midline structure in which efferents from the medial habenula terminate. Microinjection of MnCl2 into the habenular complex using a protocol that maintained spontaneous neuronal activity resulted in a time-dependent increase in MEMRI signal intensity in the interpeduncular nucleus consistent with fast axonal transport of Mn2+ between these structures. Co-injection of the excitatory amino-acid agonist AMPA, increased the Mn2+-enhanced signal intensity within the interpeduncular nucleus. AMPA-induced increases in MEMRI signal were attenuated by co-injection of either the sodium channel blocker, TTX, or broad-spectrum Ca2+ channel blocker, Ni2+, and were occluded in the presence of both channel blockers. However, neither Ni2+ nor TTX, alone or in combination, attenuated the increase in signal intensity following injection of Mn2+ into the habenula. These results support the premise that changes in neuronal excitability are reflected by corresponding changes in MEMRI signal intensity. However, they also suggest that basal rates of Mn2+ uptake by neurons in the medial habenula may also occur via activity-independent mechanisms. PMID- 26009892 TI - Linking demographic processes of juvenile corals to benthic recovery trajectories in two common reef habitats. AB - Tropical reefs are dynamic ecosystems that host diverse coral assemblages with different life-history strategies. Here, we quantified how juvenile (<50 mm) coral demographics influenced benthic coral structure in reef flat and reef slope habitats on the southern Great Barrier Reef, Australia. Permanent plots and settlement tiles were monitored every six months for three years in each habitat. These environments exhibited profound differences: the reef slope was characterised by 95% less macroalgal cover, and twice the amount of available settlement substrata and rates of coral settlement than the reef flat. Consequently, post-settlement coral survival in the reef slope was substantially higher than that of the reef flat, and resulted in a rapid increase in coral cover from 7 to 31% in 2.5 years. In contrast, coral cover on the reef flat remained low (~10%), whereas macroalgal cover increased from 23 to 45%. A positive stock-recruitment relationship was found in brooding corals in both habitats; however, brooding corals were not directly responsible for the observed changes in coral cover. Rather, the rapid increase on the reef slope resulted from high abundances of broadcast spawning Acropora recruits. Incorporating our results into transition matrix models demonstrated that most corals escape mortality once they exceed 50 mm, but for smaller corals mortality in brooders was double those of spawners (i.e. acroporids and massive corals). For corals on the reef flat, sensitivity analysis demonstrated that growth and mortality of larger juveniles (21-50 mm) highly influenced population dynamics; whereas the recruitment, growth and mortality of smaller corals (<20 mm) had the highest influence on reef slope population dynamics. Our results provide insight into the population dynamics and recovery trajectories in disparate reef habitats, and highlight the importance of acroporid recruitment in driving rapid increases in coral cover following large-scale perturbation in reef slope environments. PMID- 26009891 TI - Whole-Transcriptome Analysis of Differentially Expressed Genes in the Vegetative Buds, Floral Buds and Buds of Chrysanthemum morifolium. AB - BACKGROUND: Chrysanthemum morifolium is an important floral crop that is cultivated worldwide. However, due to a lack of genomic resources, very little information is available concerning the molecular mechanisms of flower development in chrysanthemum. RESULTS: The transcriptomes of chrysanthemum vegetative buds, floral buds and buds were sequenced using Illumina paired-end sequencing technology. A total of 15.4 Gb of reads were assembled into 91,367 unigenes with an average length of 739 bp. A total of 43,137 unigenes showed similarity to known proteins in the Swissprot or NCBI non-redundant protein databases. Additionally, 25,424, 24,321 and 13,704 unigenes were assigned to 56 gene ontology (GO) categories, 25 EuKaryotic Orthologous Groups (KOG) categories, and 285 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. A total of 1,876 differentially expressed genes (DEGs) (1,516 up-regulated, 360 down-regulated) were identified between vegetative buds and floral buds, and 3,300 DEGs (1,277 up-regulated, 1,706 down-regulated) were identified between floral buds and buds. Many genes encoding important transcription factors (e.g., AP2, MYB, MYC, WRKY, NAC and CRT) as well as proteins involved in carbohydrate metabolism, protein kinase activity, plant hormone signal transduction, and the defense responses, among others, were considerably up-regulated in floral buds. Genes involved in the photoperiod pathway and flower organ determination were also identified. These genes represent important candidate genes for molecular cloning and functional analysis to study flowering regulation in chrysanthemum. CONCLUSION: This comparative transcriptome analysis revealed significant differences in gene expression and signaling pathway components between the vegetative buds, floral buds and buds of Chrysanthemum morifolium. A wide range of genes was implicated in regulating the phase transition from vegetative to reproductive growth. These results should aid researchers in the study of flower time regulation, breeding and molecular biology in chrysanthemum. PMID- 26009894 TI - A novel role for DNA methyltransferase 1 in regulating oocyte cytoplasmic maturation in pigs. AB - Maternal factors are required for oocyte maturation and embryo development. To better understand the role of DNA methyltransferase 1 (Dnmt1) in oocyte maturation and embryo development, small interfering RNA (siRNA) was conducted in porcine oocytes. In this study, our results showed that Dnmt1 localized in oocyte cytoplasm and its expression displayed no obvious change during oocyte maturation. When siRNAs targeting Dnmt1 were injected into germinal vesicle (GV) stage oocytes, Dnmt1 transcripts significantly decreased in matured oocytes (P<0.05). After Dnmt1 knockdown in GV stage oocytes, the significant reduction of glutathione content, mitochondrial DNA copy number, glucose-6-phosphate dehydrogenase activity and expression profiles of maternal factors and the severely disrupted distribution of cortical granules were observed in MII stage oocytes (P<0.05), leading to the impaired oocyte cytoplasm. Further study displayed that Dnmt1 knockdown in GV stage oocytes significantly reduced the development of early embryos generated through parthenogenetic activation, in vitro fertilization and somatic cell nuclear transfer (P<0.05). In conclusion, Dnmt1 was indispensable for oocyte cytoplasmic maturation, providing a novel role for Dnmt1 in the regulation of oocyte maturation. PMID- 26009893 TI - Genotypic and phenotypic characterization of P23H line 1 rat model. AB - Rod-cone dystrophy, also known as retinitis pigmentosa (RP), is the most common inherited degenerative photoreceptor disease, for which no therapy is currently available. The P23H rat is one of the most commonly used autosomal dominant RP models. It has been created by incorporation of a mutated mouse rhodopsin (Rho) transgene in the wild-type (WT) Sprague Dawley rat. Detailed genetic characterization of this transgenic animal has however never been fully reported. Here we filled this knowledge gap on P23H Line 1 rat (P23H-1) and provide additional phenotypic information applying non-invasive and state-of-the-art in vivo techniques that are relevant for preclinical therapeutic evaluations. Transgene sequence was analyzed by Sanger sequencing. Using quantitative PCR, transgene copy number was calculated and its expression measured in retinal tissue. Full field electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT) were performed at 1-, 2-, 3- and 6-months of age. Sanger sequencing revealed that P23H-1 rat carries the mutated mouse genomic Rho sequence from the promoter to the 3' UTR. Transgene copy numbers were estimated at 9 and 18 copies in the hemizygous and homozygous rats respectively. In 1-month old hemizygous P23H-1 rats, transgene expression represented 43% of all Rho expressed alleles. ERG showed a progressive rod-cone dysfunction peaking at 6 months-of-age. SD-OCT confirmed a progressive thinning of the photoreceptor cell layer leading to the disappearance of the outer retina by 6 months with additional morphological changes in the inner retinal cell layers in hemizygous P23H-1 rats. These results provide precise genotypic information of the P23H-1 rat with additional phenotypic characterization that will serve basis for therapeutic interventions, especially for those aiming at gene editing. PMID- 26009895 TI - Growth and Physiological Responses to Water Depths in Carex schmidtii Meinsh. AB - A greenhouse experiment was performed to investigate growth and physiological responses to water depth in completely submerged condition of a wetland plant Carex schmidtii Meinsh., one of the dominant species in the Longwan Crater Lake wetlands (China). Growth and physiological responses of C. schmidtii were investigated by growing under control (non-submerged) and three submerged conditions (5 cm, 15 cm and 25 cm water level). Total biomass was highest in control, intermediate in 5 cm treatment and lowest in the other two submerged treatments. Water depth prominently affected the first-order lateral root to main root mass ratio. Alcohol dehydrogenase (ADH) activity decreased but malondialdehyde (MDA) content increased as water depth increased. The starch contents showed no differences among the various treatments at the end of the experiment. However, soluble sugar contents were highest in control, intermediate in 5 cm and 15 cm treatments and lowest in 25 cm treatment. Our data suggest that submergence depth affected some aspects of growth and physiology of C. schmidtii, which can reduce anoxia damage not only through maintaining the non-elongation strategy in shoot part but also by adjusting biomass allocation to different root orders rather than adjusting root-shoot biomass allocation. PMID- 26009896 TI - Job-related burnout among juvenile probation officers: Implications for mental health stigma and competency. AB - The high demands and responsibilities of probation work, particularly with juvenile clients, may lead to burnout, which can negatively impact how probation officers work with clients, particularly individuals with behavioral health concerns. Yet, research examining burnout and related outcomes among juvenile probation officers (JPOs) is limited. We surveyed 246 JPOs in a Midwestern state to identify the prevalence, predictors, and potential outcomes of burnout. JPOs reported moderate levels of burnout; about 30% of the sample scored in the high range for emotional exhaustion and cynicism. Contrary to study hypotheses, there were no group-level differences in burnout scores across gender, race/ethnicity, age, or education. In regression models, burnout was predicted by being White (vs. minority), serving in an urban (vs. rural) county, dissatisfaction with department guidelines, job dissatisfaction, viewing job role as more treatment oriented along the enforcement-treatment continuum, and turnover intention. JPOs with burnout were more likely to endorse mental health stigma and lack of mental health competency to address juvenile clients with behavioral health concerns. Findings suggest burnout prevention and intervention programs should be considered for JPOs to increase job satisfaction, limit job turnover, reduce burnout, and possibly increase effective practices for managing juvenile clients with behavioral health needs. PMID- 26009897 TI - Deregulation of HMGA1 expression induces chromosome instability through regulation of spindle assembly checkpoint genes. AB - The mitotic spindle assembly checkpoint (SAC) is an essential control system of the cell cycle that contributes to mantain the genomic stability of eukaryotic cells. SAC genes expression is often deregulated in cancer cells, leading to checkpoint impairment and chromosome instability. The mechanisms responsible for the transcriptional regulation and deregulation of these genes are still largely unknown. Herein we identify the nonhistone architectural nuclear proteins High Mobility Group A1 (HMGA1), whose overexpression is a feature of several human malignancies and has a key role in cancer progression, as transcriptional regulators of SAC genes expression. In particular, we show that HMGA1 proteins are able to increase the expression of the SAC genes Ttk, Mad2l1, Bub1 and Bub1b, binding to their promoter regions. Consistently, HMGA1-depletion induces SAC genes downregulation associated to several mitotic defects. In particular, we observed a high number of unaligned chromosomes in metaphase, a reduction of prometaphase time, a delay of anaphase, a higher cytokinesis time and a higher percentage of cytokinesis failure by using live-cell microscopy. Finally, a significant direct correlation between HMGA1 and SAC genes expression was detected in human colon carcinomas indicating a novel mechanism by which HMGA1 contributes to cancer progression. PMID- 26009898 TI - The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5. AB - Carfilzomib (CFZ) is a second generation proteasome inhibitor approved for the treatment of patients with multiple myeloma. It induces apoptosis in human cancer cells; but the underlying mechanisms remain undefined. In the present study, we show that CFZ decreases the survival of several human cancer cell lines and induces apoptosis. Induction of apoptosis by CFZ occurs, at least in part, due to activation of the extrinsic apoptotic pathway, since FADD deficiency protected cancer cells from undergoing apoptosis. CFZ increased total and cell surface levels of DR5 in different cancer cell lines; accordingly it enhanced TRAIL induced apoptosis. DR5 deficiency protected cancer cells from induction of apoptosis by CFZ either alone or in combination with TRAIL. These data together convincingly demonstrate that DR5 upregulation is a critical mechanism accounting for CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis. CFZ inhibited the degradation of DR5, suggesting that DR5 stabilization contributes to CFZ-induced DR5 upregulation. In summary, the present study highlights the important role of DR5 upregulation in CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis in human cancer cells. PMID- 26009900 TI - THEMATIC ABSTRACT REVIEW: Understanding Peri-implantitis Through the Lens of the Oral Microbiome. PMID- 26009899 TI - Identification of the interplay between SOX9 and S100P in the metastasis and invasion of colon carcinoma. AB - Elevated expression of S100P has been detected in several tumor types and suggested to be responsible for tumor metastasis and invasion, but the upstream regulatory mechanisms promoting S100P overexpression are largely unknown. Here, we report that SOX9 was predicted and verified as a transcription factor of S100P. SOX9 and S100P were both overexpressed in colon cancer. SOX9 bound to and activated the S100P promoter. Knockdown of SOX9 expression down-regulated S100P expression, resulting in reduced invasiveness and metastasis of colon cancer cells by inhibiting the activation of receptor for advanced glycation end products (RAGE)/ERK signaling and epithelial-mesenchymal transition (EMT). Further, decreased expression of SOX9 dramatically inhibited the tumor growth and peritoneal metastasis in nude mice. More importantly, S100P was found to be critical for SOX9-mediated metastasis and invasion in colon cancer. Knockdown of S100P in SOX9-overexpressing colon cancer cells dramatically suppressed metastasis and invasion both in vitro and in mice. We also detected SOX9 and S100P expression in a tissue microarray with 90 colon cancer cases to provide their clinical relevance. There was a strong correlation between SOX9 and S100P expression in colon carcinomas. In conclusion, our results suggest that SOX9 promotes tumor metastasis and invasion through regulation of S100P expression. PMID- 26009902 TI - Use of confocal microscopy for quantification of plastic remnants on rough titanium after instrumentation and evaluation of efficacy of removal. AB - PURPOSE: Many experts have proposed the treatment of titanium surfaces with plastic or nonmetal tips to prevent damage to implant surfaces by metal instruments during professional cleaning. It is also known that any material that is softer than titanium may leave remnants of itself on the treated surface. The aim of this study was to quantify the surface area covered by plastic remnants after instrumentation with various plastic instruments and to evaluate the efficacy of the removal of these remnants by confocal microscopy. MATERIALS AND METHODS: Twenty-seven rough-surfaced titanium disks were used for quantification of plastic remnants. Nine disks each were cleaned with (1) a plastic tip on ultrasonic scaler A, (2) a carbon tip on ultrasonic scaler B, or (3) a plastic curette. Three disks from each group were cleaned with a three-way syringe for 10 seconds, and three other disks were cleaned with 0.2% chlorhexidine-soaked cotton pellets. Images were obtained at random areas on each disk with a confocal microscope, and a digital image analysis program was used to quantify the area with autofluorescence. RESULTS: Approximately 10% to 20% of the surface was covered with plastic remnants of the instrument, irrespective of the instrument used. These remnants were not removed with a three-way syringe or chlorhexidine soaked cotton pellets. CONCLUSION: Plastic remnants remained after instrumentation, regardless of the instrument used. Moreover, the study highlighted the difficulty of removing all remnants with water spray or a chlorhexidine-soaked cotton pellet. This study suggests that confocal microscopy is a reproducible method for quantification that may be applied for future comparisons of methods to remove plastic residue. Further research is warranted to evaluate the biologic effects of plastic remnants. PMID- 26009901 TI - Biochemical Responses of Anodized Titanium Implants with a Poly(lactide-co glycolide)/Bone Morphogenic Protein-2 Submicron Particle Coating. Part 1: An In Vitro Study. AB - PURPOSE: This study was conducted to examine the effects of coating poly(D,L lactide-co-glycolide) (PLGA)/recombinant human bone morphogenetic protein-2 (rhBMP-2) submicron particles by electrospray onto titanium (Ti) implants on the proliferation and differentiation capacity of mesenchymal stem cells. In addition, the duration of rhBMP-2 release was investigated. MATERIALS AND METHODS: Ti disks were fabricated and divided into four groups as follows. Group C (control) was anodized at 300 V, group P was anodized and then coated with 0.2% PLGA, group B1 was anodized and then coated with PLGA/rhBMP-2 submicron particles at 200 ng per disk, and group B2 was anodized and then coated with PLGA/rhBMP-2 submicron particles at 600 ng per disk. The topography of the PLGA/rhBMP-2-coated Ti surfaces was examined, and proliferation assays, alkaline phosphatase activity tests, and rhBMP-2 releasing tests were conducted in vitro. RESULTS: There was no difference in the roughness of control Ti disks and Ti disks coated with PLGA/rhBMP-2 submicron particles by electrospray. The proliferation of mesenchymal stem cells increased over time; at 7 days, cell proliferation on the Ti disks coated with rhBMP-2 was significantly higher than the other groups. Anodized Ti disks coated with PLGA/rhBMP-2 (groups B1 and B2) released rhBMP-2 for approximately 21 days. In accordance with the amount of rhBMP-2 released from the PLGA/rhBMP-2 construct, the differentiation capacity of mesenchymal stem cells on the PLGA/rhBMP-2-coated disks was increased significantly. CONCLUSION: Submicron PLGA/rhBMP-2 coating on Ti implants by electrospray facilitated cell proliferation and differentiation, which is important for early healing and integration of implants. PMID- 26009903 TI - Comparison of design and torque measurements of various manual wrenches. AB - PURPOSE: Accurate torque application and determination of the applied torque during surgical and prosthetic treatment is important to reduce complications. A study was performed to determine and compare the accuracy of manual wrenches, which are available in different designs with a large range of preset torques. MATERIALS AND METHODS: Thirteen different wrench systems with a variety of preset torques ranging from 10 to 75 Ncm were evaluated. Three different designs were available, with a spring-in-coil or toggle design as an active mechanism or a beam as a passive mechanism, to select the preset torque. To provide a clinically relevant analysis, a total of 1,170 torque measurements in the range of 10 to 45 Ncm were made in vitro using an electronic torque measurement device. RESULTS: The absolute deviations in Ncm and percent deviations across all wrenches were small, with a mean of -0.24 +/- 2.15 Ncm and -0.84% +/- 11.72% as a shortfall relative to the preset value. The greatest overage was 8.2 Ncm (82.5%), and the greatest shortfall was 8.47 Ncm (46%). However, extreme values were rare, with 95th-percentile values of -1.5% (lower value) and -0.16% (upper value). A comparison with respect to wrench design revealed significantly higher deviations for coil and toggle-style wrenches than for beam wrenches. CONCLUSION: Beam wrenches were associated with a lower risk of rare extreme values thanks to their passive mechanism of achieving the selected preset torque, which minimizes the risk of harming screw connections. PMID- 26009904 TI - Evaluation of Different Implant Designs in a Ligature-Induced Peri-implantitis Model: A Canine Study. AB - PURPOSE: Peri-implantitis is a challenging situation that leads to tissue destruction and eventual implant failure. The purpose of this study was to evaluate and compare, clinically and histologically, the influence of ligature induced peri-implantitis on two implant designs in a canine extraction socket model. MATERIALS AND METHODS: Sixty-four implants (4.1 * 13 mm) were placed bilaterally in eight dogs immediately after extraction of the mandibular premolars (P3, P4) and molars (M1, M2). Thirty-two conventional threaded implants (group A) and 32 tantalum-based porous implants (group B) were placed. After 12 weeks of normal healing, experimental peri-implantitis was induced in four dogs via the placement of ligatures subgingivally around the implant necks in the treatment group; the control group remained ligature-free. Two dogs in each group were euthanized after 12 or 26 weeks of plaque accumulation (control group dogs received regular cleanings). Clinical evaluations were conducted during the observation period and histologic sections were obtained for histologic and histomorphometric assessments. RESULTS: All the implants exhibited clinical and histologic osseointegration. The treatment group showed significant loss of peri implant tissue from the induced peri-implantitis. Pocket probing depths for the treatment groups were significantly greater than those of the control groups. Mean bone-to-implant-contact values were not statistically different for control vs treatment groups or for group A vs group B. In the treatment group, group B implants exhibited mean bone ingrowth of 28.4% to 36.3% and achieved more bone formation along the length of the implant than group A implants in the treatment group. CONCLUSION: Implant design did not influence the tissue response or histomorphometric findings under induced peri-implantitis in the canine extraction socket. PMID- 26009905 TI - In vitro fatigue and fracture resistance of one- and two-piece CAD/CAM zirconia implant abutments. AB - PURPOSE: All-ceramic abutments are employed increasingly often in implant dentistry for esthetic reasons. In vitro stress testing is required to evaluate the suitability of these constructions, especially in load-bearing posterior regions. The purpose of the study was to assess and compare the fatigue and fracture resistance of one- and two-piece computer-aided design/computer-assisted manufacture (CAD/CAM) zirconia implant abutments with an internal-hex connection and prefabricated commercially available zirconia stock abutments. MATERIALS AND METHODS: Twenty-one abutment-crown specimens were prepared for three test groups. Control group 1 (SZ) included specimens with unprepared stock zirconia abutments, test group 2 (OP) included one-piece CAD/CAM zirconia abutments, and test group 3 (TP) included two-piece CAD/CAM zirconia abutments. All 21 specimens underwent thermocycling and fatigue testing. Finally, all specimens were tested for fracture resistance with a universal testing machine. The maximum load was applied to the tapered occlusal area of each crown at a 30-degree angle and a crosshead speed of 0.5 mm/min until the implant-abutment connection failed. Kolmogorov-Smirnov, Shapiro-Wilk, and post-hoc Scheffe tests were used for statistical analysis. RESULTS: All abutments in groups SZ and OP fractured into two or more pieces after fracture resistance testing. None of the TP abutments displayed apparent disintegration, but failure was evidenced by bending of the retention screw. OP abutments (232.1 +/- 29.8 N) and SZ abutments (251.8 +/- 23.2 N) showed lower fracture loads than the TP abutments (291.4 +/- 27.8 N). However, only the difference between the OP and TP groups was statistically significant. Further load-displacement analyses corroborated the higher mechanical stability of the TP abutments. CONCLUSION: Superior resistance was achieved for two-piece hybrid CAD/CAM zirconia abutments. These abutments might be clinically beneficial in high-load areas, such as premolar and molar regions. PMID- 26009906 TI - Two different implant designs and impact of related drilling protocols on primary stability in different bone densities: an in vitro comparison study. AB - PURPOSE: To conduct an in vitro comparison study on the primary stability of two different clinically used dental implant designs. MATERIALS AND METHODS: Eighteen pairs of osteotomies were prepared in fresh bovine bone specimens. The control implant had a subtle tapering and was placed using straight drills. The test implant had a marked tapering and was placed using tapered drills. The bone density at the experimental sites was determined in Hounsfield units (HUs) by using cone beam computed tomography and imaging software. The implants were inserted during continuous registration of insertion torque. The bone blocks were embedded in plaster for firm fixation in a rig for displacement measurements. Resonance frequency analysis (RFA) measurements were taken. A lateral force of 15 N was applied to the RFA transducer and the displacement measured in micrometers. A flex constant (MUm/N) was calculated for each measurement. RESULTS: The test implants displayed statistically significantly higher primary stability than the control implants for all parameters. There was a marked difference in displacement and flex constant in low-density bone in favor of the test implant, but there was no obvious difference in higher-density bone. CONCLUSION: In this study, placement of a tapered implant design using tapered drills resulted in higher primary stability than a control implant with subtle tapering using straight drills. The results indicate that the novel implant may work particularly well in soft bone densities such as the posterior maxilla. However, clinical studies are needed to confirm this. PMID- 26009907 TI - Salivary Pellicle vs Whole Saliva: The Response of Oral Fibroblasts Based on a Genome-Wide Microarray. AB - PURPOSE: Whole saliva comprises components of the salivary pellicle that spontaneously forms on surfaces of implants and teeth. However, there are no studies that functionally link the salivary pellicle with a possible change in gene expression. MATERIALS AND METHODS: This study examined the genetic response of oral fibroblasts exposed to the salivary pellicle and whole saliva. Oral fibroblasts were seeded onto a salivary pellicle and the respective untreated surface. Oral fibroblasts were also exposed to freshly harvested sterile-filtered whole saliva. A genome-wide microarray of oral fibroblasts was performed, followed by gene ontology screening with DAVID functional annotation clustering, KEGG pathway analysis, and the STRING functional protein association network. RESULTS: Exposure of oral fibroblasts to saliva caused 61 genes to be differentially expressed (P < .05). Gene ontology screening assigned the respective genes into 262 biologic processes, 3 cellular components, 13 molecular functions, and 7 pathways. Most remarkable was the enrichment in the inflammatory response. None of the genes regulated by whole saliva was significantly changed when cells were placed onto a salivary pellicle. CONCLUSION: The salivary pellicle per se does not provoke a significant inflammatory response of oral fibroblasts in vitro, whereas sterile-filtered whole saliva does produce a strong inflammatory response. PMID- 26009908 TI - The effect of platelet-rich fibrin on implant stability. AB - PURPOSE: Achieving accelerated implant osseointegration could make immediate or early loading of implants more predictable. Platelet-rich fibrin (PRF) is frequently used to accelerate soft and hard tissue healing. The activated platelets in PRF release growth factors, resulting in cellular proliferation, collagen synthesis, and osteoid production. The aim of this study was to compare the stability of dental implants inserted in a one-stage surgical protocol with or without PRF application. MATERIALS AND METHODS: Twenty healthy patients with adequate alveolar bone and two or more adjacent missing teeth extracted at least 6 months previously were included in this study. A minimum of two tapered implants (Ankylos, Dentsply/Friadent) were placed in each patient. After surgical preparation of the implant sockets, PRF that had been prepared preoperatively was placed randomly into one of the sockets (PRF+). The acellular plasma portion of PRF was used to wet the implant placed into the PRF-coated socket. Resonance frequency measurements were made after implant placement and at 1 week and 1 month postoperatively. RESULTS: Mean implant stability quotients (ISQs) of the PRF+ implants was 69.3 +/- 10.5, and mean ISQs for the PRF- implants was 64.5 +/- 12.2 at the end of the first week. The mean ISQs at 4 weeks postoperatively were 77.1 +/- 7.1 for the PRF+ group and 70.5 +/- 7.7 for the PRF- group. CONCLUSION: In this study, PRF application increased implant stability during the early healing period, as evidenced by higher ISQ values. Simple application of this material seems to provide faster osseointegration. PMID- 26009909 TI - Identification of Enterococcus Faecalis and Pseudomonas Aeruginosa on and in Implants in Individuals with Peri-implant Disease: A Cross-Sectional Study. AB - PURPOSE: To verify whether the parts of dental implants can be contaminated by opportunistic pathogens. MATERIALS AND METHODS: In this cross-sectional study, 38 individuals (52 implants) were investigated. Samples for microbiologic analysis (for a total of 180 sites) were obtained from each individual, from three types of sites in the following order: (1) the peri-implant sulcus of each implant, (2) the gingival sulcus of adjacent teeth, and (3) inside the implant-abutment connection and the abutment of each implant. Swabs from the oral mucosa (cheeks, tongue, and pharynx) were also collected. Quantitative real-time polymerase chain reaction was carried out for total bacterial counts of Enterococcus faecalis and Pseudomonas aeruginosa. Two-way analysis of variance (sites, species) and Holm Sidak tests were used for statistical analyses. RESULTS: No opportunistic bacteria were found in the gingival sulcus specimens (38 sites). E faecalis was detected in the peri-implant sulcus (3 of 52 sites) and the inner connection/abutment portion (3 of 52 sites). P aeruginosa was identified only in the oral mucosa swabs (1 of 38 sites) and represented the highest bacterial number (3.5 * 106). Statistically significant differences were only found between species and in the peri-implant sulcus. CONCLUSION: Within the limitations of this study, significant differences in the presence and levels of nosocomial bacteria were detected in the peri-implant environment of diseased implants. From a clinical point of view, data from this study might suggest that, in patients affected by peri-implantitis, prostheses should be removed and the implant abutment connection disinfected routinely, along with implant surface decontamination. PMID- 26009911 TI - Alveolar ridge split on horizontal bone augmentation: a systematic review. AB - PURPOSE: Many techniques have been proposed to overcome the limitations displayed by maxillary atrophy. The aim of this systematic review was to assess the predictability, dimensional changes, and associated factors to successfully perform the alveolar ridge split (ARS) technique of augmentation. MATERIALS AND METHODS: An electronic and manual literature searches was conducted by two independent reviewers in several databases, including Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register, for articles written in English up to February 2014. A manual search was also performed to ensure a thorough screening process. Based on the PICO (problem, intervention, comparison, outcome) model, the chief question of this study was: Can patients with horizontal ridge deficiency be successfully treated with the ARS technique and implant therapy? RESULTS: Overall, 17 articles met the inclusion criteria, and a subsequent meta-analysis was performed. A Cohen kappa interagreement rate of 0.82 was reached. The implant survival rate of the included studies was 97.0% (range, 94.4% to 100%) with the full-thickness flap (FTF) approach and 95.7% (range, 86.6% to 100%) with the partial-thickness flap (PTF) approach. The weighted mean (WM) of horizontal bone width gain was calculated for included studies using FTF for the ARS technique. Four studies that had data were included in the meta-analysis. The WM +/- standard deviation of bone width gain was 3.19 +/- 1.19 mm (range, 2.00 to 4.03 mm). For studies using PTF for ARS, only one study provided mean and standard deviation of horizontal bone width gain (4.13 +/- 3.13 mm); hence, meta-analysis could not be performed. Buccal wall fracture represented the most frequent postoperative complication, followed by postoperative ridge resorption. CONCLUSION: In selected scenarios, the ARS technique might represent a predictable approach as demonstrated by a high implant survival rate, adequate horizontal bone gain, and minimal intra- and postoperative complications. Further research is needed to determine the influence of the grafting materials inserted and flap tissue biotype, as well as the anatomical characteristics on final bone augmentation outcomes. PMID- 26009910 TI - Assessment of the Effect of CO2 Laser Irradiation on the Reduction of Bacteria Seeded on Commercially Available Sandblasted Acid-Etched Titanium Dental Implants: An In Vitro Study. AB - PURPOSE: To evaluate the capability of carbon dioxide (CO2) laser in reducing Escherichia coli on sandblasted acid-etched (SAE) titanium dental implants. MATERIALS AND METHODS: SAE dental implants were contaminated with E coli, incubated in a sterile bacterial culture medium for 24 hours, and then exposed to CO2 laser (10,600-nm wavelength) in superpulsed waves (SPW) at 1.5, 1.7, and 2 W at 100-Hz frequency and continuous wave (CW) at 1.5, 2, and 2.5 W. The presence of bacteria trapped in the implant surfaces after contamination and decontamination was verified using spectrophotometry. Scanning electron microscopy (SEM) was used to evaluate the topography of laser irradiation. After implant surface contamination was verified, implants were exposed to CO2 laser irradiation, and bacterial growth was measured with spectrophotometry. RESULTS: The control implants showed the highest bacterial growth (100% growth). Implants exposed to laser showed progressive increase in the percentage of decontamination (DC%) corresponding to the higher wattage in the SPW and CW groups. The DC% were 20.4%, 49.6%, and 51.7% in the SPW group at 100 Hz, at 1.5, 1.7, and 2 W of power, respectively. In the CW group, the DC% were 34.3%, 69.9%, and 85.5% at 1.7, 2, and 2.5 W, respectively. Kruskal-Wallis statistical analysis showed a significant difference between the groups (P < .05). In the pulsed mode (100-Hz) group, statistical analysis showed that the DC% of 1.5 W was significantly lower than the 2 W power. In the CW group, statistical analysis showed that the DC% at 1.7 W was significantly lower (P < .05) than with the other treatments. SEM assessment showed craterlike wear damages and accretions to the implant surfaces that increased progressively as the laser wattage increased. CONCLUSION: CO2 laser irradiation failed to completely decontaminate the implant surfaces. SEM analysis demonstrated damage to the top of the dental implant threads at all settings studied. Thus, CO2 laser irradiation may not be the optimal method to decontaminate implants. PMID- 26009912 TI - Time-dependent supraimplant mucosa changes: short communication. AB - PURPOSE: The aim of this short communication was to analyze time-dependent changes of the supraimplant mucosa architecture in the esthetic zone. MATERIALS AND METHODS: Five patients underwent single-tooth replacement with implant crowns in the anterior maxilla. The supraimplant soft tissue was conditioned with fixed provisional crowns. Quadrantlike digital impressions were taken with an intraoral optical scanning device at three time points: t0, immediately after removal of the provisional (baseline); t1, after 5 minutes; and t2, after 10 minutes. To analyze time-dependent mucosal changes, the corresponding digital files were superimposed for each patient, and baseline (t0) scans were compared with t1 and t2 scans, respectively. Wilcoxon rank sum tests were used for statistical calculations with a strict level of significance at P < .01. RESULTS: Mean values for supraimplant soft tissue changes were statistically significantly different after 5 minutes (5.5%; standard deviation +/- 0.3%) in comparison to the results after 10 minutes (21.7%; standard deviation +/- 1.8%). The direction of mucosa shrinkage showed a trend toward palatal sites. CONCLUSION: Based on the findings of this analysis, changes in supraimplant mucosa architecture seem to be affected only slightly during the first 5 minutes after removal of soft tissue support. PMID- 26009913 TI - A multicenter randomized comparative trial of implants with different abutment interfaces to replace anterior maxillary single teeth. AB - PURPOSE: The implant-abutment interface may affect peri-implant mucosal architecture, and influence health and esthetics. The goal of this 1-year follow up report of a 5-year clinical investigation was to examine the peri-implant mucosal tissue responses to different implant-abutment interface designs. MATERIALS AND METHODS: Subjects requiring an anterior maxillary implant were recruited. Tooth extractions, with or without preservation or ridge augmentation procedures, were performed as required. After 5 months of healing, one of three different implant-abutment combinations (conical interface [CI] n = 48); flat-to flat interface [FI] n = 49); or platform switch interface [PS] n = 44) was placed and provisionalized. Twelve weeks later, permanent crowns were placed and data gathered throughout the first year. Peri-implant mucosal architecture and bone levels were evaluated clinically, photographically, and radiographically. RESULTS: At 1 year, seven FI and six PS implants failed and two FI and two PS implant participants were lost to follow-up, resulting in survival rates of 100% (CI), 85.7% (FI), and 86.4% (PS) (90.8% overall). Marginal bone level changes were -0.22 mm (CI, P < .05), -1.2 mm (FI, P < .05), and -1.32 mm (PS, P < .05) after 1 year. Marginal bone level stability (<= 0.5-mm bone loss or gain) was recorded for 87% (CI), 8% (FI), and 27% (PS) of implants. Measurement of midbuccal mucosal zenith and papilla positions revealed no change in the mucosal positions and 0.2 to 0.3 mm of gain in papilla dimensions in all groups. CONCLUSION: Significant differences in marginal bone loss were observed among the three implant-abutment interfaces. At 1 year follow-up, changes in the buccal mucosal zenith position or papilla dimensions were not discernable. A continued longitudinal evaluation of peri-implant bone and mucosal changes around these different interfaces is ongoing. PMID- 26009914 TI - A retrospective study of clinical and radiologic outcomes of 69 consecutive maxillary sinus augmentations associated with functional endoscopic sinus surgery. AB - PURPOSE: The aim of this clinical investigation was to evaluate the clinical and radiologic outcomes of a single-step surgical procedure that includes functional endoscopic sinus surgery (FESS) and maxillary sinus elevation by the lateral window approach in patients with reversible contraindications to sinus elevation. MATERIALS AND METHODS: Thirty-eight patients with insufficient bone height in the posterior maxilla caused by pneumatization of the sinus and with reversible ear nose-throat (ENT) contraindications to sinus elevation were recruited for this investigation between January 2010 and January 2012. All patients were treated in a single session under general anesthesia for a total of 69 consecutive sinus augmentations. FESS was performed by an ENT specialist, and an oral surgeon carried out sinus elevation through the lateral window approach. Particulate xenograft was used beneath the sinus membrane. Intraoperative and postoperative complications (eg, membrane tears, rhinosinusitis, graft infection or loss) were reported. Nasal endoscopies were performed at 7, 14, and 30 days and 3 months after treatment. After a healing period of 6 months, 137 implants were inserted. Computed tomography scans were performed after 6 months and 1 year. RESULTS: Intraoperative membrane perforation occurred in only one case. No implant failures were recorded during the follow-up period. Radiologic and clinical findings showed the resolution of ENT disease and good bone graft integration after 1 year. A relapse of mucosal thickening observed in some patients did not influence the graft healing. CONCLUSION: Preliminary rhinosinusal evaluation by an ENT specialist and computed tomography of the ostiomeatal complex are necessary in patients needing maxillary sinus elevation. A single-step approach to FESS and sinus elevation is a predictable technique to manage patients with ENT reversible contraindications to sinus elevation. PMID- 26009915 TI - Amnion membrane as a novel barrier in the treatment of intrabony defects: a controlled clinical trial. AB - PURPOSE: The purpose of this 6-month randomized, controlled, blinded, clinical trial was to evaluate and compare the efficacy of amnion membrane (AM) with deproteinized bovine bone mineral (BBM) and a collagen membrane (CM) with BBM in guided tissue regeneration (GTR) for the treatment of intrabony periodontal defects. MATERIALS AND METHODS: Ten chronic periodontitis patients with bilateral intrabony defects with radiographic evidence of intrabony component >= 4 mm and probing pocket depths (PPDs) >= 6 mm were treated with AM+BBM, and the control group was managed with CM+BBM. Periodontal clinical parameters were recorded at baseline and at 6 months after treatment. RESULTS: PPD, clinical attachment level (CAL), and probing bone (PB) showed significant improvements after 6 months in both the test and control groups. Gingival recession showed a significant increase in the control group but not in the test group. The changes in mean PPD, PB, and CAL preoperatively and postoperatively between the groups were not significant. There was no significant relationship between the depth of the baseline bony defect and CAL gain. CONCLUSION: Both AM and CM in conjunction with BBM provided improvement of clinical periodontal parameters. AM did not induce significant gingival recession and is suggested as a new barrier membrane in GTR treatment. PMID- 26009916 TI - Comparison of implant and provisional placement protocols in sinus-augmented bone: a preliminary report. AB - PURPOSE: To evaluate preliminary data on clinical outcomes associated with timing of placement of single implant-supported provisional crowns and implants in augmented bone. MATERIALS AND METHODS: Twenty patients underwent sinus elevation bone grafting followed by a 6-month healing period before implant placement and immediate placement of a provisional crown (group [G] 1); 20 patients received sinus elevation bone grafting at the time of implant placement and immediate placement of a provisional crown (G2); 20 patients required no bone augmentation before implant placement and immediate placement of a provisional crown (G3); and 20 patients received sinus elevation bone grafting followed by a 6-month healing period before implant placement followed by a 6-month healing period before restoration (G4). The height of the crestal bone was measured and recorded to determine mean bone changes, and success rates were determined. RESULTS: Mean bone level comparisons were made between G2 and G3, G2 and G4, and G3 and G4. No statistically significant differences were found between the groups (P < .05). G1 was discontinued based on the initial results: two implants did not meet the 35 Ncm insertion test, and one implant failed within 1 month after implant placement. The 1-year implant survival rates were 86% (n = 12/14), 95% (n = 19/20), and 100% (n = 16/16) for G2, G3, and G4, respectively. Differences in survival rates between the groups were not statistically significant (P < .05). CONCLUSION: Implant survival is affected by the timing of sinus augmentation and implant placement in relation to the timing of crown placement. Implants that were restored immediately regardless of the timing of bone augmentation showed greater failure rates than implants in augmented bone with delayed restoration protocols or those that were restored immediately in sites without bone augmentation. Neither the timing of loading nor timing of implant placement in relation to bone augmentation surgery affected mean bone loss. PMID- 26009917 TI - Investigation of mucosa-induced residual ridge resorption under implant-retained overdentures and complete dentures in the mandible. AB - PURPOSE: This study aimed to investigate and compare the residual ridge resorption (RRR) induced by an implant-retained overdenture (IRO) and associative biomechanics and by a conventional complete denture (CD) without implants. MATERIALS AND METHODS: Cone beam computed tomography was used to quantify RRR in a three-dimensional (3D) manner before and after 1 year of treatment with either IROs or CDs. Twenty patients were treated with IROs, and nine patients were treated with CDs in the mandible. Their maximum bite forces were recorded. The same sets of high-resolution scan images were used to create patient-specific 3D finite element analysis models. The hydrostatic stresses, contact surface deformation, and strain energy absorption in soft tissue mucosa were correlated with the changes in RRR for patients with and without implants. RESULTS: With the IROs, contact surface deformation on the mucosa was two times greater than with CDs (0.32 +/- 0.23 mm vs 0.16 +/- 0.06 mm) and was in agreement with the amount of RRR measured, which was also two times higher for the IRO than the CD (-3.8% +/- 4.5% vs -1.9% +/- 0.4%). Taking into account the differences in bite forces with and without implants, which again were twice as high with IROs, the hydrostatic stress within the mucosa was found to correlate well to the RRR map measured over the 1-year interval of treatment. CONCLUSION: IROs resulted in at least twice the RRR as CDs. This could be caused by the higher hydrostatic stress and less effective energy absorption capabilities of the mucosa underneath the IRO. While implants associated with the IRO provide stronger bite force, they could potentially concentrate hydrostatic stress and cause greater RRR compared to a conventional CD. PMID- 26009918 TI - Effects of implant morphology on rotational stability during immediate implant placement in the esthetic zone. AB - PURPOSE: Primary implant stability is critical to achieving implant success, especially in a situation with immediate implant placement and provisionalization (IIPP) when bone quality and quantity are compromised. The purpose of this study was to examine the effects of implant morphology (tapered vs cylindric) and the final drill-implant diameter discrepancy (FD-IDD) of six implant systems on the incidence of rotational instability during IIPP in the esthetic zone. MATERIALS AND METHODS: One hundred seventy-one implants in 112 patients were evaluated. Implants that exhibited inadequate resistance to the torque generated by the surgeon's hand during implant placement were classified as rotationally unstable. RESULTS: The overall incidence of rotational instability for the tapered implants (1.1%) was significantly lower than that exhibited by the cylindric (nontapered) implants (20.5%). Among the cylindric implants, those with < 0.5 mm FD-IDD experienced a significantly higher incidence of rotational instability (36.6%) than groups with >= 0.5 mm FD-IDD. The incidence of rotational instability of cylindric implants with >= 0.5 mm FD-IDD was significantly greater than that of the tapered implants with a comparable FD-IDD. CONCLUSION: Within the confines of this study, the use of a tapered implant with an FD-IDD of >= 0.5 mm minimized the incidence of rotational implant instability for the IIPP procedure. PMID- 26009919 TI - Immediate occlusal loading of one-piece zirconia implants: five-year radiographic and clinical evaluation. AB - PURPOSE: To evaluate radiographic and clinical outcomes of immediate occlusally loaded one-piece zirconia implants after 5 years of follow-up. MATERIALS AND METHODS: This longitudinal clinical investigation included patients older than 18 years, in need of implant-supported single-unit dental rehabilitations. One-piece zirconia in healed and postextraction sites and immediately restored with provisional crowns in light occlusal contact. Definitive zirconia-ceramic restorations were delivered 3 to 4 months after surgery. Primary estimated outcomes were implant survival and success. Periapical radiographs were taken at implant insertion (T0), after 1 year (T1), and after 5 years (T2) to assess marginal bone loss (MBL). Probing depth (PD), modified Bleeding Index (mBI), modified Plaque Index (mPI), and gingival recession (REC) were also measured repeatedly for implants and reference teeth. Changes in parameters over time were assessed using the Wilcoxon signed rank test. In addition, multilevel mixed effects linear and logistic regression models were fitted to take into account within-subject correlations and baseline values. RESULTS: Thirty-two implants were inserted in postextraction and healed sites (n = 16 of each) in 17 patients. One immediate implant was lost after 3 months, and one patient with one implant dropped out after T1. Therefore, the cumulative survival rates were 96.9% at T1 and 96.8% at T2 (4.3 to 6 years). No significant differences were observed in mean MBL between immediate and delayed implants at either T1 or T2. Moreover, different baseline parameters (sex, arch, implant location, smoking habits, grafting) did not show any influence on MBL at either time. In general, for all clinical parameters (PD, mBI, mPI, REC), implants seemed to perform similar to if not better than natural teeth. CONCLUSION: Radiographic and clinical evaluations after 5 years showed satisfactory amounts of MBL and acceptable soft tissue health. PMID- 26009920 TI - Facial Peri-implant Soft Tissue Topography of Posterior Single Implant-Supported Restorations and Relationship to Adjacent Teeth: A Retrospective Analysis. AB - PURPOSE: The aim of this study was to retrospectively evaluate the factors affecting facial peri-implant mucosa topography of posterior single implant supported restorations. MATERIALS AND METHODS: The cohort comprised 25 patients with a single implant-supported restoration with platform switching and Morse taper-connection implants. Patients were divided into three groups based on facial soft tissue topography. Patients of group A (n = 8), group B (n = 9), and group C (n = 8) had a facial peri-implant tissue margin at the level of, coronal to, and apical to the zenith of the facial gingival margins of the adjacent teeth, respectively. Variables possibly associated with the facial peri-implant tissue margin level were obtained from clinical measurements, periapical radiographs, and cone beam computed tomograms. RESULTS: Implants in group C were placed in a more subcrestal position than implants of group B (1.50 +/- 0.53 mm vs 0.44 +/- 0.88 mm). Implants in group C had their platform in a more apical position in relation to the bone level of the adjacent teeth than implants of group B (3.45 +/- 1.32 mm vs 1.53 +/- 1.17 mm). The horizontal distance between adjacent teeth was greater for group C than for group A and group B (13.53 +/- 2.37 mm vs 10.65 +/- 2.09 mm and 9.82 +/- 1.77 mm, respectively). CONCLUSION: In this study, facial peri-implant mucosa margins for implants in the posterior region with platform switching and a Morse taper connection were significantly affected by the distances from the implant platform to the buccal aspect of the ridge at the time of implant placement and from the implant platform to the bone level of the adjacent teeth and by the horizontal spaces between the adjacent teeth. PMID- 26009921 TI - Mandibular bone block harvesting from the retromolar region: a 10-year prospective clinical study. AB - PURPOSE: The aim of this prospective study was to evaluate the outcome of bone block harvesting from the external oblique ridge with the MicroSaw, assess the volume of the harvested block, and identify possible morbidity and complications related to the procedure. MATERIALS AND METHODS: Bone blocks were harvested from the external oblique line of the mandible according to the MicroSaw protocol. The bone blocks were split into two thinner blocks with a diamond disk according to the split bone block (SBB) technique for biologic grafting procedures. RESULTS: In all, 3,874 bone blocks were harvested from the external oblique line of the mandible in 3,328 patients. Four hundred nineteen patients (12.59%) underwent bilateral bone block harvesting, and 127 patients (3.82%) had more than one block harvested from the same area during the study period. In 431 cases (11.12%), only one block was required, so the second was repositioned to reconstruct its donor site. The average harvesting time was 6.5 +/- 2.5 minutes, and a mean volume of 1.9 +/- 0.9 cm3 was obtained (maximum 4.4 cm3). In 168 (4.33%) cases, the alveolar nerve was exposed, leading to sensory problems lasting up to 6 months. In 20 cases (0.5%), minor nerve injury resulted in hypesthesia or paresthesia that lasted for up to 1 year in most patients. No major nerve lesions with permanent anesthesia were observed. Sixty-one (1.58%) donor sites showed primary healing complications, most in smokers (80.4%). Reentry of 16 reimplanted harvested areas was performed between 6 and 40 months later, showing a well regenerated and healed external oblique ridge. CONCLUSION: This study demonstrated that relatively large volumes of bone block graft can be retrieved in the mandible with a low complication rate. Reimplantation of half of the bone block offers the possibility for complete regeneration of the donor site. PMID- 26009922 TI - A clinical comparison of guided bone regeneration with platelet-derived growth factor-enhanced bone ceramic versus autogenous bone block grafting. AB - PURPOSE: The objective of this study was to evaluate the efficacy of guided bone regeneration (GBR) employing recombinant human platelet-derived growth factor-BB (rhPDGF-BB) incorporated into a beta-tricalcium phosphate (beta TCP)/hydroxyapatite (HA) carrier as a graft material and to compare it to autogenous bone block grafting. MATERIALS AND METHODS: Adult patients with a site that required bone grafting to increase the thickness of the alveolar bone ridge were treated. After mucoperiosteal flap elevation, experimental bone defects were treated by GBR with rhPDGF incorporated into beta-TCP/HA, and control defects were treated with autogenous bone. Primary tension-free wound closure was obtained for all treated sites. RESULTS: Thirty patients were treated. No significant differences were observed between the groups for any of the parameters evaluated, including the amount of bone regeneration and a need for additional grafting. CONCLUSION: A composite bone ceramic graft that incorporated rhPDGF appears to be a suitable substitute for autogenous bone block grafting when employed in conjunction with GBR in humans. PMID- 26009924 TI - Influence of Alveolar Bone Loss and Different Alloys on the Biomechanical Behavior of Internal-and External-Connection Implants: A Three-Dimensional Finite Element Analysis. AB - PURPOSE: The purpose of this study was to evaluate the stress distribution during application of occlusal loads to maxillary anterior single external- and internal connection implant-supported restorations with different amounts of bone loss and with the use of different metal alloys for restorations and fixation screws. MATERIALS AND METHODS: Models of external- and internal-connection implants, corresponding abutments/crowns, and fixation screws were developed. These models were then imported into finite element analysis software to study the impact of forces on different implant connections and materials. Each prosthesis was subjected to a 200-N compressive shear force applied at 130 degrees relative to the long axis of the implant. The materials were considered linear, isotropic, and homogenous. The parameters changed for each connection type included: bone resorption in relation to the prosthetic platform (no, 2 mm, or 4 mm of resorption); alloys of the restorations (nonprecious vs precious); and alloys of the abutment screws (titanium vs gold). Von Mises stresses were used to display the stress in five models: implant, restoration, screw, cancellous bone, and cortical bone. RESULTS: Statistically significant differences in the stresses of all involved structures occurred when the bone level decreased by 2 mm and by 4 mm. The connection type contributed to statistically significant differences in the stresses in both the restoration and the screw. The alloy type resulted in statistically significant differences in the implant, the superstructure, and the cortical bone stresses. CONCLUSION: As bone resorbed, the stresses generated within the internal-connection implant were greater than those generated in the external-connection implant. The same findings applied for the restoration and for cancellous and cortical bone. The stresses generated in the fixation screw were greater in the external-connection implant than in the internal-connection implant for all bone resorption scenarios. PMID- 26009923 TI - Effect of targeted delivery of bone morphogenetic protein-2 on bone formation in type 1 diabetes. AB - PURPOSE: Bone formation and healing are diminished in experimental type 1 diabetes. The present study investigated whether controlled local release of recombinant human bone morphogenetic protein 2 (rhBMP-2) stimulates bone defect healing in diabetes as a consequence of its anabolic effects on bone. MATERIALS AND METHODS: Bilateral experimental circular bone defects were created in the temporal bones of 64 BALB/cByJ mice. Defects were treated with acellular collagen sponge plus 0.4 or 1.8 MUg of rhBMP-2 per defect, and untreated defects served as controls. The healing of the defects over a 14-day period in diabetic and nondiabetic mice was analyzed histomorphometrically. RESULTS: Diabetes inhibited bone formation in both untreated and BMP-treated bone defects. Controlled local release of rhBMP-2 significantly stimulated bone formation in diabetic animals, bringing it nearly to normal levels, and enhanced bone regeneration in normal animals. CONCLUSION: Recombinant human BMP-2 may be beneficial in treating deficient intramembranous bone formation in diabetes. PMID- 26009925 TI - The use of virtual models to estimate the amount of grafting material: a case study. AB - The authors present a case study in which a virtual model was created from a patient's cone beam computed tomographic scans that simulated a dentoalveolar defect associated with periapical pathosis. With the information provided by the virtual model, the tooth was extracted, and both defect and alveolus were virtually grafted. The virtual amount calculated was similar to the amount used in the actual site. PMID- 26009926 TI - Excretion of cytoplasmic proteins (ECP) in Staphylococcus aureus. AB - Excretion of cytoplasmic proteins (ECP) is a common physiological feature in bacteria and eukaryotes. However, how these proteins without a typical signal peptide are excreted in bacteria is poorly understood. We studied the excretion pattern of cytoplasmic proteins using two glycolytic model enzymes, aldolase and enolase, and show that their excretion takes place mainly during the exponential growth phase in Staphylococcus aureus very similar to that of Sbi, an IgG-binding protein, which is secreted via the Sec-pathway. The amount of excreted enolase is substantial and is comparable with that of Sbi. For localization of the exit site, we fused aldolase and enolase with the peptidoglycan-binding motif, LysM, to trap the enzymes at the cell wall. With both immune fluorescence labeling and immunogold localization on electron microscopic thin sections aldolase and enolase were found apart from the cytoplasmic area particularly in the cross wall and at the septal cleft of dividing cells, whereas the non-excreted Ndh2, a soluble NADH:quinone oxidoreductase, is only seen attached to the inner side of the cytoplasmic membrane. The selectivity, the timing and the localization suggest that ECP is not a result of unspecific cell lysis but is mediated by an as yet unknown mechanism. PMID- 26009927 TI - Enhanced Performance of Perovskite CH3NH3PbI3 Solar Cell by Using CH3NH3I as Additive in Sequential Deposition. AB - Sequential deposition is a widely adopted method to prepare CH3NH3PbI3 on mesostructured TiO2 electrode for organic lead halide perovskite solar cells. However, this method often suffers from the uncontrollable crystal size, surface morphology, and residual PbI2 in the resulting CH3NH3PbI3, which are all detrimental to the device performance. We herein present an optimized sequential solution deposition method by introducing different amount of CH3NH3I in PbI2 precursor solution in the first step to prepare CH3NH3PbI3 absorber on mesoporous TiO2 substrates. The addition of CH3NH3I in PbI2 precursor solution can affect the crystallization and composition of PbI2 raw films, resulting in the variation of UV-vis absorption and surface morphology. Proper addition of CH3NH3I not only enhances the absorption but also improves the efficiency of CH3NH3PbI3 solar cells from 11.13% to 13.37%. Photoluminescence spectra suggest that the improvement of device performance is attributed to the decrease of recombination rate of carriers in CH3NH3PbI3 absorber. This current method provides a highly repeatable route for enhancing the efficiency of CH3NH3PbI3 solar cell in the sequential solution deposition method. PMID- 26009928 TI - Genetic approach identifies distinct asthma pathways in overweight vs normal weight children. AB - The pathogenesis of asthma in the context of excess body weight may be distinct from asthma that develops in normal weight children. The study's objective was to explore the biology of asthma in the context of obesity and normal weight status using genetic methodologies. Associations between asthma and SNPs in 49 genes were assessed, as well as, interactions between SNPs and overweight status in child participants of the Greater Cincinnati Pediatric Clinic Repository. Asthma was significantly associated with weight (OR = 1.38; P = 0.037). The number of genes and the magnitude of their associations with asthma were notably greater when considering overweight children alone vs normal weight and overweight children together. When considering weight, distinct sets of asthma-associated genes were observed, many times with opposing effects. We demonstrated that the underlying heterogeneity of asthma is likely due in part to distinct pathogenetic pathways that depend on preceding/comorbid overweight and/or allergy. It is therefore important to consider both obesity and asthma when conducting studies of asthma. PMID- 26009929 TI - Celecoxib for the treatment of mild-to-moderate depression due to acute brucellosis: a double-blind, placebo-controlled, randomized trial. AB - WHAT IS KNOWN AND OBJECTIVE: Depression is a debilitating complication of brucellosis and how best to treat this is a matter of debate. Inflammatory processes are involved in the pathogenesis of both brucellosis and depression. Therefore, we hypothesized that celecoxib could be beneficial for the treatment of depression due to brucellosis. METHODS: Forty outpatients with depression due to brucellosis with a Hamilton Depression Rating Scale score (HDRS) <19 participated in a randomized, double-blind, placebo-controlled trial and underwent 8 weeks of treatment with either celecoxib (200 mg bid) or placebo as an adjunctive to antibiotic therapy. Patients were evaluated using HDRS at baseline and weeks 4 and 8. RESULT AND DISCUSSION: Repeated-measures analysis demonstrated significant effect for time * treatment interaction on the HDRS score [F (1.43, 57.41) = 37.22, P < 0.001]. Significantly greater response to treatment occurred in the celecoxib group than in the placebo group at the study end [10 patients (50%) vs. no patient (0%), respectively, P < 0.001]. No serious adverse event was observed. WHAT IS NEW AND CONCLUSION: Celecoxib is a safe and effective treatment for depression due to brucellosis when compared with placebo. PMID- 26009930 TI - Compressive Residual Strains in Mineral Nanoparticles as a Possible Origin of Enhanced Crack Resistance in Human Tooth Dentin. AB - The tough bulk of dentin in teeth supports enamel, creating cutting and grinding biostructures with superior failure resistance that is not fully understood. Synchrotron-based diffraction methods, utilizing micro- and nanofocused X-ray beams, reveal that the nm-sized mineral particles aligned with collagen are precompressed and that the residual strains vanish upon mild annealing. We show the link between the mineral nanoparticles and known damage propagation trajectories in dentin, suggesting a previously overlooked compression-mediated toughening mechanism. PMID- 26009931 TI - Cultural universality and specificity of student engagement in school: The results of an international study from 12 countries. AB - BACKGROUND: A comprehensive understanding of the contextual factors that are linked to student engagement requires research that includes cross-cultural perspectives. AIMS: This study investigated how student engagement in school is associated with grade, gender, and contextual factors across 12 countries. It also investigated whether these associations vary across countries with different levels of individualism and socio-economic development. SAMPLES: The participants were 3,420 7th, 8th, and 9th grade students from Austria, Canada, China, Cyprus, Estonia, Greece, Malta, Portugal, Romania, South Korea, the United Kingdom, and the United States. METHODS: The participants completed a questionnaire to report their engagement in school, the instructional practices they experienced, and the support they received from teachers, peers, and parents. Hierarchical linear modelling was used to examine the effects at both student and country levels. RESULTS: The results across countries revealed a decline in student engagement from Grade 7 to Grade 9, with girls reporting higher engagement than boys. These trends did not vary across the 12 countries according to the Human Development Index and Hofstede's Individualism Index. Most of the contextual factors (instructional practices, teacher support, and parent support) were positively associated with student engagement. With the exception that parent support had a stronger association with student engagement in countries with higher collectivism, most of the associations between the contextual factors and student engagement did not vary across countries. CONCLUSIONS: The results indicate both cultural universality and specificity regarding contextual factors associated with student engagement in school. They illustrate the advantages of integrating etic and emic approaches in cross-cultural investigations. PMID- 26009932 TI - Intrinsic Chemiluminescence Generation during Advanced Oxidation of Persistent Halogenated Aromatic Carcinogens. AB - The ubiquitous distribution coupled with their carcinogenicity has raised public concerns on the potential risks to both human health and the ecosystem posed by the halogenated aromatic compounds (XAr). Recently, advanced oxidation processes (AOPs) have been increasingly favored as an "environmentally-green" technology for the remediation of such recalcitrant and highly toxic XAr. Here, we show that AOPs-mediated degradation of the priority pollutant pentachlorophenol and all other XAr produces an intrinsic chemiluminescence that directly depends on the generation of the extremely reactive hydroxyl radicals. We propose that the hydroxyl radical-dependent formation of quinoid intermediates and electronically excited carbonyl species is responsible for this unusual chemiluminescence production. A rapid, sensitive, simple, and effective chemiluminescence method was developed to quantify trace amounts of XAr and monitor their real-time degradation kinetics. These findings may have broad biological and environmental implications for future research on this important class of halogenated persistent organic pollutants. PMID- 26009933 TI - Concordance of DSM-5 and DSM-IV-TR classifications for autism spectrum disorder. AB - BACKGROUND: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in May 2013. Autism spectrum disorder (ASD) has been structured for the three subtypes of pervasive developmental disorder (PDD), but the number of impairment in social and communication dimension is not stated. METHODS: The subjects were 68 children who visited the Department of Psychology and Development at Nagoya City University Hospital for the first time between the ages of 6 and 15 years old. We retrospectively re-examined the subjects using DSM IV-TR criteria and DSM-5 criteria with two rules (two of three and one of three on the social and communication dimension) and examined the concordance rate. RESULTS: Forty subjects were diagnosed with PDD, and 28 were not. The mean PDD subject age was 9.4 years, and mean IQ was 84.0 on the Wechsler Intelligence Scale for Children III or 62.7 on the Tanaka-Binet test. Twenty-seven (68%) of the PDD subjects were classified with ASD using DSM-5 criteria when the two of three rule was applied, while 32 (80%) were classified with ASD when the one of three rule was applied. All subjects without PDD were not diagnosed with ASD on DSM-5 criteria. CONCLUSION: DSM-5 criteria may exclude high functioning and older subjects from ASD because they tend to be atypical. The diagnostic procedure for DSM-5 criteria is ambiguous, especially in high functioning subjects and those diagnosed at an older age. PMID- 26009934 TI - Engineered Expression Vectors Significantly Enhanced the Production of 2-Keto-D gluconic Acid by Gluconobacter oxidans. AB - 2-Keto-D-gluconic acid (2KGA), a precursor of the important food antioxidant erythorbic acid, can be produced by Gluconobacter oxidans. To genetically engineer G. oxidans for improved 2KGA production, six new expression vectors with increased copy numbers based on pBBR1MCS-5 were constructed via rational mutagenesis. The utility of the mutant vectors was demonstrated by the increased ga2dh mRNA abundance, enzyme activity, and 2KGA production when the ga2dh gene was overexpressed using these vectors. Among the obtained constructs, G. oxidans/pBBR-3510-ga2dh displayed the highest oxidative activity toward gluconic acid (GA). In a batch biotransformation process, the G. oxidans/pBBR-3510-ga2dh strain exhibited 2KGA productivity (0.63 g/g CWW/h) higher than that obtained using strain G. oxidans/pBBR-ga2dh (0.40 g/g CWW/h). When sufficient oxygen was supplied during the biotransformation, up to 480 g/L GA was exhausted in 45 h by the G. oxidans/pBBR-3510-ga2dh strain and approximately 486 g/L 2KGA was produced, generating the productivity of 0.54 g/g CWW/h. PMID- 26009935 TI - Surgical Site Infection 18 Months Following Intrathecal Pump Placement Secondary to an Asymptomatic Bowel Injury. AB - Surgical site infections following the implantation of intrathecal drug delivery systems typically present during the first 1 to 2 months following surgery. Surgical site infections occurring outside of this window are rare entities and require special attention to identify the source or underlying cause. In this report, we present a case of pump pocket infection 18 months following implantation due to an asymptomatic and unrecognized bowel injury associated with the catheter. This case highlights the need for a thorough evaluation in a patient with suspected infections more than 2 months after surgery to ensure adequate treatment. PMID- 26009936 TI - The effect of executive function on stress, depression, anxiety, and quality of life in multiple sclerosis. AB - The experience of cognitive deficits and emotional dysfunction are prevalent in people with multiple sclerosis (PwMS), although research examining their interaction has provided inconsistent findings. The current study examined the ability of executive function to predict psychosocial adjustment in PwMS. One hundred and seven PwMS underwent cognitive assessment and completed measures of stress, depression, anxiety, and quality of life (QoL). There was limited support for a relationship. There was no relationship between objective cognitive tasks and state or trait anxiety, mental health QoL, overall QoL, or stress frequency. The only relationship with depression was found when the Beck Depression Inventory Fast-Screen was used, with a task of planning when the timing element was removed. A measure of error rates on a task of cognitive flexibility predicted physical health QoL, and severity, but not frequency, of stress was predicted by a task of working memory. The results of this study highlight the need for further research into the relationship between cognitive deficits and psychosocial adjustment because of the conflicting findings between studies and call for a common measurement framework for future investigation. PMID- 26009937 TI - Random mutagenesis of the nucleotide-binding domain of NRC1 (NB-LRR Required for Hypersensitive Response-Associated Cell Death-1), a downstream signalling nucleotide-binding, leucine-rich repeat (NB-LRR) protein, identifies gain-of function mutations in the nucleotide-binding pocket. AB - Plant nucleotide-binding, leucine-rich repeat (NB-LRR) proteins confer immunity to pathogens possessing the corresponding avirulence proteins. Activation of NB LRR proteins is often associated with induction of the hypersensitive response (HR), a form of programmed cell death. NRC1 (NB-LRR Required for HR-Associated Cell Death-1) is a tomato (Solanum lycopersicum) NB-LRR protein that participates in the signalling cascade leading to resistance to the pathogens Cladosporium fulvum and Verticillium dahliae. To identify mutations in NRC1 that cause increased signalling activity, we generated a random library of NRC1 variants mutated in their nucleotide-binding domain and screened them for the ability to induce an elicitor-independent HR in Nicotiana tabacum. Screening of 1920 clones retrieved 11 gain-of-function mutants, with 10 of them caused by a single amino acid substitution. All substitutions are located in or very close to highly conserved motifs within the nucleotide-binding domain, suggesting modulation of the signalling activity of NRC1. Three-dimensional modelling of the nucleotide binding domain of NRC1 revealed that the targeted residues are centred around the bound nucleotide. Our mutational approach has generated a wide set of novel gain of-function mutations in NRC1 and provides insight into how the activity of this NB-LRR is regulated. PMID- 26009938 TI - Understanding mental health intervention and assessment within a multi-tiered framework: Contemporary science, practice, and policy. AB - This special topic section features research regarding practices that will support mental health service delivery within a school-based multitiered framework. The articles include data and discussions regarding the evaluation of universal, targeted, or intensive intervention addressing mental health concerns and assessment tools intended for use in screening, progress monitoring, or problem identification. The featured interventions and assessment practices are suitable for use within a service delivery model that prioritizes ecological theory, data-based decision making, and problem solving logic. Each article includes a conceptualization of how the intervention/assessment of interest fits into a school-based multitiered framework and information about feasibility and utility of the practice in school-based settings. These articles highlight the use of mental health intervention and assessment within a multitiered problem solving framework, and will hopefully stimulate interest in and further scholarship on this important topic. PMID- 26009939 TI - Correction to Nickerson and Mele-Taylor (2014). PMID- 26009940 TI - C14-polyacetylene glucosides from Codonopsis pilosula. AB - Seven new C14-polyacetylene glucosides codonopilodiynosides A-G (1-7) were isolated from an aqueous extract of the Codonopsis pilosula roots. Their structures were determined by spectroscopic and chemical methods as (-) (5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5,14-triol 5-O-beta-D-glucopyranoside (1), (-)-(5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5,14-triol 5-O-beta-D glucopyranosyl-(1" -> 2')-beta-D-glucopyranoside (2), (-)-(5S,6E,12E)-tetradeca 6,12-dien-8,10-diyn-1,5,14-triol 5,14-di-O-beta-D-glucopyranoside (3), (-) (5S,6E)-tetradeca-6-en-8,10-diyn-1,5,14-triol 5-O-beta-D-glucopyranoside (4), (-) (5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5-diol 5-O-beta-D-glucopyranosyl-(1" > 2')-beta-D-glucopyranoside (5), (-)-(6S,4E,12E)-tetradeca-4,12-dien-8,10-diyn 1,6-diol 6-O-beta-D-glucopyranosyl-(1" -> 2')-beta-D-glucopyranoside (6), and (-) (5S,6E)-tetradeca-6-en-1,5-epoxy-8,10-diyn-14-ol 14-O-beta-D-glucopyranosyl-(1" > 2')-beta-D-glucopyranoside (7), respectively. The absolute configurations of 1 7 were assigned by enzymatic hydrolysis followed by isolation of glucose and aglycones (1a and 4a-7a), and subsequent comparison of specific rotation, TLC, and (1)H NMR data of the glucose with an authentic sugar sample and application of modified Mosher's method based on the MPA determination rule of Deltadelta(RS) values for 1a and 4a, and Deltadelta(S) values for 6a. The configuration of 7 was assigned by electronic circular dichroism calculations based on the quantum mechanical time-dependent density functional theory. PMID- 26009941 TI - Simkania negevensis and acute cellular rejection in lung transplant recipients. AB - Simkania negevensis infection has been hypothesized to play a role in lung transplant rejection. The incidence of S. negevensis infection and its association with acute cellular rejection (ACR) were determined in a prospective cohort study of 78 lung transplant recipients (LTRs) in Toronto, Canada, and Pittsburgh, USA, from July 2007 to January 2010. Simkania negevensis testing was detected by quantitative polymerase chain reaction (PCR) on bronchoalveolar lavage fluid. The relationship between S. negevensis and ACR was examined using Cox proportional hazards models and generalized linear and latent mixed models. Cumulative incidence estimates for time-to-ACR in S. negevensis PCR-positive vs. PCR-negative LTRs were 52.7% vs. 31.1% at six months and 68.9% vs. 44.6% at one yr, respectively. Although not statistically significant, there was a trend toward a higher risk of ACR among S. negevensis PCR-positive vs. PCR-negative LTRs in all statistical models. PMID- 26009943 TI - Assessing health in an Alaska native cultural context: The Yup'ik Wellness Survey. AB - OBJECTIVES: The development and validation of a wellness measure among the Yup'ik of the Yukon-Kuskokwim Delta in western Alaska is presented, with the overarching goal of supporting locally relevant health practices in this Alaska Native population. METHOD: A survey containing the wellness measure and several additional psychosocial variables was completed by 493 Yup'ik individuals from 7 different highly rural communities in western Alaska. Participants ranged in age from 14 to 94 (M = 38.55, SD = 17.14), and slightly more than half were female (58.62%). RESULTS: Individuals who scored higher on the wellness measure reported greater happiness, greater overall health, greater communal mastery, a larger and more satisfying social support network, and coping styles that were more likely to be active, accepting, and growth-oriented, and less likely to involve drugs and alcohol. CONCLUSIONS: This project advances research on the health implications of enculturation by specifying particular patterns of culturally sanctioned beliefs and behaviors that appear most beneficial. PMID- 26009944 TI - The Multicultural Identity Integration Scale (MULTIIS): Developing a comprehensive measure for configuring one's multiple cultural identities within the self. AB - OBJECTIVES: The research investigating how one's multiple cultural identities are configured within the self has yet to account for existing cultural identity configurations aside from integration, and for identifying with more than 2 cultural groups at once. The current research addresses these issues by constructing the Multicultural Identity Integration Scale (MULTIIS) to examine 3 different multicultural identity configurations, and their relationship to well being based on Amiot and colleagues' (2007) cognitive-developmental model of social identity integration (CDSMII). METHOD: Diverse samples of multicultural individuals completed the MULTIIS along with identity and well-being measures. (Study 1A: N = 407; 1B: N = 310; 2A = 338 and 2A = 254) RESULTS: Reliability and confirmatory factorial analyses (Studies 1A and 2A) all supported the factorial structure of the MULTIIS. Regression analyses (Studies 1B and 2B) confirmed that the integration subscale of the MULTIIS positively predicted well-being, whereas compartmentalization negatively predicted well-being. Categorization was inconsistently related to well-being. CONCLUSIONS: These findings support the CDSMII and the usefulness of the MULTIIS measure, and suggest that each identity configuration is uniquely related to well-being outcomes. PMID- 26009942 TI - "They were just making jokes": Ethnic/racial teasing and discrimination among adolescents. AB - OBJECTIVES: The effects of peer-based discrimination are especially harmful for adolescents given the heightened role of social feedback during this period. The current study aimed to understand the unique expressions of discrimination that adolescents experience between close peers and friends, as well as the daily influence of such experiences. METHOD: Study 1 included semistructured interviews (10 interviews, 2 focus groups; Mage = 17.3) with an ethnic/racially diverse sample of adolescence. Study 2 (n = 79; Mage = 15.72) used a 21-day daily diary study with a different sample of ethnic/racially diverse adolescents. RESULTS: Study 1 found that, among close peers and friends, adolescents experienced "ethnic/racial teasing," a unique form of discrimination characterized by humor. Additionally, adolescents consistently dismissed the negative messages as innocuous based on the supposedly humorous nature of such interactions. Study 2 found that when adolescents were targeted for ethnic/racial teasing, individuals who were already anxious experienced increased daily anxiety, and that increases in social anxiety persisted across days. CONCLUSIONS: The current study suggests that among peers, ethnic/racial teasing is a common way that adolescents interact around ethnicity/race. Further, this study points to the complexity of these experiences; though they were largely considered normative and harmless, they also had negative psychological effects for some adolescents. Implications for our conceptual understanding of discrimination and teasing during adolescence are discussed. PMID- 26009946 TI - Learning from peers and patients. PMID- 26009945 TI - Acute Effects of Classroom Exercise Breaks on Executive Function and Math Performance: A Dose-Response Study. AB - PURPOSE: The purpose of this study was to determine the acute dose-response relationship of classroom exercise breaks with executive function and math performance in 9- to 12-year-old children by comparing 5-min, 10-min, or 20-min classroom exercise breaks to 10 min of sedentary classroom activity. METHOD: This study used a within-subjects experimental design conducted in the spring of 2012. Ninety-six 4th- and 5th-grade students in 5 classrooms in South Carolina were randomized to receive each of 4 treatments: 5-min, 10-min, or 20-min exercise breaks or 10 min of a sedentary lesson led by research staff. Students completed the Trail-Making Test, an Operational Digit Recall test, and a math fluency test immediately before and after each condition. Planned linear contrasts were used to compare posttest scores between conditions using a repeated-measures mixed model, adjusted for gender, classroom, and the time-varying pretest scores. Potential effect modifiers were added as interaction terms. RESULTS: Math scores were higher after the 10-min and 20-min exercise breaks compared with the sedentary condition (d = 0.24, p = .04, and d = 0.27, p = .02, respectively), and an interaction was observed with gender, IQ, aerobic fitness, and lower engagement in some of the conditions. There were no improvements in executive function tasks. CONCLUSIONS: A 10-min and 20-min classroom exercise break moderately improved math performance in students compared with a seated classroom lesson. PMID- 26009947 TI - Patients as teachers: promoting their authentic and autonomous voices. PMID- 26009948 TI - The flipped classroom for medical students. AB - BACKGROUND: The objectives of this curricular innovation project were to implement a flipped classroom curriculum for the gynaecologic oncology topics of the obstetrics and gynaecology medical student clerkship, and to evaluate student satisfaction with the change. METHODS: Four short online videos on the topics of endometrial hyperplasia, cervical dysplasia, evaluation of an adnexal mass, and ovarian cancer were created, and students were instructed to view them prior to a class-time active learning session. The Learning Activity Management System (lams) open-source online platform was used to create an active learning class time activity that consisted of a coached discussion of cases. Student satisfaction with the two aspects of the flipped curriculum was obtained. In addition, lecture assessment for the gynaecologic oncology topics and aggregate student performance on the gynaecological oncology questions of the US National Board of Medical Examiners (NBME) Subject Examination were compared before and after implementation of the curriculum. RESULTS: Eighty-nine students rotated on the clerkship during the pilot period of analysis. Seventy-one students (80%) viewed the videos prior to the class session, and 84 (94%) attended the session. Student satisfaction was very high for both parts of the curriculum. There was no significant difference in aggregate student performance on the gynaecological oncology questions of the NBME Subject Examination. The flipped classroom curriculum demonstrates a promising platform for using technology to make better use of students' time DISCUSSION: Our implementation of the flipped classroom curriculum for the gynaecologic oncology topics successfully demonstrates a promising platform for using technology to make better use of our students' time, and for increasing their satisfaction with the necessary didactic learning of the clerkship. PMID- 26009949 TI - Hockey lines for simulation-based learning. AB - BACKGROUND: Simulation-based health professional education is often limited in accommodating large numbers of students. Most organisations do not have enough simulation suites or staff to support growing demands. CONTEXT: We needed to find ways to make simulation sessions more accommodating for larger groups of learners, so that more than a few individuals could be active in a simulation scenario at any one time. Moreover, we needed to make the experience meaningful for all participating learners. INNOVATION: We used the metaphor of (ice) hockey lines and substitution 'on the fly' to effectively double the numbers of learners that can be actively engaged at once. Team players must communicate clearly, and observe keenly, so that currently playing members understand what is happening from moment to moment and incoming substitutes can take over their roles seamlessly. Most organisations do not have enough simulation suites or staff to support growing demands IMPLICATIONS: We found that this hockey lines approach to simulation-based team scenarios will raise learners' levels of engagement, reinforce good crew resource management (CRM) practices, enhance closed-loop communication, and help learners to understand their cognitive biases and limitations when working in high-pressure situations. During our continuing refinement of the hockey-lines approach, we developed a number of variations on the basic activity model, with various benefits and applications. Both students and teachers have been enthusiastically positive about this approach when it was introduced at our various courses and participating institutions. PMID- 26009950 TI - Teaching high-value care: a novel morning report. AB - BACKGROUND: Despite rising health care costs and calls for the incorporation of high-value care (HVC) into medical training, there are few described curricula to address this need. METHODS: We designed a single-group pre/post comparison to evaluate the impact of a 45-minute HVC morning report in one academic internal medicine programme on the trainees' self-reported knowledge of costs for common diagnostic tests, impact on future ordering practices and the educational value of the intervention. Medical trainees completed a diagnostic evaluation for a hypothetical case within the constraints of a budget during the morning report. Trainees completed a pre/post intervention survey regarding knowledge and attitudes towards HVC, and an evaluation of the intervention. The Wilcoxon signed rank test was used to determine differences between the pre/post intervention survey responses. There are few described curricula to address the need for the incorporation of high-value care into medical training RESULTS: Fifty-eight trainees participated in the educational activity: 57 completed the survey and 54 completed the evaluation. Our results indicate a significant increase following the morning report intervention in: the trainees' self-reported understanding of the cost for diagnostic tests (p < 0.001); the likelihood the cost of diagnostic tests would affect their future ordering practices (p < 0.001); and the likelihood that the cost of diagnostic tests would affect their timing of a diagnostic evaluation (p <= 0.001). The results also indicated a significant decrease in the likelihood that trainees would order extra diagnostic evaluations following the intervention (p = 0.015), and 96 per cent felt that the session was educationally valuable. DISCUSSION: A morning report incorporating cost of care can significantly increase trainees' perceived understanding of cost and affect self-reported ordering practices in an educationally valuable intervention. PMID- 26009951 TI - 'The Diamond': a structure for simulation debrief. AB - BACKGROUND: Despite debriefing being found to be the most important element in providing effective learning in simulation-based medical education reviews, there are only a few examples in the literature to help guide a debriefer. The diamond debriefing method is based on the technique of description, analysis and application, along with aspects of the advocacy-inquiry approach and of debriefing with good judgement. It is specifically designed to allow an exploration of the non-technical aspects of a simulated scenario. CONTEXT: The debrief diamond, a structured visual reminder of the debrief process, was developed through teaching simulation debriefing to hundreds of faculty members over several years. The diamond shape visually represents the idealised process of a debrief: opening out a facilitated discussion about the scenario, before bringing the learning back into sharp focus with specific learning points. Debriefing is the most important element in providing effective learning in simulation-based medical education reviews INNOVATION: The Diamond is a two-sided prompt sheet: the first contains the scaffolding, with a series of specifically constructed questions for each phase of the debrief; the second lays out the theory behind the questions and the process. IMPLICATION: The Diamond encourages a standardised approach to high-quality debriefing on non-technical skills. Feedback from learners and from debriefing faculty members has indicated that the Diamond is useful and valuable as a debriefing tool, benefiting both participants and faculty members. It can be used by junior and senior faculty members debriefing in pairs, allowing the junior faculty member to conduct the description phase, while the more experienced faculty member leads the later and more challenging phases. The Diamond gives an easy but pedagogically sound structure to follow and specific prompts to use in the moment. PMID- 26009952 TI - Medical students' comfort with children. AB - OBJECTIVE: To examine the comfort level of medical students beginning their paediatric clerkships, and to identify students' perceived concerns around interacting with children in a medical setting. METHODS: Prior to beginning required paediatric clerkships, third-year students in two south-eastern US medical schools completed an anonymous, 13-item questionnaire eliciting prior personal experiences with children, as well as comfort levels with selected aspects of paediatric care. RESULTS: Based on 237 responses (76.2% response rate), medical students' total child-related experiences were significantly associated with self-assessed comfort delivering paediatric care. Female students reported more prior experiences than male medical students; however, gender was not associated with comfort working with children. A dose-response curve of experience shows a critical level of two types of experiences for comfort in working with children. Students reported significantly lower levels of comfort in performing a physical exam on a child versus obtaining a child's medical history from a parent/caregiver. Students' child-related experiences were significantly associated with self-assessed comfort delivering paediatric care CONCLUSIONS: Medical students with little to no prior experience with children expressed significantly less comfort interacting with children in paediatric clerkships. A diversity of past experiences appeared to be a more meaningful correlate, as opposed to experience in a specific setting or context. Providing some general exposure to children during the preclinical years could instill in students greater comfort approaching their paediatric training. PMID- 26009953 TI - Reaching out: medical students leading in local communities. AB - BACKGROUND: Queen's University Red Cross is a medical student-led volunteer group with a key aim of promoting social change within local communities and empowering young people to aspire to higher education. We describe 'The Personal Development Certificate', a 12-week community development programme devised by third-year medical students at Queen's University Belfast to target young people who are lacking educational motivation, are disengaged at home or are marginalised through social circumstances. CONTEXT: Community-based education is of increasing importance within undergraduate and postgraduate medical education in the UK, and further afield. We evaluated the perceived improvements in key skills such as teamwork, leadership, communication, and problem solving in students following participation in this programme, and the extent to which their attitude and appreciation of community-based medicine changed. INNOVATION: [Students] appreciated the opportunity to translate a series of classroom-learned skills to real-life environments Following facilitation of this community-based initiative, all students reported a perceived improvement in the acquired skill sets. Students made strong links from this programme to previous clinical experiences and appreciated the opportunity to translate a series of classroom-learned skills to real-life environments and interactions. The students' appreciation and understanding of community-based medicine was the single most improved area of our evaluation. IMPLICATIONS: We have demonstrated that medical students possess the skills to develop and facilitate their own educational projects. Non clinical, student-led community projects have the potential to be reproduced using recognised frameworks and guidelines to complement the current undergraduate medical curriculum. PMID- 26009955 TI - Peer training and co-learning in global health care. AB - BACKGROUND: The Zambia Anaesthesia Development Project (ZADP) is a an international health care partnership between the UK and Zambia, designed to mutually benefit anaesthetic registrars from both countries in aspects deficient in their native training schemes. CONTEXT: The ZADP evolved from an initial plan to support a new anaesthesia training programme in Zambia, with visiting trainees providing continuity that was missing from short-term consultant visits. The primary goal of the project was to improve patient safety and care by delivering teaching, and by developing management, leadership and governance structures. An important reciprocal goal was to provide a unique training experience for a UK registrar in a resource-poor environment, including the resulting clinical and non-clinical challenges. This model adds a useful dimension to the educational support provided, and also embodies the principle of co-development IMPLICATIONS: The ZADP and the Zambia Master of Medicine (MMed) Anaesthesia programme provides an example of a cross-cultural peer-directed co-learning model that benefits trainees from developed and developing postgraduate training programmes. This synergistic model is one that could be applied to other educational initiatives supported from overseas. This model not only adds a useful dimension to the educational support provided, but also embodies the principle of co-development that is so important to the sustainability of such projects. PMID- 26009954 TI - A solid grounding: prescribing skills training. AB - BACKGROUND: Prescribing is an error-prone process for all doctors, from those who are newly qualified through to those at consultant level. Newly qualified doctors write the majority of in-patient prescriptions and therefore represent an opportunity for safety improvement. Attention to prescribing as a patient-safety issue and potential educational interventions to help improve the situation have been published, but offer little to inform educators why and how any interventions may succeed. In order to identify areas of good practice, and to provide evidence of areas requiring further investigation and innovation, we aimed to ascertain the full range of prescribing practices for final-year medical students and newly qualified doctors across a large geopolitical region of the UK. METHODS: A questionnaire methodology was used. One questionnaire was sent to those responsible for final-year education, and a further, different questionnaire was sent to those responsible for the training of newly qualified doctors, asking about prescribing education in their locality. Questionnaires were sent to 15 hospitals in total. Prescribing is an error-prone process for all doctors RESULTS: Twelve hospitals contributed to final-year medical student data: a response rate of 80 per cent. A variety of methods, including student assistantship, pharmacist-led skills sessions and practical assessment, were offered to varying degrees. Free-text responses identified opportunities for different prescribing education and support. All 15 hospitals provided data on doctors' education, with interventions including e-learning, assessment and support from ward-based pharmacists. DISCUSSION: Current education focuses on the technical and knowledge-based paradigm of prescribing. Human factors and the impact of electronic prescribing should play a part in future developments in prescribing education. PMID- 26009956 TI - Peer-assisted bedside teaching rounds. AB - BACKGROUND: Although postgraduate trainees play a well-accepted role in medical education, little consideration has traditionally been given to senior undergraduate trainees as teachers. Recently, research has shown senior medical students (SMS) can play an effective teaching role for junior medical students (JMS) in non-clinical medical settings. PURPOSE: The purpose of our study was to understand the perceptions of SMSs as teachers in a clinical environment for JMS. METHOD: All students who participated in our peer-led bedside teaching programme from September 2010 to May 2012 were invited to complete a questionnaire following their teaching session. Fifty-six of 70 JMS (80%) and 15 of 15 SMS (100%) participated. Survey questions addressed learning, bedside experiences, teacher effectiveness and the overall usefulness of these sessions. The data collected were analysed for significance of the perceptions reported. RESULTS: We found students reported positive and statistically significant results in all domains examined. JMS reported that sessions were highly valuable learning, improved confidence and comfort at the bedside, had excellent teaching and were a valuable addition to their clinical skills training. SMS reported getting highly valuable learning through preparation and developing improved comfort in a teaching role. Little consideration has traditionally been given to senior undergraduate trainees as teachers CONCLUSIONS: Our findings demonstrate that peer-directed learning in undergraduate medical education can be effectively implemented in the clinical arena. PMID- 26009957 TI - Receiving feedback from peers: medical students' perceptions. AB - BACKGROUND: During peer assessment activities, students are often required to provide feedback to their peers. The quality of such feedback can be perceived by recipients to be superior, and better received, than feedback given by academic staff. The aim of this study was to investigate students' views on receiving verbal feedback from their peers during their formative long case examination. METHODS: During 2013, year-4 students (n = 48) were assessed on their formative long case presentation and discussion by a student examiner, alongside an academic co-examiner. The student examinee was then provided with verbal feedback by both the student examiner and the academic co-examiner. To gain insight into students' views on receiving feedback from their peers, two focus groups were held. Students are often required to provide feedback to their peers RESULTS: Of the 48 participants, 35 per cent (17/48) attended focus groups. Students did not like receiving peer feedback during the scheduled examination time, in the presence of the academic co-examiner. They did value peer feedback, but preferred to receive this in a relaxed environment, after the examination. CONCLUSION: In the formative examination, students perceived the feedback given by their peer co examiner to be less constructive, less accurate and less helpful than the feedback given by the academic co-examiner. These findings may have implications for the feedback process for future iterations of the formative long case examination. PMID- 26009958 TI - Significance in medical education research. PMID- 26009959 TI - Reflections of a trainee geriatrician. PMID- 26009960 TI - Tablets for tomorrow's doctors. PMID- 26009963 TI - Teaching and assessing non-technical skills. PMID- 26009964 TI - Limitations of medical student mentor programmes. PMID- 26009965 TI - Limitations of medical student mentor programmes: a response. PMID- 26009966 TI - Single dose vaccination of the ASO3-adjuvanted A(H1N1)pdm09 monovalent vaccine in health care workers elicits homologous and cross-reactive cellular and humoral responses to H1N1 strains. AB - Healthcare workers (HCW) were prioritized for vaccination during the 2009 influenza A(H1N1)pdm09 pandemic. We conducted a clinical trial in October 2009 where 237 HCWs were immunized with a AS03-adjuvanted A(H1N1)pdm09 monovalent vaccine. In the current study, we analyzed the homologous and cross-reactive H1N1 humoral responses using prototype vaccine strains dating back to 1977 by the haemagglutinin inhibition (HI), single radial hemolysis SRH), antibody secreting cell (ASC) and memory B cell (MBC) assays. The cellular responses were assessed by interferon-gamma (IFN-gamma) ELISPOT and by intracellular staining (ICS) for the Th1 cytokines IFN-gamma, interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha). All assays were performed using blood samples obtained prior to (day 0) and 7, 14 and 21 d post-pandemic vaccination, except for ASC (day 7) and ICS (days 0 and 21). Vaccination elicited rapid HI, SRH and ASC responses against A(H1N1)pdm09 which cross reacted with seasonal H1N1 strains. MBC responses were detected against the homologous and seasonal H1N1 strains before vaccination and were boosted 2 weeks post-vaccination. An increase in cellular responses as determined by IFN-gamma ELISPOT and ICS were observed 1-3 weeks after vaccination. Collectively, our data show that the AS03-adjuvanted A(H1N1)pdm09 vaccine induced rapid cellular and humoral responses against the vaccine strain and the response cross-reacted against prototype H1N1 strains dating back to 1977. PMID- 26009971 TI - Integrating Family-Based Treatment and Dialectical Behavior Therapy for Adolescent Bulimia Nervosa: Preliminary Outcomes of an Open Pilot Trial. AB - Adolescent bulimia nervosa (BN) remains relatively understudied, and the complex interaction between core eating psychopathology and emotional regulation difficulties provides ongoing challenges for full symptom remission. In an open pilot trial, we aimed to investigate the efficacy of a program integrating family based treatment (FBT) and dialectical behavior therapy (DBT) in treating adolescent BN, without exclusion criteria. Participants were 35 adolescents who underwent partial hospital treatment for BN, and outcomes included measures of core BN pathology and emotional regulation difficulties, as well as parental measures of self-efficacy, completed at intake and discharge. Results indicate significant improvements in overall eating disorder pathology, t(68) = 4.52, p = .002, and in core BN symptoms, including objective binge episodes, t(68) = 2.01, p = .041, and self-induced vomiting, t(68) = 2.90, p = .005. Results also illustrated a significant increase in parental efficacy throughout the course of treatment, t(20) = .081, p = .001, although no global improvement in difficulties in emotion regulation was noted, t(68) = 1.12, p = .285. These preliminary findings support the utility of this integration of FBT and DBT, although raise interesting questions as to the mechanism of symptom remission. PMID- 26009967 TI - Role transitions and young adult maturing out of heavy drinking: evidence for larger effects of marriage among more severe premarriage problem drinkers. AB - BACKGROUND: Research has shown a developmental process of "maturing out" of problem drinking beginning in young adulthood. Perhaps surprisingly, past studies suggest that young adult drinking reductions may be particularly pronounced among those exhibiting relatively severe forms of problem drinking earlier in emerging adulthood. This may occur because more severe problem drinkers experience stronger ameliorative effects of normative young adult role transitions like marriage. METHODS: The hypothesis of stronger marriage effects among more severe problem drinkers was tested using 3 waves of data from a large ongoing study of familial alcohol disorder (N = 844; 51% children of alcoholics). RESULTS: Longitudinal growth models characterized (i) the curvilinear trajectory of drinking quantity from ages 17 to 40, (ii) effects of marriage on altering this age-related trajectory, and (iii) moderation of this effect by premarriage problem drinking levels (alcohol consequences and dependence symptoms). Results confirmed the hypothesis that protective marriage effects on drinking quantity trajectories would be stronger among more severe premarriage problem drinkers. Supplemental analyses showed that results were robust to alternative construct operationalizations and modeling approaches. CONCLUSIONS: Consistent with role incompatibility theory, findings support the view of role conflict as a key mechanism of role-driven behavior change, as greater problem drinking likely conflicts more with demands of roles like marriage. This is also consistent with the developmental psychopathology view of transitions and turning points. Role transitions among already low-severity drinkers may merely represent developmental continuity of a low-risk trajectory, whereas role transitions among higher-severity problem drinkers may represent developmentally discontinuous "turning points" that divert individuals from a higher- to a lower-risk trajectory. Practically, findings support the clinical relevance of role-related "maturing out processes" by suggesting that they often reflect natural recovery from clinically significant problem drinking. Thus, understanding these processes could help clarify the nature of pathological drinking and inform interventions. PMID- 26009972 TI - Mycosis fungoides with epidermal mucinosis: a variant of mycosis fungoides with a spongiosis-like pattern. AB - BACKGROUND: The histopathologic diagnosis of mycosis fungoides (MF) has classically relied on the presence of atypical epidermotropic T-lymphocytes predominating over spongiosis. However, in some cases of MF, prominent epidermal mucinosis in a spongiosis-like pattern mimics a spongiotic dermatitis. To our knowledge, only one series in the literature has thus far recognized the presence of epidermal mucinosis in MF. METHODS: We evaluated 30 skin biopsies from 18 patients with the clinical diagnosis of MF, which fulfilled all histopathologic criteria for patch- or plaque-stage MF, but also showed epidermal mucinosis in a spongiosis-like pattern. A total of 15 specimens were studied by immunohistochemistry, and seven were tested for T-cell receptor (TCR) gene rearrangements. Twenty biopsies of spongiotic dermatitides were included as controls. RESULTS: We confirmed the presence of epidermal mucinosis in all 30 cases of MF with a spongiosis-like pattern based on histopathologic criteria and the colloidal iron stain for mucin. Immunohistochemistry in 15 specimens showed significant loss of pan-T-cell antigens CD5 (10/15) and CD7 (14/15); and TCR clonality was detected in 7 specimens from 6 patients, supporting the diagnosis of MF. CONCLUSIONS: We report helpful histopathologic criteria for distinguishing MF with epidermal mucinosis in a spongiosis-like pattern from spongiotic dermatitis. PMID- 26009973 TI - Older people and oral health: setting a patient-centred research agenda. AB - OBJECTIVE: The aim of this pilot study was to provide the opportunity to enable older people to prioritise the research agenda to improve their own oral health. BACKGROUND: Little is known about the ageing population's views about their oral health from their perspective. Priority Setting Partnerships (PSPs) incorporate users' perspectives to prioritise research agendas and are based on a series of sequential steps to build consensus. This structured approach ensures their narrative and thoughts are heard and helps counter the 'top-down' medical model that can dominate healthcare services. MATERIALS AND METHODS: A PSP was undertaken with four key stakeholder groups: service users, carers, third sector and specialists. Six initial questions were posed to each group prior to a facilitated discussion led by one of the research team. Collective responses where then considered by a final consensus group. The views of the different groups were recorded, transcribed verbatim and underwent thematic analysis. RESULTS: The top three research priorities identified by the final group were to: (i) identify 'best practice' in the prevention and treatment of oral diseases for older people, (ii) identify the training needs for the dental profession and (iii) understand the key issues for older people from their perspective. Improving access to services, the importance of client appropriate information and the need for effective primary and secondary prevention were also articulated. CONCLUSION: Asking older people to prioritise the research agenda proved to be a positive experience. Key issues related to improving communication and the availability of appropriate evidence-based information on primary, secondary and tertiary prevention. PMID- 26009974 TI - Review of natural product databases. AB - OBJECTIVES: Many natural products have pharmacological or biological activities that can be of therapeutic benefit in treating diseases, and are also an important source of inspiration for development of potential novel drugs. The past few decades have witnessed extensive study of natural products for their promising prospects in application of medicinal chemistry, molecular biology and pharmaceutical sciences. MATERIALS AND METHODS: Natural product databases have provided systematic collection of information concerning natural products and their derivatives, including structure, source and mechanisms of action, which significantly support modern drug discovery. RESULTS: Currently, a considerable number of natural product databases, such as TCM Database@Taiwan, TCMID, CEMTDD, SuperToxic and SuperNatural, have been developed, providing data such as integrated medicinal herbs, ingredients, 2D/3D structures of the compounds, related target proteins, relevant diseases, and metabolic toxicity and more. CONCLUSIONS: We focus on an analytical overview of current natural product databases, and further discuss the good, bad or imperfection of current ones, in the hope of better integrating existing relevant outcomes, thus providing new routes for future drug discovery. PMID- 26009975 TI - People-centred and integrated health services. PMID- 26009976 TI - Industry and rural health: part of the problem or part of the solution? PMID- 26009977 TI - Outcomes of clinical decision support (CDS) and correlates of CDS use for home care patients with high medication regimen complexity: a randomized trial. AB - RATIONALE, AIMS AND OBJECTIVES: To assess the outcomes of a clinical decision support (CDS) intervention designed for home care patients with high medication regimen complexity (MRC) and to examine correlates of CDS use. METHOD: The CDS consisted of a computerized algorithm that identified high MRC patients, electronic alerts and a care management module. Nurses were randomized upon identification of an eligible patient. Full intention to treat and intervention group-only analyses were completed. Regression-adjusted outcomes were hospitalization, emergency department use and reduction in MRC. RESULTS: Five hundred nurses were randomized with 7919 of their patients. Approximately 20% of the intervention group was hospitalized versus 21% in the control group; 16.5% versus 16.7% had an emergency department visit; and 6% in each group dropped below the high MRC threshold. No statistically significant differences were found in the intention to treat analysis. Eighty-two percent of intervention nurses used the CDS but for only 42% of their patients. Among intervention patients, CDS use (vs. non-use) was associated with reduced MRC and hospitalization. CDS use was associated with various clinician and patient characteristics. CONCLUSION: CDS use was limited, negating the impact of the intervention overall. Findings on correlates of CDS use and the relationship between CDS use and positive outcomes suggest that CDS use and outcomes could be enhanced by avoiding short patient lengths of stay, improving continuity of care, increasing reliance on salaried nurses and/or increasing per diem nurses' incentives to use CDS. PMID- 26009978 TI - A pilot study to assess tobacco use among sexual minorities in Houston, Texas. AB - BACKGROUND AND OBJECTIVES: To assess tobacco use among lesbian, gay, bisexual, and transgender (LGBT) individuals from the 2014 Houston Pride Parade and Festival in Houston, Texas (TX). METHODS: Cross-sectional study using convenience sample of LGBT individuals (n = 99) examining tobacco use, sexual orientation, and other socio-demographic factors through survey participation. RESULTS: Findings showed a high prevalence of tobacco and electronic cigarettes use. White LGBT individuals had greater odds of using any type of tobacco product. DISCUSSION AND CONCLUSIONS: Despite a high smoking prevalence among the surveyed LGBT individuals, this study sample did not identify tobacco use as a health issue. SCIENTIFIC SIGNIFICANCE: Supports the need for further investigation on tobacco-related disparities among LGBT individuals in Houston, TX. PMID- 26009979 TI - Editorial Comment from Dr Jakobsen to Usefulness of sonourethrography for penile abscess as a result of xanthogranulomatous granuloma in the corpus cavernosum of an adult: A case report. PMID- 26009980 TI - Progressive retinal atrophy in the Polski Owczarek Nizinny dog: a clinical and genetic study. AB - OBJECTIVE: To describe ophthalmic, functional, structural, and genetical characteristics of progressive retinal atrophy (PRA) in the polski owczarek nizinny (PON) breed of dog. ANIMALS STUDIED CLINICALLY: Client-owned PON dogs (n = 82) from Sweden. PROCEDURES: Routine examination for presumed inherited eye disease was performed in all dogs. Bilateral full-field electroretinography (ERG) was performed in 11 affected and 4 control dogs. Eyes from one affected dog were studied with light microscopy. DNA samples from 34 Swedish and 30 PON dogs collected by Michigan State University (MSU) were tested for the mutations causing the rcd4 and prcd forms of PRA. RESULTS: Sixteen of the eighty-two Swedish dogs were diagnosed with PRA. Slight vascular attenuation, first seen at 4.5 years of age, preceded changes in tapetal reflectivity. The initial ERG changes in affected dogs showed markedly diminished rod responses, while cone responses were barely affected. Eventually, cone responses were also reduced. Retinal morphology showed approximately a 50% reduction of photoreceptor nuclei in the outer nuclear layer. Fourteen of fifteen PRA-affected Swedish dogs and eighteen of twenty of the MSU PRA-affected dogs tested genetically were positive for the rcd4 mutation. All tested dogs were negative for the mutation causing prcd-PRA. CONCLUSIONS: PRA of PON dogs is a late-onset degenerative disease with slow progression. There is early loss of rod function, while the cone system deteriorates later. The rcd4 mutation in the C2ORF71 gene was associated with the majority of the PRA cases tested. The possibility of additional forms of PRA in the breed cannot be excluded. PMID- 26009981 TI - Postinfectious irritable bowel syndrome after travelers' diarrhea--a cohort study. AB - BACKGROUND: There is sound evidence for the role of gastrointestinal infections in the development of postinfectious irritable bowel syndrome (PI-IBS), but understanding the interaction between mental factors and the infection remains incomplete. This study aims to (i) assess the occurrence of PI-IBS in a cohort of patients with self-reported travelers' diarrhea (TD), (ii) assess risk factors for PI-IBS development, and (iii) investigate the prognosis of PI-IBS after 1 year. METHODS: Patients consulting the travel clinic at the University Hospital Tuebingen, Germany (in 2009 and 2010) were identified from records and questioned in follow-ups in 2011 and 2012. We used the Rome III modular questionnaire to assess IBS, the Hospital Anxiety and Depression Scale to assess anxiety and depression, and the Patient Health Questionnaire to assess somatization. KEY RESULTS: We identified 529 eligible subjects from the clinical records. Of 135 subjects (age: 36.6 +/- 14.6 years, 58.5% female) included in the study sample 6.7% (95% CI 3.0-11.1) had PI-IBS. We found more females (88.9% vs 56.3%, p = 0.08) and younger age subjects (mean 29.3 vs 37.1 years, p = 0.02) among the PI IBS subjects. A multivariable regression model revealed vomiting at baseline and high somatization scores as strong and independent PI-IBS risk factors. One year later PI-IBS occurrence decreased to 3.3% (three cases of 90). CONCLUSIONS & INFERENCES: Our findings underline the close linkage of mental and somatic processes for the manifestation of PI-IBS. Screening for psychiatric comorbidities in patients with severe gastrointestinal infections may allow identifying groups at high risk for PI-IBS. PMID- 26009982 TI - Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells. AB - Metabolism is closely linked with cellular state and biological processes, but the mechanisms controlling metabolic properties in different contexts remain unclear. Cellular senescence is an irreversible growth arrest induced by various stresses, which exhibits active secretory and metabolic phenotypes. Here, we show that retinoblastoma protein (RB) plays a critical role in promoting the metabolic flow by activating both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) in cells that have undergone oncogene-induced senescence (OIS). A combination of real-time metabolic monitoring, and metabolome and gene expression analyses showed that OIS-induced fibroblasts developed an accelerated metabolic flow. The loss of RB downregulated a series of glycolytic genes and simultaneously reduced metabolites produced from the glycolytic pathway, indicating that RB upregulates glycolytic genes in OIS cells. Importantly, both mitochondrial OXPHOS and glycolytic activities were abolished in RB-depleted or downstream glycolytic enzyme-depleted OIS cells, suggesting that RB-mediated glycolytic activation induces a metabolic flux into the OXPHOS pathway. Collectively, our findings reveal that RB essentially functions in metabolic remodeling and the maintenance of the active energy production in OIS cells. PMID- 26009984 TI - Mutations in hippocalcin and autosomal recessive dystonia: a role for perturbed calcium signaling? PMID- 26009983 TI - Public Interest in Medical Research Participation: Does It Matter if Patients or Community Members Have Helped Design the Study? AB - PURPOSE: We determined national levels of public participation in medical research study design. We compared public interest in medical research participation (MRP) in studies overall, versus studies explicitly designed with public involvement. METHOD: Cross-sectional household survey of US population in June 2013. Descriptive statistics estimated participation in medical research study design. Chi-square test compared levels of interest in MRP if respondent knew patients or community members helped design the study. RESULTS: Of 2,048 respondents (participation rate 60%), 5% knew someone who had helped design a medical research study. There was no association between having known someone or personal participation in study design and willingness to engage in MRP. Although the overall proportion of respondents who would consider MRP initially (51%) was similar to the proportion who would consider MRP with community member involvement in study design (49%), the changes in respondents' views across the different scenarios were significantly greater than what would have been expected by chance. CONCLUSIONS: We found similar levels of interest in MRP whether or not the public is involved in medical research study design. This finding may indicate that public involvement in study design, like community-based participatory research, may not affect overall rates of MRP. PMID- 26009985 TI - Comparison of free amino acids, antioxidants, soluble phenolic acids, cytotoxicity and immunomodulation of fermented mung bean and soybean. AB - BACKGROUND: Mung bean and soybean have been individually reported previously to have antioxidant, cytotoxic and immunomodulatory effects, while fermentation is a well-known process to enhance the bioactive compounds that contribute to higher antioxidant, cytotoxic and immunomodulation effects. In this study, the free amino acids profile, soluble phenolic acids content, antioxidants, cytotoxic and immunomodulatory effects of fermented and non-fermented mung bean and soybean were compared. RESULTS: Fermented mung bean was recorded to have the highest level of free amino acids, soluble phenolic acids (especially protocatechuic acid) and antioxidant activities among all the tested products. Both fermented mung bean and soybean possessed cytotoxicity activities against breast cancer MCF 7 cells by arresting the G0/G1 phase followed by apoptosis. Moreover, fermented mung bean and soybean also induced splenocyte proliferation and enhanced the levels of serum interleukin-2 and interferon-gamma. CONCLUSION: Augmented amounts of free amino acids and phenolic acids content after fermentation enhanced the antioxidants, cytotoxicity and immunomodulation effects of mung bean and soybean. More specifically, fermented mung bean showed the best effects among all the tested products. This study revealed the potential of fermented mung bean and soybean as functional foods for maintenance of good health. PMID- 26009986 TI - The SYNERGY biodegradable polymer everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety study. AB - AIMS: SYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly-lactide-co-glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent. METHODS AND RESULTS: SYNERGY stents were implanted in arteries of domestic swine. Devices were explanted at predetermined time points (up to 120 days) and the extent of PLGA coating or everolimus remaining on the stents was quantified. Everolimus levels in the arterial tissue were also evaluated. A pathological analysis on coronary arteries of single and overlapping stents was performed at time points between 5 and 270 days. PLGA bioabsorption began immediately after implantation, and drug release was essentially complete by 90 days; PLGA absorption was substantially complete by 120 days (>90% of polymer was absorbed) leaving a bare metal SYNERGY stent. Vascular response was similar among SYNERGY and control stents (bare metal, polymer-only, and 3* polymer-only). Mild increases in para-strut fibrin were seen for SYNERGY at an early time point with no significant differences in all other morphological and morphometric parameters through 270 days or endothelial function (eNOS immunostaining) at 90 or 180 days. Inflammation was predominantly minimal to mild for all device types. CONCLUSION: In a swine model, everolimus was released by 90 days and PLGA bioabsorption was complete shortly thereafter. The SYNERGY stent and its biodegradable polymer, even at a 3* safety margin, demonstrated vascular compatibility similar to bare metal stent controls. PMID- 26009987 TI - A less-biased analysis of metalloproteins reveals novel zinc coordination geometries. AB - Zinc metalloproteins are involved in many biological processes and play crucial biochemical roles across all domains of life. Local structure around the zinc ion, especially the coordination geometry (CG), is dictated by the protein sequence and is often directly related to the function of the protein. Current methodologies in characterizing zinc metalloproteins' CG consider only previously reported CG models based mainly on nonbiological chemical context. Exceptions to these canonical CG models are either misclassified or discarded as "outliers." Thus, we developed a less-biased method that directly handles potential exceptions without pre-assuming any CG model. Our study shows that numerous exceptions could actually be further classified and that new CG models are needed to characterize them. Also, these new CG models are cross-validated by strong correlation between independent structural and functional annotation distance metrics, which is partially lost if these new CGs models are ignored. Furthermore, these new CG models exhibit functional propensities distinct from the canonical CG models. PMID- 26009988 TI - Multiplexed paper analytical device for quantification of metals using distance based detection. AB - Exposure to metal-containing aerosols has been linked with adverse health outcomes for almost every organ in the human body. Commercially available techniques for quantifying particulate metals are time-intensive, laborious, and expensive; often sample analysis exceeds $100. We report a simple technique, based upon a distance-based detection motif, for quantifying metal concentrations of Ni, Cu, and Fe in airborne particulate matter using microfluidic paper-based analytical devices. Paper substrates are used to create sensors that are self contained, self-timing, and require only a drop of sample for operation. Unlike other colorimetric approaches in paper microfluidics that rely on optical instrumentation for analysis, with distance-based detection, analyte is quantified visually based on the distance of a colorimetric reaction, similar to reading temperature on a thermometer. To demonstrate the effectiveness of this approach, Ni, Cu, and Fe were measured individually in single-channel devices; detection limits as low as 0.1, 0.1, and 0.05 MUg were reported for Ni, Cu, and Fe. Multiplexed analysis of all three metals was achieved with detection limits of 1, 5, and 1 MUg for Ni, Cu, and Fe. We also extended the dynamic range for multi-analyte detection by printing concentration gradients of colorimetric reagents using an off-the-shelf inkjet printer. Analyte selectivity was demonstrated for common interferences. To demonstrate utility of the method, Ni, Cu, and Fe were measured from samples of certified welding fume; levels measured with paper sensors matched known values determined gravimetrically. PMID- 26009989 TI - A prospective randomized cohort study evaluating 3 weeks vs 6 weeks of oral antibiotic treatment in the setting of "maximal medical therapy" for chronic rhinosinusitis. AB - BACKGROUND: Surprisingly, little literature exists evaluating the optimal duration of antibiotic treatment in "maximal medical therapy" for chronic rhinosinusitis (CRS). As such, we investigated whether 3 weeks vs 6 weeks of antibiotic therapy resulted in significant differences in clinical response. METHODS: A prospective, randomized cohort study was performed with patients assigned to 3-week or 6-week cohorts. Our primary outcome was failure of "maximal medical therapy" and surgical recommendation. Secondary outcomes included changes in pretherapy and posttherapy scores for the Rhinosinusitis Disability Index (RSDI), Chronic Sinusitis Survey (CSS), and computed tomography (CT)-based Lund Mackay (LM) evaluation. Analyses were substratified based on presence of nasal polyps. RESULTS: Forty patients were randomized to the 3-week or 6-week treatment cohorts, with near-complete clinical follow-up achieved. No significant difference was found between the proportion of patients who failed medical therapy and were deemed surgical candidates between the 2 cohorts (71% vs 68%, p = 1.000). No significant difference was found in the change of RSDI or CSS scores in the 3 vs 6 weeks of treatment groups (mean +/- standard error of the mean [SEM]; RSDI: 9.62 +/- 4.14 vs 1.53 +/- 4.01, p = 0.868; CSS: 5.75 +/- 4.36 vs 9.65 +/- 5.34, p = 0.573). Last, no significant difference was found in the change of LM scores (3.35 +/- 1.11 vs 1.53 +/- 0.81, p = 0.829). CONCLUSION: Based on this data, there is little difference in clinical outcomes between 3 weeks vs 6 weeks of antibiotic treatment as part of "maximal medical therapy" for CRS. Increased duration of antibiotic treatment theoretically may increase risk from side effects and creates higher healthcare costs. PMID- 26009990 TI - Impact of mobile phone use on car-following behaviour of young drivers. AB - Multitasking, such as the concurrent use of a mobile phone and operating a motor vehicle, is a significant distraction that impairs driving performance and is becoming a leading cause of motor vehicle crashes. This study investigates the impact of mobile phone conversations on car-following behaviour. The CARRS-Q Advanced Driving Simulator was used to test a group of young Australian drivers aged 18-26 years on a car-following task in three randomised phone conditions: baseline (no phone conversation), hands-free and handheld. Repeated measure ANOVA was applied to examine the effect of mobile phone distraction on selected car following variables such as driving speed, spacing, and time headway. Overall, drivers tended to select slower driving speeds, larger vehicle spacings, and longer time headways when they were engaged in either hands-free or handheld phone conversations, suggesting possible risk compensatory behaviour. In addition, phone conversations while driving influenced car-following behaviour such that variability was increased in driving speeds, vehicle spacings, and acceleration and decelerations. To further investigate car-following behaviour of distracted drivers, driver time headways were modelled using Generalized Estimation Equation (GEE). After controlling for various exogenous factors, the model predicts an increase of 0.33s in time headway when a driver is engaged in hands-free phone conversation and a 0.75s increase for handheld phone conversation. The findings will improve the collective understanding of distraction on driving performance, in particular car following behaviour which is most critical in the determination of rear-end crashes. PMID- 26009991 TI - Phosphorylation of interleukin (IL)-24 is required for mediating its anti-cancer activity. AB - Interleukin (IL)-24 is a tumor suppressor/cytokine gene that undergoes post translational modifications (PTMs). Glycosylation and ubiquitination are important for IL-24 protein stabilization and degradation respectively. Little is known about IL-24 protein phosphorylation and its role in IL-24-mediated anti tumor activities. In this study we conducted molecular studies to determine whether IL-24 phosphorylation is important for IL-24-mediated anti-cancer activity.Human H1299 lung tumor cell line that was stably transfected with a doxycycline (DOX)-inducible (Tet-on) plasmid vector carrying the cDNA of IL-24 wild-type (IL-24wt) or IL-24 with all five phosphorylation sites replaced (IL 24mt) was used in the present study. Inhibition of tumor cell proliferation, cell migration and invasion, and induction of G2/M cell cycle arrest was observed in DOX-induced IL-24wt-expressing cells but not in IL-24mt-expressing cells. Secretion of IL-24mt protein was greatly reduced compared to IL-24wt protein. Further, IL-24wt and IL-24mt proteins markedly differed in their subcellular organelle localization. IL-24wt but not IL-24mt inhibited the AKT/mTOR signaling pathway. SiRNA-mediated AKT knockdown and overexpression of myristolyated AKT protein confirmed that IL-24wt but not IL-24mt mediated its anti-cancer activity by inhibiting the AKT signaling pathway.Our results demonstrate that IL-24 phosphorylation is required for inhibiting the AKT/mTOR signaling pathway and exerting its anti-cancer activities. PMID- 26009992 TI - Molecular characterization of patients with pathologic complete response or early failure after neoadjuvant chemotherapy for locally advanced breast cancer using next generation sequencing and nCounter assay. AB - Neoadjuvant chemotherapy (NAC) has the added advantage of increasing breast conservation rates with equivalent survival outcomes compared with adjuvant chemotherapy. A subset of breast cancer patients who received NAC experienced early failure (EF) during the course of therapy or within a short period after curative breast surgery. In contrast, patients with pathological complete response (pCR) were reported to have markedly favorable outcomes. This study was performed to identify actionable mutation(s) and to explain refractoriness and responsiveness to NAC. Included in this analysis were 76 patients among 397 with locally advanced breast cancer for whom a preoperative fresh-frozen paraffin embedded tumor block was available for next-generation sequencing using AmpliSeq. The incidence of missense mutations in KRAS was much higher in patients with EF than in other groups (p < 0.01). In contrast, polymorphisms of the cMET gene were found in patients with pCR exclusively (p < 0.01). PMID- 26009993 TI - A dominant-negative F-box deleted mutant of E3 ubiquitin ligase, beta-TrCP1/FWD1, markedly reduces myeloma cell growth and survival in mice. AB - Treatment of multiple myeloma with bortezomib can result in severe adverse effects, necessitating the development of targeted inhibitors of the proteasome. We show that stable expression of a dominant-negative F-box deleted (a??F) mutant of the E3 ubiquitin ligase, SCFbeta-TrCP/FWD1, in murine 5TGM1 myeloma cells dramatically attenuated their skeletal engraftment and survival when inoculated into immunocompetent C57BL/KaLwRij mice. Similar results were obtained in immunodeficient bg-nu-xid mice, suggesting that the observed effects were independent of host recipient immune status. Bone marrow stroma offered no protection for 5TGM1-a??F cells in cocultures treated with tumor necrosis factor (TNF), indicating a cell-autonomous anti-myeloma effect. Levels of p100, IkappaBalpha, Mcl-1, ATF4, total and cleaved caspase-3, and phospho-beta-catenin were elevated in 5TGM1-a??F cells whereas cIAP was down-regulated. TNF also activated caspase-3 and downregulated Bcl-2, correlating with the enhanced susceptibility of 5TGM1-a??F cells to apoptosis. Treatment of 5TGM1 tumor-bearing mice with a beta-TrCP1/FWD1 inhibitor, pyrrolidine dithiocarbamate (PDTC), significantly reduced tumor burden in bone. PDTC also increased levels of cleaved Mcl-1 and caspase-3 in U266 human myeloma cells, correlating with our murine data and validating the development of specific beta-TrCP inhibitors as an alternative therapy to nonspecific proteasome inhibitors for myeloma patients. PMID- 26009994 TI - RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. AB - PURPOSE: The miniature biodegradable implant siG12D-LODERTM was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC). METHODS: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death. RESULTS: Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%. CONCLUSIONS: The combination of siG12D LODERTM and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785. PMID- 26009995 TI - Simultaneous Nano- and Microscale Control of Nanofibrous Microspheres Self Assembled from Star-Shaped Polymers. AB - Star-shaped polymers with varying arm numbers and arm lengths are synthesized, and self-assembled into microspheres, which are either smooth or fibrous on the nanoscale, and either nonhollow, hollow, or spongy on the microscale. The molecular architecture and functional groups determine the structure on both length scales. This exciting mechanistic discovery guides simultaneous control of both the nano- and microfeatures of the microspheres. PMID- 26009996 TI - Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and treatment of respiratory distress syndrome. AB - BACKGROUND: A wide variety of surfactant preparations have been developed and tested including synthetic surfactants and surfactants derived from animal sources. Although clinical trials have demonstrated that both synthetic surfactant and animal derived surfactant preparations are effective, comparison in animal models has suggested that there may be greater efficacy of animal derived surfactant products, perhaps due to the protein content of animal derived surfactant. OBJECTIVES: To compare the effect of animal derived surfactant to protein free synthetic surfactant preparations in preterm infants at risk for or having respiratory distress syndrome (RDS). SEARCH METHODS: Searches were updated of the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014), PubMed, CINAHL and EMBASE (1975 through November 2014). All languages were included. SELECTION CRITERIA: Randomized controlled trials comparing administration of protein free synthetic surfactants to administration of animal derived surfactant extracts in preterm infants at risk for or having respiratory distress syndrome were considered for this review. DATA COLLECTION AND ANALYSIS: Data collection and analysis were conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Fifteen trials met the inclusion criteria. The meta-analysis showed that the use of animal derived surfactant rather than protein free synthetic surfactant resulted in a significant reduction in the risk of pneumothorax [typical relative risk (RR) 0.65, 95% CI 0.55 to 0.77; typical risk difference (RD) -0.04, 95% CI -0.06 to 0.02; number needed to treat to benefit (NNTB) 25; 11 studies, 5356 infants] and a marginal reduction in the risk of mortality (typical RR 0.89, 95% CI 0.79 to 0.99; typical RD -0.02, 95% CI -0.04 to -0.00; NNTB 50; 13 studies, 5413 infants).Animal derived surfactant was associated with an increase in the risk of necrotizing enterocolitis [typical RR 1.38, 95% CI 1.08 to 1.76; typical RD 0.02, 95% CI 0.01 to 0.04; number needed to treat to harm (NNTH) 50; 8 studies, 3462 infants] and a marginal increase in the risk of any intraventricular hemorrhage (typical RR 1.07, 95% CI 0.99 to 1.15; typical RD 0.02, 95% CI 0.00 to 0.05; 10 studies, 5045 infants) but no increase in Grade 3 to 4 intraventricular hemorrhage (typical RR 1.08, 95% CI 0.91 to 1.27; typical RD 0.01, 95% CI -0.01 to 0.03; 9 studies, 4241 infants).The meta-analyses supported a marginal decrease in the risk of bronchopulmonary dysplasia or mortality associated with the use of animal derived surfactant preparations (typical RR 0.95, 95% CI 0.91 to 1.00; typical RD -0.03, 95% CI -0.06 to 0.00; 6 studies, 3811 infants). No other relevant differences in outcomes were noted. AUTHORS' CONCLUSIONS: Both animal derived surfactant extracts and protein free synthetic surfactant extracts are effective in the treatment and prevention of respiratory distress syndrome. Comparative trials demonstrate greater early improvement in the requirement for ventilator support, fewer pneumothoraces, and fewer deaths associated with animal derived surfactant extract treatment. Animal derived surfactant may be associated with an increase in necrotizing enterocolitis and intraventricular hemorrhage, though the more serious hemorrhages (Grade 3 and 4) are not increased. Despite these concerns, animal derived surfactant extracts would seem to be the more desirable choice when compared to currently available protein free synthetic surfactants. PMID- 26009997 TI - Patients with chronic hepatitis B should be screened for hepatocellular carcinoma regardless of liver stiffness measurement. PMID- 26009998 TI - The inconveniences of polysemy in the database era--don't call it "drug" unless you mean it. PMID- 26010003 TI - Evaluation of DNA methylation markers and their potential to predict human aging. AB - We present epigenetic methylation data for two genetic loci, GRIA2, and NPTX2, which were tested for prediction of age from different donors of biofluids. We analyzed 44 saliva samples and 23 blood samples from volunteers with ages ranging from 5 to 72 years. DNA was extracted and bisulfite modified using commercial kits. Specific primers were used for amplification and methylation profiles were determined by pyrosequencing. Methylation data from both markers and their relationship with age were determined using linear regression analysis, which indicates a positive correlation between methylation and age. Older individuals tend to have increased methylation in both markers compared to younger individuals and this trend was more pronounced in the GRIA2 locus when compared to NPTX2. The epigenetic predicted age, calculated using a GRIA2 regression analysis model, was strongly correlated to chronological age (R(2) = 0.801), with an average difference of 6.9 years between estimated and observed ages. When using a NPTX2 regression model, we observed a lower correlation between predicted and chronological age (R(2) = 0.654), with an average difference of 9.2 years. These data indicate these loci can be used as a novel tool for age prediction with potential applications in many areas, including clinical and forensic investigations. PMID- 26010004 TI - Association of N-cadherin levels and downstream effectors of Rho GTPases with dendritic spine loss induced by chronic stress in rat hippocampal neurons. AB - Chronic stress promotes cognitive impairment and dendritic spine loss in hippocampal neurons. In this animal model of depression, spine loss probably involves a weakening of the interaction between pre- and postsynaptic cell adhesion molecules, such as N-cadherin, followed by disruption of the cytoskeleton. N-cadherin, in concert with catenin, stabilizes the cytoskeleton through Rho-family GTPases. Via their effector LIM kinase (LIMK), RhoA and ras related C3 botulinum toxin substrate 1 (RAC) GTPases phosphorylate and inhibit cofilin, an actin-depolymerizing molecule, favoring spine growth. Additionally, RhoA, through Rho kinase (ROCK), inactivates myosin phosphatase through phosphorylation of the myosin-binding subunit (MYPT1), producing actomyosin contraction and probable spine loss. Some micro-RNAs negatively control the translation of specific mRNAs involved in Rho GTPase signaling. For example, miR 138 indirectly activates RhoA, and miR-134 reduces LIMK1 levels, resulting in spine shrinkage; in contrast, miR-132 activates RAC1, promoting spine formation. We evaluated whether N-cadherin/beta-catenin and Rho signaling is sensitive to chronic restraint stress. Stressed rats exhibit anhedonia, impaired associative learning, and immobility in the forced swim test and reduction in N-cadherin levels but not beta-catenin in the hippocampus. We observed a reduction in spine number in the apical dendrites of CA1 pyramidal neurons, with no effect on the levels of miR-132 or miR-134. Although the stress did not modify the RAC-LIMK cofilin signaling pathway, we observed increased phospho-MYPT1 levels, probably mediated by RhoA-ROCK activation. Furthermore, chronic stress raises the levels of miR-138 in accordance with the observed activation of the RhoA-ROCK pathway. Our findings suggest that a dysregulation of RhoA-ROCK activity by chronic stress could potentially underlie spine loss in hippocampal neurons. PMID- 26010006 TI - Training Paediatric Therapists to Deliver Constraint-Induced Movement Therapy (CIMT) in Sub-Saharan Africa. AB - Hospitals and therapists in developing countries often seek to learn how to deliver new forms of evidenced-based practice (EBP), including paediatric constraint-induced movement therapy (CIMT). This study examines a partnership implemented in Ethiopia, which trained therapists in CIMT and proposes a framework for sustainable EBP training. The aim of this study is to apply a translational and implementation framework to build capacity for CIMT in Addis Ababa, Ethiopia, that included intensive in-country training and hands-on delivery with patients, followed by clinical implementation and feedback. A goal was to develop a locally feasible, culturally relevant form of CIMT. We framed our partnership model in terms of an implementation science model for therapists from multiple hospitals in Addis Ababa. Measures included workshop attendance, delivery of the curriculum and assessment of therapist's knowledge, skills and feedback postworkshop. We established a successful partnership with a lead hospital and completed training for 12 therapists from five hospitals who demonstrated increases in knowledge and skills following training. We developed a new, practically useful, culturally appropriate form of CIMT for later implementation. This partnership was limited to training of paediatric therapists in sub-Saharan Africa. Future studies will report on therapists' ability to integrate this EBP training into clinical practice as well as future training. PMID- 26010005 TI - The cost of circadian desynchrony: Evidence, insights and open questions. AB - Coordinated daily rhythms are evident in most aspects of our physiology, driven by internal timing systems known as circadian clocks. Our understanding of how biological clocks are built and function has grown exponentially over the past 20 years. With this has come an appreciation that disruption of the clock contributes to the pathophysiology of numerous diseases, from metabolic disease to neurological disorders to cancer. However, it remains to be determined whether it is the disruption of our rhythmic physiology per se (loss of timing itself), or altered functioning of individual clock components that drive pathology. Here, we review the importance of circadian rhythms in terms of how we (and other organisms) relate to the external environment, but also in relation to how internal physiological processes are coordinated and synchronized. These issues are of increasing importance as many aspects of modern life put us in conflict with our internal clockwork. PMID- 26010007 TI - Adolescents in conflict: Intercultural contact attitudes of immigrant mothers and adolescents as predictors of family conflicts. AB - Recent research demonstrates that intergenerational differences in immigrant families' adaptation can be detrimental for family functioning. However, most of the findings originate from immigrant groups in North America who face different situations compared with European Diaspora returnees. This comparative study investigated whether ethnic German Diaspora immigrant adolescents' and mothers' disagreement about the desirability of adolescents' intercultural contact with native peers relates to more conflict in the family domain. In addition, we accounted for general developmental factors predicting family conflict by considering adolescents' background in terms of prosocial behaviour and hyperactivity. Participants comprised 185 Diaspora immigrant mother-adolescent dyads from the former Soviet Union living in Germany (adolescents: mean age 15.7 years, 60% female) and 197 native German mother-adolescent dyads (adolescents: mean age 14.7 years, 53% female). Results indicated a similar level of family conflict in immigrant and native families. However, conflict was elevated in those immigrant families disagreeing on intercultural contact attitudes, independent of the significant effects of adolescents' background of prosocial behaviour or hyperactivity. Our study highlights potential side effects in the family domain, if immigrant adolescents and parents disagree in their attitude regarding adaptation to the host culture's life domains, such as contact with native peers. PMID- 26010008 TI - Compound heterozygous myotonic dystrophy type 1. PMID- 26010010 TI - The three-dimensional structure of "Lonely Guy" from Claviceps purpurea provides insights into the phosphoribohydrolase function of Rossmann fold-containing lysine decarboxylase-like proteins. AB - The recently discovered cytokinin (CK)-specific phosphoribohydrolase "Lonely Guy" (LOG) is a key enzyme of CK biosynthesis, converting inactive CK nucleotides into biologically active free bases. We have determined the crystal structures of LOG from Claviceps purpurea (cpLOG) and its complex with the enzymatic product phosphoribose. The structures reveal a dimeric arrangement of Rossmann folds, with the ligands bound to large pockets at the interface between cpLOG monomers. Structural comparisons highlight the homology of cpLOG to putative lysine decarboxylases. Extended sequence analysis enabled identification of a distinguishing LOG sequence signature. Taken together, our data suggest phosphoribohydrolase activity for several proteins of unknown function. PMID- 26010011 TI - Flexible MoS2 Field-Effect Transistors for Gate-Tunable Piezoresistive Strain Sensors. AB - Atomically thin molybdenum disulfide (MoS2) is a promising two-dimensional semiconductor for high-performance flexible electronics, sensors, transducers, and energy conversion. Here, piezoresistive strain sensing with flexible MoS2 field-effect transistors (FETs) made from highly uniform large-area films is demonstrated. The origin of the piezoresistivity in MoS2 is the strain-induced band gap change, which is confirmed by optical reflection spectroscopy. In addition, the sensitivity to strain can be tuned by more than 1 order of magnitude by adjusting the Fermi level via gate biasing. PMID- 26010009 TI - IGF1 Promotes Adipogenesis by a Lineage Bias of Endogenous Adipose Stem/Progenitor Cells. AB - Adipogenesis is essential for soft tissue reconstruction following trauma or tumor resection. We demonstrate that CD31(-)/34(+)/146(-) cells, a subpopulation of the stromal vascular fraction (SVF) of human adipose tissue, were robustly adipogenic. Insulin growth factor-1 (IGF1) promoted a lineage bias towards CD31( )/34(+)/146(-) cells at the expense of CD31(-)/34(+)/146(+) cells. IGF1 was microencapsulated in poly(lactic-co-glycolic acid) scaffolds and implanted in the inguinal fat pad of C57Bl6 mice. Control-released IGF1 induced remarkable adipogenesis in vivo by recruiting endogenous cells. In comparison with the CD31( )/34(+)/146(+) cells, CD31(-)/34(+)/146(-) cells had a weaker Wnt/beta-catenin signal. IGF1 attenuated Wnt/beta-catenin signaling by activating Axin2/PPARgamma pathways in SVF cells, suggesting IGF1 promotes CD31(-)/34(+)/146(-) bias through tuning Wnt signal. PPARgamma response element (PPRE) in Axin2 promoter was crucial for Axin2 upregulation, suggesting that PPARgamma transcriptionally activates Axin2. Together, these findings illustrate an Axin2/PPARgamma axis in adipogenesis that is particularly attributable to a lineage bias towards CD31( )/34(+)/146(-) cells, with implications in adipose regeneration. PMID- 26010012 TI - Pd(II)-Directed Encapsulation of Hydrogenase within the Layer-by-Layer Multilayers of Carbon Nanotube Polyelectrolyte Used as a Heterogeneous Catalyst for Oxidation of Hydrogen. AB - A metal-directed assembling approach has been developed to encapsulate hydrogenase (H2ase) within a layer-by-layer (LBL) multilayer of carbon nanotube polyelectrolyte (MWNT-PVPMe), which showed efficient biocatalytic oxidation of H2 gas. The MWNT-PVPMe was prepared via a diazonium process and addition reactions with poly(4-vinylpyridine) (PVP) and methyl iodide (MeI). The covalently attached polymers and organic substituents in the polyelectrolyte comprised 60-70% of the total weight. The polyelectrolyte was then used as a substrate for H2ase binding to produce MWNT-PVPMe@H2ase bionanocomposites. X-ray photoelectron spectra revealed that the bionanocomposites included the elements of Br, S, C, N, O, I, Fe, and Ni, which confirmed that they were composed of MWNT-PVPMe and H2ase. Field emission transmission electron microscope images revealed that the H2ase was adsorbed on the surface of MWNT-PVPMe with the domains ranging from 20 to 40 nm. Further, with the use of the bionanocomposites as nanolinkers and Na2PdCl4 as connectors, the (Pd/MWNT-PVPMe@H2ase)n multilayers were constructed on the quartz and gold substrate surfaces by the Pd(II)-directed LBL assembling technique. Finally, the as-prepared LBL multilayers were used as heterogeneous catalysts for hydrogen oxidation with methyl viologen (MV(2+)) as an electron carrier. The dynamic processes for the reversible color change between blue-colored MV(+) and colorless MV(2+) (catalyzed by the LBL multilayers) were video recorded, which confirmed that the H2ase encapsulated within the present LBL multilayers was of much stronger stability and higher biocatalytic activity of H2 oxidation resulting in potential applications for the development of H2 biosensors and fuel cells. PMID- 26010013 TI - Reversible Fermi Level Tuning of a Sb2Te3 Topological Insulator by Structural Deformation. AB - For three-dimensional (3D) topological insulators that have a layered structure, strain was used to control critical physical properties. Here, we show that tensile strain decreases bulk carrier density while accentuating transport of topological surface state using temperature-dependent resistance and magneto resistance measurements, terahertz-time domain spectroscopy and density functional theory calculations. The induced strain was confirmed by transmittance X-ray scattering measurements. The results show the possibility of reversible topological surface state device control using structural deformation. PMID- 26010014 TI - Transfer of penicillin resistance from Streptococcus oralis to Streptococcus pneumoniae identifies murE as resistance determinant. AB - Beta-lactam resistant clinical isolates of Streptococcus pneumoniae contain altered penicillin-binding protein (PBP) genes and occasionally an altered murM, presumably products of interspecies gene transfer. MurM and MurN are responsible for the synthesis of branched lipid II, substrate for the PBP catalyzed transpeptidation reaction. Here we used the high-level beta-lactam resistant S. oralis Uo5 as donor in transformation experiments with the sensitive laboratory strain S. pneumoniae R6 as recipient. Surprisingly, piperacillin-resistant transformants contained no alterations in PBP genes but carried murEUo5 encoding the UDP-N-acetylmuramyl tripeptide synthetase. Codons 83-183 of murEUo5 were sufficient to confer the resistance phenotype. Moreover, the promoter of murEUo5 , which drives a twofold higher expression compared to that of S. pneumoniae R6, could also confer increased resistance. Multiple independent transformations produced S. pneumoniae R6 derivatives containing murEUo5 , pbp2xUo5 , pbp1aUo5 and pbp2bUo5 , but not murMUo5 sequences; however, the resistance level of the donor strain could not be reached. S. oralis Uo5 harbors an unusual murM, and murN is absent. Accordingly, the peptidoglycan of S. oralis Uo5 contained interpeptide bridges with one L-Ala residue only. The data suggest that resistance in S. oralis Uo5 is based on a complex interplay of distinct PBPs and other enzymes involved in peptidoglycan biosynthesis. PMID- 26010016 TI - Evaluation of the appropriateness of dosing, indication and safety of rivaroxaban in a community hospital. AB - WHAT IS KNOWN AND OBJECTIVE: For over 50 years, warfarin was the only oral anticoagulant approved in the United States. In 2011, the Food and Drug Administration (FDA) approved rivaroxaban. Since its introduction, rivaroxaban has served as an alternative to warfarin to minimize drug interactions and avoid drug monitoring. The objective of this study was to evaluate the appropriateness of rivaroxaban dosing, indication and safety in a community hospital and to identify areas for improvement in its use. METHODS: This single-centre, retrospective review evaluated patients who received at least one dose of rivaroxaban between November 2011 and July 2013. The primary outcome included appropriateness of the first day of therapy based on indication and renal function per FDA-approved dosing recommendations for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) and for the treatment or prevention of venous thromboembolism (VTE). The secondary outcome included incidence of major bleeding or non-major clinically relevant bleeding. RESULTS AND DISCUSSION: Of the 445 patients evaluated, 36.9% of patients treated for NVAF and 12.4% treated for VTE were on an inappropriate regimen. Major bleeding within 12 months occurred in 3.5% of patients treated for NVAF, 1.2% for VTE and 0% for off-label indications with a similar trend for non-major clinically relevant bleeding (3.8%, 1.8% and 0%, respectively). WHAT IS NEW AND CONCLUSION: Though offering potential advantages over warfarin, the use of rivaroxaban should be monitored to increase appropriateness of therapy and improve patient safety. Therapeutic interchanges, pharmacist-directed interventions and other initiatives can be implemented to ensure appropriate use. PMID- 26010015 TI - C1 inhibitor function using contact-phase proteases as target: evaluation of an innovative assay. AB - BACKGROUND: Controlling prekallikrein activation by C1 inhibitor (C1Inh) represents the most essential mechanism for angioedema patient protection. C1Inh function in the plasma is usually measured based on the residual activity of the C1s protease not involved in the pathological process. We have hereby proposed an alternative enzymatic measurement of C1Inh function based on contact-phase activation and correlation with angioedema diagnostic requirements. METHODS: The contact phase was reconstituted using the purified components, with C1Inh standard or plasma sample. The kinetics of the amidase activity were monitored using Pro-Phe-Arg-pNA, independently of alpha2-macroglobulin. We prevented any interference from a possible high plasma kininogenase activity by preincubating the samples with protease inhibitor. Receiver operating characteristics (ROC) were used to calculate the assay's diagnostic performance. RESULTS: The calibration curve was built using C1Inh standard (threshold limit 0.10 * 10(-3) U, i.e., 0.2 pmol), and C1Inh function was quantified in the sample, with a reference interval established based on healthy individuals (n = 281; men: 0.61 1.10 U/ml, median: 0.85 U/ml; women: 0.42-1.08 U/ml, median: 0.74 U/ml). The median values of female donors were lower than those of the others due to estrogen, yet C1Inh function remained within the reference interval. The ROC curve calculation provided the following optimum diagnostic cutoff values: women 0.36 U/ml (area under curve [AUC]: 0.99; sensitivity: 93.48%; specificity: 99.37%); and men 0.61 U/ml (AUC: 1; sensitivity: 100.0%; specificity: 100.0%). CONCLUSION: The performance outcome provided features suitable for angioedema diagnostic or follow-up. Established by means of the kinin formation process, this assay should be preferred over the method based on a C1s protease target. PMID- 26010017 TI - Information processing speed and attention in multiple sclerosis: Reconsidering the Attention Network Test (ANT). AB - OBJECTIVE: The Attention Network Test (ANT) assesses attention in terms of discrepancies between response times to items that differ in the burden they place on some facet of attention. However, simple arithmetic difference scores commonly used to capture these discrepancies fail to provide adequate control for information processing speed, leading to distorted findings when patient and control groups differ markedly in the speed with which they process and respond to stimulus information. This study examined attention networks in patients with multiple sclerosis (MS) using simple difference scores, proportional scores, and residualized scores that control for processing speed through statistical regression. METHOD: Patients with relapsing-remitting (N = 20) or secondary progressive (N = 20) MS and healthy controls (N = 40) of similar age, education, and gender completed the ANT. RESULTS: Substantial differences between patients and controls were found on all measures of processing speed. Patients exhibited difficulties in the executive control network, but only when difference scores were considered. When deficits in information processing speed were adequately controlled using proportional or residualized score, deficits in the alerting network emerged. The effect sizes for these deficits were notably smaller than those for overall information processing speed and were also limited to patients with secondary progressive MS. CONCLUSIONS: Deficits in processing speed are more prominent in MS than those involving attention, and when the former are properly accounted for, differences in the latter are confined to the alerting network. PMID- 26010018 TI - Synthesis and biological evaluation of boswellic acid-NSAID hybrid molecules as anti-inflammatory and anti-arthritic agents. AB - Methyl esters of the beta-boswellic acid (BA) and 11-keto-beta-boswellic acid (KBA) obtained from Boswellia serrata resin were subjected to Steglich esterification with the different non-steroidal anti-inflammatory drugs (NSAID) viz., ibuprofen, naproxen, diclophenac and indomethacin. The novel hybrids of methyl boswellate (5-8) and that of methyl 11-keto boswellate (9-12) were evaluated for anti-inflammatory activity by carrageenan-induced rat hind paw edema model and anti-arthritic activity by Complete Freund's Adjuvant (CFA) induced arthritis in Wister albino rat. Significant inhibition on carrageenan induced paw edema has been observed with 5, 6 and 10 where as in CFA induced rats, hybrids 5, 8, 9 and 12 exhibited pronounced antiarthritic activity. Hybrid molecules 5 and 9 have been found to be more effective in inhibiting in-vivo COX 2 than ibuprofen by itself, thus showing the synergistic effect. Hybrid 5 and 9 tested for in-vitro lipoxygenase and cyclooxygenase-2 (LOX/COX-2) inhibitory activity. The studies revealed that both 5 and 9 inhibited COX-2 relatively better than LOX enzyme. PMID- 26010019 TI - Prognostic factors of drug-resistant epilepsy in childhood: An Italian study. AB - BACKGROUND: Epilepsy is drug resistant in 30-40% of cases. We studied, retrospectively, the prognostic factors of drug resistance (DR) during a 15 year period, in an Italian sample of patients with childhood epilepsy. METHODS: A total of 117 patients were divided into two groups: one with DR, and the other without DR. The two groups were compared at the following time points: epilepsy onset (T0), and at 2, 5, 8 and 10 years after seizure onset (T2, T5, T8 and T10, respectively) using Fisher's exact test and randomization test. Multiple logistic regression analysis was then used to identify the most reliable predictive model of DR. RESULTS: Positive neurological examination at onset, symptomatic/probable symptomatic etiology, lack of response to the first drug, seizure clustering during follow up, intelligence quotient <= 70, altered neuropsychological examination at onset, and presence of cerebral lesions were predominant in cases of DR. The most reliable combinations of predictors of DR included partial or no response to the first drug, presence of seizure clustering during follow up, altered neurological examination at onset, and long latency between epilepsy onset and first drug at T2; partial or absent response to the first drug and positive magnetic resonance imaging (MRI) at T5; positive MRI and absence of generalized seizures at T8; and positive MRI at T10. DR also sometimes appeared after discontinuation of an effective therapy. CONCLUSIONS: Predictive factors of DR can be recognized in a large number of patients with epilepsy at disease onset, although the current possibility of predicting epilepsy outcome remains limited. In the long term, evidence of cerebral lesions appears to become the most significant prognostic factor. PMID- 26010020 TI - Does mood influence text processing and comprehension? Evidence from an eye movement study. AB - BACKGROUND: Previous research has indicated that mood influences cognitive processes. However, there is scarce data regarding the link between everyday emotional states and readers' text processing and comprehension. AIM: We aim to extend current research on the effects of mood induction on science text processing and comprehension, using eye-tracking methodology. We investigated whether a positive-, negative-, and neutral-induced mood influences online processing, as revealed by indices of visual behaviour during reading, and offline text comprehension, as revealed by post-test questions. We were also interested in the link between text processing and comprehension. SAMPLE: Seventy eight undergraduate students randomly assigned to three mood-induction conditions. METHODS: Students were mood-induced by watching a video clip. They were then asked to read a scientific text while eye movements were registered. Pre- and post-reading knowledge was assessed through open-ended questions. RESULTS: Experimentally induced moods lead readers to process an expository text differently. Overall, students in a positive mood spent significantly longer on the text processing than students in the negative and neutral moods. Eye-movement patterns indicated more effective processing related to longer proportion of look back fixation times in positive-induced compared with negative-induced readers. Students in a positive mood also comprehended the text better, learning more factual knowledge, compared with students in the negative group. Only for the positive-induced readers did the more purposeful second-pass reading positively predict text comprehension. CONCLUSIONS: New insights are given on the effects of normal mood variations and students' text processing and comprehension by the use of eye-tracking methodology. Important implications for the role of emotional states in educational settings are highlighted. PMID- 26010021 TI - Incidental learning of probability information is differentially affected by the type of visual working memory representation. AB - In this study, we investigated whether the ability to learn probability information is affected by the type of representation held in visual working memory. Across 4 experiments, participants detected changes to displays of coloured shapes. While participants detected changes in 1 dimension (e.g., colour), a feature from a second, nonchanging dimension (e.g., shape) predicted which object was most likely to change. In Experiments 1 and 3, items could be grouped by similarity in the changing dimension across items (e.g., colours and shapes were repeated in the display), while in Experiments 2 and 4 items could not be grouped by similarity (all features were unique). Probability information from the predictive dimension was learned and used to increase performance, but only when all of the features within a display were unique (Experiments 2 and 4). When it was possible to group by feature similarity in the changing dimension (e.g., 2 blue objects appeared within an array), participants were unable to learn probability information and use it to improve performance (Experiments 1 and 3). The results suggest that probability information can be learned in a dimension that is not explicitly task-relevant, but only when the probability information is represented with the changing dimension in visual working memory. PMID- 26010022 TI - CSBBCS at Ryerson University and the embodied cognition debate. AB - Introduces a series of articles in the current issue of the Canadian Journal of Experimental Psychology that focuses on embodied cognition. Embodied cognition is the role of sensorimotor processes in cognition. In organizing the Past President's Symposium at the Canadian Society for Brain, Behaviour and Cognitive Science's annual meeting, the outgoing past-president chose embodied cognition as the focus, and invited a proponent of the embodied position as well as one of the abstract position to present their views. The material from the symposium was used to create this series of articles. PMID- 26010023 TI - Toward a deeper understanding of embodiment. AB - This article sets the stage for a debate, played out in two subsequent articles in this issue by Glenberg and by Mahon, regarding the role of embodied conceptual representations in cognitive operations such as language understanding and object identification. On an embodied view of cognition, championed by Glenberg, conceptual knowledge and thought are necessarily grounded in sensorimotor representations. The contrary position, advocated by Mahon, is that symbolic thought is the foundation for cognition and is independent of such representations, although it may coincidentally evoke them. I review a few of the many available demonstrations showing that cognition is influenced by sensorimotor representations. Then, taking Mahon's perspective, I illustrate how examples from various classes of these demonstrations can be explained by mechanisms other than embodiment of conceptual representations. I close with an example of what can be taken as evidence for the representation of a behavioural goal that is abstract in the sense that it is not coded directly as an embodied action. PMID- 26010024 TI - Few believe the world is flat: How embodiment is changing the scientific understanding of cognition. AB - Science has changed many of our dearly held and commonsensical (but incorrect) beliefs. For example, few still believe the world is flat, and few still believe the sun orbits the earth. Few still believe humans are unrelated to the rest of the animal kingdom, and soon few will believe human thinking is computer-like. Instead, as with all animals, our thoughts are based on bodily experiences, and our thoughts and behaviors are controlled by bodily and neural systems of perception, action, and emotion interacting with the physical and social environments. We are embodied; nothing more. Embodied cognition is about cognition formatted in sensorimotor experience, and sensorimotor systems make those thoughts dynamic. Even processes that seem abstract, such as language comprehension and goal understanding, are embodied. Thus, embodied cognition is not limited to 1 type of thought or another: It is cognition. PMID- 26010025 TI - The burden of embodied cognition. AB - The thesis of embodied cognition has developed as an alternative to the view that cognition is mediated, at least in part, by symbolic representations. A useful testing ground for the embodied cognition hypothesis is the representation of concepts. An embodied view of concept representation argues that concepts are represented in a modality-specific format. I argue that questions about representational format are tractable only in the context of explicit hypotheses about how information spreads among conceptual representations and sensorimotor systems. When reasonable alternatives to the embodied cognition hypothesis are clearly defined, the available evidence does not distinguish between the embodied cognition hypothesis and those alternatives. Furthermore, I argue, the available data that are theoretically constraining indicate that concepts are more than just sensory and motor content. As such, the embodied/nonembodied debate is either largely resolved or at a point where the embodied and nonembodied approaches are no longer coherently distinct theories. This situation merits a reconsideration of what the available evidence can tell us about the structure of the conceptual system. I suggest that it is the independence of thought from perception and action that makes human cognition special-and that independence is made possible by the representational distinction between concepts and sensorimotor representations. PMID- 26010026 TI - Response to Glenberg: Conceptual content does not constrain the representational format of concepts. AB - Replies to comments by A. M. Glenberg (see record 2015-22897-006) on the author's original article (see record 2015-22897-004) on the embodied cognition debate. The core issue at stake in the debate is whether the format of thought is amodal or modality-specific. In his paper, Glenberg argues that "embodied systems do just fine accounting for perception, action, concrete cognition, and abstract cognition" and goes on to suggest that "Now the onus is on traditional cognitive scientists, those who wish to maintain a Cartesian distinction between human thought and action, a cherished and seemingly obvious belief, but ultimately, a type of flat-world hypothesis." But, is it really a "type of flat-world hypothesis" to maintain that cognitive processes can be amodal in their representational format? Mahon does not believe that it is. There is a reasonable theoretical alternative to the embodied cognition hypothesis that can account for the extant data, and which does not require adopting the view that "cognition is sensorimotor processing." That theoretical alternative (a) maintains a strict representational distinction between amodal concepts and sensorimotor systems and (b) argues that sensorimotor activation during conceptual processing reflects the structure and dynamics of connectivity between amodal representations and sensorimotor systems. The types of findings that Glenberg (2015) cites as support for embodied cognition do not distinguish between the embodied cognition hypothesis and this theoretical alternative. Furthermore, neuropsychological data indicate that sensorimotor impairments can occur without concomitant conceptual level deficits. PMID- 26010027 TI - Response to Mahon: Unburdening cognition from abstract symbols. AB - B. Z. Mahon (see record 2015-22897-004) has provided a real service to those researchers investigating human cognition by clearly framing much of the debate between an embodied approach to cognition and an abstract alternative. There are several areas in which Mahon and A. M. Glenberg agree. For example, Glenberg (although not all embodiment theorists) agrees that a major question is the degree to which bodily and neural sensorimotor activity constitutes cognition. In addition, the evidence is clear that there is something akin to a spread of activation amongst systems, and the very fact of this spread makes it difficult to distinguish embodied from nonembodied positions. There are also several areas about which the authors disagree. For example, Mahon suggests that we need to consider predictions of alternative hypotheses. The alternative he offers is that there is a distinction between concepts and sensorimotor activity. Although it is reasonable to consider this alternative, there is no description of what these nonembodied concepts are in Mahon's essay, just that they are not sensorimotor. Glenberg offers a partial compromise to the argument. PMID- 26010029 TI - Implementation and Operational Research: A Randomized Noninferiority Trial of AccuCirc Device Versus Mogen Clamp for Early Infant Male Circumcision in Zimbabwe. AB - BACKGROUND: Early infant male circumcision (EIMC) is a potential key HIV prevention intervention, providing it can be safely and efficiently implemented in sub-Saharan Africa. Here, we present results of a randomized noninferiority trial of EIMC comparing the AccuCirc device with Mogen clamp in Zimbabwe. METHODS: Between January and June 2013, eligible infants were randomized to EIMC through either AccuCirc or Mogen clamp conducted by a doctor, using a 2:1 allocation ratio. Participants were followed for 14 days post-EIMC. Primary outcomes for the trial were EIMC safety and acceptability. RESULTS: One hundred fifty male infants were enrolled in the trial and circumcised between 6 and 54 days postpartum (n = 100 AccuCirc; n = 50 Mogen clamp). Twenty-six infants (17%) were born to HIV-infected mothers. We observed 2 moderate adverse events (AEs) [2%, 95% confidence interval (CI): 0.2 to 7.0] in the AccuCirc arm and none (95% CI: 0.0 to 7.1) in the Mogen clamp arm. The cumulative incident risk of AEs was 2.0% higher in the AccuCirc arm compared with the Mogen Clamp arm (95% CI: -0.7 to 4.7). As the 95% CI excludes the predefined noninferiority margin of 6%, the result provides evidence of noninferiority of AccuCirc compared with the Mogen clamp. Nearly all mothers (99.5%) reported great satisfaction with the outcome. All mothers, regardless of arm said they would recommend EIMC to other parents, and would circumcise their next son. CONCLUSIONS: This first randomized trial of AccuCirc versus Mogen clamp for EIMC demonstrated that EIMC using these devices is safe and acceptable to parents. There was no difference in the rate of AEs by device. PMID- 26010028 TI - Feasibility of a Combination HIV Prevention Program for Men Who Have Sex With Men in Blantyre, Malawi. AB - INTRODUCTION: The use of combination HIV prevention interventions (CHPI) now represent the standard of care to minimize HIV acquisition risks among men who have sex with men (MSM). There has been limited evaluation of these approaches in generalized HIV epidemics and/or where MSM are stigmatized. A peer-based CHPI program to target individual, social, and structural risks for HIV was developed for MSM in Blantyre, Malawi. METHODS: To test the feasibility of CHPI, adult MSM were followed prospectively from January 2012 to May 2013. Participants (N = 103) completed sociobehavioral surveys and HIV testing at each of the 3 follow-up study visits. RESULTS: Approximately 90% of participants attended each study visit and 93.2% (n = 96) completed the final visit. Participants met with peer educators a median of 3 times (range: 1-10) in the follow-up visits 2 and 3. Condom use at last sex improved from baseline through follow-up visit 3 with main (baseline: 62.5%, follow-up 3: 77.0%; P = 0.02) and casual male partners (baseline: 70.7%, follow-up 3: 86.3%; P = 0.01). Disclosure of sexual behaviors/orientation to family increased from 25% in follow-up 1 to 55% in follow-up 3 (P < 0.01). DISCUSSION: Participants maintained a high level of retention in the study highlighting the feasibility of leveraging community-based organizations to recruit and retain MSM in HIV prevention and treatment interventions in stigmatizing settings. Group-level changes in sexual behavior and disclosure in safe settings for MSM were noted. CHPI may represent a useful model to providing access to other HIV prevention for MSM and aiding retention in care and treatment services for MSM living with HIV in challenging environments. PMID- 26010030 TI - Influence of Genetic Background on Anthocyanin and Copigment Composition and Behavior during Thermoalkaline Processing of Maize. AB - Visual color is a primary quality factor for foods purchase; identifying factors that influence in situ color quality of pigmented maize during processing is important. Twenty-four genetically distinct pigmented maize hybrids (red/blue, blue, red, and purple) were used to investigate the effect of pigment and copigment composition on color stability during nixtamalization and tortilla chip processing. The red/blue and blue samples generally contained higher proportions of acylated anthocyanins (mainly cyanidin-3-(6"-malonylglucoside)) than the red and purple color classes. Phenolic amides were the major extractable copigments in all samples (450-764 MUg/g), with red samples containing the most putrescines and blue samples containing the most spermidines. Even though samples with higher proportions of acylated anthocyanins retained more pigments during processing, this did not relate to final product color quality. In general, the red/blue samples retained their color quality the best and thus are good candidates for genetic improvement for direct processing into alkalized products. PMID- 26010031 TI - Natural Gas and Cellulosic Biomass: A Clean Fuel Combination? Determining the Natural Gas Blending Wall in Biofuel Production. AB - Natural gas has the potential to increase the biofuel production output by combining gas- and biomass-to-liquids (GBTL) processes followed by naphtha and diesel fuel synthesis via Fischer-Tropsch (FT). This study reflects on the use of commercial-ready configurations of GBTL technologies and the environmental impact of enhancing biofuels with natural gas. The autothermal and steam-methane reforming processes for natural gas conversion and the gasification of biomass for FT fuel synthesis are modeled to estimate system well-to-wheel emissions and compare them to limits established by U.S. renewable fuel mandates. We show that natural gas can enhance FT biofuel production by reducing the need for water-gas shift (WGS) of biomass-derived syngas to achieve appropriate H2/CO ratios. Specifically, fuel yields are increased from less than 60 gallons per ton to over 100 gallons per ton with increasing natural gas input. However, GBTL facilities would need to limit natural gas use to less than 19.1% on a LHV energy basis (7.83 wt %) to avoid exceeding the emissions limits established by the Renewable Fuels Standard (RFS2) for clean, advanced biofuels. This effectively constitutes a blending limit that constrains the use of natural gas for enhancing the biomass to-liquids (BTL) process. PMID- 26010032 TI - Kinetics of biofilm formation by drinking water isolated Penicillium expansum. AB - Current knowledge on drinking water (DW) biofilms has been obtained mainly from studies on bacterial biofilms. Very few reports on filamentous fungi (ff) biofilms are available, although they can contribute to the reduction in DW quality. This study aimed to assess the dynamics of biofilm formation by Penicillium expansum using microtiter plates under static conditions, mimicking water flow behaviour in stagnant regions of drinking water distribution systems. Biofilms were analysed in terms of biomass (crystal violet staining), metabolic activity (resazurin, fluorescein diacetate and 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide [MTT]) and morphology (epifluorescence [calcofluor white M2R, FUN-1, FDA and acridine orange] and bright-field microscopies). Biofilm development over time showed the typical sigmoidal curve with noticeable different phases in biofilm formation (induction, exponential, stationary, and sloughing off). The methods used to assess metabolic activity provided similar results. The microscope analysis allowed identification of the involvement of conidia in initial adhesion (4 h), germlings (8 h), initial monolayers (12 h), a monolayer of intertwined hyphae (24 h), mycelial development, hyphal layering and bundling, and development of the mature biofilms (>=48 h). P. expansum grows as a complex, multicellular biofilm in 48 h. The metabolic activity and biomass of the fungal biofilms were shown to increase over time and a correlation between metabolism, biofilm mass and hyphal development was found. PMID- 26010033 TI - Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures. AB - IMPORTANCE: The risk of bleeding and recurrent venous thromboembolism (VTE) among patients receiving long-term warfarin sodium therapy for secondary VTE prevention who require temporary interruption of anticoagulant therapy for surgery or invasive diagnostic procedures has not been adequately described. OBJECTIVE: To describe the rates of clinically relevant bleeding and recurrent VTE among patients in whom warfarin therapy is interrupted for invasive procedures and compare these rates among patients who did and did not receive bridge therapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at Kaiser Permanente Colorado, an integrated health care delivery system. Patients in whom warfarin therapy was interrupted for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified via queries of administrative data sets. A total of 1812 procedures in 1178 patients met inclusion criteria. Data on outcomes and exposures were collected between June 1, 2005, and April 30, 2012. EXPOSURES: Use of bridge therapy vs no bridge therapy during warfarin interruption. MAIN OUTCOMES AND MEASURES: Thirty-day clinically relevant bleeding, recurrent VTE, and all-cause mortality. Outcomes were verified via manual review of medical records. RESULTS: Among the 1178 patients, the mean (SD) age was 66.1 (12.7) years, 830 procedures (45.8%) were in men, and the most common indication for warfarin therapy was deep vein thrombosis (56.3%). Most patients were considered to be at low risk for VTE recurrence at the time of warfarin interruption (1431 procedures [79.0%]) according to the consensus guidelines of the American College of Chest Physicians. Clinically relevant bleeding within 30 days after the procedure in the bridge therapy and non-bridge therapy groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95% CI, 3.9-75.1). There was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups (0 vs 3; P = .56). No deaths occurred in either group. CONCLUSIONS AND RELEVANCE: Bridge therapy was associated with an increased risk of bleeding during warfarin therapy interruption for invasive procedures in patients receiving treatment for a history of VTE and is likely unnecessary for most of these patients. Further research is needed to identify patient- and procedure related characteristics associated with a high risk of perioperative VTE recurrence during warfarin therapy interruption. PMID- 26010034 TI - Letters. TO THE EDITOR: Linton SJ, Nicholas M, MacDonald S. Development of a short form of the Orebro Musculoskeletal Pain Screening Questionnaire. Spine (Phila Pa 1976) 2011;36:1891-5. PMID- 26010035 TI - Complete Remodeling After Conservative Treatment of a Severely Angulated Odontoid Fracture in a Patient With Osteogenesis Imperfecta: A Case Report. AB - STUDY DESIGN: Case report. OBJECTIVE: This is the first case report describing successful healing and remodeling of a traumatic odontoid fracture that was dislocated and severely angulated in a patient with osteogenesis imperfecta who was treated conservatively. SUMMARY OF BACKGROUND DATA: Osteogenesis imperfecta (OI) is a rare genetic disorder resulting in a low bone mass and bone fragility, predisposing these patients to fractures that often occur at a young age. Although any bone in the body may be involved, odontoid fractures are uncommon in this population. Because of a very high fusion rate, conservative management is accepted as a safe and efficient treatment of fractures of the odontoid in children. Several authors, however, recommend surgical treatment of patients who have failure of conservative treatment and have severe angulation or displacement of the odontoid. METHODS: A 5-year-old female, diagnosed with OI type I, presented with neck pain without any neurological deficits after falling out of a rocking chair backward, with her head landing first on the ground. Computed tomography confirmed a type III odontoid fracture without dislocation and she was initially treated with a rigid cervical orthosis. At 1 and 2 months of follow-up, progressive severe angulation of the odontoid was observed but conservative treatment was maintained as the space available for the spinal cord was sufficient and also considering the patient's history of OI. RESULTS: Eight months postinjury, she had no clinical symptoms and there was osseous healing of the fracture with remodeling of the odontoid to normal morphology. CONCLUSION: Even in patients with OI, severely angulated odontoid fractures might have the capacity for osseous healing and complete remodeling under conservative treatment. LEVEL OF EVIDENCE: 5. PMID- 26010036 TI - Type of bone graft or substitute does not affect outcome of spine fusion with instrumentation for adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To compare clinical outcomes after spine instrumentation and fusion using 3 different bone grafts in children with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Autogenous iliac crest bone graft (AIC) is the "gold standard" to promote fusion in posterior AIS operations, although the morbidity of harvest is a concern. There is limited data comparing outcomes after AIS surgery based on types of bone grafts. METHODS: Children (10-18 yr) with AIS who underwent deformity correction via a posterior approach were identified in the Spinal Deformity Study Group database. All had a minimum of 2-year follow-up. Patients were subdivided into 3 groups based on bone graft used: AIC, allograft, and bone substitute (BS). Clinical data included patient demographics, operative details, postoperative analgesic use, and perioperative complications. Lenke curve type and curve magnitude changes were radiographically analyzed. The Scoliosis Research Society 30 questionnaire was used to assess clinical outcomes. RESULTS: 461 patients met inclusion criteria (girls: 381, boys: 80; average age 14.7 +/- 1.7) and consisted of 152 AIC patients (124 girls, 28 boys), 199 allograft patients (167 girls, 32 boys), and 110 BS patients (90 girls, 20 boys). There was no difference in age (P = 0.41) or gender (P = 0.82). The BS group had significantly smaller preoperative curves and shorter operative times. Postoperatively, patients who received BS had significantly longer hospital stays, used higher quantities of patient-controlled intravenous analgesia and used epidurals longer. The AIC group used patient controlled intravenous analgesia significantly longer. There were no differences between the groups in regards to curve type, number of levels fused, postoperative infections, pseudarthrosis, reoperations for any indication, and Scoliosis Research Society-30 scores at the latest follow-up. CONCLUSION: Outcomes after primary posterior spinal fusion with instrumentation are not influenced by type of bone graft or substitute. LEVEL OF EVIDENCE: 3. PMID- 26010037 TI - Short-term improvements in disability mediate patient satisfaction after epidural corticosteroid injections for symptomatic lumbar spinal stenosis. AB - STUDY DESIGN: Secondary analysis of data from a double-blind randomized controlled trial. OBJECTIVE: To identify mediators of the effect of lumbar epidural injections of corticosteroid plus lidocaine on patient satisfaction at 6 weeks postinjection in patients with lumbar spinal stenosis. We hypothesized that short-term (<=3 wk) change in leg pain would be a significant mediator of satisfaction. SUMMARY OF BACKGROUND DATA: No prior studies have identified mediators of effects of epidural injections on patient satisfaction with treatment of lumbar spinal stenosis. METHODS: We used mediation analysis methods to examine selected intermediate variables (adverse events and change in leg pain, back pain, disability, depression, and fatigue at 3 wk) as potential mediators of the effect of lumbar epidural injections of corticosteroid plus lidocaine on patient satisfaction with treatment. We used the overall satisfaction item from the Swiss Spinal Stenosis Questionnaire as our primary outcome to measure patient satisfaction with the injection procedure at 6 weeks. RESULTS: Among 400 patients randomized to receive epidural injections with corticosteroid plus lidocaine or with lidocaine alone, 369 had complete data for the satisfaction outcome and potential mediators and served as the analysis sample. Contrary to our expectations, 3-week change in leg pain intensity did not have significant mediation effects on patient satisfaction. Three-week change in disability as measured by the Roland-Morris Disability Questionnaire was a significant mediator of the effects of lumbar epidural corticosteroid injections on patient satisfaction at 6 weeks, explaining 48% to 60% of the treatment effect on satisfaction. Changes in pain intensity in the leg and back together explained very little of the treatment effect on satisfaction beyond the information contributed by disability change alone. We did not find other intermediate variables to be mediators of patient satisfaction. CONCLUSION: These findings support the current approach of examining disability as a primary patient reported outcome in comparative effectiveness studies of lumbar spinal stenosis. LEVEL OF EVIDENCE: 2. PMID- 26010038 TI - Dr. Russell A. Hibbs: Pioneer of Spinal Fusion. PMID- 26010039 TI - Central role of FaGAMYB in the transition of the strawberry receptacle from development to ripening. AB - The receptacle of the strawberry (Fragaria * ananassa) fruit accounts for the main properties of the ripe fruit for human consumption. As it ripens, it undergoes changes similar to other fruits in sugar : acid ratio, volatile production and cell wall softening. However, the main regulators of this process have not yet been reported. The white stage marks the initiation of the ripening process, and we had previously reported a peak of expression for a FaGAMYB gene. Transient silencing of FaGAMYB using RNAi and further determination of changes in global gene expression by RNAseq, and composition of primary and secondary metabolites have been used to investigate the role played by this gene during the development of the receptacle. Down-regulation of FaGAMYB caused an arrest in the ripening of the receptacle and inhibited colour formation. Consistent with this, several transcription factors associated with the regulation of flavonoid biosynthetic pathway showed altered expression. FaGAMYB silencing also caused a reduction of ABA biosynthesis and sucrose content. Interestingly, exogenous ABA application to the RNAI-transformed receptacle reversed most defects caused by FaGAMYB down-regulation. The study assigns a key regulatory role to FaGAMYB in the initiation of strawberry receptacle ripening and acting upstream of the known regulator ABA. PMID- 26010040 TI - Comorbidity in the Tunisian population. AB - Genetic diseases in the Tunisian population represent a real problem of public health as their spectrum encompasses more than 400 disorders. Their frequency and distribution in the country have been influenced by demographic, economic and social features especially consanguinity. In this article, we report on genetic disease association referred to as comorbidity and discuss factors influencing their expressivity. Seventy-five disease associations have been reported among Tunisian families. This comorbidity could be individual or familial. In 39 comorbid associations, consanguinity was noted. Twenty-one founder and 11 private mutations are the cause of 34 primary diseases and 13 of associated diseases. As the information dealing with this phenomenon is fragmented, we proposed to centralize it in this report in order to draw both clinicians' and researcher's attention on the occurrence of such disease associations in inbred populations as it makes genetic counseling and prenatal diagnosis challenging even when mutations are known. PMID- 26010041 TI - Angiolymphoid hyperplasia with eosinophilia developing within a port wine stain. AB - A 19-year-old male with a port wine stain on the base of his neck presented with a 5-month history of gradual thickening of the involved skin which interfered with clothing and caused repeated bleeding. The lesion was excised and histopathologic examination revealed angiolymphoid hyperplasia with eosinophilia (ALHE) arising from the pre-existing port wine stain - a rare finding with only one previously reported case. Additionally the lesion was associated with elevated serum renin levels which virtually normalized following excision of the lesion. We further demonstrated the expression of angiotensin converting enzyme and angiotensin II receptors 1 and 2 by the lesion and discuss the possible role of the renin-angiotensin system in this condition. PMID- 26010042 TI - Ecosystem-level effects of a globally spreading invertebrate invader are not moderated by a functionally similar native. AB - Biological invasions are a key element of human-induced global environmental change. However, lack of knowledge of the indirect consequences of invasions, combined with poor understanding of how their ecological effects depend upon competitive attributes of the receiving community, hinders our ability to manage and predict the effects of invasive species on ecosystems. We established an experiment using a combination of both additive and substitutive experimental designs to explore the effects of the globally spreading mysid shrimp Hemimysis anomala on the biological structure of outdoor pond mesocosms in the absence and presence of a functionally similar native competitor, Mysis salemaai. The naturally smaller H. anomala had considerably stronger effects on primary producers, multiple aspects of consumer assemblages and overall biological structure of the ponds in comparison with the functionally similar native. Moreover, the magnitude of these effects was generally independent of the presence of M. salemaai and even total mysid density. Hemimysis anomala reduced both the abundance and diversity of zooplankton assemblages significantly, triggering a strong trophic cascade on phytoplankton and a simultaneous increase of benthic invertebrate biomass. These findings indicate that invasion by H. anomala may exacerbate the effects of nutrient enrichment on lakes. Our results demonstrate that introduced species can, irrespective of the presence of functionally similar natives, induce complex changes to ecosystems that reach beyond direct consumptive effects. Moreover, the cascading indirect effects of invasion can exacerbate the impacts of other stressors. Disregarding the complexity of indirect effects therefore risks underestimating significantly the global ecological footprint of biological invasions. PMID- 26010043 TI - Cross talk in promoter recognition between six NarL-family response regulators of Escherichia coli two-component system. AB - Bacterial two-component system (TCS) is composed of the sensor kinase (SK) and the response regulator (RR). After monitoring an environmental signal or condition, SK activates RR through phosphorylation, ultimately leading to the signal-dependent regulation of genome transcription. In Escherichia coli, a total of more than 30 SK-RR pairs exist, each forming a cognate signal transduction system. Cross talk of the signal transduction takes place at three stages: signal recognition by SK (stage 1); RR phosphorylation by SK (stage 2); and target recognition by RR (stage 3). Previously, we analyzed the stage 2 cross talk between the whole set of E. coli SK-RR pairs and found that the cross talk takes place for certain combinations. As an initial attempt to identify the stage 3 cross talk at the step of target promoter recognition by RR, we analyzed in this study the cross-recognition of target promoters by six NarL-family RRs, EvgA, NarL, NarP, RcsB, UhpA, and UvrY. Results of both in vivo and in vitro studies indicated that the stage 3 cross talk takes place for limited combinations, in particular, including a multifactor-regulated ydeP promoter. PMID- 26010044 TI - Non-HLA genomics: does it have a role in predicting haematopoietic stem cell transplantation outcome? AB - Haematopoietic stem cell transplantation (HSCT) remains the only cure for many haematological neoplasms; however, the mortality rate remains high, at around 30 80%. Complications after HSCT include relapse, graft-versus-host disease, graft rejection and infection. High-resolution HLA matching has improved survival in HSCT over recent years; however, GVHD still remains a serious complication. Single nucleotide polymorphisms (SNPS) within genes that are involved with an individual's capability to mount an immune response to infectious pathogens, residual leukaemia, alloantigens or genes involved in drug metabolism have been studied for their association with HSCT outcome. Indeed, over the last 15 years, several groups, including ourselves, have demonstrated that non-HLA gene polymorphisms can be predictive of HSCT outcome. Can genetic characteristics of the patient and donor be used in the future to tailor HSCT protocols and determine GVHD prophylaxis? This review summarizes some of the recent SNP association studies in HSCT and highlights some of the disparities therein, discussing the integral problems of performing genetic association studies on diseases with complex outcomes using heterogeneous cohorts. The review will comment on recent genomewide association studies (GWAS) and discuss their relevance in this field, and it will also comment on recent meta-analysis combining GWAS studies with other studies such as gene expression micro array data in the field of autoimmune disease and solid organ transplantation. It will mention possible novel candidate gene polymorphisms, for example SNPS in microRNAs. In addition, it will discuss some of the inherent problems associated with gene association studies including the GRIPs (genetic risk prediction studies) recommendations. In summary, this review will assess the usefulness of non-HLA genomic studies in HSCT with regard to predicting outcome and modifying therapy. PMID- 26010045 TI - A Comparison of Survey Measures and Biomarkers of Secondhand Tobacco Smoke Exposure among Nonsmokers. AB - OBJECTIVES: Secondhand tobacco smoke (SHS) exposure causes several adverse physical health outcomes. Conceptual differences in survey measures of 'psychosocial' (SHS exposure from smokers in an individual's life) and 'physical' (environments where an individual is exposed to SHS) SHS exposure exist. Few studies have examined the association between psychosocial and physical SHS exposures measures in comparison to biomarkers of SHS exposure. DESIGN AND SAMPLE: A secondary analysis of cross-sectional data was examined among a convenience sample of 20 adults. MEASURES: Data included survey items on SHS exposure and hair nicotine and saliva cotinine levels. Spearman analysis was used to assess correlations among variables. RESULTS: Medium and strong correlations were found among SHS exposure measures with the exception of saliva cotinine levels. Strong correlations were found among and between psychosocial and physical SHS exposure measures. Hair nicotine levels had medium strength associations with only perceived frequency of SHS exposure. DISCUSSION: As psychosocial measures of exposure were associated with biomarkers, such measures (particularly perceived frequency of SHS exposure) should be added to surveys in addition to physical SHS exposure measures to enhance accuracy of SHS measurement. Future explorations with robust sample sizes should further examine the strength of relationship between psychosocial and physical SHS exposure measures. PMID- 26010046 TI - The Multidisciplinary Translational Team (MTT) Model for Training and Development of Translational Research Investigators. AB - Multiinstitutional research collaborations now form the most rapid and productive project execution structures in the health sciences. Effective adoption of a multidisciplinary team research approach is widely accepted as one mechanism enabling rapid translation of new discoveries into interventions in human health. Although the impact of successful team-based approaches facilitating innovation has been well-documented, its utility for training a new generation of scientists has not been thoroughly investigated. We describe the characteristics of how multidisciplinary translational teams (MTTs) promote career development of translational research scholars through competency building, interprofessional integration, and team-based mentoring approaches. Exploratory longitudinal and outcome assessments from our experience show that MTT membership had a positive effect on the development of translational research competencies, as determined by a self-report survey of 32 scholars. We also observed that all trainees produced a large number of collaborative publications that appeared to be associated with their CTSA association and participation with MTTs. We conclude that the MTT model provides a unique training environment for translational and team-based learning activities, for investigators at early stages of career development. PMID- 26010047 TI - Bladder cancer incidence and mortality in patients treated with radiation for uterine cancer. AB - OBJECTIVE: To estimate the effect of radiation therapy (RT) administered for uterine cancer (UtC) on bladder cancer (BC) incidence, tumour characteristics at presentation, and mortality. PATIENTS AND METHODS: In this retrospective cohort study, records of 56 681 patients diagnosed with UtC as their first primary malignancy during 1980-2005 were obtained from the Surveillance, Epidemiology and End-Results (SEER) database. Follow-up for incident BC ended on 31 December 2008. Occurrences of BC diagnoses and BC deaths in patients with UtC managed with or without RT were summarised with counts and person-time incidence rates (counts divided by person-years of observation). Age adjustment of rates was performed by direct standardisation. Incident BC cases were described in terms of histological types, grades and stages. RESULTS: With a mean follow-up of 15 years, BC was diagnosed in 146 (0.93%) of 15 726 patients with UtC managed with RT, and in 197 (0.48%) of 40 955 patients with UtC managed without RT, with an age-adjusted rate ratio of 2.0 (95% confidence interval [CI] 1.6-2.5). Fatal BC occurred in 39 (0.25%) and 36 (0.09%) of patients with UtC managed with vs without RT, respectively, with an age-adjusted rate ratio of 2.9 (95% CI 1.8-4.6). Incident BC cases diagnosed in patients with UtC managed with vs without RT had similar distributions of histological types, grades, and stages. CONCLUSIONS: Use of RT for UtC is associated with increased BC incidence and mortality later in life. Heightened awareness should help identify women with new voiding symptoms or haematuria, all of which should be fully evaluated. PMID- 26010048 TI - Two-sided urethra-sparing reconstruction combining dorsal preputial skin plus ventral buccal mucosa grafts for tight bulbar strictures. AB - OBJECTIVES: To report our initial experience with urethra-sparing reconstruction combining dorsal preputial skin and ventral buccal mucosa grafts for tight bulbar urethral strictures. METHODS: Between November 2006 and September 2012, 26 patients with tight bulbar strictures underwent urethroplasty. Using a ventral urethrotomy approach, the two-sided urethral reconstruction was carried out avoiding the transection of urethra and augmenting the preserved urethral plate by dorsal preputial skin plus ventral buccal mucosa grafts. The primary outcome was the objective urinary result, defined as the absence of stricture recurrence. The outcome was considered a failure when any postoperative instrumentation was required. Postoperative sexual dysfunctions were investigated using a validated questionnaire. RESULTS: Mean follow up was 30.1 months (range 12-79 months). Mean stricture length was 3.3 cm (range 1.5-6 cm). Mean length for dorsal preputial skin and ventral buccal mucosa grafts was 3.2 cm (range 2-7 cm) and 4.9 cm (range 4-6 cm), respectively. Of 26 cases, 23 (88.5%) were successful and three (11.5%) were failures with stricture recurrence. Failures were treated with perineal urethrostomy in one case, ventral buccal graft urethroplasty in one case and internal urethrotomy in one case. Among 12 sexually active men preoperatively, none reported postoperative penile curvature/shortening, impaired erection or dissatisfaction regarding erection; sexual activity was unaltered pre- and post surgery. CONCLUSIONS: In tight bulbar urethra strictures, the two-sided urethroplasty combining dorsal preputial skin and ventral buccal mucosa grafts provides a safe and effective semi-circumferential reconstruction by augmenting the preserved urethral plate, with no impact on sexual function. PMID- 26010050 TI - Establishing and delivering pulmonary rehabilitation in rural and remote settings: The opinions, attitudes and concerns of health care professionals. AB - OBJECTIVE: Pulmonary rehabilitation is recommended for people with chronic lung disease however access remains limited in rural and remote settings. The aim of this project was to explore the perspectives of rural and remote health care professionals regarding the establishment and delivery of pulmonary rehabilitation. SETTING: Rural (NSW) and remote (NT) Australian healthcare settings. PARTICIPANTS: Health care professionals (n = 25) who attended a training program focussing on the delivery of pulmonary rehabilitation. MAIN OUTCOME MEASURE(S): Surveys with open written questions were completed by participants following the training program. Key informants also participated in face-to-face interviews. Thematic analysis was undertaken of data collected on participant opinions, attitudes and concerns regarding the establishment and delivery of pulmonary rehabilitation in their individual situation. RESULTS: Participating health care professionals (predominantly nurses and physiotherapists) identified a number of issues relating to establishing and delivering pulmonary rehabilitation; including staffing, time and case load constraints, patient and community attitudes, lack of professional knowledge and confidence and inability to ensure sustainability. The practicalities of delivering pulmonary rehabilitation, particularly exercise prescription and training, were also important concerns raised. CONCLUSIONS: Lack of health care professional staffing, knowledge and confidence were reported to be factors impacting the establishment and delivery of pulmonary rehabilitation. This study has facilitated a greater understanding of the issues surrounding the establishment and delivery of pulmonary rehabilitation in rural and remote settings. Further research is required to investigate the contribution of health professional training and associated factors to improving the availability and delivery of pulmonary rehabilitation in rural and remote settings. PMID- 26010049 TI - Factor Structure of Subjective Responses to Alcohol in Light and Heavy Drinkers. AB - BACKGROUND: Subjective responses (SRs) to alcohol have been implicated in alcoholism etiology, yet less is known about the latent factor structure of alcohol responses. The aim of this study was to examine the factor structure of SR using a battery of self-report measures during a controlled alcohol challenge. METHODS: Nontreatment seeking drinkers (N = 242) completed an intravenous alcohol challenge including the following SR measures: Biphasic Alcohol Effects Scale, Subjective High Assessment Scale, Profile of Mood States, Alcohol Urge Questionnaire, and single items assessing alcohol "Liking" and "Wanting." Ascending limb target breath alcohol concentrations were 0.02, 0.04, and 0.06, and descending limb target was 0.04 g/dl. Exploratory factor analyses were conducted separately on estimates of mean and dose responses on the ascending limb and on descending limb data. To examine the generalizability of this factor structure, these analyses were repeated in heavy drinkers (>=14 drinks/wk for men, >=7 for women; n = 132) and light drinkers (i.e., nonheavy drinkers; n = 110). RESULTS: In the full sample, a 4-factor solution was supported for ascending limb mean and dose responses and descending limb data representing the following SR domains: Stimulation/Hedonia, Craving/Motivation, Sedation/Motor Intoxication, and Negative Affect. This 4-factor solution was replicated in heavy drinkers. In light drinkers, however, SR was better summarized by a 3-factor solution where ascending mean and descending limb responses consisted of Stimulation/Hedonia, Craving/Motivation, and a general negative valence factor, and dose responses consisted of a general positive valence factor, Sedation/Motor Intoxication, and Negative Affect. CONCLUSIONS: These findings suggest that SR represents a multifaceted construct with consistent factor structure across both ascending and descending limbs. Further, as drinking levels escalate, more defined Craving/Motivation and negative valence dimensions may emerge. Longitudinal studies examining these constructs are needed to further our understanding of SR as potentially sensitive to alcohol-induced neuroadaptation. PMID- 26010051 TI - Collaborative Care: The New Maudsley Model. AB - The aim of this article is to describe the rationale and practice of the New Maudsley collaborative care intervention for families of people with eating disorders. The intervention teaches carers the underpinning theory with practical examples on how to optimize their care giving, communication, and coping skills. This includes moderating high expressed emotion and reducing the tendency to accommodate and/or enable illness behaviors. Transcripts are used to give examples of this approach in action. The emerging evidence base indicates that this approach improves both carer and patient well-being and also is associated with a more efficient use of resources. PMID- 26010052 TI - Morphology and Molecular Phylogeny of Two New Brackish Water Ciliates of Bakuella (Ciliophora: Urostylida: Bakuellidae) from South Korea. AB - Two new species of Bakuella, B. (B.) incheonensis n. sp. and B. (Pseudobakuella) litoralis n. sp., were discovered in brackish water near Aamdo Shore Park, Incheon, South Korea. We conducted a morphological study based on live observations and protargol-impregnated specimens, and a molecular analysis using nuclear SSU rRNA gene sequences. Bakuella (B.) incheonensis is diagnosed by: body size 70-105 * 20-40 MUm in vivo, 21-25 adoral membranelles, three or four frontoterminal cirri, midventral complex composed of 7-10 midventral pairs with one or two rows and terminating at about 62% of body length, 20-28 left and 25-32 right marginal cirri, 58-87 macronuclear nodules, and yellowish cortical granules. Bakuella (Pseudobakuella) litoralis is diagnosed by: body size 90-125 * 30-40 MUm in vivo, 25-33 adoral membranelles, 3-5 buccal cirri, midventral complex composed 10-15 midventral pairs with one or two rows and terminated at 70% of body length, one or two pretransverse cirri, 3-6 transverse cirri, 26-39 left and 29-47 right marginal cirri, 49-84 macronuclear nodules, and two types of cortical granules. Molecular phylogeny using SSU rRNA gene sequences shows a nonmonophyletic relationship among Bakuella species and emphasizes the need for further morphogenetic studies of this genus and other related hypotrichs. PMID- 26010053 TI - Diffuse Axonal Injury-A Distinct Clinicopathological Entity in Closed Head Injuries. AB - The knowledge about the diffuse axonal injury (DAI) as a clinicopathological entity has matured in the last 30 years. It has been defined clinically (immediate and prolonged unconsciousness leading to death or severe disability) and pathologically (the triad of DAI specific changes). In terms of its biomechanics, DAI is occurring as a result of acceleration forces of longer duration and has been fully reproduced experimentally.In the process of diagnosing DAI, the performance of a complete forensic neuropathological examination is essential and the immunohistochemistry method using antibodies against beta-amyloid precursor protein (beta-APP) has been proved to be highly sensitive and specific, selectively targeting the damaged axons.In this review, we are pointing to the significant characteristics of DAI as a distinct clinicopathological entity that can cause severe impairment of the brain function, and in the forensic medicine setting, it can be found as the concrete cause of death. We are discussing not only its pathological feature, its mechanism of occurrence, and the events on a cellular level but also the dilemmas about DAI that still exist in science: (1) regarding the strict criteria for its diagnosis and (2) regarding its biomechanical significance, which can be of a big medicolegal importance. PMID- 26010054 TI - An Enigmatic Death in Farm Chopping Machine: Is This the Perfect Murder? AB - Forensic autopsy, like the other sectors in medicine, has benefited from the technological progress and the creation of multidisciplinary teams to unveil more and more finely planned criminal intents.Forensic pathologists, however, can sometimes deal with very enigmatic cases, meeting so with the limits of their own knowledge. Therefore, in these cases, they must not allow themselves to be pressured by inquiring agencies, remaining instead always faithful to empiric observations.With regard to that, we present a peculiar case of death by shredding inside a grinding machinery. The magistrature consequently opened a dossier for willful murder. Lots of figures were appointed to solve the case and among them is the forensic pathologist. However, a great number of obstacles were put in the investigators' inquiries.Was it a perfect murder? PMID- 26010055 TI - Analysis of Closed Soft Tissue Subcutaneous Injuries-"Impact Decollement" in Fatal Free Falls From Height-Forensic Aspect. AB - The aim of this study was to assess the frequency of "decollement," traumatic lesions of subcutaneous soft tissue, among victims fatally injured because of falls from different heights. Three hundred seventy-five cases of fatalities due to injuries acquired when falling from various heights onto a solid, flat surface, in which the complete forensic autopsy was performed, were analyzed. Decollement was noted in 125 (33%) of the cases. Comparative analysis of groups with and without decollement and observed factors has shown that the height of fall and the manner of death have statistically significant influence on decollement appearance. With regard to suicidal, accidental, or undefined origin of death decollement is statistically more common in accidental deaths. Decollement provides important clues for forensic reconstruction and could be a significant indicator of the body's position at primary impact and the height from which the victim has either jumped or fallen. PMID- 26010056 TI - Spontaneous Coronary Artery Dissection: Report of 3 Cases and Literature Review Hormonal, Autoimmune, Morphological Factors. AB - The number of cases with spontaneous coronary artery dissection (SCAD) is considered to be being underestimated because of a large amount of SCAD leading to sudden death without previous diagnosis. Besides, not only in clinics but also in autopsy practice, correct diagnosis of SCAD is important to prevent forensic malpractice.The article is intended to discuss the pathological findings through the forensic point of view for improving the malpractice expertise in scope of clinicians' timely antemortem diagnosis according to risk factors and in scope of forensic pathologists' the cause of death determination ability according to macroscopical and microscopical findings of the autopsy.In 3 cases reported, the main characteristics were the female sex, pregnancy history and a sudden death without any trauma. However, although there are many women giving birth or using oral contraceptives, only some of them are facing with SCAD. This suggests the possibility of some hereditary factors, whereas hereditary characteristics may be understood in many different ways like hormone-releasing regulating mechanisms as well as immunity, morphology, or any other mechanism. For instance, autoimmunity has been also a hereditary underlying factor for vessel injury considered in presented cases. PMID- 26010057 TI - Adolescents' Sedentary Behaviors in Two European Cities. AB - PURPOSE: The aim of this study was to determine and compare the correlates of objective sedentary behavior (SB) and nonschool self-reported SB in adolescents from 2 midsized cities, 1 in France (Tarbes) and 1 in Spain (Huesca). Stability of objective SB and nonschool self-reported SB were also assessed at different time points during 1 academic year. METHOD: Starting with a total of 829 participants and after applying inclusion criteria, objective SB was assessed for 646 adolescents (Mage = 14.30 +/- 0.71 years) with GT3X accelerometers for 7 days at 2 time points. Nonschool self-reported SB was measured for 781 adolescents (Mage = 14.46 +/- 0.76 years) at 3 time points by means of a questionnaire. Data were analyzed using multiple regression analysis. RESULTS: Gender and ambient temperature emerged as the main statistically significant correlates in all objective SB models, showing higher objective SB levels in girls and lower objective SB levels when ambient temperature was higher. According to nonschool self-reported SB, a gender effect was found in almost all behaviors. Whereas boys spent more time playing with video games as well as games on their mobile phones, girls spent more time studying and using their computers and mobile phones to communicate with each other. The findings showed a statistically significant city effect on study time (Huesca > Tarbes) and video games and telephone communication time (Tarbes > Huesca). CONCLUSION: Nonschool self-reported SB patterns were different in Huesca and Tarbes. Intervention programs should be adapted to target the reduction of adolescents' SB according to different contexts. PMID- 26010058 TI - Esophagogastric junction morphology is associated with a positive impedance-pH monitoring in patients with GERD. AB - BACKGROUND: High-resolution manometry (HRM) provides information on esophagogastric junction (EGJ) morphology, distinguishing three different subtypes. Data on the correlation between EGJ subtypes and impedance-pH detected reflux patterns are lacking. We aimed to correlate the EGJ subtypes with impedance-pH findings in patients with reflux symptoms. METHODS: Consecutive patients with suspected gastroesophageal reflux disease (GERD) were enrolled. All patients underwent HRM and impedance-pH testing off-therapy. EGJ was classified as: Type I, no separation between the lower esophageal sphincter (LES) and crural diaphragm (CD); Type II, minimal separation (>1 and <2 cm); Type III, >= 2 cm separation. We measured esophageal acid exposure time (AET), number of total reflux episodes and symptom association analysis. KEY RESULTS: We enrolled 130 consecutive patients and identified 46.2% Type I EGJ, 38.5% Type II, and 15.4% Type III patients. Type III subjects had a higher number of reflux episodes (61 vs 45, p < 0.03, vs 25, p < 0.001), a greater mean AET (12.4 vs 4.2, p < 0.02, vs 1.5, p < 0.001) and a greater positive symptom association (75% vs 72%, p = 0.732 vs 43.3%, p < 0.02) compared with Type II and I patients, respectively. Furthermore, Type II subjects showed statistically significant (overall p < 0.01) increased reflux when compared with Type I patients. Type III and II EGJ morphologies had a more frequent probability to show a positive multichannel intraluminal impedance pH monitoring than Type I (95% vs 84% vs 50%, p < 0.001). CONCLUSIONS & INFERENCES: Increasing separation between LES and CD can cause a gradual and significant increase in reflux. EGJ morphology may be useful to estimate an abnormal impedance-pH testing in GERD patients. PMID- 26010059 TI - Structural Insight into the Complex of Ferredoxin and [FeFe] Hydrogenase from Chlamydomonas reinhardtii. AB - The transfer of photosynthetic electrons by the ferredoxin PetF to the [FeFe] hydrogenase HydA1 in the microalga Chlamydomonas reinhardtii is a key step in hydrogen production. Electron delivery requires a specific interaction between PetF and HydA1. However, because of the transient nature of the electron-transfer complex, a crystal structure remains elusive. Therefore, we performed protein protein docking based on new experimental data from a solution NMR spectroscopy investigation of native and gallium-substituted PetF. This provides valuable information about residues crucial for complex formation and electron transfer. The derived complex model might help to pinpoint residue substitution targets for improved hydrogen production. PMID- 26010060 TI - Eicosapentaenoic acid but not docosahexaenoic acid restores skeletal muscle mitochondrial oxidative capacity in old mice. AB - Mitochondrial dysfunction is often observed in aging skeletal muscle and is implicated in age-related declines in physical function. Early evidence suggests that dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve mitochondrial function. Here, we show that 10 weeks of dietary eicosapentaenoic acid (EPA) supplementation partially attenuated the age-related decline in mitochondrial function in mice, but this effect was not observed with docosahexaenoic acid (DHA). The improvement in mitochondrial function with EPA occurred in the absence of any changes in mitochondrial abundance or biogenesis, which was evaluated from RNA sequencing, large-scale proteomics, and direct measurements of muscle mitochondrial protein synthesis rates. We find that EPA improves muscle protein quality, specifically by decreasing mitochondrial protein carbamylation, a post-translational modification that is driven by inflammation. These results demonstrate that EPA attenuated the age-related loss of mitochondrial function and improved mitochondrial protein quality through a mechanism that is likely linked with anti-inflammatory properties of n-3 PUFAs. Furthermore, we demonstrate that EPA and DHA exert some common biological effects (anticoagulation, anti-inflammatory, reduced FXR/RXR activation), but also exhibit many distinct biological effects, a finding that underscores the importance of evaluating the therapeutic potential of individual n-3 PUFAs. PMID- 26010061 TI - Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes. AB - The GLI transcription factors, GLI1, GLI2, and GLI3, transduce Hedgehog and non hedgehog signals and are involved in regulating development and tumorgenesis. Surprisingly, they were recently found to modulate important functions of mature liver. However, less is known about their mutual interactions and possible target genes in mature hepatocytes. To get a deeper insight into these interactions cultured mouse hepatocytes were transfected with siRNAs against each GLI factor. RNA was extracted at different times and the expression levels of the genes of interest were determined by quantitative real-time PCR. The time-dependent data were analysed by a fuzzy logic-based modelling approach. The results indicated that the GLI factors constitute an interconnected network. GLI2 inhibited GLI1 expression and was coupled with GLI3 by a positive feedback loop. The regulatory activity between GLI1 and GLI3 was more complex switching between a positive and a negative feedback loop depending on whether the level of GLI2 is low or high, respectively. Generally, this network structure enables a dynamic behaviour. When GLI2 is low, it may keep GLI1 and GLI3 activity balanced favouring the appropriate modulation of transcription factors like the Ppars and Srebp1. When GLI2 is high, it may prevent an uncontrolled amplification that may lead to cancer. In conclusion, the three GLI factors in mature hepatocytes form an interactive transcriptional network that is involved in the control of target genes associated with metabolic zonation as well as with lipid and drug metabolism. Its structure in mature cells seems different from embryonic cells. PMID- 26010062 TI - "A bend in time": Shaping the sheath facilitates left atrial appendage closure. AB - OBJECTIVES: The purpose of this study is to determine feasibility, safety, and effectiveness of the "shape-the-sheath" method in left atrial appendage closure. BACKGROUND: LAA occlusion is often a difficult procedure, due to not just the learning curve but also the three-dimensional variable nature of the left atrial appendage. Multiple sheaths have been created for various takeoffs. The purpose of this article is to show the feasibility of the "shape-the-sheath" method in left atrial appendage closure. METHODS: Ten consecutive patients undergoing LAA occlusion without the "shape-the-sheath" method were compared to 10 consecutive patients undergoing LAA occlusion with the "shape-the-sheath" method using the Amplatzer Cardiac Plug (ACP) system and the Amplatzer TorqVue 45*45 sheath. RESULTS: The "shape-the-sheath" method resulted in significant decreases in fluoroscopy time (7.2+/-3.0 min vs. 13.7+/-6.7 min, P<0.05), number of partial recaptures (0% vs. 50%, P<0.05), with a trend toward decrease in the number of complete recaptures (0 vs. 40%, P=0.09) compared to conventional sheath use. CONCLUSIONS: Shaping-the-sheath is a simple, elegant way to help conform delivery systems to better access the LAA and ensure stable position. Further experience with this procedure optimization step is warranted. PMID- 26010063 TI - Epidemiology and economic burden of asthma. AB - BACKGROUND: The "asthma epidemic" is on the rise, with the Center for Disease Control (CDC) epidemiological studies reporting a 3.0% asthma prevalence in the United States in 1970, 5.5% in 1996, and 7.8% in 2006 to 2008. This results in an immense economic burden, with asthma costing an estimated $56 billion in the United States in 2007, which is a 6% increase from the $53 billion that was spent in 2002. METHODS: A review of the current literature and CDC reports were used to thoroughly examine and summarize the epidemiology and economic burden of asthma domestically and globally. RESULTS: Asthma shows a male predominance before puberty, and a female predominance in adulthood. Studies show Puerto Ricans to be the most commonly affected ethnicity, and a higher prevalence of asthma is found in lower income populations. Asthma is related to some of the more common otolaryngologic diseases such as allergy and obstructive sleep apnea. The condition results in significant morbidity, such as an increase in emergency department visits and a decrease in productivity due to missed school and works days. CONCLUSION: Epidemiological statistics report an undisputable increase of asthma both domestically and worldwide, which means the economic burden of this disease is also on the rise. Better access to healthcare, improved asthma education, and bridging the gap between ethnic and racial disparities in the treatment and management of asthma may help to control this epidemic, promote better outcomes, and prevent continued rising costs related to the management of this widespread disease. PMID- 26010064 TI - Guidelines for the Synthesis of Block Copolymer Particles of Various Morphologies by RAFT Dispersion Polymerization. AB - This article presents the recent developments of radical dispersion polymerizaton controlled by reversible addition fragmentation chain transfer (RAFT) for the production of block copolymer particles of various morphologies, such as core shell spheres, worms, or vesicles. It is not meant to be an exhaustive review but it rather provides guidelines for non-specialists. The article is subdivided into eight sections. After a general introduction, the mechanism of polymerization induced self-assembly (PISA) through RAFT-mediated dispersion polymerization is presented and the different parameters that control the morphology produced are discussed. The next two sections are devoted to the choice of the monomer/solvent pair and the macroRAFT agent. Afterwards, post-polymerization morphological order to-order transitions (i.e. morphological transitions triggered by extrinsic stimuli) or order-to-disorder transitions (i.e. disassembly of chains) are discussed. Assemblies based on more complex polymer architectures, such as triblock copolymers, are presented next, and finally the possibility to stabilize these structures by crosslinking is reported. The manuscript ends with a short conclusion and an outlook. PMID- 26010065 TI - Use of principal factor analysis to generate a corn silage fermentative quality index to rank well- or poorly preserved forages. AB - BACKGROUND: To investigate corn silage fermentative quality, a principal factor analysis was carried out on a database consisting of 196 corn silages sampled from the core, lateral and apical parts of silo feed-out face and characterised by 36 variables. Eleven principal factor components (PCs) were retained and interpreted. Two PCs were related to chemical and digestibility variables; four PCs were characterised by end-products associated with clostridia, heterolactic, homolactic or aerobic fermentations; two PCs were associated with mycotoxins produced by Penicillium roqueforti or by Aspergillus fumigatus and Fusarium spp., while three PCs explained ensiling procedures adopted to store corn silages. RESULTS: Lower (P < 0.05) yeast or mould counts and greater (P < 0.05) aerobic stability were measured in core than in peripheral samples. Excluding PCs related to ensiling procedures, other PCs were able to predict microbiological counts, aerobic stability or biogenic amine content as verified by multiple linear regression analysis. Based on these results, several corn silage quality index calculations were computed by using a summative equation approach in which different PCs as well as diverse relative weights multiplying each PCs were combined. To compute definitive index calculation, only PCs explaining clostridia, heterolactic and homolactic fermentations were used with relative weights of 30%, 50% and 20%. CONCLUSIONS: The new proposed fermentative quality index was highly correlated to parameters related to corn silage fermentative quality, such as microbiological counts, aerobic stability or biogenic amines and it properly discriminated well- and poorly preserved forages. PMID- 26010066 TI - The psychophysics of comic: Effects of incongruity in causality and animacy. AB - According to several theories of humour (see Berger, 2012; Martin, 2007), incongruity - i.e., the presence of two incompatible meanings in the same situation - is a crucial condition for an event being evaluated as comical. The aim of this research was to test with psychophysical methods the role of incongruity in visual perception by manipulating the causal paradigm (Michotte, 1946/1963) to get a comic effect. We ran three experiments. In Experiment 1, we tested the role of speed ratio between the first and the second movement, and the effect of animacy cues (i.e. frog-like and jumping-like trajectories) in the second movement; in Experiment 2, we manipulated the temporal delay between the movements to explore the relationship between perceptual causal contingencies and comic impressions; in Experiment 3, we compared the strength of the comic impressions arising from incongruent trajectories based on animacy cues with those arising from incongruent trajectories not based on animacy cues (bouncing and rotating) in the second part of the causal event. General findings showed that the paradoxical juxtaposition of a living behaviour in the perceptual causal paradigm is a powerful factor in eliciting comic appreciations, coherently with the Bergsonian perspective in particular (Bergson, 2003), and with incongruity theories in general. PMID- 26010067 TI - Exosome enrichment of human serum using multiple cycles of centrifugation. AB - In this work, we compared the use of repeated cycles of centrifugation at conventional speeds for enrichment of exosomes from human serum compared to the use of ultracentrifugation (UC). After removal of cells and cell debris, a speed of 110 000 * g or 40 000 * g was used for the UC or centrifugation enrichment process, respectively. The enriched exosomes were analyzed using the bicinchoninic acid assay, 1D gel separation, transmission electron microscopy, Western blotting, and high-resolution LC-MS/MS analysis. It was found that a five cycle repetition of UC or centrifugation is necessary for successful removal of nonexosomal proteins in the enrichment of exosomes from human serum. More significantly, 5* centrifugation enrichment was found to provide similar or better performance than 5* UC enrichment in terms of enriched exosome protein amount, Western blot band intensity for detection of CD-63, and numbers of identified exosome-related proteins and cluster of differentiation (CD) proteins. A total of 478 proteins were identified in the LC-MS/MS analyses of exosome proteins obtained from 5* UCs and 5* centrifugations including many important CD membrane proteins. The presence of previously reported exosome-related proteins including key exosome protein markers demonstrates the utility of this method for analysis of proteins in human serum. PMID- 26010069 TI - A new F-box protein 7 gene mutation causing typical Parkinson's disease. AB - BACKGROUND: Recessive mutations in the F-box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian-pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations. METHODS: Whole exome and targeted Sanger sequencing were performed for genetic analysis in a family with two members affected by Parkinson's disease (PD). All family members underwent detailed clinical, mental, and neurological examination. RESULTS: The new p.L34R (c.101 T>G) FBXO7 mutation was detected in a homozygous state in two Turkish sibs with typical levodopa-responsive PD. CONCLUSION: This is the first time a FBXO7 mutation has been identified that causes a phenotype compatible with typical idiopathic PD and presents with some of its common nonmotor features, such as rapid eye movement sleep behavior disorder, depression, and anxiety. PMID- 26010070 TI - 35(th) Annual David W Smith Workshop on Malformations and Morphogenesis: abstracts of the 2014 annual meeting. AB - The 35(th) Annual David W Smith Workshop on Malformations and Morphogenesis was held on July 25-30, 2014 at the University of Wisconsin, Madison, Wisconsin. The conference, which honors the legacy of David Smith, brought together over 130 clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. As is the tradition of the meeting, the Workshop highlighted five themes besides mechanisms of morphogenesis: Evolution and Development, Minor Malformations, CHARGE syndrome, Craniofacial Development/ Malformations, and Disorders of Chromatin Remodeling. This Conference Report includes the abstracts presented at the Workshop. PMID- 26010068 TI - Insulin-like growth factor binding protein 5 (IGFBP5) functions as a tumor suppressor in human melanoma cells. AB - The insulin-like growth factor binding protein 5 (IGFBP5), which is often dysregulated in human cancers, plays a crucial role in carcinogenesis and cancer development. However, the function and underlying mechanism of IGFBP5 in tumor growth and metastasis has been elusive, particularly in malignant human melanoma. Here, we reported that IGFBP5 acts as an important tumor suppressor in melanoma tumorigenicity and metastasis by a series of experiments including transwell assay, xenograft model, in vivo tumor metastasis experiment, and RNA-Seq. Overexpression of IGFBP5 in A375, a typical human melanoma cell line, inhibited cell malignant behaviors significantly, including in vitro proliferation, anchorage-independent growth, migration and invasion, as well as in vivo tumor growth and pulmonary metastasis. In addition, overexpression of IGFBP5 suppressed epithelial-mesenchymal transition (EMT), and decreased the expression of E cadherin and the key stem cell markers NANOG, SOX2, OCT4, KLF4, and CD133. Furthermore, IGFBP5 exerts its inhibitory activities by reducing the phosphorylation of IGF1R, ERK1/2, and p38-MAPK kinases and abating the expression of HIF1alpha and its target genes, VEGF and MMP9. All these findings were confirmed by IGFBP5 knockdown in human melanoma cell line A2058. Taken together, these results shed light on the mechanism of IGFBP5 as a potential tumor suppressor in melanoma progression, indicating that IGFBP5 might be a novel therapeutic target for human melanoma. PMID- 26010071 TI - Carrier-Density Control of the SrTiO3 (001) Surface 2D Electron Gas studied by ARPES. AB - The origin of the 2D electron gas (2DEG)stabilized at the bare surface of SrTiO3 (001) is investigated. Using high-resolution angle-resolved photoemission and core-level spectroscopy, it is shown conclusively that this 2DEG arises from light-induced oxygen vacancies. The dominant mechanism driving vacancy formation is identified, allowing unprecedented control over the 2DEG carrier density. PMID- 26010072 TI - Increased bone marrow FDG uptake at PET/CT is not a sufficient proof of bone marrow involvement in diffuse large B-cell lymphoma. PMID- 26010073 TI - Income Elasticity of Vaccines Spending versus General Healthcare Spending. AB - Using cross-country data on gross domestic product and national expenditure on vaccines, we estimate and compare the income elasticity of vaccine expenditure and general curative healthcare expenditure. This study provides the first evidence on the national income elasticity of vaccination spending. Both fixed and random effects models are applied to data from 84 countries from 2010 to 2011. The income elasticities for healthcare expenditure and vaccine expenditure are 0.844 and 0.336, respectively. Despite vaccines' high cost-effectiveness, the national propensity to spend income on vaccines as income increases lags behind general health care. The low income elasticity of vaccine spending means that relying on economic growth alone will provide an unacceptably slow trajectory to achieving high vaccine coverage levels. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010074 TI - Interleukin-6 and interleukin-6 receptor expression, localization, and involvement in pain-sensing neuron activation in a mouse intervertebral disc injury model. AB - The pathological mechanism of intractable low back pain is unclear. However, intervertebral disc (IVD) degeneration is a primary cause of low back pain, and pain-related mediators, such as interleukin-6 (IL-6), have been correlated with discogenic pain. The objective of this study is to elucidate the mechanism of local IL-6 and IL-6 receptor (IL-6R) expression after IVD injury as well as determine the involvement of IL-6/IL-6 signaling in discogenic pain. To do this, quantitative and immunohistological analyses in a mouse model of IVD injury were performed. Firstly, we measured the local expression levels of IL-6 and IL-6R in IVDs by enzyme-linked immunosorbent assay (ELISA). Secondly, we immunohistochemically confirmed their localization in injured IVDs. Lastly, we evaluated the effects of intradiscal injection of an IL-6 inhibitor by evaluating pain-related protein, calcitonin gene-related peptide (CGRP), expression in dorsal root ganglia (DRG) neurons that innervate IVDs. Injured IVDs showed increased production of IL-6 and IL-6R. IL-6 and IL-6R expression in the injured IVD were predominantly localized in the annulus fibrosus and endplate, and intradiscal injection of the IL-6 inhibitor suppressed CGRP expression in the DRG neurons. These results show that IL-6 and IL-6R expression levels are responsive to IVD injury and that inhibition of IL-6/IL-6R signaling may be a promising analgesic treatment for degenerative disc diseases. PMID- 26010075 TI - "Hit-and-run": Transcription factors get caught in the act. AB - A key challenge for understanding transcriptional regulation is being able to measure transcription factor (TF)-DNA binding events with sufficient spatial and temporal resolution; that is, when and where TFs occupy their cognate sites. A recent study by Para et al. has highlighted the dynamics underlying the activation of gene expression by a master regulator TF. This study provides concrete evidence for a long-standing hypothesis in biology, the "hit-and-run" mechanism, which was first proposed decades ago. That is, gene expression is dynamically controlled by a TF that transiently binds and activates a target gene, which might stay in a transcriptionally active state after the initial binding event has ended. Importantly, the experimental procedure introduced, TARGET, provides a useful way for identifying multiple target genes transiently bound by their regulators, which can be used in conjunction with other well established methods to improve our understanding of transcriptional regulatory dynamics. PMID- 26010076 TI - Acute hepatitis C virus infection induces anti-host cell receptor antibodies with virus-neutralizing properties. AB - Hepatitis C virus (HCV) causes persistent infection in the majority of infected individuals. The mechanisms of persistence and clearance are only partially understood. Antibodies (Abs) against host cell entry receptors have been shown to inhibit HCV infection in cell culture and animal models. In this study, we aimed to investigate whether anti-receptor Abs are induced during infection in humans in vivo and whether their presence is associated with outcome of infection. We established an enzyme-linked immunosorbant assay using a recombinant CD81-claudin 1 (CLDN1) fusion protein to detect and quantify Abs directed against extracellular epitopes of the HCV CD81-CLDN1 coreceptor complex. The presence of anti-receptor Abs was studied in serum of patients from a well-defined cohort of a single-source HCV outbreak of pregnant women and several control groups, including uninfected pregnant women, patients with chronic hepatitis B and D virus (HBV/HDV) infection, and healthy individuals. Virus-neutralizing activity of Abs was determined using recombinant cell culture-derived HCV (HCVcc). Our results demonstrate that HCV-infected patients have statistically significantly higher anti-CD81/CLDN1 Ab titers during the early phase of infection than controls. The titers were significantly higher in resolvers compared to persisters. Functional studies using immunoadsorption and HCV cell culture models demonstrate that HCV-neutralizing anti-receptor Abs are induced in the early phase of HCV infection, but not in control groups. CONCLUSION: The virus neutralizing properties of these Abs suggest a role for control of viral infection in conjunction with antiviral responses. Characterization of these anti receptor Abs opens new avenues to prevent and treat HCV infection. PMID- 26010077 TI - Prevalence of Eating Disorder Risk and Associations with Health-related Quality of Life: Results from a Large School-based Population Screening. AB - OBJECTIVE: The objective of this study was to investigate the prevalence of eating disorder (ED) risk as well as associated psychopathology and health related quality of life (HrQoL) in a large population sample of Austrian adolescents. METHOD: A sample of 3610 adolescents aged 10-18 years was recruited from 261 schools representative for the Austrian population. The SCOFF questionnaire was used to identify participants at risk for EDs, and the Youth Self-Report and KIDSCREEN were used to assess general psychopathology and HrQoL. RESULTS: In total, 30.9% of girls and 14.6% of boys were screened at risk for EDs. SCOFF scores were significantly associated with internalising and externalising behavioural problems as well as HrQoL after controlling for sex, age and body mass index. The SCOFF score further turned out to be an independent predictor of HrQoL. DISCUSSION: The high prevalence of ED risk among Austrian adolescents points out the need for prevention in this field. Variables indicating eating pathology should be included in general mental health screenings. PMID- 26010078 TI - Development of Femoral Head Interior Supporting Device and 3D Finite Element Analysis of its Application in the Treatment of Femoral Head Avascular Necrosis. AB - BACKGROUND: The aim of this study was to develop and perform the 3D finite element analysis of a femoral head interior supporting device (FHISD). MATERIAL AND METHODS: The 3D finite element model was developed to analyze the surface load of femoral head and analyze the stress and strain of the femoral neck, using the normal femoral neck, decompressed bone graft, and FHISD-implanted bone graft models. RESULTS: The stress in the normal model concentrated around the femoral calcar, with displacement of 0.3556+/-0.1294 mm. In the decompressed bone graft model, the stress concentrated on the femur calcar and top and lateral sides of femoral head, with the displacement larger than the normal (0.4163+/-0.1310 mm). In the FHISD-implanted bone graft model, the stress concentrated on the segment below the lesser trochanter superior to the femur, with smaller displacement than the normal (0.1856+/-0.0118 mm). CONCLUSIONS: FHISD could effectively maintain the biomechanical properties of the femoral neck. PMID- 26010079 TI - Latin American immigrant parents and their children's teachers in U.S. early childhood education programmes. AB - For many immigrants, their children's schools offer their first sustained interaction with the major societal institutions of their new countries, and so exploring the ways in which immigrant parents manage their children's educational experiences offers insight into how they adapt to new cultural norms, customs and expectations and how they are treated in return. This study delved into the involvement of Latin American immigrant parents in U.S. education, shifting the traditional focus down from elementary and secondary school to early childhood education. Statistical analysis of nationally representative data revealed that Latina immigrants had lower frequencies of most home- and community-based involvement behaviours than U.S.-born and foreign-born parents of varying racial/ethnic backgrounds but higher frequencies of involvement behaviours requiring participation in early childhood education programmes. As a window into these national patterns, qualitative data from an early childhood programme in an immigration-heavy state revealed that Latina immigrant mothers and their children's teachers often talked about each other as partners in supporting children's educational experiences but that their actual interactions tended to socialise mothers into being more passive recipients of teachers' directives. PMID- 26010081 TI - Nanofluidics Approach to Separate between Static and Kinetic Nanoconfinement Effects on the Crystallization of Polymers. AB - Here we report a nanofluidics approach that allows one to discriminate, for the first time, between static and kinetic effects on the crystallization of polymers in 2-dimensional nanoconfinement. Nanofluidics cells designed to monitor in real time, via permittivity measurements, the flow process of polymers into cylindrical nanopores were employed to investigate the crystallization of poly(vinylidenefluoride-co-trifluoroethylene) (PVDF-TrFE) under static and under kinetic confinement conditions. A significant separation between static confinement effects and flow effects in confinement is reported. A characteristic time is deduced, to quantify the impact of flow on the crystallization process of polymers taking place under conditions of 2D geometrical nanoconfinement. PMID- 26010080 TI - Direct Synthetic Control over the Size, Composition, and Photocatalytic Activity of Octahedral Copper Oxide Materials: Correlation Between Surface Structure and Catalytic Functionality. AB - We report a synthetic approach to form octahedral Cu2O microcrystals with a tunable edge length and demonstrate their use as catalysts for the photodegradation of aromatic organic compounds. In this particular study, the effects of the Cu(2+) and reductant concentrations and stoichiometric ratios were carefully examined to identify their roles in controlling the final material composition and size under sustainable reaction conditions. Varying the ratio and concentrations of Cu(2+) and reductant added during the synthesis determined the final morphology and composition of the structures. Octahedral particles were prepared at selected Cu(2+):glucose ratios that demonstrated a range of photocatalytic reactivity. The results indicate that material composition, surface area, and substrate charge effects play important roles in controlling the overall reaction rate. In addition, analysis of the post-reacted materials revealed photocorrosion was inhibited and that surface etching had preferentially occurred at the particle edges during the reaction, suggesting that the reaction predominately occurred at these interfaces. Such results advance the understanding of how size and composition affect the surface interface and catalytic functionality of materials. PMID- 26010082 TI - Influence of Flexibility and Dimensions of Nanocelluloses on the Flow Properties of Their Aqueous Dispersions. AB - We report that the intrinsic viscosity [eta] of nanocellulose dispersions can be solely expressed as a function of the aspect ratio p of the nanocellulose. Both short rod-like nanocrystalline and long spaghetti-like nanofibrillated celluloses were prepared as dispersions in water. The influence of the flexibility and dimensions of the nanocelluloses on the flow properties of their dispersions was investigated by experimental and theoretical approaches using seven nanocellulose samples with different widths (2.6-14.4 nm) and aspect ratios (23-376). As the aspect ratio of a nanocellulose increases, it becomes more flexible, and its dispersion has higher viscosity. Irrespective of the flexibility and dimensions of these nanocelluloses, the relationship between [eta] and p was rho[eta] = 0.15 * p(1.9), where rho is the density of the nanocellulose. PMID- 26010083 TI - Molecular Dynamics Study of the Photodesorption of CO Ice. AB - Photodesorption of CO ice is suggested to be the main process that maintains a measurable amount of gaseous CO in cold interstellar clouds. A classical molecular dynamics simulation is used to gain insight into the underlying mechanism. Site-site pair potentials were developed on the basis of ab initio calculations for the ground and excited nonrigid CO dimer. Both amorphous and crystalline CO clusters were created and characterized by their densities, expansion coefficients, binding energies, specific heats, and radial distribution functions. Selected CO molecules were electronically excited with 8.7-9.5 eV photons. CO returns to the ground state after a finite lifetime on the excited potential surface. Two desorption mechanisms are found: (1) direct desorption where excited CO itself is released from the cluster after landing on the ground state in an unfavorable orientation; (2) "kick-out" desorption where excited CO kicks out a neighboring CO molecule. These findings are in accord with laboratory experiments. Little dependence on size of the cluster, excitation energy and temperature in the 6-18 K range was found. The predicted photodesorption probability is 4.0 * 10(-3) molecules photon(-1), smaller by a factor of 3-11 than that given by experiments. PMID- 26010084 TI - Cluster survey evaluation of a measles vaccination campaign in Jharkhand, India, 2012. AB - INTRODUCTION: India was the last country in the world to implement a two-dose strategy for measles-containing vaccine (MCV) in 2010. As part of measles second dose introduction, phased measles vaccination campaigns were conducted during 2010-2013, targeting 131 million children 9 months to <10 years of age. We performed a post-campaign coverage survey to estimate measles vaccination coverage in Jharkhand state. METHODS: A multi-stage cluster survey was conducted 2 months after the phase 2 measles campaign occurred in 19 of 24 districts of Jharkhand during November 2011-March 2012. Vaccination status of children 9 months to <10 years of age was documented based on vaccination card or mother's recall. Coverage estimates and 95% confidence intervals (95% CI) for 1,018 children were calculated using survey methods. RESULTS: In the Jharkhand phase 2 campaign, MCV coverage among children aged 9 months to <10 years was 61.0% (95% CI: 54.4-67.7%). Significant differences in coverage were observed between rural (65.0%; 95% CI: 56.8-73.2%) and urban areas (45.6%; 95% CI: 37.3-53.9%). Campaign awareness among mothers was low (51.5%), and the most commonly reported reason for non-vaccination was being unaware of the campaign (69.4%). At the end of the campaign, 53.7% (95% CI: 46.5-60.9%) of children 12 months to <10 years of age received >= 2 MCV doses, while a large proportion of children remained under vaccinated (34.0%, 95% CI: 28.0-40.0%) or unvaccinated (12.3%, 95% CI: 9.3 16.2%). CONCLUSIONS: Implementation of the national measles campaign was a significant achievement towards measles elimination in India. In Jharkhand, campaign performance was below the target coverage of >= 90% set by the Government of India, and challenges in disseminating campaign messages were identified. Efforts towards increasing two-dose MCV coverage are needed to achieve the recently adopted measles elimination goal in India and the South-East Asia region. PMID- 26010085 TI - Blood BDNF level is gender specific in severe depression. AB - Though the role of brain derived neurotrophic factor (BDNF) as a marker for major depressive disorder (MDD) and antidepressant efficacy has been widely studied, the role of BDNF in distinct groups of patients remains unclear. We evaluated the diagnostic value of BDNF as a marker of disease severity measured by HAM-D scores and antidepressants efficacy among MDD patients. Fifty-one patients who met DSM IV criteria for MDD and were prescribed antidepressants and 38 controls participated in this study. BDNF in serum was measured at baseline, 1st, 2nd and 8th treatment weeks. Depression severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D). BDNF polymorphism rs6265 (val66met) was genotyped. We found a positive correlation between blood BDNF levels and severity of depression only among untreated women with severe MDD (HAM-D>24). Serum BDNF levels were lower in untreated MDD patients compared to control group. Antidepressants increased serum BDNF levels and reduced between-group differences after two weeks of treatment. No correlations were observed between BDNF polymorphism, depression severity, duration of illness, age and BDNF serum levels. Further supporting the role of BDNF in the pathology and treatment of MDD, we suggest that it should not be used as a universal biomarker for diagnosis of MDD in the general population. However, it has diagnostic value for the assessment of disease progression and treatment efficacy in individual patients. PMID- 26010086 TI - The Effect of an Alternate Start Codon on Heterologous Expression of a PhoA Fusion Protein in Mycoplasma gallisepticum. AB - While the genomes of many Mycoplasma species have been sequenced, there are no collated data on translational start codon usage, and the effects of alternate start codons on gene expression have not been studied. Analysis of the annotated genomes found that ATG was the most prevalent translational start codon among Mycoplasma spp. However in Mycoplasma gallisepticum a GTG start codon is commonly used in the vlhA multigene family, which encodes a highly abundant, phase variable lipoprotein adhesin. Therefore, the effect of this alternate start codon on expression of a reporter PhoA lipoprotein was examined in M. gallisepticum. Mutation of the start codon from ATG to GTG resulted in a 2.5 fold reduction in the level of transcription of the phoA reporter, but the level of PhoA activity in the transformants containing phoA with a GTG start codon was only 63% of that of the transformants with a phoA with an ATG start codon, suggesting that GTG was a more efficient translational initiation codon. The effect of swapping the translational start codon in phoA reporter gene expression was less in M. gallisepticum than has been seen previously in Escherichia coli or Bacillus subtilis, suggesting the process of translational initiation in mycoplasmas may have some significant differences from those used in other bacteria. This is the first study of translational start codon usage in mycoplasmas and the impact of the use of an alternate start codon on expression in these bacteria. PMID- 26010087 TI - Variability in the practice of fertility preservation for patients with cancer. AB - Fertility is important to women and men with cancer. While options for fertility preservation (FP) are available, knowledge regarding the medical application of FP is lacking. Therefore we examined FP practices for cancer patients among reproductive endocrinologists (REs). A 36 item survey was sent to board-certified REs. 98% of respondents reported counseling women with cancer about FP options. Oocyte and embryo cryopreservation were universally offered by these providers, but variability was noted in reported management of these cases-particularly for women with breast cancer. 86% of the respondents reported using letrozole during controlled ovarian stimulation (COS) in patients with estrogen receptor positive (ER+) breast cancer to minimize patient exposure to estrogen. 49% of respondents who reported using letrozole in COS for patients with ER+ breast cancer reported that they would also use letrozole in COS for women with ER negative breast cancer. Variability was also noted in the management of FP for men with cancer. 83% of participants reported counseling men about sperm banking with 22% recommending against banking for men previously exposed to chemotherapy. Overall, 79% of respondents reported knowledge of American Society for Clinical Oncology FP guidelines-knowledge that was associated with providers offering gonadal tissue cryopreservation (RR 1.82, 95% CI 1.14-2.90). These findings demonstrate that RE management of FP in cancer patients varies. Although some variability may be dictated by local resources, standardization of FP practices and communication with treating oncologists may help ensure consistent recommendations and outcomes for patients seeking FP. PMID- 26010088 TI - Plant Essential Oils Synergize and Antagonize Toxicity of Different Conventional Insecticides against Myzus persicae (Hemiptera: Aphididae). AB - Plant-derived products can play an important role in pest management programs. Essential oils from Lavandula angustifolia (lavender) and Thymus vulgaris (thyme) and their main constituents, linalool and thymol, respectively, were evaluated for insecticidal activity and synergistic action in combination with insecticides against green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae). The essential oils and their main constituents exerted similar insecticidal activity when aphids were exposed by direct sprays, but were non-toxic by exposure to treated leaf discs. In synergism experiments, the toxicity of imidacloprid was synergized 16- to 20-fold by L. angustifolia and T. vulgaris essential oils, but far less synergism occurred with linalool and thymol, indicating that secondary constituents of the oils were probably responsible for the observed synergism. In contrast to results with imidacloprid, the insecticidal activity of spirotetramat was antagonized by L. angustifolia and T. vulgaris essential oils, and linalool and thymol. Our results demonstrate the potential of plant essential oils as synergists of insecticides, but show that antagonistic action against certain insecticides may occur. PMID- 26010089 TI - Efficient Multiple Genome Modifications Induced by the crRNAs, tracrRNA and Cas9 Protein Complex in Zebrafish. AB - The type II clustered regularly interspaced short palindromic repeats (CRISPR) associated with Cas9 endonuclease (CRISPR/Cas9) has become a powerful genetic tool for understanding the function of a gene of interest. In zebrafish, the injection of Cas9 mRNA and guide-RNA (gRNA), which are prepared using an in vitro transcription system, efficiently induce DNA double-strand breaks (DSBs) at the targeted genomic locus. Because gRNA was originally constructed by fusing two short RNAs CRISPR RNA (crRNA) and trans-activating crRNA (tracrRNA), we examined the effect of synthetic crRNAs and tracrRNA with Cas9 mRNA or Cas9 protein on the genome editing activity. We previously reported that the disruption of tyrosinase (tyr) by tyr-gRNA/Cas9 mRNA causes a retinal pigment defect, whereas the disruption of spns2 by spns2-gRNA1/Cas9 mRNA leads to a cardiac progenitor migration defect in zebrafish. Here, we found that the injection of spns2-crRNA1, tyr-crRNA and tracrRNA with Cas9 mRNA or Cas9 protein simultaneously caused a migration defect in cardiac progenitors and a pigment defect in retinal epithelial cells. A time course analysis demonstrated that the injection of crRNAs and tracrRNA with Cas9 protein rapidly induced genome modifications compared with the injection of crRNAs and tracrRNA with Cas9 mRNA. We further show that the crRNA-tracrRNA-Cas9 protein complex is functional for the visualization of endogenous gene expression; therefore, this is a very powerful, ready-to-use system in zebrafish. PMID- 26010090 TI - Simple amides of oleanolic acid as effective penetration enhancers. AB - Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Furst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented. PMID- 26010091 TI - Liraglutide improves hypertension and metabolic perturbation in a rat model of polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with a prevalence of 5-8%. Type 2 diabetes and cardiovascular disease (CVD) are its long-term complications. Targeted therapies addressing both these complications together are lacking. Glucagon like peptide-1 (GLP-1) agonists that are used to treat type 2 diabetes mellitus have beneficial effects on the cardiovascular system. Hence we hypothesized that a GLP-1 agonist would improve both cardiovascular and metabolic outcomes in PCOS. To test this hypothesis, we used an established rat model of PCOS. Prepubertal female Sprague Dawley rats were sham-implanted or implanted s.c. with dihydrotestosterone (DHT) pellets (90 day release; 83 MUg/day). At 12 wks of age, sham implanted rats received saline injections and the DHT treated animals were administered either saline or liraglutide (0.2 mg/kg s.c twice daily) for 4 weeks. Subgroups of rats were implanted with telemeters between 12-13 weeks of age to monitor blood pressure. DHT implanted rats had irregular estrus cycles and were significantly heavier than the control females at 12 weeks (mean+/- SEM 251.9+/-3.4 vs 216.8+/ 3.4 respectively; p<0.05) and 4 weeks of treatment with liraglutide in DHT treated rats significantly decreased body weight (mean+/- SEM 294.75 +/-3.2 in DHT+ saline vs 276.25+/-2.7 in DHT+ liraglutide group respectively; p<0.01). Liraglutide treatment in the DHT implanted rats significantly improved glucose excursion during oral glucose tolerance test (area under the curve: DHT+ saline 28674+/-310 vs 24990+/- 420 in DHT +liraglutide p <0.01). DHT rats were hypertensive and liraglutide treatment significantly improved mean arterial pressure. These results suggest that GLP-1 treatment could improve DHT-induced metabolic and blood pressure deficits associated with PCOS. PMID- 26010092 TI - Effect of neonatal asphyxia on the impairment of the auditory pathway by recording auditory brainstem responses in newborn piglets: a new experimentation model to study the perinatal hypoxic-ischemic damage on the auditory system. AB - INTRODUCTION: Hypoxia-ischemia (HI) is a major perinatal problem that results in severe damage to the brain impairing the normal development of the auditory system. The purpose of the present study is to study the effect of perinatal asphyxia on the auditory pathway by recording auditory brain responses in a novel animal experimentation model in newborn piglets. METHOD: Hypoxia-ischemia was induced to 1.3 day-old piglets by clamping 30 minutes both carotid arteries by vascular occluders and lowering the fraction of inspired oxygen. We compared the Auditory Brain Responses (ABRs) of newborn piglets exposed to acute hypoxia/ischemia (n = 6) and a control group with no such exposure (n = 10). ABRs were recorded for both ears before the start of the experiment (baseline), after 30 minutes of HI injury, and every 30 minutes during 6 h after the HI injury. RESULTS: Auditory brain responses were altered during the hypoxic-ischemic insult but recovered 30-60 minutes later. Hypoxia/ischemia seemed to induce auditory functional damage by increasing I-V latencies and decreasing wave I, III and V amplitudes, although differences were not significant. CONCLUSION: The described experimental model of hypoxia-ischemia in newborn piglets may be useful for studying the effect of perinatal asphyxia on the impairment of the auditory pathway. PMID- 26010093 TI - Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats. AB - BACKGROUND: There is growing interest in sex differences and RAS components. However, whether gender influences cardiac angiotensin I-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity is still unknown. In the present work, we determined the relationship between ACE and ACE2 activity, left ventricular function and gender in spontaneously hypertensive rats (SHRs). METHODOLOGY/PRINCIPAL FINDINGS: Twelve-week-old female (F) and male (M) SHRs were divided into 2 experimental groups (n = 7 in each group): sham (S) and gonadectomized (G). Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt maximum left ventricle (LV) and dP/dt minimum LV, respectively), hypertrophy (morphometric analysis) and ACE and ACE2 catalytic activity (fluorimetrically). Expression of calcium handling proteins was measured by western blot. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy decreased the activity of these enzymes and hypertrophy, while ovariectomy increased hypertrophy and ACE2, but did not change ACE activity. For cardiac function, the male sham group had a lower +dP/dt than the female sham group. After gonadectomy, the +dP/dt increased in males and reduced in females. The male sham group had a lower -dP/dt than the female group. After gonadectomy, the -dP/dt increased in the male and decreased in the female groups when compared to the sham group. No difference was observed among the groups in SERCA2a protein expression. Gonadectomy increased protein expression of PLB (phospholamban) and the PLB to SERCA2a ratio in female rats, but did not change in male rats. CONCLUSION: Ovariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, whereas in males the removal of testosterone has the opposite effects on RAS components. PMID- 26010094 TI - AMP-Activated Protein Kinase Regulates the Cell Surface Proteome and Integrin Membrane Traffic. AB - The cell surface proteome controls numerous cellular functions including cell migration and adhesion, intercellular communication and nutrient uptake. Cell surface proteins are controlled by acute changes in protein abundance at the plasma membrane through regulation of endocytosis and recycling (endomembrane traffic). Many cellular signals regulate endomembrane traffic, including metabolic signaling; however, the extent to which the cell surface proteome is controlled by acute regulation of endomembrane traffic under various conditions remains incompletely understood. AMP-activated protein kinase (AMPK) is a key metabolic sensor that is activated upon reduced cellular energy availability. AMPK activation alters the endomembrane traffic of a few specific proteins, as part of an adaptive response to increase energy intake and reduce energy expenditure. How increased AMPK activity during energy stress may globally regulate the cell surface proteome is not well understood. To study how AMPK may regulate the cell surface proteome, we used cell-impermeable biotinylation to selectively purify cell surface proteins under various conditions. Using ESI MS/MS, we found that acute (90 min) treatment with the AMPK activator A-769662 elicits broad control of the cell surface abundance of diverse proteins. In particular, A-769662 treatment depleted from the cell surface proteins with functions in cell migration and adhesion. To complement our mass spectrometry results, we used other methods to show that A-769662 treatment results in impaired cell migration. Further, A-769662 treatment reduced the cell surface abundance of beta1-integrin, a key cell migration protein, and AMPK gene silencing prevented this effect. While the control of the cell surface abundance of various proteins by A-769662 treatment was broad, it was also selective, as this treatment did not change the cell surface abundance of the transferrin receptor. Hence, the cell surface proteome is subject to acute regulation by treatment with A-769662, at least some of which is mediated by the metabolic sensor AMPK. PMID- 26010095 TI - The First High-Density Genetic Map Construction in Tree Peony (Paeonia Sect. Moutan) using Genotyping by Specific-Locus Amplified Fragment Sequencing. AB - Genetic linkage maps, permitting the elucidation of genome structure, are one of most powerful genomic tools to accelerate marker-assisted breeding. However, due to a lack of sufficient user-friendly molecular markers, no genetic linkage map has been developed for tree peonies (Paeonia Sect. Moutan), a group of important horticultural plants worldwide. Specific-locus amplified fragment sequencing (SLAF-seq) is a recent molecular marker development technology that enable the large-scale discovery and genotyping of sequence-based marker in genome-wide. In this study, we performed SLAF sequencing of an F1 population, derived from the cross P. ostti 'FenDanBai' * P. * suffruticosa 'HongQiao', to identify sufficient high-quality markers for the construction of high-density genetic linkage map in tree peonies. After SLAF sequencing, a total of 78 Gb sequencing data and 285,403,225 pair-end reads were generated. We detected 309,198 high-quality SLAFs from these data, of which 85,124 (27.5%) were polymorphic. Subsequently, 3518 of the polymorphic markers, which were successfully encoded in to Mendelian segregation types, and were in conformity with the criteria of high-quality markers, were defined as effective markers and used for genetic linkage mapping. Finally, we constructed an integrated genetic map, which comprised 1189 markers on the five linkage groups, and spanned 920.699 centiMorgans (cM) with an average inter-marker distance of 0.774 cM. There were 1115 'SNP-only' markers, 18 'InDel only' markers, and 56 'SNP&InDel' markers on the map. Among these markers, 450 (37.85%) showed significant segregation distortion (P < 0.05). In conclusion, this investigation reported the first large-scale marker development and high density linkage map construction for tree peony. The results of this study will serve as a solid foundation not only for marker-assisted breeding, but also for genome sequence assembly for tree peony. PMID- 26010096 TI - The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits. AB - The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)-induced acute phase response (APR) on the pharmaco kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 +/- 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 MUg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples were collected from the auricular vein before drug administration and at different times between 0.05 and 24.0 h after treatment. FFC and florfenicol-amine (FFC-a) were extracted from the plasma, and their concentrations were determined by high performance liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using the paired Student t-test. The mean values of AUC0-infinity in the endotoxaemic rabbits (26.3 +/- 2.7 MUg.h/mL) were significantly higher (P < 0.05) than values observed in healthy rabbits (17.2 +/- 0.97 MUg.h/mL). The total mean plasma clearance (CLT ) decreased from 1228 +/- 107.5 mL.h/kg in the control group to 806.4 +/- 91.4 mL.h/kg in the LPS-treated rabbits. A significant increase (P < 0.05) in the half life of elimination was observed in the endotoxaemic rabbits (5.59 +/- 1.14 h) compared to the values observed in healthy animals (3.44 +/- 0.57 h). In conclusion, the administration of repeated doses of 1 MUg/kg E. coli LPS induced an APR in rabbits, producing significant modifications in plasma concentrations of FFC leading to increases in the AUC, terminal half-life and mean residence time (MRT), but a significant decrease in CLT of the drug. As a consequence of the APR induced by LPS, there was a reduction in the metabolic conversion of FFC to their metabolite FFC-a in the liver, suggesting that the mediators released during the APR induced significant inhibitory effects on the hepatic drug metabolizing enzymes. PMID- 26010097 TI - Controlled Styrene Monolayer Capping of Silicon Nanocrystals by Room Temperature Hydrosilylation. AB - Undecanoic acid facilitates attachment of styrene to hydride-terminated Si nanocrystals at room temperature, avoiding polymerization of styrene, yielding free-standing styrene-terminated Si nanocrystals. The nanocrystals have diamond cubic crystal structure, with photophysical properties similar to typical alkene capped Si nanocrystals, such as bright photoluminescence with relatively long radiative lifetimes. We propose a reaction mechanism for room temperature styrene addition in which the resonance form of undecanoic acid coordinates to surface Si H and facilitates H(-) attack at terminal C?C of styrene. PMID- 26010098 TI - Factors affecting the sorption of cesium in a nutrient-poor boreal bog. AB - (135)Cs is among the most important radionuclides in the long-term safety assessments of spent nuclear fuel, due to its long half-life of 2.3 My and large inventory in spent nuclear fuel. Batch sorption experiments were conducted to evaluate the sorption behavior of radiocesium ((134)Cs) in the surface moss, peat, gyttja, and clay layers of 7-m-deep profiles taken from a nutrient-poor boreal bog. The batch distribution coefficient (Kd) values of radiocesium increased as a function of sampling depth. The highest Kd values, with a geometric mean of 3200 L/kg dry weight (DW), were observed in the bottom clay layer and the lowest in the 0.5-1.0 m peat layer (50 L/kg DW). The maximum sorption in all studied layers was observed at a pH between 7 and 9.5. The in situ Kd values of (133)Cs in surface Sphagnum moss, peat and gyttja samples were one order of magnitude higher than the Kd values obtained using the batch method. The highest in situ Kd values (9040 L/kg DW) were recorded for the surface moss layer. The sterilization of fresh surface moss, peat, gyttja and clay samples decreased the sorption of radiocesium by 38%, although the difference was not statistically significant. However, bacteria belonging to the genera Pseudomonas, Paenibacillus, Rhodococcus and Burkholderia isolated from the bog were found to remove radiocesium from the solution under laboratory conditions. The highest biosorption was observed for Paenibacillus sp. V0-1-LW and Pseudomonas sp. PS-0-L isolates. When isolated bacteria were added to sterilized bog samples, the removal of radiocesium from the solution increased by an average of 50% compared to the removal recorded for pure sterilized peat. Our results demonstrate that the sorption of radiocesium in the bog environment is dependent on pH and the type of the bog layer and that common environmental bacteria prevailing in the bog can remove cesium from the solution phase. PMID- 26010099 TI - Identification of 4-Trimethylaminobutyraldehyde Dehydrogenase (TMABA-DH) as a Candidate Serum Autoantibody Target for Kawasaki Disease. AB - Kawasaki disease (KD), an acute vasculitis that preferentially affects coronary arteries, is still the leading cause of acquired heart disease in children. Although the involvement of immune system malfunction in the onset of KD is suggested, its etiology still remains to be clarified. We investigated autoantibodies in KD patients, which are frequently found in sera from patients with autoimmune diseases, vasculitides and arteritides. We performed two dimensional western blotting and LC-MS/MS to analyze the antigens of autoantibodies, detected two protein spots with 4 out of 24 sera from KD patients but not with 6 control sera, and identified the antigens as 4 trimethylaminobutyraldehyde dehydrogenase (TMABA-DH). A slot blot analysis with TMABA-DH as an antigen also revealed higher reactivities of patients' sera than control sera (positive rates: 18/43 vs 3/41). Using an enzyme-linked immunosorbent assay (ELISA), we found that the reactivity of anti-TMABA-DH antibodies in sera from KD patients was significantly higher than that in sera from age-matched controls. The optimal cut-off value of 0.043 had a sensitivity of 83.7% and a specificity of 80.0% in detecting KD patients (positive rates: 37/43 for KD patients, 9/41 for controls). Immunohistochemistry performed on thin sections of rat heart revealed that TMABA-DH colocalized with myosin light chains in cardiac myocytes. Patient sera with high reactivity gave similar immunostaining pattern. These results suggest that the detection of anti-TMABA-DH autoantibody could be a potential strategy for a diagnosis of KD. PMID- 26010101 TI - Structured Coupling of Probability Loss Distributions: Assessing Joint Flood Risk in Multiple River Basins. AB - Losses due to natural hazard events can be extraordinarily high and difficult to cope with. Therefore, there is considerable interest to estimate the potential impact of current and future extreme events at all scales in as much detail as possible. As hazards typically spread over wider areas, risk assessment must take into account interrelations between regions. Neglecting such interdependencies can lead to a severe underestimation of potential losses, especially for extreme events. This underestimation of extreme risk can lead to the failure of riskmanagement strategies when they are most needed, namely, in times of unprecedented events. In this article, we suggest a methodology to incorporate such interdependencies in risk via the use of copulas. We demonstrate that by coupling losses, dependencies can be incorporated in risk analysis, avoiding the underestimation of risk. Based on maximum discharge data of river basins and stream networks, we present and discuss different ways to couple loss distributions of basins while explicitly incorporating tail dependencies. We distinguish between coupling methods that require river structure data for the analysis and those that do not. For the later approach we propose a minimax algorithm to choose coupled basin pairs so that the underestimation of risk is avoided and the use of river structure data is not needed. The proposed methodology is especially useful for large-scale analysis and we motivate and apply our method using the case of Romania. The approach can be easily extended to other countries and natural hazards. PMID- 26010102 TI - Microsurgical Reconstruction of Complex Scalp Defects: An Appraisal of Flap Selection and the Timing of Complications. AB - BACKGROUND: The purposes of this study were to report a 7-year experience of microvascular reconstruction of scalp defects, compare flap type and outcomes, and evaluate the implications of short and long term complications. METHODS: Following institutional review board approval, a single surgeon's patients requiring microvascular scalp reconstruction were retrospectively reviewed from 2005 to 2011. Flap choice, complications, and outcomes were statistically analyzed. RESULTS: Nineteen patients met inclusion criteria (10 male and 9 female) with a mean age of 60.2 +/- 21.4 years (range, 23-90 years). All free tissue transfers (n = 20) achieved 100% soft tissue coverage. Mean size calvarial defect was 106.6 +/- 67.2 cm(2) (range, 35-285 cm(2)), with 11 requiring cranioplasty. Free flaps included the following: 13 anteriolateral thigh, 5 ulnar, 1 latissimus dorsi, and 1 thoracodorsal artery perforator. Mean flap size was 154.1 +/- 87.3 cm(2) (range, 42-336 cm(2)). Early complications (<30 days following surgery) occurred in 21.1% of patients and late complications (>30 days following surgery) in 52.6% of patients. Patients with an early complication were 2 times more likely to develop a late complication (relative risk, 2.1) but did not reach statistical significance. Late complications were more likely to require surgical intervention, 84.2% versus 60% of early complications (P = 0.079). CONCLUSIONS: Microvascular free tissue transfer is the mainstay of complex scalp defects but carries a high likelihood of future reoperations. Early complications are less concerning than late complications, as the need for future surgical intervention is associated with late complications. There is lack of evidence to support a superior flap choice. PMID- 26010100 TI - Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. AB - Calcineurin plays essential roles in virulence and growth of pathogenic fungi and is a target of the natural products FK506 and Cyclosporine A. In the pathogenic mucoralean fungus Mucor circinelloides, calcineurin mutation or inhibition confers a yeast-locked phenotype indicating that calcineurin governs the dimorphic transition. Genetic analysis in this study reveals that two calcineurin A catalytic subunits (out of three) are functionally diverged. Homology modeling illustrates modes of resistance resulting from amino substitutions in the interface between each calcineurin subunit and the inhibitory drugs. In addition, we show how the dimorphic transition orchestrated by calcineurin programs different outcomes during host-pathogen interactions. For example, when macrophages phagocytose Mucor yeast, subsequent phagosomal maturation occurs, indicating host cells respond appropriately to control the pathogen. On the other hand, upon phagocytosis of spores, macrophages fail to form mature phagosomes. Cytokine production from immune cells differs following exposure to yeast versus spores (which germinate into hyphae). Thus, the morphogenic transition can be targeted as an efficient treatment option against Mucor infection. In addition, genetic analysis (including gene disruption and mutational studies) further strengthens the understanding of calcineurin and provides a foundation to develop antifungal agents targeting calcineurin to deploy against Mucor and other pathogenic fungi. PMID- 26010103 TI - Telemedicine in Cleft Care: Reliability and Predictability in Regional and International Practice Settings. AB - BACKGROUND: Regional and international cleft care providers are challenged in their ability to deliver reliable, comprehensive care. Our institution utilizes video teleconferencing to facilitate initial evaluation and postoperative cleft care. This study describes our experience using telemedicine, generates a perioperative treatment algorithm using this technology, and compares cost utility of telemedicine to in-person ambulatory visits when regional practices are involved. METHODS: A 5-year retrospective review of all cleft patients evaluated in an ambulatory setting was conducted. Patient demographics and location, number, and type of telemedicine visits were recorded. Specific treatment algorithms utilizing telemedicine for perioperative care for primary and secondary cleft lip and nasal repair, palatoplasty, and operation for velopharyngeal insufficiency are described. A cost-utility analysis was performed comparing distances between patient homes and primary hub versus telemedicine clinic sites. RESULTS: Five hundred nineteen patients were identified; 18.1% attended at least 1 teleconferencing visit. Postoperative follow-up was 100%. The majority of screening, preoperative, and postoperative care was provided using telemedicine. In-person evaluations were performed when intraoral assessments were necessary. Telemedicine visits were associated with an average savings of 239 miles per visit in the United States and 578 miles per visit in Mexico. CONCLUSIONS: Video teleconferencing can be used to provide comprehensive regional and international cleft care to facilitate initial evaluations and consistent follow-up. This technology can alleviate the travel burden on families and cleft care providers practicing over a large geographic radius. PMID- 26010104 TI - Cleft and Craniofacial Care During Military Pediatric Plastic Surgery Humanitarian Missions. AB - BACKGROUND: Military pediatric plastic surgery humanitarian missions in the Western Hemisphere have been initiated and developed since the early 1990 s using the Medical Readiness Education and Training Exercise (MEDRETE) concept. Despite its initial training mission status, the MEDRETE has developed into the most common and advanced low level medical mission platform currently in use. The objective of this study is to report cleft- and craniofacial-related patient outcomes after initiation and evolution of a standardized treatment protocol highlighting lessons learned which apply to civilian plastic surgery missions. METHODS: A review of the MEDRETE database for pediatric plastic surgery/cleft and craniofacial missions to the Dominican Republic from 2005 to 2009 was performed. A multidisciplinary team including a craniofacial surgeon evaluated all patients with a cleft/craniofacial and/or pediatric plastic condition. A standardized mission time line included predeployment site survey and predeployment checklist, operational brief, and postdeployment after action report. Deployment data collection, remote patient follow-up, and coordination with larger land/amphibious military operations was used to increase patient follow-up data. Data collected included sex, age, diagnosis, date and type of procedure, surgical outcomes including speech scores, surgical morbidity, and mortality. RESULTS: Five hundred ninety-four patients with cleft/craniofacial abnormalities were screened by a multidisciplinary team including craniofacial surgeons over 4 years. Two hundred twenty-three patients underwent 330 surgical procedures (cleft lip, 53; cleft palate, 73; revision cleft lip/nose, 73; rhinoplasty, 15; speech surgery, 24; orthognathic/distraction, 21; general pediatric plastic surgery, 58; fistula repair, 12). Average follow-up was 30 months (range, 1-60). The complication rate was 6% (n = 13) (palate fistula, lip revision, dental/alveolar loss, revision speech surgery rate). The average pre-surgical (Pittsburgh Weighted Speech Score) speech score was 12 (range, 6-24). The average postsurgical speech score was 6 (range, 0-21). Average hospital stay was 3 days for cleft surgery. There were no major complications or mortality, 1 reoperation for bleeding or infection, and 12 patients required secondary operations for palatal fistula, unsatisfactory aesthetic result, malocclusion, or velopharygeal dysfunction. CONCLUSIONS: Military pediatric plastic surgery humanitarian missions can be executed with similar home institution results after the initiation and evolution of a standardized approach to humanitarian missions. The incorporation of a dedicated logistics support unit, a dedicated operational specialist (senior noncommissioned officer), a speech language pathologist, remote internet follow up, an liaison officer (host nation liaison physician participation), host nation surgical resident participation, and support from the embassy, Military Advisory Attachment Group, and United States Aid and International Development facilitated patient accurate patient evaluation and posttreatment follow-up. Movement of the mission site from a remote more austere environment to a centralized better equipped facility with host nation support to transport patients to the site facilitated improved patient safety and outcomes despite increasing the complexity of surgery performed. PMID- 26010105 TI - Comparative analysis of flow cytometry and morphology for the detection of acute myeloid leukaemia cells in cerebrospinal fluid. PMID- 26010106 TI - Force Field Benchmark of Organic Liquids. 2. Gibbs Energy of Solvation. AB - Quantitative prediction of physical properties of liquids is a longstanding goal of molecular simulation. Here, we evaluate the predictive power of the Generalized Amber Force Field (Wang et al. J. Comput. Chem. 2004, 25, 1157-1174) for the Gibbs energy of solvation of organic molecules in organic solvents using the thermodynamics integration (TI) method. The results are compared to experimental data, to a model based on quantitative structure property relations (QSPR), and to the conductor-like screening models for realistic solvation (COSMO RS) model. Although the TI calculations yield slightly better correlation to experimental results than the other models, in all fairness we should conclude that the difference between the models is minor since both QSPR and COSMO-RS yield a slightly lower RMSD from that of the experiment (<3.5 kJ/mol). By analyzing which molecules (either as solvents or solutes) are outliers in the TI calculations, we can pinpoint where additional parametrization efforts are needed. For the force field based TI calculations, deviations from the experiment occur in particular when compounds containing nitro or ester groups are solvated into other liquids, suggesting that the interaction between these groups and solvents may be too strong. In the COSMO-RS calculations, outliers mainly occur when compounds containing (in particular aromatic) rings are solvated despite using a ring correction term in the calculations. PMID- 26010107 TI - Investigating the dissociative subtype of posttraumatic stress disorder in a sample of traumatized detained youth. AB - In this study, we tested the validity of a dissociative subtype in a sample of 225 detained adolescents (142 boys, 83 girls) likely meeting full or partial criteria for posttraumatic stress disorder (PTSD). Competing theories of dissociation pose controversy regarding dissociation as a taxon versus a continuum, and results of the current study contribute to this debate by providing evidence of distinct group differences between those high and low in dissociation. Mixture modeling revealed 2 groups of youth with differing levels of depersonalization/derealization dissociative symptoms. Differences between the 2 groups of youth were investigated regarding trauma exposure and several posttraumatic reactions: posttraumatic stress symptoms (PTSS), emotion dysregulation, and emotional numbing. Compared with youth classified in the low dissociation group, youth who exhibited high levels of dissociation demonstrated higher levels of total PTSS, posttraumatic symptom clusters of emotional numbing, intrusion, and associated features, as well as reporting more difficulties with emotion dysregulation. To test theory regarding the factors that increase the likelihood of persistent dissociation, bootstrapped regression analyses were performed to examine the possibility of an indirect effect of peritraumatic dissociation. Results consistent with statistical mediation suggested that the presence of peritraumatic dissociation at the time of trauma may contribute to the continuation of dissociative symptoms as a more generalized pattern. The results of the current study have implications for clinical treatment with traumatized youth. PMID- 26010108 TI - Yoga for military service personnel with PTSD: A single arm study. AB - This study evaluated the effects of yoga on posttraumatic stress disorder (PTSD) symptoms, resilience, and mindfulness in military personnel. Participants completing the yoga intervention were 12 current or former military personnel who met the Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition Text Revision (DSM-IV-TR) diagnostic criteria for PTSD. Results were also benchmarked against other military intervention studies of PTSD using the Clinician Administered PTSD Scale (CAPS; Blake et al., 2000) as an outcome measure. Results of within-subject analyses supported the study's primary hypothesis that yoga would reduce PTSD symptoms (d = 0.768; t = 2.822; p = .009) but did not support the hypothesis that yoga would significantly increase mindfulness (d = 0.392; t = -0.9500; p = .181) and resilience (d = 0.270; t = 1.220; p = .124) in this population. Benchmarking results indicated that, as compared with the aggregated treatment benchmark (d = 1.074) obtained from published clinical trials, the current study's treatment effect (d = 0.768) was visibly lower, and compared with the waitlist control benchmark (d = 0.156), the treatment effect in the current study was visibly higher. PMID- 26010110 TI - Core beliefs shaken by an earthquake correlate with posttraumatic growth. AB - Posttraumatic growth (PTG), psychological growth as a result of personal struggle with trauma, is hypothesized to occur when a highly stressful life event, such as a natural disaster, forces people to reexamine their core beliefs. To the authors' knoweldge, the present study is the first investigation in Japanese people examining the role of core beliefs, intrusive rumination, and deliberate rumination in PTG. Hypotheses that the level of reexamination of core beliefs, intrusive rumination, and deliberate rumination correlate with the seismicity of an earthquake and that the challenge to core beliefs is the major determinant of PTG were tested. Japanese undergraduate students who experienced the Great East Japan Earthquake on March 11, 2011 (N = 314) participated in this study and completed the Japanese version of the Core Beliefs Inventory (CBI), the Event Related Rumination Inventory (ERRI), and the Posttraumatic Growth Inventory (PTGI). Results indicated that core beliefs were less likely to be challenged and that ruminations were less likely to be activated in Japanese people who were in the southern area with an approximate Richter magnitude of 4 or lower. PTG was more likely to occur when core beliefs were reexamined following the earthquake. Also, younger participants and those who recalled having engaged in both deliberate and intrusive rumination reported more PTG. Future studies should investigate which aspects of trauma can trigger or suppress the reexamination of one's core beliefs, for they are likely to be the major determinants of PTG, and should look at change longitudinally. PMID- 26010109 TI - Veterans' PTSD symptoms and their partners' desired changes in key relationship domains. AB - There is a growing literature investigating the connection between veterans' posttraumatic stress disorder (PTSD) symptoms and intimate relationship problems. Little to no work, however, has examined the connection between veterans' PTSD symptoms and their partners' perceptions of specific relationship areas in need of change. We examined associations between overall PTSD symptoms and symptom cluster scores with partners' desired changes in the areas of intimacy, shared activities, and responsibilities. The sample consisted of 249 male veterans of different service eras and their female partners. Results indicated that veterans' PTSD symptoms were associated with greater desired changes from their partners in the veterans' intimacy behaviors and participation in shared activities. When examining the contribution of each symptom cluster individually, only the veterans' emotional numbing symptoms emerged as a significant unique predictor and were associated with partners' desired changes in intimacy. The findings suggest that intimacy and shared activities may be relevant areas to address in PTSD treatment for veterans and their partners and highlight the particular significance of emotional numbing symptoms to intimacy in veterans' relationships. PMID- 26010111 TI - Disclosing traumatic experiences: Correlates, context, and consequences. AB - The type and severity of traumatic events differentially predict negative posttraumatic outcomes, with betrayal traumas (in which the victim is perpetrated by someone s/he trusts) touted as the most harmful. Although disclosure is considered an important component of the "healing process," nondisclosure and delayed disclosure persist. This study explored factors predicting and the context surrounding disclosure as well as the link between disclosure timing and a trauma survivor's experience with depression. Participants (N = 124) were attendees of a Mental Health Awareness event who had experienced a traumatic event. Participant report of traumatic experiences revealed that 28.2%, 36.3%, and 35.5% of participants had experienced a low betrayal (LB), medium betrayal (MB), and high betrayal (HB) trauma, respectively. Almost half (43.5%) disclosed immediately after the trauma, 32.3% disclosed within a month, and 24.2% disclosed after 1 month or more. Betrayal trauma level significantly predicted disclosure timing with individuals who had experienced HB traumas significantly more likely to delay disclosure (HB:LB, odds ratio [OR] = 21.79; MB:LB, OR = 4.57). Trauma survivors predominantly first disclosed to informal support sources (e.g., friends, family), typically citing that they thought it would allow them to feel better or they perceived the other person to be concerned about their well-being as their reason for disclosing. Experiencing a HB trauma predicted subsequent depression severity, but disclosure status was not predictive of subsequent depression. Results will be discussed with respect to implications for assessment and interventions for trauma survivors. PMID- 26010112 TI - Do scores on the Beck Depression Inventory-II predict outcome in cognitive processing therapy? AB - Current treatment guidelines for posttraumatic stress disorder (PTSD) recognize that severe depression may limit the effectiveness of trauma-focused interventions, making it necessary to address depression symptomatology first. However, there is a paucity of research providing specific treatment recommendations using a common depression measure like the Beck Depression Inventory-II (BDI-II). Accordingly, we examined the utility of using BDI-II cutoff scores for predicting response to cognitive processing therapy (CPT). Our sample was 757 military veterans receiving outpatient therapy at a Department of Veterans Affairs specialty clinic. At baseline, the majority of participants (58.9%) reported BDI-II scores suggestive of severe depression, and 459 (60.7%) met DSM-IV diagnostic criteria for major depressive disorder (MDD). Despite this high level of depression severity, most participants who completed therapy experienced a clinically significant reduction in symptoms (75.1%). No differences were observed across BDI-II groups on rates of clinically significant change in PTSD symptoms or on rates of treatment completion. Taken together, results suggest that CPT is an effective treatment, even in cases of severe co occurring depression. Limitations and implications for treatment guidelines are discussed. PMID- 26010113 TI - Efficacy of a brief treatment for nightmares and sleep disturbances for veterans. AB - Nightmares and sleep disturbances are common complaints among military Veterans (Plumb & Zelman, 2009) and may be difficult to eradicate (Forbes, Phelps, & McHugh, 2001). A treatment protocol (Exposure, Relaxation, and Rescription Therapy [ERRT]) targeting nightmares and sleep disturbances, which has been used effectively in civilian populations, was adapted for the military (ERRT-M). A pilot study evaluated the efficacy of ERRT-M in improving sleep quality and quantity and reducing nightmares, symptoms of posttraumatic stress disorder, and depression in a trauma-exposed, Veteran sample (N = 19). At 1 week after treatment, analyses revealed improvements in nightmare frequency and severity, depression, sleep quality, and insomnia severity. Treatment gains were maintained at a 2-month follow-up. Fifty percent of the sample was considered treatment responders (i.e., no nightmares in the previous week). Results of this pilot study suggest that directly targeting sleep and nightmares is successful in alleviating sleep disturbances and related psychopathology in some Veterans. PMID- 26010114 TI - Examining trauma and posttraumatic stress disorder symptoms in court-mandated intimate partner violence perpetrators. AB - There is a dearth of empirical literature characterizing the various forms of trauma experienced by men court mandated to intervention for intimate partner violence (IPV) perpetration. We investigated the potentially traumatic events (PTEs) experienced by men (N = 217) court mandated to enroll in a 41-week group IPV perpetrator program, as well as the relationships between PTEs, posttraumatic stress disorder (PTSD) symptoms, and IPV. Findings indicated that 94% of participants reported experiencing at least 1 PTE in their lifetime, and participants experienced an average of over 6 out of 14 types of PTEs. A significant association was found between the number of PTEs experienced and frequency of self-reported perpetration of physical and psychological IPV. PTSD symptoms were also related to both forms of IPV perpetration and mediated the relationship between experiencing PTEs and psychological IPV perpetration. Our findings have implications for understanding how trauma and PTSD symptoms may increase risk for IPV and for developing trauma-informed interventions for this population. PMID- 26010115 TI - Coverage of child maltreatment in abnormal psychology textbooks: Reviewing the adequacy of the content. AB - Abnormal psychology courses introduce undergraduate students to the range, causes, and treatments of psychological disorders. These courses present important opportunities to instruct students about disorders and treatments associated with childhood maltreatment (CM) as well as its prevalence. Little research has examined the adequacy with which abnormal psychology textbooks present information about CM. The present study reviewed the CM content of 10 abnormal psychology textbooks. The content was assessed in terms of the number of times CM was mentioned, the number of psychological disorders linked to CM, and the number of CM-related research citations. In addition, the authors conducted a content analysis to examine the significance, depth of detail, and organizational structure of the information provided within the sections of text addressing CM. There were significant differences in scores and the accuracy of coverage of CM across textbooks. Most of the textbooks lack key information on CM. The information presented in many textbooks is not consistent with current research and is overly focused on controversies. These findings are concerning because research has linked many psychological disorders and problematic outcomes to CM, but this information is not adequately conveyed to students via abnormal psychology textbooks. The authors make recommendations for improving the coverage of CM in abnormal psychology textbooks. PMID- 26010116 TI - Echo-Tracking Method Improves the Reliability in Flow-Mediated Dilation Assessment by Measuring Brachial Artery Reactivity. AB - The purpose of the study was to compare the intraobserver and interobserver reliability and agreement for measurement of flow-mediated dilation (FMD) between B-mode method and echo-tracking (ET) method. Twenty healthy volunteers (mean age, 31.6 +/- 9.2 years) underwent ultrasound examination by both B-mode and ET methods. Baseline brachial artery diameter, post-cuff release diameter, and FMD percent were assessed by each sonologist on 2 consecutive days. Reliability was assessed by intraclass correlation coefficients, and Bland-Altman plots were used to visually compare measurement bias and agreement by the 2 ultrasound methods. A total of 40 pairs of data were available for analysis. Excellent intraobserver and interobserver reliability values were found for all variables assessed by the 2 methods. The intraclass correlation coefficient values were higher for ET in both intraobserver and interobserver evaluations, but only for interobserver evaluations for post-cuff release diameter and FMD was there no overlap in the 95% confidence interval. The Bland-Altman plots showed that in 95% of the measurements, the percentage difference between ET and B-mode ultrasound techniques was within 18.1%, 19.4%, and 17.3% for baseline brachial artery diameter, post-cuff release diameter, and FMD percent, respectively. The results suggest that ET and B-mode methods are reproducible in assessing the FMD. The ET method improves the reliability of FMD assessment, but we cannot determine which measurement is better for FMD. PMID- 26010118 TI - Microbial dechlorination of polychlorinated biphenyls, dibenzo-p-dioxins, and furans at the Portland Harbor Superfund site, Oregon, USA. AB - The Portland Harbor (Oregon, USA) has been declared a "Superfund" site because it is impacted by a variety of contaminants, including polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and -furans (PCDD/Fs). Using data collected in the remedial investigation, concentrations of PCBs and PCDD/Fs in sediment and water were examined using positive matrix factorization to look for evidence that PCBs and PCDD/Fs are dechlorinated by anaerobic bacteria. This process has long been known to occur in sediments. Recently, it has been recognized that PCB and PCDD/F dechlorination may also occur in other anaerobic environments, such as in landfills, sewers, and groundwater. The results indicate that a factor related to the dechlorination of PCBs and PCDD/Fs was present in the water but not in the sediment. Spatial patterns in dechlorination products suggest that they come primarily from groundwater. Dechlorination products comprise 22% of the PCBs in the water. The Portland Harbor therefore represents the third major US watershed in which PCBs appear to undergo dechlorination in an environment other than sediment, suggesting that the microbial dechlorination of PCBs and PCDD/Fs is more common than previously assumed. In addition, the Portland Harbor is impacted by PCBs generated inadvertently during the production of pigments, such as PCB 11, which alone exceeded the 64 pg/L federal water quality standard for the sum of PCBs in two of 120 whole water samples. PMID- 26010117 TI - Bacterial-induced calcium oscillations are common to nitrogen-fixing associations of nodulating legumes and nonlegumes. AB - Plants that form root-nodule symbioses are within a monophyletic 'nitrogen fixing' clade and associated signalling processes are shared with the arbuscular mycorrhizal symbiosis. Central to symbiotic signalling are nuclear-associated oscillations in calcium ions (Ca(2+) ), occurring in the root hairs of several legume species in response to the rhizobial Nod factor signal. In this study we expanded the species analysed for activation of Ca(2+) oscillations, including nonleguminous species within the nitrogen-fixing clade. We showed that Ca(2+) oscillations are a common feature of legumes in their association with rhizobia, while Cercis, a non-nodulating legume, does not show Ca(2+) oscillations in response to Nod factors from Sinorhizobium fredii NGR234. Parasponia andersonii, a nonlegume that can associate with rhizobia, showed Nod factor-induced calcium oscillations to S. fredii NGR234 Nod factors, but its non-nodulating sister species, Trema tomentosa, did not. Also within the nitrogen-fixing clade are actinorhizal species that associate with Frankia bacteria and we showed that Alnus glutinosa induces Ca(2+) oscillations in root hairs in response to exudates from Frankia alni, but not to S. fredii NGR234 Nod factors. We conclude that the ability to mount Ca(2+) oscillations in response to symbiotic bacteria is a common feature of nodulating species within the nitrogen-fixing clade. PMID- 26010120 TI - Validation of the cocaine versions of the Obsessive Compulsive Drug Use Scale and the Desires for Drug Questionnaire. AB - BACKGROUND: The Obsessive Compulsive Drug Use Scale (OCDUS) and the Desires for Drug Questionnaire (DDQ) are two frequently used drug craving questionnaires. Although both heroin and cocaine versions of the questionnaires exist, only the heroin versions have been psychometrically evaluated. The present study was conducted to evaluate the psychometric qualities of the cocaine versions of the OCDUS (OCDUS-C) and DDQ (DDQ-C). METHODS: Cocaine-dependent inpatients (n = 101) completed both scales as well as a Visual Analogue Craving Scale (VACS), an alternative, one-item index for assessing momentary craving. We examined the reliability (internal consistency), construct validity (factor structure), and concurrent validity (correlations among both questionnaires, the VACS, and indicators of severity of dependence). A subsample also completed the OCDUS-C and DDQ-C for a second time, one week after the initial administration to obtain a preliminary investigation of the test-retest reliability. RESULTS: In general, both questionnaires displayed good internal consistency, test-retest reliability, and concurrent validity. Further, the construct validity of both the DDQ and OCDUS was demonstrated by means of confirmatory factor analyses showing the expected three-factor models. CONCLUSION: Our results indicate that the OCDUS and DDQ for cocaine are both easy to administer and reliable instruments to assist the clinical practitioner or researcher to measure craving in cocaine dependent subjects. Moreover, the factor structure for the cocaine versions were similar to the heroin versions, indicating the OCDUS and the DDQ can be reliably used to measure craving for both substances, enabling a direct comparison between heroin and cocaine craving. PMID- 26010119 TI - Epidemiology of the Homebound Population in the United States. AB - IMPORTANCE: Increasing numbers of older, community-dwelling adults have functional impairments that prevent them from leaving their homes. It is uncertain how many people who live in the United States are homebound. OBJECTIVES: To develop measures of the frequency of leaving and ability to leave the home and to use these measures to estimate the size of the homebound population in the US population. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional data from the National Health and Aging Trends Study collected in 2011 in the contiguous United States. Participants were a nationally representative sample of 7603 noninstitutionalized Medicare beneficiaries 65 years and older. MAIN OUTCOMES AND MEASURES: We defined homebound persons as those who never (completely homebound) or rarely (mostly homebound) left the home in the last month. We defined semihomebound persons as those who only left the home with assistance or had difficulty or needed help leaving the home. We compared demographic, clinical, and health care utilization characteristics across different homebound status categories. RESULTS: In 2011, the prevalence of homebound individuals was 5.6% (95% CI, 5.1%-6.2%), including an estimated 395,422 people who were completely homebound and 1,578,984 people who were mostly homebound. Among semihomebound individuals, the prevalence of those who never left home without personal assistance was 3.3% (95% CI, 2.8%-3.8%), and the prevalence of those who required help or had difficulty was 11.7% (95% CI, 10.9% 12.6%). Completely homebound individuals were more likely to be older (83.2 vs 74.3 years, P < .001), female (67.9% vs 53.4%, P < .006), and of nonwhite race (34.1% vs 17.6%, P < .001) and have less education and income than nonhomebound individuals. They also had more chronic conditions (4.9 vs 2.5) and were more likely to have been hospitalized in the last 12 months (52.1% vs 16.2%) (P < .001 for both). Only 11.9% of completely homebound individuals reported receiving primary care services at home. CONCLUSIONS AND RELEVANCE: In total, 5.6% of the elderly, community-dwelling Medicare population (approximately 2 million people) were completely or mostly homebound in 2011. Our findings can inform improvements in clinical and social services for these individuals. PMID- 26010121 TI - ALMS1 null mutations: a common cause of Leber congenital amaurosis and early onset severe cone-rod dystrophy. AB - In our previous studies, mutations in known candidate genes were detected in approximately 50% of Chinese patients with various forms of retinal degeneration. The next stage, identifying additional causative mutations in patients with various forms of genetic eye diseases based on whole exome sequencing of 1220 samples, revealed frequent homozygous or compound heterozygous null mutations in ALMS1, which are known to associate with Alstrom syndrome as well as individuals diagnosed with Leber congenital amaurosis (LCA) or early-onset severe cone-rod dystrophy (CORD) without signs of systemic phenotypes except that one had a congenital heart abnormity. Sanger sequencing, co-segregation analysis and analysis of normal individuals identified a total of 13 null mutations in ALMS1 in 11 probands, including 4 probands with homozygous mutations and 7 with compound heterozygous mutations. Follow-up examinations revealed absent or mild systemic manifestations of Alstrom syndrome in those available: 9 of 15 patients in 11 families. These findings not only expand the spectrum of phenotypes associated with ALMS1 mutations but also suggest that ALMS1 should be regarded as a candidate causative gene in patients diagnosed with isolated LCA and early onset severe CORD. PMID- 26010122 TI - Impairing the radioresistance of cancer cells by hydrogenated nanodiamonds. AB - Hydrogenated nanodiamonds (H-NDs) exhibit a negative electron affinity that confers a high reactivity with oxygen species and a positive charge in aqueous solutions. It allows electron emission from H-NDs following irradiation by photons and in consequence may enhance the effects of radiation on cancer cells. By using three human radioresistant cancer cell lines, we showed a potentialization of cytotoxicity after a co-exposure to H-NDs and irradiation; an event occurring through the induction of DNA damage and reactive oxygen species. This occurred together with a decrease in cell impedance, the activation of G1/S, an unlocking of G2 cell cycle check-points and early low cell death rate. At later stage of exposure, persistent increases in heterochromatinization, large gamma-H2AX foci and beta-galactosidase activity were detected providing evidence of cells' entrance into senescence. Similar potentialization was observed with neocarzinostatin (NCS), a radiomimetic drug. This original finding underlines a wide clinical potential of H-NDs to intensify radiation effects on radio resistant cancer cells. PMID- 26010123 TI - Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma. AB - Although it is generally regarded appropriate to start chemotherapy promptly after a diagnosis of diffuse large B-cell lymphoma (DLBCL), the optimal time from diagnosis to treatment (TDT) is unknown. A total of 689 patients diagnosed with DLBCL and treated with >= 1 cycle of CHOP-R with curative intent during 2003-2008 in British Columbia were identified: 347 (50%) TDT <= 4 weeks, 277 (40%) TDT 5-8 weeks, 65 (10%) TDT > 8 weeks. For the respective TDT groups, 5-year OS estimates were 61%, 74%, 63% (p = 0.006); 5-year PFS 57%, 70%, 61% (p = 0.006); and 5-year DSS 64%, 80%, 77% (p <0.001). In multivariate analysis, TDT >8 weeks was associated with worse OS (HR 1.20 (95% CI 1.03, 1.41), p = 0.020), PFS (HR 1.33 (95% CI 1.15, 1.54), p < 0.001), and DSS (HR 1.40 (95% CI 1.10, 1.78), p = 0.006). Clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established. PMID- 26010124 TI - Effect of beta-glucan on MUC4 and MUC5B expression in human airway epithelial cells. AB - BACKGROUND: beta-Glucan is found in the cell walls of fungi, bacteria, and some plant tissues, and is detected by the innate immune system. Furthermore, this recognition is known to worsen respiratory symptoms in patients with allergic and inflammatory airway diseases. However, the means by which beta-glucan affects the secretion of major mucins by human airway epithelial cells has not been elucidated. Therefore, in this study, the effect and signaling pathway of beta glucan on mucins MUC4 and MUC5B were investigated in human airway epithelial cells. METHODS: In NCI-H292 cells and human normal nasal epithelial cells, the effect and signaling pathway of beta-glucan on MUC4 and MUC5B expression were investigated using reverse transcriptase-polymerase chain reaction (RT-PCR), real time PCR, enzyme immunoassay, and immunoblot analysis with specific inhibitors and small interfering RNA (siRNA). RESULTS: beta-Glucan increased MUC4 and MUC5B expression and activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). SB203580 (a p38 MAPK inhibitor) and pyrrolidine dithiocarbamate (PDTC; a NF-kappaB inhibitor) inhibited beta-glucan-induced MUC4 and MUC5B expression. In addition, siRNA knockdown of p38 MAPK blocked beta-glucan-induced MUC4 and MUC5B mRNA expression and beta-glucan-activated phosphorylation of NF kappaB. Furthermore, Toll-like receptor 4 (TLR4) mRNA expression was increased by beta-glucan, and siRNA knockdown of TLR4 blocked beta-glucan-induced MUC4 and MUC5B mRNA expression and beta-glucan-activated phosphorylation of p38 MAPK and NF-kappaB. CONCLUSION: These results demonstrate that in human airway epithelial cells beta-glucan induces MUC4 and MUC5B expression via the TLR4-p38 MAPK-NF kappaB signaling pathway. PMID- 26010125 TI - [Knowledge, practices and attitudes toward volunteer work in an influenza pandemic: cross-sectional study with Peruvian medical students]. AB - INTRODUCTION: Reductions in health personnel during disasters or epidemics such as an influenza pandemic may need to include volunteer students. OBJECTIVE: The aim of this article is to determine knowledge and practices about pandemic influenza and the attitudes towards volunteer work in Peruvian medical students. METHODS: We performed a cross-sectional analytic study by simple sampling using a survey regarding ?"knowledge and practices"? about pandemic influenza and the attitudes to volunteer work. RESULTS: From the group of 865 students who were surveyed, 848 accepted to participate in the investigation (54% were male and their mean age was 22.1 +/- 3.0). Ninety-seven percent correctly identified the spread routes of influenza and 81% knew its treatment. Regarding preventive measures, covering the mouth when coughing/sneezing and hand-washing were the most commonly recognized options (95% y 92%, respectively), and vaccination was the less recognized one (54%). The most common practice, readily acknowledged as preventive, was covering when coughing/sneezing (86%). Regarding volunteer works, students answered that it is a moral/ethical/professional obligation (77%); that a contingency university service needs to be established (88%), that it does not have to substitute for the lack of workers (49%), and that its role should be related to hospital work (83%). Coming from a public university was more associated to the concept that volunteer work was a moral obligation and that the student should be punished if he/she refuses to be a volunteer, whereas being from a private university was more related to a history of been involved in volunteering programs. CONCLUSIONS: In general, medical students have good knowledge and practices toward influenza. There is a good disposition to volunteer their work and skills, recognizing it as a moral/ethical/professional obligation. PMID- 26010126 TI - Validity of self-reported sleep bruxism among myofascial temporomandibular disorder patients and controls. AB - Sleep bruxism (SB), primarily involving rhythmic grinding of the teeth during sleep, has been advanced as a causal or maintenance factor for a variety of oro facial problems, including temporomandibular disorders (TMD). As laboratory polysomnographic (PSG) assessment is extremely expensive and time-consuming, most research testing this belief has relied on patient self-report of SB. The current case-control study examined the accuracy of those self-reports relative to laboratory-based PSG assessment of SB in a large sample of women suffering from chronic myofascial TMD (n = 124) and a demographically matched control group without TMD (n = 46). A clinical research coordinator administered a structured questionnaire to assess self-reported SB. Participants then spent two consecutive nights in a sleep laboratory. Audiovisual and electromyographic data from the second night were scored to assess whether participants met criteria for the presence of 2 or more (2+) rhythmic masticatory muscle activity episodes accompanied by grinding sounds, moderate SB, or severe SB, using previously validated research scoring standards. Contingency tables were constructed to assess positive and negative predictive values, sensitivity and specificity, and 95% confidence intervals surrounding the point estimates. Results showed that self-report significantly predicted 2+ grinding sounds during sleep for TMD cases. However, self-reported SB failed to significantly predict the presence or absence of either moderate or severe SB as assessed by PSG, for both cases and controls. These data show that self-report of tooth grinding awareness is highly unlikely to be a valid indicator of true SB. Studies relying on self-report to assess SB must be viewed with extreme caution. PMID- 26010127 TI - The sign of cascading predator effects varies with prey traits in a detrital system. AB - Theory and experiments show that the nature of 'green' trophic cascades, between predators, herbivores and plants, varies with several key species traits: predator hunting mode and predator and prey habitat domains. Meanwhile, 'brown' cascades between predators, environment-modifying detritivores and plants have been largely overlooked and the roles of species traits, particularly prey traits, in determining the nature of these cascades remains unclear. We hypothesize that, in predator-detritivore-plant interaction chains, the burrowing ability of plant-facilitating detritivores determines their response to predators and thus the sign of indirect effect transmitted. In the dung-decomposer food web of an alpine meadow, we predicted that in the presence of above-ground predacious beetles: (i) non-burrowing detritivores will suffer mortality due to predation and transmit negative indirect effects to plants, whereas (ii) burrowing detritivores will escape predation by retreating deeper into the soil, transmitting positive indirect effects to plants. In support of predictions, experiments showed that a single species of predacious beetle (i) reduced the density of the non-burrowing species and indirectly reduced dung loss rate, soil nutrient concentrations and plant biomass, but (ii) drove the burrowing species deeper, indirectly improved soil conditions and increased plant biomass. These results show that the burrowing ability of a detritivore can determine whether it transmits a negative indirect effect mediated by a reduction in its density, or a positive indirect effect mediated by its behavioural response to predation risk. We call for further tests of our detritivore-trait hypothesis in different regions and ecosystems to further develop a general trait-based framework for trophic cascades in detrital food webs. We further advance the general hypothesis that the locomotion traits of prey species (e.g. burrowing/flying ability) may help explain their behavioural response to predation risk and the nature of indirect effect they transmit from predators to plants. PMID- 26010128 TI - Postprandial Hemodynamics in Hypertrophic Cardiomyopathy. AB - OBJECTIVES: Prior analysis at our institution found that patients with hypertrophic cardiomyopathy (HCM) who experience postprandial symptoms (PPS) are more likely to have resting left ventricular outflow tract (LVOT) obstruction and reduced quality of life. Our objective was to determine whether PPS in patients with HCM vs healthy subjects occur as a result of measurable hemodynamic alterations in the postprandial hemodynamic response. METHODS: We conducted a prospective cross-sectional study examining 45 patients with HCM and 10 controls who underwent fasting and postprandial 2-dimensional Doppler echocardiography. Postprandial echocardiographic measurements were obtained at symptom onset or 30 minutes after consumption of a standardized meal, whichever occurred first. RESULTS: The HCM population included 18 (40%) patients with PPS and 27 (60%) without PPS. Compared to controls, mean resting peak LVOT gradient was 23.4 +/- 17.6 mmHg in HCM patients with PPS and 25.1 +/- 33.1 mmHg in those without PPS (P = 0.10). The mean change in peak LVOT gradient after a meal was 0.7 +/- 1.1 mmHg for controls, 5.0 +/- 8.3 mmHg for HCM patients with PPS, and 1.5 +/- 18.2 mmHg for HCM patients without PPS (P = 0.64). CONCLUSION: Although the ability to provoke an increased LVOT gradient with a postprandial, upright exercise study protocol was recently reported, the current study suggests that a resting, supine, postprandial protocol does not elicit evidence of LVOT obstruction. Therefore, future investigations should consider whether simply performing an upright postprandial study in HCM patients with PPS will provide evidence of dynamic LVOT or if the addition of an exercise component is necessary. PMID- 26010130 TI - The association between biological rhythms, depression, and functioning in bipolar disorder: a large multi-center study. AB - OBJECTIVE: We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional impairment. METHOD: Bipolar patients (n = 260) and healthy controls (n = 191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity. RESULTS: Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F = 49.367; df = 2, P < 0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning (F = 12.841, df = 6, P < 0.001, R2 = 0.443). CONCLUSION: Our study shows a dose-dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long term management of bipolar disorder and may aid in the improvement of functioning. PMID- 26010129 TI - Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+ T cells in aged humans. AB - Insight into the maintenance of naive T cells is essential to understand defective immune responses in the context of aging and other immune compromised states. In humans, naive CD4+ T cells, in contrast to CD8+ T cells, are remarkably well retained with aging. Here, we show that low-affinity TCR engagement is the main driving force behind the emergence and accumulation of naive-like CD4+ T cells with enhanced sensitivity to IL-2 in aged humans. In vitro, we show that these CD45RA(+) CD25(dim) CD4(+) T cells can develop from conventional naive CD25(-) CD4+ T cells upon CD3 cross-linking alone, in the absence of costimulation, rather than via stimulation by the homeostatic cytokines IL-2, IL-7, or IL-15. In vivo, TCR engagement likely occurs in secondary lymphoid organs as these cells were detected in lymph nodes and spleen where they showed signs of recent activation. CD45RA(+) CD25(dim) CD4+ T cells expressed a broad TCRVbeta repertoire and could readily differentiate into functional T helper cells. Strikingly, no expansion of CD45RA(+) CD25(dim) CD8+ T cells was detected with aging, thereby implying that maintenance of naive CD4+ T cells is uniquely regulated. Our data provide novel insight into the homeostasis of naive T cells and may guide the development of therapies to preserve or restore immunity in the elderly. PMID- 26010131 TI - Re: Management strategy for biliary stricture following laparoscopic cholecystectomy. PMID- 26010132 TI - Response to Re: Management strategy for biliary stricture following laparoscopic cholecystectomy. PMID- 26010134 TI - Up to 100% Improvement in Dynamic Nuclear Polarization Solid-State NMR Sensitivity Enhancement of Polymers by Removing Oxygen. AB - High-field dynamic nuclear polarization (DNP) has emerged as a powerful technique for improving the sensitivity of solid-state NMR (SSNMR), yielding significant sensitivity enhancements for a variety of samples, including polymers. Overall, depending upon the type of polymer, the molecular weight, and the DNP sample preparation method, sensitivity enhancements between 5 and 40 have been reported. These promising enhancements remain, however, far from the theoretical maximum (>1000). Crucial to the success of DNP SSNMR is the DNP signal enhancement (epsilonDNP ), which is the ratio of the NMR signal intensities with and without DNP. It is shown here that, for polymers exhibiting high affinity toward molecular oxygen (e.g., polystyrene), removing part of the absorbed (paramagnetic) oxygen from the solid-state samples available as powders (instead of dissolved or dispersed in a solvent) increases proton nuclear relaxation times and epsilonDNP, hereby providing up to a two-fold sensitivity increase (i.e., a four-fold reduction in experimental time). PMID- 26010133 TI - The influence of social support on quality of life of men who have sex with men in China: a preliminary study. AB - The quality of life (QOL) of men who have sex with men (MSM) has received increasing attention in recent years. Our study surveyed the QOL and explored the influence of social support on QOL in Chinese MSM. A cross-sectional survey was conducted from September 2013 to March 2014 of 438 MSM in Huludao and Zhengzhou City, China. The results of univariate analysis showed that higher QOL scores were associated with receiving psychosocial counseling, higher health education, younger age and marital status of being single or unmarried p < 0.05). The structural equation model fitted well, with chi2 = 2083.47 (p < 0.05), RMSEA = 0.07, and GFI = 0.88. Among the latent factors, social support, with a factor load of 0.47, had greater impact on QOL than demographic characteristics. Within social support, the item loads for psychosocial counseling and health education were 0.17 and 0.29, respectively. Basic demographic characteristics also influenced social support, with a factor load of -0.65. For demographic characteristics, the greatest item loads were for marital status and age (0.77 and 0.71, respectively). These findings suggest that strengthening social support, especially for older and married individuals, would improve QOL in MSM in China. PMID- 26010135 TI - Geographic variation in plant community structure of salt marshes: species, functional and phylogenetic perspectives. AB - In general, community similarity is thought to decay with distance; however, this view may be complicated by the relative roles of different ecological processes at different geographical scales, and by the compositional perspective (e.g. species, functional group and phylogenetic lineage) used. Coastal salt marshes are widely distributed worldwide, but no studies have explicitly examined variation in salt marsh plant community composition across geographical scales, and from species, functional and phylogenetic perspectives. Based on studies in other ecosystems, we hypothesized that, in coastal salt marshes, community turnover would be more rapid at local versus larger geographical scales; and that community turnover patterns would diverge among compositional perspectives, with a greater distance decay at the species level than at the functional or phylogenetic levels. We tested these hypotheses in salt marshes of two regions: The southern Atlantic and Gulf Coasts of the United States. We examined the characteristics of plant community composition at each salt marsh site, how community similarity decayed with distance within individual salt marshes versus among sites in each region, and how community similarity differed among regions, using species, functional and phylogenetic perspectives. We found that results from the three compositional perspectives generally showed similar patterns: there was strong variation in community composition within individual salt marsh sites across elevation; in contrast, community similarity decayed with distance four to five orders of magnitude more slowly across sites within each region. Overall, community dissimilarity of salt marshes was lowest on the southern Atlantic Coast, intermediate on the Gulf Coast, and highest between the two regions. Our results indicated that local gradients are relatively more important than regional processes in structuring coastal salt marsh communities. Our results also suggested that in ecosystems with low species diversity, functional and phylogenetic approaches may not provide additional insight over a species based approach. PMID- 26010136 TI - Perspectives on pasture versus indoor feeding of dairy cows. AB - The dairy industry in many regions of the world has moved towards a high input/high-output system maximising annual milk production per cow, primarily through increasing concentrate-based total mixed rations fed indoors year round, as opposed to allowing cows to feed on pasture. Pasture-based dairy systems in regions like New Zealand and Ireland are oriented towards maximum milk yield per unit of pasture, which has led to Holstein strains that are 50 to 100 kg lighter, exhibit a higher body condition score, and produce roughly half the annual amount of milk as compared to their Holstein counterparts kept in confinement in North America and Europe. Freedom from hunger might not be guaranteed when high yielding dairy cows are kept on pasture without any supplemental feed, but at the same time no access to pasture can be considered an animal welfare concern, because pasturing is generally beneficial to the animals' health. On pasture, lighter-weight dairy cows with a medium milk production potential have proven to be superior with regard to feed efficiency and fertility. The year-round indoor feeding of high-yielding dairy cows with total mixed rations containing substantial amounts of human-edible crops from arable land puts global food security at risk and fails to utilise the evolutionary advantages of ruminants. PMID- 26010137 TI - Evaluating scale-up rules of a high-shear wet granulation process. AB - This work aimed to evaluate the commonly used scale-up rules for high-shear wet granulation process using a microcrystalline cellulose-lactose-based low drug loading formulation. Granule properties such as particle size, porosity, flow, and tabletability, and tablet dissolution were compared across scales using scale up rules based on different impeller speed calculations or extended wet massing time. Constant tip speed rule was observed to produce slightly less granulated material at the larger scales. Longer wet massing time can be used to compensate for the lower shear experienced by the granules at the larger scales. Constant Froude number and constant empirical stress rules yielded granules that were more comparable across different scales in terms of compaction performance and tablet dissolution. Granule porosity was shown to correlate well with blend tabletability and tablet dissolution, indicating the importance of monitoring granule densification (porosity) during scale-up. It was shown that different routes can be chosen during scale-up to achieve comparable granule growth and densification by altering one of the three parameters: water amount, impeller speed, and wet massing time. PMID- 26010138 TI - Ligamentum flavum hypertrophy in asymptomatic and chronic low back pain subjects. AB - PURPOSE: To examine ligamentum flavum thickness using magnetic resonance (MR) images to evaluate its association with low back pain symptoms, age, gender, lumbar level, and disc characteristics. MATERIALS AND METHODS: Sixty-three individuals were part of this IRB-approved study: twenty-seven with chronic low back pain, and thirty-six as asymptomatic. All patients underwent MR imaging and computed tomography (CT) of the lumbar spine. The MR images at the mid-disc level were captured and enlarged 800% using a bilinear interpolation size conversion algorithm that allowed for enhanced image quality. Ligamentum flavum thickness was assessed using bilateral medial and lateral measurements. Disc height at each level was measured by the least-distance measurement method in three-dimensional models created by CT images taken of the same subject. Analysis of variance and t tests were carried out to evaluate the relationship between ligamentum flavum thickness and patient variables. RESULTS: Ligamentum flavum thickness was found to significantly increase with older age, lower lumbar level, and chronic low back pain (p < 0.03). No difference in ligamentum flavum thickness was observed between right and left sided measurements, or between male and female subjects. Disc height and both ligamentum flavum thickness measurements showed low to moderate correlations that reached significance (p < 0.01). Additionally, a moderate and significant correlation between disc degeneration grade and ligamentum flavum thickness does exist (p <0.001). CONCLUSION: By measuring ligamentum flavum thickness on MR images at two different sites and comparing degrees of disc degeneration, we found that ligamentum flavum thickness may be closely related to the pathogenesis of pain processes in the spine. PMID- 26010139 TI - Synthesis and anticholinergic activity of 4-hydroxycoumarin derivatives containing substituted benzyl-1,2,3-triazole moiety. AB - A series of 4-hydroxycoumarin-derived compounds 8a-p containing N-benzyl-1,2,3 triazole motif were designed as AChE inhibitors. The title compounds were obtained conveniently using multicomponent click reaction. The in vitro anticholinesterase evaluation of synthesized compounds against AChE and BuChE showed that some of them are potent and selective inhibitors of AChE. Among them, 2-chlorobenzyl derivative 8k showed the most potent activity against AChE (IC50 = 0.18 MUm). Its activity was also superior to that of standard drug tacrine. The kinetic study and molecular docking simulation of the most potent compound 8k were also described. PMID- 26010140 TI - Editorial Comment to p.Leu636Pro mutation is associated with cystic fibrosis transmembrane conductance regulator-related disorders (congenital bilateral absence of vas deferens). PMID- 26010141 TI - Managers' perceptions of the value and impact of HAZWOPER worker health and safety training. AB - BACKGROUND: Worker training is a core component of the OSHA Hazardous Waste Operations and Emergency Response (HAZWOPER) standard, but few studies have considered what motivates managers to provide HAZWOPER training to employees or what they value in that training. METHODS: In 2012, four university-based programs conducted an exploratory survey of managers who sent employees to HAZWOPER courses. Results from 109 respondents were analyzed. RESULTS: Forty-two percent of respondents cited regulations as the most important reason to provide HAZWOPER training; many indicated they would provide less training if there were no standard in place. Three-quarters (74%) reported training had improved workplace conditions. Fewer than half said they were likely to involve trained employees in aspects of the organization's H&S program. DISCUSSION: Compliance with regulatory requirements is an important factor shaping managers' training delivery decisions. Managers recognize positive impacts of training. These impacts could be enhanced by further leveraging employee H&S knowledge and skills. PMID- 26010142 TI - Reply: Suicidality in Huntington's Disease: Distinguishing lithium from other psychotropic medications. PMID- 26010143 TI - Effect of GABA Extract of Black Sticky Rice with Giant Embryo on Alcohol-Related Indices After Acute Alcohol Intake in Social Drinkers. AB - BACKGROUND: This study was performed to evaluate the effect and safety of a high gamma-aminobutyric acid-containing extract (GABA extract) of black sticky rice with giant embryo (BSRGE) on alcohol-related indices after acute alcohol intake in social drinkers. METHODS: Subjects were randomized to the GABA extract (G) group, GABA extract and alcohol drinking (GA) group, or placebo intake and alcohol drinking (PA) group in a double-blind design. All subjects were administered GABA extract (200 mg GABA) or placebo at 9 am on study days 2 and 3, respectively. Subjects in the GA and PA groups were administered an equivalent dose of alcohol that was diluted in a drinking beverage for a total amount of 240 ml at 11 am on day 3. Blood alcohol concentration (BAC) and the Biphasic Alcohol Effects Scale were measured just before alcohol drinking, and 6 times after alcohol drinking. RESULTS: The peak and area under the curve (AUC) of the total stimulation scale score after alcohol intake in females were significantly higher in the GA than in the PA group, whereas no significant difference was found between the 2 groups in males. The peak and AUC of the total score on the sedation scale after alcohol intake in males were significantly lower in the GA than in the PA group, whereas both were significantly higher in the GA than in the PA group of females. The AUC for BAC in males was significantly lower in the GA than in the PA group, whereas no significant difference was found in females. No adverse events were reported in any of the groups including the G group. CONCLUSIONS: Coadministration of a GABA extract to social drinkers while drinking alcohol is supposed to affect alcohol-related indices in terms of pharmacodynamics and pharmacokinetics and did not induce any adverse events. PMID- 26010144 TI - Development of Cryopreservation Techniques for Gorgonian (Junceella juncea) Oocytes through Vitrification. AB - Gorgonian corals are slowly declining due to human interaction and environmental impacts. Cryopreservation of gorgonian corals is an ex-situ method of conservation, ensuring future reproduction. The present study assessed the vitrification properties of cryoprotectant (CPT) mixtures using the cryotop, cryoloop and open pulled straw (OPS) cryopereservation methods prior to experimentation on gorgonian (Junceella juncea) oocytes. Investigations of the equilibration and vitrification solutions' (ES and VS) effect on oocytes throughout different incubation periods were conducted. The cryotop method was found to be the most successful in ensuring vitrification. The most favourable VS was composed of propylene glycol (PG), ethylene glycol (EG) and methanol with concentrations of 3.5 M, 1.5 M and 2 M respectively. Experiments were performed using the cryotop method to cryopreserve Junceella juncea oocytes using VS2, the solution had the least impact on oocytes at 5 degrees C rather than at 26 degrees C. The success of the vitrification procedures was determined by adenosine triphosphate (ATP) levels in cooled-thaw oocytes and the highest viability obtained from the present study was 76.6 +/- 6.2%. This study provides information regarding gorgonian corals' tolerance and viability throughout vitrification to further advance the vitrification protocol on whip corals. PMID- 26010145 TI - Highly monodisperse low-magnetization magnetite nanocubes as simultaneous T(1) T(2) MRI contrast agents. AB - We report the first study of highly monodisperse and crystalline iron oxide nanocubes with sub-nm controlled size distribution (9.7 +/- 0.5 nm in size) that achieve simultaneous contrast enhancement in both T1- and T2-weighted magnetic resonance imaging (MRI). Here, we confirmed the magnetite structure of iron oxide nanocubes by X-ray diffraction (XRD), selected area electron diffraction (SAED) pattern, optical absorption and Fourier transformed infrared (FT-IR) spectra. These magnetite nanocubes exhibit superparamagnetic and paramagnetic behavior simultaneously by virtue of their finely controlled shape and size. The magnetic measurements reveal that the magnetic moment values are favorably much lower because of the small size and cubic shape of the nanoparticles, which results in an enhanced spin canting effect. As a proof-of-concept demonstration, we showed their potential as dual contrast agents for both T1- and T2-weighted MRI via phantom studies, in vivo imaging and relaxivity measurements. Therefore, these low-magnetization magnetite nanocubes, while being non-toxic and bio-compatible, hold great promise as excellent dual-mode T1 and T2 contrast agents for MRI. PMID- 26010146 TI - Sequence analysis of the HBV S protein in Chinese patients with coexisting HBsAg and anti-HBs antibodies. AB - The coexistence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in patients with hepatitis B virus (HBV) infection has been discovered and explained for several decades, but debate still exists. This study was to explore the relationship between this special serological pattern and mutations in S gene region. Fifteen patients with coexisting HBsAg and anti-HBs were selected as the experimental group, and 27 patients with HBsAg positive only were selected as the control group. The S gene region was amplified and sequenced. No significant differences were observed between the two groups with regard to age, gender, alanine aminotransferase level, HBsAg titer, genotype, and HBV DNA level. The patients from the two groups were infected with HBV of the genotype B and C. Compared with the control group, the experimental group showed a higher variability in amino acid within the N-terminal region and the MHR, especially the "a" determinant. The most frequent change in patients from the experimental group was located at positions s126. The coexistence of HBsAg and anti-HBs might be associated with the increased amino acid mutations in the "a" determinant. Further studies should be performed to determine the clinical implication of this serological pattern, including the binding of anti-HBs to HBsAg, escape from immune system, and efficacy of antiviral therapy. PMID- 26010147 TI - Non-Linear Association between Exposure to Ambient Temperature and Children's Hand-Foot-and-Mouth Disease in Beijing, China. AB - BACKGROUND: Hand, foot and mouth disease (HFMD) was listed as a notifiable communicable disease in 2008 and is an emerging public health problem in China, especially for children. However, few data are available on the risk assessment of the potential reasons for HFMD in Beijing. This study examined the association of temperature with the incidence of children's HFMD in Beijing at the daily scale for the first time. METHODS: A newly developed case-crossover design with a distributed lag nonlinear model (DLNM) was used to assess the delayed and cumulative associations of daily temperature with gender- and age-specific HFMD in Beijing, China, during 2010-2012. Relative humidity, day of the week, public holiday, season and long-term trends were controlled in the model. RESULTS: Among the total of 113,475 cases, the ratio between males and females was 1.52:1. HFMD was more prevalent in May-July. The temperature-HFMD relationships were non linear in most age groups except for children aged 6-15 years, with a peak at 25.0~27.5 degrees C. The high-temperature risks were greater, appeared earlier and lasted longer than the low-temperature risks. The relative risks for female children and those aged 6-15 years were higher than those among other groups. CONCLUSION: Rising temperatures increased the incidence of children's HFMD, with the largest association at 25.0~27.5 degrees C. Females and children aged 6-15 years were more vulnerable to changes in temperature with regard to the transmission of HFMD than males and other age groups, respectively. Further studies are warranted to confirm these findings in other populations. PMID- 26010148 TI - Analysis of radiation dose to pediatric patients during computed tomography examinations. AB - BACKGROUND: Computed tomography (CT) utilization has increased rapidly over the past 15 years. CT is the most common source for radiation exposure. OBJECTIVES: The objective was to measure the effective dose of radiation delivered during routine head and abdominal CT examinations at a children's hospital. METHODS: This was a retrospective study of emergency department (ED) patients < 20 years of age who underwent head or abdominal CT scans in 2012 at a single children's hospital. The authors abstracted the dose-length product from the CT scanners and calculated the effective radiation dose delivered. Patient demographics were abstracted from the medical record. The relationship between effective dose and age, patient weight, and reason for examination were evaluated. RESULTS: A total of 478 subjects were included: 255 underwent head CT, and 223 underwent abdominal CT. The median age was 8.1 years (interquartile range = 2.71 to 14.40 years) and 56.9% were male. The median effective dose for head CT was 2.68 mSv (95% confidence interval [CI] = 2.54 to 2.84 mSv) and decreased as age increased. For abdominal CT, the median effective dose was 5.06 mSv (95% CI = 4.58 to 6.03 mSv) and increased as age increased (3.67 to 11.12 mSv, p < 0.001). For abdominal CT, 8% of 5- to 10-year-olds, 28% of those 10 to 15 years, and 60% of patients over age 15 years received effective doses over 10 mSv. CONCLUSIONS: The amount of radiation delivered to pediatric patients during routine CT examinations of the head and abdomen was low. Regardless, a large proportion of older patients were exposed to elevated effective doses of radiation during abdominal CT. PMID- 26010149 TI - Reverse Correlation between MicroRNA-145 and FSCN1 Affecting Gastric Cancer Migration and Invasion. AB - MicroRNAs (miRs) play important roles in modulating gene expression during the processes of tumorigenesis and tumor development. Previous studies have found that miR-145 is down-regulated in the stomach neoplasm and is related to tumor migration and invasion. However, both the molecular mechanism and function of miR 145 in gastric cancer remain unclear. The present study is the first demonstration of the significant down-regulation of miR-145 expression in infiltrative gastric cancer compared to expanding gastric cancer. Additionally, correlation analyses revealed strong inverse correlations between miR-145 and FSCN1 expression levels in infiltrative gastric cancer. Furthermore, we demonstrated that miR-145 directly targets FSCN1 and suppresses cell migration and invasion in gastric cancer. Knocking down the expression of FSCN1 led to the suppression of migration and invasion in gastric cancer cells, and re-expressing FSCN1 in miR-145-overexpressing cells reversed their migration and invasion defects. Thus, we concluded that miR-145 regulates cell migration and invasion in gastric cancer primarily by directly targeting FSCN1. PMID- 26010150 TI - Drug-Metabolizing Activity, Protein and Gene Expression of UDP Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients. AB - UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either V(max) (maximum reaction rate, R(max) for UGT1A1) or the clearance rates (V(max)/K(m), Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which would provide an important insight for toxicity or efficacy determination of chemotherapeutic drugs, and even bring a new strategy for clinical regimen in the health cares for the relative patients. PMID- 26010151 TI - Large-Scale Examination of Spatio-Temporal Patterns of Drifting Fish Aggregating Devices (dFADs) from Tropical Tuna Fisheries of the Indian and Atlantic Oceans. AB - Since the 1990s, massive use of drifting Fish Aggregating Devices (dFADs) to aggregate tropical tunas has strongly modified global purse-seine fisheries. For the first time, a large data set of GPS positions from buoys deployed by French purse-seiners to monitor dFADs is analysed to provide information on spatio temporal patterns of dFAD use in the Atlantic and Indian Oceans during 2007-2011. First, we select among four classification methods the model that best separates "at sea" from "on board" buoy positions. A random forest model had the best performance, both in terms of the rate of false "at sea" predictions and the amount of over-segmentation of "at sea" trajectories (i.e., artificial division of trajectories into multiple, shorter pieces due to misclassification). Performance is improved via post-processing removing unrealistically short "at sea" trajectories. Results derived from the selected model enable us to identify the main areas and seasons of dFAD deployment and the spatial extent of their drift. We find that dFADs drift at sea on average for 39.5 days, with time at sea being shorter and distance travelled longer in the Indian than in the Atlantic Ocean. 9.9% of all trajectories end with a beaching event, suggesting that 1,500 2,000 may be lost onshore each year, potentially impacting sensitive habitat areas, such as the coral reefs of the Maldives, the Chagos Archipelago, and the Seychelles. PMID- 26010152 TI - Genetic Map Construction and Quantitative Trait Locus (QTL) Detection of Six Economic Traits Using an F2 Population of the Hybrid from Saccharina longissima and Saccharina japonica. AB - Saccharina (Laminaria) is one of the most important economic seaweeds. Previously, four genetic linkage maps of Saccharina have been constructed and five QTLs have been identified. However, they were not enough for its breeding. In this work, Saccharina longissima (?) and Saccharina japonica (?), which showed obvious differences in morphology and genetics, were applied in hybridization to yield the F2 mapping population with 102 individuals. Using these 102 F2 hybrids, the genetic linkage map of Saccharina was constructed by MapMaker software based on 37 amplified fragment length polymorphisms (AFLPs), 22 sequence-related amplified polymorphisms (SRAPs) and 139 simple sequence repeats (SSRs) markers. Meanwhile, QTL analysis was performed for six economic traits. The linkage map constructed in this research consisted of 422 marker loci (137 AFLPs, 57 SRAPs and 228 SSRs), which formed 45 linkage groups (LGs) with an average marker space of 7.92 cM; they spanned a total length of 2233.1 cM, covering the whole estimated genome size. A total of 29 QTLs were identified for six economic traits, which explained 1.06 to 64.00% of phenotypic variation, including three QTLs for frond length (FL) and raw weight (RW), five QTLs for frond width (FW), two QTLs for frond fascia width (FFW) and frond thickness (FT), and fourteen QTLs for base shape (BS). The results of this research will improve the breeding efficiency and be beneficial for marker-assisted selection (MAS) schemes in Saccharina breeding. PMID- 26010153 TI - Temporal Beta Diversity of Bird Assemblages in Agricultural Landscapes: Land Cover Change vs. Stochastic Processes. AB - Temporal variation in the composition of species assemblages could be the result of deterministic processes driven by environmental change and/or stochastic processes of colonization and local extinction. Here, we analyzed the relative roles of deterministic and stochastic processes on bird assemblages in an agricultural landscape of southwestern France. We first assessed the impact of land cover change that occurred between 1982 and 2007 on (i) the species composition (presence/absence) of bird assemblages and (ii) the spatial pattern of taxonomic beta diversity. We also compared the observed temporal change of bird assemblages with a null model accounting for the effect of stochastic dynamics on temporal beta diversity. Temporal assemblage dissimilarity was partitioned into two separate components, accounting for the replacement of species (i.e. turnover) and for the nested species losses (or gains) from one time to the other (i.e. nestedness-resultant dissimilarity), respectively. Neither the turnover nor the nestedness-resultant components of temporal variation were accurately explained by any of the measured variables accounting for land cover change (r(2)<0.06 in all cases). Additionally, the amount of spatial assemblage heterogeneity in the region did not significantly change between 1982 and 2007, and site-specific observed temporal dissimilarities were larger than null expectations in only 1% of sites for temporal turnover and 13% of sites for nestedness-resultant dissimilarity. Taken together, our results suggest that land cover change in this agricultural landscape had little impact on temporal beta diversity of bird assemblages. Although other unmeasured deterministic process could be driving the observed patterns, it is also possible that the observed changes in presence/absence species composition of local bird assemblages might be the consequence of stochastic processes in which species populations appeared and disappeared from specific localities in a random-like way. Our results might be case-specific, but if stochastic dynamics are generally dominant, the ability of correlative and mechanistic models to predict land cover change effects on species composition would be compromised. PMID- 26010154 TI - Up-Regulation of miR-21 Is Associated with Cervicitis and Human Papillomavirus Infection in Cervical Tissues. AB - MicroRNA-21 (miR-21) is recognized as an oncomir and shows up-regulation in many types of human malignancy. The aim of this study was to investigate the association of miR-21 expression associated with HPV infection in normal and abnormal cervical tissues. Cervical tissue samples with different cytological or histopathological grades were investigated for HPV by PCR and for miR-21 and programmed cell death, protein 4 (PDCD4) expression using quantitative real-time PCR (qRT-PCR). Laser capture microdissection (LCM) of stromal and epithelial tissues and in situ hybridization (ISH) using locked nucleic acid (LNA) probes were performed on a subset of fixed specimens. Cell line experiments were conducted on fibroblasts stimulated in culture media from HeLa cells, which were then assessed for miR-21, PDCD4, IL-6 and alpha-SMA expression by qRT-PCR. Twenty normal cervical cell, 12 cervicitis, 14 cervical intraepithelial neoplastic I (CIN I), 22 CIN II-III and 43 cervical squamous cell carcinoma (SCC) specimens were investigated. miR-21 levels were significantly lower in normal than in abnormal tissues. The expression of miR-21 in HPV negative normal cytology was significantly lower than in HPV positive samples in abnormal tissue and SCC. The miR-21 expression was significantly higher in HPV negative cervicitis than HPV negative normal cells. LCM and ISH data showed that miR-21 is primarily expressed in the tumor-associated stromal cell microenvironment. Fibroblasts treated with HeLa cell culture media showed up-regulated expression of miR-21, which correlated with increased expression of alpha-SMA and IL-6 and with down regulation of PDCD4. These results demonstrate that miR-21 is associated with HPV infection and involved in cervical lesions as well as cervicitis and its up regulation in tumor-stroma might be involved in the inflammation process and cervical cancer progression. PMID- 26010155 TI - A Systematic Analysis on mRNA and MicroRNA Expression in Runting and Stunting Chickens. AB - Runting and stunting syndrome (RSS), which is characterized by lower body weight, widely occurs in broilers. Some RSS chickens simply exhibit slow growth without pathological changes. An increasing number of studies indicate that broiler strains differ in susceptibility to infectious diseases, most likely due to their genetic differences. The objective of this study was to detect the differentially expressed miRNAs and mRNAs in RSS and normal chickens. By integrating miRNA with mRNA expression profiling, potential molecular mechanisms involved in RSS could be further explored. Twenty-two known miRNAs and 1,159 genes were differentially expressed in RSS chickens compared with normal chickens (P < 0.05). qPCR validation results displayed similar patterns. The differentially expressed genes were primarily involved in energy metabolism pathways. The antisense transcripts were extensively expressed in chicken liver albeit with reduced abundance. Dual luciferase reporter assay indicated that gga-miR-30b/c directly target CARS through binding to its 3'UTR. The miR-30b/c: CARS regulation mainly occurred in liver. In thigh muscle and the hypothalamus, miR-30b/c are expressed at higher levels in RSS chickens compared with normal chickens from 2 to 6 w of age, and notably significant differences are observed at 4 w of age. PMID- 26010157 TI - Does Commuting Affect Health? AB - This paper analyzes the relation between commuting time and health in the UK. I focus on four different types of health outcomes: subjective health measures, objective health measures, health behavior, and healthcare utilization. Fixed effect models are estimated with British Household Panel Survey data. I find that whereas objective health and health behavior are barely affected by commuting time, subjective health measures are clearly lower for people who commute longer. A longer commuting time is, moreover, related to more visits to the general practitioner. Effects turn out to be more pronounced for women and for commuters driving a car. For women, commuting time is also negatively related to regular exercise and positively to calling in sick. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010156 TI - Effects of hybridization and evolutionary constraints on secondary metabolites: the genetic architecture of phenylpropanoids in European populus species. AB - The mechanisms responsible for the origin, maintenance and evolution of plant secondary metabolite diversity remain largely unknown. Decades of phenotypic studies suggest hybridization as a key player in generating chemical diversity in plants. Knowledge of the genetic architecture and selective constraints of phytochemical traits is key to understanding the effects of hybridization on plant chemical diversity and ecological interactions. Using the European Populus species P. alba (White poplar) and P. tremula (European aspen) and their hybrids as a model, we examined levels of inter- and intraspecific variation, heritabilities, phenotypic correlations, and the genetic architecture of 38 compounds of the phenylpropanoid pathway measured by liquid chromatography and mass spectrometry (UHPLC-MS). We detected 41 quantitative trait loci (QTL) for chlorogenic acids, salicinoids and flavonoids by genetic mapping in natural hybrid crosses. We show that these three branches of the phenylpropanoid pathway exhibit different geographic patterns of variation, heritabilities, and genetic architectures, and that they are affected differently by hybridization and evolutionary constraints. Flavonoid abundances present high species specificity, clear geographic structure, and strong genetic determination, contrary to salicinoids and chlorogenic acids. Salicinoids, which represent important defence compounds in Salicaceae, exhibited pronounced genetic correlations on the QTL map. Our results suggest that interspecific phytochemical differentiation is concentrated in downstream sections of the phenylpropanoid pathway. In particular, our data point to glycosyltransferase enzymes as likely targets of rapid evolution and interspecific differentiation in the 'model forest tree' Populus. PMID- 26010158 TI - Quantifying seasonal fallback on invertebrates, pith, and bromeliad leaves by white-faced capuchin monkeys (Cebus capucinus) in a tropical dry forest. AB - OBJECTIVES: Fallback foods (FBFs) are hypothesized to shape the ecology, morphology, and behavior of primates, including hominins. Identifying FBFs is therefore critical for revealing past and present foraging adaptations. Recent research suggests invertebrates act as seasonal FBFs for many primate species and human populations. Yet, studies measuring the consumption of invertebrates relative to ecological variation are widely lacking. We address this gap by examining food abundance and entomophagy by primates in a seasonal forest. MATERIALS AND METHODS: We study foraging behavior of white-faced capuchins (Cebus capucinus)-a species renowned for its intelligence and propensity for extractive foraging-along with the abundance of invertebrates, dietary ripe fruits, pith, and bromeliads. Consumption events and processing time are recorded during focal animal samples. We determine abundance of vegetative foods through phenological and density records. Invertebrates are collected in malaise, pan, and terrestrial traps; caterpillar abundance is inferred from frass traps. RESULTS: Invertebrates are abundant throughout the year and capuchins consume invertebrates-including caterpillars-frequently when fruit is abundant. However, capuchins spend significantly more time processing protected invertebrates when fruit and caterpillars are low in abundance. DISCUSSION: Invertebrate foraging patterns are not uniform. Caterpillar consumption is consistent with a preferred strategy, whereas capuchins appear to fallback on invertebrates requiring high handling time. Capuchins are convergent with hominins in possessing large brains and high levels of sensorimotor intelligence, thus our research has broad implications for primate evolution, including factors shaping cognitive innovations, brain size, and the role of entomophagy in the human diet. PMID- 26010159 TI - Nonpegylated liposomal doxorubicin: reduction in cardiotoxicity, although still severe alopecia. PMID- 26010161 TI - Positional Scanning Synthesis of a Peptoid Library Yields New Inducers of Apoptosis that Target Karyopherins and Tubulin. AB - We describe the synthesis of a library of 11, 638 N-alkylglycine peptoid trimers in a positional scanning format with adjustment of reaction conditions to account for different reactivities of the monomer building blocks. Evaluation of the library by high-content phenotypic screening for modulators of the cytoskeleton and mitosis resulted in the identification of two apoptosis-inducing peptoids, which, despite their structural similarity, target different proteins and cellular mechanisms. Whereas one peptoid binds to karyopherins, which mediate nuclear transport, the other N-alkylglycine trimer binds tubulin at the vinca alkaloid binding site. PMID- 26010160 TI - Positive surgical margins in radical prostatectomy patients do not predict long term oncological outcomes: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. AB - OBJECTIVE: To assess the impact of positive surgical margins (PSMs) on long-term outcomes after radical prostatectomy (RP), including metastasis, castrate resistant prostate cancer (CRPC), and prostate cancer-specific mortality (PCSM). PATIENTS AND METHODS: Retrospective study of 4,051 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort treated by RP from 1988 to 2013. Proportional hazard models were used to estimate hazard ratios (HRs) of PSMs in predicting biochemical recurrence (BCR), CRPC, metastases, and PCSM. To determine if PSMs were more predictive in certain patients, analyses were stratified by pathological Gleason score, stage, and preoperative prostate-specific antigen (PSA) level. RESULTS: The median (interquartile range) follow-up was 6.6 (3.2 10.6) years and 1 127 patients had >10 years of follow-up. During this time, 302 (32%) men had BCR, 112 (3%) developed CRPC, 144 (4%) developed metastases, and 83 (2%) died from prostate cancer. There were 1,600 (40%) men with PSMs. In unadjusted models, PSMs were significantly associated with all adverse outcomes: BCR, CRPC, metastases and PCSM (all P <= 0.001). After adjusting for demographic and pathological characteristics, PSMs were associated with increased risk of only BCR (HR 1.98, P < 0.001), and not CRPC, metastases, or PCSM (HR <=1.29, P > 0.18). Similar results were seen when stratified by pathological Gleason score, stage, or PSA level, and when patients who underwent adjuvant radiotherapy were excluded. CONCLUSIONS: PSMs after RP are not an independent risk factor for CRPC, metastasis, or PCSM overall or within any subset. In the absence of other high risk features, PSMs alone may not be an indication for adjuvant radiotherapy. PMID- 26010162 TI - Dielectrophoretic immobilization of proteins: Quantification by atomic force microscopy. AB - The combination of alternating electric fields with nanometer-sized electrodes allows the permanent immobilization of proteins by dielectrophoretic force. Here, atomic force microscopy is introduced as a quantification method, and results are compared with fluorescence microscopy. Experimental parameters, for example the applied voltage and duration of field application, are varied systematically, and the influence on the amount of immobilized proteins is investigated. A linear correlation to the duration of field application was found by atomic force microscopy, and both microscopical methods yield a square dependence of the amount of immobilized proteins on the applied voltage. While fluorescence microscopy allows real-time imaging, atomic force microscopy reveals immobilized proteins obscured in fluorescence images due to low S/N. Furthermore, the higher spatial resolution of the atomic force microscope enables the visualization of the protein distribution on single nanoelectrodes. The electric field distribution is calculated and compared to experimental results with very good agreement to atomic force microscopy measurements. PMID- 26010164 TI - A Top-down Approach to Elucidate the Role of Matrix-Bound Phosphoproteins in Control of Collagen Biomineralization. AB - The periodontium is the set of tissues responsible for tooth anchorage, and consists of interconnected layers of mineralized and unmineralized tissues (bone, ligament and cementum). The ligament-cementum interface is a particularly elegant example of biological control of mineralization and the controlling factors are poorly understood. Here we use a tissue-based in vitro model of mineralization, in which sections of demineralized mouse jaw remineralize with the same selectivity as found in vivo, to probe the molecular mechanism of control over collagen mineralization in the periodontium. Removal or enzymatic cleavage of noncollagenous proteins have very similar effects: a reduction in the rate of remineralization that is much more drastic in cementum than in dentin. The periodontal ligament does not mineralize within experimental parameters even after protein removal/digestion. Dephosphorylation results in a slight reduction in mineralization in dentin and cementum. Understanding the mechanisms controlling selective mineralization in the periodontium will help elucidate the molecular factors controlling collagen biomienralization, and provide inspiration for the development of scaffolds for regeneration of hard-soft tissue interfaces. PMID- 26010163 TI - Investigation of the role of TCF4 rare sequence variants in schizophrenia. AB - Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. PMID- 26010165 TI - Enabling professional development in mental health nursing: the role of clinical leadership. AB - Clinical leadership is acknowledged as important to the nursing profession. While studies continue to identify its significance in contributing to positive outcomes for consumers, the role that clinical leadership has in enabling and supporting professional development in mental health nursing is poorly understood. This study utilized a grounded theory methodology to explore the characteristics clinicians consider important for clinical leadership and its significance for mental health nursing in day-to-day clinical practice. Individual face-to-face, semi-structured interviews were conducted with nurses working in mental health settings. Participants described the important role that clinical leaders play in enabling professional development of others through role modelling and clinical teaching. They describe how nurses, whom they perceive as clinical leaders, use role modelling and clinical teaching to influence the professional development of nursing staff and undergraduate nursing students. Attributes such as professionalism and honesty were seen, by participants, as enablers for clinical leaders in effectively and positively supporting the professional development of junior staff and undergraduate nurses in mental health nursing. This paper examines clinical leadership from the perspective of mental health nurses delivering care, and highlights the important role of clinical leaders in supporting professional development in mental health nursing. PMID- 26010166 TI - Multi-Family Therapy for Bulimia Nervosa in Adolescence. AB - Existing randomized controlled trials of family therapy for treatment of bulimia nervosa in adolescence highlight the need for further development of treatments. This article describes the development of multi-family treatment for bulimia nervosa in adolescents aged 13-18. It outlines the theory guiding this development, the areas of need identified by previous studies, and the treatment that has been designed to meet these needs. Particular attention is given to the need to increase communication between family members, strategies to reduce high levels of criticism or hostility, and skills to manage emotion dysregulation and low tolerance for negative emotions. To these ends the program draws on the multi family treatment for anorexia nervosa, cognitive behavioral therapy techniques, and dialectical behavior therapy. PMID- 26010167 TI - Metabolic analysis of knee synovial fluid as a potential diagnostic approach for osteoarthritis. AB - Osteoarthritis (OA) is a leading cause of chronic joint pain in the older human population. Diagnosis of OA at an earlier stage may enable the development of new treatments to one day effectively modify the progression and prognosis of the disease. In this work, we explore whether an integrated metabolomics approach could be utilized for the diagnosis of OA. Synovial fluid (SF) samples were collected from symptomatic chronic knee OA patients and normal human cadaveric knee joints. The samples were analyzed using (1)H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) followed by multivariate statistical analysis. Based on the metabolic profiles, we were able to distinguish OA patients from the controls and validate the statistical models. Moreover, we have integrated the (1)H NMR and GC-MS results and we found that 11 metabolites were statistically important for the separation between OA and normal SF. Additionally, statistical analysis showed an excellent predictive ability of the constructed metabolomics model (area under the receiver operating characteristic curve = 1.0). Our findings indicate that metabolomics might serve as a promising approach for the diagnosis and prognosis of degenerative changes in the knee joint and should be further validated in clinical settings. PMID- 26010168 TI - Evolutionary analyses of caspase-8 and its paralogs: Deep origins of the apoptotic signaling pathways. AB - Although Caenorhabditis and Drosophila proved invaluable in unraveling the molecular mechanisms of apoptosis, it is now clear that these animals are of limited value for understanding the evolution of apoptotic systems. Whereas data from these invertebrates led to the assumption that the extrinsic apoptotic pathway is restricted to vertebrates, recent data from cnidarians and sponges indicate that this pathway predates bilaterian origins. Here we review the phylogenetic distribution of caspase-8, the initiator caspase of the extrinsic apoptotic pathway, its paralogs and other components of the network. The ancestral caspase-8 gave rise to four paralogs early in vertebrate evolution, and these have been maintained in many tetrapods. However, eutherians have lost caspase-18 and myomorph rodents have lost caspase-10, these losses suggesting functional redundancy amongst caspase-8 paralogs. The apoptotic network of the eumetazoan ancestor appears to have been complex and vertebrate like, and is only now being revealed by studying simple animals. PMID- 26010169 TI - Breath testing and personal exposure--SIFT-MS detection of breath acetonitrile for exposure monitoring. AB - Breath testing has potential for the rapid assessment of the source and impact of exposure to air pollutants. During the development of a breath test for acetonitrile using selected ion flow tube mass spectrometry (SIFT-MS) raised acetonitrile concentrations in the breath of volunteers were observed that could not be explained by known sources of exposure. Workplace/laboratory exposure to acetonitrile was proposed since this was common to the volunteers with increased breath concentrations. SIFT-MS measurements of acetonitrile in breath and air were used to confirm that an academic chemistry laboratory was the source of exposure to acetonitrile, and quantify the changes that occurred to exhaled acetonitrile after exposure. High concentrations of acetonitrile were detected in the air of the chemistry laboratory. However, concentrations in the offices were not significantly different across the campus. There was a significant difference in the exhaled acetonitrile concentrations of people who worked in the chemistry laboratories (exposed) and those who did not (non-exposed). SIFT-MS testing of air and breath made it possible to determine that occupational exposure to acetonitrile in the chemistry laboratory was the cause of increased exhaled acetonitrile. Additionally, the sensitivity was adequate to measure the changes to exhaled amounts and found that breath concentrations increased quickly with short exposure and remained increased even after periods of non-exposure. There is potential to add acetonitrile to a suite of VOCs to investigate source and impact of poor air quality. PMID- 26010170 TI - Distressing Sexual Problems and Dyadic Adjustment in Heterosexuals, Gay Men, and Lesbian Women. AB - Empirical studies have focused on dyadic adjustment and sexual satisfaction in men and women. Nevertheless, little is known regarding the role of dyadic adjustment in sexual problems among individuals in same-sex and mixed-sex dyads. The aim of the current study was to analyze the differences in dyadic adjustment between gay and heterosexual men, and lesbian and heterosexual women, with and without distressing sexual problems. One hundred and sixty men (80 gay and 80 heterosexual) and 184 women (92 lesbian and 92 heterosexual) completed an online survey. Participants responded to the Dyadic Adjustment Scale-Short Version and to questions about self-perceived sexual problems and associated levels of distress. A 2 (gender) * 2 (sexual orientation) * 2 (group with or without sexual problems) univariate analysis of covariance was performed. The findings suggested that individuals with distressing sexual problems, regardless of gender or sexual orientation, scored significantly lower on the Dyadic Adjustment Scale. Additionally, lesbian women, regardless of having or not having a distressing sexual problem, scored significantly higher on the Dyadic Adjustment Scale, compared to heterosexual women. No gender differences were found. Overall, our findings emphasize the negative association between dyadic adjustment and distressing sexual problems, regardless of gender and sexual orientation. PMID- 26010171 TI - Long-term consequences of pain, anxiety and agitation for critically ill older patients after an intensive care unit stay. AB - AIMS AND OBJECTIVES: This study investigated whether an intensive care unit (ICU) stay is associated with persistent pain, anxiety and agitation in critically ill older patients. BACKGROUND: Patients hospitalised in the ICU are at risk for experiencing pain, anxiety and agitation, but long-term consequences for older patients have rarely been investigated. DESIGN: Prospective nonrandomised longitudinal study. METHODS: Pain, anxiety and agitation, measured with a numeric rating scale (0-10), were assessed in older patients (>=65 years) hospitalised in the medical-surgical ICU of a university hospital. Agitation during the ICU was assessed with the Richmond Agitation-Sedation Scale. Data collection occurred during the ICU, one week after the stay and six and 12 months after hospital discharge. Data were collected from an age-matched community-based comparison group at recruitment and after six and 12 months. Study recruitment took place from December 2008-April 2011. RESULTS: This study included 145 older patients (ICU group) and 146 comparison group participants. Pain was higher in the ICU group one week after discharge, although pain levels in general were low. Both groups reported no or low levels of pain after six and 12 months. Anxiety levels in general were low, although higher in the ICU group one week after ICU discharge. After six and 12 months, anxiety in both groups was comparable. Throughout the study, levels of agitation were similar in both groups. CONCLUSIONS: Critically ill older patients did not experience increased pain, anxiety or agitation 12 months after an ICU stay. RELEVANCE TO CLINICAL PRACTICE: This study positively shows that an ICU stay is not associated with persistent pain, anxiety and agitation thus providing additional information to older patients and their families when making intensive care treatment decisions. Adequate management of pain during and after an ICU stay may minimise the suffering of older patients. PMID- 26010172 TI - Peptide-Metal Organic Framework Swimmers that Direct the Motion toward Chemical Targets. AB - Highly efficient and robust chemical motors are expected for the application in microbots that can selectively swim toward targets and accomplish their tasks in sensing, labeling, and delivering. However, one of major issues for such development is that current artificial swimmers have difficulty controlling their directional motion toward targets like bacterial chemotaxis. To program synthetic motors with sensing capability for the target-directed motion, we need to develop swimmers whose motions are sensitive to chemical gradients in environments. Here we create a new intelligent biochemical swimmer by integrating metal organic frameworks (MOFs) and peptides that can sense toxic heavy metals in solution and swim toward the targets. With the aid of Pb-binding enzymes, the peptide-MOF motor can directionally swim toward PbSe quantum dots (QD) by sensing pH gradient and eventually complete the motion as the swimmer reaches the highest gradient point at the target position in solution. This type of technology could be evolved to miniaturize chemical robotic systems that sense target chemicals and swim toward target locations. PMID- 26010173 TI - Theoretical Investigation on Mechanistic and Kinetic Transformation of 2,2',4,4',5-Pentabromodiphenyl Ether. AB - This study investigates the decomposition of 2,2',4,4',5-pentabrominated diphenyl ether (BDE99), a commonly detected pollutant in the environment. Debromination channels yielding tetrabrominated diphenyl ethers and hydrogen abstracting aromatic bromine atom formations play significant roles in the reaction of BDE99 + H, in which the former absolutely predominates bimolecular reactions. Polybrominated dibenzo-p-dioxins (PBDDs) and polybrominated dibenzofurans (PBDFs) can be produced during BDE99 pyrolysis, especially for PBDFs under inert conditions. The expected dominant pathways in a closed system are debromination products and PBDF formations. The bimolecular reaction with hydroxyl radical mainly leads to hydroxylated BDE99s rather than hydroxylated tetrabrominated diphenyl ethers. PBDDs are then generated from ortho-hydroxylated PBDEs. HO2 radical reactions rarely proceed. The total rate constants for the BDE99 reaction with hydrogen atoms and hydroxyl radicals exhibit positive dependence on temperature with values of 1.86 * 10(-14) and 5.24 * 10(-14) cm(3) molecule(-1) s(-1) at 298.15 K, respectively. PMID- 26010174 TI - Applying artificial neural networks to predict communication risks in the emergency department. AB - AIMS: To describe the utility of artificial neural networks in predicting communication risks. BACKGROUND: In health care, effective communication reduces the risk of error. Therefore, it is important to identify the predictive factors of effective communication. Non-technical skills are needed to achieve effective communication. This study explores how artificial neural networks can be applied to predict the risk of communication failures in emergency departments. DESIGN: A multicentre observational study. METHODS: Data were collected between March-May 2011 by observing the communication interactions of 840 nurses with their patients during their routine activities in emergency departments. The tools used for our observation were a questionnaire to collect personal and descriptive data, level of training and experience and Guilbert's observation grid, applying the Situation-Background-Assessment-Recommendation technique to communication in emergency departments. RESULTS: A total of 840 observations were made on the nurses working in the emergency departments. Based on Guilbert's observation grid, the output variables is likely to influence the risk of communication failure were 'terminology'; 'listening'; 'attention' and 'clarity', whereas nurses' personal characteristics were used as input variables in the artificial neural network model. A model based on the multilayer perceptron topology was developed and trained. The receiver operator characteristic analysis confirmed that the artificial neural network model correctly predicted the performance of more than 80% of the communication failures. CONCLUSION: The application of the artificial neural network model could offer a valid tool to forecast and prevent harmful communication errors in the emergency department. PMID- 26010175 TI - Guidewire-induced coronary perforation successfully treated with subcutaneous fat embolisation: A simple technique available to all. AB - A 62-year-old man presented with an anterior ST elevation myocardial infarction and underwent primary percutaneous coronary intervention to an occluded diagonal artery. Following stenting, a type III distal guidewire-induced coronary perforation of the diagonal branch was recognized with extravasation of contrast into the pericardial space. Prolonged balloon inflations proximal to the site of the perforation were unsuccessful. Subcutaneous fat was therefore harvested from the patients upper thigh under local anesthetic and embolized through an Export catheter into the distal diagonal vessel, resulting in the immediate cessation of leak through the site of perforation. We discuss the technical aspects of this technique as well as alternative methods of distal embolization and the potential complications that must be considered. PMID- 26010176 TI - Gene-diet interactions in exposure to heterocyclic aromatic amines and bulky DNA adduct levels in blood leukocytes. AB - Heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, are an emerging biologic explanation for the meat-colorectal cancer relationship. HAAs form DNA adducts; left unrepaired, adducts can induce mutations, which may initiate/promote carcinogenesis. The purpose of this research was to investigate the relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct levels. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood measured using (32)P-postlabeling among 99 healthy volunteers. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. No main effects of dietary HAAs on bulky DNA adduct levels was found. However, those with the putative NAT1 rapid acetylator phenotype had lower adduct levels than those with the slow acetylator phenotype (P = 0.02). Furthermore, having five or more 'at risk' genotypes was associated with higher bulky DNA adduct levels (P = 0.03). Gene-diet interactions were observed between NAT1 polymorphisms and dietary HAAs (P < 0.05); among the slow acetylator phenotype, higher intakes of HAAs were associated with an increase in DNA adduct levels compared to lower intakes. This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. However, the lack of a strong main effect of HAAs suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this population; future studies should consider relevant gene-diet interactions to clarify the role of HAAs in carcinogenesis. PMID- 26010177 TI - Inferior outcome after allogeneic transplant in first remission in high-risk AML patients who required more than two cycles of induction therapy. AB - While some patients with high-risk acute myeloid leukemia (AML) require one or two cycles of induction chemotherapy to achieve a complete remission (CR), others require more than two cycles. We examined the outcomes of patients with high-risk AML who received allogeneic HPC transplant in CR1. Forty five consecutive high risk AML patients in CR1 were included. All 45 patients had adverse cytogenetics, FLT 3 mutations, or secondary AML. Group A patients (n = 33) received one or two cycles, and Group B (n = 12) three or more cycles of induction chemotherapy. The patients were comparable in age, sex, white cell count at presentation, and time from diagnosis and from last chemotherapy to transplant. The 100-day mortality rate was higher in Group B patients (50% vs. 9%, P = 0.006). They had a higher non-relapse mortality (33% vs. 6%, P = 0.035) and a longer length of hospital stay from the day of stem cell infusion (median 21 vs. 20, P = 0.02; third quartile 22 vs. 28, P = 0.02). There was also a trend toward inferior event-free survival and overall survival. High-risk AML patients undergoing allogeneic transplant in CR1 after three or more cycles of induction chemotherapy have an inferior outcome and higher mortality when compared to those who only needed one or two cycles of induction chemotherapy. Novel strategies are needed to reduce the transplant-related mortality in high-risk AML patients needing more than two cycles of induction chemotherapy prior to allogeneic transplant in CR1. PMID- 26010178 TI - Improving Performance via Blocking Layers in Dye-Sensitized Solar Cells Based on Nanowire Photoanodes. AB - Electron recombination in dye-sensitized solar cells (DSSCs) results in significant electron loss and performance degradation. However, the reduction of electron recombination via blocking layers in nanowire-based DSSCs has rarely been investigated. In this study, HfO2 or TiO2 blocking layers are deposited on nanowire surfaces via atomic layer deposition (ALD) to reduce electron recombination in nanowire-based DSSCs. The control cell consisting of ITO nanowires coated with a porous shell of TiO2 by TiCl4 treatment yields an efficiency of 2.82%. The efficiency increases dramatically to 5.38% upon the insertion of a 1.3 nm TiO2 compact layer between the nanowire surface and porous TiO2 shell. This efficiency enhancement implies that porous sol-gel coatings on nanowires (e.g., via TiCl4 treatment) result in significant electron recombination in nanowire-based DSSCs, while compact coatings formed by ALD are more advantageous because of their ability to act as a blocking layer. By comparing nanowire-based DSSCs with their nanoparticle-based counterparts, we find that the nanowire-based DSSCs suffer more severe electron recombination from ITO due to the much higher surface area exposed to the electrolyte. While the insertion of a high band gap compact layer of HfO2 between the interface of the conductive nanowire and TiO2 shell improves performance, a comparison of the cell performance between TiO2 and HfO2 compact layers indicates that charge collection is suppressed by the difference in energy states. Consequently, the use of high band gap materials at the interface of conductive nanowires and TiO2 is not recommended. PMID- 26010179 TI - REAL-PANLAR Project for the Implementation and Accreditation of Centers of Excellence in Rheumatoid Arthritis Throughout Latin America: A Consensus Position Paper From REAL-PANLAR Group on Improvement of Rheumatoid Arthritis Care in Latin America Establishing Centers of Excellence. AB - OBJECTIVE: A consensus meeting of representatives of 16 Latin American and Caribbean countries and the REAL-PANLAR group met in the city of Bogota to provide recommendations for improving quality of care of patients with rheumatoid arthritis (RA) in Latin America, defining a minimum standards of care and the concept of center of excellence in RA. METHODS: Twenty-two rheumatologists from 16 Latin American countries with a special interest in quality of care in RA participated in the consensus meeting. Two RA Colombian patients and 2 health care excellence advisors were also invited to the meeting. A RAND-modified Delphi procedure of 5 steps was applied to define categories of centers of excellence. During a 1-day meeting, working groups were created in order to discuss and validate the minimum quality-of-care standards for the 3 proposed types of centers of excellence in RA. Positive votes from at least 60% of the attending leaders were required for the approval of each standard. RESULTS: Twenty-two opinion leaders from the PANLAR countries and the REAL-PANLAR group participated in the discussion and definition of the standards. One hundred percent of the participants agreed with setting up centers of excellence in RA throughout Latin America. Three types of centers of excellence and its criteria were defined, according to indicators of structure, processes, and outcomes: standard, optimal, and model. The standard level should have basic structure and process indicators, the intermediate or optimal level should accomplish more structure and process indicators, and model level should also fulfill outcome indicators and patient experience. CONCLUSIONS: This is the first Latin American effort to standardize and harmonize the treatment provided to RA patients and to establish centers of excellence that would offer to RA patients acceptable clinical results and high levels of safety. PMID- 26010180 TI - Affective tone in medical encounters and its relationship with treatment adherence in a multiethnic cohort of patients with rheumatoid arthritis. AB - BACKGROUND: Tone of voice in communication between patients and rheumatologists may offer insight into problems of treatment adherence in patients with rheumatoid arthritis. OBJECTIVE: The aim of this study was to evaluate physician patient affective vocal tone within the medical encounter and its relationship to treatment adherence in ethnically diverse patients with rheumatoid arthritis. METHODS: The consultations of 174 patients with rheumatoid arthritis were audio recorded at a baseline visit. Of these, 135 completed follow-up adherence measures at 3 months. The positive and negative affective tones of patients, physicians, and interpreters (and distressed tones of patients and interpreters) were assessed using the Roter Interaction Analysis System affective communication scale. Treatment adherence was evaluated at baseline and at 3 months using the Compliance Questionnaire Rheumatology. RESULTS: A total of 117 baseline consultations were in English (n = 42, 36, and 39 white, African American, and Hispanic patients, respectively), 24 in Spanish, and 33 with an interpreter (total = 174). Patients reporting poorer adherence were rated as having more distressed affect and less positive affect than patients reporting greater adherence. Physicians expressed more positive affect to more educated patients. Physicians and patients reciprocated one another's positive and negative affect. Controlling for baseline adherence, physician negative affect predicted greater adherence at 3 months for Hispanic patients, regardless of language choice, compared with white patients. CONCLUSIONS: Patients' affective tones offer clues to problems patients may have with treatment adherence and well-being. More research is needed regarding why physicians' expression of negative affect may facilitate adherence for some groups of patients. PMID- 26010181 TI - Validation of administrative codes for calcium pyrophosphate deposition: a Veterans Administration study. AB - BACKGROUND: Despite high prevalence, progress in calcium pyrophosphate deposition (CPPD) has been limited by poor awareness and absence of validated approaches to study it in large data sets. OBJECTIVES: We aimed to determine the accuracy of administrative codes for the diagnosis of CPPD as a foundational step for future studies. METHODS: We identified all patients with an International Classification of Diseases, Ninth Revision, Clinical Modification code for chondrocalcinosis (712.1-712.39) or pseudogout/other disorders of mineral metabolism (275.49), and convenience sample selected a comparison group with gout (274.00-03 or 274.8-9), or rheumatoid arthritis (714.0) from 2009 to 2011 at a Veterans Affairs medical center. Each patient was categorized as having definite, probable, or possible CPPD or absence of CPPD based on the McCarty and Ryan criteria using chart abstracted data including crystal analysis, radiographs, and arthritis history. RESULTS: Two hundred forty-nine patients met the clinical gold standard criteria for CPPD based on medical records, whereas 48 patients met definite criteria, 183 probable, and 18 met possible criteria. The accuracy of administrative claims with a code of 712 or 275.49 for definite or probable CPPD was as follows: 98% sensitivity (95% confidence interval, 96%-99%), 78% specificity (74%-83%), 91% positive predictive value, and 94% negative predictive value. CONCLUSIONS: At this center, single administrative code 275.49 or 712 accurately identifies patients with CPPD with a positive predictive value of 91%. These findings suggest that administrative codes can have strong clinical accuracy and merit further validation to allow adoption in future epidemiologic studies of CPPD. PMID- 26010182 TI - Antimalarial drugs alone may still have a role in rheumatoid arthritis. AB - OBJECTIVES: Antimalarials have been used for the treatment of rheumatoid arthritis (RA) for several decades. Current guidelines do not include the use of these drugs alone for RA patients. The purpose of the study is to review RA patients, to find those who have done well on antimalarials alone, and see if there are common features that predict good treatment outcome with these drugs. METHODS: This is a retrospective chart review of patients who have been successfully treated with antimalarials alone. Patients who were attending routine follow-up and were seemingly in remission defined by no swollen or tender joints were selected over a 6-month period. Those who had being doing well but were now or had been on other agents were not included. The background data were reviewed to see if there were any common initial characteristics. RESULTS: Thirty three patients were seen who had been administered antimalarials alone and where initial data were available. Patients remain in clinical remission. Based on clinical observation, inflammatory markers, and radiographic reports, in the follow-up visits, they remain with no signs of inflammation and no new erosions on radiograph. Initial bone erosions on 2 patients remain stable over the years. CONCLUSIONS: There are some patients with confirmed RA who without doubt respond well to antimalarials alone. It is hard to objectively measure whether mild disease activity, early treatment initiation, lack of smoking, or other factors are contributing to a good treatment response. PMID- 26010183 TI - Acute bacterial arthritis: how long should you wait for culture results? AB - BACKGROUND: The optimal incubation period for synovial fluid cultures is unknown. OBJECTIVES: Our study was designed to determine the positivity rate and time to positivity of synovial fluid cultures from adults with suspected acute bacterial arthritis. METHODS: We reviewed the charts of 94 adults who had acute monoarthritis. Patients were classified as low risk or high risk for acute bacterial arthritis. The positivity rate and time to positivity of synovial fluid in combined agar plate and broth culture were calculated. RESULTS: The overall positivity rate was 22.3% (21 of 94). None of the 21 low-risk patients had a positive culture. Twenty-one (28.7%) of 73 high-risk subjects showed growth, with a mean time to positivity of 36.7 +/- 27.1 hours. While half of these turned positive within a day of incubation, growth was detected at up to 90 hours. CONCLUSIONS: In patients with acute monoarthritis, especially those at high risk for infection, it is reasonable to incubate cultures for 4 days before considering them to be negative. PMID- 26010184 TI - Advocacy for rheumatology. PMID- 26010185 TI - Ultrasound-guided procedures in rheumatology. What is the evidence? AB - Ultrasound (US) is a cost-effective, noninvasive, and accessible imaging modality that clinicians use at the point of care to assess disease activity and therapeutic efficacy in different rheumatic conditions. It can play a relevant role in invasive procedures performed by the rheumatologist, potentially ensuring a higher degree of accuracy. However, US-guided injections are still underused, and the conventional blind injection the most commonly adopted approach. In this article, we analyze the current evidence supporting the use of US-guided procedures, emphasizing comparative studies between conventional and US-guided procedures and their benefits in the daily rheumatological practice. PMID- 26010186 TI - Pleural effusion, pneumothorax, and lung entrapment in rheumatoid arthritis. AB - Rheumatoid arthritis (RA)-associated pleural effusions are usually small and asymptomatic with no need for intervention, but complex and symptomatic rheumatoid pleural effusions may be seen and are associated with significant morbidity and mortality. Pleural effusions may develop before, concurrently with, or after the joint manifestations of RA. The classic features of RA-associated pleural effusions include high cell counts and protein, lipid, and lactate dehydrogenase levels and very low glucose levels, along with distinctive cytopathologic findings: slender spindle-shaped cells, multinucleated giant cells, eosinophilic granular debris, and the absence of mesothelial cells. Rarely, rheumatoid pleural involvement can include pneumothorax or can be severe enough to progress to lung entrapment, which may cause significant restrictive lung disease and require surgical therapy. Rheumatoid pleural involvement may not always correlate with joint activity but can be a significant cause of shortness of breath for patients with RA. PMID- 26010187 TI - Arterial Calcification Due to Deficiency of CD73 (ACDC) As One of Rheumatic Diseases Associated With Periarticular Calcification. AB - In 2011, St Hilaire et al (N Engl J Med. 2011;364:432-442) identified mutations in the ecto-5'-nucleotidase (NT5E) gene, which encodes CD73, in members of 3 families with symptomatic arterial and joint calcifications. The deficiency of CD73 involves the extracellular adenosine metabolism that influences inorganic pyrophosphate and phosphate metabolism and leads to tissue calcification. Herein, we report an additional case with arterial calcification due to deficiency of CD73. Genetic analyses revealed that the patient was a compound heterozygote of mutations in the NT5E gene. The present case had intermittent monoarthritis of the finger joints and early-onset osteoarthritis in the hands. Occlusion of calcified peripheral arteries is the most important outcome of the disease. However, the rheumatic manifestations may be important clues to the diagnosis. Rheumatologists should recognize deficiency of CD73 as a rheumatic disease. PMID- 26010188 TI - Ureaplasma septic arthritis in an immunosuppressed patient with juvenile idiopathic arthritis. AB - Mycoplasmas, including Ureaplasma and Mycoplasma species, are uncommon but important causes of septic arthritis, especially affecting immunosuppressed patients. Many of the reported cases have been associated with congenital immunodeficiency disorders, especially hypogammaglobulinemia. Mycoplasmas are difficult to grow in the laboratory, and these infections may be underdiagnosed using culture techniques. We report a case of a 21-year-old woman with juvenile idiopathic arthritis and hip arthroplasties treated with rituximab and adalimumab who developed urogenital infections and soft tissue abscesses followed by knee arthritis with negative routine cultures. Ureaplasma species was identified from synovial fluid on 2 separate occasions using a broad-range 16S ribosomal RNA gene polymerase chain reaction. Azithromycin led to rapid improvement in symptoms, but after completion of therapy, involvement of the hip prosthesis became apparent, and again, 16S rRNA gene polymerase chain reaction was positive for Ureaplasma species. The literature is reviewed with a discussion of risk factors for Mycoplasma septic arthritis, clinical presentation, methods of diagnosis, and treatment. PMID- 26010190 TI - Recovery of barium swallow radiographic abnormalities in a patient with dermatomyositis and severe dysphagia after high-dose intravenous immunoglobulins. PMID- 26010189 TI - An internet survey of common treatments used by patients with gout including cherry extract and juice and other dietary supplements. PMID- 26010191 TI - Rheumatoid hand. PMID- 26010193 TI - Tuberculous cervical lymphadenitis in a gouty patient treated with anakinra. PMID- 26010194 TI - Inference by exclusion in lion-tailed macaques (Macaca silenus), a hamadryas baboon (Papio hamadryas), capuchins (Sapajus apella), and squirrel monkeys (Saimiri sciureus). AB - Previous research has suggested that several primate species may be capable of reasoning by exclusion based on the finding that they can locate a hidden object when given information about where the object is not. The present research replicated and extended the literature by testing 2 Old World monkey species, lion-tailed macaques (Macaca silenus) and a hamadryas baboon (Papio hamadryas), and 2 New World species, capuchin monkeys (Sapajus apella) and squirrel monkeys (Saimiri sciureus). The New World monkeys were tested on the traditional 2-way object choice task, and all 4 species were also tested on a more complex 3-way object choice task. In addition, the squirrel monkeys were tested on a 2-way object choice task with auditory information. The results showed that, whereas the Old World species were able to infer by exclusion on the 3-object task, some of the capuchin monkeys had difficulty on each of the 2- and 3-cup tasks. All but 1 of the squirrel monkeys failed to infer successfully, and their strategies appeared to differ between the visual and auditory versions of the task. Taken together, this research suggests that the ability to succeed on this inference task may be present throughout Old World monkey species, but is fragile in the New World species tested thus far. (PsycINFO Database Record PMID- 26010195 TI - Performance of Pugs, German Shepherds, and Greyhounds (Canis lupus familiaris) on an odor-discrimination task. AB - Public opinion and the scientific literature alike reflect a widespread assumption that there are differences in behavior between dog breeds. Direct empirical behavioral assessments of such differences, however, are rare and have produced mixed results. One area where breed differences are often assumed is olfaction, where German Shepherds, hounds, and Labradors are commonly used for odor-detection work, whereas toy breeds and brachycephalic dogs, such as Pugs, are not. Choice of breed for scent detection work, however, may be driven more by historical choices than data. In this article we directly assessed the ability of German Shepherds, Pugs, and Greyhounds to acquire a simple olfactory discrimination, and their ability to maintain performance when the target odorant was diluted. Our results show that contrary to expectations, Pugs significantly outperformed the German Shepherds in acquiring the odor discrimination and maintaining performance when the odorant concentration was decreased. Nine of 10 Greyhounds did not complete acquisition training because they failed a motivation criterion. These results indicate that Pugs outperformed German Shepherds in the dimensions of olfaction assessed. Greyhounds showed a general failure to participate. Overall, our results highlight the importance of direct behavioral measurement of assumed behavioral breed differences. PMID- 26010196 TI - Reasoning by exclusion in New Caledonian crows (Corvus moneduloides) cannot be explained by avoidance of empty containers. AB - Whether animals can reason or merely learn associatively is a long-standing debate. Researchers have approached this question by investigating whether dogs, birds, and primates can reason by exclusion (choosing by logically excluding all other alternatives). However, these studies have not resolved whether animals are capable of inferring which option is rewarded or are merely avoiding options known to be incorrect. Here, we used a forced-choice tubes task, where strategies of "reasoning by exclusion" and "avoidance of empty containers" predicted different responses. Two tubes (1 straight, 1 bent) were presented in 5 types of orientation, varying whether the rewarded location could be inferred. We compared predictions from both strategies with the observed performance of 8 wild-caught New Caledonian crows. Two of the 8 birds' choices were entirely consistent with reasoning by exclusion only. A further 4 birds followed a mixed strategy, where both reasoning and avoidance could have influenced their decisions. Thus, although avoidance plays a role, it cannot fully explain the crows' choices. Confirming how animals naturally solve problems is increasingly important in animal cognition; we demonstrate that NC crows can inferentially reason without explicit training, but, like humans, most do not rely solely on reasoning to make decisions. PMID- 26010197 TI - Evidence that monkeys (Macaca tonkeana and Sapajus apella) read moves, but no evidence that they read goals. AB - Whereas most experiments indicate that monkeys have no theory of mind, a study carried out by Wood and collaborators (2007) claimed that they can make inferences about the intentions of another individual. We applied the experimental procedure devised by these authors to investigate whether monkeys can recognize goal-directed actions. We tested 16 Tonkean macaques (Macaca tonkeana) and 12 tufted capuchin monkeys (Sapajus apella). Each subject was submitted to 24 trials in randomized order. The experimenter presented 2 containers, 1 of which was potentially baited with a food reward. After the experimenter had either intentionally or accidentally made an action on 1 of the containers, the subject was asked to select 1 of them. We found that individuals in both species failed to distinguish between accidental and intentional actions. However, they displayed a significant preference for the container touched by the experimenter in the hand conditions, and not in the elbow conditions. These results do not support those reported by Wood and collaborators, but they are consistent with other studies concluding that monkeys are not capable of mind reading. PMID- 26010198 TI - Alternative health eating index and the Dietary Guidelines from American Diabetes Association both may reduce the risk of cardiovascular disease in type 2 diabetes patients. AB - BACKGROUND: In the general population, a higher Alternate Healthy Eating Index (AHEI)-2010 score is related to decreased cardiovascular disease (CVD) risk. Few studies have described the dietary patterns that reduce the risk of CVD or coronary heart disease (CHD) in type 2 diabetes mellitus (T2DM) patients. In the present study, the association between the American Diabetes Association (ADA) recommended dietary pattern, AHEI-2010 , and CVD risk factors and the CVD incidence over 52 months in T2DM patients was evaluated. METHODS: The ADA score was developed from the ADA dietary recommendations. In this prospective study, the 24-h dietary recall of 124 adult T2DM patients without nephropathy or chronic kidney disease was collected. The CVD risk factors were collected at baseline and at 6-month follow-up. RESULTS: Compared with lower ADA and AHEI-2010 score participants, the higher score participants exhibited a significantly lower waist circumference, serum low-density lipoprotein cholesterol level and 10-year risk of CHD. Participants with higher ADA dietary scores had a significantly reduced risk of central obesity and systolic blood pressure >140 mmHg. Higher AHEI-2010 scores were significantly related to a reduced risk of serum low-density lipoprotein cholesterol > 100 mg dL(-1) . Seven participants had their first-ever CVD during the follow-up period, although neither ADA score, nor AHEI-2010 score could predict CVD incidence. CONCLUSIONS: The ADA-recommended dietary pattern and a higher AHEI-2010 score might both exhibit reduced risk factors of CVD in T2DM patients. PMID- 26010199 TI - A functional perspective on personality. AB - Personality psychology has made enormous progresses over the years by accumulating empirical evidence on how patterns of stable individual differences in behaviours can be clustered systematically at different levels of abstraction (i.e. traits and facets) and how they can predict important consequential outcomes. At the same time, functionally orientated researchers have accumulated a vast body of knowledge on environment-behaviour relations and the underlying behavioural principles, that is, abstract descriptions of the way in which behaviour is a function of elements in the past and present environment. We explore a functional perspective on personality that attempts to bridge the two domains and to exploit the best of both worlds. From this functional perspective, personality refers to the impact of the individual on different types of environment-behaviour relations as well as on the way other factors moderate those relations. We discuss the potential of this functional perspective on personality to organise existing scientific knowledge and inspire future research. PMID- 26010200 TI - Aqueous Solutions of Poly(ethylene oxide)-Poly(N-isopropylacrylamide): Thermosensitive Behavior and Distinct Multiple Assembly Processes. AB - Detailed phase transition and conformational changes taking place as a function of temperature in poly(ethylene oxide)-b-poly(N-isopropylacrylamide) (PEO-b PNIPAM) semidiluted aqueous solutions are elucidated in the present study. By the use of elaborate vibrational spectroscopy techniques in combination with two dimensional correlation spectroscopy (2Dcos), three transition regions including respective rich domains (<29 degrees C), loose aggregations (30-36 degrees C), and dense sphere micelles (>37 degrees C) are depicted. In particular, subtle variations of hydrogen bonds are detected even under the lower critical solution temperature (LCST), and the respective rich domain regime is marked with strong participation from hydrogen bonding at different concentrations and compositions. Both the formation of intermolecular hydrogen bonds and the less hydration degrees of PNIPAM segments compared with PNIPAM homopolymer at elevated temperatures verify the evolution of PNIPAM from their own domains to loose aggregations with PEO shells. Dense micelles are formed beyond the LCST of PNIPAM, while the outmost PEOs act as buffer layers and postpone the shrinkage of PNIPAM chains. Due to the existence of a buffer layer, higher phase transition temperatures compared with PNIPAM homopolymer are observed. PMID- 26010201 TI - Modeling Finite-Time Failure Probabilities in Risk Analysis Applications. AB - In this article, we introduce a framework for analyzing the risk of systems failure based on estimating the failure probability. The latter is defined as the probability that a certain risk process, characterizing the operations of a system, reaches a possibly time-dependent critical risk level within a finite time interval. Under general assumptions, we define two dually connected models for the risk process and derive explicit expressions for the failure probability and also the joint probability of the time of the occurrence of failure and the excess of the risk process over the risk level. We illustrate how these probabilistic models and results can be successfully applied in several important areas of risk analysis, among which are systems reliability, inventory management, flood control via dam management, infectious disease spread, and financial insolvency. Numerical illustrations are also presented. PMID- 26010202 TI - Potential of rapid adjustment of brief interceptive action using predicted information. AB - Interceptive actions, such as hitting a ball in baseball or tennis, feature a moving target whose parameters (i.e., velocity or trajectory) differ across trials. This means that players are required to make rapid trial-by-trial adjustments. The purpose of this study was to determine whether a brief interceptive action could be adjusted using predicted sensory consequence of movement (pSCM) information, even under severe time constraints where the participants could not adjust their movement using only visual feedback. Participants performed an interceptive action for targets with two different velocities with different occurrence probabilities (20%, 50%, and 80%). Prior to movement onset, we applied transcranial magnetic stimulation (TMS) to the supplementary motor area (SMA), as TMS of the SMA is known to disrupt pSCM activity. We hypothesized that if pSCM information were used to adjust the motor parameters of a brief interception, then TMS would significantly increase the constant temporal error (i.e., the difference between the sum of reaction time and movement time and the total target visible time) for a target velocity with a low probability (20%). This hypothesis is based on the previous findings that the pSCM plays an important role in the adjustment of relatively brief interception. We found that while interceptions that lasted about 250 ms after movement onset were unaffected, interceptions that lasted about 350 ms after movement onset could be influenced by TMS. However, TMS interfered with performance provided that the delivery of the pulse occurred 100 ms before movement onset. This finding suggests that pSCM information that is used for a rapid adjustment is generated only in that specific time interval. PMID- 26010203 TI - A rare but recurrent t(8;13)(q24;q14) translocation in B-cell chronic lymphocytic leukaemia causing MYC up-regulation and concomitant loss of PVT1, miR-15/16 and DLEU7. PMID- 26010204 TI - Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: prognostic factors and clinical outcomes. AB - This study investigated the prognostic factors and clinical outcomes of preemptive chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion (Chemo-DLI) according to minimal residual disease (MRD) status in patients with acute leukemia and myelodysplastic syndromes who received allogeneic hematopoietic stem cell transplantation (HSCT) (n = 101). Patients received immunosuppressive drugs to prevent graft-vs.-host disease (GVHD) after Chemo-DLI. The 3-yr cumulative incidences of relapse, non-relapse mortality, and disease-free survival (DFS) after HSCT were 39.5%, 9.6%, and 51.7%, respectively. The cumulative incidences of relapse and DFS were significantly poorer in patients who exhibited early-onset MRD. Forty-four patients turned MRD negative 1 month after Chemo-DLI; their cumulative incidences of relapse and DFS were significantly better than those with persistent MRD 1 month after preemptive Chemo-DLI (relapse: 19.8% vs. 46.8%, P = 0.001; DFS: 69.6% vs. 46.4%, P = 0.004). The cumulative incidences of relapse and DFS after HSCT were significantly better in patients with chronic GVHD (cGVHD) than those without cGVHD (relapse: 19.6% vs. 63.7%, P < 0.001; DFS: 74.4% vs. 23.8%, P < 0.001). Early-onset MRD, persistent MRD after Chemo-DLI, and non-cGVHD after Chemo-DLI, which were associated with increased relapse and impaired DFS, suggest unsatisfactory response to preemptive Chemo-DLI. PMID- 26010205 TI - Influence of CYP2C9 polymorphism on the fall in International Normalized Ratio in patients interrupting warfarin therapy before elective surgery. AB - BACKGROUND: Patients on warfarin are normally required to stop treatment for a fixed number of days prior to an invasive procedure. However, the anticoagulant activity of warfarin subsides at different rates among different patients. OBJECTIVES: The aim of this study was to investigate the potential influence of CYP2C9 polymorphism on the variable rate of fall in the International Normalized Ratio (INR) in patients withdrawing from warfarin treatment prior to elective surgery. PATIENTS/METHODS: One hundred and fifty-two patients aged 43-93 years were recruited. Demographic data on age, height, weight, gender, daily warfarin dose, indication for anticoagulation therapy, medical diagnosis, surgical operation planned and concomitant medication were recorded. A blood sample was taken for later CYP2C9 genotyping. RESULTS: For patients with two CYP2C9 variant alleles (CYP2C9*2*2 or CYP2C9*2*3), the odds of having an INR of >= 1.5 before the planned day of surgery were 8.64 times greater (95% confidence interval [CI] 2.25-33.25) than for other patients. Multiple regression analysis revealed that the rate of fall in the INR was reduced in the presence of two CYP2C9 variant alleles, as well as increasing patient age, weight and number of comorbidities, and increased with increasing initial INR (F5,132 = 242.9, P < 0.0001), all of which accounted for ~ 90% of the interindividual variability in the fall in INR. CONCLUSION: A genotype-guided protocol to tailor warfarin withdrawal according to an individual patient's CYP2C9 genotype could reduce cancellation or delays of planned procedures, and could also be beneficial when transitioning patients from warfarin to one of the new oral anticoagulants. PMID- 26010206 TI - Dose-response relationship of specific allergen exposure-induced immunological tolerance: a mouse model. AB - BACKGROUND: It is believed that adequate allergen preimmunization exposure could induce immunologic tolerance. The purpose of this study was to investigate the dose-dependent mechanisms related to antigen-specific tolerance induction in a mouse model. METHODS: Mice were assigned to 5 groups: the control (Cont) group received phosphate-buffered saline (PBS) preimmunization exposure and PBS sham immunization; the other 4 groups were exposed preimmunization to PBS (PBS group) or ovalbumin (OVA) (first mucosal doses: 1.25%, 2.5%, or 5% wt/vol aerosol from days -3 to -1) prior to OVA immunization. The OVA-immunized mice received intraperitoneal doses of 20 MUg OVA (on days 1, 7, and 14), and then a second set of mucosal doses with 0.5% wt/vol OVA aerosol (on days 18 to 20). After assessment of airway hyperresponsiveness (AHR), the mice were euthanized and their blood, bronchoalveolar lavage fluids (BALFs), and lung tissues were collected for further analyses. RESULTS: OVA-immunized mice exposed to OVA preimmunization had reduced AHR and immunoglobulin E production when compared to the PBS group. OVA preimmunization exposure inhibited eosinophilic inflammation in lung tissues. The proportions of BALF eosinophil counts from the groups exposed to OVA preimmunization were significantly decreased when compared with those exposed to PBS preimmunization. The balance of T helper 2 (Th2) and T regulatory (Treg) cytokines in BALFs were additionally observed in this mouse model. CONCLUSION: Our results suggest that preimmunization exposure to an appropriate dose of a specific antigen could suppress allergic airway inflammation by induction of immunological tolerance. PMID- 26010207 TI - Typical Versus Atypical Anorexia Nervosa Among Adolescents: Clinical Characteristics and Implications for ICD-11. AB - There is scant research on the clinical utility of differentiating International Classification of Diseases (ICD) 10 diagnoses F50.0 anorexia nervosa (typical AN) and F50.1 atypical anorexia. We reviewed systematically records of 47 adolescents who fulfilled criteria for ICD-10 F50.0 (n = 34) or F50.1 (n = 13), assessing the impact of diagnostic subtype, comorbidity, background factors and treatment choices on recovery. Atypical AN patients were significantly older (p = 0.03), heavier (minimum body mass index 16.7 vs 15.1 kg/m(2) , p = 0.003) and less prone to comorbidities (38% vs 71%, p = 0.04) and had shorter, less intensive and less costly treatments than typical AN patients. The diagnosis of typical versus atypical AN was the sole significant predictor of treatment success: recovery from atypical AN was 4.3 times (95% confidence interval [1.1, 17.5]) as likely as recovery from typical AN. Overall, our findings indicate that a broader definition of AN may dilute the prognostic value of the diagnosis, and therefore, ICD-11 should retain its distinction between typical and atypical AN. PMID- 26010208 TI - Paraneoplastic neuromyelitis optica spectrum disorders: three new cases and a review of the literature. AB - Neuromyelitis optica spectrum disorders (NMOSD) occasionally develop in patients with tumor in relation to aquaporin-4 IgG (AQP4-IgG), representing a new paraneoplastic phenomenon. We reported three patients with paraneoplastic NMOSD and provided a comprehensive review of the literature. A total of 34 cases with paraneoplastic NMOSD were identified from our own case database (n = 3) and the previous literature (n = 31). The median age at NMOSD-related symptom onset was 50.5 years, and 91% of the cases were female. 11 (32%) cases had breast carcinoma. In 15 (44%) cases, NMOSD-related symptoms preceded tumor detection [median, 4 (range 1-180) months], and in 19 (56%) cases, symptoms followed tumor detection [median, 12 (range 3-180) months]. 5/14 (36%) cases had hiccups and vomiting as the initial symptoms, with the involvement of medulla oblongata. In 10/14 (71%) cases, cervical spinal cord was involved. In contrast to idiopathic NMO, NMOSD is more likely to be paraneoplastic than in patients aged over 50 years at the onset of symptoms, especially for female patients. Breast carcinoma is the most common tumor associated with paraneoplastic NMOSD, accounting for nearly a third of all types of tumors. Paraneoplastic NMOSD usually involves medulla oblongata and cervical spinal cord. We recommend adding AQP4-IgG as an onconeural antibody, but its clinical utility warrants further investigations. PMID- 26010209 TI - Dynamic change in magnetic resonance imaging of patients with neuromyelitis optica. AB - OBJECTIVE: To analyze changes in magnetic resonance imaging (MRI) of spinal cord lesions in neuromyelitis optica (NMO) and the correlation between segmental length of spinal cord lesions and expanded disability status scale (EDSS) scores. METHODS: Twenty-five patients with confirmed NMO were examined from the Second Affiliated Hospital of Guangzhou Medical University, China. The information collected included their treatment, MRI, laboratory tests, and EDSS scores at different stages. RESULTS: All cases exhibited spinal cord lesions, with 23 (92%) having longitudinally extensive transverse myelitis (extending >=3 vertebral segments). There was a positive correlation between segmental length of spinal cord lesions and EDSS scores: during the acute phase, r = 0.430 (P = 0.032); during remission, r = 0.605 (P = 0.002). Enlarged spinal cord lesions and swelling were found in 18 cases (72%) during the acute phase, and 4 cases (16%, P = 0.000) after 6 months of treatment. Lesion enhancements were found in 17 cases (68%) during the acute phase, and 8 cases (32%, P = 0.023) after 6 months of treatment. Leptomeningeal enhancement was found in three cases during the acute phase, which disappeared after treatment. Atrophy of spinal cord lesions occurred in two cases. Change in lesions was statistically significant (P = 0.006) after 12 months of treatment. CONCLUSION: Positive correlation was found between segmental length of spinal cord lesions and EDSS scores, which was more significant during remission. After 6 months of regular treatment, restorative changes compared with the acute phase were found by MRI. PMID- 26010210 TI - Hydrocephalus after decompressive craniectomy for malignant hemispheric cerebral infarction. AB - PURPOSE: Several studies have investigated the incidence and risk factors of hydrocephalus after decompressive craniectomy (DC) for malignant hemispheric cerebral infarction. However, the results are controversial. Therefore, the following is a retrospective cohort study to determine the incidence and risk factors of hydrocephalus after DC for malignant hemispheric cerebral infarction. MATERIALS AND METHODS: From January 2004 to June 2014, patients at two medical centres in south-west China, who underwent DC for malignant hemispheric cerebral infarction, were included. The patients' clinical and radiologic findings were retrospectively reviewed. A chi-square test, Mann-Whitney U-test and logistic regression model were used to identify the risk factors. RESULTS: A total of 128 patients were included in the study. The incidence of ventriculomegaly and shunt dependent hydrocephalus were 42.2% (54/128) and 14.8% (19/128), respectively. Lower preoperative Glasgow Coma Scale (GCS) score and presence of subarachnoid haemorrhage (SAH) were factors significantly associated with the development of post-operative hydrocephalus after DC. CONCLUSIONS: Cerebral infarction patients receiving DC have a moderate tendency to suffer from post-operative hydrocephalus. A poor GCS score and the presence of SAH were significantly associated with the development of hydrocephalus after DC. PMID- 26010211 TI - Effects of electromagnetic field (PEMF) exposure at different frequency and duration on the peripheral nerve regeneration: in vitro and in vivo study. AB - PURPOSE: The purpose was to clarify the influence of frequency and exposure time of pulsed electromagnetic fields (PEMF) on the peripheral nerve regeneration. MATERIALS AND METHODS: Immortalized rat Schwann cells (iSCs) (1 * 10(2)/well) were exposed at four different conditions in 1 mT (50 Hz 1 h/d, 50 Hz 12 h/d, 150 Hz 1 h/d and 150 Hz 12h/d). Cell proliferation, mRNA expression of S100 and brain derived neurotrophic factor (BDNF) were analyzed. Sprague-Dawley rats (200-250 g) were divided into six groups (n = 10 each): control, sham, 50 Hz 1 h/d, 50 Hz 12 h/d, 150 Hz 1 h/d and 150 Hz 12 Hr/d. Mental nerve was crush-injured and exposed at four different conditions in 1 mT (50 Hz 1 Hr/d, 50 Hz 12 Hr/d, 150 Hz 1 h/d and 150 Hz 12 h/d). Nerve regeneration was evaluated with functional test, histomorphometry and retrograde labeling of trigeminal ganglion. RESULTS: iSCs proliferation with 50 Hz, 1 h/d was increased from fourth to seventh day; mRNA expression of S100 and BDNF was significantly increased at the same condition from first week to third week (p < .05 vs. control); difference score was increased at the second and third week, and gap score was increased at the third under 50 Hz 1 h PEMF compared with control while other conditions showed no statistical meaning. Axon counts and retrograde labeled neurons were significantly increased under PEMF of four different conditions compared with control. Although there was no statistical difference, 50 Hz, 1 h PEMF showed highest regeneration ability than other conditions. CONCLUSION: PEMF enhanced peripheral nerve regeneration, and that it may be due to cell proliferation and increase in BDNF and S100 gene expression. PMID- 26010212 TI - Plasma antioxidant status and motor features in de novo Chinese Parkinson's disease patients. AB - PURPOSE: This study aimed to explore plasma antioxidant status in de novo Chinese Parkinson's disease (PD) patients and investigate its relationship with specific motor features of PD. PATIENTS AND METHODS: Sixty-four de novo Chinese PD patients and 40 age- and sex-matched healthy controls were recruited. Each motor feature of PD patients was assessed by unified Parkinson's disease rating scale. Plasma antioxidant status, including plasma level of glutathione (GSH) and plasma activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), was detected using enzyme-linked immunosorbent assay. The relationship between the plasma antioxidant status and motor features of PD was evaluated by Spearman's coefficient. RESULTS: Plasma GSH level and plasma activities of GSH Px, CAT and SOD of PD patients were lower than those of healthy controls. Moreover, the declining activity of plasma CAT was related with the increasing mean postural instability and gait disorder (PIGD) score and growing age. In contrast, the severity of tremor was positively correlated with plasma SOD activity. CONCLUSION: Our study demonstrates that the plasma antioxidant status is impaired in de novo Chinese PD patients. The complex relationship between the plasma antioxidant status and different motor features indicates that the antioxidant mechanisms underlying tremor and PIGD of PD may be different. PMID- 26010213 TI - Factors modulating social influence on spatial choice in rats. AB - Three experiments examined the conditions under which the spatial choices of rats searching for food are influenced by the choices made by other rats. Model rats learned a consistent set of baited locations in a 5 * 5 matrix of locations, some of which contained food. In Experiment 1, subject rats could determine the baited locations after choosing 1 location because all of the baited locations were on the same side of the matrix during each trial (the baited side varied over trials). Under these conditions, the social cues provided by the model rats had little or no effect on the choices made by the subject rats. The lack of social influence on choices occurred despite a simultaneous social influence on rats' location in the testing arena (Experiment 2). When the outcome of the subject rats' own choices provided no information about the positions of other baited locations, on the other hand, social cues strongly controlled spatial choices (Experiment 3). These results indicate that social information about the location of food influences spatial choices only when those cues provide valid information that is not redundant with the information provided by other cues. This suggests that social information is learned about, processed, and controls behavior via the same mechanisms as other kinds of stimuli. PMID- 26010214 TI - Cranio-facial clefts in pre-hispanic America. AB - Among the representations of congenital malformations in Moche ceramic art, cranio-facial clefts have been portrayed in pottery found in Moche burials. These pottery vessels were used as domestic items during lifetime and funerary offerings upon death. The aim of this study was to examine archeological evidence for representations of cranio-facial cleft malformations in Moche vessels. Pottery depicting malformations of the midface in Moche collections in Lima-Peru were studied. The malformations portrayed on pottery were analyzed using the Tessier classification. Photographs were authorized by the Larco Museo.Three vessels were observed to have median cranio-facial dysraphia in association with midline cleft of the lower lip with cleft of the mandible. ML001489 portrays a median cranio-facial dysraphia with an orbital cleft and a midline cleft of the lower lip extending to the mandible. ML001514 represents a median facial dysraphia in association with an orbital facial cleft and a vertical orbital dystopia. ML001491 illustrates a median facial cleft with a soft tissue cleft. Three cases of midline, orbital and lateral facial clefts have been portrayed in Moche full-figure portrait vessels. They represent the earliest registries of congenital cranio-facial malformations in ancient Peru. PMID- 26010215 TI - How Does the Methodology of 3D Structure Preparation Influence the Quality of pKa Prediction? AB - The acid dissociation constant is an important molecular property, and it can be successfully predicted by Quantitative Structure-Property Relationship (QSPR) models, even for in silico designed molecules. We analyzed how the methodology of in silico 3D structure preparation influences the quality of QSPR models. Specifically, we evaluated and compared QSPR models based on six different 3D structure sources (DTP NCI, Pubchem, Balloon, Frog2, OpenBabel, and RDKit) combined with four different types of optimization. These analyses were performed for three classes of molecules (phenols, carboxylic acids, anilines), and the QSPR model descriptors were quantum mechanical (QM) and empirical partial atomic charges. Specifically, we developed 516 QSPR models and afterward systematically analyzed the influence of the 3D structure source and other factors on their quality. Our results confirmed that QSPR models based on partial atomic charges are able to predict pKa with high accuracy. We also confirmed that ab initio and semiempirical QM charges provide very accurate QSPR models and using empirical charges based on electronegativity equalization is also acceptable, as well as advantageous, because their calculation is very fast. On the other hand, Gasteiger-Marsili empirical charges are not applicable for pKa prediction. We later found that QSPR models for some classes of molecules (carboxylic acids) are less accurate. In this context, we compared the influence of different 3D structure sources. We found that an appropriate selection of 3D structure source and optimization method is essential for the successful QSPR modeling of pKa. Specifically, the 3D structures from the DTP NCI and Pubchem databases performed the best, as they provided very accurate QSPR models for all the tested molecular classes and charge calculation approaches, and they do not require optimization. Also, Frog2 performed very well. Other 3D structure sources can also be used but are not so robust, and an unfortunate combination of molecular class and charge calculation approach can produce weak QSPR models. Additionally, these 3D structures generally need optimization in order to produce good quality QSPR models. PMID- 26010216 TI - Do time-averaged, whole-building, effective volatile organic compound (VOC) emissions depend on the air exchange rate? A statistical analysis of trends for 46 VOCs in U.S. offices. AB - We used existing data to develop distributions of time-averaged air exchange rates (AER), whole-building 'effective' emission rates of volatile organic compounds (VOC), and other variables for use in Monte Carlo analyses of U.S. offices. With these, we explored whether long-term VOC emission rates were related to the AER over the sector, as has been observed in the short term for some VOCs in single buildings. We fit and compared two statistical models to the data. In the independent emissions model (IEM), emissions were unaffected by other variables, while in the dependent emissions model (DEM), emissions responded to the AER via coupling through a conceptual boundary layer between the air and a lumped emission source. For 20 of 46 VOCs, the DEM was preferable to the IEM and emission rates, though variable, were higher in buildings with higher AERs. Most oxygenated VOCs and some alkanes were well fit by the DEM, while nearly all aromatics and halocarbons were independent. Trends by vapor pressure suggested multiple mechanisms could be involved. The factors of temperature, relative humidity, and building age were almost never associated with effective emission rates. Our findings suggest that effective emissions in real commercial buildings will be difficult to predict from deterministic experiments or models. PMID- 26010217 TI - Atmospheric Sink of (E)-3-Hexen-1-ol, (Z)-3-Hepten-1-ol, and (Z)-3-Octen-1-ol: Rate Coefficients and Mechanisms of the OH-Radical Initiated Degradation. AB - A kinetic study of the gas-phase reactions of OH radicals with three unsaturated biogenic alcohols, (E)-3-hexen-1-ol, (Z)-3-hepten-1-ol, and (Z)-3-octen-1-ol, has been performed. The rate coefficients obtained are (in units of 10(-10) cm(3) molecule(-1) s(-1)) k1 (OH + (E)-CH2(OH)CH2CH?CHCH2CH3) = (1.14 +/- 0.14), k2 (OH + (Z)-CH2(OH)CH2CH?CHCH2CH2CH3) = (1.28 +/- 0.23), and k3 (OH + (Z) CH2(OH)CH2CH?CHCH2CH2CH2CH3) = (1.49 +/- 0.35). In addition, a product study on the reactions of OH with (E)-3-hexen-1-ol and (Z)-3-hepten-1-ol is reported. All the experiments were performed at (298 +/- 2) K and 1 atm of NOx-free air in a 1080 L photoreactor with in situ FTIR detection of organics. This work constitutes the first kinetic study of the reactions of OH radicals with (Z)-3 hepten-1-ol and (Z)-3-octen-1-ol as well as the first determination of the fate of the hydroxy alkoxy radicals formed in the title reactions. An analysis of the available rates of addition of OH and Cl to the double bond of different unsaturated alcohols at 298 K has shown that they can be related by the expression log kOH = (0.29 +/- 0.04) log kCl - 10.8. The atmospheric lifetimes of the alcohols studies were estimated to be around 1 h for reaction with OH radicals. The products formed in the title reactions are mainly carbonylic compounds that can contribute to the formation of ozone and PANs-type compounds in the troposphere. PMID- 26010218 TI - The microwell-mesh: A novel device and protocol for the high throughput manufacturing of cartilage microtissues. AB - Microwell platforms are frequently described for the efficient and uniform manufacture of 3-dimensional (3D) multicellular microtissues. Multiple partial or complete medium exchanges can displace microtissues from discrete microwells, and this can result in either the loss of microtissues from culture, or microtissue amalgamation when displaced microtissues fall into common microwells. Herein we describe the first microwell platform that incorporates a mesh to retain microtissues within discrete microwells; the microwell-mesh. We show that bonding a nylon mesh with an appropriate pore size over the microwell openings allows single cells to pass through the mesh into the microwells during the seeding process, but subsequently retains assembled microtissues within discrete microwells. To demonstrate the utility of this platform, we used the microwell mesh to manufacture hundreds of cartilage microtissues, each formed from 5 * 10(3) bone marrow-derived mesenchymal stem/stromal cells (MSC). The microwell mesh enabled reliable microtissue retention over 21-day cultures that included multiple full medium exchanges. Cartilage-like matrix formation was more rapid and homogeneous in microtissues than in conventional large diameter control cartilage pellets formed from 2 * 10(5) MSC each. The microwell-mesh platform offers an elegant mechanism to retain microtissues in microwells, and we believe that this improvement will make this platform useful in 3D culture protocols that require multiple medium exchanges, such as those that mimic specific developmental processes or complex sequential drug exposures. PMID- 26010219 TI - Early panretinal abnormalities on fundus autofluorescence and spectral domain optical coherence tomography after intravitreal ocriplasmin. PMID- 26010220 TI - The VCU Pressure Ulcer Summit: Collaboration to Operationalize Hospital-Acquired Pressure Ulcer Prevention Best Practice Recommendations. AB - This executive summary reports outcomes of an interprofessional collaboration between experts in pressure ulcer prevention, bedside clinicians, regulatory agencies, quality improvement, informatics experts, and professional nursing organizations. The goal of the collaboration was to develop a framework to assist facilities to operationalize best practice recommendations to sustain organizational culture change in hospital-acquired pressure ulcer prevention, to develop a hospital-acquired pressure ulcer severity score, and to address topics related to the unavoidable pressure ulcer. PMID- 26010221 TI - An Unreported Congenital Anomaly: Aneurysm of the Lateral Half of the Mitral Valve. AB - This case draws our attention to a new type of mitral valve anomaly, which seems to be congenital. A 42-year-old man with symptomatic primary severe mitral regurgitation was admitted to our hospital. Echocardiography revealed an aneurysm of the half of the valve, on the anterolateral commissure side, with significant excess tissue. The other half of the valve was normal. The two parts seemed to be separated by a continuous fibrous raphe. The anterolateral papillary muscle was hyperplasic and gave the main part of chordae tendinae. PMID- 26010222 TI - Effectiveness of an Antimicrobial Stewardship Approach for Urinary Catheter Associated Asymptomatic Bacteriuria. AB - IMPORTANCE: Overtreatment of asymptomatic bacteriuria (ASB) in patients with urinary catheters remains high. Health care professionals have difficulty differentiating cases of ASB from catheter-associated urinary tract infections. OBJECTIVES: To evaluate the effectiveness and sustainability of an intervention to reduce urine culture ordering and antimicrobial prescribing for catheter associated ASB compared with standard quality improvement methods. DESIGN, SETTING, AND PARTICIPANTS: A preintervention and postintervention comparison with a contemporaneous control group from July 2010 to June 2013 at 2 Veterans Affairs health care systems. Study populations were patients with urinary catheters on acute medicine wards and long-term care units and health care professionals who order urine cultures and prescribe antimicrobials. INTERVENTION: A multifaceted guidelines implementation intervention. MAIN OUTCOMES AND MEASURES: The primary outcomes were urine cultures ordered per 1000 bed-days and cases of ASB receiving antibiotics (overtreatment) during intervention and maintenance periods compared with baseline at both sites. Patient-level analysis of inappropriate antimicrobial use adjusted for individual covariates. RESULTS: Study surveillance included 289,754 total bed-days. The overall rate of urine culture ordering decreased significantly during the intervention period (from 41.2 to 23.3 per 1000 bed-days; incidence rate ration [IRR], 0.57; 95% CI, 0.53-0.61) and further during the maintenance period (to 12.0 per 1000 bed-days; IRR, 0.29; 95% CI, 0.26 0.32) (P < .001 for both). At the comparison site, urine cultures ordered did not change significantly across all 3 periods. There was a significant difference in the number of urine cultures ordered per month over time when comparing the 2 sites using longitudinal linear regression (P < .001). Overtreatment of ASB at the intervention site fell significantly during the intervention period (from 1.6 to 0.6 per 1000 bed-days; IRR, 0.35; 95% CI, 0.22-0.55), and these reductions persisted during the maintenance period (to 0.4 per 1000 bed-days; IRR, 0.24; 95% CI, 0.13-0.42) (P < .001 for both). Overtreatment of ASB at the comparison site was similar across all periods (odds ratio, 1.32; 95% CI, 0.69-2.52). When analyzed by type of ward, the decrease in ASB overtreatment was significant in long-term care. CONCLUSIONS AND RELEVANCE: A multifaceted intervention targeting health care professionals who diagnose and treat patients with urinary catheters reduced overtreatment of ASB compared with standard quality improvement methods. These improvements persisted during a low-intensity maintenance period. The impact was more pronounced in long-term care, an emerging domain for antimicrobial stewardship. PMID- 26010223 TI - Hospital readmissions of patients with heart failure: the impact of hospital and primary care organizational factors in Northern Italy. AB - BACKGROUND: Primary health care is essential for an appropriate management of heart failure (HF), a disease which is a major clinical and public health issue and a leading cause of hospitalization. The aim of this study was to evaluate the impact of different organizational factors on readmissions of patients with HF. METHODS: The study population included elderly resident in the Local Health Authority of Bologna (Northern Italy) and discharged with a diagnosis of HF from January to December 2010. Unplanned hospital readmissions were measured in four timeframes: 30 (short-term), 90 (medium-term), 180 (mid-long-term), and 365 days (long-term). Using multivariable multilevel Poisson regression analyses, we investigated the association between readmissions and organizational factors (discharge from a cardiology department, general practitioners' monodisciplinary organizational arrangement, and implementation of a specific HF care pathway). RESULTS: The 1873 study patients had a median age of 83 years (interquartile range 77-87) and 55.5% were females; 52.0% were readmitted to the hospital for any reason after a year, while 20.1% were readmitted for HF. The presence of a HF care pathway was the only factor significantly associated with a lower risk of readmission for HF in the short-, medium-, mid-long- and long-term period (short term: IRR [incidence rate ratio]=0.57, 95%CI [confidence interval]=0.35-0.92; medium-term: IRR=0.70, 95%CI=0.51-0.96; mid-long-term: IRR=0.79, 95%CI=0.64-0.98; long-term: IRR=0.82, 95%CI=0.67-0.99), and with a lower risk of all-cause readmission in the short-term period (IRR=0.73, 95%CI=0.57-0.94). CONCLUSION: Our study shows that the HF care specific pathway implemented at the primary care level was associated with lower readmission rate for HF in each timeframe, and also with lower readmission rate for all causes in the short-term period. Our results suggest that the engagement of primary care professionals starting from the early post-discharge period may be relevant in the management of patients with HF. PMID- 26010224 TI - Gap Arthroplasty versus Interpositional Arthroplasty for Temporomandibular Joint Ankylosis: A Meta-Analysis. AB - Gap arthroplasty (GA) and interpositional arthroplasty (IA) are widely used for the treatment of temporomandibular joint ankylosis (TMJA). However, controversy remains as to whether IA is superior to GA. PubMed, EMBASE, the Cochrane Library, the Web of science and the China National Knowledge Infrastructure were searched for literature regarding these procedures (published from 1946 to July 28, 2014). A study was included in this analysis if it was: (1) a randomized controlled trial or non-randomized observational cohort study; (2) comparing the clinical outcomes between GA and IA with respect to the maximal incisal opening (MIO) and reankylosis; (3) with a follow-up period of at least 12 months. The methodological quality of the included studies was evaluated according to the Newcastle-Ottawa Scale Eight non-randomized observational cohort studies with 272 patients were included. All the statistical analyses were performed using the RevMan 5.3 and Stat 12. The pooled analysis showed no significant difference in the incidence of reankylosis between the IA group (13/120) and the GA group (29/163) (RR= 0.67, 95% CI=0.38 to 1.16; Z=1.43, p=0.15). The IA group showed a significantly larger MIO than the GA group (MD=1.96, 95% CI=0.21 to 3.72, Z=2.19, p=0.03, I(2)=0%). In conclusion, patients with TMJA could benefit more from IA than GA, with a larger MIO and a similar incidence of reankylosis. IA shows to be an adequate option in the treatment of TMJA based on the results of maximal incisal opening. PMID- 26010225 TI - A member of the Phosphate transporter 1 (Pht1) family from the arsenic hyperaccumulating fern Pteris vittata is a high-affinity arsenate transporter. AB - Pteris vittata exhibits enhanced arsenic uptake, but the corresponding mechanisms are not well known. The prevalent form of arsenic in most soils is arsenate, which is a phosphate analog and a substrate for Phosphate transporter 1 (Pht1) transporters. Herein we identify and characterize three P. vittata Pht1 transporters. Pteris vittata Pht1 cDNAs were isolated and characterized via heterologous expression in Saccharomyces cerevisiae (yeast) and Nicotiana benthamiana leaves. Expression of the PvPht1 loci in P. vittata gametophytes was also examined in response to phosphate deficiency and arsenate exposure. Expression of each of the PvPht1 cDNAs complemented the phosphate uptake defect of a yeast mutant. Compared with yeast cells expressing Arabidopsis thaliana Pht1;5, cells expressing PvPht1;3 were more sensitive to arsenate, and accumulated more arsenic. Uptake assays with yeast cells and radiolabeled (32)P revealed that PvPht1;3 and AtPht1;5 have similar affinities for phosphate, but the affinity of PvPht1;3 for arsenate is much greater. In P. vittata gametophytes, PvPht1;3 transcript levels increased in response to phosphate (Pi) deficiency and arsenate exposure. PvPht1;3 is induced by Pi deficiency and arsenate, and encodes a phosphate transporter that has a high affinity for arsenate. PvPht1;3 probably contributes to the enhanced arsenate uptake capacity and affinity exhibited by P. vittata. PMID- 26010226 TI - Polyaspartamide-Polylactide Graft Copolymers with Tunable Properties for the Realization of Fluorescent Nanoparticles for Imaging. AB - Here, the synthesis and the characterization of novel amphiphilic graft copolymers with tunable properties, useful in obtaining polymeric fluorescent nanoparticles for application in imaging, are described. These copolymers are obtained by chemical conjugation of rhodamine B (RhB) moieties, polylactic acid (PLA), and O-(2-aminoethyl)-O'-methyl poly(ethylene glycol) (PEG) on alpha,beta poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA). In particular, PHEA is first functionalized with RhB to obtain PHEA-RhB with a derivatization degree in RhB (DDRhB ) equal to 0.55 mol%. By varying the reaction conditions, different amounts of PLA are grafted on PHEA-RhB to obtain PHEA-RhB-PLA with DDPLA equal to 1.9, 4.0, and 6.2 mol%. Then, PEG chains are grafted on PHEA-RhB-PLA derivatives to obtain PHEA-RhB-PLA-PEG graft copolymers. The preparation of polymeric fluorescent nanoparticles with tunable properties and spherical shape is described by using PHEA-RhB-PLA-PEG with DD in PLA and PEG equal to 4.0 and 4.9 mol%, by following easily scaling up processes, such as emulsion-solvent evaporation and high pressure homogenization (HPH)-solvent evaporation techniques. PMID- 26010227 TI - Editorial Comment from Dr Goh to Usefulness of sonourethrography for penile abscess as a result of xanthogranulomatous granuloma in the corpus cavernosum of an adult: A case report. PMID- 26010228 TI - Assessing the impact of safety monitoring on the efficacy analysis in large Phase III group sequential trials with non-trivial safety event rate. AB - In Phase III clinical trials for life-threatening conditions, some serious but expected adverse events, such as early deaths or congestive heart failure, are often treated as the secondary or co-primary endpoint, and are closely monitored by the Data and Safety Monitoring Committee (DSMC). A naive group sequential design (GSD) for such a study is to specify univariate statistical boundaries for the efficacy and safety endpoints separately, and then implement the two boundaries during the study, even though the two endpoints are typically correlated. One problem with this naive design, which has been noted in the statistical literature, is the potential loss of power. In this article, we develop an analytical tool to evaluate this negative impact for trials with non trivial safety event rates, particularly when the safety monitoring is informal. Using a bivariate binary power function for the GSD with a random-effect component to account for subjective decision-making in safety monitoring, we demonstrate how, under common conditions, the power loss in the naive design can be substantial. This tool may be helpful to entities such as the DSMCs when they wish to deviate from the prespecified stopping boundaries based on safety measures. PMID- 26010229 TI - A pilot study of the relationship between Doppler-estimated carotid and brachial artery flow and cardiac index. AB - We measured carotid and brachial artery blood flow by Doppler ultrasound in 11 human volunteers, and related these to cardiac index and to each other. The median (IQR [range]) carotid arterial blood flow was 0.334 (0.223-0.381 [0.052 0.563]) l.min(-1) on the right and 0.315 (0.223-0.369 [0.061-0.690]) l.min(-1) on the left. The brachial arterial blood flow was 0.049 (0.033-0.062 [0.015-0.204]) l.min(-1) on the right and 0.039 (0.027-0.054 [0.011-0.116]) on the left. Cardiac index was 3.2 (2.8-3.5 [1.9-5.4]) l.min(-1) .m(-2) . There was a moderate to good correlation between right-and left-sided flows (brachial: rho = 0.45; carotid: rho = 0.567). Brachial and carotid flow had no or a negative correlation with cardiac index (right brachial: rho = -0.145, left brachial: rho = -0.349; right carotid: rho = -0.376, left carotid: rho = -0.285). In contrast to some previous studies, we found that Doppler-estimated peripheral arterial blood flows only show a weak correlation with cardiac index and cannot be used to provide non invasive estimates of cardiac index in man. PMID- 26010230 TI - Steelhead trout Oncorhynchus mykiss metabolic rate is affected by dietary Aloe vera inclusion but not by mounting an immune response against formalin-killed Aeromonas salmonicida. AB - The oxygen consumption (MO2) of two groups of 10 degrees C acclimated steelhead trout Oncorhynchus mykiss was measured for 72 h after they were given a 100 ul kg(-1) intraperitoneal injection of formalin-killed Aeromonas salmonicida (ASAL) or phosphate-buffered saline (PBS). In addition, plasma cortisol levels were measured in fish from both groups prior to, and 1 and 3 h after, they were given a 30 s net stress. The first group was fed an unaltered commercial diet for 4 weeks, whereas the second group was fed the same diet but with 0.5% (5 g kg(-1) ) Aloe vera powder added; A. vera has potential as an immunostimulant for use in aquaculture, but its effects on basal and acute phase response (APR)-related metabolic expenditures and stress physiology, are unknown. Injection of ASAL v. PBS had no measurable effect on the MO2 of O. mykiss indicating that the APR in this species is not associated with any net increase in energy expenditure. In contrast, incorporating 0.5% A. vera powder into the feed decreased routine metabolic rate by c. 8% in both injection groups and standard metabolic rate in the ASAL-injected group (by c. 4 mg O2 kg(-1) h(-1) ; 5%). Aloe vera fed fish had resting cortisol levels that were approximately half of those in fish on the commercial diet (c. 2.5 v. 5.0 ng ml(-1) ), but neither this difference nor those post-stress reached statistical significance (P > 0.05). PMID- 26010232 TI - Diaries and memories following an ICU stay: a 2-month follow-up study. AB - BACKGROUND: Many patients lack a clear recollection from their stay in the intensive care unit (ICU). Diaries have been introduced as a tool to complete memories and reduce the risk of posttraumatic stress disorder (PTSD). AIMS: To describe and compare patients' memories and PTSD in relation to having received and read or not received a diary and patients' experiences of having received and read their diary, without having discussed the contents with ICU staff. DESIGN: Descriptive and comparative. METHODS: Patients received their diaries at ICU discharge. After 2 months patients answered the ICU Memory Tool, a screening instrument for PTSD (PTSS-14) and a questionnaire including space for own comments about the diaries. RESULTS: Of 96 patients, 52(54%) received a diary, 44 did not. Patients with diaries had significantly longer stay and more mechanical ventilation. Of these, 40 patients responded to PTSS-14 and had evaluated and read the diary and 34 patients served as controls. No significant differences were found in presence/absence of memories between these groups. In the diary group patients with emotional memories had lower APACHE. Feelings of being anxious or frightened were more common in the diary-group. At 2 months, 12% scored above cut-off on the PTSS14 with no difference between groups. The diaries were helpful for understanding the ICU-stay. CONCLUSIONS: Diaries seem valuable in understanding what happened, as an act of caring and as a tool for discussion with relatives and friends. Patients valued reading their diaries. None expressed the wish to have read the diary together with a member of staff. The diary and non-diary groups however reported similar memories. RELEVANCE TO CLINICAL PRACTICE: Diaries seem to be valuable in understanding what happened, giving a feeling of trust and for talking about their ICU-stay. As many patients described stressful memories, sessions should be offered with ICU staff. PMID- 26010231 TI - MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging. AB - Ependymal cells (ECs) form a barrier responsible for selective movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. Here, we demonstrate that metabolic and barrier functions in ECs decline significantly during aging in mice. The longevity of these functions in part requires the expression of the myristoylated alanine-rich protein kinase C substrate (MARCKS). Both the expression levels and subcellular localization of MARCKS in ECs are markedly transformed during aging. Conditional deletion of MARCKS in ECs induces intracellular accumulation of mucins, elevated oxidative stress, and lipid droplet buildup. These alterations are concomitant with precocious disruption of ependymal barrier function, which results in the elevation of reactive astrocytes, microglia, and macrophages in the interstitial brain tissue of young mutant mice. Interestingly, similar alterations are observed during normal aging in ECs and the forebrain interstitium. Our findings constitute a conceptually new paradigm in the potential role of ECs in the initiation of various conditions and diseases in the aging brain. PMID- 26010233 TI - Serological evidence of human infection with Pteropine orthoreovirus in Central Vietnam. AB - Pteropine orthoreovirus, potentially of bat origin, has been reported to cause respiratory tract infections among human beings in Southeast Asia. Twelve IgG ELISA-positive cases with antibodies against Pteropine orthoreovirus were detected among 272 human serum samples collected between March and June 2014 from in and around Hue City, Central Vietnam. These 12 cases were IgM ELISA negative. Neutralizing antibodies were also detected among six of these cases with the highest titer of 1:1,280 in 2 cases (both female, 32 and 68 years old, respectively). This is the first report of human infection with Pteropine orthoreovirus in Central Vietnam. These findings indicate the need for surveillance on Pteropine orthoreovirus infections in Southeast Asia to enable prevention and control strategies to be developed should a change in virulence occur. PMID- 26010234 TI - SEGEL: A Web Server for Visualization of Smoking Effects on Human Lung Gene Expression. AB - Cigarette smoking is a major cause of death worldwide resulting in over six million deaths per year. Cigarette smoke contains complex mixtures of chemicals that are harmful to nearly all organs of the human body, especially the lungs. Cigarette smoking is considered the major risk factor for many lung diseases, particularly chronic obstructive pulmonary diseases (COPD) and lung cancer. However, the underlying molecular mechanisms of smoking-induced lung injury associated with these lung diseases still remain largely unknown. Expression microarray techniques have been widely applied to detect the effects of smoking on gene expression in different human cells in the lungs. These projects have provided a lot of useful information for researchers to understand the potential molecular mechanism(s) of smoke-induced pathogenesis. However, a user-friendly web server that would allow scientists to fast query these data sets and compare the smoking effects on gene expression across different cells had not yet been established. For that reason, we have integrated eight public expression microarray data sets from trachea epithelial cells, large airway epithelial cells, small airway epithelial cells, and alveolar macrophage into an online web server called SEGEL (Smoking Effects on Gene Expression of Lung). Users can query gene expression patterns across these cells from smokers and nonsmokers by gene symbols, and find the effects of smoking on the gene expression of lungs from this web server. Sex difference in response to smoking is also shown. The relationship between the gene expression and cigarette smoking consumption were calculated and are shown in the server. The current version of SEGEL web server contains 42,400 annotated gene probe sets represented on the Affymetrix Human Genome U133 Plus 2.0 platform. SEGEL will be an invaluable resource for researchers interested in the effects of smoking on gene expression in the lungs. The server also provides useful information for drug development against smoking related diseases. The SEGEL web server is available online at http://www.chengfeng.info/smoking_database.html. PMID- 26010235 TI - Computer-Delivered Screening and Brief Intervention for Alcohol Use in Pregnancy: A Pilot Randomized Trial. AB - BACKGROUND: Although screening and brief intervention (SBI) for unhealthy alcohol use has demonstrated efficacy in some trials, its implementation has been limited. Technology-delivered approaches are a promising alternative, particularly during pregnancy when the importance of alcohol use is amplified. The present trial evaluated the feasibility and acceptability of an interactive, empathic, video-enhanced, and computer-delivered SBI (e-SBI) plus 3 tailored mailings, and estimated intervention effects. METHODS: We recruited 48 pregnant women who screened positive for alcohol risk at an urban prenatal care clinic. Participants were randomly assigned to the e-SBI plus mailings or to a control session on infant nutrition, and were re-evaluated during their postpartum hospitalization. The primary outcome was 90-day period prevalence abstinence as measured by timeline follow-back interview. RESULTS: Participants rated the intervention as easy to use and helpful (4.7 to 5.0 on a 5-point scale). Blinded follow-up evaluation at childbirth revealed medium-size intervention effects on 90-day period prevalence abstinence (OR = 3.4); similarly, intervention effects on a combined healthy pregnancy outcome variable (live birth, normal birthweight, and no neonatal intensive care unit stay) were also of moderate magnitude in favor of e-SBI participants (OR = 3.3). As expected in this intentionally underpowered pilot trial, these effects were nonsignificant (p = 0.19 and 0.09, respectively). CONCLUSIONS: This pilot trial demonstrated the acceptability and preliminary efficacy of e-SBI plus tailored mailings for alcohol use in pregnancy. These findings mirror the promising results of other trials using a similar approach and should be confirmed in a fully powered trial. PMID- 26010236 TI - Utility of Exercise Testing and Adenosine Response for Risk Assessment in Children with Wolff-Parkinson-White Syndrome. AB - BACKGROUND: We aimed to determine the correlation between noninvasive testing (exercise stress testing [EST] and adenosine responsiveness of accessory pathway [AP] ) and invasive electrophysiology study (EPS) for assessment antegrade conduction of the AP in Wolff-Parkinson-White syndrome. PATIENTS AND METHOD: This prospective, observational study enrolled 40 children (58% male children, median age of 13 years, and median weight of 47.5 kg) with Wolff-Parkinson-White syndrome. Conduction through the AP to a cycle length of <=250 ms was considered rapid or high-risk; otherwise, patients were nonrapid or low-risk. RESULTS: The sudden disappearance of the delta-wave was seen in 10 cases (25%) during EST. Accessory pathway was found to be high-risk in 13 cases (13/40, 32.5%) while the accessory path was identified as low-risk in 27 cases; however, six patients (15%) had blocked AP conduction with adenosine during EPS. Low-risk classification by EST alone to identify patients with nonrapid conduction in baseline EPS had a specificity of 93% and a positive predictive value of 90% (accuracy 54%). Blocked AP conduction with adenosine as a marker of nonrapid baseline AP conduction had a specificity of 93% and a positive predictive value of 84%. Finally, AP was adenosine nonresponsive in the majority of patients (28/30, 93%) with persistent delta-waves, 40% of those who had a sudden disappearance of delta-waves had an adenosine-responsive AP (P value: .028). CONCLUSION: Abrupt loss of preexcitation during EST and blocked AP conduction with adenosine had high specificity and positive predictive value for nonrapid and low-risk antegrade conduction during baseline invasive EPS. Successful risk stratification of pediatric patients with Wolff-Parkinson-White is possible through the use of EST and the adenosine responsiveness of AP. PMID- 26010237 TI - A cohort study of psychosocial work stressors on work ability among Brazilian hospital workers. AB - BACKGROUND: Hospital work is characterized by stressors that can influence work ability. The present study aims to assess the association between psychosocial work stressors and changes in work ability in a group of Brazilian hospital employees. METHODS: From 1,022 workers included in a 3-year cohort started in 2009, 423 (41.4%) returned the applied questionnaires in 2012. Changes in work ability were considered as the dependent variable and the investigated psychosocial work stressors as independent variables. Logistic regression models adjusted for potential con-founders (demographic, occupational features, social support, overcommitment, and situations liable to cause pain/injury). RESULTS: High levels of exposure to psychosocial work stressors were significantly associated with decreased work ability: job strain (OR = 2.81), effort-reward imbalance (OR = 3.21). CONCLUSION: Strategies to reduce psychosocial work stressors should be considered to maintain hospital employees' work ability. Such strategies have implications for institutional and social policies and might be included in quality management programs. PMID- 26010238 TI - Polymeric AIE-based nanoprobes for biomedical applications: recent advances and perspectives. AB - The development of polymeric luminescent nanomaterials for biomedical applications has recently attracted a large amount of attention due to the remarkable advantages of these materials compared with small organic dyes and fluorescent inorganic nanomaterials. Among these polymeric luminescent nanomaterials, polymeric luminescent nanomaterials based on dyes with aggregation induced emission (AIE) properties should be of great research interest due to their unique AIE properties, the designability of polymers and their multifunctional potential. In this review, the recent advances in the design and biomedical applications of polymeric luminescent nanomaterials based on AIE dyes is summarized. Various design strategies for incorporation of these AIE dyes into polymeric systems are included. The potential biomedical applications such as biological imaging, and use in biological sensors and theranostic systems of these polymeric AIE-based nanomaterials have also been highlighted. We trust this review will attract significant interest from scientists from different research fields in chemistry, materials, biology and interdisciplinary areas. PMID- 26010239 TI - Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS. AB - This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters. PMID- 26010240 TI - Effect of resection depth of early glottic cancer on vocal outcome: an optimized finite element simulation. AB - OBJECTIVES/HYPOTHESIS: To test the hypothesis that subligamental cordectomy produces superior acoustic outcome than subepithelial cordectomy for early (T1-2) glottic cancer that requires complete removal of the superficial lamina propria but does not involve the vocal ligament. STUDY DESIGN: Computer simulation. METHODS: A computational tool for vocal fold surgical planning and simulation (the National Center for Voice and Speech Phonosurgery Optimizer-Simulator) was used to evaluate the acoustic output of alternative vocal fold morphologies. Four morphologies were simulated: normal, subepithelial cordectomy, subligamental cordectomy, and transligamental cordectomy (partial ligament resection). The primary outcome measure was the range of fundamental frequency (F0 ) and sound pressure level (SPL). A more restricted F0 -SPL range was considered less favorable because of reduced acoustic possibilities given the same range of driving subglottic pressure and identical vocal fold posturing. RESULTS: Subligamental cordectomy generated solutions covering an F0 -SPL range 82% of normal for a rectangular vocal fold. In contrast, transligamental and subepithelial cordectomies produced significantly smaller F0 -SPL ranges, 57% and 19% of normal, respectively. CONCLUSION: This study illustrates the use of the Phonosurgery Optimizer-Simulator to test a specific hypothesis regarding the merits of two surgical alternatives. These simulation results provide theoretical support for vocal ligament excision with maximum muscle preservation when superficial lamina propria resection is necessary but the vocal ligament can be spared on oncological grounds. The resection of more tissue may paradoxically allow the eventual recovery of a better speaking voice, assuming glottal width is restored. Application of this conclusion to surgical practice will require confirmatory clinical data. LEVEL OF EVIDENCE: N/A. PMID- 26010241 TI - Microelectrode recordings and deep brain stimulation surgery--reasoned discussion? PMID- 26010242 TI - Primary Angiosarcoma of the Breast with Pulmonary Metastasis. PMID- 26010243 TI - What are the Costs and Benefits of Providing Comprehensive Seven-day Services for Emergency Hospital Admissions? AB - The English National Health Service is moving towards providing comprehensive 7 day hospital services in response to higher death rates for emergency weekend admissions. Using Hospital Episode Statistics between 1st April 2010 and 31st March 2011 linked to all-cause mortality within 30 days of admission, we estimate the number of excess deaths and the loss in quality-adjusted life years associated with emergency weekend admissions. The crude 30-day mortality rate was 3.70% for weekday admissions and 4.05% for weekend admissions. The excess weekend death rate equates to 4355 (risk adjusted 5353) additional deaths each year. The health gain of avoiding these deaths would be 29 727-36 539 quality-adjusted life years per year. The estimated cost of implementing 7-day services is L1.07-L1.43 bn, which exceeds by L339-L831 m the maximum spend based on the National Institute for Health and Care Excellence threshold of L595 m-L731 m. There is as yet no clear evidence that 7-day services will reduce weekend deaths or can be achieved without increasing weekday deaths. The planned cost of implementing 7 day services greatly exceeds the maximum amount that the National Health Service should spend on eradicating the weekend effect based on current evidence. Policy makers and service providers should focus on identifying specific service extensions for which cost-effectiveness can be demonstrated. PMID- 26010244 TI - Multi-Faceted Characterization of a Novel LuxR-Repressible Promoter Library for Escherichia coli. AB - The genetic elements regulating the natural quorum sensing (QS) networks of several microorganisms are widely used in synthetic biology to control the behaviour of single cells and engineered bacterial populations via ad-hoc constructed synthetic circuits. A number of novel engineering-inspired biological functions have been implemented and model systems have also been constructed to improve the knowledge on natural QS systems. Synthetic QS-based parts, such as promoters, have been reported in literature, to provide biological components with functions that are not present in nature, like modified induction logic or activation/repression by additional molecules. In this work, a library of promoters that can be repressed by the LuxR protein in presence of the QS autoinducer N-3-oxohexanoyl-L-homoserine lactone (AHL) was reported for Escherichia coli, to expand the toolkit of genetic parts that can be used to engineer novel synthetic QS-based systems. The library was constructed via polymerase chain reaction with highly constrained degenerate oligonucleotides, designed according to the consensus -35 and -10 sequences of a previously reported constitutive promoter library of graded strength, to maximize the probability of obtaining functional clones. All the promoters have a lux box between the -35 and -10 regions, to implement a LuxR-repressible behaviour. Twelve unique library members of graded strength (about 100-fold activity range) were selected to form the final library and they were characterized in several genetic contexts, such as in different plasmids, via different reporter genes, in presence of a LuxR expression cassette in different positions and in response to different AHL concentrations. The new obtained regulatory parts and corresponding data can be exploited by synthetic biologists to implement an artificial AHL dependent repression of transcription in genetic circuits. The target transcriptional activity can be selected among the available library members to meet the design specifications of the biological system. PMID- 26010245 TI - Isotopic evidence of weaning in hunter-gatherers from the late holocene in Lake Salitroso, Patagonia, Argentina. AB - OBJECTIVES: The timing and duration of breastfeeding and weaning in past hunter gatherer populations are discussed based on the results of stable carbon and nitrogen isotope analyses undertaken on a Late Holocene skeletal sample from Lake Salitroso in the Patagonian steppe (Argentina). Research in Lake Salitroso is part of a regional project that studies the relationship between hunter-gatherer societies, their organizational systems and the environmental changes during the last 3,000 years in Patagonia. METHODS: The sample included 52 individuals: 33 subadults and 19 adults of both sexes. They were recovered from 24 burial stone structures, locally called chenques, with dates ranging from ca. 800 BP to 350 BP. Ribs were selected for collagen extraction and measurement of (13) C/(12) C and (15) N/(14) N ratios. RESULTS: A delta(13) C mean value of -18.70/00 +/- 0.50/00 was obtained, with a range between -19.80/00 and -17.10/00 whereas delta(15) N recorded a mean of 11.90/00 +/- 1.10/00 with a range between 10.10/00 and 14.80/00. delta(15) N data showed an age-related pattern with particularly marked difference between values for subadults under the age of 4 and older individuals. As opposed to delta(15) N, delta(13) C showed little variation with age. CONCLUSIONS: An early incorporation of supplementary solid food between 0.75 and 2 years of age and a late cessation of breastfeeding at about 5-6 years of age were inferred. This suggests that among this Patagonian hunter-gatherer population weaning was a gradual and lengthy process. These results are consistent with the patterns observed in cross-cultural studies and archaeological samples of hunter-gatherer groups. PMID- 26010246 TI - A Highly Sensitive Diagnostic System for Detecting Dengue Viruses Using the Interaction between a Sulfated Sugar Chain and a Virion. AB - We propose a novel method of detecting trace amounts of dengue virus (DENVs) from serum. Our method is based on the interaction between a sulfated sugar chain and a DENV surface glycoprotein. After capturing DENV with the sulfated sugar chain immobilized gold nanoparticles (SGNPs), the resulting complex is precipitated and viral RNA content is measured using the reverse-transcription quantitative polymerase chain reaction SYBR Green I (RT-qPCR-Syb) method. Sugar chains that bind to DENVs were identified using the array-type sugar chain immobilized chip (Sugar Chip) and surface plasmon resonance (SPR) imaging. Heparin and low molecular-weight dextran sulfate were identified as binding partners, and immobilized on gold nanoparticles to prepare 3 types of SGNPs. The capacity of these SGNPs to capture and concentrate trace amounts of DENVs was evaluated in vitro. The SGNP with greatest sensitivity was tested using clinical samples in Indonesia in 2013-2014. As a result, the novel method was able to detect low concentrations of DENVs using only 6 MUL of serum, with similar sensitivity to that of a Qiagen RNA extraction kit using 140 MUL of serum. In addition, this method allows for multiplex-like identification of serotypes of DENVs. This feature is important for good healthcare management of DENV infection in order to safely diagnose the dangerous, highly contagious disease quickly, with high sensitivity. PMID- 26010247 TI - Successful implementation of a packed red blood cell and fresh frozen plasma transfusion protocol in the surgical intensive care unit. AB - BACKGROUND: Blood product transfusions are associated with increased morbidity and mortality. The purpose of this study was to determine if implementation of a restrictive protocol for packed red blood cell (PRBC) and fresh frozen plasma (FFP) transfusion safely reduces blood product utilization and costs in a surgical intensive care unit (SICU). STUDY DESIGN: We performed a retrospective, historical control analysis comparing before (PRE) and after (POST) implementation of a restrictive PRBC/FFP transfusion protocol for SICU patients. Univariate analysis was utilized to compare patient demographics and blood product transfusion totals between the PRE and POST cohorts. Multivariate logistic regression models were developed to determine if implementation of the restrictive transfusion protocol is an independent predictor of adverse outcomes after controlling for age, illness severity, and total blood products received. RESULTS: 829 total patients were included in the analysis (PRE, n=372; POST, n=457). Despite higher mean age (56 vs. 52 years, p=0.01) and APACHE II scores (12.5 vs. 11.2, p=0.006), mean units transfused per patient were lower for both packed red blood cells (0.7 vs. 1.2, p=0.03) and fresh frozen plasma (0.3 vs. 1.2, p=0.007) in the POST compared to the PRE cohort, respectively. There was no difference in inpatient mortality between the PRE and POST cohorts (7.5% vs. 9.2%, p=0.39). There was a decreased risk of urinary tract infections (OR 0.47, 95%CI 0.28-0.80) in the POST cohort after controlling for age, illness severity and amount of blood products transfused. CONCLUSIONS: Implementation of a restrictive transfusion protocol can effectively reduce blood product utilization in critically ill surgical patients with no increase in morbidity or mortality. PMID- 26010248 TI - Resting Heart Rate Is Not a Good Predictor of a Clustered Cardiovascular Risk Score in Adolescents: The HELENA Study. AB - BACKGROUND: Resting heart rate (RHR) reflects sympathetic nerve activity a significant association between RHR and all-cause and cardiovascular mortality has been reported in some epidemiologic studies. METHODS: To analyze the predictive power and accuracy of RHR as a screening measure for individual and clustered cardiovascular risk in adolescents. The study comprised 769 European adolescents (376 boys) participating in the HELENA cross-sectional study (2006 2008) were included in this study. Measurements on systolic blood pressure, HOMA index, triglycerides, TC/HDL-c, VO2max and the sum of four skinfolds were obtained, and a clustered cardiovascular disease (CVD) risk index was computed. The receiver operating characteristics curve was applied to calculate the power and accuracy of RHR to predict individual and clustered CVD risk factors. RESULTS: RHR showed low accuracy for screening CVD risk factors in both sexes (range 38.5%-54.4% in boys and 45.5%-54.3% in girls). Low specificity's (15.6% 19.7% in boys; 18.1%-20.0% in girls) were also found. Nevertheless, the sensitivities were moderate-to-high (61.4%-89.1% in boys; 72.9%-90.3% in girls). CONCLUSION: RHR is a poor predictor of individual CVD risk factors and of clustered CVD and the estimates based on RHR are not accurate. The use of RHR as an indicator of CVD risk in adolescents may produce a biased screening of cardiovascular health in both sexes. PMID- 26010249 TI - Selective Blockade of Interferon-alpha and -beta Reveals Their Non-Redundant Functions in a Mouse Model of West Nile Virus Infection. AB - Although type I interferons (IFNs) were first described almost 60 years ago, the ability to monitor and modulate the functional activities of the individual IFN subtypes that comprise this family has been hindered by a lack of reagents. The major type I IFNs, IFN-beta and the multiple subtypes of IFN-alpha, are expressed widely and induce their effects on cells by interacting with a shared heterodimeric receptor (IFNAR). In the mouse, the physiologic actions of IFN alpha and IFN-beta have been defined using polyclonal anti-type I IFN sera, by targeting IFNAR using monoclonal antibodies or knockout mice, or using Ifnb-/- mice. However, the corresponding analysis of IFN-alpha has been difficult because of its polygenic nature. Herein, we describe two monoclonal antibodies (mAbs) that differentially neutralize murine IFN-beta or multiple subtypes of murine IFN alpha. Using these mAbs, we distinguish specific contributions of IFN-beta versus IFN-alpha in restricting viral pathogenesis and identify IFN-alpha as the key mediator of the antiviral response in mice infected with West Nile virus. This study thus suggests the utility of these new reagents in dissecting the antiviral and immunomodulatory roles of IFN-beta versus IFN-alpha in murine models of infection, immunity, and autoimmunity. PMID- 26010250 TI - Colonization history, host distribution, anthropogenic influence and landscape features shape populations of white pine blister rust, an invasive alien tree pathogen. AB - White pine blister rust is caused by the fungal pathogen Cronartium ribicola J.C. Fisch (Basidiomycota, Pucciniales). This invasive alien pathogen was introduced into North America at the beginning of the 20th century on pine seedlings imported from Europe and has caused serious economic and ecological impacts. In this study, we applied a population and landscape genetics approach to understand the patterns of introduction and colonization as well as population structure and migration of C. ribicola. We characterized 1,292 samples of C. ribicola from 66 geographic locations in North America using single nucleotide polymorphisms (SNPs) and evaluated the effect of landscape features, host distribution, and colonization history on the structure of these pathogen populations. We identified eastern and western genetic populations in North America that are strongly differentiated. Genetic diversity is two to five times higher in eastern populations than in western ones, which can be explained by the repeated accidental introductions of the pathogen into northeastern North America compared with a single documented introduction into western North America. These distinct genetic populations are maintained by a barrier to gene flow that corresponds to a region where host connectivity is interrupted. Furthermore, additional cryptic spatial differentiation was identified in western populations. This differentiation corresponds to landscape features, such as mountain ranges, and also to host connectivity. We also detected genetic differentiation between the pathogen populations in natural stands and plantations, an indication that anthropogenic movement of this pathogen still takes place. These results highlight the importance of monitoring this invasive alien tree pathogen to prevent admixture of eastern and western populations where different pathogen races occur. PMID- 26010251 TI - Adverse pathology and undetectable ultrasensitive prostate-specific antigen after radical prostatectomy: is adjuvant radiation warranted? AB - OBJECTIVES: To determine if men with adverse pathology but undetectable ultrasensitive (<0.01 ng/mL) PSA are at high-risk for biochemical recurrence (BCR), or if there is a subset of patients at low-risk for whom the benefit of adjuvant radiation therapy might be limited. PATIENTS AND METHODS: We evaluated 411 patients treated with RP from 2001 to 2013 without adjuvant radiation who had an undetectable (<0.01 ng/mL) PSA level after RP but with adverse pathology [positive surgical margins (PSMs), extraprostatic extension (EPE), and/or seminal vesicle invasion (SVI)]. Multivariable Cox regression analyses tested the relationship between pathological characteristics and BCR to identify groups of men at highest risk of early BCR. RESULTS: On multivariable analysis, only pathological Gleason 7 (4 + 3), Gleason >=8, and SVI independently predicted BCR (P = 0.019, P < 0.001, and P = 0.001, respectively), although on two-way analysis men with Gleason 7 (4 + 3) did not have significantly higher rates of BCR compared with patients with Gleason <=6 (log-rank, P = 0.074). Men with either Gleason >=8 (with PSMs or EPE) or SVI (15% of the cohort) defined a high-risk group vs men without these characteristics (3-year BCR risk of 50.4% vs 11.9%, log-rank, P < 0.001). CONCLUSIONS: Among men with adverse pathology but an undetectable (<0.01 ng/mL) PSA level after RP, the benefits of adjuvant radiation are probably limited except for men with Gleason 8-10 (with PSMs or EPE) or SVI who are at high-risk of early BCR. PMID- 26010252 TI - MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy. AB - MDI 301 is a novel 9-cis retinoic acid derivative in which the terminal carboxylic acid group has been replaced by a picolinate ester. MDI 301, a retinoic acid receptor-alpha - agonist, suppressed the growth of several human myeloid leukemia cell lines (HL60, NB4, OCI-M2, and K562) in vitro and induced cell-substrate adhesion in conjunction with upregulation of CD11b. Tumor growth in HL60-injected athymic nude mice was reduced. In vitro, MDI 301 was comparable to all-trans retinoic acid (ATRA) whereas in vivo, MDI 301 was slightly more efficacious than ATRA. Most importantly, unlike what was found with ATRA treatment, MDI 301 did not induce a cytokine response in the treated animals and the severe inflammatory changes and systemic toxicity seen with ATRA did not occur. A retinoid with these characteristics might be valuable in the treatment of promyelocytic leukemia, or, perhaps, other forms of myeloid leukemia. PMID- 26010253 TI - Cellular Antisense Activity of PNA-Oligo(bicycloguanidinium) Conjugates Forming Self-Assembled Nanoaggregates. AB - A series of peptide nucleic acid-oligo(bicycloguanidinium) (PNA-BGn ) conjugates were synthesized and characterized in terms of cellular antisense activity by using the pLuc750HeLa cell splice correction assay. PNA-BG4 conjugates exhibited low micromolar antisense activity, and their cellular activity required the presence of a hydrophobic silyl terminal protecting group on the oligo(BG) ligand and a minimum of four guanidinium units. Surprisingly, a nonlinear dose-response with an activity threshold around 3-4 MUM, indicative of large cooperativity, was observed. Supported by light scattering and electron microscopy analyses, we propose that the activity, and thus cellular delivery, of these lipo-PNA-BG4 conjugates is dependent on self-assembled nanoaggregates. Finally, cellular activity was enhanced by the presence of serum. Therefore we conclude that the lipo-BG-PNA conjugates exhibit an unexpected mechanism for cell delivery and are of interest for further in vivo studies. PMID- 26010254 TI - Weight loss interventions for breast cancer survivors: impact of dietary pattern. AB - Body weight management is not emphasized in clinical practice guidelines for breast cancer survivors, reflecting the lack of evidence that weight loss improves prognosis. Even if this situation changes, the optimal design for weight loss interventions is unclear. We conducted a 6-month non-randomized, controlled weight loss intervention in 249 post-menopausal breast cancer survivors. This paper reports effects on two secondary endpoints, change in body weight and composition. Participants were predominantly non-Hispanic whites (89%) with a mean age of 54.9 +/- 9.2 years, a mean BMI of 29.0 +/- 2.6 kg/m: (2) and an average of 43 +/- 5% body fat. Two dietary interventions, low fat or low carbohydrate, were investigated and consisted of a 42 day cycle of menus and recipes. Weight loss counseling and anthropometric assessment were provided at monthly clinic visits. One hundred ninety-two women completed the trial (77% retention). In comparison to the nonintervention control, both intervention arms achieved significant decreases in body weight (12.5%), body fat (27.5%), waist circumference (9.5%), and hip circumference (7.8%) (all p < 0.001) with minimal effects on lean mass (1.3% decrease). Median time to 5 and 10% weight loss was 2 (95% confidence interval = 1 to 3) and 4 (95% confidence interval = 3 to 5) months, respectively, and 23% of participants experienced >= 15% weight loss. Loss of body weight and fat mass was rapid and substantial irrespective of dietary approach when a structured program was provided with monthly anthropometric assessment and weight loss counseling. TRIAL REGISTRATION: ClinicalTrials.gov NCT01315483. PMID- 26010255 TI - Electrothermal pumping with interdigitated electrodes and resistive heaters. AB - Interdigitated electrodes are used in electrokinetic lab-on-a-chip devices for dielectrophoretic trapping and characterization of suspended particles, as well as the production of field-induced fluid flow via AC electroosomosis and electrothermal mechanisms. However, the optimum design for dielectrophoresis, that if symmetrical electrodes, cannot induce bulk electrohydrodynamic pumping. In addition, the mechanism of intrinsic electrothermal pumping is affected by the properties of the fluid, with thermal fields being generated by Joule Heating. This work demonstrates the incorporation of an underlying thin film heater, electrically isolated from the interdigitated electrodes by an insulator layer, to enhance bulk electrothermal pumping. The use of integrated heaters allows the thermal field generation to be controlled independently of the electric field. Numerical simulations are performed to demonstrate the importance of geometrical arrangement of the heater with respect to the interdigitated electrodes, as well as electrode size, spacing, and arrangement. The optimization of such a system is a careful balance between electrokinetics, heat transfer, and fluid dynamics. The heater location and electrode spacing influence the rate of electrothermal pumping significantly more than electrode width and insulator layer thickness. This demonstration will aid in the development of microfluidic electrokinetic systems that want to utilize the advantages associated with electrothermal pumping while simultaneously applying other lab-on-a-chip electrokinetics like dielectrophoresis. PMID- 26010257 TI - New Developments in Liposomal Drug Delivery. PMID- 26010256 TI - Family material hardship and chinese adolescents' problem behaviors: a moderated mediation analysis. AB - In the current study, we examined a moderated mediation model using the risk and resilience framework. Specifically, the impact of family material hardship on adolescent problem behaviors was examined in a Chinese sample; we used the family stress model framework to investigate parental depression and negative parenting as potential mediators of the relation between family material hardship and adolescents' problem behaviors. In addition, based on resilience theory, we investigated adolescents' resilience as a potential protective factor in the development of their internalizing and externalizing problems. Participants included 1,419 Chinese adolescents (mean age = 15.38 years, SD = 1.79) and their primary caregivers. After controlling for covariates (age, gender, location of family residence, and primary caregiver), we found that parental depression and negative parenting mediated the association between family material hardship and adolescents' problem behaviors. Furthermore, the adolescent resilience moderated the relationship between negative parenting and internalizing problems in a protective-stabilizing pattern; in addition, a protective-reactive pattern also emerged when adolescent resilience was examined as a moderator of the relationship between negative parenting and externalizing problems. These findings contribute to a comprehensive understanding of the mechanisms of risk and resilience in youth development. Moreover, the findings have important implications for the prevention of adolescent problem behaviors. PMID- 26010258 TI - Enzymological Characterization of Atm, the First Laccase from Agrobacterium sp. S5-1, with the Ability to Enhance In Vitro digestibility of Maize Straw. AB - Laccase is an enzyme that catalyzes oxidation of phenolic compounds, diamines and aromatic amines. In this study, a novel laccase-like gene (atm) in a ligninolyitic isolate Agrobacterium sp. S5-1 from soil humus was identified and heterologously expressed in Escherichia coli. Atm exhibited its maximal activity at pH 4.5 and at 50 degrees C. This enzyme was tolerant to high temperature, a broad range of pH, heavy metal ions (Co3+, Mn2+, Cu2+ and Ni2+, 20 mM) and all tested organic solvents. Furthermore, Atm significantly (p<0.05) increased dry matter digestibility of maize straw from 23.44% to 27.96% and from 29.53% to 37.10% after 8 or 24 h of digestion and improved acid detergent fiber digestibility from 5.81% to 10.33% and from 12.80% to 19.07% after 8 or 24 h of digestion, respectively. The combination of Atm and fibrolytic enzymes significantly (p<0.05) enhanced neutral detergent fiber digestibility from 19.02% to 24.55% after 24 h of digestion respectively. Results showed treatment with Atm effectively improved in vitro digestibility of maize straw, thus suggesting that Atm has an application potential for bioconversion of lignin rich agricultural byproducts into animal feed and cellulosic ethanol. PMID- 26010259 TI - An audit of nursing reports for First-Tier Tribunals in a secure inpatient service. AB - ACCESSIBLE SUMMARY: Very little research has been conducted into the role of nurses in relation to patients' mental health tribunals (known in some countries as review panels). In England nurses are playing an increasingly important role in giving evidence at tribunals and, since October 2013, are required to provide much more detailed written reports than previously. This is the first published study to examine the content of nursing tribunal reports. Overall, the quality of nursing reports was patchy and not as good as those of psychiatrists or social workers, but there was improvement when the audit was repeated. Writing reports for tribunals is a comparatively new and perhaps unfamiliar requirement for nursing staff. Nurses need training in report writing and protected time and a quiet area to write reports. Providing these things is a real challenge on busy inpatient wards. ABSTRACT: In October 2013, the Tribunals Judiciary of England issued a new practice direction stipulating how tribunal reports should be completed. This paper aimed to study the quality of nursing tribunal reports in a secure inpatient service before and after the introduction of the latest practice direction and the issuing of a local template to aid report writing. A total of 160 reports (80 written in 2013 and 80 in 2014) were scored on the presence of 24 key items derived from the latest practice direction. The quality of nursing reports improved in the re-audit from an average of 36.3% of key items present to 51.3% but still lagged behind that of medical and social circumstances reports. Even in the second audit, few reports were signed or commented on why the patient should remain detained. Report length increased from a mean of 2.9 to 4.0 pages but only 27.5% of reports used the template despite widespread publicity. Use of the template resulted in better quality reports. Among other interventions, a training programme in report writing is now underway to assist nurses with meeting the new practice direction requirements. Nurses also need supervision, protected time and a quiet area for report writing. PMID- 26010260 TI - A semi-automated image analysis procedure for in situ plankton imaging systems. AB - Plankton imaging systems are capable of providing fine-scale observations that enhance our understanding of key physical and biological processes. However, processing the large volumes of data collected by imaging systems remains a major obstacle for their employment, and existing approaches are designed either for images acquired under laboratory controlled conditions or within clear waters. In the present study, we developed a semi-automated approach to analyze plankton taxa from images acquired by the ZOOplankton VISualization (ZOOVIS) system within turbid estuarine waters, in Chesapeake Bay. When compared to images under laboratory controlled conditions or clear waters, images from highly turbid waters are often of relatively low quality and more variable, due to the large amount of objects and nonlinear illumination within each image. We first customized a segmentation procedure to locate objects within each image and extracted them for classification. A maximally stable extremal regions algorithm was applied to segment large gelatinous zooplankton and an adaptive threshold approach was developed to segment small organisms, such as copepods. Unlike the existing approaches for images acquired from laboratory, controlled conditions or clear waters, the target objects are often the majority class, and the classification can be treated as a multi-class classification problem. We customized a two-level hierarchical classification procedure using support vector machines to classify the target objects (< 5%), and remove the non-target objects (> 95%). First, histograms of oriented gradients feature descriptors were constructed for the segmented objects. In the first step all non-target and target objects were classified into different groups: arrow-like, copepod-like, and gelatinous zooplankton. Each object was passed to a group-specific classifier to remove most non-target objects. After the object was classified, an expert or non-expert then manually removed the non-target objects that could not be removed by the procedure. The procedure was tested on 89,419 images collected in Chesapeake Bay, and results were consistent with visual counts with >80% accuracy for all three groups. PMID- 26010261 TI - The Venus Fly Trap and the Land Mine: Novel Tools for Eating Disorder Treatment. PMID- 26010264 TI - Intraneural GJB1 gene delivery improves nerve pathology in a model of X-linked Charcot-Marie-Tooth disease. AB - OBJECTIVE: X-linked Charcot-Marie-Tooth disease (CMT1X) is a common inherited neuropathy caused by mutations in the GJB1 gene encoding the gap junction protein connexin32 (Cx32). Clinical studies and disease models indicate that neuropathy mainly results from Schwann cell autonomous, loss-of-function mechanisms; therefore, CMT1X may be treatable by gene replacement. METHODS: A lentiviral vector LV.Mpz-GJB1 carrying the GJB1 gene under the Schwann cell-specific myelin protein zero (Mpz) promoter was generated and delivered into the mouse sciatic nerve by a single injection immediately distal to the sciatic notch. Enhanced green fluorescent protein (EGFP) reporter gene expression was quantified and Cx32 expression was examined on a Cx32 knockout (KO) background. A gene therapy trial was performed in a Cx32 KO model of CMT1X. RESULTS: EGFP was expressed throughout the length of the sciatic nerve in up to 50% of Schwann cells starting 2 weeks after injection and remaining stable for up to 16 weeks. Following LV.Mpz-GJB1 injection into Cx32 KO nerves, we detected Cx32 expression and correct localization in non-compact myelin areas where gap junctions are normally formed. Gene therapy trial by intraneural injection in groups of 2-month-old Cx32 KO mice, before demyelination onset, significantly reduced the ratio of abnormally myelinated fibers (p = 0.00148) and secondary inflammation (p = 0.0178) at 6 months of age compared to mock-treated animals. INTERPRETATION: Gene delivery using a lentiviral vector leads to efficient gene expression specifically in Schwann cells. Restoration of Cx32 expression ameliorates nerve pathology in a disease model and provides a promising approach for future treatments of CMT1X and other inherited neuropathies. PMID- 26010265 TI - Empathy as a Mediator of Attitudes Toward Infidelity Among College Students. AB - This study examined attitudes about infidelity among college students. Due to increased sexual opportunities and normalization of casual sex in the college campus environment, commitment level is generally more likely to be lower than for post-college-aged individuals. While lower commitment may contribute to infidelity among college students, we aimed to more closely examine the relative role of individual characteristics. The literature has shown that individuals with certain personality traits, such as narcissism and an insecure attachment style, are more likely to commit infidelity, but less is known about the interaction between sex and these traits and about possible underlying mechanisms that account for why some people resist the temptation to be unfaithful and others don't. Working under the assumption that higher empathy might be the underlying mechanism that enables individuals to resist the temptation to be unfaithful, we demonstrated that empathy partially mediates the relationship between sex, narcissism, entitlement, attachment style and attitudes toward infidelity in college students. Thus, college students who are securely attached, low in narcissism, and high in empathy are more likely to oppose sexual behavior outside of their dating relationships despite the fact that their commitment level may be relatively low. PMID- 26010266 TI - Squeezing Photons into a Point-Like Space. AB - Confining photons in the smallest possible volume has long been an objective of the nanophotonics community. In this Letter, we propose and demonstrate a three dimensional (3D) gap-plasmon antenna that enables extreme photon squeezing in a 3D fashion with a modal volume of 1.3 * 10(-7) lambda(3) (~4 * 10 * 10 nm(3)) and an intensity enhancement of 400 000. A three-dimensionally tapered 4 nm air-gap is formed at the center of a complementary nanodiabolo structure by ion-milling 100 nm-thick gold film along all three dimensions using proximal milling techniques. From a 4 nm-gap antenna, a nonlinear second-harmonic signal more than 27 000-times stronger than that from a 100 nm-gap antenna is observed. In addition, scanning cathodoluminescence images confirm unambiguous photon confinement in a resolution-limited area 20 * 20 nm(2) on top of the nano gap. PMID- 26010263 TI - Mitochondrial quality control pathways as determinants of metabolic health. AB - Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age-related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy - termed mitophagy - and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context- and time-dependent network of mitochondrial quality control that is implicated in healthy aging. PMID- 26010267 TI - 'Rapid discharge': issues for hospital-based nurses in discharging cancer patients home to die. AB - AIMS AND OBJECTIVES: To explore issues for hospital-based nurses in arranging rapid home discharge for imminently dying cancer patients in a Singapore acute hospital. BACKGROUND: Dying at home is an important measure of a 'good death'. For hospitalised terminally ill patients, achieving home death can be of paramount importance to them and their family. Nurses experience many challenges in discharging imminently dying cancer patients home, due to time limitations and complex needs of patients and their families. DESIGN: Qualitative interpretive description. METHOD: Using purposive sampling, 14 registered nurses from an oncology ward in a Singapore hospital were recruited to participate in individual, semi-structured interviews. RESULTS: Nursing issues in facilitating rapid discharge fell into three categories: time, discharge processes and family preparation. Decisions to die at home appeared solely family/patient driven, and were made when death appeared imminent. Discharge then became time-critical, as nurses needed to complete multiple tasks within short timeframes. Stress was further exacerbated by nurses' inexperience and the infrequent occurrence of rapid discharge, as well as absence of standardised discharge framework for guidance. Together, the lack of time and discharge processes to enable smooth hospital-to-home transition potentially affected nurses' capacity to adequately prepare families, and may contribute to caregiver anxiety. CONCLUSION: Rapid discharge processes are needed as sudden patient/family decisions to die at home will continue. Earlier involvement of palliative care and implementation of a discharge pathway can potentially help nurses address their multiple responsibilities to ensure a successful transition from hospital to home. RELEVANCE TO CLINICAL PRACTICE: Recognition of nursing issues and challenges during rapid discharge has implications for clinical improvements in supporting nurses during this challenging situation. Results of this study can be used to inform the conceptualisation of clinical interventions to facilitate urgent discharges of imminently dying patients. PMID- 26010268 TI - Workplace bullying prevention: a critical discourse analysis. AB - AIM: The aim of this study was to analyse the discourses of workplace bullying prevention of hospital nursing unit managers and in the official documents of the organizations where they worked. BACKGROUND: Workplace bullying can be a self perpetuating problem in nursing units. As such, efforts to prevent this behaviour may be more effective than efforts to stop ongoing bullying. There is limited research on how healthcare organizations characterize their efforts to prevent workplace bullying. DESIGN: This was a qualitative study. METHOD: Critical discourse analysis and Foucault's writings on governmentality and discipline were used to analyse data from interviews with hospital nursing unit managers (n = 15) and organizational documents (n = 22). Data were collected in 2012. FINDINGS: The discourse of workplace bullying prevention centred around three themes: prevention of workplace bullying through managerial presence, normalizing behaviours and controlling behaviours. All three are individual level discourses of workplace bullying prevention. CONCLUSION: Current research indicates that workplace bullying is a complex issue with antecedents at the individual, departmental and organizational level. However, the discourse of the participants in this study only focused on prevention of bullying by moulding the behaviours of individuals. The effective prevention of workplace bullying will require departmental and organizational initiatives. Leaders in all types of organizations can use the results of this study to examine their organizations' discourses of workplace bullying prevention to determine where change is needed. PMID- 26010269 TI - A pathway to earlier discharge following TAVI: Assessment of safety and resource utilization. AB - INTRODUCTION: There is considerable variability within the population of patients treated with transcatheter aortic valve implantation (TAVI), the procedural approach and time to discharge. In Belfast, from the commencement of our program, our approach has been to perform TAVI by the least invasive approach, where feasible, utilizing a percutaneous transfemoral route and local anesthetic. By analyzing our Belfast TAVI database we identified factors that predicted shorter admission times without impacting adversely on patient safety. Following this, we developed an early discharge pathway. The aim of this current study was to perform a prospective analysis of outcomes in our unit since implementation of this pathway assessing discharge time, mortality, serious adverse events, readmission, and resource implications for patients according to time to discharge. METHODS: Consecutive patients who underwent TAVI and were successfully discharged from 2013 to 2014 over a 14 month period were included, and analyzed according to time to discharge. Baseline and procedural characteristics, mortality, serious adverse events, readmission, and cost were assessed. RESULTS: In total 120 patients were included, 26 (21.7%) were discharged the same/next day, 39 (32.5%) early (>1-4 days), and 55 (45.8%) discharged in the late group. There was no significant difference in baseline or preprocedural characteristics. The incidence of complications was low, and there was no difference in 30-day mortality (P = 0.167) or readmission rates between groups (P = 0.952). Resource analysis revealed the late discharge group cost L3,091.6 more per patient per TAVI than same/next day discharge group. CONCLUSION: Same/next day discharge can be performed safely in appropriately selected patients. Although this will be achieved in a minority of patients (21.7% in this study using an early discharge pathway) it has potential for resource and cost savings. (c) 2015 Wiley Periodicals, Inc. PMID- 26010270 TI - Assessment of the mutagenic potential of Cr(VI) in the oral mucosa of Big Blue(r) transgenic F344 rats. AB - Exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water was associated with an increased incidence of oral tumors in F344 rats in a 2 year cancer bioassay conducted by the National Toxicology Program. These tumors primarily occurred at 180 ppm Cr(VI) and appeared to originate from the gingival mucosa surrounding the upper molar teeth. To investigate whether these tumors could have resulted from a mutagenic mode of action (MOA), a transgenic mutation assay based on OECD Test Guideline 488 was conducted in Big Blue((r)) TgF344 rats. The mutagenic oral carcinogen 4-nitroquinoline-1-oxide (4-NQO) served as a positive control. Mutant frequency was measured in the inner gingiva with adjacent palate, and outer gingiva with adjacent buccal tissue. Exposure to 10 ppm 4-NQO in drinking water for 28 days increased mutant frequency in the cII transgene significantly, from 39.1 +/- 7.5 * 10(-6) to 688 +/- 250 * 10(-6) in the gingival/buccal region, and from 49.8 +/- 17.8 * 10(-6) to 1818 +/- 362 * 10( 6) in the gingival/palate region. Exposure to 180 ppm Cr(VI) in drinking water for 28 days did not significantly increase the mutant frequency in the gingival/buccal (44.4 +/- 25.4 * 10(-6)) or the gingival/palate (57.8 +/- 9.1 * 10(-6)) regions relative to controls. These data indicate that high (~180,000 times expected human exposure), tumorigenic concentrations of Cr(VI) did not significantly increase mutations in the gingival epithelium, and suggest that Cr(VI) does not act by a mutagenic MOA in the rat oral cavity. PMID- 26010271 TI - Temozolomide induced bone marrow Suppression--A single institution outcome analysis and review of the literature. PMID- 26010272 TI - Highly Flexible and Planar Supercapacitors Using Graphite Flakes/Polypyrrole in Polymer Lapping Film. AB - Flexible supercapacitor electrodes have been fabricated by simple fabrication technique using graphite nanoflakes on polymer lapping films as flexible substrate. An additional thin layer of conducting polymer polypyrrole over the electrode improved the surface conductivity and exhibited excellent electrochemical performances. Such capacitor films showed better energy density and power density with a maximum capacitance value of 37 mF cm(-2) in a half cell configuration using 1 M H2SO4 electrolyte, 23 mF cm(-2) in full cell, and 6 mF cm(-2) as planar cell configuration using poly(vinyl alcohol) (PVA)/phosphoric acid (H3PO4) solid state electrolyte. Moreover, the graphite nanoflakes/polypyrrole over polymer lapping film demonstrated good flexibility and cyclic stability. PMID- 26010274 TI - Health System Chief Nursing Officers: Is an MBA the Degree of Choice? AB - This thought-provoking column is submitted by a senior executive at Witt/Kieffer based on recent recruiting experience of system chief nursing executive candidates. PMID- 26010273 TI - An overhang-based DNA block shuffling method for creating a customized random library. AB - We present an overhang-based DNA block shuffling method to create a customized random DNA library with flexible sequence design and length. Our method enables the efficient and seamless assembly of short DNA blocks with dinucleotide overhangs through a simple ligation process. Next generation sequencing analysis of the assembled DNA library revealed that ligation was accurate, directional and unbiased. This straightforward DNA assembly method should fulfill the versatile needs of both in vivo and in vitro functional screening of random peptides and RNA created with a desired amino acid and nucleotide composition, as well as making highly repetitive gene constructs that are difficult to synthesize de novo. PMID- 26010275 TI - State of the research on credentialing: the Institute of Medicine Standing Committee on Credentialing Research in Nursing. AB - This column is presented to report an update on the status of research on credentialing in nursing by the director of the Institute for Credentialing Research at the American Nurses Credentialing Center. The author presents an overview of the 5 meetings held to explore this topic and recommendations for further study. PMID- 26010276 TI - Nebraska biocontainment unit design and operations. AB - Planning and design of a unique biocontainment unit specifically for care of patients with rare and highly infectious diseases presented an opportunity for nurse leaders to engage staff in crucial groundbreaking decisions. The Magnet(r) philosophy and framework were used to structure committees with key stakeholders and staff to ensure best and safe practices. Members of the biocontainment unit are engaged in active research and outreach training. PMID- 26010277 TI - Nursing Education: A Solution to Healthcare's Gordian Knot? AB - The Patient Protection and Affordable Care Act is dramatically increasing the complexity of the healthcare industry. In order to respond to the call for increased access and improved quality at lower costs, healthcare executives need new competencies to develop innovative solutions to complex problems. This column identifies and compares a few of the new nursing leadership competencies needed to current academic curricula. PMID- 26010278 TI - Strategic agility for nursing leadership. AB - This department highlights change management strategies that may be successful in strategically planning and executing organizational change. In this article, the author discusses strategic agility as an important leadership competency and offers approaches for incorporating strategic agility in healthcare systems. A strategic agility checklist and infrastructure-building approach are presented. PMID- 26010279 TI - Designing tomorrow when the sun sets on today. AB - The author of this column relates her experience as she discusses transitions, dilemmas, and opportunities for nurse executives as we meet new professional and personal challenges. PMID- 26010280 TI - Avenues of action in ethically complex situations: a critical incident study. AB - OBJECTIVES: The aims of this study were to explore nurse leaders' experiences with ethically difficult situations, perceptions about risk factors, and specific actions for ethical conflicts. BACKGROUND: Research indicates that nurses are reluctant to bring ethical concerns to nurse leaders for fear of creating trouble, and yet, nurse leaders are key figures in supporting ethics-minded clinicians and cultures. METHODS: The critical incident technique was used to collect descriptions from 100 nurse leaders in California. Responses were qualitatively coded, categorized, and counted. RESULTS: End-of-life situations accounted for the majority of incidents. Most situations had 3 to 4 ethical issues. Healthcare provider and system-level factors were perceived to increase the likelihood of ethical conflicts more often than family and patient factors. Respondents were more likely to identify leader actions that address specific situations rather than specify system-level actions addressing root causes of conflicts. CONCLUSIONS: Findings can be used to help leaders create ethics competencies, policies, and education. PMID- 26010281 TI - Leadership style and patient safety: implications for nurse managers. AB - OBJECTIVE: The purpose of this study was to explore the relationship between nurse manager (NM) leadership style and safety climate. BACKGROUND: Nursing leaders are needed who will change the environment and increase patient safety. Hospital NMs are positioned to impact day-to-day operations. Therefore, it is essential to inform nurse executives regarding the impact of leadership style on patient safety. METHODS: A descriptive correlational study was conducted in 41 nursing departments across 9 hospitals. The hospital unit safety climate survey and multifactorial leadership questionnaire were completed by 466 staff nurses. Bivariate and regression analyses were conducted to determine how well leadership style predicted safety climate. RESULTS: Transformational leadership style was demonstrated as a positive contributor to safety climate, whereas laissez-faire leadership style was shown to negatively contribute to unit socialization and a culture of blame. CONCLUSIONS: Nursing leaders must concentrate on developing transformational leadership skills while also diminishing negative leadership styles. PMID- 26010282 TI - Creating disability inclusive work environments for our aging nursing workforce. AB - The workforce is aging, and the implications of an older nursing workforce are profound. As nurses age, injuries and disabilities are more prevalent. If disabilities were more commonly recognized and accommodated in the design of our nursing work environments, we could meet future needs. This article explores the literature on accommodations for an aging workforce, reports disabilities commonly seen in this population, and introduces universal design. PMID- 26010283 TI - Evaluating the Short- and Long-term Outcomes of a Post-BSN Residency Program: Findings of a Retrospective Study of Nurse Residents, 2005-2012. AB - OBJECTIVE: This retrospective study evaluates short- and long-term outcomes of the nurse residency program (NRP) at NYU Langone Medical Center from the perspective of former residents. BACKGROUND: Studies of NRPs focus primarily on retention rates. Little is known about the careers of former residents beyond completion of the program or their perceptions of the value of the NRP on their careers. METHODS: An online survey to 671 former residents from 2005 to 2012, who remain employed at NYU Langone Medical Center, was conducted in fall 2013 to assess their current employment and professional characteristics and assessment of program components. RESULTS: Findings from the 425 respondents (65.8%) revealed significant variations among the cohorts over time, suggesting that the perceived value of some program components emerge long after completion of NRP. CONCLUSION: The experiences and assessments of former residents demonstrate that certain program outcomes require longer time to emerge. PMID- 26010284 TI - Inpatient ambulation: use of an ambulation platform apparatus. AB - Ambulation has proven to be an important part of recovery for medical-surgical patients. This study provides original research on the use of a platform apparatus for ambulation of patients on a medical-surgical unit. Outcomes included number of ambulation attempts, distance of ambulation, length of hospital stay, number of staff necessary to ambulate, and discharge destination. Compared with a control group, patients who had access to the ambulation platform apparatus had a shorter length of stay with fewer nurses and other staff needed to ambulate. Staff rated ambulation with the apparatus as easier than without and noted that patients were more willing to ambulate on their own with the ambulation platform apparatus. PMID- 26010285 TI - Nurse residency programs and the transition to child health nursing practice. AB - Nurse residency programs for newly licensed RNs are a critical component in bridging the clinical practice gap between education and practice. In May 2013, the Institute of Pediatric Nursing invited leaders from pediatric nursing organizations and children's hospitals to attend a forum on nurse residency programs for pediatric nurses. This article presents a summary of the discussions that occurred during the forum and makes recommendations for addressing issues related to nurse residency programs. PMID- 26010286 TI - Religious practices in cross-cultural contexts: Indonesian male science students' adjustment in Taiwan. AB - Since the terrorist attacks of September 11, 2001, little is known about how Muslims, as a minority group, cope with the challenges associated with engaging their religious practices in a predominantly non-Islamic context. This study aims to investigate how international Muslim science students dealt with the difficulties they faced in their religious practices in a foreign context, and specifically in their research laboratories and in the wider Taiwanese society with its pluralistic spiritual beliefs. Fourteen male Muslim graduate students from Indonesia were recruited to participate in a qualitative interview. In terms of conventional content analysis, their adjustment issues were related to their religious issues, including gender roles both inside and outside of the laboratory, inconvenient practices relating to prayer needs, and eating halal foods and having to face social discrimination off campus. Two types of major adaptation strategies were identified for dealing with such struggles, including religious coping through their Islamic beliefs and bicultural connections. Their major concerns about religious practices (e.g., praying 5 times per day) were resolved by communicating their needs directly with their laboratory classmates and advisors; however, they navigated the gender boundaries in the laboratory both subtly and inwardly through their Islamic beliefs. The practical implications regarding counseling and education are discussed both in a local and a global context. PMID- 26010287 TI - Crying as communication in psychotherapy: The influence of client and therapist attachment dimensions and client attachment to therapist on amount and type of crying. AB - Nelson (2005) associated 3 types of crying (inhibited, protest, despair) with 3 dimensions of attachment (avoidant, anxious, and secure). To test this theory, trained judges rated the intensity of inhibition, protest, and despair in 347 crying episodes for 40 clients and 14 therapists in 1,074 psychotherapy sessions. Crying occurred once out of every 7 sessions, and usually was characterized by protest or inhibition. Pre-therapy attachment dimensions of both therapist and client influenced crying. Therapists with high attachment avoidance had clients who cried frequently but less over time, whereas therapists with high attachment anxiety had clients who cried with more protest over time. Clients with high attachment anxiety initially cried with more protest and inhibition, but decreased over time, whereas clients with low attachment anxiety increased protest over time. Throughout the course of psychotherapy, therapists who were seen by their clients as establishing a secure attachment elicited more overall crying and a higher intensity of protest, whereas therapists who were seen by their clients as establishing insecure attachments had clients who cried less. Clients who established a secure or avoidant relationship with their therapists, relative to other clients of that therapist, cried infrequently and with inhibition, whereas clients who established a preoccupied relationship cried relatively often. Changes are suggested for Nelson's (2005) typology. PMID- 26010288 TI - Development of the Sources of Spirituality Scale. AB - Most measures of spirituality privilege religious spirituality, but people may experience spirituality in a variety of ways, including a sense of closeness, oneness, or connection with a theistic being, the transcendent (i.e., something outside space and time), oneself, humanity, or nature. The overall purpose of the present 4 studies was to develop the Sources of Spirituality (SOS) Scale to measure these different elements of spirituality. In Study 1, we created items, had them reviewed by experts, and used data from a sample of undergraduates (N = 218) to evaluate factor structure and inform initial measurement revisions. The factor structure replicated well in another sample of undergraduates (N = 200; Study 2), and in a sample of community adults (N = 140; Study 3). In a sample of undergraduates (N = 200; Study 4), we then evaluated evidence of construct validity by examining associations between SOS Scale scores and religious commitment, positive attitudes toward the Sacred, and dispositional connection with nature. Moreover, based on latent profile analyses results, we found 5 distinct patterns of spirituality based on SOS subscales. We consider implications for therapy and relevance of the findings for models of spirituality and future research. PMID- 26010289 TI - A relational model of sexual minority mental and physical health: The negative effects of shame on relationships, loneliness, and health. AB - Sexual minorities (e.g., lesbians, gay men, bisexual individuals) are at an increased risk for poorer mental and physical health outcomes than heterosexuals, and some of these health disparities relate to minority stressors such as discrimination. Yet, there is little research elucidating pathways that predict health or that promote resiliency among sexual minorities. Building on the minority stress model, the present study utilized relational cultural theory to situate sexual minority health within a relational framework. Specifically, the study tested mediators of the relationships between distal (i.e., discrimination, rejection, victimization) and proximal stressors (i.e., internalized homophobia, sexual orientation concealment) and psychological and physical distress for sexual minorities. Among 719 sexual minority adults, structural equation modeling analyses were used to test 4 models reflecting the mediating effects of shame, poorer relationships with a close peer and the lesbian/gay/bisexual/transgender (LGBT) community, and loneliness on the associations between minority stressors and psychological distress (i.e., depression and anxiety) and physical distress (i.e., distressing physical symptoms). As hypothesized, the associations between distal and proximal minority stressors and distress were mediated by shame, poorer relationships with a close peer and the LGBT community, and loneliness. Findings underscore the possible relational and interpersonal mechanisms by which sexual minority stressors lead to psychological and physical distress. PMID- 26010291 TI - Thermal Behavior of Long-Chain Alcohols on Sapphire Substrate. AB - Structures of amphiphilic molecules at the liquid/solid and solid/solid interfaces are important in understanding lubrication, colloid stabilization, chromatography, and nucleation. Here, we have used interface-sensitive sum frequency generation (SFG) spectroscopy to characterize the interfacial structures of long-chain alcohols above and below the bulk melting temperature (Tm). The melting temperature of the ordered hexadecanol monolayer was measured to be around 30 degrees C above the bulk Tm, consistent with the transition temperature reported using X-ray reflectivity [ Phys. Rev. Lett. 2011 , 106 , 137801 ]. The disruption of hydrogen bonds between the sapphire and the alcohol hydroxyl groups was directly measured as a function of temperature. The strength of this hydrogen-bonding interaction, which explained the monolayer thermal stability above Tm, was calculated using the Badger-Bauer equation. Below Tm, the ordered self-assembled monolayer influenced the structure of the interfacial crystalline layer, and the transition from the ordered monolayer to the bulk crystalline phases (alpha rotator phase, beta crystalline phase, and gamma crystalline phase) resulted in packing frustrations at the interface. PMID- 26010290 TI - Dual Effect of Adenosine A1 Receptor Activation on Renal O2 Consumption. AB - The high requirement of O2 in the renal proximal tubule stems from a high rate of Na(+) transport. Adenosine A1 receptor (A1R) activation regulates Na(+) transport in this nephron segment. Thus, the effect of the acute activation and the mechanisms of A1R on the rate of O2 consumption were evaluated. The A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX) and adenosine deaminase (ADA), which metabolize endogenous adenosine, reduced O2 consumption (40-50%). Replacing Na(+) in the buffer reversed the ADA- or CPX-mediated reduction of O2 consumption. Blocking the Na/H-exchanger activity, which decreases O2 usage per se, did not enhance the ADA- or CPX-induced inhibition of O2 consumption. These data indicate that endogenous adenosine increases O2 usage via the activation of Na(+) transport. In the presence of endogenous adenosine, A1R was further activated by the A1R-agonist N(6)-cyclopentyladenosine (CPA); CPA inhibited O2 usage (30%) and this effect also depended on Na(+) transport. Moreover, a low concentration of CPA activated O2 usage in tissue pretreated with ADA, whereas a high concentration of CPA inhibited O2 usage; both effects depended on Na(+). Protein kinase C signaling mediated the inhibitory effect of A1R, while adenylyl cyclase mediated its stimulatory effect on O2 consumption. In summary, increasing the local concentrations of adenosine can either activate or inhibit O2 consumption via A1R, and this mechanism depends on Na(+) transport. The inhibition of O2 usage by A1R activation might restore the compromised balance between energy supply and demand under pathophysiological conditions, such as renal ischemia, which results in high adenosine production. PMID- 26010292 TI - Effect of retinal image defocus on the thickness of the human choroid. AB - PURPOSE: To describe the time-course and amplitude of changes to sub-foveal choroidal thickness (SFCT) induced by imposed hyperopic and myopic retinal defocus and to compare the responses in emmetropic and myopic subjects. METHODS: Twelve East Asian subjects (age: 18-34 years; six were emmetropic and six had myopia between -2.00 and -5.00 dioptres (D)) viewed a distant target (video movie at 6 m) for 60 min on two separate occasions while optical coherence tomography (OCT) images of the choroid were taken in both eyes every 5 min to monitor SFCT. On each occasion, one eye was optimally corrected for distance with a contact lens while the other eye wore a contact lens imposing either 2.00 D hyperopic or 2.00 D myopic retinal defocus. RESULTS: Baseline SFCT in myopic eyes (mean +/- S.D.): 256 +/- 42 MUm was significantly less than in emmetropic eyes (423 +/- 62 MUm; p < 0.01) and was correlated with magnitude of myopia (-39 MUm per dioptre of myopia, R(2) = 0.67: p < 0.01). Repeated measures anova (General Linear Model) analysis revealed that in both subject groups, 2.00 D of myopic defocus caused a rapid increase in SFCT in the defocussed eye (significant by 10 min, increasing to approximately 20 MUm within 60 min: p < 0.01), with little change in the control eye. In contrast, 2.00 D of hyperopic defocus caused a decrease in SFCT in the experimental eye (significant by 20-35 min. SFCT decreased by approximately 20 MUm within 60 min: p < 0.01) with little change in the control eye. CONCLUSIONS: Small but significant changes in SFCT (5-8%) were caused by retinal defocus. SFCT increased within 10 min of exposure to 2.00 D of monocular myopic defocus, but decreased more slowly in response to 2.00 D of monocular hyperopic defocus. In our relatively small sample we could detect no difference in the magnitude of changes to SFCT caused by defocus in myopic eyes compared to emmetropic eyes. PMID- 26010293 TI - Circulating plasma cells in newly diagnosed symptomatic multiple myeloma as a possible prognostic marker for patients with standard-risk cytogenetics. AB - Detection of circulating plasma cells (PCs) in multiple myeloma (MM) patients is a well-known prognostic factor. We evaluated circulating PCs by flow cytometry (FC) in 104 patients with active MM at diagnosis by gating on CD38(+) CD45(-) cells and examined their relationship with cytogenetic risk. Patients had an average follow-up of 36 months. By using a receiver operating characteristics analysis, we estimated the optimal cut-off of circulating PCs for defining poor prognosis to be 41. Patients with high-risk cytogenetics (n = 24) had poor prognosis, independently of circulating PC levels [PC < 41 vs. PC >= 41: overall survival (OS) = 0% vs. OS = 17%, P = not significant (n.s.); progression-free survival (PFS) = 0% vs. 17%, P = n.s.]. Patients with standard-risk cytogenetics (n = 65) showed a better prognosis when associated with a lower number of circulating PCs (PC < 41 vs. PC >= 41: OS = 62% vs. 24%, P = 0.008; PFS = 48% vs. 21%, P = 0.001). Multivariate analysis on the subgroup with standard-risk cytogenetics confirmed that the co-presence of circulating PCs >= 41, older age, Durie-Salmon stage >I and lack of maintenance adversely affected PFS, while OS was adversely affected only by lactate dehydrogenase, older age and lack of maintenance. Our results indicate that the quantification of circulating PCs by a simple two-colour FC analysis can provide useful prognostic information in newly diagnosed MM patients with standard-risk cytogenetics. PMID- 26010295 TI - Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study: reply. PMID- 26010294 TI - Differential antigen expression and aberrant signaling via PI3/AKT, MAP/ERK, JAK/STAT, and Wnt/beta catenin pathways in Lin-/CD38-/CD34+ cells in acute myeloid leukemia. AB - Acute myeloid leukemia is often called as stem cell disease that presents with treatment failure and poor disease outcome. Leukemic stem cells in acute myeloid leukemia (AML) are enriched in Lineage-/CD38-/CD34+ compartment of CD34-positive AML. Many markers important for stem cell biology have been reported for their association with leukemic stem cell population, but what remains clinically most important is a rapid identification of prognostic information. In this study, we evaluated four signal transduction pathways and thirteen markers on Lin-/CD38 /CD34+ population in AML. Expressions were compared in different AML subtypes, survival, and treatment outcome groups. We observed that markers important in homing, cell quiescence, and signal propagation such as CD44, CD96, CD90, WT-1, CD123 and CD25 were most significantly differentially expressed on Lin-/CD38 /CD34+ population in AML from their normal counterparts (P < 0.05, Mann-Whitney). Constitutive activation of phospho ERK, AKT, and STAT5 in these cells was associated with poor outcome. Also, an increased frequency of putative leukemic stem cell population shows negative impact on treatment outcome and overall survival, suggesting that initial evaluation of AML samples for pLSC frequency and constitutively activated signaling pathway can provide prognostic and therapeutic information at the time of diagnosis. PMID- 26010299 TI - Eating Disorder Symptoms and Suicidal Ideation: The Moderating Role of Disgust. AB - Disgust has been implicated as a factor that maintains and exacerbates eating disorder (ED) symptoms. Emerging research suggests that disgust may be a risk factor for suicidality. Given the high rates of suicidality among individuals with EDs, we propose that disgust may contribute to the link between EDs and suicidality. To test this hypothesis, self-report data were collected from 341 young adults (66% women). Cross-sectional associations between disgust with the self, others and the world and disgust sensitivity and propensity, ED symptoms and suicidal ideation were examined using multivariate regression analyses. ED symptoms and body dissatisfaction were associated with increased suicidal ideation at high levels of disgust with the self and the world; at low levels of disgust, ED symptoms and body dissatisfaction did not significantly relate to suicidal ideation. Disgust may indicate risk for suicidal ideation among individuals with eating psychopathology. PMID- 26010298 TI - Volumetric computed tomography analysis of the olfactory cleft in patients with chronic rhinosinusitis. AB - BACKGROUND: Commonly used computed tomography (CT) staging systems for chronic rhinosinusitis (CRS) focus on the sinuses and do not quantify disease in the olfactory cleft. The goal of the current study was to determine whether precise measurements of olfactory cleft opacification better correlate with olfaction in patients with CRS. METHODS: Olfaction was assessed using the 40-item Smell Identification Test (SIT-40) before and after sinus surgery in adult patients. Olfactory cleft opacification was quantified precisely using three-dimensional (3D), computerized volumetric analysis, as well as via semiquantitative Likert scale estimations at predetermined anatomic sites. Sinus opacification was also quantified using the Lund-Mackay staging system. RESULTS: The overall cohort (n = 199) included 89 (44.7%) patients with CRS with nasal polyposis (CRSwNP) and 110 (55.3%) with CRS without nasal polyposis (CRSsNP). The olfactory cleft opacified volume correlated with objective olfaction as determined by the SIT-40 (Spearman's rank correlation coefficient [Rs ] = -0.461; p < 0.001). The correlation was significantly stronger in the CRSwNP subgroup (Rs = -0.573; p < 0.001), whereas no appreciable correlation was found in the CRSsNP group (Rs = 0.141; p = 0.141). Correlations between sinus-specific Lund-Mackay CT scoring and SIT-40 scores were weaker in the CRSwNP (Rs = -0.377; p < 0.001) subgroup but stronger in the CRSsNP (Rs = -0.225; p = 0.018) group when compared to olfactory cleft correlations. Greater intraclass correlations (ICCs) were found between quantitative volumetric measures of olfactory cleft opacification (ICC = 0.844; p < 0.001) as compared with semiquantitative Likert grading (ICC = 0.627; p < 0.001). CONCLUSION: Quantitative measures of olfactory cleft opacification correlate with objective olfaction, with the strongest correlations seen in patients with nasal polyps. PMID- 26010300 TI - Therapeutic Potential of Mesenchymal Stem Cells on Early and Late Experimental Hepatic Schistosomiasis Model. AB - Cell-based therapy is emerging as a promising therapeutic approach for a wide range of liver diseases. This study aimed to investigate the regenerative and antifibrotic therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in an early and late experimental hepatic schistosomiasis model. BM MSCs were isolated from 6-wk-old BALB/c donor male mice, then grown and propagated in culture until cell count was 5-8 * 10(6)/ml. MSCs were then separated and injected into Schistosoma mansoni -infected female BALB/c mice on their 6, 10, 14, and 18 wk post-infection. Mice were sacrificed on the fourth and eighth week after BM-MSCs transplantation in each group. Homing of BM-MSCs was confirmed by PCR detection of male Y-chromosome gene (sry) in the liver tissue of the recipient female mice. The regenerative and antifibrotic potential of BM-MSCs was assessed by histopathological examination, morphometric analysis, electron microscopy, and liver function tests. Schistosoma-infected mice, which were treated with BM-MSCs, showed a decrease in the granuloma size, percentage and density of the fibrotic area, formation of new hepatocytes, and improvement of the liver function tests. Immunohistochemical examination of alpha-smooth muscle actin revealed a significant decrease in the immunoreactive hepatic stellate cells in mice treated with MSCs. Early granulomas (acute infection) showed better response to MSC injection than did later granulomas (chronic infection). Dosing and timing of MSCs transplantation should undergo more investigations in long term experiments before application to the clinical field. This study is the first to assess and compare the effect of MSCs treatment on early and late granulomas. PMID- 26010301 TI - Social norms and rank-based nudging: Changing willingness to pay for healthy food. AB - People's evaluations in the domain of healthy eating are at least partly determined by the choice context. We systematically test reference level and rank based models of relative comparisons against each other and explore their application to social norms nudging, an intervention that aims at influencing consumers' behavior by addressing their inaccurate beliefs about their consumption relative to the consumption of others. Study 1 finds that the rank of a product or behavior among others in the immediate comparison context, rather than its objective attributes, influences its evaluation. Study 2 finds that when a comparator is presented in isolation the same rank-based process occurs based on information retrieved from memory. Study 3 finds that telling people how their consumption ranks within a normative comparison sample increases willingness to pay for a healthy food by over 30% relative to the normal social norms intervention that tells them how they compare to the average. We conclude that social norms interventions should present rank information (e.g., "you are in the most unhealthy 10% of eaters") rather than information relative to the average (e.g., "you consume 500 calories more than the average person"). PMID- 26010302 TI - Frequent incidence of BARD1-truncating mutations in germline DNA from triple negative breast cancer patients. AB - Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers (BCs), and conventional chemotherapy is the only effective systemic treatment. Germline BRCA1/2 mutations are found in approximately 15% of TNBC patients. In the past, we have documented pathogenic mutations in BARD1, a BRCA1 interacting protein, in families at high risk for BC. In this study, we have analyzed germline DNA from 61 estrogen receptor negative patients (of which 42 were TNBC) for the presence of mutations in the BRCA1, BRCA2 and BARD1 gene. BRCA1/2 mutations were found in 8 out of 42 (19%) TNBC patients, but not in the ER-/HER2+ cohort. We also found four good candidate pathogenic BARD1 mutations in the TNBC cohort, including two protein-truncating mutations (p.Gln564Ter and p.Arg641Ter). Our data suggest that TNBC patients are enriched for pathogenic BARD1 germline mutations as compared to control samples and high BC risk families. Ten of the 42 investigated TNBC patients carry a BRCA pathway mutation (in BRCA1, BRCA2 or BARD1) rendering them susceptible to homologous recombination deficiency. These patients should become eligible for exploring the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors. PMID- 26010303 TI - The Phosphoinositide-Gated Lysosomal Ca(2+) Channel, TRPML1, Is Required for Phagosome Maturation. AB - Macrophages internalize and sequester pathogens into a phagosome. Phagosomes then sequentially fuse with endosomes and lysosomes, converting into degradative phagolysosomes. Phagosome maturation is a complex process that requires regulators of the endosomal pathway including the phosphoinositide lipids. Phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2 ), which respectively control early endosomes and late endolysosomes, are both required for phagosome maturation. Inhibition of PIKfyve, which synthesizes PtdIns(3,5)P2 , blocked phagosome-lysosome fusion and abated the degradative capacity of phagosomes. However, it is not known how PIKfyve and PtdIns(3,5)P2 participate in phagosome maturation. TRPML1 is a PtdIns(3,5)P2 gated lysosomal Ca(2+) channel. Because Ca(2+) triggers membrane fusion, we postulated that TRPML1 helps mediate phagosome-lysosome fusion. Using Fcgamma receptor-mediated phagocytosis as a model, we describe our research showing that silencing of TRPML1 hindered phagosome acquisition of lysosomal markers and reduced the bactericidal properties of phagosomes. Specifically, phagosomes isolated from TRPML1-silenced cells were decorated with lysosomes that docked but did not fuse. We could rescue phagosome maturation in TRPML1-silenced and PIKfyve inhibited cells by forcible Ca(2+) release with ionomycin. We also provide evidence that cytosolic Ca(2+) concentration increases upon phagocytosis in a manner dependent on TRPML1 and PIKfyve. Overall, we propose a model where PIKfyve and PtdIns(3,5)P2 activate TRPML1 to induce phagosome-lysosome fusion. PMID- 26010304 TI - Health messages to promote fruit and vegetable consumption at different stages: A match-mismatch design. AB - OBJECTIVE: To examine the effectiveness of matching health messages promoting fruit and vegetable intake to the Health Action Process Approach stages of change. DESIGN: In a randomised controlled trial, 205 undergraduate students (non intenders n = 123; intenders n = 82) were exposed to one of three health messages, targeted at non-intenders, intenders and controls. MAIN OUTCOME MEASURES: Three longitudinal assessments of stage, fruit and vegetable intake, and social-cognitive determinants were obtained. RESULTS: Stage-specific effects of the interventions were confirmed. For self-efficacy, a stage by health message crossover interaction emerged, with both non-intenders and intenders in the matched conditions scoring higher in self-efficacy. Furthermore, in line with predictions, non-intenders in the matched condition showed higher risk perception, outcome expectancies, intention, and stage progression immediately after message exposure, and lower levels of action planning and coping planning a week later in the mismatched condition, but for these outcomes no differences across conditions were obtained among intenders. Multiple mediation analyses confirmed the facilitating role of self-efficacy and behavioural intention among non-intenders. CONCLUSIONS: Stages should be considered when designing health messages, although more interactive interventions for intenders and extended measurement time frames may be required. PMID- 26010305 TI - Charge, size, and cellular selectivity for multiwall carbon nanotubes by maize and soybean. AB - Maize (Zea mays) and soybean (Glycine max) were used as model food-chain plants to explore vegetative uptake of differently charged multiwall carbon nanotubes (MWCNTs). Three types of MWCNTs, including neutral pristine MWCNT (p-MWCNT), positively charged MWCNT-NH2, and negatively charged MWCNT-COOH, were directly taken-up and translocated from hydroponic solution to roots, stems, and leaves of maize and soybean plants at the MWCNT concentrations ranging from 10.0 to 50.0 mg/L during 18-day exposures. MWCNTs accumulated in the xylem and phloem cells and within specific intracellular sites like the cytoplasm, cell wall, cell membrane, chloroplast, and mitochondria, which was observed by transmission electron microscopy. MWCNTs stimulated the growth of maize and inhibited the growth of soybean at the exposed doses. The cumulative transpiration of water in maize exposed to 50 mg/L of MWCNT-COOHs was almost twice as much as that in the maize control. Dry biomass of maize exposed to MWCNTs was greater than that of maize control. In addition, the uptake and translocation of these MWCNTs clearly exhibited cellular, charge, and size selectivity in maize and soybean, which could be important properties for nanotransporters. This is the first report of cellular, charge, and size selectivity on the uptake by whole food plants for three differently charged MWCNTs. PMID- 26010306 TI - Yusho and its latest findings-A review in studies conducted by the Yusho Group. AB - The Yusho incident is an unprecedented mass food poisoning that occurred in Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The victims of Yusho have suffered from characteristic skin manifestations associated with systemic, ophthalmological, and mucosal symptoms for a long period of time. The Study Group of Yusho (the Yusho Group) has been conducting annual medical check-ups on Yusho victims for more than 45years. Since 2002, when concentrations of dioxins in the blood of Yusho patients started to be measured, the pharmacokinetics of dioxins, relationship between blood levels of dioxins and symptoms/signs in patients directly exposed to dioxins, and the adverse effects on the next generation have become dramatically clear. Herein we review recent findings of studies conducted by the Yusho Group to evaluate chronic dioxin-induced toxicity to the next generation as well as Yusho patients in comparison with a similar food mass poisoning, the Yucheng incident. Additionally, we summarized basic studies carried out by the Yusho Group to re-evaluate the mechanisms of dioxin toxicities in experimental models and various functions of the aryl hydrocarbon receptor (AhR), known as the dioxin receptor, pathway. PMID- 26010307 TI - Prenatal exposures to perfluoroalkyl acids and serum lipids at ages 7 and 15 in females. AB - BACKGROUND: In some cross-sectional epidemiologic studies the shape of the association between serum concentrations of perfluoroalkyl acids (PFAAs) and lipids suggests departures from linearity. OBJECTIVES: We used statistical approaches allowing for non-linearity to determine associations of prenatal exposures of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) with lipid concentrations. METHODS: PFAAs were measured in serum from pregnant women collected in 1991-1992 at enrollment in the Avon Longitudinal Study of Parents and Children and lipids in serum from their daughters at ages 7 (n=111) and 15 (n=88). The associations of PFAAs with lipids were first explored by cubic splines, followed by piecewise linear regressions by tertiles to obtain regression coefficients (beta) and their 95% confidence limits (95% CL) (in mg/dL per 1ng/mL). RESULTS: At age 7, total cholesterol was positively associated with prenatal PFOA concentrations in the lower tertile (beta=15.01; 95% CL=2.34, 27.69) but not with PFOA concentrations in the middle (beta=-3.63; 95% CL=-17.43, 10.16) and upper (beta=-1.58; 95% CL=-4.58, 1.42) tertiles. At age 15, a similar pattern was noted as well. Positive associations between LDL-C and prenatal PFOA concentration in the lower tertile were observed in daughters at ages 7 (beta=14.91; 95% CL=3.53, 28.12) and 15 (beta=13.93; 95% CL=0.60, 27.26). LDL-C was not associated with PFOA concentrations in the middle or upper tertile at any age. Neither HDL-C nor triglycerides was associated with prenatal PFOA exposure. Non-linear patterns of association of total cholesterol and LDL-C with prenatal PFOS were less consistently noted. CONCLUSION: Exposure to low levels of PFOA during prenatal development may alter lipid metabolism later in life. Given the small sample size further replication of the association in large independent cohorts is important. PMID- 26010308 TI - The Presence of Genetic Mutations at Key Loci Predicts Progression to Esophageal Adenocarcinoma in Barrett's Esophagus. AB - OBJECTIVES: Risk stratification in Barrett's esophagus (BE) is challenging. We evaluated the ability of a panel of genetic markers to predict progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). METHODS: In this case-control study, we assessed a measure of genetic instability, the mutational load (ML), in predicting progression to HGD or EAC. Cases had nondysplastic BE or low-grade dysplasia (LGD) at baseline and developed HGD/EAC >=1 year later. Controls were matched 2:1, had nondysplastic BE or LGD, and no progression at follow-up. Formalin-fixed, paraffin-embedded tissue was microdissected for the epithelium. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were assessed. ML was calculated from derangements in 10 genomic loci. High clonality LOH mutations were assigned a value of 1, low-clonality mutations were assigned a value of 0.5, and MSI 0.75 at the first loci, and 0.5 for additional loci. These values were summed to the ML. Receiver operator characteristic (ROC) curves were created. RESULTS: There were 69 patients (46 controls and 23 cases). Groups were similar in age, follow-up time, baseline histology, and the number of microdissected targets. Mean ML in pre-progression biopsies was higher in cases (2.21) than in controls (0.42; P<0.0001). Sensitivity was 100% at ML >=0.5 and specificity was 96% at ML >=1.5. Accuracy was highest at 89.9% for ML >=1. ROC curves for ML >=1 demonstrated an area under the curve (AUC) of 0.95. CONCLUSIONS: ML in pre-progression BE tissue predicts progression to HGD or EAC. Although further validation is necessary, ML may have utility as a biomarker in endoscopic surveillance of BE. PMID- 26010309 TI - HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study. AB - OBJECTIVES: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01 DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS: After adjustment for DR3-DQ2 and restriction to allele frequency (AF) >=5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). CONCLUSIONS: HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA. PMID- 26010310 TI - Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis. AB - OBJECTIVES: Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment. METHODS: We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin). RESULTS: Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) >=4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI <=3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2-8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84-111.6; P=0.07). CONCLUSIONS: Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival. PMID- 26010311 TI - A Risk Prediction Index for Advanced Colorectal Neoplasia at Screening Colonoscopy. AB - OBJECTIVES: Eliciting patient preferences within the context of shared decision making has been advocated for colorectal cancer screening. Risk stratification for advanced colorectal neoplasia (ACN) might facilitate more effective shared decision making when selecting an appropriate screening option. Our objective was to develop and validate a clinical index for estimating the probability of ACN at screening colonoscopy. METHODS: We conducted a cross-sectional analysis of 3,543 asymptomatic, mostly average-risk patients 50-79 years of age undergoing screening colonoscopy at two urban safety net hospitals. Predictors of ACN were identified using multiple logistic regression. Model performance was internally validated using bootstrapping methods. RESULTS: The final index consisted of five independent predictors of risk (age, smoking, alcohol intake, height, and a combined sex/race/ethnicity variable). Smoking was the strongest predictor (net reclassification improvement (NRI), 8.4%) and height the weakest (NRI, 1.5%). Using a simplified weighted scoring system based on 0.5 increments of the adjusted odds ratio, the risk of ACN ranged from 3.2% (95% confidence interval (CI), 2.6-3.9) for the low-risk group (score <=2) to 8.6% (95% CI, 7.4-9.7) for the intermediate/high-risk group (score 3-11). The model had moderate to good overall discrimination (C-statistic, 0.69; 95% CI, 0.66-0.72) and good calibration (P=0.73-0.93). CONCLUSIONS: A simple 5-item risk index based on readily available clinical data accurately stratifies average-risk patients into low- and intermediate/high-risk categories for ACN at screening colonoscopy. Uptake into clinical practice could facilitate more effective shared decision making for CRC screening, particularly in situations where patient and provider test preferences differ. PMID- 26010312 TI - Attitudes Toward HIV Voluntary Counseling and Testing (VCT) Among African American Men Who Have Sex With Men: Concerns Underlying Reluctance to Test. AB - Contemporary antiretroviral therapy (ART) can produce viral suppression of HIV, maintain health, and prevent onward HIV transmission from infected persons to their sexual partners, giving rise to the concept of treatment as prevention. Successful implementation of test-and-treat strategies rests on the early detection of HIV infection through voluntary counseling and testing (VCT) followed by entry and retention in care, ART initiation and adherence, and subsequent viral suppression. In the United States, African American men who have sex with men (MSM) bear a disproportionate burden of HIV and have high rates of undetected and untreated HIV infection. However, little research has examined racial minority MSM's views about HIV testing. In this study, in-depth interviews were conducted with 96 key informants knowledgeable about racial minority MSM as well as 100 African American MSM community members in Milwaukee, Cleveland, and Miami. Most men in the sample were aware of the availability of testing and knew testing locations, but many voiced great personal ambivalence about being tested, feared knowing their HIV status, expressed concern about stigma and loss of confidentiality, and held beliefs indicative of medical mistrust. Participants did not spontaneously cite benefits of being tested, risk reduction behavior changes made as a consequence of testing, nor the benefits of testing to get early medical care for HIV infection. There is a gap between the public health field's perception of testing benefits and the beliefs about testing held by racial minority MSM in this sample. To increase the desired outcomes from VCT for minority MSM, VCT promotion should address the concerns of African American MSM and underscore the benefits of early entry into medical care. PMID- 26010313 TI - Correlates of internalized homonegativity among black men who have sex with men. AB - Black men who have sex with men (MSM) carry a disproportionate burden of HIV in the United States. Such disparities cannot be attributed to individual behavioral risk factors alone, prompting the exploration of social and contextual factors experienced by minority MSM. Societal homonegativity and the internalization of those attitudes by Black MSM may play an important role in understanding racial and ethnic disparities in HIV incidence and prevalence. This study explores the correlates of internalized homonegativity in a large multi-site sample of Black MSM. Findings reveal a number of significant contextual and psychosocial factors related to internalized homonegativity including religiosity, resilience, and gay community acculturation, which have important implications for HIV risk, HIV testing, and social and psychological wellbeing for Black MSM. PMID- 26010314 TI - Disclosure of Male Sexual Partnering and HIV Serostatus Among a Sample of Heterosexually Identified Men Who Have Sex With Men and Women. AB - This study employed qualitative methods to understand better the disclosure practices of men with their male and female sexual partners. Open-ended, in depth, semi-structured interviews were conducted with 21 heterosexually identified men who reported at least one sexual encounter with a male in the previous year but not more than one sexual encounter with a male per month. Fifty eight percent of the participants were HIV infected. Most HIV-infected participants reported disclosure of their HIV serostatus to their female sexual partners but did not disclose that they engaged in occasional sexual encounters with a male partner. Disclosure of HIV serostatus to male sexual partners was minimal and inconsistent. PMID- 26010315 TI - Effects of a Community-Based HIV Risk Reduction Intervention Among HIV-Positive Individuals: Results of a Quasi-Experimental Study in Nepal. AB - We evaluated the efficacy of a sexual risk reduction intervention utilizing protection motivation and social cognitive theories to address knowledge, threat and coping appraisals, and condom use intentions among HIV-positive individuals in Nepal. Using a quasi-experimental research design, we assigned 277 participants to intervention (n=146) and control (n=131) groups. The intervention group received six sessions on sexual risk reduction strategies and the control group six sessions on medication adherence, smoking, and mental health. Data were collected at baseline and immediately after the intervention. Results indicate that the sexual risk reduction intervention produced a significant increase in HIV transmission knowledge, perceived threat and coping appraisals, and intentions to use condoms with regular, HIV-positive, and HIV-negative partners. The positive effects of the intervention remained significant after adjusting for baseline scores and other potential confounders. In conclusion, our theory-based sexual risk reduction intervention was effective in improving HIV transmission knowledge, perceived threat and coping appraisals, and condom use intentions. Further studies are needed to evaluate the long-term efficacy of the intervention in increasing protection motivation and maintaining preventive behaviors. PMID- 26010316 TI - Younger Gay and Bisexual Men's Condom Use With Main Regular Sexual Partner in New Zealand. AB - Main partners are a common source of new HIV infections among men who have sex with men (MSM). National behavioral surveillance data (2006-2011) for younger MSM (YMSM, aged 16-29) in New Zealand were analyzed to investigate condom use during anal intercourse with a regular partner (boyfriend/fuckbuddy) by sexual position (insertive/receptive). Backward-stepwise multivariate multinomial logistic regression was used to identify demographic, relational, behavioral, and cognitive factors associated with condom use frequency (high, medium, low). Most YMSM who reported a current regular partner (n=1,221) classified them as a boyfriend (59.5%) versus fuckbuddy (40.5%), though condom use was higher with the latter partner type. Condom use or nonuse was habitual across partners, although insertive sexual position was positively associated with condom use. YMSM who believed condoms reduce sensitivity reported lower condom use. Condoms remain the leading HIV/STI prevention tool for YMSM; efforts to improve condom use must consider sexual position and relationship factors. PMID- 26010317 TI - Impact of a community popular opinion leader intervention among African American adults in a southeastern United States community. AB - We examine the impact of an adapted community popular opinion leader (C-POL) intervention targeting alcohol-using social networks in Southeast Louisiana. A pre-post C-POL was conducted between October 2009 and April 2013, targeting alcohol users. A total of 65 popular opinion leaders were recruited, trained, and deployed into their social networks to diffuse intervention messages. Anonymous community surveys conducted within the venues among 99 male and female participants at baseline and 197 at 6 months to 1 year later revealed significant behavioral and knowledge changes. Average sexual risk score based on 7 sexual risk items declined from 15.3 to 11.9 (p<0.001); the number of vaginal and anal sex partners in the last year decreased from 11.3 to 7.7 and 3.9 to 2.3, respectively (p<0.01); and HIV knowledge score (based on % correct) increased from 67.2 to 76.8% (p<0.001). Findings add to the evidence base surrounding peer interventions. PMID- 26010318 TI - Childhood Sexual Violence and Consistent, Effective Contraception Use among Young, Sexually Active Urban Women. AB - Unintended pregnancy (UP) is a significant public health problem. The consistent use of effective contraception is the primary method to prevent UP. We examined the role of childhood sexual and physical violence and current interpersonal violence on the risk of unintended pregnancy among young, urban, sexually active women. In particular, we were interested in examining the role of childhood violence and interpersonal violence while recognizing the psychological correlates of experiencing violence (i.e., high depressive symptoms and low self esteem) and consistent use of contraception. For this assessment, 315 sexually active women living in Philadelphia PA were recruited from family planning clinics in 2013. A self-administered, computer-assisted interview was used to collect data on method of contraception use in the past month, consistency of use, experiences with violence, levels of depressive symptoms, self-esteem and sexual self-efficacy, substance use and health services utilization. Fifty percent of young sexually active women reported inconsistent or no contraception use in the past month. Inconsistent users were significantly more likely to report at least one prior episode of childhood sexual violence and were significantly less likely to have received a prescription for contraception from a health care provider. Inconsistent contraception users also reported significantly higher levels of depressive symptoms and significantly lower levels of self-esteem. The relation between childhood sexual violence and UP remained unchanged in the multivariate models adjusting for self-esteem or depressive symptoms. These findings highlight the long-term consequences of childhood sexual violence, independent of current depressive symptoms and low self-esteem, on consistent use of contraception. PMID- 26010319 TI - Ophthalmological findings in relation to auxological data in moderate-to-late preterm preschool children. AB - PURPOSE: To evaluate ophthalmological findings in preschool children born moderate-to- late preterm (MLP) and relate the findings to auxological data at birth and at 5.5 years of age. METHODS: Seventy-eight MLP children [gestational age (GA) 32-36 weeks; 34 girls; mean age 5.7 years] were investigated. Gestational age, weight, length and head circumference at birth and at the time of assessment were registered. Visual acuity (VA), refraction, orthoptic evaluation, slit-lamp examination and ophthalmoscopy were conducted, and a history of visuoperceptual problems was recorded. The data were compared with age and sex-matched controls born full term (n = 35). RESULTS: Ophthalmological abnormalities were noted in 82% of MLP children and 47% of controls (p = 0.0004). There was a significant difference with regard to impaired motility (p = 0.03), heterophoria at distance (p = 0.006) and refraction expressed as spherical equivalent dioptre (p = 0.01). Amongst auxological data at birth, birthweight (BW) was the strongest predictor to ophthalmological abnormalities (p = 0.0003). In a stepwise logistic regression, GA was the strongest predictor of VA outcome at time of assessment (p = 0.0036). Moderate-to-late preterm birth showed a 2.4 fold increased risk of refractive errors compared with full-term children (RR 2.39: 95% CI 1.10-5.20; p = 0.02). CONCLUSION: Based on our findings, MLP birth may be associated with increased ocular morbidity compared with their full-term counterparts. Auxological data at birth, especially BW, seems to be an important factor when conducting an ophthalmological diagnosis in preschool MLP children, and an increased VA was correlated to a higher GA. PMID- 26010320 TI - Changes in Right Ventricular Shape and Deformation Following Coronary Artery Bypass Surgery-Insights from Echocardiography with Strain Rate and Magnetic Resonance Imaging. AB - BACKGROUND: This study was designed to assess whether altered RV geometry and deformation parameters persisted well into the recovery period after presumably uncomplicated coronary artery bypass grafting (CABG). It was our hypothesis that the altered geometry of and load in the RV following pericardial opening would change both regional and global deformation indices for an extensive period postoperatively. METHODS AND RESULTS: Fifty-seven patients scheduled for CABG underwent preoperative and 8-10 months postoperative magnetic resonance imaging (MRI) for RV volume measurements, and resting echocardiography with assessment of geometry and RV mechanical function determined by tissue Doppler imaging (TDI) based longitudinal strain. Both MRI and echocardiography revealed postoperative dilatation of the RV apex, shortened longitudinal RV length but unchanged RV ejection fraction. Echocardiography parameters associated with filling of the right atrium showed signs of constraint with a reduced systolic filling fraction and increased right atrial size. Right ventricular segmental strain (-20 +/- 13% vs. -29 +/- 20% preoperatively; mean +/-SD, P < 0.0001) was reduced postoperatively in parallel with TAPSE (1.3 +/- 0.3 cm vs. 2.2 +/- 0.4 cm; P < 0.0001). CONCLUSION: Post-CABG longitudinal motion of the RV lateral wall is reduced after uneventful CABG despite preserved RV ejection fraction and stroke volume. The discrepancy in various RV systolic performance indicators results from increased sphericity of the RV following opening the pericardium during surgery. Therefore, longitudinal functional parameters may underestimate RV systolic function for at least 8-10 months post-CABG. Changes in deformation parameters should thus always be interpreted in relation to changes in geometry. PMID- 26010321 TI - The AC5 protein encoded by Mungbean yellow mosaic India virus is a pathogenicity determinant that suppresses RNA silencing-based antiviral defenses. AB - It is generally accepted that begomoviruses in the family Geminiviridae encode four proteins (from AC1/C1 to AC4/C4) using the complementary-sense DNA as template. Although AC5/C5 coding sequences are increasingly annotated in databases for many begomoviruses, the evolutionary relationships and functions of this putative protein in viral infection are obscure. Here, we demonstrate several important functions of the AC5 protein of a bipartite begomovirus, Mungbean yellow mosaic India virus (MYMIV). Mutational analyses and transgenic expression showed that AC5 plays a critical role in MYMIV infection. Ectopic expression of AC5 from a Potato virus X (PVX) vector resulted in severe mosaic symptoms followed by a hypersensitive-like response in Nicotiana benthamiana. Furthermore, MYMIV AC5 effectively suppressed post-transcriptional gene silencing induced by single-stranded but not double-stranded RNA. AC5 was also able to reverse transcriptional gene silencing of a green fluorescent protein transgene by reducing methylation of promoter sequences, probably through repressing expression of a CHH cytosine methyltransferase (DOMAINS REARRANGED METHYLTRANSFERASE2) in N. benthamiana. Our results demonstrate that MYMIV AC5 is a pathogenicity determinant and a potent RNA silencing suppressor that employs novel mechanisms to suppress antiviral defenses, and suggest that the AC5 function may be conserved among many begomoviruses. PMID- 26010323 TI - Volatile and semi-volatile organic compounds of respiratory health relevance in French dwellings. AB - Over the last decades, the prevalence of childhood respiratory conditions has dramatically increased worldwide. Considering the time spent in enclosed spaces, indoor air pollutants are of major interest to explain part of this increase. This study aimed to measure the concentrations of pollutants known or suspected to affect respiratory health that are present in dwellings in order to assess children's exposure. Measurements were taken in 150 homes with at least one child, in Brittany (western France), to assess the concentrations of 18 volatile organic compounds (among which four aldehydes and four trihalomethanes) and nine semi-volatile organic compounds (seven phthalates and two synthetic musks). In addition to descriptive statistics, a principal component analysis (PCA) was used to investigate grouping of contaminants. Formaldehyde was highly present and above 30 MUg/m(3) in 40% of the homes. Diethyl phthalate, diisobutyl phthalate, and dimethylphthalate were quantified in all dwellings, as well as Galaxolide and Tonalide. For each chemical family, the groups appearing in the PCA could be interpreted in term of sources. The high prevalence and the levels of these compounds, with known or suspected respiratory toxicity, should question regulatory agencies to trigger prevention and mitigation actions. PMID- 26010322 TI - FRAP, FLIM, and FRET: Detection and analysis of cellular dynamics on a molecular scale using fluorescence microscopy. AB - The combination of fluorescent-probe technology plus modern optical microscopes allows investigators to monitor dynamic events in living cells with exquisite temporal and spatial resolution. Fluorescence recovery after photobleaching (FRAP), for example, has long been used to monitor molecular dynamics both within cells and on cellular surfaces. Although bound by the diffraction limit imposed on all optical microscopes, the combination of digital cameras and the application of fluorescence intensity information on large-pixel arrays have allowed such dynamic information to be monitored and quantified. Fluorescence lifetime imaging microscopy (FLIM), on the other hand, utilizes the information from an ensemble of fluorophores to probe changes in the local environment. Using either fluorescence-intensity or lifetime approaches, fluorescence resonance energy transfer (FRET) microscopy provides information about molecular interactions, with Angstrom resolution. In this review, we summarize the theoretical framework underlying these methods and illustrate their utility in addressing important problems in reproductive and developmental systems. PMID- 26010324 TI - Long-term Follow-up of Placental Transfusion in Full-term Infants. PMID- 26010325 TI - Anticipatory and reactive responses to chocolate restriction in frequent chocolate consumers. AB - OBJECTIVE: Many individuals have difficulty adhering to a weight loss diet. One possible explanation could be that dietary restriction paradoxically contributes to overconsumption. The objective of this study was to examine ingestive behavior under a forced chocolate restriction with a focus on the anticipatory restriction period and the post-restriction period in frequent chocolate consumers. METHODS: Fifty-six male (N = 18) and female (N = 38) high chocolate consumers with high (N = 25) or low (N = 31) cognitive disinhibition participated. Chocolate snacks were provided for a week each to establish baseline, pre-restriction, and post restriction consumption, Chocolate snacks were replaced with nonchocolate snacks during a 3-week chocolate restriction period. RESULTS: Highly disinhibited participants felt more guilty and consumed significantly more energy than low disinhibited participants across snack conditions. Low disinhibited participants consumed significantly less in the post-restriction period compared to baseline and the pre-restriction period, while high disinhibited participants consumed the same amount across all conditions. Aggregating the data, high and low disinhibited chocolate consumers ate snacks more frequently in the pre- and post restriction periods compared to the baseline period. CONCLUSIONS: This study suggests that for some individuals, restriction of a preferred food like chocolate may be contraindicated for energy restriction and weight management. PMID- 26010326 TI - Objective assessment of changes in physical activity and sedentary behavior: Pre- through 3 years post-bariatric surgery. AB - OBJECTIVE: To evaluate change in sedentary behavior (SB) and physical activity (PA) over 3 years following bariatric surgery. METHODS: A subset of participants in an observational study (n = 473 of 2,458; 79% female, median body mass index 45 kg m(-2) ) wore an activity monitor presurgery and at 1-3 annual postsurgery assessments. RESULTS: Over the first year, on average, sedentary time decreased from 573 (95% CI: 563-582) to 545 (95% CI: 534-555) min days(-1) and moderate- to vigorous-intensity PA (MVPA) increased from 77 (95% CI: 71-84) to 106 (95% CI: 98 116) min week(-1) , or 7 (95% CI: 5-10) to 24 (95% CI: 18-29) min week(-1) in MVPA bouts >=10 min. There were no changes in these parameters from years 1 to 3 (P for all > 0.05). The percentage of participants achieving >=150 min week(-1) of bout-related MVPA was not different at year 3 [6.5% (95% CI: 3.1-12.7)] vs. presurgery [3.4% (95% CI: 1.8-5.0); P = 0.45]. Most participants followed SB and PA trajectories that paralleled mean change and were consistent with their presurgery position in relation to the group. CONCLUSIONS: On average, bariatric surgical patients make small reductions in SB and increases in PA during the first postsurgery year, which are maintained through 3 years. Still, postsurgery PA levels fall short of PA guidelines for general health or weight control. PMID- 26010327 TI - Skeletal muscle myotubes in severe obesity exhibit altered ubiquitin-proteasome and autophagic/lysosomal proteolytic flux. AB - OBJECTIVE: Whole-body protein metabolism is dysregulated with obesity. The goal of the study was to determine whether activity and expression of major protein degradation pathways are compromised specifically in human skeletal muscle with obesity. METHODS: Primary human skeletal muscle (HSkM) cell cultures were utilized since cellular mechanisms can be studied absent of hormones and contractile activity that could independently influence metabolism. HSkM from 10 lean women (BMI <= 26.0 kg/m(2) ) and 8 women with severe obesity (BMI >= 39.0) were examined basally and when stimulated to atrophy (serum and amino acid starvation). RESULTS: HSkM from obese donors had a lower proportion of type I myosin heavy chain and slower flux through the autophagic/lysosomal pathway. During starvation, flux through the ubiquitin-proteasome system diverged according to obesity status, with a decrease in lean subjects and an increase in HSkM from subjects with obesity. HSkM in obesity also displayed elevated proteasome activity despite no difference in proteasome content. Atrophy-related gene expression and myotube area were similar in myotubes derived from individuals with and without obesity under basal and starved conditions. CONCLUSIONS: Our data indicate that muscle cells in lean individuals and in those with severe obesity have innate differences in management of protein degradation, which may explain their metabolic differences. PMID- 26010328 TI - Lifestyle and weight predictors of a healthy overweight profile over a 20-year follow-up. AB - OBJECTIVE: To examine whether changes in modifiable risk factors [physical activity, cardiorespiratory fitness (CRF), body weight, and diet composition] are associated with the transition to metabolically healthy overweight/obese (MHOW) versus metabolically abnormal overweight/obese. METHODS: Analysis included 1,358 adults [aged 25.0 (3.5) years] from the CARDIA study who were healthy at baseline and had overweight/obesity at follow-up. Participants with zero or one of the following six risk factors were classified as MHOW: elevated triglycerides, LDL, blood pressure, fasting glucose, and HOMA-insulin resistance and low HDL. RESULTS: Over the 20-year follow-up, the sample gained weight (BMI 24.5 to 31.1 kg/m(2) ), and the prevalence of MHOW was 47% at follow-up. After adjusting for changes in CRF, diet, and weight change, physical activity and macronutrient intake were not independently associated with MHOW (P > 0.05), while changes in CRF [fit-unfit: RR (95%) = 0.58, 0.52-0.66; unfit-unfit: RR = 0.67, 0.58-0.76, versus fit-fit] and weight [gain: RR (95%) = 0.54, 0.43-0.67; cycle: RR = 0.74, 0.57-0.94, versus stable] were independently associated with MHOW. CONCLUSIONS: Focusing on high CRF and strategies to limit weight gain may be important for individuals with overweight and obesity in early to mid-adulthood to maintain a metabolically healthy profile. PMID- 26010329 TI - Comparative pattern of genetic structure in two Mediterranean killifishes Aphanius fasciatus and Aphanius iberus inferred from both mitochondrial and nuclear data. AB - In this study, genetic variation was assessed in Aphanius fasciatus and Aphanius iberus characterized by similar ecological traits but with very different distribution ranges in the Mediterranean area. Five populations of A. iberus and five of A. fasciatus were analysed using five polymorphic microsatellite loci and partial mitochondrial control region (D-loop) sequences. Congruent results were found with both nuclear and mitochondrial molecular markers. The results showed that similar levels of genetic divergence, based on mitochondrial control region sequences, are present among populations of A. iberus and among populations of A. fasciatus despite the very different geographic distance existing among the examined populations of the two species (low geographic distance in A. iberus and high in A. fasciatus). A possible explanation could be that the populations of A. iberus were isolated for a longer time than the populations of A. fasciatus supporting the hypothesis that the split in the lineage leading to A. iberus is older than the split in the lineage leading to A. fasciatus. The possibility that the wide circum-Mediterranean distribution of A. fasciatus ensures the high connectivity of its populations, preventing, in some cases, local differentiation, however, cannot be ruled out. PMID- 26010331 TI - Binary classification using multivariate receiver operating characteristic curve for continuous data. AB - The classification scenario needs handling of more than one biomarker. The main objective of the work is to propose a multivariate receiver operating characteristic (MROC) model which linearly combines the markers to classify them into one of the two groups and also to determine an optimal cut point. Simulation studies are conducted for four sets of mean vectors and covariance matrices and a real dataset is also used to demonstrate the proposed model. Linear and quadratic discriminant analysis has also been applied to the above datasets in order to explain the ease of the proposed model. Bootstrapped estimates of the parameters of the ROC curve are also estimated. PMID- 26010330 TI - A herbal medicine for Alzheimer's disease and its active constituents promote neural progenitor proliferation. AB - Aberrant neural progenitor cell (NPC) proliferation and self-renewal have been linked to age-related neurodegeneration and neurodegenerative disorders including Alzheimer's disease (AD). Rhizoma Acori tatarinowii is a traditional Chinese herbal medicine against cognitive decline. In this study, we found that the extract of Rhizoma Acori tatarinowii (AT) and its active constituents, asarones, promote NPC proliferation. Oral administration of AT enhanced NPC proliferation and neurogenesis in the hippocampi of adult and aged mice as well as that of transgenic AD model mice. AT and its fractions also enhanced the proliferation of NPCs cultured in vitro. Further analysis identified alpha-asarone and beta asarone as the two active constituents of AT in promoting neurogenesis. Our mechanistic study revealed that AT and asarones activated extracellular signal regulated kinase (ERK) but not Akt, two critical kinase cascades for neurogenesis. Consistently, the inhibition of ERK activities effectively blocked the enhancement of NPC proliferation by AT or asarones. Our findings suggest that AT and asarones, which can be orally administrated, could serve as preventive and regenerative therapeutic agents to promote neurogenesis against age-related neurodegeneration and neurodegenerative disorders. PMID- 26010332 TI - Olive Fruit Fly (Bactrocera oleae) Population Dynamics in the Eastern Mediterranean: Influence of Exogenous Uncertainty on a Monophagous Frugivorous Insect. AB - Despite of the economic importance of the olive fly (Bactrocera oleae) and the large amount of biological and ecological studies on the insect, the factors driving its population dynamics (i.e., population persistence and regulation) had not been analytically investigated until the present study. Specifically, our study investigated the autoregressive process of the olive fly populations, and the joint role of intrinsic and extrinsic factors molding the population dynamics of the insect. Accounting for endogenous dynamics and the influences of exogenous factors such as olive grove temperature, the North Atlantic Oscillation and the presence of potential host fruit, we modeled olive fly populations in five locations in the Eastern Mediterranean region. Our models indicate that the rate of population change is mainly shaped by first and higher order non-monotonic, endogenous dynamics (i.e., density-dependent population feedback). The olive grove temperature was the main exogenous driver, while the North Atlantic Oscillation and fruit availability acted as significant exogenous factors in one of the five populations. Seasonal influences were also relevant for three of the populations. In spite of exogenous effects, the rate of population change was fairly stable along time. We propose that a special reproductive mechanism, such as reproductive quiescence, allows populations of monophagous fruit flies such as the olive fly to remain stable. Further, we discuss how weather factors could impinge constraints on the population dynamics at the local level. Particularly, local temperature dynamics could provide forecasting cues for management guidelines. Jointly, our results advocate for establishing monitoring programs and for a major focus of research on the relationship between life history traits and populations dynamics. PMID- 26010333 TI - Association between Dietary Magnesium Intake and Radiographic Knee Osteoarthritis. AB - OBJECTIVE: To examine the cross-sectional associations between dietary magnesium (Mg) intake and radiographic knee osteoarthritis (OA), joint space narrowing (JSN), and osteophytes (OST) respectively. METHODS: A total of 1626 subjects were included in the study. Dietary intake was assessed using a validated semi quantitative food frequency questionnaire. Radiographic knee OA was defined as Kellgren-Lawrence (K-L) Grade 2 in at least one leg. JSN and OST were assessed individually according to the Osteoarthritis Research Society International (OARSI) atlas. A multivariable logistic analysis model was applied to test the various associations after adjusting for potentially confounding factors. RESULTS: The relative odds of radiographic knee OA were decreased by 0.53 times in the third quintile of Mg intake [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.28-1.01], 0.40 times in the fourth quintile (OR 0.40, 95% CI 0.17-0.94) and 0.34 times in the fifth quintile (OR 0.34, 95% CI 0.11-1.00) compared with those in the lowest quintile, while P for trend was 0.111. The relative odds of JSN were decreased by 0.49 times in the third quintile of Mg intake (OR 0.49, 95% CI 0.28-0.88) and 0.37 times in the fifth quintile (OR 0.37, 95% CI 0.14-0.98) compared with those in the lowest quintile, while P for trend was 0.088. There was no significant relationship between dietary Mg intake and the presence of OST. CONCLUSIONS: The findings of this cross-sectional study indicate that Mg intake is inversely associated with radiographic knee OA and JSN. It supports potential role of Mg in the prevention of knee OA. LEVEL OF EVIDENCE: LevelIII, cross-sectional study. PMID- 26010334 TI - Enterovirus spectrum from the active surveillance of hand foot and mouth disease patients under the clinical trial of inactivated Enterovirus A71 vaccine in Jiangsu, China, 2012-2013. AB - Epidemiological data from active surveillance on human enterovirus, which could cause hand, foot, and mouth disease, were limited. An active surveillance system was used to investigate the enterovirus spectrum and the incidence of different enteroviruses in infants aged 6-35 months in Jiangsu Province from 2012 to 2013. Fifty-nine infants were randomly selected from 522 non-EV-A71/CV-A16 HFMD patients. We collected 173 throat swabs and 174 rectal swabs from these infants. RT-PCR was used to amplify 5'-UTR and VP1 regions of enteroviruses and the serotypes were determined by the sequence comparison using BLAST. Twenty-one non EV-A71/CA16 enterovirus serotypes were detected in those infants. E16, E18 were firstly reported in HFMD patients. The four top common non-EV-A71/CV-A enteroviruses among infants were CV-B3, CV-A10, CV-A6, and E9 with the HFMD incidence rates at 1.4%, 0.84%, 0.56%, and 0.47%, respectively. Over 20.8% patients were co-infected with multiple enteroviruses. Neither the course of sickness nor clinical symptoms of the co-infected patients was more severe than those infected with single enterovirus. Two patients were infected different enterovirus successively within 2 months. Several new enterovirus serotypes and multiple models of infection associated with HFMD were discovered through the active surveillance system. These data provide a better understanding of the viral etiology of HFMD. PMID- 26010335 TI - A mathematical model of the evolution of individual differences in developmental plasticity arising through parental bet-hedging. AB - Children vary in the extent to which their development is shaped by particular experiences (e.g. maltreatment, social support). This variation raises a question: Is there no single level of plasticity that maximizes biological fitness? One influential hypothesis states that when different levels of plasticity are optimal in different environmental states and the environment fluctuates unpredictably, natural selection may favor parents producing offspring with varying levels of plasticity. The current article presents a mathematical model assessing the logic of this hypothesis--specifically, it examines what conditions are required for natural selection to favor parents to bet-hedge by varying their offspring's plasticity. Consistent with existing theory from biology, results show that between-individual variation in plasticity cannot evolve when the environment only varies across space. If, however, the environment varies across time, selection can favor differential plasticity, provided fitness effects are large (i.e. variation in individuals' plasticity is correlated with substantial variation in fitness). Our model also generates a novel restriction: Differential plasticity only evolves when the cost of being mismatched to the environment exceeds the benefits of being well matched. Based on mechanistic considerations, we argue that bet-hedging by varying offspring plasticity, if it were to evolve, would be more likely instantiated via epigenetic mechanisms (e.g. pre- or postnatal developmental programming) than genetic ones (e.g. mating with genetically diverse partners). Our model suggests novel avenues for testing the bet-hedging hypothesis of differential plasticity, including empirical predictions and relevant measures. We also discuss several ways in which future work might extend our model. PMID- 26010336 TI - Mitochondrial and lipogenic effects of vitamin D on differentiating and proliferating human keratinocytes. AB - Even in cells that are resistant to the differentiating effects of vitamin D, the activated vitamin D receptor (VDR) can downregulate the mitochondrial respiratory chain and sustain cell growth through enhancing the activity of biosynthetic pathways. The aim of this study was to investigate whether vitamin D is effective also in modulating mitochondria and biosynthetic metabolism of differentiating cells. We compared the effect of vitamin D on two cellular models: the primary human keratinocytes, differentiating and sensitive to the genomic action of VDR, and the human keratinocyte cell line HaCaT, characterized by a rapid growth and resistance to vitamin D. We analysed the nuclear translocation and features of VDR, the effects of vitamin D on mitochondrial transcription and the consequences on lipid biosynthetic fate. We found that the negative modulation of respiratory chain is a general mechanism of action of vitamin D, but at high doses, the HaCaT cells became resistant to mitochondrial effects by upregulating the catabolic enzyme CYP24 hydroxylase. In differentiating keratinocytes, vitamin D treatment promoted intracellular lipid deposition, likewise the inhibitor of respiratory chain stigmatellin, whereas in proliferating HaCaT, this biosynthetic pathway was not inducible by the hormone. By linking the results on respiratory chain and lipid accumulation, we conclude that vitamin D, by suppressing respiratory chain transcription in all keratinocytes, is able to support both the proliferation and the specialized metabolism of differentiating cells. Through mitochondrial control, vitamin D can have an essential role in all the metabolic phenotypes occurring in healthy and diseased skin. PMID- 26010338 TI - Growth, Persistence, and Desistance of Alcohol Use for At-Risk Men in Their 30s. AB - BACKGROUND: Little is known about heterogeneity in men's drinking behaviors and their related consequences across mid-adulthood, and moreover, whether individual or social factors may predict such differences. This study examined 3 indicators of alcohol use, namely alcohol volume, heavy episodic drinking (HED), and drinking-related problems for men in their 30s. METHODS: Participants were 197 at risk men from the Oregon Youth Study assessed 5 times across ages 29 to 38 years. Growth mixture modeling with count outcomes was used to examine unobserved heterogeneity in alcohol trajectories. Associations of latent classes of alcohol users with (i) classes for the other alcohol indicators, (ii) alcohol use by peers and romantic partners, (iii) alcohol classes previously extracted from ages 18 to 29 years, and (iv) past year alcohol use disorder (AUD) diagnostic status at ages 35 to 36 years were examined. RESULTS: A 3-class solution afforded the best fit for each alcohol indicator. Alcohol problems were relatively established in the 30s, with an ascending use class found only for volume. Although relatively few men were in higher classes for all 3 indicators, 45% of the sample was in the highest class on at least 2 indicators of use. Peer drunkenness was a robust predictor of the alcohol classes. Concordance among classes of alcohol users was seen from the 20s to the 30s, with prior desistance likely to be maintained for alcohol volume and HED. AUD diagnoses at ages 35 to 36 years were more common in the higher classes obtained for alcohol volume and alcohol problems. CONCLUSIONS: Many men in their 30s engaged in a high volume of alcohol use without frequent engagement in HED, likely relating to continuing alcohol problems. The convergence of men's alcohol use with that of their peers found at younger ages was maintained into early mid-adulthood. PMID- 26010337 TI - The Group 3 Innate Lymphoid Cell Defect in Aryl Hydrocarbon Receptor Deficient Mice Is Associated with T Cell Hyperactivation during Intestinal Infection. AB - Intestinal infection with the intracellular parasite Toxoplasma gondii results in the translocation of commensal bacteria to peripheral organs and the development of a T cell response specific to the microbiota. In naive mice, the recently described RORgammat+ group 3 innate lymphoid cell (ILC) population plays a critical role in promoting intestinal barrier function and limiting responses to gut-resident commensal bacteria. Given this role for group 3 ILCs, studies were performed to evaluate whether these cells might influence the immune response to mucosal infection with T. gondii. Phenotypic characterization of RORgammat+ ILCs in T. gondii infected mice revealed that this population decreased following challenge but the population that remained expressed costimulatory molecules and IL-22. One factor that influences the maintenance of RORgammat+ ILCs is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and Ahr-/- mice have a marked defect in the lamina propria group 3 ILC population. When Ahr /- mice were challenged with T. gondii, they lost more weight than wild type controls. This disease course in Ahr-/- animals was associated with increased T cell responses to Toxoplasma antigen and crude commensal antigen preparations. Together, these data suggest that group 3 ILCs have a role in limiting T cell activation during intestinal infection. PMID- 26010339 TI - Urine testing for antipsychotics: a pilot trial for a method to determine detection levels. AB - OBJECTIVE: The goal of the present study was to demonstrate that the analytical assay of interest can detect antipsychotics in human urine specimens. METHOD: Forty inpatients treated with haloperidol, quetiapine, risperidone, or olanzapine were recruited to participate in a one visit study. During the study visit, demographic and clinical information was collected as well as one urine sample that was forwarded to the Ameritox Laboratory and assayed for the presence of antipsychotic medications and/or metabolites. Urine samples were analyzed to determine detection sensitivity for four antipsychotic medications and their metabolites (risperidone, quetiapine, olanzapine, and/or haloperidol) using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry. RESULTS: All urine samples produced positive results for the antipsychotic(s) the participants were known to be taking. Urine concentrations (level of quantification) for parent drugs ranged from <25-417 ng/mL for haloperidol, <25-4017 ng/mL for quetiapine, 0 997 ng/mL for risperidone, and 57-700 ng/mL for olanzapine. CONCLUSION: The analytical assay produced by Ameritox, Ltd using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry can qualitatively detect antipsychotics in human urine specimens. The present study highlights the potential utility of the urine assay to help monitor adherence to antipsychotic medications. PMID- 26010341 TI - A hierarchical carbon nanotube-loaded glass-filter composite paper interlayer with outstanding electrolyte uptake properties for high-performance lithium sulphur batteries. AB - A hierarchical CNT-loaded GF composite paper interlayer was fabricated by a sonication method. In this study, the GF paper offers outstanding electrolyte uptake, which is essential for preserving dissolved polysulphides, and the CNT networks provide a fast electron pathway for insulating the active materials. The GF/CNT interlayer-loaded Li-S cell exhibited a high capacity and long-term cycling performance. PMID- 26010340 TI - Patient Preference and Perception of Care Provided by Advance Nurse Practitioners and Physicians in Outpatient Adult Congenital Clinics. AB - OBJECTIVE: Nurse practitioners (NPs) have an established role for delivering competent care to patients in the primary care setting. The aim of this study was to compare satisfaction of patients managed by NPs vs. physicians in the outpatient adult congenital heart disease (CHD) clinic. DESIGN: A prospective study conducted in two outpatient adult CHD clinics to assess patient satisfaction through standardized surveys. Demographic data included CHD diagnosis, age, and New York Heart Association functional class. All patients completed a Short-Form-12 to assess health status. RESULTS: Of the 371 patients recruited (52% men; median age 29 years, severe CHD complexity 31.5%) and seen by NP (n = 187) or physician (n = 184), physician-managed practices had higher perceived: overall experience, courtesy of provider (P < 0.05) and confidence (trust) in provider (P < 0.1). Overall, patients reported satisfaction with an NP providing care (98%), the NP was able to effectively deal with illness/CHD (95%), and an increased chance (94%) or willingness to see an NP at a future visit. Only 73% reported an understanding of NP training and how an NP differed from a registered nurse. There was a stronger perception of how an NP differed from a physician (83%). CONCLUSION: Patient satisfaction was high regardless of whether care was provided by physicians or NPs. However, patients appear to make distinctions in what they believe the type of care each practitioner is best at providing. Patient education regarding competence of the different health care providers may continue to improve patient satisfaction. PMID- 26010342 TI - Viral load and mRNA expression of HPV type 6 among cases with recurrent respiratory papillomatosis. AB - OBJECTIVES/HYPOTHESIS: To determine viral load of human papillomavirus type 6 (HPV6), physical state of HPV6-DNA, and transcription level of HPV6 E7-mRNA in laryngeal papilloma and in adjacent healthy mucosa. STUDY DESIGN: Case series. METHODS: A papilloma biopsy was collected from each of 25 adult patients with respiratory recurrent papillomatosis. From 14 of the 25 patients, we first collected a biopsy from healthy mucosa of the false vocal fold and another from the papilloma. Quantity of HPV6 and E7-mRNA was measured by polymerase chain reaction. RESULTS: For the papilloma, the median load of HPV6 was 41 copies/cell, and the lowest amount was 5.4 copies/cell. Human papillomavirus type 6 was detected in 50% (7/14) of the healthy mucosa, with a median of 1.1 copies/cell, and the highest amount was 6.6 copies/cell. Overall, viral load was higher in papilloma than in healthy mucosa (P < 0.05). The average HPV6 E2/E7-DNA ratio was 1.3, indicating an episomal state. Human papillomavirus type 6-mRNA was detected in all HPV6-DNA-positive samples. The transcription median ratio of HPV6 mRNA/HPV6-DNA was 1.5 in papilloma and 3.8 in healthy mucosa. CONCLUSION: The amount of HPV6-DNA was consistently higher in the papilloma than in healthy mucosa. The transcription level of HPV6 E7 mRNA was similar in the papilloma and in normal mucosa. We suggest that interfering with replication of HPV6 and suppression of HPV6 to fewer than five copies/cell may be curative. PMID- 26010343 TI - Triage for action: Systematic assessment and dissemination of construction health and safety research. AB - BACKGROUND: Research translation too often relies on passive methods that fail to reach those who can impact the workplace. The need for better research to practice (r2p) approaches is especially pressing in construction, where a disproportionate number of workers suffer serious injury illness. METHODS: A triage process was designed and used to systematically review completed research, assess r2p readiness, establish priorities, and launch dissemination follow-up efforts. A mixed quantitative and qualitative approach was used. RESULTS: The process proved effective in ensuring that significant findings and evidence-based solutions are disseminated actively. Key factors emerged in the selection of follow-up priorities, including availability of partners able to reach end users, windows of opportunity, and cross-cutting approaches that can benefit multiple dissemination efforts. CONCLUSIONS: Use of a systematic triage process may have an important role to play in building r2p capacity in construction safety and health. PMID- 26010344 TI - Selective Oxidation of Methionine and Tryptophan Residues in a Therapeutic IgG1 Molecule. AB - Oxidation of methionine and tryptophan are common degradation pathways for monoclonal antibodies and present major analytical challenges in biotechnology. Generally, protein oxidation is detectable in stability and/or stressed samples (e.g., exposed to hydrogen peroxide, UV light, or metal ions). The induced chemical modifications may impact the biological activity of antibodies and may have biological consequences. However, these effects and the contribution of individual protein modifications are difficult to delineate as different amino acids are often oxidized simultaneously and accompanied by other degradants such as aggregates, especially in forced degradation studies. Here, we report a new method to obtain selective oxidation of methionine or tryptophan by using oxidation reagents combined with large excess of free tryptophan or methionine, correspondingly. More specifically, using hydrogen peroxide or tert-butyl hydroperoxide in combination with addition of free tryptophan allowed for selective oxidation of methionine. Conversely, the use of 2,2-azobis(2 amidinopropane) dihydrochloride in combination with free methionine resulted in selective tryptophan oxidation, whereas methionine oxidation was not significantly altered. This novel stress model system may prove to be valuable tool in future mechanistic studies of oxidative degradation of protein therapeutics. PMID- 26010345 TI - Response to Miller et al. PMID- 26010346 TI - Applications of three-dimensional printing technology in urological practice. AB - A rapid expansion in the medical applications of three-dimensional (3D)-printing technology has been seen in recent years. This technology is capable of manufacturing low-cost and customisable surgical devices, 3D models for use in preoperative planning and surgical education, and fabricated biomaterials. While several studies have suggested 3D printers may be a useful and cost-effective tool in urological practice, few studies are available that clearly demonstrate the clinical benefit of 3D-printed materials. Nevertheless, 3D-printing technology continues to advance rapidly and promises to play an increasingly larger role in the field of urology. Herein, we review the current urological applications of 3D printing and discuss the potential impact of 3D-printing technology on the future of urological practice. PMID- 26010347 TI - Preface. PMID- 26010349 TI - The origins of the directionality of noncovalent intermolecular interactions. AB - The recent sigma-hole concept emphasizes the contribution of electrostatic attraction to noncovalent bonds, and implies that the electrostatic force has an angular dependency. Here a set of clusters, which includes hydrogen bonding, halogen bonding, chalcogen bonding, and pnicogen bonding systems, is investigated to probe the magnitude of covalency and its contribution to the directionality in noncovalent bonding. The study is based on the block-localized wavefunction (BLW) method that decomposes the binding energy into the steric and the charge transfer (CT) (hyperconjugation) contributions. One unique feature of the BLW method is its capability to derive optimal geometries with only steric effect taken into account, while excluding the CT interaction. The results reveal that the overall steric energy exhibits angular dependency notably in halogen bonding, chalcogen bonding, and pnicogen bonding systems. Turning on the CT interactions further shortens the intermolecular distances. This bond shortening enhances the Pauli repulsion, which in turn offsets the electrostatic attraction, such that in the final sum, the contribution of the steric effect to bonding is diminished, leaving the CT to dominate the binding energy. In several other systems particularly hydrogen bonding systems, the steric effect nevertheless still plays the major role whereas the CT interaction is minor. However, in all cases, the CT exhibits strong directionality, suggesting that the linearity or near linearity of noncovalent bonds is largely governed by the charge-transfer interaction whose magnitude determines the covalency in noncovalent bonds. PMID- 26010350 TI - Propranolol Therapy for Problematic Infantile Hemangioma. AB - BACKGROUND: Infantile hemangioma (IH) is a common, benign tumor occurring in up to 10% of white infants. Propranolol has emerged as a front-line therapy for IH. The retrospective study examined the response of propranolol therapy on hemangioma size. METHODS: Twenty-seven children (4 to 20 weeks old) with IH were enrolled into the study of oral propranolol solution 2 mg/kg per day divided 3 times daily for 10 months. Response was assessed by size measurements at pretreatment and posttreatment. Scoring was stratified into no response, plateau, and regression groups. Secondary outcomes measured were drug compliance and complications. RESULTS: Twenty-seven consecutive patients with IH were treated with propranolol, of whom 67% completed a 6-month therapy. No correlation was demonstrated between tumor size and age at therapy initiation or patient (P = 0.7 and P = 0.7, respectively). A large number of infants responded to therapy (85.2%). Response was first observed sooner in the regression group compared to plateau responders (15.15 +/- 8.06 and 20.5 +/- 18.42 days, respectively). A significant difference in median pretreatment and posttreatment tumor size was noted (4.50 vs 1.55 cm, P = 0.02). Attrition was secondary to drug-induced side effects, no response, and dosing noncompliance. CONCLUSIONS: Propranolol is a safe and effective first-line therapy for problematic IHs. Therapy should show significant response by 2 weeks. If no response is observed by 3 weeks, then other treatment should be sought. PMID- 26010351 TI - Dorsal Intercostal Artery Perforator Propeller Flaps: A Reliable Option in Reconstruction of Large Meningomyelocele Defects. AB - Several options have been reported for the reconstruction of myelomeningocele defects. In this article, we present our experience on soft tissue reconstruction of myelomeningocele defects by using island propeller dorsal intercostal artery perforator (DIAP) flaps. Between January 2008 and February 2014, all newborns with large myelomeningocele defects (13 newborns) were reconstructed with island propeller DIAP flaps. All flaps survived completely. In 8 patients out of 13, venous insufficiency was observed which then resolved spontaneously. Flap donor sites were closed primarily. Myelomeningocele defects with a diameter larger than 5 cm require reconstruction with flaps. To mobilize a well-vascularized tissue over the defect without tension in which the suture lines will not overlap over the midline where the dura is repaired and over the meninges is one of the goals of reconstruction for such defects. Perforator propeller flaps enable us to reach those goals. Use of perforator flaps provides 2 important advantages, namely, more predictability and also more freedom in mobilizing flaps toward the defect. This study proves the reliability of DIAP propeller flaps in the reconstruction of myelomeningocele defects. PMID- 26010352 TI - Accessibility of Academic Plastic Surgeons as Mentors to Medical Students: Reply. PMID- 26010353 TI - Comparison of Delayed and Immediate Tissue Expander Breast Reconstruction in the Setting of Postmastectomy Radiation Therapy: Reply. PMID- 26010354 TI - Hypothenar Hammer Syndrome: Long-Term Results After Vascular Reconstruction. AB - BACKGROUND: Hypothenar hammer syndrome is a rare vascular lesion of the distal ulnar artery in Guyon tunnel caused by acute or repetitive blunt trauma to the hypothenar eminence. Described treatment options vary greatly, from nonoperative management treatments to surgical interventions. The aim of this study was to evaluate the long-term outcomes of patients after surgical reconstruction of the ulnar artery. METHODS: In this retrospective study, the results of 12 patients treated for hypothenar hammer syndrome were evaluated. Preoperative and postoperative examinations of the hand were recorded. Function impairment was assessed with the "Disabilites of the Arm, Shoulder and Hand" questionnaire. Comparisons were also made based on ulnar artery patency versus occlusion. All patients were evaluated for ulnar artery patency as determined by Allen's test and magnetic resonance angiography. RESULTS: All patients were men with an average age of 42.8 years. In 3 patients, a direct end-to-end anastomosis of the ulnar artery was performed, and 9 patients received a reconstruction with a reverse interpositional vein graft. Nine vascular reconstructions remained patent after a mean follow-up period of 56.9 months. These patients had a complete or at least partial relief of their pain, dysesthesia, and cold intolerance compared with preoperatively. Patients with reoccluded ulnar arteries were statistically significant younger (P = 0.036) than patients with patent ulnar artery. They also had a higher pain level (P = 0.009) and a longer follow-up period (P = 0.036) than those with patent reconstruction. There was a trend for higher functional impairment in patients with reoccluded ulnar artery (P = 0.100). Smoking habits showed no influence on ulnar artery patency. CONCLUSIONS: For patients with symptomatic hypothenar hammer syndrome and failed nonoperative treatment, surgical intervention is a good option. After more than 4.5 years after surgery 9 of 12 vascular reconstructions remained patent (75% patency rate), ensuring an immediate and long-term improvement of symptoms. PMID- 26010355 TI - Prime-boost vaccination with toxoplasma lysate antigen, but not with a mixture of recombinant protein antigens, leads to reduction of brain cyst formation in BALB/c mice. AB - INTRODUCTION: Infection with the ubiquitous parasite Toxoplasma gondii is a threat for immunocompromised patients and pregnant women and effective immune prophylaxis is still lacking. METHODS: Here we tested a mixture of recombinant T. gondii antigens expressed in different developmental stages, i.e., SAG1, MAG1 and GRA7 (SMG), and a lysate derived from T. gondii tachyzoites (TLA) for prophylactic vaccination against cyst formation. Both vaccine formulations were applied systemically followed by an oral TLA-booster in BALB/c mice. RESULTS: Systemic priming with SMG and oral TLA-booster did not show significant induction of protective immune responses. In contrast, systemic priming and oral booster with TLA induced higher levels of Toxoplasma-specific IgG, IgG1 and IgG2a in sera as well as high levels of Toxoplasma-specific IgG1 in small intestines. Furthermore, high levels of Toxoplasma-specific Th1-, Th17- and Th2-associated cytokines were only detected in restimulated splenocytes of TLA-vaccinated mice. Importantly, in mice orally infected with T. gondii oocysts, only TLA-vaccination and booster reduced brain cysts. Furthermore, sera from these mice reduced tachyzoites invasion of Vero cells in vitro, indicating that antibodies may play a critical role for protection against Toxoplasma infection. Additionally, supernatants from splenocyte cultures of TLA-vaccinated mice containing high levels of IFN-gamma lead to substantial production of nitric oxide (NO) after incubation with macrophages in vitro. Since NO is involved in the control of parasite growth, the high levels of IFN-gamma induced by vaccination with TLA may contribute to the protection against T. gondii. CONCLUSION: In conclusion, our data indicate that prime-boost approach with TLA, but not with the mixture of recombinant antigens SMG, induces effective humoral and cellular Toxoplasma specific responses and leads to significant reduction of cerebral cysts, thereby presenting a viable strategy for further vaccine development against T. gondii infection. PMID- 26010356 TI - The application of fluorescence in situ hybridization in different ploidy levels cross-breeding of lily. AB - 21 crossing were conducted between Asiatic Lily with different ploidy levels, the results showed that the interploidy hybridization between diploid and tetraploid lilies was not as successful as intraploidy hybridization. Regardless of male sterility, triploid lilies could be used as female parents in the hybridization which the progenies were aneuploidy. 3x*4x crosses could be cultured more successfully than 3x*2x crosses. 45S rDNA was mapped on the chromosomes of seven Lilium species and their progenies using fluorescence in situ hybridization (FISH). FISH revealed six to sixteen 45S rDNA gene loci, and normally the sites were not in pairs. The asymmetry indexes of LA (Longiflorum hybrids * Asiatic hybrids) hybrids was higher than Asiatic hybrids, the evolution degree was LA hybrids > Asiatic hybrids. 45S rDNA distributed variably on chromosome 1-10 and 12 among Asiatic hybrids. Chromosome 1 had invariable sites of 45S rDNA in all Asiatic hybrids, which could be considered as the characteristic of Asiatic hybrids. LA hybrid 'Freya' had two sites of 45S rDNA on one homologous chromosome 5, and also it could be found in the progenies. The karyotype and fluorescence in situ hybridization with 45S rDNA as probe were applied to identify the different genotypes of 9 hybrids. Typical chromosomes with parental signal sites could be observed in all the genotypes of hybrids, it was confirmed that all the hybrids were true. PMID- 26010357 TI - Preparation of Fluorescent Microcystin Derivatives by Direct Arginine Labelling and Their Biological Evaluation. AB - Microcystin is the most prevalent toxin produced by cyanobacteria and poses a severe threat to livestock, humans and entire ecosystems. We report the preparation of a series of fluorescent microcystin derivatives by direct arginine labelling of the unprotected peptides at the guanidinium side chain. This new method allows a simple late-stage diversification strategy for native peptides devoid of protecting groups under mild conditions. A series of fluorophores were conjugated to microcystin-LR in good to very good yield. The fluorescent probes displayed biological activity comparable to that of unlabelled microcystin, in both phosphatase inhibition assays and toxicity tests on the crustacean Thamnocephalus platyurus. In addition, we demonstrate that the fluorescent probes penetrated Huh7 cells. Whole-animal imaging was performed on T. platyurus: labelled compound was mainly observed in the digestive tract. PMID- 26010358 TI - Bronsted Acid-Mediated Annulation of alpha-Oxo Ketene Dithioacetals with Pyrroles: Efficient Synthesis of Structurally Diverse Cyclopenta[b]pyrroles. AB - Bronsted acid-mediated annulation of internal olefins alpha-oxo ketene dithioacetals to pyrroles was efficiently achieved to afford cyclopenta[b]pyrroles. A pair of Bronsted acids with acid strengths, that is, trifluoroacetic acid, and para-toluenesulfonic acid hydrate, were applied to promote the annulation reactions. The resultant products were readily oxidized to sulfones by meta-chloroperoxybenzoic acid. Subsequent treatment with 1,8 diazabicyclo[5.4.0]undec-7-ene gave desulfurized terminal olefins or [2+2] cycloaddition products from the desulfurized olefin intermediates. The present protocol provides facile access to structurally diverse cyclopenta[b]pyrrole derivatives under mild conditions. PMID- 26010359 TI - Development of an accelerometer-linked online intervention system to promote physical activity in adolescents. AB - Most adolescents do not achieve the recommended levels of moderate-to-vigorous physical activity (MVPA), placing them at increased risk for a diverse array of chronic diseases in adulthood. There is a great need for scalable and effective interventions that can increase MVPA in adolescents. Here we report the results of a measurement validation study and a preliminary proof-of-concept experiment testing the impact of Zamzee, an accelerometer-linked online intervention system that combines proximal performance feedback and incentive motivation features to promote MVPA. In a calibration study that parametrically varied levels of physical activity in 31 12-14 year-old children, the Zamzee activity meter was shown to provide a valid measure of MVPA (sensitivity in detecting MVPA = 85.9%, specificity = 97.5%, and r = .94 correspondence with the benchmark RT3 accelerometer system; all p < .0001). In a subsequent randomized controlled multi site experiment involving 182 middle school-aged children assessed for MVPA over 6 wks, intent-to-treat analyses found that those who received access to the Zamzee intervention had average MVPA levels 54% greater than those of a passive control group (p < 0.0001) and 68% greater than those of an active control group that received access to a commercially available active videogame (p < .0001). Zamzee's effects on MVPA did not diminish significantly over the course of the 6 wk study period, and were statistically significant in both females and males, and in normal- vs. high-BMI subgroups. These results provide promising initial indications that combining the Zamzee activity meter with online proximal performance feedback and incentive motivation features can positively impact MVPA levels in adolescents. PMID- 26010360 TI - Physiologically Based Pharmacokinetic Modeling Is Essential in 90Y-Labeled Anti CD66 Radioimmunotherapy. AB - INTRODUCTION: Radioimmunotherapy (RIT) with 90Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of 111In labeled anti-CD66 antibody. Equal pre-therapeutic and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients. AIMS: The aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetry in 90Y-labeled anti-CD66 RIT, 2) that pre-therapeutic and therapeutic biodistributions differ, and most importantly 3) that this difference in biodistributions can be accurately predicted using a refined model. MATERIALS AND METHODS: Two new PBPK models were developed considering fully, half and non immunoreactive antibodies and constraints for estimating the RM antigen number. Both models were fitted to gamma camera and serum measurements of 27 patients. Akaike weights were used for model averaging. Time-integrated activity coefficients for total body, liver, spleen, RM and serum were calculated. Model based predictions of the serum biokinetics during therapy were compared to actual measurements. RESULTS: Variability of the RM time-integrated activity coefficients ((37.3 +/- 7.5) h) indicates the need for patient-specific dosimetry. The relative differences between pre-therapeutic and therapeutic serum time-activity curves were (-25 +/- 16)%. The prediction accuracy of these differences using the refined PBPK models was (-3 +/- 20)%. CONCLUSION: Individual treatment is needed due to biological differences between patients in RIT with 90Y-labeled anti-CD66 antibody. Differences in pre-therapeutic and therapeutic biokinetics are predominantly caused by different degrees of saturation due to different amounts of administered antibody. These differences could be predicted using the PBPK models. PMID- 26010361 TI - Clinical and therapeutic aspects of candidemia: a five year single centre study. AB - BACKGROUND: Candida is an important cause of bloodstream infections (BSI) in nosocomial settings causing significant mortality and morbidity. This study was performed to evaluate contemporary epidemiology, species distribution, antifungal susceptibility and outcome of candida BSI in an Italian hospital. METHODS: All consecutive patients who developed candidemia at Santa Maria della Misericordia University Hospital (Italy) between January 2009 and June 2014 were enrolled in the study. RESULTS: A total of 204 episodes of candidemia were identified during the study period with an incidence of 0.79 episodes/1000 admissions. C. albicans was isolated in 60.3% of cases, followed by C. parapsilosis (16.7%), C. glabrata (11.8%) and C. tropicalis (6.4%). Of all Candida BSI, 124 (60.8 %) occurred in patients admitted to IMW, 31/204 (15.2 %) in ICUs, 33/204 (16.2%) in surgical units and 16/204 (7.8%) in Hematology/Oncology wards. Overall, 47% of patients died within 30 days from the onset of candidemia. C. parapsilosis and C. glabrata candidemia were associated with the lowest mortality rate (36%), while patients with C. tropicalis BSI had the highest mortality rate (58.3%). Lower mortality rates were detected in patients receiving therapy within 48 hours from the time of execution of the blood cultures (57,1% vs 38,9%, P < 0.05). At multivariate analysis, steroids treatment (OR = 0.27, p = 0.005) and CVC removal (OR = 3.77, p = 0.014) were independently associated with lower and higher survival probability, respectively. Candidemia in patients with peripherally inserted central catheters (PICC) showed to be associated with higher mortality in comparison with central venous catheters (CVC, Short catheters and Portacath) and no CVC use. For each point increase of APACHE III score, survival probability decreased of 2%. Caspofungin (OR = 3.45, p = 0.015) and Amphothericin B lipid formulation (OR = 15.26, p = 0.033) were independently associated with higher survival probability compared with no treatment. PMID- 26010363 TI - The vertical monitor position for presbyopic computer users with progressive lenses: how to reach clear vision and comfortable head posture. AB - When presbyopic employees are wearing general-purpose progressive lenses, they have clear vision only with a lower gaze inclination to the computer monitor, given the head assumes a comfortable inclination. Therefore, in the present intervention field study the monitor position was lowered, also with the aim to reduce musculoskeletal symptoms. A comparison group comprised users of lenses that do not restrict the field of clear vision. The lower monitor positions led the participants to lower their head inclination, which was linearly associated with a significant reduction in musculoskeletal symptoms. However, for progressive lenses a lower head inclination means a lower zone of clear vision, so that clear vision of the complete monitor was not achieved, rather the monitor should have been placed even lower. The procedures of this study may be useful for optimising the individual monitor position depending on the comfortable head and gaze inclination and the vertical zone of clear vision of progressive lenses. PRACTITIONER SUMMARY: For users of general-purpose progressive lenses, it is suggested that low monitor positions allow for clear vision at the monitor and for a physiologically favourable head inclination. Employees may improve their workplace using a flyer providing ergonomic-optometric information. PMID- 26010364 TI - Antibody biomarkers in CNS demyelinating diseases - a long and winding road. AB - Over several decades, studies sought potential markers to diagnose and to predict the clinical course of central nervous system (CNS) demyelinating disorders, especially in multiple sclerosis, acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. Reliable biomarkers would ensure correct diagnoses, determine future disease evolvements, stratify patients for appropriate treatments and monitor disease activity and treatment effects - in summary, meet the longing for personalized medicine in these diseases. Out of a plethora of potential biomarker candidates antibodies have turned (again) into the scientific focus, due to pivotal immunological and neuropathological findings in the past 20 years. A major breakthrough and stimulus for further research was the identification of anti-aquaporin-4 antibodies in neuromyelitis optica. Various other myelin and non-myelin antigens were investigated in detail for diagnostic and prognostic purposes, such as antibodies to myelin oligodendrocyte glycoprotein or to the potassium channel KIR4.1. Further, the use of biopharmaceutical treatments in multiple sclerosis led to intense research activities to identify anti-treatment neutralizing antibodies and their clinical consequences. This review briefly summarizes the current knowledge on antibodies in the diagnosis, prognosis, disease and treatment monitoring of CNS demyelinating disorders. PMID- 26010362 TI - New perspectives on microbial community distortion after whole-genome amplification. AB - Whole-genome amplification (WGA) has become an important tool to explore the genomic information of microorganisms in an environmental sample with limited biomass, however potential selective biases during the amplification processes are poorly understood. Here, we describe the effects of WGA on 31 different microbial communities from five biotopes that also included low-biomass samples from drinking water and groundwater. Our findings provide evidence that microbiome segregation by biotope was possible despite WGA treatment. Nevertheless, samples from different biotopes revealed different levels of distortion, with genomic GC content significantly correlated with WGA perturbation. Certain phylogenetic clades revealed a homogenous trend across various sample types, for instance Alpha- and Betaproteobacteria showed a decrease in their abundance after WGA treatment. On the other hand, Enterobacteriaceae, an important biomarker group for fecal contamination in groundwater and drinking water, were strongly affected by WGA treatment without a predictable pattern. These novel results describe the impact of WGA on low biomass samples and may highlight issues to be aware of when designing future metagenomic studies that necessitate preceding WGA treatment. PMID- 26010365 TI - Genomics is changing Evo-Devo. PMID- 26010366 TI - Antenatal syphilis screening using point-of-care testing in low- and middle income countries in Asia and Latin America: a cost-effectiveness analysis. AB - BACKGROUND: Untreated syphilis in pregnancy is associated with adverse clinical outcomes to the infant. In low- and middle-income countries in Asia and Latin America, 20%-30% of women are not tested for syphilis during pregnancy. We evaluated the cost-effectiveness of increasing the coverage for antenatal syphilis screening in 11 Asian and 20 Latin American countries, using a point-of care immunochromatographic strip (ICS) test. METHODS: The decision analytical cost-effectiveness models reported incremental costs per disability-adjusted life years (DALYs) averted from the perspectives of the national health care payer. Clinical outcomes were stillbirths, neonatal deaths, and congenital syphilis. DALYs were computed using WHO disability weights. Costs included the ICS test, three injections of benzathine penicillin, and nurse wages. Country-specific inputs included the antenatal prevalence of syphilis and the proportion of women in the antenatal care setting that are screened for syphilis infection as reported in the 2014 WHO baseline report on global sexually transmitted infection surveillance. Country-specific data on the annual number of live births, proportion of women with at least one antenatal care visit, and per capita gross national income were also included in the model. RESULTS: The incremental cost/DALY averted of syphilis screening is US$53 (range: US$10-US$332; Prob<1*per capita GDP=99.71%) in Asia and US$60 (range: US$5-US$225; Prob<1*per capita GDP=99.77%) in Latin America. Universal screening may reduce the annual number of stillbirths by 20,344 and 4,270, neonatal deaths by 8,201 and 1,721, cases of congenital syphilis by 10,952 and 2,298, and avert 925,039 and 197,454 DALYs in the aggregate Asian and Latin American panel, respectively. CONCLUSION: Antenatal syphilis screening is highly cost-effective in all the 11 Asian and 20 Latin American countries assessed. Our findings support the decision to expand syphilis screening in countries with currently low screening rates or continue national syphilis screening programs in countries with high rates. PMID- 26010367 TI - Comprehensive assessment of genetic sequence variants in the antioxidant 'master regulator' NRF2 in idiopathic Parkinson's disease. AB - Parkinson's disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown; however, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model generated from biopsies of the olfactory mucosa, termed hONS cells, in which the NRF2-mediated antioxidant response pathway genes were among the most differentially-expressed. To date, few studies have examined the role of the NRF2 encoding gene, NFE2L2, and PD. In this study, we comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1338, controls=1379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948), P = 0.004). Further genetic screening in hONS cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. Finally, we investigated the relationship between xenobiotic exposures and NRF2 function, through gene-environment interactions, between NFE2L2 SNPs and smoking or pesticide exposure. Our results demonstrated a significant interaction between rs2706110 and pesticide exposure (OR = 0.597 (0.393-0.900), P = 0.014). In addition, we were able to identify some age-at-onset modifying SNPs and replicate an 'early-onset' haplotype that contains a previously identified 'functional promoter' SNP (rs6721961). Our results suggest a role of NFE2L2 genetic variants in modifying PD susceptibility and onset. Our findings also support the utility of testing gene-environment interactions in genetic studies of PD. PMID- 26010368 TI - Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting. AB - BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients. PMID- 26010369 TI - The views and experiences of smokers who quit smoking unassisted. A systematic review of the qualitative evidence. AB - BACKGROUND: Unassisted cessation - quitting without pharmacological or professional support - is an enduring phenomenon. Unassisted cessation persists even in nations advanced in tobacco control where cessation assistance such as nicotine replacement therapy, the stop-smoking medications bupropion and varenicline, and behavioural assistance are readily available. We review the qualitative literature on the views and experiences of smokers who quit unassisted. METHOD: We systematically searched for peer-reviewed qualitative studies reporting on smokers who quit unassisted. We identified 11 studies and used a technique based on Thomas and Harden's method of thematic synthesis to discern key themes relating to unassisted cessation, and to then group related themes into overarching concepts. FINDINGS: The three concepts identified as important to smokers who quit unassisted were: motivation, willpower and commitment. Motivation, although widely reported, had only one clear meaning, that is 'the reason for quitting'. Willpower was perceived to be a method of quitting, a strategy to counteract cravings or urges, or a personal quality or trait fundamental to quitting success. Commitment was equated to seriousness or resoluteness, was perceived as key to successful quitting, and was often used to distinguish earlier failed quit attempts from the final successful quit attempt. Commitment had different dimensions. It appeared that commitment could be tentative or provisional, and also cumulative, that is, commitment could be built upon as the quit attempt progressed. CONCLUSION: A better understanding of what motivation, willpower and commitment mean from the smoker's perspective may provide new insights and direction for smoking cessation research and practice. PMID- 26010370 TI - Intraoperative flap design using ICG monitoring of a conjoined fabricated anterolateral thigh/tensor fasciae latae perforator flap in a case of extensive soft tissue reconstruction at the lower extremity. AB - In this report, we present a case of the use of a conjoined fabricated free anterolateral thigh (ALT)/tensor fascia latae (TFL) perforator flap for reconstruction of the lower extremity with intraoperative flap design using intraoperative indocyanine green (ICG) monitoring. The flap was used for reconstruction of a 16 cm * 28 cm sized defect of the lower leg in a 24-year-old man. The defect was caused by a third degree open fracture to the tibia. Upon dissection of the ALT perforators, ICG monitoring showed that both dominant ALT perforators did not yield a sufficient perforasome (~16 cm * 17 cm) for the larger flap needed. An adjacent TFL perforator also supplied a large perforasome (~15 cm * 11 cm), so a conjoined fabricated flap was harvested and transplanted to cover an extensive lower leg defect. The artery of the TFL perforator pedicle was being in-flap anastomosed to a side branch of the ALT pedicle. Postoperative course was uneventful and there were no complications. Length of follow-up was 6 months, aesthetic and functional outcome was good. The patient was very satisfied with the aesthetic outcome. Both legs were fully mobile after intensive physiotherapy for the reconstructed leg. The leg where the flap had been harvested showed full strength in knee joint flexion. This case could show that identification of the supplying vessels may be possible by ICG monitoring. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:684-688, 2016. PMID- 26010371 TI - Couple-Based Interventions for Adults With Eating Disorders. AB - A significant number of adults with eating disorders fail to achieve relief from the disorder, with many dropping out of treatment or relapsing. The standard treatment remains individual therapy despite partners being negatively affected and typically wanting to help in an effective and loving way. We propose that couple-based interventions, which leverage the support of a partner and the relationship in treatment, may improve outcome and recovery rates for adults with eating disorders. In this article, we survey the empirical literature supporting the treatment of adults in a couple context and describe our existing and emerging couple-based interventions for eating disorders. PMID- 26010372 TI - Diastereoselective Synthesis of Cyclic Five-Membered trans,trans-Configured Nitrodiols by Double Henry Reaction of 1,4-Dialdehydes. AB - Conformationally constrained perhydroquinoxalines 4 show high kappa receptor affinity, selectivity over related receptors and full agonistic activity. Since the kappa affinity can be correlated with the dihedral angle of the ethylenediamine pharmacophore (4a: 55 degrees /71 degrees ), the dihedral angles of the postulated cyclopentane derivative 5a (73 degrees /84 degrees ) and indane derivative 6a (77 degrees /81 degrees ) were calculated. The first step of the synthesis represents a double Henry reaction of 1,4-dialdehydes 8 and 10 with nitromethane, leading predominantly to the trans,trans-configured nitrodiols 9 and 11. X-ray crystal structure analyses of 9 and 11 led to dihedral angles O2 N C-C-OH of 73.4 and 88.3 degrees , respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a. PMID- 26010373 TI - Prevalence and Predictors of Complementary and Alternative Medicine (CAM) Use Among Ivy League College Students: Implications for Student Health Services. AB - OBJECTIVE: Determine prevalence and types of complementary and alternative medicine (CAM) therapies used and test the significance of demographics and social cognitive constructs as predictors of CAM use in a college sample. Secondary purpose was to guide the integration of CAM therapies into college health services. PARTICIPANTS: Random, stratified sample of 2,553 undergraduates and graduate students enrolled at Columbia University. METHODS: Web-based survey e-mailed to a random sample of 6,482 students. Regression analyses used to determine predictors of CAM use. RESULTS: Nearly 82% of respondents reported using at least 1 form of CAM in the last 12 months, the most common being nonvitamin, nonmineral (NVNM) products, yoga, deep breathing exercises, massage therapy, and meditation. Sex, student home origin, outcome expectancies, observational learning, and attitude toward CAM were found as significant predictors of CAM use. CONCLUSIONS: Ongoing assessment of CAM use can assist administrators and providers to enhance college health services and programs. PMID- 26010374 TI - Comparison of radiation dose between different fluoroscopy systems in the modern catheterization laboratory: Results from bench testing using an anthropomorphic phantom. AB - BACKGROUND: Variations in radiation dose between various X-ray systems have received limited study. OBJECTIVE: We examined the impact of X-ray system type on patient radiation dose during cardiac catheterization. METHODS: An anthropomorphic phantom was used in a series of standardized experiments that involved 15 sec of continuous cineangiography in 7 projections. Three to seven experiments were performed in four commonly used X-ray systems: Innova IGS (GE Healthcare), Integris Allura FD20 (Philips), Allura Clarity (Philips), and Artis one (Siemens). Phantom radiation dose was measured with a dedicated X-ray dosimetry system (Gafchromic radiology film and Film QA XR software, Ashland) that was precalibrated at 0, 1, 2, 3, and 4 Gray, and with the X-ray system built in functions. RESULTS: Radiation dose was lowest with the Allura Clarity system [average film dose 4.2+/-0.1 cGray, peak film dose 18.3+/-1.6 cGray, Air Kerma (AK) dose 0.310+/-0.002 Gray, Dose Area Product (DAP) dose 23.72+/-0.84 Gray*cm2], intermediate with the Integris Allura FD20 (average film dose 4.4+/ 1.1 cGray, peak film dose 29.4+/-15.5 cGray, AK 0.482+/-0.189 Gray, DAP 45.18+/ 21.90 Gray*cm2), and highest with the Artis one system (average film dose 7.4+/ 0.8 cGray, peak film dose 66.9+/-0.09 cGray, AK 0.746+/-0.085 Gray, DAP 75.93+/ 9.11 Gray*cm2) and the Innova IGS system (average film dose 7.2+/-1.0 cGray, peak film dose 49.3+/-28.9 cGray, AK 0.874+/-0.340 Gray, DAP 92.28+/-14.73 Gray*cm2; P=0.011 for average film dose, P=0.019 for maximum film dose, P=0.033 for AK, and P=0.008 for DAP). CONCLUSIONS: The X-ray system type has significant impact on patient radiation dose during cardiac catheterization. PMID- 26010375 TI - Single-Step Soft-Imprinted Large-Area Nanopatterned Antireflection Coating. AB - We demonstrate an effective nanopatterned antireflection coating on glass that is based on sol-gel chemistry and large-area substrate-conformal soft-imprint technology. The printed 120 nm tall silica nanocylinders with a diameter of 245 nm in a square array with 325 nm pitch form an effective-index (n = 1.20) antireflection coating that reduces the double-sided reflection from a borosilicate glass slide from 7.35% to 0.57% (averaged over the visible spectral range) with a minimum reflectance <0.05% at 590 nm. The nanoglass coating is made using a simple process involving only spin-coating and an imprint step, without vacuum technology or annealing required. The refractive index of the nanoglass layers can be tailored over a broad range by controlling the geometry (1.002 < n < 1.44 in theory), covering a wide range that is not achievable with natural materials. We demonstrate that the nanoglass coating effectively eliminates glare from smart-phone display windows and significantly improves the efficiency of glass-encapsulated solar cells. These features, that are achieved over an angular range as wide as +/-50 degrees , together with strong hydrophobicity and mechanical durability, make nanoglass coatings a promising technology to improve the functionality of optoelectronic devices based on glass encapsulation. PMID- 26010376 TI - Patchy particles. PMID- 26010377 TI - Haemocyanin is essential for embryonic development and survival in the migratory locust. AB - Haemocyanins are commonly known as copper-containing oxygen carriers within the haemolymph of arthropods, and have been found in many orders of insects. However, it remains unresolved why haemocyanins persist in insects that possess elaborate tracheal systems for oxygen diffusion to cells. Here we identified haemocyanins in the migratory locust Locusta migratoria that consists of two distinct subunits, Hc1 and Hc2. Genomic sequence analysis indicated that Hc1 and Hc2 have four and three gene copies, respectively, which may have evolved via gene duplication followed by divergent evolution of introns. The two subunits exhibit abundant and embryonic-specific expression at the mRNA and protein level; their expression peaks in the mid-term embryo and is not detectable in the late nymphal and adult stages. A larger proportion of the haemocyanins is present in the yolk compared with that in the embryo. Immunostaining shows that haemocyanins in the embryo are mainly expressed in the epidermis. Knockdown of Hc1 and Hc2 results in significant embryonic developmental delay and abnormality as well as reduced egg hatchability, ie the proportion of hatched eggs. These results reveal a previously unappreciated and fundamental role for haemocyanins in embryonic development and survival in insects, probably involving the exchange of molecules (eg O2 ) between the embryo and its environment. PMID- 26010378 TI - Light interaction in sapphire/MgF2/Al triple-layer omnidirectional reflectors in AlGaN-based near ultraviolet light-emitting diodes. AB - This study examined systematically the mechanism of light interaction in the sapphire/MgF2/Al triple-layer omnidirectional reflectors (ODR) and its effects on the light output power in near ultraviolet light emitting diodes (NUV-LEDs) with the ODR. The light output power of NUV-LEDs with the triple-layer ODR structure increased with decreasing surface roughness of the sapphire backside in the ODR. Theoretical modeling of the roughened surface suggests that the dependence of the reflectance of the triple-layer ODR structure on the surface roughness can be attributed mainly to light absorption by the Al nano-structures and the trapping of scattered light in the MgF2 layer. Furthermore, the ray tracing simulation based upon the theoretical modeling showed good agreement with the measured reflectance of the ODR structure in diffuse mode. PMID- 26010379 TI - A concept analysis of 'Meaning in work' and its implications for nursing. AB - AIM: To report an analysis of the concept of 'meaning in work'. BACKGROUND: Associated with initiatives to improve the quality of working life and the emerging movement of positive organizations, 'meaning in work' has been studied as a positive individual-level state. 'Meaning in work' has potential benefits that will improve the nursing workforce if this concept is embraced in nursing. However, the concept is not clearly defined because it has been approached from diverse theoretical perspectives and used interchangeably with analogous terms. DESIGN: A concept analysis. DATA SOURCES: Three key terms (using 'work', 'meaning' or 'meaningful', 'meaning of work', 'logotherapy') were searched in the CINAHL, PsycINFO, Business Source Complete and ABI/INFORM Global online databases from January 1940-March 2015. Among 346 articles retrieved, 28 studies were included for this concept analysis. METHODS: The procedure of concept analysis developed by Walker and Avant (2011) was used. RESULTS: Four critical attributes are identified: (1) experienced positive emotion at work; (2) meaning from work itself; (3) meaningful purpose and goals of work; and (4) work as a part of life that contributes towards meaningful existence. The identified antecedent of 'meaning in work' was a cognitive shift and the identified consequences were positive personal experience and positive impact on peers and organizations. CONCLUSION: This article provides a clear definition of 'meaning in work'. The resulting coherent definition will facilitate the use of 'meaning in work' in nursing research. PMID- 26010380 TI - Correlating the Local Defect-Level Density with the Macroscopic Composition and Energetics of Chalcopyrite Thin-Film Surfaces. AB - The unusual defect chemistry of polycrystalline Cu(In,Ga)Se2 (CIGSe) thin films is a main issue for a profound understanding of recombination losses in chalcopyrite thin-film solar cells. Especially, impurity-driven passivation of electronic levels due to point defects segregating at the surface and at grain boundaries is extensively debated. By combining current imaging tunneling spectroscopy with photoelectron spectroscopy, the local defect-level density and unusual optoelectronic grain-boundary properties of this material are correlated with the macroscopic energy levels and surface composition. Vacuum annealing of different CIGSe materials provides evidence that Na diffusion from the glass substrate does not affect the surface defect passivation or grain-boundary properties of standard Cu-poor materials. Furthermore, we find no major impact on the observed thermally activated dipole compensation or the accompanying change in surface band bending (up to 0.6 eV) due to Na. In contrast, Cu-rich CIGSe shows an opposing surface defect chemistry with only minor heat-induced band bending. Our results lead to a comprehensive picture, where the highly desirable type inversion at the p/n interface in standard chalcopyrite thin-film solar cells is dominated by band bending within the CIGSe absorber rather than the result of Na impurities or an n-type defect phase segregating at the interface. This is in accordance with recent studies suggesting a surface reconstruction as the origin for Cu depletion and band-gap widening at the surface of chalcopyrite thin films. PMID- 26010381 TI - Historical variation in young adult binge drinking trajectories and its link to historical variation in social roles and minimum legal drinking age. AB - This study examines historical variation in age 18 to 26 binge drinking trajectories, focusing on differences in both levels of use and rates of change (growth) across cohorts of young adults over 3 decades. As part of the national Monitoring the Future Study, over 64,000 youths from the high school classes of 1976 to 2004 were surveyed at biennial intervals between ages 18 and 26. We found that, relative to past cohorts, recent cohorts both enter the 18 to 26 age band engaging in lower levels and exit the 18 to 26 age band engaging in higher levels of binge drinking. The reason for this reversal is that, relative to past cohorts, binge drinking among recent cohorts accelerates more quickly across ages 18 to 22 and decelerates more slowly across ages 22 to 26. Moreover, we found that historical increases in minimum legal drinking age account for a portion of the historical decline in age 18 level, whereas historical variation in social role acquisition (e.g., marriage, parenthood, and employment) accounts for a portion of the historical acceleration in age 18 to 22 growth. We also found that historical variation in the age 18 to 22 and age 22 to 26 growth rates was strongly and positively connected, suggesting common mechanism(s) underlie historical variation of both growth rates. Findings were generally consistent across gender and indicate that historical time is an important source of individual differences in young adult binge drinking trajectories. Beyond binge drinking, historical time may also inform the developmental course of other young adult risk behaviors, highlighting the interplay of epidemiology and etiology. PMID- 26010382 TI - The social self in early adolescence: Two longitudinal investigations in the United States and China. AB - This research examined how children's inclusion of social personal attributes (e.g., talkative and argumentative) in their views of themselves changes over early adolescence in the United States and China. In 2 studies (N = 825 in Study 1 and 394 in Study 2) using open-ended methods (e.g., completion of "I . . ." stems), American and Chinese children described themselves multiple times during the 7th and 8th grades. Conceptions of the self in terms of personal attributes were the norm in both the United States and China, but personal attributes that are social became more common over early adolescence in only the United States. Study 1 indicated that increases in social personal attributes were accompanied by heightened psychological and positive descriptions of the self in both countries. Study 2 ruled out potential confounds (e.g., pubertal status) in the differences in American and Chinese children's use of social personal attributes to define themselves. PMID- 26010383 TI - Executive function skills and academic achievement gains in prekindergarten: Contributions of learning-related behaviors. AB - Although research suggests associations between children's executive function skills and their academic achievement, the specific mechanisms that may help explain these associations in early childhood are unclear. This study examined whether children's (N = 1,103; M age = 54.5 months) executive function skills at the beginning of prekindergarten (pre-K) predict their learning-related behaviors in the classroom and whether these behaviors then mediate associations between children's executive function skills and their pre-K literacy, language, and mathematic gains. Learning-related behaviors were quantified in terms of (a) higher levels of involvement in learning opportunities; (b) greater frequency of participation in activities that require sequential steps; (c) more participation in social-learning interactions; and (d) less instances of being unoccupied, disruptive, or in time out. Results indicated that children's learning-related behaviors mediated associations between executive function skills and literacy and mathematics gains through children's level of involvement, sequential learning behaviors, and disengagement from the classroom. The implications of the findings for early childhood education are discussed. PMID- 26010384 TI - Sense of purpose as a psychological resource for aging well. AB - Having a sense of purpose is recognized as an important resource for maintaining health and well-being over the life span. We examined associations of individual differences in sense of purpose with levels and rates of change in indices of aging well (health, cognition, and depressive symptoms) in a sample of 1,475 older adults (Mage = 77.06 years, SD = 6.27; 50% female) assessed on up to 6 occasions over 18 years. We also conducted survival analysis to examine associations of purpose with longevity. We hypothesized that a higher sense of purpose would be associated with better performance on the aging well measures, and that those with a higher sense of purpose would show shallower declines in aging well over time. Results indicated that participants who scored higher on sense of purpose reported lower levels of functional disability, performed better on cognitive tests (episodic memory and speed of processing), and reported better self-rated health and fewer depressive symptoms. Sense of purpose was not associated with individual differences in rates of change in the aging well indices with the exception of speed of processing, for which a higher sense of purpose was associated with marginally shallower rates of decline. Higher sense of purpose was also associated with increased probability of survival, although this association became weaker over time. The findings support the notion that purposeful living contributes to health and well-being. At the same time, higher sense of purpose may not buffer against more pervasive losses in health that become more common in oldest-old adulthood. PMID- 26010386 TI - Developmental associations between short-term variability and long-term changes: Intraindividual correlation of positive and negative affect in daily life and cognitive aging. AB - Conceptual notions and empirical evidence suggest that the intraindividual correlation (iCorr) of positive affect (PA) and negative affect (NA) is a meaningful characteristic of affective functioning. PA and NA are typically negatively correlated within-person. Previous research has found that the iCorr of PA and NA is relatively stable over time within individuals, that it differs across individuals, and that a less negative iCorr is associated with better resilience and less vulnerability. However, little is known about how the iCorr of PA and NA relates to cognitive aging. This project examined how the association between PA and NA in everyday life is associated with long-term cognitive aging trajectories. To do so, we linked microlongitudinal data on PA and NA obtained on up to 33 occasions over 6 consecutive days with macrolongitudinal data on fluid and crystallized cognitive abilities obtained over 15 years from a subsample of Berlin Aging Study participants (N = 81, mean age at the microlongitudinal study = 81 years, range 73-98; 41% women). Over and above age, gender, education, overall levels of PA and NA, and number of health conditions, a less negative iCorr of PA and NA was associated with lower levels of cognitive ability and steeper cognitive declines, particularly for fluency and knowledge abilities. We discuss possible mechanisms for this finding and argue that a less negative iCorr of PA and NA may be indicative of deficits in emotional integration that are tied to changes in crystallized aspects of cognitive abilities. PMID- 26010385 TI - Parenting and children's representations of family predict disruptive and callous unemotional behaviors. AB - Data from a large prospective longitudinal study (n = 1,239) was used to investigate the association between observed sensitive parenting in early childhood and children's representations of family relationships as measured by the Family Drawing Paradigm (FDP) in first grade as well as the extent to which these representations partially mediate the influences of early caregiving experiences on later conduct problems and callous-unemotional behaviors. A structural equation modeling approach revealed that less sensitive parenting at 24, 36, and 58 months predicts higher levels of conduct problems (CP) and callous unemotional (CU) behaviors in first grade controlling for earlier measures of CP and CU behaviors. Results also indicated that greater dysfunctional family representations, as assessed with the FDP, are significantly associated with higher CU behaviors in the first grade, but not CP. Finally, a test of the indirect pathway suggests that children's dysfunctional family representations may, in part, account for the association between sensitive parenting and CU behaviors. PMID- 26010388 TI - Varieties of quantity estimation in children. AB - In the number-to-position task, with increasing age and numerical expertise, children's pattern of estimates shifts from a biased (nonlinear) to a formal (linear) mapping. This widely replicated finding concerns symbolic numbers, whereas less is known about other types of quantity estimation. In Experiment 1, Preschool, Grade 1, and Grade 3 children were asked to map continuous quantities, discrete nonsymbolic quantities (numerosities), and symbolic (Arabic) numbers onto a visual line. Numerical quantity was matched for the symbolic and discrete nonsymbolic conditions, whereas cumulative surface area was matched for the continuous and discrete quantity conditions. Crucially, in the discrete condition children's estimation could rely either on the cumulative area or numerosity. All children showed a linear mapping for continuous quantities, whereas a developmental shift from a logarithmic to a linear mapping was observed for both nonsymbolic and symbolic numerical quantities. Analyses on individual estimates suggested the presence of two distinct strategies in estimating discrete nonsymbolic quantities: one based on numerosity and the other based on spatial extent. In Experiment 2, a non-spatial continuous quantity (shades of gray) and new discrete nonsymbolic conditions were added to the set used in Experiment 1. Results confirmed the linear patterns for the continuous tasks, as well as the presence of a subset of children relying on numerosity for the discrete nonsymbolic numerosity conditions despite the availability of continuous visual cues. Overall, our findings demonstrate that estimation of numerical and non numerical quantities is based on different processing strategies and follow different developmental trajectories. PMID- 26010387 TI - Eye tracking reveals a crucial role for facial motion in recognition of faces by infants. AB - Current knowledge about face processing in infancy comes largely from studies using static face stimuli, but faces that infants see in the real world are mostly moving ones. To bridge this gap, 3-, 6-, and 9-month-old Asian infants (N = 118) were familiarized with either moving or static Asian female faces, and then their face recognition was tested with static face images. Eye-tracking methodology was used to record eye movements during the familiarization and test phases. The results showed a developmental change in eye movement patterns, but only for the moving faces. In addition, the more infants shifted their fixations across facial regions, the better their face recognition was, but only for the moving faces. The results suggest that facial movement influences the way faces are encoded from early in development. PMID- 26010389 TI - Development of the adverse outcome pathway "alkylation of DNA in male premeiotic germ cells leading to heritable mutations" using the OECD's users' handbook supplement. AB - The Organisation for Economic Cooperation and Development's (OECD) Adverse Outcome Pathway (AOP) programme aims to develop a knowledgebase of all known pathways of toxicity that lead to adverse effects in humans and ecosystems. A Users' Handbook was recently released to provide supplementary guidance on AOP development. This article describes one AOP-alkylation of DNA in male premeiotic germ cells leading to heritable mutations. This outcome is an important regulatory endpoint. The AOP describes the biological plausibility and empirical evidence supporting that compounds capable of alkylating DNA cause germ cell mutations and subsequent mutations in the offspring of exposed males. Alkyl adducts are subject to DNA repair; however, at high doses the repair machinery becomes saturated. Lack of repair leads to replication of alkylated DNA and ensuing mutations in male premeiotic germ cells. Mutations that do not impair spermatogenesis persist and eventually are present in mature sperm. Thus, the mutations are transmitted to the offspring. Although there are some gaps in empirical support and evidence for essentiality of the key events for certain aspects of this AOP, the overall AOP is generally accepted as dogma and applies broadly to any species that produces sperm. The AOP was developed and used in an iterative process to test and refine the Users' Handbook, and is one of the first publicly available AOPs. It is our hope that this AOP will be leveraged to develop other AOPs in this field to advance method development, computational models to predict germ cell effects, and integrated testing strategies. PMID- 26010390 TI - Chain Length and Grafting Density Dependent Enhancement in the Hydrolysis of Ester-Linked Polymer Brushes. AB - Poly(N,N-dimethylacrylamide) (PDMA) brushes with different grafting density and chain length were grown from an ester group-containing initiator using surface initiated polymerization. Hydrolysis of the PDMA chains from the surface was monitored by measuring thickness of the polymer layer by ellipsometry and extension length by atomic force microscopy. It was found that the initial rate of cleavage of one end-tethered PDMA chains was dependent on the grafting density and chain length; the hydrolysis rate was faster for high grafting density brushes and brushes with higher molecular weights. Additionally, the rate of cleavage of polymer chains during a given experiment changed by up to 1 order of magnitude as the reaction progressed, with a distinct transition to a lower rate as the grafting density decreased. Also, polymer chains undergo selective cleavage, with longer chains in a polydisperse brush being preferentially cleaved at one stage of the hydrolysis reaction. We suggest that the enhanced initial hydrolysis rates seen at high grafting densities and high chain lengths are due to mechanical activation of the ester bond connecting the polymer chains to the surface in association with high lateral pressure within the brush. These results have implications for the preparation of polymers brushes, their stability under harsh conditions, and the analysis of polymer brushes from partial hydrolysates. PMID- 26010391 TI - Prothrombin complex concentrate for factor VII replacement in a patient undergoing left ventricular assist device implantation with factor VII deficiency. PMID- 26010392 TI - Predictors of Suicidal Ideation Across Deployment: A Prospective Study. AB - OBJECTIVE: Concurrent and prospective predictors of suicidal ideation were examined in a sample of 318 United States Air Force Security Forces across a 1 year deployment in Iraq and 6- to 9-month follow-up. METHOD: Participants included 294 male and 24 female Airmen ranging in age from 18 to 46 years, predominantly (67%) Caucasian. Measures included self-reports of postdeployment suicidal ideation, posttraumatic stress and depressive symptoms, alcohol use, combat experiences, relationship distress, social support, and postdeployment readjustment. RESULTS: Problem drinking before deployment prospectively predicted postdeployment suicidal ideation in univariate analyses. Depressive symptoms and problem drinking were significant independent predictors of postdeployment suicidal ideation. Findings demonstrated a ninefold increase in suicidal ideation among service members with even mild depressive symptoms if moderate problem drinking was also present. CONCLUSIONS: Predeployment problem drinking may serve as a modifiable target for early intervention of suicidal ideation. Findings illuminate the compound risk of comorbid depressive symptoms and moderate problem drinking in predicting suicidal ideation. PMID- 26010393 TI - Correlations among cognitive and behavioural assessments in patients with dementia due to Alzheimer's disease. AB - AIMS: Primarily, we sought to verify correlations among assessments for cognition, behaviour and functional independence in a sample of patients with dementia due to Alzheimer's disease (AD). Secondarily, impacts of education, APOE haplotypes, length of dementia, age and alcohol use over the neuropsychiatric assessment were estimated. METHODS: Patients with AD were assessed for demographic features, neuropsychiatric symptoms, cognitive test scores, functional impairment, caregiver burden and APOE haplotypes. Statistical comparisons were undertaken by way of Kruskal-Wallis test, linear regressions and Spearman correlations, significance at rho < 0.05. RESULTS: A total of 217 patients were included. Mean schooling was 4.21 +/- 3.7 years, with significant impacts over cognitive tests. Mean age at examination was 78 +/- 6.19 years-old, significantly influencing instrumental functionality. The mean length of the dementia syndrome was 5.4 +/- 2.9 years, significantly impacting cognitive decline and functionality. Apathy was the most common behavioural symptom, negatively correlated with anxiety and delusions, and positively correlated with lifetime alcohol load. Patients with previous smoking or drinking habits were more likely to continue smoking or drinking later in life. APOE4+ haplotypes led to earlier dementia onset and significantly lower caregiver burden in mild dementia stages. CONCLUSIONS: Most correlations among test results were highly significant, confirming that cognition, behaviour and functionality are usually interrelated in all stages of AD. Caregiver burden was correlated with behaviour, but not with cognition, and was lower for patients with APOE4+ haplotypes in mild dementia stages. Education is a major impact factor for cognitive performance. PMID- 26010394 TI - Solitary tumour-like mass lesions of the central nervous system: Primary angiitis of the CNS and inflammatory pseudotumour. PMID- 26010395 TI - Perceived influence, decision-making and access to information in family services as factors of parental empowerment: a cross-sectional study of parents with young children. AB - BACKGROUND: Parental empowerment is known to increase parents' resources and to reduce stress, and therefore to improve family well-being. Professionals working in family services (child health clinics, school health care, day care, preschool and primary school) encounter families in various everyday settings and can significantly support parental empowerment. AIM: This study aimed (i) to identify associations between parental empowerment and demographic and family service characteristics (i.e. parents' participation and perceived influence, decision making and access to information) and (ii) to identify predictors of maternal and paternal empowerment. METHOD: Study design was cross-sectional. Participants were mothers (n = 571) and fathers (n = 384) of children aged 0-9 who were selected by stratified random sampling in 2009. Associations were analysed by t-test, one-way analysis of variance and multiple linear regression analysis. RESULTS: Sufficient perceived influence and joint decision-making by family and professionals on family service appointments emerged as significant variables of increased parental empowerment. Access to adequate information about municipal services was also associated with high empowerment. These family service characteristics were associated with parents' sense that they were able to manage in everyday life and had influence on specific service situations and family services in general. Mothers with a child aged under 3 or a child in home care or primary school, and fathers with a lower education feel less empowered in family services than other parents. CONCLUSION: Knowledge about the factors associated with parental empowerment can contribute to further reinforce parental empowerment, help identify parents who need special attention and contribute to the development of family services. PMID- 26010397 TI - Is thrombophilia associated with placenta-mediated complications? A prospective cohort study: comment. PMID- 26010398 TI - Cecropin-P17, an analog of Cecropin B, inhibits human hepatocellular carcinoma cell HepG-2 proliferation via regulation of ROS, Caspase, Bax, and Bcl-2. AB - Cecropin-P17 is a peptide derived from Cecropin B. In this study, we investigated the effects and relative mechanisms of Cecropin-P17 in a human liver cancer cell line (HepG-2) in vitro and in vivo. A cell viability assay, Annexin V/propidium iodide assay, western blot, flow cytometry, quantitative real-time polymerase chain reaction, and a tumor-xenograft model were applied to elucidate the mechanism exerted by Cecropin-P17 on HepG-2 cells. Cecropin-P17 significantly inhibited the proliferation of HepG-2 cells and demonstrated low cytotoxicity to normal liver cells in vitro. The apoptotic rate of HepG-2 cells was increased after Cecropin-P17 treatment together with increased production of reactive oxygen species. Moreover, Cecropin-P17 stimulated caspase-3, caspase-9, and Bax and inhibited Bcl-2 on both the transcriptional and translational levels. Finally, Cecropin-P17 significantly suppressed tumor growth in a HepG-2-bearing nude mouse model. All of these results indicated that Cecropin-P17 could be a potential agent for the treatment of liver cancer. PMID- 26010396 TI - Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis. AB - RUNX1 (previously termed AML1) is a frequent target of human leukaemia-associated gene aberrations, and it encodes the DNA-binding subunit of the Core-Binding Factor transcription factor complex. RUNX1 expression is essential for the initiation of definitive haematopoiesis, for steady-state thrombopoiesis, and for normal lymphocytes development. Recent studies revealed that protein arginine methyltransferase 1 (PRMT1), which accounts for the majority of the type I PRMT activity in cells, methylates two arginine residues in RUNX1 (R206 and R210), and these modifications inhibit corepressor-binding to RUNX1 thereby enhancing its transcriptional activity. In order to elucidate the biological significance of these methylations, we established novel knock-in mouse lines with non methylable, double arginine-to-lysine (RTAMR-to-KTAMK) mutations in RUNX1. Homozygous Runx1(KTAMK) (/) (KTAMK) mice are born alive and appear normal during adulthood. However, Runx1(KTAMK) (/) (KTAMK) mice showed a reduction in CD3(+) T lymphoid cells and a decrease in CD4(+) T cells in peripheral lymphoid organs, in comparison to their wild-type littermates, leading to a reduction in the CD4(+) to CD8(+) T-cell ratio. These findings suggest that arginine-methylation of RUNX1 in the RTAMR-motif is dispensable for the development of definitive haematopoiesis and for steady-state platelet production, however this modification affects the role of RUNX1 in the maintenance of the peripheral CD4(+) T-cell population. PMID- 26010399 TI - Interactions of Phytophthora capsici with Resistant and Susceptible Pepper Roots and Stems. AB - Using host resistance is an important strategy for managing pepper root and crown rot caused by Phytophthora capsici. An isolate of P. capsici constitutively expressing a gene for green fluorescent protein was used to investigate pathogen interactions with roots, crowns, and stems of Phytophthora-susceptible bell pepper 'Red Knight', Phytophthora-resistant bell pepper 'Paladin', and Phytophthora-resistant landrace Criollos de Morelos 334 (CM-334). In this study, the same number of zoospores attached to and germinated on roots of all cultivars 30 and 120 min postinoculation (pi), respectively. At 3 days pi, significantly more secondary roots had necrotic lesions on Red Knight than on Paladin and CM 334 plants. By 4 days pi, necrotic lesions had formed on the taproot of Red Knight but not Paladin or CM-334 plants. Although hyphae were visible in the crowns and stems of all Red Knight plants observed at 4 days pi, hyphae were observed in crowns of only a few Paladin and in no CM-334 plants, and never in stems of either resistant cultivar at 4 days pi. These results improve our understanding of how P. capsici infects plants and may contribute to the use of resistant pepper cultivars for disease management and the development of new cultivars. PMID- 26010400 TI - Can different geographic conditions affect the formation of striae gravidarum? A multicentric study. AB - AIM: Striae gravidarum (SG) is a most common physiological skin change that many pregnant women experience during pregnancy. We investigated the effects of geographic conditions and altitude on the formation of SG. MATERIAL AND METHODS: A total of 508 nulliparous women with singleton gestation were included in the study from three different geographic locations. The first city is located in the mountainous area at an altitude of approximately 1900 m (approximately 6233 ft). The second city is located on a plain in the middle of the country at an altitude of 900 m (approximately 2952 ft). The third city is located by the seaside (altitude 26 m, 85 ft). Twelve variables were recorded for each woman in the prepartum period, and striae were scored using the numerical scoring system of Atwal et al. RESULTS: We found that striae formation was significantly more common in higher areas. According to the regression analyses, when the third region, located at sea level, was taken as a reference point, the appearance of SG was 2.1- and 1.8-fold more common in the first region (altitude 1900 m) and the second region (altitude 900 m), respectively (P = 0.020). CONCLUSION: To the best of our knowledge, this study is the first to evaluate the effect of environmental factors on SG formation. Moreover, our study group is one of the largest in the published work. Environmental factors can affect the formation of striae gravidarum. Further studies with different ethnic groups are needed. PMID- 26010403 TI - A nodule on the scalp of an elderly patient. PMID- 26010401 TI - A perspective on the enhancer dependent bacterial RNA polymerase. AB - Here we review recent findings and offer a perspective on how the major variant RNA polymerase of bacteria, which contains the sigma54 factor, functions for regulated gene expression. We consider what gaps exist in our understanding of its genetic, biochemical and biophysical functioning and how they might be addressed. PMID- 26010404 TI - Large defects in aplasia cutis congenita treated by large-sized thin split thickness skin grafting: long-term follow-up of 18 patients. AB - OBJECTIVE: To evaluate the long-term results of using surgical large-sized thin split-thickness skin grafting to treat aplasia cutis congenita (ACC) in neonates. METHODS: This study included 18 ACC neonates with large skin defects who underwent large-sized thin split-thickness skin grafting at our hospital from March 2002 to November 2011. The size of the lesion was >10% of the total body surface area (TBSA) in 16 patients, 7% of TBSA in one patient, and 3% of TBSA in another patient. The size of the skin graft was designed to be equal to or slightly larger than the size of the lesion. RESULTS: Skin grafts in 16 patients who were followed for periods of 6 months-7 years after surgery showed good survival; however, two patients were lost to follow-up. The wound healed completely without scarring in five patients. One of the five patients who healed without scarring had failed previous conservative treatment. Several mild hypertrophic scars occurred in one patient, and flat, thin, shiny, soft, parchment-like scars were noted in five other patients. Dark red, hard, raised hypertrophic scars occurred in five patients who had partial necrosis in the skin graft after surgery. CONCLUSION: A large-sized thin split-thickness skin graft can be used to effectively close a wound and permit healing to occur with reduced long-term scarring. This procedure is ideal for treating skin defects in patients with ACC. PMID- 26010405 TI - Topical timolol in nasal tip hemangioma: a viable alternative to systemic therapy. PMID- 26010406 TI - Ferrocene-Based Tetradentate Schiff Bases as Supporting Ligands in Uranium Chemistry. AB - Uranyl(VI), uranyl(V), and uranium(IV) complexes supported by ferrocene-based tetradentate Schiff-base ligands were synthesized, and their solid-state and solution structures were determined. The redox properties of all complexes were investigated by cyclic voltammetry. The bulky salfen-(t)Bu2 allows the preparation of a stable uranyl(V) complex, while a stable U(IV) bis-ligand complex is obtained from the salt metathesis reaction between [UI4(OEt2)2] and K2salfen. The reduction of the [U(salfen)2] complex leads to an unprecedented intramolecular reductive coupling of the Schiff-base ligand resulting in a C-C bond between the two ferrocene-bound imino groups. PMID- 26010408 TI - Does the early intensification of intrathecal therapy improve outcomes in pediatric acute lymphoblastic leukemia patients with CNS2/TLP+ status at diagnosis? AB - OBJECTIVES: We aimed to determine whether the addition of two extra intrathecal methotrexate (ITM) doses during induction in acute lymphoblastic leukemia (ALL) patients eliminate the prognostic significance of CNS2/TLP+ status. METHODS: We retrospectively analyzed 224 patients according to the central nervous system (CNS) involvement at diagnosis: CNS1, CNS2, or CNS3. Patients with CNS2/TLP+ received two additional ITM doses during induction. Patients were treated according to the Children's Cancer Group (CCG)-1991/1961 protocols between January 2001 and December 2007. RESULTS: The 5-year relapse-free survival (RFS) rates for the ALL patients in the CNS1, CNS2, and CNS3 groups were 80.4 +/- 3.0, 100, and 73.5 +/- 11.3%, respectively; a non-significant difference was observed between the groups (P = 0.063). However, the patients with CNS2 had significantly better survival compared with the CNS3 patients (P = 0.03). The 5-year cumulative incidence of relapse (CIR) rates for the three groups were 17 (95% confidence interval (CI): 11.9-22.9), 0, and 18.8% (95% CI: 4.3-41.1), respectively; (P = 0.214) and those of isolated or combined CNS relapse were 9.6 (95% CI: 5.8-14.5), 0 and 6.3% (95% CI: 0.3-25.8), respectively (P = 0.424). CONCLUSIONS: This study shows that the intensification of ITM therapy during induction improves outcomes in patients with CNS2/TLP+ status and eliminates its prognostic significance. This suggests that early intensification using CNS-directed therapy is beneficial in controlling minimal CNS disease. PMID- 26010409 TI - Molecular characterization of a transmembrane C-type lectin receptor gene from ayu (Plecoglossus altivelis) and its effect on the recognition of different bacteria by monocytes/macrophages. AB - C-type lectin receptors (CTLRs) play vital roles in immune responses as pattern recognition receptors (PRRs). In this study, we identified a novel C-type lectin receptor (PaCTLRC) gene from ayu, Plecoglossus altivelis. Predicted PaCTLRC is a single transmembrane receptor with a typical carbohydrate recognition domain (CRD) at its C-terminus. Sequence comparison and phylogenetic tree analysis showed that PaCTLRC was most closely related to Atlantic salmon (Salmo salar) CLRC, but was significantly different from two other ayu CTLRs, aCLR and PaCD209L. PaCTLRC transcript was detected in all tested tissues and cells, with high levels in the liver; and its expression was significantly altered upon Vibrio anguillarum infection. Refolded recombinant PaCTLRC (rPaCTLRC) agglutinated three types of Gram-positive bacteria (Listeria monocytogenes, Staphylococcus aureus and Streptococcus iniae) and four types of Gram-negative bacteria (Aeromonas hydrophila, Escherichia coli, V. anguillarum and Vibrio parahaemolyticus) in a Ca(2+)-dependent manner in vitro, and Gram-positive bacteria were shown to be biologically relevant ligands for PaCTLRC. rPaCTLRC bound to d-mannose, d-galactose, l-fucose, N-acetyl-d-glucosamine (GlcNAc), lipopolysaccharide (LPS) and peptidoglycan (PGN), exhibiting a relative binding strength to d-mannose and PGN. d-Mannose, l-fucose, GlcNAc, LPS and PGN could inhibit the agglutinating activity of rPaCTLRC, while d-galactose did not functioned. PaCTLRC neutralization using anti-PaCTLRC IgG resulted in the inhibition of phagocytosis by ayu monocytes/macrophages (MO/MPhi) of S. aureus but not of E. coli, and produced a consistently higher survival rate of S. aureus than that of E. coli. d-Mannose, LPS and PGN treatment had no significant influence on the phagocytosis of ayu MO/MPhi. These results suggest that PaCTLRC may serve as a Gram-positive bacteria-preferred PRR which is involved in pathogen recognition and signal transduction in ayu MO/MPhi. PMID- 26010407 TI - GSK-3beta Phosphorylation of Cytoplasmic Dynein Reduces Ndel1 Binding to Intermediate Chains and Alters Dynein Motility. AB - Glycogen synthase kinase 3 (GSK-3) has been linked to regulation of kinesin dependent axonal transport in squid and flies, and to indirect regulation of cytoplasmic dynein. We have now found evidence for direct regulation of dynein by mammalian GSK-3beta in both neurons and non-neuronal cells. GSK-3beta coprecipitates with and phosphorylates mammalian dynein. Phosphorylation of dynein intermediate chain (IC) reduces its interaction with Ndel1, a protein that contributes to dynein force generation. Two conserved residues, S87/T88 in IC-1B and S88/T89 in IC-2C, have been identified as GSK-3 targets by both mass spectrometry and site-directed mutagenesis. These sites are within an Ndel1 binding domain, and mutation of both sites alters the interaction of IC's with Ndel1. Dynein motility is stimulated by (i) pharmacological and genetic inhibition of GSK-3beta, (ii) an insulin-sensitizing agent (rosiglitazone) and (iii) manipulating an insulin response pathway that leads to GSK-3beta inactivation. Thus, our study connects a well-characterized insulin-signaling pathway directly to dynein stimulation via GSK-3 inhibition. PMID- 26010410 TI - Localization and dynamics of primordial germ cells in the bivalve species Ruditapes philippinarum. PMID- 26010411 TI - Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer cells. AB - BACKGROUND: Identification and validation of a targeted therapy for triple negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFalpha, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC. METHODS: We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines. RESULTS: D1(A12) was found to significantly inhibit the release of TGFalpha, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells. CONCLUSION: Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells. PMID- 26010412 TI - Modelling the cost-effectiveness of public awareness campaigns for the early detection of non-small-cell lung cancer. AB - BACKGROUND: Survival rates in lung cancer in England are significantly lower than in many similar countries. A range of Be Clear on Cancer (BCOC) campaigns have been conducted targeting lung cancer and found to improve the proportion of diagnoses at the early stage of disease. This paper considers the cost effectiveness of such campaigns, evaluating the effect of both the regional and national BCOC campaigns on the stage distribution of non-small-cell lung cancer (NSCLC) at diagnosis. METHODS: A natural history model of NSCLC was developed using incidence data, data elicited from clinical experts and model calibration techniques. This structure is used to consider the lifetime cost and quality adjusted survival implications of the early awareness campaigns. Incremental cost effectiveness ratios (ICERs) in terms of additional costs per quality-adjusted life-years (QALYs) gained are presented. Two scenario analyses were conducted to investigate the role of changes in the 'worried-well' population and the route of diagnosis that might occur as a result of the campaigns. RESULTS: The base-case theoretical model found the regional and national early awareness campaigns to be associated with QALY gains of 289 and 178 QALYs and ICERs of L13 660 and L18 173 per QALY gained, respectively. The scenarios found that increases in the 'worried well' population may impact the cost-effectiveness conclusions. CONCLUSIONS: Subject to the available evidence, the analysis suggests that early awareness campaigns in lung cancer have the potential to be cost-effective. However, significant additional research is required to address many of the limitations of this study. In addition, the estimated natural history model presents previously unavailable estimates of the prevalence and rate of disease progression in the undiagnosed population. PMID- 26010413 TI - Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab treated metastatic melanoma patients. AB - BACKGROUND: Ipilimumab improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment. The aim of this study was to identify an upfront marker for treatment benefit. METHODS: A total of 187 metastatic melanoma patients treated in three Italian Institutions with 3 mg kg(-1) ipilimumab, and 27 patients treated with 10 mg kg(-1) ipilimumab, were evaluated. Neutrophil-to lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors. RESULTS: In the training cohort of 69 patients treated at European Institute of Oncology, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR=0.38; 95% CI: 0.22-0.66; P=0.0006) and OS (HR=0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR?5. Associations of low NLR with improved survival were confirmed in three validation cohorts of patients. CONCLUSION: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve to identify patients most likely to benefit from this therapy. PMID- 26010415 TI - Left Ventricular Pseudoaneurysm after Aortic Valve Bypass Implantation. PMID- 26010414 TI - Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas. AB - BACKGROUND: Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-1alpha target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF A inhibition and RT (a.k.a. trimodality therapy). METHODS: Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. RESULTS: In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell specific apoptosis than bimodality therapies, and microvessel density and HIF 1alpha activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. CONCLUSIONS: The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1alpha activity. PMID- 26010416 TI - A qualitative exploration of the experiences of children with spina bifida and their parents around incontinence and social participation. AB - BACKGROUND: Urinary incontinence is frequently experienced by children with spina bifida, putting them at increased risk for low self-esteem and impacting upon participation in home, school and leisure activities. However, little is known about children's experiences of these continence issues. OBJECTIVE: This study explored the experiences of children and young people with spina bifida around continence issues, social participation and peer relationships, in order to identify potential areas of support healthcare professionals can provide. METHODS: Children and youth aged 6-18 years with diagnoses of spina bifida and neurogenic bladder and their parents were invited to participate in semi structured interviews. Descriptive thematic analysis was employed. RESULTS: Eleven children (with a range of mobility levels, types of spina bifida and degrees of bladder control) and their parents participated in the study. Three broad themes were identified, which encompassed the following: (1) normal versus different; (2) independence, ownership and the road to continence; and (3) peer relationships and acceptance. DISCUSSION: The experiences discussed by the children and parents in this study ranged from minimal impact of incontinence on their day-to-day living to significant social isolation and rejection. The stigma of incontinence was apparent in all interviews. Children and youth who were able to control their bladder with minimal accidents had greater independence and more opportunities for social participation. Healthcare professionals need to take into account that parents and their children may differ in attitudes and desires about the management of incontinence. PMID- 26010417 TI - Xylem cavitation resistance can be estimated based on time-dependent rate of acoustic emissions. AB - Acoustic emission (AE) analysis allows nondestructive monitoring of embolism formation in plant xylem, but signal interpretation and agreement of acoustically measured hydraulic vulnerability with reference hydraulic techniques remain under debate. We compared the hydraulic vulnerability of 16 species and three crop tree cultivars using hydraulic flow measurements and acoustic emission monitoring, proposing the use of time-dependent AE rates as a novel parameter for AE analysis. There was a linear correlation between the water potential (Psi) at 50% loss of hydraulic conductivity (P50 ) and the Psi at maximum AE activity (Pmaxrate ), where species with lower P50 also had lower Pmaxrate (P < 0.001, R(2) = 0.76). Using AE rates instead of cumulative counts for AE analysis allows more efficient estimation of P50 , while excluding problematic AE at late stages of dehydration. PMID- 26010418 TI - Effect of Delayed Cord Clamping on Neurodevelopment at 4 Years of Age: A Randomized Clinical Trial. AB - IMPORTANCE: Prevention of iron deficiency in infancy may promote neurodevelopment. Delayed umbilical cord clamping (CC) prevents iron deficiency at 4 to 6 months of age, but long-term effects after 12 months of age have not been reported. OBJECTIVE: To investigate the effects of delayed CC compared with early CC on neurodevelopment at 4 years of age. DESIGN, SETTING, AND PARTICIPANTS: Follow-up of a randomized clinical trial conducted from April 16, 2008, through May 21, 2010, at a Swedish county hospital. Children who were included in the original study (n = 382) as full-term infants born after a low risk pregnancy were invited to return for follow-up at 4 years of age. Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Movement Assessment Battery for Children (Movement ABC) scores (collected between April 18, 2012, and July 5, 2013) were assessed by a blinded psychologist. Between April 11, 2012, and August 13, 2013, parents recorded their child's development using the Ages and Stages Questionnaire, Third Edition (ASQ) and behavior using the Strengths and Difficulties Questionnaire. All data were analyzed by intention to treat. INTERVENTIONS: Randomization to delayed CC (>=180 seconds after delivery) or early CC (<=10 seconds after delivery). MAIN OUTCOMES AND MEASURES: The main outcome was full-scale IQ as assessed by the WPPSI-III. Secondary objectives were development as assessed by the scales from the WPPSI-III and Movement ABC, development as recorded using the ASQ, and behavior using the Strengths and Difficulties Questionnaire. RESULTS: We assessed 263 children (68.8%). No differences were found in WPPSI-III scores between groups. Delayed CC improved the adjusted mean differences (AMDs) in the ASQ personal-social (AMD, 2.8; 95% CI, 0.8-4.7) and fine-motor (AMD, 2.1; 95% CI, 0.2-4.0) domains and the Strengths and Difficulties Questionnaire prosocial subscale (AMD, 0.5; 95% CI, >0.0-0.9). Fewer children in the delayed-CC group had results below the cutoff in the ASQ fine-motor domain (11.0% vs 3.7%; P = .02) and the Movement ABC bicycle-trail task (12.9% vs 3.8%; P = .02). Boys who received delayed CC had significantly higher AMDs in the WPPSI-III processing-speed quotient (AMD, 4.2; 95% CI, 0.8 7.6; P = .02), Movement ABC bicycle-trail task (AMD, 0.8; 95% CI, 0.1-1.5; P = .03), and fine-motor (AMD, 4.7; 95% CI, 1.0-8.4; P = .01) and personal-social (AMD, 4.9; 95% CI, 1.6-8.3; P = .004) domains of the ASQ. CONCLUSIONS AND RELEVANCE: Delayed CC compared with early CC improved scores in the fine-motor and social domains at 4 years of age, especially in boys, indicating that optimizing the time to CC may affect neurodevelopment in a low-risk population of children born in a high-income country. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01581489. PMID- 26010420 TI - Carcass feeding as a cryptic foraging mode in round goby Neogobius melanostomus. AB - Round gobies Neogobius melanostomus were observed readily consuming soft tissue from carcasses of larger fishes under both laboratory and field conditions. Consumption normally progressed in a typical sequence, starting with soft and easily accessible tissues such as the eyes, followed by puncture of the abdominal cavity, gut consumption and then muscle consumption. Carcass feeding has not previously been seen in N. melanostomus and has potential consequences for transfer of nutrients and contaminants. PMID- 26010419 TI - Optimal Duration of Dual Antiplatelet Therapy after Drug-Eluting Stents: Meta Analysis of Randomized Trials. AB - INTRODUCTION: The optimal duration of dual antiplatelet therapy (DAPT) after drug eluting stent implantation (DES) is not certain. The AHA/ACC guidelines recommend 12 months of DAPT based on observational trials. Recently, several large randomized controlled trials (RCT) suggested a noninferiority of shorter duration of DAPT and other trials showed a benefit from extended duration of DAPT after 12 months of DES implantation. METHODS: PubMed databases were searched for RCTs comparing the continued use of DAPT to shorter duration of DAPT (aspirin alone) for variable durations beyond 3 months of DES implantation. Our analysis was limited to trials with clinical outcomes. Odds ratio (OR) and 95% confidence intervals (CI) were calculated using fixed and random-effects models. Subgroup analyses were performed for second generation DES and for trials comparing 12 months of DAPT vs. earlier interruption or longer duration of DAPT. RESULTS: We identified 10 RCTs including 32,136 subjects randomized to continued use of DAPT vs. aspirin alone for variable durations after 3 months of DES implantation. There was no significant heterogeneity among studies (Q test P > 0.1). Compared to shorter DAPT, longer DAPT resulted in a significant reduction in stent thrombosis (0.3% vs. 0.7%, P < 0.01) and myocardial infarction (1.3% vs. 2%, P < 0.01), and a significant increase in major bleeding (0.8% vs. 0.4%, P < 0.01). There was no difference in cardiac deaths or stroke. All-cause deaths were slightly lower with shorter DAPT compared to longer DAPT (OR 0.8, 95% CI 0.7 to 0.99, P = 0.04). A small number of subjects were included between 3 and 6 months after DES implantation. CONCLUSION: DAPT continued beyond 6 months after second generation DES implantation decreases stent thrombosis and myocardial infarction, but increases major bleeding and all-causes mortality compared to shorter DAPT (aspirin alone). There was no difference in cardiac mortality or stroke. PMID- 26010421 TI - Novel digital imaging techniques to assess the outcome in oral rehabilitation with dental implants: a narrative review. AB - AIM: To examine the literature on novel digital imaging techniques for the assessment of outcomes in oral rehabilitation with dental implants. MATERIAL AND METHODS: An electronic search of Medline and Embase databases including studies published prior to 28th December 2014 was performed and supplemented by a manual search. A synthesis of the publications was presented describing the use of computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography, optical scanning, spectrophotometry or optical coherence tomography (OCT) related to the outcome measures in implant therapy. RESULTS AND CONCLUSIONS: Most of the digital imaging techniques have not yet sufficiently been validated to be used for outcome measures in implant dentistry. In clinical research, cone beam CT (CBCT) is increasingly being used for 3D assessment of bone and soft tissue following augmentation procedures and implant placement. Currently, there are no effective methods for the reduction of artifacts around implants in CBCT. Optical scanning is being used for the 3D assessment of changes in the soft tissue contour. The combination of optical scan with pre-operative CBCT allows the determination of the implant position and its spatial relation to anatomical structures. Spectrophotometry is the method most commonly used to objectively assess the color match of reconstructions and peri-implant mucosa to natural dentition and gingiva. New optical imaging techniques may be considered possible approaches for monitoring peri-implant soft tissue health. MRI and ultrasonography appear promising non-ionizing radiation imaging modalities for the assessment of soft tissue and bone defect morphologies. Optical scanners and OCT may represent efficient clinical methods for accurate assessment of the misfit between the reconstructions and the implants. PMID- 26010422 TI - Estimation of treatment effect in a subpopulation: An empirical Bayes approach. AB - It is well recognized that the benefit of a medical intervention may not be distributed evenly in the target population due to patient heterogeneity, and conclusions based on conventional randomized clinical trials may not apply to every person. Given the increasing cost of randomized trials and difficulties in recruiting patients, there is a strong need to develop analytical approaches to estimate treatment effect in subpopulations. In particular, due to limited sample size for subpopulations and the need for multiple comparisons, standard analysis tends to yield wide confidence intervals of the treatment effect that are often noninformative. We propose an empirical Bayes approach to combine both information embedded in a target subpopulation and information from other subjects to construct confidence intervals of the treatment effect. The method is appealing in its simplicity and tangibility in characterizing the uncertainty about the true treatment effect. Simulation studies and a real data analysis are presented. PMID- 26010423 TI - Dietary forage concentration and particle size affect sorting, feeding behaviour, intake and growth of Chinese Holstein male calves. AB - The objective of study was to evaluate the effect of forage concentration (F:C) and forage particle length (FPL) on sorting, feeding behaviour, intake, growth and body measurements of growing calves. Twenty-eight weaned calves of body weight 156.79 +/- 33.44 (mean +/- SD) were used in 2 * 2 factorial arrangements with the factors FPL of hay grass (full and short) and hay grass concentrations (low, 50% and high, 65%). The treatments were as follows: full length (FL) with low F:C (50:50), FL with high F:C(65:35), short length (SL) with low F:C (50:50) and SL with high F:C (65:35). Increasing F:C and decreasing FPL enhanced sorting for short and fine particle and sorting against long particle (p < 0.05). Dry matter intake (DMI) was decreased by decreasing the FPL (p < 0.05). Increasing F:C (65:35) increased the DMI (p < 0.05). A positive interaction between FPL and F:C was found for (daily weight gain) DWG, weight gain (WG) and feed conversation ratio (FCR) (p < 0.05). In case of feeding behaviour, interaction for eating time and eating time per kilogram DM was present. Increasing the F:C increased the eating time in both FL and SL (p < 0.05). Chopping of hay had decreased the chewing time (p < 0.05). Increasing F:C increased chewing time per kilogram DMI. High F:C decreased the lying time (p < 0.05) in FL and SL treatments (p < 0.05). Increasing F:C reduced the overall abnormal behaviour (p < 0.05). These results suggested that animals performed better at higher F:C at SL diet. Intensity of sorting for short and fine particle and against long particle increased at higher F:C and SL diets. Eating time and eating time per kilogram DMI increased by increasing F:C level in both FL and SL treatments. Chewing time increased by increasing the FPL, while increasing the F:C enhanced the chewing time per kilogram DMI and reduced animal's abnormal behaviour. PMID- 26010424 TI - Clinical and biological determinants of melanoma progression: Should all be considered for clinical management? AB - Cutaneous melanoma is a heterogeneous disease affecting the regulation of multiple genes and proteins that contribute to melanoma progression. Survival for patients with locally invasive disease varies greatly, even within tumour stages based on current prognostic criteria. This has prompted investigations into the value of additional clinical or biological parameters predicting survival. In particular, the improved knowledge of tumour biology has fed the hope that the outcome may be predicted at the molecular level. The prognostic value of numerous potential biomarkers has therefore been evaluated in protein and gene expression studies, and genomic associations with melanoma prognosis are beginning to emerge. These potential biomarkers interrogate key tumour and host processes important for tumour development and progression, such as proliferation, invasion and migration through epithelial mesenchymal transition or the host immune or vascular responses. This research may allow more individualised information on prognosis if the challenges regarding the quality and validation of studies are overcome. PMID- 26010425 TI - The Parallel Analysis of Phase Sensitive Inversion Recovery (PSIR) and Double Inversion Recovery (DIR) Images Significantly Improves the Detection of Cortical Lesions in Multiple Sclerosis (MS) since Clinical Onset. AB - BACKGROUND: Double inversion recovery (DIR) detects only a minority (<20%) of cortical lesions (CL) in multiple sclerosis (MS). Phase-sensitive inversion recovery (PSIR) was suggested to be substantially superior to DIR in the detection of cortical lesions (CL). These two sequences might be complementary. OBJECTIVES: To analyze CL frequency and type in MS patients having different disease duration and disability, including patients at clinical onset, and to discern more correctly the artifacts, by combining DIR and PSIR images. PATIENTS AND METHODS: 40 patients were enrolled in the study: 10 clinically isolated syndrome/early relapsing remitting MS (CIS/eRRMS), 24 relapsing remitting MS (RRMS), 6 secondary progressive MS (SPMS). DIR and PSIR images were jointly used to classify lesions as purely intracortical (IC), leukocortical (LC) and juxtacortical (JC). RESULTS: PSIR disclosed CL in 100% of the patients and was capable of identifying more than four times lesions (455.5%, p<0.00001), especially IC (mean numbers: 36.5 in CIS/eRRMS, 45.0 in RRMS and 52.3 in SPMS) and LC (mean numbers: 10.9 in CIS/eRRMS, 20.1 in RRMS and 25.3 in SPMS), compared to DIR (p<0.00001). CL number was significantly higher in SPMS compared to RRMS (p<0.0001). Artifacts were more accurately identified by comparing the two sequences. CONCLUSIONS: Our study confirms the higher ability of PSIR in disclosing and classifying CL. The presence of CL in all CIS patients further points out the relevance of cortical pathology in MS. Whether the parallel analysis of DIR and PSIR images may be useful for diagnostic purposes, especially when a diagnosis of MS is suspected but not confirmed by routine MRI, needs to be evaluated in larger patient series. The analysis of the cortex by DIR and PSIR may also allow a better stratification of the patients for prognostic and counseling purposes, as well as for their inclusion in clinical studies. PMID- 26010426 TI - Foxp1 regulates cortical radial migration and neuronal morphogenesis in developing cerebral cortex. AB - FOXP1 is a member of FOXP subfamily transcription factors. Mutations in FOXP1 gene have been found in various development-related cognitive disorders. However, little is known about the etiology of these symptoms, and specifically the function of FOXP1 in neuronal development. Here, we report that suppression of Foxp1 expression in mouse cerebral cortex led to a neuronal migration defect, which was rescued by overexpression of Foxp1. Mice with Foxp1 knockdown exhibited ectopic neurons in deep layers of the cortex postnatally. The neuronal differentiation of Foxp1-downregulated cells was normal. However, morphological analysis showed that the neurons with Foxp1 deficiency had an inhibited axonal growth in vitro and a weakened transition from multipolar to bipolar in vivo. Moreover, we found that the expression of Foxp1 modulated the dendritic maturation of neurons at a late postnatal date. Our results demonstrate critical roles of Foxp1 in the radial migration and morphogenesis of cortical neurons during development. This study may shed light on the complex relationship between neuronal development and the related cognitive disorders. PMID- 26010427 TI - Randomized trial of low-dose peginterferon alpha-2b plus low and escalating doses of ribavirin in older patients with chronic hepatitis C with high viral load genotype 1. AB - Elderly patients with chronic hepatitis C cannot tolerate standard combination therapy of peginterferon and ribavirin, which remains the backbone of therapy in many countries, including Japan. The efficacy and safety of low-dose peginterferon alpha-2b in combination with low and escalating doses of ribavirin in older patients with high viral load genotype 1 were investigated in this randomized controlled trial. Thirty-two patients (age >= 60 years) were randomized into standard (group 1) or low (group 2) doses of peginterferon alpha 2b in combination with low and escalating doses of ribavirin. Patients were evaluated for safety and efficacy of treatment. There was a higher virological response rate in group 1 than in group 2. However, the response in men was higher than in women in the early treatment phase and 24 weeks after treatment (P = 0.008). There was no significant difference between the two groups in the virological response rate in men and women. Completion of therapy was higher in group 2 than in group 1 (31% vs. 13%, P = 0.200). Dose modification of ribavirin was less frequent in group 2 than in group 1 (69% vs. 88%, P = 0.200). These data suggest that combination therapy with low-dose peginterferon plus low and escalating doses of ribavirin may be safer in older patients than that with standard dose peginterferon, without impairing the treatment response. PMID- 26010429 TI - Commentary on Maurage et al.: Theory of Mind Difficulties in Patients with Alcohol Dependence. PMID- 26010428 TI - Individual topographic variability is inherent to cortical physiology but task related differences may be noise. AB - The observation of highly variable sets of association neocortical areas across individuals, containing the estimated generators of Slow Potentials (SPs) and beta oscillations, lead to the persistence in individual analyses. This brought to notice an unexpected within individual topographic similarity between task conditions, despite our original interest in task-related differences. A recent related work explored the quantification of the similarity in beta topography between largely differing tasks. In this article, we used Independent Component Analysis (ICA) for the decomposition of beta activity from a visual attention task, and compared it with quiet resting, recorded by 128-channel EEG in 62 subjects. We statistically tested whether each ICA component obtained in one condition could be explained by a linear regression model based on the topographic patterns from the other condition, in each individual. Results were coherent with the previous report, showing a high topographic similarity between conditions. From an average of 12 beta component maps obtained for each task, over 80% were satisfactorily explained by the complementary task. Once more, the component maps including those considered unexplained, putatively "task specific", had their scalp distribution and estimated cortical sources highly variable across subjects. These findings are discussed along with other studies based on individual data and the present fMRI results, reinforcing the increasingly accepted view that individual variability in sets of active neocortical association areas is not noise, but intrinsic to cortical physiology. Actual 'noise', mainly stemming from group "brain averaging" and the emphasis on statistical differences as opposed to similarities, may explain the overall hardship in replication of the vast literature on supposed task-specific forms of activity, and the ever inconclusive status of a universal functional mapping of cortical association areas. A new hypothesis, that individuals may use the same idiosyncratic sets of areas, at least by their fraction of activity in the sub delta and beta range, in various non-sensory-motor forms of conscious activities, is a corollary of the discussed variability. PMID- 26010431 TI - Risky drug use and effects on sleep quality and daytime sleepiness. AB - OBJECTIVE: Sleep problems are commonly reported following alcohol and cannabis abuse, but our understanding of sleep in non-clinical drug using populations is limited. The present study examined the sleep characteristics of alcohol and cannabis users recruited from the wider community. METHODS: Two hundred forty eight self-identified alcohol and/or cannabis users (131 women and 117 men) with a mean age of 26.41 years completed an online study that was advertised via online forums, print media and flyers. As part of the study, participants completed validated sleep scales assessing sleep quality (Pittsburgh Sleep Quality Index) and excessive daytime sleepiness (Epworth Sleepiness Scale) in addition to validated drug scales assessing alcohol (Alcohol Use Disorders Identification Test) and cannabis (Marijuana Screening Inventory) use. RESULTS: Problems with sleep quality were more commonly reported than were complaints of excessive daytime sleepiness. Clinically significant poor sleep quality was associated with comorbid problem alcohol and cannabis use. Women reporting problem alcohol and cannabis use had poorer sleep outcomes than men. CONCLUSIONS: Social drug users who report risky alcohol and cannabis use also report poor sleep. Poor sleep quality likely exacerbates any drug-associated problems in non clinical populations. PMID- 26010430 TI - Sirtuin-6 deficiency exacerbates diabetes-induced impairment of wound healing. AB - Delayed wound healing is one of the major complications in diabetes and is characterized by chronic proinflammatory response, and abnormalities in angiogenesis and collagen deposition. Sirtuin family proteins regulate numerous pathophysiological processes, including those involved in promotion of longevity, DNA repair, glycolysis and inflammation. However, the role of sirtuin 6 (SIRT6), a NAD+-dependent nuclear deacetylase, in wound healing specifically under diabetic condition remains unclear. To analyse the role of SIRT6 in cutaneous wound healing, paired 6-mm stented wound was created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and nonsense siRNA served as controls). Wound time to closure was assessed by digital planimetry, and wounds were harvested for histology, immunohistochemistry and Western blotting. SIRT6-siRNA-treated diabetic wound showed impaired healing, which was associated with reduced capillary density (CD31-staining vessels) when compared to control treatment. Interestingly, SIRT6 deficiency decreased vascular endothelial growth factor expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor-kappaB (NF kappaB) activation resulting in increased expression of proinflammatory markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-alpha and interleukin-1beta) and increased oxidative stress. Collectively, our findings demonstrate that loss of SIRT6 in cutaneous wound aggravates proinflammatory response by increasing NF-kappaB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that the activation of SIRT6 signalling might be a potential therapeutic approach for promoting wound healing in diabetics. PMID- 26010433 TI - Embolization of Veno-venous Collaterals after the Fontan Operation Is Associated with Decreased Survival. AB - OBJECTIVE: After Fontan operation, hemodynamically significant veno-venous collateral (VVC) vessels can lead to systemic arterial desaturation. Outcomes after embolization of VVCs have not been determined. We sought to determine the frequency of and outcomes for patients undergoing VVCs embolization after Fontan operation. DESIGN: We retrospectively analyzed clinical and hemodynamic data of patients who underwent cardiac catheterization after the Fontan operation from 1995 to 2014 at Mayo Clinic. Clinical, imaging, and hemodynamic data from patients with VVCs were compared based on intervention (embolization) vs. nonintervention. RESULTS: Four hundred ninety-six patients with prior Fontan operation had catheterization; 109 VVCs were identified in 72 patients (37 males, mean age 26 +/- 12 years). Embolization was performed in 31/72 patients (43%). Following embolization, no improvement was demonstrated in oxygen saturation or hemoglobin concentration at ambulatory follow-up (2.5 +/- 2 years), and cardiac index declined at follow-up catheterization (5.6 +/- 3 years). Overall, 15 patients (21%) died at a mean of 2.8 +/- 4 years after embolization. Fifty percent of deaths after embolization occurred in patients with Fontan pressures >=18 mm Hg. Five-year survival of patients with VVCs undergoing embolization was 74% compared with 92% in those patients who did not undergo embolization (P < .01). In multivariate analysis, significant predictors of death on follow-up were embolization [hazard ratio (HR) = 9.3 (95% confidence interval [CI], 2.8-42), P = .0001], atrio-pulmonary Fontan (HR = 4.2 [95% CI, 1.4-15], P = .01), and heterotaxy (HR = 3.7 [95% CI, 1.0-15], P = .05). CONCLUSION: We observed decreased 5-year survival in patients who had VVC embolization. Embolization of VVC in patients after Fontan should be evaluated very carefully in patients with atrio-pulmonary type Fontan, heterotaxy, and those with Fontan pressure above 18 mm Hg. These patients may benefit from the "natural" fenestration that VVCs provide. PMID- 26010432 TI - Rethinking the concepts of 'local or global processors': evidence from Williams syndrome, Down syndrome, and Autism Spectrum Disorders. AB - Both Williams syndrome (WS) and Autism Spectrum Disorder (ASD) have been characterized as preferentially processing local information, whereas in Down syndrome (DS) the reported tendency is to process stimuli globally. We designed a cross-syndrome, cross-task comparison to reveal similarities and differences in local/global processing in these disorders. Our in-depth study compared local/global processing across modalities (auditory-verbal/visuo-spatial) and levels of processing (high/low) in the three syndromes. Despite claims in the literature, participants with ASD or WS failed to show a consistent local processing bias, while those with DS failed to show a reliable global processing bias. Depending on the nature of the stimuli and the task, both local and global processing biases were evident in all three neurodevelopmental disorders. These findings indicate that individuals with neurodevelopmental disorders cannot simply be characterized as local or global processors. PMID- 26010434 TI - Occupational exposure to solvents and risk of breast cancer. AB - BACKGROUND: Occupational exposure to some organic solvents may increase risk of breast cancer. METHODS: In a population-based case-control study, 1,205 women diagnosed with primary breast cancer between 2009 and 2011 were drawn from the Western Australian Cancer Registry and matched to 1,789 controls from the electoral roll. Exposure to solvents was determined through telephone interviews using OccIDEAS. RESULTS: About a third of women were occupationally exposed to solvents. Age adjusted breast cancer risks were elevated for women who had been exposed to aliphatic solvents odds ratio (OR) 1.21 (95%CI 0.99-1.48) and aromatic solvents OR 1.21 (95%CI 0.97-1.52). For most solvents the ORs were higher for those diagnosed before menopause. CONCLUSIONS: This study suggests that there may be an association between occupational exposure to aliphatic and aromatic solvents and the risk of breast cancer at the low levels of exposure experienced by women in this study. PMID- 26010435 TI - Systematic review of exercise for Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well-powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear. PMID- 26010438 TI - Structure and stability of supramolecular crown ether complexes. AB - Despite the fact that the complexation of ammonium cations with ionophores like crown ethers plays an important role in biological and industrial processes, there is still a lack of theoretical methods to reproduce or even predict the host-guest complex structures or their thermodynamic stabilities in an accurate manner. Hence, the development of ionophores has often relied on a trial-and error approach and the synthetic efforts associated with this have been enormous, so far. Therefore, theoretical methods for the reliable prediction of binding affinities of crown ether derivatives with ammonium ions would be an indispensable tool for the rational design of new receptors with tailored properties. Here, we suggest a computationally efficient but still accurate theoretical approach. It is tested for a model system consisting of 18-crown-6 ether and an ammonium cation, but is invented for application to much larger complexes. The accuracy of various approximate quantum-chemical methods, based on density functional theory (DFT) and many-body perturbation theory, is evaluated against the gold standard CCSD(T) in the basis set limit as internal reference. An important aspect is the consideration of dispersion interactions in DFT methods, for which the dispersion-correction by Grimme was employed. For all selected methods, the basis-set dependence of calculated interaction energies was investigated. PMID- 26010437 TI - A Versatile Strategy for the Semisynthetic Production of Ser65 Phosphorylated Ubiquitin and Its Biochemical and Structural Characterisation. AB - Ubiquitin phosphorylation is emerging as an important regulatory layer in the ubiquitin system. This is exemplified by the phosphorylation of ubiquitin on Ser65 by the Parkinson's disease-associated kinase PINK1, which mediates the activation of the E3 ligase Parkin. Additional phosphorylation sites on ubiquitin might also have important cellular roles. Here we report a versatile strategy for preparing phosphorylated ubiquitin. We biochemically and structurally characterise semisynthetic phospho-Ser65-ubiquitin. Unexpectedly, we observed disulfide bond formation between ubiquitin molecules, and hence a novel crystal form. The method outlined provides a direct approach to study the combinatorial effects of phosphorylation on ubiquitin function. Our analysis also suggests that disulfide engineering of ubiquitin could be a useful strategy for obtaining alternative crystal forms of ubiquitin species thereby facilitating structural validation. PMID- 26010439 TI - Electrophysiologic monitoring correlates of recurrent laryngeal nerve heat thermal injury in a porcine model. AB - OBJECTIVES/HYPOTHESIS: Thermal injury to the recurrent laryngeal nerve (RLN) may not be visually apparent and may go unrecognized intraoperatively. This study aimed to investigate the heat thermal tolerance of RLN and evaluate the electrophysiologic correlates of electromyographic (EMG) signal change during an acute RLN heat damage. STUDY DESIGN: Prospective porcine model with continuous intraoperative neuromonitoring (CIONM). METHODS: Ten pigs (20 RLNs) undergoing CIONM had their EMG tracings recorded and correlated with heated normal saline (NS) irrigation of varying temperature and duration. RESULTS: In the initial pilot study, the EMG was without change during incremental heated NS irrigation (40/45/50/55 degrees C for 60 seconds), but adverse EMG combined events (CE) (amplitude decrease with a concordant latency increase) occurred and degraded to loss of signal (LOS) (by 17.5 +/- 1.3 seconds) when the temperature was elevated to 60 degrees C (n = 4). Another 16 RLNs were evaluated to further compare the EMG pattern after various degrees of thermal stress (60/70 degrees C for 30/20 seconds). Electromyographic recordings showed CEs and LOS in all RLNs, and only six of eight RLNs with 60 degrees C exposure showed slight EMG amplitude recovery (16%-35%) after 20 minutes. None of the injured nerve segments were visually apparent, but all were detectable by IONM. CONCLUSION: Sixty degrees Celsius is a critical temperature to cause RLN thermal injury. Continuous intraoperative neuromonitoring can be used as a tool for the early detection of acute thermal stress and may guide use of energy-based devices during thyroid procedures. LEVEL OF EVIDENCE: N/A. PMID- 26010440 TI - Modulation of Cytochrome P450 Activity by 18beta-Glycyrrhetic Acid and its Consequence on Buspirone Pharmacokinetics in Rats. AB - The aim of this study was to elucidate the inhibition mechanism of 18beta glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC50 of 20.1 +/- 10.7 MUM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration-time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12-1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A-mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A-mediated drug metabolism in vivo. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010441 TI - Routine Preoperative Liver-specific Magnetic Resonance Imaging Does Not Exclude the Necessity of Contrast-enhanced Intraoperative Ultrasound in Hepatic Resection for Colorectal Liver Metastasis. AB - OBJECTIVES: To assess the usefulness of contrast-enhanced intraoperative ultrasound (CE-IOUS) during surgery for colorectal liver metastases (CRLM) when gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) is performed as a part of preoperative imaging work up. BACKGROUND: EOB-MRI is expected to supersede CE-IOUS, which is reportedly indispensable in surgery for CRLM. METHODS: One hundred consecutive patients underwent EOB-MRI, contrast-enhanced computed tomography (CE-CT), and contrast enhanced ultrasound within 1 month before surgery for CRLM. Conventional IOUS and subsequent CE-IOUS using perflubutane were performed after the laparotomy. All the nodules identified in any of the preoperative or intraoperative examinations were resected and were submitted for histological examination, in principle. RESULTS: Preoperative imaging examinations identified 242 nodules; 25 additional nodules were newly identified using IOUS, 22 additional nodules were newly identified during CE-IOUS, and a histological examination further identified 4 nodules. Among the 25 nodules newly identified using IOUS, all 21 histologically proven CRLMs and 3 of the 4 benign nodules were correctly diagnosed using CE IOUS. Among the 22 nodules newly identified using CE-IOUS, 17 nodules in 16 patients were histologically diagnosed as CRLMs. The planned surgical procedure was modified on the basis of IOUS and CE-IOUS findings in 12 and 14 patients, respectively. The sensitivity, positive-predictive value, and accuracy of CE-IOUS were 99%, 98%, and 97%, respectively. Those values of EOB-MRI (82%, 99%, 83%, respectively) were similar to CE-CT (81%, 99%, 81%, respectively). CONCLUSIONS: CE-IOUS is useful in hepatic resection for CRLM, even if EOB-MRI and CE-CT are performed. PMID- 26010442 TI - Is leadership a reliable concept in animals? An empirical study in the horse. AB - Leadership is commonly invoked when accounting for the coordination of group movements in animals, yet it remains loosely defined. In parallel, there is increased evidence of the sharing of group decisions by animals on the move. How leadership integrates within this recent framework on collective decision-making is unclear. Here, we question the occurrence of leadership in horses, a species in which this concept is of prevalent use. The relevance of the three main definitions of leadership--departing first, walking in front travel position, and eliciting the joining of mates--was tested on the collective movements of two semi-free ranging groups of Przewalski horses (Equus ferus przewalskii). We did not find any leader capable of driving most group movements or recruiting mates more quickly than others. Several group members often displayed pre-departure behaviours at the same time, and the simultaneous departure of several individuals was common. We conclude that the decision-making process was shared by several group members a group movement (i.e., partially shared consensus) and that the leadership concept did not help to depict individual departure and leading behaviour across movements in both study groups. Rather, the different proxies of leadership produced conflicting information about individual contributions to group coordination. This study discusses the implications of these findings for the field of coordination and decision-making research. PMID- 26010443 TI - Structural Basis of pH Dependence of Neoculin, a Sweet Taste-Modifying Protein. AB - Among proteins utilized as sweeteners, neoculin and miraculin are taste-modifying proteins that exhibit pH-dependent sweetness. Several experiments on neoculin have shown that His11 of neoculin is responsible for pH dependence. We investigated the molecular mechanism of the pH dependence of neoculin by molecular dynamics (MD) calculations. The MD calculations for the dimeric structures of neoculin and His11 mutants showed no significant structural changes for each monomer at neutral and acidic pH levels. The dimeric structure of neoculin dissociated to form isolated monomers under acidic conditions but was maintained at neutral pH. The dimeric structure of the His11Ala mutant, which is sweet at both neutral and acidic pH, showed dissociation at both pH 3 and 7. The His11 residue is located at the interface of the dimer in close proximity to the Asp91 residue of the other monomer. The MD calculations for His11Phe and His11Tyr mutants demonstrated the stability of the dimeric structures at neutral pH and the dissociation of the dimers to isolated monomers. The dissociation of the dimer caused a flexible backbone at the surface that was different from the dimeric interface at the point where the other monomer interacts to form an oligomeric structure. Further MD calculations on the tetrameric structure of neoculin suggested that the flexible backbone contributed to further dissociation of other monomers under acidic conditions. These results suggest that His11 plays a role in the formation of oligomeric structures at pH 7 and that the isolated monomer of neoculin at acidic pH is responsible for sweetness. PMID- 26010444 TI - Correction: comparative phylogeography of Mississippi embayment fishes. PMID- 26010445 TI - A First Generation Comparative Chromosome Map between Guinea Pig (Cavia porcellus) and Humans. AB - The domesticated guinea pig, Cavia porcellus (Hystricomorpha, Rodentia), is an important laboratory species and a model for a number of human diseases. Nevertheless, genomic tools for this species are lacking; even its karyotype is poorly characterized. The guinea pig belongs to Hystricomorpha, a widespread and important group of rodents; so far the chromosomes of guinea pigs have not been compared with that of other hystricomorph species or with any other mammals. We generated full sets of chromosome-specific painting probes for the guinea pig by flow sorting and microdissection, and for the first time, mapped the chromosomal homologies between guinea pig and human by reciprocal chromosome painting. Our data demonstrate that the guinea pig karyotype has undergone extensive rearrangements: 78 synteny-conserved human autosomal segments were delimited in the guinea pig genome. The high rate of genome evolution in the guinea pig may explain why the HSA7/16 and HSA16/19 associations presumed ancestral for eutherians and the three syntenic associations (HSA1/10, 3/19, and 9/11) considered ancestral for rodents were not found in C. porcellus. The comparative chromosome map presented here is a starting point for further development of physical and genetic maps of the guinea pig as well as an aid for genome assembly assignment to specific chromosomes. Furthermore, the comparative mapping will allow a transfer of gene map data from other species. The probes developed here provide a genomic toolkit, which will make the guinea pig a key species to unravel the evolutionary biology of the Hystricomorph rodents. PMID- 26010446 TI - Fate of the molar dental lamina in the monophyodont mouse. AB - The successional dental lamina (SDL) plays an essential role in the development of replacement teeth in diphyodont and polyphyodont animals. A morphologically similar structure, the rudimental successional dental lamina (RSDL), has been described in monophyodont (only one tooth generation) lizards on the lingual side of the developing functional tooth. This rudimentary lamina regresses, which has been proposed to play a role in preventing the formation of future generations of teeth. A similar rudimentary lingual structure has been reported associated with the first molar in the monophyodont mouse, and we show that this structure is common to all murine molars. Intriguingly, a lingual lamina is also observed on the non-replacing molars of other diphyodont mammals (pig and hedgehog), initially appearing very similar to the successional dental lamina on the replacing teeth. We have analyzed the morphological as well as ultrastructural changes that occur during the development and loss of this molar lamina in the mouse, from its initiation at late embryonic stages to its disappearance at postnatal stages. We show that loss appears to be driven by a reduction in cell proliferation, down-regulation of the progenitor marker Sox2, with only a small number of cells undergoing programmed cell death. The lingual lamina was associated with the dental stalk, a short epithelial connection between the tooth germ and the oral epithelium. The dental stalk remained in contact with the oral epithelium throughout tooth development up to eruption when connective tissue and numerous capillaries progressively invaded the dental stalk. The buccal side of the dental stalk underwent keratinisation and became part of the gingival epithelium, while most of the lingual cells underwent programmed cell death and the tissue directly above the erupting tooth was shed into the oral cavity. PMID- 26010447 TI - Somatostatin Derivate (smsDX) Attenuates the TAM-Stimulated Proliferation, Migration and Invasion of Prostate Cancer via NF-kappaB Regulation. AB - Tumor development and progression are influenced by macrophages of the surrounding microenvironment. To investigate the influences of an inflammatory tumor microenvironment on the growth and metastasis of prostate cancer, the present study used a co-culture model of prostate cancer (PCa) cells with tumor associated macrophage (TAM)-conditioned medium (MCM). MCM promoted PCa cell (LNCaP, DU145 and PC-3) growth, and a xenograft model in nude mice consistently demonstrated that MCM could promote tumor growth. MCM also stimulated migration and invasion in vitro. Somatostatin derivate (smsDX) significantly attenuated the TAM-stimulated proliferation, migration and invasion of prostate cancer. Immunohistochemistry revealed that NF-kappaB was over-expressed in PCa and BPH with chronic inflammatory tissue specimens and was positively correlated with macrophage infiltration. Further investigation into the underlying mechanism revealed that NF-kappaB played an important role in macrophage infiltration. SmsDX inhibited the paracrine loop between TAM and PCa cells and may represent a potential therapeutic agent for PCa. PMID- 26010448 TI - Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin. AB - Malaria is one of the most devastating parasitic diseases worldwide. Plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. Chloroquine (CQ) and artemisinin (ART) are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for CQ) and increasing oxidative stress. Besides the contribution of the CQ resistance transporter (PfCRT) and the multidrug resistant gene (pfmdr), CQ resistance has also been associated with increased parasite glutathione (GSH) levels. ART resistance was recently shown to be associated with mutations in the K13-propeller protein. To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium berghei parasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs) encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko) or higher (pbggcs-oe) levels of GSH than wild type parasites. In addition, GSH levels were determined in P. berghei parasites resistant to CQ and mefloquine (MQ). Increased GSH levels were detected in both, CQ and MQ resistant parasites, when compared to the parental sensitive clone. Sensitivity to CQ and ART remained unaltered in both pgggcs-ko and pbggcs-oe parasites when tested in a 4 days drug suppressive assay. However, recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART treatment. These results suggest that GSH levels influence Plasmodium berghei response to ART treatment. PMID- 26010449 TI - High Throughput Sequencing of Small RNAs in the Two Cucurbita Germplasm with Different Sodium Accumulation Patterns Identifies Novel MicroRNAs Involved in Salt Stress Response. AB - MicroRNAs (miRNAs), a class of small non-coding RNAs, recognize their mRNA targets based on perfect sequence complementarity. MiRNAs lead to broader changes in gene expression after plants are exposed to stress. High-throughput sequencing is an effective method to identify and profile small RNA populations in non-model plants under salt stresses, significantly improving our knowledge regarding miRNA functions in salt tolerance. Cucurbits are sensitive to soil salinity, and the Cucurbita genus is used as the rootstock of other cucurbits to enhance salt tolerance. Several cucurbit crops have been used for miRNA sequencing but salt stress-related miRNAs in cucurbit species have not been reported. In this study, we subjected two Cucurbita germplasm, namely, N12 (Cucurbita. maxima Duch.) and N15 (Cucurbita. moschata Duch.), with different sodium accumulation patterns, to Illumina sequencing to determine small RNA populations in root tissues after 4 h of salt treatment and control. A total of 21,548,326 and 19,394,108 reads were generated from the control and salt-treated N12 root tissues, respectively. By contrast, 19,108,240 and 20,546,052 reads were obtained from the control and salt treated N15 root tissues, respectively. Fifty-eight conserved miRNA families and 33 novel miRNAs were identified in the two Cucurbita germplasm. Seven miRNAs (six conserved miRNAs and one novel miRNAs) were up-regulated in salt-treated N12 and N15 samples. Most target genes of differentially expressed novel miRNAs were transcription factors and salt stress-responsive proteins, including dehydration induced protein, cation/H+ antiporter 18, and CBL-interacting serine/threonine protein kinase. The differential expression of miRNAs between the two Cucurbita germplasm under salt stress conditions and their target genes demonstrated that novel miRNAs play an important role in the response of the two Cucurbita germplasm to salt stress. The present study initially explored small RNAs in the response of pumpkin to salt stress, and provided valuable information on novel miRNAs and their target genes in Cucurbita. PMID- 26010451 TI - Amplicon sequencing of colorectal cancer: variant calling in frozen and formalin fixed samples. AB - Next generation sequencing (NGS) is an emerging technology becoming relevant for genotyping of clinical samples. Here, we assessed the stability of amplicon sequencing from formalin-fixed paraffin-embedded (FFPE) and paired frozen samples from colorectal cancer metastases with different analysis pipelines. 212 amplicon regions in 48 cancer related genes were sequenced with Illumina MiSeq using DNA isolated from resection specimens from 17 patients with colorectal cancer liver metastases. From ten of these patients, paired fresh frozen and routinely processed FFPE tissue was available for comparative study. Sample quality of FFPE tissues was determined by the amount of amplifiable DNA using qPCR, sequencing libraries were evaluated using Bioanalyzer. Three bioinformatic pipelines were compared for analysis of amplicon sequencing data. Selected hot spot mutations were reviewed using Sanger sequencing. In the sequenced samples from 16 patients, 29 non-synonymous coding mutations were identified in eleven genes. Most frequent were mutations in TP53 (10), APC (7), PIK3CA (3) and KRAS (2). A high concordance of FFPE and paired frozen tissue samples was observed in ten matched samples, revealing 21 identical mutation calls and only two mutations differing. Comparison of these results with two other commonly used variant calling tools, however, showed high discrepancies. Hence, amplicon sequencing can potentially be used to identify hot spot mutations in colorectal cancer metastases in frozen and FFPE tissue. However, remarkable differences exist among results of different variant calling tools, which are not only related to DNA sample quality. Our study highlights the need for standardization and benchmarking of variant calling pipelines, which will be required for translational and clinical applications. PMID- 26010450 TI - Comparison of Bone Mineral Density in Lumbar Spine and Fracture Rate among Eight Drugs in Treatments of Osteoporosis in Men: A Network Meta-Analysis. AB - CONTEXT: The preferred treatment for osteoporosis in men is debated, and pairwise meta-analysis cannot obtain hierarchies of these treatments. OBJECTIVE: The objective of this study was to integrate the evidence and provide hierarchies of eight drugs based on their effect on the bone mineral density in the lumbar spine (BMD in LS) and the fracture rate. DATA SOURCES: Eligible studies were identified by searching Amed, British Nursing Index, EMBASE, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, SIGLE, the National Technical Information Service, the National Research Register (UK), and the Current Controlled Trials databases. STUDY SELECTION: RCTs or quasi-RCTs reporting at least two drugs (two active drugs or one active drug and a placebo) used to treat osteoporosis in men were selected by two authors. DATA EXTRACTION: Two authors independently extracted the data. DATA SYNTHESIS: Thirteen studies involving 3647 patients were included. Compared with placebo therapy, zoledronate (SMDs 13.48, 95% credible intervals 11.88-15.08) yielded the most significant effect on increasing the BMD in LS, followed by alendronate (11.04, 9.68-12.41), teriparatide (20mcg) + risedronate (10.98, 8.55-13.48), risedronate (10.33, 8.68 12.01), teriparatide (20mcg) (9.33, 6.87-11.76), strontium ranelate (8.88, 7.51 10.24), ibandronate (5.49, 3.82-7.16), parathyroid hormone (1-84) (4.89, 3.12 6.62) and alfacalcidol (3.42, 1.7-5.2). Placebo therapy had a significantly higher fracture rate in contrast to risedronate (OR 2.51, 95% CrI 1.23-4.24) or zoledronate (2.92, 1.29-5.62) or teriparatide (20mcg) (4.04, 1.36-8.49) or teriparatide (40mcg) (3.5, 1.14-8.34). Zoledronate ranked first for increasing the BMD in LS, and teriparatide (20mg) was ranked first for decreasing the fracture rate. CONCLUSIONS: Zoledronate might be the best choice to increase the BMD in LS and teriparatide (20mg) might lead to the lowest fracture rate. PMID- 26010452 TI - Targeted control of the saddle gall midge, Haplodiplosis marginata (von Roser) (Diptera: Cecidomyiidae), and the benefits of good control of this pest to winter wheat yield. AB - BACKGROUND: Since 2010 there has been a resurgence of the saddle gall midge, Haplodiplosis marginata (von Roser), in Belgium and several other European countries, with this pest sometimes causing severe damage in cereals. In 2012 and 2013, field trials were conducted in heavily infested fields to assess its impact on winter wheat crops and to determine efficient ways of dealing with severe infestations. RESULTS: Crop exposure to H. marginata varied with the different protection methods tried. These methods included 1-4 successive applications of lambda-cyhalothrin. Yield losses were significant, reaching 6% in 2012 and as high as 15% in 2013, and these losses were linearly related to the number of galls on stems. CONCLUSION: The trials showed that insecticide applications needed to be synchronised with H. marginata flight peaks and to target the egg hatching period. They also revealed that insecticides applied to coincide with the first flight could, in humid conditions, also reach the larvae close to the soil surface, prior to their pupation. PMID- 26010453 TI - Quantification of myo-inositol, 1,5-anhydro- D-sorbitol, and D-chiro-inositol using high-performance liquid chromatography with electrochemical detection in very small volume clinical samples. AB - Inositol is a six-carbon sugar alcohol and is one of nine biologically significant isomers of hexahydroxycyclohexane. Myo-inositol is the primary biologically active form and is present in higher concentrations in the fetus and newborn than in adults. It is currently being examined for the prevention of retinopathy of prematurity in newborn preterm infants. A robust method for quantifying myo-inositol (MI), D-chiro-inositol (DCI) and 1,5-anhydro- D-sorbitol (ADS) in very small-volume (25 MUL) urine, blood serum and/or plasma samples was developed. Using a multiple-column, multiple mobile phase liquid chromatographic system with electrochemical detection, the method was validated with respect to (a) selectivity, (b) accuracy/recovery, (c) precision/reproducibility, (d) sensitivity, (e) stability and (f) ruggedness. The standard curve was linear and ranged from 0.5 to 30 mg/L for each of the three analytes. Above-mentioned performance measures were within acceptable limits described in the Food and Drug Administration's Guidance for Industry: Bioanalytical Method Validation. The method was validated using blood serum and plasma collected using four common anticoagulants, and also by quantifying the accuracy and sensitivity of MI measured in simulated urine samples recovered from preterm infant diaper systems. The method performs satisfactorily measuring the three most common inositol isomers on 25 MUL clinical samples of serum, plasma, milk, and/or urine. Similar performance is seen testing larger volume samples of infant formulas and infant formula ingredients. MI, ADS and DCI may be accurately tested in urine samples collected from five different preterm infant diapers if the urine volume is greater than 2-5 mL. PMID- 26010454 TI - Cranial Arterial Patterning in Greyhounds: Another Case of Internal Intraspecific Variation. AB - The greyhound is a dog breed highly specialized to run fast (17 m/s) over short distances (Usherwood and Wilson, 2005). As a result, there are many anatomical structures correlated with this sprinting function. The branching patterns of vasculature supplying blood to the head, forelimbs and thorax (subclavian arteries and its branches) were described in 34 adult greyhound cadavers (22 male, 12 female) (donated with owner consent and used under a memorandum of understanding with the University of Adelaide Animal Ethics Committee) from silicone casts of the arch of the aorta and the cranial arteries. Chi-squared analysis was used to test for pattern frequency differences, and t-tests were used to analyse the differences between sex and symmetry. All measurements were scaled to a fixed measure, the Open Thorax Length (OTL), to correct for size variation between individuals. Significant differences were found between the left and right subclavian arteries in the greyhound. The length to the first branch as a percentage of the OTL was greater in the right subclavian artery than the left subclavian artery (P < 0.001). The interval between the first and last branches (branching interval) as a percentage of the OTL was larger in the left subclavian artery than the right subclavian artery (P < 0.001). The reason for these differences remains unclear. Nonetheless, intraspecific variations of the branching patterns of the subclavian arteries have been described in the greyhound, thus suggesting that breed-specific variations in the cardiovascular system are likely to occur throughout domestic dogs. PMID- 26010455 TI - Interactions between semiconductor nanowires and living cells. AB - Semiconductor nanowires are increasingly used for biological applications and their small dimensions make them a promising tool for sensing and manipulating cells with minimal perturbation. In order to interface cells with nanowires in a controlled fashion, it is essential to understand the interactions between nanowires and living cells. The present paper reviews current progress in the understanding of these interactions, with knowledge gathered from studies where living cells were interfaced with vertical nanowire arrays. The effect of nanowires on cells is reported in terms of viability, cell-nanowire interface morphology, cell behavior, changes in gene expression as well as cellular stress markers. Unexplored issues and unanswered questions are discussed. PMID- 26010456 TI - Measuring age-dependent myocardial stiffness across the cardiac cycle using MR elastography: A reproducibility study. AB - PURPOSE: To assess reproducibility in measuring left ventricular (LV) myocardial stiffness in volunteers throughout the cardiac cycle using MR elastography (MRE) and to determine its correlation with age. METHODS: Cardiac MRE (CMRE) was performed on 29 normal volunteers, with ages ranging from 21 to 73 years. For assessing reproducibility of CMRE-derived stiffness measurements, scans were repeated per volunteer. Wave images were acquired throughout the LV myocardium, and were analyzed to obtain mean stiffness during the cardiac cycle. CMRE-derived stiffness values were correlated to age. RESULTS: Concordance correlation coefficient revealed good interscan agreement with rc of 0.77, with P-value < 0.0001. Significantly higher myocardial stiffness was observed during end-systole (ES) compared with end-diastole (ED) across all subjects. Additionally, increased deviation between ES and ED stiffness was observed with increased age. CONCLUSION: CMRE-derived stiffness is reproducible, with myocardial stiffness changing cyclically across the cardiac cycle. Stiffness is significantly higher during ES compared with ED. With age, ES myocardial stiffness increases more than ED, giving rise to an increased deviation between the two. PMID- 26010457 TI - Use of aspirin combinations with caffeine and increasing headache frequency: a prospective population-based study. AB - Combinations of analgesics with caffeine have been discussed as bearing a risk for headache chronicity. We investigated whether aspirin with caffeine (ASA+) increases headache frequency compared with aspirin alone in migraine, tension type headache (TTH), and migraine + TTH (MigTTH). The population-based German Headache Consortium Study, which included participants aged 18 to 65 years, collected information about headache and analgesics at baseline (2003-2007, t0, response rate: 55.2%), first follow-up after 1.87 +/- 0.39 years (t1, 37.2%), and second follow-up after 3.26 +/- 0.60 years (t2, 38.8%). We included participants with headache at t0, aspirin intake, ASA+ or no analgesics at t0 and t2, and known headache frequency. Linear regression was used to estimate changes of headache frequency (Deltat2-t0) and 95% confidence intervals depending on analgesic intake, stratified by headache subtypes, adjusting for sex, age, analgesics at t1, changes of headache frequency at t1, drinking, smoking, body mass index, education, headache frequency at t0. Of 509 participants (56.0% women, 42.0 +/- 11.8 years [mean +/- SD]), 45.2% reported aspirin intake (41.3 +/ 10.9 years, 59.6% women, headache days at t0: 2.8 +/- 3.1 d/mo, t2: 3.6 +/- 4.1 d/mo), 11.8% ASA+ intake (46.0 +/- 9.8 years, 73.3%, t0: 4.8 +/- 6.1 d/mo, t2: 5.3 +/- 5.1 d/mo), and 43.0% no analgesics (41.6 +/- 13.1 years, 47.5%, t0: 3.8 +/- 6.2 d/mo, t2: 5.3 +/- 6.6 d/mo). There was no increase in headache frequency in participants with ASA+ intake compared with aspirin (adjusted, all headache: 0.34 d/mo [95% confidence intervals: -2.50 to 1.82], migraine: -1.36 d/mo [-4.76 to 2.03], TTH: -0.57 d/mo [-4.97 to 3.84], MigTTH: 2.46 d/mo [-5.19 to 10.10]) or no analgesics (all headache: -2.24 d/mo [-4.54 to 0.07], migraine: -3.77 d/mo [ 9.22 to 1.68], TTH: -4.68 d/mo [-9.62 to 0.27]; MigTTH: -3.22 d/mo [-10.16 to 3.71]). In our study, ASA+ intake did not increase headache frequency compared with aspirin or no analgesics. PMID- 26010459 TI - Chronic pain in the pelvic area or lower extremities after rectal cancer treatment and its impact on quality of life: a population-based cross-sectional study. AB - The aim of this investigation was to examine the prevalence of and factors associated with chronic pain in the pelvic area or lower extremities after rectal cancer treatment and its impact on quality of life (QoL). This is a population based cross-sectional study of chronic pain and QoL in patients treated for rectal cancer from 2001 to 2007. A modified version of the Brief Descriptive Danish Pain Questionnaire and the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire were mailed to 1713 Danish patients. Informative answers were obtained from 1369 patients (80%). A total of 426 patients (31%) reported chronic pain in the pelvic area or lower extremities, 173 (41%) of whom had daily pain. Pain in other parts of the body was associated with the presence of pain in the pelvic region (odds ratio [OR] 4.81 [3.63-6.38], P < 0.001). Multivariate logistic regression analysis showed an association with chronic pain in female patients (OR 1.91 [1.51-2.43], P < 0.001) and in those who received radio(chemo)therapy (OR 1.31 [1.01-1.7], P = 0.041) or underwent abdominoperineal excision (OR 1.71 [1.19-2.44], P = 0.003), total mesorectal excision (OR 1.39 [1.01-1.90], P = 0.041), and Hartmann procedure (OR 1.72 [1.04 2.84], P = 0.33) compared with partial mesorectal excision. Ordinal regression analysis showed a strong association between all QoL subgroups and pelvic pain. Chronic pain in the pelvic region or lower extremities after rectal cancer treatment is a common but largely neglected problem that is associated with female gender, type of surgery, radio(chemo)therapy, and young age, all of which impact the patient's QoL. PMID- 26010460 TI - Diffuse noxious inhibitory controls and nerve injury: restoring an imbalance between descending monoamine inhibitions and facilitations. AB - Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. alpha2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (MU-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain. PMID- 26010458 TI - The posterior medial cortex in urologic chronic pelvic pain syndrome: detachment from default mode network-a resting-state study from the MAPP Research Network. AB - Altered resting-state (RS) brain activity, as a measure of functional connectivity (FC), is commonly observed in chronic pain. Identifying a reliable signature pattern of altered RS activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed RS functional magnetic resonance imaging data from female patients with urologic chronic pelvic pain syndrome (N = 45) and matched healthy participants (N = 45) as part of an NIDDK-funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased FC of the default mode network to 2 regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and the left precuneus (threshold-free cluster enhancement, family-wise error corrected P < 0.05). Further investigation revealed that patients demonstrated increased FC between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (eg, insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased FC to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships, and self-esteem levels in patients. Collectively, these findings indicate that in patients with urologic chronic pelvic pain syndrome, regions of the PMC are detached from the default mode network, whereas neurological processes of self referential thought and introspection may be joined to pain and emotion regulatory processes. PMID- 26010461 TI - Activation of mitochondrial transient receptor potential vanilloid 1 channel contributes to microglial migration. AB - Microglia, the resident immune cells in the brain, survey the environment of the healthy brain. Microglial migration is essential for many physiological and pathophysiological processes. Although microglia express some members of the transient receptor potential (TRP) channel family, there is little knowledge regarding the physiological roles of TRP channels in microglia. Here, we explored the role of TRP vanilloid 1 (TRPV1), a channel opened by capsaicin, heat, protons, and endovanilloids, in microglia. We found that application of capsaicin induced concentration-dependent migration in microglia derived from wild-type mice but not in those derived from TRPV1 knockout (TRPV1-KO) mice. Capsaicin induced microglial migration was significantly inhibited by co-application of the TRPV1 blocker SB366791 and the Ca(2+) chelator BAPTA-AM. Using RT-PCR and immunocytochemistry, we validated that TRPV1 was expressed in microglia. Electrophysiological recording, intracellular Ca(2+) imaging, and immunocytochemistry indicated that TRPV1 was localized primarily in intracellular organelles. Treatment with capsaicin induced an increase in intramitochondrial Ca(2+) concentrations and mitochondrial depolarization. Furthermore, microglia derived from TRPV1-KO mice showed delayed Ca(2+) efflux compared with microglia derived from wild-type mice. Capsaicin-induced microglial migration was inhibited by membrane-permeable antioxidants and MAPK inhibitors, suggesting that mitochondrial TRPV1 activation induced Ca(2+) -dependent production of ROS followed by MAPK activation, which correlated with an augmented migration of microglia. Moreover, a mixture of three endovanilloids augmented microglial migration via TRPV1 activation. Together, these results indicate that mitochondrial TRPV1 plays an important role in inducing microglial migration. Activation of TRPV1 triggers an increase in intramitochondrial Ca(2+) concentration and following depolarization of mitochondria, which results in mtROS production, MAPK activation, and enhancement of chemotactic activity in microglia. PMID- 26010462 TI - Acquired aortic atresia: Catheter therapy using covered stents. AB - INTRODUCTION: To maintain aortic continuity, aortic arch interruption is usually treated surgically. We present our experience of aortic arch reconstruction using percutaneous implantation of covered stents and mid-term follow-up. OBJECTIVE: To describe the feasibility, safety, and effectiveness using percutaneous placement of covered stents for functional aortic atresia and mid-term follow-up. METHODS: Nine patients (7 males), mean age of 30.8 +/-16.2 years (range 13-58 years) and mean body weight of 65.7+/- 14.9 kg (range 52-95 kg), were investigated for systemic hypertension and found to have functional aortic interruption. All were treated with percutaneous perforation, combined with balloon dilation and implantation of covered stents. After stent implantation, control angiograms were performed. RESULTS: All the patients had functional aortic interruption and continuity was established by perforating the atretic segment with trans-septal Brockenbrough needle or the stiff end of a guide wire. A covered Cheatham Platinum CP stent was used to establish the luminal continuity of the aortic arch. Angiograms after stent deployment showed good forward flow through the stent and hemodynamic assessment revealed minimal gradients across the stent. The mean invasive descending aortic systolic blood pressure before stenting was 86.6 +/- 14.3 mm Hg, which increased to 116.5 +/- 16.3 mm Hg, after stenting (P = 0.004). The mean invasive descending aortic diastolic blood pressure before stenting was 63.6 +/- 8.1 mm Hg, which increased to 79.7 +/- 13.3 mm Hg after stenting (P = 0.002). CONCLUSION: Percutaneous treatment of functional aortic atresia with covered stents is feasible, safe, and effective alternative to surgery with excellent short- and mid-term results. PMID- 26010463 TI - Hepatitis B virus seroconversion rates among health sciences students in the southeastern United States. AB - OBJECTIVE: To investigate the hepatitis B virus (HBV) seroconversion rate among health sciences students. PARTICIPANTS: The study included pharmacy, doctor of nursing, and medical students over 18 years of age enrolled at the University of South Carolina between 2007 and 2011. METHODS: The primary end point was HBV seroconversion rates among students at the initial reporting period. Seroconversion was defined as hepatitis B surface antibody (anti-HBs) level greater than or equal to 10 mIU/mL. Multivariate regression analysis was used to determine predictive factors of seroconversion. RESULTS: Of 777 records, data were available for 709 students. An 83.9% seroconversion rate was observed after a mean of 10 years between vaccine receipt and anti-HBs evaluation. Students with incomplete HBV vaccine series and longer time between initial series and evaluation were less likely to exhibit antibody response. CONCLUSIONS: These data highlight the importance of assessment and documentation of HBV vaccination series among health sciences students prior to direct patient care activities. PMID- 26010464 TI - Effectiveness of a Social Marketing Campaign Promoting Use of a Sexual Health Text Service by Teens. AB - Sexual health text message services are becoming an increasingly popular way to provide adolescents with accurate sexual health information, but promotion of such services is often limited. This study uses three quantitative methods (service use data, a text message-based questionnaire, and an in-school online survey) to assess the effectiveness of an in-school social marketing campaign promoting a sexual health text message service that connects teens directly with a health educator. The 3-month campaign was associated with increased service use, but use was still relatively low. Follow-up qualitative work that included focus groups and interviews found a number of barriers to use. Teens indicated they did not have sexual health questions, did not think of the service, or were unsure how to use it. Teens also brought up additional barriers such as concern over parents seeing the messages. Implications for text message service providers and health educators are discussed. PMID- 26010465 TI - Ethanol Gas Detection Using a Yolk-Shell (Core-Shell) alpha-Fe2O3 Nanospheres as Sensing Material. AB - Three-dimensional (3D) nanostructures of alpha-Fe2O3 materials, including both hollow sphere-shaped and yolk-shell (core-shell)-shaped, have been successfully synthesized via an environmentally friendly hydrothermal approach. By expertly adjusting the reaction time, the solid, hollow, and yolk-shell shaped alpha-Fe2O3 can be selectively synthesized. Yolk-shell alpha-Fe2O3 nanospheres display outer diameters of 350 nm, and the interstitial hollow spaces layer is intimately sandwiched between the inner and outer shell of alpha-Fe2O3 nanostructures. The possible growth mechanism of the yolk-shell nanostructure is proposed. The results showed that the well-defined bilayer interface effectively enhanced the sensing performance of the alpha-Fe2O3 nanostructures (i.e., yolk-shell alpha Fe2O3@alpha-Fe2O3), owing predominantly to the unique nanostructure, thus facilitated the transport rate and augmented the adsorption quantity of the target gas molecule under gas detection. PMID- 26010466 TI - Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year-old: A study from the acute leukemia working party (ALWP) of the European group of blood and marrow transplantation (EBMT). AB - Acute myeloid leukemia with monosomal karyotype (MK AML) carries a very poor prognosis, even after allogeneic stem cell transplantation (SCT). However, SCT remains the only curative option in this high-risk population. Because myeloablative conditioning regimen (MAC) is associated with less relapse, we hypothesized that more intensive conditioning regimen might be beneficial for MK AML patients. We reviewed 303 patients over age 45 diagnosed with either de novo or secondary MK AML. One hundred and five patients received a MAC and 198 a reduced-intensity conditioning (RIC). The median age at SCT was 57-year-old, significantly lower in the MAC (53-year-old) than in the RIC group (59-year-old). The median follow-up was 42 months (range, 3 - 156 months). The 3-year overall survival (OS), leukemia-free survival (LFS), and relapse rate (RR) were not significantly different between both groups with overall values of 34%, 29%, and 51%, respectively. On the contrary, the 3-year nonrelapse mortality (NRM) was significantly higher in MAC recipients (28%) compared with RIC patients (16%, P = 0.004). The incidence of Grades II to IV acute graft-versus-host disease (GvHD) was significantly higher after a MAC (30.5%) than after a RIC (19.3%, P = 0.02). That of chronic GvHD was comparable between both groups (35%) and did not impact on LFS. Interestingly, within our MK AML cohort, hypodiploidy was significantly associated with worse outcomes. Due to reduced toxicity and comparable OS, LFS, and RR, RIC appears as a good transplant option in the very high-risk population, including older patients, diagnosed with MK AML. PMID- 26010468 TI - Vesicle Fusion Triggered by Optically Heated Gold Nanoparticles. AB - Membrane fusion can be accelerated by heating that causes membrane melting and expansion. We locally heated the membranes of two adjacent vesicles by laser irradiating gold nanoparticles, thus causing vesicle fusion with associated membrane and cargo mixing. The mixing time scales were consistent with diffusive mixing of the membrane dyes and the aqueous content. This method is useful for nanoscale reactions as demonstrated here by I-BAR protein-mediated membrane tubulation triggered by fusion. PMID- 26010467 TI - Do bacterial and fungal communities assemble differently during primary succession? AB - High-throughput sequencing technologies are now allowing us to study patterns of community assembly for diverse microbial assemblages across environmental gradients and during succession. Here we discuss potential explanations for similarities and differences in bacterial and fungal community assembly patterns along a soil chronosequence in the foreland of a receding glacier. Although the data are not entirely conclusive, they do indicate that successional trajectories for bacteria and fungi may be quite different. Recent empirical and theoretical studies indicate that smaller microbes (like most bacteria) are less likely to be dispersal limited than are larger microbes - which could result in a more deterministic community assembly pattern for bacteria during primary succession. Many bacteria are also better adapted (than are fungi) to life in barren, early successional sediments in that some can fix nitrogen and carbon from the atmosphere - traits not possessed by any fungi. Other differences between bacteria and fungi are discussed, but it is apparent from this and other recent studies of microbial succession that we are a long way from understanding the mechanistic underpinnings of microbial community assembly during ecosystem succession. We especially need a better understanding of global and regional patterns of microbial dispersal and what environmental factors control the development of microbial communities in complex natural systems. PMID- 26010469 TI - Mechanism of Lipid Vesicles Spreading and Bilayer Formation on a Au(111) Surface. AB - Spreading of small unilamellar vesicles on solid surfaces is one of the most common ways to obtain supported lipid bilayers. Although the method has been used successfully for many years, the details of this process are still the subject of intense debate. Particularly controversial is the mechanism of bilayer formation on metallic surfaces like gold. In this work, we have employed scanning probe microscopy techniques to evaluate the details of lipid vesicles spreading and formation of the lipid bilayer on a Au(111) surface in a phosphate-buffered saline solution. Nanoscale imaging revealed that the mechanism of this process differs significantly from that usually assumed for hydrophilic surfaces such as mica, glass, and silicon oxide. Formation of the bilayer on gold involves several steps. Initially, the vesicles accumulate on a gold surface and release lipid molecules that adsorb on a Au(111) surface, giving rise to the appearance of highly ordered stripelike domains. The latter serve as a template for the buildup of a hemimicellar film, which contributes to the increased hydrophilicity of the external surface and facilitates further adsorption and rupture of the vesicles. As a result, the bilayer is spread over a hemimicellar film, and then it is followed by slow fusion between coupled layers leading to formation of a single bilayer supported on a gold surface. We believe that the results presented in this work may provide some new insights into the area of research related to supported lipid bilayers. PMID- 26010470 TI - Controlled rejuvenation of amorphous metals with thermal processing. AB - Rejuvenation is the configurational excitation of amorphous materials and is one of the more promising approaches for improving the deformability of amorphous metals that usually exhibit macroscopic brittle fracture modes. Here, we propose a method to control the level of rejuvenation through systematic thermal processing and clarify the crucial feasibility conditions by means of molecular dynamics simulations of annealing and quenching. We also experimentally demonstrate rejuvenation level control in Zr(55)Al(10)Ni(5)Cu(30) bulk metallic glass. Our local heat-treatment recipe (rising temperature above 1.1T(g), followed by a temperature quench rate exceeding the previous) opens avenue to modifying the glass properties after it has been cast and processed into near component shape, where a higher local cooling rate may be afforded by for example transient laser heating, adding spatial control and great flexibility to the processing. PMID- 26010471 TI - M13 Bacteriophage and Adeno-Associated Virus Hybrid for Novel Tissue Engineering Material with Gene Delivery Functions. PMID- 26010472 TI - Is it useful to also image the asymptomatic leg in patients with suspected deep vein thrombosis?: reply. PMID- 26010473 TI - Plasmonic Ag-pillared rectorite as catalyst for degradation of 2,4-DCP in the H2O2-containing system under visible light irradiation. AB - This study aims at photocatalytic degradation of 2,4-DCP with the assistance of H2O2 in aqueous solution by a composite catalyst of Ag-rectorite. The catalysts were prepared via a novel thermal decomposition method followed after the cation exchange process. The synthesized nano-materials were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller (BET) surface analyzer, Ultraviolet-visible light (UV-vis) absorption spectra, field-emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM). The different mechanisms of degradation process with or without visible light irradiation were discussed, respectively. Moreover, the degradation efficiency of 2,4-DCP wastewater under Ag-rectorite/H2O2/visible light system was investigated by series of experiments, concerning on effects of major operation factors, such as H2O2 dosage and the initial pH value. The highest degradation rate was observed when adding 0.18 mL H2O2 into 50 mL 2,4-DCP solution, and the optimal pH value was 4 for the reaction. Afterwards, total organic carbon (TOC) experiments were carried out to evaluate the mineralization ratio of 2,4-DCP. PMID- 26010474 TI - Time-dependent effect of graphene on the structure, abundance, and function of the soil bacterial community. AB - The increased application of graphene raises concerns about its environmental impact, but little information is available on the effect of graphene on the soil microbial community. This study evaluated the impact of graphene on the structure, abundance and function of the soil bacterial community based on quantitative real-time polymerase chain reaction (qPCR), pyrosequencing and soil enzyme activities. The results show that the enzyme activities of dehydrogenase and fluorescein diacetate (FDA) esterase and the biomass of the bacterial populations were transiently promoted by the presence of graphene after 4 days of exposure, but these parameters recovered completely after 21 days. Pyrosequencing analysis suggested a significant shift in some bacterial populations after 4 days, and the shift became weaker or disappeared as the exposure time increased to 60 days. During the entire exposure process, the majority of bacterial phylotypes remained unaffected. Some bacterial populations involved in nitrogen biogeochemical cycles and the degradation of organic compounds can be affected by the presence of graphene. PMID- 26010475 TI - A multivariate study for characterizing particulate matter (PM(10), PM(2.5), and PM(1)) in Seoul metropolitan subway stations, Korea. AB - Given that around eight million commuters use the Seoul Metropolitan Subway (SMS) each day, the indoor air quality (IAQ) of its stations has attracted much public attention. We have monitored the concentration of particulate matters (PMx) (i.e., PM10, PM2.5, and PM1) in six major transfer stations per minute for three weeks during the summer, autumn, and winter in 2014 and 2015. The data were analyzed to investigate the relationship between PMx concentration and multivariate environmental factors using statistical methods. The average PM concentration observed was approximately two or three times higher than outdoor PM10 concentration, showing similar temporal patterns at concourses and platforms. This implies that outdoor PM10 is the most significant factor in controlling indoor PM concentration. In addition, the station depth and number of trains passing through stations were found to be additional influences on PMx. Principal component analysis (PCA) and self-organizing map (SOM) were employed, through which we found that the number of trains influences PM concentration in the vicinity of platforms only, and PMx hotspots were determined. This study identifies the external and internal factors affecting PMx characteristics in six SMS stations, which can assist in the development of effective IAQ management plans to improve public health. PMID- 26010476 TI - Zinc oxide nanoparticles induce eosinophilic airway inflammation in mice. AB - Zinc oxide nanoparticles (ZnO NPs) have been widely used in industry. The metal composition of PM2.5 might contribute to the higher prevalence of asthma. To investigate the effects of ZnO NPs on allergic airway inflammation, mice were first exposed to different concentrations of ZnO NPs (0.1 mg/kg, 0.5 mg/kg) or to a combination of ZnO NPs and chicken egg ovalbumin (OVA) by oropharyngeal aspiration on day 0 and day 7 and then were sacrificed 5 days later. The subsequent time course of airway inflammation in the mice after ZnO NPs exposure was evaluated on days 1, 7, and 14. To further determine the role of zinc ions, ZnCl2 was also administered. The inflammatory cell count, cytokine levels in the bronchoalveolar lavage fluid (BALF), and lung histopathology were examined. We found significant neutrophilia after exposure to high-dose ZnO NPs on day 1 and significant eosinophilia in the BALF at 7 days. However, the expression levels of the T helper 2 (Th2) cytokines IL-4, IL-5, and IL-13 increased significantly after 24h of exposure to only ZnO NPs and then decreased gradually. These results suggested that ZnO NPs could cause eosinophilic airway inflammation in the absence of allergens. PMID- 26010477 TI - Bacterial vaccines in chronic obstructive pulmonary disease: effects on clinical outcomes and cytokine levels. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. Exacerbation episodes impair lung function leading to disease progression. Levels of inflammation markers correlate with disease severity. Bacterial immunomodulators have shown a beneficial effect in COPD, improving symptoms and reducing the rate of exacerbations. This is an observational prospective study on 30 patients diagnosed with bronchiectasis and COPD, who received bacterial autogenous vaccine for 12 months. The rate of exacerbation, severity of symptoms and lung function were studied at baseline and after treatment. In addition, plasma levels CRP, IL6, IL8, and TNFalpha were measured. After treatment we found a reduction in mean acute respiratory infections and signs of lung disease. Acute phase proteins IL6 and CRP increased in blood and IL8 decreased. These changes may be related to the repeated injection of inactivated bacteria. Given the implication of these factors in the pathogenesis of COPD, particularly the production of IL8, the causes and consequences of cytokine modulation by bacterial vaccines should be investigated. Vaccination with autogenous vaccines for 1 year can produce a significant clinical improvement in COPD patients, reducing the frequency of exacerbations associated to changes in the profile of markers of inflammation. PMID- 26010478 TI - THE VALIDITY OF THE MOOD DISORDER QUESTIONNAIRE FOR SCREENING BIPOLAR DISORDER: A META-ANALYSIS. AB - We conducted a meta-analysis to review the diagnostic accuracy of the Mood Disorder Questionnaire (MDQ) among patients with mood disorders. We used a bivariate random effects model to calculate summary sensitivity and specificity. Twenty-one studies were included. At the standard or modified cutoff value of 7, summary sensitivity was .62 and summary specificity was .85. When we pooled 11 studies including both patients with bipolar disorder (BD) and those with unipolar depression, the summary sensitivity was .76 and summary specificity was .81. However, among the six studies that excluded patients with known BD, the summary sensitivity was significantly reduced to .37 and summary specificity was .88. There were no significant differences on the diagnostic accuracy of the MDQ between studies from Eastern and Western countries after adjusting for various clinical correlates. The overall diagnostic accuracy of the MDQ was relatively good. However, when the MDQ is applied among patients with depression without previous diagnoses of BD, its sensitivity was significantly reduced. This suggests that when the MDQ is applied among this population, its optimal cutoff value should be adjusted to enhance its sensitivity. PMID- 26010479 TI - Clinico-biological features, treatment and survival of 457 patients with histological Grades 3A and 1-2 follicular lymphoma mostly treated with immunochemotherapy. PMID- 26010480 TI - Primary afferent neurons containing calcitonin gene-related peptide but not substance P in forepaw skin, dorsal root ganglia, and spinal cord of mice. AB - In mice dorsal root ganglia (DRG), some neurons express calcitonin gene-related peptide (CGRP) without substance P (SP; CGRP(+) SP(-) ). The projections and functions of these neurons are unknown. Therefore, we combined in vitro axonal tracing with multiple-labeling immunohistochemistry to neurochemically define these neurons and characterize their peripheral and central projections. Cervical spinal cord, DRG, and forepaw skin were removed from C57Bl/6 mice and multiple labeled for CGRP, SP, and either marker for the sensory neuron subpopulations transient receptor potential vanilloid type 1 (TRPV1), neurofilament 200 (NF200), or vesicular glutamate transporter 2 (VGluT1). To determine central projections of CGRP(+) SP(-) neurons, Neurobiotin (NB) was applied to the C7 ventral ramus and visualized in DRG and spinal cord sections colabeled for CGRP and SP. Half (50%) of the CGRP-immunoreactive DRG neurons lacked detectable SP and had a mean soma size of 473 +/- 14 MUm(2) (n = 5); 89% of the CGRP(+) SP(-) neurons expressed NF200 (n = 5), but only 32% expressed TRPV1 (n = 5). Cutaneous CGRP(+) SP(-) fibers were numerous within dermal papillae and around hair shafts (n = 4). CGRP(+) SP(-) boutons were prevalent in lateral lamina I and in lamina IV/V of the dorsal horn (n = 5). NB predominantly labeled fibers penetrating lamina IV/V, 6 +/- 3% contained CGRP (n = 5), and 21 +/- 2% contained VGluT1 (n = 3). CGRP(+) SP(-) afferent neurons are likely to be non-nociceptive. Their soma size, neurochemical profile, and peripheral and central targets suggest that CGRP(+) SP(-) neurons are polymodal mechanoceptors. PMID- 26010481 TI - Generalization versus contextualization in automatic evaluation revisited: A meta analysis of successful and failed replications. AB - To account for disparate findings in the literature on automatic evaluation, Gawronski, Rydell, Vervliet, and De Houwer (2010) proposed a representational theory that specifies the contextual conditions under which automatic evaluations reflect initially acquired attitudinal information or subsequently acquired counterattitudinal information. The theory predicts that automatic evaluations should reflect the valence of expectancy-violating counterattitudinal information only in the context in which this information had been learned. In contrast, automatic evaluations should reflect the valence of initial attitudinal information in any other context, be it the context in which the initial attitudinal information had been acquired (ABA renewal) or a novel context in which the target object had not been encountered before (ABC renewal). The current article presents a meta-analysis of all published and unpublished studies from the authors' research groups regardless of whether they produced the predicted pattern of results. Results revealed average effect sizes of d = 0.249 for ABA renewal (30 studies, N = 3,142) and d = 0.174 for ABC renewal (27 studies, N = 2,930), both of which were significantly different from zero. Effect sizes were moderated by attention to context during learning, order of positive and negative information, context-valence contingencies during learning, and sample country. Although some of the obtained moderator effects are consistent with the representational theory, others require theoretical refinements and future research to gain deeper insights into the mechanisms underlying contextual renewal. PMID- 26010482 TI - Competition makes observers remember faces as more aggressive. AB - People use facial appearance to predict social behavior, but can social context also influence face perception? Leveraging a link between competition and aggression, we investigated the effects of competitive interactions with confederates on participants' performance in a face reconstruction task. Participants played a game either in competition or cooperation with confederates and were then asked to create facial portraits of these confederates by arranging their component features into their best estimate of an accurate configuration. Across 2 experiments, participants who played in a competitive context reconstructed faces in a more aggressive configuration-with higher width-to height ratios-than did participants who played cooperatively or alone. This result demonstrates that the social perception of faces is not merely a feed forward process, but instead that the social contexts in which people interact can shape memory for faces. PMID- 26010483 TI - Language specificity of lexical-phonological therapy in bilingual aphasia: A clinical and electrophysiological study. AB - Based on findings for overlapping representations of bilingual people's first (L1) and second (L2) languages, unilingual therapies of bilingual aphasia have been proposed to benefit the untrained language. However, the generalisation patterns of intra- and cross-language and phonological therapy and their neural bases remain unclear. We tested whether the effects of an intensive lexical phonological training (LPT) in L2 transferred to L1 word production in a Persian French bilingual stroke patient with Broca's aphasia. Language performance was assessed using the Bilingual Aphasia Test, a 144-item picture naming (PN) task and a word-picture verification (WPV) task. Electroencephalography (EEG) was recorded during PN and WPV in both languages before and after an LPT in French on a wordlist from the PN task. After the therapy, naming improved only for the treated L2 items. The naming performance improved neither in the untrained L2 items nor in the corresponding items in L1. EEG analyses revealed a Language x Session topographic interaction at 540 ms post-stimulus, driven by a modification of the electrophysiological response to the treated L2 but not L1 items. These results indicate that LPT modified the brain networks engaged in the phonological phonetic processing during naming only in the trained language for the trained items. PMID- 26010484 TI - Association Study between the CD157/BST1 Gene and Autism Spectrum Disorders in a Japanese Population. AB - CD157, also referred to as bone marrow stromal cell antigen-1 (BST-1), is a glycosylphosphatidylinositol-anchored molecule that promotes pre-B-cell growth. Previous studies have reported associations between single-nucleotide polymorphisms (SNPs) of the CD157/BST1 gene with Parkinson's disease. In an attempt to determine whether SNPs or haplotypes in the CD157/BST1 are associated with other brain disorders, we performed a case-control study including 147 autism spectrum disorder (ASD) patients at Kanazawa University Hospital in Japan and 150 unselected Japanese volunteers by the sequence-specific primer-polymerase chain reaction method combined with fluorescence correlation spectroscopy. Of 93 SNPs examined, two SNPs showed significantly higher allele frequencies in cases with ASDs than in unaffected controls (rs4301112, OR = 6.4, 95% CI = 1.9 to 22, p = 0.0007; and rs28532698, OR = 6.2, 95% CI = 1.8 to 21, p = 0.0012; Fisher's exact test; p < 0.002 was considered significant after multiple testing correction). In addition, CT genotype in rs10001565 was more frequently observed in the ASD group than in the control group (OR = 15, 95% CI = 2.0 to 117, p = 0.0007; Fisher's exact test). The present data indicate that genetic variation of the CD157/BST1 gene might confer susceptibility to ASDs. PMID- 26010485 TI - Acute Stress Dysregulates the LPP ERP Response to Emotional Pictures and Impairs Sustained Attention: Time-Sensitive Effects. AB - Stress can increase emotional vigilance at the cost of a decrease in attention towards non-emotional stimuli. However, the time-dependent effects of acute stress on emotion processing are uncertain. We tested the effects of acute stress on subsequent emotion processing up to 40 min following an acute stressor. Our measure of emotion processing was the late positive potential (LPP) component of the visual event-related potential (ERP), and our measure of non-emotional attention was the sustained attention to response task (SART). We also measured cortisol levels before and after the socially evaluated cold pressor test (SECPT) induction. We found that the effects of stress on the LPP ERP emotion measure were time sensitive. Specifically, the LPP ERP was only altered in the late time point (30-40 min post-stress) when cortisol was at its highest level. Here, the LPP no longer discriminated between the emotional and non-emotional picture categories, most likely because neutral pictures were perceived as emotional. Moreover, compared to the non-stress condition, the stress-condition showed impaired performance on the SART. Our results support the idea that a limit in attention resources after an emotional stressor is associated with the brain incorrectly processing non-emotional stimuli as emotional and interferes with sustained attention. PMID- 26010487 TI - Gene expression kinetics in individual plasmodial cells reveal alternative programs of differential regulation during commitment and differentiation. AB - During its life cycle, the amoebozoon Physarum polycephalum forms multinucleate plasmodial cells that can grow to macroscopic size while maintaining a naturally synchronous population of nuclei. Sporulation-competent plasmodia were stimulated through photoactivation of the phytochrome photoreceptor and the expression of sporulation marker genes was analyzed quantitatively by repeatedly taking samples of the same plasmodial cell at successive time points after the stimulus pulse. Principal component analysis of the gene expression data revealed that plasmodial cells take different trajectories leading to cell fate decision and differentiation and suggested that averaging over individual cells is inappropriate. Queries for genes with pairwise correlated expression kinetics revealed qualitatively different patterns of co-regulation, indicating that alternative programs of differential regulation are operational in individual plasmodial cells. At the single cell level, the response to stimulation of a non sporulating mutant was qualitatively different as compared to the wild type with respect to the differentially regulated genes and their patterns of co regulation. The observation of individual differences during commitment and differentiation supports the concept of a Waddington-type quasipotential landscape for the regulatory control of cell differentiation. Comparison of wild type and sporulation mutant data further supports the idea that mutations may impact the topology of this landscape. PMID- 26010486 TI - Sex differences in behavioral outcomes following temperature modulation during induced neonatal hypoxic ischemic injury in rats. AB - Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen. PMID- 26010489 TI - Effects of cognitive load on trusting behavior--an experiment using the trust game. AB - Last decades have witnessed a progressing decline of social trust, which has been predominantly linked to worsening economic conditions and increasing social inequality. In the present research we propose a different type of explanation for the observed decline - cognitive load related to technological development and the accelerating pace of modern life. In an experimental study participants played the trust game while performing one of two different secondary tasks - listening to a disturbing noise or memorizing a sequence of characters - or with no additional task in the control condition. Results show that in both cognitive load conditions participants expressed significantly less trust in the trust game than in case of no cognitive load. Additionally, when cognitive resources were limited, participants' behavior was more impulsive than when their resources were fully available. PMID- 26010488 TI - Characterization of the Copper(II) Binding Sites in Human Carbonic Anhydrase II. AB - Human carbonic anhydrase (CA) is a well-studied, robust, mononuclear Zn containing metalloprotein that serves as an excellent biological ligand system to study the thermodynamics associated with metal ion coordination chemistry in aqueous solution. The apo form of human carbonic anhydrase II (CA) binds 2 equiv of copper(II) with high affinity. The Cu(2+) ions bind independently forming two noncoupled type II copper centers in CA (CuA and CuB). However, the location and coordination mode of the CuA site in solution is unclear, compared to the CuB site that has been well-characterized. Using paramagnetic NMR techniques and X ray absorption spectroscopy we identified an N-terminal Cu(2+) binding location and collected information on the coordination mode of the CuA site in CA, which is consistent with a four- to five-coordinate N-terminal Cu(2+) binding site reminiscent to a number of N-terminal copper(II) binding sites including the copper(II)-amino terminal Cu(2+) and Ni(2+) and copper(II)-beta-amyloid complexes. Additionally, we report a more detailed analysis of the thermodynamics associated with copper(II) binding to CA. Although we are still unable to fully deconvolute Cu(2+) binding data to the high-affinity CuA site, we derived pH- and buffer-independent values for the thermodynamics parameters K and DeltaH associated with Cu(2+) binding to the CuB site of CA to be 2 * 10(9) and -17.4 kcal/mol, respectively. PMID- 26010490 TI - Creatinine as predictor value of mortality and acute kidney injury in rhabdomyolysis. AB - BACKGROUND: Rhabdomyolysis (RB) is a syndrome characterised by decomposition of skeletal muscle that could be life threatening, so the identification of biomarkers of its severity could help us in its treatment. Creatine kinase (CK) is usually taken as a reference in patients with RB in order to stratify prognosis, however that is not probably the most effective parameter. AIMS: The present study was designed to analyse the specific features and mortality of patients with RB and the relation between creatinine, CK and mortality. METHODS: Retrospective cohort analysis among patients admitted to San Pedro Hospital in Logrono (Spain) with RB (CK levels higher than 2000 U/L) diagnosed since 1 January 2009 until 31 December 2; 013 522 patients with RB patients diagnosed of RB were collected. The aetiology and the analytical feature (creatinine, CK, calcium, phosphorus, pH and bicarbonate), as well as 30-year mortality, were investigated. RESULTS: Among the 522 patients, there were 138 deaths. Four patients required renal replacement therapy. The most common cause of RB was trauma (29%). Infectious aetiology had the highest mortality (41.2%). The median CK was 3451 u/L (interquartile range 3348), and the mean creatinine at admission was 132.6 umol/L (+/-110.5). Initial CK levels do not have predictive ability on mortality or renal dysfunction in contrast to initial creatinine values. Each state of acute kidney injury (AKI) increased mortality compared with those who have not presented this renal dysfunction (P < 0.0001). Age, calcium, phosphorus, bicarbonate and pH are associated with AKI. CONCLUSION: Despite being a diagnostic marker for RB, initial CK levels do not predict mortality. However, creatinine initial levels are related to progression to acute renal injury and mortality at 30 days. PMID- 26010491 TI - Chronic intermittent hypoxia is independently associated with reduced postoperative opioid consumption in bariatric patients suffering from sleep disordered breathing. AB - BACKGROUND: Evidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO2) < 90% and minimum nocturnal SaO2 on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery. METHODS: With Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO2 < 90%, (b) the minimum nocturnal SaO2, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders. RESULTS: Two hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO2 < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO2 < 90% was not associated with pain. The minimum nocturnal SaO2 was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep. CONCLUSIONS: Preoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids. PMID- 26010493 TI - Assessment of DSM-5 Personality Disorder. AB - The purpose of this article is to present an approach to defining, identifying, and assessing personality disorders, including the links between these definitions and personality assessment, with a particular reference to the proposed revisions to the personality disorders section of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2013 ). The article discusses measures of maladaptive variants of the Five-factor model (FFM) that are coordinated with both the traditional personality disorder syndromes as well as the DSM-5 dimensional trait model. Discussed as well is the assessment of the more psychodynamically oriented deficits in sense of self and interpersonal relatedness that are also included within the hybrid model proposed for DSM-5. PMID- 26010492 TI - Periodontal therapy and systemic inflammation in type 2 diabetes mellitus: a meta analysis. AB - AIM: The aim of this systematic review was to assess the effect of periodontal therapy (PT) on serum levels of inflammatory markers in people with type 2 diabetes mellitus (T2DM). METHODS OF STUDY SELECTION: A literature search was carried out using MEDLINE via Pubmed, EMBASE, LILACS and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Randomized-controlled trials (RCTs) and controlled clinical trials (CCTs) evaluating the effect of PT on systemic inflammatory markers were deemed eligible. Case series (CS), reports and pilot trials were excluded. Study quality was assessed using the Cochrane Collaboration's risk assessment tool. Meta-analysis was carried out using random effect methods. RESULTS: The search strategy identified 3,164 potential studies of which 61 were assessed for eligibility and 9 (6 RCTs and 3 CCTs) were included in this systematic review. Three RCTs were classified by the authors as being at low risk of bias and three were "unclear" and classified as uncertain risk of bias. All CCTs were considered to be at a high risk of bias. The meta-analysis showed a statistically significant mean difference (MD) for TNF- alpha (-1.33 pg/ml, 95% CI: -2.10; -0.56, p<0.001) and CRP (-1.28 mg/l, 95% CI: -2.07; - 0.48, p<0.001) favoring periodontal intervention versus control. CONCLUSION: The results of this meta-analysis support the hypothesis that PT reduces serum levels of TNF- alpha and CRP in T2DM individuals. The decrease of inflammatory burden has important implications for metabolic control and can, in part, explain the mechanisms linking periodontitis and increased risk for complications in people with T2DM. PMID- 26010494 TI - Policy evaluation in diabetes prevention and treatment using a population-based macro simulation model: the MICADO model. AB - AIMS: To test a simulation model, the MICADO model, for estimating the long-term effects of interventions in people with and without diabetes. METHODS: The MICADO model includes micro- and macrovascular diseases in relation to their risk factors. The strengths of this model are its population scope and the possibility to assess parameter uncertainty using probabilistic sensitivity analyses. Outcomes include incidence and prevalence of complications, quality of life, costs and cost-effectiveness. We externally validated MICADO's estimates of micro and macrovascular complications in a Dutch cohort with diabetes (n = 498,400) by comparing these estimates with national and international empirical data. RESULTS: For the annual number of people undergoing amputations, MICADO's estimate was 592 (95% interquantile range 291-842), which compared well with the registered number of people with diabetes-related amputations in the Netherlands (728). The incidence of end-stage renal disease estimated using the MICADO model was 247 people (95% interquartile range 120-363), which was also similar to the registered incidence in the Netherlands (277 people). MICADO performed well in the validation of macrovascular outcomes of population-based cohorts, while it had more difficulty in reflecting a highly selected trial population. CONCLUSIONS: Validation by comparison with independent empirical data showed that the MICADO model simulates the natural course of diabetes and its micro- and macrovascular complications well. As a population-based model, MICADO can be applied for projections as well as scenario analyses to evaluate the long-term (cost-)effectiveness of population-level interventions targeting diabetes and its complications in the Netherlands or similar countries. PMID- 26010495 TI - Epigallocatechin gallate attenuates fibroblast proliferation and excessive collagen production by effectively intervening TGF-beta1 signalling. AB - Pulmonary fibrosis (PF) poses a huge burden to the patients and society due to lack of an effective treatment drug. Activation of fibrocyte, fibroblast and myofibroblasts are important steps in the development of PF. Targeting this common pathway with natural chemicals may lead to the development of new drug regimens for PF treatment. In this study, PF was induced in male Wistar rats by intratracheal administration of Bleomycin (BLM). Epigallocatechin gallate (EGCG) was administered to one of the groups of rats to test its efficacy against the development of PF. Bleomycin-induction resulted in significant elevation of matrix metalloproteinase (MMP)-2 and -9 expression, increased RNA and protein expression of transforming growth factor (TGF)-beta1, Smads and alpha-smooth muscle actin (alpha-SMA). EGCG treatment normalized the BLM induced aberrations in these rats. The protective role of EGCG was also validated in vitro using the WI-38 fibroblast cell line. TGF-beta1 incubated cells exhibited increased fibroblast proliferation and hydroxyproline levels with a concomitant decrease in the expression of MMPs 2 and 9. An increase in protein expression levels of p Smad, alpha-SMA and type I collagen (COL1A) was also exhibited by fibroblasts upon TGF-beta1 incubation. Simultaneous treatment of EGCG to WI-38 cells significantly decreased these protein expressions alongside normalizing the MMPs expression. The study revealed that EGCG inhibited fibroblast activation and collagen accumulation by inhibiting TGF-beta1 signalling and thus can be considered as an effective drug against PF. PMID- 26010496 TI - How many infants are temperamentally difficult? Comparing norms from the Revised Infant Temperament Questionnaire to a population sample of UK infants. AB - The original norms for the Revised Infant Temperament Questionnaire (RITQ) were published in 1978 and were based on a small sample from the US. The aim of this study is to compare temperament scores from the original RITQ against scores from a large population-based cohort of infants from the UK. This study consists of 10,937 infants from the Avon Longitudinal Study of Parents and Children (ALSPAC) born between April 1991 and December 1992 in the southwest of England. Infant temperament at 6 months of age was reported by parents using the adapted RITQ. Responses were scored according to the RITQ manual and then categorized into temperament groups (easy, intermediate low, intermediate high, and difficult) using either the RITQ norms or norms derived from the data. The scores for each temperament subscale and the proportion of children in each temperament group were compared across the two methods. Subscale scores for the ALSPAC sample were higher (more "difficult") than the RITQ norms for rhythmicity, approach, adaptability, intensity, and distractibility. When RITQ norms were applied, 24% infants were categorized as difficult and 25% as easy, compared with 15% difficult and 38% easy when ALSPAC norms were used. There are discrepancies between RITQ norms and the ALSPAC norms which resulted in differences in the distribution of temperament groups. There is a need to re-examine RITQ norms and categorization for use in primary care practice and contemporary population-based studies. PMID- 26010497 TI - Promoting adoption of fall prevention measures among Latino workers and residential contractors: formative research findings. AB - BACKGROUND: Falls from heights remain a concern in construction, particularly for foreign-born Latino construction workers employed by small residential contractors. The social ecological model provides a framework to assess the individual and contextual factors influencing the risk for falls. METHODS: Five focus groups and thirteen in-depth interviews with workers, small residential contractors, and key informants were conducted in 2012 in San Francisco and Philadelphia. Data were analyzed with qualitative methods. RESULTS: Economic conditions in residential construction, coupled with a lack of enforcement and vulnerabilities of the foreign-born workforce, are principal contributors to risk for falls. Small contractors perceive strong economic disincentives for implementation of fall protection and foreign-born Latino workers experience a variety of social, cultural and occupational pressures impeding its use. CONCLUSIONS: Increased adoption of fall protection cannot be accomplished solely by targeting Latino construction workers. Research is needed on incentives to influence contractor behavior and facilitate adoption of fall protection measures. PMID- 26010498 TI - Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20. AB - An extremely drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with two potent antiviral investigational inhibitors. GRL 5010A and GRL-4410A were designed to introduce hydrogen bond interactions with the flexible flaps of the PR by incorporating gem-difluorines and alkoxy, respectively, at the C4 position of the bis-THF of darunavir. PR20 provides an excellent model for high level resistance, since clinical inhibitors are >1000 fold less active on PR20 than on wild-type enzyme. GRL-5010A and GRL-4410A show inhibition constants of 4.3 +/- 7.0 and 1.7 +/- 1.8 nM, respectively, for PR20, compared to the binding affinity of 41 +/- 1 nM measured for darunavir. Crystal structures of PR20 in complexes with the two inhibitors confirmed the new hydrogen bond interactions with Gly 48 in the flap of the enzyme. The two new compounds are more effective than darunavir in inhibiting mature PR20 and show promise for further development of antiviral agents targeting highly resistant PR mutants. PMID- 26010499 TI - Enhancement of immune response to a hepatitis C virus E2 DNA vaccine by an immunoglobulin Fc fusion tag. AB - Neutralizing antibodies and cellular immune response both play essential roles in the clearance of Hepatitis C virus (HCV) infection. The envelope glycoprotein E2 is a major target for producing neutralizing antibodies against HCV. Here, we constructed a recombinant plasmid, termed pcDNA3.1-E2-Fc, to express HCV E2 with an immunoglobulin Fc fusion tag (E2-Fc). Importantly, we found that the titers of E2-specific IgG from mice immunized with pcDNA3.1-E2-Fc were significantly higher than that from mice immunized with pcDNA3.1-E2. Moreover, pcDNA3.1-E2-Fc immunization could boost E2-specific lymphocyte proliferation and enhance the secretion of IFN-gamma by lymphocytes upon in vitro stimulation with soluble E2 compared to pcDNA3.1-E2 immunization. Neutralization assays showed that serum from pcDNA3.1-E2-Fc immunized mice exhibited more effective neutralizing capacity of HCVpp entry into Huh-7 cells compared with that from pcDNA3.1-E2 immunized mice, although both of the sera could inhibit the virus entry. Taken together, our results imply that pcDNA3.1-E2-Fc immunization could enhance E2-specific humoral and cellular immune response in mice and thus provide a promising candidate for the development of an HCV vaccine. PMID- 26010501 TI - Response to 'Are the studies on cancer risk from CT scans biased by indication? Elements of answer from a large-scale cohort study in France'. PMID- 26010500 TI - Mediterranean diet and risk of endometrial cancer: a pooled analysis of three Italian case-control studies. AB - BACKGROUND: Some components of the Mediterranean diet have favourable effects on endometrial cancer, and the Mediterranean diet as a whole has been shown to have a beneficial role on various neoplasms. METHODS: We analysed this issue pooling data from three case-control studies carried out between 1983 and 2006 in various Italian areas and in the Swiss Canton of Vaud. Cases were 1411 women with incident, histologically confirmed endometrial cancer, and controls were 3668 patients in hospital for acute diseases. We measured the adherence to the Mediterranean diet using a Mediterranean Diet Score (MDS), based on the nine dietary components characteristics of this diet, that is, high intake of vegetables, fruits/nuts, cereals, legumes, fish; low intake of dairy products and meat; high monounsaturated to saturated fatty acid ratio; and moderate alcohol intake. We estimated the odds ratios (OR) and the corresponding 95% confidence intervals (CI) for increasing levels of the MDS (varying from 0, no adherence, to 9, maximum adherence) using multiple logistic regression models, adjusted for major confounding factors. RESULTS: The adjusted OR for a 6-9 components of the MDS (high adherence) compared with 0-3 (low adherence) was 0.43 (95% CI 0.34 0.56). The OR for an increment of one component of MDS diet was 0.84 (95% CI 0.80 0.88). The association was consistent in strata of various covariates, although somewhat stronger in older women, in never oral contraceptive users and in hormone-replacement therapy users. CONCLUSIONS: Our study provides evidence for a beneficial role of the Mediterranean diet on endometrial cancer risk, suggesting a favourable effect of a combination of foods rich in antioxidants, fibres, phytochemicals, and unsaturated fatty acids. PMID- 26010502 TI - Comment on 'Are the studies on cancer risk from CT scans biased by indication? Elements of answer from a large-scale cohort study in France'-Evidence of confounding by predisposing factors unclear. PMID- 26010503 TI - Comment on: Are the studies on cancer risk from CT scans biased by indication? Elements of answer from a large-scale cohort study in France. PMID- 26010504 TI - Hepatitis B virus infection and gastric cancer risk: pitfalls in the potential association. PMID- 26010505 TI - Treatment of male androgenetic alopecia with topical products containing Serenoa repens extract. AB - BACKGROUND/OBJECTIVES: Male androgenetic alopecia (AGA) is a common hair problem. Serenoa repens extract has been shown to inhibit both types of 5-alpha reductase and, when taken orally, has been shown to increase hair growth in AGA patients. The aim of this study was to assess the efficacy of topical products containing S. repens extract for the treatment of male AGA. METHODS: This was a pilot, prospective, open, within-subject comparison limited to 24 weeks using no placebo controls. In all, 50 male volunteers aged between 20 and 50 years received topical S. repens products for 24 weeks. The primary end-point was a hair count in an area of 2.54 cm(2) at week 24. Secondary end-points included hair restoration, investigators' photographic assessment, patients' evaluation and discovering adverse events. RESULTS: The average hair count and terminal hair count increased at weeks 12 and 24 compared to baseline. Some of these positive results levelled off at week 24, presumably because the concentrated topical product containing S. repens extract was stopped after 4 weeks. The patients were satisfied with the products and the side-effects were limited. CONCLUSIONS: The topical application of S. repens extract could be an alternative treatment in male pattern baldness in male patients who do not want or cannot tolerate the side-effects of standard medications, but the use of a concentrated S. repens product beyond 4 weeks may be necessary for sustained efficacy. PMID- 26010506 TI - Biomarker informed add-arm design for unimodal response. AB - In this article, we propose a biomarker informed add-arm design for unimodal response. The new design contributes to optimizing the procedure of dose-finding when a biomarker of the study primary endpoint exists and prior evidence indicates a unimodal dose-response relationship. Designs with up to seven active treatment arms were considered. We propose the statistical approach for the Type I error control and carry out extensive simulation studies for the power performance of the design. The proposed design is shown to outperform the corresponding biomarker informed two-stage winner design in power on an average. PMID- 26010507 TI - Practice- and Community-Based Interventions to Increase Human Papillomavirus Vaccine Coverage: A Systematic Review. AB - IMPORTANCE: Vaccines against human papillomavirus (HPV) are recommended for routine use in adolescents aged 11 to 12 years in the United States, but uptake remains suboptimal. Educational interventions focused on parents and patients to increase coverage have not generally demonstrated effectiveness. OBJECTIVE: To systematically review the literature on effectiveness of interventions conducted at the practice or community level to increase uptake of HPV vaccines in the United States. EVIDENCE REVIEW: Keyword searches of the PubMed, Web of Science, and MEDLINE databases identified studies of adolescents that included the outcome of HPV vaccination published through July 2014. References of identified articles were also reviewed. A total of 366 records were screened, 38 full-text articles were reviewed, and 14 published studies were included. Results were summarized by different intervention approaches. FINDINGS: Practice- and community-based intervention approaches included reminder and recall (n = 7), physician-focused interventions (eg, audit and feedback) (n = 6), school-based programs (n = 2), and social marketing (n = 2) (2 interventions tested multiple approaches). Seven studies used a randomized design, and 8 used quasiexperimental approaches (one used both). Thirteen studies included girls, and 2 studies included boys. Studies were conducted in a variety of populations and geographic locations. Twelve studies reported significant increases in at least one HPV vaccination outcome, one reported a nonsignificant increase, and one reported mixed effects. CONCLUSIONS AND RELEVANCE: Most practice- and community-based interventions significantly increased HPV vaccination rates using varied approaches across diverse populations. This finding is in stark contrast to a recent review that did not find effects to warrant widespread implementation for any educational intervention. To address the current suboptimal rates of HPV vaccination in the United States, future efforts should focus on programs that can be implemented within health care settings, such as reminder and recall strategies and physician focused efforts, as well as the use of alternative community-based locations, such as schools. PMID- 26010509 TI - The path of no return--Truncated protein N-termini and current ignorance of their genesis. AB - Almost all regulatory processes in biology ultimately lead to or originate from modifications of protein function. However, it is unclear to which extent each mechanism of regulation actually affects proteins and thus phenotypes. We assessed the extent of N-terminal protein truncation in a global analysis of N terminomics data and find that most proteins have N-terminally truncated proteoforms. Because N-terminomics analyses do not identify the process generating the identified N-termini, we compared identified termini to the three N-termini generating events: protein cleavage, alternative translation, and alternative splicing. Of these, we sought to identify the most likely cause of N terminal protein truncations in the human proteome. We found that protease cleavage and alternative protein translation are the likely cause for most shortened proteoforms. However, the vast majority (about 90%) of N-termini remain unexplained by any of these processes identified to date, so revealing large gaps in our knowledge of protein termini and their genesis. Further analysis and annotation of terminomics data is required, to which end we have created the TopFIND database, a major systematic annotation effort for protein termini. We outline the new features in version 3.0 of the updated database and the new bioinformatics tools available and encourage submission of generated data to fill current knowledge gaps. PMID- 26010510 TI - Biological Perspectives: Huntington's Disease. PMID- 26010512 TI - Impact of relationships between test and training animals and among training animals on reliability of genomic prediction. AB - One of the factors affecting the reliability of genomic prediction is the relationship among the animals of interest. This study investigated the reliability of genomic prediction in various scenarios with regard to the relationship between test and training animals, and among animals within the training data set. Different training data sets were generated from EuroGenomics data and a group of Nordic Holstein bulls (born in 2005 and afterwards) as a common test data set. Genomic breeding values were predicted using a genomic best linear unbiased prediction model and a Bayesian mixture model. The results showed that a closer relationship between test and training animals led to a higher reliability of genomic predictions for the test animals, while a closer relationship among training animals resulted in a lower reliability. In addition, the Bayesian mixture model in general led to a slightly higher reliability of genomic prediction, especially for the scenario of distant relationships between training and test animals. Therefore, to prevent a decrease in reliability, constant updates of the training population with animals from more recent generations are required. Moreover, a training population consisting of less related animals is favourable for reliability of genomic prediction. PMID- 26010511 TI - Identification of Non-HIV Immunogens That Bind to Germline b12 Predecessors and Prime for Elicitation of Cross-clade Neutralizing HIV-1 Antibodies. AB - A fundamental challenge for developing an effective and safe HIV-1 vaccine is to identify vaccine immunogens that can initiate and maintain immune responses leading to elicitation of broadly neutralizing HIV-1 antibodies (bnAbs) through complex maturation pathways. We have previously found that HIV-1 envelope glycoproteins (Env) lack measurable binding to putative germline predecessors of known bnAbs and proposed to search for non-HIV immunogens that could initiate their somatic maturation. Using bnAb b12 as a model bnAb and yeast display technology, we isolated five (poly)peptides from plant leaves, insects, E. coli strains, and sea water microbes that bind to b12 putative germline and intermediate antibodies. Rabbit immunization with the (poly)peptides alone induced high titers of cross-reactive antibodies that neutralized HIV-1 isolates SF162 and JRFL. Priming rabbits with the (poly)peptides followed by boosts with trimeric gp140SF162 and then resurfaced Env (RSC3) induced antibodies that competed with mature b12 and neutralized tier 1 and 2 viruses from clade B, C and E, while control rabbits without (poly)peptide priming induced antibodies that did not compete with mature b12 and neutralized fewer isolates. The degree of competition with mature b12 for binding to gp140SF162 correlated with the neutralizing activity of the rabbit IgG. Reversing the order of the two boosting immunogens significantly affected the binding profile and neutralization potency of the rabbit IgG. Our study is the first to provide evidence that appears to support the concept that non-HIV immunogens may initiate immune responses leading to elicitation of cross-clade neutralizing antibodies. PMID- 26010514 TI - Neuropeptide Y restores non-receptor-mediated vasoconstrictive action in superior mesenteric arteries in portal hypertension. AB - BACKGROUND & AIMS: Vascular hyporeactivity to vasoconstrictors contributes to splanchnic arterial vasodilatation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY), a sympathetic cotransmitter, has been shown to improve adrenergic vascular contractility in portal hypertensive rats and markedly attenuate hyperdynamic circulation. To further characterize the NPY effects in portal hypertension, we investigated its role for non-receptor mediated vasoconstriction in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham-operated rats. METHODS: Ex vivo SMA perfusion of PVL and sham rats was used to analyse the effects of NPY on pressure response to non receptor-mediated vasoconstriction. Dose-response curves to KCl (30-300 mM) were used to bypass G protein-coupled receptor mechanisms. Potential involvement of the cyclooxygenase-pathway was tested by non-selective cyclooxygenase-inhibition using indomethacin. RESULTS: KCl-induced vascular contractility but not vascular sensitivity was significantly attenuated in PVL rats as compared with sham rats. Administration of NPY resulted in an augmentation of KCl-evoked vascular sensitivity being not different between study groups. However, KCl-induced vascular contractility was markedly more enhanced in PVL rats, thus, vascular response was no more significantly different between PVL and sham rats after addition of NPY. Administration of indomethacin abolished the NPY-induced enhancement of vasoconstriction. CONCLUSIONS: Receptor-independent vascular contractility is impaired in mesenteric arteries in portal hypertension. NPY improves non-receptor mediated mesenteric vasoconstriction more effective in portal hypertension than in healthy conditions correcting splanchnic vascular hyporesponsiveness. This beneficial vasoactive action of NPY adds to its well known more pronounced effects on adrenergic vasoconstriction in portal hypertension making it a promising therapeutic agent in portal hypertension. PMID- 26010513 TI - DPP-4 Inhibitor Linagliptin Attenuates Abeta-induced Cytotoxicity through Activation of AMPK in Neuronal Cells. AB - AIM: It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative disease, particularly Alzheimer's disease (AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid beta (Abeta)-induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase-4 (DPP 4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in Abeta-mediated neurotoxicity have not yet been investigated. METHODS: In the present study, we evaluated the mechanisms by which linagliptin protects against Abeta-induced impaired insulin signaling and cytotoxicity in cultured SK N-MC human neuronal cells. RESULTS: Our results showed that Abeta impairs insulin signaling and causes cell death. However, linagliptin significantly protected against Abeta-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3beta (GSK3beta) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated Abeta-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5' AMP-activated protein kinase (AMPK)-Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin. CONCLUSIONS: Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by Abeta in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing Abeta-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis. PMID- 26010515 TI - An assessment of the microbiological safety of fresh whole-leaf herbs from retail premises in the United Kingdom with a focus on Salmonella spp. AB - AIMS: Fresh herbs have been associated with a number of outbreaks in recent years, in the United Kingdom and elsewhere. A study of fresh herbs was carried out to assess their microbiological safety in relation to Salmonella contamination and levels of Escherichia coli. METHODS AND RESULTS: Between January and March 2014, 774 samples of ready-to-eat, fresh, whole-leaf herbs were collected from retail premises in the United Kingdom. Overall, Salmonella was detected in nine samples (1.2%). Of these, five were curry leaves. Other herbs contaminated with Salmonella were basil (two samples), walleria (1) and coriander (1). Escherichia coli was detected in 13% of samples, with 11% containing unsatisfactory levels (>=10(2) g(-1)). CONCLUSIONS: Whilst 88% of samples in this study were of an acceptable microbiological quality, the presence of Salmonella and/or elevated E. coli levels in 12% is a cause for concern. Curry leaves, in particular, had significantly higher rates of contamination with both Salmonella and E. coli than other herbs. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the potential public health risk associated with the consumption of certain ready-to-eat fresh herbs, and the need for good hygiene practices and effective decontamination procedures during the growth, harvesting and subsequent handling of these products. PMID- 26010516 TI - Engineering cartilaginous grafts using chondrocyte-laden hydrogels supported by a superficial layer of stem cells. AB - During postnatal joint development, progenitor cells that reside in the superficial region of articular cartilage first drive the rapid growth of the tissue and later help direct the formation of mature hyaline cartilage. These developmental processes may provide directions for the optimal structuring of co cultured chondrocytes (CCs) and multipotent stromal/stem cells (MSCs) required for engineering cartilaginous tissues. The objective of this study was to engineer cartilage grafts by recapitulating aspects of joint development where a population of superficial progenitor cells drives the development of the tissue. To this end, MSCs were either self-assembled on top of CC-laden agarose gels (structured co-culture) or were mixed with CCs before being embedded in an agarose hydrogel (mixed co-culture). Porcine infrapatellar fat pad-derived stem cells (FPSCs) and bone marrow-derived MSCs (BMSCs) were used as sources of progenitor cells. The DNA, sGAG and collagen content of a mixed co-culture of FPSCs and CCs was found to be lower than the combined content of two control hydrogels seeded with CCs and FPSCs only. In contrast, a mixed co-culture of BMSCs and CCs led to increased proliferation and sGAG and collagen accumulation. Of note was the finding that a structured co-culture, at the appropriate cell density, led to greater sGAG accumulation than a mixed co-culture for both MSC sources. In conclusion, assembling MSCs onto CC-laden hydrogels dramatically enhances the development of the engineered tissue, with the superficial layer of progenitor cells driving CC proliferation and cartilage ECM production, mimicking certain aspects of developing cartilage. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010518 TI - Relationship between buccal bone and gingival thickness revisited using non invasive registration methods. AB - OBJECTIVE: To determine the relationship between buccal bone and soft tissue thickness at teeth in the premaxilla by means of non-invasive registration methods. MATERIALS AND METHODS: Buccal bone thickness at central incisors, lateral incisors and canines was measured at five reference points (1-5 mm from the top of the alveolar crest) on CB-CT scans of 21 patients. The corresponding buccal gingival thickness was measured by the use of an ultrasonic device. Spearman's correlation coefficient was calculated to assess the correlation between buccal bone and soft tissue thickness at each tooth type. RESULTS: Mean buccal bone thickness (SD) at central incisors, lateral incisors and canines was 1.07 mm (0.34 mm), 1.16 mm (0.54 mm) and 0.98 mm (0.37 mm), respectively. For central incisors, 68% of all sites had a thickness <1 mm and 32% had a thickness between 1.0 and 2.0 mm. At lateral incisors, 44% demonstrated buccal bone thickness between 0 and 1.0 mm, 48% between 1.0 and 2.0 mm and 8% >=2 mm. For canines, 57% of the sites were <1 mm thick; 41% were between 1.0 and 2.0 mm thick, and 2% demonstrated >=2 mm thickness. Mean gingival thickness (SD) at central incisors, lateral incisors and canines was 1.37 mm (0.32 mm), 1.33 mm (0.32 mm) and 1.08 mm (0.25 mm), respectively. The correlation between buccal bone and soft tissue thickness was moderately positive (rho = 0.406; P < 0.001). CONCLUSIONS: A thin buccal bone wall (<1 mm) may be expected in over half of the central incisors and canines. The correlation between buccal bone and soft tissue thickness was moderately positive. PMID- 26010517 TI - Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult. AB - The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or beta-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and magnitude of the stimuli, may play a role in the development of an adaptive or maladaptive phenotype. PMID- 26010519 TI - Feeling energetic? New strategies to prevent metabolic reprogramming in melanoma. PMID- 26010520 TI - On-table Extubation after Open Heart Surgery in Children: An Experience from a Tertiary Care Hospital in a Developing Country. AB - BACKGROUND: Recent advances in various disciplines of medicine have significantly changed the courses following cardiac surgery in children. On-table extubation (OTE) after open heart surgery in children is evolving. OBJECTIVE: To assess the rate of postoperative complications in children extubated on table after open heart surgery. DESIGN: This is a retrospective, descriptive study. SETTING: Operating room (OR) then admitted to the pediatric intensive care unit (PICU). PATIENTS: All pediatric patients (between 0 and 18 years) undergoing open heart surgery between January 2011 and June 2013. INTERVENTION: On-table extubation. OUTCOME MEASURES: Rates of immediate postoperative complications, i.e., re intubation, significant bleeding, low cardiac output syndrome, and arrhythmia in PICU, were assessed. Data are presented as frequencies and mean +/- standard deviation. RESULTS: A total of 82 patients were included. Mean age at time of operation was 7.25 +/- 6.6 years. Fifty-three percent (n = 44) were <5 years old and 64% (n = 53) were men. Ventricular septal defect (47%, n = 39) was the most common lesion, followed by atrial septal defect (36%, n = 30), and tetralogy of Fallot (15%, n = 12), which were repaired. Cardiopulmonary bypass and aortic cross clamp time were 72.3 +/- 34.2 and 47.3 +/- 27.8 minutes, respectively. The mean inotrope score was 2.66 +/- 3.53. There was no mortality in the cohort, whereas 97.8% (n = 80) had no complications during PICU stay. One patient (1.1%) required re-intubation for respiratory failure and one patient (1.1%) had arrhythmia that was medically managed. The mean length of PICU stay was 1.77 +/- 0.985 days. CONCLUSION: On-table extubation in children after open heart surgery was feasible and safe in selected group of patients. There was no major complication observed in the PICU. PMID- 26010522 TI - Signature of protein unfolding in chemical exchange saturation transfer imaging. AB - Chemical exchange saturation transfer (CEST) allows the detection of metabolites of low concentration in tissue with nearly the sensitivity of MRI with water protons. With this spectroscopic imaging approach, several tissue-specific CEST effects have been observed in vivo. Some of these originate from exchanging sites of proteins, such as backbone amide protons, or from aliphatic protons within the hydrophobic protein core. In this work, we employed CEST experiments to detect global protein unfolding. Spectral evaluation revealed exchange- and NOE-mediated CEST effects that varied in a highly characteristic manner with protein unfolding tracked by fluorescence spectroscopy. We suggest the use of this comprehensive spectral signature for the detection of protein unfolding by CEST, as it relies on several spectral hallmarks. As proof of principle, we demonstrate that the presented signature is readily detectable using a whole-body MR tomograph (B0 = 7 T), not only in denatured aqueous protein solutions, but also in heat-shocked yeast cells. A CEST imaging contrast with the potential to detect global protein unfolding would be of particular interest regarding protein unfolding as a marker for stress, ageing, and disease. PMID- 26010521 TI - Pharmacological, sensorimotor, and expectancy effects on tobacco withdrawal: a preliminary study. AB - OBJECTIVE: Research designs for parsing the mechanisms underlying tobacco withdrawal are scant. This study introduced a novel research design that simultaneously manipulated three tobacco withdrawal mechanisms: pharmacological (nicotine dissipation), sensorimotor (elimination of the smoking ritual), and expectancy (activation of beliefs regarding the effects of nicotine deprivation), permitting examination of the effects of each mechanism while holding the other two mechanisms constant. METHODS: Following overnight abstinence, 32 regular cigarette smokers were randomized in a 2 (expectancy: told patch contains nicotine versus told placebo patch) * 2 (drug: receive 21-mg transdermal nicotine patch versus receive placebo patch) * 2 (sensorimotor: smoke very low nicotine content cigarettes versus no smoking) full factorial between-subjects design. Participants repeatedly completed measures of craving, affect, and anticipated pleasure from and desire for rewarding experiences, followed by a smoking lapse analog task. RESULTS: Receiving nicotine (versus placebo) increased positive affect and anticipated pleasure from and desire for reward. Expecting nicotine (versus placebo) reduced negative affect and increased smoking delay. Sensorimotor stimulation from smoking (versus no smoking) reduced smoking urge and behavior. CONCLUSION: Results provided initial validation of this novel three mechanism design. This design can be used in the future to advance understanding and treatment of tobacco withdrawal. PMID- 26010523 TI - Paraxis is required for somite morphogenesis and differentiation in Xenopus laevis. AB - BACKGROUND: In most vertebrates, the segmentation of the paraxial mesoderm involves the formation of metameric units called somites through a mesenchymal epithelial transition. However, this process is different in Xenopus laevis because it does not form an epithelial somite. Xenopus somitogenesis is characterized by a complex cells rearrangement that requires the coordinated regulation of cell shape, adhesion, and motility. The molecular mechanisms that control these cell behaviors underlying somite formation are little known. Although the Paraxis has been implicated in the epithelialization of somite in chick and mouse, its role in Xenopus somite morphogenesis has not been determined. RESULTS: Using a morpholino and hormone-inducible construction approaches, we showed that both gain and loss of function of paraxis affect somite elongation, rotation and alignment, causing a severe disorganization of somitic tissue. We further found that depletion or overexpression of paraxis in the somite led to the downregulation or upregulation, respectively, of cell adhesion expression markers. Finally, we demonstrated that paraxis is necessary for the proper expression of myotomal and sclerotomal differentiation markers. CONCLUSIONS: Our results demonstrate that paraxis regulates the cell rearrangements that take place during the somitogenesis of Xenopus by regulating cell adhesion. Furthermore, paraxis is also required for somite differentiation. PMID- 26010524 TI - Effects of Cognitive Behavioral Stress Management on Negative Mood and Cardiac Autonomic Activity in ICD Recipients. AB - BACKGROUND: Behavioral intervention studies in patients with an implantable cardioverter-defibrillator (ICD) show promise in improving psychosocial outcomes but inconclusive effects on cardiovascular outcome. We assessed the effects of cognitive behavioral stress management (CBSM) on mood state and potentially arrhythmogenic cardiovascular responses to mental stress in ICD patients, in support of further larger scale arrhythmia trials. METHODS: A total of 103 ICD recipients were randomly assigned to 10-week programs of CBSM or "Patient Education" (ED). Of these, 83 patients continued to either CBSM (n = 44) or ED (n = 39) intervention. Study end points were mood change, heart rate variability (HRV), double product elevation (DP = heart rate * systolic blood pressure) by math and anger-recall stress, and arrhythmia up to 6 months follow-up. RESULTS: Adjusting for multiple testing, CBSM was associated with moderate effect size reductions in tension/anxiety (P = 0.010), anger/hostility (P = 0.020), perceived stress (P = 0.037), and total mood disturbance (P = 0.025), greatest immediately following intervention (P < 0.05), and partially attributable to increased negative mood following ED (P < 0.01). No significant intervention effects on high frequency or low frequency spectral power of HRV, DP responses, or cardiac arrhythmias were demonstrated. CONCLUSIONS: CBSM intervention in ICD recipients resulted in reduced anxiety, anger, and perceived stress, not sustained at 6 months follow-up, and without conclusive effect on cardiac autonomic or hemodynamic responses to mental stress, or arrhythmia. Findings support conduct of larger behavioral intervention arrhythmia trial, with consideration of reinforcement training and targeting of subgroup responders to therapy. PMID- 26010525 TI - Analysis of nucleotide insertion opposite 2,2,4-triamino-5(2H)-oxazolone by eukaryotic B- and Y-family DNA polymerases. AB - Mutations induced by oxidative DNA damage can cause diseases such as cancer. In particular, G:C-T:A and G:C-C:G transversions are caused by oxidized guanine and have been observed in the p53 and K-ras genes. We focused on an oxidized form of guanine, 2,2,4-triamino-5(2H)-oxazolone (Oz), as a cause of G:C-C:G transversions based on our earlier elucidation that DNA polymerases (Pols) alpha, beta, gamma, epsilon, eta, I, and IV incorporate dGTP opposite Oz. The nucleotide insertion and extension of Pols delta, zeta, iota, kappa, and REV1, belonging to the B- and Y-families of DNA polymerases, were analyzed for the first time. Pol delta incorporated dGTP, in common with other replicative DNA polymerases. Pol zeta incorporated dGTP and dATP, and the efficiency of elongation up to full-length beyond Oz was almost the same as that beyond G. Although nucleotide incorporation by Pols iota or kappa was also error-prone, they did not extend the primer. On the other hand, the polymerase REV1 predominantly incorporated dCTP opposite Oz more efficiently than opposite 8-oxo-7,8-dihydroguanine, guanidinohydantoin, or tetrahydrofuran. Here, we demonstrate that Pol zeta can efficiently replicate DNA containing Oz and that REV1 can prevent G:C-C:G transversions caused by Oz. PMID- 26010527 TI - Physiological responses and partisan bias: beyond self-reported measures of party identification. AB - People are biased partisans: they tend to agree with policies from political parties they identify with, independent of policy content. Here, we investigate how physiological reactions to political parties shape bias. Using changes in galvanic skin conductance responses to the visual presentation of party logos, we obtained an implicit and physiological measure of the affective arousal associated with political parties. Subsequently, we exposed subjects to classical party cue experiments where the party sponsors of specific policies were experimentally varied. We found that partisan bias only obtains among those exhibiting a strong physiological reaction to the party source; being a self reported party identifier is not sufficient on its own. This suggests that partisan bias is rooted in implicit, affective reactions. PMID- 26010526 TI - Natural disturbance impacts on ecosystem services and biodiversity in temperate and boreal forests. AB - In many parts of the world forest disturbance regimes have intensified recently, and future climatic changes are expected to amplify this development further in the coming decades. These changes are increasingly challenging the main objectives of forest ecosystem management, which are to provide ecosystem services sustainably to society and maintain the biological diversity of forests. Yet a comprehensive understanding of how disturbances affect these primary goals of ecosystem management is still lacking. We conducted a global literature review on the impact of three of the most important disturbance agents (fire, wind, and bark beetles) on 13 different ecosystem services and three indicators of biodiversity in forests of the boreal, cool- and warm-temperate biomes. Our objectives were to (i) synthesize the effect of natural disturbances on a wide range of possible objectives of forest management, and (ii) investigate standardized effect sizes of disturbance for selected indicators via a quantitative meta-analysis. We screened a total of 1958 disturbance studies published between 1981 and 2013, and reviewed 478 in detail. We first investigated the overall effect of disturbances on individual ecosystem services and indicators of biodiversity by means of independence tests, and subsequently examined the effect size of disturbances on indicators of carbon storage and biodiversity by means of regression analysis. Additionally, we investigated the effect of commonly used approaches of disturbance management, i.e. salvage logging and prescribed burning. We found that disturbance impacts on ecosystem services are generally negative, an effect that was supported for all categories of ecosystem services, i.e. supporting, provisioning, regulating, and cultural services (P < 0.001). Indicators of biodiversity, i.e. species richness, habitat quality and diversity indices, on the other hand were found to be influenced positively by disturbance (P < 0.001). Our analyses thus reveal a 'disturbance paradox', documenting that disturbances can put ecosystem services at risk while simultaneously facilitating biodiversity. A detailed investigation of disturbance effect sizes on carbon storage and biodiversity further underlined these divergent effects of disturbance. While a disturbance event on average causes a decrease in total ecosystem carbon by 38.5% (standardized coefficient for stand replacing disturbance), it on average increases overall species richness by 35.6%. Disturbance-management approaches such as salvage logging and prescribed burning were neither found significantly to mitigate negative effects on ecosystem services nor to enhance positive effects on biodiversity, and thus were not found to alleviate the disturbance paradox. Considering that climate change is expected to intensify natural disturbance regimes, our results indicate that biodiversity will generally benefit from such changes while a sustainable provisioning of ecosystem services might come increasingly under pressure. This underlines that disturbance risk and resilience require increased attention in ecosystem management in the future, and that new approaches to addressing the disturbance paradox in management are needed. PMID- 26010528 TI - Review peptide-targeted liposomes for selective drug delivery: Advantages and problematic issues. AB - We describe the use of bioactive peptides to drive liposomal drugs on target receptors overexpressed in cancer cells. A detailed description for several targeting liposomes derivatized with different peptides and thus able to target relevant receptors for cancer therapy is reported. Even if the development of peptide-targeted liposomes represents a great advance in the use of liposomal drugs for cancer therapy, many critical issues are still unsolved in the development of these innovative drug delivery systems. Advantages and drawbacks of the peptide-mediated active targeting are discussed. PMID- 26010529 TI - Reaching Back to Jump Forward: Recent Efforts towards a Systems-Level Hypothesis for an Early RNA World. AB - In the spring of the world: Reductive homologation of cyanidic precursors creates the carbon scaffold for multiple classes of biologically relevant compounds. This chemistry underpins a scenario for the formation of a protometabolism on the way to an RNA world. PMID- 26010530 TI - Multimodal approach to assess tumour vasculature and potential treatment effect with DCE-US and DCE-MRI quantification in CWR22 prostate tumour xenografts. AB - The aim of this study was to compare intratumoural heterogeneity and longitudinal changes assessed by dynamic contrast-enhanced ultrasound (DCE-US) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in prostate tumour xenografts. In vivo DCE-US and DCE-MRI were obtained 24 h pre- (day 0) and post- (day 2) radiation treatment with a single dose of 7.5 Gy. Characterization of the tumour vasculature was determined by Brix pharmacokinetic analysis of the time intensity curves. Histogram analysis of voxels showed significant changes (p < 0.001) from day 0 to day 2 in both modalities for kep , the exchange rate constant from the extracellular extravascular space to the plasma, and kel , the elimination rate constant of the contrast. In addition, kep and kel values from DCE-US were significantly higher than those derived from DCE-MRI at day 0 (p < 0.0001) for both groups. At day 2, kel followed the same tendency for both groups, whereas kep showed this tendency only for the treated group in intermediate-enhancement regions. Regarding kep median values, longitudinal changes were not found for any modality. However, at day 2, kep linked to DCE-US was correlated to MVD in high-enhancement areas for the treated group (p = 0.05). In contrast, correlation to necrosis was detected for the control group in intermediate-enhancement areas (p < 0.1). Intratumoural heterogeneity and longitudinal changes in tumour vasculature were assessed for both modalities. Microvascular parameters derived from DCE-US seem to provide reliable biomarkers during radiotherapy as validated by histology. Furthermore, DCE-US could be a stand-alone or a complementary technique. PMID- 26010531 TI - Coronary artery calcification score is an independent predictor of the no-reflow phenomenon after reperfusion therapy in acute myocardial infarction. AB - AIM/BACKGROUND: Abundant evidence shows that coronary artery calcification (CAC) is a strong marker of structural and functional changes within the artery wall. Thus far, the implications of CAC in patients with acute coronary syndromes remain unclear. We aimed to investigate whether the CAC score is associated with impaired reperfusion during the acute phase of ST-elevation myocardial infarction (STEMI). METHODS: We enrolled 60 consecutive STEMI patients to undergo cardiac computed tomography for assessment of the CAC score within 1 week after STEMI. Coronary thrombus burden, coronary blood flow (TIMI flow), and myocardial blush grade (MBG) were evaluated systematically. Patients with maximal TIMI flow and MBG were grouped as optimal reperfusion (n=27) and their counterparts as no reflow (NR, n=33). RESULTS: There were no differences in the clinical characteristics between groups. Patients in the NR group had higher heart rate, coronary angiographic severity, and CAC score. CAC score greater than 100 was associated independently with the presence of NR (odds ratio 4.4, 95% confidence interval 1.17-16.3). The CAC score of nonculprit coronary arteries was higher in NR individuals than in their counterparts (P=0.04). In addition, the CAC score of the isnfarct-related artery correlated negatively with the TIMI-flow rate (r= 0.54, P<0.001) and with the MBG (r=-0.32, P=0.04). CONCLUSION: The CAC score is associated with the presence of the NR phenomenon in STEMI patients. PMID- 26010532 TI - Comparison of coronary artery lesion length by NIRS-IVUS versus angiography alone. AB - BACKGROUND: Intravascular ultrasound (IVUS) studies analyzing target lesion plaque burden (PB) have established that invasive coronary angiography commonly underestimates lesion length, predisposing to 'geographic miss' during a percutaneous coronary intervention, which has been associated with adverse outcomes. Plaque composition may also influence stent outcome. The present study used near-infrared spectroscopy and IVUS (NIRS-IVUS) to assess the prevalence of PB and lipid-core plaque (LCP) extending beyond angiographic borders of target lesions. METHODS: Fifty-eight patients (58 lesions) undergoing NIRS-IVUS were identified. By invasive coronary angiography, target lesion length and minimum lumen diameter were measured. Plaque, defined as NIRS-IVUS atheroma (either PB>40% or LCP), was identified adjacent to the angiographic-defined lesion margins. RESULTS: By NIRS-IVUS, atheroma (either PB>40% or LCP) was identified beyond angiographic lesion margins in 52/58 (90%) lesions. The mean lesion length was 13.4+/-5.9 mm by angiography and 19.8+/-7.0 mm (P<0.0001) by NIRS-IVUS. LCP extending beyond the angiographic border was observed in 30/58 (52%) lesions. CONCLUSION: NIRS-IVUS imaging shows that target lesion length is commonly underestimated by angiography alone. This finding may have implications for stent length selection and avoidance of geographic miss. PMID- 26010533 TI - Low mortality from intracranial haemorrhage in paediatric patients with haemophilia. AB - INTRODUCTION: Intracranial haemorrhage (ICH) in patients with haemophilia has an estimated mortality rate of 20%. Advances in haemophilia care have significantly reduced many bleeding complications but it is unclear if these advances have impacted mortality from ICH. AIM: To determine the in-hospital mortality from intracranial ICH in paediatric patients with haemophilia. METHODS: This retrospective multicentre cohort study utilized the Pediatric Health Information System administrative database with data from 43 paediatric tertiary care hospitals in the United States from January 1, 2002-December 31, 2011. Subjects included were male < 21 years of age with an ICD-9-CM code for haemophilia A or B. ICH events were identified using ICD-9-CM codes. RESULTS: There were 8325 admissions for 3133 male subjects with haemophilia. About 271 (3.3%) admissions had an ICH event in 236 (7.5%) individual subjects. The proportion of ICH events was stable over time (P = 0.13). The median age of ICH was 2 years (interquartile range 0.6-7.3). In 28.4% (77/271) of the ICH events the subject had an inhibitor. Twenty-one deaths occurred in the entire cohort (0.7%). Six (28.6%) of these deaths were in patients with an ICH for an ICH mortality rate of 2.5% (6/236). CONCLUSIONS: Mortality from ICH in paediatric patients has significantly improved from prior estimates of 20% to the current estimate of 2.5%. Unfortunately the rate of ICH events remains constant and further efforts are needed to identify alternative strategies of prevention. PMID- 26010535 TI - Correction: Intrapersonal and Interpersonal Concomitants of Facial Blushing during Everyday Social Encounters. PMID- 26010534 TI - Diagnosis and treatment of acute sinusitis in the primary care setting: A retrospective cohort. AB - OBJECTIVES AND HYPOTHESIS: Our objectives were to characterize the quality of acute sinusitis care and to identify nonclinical factors associated with antibiotic use for acute sinusitis. We hypothesized that we would identify provider-level factors associated with antibiotic use. STUDY DESIGN: Retrospective cohort at a single academic institution. METHODS: We developed and clinically annotated an administrative dataset of adult patients diagnosed with acute sinusitis between January 1, 2005, and December 31, 2006. We used identify factors associated with receipt of antibiotics. RESULTS: We find that 66.0% of patients with mild symptoms of short duration are given antibiotics, and that nonclinical factors, including the individual provider, the provider's specialty, and the presence of a medical trainee, significantly influence antibiotic use. Relative to internal medicine providers, family medicine providers use fewer antibiotics, and emergency medicine providers use more antibiotics for acute sinusitis. CONCLUSIONS: Antibiotics continue to be overused for patients with mild acute sinusitis of short duration. Nonclinical characteristics, including the individual provider, the provider's specialty, and the presence of a medical trainee, significantly influence use of antibiotics for acute sinusitis. LEVEL OF EVIDENCE: 4. PMID- 26010536 TI - Identification and quantification of Cu-chlorophyll adulteration of edible oils. AB - Cu-pyropheophytin a, the major Cu-pigment of Cu-chlorophyll, was determined in edible oil by high-resolution mass spectrometry with a high-performance liquid chromatography-quadrupole (HPLC-Q)-Orbitrap system and by HPLC coupled with a photodiode-array detector. Respective limit of detection and limit of quantification levels of 0.02 MUg/g and 0.05 MUg/g were obtained. Twenty-nine commercial oil products marked as olive oil, grapeseed oil and blended oil, all sourced directly from a food company that committed adulteration with Cu chlorophyll, were investigated. In this company, four green dyes illegally used in oils were seized during factory investigation by the health authorities. The food additive Cu-pyropheophytin a was found in all confiscated samples in concentrations between 0.02 and 0.39 MUg/g. Survey results of another 235 commercial oil samples manufactured from other companies, including olive pomace oil, extra virgin olive oil, olive oil, grapeseed oil and blended oil, indicated high positive incidences of 63%, 39%, 44%, 97% and 8%, respectively, with a concentration range between 0.02 and 0.54 MUg/g. High Cu-chlorophyll concentrations are indications for fraudulent adulteration of oils. PMID- 26010538 TI - Isolation of oxidative degradation products of atorvastatin with supercritical fluid chromatography. AB - The isolation of four oxidative degradation products of atorvastatin using preparative high-performance liquid chromatography applying at least two chromatographic steps is known from the literature. In this paper it is shown that the same four impurities could be isolated from similarly prepared mixtures in only one step using supercritical fluid chromatography. The methods for separation were developed and optimized. The preparation of the mixtures was altered in such a way as to enhance the concentration of desired impurities. Appropriate solvents were applied for collection of separated impurities in order to prevent degradation. The structures of the isolated impurities were confirmed and their purity determined. The preparative supercritical fluid chromatography has proven to be superior to preparative HPLC regarding achieved purity of standards applying fewer chromatographic as well as isolation steps. PMID- 26010537 TI - Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules. AB - Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI. PMID- 26010540 TI - Effects of blood transfusion on exercise capacity in thalassemia major patients. AB - Anemia has an important role in exercise performance. However, the direct link between rapid changes of hemoglobin and exercise performance is still unknown.To find out more on this topic, we studied 18 beta-thalassemia major patients free of relevant cardiac dysfunction (age 33.5+/-7.2 years,males = 10). Patients performed a maximal cardiopulmolmonary exercise test (cycloergometer, personalized ramp protocol, breath-by-breath measurements of expired gases) before and the day after blood transfusion (500 cc of red cell concentrates). After blood transfusion, hemoglobin increased from 10.5+/-0.8 g/dL to 12.1+/-1.2 (p<0.001), peak VO2 from 1408 to 1546mL/min (p<0.05), and VO2 at anaerobic threshold from 965 to 1024mL/min (p<0.05). No major changes were observed as regards heart and respiratory rates either at peak exercise or at anaerobic threshold. Similarly, no relevant changes were observed in ventilation efficiency, as evaluated by the ventilation vs. carbon dioxide production relationship, or in O2 delivery to the periphery as analyzed by the VO2 vs. workload relationship. The relationship between hemoglobin and VO2 changes showed, for each g/dL of hemoglobin increase, a VO2 increase = 82.5 mL/min and 35 mL/min, at peak exercise and at anaerobic threshold, respectively. In beta thalassemia major patients, an acute albeit partial anemia correction by blood transfusion determinates a relevant increase of exercise performance, observed both at peak exercise and at anaerobic threshold. PMID- 26010542 TI - MZF-1/Elk-1 Complex Binds to Protein Kinase Calpha Promoter and Is Involved in Hepatocellular Carcinoma. AB - In this study, the molecular mechanism of protein kinase C alpha (PKCalpha) gene regulation in hepatocellular carcinoma (HCC) involving Ets-like protein-1 (Elk-1) and myeloid zinc finger-1 (MZF-1) was investigated. The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCalpha gene transcription activity, and the transcriptional activity decreased when the transfection included a DNA-binding deficient (?DBD) gene vector of either MZF-1 or Elk-1 DNA-binding deficiency (MZF 1?DBD or Elk-1?DBD), thereby indicating that the enhanced expression of PKCalpha was caused by the binding of MZF-1 and/or Elk-1 with the PKCalpha promoter. We investigated MZF-1 and Elk-1 to determine whether they bind to each other. The results of immunoprecipitation (IP), Co-IP, chromatin IP (ChIP), and Re-ChIP analyses indicated that Elk-1 can directly bind to the N-terminal region of MZF-1 and MZF-1 can directly bind to the C-terminal region of Elk-1 to form a complex before attaching to the PKCalpha promoter. Furthermore, when MZF-1?DBD or Elk 1?DBD was added to the cells, PKCalpha expression decreased, and cell proliferation, migration, invasion, and tumorigenicity also decreased. These findings suggest that PKCalpha expression in HCC could be stimulated by the formation of MZF-1/Elk-1 complex, which directly binds to the PKCalpha promoter. PMID- 26010541 TI - Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties. AB - Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 MUM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-alpha or interleukin-1 beta-induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration. PMID- 26010543 TI - Transcriptome Profiling of the Potato (Solanum tuberosum L.) Plant under Drought Stress and Water-Stimulus Conditions. AB - Drought stress can seriously affect tuberization, yield and quality of potato plant. However, the precise molecular mechanisms governing potato stolon's response to drought stress and water supply are not very well understood. In this work, a potato (Solanum tuberosum L.) variant, Ningshu 4, was subjected to severe drought stress treatment (DT) and re-watering treatment (RWT) at tuber bulking stage. Strand-specific cDNA libraries of stolon materials were constructed for paired-end transcriptome sequencing analyses and differentially expressed gene (DEG) examination. In comparison to untreated-control (CT) plants, 3189 and 1797 DEGs were identified in DT and RWT plants and 4154 solely expressed DEGs were screened out from these two comparison groups. Interestingly, 263 genes showed opposite expression patterns in DT and RWT plants. Among them, genes homologous to Protein Phosphatase 2C (PP2C), Aspartic protease in guard cell 1 (ASPG1), auxin-responsive protein, Arabidopsis pseudo response regualtor 2 (APRR2), GA stimulated transcripts in Arabidopsis 6 (GASA6), Calmodulin-like protein 19 (CML19), abscisic acid 8'-hydroxylases and calcium-transporting ATPase, et al. were related with drought-stress and water stimulus response. Sixteen DEGs involved in starch synthesis, accumulation and tuber formation exhibited significantly different expression upon re-watering. In addition, 1630, 1527 and 1596 transcription factor encoding genes were detected in CT, DT and RWT. DEGs of ERF, bHLH, MYB, NAC, WRKY, C2H2, bZIP and HD-ZIP families accounted for 50% in three comparison groups, respectively. Furthermore, characteristics of 565 gene ontology (GO) and 108 Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) were analyzed with the 4154 DEGs. All these results suggest that the drought- and water-stimulus response could be implemented by the regulated expression of metabolic pathway DEGs, and these genes were involved in the endogenous hormone biosynthesis and signal transduction pathways. Our data provide more direct information for future study on the interaction between key genes involved in various metabolic pathways under drought stress in potato. PMID- 26010544 TI - CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis. AB - CD47 is a widely expressed receptor that regulates immunity by engaging its counter-receptor SIRPalpha on phagocytes and its secreted ligand thrombospondin 1. Mice lacking CD47 can exhibit enhanced or impaired host responses to bacterial pathogens, but its role in fungal immunity has not been examined. cd47-/- mice on a C57BL/6 background showed significantly increased morbidity and mortality following Candida albicans infection when compared with wild-type mice. Despite normal fungal colonization at earlier times, cd47-/- mice at four days post infection had increased colonization of brain and kidneys accompanied by stronger inflammatory reactions. Neutrophil and macrophage numbers were significantly elevated in kidneys and neutrophils in the brains of infected cd47-/- mice. However, no defect in phagocytic activity towards C. albicans was observed in cd47-/- bone-marrow-derived macrophages, and neutrophil and macrophage killing of C. albicans was not impaired. CD47-deficiency did not alter the early humoral immune response to C. albicans. Th1, Th2, and Th17 population of CD4+ T cells were expanded in the spleen, and gene expression profiles of spleen and kidney showed stronger pro-inflammatory signaling in infected cd47-/- mice. The chemoattractant chemokines MIP-2alpha and MIP-2beta were highly expressed in infected spleens of cd47-/- mice. G-CSF, GM-CSF, and the inflammasome component NLRP3 were more highly expressed in infected cd47-/- kidneys than in infected wild-type controls. Circulating pro- (TNF-alpha, IL-6) and anti-inflammatory cytokines (IL-10) were significantly elevated, but IL-17 was decreased. These data indicate that CD47 plays protective roles against disseminated candidiasis and alters pro-inflammatory and immunosuppressive pathways known to regulate innate and T cell immunity. PMID- 26010546 TI - Cluster formation and phase separation in heteronuclear Janus dumbbells. AB - We have recently investigated the phase behavior of model colloidal dumbbells constituted by two identical tangent hard spheres, with the first being surrounded by an attractive square-well interaction (Janus dumbbells, Munao et al 2014 Soft Matter 10 5269). Here we extend our previous analysis by introducing in the model the size asymmetry of the hard-core diameters and study the enriched phase scenario thereby obtained. By employing standard Monte Carlo simulations we show that in such 'heteronuclear Janus dumbbells' a larger hard-sphere site promotes the formation of clusters, whereas in the opposite condition a gas liquid phase separation takes place, with a narrow interval of intermediate asymmetries wherein the two phase behaviors may compete. In addition, some peculiar geometrical arrangements, such as lamellae, are observed only around the perfectly symmetric case. A qualitative agreement is found with recent experimental results, where it is shown that the roughness of molecular surfaces in heterogeneous dimers leads to the formation of colloidal micelles. PMID- 26010545 TI - Structural Basis for the Inhibition of Helicobacter pylori alpha-Carbonic Anhydrase by Sulfonamides. AB - Periplasmic alpha-carbonic anhydrase of Helicobacter pylori (HpalphaCA), an oncogenic bacterium in the human stomach, is essential for its acclimation to low pH. It catalyses the conversion of carbon dioxide to bicarbonate using Zn(II) as the cofactor. In H. pylori, Neisseria spp., Brucella suis and Streptococcus pneumoniae this enzyme is the target for sulfonamide antibacterial agents. We present structural analysis correlated with inhibition data, on the complexes of HpalphaCA with two pharmacological inhibitors of human carbonic anhydrases, acetazolamide and methazolamide. This analysis reveals that two sulfonamide oxygen atoms of the inhibitors are positioned proximal to the putative location of the oxygens of the CO2 substrate in the Michaelis complex, whilst the zinc coordinating sulfonamide nitrogen occupies the position of the catalytic water molecule. The structures are consistent with acetazolamide acting as site directed, nanomolar inhibitors of the enzyme by mimicking its reaction transition state. Additionally, inhibitor binding provides insights into the channel for substrate entry and product exit. This analysis has implications for the structure-based design of inhibitors of bacterial carbonic anhydrases. PMID- 26010547 TI - Silver nanoparticles temporarily retard NO2 - production without significantly affecting N2 O release by Nitrosomonas europaea. AB - Nitrifying bacteria are highly susceptible to silver nanoparticles (AgNPs). However, the effect of sublethal exposure to AgNPs after their release of nitrogenous compounds of environmental concern (e.g., the greenhouse gas nitrous oxide [N2 O] and the common water pollutant nitrite [NO2 -]) has not been systematically investigated. The present study reports the effect of AgNPs (and potentially released silver ions [Ag(+) ]) on NO2 - and N2 O production by Nitrosomonas europaea, and on the transcription of the associated genes. The release of NO2 - was more negatively affected than the production of N2 O. For example, exposure to AgNPs at 0.075 mg/L temporarily enhanced N2 O production (by 12%) without affecting nitrite release, whereas higher AgNP concentrations (>0.25 mg/L) inhibited NO2 - release (by >12%) but not N2 O production. Transcriptomic analyses corroborated these trends; AgNPs at 0.075 mg/L increased the expression of the nitric oxide reductase gene (norQ) associated with N2 O production (by 5.3 fold to 12.8-fold), whereas both 0.075 mg/L of Ag(+) and 0.75 mg/L of AgNPs down regulated the ammonia monooxygenase gene (amoA2; by 0.08-fold to 0.15-fold and 0.32-fold to 0.64-fold, respectively), the nitrite reductase gene (nirK; by 0.01 fold to 0.02-fold and 0.22-fold to 0.44-fold, respectively), and norQ (by 0.11 fold to 0.15-fold and 0.32-fold to 0.57-fold, respectively). These results suggest that AgNP release to sewage treatment plants and land application of AgNP containing biosolids should be minimized because of their potential temporary stimulation of N2 O release and interference with nitrification. Environ Toxicol Chem 2015;34:2231-2235. (c) 2015 SETAC. PMID- 26010548 TI - Impact of ultra-long second-generation drug-eluting stent implantation. AB - OBJECTIVES: This study investigated the safety and prognosis of ultra-long second DES (UL-2nd DES) implantation in real-world practice. BACKGROUND: Long stenting is a widely known predictor of stent thrombosis (ST) or target lesion revascularization (TLR) in first-generation drug-eluting stents (DES). METHODS: Participants were 1,669 patients (2,763 lesions) who had undergone successful second DES implantation; they were assigned to one of three groups: ultra-long 2nd DES (UL-DES; >50 mm, 166 patients, 259 lesions), long second DES (L-DES; 20 50 mm, 758 patients, 1,212 lesions), or short second DES (S-DES; <20 mm, 745 patients, 1,292 lesions). The primary endpoint was TLR, and secondary endpoints were ST, cardiac death, and major adverse cardiac events (MACE; composite of TLR, ST and cardiac death). A Cox proportional hazards model was used to identify independent predictors of TLR. RESULTS: Patient characteristics including dual antiplatelet therapy duration were similar across groups. Follow-up data were obtained from hospital charts, by contacting patients. Target lesion characteristics in the UL-DES group showed higher right coronary artery and chronic total occlusion lesion rates. TLR rates (23.1 +/- 13.2 months) were significantly higher in the UL-DES group relative to other groups during follow up (P < 0.001). TLR rate was similar between S-DES and L-DES (P = 0.30). The incidence of ST was similar across groups (P = 0.40). MACE was significantly higher in the UL-DES group relative to other groups due to higher TLR rates (P = 0.01). In a Cox proportional hazard model, hemodialysis (RR: 2.53, 95% CI: 1.69 3.67, P < 0.001) and total stent length of >50 mm (RR: 1.67, 95% CI: 1.07-2.55, P = 0.02) were independent predictors of TLR. CONCLUSIONS: Ultra-long DES implantation was associated with higher TLR rates but did not increase ST, while long DES implantation up to 50 mm was safe and acceptable. PMID- 26010549 TI - Who uses alcohol mixed with energy drinks? Characteristics of college student users. AB - OBJECTIVE: To examine characteristics associated with alcohol mixed with energy drink (AmED) use in a sample of college students. PARTICIPANTS: College students (N = 614, 53% female) in their second year of college participated during the fall of 2008. METHODS: Students completed a cross-sectional survey with questions regarding AmED use. RESULTS: AmED use in the last 30 days was reported by 27% of participants. Logistic regression analyses found that risk factors for AmED included participating in a fraternity/sorority; participating in athletics; living off-campus; having greater fun/social, relax, and image motives for alcohol consumption; and binge drinking. Protective factors included early morning classes, honors program participation, and greater physical/behavioral motives for not drinking. CONCLUSIONS: Risk factors for AmED use can identify college students most likely to consume AmEDs and thereby inform screening and intervention efforts to reduce negative AmED-related consequences. PMID- 26010550 TI - Validation of a new T2* algorithm and its uncertainty value for cardiac and liver iron load determination from MRI magnitude images. AB - PURPOSE: To validate an automatic algorithm for offline T2* measurements, providing robust, vendor-independent T2*, and uncertainty estimates for iron load quantification in the heart and liver using clinically available imaging sequences. METHODS: A T2* region of interest (ROI)-based algorithm was developed for robustness in an offline setting. Phantom imaging was performed on a 1.5 Tesla system, with clinically available multiecho gradient-recalled-echo (GRE) sequences for cardiac and liver imaging. A T2* single-echo GRE sequence was used as reference. Simulations were performed to assess accuracy and precision from 2000 measurements. Inter- and intraobserver variability was obtained in a patient study (n = 23). RESULTS: Simulations: Accuracy, in terms of the mean differences between the proposed method and true T2* ranged from 0-0.73 ms. Precision, in terms of confidence intervals of repeated measurements, was 0.06-4.74 ms showing agreement between the proposed uncertainty estimate and simulations. Phantom study: Bias and variability were 0.26 +/- 4.23 ms (cardiac sequence) and -0.23 +/ 1.69 ms (liver sequence). Patient study: Intraobserver variability was similar for experienced and inexperienced observers (0.03 +/- 1.44 ms versus 0.16 +/- 2.33 ms). Interobserver variability was 1.0 +/- 3.77 ms for the heart and -0.52 +/- 2.75 ms for the liver. CONCLUSION: The proposed algorithm was shown to provide robust T2* measurements and uncertainty estimates over the range of clinically relevant T2* values. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance. PMID- 26010552 TI - The Relation Between Having a Usual Source of Care and Ratings of Care Quality: Does Patient-Centered Communication Play a Role? AB - Having a usual source of health care has been consistently associated with greater use of preventive services, decreased use of emergency services, and with patients' ratings of quality and satisfaction with care. Ongoing patient-provider relationships may be, in part, fostered by patient-centered communication. Growing evidence demonstrates that positive patient-centered communication improves adherence to treatment recommendations, management of chronic disease, quality of life, and disease-related outcomes. We aimed to determine how patient centered communication between patients and physicians might mediate the relation between having a source of usual care and ratings of health care quality. We analyzed data from Cycle 1 of the fourth iteration of the Health Information National Trends Survey. Data were collected through mailed questionnaire in October 2011 through February 2012 (N = 3,959). Overall, individuals with a usual source of care reported more patient-centered communication experiences and had higher ratings of quality of care. Parameter estimates for each pathway in the mediation model were estimated through regression analysis. Results confirm the importance of patient-centered communication in shaping patients' perceptions of the quality of their care, accounting for a significant portion of the observed relation between having a usual source of care and ratings of quality. PMID- 26010553 TI - Micromechanism in Self-Lubrication of TiB2/Al Composite. AB - The authors discovered the self-lubrication behavior of TiB2/Al composite and pointed out that the materials responsible for the self-lubrication behavior comes from the oxidation of TiB2. Atomic/friction force microscopy and first principles calculations have been employed to study the self-lubrication microscopic mechanism of TiB2/Al composite. Atomic force microscopy confirms the existence of a soft film with nanometer thickness on the TiB2 surface, which was attributed to H3BO3 film. Friction measurements revealed much smaller friction force on this H3BO3 nanofilm than that on Al matrix. The detailed structure and interactions among H3BO3 molecules and between the H3BO3 sheet and substrate were explored by density functional theory based calculations. The details of adsorption of H3BO3 sheet on TiB2 and TiO2 surface were scrutinized and the potential of the relative movement between H3BO3 sheets were scanned and compared with that of graphite. The generation of H3BO3 film, the strong chemical adsorption of H3BO3 film on the surface of the composite, the strong hydrogen bonding in H3BO3 film, and small potential in the relative slide between H3BO3 sheets warrant the good self-lubricant properties of TiB2/Al metal matrix composites. PMID- 26010551 TI - Effects of Microglia on Neurogenesis. AB - This review summarizes and organizes the literature concerning the effects of microglia on neurogenesis, particularly focusing on the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) of the lateral ventricles, in which the neurogenic potential is progressively restricted during the life of the organism. A comparison of microglial roles in neurogenesis in these two regions indicates that microglia regulate neurogenesis in a temporally and spatially specific manner. Microglia may also sense signals from the surrounding environment and have regulatory effects on neurogenesis. We speculate microglia function as a hub for the information obtained from the inner and outer brain regions for regulating neurogenesis. PMID- 26010554 TI - Deep serum discoveries: SDF-1alpha and HSA fragments in myelodysplastic syndromes. PMID- 26010555 TI - Efficient and Practical Oxidative Bromination and Iodination of Arenes and Heteroarenes with DMSO and Hydrogen Halide: A Mild Protocol for Late-Stage Functionalization. AB - An efficient and practical system for inexpensive bromination and iodination of arenes as well as heteroarenes by using readily available dimethyl sulfoxide (DMSO) and HX (X = Br, I) reagents is reported. This mild oxidative system demonstrates a versatile protocol for the synthesis of aryl halides. HX (X = Br, I) are employed as halogenating reagents when combined with DMSO which participates in the present chemistry as a mild and inexpensive oxidant. This oxidative system is amenable to late-stage bromination of natural products. The kilogram-scale experiment (>95% yield) shows great potential for industrial application. PMID- 26010557 TI - Microdroplets Impinging on Freely Suspended Smectic Films: Three Impact Regimes. AB - We employ high-speed video imaging to study microdroplets of a few picoliters volume impacting freely suspended smectic liquid-crystal films. Depending on the impact parameters, in particular, droplet velocity and mass, three different regimes are observed such as trapping, rebounding, and tunneling. Fast droplets penetrate the films completely. After they have passed the film, they are coated with a layer of film material while the original smectic film remains intact. Droplets in a certain intermediate velocity range bounce back from the film. After impact, the film deforms and hurls the droplet back, depleting a substantial share of the initial kinetic energy. Slow droplets are caught and embedded in the film. During impact and tunneling, an appreciable amount of kinetic energy is lost. The energy is partially dissipated during droplet impact and during subsequent mechanical vibrations and oscillations of the film and the droplet. The tunneling process of high-speed droplets can be exploited to prepare smectic shells of well-defined sizes that enclose picoliters of an immiscible liquid. PMID- 26010558 TI - Spoken word recognition in early childhood: Comparative effects of vowel, consonant and lexical tone variation. AB - The majority of the world's languages exploit consonants, vowels and lexical tones to contrast the meanings of individual words. However, the majority of experimental research on early language development focuses on consonant-vowel languages. In the present study, the role of consonants, vowels and lexical tones in emergent word knowledge are directly compared in toddlers (2.5-3.5 years) and preschoolers (4-5 years) who were bilingual native learners of a consonant-vowel tone language (Mandarin Chinese). Using a preferential looking paradigm, participants were presented with correct pronunciations and consonantal, vowel, and tonal variations of known words. Responses to each type of variation were assessed via gaze fixations to a visual target. When their labels were correctly pronounced, visual targets were reliably identified at both age groups. However, in toddlers, there was a high degree of sensitivity to mispronunciations due to variation in lexical tones relative to those due to consonants and vowels. This pattern was reversed in preschoolers, who were more sensitive to consonant and vowel variation than to tone variation. Findings are discussed in terms of properties of tones, vowels and consonants and the respective role of each source of variation in tone languages. PMID- 26010560 TI - Resolving the locus of cAsE aLtErNaTiOn effects in visual word recognition: Evidence from masked priming. AB - Determining the factors that modulate the early access of abstract lexical representations is imperative for the formulation of a comprehensive neural account of visual-word identification. There is a current debate on whether the effects of case alternation (e.g., tRaIn vs. train) have an early or late locus in the word-processing stream. Here we report a lexical decision experiment using a technique that taps the early stages of visual-word recognition (i.e., masked priming). In the design, uppercase targets could be preceded by an identity/unrelated prime that could be in lowercase or alternating case (e.g., table-TABLE vs. crash-TABLE; tAbLe-TABLE vs. cRaSh-TABLE). Results revealed that the lowercase and alternating case primes were equally effective at producing an identity priming effect. This finding demonstrates that case alternation does not hinder the initial access to the abstract lexical representations during visual word recognition. PMID- 26010559 TI - A decision network account of reasoning about other people's choices. AB - The ability to predict and reason about other people's choices is fundamental to social interaction. We propose that people reason about other people's choices using mental models that are similar to decision networks. Decision networks are extensions of Bayesian networks that incorporate the idea that choices are made in order to achieve goals. In our first experiment, we explore how people predict the choices of others. Our remaining three experiments explore how people infer the goals and knowledge of others by observing the choices that they make. We show that decision networks account for our data better than alternative computational accounts that do not incorporate the notion of goal-directed choice or that do not rely on probabilistic inference. PMID- 26010561 TI - CORRIGENDUM: Emergent photovoltage on SmB6 surface upon bulk-gap evolution revealed by pump-and-probe photoemission spectroscopy. PMID- 26010562 TI - CD4(+) Foxp3(+) regulatory T-cell number increases in the gastric tissue of C57BL/6 mice infected with Helicobacter pylori. AB - Helicobacter pylori (H. pylori), one of the most common infections, is associated with various clinical outcomes. In addition to inducing inflammation, immunological clearance of the pathogen is often incomplete. Regulatory T cells (Treg cells) have been recently demonstrated to play an important role in H. pylori infection and the final clinical outcome. The aim of this study was to investigate the number and localization of CD4(+) Foxp3(+) Treg cells in stomachs and spleens of H. pylori-infected mice. The expression levels of Foxp3 as well as anti- and pro-inflammatory cytokines before and after H. pylori triple eradication therapy were examined. We found that the percentages of CD4(+) Foxp3(+) Treg cells out of the lamina propria lymphocytes (LPLs) and spleen lymphocytes in the infection group were higher than the PBS negative control group and the treatment group. H. pylori antigen stimulation was associated with an increased number of Treg cells in vitro. Furthermore, compared with the PBS and treatment groups, a higher mRNA expression level of Foxp3 in the gastric tissue was detected in the infection group. IL-10 and TGF-beta1 contents were increased significantly in the culture supernatant of spleen lymphocyte stimulated with H. pylori antigen. A marked elevation in serum IFN-gamma level was observed in H. pylori-infected mice. In addition, gastric tissues of the infection group contained more Foxp3(+) cells. These results indicate that the percentage of CD4(+) Foxp3(+) Treg cells are increased in H. pylori-infected mice, suggesting a role of Treg cells in H. pylori-induced pathologies, even at the early stages of chronic gastritis and gastric tumorigenesis. PMID- 26010563 TI - Bulk size crystal growth, spectroscopic, dielectric and surface studies of 4-N,N dimethylamino-4-N'-methylstilbazolium m-nitrobenzenesulfonate (DSMNS): A potential THz crystal of stilbazolium family. AB - The synthesis and growth of a potentially useful and efficient nonlinear optical organic single crystal of 4-N,N-dimethylamino-4-N'-methylstilbazolium m nitrobenzenesulfonate (DSMNS) is reported. The growth experiment involved the slope nucleation method coupled with slow cooling as well as slow solvent evaporation techniques. Single crystal X-ray diffraction (XRD), Fourier transform infrared (FT-IR), FT-Raman and nuclear magnetic resonance (NMR) techniques have been employed to ascertain the structure and composition of the crystal. Second harmonic generation (SHG) efficiency of the sample has been examined by Kurtz and Perry powder test. Thermogravimetry (TG), differential thermal analysis (DTA) and differential scanning calorimetry (DSC) techniques are employed to investigate the thermal behavior of the grown crystal. The frequency/temperature dependent dielectric properties of the organic crystal of DSMNS are studied. The surface features of the grown crystal are investigated by chemical etching study and atomic force microscopy (AFM). PMID- 26010564 TI - Optical spectroscopy of Sm(3+) doped Na2O-ZnO-La2O3-TeO2 glasses. AB - Telluride glasses with the composition xSm2O3-(7-x)La2O3-3Na2O-25ZnO-65TeO2 (where x=0.1, 1, 2, 5 and 7 mol%) were obtained by the melt quenching technique. Electronic absorption and fluorescence spectra as well as fluorescence dynamics of the Sm(3+)-doped title glasses are presented and analysed in detail. A Judd Ofelt intensity analysis of the absorption spectrum at 300 K has been applied for determination of Omegalambda parameters (Omega2=3.10, Omega4=3.80, Omega6=1.61*10(-20) cm(2)) which in turn have been used for calculations of the radiative transition probabilities (AT), the natural (radiative) lifetimes (tauR) of the (4)G5/2 level of Sm(3+), the fluorescence branching ratios (beta) and the emission cross-sections (sigmaem). The tauR value of the (4)G5/2 level amount to 1546 MUs and is slightly higher than the measured decay time of 1306 MUs. With the increasing of Sm2O3 concentration from 0.1 to 7.0 mol% the experimental lifetime of the fluorescent level decreases from 1306 to 41 MUs. An analysis of the non-radiative decay was based on the cross-relaxation mechanisms. The optical achieved results indicate that the investigated glasses are potentially applicable as an orange and/or red laser host. PMID- 26010556 TI - Evolutionary history of Purple cone spruce (Picea purpurea) in the Qinghai-Tibet Plateau: homoploid hybrid origin and Pleistocene expansion. AB - Hybridization and introgression can play an important role in speciation. Here, we examine their roles in the origin and evolution of Picea purpurea, a diploid spruce species occurring on the Qinghai-Tibet Plateau (QTP). Phylogenetic relationships and ecological differences between this species and its relatives, P. schrenkiana, P. likiangensis and P. wilsonii, are unclear. To clarify them, we surveyed sequence variation within and between them for 11 nuclear loci, three chloroplast (cp) and two mitochondrial (mt) DNA fragments, and examined their ecological requirements using ecological niche modelling. Initial analyses based on 11 nuclear loci rejected a close relationship between P. schrenkiana and P. purpurea. BP&P tests and ecological niche modelling indicated substantial divergence between the remaining three species and supported the species status of P. purpurea, which contained many private alleles as expected for a well established species. Sequence variation for cpDNA and mtDNA suggested a close relationship between P. purpurea and P. wilsonii, while variation at the nuclear se1364 gene suggested P. purpurea was more closely related to P. likiangensis. Analyses of genetic divergence, Bayesian clustering and model comparison using approximate Bayesian computation (ABC) of nuclear (nr) DNA variation all supported the hypothesis that P. purpurea originated by homoploid hybrid speciation from P. wilsonii and P. likiangensis. The ABC analysis dated the origin of P. purpurea at the Pleistocene, and the estimated hybrid parameter indicated that 69% of its nuclear composition was contributed by P. likiangensis and 31% by P. wilsonii. Our results further suggested that during or immediately following its formation, P. purpurea was subject to organelle DNA introgression from P. wilsonii such that it came to possess both mtDNA and cpDNA of P. wilsonii. The estimated parameters indicated that following its origin, P. purpurea underwent an expansion during/after the largest Pleistocene glaciation recorded for the QTP. PMID- 26010565 TI - Using FT-NIR spectroscopy technique to determine arginine content in fermented Cordyceps sinensis mycelium. AB - This research investigated the feasibility of using Fourier transform near infrared (FT-NIR) spectral technique for determining arginine content in fermented Cordyceps sinensis (C. sinensis) mycelium. Three different models were carried out to predict the arginine content. Wavenumber selection methods such as competitive adaptive reweighted sampling (CARS) and successive projections algorithm (SPA) were used to identify the most important wavenumbers and reduce the high dimensionality of the raw spectral data. Only a few wavenumbers were selected by CARS and CARS-SPA as the optimal wavenumbers, respectively. Among the prediction models, CARS-least squares-support vector machine (CARS-LS-SVM) model performed best with the highest values of the coefficient of determination of prediction (Rp(2)=0.8370) and residual predictive deviation (RPD=2.4741), the lowest value of root mean square error of prediction (RMSEP=0.0841). Moreover, the number of the input variables was forty-five, which only accounts for 2.04% of that of the full wavenumbers. The results showed that FT-NIR spectral technique has the potential to be an objective and non-destructive method to detect arginine content in fermented C. sinensis mycelium. PMID- 26010566 TI - Green chemistry focus on optimization of silver nanoparticles using response surface methodology (RSM) and mosquitocidal activity: Anopheles stephensi (Diptera: Culicidae). AB - There is an exigent necessity for development of environmental friendly bio control agent(s) for elimination of mosquito due to increased resistance resurgence against synthetic control agents. Mosquito control strategy will lay a strong foundation to malaria exclusion or it can be curbed to certain level especially in the developing nations. In this study, silver nanoparticles were synthesized by green chemistry approach using Tridax procumbens leaf extract as a reducing agent. The reaction medium involved in the synthesis process was optimized by statistical experimental design using response surface methodology to obtain better yield, uniform size, shape and stability. Further, these synthesized nanoparticles were confirmed through UV-Visible, FT-IR spectroscopy, PSA and SEM Subsequently, the bioefficacy of these particles were investigated on Anopheles stephensi for larvicidal and pupicidal activity. Interestingly, time period of 90 min, temperature of 76+/-2 degrees C, pH 7.2+/-2, 2 mM silver nitrate (AgNO3), 3mM PEG and 2mM PVP showed excellent parameters for bioprocess design for large scale production of stabilized nanoparticles. A concentration of 5 ppm of PVP stabilized nanoparticles exhibited 100% mortality. Thus, the obtained results clearly suggest that silver nanoparticles stabilized by PEG and PVP may have important function as stabilizers, dispersants as well as larvicides for mosquito control. PMID- 26010567 TI - Discriminant analysis of Chinese patent medicines based on near-infrared spectroscopy and principal component discriminant transformation. AB - Principal component discriminant transformation was applied for discrimination of different Chinese patent medicines based on near-infrared (NIR) spectroscopy. In the method, an optimal set of orthogonal discriminant vectors, which highlight the differences between the NIR spectra of different classes, is designed by maximizing Fisher's discriminant function. Therefore, a model for discriminating a class and the others can be obtained with the tiny differences between the NIR spectra of different classes. Furthermore, because NIR spectra contain a large amount of redundant information, principal component analysis (PCA) is employed to reduce the dimension. On the other hand, continuous wavelet transform (CWT) is taken as the pretreatment method to remove the variant background. For identifying the method, different medicines and the same medicine from different manufactures were studied. The results show that all the models can provide 100% discrimination. PMID- 26010568 TI - Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia. AB - Fanconi anaemia (FA) is an inherited disorder characterized by pancytopenia, congenital malformations and a predisposition to develop malignancies. Alterations in the haematopoietic microenvironment of FA patients have been reported, but little is known regarding the components of their bone marrow (BM) stroma. We characterized mesenchymal stromal cells (MSCs) isolated from BM of 18 FA patients both before and after allogeneic haematopoietic stem cell transplantation (HSCT). Morphology, fibroblast colony-forming unit (CFU-F) ability, proliferative capacity, immunophenotype, differentiation potential, ability to support long-term haematopoiesis and immunomodulatory properties of FA MSCs were analysed and compared with those of MSCs expanded from 15 age-matched healthy donors (HD-MSCs). FA-MSCs were genetically characterized through conventional karyotyping, diepoxybutane-test and array-comparative genomic hybridization. FA-MSCs generated before and after HSCT were compared. Morphology, immunophenotype, differentiation potential, ability in vitro to inhibit mitogen induced T-cell proliferation and to support long-term haematopoiesis did not differ between FA-MSCs and HD-MSCs. CFU-F ability and proliferative capacity of FA-MSCs isolated after HSCT were significantly lower than those of HD-MSCs. FA MSCs reached senescence significantly earlier than HD-MSCs and showed spontaneous chromosome fragility. Our findings indicate that FA-MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages; whether these defects are involved in pathophysiology of BM failure syndromes deserves further investigation. PMID- 26010569 TI - Cell Interactions with Vascular Regenerative MAA-Based Materials in the Context of Wound Healing. AB - In diabetic patients the development of chronic non-healing wounds is a common complication. A methacrylic acid-based biomaterial is a vascular regenerative material that enhances diabetic healing without the use of cells or growth factors. The bioactive nature of this material is thought to be associated with its anionic charge or surface chemistry. Contact between the methacrylic acid based biomaterial and tissue begins with protein (including complement) adsorption and is followed by interaction of the biomaterial with resident and infiltrating cells in the wound bed (e.g., macrophages and endothelial cells). This results in changes to their surface receptors to activate phosphorylation cascades that lead to differential activation of signalling pathways such as those involving osteopontin and sonic hedgehog. These changes modulate the phenotype of the cells in the wound bed, eventually improving vessel formation and wound healing. Understanding the molecular and cellular mechanisms will have broad implications for biomaterials, not just the methacrylic acid-based material, and will facilitate the advancement of regenerative biomaterials for diverse applications. PMID- 26010570 TI - Multibow: digital spectral barcodes for cell tracing. AB - We introduce a multicolor labeling strategy (Multibow) for cell tracing experiments in developmental and regenerative processes. Building on Brainbow based approaches that produce colors by differential expression levels of different fluorescent proteins, Multibow adds a layer of label diversity by introducing a binary code in which reporters are initially OFF and then probabilistically ON or OFF following Cre recombination. We have developed a library of constructs that contains seven different colors and three different subcellular localizations. Combining constructs from this library in the presence of Cre generates cells labeled with multiple independently expressed colors based on if each construct is ON or OFF following recombination. These labels form a unique "barcode" that allows the tracking of the cell and its clonal progenies in addition to expression level differences of each color. We tested Multibow in zebrafish which validates its design concept and suggests its utility for cell tracing applications in development and regeneration. PMID- 26010571 TI - Depression Affects the Scores of All Facets of the WHOQOL-BREF and May Mediate the Effects of Physical Disability among Community-Dwelling Older Adults. AB - BACKGROUND: Geriatric depression is associated with the overall quality of life (QOL). However, how depressive symptoms affect the different domains and facets of QOL in older adults, and whether depressive symptoms mediate the relationship between physical disability and QOL in older adults are unclear. METHODS: A total of 490 ambulatory community-dwelling older adults aged 65 years or above were interviewed using the brief version of the World Health Organisation Quality of Life instrument (WHOQOL-BREF), the Modified Barthel Index (MBI), the 15-item Geriatric Depression Scale (GDS-15), and the Mini-Mental State Examination (MMSE). Sequential models for multiple linear regressions were analysed to determine if the MBI, GDS-15 and MMSE scores predict the WHOQOL-BREF scores. The potential mediation effects of depression (as determined by the GDS-15) on the relationship between MBI and WHOQOL-BREF were also analysed. RESULTS: The GDS-15 score was predictive of the scores of the four domains and all 26 facets of the WHOQOL-BREF. The significant predictive effects of the MBI score on 15 of the 26 facets of the WHOQOL-BREF were reduced to three after the adjustment for the GDS 15 score. Depression (as assessed by the GDS-15) is a mediator of the relationship between MBI and the physical, psychological and environmental domains of the WHOQOL-BREF. CONCLUSIONS: Depression (assessed by the GDS-15) may affect the scores of every domain and all facets of the WHOQOL-BREF in the elderly. Furthermore, it may mediate the relationship between the MBI and on QOL scores. We recommend taking depressive symptoms into consideration when measuring community-dwelling older adults' QOL and providing active ageing programs. PMID- 26010572 TI - Up-Regulation of MiR-300 Promotes Proliferation and Invasion of Osteosarcoma by Targeting BRD7. AB - Increasing reports suggest that deregulated microRNAs (miRNAs) might provide novel therapeutic targets for cancers. However, the expression and function of miR-300 in osteosarcoma is still unknown. In our study, we found that the expression of miR-300 was up-regulated in osteosarcoma tissues and cells compared with paired adjacent non-tumor bone tissues and osteoblastic cells using RT-qPCR. The enforced expression of miR-300 could promote cell proliferation, invasion and epithelial-mesenchymal transition (EMT). Moreover, we identified that bromodomain containing protein 7 (BRD7), a new tumor suppressor gene, was a direct target of miR-300. Ectopic expression of BRD7 could significantly inhibit miR-300-promoted proliferation, invasion and EMT. Therefore, our results identify an important role for miR-300 in osteosarcoma through regulating BRD7 expression. PMID- 26010573 TI - Transfer and maintenance effects of online working-memory training in normal ageing and mild cognitive impairment. AB - Working memory (WM) is one of the cognitive functions that is susceptible to ageing-related decline. Interventions that are able to improve WM functioning at older age are thus highly relevant. In this pilot study, we explored the transfer effects of core WM training on the WM domain and other cognitive domains in 23 healthy older adults and 18 patients with amnestic mild cognitive impairment (MCI). Performance on neuropsychological tests was assessed before and after completion of the online five-week adaptive WM training, and after a three-month follow-up period. After training, both groups improved on the Digit Span and Spatial Span, gains that were maintained at follow-up. At an individual level, a limited number of participants showed reliable training gain. Healthy older adults, and to a lesser extent MCI patients, additionally improved on figural fluency at group level, but not at individual level. Results furthermore showed that global brain atrophy and hippocampal atrophy, as assessed by MRI, may negatively affect training outcome. Our study examined core WM training, showing gains on trained and untrained tasks within the WM domain, but no broad generalisation to other cognitive domains. More research is needed to evaluate the clinical relevance of these findings and to identify participant characteristics that are predictive of training gain. PMID- 26010575 TI - Thrill of victory or agony of defeat? Perceivers fail to utilize information in facial movements. AB - Although the distinction between positive and negative facial expressions is assumed to be clear and robust, recent research with intense real-life faces has shown that viewers are unable to reliably differentiate the valence of such expressions (Aviezer, Trope, & Todorov, 2012). Yet, the fact that viewers fail to distinguish these expressions does not in itself testify that the faces are physically identical. In Experiment 1, the muscular activity of victorious and defeated faces was analyzed. Higher numbers of individually coded facial actions- particularly smiling and mouth opening--were more common among winners than losers, indicating an objective difference in facial activity. In Experiment 2, we asked whether supplying participants with valid or invalid information about objective facial activity and valence would alter their ratings. Notwithstanding these manipulations, valence ratings were virtually identical in all groups, and participants failed to differentiate between positive and negative faces. While objective differences between intense positive and negative faces are detectable, human viewers do not utilize these differences in determining valence. These results suggest a surprising dissociation between information present in expressions and information used by perceivers. PMID- 26010576 TI - SP1 promotes the odontoblastic differentiation of dental papilla cells. AB - Odontoblasts are a type of terminally differentiated and matrix-secreting cells that are responsible for dentinogenesis. The process of odontoblast differentiation is regulated by a variety of transcription factors. The transcription factor SP1 is known to play an essential regulatory role in cell proliferation and differentiation. The purpose of this study was to investigate the role of SP1 in odontoblastic differentiation. Immunohistochemistry verified that SP1 was specifically expressed in polarizing and secretory odontoblasts in vivo. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence revealed that the expression of SP1 was significantly upregulated during odontoblastic differentiation of mDPC6T cells, a dental papilla cell line. Overexpression of SP1 significantly increased the expression of odontoblast-related genes, including DSPP, DMP1 and ALP, and promoted the formation of mineralized nodules. Meanwhile, knockdown of SP1 decreased the expression of these odontoblast-related genes and suppressed the formation of mineralized nodules. Our results demonstrate that SP1 promotes the odontoblastic differentiation and mineralization of dental papilla cells. PMID- 26010574 TI - Emotion recognition in frontotemporal dementia and Alzheimer's disease: A new film-based assessment. AB - Deficits in recognizing others' emotions are reported in many psychiatric and neurological disorders, including autism, schizophrenia, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Most previous emotion recognition studies have required participants to identify emotional expressions in photographs. This type of assessment differs from real-world emotion recognition in important ways: Images are static rather than dynamic, include only 1 modality of emotional information (i.e., visual information), and are presented absent a social context. Additionally, existing emotion recognition batteries typically include multiple negative emotions, but only 1 positive emotion (i.e., happiness) and no self-conscious emotions (e.g., embarrassment). We present initial results using a new task for assessing emotion recognition that was developed to address these limitations. In this task, respondents view a series of short film clips and are asked to identify the main characters' emotions. The task assesses multiple negative, positive, and self-conscious emotions based on information that is multimodal, dynamic, and socially embedded. We evaluate this approach in a sample of patients with bvFTD, AD, and normal controls. Results indicate that patients with bvFTD have emotion recognition deficits in all 3 categories of emotion compared to the other groups. These deficits were especially pronounced for negative and self-conscious emotions. Emotion recognition in this sample of patients with AD was indistinguishable from controls. These findings underscore the utility of this approach to assessing emotion recognition and suggest that previous findings that recognition of positive emotion was preserved in dementia patients may have resulted from the limited sampling of positive emotion in traditional tests. PMID- 26010577 TI - Exploring the feasibility of multi-site flow cytometric processing of gut associated lymphoid tissue with centralized data analysis for multi-site clinical trials. AB - The purpose of this study was to determine whether the development of a standardized approach to the collection of intestinal tissue from healthy volunteers, isolation of gut associated lymphoid tissue mucosal mononuclear cells (MMC), and characterization of mucosal T cell phenotypes by flow cytometry was sufficient to minimize differences in the normative ranges of flow parameters generated at two trial sites. Forty healthy male study participants were enrolled in Pittsburgh and Los Angeles. MMC were isolated from rectal biopsies using the same biopsy acquisition and enzymatic digestion protocols. As an additional comparator, peripheral blood mononuclear cells (PBMC) were collected from the study participants. For quality control, cryopreserved PBMC from a single donor were supplied to both sites from a central repository (qPBMC). Using a jointly optimized standard operating procedure, cells were isolated from tissue and blood and stained with monoclonal antibodies targeted to T cell phenotypic markers. Site-specific flow data were analyzed by an independent center which analyzed all data from both sites. Ranges for frequencies for overall CD4+ and CD8+ T cells, derived from the qPBMC samples, were equivalent at both UCLA and MWRI. However, there were significant differences across sites for the majority of T cell activation and memory subsets in qPBMC as well as PBMC and MMC. Standardized protocols to collect, stain, and analyze MMC and PBMC, including centralized analysis, can reduce but not exclude variability in reporting flow data within multi-site studies. Based on these data, centralized processing, flow cytometry, and analysis of samples may provide more robust data across multi-site studies. Centralized processing requires either shipping of fresh samples or cryopreservation and the decision to perform centralized versus site processing needs to take into account the drawbacks and restrictions associated with each method. PMID- 26010578 TI - Immunogold characteristics of VGLUT3-positive GABAergic nerve terminals suggest corelease of glutamate. AB - There is compelling evidence that glutamate can act as a cotransmitter in the mammalian brain. Interestingly, the third vesicular glutamate transporter (VGLUT3) is primarily found in neurons that were anticipated to be nonglutamatergic. Whereas the function of VGLUT3 in acetylcholinergic and serotoninergic neurons has been elucidated, the role of VGLUT3 in neurons releasing gamma-aminobutyric acid (GABA) is not settled. We have previously shown that VGLUT3 is found together with the vesicular GABA transporter (VIAAT) on synaptic vesicle membranes in the hippocampus. Now we provide novel electron microscopic data from the rat hippocampus suggesting that glutamate is enriched in inhibitory nerve terminals containing VGLUT3 compared to those lacking VGLUT3. The opposite was found for GABA; VGLUT3-positive inhibitory terminals contained lower density of GABA labeling compared to VGLUT3-negative inhibitory terminals. In addition, semiquantitative confocal immunofluorescence showed that N-methyl-D aspartate (NMDA)-receptor labeling was present more frequently in VGLUT3 positive/VIAAT-positive synapses versus in VGLUT3-negative/VIAAT-positive synapses. Electron microscopic immunogold data further suggest that NMDA receptors are enriched in VGLUT3 containing inhibitory terminals. Our data reveal new chemical characteristics of a subset of GABAergic interneurons in the hippocampus. The analyses suggest that glutamate is coreleased with GABA from hippocampal basket cell-synapses to act on NMDA receptors. PMID- 26010579 TI - Climatic tolerance or geographic breadth: what are we measuring? PMID- 26010580 TI - Prevalence of sexually transmitted pathogens associated with HPV infection in cervical samples in a Mexican population. AB - Cervical cancer development has been mainly associated with persistent human papillomavirus (HPV) infections. However, HPV infection is unlikely to be sufficient to cause cervical cancer, and the contribution of other sexually transmitted infections (STIs) could be the determining factor for cervical lesion progression. The aim of this study was to estimate the prevalence of STIs associated with HPV-positivity in 201 cervical samples from patients who underwent annual routine gynecological exams. The overall prevalence of STIs was 57.7%, and the most frequent infection was Ureaplasma spp (UP) (39.8%), followed by Gardnerella vaginalis (GV) (25.9%), alpha-HPV (18.4%), Chlamydia trachomatis (CT) (1.5%), and Mycoplasma genitalium (MG) (0.5%). The highest prevalence rate of multiple non-HPV infections was observed for the age-range 31-40; for papillomavirus infection, the age-range was 21-30. In normal cervical samples, HPV16 was the most prevalent genotype (24.3%), followed by genotypes 58 (13.5%) and 52 (10.8%). Intriguingly, HPV18 was not detected in the study population, and genotypes 52 and 58 were found exclusively in samples with abnormal cytology. Papillomavirus infection with oncogenic types was significantly associated with GV (P = 0.025) and strongly associated with multiple non-HPV pathogens (P = 0.002). The following variables correlated significantly with cytological diagnosis of low-grade squamous intraepithelial lesion (LSIL): GV (P = 0.028), multiple non-HPV infections (P = 0.001), and high-risk HPV positivity (P = 0.001). Epidemiological data from this study will contribute to the molecular detection of sexually transmitted pathogens from screening programs to identify those women who are at risk for developing cervical lesions. PMID- 26010581 TI - Papilledema From Intraventricular Neurocysticercosis. PMID- 26010582 TI - Prospective outcomes in patients with acute exacerbations of chronic obstructive pulmonary disease presenting to hospital: a generalisable clinical audit. AB - BACKGROUND AND AIM: To determine predictors of short- and long-term outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) (AECOPD) presenting to hospital. METHODS: A prospective clinical audit of AECOPD attendances to the only public acute general hospital in Southern Tasmania, Australia. Out of 416 attendances with AECOPD to the emergency department (ED) between November 2006 and July 2008, 150 patients with 218 attendances were followed to March 2009. Predictors of hospital admission from ED, in-hospital death, length of hospital stay, post-discharge mortality and re-attendance rate for AECOPD were the main outcomes. RESULTS: There were no clear differences between patients admitted to hospital and those sent home from ED. Predictors of in-hospital death were initial physiologic parameters, that is, arterial pH, PaCO2 , oxygen saturation and blood pressure. Longer hospital stay was associated with older age, current smoking, hyperglycaemia, lower blood pressure and lower oxygen saturation. Risk of mortality after discharge was associated with a history of myocardial infarction, nursing home residence and severity of COPD. Re attendance rate was associated with osteoporosis, younger age and severity of COPD. CONCLUSIONS: Further investigation into the process of decision making about which AECOPD patients are admitted from the ED is required. Short-term outcomes, in-hospital death and length of hospital stay are mainly predicted by severity of the acute exacerbation and patient demographics. Although severity of COPD was a predictor of long-term outcomes, the main predictors of these were presence of co-morbidities. PMID- 26010583 TI - Pitfalls in histone propionylation during bottom-up mass spectrometry analysis. AB - Despite their important role in regulating gene expression, posttranslational histone modifications remain technically challenging to analyze. For identification by bottom-up MS, propionylation is required prior to and following trypsin digestion. Hereby, more hydrophobic peptides are generated enabling RP HPLC separation. When histone dynamics are studied in a quantitative manner, specificity, and efficiency of this chemical derivatization are crucial. Therefore we examined eight different protocols, including two different propionylation reagents. This revealed amidation (up to 70%) and methylation (up to 9%) of carboxyl groups as a side reaction. Moreover, incomplete (up to 85%) as well as a specific propionylation (up to 63%) can occur, depending on the protocol. These results highlight the possible pitfalls and implications for data analysis when doing bottom-up MS on histones. PMID- 26010584 TI - Relevance of Candida and other mycoses for morbidity and mortality in severe sepsis and septic shock due to peritonitis. AB - This single-centre retrospective cohort study evaluated the incidence and outcome of mycoses in critical ill patients (n = 283) with sepsis due to peritonitis. Overall mortality was 41.3%, and the 28-day mortality was 29.3%. Fungal pathogens were found in 51.9%. The common first location was the respiratory tract (66.6%), followed by the abdominal site (19.7%). Candida colonisation was found in 64.6%, and invasive Candida infection in 34.0%. Identified fungi were Candida spp. in 98.6% and Aspergillus spp. in 6.1%. Patients with fungal pathogens showed a higher rate of postoperative peritonitis, APACHE II and tracheotomy. In comparison to patients without fungal pathogens, these patients showed a longer duration on mechanical ventilation, and a higher overall mortality. Patients with Candida-positive swabs from abdominal sites had more fascia dehiscence and anastomosis leakage. Seventy-two patients (48.9%) received antifungal therapy, 26 patients were treated empirically. Antifungal therapy was not associated with a decrease in mortality. Age and renal replacement therapy were associated with mortality. In conclusion, fungi are common pathogens in critically ill patients with peritonitis, and detection of fungi is associated with an increase in overall mortality. Particularly, Candida-positive abdominal swabs are associated with an increase in morbidity. However, we were not able to demonstrate a survival benefit for antifungal therapy in peritonitis patients. PMID- 26010585 TI - Structure-Activity Relationships of Neplanocin A Analogues as S Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities. AB - On the basis of the potent inhibitory activity of neplanocin A (1) against S adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure activity relationships by modifying the adenine and carbasugar moiety of 1 to find the pharmacophore in the active site of the enzyme. The introduction of 7 deazaadenine instead of adenine eliminated the inhibitory activity against the AdoHcy hydrolase, while 3-deazaadenine maintained the inhibitory activity of the enzyme, indicating that N-7 is essential for its role as a hydrogen bonding acceptor. The substitution of hydrogen at the 6'-position with fluorine increased the inhibitory activity of the enzyme. The one-carbon homologation at the 5' position generally decreased the inhibitory activity of the enzyme, indicating that steric repulsion exists. A molecular docking study also supported these experimental data. In this study, 6'-fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC50 = 0.24 MUM). It showed a potent anti-VSV activity (EC50 = 0.43 MUM) and potent anticancer activity in all the human tumor cell lines tested. PMID- 26010586 TI - The Role of Religiousness and Gender in Sexuality Among Mexican Adolescents. AB - This study examined the role of religiousness and gender in age at first intercourse, and sexual expectations and values in Mexico, a macrocontext where the majority is Mexican and Catholic (83%). Participants were Catholic and nonreligious adolescents (54% girls) attending middle (71%) or high school. Findings indicated that Catholic adolescents engaged in sexual intercourse at later ages than nonreligious adolescents. Both religious attendance and importance of religion and values in sexual decision making were associated with more conservative sexual values. Boys who were raised Catholic were more likely to endorse female virginity values and were less likely to expect to wait to have sex until married than nonreligious boys. These associations were not significant among girls. Catholic boys may be more likely to internalize sexual double standard beliefs regarding premarital sex than nonreligious boys. This study expands our understanding of the role of religiousness in Mexican adolescents' sexuality. PMID- 26010587 TI - Exploring the relationship between age and tenure with length of disability. AB - BACKGROUND: The aging of the workforce, coupled with the changing nature of career tenure has raised questions about the impact of these trends on work disability. This study aimed to determine if age and tenure interact in relating to work disability duration. METHODS: Relationships were investigated using random effects models with 239,359 work disability claims occurring between 2008 and 2012. RESULTS: A 17-day difference in the predicted length of disability was observed from ages 25 to 65. Tenure moderated the relationship between age and length of disability. At younger ages, the length of disability decreased as tenure increased, but at older age, the length of disability increased as tenure increased. DISCUSSION: Results indicate that although there is a relationship between length of disability and tenure, age makes a greater unique contribution to explaining variance in length of disability. Future research is needed to better understand why specifically age shows a strong relationship with length of disability and why that relationship varies with age. PMID- 26010589 TI - Distinct contributions of attention and working memory to visual statistical learning and ensemble processing. AB - The brain exploits redundancies in the environment to efficiently represent the complexity of the visual world. One example of this is ensemble processing, which provides a statistical summary of elements within a set (e.g., mean size). Another is statistical learning, which involves the encoding of stable spatial or temporal relationships between objects. It has been suggested that ensemble processing over arrays of oriented lines disrupts statistical learning of structure within the arrays (Zhao, Ngo, McKendrick, & Turk-Browne, 2011). Here we asked whether ensemble processing and statistical learning are mutually incompatible, or whether this disruption might occur because ensemble processing encourages participants to process the stimulus arrays in a way that impedes statistical learning. In Experiment 1, we replicated Zhao and colleagues' finding that ensemble processing disrupts statistical learning. In Experiments 2 and 3, we found that statistical learning was unimpaired by ensemble processing when task demands necessitated (a) focal attention to individual items within the stimulus arrays and (b) the retention of individual items in working memory. Together, these results are consistent with an account suggesting that ensemble processing and statistical learning can operate over the same stimuli given appropriate stimulus processing demands during exposure to regularities. PMID- 26010588 TI - Incidental auditory category learning. AB - Very little is known about how auditory categories are learned incidentally, without instructions to search for category-diagnostic dimensions, overt category decisions, or experimenter-provided feedback. This is an important gap because learning in the natural environment does not arise from explicit feedback and there is evidence that the learning systems engaged by traditional tasks are distinct from those recruited by incidental category learning. We examined incidental auditory category learning with a novel paradigm, the Systematic Multimodal Associations Reaction Time (SMART) task, in which participants rapidly detect and report the appearance of a visual target in 1 of 4 possible screen locations. Although the overt task is rapid visual detection, a brief sequence of sounds precedes each visual target. These sounds are drawn from 1 of 4 distinct sound categories that predict the location of the upcoming visual target. These many-to-one auditory-to-visuomotor correspondences support incidental auditory category learning. Participants incidentally learn categories of complex acoustic exemplars and generalize this learning to novel exemplars and tasks. Further, learning is facilitated when category exemplar variability is more tightly coupled to the visuomotor associations than when the same stimulus variability is experienced across trials. We relate these findings to phonetic category learning. PMID- 26010590 TI - Executive attentional resources in timing: Effects of inhibitory control and cognitive aging. AB - This research is based on an executive resource theory of timing, which postulates that time perception relies on specialized attentional resources that support executive cognitive functions. In 4 experiments, older and younger participants performed a timing task and an executive task emphasizing inhibitory control under both single-task and dual-task conditions. The timing task in each experiment was serial temporal production. The executive tasks, representing different types of inhibitory control, were the flanker task (Experiment 1), the number-letter task (Experiment 2), the go/no-go task (Experiment 3), and the antisaccade task (Experiment 4). The results showed (a) a pattern of bidirectional interference in each experiment, in that the concurrent inhibition tasks interfered with timing performance and concurrent timing interfered with inhibition performance, (b) the older participants demonstrated a stronger bidirectional interference effect relative to younger participants in 3 experiments, and (c) weaker versions of the inhibition tasks produced weaker interference effects. These findings support the idea that temporal processing relies on executive attentional resources. PMID- 26010591 TI - Contextual consistency facilitates long-term memory of perceptual detail in barely seen images. AB - It is long known that contextual information affects memory for an object's identity (e.g., its basic level category), yet it is unclear whether schematic knowledge additionally enhances memory for the precise visual appearance of an item. Here we investigated memory for visual detail of merely glimpsed objects. Participants viewed pairs of contextually related and unrelated stimuli, presented for an extremely brief duration (24 ms, masked). They then performed a forced-choice memory-recognition test for the precise perceptual appearance of 1 of 2 objects within each pair (i.e., the "memory-target" item). In 3 experiments, we show that memory-target stimuli originally appearing within contextually related pairs are remembered better than targets appearing within unrelated pairs. These effects are obtained whether the target is presented at test with its counterpart pair object (i.e., when reiterating the original context at encoding) or whether the target is presented alone, implying that the contextual consistency effects are mediated predominantly by processes occurring during stimulus encoding, rather than during stimulus retrieval. Furthermore, visual detail encoding is improved whether object relations involve implied action or not, suggesting that, contrary to some prior suggestions, action is not a necessary component for object-to-object associative "grouping" processes. Our findings suggest that during a brief glimpse, but not under long viewing conditions, contextual associations may play a critical role in reducing stimulus competition for attention selection and in facilitating rapid encoding of sensory details. Theoretical implications with respect to classic frame theories are discussed. (PsycINFO Database Record PMID- 26010593 TI - Peripheral processing of gaze. AB - When looking at someone, we combine information about their head orientation and eye deviation to judge their direction of gaze. What remains unknown, however, is how these cues combine when we are not looking directly at the person, but rather are using our peripheral vision. Given that peripheral vision helps direct future attention, understanding how we perceive other people's gaze is key to determining their future actions. To examine this, we asked participants to categorize gaze direction in faces whose heads were turned in different directions, and which were viewed using either central or peripheral vision. We report that the weight given to head orientation increases in the periphery, in which forward-facing heads were categorized as "direct" over a wider range of eye deviations than when viewed centrally. When peripheral heads were turned, the number of "direct" responses fell for all gaze deviations with no consistent shift in left-right responses toward the head rotation. For centrally presented heads, head orientation typically repulsed the perceived direction of gaze, and our finding of no consistent shift in responses indicates that such effects are reduced in the periphery. This is not simply the result of poorer spatial resolution in the periphery-other influences, such as crowding and priors for gaze or head direction, may play a role. (PsycINFO Database Record PMID- 26010592 TI - Discovering functional units in continuous speech. AB - Language learning requires that listeners discover acoustically variable functional units like phonetic categories and words from an unfamiliar, continuous acoustic stream. Although many category learning studies have examined how listeners learn to generalize across the acoustic variability inherent in the signals that convey the functional units of language, these studies have tended to focus upon category learning across isolated sound exemplars. However, continuous input presents many additional learning challenges that may impact category learning. Listeners may not know the timescale of the functional unit, its relative position in the continuous input, or its relationship to other evolving input regularities. Moving laboratory-based studies of isolated category exemplars toward more natural input is important to modeling language learning, but very little is known about how listeners discover categories embedded in continuous sound. In 3 experiments, adult participants heard acoustically variable sound category instances embedded in acoustically variable and unfamiliar sound streams within a video game task. This task was inherently rich in multisensory regularities with the to-be-learned categories and likely to engage procedural learning without requiring explicit categorization, segmentation, or even attention to the sounds. After 100 min of game play, participants categorized familiar sound streams in which target words were embedded and generalized this learning to novel streams as well as isolated instances of the target words. The findings demonstrate that even without a priori knowledge, listeners can discover input regularities that have the best predictive control over the environment for both non-native speech and nonspeech signals, emphasizing the generality of the learning. PMID- 26010594 TI - An empirical analysis of the methodology of automatic imitation research in a strategic context. AB - Since the discovery of the mirror neuron system, it has been proposed that the automatic tendency to copy observed actions exists in humans and that this mechanism might be responsible for a range of social behavior. A strong argument for automatic behavior can be made when actions are executed against motivation to do otherwise. Strategic games in which imitation is disadvantageous serve as ideal designs for studying the automatic nature of participants' behavior. Most recently, Belot, Crawford, and Heyes (2013) conducted an explorative study using a modified version of the Rock-Paper-Scissors game, and suggested that in the case of asynchrony in the execution of the gestures, automatic imitation can be observed early on after the opponent's presentation. In our study, we video recorded the games, which allowed us to examine the effect of delay on imitative behavior as well as the sensitivity of the previously employed analyses. The examination of the recorded images revealed that more than 80% of the data were irrelevant to the study of automatic behavior. Additional bias in the paradigm became apparent, as previously presented gestures were found to affect the behavior of the players. After noise filtering, we found no evidence of automatic imitation in either the whole filtered data set or in selected time windows based on delay length. Besides questioning the strength of the results of previous analyses, we propose several experimental and statistical modifications for further research on automatic imitation. PMID- 26010595 TI - Oral and gastric Helicobacter pylori: effects and associations. AB - INTRODUCTION: This study consisted in the comparison of the prevalence of Helicobacter pylori (H. pylori) present in the stomach and in saliva of a sample of Portuguese adolescents and the assessment of the association between H. pylori infection with socio-demographic variables and prevalence of dental caries. MATERIALS AND METHODS: A cross-sectional study was designed including a sample of 447 adolescents aged 12 to 19 years old, attending a public school in Satao, Portugal. A questionnaire about socio-demographic variables and oral health behaviors was applied. Gastric H. pylori infection was determined using the urease breath test (UBT). Saliva collection was obtained and DNA was extracted by Polymerase Chain Reaction (PCR) in order to detect the presence of oral H. pylori. RESULTS: The prevalence of gastric H. pylori detected by UBT was 35.9%. Within the adolescents with a gastric UBT positive, only 1.9% were positive for oral H. pylori. The presence of gastric H. pylori was found to be associated with age (>15years, Odds ratio (OR)=1.64, 95%CI=1.08-2.52), residence area (urban, OR=1.48, 95%CI=1.03-2.29) and parents' professional situation (unemployed, OR=1.22, 95%CI=1.02-1.23). Among those with detected dental caries during the intra-oral observation, 37.4% were positive for gastric H. pylori and 40.2% negative for the same bacterial strain (p=0.3). CONCLUSIONS: The oral cavity cannot be considered a reservoir for infection of H. pylori. Gastric H. pylori infection was found to be associated with socio-demographic variables such as age, residence area and socioeconomic status. PMID- 26010597 TI - B cells and rheumatoid factors in autoimmunity. PMID- 26010596 TI - Sesamol decreases melanin biosynthesis in melanocyte cells and zebrafish: Possible involvement of MITF via the intracellular cAMP and p38/JNK signalling pathways. AB - The development of antimelanogenic agents is important for the prevention of serious aesthetic problems such as melasma, freckles, age spots and chloasma. The aim of this study was to investigate the antimelanogenic effect of sesamol, an active lignan isolated from Sesamum indicum, in melan-a cells. Sesamol strongly inhibited melanin biosynthesis and the activity of intracellular tyrosinase by decreasing cyclic adenosine monophosphate (cAMP) accumulation. Sesamol significantly decreased the expression of melanogenesis-related genes, such as tyrosinase, tyrosinase-related protein-1,2 (TRP-1,2), microphthalmia-associated transcription factor (MITF) and melanocortin 1 receptor (MC1R). In addition, sesamol also induces phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). Moreover, sesamol dose-dependently decreased zebrafish pigment formation, tyrosinase activity and expression of melanogenesis-related genes. These findings indicate that sesamol inhibited melanin biosynthesis by down-regulating tyrosinase activity and melanin production via regulation of gene expression of melanogenesis-related proteins through modulation of MITF activity, which promoted phosphorylation of p38 and JNK in melan-a cells. Together, these results suggest that sesamol strongly inhibits melanin biosynthesis, and therefore, sesamol represents a new skin whitening agent for use in cosmetics. PMID- 26010598 TI - Clinical profile of 266 Filipino patients with rheumatoid arthritis included in the rheumatoid arthritis database and registry (RADAR) of the Philippine General Hospital. AB - AIM: To describe Filipino patients with rheumatoid arthritis (RA) entered in the Rheumatoid arthritis database and registry (RADAR) of the Philippine General Hospital. METHODS: Cases entered to RADAR from 2010-2012 were included. All fulfilled the 1987 American College of Rheumatology criteria for classification of RA. Included cases gave written infomed consent. Data extracted were demographics, clinical presentation, laboratory tests, treatment and disease course. Means and proportions were used for population characteristics. RESULTS: Two hundred and sixty-six cases were included. Mean age was 44 years, with 9 : 1 female preponderance and mean diagnosis time of 5 years. There was symmetrical polyarthritis with high tender and swollen joint count and mean Disease Activity Score of 28 joints, erythrocyte sedimentation rate of 5.27 (3.39, 8.13). Rheumatoid factor was positive in 2/3 of cases. Hypertension, tuberculosis and diabetes were important co-morbidities. Treatment included prednisone, non steroidal anti-inflammatory drugs and methotrexate. At 12 months of treatment, evaluable cases (< 20%) showed improvement from high to moderate disease activity. Methotrexate average dose was 8.6 mg/week. Nine cases received biologic agents. Factors affecting treatment included access to rheumatology centers, low socioeconomic status, presence of co-morbid diseases and treatment adverse events. CONCLUSION: This study reports a cohort of Filipino RA patients seen in a government arthritis unit whose disease characteristics are similar to what is reported worldwide. This cohort differs from most studies in having a high female to male ratio, a long delay in diagnosis, and high attrition rate. Mean methotrexate dose was low and there was less access to biologic disease-modifying anti-rheumatic drugs. PMID- 26010599 TI - Median-based incremental cost-effectiveness ratios with censored data. AB - Cost-effectiveness is an essential part of treatment evaluation, in addition to effectiveness. In the cost-effectiveness analysis, a measure called the incremental cost-effectiveness ratio (ICER) is widely utilized, and the mean cost and the mean (quality-adjusted) life years have served as norms to summarize cost and effectiveness for a study population. Recently, the median-based ICER was proposed for complementary or sensitivity analysis purposes. In this article, we extend this method when some data are censored. PMID- 26010600 TI - Does Timing of Implant Placement Affect Implant Therapy Outcome in the Aesthetic Zone? A Clinical, Radiological, Aesthetic, and Patient-Based Evaluation. AB - PURPOSE: To compare five different implant treatment protocols in the anterior maxilla, including immediate, early, and delayed implant placement, as well as implant placement in conjunction with simultaneous guided bone regeneration and implant placement 3 months following horizontal autologous bone block grafting. MATERIAL AND METHODS: Aesthetic indices used included the Pink Esthetic Score (PES), Papilla Index (PI), Subjective Esthetic Score (SES), and White Esthetic Score (WES). Subjective evaluation of implant aesthetics was performed using a visual analogue scale (VAS). The VAS consisted of a 10 cm-long line representing the degree of discontent (0%) or satisfaction (100%). RESULTS: A total of 153 implants in 153 patients (80 women, 73 men) were evaluated after a mean follow-up of 4.5 +/- 2.9 years. Mean peri-implant bone loss was 1.6 +/- 0.9 mm and not affected by treatment protocol, time after implant placement, or crown length. Papilla presence, by contrast, differed significantly between the protocols: Papilla formation was more pronounced following delayed and immediate implant placement. No statistical significance was found among treatment modalities with regard to PES, SES, or WES. Longer crowns were associated with lower PES and PI ratings and correlated with greater midfacial recession. SES was also influenced by time after implant placement and keratinized mucosa. Patient satisfaction differed significantly among treatment protocols, favoring immediate implant placement. Agreement between objective and subjective aesthetic ratings was low. CONCLUSION: The present study suggests that comparable clinical, radiological, and aesthetic results can be achieved with all treatment protocols. Gingival recession, however, seems to occur in the long term irrespective of the technique used. PMID- 26010601 TI - Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B Cell Lymphoma and Its Therapeutic Implications. AB - Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC) DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients. PMID- 26010602 TI - The role of intracellular calcium for the development and treatment of neuroblastoma. AB - Neuroblastoma is the second most common paediatric cancer. It developsfrom undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, theaetiology behind the development of neuroblastoma is still not fully understood. Intracellularcalcium ([Ca2+]i) is a secondary messenger which regulates numerous cellular processesand, therefore, its concentration is tightly regulated. This review focuses on the role of[Ca2+]i in differentiation, apoptosis and proliferation in neuroblastoma. It describes themechanisms by which [Ca2+]i is regulated and how it modulates intracellular pathways.Furthermore, the importance of [Ca2+]i for the function of anti-cancer drugs is illuminatedin this review as [Ca2+]i could be a target to improve the outcome of anti-cancer treatmentin neuroblastoma. Overall, modulations of [Ca2+]i could be a key target to induce apoptosisin cancer cells leading to a more efficient and effective treatment of neuroblastoma. PMID- 26010603 TI - Voltage-gated ion channels in cancer cell proliferation. AB - Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K+, Ca++, Cl. PMID- 26010606 TI - Pulling Mobile Assisted Language Learning (MALL) into the Mainstream: MALL in Broad Practice. AB - The researcher designed a smartphone app to help college students to learn English (L2) vocabulary. The app contained 3,402 English words that were compiled into an alphabetic wordlist with each word displayed on three features; namely: spelling, pronunciation and Chinese definitions. To test the effectiveness of the app, an experimental group (with app) was compared with a control group (without app) and knowledge of words was tested before and after the research. The study revealed that the students using the program significantly outperformed those in the control group in vocabulary acquisition. This paper introduced a research design method and set up a pedagogical paradigm which can be followed as a way to practice MALL. PMID- 26010604 TI - The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells. AB - The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of beta-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors. PMID- 26010605 TI - Effects of age on the detection and management of breast cancer. AB - Currently, breast cancer affects approximately 12% of women worldwide. While the incidence of breast cancer rises with age, a younger age at diagnosis is linked to increased mortality. We discuss age related factors affecting breast cancer diagnosis, management and treatment, exploring key concepts and identifying critical areas requiring further research. We examine age as a factor in breast cancer diagnosis and treatment relating it to factors such as genetic status, breast cancer subtype, hormone factors and nodal status. We examine the effects of age as seen through the adoption of population wide breast cancer screening programs. Assessing the incidence rates of each breast cancer subtype, in the context of age, we examine the observed correlations. We explore how age affects patient's prognosis, exploring the effects of age on stage and subtype incidence. Finally we discuss the future of breast cancer diagnosis and treatment, examining the potential of emerging tests and technologies (such as microRNA) and how novel research findings are being translated into clinically relevant practices. PMID- 26010607 TI - Characterization of regional left ventricular function in nonhuman primates using magnetic resonance imaging biomarkers: a test-retest repeatability and inter subject variability study. AB - Pre-clinical animal models are important to study the fundamental biological and functional mechanisms involved in the longitudinal evolution of heart failure (HF). Particularly, large animal models, like nonhuman primates (NHPs), that possess greater physiological, biochemical, and phylogenetic similarity to humans are gaining interest. To assess the translatability of these models into human diseases, imaging biomarkers play a significant role in non-invasive phenotyping, prediction of downstream remodeling, and evaluation of novel experimental therapeutics. This paper sheds insight into NHP cardiac function through the quantification of magnetic resonance (MR) imaging biomarkers that comprehensively characterize the spatiotemporal dynamics of left ventricular (LV) systolic pumping and LV diastolic relaxation. MR tagging and phase contrast (PC) imaging were used to quantify NHP cardiac strain and flow. Temporal inter-relationships between rotational mechanics, myocardial strain and LV chamber flow are presented, and functional biomarkers are evaluated through test-retest repeatability and inter subject variability analyses. The temporal trends observed in strain and flow was similar to published data in humans. Our results indicate a dominant dimension based pumping during early systole, followed by a torsion dominant pumping action during late systole. Early diastole is characterized by close to 65% of untwist, the remainder of which likely contributes to efficient filling during atrial kick. Our data reveal that moderate to good intra-subject repeatability was observed for peak strain, strain rates, E/circumferential strain-rate (CSR) ratio, E/longitudinal strain-rate (LSR) ratio, and deceleration time. The inter-subject variability was high for strain dyssynchrony, diastolic strain-rates, peak torsion and peak untwist rate. We have successfully characterized cardiac function in NHPs using MR imaging. Peak strain, average systolic strain-rate, diastolic E/CSR and E/LSR ratios, and deceleration time were identified as robust biomarkers that could potentially be applied to future pre-clinical drug studies. PMID- 26010608 TI - Functional Genetic Variations at the microRNA Binding-Site in the CD44 Gene Are Associated with Risk of Colorectal Cancer in Chinese Populations. AB - CD44 as one of the most putative stem cell markers plays a key role in many cellular processes, including cancer cell growth and migration. Functional single nucleotide polymorphisms (SNPs) of CD44 may modulate its gene functions and thus cancer risk. In the current study, we investigated if polymorphisms in the 3' untranslated region (UTR) of CD44 are associated with increased susceptibility to colorectal cancer (CRC) by conducting a case-control study of 946 CRC patients and 989 cancer-free controls. Three polymorphisms (rs13347C/T, rs10836347C/T, rs11821102G/A) in the 3'-UTR of CD44 were genotyped. We found that the variant genotypes (CT and TT) of rs13347 (adjusted odds ratio (OR)=1.79, 95% confidence interval (CI)=1.50-2.17) increased an individual's susceptibility to CRC, compared with rs13347CC homozygous genotypes. We also found that CRC patients with the CT/TT genotype had a 1.6-fold increased risk for developing advanced (stage III + IV) CRC. Furthermore, functional assays showed that the C to T base change at rs13347C/T disrupts the binding site for the microRNA hsa-mir-509-3p, thereby increasing CD44 transcriptional activity and expression level. These findings suggest that the rs13347C/T in microRNA binding site may be potential biomarkers for genetic susceptibility to CRC. PMID- 26010609 TI - Potential interactions of calcium-sensitive reagents with zinc ion in different cultured cells. AB - BACKGROUND: Several chemicals have been widely used to evaluate the involvement of free Ca(2+) in mechanisms underlying a variety of biological responses for decades. Here, we report high reactivity to zinc of well-known Ca(2+)-sensitive reagents in diverse cultured cells. METHODOLOGY/PRINCIPAL FINDINGS: In rat astrocytic C6 glioma cells loaded with the fluorescent Ca(2+) dye Fluo-3, the addition of ZnCl2 gradually increased the fluorescence intensity in a manner sensitive to the Ca(2+) chelator EGTA irrespective of added CaCl2. The addition of the Ca(2+) ionophore A23187 drastically increased Fluo-3 fluorescence in the absence of ZnCl2, while the addition of the Zn(2+) ionophore pyrithione rapidly and additionally increased the fluorescence in the presence of ZnCl2, but not in its absence. In cells loaded with the zinc dye FluoZin-3 along with Fluo-3, a similarly gradual increase was seen in the fluorescence of Fluo-3, but not of FluoZin-3, in the presence of both CaCl2 and ZnCl2. Further addition of pyrithione drastically increased the fluorescence intensity of both dyes, while the addition of the Zn(2+) chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2 diamine (TPEN) rapidly and drastically decreased FluoZin-3 fluorescence. In cells loaded with FluoZin-3 alone, the addition of ZnCl2 induced a gradual increase in the fluorescence in a fashion independent of added CaCl2 but sensitive to EGTA. Significant inhibition was found in the vitality to reduce 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide in a manner sensitive to TPEN, EDTA and BAPTA in C6 glioma cells exposed to ZnCl2, with pyrithione accelerating the inhibition. Similar inhibition occurred in an EGTA-sensitive fashion after brief exposure to ZnCl2 in pluripotent P19 cells, neuronal Neuro2A cells and microglial BV2 cells, which all expressed mRNA for particular zinc transporters. CONCLUSIONS/SIGNIFICANCE: Taken together, comprehensive analysis is absolutely required for the demonstration of a variety of physiological and pathological responses mediated by Ca(2+) in diverse cells enriched of Zn(2+). PMID- 26010610 TI - Metabolomic fingerprint of heart failure with preserved ejection fraction. AB - BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly recognized as an important clinical entity. Preclinical studies have shown differences in the pathophysiology between HFpEF and HF with reduced ejection fraction (HFrEF). Therefore, we hypothesized that a systematic metabolomic analysis would reveal a novel metabolomic fingerprint of HFpEF that will help understand its pathophysiology and assist in establishing new biomarkers for its diagnosis. METHODS AND RESULTS: Ambulatory patients with clinical diagnosis of HFpEF (n = 24), HFrEF (n = 20), and age-matched non-HF controls (n = 38) were selected for metabolomic analysis as part of the Alberta HEART (Heart Failure Etiology and Analysis Research Team) project. 181 serum metabolites were quantified by LC-MS/MS and 1H-NMR spectroscopy. Compared to non HF control, HFpEF patients demonstrated higher serum concentrations of acylcarnitines, carnitine, creatinine, betaine, and amino acids; and lower levels of phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins. Medium and long-chain acylcarnitines and ketone bodies were higher in HFpEF than HFrEF patients. Using logistic regression, two panels of metabolites were identified that can separate HFpEF patients from both non-HF controls and HFrEF patients with area under the receiver operating characteristic (ROC) curves of 0.942 and 0.981, respectively. CONCLUSIONS: The metabolomics approach employed in this study identified a unique metabolomic fingerprint of HFpEF that is distinct from that of HFrEF. This metabolomic fingerprint has been utilized to identify two novel panels of metabolites that can separate HFpEF patients from both non-HF controls and HFrEF patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02052804. PMID- 26010613 TI - IRF5: a rheostat for tumor-infiltrating lymphocyte trafficking in breast cancer? PMID- 26010611 TI - Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells. AB - BACKGROUND: Diabetes mellitus is linked to pancreatic cancer. We hypothesized a role for pancreatic stellate cells (PSC) in the hyperglycemia induced deterioration of pancreatic cancer and therefore studied two human cell lines (RLT-PSC, T3M4) in hyperglycemic environment. METHODOLOGY/PRINCIPAL FINDINGS: The effect of chronic hyperglycemia (CHG) on PSCs was studied using mRNA expression array with real-time PCR validation and bioinformatic pathway analysis, and confirmatory protein studies. The stress fiber formation (IC: alphaSMA) indicated that PSCs tend to transdifferentiate to a myofibroblast-like state after exposure to CHG. The phosphorylation of p38 and ERK1/2 was increased with a consecutive upregulation of CDC25, SP1, cFOS and p21, and with downregulation of PPARgamma after PSCs were exposed to chronic hyperglycemia. CXCL12 levels increased significantly in PSC supernatant after CHG exposure independently from TGF-beta1 treatment (3.09-fold with a 2.73-fold without TGF-beta1, p<0.05). The upregualtion of the SP1 transcription factor in PSCs after CHG exposure may be implicated in the increased CXCL12 and IGFBP2 production. In cancer cells, hyperglycemia induced an increased expression of CXCR4, a CXCL12 receptor that was also induced by PSC's conditioned medium. The receptor-ligand interaction increased the phosphorylation of ERK1/2 and p38 resulting in activation of MAP kinase pathway, one of the most powerful stimuli for cell proliferation. Certainly, conditioned medium of PSC increased pancreatic cancer cell proliferation and this effect could be partially inhibited by a CXCR4 inhibitor. As the PSC conditioned medium (normal glucose concentration) increased the ERK1/2 and p38 phosphorylation, we concluded that PSCs produce other factor(s) that influence(s) pancreatic cancer behaviour. CONCLUSIONS: Hyperglycemia induces increased CXCL12 production by the PSCs, and its receptor, CXCR4 on cancer cells. The ligand-receptor interaction activates MAP kinase signaling that causes increased cancer cell proliferation and migration. PMID- 26010612 TI - Wireless Ultrasound Guidance for Femoral Venous Cannulation in Electrophysiology: Impact on Safety, Efficacy, and Procedural Delay. AB - BACKGROUND: Ultrasound (US) guidance increases safety and efficacy in vascular cannulation and is considered the standard of care. However, barriers including workflow interference and the need to be assisted by a second operator limit its adoption in clinical routine. The use of wireless US (WUS) may overcome these barriers. The aim of this study was to assess the impact of a novel WUS probe during its initial implantation in an electrophysiology (EP) laboratory. METHODS: Thirty-six patients requiring femoral venous cannulation for EP procedures were included in this single center, prospective, observational study, comparing WUS guidance with the anatomical landmark approach. The primary endpoint was time to successful cannulation. Secondary endpoints included rate of unsuccessful punctures, accidental arterial punctures, and workflow interference. RESULTS: Compared with anatomical landmark approach, WUS guidance significantly reduced mean time to successful cannulation (87.3 +/- 94.3 vs 238.1 +/- 294.7 seconds, P < 0.01). Workflow interference was predominantly nonexistent or mild and decreased after the first three weeks of use. In addition, WUS guidance improved safety and efficacy, reducing the rate of accidental arterial punctures (0.02 +/- 0.1 vs 0.25 +/- 0.5 arterial punctures per cannulation, P < 0.05) and unsuccessful attempts (0.26 +/- 0.8 vs 1.75 +/- 2.1 attempts per cannulation, P < 0.01). CONCLUSIONS: WUS guidance resulted in faster, safer, and more effective femoral venous cannulation than the anatomical landmark approach without adding significant workflow interference. The application of wireless technology in this setting contributed to overcoming some of the barriers preventing a more widespread clinical use of US guidance. PMID- 26010614 TI - An Antioxidant Extract of the Insectivorous Plant Drosera burmannii Vahl. Alleviates Iron-Induced Oxidative Stress and Hepatic Injury in Mice. AB - Free iron typically leads to the formation of excess free radicals, and additional iron deposition in the liver contributes to the oxidative pathologic processes of liver disease. Many pharmacological properties of the insectivorous plant Drosera burmannii Vahl. have been reported in previous studies; however, there is no evidence of its antioxidant or hepatoprotective potential against iron overload. The antioxidant activity of 70% methanolic extract of D. burmannii (DBME) was evaluated. DBME showed excellent DPPH, hydroxyl, hypochlorous, superoxide, singlet oxygen, nitric oxide, peroxynitrite radical and hydrogen peroxide scavenging activity. A substantial iron chelation (IC50 = 40.90 +/- 0.31 MUg/ml) and supercoiled DNA protection ([P]50 = 50.41 +/- 0.55 MUg) were observed. DBME also displayed excellent in vivo hepatoprotective activity in iron overloaded Swiss albino mice compared to the standard desirox treatment. Administration of DBME significantly normalized serum enzyme levels and restored liver antioxidant enzymes levels. DBME lowered the raised levels of liver damage parameters, also reflected from the morphological analysis of the liver sections. DBME also reduced liver iron content by 115.90% which is also seen by Perls' staining. A phytochemical analysis of DBME confirms the presence of various phytoconstituents, including phenols, flavonoids, carbohydrates, tannins, alkaloids and ascorbic acid. Alkaloids, phenols and flavonoids were abundantly found in DBME. An HPLC analysis of DBME revealed the presence of purpurin, catechin, tannic acid, reserpine, methyl gallate and rutin. Purpurin, tannic acid, methyl gallate and rutin displayed excellent iron chelation but exhibited cytotoxicity toward normal (WI-38) cells; while DBME found to be non-toxic to the normal cells. These findings suggest that the constituents present in DBME contributed to its iron chelation activity. Additional studies are needed to determine if DBME can be used as a treatment for iron overload diseases. PMID- 26010617 TI - The last Civil War veteran: Larry Rivers. PMID- 26010615 TI - Depression in persons with diabetes by age and antidiabetic treatment: a cross sectional analysis with data from the Hordaland Health Study. AB - BACKGROUND: Persons with diabetes have increased risk of depression, however, studies addressing whether the risk varies by age and type of antidiabetic treatment have yielded conflicting results. The aim of this study was to investigate if the association between diabetes and depression varied by type of antidiabetic treatment in a large community based sample of middle-aged (40-47 years) and older adults (70-72 years). METHODS: Data from 21845 participants in the Hordaland Health Study (HUSK) were analyzed in a cross-sectional design. Diabetes was assessed by self-report and classified as un-medicated, treated by oral antidiabetic agents or by insulin. Depression was defined as a score >= 8 on the depression subscale of the Hospital Anxiety and Depression Scale and/or self reported use of antidepressant agents. Associations between diabetes and depression were estimated using logistic regression. RESULTS: Persons in their forties with diabetes had a doubled prevalence of depression (OR: 1.96 (95% C.I.: 1.35, 2.83)) compared to persons without diabetes, while a lower and non significant association was found among persons in their seventies. Persons in their forties with orally treated diabetes had about three times higher prevalence of depression (OR: 2.92 (95% C.I.: 1.48, 5.77)) after adjustment for gender, BMI, physical activity, alcohol consumption and education, compared to non-diabetic persons in the same age-group. No association between depression and insulin or un-medicated diabetes was found. CONCLUSIONS: Clinicians should be aware that persons in their forties with orally treated diabetes are at a marked increased risk of depression. PMID- 26010618 TI - Using health care data to track and improve public health. PMID- 26010629 TI - A piece of my mind. The art of discharge. PMID- 26010630 TI - Cognitive phenotypes and genomic copy number variations. PMID- 26010631 TI - The Eighth International Congress on Peer Review and Biomedical Publication: A call for research. PMID- 26010635 TI - Variation in prostate cancer care. PMID- 26010633 TI - Copy number variations and cognitive phenotypes in unselected populations. AB - IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency <=0.05%; size >=250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, <=0.05%; >=250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51 5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (>=250 kb) deletion carriers and 3.69 (P = 5.024e 05) among 115 duplication carriers (>=1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health. PMID- 26010636 TI - Cluster randomized trials: evaluating treatments applied to groups. PMID- 26010637 TI - Perioperative use of beta-blockers in cardiac and noncardiac surgery. AB - CLINICAL QUESTION: Are beta-blockers associated with lower rates of mortality and morbidity after cardiac or noncardiac surgery? BOTTOM LINE: In cardiac surgery, beta-blockers are associated with a lower incidence of supraventricular tachycardias (SVTs) and ventricular arrhythmias. In noncardiac surgery, beta blockers are associated with a possible increase in mortality and strokes, a lower incidence of acute myocardial infarctions (AMIs) and SVTs, and an increase in bradycardia and hypotension. If tolerated, long-term beta-blocker treatment should be continued perioperatively, whereas the decision to start a beta-blocker should be individualized, weighing risks and benefits. PMID- 26010634 TI - Subclinical thyroid dysfunction and fracture risk: a meta-analysis. AB - IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH >=4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS: Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures. PMID- 26010632 TI - Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial. AB - IMPORTANCE: Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. OBJECTIVE: To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. INTERVENTIONS: Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. RESULTS: Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. CONCLUSIONS AND RELEVANCE: Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01052116. PMID- 26010638 TI - Association of aflatoxin with gallbladder cancer in Chile. PMID- 26010639 TI - Mortality and ratio of blood products used in patients with severe trauma. PMID- 26010640 TI - Mortality and ratio of blood products used in patients with severe trauma. PMID- 26010641 TI - Mortality and ratio of blood products used in patients with severe trauma. PMID- 26010642 TI - Mortality and ratio of blood products used in patients with severe trauma--reply. PMID- 26010643 TI - Electronic devices and applications to track physical activity. PMID- 26010644 TI - Electronic devices and applications to track physical activity--reply. PMID- 26010646 TI - The lead treatment of cancer. PMID- 26010647 TI - JAMA patient page. Deep vein thrombosis. PMID- 26010648 TI - Peramorphic traits in the tokay gecko skull. AB - Traditionally, geckos have been conceived to exhibit paedomorphic features relative to other lizards (e.g., large eyes, less extensively ossified skulls, and amphicoelous and notochordal vertebrae). In contrast, peramorphosis has not been considered an important process in shaping their morphology. Here, we studied different sized specimens of Gekko gecko to document ontogenetic changes in cranial anatomy, especially near maturity. Comparison of this species with available descriptions of other geckos resulted in the identification of 14 cranial characteristics that are expressed more strongly with size increase. These characteristics become move evident in later stages of post-hatching development, especially near maturation, and are, therefore, attributed to peramorphosis (hyperossification). ACCTRAN and DELTRAN character optimizations were applied to these characters using a tree of 11 genera derived from a gekkotan molecular phylogeny. This analysis revealed that G. gecko expresses the majority of these putative peramorphic features near maturity, and that some of these features are also expressed in species closely related to G. gecko. The characters studied have the potential to be applied in future phylogenetic and taxonomic studies of this group of lizards. PMID- 26010649 TI - Supporting the Sexual Intimacy Needs of Patients in a Longer Stay Inpatient Forensic Setting. AB - PURPOSE: To explore perceptions of nurses and patients regarding sexual intimacy in a long-term mental health unit. DESIGN AND METHODS: Qualitative exploratory design including in-depth semi-structured individual interviews with 12 registered nurses and 10 long-term patients of a forensic mental health hospital. FINDINGS: The theme of supporting sexual intimacy was identified and described in this paper and included the following subthemes for nurses: It depends on the setting, need for guidelines and consent, and for patients-it depends on the setting; and need for support. PRACTICE IMPLICATIONS: The findings suggest that current guidelines regarding sexual intimacy in acute inpatient settings may not be appropriate in long-term facilities, with a need for guidelines to specifically address this setting. Furthermore, support for sexual intimacy needs of patients was identified as a strong need for patients and they believed not currently met. Nurses have an important role to play as part of their holistic approach to care and barriers to providing this aspect of care must be overcome to ensure patients' rights are respected. PMID- 26010650 TI - Durable dermatology life quality index improvements in patients on biologics associated with psoriasis areas and severity index: a longitudinal study. AB - BACKGROUND/OBJECTIVES: Patients with psoriasis experience higher rates of depression, anxiety and suicidal ideation than the general population. With effective treatment, there is evidence that with the initial decrease in the psoriasis area and severity index (PASI) score, patients' quality of life (QoL), measured by the dermatology life quality index (DLQI) improves. However, to date, there have been no studies demonstrating that patients' QoL remains improved. We investigated the association between the DLQI and PASI of patients with psoriasis on biologic agents for an extended period of time of up to 6.5 years. METHODS: The data for this longitudinal, retrospective study was collected from a large tertiary teaching hospital in South Australia. Data was collected from all patients with psoriasis who had been on biologic agents for 2 or more years (n = 54). RESULTS: PASI and DLQI were highly correlated over all time points (rho = 0.50), P < 0.001. DLQI scores significantly decreased by 0.8 (95% CI: 0.30, 1.26) units per year from 12 months to 6.5 years, P = 0.002. After 12 months, PASI scores declined by 0.19 (95% CI: 0.13, 0.52) units per year, P = 0.24. CONCLUSION: This study demonstrates that DLQI and PASI remain low after 12 months, and, in fact, both gradually decline further with time. Patients on biologic agents for prolonged periods maintained their improvement in QoL for up to 6.5 years. PMID- 26010651 TI - Regulation of integrins in platelets. AB - Blood platelets prevent bleeding after trauma by forming occlusive aggregates at sites of vascular injury. Platelet aggregation is mediated by the integrin heterodimer alphaIIbbeta3 and occurs when platelet agonists generated at the injury site convert alphaIIbbeta3 from its resting to its active conformation. Active alphaIIbbeta3 is then able to bind macromolecular ligands such as fibrinogen that crosslink adjacent platelets into hemostatic aggregates. Platelets circulate in a plasma milieu containing high concentrations of the principal alphaIIbbeta3 ligand fibrinogen. Thus, alphaIIbbeta3 activity is tightly regulated to prevent the spontaneous formation of platelet aggregates. alphaIIbbeta3 activity is regulated at least three levels. First, intramolecular interactions involving motifs located in the membrane-proximal stalk regions, transmembrane domains, and the membrane-proximal cytosolic tails of alphaIIb and beta3 maintain alphaIIbbeta3 in its inactive conformation. Transmembrane domain interactions appear particularly important because disrupting these interactions causes constitutive alphaIIbbeta3 activation. Second, the agonist-stimulated binding of the cytosolic proteins talin and kindlin-3 to the beta3 cytosolic tail rapidly causes alphaIIbbeta3 activation by disrupting the intramolecular interactions constraining alphaIIbbeta3 activity. Third, the strength of ligand binding to active alphaIIbbeta3 seems to be allosterically regulated. Thus, alphaIIbbeta3 exists in a minimum of three interconvertible states: an inactive (resting) state that does not interact with ligands and two active ligand binding states that differ in their affinity for fibrinogen and in the mechanical stability of fibrinogen complexes they form. PMID- 26010652 TI - Inexpensive production of near-native engineered stromas. AB - Although the self-assembly approach is an efficient method for the production of engineered physiological and pathological tissues, avoiding the use of exogenous materials, it nevertheless remains expensive and requires dexterity, which are features incompatible with large-scale production. We propose a modification to this technique to make easier the production of mesenchymal compartment, to reduce the cost and to improve the histological quality of the self-assembled tissues. The stroma produced by this novel approach allowed epithelial cell differentiation, resulting in a pseudostratified epithelium that shared several features with native tissues. The incorporation of endothelial cells in the reconstructed mesenchyme formed a three-dimensional capillary-like network, positive for CD31 and von Willebrand factor and surrounded by NG2 positive cells. It could limit self-contraction of the resulting tissue by recruiting alpha Smooth Muscle Actin positive cells. With this new technique, which is relatively inexpensive and easy to use in a research laboratory set-up, near-native stromas can now be produced with minimal handling time. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010653 TI - No association between the COMT Val158Met polymorphism and the long-term clinical response in obsessive-compulsive disorder in the Japanese population. AB - OBJECTIVE: Catechol-O-methyltransferase (COMT) is an enzyme that participates in the metabolic inactivation of dopamine and norepinephrine, and the Met allele of the COMT Val158Met polymorphism is associated with lower enzymatic activity. The purpose of the present study was to investigate whether this functional variant is associated with obsessive-compulsive disorder (OCD) and the clinical responses in OCD. METHODS: We first performed a case-control association study between the COMT Val158Met polymorphism and OCD (171 cases and 944 controls). Then, we examined the association between this polymorphism and the clinical responses in 91 of the OCD patients. RESULTS: Our study did not find a significant association between the Met allele and OCD risk or between the Met allele and clinical responses (p > 0.05). CONCLUSION: The present case-control/pharmacogenetic study did not provide clear evidence that the COMT Val158Met polymorphism is a predictor of OCD or of OCD patients' clinical responses. PMID- 26010654 TI - Optogenetic excitation of preBotzinger complex neurons potently drives inspiratory activity in vivo. AB - KEY POINTS: This study investigates the effects on ventilation of an excitatory stimulus delivered in a spatially and temporally precise manner to the inspiratory oscillator, the preBotzinger complex (preBotC). We used an adeno associated virus expressing channelrhodopsin driven by the synapsin promoter to target the region of the preBotC. Unilateral optogenetic stimulation of preBotC increased respiratory rate, minute ventilation and increased inspiratory modulated genioglossus muscle activity. Unilateral optogenetic stimulation of preBotC consistently entrained respiratory rate up to 180 breaths min(-1) both in presence of ongoing respiratory activity and in absence of inspiratory activity. Unilateral optogenetic stimulation of preBotC induced a strong phase-independent Type 0 respiratory reset, with a short delay in the response of 100 ms. We identified a refractory period of ~200 ms where unilateral preBotC optogenetic stimulation is not able to initiate the next respiratory event. ABSTRACT: Understanding the sites and mechanisms underlying respiratory rhythmogenesis is of fundamental interest in the field of respiratory neurophysiology. Previous studies demonstrated the necessary and sufficient role of preBotzinger complex (preBotC) in generating inspiratory rhythms in vitro and in vivo. However, the influence of timed activation of the preBotC network in vivo is as yet unknown given the experimental approaches previously used. By unilaterally infecting preBotC neurons using an adeno-associated virus expressing channelrhodopsin we photo-activated the network in order to assess how excitation delivered in a spatially and temporally precise manner to the inspiratory oscillator influences ongoing breathing rhythms and related muscular activity in urethane-anaesthetized rats. We hypothesized that if an excitatory drive is necessary for rhythmogenesis and burst initiation, photo-activation of preBotC not only will increase respiratory rate, but also entrain it over a wide range of frequencies with fast onset, and have little effect on ongoing respiratory rhythm if a stimulus is delivered during inspiration. Stimulation of preBotC neurons consistently increased respiratory rate and entrained respiration up to fourfold baseline conditions. Furthermore, brief pulses of photostimulation delivered at random phases between inspiratory events robustly and consistently induced phase independent (Type 0) respiratory reset and recruited inspiratory muscle activity at very short delays (~100 ms). A 200 ms refractory period following inspiration was also identified. These data provide strong evidence for a fine control of inspiratory activity in the preBotC and provide further evidence that the preBotC network constitutes the fundamental oscillator of inspiratory rhythms. PMID- 26010655 TI - Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation. AB - Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 * 10(-3) , as well as for autism, P = 2.7 * 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. PMID- 26010656 TI - Subretinal fluid in eyes with active ocular toxoplasmosis observed using spectral domain optical coherence tomography. AB - PURPOSE: To describe the clinical finding of subretinal fluid (SRF) in the posterior pole by spectral domain optical coherence tomography (SD-OCT) in eyes with active ocular toxoplasmosis (OT). DESIGN: Retrospective case series. PARTICIPANTS: Thirty-nine eyes from 38 patients with active OT [corrected].. METHODS: Eyes with active OT which underwent SD-OCT were reviewed. SRFs in the posterior pole were further analyzed. MAIN OUTCOME MEASURES: Presence of SRF; its accompanying features, e.g. retinal necrosis, cystoid macular edema (CME), choroidal neovascularization (CNV); and longitudinal changes of SRF, including maximum height and total volume before and after treatment. RESULTS: SRF presented in 45.5% (or 15/33) of eyes with typical active OT and in 51.3% (or 20/39) of eyes with active OT. The mean maximum height and total volume of SRF were 161.0 (range: 23-478) um and 0.47 (range: 0.005-4.12) mm3, respectively. For 12 eyes with SRF related to active retinal necrosis, SRF was observed with complete absorption after conventional anti-toxoplasmosis treatment. The mean duration for observation of SRF clearance was 33.8 (range: 7-84) days. The mean rate of SRF clearance was 0.0128 (range: 0.0002-0.0665) mm3/day. CONCLUSIONS: SRF (i.e., serous retinal detachment) is a common feature in patients with active OT when SD-OCT is performed. The majority of SRF was associated with retinal necrosis and reacted well to conventional therapy, regardless of total fluid volume. However, SRF accompanying with CME or CNV responded less favorably or remained refractory to conventional or combined intravitreal treatment, even when the SRF was small in size. PMID- 26010657 TI - Exposure of hairdressers to the main cosmetics used in hairdressing salons in France: A preliminary study. AB - In recent years, more attention has been given to chemical exposure in hairdressers. This increasing interest is largely due to the various respiratory and skin symptoms observed in hairdressers. According to these symptoms, hairdressers are in contact with various sources of exposure. Particularly in France, little information is available to assess professional exposure of hairdressers. In order to gather information to assess exposure in hairdressers, 11 hairdressing salons were visited. All the salons were located in Brest City (France). Preferentially, small hairdressing salons were visited. Observations were performed to obtain salon characteristics and to record workers' practices. Calculations revealed that in the worst-case scenario, dermal professional exposure reaches 14.68 and 13.67 mg/kg/day for hair coloring and highlighting mixtures, respectively. Inhalation exposure represents 14.2 and 18.1 mg/kg/day for hair coloring and highlighting mixtures, respectively. These exposure values represent baseline values for exposure of French hairdressers working in small hairdressing salons. PMID- 26010659 TI - Empirical evidence for source-sink populations: a review on occurrence, assessments and implications. AB - Assessing the role of local populations in a landscape context has become increasingly important in the fields of conservation biology and ecology. A growing number of studies attempt to determine the source-sink status of local populations. As the source-sink concept is commonly used for management decisions in nature conservation, accurate assessment approaches are crucial. Based on a systematic literature review of studies published between 2002 and 2013, we evaluated a priori predictions on methodological and biological factors that may influence the occurrence of source or sink populations. The review yielded 90 assessments from 73 publications that included qualitative and quantitative evidence for either source or sink population(s) for one or multiple species. Overall, sink populations tended to occur more often than source populations. Moreover, the occurrence of source or sink populations differed among taxonomic classes. Sinks were more often found than sources in mammals, while there was a non-significant trend for the opposite to be true for amphibians. Univariate and multivariate analyses showed that the occurrence of sources was positively related to connectivity of local populations. Our review furthermore highlights that more than 25 years after Pulliam's widely cited publication on 'sources, sinks, and population regulation', in-depth assessments of the source-sink status of populations based on combined consideration of demographic parameters such as fecundity, survival, emigration and immigration are still scarce. To increase our understanding of source-sink systems from ecological, evolutionary and conservation-related perspectives, we recommend that forthcoming studies on source-sink dynamics should pay more attention to the study design (i.e. connectivity of study populations) and that the assessment of the source-sink status of local populations is based on lambda values calculated from demographic rates. PMID- 26010658 TI - A genome-wide copy number variant study of suicidal behavior. AB - Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior. PMID- 26010660 TI - Facile Fabrication of Near-Infrared-Resonant and Magnetic Resonance Imaging Capable Nanomediators for Photothermal Therapy. AB - Although many techniques exist for fabricating near-infrared (NIR)-resonant and magnetic resonance imaging (MRI)-capable nanomediators for photothermal cancer therapy, preparing them in an efficient and scalable process remains a significant challenge. In this report, we exploit one-step siloxane chemistry to facilely conjugate NIR-absorbing satellites onto a well-developed polysiloxane containing polymer-coated iron oxide nanoparticle (IONP) core to generate dual functional core-satellite nanomediators for photothermal therapy. An advantage of this nanocomposite design is the variety of potential satellites that can be simply attached to impart NIR resonance, which we demonstrate using NIR-resonant gold sulfide nanoparticles (Au2SNPs) and the NIR dye IR820 as two example satellites. The core-satellite nanomediators are fully characterized by using absorption spectra, dynamic light scattering, zeta potential measurements, and transmission electron microscopy. The enhanced photothermal effect under the irradiation of NIR laser light is identified through in vitro solutions and in vivo mice studies. The MRI capabilities as contrast agents are demonstrated in mice. Our data suggest that polysiloxane-containing polymer-coated IONPs can be used as a versatile platform to build such dual functional nanomediators for translatable, MRI-guided photothermal cancer therapy. PMID- 26010661 TI - Interaction of beta(3) /beta(2) -peptides, consisting of Val-Ala-Leu segments, with POPC giant unilamellar vesicles (GUVs) and white blood cancer cells (U937)- a new type of cell-penetrating peptides, and a surprising chain-length dependence of their vesicle- and cell-lysing activity. AB - Many years ago, beta(2) /beta(3) -peptides, consisting of alternatively arranged beta(2) - and beta(3) h-amino-acid residues, have been found to undergo folding to a unique type of helix, the 10/12-helix, and to exhibit non-polar, lipophilic properties (Helv. Chim. Acta 1997, 80, 2033). We have now synthesized such 'mixed' hexa-, nona-, dodeca-, and octadecapeptides, consisting of Val-Ala-Leu triads, with N-terminal fluorescein (FAM) labels, i.e., 1-4, and studied their interactions with POPC (=1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) giant unilamellar vesicles (GUVs) and with human white blood cancer cells U937. The methods used were microfluidic technology, fluorescence correlation spectroscopy (FCS), a flow-cytometry assay, a membrane-toxicity assay with the dehydrogenase G6PDH as enzymatic reporter, and visual microscopy observations. All beta(3) /beta(2) -peptide derivatives penetrate the GUVs and/or the cells. As shown with the isomeric beta(3) /beta(2) -, beta(3) -, and beta(2) -nonamers, 2, 5, and 6, respectively, the derivatives 5 and 6 consisting exclusively of beta(3) - or beta(2) -amino-acid residues, respectively, interact neither with the vesicles nor with the cells. Depending on the method of investigation and on the pretreatment of the cells, the beta(3) /beta(2) -nonamer and/or the beta(3) /beta(2) -dodecamer derivative, 2 and/or 3, respectively, cause a surprising disintegration or lysis of the GUVs and cells, comparable with the action of tensides, viral fusion peptides, and host-defense antimicrobial peptides. Possible sources of the chain-length-dependent destructive potential of the beta(3) /beta(2) -nona- and beta(3) /beta(2) -dodecapeptide derivatives, and a possible relationship with the phosphate-to-phosphate and hydrocarbon thicknesses of GUVs, and eukaryotic cells are discussed. Further investigations with other types of GUVs and of eukaryotic or prokaryotic cells will be necessary to elucidate the mechanism(s) of interaction of 'mixed' beta(3) /beta(2) -peptides with membranes and to evaluate possible biomedical applications. PMID- 26010662 TI - Cumin (Cuminum cyminum L.) from traditional uses to potential biomedical applications. AB - Cumin (Cuminum cyminum L.) is a small annual and herbaceous plant belonging to the Apiaceae family. It is a multipurpose plant species cultivated in the Middle East, India, China, and several Mediterranean countries, including Tunisia. Its fruit, known as cumin seed, is most widely used for culinary and medicinal purposes. It is generally used as a food additive, popular spice, and flavoring agent in many cuisines. Cumin has also been widely used in traditional medicine to treat a variety of diseases, including hypolipidemia, cancer, and diabetes. The literature presents ample evidence for the biological and biomedical activities of cumin, which have generally been ascribed to its content and action of its active constituents, such as terpens, phenols, and flavonoids. The present paper provides an overview of phytochemical profile, biological activities, and ethnomedical and pharmacological uses of Cumin. PMID- 26010663 TI - The peptaibiotics database--a comprehensive online resource. AB - In this work, we present the 'Peptaibiotics Database' (PDB), a comprehensive online resource, which intends to cover all Aib-containing non-ribosomal fungal peptides currently described in scientific literature. This database shall extend and update the recently published 'Comprehensive Peptaibiotics Database' and currently consists of 1,297 peptaibiotic sequences. In a literature survey, a total of 235 peptaibiotic sequences published between January 2013 and June 2014 have been compiled, and added to the list of 1,062 peptides in the recently published 'Comprehensive Peptaibiotics Database'. The presented database is intended as a public resource freely accessible to the scientific community at peptaibiotics-database.boku.ac.at. The search options of the previously published repository and the presentation of sequence motif searches have been extended significantly. All of the available search options can be combined to create complex database queries. As a public repository, the presented database enables the easy upload of new peptaibiotic sequences or the correction of existing informations. In addition, an administrative interface for maintenance of the content of the database has been implemented, and the design of the database can be easily extended to store additional information to accommodate future needs of the 'peptaibiomics community'. PMID- 26010664 TI - Essential-oil composition and chemical variability of Senecio vulgaris L. from Corsica. AB - The chemical composition of the essential oils isolated from the aerial parts of Senecio vulgaris plants collected in 30 Corsican localities was characterized using GC-FID and GC/MS analyses. Altogether, 54 components, which accounted for 95.2% of the total oil composition, were identified in the 30 essential-oil samples. The main compounds were alpha-humulene (1; 57.3%), (E)-beta caryophyllene (2; 5.6%), terpinolene (3; 5.3%), ar-curcumene (4; 4.3%), and geranyl linalool (5; 3.4%). The chemical composition of the essential oils obtained from separate organs and during the complete vegetative cycle of the plants were also studied, to gain more knowledge about the plant ecology. The production of monoterpene hydrocarbons, especially terpinolene, seems to be implicated in the plant-flowering process and, indirectly, in the dispersal of this weed species. Comparison of the present results with the literature highlighted the originality of the Corsican S. vulgaris essential oils and indicated that alpha-humulene might be used as taxonomical marker for the future classification of the Senecio genus. A study of the chemical variability of the 30 S. vulgaris essential oils using statistical analysis allowed the discrimination of two main clusters according to the soil nature of the sample locations. These results confirmed that there is a relation between the soil nature, the chemical composition of the essential oils, and morphological plant characteristics. Moreover, they are of interest for commercial producers of essential oil in selecting the most appropriate plants. PMID- 26010665 TI - Distribution and variability of n-alkanes in epicuticular waxes of sedum species from the central Balkan Peninsula: chemotaxonomic importance. AB - For the first time, the n-alkane distribution and variability of the epicuticular waxes within 22 Sedum taxa was reported with focus on the chemotaxonomy of native Sedum representatives from the central Balkan Peninsula, compared to their relations with four other species of the Crassulaceae family. By GC/MS and GC-FID identification and quantification, it was established that n-alkanes C27 , C29 , C31 , C33 , and C35 were the dominant constituents of the examined epicuticular wax samples. Applying multivariate statistical analyses including agglomerative hierarchical clustering (AHC) and principal component analysis (PCA), the relation according to the n-alkane composition between the examined samples was established. It was shown that the n-alkane variability of the central Balkan Sedum species was considerable and that n-alkanes might not be very reliable taxonomic markers for these species. PMID- 26010666 TI - Volatile constituents of the aerial parts of Pulicaria sicula (L.) Moris growing wild in Sicily: chemotaxonomic volatile markers of the genus Pulicaria Gaertn. AB - The chemical composition of the essential oil isolated from the aerial parts of Pulicaria sicula (L.) Moris was characterized by GC-FID and GC/MS analyses. The oil was particularly rich in oxygenated terpenoids. Among the oxygenated monoterpenes (content of 44.5%), the most abundant were borneol (23.7%), bornyl acetate (6.5%), and isothymol isobutyrate (6.2%). Caryophyllene oxide (10.2%), caryophylladienol I (4.3%), and caryophylla-3,8(13)-dien-5beta-ol (4.4%) were identified as the main constituents among the oxygenated sesquiterpenes. Furthermore, a complete literature review on the composition of the essential oils of all the Pulicaria taxa studied so far was performed and a principal component analysis (PCA) was carried out. PMID- 26010667 TI - Chemodiversity in the fingerprint analysis of volatile organic compounds (VOCs) of 35 old and 7 modern apple cultivars determined by proton-transfer-reaction mass spectrometry (PTR-MS) in two different seasons. AB - Volatile organic compounds (VOCs) are chemical species that play an important role in determining the characteristic aroma and flavor of fruits. Apple (Malus * domestica Borkh.) cultivars differ in their aroma and composition of VOCs. To determine varietal differences in the aroma profiles, VOCs emitted by 7 modern and 35 old apple cultivars were analyzed using Proton Transfer Reaction Mass Spectrometry (PTR-MS). PTR-MS is a rapid, reproducible, and non-destructive spectrometric technique for VOC analysis of single fruits, developed for direct injection analysis. In the present study, we analyzed the differences in the emission of VOCs from single fruits at harvest and after a storage period of 60+/ 10 days, followed by 3 d of shelf life. Our results show that VOC profile differences among apple cultivars were more pronounced after storage than at harvest. Furthermore, chemodiversity was higher in old cultivars compared to modern cultivars, probably due to their greater genetic variability. Our data highlight the importance of storage and shelf life are crucial for the development of the typical aroma and flavor of several apple cultivars. The validity of the method is demonstrated by comparison of two different harvest years. PMID- 26010668 TI - Synthesis and in vitro antiviral activities of [(dihydrofuran-2-yl)oxy]methyl phosphonate nucleosides with 2-substituted adenine as base. AB - The synthesis of [(2',5'-dihydrofuran-2-yl)oxy]methyl-phosphonate nucleosides with a 2-substituted adenine base moiety starting from 2-deoxy-3,5-bis-O-(4 methylbenzoyl)-alpha-L-ribofuranosyl chloride and 2,6-dichloropurine is described. The key step is the regiospecific and stereoselective introduction of a phosphonate synthon at C(2) of the furan ring. None of the synthesized compounds showed significant in vitro activity against HIV, BVDV, and HBV. PMID- 26010669 TI - Chemical characterization and insecticidal properties of essential oils from different wild populations of Mentha suaveolens subsp. timija (Briq.) Harley from Morocco. AB - The present study is the first investigation of the volatile-oil variability and insecticidal properties of the endemic Moroccan mint Mentha suaveolens subsp. timija (mint timija). The yield of essential oils (EOs) obtained from different wild mint timija populations ranged from 0.20+/-0.02 to 1.17+/-0.25% (v/w). GC/MS Analysis revealed the presence of 44 oil constituents, comprising 97.3-99.9% of the total oil compositions. The main constituents were found to be menthone (1.2 62.6%), pulegone (0.8-26.6%), cis-piperitone epoxide (2.9-25.5%), piperitone (0.3 35.5%), trans-piperitone epoxide (8.1-15.7%), piperitenone (0.2-9.6%), piperitenone oxide (0.5-28.6%), (E)-caryophyllene (1.5-11.0%), germacrene D (1.0 15.7%), isomenthone (0.3-7.7%), and borneol (0.2-7.3%). Hierarchical-cluster analysis allowed the classification of the EOs of the different mint timija populations into four main groups according to the contents of their major components. This variability within the species showed to be linked to the altitude variation of the mint timija growing sites. The results of the insecticidal tests showed that all samples exhibited interesting activity against adults of Tribolium castaneum, but with different degrees. The highest toxicity was observed for the EOs belonging to Group IV, which were rich in menthone and pulegone, with LC50 and LC90 values of 19.0-23.4 and 54.9-58.0 MUl/l air in the fumigation assay and LC50 and LC90 values of 0.17-0.18 and 0.40-0.52 MUl/cm(2) in the contact assay. PMID- 26010670 TI - Contact toxicity and repellency of the essential oil from Mentha haplocalyx Briq. against Lasioderma serricorne. AB - The chemical composition of the essential oil obtained by hydrodistillation from the aerial parts of Mentha haplocalyx was investigated by GC-FID and GC/MS analyses. In sum, 23 components, representing 92.88% of the total oil composition, were identified, and the main compounds were found to be menthol (59.71%), menthyl acetate (7.83%), limonene (6.98%), and menthone (4.44%). By bioassay-guided fractionation (contact toxicity), three compounds were obtained from the essential oil and identified as menthol, menthyl acetate, and limonene. The essential oil and the three isolated compounds exhibited potent contact toxicity against Lasioderma serricorne adults, with LD50 values of 16.5, 7.91, 5.96, and 13.7 MUg/adult, respectively. Moreover, the oil and its isolated compounds also exhibited strong repellency against L. serricorne adults. At the lower concentrations tested and at 2 h after exposure, menthol showed even significantly stronger repellency than the positive control DEET. The study revealed that the bioactivity properties of the essential oil can be attributed to the synergistic effects of its diverse major and minor components, which indicates that the M. haplocalyx oil and its isolated compounds have potential for the development as natural insecticides and/or repellents to control insects in stored grains and traditional Chinese medicinal materials. PMID- 26010671 TI - Quality of care and short- and long-term outcomes of laryngeal cancer care in the elderly. AB - OBJECTIVES/HYPOTHESIS: To examine associations between quality of care, short- and long-term treatment-related outcomes, and costs in elderly patients treated for laryngeal squamous cell cancer (SCCA). STUDY DESIGN: Retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data. METHODS: We evaluated longitudinal data from 2,370 patients diagnosed with laryngeal SCCA from 2004 to 2007 using cross-tabulations, multivariate regression, and survival analysis. Using quality indicators derived from guidelines for recommended care and performance measures, an overall summary measure of quality was calculated incorporating summary quality measures for diagnosis, initial treatment, performance, surveillance, treatment for recurrence, and end-of-life care. RESULTS: Higher-quality care was associated with a lower likelihood of long-term weight loss (odds ratio [OR] = 0.6 [0.5-0.8]), stricture (OR = 0.5 [0.3-0.8]), gastrostomy dependence (OR = 0.5 [0.4-0.7]), airway obstruction (OR = 0.7 [0.6 0.9]), tracheostomy (OR = 0.5 [0.3-0.7]), and pneumonia (OR = 0.7 [0.5-0.9]), but had no impact on the likelihood of dysphagia. Higher-quality care was associated with lower risk of death in patients with dysphagia (hazard ratio [HR] = 0.7 [0.6 0.8]), weight loss (HR = 0.8 [0.6-0.9]), airway obstruction (HR = 0.7 [0.6-0.8]), tracheostomy (HR = 0.7 [0.5-0.9]), and pneumonia (HR = 0.8 [0.6-0.9]), but was not associated with survival differences in patients with gastrostomy dependence or stricture. Costs associated with dysphagia, weight loss, stricture, airway obstruction, and pneumonia were lower for patients receiving higher-quality care. CONCLUSIONS: Higher-quality larynx cancer care was associated with a reduced incidence of late airway and swallowing impairment after laryngeal SCCA treatment in elderly patients, with improved survival and reduced costs. These data suggest that greater attention to evidence-based practices associated with quality indicators may lead to improved functional outcomes in the elderly. LEVEL OF EVIDENCE: 2c. PMID- 26010672 TI - Global hypomethylation in myeloma is associated with poor prognosis. PMID- 26010673 TI - Different types of errors in saccadic task are sensitive to either time of day or chronic sleep restriction. AB - Circadian rhythms and restricted sleep length affect cognitive functions and, consequently, the performance of day to day activities. To date, no more than a few studies have explored the consequences of these factors on oculomotor behaviour. We have implemented a spatial cuing paradigm in an eye tracking experiment conducted four times of the day after one week of rested wakefulness and after one week of chronic partial sleep restriction. Our aim was to verify whether these conditions affect the number of a variety of saccadic task errors. Interestingly, we found that failures in response selection, i.e. premature responses and direction errors, were prone to time of day variations, whereas failures in response execution, i.e. omissions and commissions, were considerably affected by sleep deprivation. The former can be linked to the cue facilitation mechanism, while the latter to wake state instability and the diminished ability of top-down inhibition. Together, these results may be interpreted in terms of distinctive sensitivity of orienting and alerting systems to fatigue. Saccadic eye movements proved to be a novel and effective measure with which to study the susceptibility of attentional systems to time factors, thus, this approach is recommended for future research. PMID- 26010674 TI - Computational Study of Acidic and Basic Functionalized Crystalline Silica Surfaces as a Model for Biomaterial Interfaces. AB - In silico modeling of acidic (CH2COOH) or basic (CH2NH2) functionalized silica surfaces has been carried out by means of a density functional approach based on a gradient-corrected functional to provide insight into the characterization of experimentally functionalized surfaces via a plasma method. Hydroxylated surfaces of crystalline cristobalite (sporting 4.8 OH/nm(2)) mimic an amorphous silica interface as unsubstituted material. To functionalize the silica surface we transformed the surface Si-OH groups into Si-CH2COOH and Si-CH2NH2 moieties to represent acidic/basic chemical character for the substitution. Structures, energetics, electronic, and vibrational properties were computed and compared as a function of the increasing loading of the functional groups (from 1 to 4 per surface unit cell). Classical molecular dynamics simulations of selected cases have been performed through a Reax-FF reactive force field to assess the mobility of the surface added chains. Both DFT and force field calculations identify the CH2NH2 moderate surface loading (1 group per unit cell) as the most stable functionalization, at variance with the case of the CH2COOH group, where higher loadings are preferred (2 groups per unit cell). The vibrational fingerprints of the surface functionalities, which are the nu(C?O) stretching and delta(NH2) bending modes for acidic/basic cases, have been characterized as a function of substitution percentage in order to guide the assignment of the experimental data. The final results highlighted the different behavior of the two types of functionalization. On the one hand, the frequency associated with the nu(C?O) mode shifts to lower wavenumbers as a function of the H-bond strength between the surface functionalities (both COOH and SiOH groups), and on the other hand, the delta(NH2) frequency shift seems to be caused by a subtle balance between the H bond donor and acceptor abilities of the NH2 moiety. Both sets of data are in general agreement with experimental measurements on the corresponding silica functionalized materials and provide finer details for a deeper interpretation of experimental spectra. PMID- 26010675 TI - Frequency Extension to the THz Range in the High Pressure ESR System and Its Application to the Shastry-Sutherland Model Compound SrCu2(BO3)2. AB - We have made a survey of ceramics for the inner parts of the transmission-type pressure cell to achieve the high pressure and the high transmission in the THz range. By using the optimal combination of ZrO2-based ceramic and Al2O3 ceramic, we have succeeded in obtaining a pressure up to 1.5 GPa and a frequency region up to 700 GHz simultaneously. We show the high-pressure ESR results of the Shastry Sutherland compound SrCu2(BO3)2 as an application. We observed the direct ESR transition modes between the singlet ground state and the triplet excited states up to a pressure of 1.51 GPa successfully, and obtained the precise pressure dependence of the gap energy. The gap energy is directly proved to be suppressed by the pressure. Moreover, we found that the system approaches the quantum critical point with pressure by comparing the obtained data with the theory. This result also shows the usefulness of high-pressure ESR measurement in the THz region to study quantum spin systems. PMID- 26010676 TI - Effects of bisphenol A on key enzymes in cellular respiration of soybean seedling roots. AB - The environmental endocrine disrupter bisphenol A (BPA) is ubiquitous in the environment, with potential toxic effects on plants. Previous studies have found a significant effect of BPA on levels of mineral nutrients in plant roots, but the underlying mechanism remains unknown. To determine how BPA influences root mineral nutrients, the effects of BPA (1.5 mg L(-1) , 3.0 mg L(-1) , 6.0 mg L(-1) , 12.0 mg L(-1) , 24.0 mg L(-1) , 48.0 mg L(-1) , and 96.0 mg L(-1) ) on activities of critical respiratory enzymes (hexokinase, phosphofructokinase, pyruvate kinase, isocitrate dehydrogenase, and cytochrome c oxidase) were investigated in soybean seedling roots. After BPA exposure for 7 d, the low concentrations of BPA increased the activities of critical respiratory enzymes in roots, whereas opposite effects were observed in roots exposed to high concentrations of BPA, and the inhibitory effect was greater for higher BPA concentrations. In addition, evident morphological anomalies and decreases in root lengths and volumes were induced by high concentrations of BPA. Following withdrawal of BPA exposure after 7 d, the activities of respiratory enzymes and visible signs of toxicity recovered, and the extent of recovery depended on the type of enzyme and the BPA concentration. Furthermore, correlation analysis showed that the disturbance by BPA to activities of respiratory enzymes, which led to interference in the energy metabolism in roots, might be an effect mechanism of BPA on mineral element accumulation in plant roots. PMID- 26010677 TI - Open-Flask Synthesis of Amine-Boranes via Tandem Amine-Ammonium Salt Equilibration-Metathesis. AB - An amine-ammonium salt equilibration-metathesis sequence provides high-purity amine-boranes in excellent yields from sodium borohydride in refluxing reagent grade tetrahydrofuran in an open flask. PMID- 26010678 TI - Integrated analysis of safety data from 12 clinical interventional studies of plasma- and albumin-free recombinant factor VIII (rAHF-PFM) in haemophilia A. AB - INTRODUCTION: Antihaemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM) is a human recombinant full-length factor VIII (FVIII) approved worldwide for the control and prevention of bleeding episodes, routine prophylaxis and perioperative management in adults and children with haemophilia A. AIM: To evaluate rAHF-PFM safety [including adverse events (AEs) and inhibitor incidence] from 12 interventional studies spanning >10 years. METHODS: The study population comprised 418 treated patients (median age = 18.7 years) with FVIII levels <=2% of normal, including 55 previously untreated or minimally treated patients (PUPs/MTPs) from all rAHF-PFM phase I-IV studies, excluding observational safety studies. RESULTS: Most AEs were non-serious; only 93 AEs in 45 patients (10.8%) were related to rAHF-PFM. A total of 106 serious AEs (SAEs) occurred in 69 patients (16.5%); the most common were FVIII inhibitors (4.1%), device-related infection (1.0%) and pyrexia (0.7%). The 17 SAEs considered related to treatment consisted of FVIII inhibitors in 1 previously treated patient (PTP) (<=5 Bethesda Units [BU]) and 16 PUPs/MTPs [7/55 high titre (>5 BU), 12.7%; 9/55 low titre (<=5 BU), 16.4%]. Overall, the incidence of FVIII inhibitors was 0.36% in PTPs and 29.1% in PUPs/MTPs. No deaths or cases of hypersensitivity related to rAHF-PFM occurred. CONCLUSION: This integrated safety analysis evaluated the safety and tolerability of rAHF-PFM in children and adults with moderately severe or severe haemophilia A in all interventional studies completed to date. It was important to review consolidated evidence as some AEs are rare. There were no new safety signals in a wide variety of clinical settings. PMID- 26010679 TI - Environmental assessment reveals the presence of MLB-1 human astrovirus in Uruguay. AB - AIMS: The aim of this study was to investigate the presence of the recently identified human astrovirus (HAstV) and to increase the knowledge of the molecular epidemiology of classical HAstV detected in Uruguay. METHODS AND RESULTS: Recently identified and classical HAstV genotypes were investigated by RT-PCR targeting the ORF1b and ORF2 genome regions in 20 samples obtained between September 2011 and April 2013 in two cities of the eastern region of Uruguay. Four of 20 samples (20%) were identified as MLB-1 genotype and it was found a new MLB-1 classification through the segregation of the worldwide reported MLB-1 strains in two genetic lineages proposed and named: MLB-1a and MLB-1b. Fourteen (70%) samples were positive for classical HAstV and 12 of them were successfully sequenced and genotyped as: HAstV-1 (n = 10), HAstV-2 and HAstV-5 (one sample each). CONCLUSION: These results constitute the first report in the Latin American region concerning the molecular detection and characterization of MLB-1 HAstV strains in environmental samples. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the benefits of an environmental surveillance to study emerging enteric viruses circulating in human societies. PMID- 26010681 TI - MRS: a noninvasive window into cardiac metabolism. AB - A well-functioning heart requires a constant supply of a balanced mixture of nutrients to be used for the production of adequate amounts of adenosine triphosphate, which is the main energy source for most cellular functions. Defects in cardiac energy metabolism are linked to several myocardial disorders. MRS can be used to study in vivo changes in cardiac metabolism noninvasively. MR techniques allow repeated measurements, so that disease progression and the response to treatment or to a lifestyle intervention can be monitored. It has also been shown that MRS can predict clinical heart failure and death. This article focuses on in vivo MRS to assess cardiac metabolism in humans and experimental animals, as experimental animals are often used to investigate the mechanisms underlying the development of metabolic diseases. Various MR techniques, such as cardiac (31) P-MRS, (1) H-MRS, hyperpolarized (13) C-MRS and Dixon MRI, are described. A short overview of current and emerging applications is given. Cardiac MRS is a promising technique for the investigation of the relationship between cardiac metabolism and cardiac disease. However, further optimization of scan time and signal-to-noise ratio is required before broad clinical application. In this respect, the ongoing development of advanced shimming algorithms, radiofrequency pulses, pulse sequences, (multichannel) detection coils, the use of hyperpolarized nuclei and scanning at higher magnetic field strengths offer future perspective for clinical applications of MRS. PMID- 26010680 TI - MMPs and angiogenesis affect the metastatic potential of a human vulvar leiomyosarcoma cell line. AB - Gynaecological leiomyosarcoma (gLMS) represent a heterogeneous group of soft tissue sarcoma, characterized by rare incidence, high aggressiveness and propensity to infiltrate secondary organs, poor prognosis and lethality, because of the lack of biological mechanisms that underlying their progression and effective pharmaceutical treatments. This study was focused on some of the aspects of progression and dissemination of a subtype of gLMS namely vulvar LMS (vLMS). We therefore used a vulvar LMS-derived cell line namely SK-LMS-1, coupled with in vitro and in vivo assays. We observed that SK-LMS-1 cells have a strong invasive capacity in vitro, through the activity of matrix metalloproteinases 2 and 9, while in vivo these cells induce a strong angiogenic response and disseminate to the chick embryo liver. Therefore, we postulate that metalloproteinases are involved in the spreading behaviour of SK-LMS-1. Further investigations are necessary to better understand the molecular and cellular machinery involved in the progression of this malignancy. PMID- 26010683 TI - MYC protein expression is associated with poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system. AB - MYC and BCL2 gene translocations and protein expression have recently demonstrated to be of prognostic significance in systemic diffuse large B-cell lymphoma (DLBCL). However, their role in primary central nervous system DLBCL (CNS-DLBCL) prognosis has been scarcely analyzed. We studied the immunophenotype, the status of the MYC, BCL2, and BCL6 genes and the clinical features of a series of 42 CNS-DLBCL and evaluated their prognostic significance. We found high MYC protein expression in 43% of cases, and this was associated with lower overall survival (OS). Cases with concurrent expression of MYC and BCL2 showed a lower OS, although the difference did not reach statistical significance. Translocations involving the MYC or BCL2 genes were not detected. The BCL6 gene was frequently translocated, but was unrelated to survival. We conclude that MYC protein expression detected by immunohistochemistry identifies a CNS-DLBCL subset with worse prognosis and may contribute to a more accurate risk stratification of CNS-DLBCL patients. PMID- 26010684 TI - Histoplasmosis and skin lesions in HIV: a safe and accurate diagnosis. AB - Human histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. This infection can run asymptomatic or be life-threatening, depending fundamentally on the host's immune status. Immunocompromised patients can present disseminated disease to the skin, making the biopsy an accessible approach. The current diagnosis gold standard is fungal culture which takes several days or weeks to grow and must be handled in a biosafe laboratory which is avoided if we use the technique here described. We propose the use of molecular biology for diagnosis confirmation, considering it can shorten diagnosis lapse, has good specificity and sensitivity and reduces the risk of infection for the medical and laboratory personnel. Seven paraffin-embedded skin biopsy samples were included from patients with confirmed HIV and histoplasmosis diagnosis. Total DNA was isolated and molecular typing of H. capsulatum var. capsulatum. All samples were positive. This is a safe and accurate method for skin histoplasmosis diagnosis. PMID- 26010682 TI - Critical Appraisal of Bivalirudin versus Heparin for Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Trials. AB - Percutaneous coronary intervention with bivalirudin plus bail-out glycoprotein IIb/IIIa inhibitors has been shown to be as effective as unfractionated heparin plus routine glycoprotein IIb/IIIa inhibitors in preventing cardiac ischemic events, but with a lower bleeding risk. It is unknown whether bivalirudin would have the same beneficial effects if compared with heparin when the use of glycoprotein IIb/IIIa inhibitors was similar between treatment arms. We searched the MEDLINE, Web of Science, and Cochrane databases from inception until March 2015 for randomized trials that compared bivalirudin to heparin in patients undergoing percutaneous coronary intervention. We required that the intended use of glycoprotein IIb/IIIa inhibitors was similar between the study groups. Summary estimates were principally constructed by the Peto method. Fifteen trials met our inclusion criteria, which yielded 25,824 patients. Bivalirudin versus heparin was associated with an increased hazard of stent thrombosis (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.15-1.92, P = .002, I2 = 16.9%), with a similar hazard of myocardial infarction (OR 1.09, 95% CI 0.98-1.22, P = .11, I2 = 35.8%), all-cause mortality (OR 0.88, 95% CI 0.72-1.08, P = .21, I2 = 31.5%) and major adverse cardiac events (OR 1.04, 95% CI 0.94-1.14, P = .46, I2 = 53.9%). Bivalirudin was associated with a reduced hazard of major bleeding (OR 0.80, 95% CI 0.70-0.92, P = .001, I2 = 63.5%). The dose of heparin in the control arm modified this association; when the dose of unfractionated heparin in the control arm was >= 100 units/kg, bivalirudin was associated with a reduction in major bleeding (OR 0.55, 95% CI 0.45-0.68, P < .0001), but when the dose of unfractionated heparin was <= 75 units/kg, bivalirudin was not associated with reduction in bleeding (OR 1.09, 95% CI 0.91-1.31, P = .36). Among patients undergoing PCI, bivalirudin was associated with an increased hazard of stent thrombosis. Bivalirudin may be associated with a reduced hazard of major bleeding; however, this benefit was no longer apparent when compared with a dose of unfractionated heparin <= 75 units/kg. PMID- 26010685 TI - Glibenclamide Improves Survival and Neurologic Outcome After Cardiac Arrest in Rats. AB - OBJECTIVES: Glibenclamide confers neuroprotection in animal models as well as in retrospective clinical studies. This study determines whether glibenclamide improves outcome after cardiac arrest in rats. DESIGN: Prospective randomized laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague Dawley rats (n = 126). INTERVENTIONS: Rats successfully resuscitated from 8 minute asphyxial cardiac arrest were randomized to glibenclamide or vehicle group. Rats in the glibenclamide group were intraperitoneally administered glibenclamide with a loading dose of 10 MUg/kg at 10 minutes and a maintenance dose of 1.2 MUg at 6, 12, 18, and 24 hours after return of spontaneous circulation, whereas rats in the vehicle group received equivalent volume of vehicle solution. MEASUREMENTS AND MAIN RESULTS: Survival was recorded every day, and neurologic deficit scores were assessed at 24, 48, and 72 hours and 7 days after return of spontaneous circulation (n = 22 in each group). Results showed that glibenclamide treatment increased 7-day survival rate, reduced neurologic deficit scores, and prevented neuronal loss in the hippocampal cornu ammonis 1 region. To investigate the neuroprotective effects of glibenclamide in acute phase, we observed neuronal injury at 24 hours after return of spontaneous circulation and found that glibenclamide significantly decreased the rate of neuronal necrosis and apoptosis. In addition, glibenclamide reduced the messenger RNA expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in the cortex after return of spontaneous circulation. Furthermore, the sulfonylurea receptor 1 and transient receptor potential M4 heteromers, the putative therapeutic targets of glibenclamide, were up-regulated after cardiac arrest and cardiopulmonary resuscitation, indicating that they might be involved in neuroprotective effect of glibenclamide. CONCLUSIONS: Glibenclamide treatment substantially improved survival and neurologic outcome throughout a 7-day period after return of spontaneous circulation. The salutary effects of glibenclamide were associated with suppression of neuronal necrosis and apoptosis, as well as inflammation in the brain. PMID- 26010688 TI - Anticholinergic Medication Use and Transition to Delirium in Critically Ill Patients: A Prospective Cohort Study. AB - OBJECTIVE: Although cholinergic deficiency is presumed to increase delirium risk and use of medication with anticholinergic properties in the ICU is frequent, the relationship between anticholinergic medication use and delirium in this setting remains unclear. We investigated whether exposure to medication with anticholinergic properties increases the probability of transitioning to delirium in critically ill adults and whether this relationship is affected by age or the presence of acute systemic inflammation. DESIGN: Prospective cohort study. SETTING: A 32-bed medical-surgical ICU at an academic medical center. PATIENTS: Critically ill adults admitted to the ICU for more than 24 hours without an acute neurological disorder or another condition that would hamper delirium assessment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily anticholinergic burden was calculated for each patient based on the sum of the Anticholinergic Drug Scale score for each medication administered. Daily mental status was classified as "coma," "delirium," or an "awake without delirium" state. The primary outcome, the daily transition from an "awake without delirium" state to "delirium," was analyzed using a first-order Markov model that adjusted for eight covariables. A total of 1,112 patients were evaluated over 9,867 ICU days. The daily median summed Anticholinergic Drug Scale score was 2 (interquartile range, 1-3). The transition from being in an "awake without delirium" state to "delirium" occurred on 562 of ICU days (6%). After correcting for confounding, a one-unit increase in the Anticholinergic Drug Scale score resulted in a nonsignificant increase in the probability of delirium occurring the next day (odds ratio, 1.05; 95% CI, 0.99 1.10). Neither age nor the presence of acute systemic inflammation modified this relationship. CONCLUSIONS: Exposure to medication with anticholinergic properties, as defined by the Anticholinergic Drug Scale, does not increase the probability of delirium onset in patients who are awake and not delirious in the ICU. PMID- 26010686 TI - Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats. AB - OBJECTIVES: Progranulin has been reported to have neuroprotective actions in cultured neurons. This study investigated the effect of recombinant rat progranulin on early brain injury after subarachnoid hemorrhage. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory. SUBJECTS: Two hundred thirty adult male Sprague-Dawley rats weighing 280-320 g. INTERVENTIONS: Subarachnoid hemorrhage was induced in rats by endovascular perforation. Rat recombinant progranulin (1 and 3 ng) was administrated intracerebroventricularly at 1.5 hours after subarachnoid hemorrhage. Progranulin small interfering RNA was administrated by intracerebroventricularly at 1 day before subarachnoid hemorrhage induction. Subarachnoid hemorrhage grade, neurologic score, and brain water content were measured at 24 and 72 hours after subarachnoid hemorrhage. Neural apoptosis was evaluated by double immunofluorescence staining using terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick-end labeling and neuronal nuclei. For mechanistic study, the expression of progranulin, phosphorylated Akt, Akt, p-Erk, Erk, Bcl-2, and cleaved caspase-3 were analyzed by Western blot at 24 hours after subarachnoid hemorrhage. siRNA for sortilin 1 (a progranulin receptor) was used to intervene the downstream pathway. MEASUREMENTS AND MAIN RESULTS: The expression of progranulin decreased and reached the lowest point at 24 hours after subarachnoid hemorrhage. Administration of rat recombinant progranulin decreased brain water content and improved neurologic functions at both 24 and 72 hours after subarachnoid hemorrhage, while knockdown of endogenous progranulin aggravated neurologic deficits after subarachnoid hemorrhage. Rat recombinant progranulin treatment reduced neuronal apoptosis, while progranulin deficiency promoted neuronal apoptosis at 24 hours after subarachnoid hemorrhage. Rat recombinant progranulin promoted Akt activation, increased Bcl-2 level, but reduced caspase-3 level. Knockdown of progranulin binding factor sortilin 1 abolished the beneficial effects of rat recombinant progranulin at 24 hours after subarachnoid hemorrhage. CONCLUSION: Rat recombinant progranulin alleviated neuronal death via sortilin 1-mediated and Akt-related antiapoptosis pathway. Rat recombinant progranulin may have potentials to ameliorate early brain injury for subarachnoid hemorrhage patients. PMID- 26010687 TI - Talactoferrin in Severe Sepsis: Results From the Phase II/III Oral tAlactoferrin in Severe sepsIS Trial. AB - OBJECTIVE: Talactoferrin alfa is a recombinant form of the human glycoprotein, lactoferrin, which has been shown to have a wide range of effects on the immune system. This phase II/III clinical trial compared talactoferrin with placebo, in addition to standard of care, in patients with severe sepsis. DESIGN: Multicenter, randomized, placebo-controlled, phase II/III clinical study. SETTING: Seventy-seven centers in 10 countries. PATIENTS: Adult (> 18 yr) patients admitted to one of the participating centers with severe sepsis who were receiving antimicrobial therapy and able to take liquid medication by mouth or feeding tube. INTERVENTIONS: Patients were randomized to receive either talactoferrin (1.5 g, 15 mL) or placebo three times a day orally or by another enteral route for 28 days or until ICU discharge. MEASUREMENTS AND MAIN RESULTS: The study was terminated after 305 patients had been enrolled (153 talactoferrin and 152 placebo) because of futility and safety concerns identified by the Data Safety Monitoring Board. There were no significant differences between groups in baseline characteristics including age, sex, site of infection, and severity scores. Twenty-eight-day mortality was higher in talactoferrin-treated patients although this difference was not statistically significant (24.8% vs 17.8% placebo; p = 0.117). The difference was largely the result of differences in patients with shock (talactoferrin, 33/105 [31.4%] vs placebo, 21/104 [20.2%]; p = 0.064); no mortality difference was seen in patients without shock (talactoferrin, 5/48 [10.4%] vs placebo, 6/48 [12.5%]; p = 0.806). In-hospital (43/153 [28.1%] vs 27/152 [17.8%]; p = 0.037) and 3-month (46/153 [30.1%] vs 31/152 [20.4%]; p = 0.036) mortality rates were significantly higher in talactoferrin-treated patients than in patients in the placebo group. The occurrence of treatment-related adverse or serious adverse events was similar between groups. CONCLUSIONS: Administration of oral talactoferrin was not associated with reduced 28-day mortality in patients with severe sepsis and may even be harmful. PMID- 26010689 TI - Research Participation for Bereaved Family Members: Experience and Insights From a Qualitative Study. AB - BACKGROUND: Research has highlighted potential negative health outcomes for bereaved family members after loss of a loved one in the ICU and has helped identify areas for intervention. The findings exist because these family members agreed to participate in research studies; but little is known about their experience of research participation. OBJECTIVE: To understand why family members participate in bereavement research and the benefits of participating in such research. DESIGN: Qualitative study using interviews with bereaved family members as well as letters written by bereaved family members. SETTING: Forty-one ICUs in France. SUBJECTS: Family members who lost a loved one in the ICU. MEASUREMENTS AND MAIN RESULTS: Thematic analysis was used and was based on 54 narratives, 52 letters, and written annotations on 150 questionnaires. Regarding reasons to participate and benefits of research participation, 6 themes emerged: 1) to say thank you to the ICU team, 2) to help other bereaved family members, 3) to express myself from a distance, 4) to not feel abandoned, 5) to share difficult emotions and to help make meaning of the death, and 6) to receive support and care. CONCLUSION: Bereavement research is possible after loss of a loved one in the ICU and may even be beneficial for family members. Exploring families' experiences of research participation helps define specific family needs in this setting. After the loss of a loved one in the ICU, bereaved families need opportunities to voice their feelings about their experience in the ICU and to give meaning to the end-of-life process; families also need to feel that they are still cared for. Support for the family may need to be developed after loss of a loved one in the ICU in the form of condolence letters, phone calls, or postintensive care meetings. PMID- 26010691 TI - Contribution to interplay between a delamination test and a sensory analysis of mid-range lipsticks. AB - BACKGROUND: Lipstick is currently one of the most sold products of cosmetics industry, and the competition between the various manufacturers is significant. Customers mainly seek products with high spreadability, especially long-lasting or long wear on the lips. Evaluation tests of cosmetics are usually performed by sensory analysis. This can then represent a considerable cost. OBJECTIVES: The object of this study was to develop a fast and simple test of delamination (objective method with calibrated instruments) and to interplay the obtained results with those of a discriminative sensory analysis (subjective method) in order to show the relevance of the instrumental test. METHODS: Three mid-range lipsticks were randomly chosen and were tested. They were made of compositions as described by the International Nomenclature of Cosmetic Ingredients (INCI). Instrumental characterization was performed by texture profile analysis and by a special delamination test. The sensory analysis was voluntarily conducted with an untrained panel as blind test to confirm or reverse the possible interplay. RESULTS: The two approaches or methods gave the same type of classification. The high-fat lipstick had the worst behaviour with the delamination test and the worst notation of the intensity of descriptors with the sensory analysis. CONCLUSION: There is a high correlation between the sensory analysis and the instrumental measurements in this study. The delamination test carried out should permit to quickly determine the lasting (screening test) and in consequence optimize the basic formula of lipsticks. PMID- 26010690 TI - Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome. AB - OBJECTIVE: The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort. DESIGN: Prospective cohort. SETTING: Tertiary care center. PATIENTS: Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion) INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with nonpulmonary sepsis as the primary acute respiratory distress syndrome risk factor (n = 212), 39% of those with acute respiratory distress syndrome were current smokers by history compared with 22% of those without acute respiratory distress syndrome (odds ratio, 2.28; 95% CI, 1.24-4.19; p = 0.008). Likewise, cigarette smoke exposure as measured by urine 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol was significantly associated with acute respiratory distress syndrome in this group. The increased risk of acute respiratory distress syndrome in nonpulmonary sepsis was restricted to patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels consistent with active smoking and was robust to adjustment for other acute respiratory distress syndrome predictors. Cigarette smoke exposure as measured by history or 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol was not associated with acute respiratory distress syndrome in patients with other risk factors (e.g., pneumonia and aspiration). CONCLUSIONS: Cigarette smoking measured both by history and biomarker is associated with an increased risk of acute respiratory distress syndrome in patients with nonpulmonary sepsis. This finding has important implications for tobacco product regulation and for understanding the pathogenesis of acute respiratory distress syndrome. PMID- 26010692 TI - Disability Within US Public Health School and Program Curricula. AB - OBJECTIVE: To describe the percentage of US public health schools and programs offering graduate-level courses with disability content as a potential baseline measurement for Healthy People 2020 objective DH-3 and compare the percentage of public health schools that offered disability coursework in 1999 with those in 2011. DESIGN: In 2011, using SurveyMonkey.com, cross-sectional information was collected from the deans, associate deans, directors, or chairpersons of master of public health-granting public health schools and programs that were accredited and listed with the Council on Education for Public Health. Two rounds of follow up were conducted at 4-month intervals by e-mails and phone calls to program contacts who had not responded. The responses from schools and programs were calculated and compared. RESULTS: There were 78 responses (34 schools and 44 programs) for a response rate of 63%. Fifty percent of public health schools and programs offered some disability content within their graduate-level courses. A greater percentage of schools than programs (71% vs 34%; P = .003) offered some graduate-level disability coursework within their curricula. The percentage of schools that offered disability coursework was similar in 1999 and 2011. CONCLUSION: This assessment provides a potential baseline measurement for Healthy People 2020 objective DH-3. Future assessments should focus on clarifying disability content within courses and identifying capacity to offering disability training within public health schools and programs. PMID- 26010693 TI - The elusive "holy grail" of organizational culture and the power of like. PMID- 26010694 TI - Living longer better: a call to action to promote the health of older adults and their communities. PMID- 26010695 TI - Public health perceptions of community pharmacy partnership opportunities. PMID- 26010696 TI - A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34. AB - IMPORTANCE: Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified. OBJECTIVE: To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTS: Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURES: Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing. RESULTS: Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCE: Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids. PMID- 26010697 TI - Simultaneous determination of ginkgolides A, B, C and bilobalide by LC-MS/MS and its application to a pharmacokinetic study in rats. AB - The study of pharmacokinetics of Ginkgo biloba extracts in Traditional Chinese Medicine was relatively recent. In this study, a simple, quick and sensitive LC MS/MS analytical method was developed for the determination of ginkgolides A, B, C and bilobalide in rat plasma. The analytes were completely separated from the endogenous compounds on an Agilent Zorbax Eclipse plus C18 column (50 mm * 3.0 mm, 1.8 um) using an isocratic elution. The single-run analysis time was as short as 5.0 min. Sample preparation for protein removal was accomplished used a simple methanol precipitation method, after SPE showing a simultaneous extraction and cleanup of extracts allowing for a direct analysis. Extraction recoveries in rat plasma for ginkgolides A, B, C and bilobalide ranged from 75.6% to 89.0%. The calibration curves were determined over the ranges 0.5-20,000 ng/mL for ginkgolides A, B, C and bilobalide respectively. The lower limits of quantification (LLOQ) of the analytes were 0.5 ng/mL. Inter-day and intra-day precision and accuracy were below 15% and between 85 and 115%, respectively. Finally, the developed method was successfully applied to a pharmacokinetic study following oral administration of the Ginkgo biloba extracts to the male ICR rats. PMID- 26010699 TI - Contact immunotherapy-resistant alopecia areata totalis/universalis reactive to topical corticosteroid. PMID- 26010700 TI - Behaviour of magnetic Janus-like colloids. AB - We present a theoretical study of Janus-like magnetic particles at low temperature. To describe the basic features of the Janus-type magnetic colloids, we put forward a simple model of a spherical particle with a dipole moment shifted outwards from the centre and oriented perpendicular to the particle radius. Using direct calculations and molecular dynamics computer simulations, we investigate the ground states of small clusters and the behaviour of bigger systems at low temperature. In both cases the important parameter is the dipolar shift, which leads to different ground states and, as a consequence, to a different microscopic behaviour in the situation when the thermal fluctuations are finite. We show that the head-to-tail orientation of dipoles provides a two particle energy minima only if the dipoles are not shifted from the particle centres. This is one of the key differences from the system of shifted dipolar particles (sd-particles), in which the dipole was shifted outwards radially, studied earlier (Kantorovich et al 2011 Soft Matter 7 5217-27). For sd-particles the dipole could be shifted out of the centre for almost 40% before the head-to tail orientation was losing its energetic advantage. This peculiarity manifests itself in the topology of the small clusters in the ground state and in the response of the Janus-like particle systems to an external magnetic field at finite temperatures. PMID- 26010698 TI - Projections from the subparaventricular zone define four channels of output from the circadian timing system. AB - The subparaventricular zone of the hypothalamus (SPZ) is the main efferent target of neural projections from the suprachiasmatic nucleus (SCN) and an important relay for the circadian timing system. Although the SPZ is fairly homogeneous cytoarchitecturally and neurochemically, it has been divided into distinct functional and connectional subdivisions. The dorsal subdivision of the SPZ (dSPZ) plays an important role in relaying signals from the SCN controlling body temperature rhythms, while the ventral subdivision (vSPZ) is critical for rhythms of sleep and locomotor activity (Lu et al. [] J Neurosci 21:4864-4874). On the other hand, the medial part of the SPZ receives input mainly from the dorsomedial SCN, whereas the lateral SPZ receives input from the ventrolateral SCN and the retinohypothalamic tract (Leak and Moore [] J Comp Neurol 433:312-334). We therefore investigated whether there are corresponding differences in efferent outputs from these four quadrants of the SPZ (dorsolateral, ventrolateral, dorsomedial, and ventromedial) by a combination of anterograde and retrograde tracing. We found that, while all four subdivisions of the SPZ share a similar backbone of major projection pathways to the septal region, thalamus, hypothalamus, and brainstem, each segment of the SPZ has a specific set of targets where its projections dominate. Furthermore, we observed intra-SPZ projections of varying densities between the four subdivisions. Taken together, this pattern of organization suggests that the circadian timing system may have several parallel neural outflow pathways that provide a road map for understanding how they subserve different functions. PMID- 26010702 TI - Temperature dependent Raman and DFT study of creatine. AB - Temperature dependent Raman spectra of creatine powder have been recorded in the temperature range 420-100K at regular intervals and different clusters of creatine have been optimized using density functional theory (DFT) in order to determine the effect of temperature on the hydrogen bonded network in the crystal structure of creatine. Vibrational assignments of all the 48 normal modes of the zwitterionic form of creatine have been done in terms of potential energy distribution obtained from DFT calculations. Precise analysis gives information about thermal motion and intermolecular interactions with respect to temperature in the crystal lattice. Formation of higher hydrogen bonded aggregates on cooling can be visualized from the spectra through clear signature of phase transition between 200K and 180K. PMID- 26010703 TI - Theoretical investigations of electronic, optical and mechanical properties for GaSb and AlSb semiconductors under the influence of temperature. AB - In this paper we explore the effects of temperature on the electronic and mechanical properties of GaSb and AlSb semiconductors by using the local empirical pseudo-potential method. Our results show that the band gaps, refractive index, optical dielectric constant, elastic constants (C11, C12, C44), bulk modulus, shear modulus and Young modulus of these compounds vary with the change in temperature. The comparison of some of our results with the available experimental data confirms the accurateness of our theoretical approach, which also infers the reliability of our other theoretical results. As, for some of the present calculations a little experimental data is available for comparison, therefore these results can be used as a reference work in the future studies. PMID- 26010701 TI - Generation of a tamoxifen inducible Tnnt2MerCreMer knock-in mouse model for cardiac studies. AB - Tnnt2, encoding thin-filament sarcomeric protein cardiac troponin T, plays critical roles in heart development and function in mammals. To develop an inducible genetic deletion strategy in myocardial cells, we generated a new Tnnt2:MerCreMer (Tnnt2(MerCreMer/+)) knock-in mouse. Rosa26 reporter lines were used to examine the specificity and efficiency of the inducible Cre recombinase. We found that Cre was specifically and robustly expressed in the cardiomyocytes at embryonic and adult stages following tamoxifen induction. The knock-in allele on Tnnt2 locus does not impact cardiac function. These results suggest that this new Tnnt2(MerCreMer/+) mouse could be applied towards the temporal genetic deletion of genes of interests in cardiomyocytes with Cre-LoxP technology. The Tnnt2(MerCreMer/+) mouse model also provides a useful tool to trace myocardial lineage during development and repair after cardiac injury. PMID- 26010704 TI - A highly selective fluorescent probe for Al(3+) based on quinoline derivative. AB - A novel Schiff base fluorescent probe, 1-phenyl-3-methyl-5-hydroxypyrazole-4 carbaldehyde (2'-methylquinoline-4'-formyl) hydrazone (PMHCH), for selective detection of Al(3+) has been designed and synthesized. Upon addition of various metal ions, the receptor only shows 286-fold enhancement of fluorescence intensity which might be attributed to a 1:1 stoichiometry between PMHCH and Al(3+) and the photo-induced electron transfer progress in the present of Al(3+) at 505n m. More importantly, the detection limit of PMHCH for Al(3+) could reach at 10(-7) M level. PMID- 26010705 TI - Spectroscopic study on binding of gentisic acid to bovine serum albumin. AB - The interaction of (gentisic acid) GA with (bovine serum albumin) BSA has been studied by different spectroscopic techniques. GA is a monoanionic specie at the working pH of 7.4, it was determined by combining UV-Vis absorption spectroscopy and theoretical calculations. A set of fluorescence quenching experiments at different temperatures was carried out employing the native fluorescence of BSA. A Stern-Volmer constant (KSV) of (2.07+/-0.12)*10(4) mol(-1) L and a binding constant (Ka) of (8.47+/-4.39)*10(3) were determined at 310 K. The static quenching caused by the BSA-GA complex formation seems to play a significant role in the overall quenching process. A single binding site on BSA for GA was observed. DeltaH=-55.6+/-0.2 kJ mol(-1) and DeltaS=-104.3+/-0.6 J mol(-1) K(-1) were determined in a set of experiments on the dependence of Ka with the temperature. The binding process is, therefore, spontaneous and enthalpy-driven. Van der Waals forces and hydrogen bonds could also play the major role in the binding mode. The secondary structure changes of BSA in the absence and presence of GA were studied by FTIR and UV-Vis absorption spectroscopy. PMID- 26010706 TI - Lithium Formate for EPR Dosimetry (2): Secondary Radicals in X-Irradiated Crystals. AB - The secondary radiation-induced radicals in lithium formate monohydrate were studied using electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR) and ENDOR-induced EPR (EIE) techniques complemented with periodic density functional theory (DFT) calculations. Single crystals of lithium formate monohydrate were X irradiated at 77 K and at room temperature. The main radicals present after irradiation at 77 K are the CO(2)(*-) radical (R1), the recently identified protonated electron-gain product, HCOOH(*-) (R2) (Krivokapic et al., Radiat Res 2014: 181:503-11), and a different geometrical conformation of this latter radical, a species that, up until now, has remained unidentified (R3). The successful quantum chemical modeling of R3 confirmed its structure and also provided a possible mechanism for its formation. After irradiation at 295 K, the crystals were investigated both shortly after irradiation and after storage for eight months at room temperature in ambient environments. After long-term storage the CO(2)(*-) radical had significantly decayed and the EPR spectra were dominated by two minority radicals. Both of these radicals are most likely formate-centered pi-radicals, and based on the observed EPR parameters (g- and hyperfine coupling tensors) tentative candidates are the CO(*-) radical and the dimer formed by the CO(2)(*-) radical and a neighboring formate molecule yielding the radical (-)O(2)C.O.(*)CH.O(-). PMID- 26010707 TI - Dose Estimation for a Study of Nuclear Workers in France, the United Kingdom and the United States of America: Methods for the International Nuclear Workers Study (INWORKS). AB - In the framework of the International Nuclear Workers Study conducted in France, the UK and the U.S. (INWORKS), updated and expanded methods were developed to convert recorded doses of ionizing radiation to estimates of organ doses or individual personal dose equivalent [H(p)(10)] for a total number of 308,297 workers, including 40,035 women. This approach accounts for differences in dosimeter response to predominant workplace energy and geometry of exposure and for the recently published ICRP report on dose coefficients for men and women separately. The overall mean annual individual personal dose equivalent, including zero doses, is 1.73 mSv [median = 0.42; interquartile range (IQR): 0.07, 1.59]. Associated individual organ doses were estimated. INWORKS includes workers who had potential for exposure to neutrons. Therefore, we analyzed neutron dosimetry data to identify workers potentially exposed to neutrons. We created a time-varying indicator for each worker, classifying them according to whether they had a positive recorded neutron dose and if so, whether their neutron dose ever exceeded 10% of their total external penetrating radiation dose. The number of workers flagged as being exposed to neutrons was 13% for the full cohort, with 15% of the cohort in France, 12% of the cohort in the UK and 14% in the U.S. We also used available information on in vivo and bioassay monitoring to identify workers with known depositions or suspected internal contaminations. As a result of this work, information is now available that will allow various types of sensitivity analyses. PMID- 26010709 TI - Cancer Mortality through 2005 among a Pooled Cohort of U.S. Nuclear Workers Exposed to External Ionizing Radiation. AB - Nuclear workers worldwide have been studied for decades to estimate associations between their exposure to ionizing radiation and cancer. The low-level exposure of these workers requires pooling of large cohorts studied over many years to obtain risk estimates with appropriate latency and good precision. We assembled a pooled cohort of 119,195 U.S. nuclear workers at four Department of Energy nuclear weapons facilities (Hanford site, Idaho National Laboratory, Oak Ridge National Laboratory and Savannah River site) and at the Portsmouth Naval Shipyard. The cohort was followed at the start of the workers beginning their radiation work (at earliest, between 1944 and 1952) through 2005, and we compared its mortality to that of the U.S. POPULATION: We also conducted regression modeling analysis to evaluate dose-response associations for external radiation exposure and outcomes: all cancers, smoking- and nonsmoking-related cancers, all lymphatic and hematopoietic cancers, leukemia (excluding chronic lymphocytic), multiple myeloma, cardiovascular disease and others. The mean dose observed among the cohort was 20 mSv. For most outcomes, mortality was below expectation compared to the general population, but mesothelioma and pleura cancers were highly elevated. We found an excess relative risk (ERR) per 10 mSv of 0.14% [95% confidence interval (CI): -0.17%, 0.48%] for all cancers excluding leukemia. Estimates were higher for nonsmoking-related cancers (0.70%, 95% CI: 0.058%, 1.5%) and lower for smoking-related cancers (-0.079%, 95% CI: -0.43%, 0.32%). The ERR per 10 mSv was 1.7% (95% CI: -0.22%, 4.7%) for leukemia, which was similar to the estimate of 1.8% (95% CI: 0.027%, 4.4%) for all lymphatic and hematopoietic cancers. The ERR per 10 mSv for multiple myeloma was 3.9% (95% CI: 0.60%, 9.5%). The ERR per 10 mSv for cardiovascular disease was 0.026% (-0.25%, 0.32%). Little evidence of heterogeneity was seen by facility, birth cohort or sex for most outcomes. The estimates observed here are similar to those found in previous large pooled nuclear worker studies and also (with the exception of multiple myeloma) to those conducted in the Life Span Study of Japanese atomic bomb survivors. The tendency of observed risks to persist many years after exposure for most outcomes illustrates the importance of continued follow-up of nuclear worker cohorts. PMID- 26010708 TI - Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model. AB - Glutathione S-transferase alpha 4 (GSTA4-4) is one of the enzymes responsible for the removal of 4-hydroxynonenal (4-HNE), an electrophilic product of lipid peroxidation in cellular membranes during oxidative stress. 4-HNE is a direct activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor with many target genes encoding antioxidant and anti-electrophile enzymes. We have previously shown that Gsta4-null mice on a 129/Sv background exhibited increased activity of Nrf2 in the heart. Here we examined the sensitivity of this Gsta4-null mouse model towards cardiac function and structure loss due to local heart irradiation. Male Gsta4-null and wild-type mice were exposed to a single X ray dose of 18 Gy to the heart. Six months after irradiation, immunohistochemical staining for respiratory complexes 2 and 5 indicated that radiation exposure had caused most pronounced alterations in mitochondrial morphology in Gsta4-null mice. On the other hand, wild-type mice showed a decline in cardiac function and an increase in plasma levels of troponin-I, while no such changes were observed in Gsta4-null mice. Radiation-induced Nrf2-target gene expression only in Gsta4 null mice. In conclusion, although loss of GSTA4-4 led to enhanced susceptibility of cardiac mitochondria to radiation-induced loss of morphology, cardiac function was preserved in Gsta4-null mice. We propose that this protection against cardiac function loss may occur, at least in part, by upregulation of the Nrf2 pathway. PMID- 26010710 TI - Evidence from Animal Models: Is a Restricted or Conventional Intestinal Microbiota Composition Predisposing to Risk for High-LET Radiation Injury? AB - Intestinal microbiota affect cell responses to ionizing radiation at the molecular level and can be linked to the development of the immune system, controlled cell death or apoptosis. We have developed a microbiota mouse model and report here that high-linear energy transfer (LET) radiation induced the repair of chromosomal DNA lesions more efficiently in conventional than in restricted intestinal microbiota mice. Based on different phylotype densities after whole-body irradiation, bacterial indicator phylotypes were found to be more abundant in restricted in microbiota than in conventional microbiota. Genotoxic phenotypes of irradiated restricted and conventional microbiota mice were compared with ataxia telangiectasia-deficient restricted and conventional microbiota mice, respectively. Those indicator phylotypes, including Bacteroides (Gram-negative bacterium cTPY-13), Barnesiella intestinihominis and others, which were identified in nonirradiated restricted microbiota mice, increase in radiation-exposed conventional microbiota along with a reduction of persistent DNA double-strand breaks in blood lymphocytes. The dynamic change of phylotype abundances elucidated a feedback mechanism and effect of intestinal microbiota composition on the adaptive response to high-LET radiation. Several other bacterial phylotypes ( Helicobacter hepaticus , Helicobacter spp and others) were found to be more abundant in conventional than restricted microbiota. In this commentary, mouse models used in cancer research and radiotherapy for the study on the effects of intestinal microbiota composition on normal tissue radiation response are characterized and discussed. Highlights of this commentary: 1. Restricted microbiota phylotypes were correlated with persistent DNA double strand breaks (DSBs) and were found to orchestrate onco-protective controlled cell death after radiation; 2. Restricted microbiota composition reduced proinflammatory extracellular-stimulated immune responses, but specifically increased anti-neoplastic cytolytic memory CD8(+) T cells by low taxonomic diversity and 3. DNA damage repair efficiency induced by a model of conventional microbiota most likely initiates an adaptive response to radiation through microbiota-induced intestinal sub-symptomatic inflammation. PMID- 26010711 TI - MRI-Tracked Tumor Vascular Changes in the Hours after Single-Fraction Irradiation. AB - The purpose of this study was to characterize changes in tumor vascular parameters hours after a single radiation exposure in an orthotopic brain tumor model. U-251 human brain tumors were established intracerebrally in rat brains, and tumor blood flow, forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) were measured using magnetic resonance imaging (MRI). Tumors were exposure to a single stereotactic radiation treatment of 20 Gy. Vascular parameters were assessed one additional time between 2 and 24 h after irradiation. After the second MRI session, brain tissue histology was examined for gross changes and apoptosis. In separate studies, cerebral blood flow was measured in nonimplanted controls before radiation exposure and 2 and 24 h after 20 Gy irradiation, and in implanted rats before radiation exposure and at 2 and 24 h after 6 Gy irradiation. Significant changes were observed in tumor bearing rat brains in the hours after 20 Gy irradiation. Two hours after 20 Gy irradiation, tumor blood flow decreased nearly 80% and ve decreased by 30%. At 4 h, the K(trans) increased by 30% over preirradiation values. Extensive vacuolization and an increase in apoptosis were evident histologically in rats imaged 2 h after irradiation. Between 8 and 12 h after irradiation, all vascular parameters including blood flow returned to near preirradiation values. One day after irradiation, tumor blood flow was elevated 40% over preirradiation values, and other vascular parameters, including K(trans) and ve, were 20-40% below preirradiation values. In contrast, changes in vascular parameters observed in the normal brain 2 or 24 h after 20 Gy irradiation were not significantly different from preirradiation values. Also, tumor blood flow appeared to be unchanged at 2 h after 6 Gy irradiation, with a small increase observed at 24 h, unlike the tumor blood flow changes after 20 Gy irradiation. Large and significant changes in vascular parameters were observed hours after 20 Gy irradiation using noninvasive MRI techniques. It is hypothesized that cellular swelling hours after a high dose of radiation, coinciding with vacuolization, led to a decrease in tumor blood flow and v(e). Four hours after radiation exposure, K(trans) increased in concert with an increase in tumor blood flow. Vascular permeability normalized, 24 h after 20 Gy irradiation, as characterized by a decrease in K(trans). Vascular parameters did not change significantly in the normal brain after 20 Gy irradiation or in the tumor-bearing brain after 6 Gy irradiation. PMID- 26010712 TI - 28Silicon Irradiation Impairs Contextual Fear Memory in B6D2F1 Mice. AB - The space radiation environment consists of multiple species of charged particles, including (28)Si, (48)Ti and protons that may impact cognition, but their damaging effects have been poorly defined. In mouse studies, C57Bl6/J homozygous wild-type mice and genetic mutant mice on a C57Bl6/J background have typically been used for assessing effects of space radiation on cognition. In contrast, little is known about the radiation response of mice on a heterozygous background. Therefore, in the current study we tested the effects of (28)Si, (48)Ti and proton radiation on hippocampus-dependent contextual fear memory and hippocampus-independent cued fear memory in C57Bl6/J * DBA2/J F1 (B6D2F1) mice three months after irradiation. Contextual fear memory was impaired at a 1.6 Gy dose of (28)Si radiation, but not cued fear memory. (48)Ti or proton irradiation did not affect either type of memory. Based on earlier space radiation cognitive data in C57Bl6/J mice, these data highlight the importance of including different genetic backgrounds in studies aimed at assessing cognitive changes after exposure to space radiation. PMID- 26010713 TI - A Comprehensive Metabolomic Investigation in Urine of Mice Exposed to Strontium 90. AB - Internal emitters such as Strontium-90 ((90)Sr) pose a substantial health risk during and immediately after a nuclear disaster or detonation of an improvised device. The environmental persistency and potency of (90)Sr calls for urgent development of high-throughput tests to establish levels of exposure and to help triage potentially exposed individuals who were in the immediate area of the disaster. In response to these concerns, our team focused on developing a robust metabolomic profile for (90)Sr exposure in urine using a mouse model. The sensitivity of modern time-of-flight mass spectrometry (TOFMS) combined with the separation power of ultra performance liquid chromatography (UPLC) was used to determine perturbations in the urinary metabolome of mice exposed to (90)Sr. The recently developed statistical suite, MetaboLyzer, was used to explore the mass spectrometry data. The results indicated a significant change in the urinary abundances of metabolites pertaining to butanoate metabolism, vitamin B metabolism, glutamate and fatty acid oxidation. All of these pathways are either directly or indirectly connected to the central energy production pathway, the tricarboxylic acid (TCA) cycle. To our knowledge, this is the first in vivo metabolomics to evaluate the effects of exposure to (90)Sr using the easily accessible biofluid, urine. PMID- 26010715 TI - Alkene isomerization-hydroboration promoted by phosphine-ligated cobalt catalysts. AB - Generated in situ from air-stable cobalt precursors or readily synthesized using NaHBEt3, (PPh3)3CoH(N2) was found to be an effective catalyst for the hydroboration of alkenes. Unlike previous base-metal catalysts for alkene isomerization-hydroboration which favor the incorporation of boron at terminal positions, (PPh3)3CoH(N2) promotes boron incorporation adjacent to pi-systems even in substrates where the alkene is at a remote position, enabling a unique route to 1,1-diboron compounds from alpha,omega-dienes. PMID- 26010714 TI - Ciprofloxacin Therapy Results in Mitigation of ATP Loss after Irradiation Combined with Wound Trauma: Preservation of Pyruvate Dehydrogenase and Inhibition of Pyruvate Dehydrogenase Kinase 1. AB - Ionizing radiation exposure combined with wound injury increases animal mortalities than ionizing radiation exposure alone. Ciprofloxacin (CIP) is in the fluroquinolone family of synthetic antibiotic that are available from the strategic national stockpile for emergency use and is known to inhibit bacterial sepsis. The purpose of this study was to evaluate the efficacy of ciprofloxacin as a countermeasure to combined injury mortality and determine the signaling proteins involved in energy machinery. B6D2F1/J female mice were randomly assigned to receive either 9.75 Gy irradiation with Co-60 gamma rays followed by skin wounding (combined injury; CI) or sham procedure (sham). Either ciprofloxacin (90 mg/kg/day) or vehicle (VEH) (water) was administered orally to these mice 2 h after wounding and thereafter daily for 10 days. Determination of tissue adenosine triphosphate (ATP) was conducted, and immunoblotting for signaling proteins involved in ATP machinery was performed. Combined injury resulted in 60% survival after 10 days compared to 100% survival in the sham group. Furthermore, combined injury caused significant reductions of ATP concentrations in ileum, pancreas, brain, spleen, kidney and lung (-25% to -95%) compared to the sham group. Ciprofloxacin administration after combined injury resulted in 100% survival and inhibited reductions in ileum and kidney ATP production. Ileum protein levels of heat-shock protein 70 kDa (HSP-70, a chaperone protein involved in ATP synthesis) and pyruvate dehydrogenase (PDH, an enzyme complex crucial to conversion of pyruvate to acetyl CoA for entrance into TCA cycle) were significantly lower in the CI group (vs. sham group). Using immunoprecipitation and immunoblotting, HSP-70-PDH complex was found to be present in the ileum tissue of CI mice treated with ciprofloxacin. Furthermore, phosphorylation of serine residues of PDH resulting in inactivating PDH enzymatic activity, which occurred after combined injury, was inhibited with ciprofloxacin treatment, thus enabling PDH to increase ATP production. Increased ileum levels of pyruvate dehydrogenase kinase 1 protein (PDK1, an enzyme responsible for PDH phosphorylation) after combined injury were also prevented by ciprofloxacin treatment. Taken together, these data suggest that ciprofloxacin oral administration after combined injury had a role in sustained ileum ATP levels, and may have acted through preservation of PDH by HSP-70 and inhibition of PDK1. These molecular changes in the ileum are simply one of a host of mechanisms working in concert with one another by which ciprofloxacin treatment mitigates body weight loss and drastically enhances subsequent survival after combined injury. To this end, our findings indicate that oral treatment of ciprofloxacin is a valuable therapeutic treatment after irradiation with combined injury and warrants further analyses to elucidate the precise mechanisms involved. PMID- 26010716 TI - An improved workflow for quantitative N-terminal charge-based fractional diagonal chromatography (ChaFRADIC) to study proteolytic events in Arabidopsis thaliana. AB - We applied an extended charge-based fractional diagonal chromatography (ChaFRADIC) workflow to analyze the N-terminal proteome of Arabidopsis thaliana seedlings. Using iTRAQ protein labeling and a multi-enzyme digestion approach including trypsin, GluC, and subtilisin, a total of 200 MUg per enzyme, and measuring only one third of each ChaFRADIC-enriched fraction by LC-MS, we quantified a total of 2791 unique N-terminal peptides corresponding to 2249 different unique N-termini from 1270 Arabidopsis proteins. Our data indicate the power, reproducibility, and sensitivity of the applied strategy that might be applicable to quantify proteolytic events from as little as 20 MUg of protein per condition across up to eight different samples. Furthermore, our data clearly reflect the methionine excision dogma as well as the N-end rule degradation pathway (NERP) discriminating into a stabilizing or destabilizing function of N terminal amino acid residues. We found bona fide NERP destabilizing residues underrepresented, and the list of neo N-termini from wild type samples may represent a helpful resource during the evaluation of NERP substrate candidates. All MS data have been deposited in the ProteomeXchange with identifier PXD001855 (http://proteomecentral.proteomexchange.org/dataset/PXD001855). PMID- 26010718 TI - Data-prompted interviews: Using individual ecological data to stimulate narratives and explore meanings. AB - OBJECTIVE: An emerging trend in qualitative research is to use individual participant data to stimulate narratives in interviews. This article describes the method of the data-prompted interview (DPI) and highlights its potential benefits and challenges. METHOD: DPIs use personal ecological data gathered prior to the interview to stimulate discussion during the interview. Various forms of data can be used including photographs, videos, audio recordings, graphs, and text. This data can be gathered by the researcher or generated by the participant and may utilize ecological momentary assessment. RESULTS: Using individual data in DPIs can stimulate visual and auditory senses, enhance memory, and prompt rich narratives anchored in personal experiences. For the researcher, DPIs provide an opportunity to explore the meaning of the data and to explain data patterns. For the participant, presented stimuli give guidance for discussion and allow them to reflect. The challenges associated with conducting DPIs include practical issues such as data selection and presentation. Data analyses require narratives to be interpreted together with the data. Ethical challenges of DPI include concerns around data anonymity and sensitivity. CONCLUSIONS: Combining various sources of data to stimulate the interview provides a novel opportunity to enhance participants' memories and to meaningfully assess and analyze data patterns. In the context of health promotion and illness prevention, DPI offers a unique opportunity to explore reasons, opinions, and motivations for health-related behaviors in the light of previously gathered data. PMID- 26010719 TI - Predictors of condom use with main and casual partners among HIV-positive men over 50. AB - OBJECTIVE: Sexual health among the growing population of older adults living with HIV has garnered increased research attention. Previous studies have identified alcohol and drug use as factors increasing rates of sexual activity and sex risk behavior in this population. However, the influence of partner type (whether main or casual) on the links between substance use and sexual behavior in older men living with HIV remains understudied and was the focus of the current study. METHOD: Data were collected from telephone interviews with 378 men, aged 50 years or older, living with HIV and residing in the New York City area. The sample included 224 (59%) men who identified as gay or bisexual and 154 (41%) who identified as heterosexual. The majority of the sample identified as Black (66%), and the average age was 55 years. Participants reported on recent sexual behavior, substance use, and viral load/detectability status. RESULTS: Results of multinomial logistic regression analyses found that substance use was associated with increased rates of condomless sex with casual partners but not with main partners, whereas self-reported viral load (perceptions of immunological health) was a factor associated with condomless sex with main partners but not with casual partners. CONCLUSIONS: The findings indicate that different factors are involved in instances of condomless sex depending on whether the partner is a main or casual partner. Research and intervention efforts aimed at reducing risk factors for older men living with HIV and their partners need to take into account the relational context of sexual behavior. PMID- 26010720 TI - Was it so bad? The role of retrospective memory in symptom reporting. AB - OBJECTIVE: Retrospective symptom reports are an important source of information in both laboratory and clinical settings. The present study investigated memory for experimentally induced pain and dyspnea in high and low habitual symptom reporters (HSR). METHODS: Healthy women (N = 48; 24 high/24 low HSR) participated in 2 laboratory studies. One study included 2 pain episodes (cold pressor task), the other study included 2 dyspnea episodes (rebreathing task). Pain and dyspnea ratings were collected (a) continuously during symptom inductions, (b) after each trial, (c) immediately after the experiment, and (d) at 2-week follow-up. Symptom ratings, negative affect (NA), and anxiety measures were also completed following each trial. RESULTS: Although the retrospective pain ratings were higher in the high compared with the low HSR group (p = .01), both groups rated recalled dyspnea higher relative to concurrent dyspnea (p < .001). A further increase in bias over time was only found for dyspnea in high HSR (p = .02). Moreover, dyspnea induction was associated with higher state NA (p = .03) and anxiety (p = .007) than pain induction. CONCLUSIONS: Our findings show that even though memory for pain and dyspnea is overall distorted, the extent of bias in symptom recall clearly differs between symptoms and groups. The observed increase of dyspnea reporting over time may have important implications for diagnostic assessment based on symptom reporting. PMID- 26010717 TI - NG2-glia and their functions in the central nervous system. AB - In the central nervous system, NG2-glia represent a neural cell population that is distinct from neurons, astrocytes, and oligodendrocytes. While in the past the main role ascribed to these cells was that of progenitors for oligodendrocytes, in the last years it has become more obvious that they have further functions in the brain. Here, we will discuss some of the most current and highly debated issues regarding NG2-glia: Do these cells represent a heterogeneous population? Can they give rise to different progenies, and does this change under pathological conditions? How do they respond to injury or pathology? What is the role of neurotransmitter signaling between neurons and NG2-glia? We will first give an overview on the developmental origin of NG2-glia, and then discuss whether their distinct properties in different brain regions are the result of environmental influences, or due to intrinsic differences. We will then review and discuss their in vitro differentiation potential and in vivo lineage under physiological and pathological conditions, together with their electrophysiological properties in distinct brain regions and at different developmental stages. Finally, we will focus on their potential to be used as therapeutic targets in demyelinating and neurodegenerative diseases. Therefore, this review article will highlight the importance of NG2-glia not only in the healthy, but also in the diseased brain. PMID- 26010721 TI - Longitudinal changes in spouses' HPA responses: Convergence in cortisol patterns during the early years of marriage. AB - OBJECTIVE: Drawing on theories of bidirectional influence between relationship partners (Butler, 2011; Diamond & Aspinwall, 2003), the authors applied dyadic analytic methods to test convergence in cortisol patterns over time in newlywed couples. METHOD: Previous studies of bidirectional influence in couples' cortisol levels (Liu, Rovine, Klein, & Almeida, 2013; Papp, Pendry, Simon, & Adam, 2013; Saxbe & Repetti, 2010) found significant covariation in couples' daily cortisol levels over several days, but no studies have tested whether cortisol response similarity increases over time using a longitudinal design. In the present study, 183 opposite sex couples (366 participants) engaged in a conflict discussion in a laboratory visit about 6 months after their marriage, and again about 2 years into the marriage. At each visit, spouses provided saliva samples that indexed cortisol levels before, during, and after the discussion. This multimeasure procedure enabled modeling of spouses' cortisol trajectories around the conflict discussion. RESULTS: Findings showed significant convergence in couples' cortisol trajectories across the early years of marriage; couples showed significantly greater similarity in cortisol trajectories around the conflict discussion as their relationship matured. Cohabitation length predicted stronger convergence in cortisol slopes prior to the conflict discussion. Couples' relationship dissatisfaction was associated with a greater degree of convergence in spouses' acute cortisol levels during the conflict discussion. CONCLUSIONS: Findings suggest that spouses increasingly shape each other's cortisol responses as their relationship matures. Findings also indicated that increased similarity in acute cortisol levels during conflict may be associated with poorer relationship functioning. PMID- 26010722 TI - Mutated genes and driver pathways involved in myelodysplastic syndromes-a transcriptome sequencing based approach. AB - Myelodysplastic syndromes are a heterogeneous group of clonal disorders of hematopoietic progenitors and have potentiality to progress into acute myelogenous leukemia. Development of effective treatments has been impeded by limited insight into pathogenic pathways. In this study, we applied RNA-seq technology to study the transcriptome on 20 MDS patients and 5 age-matched controls, and developed a pipeline for analyzing this data. After analysis, we identified 38 mutated genes contributing to MDS pathogenesis. 37 out of 38 genes have not been reported previously, suggesting our pipeline is critical for identifying novel mutated genes in MDS. The most recurrent mutation happened in gene IFRD1, which involved 30% of patient samples. Biological relationships among these mutated genes were mined using Ingenuity Pathway Analysis, and the results demonstrated that top two networks with highest scores were highly associated with cancer and hematological diseases, indicating that the mutated genes identified by our method were highly relevant to MDS. We then integrated the pathways in KEGG database and the identified mutated genes using our novel rule based mutated driver pathway scoring approach for detecting mutated driver pathways. The results indicated two mutated driver pathways are important for the pathogenesis of MDS: pathway in cancer and in regulation of actin cytoskeleton. The latter, which likely contributes to the hallmark morphologic dysplasia observed in MDS, has not been reported, to the best of our knowledge. These results provide us new insights into the pathogenesis of MDS, which, in turn, may lead to novel therapeutics for this disease. PMID- 26010723 TI - CORRIGENDUM: Reversible switching of magnetic states by electric fields in nitrogenized-divacancies graphene decorated by tungsten atoms. PMID- 26010724 TI - Trans-subclavian versus transapical access for transcatheter aortic valve implantation: A multicenter study. AB - OBJECTIVES: To compare the outcomes of trans-subclavian (TS) and transapical (TA) access for transcatheter aortic valve implantation (TAVI). BACKGROUND: A considerable proportion of patients undergoing TAVI are not eligible for transfemoral approach. To date, there are few data to guide the choice between alternative vascular access routes. METHODS: Among 874 consecutive patients who underwent TAVI, 202 procedures were performed through TA (n = 142, 70.3%) or TS (n = 60, 29.7%) access. Medtronic Corevalve (CV, Medtronic, Minneapolis, MN) was implanted in 17.3% of the patients, the Edwards-Sapien (ES, Edwards Lifesciences Inc., Irvine, CA) in 81.2% and other prostheses in 0.1%. In-hospital and long term outcome were assessed using the Valve Academic Research Consortium (VARC)-2 definitions. RESULTS: Mean age was 82 +/- 6 years, STS score 9.3 +/- 7.9%. The 2 groups showed a relevant imbalance in baseline characteristics. In hospital mortality was 6.4% (1.7% TS vs. 8.4% TA, P = 0.06), stroke 2.0%, acute myocardial infarction 1.0%, acute kidney injury 39.4%, sepsis 4.0% with no significant differences between groups, while bleeding was more frequent in TA patients (53.5% vs. 11.7% TS, P < 0.001). One- and 2-year survival was 85.2% and 73.2% in TS patients, and 83.9% and 74.9% in TA patients (P = ns for both). Access site was not an independent predictor of mortality at multivariable analysis. CONCLUSION: Transapical compared with trans-subclavian access for TAVI was associated with a nonsignificant trend to increased periprocedural events. However, 1- and 2-year survival appears similar. PMID- 26010726 TI - Synthesis and Use of Stable-Isotope-Labeled Internal Standards for Quantification of Phosphorylated Metabolites by LC-MS/MS. AB - Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is a highly specific and sensitive technique for measuring metabolites. However, coeluting components in tissue extracts can interfere with ionization at the interface of the LC and MS/MS phases, causing under- or overestimation of metabolite concentrations. Spiking of samples with known amounts of stable-isotope-labeled internal standards (SIL-IS) allows measurements of the corresponding metabolites to be corrected for such matrix effects. We describe criteria for selection of suitable SIL-IS and report the enzymatic synthesis and purification of nine SIL IS for hexose-, pentose-, and triose-phosphates, UDP-glucose, and adenosine monophosphate (AMP). Along with commercially available SIL-IS for seven other metabolites, these were validated by LC-MS/MS analyses of extracts from leaves, nonphotosynthetic plant tissues, mouse liver, and cells of Chlamydomonas reinhardtii, Escherichia coli and baker's yeast (Saccharomyces cerevisiae). With only a few exceptions, spiking with SIL-IS significantly improved the reproducibility of LC-MS/MS-based metabolite measurements across a wide range of extract dilutions, indicating effective correction for matrix effects by this approach. With use of SIL-IS to correct for matrix effects, LC-MS/MS offers unprecedented scope for reliable determination of photosynthetic and respiratory intermediates in a diverse range of organisms. PMID- 26010725 TI - Mycobacterium avium Possesses Extracellular DNA that Contributes to Biofilm Formation, Structural Integrity, and Tolerance to Antibiotics. AB - Mycobacterium avium subsp. hominissuis is an opportunistic pathogen that is associated with biofilm-related infections of the respiratory tract and is difficult to treat. In recent years, extracellular DNA (eDNA) has been found to be a major component of bacterial biofilms, including many pathogens involved in biofilm-associated infections. To date, eDNA has not been described as a component of mycobacterial biofilms. In this study, we identified and characterized eDNA in a high biofilm-producing strain of Mycobacterium avium subsp. hominissuis (MAH). In addition, we surveyed for presence of eDNA in various MAH strains and other nontuberculous mycobacteria. Biofilms of MAH A5 (high biofilm-producing strain) and MAH 104 (reference strain) were established at 22 degrees C and 37 degrees C on abiotic surfaces. Acellular biofilm matrix and supernatant from MAH A5 7 day-old biofilms both possess abundant eDNA, however very little eDNA was found in MAH 104 biofilms. A survey of MAH clinical isolates and other clinically relevant nontuberculous mycobacterial species revealed many species and strains that also produce eDNA. RAPD analysis demonstrated that eDNA resembles genomic DNA. Treatment with DNase I reduced the biomass of MAH A5 biofilms when added upon biofilm formation or to an already established biofilm both on abiotic surfaces and on top of human pharyngeal epithelial cells. Furthermore, co-treatment of an established biofilm with DNase 1 and either moxifloxacin or clarithromycin significantly increased the susceptibility of the bacteria within the biofilm to these clinically used antimicrobials. Collectively, our results describe an additional matrix component of mycobacterial biofilms and a potential new target to help treat biofilm associated nontuberculous mycobacterial infections. PMID- 26010727 TI - Who's Missing? Predictors of Attrition Following Participation in Culturally Targeted Educational Breast and Cervical Cancer Outreach Programs for Latinas. AB - Rates of breast and cervical cancer screening among Latinas are suboptimal. The Esperanza y Vida program was developed to increase awareness of screening methods among Latinas. Lay health advisor cancer survivors are trained to deliver the program and use a narrative communication approach to promote breast and cervical cancer awareness and screening. This study aimed to identify characteristics of participants, within the larger study, who were lost, due to attrition, for follow-up assistance. Participants (N = 908) completed questionnaires that assessed knowledge, perceptions, and beliefs about breast and cervical cancer and were contacted after the program to assess screening and offer assistance in obtaining screening exams. Latinas who were younger than 40 years of age and who felt that the survivor's story would prompt them to make an appointment for screening were more likely to be lost to follow-up at 2 months. These findings have implications for future breast and cervical cancer outreach programs and interventions. PMID- 26010728 TI - Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists. AB - Trace amine associated receptor 1 (TAAR1) is a G protein coupled receptor (GPCR) expressed in brain and periphery activated by a wide spectrum of agonists that include, but are not limited to, trace amines (TAs), amphetamine-like psychostimulants, and endogenous thyronamines such as thyronamine (T0AM) and 3 iodothyronamine (T1AM). Such polypharmacology has made it challenging to understand the role and the biology of TAAR1. In an effort to understand the molecular basis of TAAR1 activation, we rationally designed and synthesized a small family of thyronamine derivatives. Among them, compounds 2 and 3 appeared to be a good mimic of the parent endogenous thyronamine, T0AM and T1AM, respectively, both in vitro and in vivo. Thus, these compounds offer suitable tools for studying the physiological roles of mouse TAAR1 and could represent the starting point for the development of more potent and selective TAAR1 ligands. PMID- 26010729 TI - Towards a global assessment of pyrogenic carbon from vegetation fires. AB - The production of pyrogenic carbon (PyC; a continuum of organic carbon (C) ranging from partially charred biomass and charcoal to soot) is a widely acknowledged C sink, with the latest estimates indicating that ~50% of the PyC produced by vegetation fires potentially sequesters C over centuries. Nevertheless, the quantitative importance of PyC in the global C balance remains contentious, and therefore, PyC is rarely considered in global C cycle and climate studies. Here we examine the robustness of existing evidence and identify the main research gaps in the production, fluxes and fate of PyC from vegetation fires. Much of the previous work on PyC production has focused on selected components of total PyC generated in vegetation fires, likely leading to underestimates. We suggest that global PyC production could be in the range of 116-385 Tg C yr(-1) , that is ~0.2-0.6% of the annual terrestrial net primary production. According to our estimations, atmospheric emissions of soot/black C might be a smaller fraction of total PyC (<2%) than previously reported. Research on the fate of PyC in the environment has mainly focused on its degradation pathways, and its accumulation and resilience either in situ (surface soils) or in ultimate sinks (marine sediments). Off-site transport, transformation and PyC storage in intermediate pools are often overlooked, which could explain the fate of a substantial fraction of the PyC mobilized annually. We propose new research directions addressing gaps in the global PyC cycle to fully understand the importance of the products of burning in global C cycle dynamics. PMID- 26010730 TI - Role of long-term mechanical circulatory support in patients with advanced heart failure. AB - Advanced heart failure represents a small proportion of patients with heart failure that possess high-risk features associated with high hospital readmission rates, significant functional impairment and mortality. Identification of those who have progressed to, or are near a state of advanced heart failure should prompt referral to a service that offers therapies in mechanical circulatory support (MCS) and cardiac transplantation. MCS has grown as a management strategy in the care of these patients, most commonly as a bridge to cardiac transplantation. The predominant utilisation of MCS is implantation of left ventricular assist devices (LVAD), which have evolved significantly in their technology and application over the past 15-20 years. The technology has evolved to such an extent that Destination Therapy is now being utilised as a strategy in management of advanced heart failure in appropriately selected patients. Complication rates have decreased with VAD implantation, but remain a significant consideration in the decision to implant a device, and in the follow up of these patients. PMID- 26010731 TI - Moderately impaired renal function increases morning cortisol and cortisol levels at dexamethasone suppression test in patients with incidentally detected adrenal adenomas. AB - OBJECTIVE: Patients with incidentally detected adrenal adenomas may have subclinical hypercortisolism. We hypothesized that impaired renal function could lead to increased cortisol levels in these patients. DESIGN: Descriptive retrospective study of consecutive patients. PATIENTS: A total of 166 patients with incidentally detected unilateral adrenal adenomas were examined during 2008 2013. MEASUREMENTS: Levels of cortisol, ACTH and cortisol at 1 mg overnight dexamethasone suppression test (DST) were measured. The estimated glomerular filtration rate (eGFR) was calculated using the MDRD equation. RESULTS: Renal function was normal, mildly impaired, moderately impaired or severely impaired (eGFR >90, 60-90, 30-60 and 15-30 ml/min/1.73 m(2)) in 34, 54, 10 and 1% of the patients, respectively. Patients with normal and mildly impaired renal function had similar cortisol levels. Patients with moderately impaired renal function, compared to all the patients with eGFR >60 ml/min/1.73 m(2), exhibited increased cortisol (541 vs 456 nmol/l, P = 0.02), increased cortisol at DST (62 vs 37 nmol/l, P = 0.001), but similar ACTH levels (4.1 vs 2.9 pmol/l, P = 0.21). Patients with moderately impaired renal function thus exhibited cortisol at DST >= 50 nmol/l, more often than patients with eGFR >60 ml/min/1.73 m(2) (76% vs 30%, P = 0.000), while the prevalence of ACTH below 2 pmol/l was similar (24% vs 31%, P = 0.51). CONCLUSIONS: Moderately impaired renal function increases cortisol and cortisol at DST in patients with adrenal adenomas, while mildly impaired renal function has no such effect. Cortisol level at DST >= 50 nmol/l therefore seems to have low specificity in diagnosing subclinical adrenal hypercortisolism, and an additional criterion, for example low ACTH, is required. PMID- 26010732 TI - Eosinophilic airway disease in a patient with a negative skin prick test, but a positive patch test with platinum salts--implications for medical surveillance. AB - We present the case of a 52-year-old woman with a topic dermatitis since adolescence who developed work-related hand eczema, cough and runny nose 12 years after she had started working as a laboratory technician at a precious metals refinery. While skin prick test with sodium hexachloroplatinate (SPTPt ) was negative, patch testing with ammonium tetrachloroplatinate was positive after 24, 48, 72, and 96 hr. Inhalation challenge with sodium hexachloroplatinate yielded cough, mild shortness of breath, and a maximal decrease of FEV1 of 8% from baseline 24 hr after the challenge. Significant increases of bronchial hyperresponsiveness, exhaled nitric monoxide and sputum eosinophils were documented after the challenge. We conclude that eosinophilic airway disease due to platinum salts may occur in SPTPt negative subjects. Both, patch testing and inhalation challenge with platinum salts should be considered in SPT negative subjects with occupational exposure to precious metal salts and work-related allergic symptoms. PMID- 26010733 TI - Early development of circadian rhythmicity in the suprachiamatic nuclei and pineal gland of teleost, flounder (Paralichthys olivaeus), embryos. AB - Circadian rhythms enable organisms to coordinate multiple physiological processes and behaviors with the earth's rotation. In mammals, the suprachiasmatic nuclei (SCN), the sole master circadian pacemaker, has entrainment mechanisms that set the circadian rhythm to a 24-h cycle with photic signals from retina. In contrast, the zebrafish SCN is not a circadian pacemaker, instead the pineal gland (PG) houses the major circadian oscillator. The SCN of flounder larvae, unlike that of zebrafish, however, expresses per2 with a rhythmicity of daytime/ON and nighttime/OFF. Here, we examined whether the rhythm of per2 expression in the flounder SCN represents the molecular clock. We also examined early development of the circadian rhythmicity in the SCN and PG. Our three major findings were as follows. First, rhythmic per2 expression in the SCN was maintained under 24 h dark (DD) conditions, indicating that a molecular clock exists in the flounder SCN. Second, onset of circadian rhythmicity in the SCN preceded that in the PG. Third, both 24 h light (LL) and DD conditions deeply affected the development of circadian rhythmicity in the SCN and PG. This is the first report dealing with the early development of circadian rhythmicity in the SCN in fish. PMID- 26010734 TI - Shared selective pressure and local genomic landscape lead to repeatable patterns of genomic divergence in sunflowers. AB - The repeated evolution of traits in organisms facing similar environmental conditions is considered to be fundamental evidence for the role of natural selection in moulding phenotypes. Yet, aside from case studies of parallel evolution and its genetic basis, the repeatability of evolution at the level of the whole genome remains poorly characterized. Here, through the use of transcriptome sequencing, we examined genomic divergence for three pairs of sister species of sunflowers. Two of the pairs (Helianthus petiolaris - H. debilis and H. annuus - H. argophyllus) have diverged along a similar latitudinal gradient and presumably experienced similar selective pressure. In contrast, a third species pair (H. exilis - H. bolanderi) diverged along a longitudinal gradient. Analyses of divergence, as measured in terms of FST, indicated little repeatability across the three pairs of species for individual genetic markers (SNPs), modest repeatability at the level of individual genes and the highest repeatability when large regions of the genome were compared. As expected, higher repeatability was observed for the two species pairs that have diverged along a similar latitudinal gradient, with genes involved in flowering time among the most divergent genes. Genes showing extreme low or high differentiation were more similar than genes showing medium levels of divergence, implying that both purifying and divergent selection contributed to repeatable patterns of divergence. The location of a gene along the chromosome also predicted divergence levels, presumably because of shared heterogeneity in both recombination and mutation rates. In conclusion, repeated genome evolution appeared to result from both similar selective pressures and shared local genomic landscapes. PMID- 26010735 TI - Accelerating T1rho cartilage imaging using compressed sensing with iterative locally adapted support detection and JSENSE. AB - PURPOSE: To accelerate T1rho quantification in cartilage imaging using combined compressed sensing with iterative locally adaptive support detection and JSENSE. METHODS: To reconstruct T1rho images from accelerated acquisition at different time of spin-lock (TSLs), we propose an approach to combine an advanced compressed sensing (CS) based reconstruction technique, LAISD (locally adaptive iterative support detection), and an advanced parallel imaging technique, JSENSE. Specifically, the reconstruction process alternates iteratively among local support detection in the domain of principal component analysis, compressed sensing reconstruction of the image sequence, and sensitivity estimation with JSENSE. T1rho quantification results from accelerated scans using the proposed method are evaluated using in vivo knee cartilage data from bilateral scans of three healthy volunteers. RESULTS: T1rho maps obtained from accelerated scans (acceleration factors of 3 and 3.5) using the proposed method showed results comparable to conventional full scans. The T1rho errors in all compartments are below 1%, which is well below the in vivo reproducibility of cartilage T1rho reported from previous studies. CONCLUSION: The proposed method can significantly accelerate the acquisition process of T1rho quantification on human cartilage imaging without sacrificing accuracy, which will greatly facilitate the clinical translation of quantitative cartilage MRI. PMID- 26010736 TI - Treatment of Hypertension in Children With Catecholamine-Secreting Tumors: A Systematic Approach. AB - Management of blood pressure in children with pheochromocytoma and other catecholamine-secreting tumors (CSTs) is unique and challenging. The authors report a single-center experience using sequential alpha-adrenergic blockade (phenoxybenzamine), increased fluid intake, and beta-blockade for presurgical management of 10 CSTs in children. In this retrospective review, mean duration for blood pressure control in preparation for surgery was 4.5+/-2.6 weeks. Intraoperative hypertension was noted transiently (<2 hours) in eight patients (80%) and was treated with continuous infusion of short-acting antihypertensive agents. Two (20%) patients required vasopressor medication infusion to manage intraoperative hypotension. Only two (20%) patients developed postoperative hypotension and required vasopressor medication infusion for <24 hours. All antihypertensive medications were discontinued in the immediate (<=4 days) postoperative period in 80% of patients. In conclusion, a systematic and multidisciplinary approach utilizing adrenergic blockade is effective in treating children with CSTs. PMID- 26010738 TI - Performance of baited underwater video: does it underestimate abundance at high population densities? AB - Video survey techniques are now commonly used to estimate animal abundance under the assumption that estimates relate to true abundance, a key property needed to make video a valid survey tool. Using the spiny lobster Palinurus elephas as our model organism, we evaluate the effectiveness of baited underwater video (BUV) for estimating abundance in areas with widely different population density. We test three BUV abundance metrics and compare the results with an independently obtained abundance index from trammel-net surveys (Trammel). Video metrics used to estimate relative abundance include a value for total number of individuals per recording (TotN), the traditional maximum number of fish observed in a single video frame (MaxN), and the recently suggested alternative, the average of the mean MaxN from 5-minute periods throughout the duration of the recording (MeanN). This is the first video study of a wild population to include an estimate for TotN. Comparison of TotN with the other two BUV relative abundance metrics demonstrates that both of the latter lack resolution at high population densities. In spite of this, the three BUV metrics tested, as well as the independent estimate Trammel, distinguished high density areas from low density areas. Thus they could all be used to identify areas of differing population density, but MaxN and MeanN would not be appropriate metrics for studies aimed at documenting increases in abundance, such as those conducted to assess marine protected area effectiveness, as they are prone to sampling saturation. We also demonstrate that time of first arrival (T1) is highly correlated with all of the abundance indices; suggesting T1 may be a potentially useful index of abundance. However, these relationships require further investigation as our data suggests T1 may not adequately represent lobster abundance in areas of high density. PMID- 26010739 TI - Nanomaterials for Engineering Stem Cell Responses. AB - Recent progress in nanotechnology has stimulated the development of multifunctional biomaterials for tissue engineering applications. Synergistic interactions between nanomaterials and stem cell engineering offer numerous possibilities to address some of the daunting challenges in regenerative medicine, such as controlling trigger differentiation, immune reactions, limited supply of stem cells, and engineering complex tissue structures. Specifically, the interactions between stem cells and their microenvironment play key roles in controlling stem cell fate, which underlines therapeutic success. However, the interactions between nanomaterials and stem cells are not well understood, and the effects of the nanomaterials shape, surface morphology, and chemical functionality on cellular processes need critical evaluation. In this Review, focus is put on recent development in nanomaterial-stem cell interactions, with specific emphasis on their application in regenerative medicine. Further, the emerging technologies based on nanomaterials developed over the past decade for stem cell engineering are reviewed, as well as the potential applications of these nanomaterials in tissue regeneration, stem cell isolation, and drug/gene delivery. It is anticipated that the enhanced understanding of nanomaterial-stem cell interactions will facilitate improved biomaterial design for a range of biomedical and biotechnological applications. PMID- 26010737 TI - Environmental mold and mycotoxin exposures elicit specific cytokine and chemokine responses. AB - BACKGROUND: Molds can cause respiratory symptoms and asthma. We sought to use isolated peripheral blood mononuclear cells (PBMCs) to understand changes in cytokine and chemokine levels in response to mold and mycotoxin exposures and to link these levels with respiratory symptoms in humans. We did this by utilizing an ex vivo assay approach to differentiate mold-exposed patients and unexposed controls. While circulating plasma chemokine and cytokine levels from these two groups might be similar, we hypothesized that by challenging their isolated white blood cells with mold or mold extracts, we would see a differential chemokine and cytokine release. METHODS AND FINDINGS: Peripheral blood mononuclear cells (PBMCs) were isolated from blood from 33 patients with a history of mold exposures and from 17 controls. Cultured PBMCs were incubated with the most prominent Stachybotrys chartarum mycotoxin, satratoxin G, or with aqueous mold extract, ionomycin, or media, each with or without PMA. Additional PBMCs were exposed to spores of Aspergillus niger, Cladosporium herbarum and Penicillium chrysogenum. After 18 hours, cytokines and chemokines released into the culture medium were measured by multiplex assay. Clinical histories, physical examinations and pulmonary function tests were also conducted. After ex vivo PBMC exposures to molds or mycotoxins, the chemokine and cytokine profiles from patients with a history of mold exposure were significantly different from those of unexposed controls. In contrast, biomarker profiles from cells exposed to media alone showed no difference between the patients and controls. CONCLUSIONS: These findings demonstrate that chronic mold exposures induced changes in inflammatory and immune system responses to specific mold and mycotoxin challenges. These responses can differentiate mold-exposed patients from unexposed controls. This strategy may be a powerful approach to document immune system responsiveness to molds and other inflammation-inducing environmental agents. PMID- 26010740 TI - Coping With Antigay Violence: In-Depth Interviews With Flemish LGB Adults. AB - In view of the possible negative mental health outcomes of antigay violence and the limited understanding of how lesbian, gay, and bisexual (LGB) men and women cope with such experiences, this study examined the coping and social support seeking strategies that victims adopt. In 2012, in-depth interviews were conducted with 19 Flemish sexual minority victims of violence. These in-depth interviews show that antigay violence can generate profound negative outcomes. However, the respondents employed a range of coping strategies, of which four were discerned: (1) avoidance strategies, (2) assertiveness and confrontation, (3) cognitive change, and (4) social support. Applying a diverse set of coping strategies and actively attaching meaning to negative experiences helps victims of antigay violence to overcome negative effects such as fear, embarrassment, or depressive feelings. However, the presence of a supportive network seems an important condition in order for these positive outcomes to occur. PMID- 26010742 TI - In vivo study for the discrimination of cancerous and normal skin using fibre probe-based Raman spectroscopy. AB - Raman spectroscopy has proved its capability as an objective, non-invasive tool for the detection of various melanoma and non-melanoma skin cancers (NMSC) in a number of studies. Most publications are based on a Raman microspectroscopic ex vivo approach. In this in vivo clinical evaluation, we apply Raman spectroscopy using a fibre-coupled probe that allows access to a multitude of affected body sites. The probe design is optimized for epithelial sensitivity, whereby a large part of the detected signal originates from within the epidermal layer's depth down to the basal membrane where early stages of skin cancer develop. Data analysis was performed on measurements of 104 subjects scheduled for excision of lesions suspected of being malignant melanoma (MM) (n = 36), basal cell carcinoma (BCC) (n = 39) and squamous cell carcinoma (SCC) (n = 29). NMSC were discriminated from normal skin with a balanced accuracy of 73% (BCC) and 85% (SCC) using partial least squares discriminant analysis (PLS-DA). Discriminating MM and pigmented nevi (PN) resulted in a balanced accuracy of 91%. These results lie within the range of comparable in vivo studies and the accuracies achieved by trained dermatologists using dermoscopy. Discrimination proved to be unsuccessful between cancerous lesions and suspicious lesions that had been histopathologically verified as benign by dermoscopy. PMID- 26010741 TI - Circulating bacterial-derived DNA fragment level is a strong predictor of cardiovascular disease in peritoneal dialysis patients. AB - BACKGROUND: Circulating bacterial DNA fragment is related to systemic inflammatory state in peritoneal dialysis (PD) patients. We hypothesize that plasma bacterial DNA level predicts cardiovascular events in new PD patients. METHODS: We measured plasma bacterial DNA level in 191 new PD patients, who were then followed for at least a year for the development of cardiovascular event, hospitalization, and patient survival. RESULTS: The average age was 59.3 +/- 11.8 years; plasma bacterial DNA level 34.9 +/- 1.5 cycles; average follow up 23.2 +/- 9.7 months. At 24 months, the event-free survival was 86.1%, 69.8%, 55.4% and 30.8% for plasma bacterial DNA level quartiles I, II, III and IV, respectively (p < 0.0001). After adjusting for confounders, plasma bacterial DNA level, baseline residual renal function and malnutrition-inflammation score were independent predictors of composite cardiovascular end-point; each doubling in plasma bacterial DNA level confers a 26.9% (95% confidence interval, 13.0 - 42.5%) excess in risk. Plasma bacterial DNA also correlated with the number of hospital admission (r = -0.379, p < 0.0001) and duration of hospitalization for cardiovascular reasons (r = -0.386, p < 0.0001). Plasma bacterial DNA level did not correlate with baseline arterial pulse wave velocity (PWV), but with the change in carotid-radial PWV in one year (r = -0.238, p = 0.005). CONCLUSIONS: Circulating bacterial DNA fragment level is a strong predictor of cardiovascular event, need of hospitalization, as well as the progressive change in arterial stiffness in new PD patients. PMID- 26010743 TI - A clustering algorithm for multivariate longitudinal data. AB - Latent growth modeling approaches, such as growth mixture models, are used to identify meaningful groups or classes of individuals in a larger heterogeneous population. But when applied to multivariate repeated measures computational problems are likely, due to the high dimension of the joint distribution of the random effects in these mixed-effects models. This article proposes a cluster algorithm for multivariate repeated data, using pseudo-likelihood and ideas based on k-means clustering, to reveal homogenous subgroups. The algorithm was demonstrated on an electro-encephalogram dataset set quantifying the effect of psychoactive compounds on the brain activity in rats. PMID- 26010744 TI - Pseudo Pseudo A-A-V Response: What is the Mechanism? PMID- 26010747 TI - Details of human middle ear morphology based on micro-CT imaging of phosphotungstic acid stained samples. AB - A multitude of morphological aspects of the human middle ear (ME) were studied qualitatively and/or quantitatively through the postprocessing and interpretation of micro-CT (micro X-ray computed tomography) data of six human temporal bones. The samples were scanned after phosphotungstic acid staining to enhance soft tissue contrast. The influence of this staining on ME ossicle configuration was shown to be insignificant. Through postprocessing, the image data were converted into surface models, after which the approaches diverged depending on the topics of interest. The studied topics were: the ME ligaments; morphometric and mechanical parameters of the ossicles relating to inertia and the ossicular lever arm ratio; the morphology of the distal incus; the contact surface areas of the tympanic membrane (TM) and of the stapes footplate; and the thickness of the TM, round window of the cochlea, ossicle joint spaces, and stapedial annular ligament. Some of the resulting insights are relevant in ongoing discussions concerning ME morphology and mechanical functions, while other results provide quantitative data to add to existing data. All findings are discussed in the light of other published data and many are relevant for the construction of mechanical finite element simulations of the ME. PMID- 26010745 TI - 1-Methyl-4-phenylpyridinium stereotactic infusion completely and specifically ablated the nigrostriatal dopaminergic pathway in rhesus macaque. AB - INTRODUCTION: Complete and specific ablation of a single dopaminergic (DA) pathway is a critical step to distinguish the roles of DA pathways in vivo. However, this kind of technique has not been reported in non-human primates. This study aimed to establish a lesioning method with a complete and specific ablation. METHOD: A carefully designed infusion route based on a MRI stereotactic technique was developed to deliver the highly selective dopaminergic toxin 1 methyl-4-phenylpyridinium (MPP+) unilaterally into multiple sites of compact part of substantia nigra (SNc) and striatum in monkeys. The nigrostriatal DA pathway was selected because lesioning of this pathway may induce symptoms that are suitable for evaluation. The pathological, behavioral, neuropharmacological, and clinical laboratorial data were collected to evaluate the lesioning effects. RESULT: Pathological examination revealed a complete ablation of tyrosine hydroxylase positive (TH+) neurons in the SNc, while preserving intact TH+ neurons in the ventral tegmental area (VTA) nearby. TH+ projections in the striatum were also unilaterally lost. The monkeys displayed stable (>28 weeks) rotations and symptoms which were expected with loss of DA neurons in the SNc, with rest tremor being an exception. No item implied the presence of a severe side effect caused by the operation or the intracerebral MPP+ infusion. The results suggested that rest tremor may not directly rely on the nigrostriatal pathway. CONCLUSION: Taken together, in addition to providing a specific nigrostriatal DA lesioned model, this method, combined with brain stimulation or other techniques, can be applied as a powerful tool for the complete lesion of any desired DA pathway in order to study its specific functions in the brain. PMID- 26010748 TI - Worktime control access, need and use in relation to work-home interference, fatigue, and job motivation. AB - OBJECTIVE: Worktime control (WTC) has been suggested as a tool to reduce employees' work-home interference and fatigue and improve job motivation. The purpose of this study was twofold: (i) to examine the prevalence of employees' need for, access to, and use of WTC, as well as the incongruence between need for and access to WTC (ie, mismatch); and (ii) to examine the associations of this mismatch and the use of WTC with employees' work-home interference (WHI), fatigue and job motivation. METHODS: Questionnaire data were collected among a large (N=2420) quasi-representative sample of Dutch employees. The prevalence of WTC need, access, use, and mismatch was assessed by means of descriptive statistics. Associations with employees' outcomes were assessed by analyses of covariance. RESULTS: The need for WTC was highly prevalent. For many employees, we observed a negative mismatch between access to and need for WTC (ie, access0.59) were found between conditions for horizontal GRF, propulsive phase duration, average EMG amplitude, and duration of EMG activity during the countermovement. Participants reported higher comfort ratings when shod compared with barefoot and minimal shoes for both jumps. Participants also perceived better performance when shod compared with barefoot and minimal shoes for the VJ only. No acute differences in displacement were observed between barefoot, minimal shoes, and cross-trainer shoes during vertical and horizontal jumps. Some differences in muscle activation and timing seem to be present, and thus, training effects between footwear conditions should be examined. Footwear familiarization may prove beneficial, as acute increases in comfort seem unrelated to performance improvements. PMID- 26010800 TI - A retrospective study on anthropometrical, physical fitness, and motor coordination characteristics that influence dropout, contract status, and first team playing time in high-level soccer players aged eight to eighteen years. AB - The goal of this article was twofold, and a 2-study approach was conducted. The first study aimed to expose the anthropometrical, physical performance, and motor coordination characteristics that influence dropout from a high-level soccer training program in players aged 8-16 years. The mixed-longitudinal sample included 388 Belgian youth soccer players who were assigned to either a "club group" or a "dropout group." In the second study, cross-sectional data of anthropometry, physical performance, and motor coordination were retrospectively explored to investigate which characteristics influence future contract status (contract vs. no contract group) and first-team playing time for 72 high-level youth soccer players (mean age = 16.2 years). Generally, club players outperformed their dropout peers for motor coordination, soccer-specific aerobic endurance, and speed. Anthropometry and estimated maturity status did not discriminate between club and dropout players. Contract players jumped further (p = 0.011) and had faster times for a 5-m sprint (p = 0.041) than no contract players. The following prediction equation explains 16.7% of the variance in future playing minutes in adolescent youth male soccer players: -2,869.3 + 14.6 * standing broad jump. Practitioners should include the evaluation of motor coordination, aerobic endurance, and speed performances to distinguish high-level soccer players further succeeding a talent development program and future dropout players, between 8 and 16 years. From the age of 16 years, measures of explosivity are supportive when selecting players into a future professional soccer career. PMID- 26010801 TI - Heart rate-based training intensity and its impact on injury incidence among elite-level professional soccer players. AB - Elite-level professional soccer players are suggested to have increased physical, technical, tactical, and psychological capabilities when compared with their subelite counterparts. Ensuring these players remain at the elite level generally involves training many different bodily systems to a high intensity or level within a short duration. This study aimed to examine whether an increase in training volume at high-intensity levels was related to injury incidence, or increased the odds of sustaining an injury. Training intensity was monitored through time spent in high-intensity (T-HI) and very high-intensity (T-VHI) zones of 85-<90% and >=90% of maximal heart rate (HRmax), and all injuries were recorded over 2 consecutive seasons. Twenty-three, elite professional male soccer players (mean +/- SD age, 25.6 +/- 4.6 years; stature, 181.8 +/- 6.8 cm; and body mass, 79.3 +/- 8.1 kg) were studied throughout the 2-years span of the investigation. The results showed a mean total injury incidence of 18.8 (95% confidence interval [CI], 14.7-22.9) injuries per 1,000 hours of exposure. Significant correlations were found between training volume at T-HI and injury incidence (r = 0.57, p = 0.005). Further analysis revealed how players achieving more time in the T-VHI zone during training increased the odds of sustaining a match injury (odds ratio = 1.87; 95% CI, 1.12-3.12, p = 0.02) but did not increase the odds of sustaining a training injury. Reducing the number of competitive match injuries among elite-level professional players may be possible if greater focus is placed on the training intensity and volume over a period of time ensuring the potential reduction of fatigue or overuse injuries. In addition, it is important to understand the optimal training load at which adaptation occurs without raising the risk of injury. PMID- 26010804 TI - Phase behaviour of inverse patchy colloids: effect of the model parameters. AB - The phase behaviour of inverse patchy colloid systems composed of spherical particles with two oppositely charged patches at the poles is investigated by simulation-based thermodynamic integration schemes. The interaction between the particles is derived via a coarse-grained model characterized by three system parameters: the charge imbalance between the bare colloid and the patches, the patch surface extension and the particle interaction range. Starting from a set of parameters for which a stacking of parallel layers is thermodynamically stable, the effect of each of these three parameters on the phase diagram is studied. Our results show that the region of stability of the layered solid phase can be expanded by increasing the charge imbalance and/or by reducing the interaction range. A larger patch size, on the other hand, stabilizes the layered structure with respect to the competing face centered cubic solid at high pressures but destabilizes it with respect to the fluid phase at low pressures. The location of the liquid-vapour critical point in the temperature versus density plane is also investigated: while the charge imbalance and the patch size affect mainly the critical density, a change of the interaction range has a substantial impact also on the critical temperature. PMID- 26010803 TI - Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial. AB - IMPORTANCE: Thromboembolism is the most common complication in coiling for an unruptured aneurysm and is frequent in patients with high on-treatment platelet reactivity (HTPR) who are prescribed a standard antiplatelet preparation for its prevention. OBJECTIVE: To evaluate the effect of a modified antiplatelet preparation compared with a standard preparation in patients with HTPR undergoing coiling. DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized open-label active-control trial with blinded outcome assessment at the Seoul National University Bundang Hospital from May 27, 2013, to April 7, 2014. Patients with HTPR were randomly assigned (1 to 1) to the standard or modified preparation group. Patients without HTPR were assigned to the non-HTPR group. A total of 228 patients undergoing coiling for unruptured aneurysms were enrolled and allocated to the study, 126 in the HTPR group (63 to the standard preparation group and 63 to the modified preparation group) and 102 to the non-HTPR group. Intent-to-treat analysis was performed. INTERVENTIONS: The modified preparation (HTPR to aspirin, 300 mg of aspirin and 75 mg of clopidogrel bisulfate; and HTPR to clopidogrel, 200 mg of cilostazol added to the standard regimen) was performed before coiling in the modified preparation group. Standard preparation (100 mg of aspirin and 75 mg of clopidogrel) was maintained in the standard preparation and non-HTPR groups. MAIN OUTCOMES AND MEASURES: The primary outcome was a thromboembolic event defined as thromboembolism during coiling and a transient ischemic attack or ischemic stroke within 7 days after coiling. The principal secondary outcome was a bleeding complication according to Thrombolysis in Myocardial Infarction bleeding criteria within 30 days after coil embolization. RESULTS: The thromboembolic event rate was low in the modified preparation group (1 of 63 [1.6%]) compared with the standard preparation group (7 of 63 [11.1%]; adjusted risk difference, -11.7% [95% CI, -21.3% to -2.0%]; P = .02), which had a higher thromboembolic risk than the non-HTPR group (1 of 102 [1.0%]; adjusted risk difference, 8.6% [95% CI, 1.0% to 16.3%]; P = .03). All bleeding complications were of minimal grade according to Thrombolysis in Myocardial Infarction bleeding criteria. The bleeding rate was not different between the modified (6 of 63 [9.5%]) and standard (4 of 63 [6.3%]) preparation groups (adjusted risk difference, 5.6% [95% CI, -4.2% to 15.4%]; P = .26). CONCLUSIONS AND RELEVANCE: Modified antiplatelet preparation for patients with HTPR compared with standard antiplatelet preparation reduced the thromboembolic event rate in coiling for an unruptured aneurysm without increasing bleeding. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0000804. PMID- 26010802 TI - Identification of B6SJL mSOD1(G93A) mouse subgroups with different disease progression rates. AB - Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3-5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1(G93A) mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS. PMID- 26010805 TI - The giraffe kidney tolerates high arterial blood pressure by high renal interstitial pressure and low glomerular filtration rate. AB - BACKGROUND: The tallest animal on earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension-related damage. We hypothesized that a species-specific evolutionary adaption in the giraffe kidney allows normal for size renal haemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals. METHODS: Fourteen anaesthetized giraffes were instrumented with vascular and bladder catheters to measure glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal interstitial hydrostatic pressure (RIHP) was assessed by inserting a needle into the medullary parenchyma. Doppler ultrasound measurements provided renal artery resistive index (RI). Hormone concentrations as well as biomechanical, structural and histological characteristics of vascular and renal tissues were determined. RESULTS: GFR averaged 342 +/- 99 mL min(-1) and ERPF 1252 +/- 305 mL min(-1) . RIHP varied between 45 and 140 mmHg. Renal pelvic pressure was 39 +/- 2 mmHg and renal venous pressure 32 +/- 4 mmHg. A valve-like structure at the junction of the renal and vena cava generated a pressure drop of 12 +/- 2 mmHg. RI was 0.27. The renal capsule was durable with a calculated burst pressure of 600 mmHg. Plasma renin and AngII were 2.6 +/- 0.5 mIU L(-1) and 9.1 +/- 1.5 pg mL(-1) respectively. CONCLUSION: In giraffes, GFR, ERPF and RI appear much lower than expected based on body mass. A strong renal capsule supports a RIHP, which is >10-fold that of other mammals effectively reducing the net filtration pressure and protecting against the high MAP. PMID- 26010806 TI - Silenorubicoside E-I, five new triterpenoid saponins isolated from Silene rubicunda Franch. PMID- 26010807 TI - Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients. AB - Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by extraordinary sensitivity to sunlight, resulting in cutaneous malignant tumors. Among XP, XP-F presents relatively uniquely in Japanese. To clarify the characteristics of this group, we describe a case of XP-F and review Japanese cases previously reported. A 50-year-old Japanese woman was referred to us with multiple, variously sized, light- or dark-brown macules on the face and sunlight-exposed extremities. She had experienced bulla formation with approximately 10 min of sunlight exposure during her elementary school years. Her parents had been first cousins, and her mother and sister had photosensitivity. She showed no neurological or developmental abnormalities. Ultraviolet (UV) irradiation testing revealed normal levels for minimal erythema dose with UV-A and UV-B. Sensitivity to UV-C and DNA repair ability in the patient's fibroblasts were indicated between that in normal individuals and that in an XP-A patient. Complementation assay revealed that transfection of the XPF gene led most efficient DNA repair compared with the other XP genes. Therefore, the patient was diagnosed with XP-F. Twenty-three cases of Japanese patients (six males, 17 females) with XP-F have been reported, including the present case. Our review suggested a relatively high prevalence of 50% (11/22) for cutaneous malignant tumors. A significant difference was evident in the mean age at first medical consultation between patients with cutaneous malignant tumors (53.6 years) and patients without such tumors (30.8 years). This suggests that cutaneous malignant tumors could occur in the age range of 30-50 years in XP-F patients. PMID- 26010809 TI - The antioxidant effects of pomegranate extract on local and remote organs in a mesenteric ischemia and reperfusion model. AB - OBJECTIVES: We investigated whether pomegranate extract plays a protective antioxidant role against mesenteric ischemia-reperfusion injury (IR), which can lead to a systemic response and damage distant organs, such as the lung, liver, and kidney. METHODS: Forty female Wistar-Albino rats were separated into four groups: laparotomy, laparotomy + PG, mesenteric IR, and mesenteric IR and pomegranate (IR + PG). In the laparotomy + PG and IR + PG groups, pomegranate (225 mg/kg) was given by oral gavage at the beginning of the study. Ischemia was induced for 30 minutes, and reperfusion was subsequently allowed for 60 minutes in the IR and IR + PG groups. The malondialdehyde (MDA) and total antioxidant activity (AOA) levels were evaluated in blood samples. Additionally, all tissues were removed for the measurement of AOA and total oxidant status as well as for subsequent histopathological evaluation. The oxidative stress index was calculated. RESULTS: Histopathological changes in all organs were significantly higher in the IR group and significantly lower in the IR + PG group vs. the other groups. Serum MDA levels were significantly lower in the IR + PG group than in the IR group. No significant difference was found in AOA levels of the groups. DISCUSSION: These data may explain the positive protective effects of pomegranate based on the histopathologic findings in ischemic conditions in an intestinal IR injury model. PMID- 26010808 TI - Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. AB - The management of primary hypothyroidism with levothyroxine (L-T4) is simple, effective and safe, and most patients report improved well-being on initiation of treatment. However, a proportion of individuals continue to suffer with symptoms despite achieving adequate biochemical correction. The management of such individuals has been the subject of controversy and of considerable public interest. The American Thyroid Association (ATA) and the European Thyroid Association (ETA) have recently published guidelines on the diagnosis and management of hypothyroidism. These guidelines have been based on extensive reviews of the medical literature and include sections on the role of combination therapy with L-T4 and liothyronine (L-T3) in individuals who are persistently dissatisfied with L-T4 therapy. This position statement by the British Thyroid Association (BTA) summarises the key points in these guidelines and makes recommendations on the management of primary hypothyroidism based on the current literature, review of the published positions of the ETA and ATA, and in line with best principles of good medical practice. The statement is endorsed by the Association of Clinical Biochemistry, (ACB), British Thyroid Foundation, (BTF), Royal College of Physicians (RCP) and Society for Endocrinology (SFE). PMID- 26010810 TI - Client Perceptions of Occupational Health and Safety Management System Assistance Provided by OSHA On-Site Consultation: Results of a Survey of Colorado Small Business Consultation Clients. AB - The Occupational Safety and Health Administration (OSHA) On-Site Consultation Service provides assistance establishing occupational health and safety management systems (OHSMS) to small businesses. The Safety and Health Program Assessment Worksheet (Revised OSHA Form 33) is the instrument used by consultants to assess an organization's OHSMS and provide feedback on how to improve a system. A survey was developed to determine the usefulness of the Revised OSHA Form 33 from the perspective of Colorado OSHA consultation clients. One hundred and seven clients who had received consultation services within a six-year period responded to the survey. The vast majority of respondents indicated that the Revised OSHA Form 33 accurately reflected their OHSMS and that information provided on the Revised OSHA Form 33 was helpful for improving their systems. Specific outcomes reported by the respondents included increased safety awareness, reduced injuries, and improved morale. The results indicate that the OHSMS assistance provided by OSHA consultation is beneficial for clients and that the Revised OSHA Form 33 can be an effective tool for assessing and communicating OHSMS results to business management. Detailed comments and suggestions provided on the Revised OSHA Form 33 are helpful for clients to improve their OHSMS. PMID- 26010811 TI - Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists. AB - Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl 2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 1j) showed ~75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 MUM/1.4 MUM) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia. PMID- 26010812 TI - Synthesis of Paclitaxel. 1. Synthesis of the ABC Ring of Paclitaxel by SmI2 Mediated Cyclization. AB - A convergent synthesis of the ABC ring of antitumor natural product paclitaxel (Taxol) is described. SmI2-mediated reductive cyclization of an allylic benzoate possessing an aldehyde function, synthesized from tri-O-acetyl-d-glucal and 1,3 cyclohexanedione, smoothly afforded the highly strained 6-8-6 tricarbocyclic structure in 66% yield. PMID- 26010814 TI - Bone research: an issue of maturity. PMID- 26010815 TI - Anastomosing or plexiform ameloblastoma? PMID- 26010816 TI - CORRIGENDUM: The Evidence of Glioblastoma Heterogeneity. PMID- 26010817 TI - Cognitive and emotional functioning in binge-eating disorder: A systematic review. AB - OBJECTIVE: Binge-eating disorder (BED) is characterized by recurrent episodes of binge eating and is associated with eating disorder and general psychopathology and overweight/obesity. Deficits in cognitive and emotional functioning for eating disorders or obesity have been reported. However, a systematic review on cognitive and emotional functioning for individuals with BED is lacking. METHOD: A systematic literature search was conducted across three databases (Medline, PubMed, and PsycINFO). Overall, n = 57 studies were included in the present review. RESULTS: Regarding cognitive functioning (CoF), individuals with BED consistently demonstrated higher information processing biases compared to obese and normal-weight controls in the context of disorder-related stimuli (i.e., food and body cues), whereas CoF in the context of neutral stimuli appeared to be less affected. Thus, results suggest disorder-related rather than general difficulties in CoF in BED. With respect to emotional functioning (EmF), individuals with BED reported difficulties similar to individuals with other eating disorders, with a tendency to show less severe difficulties in some domains. In addition, individuals with BED reported greater emotional deficits when compared to obese and normal-weight controls. Findings suggest general difficulties in EmF in BED. Thus far, however, investigations of EmF in disorder-relevant situations are lacking. DISCUSSION: Overall, the cross-sectional findings indicate BED to be associated with difficulties in CoF and EmF. Future research should determine the nature of these difficulties, in regards to general and disorder-related stimuli, and consider interactions of both domains to foster the development and improvement of appropriate interventions in BED. PMID- 26010818 TI - Delay discounting, but not disinhibition or inattention, partially mediates the effects of neuroticism on disordered eating in adolescents. AB - Adolescence represents an integral developmental period for the prevention and intervention of disordered eating. Individuals with high levels of neuroticism have been shown to respond with greater impulsivity and use of disordered eating as a coping mechanism. However, the exact mechanism through which neuroticism and impulsivity affect disordered eating remains unknown. To understand the effects of personality and impulsivity on disordered eating in adolescence, the present study aimed to investigate whether impulsivity mediated the relationship between neuroticism and disordered eating. Adolescents (N=40) between the ages of 13 and 19 (Mage=18.25years; S.D.=1.30) were queried on eating attitudes and personality, as well as completed behavioral tasks assessing impulsivity (delay discounting, disinhibition and inattention). Mediation analyses revealed that neuroticism was significantly associated with patterns of disordered eating, but delay discounting, and not disinhibition and inattention, appeared to mediate the relationship between neuroticism and disordered eating. These results should guide prospective research exploring the relations between neurotic and impulsive behavior, particularly delay discounting on disordered eating, which will assist in future treatment efforts targeting the development of maladaptive eating behaviors. PMID- 26010819 TI - Variation in cerebral palsy profile by socio-economic status. AB - AIM: Socio-economic differences in maternal and child health are well recognized, but the role of individual-level and area-level determinants in cerebral palsy (CP) phenotypes is debated. We set out to examine (1) the association between area-level and individual-level measures of socio-economic deprivation and CP phenotype among children, including subtype, severity, and comorbidities; and (2) the direct effect of area-level deprivation not mediated through individual-level deprivation. METHOD: Regional data from a provincial CP register were analyzed. The outcome of interest was CP phenotype. The area-level exposure was measured using the Pampalon Deprivation Index. Individual-level socio-economic status (SES) was determined using maternal education. We conducted multiple regression models, stratified by preterm birth, controlling for key covariates, and a mediation analysis of area-level deprivation on the association between individual SES and CP phenotype. RESULTS: A socio-economic gradient in mobility was seen in our cohort, above and beyond differences in maternal and perinatal factors. The added direct effect of area-level deprivation was seen only in children whose mothers were educated to a higher level, suggesting no additional contribution of area-level deprivation in children of mothers with a lower level of education. INTERPRETATION: Contextual socio-economic factors can impact the severity of CP. These findings indicate important areas for potential community level or area-level public health intervention (i.e. neighborhood reinvestment, preventive measures), and suggest that neighborhood-level research in maternal and perinatal health should continue to be pursued. PMID- 26010820 TI - Skin Barrier Recovery is not Associated with Self-Perceived Stress. AB - The primary aim of the current study was to examine the association between self perceived stress and skin-barrier recovery. From an initial sample of 410 students, 19 high-stress and 12 low-stress Hispanic women completed a behavioural survey and were assessed for recovery of skin barrier following a tape-stripping procedure. No association was found between self-perceived stress and skin barrier recovery at either the 30-min or 3.15-h recovery period. Supplemental analysis showed a positive correlation between skin barrier recovery and self reported sleep quantity at both recovery periods. Barrier repair reflects a single, minimally invasive, measure of wound healing; thus, our findings do not necessarily contradict the notion that stress measures can be used to predict wound healing more broadly defined. Supplemental analysis demonstrated an intriguing relationship between barrier recovery and the number of hours slept, but these findings are considered tentative and will require replication with more rigorous measures of sleep quantity and quality. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010821 TI - A Near Infrared Light Triggered Hydrogenated Black TiO2 for Cancer Photothermal Therapy. AB - White TiO2 nanoparticles (NPs) have been widely used for cancer photodynamic therapy based on their ultraviolet light-triggered properties. To date, biomedical applications using white TiO2 NPs have been limited, since ultraviolet light is a well-known mutagen and shallow penetration. This work is the first report about hydrogenated black TiO2 (H-TiO2 ) NPs with near infrared absorption explored as photothermal agent for cancer photothermal therapy to circumvent the obstacle of ultraviolet light excitation. Here, it is shown that photothermal effect of H-TiO2 NPs can be attributed to their dramatically enhanced nonradiative recombination. After polyethylene glycol (PEG) coating, H-TiO2 -PEG NPs exhibit high photothermal conversion efficiency of 40.8%, and stable size distribution in serum solution. The toxicity and cancer therapy effect of H-TiO2 PEG NPs are relative systemically evaluated in vitro and in vivo. The findings herein demonstrate that infrared-irradiated H-TiO2 -PEG NPs exhibit low toxicity, high efficiency as a photothermal agent for cancer therapy, and are promising for further biomedical applications. PMID- 26010822 TI - Analysis of an advisor-advisee relationship: an exploratory study of the area of exact and Earth sciences in Brazil. AB - Scientific collaboration has been studied by researchers for decades. Several approaches have been adopted to address the question of how collaboration has evolved in terms of publication output, numbers of coauthors, and multidisciplinary trends. One particular type of collaboration that has received very little attention concerns advisor and advisee relationships. In this paper, we examine this relationship for the researchers who are involved in the area of Exact and Earth Sciences in Brazil and its eight subareas. These pairs are registered in the Lattes Platform that manages the individual curricula vitae of Brazilian researchers. The individual features of these academic researchers and their coauthoring relationships were investigated. We have found evidence that there exists positive correlation between time of advisor-advisee relationship with the advisee's productivity. Additionally, there has been a gradual decline in advisor-advisee coauthoring over a number of years as measured by the Kulczynski index, which could be interpreted as decline of the dependence. PMID- 26010823 TI - Deficient cytokine control modulates temporomandibular joint pain in rheumatoid arthritis. AB - The aim was to investigate how endogenous cytokine control of tumor necrosis factor (TNF) influences temporomandibular joint (TMJ) pain in relation to the role of anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA). Twenty-six consecutive patients with TMJ RA were included. Temporomandibular joint pain intensity was assessed at rest, on maximum mouth opening, on chewing, and on palpation. Mandibular movement capacity and degree of anterior open bite (a clinical sign of structural destruction of TMJ tissues) were also assessed. Systemic inflammatory activity was assessed using the Disease Activity Score in 28 joints (DAS28) for rheumatoid arthritis. Samples of TMJ synovial fluid and blood were obtained and analyzed for TNF, its soluble receptor, soluble TNF receptor II (TNFsRII), and ACPA. A high concentration of TNF in relation to the concentration of TNFsRII in TMJ synovial fluid was associated with TMJ pain on posterior palpation on maximum mouth opening. The ACPA concentration correlated significantly to the TNF concentration, but not to the TNFsRII concentration, indicating that increased inflammatory activity is mainly caused by an insufficient increase in anti-inflammatory mediators. This study indicates that TMJ pain on palpation in patients with RA is related to a deficiency in local cytokine control that contributes to increased inflammatory activity, including sensitization to mechanical stimuli over the TMJ. PMID- 26010824 TI - Recognition without awareness: Encoding and retrieval factors. AB - The article reports 4 experiments that explore the notion of recognition without awareness using words as the material. Previous work by Voss and associates has shown that complex visual patterns were correctly selected as targets in a 2 alternative forced-choice (2-AFC) recognition test although participants reported that they were guessing. The present experiments sought to extend this earlier work by having participants study words in different ways and then attempt to recognize the words later in a series of 4-alternative forced-choice (4-AFC) tests, some of which contained no target word. The data of interest are cases in which a target was present and participants stated that they were guessing, yet chose the correct item. This value was greater than p = .25 in all conditions of the 4 experiments, demonstrating the phenomenon of recognition without awareness. Whereas Voss and colleagues attributed their findings with kaleidoscope patterns to enhanced processing fluency of perceptual attributes, the main factor associated with different levels of recognition without awareness in the present studies was a variable criterion for the subjective state accompanying selection of the "guess" option, depending on the overall difficulty of the recognition test. We conclude by discussing some implications of the results for the distinction between implicit and explicit memory. PMID- 26010825 TI - Children's eye-movements during reading reflect the quality of lexical representations: An individual differences approach. AB - The lexical quality hypothesis (Perfetti & Hart, 2002) suggests that skilled reading requires high-quality lexical representations. In children, these representations are still developing, and it has been suggested that this development leads to more adult-like eye-movement behavior during the reading of connected text. To test this idea, a set of young adolescents (aged 11-13 years) completed a standardized measure of lexical quality and then participated in 3 eye-movement tasks: reading, scene search, and pseudoreading. The richness of participants' lexical representations predicted a variety of eye-movement behaviors in reading. Further, the influence of lexical quality was domain specific: Fixation durations in reading diverged from the other tasks as lexical quality increased. These findings suggest that eye movements become increasingly tuned to written language processing as lexical representations become more accurate and detailed. PMID- 26010826 TI - Similarity, not complexity, determines visual working memory performance. AB - A number of studies have shown that visual working memory (WM) is poorer for complex versus simple items, traditionally accounted for by higher information load placing greater demands on encoding and storage capacity limits. Other research suggests that it may not be complexity that determines WM performance per se, but rather increased perceptual similarity between complex items as a result of a large amount of overlapping information. Increased similarity is thought to lead to greater comparison errors between items encoded into WM and the test item(s) presented at retrieval. However, previous studies have used different object categories to manipulate complexity and similarity, raising questions as to whether these effects are simply due to cross-category differences. For the first time, here the relationship between complexity and similarity in WM using the same stimulus category (abstract polygons) are investigated. The authors used a delayed discrimination task to measure WM for 1 4 complex versus simple simultaneously presented items and manipulated the similarity between the single test item at retrieval and the sample items at encoding. WM was poorer for complex than simple items only when the test item was similar to 1 of the encoding items, and not when it was dissimilar or identical. The results provide clear support for reinterpretation of the complexity effect in WM as a similarity effect and highlight the importance of the retrieval stage in governing WM performance. The authors discuss how these findings can be reconciled with current models of WM capacity limits. PMID- 26010827 TI - Memory consequences of looking back to notice change: Retroactive and proactive facilitation. AB - Three experiments contrasted recollection of change with differentiation as means of avoiding retroactive interference and proactive interference. We manipulated the extent to which participants looked back to notice change between pairs of cues and targets (A-B, A-D) and measured the effects on later cued recall of either the first or second response. Two lists of word pairs were presented. Some right-hand members of pairs were changed within List 2, whereas others were changed between lists. Participants in a Within-List Back condition were instructed to detect changes that occurred only during List 2, in an effort to reduce noticing changes in pairs between lists while simultaneously differentiating the 2 lists. In contrast, participants in an N-Back condition were instructed to detect both within-list and between-list changes. Recall of first list responses that changed between lists produced retroactive facilitation for the N-Back condition but not for the Within-List Back condition. Similarly, recall of second list responses that changed between lists produced proactive facilitation for the N-Back condition but not for the Within-List Back condition. The greater extent of looking back increased detection of change and later recollection of change, which produced facilitation. When change was not recollected, detected change produced proactive interference. The recursive reminding produced when change is noticed contrasts with the simple associations of classic interference theory, and memory performance when change is recollected contrasts with the predictions of interference theory. PMID- 26010828 TI - Prior-list intrusions in serial recall are positional. AB - Henson (1996) provided a number of demonstrations of error patterns in serial recall that contradict chaining models. One such error pattern concerned when participants make intrusions from prior lists: Rather than originating from random positions in the prior list, intrusions tend to be recalled in the same position as their position in the prior list, a finding which led to the endorsement of positional models of serial recall. However, all of the demonstrations of positional intrusions occurred in designs in which relatively small sets of items were repeatedly employed as stimuli. In recent years, a number of investigations have found evidence for chaining in designs in which large sets of items are employed and items are never reused across trials (open sets). We conducted 2 experiments using open sets of items to test whether a pure chaining model is a viable model for open-set conditions. Both experiments revealed that intrusions from the immediately preceding list exhibited a strong tendency to be output in the same position as their position in the prior list, suggesting the usage of positional representations in open-set designs. A chaining model that lacks positional representations provides an inadequate account of serial recall in open-set conditions. PMID- 26010829 TI - Dissociating word frequency and predictability effects in reading: Evidence from coregistration of eye movements and EEG. AB - Two very reliable influences on eye fixation durations in reading are word frequency, as measured by corpus counts, and word predictability, as measured by cloze norming. Several studies have reported strictly additive effects of these 2 variables. Predictability also reliably influences the amplitude of the N400 component in event-related potential studies. However, previous research suggests that while frequency affects the N400 in single-word tasks, it may have little or no effect on the N400 when a word is presented with a preceding sentence context. The present study assessed this apparent dissociation between the results from the 2 methods using a coregistration paradigm in which the frequency and predictability of a target word were manipulated while readers' eye movements and electroencephalograms were simultaneously recorded. We replicated the pattern of significant, and additive, effects of the 2 manipulations on eye fixation durations. We also replicated the predictability effect on the N400, time-locked to the onset of the reader's first fixation on the target word. However, there was no indication of a frequency effect in the electroencephalogram record. We suggest that this pattern has implications both for the interpretation of the N400 and for the interpretation of frequency and predictability effects in language comprehension. PMID- 26010830 TI - Anisotropic Smoothing Improves DT-MRI-Based Muscle Fiber Tractography. AB - PURPOSE: To assess the effect of anisotropic smoothing on fiber tracking measures, including pennation angle, fiber tract length, and fiber tract number in the medial gastrocnemius (MG) muscle in healthy subjects using diffusion weighted magnetic resonance imaging (DW-MRI). MATERIALS AND METHODS: 3T DW-MRI data were used for muscle fiber tractography in the MG of healthy subjects. Anisotropic smoothing was applied at three levels (5%, 10%, 15%), and pennation angle, tract length, fiber tract number, fractional anisotropy, and principal eigenvector orientation were quantified for each smoothing level. RESULTS: Fiber tract length increased with pre-fiber tracking smoothing, and local heterogeneities in fiber direction were reduced. However, pennation angle was not affected by smoothing. CONCLUSION: Modest anisotropic smoothing (10%) improved fiber-tracking results, while preserving structural features. PMID- 26010831 TI - Modeling cognition and disease using human glial chimeric mice. AB - As new methods for producing and isolating human glial progenitor cells (hGPCs) have been developed, the disorders of myelin have become especially compelling targets for cell-based therapy. Yet as animal modeling of glial progenitor cell based therapies has progressed, it has become clear that transplanted hGPCs not only engraft and expand within murine hosts, but dynamically outcompete the resident progenitors so as to ultimately dominate the host brain. The engrafted human progenitor cells proceed to generate parenchymal astrocytes, and when faced with a hypomyelinated environment, oligodendrocytes as well. As a result, the recipient brains may become inexorably humanized with regards to their resident glial populations, yielding human glial chimeric mouse brains. These brains provide us a fundamentally new tool by which to assess the species-specific attributes of glia in modulating human cognition and information processing. In addition, the cellular humanization of these brains permits their use in studying glial infectious and inflammatory disorders unique to humans, and the effects of those disorders on the glial contributions to cognition. Perhaps most intriguingly, by pairing our ability to construct human glial chimeras with the production of patient-specific hGPCs derived from pluripotential stem cells, we may now establish mice in which a substantial proportion of resident glia are both human and disease-derived. These mice in particular may provide us new opportunities for studying the human-specific contributions of glia to psychopathology, as well as to higher cognition. As such, the assessment of human glial chimeric mice may provide us new insight into the species-specific contributions of glia to human cognitive evolution, as well as to the pathogenesis of human neurological and neuropsychiatric disease. PMID- 26010832 TI - Determination of benefits of cochlear implantation in children with auditory neuropathy. AB - BACKGROUND: Auditory neuropathy (AN) is a recently recognized hearing disorder characterized by intact outer hair cell function, disrupted auditory nerve synchronization and poor speech perception and recognition. Cochlear implants (CIs) are currently the most promising intervention for improving hearing and speech in individuals with AN. Although previous studies have shown optimistic results, there was large variability concerning benefits of CIs among individuals with AN. The data indicate that different criteria are needed to evaluate the benefit of CIs in these children compared to those with sensorineural hearing loss. We hypothesized that a hierarchic assessment would be more appropriate to evaluate the benefits of cochlear implantation in AN individuals. METHODS: Eight prelingual children with AN who received unilateral CIs were included in this study. Hearing sensitivity and speech recognition were evaluated pre- and postoperatively within each subject. The efficacy of cochlear implantation was assessed using a stepwise hierarchic evaluation for achieving: (1) effective audibility, (2) improved speech recognition, (3) effective speech, and (4) effective communication. RESULTS: The postoperative hearing and speech performance varied among the subjects. According to the hierarchic assessment, all eight subjects approached the primary level of effective audibility, with an average implanted hearing threshold of 43.8 +/- 10.2 dB HL. Five subjects (62.5%) attained the level of improved speech recognition, one (12.5%) reached the level of effective speech, and none of the subjects (0.0%) achieved effective communication. CONCLUSION: CIs benefit prelingual children with AN to varying extents. A hierarchic evaluation provides a more suitable method to determine the benefits that AN individuals will likely receive from cochlear implantation. PMID- 26010833 TI - Impacts of nitrogen addition on plant biodiversity in mountain grasslands depend on dose, application duration and climate: a systematic review. AB - Although the influence of nitrogen (N) addition on grassland plant communities has been widely studied, it is still unclear whether observed patterns and underlying mechanisms are constant across biomes. In this systematic review, we use meta-analysis and metaregression to investigate the influence of N addition (here referring mostly to fertilization) upon the biodiversity of temperate mountain grasslands (including montane, subalpine and alpine zones). Forty-two studies met our criteria of inclusion, resulting in 134 measures of effect size. The main general responses of mountain grasslands to N addition were increases in phytomass and reductions in plant species richness, as observed in lowland grasslands. More specifically, the analysis reveals that negative effects on species richness were exacerbated by dose (ha(-1) year(-1) ) and duration of N application (years) in an additive manner. Thus, sustained application of low to moderate levels of N over time had effects similar to short-term application of high N doses. The climatic context also played an important role: the overall effects of N addition on plant species richness and diversity (Shannon index) were less pronounced in mountain grasslands experiencing cool rather than warm summers. Furthermore, the relative negative effect of N addition on species richness was more pronounced in managed communities and was strongly negatively related to N-induced increases in phytomass, that is the greater the phytomass response to N addition, the greater the decline in richness. Altogether, this review not only establishes that plant biodiversity of mountain grasslands is negatively affected by N addition, but also demonstrates that several local management and abiotic factors interact with N addition to drive plant community changes. This synthesis yields essential information for a more sustainable management of mountain grasslands, emphasizing the importance of preserving and restoring grasslands with both low agricultural N application and limited exposure to N atmospheric deposition. PMID- 26010834 TI - Clinical Use of Pulse Wave Analysis: Proceedings From a Symposium Sponsored by North American Artery. AB - The use of pulse wave analysis may guide the provider in making choices about blood pressure treatment in prehypertensive or hypertensive patients. However, there is little clinical guidance on how to interpret and use pulse wave analysis data in the management of these patients. A panel of clinical researchers and clinicians who study and clinically use pulse wave analysis was assembled to discuss strategies for using pulse wave analysis in the clinical encounter. This manuscript presents an approach to the clinical application of pulse waveform analysis, how to interpret central pressure waveforms, and how to use existing knowledge about the pharmacodynamic effect of antihypertensive drug classes in combination with brachial and central pressure profiles in clinical practice. The discussion was supplemented by case-based examples provided by panel members, which the authors hope will provoke discussion on how to understand and incorporate pulse wave analysis into clinical practice. PMID- 26010835 TI - Exploring the Potential of Stable Isotope (Resonance) Raman Microspectroscopy and Surface-Enhanced Raman Scattering for the Analysis of Microorganisms at Single Cell Level. AB - Raman microspectroscopy is a prime tool to characterize the molecular and isotopic composition of microbial cells. However, low sensitivity and long acquisition times limit a broad applicability of the method in environmental analysis. In this study, we explore the potential, the applicability, and the limitations of stable isotope Raman microspectroscopy (SIRM), resonance SIRM, and SIRM in combination with surface-enhanced Raman scattering (SERS) for the characterization of single bacterial cells. The latter two techniques have the potential to significantly increase sensitivity and decrease measurement times in SIRM, but to date, there are no (SERS-SIRM) or only a limited number (resonance SIRM) of studies in environmental microbiology. The analyzed microorganisms were grown with substrates fully labeled with the stable isotopes (13)C or (2)H and compounds with natural abundance of atomic isotopes ((12)C 98.89% or (1)H 99.9844%, designated as (12)C or (1)H, respectively). Raman bands of bacterial cell compounds in stable isotope-labeled microorganisms exhibited a characteristic red-shift in the spectra. In particular, the sharp phenylalanine band was found to be an applicable marker band for SIRM analysis of the Deltaproteobacterium strain N47 growing anaerobically on (13)C-naphthalene. The study of G. metallireducens grown with (13)C- and (2)H-acetate showed that the information on the chromophore cytochrome c obtained by resonance SIRM at 532 nm excitation wavelength can be successfully complemented by whole-organism fingerprints of bacteria cells achieved by regular SIRM after photobleaching. Furthermore, we present here for the first time the reproducible SERS analysis of microbial cells labeled with stable isotopes. Escherichia coli strain DSM 1116 cultivated with (12)C- or (13)C-glucose was used as a model organism. Silver nanoparticles synthesized in situ were applied as SERS media. We observed a reproducible red-shift of an adenine-related marker band from 733 to 720 cm(-1) in SERS spectra for (13)C-labeled cells. Additionally, Raman measurements of (12)C/(13)C-glucose and -phenylalanine mixtures were performed to elucidate the feasibility of SIRM for nondestructive quantitative and spatially resolved analysis. The performed analysis of isotopically labeled microbial cells with SERS-SIRM and resonance SIRM paves the way toward novel approaches to apply Raman microspectroscopy in environmental process studies. PMID- 26010836 TI - Environmental harshness, latitude and incipient speciation. AB - Are rates of evolution and speciation fastest where diversity is greatest - the tropics? A commonly accepted theory links the latitudinal diversity gradient to a speciation pump model whereby the tropics produce species at a faster rate than extra-tropical regions. In this issue of Molecular Ecology, Botero et al. () test the speciation pump model using subspecies richness patterns for more than 9000 species of birds and mammals as a proxy for incipient speciation opportunity. Rather than using latitudinal centroids, the authors investigate the role of various environmental correlates of latitude as drivers of subspecies richness. Their key finding points to environmental harshness as a positive predictor of subspecies richness. The authors link high subspecies richness in environmental harsh areas to increased opportunities for geographic range fragmentation and/or faster rates of trait evolution as drivers of incipient speciation. Because environmental harshness generally increases with latitude, these results suggest that opportunity for incipient speciation is lowest where species richness is highest. The authors interpret this finding as incompatible with the view of the tropics as a cradle of diversity. Their results are consistent with a growing body of evidence that reproductive isolation and speciation occur fastest at high latitudes. PMID- 26010838 TI - Missed Opportunities in the Patient-Focused Drug Development Public Meeting and Scientific Workshop on Female Sexual Dysfunction Held at the FDA, October 2014. AB - There were numerous missed opportunities at the October 2014 U.S. Food and Drug Administration (FDA) meeting on female sexual dysfunction (FSD). They included opportunities to hear from a diverse range of patients and to engage in evidence based discussions of unmet medical needs, diagnostic instruments, trial end points, and inclusion criteria for clinical trials. Contributions of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) nomenclature, based on extensive research, were dismissed in favor of language favoring a seemingly clear but scientifically unsupportable distinction between women's sexual desire and arousal. Numerous participants, including patients recruited by their physicians, acknowledged travel expenses paid for by interested pharmaceutical companies. Conflicts of interest were manifold. The meeting did not advance the FDA's understanding of women's sexual distress and represents a setback for our field. PMID- 26010837 TI - Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. AB - The anti-tumor effects of chemotherapy and radiation are thought to be mediated by triggering G1/S or G2/M cell cycle checkpoints, while spindle poisons, such as paclitaxel, block metaphase exit by initiating the spindle assembly checkpoint. In contrast, we have found that 150 kilohertz (kHz) alternating electric fields, also known as Tumor Treating Fields (TTFields), perturbed cells at the transition from metaphase to anaphase. Cells exposed to the TTFields during mitosis showed normal progression to this point, but exhibited uncontrolled membrane blebbing that coincided with metaphase exit. The ability of such alternating electric fields to affect cellular physiology is likely to be dependent on their interactions with proteins possessing high dipole moments. The mitotic Septin complex consisting of Septin 2, 6 and 7, possesses a high calculated dipole moment of 2711 Debyes (D) and plays a central role in positioning the cytokinetic cleavage furrow, and governing its contraction during ingression. We showed that during anaphase, TTFields inhibited Septin localization to the anaphase spindle midline and cytokinetic furrow, as well as its association with microtubules during cell attachment and spreading on fibronectin. After aberrant metaphase exit as a consequence of TTFields exposure, cells exhibited aberrant nuclear architecture and signs of cellular stress including an overall decrease in cellular proliferation, followed by apoptosis that was strongly influenced by the p53 mutational status. Thus, TTFields are able to diminish cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death. PMID- 26010839 TI - Vascular complications in steroid treated patients undergoing transfemoral aortic valve implantation. AB - OBJECTIVE: To assess the rate of Vascular complications in steroid treated patients undergoing transfemoral aortic valve implantation (TAVI). BACKGROUND: Steroid therapy has been associated with increased post-surgical bleeding. Vascular complications are a major concern in patients undergoing TAVI. However, the effect of corticosteroids on vascular complications has not been assessed in these patients. METHODS: We conducted a retrospective analysis of 220 consecutive patients undergoing transfemoral TAVI at our institute between 2009 and 2013. Patients who were on steroids at the time of the procedure (n = 25) were compared with those who were not (n = 195). RESULTS: Baseline characteristics between groups were similar except for greater incidence of chronic renal failure (52 vs. 25%, P = 0.05) and lower left ventricular ejection fraction (50.3 vs. 55.8%, P = 0.037) in the steroid group. The rate of procedural success and nonvascular complication were similar in both groups with the exception of more temporary AV block in the steroid group (24 vs. 8%, P = 0.016). Patients treated with steroids had significantly more minor vascular complication (44 vs. 23%, P = 0.024), and significantly more femoral artery stenosis (16 vs. 5%, P = 0.036), occlusion (8 vs. 1%, P = 0.014), need for femoral artery percutaneous transluminal angioplasty (PTA) (32 vs. 12%, P = 0.009), and femoral artery PTA or stenting (32% vs. 15%, P = 0.031). On multivariate analysis steroid treatment was the only predictor of minor vascular complications (RR=2.65, 95% CI 1.04-6.8, P = 0.042). CONCLUSIONS: Concurrent corticosteroid treatment is associated with a higher rate of minor vascular complication following transfemoral TAVI. Operators should be aware of this risk when assessing patients for the procedure. PMID- 26010840 TI - The diagnostic accuracy of urine lipoarabinomannan test for tuberculosis screening in a South African correctional facility. AB - BACKGROUND: We evaluated the diagnostic accuracy of the urine lipoarabinomannan (LAM) antigen detection assay (Clearview TB-ELISA) to screen for tuberculosis in a South African correctional facility. METHODS: Between September 2009 and October 2010, male offenders were screened for tuberculosis (symptoms, chest radiograph, two spot sputum specimens for microscopy and culture), and urine tested for LAM. Sensitivity, specificity and predictive values of LAM were calculated using definite and probable tuberculosis combined as our gold standard. FINDINGS: 33/871 (3.8%) participants (26% HIV-positive) had tuberculosis. Amongst HIV-positive vs. HIV-negative offenders the sensitivity and specificity of LAM was 7.1% vs. 0% and 98.5% vs. 99.8% respectively. CONCLUSION: Urine LAM ELISA has inadequate sensitivity for TB screening in this population. PMID- 26010842 TI - [Elderly seeking emergency care should receive special care. Contact patterns and underlying diagnoses in retrospective cross-sectional study]. AB - We investigated and documented the most common presenting complaints of elderly patients >=80 years of age in Vasterbotten at the emergency department of Umea University hospital. We found that the ten most common presenting complaints represented more than half of all emergency department visits. The three most common presenting complaints were abdominal pain, chest pain and dyspnoea. On average, around 80 % of all patients were admitted to a ward and for the three most common presenting complaints the number was even higher. The main conclusions from this study were that a surprisingly high proportion of elderly patients are admitted to a ward after the emergency department visit at Umea University hospital and that patients seeking with one of the three most common presenting complaints often had complex discharge diagnoses involving typically chronic geriatric diseases which were hidden behind general presenting complaints. PMID- 26010841 TI - Customized Internal Reference Controls for Improved Assessment of Circulating MicroRNAs in Disease. AB - BACKGROUND: Altered levels of circulating extracellular miRNA in plasma and serum have shown promise as non-invasive biomarkers of disease. However, unlike the assessment of cellular miRNA levels for which there are accepted housekeeping genes, analogous reference controls for normalization of circulating miRNA are lacking. Here, we provide an approach to identify and validate circulating miRNA reference controls on a de novo basis, and demonstrate the advantages of these customized internal controls in different disease settings. Importantly, these internal controls overcome key limitations of external spike-in controls. METHODS: Using a global RT-qPCR screen of 1066 miRNAs in plasma from pulmonary hypertension patients (PAH) and healthy subjects as a case example, we identified a large pool of initial candidate miRNAs that were systematically ranked according to their plasma level stability using a predefined algorithm. The performance of the top candidates was validated against multiple comparators, and in a second independent cohort of PAH and control subjects. The broader utility of this approach was demonstrated in a completely different disease setting with 372 miRNAs screened in plasma from septic shock patients and healthy controls. RESULTS: Normalization of data with specific internal reference controls significantly reduced the overall variation in circulating miRNA levels between subjects (relative to raw data), provided a more balanced distribution of up- and down-regulated miRNAs, replicated the results obtained by the benchmark geometric averaging of all detected miRNAs, and outperformed the commonly used external spike-in strategy. CONCLUSIONS: We demonstrate the feasibility of identifying circulating reference controls that can reduce extraneous technical variations, and improve the assessment of disease-related changes in plasma miRNA levels. This study provides a novel conceptual framework that addresses a critical and previously unmet need if circulating miRNAs are to advance as reliable diagnostic tools in medicine. PMID- 26010843 TI - [High altitude medicine is a concern also for Swedish primary care. Knowledge needed to identify high risk patients and provide appropriate advice]. AB - With the increasing amount of people traveling to high altitude regions, the number of people at risk of acquiring altitude illness increases. Altitude illness entails three syndromes; acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. These syndromes are potentially lethal acquired medical conditions that in most cases are preventable. Health care providers need to inform travelers of the risks associated with mountaineering and the prophylactic measures available as well as identify underlying conditions that require specific considerations. This article provides a summary of the pathophysiology, symptoms and treatment of altitude illness and aims to be an orientation for general practitioners. PMID- 26010844 TI - [Safe care also in the home: a future challenge]. PMID- 26010845 TI - [Elderly with multiple diseases need individualized emergency care]. PMID- 26010846 TI - [Payment for performance had no effect on mortality. English reimbursement system in primary care did not live up to expectations]. PMID- 26010847 TI - [American physicians "burnout" and Swedish physicians "exhaustion". Stress related mental illness is increasing also among Swedish medical staff]. PMID- 26010848 TI - [Among colleagues and patients in Abu Dhabi. Swedish physician talks about everyday life at the largest hospital]. PMID- 26010850 TI - [Not Available]. PMID- 26010849 TI - [Early introduction of peanuts prevents peanut allergy. New Swedish guidelines needed]. PMID- 26010851 TI - [Not Available]. PMID- 26010852 TI - [Cooperation promotes health promotion]. PMID- 26010853 TI - [Introduce vegetarian diet in health care]. PMID- 26010854 TI - ["Correction" on coercion undermines patient safety]. PMID- 26010855 TI - [Not Available]. PMID- 26010856 TI - [What health care can learn from Japanese women's teams. Tightly welded japanese beats "lean"]. PMID- 26010857 TI - [Risk of more harm than good: "Re-evaluate screening for abdominal aortic aneurysm"]. PMID- 26010858 TI - Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. AB - BACKGROUND: Ipilimumab (Yervoy; Bristol-Myers Squibb) is a novel fully humanised monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4, an immune checkpoint molecule, to augment anti-tumour T-cell responses. It is associated with significant immune-related side-effects including hypophysitis. AIM: We reviewed the clinical and biochemical characteristics of 10 patients with ipilimumab-induced hypophysitis (IH), and developed guidelines for the early detection and management of IH based on our experiences at three major teaching hospitals in Sydney. METHODS: All patients were evaluated at the Crown Princess Mary Cancer Centre and Department of Endocrinology, Westmead Hospital, Department of Endocrinology, Royal Prince Alfred Hospital, the Melanoma Institute Australia and Macarthur Cancer Therapy Centre, Campbelltown Hospital from 2010 to 2014. Relevant data were extracted by review of medical records. Main outcome measures included clinical features, hormone profile and radiological findings associated with IH, and presence of pituitary recovery. RESULTS: Ten patients were identified with IH. In four patients who underwent monitoring of plasma cortisol, there was a fall in levels in the weeks prior to presentation. The pituitary adrenal and pituitary-thyroid axes were affected in the majority of patients, with the need for physiological hormone replacement. Imaging abnormalities were identified in five of 10 patients, and resolved without high-dose glucocorticoid therapy. To date, all patients remain on levothyroxine and hydrocortisone replacement, where appropriate. CONCLUSIONS: There is significant morbidity associated with development of IH. We suggest guidelines to assist with early recognition and therapeutic intervention. PMID- 26010859 TI - Culture temperature affects human chondrocyte messenger RNA expression in monolayer and pellet culture systems. AB - Cell-based therapy has been explored for articular cartilage regeneration. Autologous chondrocyte implantation is a promising cell-based technique for repairing articular cartilage defects. However, there are several issues such as chondrocyte de-differentiation. While numerous studies have been designed to overcome some of these issues, only a few have focused on the thermal environment that can affect chondrocyte metabolism and phenotype. In this study, the effects of different culture temperatures on human chondrocyte metabolism- and phenotype related gene expression were investigated in 2D and 3D environments. Human chondrocytes were cultured in a monolayer or in a pellet culture system at three different culture temperatures (32 degrees C, 37 degrees C, and 41 degrees C) for 3 days. The results showed that the total RNA level, normalized to the threshold cycle value of internal reference genes, was higher at lower temperatures in both culture systems. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and citrate synthase (CS), which are involved in glycolysis and the citric acid cycle, respectively, were expressed at similar levels at 32 degrees C and 37 degrees C in pellet cultures, but the levels were significantly lower at 41 degrees C. Expression of the chondrogenic markers, collagen type IIA1 (COL2A1) and aggrecan (ACAN), was higher at 37 degrees C than at 32 degrees C and 41 degrees C in both culture systems. However, this phenomenon did not coincide with SRY (sex determining region Y)-box 9 (SOX9), which is a fundamental transcription factor for chondrogenesis, indicating that a SOX9-independent pathway might be involved in this phenomenon. In conclusion, the expression of chondrocyte metabolism related genes at 32 degrees C was maintained or enhanced compared to that at 37 degrees C. However, chondrogenesis-related genes were further induced at 37 degrees C in both culture systems. Therefore, manipulating the culture temperature may be an advantageous approach for regulating human chondrocyte metabolic activity and chondrogenesis. PMID- 26010860 TI - Fatty acid metabolism and its longitudinal relationship with the hypothalamic pituitary-adrenal axis in major depression: Associations with prospective antidepressant response. AB - BACKGROUND: Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better understand these associations, we might identify novel targets for add-on therapy to increase antidepressant-response, and/or early indicators to improve response prediction. OBJECTIVE: To determine whether alterations in FA-metabolism, and their relationship with the HPA-axis, are associated with prospective response to the antidepressant paroxetine in MDD. DESIGN: We first compared 70 initially unmedicated MDD-patients with 51 age- and gender-matched controls at study-entry, regarding salivary cortisol and erythrocyte membrane FAs [omega-3 docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), FA-chain length, -unsaturation and peroxidizability]. Subsequently, we treated patients with 6 weeks 20mg/day selective serotonin reuptake inhibitor paroxetine. After 6 weeks, we continued this treatment in responders (i.e. showing >=50% decrease in Hamilton depression rating scale-score), and randomized non-responders to a 6-week, double-blind, placebo-controlled dose-escalation up to 50mg/day. We repeated cortisol and FA measures in patients after 6 and 12 weeks. RESULTS: Compared to controls, patients showed higher FA-chain length, FA-unsaturation and FA-peroxidation, and more negative relationships of FA-unsaturation and FA-peroxidation with cortisol. Moreover, these negative relationships were associated with paroxetine nonresponse. Nonresponse was also associated with low DHA, which was related to low fatty fish intake. Furthermore, early responders showed initial low FA-chain length, FA-peroxidation and EPA that increased during the study, while non responders exhibited opposite patterns. CONCLUSIONS: FA-metabolism alterations, and their relationship with cortisol, are associated with prospective paroxetine response in MDD, and may therefore form an early indicator of treatment effectiveness. Moreover, dietary fatty fish intake may improve antidepressant response through an effect on FA-metabolism. PMID- 26010861 TI - Distinct cognitive effects of estrogen and progesterone in menopausal women. AB - The effects of postmenopausal hormone treatment on cognitive outcomes are inconsistent in the literature. Emerging evidence suggests that cognitive effects are influenced by specific hormone formulations, and that progesterone is more likely to be associated with positive outcomes than synthetic progestin. There are very few studies of unopposed progesterone in postmenopausal women, and none that use functional neuroimaging, a sensitive measure of neurobiological function. In this study of 29 recently postmenopausal women, we used functional MRI and neuropsychological measures to separately assess the effects of estrogen or progesterone treatment on visual and verbal cognitive function. Women were randomized to receive 90 days of either estradiol or progesterone counterbalanced with placebo. After each treatment arm, women were given a battery of verbal and visual cognitive function and working memory tests, and underwent functional MRI including verbal processing and visual working memory tasks. We found that both estradiol and progesterone were associated with changes in activation patterns during verbal processing. Compared to placebo, women receiving estradiol treatment had greater activation in the left prefrontal cortex, a region associated with verbal processing and encoding. Progesterone was associated with changes in regional brain activation patterns during a visual memory task, with greater activation in the left prefrontal cortex and right hippocampus compared to placebo. Both treatments were associated with a statistically non-significant increase in number of words remembered following the verbal task performed during the fMRI scanning session, while only progesterone was associated with improved neuropsychological measures of verbal working memory compared to placebo. These results point to potential cognitive benefits of both estrogen and progesterone. PMID- 26010863 TI - Mating in the box jellyfish Copula sivickisi--Novel function of cnidocytes. AB - Within cubozoans, a few species have developed a sexual reproduction system including mating and internal fertilization. One species, Copula sivickisi, is found in a large area of the indo pacific. They have separate sexes and when mature males and females meet they entangle their tentacles and the males transfer a sperm package, a spermatozeugmata, which is ingested by the female fertilizing her eggs internally. After 2-3 days, the females lay an embryo strand that sticks to the substrate and after another 2-3 days, the fully developed larvae leave the strand. We have examined the ultrastructure of the gonads and spermatozeugmata to look for structural adaptations to this specialized way of reproduction and understand how the fertilization takes place. Surprisingly, we discovered that the male gonads were heavily packed with cnidocytes of the isorhiza type and that they are transferred to the spermatozeugmata. The spermatozeugmata does not dissolve in the female gastrovascular cavity but is attached to the female gonad probably using the isorhizas. Here, the sperm cells are partly digested and the nuclei are released. The actual fertilization seems to happen through phagocytosis of the released nuclei by the epithelial cells. The female gonads are likewise packed with cnidocytes but of the eurytele type. They do not mature inside the female and putatively serve to protect the developing larvae once the embryo strand is laid. This specialized way of fertilization is to our knowledge novel and so is this first account of cnidocytes being directly involved in cnidarian reproduction. PMID- 26010862 TI - The association between fibrinogen reactivity to mental stress and high sensitivity cardiac troponin T in healthy adults. AB - BACKGROUND: Plasma fibrinogen is considered as a positive mediator between mental stress and cardiovascular disease because it is an acute-phase protein released in response to mental stress and a coagulation factor. However those three factors have never been studied together within a single integrated framework, using cardiac troponin T as a marker of cardiovascular risk. METHODS: 491 disease free men and women aged 53-76 were tested for fibrinogen levels before, immediately after, and following recovery from standardized mental stress tasks. We measured plasma cardiac troponin T using a high-sensitivity assay (HS-CTnT) and coronary calcification using electron-beam dual-source computed tomography. RESULTS: The average fibrinogen concentration increased by 5.1% (s.d.=7.3) in response to stress and then tended to return to baseline values. People with higher baseline fibrinogen values had smaller increases (blunted responses) following the stress task (P=0.001), and people with higher stress responses showed better recovery (P<0.001). In unadjusted analyses, higher baseline fibrinogen was associated with higher chances of having detectable HS-CTnT (P=0.072) but, conversely, higher fibrinogen response was associated with lower chances of having detectable HS-CTnT (P=0.007). The adjustment for clinical, inflammatory, and haemostatic factors, as well as for coronary calcification eliminated the effect of baseline fibrinogen, whereas the negative association between fibrinogen response and HS-CTnT remained robust: the odds of detectable HS-CTnT halved for each 10% increase in fibrinogen concentration due to stress (OR=0.49, P=0.007, 95% CI=0.30-0.82). CONCLUSIONS: Greater fibrinogen responses to mental stress are associated with lower likelihood of detectable high sensitivity troponin T plasma concentration. A more dynamic fibrinogen response appears to be advantageous for cardiovascular health. PMID- 26010864 TI - In Vivo Assessment of Cold Tolerance through Chlorophyll-a Fluorescence in Transgenic Zoysiagrass Expressing Mutant Phytochrome A. AB - Chlorophyll-a fluorescence analysis provides relevant information about the physiology of plants growing under abiotic stress. In this study, we evaluated the influence of cold stress on the photosynthetic machinery of transgenic turfgrass, Zoysia japonica, expressing oat phytochrome A (PhyA) or a hyperactive mutant phytochrome A (S599A) with post-translational phosphorylation blocked. Biochemical analysis of zoysiagrass subjected to cold stress revealed reduced levels of hydrogen peroxide, increased proline accumulation, and enhanced specific activities of antioxidant enzymes compared to those of control plants. Detailed analyses of the chlorophyll-a fluorescence data through the so-called OJIP test exhibited a marked difference in the physiological status among transgenic and control plants. Overall, these findings suggest an enhanced level of cold tolerance in S599A zoysiagrass cultivars as reflected in the biochemical and physiological analyses. Further, we propose that chlorophyll-a fluorescence analysis using OJIP test is an efficient tool in determining the physiological status of plants under cold stress conditions. PMID- 26010866 TI - Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon. AB - Huntington's disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC) lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease. PMID- 26010867 TI - Ubiquitin-Like Protein SAMP1 and JAMM/MPN+ Metalloprotease HvJAMM1 Constitute a System for Reversible Regulation of Metabolic Enzyme Activity in Archaea. AB - Ubiquitin/ubiquitin-like (Ub/Ubl) proteins are involved in diverse cellular processes by their covalent linkage to protein substrates. Here, we provide evidence for a post-translational modification system that regulates enzyme activity which is composed of an archaeal Ubl protein (SAMP1) and a JAMM/MPN+ metalloprotease (HvJAMM1). Molybdopterin (MPT) synthase activity was found to be inhibited by covalent linkage of SAMP1 to the large subunit (MoaE) of MPT synthase. HvJAMM1 was shown to cleave the covalently linked inactive form of SAMP1-MoaE to the free functional individual SAMP1 and MoaE subunits of MPT synthase, suggesting reactivation of MPT synthase by this metalloprotease. Overall, this study provides new insight into the broad idea that Ub/Ubl modification is a post-translational process that can directly and reversibly regulate the activity of metabolic enzymes. In particular, we show that Ub/Ubl linkages on the active site residues of an enzyme (MPT synthase) can inhibit its catalytic activity and that the enzyme can be reactivated through cleavage by a JAMM/MPN+ metalloprotease. PMID- 26010865 TI - Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes. AB - BACKGROUND: Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome. METHODS: Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling-ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components-COL4A1, COL4A2 and M1 family aminopeptidases-ERAP1, ERAP2 and LNPEP. RESULTS/CONCLUSION: Major common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE. PMID- 26010868 TI - Equine Herpesvirus-1 Myeloencephalopathy, an Emerging Threat of Working Equids in Ethiopia. AB - Although equine herpesvirus myeloencephalopathy (EHM) is a sporadic and relatively uncommon manifestation of equine herpesvirus-1 (EHV-1), it has the potential for causing devastating outbreaks in horses. Up till now, there were no reported EHM outbreaks in donkeys and mules. This study describes the isolation and molecular characterization of EHV-1 from clinically EHM-affected horses (n = 6), mules (n = 3) and donkeys (n = 82) in Ethiopia during outbreaks from May 2011 to December 2013. The incidence of EHM cases was higher from April to mid-June. EHM in donkeys was more severe and death without clinical signs of paralysis, and recumbency was frequently observed. The main age of affected equines ranged from 7 to 10 years (n = 51; 56.0%), and females (n = 58; 63.7%) were more affected than males. The incidence of neuropathogenic (D752 ) and non-neuropathogenic (N752 ) variants of EHV-1 from EHM-affected equines in Ethiopia was assessed by sequencing the DNA polymerase gene (ORF30) of the EHV-1 isolates. The results indicated that from the total of 91 clinically affected equines, 90 (98.9%) of them had an ORF30 D752 genotype. An ORF30 N752 variant was only found in one donkey. Analysis of ORF68 as grouping marker for geographical differences showed that the Ethiopian EHV-1 isolates belong to geographical group 4. Due to the fatal nature of EHV-1 in donkeys, it would be interesting to examine the pathogenesis of EHM in this species. At present, there is no vaccine available in Ethiopia, and therefore, outbreaks of EHV-1 should be controlled by proper management adaptations. In addition, it is important to test the efficacy of the commercial vaccines not only in horses, but also in donkeys and mules. PMID- 26010869 TI - Engineering high alpha-amylase levels in wheat grain lowers Falling Number but improves baking properties. AB - Late maturity alpha-amylase (LMA) and preharvest sprouting (PHS) are genetic defects in wheat. They are both characterized by the expression of specific isoforms of alpha-amylase in particular genotypes in the grain prior to harvest. The enhanced expression of alpha-amylase in both LMA and PHS results in a reduction in Falling Number (FN), a test of gel viscosity, and subsequent downgrading of the grain, along with a reduced price for growers. The FN test is unable to distinguish between LMA and PHS; thus, both defects are treated similarly when grain is traded. However, in PHS-affected grains, proteases and other degradative process are activated, and this has been shown to have a negative impact on end product quality. No studies have been conducted to determine whether LMA is detrimental to end product quality. This work demonstrated that wheat in which an isoform alpha-amylase (TaAmy3) was overexpressed in the endosperm of developing grain to levels of up to 100-fold higher than the wild-type resulted in low FN similar to those seen in LMA- or PHS affected grains. This increase had no detrimental effect on starch structure, flour composition and enhanced baking quality, in small-scale 10-g baking tests. In these small-scale tests, overexpression of TaAmy3 led to increased loaf volume and Maillard-related browning to levels higher than those in control flours when baking improver was added. These findings raise questions as to the validity of the assumption that (i) LMA is detrimental to end product quality and (ii) a low FN is always indicative of a reduction in quality. This work suggests the need for a better understanding of the impact of elevated expression of specific alpha amylase on end product quality. PMID- 26010870 TI - Interruption of Pacing Following Nonsustained Ventricular Tachycardia in an AAI Programmed Implantable Cardioverter Defibrillator. AB - BACKGROUND: Unnecessary ventricular pacing from cardiac implantable electronic devices has been associated with long-term risks (heart failure, atrial fibrillation, and possibly stroke). Several device programming strategies are available to minimize ventricular pacing, each potentially associated with unintended consequences. Occasionally, the only effective means is to program to the AAI(R) pacing mode. However, in one manufacturer's implantable cardioverter defibrillators (ICDs), the AAI(R) mode has the potential risk of prolonged pacing cessation following a nonsustained ventricular tachycardia (NSVT). METHOD: Patients with ICDs, managed through the Cleveland Clinic device clinic, follow the Heart Rhythm Society consensus document recommendations for device monitoring with remote interrogations (every three months) and yearly in-person evaluations. Clinically significant findings also trigger additional evaluations by the nurse and physician. RESULTS: Two patients having Boston Scientific ICDs (E110 Teligen 100; Boston Scientific Corp., Natick, MA, USA), had asystole and marked bradycardia following untreated NSVT. These pauses in pacing were due to use of the AAI(R) pacing mode. In order to enhance ventricular tachycardia detection, by design atrial pacing is disabled during, and for a time after, an episode of ventricular tachycardia when the device operates in the "ventricular tachycardia response" (VTR) phase. Thus, following spontaneous termination of the NSVT, no pacing occurred in these patients until the VTR period ended. Nonconventional programming was utilized to permit AAI(R) pacing while avoiding these asystolic and bradycardic events during VTR. CONCLUSIONS: Unintended consequences can occur when complex VT detection parameters interact with specific pacing modes. At times, nonconventional programming can avoid these interactions while still achieving effective AAI(R) pacing. PMID- 26010872 TI - Robot-assisted intersphincteric resection for rectal submucosal tumour. AB - BACKGROUND: Rectal submucosal tumours are rare. The purpose of this study was to evaluate the safety and feasibility of robot-assisted rectal surgery. METHODS: Patients who received robot-assisted intersphincteric resection (ISR) were included in the present study. Clinical outcomes, operating time, length of hospital stay and pathological status were analysed. RESULTS: There were three patients with gastrointestinal tumours and three patients diagnosed with neuroendocrine tumours. The mean operating time was 369.2 min and the estimated blood loss was 66.7 ml. There were neither intraoperative complications nor conversions. On pathological examination, the mean number of lymph nodes harvested was 10.3 (range 3-16), the mean distal resection margin was 1.1 (range 0.1-3) cm and all six patients had the circumferential resection margins clear. CONCLUSIONS: Our data show that robotic surgery is feasible and safe, with no morbidity or mortality, and that ISR provides bowel continuity and eliminates the need for colostomy. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010871 TI - Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells. AB - Ezrin belongs to the ERM (ezrin-radixin-moesin) protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type dependant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton- and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells. PMID- 26010873 TI - Illness Perceptions of Cystic Fibrosis: A Comparison of Young Adults with CF and Same-Aged Peers. AB - In the last two decades, the life expectancy for individuals with Cystic Fibrosis (CF) has increased significantly. The limited research examining the psychosocial experiences of young adults with CF indicates that other young adults lack awareness and understanding of CF. Using the Illness Perception Questionnaire, perceptions of CF were examined in individuals with CF aged 16 to 25 and two groups of same-aged peers: those who did, or did not, know someone with CF. ANOVA with pairwise comparisons revealed that individuals with CF perceived significantly fewer physical symptoms of illness and fewer emotional and practical consequences of CF than both groups of peers. Individuals with CF also perceived significantly more personal control and greater understanding of CF than peers without experience of CF. Implications for enhancing opportunities for social engagement and for the provision of social support for young people with CF are identified. PMID- 26010874 TI - Completed suicide among nursing home residents: a systematic review. AB - OBJECTIVE: The aim of this study is to systematically review published research describing the frequency, nature, and contributing factors of completed suicides among nursing home residents. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, this review examined all original, peer-reviewed literature published in English between 1 January 1949 and 31 December 2013 describing completed suicides among nursing home residents. Information extracted for analysis included: study and population characteristics, method of suicide, potential risk factors, and interventions. RESULTS: Eight studies were identified; the majority (n = 5) conducted in the United States of America. There were 113 suicides in nursing homes reported in the literature, 101 with detailed information available for aggregate analysis. The majority were male (n = 62, 61.4%), aged between 61 and 93 years. Suicide was most commonly by hanging (n = 27, 38.0%) or falling from a height (n = 27, 38.0%). Risk factors were considered in a proportion of studies. Depression was examined in 27 cases and present in 18 (67%). Duration of residence was examined in 25 cases, 13 (52%) of which had resided in the nursing home less than 12 months. Physical health was examined in 22 cases, 11 (50%) of whom were experiencing physical decline. Prior suicidal behaviour, cognitive function, and personal loss were also examined. Organizational risk factors and intervention strategies were rarely considered. CONCLUSIONS: There is a paucity of research describing completed suicide among nursing home residents. More large-scale research is required using standardized methods for reporting information to better understand and prevent completed suicides in this setting. PMID- 26010876 TI - MicroRNAs Regulate Cellular ATP Levels by Targeting Mitochondrial Energy Metabolism Genes during C2C12 Myoblast Differentiation. AB - In our previous study, we identified an miRNA regulatory network involved in energy metabolism in porcine muscle. To better understand the involvement of miRNAs in cellular ATP production and energy metabolism, here we used C2C12 myoblasts, in which ATP levels increase during differentiation, to identify miRNAs modulating these processes. ATP level, miRNA and mRNA microarray expression profiles during C2C12 differentiation into myotubes were assessed. The results suggest 14 miRNAs (miR-423-3p, miR-17, miR-130b, miR-301a/b, miR-345, miR 15a, miR-16a, miR-128, miR-615, miR-1968, miR-1a/b, and miR-194) as cellular ATP regulators targeting genes involved in mitochondrial energy metabolism (Cox4i2, Cox6a2, Ndufb7, Ndufs4, Ndufs5, and Ndufv1) during C2C12 differentiation. Among these, miR-423-3p showed a high inverse correlation with increasing ATP levels. Besides having implications in promoting cell growth and cell cycle progression, its function in cellular ATP regulation is yet unknown. Therefore, miR-423-3p was selected and validated for the function together with its potential target, Cox6a2. Overexpression of miR-423-3p in C2C12 myogenic differentiation lead to decreased cellular ATP level and decreased expression of Cox6a2 compared to the negative control. These results suggest miR-423-3p as a novel regulator of ATP/energy metabolism by targeting Cox6a2. PMID- 26010875 TI - The mitochondrial uncoupler DNP triggers brain cell mTOR signaling network reprogramming and CREB pathway up-regulation. AB - Mitochondrial metabolism is highly responsive to nutrient availability and ongoing activity in neuronal circuits. The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown. Mild mitochondrial uncoupling enhances cellular energy expenditure in mitochondria and can be induced with 2,4-dinitrophenol (DNP), a proton ionophore previously used for weight loss. We found that DNP treatment reduces mitochondrial membrane potential, increases intracellular Ca(2+) levels and reduces oxidative stress in cerebral cortical neurons. Gene expression profiling of the cerebral cortex of DNP-treated mice revealed reprogramming of signaling cascades that included suppression of the mammalian target of rapamycin (mTOR) and insulin--PI3K - MAPK pathways, and up-regulation of tuberous sclerosis complex 2, a negative regulator of mTOR. Genes encoding proteins involved in autophagy processes were up-regulated in response to DNP. CREB (cAMP-response element-binding protein) signaling, Arc and brain-derived neurotrophic factor, which play important roles in synaptic plasticity and adaptive cellular stress responses, were up-regulated in response to DNP, and DNP-treated mice exhibited improved performance in a test of learning and memory. Immunoblot analysis verified that key DNP-induced changes in gene expression resulted in corresponding changes at the protein level. Our findings suggest that mild mitochondrial uncoupling triggers an integrated signaling response in brain cells characterized by reprogramming of mTOR and insulin signaling, and up-regulation of pathways involved in adaptive stress responses, molecular waste disposal, and synaptic plasticity. Physiological bioenergetic challenges such as exercise and fasting can enhance neuroplasticity and protect neurons against injury and neurodegeneration. Here, we show that the mitochondrial uncoupling agent 2,4 dinitrophenol (DNP) elicits adaptive signaling responses in the cerebral cortex involving activation of Ca(2+) -CREB and autophagy pathways, and inhibition of mTOR and insulin signaling pathways. The molecular reprogramming induced by DNP, which is similar to that of exercise and fasting, is associated with improved learning and memory, suggesting potential therapeutic applications for DNP. PMID- 26010877 TI - Association of plasma adipokines with chronic obstructive pulmonary disease severity and progression. AB - RATIONALE: Two adipokines, leptin and adiponectin, regulate metabolic and inflammatory systems reciprocally. The role of adiponectin in chronic obstructive pulmonary disease (COPD) has been studied. However, there are few data evaluating the relationship of plasma leptin with COPD severity or progression. OBJECTIVES: The objective of this study was to evaluate the relationship of leptin, adiponectin, and the leptin/adiponectin ratio with COPD severity and progression according to COPD phenotypes. METHODS: Plasma leptin and adiponectin levels were measured in 196 subjects with COPD selected from the Korean Obstructive Lung Disease cohort. Using a linear regression model and mixed linear regression, we determined the relationship of plasma leptin and adiponectin levels and the leptin/adiponectin ratio to COPD severity and progression over 3 years. MEASUREMENTS AND MAIN RESULTS: The concentration of adiponectin in plasma positively correlated with percent emphysema on initial computed tomography (CT) (adjusted P = 0.022), whereas plasma leptin concentrations and the leptin/adiponectin ratio exhibited a significant inverse correlation with initial FEV1 (adjusted P = 0.013 for leptin and adjusted P = 0.041 for leptin/adiponectin ratio). Increased plasma leptin and leptin/adiponectin ratio were significantly associated with change in percent emphysema over 3 years (adjusted P = 0.037 for leptin and adjusted P = 0.029 for leptin/adiponectin ratio), whereas none of the adipokines demonstrated an association with FEV1 decline over the 3-year period. CONCLUSIONS: Plasma adiponectin and leptin vary according to COPD phenotypes. Plasma leptin and the leptin/adiponectin ratio, but not adiponectin, were significantly associated with changes in CT-assessed emphysema, suggesting a potential role as a biomarker in emphysema progression in patients with COPD. PMID- 26010878 TI - Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin. AB - Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one's "self," "ego," or "I" is disintegrating or that the border between one's self and the external world is dissolving, "ego-disintegration" or "dissolution" is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in "magic mushrooms"). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to "ego-dissolution", was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a "disintegration" of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of "self"or "ego," as a perceptual phenomenon, may rest on the normal functioning of these systems. PMID- 26010879 TI - Secondary anchor targeted cell release. AB - Personalized medicine offers the promise of tailoring therapy to patients, based on their cellular biomarkers. To achieve this goal, cellular profiling systems are needed that can quickly and efficiently isolate specific cell types without disrupting cellular biomarkers. Here we describe the development of a unique platform that facilitates gentle cell capture via a secondary, surface-anchoring moiety, and cell release. The cellular capture system consists of a glass surface functionalized with APTES, d-desthiobiotin, and streptavidin. Biotinylated mCD11b and hIgG antibodies are used to capture mouse macrophages (RAW 264.7) and human breast cancer (MCF7-GFP) cell lines, respectively. The surface functionalization is optimized by altering assay components, such as streptavidin, d-desthiobiotin, and APTES, to achieve cell capture on 80% of the functionalized surface and cell release upon biotin treatment. We also demonstrate an ability to capture 50% of target cells within a dual-cell mixture. This engineering advancement is a critical step towards achieving cell isolation platforms for personalized medicine. PMID- 26010880 TI - The Stapled AKAP Disruptor Peptide STAD-2 Displays Antimalarial Activity through a PKA-Independent Mechanism. AB - Drug resistance poses a significant threat to ongoing malaria control efforts. Coupled with lack of a malaria vaccine, there is an urgent need for the development of new antimalarials with novel mechanisms of action and low susceptibility to parasite drug resistance. Protein Kinase A (PKA) has been implicated as a critical regulator of pathogenesis in malaria. Therefore, we sought to investigate the effects of disrupted PKA signaling as a possible strategy for inhibition of parasite replication. Host PKA activity is partly regulated by a class of proteins called A Kinase Anchoring Proteins (AKAPs), and interaction between HsPKA and AKAP can be inhibited by the stapled peptide Stapled AKAP Disruptor 2 (STAD-2). STAD-2 was tested for permeability to and activity against Plasmodium falciparum blood stage parasites in vitro. The compound was selectively permeable only to infected red blood cells (iRBC) and demonstrated rapid antiplasmodial activity, possibly via iRBC lysis (IC50 ~ 1 MUM). STAD-2 localized within the parasite almost immediately post-treatment but showed no evidence of direct association with PKA, indicating that STAD-2 acts via a PKA-independent mechanism. Furosemide-insensitive parasite permeability pathways in the iRBC were largely responsible for uptake of STAD-2. Further, peptide import was highly specific to STAD-2 as evidenced by low permeability of control stapled peptides. Selective uptake and antiplasmodial activity of STAD-2 provides important groundwork for the development of stapled peptides as potential antimalarials. Such peptides may also offer an alternative strategy for studying protein-protein interactions critical to parasite development and pathogenesis. PMID- 26010882 TI - Photogenerated Quartet State Formation in a Compact Ring-Fused Perylene Nitroxide. AB - We report on a novel small organic molecule comprising a perylene chromophore fused to a six-membered ring containing a persistent nitroxide radical to give a perylene-nitroxide, or PerNO(*). This molecule is a robust, compact molecule in which the radical is closely bound to the chromophore but separated by saturated carbon atoms, thus limiting the electronic coupling between the chromophore and radical. We present both ultrafast transient absorption experiments and time resolved EPR (TREPR) studies to probe the spin dynamics of photoexcited PerNO(*) and utilize X-ray crystallography to probe the molecular structure and stacking motifs of PerNO(*) in the solid state. The ability to control both the structure and electronic properties of molecules having multiple spins as well as the possibility of assembling ordered solid state materials from them is important for implementing effective molecule-based spintronics. PMID- 26010881 TI - Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model. AB - BACKGROUND: The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI). METHODS: African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033 mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3: control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis. FINDINGS: TMC353121 showed a dose-dependent antiviral activity, varying from 1 log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 MUg/mL) and was associated with a dose-dependent reduction in INFgamma, IL6 and MIP1alpha. TMC353121 administered as CI for 16 days was generally well tolerated. CONCLUSION: TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study. PMID- 26010883 TI - Parathyroid hormone, cognitive function and dementia: a systematic review. AB - BACKGROUND: Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer's disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not. METHODS: We conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies. RESULTS: The twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains. CONCLUSIONS: Mixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area. PMID- 26010884 TI - Sequential FOLFIRI.3 + Gemcitabine Improves Health-Related Quality of Life Deterioration-Free Survival of Patients with Metastatic Pancreatic Adenocarcinoma: A Randomized Phase II Trial. AB - BACKGROUND: A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2) compared to gemcitabine alone (Arm 1) in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS) rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1). This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL) as a secondary endpoint of this study. METHODS: HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS) was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS. RESULTS: 98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85]), emotional functioning (0.35 [0.21-0.59]) and pain (0.50 [0.31-0.81]) than those of Arm 1. CONCLUSION: Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients' characteristics. TRIAL REGISTRATION INFORMATION: Eudract N degrees 2006-005703-34. (Name of the Trial: FIRGEM). PMID- 26010885 TI - Complete Genome Sequence of ER2796, a DNA Methyltransferase-Deficient Strain of Escherichia coli K-12. AB - We report the complete sequence of ER2796, a laboratory strain of Escherichia coli K-12 that is completely defective in DNA methylation. Because of its lack of any native methylation, it is extremely useful as a host into which heterologous DNA methyltransferase genes can be cloned and the recognition sequences of their products deduced by Pacific Biosciences Single-Molecule Real Time (SMRT) sequencing. The genome was itself sequenced from a long-insert library using the SMRT platform, resulting in a single closed contig devoid of methylated bases. Comparison with K-12 MG1655, the first E. coli K-12 strain to be sequenced, shows an essentially co-linear relationship with no major rearrangements despite many generations of laboratory manipulation. The comparison revealed a total of 41 insertions and deletions, and 228 single base pair substitutions. In addition, the long-read approach facilitated the surprising discovery of four gene conversion events, three involving rRNA operons and one between two cryptic prophages. Such events thus contribute both to genomic homogenization and to bacteriophage diversification. As one of relatively few laboratory strains of E. coli to be sequenced, the genome also reveals the sequence changes underlying a number of classical mutant alleles including those affecting the various native DNA methylation systems. PMID- 26010886 TI - Modifying Post-Operative Medical Care after EBV Implant May Reduce Pneumothorax Incidence. AB - OBJECTIVE: Endoscopic lung volume reduction (ELVR) with valves has been shown to improve COPD patients with severe emphysema. However, a major complication is pneumothoraces, occurring typically soon after valve implantation, with severe consequences if not managed promptly. Based on the knowledge that strain activity is related to a higher risk of pneumothoraces, we asked whether modifying post operative medical care with the inclusion of strict short-term limitation of strain activity is associated with a lower incidence of pneumothorax. METHODS: Seventy-two (72) emphysematous patients without collateral ventilation were treated with bronchial valves and included in the study. Thirty-two (32) patients received standard post-implantation medical management (Standard Medical Care (SMC)), and 40 patients received a modified medical care that included an additional bed rest for 48 hours and cough suppression, as needed (Modified Medical Care (MMC)). RESULTS: The baseline characteristics were similar for the two groups, except there were more males in the SMC cohort. Overall, ten pneumothoraces occurred up to four days after ELVR, eight pneumothoraces in the SMC, and only two in the MMC cohorts (p=0.02). Complicated pneumothoraces and pneumothoraces after upper lobe treatment were significantly lower in MMC (p=0.02). Major clinical outcomes showed no significant differences between the two cohorts. CONCLUSIONS: In conclusion, modifying post-operative medical care to include bed rest for 48 hours after ELVR and cough suppression, if needed, might reduce the incidence of pneumothoraces. Prospective randomized studies with larger numbers of well-matched patients are needed to confirm the data. PMID- 26010887 TI - Estrogen Receptor beta2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1alpha in Prostate Cancer. AB - The estrogen receptor (ER) beta variant ERbeta2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ERbeta2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ERbeta2 interacts with and stabilizes HIF-1alpha protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1alpha is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ERbeta2 interacts with HIF-1alpha and piggybacks to the HIF-1alpha response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ERbeta2 is mediated by HIF-1alpha and that targeting of this ERbeta2 - HIF-1alpha interaction may be a strategy to treat prostate cancer. PMID- 26010888 TI - Effects of water and nitrogen addition on ecosystem carbon exchange in a meadow steppe. AB - A changing precipitation regime and increasing nitrogen deposition are likely to have profound impacts on arid and semiarid ecosystem C cycling, which is often constrained by the timing and availability of water and nitrogen. However, little is known about the effects of altered precipitation and nitrogen addition on grassland ecosystem C exchange. We conducted a 3-year field experiment to assess the responses of vegetation composition, ecosystem productivity, and ecosystem C exchange to manipulative water and nitrogen addition in a meadow steppe. Nitrogen addition significantly stimulated aboveground biomass and net ecosystem CO2 exchange (NEE), which suggests that nitrogen availability is a primary limiting factor for ecosystem C cycling in the meadow steppe. Water addition had no significant impacts on either ecosystem C exchange or plant biomass, but ecosystem C fluxes showed a strong correlation with early growing season precipitation, rather than whole growing season precipitation, across the 3 experimental years. After we incorporated water addition into the calculation of precipitation regimes, we found that monthly average ecosystem C fluxes correlated more strongly with precipitation frequency than with precipitation amount. These results highlight the importance of precipitation distribution in regulating ecosystem C cycling. Overall, ecosystem C fluxes in the studied ecosystem are highly sensitive to nitrogen deposition, but less sensitive to increased precipitation. PMID- 26010889 TI - Eriocalyxin B Inhibits STAT3 Signaling by Covalently Targeting STAT3 and Blocking Phosphorylation and Activation of STAT3. AB - Activated STAT3 plays an important role in oncogenesis by stimulating cell proliferation and resisting apoptosis. STAT3 therefore is an attractive target for cancer therapy. We have screened a traditional Chinese herb medicine compound library and found Eriocalyxin B (EB), a diterpenoid from Isodon eriocalyx, as a specific inhibitor of STAT3. EB selectively inhibited constitutive as well as IL 6-induced phosphorylation of STAT3 and induced apoptosis of STAT3-dependent tumor cells. EB did not affect the upstream protein tyrosine kinases or the phosphatase (PTPase) of STAT3, but rather interacted directly with STAT3. The effects of EB could be abolished by DTT or GSH, suggesting a thiol-mediated covalent linkage between EB and STAT3. Site mutagenesis of cysteine in and near the SH2 domain of STAT3 identified Cys712 to be the critical amino acid for the EB-induced inactivation of STAT3. Furthermore, LC/MS/MS analyses demonstrated that an alpha, beta-unsaturated carbonyl of EB covalently interacted with the Cys712 of STAT3. Computational modeling analyses also supported a direct interaction between EB and the Cys712 of STAT3. These data strongly suggest that EB directly targets STAT3 through a covalent linkage to inhibit the phosphorylation and activation of STAT3 and induces apoptosis of STAT3-dependent tumor cells. PMID- 26010891 TI - Development of bullous pemphigoid during treatment of psoriatic onycho-pachydermo periostitis with ustekinumab. AB - Ustekinumab is a human monoclonal antibody that specifically binds to the p40 subunit of interleukin (IL)-12 and IL-23, inhibiting the activity of both cytokines, thereby blocking the T-helper (Th)1 and Th17 inflammatory pathways. While biologic agents have dramatically changed the strategies of psoriasis treatment, increasing cases of autoimmune diseases during the use of such agents have been reported. We experienced a case of bullous pemphigoid occurring during treatment of a rare variant of psoriatic arthritis, psoriatic onycho-pachydermo periostitis with ustekinumab. Only six cases of autoimmune blistering diseases during treatment with biologic agents have ever been reported including our case, and we herein review the published work of these cases. Dermatologists must be attentive to the possibility of autoimmune blistering diseases during ustekinumab treatment. PMID- 26010890 TI - Smartphone-Supported versus Full Behavioural Activation for Depression: A Randomised Controlled Trial. AB - BACKGROUND: There is need for more cost and time effective treatments for depression. This is the first randomised controlled trial in which a blended treatment--including four face-to-face sessions and a smartphone application--was compared against a full behavioural treatment. Hence, the aim of the current paper was to examine whether a blended smartphone treatment was non-inferior to a full behavioural activation treatment for depression. METHODS: This was a randomised controlled non-inferiority trial (NCT01819025) comparing a blended treatment (n=46) against a full ten-session treatment (n=47) for people suffering from major depression. Primary outcome measure was the BDI-II, that was administered at pre- and post-treatment, as well as six months after the treatment. RESULTS: Results showed significant improvements in both groups across time on the primary outcome measure (within-group Cohen's d=1.35; CI [-0.82, 3.52] to d=1.47; CI [-0.41, 3.35]; between group d=-0.13 CI [-2.37, 2.09] and d= 0.10 CI [-2.53, 2.33]). At the same time, the blended treatment reduced the therapist time with an average of 47%. CONCLUSIONS: We could not establish whether the blended treatment was non-inferior to a full BA treatment. Nevertheless, this study points to that the blended treatment approach could possibly treat nearly twice as many patients suffering from depression by using a smartphone application as add-on. More studies are needed before we can suggest that the blended treatment method is a promising cost-effective alternative to regular face-to-face treatment for depression. TRIAL REGISTRATION: Cognitive Behavioral Therapy Treatment of Depression With Smartphone Support NCT01819025. PMID- 26010892 TI - An improved method for estimating antibody titers in microneutralization assay using green fluorescent protein. AB - Viruses that express reporter genes upon infection have been recently used to evaluate neutralizing antibody responses, where a lack of reporter expression indicates specific virus inhibition. The traditional model-based methods using standard outcome of percent neutralization could be applied to the data from the assays to estimate antibody titers. However, the data produced are sometimes irregular, which can yield meaningless outcomes of percent neutralization that do not fit the typical curves for immunoassays, making automated or semi-high throughput antibody titer estimation unreliable. We developed a type of new outcomes model, which is biologically meaningful and fits typical immunoassay curves well. Our simulation study indicates that the new response approach outperforms the traditional response approach regardless of the data variability. The proposed new response approach can be used in similar assays for other disease models. PMID- 26010894 TI - Chemical removal of necrotic periodontal ligament on delayed replanted teeth by sodium hypochlorite: morphological analysis and microhardness indentation test of cementum. AB - AIM: To compare the efficacy of sodium hypochlorite (NaOCl) used at different concentrations and working times for removing necrotic periodontal ligament (PDL) from delayed replanted teeth and to observe the effects of NaOCl on surface structure and microhardness of cementum. METHODOLOGY: A total of 88 healthy premolars with a single root extracted for orthodontic purposes were selected and kept dry at room temperature for 1 h. The teeth were divided into 11 groups: group 1 (control): roots were untreated; group 2: necrotic PDL was removed with gauze; groups 3-11: teeth were immersed in NaOCl at different concentrations (1, 2.5 and 5.25%) and for different working times (5, 10 and 15 min). The specimens in each group were inspected separately for cementum integrity and the presence of PDL remnants by histomorphometric analysis, confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Another 14 healthy premolars with roots divided into two pieces were selected for Vickers microhardness indentation tests before and after NaOCl treatment. The data were analysed statistically using Wilcoxon signed-rank test of two-related samples (P = 0.05). RESULTS: In teeth treated with 1% NaOCl for 15 min or 5.25% NaOCl for 5 min, the cementum remained morphologically intact without cracks, and PDL remnants were absent. In the 1% NaOCl for 15 min group, the microstructure of cementum was arranged more regularly, as observed *8000 magnification by SEM. Teeth in each of the other groups displayed cementum damage and/or the presence of PDL remnants. Microhardness tests revealed that treatment with 1% NaOCl for 15 min or 5.25% NaOCl for 5 min significantly decreased microhardness of root cementum (P < 0.05). CONCLUSIONS: Use of either 1% NaOCl for 15 min or 5.25% NaOCl for 5 min was effective at removing necrotic PDL from the delayed replanted teeth whilst having a minimal influence on cementum integrity. However, 1% NaOCl for 15 min was less damaging to cementum. PMID- 26010893 TI - Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure. AB - KEY POINTS: A major class of mechano-nociceptors to the intestine have mechanotransduction sites on extramural and intramural arteries and arterioles ('vascular afferents'). These sensory neurons can be activated by compression or axial stretch of vessels. Using isolated preparations we showed that increasing intra-arterial pressure, within the physiological range, activated mechano nociceptors on vessels in intact mesenteric arcades, but not in isolated arteries. This suggests that distortion of the branching vascular tree is the mechanical adequate stimulus for these sensory neurons, rather than simple distension. The same rises in pressure also activated intestinal peristalsis in a partially capsaicin-sensitive manner indicating that pressure-sensitive vascular afferents influence enteric circuits. The results identify the mechanical adequate stimulus for a major class of mechano-nociceptors with endings on blood vessels supplying the gut wall; these afferents have similar endings to ones supplying other viscera, striated muscle and dural vessels. ABSTRACT: Spinal sensory neurons innervate many large blood vessels throughout the body. Their activation causes the hallmarks of neurogenic inflammation: vasodilatation through the release of the neuropeptide calcitonin gene-related peptide and plasma extravasation via tachykinins. The same vasodilator afferent neurons show mechanical sensitivity, responding to crushing, compression or axial stretch of blood vessels - responses which activate pain pathways and which can be modified by cell damage and inflammation. In the present study, we tested whether spinal afferent axons ending on branching mesenteric arteries ('vascular afferents') are sensitive to increased intravascular pressure. From a holding pressure of 5 mmHg, distension to 20, 40, 60 or 80 mmHg caused graded, slowly adapting increases in firing of vascular afferents. Many of the same afferent units showed responses to axial stretch, which summed with responses evoked by raised pressure. Many vascular afferents were also sensitive to raised temperature, capsaicin and/or local compression with von Frey hairs. However, responses to raised pressure in single, isolated vessels were negligible, suggesting that the adequate stimulus is distortion of the arterial arcade rather than distension per se. Increasing arterial pressure often triggered peristaltic contractions in the neighbouring segment of intestine, an effect that was mimicked by acute exposure to capsaicin (1 MUm) and which was reduced after desensitisation to capsaicin. These results indicate that sensory fibres with perivascular endings are sensitive to pressure induced distortion of branched arteries, in addition to compression and axial stretch, and that they contribute functional inputs to enteric motor circuits. PMID- 26010895 TI - Inhibition of the metabolic degradation of filtered albumin is a major determinant of albuminuria. AB - Inhibition of the degradation of filtered albumin has been proposed as a widespread, benign form of albuminuria. There have however been recent reports that radiolabeled albumin fragments in urine are not exclusively generated by the kidney and that in albuminuric states albumin fragment excretion is not inhibited. In order to resolve this controversy we have examined the fate of various radiolabeled low molecular weight protein degradation products (LMWDPs) introduced into the circulation in rats. The influence of puromycin aminonucleoside nephrosis on the processing and excretion of LMWDPs is also examined. The status and destinies of radiolabeled LMWDPs in the circulation are complex. A major finding is that LMWDPs are rapidly eliminated from the circulation (>97% in 2 h) but only small quantities (<4%) are excreted in urine. Small (<4%) but significant amounts of LMWDPs may have prolonged elimination (>24 h) due to binding to high molecular weight components in the circulation. If LMWDPs of albumin seen in the urine are produced by extra renal degradation it would require the degradation to far exceed the known catabolic rate of albumin. Alternatively, if an estimate of the role of extra renal degradation is made from the limit of detection of LMWDPs in plasma, then extra renal degradation would only contribute <1% of the total excretion of LMWDPs of albumin. We confirm that the degradation process for albumin is specifically associated with filtered albumin and this is inhibited in albuminuric states. This inhibition is also the primary determinant of the massive change in intact albuminuria in nephrotic states. PMID- 26010897 TI - Utility of the rio score and modified rio score in korean patients with multiple sclerosis. AB - OBJECTIVES: Early identification of suboptimal responders to multiple sclerosis (MS) treatment is critical for optimizing therapeutic decisions. The Rio score (RS) and modified Rio score (MRS) were developed to discriminate the responses to interferon-beta (IFNB) treatment in MS patients. This study was performed to evaluate the utility of RS and MRS in daily clinical practice in Korea. METHODS: This was a real-world setting, multicenter, retrospective study of MS patients treated with IFNB from 10 hospitals in Korea. We investigated whether the RS and MRS at the early stage of IFNB therapy could predict treatment responses over 3 years. Suboptimal treatment responses at 3 years were defined as the presence of clinical relapse and/or EDSS progression and/or patients who had been treated with INFB for at least for 1 year and therapy was switched due to perceived treatment failure during the 2 years of follow-up. RESULTS: Seventy patients (50 females and 20 males) were enrolled; 92% (12/13) of patients with high RS and 86% (12/14) of patients with high MRS (score 2 or 3) were suboptimal responders, whereas 93% (53/57) of patients with low RS and 93% (52/56) patients with low MRS (score 0 or 1) showed optimal responses. New active lesions on MRI with clinical relapse in high RS and MRS were the most common combination in suboptimal responders. CONCLUSIONS: We confirmed that RS and MRS at 6-15 months of IFNB therapy were useful for predicting poor responders over 3 years. PMID- 26010898 TI - Distinct roles of urinary liver-type fatty acid-binding protein in non-diabetic patients with anemia. AB - BACKGROUND: Various stresses including ischemia are known to up-regulate renal L FABP gene expression and increase the urinary excretion of L-FABP. In diabetic patients with anemia, the urinary excretion of L-FABP is significantly increased. We studied the clinical significance of urinary L-FABP and its relationship with anemia in non-diabetic patients. SUBJECTS AND METHODS: A total of 156 patients were studied in this retrospective cross-sectional analysis. The associations between anemia and urinary L-FABP levels, and the predictors of urinary L-FABP levels in non-diabetic patients were evaluated. RESULTS: Urinary L-FABP levels were significantly higher in patients with anemia compared to those in patients without anemia. Similarly, the urinary L-FABP levels were significantly higher in patients with albuminuria compared to those in patients without albuminuria. Urinary L-FABP levels correlated with urinary albumin-to-creatinine ratios, estimated glomerular filtration rates, body mass index, and hemoglobin levels. Multivariate linear regression analysis determined that hemoglobin levels (beta = -0.249, P = 0.001) and urinary albumin-to-creatinine ratios (beta = 0.349, P < 0.001) were significant predictors of urinary L-FABP levels. CONCLUSIONS: Urinary L-FABP is strongly associated with anemia in non-diabetic patients. PMID- 26010899 TI - A Comparison of Comprehension Processes in Sign Language Interpreter Videos with or without Captions. AB - One important theme in captioning is whether the implementation of captions in individual sign language interpreter videos can positively affect viewers' comprehension when compared with sign language interpreter videos without captions. In our study, an experiment was conducted using four video clips with information about everyday events. Fifty-one deaf and hard of hearing sign language users alternately watched the sign language interpreter videos with, and without, captions. Afterwards, they answered ten questions. The results showed that the presence of captions positively affected their rates of comprehension, which increased by 24% among deaf viewers and 42% among hard of hearing viewers. The most obvious differences in comprehension between watching sign language interpreter videos with and without captions were found for the subjects of hiking and culture, where comprehension was higher when captions were used. The results led to suggestions for the consistent use of captions in sign language interpreter videos in various media. PMID- 26010900 TI - Modelling and computation in the valuation of carbon derivatives with stochastic convenience yields. AB - The anthropogenic greenhouse gas (GHG) emission has risen dramatically during the last few decades, which mainstream researchers believe to be the main cause of climate change, especially the global warming. The mechanism of market-based carbon emission trading is regarded as a policy instrument to deal with global climate change. Although several empirical researches about the carbon allowance and its derivatives price have been made, theoretical results seem to be sparse. In this paper, we theoretically develop a mathematical model to price the CO2 emission allowance derivatives with stochastic convenience yields by the principle of absence of arbitrage opportunities. In the case of American options, we formulate the pricing problem to a linear parabolic variational inequality (VI) in two spatial dimensions and develop a power penalty method to solve it. Then, a fitted finite volume method is designed to solve the nonlinear partial differential equation (PDE) resulting from the power penalty method and governing the futures, European and American option valuation. Moreover, some numerical results are performed to illustrate the efficiency and usefulness of this method. We find that the stochastic convenience yield does effect the valuation of carbon emission derivatives. In addition, some sensitivity analyses are also made to examine the effects of some parameters on the valuation results. PMID- 26010896 TI - Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise. AB - Skeletal muscles comprise a substantial portion of whole body mass and are integral for locomotion and metabolic health. Increasing age is associated with declines in both muscle mass and function (e.g. strength-related performance, power) with declines in muscle function quantitatively outweighing those in muscle volume. The mechanisms behind these declines are multi-faceted involving both intrinsic age-related metabolic dysregulation and environmental influences such as nutritional and physical activity. Ageing is associated with a degree of 'anabolic resistance' to these key environmental inputs, which likely accelerates the intrinsic processes driving ageing. On this basis, strategies to sensitize and/or promote anabolic responses to nutrition and physical activity are likely to be imperative in alleviating the progression and trajectory of sarcopenia. Both resistance- and aerobic-type exercises are likely to confer functional and health benefits in older age, and a clutch of research suggests that enhancement of anabolic responsiveness to exercise and/or nutrition may be achieved by optimizing modifications of muscle-loading paradigms (workload, volume, blood flow restriction) or nutritional support (e.g. essential amino acid/leucine) patterns. Nonetheless, more work is needed in which a more holistic view in ageing studies is taken into account. This should include improved characterization of older study recruits, that is physical activity/nutritional behaviours, to limit confounding variables influencing whether findings are attributable to age, or other environmental influences. Nonetheless, on balance, ageing is associated with declines in muscle mass and function and a partially related decline in aerobic capacity. There is also good evidence that metabolic flexibility is impaired in older age. PMID- 26010902 TI - Architecture, Assembly, and Emerging Applications of Branched Functional Polyelectrolytes and Poly(ionic liquid)s. AB - Branched polyelectrolytes with cylindrical brush, dendritic, hyperbranched, grafted, and star architectures bearing ionizable functional groups possess complex and unique assembly behavior in solution at surfaces and interfaces as compared to their linear counterparts. This review summarizes the recent developments in the introduction of various architectures and understanding of the assembly behavior of branched polyelectrolytes with a focus on functional polyelectrolytes and poly(ionic liquid)s with responsive properties. The branched polyelectrolytes and poly(ionic liquid)s interact electrostatically with small molecules, linear polyelectrolytes, or other branched polyelectrolytes to form assemblies of hybrid nanoparticles, multilayer thin films, responsive microcapsules, and ion-conductive membranes. The branched structures lead to unconventional assemblies and complex hierarchical structures with responsive properties as summarized in this review. Finally, we discuss prospectives for emerging applications of branched polyelectrolytes and poly(ionic liquid)s for energy harvesting and storage, controlled delivery, chemical microreactors, adaptive surfaces, and ion-exchange membranes. PMID- 26010901 TI - Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking. AB - CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers. PMID- 26010903 TI - Screening for depression and anxiety among older Chinese immigrants living in Western countries: The use of the Geriatric Depression Scale (GDS) and the Geriatric Anxiety Inventory (GAI). AB - BACKGROUND: Depression and anxiety are two common mental health problems among older people. There is evidence that using well-validated screening tools can improve detection of depression and anxiety among this group. The review explored the use of the Geriatric Depression Scale (GDS) and the Geriatric Anxiety Inventory (GAI) for screening depression and anxiety among older Chinese immigrants, one of the largest and fastest growing groups of older immigrants in Western society. It focused on the GDS and GAI because both are designed specifically for older people. METHODS: Online literature searches were conducted in MEDLINE, CINAHL, and PsycINFO. A narrative approach was used to review included papers. RESULTS: A total of 21 articles were included. There were limited data on anxiety among older Chinese immigrants, with only one unpublished report identified. There were 13 studies (20 articles) using the GDS with this group. Results of these studies indicated that the GDS is a reliable tool in this population; however, there was limited validity data. Two versions of the GDS-15 have been used with older Chinese immigrants, including the standard GDS-15 and Mui's GDS-15. Prevalence of depression ranged between 20% and 30% in most reviewed studies. DISCUSSION: Results of this review have practical implications for clinicians in their use of these tools with older Chinese immigrants in Western countries, such as the different GDS versions. It also suggests a number of directions for future research, such as the inclusion of clinical samples and consideration of the diversity within this group. PMID- 26010904 TI - Biochemical and Proteomic Analysis of Ubiquitination of Hsc70 and Hsp70 by the E3 Ligase CHIP. AB - The E3 ubiquitin ligase CHIP is involved in protein triage, serving as a co chaperone for refolding as well as catalyzing ubiquitination of substrates. CHIP functions with both the stress induced Hsp70 and constitutive Hsc70 chaperones, and also plays a role in maintaining their balance in the cell. When the chaperones carry no client proteins, CHIP catalyzes their polyubiquitination and subsequent proteasomal degradation. Although Hsp70 and Hsc70 are highly homologous in sequence and similar in structure, CHIP mediated ubiquitination promotes degradation of Hsp70 with a higher efficiency than for Hsc70. Here we report a detailed and systematic investigation to characterize if there are significant differences in the CHIP in vitro ubiquitination of human Hsp70 and Hsc70. Proteomic analysis by mass spectrometry revealed that only 12 of 39 detectable lysine residues were ubiquitinated by UbcH5a in Hsp70 and only 16 of 45 in Hsc70. The only conserved lysine identified as ubiquitinated in one but not the other heat shock protein was K159 in Hsc70. Ubiquitination assays with K-R ubiquitin mutants showed that multiple Ub chain types are formed and that the distribution is different for Hsp70 versus Hsc70. CHIP ubiquitination with the E2 enzyme Ube2W is predominantly directed to the N-terminal amine of the substrate; however, some internal lysine modifications were also detected. Together, our results provide a detailed view of the differences in CHIP ubiquitination of these two very similar proteins, and show a clear example where substantial differences in ubiquitination can be generated by a single E3 ligase in response to not only different E2 enzymes but subtle differences in the substrate. PMID- 26010905 TI - Microarray based gene expression analysis of murine brown and subcutaneous adipose tissue: significance with human. AB - BACKGROUND: Two types of adipose tissues, white (WAT) and brown (BAT) are found in mammals. Increasingly novel strategies are being proposed for the treatment of obesity and its associated complications by altering amount and/or activity of BAT using mouse models. METHODOLOGY/PRINCIPLE FINDINGS: The present study was designed to: (a) investigate the differential expression of genes in LACA mice subcutaneous WAT (sWAT) and BAT using mouse DNA microarray, (b) to compare mouse differential gene expression with previously published human data; to understand any inter- species differences between the two and (c) to make a comparative assessment with C57BL/6 mouse strain. In mouse microarray studies, over 7003, 1176 and 401 probe sets showed more than two-fold, five-fold and ten-fold change respectively in differential expression between murine BAT and WAT. Microarray data was validated using quantitative RT-PCR of key genes showing high expression in BAT (Fabp3, Ucp1, Slc27a1) and sWAT (Ms4a1, H2-Ob, Bank1) or showing relatively low expression in BAT (Pgk1, Cox6b1) and sWAT (Slc20a1, Cd74). Multi omic pathway analysis was employed to understand possible links between the organisms. When murine two fold data was compared with published human BAT and sWAT data, 90 genes showed parallel differential expression in both mouse and human. Out of these 90 genes, 46 showed same pattern of differential expression whereas the pattern was opposite for the remaining 44 genes. Based on our microarray results and its comparison with human data, we were able to identify genes (targets) (a) which can be studied in mouse model systems to extrapolate results to human (b) where caution should be exercised before extrapolation of murine data to human. CONCLUSION: Our study provides evidence for inter species (mouse vs human) differences in differential gene expression between sWAT and BAT. Critical understanding of this data may help in development of novel ways to engineer one form of adipose tissue to another using murine model with focus on human. PMID- 26010906 TI - Radial PCI and the obesity paradox: Insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). AB - OBJECTIVE: To examine if transradial approach (TRA) negates the increased risk associated with femoral access in lean and morbidly obese patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Patients at extremes of body mass are at increased risk of bleeding after PCI. TRA has been associated with lower overall rates of bleeding compared to femoral approach. METHODS AND RESULTS: We studied patients undergoing emergent and elective PCI from 2010 to 2012 across 47 hospitals in Michigan who participate in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium PCI registry. The primary outcomes were the incidences of bleeding and postprocedure transfusion. Propensity matching (PM) was used to adjust for nonrandomized use of TRA. TRA was used in 10,235 procedures. In PM analyses, use of TRA was associated with a reduction in bleeding (0.80 vs. 1.9%, odds ratio [OR] = 0.41, 95% confidence interval [CI] = 0.32-0.54, P < 0.001) and need for transfusion (1.4 vs. 2.5%, OR = 0.56, 95% CI = 0.45-0.69, P < 0.001) compared with femoral access. The absolute difference in bleeding and transfusion associated with TRA was largest in patients with lean body mass (BMI < 25 kg/m(2)) and morbid obesity (BMI >= 40 kg/m(2)): Lean patients undergoing TRA had a rate of bleeding of 1.2 versus 2.8% for femoral access (OR = 0.43, 95% CI = 0.24-0.77, P = 0.002); and rate of transfusion of 2.4 versus 3.9% (OR = 0.61, 95% CI = 0.40-0.94, P = 0.019). The morbidly obese had a rate of bleeding of 0.8% for TRA versus 2.4% for femoral access (OR = 0.33, 95% CI = 0.44-0.72, P = 0.004); and rate of transfusion of 1.7 versus 3.0%, (OR = 0.55, 95% CI = 0.30-1.0, P = 0.051). CONCLUSIONS: Compared with the femoral approach, TRA is associated with a reduction in bleeding across all patients undergoing PCI and the absolute benefit was greatest in those with extremely low or high BMI. PMID- 26010907 TI - Profiles of Steroid Hormones in Canine X-Linked Muscular Dystrophy via Stable Isotope Dilution LC-MS/MS. AB - Golden retriever muscular dystrophy (GRMD) provides the best animal model for characterizing the disease progress of the human disorder, Duchenne muscular dystrophy (DMD). The purpose of this study was to determine steroid hormone concentration profiles in healthy golden retriever dogs (control group - CtGR) versus GRMD-gene carrier (CaGR) and affected female dogs (AfCR). Therefore, a sensitive and specific analytical method was developed and validated to determine the estradiol, progesterone, cortisol, and testosterone levels in the canine serum by isotope dilution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). To more accurately understand the dynamic nature of the serum steroid profile, the fluctuating levels of these four steroid hormones over the estrous cycle were compared across the three experimental groups using a multivariate statistical analysis. The concentration profiles of estradiol, cortisol, progesterone, and testosterone revealed a characteristic pattern for each studied group at each specific estrous phase. Additionally, several important changes in the serum concentrations of cortisol and estradiol in the CaGR and AfCR groups seem to be correlated with the status and progression of the muscular dystrophy. A comprehensive and quantitative monitoring of steroid profiles throughout the estrous cycle of normal and GRMD dogs were achieved. Significant differences in these profiles were observed between GRMD and healthy animals, most notably for estradiol. These findings contribute to a better understanding of both dog reproduction and the muscular dystrophy pathology. Our data open new venues for hormonal behavior studies in dystrophinopathies and that may affect the quality of life of DMD patients. PMID- 26010910 TI - Maternal age at first delivery is associated with the risk of metabolic syndrome in postmenopausal women: from 2008-2010 Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Recent cross-sectional studies demonstrated that earlier maternal age at first childbirth is correlated with a higher risk of diabetes in postmenopausal women. In this study, we evaluated whether the age at first delivery is associated with the risk of metabolic syndrome (MetS) in postmenopausal women. METHODS: A total of 4,261 postmenopausal women aged 45 years or older were analyzed using data generated from Korea National Health and Nutrition Examination Surveys (2008-2010). Subjects were divided into three groups according to the maternal age at first delivery as follows: <= 20 years (n=878), 21-25 years (n=2314), and >= 26 years (n=1069). RESULTS: Approximately 37% of subjects had MetS. The prevalence of MetS showed a gradual increase as maternal age at first delivery decreased (>= 26 years = 30.9% vs. 21-25 years = 39.9% vs. <= 20 years = 50.8%, respectively, p < 0.001). Central obesity indices such as trunk fat mass and waist circumference were significantly higher in the group aged <= 20 years than other groups. After adjustments for confounding factors, the odds ratios (ORs) for predicting the presence of MetS increased gradually as first delivery age decreased (>= 26 years vs. 21-25 years vs. <= 20 years: OR [95% CI] = 1 vs. 1.324 [1.118-1.567] vs. 1.641 [1.322-2.036], respectively). Among components of MetS, younger maternal age at first delivery (<= 20 years) was significantly associated with increased waist circumference (OR [95% CI] = 1.735 [1.41-2.13]), elevated blood pressure (1.261 [1.02-1.57]), high triglyceride (1.333 [1.072-1.659]), and low HDL-cholesterol (1.335[1.084-1.643]). CONCLUSIONS: Our findings suggest that younger maternal age at first delivery is independently associated with a higher risk of central obesity and MetS in postmenopausal women. PMID- 26010911 TI - Correction: MiR-506 Is Down-Regulated in Clear Cell Renal Cell Carcinoma and Inhibits Cell Growth and Metastasis via Targeting FLOT1. PMID- 26010909 TI - Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder. AB - Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field. Although quantitative measures such as proton MR spectroscopy or magnetization transfer imaging have not reproducibly revealed diffuse brain injury, preliminary data from diffusion-weighted imaging and brain tissue volumetry indicate greater white matter than gray matter degradation. These findings could be confirmed by ultrahigh-field MRI. The use of nonconventional MRI techniques may further our understanding of the pathogenic processes in NMO spectrum disorders and may help us identify the distinct radiographic features corresponding to specific phenotypic manifestations of this disease. PMID- 26010912 TI - Patients with knee osteoarthritis undergoing total knee arthroplasty have a lower risk of subsequent severe cardiovascular events: propensity score and instrumental variable analysis. AB - OBJECTIVE: This population-based study investigated the subsequent cardiovascular risk of patients with knee osteoarthritis underwent total knee arthroplasty in Taiwan. MATERIALS AND METHODS: This was a population-based follow-up study of 22931 patients diagnosed with knee osteoarthritis between 2008 and 2011. Each patient was followed for 3 years or until death. Treatment was dichotomized into conservative treatment and TKA. The association between TKA and cardiovascular disease (CVD) events was analyzed using propensity score analysis and instrumental variable analysis and two-stage least-squares regression model. RESULTS: Patients with knee osteoarthritis who underwent TKA had a lower 3-year cumulative risk of stroke and acute myocardial infarction (AMI). After adjusting for measured risk and confounding factors, propensity score showed a 0.56 fold (adjusted OR = 0.56; 95% CI, 0.51-0.61; p<0.001) risk for CVD in those with TKA. Use of instrumental variable analysis for adjusting measured and unmeasured factors and two-stage least squares regression model revealed that the average treatment effect of TKA was statistically associated with a decreased 7% risk of CVD events (95% CI, 0.2%-13.6%). CONCLUSION: Our study revealed that patients with knee osteoarthritis who underwent TKA had a lower risk of suffering from a future severe cardiovascular event. This benefit may be attributed to an improvement in physical activity, reduction of psychosocial stress, and/or a decreased use of NSAIDs as a result of having undergone TKA. PMID- 26010913 TI - Characterization of the peak at 2.06 ppm in (31) P magnetic resonance spectroscopy of human liver: phosphoenolpyruvate or phosphatidylcholine? AB - High field MR scanners can resolve a metabolite resonating at 2.06 ppm in the in vivo proton-decoupled liver (31) P MR spectrum. Traditionally this peak has been assigned to phosphoenolpyruvate (PEP), the key metabolite for gluconeogenesis. However, recent evidence supported the assignment to biliary phosphatidylcholine (PtdCh), which is produced in the liver and stored in the gall bladder. To elucidate the respective contributions of PtdCh and PEP to the in vivo resonance at 2.06 ppm (PEP-PtdCh), we made phantom measurements that confirmed that both biliary PtdCh and PEP resonate approximately at 2 ppm. The absolute quantification of PEP-PtdCh yielded concentrations ranging from 0.6 to 2.0 mmol/l, with mean coefficients of variation of 4.8% for intraday and 7.2% for interday reproducibility in healthy volunteers. The T1 relaxation time of PEP PtdCh was 0.97 +/- 0.30 s in the liver and 0.44 +/- 0.11 s in the gallbladder. Ingestion of a mixed meal decreased the concentration of PtdCh-PEP by approximately 12%. In the retrospective analysis, PEP-PtdCh was 68% higher in the liver of subjects with gallbladder infiltration of the volume of interest (VOI) compared with those without gallbladder infiltration. PEP-PtdCh was also significantly higher in the liver of cholecystectomy patients compared with volunteers without gallbladder infiltration, which suggests increased intrahepatic bile fluid as a compensation for gall bladder removal. These results show that liver PtdCh is the major component of the resonance at 2.06 ppm and that careful VOI positioning is mandatory to avoid interference from the gallbladder. PMID- 26010914 TI - Association of Leisure-Time Physical Activity to Cardiovascular Disease Prevalence in Relation to Smoking among Adult Nevadans. AB - It is well known that cigarette smoking and physical activity have significant impacts on cardiovascular disease (CVD) mortality and morbidity. Meanwhile, it is of interest to understand whether physical activity protects against CVD for smokers in a similar manner as it does for non-smokers. The present study examined how leisure-time physical activity (LTPA) is associated with the prevalence of CVD in relation to smoking status among adult Nevadans, using data from the 2010 Nevada Behavioral Risk Factor Surveillance System. Of the 3,913 survey respondents, 8.5% self-reported that they had ever been diagnosed with CVD. People with a history of CVD were significantly less likely to engage in LTPA than those with no history of CVD (p < 0.05). After adjusting for common sociodemographic variables, it was revealed that people with CVD were twice more likely to not engage in LTPA than their counterparts independent of smoking status. Without taking LTPA into account, the odds of having CVD for current and former smokers was 1.87-2.25 times higher than the odds for non-smokers. Interestingly, however, if LTPA was accounted for, there was no significant difference in the odds of having CVD between current and non-smokers. These results indicate that LTPA is inversely associated with the prevalence of CVD independent of smoking status, and that regular physical activity may protect against CVD for smokers as well as for non-smokers. Physical activity, along with smoking cessation, should be promoted to better prevent and control CVD among smokers. PMID- 26010915 TI - Effects of Flaxseed Lignan Secoisolariciresinol Diglucosideon Preneoplastic Biomarkers of Cancer Progression in a Model of Simultaneous Breast and Ovarian Cancer Development. AB - Breast cancer prevention efforts are focused increasingly on potentially beneficial dietary modifications due to their ease of implementation and wide acceptance. Secoisolariciresinol diglucoside (SDG) is a lignan found in high concentration in flaxseed that may have selective estrogen receptor modulator like effects resulting in antiestrogenic activity in a high estrogen environment. In parallel with a human phase II prevention trial, female ACI rats (n = 8 10/group) received 0, 10, or 100 ppm SDG in the feed. The 100 ppm SDG treatment produced similar blood lignan levels as those observed in our human pilot study. Mammary and ovarian cancer progression were induced using local ovarian DMBA treatment and subcutaneous sustained release 17beta-estradiol administered starting at 7 weeks of age. Mammary gland and ovarian tissues were collected at 3 mo after initiation of treatment and examined for changes in epithelial cell proliferation (Ki-67, cell counts), histopathology, and dysplasia scores, as well as expression of selected genes involved in proliferation, estrogen signaling, and cell adhesion. Treatment with SDG normalized several biomarkers in mammary gland tissue (dysplasia, cell number, and expression of several genes) that had been altered by carcinogen. There is no indication that SDG promotes preneoplastic progression in the ovarian epithelium. PMID- 26010917 TI - Is optical frequency domain imaging a promising modality for diagnosis of erosion? PMID- 26010916 TI - Flavonoid intake in European adults (18 to 64 years). AB - BACKGROUND: Flavonoids are a group of phenolic secondary plant metabolites that are ubiquitous in plant-based diets. Data from anthropological, observational and intervention studies have shown that many flavonoids are bioactive. For this reason, there is an increasing interest in investigating the potential health effects of these compounds. The translation of these findings into the context of the health of the general public requires detailed information on habitual dietary intake. However, only limited data are currently available for European populations. OBJECTIVE: The objective of this study is to determine the habitual intake and main sources of anthocyanidins, flavanols, flavanones, flavones, flavonols, proanthocyanidins, theaflavins and thearubigins in the European Union. DESIGN: We use food consumption data from the European Food Safety Authority (EFSA) and the FLAVIOLA Food Composition Database to estimate intake of flavonoids. RESULTS: Mean (+/-SEM) intake of total flavonoids in Europe was 428+/ 49 mg/d, of which 136+/-14 mg/d were monomeric compounds. Gallated flavan-3-ols (53+/-12 mg/d) were the main contributor. The lowest flavonoid intake was observed in Mediterranean countries (monomeric compounds: 95+/-11 mg/d). The distribution of intake was skewed in many countries, especially in Germany (monomeric flavonoids; mean intake: 181 mg/d; median intake: 3 mg/d). CONCLUSIONS: The habitual intake of flavonoids in Europe is below the amounts found to have a significant health effect. PMID- 26010918 TI - TaLHY, a 1R-MYB Transcription Factor, Plays an Important Role in Disease Resistance against Stripe Rust Fungus and Ear Heading in Wheat. AB - LHY (late elongated hypocotyl) is an important gene that regulates and controls biological rhythms in plants. Additionally, LHY is highly expressed in the SSH (suppression subtractive hybridization) cDNA library-induced stripe rust pathogen (CYR32) in our previous research. To identify the function of the LHY gene in disease resistance against stripe rust, we used RACE-PCR technology to clone TaLHY in the wheat variety Chuannong19. The cDNA of TaLHY is 3085 bp long with an open reading frame of 1947 bp. TaLHY is speculated to encode a 70.3 kDa protein of 648 amino acids , which has one typical plant MYB-DNA binding domain; additionally, phylogenetic tree shows that TaLHY has the highest homology with LHY of Brachypodium distachyon(BdLHY-like). Quantitative fluorescence PCR indicates that TaLHY has higher expression in the leaf, ear and stem of wheat but lower expression in the root. Infestation of CYR32 can result in up-regulated expression of TaLHY, peaking at 72 h. Using VIGS (virus-induced gene silencing) technology to disease-resistant wheat in the fourth leaf stage, plants with silenced TaLHY cannot complete their heading stage. Through the compatible interaction with the stripe rust physiological race CYR32, Chuannong 19 loses its immune capability toward the stripe rust pathogen, indicating that TaLHY may regulate and participate in the heading of wheat, as well as the defense responses against stripe rust infection. PMID- 26010921 TI - Rex Milton Butterfield: 1921-2014. PMID- 26010922 TI - Development of a technique for standing hand-assisted laparoscopic splenectomy in five horses. AB - OBJECTIVES: To develop an experimental standing hand-assisted laparoscopic splenectomy (HALS) technique, report the associated peri-operative complications and document the short-term surgical outcomes. METHODS AND RESULTS: Five healthy 300-470 kg horses that underwent standing HALS. Spleens of different weights (2.25-7.0 kg) were removed using this technique. The main complication during surgery was difficulty sectioning the gastrosplenic ligament. The postoperative complications included adhesions of the colon to the nephrosplenic ligament stump and incisional discharge in two horses. CONCLUSIONS: Standing HALS is a feasible experimental procedure for medium-sized horses, which avoids rib excision and general anaesthesia, but requires further development. PMID- 26010923 TI - An abattoir survey of equine dental abnormalities in Queensland, Australia. AB - OBJECTIVE: A cadaver study to estimate the prevalence of dental disorders in horses presented at an abattoir in Queensland, Australia. METHODS: Cadaver heads at a Queensland abattoir were examined for the presence of dental abnormalities and categorised into age groups. The prevalence of abnormalities was analysed by binomial observation of observed proportion, Pearson's Chi-square test or Fisher's exact correlation test. Strength of association was evaluated using Cramer's V test. RESULTS: Heads from horses (n=400) estimated to be between 1 and 30 years of age were placed into four age groups. The most common abnormalities were sharp enamel points (55.3%) and hooks (43%). The highest frequency of dental diseases and abnormalities were in horses 11-15 years old (97.5%). CONCLUSIONS: Common abnormalities were found in all groups and the prevalence increased with age. This study suggests that all horses should have regular complete dental examinations to detect and treat dental disorders in order to limit more severe dental pathologies later in life. PMID- 26010924 TI - Canine neural angiostrongylosis: a case-control study in Sydney dogs. AB - OBJECTIVE: To determine the risk factors for canine neural angiostrongylosis in dogs domiciled in Sydney, Australia; geographic location, age, sex, neuter status, weight and breed were assessed. PROCEDURE: Case and matched-control dogs were selected from three veterinary clinics in Sydney. Conditional logistic regression was used to identify factors associated with disease status. A scan statistic was used to identify disease clusters. RESULTS: Age (young dogs) and neuter status (entire dogs) were independent risk factors for neural angiostrongylosis diagnosis, and diagnoses predominantly occurred during autumn, with some evidence of spatial clustering. CONCLUSIONS: Veterinarians in endemic areas should be aware of these risk factors when presented with suspect canine neural angiostrongylosis cases and also should consider advising clients of preventive treatment. Potential human health risks should be further investigated, because urban dog populations might represent a useful sentinel species for disease in humans. PMID- 26010925 TI - Retrospective evaluation of the efficacy of isolating bacteria from synovial fluid in dogs with suspected septic arthritis. AB - OBJECTIVE: To evaluate the efficacy of synovial fluid culture in obtaining the causative organism from dogs with suspected septic arthritis. METHODS: In this retrospective evaluation, synovial fluid cytology and microbiology submissions from dogs with suspected septic arthritis from March 2007 to August 2011 were reviewed. Synovial fluid cytology consistent with joint sepsis was identified. Cultures of synovial fluid from dogs with clinical histories and abnormalities consistent with septic arthritis were used to evaluate the efficacy of bacterial isolation. RESULTS: In total, 36 dogs met the inclusion criteria. Initial aerobic cultures of joint fluid yielded bacterial growth in 44% of these dogs. All anaerobic cultures were negative. In 19% of the dogs with positive cultures, antibiotics had been administered prior to arthrocentesis compared with 10% of dogs with negative cultures. There was no association between culture efficacy and the administration of antimicrobial treatment prior to synovial fluid culture or recent surgery involving the affected joint (P=0.637 and P=0.106, respectively). CONCLUSION: Culture of synovial fluid from dogs with suspected septic arthritis has a low yield, necessitating a more effective means of identifying bacteria from suspected septic joints in dogs. PMID- 26010926 TI - Comparison of synovial fluid culture and 16S rRNA PCR in dogs with suspected septic arthritis. AB - OBJECTIVE: To prospectively compare the sensitivity and specificity of 16S rRNA PCR with culture for identifying the causative organism in synovial fluid obtained from dogs with suspected septic arthritis. METHODS: Synovial fluid cytology, PCR analysis and aerobic, anaerobic and Mycoplasma culture of samples from the affected joints of 18 dogs presenting with suspected septic arthritis were performed. Synovial fluid samples from the corresponding contralateral joints of 7 dogs were also analysed as negative controls. RESULTS: There was no significant difference between the sensitivity of bacterial detection via culture (63.2%) versus PCR (73.7%) of synovial fluid (P=0.728) or between culture and combined PCR and culture (89.5%) of synovial fluid (P=0.124). The specificity of PCR (42.9%) was significantly lower than culture specificity (100%) (P=0.07). CONCLUSION: Although 16S PCR may hold potential as an ancillary diagnostic test for identifying the causative organism in dogs with septic arthritis, our study failed to demonstrate improved accuracy compared with traditional synovial fluid culture. PMID- 26010927 TI - Acute renal failure associated with Amaranthus species ingestion by lambs. AB - CASE REPORT: This report documents an outbreak of acute renal failure in a flock of 9-month-old White Suffolk-cross ewe lambs. The mortality rate was moderate but the morbidity was high. The lambs had grazed a wheat stubble paddock in which there were several weed species, including Amaranthus spp. CLINICAL SIGNIFICANCE: Renal failure in livestock has been reported internationally following the ingestion of Amaranthus spp. and although it has previously been suspected in Australia no cases have been documented. It is important for Australian veterinarians and farmers to realise the toxic potential of this group of plants. PMID- 26010928 TI - Hydration in non-suckling neonatal Brahman-cross calves. AB - OBJECTIVE: To identify measures that most closely relate to hydration in healthy Brahman-cross neonatal calves that experience milk deprivation. METHODS: In a dry tropical environment, eight neonatal Brahman-cross calves were prevented from suckling for 2-3 days during which measurements were performed twice daily. RESULTS: Mean body water, as estimated by the mean urea space, was 74+/-3% of body weight at full hydration. The mean decrease in hydration was 7.3+/-1.1% per day. The rate of decrease was more than three-fold higher during the day than at night. At an ambient temperature of 39 degrees C, the decrease in hydration averaged 1.1% hourly. Measures that were most useful in predicting the degree of hydration in both simple and multiple-regression prediction models were body weight, hindleg length, girth, ambient and oral temperatures, eyelid tenting, alertness score and plasma sodium. These parameters are different to those recommended for assessing calves with diarrhoea. Single-measure predictions had a standard error of at least 5%, which reduced to 3-4% if multiple measures were used. CONCLUSION: We conclude that simple assessment of non-suckling Brahman cross neonatal calves can estimate the severity of dehydration, but the estimates are imprecise. Dehydration in healthy neonatal calves that do not have access to milk can exceed 20% (>15% weight loss) in 1-3 days under tropical conditions and at this point some are unable to recover without clinical intervention. PMID- 26010929 TI - Use of developmental temperature and gastrointestinal tract location to isolate pure Trichostrongylus vitrinus from mixed, naturally acquired trichostrongylid infections in sheep. AB - OBJECTIVE: To isolate Trichostrongylus vitrinus from naturally-acquired mixed trichostrongylid infections (predominantly Trichostrongylus spp. and Teladorsagia circumcincta) in sheep using differential larval development temperatures and the anatomical location of adults. METHODS: Faeces were collected from ewes with mixed, naturally acquired trichostrongylid infection, and incubated at low temperatures (4 degrees C or 8 degrees C) for 20-68 days depending on temperature. Harvested infective larvae were passaged through worm-free lambs, from which the first 5 m of small intestine was collected and adult worms recovered. Purity of infection with T. vitrinus was assessed by examination of spicules on 100 adult male worms. Eggs of recovered adult female worms were cultured at 25 degrees C and harvested larvae were re-passaged through worm-free lambs. RESULTS: Low temperature incubation (<=8 degrees C) successfully exploited variation in the developmental temperature required by pre-parasitic stages of small intestinal nematodes, allowing T. vitrinus to develop while others did not. Differential organ harvest from infected sheep allowed isolation of T. vitrinus from other gastrointestinal nematodes, with amplification of pure T. vitrinus achieved by passage through a further generation of lambs. CONCLUSION: A successful method for the isolation of pure T. vitrinus from mixed infections is described. The resulting pure strain of T. vitrinus has been amplified and is held by two institutions for use in research (CSIRO reference SARDI 2011 strain). PMID- 26010930 TI - Industrial relations--a fine balance. PMID- 26010932 TI - Selective neutralization of the serpin protease nexin-1 by a specific monoclonal antibody. PMID- 26010931 TI - Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration. AB - Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 MUmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2',7' dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy. PMID- 26010934 TI - Trapping of Water Drops by Line-Shaped Defects on Superhydrophobic Surfaces. AB - We have investigated the effect of line-shaped topographical defects on the motion of water drops across superhydrophobic wax surfaces using a high-speed video camera. The defects are introduced onto the superhydrophobic wax surfaces by a scratching procedure. It is demonstrated that the motion of a drop interacting with the defect can be approximated by a damped harmonic oscillator. Whether a drop passes or gets trapped by the defect is determined by the incident speed and the properties of the oscillator, specifically by the damping ratio and a nondimensional forcing constant representing the effects of gravity and pinning forces. We also show that it is possible to predict a critical trapping speed as well as an exit speed in systems with negligible viscous dissipation using a simple work-energy consideration. PMID- 26010933 TI - A clinicopathological analysis of KISS1 and KISS1R expression in colorectal cancer. AB - Kisspeptins, the products of the KISS1 gene have tumor suppressing and antimetastatic properties. We aimed to study KISS1 and KISS1R expression in colorectal cancer. We analyzed KISS1 and KISS1R expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 111 patients with colorectal adenocarcinoma. KISS1 expression was much higher in the normal than in the malignant colonic mucosa. Regarding malignant tissues, KISS1 levels were higher in larger tumors, in stage III and IV cancers, in cancers with lymph node metastasis and in tumors located in the distal part of the large intestine. Patients with greater KISS1 levels had worse prognosis. No KISS1R expression was detected in normal or malignant tissues or in liver metastases. KISS1 expression is reduced during the malignant transformation of the colonic mucosa. However, larger and advanced colorectal cancers express more KISS1, without reaching the former normal levels, and increased KISS1 levels are associated with worse prognosis. Finally, neither the normal nor the malignant colonic epithelial cells produce KISS1R. PMID- 26010935 TI - The effect of interventions aimed at improving participation outcomes for children with disabilities: a systematic review. AB - AIM: Enhancement of participation has been described as the ultimate outcome for health and educational interventions. The goal of this systematic review was to identify and critically appraise studies that aimed to improve the participation outcomes of children with disabilities. METHOD: Nine databases that index literature from the fields of health, psychology, and education were searched to retrieve information on research conducted with children with disabilities aged between 5 years and 18 years. Articles were included if the author(s) reported that participation was an intended outcome of the intervention. The articles included were limited to those reporting high-level primary research, as defined by Australia's National Health and Medical Research Council evidence hierarchy guidelines. No restrictions were placed on the type of intervention being investigated. RESULTS: Seven randomized controlled or pseudo-randomized studies were included. Only three of these studies identified participation as a primary outcome. Both individualized and group-based approaches to enhancing participation outcomes appeared to be effective. Studies of interventions with a primary focus on body function or activity level outcomes did not demonstrate an effect on participation outcomes. INTEPRETATION: Few intervention studies have focused on participation as a primary outcome measure. Approaches using individually tailored education and mentoring programmes were found to enhance participation outcomes, while exercise programmes, where participation was a secondary outcome, generally demonstrated little effect. PMID- 26010936 TI - Massive Air Trapped in the Left Atrial Appendage During Catheter Ablation of Atrial Fibrillation Without a Symptomatic Air Embolism. PMID- 26010937 TI - In appreciation of Joan M. Bathon, MD, Editor, Arthritis & Rheumatology, 2010 2015. PMID- 26010939 TI - My two favourite professional social networking sites: LinkedIn and ResearchGate how they can help you, or hurt you. PMID- 26010940 TI - Endothelial function measures: not for clinical prime time? PMID- 26010941 TI - Squamous Cell Neoplasm of the Ocular Surface in a Patient With Psoriasis Treated With Tumor Necrosis Factor-Alpha Inhibitors. AB - PURPOSE: To report a case of conjunctival squamous cell carcinoma in a patient with psoriasis treated with tumor necrosis factor-alpha inhibitors. METHODS: Case report and review of the literature. RESULTS: A 44-year-old white woman presented to our hospital 1 year after developing a rapidly growing nodular lesion with papillomatous characteristics on the bulbar conjunctiva. The patient had a medical history of psoriasis since childhood and psoriatic arthritis since 2009. She had received several immunosuppressive medications such as leflunomide, adalimumab, methotrexate, and etanercept. The lesion appeared a few months after commencing treatment with etanercept and methotrexate. A histological examination revealed a squamous intraepithelial neoplasm of the conjunctiva that was negative for human papillomavirus infection. CONCLUSIONS: Several case reports have described squamous cell carcinoma in different parts of the body in patients taking tumor necrosis factor-alpha inhibitors. Squamous cell neoplasm of the ocular surface should be considered during differential diagnosis of new conjunctival lesions in such patients. PMID- 26010945 TI - Birth of two volcanic islands in the southern Red Sea. AB - Submarine eruptions that lead to the formation of new volcanic islands are rare and far from being fully understood; only a few such eruptions have been witnessed since Surtsey Island emerged to the south of Iceland in the 1960s. Here we report on two new volcanic islands that were formed in the Zubair archipelago of the southern Red Sea in 2011-2013. Using high-resolution optical satellite images, we find that the new islands grew rapidly during their initial eruptive phases and that coastal erosion significantly modified their shapes within months. Satellite radar data indicate that two north-south-oriented dykes, much longer than the small islands might suggest, fed the eruptions. These events occurred contemporaneously with several local earthquake swarms of the type that typically accompany magma intrusions. Earthquake activity has been affecting the southern Red Sea for decades, suggesting the presence of a magmatically active zone that has previously escaped notice. PMID- 26010946 TI - Direct costs of first-generation protease inhibitors for the treatment of genotype 1 chronic hepatitis C viral infection. AB - To evaluate the cost-effectiveness of Hepatitis C therapy, robust real-world data are needed to understand the costs and benefits of treatment alternatives. The objective of this study was to evaluate the true direct cost of treatment in an unselected sequential population of patients treated at a tertiary care centre for hepatitis C virus genotype 1. A total of 200 consecutive patients were treated with interferon, ribavirin and a first-generation direct-acting antiviral agent (DAA) between 2011 and 2013. A total of 41% had cirrhosis, 31% were prior relapsers, and 41% were prior partial or null responders. Costs used were wholesale acquisition cost prices for medications, average hospital costs per day for each diagnosis code based on US inpatient hospital charges. All costs were adjusted to 2013 dollars. Sustained virologic response (SVR) was achieved in 97 patients (48.5%). A total of 14% experienced relapse, 19% breakthrough or nonresponse, and 18.5% discontinued secondary to side effects. Twenty per cent of patients had at least one hospitalization attributable to a complication of therapy. Thirty-seven per cent of patients required erythropoietin-stimulating agents, 16% received filgastrim, and 15% needed a red blood cell transfusion. The mean overall cost of treatment was $83,851 per patient. The cost per SVR was $172,889; $266,670 for patients with cirrhosis. The costs per SVR after treatment with first-generation DAAs are dependent on the stage of disease and therapy side effects. These real-world costs significantly exceed those described in prior cost-effectiveness assessments and should be used instead for future studies. PMID- 26010947 TI - Evidence for involvement of a limbic paraventricular hypothalamic inhibitory network in hypothalamic-pituitary-adrenal axis adaptations to repeated stress. AB - Emotional stressors activate a stereotyped set of limbic forebrain cell groups implicated in constraining stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation by inhibiting hypophysiotropic neurons in the paraventricular hypothalamic nucleus (PVH). We previously identified a circumscribed, anterior part of the bed nuclei of the stria terminalis (aBST) that houses stress sensitive, PVH-projecting, gamma-aminobutyric acid (GABA)-ergic neurons as representing a site of convergence of stress-inhibitory influences originating from medial prefrontal and hippocampal cortices. Here we investigate whether exaggerated HPA axis responses associated with chronic variable stress (CVS; daily exposure to different stressors at unpredictable times over 14 days, followed by restraint stress on day 15) and diminished HPA output seen following repeated (14 days) restraint-stress exposure are associated with differential engagement of the limbic modulatory network. Relative to acutely restrained rats, animals subjected to CVS showed the expected increase (sensitization) in HPA responses and diminished levels of activation (Fos) of GABAergic neurons and glutamic acid decarboxylase (GAD) mRNA expression in the aBST. By contrast, repeated restraint stress produced habituation in HPA responses, maintained levels of activation of GABAergic neurons, and increased GAD expression in the aBST. aBST-projecting neurons in limbic sites implicated in HPA axis inhibition tended to show diminished activational responses in both repeated-stress paradigms, with the exception of the paraventricular thalamic nucleus, in which responsiveness was maintained in repeatedly restrained animals. The results are consistent with the view that differential engagement of HPA inhibitory mechanisms in the aBST may contribute to alterations in HPA axis responses to emotional stress in sensitization and habituation paradigms. PMID- 26010949 TI - Multi-scale modeling of Arabidopsis thaliana response to different CO2 conditions: From gene expression to metabolic flux. AB - Multi-scale investigation from gene transcript level to metabolic activity is important to uncover plant response to environment perturbation. Here we integrated a genome-scale constraint-based metabolic model with transcriptome data to explore Arabidopsis thaliana response to both elevated and low CO2 conditions. The four condition-specific models from low to high CO2 concentrations show differences in active reaction sets, enriched pathways for increased/decreased fluxes, and putative post-transcriptional regulation, which indicates that condition-specific models are necessary to reflect physiological metabolic states. The simulated CO2 fixation flux at different CO2 concentrations is consistent with the measured Assimilation-CO2intercellular curve. Interestingly, we found that reactions in primary metabolism are affected most significantly by CO2 perturbation, whereas secondary metabolic reactions are not influenced a lot. The changes predicted in key pathways are consistent with existing knowledge. Another interesting point is that Arabidopsis is required to make stronger adjustment on metabolism to adapt to the more severe low CO2 stress than elevated CO2 . The challenges of identifying post-transcriptional regulation could also be addressed by the integrative model. In conclusion, this innovative application of multi-scale modeling in plants demonstrates potential to uncover the mechanisms of metabolic response to different conditions. PMID- 26010948 TI - Epidemiological Surveillance of HIV-1 Transmitted Drug Resistance in Spain in 2004-2012: Relevance of Transmission Clusters in the Propagation of Resistance Mutations. AB - Our objectives were to carry out an epidemiological surveillance study on transmitted drug resistance (TDR) among individuals newly diagnosed of HIV-1 infection during a nine year period in Spain and to assess the role of transmission clusters (TC) in the propagation of resistant strains. An overall of 1614 newly diagnosed individuals were included in the study from January 2004 through December 2012. Individuals come from two different Spanish regions: Galicia and the Basque Country. Resistance mutations to reverse transcriptase inhibitors (RTI) and protease inhibitors (PI) were analyzed according to mutations included in the surveillance drug-resistance mutations list updated in 2009. TC were defined as those comprising viruses from five or more individuals whose sequences clustered in maximum likelihood phylogenetic trees with a bootstrap value >=90%. The overall prevalence of TDR to any drug was 9.9%: 4.9% to nucleoside RTIs (NRTIs), 3.6% to non-nucleoside RTIs (NNRTIs), and 2.7% to PIs. A significant decrease of TDR to NRTIs over time was observed [from 10% in 2004 to 2% in 2012 (p=0.01)]. Sixty eight (42.2%) of 161 sequences with TDR were included in 25 TC composed of 5 or more individuals. Of them, 9 clusters harbored TDR associated with high level resistance to antiretroviral drugs. T215D revertant mutation was transmitted in a large cluster comprising 25 individuals. The impact of epidemiological networks on TDR frequency may explain its persistence in newly diagnosed individuals. The knowledge of the populations involved in TC would facilitate the design of prevention programs and public health interventions. PMID- 26010950 TI - Evaluation of follicular synchronization caused by estrogen administration and its reproductive outcome. AB - To evaluate multiple follicular development synchronization after estrogen stimulation in prepubertal mice, follicular responsiveness to gonadotropin superovulation, the prospective reproductive potential and ovarian polycystic ovary syndrome (PCOS)-like symptoms at adulthood, prepubertal mice were intraperitoneally injected with estrogen to establish an animal model with solvent as control. When synchronized tertiary follicles in ovaries, in vitro oocyte maturation and fertilization rates, blastocyst formation rate, developmental potential into offspring by embryo transfer, adult fertility and PCOS-like symptoms, and involved molecular mechanisms were focused, it was found that estrogen stimulation (10 MUg/gBW) leads to follicular development synchronization at the early tertiary stage in prepubertal mice; reproduction from oocytes to offspring could be realized by means of the artificial reproductive technology though the model mice lost their natural fertility when they were reared to adulthood; and typical symptoms of PCOS, except changes in inflammatory pathways, were not remained up to adulthood. So in conclusion, estrogen can lead to synchronization in follicular development in prepubertal mice, but does not affect reproductive outcome of oocytes, and no typical symptoms of PCOS remained at adulthood despite changes related to inflammation. PMID- 26010951 TI - Robot-assisted sialolithotomy with sialendoscopy for the management of large submandibular gland stones. AB - OBJECTIVES/HYPOTHESIS: The objectives of this study were to describe robot assisted sialolithotomy with sialendoscopy (RASS) for the management of large palpable hilar submandibular gland (SMG) stones and analyze procedural success and lingual nerve damage following RASS in comparison to the combined transoral sialendoscopic approach. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was performed on patients with large palpable hilar SMG stones managed with RASS following institutional review board approval. Large stones were defined as >=5 mm, the upper limit that can be removed via sialendoscopy. Twenty-two patients between January 2012 and June 2014, with mean stone size of 12.3 mm, were identified. Data collected included symptoms of recurrence, postoperative lingual nerve function, and patient satisfaction at a mean follow-up of 14 months. Procedural success was defined as absence of symptom recurrence in conjunction with gland preservation. These measures were compared with the combined approach (CA) outcomes reported in the English literature. RESULTS: Procedural success was 100% (22/22) for our cohort. No patients reported symptoms of lingual nerve damage at follow-up, whereas four patients reported transient lingual nerve paresthesia (mean duration, 2.5 weeks). Mean patient satisfaction was 9.9 out of 10. Literature review identified 135 patients in the CA cohort. Procedural success rate for these patients was 75%, and lingual nerve damage was reported in 2% of patients. CONCLUSIONS: Our study demonstrates the safety and efficacy of RASS in the management of large SMG sialoliths. We attribute this preliminary success of RASS to the enhanced visualization, magnification, and technical advantages of the procedure. LEVEL OF EVIDENCE: 4. PMID- 26010952 TI - Hyperbaric oxygen therapy can diminish fibromyalgia syndrome--prospective clinical trial. AB - BACKGROUND: Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2-4% of the population, with 9:1 female-to-male incidence ratio. FMS is an important representative example of central nervous system sensitization and is associated with abnormal brain activity. Key symptoms include chronic widespread pain, allodynia and diffuse tenderness, along with fatigue and sleep disturbance. The syndrome is still elusive and refractory. The goal of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on symptoms and brain activity in FMS. METHODS AND FINDINGS: A prospective, active control, crossover clinical trial. Patients were randomly assigned to treated and crossover groups: The treated group patients were evaluated at baseline and after HBOT. Patients in the crossover control group were evaluated three times: baseline, after a control period of no treatment, and after HBOT. Evaluations consisted of physical examination, including tender point count and pain threshold, extensive evaluation of quality of life, and single photon emission computed tomography (SPECT) imaging for evaluation of brain activity. The HBOT protocol comprised 40 sessions, 5 days/week, 90 minutes, 100% oxygen at 2ATA. Sixty female patients were included, aged 21-67 years and diagnosed with FMS at least 2 years earlier. HBOT in both groups led to significant amelioration of all FMS symptoms, with significant improvement in life quality. Analysis of SPECT imaging revealed rectification of the abnormal brain activity: decrease of the hyperactivity mainly in the posterior region and elevation of the reduced activity mainly in frontal areas. No improvement in any of the parameters was observed following the control period. CONCLUSIONS: The study provides evidence that HBOT can improve the symptoms and life quality of FMS patients. Moreover, it shows that HBOT can induce neuroplasticity and significantly rectify abnormal brain activity in pain related areas of FMS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01827683. PMID- 26010953 TI - Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population. AB - BACKGROUND: Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty acid metabolism. A group of genes, namely CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, encode for three carnitine acyltransferases that are important for the oxidation of fatty acids, a critical step in their metabolism. METHODS: Exome sequencing and SNP array genotyping were used to examine the genetic variations in the six genes encoding for the carnitine acyltransferases in 113 Nunavik Inuit individuals. RESULTS: Altogether ten missense variants were found in genes CPT1A, CPT1B, CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific variant CPT1A p.P479L (rs80356779). The latter has the highest frequency (0.955) compared to other Inuit populations. We found that by comparison to Asians or Europeans, the Nunavik Inuit have an increased mutation burden in CPT1A, CPT2 and CRAT; there is also a high level of population differentiation based on carnitine acyltransferase gene variations between Nunavik Inuit and Asians. CONCLUSION: The increased number and frequency of deleterious variants in these fatty acid metabolism genes in Nunavik Inuit may be the result of genetic adaptation to their diet and/or the extremely cold climate. In addition, the identification of these variants may help to understand some of the specific health risks of Nunavik Inuit. PMID- 26010954 TI - Medical Exercise Therapy for Treating Musculoskeletal Pain: A Narrative Review of Results from Randomized Controlled Trials with a Theoretical Perspective. AB - BACKGROUND AND PURPOSE: The purpose of this narrative review is to present an overview and theoretical rationale of medical exercise therapy (MET) as a physiotherapeutic rehabilitation treatment for musculoskeletal pain conditions. Results from randomized controlled trials (RCTs) conducted on MET are also presented. METHODS: Computerized searches for any RCTs were conducted on the MET concept in the databases PubMed, Medline, Embase and ISI Web of science up to 2013. RESULTS: Overall findings from five included MET RCTs are long-term (>=1 year) reductions in pain and improved physical and functional capabilities. These results are interpreted in the context of the biopsychosocial model, advancing the view of a dynamic interaction among physiologic, psychological and social factors that influence pain modulation. DISCUSSION: MET is a biopsychosocial treatment that reduces pain and improves activities of daily living in patients with a musculoskeletal pain condition. Pain modulation is a key feature of MET, and an important area for further research is to elucidate the specific mechanisms behind the treatment effects. PMID- 26010957 TI - When Membership Gives Strength to Act: Inclusion of the Group Into the Self and Feeling of Personal Agency. AB - Identity fusion theory suggests that merging groups into one's personal identity should result in heightened levels of group agency. Research on the self expansion model complementarily indicates that including others into the self is linked to a greater feeling of self-efficacy. Across three correlational studies, we examined whether personal and group identity fusion is associated with stronger feelings of personal agency, and we propose that relatively stable feelings of clarity of self-concept would mediate this association. Individuals strongly fused with a country (Studies 1-3) and family (Study 2) exhibited greater feelings of agency and goal-adherence, and self-concept clarity emerged as a significant mediator of this association when controlling for group identification measures. PMID- 26010956 TI - Twelve-Month Antiretroviral Therapy Suppresses Plasma and Genital Viral Loads but Fails to Alter Genital Levels of Cytokines, in a Cohort of HIV-Infected Rwandan Women. AB - BACKGROUND: Genital viral load (GVL) is the main determinant of sexual transmission of human immune-deficiency virus (HIV). The effect of antiretroviral therapy (ART) on local cervico-vaginal immunological factors associated with GVL is poorly described. We aimed to identify the risk factors of detectable GVL, and the impact of ART on HIV genital shedding and its correlates in a cohort of HIV infected women, attending HIV care in Kigali, Rwanda. MATERIALS AND METHODS: All participants were evaluated for GVL, plasma viral load (PVL), CD4 count, various sexually-transmitted infections (STIs) at baseline and at month 12. Genital concentration of 19 cytokines and mRNA expression of APOBEC3G and BST2, two host HIV restriction factors, were evaluated at baseline in all participants. Cytokine levels were re-assessed at month 12 only in participants eligible for ART at baseline. Risk factors of GVL >= 40 copies/mL at baseline and month 12 were assessed using logistic regression. Effect of 12-month ART on various local and systemic immunological parameters was examined using a paired t-test and McNemar as appropriate. RESULTS: 96 of the 247 women enrolled in the study were eligible for ART. After 12 months of ART, PVL and GVL decreased to undetectable level in respectively 74 and 88% of treated participants. ART did not affect cytokine levels. HIV genital shedding occurred only when PVL was detectable. At baseline, GVL was independently associated with IL-1beta after controlling for PVL, age and N. gonorrhea infection (95% CI 1.32-2.15) and at month 12 with MIP-1beta (95% CI 0.96-21.32) after controlling for baseline GVL, PVL and month 12 IL-8. CONCLUSION: Suppressive ART does not necessarily reduce genital level of immune activation. Minimizing all conditions favoring genital inflammation, including active detection and treatment of STIs, might reduce the risk of HIV transmission as supplement to the provision of potent ART. PMID- 26010958 TI - Inverse patchy colloids with small patches: fluid structure and dynamical slowing down. AB - Inverse patchy colloids (IPCs) differ from conventional patchy particles because their patches repel (rather than attract) each other and attract (rather than repel) the part of the colloidal surface that is free of patches. These particular features occur, e.g. in heterogeneously charged colloidal systems. Here we consider overall neutral IPCs carrying two, relatively small, polar patches. Previous studies of the same model under planar confinement have evidenced the formation of branched, disordered aggregates composed of ring-like structures. We investigate here the bulk behavior of the system via molecular dynamics simulations, focusing on both the structure and the dynamics of the fluid phase in a wide region of the phase diagram. Additionally, the simulation results for the static observables are compared to the Associative Percus Yevick solution of an integral equation approach based on the multi-density Ornstein Zernike theory. A good agreement between theoretical and numerical quantities is observed even in the region of the phase diagram where the slowing down of the dynamics occurs. PMID- 26010955 TI - Replication stress in Mammalian cells and its consequences for mitosis. AB - The faithful transmission of genetic information to daughter cells is central to maintaining genomic stability and relies on the accurate and complete duplication of genetic material during each cell cycle. However, the genome is routinely exposed to endogenous and exogenous stresses that can impede the progression of replication. Such replication stress can be an early cause of cancer or initiate senescence. Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability. The traces of replication stress can be detected in the daughter cells during G1 phase. Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome. Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability. PMID- 26010959 TI - New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy. AB - New-onset refractory status epilepticus (NORSE) is defined as a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24h despite optimal therapy. Management of NORSE is challenging, and the role of immunotherapy (IT) is unclear. We identified patients fulfilling the criteria for NORSE at a single institution. These patients were described, analyzed, and compared with NORSE cases available from the literature. Finally, a pooled analysis of available case series was conducted to compare the outcomes in patients who received IT with those not treated with IT during the course of NORSE in order to generate hypotheses for further research. In our case series, NORSE was diagnosed in 11 patients (9 females) with a mean age of 48 years and a mean duration of 54.4 days. Autoantibodies were identified in 7 patients, of which anti-GAD (glutamic acid decarboxylase) and anti-NMDAR (N-methyl-D-aspartate receptor) were most frequent. Of the 11 patients, 8 were treated with IT (intravenous steroids, immunoglobulins, plasmapheresis, or a combination), and 4 received chemotherapy. Of the 8 patients treated with IT, 6 had favorable outcomes (defined as any outcome other than death, vegetative state, or inability to take care of oneself) compared with 0 out of 3 patients who did not receive IT. Difference in outcomes was significant (p=0.026). Pooled analysis of all identified case series, including ours, showed a statistically significant effect (p=0.022), with favorable outcomes in 42% of the patients who received any IT compared with 20% in those who did not. In all patients with refractory SE and negative comprehensive investigations, a diagnosis of NORSE should be considered. This would aid planning for early immunotherapy. Currently, only Class IV evidence for the use of immunotherapy in NORSE is available. Prospective multicenter studies are necessary to assess the true efficacy of IT in NORSE. PMID- 26010960 TI - Ragweed pollen: is climate change creating a new aeroallergen problem in the UK? PMID- 26010961 TI - The Spinal Cord Injury--Quality of Life (SCI-QOL) measurement system: Development, psychometrics, and item bank calibration. PMID- 26010962 TI - Overview of the Spinal Cord Injury--Quality of Life (SCI-QOL) measurement system. AB - CONTEXT/OBJECTIVE: The Spinal Cord Injury--Quality of Life (SCI-QOL) measurement system was developed to address the shortage of relevant and psychometrically sound patient reported outcome (PRO) measures available for clinical care and research in spinal cord injury (SCI) rehabilitation. Using a computer adaptive testing (CAT) approach, the SCI-QOL builds on the Patient Reported Outcomes Measurement Information System (PROMIS) and the Quality of Life in Neurological Disorders (Neuro-QOL) initiative. This initial manuscript introduces the background and development of the SCI-QOL measurement system. Greater detail is presented in the additional manuscripts of this special issue. DESIGN: Classical and contemporary test development methodologies were employed. Qualitative input was obtained from individuals with SCI and clinicians through interviews, focus groups, and cognitive debriefing. Item pools were field tested in a multi-site sample (n=877) and calibrated using item response theory methods. Initial reliability and validity testing was performed in a new sample of individuals with traumatic SCI (n=245). SETTING: Five Model SCI System centers and one Department of Veterans Affairs Medical Center across the United States. PARTICIPANTS: Adults with traumatic SCI. INTERVENTIONS: n/a OUTCOME MEASURES: n/a RESULTS: The SCI-QOL consists of 19 item banks, including the SCI-Functional Index banks, and 3 fixed-length scales measuring physical, emotional, and social aspects of health-related QOL (HRQOL). CONCLUSION: The SCI-QOL measurement system consists of psychometrically sound measures for individuals with SCI. The manuscripts in this special issue provide evidence of the reliability and initial validity of this measurement system. The SCI-QOL also links to other measures designed for a general medical population. PMID- 26010963 TI - Methodology for the development and calibration of the SCI-QOL item banks. AB - OBJECTIVE: To develop a comprehensive, psychometrically sound, and conceptually grounded patient reported outcomes (PRO) measurement system for individuals with spinal cord injury (SCI). METHODS: Individual interviews (n=44) and focus groups (n=65 individuals with SCI and n=42 SCI clinicians) were used to select key domains for inclusion and to develop PRO items. Verbatim items from other cutting edge measurement systems (i.e. PROMIS, Neuro-QOL) were included to facilitate linkage and cross-population comparison. Items were field tested in a large sample of individuals with traumatic SCI (n=877). Dimensionality was assessed with confirmatory factor analysis. Local item dependence and differential item functioning were assessed, and items were calibrated using the item response theory (IRT) graded response model. Finally, computer adaptive tests (CATs) and short forms were administered in a new sample (n=245) to assess test-retest reliability and stability. PARTICIPANTS AND PROCEDURES: A calibration sample of 877 individuals with traumatic SCI across five SCI Model Systems sites and one Department of Veterans Affairs medical center completed SCI-QOL items in interview format. RESULTS: We developed 14 unidimensional calibrated item banks and 3 calibrated scales across physical, emotional, and social health domains. When combined with the five Spinal Cord Injury--Functional Index physical function banks, the final SCI-QOL system consists of 22 IRT-calibrated item banks/scales. Item banks may be administered as CATs or short forms. Scales may be administered in a fixed-length format only. CONCLUSIONS: The SCI-QOL measurement system provides SCI researchers and clinicians with a comprehensive, relevant and psychometrically robust system for measurement of physical-medical, physical-functional, emotional, and social outcomes. All SCI-QOL instruments are freely available on Assessment CenterSM. PMID- 26010964 TI - Development and psychometric characteristics of the SCI-QOL Bladder Management Difficulties and Bowel Management Difficulties item banks and short forms and the SCI-QOL Bladder Complications scale. AB - OBJECTIVE: To describe the development and psychometric properties of the Spinal Cord Injury--Quality of Life (SCI-QOL) Bladder Management Difficulties and Bowel Management Difficulties item banks and Bladder Complications scale. DESIGN: Using a mixed-methods design, a pool of items assessing bladder and bowel-related concerns were developed using focus groups with individuals with spinal cord injury (SCI) and SCI clinicians, cognitive interviews, and item response theory (IRT) analytic approaches, including tests of model fit and differential item functioning. SETTING: Thirty-eight bladder items and 52 bowel items were tested at the University of Michigan, Kessler Foundation Research Center, the Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital, and the James J. Peters VA Medical Center, Bronx, NY. PARTICIPANTS: Seven hundred fifty-seven adults with traumatic SCI. RESULTS: The final item banks demonstrated unidimensionality (Bladder Management Difficulties CFI=0.965; RMSEA=0.093; Bowel Management Difficulties CFI=0.955; RMSEA=0.078) and acceptable fit to a graded response IRT model. The final calibrated Bladder Management Difficulties bank includes 15 items, and the final Bowel Management Difficulties item bank consists of 26 items. Additionally, 5 items related to urinary tract infections (UTI) did not fit with the larger Bladder Management Difficulties item bank but performed relatively well independently (CFI=0.992, RMSEA=0.050) and were thus retained as a separate scale. CONCLUSION: The SCI-QOL Bladder Management Difficulties and Bowel Management Difficulties item banks are psychometrically robust and are available as computer adaptive tests or short forms. The SCI-QOL Bladder Complications scale is a brief, fixed-length outcomes instrument for individuals with a UTI. PMID- 26010965 TI - Development and psychometric characteristics of the SCI-QOL Pressure Ulcers scale and short form. AB - OBJECTIVE: To develop a self-reported measure of the subjective impact of pressure ulcers on health-related quality of life (HRQOL) in individuals with spinal cord injury (SCI) as part of the SCI quality of life (SCI-QOL) measurement system. DESIGN: Grounded-theory based qualitative item development methods, large scale item calibration testing, confirmatory factor analysis (CFA), and item response theory-based psychometric analysis. SETTING: Five SCI Model System centers and one Department of Veterans Affairs medical center in the United States. PARTICIPANTS: Adults with traumatic SCI. MAIN OUTCOME MEASURES: SCI-QOL Pressure Ulcers scale. RESULTS: 189 individuals with traumatic SCI who experienced a pressure ulcer within the past 7 days completed 30 items related to pressure ulcers. CFA confirmed a unidimensional pool of items. IRT analyses were conducted. A constrained Graded Response Model with a constant slope parameter was used to estimate item thresholds for the 12 retained items. CONCLUSIONS: The 12-item SCI-QOL Pressure Ulcers scale is unique in that it is specifically targeted to individuals with spinal cord injury and at every stage of development has included input from individuals with SCI. Furthermore, use of CFA and IRT methods provide flexibility and precision of measurement. The scale may be administered in its entirety or as a 7-item "short form" and is available for both research and clinical practice. PMID- 26010966 TI - Measuring anxiety after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Anxiety item bank and linkage with GAD-7. AB - OBJECTIVE: To develop a calibrated item bank and computer adaptive test to assess anxiety symptoms in individuals with spinal cord injury (SCI), transform scores to the Patient Reported Outcomes Measurement Information System (PROMIS) metric, and create a statistical linkage with the Generalized Anxiety Disorder (GAD)-7, a widely used anxiety measure. DESIGN: Grounded-theory based qualitative item development methods; large-scale item calibration field testing; confirmatory factor analysis; graded response model item response theory analyses; statistical linking techniques to transform scores to a PROMIS metric; and linkage with the GAD-7. Setting Five SCI Model System centers and one Department of Veterans Affairs medical center in the United States. Participants Adults with traumatic SCI. MAIN OUTCOME MEASURES: Spinal Cord Injury-Quality of Life (SCI-QOL) Anxiety Item Bank RESULTS: Seven hundred sixteen individuals with traumatic SCI completed 38 items assessing anxiety, 17 of which were PROMIS items. After 13 items (including 2 PROMIS items) were removed, factor analyses confirmed unidimensionality. Item response theory analyses were used to estimate slopes and thresholds for the final 25 items (15 from PROMIS). The observed Pearson correlation between the SCI-QOL Anxiety and GAD-7 scores was 0.67. CONCLUSIONS: The SCI-QOL Anxiety item bank demonstrates excellent psychometric properties and is available as a computer adaptive test or short form for research and clinical applications. SCI-QOL Anxiety scores have been transformed to the PROMIS metric and we provide a method to link SCI-QOL Anxiety scores with those of the GAD-7. PMID- 26010967 TI - Measuring psychological trauma after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Psychological Trauma item bank and short form. AB - OBJECTIVE: To describe the development and psychometric properties of the SCI-QOL Psychological Trauma item bank and short form. DESIGN: Using a mixed-methods design, we developed and tested a Psychological Trauma item bank with patient and provider focus groups, cognitive interviews, and item response theory based analytic approaches, including tests of model fit, differential item functioning (DIF) and precision. SETTING: We tested a 31-item pool at several medical institutions across the United States, including the University of Michigan, Kessler Foundation, Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital and the James J. Peters/Bronx Veterans Administration hospital. PARTICIPANTS: A total of 716 individuals with SCI completed the trauma items RESULTS: The 31 items fit a unidimensional model (CFI=0.952; RMSEA=0.061) and demonstrated good precision (theta range between 0.6 and 2.5). Nine items demonstrated negligible DIF with little impact on score estimates. The final calibrated item bank contains 19 items CONCLUSION: The SCI-QOL Psychological Trauma item bank is a psychometrically robust measurement tool from which a short form and a computer adaptive test (CAT) version are available. PMID- 26010968 TI - Measuring depression after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Depression item bank and linkage with PHQ-9. AB - OBJECTIVE: To develop a calibrated spinal cord injury-quality of life (SCI-QOL) item bank, computer adaptive test (CAT), and short form to assess depressive symptoms experienced by individuals with SCI, transform scores to the Patient Reported Outcomes Measurement Information System (PROMIS) metric, and create a crosswalk to the Patient Health Questionnaire (PHQ)-9. DESIGN: We used grounded theory based qualitative item development methods, large-scale item calibration field testing, confirmatory factor analysis, item response theory (IRT) analyses, and statistical linking techniques to transform scores to a PROMIS metric and to provide a crosswalk with the PHQ-9. SETTING: Five SCI Model System centers and one Department of Veterans Affairs medical center in the United States. PARTICIPANTS: Adults with traumatic SCI. MAIN OUTCOME MEASURES: Spinal Cord Injury--Quality of Life (SCI-QOL) Depression Item Bank RESULTS: Individuals with SCI were involved in all phases of SCI-QOL development. A sample of 716 individuals with traumatic SCI completed 35 items assessing depression, 18 of which were PROMIS items. After removing 7 non-PROMIS items, factor analyses confirmed a unidimensional pool of items. We used a graded response IRT model to estimate slopes and thresholds for the 28 retained items. The SCI-QOL Depression measure correlated 0.76 with the PHQ-9. CONCLUSIONS: The SCI-QOL Depression item bank provides a reliable and sensitive measure of depressive symptoms with scores reported in terms of general population norms. We provide a crosswalk to the PHQ 9 to facilitate comparisons between measures. The item bank may be administered as a CAT or as a short form and is suitable for research and clinical applications. PMID- 26010969 TI - Measuring grief and loss after spinal cord injury: Development, validation and psychometric characteristics of the SCI-QOL Grief and Loss item bank and short form. AB - OBJECTIVE: To develop an item response theory (IRT) calibrated Grief and Loss item bank as part of the Spinal Cord Injury--Quality of Life (SCI-QOL) measurement system. DESIGN: A literature review guided framework development of grief/loss. New items were created from focus groups. Items were revised based on expert review and patient feedback and were then field tested. Analyses included confirmatory factor analysis (CFA), graded response IRT modeling and evaluation of differential item functioning (DIF). SETTING: We tested a 20-item pool at several rehabilitation centers across the United States, including the University of Michigan, Kessler Foundation, Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital and the James J. Peters/Bronx Department of Veterans Affairs hospital. PARTICIPANTS: A total of 717 individuals with SCI answered the grief and loss questions. RESULTS: The final calibrated item bank resulted in 17 retained items. A unidimensional model was observed (CFI=0.976; RMSEA=0.078) and measurement precision was good (theta range between -1.48 to 2.48). Ten items were flagged for DIF, however, after examination of effect sizes found this to be negligible with little practical impact on score estimates. CONCLUSIONS: This study indicates that the SCI-QOL Grief and Loss item bank represents a psychometrically robust measurement tool. Short form items are also suggested and computer adaptive tests are available. PMID- 26010970 TI - Measuring positive affect and well-being after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Positive Affect and Well-being bank and short form. AB - OBJECTIVE: To develop an item response theory (IRT)-calibrated spinal cord injury (SCI)-specific Positive Affect and Well-being (PAWB) item bank with flexible options for administration. DESIGN: Qualitative feedback from patient and provider focus groups was used to expand on the Neurological Disorders and Quality of Life (Neuro-QOL) positive affect & well-being item bank for use in SCI. New items were created and revised based on expert review and patient feedback and were then field tested. Analyses included confirmatory factor analysis, graded response IRT modeling and evaluation of differential item functioning (DIF). SETTING: We tested a 32-item pool at several rehabilitation centers across the United States, including the University of Michigan, Kessler Foundation, Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital and the James J. Peters/Bronx Department of Veterans Affairs hospital. PARTICIPANTS: A total of 717 individuals with SCI answered the PAWB questions. RESULTS: A unidimensional model was observed (Confirmatory Fit Index=0.947; Root Mean Square Error of Approximation=0.094) and measurement precision was good (reliability in theta of -2.9 to 1.2 is roughly equivalent to classical reliability of 0.95 or above). Twelve items were flagged for DIF, however, after examination of effect sizes, the DIF was determined to be negligible and would have little practical impact on score estimates. The final calibrated item bank resulted in 28 retained items CONCLUSIONS: This study indicates that the Spinal Cord Injury--Quality of Life PAWB bank represents a psychometrically robust measurement tool. Short form items are also suggested and a computer adaptive test is available. PMID- 26010972 TI - Measuring self-esteem after spinal cord injury: Development, validation and psychometric characteristics of the SCI-QOL Self-esteem item bank and short form. AB - OBJECTIVE: To describe the development and psychometric properties of the Spinal Cord Injury-Quality of Life (SCI-QOL) Self-esteem item bank. DESIGN: Using a mixed-methods design, we developed and tested a self-esteem item bank through the use of focus groups with individuals with SCI and clinicians with expertise in SCI, cognitive interviews, and item-response theory-(IRT) based analytic approaches, including tests of model fit, differential item functioning (DIF) and precision. SETTING: We tested a pool of 30 items at several medical institutions across the United States, including the University of Michigan, Kessler Foundation, the Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital, and the James J. Peters/Bronx Department of Veterans Affairs hospital. PARTICIPANTS: A total of 717 individuals with SCI completed the self-esteem items. RESULTS: A unidimensional model was observed (CFI=0.946; RMSEA=0.087) and measurement precision was good (theta range between -2.7 and 0.7). Eleven items were flagged for DIF; however, effect sizes were negligible with little practical impact on score estimates. The final calibrated item bank resulted in 23 retained items. CONCLUSION: This study indicates that the SCI-QOL Self-esteem item bank represents a psychometrically robust measurement tool. Short form items are also suggested and computer adaptive tests are available. PMID- 26010971 TI - Measuring resilience after spinal cord injury: Development, validation and psychometric characteristics of the SCI-QOL Resilience item bank and short form. AB - OBJECTIVE: To describe the development and psychometric properties of the Spinal Cord Injury--Quality of Life (SCI-QOL) Resilience item bank and short form. DESIGN: Using a mixed-methods design, we developed and tested a resilience item bank through the use of focus groups with individuals with SCI and clinicians with expertise in SCI, cognitive interviews, and item-response theory based analytic approaches, including tests of model fit and differential item functioning (DIF). SETTING: We tested a 32-item pool at several medical institutions across the United States, including the University of Michigan, Kessler Foundation, the Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital and the James J. Peters/Bronx Department of Veterans Affairs medical center. PARTICIPANTS: A total of 717 individuals with SCI completed the Resilience items. RESULTS: A unidimensional model was observed (CFI=0.968; RMSEA=0.074) and measurement precision was good (theta range between 3.1 and 0.9). Ten items were flagged for DIF, however, after examination of effect sizes we found this to be negligible with little practical impact on score estimates. The final calibrated item bank resulted in 21 retained items. CONCLUSION: This study indicates that the SCI-QOL Resilience item bank represents a psychometrically robust measurement tool. Short form items are also suggested and computer adaptive tests are available. PMID- 26010973 TI - Measuring stigma after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Stigma item bank and short form. AB - OBJECTIVE: To develop a calibrated item bank and computer adaptive test (CAT) to assess the effects of stigma on health-related quality of life in individuals with spinal cord injury (SCI). DESIGN: Grounded-theory based qualitative item development methods, large-scale item calibration field testing, confirmatory factor analysis, and item response theory (IRT)-based psychometric analyses. SETTING: Five SCI Model System centers and one Department of Veterans Affairs medical center in the United States. PARTICIPANTS: Adults with traumatic SCI. MAIN OUTCOME MEASURES: SCI-QOL Stigma Item Bank RESULTS: A sample of 611 individuals with traumatic SCI completed 30 items assessing SCI-related stigma. After 7 items were iteratively removed, factor analyses confirmed a unidimensional pool of items. Graded Response Model IRT analyses were used to estimate slopes and thresholds for the final 23 items. CONCLUSIONS: The SCI-QOL Stigma item bank is unique not only in the assessment of SCI-related stigma but also in the inclusion of individuals with SCI in all phases of its development. Use of confirmatory factor analytic and IRT methods provide flexibility and precision of measurement. The item bank may be administered as a CAT or as a 10 item fixed-length short form and can be used for research and clinical applications. PMID- 26010974 TI - Development and psychometric characteristics of the SCI-QOL Ability to Participate and Satisfaction with Social Roles and Activities item banks and short forms. AB - OBJECTIVE: To develop a spinal cord injury (SCI)-focused version of PROMIS and Neuro-QOL social domain item banks; evaluate the psychometric properties of items developed for adults with SCI; and report information to facilitate clinical and research use. DESIGN: We used a mixed-methods design to develop and evaluate Ability to Participate in Social Roles and Activities and Satisfaction with Social Roles and Activities items. Focus groups helped define the constructs; cognitive interviews helped revise items; and confirmatory factor analysis and item response theory methods helped calibrate item banks and evaluate differential item functioning related to demographic and injury characteristics. SETTING: Five SCI Model System sites and one Veterans Administration medical center. PARTICIPANTS: The calibration sample consisted of 641 individuals; a reliability sample consisted of 245 individuals residing in the community. RESULTS: A subset of 27 Ability to Participate and 35 Satisfaction items demonstrated good measurement properties and negligible differential item functioning related to demographic and injury characteristics. The SCI-specific measures correlate strongly with the PROMIS and Neuro-QOL versions. Ten item short forms correlate >0.96 with the full banks. Variable-length CATs with a minimum of 4 items, variable-length CATs with a minimum of 8 items, fixed-length CATs of 10 items, and the 10-item short forms demonstrate construct coverage and measurement error that is comparable to the full item bank. CONCLUSION: The Ability to Participate and Satisfaction with Social Roles and Activities CATs and short forms demonstrate excellent psychometric properties and are suitable for clinical and research applications. PMID- 26010975 TI - Development and initial evaluation of the SCI-FI/AT. AB - OBJECTIVES: To describe the domain structure and calibration of the Spinal Cord Injury Functional Index for samples using Assistive Technology (SCI-FI/AT) and report the initial psychometric properties of each domain. DESIGN: Cross sectional survey followed by computerized adaptive test (CAT) simulations. SETTING: Inpatient and community settings. PARTICIPANTS: A sample of 460 adults with traumatic spinal cord injury (SCI) stratified by level of injury, completeness of injury, and time since injury. INTERVENTIONS: None MAIN OUTCOME MEASURE: SCI-FI/AT RESULTS: Confirmatory factor analysis (CFA) and Item response theory (IRT) analyses identified 4 unidimensional SCI-FI/AT domains: Basic Mobility (41 items) Self-care (71 items), Fine Motor Function (35 items), and Ambulation (29 items). High correlations of full item banks with 10-item simulated CATs indicated high accuracy of each CAT in estimating a person's function, and there was high measurement reliability for the simulated CAT scales compared with the full item bank. SCI-FI/AT item difficulties in the domains of Self-care, Fine Motor Function, and Ambulation were less difficult than the same items in the original SCI-FI item banks. CONCLUSION: With the development of the SCI-FI/AT, clinicians and investigators have available multidimensional assessment scales that evaluate function for users of AT to complement the scales available in the original SCI-FI. PMID- 26010976 TI - Serum quantitative proteomic analysis reveals potential zinc-associated biomarkers for nonbacterial prostatitis. AB - BACKGROUND: Prostatitis is one of the most common urological problems afflicting adult men. The etiology and pathogenesis of nonbacterial prostatitis, which accounts for 90-95% of cases, is largely unknown. As serum proteins often indicate the overall pathologic status of patients, we hypothesized that protein biomarkers of prostatitis might be identified by comparing the serum proteomes of patients with and without nonbacterial prostatitis. METHODS: All untreated samples were collected from subjects attending the Fangchenggang Area Male Health and Examination Survey (FAMHES). We profiled pooled serum samples from four carefully selected groups of patients (n = 10/group) representing the various categories of nonbacterial prostatitis (IIIa, IIIb, and IV) and matched healthy controls using a mass spectrometry-based 4-plex iTRAQ proteomic approach. More than 160 samples were validated by ELISA. RESULTS: Overall, 69 proteins were identified. Among them, 42, 52, and 37 proteins were identified with differential expression in Category IIIa, IIIb, and IV prostatitis, respectively. The 19 common proteins were related to immunity and defense, ion binding, transport, and proteolysis. Two zinc-binding proteins, superoxide dismutase 3 (SOD3), and carbonic anhydrase I (CA1), were significantly higher in all types of prostatitis than in the control. A receiver operating characteristic curve estimated sensitivities of 50.4 and 68.1% and specificities of 92.1 and 83.8% for CA1 and SOD3, respectively, in detecting nonbacterial prostatitis. The serum CA1 concentration was inversely correlated to the zinc concentration in expressed prostatic secretions. CONCLUSIONS: Our findings suggest that SOD3 and CA1 are potential diagnostic markers of nonbacterial prostatitis, although further large scale studies are required. The molecular profiles of nonbacterial prostatitis pathogenesis may lay a foundation for discovery of new therapies. PMID- 26010977 TI - Interactions of Francisella tularensis with Alveolar Type II Epithelial Cells and the Murine Respiratory Epithelium. AB - Francisella tularensis is classified as a Tier 1 select agent by the CDC due to its low infectious dose and the possibility that the organism can be used as a bioweapon. The low dose of infection suggests that Francisella is unusually efficient at evading host defenses. Although ~50 cfu are necessary to cause human respiratory infection, the early interactions of virulent Francisella with the lung environment are not well understood. To provide additional insights into these interactions during early Francisella infection of mice, we performed TEM analysis on mouse lungs infected with F. tularensis strains Schu S4, LVS and the O-antigen mutant Schu S4 waaY::TrgTn. For all three strains, the majority of the bacteria that we could detect were observed within alveolar type II epithelial cells at 16 hours post infection. Although there were no detectable differences in the amount of bacteria within an infected cell between the three strains, there was a significant increase in the amount of cellular debris observed in the air spaces of the lungs in the Schu S4 waaY::TrgTn mutant compared to either the Schu S4 or LVS strain. We also studied the interactions of Francisella strains with human AT-II cells in vitro by characterizing the ability of these three strains to invade and replicate within these cells. Gentamicin assay and confocal microscopy both confirmed that F. tularensis Schu S4 replicated robustly within these cells while F. tularensis LVS displayed significantly lower levels of growth over 24 hours, although the strain was able to enter these cells at about the same level as Schu S4 (1 organism per cell), as determined by confocal imaging. The Schu S4 waaY::TrgTn mutant that we have previously described as attenuated for growth in macrophages and mouse virulence displayed interesting properties as well. This mutant induced significant airway inflammation (cell debris) and had an attenuated growth phenotype in the human AT-II cells. These data extend our understanding of early Francisella infection by demonstrating that Francisella enter significant numbers of AT-II cells within the lung and that the capsule and LPS of wild type Schu S4 helps prevent murine lung damage during infection. Furthermore, our data identified that human AT-II cells allow growth of Schu S4, but these same cells supported poor growth of the attenuated LVS strain in vitro. Collectively, these data further our understanding of the role of AT-II cells in Francisella infections. PMID- 26010978 TI - Correction: Effects of the I559P gp41 Change on the Conformation and Function of the Human Immunodeficiency Virus (HIV-1) Membrane Envelope Glycoprotein Trimer. PMID- 26010979 TI - Ambulatory Blood Pressure Monitoring to Assess Cardiovascular Risk in Sub-Saharan Africa. PMID- 26010980 TI - Weight suppression predicts total weight gain and rate of weight gain in outpatients with anorexia nervosa. AB - OBJECTIVE: The present study sought to replicate the finding of Wildes and Marcus, Behav Res Ther, 50, 266-274, 2012 that higher levels of weight suppression at pretreatment predict greater total weight gain, faster rate of weight gain, and bulimic symptoms amongst patients admitted with anorexia nervosa. METHOD: Participants were 56 women with anorexia nervosa diagnosed by using strict or lenient weight criteria, who were participating in a randomized controlled psychotherapy trial (McIntosh et al., Am J Psychiatry, 162, 741-747, 2005). Thirty-five women completed outpatient treatment and post-treatment assessment. Weight suppression was the discrepancy between highest lifetime weight at adult height and weight at pretreatment assessment. Outcome variables were total weight gain, rate of weight gain, and bulimic symptoms in the month prior to post-treatment assessment [assessed using the Eating Disorders Examination (Fairburn et al., Binge-Eating: Nature, Assessment and Treatment. New York: Guilford, 1993)]. RESULTS: Weight suppression was positively associated with total weight gain and rate of weight gain over treatment. Regression models showed that this association could not be explained by covariates (age at onset of anorexia nervosa and treatment modality). Weight suppression was not significantly associated with bulimic symptoms in the month prior to post treatment assessment, regardless of whether bulimic symptoms were examined as continuous or dichotomous variables. DISCUSSION: The present study reinforces the previous finding that weight suppression predicts total weight gain and rate of weight gain amongst patients being treated for anorexia nervosa. Methodological issues may explain the failure of the present study to find that weight suppression predicts bulimic symptoms. Weight suppression at pretreatment for anorexia nervosa should be assessed routinely and may inform treatment planning. PMID- 26010982 TI - Penetration of Combustion Aerosol Particles Through Filters of NIOSH-Certified Filtering Facepiece Respirators (FFRs). AB - Filtering facepiece respirators (FFRs) are commonly worn by first responders, first receivers, and other exposed groups to protect against exposure to airborne particles, including those originated by combustion. Most of these FFRs are NIOSH certified (e.g., N95-type) based on the performance testing of their filters against charge-equilibrated aerosol challenges, e.g., NaCl. However, it has not been examined if the filtration data obtained with the NaCl-challenged FFR filters adequately represent the protection against real aerosol hazards such as combustion particles. A filter sample of N95 FFR mounted on a specially designed holder was challenged with NaCl particles and three combustion aerosols generated in a test chamber by burning wood, paper, and plastic. The concentrations upstream (Cup) and downstream (Cdown) of the filter were measured with a TSI P Trak condensation particle counter and a Grimm Nanocheck particle spectrometer. Penetration was determined as (Cdown/Cup) *100%. Four test conditions were chosen to represent inhalation flows of 15, 30, 55, and 85 L/min. Results showed that the penetration values of combustion particles were significantly higher than those of the "model" NaCl particles (p < 0.05), raising a concern about applicability of the N95 filters performance obtained with the NaCl aerosol challenge to protection against combustion particles. Aerosol type, inhalation flow rate and particle size were significant (p < 0.05) factors affecting the performance of the N95 FFR filter. In contrast to N95 filters, the penetration of combustion particles through R95 and P95 FFR filters (were tested in addition to N95) were not significantly higher than that obtained with NaCl particles. The findings were attributed to several effects, including the degradation of an N95 filter due to hydrophobic organic components generated into the air by combustion. Their interaction with fibers is anticipated to be similar to those involving "oily" particles. The findings of this study suggest that the efficiency of N95 respirator filters obtained with the NaCl aerosol challenge may not accurately predict (and rather overestimate) the filter efficiency against combustion particles. PMID- 26010981 TI - A novel chitin binding crayfish molar tooth protein with elasticity properties. AB - The molar tooth of the crayfish Cherax quadricarinatus is part of the mandible, and is covered by a layer of apatite (calcium phosphate). This tooth sheds and is regenerated during each molting cycle together with the rest of the exoskeleton. We discovered that molar calcification occurs at the pre-molt stage, unlike calcification of the rest of the new exoskeleton. We further identified a novel molar protein from C. quadricarinatus and cloned its transcript from the molar forming epithelium. We termed this protein Cq-M13. The temporal level of transcription of Cq-M13 in an NGS library of molar-forming epithelium at different molt stages coincides with the assembly and mineralization pattern of the molar tooth. The predicted protein was found to be related to the pro-resilin family of cuticular proteins. Functionally, in vivo silencing of the transcript caused molt cycle delay and a recombinant version of the protein was found to bind chitin and exhibited elastic properties. PMID- 26010983 TI - Changing mortality patterns in Kimberley Aborigines. AB - BACKGROUND/AIMS: To examine the causes of officially reported deaths from several categories among Aboriginal and non-Aboriginal people in a statistical division of north-west Australia from 2002 to 2011. METHODS: A cross-sectional analysis of official Death Registration data to calculate mortality rate ratios (Aboriginal against non-Aboriginal) for that decade in six major International Classification of Disease (ICD)-10 categories. The study setting was the West Kimberley Health District in the far north of Western Australia. RESULTS: Death rates of Aborigines relative to non-Aborigines were much higher, by more than 10 times in some categories. Most of the excess deaths in these categories were due to circulatory diseases, injury and poisonings, neoplasms, diabetes, respiratory, and genitourinary conditions. CONCLUSION: This study has documented the heavy burden of mortality in West Kimberley Aborigines compared with the pattern found in non-Aboriginal people living in the same region. PMID- 26010984 TI - A case of intravascular lymphoma diagnosed in an explanted liver after liver transplantation. AB - Intravascular lymphoma (IVL) is a rare form of B-cell lymphoma. We encountered a rare case of IVL diagnosed in an explanted liver. A 49-year-old man visited a clinic with high fever. Because of elevated liver function, he was diagnosed with acute liver failure. Deceased donor liver transplantation (LT) was performed 16 days after admission. The post-transplantation course was uneventful until IVL was reported in the explanted liver on postoperative day (POD) 21. Rituximab was administered on POD 27, and rituximab-cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (R-CHOP) treatment administered on POD 38. The R-CHOP treatment was repeated for eight cycles, and the patient remains free of recurrence 1 year post-transplantation. Although systemic lymphoma is a contraindication to transplantation, our experience indicates that IVL can be successfully treated by the administration of prompt chemotherapy after LT for fulminant hepatitis. PMID- 26010986 TI - An evaluation of public genomic references for mapping RNA-Seq data from Chinese hamster ovary cells. AB - While RNA-Seq is increasingly used as the method of choice for transcriptome analysis of mammalian cell culture processes, no universal genomic reference for mapping RNA-Seq reads from CHO cells has been reported. In previous publications, de novo transcriptomes assembled using these RNA-Seq reads were subsequently used for mapping. Potential caveats with this approach include the incomplete coverage and the non-universal nature of the de novo assemblies, leading to challenges in comparing results across studies. In order to facilitate future RNA-Seq studies in CHO cells, we performed a comprehensive evaluation of four public genomic references for CHO cells hosted by the NCBI Reference Sequence Database (RefSeq), including two annotated genomes released in 2012 and 2014 and their accompanying transcriptomes. Each genome showed significantly higher mapped rates compared to its accompanying transcriptome. Furthermore, higher mapped rates in deep intra genic regions, especially within exons, were observed for the more recent genome release (2014) compared to the older one (2012), indicating that the 2014 genome was the preeminent reference among the four. Sequential addition of human and mouse genomes increased the total mapped rate to 87.3 and 89.7%, respectively, from 73.5% using the 2014 Chinese hamster genome alone. Thus, the sequential combination of the 2014 RefSeq Chinese hamster genome, the Ensembl human genome (h38), and the Ensembl mouse genome (m38) was suggested as the most effective strategy for mapping RNA-Seq data from CHO cells. PMID- 26010987 TI - Relationship between Torsion and Anisotropic Exchange Coupling in a Tb(III) Radical-Based Single-Molecule Magnet. AB - The incorporation of paramagnetic ligands within rare-earth ion clusters exhibiting large magnetic anisotropy has provided significant advancement in the design of single-molecule magnets (SMMs) with large blocking temperatures. However, the exchange interaction in such systems is complex and difficult to probe by conventional magnetometry techniques, and little is known about the structural relationships. Inelastic neutron scattering and terahertz electron paramagnetic resonance measurements are used complimentarily to investigate the large exchange interaction between a rare earth-radical pair in a Tb(III)-based SMM complex. The origin of the exchange interaction is investigated for two molecular species in the crystallographic unit cell that exhibit different bonding structures between Tb(III) and a 2pyNO radical. A correlation between the Tb-O-N-C torsion angles and the magnitudes of exchange couplings is found. Interestingly, a large nondegeneracy within the ground-state doublet is present for the larger torsion angle species. It is essential to consider the balance of two channels of exchange coupling, 2p-4f hybridization and 2p-5d charge transfer, to explain this characteristic behavior. The former channel gives the antiferromagnetic interaction, and the latter gives the ferromagnetic one. When an effective J = (1)/2 Ising-type Hamiltonian is applied, the exchange couplings are evaluated to be antiferromagnetic J(z) = 9.89 meV (79.8 cm(-1)) for the low torsion angle (3.8 degrees ) species and J(z) = 7.39 meV (59.6 cm(-1)) for the larger torsion angle (15.8 degrees ) species. It is also found that a small percentage of the transverse exchange component must be included for the larger torsion angle to account for the observed nondegenerate ground state. The symmetry of the exchange couplings is discussed by considering the characters of d and f orbitals. PMID- 26010985 TI - Natural Product Inspired N-Terminal Hsp90 Inhibitors: From Bench to Bedside? AB - The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the rematuration of denatured proteins. Proteins dependent upon Hsp90 are associated with all six hallmarks of cancer. Upon Hsp90 inhibition, protein substrates are degraded via the ubiquitin proteasome pathway. Consequentially, inhibition of Hsp90 offers a therapeutic opportunity for the treatment of cancer. Natural product inhibitors of Hsp90 have been identified in vitro, which have served as leads for the development of more efficacious inhibitors and analogs that have entered clinical trials. This review highlights the development of natural product analogs, as well as the development of clinically important inhibitors that arose from natural products. PMID- 26010991 TI - Study of the influence of genes related to muscle oxidative processes on beef color. AB - The biochemical bases of meat color are determined by the concentration and redox state of myoglobin, hemoglobin, cytochromes, and other pigments. Post-mortem depletion of cellular oxygen results in oxidative stresses that consume NADH and affects reducing activity, while enzymatic detoxification influences the cellular oxidative processes, both affecting meat color. The aim of this work was to study the influence of several genes related to cellular oxidative processes that could affect CIELAB meat color parameters. The study was performed in steers that received a grass-based diet combined with grain, hays and silages. Results suggest a possible link between colorimetric parameters (a*, b* and chroma) and SNPs in the GSTP1 gene (P<0.05). Although the influence of the enzymes, encoded by GSTP1 gene, on meat color has been proposed previously at biochemical level and protein expression level, further association studies in different populations and functional studies of proteins are needed to confirm the genetic determination of that gene on meat color. PMID- 26010992 TI - Association of the expression levels in the longissimus muscle and a SNP in the CDC10 gene with marbling in Japanese Black beef cattle. AB - The septin 7 (CDC10) gene, involved in cellular proliferation, has been previously shown to be expressed at different levels in the longissimus muscle (LM) between low-marbled and high-marbled steer groups by differential-display PCR. It is located within the genomic region of a quantitative trait locus for marbling, and thus was considered as a positional functional candidate gene for marbling. In this study, we showed that the CDC10 expression levels in the LM were positively correlated with marbling in Japanese Black (JB) steers (P<0.0001). Further, an association analysis indicated that a SNP in the promoter region of the CDC10 gene was associated with marbling using 99 JB sires (P=0.03) and 542 JB paternal half-sib progeny steers from a sire homozygous for G allele at the SNP (P<0.0001). These findings suggest possible effects of the expression levels in the LM and the SNP of the CDC10 gene on marbling in JB cattle. PMID- 26010993 TI - Overexpression of GsGSTU13 and SCMRP in Medicago sativa confers increased salt alkaline tolerance and methionine content. AB - Tau-class glutathione S-transferases (GSTUs) are ubiquitous proteins encoded by a large gene family in plants, which play important roles in combating different environmental stresses. In previous studies, we constructed a Glycine soja transcriptional profile, and identified three GSTUs (GsGSTU13, GsGSTU14 and GsGSTU19) as potential salt-alkaline stress-responsive genes. Two of them, GsGSTU14 and GsGSTU19, have been shown to positively regulate plant salt-alkaline tolerance. In this study, we further demonstrated the positive function of GsGSTU13 in plant salt-alkaline stress responses by overexpressing it in Medicago sativa. Stress tolerance tests suggested that GsGSTU13 transgenic lines showed better growth and physiological indicators than wild alfalfa (cv. Zhaodong) under alkaline stress. Considering the shortage of methionine in alfalfa, we then co transformed GsGSTU13 into two main alfalfa cultivars in Heilongjiang Province (cv. Zhaodong and cv. Nongjing No. 1) together with SCMRP, a synthesized gene that could improve the methionine content. We found that GsGSTU13/SCMRP transgenic alfalfa displayed not only higher methionine content but also higher tolerance to alkaline and salt stresses, respectively. Taken together, our results demonstrate that GsGSTU13 acts as a positive regulator in plant responses to salt and alkaline stresses, and can be used as a good candidate for generation of salt-alkaline tolerant crops. PMID- 26010996 TI - Microfluidics for research and applications in oncology. AB - Cancer is currently one of the top non-communicable human diseases, and continual research and developmental efforts are being made to better understand and manage this disease. More recently, with the improved understanding in cancer biology as well as the advancements made in microtechnology and rapid prototyping, microfluidics is increasingly being explored and even validated for use in the detection, diagnosis and treatment of cancer. With inherent advantages such as small sample volume, high sensitivity and fast processing time, microfluidics is well-positioned to serve as a promising platform for applications in oncology. In this review, we look at the recent advances in the use of microfluidics, from basic research such as understanding cancer cell phenotypes as well as metastatic behaviors to applications such as the detection, diagnosis, prognosis and drug screening. We then conclude with a future outlook on this promising technology. PMID- 26010995 TI - Adolescent development of inhibition as a function of SES and gender: Converging evidence from behavior and fMRI. AB - The ability to adaptively inhibit responses to tempting/distracting stimuli in the pursuit of goals is an essential set of skills necessary for adult competence and wellbeing. These inhibitory capacities develop throughout childhood, with growing evidence of important maturational changes occurring in adolescence. There also has been intense interest in the role of social adversity on the development of executive function, including inhibitory control. We hypothesized that the onset of adolescence could be a time of particular opportunity/vulnerability in the development of inhibition due to the large degree of maturational changes in neural systems involved in regulatory control. We investigated this hypothesis in a longitudinal study of adolescents by examining the impact of socioeconomic status (SES) on the maturation of inhibition and concurrent brain function. Furthermore, we examined gender as a potential moderator of this relationship, given evidence of gender-specificity in the developmental pathways of inhibition as well as sex differences in adolescent development. Results reveal that lower SES is associated with worse behavioral inhibition over time and a concurrent increase in anterior cingulate (ACC) activation, but only in girls. We also found that lower SES girls exhibited decreased ACC <-> dorsolateral prefrontal cortex (dlPFC) coupling over time. Our findings suggest that female adolescents with lower SES appear to develop less efficient inhibitory processing in dlPFC, requiring greater and relatively unsuccessful compensatory recruitment of ACC. In summary, the present study provides a novel window into the neural mechanisms by which the influence of SES on inhibition may be transmitted during adolescence. PMID- 26010994 TI - Detecting gene-environment interactions in human birth defects: Study designs and statistical methods. AB - BACKGROUND: The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G*E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G*E effects that use varying combinations of individuals drawn from available triads. METHODS: In this study, we discuss important considerations in the collection of genetic data and environmental exposures. RESULTS: We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages. CONCLUSION: A range of approaches can be used to evaluate potentially important G*E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results. PMID- 26010997 TI - How to attract health students to remote areas in Indonesia: a discrete choice experiment. AB - BACKGROUND: Remote areas of Indonesia lack sufficient health workers to meet the health-care needs of the population. There is an urgent need for evidence regarding interventions to attract health workers and specifically health students to serve in remote areas. The aim of this research was to analyze the job preferences of health students to develop effective policies to improve the recruitment and retention of health students in remote areas. METHODS: A discrete choice experiment was conducted to investigate health students' preferences regarding job characteristics. This study was conducted in three different regions of Indonesia, with a total included 400 health students. Mixed logit models were used to explore the stated preferences for each attribute. RESULTS: Data were collected from 150 medical, 150 nursing and 100 midwifery students. Medical students gave the highest preference for receiving study assistance, while nursing students viewed salary as the most important. Midwifery students valued advanced quality facilities as an important attribute. CONCLUSIONS: This study confirmed the importance of combination interventions in attracting and retaining health workers in remote areas of Indonesia. Money is not the only factor affecting student preferences to take up a rural post; good management and better facilities were viewed as important by all health students. Addressing health student preferences, which are the candidate of future health workforce, would help the nation solve the recruitment and retention issues. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26010998 TI - Mammalian designer cells: Engineering principles and biomedical applications. AB - Biotechnology is a widely interdisciplinary field focusing on the use of living cells or organisms to solve established problems in medicine, food production and agriculture. Synthetic biology, the science of engineering complex biological systems that do not exist in nature, continues to provide the biotechnology industry with tools, technologies and intellectual property leading to improved cellular performance. One key aspect of synthetic biology is the engineering of deliberately reprogrammed designer cells whose behavior can be controlled over time and space. This review discusses the most commonly used techniques to engineer mammalian designer cells; while control elements acting on the transcriptional and translational levels of target gene expression determine the kinetic and dynamic profiles, coupling them to a variety of extracellular stimuli permits their remote control with user-defined trigger signals. Designer mammalian cells with novel or improved biological functions not only directly improve the production efficiency during biopharmaceutical manufacturing but also open the door for cell-based treatment strategies in molecular and translational medicine. In the future, the rational combination of multiple sets of designer cells could permit the construction and regulation of higher-order systems with increased complexity, thereby enabling the molecular reprogramming of tissues, organisms or even populations with highest precision. PMID- 26010999 TI - Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis. AB - A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-d-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel. PMID- 26011000 TI - AFM force spectroscopy reveals how subtle structural differences affect the interaction strength between Candida albicans and DC-SIGN. AB - The fungus Candida albicans is the most common cause of mycotic infections in immunocompromised hosts. Little is known about the initial interactions between Candida and immune cell receptors, such as the C-type lectin dendritic cell specific intracellular cell adhesion molecule-3 (ICAM-3)-grabbing non-integrin (DC-SIGN), because a detailed characterization at the structural level is lacking. DC-SIGN recognizes specific Candida-associated molecular patterns, that is, mannan structures present in the cell wall of Candida. The molecular recognition mechanism is however poorly understood. We postulated that small differences in mannan-branching may result in considerable differences in the binding affinity. Here, we exploit atomic force microscope-based dynamic force spectroscopy with single Candida cells to gain better insight in the carbohydrate recognition capacity of DC-SIGN. We demonstrate that slight differences in the N mannan structure of Candida, that is, the absence or presence of a phosphomannan side chain, results in differences in the recognition by DC-SIGN as follows: (i) it contributes to the compliance of the outer cell wall of Candida, and (ii) its presence results in a higher binding energy of 1.6 kB T. The single-bond affinity of tetrameric DC-SIGN for wild-type C. albicans is ~10.7 kB T and a dissociation constant kD of 23 MUM, which is relatively strong compared with other carbohydrate-protein interactions described in the literature. In conclusion, this study shows that DC-SIGN specifically recognizes mannan patterns on C. albicans with high affinity. Knowledge on the binding pocket of DC-SIGN and its pathogenic ligands will lead to a better understanding of how fungal-associated carbohydrate structures are recognized by receptors of the immune system and can ultimately contribute to the development of new anti-fungal drugs. PMID- 26011001 TI - Impact of cabin ozone concentrations on passenger reported symptoms in commercial aircraft. AB - Due to elevated ozone concentrations at high altitudes, the adverse effect of ozone on air quality, human perception and health may be more pronounced in aircraft cabins. The association between ozone and passenger-reported symptoms has not been investigated under real conditions since smoking was banned on aircraft and ozone converters became more common. Indoor environmental parameters were measured at cruising altitude on 83 US domestic and international flights. Passengers completed a questionnaire about symptoms and satisfaction with the indoor air quality. Average ozone concentrations were relatively low (median: 9.5 ppb). On thirteen flights (16%) ozone levels exceeded 60 ppb, while the highest peak level reached 256 ppb for a single flight. The most commonly reported symptoms were dry mouth or lips (26%), dry eyes (22.1%) and nasal stuffiness (18.9%). 46% of passengers reported at least one symptom related to the eyes or mouth. A third of the passengers reported at least one upper respiratory symptom. Using multivariate logistic (individual symptoms) and linear (aggregated continuous symptom variables) regression, ozone was consistently associated with symptoms related to the eyes and certain upper respiratory endpoints. A concentration-response relationship was observed for nasal stuffiness and eye and upper respiratory symptom indicators. Average ozone levels, as opposed to peak concentrations, exhibited slightly weaker associations. Medium and long duration flights were significantly associated with more symptoms compared to short flights. The relationship between ultrafine particles and ozone on flights without meal service was indicative of ozone-initiated chemistry. PMID- 26011003 TI - Optimizing dose regimens and fixed dose combination ratios in clinical trials. AB - Successful treatment of many diseases depends on the level of drug concentration in blood and its maintenance over a period of time around a value considered as therapeutic. The dose regimen that minimizes the underexposure and overexposure around the target concentration maximizes efficacy and safety, resulting in increased chances of a successful patient recovery. We present a method of computer-assisted dose finding by explicit optimization of a target criterion. We develop a general theory for such dose regimens and propose criteria for their computation. This approach is likely to supersede "brute force" techniques exclusively based on simulation. In case of a combination of two drugs in a single dosing unit, it is crucial that the optimal combination ratio is identified during the developmental process and is taken forward to further trials or approval. The algorithm computes the optimal ratio along with the optimal dose regimen. If the interest is in restricting the concentration profile of the drug to a therapeutic range, we adapt the algorithm to determine the optimal dose regimen. In future, this work is intended to aid the development of fixed dose combinations, especially antimalarials and other anti-infectives. The methodology also has potential applications in randomized concentration controlled trials where adherence to the target concentration is a fundamental requirement. PMID- 26011004 TI - Indirect localization of a magnetic domain wall mediated by quasi walls. AB - The manipulation of magnetic domain walls in thin films and nanostructures opens new opportunities for fundamental and applied research. But controlling reliably the position of a moving domain wall still remains challenging. So far, most of the studies aimed at understanding the physics of pinning and depinning processes in the magnetic layer in which the wall moves (active layer). In these studies, the role of other magnetic layers in the stack has been often ignored. Here, we report an indirect localization process of 180 degrees domain walls that occurs in magnetic tunnel junctions, commonly used in spintronics. Combining Scanning Transmission X-Ray Microscopy and micromagnetic simulations, magnetic configurations in both layers are resolved. When nucleating a 180 degrees domain wall in the active layer, a quasi wall is created in the reference layer, atop the wall. The wall and its quasi wall must then be moved or positioned together, as a unique object. As a mutual effect, a localized change of the magnetic properties in the reference layer induces a localized quasi wall in the active layer. The two types of quasi walls are shown to be responsible for an indirect localization process of the 180 degrees domain wall in the active layer. PMID- 26011005 TI - Universal Route to Polycyclic Aromatic Hydrocarbon Analysis in Foodstuff: Two Dimensional Heart-Cut Liquid Chromatography-Gas Chromatography-Mass Spectrometry. AB - Analysis of polycyclic aromatic hydrocarbons (PAHs) in complex foodstuff is associated with complicated and work-intensive sample preparation. Chromatographic interference has to be faced in many situations. The scope of the current work was the development of a highly efficient two-dimensional heart-cut LC-LC-GC-MS method. Detection was performed with a time-of-flight mass spectrometer (TOF-MS) to allow for a comprehensive evaluation of the obtained data in terms of cleanup efficiency. Additionally, routine detection was performed with single quadrupole MS. An easy and quick generic sample preparation protocol was realized as a first step. During method development, focus was given to optimizing HPLC cleanup for complex foodstuff. Silica-, polymeric-, and carbon based HPLC phases were tested. Coupling of silica gel to pi-electron acceptor modified silica gel showed the best cleanup properties. A four rotary valve configuration allowed the usage of a single binary HPLC pump. Screening of several fatty and nonfatty food matrices showed the absence of unwanted matrix compounds in the cleaned-up PAH fraction down to the low picogram range using TOF MS. Limits of quantitation (LOQ) were below 0.1 MUg/kg for all EU priority PAHs. Recovery rates ranged from 82 to 111%. Validation data fully complied with EU Regulation 836/2011. Sample preparation was possible in 20 min. Interlacing of HPLC and GC allowed an average method runtime of 40 min per sample. PMID- 26011002 TI - Phylogeography and support vector machine classification of colour variation in panther chameleons. AB - Lizards and snakes exhibit colour variation of adaptive value for thermoregulation, camouflage, predator avoidance, sexual selection and speciation. Furcifer pardalis, the panther chameleon, is one of the most spectacular reptilian endemic species in Madagascar, with pronounced sexual dimorphism and exceptionally large intraspecific variation in male coloration. We perform here an integrative analysis of molecular phylogeography and colour variation after collecting high-resolution colour photographs and blood samples from 324 F. pardalis individuals in locations spanning the whole species distribution. First, mitochondrial and nuclear DNA sequence analyses uncover strong genetic structure among geographically restricted haplogroups, revealing limited gene flow among populations. Bayesian coalescent modelling suggests that most of the mitochondrial haplogroups could be considered as separate species. Second, using a supervised multiclass support vector machine approach on five anatomical components, we identify patterns in 3D colour space that efficiently predict assignment of male individuals to mitochondrial haplogroups. We converted the results of this analysis into a simple visual classification key that can assist trade managers to avoid local population overharvesting. PMID- 26011007 TI - Is Implantation of a Left Ventricular Assist Device in Patients With Critical or Impending Cardiogenic Shock an Absolute Contraindication? Looking Back at Our Past Experience Trying to Identify Contraindicative Risk Factors. AB - Poor survival has been demonstrated after ventricular assist device (VAD) implantation for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 and 2 patients compared with more stable levels. However, risk factors within this high-risk cohort have not been determined so far. The aim of the present study was to identify risk factors associated with this very high mortality rate. Between February 1993 and January 2013, 298 patients underwent VAD implantation in our institution. One hundred nine patients were in INTERMACS level 1 and 49 patients were in INTERMACS level 2 and were therefore defined as hemodynamically critical (overall 158 patients). Assist devices implanted were: HVAD HeartWare n = 18; Incor n = 11; VentrAssist n = 2; DeBakey n = 22; and pulsatile systems n = 105. After cumulative support duration of 815.35 months, Kaplan-Meier analysis revealed a survival of 63.9, 48.8, and 40.3% at 1, 6, and 12 months, respectively. Cox regression analyses identified age > 50 (P = 0.001, odds ratio [OR] 2.48), white blood cell count > 13.000/MUL (P = 0.01, OR 2.06), preoperative renal replacement therapy (P = 0.001, OR 2.63), and postcardiotomy failure (P < 0.001, OR 2.79) as independent predictors of mortality. Of note, last generation VADs were not associated with significantly better 6-month survival (P = 0.59). Patients without the aforementioned risk factors could yield a survival of 79.2% at 6 months. This single-center experience shows that VAD implantation in hemodynamically unstable patients generally results in poor early outcome, even in third-generation pumps. However, avoiding the aforementioned risk factors could result in improved outcome. PMID- 26011006 TI - No impact of DvSnf7 RNA on honey bee (Apis mellifera L.) adults and larvae in dietary feeding tests. AB - The honey bee (Apis mellifera L.) is the most important managed pollinator species worldwide and plays a critical role in the pollination of a diverse range of economically important crops. This species is important to agriculture and historically has been used as a surrogate species for pollinators to evaluate the potential adverse effects for conventional, biological, and microbial pesticides, as well as for genetically engineered plants that produce pesticidal products. As part of the ecological risk assessment of MON 87411 maize, which expresses a double-stranded RNA targeting the Snf7 ortholog (DvSnf7) in western corn rootworm (Diabrotica virgifera virgifera), dietary feeding studies with honey bee larvae and adults were conducted. Based on the mode of action of the DvSnf7 RNA in western corn rootworm, the present studies were designed to be of sufficient duration to evaluate the potential for adverse effects on larval survival and development through emergence and adult survival to a significant portion of the adult stage. Testing was conducted at concentrations of DvSnf7 RNA that greatly exceeded environmentally relevant exposure levels based on expression levels in maize pollen. No adverse effects were observed in either larval or adult honey bees at these high exposure levels, providing a large margin of safety between environmental exposure levels and no-observed-adverse-effect levels. PMID- 26011008 TI - Apical periodontitis and incident cardiovascular events in the Baltimore Longitudinal Study of Ageing. AB - AIM: To evaluate whether the presence of apical periodontitis (AP), root canal treatment (RCT) and endodontic burden (EB) - as the sum of AP and RCT sites - were associated with long-term risk of incident cardiovascular events (CVE), including cardiovascular-related mortality, using data on participants in the Baltimore Longitudinal Study of Ageing (BLSA). METHODOLOGY: This retrospective cohort included 278 dentate participants in the BLSA with complete medical and dental examinations. Periodontal disease (PD) and missing teeth were recorded. The total number of AP and RCT sites was determined from panoramic radiographs. EB was calculated as the sum of AP and RCT sites. Oral inflammatory burden (OIB) was calculated combining PD and EB. The main outcome was incident CVE including angina, myocardial infarction and cardiovascular-related death. Participants were monitored for up to 44 years (mean = 17.4+/- 11.1 years) following dental examination. Relative risks (RRs) were calculated through Poisson regression models, estimating the relationship between AP, RCT, EB, PD, OIB and incident CVE. RESULTS: Mean age at baseline was 55.0 +/-16.8 years and 51.4% were men. Sixty-two participants (22.3%) developed CVE. Bivariate analysis showed that PD, EB, number of teeth and OIB were associated with incident CVE. Multivariate models, adjusted for socio-demographic and medical variables, showed that age >=60 years (RR = 3.07, 95% CI =1.68-5.62), hypertension (RR = 2.0, 95% CI = 1.16 3.46) and EB >=3 (RR = 1.77, 95% CI = 1.04-3.02) were independently associated with incident CVE. The association between OIB and incident CVE was reduced to nonsignificance after adjustments (RR = 1.97, 95% CI = 0.83-4.70). CONCLUSIONS: EB in midlife was an independent predictor of CVE amongst community-dwelling participants in the BLSA. Prospective studies are required to evaluate cardiovascular risk reduction with the treatment of AP. PMID- 26011010 TI - Morphology of the teleost ampullary organs in marine salmontail catfish Neoarius graeffei (Pisces: Ariidae) with comparative analysis to freshwater and estuarine conspecifics. AB - We hypothesized that due to the relative conductivity of the environment, and to maintain sensory function, ampullary organs of marine Neoarius graeffei would differ morphologically from those described previously for estuarine and freshwater conspecifics. Unlike the ampullary systems of N. graeffei from freshwater and estuarine habitats, the ampullary pores of marine specimens occur in two distinct patterns; numerous pores seemingly randomly scattered on the head and ventro-lateral regions of the body, and pores arranged in distinctive vertical lines above the lateral line on the dorso-lateral body of the fish. Light and electron microscopy revealed that the ampullary organs also differed morphologically from estuarine and freshwater specimens in the presence of longer ampullary canals, a hitherto unreported canal wall composition, and in the collagen sheath surrounding both the canal and the ampulla proper within dermal connective tissues. Ampullary pores were wider in marine individuals and opened to the longest ampullary canals reported for this species. The canal wall was lined by cuboidal and squamous epithelial cells. Each ampullary canal opened into a single ampulla proper containing significantly more receptor cells than estuarine and freshwater conspecifics. The distribution of ampullary pores as well as the microstructure of the ampullary organs indicates that the electrosensory system of marine N. graeffei differs from those of estuarine and freshwater specimens in ways that would be expected to maintain the functionality of the system in a highly conductive, fully marine environment, and reveals the remarkable plasticity of this species' ampullary system in response to habitat conductivity. PMID- 26011009 TI - Long-Term Therapy With Omega-3 Ameliorates Myonecrosis and Benefits Skeletal Muscle Regeneration in Mdx Mice. AB - In Duchenne muscle dystrophy (DMD) and in the mdx mouse model of DMD, a lack of dystrophin leads to myonecrosis and cardiorespiratory failure. Several lines of evidence suggest a detrimental role of the inflammatory process in the dystrophic process. Previously, we demonstrated that short-term therapy with eicosapentaenoic acid (EPA), at early stages of disease, ameliorated dystrophy progression in the mdx mouse. In the present study, we evaluated the effects of a long-term therapy with omega-3 later in dystrophy progression. Three-month-old mdx mice received omega-3 (300 mg/kg) or vehicle by gavage for 5 months. The quadriceps and diaphragm muscles were removed and processed for histopathology and Western blot. Long-term therapy with omega-3 increased the regulatory protein MyoD and muscle regeneration and reduced markers of inflammation (TNF-alpha and NF-kB) in both muscles studied. The present study supports the long-term use of omega-3 at later stages of dystrophy as a promising option to be investigated in DMD clinical trials. PMID- 26011011 TI - Vitamin E pretreatment prevents histopathological effects in tilapia (Oreochromis niloticus) acutely exposed to cylindrospermopsin. AB - Cylindrospermopsin (CYN) is a cyanotoxin frequently involved in blooms with a predominantly extracellular availability, which makes it easily taken up by a variety of aquatic organisms. CYN is a potent protein and glutathione synthesis inhibitor, and also induces genotoxicity, oxidative stress and several histopathological lesions. The present study investigates the protective role of a vitamin E pretreatment (700 mg vit E/kg fish bw/day, for 7 days) on the histopathological alterations induced in different organs of tilapia (Oreochromis niloticus) acutely exposed to a single oral dose of 400 ug pure CYN/kg bw fish. The major histological changes observed were degenerative glucogenic process and loss of the hepatic structure in the liver, glomerulopathy and tubular tumefaction in the kidney, myofibrolysis and edema in the heart, catarrhal enteritis and necrosis in the gastrointestinal tract, hyperemic processes in the gill lamellae, and high basophilia, degeneration and tumefaction of granular neurons in the brain. Vitamin E pretreatment was effective in preventing or ameliorating the abovementioned alterations induced by CYN. In addition, a morphometric study indicated that the average nuclear diameter of hepatocytes, and cross-sections of proximal and distal convoluted tubules, together with the cardiac fiber and capillaries diameters represent a useful tool to evaluate the damage induced by CYN. This is the first study reporting vitamin E prevention of histopathological damage in tissues (liver, kidney, heart, gastrointestinal tract, gills and brain) of fish intoxicated with CYN. Therefore, vitamin E can be considered a useful chemoprotectant in the treatment of histopathological changes induced in CYN-intoxicated fish. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1469-1485, 2016. PMID- 26011012 TI - Thoracic insufficiency syndrome in an elderly patient: An autopsy case. PMID- 26011013 TI - The effect of maternal Inflammation on foetal programming of metabolic disease. AB - Maternal obesity during pregnancy increases the child's risk of developing obesity and obesity-related diseases later in life. Key components in foetal programming of metabolic risk remain to be identified; however, chronic low-grade inflammation associated with obesity might be responsible for metabolic imprinting in the offspring. We have therefore surveyed the literature to evaluate the role of maternal obesity-induced inflammation in foetal programming of obesity and related diseases. The literature on this topic is limited, so this review also includes animal models where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS). An LPS challenge results in an immunological response that resembles the obesity-induced immune profile, although LPS injections provoke a stronger response than the subclinical obesity associated response. Maternal LPS or cytokine exposures result in increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. The cytokine levels might be specifically important for the metabolic imprinting, as cytokines are both transferable from maternal to foetal circulation and have the capability to modulate placental nutrient transfer. However, the immune response associated with obesity is moderate and therefore potentially weakened by the pregnancy driven immune modulation, dominated by anti-inflammatory Treg and Th2 cells. We know from other low-grade inflammatory diseases, such as rheumatoid arthritis, that pregnancy can improve disease state. If pregnancy is also capable of suppressing the obesity-associated inflammation, the immunological markers might be less likely to affect metabolic programming in the developing foetus than otherwise implied. PMID- 26011015 TI - Association between Chronic Rhinosinusitis and Health-Related Quality of Life in Adults with Cystic Fibrosis. AB - RATIONALE: Over the past four decades, the median age of survival has nearly doubled for individuals living with cystic fibrosis (CF). Chronic diseases such as chronic rhinosinusitis increase in prevalence with age. In the non-CF population, chronic rhinosinusitis is associated with reduced health-related quality of life. OBJECTIVES: Our objectives were to determine the prevalence of chronic rhinosinusitis among adults with CF and to evaluate the impact of chronic rhinosinusitis on health-related quality of life. METHODS: Individuals from a large academic teaching hospital in Vancouver, British Columbia, Canada, were eligible to participate in this cross-sectional study. Included subjects were at least 19 years of age, had a confirmed diagnosis of CF, and attended the CF clinic between September 2013 and April 2014. Participants completed a CF specific health-related quality of life questionnaire (the Cystic Fibrosis Questionnaire-Revised for adolescents and adults over 14 years of age [CFQ-R 14+]) and underwent symptom and endoscopic assessment for diagnosis of chronic rhinosinusitis. Medical charts were reviewed for potential confounders, including sociodemographic (age, sex, and body mass index) and clinical (age at CF diagnosis, type of CF mutation, lung function, and chronic Pseudomonas aeruginosa infection) factors. Multivariable linear regression was used to model the relationship between chronic rhinosinusitis and CFQ-R 14+ domains, adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS: A total of 121 individuals were contacted in the clinic, of whom 113 (93.4%) consented to participate. The prevalence of chronic rhinosinusitis was found to be 59.2% (95% confidence interval [CI], 49.6-68.2%). Sociodemographic and clinical factors were similarly distributed between chronic rhinosinusitis-positive and chronic rhinosinusitis negative groups. Lung function, as measured by FEV1 (% predicted value), did not significantly differ between participants with versus those without chronic rhinosinusitis (mean difference, 2.0%; 95% CI, -8.1% to 13.0%). Following adjustment for sex and lung function, individuals with chronic rhinosinusitis reported significantly worse scores on the respiratory symptoms domains compared with their counterparts without chronic rhinosinusitis (regression coefficient, 3.93; 95% CI, -8.02 to 0.15). CONCLUSIONS: The majority of adults with CF have evidence of concomitant chronic rhinosinusitis. Chronic rhinosinusitis is independently associated with worse respiratory symptom on the CFQ-R 14+. Chronic rhinosinusitis should be diagnosed and managed to optimize the health-related quality of life of adults with CF. Clinical trial registered with clinicaltrials.gov (NCT02003079). PMID- 26011014 TI - Moss-made pharmaceuticals: from bench to bedside. AB - Over the past two decades, the moss Physcomitrella patens has been developed from scratch to a model species in basic research and in biotechnology. A fully sequenced genome, outstanding possibilities for precise genome-engineering via homologous recombination (knockout moss), a certified GMP production in moss bioreactors, successful upscaling to 500 L wave reactors, excellent homogeneity of protein glycosylation, remarkable batch-to-batch stability and a safe cryopreservation for master cell banking are some of the key features of the moss system. Several human proteins are being produced in this system as potential biopharmaceuticals. Among the products are tumour-directed monoclonal antibodies with enhanced antibody-dependent cytotoxicity (ADCC), vascular endothelial growth factor (VEGF), complement factor H (FH), keratinocyte growth factor (FGF7/KGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), asialo erythropoietin (asialo-EPO, AEPO), alpha-galactosidase (aGal) and beta glucocerebrosidase (GBA). Further, an Env-derived multi-epitope HIV protein as a candidate vaccine was produced, and first steps for a metabolic engineering of P. patens have been made. Some of the recombinant biopharmaceuticals from moss bioreactors are not only similar to those produced in mammalian systems such as CHO cells, but are of superior quality (biobetters). The first moss-made pharmaceutical, aGal to treat Morbus Fabry, is in clinical trials. PMID- 26011016 TI - Vesicles and pustules on the fingers as an initial manifestation of eosinophilic pustular folliculitis. PMID- 26011017 TI - Education modifies the type of subjective memory complaints in older people. AB - OBJECTIVE: The aim of the study is to analyze the relationship between the level of education and the profile of subjective memory complaints (SMC). METHODS: Participants were healthy volunteers aged >50 years old, from a community-based sample. Educational attainment was self-reported, and participants were subsequently assembled in four groups, according to the highest grade achieved in school. Additionally, they were questioned about their own memory abilities using an SMC scale (total score 0-21) and assessed for the presence of depressive symptoms. RESULTS: A total of 841 participants aged 50-92 years old were included. The mean total score on the SMC scale was 5.3 +/- 3.2, and 80.4% of the subjects reported at least one minor complaint about their memory. There was no correlation between total SMC score and higher educational level, even after accounting for the presence of depressive symptoms. However, regarding specific SMC, the use of notes to avoid forgetting was more frequent in higher levels of education, whereas the opposite trend was observed for complaints of transient confusion. CONCLUSION: Educational attainment possibly modulates the frequency and type of SMC in normal aging. Because these complaints are a major symptom for the diagnosis of cognitive decline, it seems relevant to consider the level of education when interpreting subjective reports on memory. PMID- 26011018 TI - Metal allergy to everolimus-eluting cobalt chromium stents confirmed by positive skin testing as a cause of recurrent multivessel in-stent restenosis. AB - A 54-year-old woman treated with cobalt-chromium everolimus eluting stents (CoCr EES) for her left distal circumflex and diagonal branch lesions suffered from repeated in-stent restenosis in both lesions. Neointimal proliferation occurred rapidly and almost simultaneously in the two lesions. The cause was established to be metal allergy, as determined by patch tests which were strongly positive for bare metal stents and weakly positive for CoCr-EES. Following the third successive angioplasty, we initiated treatment with prednisolone (30 mg daily) and the anti-allergic and anti-proliferative drug tranilast (300 mg daily). An elective angiogram performed 3 months later showed no evidence of in-stent restenosis in any of the stented lesions. Furthermore, the patient has remained angina-free for 15 months. The unique features of this case include: (1) near simultaneous repeated multivessel in-stent restenosis in a patient with skin test documented metal allergy to cobalt-chromium stents; (2) adjunctive systemic medical therapy with prednisolone and tranilast appeared to terminate the malignant restenotic cycle. PMID- 26011019 TI - The Inhibitory Efficacy of Methylseleninic Acid Against Colon Cancer Xenografts in C57BL/6 Mice. AB - Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo. We tested the hypothesis that oral dosing methylseleninic acid (MSeA), a methylselenol precursor, inhibits the growth of colon cancer xenografts in C57BL/6 mice fed a Se adequate diet. In this study, MSeA supplementation was given by an oral dose (0, 1, or 3 mg/kg body weight) regimen. MSeA increased Se content of liver, kidney, muscle, stomach (w/intestine) and plasma, and elevated blood glutathione peroxidase (GPx) activities. However, MSeA did not change lean/fat body composition, food consumption, levels of plasma leptin/adiponectin, and body weight gain. MSeA (3 mg/kg body weight) inhibited tumor growth up to 61% when compared to the control group, and this inhibition was associated with a reduction of plasma tumor necrosis factor (TNFalpha)/interleukin 6 (IL6) level but elevated blood GPx activities. In addition, MSeA (1 mg/kg body weight) increased the activation of caspase-3, a major apoptotic enzyme, in tumor tissues. Taken together, our MSeA oral dosing regimen was at safe levels; and high blood GPx activities, caspase-3 activities in tumor tissue and a reduction of plasma TNFalpha/IL6 level, play critical roles in inhibiting colon tumor growth in an immune-competent C57BL/6 mouse model. PMID- 26011020 TI - Cytoprotective and anti-apoptotic effects of Satureja khuzestanica essential oil against busulfan-mediated sperm damage and seminiferous tubules destruction in adult male mice. AB - We studied the protective effect of Satureja khuzestanica essential oil (SKEO) against damage caused by busulfan on testis in male mice. The NMRI mice (n = 40) were assigned to four groups including: G1: control, G2: treated with busulfan for 4 days (3.2 mg kg(-1)), G3: receive busulfan (4 days, 3.2 mg kg(-1)) and SKEO (28 days, 225 mg kg(-1)) at the same time, G4: pre-treated with SKEO (7 days, 225 mg kg(-1)) and subsequently cotreated with busulfan (4 days, 3.2 mg kg(-1)) and SKEO (28 days, 225 mg kg(-1)). The histological changes of testis were analysed using H&E staining. Sperm parameters, cytotoxic and apoptotic factors were also studied by computer-aided sperm analyzer, MTT and TUNEL assays respectively. Our results showed that SKEO pre-administration significantly improved all parameters of epididymal spermatozoa and decreased germinal epithelium destruction following busulfan chemotherapy. We also found lower MTT levels and TUNEL-positive cells in SKEO pre-treated groups. In conclusion, SKEO possesses beneficial effects on sperm parameters when taken before chemotherapy and continued during and after chemotherapy for a long time, than when used short-term coinciding with the chemotherapy. Our results support valuable data about the application of SKEO for protection against adverse effects of busulfan on male genital system in patients under chemotherapy. PMID- 26011021 TI - Copper-Based Ultrathin Nickel Nanocone Films with High-Efficiency Dropwise Condensation Heat Transfer Performance. AB - We report a type of copper-based ultrathin nickel nanocone films with high efficiency dropwise condensation heat transfer (DCHT) performance, which can be fabricated by facile electrodeposition and low-surface-energy chemistry modification. Compared with flat copper samples, our nanosamples show condensate microdrop self-propelling (CMDSP) function and over 89% enhancement in the DCHT coefficient. Such remarkable enhancement may be ascribed to the cooperation of surface nanostructure-induced CMDSP function as well as in situ integration and ultrathin nature of nanofilms. These findings are very significant to design and develop advanced DCHT materials and devices, which help improve the efficiency of thermal management and energy utilization. PMID- 26011023 TI - Polyampholyte Brushes Grafted on the Surface of a Spherical Cavity: Effect of the Charged Monomer Sequence, Grafting Density, and Chain Stiffness. AB - Molecular dynamics simulations are used to study the conformational behaviors of the flexible and semiflexible polyampholytes coated onto the internal surface of a spherical cavity. Dependences of the brush structure and the local conformation of grafted chains on the sequence of charged monomers, the grafting density, and the chain stiffness are addressed. In the range of parameters studied, it was found that a significant transition of the brush structure occurs due to the variation of the charged monomer sequence. As the number of repeat charged monomers increases, both the flexible and semiflexible polyampholyte brushes change to the collapsed conformation. The spherical concave geometry tends to exclude the conformation of chains perpendicular to the grafting surface for the semiflexible case. In addition, we find that most counterions are depleted in the polyampholyte brush due to the strong electrostatic correlation between the oppositely charged monomers. PMID- 26011022 TI - Triarylmethyl Labels: Toward Improving the Accuracy of EPR Nanoscale Distance Measurements in DNAs. AB - Triarylmethyl (trityl, TAM) based spin labels represent a promising alternative to nitroxides for EPR distance measurements in biomolecules. Herewith, we report synthesis and comparative study of series of model DNA duplexes, 5'-spin-labeled with TAMs and nitroxides. We have found that the accuracy (width) of distance distributions obtained by double electron-electron resonance (DEER/PELDOR) strongly depends on the type of radical. Replacement of both nitroxides by TAMs in the same spin-labeled duplex allows narrowing of the distance distributions by a factor of 3. Replacement of one nitroxide by TAM (orthogonal labeling) leads to a less pronounced narrowing but at the same time gains sensitivity in DEER experiment due to efficient pumping on the narrow EPR line of TAM. Distance distributions in nitroxide/nitroxide pairs are influenced by the structure of the linker: the use of a short amine-based linker improves the accuracy by a factor of 2. At the same time, a negligible dependence on the linker length is found for the distribution width in TAM/TAM pairs. Molecular dynamics calculations indicate greater conformational disorder of nitroxide labels compared to TAM ones, thus rationalizing the experimentally observed trends. Thereby, we conclude that double spin-labeling using TAMs allows obtaining narrower spin-spin distance distributions and potentially more precise distances between labeling sites compared to traditional nitroxides. PMID- 26011024 TI - Continuous versus group sequential analysis for post-market drug and vaccine safety surveillance. AB - The use of sequential statistical analysis for post-market drug safety surveillance is quickly emerging. Both continuous and group sequential analysis have been used, but consensus is lacking as to when to use which approach. We compare the statistical performance of continuous and group sequential analysis in terms of type I error probability; statistical power; expected time to signal when the null hypothesis is rejected; and the sample size required to end surveillance without rejecting the null. We present a mathematical proposition to show that for any group sequential design there always exists a continuous sequential design that is uniformly better. As a consequence, it is shown that more frequent testing is always better. Additionally, for a Poisson based probability model and a flat rejection boundary in terms of the log likelihood ratio, we compare the performance of various continuous and group sequential designs. Using exact calculations, we found that, for the parameter settings used, there is always a continuous design with shorter expected time to signal than the best group design. The two key conclusions from this article are (i) that any post-market safety surveillance system should attempt to obtain data as frequently as possible, and (ii) that sequential testing should always be performed when new data arrives without deliberately waiting for additional data. PMID- 26011025 TI - Congenital mirror movements caused by a mutation in the DCC gene. PMID- 26011026 TI - Sources of Variation in a Two-Step Monitoring Protocol for Species Clustered in Conspicuous Points: Dolichotis patagonum as a Case Study. AB - In species showing distributions attached to particular features of the landscape or conspicuous signs, counts are commonly made by making focal observations where animals concentrate. However, to obtain density estimates for a given area, independent searching for signs and occupancy rates of suitable sites is needed. In both cases, it is important to estimate detection probability and other possible sources of variation to avoid confounding effects on measurements of abundance variation. Our objective was to assess possible bias and sources of variation in a two-step protocol in which random designs were applied to search for signs while continuously recording video cameras were used to perform abundance counts where animals are concentrated, using mara (Dolichotis patagonum) as a case study. The protocol was successfully applied to maras within the Peninsula Valdes protected area, given that the protocol was logistically suitable, allowed warrens to be found, the associated adults to be counted, and the detection probability to be estimated. Variability was documented in both components of the two-step protocol. These sources of variation should be taken into account when applying this protocol. Warren detectability was approximately 80% with little variation. Factors related to false positive detection were more important than imperfect detection. The detectability for individuals was approximately 90% using the entire day of observations. The shortest sampling period with a similar detection capacity than a day was approximately 10 hours, and during this period, the visiting dynamic did not show trends. For individual mara, the detection capacity of the camera was not significantly different from the observer during fieldwork. The presence of the camera did not affect the visiting behavior of adults to the warren. Application of this protocol will allow monitoring of the near-threatened mara providing a minimum local population size and a baseline for measuring long-term trends. PMID- 26011028 TI - Children's Temperament and Academic Skill Development During First Grade: Teachers' Interaction Styles as Mediators. AB - The present study followed 156 Finnish children (Mage = 7.25 years) during the first grade of primary school to examine to what extent parent- and teacher-rated temperament impacts children's math and reading skill development during the first grade, and the extent to which this impact would be mediated by teachers' interaction styles with the children. The results showed that the impact of children's low task orientation and negative emotionality on their math skill development was mediated via teachers' behavioral control and, among girls, also by psychological control. The negative impact of children's inhibition on math skill development, in turn, was not mediated via teachers' interaction styles. Temperament did not predict the children's reading skill development during first grade. PMID- 26011027 TI - Development and analysis of furazolidone-resistant Escherichia coli mutants. AB - Furazolidone-resistant mutants were obtained from four clinical isolates of diarrhoeagenic Escherichia coli. The stability of the resistance and the frequency of mutation were established. The minimal inhibitory concentration of furazolidone, nitrofurantoin, nalidixic acid, ampicillin, chloramphenicol and tetracycline was established both in the presence and absence of the efflux pump inhibitor Phe-Arg-beta-Naphtylamyde. The presence of mutations in the nitroreductase genes nfsA and nfsB was analysed by PCR; sequencing and their enzymatic activity was assessed by a spectrophotometric assay. Alterations in outer membrane proteins were studied by SDS-PAGE. The frequency of mutation ranged from <9.6 * 10(-10) to 9.59 * 10(-7) . Neither an effect on efflux pumps inhibited by Phe-Arg-beta-Naphtylamyde nor cross-resistance with the antibiotics studied was observed. Nineteen mutants (52.94%) presented mutations in the nitroreductase-encoding genes: 17 in the nfsA gene (15 mutants with an internal stop codon, 2 with amino acid changes), 2 in the nfsB (all amino acid changes). Alterations in the outer membrane proteins OmpA and OmpW were also observed. Although more studies are necessary to find other resistance mechanisms, present data showed the low potential of selecting furazolidone-resistant mutants, together with the lack of cross-resistance with unrelated antimicrobial agents. PMID- 26011029 TI - Estimated glomerular filtration rate progression in UK primary care patients with type 2 diabetes and diabetic kidney disease: a retrospective cohort study. AB - AIMS: To examine the rates of diabetic kidney disease (DKD) progression and associated factors, we undertook a study of estimated glomerular filtration rate (eGFR) in a historical cohort of UK primary care patients with type 2 diabetes mellitus (T2DM) and associated DKD from the Clinical Practice Research Datalink. METHODS: Our eligible population were patients with definitive T2DM from a recorded diagnostic code with either a diagnosis of chronic kidney disease (CKD) or renal function test values and renal abnormalities consistent with a CKD diagnosis, identified between 1 October 2006 and 31 December 2011. Only patients with albuminuria results reported in mg/l were used for the longitudinal statistical analyses of the eGFR rate of change using multilevel models. RESULTS: We identified 111,030 patients with T2DM. Among them 58.6% (95% confidence interval (CI): 58.3-58.9) had CKD and 37.2% (95% CI: 36.9-37.5%) had presumed DKD at baseline. Only 19.4% of patients had urinary albumin test results expressed as mg/l in the year prior to index date. Almost two-thirds (63.8%) of patients with T2DM and presumed DKD received prescriptions for angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor blockers (ARB) or both. Time dependent variables that predict subsequent eGFR decline include increased albuminuria, time from index date and older age. CONCLUSION: Only a minority of diabetic patients with DKD had quantitative albuminuria assessments. The relatively low proportion of DKD patients with ACEi or ARB prescriptions suggests a gap between healthcare practice and available scientific evidence during the study period. Increased albuminuria and older age were the most consistent predictors of subsequent eGFR decline. PMID- 26011030 TI - New cardiovascular guidelines: Clinical practice evidence for the nurse practitioner. AB - PURPOSE: Guidelines for the prevention and treatment of cardiovascular disease (CVD) have recently changed. Goals of these guidelines have shifted to the promotion of health and control of risk rather than solely on treatment of CVD. This article summarizes the six new cardiovascular screening, prevention, and treatment guidelines for use in practice. DATA SOURCES: Published and peer reviewed guidelines published jointly and in collaboration with the National Heart Lung and Blood Institute by the American Heart Association and the American College of Cardiology constitute the evidence base for this article. CONCLUSIONS: The potential for making lifestyle changes a way of life instead of a diet or program is an important point to make in clinical visits. If nurse practitioners (NPs) could promote a way-of-life lifestyle change to individuals in America, even change at a modest level, we could improve the health of the nation. IMPLICATIONS FOR PRACTICE: NPs need to be aware of new guidelines and best practices to improve the cardiovascular health of their patients. We summarized these new guidelines into an easy-to-interpret format for use in practice. PMID- 26011031 TI - Impact on Clinical Outcome of Premature Interruption of Cryoenergy Delivery Due to Phrenic Nerve Palsy During Second Generation Cryoballoon Ablation for Paroxysmal Atrial Fibrillation. AB - INTRODUCTION: Right phrenic nerve paralysis (PNP) is the most frequently observed complication occurring during cryoballoon ablation (CB). Our aim was to analyze the impact of the premature interruption (PI) of cryoenergy delivery in a large series of consecutive patients during ablation in the right-sided veins on clinical outcome. METHODS AND RESULTS: All consecutive patients having undergone second-generation CB ablation for paroxysmal atrial fibrillation (AF) from July 2012 to September 2014 were included in our analysis. Exclusion criteria were persistent AF, presence of an intracavitary thrombus, uncontrolled heart failure, moderate or severe valvular disease, left atrium (LA) diameter >=55 mm, and contraindications to general anesthesia. A total 287 consecutive patients with drug-resistant paroxysmal AF having undergone pulmonary vein isolation by means of CB technology (male 65%, age 57.6 +/- 13.1 years) were included. The incidence of PNP in the study population was 8.0% (23/287). At a mean follow-up of 11.5 +/- 3.9 months, the success rate without antiarrhythmic therapy was 81.6%. Patients with PNP had similar rates of AF recurrence compared with those without PNP (17.4% vs. 17.8%; P = 0.9); the former had a mean follow-up of 10.9 +/- 3.7 months, the latter 11.8 +/- 4.5 months (P = 0.3). CONCLUSION: Conclusion: Our findings show that patients in whom freezing was interrupted due to PNP had a similar outcome on 1-year follow-up compared with those in whom freezing cycles were completed in the septal veins. No baseline clinical or procedural characteristics were found to predict AF recurrence in patients having experienced PNP. PMID- 26011032 TI - Strong coronal channelling and interplanetary evolution of a solar storm up to Earth and Mars. AB - The severe geomagnetic effects of solar storms or coronal mass ejections (CMEs) are to a large degree determined by their propagation direction with respect to Earth. There is a lack of understanding of the processes that determine their non radial propagation. Here we present a synthesis of data from seven different space missions of a fast CME, which originated in an active region near the disk centre and, hence, a significant geomagnetic impact was forecasted. However, the CME is demonstrated to be channelled during eruption into a direction +37+/-10 degrees (longitude) away from its source region, leading only to minimal geomagnetic effects. In situ observations near Earth and Mars confirm the channelled CME motion, and are consistent with an ellipse shape of the CME-driven shock provided by the new Ellipse Evolution model, presented here. The results enhance our understanding of CME propagation and shape, which can help to improve space weather forecasts. PMID- 26011033 TI - Importance of surveillance and risk factor evaluation in patients with multiple curable malignancies. PMID- 26011035 TI - Emotional dysfunctions in neurodegenerative diseases. AB - Neurodegenerative diseases are characterized primarily by motor signs but are also accompanied by emotional disturbances. Because of the limited knowledge about these dysfunctions, this Review provides an overview of emotional competencies in Huntington's disease (HD), Parkinson's disease (PD), and multiple sclerosis (MS), with a focus on emotion recognition, emotion regulation, and depression. Most studies indicate facial emotion recognition deficits in HD and PD, whereas data for MS are inconsistent. On a neural level, dysfunctions of amygdala and striatum, among others, have been linked to these impairments. These dysfunctions also tap brain regions that are part of the emotion regulation network, suggesting problems in this competency, too. Research points to dysfunctional emotion regulation in MS, whereas findings for PD and HD are missing. The high prevalence of depression in all three disorders emphasizes the need for effective therapies. Research on emotional disturbances might improve treatment, thereby increasing patients' and caregivers' well-being. PMID- 26011034 TI - Clinic Network Collaboration and Patient Tracing to Maximize Retention in HIV Care. AB - BACKGROUND: Understanding retention and loss to follow up in HIV care, in particular the number of people with unknown outcomes, is critical to maximise the benefits of antiretroviral therapy. Individual-level data are not available for these outcomes in Australia, which has an HIV epidemic predominantly focused amongst men who have sex with men. METHODS AND FINDINGS: A network of the 6 main HIV clinical care sites was established in the state of Victoria, Australia. Individuals who had accessed care at these sites between February 2011 and June 2013 as assessed by HIV viral load testing but not accessed care between June 2013 and February 2014 were considered individuals with potentially unknown outcomes. For this group an intervention combining cross-referencing of clinical data between sites and phone tracing individuals with unknown outcomes was performed. 4966 people were in care in the network and before the intervention estimates of retention ranged from 85.9%-95.8% and the proportion with unknown outcomes ranged from 1.3-5.5%. After the intervention retention increased to 91.4 98.8% and unknown outcomes decreased to 0.1-2.4% (p<.01 for all sites for both outcomes). Most common reasons for disengagement from care were being too busy to attend or feeling well. For those with unknown outcomes prior to the intervention documented active psychiatric illness at last visit was associated with not re entering care (p = 0.04). CONCLUSIONS: The network demonstrated low numbers of people with unknown outcomes and high levels of retention in care. Increased levels of retention in care and reductions in unknown outcomes identified after the intervention largely reflected confirmation of clinic transfers while a smaller number were successfully re-engaged in care. Factors associated with disengagement from care were identified. Systems to monitor patient retention, care transfer and minimize disengagement will maximise individual and population level outcomes for populations with HIV. PMID- 26011036 TI - Structural studies of a thermophilic esterase from a new Planctomycetes species, Thermogutta terrifontis. AB - Thermogutta terrifontis esterase (TtEst), a carboxyl esterase identified in the novel thermophilic bacterium T. terrifontis from the phylum Planctomycetes, has been cloned and over-expressed in Escherichia coli. The enzyme has been characterized biochemically and shown to have activity towards small p nitrophenyl (pNP) carboxylic esters, with optimal activity for pNP-propionate. The enzyme retained 95% activity after incubation for 1 h at 80 degrees C. The crystal structures of the native TtEst and its complexes with the substrate analogue D-malate and the product acetate have been determined to high resolution. The bound ligands have allowed the identification of the carboxyl and alcohol binding pockets in the enzyme active site. Comparison of TtEst with structurally related enzymes provides insight into how differences in their catalytic activity can be rationalized based upon the properties of the amino acid residues in their active site pockets. The mutant enzymes L37A and L251A have been constructed to extend the substrate range of TtEst towards the larger butyrate and valerate pNP-esters. These mutant enzymes have also shown a significant increase in activity towards acetate and propionate pNP esters. A crystal structure of the L37A mutant was determined with the butyrate product bound in the carboxyl pocket of the active site. The mutant structure shows an expansion of the pocket that binds the substrate carboxyl group, which is consistent with the observed increase in activity towards pNP-butyrate. PMID- 26011037 TI - Surgical margins and primary site resection in achieving local control in oral cancer resections. AB - OBJECTIVES/HYPOTHESIS: Evaluate effectiveness of resection of oral cavity cancer with a standardized approach for margin evaluation. Primary end points were local control and survival. STUDY DESIGN: Retrospective, nonrandomized, single institution. METHODS: One hundred eight patients who underwent surgery for oral cancer were evaluated using specific anatomical pathology criteria. Frozen section was performed with the surgeon and pathologist agreeing where on the specimen the frozen sections should be taken in most cases. RESULTS: Ninety-one patients (84.3%) had frozen sections taken from the specimen, eight from the tumor bed, and nine had none taken at the time of surgery. Overall local recurrence rate was 18.5%, 25% in patients who had margins taken from the tumor bed and 17.6% when taken from the specimen. Twenty-nine patients had margins >=5 mm, 53 <5 mm and clear, and 14 positive re-resected to negative with local recurrence rates of 3.4%, 26.4%, and 28.6%, respectively. The radial distance of the resection margin was shown to have an impact on overall survival (hazard ratio [HR] = 3.59, 95% confidence interval [CI] = 1.12-11.57), disease-free survival (HR = 7.00, 95% CI = 1.89-25.95), and local recurrence-free survival (HR = 28.80, 95% CI = 3.00-276.82). CONCLUSIONS: Assessing margins from the resection specimen rather than the tumor bed consistently predicts local control. There is a statistical improvement in local control, disease-free, and overall survival with increasing radial margin distance from the tumor, and 5 mm should be agreed upon as the definition of a clear resection margin. Frozen sections can be used to revise positive or close resection margins intraoperatively with improved outcomes. LEVEL OF EVIDENCE: 4. PMID- 26011038 TI - Training specialists in oral medicine. PMID- 26011040 TI - Interrogations, confessions, and adolescent offenders' perceptions of the legal system. AB - The potential consequences of interrogations and false confessions have been discussed primarily in terms of the risk for wrongful conviction, especially among adolescents and other vulnerable populations. However, it is possible that such experiences influence adolescents' perceptions of the legal system more generally. In the present study, we examined whether incarcerated male juvenile offenders' (n = 193) perceptions of police and the courts were related to their confession and interrogation experiences. High-pressure interrogation experiences and self-reported false confessions to police were associated with more negative perceptions of police. However, self-reported true confessions were not significantly associated with youths' perceptions of the police. Neither interrogation nor confession experiences (true or false) were related to youths' perceptions of the courts. Results provide additional support for policy reform of interrogation practices with young suspects. A more developmentally appropriate approach to criminal interrogations with youth may simultaneously improve police-youth relations and protect vulnerable suspects in the interrogation room. PMID- 26011039 TI - Coronary artery calcification, epicardial fat burden, and cardiovascular events in chronic obstructive pulmonary disease. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) suffer from significantly more cardiovascular comorbidity and mortality than would be anticipated from conventional risk factors. The aim of this study was to determine whether COPD patients have a higher coronary artery calcium score (CACS) and epicardial fat burden, compared to control subjects, and their association with cardiovascular events. METHODS: From a registry of 1906 patients 81 patients with clinically diagnosed COPD were one-to-one matched to 81 non-COPD control subjects with a smoking history, according to their age, sex, and the number of classic cardiovascular risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, family history of premature coronary artery disease). CACS, epicardial fat, and subsequent major adverse cardiovascular events (MACE) during follow-up were compared between groups. RESULTS: Patients with COPD (Global Initiative for Chronic Obstructive Lung Disease-classification I: 5%, II: 23%, III: 16% and IV: 56%) showed no difference in CACS (median difference 68 Agatston Units [95% confidence interval -176.5 to 192.5], p=0.899) or epicardial fat volume (mean difference -0.5 cm3 [95% confidence interval -20.9 to 21.9], p=0.961) compared with controls. After a median follow-up of 42.6 months a higher incidence of MACE was observed in COPD patients (RR=2.80, p=0.016) compared with controls. Cox proportional hazard regression identified cardiac ischemias and CACS as independent predictors for MACE. CONCLUSION: COPD patients experienced a higher MACE incidence compared to controls despite no baseline differences in coronary calcification and epicardial fat burden. Other mechanisms such as undersupply of medication seem to account for an excess cardiovascular comorbidity in COPD patients. PMID- 26011041 TI - Remorse, psychopathology, and psychopathy among adolescent offenders. AB - Remorse has long been important to the juvenile justice system. However, the nature of this construct has not yet been clearly articulated, and little research has examined its relationships with other theoretically and forensically relevant variables. The present study was intended to address these issues by examining relationships among remorse, psychopathology, and psychopathy in a sample of adolescent offenders (N = 97) using the theoretically and empirically established framework of guilt and shame (Tangney & Dearing, 2002). Findings indicated that shame was positively related to behavioral features of psychopathy, whereas guilt was negatively related to psychopathic characteristics more broadly. In addition, shame was positively associated with numerous mental health problems whereas guilt was negatively associated with anger, depression, and anxiety. These results provide empirical support for theory that psychopathy is characterized by lack of remorse (e.g., Hare, 1991), and also underscore shame and guilt as potentially important treatment targets for adolescent offenders. PMID- 26011042 TI - Comparison of minimalist footwear strategies for simulating barefoot running: a randomized crossover study. AB - Possible benefits of barefoot running have been widely discussed in recent years. Uncertainty exists about which footwear strategy adequately simulates barefoot running kinematics. The objective of this study was to investigate the effects of athletic footwear with different minimalist strategies on running kinematics. Thirty-five distance runners (22 males, 13 females, 27.9 +/- 6.2 years, 179.2 +/- 8.4 cm, 73.4 +/- 12.1 kg, 24.9 +/- 10.9 km x week(-1)) performed a treadmill protocol at three running velocities (2.22, 2.78 and 3.33 m x s(-1)) using four footwear conditions: barefoot, uncushioned minimalist shoes, cushioned minimalist shoes, and standard running shoes. 3D kinematic analysis was performed to determine ankle and knee angles at initial foot-ground contact, rate of rear-foot strikes, stride frequency and step length. Ankle angle at foot strike, step length and stride frequency were significantly influenced by footwear conditions (p<0.001) at all running velocities. Posthoc pairwise comparisons showed significant differences (p<0.001) between running barefoot and all shod situations as well as between the uncushioned minimalistic shoe and both cushioned shoe conditions. The rate of rear-foot strikes was lowest during barefoot running (58.6% at 3.33 m x s(-1)), followed by running with uncushioned minimalist shoes (62.9%), cushioned minimalist (88.6%) and standard shoes (94.3%). Aside from showing the influence of shod conditions on running kinematics, this study helps to elucidate differences between footwear marked as minimalist shoes and their ability to mimic barefoot running adequately. These findings have implications on the use of footwear applied in future research debating the topic of barefoot or minimalist shoe running. PMID- 26011044 TI - The Future of Research in Myasthenia. PMID- 26011043 TI - Clinical characteristics and molecular epidemiology of noroviruses in outpatient children with acute gastroenteritis in Huzhou of China. AB - BACKGROUND: Noroviruses (NoVs) are considered major causative pathogens associated with the morbidity and mortality of young children with acute gastroenteritis. However, few studies have examined NoVs causing acute diarrhea among outpatient children worldwide. This study was conducted to investigate the clinical features and molecular epidemiology of NoVs in outpatient children with acute gastroenteritis in Huzhou, China, between April 2013 and April 2014. METHODS: Stool specimens from 1346 outpatient children enrolled (under 5 years of age) with acute gastroenteritis were examined for NoVs by multiplex RT-PCR, and sequences of the partial capsids of NoVs were analyzed phylogenetically, while the relevant clinical data were analyzed statistically. RESULTS: Of 1346 specimens, 383 (28.5%, 383/1346) were positive for NoVs. The proportion of GII genotypes (26.9%) was significantly higher than that of GI genotypes (1.6%). The GII.4 genotype was the most prevalent of GII genotypes and was clustered into GII.4/Sydney (37.8%) and GII.4/2006b (62.2%), whereas GI strains were clustered into GI.1. Additionally, the younger children (12 to <24 months of age) were more susceptible to NoVs than children in other age groups, and the highest percentage of NoV infections occurred in April 2013. The diarrheal frequency (times/d) and WBC counts of the infected outpatient group with NoVs were significantly higher than were those of the uninfected outpatient group. CONCLUSION: NoVs were confirmed to be the major viral agents responsible for acute gastroenteritis in outpatient children in Huzhou, China, and GII.4/Sydney and GII.4/2006b variants were identified as the predominant strains in this study. PMID- 26011045 TI - Mortality in People with Intellectual Disabilities. AB - This paper reviews why an understanding of mortality data in general, and in relation to people with intellectual disabilities in particular, is an important area of concern, and introduces the papers in this Special Edition. PMID- 26011046 TI - Addendum: Brousse, G.; et al. Alcohol risk reduction in France: a modernised approach related to alcohol misuse disorders. Int. J. Environ. Res. Public health 2014, 11, 11664-11675. AB - The author would like to update "Conflicts of Interest" section of their previous publication [1] as follows: Conflicts of Interest Georges Brousse has received sponsorship to attend scientific meetings, speaker honoraria, and consultancy fees from Lundbeck and Merck-Lipha. Patrick Bendimerad received honoraria and travel reimbursements for conferences and consultancy by Lundbeck Laboratory and participated as a coinvestigator.in the multicenter investigational drug studies of Lundbeck. [...]. PMID- 26011047 TI - Cough during infancy and subsequent childhood asthma. AB - OBJECTIVES: Wheezing in infancy has been associated with subsequent asthma, but whether cough similarly influences asthma risk has been little studied. We sought to determine whether prolonged cough and cough without cold in the first year of life are associated with childhood asthma. METHODS: Participants in the Infant Immune Study, a non-selected birth cohort, were surveyed 7 times in the first 9 months of life regarding the presence of wheeze and cough. Cough for more than 28 days was defined as prolonged. Parents were asked at 1 year if the child ever coughed without a cold. Asthma was defined as parental report of physician diagnosis of asthma, with symptoms or medication use between 2 and 9 years. Logistic regression was used to assess adjusted odds for asthma associated with cough characteristics. RESULTS: A total of 24% (97) of children experienced prolonged cough and 23% (95) cough without cold in the first 9 months, respectively. Prolonged cough was associated with increased risk of asthma relative to brief cough (OR 3.57, CI: 1.88, 6.76), with the risk being particularly high among children of asthmatic mothers. Cough without cold (OR 3.13, 95% CI: 1.76, 5.57) was also independently associated with risk of childhood asthma. Both relations persisted after adjustment for wheeze and total IgE at age 1. CONCLUSIONS AND CLINICAL RELEVANCE: Prolonged cough in infancy and cough without cold are associated with childhood asthma, independent of infant wheeze. These findings suggest that characteristics of cough in infancy are early markers of asthma susceptibility, particularly among children with maternal asthma. PMID- 26011048 TI - Community Cleavages: Gay and Bisexual Men's Perceptions of Gay and Mainstream Community Acceptance in the Post-AIDS, Post-Rights Era. AB - Changes in gay and bisexual men's connectedness to the gay community are related to the declining public visibility of HIV/AIDS and greater acceptance for homosexuality and bisexuality in mainstream society. Little work, however, has focused on perceived acceptance for subgroups within the gay community or broader society. Using interviews (n = 20) and a survey (n = 202) of gay and bisexual men in a mid-sized Canadian city, we find perceived hierarchies of acceptance for the various subgroups as well as an age effect wherein middle-aged men perceive the least acceptance for all groups. These differences are linked with the uneven impact of social, political, and institutional changes relevant to gay and bisexual men in Canada. PMID- 26011049 TI - Simple method for the synthesis of inverse patchy colloids. AB - Inverse patchy colloids (IPC's) have recently been introduced as a conceptually simple model to study the phase-behavior of heterogeneously charged units. This class of patchy particles is referred to as inverse to highlight that the patches repel each other in contrast to the attractive interactions of conventional patches. IPCs demonstrate a complex interplay between attractions and repulsions that depend on their patch size and charge, their relative orientations as well as on charge of the substrate below; the resulting wide array of different types of aggregates that can be formed motivates their fabrication and use as model system. We present a novel method that does not rely on clean-room facilities and that is easily scalable to modify the surface of colloidal particles to create two polar regions with the opposite charge with respect to that of the equatorial region. The patch size is characterized by electron microscopy and fluorescently labeled to facilitate using confocal microscopy to study their phase behavior. We show that the pH can be used to tune the charges of the IPCs thus offering a tool to steer the self assembly. PMID- 26011050 TI - Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study. AB - AIM: We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODS: A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (DeltaDeltaQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of DeltaDeltaQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in DeltaDeltaQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. RESULTS: There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 +/- 0.6 vs. 2.98 +/- 0.7 ug ml(-1) ), DeltaDeltaQTc F (9.63 +/- 1.15 vs. 11.46 +/- 1.19 ms at Cmax of 3.07 ug ml(-1) ) and concentration-response slopes (2.58 +/- 0.62 vs. 2.34 +/- 0.64 ms per ug ml(-1) ). The difference in the two DeltaDeltaQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. CONCLUSIONS: Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study. PMID- 26011052 TI - Application of composite small calibration objects in traffic accident scene photogrammetry. AB - In order to address the difficulty of arranging large calibration objects and the low measurement accuracy of small calibration objects in traffic accident scene photogrammetry, a photogrammetric method based on a composite of small calibration objects is proposed. Several small calibration objects are placed around the traffic accident scene, and the coordinate system of the composite calibration object is given based on one of them. By maintaining the relative position and coplanar relationship of the small calibration objects, the local coordinate system of each small calibration object is transformed into the coordinate system of the composite calibration object. The two-dimensional direct linear transformation method is improved based on minimizing the reprojection error of the calibration points of all objects. A rectified image is obtained using the nonlinear optimization method. The increased accuracy of traffic accident scene photogrammetry using a composite small calibration object is demonstrated through the analysis of field experiments and case studies. PMID- 26011051 TI - Barriers to and facilitators of compliance with clinic-based cervical cancer screening: population-based cohort study of women aged 23-60 years. AB - OBJECTIVE: This study aims to identify possible barriers to and facilitators of cervical cancer screening by (a) estimating time and travel costs and other direct non-medical costs incurred in attending clinic-based cervical cancer screening, (b) investigating screening compliance and reasons for noncompliance, (c) determining women's knowledge of human papillomavirus (HPV), its relationship to cervical cancer, and HPV and cervical cancer prevention, and (d) investigating correlates of HPV knowledge and screening compliance. MATERIALS AND METHODS: 1510 women attending the clinic-based cervical cancer screening program in Stockholm, Sweden were included. Data on sociodemographic characteristics, time and travel costs and other direct non-medical costs incurred in attending (e.g., indirect cost of time needed for the screening visit, transportation costs, child care costs, etc.), mode(s) of travel, time, distance, companion's attendance, HPV knowledge, and screening compliance were obtained via self-administered questionnaire. RESULTS: Few respondents had low socioeconomic status. Mean total time and travel costs and direct non-medical cost per attendance, including companion (if any) were ?55.6. Over half (53%) of the respondents took time off work to attend screening (mean time 147 minutes). A large portion (44%) of the respondents were noncompliant (i.e., did not attend screening within 1 year of the initial invitation), 51% of whom stated difficulties in taking time off work. 64% of all respondents knew that HPV vaccination was available; only 34% knew it was important to continue to attend screening following vaccination. Age, education, and income were the most important correlates of HPV knowledge and compliance; and additional factors associated with compliance were time off work, accompanying companion and HPV knowledge. CONCLUSION: Time and travel costs and other direct non-medical costs for clinic-based screening can be considerable, may affect the cost-effectiveness of a screening program, and may constitute barriers to screening while HPV knowledge may facilitate compliance with screening. PMID- 26011053 TI - Ambulatory Blood Pressure Measurement Provides True and Prognostic Information on Blood Pressure Variability in Hypertensive Patients. PMID- 26011054 TI - Development, psychometric properties and preliminary clinical validation of a brief, session-by-session measure of eating disorder cognitions and behaviors: The ED-15. AB - OBJECTIVE: In the treatment research literature on other psychological disorders, there is a move towards session-by-session symptom measurement. The necessary measures need to be brief, focused on core features since the last session, and readily available to clinicians. There is no measure in the eating disorders that meets those criteria. This research reports the development and validation of such a self-report questionnaire. METHOD: The authors generated and refined a brief set of attitudinal and behavioral items. The resulting questionnaire (the ED-15) and an existing measure (Eating Disorders Examination-Questionnaire; EDE Q) were completed by a large nonclinical adult sample (N = 531), a group of self reported eating disorder sufferers (N = 63), and a group of women (N = 33) diagnosed with bulimia nervosa or atypical bulimia nervosa and undertaking cognitive-behavioral therapy. RESULTS: Factor analysis identified two scales (Weight and Shape Concerns; Eating Concerns), with strong internal consistency and test-retest reliability. Correlations with the EDE-Q (r = 0.889) indicates that the ED-15 and EDE-Q measure near-identical constructs. The ED-15 differentiated self-reported eating-disordered and nonclinical groups to the same degree as the longer EDE-Q. Session-by-session analysis of the CBT treatment group demonstrated that the different ED-15 scales changed in different patterns across therapy. DISCUSSION: The ED-15 is not proposed as an alternative to existing measures, but as a complementary tool, used to measure session-by session change for clinical and research purposes. Future research will track changes in ED-15 scores across therapy, to determine the importance of very early response to therapy and sudden changes. PMID- 26011055 TI - Extracorporeal photo-immunotherapy for circulating tumor cells. AB - It is well established that metastasis through the circulatory system is primarily caused by circulating tumor cells (CTCs). In this preliminary effort, we report an approach to eliminate circulating tumor cells from the blood stream by flowing the blood though an extracorporeal tube and applying photodynamic therapy (PDT). Chlorin e6 (Ce6), a photosensitizer, was conjugated to CD44 antibody in order to target PC-3, a prostate cancer cell line. PC-3 cells were successfully stained by the Ce6-CD44 antibody conjugate. PDT was performed on whole blood spiked with stained PC-3 cells. As the blood circulated through a thin transparent medical tube, it was exposed to light of 660 nm wavelength generated by an LED array. An exposure of two minutes was sufficient to achieve selective cancer cell necrosis. In comparison, to PDT of cells growing inside a tissue culture, the PDT on thin tube exhibited significantly enhanced efficiency in cell killing, by minimizing light attenuation by blood. It suggests a new extracorporeal methodology of PDT for treating CTCs as well as other hematological pathogens. PMID- 26011057 TI - Statistical Modeling of Occupational Exposure to Polycyclic Aromatic Hydrocarbons Using OSHA Data. AB - Polycyclic aromatic hydrocarbons (PAHs) are a group of pollutants with multiple variants classified as carcinogenic. The Occupational Safety and Health Administration (OSHA) provided access to two PAH exposure databanks of United States workplace compliance testing data collected between 1979 and 2010. Mixed effects logistic models were used to predict the exceedance fraction (EF), i.e., the probability of exceeding OSHA's Permissible Exposure Limit (PEL = 0.2 mg/m3) for PAHs based on industry and occupation. Measurements of coal tar pitch volatiles were used as a surrogate for PAHs. Time, databank, occupation, and industry were included as fixed-effects while an identifier for the compliance inspection number was included as a random effect. Analyses involved 2,509 full shift personal measurements. Results showed that the majority of industries had an estimated EF < 0.5, although several industries, including Standardized Industry Classification codes 1623 (Water, Sewer, Pipeline, and Communication and Powerline Construction), 1711 (Plumbing, Heating, and Air-Conditioning), 2824 (Manmade Organic Fibres), 3496 (Misc. Fabricated Wire products), and 5812 (Eating Places), and Major group's 13 (Oil and Gas Extraction) and 30 (Rubber and Miscellaneous Plastic Products), were estimated to have more than an 80% likelihood of exceeding the PEL. There was an inverse temporal trend of exceeding the PEL, with lower risk in most recent years, albeit not statistically significant. Similar results were shown when incorporating occupation, but varied depending on the occupation as the majority of industries predicted at the administrative level, e.g., managers, had an estimated EF < 0.5 while at the minimally skilled/laborer level there was a substantial increase in the estimated EF. These statistical models allow the prediction of PAH exposure risk through individual occupational histories and will be used to create a job-exposure matrix for use in a population-based case-control study exploring PAH exposure and breast cancer risk. PMID- 26011056 TI - Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number. AB - Childhood lead (Pb2+) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb2+ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb2+ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb2+ neurotoxicity, we show that Pb2+ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb2+ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development. PMID- 26011059 TI - Correction: hypoxia-ischemia and therapeutic hypothermia in the neonatal mouse brain-a longitudinal study. PMID- 26011058 TI - Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently. AB - Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0->infinity decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0->infinity in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0->infinity remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0->infinity ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6 fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences. PMID- 26011060 TI - Novel use of immunohistochemistry for phenotypic evaluation of circulating neoplastic lymphocyte populations. AB - CASE HISTORY: A 5-year-old male neutered Poodle cross presented with a 2-week history of non-specific gastrointestinal signs including vomiting, inappetence and lethargy (Case 1). A 14-year-old male neutered Staffordshire Bull Terrier presented with a 6-week history of progressive inappetence and lethargy (Case 2). CLINICAL FINDINGS: On presentation, Case 1 was dehydrated and had repeatable cranial abdominal pain. Mild hypoproteinemia with hypoalbuminemia, and electrolyte disturbances were found on biochemistry profile. Abdominal ultrasonography showed moderate diffuse small intestinal wall irregularity and moderate local lymphadenopathy. Haematology was repeated 2 days after initial presentation and showed a marked leucocytosis associated with an elevated circulating neoplastic cell population. On presentation, Case 2 was dehydrated, had palpable hepatomegaly and a mild generalised lymphadenopathy. A low number of large, atypical lymphocytes were found on haematology. Sonographically there was hepatomegaly with diffuse parenchymal changes and severe mesenteric lymphadenopathy. LABORATORY FINDINGS: Aspirates from the abdominal lymph nodes (Cases 1 and 2) and liver (Case 2), and blood smears revealed atypical neoplastic lymphoid populations, predominantly comprising large lymphocytes. Immunocytochemistry failed to determine the lymphoid phenotype in Case 1 but supported a T cell phenotype in Case 2. Immunohistochemistry of formalin-fixed paraffin-embedded (FF-PE) blood clots was able to identify a T cell phenotype in both cases. PCR for antigen receptor rearrangement results from both cases were consistent with an expanded T cell population. DIAGNOSIS: In both cases, immunohistochemistry on FF-PE blood clots revealed a circulating T cell lymphocyte population, consistent with T cell lymphoproliferative neoplasia. CLINICAL RELEVANCE: Immunohistochemistry on FF-PE blood clots offers clinicians a reliable, inexpensive and minimally invasive method of phenotyping neoplastic cells in circulation. Compared to other available methods, prolonged sample stability allowing for transport and retrospective examination is a distinct advantage. This technique should be considered a useful adjunct to the currently available methods for the phenotypic evaluation of lymphoid leukaemia in dogs. PMID- 26011061 TI - Prevalence of abdominal aortic calcifications in older living renal donors and its effect on graft function and histology. AB - We assessed the prevalence of abdominal aortic calcification (AAC) in older living kidney donors and its effect on recipient eGFR and graft histology. A total of 292 consecutive living pairs with donor age >=50 from 2003 to 2013 were identified (mean age 56; range 50-78; F/M: 1.8). Donor AAC was determined by prenephrectomy unenhanced CT. Recipient eGFR and spot urine protein: creatinine ratios (UPCRs) were recorded. A total of 180 recipients had 6-month protocol biopsies. AAC was present in 40.7% of donors, and they were older (58.6 versus 54.7 years old, P < 0.0001) and more likely to be male (77.6% vs. 37.3%, P = 0.004). There was no significant difference in eGFR or spot UPCR up to 36 months in recipients of allografts from donors with versus without AAC. At 6-month biopsy, there was a higher percentage of allografts with vascular fibrous intimal thickening and arteriolar hyaline thickening from donors with versus without AAC (vascular fibrous intimal thickening: 38.8% vs. 7.1% and arteriolar hyaline thickening: 35.8% vs. 7.1%; P < 0.001 for both). The presence of donor AAC predicts the presence of vascular disease [vascular fibrous intimal thickening (OR: 7.2; CI:2.9-17.9) and arteriolar hyaline thickening (OR:5.7; CI:2.3-14.1)] in allografts at 6 months. Donor AAC is predictive of renal vascular disease and may help to improve the screening of potential donors and inform post-transplant management. PMID- 26011063 TI - Effect of small interfering RNA against Paracin 1.7 bacteriocin produced by Lactobacillus paracasei HD1-7. AB - Lactobacillus paracasei HD1-7 (CCTCCM 205015), isolated from Chinese sauerkraut fermentation broth, contains the bacteriocin Paracin 1.7 which possesses broad spectrum antibacterial activity. The gene-silencing effect of small interfering RNA (siRNA) is a potential strategy for further understanding the mechanism of production of Paracin 1.7 by L. paracasei HD1-7. In this study, the effect of siRNA on the expression of the most important proteins in the production of Paracin 1.7, sensor kinase (prcK) and response regulator (prcR), was investigated. SiRNA were designed against prcK and prcR, and qRT-PCR was performed to examine the expression of prcK and prcR mRNA. The efficacy of siRNA was determined by comparing the level of antimicrobial activity of the strains. qRT-PCR showed that siRNA-K4 and siRNA-K5 significantly inhibited the expression of prcK mRNA, and siRNA-R4 and siRNA-R6 significantly inhibited the expression of prcR mRNA. The proteins levels and antibacterial activities of mutant strains were lower than the original and control groups, respectively. The results demonstrate that siRNA inhibited both mRNA expression and the production of Paracin 1.7 in L. paracasei HD1-7. Targeting of prcK and prcR with siRNA appears to be a novel strategy for researching the mechanism of Paracin 1.7 production by L. paracasei HD1-7. PMID- 26011062 TI - A binational registry of adults with pulmonary arterial hypertension complicating congenital heart disease. AB - BACKGROUND: The management of children with congenital heart disease (CHD) has improved over recent decades and several patients surviving with CHD into adulthood are increasing. In developed countries, there are now as many adults as there are children living with CHD. Pulmonary arterial hypertension (PAH) occurs in ~ 5% of patients with CHD. AIM: We aimed to understand the characteristics and outcomes of this emerging population. METHODS: We collected data retrospectively and prospectively from 12 contributing centres across Australia and New Zealand (2010-2013). Patients were included if they had been diagnosed with PAH and CHD and had been seen once in an adult centre after 1 January 2000. RESULTS: Of 360 patients with CHD-PAH, 60% were female and 90% were New York Heart Association functional class II or III at the time of adult diagnosis of PAH. Mean age at diagnosis of PAH in adulthood was 31.2 +/- 14 years, and on average, patients were diagnosed with PAH 6 years after symptom onset. All-cause mortality was 12% at 5 years, 21% at 10 years and 31% at 15 years. One hundred and six patients (30%) experienced 247 hospitalisations during 2936 patient years of follow up. Eighty-nine per cent of patients were prescribed PAH specific therapy (mean exposure of 4.0 years). CONCLUSIONS: Adults with PAH and CHD often have this diagnosis made after significant delay, and have substantial medium-term morbidity and mortality. This suggests a need for children transitioning to adult care with CHD to be closely monitored for this complication. PMID- 26011064 TI - Metal and Metal Carbide Nanoparticle Synthesis Using Electrical Explosion of Wires Coupled with Epoxide Polymerization Capping. AB - In this study, metal-containing nanoparticles (NPs) were produced using electrical explosion of wires (EEW) in organic solvents. The explosion chamber was constructed from Teflon to withstand the shockwave, allow growth and reaction of the incipient NPs in various organic solvents containing dissolved ligands, and allow a constant flow of argon to maintain an inert environment. A survey of different transition d-block metals was conducted with metals from groups 4-8, affording metal carbide NPs, while metals from groups 9-12 gave elemental metallic NPs. Tungsten carbide phase WC1-x, which has not been previously isolated as a single-phase material, was exclusively formed during EEW. We used polymerization initiation by electron-rich metallic nanoparticles (PIERMEN) as a capping technique for the nascent NPs with an alkyl epoxide employed as the monomers. Transmission electron microscopy showed spherical particles with the metallic core embedded in a polymer matrix with predominantly smaller particles (<50 nm), but also a broad size distribution with some larger particles (>100 nm). Powder X-ray diffraction (PXRD) was used to confirm the identity of the metallic NPs. The capping agents were characterized using ATR-FTIR spectroscopy. No evidence is observed for the formation of crystalline oxides during EEW for any metals used. Differential scanning calorimetry/thermal gravimetric analysis was used to study the NP's behavior upon heating under an air flow up to 800 degrees C with the product oxides characterized by PXRD. The bifurcation between metal-carbide NPs and metal NPs correlates with the enthalpy of formation of the product carbides. We observed PIERMEN capping of elemental metal NPs only when the metal has negative standard electrode potentials (relative to a bis(biphenyl) chromium(I)/(0) reference electrode). PMID- 26011067 TI - Targeted next-generation sequencing in Uyghur families with non-syndromic sensorineural hearing loss. AB - The mutation spectrum of deafness genes may vary in different ethnical groups. In this study, we investigated the genetic etiology of nonsyndromic deafness in four consanguineous and two multiplex Uyghur families in which mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1 were excluded. Targeted next-generation sequencing of 97 deafness genes was performed in the probands of each family. Novel pathogenic mutations were identified in four probands including the p.L416R/p.A438T compound heterozygous mutations in TMC1, the homozygous p.V1880E mutation in MYO7A, c.1238delT frameshifting deletion in PCDH15 and c.9690+1G>A splice site mutation in MYO15A. Co-segregation of the mutations and the deafness were confirmed within each family by Sanger sequencing. No pathogenic mutations were identified in one multiplex family and one consanguineous family. Our study provided a useful piece of information for the genetic etiology of deafness in Uyghurs. PMID- 26011068 TI - Non-Hodgkin lymphoma in children with an associated inherited condition: A retrospective analysis of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). AB - BACKGROUND: Inherited conditions affecting genetic aberration, viral oncogenesis, reduced immune surveillance, and long-lasting antigen stimulation may build the way to lymphomagenesis in humans. METHODS: We extracted from the database of 4 consecutive trials for pediatric non-Hodgkin lymphoma (NHL) all cases with an associated genetic disease. RESULTS: Among 1,430 patients, 34 (2.4%) had an associated inherited condition and a mature B-lineage (n = 28), anaplastic large cell lymphoma (n = 4), or T-lineage (n = 2) NHL. Their median age at the diagnosis was 9.3 years (range, 2.6-17.8 years). In 14 cases (41%) the underlying condition was considered to be a potential cause for undue toxicity if the expected therapy was applied. Thus, treatment modification had been planned in advance. The overall survival was 89% (standard error [SE] 1%), 73% (SE 10%), and 73% (SE 23%) at 3 years for registered patients with no inherited condition associated, with genetic abnormalities and with underlying condition causing an immune deficiency, respectively (P = 0.003). CONCLUSION: In our cohort, patients with NHL with an underlying constitutional condition represent the 2.4% of the cases. In the subset of patients with primary immune deficiency, which may have contributed to lymphomagenesis, allogeneic hematopoietic stem cell transplantation may be required. In the remaining patients, the association with lymphoma remains apparently unexplained and could be not causative. Detailed reporting of such cases may contribute to disclose even rare and fully unexpected association, which may have implications for research in the field of lymphomagenesis. PMID- 26011069 TI - The relationship between self-harm and alexithymia. AB - This paper presents a systematic review of the literature concerning the relationship between alexithymia and self-harm. Fifteen studies were selected following a systematic search of relevant databases. Results indicate significantly higher levels of alexithymia in women who self-harm compared with women who do not self-harm. Studies of men were less conclusive and require further investigation. A subsample of the studies found that childhood abuse and bullying were more likely to be associated with self-harm if alexithymia was present as a mediator. Other studies found that depression mediated between alexithymia and self-harm. The results indicate that the poor emotional cognition and expression associated with alexithymia may increase vulnerability to self harm, particularly in women. PMID- 26011070 TI - Comment on "Unexpected occurrence of volatile dimethylsiloxanes in Antarctic soils, vegetation, phytoplankton, and krill". PMID- 26011072 TI - Hydroxyalkylation-initiated radical cyclization of N-allylbenzamide for direct construction of isoquinolinone. AB - A metal-free hydroxyalkylation-initiated radical six-membered heterocycle formation reaction of N-allylbenzamide is developed. This reaction proceeds through C(sp(3))-H bond cleavage, oxyalkylation of the double bond, and intramolecular cyclization, which provides a new route toward 4-substituted 3,4 dihydroisoquinolin-1(2H)-one derivatives. PMID- 26011073 TI - Using Synoptic Systems' Typical Wind Trajectories for the Analysis of Potential Atmospheric Long-Distance Dispersal of Lumpy Skin Disease Virus. AB - Lumpy skin disease virus (LSDV) is an infectious, arthropod-borne virus that affects mostly cattle. Solitary outbreaks have occurred in Israel in 1989 and 2006. In both years, the outbreaks occurred parallel to a severe outbreak in Egypt, and LSDV was hypothesized to be transmitted from Egypt to Israel via long distance dispersal (LDD) of infected vectors by wind. The aim of this study was to identify possible events of such transport. At the first stage, we identified the relevant synoptic systems that allowed wind transport from Egypt to Israel during the 3 months preceding each outbreak. Three-dimensional backwards Lagrangian trajectories were calculated from the receptor sites in Israel for each occurrence of such relevant synoptic system. The analysis revealed several events in which atmospheric connection routes between the affected locations in Egypt and Israel were established. Specifically, during the 1989, Damietta and Port Said stand out as likely sources for the outbreak in Israel. In 2006, different locations acted simultaneously as potential sources of the outbreak in Israel. These locations were situated in the Nile delta, the Suez Canal and in northern Sinai. The analysis pointed out Sharav low and Shallow Cyprus low to the North to be the most likely systems to enable windborne transport from Egypt to Israel. These findings are of high importance for the analysis of the risk of transmission of vectorborne viruses in the eastern Mediterranean region. PMID- 26011071 TI - Sky island diversification meets the multispecies coalescent - divergence in the spruce-fir moss spider (Microhexura montivaga, Araneae, Mygalomorphae) on the highest peaks of southern Appalachia. AB - Microhexura montivaga is a miniature tarantula-like spider endemic to the highest peaks of the southern Appalachian mountains and is known only from six allopatric, highly disjunct montane populations. Because of severe declines in spruce-fir forest in the late 20th century, M. montivaga was formally listed as a US federally endangered species in 1995. Using DNA sequence data from one mitochondrial and seven nuclear genes, patterns of multigenic genetic divergence were assessed for six montane populations. Independent mitochondrial and nuclear discovery analyses reveal obvious genetic fragmentation both within and among montane populations, with five to seven primary genetic lineages recovered. Multispecies coalescent validation analyses [guide tree and unguided Bayesian Phylogenetics and Phylogeography (BPP), Bayes factor delimitation (BFD)] using nuclear-only data congruently recover six or seven distinct lineages; BFD analyses using combined nuclear plus mitochondrial data favour seven or eight lineages. In stark contrast to this clear genetic fragmentation, a survey of secondary sexual features for available males indicates morphological conservatism across montane populations. While it is certainly possible that morphologically cryptic speciation has occurred in this taxon, this system may alternatively represent a case where extreme population genetic structuring (but not speciation) leads to an oversplitting of lineage diversity by multispecies coalescent methods. Our results have clear conservation implications for this federally endangered taxon and illustrate a methodological issue expected to become more common as genomic-scale data sets are gathered for taxa found in naturally fragmented habitats. PMID- 26011074 TI - A novel and simple method for rapid generation of recombinant porcine adenoviral vectors for transgene expression. AB - Many human (different serotypes) and nonhuman adenovirus vectors are being used for gene delivery. However, the current system for isolating recombinant adenoviral vectors is either time-consuming or expensive, especially for the generation of recombinant non-human adenoviral vectors. We herein report a new and simple cloning approach for the rapid generation of a porcine adenovirus (PAdV-3) vector which shows promise for gene transfer to human cells and evasion of human adenovirus type 5 (HAdV-5) immunity. Based on the final cloning plasmid, pFPAV3-CcdB-Cm, and our modified SLiCE strategy (SLiCE cloning and lethal CcdB screening), the process for generating recombinant PAdV-3 plasmids required only one step in 3 days, with a cloning efficiency as high as 620 +/- 49.56 clones/ng and zero background (100% accuracy). The recombinant PAdV-3 plasmids could be successfully rescued in porcine retinal pigment epithelium cells (VR1BL), which constitutively express the HAdV-5 E1 and PAdV-3 E1B 55k genes, and the foreign genes were highly expressed at 24 h after transduction into swine testicle (ST) cells. In conclusion, this strategy for generating recombinant PAdV-3 vectors based on our modified SLiCE cloning system was rapid and cost-efficient, which could be used as universal cloning method for modification the other regions of PAdV-3 genome as well as other adenoviral genomes. PMID- 26011075 TI - Surgical Findings in Transfusion-Associated Necrotizing Enterocolitis. AB - Introduction The extent of intestinal damage in transfusion-associated necrotizing enterocolitis (TNEC) has been scarcely studied. The aim of this investigation was to study surgical findings in TNEC and determine their severity considering the extent of the disease and risk of bowel perforation. Materials and Methods Neonates who required surgical treatment for necrotizing enterocolitis (NEC) were studied retrospectively. Patients who developed NEC within 48 hours after a red blood cell transfusion (RBCT) formed group TR48 and patients who did not receive a RBCT 48 hours before the diagnosis of NEC became group CN (conventional NEC). Both groups were compared: main outcomes were the extent of the disease (isolated, multifocal, or panintestinal), the existence of perforated NEC, and mortality. Categorical variables were analyzed with the chi square test and continuous variables with the Mann-Whitney u-test. The relationship between RBCTs 48 hours before the diagnosis and the extent of intestinal disease was evaluated by ordinal logistic regression. Results Forty seven patients were included in the study: 16 patients in TR48 and 31 in CN. The odds ratio of multifocal or panintestinal NEC for patients in TR48 was 0.5 (95% CI: 0.148-1.68). Neonates in TR48 had a relative risk (RR) of perforated NEC of 1.2 (95% CI: 0.76-1.85). The RR of death was 1.55 (95% CI: 0.76-3.14) in group TR48. Conclusion No differences in surgical findings between TR48 and CN could be demonstrated in this investigation; therefore, the hypothesis that intestinal damage might be more severe in TNEC was not confirmed. PMID- 26011076 TI - Modification of U-Stitch Laparoscopic Gastrostomy Technique to Minimize Suture Knot Abscess Formation. AB - Aim U-stitch laparoscopic gastrostomy is a commonly used technique for placement of balloon gastrostomy for pediatric patients. The U-stitch method was modified by others whereby the stay sutures are placed in a subcutaneous tissue. Although this modification has been reported to be superior, it has led to suture knot abscess formation which was not reported in the original method. We developed further modification whereby the stay-suture knots are positioned within the gastrostomy tract instead of the subcutaneous tissue which minimizes suture knot abscess formation. Methods Modified U-stitch technique was used to place the balloon gastrostomy. The U-stitch stay sutures are placed to hold the stomach to the abdominal wall. These sutures are subcutaneously tunneled toward the gastrostomy tract and tied to the opposing sutures with the resulting knots lying within the tract of the gastrostomy. Chart reviews of patients who underwent this modified U-stitch method were done. Results A total of 27 consecutive patients were evaluated. Minimal follow-up period was 6 months. No suture knot abscess complication was found. One patient for whom we used a polyglactin (Vicryl; Ethicon Inc., Cincinnati, Ohio, United States) suture developed cellulitis around the gastrostomy site which cleared with antibiotic. Remaining 10 patients for whom we used Vicryl suture and 16 patients for whom polydioxanone (PDS; Ethicon Inc.) suture was used did not develop any infections. Conclusion Subcutaneous placement of stay suture within the open gastrostomy tract rather than within closed subcutaneous tissue may minimize suture knot abscess formation. PMID- 26011077 TI - Digital Microfluidic Approach for Efficient Electroporation with High Productivity: Transgene Expression of Microalgae without Cell Wall Removal. AB - A unique digital microfluidic electroporation (EP) system successfully demonstrates higher transgene expression than that of conventional techniques, in addition to reliable productivity and feasible integrated processes. By systematic investigations into the effects of the droplet EP conditions for a wild-type microalgae, 1 order of magnitude higher transgene expression is accomplished without cell wall removal over the conventional bulk EP system. In addition, the newly proposed droplet EP method by a droplet contact charging phenomena shows a great potential for the integration of EP processes and on-chip cell culture providing easy controllability of each process. Finally, the implications of the accomplishments and future directions for development of the proposed technology are discussed. PMID- 26011079 TI - Detection and prediction limits for identifying highly confusable drug names from experimental data. AB - Confusions between drug names that look and sound alike are common, costly, harmful, and difficult to prevent. One prevention strategy is to screen proposed new drug names for confusability before approving them. Widespread acceptance of preapproval tests of confusability is compromised by the lack of experimental designs and statistical methods to support valid inferences about whether a proposed new name is unacceptably confusing. One way of identifying confusing names is to conduct memory and perception experiments on a set of drug names which would include both the new name and a set of control names (e.g., names already on the market). The experiment would yield an observed error rate for every name. Inferences about the acceptability of the new name can be made by comparing the error rate of the new name to the distribution of error rates of the control names. We describe four memory and perception experiments on drug names, carried out using clinicians as participants. Each experiment included drug names designated as test and control names. We demonstrate how to use a combination of logistic regression, Poisson prediction limits, and highly assured credible intervals to identify and apply a threshold for identifying unacceptably confusing names. Our models show an excellent fit to the data. These experimental designs and analytic methods should be useful in the preapproval testing of proposed new drug names and in similar regulatory scenarios where it is necessary to draw inferences about the comparative safety or effectiveness of new vs. old products. PMID- 26011078 TI - Systematic Genome-wide Screening and Prediction of microRNAs in EBOV During the 2014 Ebolavirus Outbreak. AB - Recently, several thousand people have been killed by the Ebolavirus disease (EVD) in West Africa, yet no current antiviral medications and treatments are available. Systematic investigation of ebolavirus whole genomes during the 2014 outbreak may shed light on the underlying mechanisms of EVD development. Here, using the genome-wide screening in ebolavirus genome sequences, we predicted four putative viral microRNA precursors (pre-miRNAs) and seven putative mature microRNAs (miRNAs). Combing bioinformatics analysis and prediction of the potential ebolavirus miRNA target genes, we suggest that two ebolavirus coding possible miRNAs may be silence and down-regulate the target genes NFKBIE and RIPK1, which are the central mediator of the pathways related with host cell defense mechanism. Additionally, the ebolavirus exploits the miRNAs to inhibit the NF-kB and TNF factors to evade the host defense mechanisms that limit replication by killing infected cells, or to conversely trigger apoptosis as a mechanism to increase virus spreading. This is the first study to use the genome wide scanning to predict microRNAs in the 2014 outbreak EVD and then to apply systematic bioinformatics to analyze their target genes. We revealed a potential mechanism of miRNAs in ebolavirus infection and possible therapeutic targets for Ebola viral infection treatment. PMID- 26011080 TI - Uptake and toxicity of methylmethacrylate-based nanoplastic particles in aquatic organisms. AB - The uptake and toxicity of 2 poly(methylmethacrylate)-based plastic nanoparticles (PNPs) with different surface chemistries (medium and hydrophobic) were assessed using aquatic organisms selected for their relevance based on the environmental behavior of the PNPs. Pure poly(methylmethacrylate) (medium; PMMA PNPs) and poly(methylmethacrylate-co-stearylmethacrylate) copolymer (hydrophobic; PMMA-PSMA PNPs) of 86 nm to 125 nm were synthesized using a miniemulsion polymerization method. Fluorescent analogs of each PNP were also synthesized using monomer 7-[4 (trifluoromethyl)coumarin]acrylamide and studied. Daphnia magna, Corophium volutator, and Vibrio fischeri were employed in a series of standard acute ecotoxicity tests, being exposed to the PNPs at 3 different environmentally realistic concentrations (0.01 mg/L, 0.1 mg/L, and 1.0 mg/L) and a high concentration 500 mg/L to 1000 mg/L. In addition, sublethal effects of PNPs in C. volutator were determined using a sediment reburial test, and the uptake and depuration of fluorescent PNPs was studied in D. magna. The PNPs and fluorescent PNPs did not exhibit any observable toxicity at concentrations up to 500 mg/L to 1000 mg/L in any of the tests except for PMMA-PSMA PNPs and fluorescent PNPs following 48-h exposure to D. magna (median lethal concentration values of 879 mg/L and 887 mg/L, respectively). No significant differences were observed between labeled and nonlabeled PNPs, indicating the suitability of using fluorescent labeling. Significant uptake and rapid excretion of the fluorescent PNPs was observed in D. magna. Environ Toxicol Chem 2016;35:1641-1649. (c) 2015 SETAC. PMID- 26011082 TI - Influences of dominance and evolution of sex in finite diploid populations. AB - Most eukaryotes reproduce sexually. Although the benefits of sex in diploids mainly stem from recombination and segregation, the relative effects of recombination and segregation are relatively less known. In this study, we adopt an infinite loci model to illustrate how dominance coefficient of mutations affects the above-mentioned genetic events. However, we assume mutational effects to be independent and also ignore the effects of epistasis within loci. Our simulations show that with different levels of dominance, segregation and recombination may play different roles. In particular, recombination more commonly has a major impact on the evolution of sex when deleterious mutations are partially recessive. In contrast, when deleterious mutations are dominant, segregation becomes more important than recombination, a finding that is consistent with previous studies stating that segregation, rather than recombination, is more likely to drive the evolution of sex. Moreover, beneficial mutations alone remarkably increases the effects of recombination. We also note that populations favor sexual reproduction when deleterious mutations become more dominant or beneficial mutations become more recessive. Overall, these results illustrate that the existence of dominance is an important mechanism that affects the evolution of sex. PMID- 26011081 TI - Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release. AB - The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-beta erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. PMID- 26011083 TI - The Hemodynamic Effects of Hemodialysis Needle Rotation and Orientation in an Idealized Computational Model. AB - Maintaining the patency of vascular access is essential for performing efficient hemodialysis. Appropriate cannulation technique is critical in maintaining the integrity of vascular access. This study focused on analyzing the hemodynamic effect of needle rotation, which is performed to alleviate the pressure if the needle becomes attached to the blood vessel wall. The hemodynamic benefits (normal wall shear stress [WSS] and smooth flow with no oscillatory motion) of this technique are investigated in an idealized model of the cephalic vein in order to determine a needle position that will reduce conditions known to contribute to vascular access failure. A computational fluid dynamics study was conducted, with antegrade and retrograde orientations simulated on the arterial needle, whereas the venous needle is placed in the antegrade orientation. In every case, needle rotation offered no hemodynamic benefit in minimizing the conditions known to cause endothelial damage, a precursor to vascular access failure. Venous needle rotation reduced the maximum WSS by 30%. However, the WSS was above the range, which may damage the endothelial layer. The arterial needle in the antegrade orientation produced a large region of oscillatory shear, whereas a retrograde orientation produced a region of smooth flow in the vicinity of the needle with only a small region of oscillatory shear. The flow through the venous needle back eye was negligible, whereas the arterial needle back eye was more efficient in the retrograde orientation. Therefore, the venous needle should not be rotated, whereas the arterial needle may be rotated to alleviate pressure with consideration given to the orientation of the needle. PMID- 26011084 TI - The cultivable microbiota of primary and secondary infected root canals, their susceptibility to antibiotics and association with the signs and symptoms of infection. AB - AIM: To examine the presence of microbial species in primary and secondary infections and identify the signs and symptoms associated with them. METHODOLOGY: A total number of 37 root canals from 33 patients undergoing root canal treatment were selected. Samples were taken using a sterile paper point following chemomechanical canal instrumentation. Microbiological identification was performed by macromorphological, micromorphological and commercial biochemical tests (ATB system). The antibiotic susceptibility profile of isolated Enterococcus, Streptococcus and Propionibacterium spp. was evaluated. RESULTS: A total number of 54 species were isolated. The most common was E. faecalis followed by Propionibacterium acnes and Streptococcus spp. Five multidrug resistant enterococcal strains were isolated. However, resistance to linezolid or glycopeptides was not found. Radiolucency was observed significantly more often in symptomatic infections (P = 0.0061) caused by Actinomyces spp. than in asymptomatic ones. CONCLUSIONS: Enterococci and streptococci were the most commonly isolated bacteria from root canals. The resistance of enterococci to many antimicrobials may pose a problem in their eradication. PMID- 26011085 TI - Fluoride impairs oocyte maturation and subsequent embryonic development in mice. AB - The damage caused by fluorosis is permanent, and has been recognized as a public health problem in a number of regions of the world. Although multiple studies provided evidence that sodium fluoride (NaF) elicits adverse effects on reproductive function, the effect of fluoride on female germ cell development is not well understood. Therefore, the present study aimed at evaluating the effect of fluoride treatments on in vivo maturation and developmental potential of mouse oocytes, in which female ICR mice were treated with a range of doses (0, 30, 60, and 150 mg/L) of NaF. After treatment, mice were superovulated to collect ovulated oocytes. The effects of NaF on oocyte quality, fertilization potential and early embryonic development were evaluated, as well as the underlying mechanisms were primarily investigated. The findings of this study showed that NaF treatment resulted in abnormal spindle configuration, actin cap formation, and cortical granule-free domain formation. Additionally, overexposure of mice to NaF notably reduced ATP production and mitochondrial membrane potential, further influencing in vitro fertilization and subsequent embryonic development. These results indicated that NaF treatment impairs the subsequent embryonic developmental potential of the oocytes. In conclusion, overexposure to fluoride in vivo was associated with a significant disruption of cytoskeletal dynamics and decreased oocyte quality, affecting the oocyte's subsequent fertilization and embryonic development. Results of this study provide a rationale for treating reproductive diseases such as infertility or miscarriage caused by environmental contaminants. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1486-1495, 2016. PMID- 26011087 TI - Dental root size in bats with diets of different hardness. AB - The relationship between tooth roots and diet is relatively unexplored, although a logical relationship between harder diets and increased root surface area (RSA) is suggested. This study addresses the interaction between tooth morphology, diet, and bite force in small mammals, phyllostomid bats. Using micro computed tomography (microCT), tooth root morphology of two fruit-eating species (Carollia perspicillata and Chiroderma villosum) and two insect-eating species (Mimon bennettii and Macrotus californicus) was compared. These species did not differ in skull or estimated body size. Food hardness, rather than dietary classification, proved to be the strongest grouping factor, with the two insectivores and the seed-processing frugivore (C. villosum) having significantly larger RSAs. Bite force was estimated using skull measurements; bite force significantly correlated with tooth RSA but not with body size. Although the three durophagous species did exhibit larger crowns, the area of the occlusal surface did not vary among the four species. There was a linear relationship between root size and crown size, indicating that the roots were not expanded disproportionately; instead the entire tooth was larger in the hard diet species. MicroCT allows the nondestructive quantification of previously difficult-to access tooth morphology; this method shows the potential for tooth roots to provide valuable dietary, behavioral, and ecological information in small mammals. J. Morphol. 276:1065-1074, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26011086 TI - Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder. AB - Children with autism spectrum disorder (ASD) may present with multiple medical conditions in addition to ASD symptoms. This study investigated whether there are predictive patterns of medical conditions that co-occur with ASD, which could inform medical evaluation and treatment in ASD, as well as potentially identify etiologically meaningful subgroups. Medical history data were queried in the multiplex family Autism Genetic Resource Exchange (AGRE). Fourteen medical conditions were analyzed. Replication in the Simons Simplex Collection (SSC) was attempted using available medical condition data on gastrointestinal disturbances (GID), sleep problems, allergy and epilepsy. In the AGRE cohort, no discrete clusters emerged among 14 medical conditions. GID and seizures were enriched in unaffected family members, and together with sleep problems, were represented in both AGRE and SSC. Further analysis of these medical conditions identified predictive co-occurring patterns in both samples. For a child with ASD, the presence of GID predicts sleep problems and vice versa, with an approximately 2 fold odds ratio in each direction. These risk patterns were replicated in the SSC sample, and in addition, there was increased risk for seizures and sleep problems to co-occur with GID. In these cohorts, seizure alone was not predictive of the other conditions co-occurring, but behavioral impairments were more severe as the number of co-occurring medical symptoms increased. These findings indicate that interdisciplinary clinical care for children with ASD will benefit from evaluation for specific patterns of medical conditions in the affected child and their family members. PMID- 26011088 TI - Impact of care settings on residents' functional and psychosocial status, physical activity and adverse events. AB - BACKGROUND: Internationally, as the number of older adults increases, different types of care settings are evolving to address the care needs of this growing group of individuals. AIMS AND OBJECTIVES: The purpose of this study was to describe and compare clinical outcomes of residents with moderate to severe cognitive impairment living in residential care facilities (RCFs) and nursing homes (NHs). DESIGN: This was a secondary data analysis that included data from two studies testing a Function-Focused Care for Cognitively Impaired (FFC-CI) Intervention. METHODS: A total of 96 participants were from RCFs and 103 were from NHs. Change scores over a 6-month period in RCF and NH residents were evaluated using a multivariate analysis of variance. RESULTS: Residential care facilities residents had more agitation, better function and engaged in approximately twice as much physical activity as those in NH settings at baseline. Controlling for treatment status and baseline differences, over 6 months, RCF residents showed a decrease of -22.77 +/- 41.47 kilocalories used in 24 hours while those in NHs increased to a mean of 10.49 +/- 33.65 kilocalories used. With regard to function, residents in RCFs declined 10.97 +/- 18.35 points on the Barthel Index, while those in NHs increased 10.18 +/- 19.56 points. CONCLUSIONS: In this sample, NH residents were more likely to be African American, had more comorbidities, less cognitive impairment, engaged in less physical activity, were more impaired functionally and had less agitation than those in RCFs. Controlling for treatment group status and baseline differences in comorbidities, cognitive status and race, residents in RCFs declined more in terms of functional and physical activity over a 6-month period. IMPLICATIONS FOR PRACTICE: Ongoing research and clinical work is needed to understand the impact of care settings on clinical outcomes. PMID- 26011089 TI - A myo-inositol-1-phosphate synthase gene, IbMIPS1, enhances salt and drought tolerance and stem nematode resistance in transgenic sweet potato. AB - Myo-inositol-1-phosphate synthase (MIPS) is a key rate limiting enzyme in myo inositol biosynthesis. The MIPS gene has been shown to improve tolerance to abiotic stresses in several plant species. However, its role in resistance to biotic stresses has not been reported. In this study, we found that expression of the sweet potato IbMIPS1 gene was induced by NaCl, polyethylene glycol (PEG), abscisic acid (ABA) and stem nematodes. Its overexpression significantly enhanced stem nematode resistance as well as salt and drought tolerance in transgenic sweet potato under field conditions. Transcriptome and real-time quantitative PCR analyses showed that overexpression of IbMIPS1 up-regulated the genes involved in inositol biosynthesis, phosphatidylinositol (PI) and ABA signalling pathways, stress responses, photosynthesis and ROS-scavenging system under salt, drought and stem nematode stresses. Inositol, inositol-1,4,5-trisphosphate (IP3 ), phosphatidic acid (PA), Ca(2+) , ABA, K(+) , proline and trehalose content was significantly increased, whereas malonaldehyde (MDA), Na(+) and H2 O2 content was significantly decreased in the transgenic plants under salt and drought stresses. After stem nematode infection, the significant increase of inositol, IP3 , PA, Ca(2+) , ABA, callose and lignin content and significant reduction of MDA content were found, and a rapid increase of H2 O2 levels was observed, peaked at 1 to 2 days and thereafter declined in the transgenic plants. This study indicates that the IbMIPS1 gene has the potential to be used to improve the resistance to biotic and abiotic stresses in plants. PMID- 26011090 TI - Cost-utility in medical intensive care patients. Rationalizing ongoing care and timing of discharge from intensive care. AB - RATIONALE: Intensive care unit (ICU) treatment costs pose special challenges in developing countries. OBJECTIVES: To determine the prognostic value of the "utility" score and evaluate the relationship of willingness to pay assessment to utility score during ICU admission. METHODS: We performed a prospective study spanning 12 months in a 24-bed medical ICU in India. Treatment cost was estimated by direct measurement. Global utility score was assessed daily by healthcare providers on a Likert scale (0-1 in increments of 0.1, with 0 indicating death/severe disability and 1 indicating cure/perfect health). The sensitivity, specificity, and likelihood ratios of utility in predicting ICU mortality was calculated. Receiver operating characteristic curves were generated to compare Day 2 utility with APACHE II. The caregiver's willingness to pay for treatment was assessed on alternate days using the bidding method by presenting a cost bid. Based on the response ("yes" or "no"), bids were increased or decreased in a prespecified manner until a final bid value was reached. Simultaneously, treating doctors were asked how much institutional funds they would be willing to spend for treatment. MEASUREMENTS AND MAIN RESULTS: Primary diagnosis in 499 patients included infection (26%) and poisoning (21%). The mean (SD) APACHE II score was 13.9 (5.8); 86% were ventilated. ICU stay was 7.8 (5.5) days. ICU mortality was 23.9% (95% confidence interval, 20.3-27.8). Survival without disability was 8.3% (2/24) for Day 2 utility score <=0.3 and 95.8% (53/56) for Day 5 score >0.8 (P < 0.001). The likelihood ratio to predict mortality increased as utility values decreased and was highest (5.85) for utility 0.2. Area under the receiver operating characteristic curves for utility and APACHE II were similar. Willingness to pay by the caregiver was 53% of treatment cost and was not influenced by utility. Willingness to pay by ICU doctors showed an inverted U shaped relationship with utility. CONCLUSIONS: Utility scores help prognosticate, with Day 2 score <=0.3 associated with poor outcome and >=0.8 Day 5 score with survival. The caregiver's willingness to pay was inadequate to meet treatment cost. ICU doctors were willing to spend more for moderate utility scores than for very high or low utility values. Further prospective studies are needed to optimize the utilization of scarce ICU resources by identifying patients for appropriate step-down care using utility and willingness to pay. PMID- 26011091 TI - Schizophrenia in 2020: Trends in diagnosis and therapy. AB - Schizophrenia research is providing an increasing number of studies and important insights into the condition's etiopathogenesis based on genetic, neuropsychological and cranial neuroimaging studies. However, research progress has not yet led to the incorporation of such findings into the revised classification criteria of mental disorders or everyday clinical practice. By 2020, schizophrenia will most likely still be a clinically defined primary psychotic disorder. While there is some hope that treatment will be improved with new antipsychotic drugs, drugs addressing negative symptoms, more refined psychotherapy approaches and the introduction of new treatment modalities like transcranial magnetic stimulation, an additional hope is to improve early detection and prevention. As the results of new research into the etiopathogenesis of schizophrenia are promising to improve diagnosis, classification and therapy in the future, a picture of complex brain dysfunction is currently emerging requiring sophisticated mathematical methods of analysis. The imminent clinical challenge will be to develop comprehensive diagnostic and treatment modules individually tailored to the time-variable needs of patients and their families. PMID- 26011092 TI - Electron microscopic observation of cholesterotic fibrous histiocytoma of the finger. PMID- 26011093 TI - Caregiving for patients with Alzheimer's disease or dementia and its association with psychiatric and clinical comorbidities and other health outcomes in Brazil. AB - OBJECTIVES: Individuals with dementia due to Alzheimer's disease often receive care from family members who experience associated burden. This study provides the first broad, population-based account of caregiving-related health outcome burden in Brazil. METHODS: Data were analyzed from the 2012 National Health and Wellness Survey in Brazil (n = 12,000), an Internet-based survey of adults (aged 18+ years), using stratified sampling by sex and age to ensure demographic representation of Brazil's adult population. Caregivers of individuals with Alzheimer's disease or dementia were compared with non-caregivers on comorbidities, productivity impairment, health-related quality of life, resource utilization, sociodemographic/health characteristics and behaviors, and Charlson comorbidity index scores. Regression models assessed outcomes associated with caregiving, adjusting for potential confounds. RESULTS: Among 10,853 respondents, caregivers' (n = 209) average age was 42.1 years, 53% were female, and 52% were married/living with a partner. Caregivers versus non-caregivers (n = 10,644) were more frequently obese, smokers, insured, employed, college-educated, and wealthier and had higher Charlson comorbidity index, all p < 0.05. Adjusting for covariates, caregiving was associated with significantly increased risk of depressive symptoms (odds ratio [OR] = 2.008), major depressive disorder (OR = 1.483), anxiety (OR = 1.714), insomnia (OR = 1.644), hypertension (OR = 1.584), pain (OR = 1.704), and diabetes (OR = 2.103), all p < 0.015. Caregiving was also associated with lower health utilities (-0.024 points) and mental health status ( 1.70 points), higher rates of presenteeism-related impairment (32.7% greater) and overall work impairment (35.9% greater), and higher traditional provider visit rates (28.7% greater), all p < 0.035. CONCLUSIONS: Caregiver status was found to be a factor associated with worse health outcomes and psychiatric and clinical disorders. PMID- 26011094 TI - A novel method to bail out coronary perforation: Micro-catheter distal perfusion technique. AB - Coronary perforation is a rare, but life-threatening complication during percutaneous coronary intervention. Prolonged balloon inflation is one option for achieving hemostasis, but it often causes ST elevation, chest pain, decreased blood pressure, or fatal arrhythmia due to ischemia. We present the case of a 73 year-old woman who suffered severe coronary perforation after stent implantation and post-dilatation. To allow prolonged balloon inflation without ischemia, we perfused the distal area with the patient's own arterial blood injected via micro catheter. With this method, we could prolong balloon inflation for 20 min, successfully achieving hemostasis. This novel technique, which we named the "distal perfusion technique," is useful to minimize ischemia during prolonged balloon inflation. PMID- 26011095 TI - Protective effects of thymoquinone on experimental testicular ischaemia reperfusion injury: an apoptotic, proliferative and biochemical study. AB - The objective of this study was to examine the effects of thymoquinone (TQ), which has antioxidant properties in the experimental testicular I/R model in rats in terms of its anti-apoptotic, proliferative and biochemical attributes. In our study, 24 male rats were divided into three groups: control group, I/R group and I/R+TQ group. Testicular torsion was created by rotating the left testis 720 degrees in a clockwise direction. The ischaemia period was 4 h, and an orchiectomy was performed after 4 h of detorsion. Spermatogenesis and the mean seminiferous tubule diameter were significantly decreased in the I/R groups compared to the control group. Furthermore, TQ-treated animals displayed an improved histological appearance in the I/R group. It was also observed that treatment with TQ increased the activity of PCNA, which decreased as a result of I/R, and this treatment also reduced the number of TUNEL-positive cells. The I/R+TQ group showed a decrease in malondialdehyde levels and an increase in the activities of superoxide dismutase, catalase and glutathione peroxidase in comparison with the I/R group. It could be concluded that cytoprotective effects of TQ on the I/R testicles are via reduction of apoptosis, oxidative stress and lipid peroxidation. PMID- 26011096 TI - alpha-Linolenic Fatty Acid Supplementation Decreases Tumor Growth and Cachexia Parameters in Walker 256 Tumor-Bearing Rats. AB - Fish oil (FO) has been shown to affect cancer cachexia, tumor mass, and immunity cell. n-3 PUFA, specifically alpha-linolenic fatty acid (ALA), has controversial effects. We investigated this in nontumor-bearing Wistar rats fed regular chow (C), fed regular chow and supplemented with FO or Oro Inca oil (OI), and Walker 256 tumor-bearing rats fed regular chow (W), fed regular chow and supplemented with FO (WFO) or OI (WOI). Rats were supplemented (1g/kg body weight/day) during 4 wk and then the groups tumor-bearing were inoculated with Walker 256 tumor cells suspension and 14 days later the animals were killed. WFO increased EPA fivefold and DHA 1.5-fold in the tumor tissue compared to W (P < 0.05). OI supplementation increased of threefold of ALA when compared to W (P < 0.05). Tumor mass in WFO and OI was of 2.3-fold lower, as well as tumor cell proliferation of 3.0-fold tumor tissue lipoperoxidation increased of 76.6% and cox-2 expression was 20% lower. Cachexia parameters were attenuate, blood glucose (25% higher), Triacylglycerolemia (50% lower), and plasma TNF-alpha (65% lower; P < 0.05) and IL-6 (62.5% lower). OI, rich in ALA, caused the same effect on cancer as those seen in FO. PMID- 26011097 TI - Magnesium-Doped Li1.2[Co0.13Ni0.13Mn0.54]O2 for Lithium-Ion Battery Cathode with Enhanced Cycling Stability and Rate Capability. AB - Mg-doped Li[Li0.2-2xMgxCo0.13Ni0.13Mn0.54]O2 is synthesized by introducing Mg ions into the transition-metal (TM) layer of this layered compound for substituting Li ions through a simple polymer-pyrolysis method. The structural and morphological characterization reveals that the doped Mg ions are uniformly distributed in the bulk lattice, showing an insignificant impact on the layered structure. Electrochemical experiments reveal that, at a Mg doping of 4%, the Li[Li0.16Mg0.04Co0.13Ni0.13Mn0.54]O2 electrode can deliver a larger initial reversible capacity of 272 mAh g(-1), an improved rate capability with 114 mAh g( 1) at 8 C, and an excellent cycling stability with 93.3% capacity retention after 300 cycles. The superior electrochemical performances of the Mg-doped material are possibly due to the enhancement of the structural stability by substitution of Li by Mg in the TM layer, which effectively suppresses the cation mixing arrangement, leading to the alleviation of the phase change during lithium-ion insertion and extraction. PMID- 26011098 TI - Non-Close-Packed Breath Figures via Ion-Partitioning-Mediated Self-Assembly. AB - We report a one-step method of forming non-close-packed (NCP) pore arrays of micro- and sub-micropores using chloroform-based solutions of polystyrene acidified with hydrogen bromide for breath figure (BF) patterning. As BF patterning takes place, water vapor condenses onto the polystyrene solution, forming water droplets on the solution surface. Concurrently, preferential ion partitioning of hydrogen bromide leads to positively charged water droplets, which experience interdroplet electrostatic repulsion. Self-organization of charged water droplets because of surface flow and subsequent evaporation of the droplet templates result in ordered BF arrays with pore separation/diameter (L/D) ratios of up to 16.5. Evidence from surface potential scans show proof for preferential ion partitioning of HBr. Radial distribution functions and Voronoi polygon analysis of pore arrays show that they possess a high degree of conformational order. Past fabrication methods of NCP structures typically require multi-step processes. In contrast, we have established a new route for facile self-assembly of previously inaccessible patterns, which comprises of only a single operational step. PMID- 26011099 TI - Comorbidity in developmental coordination disorder and active epilepsy. PMID- 26011100 TI - Patient characteristics and treatment patterns for patients with benign prostatic hyperplasia, erectile dysfunction or co-occurring benign prostatic hyperplasia and erectile dysfunction in general practices in the UK: a retrospective observational study. AB - AIMS: The aim of this study was to assess patient characteristics, medication treatment patterns and healthcare resource utilization among men with existing erectile dysfunction (ED) or benign prostatic hyperplasia (BPH), who are newly diagnosed with the second condition (BPH or ED) compared with those with only one condition. METHODS: This retrospective cohort study utilized the Clinical Practice Research Datalink. Males, aged 40 years or older, newly diagnosed with ED or symptomatic BPH between 1 June 2010 and 31 May 2011, were selected. Patient demographics, existing comorbidities and baseline medication use were analysed. Treatments initiated for the incident condition and treatment patterns were reported at 6, 12, 18 and 24-months postdiagnosis. Referrals to urologists and visits to general practitioners were reported around diagnosis and during follow up. RESULTS: This study included 11,501 incident patients with BPH, of which 23% had a prior ED diagnosis and 9,734 incident patients with ED, of which 17% had a prior BPH diagnosis. The average age at diagnosis of BPH was similar across both cohorts. Among incident patients with ED, those with prior diagnosis of BPH were diagnosed at an older average age (65 +/- 9.2 years) compared to those without BPH (57 +/- 9.1 years). The majority of patients in both incident BPH cohorts (62.9-65.5%) were prescribed alpha-blockers as initial treatment. The majority of patients in both incident ED cohorts (49.6-51.6%) were prescribed sildenafil as initial treatment followed by tadalafil (24.3-26.0%). At 12 months, 50% of incident patients with BPH and 80% of patients with ED had discontinued the therapy initiated. CONCLUSION: This study found that in the UK, patients with co occurring BPH and ED when newly diagnosed with the second condition initiated the same treatments as those without prior ED or BPH. During the first year, treatment patterns including discontinuation were comparable in the groups with one of the conditions and co-occurring BPH and ED. PMID- 26011101 TI - Attention to Faces Expressing Negative Emotion at 7 Months Predicts Attachment Security at 14 Months. AB - To investigate potential infant-related antecedents characterizing later attachment security, this study tested whether attention to facial expressions, assessed with an eye-tracking paradigm at 7 months of age (N = 73), predicted infant-mother attachment in the Strange Situation Procedure at 14 months. Attention to fearful faces at 7 months predicted attachment security, with a smaller attentional bias to fearful expressions associated with insecure attachment. Attachment disorganization in particular was linked to an absence of the age-typical attentional bias to fear. These data provide the first evidence linking infants' attentional bias to negative facial expressions with attachment formation and suggest reduced sensitivity to facial expressions of negative emotion as a testable trait that could link attachment disorganization with later behavioral outcomes. PMID- 26011102 TI - Increased tumor cell expression of Axl is a marker of aggressive features in breast cancer among African women. AB - Axl, a receptor tyrosine kinase belonging to the Tyro/Axl/Mer (TAM) family, has been shown to be overexpressed in breast cancer with poor outcome. Moreover, Axl was associated with a basal-like phenotype (BLP) in these tumors. Our aim was to investigate Axl expression in breast cancers from an African population since these tumors are known to be aggressive and have a high frequency of the basal like phenotype. We studied 170 paraffin-embedded breast carcinoma cases by tissue microarrays and immunohistochemical methods. In total, 128 tumor cases (75%) had strong Axl expression and 42 cases (25%) had weak or negative staining. Strong expression of Axl was associated with high tumor grade (p < 0.0005), estrogen receptor (ER) negativity (p = 0.024), p53 expression (p = 0.004), P-cadherin positivity (p = 0.017), and basal-like phenotypic profiles BLP2 (p = 0.033) and BLP3 (p = 0.022). In addition, Axl overexpression also showed an association with markers of tumor cell proliferation and tumor angiogenesis. In conclusion, our findings indicate strong expression of Axl in a high proportion of breast cancer cases among African women and associations with markers of aggressive features, indicating poor prognosis. These findings suggest Axl as a potential therapeutic target in this population. PMID- 26011103 TI - Cytologic features of nipple adenoma: a report of four cases of adenoma of the nipple. AB - We report four cases of adenoma of the nipple, a rare benign epithelial benign tumor occurring under the nipple and areola. Clinically, erosion findings of the nipple require discrimination from Paget's disease. In addition, a mass found in the nipple warrants discrimination from ductal carcinoma. Two cases underwent aspiration biopsy cytology and the other underwent tumor imprint cytology, respectively, revealing a large number of epithelial cell populations in the necrotic background material. These large cell clusters had a papillary or sheet structure and exhibited decreased cell cohesiveness at the cluster part. In addition, small clusters and solitary epithelial cells were also present. Furthermore, a two-cell pattern comprising both duct epithelial and myoepithelial cells was observed in the cell clusters. Two other cases underwent nipple brush cytology, revealing a few small papillary clusters with isolated epithelial cells in the hemorrhagic background. The clusters appeared as benign duct proliferative lesions such as papilloma, papillomatosis, and adenosis. An accurate diagnosis warrants the recognition of regular nuclei with bland chromatin and myoepithelial cells and the identification of the lesion location. PMID- 26011105 TI - Cancer of unknown primary is associated with diabetes. AB - The incidences of both type 1 diabetes (T1D) and T2D are increasing worldwide. T2D is associated with many cancers. However, no data are available on cancer of unknown primary (CUP), a relatively common, fatal cancer for which tobacco smoking is the only known risk factor. At diagnosis, CUP metastases are found in various organs, which has implications for prognosis. We carried out a nationwide study on the association of CUP with T1D and T2D. 32 600 T1D patients and 178 000 T2D patients were identified from the national healthcare registers and these were linked to the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP from 1997 through 2010 using anyone without diabetes as a reference. The SIR of CUP in 421 diabetic patients was 1.71, highest for CUP with liver (2.17) and respiratory system (1.95) metastases. The SIR was 2.91 for T1D, but with a small number of patients, 1.38 for T2D with insulin treatment, and 1.78 for the main group of T2D. CUP with liver and respiratory system metastases increased for each diabetic type; however, for T2D, CUP with gastrointestinal and bone metastases also increased. The results provide the first demonstration that CUP is one of the cancers associated with diabetes, with definite evidence on T2D. CUP has a poor prognosis, which may be even worse when diabetes is the underlying comorbidity. A mechanistic question for future work is to determine whether diabetes promotes primaries that escape detection or their metastatic spread. PMID- 26011104 TI - Prospective study of seaweed consumption and thyroid cancer incidence in women: the Japan collaborative cohort study. AB - Excess intake of iodine is a suspected risk factor for thyroid cancer. Previous epidemiological research from Japan reported that daily intake of seaweed was associated with a four-fold higher risk in postmenopausal women, whereas others reported a null association. A major source of iodine intake in Japan is from edible seaweeds, and it is reported to be among the highest in the world. We examined the association between seaweed intake frequency and the risk of thyroid cancer in women in the Japan Collaborative Cohort Study followed from 1988 to 2009. Seaweed intake, together with other lifestyle-related information was collected using a self-administered questionnaire at baseline. Seaweed intake frequency was categorized as follows: 1-2 times/week or less, 3-4 times/week, and almost daily. Hazard ratios and the 95% confidence intervals of thyroid cancer incidence according to seaweed intake frequency were estimated using Cox proportional hazards regression. During 447 876 person-years of follow-up (n=35 687), 94 new cases of thyroid cancer were identified. The crude incidence rate was 20.9 per 100 000 person-years. The hazard ratio of thyroid cancer in women who consumed seaweed daily compared with women who ate it 1-2 times/week or less was 1.15 (95% confidence interval: 0.69-1.90, P for trend=0.59). Further analyses did not indicate any association between seaweed intake and the risk of thyroid cancer on statistically adjusting for potential confounding variables as well as on stratification by menopausal status. The present study did not find an association between seaweed intake and thyroid cancer incidence in premenopausal or in postmenopausal women. PMID- 26011107 TI - AF News. PMID- 26011106 TI - Quantifying the ozone and ultraviolet benefits already achieved by the Montreal Protocol. AB - Chlorine- and bromine-containing ozone-depleting substances (ODSs) are controlled by the 1987 Montreal Protocol. In consequence, atmospheric equivalent chlorine peaked in 1993 and has been declining slowly since then. Consistent with this, models project a gradual increase in stratospheric ozone with the Antarctic ozone hole expected to disappear by ~2050. However, we show that by 2013 the Montreal Protocol had already achieved significant benefits for the ozone layer. Using a 3D atmospheric chemistry transport model, we demonstrate that much larger ozone depletion than observed has been avoided by the protocol, with beneficial impacts on surface ultraviolet. A deep Arctic ozone hole, with column values <120 DU, would have occurred given meteorological conditions in 2011. The Antarctic ozone hole would have grown in size by 40% by 2013, with enhanced loss at subpolar latitudes. The decline over northern hemisphere middle latitudes would have continued, more than doubling to ~15% by 2013. PMID- 26011108 TI - Tap water irrigation for burn injury. PMID- 26011110 TI - The mummified brain of a pleistocene woolly mammoth (Mammuthus primigenius) compared with the brain of the extant African elephant (Loxodonta africana). AB - This study presents the results of an examination of the mummified brain of a pleistocene woolly mammoth (Mammuthus primigenius) recovered from the Yakutian permafrost in Siberia, Russia. This unique specimen (from 39,440-38,850 years BP) provides the rare opportunity to compare the brain morphology of this extinct species with a related extant species, the African elephant (Loxodonta africana). An anatomical description of the preserved brain of the woolly mammoth is provided, along with a series of quantitative analyses of various brain structures. These descriptions are based on visual inspection of the actual specimen as well as qualitative and quantitative comparison of computed tomography imaging data obtained for the woolly mammoth in comparison with magnetic resonance imaging data from three African elephant brains. In general, the brain of the woolly mammoth specimen examined, estimated to weigh between 4,230 and 4,340 g, showed the typical shape, size, and gross structures observed in extant elephants. Quantitative comparative analyses of various features of the brain, such as the amygdala, corpus callosum, cerebellum, and gyrnecephalic index, all indicate that the brain of the woolly mammoth specimen examined has many similarities with that of modern African elephants. The analysis provided here indicates that a specific brain type representative of the Elephantidae is likely to be a feature of this mammalian family. In addition, the extensive similarities between the woolly mammoth brain and the African elephant brain indicate that the specializations observed in the extant elephant brain are likely to have been present in the woolly mammoth. PMID- 26011109 TI - Quantifying and optimizing single-molecule switching nanoscopy at high speeds. AB - Single-molecule switching nanoscopy overcomes the diffraction limit of light by stochastically switching single fluorescent molecules on and off, and then localizing their positions individually. Recent advances in this technique have greatly accelerated the data acquisition speed and improved the temporal resolution of super-resolution imaging. However, it has not been quantified whether this speed increase comes at the cost of compromised image quality. The spatial and temporal resolution depends on many factors, among which laser intensity and camera speed are the two most critical parameters. Here we quantitatively compare the image quality achieved when imaging Alexa Fluor 647 immunolabeled microtubules over an extended range of laser intensities and camera speeds using three criteria - localization precision, density of localized molecules, and resolution of reconstructed images based on Fourier Ring Correlation. We found that, with optimized parameters, single-molecule switching nanoscopy at high speeds can achieve the same image quality as imaging at conventional speeds in a 5-25 times shorter time period. Furthermore, we measured the photoswitching kinetics of Alexa Fluor 647 from single-molecule experiments, and, based on this kinetic data, we developed algorithms to simulate single molecule switching nanoscopy images. We used this software tool to demonstrate how laser intensity and camera speed affect the density of active fluorophores and influence the achievable resolution. Our study provides guidelines for choosing appropriate laser intensities for imaging Alexa Fluor 647 at different speeds and a quantification protocol for future evaluations of other probes and imaging parameters. PMID- 26011111 TI - Effects of IL6 C-634G polymorphism on tooth loss and their interaction with smoking habits. AB - OBJECTIVE: To examine the association between an IL6 (Interleukin-6) polymorphism (C-634G or rs1800796) and tooth loss, and an interaction between the polymorphism and smoking habits for the loss. MATERIAL AND METHODS: Our subjects were 4917 check-up examinees ages 35-69. They reported tooth loss and lifestyle in a questionnaire. We regressed the number of teeth on the IL6 genotype, gender, age, smoking, drinking, diabetes, hypertension, physical activity, energy intake, education, and brushing. We further estimated multivariate-adjusted odds ratios (ORs) for having <20 teeth. RESULTS: Participants with a GG genotype tended to have less teeth than those with CC; beta = -0.798 (95% confidence interval [CI] = -1.501--0.096). Subjects with a GG genotype were more likely to have <20 teeth than those with CC; OR was 1.56 (95% CI = 1.08-2.25). Association between current smoking and tooth loss was stronger among those with GG than among those with CC. In a multiple regression analysis, a significant interaction was found between GG genotype and current smoking in the prediction of tooth loss (P = 0.018). CONCLUSION: The IL6 C-634G polymorphism was significantly associated with tooth loss. Our results suggest greater effects of smoking on tooth loss in GG genotype individuals. PMID- 26011112 TI - Deficits in auditory processing contribute to impairments in vocal affect recognition in autism spectrum disorders: A MEG study. AB - OBJECTIVE: The primary aim of this study was to examine whether there is an association between magnetoencephalography-based (MEG) indices of basic cortical auditory processing and vocal affect recognition (VAR) ability in individuals with autism spectrum disorder (ASD). METHOD: MEG data were collected from 25 children/adolescents with ASD and 12 control participants using a paired-tone paradigm to measure quality of auditory physiology, sensory gating, and rapid auditory processing. Group differences were examined in auditory processing and vocal affect recognition ability. The relationship between differences in auditory processing and vocal affect recognition deficits was examined in the ASD group. RESULTS: Replicating prior studies, participants with ASD showed longer M1n latencies and impaired rapid processing compared with control participants. These variables were significantly related to VAR, with the linear combination of auditory processing variables accounting for approximately 30% of the variability after controlling for age and language skills in participants with ASD. CONCLUSIONS: VAR deficits in ASD are typically interpreted as part of a core, higher order dysfunction of the "social brain"; however, these results suggest they also may reflect basic deficits in auditory processing that compromise the extraction of socially relevant cues from the auditory environment. As such, they also suggest that therapeutic targeting of sensory dysfunction in ASD may have additional positive implications for other functional deficits. PMID- 26011113 TI - Neurocognitive predictors of mathematical processing in school-aged children with spina bifida and their typically developing peers: Attention, working memory, and fine motor skills. AB - OBJECTIVE: Math and attention are related in neurobiological and behavioral models of mathematical cognition. This study employed model-driven assessments of attention and math in children with spina bifida myelomeningocele (SBM), who have known math difficulties and specific attentional deficits, to more directly examine putative relations between attention and mathematical processing. The relation of other domain general abilities and math was also investigated. METHOD: Participants were 9.5-year-old children with SBM (n = 44) and typically developing children (n = 50). Participants were administered experimental exact and approximate arithmetic tasks, and standardized measures of math fluency and calculation. Cognitive measures included the Attention Network Test (ANT), and standardized measures of fine motor skills, verbal working memory (WM), and visual-spatial WM. RESULTS: Children with SBM performed similarly to peers on exact arithmetic, but more poorly on approximate and standardized arithmetic measures. On the ANT, children with SBM differed from controls on orienting attention, but not on alerting and executive attention. Multiple mediation models showed that fine motor skills and verbal WM mediated the relation of group to approximate arithmetic; fine motor skills and visual-spatial WM mediated the relation of group to math fluency; and verbal and visual-spatial WM mediated the relation of group to math calculation. Attention was not a significant mediator of the effects of group for any aspect of math in this study. CONCLUSION: Results are discussed with reference to models of attention, WM, and mathematical cognition. PMID- 26011114 TI - Absence of practice effects in preclinical Alzheimer's disease. AB - OBJECTIVE: To describe how practice effects influence cognitive trajectories and determine if a reduction in practice effects is a potential marker of Stage-III preclinical Alzheimer's disease (AD). METHOD: Participants included 263 older adults who were cognitively normal at baseline (i.e., had a Clinical Dementia Rating [CDR] of 0; Morris, 1993) and returned for an average of 9.5 annual visits. Participants completed standard tests of episodic memory, visuospatial ability, semantic memory, and executive function. Progressors (n = 66) converted to CDR > 0 with a diagnosis of symptomatic AD after a minimum of 3 visits and stable participants (n = 197) never progressed to CDR > 0. Practice effects, defined as the slope of performance across Visits 1-3, were compared between groups and used within subjects to predict risk of conversion. Change-point models that accounted for retest were contrasted with linear models that ignored retest. RESULTS: The stable group showed practice effects on episodic-memory measures (beta = 0.14, SE = .02, p < .0001) but the progressor group did not (beta = 0.03, SE = .03, p = .343). Across all participants, practice effects on episodic-memory tests were associated with a decreased risk of progression to AD as indicated by the subdistribution hazards model (SHR; Fine & Gray, 1999); SHR = .110, 95% CI [.032, .384], p = .001). Finally, use of change-point models dramatically altered rate-of-change estimates compared with models that ignored practice. CONCLUSION: Our results indicate that preclinical AD is marked by a reduction in practice effects in episodic memory and that the magnitude of gain from retesting is inversely related to progression risk. Assessment of practice effects may be a face-valid indicator of Stage-III preclinical AD. PMID- 26011115 TI - Mental time line distortion in right-brain-damaged patients: Evidence from a dynamic spatiotemporal task. AB - OBJECTIVE: Time is an elusive phenomenon that is difficult to grasp with our senses. Recent work has shown how spatial representations often lie beneath temporal ones, as shown by a family of spatiotemporal congruency effects. For instance, individuals who have been exposed to left-to-right orthographic systems are better at judging short durations with their left effector and long durations with their right effector than vice versa, a phenomenon known as the spatial temporal association of response codes (STEARC) effect. In the present neuropsychological study, we aimed to provide evidence that spatial attention mechanisms play a crucial role in generating this spatially organized mental time line. METHOD: A group of 13 patients suffering from right hemisphere lesions with different degrees of spatial neglect signs and a control group of 15 age- and education-matched neurologically healthy participants were administered a unimanual version of a spatiotemporal compatibility task (STEARC task). RESULTS: The main results showed that the more a patient suffered from spatial neglect signs, the smaller the accuracy difference was between the left and right side responses for short durations. CONCLUSIONS: These findings corroborate the hypothesis that the presence of disorders in spatial attention affects the left to-right mental time line representation, especially in its leftward segment, proportionally with the amount of deficit. This study therefore suggests the critical role of spatial attention for the emergence of a spatial representation of time durations. PMID- 26011116 TI - The impact of subjective cognitive decline on Iowa Gambling Task performance. AB - OBJECTIVE: To ascertain whether the Iowa Gambling Task (IGT) could be used to detect and identify measurable cognitive differences between older adults with subjective cognitive decline (SCD) as compared with healthy older controls (HC). METHOD: Older adults with self-identified SCD and age-matched controls completed a comprehensive neuropsychological assessment battery including the clinical version of the IGT, as well as self-report measures of mood and personality. RESULTS: The groups did not differ on clinically normed scores on the IGT. However, the groups did differ in the specific decks chosen as they progressed through the task, with the SCD group choosing the advantageous, high loss frequency deck (Deck C) more often toward the end of the task. Using hierarchical Bayesian parameter estimation, we show that the prospect valence learning (PVL) model outperforms the expectancy valence learning (EVL) model in parsimoniously accounting for task performance by both groups. The PVL model explains the difference in deck choices between groups as being because of an underlying difference in their learning rate, with the SCD group emphasizing the current outcome over past outcomes more than the HC group. CONCLUSIONS: Behavioral results indicate measureable differences in risky decision making in older adults with SCD as compared with healthy controls. Modeling results allow us to interpret this difference as potentially being because of rapid forgetting of trial-to-trial information. This work furthers our understanding of SCD, while demonstrating the use of computational modeling in the interpretation of neuropsychological data. PMID- 26011118 TI - The Antidepressant Effect of Hospice: Need for a More Potent Prescription. PMID- 26011119 TI - Detection of circulating melanoma cells in the blood of melanoma patients: a preliminary study. AB - Significant prognostic heterogeneity exists within the substages of melanoma; therefore, novel prognostic biomarkers are needed to provide information on the risk of recurrence. Limited available data suggest prognostic significance for circulating melanoma cells (CMCs); there is a need for a sensitive, reproducible, and standardized identification technique. Using a semiautomated technology, we sought to determine whether CMCs could be identified reliably in stage I-IV melanoma patients and whether the presence of CMC correlated with known prognostic factors. CMCs were detected in the peripheral blood (7.5 ml) of patients with stage I-IV melanoma (n=89) using the CellSearch system. CD146 cells were immunomagnetically enriched; nucleated HMW-MAA/CD45/CD34 cells were considered CMCs. One or more CMCs was detected in 45% of all patients, varying with stage of disease (stages I/II, III, and IV: 35, 44, and 86%, respectively; P=0.03, for stage I/II vs. stage IV); 55% had one CMC, 32% had two CMCs, and 13% had three or more CMCs identified. The presence of CMCs in the blood was associated with histologic subtype, particularly in patients with stage I/II disease (superficial spreading 18% vs. acral lentiginous 75%). Using a semiautomated technique, CMCs can be identified in a significant number of melanoma patients. These data support further study with longer follow-up and longitudinal/serial time points to better determine the identification rates and prognostic significance of CMCs in stage I-IV melanoma patients. PMID- 26011120 TI - Physical Punishment, Mental Health and Sense of Coherence Among Parents of Children with Intellectual Disability in Japan. AB - BACKGROUND: Although sense of coherence (SOC) moderates parental stress, the relationship between SOC, parental mental health and physical punishment of children with intellectual disabilities remains uncertain. The present authors describe parental physical punishment towards children with intellectual disabilities and investigate its related demographic characteristics, SOC and parental mental health. MATERIALS AND METHODS: With the cooperation of Tokyo's 10 special needs schools, the present authors obtained 648 questionnaire responses from parents of children with intellectual disabilities. RESULTS: Of the parents, 69.7% reported having physically punished their children with intellectual disabilities. This was positively associated with parents' younger age, poorer mental health, lower SOC, children's younger age, birth order (firstborns) and disability type (autism/pervasive developmental disorder). CONCLUSIONS: This is the first study supporting the relationship between SOC, mental health and physical punishment use among parents of children with intellectual disabilities. It may assist the development of strategies to prevent physical abuse of children with disabilities. PMID- 26011117 TI - Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease. AB - OBJECTIVE: Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington Disease (PREDICT-HD) study. METHOD: We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2,716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories. RESULTS: In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least 2 groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms-one with a very low level of depression and the other with a higher level of depression. CONCLUSIONS: Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials. PMID- 26011121 TI - Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer. AB - O6-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O6 methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterations in the form of nucleotide polymorphism may result in altered protein structure that in turn can lead to the loss of function. In the present study, we focused on the population feared for high exposure to alkylating agents owing to their typical and specialized dietary habits. To this end, gastric cancer patients pooled out from the population were selected for the mutational screening of a specific error prone region of MGMT gene. We found that nearly 40% of the studied neoplastic samples harbored missense mutation at codon151 resulting into Serine to Isoleucine variation. This variation resulted in bringing about the structural disorder, subsequently ensuing into a major stoichiometric variance in recognition domain, substrate binding and selectivity loop of the active site of the MGMT protein, as observed under virtual microscope of molecular dynamics simulation (MDS). The atomic insight into MGMT protein by computational approach showed a significant change in the intra molecular hydrogen bond pattern, thus leading to the observed structural anomalies. To further examine the mutational implications on regulatory plugs of MGMT that holds the protein in a DNA-Binding position, a MDS based analysis was carried out on, all known physically interacting amino acids essentially clustered into groups based on their position and function. The results generated by physical-functional clustering of protein indicated that the identified mutation in the vicinity of the active site of MGMT protein causes the local and global destabilization of a protein by either eliminating the stabilizing salt bridges in cluster C3, C4, and C5 or by locally destabilizing the "protein stabilizing hing" mapped on C3-C4 cluster, preceding the active site. PMID- 26011122 TI - MYB46 directly regulates the gene expression of secondary wall-associated cellulose synthases in Arabidopsis. AB - Cellulose is the most abundant biopolymer on Earth. Three cellulose synthases (CESA4, CESA7 and CESA8) are necessary for cellulose production in the secondary cell walls of Arabidopsis. Little is known about how expression of these CESA genes is regulated. We recently identified a cis-regulatory element (M46RE) that is recognized by MYB46, which is a master switch for secondary wall formation in Arabidopsis. A genome-wide survey of promoter sequences for the presence of M46REs led to the hypothesis that MYB46 may function as a direct regulator of all three secondary wall-associated cellulose synthase genes: CESA4, CESA7 and CESA8. We tested this hypothesis using several lines of experimental evidence. All three CESA genes are highly up-regulated by both constitutive and inducible over expression of MYB46 in planta. Using a steroid receptor-based inducible activation system, we show that MYB46 directly activates transcription of the three CESA genes. We then used an electrophoretic mobility shift assay and chromatin immunoprecipitation analysis to confirm that MYB46 protein directly binds to the promoters of the three CESA genes both in vitro and in vivo. Furthermore, ectopic up-regulation of MYB46 resulted in a significant increase of crystalline cellulose content in Arabidopsis. Taken together, we have identified MYB46 as a transcription factor that directly regulates all three secondary wall associated CESA genes. Yeast one-hybrid screening identified additional transcription factors that regulate the CESA genes. However, none of the putative regulators appears to be regulated by MYB46, suggesting the multi-faceted nature of transcriptional regulation of secondary wall cellulose biosynthesis. PMID- 26011123 TI - Differences in Trauma Experience Between Patients With Bipolar I Disorder, Patients With Major Depressive Disorder, and Healthy Controls. AB - The aim of this study was to compare differences in traumatic experiences between patients with bipolar I disorder, patients with major depressive disorder (MDD), and controls. The traumatic experiences (as measured by the Trauma Experience Questionnaire) of 40 participants with bipolar I disorder were compared with those of 38 participants with MDD and 92 controls. Participants with bipolar I disorder exhibited a significantly higher frequency of traumatic experiences and higher impact ratings when traumas did occur than did patients with MDD and controls. In addition, the present impact of past trauma for patients in the bipolar I disorder and MDD groups was significantly higher than for controls. The bipolar I disorder group reported more severe traumatic experiences than did both the MDD and control groups, and the MDD group in turn reported more severe traumatic experiences than did the control group. PMID- 26011124 TI - Protein corona changes mediated by surface modification of amorphous silica nanoparticles suppress acute toxicity and activation of intrinsic coagulation cascade in mice. AB - Recently, nanomaterial-mediated biological effects have been shown to be governed by the interaction of nanomaterials with some kinds of proteins in biological fluids, and the physical characteristics of the nanomaterials determine the extent and type of their interactions with proteins. Here, we examined the relationships between the surface properties of amorphous silica nanoparticles with diameters of 70 nm (nSP70), their interactions with some proteins in biological fluids, and their toxicity in mice after intravenous administration. The surface modification of nSP70 with amino groups (nSP70-N) prevented acute lethality and abnormal activation of the coagulation cascade found in the nSP70 treated group of mice. Since our previous study showed that coagulation factor XII played a role in the nSP70-mediated abnormal activation of the coagulation cascade, we examined the interaction of nSP70 and nSP70-N with coagulation factor XII. Coagulation factor XII bonded to the surface of nSP70 to a greater extent than that observed for nSP70-N, and consequently more activation of coagulation factor XII was observed for nSP70 than for nSP70-N. Collectively, our results suggest that controlling the interaction of nSP70 with blood coagulation factor XII by modifying the surface properties would help to inhibit the nSP70-mediated abnormal activation of the blood coagulation cascade. PMID- 26011127 TI - The influence of obturators on the respiration of patients with maxillary defects: a clinical study. AB - The study evaluated the effects of obturators on respiratory function by analyzing the changes in nasal anatomic structures and physiologic function in maxillectomy patients with and without obturators. Twenty-six patients who underwent maxillectomy were chosen and rehabilitated with obturators by a single maxillofacial prosthodontist. The geometric shape of the nasal cavity, the nasal airway resistance, and the ratio of residual volume to total lung capacity (RV/TLC) were evaluated using acoustic rhinometry, rhinomanometry, and a pulmonary function test apparatus, respectively. All patients were tested twice, with and without their obturators. The results were statistically analyzed with a paired t-test. The nasal cavities (0-7 cm to the anterior nostril) of the patients with obturators had a significantly smaller volume ([-8.92, -0.60], P = 0.027), smaller effective nasal cross-sectional area MCA2 ([-3.80, -1,81], P < 0.0001), increased airflow in the nasal cavity ([17.76, 147.39], P = 0.015), reduced nasal airway resistance ([-0.11, -0.02], P = 0.009), and reduced RV/TLC ([-5.32, -1.30], P = 0.004) compared with the patients without obturators. According to the results of this study, obturators can improve respiratory function by effectively decreasing the volume of enlarged nasal cavities as well as the nasal air resistance and volume of anatomical dead space after maxillectomy. PMID- 26011126 TI - A Function for the hnRNP A1/A2 Proteins in Transcription Elongation. AB - The hnRNP A1 and A2 proteins regulate processes such as alternative pre-mRNA splicing and mRNA stability. Here, we report that a reduction in the levels of hnRNP A1 and A2 by RNA interference or their cytoplasmic retention by osmotic stress drastically increases the transcription of a reporter gene. Based on previous work, we propose that this effect may be linked to a decrease in the activity of the transcription elongation factor P-TEFb. Consistent with this hypothesis, the transcription of the reporter gene was stimulated when the catalytic component of P-TEFb, CDK9, was inhibited with DRB. While low levels of A1/A2 stimulated the association of RNA polymerase II with the reporter gene, they also increased the association of CDK9 with the repressor 7SK RNA, and compromised the recovery of promoter-distal transcription on the Kitlg gene after the release of pausing. Transcriptome analysis revealed that more than 50% of the genes whose expression was affected by the siRNA-mediated depletion of A1/A2 were also affected by DRB. RNA polymerase II-chromatin immunoprecipitation assays on DRB-treated and A1/A2-depleted cells identified a common set of repressed genes displaying increased occupancy of polymerases at promoter-proximal locations, consistent with pausing. Overall, our results suggest that lowering the levels of hnRNP A1/A2 elicits defective transcription elongation on a fraction of P-TEFb dependent genes, hence favoring the transcription of P-TEFb-independent genes. PMID- 26011128 TI - Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. AB - AIM: Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. METHODS: Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F). RESULTS: PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). CONCLUSIONS: Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy. PMID- 26011129 TI - A detailed family history of myocardial infarction and risk of myocardial infarction--a nationwide cohort study. AB - BACKGROUND: Family history of myocardial infarction (MI) is an independent risk factor for MI. Several genetic variants are associated with increased risk of MI and family history of MI in a first-degree relative doubles MI risk. However, although family history of MI is not a simple dichotomous risk factor, the impact of specific, detailed family histories has not received much attention, despite its high clinical relevance. We examined risk of MI by MIs in first- and second degree relatives and by number and age of affected relatives. METHODS AND FINDINGS: Using Danish national registers, we established a nationwide cohort of persons born between 1930 and 1992 with identifiable first- or second-degree relatives. Incident MIs in both cohort members and relatives aged >=20 years were identified. We calculated incidence rate ratios (IRRs) for MI by family history of MI, by Poisson regression. In 4.4 million persons followed for 104 million person-years, we identified 128,384 incident MIs. IRRs with 95% confidence intervals [CIs] for MI by history of MI in 1, 2 or >=3 first-degree relatives were 1.46 (1.42-1.49), 2.38 (2.22-2.56) and 3.58 (2.66-4.81), respectively. Corresponding estimates for second-degree relatives were 1.17 (1.05-1.30), 1.87 (1.46-2.38) and 2.18 (1.09-4.36). A history of MI in combinations of first- and second-degree relatives increased risks 1.8- to 7-fold in middle-aged persons (36 to 55 years). Estimates were robust to adjustment for diabetes, hypertension, dyslipidemia and use of cardiovascular medications. CONCLUSION: A detailed family history, particularly number of affected first- and second-degree relatives, contributes meaningfully to risk assessment, especially in middle-aged persons. Future studies should test for potential improvement of risk algorithm prediction using detailed family histories. PMID- 26011130 TI - Cell stimulation and calcium mobilization by picosecond electric pulses. AB - We tested if picosecond electric pulses (psEP; 190 kV/cm, 500 ps at 50% height), which are much shorter than channel activation time, can activate voltage-gated (VG) channels. Cytosolic Ca(2+) was monitored by Fura-2 ratiometric imaging in GH3 and NG108 cells (which express multiple types of VG calcium channels, VGCC), and in CHO cells (which express no VGCC). Trains of up to 100 psEP at 1 kHz elicited no response in CHO cells. However, even a single psEP significantly increased Ca(2+) in both GH3 (by 114 +/- 48 nM) and NG108 cells (by 6 +/- 1.1 nM). Trains of 100 psEP amplified the response to 379 +/- 33 nM and 719 +/- 315 nM, respectively. Ca(2+) responses peaked within 2-15s and recovered for over 100 s; they were 80-100% inhibited by verapamil and omega-conotoxin, but not by the substitution of Na(+) with N-methyl-D-glucamine. There was no response to psEP in Ca(2+)-free medium, but adding external Ca(2+) even 10s later evoked Ca(2+) response. We conclude that electrical stimuli as short as 500 ps can cause long lasting opening of VGCC by a mechanism which does not involve conventional electroporation, heating (which was under 0.06 K per psEP), or membrane depolarization by opening of VG Na(+) channels. PMID- 26011131 TI - Label free aptasensor for Lysozyme detection: A comparison of the analytical performance of two aptamers. PMID- 26011132 TI - Surface modifications for enhanced enzyme immobilization and improved electron transfer of PQQ-dependent glucose dehydrogenase anodes. AB - Pyrroloquinoline quinone dependent soluble glucose dehydrogenase (PQQ-sGDH) enzymatic MWCNT electrodes were p roduced using 1-pyrenecarboxylic acid (PCA) activated through carbodiimide functionalization and 1-Pyrenebutyric acid N hydroxysuccinimide ester (PBSE) as tethering agents. At 600 mV potential, the current density generated by the activated-PCA tethered PQQ-sGDH anode was significantly greater than the current density generated by the untethered PQQ sGDH and PBSE tethered anodes, and performance was nearly identical to the performance of a covalently bound PQQ-sGDH anode. A technique for covalently bonding heme-b (hemin), a natural quinohemoprotein porphyrin redox cofactor, to carbon nanotubes modified with arylamine groups is reported. The resulting performance of the covalently bound hemin PQQ-sGDH anode is considerably higher than that of any other PQQ-sGDH anodes tested. PMID- 26011133 TI - 15-Deoxy-Delta12,14-prostaglandin J2 as an electrophilic mediator. AB - Lipid-derived electrophilic molecules are endogenously generated and are causally involved in many pathophysiological effects. Prostaglandin D2, a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the J-series PGs such as 15-deoxy-Delta(12,14)-PGJ2 (15d PGJ2). Because of the electrophilic alpha,beta-unsaturated ketone moiety present in its cyclopentenone ring, 15d-PGJ2 acts as an endogenous electrophile. 15d-PGJ2 can covalently react via the Michael addition reaction with critical cellular nucleophiles, such as the free cysteine residues of proteins that play a key role in the regulation of the intracellular signaling pathways. Covalent modification of cellular proteins by 15d-PGJ2 may be one of the most important mechanisms by which 15d-PGJ2 induces many biological responses involved in the pathophysiological effects associated with inflammation. This current review is intended to provide a comprehensive summary of 15d-PGJ2 as an endogenous electrophilic mediator of biological activities. PMID- 26011134 TI - Capsaicin alleviates abnormal intestinal motility through regulation of enteric motor neurons and MLCK activity: Relevance to intestinal motility disorders. AB - SCOPE: Capsaicin is an active component of chili peppers, having diverse effects. However, the effects of capsaicin on intestinal motility are still controversial. The present study aimed to investigate the effects of capsaicin on intestinal motility disorder and uncover related mechanisms. MATERIALS AND RESULTS: A rat model with intestinal motility disorder was established in vitro through adding different stimuli into tissue bath; in vivo using constipation and diarrhea model, respectively. Capsaicin exerted dual effects on intestinal motility, i.e. the relaxation and contraction of jejunum induced by corresponding stimulus were, respectively, regulated to be normal contraction by capsaicin. The mechanisms underlined capsaicin-induced dual effects were investigated using Western blotting, qRT-PCR, and whole-cell patch clamp, respectively. Results showed that cholinergic excitatory nerves, adrenergic nerves, and neurons containing nitric oxide synthase, which are the main muscle motor neurons in enteric nervous system (ENS), are involved in capsaicin-induced dual effects. The competition for regulation of Ca(2+) influx by capsaicin induced the interaction with components of the ENS. Capsaicin significantly increased myosin light chain kinase (MLCK) expression and myosin phosphorylation extent in jejunal segments of constipation prominent rats and significantly decreased MLCK expression and myosin phosphorylation extent in jejunal segments of diarrhea-prominent rats. CONCLUSION: In summary, capsaicin alleviates abnormal intestinal motility through regulating enteric motor neurons and MLCK activity, which is beneficial for the treatment of gastrointestinal motility disorders. PMID- 26011135 TI - Salinity-dependent toxicities of zinc oxide nanoparticles to the marine diatom Thalassiosira pseudonana. AB - This study comprehensively investigated the influences of salinity, exposure concentration and time on the aggregate size, surface charge and dissolution of zinc oxide nanoparticles (ZnO-NPs; 20nm) in seawater, and examined the interacting effect of salinity and waterborne exposure of ZnO-NPs on the marine diatom Thalassiosira pseudonana for 96h. We found that aggregate sizes of ZnO-NPs significantly increased with increasing salinity, but generally decreased with increasing exposure concentration. Ion release decreased with increasing salinity, whereas the surface charge of the particles was not affected by salinity. The increased aggregate size and decreased ion release with increasing salinity, and consequently lower concentration of bioavailable zinc ions, resulted in decreased toxicity of ZnO-NPs at higher salinity in general in terms of growth inhibition (IC50) and chlorophyll fluorescence (EC50 - FPo and EC50 - F2). However, IC50s and EC50s of ZnO-NPs were smaller than those of Zn(2+) (from ZnO-NPs ultrafiltrate and ZnCl2), indicating that dissolved Zn(2+) can only partially explain the toxicity of ZnO-NPs. SEM images showed that ZnO-NPs attached on the diatom frustule surface, suggesting that the interaction between the nanoparticles and the cell surface may acerbate the toxicity of ZnO-NPs. Our results linked the physicochemical characteristics of ZnO-NPs in seawater with their toxicities to the marine diatom and highlighted the importance of salinity as an influential environmental factor governing the aggregation, dissolution and the toxicity of ZnO-NPs. PMID- 26011136 TI - A review on polyamide thin film nanocomposite (TFN) membranes: History, applications, challenges and approaches. AB - This review focuses on the development of polyamide (PA) thin film nanocomposite (TFN) membranes for various aqueous media-based separation processes such as nanofiltration, reverse osmosis and forward osmosis since the concept of TFN was introduced in year 2007. Although the total number of published TFN articles falls far short of the articles of the well-known thin film composite (TFC) membranes, its growth rate is significant, particularly since 2012. Generally, by incorporating an appropriate amount of nanofiller into a thin selective PA layer of a composite membrane, one could produce TFN membranes with enhanced separation characteristics as compared to the conventional TFC membrane. For certain cases, the resulting TFN membranes demonstrate not only excellent antifouling resistance and/or greater antibacterial effect, but also possibly overcome the trade-off effect between water permeability and solute selectivity. Furthermore, this review attempts to give the readers insights into the difficulties of incorporating inorganic nanomaterials into the organic PA layer whose thickness usually falls in a range of several-hundred nanometers. It is also intended to show new possible approaches to overcome these challenges in TFN membrane fabrication. PMID- 26011137 TI - Inadequate Blood Pressure Control in Hypertensive Patients Referred for Cardiac Stress Test. AB - The current study examined the degree of blood pressure (BP) control and incidence of myocardial ischemia in hypertensive patients (n=2039) referred for cardiac stress test. Patients were categorized into well-controlled (<140/90 mm Hg), poorly controlled (140-160/90-100 mm Hg), and very poorly controlled (>160/100 mm Hg) groups according to their resting BP. The mean age[+/-standard error of the mean] of the patients was 68+/-13 years, and 885 (43.4%) were men. The prevalence of well-controlled hypertension (HTN) was 47.2%, poorly controlled HTN was 29.5%, and very poorly controlled HTN was 23.3%. Evidence of ischemia was seen in 19.8% and 19.3% of the well-controlled and poorly controlled groups, respectively. The very poorly controlled group had the lowest incidence of ischemia (14.3%) (P<.05) compared with the other two groups. Symptoms that mimic ischemic heart disease in hypertensive patients may be partly explained by poorly controlled BP. Quality of care might be improved by optimally controlling BP in patients with angina symptoms prior to ordering diagnostic testing associated with radiation exposure and cost. PMID- 26011138 TI - Individualized vancomycin dosing in obese patients: a two-sample measurement approach improves target attainment. AB - STUDY OBJECTIVE: To compare the likelihood of vancomycin target trough concentration attainment based on infectious diagnosis and/or minimum inhibitory concentration for the organism by using a two-sample approach versus the prior institutional standard of a trough-only approach in obese patients receiving vancomycin. DESIGN: Preintervention and postintervention study. SETTING: Community acute care hospital. PATIENTS: One hundred fifty hospitalized adults with a body mass index (BMI) of 30 kg/m(2) or greater and treated with vancomycin for at least 48 hours between July 2013 and March 2014 were evaluated to compare the frequency of steady-state therapeutic trough concentration attainment between two approaches: a trough-only dosing method (preintervention group [75 patients]) and a dosing strategy measuring two vancomycin serum concentrations during the elimination phase (peak and trough) to calculate pharmacokinetic parameters and individualize the maintenance regimen (postintervention group [75 patients]). Data for the preintervention group were retrospectively retrieved from a 4-month period for patients admitted between July and October 2013, prior to implementation of the two-point vancomycin dosing protocol. Initial vancomycin empiric dose selection for both groups utilized the same population-based pharmacokinetic equations. MEASUREMENTS AND MAIN RESULTS: Median (5th-95th percentile) age, weight, and BMI were 59 (34-80) years, 105 (79.8-164) kg, and 34.5 (30.0-55.1) kg/m(2) , respectively, for all patients. The percentages of initial therapeutic trough concentrations achieved in the preintervention and postintervention groups were 32.0% and 42.7%, respectively (p=0.117). For patients with a second trough measurement, 31.0% in the preintervention group and 65.2% in the postintervention group were within the therapeutic range (p=0.024). CONCLUSION: Measurement of two serum vancomycin concentrations significantly improves subsequent target trough concentration attainment in the obese population. PMID- 26011139 TI - Impact of a Stewardship-Initiated Restriction on Empirical Use of Ciprofloxacin on Nonsusceptibility of Escherichia coli Urinary Isolates to Ciprofloxacin. AB - STUDY OBJECTIVE: To evaluate the impact of a stewardship-initiated restriction on empirical use of ciprofloxacin on the nonsusceptibility of Escherichia coli urinary isolates to ciprofloxacin over time while controlling for the use of other key antibiotics with gram-negative activity. DESIGN: Retrospective single center study. SETTING: Large tertiary and quaternary care academic medical center. ISOLATES: Of 3714 E. coli urinary isolates. MEASUREMENTS AND MAIN RESULTS: The susceptibilities of the E. coli urinary isolates to ciprofloxacin, ceftriaxone, cefepime, piperacillin-tazobactam, meropenem, trimethoprim sulfamethoxazole, and nitrofurantoin obtained over a 7-year period (January 1, 2006-December 31, 2012) from adult inpatients were evaluated for potential relationships with antibiotic use over time by using multiple variable regression analysis. After introduction of the restriction on empirical use of ciprofloxacin in the first quarter of 2011, ciprofloxacin use declined from 141.1-39.8 defined daily doses/1000 patient-days, and the percentage of E. coli isolates that were not susceptible to ciprofloxacin decreased from 41.5-32.8%. With all antibiotics evaluated included in the model, no apparent relationships were found between the percentage of E. coli isolates nonsusceptible to ciprofloxacin and antibiotic use. However, when nonsignificant variables were eliminated (p>0.20), ciprofloxacin use was found to be positively associated with the percentage of E. coli isolates nonsusceptible to ciprofloxacin (p=0.037), whereas ceftriaxone use was negatively associated (p=0.045). CONCLUSION: The restriction and subsequent reduction of ciprofloxacin use was found to have a positive effect on the susceptibility of E. coli urinary isolates to ciprofloxacin. PMID- 26011140 TI - Alfuzosin treatment improves the rate and time for stone expulsion in patients with distal uretral stones: a prospective randomized controlled study. AB - OBJECTIVE: To evaluate the safety and efficacy of alfuzosin treatment on rate and time of stone expulsion in patients with uncomplicated distal ureteral stones. PATIENTS AND METHODS: Prospective, randomized, open-label, controlled study. Patients > 18 years of age presenting to the outpatient urology clinic with uncomplicated radio-opaque stones located in the distal third of the ureter and of size <= 10 mm were included. Patients were randomly assigned to either a control group (n=26) and received standard of care management (daily oral hydration and diclofenac 75 mg IM on demand) or to the alfuzosin group (n=28) and received alfuzosin SR 5 mg twice daily in addition to standard of care management. Patients were followed weekly at office visits and twice weekly by telephone for 4 weeks or until stone expulsion. Assessments included stone passage rate and time, and patients were monitored for occurrence of adverse drug events, complications, number of pain episodes, analgesic consumption, and number of hospital revisits. Mann-Whitney, chi(2) , and Fisher exact test were used for data analysis. RESULTS: All 54 patients completed the study. Stone expulsion rate was higher in the alfuzosin arm (53.6%, 15/28) compared to the control arm (26.9%, 7/26, p=0.04). Median stone passage time was lower in the alfuzosin group than in the control group (9 vs 19 days, respectively, p=0.006). Ureteral sepsis, uncontrollable pain, and hospitalization readmissions were reported in the control group only. There were no differences between groups in number of pain episodes, pain scores, or analgesic consumption. Alfuzosin therapy was tolerable with only minor adverse effects (headache, dizziness, mild postural hypotension, and rhinitis). CONCLUSION: Alfuzosin is safe and effective in increasing stone expulsion rates and shortening stone passage times for uncomplicated distal ureteral stones. PMID- 26011142 TI - Medication management of cardiac allograft vasculopathy after heart transplantation. AB - Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans >= 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV. PMID- 26011141 TI - Relative bioavailability of orally administered fosphenytoin sodium injection compared with phenytoin sodium injection in healthy volunteers. AB - STUDY OBJECTIVE: To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. DESIGN: Open label, randomized, single-dose, two-period, two-sequence crossover study. SETTING: University-affiliated clinical research center funded by the National Center of Research Resources. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7 14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). MEASUREMENTS AND MAIN RESULTS: The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. CONCLUSION: FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted. PMID- 26011143 TI - Riociguat: a novel new drug for treatment of pulmonary hypertension. AB - Riociguat is the first approved medication from the novel class of soluble guanylate cyclase (sGC) stimulators and the only agent approved for treating both chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH). The novel mechanism of riociguat lies in its ability to restore the homeostatic and therapeutic effects of nitric oxide that are diminished as a result of phenotypic alterations associated with pulmonary hypertension (PH). Improvements in 6-minute walk distance (6MWD) in patients with PAH during the phase 3 PATENT-1 trial were comparable to other oral agents approved for the treatment of PAH. Improvements in 6MWD in patients with CTEPH during the phase 3 CHEST-1 trial were greater than those previously observed with other oral PAH directed therapies. Hypotension is the dose-limiting adverse effect of riociguat and dose titration is performed gradually according to systolic blood pressure. Riociguat was tolerated at maximal doses by most patients during PATENT-1 and CHEST-1 and was well tolerated during long-term extension studies. Key factors to consider with riociguat are a patient's systolic blood pressure, drug interactions mediated by CYP1A1, CYP3A4, and P-glycoprotein, cost, and teratogenicity requiring enrollment in a Risk Evaluation and Mitigation Strategy program. Recently published guidelines recommend riociguat monotherapy as an option for treatment-naive patients with World Health Organization Functional Class (WHO FC) II or III symptoms or as add-on therapy for patients with persistent WHO FC III or IV symptoms being treated with an ERA or inhaled prostanoid. Postmarketing experience and ongoing clinical investigations will further define the safety and role of riociguat in patients with PAH and other types of PH. PMID- 26011145 TI - Combination of Quercetin and 2-Methoxyestradiol Enhances Inhibition of Human Prostate Cancer LNCaP and PC-3 Cells Xenograft Tumor Growth. AB - Quercetin and 2-Methoxyestradiol (2-ME) are promising anti-cancer substances. Our previous in vitro study showed that quercetin synergized with 2-Methoxyestradiol exhibiting increased antiproliferative and proapoptotic activity in both androgen dependent LNCaP and androgen-independent PC-3 human prostate cancer cell lines. In the present study, we determined whether their combination could inhibit LNCaP and PC-3 xenograft tumor growth in vivo and explored the underlying mechanism. Human prostate cancer LNCaP and PC-3 cells were inoculated subcutaneously in male BALB/c nude mice. When xenograft tumors reached about 100 mm3, mice were randomly allocated to vehicle control, quercetin or 2-Methoxyestradiol singly treated and combination treatment groups. After therapeutic intervention for 4 weeks, combination treatment of quercetin and 2-ME i) significantly inhibited prostate cancer xenograft tumor growth by 46.8% for LNCaP and 51.3% for PC-3 as compared to vehicle control group, more effective than quercetin (28.4% for LNCaP, 24.8% for PC3) or 2-ME (32.1% for LNCaP, 28.9% for PC3) alone; ii) was well tolerated by BALB/c mice and no obvious toxic reactions were observed; iii) led to higher Bax/Bcl-2 ratio, cleaved caspase-3 protein expression and apoptosis rate; and iv) resulted in lower phosphorylated AKT (pAKT) protein level, vascular endothelial growth factor protein and mRNA expression, microvascular density and proliferation rate than single drug treatment. These effects were more remarkable compared to vehicle group. Therefore, combination of quercetin and 2-ME can serve as a novel clinical treatment regimen owning the potential of enhancing antitumor effect on prostate cancer in vivo and lessening the dose and side effects of either quercetin or 2-ME alone. These in vivo results will lay a further solid basis for subsequent researches on this novel therapeutic regimen in human prostate cancer. PMID- 26011147 TI - Mass spectral analysis of urine proteomic profiles of dairy cows suffering from clinical ketosis. AB - BACKGROUND: Ketosis is an important metabolic disorder in dairy cows during the transition period. The urine proteomics of ketosis has not been investigated using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). OBJECTIVE: The aim is to determine differences between urine proteomic profiles of healthy cows and those with clinical ketosis, and facilitate studies of the underlying physiological and biochemical mechanisms that lead to liver pathology in ketosis. ANIMALS AND METHODS: We analyzed the urine samples of 20 cows with clinical ketosis (group 1) and 20 control cows (group 2) using SELDI-TOF-MS. RESULTS: Thirty-nine peptide peaks differed between both groups. Polypeptides corresponding to 26 of these differential peptide peaks were identified using the SWISS-PROT protein database. We found that the peaks of 11 distinct polypeptides from the urine samples of the ketosis group were significantly reduced, compared with those of the control group as based on the Wilcoxon rank sum test. Among these were VGF (non-acronymic) protein, amyloid precursor protein, serum amyloid A (SAA), fibrinogen, C1INH, apolipoprotein C III, cystatin C, transthyretin, hepcidin, human neutrophil peptides, and osteopontin. CONCLUSION: These proteins may represent novel biomarkers of the metabolic changes that occur in dairy cows with ketosis. Our results will help to better understand the physiological changes and pathogenesis observed in cows with ketosis. CLINICAL IMPORTANCE: The SELDI-TOF-MS can be used to understand the physiological and biochemical mechanisms of ketosis and identify biomarkers of the disease. PMID- 26011146 TI - Inhibition of 11beta-Hydroxysteroid Dehydrogenase Type II Suppresses Lung Carcinogenesis by Blocking Tumor COX-2 Expression as Well as the ERK and mTOR Signaling Pathways. AB - Lung cancer is by far the leading cause of cancer death. Early diagnosis and prevention remain the best approach to reduce the overall morbidity and mortality. Experimental and clinical evidence have shown that cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) contributes to lung tumorigenesis. COX-2 inhibitors suppress the development and progression of lung cancer. However, increased cardiovascular risks of COX-2 inhibitors limit their use in chemoprevention of lung cancers. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2)-mediated metabolism. We found that 11betaHSD2 expression was increased in human lung cancers and experimental lung tumors. Inhibition of 11betaHSD2 activity enhanced glucocorticoid-mediated COX-2 inhibition in human lung carcinoma cells. Furthermore, 11betaHSD2 inhibition suppressed lung tumor growth and invasion in association with increased tissue active glucocorticoid levels, decreased COX-2 expression, inhibition of ERK and mTOR signaling pathways, increased tumor endoplasmic reticulum stress as well as increased lifespan. Therefore, 11betaHSD2 inhibition represents a novel approach for lung cancer chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity and/or inhibits the ERK and mTOR signaling pathways. PMID- 26011148 TI - An Evaluation of the Physiological Strain Experienced by Electrical Utility Workers in North America. AB - The purpose of this study was to assess the physiological strain experienced by North American electrical utility workers during the performance of their normal work duties in heat stressed conditions. Three common job categories were monitored as they are normally performed in 32 electrical utility workers: (i) Ground Work (n = 11); (ii) Bucket Work (n = 9); and (iii) Manual Pole Work (n = 12). Worker hydration status (urine specific gravity (USG)) was measured prior to and following the work monitoring period (duration: 187 +/- 104 min). Core and skin temperatures as well as heart rate were measured continuously. Physiological Strain Index (PSI) was calculated from the measurements of core temperature and heart rate. Prior to the start of the work shift, 38% of workers were euhydrated (USG < 1.020; n = 12) whereas the majority of workers were dehydrated (USG > 1.020; prevalence: 75%; p < 0.01) following work. The overall mean and peak core temperatures for all monitored workers were 37.9 +/- 0.3 degrees C and 38.3 +/- 0.5 degrees C, respectively. When responses were compared between job categories, greater mean and peak increases in core temperature were observed in Manual Pole Work relative to the other job categories (both p < 0.04). In fact, six workers performing Manual Pole Work achieved core temperatures in excess of 38.5 degrees C, while only one other worker surpassed this threshold in Bucket Work. The high levels of thermal strain were paralleled by elevated mean and peak heart rate and PSI responses, which were greater in Manual Pole Work in comparison to the other job categories (all p <= 0.05). Furthermore, two workers performing Manual Pole Work achieved severely elevated core temperatures reaching or exceeding 39.5 degrees C along with prolonged periods of near maximal heart rate responses (i.e., >90% of heart rate reserve). We report elevated levels of thermal and cardiovascular strain in electrical utility workers during work in the heat and potentially dangerous levels of hyperthermia during particularly strenuous work. PMID- 26011149 TI - Pseudomonas aeruginosa PAO1 induces distinct cell death mechanisms in H9C2 cells and its differentiated form. AB - Bacterial infections in myocardium may lead to the myocardial damage, which may progress to dilated cardiomyopathy and cardiac arrest. Pseudomonas aeruginosa has been reported to cause myocarditis and other systemic infections especially in immunocompromised patients. To understand the cellular responses during the establishment of infection in myocardium, we challenged differentiated H9C2 cells with P. aeruginosa PAO1. We also did comparison studies with infected undifferentiated form of H9C2 cells. Invasion studies revealed that PAO1 can invade both forms of cells and is able to survive and replicate within the host. Internalization of PAO1 was confirmed by live cell imaging and flow cytometry analysis. Though invasion of the pathogen triggered an increased ROS production in the host cells at earlier post-infection periods, it was decreased at later post-infection periods. Invasion of PAO1 induced cell death through apoptosis in differentiated H9C2 cells. Significant decrease in cell size, formation of polarized mitochondria, and nuclear fragmentation were observed in the infected differentiated cells. On the contrary, cell death preceded by multinucleation was observed in infected undifferentiated H9C2 cells. Morphological markers such as multinuclei and micro nuclei were observed. Cell cycle arrest in G2/M phase corroborates that the undifferentiated H9C2 cells experienced cell death preceded by multinucleation. PMID- 26011150 TI - Chelating and Linking S4O13(2-) Anions: Synthesis and Characterization of the Bis (tetrasulfato) Palladates M2[Pd(S4O13)2] (M = NH4, Rb, NO) and the Sodium Palladium Tetrasulfate Na2Pd(S4O13)2. AB - The reaction of SO3 with either the palladium chlorides M2PdCl6 (M = Rb, NH4) or the nitrato-palladate (NO)2[Pd(NO3)4] at elevated temperature led to yellow single crystals of the complex palladates M2[Pd(S4O13)2] (M = NH4: triclinic, P1, a = 7.3882(3) A, b = 8.5223(3) A, c = 9.2712(4) A, alpha = 71.945(2) degrees , beta = 88.910(2) degrees , gamma = 72.603(2) degrees , V = 527.88(4) A3; M = NO: triclinic, P1, a = 7.2881(3) A, b = 8.9125(2) A, c = 8.9220(4) A, alpha = 75.546(2) degrees , beta = 89.151(2) degrees , gamma = 69.516(2) degrees , V = 524.02(4) A3; M = Rb: triclinic, P1, a = 7.4468(4) A, b = 8.5066(4) A, c = 9.2477(4) A, alpha = 72.321(2) degrees , beta = 88.512(2) degrees , gamma = 72.128(2) degrees , V = 529.75(4) A3). In the isotypic compounds, the Pd atom is in square planar oxygen coordination, achieved by two bidentate-chelating tetrasulfate anions. The reaction of Na2PdCl6 with neat SO3 afforded yellow crystals of Na2Pd(S4O13)2 (monoclinic, P21/c, a = 6.9953(4) A, b = 15.9420(9) A, c = 9.2299(5) A, beta = 100.235(2) degrees , V = 1012.45(1) A3). The structure exhibits no palladate complexes but an anionic two-dimensional network, according to infinity2[Pd(S4O13)(4/2)]2-. The latter shows the tetrasulfate anions acting as bidentate-bridging ligands. The tetrasulfato-palladates were studied in more detail by means of thermal analyses and infrared (IR) spectroscopy. The observed IR bands were assigned according to quantum chemical calculations performed on the anion [Pd(S4O13)2]2-. PMID- 26011155 TI - Victorian Stroke Telemedicine Project: implementation of a new model of translational stroke care for Australia. AB - BACKGROUND: Stroke telemedicine is widely used to treat patients with acute stroke in Europe and North America but is seldom used in Australia. The Victorian Stroke Telemedicine (VST) programme aims to enhance acute stroke care in regional Australia. METHODS: Twelve-month pilot prospective, historical-controlled, implementation cohort study. Emergency Department (ED) at a large regional hospital in Victoria. Patients >= 18 years of age arriving < 4.5 h in the ED with a possible diagnosis of acute stroke. Telemedicine consultation by a Melbourne based stroke specialist. Stroke thrombolysis rate, timelines for clinical processes, discharge outcomes. RESULTS: In the initial 12 month VST implementation, 62 patients arrived < 4.5 h of stroke onset (60% male; median age 75 years). Compared to pre-VST data (n = 58; 52% male; median age 77 years), stroke thrombolysis use increased from 17% to 26% (P = 0.26). Clinical process timelines improved including door to computed tomography time (reduced by 29 min, P = 0.006), and door to needle time (reduced by 21 min, P = 0.21). There was no significant increase in deaths (pre-VST 7% vs VST 10%), or symptomatic intracerebral haemorrhage (n = 1 tPA patient). More patients who received tPA were discharged to home or rehabilitation (pre-VST 33% vs VST 80%, P = 0.02), with significantly fewer transfers to other acute care services. CONCLUSIONS: The VST pilot implementation provides evidence that telemedicine can enhance the quality of acute stroke care in a regional hospital. Expanding VST to 16 regional hospitals, Australia's largest telestroke programme, will allow for a more comprehensive clinical and economic analysis. PMID- 26011156 TI - Maternal use of methadone and risk of sudden neonatal death. AB - AIM: To identify and describe infant deaths presenting suddenly and unexpectedly in whom there was a history of maternal methadone consumption or misuse of drugs during pregnancy. METHODS: Retrospective review of neonatal postmortem examinations between 2004 and 2011. RESULTS: A total of 138 autopsies were performed in infants up to 28 days. Thirty-two cases (23%) presented suddenly and unexpectedly. In 12 of 32 (37.5%), in whom the cause of death remained unexplained after a thorough postmortem, there was a history of methadone use and/or other drugs of abuse during pregnancy. Their mean age at death was 11 days (range 1-28 days). Multiple risk factors for sudden infant death syndrome were present in these 12 cases: smoking (10), prematurity (7), and inappropriate sleeping place (8). Five mothers were positive for hepatitis C. The history was inconsistent with the findings in only one case. CONCLUSION: An unexpectedly high proportion of infants dying suddenly and unexpectedly in the first month had a history of maternal substance misuse. All had multiple risk factors, for sudden infant death syndrome many avoidable. We would stress the need to emphasise the 'Safe Sleep' message with these families at every contact with health professionals. PMID- 26011157 TI - Do attitudes and beliefs regarding complementary and alternative medicine impact its use among patients with cancer? A cross-sectional survey. AB - BACKGROUND: Complementary and alternative medicine (CAM) incorporates treatments used by cancer survivors in an attempt to improve their quality of life. Although population studies have identified factors associated with its use, to the best of the authors knowledge, assessment of why patients use CAM or the barriers against its use have not been examined to date. METHODS: The authors conducted a cross-sectional survey study in the thoracic, breast, and gastrointestinal medical oncology clinics at an academic cancer center. Clinical and demographic variables were collected by self-report and chart abstraction. Attitudes and beliefs were measured using the validated Attitudes and Beliefs about CAM (ABCAM) instrument. This instrument divides attitudes and beliefs into 3 domains: expected benefits, perceived barriers, and subjective norms. RESULTS: Among 969 participants (response rate, 82.7%) surveyed between June 2010 and September 2011, patient age <=65 years, female sex, and college education were associated with a significantly greater expected benefit from CAM (P<.0001 for all). Nonwhite patients reported more perceived barriers to CAM use compared with white patients (P<.0001), but had a similar degree of expected benefit (P = .76). In a multivariate logistic regression analysis, all domains of the ABCAM instrument were found to be significantly associated with CAM use (P<.01 for all) among patients with cancer. Attitudes and beliefs regarding CAM explained much more variance in CAM use than clinical and demographic variables alone. CONCLUSIONS: Attitudes and beliefs varied by key clinical and demographic characteristics, and predicted CAM use. By developing CAM programs based upon attitudes and beliefs, barriers among underserved patient populations may be removed and more patient centered care may be provided. PMID- 26011158 TI - Durable Suppression of HIV-1 after Virologic Monitoring-Based Antiretroviral Adherence Counseling in Rakai, Uganda. AB - OBJECTIVES: HIV viral load is recommended for monitoring antiretroviral treatment and identifying treatment failure. We assessed the durability of viral suppression after viral load-triggered adherence counseling among patients with HIV viremia 6 months after ART initiation. DESIGN: Observational cohort enrolled in an antiretroviral treatment program in rural Uganda. METHODS: Participants who underwent routine viral load determination every 24 weeks and had at least 48 weeks of follow-up were included in this analysis. Patients with viral loads >400 copies/ml at 24 weeks of treatment were given additional adherence counseling, and all patients were followed to assess the duration of viral suppression and development of virologic failure. RESULTS: 1,841 participants initiating antiretroviral therapy were enrolled in the Rakai Health Sciences Program between June 2005 and June 2011 and were followed with viral load monitoring every 24 weeks. 148 (8%) of patients did not achieve viral suppression at 24 weeks and were given additional adherence counseling. 85 (60%) of these patients had undetectable viral loads at 48 weeks, with a median duration of viral suppression of 240 weeks (IQR 193-288 weeks). Failure to achieve an undetectable viral load at 48 weeks was associated with age <30 years and 24 week viral load >2,000 copies/ml in multivariate logistic regression analysis. CONCLUSIONS: The majority of patients with persistent viremia who were provided adherence counseling achieved robust viral suppression for a median 4.6 years. Access to virologic monitoring and adherence counseling is a priority in resource-limited settings. PMID- 26011159 TI - Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome. AB - Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired-like homeobox 2b (PHOX2B) non-polyalanine-repeat-expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine-repeat-expansion mutation (PARM) (genotype 20/33) and developed high-risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I(131) metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities. PMID- 26011161 TI - Correction: human, oceanographic and habitat drivers of central and Western pacific coral reef fish assemblages. PMID- 26011160 TI - Xanthohumol inhibits Notch signaling and induces apoptosis in hepatocellular carcinoma. AB - Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and understand the mechanism of its action in HCC. The effects of XN on a panel of HCC cell lines were assessed for cell viability, colony forming ability, and cellular proliferation. Cell lysates were analyzed for pro-apoptotic (c-PARP and cleaved caspase-3) and anti-apoptotic markers (survivin, cyclin D1, and Mcl-1). XN concentrations of 5 MUM and above significantly reduced the cell viability, colony forming ability and also confluency of all four HCC cell lines studied. Furthermore, growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. Importantly, XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins. Ectopic expression of Notch1 in HCC cells reverses the anti-proliferative effect of XN as evidenced by reduced growth suppression compared to control. Taken together these results suggested that XN mediated growth suppression is appeared to be mediated by the inhibition of the Notch signaling pathway. Therefore, our findings warrants further studies on XN as a potential agent for the treatment for HCC. PMID- 26011162 TI - Training counting skills and working memory in preschool. AB - Previous studies have shown that early numeracy skills predict later mathematics learning and that they can be improved by training. Cognitive abilities, especially working memory (WM), play an important role in early numeracy, as well. Several studies have shown that working memory is related to early numeracy. So far, existing literature offers a good few examples of studies in which WM training has led to improvements in early numerical performance as well. In this study, we aim at investigating the effects of two different training conditions: (1) counting training; and (2) simultaneous training of WM and counting on five- to six-year-old preschoolers' (N = 61) counting skills. The results show that domain-specific training in mathematical skills is more effective in improving early numerical performance than WM and counting training combined. Based on our results, preschool-aged children do not seem to benefit from short period group training of WM skills. However, because of several intervening factors, one should not conclude that young children's WM training is ineffectual. Instead, future studies should be conducted to further investigate the issue. PMID- 26011163 TI - A perfusion bioreactor system efficiently generates cell-loaded bone substitute materials for addressing critical size bone defects. AB - Critical size bone defects and non-union fractions are still challenging to treat. Cell-loaded bone substitutes have shown improved bone ingrowth and bone formation. However, a lack of methods for homogenously colonizing scaffolds limits the maximum volume of bone grafts. Additionally, therapy robustness is impaired by heterogeneous cell populations after graft generation. Our aim was to establish a technology for generating grafts with a size of 10.5 mm in diameter and 25 mm of height, and thus for grafts suited for treatment of critical size bone defects. Therefore, a novel tailor-made bioreactor system was developed, allowing standardized flow conditions in a porous poly(L-lactide-co-caprolactone) material. Scaffolds were seeded with primary human mesenchymal stem cells derived from four different donors. In contrast to static experimental conditions, homogenous cell distributions were accomplished under dynamic culture. Additionally, culture in the bioreactor system allowed the induction of osteogenic lineage commitment after one week of culture without addition of soluble factors. This was demonstrated by quantitative analysis of calcification and gene expression markers related to osteogenic lineage. In conclusion, the novel bioreactor technology allows efficient and standardized conditions for generating bone substitutes that are suitable for the treatment of critical size defects in humans. PMID- 26011164 TI - Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat. AB - NEW FINDINGS: What is the central question of this study? We examined, in hypertensive rats, whether the angiotensin-converting enzyme-independent enzymes generating angiotensin II in the tissues modulate blood pressure, peripheral circulation and renal function. What is the main finding and its importance? The results suggest that chymostatin-sensitive enzymes diminish vascular tone in renal and extrarenal vascular beds. Chymase or similar chymostatin-sensitive enzymes have a significant role in the synthesis of angiotensin II in different tissues but do not control blood pressure in the short term, similarly in salt dependent or Goldblatt-type rat hypertension. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing the angiotensin II content in the kidney. Chymase is presumed to be a crucial enzyme of the non-angiotensin-converting enzyme pathway of angiotensin II (Ang II) generation in tissues, a process involved in vascular remodelling and development of hypertension. We examined the role of chymase in hypertension induced by exposure of uninephrectomized rats to high dietary salt intake (UNX HS) and in the Goldblatt renal artery stenosis (two-kidney, one-clip) model. In acute experiments with anaesthetized rats of either model, chymostatin at 2 mg kg(-1) h(-1) or 0.05% DMSO solvent was infused i.v. Mean arterial blood pressure, heart rate, iliac blood flow (a measure of hindlimb perfusion), total renal blood flow and intrarenal regional perfusion (laser-Doppler technique) were measured continuously, along with the glomerular filtration rate and renal excretion. In both models, chymase blockade distinctly decreased plasma and tissue Ang II without lowering mean blood pressure or consistently altering the other functional parameters measured. Unexpectedly, in Goldblatt hypertensive rats the blockade increased the renal and hindlimb vascular resistances by 51 and 33%, respectively (P < 0.05). In UNX HS hypertensive rats, chymase blockade abolished the solvent-induced decrease in outer medullary blood flow. We conclude that chymase or similar chymostatin-sensitive enzyme(s) has a significant role in the synthesis of Ang II in different tissues but does not participate in short-term control of blood pressure in salt-dependent or Goldblatt-type rat hypertension. In the Goldblatt model, chymase appeared to reduce the renal and hindlimb vascular resistances by an unknown mechanism. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing Ang II content in the kidney. PMID- 26011165 TI - Novel Use of PIT Tags in Sea Cucumbers: Promising Results with the Commercial Species Cucumaria frondosa. AB - The lack of a reliable and innocuous mark-recapture method has limited studies that would provide essential information for the management of commercial sea cucumbers. Tagging sea cucumbers is notoriously difficult because of their plastic nature and autolysis capacities. The markers that have so far been tested, mainly on or through the body wall, were either lost rapidly or had major drawbacks (e.g. suitable only for batch identification, requiring complex analysis, causing infections, necrosis, behavioural changes and mortality). The present study explored the efficacy of passive integrated transponder (PIT) tags for individually marking sea cucumbers by assessing retention rates and long-term side effects of tags inserted in previously unstudied tissues/organs. Individuals of the species Cucumaria frondosa were tagged in the body wall, aquapharyngeal bulb and at the base of the oral tentacles. They were monitored closely for evidence of stress, infection, change in feeding and spawning behaviour and tag retention rate. Implanting the tag in an oral tentacle to reach the hydrovascular system of the aquapharyngeal bulb achieved the best retention rates in full-size individuals: from a maximum of 92% after 30 days to 68% at the end of the experimental period (300 days). Efficacy was lower in smaller individuals (84% after 30 d and 42% after 300 d). Following a slight increase in cloacal movements for 15 h post tagging, no side effect was noted in sea cucumbers tagged in the aquapharyngeal bulb via the tentacles. Feeding and spawning behaviours were not affected and no signs of infections or abnormal cell development in the vicinity of the tags were observed. This study indicates that marking sea cucumbers with 8.2 mm long PIT tags implanted via the oral tentacle is an effective technique, yielding relatively high retention rates over long periods without any detectable physiological or behavioural effects. PMID- 26011166 TI - Is there such a thing as landscape genetics? AB - For a scientific discipline to be interdisciplinary, it must satisfy two conditions; it must consist of contributions from at least two existing disciplines, and it must be able to provide insights, through this interaction, that neither progenitor discipline could address. In this study, I examine the complete body of peer-reviewed literature self-identified as landscape genetics (LG) using the statistical approaches of text mining and natural language processing. The goal here was to quantify the kinds of questions being addressed in LG studies, the ways in which questions are evaluated mechanistically, and how they are differentiated from the progenitor disciplines of landscape ecology and population genetics. I then circumscribe the main factions within published LG studies examining the extent to which emergent questions are being addressed and highlighting a deep bifurcation between existing individual- and population-based approaches. I close by providing some suggestions on where theoretical and analytical work is needed if LGs is to serve as a real bridge connecting evolution and ecology sensu lato. PMID- 26011167 TI - Epimeric Excolides from the Stems of Excoecaria agallocha and Structural Revision of Rhizophorin A. AB - Excolides A-B (1-4) represent the first examples of a new class of secolabdanoids with an unprecedented framework, which were isolated from the stems of Excoecaria agallocha. Their structures were determined by spectroscopic analysis, chemical modifications, CD, and single-crystal X-ray analysis (1 and 4) as excolide A (1), 11-epi-excolide A (2), 11,13-di-epi-excolide A (3), and excolide B (4). In addition, the structure of rhizophorin A (7), a novel bicyclic secolabdanoid, was revised as excolide A (1). PMID- 26011168 TI - Capturing Key NANDA-I Nursing Diagnoses From Actual Clinical Data for Patients With Heart Failure. AB - PURPOSE: The purpose of the study was to identify key nursing diagnoses with related factors and signs/symptoms using NANDA-I for patients with heart failure (HF). METHODS: A retrospective descriptive design was used to address the research questions. Data were obtained from the records of patients discharged for 1 year with the medical diagnoses of HF from a Midwestern community hospital. A total of 272 inpatient records were analyzed to describe the frequency and percentage of NANDA-I diagnosis with related factors and signs/symptoms. RESULTS: The top 10 NANDA-I diagnoses associated with related factors and signs/symptoms were identified. CONCLUSION: Further research related to standardized nursing terminologies such as NANDA-I using large clinical databases from health information systems is needed to support evidence-based nursing diagnosis decision making. PMID- 26011169 TI - Fluoxetine impairs insulin secretion without modifying extracellular serotonin levels in MIN6 beta-cells. AB - INTRODUCTION: Pancreatic beta-cells synthetize and store Serotonin (5 Hydroxytriptamine, 5HT) which is co-released with insulin. It has been proposed that extracellular 5HT binds to specific cell surface receptors and modulate insulin secretion. On the other hand, Selective Serotonin Reuptake Inhibitor (SSRI) fluoxetine seems to reduce Glucose-Stimulated Insulin Secretion (GSIS). However, it is unknown whether this effect results from changes in extracellular 5HT concentration owed to the blockade of 5HT transporter (SERT) or from non-5HT dependent actions. The aims of this work were: 1) to quantify extracellular 5HT levels and GSIS in beta-cell lines, 2) to determine whether extracellular 5HT levels and GSIS are changed by fluoxetine or 5-Hydroxytryptophan (5HTP, the immediate 5HT biosynthetic precursor), and 3) to quantify the expression of Slc6a4 gene (encoding SERT) in beta-cell lines in relation to other genes involved in 5HT system. MATERIAL AND METHODS: beta-cell lines MIN6 and RINm5f were subjected to GSIS protocols, after treatment with fluoxetine, 5HTP or 5HT. Insulin and 5HT were quantified by ELISA and HPLC, respectively. Relative mRNA expression was quantified by RT-qPCR. RESULTS: MIN6 beta-cells secretes 5HT in response to glucose, showing a sharp increase in 5HT release when cells were preloaded with 5HTP. Treatment with 5HT or fluoxetine reduces GSIS. Fluoxetine fails to further increases 5HTP-induced elevation of secreted 5HT. MIN6 beta cells express both isoforms of Tryptophan Hydroxylase (Tph1 and Tph2), and have high expression levels of L-Dopa decarboxylase (Ddc), both enzymes involved in 5HT biosynthetic pathway, but do not express the 5HT transporters Slc6a4 or Slc6a3 (the Dopamine-5HT transporter) genes. CONCLUSION: The inhibitory effect of fluoxetine on beta-cell glucose stimulated insulin secretion is not mediated by blockage of 5HT transporter through SERT. PMID- 26011170 TI - The protective effect of losartan on diabetic neuropathy in a diabetic rat model. AB - AIM: Involvement of the peripheral and autonomic nervous systems is possibly the most frequent complication of diabetes. Important risk factors included hyperglycemia, dyslipidemia, hypertension, and smoking. Angiotensin-converting enzyme inhibitor (ACE) inhibitors should be beneficial in all vascular beds, including neuropathy and retinopathy. In this study we aimed to evaluate the effect of the angiotensin receptor blocker losartan on diabetic neuropathy in a diabetic rat model. MATERIAL AND METHODS: 24 male, Sprague Dawley albino mature rats were divided into 3 groups; (1) control group: No drug was administered to the remainder of rats which blood glucose levels were under 120 mg/dl, (2) diabetic control: rats were given no medication, but 4 ml per day of tap water was given by oral gavage, (3) losartan groups: rats were given 10 mg/kg/day oral of losartan for 4 weeks. Electromyography (EMG) was applied to anesthetized rats at the end of 4(th) weekend. Then, the animals were euthanized and sciatic nerve was performed for histopathological examination. RESULTS: Compound Muscle Action Potential (CMAP) amplitude of diabetic rats receiving the Saline in the EMG was significantly reduced when compared to the control group. Distal latency value and CMAP duration of diabetic rats receiving the saline were meaningfully increased when compared to the control group. CMAP amplitude and CMAP duration of diabetic rats receiving the Losartan treatment in the EMG were meaningfully reduced when compared to diabetic rats receiving the Saline.Perineural thickness in the rats receiving the Losartan treatment was found to be significantly reduced when compared to the group receiving the Saline. CONCLUSIONS: As a result, it has been shown in this study that perineural thickness of the Losartan treatment was significantly reduced when compared to saline receiving group, significantly increased the immunoexpression of NGF, and also provided a significantly recovery in EMG when compared to Saline receiving group. PMID- 26011171 TI - Effects of DSP-8658, a novel selective peroxisome proliferator-activated receptors a/gamma modulator, on adipogenesis and glucose metabolism in diabetic obese mice. AB - AIMS/INTRODUCTION: Peroxisome proliferator-activated receptors (PPARs) play a key regulating role in homeostasis. In this study, we investigated the effects of DSP 8658, a novel selective PPARa/gamma modulator, on adipogenesis and glucose metabolism in diabetic obese mice and compared these effects to those of pioglitazone, a PPARgamma full agonist. MATERIALS AND METHODS: DSP-8658 functional activity was assessed by PPARgamma-target genes expression in adipose 3T3-L1 cells and its anti-diabetic efficacy evaluated in db/db mice. The effects of DSP-8658 on adipogenesis were investigated diet induced obese (DIO) KK-A(y) mice. RESULTS: DSP-8658 reduced the expression of PPARgamma-target gene 11 beta hydroxysteroid dehydrogenase type 1 with an EC50 value 2.1-fold that of pioglitazone and 28.4-fold that of rosiglitazone. On the other hand, DSP-8658 increased the expression of fatty acid binding protein 4 and glycerol kinase genes with EC50 values 33-fold and >15-fold those of pioglitazone and 163-fold and >38-fold those of rosiglitazone, respectively. In db/db mice, DSP-8658, like pioglitazone, decreased blood glucose, HbA1c, and plasma triglyceride levels and increased plasma insulin concentration and pancreatic insulin contents. In DIO KK A(y) mice, DSP-8658, unlike pioglitazone, decreased subcutaneous adipose tissue weight and mean adipocyte size. However, both DSP-8658 and pioglitazone improved blood glucose and HbA1c levels with similar efficacy. Although DSP-8658 did not change the expression levels of fatty acid transport protein 1 and glycerol kinase genes in subcutaneous adipose tissue of KK-A(y) mice, pioglitazone increased these gene expression levels. CONCLUSION: Unlike PPARgamma full agonists, DSP-8658 ameliorates blood glucose without increasing adipogenesis in diabetic obesity mice. PMID- 26011172 TI - Radiotherapy-induced hypopituitarism in nasopharyngeal carcinoma: the tip of an iceberg. AB - BACKGROUND: Radiation-induced hypopituitarism is an important late complication of cranial radiotherapy in children and adults. The purpose of this cross sectional study was to evaluate the effects of radiotherapy on pituitary function in adult nasopharyngeal carcinoma patients. METHODS: Pituitary function was evaluated in 30 patients after cranial radiotherapy for nasopharyngeal carcinoma. Somatotroph and corticotroph axes were assessed by insulin tolerance test while gonadotroph and thyroid axes were evaluated by basal pituitary and end organ hormone levels at 10-133 months after radiotherapy. RESULTS: At least one hormonal disorder was observed in 28 (93%) patients after radiotherapy. 26 (87%) patients had one or more anterior pituitary hormone deficiencies. The rates of pituitary hormone deficiencies were 77% for growth hormone, followed by adrenocorticotropic hormone (73%), thyroid-stimulating hormone (27%) and gonadotropins (7%). Hyperprolactinemia was present in 13 (43%) patients. CONCLUSIONS: Radiation-induced hypopituitarism is more common than expected in patients with nasopharyngeal carcinoma. PMID- 26011173 TI - The Value of Total antioxidant Status and Serum Tumor Necrosis Factor-alpha Levels at 24-28 Weeks of Gestation in the Prediction of Optimal Treatment Protocol in Gestational Diabetes Mellitus. AB - Aim: The aim of this study was to investigate the serum oxidative stress markers, antioxidant enzyme and tumor necrosis factor-alpha (TNF-alpha) levels at 24-28 weeks of gestation and to evaluate the predictive value of them on the subsequent treatment protocol in gestational diabetes mellitus (GDM). Methods: A total of 58 GDM patients (30 treated with only conventional healthy dietary recommendation (CHDR), 28 treated with insulin) and 30 healthy pregnant women at 24-28 weeks of gestation, were enrolled in this prospective case-control study. The oxidative status, antioxidant enzyme and TNF-alpha levels were evaluated to determine if there is an association with the need of insulin therapy for glycemic control by using multivariable logistic regression analysis. Results: TNF-alpha (OR=11.976, 95%CI: 2.441-58.754, P=0.002) and total antioxidant status (TAS) (OR=12.769, 95%CI: 2.464-66.182, P=0.002) were found to be predictive for GDM at 24-28 weeks of gestation. Besides, further evaluation considering the treatment modality showed that increased TNF-alpha (OR=18.615, 95%CI: 2.338-148.240, P=0.006) and lower TAS levels (OR=99.471, 95%CI: 2.865-3 453.061, P=0.011) were independent predictors of the need for insulin treatment in GDM patients. Conclusions: Increased TNF-alpha levels and low TAS are significantly associated with the increased risk of insulin requirement for achieving good glycemic control in GDM. PMID- 26011174 TI - Serum leptin in neonatal lambs is associated with temperature, plasma lipids and metabolites. AB - In this study we investigated changes of serum leptin in 74 newborn lambs and associations with environmental temperature (from - 8 degrees C to + 25 degrees C), body temperature, and concentrations of plasma lipids, 3-beta-hydroxybutyric acid and blood glucose. A leptin radioimmunoassay was established, using an antiserum (rabbit) produced against a partial sequence of ovine leptin (31-44). Before measurement, serum samples were denatured. The sensitivity of the assay was 0.4 ug l(-1) and intra- and interassay coefficients of variation were 5.1% and 2.5%, respectively. Blood samples were collected immediately after birth up to 24 h postnatally (pn). Median leptin concentrations at birth and 24 h pn were 20.9 and 52.7 ug l(-1), respectively. Because of non-normal distribution, leptin concentrations were converted to log(leptin) before further statistical processing. The change in log(leptin) during the first 24 h was highly significant (p<0.0001). Correlation analysis showed significant associations between serum leptin and the following variables: environmental temperature 24 h pn (r=0.34, p<0.005), log(plasma triglycerides) 24 h pn (r=0.50, p<0.001), log(plasma 3-beta-hydroxybutyric acid) 24 h pn (r=-0.50, p<0.001), blood glucose 6 h pn (r=0.43, p<0.001) and plasma cholesterol 12 h pn (r=0.38, p=0.001). We conclude that this radioimmunoassay is suited to measure total serum ovine leptin and that total leptin is already regulated in the very early postnatal phase. Leptin is increased at higher environmental temperatures, consistent with leptin's suppressive effect on energy expenditure and appetite. Furthermore, leptin levels are associated with plasma concentrations of lipids and lipid metabolites. PMID- 26011175 TI - Objective-Induced Point Spread Function Aberrations and Their Impact on Super Resolution Microscopy. AB - This study demonstrates how different microscope objectives can lead to asymmetric imaging aberrations in the point spread function of dipolar emitters, which can adversely affect the quality of fit in super-resolution imaging. Luminescence from gold nanorods was imaged with four different objectives to measure the diffraction-limited emission and characterize deviations from the expected dipolar emission patterns. Each luminescence image was fit to a three dipole emission model to generate fit residuals that visually relay aberrations in the point spread function caused by the different microscope objectives. Output parameters from the fit model were compared to experimentally measured values, and we find that while some objectives provide high quality fits across all nanorods studied, others show significant aberrations and are inappropriate for super-resolution imaging. This work presents a simple and robust strategy for quickly assessing the quality of point spread functions produced by different microscope objectives. PMID- 26011177 TI - Application of mixed modal resin for purification of a fibrinolytic enzyme. AB - Recent advances in purification technologies for therapeutic molecules have stirred the research consortium. Mixed mode chromatography, having multiple interactions with the solute molecule, has drawn significant attention due to its overall advantage over traditional ion-exchange and reverse-phase chromatography. Capto adhere, a mixed mode chromatography resin with strong anion-exchange and reverse-phase interaction with solutes, was explored for purification of fibrinolytic enzyme from Bacillus sphaericus MTCC 3672. Static and dynamic resin binding study revealed that 30 degrees C temperature, pH 8, and 0.5 mL/min flow rate were optimum for maximum binding of fibrinolytic enzyme. Maximum static dynamic binding and breakthrough capacities for Capto adhere were 249 and 196 U/mL of resin, respectively. Final purification with Sephadex G 100 gel chromatography resulted in 38-fold purity of fibrinolytic enzyme with 39% enzyme recovery. Purified enzyme was further characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis to homogeneity, and molecular mass was found to be around 55-70 kD. Like most of the serine alkaline proteases, purified fibrinolytic enzyme was stable in a temperature range of 25 40 degrees C and pH range of 7-9. Offshoots of our research findings have revealed a broad application area of mixed mode chromatography. PMID- 26011176 TI - Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. AB - Exosomes, which are approximately 100 nm vesicles secreted by cells, have been studied with respect to cell-to-cell communication, disease diagnosis, and intracellular delivery. The cellular uptake of exosomes occurs by endocytosis; however, the cytosolic release efficiency of encapsulated molecules inside cells is low. To address this issue, here we demonstrate a simple technique for enhancing the cellular uptake and cytosolic release of exosomes by combining a pH sensitive fusogenic peptide for the fusion of endosomal and exosomal membranes inside cells. This method stimulates the efficient cytosolic release of the exosomal contents with cationic lipids that act as a "glue" to support cellular uptake. Using this simple combined technique, the effective cellular uptake and cytosolic release of an artificially encapsulated dextran macromolecule (70 kDa) in exosomes are achieved, and a marked improvement in bioactivity is attained with the artificially encapsulated ribosome-inactivating protein saporin. Our method will contribute to many biological research fields, including the assessment of the activities of exosomal contents and the development of candidate tools enabling intracellular visualisation and cellular regulation for future therapeutic applications. PMID- 26011178 TI - Mobilization of hematopoietic progenitor cells from allogeneic healthy donors using a new biosimilar G-CSF (Zarzio(r)). AB - Peripheral blood progenitor cells (PBPCs) have become the major source of hematopoietic progenitor cells for allogeneic transplantation. In February 2008, Zarzio(r) was approved by the European Medicine Agency for PBPCs mobilization, but this authorization was not based in trials analyzing safety and efficacy for PBPCs mobilization. Since August 2011, Zarzio(r) has been used at our institution for PBPCs mobilization. In total 36 healthy family donors underwent PBPCs mobilization, 18 with Neupogen(r) and 18 with Zarzio(r). Donor characteristics were equivalent between groups, and no severe adverse effects were registered in the Zarzio(r) group. The number of CD34 cells collected/Kg recipient body weight was 6.7 * 10(6) (3.8-11.1) in the Zarzio(r) group versus 8.4 * 10(6) (5.6-16.6) in the Neupogen(r) group (P = 0.04). We collected the minimal target cell dose (2 * 10(6) /kg) in all donors from each group and no significant differences were found in the collection of the optimal cell dose (5 * 10(6) /kg) between groups, although 3/18 (16.6%) donors that received Zarzio(r) failed to mobilize the optimal cell dose compared with 0% in the Neupogen(r) group. A total of 35 patients proceeded to transplantation (17 in the Zarzio(r) and 18 in the Neupogen(r) groups, respectively). Platelet and neutrophil median time to engraftment was comparable between the two groups. Our retrospective study supports the conclusion that Zarzio(r) mobilization of PBPCs in healthy donors is safe but perhaps not as effective as the reference Neupogen. However, more prospective trials are required to definitively asses the safety and efficacy of G-CSF biosimilars for PBPCs mobilization in healthy donors. PMID- 26011179 TI - The RAGE receptor and its ligands are highly expressed in astrocytes in a grade dependant manner in the striatum and subependymal layer in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG repeat in the huntingtin gene. One of the brain changes that occurs in HD is the expression of the receptor for advanced glycation end products (RAGE), a receptor protein capable of activating multiple signalling pathways by interacting with a range of ligands leading to either beneficial or harmful effects to the cell. Here, we demonstrate in human HD brains a high degree of co-localization of RAGE with its putative ligands S100B and N-carboxymethyllysine (CML) in the caudate nucleus (CN) and the subependymal layer (SEL). The level of co-staining for both RAGE-S100B and RAGE-CML was the highest in the astrocytes but was low in neurons and microglia. The immunostaining for RAGE, S100B and CML extended in a medio-lateral (SEL-CN) direction with increasing grade, such that any change in the expression and co localization pattern between grades was less prominent in the lateral CN. Additionally, signalling molecules that are downstream of RAGE activation showed changes in their activation status in HD brains. A larger number of RAGE-positive astrocytic cells had NF-kB translocated to the nucleus and the level of phospho ERK1/2 was also increased in HD brains. Interestingly, the level of mDia-1, that interacts directly with the cytoplasmic domain of RAGE, decreased in HD. Overall, the results suggest a correlation between the functions of RAGE and the HD pathology, but the influence of RAGE on astrocytes and the impact of this on HD progression requires further study. RAGE (receptor for advanced glycation end products) binds multiple types of ligand to produce either neurotrophic or neurotoxic effects. Immunohistochemical staining of HD human brains showed that both RAGE and its ligands were expressed primarily in astrocytes. The pattern of staining corresponded to the grade and region-wise pattern of neurodegeneration suggesting a possible role for RAGE in HD pathology. PMID- 26011180 TI - East African pigs have a complex Indian, Far Eastern and Western ancestry. AB - In this study, we have characterized the mitochondrial diversity of 81 swine from Uganda. Median-joining network analysis of D-loop sequences from these individuals and others characterized in previous studies allowed us to determine that Ugandan pigs cluster with populations from the West (Europe/North Africa), Far East and India. In addition, partial sequencing of the Y-chromosome UTY locus in 18 Ugandan domestic pigs revealed the segregation of a single HY1 lineage that has a cosmopolitan distribution. A Western and Far Eastern ancestry for East African pigs had been already reported, but this is the first study demonstrating an additional contribution from the Indian porcine gene pool. This result is consistent with the high frequency of zebuine alleles in cattle from East Africa. The geographic coordinates of East Africa, at the crossroads of many trading routes that, through the ages, linked Europe, Africa and Asia, might explain the rich and complex genetic heritage of livestock native to this area. PMID- 26011181 TI - HyFlex EDM: superficial features, metallurgical analysis and fatigue resistance of innovative electro discharge machined NiTi rotary instruments. AB - AIM: To evaluate the surface and microstructural alterations of new and used HyFlex EDM prototypes and to test their fatigue resistance. METHODOLOGY: Fifteen HyFlex EDM prototypes were used for in vitro instrumentation of severely curved root canals. Surface and microstructural characteristics of new and used files were compared by ESEM analysis equipped with energy dispersive X-ray spectrophotometry (EDS) and optical metallographic imaging. Usage-induced degradation was assessed. Thirty additional HyFlex EDM prototypes and 20 standard manufactured HyFlex CM files were subjected to cyclic fatigue tests. Time to fracture was recorded, and results were validated using the Kruskal-Wallis test (alpha-level 0.05). Fatigued files were analysed by ESEM for fractographic evaluation. RESULTS: Surface and microstructural characterization of EDM prototypes revealed the typical spark-machined surface of a NiTi EDM alloy. No fractures were registered during root canal instrumentation. No evident surface alterations and minor degradation were observed between new and used instruments. The metallographic analysis of new and used files disclosed a homogeneous structure, mostly composed of lenticular martensite grains, and some residual austenite. The cyclic fatigue test showed an increase of fatigue resistance up to 700% on the EDM compared to CM files. CONCLUSIONS: Spark-machined peculiar surface is the main feature of HyFlex EDM. Low degradation was observed after multiple canal instrumentations. Prototypes exhibited surprising high values of cyclic fatigue resistance and a safe in vitro use in severely curved canals. PMID- 26011182 TI - Reconciling oil palm expansion and climate change mitigation in Kalimantan, Indonesia. AB - Our society faces the pressing challenge of increasing agricultural production while minimizing negative consequences on ecosystems and the global climate. Indonesia, which has pledged to reduce greenhouse gas (GHG) emissions from deforestation while doubling production of several major agricultural commodities, exemplifies this challenge. Here we focus on palm oil, the world's most abundant vegetable oil and a commodity that has contributed significantly to Indonesia's economy. Most oil palm expansion in the country has occurred at the expense of forests, resulting in significant GHG emissions. We examine the extent to which land management policies can resolve the apparently conflicting goals of oil palm expansion and GHG mitigation in Kalimantan, a major oil palm growing region of Indonesia. Using a logistic regression model to predict the locations of new oil palm between 2010 and 2020 we evaluate the impacts of six alternative policy scenarios on future emissions. We estimate net emissions of 128.4-211.4 MtCO2 yr(-1) under business as usual expansion of oil palm plantations. The impact of diverting new plantations to low carbon stock land depends on the design of the policy. We estimate that emissions can be reduced by 9-10% by extending the current moratorium on new concessions in primary forests and peat lands, 35% by limiting expansion on all peat and forestlands, 46% by limiting expansion to areas with moderate carbon stocks, and 55-60% by limiting expansion to areas with low carbon stocks. Our results suggest that these policies would reduce oil palm profits only moderately but would vary greatly in terms of cost effectiveness of emissions reductions. We conclude that a carefully designed and implemented oil palm expansion plan can contribute significantly towards Indonesia's national emissions mitigation goal, while allowing oil palm area to double. PMID- 26011183 TI - Effects of xenoestrogens in human M1 and M2 macrophage migration, cytokine release, and estrogen-related signaling pathways. AB - Bisphenol A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and di(n-butyl)phthalate (DBP) are environmental estrogens that have been associated with a wide range of adverse health outcomes for which inflammation has also been hypothesized as a potentially involved mechanism and where macrophages play a central role. This study was carried out to evaluate if xenoestrogen (XE) treatment of classically (M1) or alternatively (M2) activated macrophages could affect their behavior. For this purpose, human peripheral blood monocyte-derived macrophages either unstimulated or activated with lipopolysaccharide (100 ng/mL, M1) or with interleukin (IL) 4 (15 ng/mL, M2) were treated with 17beta-estradiol (E2 ), BPA, DEHP and DBP alone or in combination with selective ERalpha or ERbeta antagonists. Migratory capability, cytokine release, and estrogen-associated signaling pathways were evaluated to assess macrophage function. All tested XEs had a tendency to stimulate M2 migration, an effect that followed the same direction than E2 . Moreover, all XEs significantly induced IL10 in M1 and decreased IL6 and globally decreased IL10, IL6, TNFalpha, and IL1beta release by M2 macrophages. However, DEHP and DBP significantly increased IL1beta release in M1 and M2 macrophages, respectively. Some of the effects described above were shown to be mediated by either ERalpha or ERbeta and were simultaneous to modulation of NF-kappaB, AP1, JNK, or ERK signaling pathways. We provide new evidence of the effect of XE on macrophage behavior and their mechanisms with relevance to the understanding of the action of environmental chemicals on the immune system and inflammation-associated diseases. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1496-1509, 2016. PMID- 26011185 TI - The interbranchial lymphoid tissue of Atlantic Salmon (Salmo salar L) extends as a diffuse mucosal lymphoid tissue throughout the trailing edge of the gill filament. AB - The teleost gill forms an extensive, semipermeable barrier that must tolerate intimate contact with the surrounding environment and be able to protect the body from external pathogens. The recent discovery of the interbranchial lymphoid tissue (ILT) has initiated an anatomical and functional investigation of the lymphoid tissue of the salmonid gill. In this article, sectioning of gill arches in all three primary planes revealed an elongation of the ILT outward along the trailing edge of the primary filament to the very distal end, a finding not previously described. This newly found lymphoid tissue was investigated using a range of morphological and transcriptional tools. Avoiding potential salinity related effects, the study focused on two fresh-water life stages-smoltifying juveniles and mature adults. Aggregates of T-cells continuous with the ILT were found within the thick epithelial lining of the trailing edge of the filament in considerably larger numbers than seen in the epithelium of the leading edge and of the interlamellar area. Only a few of these cells were identified as CD8alpha(+) -cells, and there was a significantly (P < 0.05) higher relative expression of CD4- than of CD8- related genes in all gill segments investigated. Numerous major histocompatibility complex class II(+) -cells were distributed uniformly throughout the filament epithelial tissue. Few Ig(+) -cells were detected. Overall, the morphological features and comparable immune gene expression of the previously described ILT and the filament trailing edge lymphoid tissue suggest a close functional and anatomical relationship. We propose that the anatomical definition of the ILT must be broadened to include both the previously described ILT (to be renamed proximal ILT) and the trailing edge lymphoid tissue (to be named distal ILT). This extended anatomical localisation identifies the ILT as a widely distributed mucosal lymphoid tissue in the gill of Atlantic salmon. PMID- 26011184 TI - Abnormalities in brain systems supporting individuation and enumeration in autism. AB - Previous work indicates that adults with autism display a decreased capacity when rapidly enumerating small sets of elements (i.e., subitizing), compared to typically developing (TD) individuals. This ability is crucial for fundamental visual functions such as object individuation and parallel processing. Thus, the deficit in autism suggests limits in these skills. To examine the neural basis of this limitation, adults with and without high functioning autism rapidly enumerated 1 to 8 randomly located squares during a neuroimaging study. Typically, adults are thought to use parallel visual processes to quantify up to three or four elements, and serial processes to enumerate more (5+) elements. We hypothesized that parietal lobe regions associated with counting would be recruited with smaller sets of elements in adults with autism, compared to TD adults. Consistent with this hypothesis, activation in parietal regions increased with smaller set sizes in adults with autism compared to TD adults. Increased activation for three elements was evident in several regions, including those thought to underlie subitizing. In addition, regions specific to the counting range in TD adults were often equally active for set sizes in the subitizing range in the adults with autism. Finally, significant deactivation was evident in TD adults, presumably reflecting relative suppression of regions specialized for competing processes, but was not apparent in adults with autism. These differences in brain function in adults with autism on a simple enumeration task suggest atypical brain organization and function that is likely to impact most visual tasks, especially those with multiple elements. PMID- 26011187 TI - Multiplexed, targeted gene editing in Nicotiana benthamiana for glyco-engineering and monoclonal antibody production. AB - Biopharmaceutical glycoproteins produced in plants carry N-glycans with plant specific residues core alpha(1,3)-fucose and beta(1,2)-xylose, which can significantly impact the activity, stability and immunogenicity of biopharmaceuticals. In this study, we have employed sequence-specific transcription activator-like effector nucleases (TALENs) to knock out two alpha(1,3)-fucosyltransferase (FucT) and the two beta(1,2)-xylosyltransferase (XylT) genes within Nicotiana benthamiana to generate plants with improved capacity to produce glycoproteins devoid of plant-specific residues. Among plants regenerated from N. benthamiana protoplasts transformed with TALENs targeting either the FucT or XylT genes, 50% (80 of 160) and 73% (94 of 129) had mutations in at least one FucT or XylT allele, respectively. Among plants regenerated from protoplasts transformed with both TALEN pairs, 17% (18 of 105) had mutations in all four gene targets, and 3% (3 of 105) plants had mutations in all eight alleles comprising both gene families; these mutations were transmitted to the next generation. Endogenous proteins expressed in the complete knockout line had N-glycans that lacked beta(1,2)-xylose and had a significant reduction in core alpha(1,3)-fucose levels (40% of wild type). A similar phenotype was observed in the N-glycans of a recombinant rituximab antibody transiently expressed in the homozygous mutant plants. More importantly, the most desirable glycoform, one lacking both core alpha(1,3)-fucose and beta(1,2)-xylose residues, increased in the antibody from 2% when produced in the wild-type line to 55% in the mutant line. These results demonstrate the power of TALENs for multiplexed gene editing. Furthermore, the mutant N. benthamiana lines provide a valuable platform for producing highly potent biopharmaceutical products. PMID- 26011188 TI - Changes in the current classification of IIP: A critical review. AB - Idiopathic interstitial pneumonias (IIP) are a heterogeneous group characterized by unknown aetiology. Establishment of a correct diagnosis of a distinct IIP requires a multidisciplinary approach integrating clinical presentation, physiological data, radiological appearance and histological findings. The 2013 update of the American Thoracic Society/European Respiratory Society classification summarises progress in the field of IIP and outlines potential areas for future research. The main entities defined by the 2002 statement on IIP are preserved, but major IIP are now distinguished from rare IIP and the new category of unclassifiable IIP is introduced. In addition, the existence of idiopathic non-specific interstitial pneumonia as a separate chronic fibrosing IIP and idiopathic pleuroparenchymal fibroelastosis as a specific rare entity are acknowledged. Moreover, the major IIP are categorized according to the features chronic fibrosing, smoking-related and acute/subacute clinical course. Furthermore, a clinical classification of IIP according to disease behaviour with suggestions for treatment goals and monitoring strategies is provided. The goal of this review is to discuss the areas of uncertainty in the updated multidisciplinary classification of IIP and point out potential consequences for clinical management. PMID- 26011186 TI - Transmission dynamics of pandemic influenza A(H1N1)pdm09 virus in humans and swine in backyard farms in Tumbes, Peru. AB - OBJECTIVES: We aimed to determine the frequency of pH1N1 transmission between humans and swine on backyard farms in Tumbes, Peru. DESIGN: Two-year serial cross sectional study comprising four sampling periods: March 2009 (pre-pandemic), October 2009 (peak of the pandemic in Peru), April 2010 (1st post-pandemic period), and October 2011 (2nd post-pandemic period). SAMPLE: Backyard swine serum, tracheal swabs, and lung sample were collected during each sampling period. MAIN OUTCOME MEASURES: We assessed current and past pH1N1 infection in swine through serological testing, virus culture, and RT-PCR and compared the results with human incidence data from a population-based active surveillance cohort study in Peru. RESULTS: Among 1303 swine sampled, the antibody prevalence to pH1N1 was 0% pre-pandemic, 8% at the peak of the human pandemic (October 2009), and 24% in April 2010 and 1% in October 2011 (post-pandemic sampling periods). Trends in swine seropositivity paralleled those seen in humans in Tumbes. The pH1N1 virus was isolated from three pigs during the peak of the pandemic. Phylogenetic analysis revealed that these viruses likely represent two separate human-to-swine transmission events in backyard farm settings. CONCLUSIONS: Our findings suggest that human-to-swine pH1N1 transmission occurred during the pandemic among backyard farms in Peru, emphasizing the importance of interspecies transmission in backyard pig populations. Continued surveillance for influenza viruses in backyard farms is warranted. PMID- 26011190 TI - Pathogenesis and association of Mycoplasma pneumoniae infection with cardiac and hepatic damage. AB - The aim of this study was to investigate the pathogenesis of Mycoplasma pneumoniae (MP) infection and its association with cardiac and hepatic damage. Between March 2013 and March 2014, 59 children with MP pneumonia (MPP) and 30 healthy children were enrolled. Serum titers of TLR4, T cell immunoglobulin and mucin-domain (TIM) 3, IL-10, TNF-alpha, and IFN-gamma were measured both in children with MPP and healthy children. Additionally, MP-specific antibody titer and creatine kinase-MB (CK-MB), and alanine transaminase (ALT) titers were measured in patients with MPP. There were significant differences between the MPP patients and healthy controls in titers of TIM1 (P < 0.01), TLR2 (P = 0.028), TLR4 (P = 0.019), IL-10 (P < 0.01), TNF-alpha (P < 0.01) and IFN-gamma (P < 0.01); however, no significant difference was found in TIM3 titers (P = 0.8181). TIM1 was correlated with CK-MB (P = 0.025), whereas both TIM1 and TLR2 titers were correlated with MP-specific antibody titers (P < 0.001; P = 0.003, respectively). Additionally, there were correlations between ALT, TIM3, and TLR2 titers (P = 0.025; P = 0.037, respectively). The titers of TIM1 were significantly higher in patients with cardiac damage (P = 0.007) than in those without it, whereas the titers of TLR2 were significantly higher in patients with hepatic damage (P = 0.026) than in those without it. TLR2, TLR4 and TIM1 may be involved in the process of MP infection. Additionally, TLR2, TLR4, TIM1 and TIM3 may play particular roles in the pathogenesis of MPP-associated cardiac and hepatic damage. PMID- 26011191 TI - Microglial Kv1.3 Channels and P2Y12 Receptors Differentially Regulate Cytokine and Chemokine Release from Brain Slices of Young Adult and Aged Mice. AB - Brain tissue damage following stroke or traumatic brain injury is accompanied by neuroinflammatory processes, while microglia play a central role in causing and regulating neuroinflammation via production of proinflammatory substances, including cytokines and chemokines. Here, we used brain slices, an established in situ brain injury model, from young adult and aged mice to investigate cytokine and chemokine production with particular focus on the role of microglia. Twenty four hours after slice preparation, higher concentrations of proinflammatory cytokines, i.e. TNF-alpha and IL-6, and chemokines, i.e. CCL2 and CXCL1, were released from brain slices of aged mice than from slices of young adult mice. However, maximal microglial stimulation with LPS for 24 h did not reveal age dependent differences in the amounts of released cytokines and chemokines. Mechanisms underlying microglial cytokine and chemokine production appear to be similar in young adult and aged mice. Inhibition of microglial Kv1.3 channels with margatoxin reduced release of IL-6, but not release of CCL2 and CXCL1. In contrast, blockade of microglial P2Y12 receptors with PSB0739 inhibited release of CCL2 and CXCL1, whereas release of IL-6 remained unaffected. Cytokine and chemokine production was not reduced by inhibitors of Kir2.1 K+ channels or adenosine receptors. In summary, our data suggest that brain tissue damage induced production of cytokines and chemokines is age-dependent, and differentially regulated by microglial Kv1.3 channels and P2Y12 receptors. PMID- 26011192 TI - Implantation of an Absorb bioresorbable vascular scaffold in the stenotic aortopulmonary collateral artery of a young child with Alagille syndrome. AB - Stent implantation in children can be problematic due to the possibility of growth incapacity and difficulties during later surgery. For these reasons, bioresorbable stents may be a good alternative to conventional stents. We report our experience with implantation of an Absorb bioresorbable stent in the stenotic major aortopulmonary collateral artery (MAPCA) of a 1-year-old girl born with pulmonary atresia with ventricular septal defect. PMID- 26011193 TI - Elastography to assess the effect of varicoceles on testes: a prospective controlled study. AB - Varicoceles are the most common and treatable cause of male infertility. The pathophysiology of varicoceles primarily includes elevated temperature, adrenal hormone reflux, gonadotoxic metabolite reflux, altered testicular blood flow, antisperm antibody formation and oxidative stress. The diagnosis of a varicocele is mainly clinical. However, a Doppler ultrasound is used to obtain clinical data and to more accurately measure testicular size. Acoustic radiation force impulse (ARFI) is an additional technique to simultaneously show different areas with different densities in a colour-coded image and a B-mode or greyscale image. This can be used for structural analysis of testicular tissue and has become an additional method for detecting pathologic tissue alterations. We enrolled 30 patients who had clinically diagnosed with left varicoceles and male infertility (Group 1). All patients were evaluated by history taking, physical examination, a spermiogram and an endocrine profile. Thirty control patients (Group 2) were randomly chosen from patients who had applied to an andrology clinic for infertility; their physical examinations and laboratory results showed normal findings. Mean elastography results were significantly different between the groups, and significantly lower in patients who had varicoceles. The relationship between hormonal profiles and elastography parameters was calculated as statistically significant negative correlations between FSH and elasticity. Additionally, a negative correlation was determined between varicocele grade and elasticity of testes. In conclusion, our prospective study showed that ARFI imaging may be more useful than palpation for determining early damage of testicular structure by varicoceles. PMID- 26011194 TI - The rebirth of International Surgery. PMID- 26011196 TI - Effect of preoperative colonic drainage for obstructing colorectal cancer. AB - Obstructing colorectal cancer (OCRC) is believed to indicate poorer long-term survival. The purpose of this study was to compare retrospectively perioperative safety and long-term results in patients undergoing surgery for OCRC following preoperative colonic decompression with that in those undergoing elective surgery alone for nonobstructing colorectal cancer (CRC). A total of 656 consecutive CRC patients undergoing colectomy between 2001 and 2011 at our institute were eligible for inclusion in the study. The patients were divided into an OCRC group, which included 104 patients undergoing colectomy with preoperative colonic decompression, and a CRC group, which included 552 patients undergoing colectomy alone. Morbidity, mortality, and prognosis were assessed. In the OCRC group, decompression was performed by nasointestinal tube in 42 patients (40.4%), transanal tube in 15 (14.4%), and colostomy in 47 (45.2%). The mortality rate was 0% in the OCRC group and 0.4% in the CRC group (2 of 552 patients). The morbidity rate was 44.8% in the OCRC group (48 of 104 patients) and 36.6% in the CRC group (202 of 552 patients). The 5-year overall survival rate was 69.5% in the OCRC group and 72.9% in the CRC group [hazard ratio 0.76; 95% confidence interval, 0.35 to 1.16; P = 0.48)]. No statistically significant difference in survival was observed between the 2 groups in stage II, III, or IV, or overall. No difference was observed in safety or survival between advanced OCRC patients undergoing preoperative colonic decompression and advanced non-obstructing CRC patients undergoing surgery alone. PMID- 26011195 TI - Management of granulomatous mastitis: a series of 13 patients who were evaluated for treatment without corticosteroids. AB - Granulomatous mastitis (GM) is a rare chronic inflammatory breast condition with unknown etiology. There is still no generally accepted optimal treatment for GM. Corticosteroid treatment and/or wide excision is most commonly reported in the literature. Incision and drainage or limited excision alone has little benefit because of a strong tendency of recurrence. Corticosteroids also have a high failure rate and possible side effects. In the current series, we treated GM patients without corticosteroids, except for one patient. We also devised multidirectional deep drainage for advanced and complicated abscesses, which are characteristic of GM. This retrospective study included 13 women who met the required histologic criteria of GM. The mean age of the patients was 41 years. All of the patients were premenopausal. Six patients had breast-fed in the last 5 years. Five patients were under medication with antidepressants. A total of 11 patients developed abscesses during the clinical course, and the abscesses penetrated the retromammary space in 4 patients. We treated 2 of these 4 patients with multidirectional deep drainage and obtained complete remission in 5 and 6.5 months, respectively. These times were much shorter than those in the other 2 patients. The time to resolution in 11 patients was 4 to 28 months. This overall outcome was comparable with that of corticosteroid treatment reported in the literature. Because the natural history of GM is thought to be self-limiting, close observation and minimally required drainage of abscesses without corticosteroid administration remain the treatment modality of choice. PMID- 26011197 TI - Perioperative Allogeneic Blood Transfusion Is Associated With Surgical Site Infection After Abdominoperineal Resection-a Space for the Implementation of Patient Blood Management Strategies. AB - Allogeneic blood transfusion (ABT) has been reported as a major risk factor for surgical site infection (SSI) in patients undergoing colorectal surgery. However, the association of ABT with SSI in patients undergoing abdominoperineal resection (APR) and total pelvic exenteration (TPE) still remains to be evaluated. Here, we aim to elucidate this association. The medical records of all patients undergoing APR and TPE at our institution in the period between January 2000 and December 2012 were reviewed. Patients without SSI (no SSI group) were compared with patients who developed SSI (SSI group), in terms of clinicopathologic features, including ABT. In addition, data for 262 patients who underwent transabdominal rectal resection at our institution in the same period were also enrolled, and their data on differential leukocyte counts were evaluated. Multivariate analysis showed that intraoperative transfusion was an independent predictive factor for SSI after APR and TPE (P = 0.004). In addition, the first-operative day lymphocyte count of patients undergoing APR, TPE, and transabdominal rectal resection was significantly higher in nontransfusion patients compared with transfusion ones (P = 0.026). ABT in the perioperative period of APR and TPE may have an important immunomodulatory effect, leading to an increased incidence of SSI. This fact should be carefully considered, and efforts to avoid allogeneic blood exposure while still achieving adequate patient blood management would be very important for patients undergoing APR and TPE as well. PMID- 26011198 TI - Giant extraluminal leiomyoma of the colon: rare cause of symptomatic pelvic mass. AB - Leiomyomas (LMs) may appear throughout the entire gastrointestinal tract but are rarely seen in the colon-rectum and only 5 of those measured greater than 15 cm in diameter. Pain and palpable abdominal mass are the most common symptoms. Surgical resection is the treatment of choice for most LMs. We here describe a case of a 46-year-old woman who presented with a 3-month history of abdominal pain associated with worsening constipation and abdominal distension. A pelvic solid, polylobulate, left-sided mass was noted on examination. Preoperative findings revealed a dishomogeneous sigmoid mass with calcified spots compressing small intestine and bladder. At laparotomy, a large polylobulate and well circumscribed mass arising from the descending colon mesentery and displacing small intestine, uterus, and ovaries. A segmental colon resection was performed. An extraluminal 18- * 12- * 5-cm paucicellular sigmoid colon leiomyoma was histologically diagnosed. Our case is one of the few giant (>15 cm) sigmoid colon LMs reported in the literature. Although rare and benign in nature, LMs of the colon can cause life-threatening complications that could require emergency treatment and they should be included in the differential diagnosis of large abdominopelvic masses. Follow-up after surgery is necessary for tumors with any atypia or mitotic activity. PMID- 26011199 TI - Desmoplastic small round cell tumor in transverse colon: report of a rare case. AB - Desmoplastic small round cell tumor (DSRCT) is an extremely rare, highly aggressive, malignant tumor of undetermined histogenesis. Adolescent males are primarily affected with a typically abdominal or pelvic mass. Diagnosis is based on histologic analysis of biopsy and cytogenetic studies. Owing to the rarity of the tumor and the unusually aggressive presentation, treatment is challenging and has not been standardized. DSRCT has a very poor prognosis, with a median survival range of 17 to 25 months. In this work, we report a case of DSRCT in the transverse colon, which has never before been reported in the literature. Our case study is of a 30-year-old Chinese female who presented with a history of 6 months abdominal discomfort and fatigue. A palpable, hardly mobile mass was detected in the right lower quadrant abdomen by physical examination. Abdominal and pelvic magnetic resonance imaging revealed an 8.0 * 10.5 * 11.1-cm mass with no pulmonary and hepatic metastasis. The patient underwent exploratory laparotomy and transverse colectomy, which revealed a mass in the transverse colon and no metastasis in the peritoneum, greater omentum, or mesentery. Immunohistochemistry findings revealed positive staining for epithelial, mesenchymal, and neural markers, which confirmed the presentation of DSRCT. A 6-month postoperative follow-up failed to find any recurrence. DSRCT is a highly aggressive, malignant, mesenchymal tumor with a very poor prognosis. No consensus has been reached for the treatment protocol of DSRCT. However, debulking surgery with postoperative chemotherapy or radiotherapy might promise more optimistic results on survival. PMID- 26011200 TI - Synchronous primary anorectal melanoma and sigmoid adenocarcinoma: a case report. AB - Synchronous primary anorectal melanoma and colorectal adenocarcinoma is extremely rare, with only 5 cases reported in the literature. Here, a case is reported and the currently available literature is summarized. A 72-year-old white male presented with changes in his bowel habits and unintentional weight loss. Colonoscopy revealed a polypoid mass in the distal rectum extending to the anal verge anteriorly and a circumferential polypoid mass in the distal sigmoid colon. Biopsies were taken, which revealed poorly differentiated melanoma of the anorectal mass and moderately differentiated adenocarcinoma of the sigmoid mass with nodal involvement. Computed tomography of the abdomen showed liver metastasis. An extended abdominoperineal resection was undertaken for palliation, relief of symptoms, and definitive histology to guide further management. Consequently, a resection of the hepatic metastasis was attempted; however, macroscopic deposits were discovered on 7 of 8 liver segments perioperatively. He was subsequently referred to medical oncology for palliative chemotherapy. Synchronous primary anorectal melanoma and colorectal adenocarcinoma is rare, this being the sixth report found in the literature. In summary of the available cases, all synchronous cancers were located in the rectosigmoid and had very similar presentations. Most presented relatively late and were generally treated with abdominoperineal resection, which appears to be the best treatment option. Overall, prognosis appears to be dismal. General and colorectal surgeons should always be aware of the possibilities of simultaneous primary cancers because this can affect treatment modalities and prognosis for the patient. PMID- 26011201 TI - Transcriptomic profiles differentiate normal rectal epithelium and adenocarcinoma. AB - Adenocarcinoma is a histologic diagnosis based on subjective findings. Transcriptional profiles have been used to differentiate normal tissue from disease and could provide a means of identifying malignancy. The goal of this study was to generate and test transcriptomic profiles that differentiate normal from adenocarcinomatous rectum. Comparisons were made between cDNA microarrays derived from normal epithelium and rectal adenocarcinoma. Results were filtered according to standard deviation to retain only highly dysregulated genes. Genes differentially expressed between cancer and normal tissue on two-groups t test (P < 0.05, Bonferroni P value adjustment) were further analyzed. Genes were rank ordered in terms of descending fold change. For each comparison (tumor versus normal epithelium), those 5 genes with the greatest positive fold change were grouped in a classifier. Five separate tests were applied to evaluate the discriminatory capacity of each classifier. Genetic classifiers derived comparing normal epithelium with malignant rectal epithelium from pooled stages had a mean sensitivity and specificity of 99.6% and 98.2%, respectively. The classifiers derived from comparing normal and stage I cancer had comparable mean sensitivities and specificities (97% and 98%, respectively). Areas under the summary receiver-operator characteristic curves for each classifier were 0.981 and 0.972, respectively. One gene was common to both classifiers. Classifiers were tested in an independent Gene Expression Omnibus-derived dataset. Both classifiers retained their predictive properties. Transcriptomic profiles comprising as few as 5 genes are highly accurate in differentiating normal from adenocarcinomatous rectal epithelium, including early-stage disease. PMID- 26011202 TI - Performance of venous port catheter insertion by a general surgeon: a prospective study. AB - As part of the vascular access procedures, venous ports, commonly referred to as catheters, are placed under the skin to enable safe and easy vascular access for administration of repeated drug treatments. 122 patients who had received a venous port catheter insertion procedure in the general surgery department between January 1012 and January 2014 were involved in this study. Patients were divided into two groups: those who had undergone a fluoroscopy (group 1) and those who had not undergone a fluoroscopy (group 2). Complications that emerged during and after the port catheter insertion procedure and successful insertion rates were recorded in the database. Data of these patients were presented in a prospective manner. There were 92 to 30 patients in groups 1 and 2, respectively. In group 1, the mean age was approximately 56.8, total catheter stay time was 20,631 days, and mean time of port use was 224.2 days. In group 2, the mean age was approximately 61.2, total catheter stay time was 13,575 days, and mean time of port use was 452.5 days. Successful insertion rate was 100% and 90% in groups 1 and 2, respectively (P < 0.05). The proper insertion of the port catheter accompanied by monitoring methods can decrease procedure-related complications. Statistical comparisons between the two groups in terms of malposition and successful insertion rates also support this view (P < 0.05). The findings support the view that in cancer patients, a venous port catheter insertion accompanied by a fluoroscopy can be safely performed by general surgeons. PMID- 26011203 TI - Solitary fibrous tumor of the greater omentum, mimicking gastrointestinal stromal tumor of the small intestine: a case report. AB - Solitary fibrous tumor (SFT) is one of the mesenchymal tumors, which rarely arises in the abdominal space. We report a very rare case of abdominal SFT, mimicking another mesenchymal tumor. A 52-year-old Japanese man was referred to our hospital for further evaluation and treatment of gallbladder polyp. Contrast enhanced computed tomography (CT) showed an enhanced nodule within the gallbladder, and incidentally, also showed a well-circumscribed mass adjacent to the small intestine. The mass was depicted as slightly high density in plain CT, and with contrast-enhancement, the mass was partially stained in early phase and the stained area spread heterogeneously in delayed phase. Magnetic resonance imaging showed that the abdominal mass was depicted as slightly high intensity on T2-weighted imaging and low intensity on T1-weighted imaging. With double-balloon endoscopy and capsule endoscopy, we did not find any tumor inside the small intestine. These visual findings lead us to diagnose it as gastrointestinal stromal tumor of the small intestine with extraluminal growth. We planned to resect both the gallbladder polyp and the intraperitoneal tumor at the same time for pathologic diagnosis and treatment. When the operation was performed, we found a milk-white lobulated tumor on the greater omentum and the tumor was entirely resected. Microscopically, the gallbladder polyp was diagnosed as tubular adenoma, and the omental tumor was diagnosed as SFT. It is important to bear in mind that omental SFTs sometimes mimic other mesenchymal tumors and should be included in the differential diagnosis of abdominal tumor not revealed by endoscopy. PMID- 26011204 TI - Screening of nutritional risk and nutritional support in general surgery patients: a survey from Shanghai, China. AB - To determine the prevalence of nutritional risk in surgical departments and to evaluate the impact of nutritional support on clinical outcomes. The nutritional risk in different surgical diseases and the different way of nutritional support on clinical outcomes in patients at nutritional risk remain unclear. Hospitalized patients from general surgical departments were screened using the Nutritional Risk Screening (NRS) 2002 questionnaire on admission. Data were collected on nutritional risk, complications, and length of stay (LOS). Overall, 5034 patients were recruited; the overall prevalence of nutritional risk on admission were 19.2%. The highest prevalence was found among patients with gastric cancer. At risk patients had more complications and longer LOS than nonrisk patients. Of the at-risk patients, the complication rate was significantly lower and LOS was significantly shorter in the nutritional-support group than in the no-support group (20.9 versus 30.0%, P < 0.05). Subgroup analysis showed reduced complication rates and LOS only in patients with gastric cancer, colorectal cancer, and hepato-pancreato-biliary (HPB) cancer. Significantly lower complication rates relative to nonsupported patients were found among patients who received enteral nutrition or who received support for 5 to 7 days, or daily support entailing 16 to 25 kcal/kg of nonprotein energy. Different surgical diseases have different levels of nutritional risk. The provision of nutritional support was associated with a lower complication rate and a shorter LOS for gastric, colorectal, and HPB cancer patients at nutritional risk. The improper use of nutritional support may not improve outcomes for at-risk patients. PMID- 26011205 TI - Laparoscopic management of complicated foreign body ingestion: a case series. AB - This study aims to demonstrate the safety and feasibility of laparoscopic management of complicated foreign body (FB) ingestion in a series of 5 patients. We present the merits of a minimally-invasive approach in this clinical setting from our series as well as published case reports. FB ingestion is occasionally complicated by abscess formation or perforation, requiring surgical intervention. Anecdotal reports of such cases managed by laparoscopic surgery have alluded to its merits over the conventional approach of open surgery. Over an 18-month period, 5 of 256 patients with FB ingestion at our unit were managed by laparoscopic surgery. Clinical and operative data were collected for this study. In all 5 cases, patients could not recall their FB ingestion and had normal plain radiographs. The diagnosis was made on a computed tomography (CT) scan. Laparoscopy was successfully employed to retrieve all FBs (fish bones), deroof abscesses, and primarily repair gastrointestinal perforations. The mean operative time was 69 minutes (55-85), utilizing 2 to 4 noncamera ports. There was no operative mortality and patients were discharged on average postoperative day (POD) 5 (2-8). Laparoscopic surgery is safe and feasible in small-diameter, complicated FB ingestion requiring surgical intervention and should be considered in similar patients. PMID- 26011206 TI - Is the male gender an independent risk factor for complication in patients undergoing laparoscopic cholecystectomy for acute cholecystitis? AB - This paper was designed to investigate the gender dependent risk of complication in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. Laparoscopic cholecystectomy is the standard procedure for benign gallbladder disorders. The role of gender as an independent risk factor for complicated laparoscopic cholecystectomy remains unclear. A retrospective single-center analysis of laparoscopic cholecystectomies performed for acute cholecystitis over a 5-year period in a community hospital was performed. Within the period of examination, 1884 laparoscopic cholecystectomies were performed. The diagnosis was acute cholecystitis in 779 cases (462 female, 317 male). The male group was significantly older (P = 0.001). Surgery lasted significantly longer in the male group (P = 0.008). Conversion was done in 35 cases (4.5%). There was no significant difference in the rate of conversion between both groups. However the rate of conversion was significantly higher in male patients > 65 years (P = 0.006). The length of postoperative hospital stay was significantly longer in the male group (P = 0.007), in the group > 65 years (P = 0.001) and following conversion to open surgery (P = 0.001). The male gender was identified as an independent risk factor for prolonged laparoscopic cholecystectomy on multivariate analysis. The male gender could be an independent risk factor for complicated or challenging surgery in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. PMID- 26011207 TI - Preoperative imatinib treatment in patients with advanced gastrointestinal stromal tumors: patient experiences and systematic review of 563 patients. AB - Preoperative IM therapy for GIST is now a research focus. Due to the low incidence of the disease, there are few RCTs on the preoperative treatment for advanced GIST, let alone relevant meta-analysis. Efficacy of this therapy and targeting population are still undetermined. Therefore, the first part of this article is composed of a controlled retrospective study and demonstrates that preoperative therapy with IM can significantly improve the outcome of advanced GIST. In the second part of the paper, we further investigated what portion of advanced GIST patients benefit more from the therapy, based on a meta-analysis. As the disease is relatively rare, we involved 563 cases in the meta-analysis, much higher than in the controlled clinical studies (51 cases). The objective of this paper is to investigate effects of surgical resection on imatinib-treated advanced GIST. Twenty-two consecutive advanced GIST patients (Group A) with preoperative IM treatment were compared to 29 patients (Group B) who underwent initial tumor resection during the same period. Subsequently, a systematic review of 563 patients was applied to identify the benefit of the advanced GIST patients receiving imatinib before surgery. Compared with Group B, less patients in Group A underwent multivisceral resection (18.2% versus 48.3%, P = 0.026) or suffered tumor rupture at time of surgery (0% versus 17.2%, P = 0.04). The 3-year estimated progression-free survival of Group A (94.4%) was also superior to that of Group B (61.4%; P = 0.045). Subsequent meta-analysis indicated that primarily unresectable patients had higher complete resection and 2-year PFS rates than recurrent/metastasis patients (P = 0.005 and 0.20, respectively); (b) stable disease (SD) patients had better outcome in resection including resectability rate (P < 0.0001), PFS (P < 0.00001) and OS (P = 0.0008) than progressive disease (PD) patients; (c) in recurrent/metastatic PD patients, surgery played a minor role, because they had a higher bulky residual disease rate (P = 0.0005) and higher progression risk (P < 0.00001) within 2 years after surgery. Preoperative IM treatment improves prognosis of advanced GISTs. Among recurrent/metastatic patients, postimatinib surgery may benefit those who have SD after IM treatment but not those resistant to IM. PMID- 26011208 TI - Comparison of modified Limberg flap and Karydakis flap operations in pilonidal sinus surgery: prospective randomized study. AB - The best surgical technique for pilonidal sinus disease (PSD) is still disputed. The objective of this prospective randomized study is to compare the short and long-term results of modified Limberg flap and Karydakis flap surgeries that have been widely used in recent years. Ninety one patients were included in the study. The patients were divided into two groups: modified Limberg flap (MLF; n = 46) and Karydakis flap (KF; n = 45). Preoperative findings of the patients, their surgical findings, and short and long-term postoperative findings were recorded and statistically compared. While no significant difference was discovered between the groups in terms of postoperative analgesic need, hospital stay, postoperative infection rate, drain stay time, painless sitting time, painless toilet-sitting time, and painless walking time, return to work or school time was shorter in the MLF group compared with the KF group (20.61 +/- 7.89 days, 23.29 +/- 6.42, respectively; P < 0.05). Cosmetically, the visual analog scale (VAS) of the KF group was significantly higher than that of the MLF group (VAS score 7.12 +/- 1.28, 5.45 +/- 1.77, respectively; P < 0.05). Considering recurrence rates, no statistically significant difference was found between the groups. Our study found out that short and long-term results of the MLF and KF procedures are similar. We believe both methods can be safely used in surgical PSD treatment given that in the MLF procedure, shorter return-to-work time is achieved, while the procedure provides better cosmetic results. PMID- 26011209 TI - Gallstone ileus with jejunum perforation managed with laparoscopic-assisted surgery: rare case report and minimal invasive management. AB - Gallstone ileus is an uncommon complication of cholelithiasis. Most patients affected by gallstone ileus are elderly and have multiple comorbidities. Symptoms are vague and insidious, which may delay the correct diagnosis for days. Here we are reporting an uncommon complication of gallstone ileus. We report on a 70-year old man with small bowel obstruction at the jejunum due to an impacted stone, which led to necrosis and perforation of the proximal bowel wall. Laparoscope assisted small bowel resection with enterolithotomy was used to successfully treat the patient's perforation and obstruction. His recovery was uneventful. Gallstone ileus commonly presents with bowel obstruction, but intestinal perforation occurs very rarely. A laparoscopic approach can provide both diagnostic and therapeutic roles in management. PMID- 26011210 TI - Our contrivances to diminish complications after pylorus-preserving pancreaticoduodenectomy. AB - The objective of this study is to diminish postoperative complications after pylorus-preserving pancreaticoduodenectomy. Pylorus-preserving pancreaticoduodenectomy is still associated with major complications, especially leakage at pancreatojejunostomy and delayed gastric emptying. Traditional pylorus preserving pancreaticoduodenectomy was performed in group A, while the novel procedure, an antecolic vertical duodenojejunostomy and internal pancreatic drainage with omental wrapping, was performed in group B (n = 40 each). We compared the following characteristics between the 2 groups: operation time, blood loss, time required before removal of nasogastric tube and resumption of food intake, length of hospital stay, and postoperative complications. The novel procedure required less time and was associated with less blood loss (both P < 0.0001). In the comparison of the 2 groups, group B showed less time for removal of nasogastric tubes and resumption of food intake, shorter hospital stays, and fewer postoperative complications (all P < 0.0001). The novel procedure appears to be a safe and effective alternative to traditional pancreaticoduodenectomy techniques. PMID- 26011211 TI - Antioxidant Activity of Syringic Acid Prevents Oxidative Stress in l-arginine Induced Acute Pancreatitis: An Experimental Study on Rats. AB - The aim of this study was to investigate the possible protective role of antioxidant treatment with syringic acid (SA) on l-arginine-induced acute pancreatitis (AP) using biochemical and histopathologic approaches. A total of 30 rats were divided into 3 groups. The control group received normal saline intraperitoneally. The AP group was induced by 3.2 g/kg body weight l-arginine intraperitoneally, administered twice with an interval of 1 hour between administrations. The AP plus SA group, after having AP induced by 3.2 g/kg body weight l-arginine, was given SA (50 mg kg(-1)) in 2 parts within 24 hours. The rats were killed, and pancreatic tissue was removed and used in biochemical and histopathologic examinations. Compared with the control group, the mean pancreatic tissue total oxidant status level, oxidative stress index, and lipid hydroperoxide levels were significantly increased in the AP group, being 30.97 +/ 7.13 (P < 0.05), 1.76 +/- 0.34 (P < 0.0001), and 19.18 +/- 4.91 (P < 0.01), respectively. However, mean total antioxidant status and sulfhydryl group levels were significantly decreased in the AP group compared with the control group, being 1.765 +/- 0.21 (P < 0.0001) and 0.21 +/- 0.04 (P < 0.0001), respectively. SA reduces oxidative stress markers and has antioxidant effects. It also augments antioxidant capacity in l-arginine-induced acute toxicity of pancreas in rats. PMID- 26011212 TI - Enzymatic debridement in necrotizing pancreatitis. AB - Multiple organ failure and pancreatic necrosis are the factors that determine prognosis in acute pancreatitis attacks. We investigated the effects of collagenase on the debridement of experimental pancreatic necrosis. The study covered 4 groups; each group had 10 rats. Group I was the necrotizing pancreatitis group. Group II was the collagenase group with pancreatic loge by isotonic irrigation following necrotizing pancreatitis. Group III was the collagenase group with pancreatic loge following necrotizing pancreatitis. Group IV was the intraperitoneal collagenase group following necrotizing pancreatitis. The progress of the groups was compared hematologically and histopathologically. There was no difference among the groups regarding the levels of leukocyte, hemogram, and urea. The differences in AST levels between Group I and II; and differences in glucose, calcium, LDH, AST, and amylase between Group II and III; between Group II and IV; between Group I and III; and between Group I and IV were statistically significant (P < 0.05). There were statistically significant differences between Group II and III, and Group II and IV regarding edema, acinar necrosis, inflammatory cell infiltration, hemorrhage, and fat necrosis (P < 0.05). In conclusion, the collagenase preparation used in this experimental pancreatitis model was found to be effective in the debridement of pancreatic necrosis. PMID- 26011213 TI - Hepatic adenomatosis: a rare but important liver disease with severe clinical implications. AB - A 56-year-old white female presented to the emergency room (ER) with acute onset of right upper quadrant abdominal pain, nausea, and vomiting, and she was found to have a sudden drop in hemoglobin. Abdominal computed tomography (CT) with and without intravenous contrast revealed multiple bilobar focal hepatic hypervascular lesions, one of them demonstrating spontaneous rupture with active intraperitoneal bleeding. A moderate hemoperitoneum was present. The patient underwent exploratory laparotomy for right hepatic posterior segmentectomy (right posterior sectionectomy) and peritoneal lavage. The histopathology evaluation revealed multiple liver adenomas. Hepatic adenomatosis is a clinical entity characterized by 10 or more hepatic adenomas. It must be distinguished from isolated hepatic adenoma as it bears a much higher risk of complications, such as spontaneous rupture, hemorrhage and malignant transformation. Here we discuss the radiologic and histopathologic findings of the current case along with a review of the English language medical literature. PMID- 26011214 TI - Recurrence-free survival of a hepatocellular carcinoma patient with tumor thrombosis of the inferior vena cava after treatment with sorafenib and hepatic resection. AB - Sorafenib (Nexabar, Bayer, Berlin, Germany), one of multikinase inhibitors, can infrequently downstage advanced hepatocellular carcinoma (HCC). There are some reports that sorafenib in combination with other modalities, such as transcatheter arterial chemoembolization (TACE) or radiation therapy, could represent a bridge to surgery. We have observed a progressive HCC case with hepatic vein tumor thrombosis proceeding to the inferior vena cava (IVC-HVTT) convert to a state of feasible curative resection after a multidisciplinary treatment which included sorafenib. The patient underwent a successful resection in consequence of this therapy. A 45-year-old male with Hepatitis B Virus associated chronic hepatitis was diagnosed as HCC with IVC-HVTT. To obtain oncological curative resection, we performed TACE, radiation therapy followed by administration of sorafenib (800 mg per day, total 72 g). The tumor including IVC HVTT remarkably shrank, therefore, an extended posterior sectionectomy and total removal of the IVC-HVTT was successfully performed. The operation time was 736 minutes and the amount of intraoperative hemorrhage was 805 mL. No postoperative complication occurred. Adjuvant therapy with sorafenib was started four weeks after the operation and continued for 6 months (800 mg per day, total 144 g). The patient is alive without recurrence for about 4 years from the initial therapy. Multidisciplinary therapy including sorafenib, TACE, radiation, and hepatic resection may be an effective strategy to treat HCC patients with IVC-HVTT. PMID- 26011215 TI - Asymptomatic Mesenchymal Hamartoma of the Chest Wall in Child With Fluorodeoxyglucose Uptake on PET/CT-Report of a Case. AB - We had experience with a case of mesenchymal hamartoma of the chest wall (MHCW) with fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT). We reported the first case of asymptomatic MHCW in a child with preoperative PET/CT. Mesenchymal hamartoma of the chest wall is a rare benign tumor that usually presents as a visible chest wall mass or respiratory problems secondary to compression of the lung in early infancy. It is often reported that malignant transformation is extraordinarily rare. Positron emission tomography/CT is useful for diagnosis of malignancy. There is no report of MHCW in a child with preoperative PET/CT before. We examined an asymptomatic 1-year old girl with an incidental finding on a chest x-ray. Scans of CT and PET/CT were performed before surgical resection. After surgery, the resected tumor was examined histologically. Chest x-ray and CT scan of the chest confirmed a 25- * 20-mm round shaped intrapleural mass containing calcification and destructing the rib, arising from the third rib. Scan of PET/CT demonstrated the mass with light FDG accumulation. Histologically, the mass was homogenous, with thick funicular of hyaline cartilage interdigitating with scattered fiber. There were no malignant cells. No malignant MHCW was demonstrated in the mass, with light FDG accumulation by PET/CT. PET/CT might be a useful tool to distinguish malignant MHCW in children. PMID- 26011216 TI - Success of Minimally Invasive Transumbilical Single-Incision Laparoscopic Surgery (T-SILS) Plus Double-Balloon Endoscopy (DBE) for Pediatric Intestinal Angiodysplasia: A Case Report. AB - We describe here a child with angiodysplasia of the small intestine, diagnosed by double-balloon endoscopy (DBE), who was treated with transumbilical single incision laparoscopic surgery (T-SILS). A 9-year-old boy presented to another hospital with intermittent fresh melena of a duration of 5 months and 4 days. Anoscopy and gastric mucosal membrane scintigraphy were unsuccessful diagnostically, and he was referred to our hospital for further examination and treatment. Under general anesthesia, we performed DBE by an anal route, with the ileum assessed for a distance of about 150 cm from the ileocecal valve. Although no bleeding lesion was found in the colon, a flat elevated venous lake approximately 20 mm in size was observed 20 cm from the ileocecal valve, suggesting angiodysplasia of the small intestine. A tattoo was made under DBE, and wedge resection by T-SILS was performed 1 month later under general anesthesia. The excised specimen appeared as a flat, elevated venous lake approximately 20 mm in size. Histopathologic analysis revealed several dilated and distorted veins within the submucosa of the small intestine. The patient was diagnosed with angiodysplasia of the small intestine. His postoperative course was uneventful, and he remained free of recurrent gastrointestinal bleeding 18 months after the operation. This is the first case report showing the diagnosis, localization, and tattooing of an obscure gastrointestinal bleeding lesion of the small intestine by preoperative DBE and removal of the lesion by subsequent T SILS in children. PMID- 26011217 TI - Clear cell "sugar" tumor of the lung: benign or malignant? AB - Clear cell "sugar" tumors of the lung are rare pulmonary tumors. This case study illustrates a patient who was found to have a persistent nodule in the left-upper lobe of the lung. Positron emission tomographic scanning showed mild-moderate 18 fluorodeoxyglucose uptake. Based on these findings, a video-assisted resection of the tumor was undertaken. The mass was identified histologically, as a clear cell "sugar" tumor of the lung. This case report discusses the benign versus malignant nature of this rare tumor. PMID- 26011218 TI - Treatment of tracheal mucoepidermoid carcinoma by argon plasma coagulation during pregnancy. AB - Mucoepidermoid carcinoma of the tracheobronchial tree is a rare airway tumor (<1% of all lung tumors). In adults, the majority of primary tracheal tumors are malignant. Management during pregnancy is complex and requires weighing maternal and fetal prognosis. Reported cases describe surgical resection following cesarean section. We report the first case to be treated by Argon-Plasma Coagulation (APC) in pregnancy. A 35-year-old Caucasian woman G1P0, at 27 weeks of gestation was admitted to the emergency department because of hemoptysis and severe dyspnea. Bronchoscopy and biopsies diagnosed primary tracheal mucoepidermoid carcinoma. Following an episode of tracheal bleeding, she was intubated. After thorough explanations to the family and obtaining informed consent, therapeutic bronchoscopy, under general anesthesia using a rigid bronchoscope, was performed. The tumor was cored out with the tip of the bronchoscope and removed with an alligator forceps. The tumor bed was coagulated with APC. The obstetrical team was ready to intervene in case of maternal emergency. Immediate follow-up was good, and she left the hospital 4 days later. She delivered at 39 weeks of gestation by cesarean section because of dystocia. Five years later, the patient is doing well without any signs or symptoms of recurrence. Pediatric follow-up is normal. Argon Plasma Coagulation for treatment of mucoepidermoid tracheal carcinoma is feasible during pregnancy. Reporting this case could lead to less aggressive management of mucoepidermoid carcinoma in pregnant patients. PMID- 26011219 TI - Maximizing use of robot-arm no. 3 in daVinci-assisted thoracic surgery. AB - We have previously reported on the importance of appropriate robot-arm settings and replacement of instrument ports in robot-assisted thoracic surgery, because the thoracic cavity requires a large space to access all lesions in various areas of the thoracic cavity from the apex to the diaphragm and mediastinum and the chest wall. (1 - 3) Moreover, it can be difficult to manipulate the da Vinci Surgical System using only arms No. 1 and No. 2 depending on the tumor location. However, arm No. 3 is usually positioned on the same side as arm No. 2, and sometimes it is only used as an assisting-arm to avoid conflict with other arms ( Fig. 1 ). In this report, we show how robot-arm No. 3 can be used with maximum effectiveness in da Vinci-assisted thoracic surgery. [Figure: see text]. PMID- 26011220 TI - Prognostic factors in peptic ulcer perforations: a retrospective 14-year study. AB - Regarding the complications of peptic ulcer, a perforation remains the most important fatal complication. The aim of our retrospective study was to determine relations between postoperative morbidity and comorbid disease or perioperative risk factors in perforated peptic ulcer. In total, 239 patients who underwent emergency surgery for perforated peptic ulcer in Ege University General Surgery Department, between June 1999 and May 2013 were included in this study. The clinical data concerning the patient characteristics, operative methods, and complications were collected retrospectively. One hundred seventy-five of the 239 patients were male (73.2%) and 64 were female (26.8%). Mean American Society of Anesthesiologists (ASA) score was 1 in the patients without morbidity, but mean ASA score was 3 in the morbidity and mortality groups. Primary suture and omentoplasty was the selected procedure in 228 of the patients. Eleven patients underwent resection. In total, 105 patients (43.9%) had comorbidities. Thirty seven patients (67.3%) in the morbidity group had comorbid diseases. Thirteen (92.9%) patients in the mortality group had comorbid diseases. Perforation as a complication of peptic ulcer disease still remains among the frequent indications of urgent abdominal surgery. Among the analyzed parameters, age, ASA score, and having comorbid disease were found to have an effect on both mortality and morbidity. The controversial subject in the present study is regarding the duration of symptoms. The duration of symptoms had no effect on mortality nor morbidity in our study. PMID- 26011221 TI - Early gastric cancer associated with gastric sarcoidosis. AB - Sarcoidosis is a multisystemic disorder that is characterized by the formation of noncaseating granulomas. Although sarcoidosis can affect any organ, gastrointestinal tract involvement in sarcoidosis is very rare, and gastric cancer associated with gastric sarcoidosis has hardly been reported. A 64-year old female with a 10-year history of the medical treatment of gastric sarcoidosis received a routine follow-up gastrointestinal endoscopy and an irregular-shaped, elevated lesion was detected in the gastric corpus. The gastric mucosal surface was nodular and ulcerated throughout the stomach. The gastric lumen was narrow, and the gastric wall was stiff and nondistensible, resembling linitis plastica. The biopsies of the elevated lesion in the gastric corpus revealed well differentiated adenocarcinoma. An endoscopic ultrasonography was then performed, but it failed to assess precisely the depth of cancer invasion because of sarcoidosis-related gastritis and fibrosis of the gastric wall. The patient underwent a laparoscopic total gastrectomy under the diagnosis of gastric cancer associated with gastric sarcoidosis. Histologic examination of the surgical specimen demonstrated well-differentiated adenocarcinoma in the gastric corpus, and the histologic mapping of cancer cells revealed that the tumor spread within the mucosal layer of the stomach. No lymph node metastasis was found. The patient's postoperative course was uneventful. We experienced a rare case of early gastric cancer associated with gastric sarcoidosis, which identified the troublesome issue that the assessment of depth of cancer invasion is difficult, because patients with longstanding gastric sarcoidosis may involve various degrees of fibrosis of the gastric wall. PMID- 26011222 TI - A long-term follow-up result of pouch plasty for severe dysfunction of jejunal pouch reconstruction after total gastrectomy: a case report. AB - A 78-year-old woman with malignant lymphoma of the stomach underwent total gastrectomy with a jejunal-pouch (J-pouch) reconstruction in 1994. Twelve years after surgery the patient began to suffer epigastric distress and reflux symptoms. Eventually, she was unable to take anything by mouth. A series of diagnostic images seemed to indicate that the main cause of the dysfunction was flaccidity of the J-pouch and deformity of the outflow route induced by chronic excessive dilatation of the pouch wall. Because all conservative managements only led to temporary improvement and ended in failure, she hoped to receive the operation. We designed "pouch plasty" capable of ameliorating the pouch dysfunction. The aim of pouch plasty was to improve uneven tension of the pouch wall and repair deformity of the outflow route of the food. After the operation, the J-pouch resumed adequate drainage and had good reservoir function. More than 7 years later, the patient had no further complications. PMID- 26011223 TI - An unusually large cavernous hemangioma of retropharyngeal space: a rare case. AB - Hemangiomas rarely occur in the retropharyngeal space with only several cases reported in the current literature. This article reports the hemangiomas of retropharyngeal space. A 55-year-old woman was referred to our institution for dysphagia. Computed tomography and magnetic resonance imaging of the neck and spine revealed a large, well-circumscribed, dense mass that extended from the retropharyngeal space to the sides of the neck. Patient underwent direct excision of the lesion. Complete regression of symptoms was observed after surgery, with no lesions found on routine 24-month follow-up. Although hemangiomas are relatively common in the head and neck, those that originate in the retropharyngeal space are very rarely observed. These benign tumors have the potential to compress adjacent tissues or organs and thereby produce associated symptoms like dysphagia and dyspnea. We present the reported case of larger hemangiomas of the retropharyngeal space and detail their management. PMID- 26011224 TI - Mean platelet volume: is it a predictive parameter in diagnosis of acute mesenteric ischemia? AB - Our objective for this study was to discuss the usability of mean platelet volume, which is associated with numerous vascular pathologies, in the early diagnosis of acute mesenteric ischemia. Acute mesenteric ischemia is an uncommon, life-threatening clinical condition mostly seen in the elderly. Early diagnosis of acute mesenteric ischemia and correction of blood circulation before necrosis occurs are important factors affecting prognosis. A total of 95 patients who underwent emergency surgery for acute mesenteric ischemia and 90 healthy volunteers as control group were included in this study. Age, gender, hemoglobin values, white blood cell counts, mean platelet volume, and platelet counts are recorded for evaluation. The mean platelet volume values were significantly higher in patients with acute mesenteric ischemia than in the controls (9.4 +/- 1.1 fL and 7.4 +/- 1.4 fL, respectively; P < 0.001). Receiver-operating characteristic analysis demonstrated a cutoff value of mean platelet volume as 8.1 fL (area under the curve, 0.862), a sensitivity of 83.2%, and a specificity of 80%. As a result, in the patients who are admitted to the hospital with acute nonspecific abdominal pain and suspected of having acute mesenteric ischemia, high mean platelet volume values in routine hemograms support the diagnosis of acute mesenteric ischemia. PMID- 26011225 TI - Electrohydrodynamic Deformation and Rotation of a Particle-Coated Drop. AB - A dielectric drop suspended in conducting liquid and subjected to a uniform electric field deforms into an ellipsoid whose major axis is either perpendicular or tilted (because of the Quincke rotation effect) relative to the applied field. We experimentally study the effect of surface-adsorbed colloidal particles on these classic electrohydrodynamic phenomena. We observe that at a high surface coverage (90%), the electrohydrodynamic flow is suppressed, oblate drop deformation is enhanced, and the threshold for tilt is decreased compared to that of the particle-free drop. The deformation data are explained well by a capsule model, which assumes that the particle monolayer acts as an elastic interface. The reduction of the threshold field for rotation is likely related to drop asphericity. PMID- 26011226 TI - Signal Transduction Reaction Monitoring Deciphers Site-Specific PI3K-mTOR/MAPK Pathway Dynamics in Oncogene-Induced Senescence. AB - We report a straightforward strategy to comprehensively monitor signal transduction pathway dynamics in mammalian systems. Combining targeted quantitative proteomics with highly selective phosphopeptide enrichment, we monitor, with great sensitivity, phosphorylation dynamics of the PI3K-mTOR and MAPK signaling networks. Our approach consists of a single enrichment step followed by a single targeted proteomics experiment, circumventing the need for labeling and immune purification while enabling analysis of selected phosphorylation nodes throughout signaling pathways. The need for such a comprehensive pathway analysis is illustrated by highlighting previously uncharacterized phosphorylation changes in oncogene-induced senescence, associated with diverse biological phenotypes and pharmacological intervention of the PI3K-mTOR pathway. PMID- 26011227 TI - Tailoring neuromotor interventions for children with cerebral palsy. PMID- 26011228 TI - Abnormality of epiphyseal plate induced by selenium deficiency diet in two generation DA rats. AB - This study aimed to observe the effects of Se deficiency on epiphyseal plates of two generation DA rats fed with artificial total synthetic low Se diet. All F0 and F1 DA rats were fed with synthetic low Se diet (SeD group) and low Se diet supplied with Se (SeS group). The levels of selenium and enzyme activities of GPx were detected in plasma of the rats. General growth of bone and articular cartilage was measured macroscopically and microscopically. The epiphyseal plate of femur heads or tibia were obtained to histological and immunohistochemical examinations. The cartilage from left knee joints and femur heads was used to detect the gene expression of collagens, ADAMTSs and several selenoproteins by RT qPCR. Two generation SeD rats showed Se insufficiency status. The thicknesses of the femur and tibial epiphyseal plates in both F0 and F1 SeD rats were significantly less than that of SeS rats. In F1 generation, SeD rats showed much fewer proliferative chondrocyte layers than SeS ones. Importantly, two generation SeD rats both showed significantly more serious pathological changes of epiphyseal plates. In two generation rats, gene expressions of COL II, GPx1 and GPx4 were significantly down-regulated in SeD rats than SeS ones; meanwhile ADAMTS-4 showed an up-regulated expression in cartilage. Dietary Se deficiency can apparently cause epiphyseal plate lesion and decrease cartilage type II collagen production and GPx1 activity in two generation DA rats fed with the artificial total synthesis low Se diet. PMID- 26011229 TI - Hepatic apoptotic markers are not predictors for the virological response to interferon-based therapy in chronic hepatitis C patients. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection is a major health problem worldwide. The majority of cases involving HCV infection develop into chronic hepatitis because of a failure to develop an effective immune response. Apoptosis of the hepatocytes plays a significant role in the pathogenesis of HCV infection: the interaction between the Fas antigen on hepatocytes and the Fas ligand on T cells corresponds to the main mechanism for hepatocyte damage. Interferon (IFN) alpha has antiviral, immunoregulatory, and antiproliferative properties, and apoptosis seems to be a critical event in the action mechanisms of both IFNs. In this study, we aimed to detect any relationship between apoptotic markers in the liver and the response to the treatment. MATERIALS AND METHODS: The study included 180 chronic HCV patients treated with IFN and ribavirin in four centers. Apoptotic markers (Fas, Fas ligand, Fas-associated death domain, caspases 3, 8, and 9, and in-situ apoptosis) were studied in the liver. The age, sex of the patients, response to therapy, ALT level, viral load, and genotype were recorded. RESULTS: The results of the study showed that the histological activity index and fibrosis correlated with CD95 staining density, caspase-8 intensiveness, and portal and parenchymal Fas ligand scores. The apoptotic parameters of the responsive cases were not significantly different from those of the unresponsive cases. CONCLUSION: The apoptotic parameters studied in liver tissue are associated with inflammation and fibrosis; however, these parameters may not predict response to treatment. PMID- 26011230 TI - Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction. AB - PURPOSE: Acid-base disturbances were investigated in patients with cirrhosis in relation to hemodynamic derangement to analyze the hyperventilatory effects and the metabolic compensation. METHODS: A total of 66 patients with cirrhosis and 44 controls were investigated during a hemodynamic study. RESULTS: Hyperventilatory hypocapnia was present in all patients with cirrhosis and progressed from Child class A to C (P<0.01). Arterial pH increased significantly from class A to C (P<0.001) and was correlated inversely to the mean arterial blood pressure (r= 0.30, P<0.02), systemic vascular resistance (r=-0.25, P<0.05), indocyanine green clearance (r=-0.37, P<0.005), and serum sodium (r=-0.38, P<0.002). Metabolic compensation was shown by a reduced standard base excess in all patients (P<0.001). Standard base excess contained elements related to changes in serum albumin, water dilution, and effects of unidentified ions (all P<0.001). A significant hepatic component in the acid-base disturbances could not be identified. CONCLUSION: Hypocapnic alkalosis is related to disease severity and hyperdynamic systemic circulation in patients with cirrhosis. The metabolic compensation includes alterations in serum albumin and water retention that may result in a delicate acid-base balance in these patients. PMID- 26011231 TI - Increased abdominal fat levels measured by bioelectrical impedance are associated with histological lesions of nonalcoholic steatohepatitis. AB - BACKGROUND/AIM: Abdominal fat is considered to play an important role in nonalcoholic fatty liver disease (NAFLD), although it is not adequately studied because abdominal fat levels cannot be estimated easily. In this study, associations between abdominal obesity, as assessed by abdominal bioelectrical impedance analysis (BIA), and the characteristics of patients with NAFLD were explored. PATIENTS AND METHODS: Seventy-four consecutive NAFLD patients who underwent measurement of abdominal fat levels by BIA were included. Levels of abdominal fat 12.5 or less and more than 12.5 were considered to be average and increased, respectively. RESULTS: The mean+/-SD BMI was 30+/-4 kg/m and the mean abdominal fat levels were 16+/-5, whereas 26% of patients had average abdominal fat levels. Patients with average compared with those with increased abdominal fat levels were more frequently women (50 vs. 12%, P=0.001), had lower BMI (27+/ 3 vs. 31+/-4 kg/m, P<0.001), lower Homeostasis Model Assessment index (2.6+/-1.4 vs. 3.9+/-2.7, P=0.045), and lower median liver stiffness on transient elastography (5.3 vs. 6.8 kPa, P=0.025). In patients with available liver biopsy, steatohepatitis was present more frequently in patients with increased compared with average abdominal fat levels (78 vs. 38%, P=0.030) and in patients with BMI 30 or more compared with less than 30 kg/m (87 vs. 48%, P=0.033), but similar in patients with increased or normal waist circumference (67 vs. 56%, P=0.693). CONCLUSION: Average levels of abdominal fat, as assessed by abdominal BIA, are mainly present in female patients with NAFLD and are associated with a lower degree of insulin resistance. Increased abdominal fat as assessed by BIA and obesity seem to represent strong risk factors for histological steatohepatitis. PMID- 26011232 TI - Impact of endoscopic ultrasound-guided fine-needle aspiration and multidisciplinary approach in the management of abdominal or mediastinal mass. AB - BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a useful tool for the diagnosis of suspected abdominal or mediastinal neoplastic lesions. AIM: To evaluate the impact of EUS-FNA and multidisciplinary approach on the diagnostic work-up and therapeutic management of patients with abdominal or mediastinal neoplastic lesions. PATIENTS AND METHODS: One hundred and twenty patients (69 men, median age 65 years) with a suspected abdominal or mediastinal neoplastic mass at computed tomography or MRI underwent EUS-FNA. All EUS-FNA findings and clinical data were evaluated by a multidisciplinary team (oncologists, surgeons, and gastroenterologists). EUS-FNA findings were compared with the final diagnosis made by histological evaluation of the surgical specimen or clinical outcome at follow-up. RESULTS: A correct diagnosis was obtained by EUS-FNA in 96/120 patients (80%), indicating benignancy of the lesion in 21 (18%) cases and confirming malignancy in 75 (62%). On the basis of EUS-FNA findings, chemotherapy was tailored in 57/75 (76%) patients with malignancy whereas the surgical strategy was changed in 21/120 (18%) of patients. Overall, the diagnostic accuracy of EUS-FNA was 85%. A multidisciplinary team approach enabled a correct diagnosis in patients in whom EUS-FNA was nondiagnostic and to identify five cases with false-negative EUS-FNA findings. CONCLUSION: EUS-FNA has a relevant impact on the management of suspected abdominal or mediastinal neoplastic lesions. A multidisciplinary team approach enables to overcome the EUS FNA methodological limitations. The combination of EUS-FNA and multidisciplinary team approach could help to diagnose and tailor therapeutic options in such patients. PMID- 26011233 TI - Keratin 19 protein expression is an independent predictor of survival in human hepatocellular carcinoma. AB - AIM: We aimed to assess the clinicopathological relevance and prognostic significance of expression of the hepatic progenitor cell markers keratin 19 (K19), epithelial cell adhesion molecule (EpCAM) and CD117 (c-KIT) in a White series of hepatocellular carcinoma (HCC). METHODS: We evaluated the immunohistochemical expression of K19, EpCAM and CD117 in 89 surgical specimens of HCC from Greek patients (mean age 66.7+/-11.3 years, male 75.2%) followed up for 39.6+/-25.3 months. RESULTS: K19, EpCAM and CD117 expression was detected in tumour cells of 10.11, 15.38 and 3.7% HCCs, respectively. Female sex was correlated with EpCAM immunohistochemical expression (P=0.035), whereas no other significant relationship with clinicopathological parameters was observed. K19 positivity tended to be correlated with microvascular invasion (P=0.054). In univariate analysis, K19 positivity and microvascular invasion were found to be associated with decreased recurrence-free survival (P<0.001 and P=0.004, respectively) and overall survival (P=0.002 and P=0.029, respectively). EpCAM and CD117 positivity was not correlated with patient survival. In multivariate analysis, K19 positivity emerged as an independent predictor of recurrence-free survival (odds ratio=7.84, 95% confidence interval=2.658-22.912, P<0.001) and overall survival (odds ratio=3.845, 95% confidence interval=1.401-10.549, P=0.009). CONCLUSION: Our study confirms the prognostic significance of K19 expression in Caucasian patients with HCCs, providing further evidence that it may be used to stratify HCC according to tumour aggressiveness. PMID- 26011234 TI - Bacterial infections in alcoholic and nonalcoholic liver cirrhosis. AB - OBJECTIVES: Longitudinal, population-based data on the occurrence, localization, and severity of bacterial infections over time in patients with alcoholic compared with nonalcoholic cirrhosis are limited. MATERIALS AND METHODS: All patients with incident cirrhosis diagnosed in 2001-2010 (area of 600,000 inhabitants) were retrospectively identified. All bacterial infections resulting in or occurring during an inpatient hospital episode during this period were registered. The etiology of cirrhosis (alcoholic vs. nonalcoholic), infection localization, and outcome as well as bacterial resistance patterns were analyzed. Patients were followed until death, transplant, or the end of 2011. RESULTS: In all, 633 cirrhotics (363 alcoholic, 270 nonalcoholic) experienced a total of 398 infections (2276 patient-years). Among patients diagnosed with cirrhosis each year from 2001 to 2010, increasing trends were noted in the occurrence of infection (from 13 to 27%, P<0.001) and infection-related in-hospital mortality (from 2 to 7%, P=0.05), the latter mainly in the alcoholic group. Although alcoholic etiology was related to the occurrence of more frequent infection (Kaplan-Meier, P<0.001), this relationship was not significant after adjustment for confounders in Cox regression analysis (P=0.056). Resistance to piperacilin tazobactam and carbapenems was more common in infections occurring in alcoholic versus nonalcoholic cirrhosis (13 vs. 5%, P=0.057 and 12 vs. 2%, P=0.009). Alcoholic etiology predicted pneumonia and infections caused by Gram-positive bacteria in multivariate analysis (P<0.05 for both). CONCLUSION: In a population based cirrhotic cohort, bacterial infections increased over time, which, in the case of alcoholic cirrhosis, was associated with pneumonia and bacterial resistance to antibiotics. However, alcoholic etiology was not related indepedently to the occurrence of bacterial infections. PMID- 26011235 TI - Transient elastography using Fibroscan is the most reliable noninvasive method for the diagnosis of advanced fibrosis and cirrhosis in alcoholic liver disease. AB - OBJECTIVE: Fibroscan (FS) is a reliable noninvasive method for the diagnosis of advanced fibrosis and cirrhosis in chronic liver disease. However, there is no clear consensus with respect to the best FS cut-off values for use in alcoholic liver disease (ALD). The aims of this study were as follows: (a) to compare the performance of FS and different biochemical markers in ALD patients; (b) to assess the best FS cut-off values for the prediction of fibrosis stage in our ALD population; and (c) to assess the influence of aspartate aminotransferase (AST) values on FS. PATIENTS AND METHODS: This retrospective study included 135 consecutive and compensated ALD patients who underwent liver biopsy between November 2006 and March 2012 at Erasme Hospital. FS, Fibrotest, FIB-4, aspartate aminotransferase to platelet ratio index (APRI), and Forns' scores were tested in all patients. RESULTS: The diagnostic accuracy of FS was 0.89 (95% confidence interval: 0.83-0.95) for the diagnosis of advanced fibrosis and 0.93 (95% confidence interval 0.90-0.97) for the diagnosis of cirrhosis. FS performed better than Fibrotest (0.81 and 0.88), APRI (0.65 and 0.75), Forns' (0.64 and 0.78), and FIB-4 (0.70 and 0.73). The optimal cut-off values of liver stiffness (LS) for predicting METAVIR fibrosis stage F>=3 and F4 disease were 10.3 and 18.0 kPa, respectively. AST showed a significant positive correlation with LS (r=0.24, P=0.001). However, exclusion of patients with AST more than 50 IU/l only lowered the LS cut-off for the diagnosis of F4 (14 vs. 18.0 kPa). CONCLUSION: FS is currently the most reliable noninvasive method for the diagnosis of advanced liver fibrosis and cirrhosis in ALD. PMID- 26011236 TI - Can adjusting BMI for age and sex provide for a better predictor of colonic neoplasia? AB - OBJECTIVE: The aim of this study was to evaluate the influence of BMI on colonic neoplasia in average-risk patients aged between 40 and 59 years, analyzed by sex. METHODS: A total of 4443 patients aged between 40 and 59 years undergoing a first time screening or average-risk colonoscopy were included in this study. Data on demographics, smoking, and BMI were collected and correlated to the presence of adenomas and advanced adenomas. RESULTS: We evaluated 1197 colonoscopies in patients aged between 40 and 49 years, and 3246 in those aged between 50 and 59 years. Among men between 40 and 49 years, increasing BMI [odds ratio (OR)=1.05, 95% confidence interval (CI): 1.00-1.09] and BMI of at least 27 (OR=1.95, 95% CI: 1.15-3.29) were predictors of adenomas. Younger men with a BMI of at least 27 were more likely to have proximal adenomas (OR=2.23, 95% CI: 1.14-4.37) but not advanced adenomas. There was no relation between BMI and adenomas in younger women. Among women aged between 50 and 59 years, increasing BMI (OR=1.03, 95% CI: 1.01-1.05) and a BMI of at least 24 (OR=1.43, 95% CI: 1.06-2.94) was found to be correlated with adenomas, and increasing BMI was also found to be associated with proximal adenomas (OR=1.67, 95% CI: 1.13-2.45). Among men aged between 50 and 59 years, there was no relation between BMI and adenomas, but there was a positive correlation for advanced adenomas (OR=1.05, 95% CI: 1.002-1.09). Among women aged between 50 and 59 years, BMI was not predictive of advanced adenomas. CONCLUSION: The association between BMI and adenoma differs by age and sex. If BMI is utilized to refine screening practices for colorectal cancer, its influence on sex and age should be taken into account. PMID- 26011237 TI - A new scheme with infusion of hepatitis B immunoglobulin combined with entecavir for prophylaxis of hepatitis B virus recurrence among liver transplant recipients. AB - OBJECTIVE: Liver transplantation significantly increases recurrence of hepatitis B virus (HBV) among high-risk patients. Hepatitis B immunoglobulin (HBIG) and antiviral nucleotide analogues are effective prophylaxis reagents in preventing HBV recurrence. However, HBV recurrence still occurs with these treatments. METHODS: To explore a more cost-effective prophylaxis protocol in patients after liver transplantation, we treated patients with an initial high dose of 10 000 IU HBIG during the anhepatic phase and a second high dose of HBIG at an optimal time point during surgery. The patients were treated with the traditional European protocol as a control, in which one dose of 10 000 IU HBIG was infused during the anhepatic phase and multiple doses of 10 000 IU HBIG were administered daily for 1 week after liver transplantation. RESULTS: There were two mortalities among 50 patients treated with the new protocol and nine mortalities among 52 patients treated with the European protocol within 3 years after liver transplantation. The new prophylaxis method markedly improved the 3-year survival without HBV recurrence in 50 treated patients. However, there were five recurrences in 52 patients treated with the European protocol. High-risk factors such as HBV DNA+, positive hepatitis B e antigen, and hepatocellular carcinoma were all detected among five patients with HBV recurrence. The suppressed HBV recurrence was associated with significantly lower serum alanine aminotransferase and aspartate aminotransferase in the new protocol-treated patients tested at 1 month and 1 week after liver surgery compared with those treated with the European protocol. CONCLUSION: Infusion of two high doses of HBIG during surgery in combination with entecavir significantly prevented HBV recurrence and improved the 3-year survival after liver transplantation. PMID- 26011239 TI - Applying Cardiac Resynchronization Criteria to Pediatric Patients: Fitting a Square Peg into a Round Hole? PMID- 26011238 TI - Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. AB - Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing beta1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities. PMID- 26011240 TI - Fear conditioned responses and PTSD symptoms in children: Sex differences in fear related symptoms. AB - Fear conditioning studies in adults have found that posttraumatic stress disorder (PTSD) is associated with heightened fear responses and impaired discrimination. The objective of the current study was to examine the association between PTSD symptoms and fear conditioned responses in children from a highly traumatized urban population. Children between 8 and 13 years old participated in a fear conditioning study in addition to providing information about their trauma history and PTSD symptoms. Results showed that females showed less discrimination between danger and safety signals during conditioning compared to age-matched males. In boys, intrusive symptoms were predictive of fear responses, even after controlling for trauma exposure. However, in girls, conditioned fear to the danger cue was predictive of self-blame and fear of repeated trauma. This study suggests there are early sex differences in the patterns of fear conditioning and that these sex differences may translate to differential risk for trauma-related psychopathology. PMID- 26011241 TI - Prospective and randomised evaluation of the protease-modulating effect of oxidised regenerated cellulose/collagen matrix treatment in pressure sore ulcers. AB - In chronic wounds, excess levels and activity of proteases such as elastase and plasmin have been detected. Oxidised regenerated cellulose/collagen matrix (ORC/collagen matrix) has been reported to ameliorate the wound microenvironment by binding and inactivating excess proteases in wound exudates. In this study, the levels and activity of elastase and plasmin in wound exudates of pressure sore ulcers were measured to determine the beneficial effect of ORC/collagen matrix treatment compared with control treatment with a foam dressing. A total of 33 patients with pressure sores were enrolled in the study and were followed up for 12 weeks after treatment. Ten control patients were treated with a foam hydropolymer dressing (TIELLE(r) , Systagenix), and the remaining 23 patients were treated with ORC/collagen matrix plus the foam dressing (TIELLE(r) , Systagenix) on top. Wound assessments were carried out over 12 weeks on a weekly basis, with dressing changes twice a week. Ulcers were photographed and wound exudates were collected on admission and at days 5, 14 and then every 14 days to provide a visual record of any changes in appearance of the ulcer and healing rate and for biochemical analysis of the wound. The levels and activity of elastase and plasmin were measured in wound exudates. Statistical analysis was performed using ANOVA and Bonferroni's post hoc test with P-values <0.05 considered to be significant. Compared with controls, ORC/collagen matrix-treated pressure sore wounds showed a significant faster healing rate, which positively correlated with a decreased activity of elastase and plasmin in wound exudates. No signs of infection or intolerance to the ORC/collagen matrix were observed. PMID- 26011242 TI - Effects of the jimpy mutation on mouse retinal structure and function. AB - The Jimpy mutant mouse has a point mutation in the proteolipid protein gene (plp1). The resulting misfolding of the protein leads to oligodendrocyte death, myelin destruction, and failure to produce adequately myelinated axons in the central nervous system (CNS). It is not known how the absence of normal myelination during development influences neural function. We characterized the Jimpy mouse retina to find out whether lack of myelination in the optic nerve during development has an effect on normal functioning and morphology of the retina. Optokinetic reflex measurements showed that Jimpy mice had, in general, a functional visual system. Both PLP1 antibody staining and reverse transcriptase polymerase chain reaction for plp1 mRNA showed that plp1 is not expressed in the wild-type retina. However, in the optic nerve, plp1 is normally expressed, and consequently, in Jimpy mutant mice, myelination of axons in the optic nerve was mostly absent. Nevertheless, neither axon count nor axon ultrastructure in the optic nerve was affected. Physiological recordings of ganglion cell activity using microelectrode arrays revealed a decrease of stimulus-evoked activity at mesopic light levels. Morphological analysis of the retina did not show any significant differences in the gross morphology, such as thickness of retinal layers or cell number in the inner and outer nuclear layer. The cell bodies in the inner nuclear layer, however, were larger in the peripheral retina of Jimpy mutant mice. Antibody labeling against cell type-specific markers showed that the number of rod bipolar and horizontal cells was increased in Jimpy mice. In conclusion, whereas the Jimpy mutation has dramatic effects on the myelination of retinal ganglion cell axons, it has moderate effects on retinal morphology and function. PMID- 26011243 TI - Linking insomnia to workplace injuries: A moderated mediation model of supervisor safety priority and safety behavior. AB - This study investigated why and how insomnia can relate to workplace injuries, which continue to have high human and economic costs. Utilizing the self regulatory resource theory, we argue that insomnia decreases workers' safety behaviors, resulting in increased workplace injuries. Moreover, in order to ultimately derive organizational interventions to alleviate the detrimental impact of insomnia on workplace injuries, we propose that supervisor safety priority can create situational strength that can prevent workers from behaving unsafely despite experiencing insomnia. Our theoretical model was examined and empirically supported using hierarchically nested data collected from supervisors (N = 482) and workers (N = 2,737) in a midsized construction services company. Results were consistent with the proposed conceptual framework; the relationship between insomnia and injuries is explained by the influence of insomnia on safety behaviors. For workers supervised by supervisors with high safety priority, both the relationship between insomnia and safety behaviors and the indirect relationship between insomnia and workplace injuries were weaker. We provide theoretical implications for future safety research and suggest tentative directions for practitioners working to reduce workplace injuries through sleep oriented interventions. PMID- 26011244 TI - Overuse of Bridging Anticoagulation for Patients With Venous Thromboembolism: First, Do No Harm. PMID- 26011245 TI - Computational Modeling to Predict Fatigue Behavior of NiTi Stents: What Do We Need? AB - NiTi (nickel-titanium) stents are nowadays commonly used for the percutaneous treatment of peripheral arterial disease. However, their effectiveness is still debated in the clinical field. In fact a peculiar cyclic biomechanical environment is created before and after stent implantation, with the risk of device fatigue failure. An accurate study of the device fatigue behavior is of primary importance to ensure a successful stenting procedure. Regulatory authorities recognize the possibility of performing computational analyses instead of experimental tests for the assessment of medical devices. However, confidence in numerical methods is only possible after verification and validation of the models used. For the case of NiTi stents, mechanical properties are strongly dependent on the device dimensions and the whole treatments undergone during manufacturing process. Hence, special attention should be paid to the accuracy of the description of the device geometry and the material properties implementation into the numerical code, as well as to the definition of the fatigue limit. In this paper, a path for setting up an effective numerical model for NiTi stent fatigue assessment is proposed and the results of its application in a specific case study are illustrated. PMID- 26011246 TI - Clinical presentation, management, in-hospital and 90-day outcomes of heart failure patients in Trivandrum, Kerala, India: the Trivandrum Heart Failure Registry. AB - OBJECTIVE: To evaluate the presentation, management, and outcomes of patients hospitalized for heart failure (HF) in Trivandrum, India. METHODS: The Trivandrum Heart Failure Registry (THFR) enrolled consecutive admissions from 13 urban and five rural hospitals in Trivandrum with a primary diagnosis of HF from January to December 2013. Clinical characteristics at presentation, treatment, in-hospital outcomes, and 90-day mortality data were collected. 'Guideline-based' medical treatment was defined as the combination of beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone receptor blockers in patients with left ventricular systolic dysfunction (LVSD). RESULTS: We enrolled 1205 cases (834 men, 69%) into the registry. Mean (standard deviation) age was 61.2 (13.7) years. The most common HF aetiology was ischaemic heart disease (IHD) (72%). Heart failure with preserved ejection fraction (>=45%) constituted 26% of the population. The median hospital stay was 6 days (interquartile range = 4-9 days) with an in-hospital mortality rate of 8.5% (95% confidence interval 6.9-10.0). The 90-day all-cause mortality rate was 2.43 deaths per 1000 person-days (95% confidence interval 2.11-2.78). Guideline-based medical treatment was given to 19% and 25% of patients with LVSD during hospital admission and at discharge, respectively. Older age, lower education, poor ejection fraction, higher serum creatinine, New York Heart Association functional class IV, and suboptimal medical treatment were associated with higher risk of 90 day mortality. CONCLUSION: Patients hospitalized with HF in the THFR were younger, more likely to be men, had a higher prevalence of IHD, reported longer length of hospital stay, and higher mortality compared with published data from other registries. We also identified key areas for improving hospital-based HF medical care in Trivandrum. PMID- 26011248 TI - A 15-year-old girl with a rapidly progressing tumor-like lesion. PMID- 26011247 TI - Cell Based Drug Delivery: Micrococcus luteus Loaded Neutrophils as Chlorhexidine Delivery Vehicles in a Mouse Model of Liver Abscesses in Cattle. AB - The recent WHO report on antibiotic resistances shows a dramatic increase of microbial resistance against antibiotics. With only a few new antibiotics in the pipeline, a different drug delivery approach is urgently needed. We have obtained evidence demonstrating the effectiveness of a cell based drug delivery system that utilizes the innate immune system as targeting carrier for antibacterial drugs. In this study we show the efficient loading of neutrophil granulocytes with chlorhexidine and the complete killing of E. coli as well as Fusobacterium necrophorum in in-vitro studies. Fusobacterium necrophorum causes hepatic abscesses in cattle fed high grain diets. We also show in a mouse model that this delivery system targets infections of F. necrophorum in the liver and reduces the bacterial burden by an order of magnitude from approximately 2*106 to 1*105. PMID- 26011249 TI - Effect of Symptom Over-Reporting on Heart Rate Variability in Veterans With Posttraumatic Stress Disorder. AB - Physiological assessment of posttraumatic stress disorder (PTSD) presents an additional avenue for evaluating the severity of PTSD symptoms. We investigated whether the presence of a high number of uncommon symptoms attenuated the relation between self-reported PTSD symptoms and heart rate variability (HRV). Participants were 115 veterans from Operation Iraqi Freedom and Operation Enduring Freedom with or without PTSD. Symptom over-report was assessed using the Miller Forensic Assessment of Symptoms Test (M-FAST). Participants completed the Clinician-Administered PTSD Scale and M-FAST and underwent physiological assessment to determine HRV. These data were then entered into a hierarchical linear regression equation to test the moderating effect of over-reporting on the relation between PTSD symptom severity and HRV. The result of this analysis failed to demonstrate a significant moderating effect of over-reporting on the PTSD and HRV relation. HRV was a significant predictor of PTSD symptom severity, and this relation did not differ across levels of over-reporting. These findings did not support the hypothesis that over-reporting would attenuate the relation between PTSD and HRV. Clinical and research implications and directions for future investigation are discussed. PMID- 26011251 TI - Contacts for organic switches with carbon-nanotube leads. AB - We focus on two classes of organic switches operating due to the photo- or field induced proton transfer (PT) process. By means of first-principles simulations, we search for the atomic contacts that strengthen diversity of the two swapped current-voltage (I-V) characteristics between two tautomers. We emphasize that the low-resistive contacts do not necessarily possess good switching properties. Very often, the higher-current flow makes it more difficult to distinguish between the logic states. Instead, the more resistive contacts multiply a current gear to a larger extent. The low- and high-bias work regimes set additional conditions, which are fulfilled by different contacts: (i) in the very low voltage regime, the direct connections to the nanotubes perform better than the popular sulfur contacts, and (ii) in the higher-voltage regime, the best are the peroxide (-O-O-) contacts. Additionally, we find that the switching-bias value is not an inherent property of the conducting molecule, but it strongly depends on the chosen contacts. PMID- 26011250 TI - OsARG encodes an arginase that plays critical roles in panicle development and grain production in rice. AB - Nitrogen is a crucial nutrient for plant growth and development. Arginine is considered to be an important amino acid for nitrogen transport and storage, playing a crucial role during plant seedling development. However, little is known about the role of arginine in nitrogen remobilization at the reproductive stage. We isolated a rice mutant nglf-1 with reduced plant height, small panicle and grain size, and low seed-setting rate (10% in nglf-1 compared to 93% in wild type). Map-based cloning revealed that the mutant phenotype was caused by loss of function of a gene (OsARG) encoding an arginine hydrolysis enzyme, which is consistent with arginine accumulation in the mutant. The phenotype was partially corrected supplying exogenous nitrogen, and fully corrected by expression of a wild-type OsARG transgene. Over-expression of OsARG in rice (cv. Kitaake) increased grain number per plant under nitrogen-limited conditions. OsARG was ubiquitously expressed in various organs, but most strongly in developing panicles. The OsARG protein was localized in the mitochondria, consistent with other arginases. Our results suggest that the arginase encoded by OsARG, a key enzyme in Arg catabolism, plays a critical role during panicle development, especially under conditions of insufficient exogenous nitrogen. OsARG is a potential target for crop improvement. PMID- 26011252 TI - Structure and Absolute Configuration of Kongiidiazadione, a New Phytotoxic 3 Substituted-5-Diazenylcyclopentendione Produced by Diaporthe Kongii. AB - A new 3-substituted-5-diazenylcyclopentendione named kongiidiazadione was isolated from culture filtrates of Diaporthe kongii, associated with stem cankers on sunflower in Australia. Kongiidiazadione was characterized by spectroscopic (essentially nuclear magnetic resonance [NMR] and high-resolution, electrospray ionization, mass spectrometry [HRESIMS]) methods as (-)-5-diazenyl-3 hydroxymethyl-cyclopent-3-en-1,2-dione. The stereochemistry of the diazenyl group was determined by IR spectroscopy, while the (R) absolute configuration at C(5) was assigned by computational analysis of its electronic circular dichroism (ECD) spectrum. When assayed on leaf disks of different plant species at 5 mM, the kongiidiazadione had a differential impact, causing clear necrosis, in particular to Helianthus annuus. Moreover, kongiidiazadione proved to have a weak antibacterial activity against gram-positive Bacillus amyloliquefaciens. PMID- 26011253 TI - Hypopigmented patches on a young man. PMID- 26011254 TI - A novel S-enantioselective amidase acting on 3,3,3-trifluoro-2-hydroxy-2 methylpropanamide from Arthrobacter sp. S-2. AB - A novel S-enantioselective amidase acting on 3,3,3-trifluoro-2-hydroxy-2 methylpropanamide was purified from Arthrobacter sp. S-2. The enzyme acted S enantioselectively on 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide to yield (S) 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid. Based on the N-terminal amino acid sequence of this amidase, the gene coding S-amidase was cloned from the genomic DNA of Arthrobacter sp. S-2 and expressed in an Escherichia coli host. The recombinant S-amidase was purified and characterized. Furthermore, the purified recombinant S-amidase with the C-His6-tag, which was expressed in E. coli as the C-His6-tag fusion protein, was used in the kinetic resolution of (+/ )-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide to obtain (S)-3,3,3-trifluoro-2 hydroxy-2-methylpropanoic acid and (R)-3,3,3-trifluoro-2-hydroxy-2 methylpropanamide. PMID- 26011255 TI - Inverted Carbon Geometries: Challenges to Experiment and Theory. AB - Disproving a long C-C-bond textbook example: The reported 1.643 A C-C bond in 5 cyano-1,3-dehydroadamantane was redetermined and "only" amounts to 1.584 A. While this value is well reproduced with ab initio methods, some common DFT approaches perform poorly and are only consistent with CCSD(T)/cc-pVTZ optimizations for noninverted carbons. Large deviations from experiment were also found for other molecules with atypical electron density distributions, e.g., cubane, bicyclo[2.2.0]hexane, and bicyclo[2.1.0]- and bicyclo[1.1.1]pentane, thereby presenting challenging structures for some DFT implementations. PMID- 26011256 TI - Construction of High Density Sweet Cherry (Prunus avium L.) Linkage Maps Using Microsatellite Markers and SNPs Detected by Genotyping-by-Sequencing (GBS). AB - Linkage maps are valuable tools in genetic and genomic studies. For sweet cherry, linkage maps have been constructed using mainly microsatellite markers (SSRs) and, recently, using single nucleotide polymorphism markers (SNPs) from a cherry 6K SNP array. Genotyping-by-sequencing (GBS), a new methodology based on high throughput sequencing, holds great promise for identification of high number of SNPs and construction of high density linkage maps. In this study, GBS was used to identify SNPs from an intra-specific sweet cherry cross. A total of 8,476 high quality SNPs were selected for mapping. The physical position for each SNP was determined using the peach genome, Peach v1.0, as reference, and a homogeneous distribution of markers along the eight peach scaffolds was obtained. On average, 65.6% of the SNPs were present in genic regions and 49.8% were located in exonic regions. In addition to the SNPs, a group of SSRs was also used for construction of linkage maps. Parental and consensus high density maps were constructed by genotyping 166 siblings from a 'Rainier' x 'Rivedel' (Ra x Ri) cross. Using Ra x Ri population, 462, 489 and 985 markers were mapped into eight linkage groups in 'Rainier', 'Rivedel' and the Ra x Ri map, respectively, with 80% of mapped SNPs located in genic regions. Obtained maps spanned 549.5, 582.6 and 731.3 cM for 'Rainier', 'Rivedel' and consensus maps, respectively, with an average distance of 1.2 cM between adjacent markers for both 'Rainier' and 'Rivedel' maps and of 0.7 cM for Ra x Ri map. High synteny and co-linearity was observed between obtained maps and with Peach v1.0. These new high density linkage maps provide valuable information on the sweet cherry genome, and serve as the basis for identification of QTLs and genes relevant for the breeding of the species. PMID- 26011258 TI - Abnormal ventilatory response to exercise in young adults operated for ventricular septal defect in early childhood: A long-term follow-up. AB - BACKGROUND: Ventricular septal defects (VSDs) are normally closed in early childhood, and postsurgical physical capacity is generally considered normal. Despite an increasing understanding of late cardiac morbidity among these patients, long-term pulmonary function remains to be investigated. Therefore, the aim of this prospective follow-up study was to describe ventilatory function during exercise in VSD-repaired adults operated in early life. METHODS: We tested cardiopulmonary exercise capacity in 27 patients and 30 healthy control subjects on an ergometer cycle. Each test was preceded by a standard spirometry, and the exercise test was performed as a maximal incremental test. Pulmonary ventilation and gas exchange were simultaneously measured breath-by-breath with minute ventilation at peak exercise as our main endpoint. RESULTS: In the VSD-group the median surgical age was 1.9 (95% CI 1.1-2.8 years) and the mean age at time of examination was 21.1 +/- 3.1 years in the VSD-group vs. 21.2 +/- 2.5 years in the control group. Mean minute ventilation at peak exercise was significantly lower in the VSD-group compared with the controls: 1.4 +/- 0.4 L/kg/min vs. 1.8 +/- 0.4 L/kg/min, p<0.01. Likewise, mean oxygen uptake was reduced: 38.0 +/- 8.2 ml/kg/min in the VSD-cohort vs. 47.9 +/- 6.5 ml/kg/min among controls, p<0.01. In terms of breath rate and ventilatory equivalents (O2 and CO2) there were no differences between the groups. CONCLUSIONS: Patients with a surgically closed VSD have a markedly abnormal ventilatory response to exercise with significantly reduced minute ventilation despite a similar breath rate. With a follow-up of almost two decades our finding most certainly reflects an unknown but persisting abnormality. PMID- 26011257 TI - Complementary phenol-enriched olive oil improves HDL characteristics in hypercholesterolemic subjects. A randomized, double-blind, crossover, controlled trial. The VOHF study. AB - SCOPE: Consumption of olive oil (OO) phenolic compounds (PCs) has beneficial effects on lipid profile. HDL functionality is currently considered to be a more important issue than its circulating quantity. Our aim was to assess whether functional virgin olive oils (FVOOs), one enriched with its own PC (500 ppm; FVOO) and another with OOPC (250 ppm) plus additional complementary PCs from thyme (250 ppm) (total: 500 ppm; FVOOT (functional virgin olive oil with thyme)), could improve HDL functionality related properties versus a virgin OO control (80 ppm; VOO). METHODS AND RESULTS: In a randomized, double-blind, crossover, controlled trial, 33 hypercholesterolemic volunteers received 25 mL/day of VOO, FVOO, and FVOOT during 3 wk. HDL cholesterol increased 5.74% (p < 0.05) versus its baseline after the FVOOT consumption in the participants without hypolipidemic medication. We detected, after FVOOT consumption, an increase in HDL2 -subclass (34.45, SD = 6.38) versus VOO intake (32.73, SD = 6.71). An increment in esterified cholesterol/free cholesterol and phospholipids/free cholesterol in HDL was observed after FVOOT consumption (1.73, SD = 0.56; 5.44, SD = 1.39) compared with VOO intervention (1.53, SD = 0.35; 4.97, SD = 0.81) and FVOO intervention (1.50, SD = 0.33; 4.97, SD = 0.81). Accordingly, lecithin cholesterol acyltransferase mass increased after FVOOT consumption (1228 MUg/mL, SD = 130), compared with VOO consumption (1160 MUg/mL, SD = 144). An improvement in HDL oxidative-status was reflected after FVOOT consumption versus its baseline, given an increment in the paraoxonase activity (118 * 10(3) U/L, SD = 24). CONCLUSION: FVOOT improves HDL-subclass distribution and composition, and metabolism/antioxidant enzyme activities. FVOOT could be a useful dietary tool in the management of high cardiovascular risk patients. PMID- 26011259 TI - Aortic regurgitation after transcatheter aortic valve implantation (TAVI) - Angiographic, echocardiographic and hemodynamic assessment in relation to one year outcome. AB - BACKGROUND: Aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) remains a relatively frequent and life-limiting complication. However, the most prognostically discriminative (and therefore preferred) technique of AR evaluation after TAVI is not yet clearly defined. The aim of this study was to compare angiographic, echocardiographic and hemodynamic assessment of AR after TAVI in relation to one year outcome. METHODS AND RESULTS: In this single center prospective cohort study, angiography (AR grading), echocardiography (AR quantification using color Doppler flow mapping) and invasive hemodynamics (AR index) were assessed before and after TAVI. All patients were followed up to at least one year. A total of 111 consecutive (very) high-risk patients with severe, symptomatic aortic valve stenosis underwent TAVI. No concordant relation could be demonstrated between angiographic, echocardiographic and invasive assessment of AR after TAVI. AR index <25 post TAVI was significantly influenced by left ventricular posterior wall thickness (odds ratio: 1.276, p=0.030) and AR index pre TAVI (odds ratio: 0.948, p=0.019). Neither angiographic nor hemodynamic AR assessments were able to discriminate between good or significantly decreased one year survival. In contrast, color Doppler flow mapping of AR after TAVI was highly reproducible, and able to differentiate between good or significantly decreased one year survival (AR grades 0-I: one year survival 87% vs. AR grades II-III-IV: one year survival 68%, p=0.035). CONCLUSION: Echocardiography using color Doppler flow mapping is the preferred technique to assess prognostically relevant AR after TAVI. PMID- 26011260 TI - Clinical severity of viral myocarditis is not associated with a mutation of dystrophin gene cleavage sites. PMID- 26011261 TI - Efficacy of electroacupuncture pretreatment for myocardial injury in patients undergoing percutaneous coronary intervention: A randomized clinical trial with a 2-year follow-up. AB - Electroacupuncture pretreatment (EAP) safely protects the heart from ischemic injury, however, the efficacy of EAP for periprocedural myocardial injury after percutaneous coronary intervention (PCI) remains unclear. Our aim was to investigate whether EAP prior to PCI reduces post-PCI myocardial injury in patients with coronary artery disease (CAD). 388 patients (>= 18 years old) with CAD, undergoing elective PCI were enrolled and randomized, out of those 204 went through the whole trial. EAP was conducted by 30-minute electrical stimulation through 4 electrodes attached to the Antiguan (PC6) and Ximen (PC4) acupoints in the forearm bilaterally 1-2h prior to PCI. The control group had sham electrodes but no electrical stimulation. The primary end point was the incidence of myocardial infarction type 4a (MI4a) based on serum cTnI values at 24h after PCI. The secondary end points included post-procedural cardiac function and the major adverse cardiac/cerebrovascular event (MACCE) rate. EAP prior to PCI significantly reduced the incidence of MI4a (serum cTnI>=0.20 ng/mL) 24h post-PCI compared to the control group (P=0.004). The echocardiography at 6 months after PCI revealed significant improvement in cardiac function in the EAP group compared with the control group. The MACCE rate was significantly decreased in the EAP group at 24 month follow-up compared to the control group (P=0.0157). Moreover, multivariate logistic regression analysis showed that EAP was associated with decreased likelihood of MACCE (odds ratio 0.327, 95% CI 0.140 0.767, P=0.010). EAP prior to PCI significantly reduced cTnI release and protected patients with CAD from subsequent myocardial injury after PCI procedure. PMID- 26011262 TI - Chemokine IP-10 is correlated with cardiac responses and status of infection with HIV and HCV in methadone maintenance patients. PMID- 26011263 TI - Pre-hospital ticagrelor in ST-segment elevation myocardial infarction: Ready for prime time? AB - In ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) peri-procedural P2Y12 antagonism - although of great importance - is often suboptimal, even with the novel oral antiplatelet agents prasugrel and ticagrelor. The concept of pre-hospital ticagrelor loading, investigated in the recently published Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC) trial, appears quite a promising strategy to optimize peri-procedural platelet inhibition and potentially clinical outcome. Implementation of such an approach when treating low risk STEMI patients in 'real life' practice might prove even more beneficial than expected from the ATLANTIC results, given the reported delays from first medical contact to primary PCI performance. PMID- 26011264 TI - Response to the letter by Tomoyuki Kawada: Diastolic function, fasting plasma glucose and left ventricular mass index. PMID- 26011265 TI - Comparison of therapy with Ticagrelor, Prasugrel or high Clopidogrel dose in PCI patients with high on treatment platelet reactivity and genotype variation. TRIPLETE RESET trial. PMID- 26011266 TI - Job stress and the metabolic syndrome with special reference to sex and age. PMID- 26011267 TI - The complex issue of TIMI frame count in patients with Takotsubo syndrome. PMID- 26011268 TI - Elastin fracture localized in ascending aorta could be one of the mechanisms of enhanced aortic pressure wave reflection in adult patients with congenital heart disease. PMID- 26011269 TI - Higher daily energy expenditure by locomotive activities is favorably associated with cardiac autonomic nervous function and arterial stiffness. PMID- 26011270 TI - The slope of the stretch-strain relationship as a non-invasive contractility index: Insights from mitral regurgitation surgery. PMID- 26011271 TI - Increased association of coronary artery calcification in apparently healthy Korean adults with hypertriglyceridemic waist phenotype: The Kangbuk Samsung Health Study. AB - BACKGROUND: Hypertriglyceridemic waist phenotype is a simple screening parameter to identify people at increased risk for cardiovascular disease. We evaluated whether hypertriglyceridemic waist (HTGW) phenotype increases the risk for coronary artery calcification (CAC) in apparently healthy Korean adults. METHODS: A total of 32,186 participants (mean age 41.3, 80.2% men) in a health screening program, in whom the coronary artery calcium score (CACS) was measured, were analyzed. Subjects were divided into four groups: 1) normal waist circumference (WC)-normal triglyceride (TG) (NWNT), 2) normal WC-high TG (NWHT), 3) enlarged WC normal TG (EWNT), and 4) enlarged WC-high TG (EWHT). Enlarged WC was defined as WC >= 90 cm for men and >= 85 cm for women; high serum TG was defined as TG >= 150 mg/dL. The presence of CAC was defined by CACS >0, and CACS was analyzed in a logarithmized form of CACS plus 1 {ln(CACS+1)}. RESULTS: A total of 14.9% of the participants had CAC. The EWHT group showed the highest mean value for ln(CACS+1) among the four groups. The EWHT group showed the highest odds ratio for CAC, with NWHT group the second, and with EWNT group the third compared with the NWNT group after adjusting for confounding variables (1.579, 1.302, and 1.266 vs. NWNT). CONCLUSIONS: The EWHT group showed the highest association for CAC, suggesting this HTGW phenotype as a useful marker for the detection of subjects with high cardiometabolic risk in healthy Korean adults. PMID- 26011272 TI - Cardiac surgery and repair of pectus deformities: When and how? AB - OBJECTIVES: There is currently a lack of recommendations about patients with pectus deformities requiring cardiac surgery. This study reports the results of our surgical strategy on this issue. METHODS: Eleven patients, from three centers treated over a 9-year period were included in this study. Pectus deformities were operated with a modified Ravitch procedure. In the case of pectus excavatum repair and concomitant cardiac surgery, subperichondrial resection of abnormal rib cartilages was always performed before the sternotomy and an easily removable retrosternal metallic strut was inserted at the end of the procedure ensuring anterior chest wall stability. During follow-up patients had to estimate their current appearance with a numeric scale ranging from 0 to 100. RESULTS: Mean age was 27 +/- 9.4 years. Pectus excavatum was present in 8 patients and pectus arcuatum in 3. There were 6 Marfan syndrome patients. Nine patients had concomitant surgery and, 2 underwent pectus repair after a history of cardiac surgery. There was no operative mortality. In the case of concomitant surgery, heart exposure through median sternotomy was facilitated by abnormal rib cartilage resection. Median follow-up was 54 months (range 16.7-119.7). Mean cosmetic result evaluated by the patients was 97.3 (+/-2.5). CONCLUSIONS: In adults, concomitant scheduled surgery is reliable and offers excellent long-term cosmetic results. Moreover, it allows a better thoracic exposition with no added perioperative risk. The modified Ravitch technique seems more adequate in these patients as it can be used in all types of pectus deformities. PMID- 26011273 TI - Transient apical wall thickening in patients with stress cardiomyopathy: Prevalence, profile, and impact on clinical course. AB - BACKGROUND: Transient apical wall thickening (TAWT), mimicking apical hypertrophic cardiomyopathy during recovery from stress cardiomyopathy (SCM), has recently been reported. However, the clinical significance of this phenomenon has not yet been assessed. We aimed to explore the prevalence, profiles, and impact on the clinical course of TAWT in patients with SCM. METHODS: We retrospectively analyzed the SCM registry from January 2009 to December 2013. Of 429 patients with SCM, 124 patients who had typical features of transient apical ballooning were included. We identified patients who showed evidence of TAWT, which became normalized on serial echocardiograms. Clinical characteristics, incidence of cardiac complications (arrhythmia, pulmonary edema, cardiogenic shock, or left ventricular thrombus), and in-hospital mortality were compared between patients with and without TAWT. RESULTS: Among 124 patients, 17 (14%) patients showed TAWT. During the follow-up period, TAWT was observed 14.6 +/- 10.3 days after the initial SCM diagnosis. Patients with TAWT showed a higher prevalence of septic shock as a triggering factor of SCM than those without TAWT (41.2% vs. 19.6%, p=0.048). Furthermore, cardiac complications were more prevalent in patients with TAWT compared to patients without (64.7% vs. 33.6%, p=0.03). Finally, in-hospital mortality was significantly higher in patients with TAWT group during the clinical course of SCM (p=0.009). CONCLUSION: TAWT in patients with SCM is not uncommon. Patients with SCM and systemic inflammation with hemodynamic instability might be susceptible to TAWT, which is often associated with cardiac complications. These patients showed worse prognosis compared to those without TAWT during recovery from SCM. PMID- 26011274 TI - Extracorporeal shockwave myocardial revascularization therapy in refractory angina patients. PMID- 26011275 TI - Within-Crop Air Temperature and Humidity Outcomes on Spatio-Temporal Distribution of the Key Rose Pest Frankliniella occidentalis. AB - Frankliniella occidentalis (Pergande) is a key pest of various crops worldwide. In this study, we analyse the dependence of the infestation of this pest on spatially distributed micro climatic factors in a rose greenhouse. Despite the importance of this subject, the few existing studies have been realized in laboratory rather than in greenhouse conditions. However, recent progress on greenhouse microclimate characterisation has highlighted the strong indoor climate heterogeneity that may influence the within-crop pest distribution. In this study, both microclimate (air temperature and humidity) and thrips distribution were simultaneously mapped in a rose greenhouse. The measurements were sensed in a horizontal plane situated at mid-height of the rose crop inside the greenhouse. Simultaneously, thrips population dynamics were assessed after an artificial and homogeneous infestation of the rose crop. The spatio-temporal distribution of climate and thrips within the greenhouse were compared, and links between thrips infestation and climatic conditions were investigated. A statistical model was used to define the favourable climate conditions for thrips adults and larvae. Our results showed that (i) the air temperature and air humidity were very heterogeneously distributed within the crop, (ii) pest populations aggregated in the most favourable climatic areas and (iii) the highest population density of thrips adults and larvae were recorded at 27 degrees C and 22 degrees C for temperature and 63% and 86% for humidity, respectively. These findings confirm, in real rose cropping conditions, previous laboratory studies on the F. occidentalis climatic optimum and provide a solid scientific support for climatic-based control methods against this pest. PMID- 26011276 TI - African-American race modifies the influence of tacrolimus concentrations on acute rejection and toxicity in kidney transplant recipients. AB - STUDY OBJECTIVE: To determine the effect of tacrolimus trough concentrations on clinical outcomes in kidney transplantation, while assessing if African-American (AA) race modifies these associations. DESIGN: Retrospective longitudinal cohort study of solitary adult kidney transplants. SETTING: Large tertiary care transplant center. PATIENTS: Adult solitary kidney transplant recipients (n=1078) who were AA (n=567) or non-AA (n=511). EXPOSURE: Mean and regressed slope of tacrolimus trough concentrations. Subtherapeutic concentrations were lower than 8 ng/ml. MEASUREMENTS AND MAIN RESULTS: AA patients were 1.7 times less likely than non-AA patients to achieve therapeutic tacrolimus concentrations (8 ng/ml or higher) during the first year after kidney transplant (35% vs 21%, respectively, p<0.001). AAs not achieving therapeutic concentrations were 2.4 times more likely to have acute cellular rejection (ACR) as compared with AAs achieving therapeutic concentrations (20.8% vs 8.5%, respectively, p<0.01) and 2.5 times more likely to have antibody-mediated rejection (AMR; 8.9% vs 3.6%, respectively, p<0.01). Rates of ACR (8.3% vs 6.7%) and AMR (2.0% vs 0.9% p=0.131) were similar in non-AAs compared across tacrolimus concentration groups. Multivariate modeling confirmed these findings and demonstrated that AAs with low tacrolimus exposure experienced a mild protective effect for the development of interstitial fibrosis/tubular atrophy (IF/TA; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.47-1.32) with the opposite demonstrated in non-AAs (HR 2.2, 95% CI 0.90-5.1). CONCLUSION: In contradistinction to non-AAs, AAs who achieve therapeutic tacrolimus concentrations have substantially lower acute rejection rates but are at risk of developing IF/TA. These findings may reflect modifiable time-dependent racial differences in the concentration-effect relationship of tacrolimus. Achievement of therapeutic tacrolimus trough concentrations, potentially through genotyping and more aggressive dosing and monitoring, is essential to minimize the risk of acute rejection in AA kidney transplant recipients. PMID- 26011277 TI - Pharmaceutical Opioid Use and Dependence among People Living with Chronic Pain: Associations Observed within the Pain and Opioids in Treatment (POINT) Cohort. AB - OBJECTIVE: There is increasing concern about the appropriateness of prescribing pharmaceutical opioids for chronic non-cancer pain (CNCP), given the risks of problematic use and dependence. This article examines pharmaceutical opioid dose and dependence and examines the correlates of each. DESIGN: Baseline data were obtained from a national sample of 1,424 people across Australia (median 58 years, 55% female and experiencing pain for a median of 10 years), who had been prescribed opioids for CNCP. Current opioid consumption was estimated in oral morphine equivalent (OME; mg per day), and ICD-10 pharmaceutical opioid dependence was assessed using the Composite International Diagnostic Interview. RESULTS: Current opioid consumption varied widely: 8.8% were taking <20 mg OME per day, 52.1% were taking 21-90 mg OME, 24.3% were taking 91-199 mg OME, and 14.8% were taking >= 200 mg OME. Greater daily OME consumption was associated with higher odds of multiple physical and mental health issues, aberrant opioid use, problems associated with opioid medication and opioid dependence. A significant minority, 8.5%, met criteria for lifetime ICD-10 pharmaceutical opioid dependence and 4.7% met criteria for past year ICD-10 pharmaceutical opioid dependence. Multivariate analysis found past-year dependence was independently associated with being younger, exhibiting more aberrant behaviors and having a history of benzodiazepine dependence. CONCLUSIONS: In this population of people taking opioids for CNCP, consumption of higher doses was associated with increased risk of problematic behaviors, and was more likely among people with a complex profile of physical and mental health problems. PMID- 26011278 TI - First Description of Sulphur-Oxidizing Bacterial Symbiosis in a Cnidarian (Medusozoa) Living in Sulphidic Shallow-Water Environments. AB - BACKGROUND: Since the discovery of thioautotrophic bacterial symbiosis in the giant tubeworm Riftia pachyptila, there has been great impetus to investigate such partnerships in other invertebrates. In this study, we present the occurrence of a sulphur-oxidizing symbiosis in a metazoan belonging to the phylum Cnidaria in which this event has never been described previously. METHODOLOGY/PRINCIPAL FINDINGS: Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM) observations and Energy-dispersive X-ray spectroscopy (EDXs) analysis, were employed to unveil the presence of prokaryotes population bearing elemental sulphur granules, growing on the body surface of the metazoan. Phylogenetic assessments were also undertaken to identify this invertebrate and microorganisms in thiotrophic symbiosis. Our results showed the occurrence of a thiotrophic symbiosis in a cnidarian identified as Cladonema sp. CONCLUSIONS/SIGNIFICANCE: This is the first report describing the occurrence of a sulphur-oxidizing symbiosis in a cnidarian. Furthermore, of the two adult morphologies, the polyp and medusa, this mutualistic association was found restricted to the polyp form of Cladonema sp. PMID- 26011279 TI - Assessment of metal species in river Ganga sediment at Varanasi, India using sequential extraction procedure and SEM-EDS. AB - Aim of the present study was to assess impact of urban drains over river water and sediments by physico-chemical and metal analysis. Metal speciation (Sequential Extraction Procedure) and elemental composition analysis (SEM-EDS) was used to quantify metal pollution load in river sediments. Metal speciation analysis showed dominance of available and labile fractions of all heavy metals (Cr, Ni, Cu, Zn, Cd and Pb) except Mn and Fe which were dominant in residual forms. Cluster analysis (CA), Principal Components Analysis (PCA) and Partial Least Square Regression (PLSR) were applied as source receptor modeling for pollutants. Results classified river stretch into three zones i.e. moderately, severely and extremely polluted, on the basis of pollutant concentration released from anthropogenic sources. SEM-EDS study revealed the elemental composition percentage in river sediments. Pollution Load Index (PLI) varied from 1.8 (S1) 3.9 (S15). The Geo accumulation index (GAI) was found highest for Cd (6.88-8.97) and Pb (2.41-3.24). PMID- 26011281 TI - Age, risk, and life expectancy in Norwegian intensive care: a registry-based population modelling study. AB - BACKGROUND: Knowledge about the expected life years gained from intensive care unit (ICU) admission could inform priority-setting decisions across groups of ICU patients and across medical specialties. The aim of this study was to estimate expected remaining lifetime for patients admitted to ICUs during 2008-2010 and to estimate the gain in life years from ICU admission. METHODS: This is a descriptive, population modelling study of 30,712 adult mixed ICU admissions from the Norwegian Intensive Care Registry. The expected remaining lifetime for each patient was estimated using a decision-analytical model. Transition probabilities were based on registered Simplified Acute Physiology Score (SAPS) II, and standard and adjusted Norwegian life-tables. RESULTS: The hospital mortality was 19.4% (n = 5,958 deaths). 24% of the patients were estimated to die within the first year after ICU admission in our model. Under an intermediate (base case), optimistic (O), and pessimistic (P) scenario with respect to long-term mortality, the average expected remaining lifetime was 19.4, 19.9, and 12.7 years. The majority of patients had a life expectancy of more than five years (84.8% in the base case, 89.4% in scenario O, and 55.6% in scenario P), and few had a life expectancy of less than one year (0.7%, 0.1%, and 12.7%). The incremental gain from ICU admission compared to counterfactual general ward care was estimated to be 0.04 (scenario P, age 85+) to 1.14 (scenario O, age < 45) extra life years per patient. CONCLUSIONS: Our research demonstrated a novel way of using routinely collected registry data to estimate and evaluate the expected lifetime outcomes for ICU patients upon admission. The majority had high life expectancies. The youngest age groups seemed to benefit the most from ICU admission. The study raises the question whether availability and rationing of ICU services are too strict in Norway. PMID- 26011282 TI - Inward Leakage Variability between Respirator Fit Test Panels - Part I. Deterministic Approach. AB - Inter-panel variability has never been investigated. The objective of this study was to determine the variability between different anthropometric panels used to determine the inward leakage (IL) of N95 filtering facepiece respirators (FFRs) and elastomeric half-mask respirators (EHRs). A total of 144 subjects, who were both experienced and non-experienced N95 FFR users, were recruited. Five N95 FFRs and five N95 EHRs were randomly selected from among those models tested previously in our laboratory. The PortaCount Pro+ (without N95-Companion) was used to measure IL of the ambient particles with a detectable size range of 0.02 to 1 MUm. The Occupational Safety and Health Administration standard fit test exercises were used for this study. IL test were performed for each subject using each of the 10 respirators. Each respirator/subject combination was tested in duplicate, resulting in a total 20 IL tests for each subject. Three 35-member panels were randomly selected without replacement from the 144 study subjects stratified by the National Institute for Occupational Safety and Health bivariate panel cell for conducting statistical analyses. The geometric mean (GM) IL values for all 10 studied respirators were not significantly different among the three randomly selected 35-member panels. Passing rate was not significantly different among the three panels for all respirators combined or by each model. This was true for all IL pass/fail levels of 1%, 2%, and 5%. Using 26 or more subjects to pass the IL test, all three panels had consistent passing/failing results for pass/fail levels of 1% and 5%. Some disagreement was observed for the 2% pass/fail level. Inter-panel variability exists, but it is small relative to the other sources of variation in fit testing data. The concern about inter-panel variability and other types of variability can be alleviated by properly selecting: pass/fail level (IL 1-5%); panel size (e.g., 25 or 35); and minimum number of subjects required to pass (e.g., 26 of 35 or 23 of 35). PMID- 26011284 TI - Intrauterine contraceptive device: cause of small bowel obstruction and ischaemia. PMID- 26011283 TI - Coproduction of detergent compatible bacterial enzymes and stain removal evaluation. AB - Most of the detergents that are presently produced contain the detergent compatible enzymes to improve and accelerate the washing performance by removing tough stains. The process is environment friendly as the use of enzymes in the detergent formulation reduces the utilization of toxic detergent constituents. The current trend is to use the detergent compatible enzymes that are active at low and ambient temperature in order to save energy and maintain fabric quality. As the detergent compatible bacterial enzymes are used together in the detergent formulation, it is important to co-produce the detergent enzymes in a single fermentation medium as the enzyme stability is assured, and production cost gets reduced enormously. The review reports on the production, purification, characterization and application of detergent compatible amylases, lipases, and proteases are available. However, there is no specific review or minireview on the concomitant production of detergent compatible amylases, lipases, and proteases. In this minireview, the coproduction of detergent compatible enzymes by bacterial species, enzyme stability towards detergents and detergent components, and stain release analysis were discussed. PMID- 26011285 TI - Changes in fitness are associated with changes in body composition and bone health in children after cancer. AB - AIM: This study examined the effects of physical activity on the fitness, body composition and mental health of children after cancer or bone marrow transplantation. METHODS: We focused on 22 children aged from seven to 14 years who had received chemotherapy and/or bone marrow transplantation in our medical centre. Ten children took part in a six-month exercise programme, and 12 children who did not exercise formed the control group. At baseline and at the end of the trial, we measured aerobic fitness, body composition, bone density and assessed the child's mood and quality of life. We pooled all participants together post hoc to compare changes in fitness with the various study outcomes. RESULTS: We found no differences between groups in changes in fitness, body composition or mental health indices. Significant correlations were found between changes in aerobic fitness and changes in lean body mass (r = 0.74, p = 0.002), bone mineral content (r = 0.57, p = 0.026) and femoral neck bone mineral density (r = 0.59, p = 0.027) in all participants. CONCLUSION: Group-based exercise training did not improve aerobic fitness in children after cancer or bone marrow transplantation. However, changes in fitness throughout the study period were associated with changes in body composition and bone health in all participants. PMID- 26011286 TI - Multicenter testing of the rapid quantification of radical oxygen species in cerebrospinal fluid to diagnose bacterial meningitis. AB - PURPOSE: Meningitis is a serious concern after traumatic brain injury (TBI) or neurosurgery. This study tested the level of reactive oxygen species (ROS) in cerebrospinal fluid (CSF) to diagnose meningitis in febrile patients several days after trauma or surgery. METHODS: Febrile patients (temperature > 38 degrees C) after TBI or neurosurgery were included prospectively. ROS were measured in CSF within 4 hours after sampling using luminescence in the basal state and after cell stimulation with phorbol 12-myristate 13-acetate (PMA). The study was conducted in a single-center cohort 1 (n = 54, training cohort) and then in a multicenter cohort 2 (n = 136, testing cohort) in the Intensive Care and Neurosurgery departments of two teaching hospitals. The performance of the ROS test was compared with classical CSF criteria, and a diagnostic decision for meningitis was made by two blinded experts. RESULTS: The production of ROS was higher in the CSF of meningitis patients than in non-infected CSF, both in the basal state and after PMA stimulation. In cohort 1, ROS production was associated with a diagnosis of meningitis with an AUC of 0.814 (95% confidence interval (CI) [0.684-0.820]) for steady-state and 0.818 (95% CI [0.655-0.821]) for PMA activated conditions. The best threshold value obtained in cohort 1 was tested in cohort 2 and showed high negative predictive values and low negative likelihood ratios of 0.94 and 0.36 in the basal state, respectively, and 0.96 and 0.24 after PMA stimulation, respectively. CONCLUSION: The ROS test in CSF appeared suitable for eliminating a diagnosis of bacterial meningitis. PMID- 26011287 TI - Lack of Melanopsin Is Associated with Extreme Weight Loss in Mice upon Dietary Challenge. AB - Metabolic disorders have been established as major risk factors for ocular complications and poor vision. However, little is known about the inverse possibility that ocular disease may cause metabolic dysfunction. To test this hypothesis, we assessed the metabolic consequences of a robust dietary challenge in several mouse models suffering from retinal mutations. To this end, mice null for melanopsin (Opn4-/-), the photopigment of intrinsically photosensitive retinal ganglion cells (ipRGCs), were subjected to five weeks of a ketogenic diet. These mice lost significantly more weight than wild-type controls or mice lacking rod and cone photoreceptors (Pde6brd1/rd1). Although ipRGCs are critical for proper circadian entrainment, and circadian misalignment has been implicated in metabolic pathology, we observed no differences in entrainment between Opn4-/- and control mice. Additionally, we observed no differences in any tested metabolic parameter between these mouse strains. Further studies are required to establish the mechanism giving rise to this dramatic phenotype observed in melanopsin-null mice. We conclude that the causality between ocular disease and metabolic disorders merits further investigation due to the popularity of diets that rely on the induction of a ketogenic state. Our study is a first step toward understanding retinal pathology as a potential cause of metabolic dysfunction. PMID- 26011288 TI - Ovary preservation in the treatment of childhood Meigs syndrome. AB - Meigs syndrome, the combination of benign ovarian tumor, ascites, and pleural effusion, is present in a small percentage of ovarian fibromas and is infrequently reported in children. When associated with elevated CA-125 suspicion is raised for malignancy, often prompting aggressive surgical intervention. We present a case of childhood Meigs syndrome and review the relevant literature with emphasis on ovary preservation. Out of nine identified pediatric cases, one involved ovary sparing treatment and none recurred or progressed to malignancy. Our report highlights the importance of presurgical identification of Meigs syndrome in order to curtail salpingo-oophorectomy when feasible. PMID- 26011289 TI - Renal Function and Bone Loss in a Cohort of Afro-Caribbean Men. AB - Poor renal function is associated with increased rates of bone loss and osteoporotic fractures in Caucasian men. The importance of kidney function for skeletal health in African ancestry men, who are a population segment with a high prevalence of chronic kidney disease as well as high peak bone mass, is not well known. We examined the relationship between estimated glomerular filtration rate (eGFR) and rates of bone loss in a large population cohort of otherwise healthy Afro-Caribbean men aged 40 years and older. Dual X-ray absorptiometry of the proximal femur and quantitative computed tomography of the proximal radius and tibia were obtained approximately 6 years apart. We calculated eGFR from serum creatinine that was measured in fasting samples in 1451 men. Impaired kidney function (IKF, eGFR<60 ml/min/1.7 m(2)) was observed in 8.6% of the cohort. The relationship between IKF and baseline BMD and annualized rate of change in BMD was analyzed controlling for potentially important confounders. IKF was not associated with baseline BMD. In contrast, men with IKF experienced a rate of decline in areal BMD at the total hip, femoral neck and trochanter and cortical volumetric BMD compared to those with normal kidney function (p<0.05 for all). Impaired kidney function was not associated with changes in trabecular volumetric BMD. In conclusion, poorer kidney function is associated with accelerated bone loss among otherwise healthy Afro-Caribbean men even after controlling for age and other important medical and lifestyle related variables. PMID- 26011290 TI - Comparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and in vivo Experiments. AB - For (64) Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators--NODA-GA ((1,4,7 triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2' (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl)diacetic acid), or CB-TE1A GA (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl-8-acetic acid-1-glutaric acid)--forms the most stable complexes resulting in PET images of highest quality. We determined the (64) Cu complex stabilities for these three chelators by a combination of complex challenge and an in vivo approach. For this purpose, bioconjugates of the chelating agents with the gastrin-releasing peptide receptor (GRPR)-affine peptide PESIN and an integrin alphav beta3 -affine c(RGDfC) tetramer were synthesized and radiolabeled with (64) Cu in excellent yields and specific activities. The (64) Cu-labeled biomolecules were evaluated for their complex stabilities in vitro by conducting a challenge experiment with the respective other chelators as challengers. The in vivo stabilities of the complexes were also determined, showing the highest stability for the (64) Cu-CB TE1A-GA complex in both experimental setups. Therefore, CB-TE1A-GA is the most appropriate chelating agent for *Cu-labeled radiotracers and in vivo imaging applications. PMID- 26011291 TI - Cerebral oxygenation in highlanders with and without high-altitude pulmonary hypertension. AB - NEW FINDINGS: What is the central question of this study? Cerebral hypoxia impairs cognitive function and exercise performance and may result in brain damage. Residents at high altitude, in particular those with high-altitude pulmonary hypertension, are prone to hypoxaemia due to the exposure to reduced barometric pressure and impaired pulmonary gas exchange. Whether highlanders have a reduced cerebral oxygenation has not been studied. What is the main finding and its importance? We found that despite a reduced arterial oxygen saturation, healthy highlanders and even those with pulmonary hypertension have a similar cerebral oxygenation to healthy lowlanders, suggesting that compensatory mechanisms protect long-term residents at high altitude from cerebral hypoxia. Abstract High-altitude pulmonary hypertension (HAPH), a chronic altitude-related illness, causes hypoxaemia and impaired exercise performance. We evaluated the hypothesis that haemodynamic limitation and hypoxaemia in patients with HAPH are associated with impaired cerebral tissue oxygenation (CTO) compared with healthy highlanders (HH) and lowlanders (LL). We studied 36 highlanders with HAPH and 54 HH at an altitude of 3250 m, and 34 LL at 760 m. Mean(+/-SD) pulmonary artery pressures were 34(+/-3), 22(+/-5) and 16(+/-4) mmHg, respectively (P < 0.05, all comparisons). The CTO was monitored by near-infrared spectroscopy along with pulse oximetry (peripheral arterial oxygen saturation, SpO2) during quiet breathing of room air (RA) and oxygen for 20 min each, and during hyperventilation with RA and oxygen, respectively. In HAPH, HH and LL breathing RA, SpO2 was 88(+/-4), 92(+/-2) and 95(+/-2)%, respectively (P < 0.001, all comparisons), and CTO was similar in the three groups, at 68(+/-3), 68(+/-4) and 69(+/-4)%, respectively (n.s., all comparisons). Breathing oxygen increased SpO2 and CTO significantly more in HAPH than in HH and LL. Hyperventilation (RA) did not reduce CTO in HAPH but did in HH and LL; hyperventilation (oxygen) increased CTO in HAPH only. Highlanders with and without HAPH studied at 3250 m had a similar CTO to healthy lowlanders at 760 m even though highlanders were hypoxaemic. The physiological response to hyperoxia and hypocapnia assessed by cerebral near-infrared spectroscopy suggests that healthy highlanders and even highlanders with HAPH effectively maintain an adequate CTO. This adaptation may be of particular relevance because adequate cerebral oxygenation is essential for vital brain functions. PMID- 26011292 TI - Near-Field Characterization of Methane Emission Variability from a Compressor Station Using a Model Aircraft. AB - A model aircraft equipped with a custom laser-based, open-path methane sensor was deployed around a natural gas compressor station to quantify the methane leak rate and its variability at a compressor station in the Barnett Shale. The open path, laser-based sensor provides fast (10 Hz) and precise (0.1 ppmv) measurements of methane in a compact package while the remote control aircraft provides nimble and safe operation around a local source. Emission rates were measured from 22 flights over a one-week period. Mean emission rates of 14 +/- 8 g CH4 s(-1) (7.4 +/- 4.2 g CH4 s(-1) median) from the station were observed or approximately 0.02% of the station throughput. Significant variability in emission rates (0.3-73 g CH4 s(-1) range) was observed on time scales of hours to days, and plumes showed high spatial variability in the horizontal and vertical dimensions. Given the high spatiotemporal variability of emissions, individual measurements taken over short durations and from ground-based platforms should be used with caution when examining compressor station emissions. More generally, our results demonstrate the unique advantages and challenges of platforms like small unmanned aerial vehicles for quantifying local emission sources to the atmosphere. PMID- 26011293 TI - Molecular evolution patterns reveal life history features of mycoplasma-related endobacteria associated with arbuscular mycorrhizal fungi. AB - The mycoplasma-related endobacteria (MRE), representing a recently discovered lineage of Mollicutes, are widely distributed across arbuscular mycorrhizal fungi (AMF, Glomeromycota). AMF colonize roots of most terrestrial plants and improve plant mineral nutrient uptake in return for plant-assimilated carbon. The role of MRE in the biology of their fungal hosts is unknown. To start characterizing this association, we assessed partitioning of MRE genetic diversity within AMF individuals and across the AMF phylogeographic range. We further used molecular evolution patterns to make inferences about MRE codivergence with AMF, their lifestyle and antiquity of the Glomeromycota-MRE association. While we did not detect differentiation between MRE derived from different continents, high levels of diversity were apparent in MRE populations within AMF host individuals. MRE exhibited significant codiversification with AMF over ecological time and the absence of codivergence over evolutionary time. Moreover, genetic recombination was evident in MRE. These patterns indicate that, while MRE transmission is predominantly vertical, their complex intrahost populations are likely generated by horizontal transmission and recombination. Based on predictions of evolutionary theory, we interpreted these observations as a suggestion that MRE may be antagonists of AMF. Finally, we detected a marginally significant signature of codivergence of MRE with Glomeromycota and the Endogone lineage of Mucoromycotina, implying that the symbiosis between MRE and fungi may predate the divergence between these two groups of fungi. PMID- 26011294 TI - Respiratory Nursing Diagnoses: Presenting Evidence for Identification of the Defining Characteristics in Neonatal and Pediatric Populations. AB - PURPOSE: To identify and summarize clinical data supporting selection of nursing diagnoses related to the respiratory system for pediatric and neonatal populations. METHOD: A literature review conducted in indexed publications was used. FINDINGS: The final sample consisted of 13 studies conducted in children with cardiac disease, respiratory infection, and asthma with nursing diagnoses such as ineffective breathing pattern, impaired gas exchange, and ineffective airway clearance. CONCLUSION: The higher frequency defining characteristics were dyspnea, abnormal breathing pattern, use of accessory muscle to breathe, change in frequency and respiratory rate, decreased SaO2 , and agitation. IMPLICATION FOR NURSING KNOWLEDGE: This literature review may provide a basis for consideration of important diagnostic criteria in the pediatric population; however, clinical validation in different stages of development is critical for ensuring diagnostic accuracy. PMID- 26011295 TI - Terminated Trials in the ClinicalTrials.gov Results Database: Evaluation of Availability of Primary Outcome Data and Reasons for Termination. AB - BACKGROUND: Clinical trials that end prematurely (or "terminate") raise financial, ethical, and scientific concerns. The extent to which the results of such trials are disseminated and the reasons for termination have not been well characterized. METHODS AND FINDINGS: A cross-sectional, descriptive study of terminated clinical trials posted on the ClinicalTrials.gov results database as of February 2013 was conducted. The main outcomes were to characterize the availability of primary outcome data on ClinicalTrials.gov and in the published literature and to identify the reasons for trial termination. Approximately 12% of trials with results posted on the ClinicalTrials.gov results database (905/7,646) were terminated. Most trials were terminated for reasons other than accumulated data from the trial (68%; 619/905), with an insufficient rate of accrual being the lead reason for termination among these trials (57%; 350/619). Of the remaining trials, 21% (193/905) were terminated based on data from the trial (findings of efficacy or toxicity) and 10% (93/905) did not specify a reason. Overall, data for a primary outcome measure were available on ClinicalTrials.gov and in the published literature for 72% (648/905) and 22% (198/905) of trials, respectively. Primary outcome data were reported on the ClinicalTrials.gov results database and in the published literature more frequently (91% and 46%, respectively) when the decision to terminate was based on data from the trial. CONCLUSIONS: Trials terminate for a variety of reasons, not all of which reflect failures in the process or an inability to achieve the intended goals. Primary outcome data were reported most often when termination was based on data from the trial. Further research is needed to identify best practices for disseminating the experience and data resulting from terminated trials in order to help ensure maximal societal benefit from the investments of trial participants and others involved with the study. PMID- 26011296 TI - The immediate and late effects of thyroid hormone (triiodothyronine) on murine coagulation gene transcription. AB - Thyroid dysfunction is associated with changes in coagulation. The aim of our study was to gain more insight into the role of thyroid hormone in coagulation control. C57Black/6J mice received a low-iodine diet and drinking water supplemented with perchlorate to suppress endogenous triiodothyronine (T3) and thyroxine (T4) production. Under these conditions, the impact of exogenous T3 on plasma coagulation, and hepatic and vessel-wall-associated coagulation gene transcription was studied in a short- (4 hours) and long-term (14 days) setting. Comparing euthyroid conditions (normal mice), with hypothyroidism (conditions of a shortage of thyroid hormone) and those with replacement by incremental doses of T3, dosages of 0 and 0.5 MUg T3/mouse/day were selected to study the impact of T3 on coagulation gene transcription. Under these conditions, a single injection of T3 injection increased strongly hepatic transcript levels of the well characterized T3-responsive genes deiodinase type 1 (Dio1) and Spot14 within 4 hours. This coincided with significantly reduced mRNA levels of Fgg, Serpinc1, Proc, Proz, and Serpin10, and the reduction of the latter three persisted upon daily treatment with T3 for 14 days. Prolonged T3 treatment induced a significant down-regulation in factor (F) 2, F9 and F10 transcript levels, while F11 and F12 levels increased. Activity levels in plasma largely paralleled these mRNA changes. Thbd transcript levels in the lung (vessel-wall-associated coagulation) were significantly up-regulated after a single T3 injection, and persisted upon prolonged T3 exposure. Two-week T3 administration also resulted in increased Vwf and Tfpi mRNA levels, whereas Tf levels decreased. These data showed that T3 has specific effects on coagulation, with Fgg, Serpinc1, Proc, Proz, Serpin10 and Thbd responding rapidly, making these likely direct thyroid hormone receptor targets. F2, F9, F10, F11, F12, Vwf, Tf and Tfpi are late responding genes and probably indirectly modulated by T3. PMID- 26011297 TI - TALENs-Assisted Multiplex Editing for Accelerated Genome Evolution To Improve Yeast Phenotypes. AB - Genome editing is an important tool for building novel genotypes with a desired phenotype. However, the fundamental challenge is to rapidly generate desired alterations on a genome-wide scale. Here, we report TALENs (transcription activator-like effector nucleases)-assisted multiplex editing (TAME), based on the interaction of designed TALENs with the DNA sequences between the critical TATA and GC boxes, for generating multiple targeted genomic modifications. Through iterative cycles of TAME to induce abundant semirational indels coupled with efficient screening using a reporter, the targeted fluorescent trait can be continuously and rapidly improved by accumulating multiplex beneficial genetic modifications in the evolving yeast genome. To further evaluate its efficiency, we also demonstrate the application of TAME for significantly improving ethanol tolerance of yeast in a short amount of time. Therefore, TAME is a broadly generalizable platform for accelerated genome evolution to rapidly improve yeast phenotypes. PMID- 26011299 TI - Sleep and neurodevelopmental disorders. PMID- 26011298 TI - TP53 transcription factor for the NEDD9/HEF1/Cas-L gene: potential targets in Non Small Cell Lung Cancer treatment. AB - Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells. PMID- 26011300 TI - POLR3A and POLR3B Mutations in Unclassified Hypomyelination. AB - OBJECTIVE: This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination. METHODS AND RESULTS: In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients. CONCLUSION: Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first. PMID- 26011303 TI - Correction: Fire and Grazing Influences on Rates of Riparian Woody Plant Expansion along Grassland Streams. PMID- 26011302 TI - Insulin Resistance but Not Visceral Adiposity Index Is Associated with Liver Fibrosis in Nondiabetic Subjects with Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, type 2 diabetes mellitus, and dyslipidemia. It is well known that the presence of visceral fat increases the risk for metabolic complications of obesity, especially NAFLD. The visceral adiposity index (VAI), a novel marker of visceral fat dysfunction, shows a strong association with insulin resistance and also cardiovascular and cerebrovascular events. However, there is conflicting data regarding the association between VAI and NAFLD. Our aim was to assess the relationship between VAI, insulin resistance, adipocytokines, and liver histology, in nondiabetic subjects with NAFLD. METHODS: A total of 215 male patients with biopsy-proven NAFLD were included. Among this group, serum levels of adiponectin, tumor necrosis factor-alpha (TNF-alpha, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) were measured in 101 patients whose blood samples were available. RESULTS: High gamma-glutamyl transferase (GGT), high total cholesterol (TC), high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), and presence of metabolic syndrome were significantly associated with higher VAI, although only higher GGT and TC were independent factors on multiple linear regression analysis. On the other hand, no significant association was found between VAI and adiponectin, TNF-alpha, IL-6, and hsCRP levels. The multivariate analysis of variables in patients with (n=124) and without (n=91) fibrosis showed that only higher homeostasis model assessment of insulin resistance value was independently associated with liver fibrosis. CONCLUSIONS: Our findings suggest that VAI is not related to the severity of hepatic inflammation or fibrosis in nondiabetic patients with NAFLD. The lack of association between the adipocytokines and VAI also implies that the VAI may not be a significant indictor of the adipocyte functions. PMID- 26011305 TI - Leukapheresis treatment in elderly acute leukemia patients with hyperleukocytosis: A single center experience. AB - AIM: Leukapheresis is an invasive treatment modality used for hyperleukocytosis. Various drugs and fluids are used during the leukapheresis. Aging itself and associated factors such as increased comorbidity, decreased tolerance to drugs, increased drug toxicity give rise to the application of other treatment modalities in elderly patients. Treatment of acute leukemia in the elderly differs from young patients. Consequently, we assumed that outcome, effectiveness, and side effects of leukapheresis treatment used for acute leukemia patients with hyperleukocytosis may be different in elderly compared to younger patients. METHODS: We retrospectively evaluated a total of 39 patients. Eighteen patients were 65 years and older. Indications for leukapheresis were determined as symptoms of leukostasis and prophylaxis. Acid citrate dextrose-A, calcium gluconate, and plasma were used during the leukapheresis. Age, sex, diagnosis, count, and indications of leukapheresis procedures, leukocyte count, and lactate dehydrogenase level were analyzed at the onset of and after leukapheresis; side effects, causes of death, early and total mortality rates were also analyzed. We compared the two groups with regard to effectiveness, clinical outcomes, and side effects. RESULTS: There were no statistically significant differences between the two groups with respect to sex, diagnosis, initial leukocyte count, lactate dehydrogenase level, number of leukapheresis procedures, rates of side effects, or early and total mortality (P > 0.05). Leukapheresis treatment was effective in both groups (P < 0.05) and no significant difference was found in its effectiveness between two groups (P > 0.05). CONCLUSION: Leukapheresis is an effective and safe treatment modality in elderly acute leukemia patients with hyperleukocytosis. PMID- 26011304 TI - Higher urinary bisphenol A concentration is associated with unexplained recurrent miscarriage risk: evidence from a case-control study in eastern China. AB - BACKGROUND: Evidence about the association between Bisphenol A (BPA) and the risk of recurrent miscarriage (RM) in human being is still limited. OBJECTIVE: We evaluated the association of urinary BPA concentrations with RM in human being. METHODS: A hospital-based 1:2 matched case-control study on RM was carried out in Suzhou and Kunshan in Jiangsu Province in China between August 2008 and November 2011. Total urinary BPA concentrations in 264 eligible urine samples (102 RM patients and 162 controls) were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The Wilcoxon test and conditional logistic regression were used to estimate the differences between the groups and odds ratios (OR) with 95% confidence intervals (CI), respectively. RESULTS: The median +/- IQR (interquartile range) (P75-P25) values of non-creatinine-adjusted total urinary BPA levels in the RM patients and the controls were 1.66 +/- 3.69 ng/ml and 0.58 +/- 1.07 ng/ml, respectively (0.98 +/- 2.67 MUg/g Cr (creatinine) and 0.40 +/- 0.77 MUg/g Cr. The adjusted BPA level was significantly higher in the RM patients than in the controls (Wilcoxon test, Z = 4.476, P < 0.001). Higher level of urinary BPA was significantly associated with an increased risk of RM (P-trend < 0.001). Compared to the groups with urinary BPA levels less than 0.16 MUg/g Cr, the women with levels of 0.40-0.93 MUg/g Cr and 0.93 MUg/g Cr or above had a significantly higher risk of RM (OR = 3.91, 95%CI: 1.23-12.45 and OR = 9.34, 95%CI: 3.06-28.44) that persisted after adjusting for confounding factors. The time from recently RM date to recruitment does not significantly influence the urinary BPA level (P = 0.090). CONCLUSION: Exposure to BPA may be associated with RM risk. PMID- 26011306 TI - Analgesia enhancement and prevention of tolerance to morphine: beneficial effects of combined therapy with omega-3 fatty acids. AB - OBJECTIVES: Recent evidence associates omega-3 fatty acids (O3) with pain reduction. The aim of this work was to evaluate the antinociceptive effect of O3, either alone or in combination with morphine after acute and chronic administration in rats. As well, a new pharmaceutical mixture that allows the concomitant administration of O3 and morphine as an oral solution was developed. METHODS: Animals were fed on a control or an experimental diet supplemented with O3. They were subjected to the hot-plate test to assess analgesic effect and tolerance to the analgesic effect of morphine. The open-field test was carried out to determine if the differences in the response latency can be related to non specific sedative effects. KEY FINDINGS: O3 dietary supplementation increased the response latency compared with the control group. Acute treatment with morphine in these groups resulted in an additive antinociceptive effect not related to locomotor activity. Chronic coadministration of morphine with O3 attenuated the development of tolerance. Oral administration of the new pharmaceutical mixture showed analgesic activity with a subtherapeutic dose of morphine. CONCLUSION: This finding suggests a role for O3 as adjuncts to opioids in pain therapy and might contribute to the reduction of the occurrence of morphine side-effects. PMID- 26011308 TI - Variations in cyclic fatigue resistance among ProTaper Gold, ProTaper Next and ProTaper Universal instruments at different levels. AB - AIM: To compare the cyclic fatigue resistance of ProTaper Gold (PTG, Dentsply Tulsa Dental Specialities, Tulsa, OK, USA), ProTaper Next (PTN, Dentsply Tulsa Dental Specialities) and ProTaper Universal (PTU, Dentsply Tulsa Dental Specialities) instruments at different levels. METHODOLOGY: A total of 72 files were used to evaluate the cyclic fatigue of PTU (F2), PTN (X2) and PTG (F2) at 5 mm (n = 12) and 8 mm (n = 12) from the tip in 3-mm-radius steel canals with a 60 degrees angle of curvature. The time to fracture was recorded. The Kolmogorov Smirnov test was used to assess the normality of the samples distribution, and the statistical analysis was performed using the independent sample t-test (P < 0.01). RESULTS: Significant differences were found amongst the instruments 5 mm from the tip (P < 0.01). The PTG files had the highest CF resistance, and the PTN files displayed greater CF resistance than the PTU files. No significant differences were found between the PTG and PTN files 8 mm from the tip (P > 0.01). The PTG and PTN files demonstrated greater CF resistance than the PTU files (P < 0.01). CONCLUSIONS: The PTG instruments were the most resistant 5 and 8 mm from the tip; however, at 8 mm, there was no difference between the PTG and PTN instruments. The PTU files had the lowest CF resistance at all levels. PMID- 26011309 TI - Fresh water fish, Channa punctatus, as a model for pendimethalin genotoxicity testing: A new approach toward aquatic environmental contaminants. AB - Pendimethalin (PND) is one of the common herbicides used worldwide. Fresh water fish, Channa punctatus, was exposed to PND in aquaria wherein its LC50 value was recorded to be 3.6 mg/L. Three sublethal (SL) concentrations, namely, 0.9, 1.8, and 2.7 mg/L were selected for the evaluation of genotoxicity and oxidative stress generated in the fish. In vivo comet assay was carried out in the blood, liver, and gill cells after exposing the fish to aforesaid SL concentrations of PND for 24, 48, 72, and 96 h. The results of the comet assay demonstrated the genotoxicity of PND in all the three tissues. Induction of oxidative stress in the gill cells was affirmed by the increased lipid peroxidation (LPO) and decreased levels of reduced glutathione, superoxide dismutase, and catalase. Frequencies of erythrocytic nuclear abnormalities (ENA) and micronuclei (MN) were also used to assess the genotoxic potential of PND on C. punctatus. MN frequency did not show any enhancement after PND exposure, but the frequency of ENA such as kidney-shaped nuclei, segmented nuclei and lobed nuclei, showed a significant increase after 24-96 h. Thus, ENA seems to be a better biomarker than MN for PND induced genotoxicity. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1520 1529, 2016. PMID- 26011307 TI - Review article: dietary fibre-microbiota interactions. AB - BACKGROUND: Application of modern rapid DNA sequencing technology has transformed our understanding of the gut microbiota. Diet, in particular plant-based fibre, appears critical in influencing the composition and metabolic activity of the microbiome, determining levels of short-chain fatty acids (SCFAs) important for intestinal health. AIM: To assess current epidemiological, experimental and clinical evidence of how long-term and short-term alterations in dietary fibre intake impact on the microbiome and metabolome. METHODS: A Medline search including items 'intestinal microbiota', 'nutrition', 'diet', 'dietary fibre', 'SCFAs' and 'prebiotic effect' was performed. RESULTS: Studies found evidence of fibre-influenced differences in the microbiome and metabolome as a consequence of habitual diet, and of long-term or short-term intervention (in both animals and humans). CONCLUSIONS: Agrarian diets high in fruit/legume fibre are associated with greater microbial diversity and a predominance of Prevotella over Bacteroides. 'Western'-style diets, high in fat/sugar, low in fibre, decrease beneficial Firmicutes that metabolise dietary plant-derived polysaccharides to SCFAs and increase mucosa-associated Proteobacteria (including enteric pathogens). Short-term diets can also have major effects, particularly those exclusively animal-based, and those high-protein, low-fermentable carbohydrate/fibre 'weight-loss' diets, increasing the abundance of Bacteroides and lowering Firmicutes, with long-term adherence to such diets likely increasing risk of colonic disease. Interventions to prevent intestinal inflammation may be achieved with fermentable prebiotic fibres that enhance beneficial Bifidobacteria or with soluble fibres that block bacterial-epithelial adherence (contrabiotics). These mechanisms may explain many of the differences in microbiota associated with long-term ingestion of a diet rich in fruit and vegetable fibre. PMID- 26011310 TI - Over-Responsiveness and Greater Variability in Roughness Perception in Autism. AB - Although sensory problems, including tactile hypersensitivity and hyposensitivity (DSM-5) are commonly associated with autism, there is a dearth of systematic and rigorous research in this domain. Here, we report findings from a psychophysical experiment that explored differences in tactile perception between individuals with autism and typically developing control participants, who, using their index finger, rated a series of surfaces on the extent of their roughness. Each surface was rated multiple times and we calculated both the average rating and the variability across trials. Relative to controls, the individuals with autism perceived the surfaces as rougher overall and exhibited greater variability in their ratings across trials. These findings characterize altered tactile perception in autism and suggest that sensory problems in autism may be the product of overly responsive and variable sensory processing. PMID- 26011311 TI - Automated production at the curie level of no-carrier-added 6-[(18)F]fluoro-L dopa and 2-[(18)F]fluoro-L-tyrosine on a FASTlab synthesizer. AB - An efficient, fully automated, enantioselective multi-step synthesis of no carrier-added (nca) 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and 2-[(18)F]fluoro-L tyrosine ([(18)F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high- performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand-alone HPLC. [(18)F]FDOPA and [(18)F]FTYR were produced in 36.3 +/- 3.0% (n = 8) and 50.5 +/- 2.7% (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95%, and the specific activity of was >740 GBq/umol. This automated synthesis provides high amount of [(18)F]FDOPA and [(18)F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment. PMID- 26011312 TI - Expression analysis of microRNA-125 in patients with polycythemia vera and essential thrombocythemia and correlation with JAK2 allele burden and laboratory findings. AB - INTRODUCTION: The JAK2V617F mutation has emerged in recent years as a diagnostic as well as a treatment target in patients with polycythemia vera (PV) and essential thrombocythemia (ET). The disease phenotype is also influenced by other factors such as microRNA (miRNA) deregulation. The aim of this study was to investigate miR-125 expression level in these patients with those obtained from healthy control subjects and its correlation with JAK2 allele burden and laboratory findings. METHODS: In total, forty patients with a clinical diagnosis of PV and ET were examined at the time of diagnosis. Ten healthy subjects were checked as controls. We performed JAK2 V617F allele burdens measurement and expression analysis of miR-125b-5p, miR-125b-3p, miR-125a-5p, and miR-125a-3p in leukocytes isolated from peripheral blood by quantitative real-time polymerase chain reaction. RESULTS: MiR-125b-5p and miR-125a-5p were upregulated in both patients with PV (P = 0.00 and P = 0.003, respectively) and ET (P = 0.02 and P = 0.002, respectively). In PV group, a significant correlation was observed between miR-125a-5p and platelet counts (P = 0.01, r = 0.531). The correlation between miRNA and JAk2 allele burden was not significant. CONCLUSION: In conclusion, our data indicate that other factors such as aberrant miR-125 expression may influence on the disease phenotype in patients with PV and ET. PMID- 26011313 TI - Impact of pulmonary nontuberculous mycobacterial treatment on pulmonary function tests in patients with and without established obstructive lung disease. AB - BACKGROUND AND OBJECTIVE: There is relatively little data regarding pulmonary function test (PFT) findings and impact of treatment on PFT in pulmonary nontuberculous mycobacterial (pNTM) disease. METHODS: We performed a retrospective study on pNTM patients. Clinical, radiographical, microbiological and PFT data were reviewed. Patients were divided into three groups based on pre existing obstructive lung disease: (i) normal (no chronic obstructive pulmonary disease (COPD) or asthma); (ii) asthma; and (iii) COPD. We studied pre-treatment PFT and assessed for PFT changes after anti-mycobacterial therapy. RESULTS: A total of 96 patients fulfilled ATS disease criteria and had pre-treatment PFT (54 'normal', 18 asthma, 24 COPD). Most common causative NTM was Mycobacterium avium complex (76%), and radiographical disease type was nodular bronchiectasis (71%). Before therapy, all groups had PFT abnormalities, including obstruction, gas trapping and at least mildly low diffusion capacity of carbon monoxide (DLCO). Pre-treatment PFT abnormalities were more pronounced among patients with asthma and COPD. A total of 44 patients had >12 months anti-mycobacterial therapy and post-treatment PFT. There tended to be small and generally not statistically significant reductions in spirometry and DLCO in most groups. Among the nine asthmatic patients, there was a small reduction in residual volume (RV) (1.5% predicted, P = 0.01) and RV/total lung capacity (by 7% predicted, P = 0.06). CONCLUSIONS: Patients with pNTM have abnormal PFT, and treatment was not associated with substantial changes therein. Asthmatics may experience some improvements in gas trapping after NTM therapy, but because the sample size and the observed change were both small, this requires further investigation. PMID- 26011315 TI - Diagnostic validation of selected serological tests for detecting scrub typhus. AB - Clinical diagnosis of scrub typhus is often difficult because the symptoms are very similar to those of other febrile illness such as dengue, leptospirosis, malaria and other viral hemorrhagic fevers. Though better diagnostic tests are available for rickettsial diseases and scrub typhus elsewhere, the Weil-Felix test is still commonly used in India, mainly because microimmunofluorescence assays (M-IFA) were not available in India till recently and relevant staff had insufficient training. The present study was performed to investigate the performance of M-IFA, IgM ELISA, and Weil-Felix test on 546 non-repeated serum samples from subjects suspected of having scrub typhus. One hundred and forty three of these 546 samples were positive by M-IFA; these cases were also confirmed clinically to have scrub typhus based on their dramatic responses to doxycycline therapy. IgM ELISA was positive in 122 of the 143 M-IFA positive cases and the Weil-Felix test in 96. Though the Weil-Felix test is a heterophile agglutination test, it was found in this study to have good specificity but far too little sensitivity to use as a routine diagnostic test. IgM ELISA can be a good substitute for M-IFA. Incorporation of multiple prototype antigens on M-IFA slides is likely one of the reasons for its superior performance. As newer and better diagnostic assays become available for scrub typhus diagnosis in developed countries, it will be imperative to also use such tests in other endemic countries to prevent over- or under-diagnosis of scrub typhus. PMID- 26011314 TI - A Virulence Essential CRN Effector of Phytophthora capsici Suppresses Host Defense and Induces Cell Death in Plant Nucleus. AB - Phytophthora capsici is a soil-borne plant pathogen with a wide range of hosts. The pathogen secretes a large array of effectors during infection of host plants, including Crinkler (CRN) effectors. However, it remains largely unknown on the roles of these effectors in virulence especially in P. capsici. In this study, we identified a cell death-inducing CRN effector PcCRN4 using agroinfiltration approach. Transient expression of PcCRN4 gene induced cell death in N. benthamiana, N. tabacum and Solanum lycopersicum. Overexpression of the gene in N. benthamiana enhanced susceptibility to P. capsici. Subcellular localization results showed that PcCRN4 localized to the plant nucleus, and the localization was required for both of its cell death-inducing activity and virulent function. Silencing PcCRN4 gene in P. capsici significantly reduced pathogen virulence. The expression of the pathogenesis-related gene PR1b in N. benthamiana was significantly induced when plants were inoculated with PcCRN4-silenced P. capsici transformant compared to the wilt-type. Callose deposits were also abundant at sites inoculated with PcCRN4-silenced transformant, indicating that silencing of PcCRN4 in P. capsici reduced the ability of the pathogen to suppress plant defenses. Transcriptions of cell death-related genes were affected when PcCRN4 silenced line were inoculated on Arabidopsis thaliana, suggesting that PcCRN4 may induce cell death by manipulating cell death-related genes. Overall, our results demonstrate that PcCRN4 is a virulence essential effector and it needs target to the plant nucleus to suppress plant immune responses. PMID- 26011316 TI - Effect of DDAH/ADMA/NOS regulation pathway on cavernae corporum cavernosorum rat penis of different age. AB - The effect of DDAH/ADMA/NOS pathway in penile tissue of rats of different age was investigated to better understand the mechanism of age-related erectile dysfunction (ED). The Sprague Dawley male rats were assigned as the young group (3 month old, n = 10) and the old group (18 month old, n = 10) respectively. Intracavernous pressure (ICP) was measured before and after papaverine intracavernous injection. Pathology structure of penile tissue was evaluated under transmission electron microscope. The expression amounts of asymmetric dimethylarginine (ADMA) and cyclic guanosine monophosphate (cGMP) in penile tissue were detected by ELISA; the expression levels of isoform-specific DDAH and NOS were assessed via Western blot. Compared with the young group, the ICP in the old group rat decreased significantly (33.46 +/- 5.37 versus 39.71 +/- 3.67 mmHg, P = 0.02) after papaverine injection. Diffused fibrosis and impairment of endothelial cell were observed in corpus cavernosum in the old group rats. Higher level of ADMA (10.83 +/- 0.96 versus 7.51 +/- 1.39 MUmol per gpro, P = 3.14 * 10( 4) ) and lower level of cGMP (29.42 +/- 3.84 versus 47.09 +/- 6.07 nmol per gpro, P = 1.57 * 10(-6) ) were detected in penile tissue of the old group compared with those of the young group. Expression of DDAH1, DDAH2, endothelial NOS (eNOS) and neuronal NOS(nNOS) all decreased significantly in penile tissue of the old group rat. The DDAH/ADMA/NOS regulation pathway changes dramatically accompanying with lower ICP in old group rat compared with those of the young group. Such findings in rats are suggestive in understanding the mechanism of age-related ED in humans. PMID- 26011318 TI - Data Mining as a Guide for the Construction of Cross-Linked Nanoparticles with Low Immunotoxicity via Control of Polymer Chemistry and Supramolecular Assembly. AB - The potential immunotoxicity of nanoparticles that are currently being approved, in different phases of clinical trials, or undergoing rigorous in vitro and in vivo characterizations in several laboratories has recently raised special attention. Products with no apparent in vitro or in vivo toxicity may still trigger various components of the immune system unintentionally and lead to serious adverse reactions. Cytokines are one of the useful biomarkers for predicting the effect of biotherapeutics on modulation of the immune system and for screening the immunotoxicity of nanoparticles both in vitro and in vivo, and they were recently found to partially predict the in vivo pharmacokinetics and biodistribution of nanomaterials. Control of polymer chemistry and supramolecular assembly provides a great opportunity for the construction of biocompatible nanoparticles for biomedical clinical applications. However, the sources of data collected regarding immunotoxicities of nanomaterials are diverse, and experiments are usually conducted using different assays under specific conditions. As a result, making direct comparisons nearly impossible, and thus, tailoring the properties of nanomaterials on the basis of the available data is challenging. In this Account, the effects of chemical structure, cross-linking, degradability, morphology, concentration, and surface chemistry on the immunotoxicity of an expansive array of polymeric nanomaterials will be highlighted, with a focus on assays conducted using the same in vitro and in vivo models and experimental conditions. Furthermore, numerical descriptive values have been utilized uniquely to stand for induction of cytokines by nanoparticles. This treatment of available data provides a simple way to compare the immunotoxicities of various nanomaterials, and the values were found to correlate well with published data. On the basis of the polymeric systems investigated in this study, valuable information has been collected that will aid in the future design of nanomaterials for biomedical applications, including the following: (a) the immunotoxicity of nanomaterials is concentration- and dose-dependent; (b) the synthesis of degradable nanoparticles is essential to decrease toxicity; PMID- 26011319 TI - Discovery and Longitudinal Evaluation of Candidate Protein Biomarkers for Disease Recurrence in Prostate Cancer. AB - When compared with hormonal therapy alone, treatment with combined hormone and radiation therapy (CHRT) gives improved disease-specific survival outcomes for patients with prostate cancer; however, a significant number of CHRT patients still succumb to recurrent disease. The purpose of this study was to use longitudinal patient samples obtained as part of an ongoing noninterventional clinical trial (ICORG06-15) to identify and evaluate a potential serum protein signature of disease recurrence. Label-free LC-MS/MS based protein discovery was undertaken on depleted serum samples from CHRT patients who showed evidence of disease recurrence (n = 3) and time-matched patient controls (n = 3). A total of 104 proteins showed a significant change between these two groups. Multiple reaction monitoring (MRM) assays were designed for a subset of these proteins as part of a panel of putative prostate cancer biomarkers (41 proteins) for evaluation in longitudinal serum samples. These data revealed significant interpatient variability in individual protein expression between time of diagnosis, disease recurrence, and beyond and serve to highlight the importance of longitudinal patient samples for evaluating the use of candidate protein biomarkers in disease monitoring. PMID- 26011317 TI - Intravascular ultrasound predictors of acute side branch occlusion in coronary artery bifurcation lesions just after single stent crossover. AB - OBJECTIVES: We aimed to assess the intravascular ultrasound (IVUS) predictors of acute side branch (SB) occlusions just after single stent crossover in percutaneous coronary intervention (PCI) for coronary bifurcation lesions. BACKGROUND: PCI for bifurcation lesions remains technically challenging and has more clinical complications such as SB occlusion than non-bifurcation lesions. Although single stent crossover is the most common approach in treating bifurcation lesions, the predictors of acute SB occlusion are unclear. METHODS: Single stent crossover was performed on 174 patients with a total of 272 bifurcation lesions who were enrolled in this study. Each patient also underwent pre-PCI IVUS in a major vessel (MV). SB was defined as ostium diameter of >=1.5 mm measured by IVUS, and occluded SB was defined as a thrombolysis in myocardial infarction flow grade of <=2 just after stent implantation. We defined the SB diameter ratio as ostial SB total diameter (media-to-media) divided by ostial SB luminal diameter (intima-to-intima). RESULTS: There were 52 SBs in the occluded group (19.1%). There were no significant differences in baseline characteristics between the SB occluded and non-SB occluded groups. Logistic-regression analysis revealed that the thickness of MV plaque on the bilateral sides of SB at the junction site and the SB diameter ratio were independent predictors of SB occlusion just after stent implantation. CONCLUSIONS: In the IVUS observation, the MV plaque thickness at the junction site and the SB diameter ratio are predictors of acute SB occlusion just after single stent crossover. PMID- 26011320 TI - Time-Resolved Imaging Study of Jetting Dynamics during Laser Printing of Viscoelastic Alginate Solutions. AB - Matrix-assisted pulsed-laser evaporation direct-write (MAPLE DW) has been successfully implemented as a promising laser printing technology for various fabrication applications, in particular, three-dimensional bioprinting. Since most bioinks used in bioprinting are viscoelastic, it is of importance to understand the jetting dynamics during the laser printing of viscoelastic fluids in order to control and optimize the laser printing performance. In this study, MAPLE DW was implemented to study the jetting dynamics during the laser printing of representative viscoelastic alginate bioinks and evaluate the effects of operating conditions (e.g., laser fluence) and material properties (e.g., alginate concentration) on the jet formation performance. Through a time-resolved imaging approach, it is found that when the laser fluence increases or the alginate concentration decreases, the jetting behavior changes from no material transferring to well-defined jetting to well-defined jetting with an initial bulgy shape to jetting with a bulgy shape to pluming/splashing. For the desirable well-defined jetting regimes, as the laser fluence increases, the jet velocity and breakup length increase while the breakup time and primary droplet size decrease. As the alginate concentration increases, the jet velocity and breakup length decrease while the breakup time and primary droplet size increase. In addition, Ohnesorge, elasto-capillary, and Weber number based phase diagrams are presented to better appreciate the dependence of jetting regimes on the laser fluence and alginate concentration. PMID- 26011322 TI - Commentary: Valproate in the treatment of epilepsy in women and girls: The need for recommendations. PMID- 26011323 TI - How to evaluate PCR assays for the detection of low-level DNA. AB - High sensitivity of PCR-based detection of very low copy number DNA targets is crucial. Much focus has been on design of PCR primers and optimization of the amplification conditions. Very important are also the criteria used for determining the outcome of a PCR assay, e.g. how many replicates are needed and how many of these should be positive or what amount of template should be used? We developed a mathematical model to obtain a simple tool for quick PCR assay evaluation before laboratory optimization and validation procedures. The model was based on the Poisson distribution and the Binomial distribution describing parameters for singleplex real-time PCR-based detection of low-level DNA. The model was tested against experimental data of diluted cell-free foetal DNA. Also, the model was compared with a simplified formula to enable easy predictions. The model predicted outcomes that were not significantly different from experimental data generated by testing of cell-free foetal DNA. Also, the simplified formula was applicable for fast and accurate assay evaluation. In conclusion, the model can be applied for evaluation of sensitivity of real-time PCR-based detection of low-level DNA, and may also assist in design of new assays before standard laboratory optimization and validation is initiated. PMID- 26011321 TI - Connecting Anxiety and Genomic Copy Number Variation: A Genome-Wide Analysis in CD-1 Mice. AB - Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional array based genotyping approaches, we detected CNVs in a mouse model consisting of two inbred mouse lines showing high (HAB) and low (LAB) anxiety-related behavior, respectively. An influence of CNVs on gene expression in the central (CeA) and basolateral (BLA) amygdala, paraventricular nucleus (PVN), and cingulate cortex (Cg) was shown by a two-proportion Z-test (p = 1.6 x 10-31), with a positive correlation in the CeA (p = 0.0062), PVN (p = 0.0046) and Cg (p = 0.0114), indicating a contribution of CNVs to the genetic predisposition to trait anxiety in the specific context of HAB/LAB mice. In order to confirm anxiety-relevant CNVs and corresponding genes in a second mouse model, we further examined CD-1 outbred mice. We revealed the distribution of CNVs by genotyping 64 CD 1 individuals using a high-density genotyping array (Jackson Laboratory). 78 genes within those CNVs were identified to show nominally significant association (48 genes), or a statistical trend in their association (30 genes) with the time animals spent on the open arms of the elevated plus-maze (EPM). Fifteen of them were considered promising candidate genes of anxiety-related behavior as we could show a significant overlap (permutation test, p = 0.0051) with genes within HAB/LAB CNVs. Thus, here we provide what is to our knowledge the first extensive catalogue of CNVs in CD-1 mice and potential corresponding candidate genes linked to anxiety-related behavior in mice. PMID- 26011324 TI - MicroRNAs in liver malignancies. Basic science applied in surgery. AB - Liver malignancies represent one of the major public health problems worldwide because of late diagnosis and failure of current treatments to offer a curative option for many of the patients. MicroRNAs (miRs) are small non-coding RNA molecules that are known to regulate the gene expression at a post transcriptional level through complementary base pairing with thousands of messenger (m)RNAs. Recent data has shown the involvement of miRs in the pathogenesis of many human cancers, including those of the liver, with huge possible impact in the clinic, mainly due to the identification of non-coding RNAs as biomarkers that can often be detected in the systemic circulation. In the current review, we present the importance of miRs in liver cancers by discussing their role in the pathobiology of these diseases, apart from their role as diagnostic and prognostic markers for liver malignancies. PMID- 26011325 TI - Surgical treatment for malignant pleural mesothelioma: extrapleural pneumonectomy, pleurectomy/decortication or extended pleurectomy? AB - Malignant pleural mesothelioma (MPM) is an asbestos-related disease with a dismal prognosis. Ethic, social, legal and economic parameters are implicated in its management. It is quite clear that multimodality therapy is necessary to improve long-term results but precise treatment schemes have not yet been equivocally accepted. The extent of surgery is questioned and radical operations are highly debatable. On the other hand, debulking or cyto-reductive surgery have been also proposed within a multimodality approach. However, the role and order of adjuvant or neoadjuvant use of chemotherapy, radiotherapy and surgery has not been established. The aim of this study was to analyze contemporary studies on the impact of different surgical approaches on outcome of patients with MPM. PMID- 26011326 TI - Ultrasonic drug delivery in Oncology. AB - Ultrasound-assisted drug delivery is an emerging technique that has the advantage of being non-invasive, efficiently and specifically targeted and controllable. While systemic drugs often show detrimental side effects, their ultrasound triggered local release at the selected tissue may improve safety and specifity of therapy. An increasing amount of animal and preclinical studies demonstrates how ultrasound can also be used for increasing the efficacy of chemotherapeutic drug release to solid tumors. In particular, this technique may be functional to reach uniform delivery of chemotherapeutic agents throughout tumors, which is naturally restricted by their abnormal vascularization and interstitial pressure. This review deals with the physical mechanisms of ultrasound, the different kinds of drug carriers (microbubbles, liposomes and micelles) and the biological phenomena useful for cancer treatment (hyperthermia, sonoporation, enhanced extravasation, sonophoresis and blood-brain barrier disruption), showing how much ultrasonic drug delivery is a promising method in the oncological field. PMID- 26011327 TI - Urothelial carcinoma: Recurrence and risk factors. AB - Urothelial carcinomas are malignant tumors that arise from the urothelial epithelium and may involve the lower and upper urinary tract. They are characterized by multiple, multifocal recurrences throughout the genitourinary tract. Bladder tumors account for 90-95% of urothelial carcinomas and are the most common malignancies of the urinary tract. Upper urinary tract urothelial carcinomas (UTUC) are relatively rare, accounting for 5% of urothelial tumors. The incidence of subsequent bladder cancer after surgical treatment for UTUC is approximately 15-50%. In contrast, patients with a primary tumor of the bladder have a low risk (2-6%) the development of UTUC. Identification of prognostic factors and early detection of recurrent disease provide a better strategy for postoperative monitoring, surveillance, and potentially improve patient outcomes. In this review study we discuss the main risk factors for UTUC recurrence after radical cystectomy, and risk factors for intravesical recurrence after radical nephroureterectomy. PMID- 26011328 TI - Diagnostic value of autofluorescence imaging combined with narrow band imaging in intraepithelial neoplasia of Barrett's esophagus. AB - PURPOSE: To evaluate the diagnostic values of Auto Fluorescence Imaging (AFI) combined with Narrow Band Imaging (NBI) in the diagnosis of the intraepithelial neoplasia of Barrett's esophagus (BE). METHODS: Seventy four suspicious BE intraepithelial lesions were assessed in 50 patients by AFI, who were further subjected to NBI mode to observe the changes of gastric mucosal capillaries and gastric pits. The corresponding lesions were biopsied for pathological examination. RESULTS: Among the 74 AFI-diagnosed cases of suspicious lesions, 44 (59.5%) were high-grade intraepithelial neoplasias (BEHGIN), while the remaining 30 cases (40.5%) were false-positive. The NBI-diagnostic results of these 44 BEHGIN lesions were as follows: 39 cases were confirmed and 5 were suspicious; among the 30 false-positive BEHGIN cases, NBI gave 7 false-positive cases. The false-positive rates decreased from 40.5% of AFI to 9.5% (7/74) of NBI-AFI (p<0.05). The positive predictive value of AFI in BEHGIN was 59.5% (44/74), while that of AFI-NBI combination was 84.8% (39/46; p<0.05). CONCLUSIONS: The AFI-NBI combination technology could significantly improve (p<0.05) the detection rate of BEHGIN. PMID- 26011329 TI - Emergency surgery for obstructing colorectal malignancy: prognostic and risk factors. AB - PURPOSE: Emergency surgery for colorectal malignant obstruction is thought to correlate with poor outcome. The main aim of our study was to identify possible factors that could predict obstruction, and risk factors of poor postoperative outcome. The second aim was to determine any differences between primary anastomosis and stoma creation in the obstruction population, especially in left sided tumors. METHODS: A retrospective review of 212 patients who underwent surgery for colorectal malignancy between January 2008 and January 2013 was performed. Fifty-five patients (26%) underwent emergency surgery for completely obstructing colorectal carcinoma, and 157 (74%) underwent elective surgery. RESULTS: The groups were comparable for age, gender, ASA score, tumor location, tumor stage, lymph node metastasis and mortality. Advanced tumor stage was recorded as the only prognostic factor of obstruction (p=0.001). Postoperative mortality rate was 9.1% in the obstruction group and 6.4% in the elective group (p=0.498). Analysis didn't reveal any risk factors for poor early outcome in the obstruction group. All patients with right-sided obstructive cancer were treated with resection and primary anastomosis, while the same procedure was performed in almost 61% of operations for left-sided tumors with no anastomotic failure. CONCLUSIONS: Obstructive colorectal malignancy presents at a more advanced stage compared with non-obstructive cancer, with, interestingly, no statistically significant differences in postoperative mortality. Risk factors of poor early outcome couldn't be identified. Resection and primary restitution of continuity is the surgical approach of choice for right-sided obstructive cancers, but it can be, also, safely performed in left-sided cancers. PMID- 26011330 TI - Feasibility of immunochemical faecal occult blood testing for colorectal cancer screening in Bulgaria. AB - PURPOSE: Colorectal carcinoma (CRC) is the second most common cancer in Europe. Screening guidelines recommend a range of screening options that include faecal occult blood tests (FOBTs). The efficacy of FOBT-based CRC screening is dependent on the participation rate, thus emphasizing the importance of the latter. This study aimed at analysing the feasibility of CRC screening with immunochemical FOBT (iFOBT). METHODS: A cross-sectional study of 600 asymptomatic persons at average risk, aged >=45years from urban and rural municipalities was performed. An educational brochure, iFOBT kit with translated colored leaflet, informed consent form and questionnaire were administered to participants by 30 general practitioners. Faecal samples were analysed for occult blood using point-of-care rapid iFOBT (cut off 10 ng(GPs)Hb/ml) by the patients themselves at home. The questionnaire aimed to establish if they encountered difficulties in self-testing and self-analysing. Direct and indirect measures of test feasibility were used difficulties for reported study participation rate. RESULTS: The participation rate was 78.8% (473 participants). Patients < 65 years (x2 =70.8, R<0.001), those with lower education level (x2 =82.1, p<0.001), and patients living in villages (x2 =4.3, p<0.05) reported difficulties more frequently and they needed help for self-testing by iFOBT. Positive test was found in 8.5% of all participants. Of them 19 persons (48.7%) had haemorrhoids, 8 (20.0%) benign neoplasms, and 3 (7.5%) had CRC. CONCLUSIONS: CRC screening study by means of iFOBT as a point-of care test proved to be feasible, since a high participation rate was obtained. PMID- 26011331 TI - Associated risk factor analysis for positive resection margins after endoscopic submucosal dissection in early-stage gastric cancer. AB - PURPOSE: To investigate the associated risk factors and the prognostic impact of positive resection margins after endoscopic submucosal dissection (ESD) of early stage gastric cancer. METHODS: A retrospective analysis of prospectively collected data was performed on 319 consecutive lesions in 316 patients who underwent ESD. Age, gender, surgeons, lesion location, maximum diameter of resected specimens, macroscopic type, depth of tumor invasion and tumor differentiation were evaluated as potential risk factors. RESULTS: A total of 27 (8.5%) patients exhibited positive resection margins after ESD. Among 25 successfully followed-up patients 13 were subjected to gastrectomy, 1 was administered chemotherapy, 2 underwent additional endoscopic resection and 9, who were initially followed-up during a median period of 11.7 months (range 1-40), had neither recurrence nor metastasis. Univariate analysis revealed that age, lesion location, depth of tumor invasion, macroscopic type and tumor differentiation were correlated with positive resection margin. By contrast, multivariate logistic regression analysis showed that only age, tumor differentiation and depth of tumor invasion were independent risk factors of positive resection margins. CONCLUSION: Age, tumor differentiation and depth of tumor invasion were independent risk factors for post-ESD positive resection margins. This result suggests that older patients, undifferentiated lesions and a greater depth of invasion increase the risk for post-ESD positive resection margins. PMID- 26011332 TI - Clinical outcome and toxicity of 3D-conformal radiotherapy combined with chemotherapy based on the Intergroup SWOG 9008/INT0116 study protocol for gastric cancer. AB - PURPOSE: To retrospectively evaluate the efficacy and toxicity of adjuvant radio chemotherapy in patients with gastric cancer and to relate them to the outcome of the landmark INT0116 study that is criticized because of the high toxicity and poor treatment compliance. METHODS: A total of 102 patients who underwent postoperative fluorouracil (5-FU)-based radio-chemotherapy in our institution between 2004 and 2010 for stage IB-IV (AJCC 6th Edn.) gastric cancer were selected. Radiotherapy to 45 Gy was defined individually and delivered with 3D conformal technique. Chemotherapy was carried out during the first 4 and the last 3 days of radiotherapy with continuous infusion of 5-FU (400mg/m2/day) and leucovorin. Patients received an additional 3 cycles of chemotherapy of 5-FU (425mg/m2/day), mostly 1 before and 2 after radio-chemotherapy. Acute hematological and gastrointestinal toxicities were evaluated according to the CTC v3.0 scale. RESULTS: Stage distribution was as follows: IB-5 (5%), II-32 (31%), III-49 (48%), and IV-14 (14%). There were 96% R0 resections; 15% of the patients had a D2 resection. Seventy-four patients (72.5%) received all 5 planned cycles and 98 (96%) completed radiotherapy. The 3- and 5-year overall survival (OS) rates were 57% and 48%, respectively. Multivariate analysis showed that variables significantly affecting OS were pT3-T4, pN2-3, R1 resection and female gender. Only 2% of the patients experienced grade 3 gastrointestinal toxicity; 7% had grade 3 or higher hematological toxicity. CONCLUSIONS: We demonstrated better treatment tolerance, compliance, OS of adjuvant radio-chemotherapy for gastric cancer in comparison with INT0116 study. Conformal radiation techniques might have contributed to this improvement. PMID- 26011333 TI - Expression of GW112 and GRIM-19 in colorectal cancer tissues. AB - PURPOSE: To investigate the expression of GW112 and GRIM-19 in colorectal cancer tissues. METHODS: Immunohistochemistry and semi-quantitative PCR were used to simultaneously detect the levels of expression of GW112 and GRIM-19 in colorectal cancer tissues and normal colorectal tissues in 39 cases. RESULTS: Expression of GW112 protein and mRNA were significantly higher in colorectal cancer tissues than in normal tissues (p<0.05). Expression of GRIM-19 protein and mRNA were significantly lower in colorectal cancer tissues than in normal tissues (p<0.05). GW112 gene mRNA copy number(GAPDH gene mRNA copy number were 0.53 +/- 0.21 and 1.81 +/- 0.65 in normal colorectal tissues and colorectal cancer tissues respectively, and GRIM-19 gene mRNA copy number/GAPDH gene mRNA copy number were 1.15 +/- 0.29 and 1.74 +/- 0.0.44 in colorectal cancer tissues and normal colorectal tissues, respectively. Expression of GW112 gene mRNA was significantly higher in colorectal cancer tissues than in normal tissues (p<0.05), and expression of GRIM- 19 gene mRNA was significantly lower in colorectal cancer tissues than in normal tissues (p<0.05). CONCLUSION: High expression of GW112 in colorectal cancer tissues and reduced expression of GRIM-19 in colorectal cancer tissues may be associated with abnormal proliferation of cancer cells and are possibly one of the reasons for development of colorectal cancer, which can provide effective targets for clinical treatment of this disease. PMID- 26011334 TI - Quality of life in colorectal cancer patients during chemotherapy in the era of monoclonal antibody therapies. AB - PURPOSE: Colorectal cancer (CRC) survivors are currently living longer due to better therapies but they also need to maintain their quality of life (QoL). QoL is increasingly being used as primary outcome measure in clinical studies. This study was designed to gain knowledge about QoL during chemotherapy across different lines and different regimens. METHODS: The study comprised 101 CRC out patients receiving chemotherapy who completed the EORTC QLQ-C30 questionnaire. The Shapiro-Wilk, Kruskal-Wallis, and Mann-Whitney U tests were used for statistical analyses. RESULTS: The demographics of the patients were evaluated for QoL. Prior surgery, prior radiotherapy, working status, stage, comorbidity and sex had no effect on global health status in CRC patients, although some other demographics such as education, monthly income, age and type of chemotherapy regimen did have an effect on global health status. Role functioning was worse in older than in younger ones (p<0.05). Adjuvant chemotherapy did not affect the QoL scores negatively but palliative chemotherapy negatively affected the cognitive function, appetite loss and nausea/vomiting scores (p<0.05). According to chemotherapy regimen, the best QoL was observed with adjuvant FUFA regimen. In the palliative setting FOLFOX/Bevacizumab was associated with the best QoL scores whereas FOLFIRI/Cetuximab were associated with the worst QoL scores. CONCLUSIONS: Palliative chemotherapy maintained QoL irrespective of the chemotherapy line in metastatic CRC (mCRC) patients. Some demographics affect QoL and different chemotherapy regimens showed different QoL scores. PMID- 26011335 TI - Diagnosis of pancreatic cancer using 18F-FDG PET/CT and CA19-9 with SUVmax association to clinical characteristics. AB - PURPOSE: To assess the ability of 18F-FDG PET/CT alone or combined with CA19-9 to diagnose pancreatic cancer and to analyze the correlation between maximal standardized uptake value (SUVmax) and clinical characteristics. METHODS: Ninety one patients diagnosed with pancreatic cancer using 18F-FDG PET/CT before treatment were analyzed. Definite diagnosis was by histology or cytology. The SUVmax of the primary tumor was used for the statistical analysis and, using the best cutoff value, the patients were divided into 2 groups: a high SUVmax group (SUV- max-5.49) and a low SUVmax group (SUVmax<=5.49). Logistic regression analysis and receiver operating characteristic (ROC) analysis were applied to analyze the effects of SUVmax and/or CA19-9 on the diagnosis of pancreatic cancer. RESULTS: Of 91 patients, 80 had pancreatic cancer and 11 had benign conditions. The ROC curve analysis of the SUVmax yielded a best cutoff value of 5.49. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT alone in the diagnosis of pancreatic cancer were 67.5, 72.73, 94.74, 23.53, and 68.13%, respectively, while these indices for 18F-FDG PET/CT combined with CA19-9 increased to 96.25, 63.64, 95.06, 70, and 92.31%, respectively. The area under the curve (AUC) of the SUVmax combined with CA19-9 was 0.94, which was significantly higher than that of the SUVmax or CA19-9 alone (p<0.05). The SUVmax value and CA19-9 levels in pancreatic cancer patients were significantly higher than those with benign conditions (p<0.05). Only the SUVmax in the pancreatic cancer patient group was associated with tumor size (p<0.05). CONCLUSIONS: 18F-FDG PET/CT is a common examination for diagnosing pancreatic cancer, and the SUVmax combined with the CA19-9 level can significantly improve the sensitivity and accuracy in the diagnosis of pancreatic cancer. SUVmax is merely indicative of the volume of pancreatic cancer. PMID- 26011336 TI - Comparison of first-line bevacizumab in combination with mFOLFOX6 or XELOX in metastatic colorectal cancer. AB - PURPOSE: Currently, there are several oxaliplatin combination regimens for first line therapy of metastatic colorectal cancer (mCRC). In this study, we compared the survival outcomes of mCRC patients treated with bevacizumab in combination with either modified 5-FU/FA/oxaliplatin (mFOL- FOX6) or capecitabine/oxaliplatin (XELOX). METHODS: We designed a two-arm retrospective study of mCRC patients with adenocarcinoma of the colon or rectum who were treated with bevacizumab and either mFOLFOX6 or XELOX and who had complete clinical and treatment data. We analysed their therapeutic responses, adverse events, progression-free survival (PFS), and overall survival (OS), and then determined whether there were any statistically significant differences. RESULTS: A total of 131 patients (85 male; 65% and 46 female; 35%) were evaluated. Fifty-seven patients (43.5%) were treated with bevacizumab and mFOLFOX6 and 74 (56.5%) with bevacizumab and XELOX. The median PFS was 9.1 months (95% CI, 4.9-13.1) and 10 months (95% CI, 4.2-15.9) in the mFOLFOX6 and XELOX arms, respectively (p=0.610). The median OS was 29 months (95% CI, 21.6- 34.3) and 27.5 months (95% CI 20-38) in the mFOLFOX6 and XELOX arms (p=0.812), respectively. The most common reason for treatment withdrawal was disease progression (102 patients; 91%) and the most common grade 3-4 toxicity was neuropathy (<=14%). CONCLUSION: Our results show that XELOX is a safe and effective alternative to mFOLFOX6 when combined with bevacizumab as first-line treatment for mCRC patients. PMID- 26011337 TI - The postoperative clinical outcomes and safety of early enteral nutrition in operated gastric cancer patients. AB - PURPOSE: This study investigated the impact of early enteral nutrition (EEN) on the clinical outcomes of gastric cancer patients after radical gastrectomy. METHODS: Four hundred gastric cancer patients undergoing radical gastrectomy of any extend with D2 nodal dissection were randomly divided into an experimental and a control group with 200 cases in each group. Patients in the control group received postoperative parenteral nutrition (PN), while patients in the experimental group received postoperative EEN. After treatment, the clinical outcomes, postoperative immune function, and nutritional status of the two groups were evaluated. RESULTS: The postoperative fever time, intestinal function recovery time, anal exhaust time, and the length of hospital stay for patients in the experimental group were significantly shorter than those of the control group. We did not find significant differences in anastomotic leak, postoperative ileus and regurgitation between the two groups. The activities of multiple immune cell types, including CD3+, CD4+, CD4+/CD8+, and natural killer (NK) cells, were significantly lower in both groups on postoperative day 1 when compared with the preoperative levels (p<0.05). The level of CD8+ was not significantly different between the two groups (p>0.05). After treatment, levels of CD3+, CD4+, CD4+/CD8+, and NK cells in the experimental group patients were 35.6 +/- 4.2, 42.2 +/- 3.0, 1.7 +/- 0.3, and 27.3 +/- 5.3%, respectively, on postoperative day 7, which were similar to the preoperative levels. The immune cell levels from the control group patients remained significantly lower when compared with preoperative values; in addition, these values were also significantly lower when compared with the EEN patients (p<0.05) CONCLUSION: For gastric cancer patients undergoing radical gastrectomy, the clinical outcome, immune function and nutritional status after EEN were significantly improved. These data suggest the widespread use of EEN in clinical practice. PMID- 26011338 TI - Evidence based whole breast hypo-fractionated radiation therapy in patients with early breast cancer. AB - PURPOSE: The aim of the current study was to evaluate the efficacy and tolerability of hypo-fractionated whole breast radiation therapy in patients with early breast cancer. METHODS: Searching electronically PubMed and the Cochrane Central Register we made a comprehensive literature review regarding the randomized controlled phase III trials for hypo-fractionated radiation therapy in early breast cancer. RESULTS: The collected and analyzed data showed that a short course of hypo-fractionated radiation therapy in early breast cancer patients is as effective as the conventional long course regarding tumor response as well as long term side effects. CONCLUSION: More data are needed about the usage and integration of a boost treatment for higher-risk women receiving neo-adjuvant or adjuvant chemotherapy, or the results in special subgroups such as women with large breast size. PMID- 26011339 TI - Chemotherapy might not be beneficial in lymph node- negative, hormone-positive, and HER2-negative breast cancer patients: a long-term retrospective analysis. AB - INTRODUCTION: In lymph node-negative, hormone-positive, and Her2-negative breast cancer patients, the benefits of adding adjuvant chemotherapy to hormonal therapy continue to be debated, especially for low to intermediate grade and small tumors. METHODS: Excluding patients with T4 disease, we retrospectively reviewed the records of patients with long-term follow-up at our center between 2003 and 2014. Among node-negative, hormone-positive and HER2-negative breast cancer patients, we compared two groups of patients: those given both chemotherapy (doxorubicin+cyclophosphamide) and hormonotherapy, and those prescribed hormonotherapy alone. The primary endpoints were progression-free (PFS) and overall survival (OS). RESULTS: Overall, no difference was observed between these two treatment groups in either DFS or OS. However, for both outcomes, there was a trend towards improved DFS and OS favoring the hormone-only group. CONCLUSIONS: In selected subgroups of breast cancer patients, administering adjuvant hormonal therapy alone seems to be at least as good if not better than combining hormonotherapy and chemotherapy. PMID- 26011340 TI - Stressful life events and breast cancer risk: a hospital-based case-control study. AB - PURPOSE: Elucidation of the factors contributing to the incidence of breast cancer is of crucial importance for the development of preventive or therapeutic strategies targeting the disease. Research on stress and breast cancer has been documented by various studies published over the years. In view of breast cancer importance as the most commonly occurring malignancy in females in Serbia, this study was undertaken to examine the association between stressful life events and breast cancer risk. METHODS: The present hospital-based case-control study comprised 120 new breast cancer cases and 120 hospital controls matched with respect to age (+/- 2 years). This study used the Paykel Life Events Scale to obtain information about stressful life events in the years before diagnosis. The SPSS statistical package was used and odds ratios (OR) and 95% confidence intervals (95% CI) were calculated from multivariate conditional logistic regression model. RESULTS: Multiple conditional logistic regression analysis revealed six independent predictors of breast cancer risk: experience of severe and moderate threats (first 25 life events from the scale) (OR=3.15, 95% CI=2.01 4.93), son's military service (OR=6.09, 95% CI=4.17-12.37), death of close family member (OR=7.98, 95% CI=2.18-9.14), moderate financial difficulties (OR=3.26, 95%CI=1.24-8.56), maternal death in childhood (OR=3.46, 95% CI=1.21-9.92) and serious financial difficulties (OR=3.55, 95% CI=1.20-10.52). CONCLUSION: Stress exposure has been proposed to contribute to the etiology of breast cancer. There is a need for understanding the differing physiological effects of types or times of stress exposure. PMID- 26011341 TI - Can we use frozen section analysis of sentinel lymph nodes mapped with methylene blue dye for decision making upon one-time axillary dissection in breast carcinoma surgery in developing countries? AB - PURPOSE: To evaluate the accuracy of intraoperative frozen section analysis (FSA) of sentinel lymph nodes (SLNs) mapped using methylene blue dye (MBD) and its usefulness for selecting patients with breast carcinomas and positive axillary lymph nodes (ALNs) for one-time axillary dissection. METHODS: 152 female patients with T1/T2 breast carcinomas and clinically negative ALNs were selected for mapping using MBD (1%) from October 2010 to December 2011. Patients underwent FSA of mapped SLNs and ALN dissection. The accuracy of SLN-FSA was tested by comparing these findings with the definite histopathology (HP) of SLNs, as well as of other ALNs. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: There was a 98%-match between FSA and definite HP findings of SLNs, suggesting high accuracy of FSA in this series. None of 3 patients with false-negative SLNs on FSA had additional axillary nodal metastases. One out of 20 (5%) patients with metastases in other ALNs had "clear" SLNs, both on FSA and definite HP (false-negative). Accuracy reached 94.1%. CONCLUSIONS: SLN-FSA enables adequate selection of patients for one-time axillary node dissection. MBD mapping technique is cheap, feasible and enables easy and precise detection of the first draining ALNs. Using FSA of SLNs mapped with MBD, patients with breast carcinoma benefit from complete surgical treatment during one hospitalization, the risk of undergoing anaesthesia twice is reduced, as well as the treatment cost, which is important in developing countries. PMID- 26011342 TI - Molecular and clinico-histological data in aggressive prostate cancer patients from Bulgaria. AB - PURPOSE: Metastatic prostate cancer (PCa) is one of the leading causes of death in men worldwide. We report Bulgarian patients with strongly aggressive, castration-resistant PCa. METHODS: PCA3 overexpression, GSTP1 promoter hyper methylation, TMPRSS2-ERG gene fusions, IVS1-27G>A in the KLF6 gene and mutations in androgen receptor (AR) gene, for diagnostic purposes were assessed. PCR, real time PCR (RT-PCR), sequencing, and bisulfite conversion of DNA were applied. We correlated the molecular data to the histological and clinical findings. RESULTS: The obtained molecular profile in 11 PCa Bulgarian patients coincided with the clinico-histological data of strongly aggressive PCa. Association was detected between the tumor stage (assessed by TNM as T3 and T4) and the detected molecular profile of aggressive cancer behavior with one exception, assessed as T2. None of our patients had positive family history of prostate cancer and no somatic mutations were detected in the AR gene. All patients showed normal genotype with respect to the KLF6 IVS1- 27G>A polymorphism. The rest of the markers were positive in fresh prostatic tissues and biopsies from all patients, whereas only one blood sample showed triple positive result. CONCLUSIONS: The appearance of PCa-specific markers in blood was considered as a predictor for a PCa (micro) dissemination into the circulation. The GSTP1 promoter hypermethylation is the earliest epigenetic alteration, which indicates cancerous changes and the first and long-lasting marker that is detectable in blood circulation. The molecular profile needs to be strictly monitored during treatment, which is of great help in determining the patient's individual response to therapy. PMID- 26011343 TI - Adjuvant dendritic cells vaccine combined with cytokine-induced-killer cell therapy after renal cell carcinoma surgery. AB - PURPOSE: To observe the efficacy and side effects of adjuvant dendritic cells' (DCs) vaccine combined with cytokine-induced killer cell (CIK) therapy after renal cell carcinoma (RCC) surgery (RCCS). METHODS: DCs vaccine and CIK that loaded the autologous tumor cell lysate were prepared in vitro. Four hundred and ten RCC patients were recruited, and the study group was given DCs-CIK immunotherapy, while the control group was given IFN-alpha therapy. RESULTS: Disease progression (recurrence, metastasis or death) showed significant differences between the two groups in clinical stage I and II patients, as well as in highly and moderately differentiated disease (p<0.05), while there was no significant difference between the two groups in patients with poorly differentiated disease (p>0.05). The 3- and 5-year overall survival rates of the DCs-CIK group (96% and 96%, respectively) exhibited significant difference compared to the IFN-alpha group (83% and 74%, respectively (p<0.01). Progression free survival (PFS) between the two groups was significantly different (p<0.01). Tumor stage and DCs-CIK treatment were independent factors concerning prognosis of RCC (p<0.05). There was no severe toxicity observed in the DCs-CIK treatment group. CONCLUSIONS: Adjuvant post-RCCS DCs-CIK treatment prolonged PFS and reduced mortality, showing better overall activity compared to interferon treatment. PMID- 26011344 TI - 3D conformal radiotherapy in primary nasopharyngeal cancer: effectiveness and prognostic factors. AB - PURPOSE: To assess the efficacy and safety of using 3D conformal radiation therapy (3DCRT) to treat nasopharyngeal cancer (NPC) in a Caucasian cohort and evaluate factors with prognostic value. METHODS: Between September 2001 and November 2012, 44 NPC patients with a mean age of 57 years underwent 3DCRT at the University Hospital of Ioannina. Nineteen patients (43%) presented with WHO type 1 and 2 histology. Thirty two patients (73%) had advanced-stage disease (stage III/IV). Thirty-one patients (70%) received chemotherapy. The mean total radiotherapy dose prescribed to the planning target volume (PTV) was 67.2 Gy. The daily dose was 1.8 Gy. RESULTS: With a median follow up of 43 months (range 8.4 125), the 4-year local relapse-free (LRFS), nodal relapse-free (NRFS), distant metastases-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 90, 87, 91, 80 and 82%, respectively. Histology was a significant prognostic factor concerning overall survival, with worst prognosis in patients with WHO type 1/2 compared to type 3. Age <70 years, absence of retropharyngeal lymph node metastasis, complete response after treatment and the completion of >=4 cycles of concurrent weekly cisplatin favored overall survival. Fifteen patients (34%) developed grade 3 late side effects (xerostomia: 6, soft tissue fibrosis: 6, hearing loss: 2, brachial plexus neuralgia: 1). CONCLUSION: 3DCRT in our Caucasian cohort, characterized by predominantly advanced-stage disease, combined with chemotherapy, is an effective treatment modality approach in patients with NPC with excellent tolerance. PMID- 26011345 TI - Factors predicting the development of distant metastases in patients with head and neck squamous cell carcinoma: A retrospective study from a single centre. AB - PURPOSE: The presence of distant metastases (DMs) after the initial treatment of head and neck squamous cell carcinoma is associated with a poor outcome. The incidence of DMs in head and neck cancer is about 4-26%. The purpose of this study was to evaluate the prevalence of distant metastases and the factors predicting the development of DMs. METHODS: Between January 2000 and December 2010, 292 patients with head and neck squamous cell carcinoma were included in this study. RESULTS: Thirty three patients (11.3%) developed local recurrences, 27 patients (9.2%) developed DMs. The median post DMs survival was 23.4 months (range 1.8-229.1). The factors that significantly increased the risk of DMs were the presence of local recurrence (p=0.0001, OR:17.32, 95% CI:4.86-19.90), pathologically positive neck (p=0.008, OR:5.97, 95% CI: 3.25-10.45), and primary tumor localized in oral cavity or lip (p=0.035, OR:2.6, 95% CI:1.43-4.65). CONCLUSION: Patients with these factors should be considered candidates for adjuvant systemic treatment and evaluated for early detection of DMs during follow-up. PMID- 26011346 TI - Primary and salvage total laryngectomy. Influential factors, complications, and survival. AB - PURPOSE: In this retrospective study we analysed patients with advanced squamous cell carcinoma of the larynx and hypopharynx treated with primary total laryngectomy (PTL) between 1990 and 2007. METHODS: The patients were treated by classical PTL, radiotherapy 60-70 Gy, concomitant radio and chemotherapy (cisplatin and 5-fluorouracil) or salvage total laryngectomy (STL). They were followed up for 5 years and complications, survival, residual/recurrent disease and metastases were registered. RESULTS: STL after previous radiotherapy (STL pRT), and after chemoradiotherapy (STL-pCTRT) caused more frequent local complications than PTL. Five-year disease-free survival (DFS) rate was significantly influenced by TNM stage and localization of the primary laryngeal tumor. For laryngeal cancer it was: 61.3% for PTL, 54.1% for STL-pC-TRT, and 47.6% for STL-pRT. Incomplete responders to initial treatment had low survival rate. PTL for hypopharyngeal carcinoma and particularly salvage laryngectomy after chemoradiotherapy were associated with more frequent local complications. The 5-year DFS for hypopharyngeal cancer was lower than for laryngeal cancer. CONCLUSION: PTL still offers the best survival rate with low complications for advanced laryngeal and hypopharyngeal squamous cell carcinoma. STL causes more frequent local complications, especially after chemoradiotherapy. Addition of chemotherapy to radiotherapy increases the survival. Five-year DFS rate depends on TNM stage and localization of the primary tumor. PMID- 26011347 TI - Detection of XRCC1 gene polymorphisms in Turkish head and neck squamous cell carcinoma patients: a comparative analysis with different populations. AB - PURPOSE: X-ray repair cross-complementing (XRCC1) is one of the most important genes for the maintenance of genomic integrity and protection of cells from DNA damage. Although tobacco and alcohol consumption are the major risk factors for the development of head and neck squamous cell carcinoma (HNSCC), sequence variation in XRCC1 gene may alter HNSCC susceptibility. Reports on the relationship between HNSCC and polymorphisms in XRCC1 gene have been inconsistent so far. The aim of this study was to investigate the association of XRCC1 Arg194Trp and Arg399Gln single nucleotide polymorphisms (SNP), smoking and alcohol consumption with the risk of HNSCC in Turkish population and also to compare to these results with the ones from both Turkish and different populations in the literature. The frequencies of Arg194Trp and Arg399Gln SNPs were studied in 55 HNSCC and 69 healthy individuals. METHODS: Genomic DNA was isolated from peripheral blood and SNP was genotyped by PCR-RFLP method. RESULTS: The genotype and allele frequencies of both polymorphisms were not statistically different between the HNSCC and control groups. On the other hand, smoking and chronic alcohol consumption were associated with risk of HNSCC, but there was no association between Arg194Trp, Arg399Gln polymorphisms, smoking and alcohol consumption in HNSCC cases. CONCLUSION: These results indicate that both Arg194Trp and Arg399Gln polymorphisms were not associated with the development of HNSCC in Turkish population. In addition, the allele frequencies of polymorphisms were in line with other Turkish population results that were studied previously. However, compared to different populations, there were marked differences in allele frequencies. PMID- 26011348 TI - Long-term efficacy of radiofrequency ablation compared to surgical resection for the treatment of small hepatocellular carcinoma. AB - PURPOSE: To compare the clinical efficacy of surgical resection (SR) and radiofrequency ablation (RFA) for the treatment of small hepatocellular carcinoma (SHC; >= 5 cm in diameter). METHODS: The clinical and follow-up data for 88 patients with SHC, including 42 cases of SR and 46 cases of RFA, were analyzed. RESULTS: The mean follow-up time was 34.36 +/- 16.93 (range 6-72) months. The 1-, 3- and 5-year tumor-free survival rates were 85.4, 40.9, and 29.2% for the SR group and 82.6, 27.7, and 16.4% for the RFA group (p=0.51). The mean tumor-free survival for the SR and RFA groups was 32.78 and 29.39 months (p=0.51), respectively. The cumulative survival rates were 100. 63.7, and 50.4% for the SR group and 100, 66.3 and 37.4% for the RFA group (p=0.67). The average survival time was 50.78 and 47.62 months (p=0.67) for the SR and RFA groups, respectively. We divided the tumors into a <= 3 cm diameter group and a 3-5 cm diameter group and found that the data for both groups were not statistically different. Cox multivariate analysis indicated that the number of tumors significantly affected overall survival (p=0.02) after the effects of various factors were excluded. The overall tumor-free survival and overall survival of the SR and RFA groups were not statistically different. CONCLUSIONS: RFA is safe and effective for the treatment of SHC, with a long-term efficacy similar to that achieved by SR. Therefore, RFA is a preferred treatment method for SHC. PMID- 26011349 TI - Effects of silymarin and silymarin-doxorubicin applications on telomerase activity of human hepatocellular carcinoma cell line HepG2. AB - PURPOSE: Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapeutics such as doxorubicin. Milk thistle extract, or its active constituent silymarin has been used by cancer patients as an alternative and complementary agent. Telomerase activation is one of the initial events of HCC. In this study, we applied doxorubicin and silymarin for 72 hrs in order to test individual and combined effect of the agents on telomerase activity. METHODS: The effects of doxorubicin, silymarin, and their combination on the proliferation of HepG2 cell line were tested by MTT assay, and Checkerboard micro plate method was applied to define the nature of doxorubicin and silymarin interactions on the cells. Lipid peroxidations were assessed by thiobarbituric acid reactive substance (TBARS) level. Telomerase activity was determined according to the telomeric repeat amplification protocol (TRAP). Untreated cells were used as control group. RESULTS: Doxorubicin-silymarin combination had indifferent antiproliferative effects on HepG2 cells. Telomerase activity of the cells incubated with IC50 of doxorubicin and silymarin decreased to 72% (p<0.05). IC50 combinations of doxorubicin and silymarin caused 70% (p<0.05) reduction. All treatments except for the 1/2IC50 of silymarin caused significant increase in lipid peroxidation levels when compared to controls. TBARS levels did not significantly increase when doxorubicin and silymarin were applied in combination, which is in concordance with the indifferent drug interaction. CONCLUSION: IC50 of both doxorubicin and silymarin alone and in combination inhibited telomerase activity. Mechanism of inhibition may be elucidated by further molecular studies. PMID- 26011350 TI - The relationship between proliferation activity and parathyroid hormone levels in parathyroid tumors. AB - PURPOSE: This article examines as to whether the Ki-67 index may be useful as a marker for cell proliferation, as well as to whether Ki-67 immunohistochemical expression and parathyroid hormone (PTH) levels are useful in distinguishing between parathyroid carcinoma (PC) and adenoma. METHODS: A retrospective analysis of 50 patients (10 with PC and 40 with adenoma) who had been previously diagnosed with primary hyperparathyroidism (PHPT) was conducted. Normal parathyroid glands served as the control group. Immunostaining of Ki-67 was estimated through image analysis and the results were statistically analyzed. RESULTS: Ki-67 was higher in PC patients (median 785.15) compared to adenoma patients (median 297.41; Mann Whitney U-test p<0.001). ROC analysis confirmed that Ki-67 has a positive predictive marker in diagnosing cancer. Mann-Whitney U-test confirmed a highly statistically significant difference in the preoperative PTH levels between the PC and adenoma group (p <0.001). The PTH serum preoperative level was higher in PC patients (median 1721) than in those with adenoma (median 189.5). A highly significant correlation was also found between Ki-67 and preoperative PTH levels (p <0.001). CONCLUSION: A higher rate of cellular proliferation was noted in malignant tumors as compared to benign tumors. Moreover, the expression profile of Ki-67 and high PTH levels in this study indicates a role for them as potential markers of malignancy. PMID- 26011353 TI - Does neoadjuvant chemotherapy plus cytoreductive surgery improve survival rates in patients with advanced epithelial ovarian cancer compared with cytoreductive surgery alone? AB - PURPOSE: To compare the outcomes of interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC/IDS) with primary debulking surgery (PDS) in patients diagnosed with advanced epithelial ovarian cancer (EOC). METHODS: A total of 292 patients with stages IIIC and IV disease who were treated with either NAC/IDS or PDS between 1995 and 2012 were retrospectively reviewed. The study population was divided into two groups: the NAC/IDS group (N=84) and the PDS group (N=208). Progression-free survival (PFS), overall survival (OS), and optimal cytoreduction were compared. RESULTS: The mean age was significantly higher in the NAC/IDS group (61.5+/-11.5 vs 57.8+/-11.1 years, p=0.01). Optimal cytoreduction was achieved in 34.5% (29/84) of the patients in the NAC/IDS group and in 32.2% (69/208) in the PDS group (p=0.825). The survival rates were comparable. The mean survival rate of patients who achieved optimal cytoreductive surgery in either the PDS or the NAC/IDS arm was significantly higher than that of patients who achieved suboptimal cytoreductive surgery (p<0.001 and p<0.001, respectively). Multivariate analysis confirmed the treatment method, amount of ascitic fluid, and optimal cytoreduction as independent factors for OS. CONCLUSIONS: No definitive evidence was noticed regarding whether NAC/IDS increases survival compared with PDS. NAC should be reserved for patients who cannot tolerate PDS or when optimal cytoreduction is not feasible. PMID- 26011351 TI - Expression of FHIT, p16, p53 and EGFR as prognostic markers in thyroid tumors of uncertain malignant potential. AB - PURPOSE: Thyroid tumors of uncertain malignant potential (TT-UMP) constitute a relatively new diagnosis. The purpose of this study was to analyze the relationship between immunohistochemical panels, prognostic parameters and TT UMP. METHODS: Group I was composed of patients diagnosed as differentiated thyroid carcinoma (DTC) and Group II of patients diagnosed as TT-UMP. The prognostic scores of patients were calculated using data according to the well known prognostic scoring systems MACIS, AMES, AGES. Evaluations of antibodies were based on the presence of nuclear staining for p16 and p53, membranous and cytoplasmic staining for epidermal growth factor receptor (EGFR) and cytoplasmic staining for fragile histidine triad (FHIT). RESULTS: Statistically significant difference was noted (p< 0.05) between Group I and Group II according to MACIS and AMES. No statistical difference was found in terms of immunostaining between groups when stained with p16, p53 and FHIT. On the other hand, in Group II a moderate positive correlation was detected between MACIS and EGFR. CONCLUSION: According to our findings p53 was not important in tumor genesis at early stages in well-differentiated thyroid carcinomas and p16 loss of expression could be used as a finding to help in difficult microscopic diagnosis. TT-UMP is a gray zone of lesions requiring specific therapeutic procedures and postoperative follow-up. A positive correlation was detected between EGFR and TT-UMP, leading to assume that this situation could be used as a new tool in the follow-up of these patients in the future. PMID- 26011352 TI - Prognostic factors in clinical stage T4N2 locally advanced non-small cell lung cancer. AB - PURPOSE: Relatively few studies have focused on T4N2 (stage IIIB) locally advanced non-small cell lung cancer (NSCLC). In this study, we tried to identify prognostic factors for patients with clinical stage T4N2 NSCLC. METHODS: We retrospectively identified 223 patients, of which 168 met the inclusion criteria. Patients treated with curative intent using concurrent chemoradiotherapy (CRT) with or without adjuvant chemotherapy, or concurrent CRT after induction chemotherapy, were included in this study. Relevant patient, treatment, and disease factors were evaluated for their prognostic significance in both univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: The median progression-free survival (PFS) was 13 months (95% confidence interval [CI], 10.6-15.4). The median overall survival (OS) was 20 months (95% CI, 16.8-23.1), and 71, 40.3 and 28.2% of the patients survived for 1, 2 and 3 years after diagnosis, respectively. Multivariate analysis showed Eastern Cooperative Oncology Group (ECOG) performance status (PS) was independent predictor of PFS (hazard ratio [HR], 0.24; 95% CI, 0.13-0.43; p=0.001), and OS [HR, 0.48; 95% CI, 0.26-0.87; p=0.015). Absence of multifocal T4 tumors was also associated with a significantly longer OS (HR, 046; 95% CI, 0.31-0.7; p=0.001). There was no statistically significant difference in OS and PFS between treatment modalities. CONCLUSION: PFS and OS were significantly shorter in patients with poor ECOG PS. OS was also significantly shorter in patients with multifocal T4 tumors. There were no differences between the two therapeutic approaches with respect to outcome. PMID- 26011354 TI - Rapamycin inhibits tumor growth of human osteosarcomas. AB - PURPOSE: Treatment options for osteosarcoma are limited due to its resistance to chemotherapy and radiotherapy. Signaling through the mammalian target of rapamycin (mTOR) pathway contributes to cell proliferation and chemoresistance of many cancers. Rapamycin, as an inhibitor of mTOR, has been developed as potentially valuable therapeutic agent. In this report, we evaluated the effects of rapamycin on human osteosarcoma cells' growth in vitro and in vivo. METHODS: Proliferation of osteosarcoma cells treated with rapamycin at different time periods was detected and changes in the cell cycle were measured by MTS and flow cytometry, respectively. Autophagy induced by rapamycin in osteosarcoma cells and the expression of cell cycle regulating proteins were detected by Western blotting. The effect of rapamycin on tumor growth in vivo was detected using mice xenograph models. RESULTS: The proliferation of osteosarcoma cells was signif- icantly inhibited by rapamycin treatment in a concentration-dependent manner and the cell cycle progression was impaired with G1 arrest. Rapamycin induced autophagy, increased the expression of p27 and decreased the expression of Cyclin D1. In addition, rapamycin suppressed the tumor growth in mice xenograph models. CONCLUSIONS: The potent antiproliferative activities of mTOR inhibitor rapamycin has been proven. Theses results strongly indicate that rapamycin may be a promising agent against osteosarcomas. PMID- 26011355 TI - Genotoxic activity of the new pharmaceutical FS-1 in Salmonella/microsome test and mouse lymphoma L5178Y cells. AB - PURPOSE: The purpose of this study was to determine possible genotoxic effects of a new very promising antibacterial/antiviral drug FS-1. METHODS: The drug was tested in TA98, TA100, TA102, TA1535 and TA1537 strains of Salmonella (Ames test) with and without metabolic activation, and also in mouse lymphoma L5178Y cells by means of micronucleus and comet assays. In microbes the drug was tested at concentrations up to 500 MUg/plate and in mouse lymphoma cells up to 2,000 MUg/ml. RESULTS: In both test-systems in all experiments completely negative results were obtained although FS-1 was tested at maximum tolerated doses. CONCLUSIONS: The drug is not genotoxic. This is advantageous because many antibacterial/antiviral drugs possess such activity. PMID- 26011356 TI - Prayer and blessings focused for healing is the most popular complementary intervention in a paediatric oncology unit in Greece. AB - PURPOSE: Increasing numbers of children with cancer are using complementary and alternative medicine (CAM) therapies. Our aim was to estimate the rate of use, the beliefs of users and non-users and factors related with the use of CAM among Greek families. METHODS: A self-reported questionnaire was given to parents of 184 children with cancer. We assessed the rate of use, types of CAM therapies and factors potentially associated with the use of CAM. RESULTS: Based on the 110 questionnaires which were completed (59.8% of the families), 23 families (21%) had used at least one complementary treatment. The most common forms were: spiritual healing/prayer/blessings 18/23 (78%), art therapies 4, dietary supplements 3, massage 3, homeopathy 2, and herbals 2. The reasons given for use included: making the child stronger 17/23 (48%, hope of stopping the cancerous process 11/23 (49%), and coping with side effects 6/23 (26%). Among the reasons given by the parents for not using CAM therapies the most common (84%) was the effective conventional treatment and, therefore, there was no need for CAM use. Another 24% reported that were unaware of these "alternative" and "complementary" therapies and a further 7% had considered using them but finally they didn't. In bivariate analysis, the use of CAM was not associated either with age, sex, nationality, education or occupation of the parents at the time of the survey, or with diagnosis, mode of therapy or age of the child at diagnosis. CONCLUSIONS: The use of CAM therapies by Greek families for their children with cancer does not appear to be very popular, although the experiences of those who did use them were generally positive. PMID- 26011357 TI - The influence of cisplatin, doxorubicin, pegylated doxorubicin, oxaliplatin and gemcitabine on mahlavu cell line. AB - PURPOSE: Hepatocellar carcinoma (HCC) remains a major health problem being the third leading cause of deaths due to cancer worldwide. Because HCC is known to be highly resistant to conventional systemic therapies, single-agent or combination of systemic therapies have been investigated. Today, sorafenib, a multikinase inhibitor, is the only approved systemic agent for the first line treatment of advanced HCC. In this study, we aimed to investigate the influence of different concentrations of cisplatin, doxorubicin, pegylated doxorubicin (PLD), oxaliplatin and gemcitabine by applying these agents either single or in combinations on mahlavu cell line. METHODS: HCC mahlavu cell line was used for the experiments. Cell death was measured by flow cytometry at 48 hrs after incubation with various concentrations (0.1 MUg/ml, 1.0 MUg/ml and 10 MUg/ml) of the drugs. RESULTS: Cell death due to gemcitabine was found to be significantly higher than cell deaths caused by the other single agents including cisplatin, oxaliplatin, doxorubicin and PLD (p<0.001, p<0.001, p<0.001 and p=0.0049, respectively). There was no significant difference between gemcitabine and both the gemcitabine combination with doxorubicin and PLD (p=0.992 and p=0.441, respectively). CONCLUSION: This is a preliminary analysis evaluating the effect of the conventional chemotherapeutic agents on mahlavu cell line in vitro. The findings of this study suggest that gemcitabine-based therapies keep on being the prefered therapeutic approach for the treatment of HCC. PMID- 26011358 TI - Association between the receptor for advanced glycation end products gene polymorphisms and cancer risk: a systematic review and meta-analysis. AB - PURPOSE: Polymorphisms in the receptor for advanced glycation end products (RAGE) gene may influence the risk of cancer, but the results are inconsistent. Therefore, we performed a systematic review to identify statistical evidence of the association between the 3 polymorphisms rs2070600 G/S (82G>S), rs1800624 T/A ( -374 T>A) and rs1800625C/T (-429 C>T) and the risk of cancer. METHODS: We searched PubMed database (http://www.ncbi. nlm.nih.gov/pubmed/), EMBASE database (http://www.elsevier.com/online-tools/embase ) and China National Knowledge Infrastructure (CNKI) database (http://www.cnki.net/) until Aug 30, 2014 to identify eligible studies. RESULTS: The pooled analysis revealed positive association between RAGE rs2070600 polymorphism and cancer risk in all genetic models (homozygous: OR=1.831, 95%CI: 1.548-2.166, p<0.001, allele: OR=1.321, 95%CI: 1.164-1.499, p<0.001, heterozygous: OR=1.42, 95%CI:1.126-1.792, p=0.003, dominant: OR=1.499, 95%CI: 1.200-1.874 ; p<0.001, recessive: OR=1.376, 95%CI: 1.197-1.583, p<0.001). We failed to get an effective conclusion about the association between the rs1800624 and rs1800625 polymorphisms and cancer risk in overall comparison. But in subgroup analysis, the rs1800624 polymorphism significantly increased lung cancer susceptibility in the homozygous model (OR=1.486, 95%CI:1.147-1.924, p=0.003) and the allele model (OR=1.15, 95%CI:1.029 1.285, p=0.014), but most likely contributed to decreased susceptibility to breast cancer in the allele model (OR=0.791 95%CI: 0.648-0.965, p=0.021), the heterozygous model (OR=0.733, 95%CI:0.577-0.931, p=0.011) and the dominant model (OR=0.741, 95%CI:0.588-0.934, p=0.011). No significant association was found between RAGE rs1088625 polymorphism and cancer risk in Caucasians, but these results should be interpreted with caution. CONCLUSION: The polymorphism of rs2070600 in the RAGE gene may increase the susceptibility to several human cancers, especially to lung cancer and to Asians. The rs1800264 most likely contributes to decreased susceptibility to breast cancer but increased susceptibility to lung cancer. However, large-scale studies involving various cancer types and different populations are needed for a precise conclusion. PMID- 26011359 TI - In vitro antiproliferative activity of partially purified Withania somnifera fruit extract on different cancer cell lines. AB - PURPOSE: Cancer is a major health problem worldwide. There is a continuous need to search for safer and more effective alternatives to overcome the side effects and resistance of the chemotherapeutic agents. Therefore, in this study we investigated the antiproliferative activity and the apoptotic potential of Withania somnifera (W. somnifera). METHODS: W. somnifera was extracted with methanol and then solvent partitioned by sequential extractions with hexane, dichloromethane and ethyl acetate. Each extract was assayed for antiproliferative activity against different cancer cell lines using MTT assay. The nuclear morphology of HepG2 cells was investigated by DNA-binding fluorescent dye (Hoechst 33342 stain). The percentage of viability, death and apoptosis were evaluated by the Tali(TM) Image-based cytometer using annex-in-V/PI (propidium iodide). A chromatographic fingerprint was constructed using high performance liquid chromatography (HPLC). RESULTS: The most potent anticancer activity of the crude extract was against HepG2 cell line (LC50=164.7MUg/ml). Dichloromethane fraction showed remarkable changes in the chromatin structure i.e., fragmentation, uniform condensation. Of the HepG2 cells 43.6% were apoptotic when treated with dichloromethane fraction for 24 hrs at 95MUg/ml concentration. HPLC showed the presence of a major peak at 11.85 min. CONCLUSION: W. somnifera may have the potential to serve as a template for future anticancer drug development. However, further investigation is required to identify the active compound/s. PMID- 26011360 TI - Prognostic role of the let-7 family in various carcinomas: A meta-analysis update. AB - PURPOSE: The role of let-7 family members in cancer prognosis has been the subject of increasing interest; however, the correlation between let-7 expression and cancer prognosis remains unknown. The goal of this study was to investigate the prognostic role of let-7 expression by performing a meta-analysis update of 31 studies. METHODS: All relevant studies were searched on PubMed and Web of Science. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and subgroup analysis was performed for overall survival (OS) and disease-free survival (DFS) to evaluate the relationship between high let-7 expression and cancer prognosis. Heterogeneity and publication bias were also investigated. RESULTS: We discovered that high let-7 expression can predict a better OS (pooled HR=0.69, 95% CI 0.60-0.80, transformed from lnHR and its 95% CI) and DFS (pooled HR=0.72, 95% CI 0.54-0.96, transformed from lnHR and its 95% CI) in various carcinomas, especially in digestive cancer. Subgroup analysis showed that high let-7 expression was significantly associated with a better DFS in Asians (pooled HR=0.50, 95% CI 0.39-0.64, transformed from lnHR and its 95% CI). CONCLUSIONS: This meta-analysis showed that high let-7 expression is a prognostic factor for better OS and DFS in cancer patients, with particularly better DFS among the Asian populations. These results suggest that clinicians should treat patients with low let-7 expression more carefully. Future studies in large-scale populations among different ethnicities and regions are needed to definitively determine if let-7 expression can be used as a predicative biomarker for clinical assessment. PMID- 26011361 TI - Informing cancer patient based on his type of personality:The self-sacrificing patient. AB - Imparting the bad news has become a hard task for the doctor, and is usually perceived as unpleasant by the patient to whom the bad news is revealed. It is vital that the physician's approach be tailored to the cancer patient's personality. Gathering by the informing process protocols already suggested the hardest step for the doctors to take is empathic understanding which, presupposes tailoring to the individual's needs. The aim of this article was to describe the self-sacrificing type of personality thoroughly, so that any physician can make a diagnosis and tailor the information strategy to their needs. As method of research was used the qualitative method through groups with doctors and nurses, while research within groups lasted for 5 years. Assessing the denial mechanism is hard for a person that regards disease as punishment and propitiation. The physician must mobilize his countertransference, the sense he gets from the discussions with the patient and their overall communication. If he finds that the patient has self-control, then the approach of imparting the news resembles that of the controlling-orderly personality. If he ascertains that the patient has a lasting embarrassment, he should be more careful and impart the news gradually, his approach resembling that of the dependent person. PMID- 26011362 TI - Ophthalmic malignancies in antiquity as depicted in two terracotta figurines. AB - Ocular and orbital wall cancers were recognized by the physicians of the antiquity as incurable, lethal, and non-operable malignant entities. Paul of Aegina (7(th)c AD) was the first to refer to this type of cancer and proposed only some palliative measures, while the same approach was also preserved by Theophanes Nonnus (10(th)c AD). However, two terracotta figurines of the Hellenistic period (323-30 BC) which depicted tumorous malformations in the eye area, raise a scientific debate on the matter. Hellenic art, once more contributed in a didactic way to preserve medical knowledge of the past, and served as an auxiliary tool in order to facilitate medical study. PMID- 26011363 TI - Management of penile tumours during the Byzantine period. AB - While conventional treatment of penile cancer consists of total penile amputation and bilateral lymphadenectomy, recently a more conservative strategy comprising penile-preserving surgery and selective lymphadenectomy has been applied in order to preserve the penis and to minimize unnecessary inguinal lymphadenectomy. A thorough literature survey was performed to see what was already known of the surgical treatment of penile tumours in ancient times. In the Byzantine period, surgery appeared to have been highly developed, as one may conclude from the surgical material included mainly in the works of Oribasius of Pergamus and Paul of Aegina. Being aware of cancer, they described in their medical encyclopaedias malignant and benign tumours of the prepuce and glans penis, as well as their surgical and non-surgical management. After local excision of malignant tumours, they strongly recommended burning to prevent relapse, whereas they discouraged simultaneous removal of external and internal preputial lesions, because of the risk of perforation of the prepuce. These surprisingly detailed descriptions prove that Byzantine surgery had reached a higher level than commonly supposed. Penile-preserving treatment, which has recently become the therapeutic strategy of choice, was already accomplished in ancient times by using adjuvant thermal or chemical burning after local tumour excision. PMID- 26011364 TI - Four historic legends in human papillomaviruses research. AB - Human papillomaviruses (HPVs) infection and HPVs-associated lesions, including skin warts in children and adults and cervical neoplasia in women, have been excessively studied since ancient years. In our article, we present briefly four major researchers from the HPVs pre-vaccination historic period: Hippokrates the Asclepiad, Domenico Antonio Rigoni-Stern, George N. Papanicolaou and Harald zur Hausen. PMID- 26011365 TI - Non-alcoholic fatty liver disease, metabolic syndrome and gastric cancer: Single center experience. PMID- 26011366 TI - Renal cell carcinoma with metastasis to the testis. PMID- 26011368 TI - Hypothesis: Should prophylactic mastectomy be indicated for breast cancer in high risk women? PMID- 26011367 TI - Unexpected progression of hepatocellular carcinoma in a patient with inactive HBsAg carrier state: pulmocranial metastasis. PMID- 26011369 TI - Extended upper sternectomy with curative intent for neglected papillary thyroid carcinoma in a fit 65-year-old man. PMID- 26011370 TI - Denosumab: Excellent response of metastatic giant cell tumor of the bone. PMID- 26011371 TI - Gastric cancer and gallbladder: single center experience. PMID- 26011372 TI - Ofatumumab in a chronic lymphocytic leukemia patient with graft versus host disease and relapse after mini-allo BMT. PMID- 26011373 TI - A Simple Regression-based Approach to Account for Survival Bias in Birth Outcomes Research. AB - In perinatal epidemiology, birth outcomes such as small for gestational age (SGA) may not be observed for a pregnancy ending with a stillbirth. It is then said that SGA is truncated by stillbirth, which may give rise to survival bias when evaluating the effects on SGA of an exposure known also to influence the risk of a stillbirth. In this article, we consider the causal effects of maternal infection with human immunodeficiency virus (HIV) on the risk of SGA, in a sample of pregnant women in Botswana. We hypothesize that previously estimated effects of HIV on SGA may be understated because they fail to appropriately account for the over-representation of live births among HIV negative mothers, relative to HIV positive mothers. A simple yet novel regression-based approach is proposed to adjust effect estimates for survival bias for an outcome that is either continuous or binary. Under certain straightforward assumptions, the approach produces an estimate that may be interpreted as the survivor average causal effect of maternal HIV, which is, the average effect of maternal HIV on SGA among births that would be live irrespective of maternal HIV status. The approach is particularly appealing, because it recovers an exposure effect which is robust to survival bias, even if the association between the risk of SGA and that of a stillbirth cannot be completely explained by adjusting for observed shared risk factors. The approach also gives a formal statistical test of the null hypothesis of no survival bias in the regression framework. PMID- 26011374 TI - Autoantibodies to Factor XII and Kininogen-Dependent Antiphosphatidylethanolamine Antibodies in Patients with Recurrent Pregnancy Loss Augment Platelet Aggregation. AB - PROBLEM: Numerous studies have suggested that factor XII (FXII) deficiency, autoantibodies to FXII (anti-FXII), and antiphosphatidylethanolamine antibodies (aPE) are associated with recurrent pregnancy loss (RPL). aPE in RPL patients recognize the LDC27 peptide of kininogen domain 3. Anti-FXII in RPL patients recognizes the heavy chain of FXII, especially the amino-terminal sequences IPP30 peptide. Previous studies suggested that LDC27 and IPP30 are the responsible sites competing for the same binding site on platelets and inhibiting augmentation of thrombin-induced platelet aggregation. Our aim was to study the influence of antibodies to LDC27 and IPP30 on platelet aggregation. METHODS OF STUDY: In fifteen healthy volunteers, platelet aggregation induced by gamma thrombin in the presence or absence of antibodies to LDC27 and IPP30 was measured. Sixteen RPL patients who were positive for anti-FXII were measured for spontaneous small platelet aggregate (SSPA) formation. RESULTS AND CONCLUSIONS: Antibodies to LDC27 and IPP30 markedly increased aggregation of normal platelets stimulated by gamma-thrombin. Augmentation of SSPA formation was more frequent in the patients with RPL who were positive for anti-FXII than in the control group (P = 0.003). This study strongly supports the hypothesis that aPE and anti-FXII may cause RPL due to disruption of the normal antithrombotic effects of kininogens and FXII. PMID- 26011375 TI - Coronary artery disease: Complex association between height and CHD-size matters. PMID- 26011376 TI - Continuous evolution of risk assessment methods for cardiac surgery and intervention. PMID- 26011378 TI - Exposure to synthetic oxytocin during delivery and its effect on psychomotor development. AB - The main objective is to examine the influence of oxytocin administration during delivery on psychomotor development at age five years. This was a retrospective cohort study involving two groups: children of mothers exposed vs. not exposed to oxytocin during labor. Of the 7,465 newborns registered in our maternity service during 2006 we randomly selected an initial sample of 400 children. Of these, 146 children were assessed using the motor scale of the Battelle Developmental Inventory. Other predictor variables that could potentially act as confounders and/or interact with the main relationship were also examined. The data were subjected to bivariate analysis, estimates of measures of strength of association, stratified analysis and multivariate binary logistic regression. The results indicate that exposure to synthetic oxytocin during delivery is an independent risk factor for a delay in gross and fine motor development. This was the case after controlling for the variables duration of labor and sex of the newborn, none of which modified the effect of oxytocin on gross and fine motor development. However, sex of the newborn were shown to be confounding gross motor development. In light of these results, and with the aim of preventing possible psychomotor alterations, further studies are now needed to analyze the effect that the oxytocin dose and the duration of perfusion may have on children's subsequent development. PMID- 26011379 TI - Clinical recommendations and practical guide for negative pressure wound therapy with instillation. AB - Effective wound management involves a comprehensive assessment of the patient and the wound to determine an optimal wound treatment plan. It is critical to identify and address factors that may impair wound healing, prior to selecting the most appropriate therapy for each patient. Negative pressure wound therapy (NPWT) is a well-established advanced therapy that has been successful in adjunctive management of acute and chronic wounds. In recent years, the introduction of topical wound solution delivery in combination with NPWT has provided further benefits to wound healing. A commercially available system now offers automated, volumetric control of instilled topical wound solutions with a dwell time in combination with NPWT (NPWTi-d; V.A.C. VeraFlo Therapy, KCI, an Acelity company, San Antonio, TX). This NPWTi-d system differs from other instillation systems in that a timed, predetermined volume of topical wound solution is intermittently delivered (versus continuously fed) and allowed to dwell in the wound bed (without NPWT), for a user-selected period of time before NPWT is resumed. This added accuracy and process simplification of solution delivery in tandem with NPWT have prompted use of NPWTi-d as first-line therapy in a wider subset of complex wounds. However, considerably more research is required to validate efficacy of NPWTi-d in various wound types. The purpose of this review is to provide a relevant overview of wound healing, describe current literature supporting the adjunctive use of NPWTi-d, propose a clinical approach for appropriate application of NPWTi-d and conclude with case studies demonstrating successful use of NPWTi-d. Based on this review, we conclude that either a large case series examining effects of NPWTi-d on different wound types or possibly a large prospective registry evaluating NPWTi-d with real-world topical wound solutions versus immediate debridement and closure would be valuable to the medical community in evaluating the efficacy of this promising therapy. PMID- 26011380 TI - 'White matter connectivity and Internet gaming disorder' and broader considerations in the field. AB - This invited commentary on the paper 'White Matter Connectivity and Internet gaming disorder' by Jeong et al. (unpublished) looks at the implications and importance of the MRI findings in the present study-one of the largest to date and also considers the broader developments of neuroimaging within the complex, emerging field of 'Internet psychology' and problematic Internet usage. PMID- 26011377 TI - Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy. AB - Cardiovascular disease is the leading cause of death worldwide. In the presence of signs and symptoms of myocardial ischaemia, women are more likely than men to have no obstructive coronary artery disease (CAD). Women have a greater burden of symptoms than men, and are often falsely reassured despite the presence of ischaemic heart disease because of a lack of obstructive CAD. Coronary microvascular dysfunction should be considered as an aetiology for ischaemic heart disease with signs and symptoms of myocardial ischaemia, but no obstructive CAD. Coronary microvascular dysfunction is defined as impaired coronary flow reserve owing to functional and/or structural abnormalities of the microcirculation, and is associated with an adverse cardiovascular prognosis. Therapeutic lifestyle changes as well as antiatherosclerotic and antianginal medications might be beneficial, but clinical outcome trials are needed to guide treatment. In this Review, we discuss the prevalence, presentation, diagnosis, and treatment of coronary microvascular dysfunction, with a particular emphasis on ischaemic heart disease in women. PMID- 26011381 TI - Changing Clinicians' Behavior: To Order or Not to Order a Urine Culture. PMID- 26011382 TI - Building resilience: A qualitative study of Spanish women who have suffered intimate partner violence. AB - The scientific literature reveals the importance of the resilience process in females who have experienced intimate partner violence (IPV). However, despite the importance of the cultural context in the process of resilience, there are no investigations exploring this phenomenon in Spain. This study used grounded theory to explore the factors that contribute to building resilience in Spanish women who have undergone IPV. A sample of 22 women who had experienced IPV participated in the study (mean age = 46.45 years, SD = 10.49). Findings revealed that these women were capable of using various factors, both individual and external, that promoted resilience. The women employed the following individual factors: physical activity, rediscovering oneself, altruism, control over one's life, creativity, spirituality, focus on the present, sense of humor, introspection, optimism, and projects and goals. The external resilience factors were housing, informal social support, and formal social support. Findings indicate that these factors can vary from one woman to the next and that some of these factors promoted the use of other factors in the development of resilience. The implications for clinical interventions with survivors are discussed. PMID- 26011383 TI - Establishing and sustaining a prospective screening program for breast cancer related lymphedema at the massachusetts general hospital: lessons learned. AB - There has been an increasing call to prospectively screen patients with breast cancer for the development of breast cancer-related lymphedema (BCRL) following their breast cancer treatment. While the components of a prospective screening program have been published, some centers struggle with how to initiate, establish, and sustain a screening program of their own. The intent of this manuscript is to share our experience and struggles in establishing a prospective surveillance program within the infrastructure of our institution. It is our hope that by sharing our history other centers can learn from our mistakes and successes to better design their own prospective screening program to best serve their patient population. PMID- 26011384 TI - Barriers prevent patient access to personalized therapies identified by molecular tumor profiling of gynecologic malignancies. AB - OBJECTIVE: This study was designed to evaluate the ability of commercial molecular tumor profiling to discover actionable mutations and to identify barriers that might prevent patient access to personalized therapies. METHODS: We conducted an IRB-approved retrospective review of 26 patients with gynecologic malignancies who underwent commercial tumor profiling at our institution during the first 18 months of test availability. Tumor profiles reported targeted therapies and clinical trials matched to patient-specific mutations. Data analysis consisted of descriptive statistics. RESULTS: Most patients who underwent tumor profiling had serous epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (46%). Patients underwent profiling after undergoing a median of two systemic therapies (range 0 to 13). A median of one targeted therapy was suggested per patient profile. Tumor profiling identified no clinically actionable mutations for seven patients (27%). Six patients sought insurance approval for a targeted therapy and two were declined (33%). One patient (4%) received a targeted therapy and this was discontinued due to tumor progression. CONCLUSIONS: There are formidable barriers to targeted therapy for patients with gynecologic malignancies. These barriers include a dearth of FDA approved targeted agents for gynecologic malignancies, lack of third party insurance coverage and limited geographic availability of clinical trials. PMID- 26011385 TI - Development of a novel experimental rat model for brachial plexus avulsion injury. AB - Brachial plexus injuries (BPI) are devastating events that frequently result in severe functional impairment of the upper extremity, and yet, present surgical reconstruction provides limited results. An animal model is an important tool to study peripheral nerve repair and regeneration. Here, a passive traction apparatus that allowed a multidirectional force exerted on a fixed forelimb was designed to produce a BPI rat model in a noninvasive manner. Behavioral and histological analyses were carried out to assess the suitability of the model. Using the apparatus, a reproducible upper BPI model was established with the forelimb abducted 30 degrees and a test weight of 2 kg. Avulsion of the nerve roots resulted in almost a total loss of forelimb function and the average Terzis score was decreased significantly compared with the sham group. No obvious recovery of shoulder and elbow movements was noted during the test period. In addition, nerve roots avulsion injury led to severe retrograde degeneration of motoneurons in the C5-C7 spinal cord segments. Nissl staining results showed that motoneurons decreased significantly in number and appeared to have irregular morphologies. These results indicated that a novel noninvasive rat model for BPI that simulates the mechanism of a human lesion could be produced using our passive traction apparatus, and it is expected to produce reliable preclinical evidence in the assessment of new therapeutic strategies for this lesion. PMID- 26011386 TI - Repeatability of functional anisotropy in navigated transcranial magnetic stimulation--coil-orientation versus response. AB - Transcranial magnetic stimulation (TMS) can be used for evaluating the function of motor pathways. According to the principles of electromagnetism and electrophysiology, TMS activates those neurons that are suitably oriented with respect to the TMS-induced electric field. We hypothesized that TMS could potentially be able to evaluate the neuronal structure, although until now, this putative application has not been exploited. We have developed a TMS-based method to evaluate the function and structure of the motor cortex concurrently in a quantitative manner. This method produced a measure, the anisotropy index (AI), which is based on the motor-evoked potentials induced at different coil orientations. The AI was demonstrated to exhibit an association with both motor cortex excitability and neuronal structure. In the present study, we evaluated the repeatability (intrasession and intersession) of AI in three consecutive measurements. In addition, we studied the repeatability of the optimal coil angle in inducing motor-evoked potentials. Two of the measurements were conducted on the same stimulation target and the third on a remapped target. The coefficient of repeatability of the AI was 0.022 for intrasession and 0.040 for intersession assessments. For the optimal stimulation angle, the coefficients of repeatability were 3.7 degrees and 5.1 degrees , respectively. Both the AI and the optimal stimulation angle demonstrated good repeatability (Cronbach's alpha>0.760). In conclusion, the results indicate that the AI can provide a reliable estimation of local functional anisotropy changes under conditions affecting the cortex, such as during stroke or focal dysplasia. PMID- 26011387 TI - Gabapentin alleviates affective pain after traumatic nerve injury. AB - Gabapentin reduces behavioral signs of stimulus-evoked allodynia and hyperalgesia in preclinical studies of traumatic nerve injury, but its effects on more clinically relevant measures of stimulus-independent pain are unclear. To address this gap, we determined whether gabapentin would relieve affective pain after spared nerve injury (SNI). Twelve days after sham or SNI surgery, we administered gabapentin over three consecutive conditioning days and then evaluated conditioned place preference. Gabapentin produced conditioned place preference and reversed mechanical hypersensitivity in SNI but not sham rats at a dose (100 mg/kg) that did not change open-field activity. These results show for the first time that gabapentin provides relief from affective pain without producing sedation, and add to the limited clinical literature suggesting that its use can be extended to treat pain arising from traumatic nerve injury. PMID- 26011389 TI - Arithmetic split effect in complex subtractions: an event-related potential study. AB - This study explores the relationship between the split effect and the use of exact versus approximate strategies in complex-subtraction calculations. One hundred and two-digit subtraction problems were presented, with half of them being small-split problems with answers +/-2 or +/-5 from 50 and the other half being large-split problems with answers +/-10 or +/-15 from 50. Participants were asked to indicate whether the answer was less than 50. The measures were speed and accuracy of task performance, and high temporal resolution event-related potentials. Behavioral data showed that participants had a longer time requirement and a lower accuracy in solving small-split problems than in solving large-split problems. Event-related potential data show that, comparatively, the small-split problems led to more-negative, more-lateralized waves as early as 250 ms at frontal, frontocentral, and central sites. Our results, which are in agreement with previous studies, suggest that the participants used exact strategies to solve small-split problems and approximate strategies to solve large-split problems when performing complex subtractions. These results further our understanding of the brain mechanisms underlying the relationship between small/large-split effects and exact/approximate strategies in this task domain. PMID- 26011388 TI - Intracellular spermine prevents acid-induced uncoupling of Cx43 gap junction channels. AB - Polyamines (PAs), such as spermine and spermidine, modulate the activity of numerous receptors and channels in the central nervous system (CNS) and are stored in glial cells; however, little attention has been paid to their role in the regulation of connexin (Cx)-based gap junction channels. We have previously shown that PAs facilitate diffusion of Lucifer Yellow through astrocytic gap junctions in acute brain slices; therefore, we hypothesized that spermine can regulate Cx43-mediated (as the most abundant Cx in astrocytes) gap junctional communication. We used electrophysiological patch-clamp recording from paired Novikoff cells endogenously expressing Cx43 and HeLaCx43-EGFP transfectants to study pH-dependent modulation of cell-cell coupling in the presence or absence of PAs. Our results showed (i) a higher increase in gap junctional communication at higher concentrations of cytoplasmic spermine, and (ii) that spermine prevented uncoupling of gap junctions at low intracellular pH. Taken together, we conclude that spermine enhances Cx43-mediated gap junctional communication and may preserve neuronal excitability during ischemia and trauma when pH in the brain acidifies. We, therefore, suggest a new role of spermine in the regulation of a Cx43-based network under (patho)physiological conditions. PMID- 26011390 TI - Lysine-specific demethylase 1 inhibitors protect cochlear spiral ganglion neurons against cisplatin-induced damage. AB - Cisplatin is a widely used chemotherapeutic drug, but one of its side effects is ototoxicity. Epigenetic-related drugs, such as lysine-specific demethylase 1 (LSD1) inhibitors, have been reported to protect against cisplatin-induced hair cell loss by preventing demethylation of histone H3K4 (H3K4me2). However, the protective effect of LSD1 inhibitors in spiral ganglion neurons (SGNs) remains unclear. To investigate whether LSD1 inhibitors exert similar protective effects on SGNs, we treated mouse cochlear explant cultures with LSD1 inhibitors (2PCPA, S2101, or CBB1007) together with cisplatin. Low concentrations of cisplatin damaged SGNs much more than high concentrations, and blocking the demethylation of H3K4me2 with LSD1 inhibitors prevented the SGNs from injury. Reactive oxygen species are also involved in the injury process, and LSD1 inhibitors protected SGNs by increasing the expression level of the antioxidant gene Slc7a11 and decreasing the level of the pro-oxidant gene lactoperoxidase (Lpo). Our findings show that LSD1 inhibitors prevent cisplatin-induced SGN loss by regulating the demethylation of H3K4 and preventing increases of reactive oxygen species levels, which might provide a potential therapeutic strategy for cisplatin-induced hearing loss. PMID- 26011391 TI - Facial expression primes and implicit regulation of negative emotion. AB - An individual's responses to emotional information are influenced not only by the emotional quality of the information, but also by the context in which the information is presented. We hypothesized that facial expressions of happiness and anger would serve as primes to modulate subjective and neural responses to subsequently presented negative information. To test this hypothesis, we conducted a functional MRI study in which the brains of healthy adults were scanned while they performed an emotion-rating task. During the task, participants viewed a series of negative and neutral photos, one at a time; each photo was presented after a picture showing a face expressing a happy, angry, or neutral emotion. Brain imaging results showed that compared with neutral primes, happy facial primes increased activation during negative emotion in the dorsal anterior cingulated cortex and the right ventrolateral prefrontal cortex, which are typically implicated in conflict detection and implicit emotion control, respectively. Conversely, relative to neutral primes, angry primes activated the right middle temporal gyrus and the left supramarginal gyrus during the experience of negative emotion. Activity in the amygdala in response to negative emotion was marginally reduced after exposure to happy primes compared with angry primes. Relative to neutral primes, angry facial primes increased the subjectively experienced intensity of negative emotion. The current study results suggest that prior exposure to facial expressions of emotions modulates the subsequent experience of negative emotion by implicitly activating the emotion regulation system. PMID- 26011393 TI - Clinical outcomes of prostate cancer patients in Yokosuka City, Japan: A comparative study between cases detected by prostate-specific antigen-based screening in Yokosuka and those detected by other means. AB - OBJECTIVES: To investigate whether prostate-specific antigen-based screening reduced the prostate cancer mortality rate in Yokosuka, Japan. METHODS: We carried out a cohort study, in which we compared clinical outcomes between patients detected by prostate-specific antigen-based screening (S group n = 524) versus those detected by other means (NS group n = 1044). Clinical and pathological factors were evaluated using Cox regression analyses and the Kaplan Meier method. RESULTS: A total of 1.5% (8/524) of patients in the S group and 6.7% (70/1044) of those in the NS group died from prostate cancer during follow up. A total of 8.0% (42/524) of patients in the S group and 11.4% (119/1044) in the NS group died from other causes. The 10-year cancer specific survival rates of the S and NS groups were 97% and 86%, respectively (P < 0.001). The median age was significantly lower in the S group than the NS group: 71 and 73 years, respectively (P < 0.001). The rate of Gleason score 8-10 was significantly lower in the S group than the NS group: 9.7% and 16.7%, respectively (P < 0.001). The rate of patients with metastasis or prostate-specific antigen 100 ng/mL or more was significantly lower in the S group than the NS group: 7.8% and 23.0%, respectively (P < 0.001). On multivariate analysis, Gleason score 8-10 compared with Gleason score 6 was independently associated with cancer-specific survival (hazard ratio 4.808, 95% confidence interval 1.044-22.14, P = 0.044). CONCLUSIONS: Prostate-specific antigen-based population screening in Yokosuka City might help to reduce the prostate cancer mortality rate. PMID- 26011394 TI - A highly selective fluorescent sensor for Al3+ and the use of the resulting complex as a secondary sensor for PPi in aqueous media: its applicability in live cell imaging. AB - An easy-to-make salicylimine (L) bearing an "O-N-O"-coordination site was used as a highly selective fluorescent sensor for Al(3+) and PPi in aqueous solution. Sensor L showed a significant fluorescence enhancement in the presence of Al(3+) over other competitive metal ions. It works based on the Al(3+)-induced formation of a 1 : 1 L-Al(3+) complex, producing a chelation-enhanced fluorescence effect, the fluorescence quantum yield reached 0.59. This L-Al(3+) ensemble is a subsequent fluorescent sensor for PPi due to the strong attraction between Al(3+) and PPi, it can selectively discriminate PPi overcoming the interference of the biological competitors including PO4(3-), ADP and ATP at physiological pH. L and L-Al(3+) exhibit high sensitivity and selectivity for Al(3+) and PPi, the detection limits were found to be as low as 2.94 * 10(-8) M and 2.74 * 10(-7) M, respectively. It was further confirmed that sensor L had potential practical applications through mapping of Al(3+) in live cells. PMID- 26011396 TI - Childhood trauma and complex posttraumatic stress disorder symptoms in older adults: A study of direct effects and social-interpersonal factors as potential mediators. AB - Childhood traumatic events may lead to long-lasting psychological effects and contribute to the development of complex posttraumatic sequelae. These might be captured by the diagnostic concept of complex posttraumatic stress disorder (CPTSD) as an alternative to classic posttraumatic stress disorder (PTSD). CPTSD comprises a further set of symptoms in addition to those of PTSD, namely, changes in affect, self, and interpersonal relationships. Previous empirical research on CPTSD has focused on middle-aged adults but not on older adults. Moreover, predictor models of CPTSD are still rare. The current study investigated the association between traumatic events in childhood and complex posttraumatic stress symptoms in older adults. The mediation of this association by 2 social interpersonal factors (social acknowledgment as a survivor and dysfunctional disclosure) was investigated. These 2 factors focus on the perception of acknowledgment by others and either the inability to disclose traumatic experiences or the ability to do so only with negative emotional reactions. A total of 116 older individuals (age range = 59-98 years) who had experienced childhood traumatic events completed standardized self-report questionnaires indexing childhood trauma, complex trauma sequelae, social acknowledgment, and dysfunctional disclosure of trauma. The results showed that traumatic events during childhood were associated with later posttraumatic stress symptoms but with classic rather than complex symptoms. Social acknowledgment and dysfunctional disclosure partially mediated this relationship. These findings suggest that childhood traumatic stress impacts individuals across the life span and may be associated with particular adverse psychopathological consequences. PMID- 26011395 TI - Ontogenic Changes of Villus Growth, Lactase Activity, and Intestinal Glucose Transporters in Preterm and Term Born Calves with or without Prolonged Colostrum Feeding. AB - Oral glucose supply is important for neonatal calves to stabilize postnatal plasma glucose concentration. The objective of this study was to investigate ontogenic development of small intestinal growth, lactase activity, and glucose transporter in calves (n = 7 per group) that were born either preterm (PT; delivered by section 9 d before term) or at term (T; spontaneous vaginal delivery) or spontaneously born and fed colostrum for 4 days (TC). Tissue samples from duodenum and proximal, mid, and distal jejunum were taken to measure villus size and crypt depth, protein concentration of mucosa and brush border membrane vesicles (BBMV), total DNA and RNA concentration of mucosa, mRNA expression and activity of lactase, and mRNA expression of sodium-dependent glucose co transporter-1 (SGLT1) and facilitative glucose transporter 2 (GLUT2) in mucosal tissue. Additionally, protein expression of SGLT1 in BBMV and GLUT2 in crude mucosal membranes and immunochemical localization of GLUT2 in the enterocytes were determined. Villus height in distal jejunum was lower in TC than in T. Crypt depth in all segments was largest and the villus height/crypt depth ratio in jejunum was smallest in TC calves. Concentration of RNA was highest in duodenal mucosa of TC calves, but neither lactase mRNA and activity nor SGLT1 and GLUT2 mRNA and protein expression differed among groups. Localization of GLUT2 in the apical membrane was greater, whereas in the basolateral membrane was lower in TC than in T and PT calves. Our study indicates maturation processes after birth for mucosal growth and trafficking of GLUT2 from the basolateral to the apical membrane. Minor differences of mucosal growth, lactase activity, and intestinal glucose transporters were seen between PT and T calves, pointing at the importance of postnatal maturation and feeding for mucosal growth and GLUT2 trafficking. PMID- 26011397 TI - The R280H X-ray cross-complementing 1 germline variant induces genomic instability and cellular transformation. AB - X-ray repair cross complementing protein 1 (XRCC1) plays an important role in base excision DNA repair (BER) as a scaffolding protein for BER enzymes. BER is one of the basic DNA repair pathways repairing greater than 20,000 endogenous lesions per cell per day. Proper functioning of XRCC1, one of the most important players in BER, was suggested to be indispensable for effective DNA repair. Despite accumulating evidence of an important role that XRCC1 plays in maintaining genomic stability, the relationship between one of its most predominant variants, R280H (rs25489), and cancer prevalence remains ambiguous. In the current study we functionally characterized the effect of the R280H variant expression on immortal non-transformed mouse mammary epithelial C127 and human breast epithelial MCF10A cells. We found that expression of R280H results in increased focus formation in mouse C127 cells and induces cellular transformation in human MCF10A cells. Cells expressing R280H showed significantly increased levels of chromosomal aberrations and accumulate double strand breaks in the G1 cell cycle phase. Our results confirm a possible link between R280H and genomic instability and suggest that individuals carrying this mutation may be at increased risk of cancer development. PMID- 26011398 TI - Influence of the doping level on the porosity of silicon nanowires prepared by metal-assisted chemical etching. AB - A systematic method to control the porosity of silicon nanowires is presented. This method is based on metal-assisted chemical etching (MACE) and takes advantage of an HF/H2O2 etching solution and a silver catalyst in the form of a thin patterned film deposited on a doped silicon wafer. It is found that the porosity of the etched nanowires can be controlled by the doping level of the wafer. For low doping concentrations, the wires are primarily crystalline and surrounded by only a very thin layer of porous silicon (pSi) layer, while for highly doped silicon, they are porous in their entire volume. We performed a series of controlled experiments to conclude that there exists a well-defined critical doping concentration separating the crystalline and porous regimes. Furthermore, transmission electron microscopy investigations showed that the pSi has also a crystalline morphology on a length scale smaller than the pore size, determined from positron annihilation lifetime spectroscopy to be mesoscopic. Based on the experimental evidence, we devise a theoretical model of the pSi formation during MACE and apply it for better control of the nanowire morphology. PMID- 26011392 TI - A simple validated method for predicting the risk of hospitalization for worsening of heart failure in ambulatory patients: the Redin-SCORE. AB - AIMS: Prevention of hospital readmissions is one of the main objectives in the management of patients with heart failure (HF). Most of the models predicting readmissions are based on data extracted from hospitalized patients rather than from outpatients. Our objective was to develop a validated score predicting 1 month and 1-year risk of readmission for worsening of HF in ambulatory patients. METHODS AND RESULTS: A cohort of 2507 ambulatory patients with chronic HF was prospectively followed for a median of 3.3 years. Clinical, echocardiographic, ECG, and biochemical variables were used in a competing risk regression analysis to construct a risk score for readmissions due to worsening of HF. Thereafter, the score was externally validated using a different cohort of 992 patients with chronic HF (MUSIC registry). Predictors of 1-month readmission were the presence of elevated natriuretic peptides, left ventricular (LV) HF signs, and estimated glomerular filtration rate (eGFR) <60 mL/min/m(2) . Predictors of 1-year readmission were elevated natriuretic peptides, anaemia, left atrial size >26 mm/m(2) , heart rate >70 b.p.m., LV HF signs, and eGFR <60 mL/min/m(2) . The C statistics for the models were 0.72 and 0.66, respectively. The cumulative incidence function distinguished low-risk (<1% event rate) and high-risk groups (>5% event rate) for 1-month HF readmission. Likewise, low-risk (7.8%), intermediate-risk (15.6%) and high-risk groups (26.1%) were identified for 1-year HF readmission risk. The C-statistics remained consistent after the external validation (<5% loss of discrimination). CONCLUSION: The Redin-SCORE predicts early and late readmission for worsening of HF using proven prognostic variables that are routinely collected in outpatient management of chronic HF. PMID- 26011399 TI - Herb extracts and collagen hydrolysate improve skin damage resulting from ultraviolet-induced aging in hairless mice. AB - We examined the effect of the daily ingestion of herb extract from Eucommia ulmoides leaves and Korean ginseng on skin damage induced by repeated UV irradiation of hairless mice. The herb extract was orally administered to mice at a dose of 1000 mg/kg/day. The hydration of mice dorsal skin decreased significantly with repeated UV irradiation, but did not decrease when the herb extract was administered for seven weeks. Transepidermal water loss (TEWL) increased with UV irradiation, but decreased with the administration of dietary herb extract. These effects were more pronounced when combined with the administration of collagen hydrolysate. Geniposidic acid from E. ulmoides leaves and ginsenoside Rg1 from Korean ginseng reduced TEWL and increased the skin moisture content of UV-damaged skin on hairless mice, respectively. We concluded that this dietary herb extract reduced the skin damage caused by UV-induced aging, with geniposidic acid and ginsenoside Rg1 detected in the blood. PMID- 26011400 TI - Modeling correction of severe urea cycle defects in the growing murine liver using a hybrid recombinant adeno-associated virus/piggyBac transposase gene delivery system. AB - Liver-targeted gene therapy based on recombinant adeno-associated viral vectors (rAAV) shows promising therapeutic efficacy in animal models and adult-focused clinical trials. This promise, however, is not directly translatable to the growing liver, where high rates of hepatocellular proliferation are accompanied by loss of episomal rAAV genomes and subsequently a loss in therapeutic efficacy. We have developed a hybrid rAAV/piggyBac transposon vector system combining the highly efficient liver-targeting properties of rAAV with stable piggyBac-mediated transposition of the transgene into the hepatocyte genome. Transposition efficiency was first tested using an enhanced green fluorescent protein expression cassette following delivery to newborn wild-type mice, with a 20-fold increase in stably gene-modified hepatocytes observed 4 weeks posttreatment compared to traditional rAAV gene delivery. We next modeled the therapeutic potential of the system in the context of severe urea cycle defects. A single treatment in the perinatal period was sufficient to confer robust and stable phenotype correction in the ornithine transcarbamylase-deficient Spf(ash) mouse and the neonatal lethal argininosuccinate synthetase knockout mouse. Finally, transposon integration patterns were analyzed, revealing 127,386 unique integration sites which conformed to previously published piggyBac data. CONCLUSION: Using a hybrid rAAV/piggyBac transposon vector system, we achieved stable therapeutic protection in two urea cycle defect mouse models; a clinically conceivable early application of this technology in the management of severe urea cycle defects could be as a bridging therapy while awaiting liver transplantation; further improvement of the system will result from the development of highly human liver-tropic capsids, the use of alternative strategies to achieve transient transposase expression, and engineered refinements in the safety profile of piggyBac transposase-mediated integration. PMID- 26011401 TI - (Diacetoxyiodo)benzene-Mediated Reaction of Ethynylcarbinols: Entry to alpha,alpha'-Diacetoxy Ketones and Glycerol Derivatives. AB - Efficient access to alpha,alpha'-diacetoxy ketones has been developed from ethynylcarbinols and PhI(OAc)2. A plausible mechanism for this was proposed on the basis of experimental studies. The usefulness of alpha,alpha'-diacetoxy ketone products has been documented, and glycerol derivatives can be easily synthesized in good yields via a one-pot reaction. PMID- 26011402 TI - Possible role of proenkephalin in psoriasis. AB - BACKGROUND: Psoriasis is a common chronic skin disease that can also affect the mucous membranes and joints. It is multifactorial in origin, occurring in genetically predisposed individuals, and triggered by various endogenous and exogenous factors. Proenkephalin (PENK) is an endogenous opioid polypeptide hormone that acts on specific opiate receptors found on nerve and mucosal cells, and on various cells in the immune system. PENK receptors are expressed on skin cells, and their activation can regulate keratinocyte and melanocyte activities. PENK expression has been found to be increased in keratinocytes in psoriatic skin, and together with its inflammatory basis, this suggests that PENK may be regulated by inflammatory stimuli. AIM: To assess the possible role of PENK in the pathogenesis of psoriasis and to assess if it is related to the severity of psoriatic lesions. METHODS: Serum and tissue PENK levels were estimated in 20 patients with psoriasis vulgaris, and compared with those of 20 healthy controls (HCs). RESULTS: PENK levels were found to be significantly increased both in serum and in psoriatic lesions in patients compared with HCs. No significant correlation was found between PENK levels and patient age, disease duration or disease severity (Psoriasis Area and Severity Index). CONCLUSION: Our results support the role of PENK in the aetiopathogenesis of psoriasis, and indicate that giving anti-PENK drugs in addition to current antipsoriatic therapies might be of value in treating this common chronic skin disease. PMID- 26011403 TI - Fabrication of Nanoscale Circuits on Inkjet-Printing Patterned Substrates. AB - Nanoscale circuits are fabricated by assembling different conducting materials (e.g., metal nanoparticles, metal nano-wires, graphene, carbon nanotubes, and conducting polymers) on inkjet-printing patterned substrates. This non-litho graphy strategy opens a new avenue for integrating conducting building blocks into nanoscale devices in a cost-efficient manner. PMID- 26011404 TI - Forty years of quality-of-life research in congenital heart disease: Temporal trends in conceptual and methodological rigor. AB - BACKGROUND: The first study on quality of life (QoL) in patients with congenital heart disease was published 40 years ago. Since then, the number of QoL articles on these patients has grown exponentially. We conducted a systematic literature review of all empirical studies on QoL in patients with congenital heart disease published since 1974, with the aim of determining the range of conceptual and methodological rigor of studies and identifying temporal trends in these parameters. METHODS: PubMed, Embase, and Cinahl were searched for empirical studies addressing QoL in children, adolescents, or adults with congenital heart disease, published between January 1, 1974, and December 31, 2014. We applied 10 review criteria that were previously developed by Gill and Feinstein in 1994 and further refined by Moons et al. in 2004. Overall, 234 articles were reviewed. RESULTS: We found slight but non-significant temporal improvements in conceptual and methodological rigor and in use of assessment methods. This indicates a trend toward a more professional and exacting approach in QoL assessments. However, the majority of articles still had substantial conceptual and methodological deficits. Furthermore, we observed that citation of the publications of Gill and Feinstein and Moons et al. in published QoL research is associated with higher quality scores, suggesting that these articles have a positive impact on conceptual and methodological caliber. CONCLUSION: Despite 40 years of QoL research in this field, this review shows that major weaknesses in methodological rigor remain highly prevalent, which may make QoL studies inconclusive. PMID- 26011405 TI - High sensitivity troponin T in adult congenital heart disease. AB - BACKGROUND: High sensitivity troponin T (hsTnT) assays enable us to detect chronic heart failure (CHF). Adult congenital heart disease (ACHD) patients are classified as being in at least stage B of CHF. The purpose of the study was to assess hsTnT levels in ACHD patients and determine its clinical significance. METHODS: This is a prospective cross-sectional study. We assessed hsTnT in 131 ACHD patients and in 30 healthy controls. All ACHD patients underwent routine clinical and echocardiographic evaluation and had hsTnT and N-terminal brain natriuretic peptide (NT-pro-BNP) level measurements. RESULTS: The cut-off value defining an abnormal hsTnT level was established as >0.005 ng/mL. 35.1% (n=46) of ACHD patients had abnormal hsTnT compared to 6.7% (n=2) of healthy controls (p=0.002). The prevalence of elevated hsTnT did not differ between simple and complex and between non-cyanotic and cyanotic congenital heart disease (CHD). The sensitivity and specificity of hsTnT for the detection of moderate or severe (significant) systemic ventricular dysfunction was 78.6% and 69.8%, respectively (OR 8.49; CI 95% 2.23-32.30; p<0,0001) whereas for significant pulmonary ventricular dysfunction it was 66.7% and 68.2%, respectively (OR 4.29; CI 95% 1.56-11.79; p=0.003). In multivariate logistic regression models elevated hsTnT, but not NT-pro-BNP, was independently associated with both significant systemic ventricular dysfunction (p=0.004) and significant pulmonary ventricular dysfunction (p=0.011). CONCLUSIONS: A troponin leak is observed in a substantial number of ACHD patients and is associated with significant systemic and pulmonary ventricular impairment. Compared to NT-pro-BNP, hsTnT is a more specific independent predictor of ventricular dysfunction in ACHD. PMID- 26011406 TI - The impact of ethnicity on the prevalence and length of hospital stay in patients with mitral regurgitation. PMID- 26011407 TI - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa and its deadly complication. PMID- 26011408 TI - Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The objective of this study was to evaluate the change of right heart size and function assessed by echocardiography during long-term treatment with riociguat. METHODS: We assessed patients who started riociguat treatment (1.0-2.5mg tid) within the trials PATENT, PATENTplus, EAS and CHEST and continued for 3-12 months. Echocardiography, 6-minute walking distance (6MWD) and further clinical parameters were analyzed at baseline, after 3, 6 and 12 months. Right heart catheterization was performed at baseline and after 3 months. For missing data we performed the last and baseline observation carried forward (LOCF, BOCF) method as sensitivity analyses. RESULTS: Thirty-nine patients (21 PAH, 18 CTEPH, mean pulmonary arterial pressure 43 +/- 2 mmHg, PVR 600 +/- 43 dyn * s * cm(-5), 56.4% treatment-naive) were included. Mean right ventricular (RV) area significantly decreased after 3 (-2.1 +/- 3.9 cm(2), equals -7.4 +/- 15.3%, p = 0.002), 6 (-4.2 +/- 3.2 cm(2), equals -16.1 +/- 11.5%, p < 0.001) and 12 months (-5.9 +/- 4.6 cm(2), equals -22.1 +/- 14.2%, p < 0.001) compared to baseline. Right atrial area significantly decreased after 12 months (-3.5 +/- 4.1cm(2), equals -16.8 +/- 19.2%, p < 0.001) and TAPSE significantly improved after 6 (+ 2 +/- 4.7, equals 12 +/- 25.8%, p = 0.025) and 12 months (+ 3.6 +/- 5.4, equals 21.0 +/- 29.6%, p = 0.002). Furthermore, RV wall thickness and 6MWD significantly improved after 3, 6 and 12 months (p < 0.05). Invasive hemodynamics significantly improved after 3 months. Both LOCF and BOCF showed similar significance and lower effect sizes. CONCLUSION: Long-term treatment with riociguat significantly reduced right heart size and improved RV function in PAH and CTEPH. Further prospective studies are needed to confirm these results. PMID- 26011409 TI - A lethal coexistence: Pulmonary hypertension with pregnancy. PMID- 26011410 TI - Long-term outcome and medical radiation exposure in patients hospitalized for cardiovascular disease. AB - BACKGROUND: Low radiation doses from diagnostic and therapeutic procedures may increase cancer incidence after decades in cardiac patients. The aim of the study was to evaluate the long-term outcome and the prognostic effect of radiological exposure. METHODS: A retrospective cohort study examined 16,311 Italian cardiac patients without cancer consecutively hospitalized between 1970 and 2009 and followed-up for a median of 10 years. Cumulative estimated effective dose was calculated for the imaging procedures. Main causes of death and primary cancer onset were the end points and their relation with radiation exposure was analyzed by Cox model. RESULTS: Over the years, there was an increasing trend of cancer, a decreasing trend of cardiovascular, with stability of other-causes death. Cumulative estimated effective radiation dose was higher in patients who died for cancer (20 +/- 19 mSv) compared to cardiovascular (17 +/- 17, P < 0.001) and other-causes deaths (15 +/- 17, p < 0.001). The cumulative estimated effective dose adjusted HR was 1.004 (95% CI 1.000-1.009, p = 0.045) for cancer death and 1.008 (95% CI 1.005-1.011, p < 0.001) for (fatal and non-fatal) cancer onset. Radiation effective dose was not predictive of cardiovascular mortality (HR = 0.991), nor it was of other types of deaths (HR = 0.995). Smoking was a predictor for cardiovascular mortality, but it was not of other types of deaths. CONCLUSIONS: Non-cardiovascular causes of death are responsible for almost half of later deaths in cardiac patients. The radiological exposure from medical imaging procedures is predictive of cancer risk and cancer death. PMID- 26011411 TI - Bias in progression-free survival analysis due to intermittent assessment of progression. AB - Cancer clinical trials are routinely designed to assess the effect of treatment on disease progression and death, often in terms of a composite endpoint called progression-free survival. When progression status is known only at periodic assessment times, the progression time is interval censored, and complications arise in the analysis of progression-free survival. Despite the advances in methods for dealing with interval-censored data, naive methods such as right endpoint imputation are widely adopted in this setting. We examine the asymptotic and empirical properties of estimators of the marginal progression-free survival functions and associated treatment effects under this scheme. Specifically, we explore the determinants of the asymptotic bias and point out that there is typically a loss in power of tests for treatment effects. PMID- 26011412 TI - Conformational Change of Self-Assembled DNA Nanotubes Induced by Two-Photon Excitation. AB - Two-photon-regulated, shape-changing DNA nanostructures are demonstrated by integrating a DNA nanotube with a two-photon photocleavable module that enables the opening of the cavities of tube, and becomes partially single-stranded in response to two-photon excitation under 800 nm fs laser pulses. PMID- 26011413 TI - Multilevel assessment of Cry1Ab Bt-maize straw return affecting the earthworm Eisenia fetida. AB - Non-target effects of two varieties of Bacillus thuringiensis (Bt)-maize straw (5422Bt1 [event Bt11] and 5422CBCL [MON810]) return on the Eisenia fetida were investigated by using multilevel assessments, compared to near-isogenic non-Bt maize (5422). 5422Bt1 straw return had no deleterious effects on adult earthworms and had significantly positive effects on juveniles over three generations. Negative, no, and positive effects on adults treated with 5422CBCL straw were observed in the 1st, 2nd and 3rd generation, respectively. Negative and positive effects were observed on juveniles produced from the 1st- and 2nd-generation adults treated with 5422CBCL straw, respectively. Glutathione peroxidase activity of earthworms from Bt-maize treatments was significantly higher than that of control on the 90th d. Translationally controlled tumour protein (TCTP) and superoxide dismutase (SOD) genes were down-regulated, while annetocin (ANN) expression was up-regulated in 5422Bt1 treatments. TCTP and SOD genes were up regulated, while ANN and heat shock protein 70 were down-regulated in E. fetida from 5422CBCL treatments. Enzyme-linked immunosorbent assay revealed that Cry1Ab released from 5422Bt1 and 5422CBCL straw degraded rapidly on the 15th and 30th d and had a slow decline in the rest testing time. Cry1Ab concentrations in the soil, casts and guts of earthworm significantly decreased over the course of the experiment. This study was the first to evaluate generational effects of Bt-maize straw return on earthworms under laboratory conditions. The responses of enzymes activity and genes expression may contribute to better understand above different effects of Bt-maize straw return on earthworms from the 1st generation. PMID- 26011414 TI - Modelling the effects of pulse exposure of several PSII inhibitors on two algae. AB - Subsequent to crop application and during precipitation events, herbicides can reach surface waters in pulses of high concentrations. These pulses can exceed the Annual Average Environmental Quality Standards (AA-EQS), defined in the EU Water Framework Directive, which aims to protect the aquatic environment. A model was developed in a previous study to evaluate the effects of pulse exposure for the herbicide isoproturon on the alga Scenedesmus vacuolatus. In this study, the model was extended to other substances acting as photosystem II inhibitors and to other algae. The measured and predicted effects were equivalent when pulse exposure of atrazine and diuron were tested on S. vacuolatus. The results were consistent for isoproturon on the alga Pseudokirchneriella subcapitata. The model is thus suitable for the effect prediction of phenylureas and triazines and for the algae used: S. vacuolatus and P. subcapitata. The toxicity classification obtained from the dose-response curves (diuron>atrazine>isoproturon) was conserved for the pulse exposure scenarios modelled for S. vacuolatus. Toxicity was identical for isoproturon on the two algae when the dose-response curves were compared and also for the pulse exposure scenarios. Modelling the effects of any pulse scenario of photosystem II inhibitors on algae is therefore feasible and only requires the determination of the dose-response curves of the substance and growth rate of unexposed algae. It is crucial to detect the longest pulses when measurements of herbicide concentrations are performed in streams because the model showed that they principally affect the cell density inhibition of algae. PMID- 26011415 TI - Dechlorination of polychlorinated biphenyls by iron and its oxides. AB - The decomposition efficiency of polychlorinated biphenyls (PCBs) was determined using elemental iron (Fe) and three iron (hydr)oxides, i.e., alpha-Fe2O3, Fe3O4, and alpha-FeOOH, as catalysts. The experiments were performed using four distinct PCB congeners (PCB-209, PCB-153, and the coplanar PCB-167 and PCB-77) at temperatures ranging from 180 degrees C to 380 degrees C and under an inert, oxidizing or reducing atmosphere composed of N2, N2+O2, or N2+H2. From these three options N2 showed to provide the best reaction atmosphere. Among the iron compounds tested, Fe3O4 showed the highest activity for decomposing PCBs. The decomposition efficiencies of PCB-209, PCB-167, PCB-153, and PCB-77 by Fe3O4 in an N2 atmosphere at 230 degrees C were 88.5%, 82.5%, 69.9%, and 66.4%, respectively. Other inorganic chlorine (Cl) products which were measured by the amount of inorganic Cl ions represented 82.5% and 76.1% of the reaction products, showing that ring cleavage of PCBs was the main elimination process. Moreover, the dechlorination did not require a particular hydrogen donor. We used X-ray photoelectron spectroscopy to analyze the elemental distribution at the catalyst's surface. The O/Fe ratio influenced upon the decomposition efficiency of PCBs: the lower this ratio, the higher the decomposition efficiency. X-ray absorption near edge structure spectra showed that alpha-Fe2O3 effectively worked as a catalyst, while Fe3O4 and alpha-FeOOH were consumed as reactants, as their final state is different from their initial state. Finally, a decomposition pathway was postulated in which the Cl atoms in ortho-positions were more difficult to eliminate than those in the para- or meta-positions. PMID- 26011417 TI - Patrol Officer Daily Noise Exposure. AB - Previous research shows that police officers are at a higher risk for noise induced hearing loss (NIHL). Little data exists on the occupational tasks, outside of the firing range, that might lead to the increased risk of NIHL. The current study collected noise dosimetry from patrol officers in a smaller department and a larger department in southern Wisconsin, United States. The noise dosimeters simultaneously measured noise in three virtual dosimeters that had different thresholds, criterion levels, and exchange rates. The virtual dosimeters were set to: the Occupational Safety and Health Administration (OSHA) hearing conservation criteria (OSHA-HC), the OSHA permissible exposure level criteria (OSHA-PEL), and the American Conference of Governmental Industrial Hygienists (ACGIH). In addition to wearing a noise dosimeter during their respective work days, officers completed a log form documenting the type of task performed, the duration of that task, if the task involved the use of a siren, and officer characteristics that may have influenced their noise exposure, such as the type of dispatch radio unit worn. Analysis revealed that the normalized 8 hour time weighted averages (TWA) for all officers fell below the recommended OSHA and ACGIH exposure limits. The tasks involving the use of the siren had significantly higher levels than the tasks without (p = 0.005). The highest noise exposure levels were encountered when patrol officers were assisting other public safety agencies such as a fire department or emergency medical services (79 dBA). Canine officers had higher normalized 8-hr TWA noise exposure than regular patrol officers (p = 0.002). Officers with an evening work schedule had significantly higher noise exposure than the officers with a day or night work schedule (p = 0.023). There were no significant differences in exposure levels between the two departments (p = 0.22). Results suggest that this study population is unlikely to experience NIHL as established by the OSHA or ACGIH occupational exposure levels from the daily occupational tasks that were monitored. PMID- 26011419 TI - Chemoselective Boron-Catalyzed Nucleophilic Activation of Carboxylic Acids for Mannich-Type Reactions. AB - The carboxyl group (COOH) is an omnipresent functional group in organic molecules, and its direct catalytic activation represents an attractive synthetic method. Herein, we describe the first example of a direct catalytic nucleophilic activation of carboxylic acids with BH3.SMe2, after which the acids are able to act as carbon nucleophiles, i.e. enolates, in Mannich-type reactions. This reaction proceeds with a mild organic base (DBU) and exhibits high levels of functional group tolerance. The boron catalyst is highly chemoselective toward the COOH group, even in the presence of other carbonyl moieties, such as amides, esters, or ketones. Furthermore, this catalytic method can be extended to highly enantioselective Mannich-type reactions by using a (R)-3,3'-I2-BINOL-substituted boron catalyst. PMID- 26011418 TI - Age-related differences in the accuracy of web query-based predictions of influenza-like illness. AB - BACKGROUND: Web queries are now widely used for modeling, nowcasting and forecasting influenza-like illness (ILI). However, given that ILI attack rates vary significantly across ages, in terms of both magnitude and timing, little is known about whether the association between ILI morbidity and ILI-related queries is comparable across different age-groups. The present study aimed to investigate features of the association between ILI morbidity and ILI-related query volume from the perspective of age. METHODS: Since Google Flu Trends is unavailable in Italy, Google Trends was used to identify entry terms that correlated highly with official ILI surveillance data. All-age and age-class-specific modeling was performed by means of linear models with generalized least-square estimation. Hold-out validation was used to quantify prediction accuracy. For purposes of comparison, predictions generated by exponential smoothing were computed. RESULTS: Five search terms showed high correlation coefficients of > .6. In comparison with exponential smoothing, the all-age query-based model correctly predicted the peak time and yielded a higher correlation coefficient with observed ILI morbidity (.978 vs. .929). However, query-based prediction of ILI morbidity was associated with a greater error. Age-class-specific query-based models varied significantly in terms of prediction accuracy. In the 0-4 and 25-44 year age-groups, these did well and outperformed exponential smoothing predictions; in the 15-24 and >= 65-year age-classes, however, the query-based models were inaccurate and highly overestimated peak height. In all but one age class, peak timing predicted by the query-based models coincided with observed timing. CONCLUSIONS: The accuracy of web query-based models in predicting ILI morbidity rates could differ among ages. Greater age-specific detail may be useful in flu query-based studies in order to account for age-specific features of the epidemiology of ILI. PMID- 26011421 TI - Airway scleromas and their extensions. AB - BACKGROUND: Scleroma is a rare, chronic, granulomatous infectious disease of the respiratory tract mucosa which begins in the nose and spreads to the respiratory tract and adjoining structures. We report on the extensions and the management of 134 cases of scleroma in the Highlands region of Papua New Guinea. METHODS: The charts and treatment records of 134 scleroma cases were retrospectively reviewed from 1995 to 2013. The staging, extensions, treatment and results of treatment were reviewed and analysed. RESULTS: Of the 134 cases, 72 (53.7%) were females and the age ranged from 6 to 65 years. The disease was confined to the nose and nasopharynx in 71 (53.0%) cases. Extension of the disease from the nose to the Eustachian tube occurred in nine (6.7%) cases and into the middle ear in four (3.0%) cases. Further extensions to the larynx and trachea were seen in 17 (12.7%) cases each and the bronchus in three (2.2%) cases. Primary laryngoscleroma without involvement of the nose and nasopharyngeal stenosis without laryngeal involvement were managed in 11 (8.2%) and nine (6.7%) cases respectively. Others cases treated were ethmoid scleroma with proptosis and scleroma involving the upper lip in one (0.75%) case each. Ninety-nine (74.9%) patients were treated medically while 35 (26.1%) patients required surgery. Cure were achieved in 83 (61.9%) cases treated medically and 26 (19.4%) had successful surgical outcome. CONCLUSION: Scleroma begins in the nose and when not arrested, extends causing obstruction to the airway and cosmetic deformity which requires surgical intervention. PMID- 26011420 TI - Prediction of Post-Weaning Fibrinogen Status during Cardiopulmonary Bypass: An Observational Study in 110 Patients. AB - BACKGROUND: After cardiac surgery with cardiopulmonary bypass (CPB), acquired coagulopathy often leads to post-CPB bleeding. Though multifactorial in origin, this coagulopathy is often aggravated by deficient fibrinogen levels. OBJECTIVE: To assess whether laboratory and thrombelastometric testing on CPB can predict plasma fibrinogen immediately after CPB weaning. PATIENTS/METHODS: This prospective study in 110 patients undergoing major cardiovascular surgery at risk of post-CPB bleeding compares fibrinogen level (Clauss method) and function (fibrin-specific thrombelastometry) in order to study the predictability of their course early after termination of CPB. Linear regression analysis and receiver operating characteristics were used to determine correlations and predictive accuracy. RESULTS: Quantitative estimation of post-CPB Clauss fibrinogen from on CPB fibrinogen was feasible with small bias (+0.19 g/l), but with poor precision and a percentage of error >30%. A clinically useful alternative approach was developed by using on-CPB A10 to predict a Clauss fibrinogen range of interest instead of a discrete level. An on-CPB A10 <=10 mm identified patients with a post-CPB Clauss fibrinogen of <=1.5 g/l with a sensitivity of 0.99 and a positive predictive value of 0.60; it also identified those without a post-CPB Clauss fibrinogen <2.0 g/l with a specificity of 0.83. CONCLUSIONS: When measured on CPB prior to weaning, a FIBTEM A10 <=10 mm is an early alert for post-CPB fibrinogen levels below or within the substitution range (1.5-2.0 g/l) recommended in case of post-CPB coagulopathic bleeding. This helps to minimize the delay to data based hemostatic management after weaning from CPB. PMID- 26011425 TI - Role of phosphate on stability and catalase mimetic activity of cerium oxide nanoparticles. AB - Cerium oxide nanoparticles (CeNPs) have been recently shown to scavenge reactive oxygen and nitrogen species (ROS and RNS) in different experimental model systems. CeNPs (3+) and CeNPs (4+) have been shown to exhibit superoxide dismutase (SOD) and catalase mimetic activity, respectively. Due to their nanoscale dimension, CeNPs are expected to interact with the components of biologically relevant buffers and medium, which could alter their catalytic properties. We have demonstrated earlier that CeNPs (3+) interact with phosphate and lose the SOD activity. However, very little is known about the interaction of CeNPs (4+) with the phosphate and other anions, predominantly present in biological buffers and their effects on the catalase mimetic-activity of these nanoparticles. In this study, we report that catalase mimetic-activity of CeNPs (4+) is resistant to the phosphate anions, pH changes and composition of cell culture media. Given the abundance of phosphate anions in the biological system, it is likely that internalized CeNPs would be influenced by cytoplasmic and nucleoplasmic concentration of phosphate. PMID- 26011424 TI - The effect of recombinant erythropoietin on plasma brain derived neurotrophic factor levels in patients with affective disorders: a randomised controlled study. AB - The study aims to investigate the effect of repeated infusions of recombinant erythropoietin (EPO) on plasma brain derived neurotrophic factor (BDNF) levels in patients with affective disorders. In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS) <= 14) (study 2). In both studies, patients were randomised to receive eight weekly EPO (Eprex; 40,000 IU) or saline (0.9% NaCl) infusions in a double-blind, placebo-controlled, parallel--group design. Plasma BDNF levels were measured at baseline and at weeks 5, 9 and at follow up, week 14. In contrast with our hypothesis, EPO down regulated plasma BDNF levels in patients with TRD (mean reduction at week 9 (95% CI): EPO 10.94 ng/l (4.51-21.41 ng/l); mean increase at week 9: Saline 0.52 ng/l, p=0.04 (-5.88-4.48 ng/l) p=0.04, partial n2=0.12). No significant effects were found on BDNF levels in partially remitted patients with BD (p=0.35). The present effects of EPO on BDNF levels in patients with TRD point to a role of neurotrophic factors in the potential effects of EPO seen in TRD and BD. The neurobiological mechanisms underlying these effects and the interaction between EPO and peripheral levels on BDNF need to be further elucidated in human studies including a broad range of biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00916552. PMID- 26011426 TI - Severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. AB - Aplastic anemia in the neonate is rare. We report a case of severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. This report highlights the importance of considering SCID early in the evaluation of neonatal aplastic anemia prior to the development of infectious complications. PMID- 26011427 TI - Efficacy of a Multi-level Intervention to Reduce Injecting and Sexual Risk Behaviors among HIV-Infected People Who Inject Drugs in Vietnam: A Four-Arm Randomized Controlled Trial. AB - INTRODUCTION: Injecting drug use is a primary driver of HIV epidemics in many countries. People who inject drugs (PWID) and are HIV infected are often doubly stigmatized and many encounter difficulties reducing risk behaviors. Prevention interventions for HIV-infected PWID that provide enhanced support at the individual, family, and community level to facilitate risk-reduction are needed. METHODS: 455 HIV-infected PWID and 355 of their HIV negative injecting network members living in 32 sub-districts in Thai Nguyen Province were enrolled. We conducted a two-stage randomization: First, sub-districts were randomized to either a community video screening and house-to-house visits or standard of care educational pamphlets. Second, within each sub-district, participants were randomized to receive either enhanced individual level post-test counseling and group support sessions or standard of care HIV testing and counseling. This resulted in four arms: 1) standard of care; 2) community level intervention; 3) individual level intervention; and 4) community plus individual intervention. Follow-up was conducted at 6, 12, 18, and 24 months. Primary outcomes were self reported HIV injecting and sexual risk behaviors. Secondary outcomes included HIV incidence among HIV negative network members. RESULTS: Fewer participants reported sharing injecting equipment and unprotected sex from baseline to 24 months in all arms (77% to 4% and 24% to 5% respectively). There were no significant differences at the 24-month visit among the 4 arms (Wald = 3.40 (3 df); p = 0.33; Wald = 6.73 (3 df); p = 0.08). There were a total of 4 HIV seroconversions over 24 months with no significant difference between intervention and control arms. DISCUSSION: Understanding the mechanisms through which all arms, particularly the control arm, demonstrated both low risk behaviors and low HIV incidence has important implications for policy and prevention programming. TRIAL REGISTRATION: ClinicalTrials.gov NCT01689545. PMID- 26011428 TI - Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells. AB - Malignant mesothelioma (MM) shows inactivation of the BRCA1-associated protein 1 (BAP1) gene. In this study, we found BAP1 mutations in 5 (26%) of the 19 cell lines that we established from Japanese MM patients, and examined functional differences between the WT and mutant BAP1. First, we studied the subcellular localization of BAP1, demonstrating that the WT primarily resides in the nucleus and that the mutant BAP1 is found in the cytoplasm of the cells. Transduction of the WT BAP1 vector into MM cells with homozygous deletion at the BAP1 3' side resulted in both inhibition of cell proliferation and anchorage-independent cell growth, whereas BAP1 mutants of a missense or C-terminal truncated form showed impaired growth inhibitory effects. Next, we studied how BAP1 is involved in MM cell survival after irradiation (IR), which causes DNA damage. After IR, we found that both WT and mutant BAP1 were similarly phosphorylated and phospho-BAP1 localized mainly in the nucleus. Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and transduction of the mutants as well as WT BAP1 increased BRCA1 proteins, suggesting that BAP1 may promote DNA repair partly through stabilizing BRCA1. Furthermore, using the MM cells with BAP1 deletion, we found that WT BAP1, and even a missense mutant, conferred a higher survival rate after IR compared to the control vector. Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions. PMID- 26011429 TI - The Role of Mitogen-Activated Protein (MAP) Kinase Signaling Components in the Fungal Development, Stress Response and Virulence of the Fungal Cereal Pathogen Bipolaris sorokiniana. AB - Mitogen-activated protein kinases (MAPKs) have been demonstrated to be involved in fungal development, sexual reproduction, pathogenicity and/or virulence in many filamentous plant pathogenic fungi, but genes for MAPKs in the fungal cereal pathogen Bipolaris sorokiniana have not been characterized. In this study, orthologues of three MAPK genes (CsSLT2, CsHOG1 and CsFUS3) and one MAPK kinase kinase (MAPKKK) gene (CsSTE11) were identified in the whole genome sequence of the B. sorokiniana isolate ND90Pr, and knockout mutants were generated for each of them. The ?Csfus3 and ?Csste11 mutants were defective in conidiation and formation of appressoria-like structures, showed hypersensitivity to oxidative stress and lost pathogenicity on non-wounded leaves of barley cv. Bowman. When inoculated on wounded leaves of Bowman, the ?Csfus3 and ?Csste11 mutants were reduced in virulence compared to the wild type. No morphological changes were observed in the ?Cshog1 mutants in comparison with the wild type; however, they were slightly reduced in growth under oxidative stress and were hypersensitive to hyperosmotic stress. The ?Cshog1 mutants formed normal appressoria-like structures but were reduced in virulence when inoculated on Bowman leaves. The ?Csslt2 mutants produced more vegetative hyphae, had lighter pigmentation, were more sensitive to cell wall degrading enzymes, and were reduced in virulence on Bowman leaves, although they formed normal appressoria like the wild type. Root infection assays indicated that the ?Cshog1 and ?Csslt2 mutants were able to infect barley roots while the ?Csfus3 and ?Csste11 failed to cause any symptoms. However, no significant difference in virulence was observed for ?Cshog1 mutants while ?Csslt2 mutants showed significantly reduced virulence on barley roots in comparison with the wild type. Our results indicated that all of these MAPK and MAPKKK genes are involved in the regulation of fungal development under normal and stress conditions and required for full virulence on barley plants. PMID- 26011430 TI - Measuring Health-Related Quality of Life in Strabismus: A Modification of the Adult Strabismus-20 (AS-20) Questionnaire Using Rasch Analysis. AB - PURPOSE: To evaluate the psychometric properties of the Adult Strabismus-20 (AS 20)- a health-related quality of life (HRQoL) questionnaire in adults with strabismus, and if flawed, to revise the AS-20 and its subscales creating valid measurement scales. METHODS: 584 adults (meanage, 27.5 years) with strabismus were recruited from an outpatient clinic at a South Indian tertiary eye care centre and were administered the AS-20 questionnaire.The AS-20 was translated and back translated into two Indian languages. The AS-20 and its two 10-item subscales - 'psychosocial' and 'function'were assessed separately for fit to the Rasch model, including an assessment of the rating scale, unidimensionality (by principal components analysis), measurement precision by person separation reliability, PSR, targeting, and differential item functioning (DIF; notable > 1.0 logits). RESULTS: Response categories were not used as intended, thereby, required re-organization and reducing their number from 5 to 3. The AS-20 had adequate measurement precision (PSR = 0.87) but lacked unidimensionality; however, deletion of the six multi-dimensionality causing items and an additional three misfitting items resulted in 11-item unidimensional questionnaire (AS-11). Two items failed to satisfy the model expectations in the 'psychosocial' subscale and were deleted - resulting in an 8-item unidimensional scale with adequate PSR (0.81) and targeting (0.23 logits). One item misfit in the 'function' subscale and was deleted-resulting in a 9 item Rasch-revised unidimensional subscale with acceptable PSR (0.80) and targeting (0.97 logits).None of the items displayed notable DIF by age, gender and level of education. CONCLUSIONS: The AS-11 and its two Rasch-revised subscales - 8-item psychosocial and 9-item function subscale may be more appropriate than the original AS-20 and its two 10-item subscales for use as unidimensional measures of HRQoL in adults with strabismus in India. Further work is required to establish the validity of the revised rating scale. PMID- 26011431 TI - IGF-I Signaling in Osterix-Expressing Cells Regulates Secondary Ossification Center Formation, Growth Plate Maturation, and Metaphyseal Formation During Postnatal Bone Development. AB - To investigate the role of IGF-I signaling in osterix (OSX)-expressing cells in the skeleton, we generated IGF-I receptor (IGF-IR) knockout mice ((OSX)IGF-IRKO) (floxed-IGF-IR mice * OSX promoter-driven GFP-labeled cre-recombinase [(OSX)GFPcre]), and monitored postnatal bone development. At day 2 after birth (P2), (OSX)GFP-cre was highly expressed in the osteoblasts in the bone surface of the metaphysis and in the prehypertrophic chondrocytes (PHCs) and inner layer of perichondral cells (IPCs). From P7, (OSX)GFP-cre was highly expressed in PHCs, IPCs, cartilage canals (CCs), and osteoblasts (OBs) in the epiphyseal secondary ossification center (SOC), but was only slightly expressed in the OBs in the metaphysis. Compared with the control mice, the IPC proliferation was decreased in the (OSX)IGF-IRKOs. In these mice, fewer IPCs invaded into the cartilage, resulting in delayed formation of the CC and SOC. Immunohistochemistry indicated a reduction of vessel number and lower expression of VEGF and ephrin B2 in the IPCs and SOC of (OSX)IGF-IRKOs. Quantitative real-time PCR revealed that the mRNA levels of the matrix degradation markers, MMP-9, 13 and 14, were decreased in the (OSX)IGF-IRKOs compared with the controls. The (OSX)IGF-IRKO also showed irregular morphology of the growth plate and less trabecular bone in the tibia and femur from P7 to 7 weeks, accompanied by decreased chondrocyte proliferation, altered chondrocyte differentiation, and decreased osteoblast differentiation. Our data indicate that during postnatal bone development, IGF-I signaling in OSX expressing IPCs promotes IPC proliferation and cartilage matrix degradation and increases ephrin B2 production to stimulate vascular endothelial growth factor (VEGF) expression and vascularization. These processes are required for normal CC formation in the establishment of the SOC. Moreover, IGF-I signaling in the OSX expressing PHC is required for growth plate maturation and osteoblast differentiation in the development of the metaphysis. PMID- 26011432 TI - Perfusion pressure and blood flow determine microvascular apparent viscosity. AB - NEW FINDINGS: What is the central question of this study? The aim was to evaluate the effect of perfusion pressure on blood flow in small arterioles. The hypothesis was that blood flow regulates the thickness of the red-cell-free layer and, therefore, blood flow determines blood apparent viscosity and local vascular resistance in vascular networks with limited myogenic or metabolic regulation of blood flow. What is the main finding and its importance? Reduced perfusion pressures lowered volumetric flow rates and increased local vascular resistance, due to increased blood apparent viscosity. Thus, the local vascular resistance of small arterioles with limited myogenic or metabolic regulation of blood flow, appeared to be determined by changes in blood rheology rather than blood vessel diameter. The study of blood flow regulation is important to understand and resolve pathological conditions. As blood is a complex non-Newtonian multiphase system, the foundations of blood rheological properties have been obtained mostly in viscometers. However, blood rheological behaviour in vivo depends on the concentration of red blood cells (RBCs), their mechanical properties and the RBC hydrodynamics, including RBC migration away from the vessel wall in shear flow. This migration promotes the formation of a RBC-depleted zone, or cell-free layer (CFL), which reduces the apparent viscosity of blood. We hypothesize that perfusion pressure determines blood apparent viscosity in microvessels, as shear rate affects axial migration of RBCs by influencing the CFL thickness. In this study, we analysed the effects of perfusion pressure on blood flow in individual arterioles within the rat cremaster muscle preparation. Perfusion pressures to this microvascular bed were controlled by occlusions of the iliac artery using a pressure cuff. Blood flow measurements were obtained from direct measurements of blood flow velocity profile, as well as determination of CFL thickness using intravital microscopy. Our results indicate that perfusion pressure determines shear rates and the CFL thickness and its variations. In addition, blood flow reduction increased local vascular resistance by augmenting blood apparent viscosity rather than vascular hindrance. In conclusion, blood rheology could act as an intrinsic mechanism to further limit blood flow to tissue with limited myogenic and metabolic responses at low perfusion pressures. PMID- 26011433 TI - Carbon-Centered Radical Addition to C=X Bonds for C-X Bond Formation. AB - Among various kinds of radical reactions, the addition of carbon-centered radicals to unsaturated bonds represents a powerful tool for the construction of different C-C and C-X (X = N, O, S, etc.) bonds, in which typically applied unsaturated bonds include alkenes, alkynes, imines, carbonyls, and even thiocarbonyls. When C=X bonds are utilized as the radical acceptors, reactions usually occur at the carbon position to generate a heteroatom radical, during which C-C coupling products are formed. This reaction mode has dominated this field for several decades. However, there is also another unconventional type of radical addition mode, in which carbon-centered radicals attack the heteroatom position of C=X bonds to generate carbon radicals, during which selective C-X bond formation is achieved. This reaction mode demonstrates an effective method for the construction of different C-X bonds, such as C-O, C-N, and C-S bonds. This Focus Review gives an overview of recent advances in this unconventional field. PMID- 26011434 TI - Synthesis of Novel Fluoropicolinate Herbicides by Cascade Cyclization of Fluoroalkyl Alkynylimines. AB - The cascade cyclization of fluoroalkyl alkynylimines with primary amines has been modified to allow the synthesis of 4-amino-5-fluoropicolinates. Use of N-trityl and acetal protecting groups in the cyclization precursor led to 5 fluoropyridines that were easily deprotected to picolinaldehyde derivatives for further elaboration to structures of interest as potential herbicides. This method provided access to picolinic acids with alkyl or aryl substituents at the 6-position that were previously inaccessible via cross-coupling chemistry. PMID- 26011435 TI - Development and Implementation of the Clinical Decision Support System for Patients With Cancer and Nurses' Experiences Regarding the System. AB - PURPOSE: The purpose of this study was to develop and implement the clinical decision support system (CDSS) for oncology nurses in the care of patients with cancer and to explore the nurses' experiences about the system. METHODS: The study was conducted using a mixed-methods research design with 14 nurses working at a gynecological oncology clinic at a university hospital in Turkey. FINDINGS: The nurses stated that they did not experience any problems during the implementation of the CDSS, and its usage facilitated the assessment of patients' needs and care management. CONCLUSIONS: The results indicated that the CDSS supported the nurses' decision-making process about patients' needs and preparation of individual care plans. PRACTICE IMPLICATIONS: The CDSS should be developed and implemented by the nurses working with patients with cancer. AMAC: Amac kanser hastalarinin bakimina yonelik klinik karar destek sistemi olusturmak, uygulamak (KKDS) ve sistemi kullanan hemsirelerin deneyimlerini incelemektir. YONTEM: Calisma kalitatif ve kantitatif arastirma yontemleri kullanilarak Turkiyede'ki bir universite hastanesinin jinekolojik onkoloji servisinde calisan 14 hemsire ile yurutulmustur. BULGULAR: Hemsireler KKDS'ni kullanirken herhangi bir sorun yasamadiklarini ve sistemin hasta gereksinimlerini degerlendirmeyi ve bakim yonetimini kolaylastirdigini belirtmislerdir. SONUC: Bulgular hastanin gereksinimlerine karar verme surecinde ve bireysel bakim planlari hazirlamada KKDS'nin hemsireleri destekledigini gostermektedir. HEMSIRELIK UYGULAMALARI ICIN ONERILER: Kanserli hastalarin bakimina yonelik KKDS gelistirilebilir ve hemsireler tarafindan klinikte kullanilabilir. PMID- 26011436 TI - Reactivity of persulfides toward strained bicyclo[6.1.0]nonyne derivatives: relevance to chemical tagging of proteins. AB - Persulfides are an emerging class of cysteine oxidative post-translational modification. They react with the bioconjugation reagents bicyclo[6.1.0]nonynes (BCNs) to engender thioethers and/or disulfides. This new reactivity of BCNs with a biologically important redox-signaling species efficiently interferes with the recent usage of strained cycloalkynes to specifically trap protein sulfenic acids. PMID- 26011437 TI - A novel highly differentially expressed gene in wheat endosperm associated with bread quality. AB - Analysis of gene expression in developing wheat seeds was used to identify a gene, wheat bread making (wbm), with highly differential expression (~1000 fold) in the starchy endosperm of genotypes varying in bread making quality. Several alleles differing in the 5'-upstream region (promoter) of this gene were identified, with one present only in genotypes with high levels of wbm expression. RNA-Seq analysis revealed low or no wbm expression in most genotypes but high expression (0.2-0.4% of total gene expression) in genotypes that had good bread loaf volume. The wbm gene is predicted to encode a mature protein of 48 amino acids (including four cysteine residues) not previously identified in association with wheat quality, possibly because of its small size and low frequency in the wheat gene pool. Genotypes with high wbm expression all had good bread making quality but not always good physical dough qualities. The predicted protein was sulphur rich suggesting the possibility of a contribution to bread loaf volume by supporting the crossing linking of proteins in gluten. Improved understanding of the molecular basis of differences in bread making quality may allow more rapid development of high performing genotypes with acceptable end-use properties and facilitate increased wheat production. PMID- 26011438 TI - Practical Recommendations for Robot-Assisted Treadmill Therapy (Lokomat) in Children with Cerebral Palsy: Indications, Goal Setting, and Clinical Implementation within the WHO-ICF Framework. AB - Active participation and the highest level of independence during daily living are primary goals in neurorehabilitation. Therefore, standing and walking are key factors in many rehabilitation programs. Despite inconclusive evidence considering the best application and efficacy of robotic tools in the field of pediatric neurorehabilitation, robotic technologies have been implemented to complement conventional therapies in recent years. A group of experienced therapists and physicians joined in an "expert panel." They compared their clinical application protocols, discussed recurring open questions, and developed experience-based recommendations for robot-assisted treadmill therapy (exemplified by the Lokomat, Hocoma, Volketswil, Switzerland) with a focus on children with cerebral palsy. Specific indications and therapeutic goals were defined considering the severity of motor impairments and the International Classification of Functioning, Disability and Health framework (ICF). After five meetings, consensus was found and recommendations for the implementation of robot assisted treadmill therapy including postsurgery rehabilitation were proposed. This article aims to provide a comprehensive overview on therapeutical applications in a fast developing field of medicine, where scientific evidence is still scarce. These recommendations can help physicians and therapists to plan the child's individual therapy protocol of robot-assisted treadmill therapy. PMID- 26011439 TI - Ankylosing Spondylitis patients with Type D personality have worse clinical status. AB - OBJECTIVES: Type D personality was identified as an important factor that can explain the differences in clinical outcomes in various diseases. The aim of this study is to clarify the relationships between Type D personality and clinical status of patients with Ankylosing Spondylitis (AS). METHODS: The scores of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), the Bath Ankylosing Spondylitis Functional Index (BASFI), the 36-Item Short-Form Health Survey (SF-36), and 14-item Type D Scale (DS-14) were noted. RESULTS: We found significantly higher levels of the BASDAI, the BASFI, and the SF-36 mental subscale scores in patients with Type D personalities compared to those who were Non-Type D (p < 0.05). The total DS-14 scores were found to be correlated with the scores of physical and mental subscales of SF-36, the BASDAI, the BASFI, ASDAS-CRP, and ESR (p < 0.05). In logistic regression analysis, the occurrence of Type D personality was found to be an independent predictor for disease activity of AS due to BASDAI and ASDAS ESR (p = 0.016, OR, 95% CI = 2.98,1.23-7.22; p = 0.022, OR, 95% CI = 2.78,1.16 6.63 respectively). CONCLUSIONS: Patients may over-rate self-reported measurements such as the BASDAI, BASFI, and SF-36 related to their interpersonal characteristics. Therefore, including the Type D personality, which is a stable construct in evaluating AS patients with brief and valid DS-14, may be noteworthy. PMID- 26011440 TI - Long-term follow-up of 124 patients with polymyositis and dermatomyositis: Statistical analysis of prognostic factors. AB - OBJECTIVES: The aims of this study were to clarify the long-term outcome of patients with polymyositis and dermatomyositis (PM/DM) and to elucidate prognostic factors using statistical analysis. METHODS: We enrolled patients with PM/DM who visited our department between 1990 and 2014. Diagnoses of PM/DM and clinically amyopathic DM were based on the definitions of Bohan and Peter, and Sontheimer, respectively. We also obtained clinical data, such as age of onset, sex, medications, and presence of interstitial lung disease and malignancies, as well as laboratory tests, including the values of creatine kinase, KL-6, and ferritin. The follow-up was conducted until June 2014. RESULTS: A total of 124 patients (PM: 46, DM: 78) were enrolled. The mean age of onset was 53.5 years, and females were predominant (64.5%). Overall survival rates were 93%, 86%, and 78% for 1, 5, and 10 years, respectively. The survival rates were significantly lower in patients with higher age of onset, with malignancies, and with hyperferritinemia in univariate analysis; however, multivariate analysis identified age of onset and serum ferritin as the most significant prognostic factors. CONCLUSIONS: Our study indicates that when age of onset and serum ferritin are used in combination, we can predict prognosis of patients with PM/DM. PMID- 26011441 TI - A rare case of hemorrhagic cystitis complicated with thrombocytopenia and hemophagocytic syndrome associated with BK virus, under immunosuppressive treatment of systemic lupus erythematosus. PMID- 26011442 TI - Novel monoclonal antibodies that recognize both rat and mouse phosphatidylserine/prothrombin complexes. PMID- 26011443 TI - Lupus enteritis during pregnancy: A case-based review. AB - Although the symptoms of systemic lupus erythematosus (SLE) worsen during pregnancy, few previous studies have reported lupus enteritis in pregnant women with SLE. A 29-year-old pregnant Japanese woman presented with acute abdomen. Six years before pain onset, she developed pure red cell aplasia and tested positive for anti-Ro (SS-A) and anti-La (SS-B) antibodies. Anti-DNA antibodies were detected two and a half years later. The patient remained asymptomatic until she developed acute abdomen. A mild increase in anti-DNA antibody levels and a mild decrease in complement levels were observed, and abdominal ultrasound and magnetic resonance imaging revealed the presence of large-volume ascites and edematous thickening of the small intestinal wall. These findings established the diagnosis of lupus enteritis. Her condition improved after treatment with prednisolone 50 mg/day, and she delivered a female infant weighing approximately 1810 g at 37 weeks of gestation. Our study suggests that lupus enteritis should be suspected in female patients with autoimmune disease who develop acute abdomen during pregnancy, and that magnetic resonance imaging is useful in its diagnosis. PMID- 26011444 TI - Examination criteria and calibration procedures for prevention trials of the Early Childhood Caries Collaborating Centers. AB - OBJECTIVES: To summarize diagnostic criteria and examiner training and calibration of the National Institute of Dental and Craniofacial Research-funded Early Childhood Caries Collaborating Centers (EC4) and report examiner calibration results from 2010 to 2014. The EC4 at Boston University, University of Colorado, and University of California San Francisco are performing randomized controlled early childhood caries (ECC) prevention trials with caries as the main outcome measure. METHODS: The EC4 with University of Iowa consultants developed standardized tooth and tooth surface status examination criteria for use in field conditions, examiner training materials, and examiner calibration and re calibration methodologies. Calibration and re-calibration were performed with 1- to 5-year-old children in the San Francisco Mission District in which assessments from each examiner to be calibrated were compared with those from a single gold standard examiner from 2010 to 2014. Cohen's kappa statistic was used to determine inter-examiner agreement. RESULTS: A total of seven examiners were successfully (re)calibrated during that period, examining a total of 231 children. Overall unweighted Cohen's kappas for 10 surface conditions exceeded the criterion of 0.70. However, separate agreement for assessment of noncavitated lesions, as in other studies, was lower. CONCLUSIONS: An experienced multidisciplinary and multi-institutional team was able to develop criteria and training materials to anticipate situations and field conditions the main trials would encounter. Examiners were successfully trained and (re)calibrated. PMID- 26011445 TI - Distribution of citrate and citrate infusion rate during donor plasmaphereses. AB - BACKGROUND: The purpose of this study was to describe the distribution of trisodium-citrate 4% (TSC) anticoagulant (AC) between the product and the donors undergoing plasma donation. SUBJECTS AND METHODS: Data of 32 regular donors of plasma initially collected for a study published in 2010 were re-analyzed to determine the amount of citrate received by the donor and the citrate infusion rate (CIR) in mg/kg/min to the donor. Donor plasmaphereses (DP) were performed with the automated Haemonetics plasma collecting system 2 (PCS2). Plasma volume was programmed at 760 ml including AC. CIR was calculated from citrate received by the donors divided by the body weight over time. RESULTS: 130 +/- 12 ml TSC was used for 760 ml plasma. An average of 110 ml TSC or 84.6% of citrate load was in collected plasma and not given to the donor. From the difference of 20 ml or 514 mg citrate an average CIR of 0.16 mg/kg/min was calculated. CONCLUSION: The total amount of citrate received by the donor is minimal and the average CIR is below the critical level of 1 mg/kg/min. PMID- 26011446 TI - Comparison of eotaxin-3 biomarker in patients with eosinophilic oesophagitis, proton pump inhibitor-responsive oesophageal eosinophilia and gastro-oesophageal reflux disease. AB - BACKGROUND: Proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) is a recently described entity which resembles oeosinophilic oesophagitis (EoE), yet responds to acid suppressive treatment. AIM: To determine whether EoE shares similar staining features with PPI-REE or with gastro-oesophageal reflux disease (GERD). METHODS: This retrospective study consisted of patients with an established diagnosis of EoE, PPI-REE, or GERD identified from a database during a 1-year period. Immunohistochemistry (IHC) analysis was performed specifically targeting eotaxin-3 antibodies. All sections were qualitatively (intensity) and quantitatively (percentage of cells stained) assessed independently by two blinded pathologists. RESULTS: The cohort consisted of three groups of patients: EoE (n = 22), PPI-REE (n = 23) and GERD (n = 23) for a total of 68 patients. Study demographics included mean age 39 (14) years, 75% male and 77% Caucasian. There was a significant difference in the eotaxin-3 staining among EoE, PPI-REE and GERD groups [mean score (s.d.): 1.2 (1.2), 0.8 (1.0), 0.3 (0.7), P = 0.006]. Staining scores of EoE patients were significantly higher compared with GERD (P = 0.002) and a trend towards significance was seen between EoE and PPI-REE (P = 0.054). There was also a significant difference in EoE staining intensity score among the three groups (P = 0.006). Intensity scores of EoE were significantly higher compared with GERD [1.0 (0.9) vs. 0.22 (0.52), P < 0.001]. There was no significant difference between EoE and PPI-REE groups [1.0 (0.0) vs. 0.52 (0.75) P = 0.094]. CONCLUSIONS: A difference in eotaxin-3 staining was seen in the three groups of patients with oesophageal eosinophilia. Eotaxin-3 can distinguish EoE from GERD, but not from proton pump inhibitor responsive-oesophageal eosinophilia. PMID- 26011447 TI - Oxidative Stress and Nano-Toxicity Induced by TiO2 and ZnO on WAG Cell Line. AB - Metallic nanoparticles are widely used in cosmetics, food products and textile industry. These particles are known to cause respiratory toxicity and epithelial inflammation. They are eventually released to aquatic environment necessitating toxicity studies in cells from respiratory organs of aquatic organisms. Hence, we have developed and characterized a new cell line, WAG, from gill tissue of Wallago attu for toxicity assessment of TiO2 and ZnO nanoparticles. The efficacy of the cell line as an in vitro system for nanoparticles toxicity studies was established using electron microscopy, cytotoxicity assays, genotoxicity assays and oxidative stress biomarkers. Results obtained with MTT assay, neutral red uptake assay and lactate dehydrogenase assay showed acute toxicity to WAG cells with IC50 values of 25.29 +/- 0.12, 34.99 +/- 0.09 and 35.06 +/- 0.09 mg/l for TiO2 and 5.716 +/- 0.1, 3.160 +/- 0.1 and 5.57 +/- 0.12 mg/l for ZnO treatment respectively. The physicochemical properties and size distribution of nanoparticles were characterized using electron microscopy with integrated energy dispersive X-ray spectroscopy and Zetasizer. Dose dependent increase in DNA damage, lipid peroxidation and protein carbonylation along with a significant decrease in activity of Superoxide Dismutase, Catalase, total Glutathione levels and total antioxidant capacity with increasing concentration of exposed nanoparticles indicated that the cells were under oxidative stress. The study established WAG cell line as an in vitro system to study toxicity mechanisms of nanoparticles on aquatic organisms. PMID- 26011448 TI - Reconstruction with modular hemipelvic endoprosthesis after pelvic tumor resection: a report of 50 consecutive cases. AB - PURPOSE: To evaluate the effectiveness of reconstruction with a modular hemipelvic endoprosthesis after pelvic tumor resection. METHODS: We retrospectively studied 50 consecutive patients diagnosed with pelvic tumor from 2003 to 2013. All patients received limb-salvage surgery and reconstruction with modular hemipelvic endoprosthesis. RESULTS: Patients were followed for an average of 54 months. At the most recent follow-up, 32 patients were alive with an estimated three-year and five-year survival rate of 66.3% and 57.5% according to the Kaplan-Meier survival analysis. Eighteen patients died from the tumor, with a mean survival of 28 months, and 9 patients experienced local recurrence at an average of 19.6 months after surgery. Patients with marginal or intracapsular surgical margins had a significantly higher recurrence rate than those with wide margins (p=0.02). Metastasis occurred in 12 cases at an average of 16 months after surgery. The perioperative complication rate was 48.0%, and the most common complications were wound healing disturbance (28.0%) and deep infection (14.0%). The endoprosthetic complication rate was 16.0%, and breakage of the pubic connection plate was the most common complication. The mean Musculoskeletal Tumor Society score was 61.4%. CONCLUSION: Reconstruction with a modular hemipelvic endoprosthesis after pelvic tumor resection can improve function, with an acceptable complication rate. PMID- 26011449 TI - Src Family Kinases (SFK) Mediate Angiotensin II-Induced Myosin Light Chain Phosphorylation and Hypertension. AB - Angiotensin (Ang) II is the major bioactive peptide of the renin-angiotensin system (RAS); it contributes to the pathogenesis of hypertension by inducing vascular contraction and adverse remodeling, thus elevated peripheral resistance. Ang II also activates Src family kinases (SFK) in the vascular system, which has been implicated in cell proliferation and migration. However, the role of SFK in Ang II-induced hypertension is largely unknown. In this study, we found that administration of a SFK inhibitor SU6656 markedly lowered the level of systemic BP in Ang II-treated mice, which was associated with an attenuated phosphorylation of the smooth-muscle myosin-light-chain (MLC) in the mesenteric resistant arteries. In the cultured human coronary artery smooth muscle cells (SMCs), pretreatment with SU6656 blocked Ang II-induced MLC phosphorylation and contraction. These results for the first time demonstrate that SFK directly regulate vascular contractile machinery to influence BP. Thus our study provides an additional mechanistic link between Ang II and vasoconstriction via SFK enhanced MLC phosphorylation in SMCs, and suggests that targeted inhibition of Src may provide a new therapeutic opportunity in the treatment of hypertension. PMID- 26011450 TI - Correction: source apportionment and risk assessment of emerging contaminants: an approach of pharmaco-signature in water systems. PMID- 26011451 TI - Decreased FOXD3 Expression Is Associated with Poor Prognosis in Patients with High-Grade Gliomas. AB - BACKGROUND: The transcription factor forkhead box D3 (FOXD3) plays important roles in the development of neural crest and has been shown to suppress the development of various cancers. However, the expression and its potential biological roles of FOXD3 in high-grade gliomas (HGGs) remain unknown. METHODS: The mRNA and protein expression levels of FOXD3 were examined using real-time quantitative PCR and western blotting in 23 HGG and 13 normal brain samples, respectively. Immunohistochemistry was used to validate the expression FOXD3 protein in 184 HGG cases. The association between FOXD3 expression and the prognosis of HGG patients were analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. In addition, we further examined the effects of FOXD3 on the proliferation and serum starvation-induced apoptosis of glioma cells. RESULTS: In comparison to normal brain tissues, FOXD3 expression was significantly decreased in HGG tissues at both mRNA and protein levels. Immunohistochemistry further validated the expression of FOXD3 in HGG tissues. Moreover, low FOXD3 expression was significantly associated with poor prognosis in HGG patients. Depletion of FOXD3 expression promoted glioma cell proliferation and inhibited serum starvation-induced apoptosis, whereas overexpression of FOXD3 inhibited glioma cell proliferation and promoted serum starvation-induced apoptosis. CONCLUSIONS: Our results indicated that FOXD3 might serve as an independent prognostic biomarker and a potential therapeutic target for HGGs, which warrant further investigation. PMID- 26011454 TI - Obstetric anal sphincter injury: the changing landscape. PMID- 26011455 TI - Labour should be induced at term: AGAINST: No proof of benefit. PMID- 26011456 TI - Labour should be induced at term: FOR: The balance of risks versus benefits favours offering term induction to all women. PMID- 26011457 TI - 150 years in pursuit of optimal pain relief during labour. PMID- 26011458 TI - Vitamin D supplementation should be routine in pregnancy: AGAINST: Proven benefits of vitamin D supplementation remain elusive. PMID- 26011459 TI - Vitamin D supplementation should be routine in pregnancy: FOR: Recent research supports routine vitamin D supplementation in pregnancy. PMID- 26011460 TI - Re: Caesarean section should be available on request. PMID- 26011461 TI - Author's reply re: Caesarean section should be available on request. PMID- 26011462 TI - Authors' reply re: Caesarean section should be available on request. PMID- 26011463 TI - Author's reply re: The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. PMID- 26011464 TI - Re: The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. PMID- 26011465 TI - Effect of androgen deprivation on the expression of aquaporins in rat prostate and seminal vesicles. AB - The aim of this study was to investigate the level of secretions of prostate and seminal vesicles and its association with the expression of AQP0, 1, 4, 5, 6 and 8 in castrated rats. Eight-week-old male Sprague-Dawley (SD) rats (n = 18) were randomly divided into control group, castrated rats group and castrated followed testosterone replacement group. Four weeks after surgery, the secretions and expression of AQP0, 1, 4, 5, 6 and 8 of prostate and seminal vesicles were determined. Serum testosterone was significantly lower in castrated groups than in control and testosterone replacement groups (P < 0.05). The level of prostate and seminal vesicle secretions and the expressions of AQP0, 1, 4, 5, 6 and 8 in prostate and seminal vesicles were significantly lower in castrated group than in control and castrated followed testosterone replacement groups (P < 0.05). The decreased prostatic and seminal vesicle secretions in castrated rats may be related to the decrease in AQP0, 1, 4, 5, 6 and 8 in prostatic tissue and seminal vesicles. PMID- 26011466 TI - Methods and Mechanisms for Cross-Electrophile Coupling of Csp(2) Halides with Alkyl Electrophiles. AB - Cross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C-H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions. Although the coupling of two different electrophiles under reducing conditions often leads primarily to symmetric dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop. A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addition to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C-C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain. Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form beta-aryl alcohols, and coupling of benzyl sulfonate esters with aryl halides to form diarylmethanes. Arylnickel(II) intermediates can insert carbon monoxide to form acylnickel(II) intermediates that react with alkyl halides to form ketones, demonstrating the connection between the mechanisms of reactions of aryl halides and acid chlorides with alkyl halides. The low reactivity of epoxides with nickel can be overcome by the use of either titanium or iodide cocatalysis to facilitate radical generation and this can also be extended to enantioselective arylation of meso-epoxides. The high reactivity of benzyl bromide with nickel, which leads to the formation of bibenzyl in attempted reactions with bromobenzene, can be overcome by using a benzyl mesylate along with cobalt phthalocyanine cocatalysis to convert the mesylate into an alkyl radical. PMID- 26011467 TI - Bivalirudin is associated with improved clinical and economic outcomes in heart failure patients undergoing percutaneous coronary intervention: Results from an observational database. AB - BACKGROUND: Outcomes with bivalirudin compare favorably with heparin +/- GPIIb/IIIa receptor inhibition (heparin +/- GPI) during percutaneous coronary intervention (PCI). Patients with congestive heart failure (CHF) have increased risk for complications. The objective was to investigate clinical and economic outcomes for bivalirudin +/- GPI vs. heparin +/- GPI among PCI patients with CHF. METHODS: Using the Premier Hospital Database, PCI patients with CHF were stratified by anticoagulant: bivalirudin, bivalirudin +/- GPI, heparin and heparin +/- GPI. The probability of receiving bivalirudin +/- GPI was estimated using individual and hospital variables. Using propensity scores, each bivalirudin +/- GPI patient was matched to a heparin +/- GPI patient. The primary outcome was in-hospital death. Bleeding rates, transfusion, length of stay and in hospital cost were ascertained. RESULTS: Overall, 116,313 patients at 315 hospitals received bivalirudin (n = 45,559) bivalirudin + GPI (n = 8,115), heparin (n = 27,972) or heparin + GPI (n = 34,667). Patients had STEMI (21.2%), NSTEMI (29.1%), unstable angina (16.6%), stable angina (5.7%) or other ischemic heart disease (24.2%). Of these, 79.1% of bivalirudin patients matched, resulting in 84,948 analyzed patients. Compared with heparin +/- GPI patients, bivalirudin +/- GPI patients had fewer deaths (3.3% vs. 3.9%; p < 0.0001), less clinically apparent bleeding (10.2% vs. 11.4%; p < 0.0001), clinically apparent bleeding with transfusion (2.7% vs. 3.2%, p <0.0001), and transfusion (8.5% vs. 9.8%, p < 0.0001). Patients receiving bivalirudin had shorter length of stay (6.3 vs. 6.8 days; p < 0.0001) and lower in-hospital cost (mean $26,706 vs. $27,166 [median $19,414 vs. $19,798]; p < 0.0001). In conclusion, this is the largest retrospective analysis of PCI patients with CHF and demonstrates bivalirudin +/- GPI compared with heparin +/- GPI is associated with lower inpatient rates of death, bleeding, and cost. PMID- 26011468 TI - Study of the relationship between mononuclear inflammatory infiltrate and Ki-67 and basement membrane and extracellular matrix protein expression in radicular cysts. AB - AIM: To evaluate the relationship between mononuclear inflammatory infiltrate and the expression of a proliferative immunomarker (Ki-67) as well as to evaluate basement membrane and extracellular matrix proteins (laminin and collagen type IV) in radicular cysts and dentigerous cysts (DC). METHODOLOGY: Immunohistochemical analyses were performed in heavily inflamed radicular cysts (HIRC), slightly inflamed radicular cysts (SIRC) and DC (n = 20) using Ki-67 (Dako((r)) , 1 : 50), anticollagen type IV (DBS((r)) , 1 : 40) and antilaminin (DBS((r)) , 1 : 20). The data were analysed using anova/Tukey's test (Ki-67) and Kruskal-Wallis/Dunn's test (collagen type IV and laminin) (P < 0.05). RESULTS: The immunoexpression of Ki-67 was significantly greater in the SIRC group compared with the HIRC and DC (P = 0.0040). Likewise, the immunoexpression of collagen type IV in the basement membrane of the SIRC group was significantly more continuous (P = 0.0475) than in the HIRC group. DC had significantly less collagen type IV in extracellular matrix immunoexpression than HIRC and SIRC (P = 0.0246). Laminin was absent in the basement membrane in the SIRC and DC groups, and the extracellular matrix of the HIRC was weak and punctate. CONCLUSION: The presence of inflammatory factors in the radicular cyst wall modified the expression of proliferation factors in the epithelial lining and the expression of collagen type IV and laminin in the basement membrane, but did not modify extracellular matrix behaviour in radicular cysts. PMID- 26011471 TI - Comparison of Atomic Force Microscopy and Scanning Ion Conductance Microscopy for Live Cell Imaging. AB - Atomic force microscopy (AFM) and scanning ion conductance microscopy (SICM) are excellent and commonly used techniques for imaging the topography of living cells with high resolution. We present a direct comparison of AFM and SICM for imaging microvilli, which are small features on the surface of living cells, and for imaging the shape of whole cells. The imaging quality on microvilli increased significantly after cell fixation for AFM, whereas for SICM it remained constant. The apparent shape of whole cells in the case of AFM depended on the imaging force, which deformed the cell. In the case of SICM, cell deformations were avoided, owing to the contact-free imaging mechanism. We estimated that the lateral resolution on living cells is limited by the cell's elastic modulus for AFM, while it is not for SICM. By long-term, time-lapse imaging of microvilli dynamics, we showed that the imaging quality decreased with time for AFM, while it remained constant for SICM. PMID- 26011470 TI - Efficient synthesis of deuterium labeled hydroxyzine and aripiprazole. AB - Hydroxyzine and aripiprazole are active pharmaceutical ingredients that have been largely acknowledged for their antipsychotic properties. Deuterium labeled isotopes of hydroxyzine and aripiprazole are internal standards that can aid in the further research of non-isotopic forms via quantification analysis using HPLC MS/MS. The synthesis of hydroxyzine-d8 was accomplished by coupling piperazine-d8 with 4-chlorobenzhydryl chloride followed by the reaction of the first intermediate with 2-(2-chloroethoxy) ethanol to afford 11.7% of hydroxyzine-d8 with 99.5% purity. The synthesis of aripiprazole-d8 was also achieved in two steps. 1,4-Dibromobutane-d8 reacted with 7-hydroxy-3,4-dihydro-2(1H)-quinolinone. The first intermediate was then coupled with 1-(2, 3-dichlorophenyl)piperazine hydrochloride to produce 33.4% of aripiprazole-d8 with 99.93% purity. PMID- 26011469 TI - A Cluster of Proteins Implicated in Kidney Disease Is Increased in High-Density Lipoprotein Isolated from Hemodialysis Subjects. AB - Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) patients treated with hemodialysis. An important contributor might be a decline in the cardioprotective effects of high-density lipoprotein (HDL). One important factor affecting HDL's cardioprotective properties may involve the alterations of protein composition in HDL. In the current study, we used complementary proteomics approaches to detect and quantify relative levels of proteins in HDL isolated from control and ESRD subjects. Shotgun proteomics analysis of HDL isolated from 20 control and 40 ESRD subjects identified 63 proteins in HDL. Targeted quantitative proteomics by isotope-dilution selective reaction monitoring revealed that 22 proteins were significantly enriched and 6 proteins were significantly decreased in ESRD patients. Strikingly, six proteins implicated in renal disease, including B2M, CST3, and PTGDS, were markedly increased in HDL of uremic subjects. Moreover, several of these proteins (SAA1, apoC-III, PON1, etc.) have been associated with atherosclerosis. Our observations indicate that the HDL proteome is extensively remodeled in uremic subjects. Alterations of the protein cargo of HDL might impact HDL's proposed cardioprotective properties. Quantifying proteins in HDL may be useful in the assessment of cardiovascular risk in patients with ESRD and in assessing response to therapeutic interventions. PMID- 26011473 TI - Ketogenic diet exhibits anti-inflammatory properties. AB - The ketogenic diet (KD) is an established treatment for refractory epilepsy, including some inflammation-induced epileptic encephalopathies. In a lipopolysaccharide (LPS)-induced fever model in rats, we found that animals given the KD for 14 days showed less fever and lower proinflammatory cytokine levels than control animals. However, KD rats exhibited a decrease in circulating levels of arachidonic acid and long-chain n-3 polyunsaturated fatty acids (PUFAs), suggesting that the anti-inflammatory effect of KD was probably not due to an increase in anti-inflammatory n-3 PUFA derivatives. These properties might be of interest in some conditions such as fever-induced refractory epileptic encephalopathy in school-aged children. PMID- 26011475 TI - The Receptor for the CD200 Tolerance-Signaling Molecule Associated with Successful Pregnancy is Expressed by Early-Stage Breast Cancer Cells in 80% of Patients and by Term Placental Trophoblasts. AB - PROBLEM: The CD200 tolerance-signaling molecule that is expressed by a wide variety of tissues, including placental trophoblast and epithelial tumor cells, lacks an intracytoplasmic tail and must act by binding to CD200 receptors that have a limited expression on lymphomyeloid cells. This binding can inhibit inflammation and NK cells, promote macrophage secretion of indoleamine-2,3 dioxygenase (IDO), and promote generation of Treg cells. Recently, CD200R1 was reported on human first trimester placental villous trophoblast cells. CD200R1 has not been described on malignant tumor cells. As malignant tumor cells exhibit a number of characteristics of trophoblast, is CD200R1 expressed? METHOD OF STUDY: Affinity-purified rabbit polyclonal antibodies to CD200 and CD200R1 were used to immunostain tissue blocks available from cases in a previous cross sectional study of Stage 1-IIIA human breast cancer cases and term placental trophoblast. RESULTS: Affinity-purified anti-CD200R1 stained primary breast cancer cells and term placental villous trophoblasts. Tumor cells were also stained by anti-CD200 as in a previous study (correlation P = 0.0042), but CD200R1 and CD200 were not correlated. Presence or absence of strong CD200 expression in the tumor did not correlate with metastasis, and a similar result was obtained with CD200R1. CONCLUSIONS: This is the first report of CD200R1 expression by human epithelial tumor cells, and specifically, early-stage human breast cancer cells. It is also the first report of CD200R1 expression by term placental villous trophoblasts. The potential biological significance of CD200R1 expression in non-hematopoietic cells is discussed. PMID- 26011474 TI - Bar-HRM for Authentication of Plant-Based Medicines: Evaluation of Three Medicinal Products Derived from Acanthaceae Species. AB - Medicinal plants are used as a popular alternative to synthetic drugs, both in developed and developing countries. The economic importance of the herbal and natural supplement industry is increasing every year. As the herbal industry grows, consumer safety is one issue that cannot be overlooked. Herbal products in Thai local markets are commonly sold without packaging or labels. Plant powders are stored in large bags or boxes, and therefore buying local herbal products poses a high risk of acquiring counterfeited, substituted and/or adulterated products. Due to these issues, a reliable method to authenticate products is needed. Here DNA barcoding was used in combination with High Resolution Melting analysis (Bar-HRM) to authenticate three medicinal Acanthaceae species (Acanthus ebracteatus, Andrographis paniculata and Rhinacanthus nasutus) commonly used in Thailand. The rbcL barcode was selected for use in primers design for HRM analysis to produce standard melting profiles of the selected species. Melting data from the HRM assay using the designed rbcL primers showed that the three chosen species could be distinguished from each other. HRM curves of all fifteen test samples indicated that three of tested products did not contain the indicated species. Two closely related species (A. paniculata and R. nasutus), which have a high level of morphological similarity, were interchanged with one another in three tested products. Incorrect information on packaging and labels of the tested herbal products was the cause of the results shown here. Morphological similarity among the species of interest also hindered the collection process. The Bar-HRM method developed here proved useful in aiding in the identification and authentication of herbal species in processed samples. In the future, species authentication through Bar-HRM could be used to promote consumer trust, as well as raising the quality of herbal products. PMID- 26011476 TI - Parent and teacher ratings of attention-deficit/hyperactivity disorder symptoms: Factor structure and normative data. AB - Comprehensive assessment of attention-deficit/hyperactivity disorder (ADHD) symptoms includes parent and teacher questionnaires. The ADHD Rating Scale-5 was developed to incorporate changes for the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013). This study examined the fit of a correlated, 2-factor structure of ADHD (i.e., DSM-5 conceptual model) and alternative models; determined whether ADHD symptom ratings varied across teacher and child demographic characteristics; and presented normative data. Two samples were included: (a) 2,079 parents and guardians (1,131 female, 948 male) completed ADHD symptom ratings for children (N = 2,079; 1,037 males, 1,042 females) between 5 and 17 years old (M = 10.68; SD = 3.75) and (b) 1,070 teachers (766 female, 304 male) completed ADHD symptom ratings for students (N = 2,140; 1,070 males, 1,070 females) between 5 and 17 years old (M = 11.53; SD = 3.54) who attended kindergarten through 12th grade. The 2-factor structure was confirmed for both parent and teacher ratings and was invariant across child gender, age, informant, informant gender, and language. In general, boys were higher in symptom frequency than girls; older children were rated lower than younger children, especially for hyperactivity-impulsivity; and non-Hispanic children were rated higher than Hispanic children. Teachers also rated non Hispanic African American children higher than non-Hispanic White, Asian, and Hispanic children. Non-Hispanic White teachers provided lower hyperactivity impulsivity ratings than non-Hispanic, African American, and Hispanic teachers. Normative data are reported separately for parent and teacher ratings by child gender and age. The merits of using the ADHD Rating Scale-5 in a multimodal assessment protocol are discussed. (PsycINFO Database Record PMID- 26011477 TI - Initial development of a treatment adherence measure for cognitive-behavioral therapy for child anxiety. AB - The measurement of treatment adherence (a component of treatment integrity defined as the extent to which a treatment is delivered as intended) is a critical element in treatment evaluation research. This article presents initial psychometric data for scores on the Cognitive-Behavioral Therapy Adherence Scale for Youth Anxiety (CBAY-A), an observational measure designed to be sensitive to common practice elements found in individual cognitive-behavioral therapy (ICBT) for youth anxiety. Therapy sessions (N = 954) from 1 efficacy and 1 effectiveness study of ICBT for youth anxiety were independently rated by 2 coders. Interrater reliability (as gauged by intraclass correlation coefficients) for the item scores averaged 0.77 (SD = 0.15; range .48 to .80). The CBAY-A item and scale (skills, model, total) scores demonstrated evidence of convergent and discriminant validity with an observational measure of therapeutic interventions and an observational measure of the alliance. The CBAY-A item and scale scores also discriminated between therapists delivering ICBT in research and practice settings and therapists delivering nonmanualized usual clinical care. We discuss the importance of replicating these psychometric findings in different samples and highlight possible application of an adherence measure in testing integrity outcome relations. PMID- 26011478 TI - Development of a brief version of the Pathological Narcissism Inventory. AB - With theoretical and empirical interest in narcissism growing, there is a need for brief measures of pathological narcissism that can be used more practically while assessing the construct comprehensively. Data from four samples (total N = 3,851) collected across two separate research groups and representing undergraduate, community, and clinical populations were used to establish the reliability, validity, and utility of the Brief-Pathological Narcissism Inventory (B-PNI). Item response theory and confirmatory factor analyses were used to determine the best-performing 28 items from the original PNI and ensure that the B-PNI exhibited a factor structure consistent with the original PNI. Items were retained for all seven pathological narcissism facet scales. Additional results also support the criterion validity of the B-PNI, suggesting that it can be used in place of the original PNI to assess the various facets of pathological narcissism effectively and without loss of information, which may enhance the ability of researchers to investigate pathological narcissism in future work. PMID- 26011479 TI - Evaluating the prevalence and impact of examiner errors on the Wechsler scales of intelligence: A meta-analysis. AB - The purpose of the present investigation was to conduct a meta-analysis of the literature on examiner errors for the Wechsler scales of intelligence. Results indicate that a mean of 99.7% of protocols contained at least 1 examiner error when studies that included a failure to record examinee responses as an error were combined and a mean of 41.2% of protocols contained at least 1 examiner error when studies that ignored errors of omission were combined. Furthermore, graduate student examiners were significantly more likely to make at least 1 error on Wechsler intelligence test protocols than psychologists. However, psychologists made significantly more errors per protocol than graduate student examiners regardless of the inclusion or exclusion of failure to record examinee responses as errors. On average, 73.1% of Full-Scale IQ (FSIQ) scores changed as a result of examiner errors, whereas 15.8%-77.3% of scores on the Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index changed as a result of examiner errors. In addition, results suggest that examiners tend to overestimate FSIQ scores and underestimate VCI scores. However, no strong pattern emerged for the PRI and WMI. It can be concluded that examiner errors occur frequently and impact index and FSIQ scores. Consequently, current estimates for the standard error of measurement of popular IQ tests may not adequately capture the variance due to the examiner. PMID- 26011481 TI - Factor structure and validity of the State-Trait Inventory for Cognitive and Somatic Anxiety. AB - The State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA; Ree, French, MacLeod, & Locke, 2008) is a relatively new measure of anxiety. The current research investigated the factor structure and reliability of scores on the STICSA and the validity of the interpretation of STICSA scores in a sample of undergraduate students. Participants completed a battery of self-report questionnaires online, including measures of anxiety, depression, affect, and social desirability. Scores on the 4 subscales of the STICSA-Trait Cognitive, Trait Somatic, State Cognitive, and State Somatic-exhibited good internal consistencies (alphas >= .92). Results of a confirmatory factor analysis provided support for a hierarchical model of the STICSA including a global anxiety factor plus 4 specific factors corresponding to the STICSA subscales. Support was also found for a four-factor model, with factors corresponding to the STICSA subscales. Pearson product-moment correlations with other measures of anxiety provided evidence of the convergent validity of the interpretation of STICSA scores, and Pearson product-moment correlations with measures of depression and affect provided evidence of the divergent validity of the interpretation of STICSA scores. The STICSA is the only existing self-report anxiety measure that contains scales measuring state and trait anxiety as well as cognitive and somatic anxiety. Comparisons between the convergent and divergent validity of test score interpretations of the STICSA and the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1983) revealed that the STICSA has better convergent validity with measures of somatic anxiety and better divergent validity with measures of depression and affect. (PsycINFO Database Record PMID- 26011480 TI - Cultural and linguistic adaptability of the Rorschach Performance Assessment System as a measure of psychotic characteristics and severity of mental disturbance in Taiwan. AB - This study investigated the cultural and linguistic adaptability of the Rorschach Performance Assessment System (R-PAS), a new Rorschach administration, scoring, and interpretation system that minimizes psychometric weaknesses of the Comprehensive System (CS). This investigation addressed the validity of R-PAS measures of psychotic characteristics and psychopathology severity in Taiwan, including the incremental validity of the R-PAS relative to the CS variables measuring the same constructs. Ninety Taiwanese individuals (75 psychiatric patients and 15 nonpatients) were tested with standard R-PAS administration and scoring. Two non-Rorschach severity of disturbance measures and 2 psychosis measures served as independent criterion measures. The R-PAS measures were found to be valid in Taiwan in assessing psychotic symptoms and psychopathology severity, thus demonstrating cultural and linguistic adaptability. Moreover, hierarchical regression analyses demonstrated incremental validity for the R-PAS variables over their CS counterparts, providing support that the R-PAS revisions enhance the test psychometrically. These research findings also demonstrate the viability of the R-PAS as a Rorschach system that can be effectively employed outside the U.S. in a different language and culture. PMID- 26011482 TI - Cognitive ability, acquiescence, and the structure of personality in a sample of older adults. AB - Acquiescence, or the tendency to respond to descriptions of conceptually distinct personality attributes with agreement/affirmation, constitutes a major challenge in personality assessment. The aim of this study was to shed light on cognitive ability as a potential source of individual differences in acquiescent responding. We hypothesized that respondents with lower cognitive ability exhibit stronger acquiescent response tendencies than respondents with higher cognitive ability and that this leads to problems in establishing the Big Five structure by means of principal component analyses (exploratory factor analysis was not applicable to these data) in the former group. Further, we hypothesized that after controlling for acquiescence by using mean-corrected instead of raw item scores, the Big Five structure holds even among respondents with lower cognitive ability. Analyses in a sample of 1,071 German adults aged 56 to 75 years using the Digit Symbol Substitution Test as a measure of cognitive ability and the BFI 10, a 10-item abbreviated version of the Big Five Inventory, as a measure of personality, corroborated these hypotheses. These findings suggest that lower cognitive ability and age-related declines in cognitive functioning more specifically are associated with higher acquiescence, which in turn leads to problems in establishing the Big Five structure among individuals with lower cognitive ability that should be addressed by controlling for acquiescence. PMID- 26011483 TI - Children's Depression Inventory: A unidimensional factor structure for American Indian and Alaskan native youth. AB - Given that American Indian and Alaskan Native (AI/AN) youth are at increased risk for a variety of depression-related outcomes and may experience depression uniquely, the fact that the factor structure of the Children's Depression Inventory (CDI; Kovacs, 1992) is unknown for these populations represents a significant obstacle. In Study 1 with an AI youth sample, we conducted confirmatory factor analyses and failed to find support for either of the 2 predominant CDI multifactor models (Craighead, Smucker, Craighead, & Ilardi, 1998; Kovacs, 1992). In subsequent exploratory structural equation modeling, we found the most support for a unidimensional factor structure. In Study 2, using confirmatory modeling with independent AI/AN youth samples, we found further support for this unidimensional model. Finally, in Study 3, we found support across AI/AN groups varying in gender and age for measurement invariance with respect to both factor structure and factor loadings. Overall, for these AI/AN youth populations, our findings support the practice of calculating total CDI scores, and they suggest a unique construction of the depression experience. PMID- 26011484 TI - Measuring the components of attention using the Dalhousie Computerized Attention Battery (DalCAB). AB - Using experimentally validated tests to measure the vigilance/alerting, orienting and executive control attention networks, we have developed a novel, theoretically driven battery for measuring attentional abilities, called the Dalhousie Computerized Attention Battery (DalCAB). The current study sought to examine the factor structure of the DalCAB as preliminary evidence for its validation as an assessment tool for the above-named attention networks. One hundred young, healthy adult participants (18 to 31 years) completed the DalCAB (simple reaction time, choice reaction time, dual task, go/no-go, visual search, vertical flanker, and item memory tasks). Exploratory factor analysis of task performance with promax rotation highlighted a 9-factor model, accounting for 54.66% of the shared variance. Factors 1, 2, and 5 are associated with measures reflecting the vigilance/alerting network (response speed, maintenance/preparation and consistency, respectively), Factor 3 is associated with the orienting network (searching measures). Factors 4, 6, 7, and 8 are associated with different aspects of the executive control network including: inhibition, working memory, filtering, and switching. The final factor is associated with vigilance/alerting (fatigue) and executive control (proactive interference). Our model provides preliminary evidence for the validation of our interpretation of the DalCAB as a measure of vigilance/alerting, orienting, and executive control attentional abilities, and contributes to the previously reported evidence for the validation of these tasks for measuring different aspects of attention. We also demonstrate the importance of each of the specific measures derived from the DalCAB tasks, and our results provide further behavioral evidence of the existence of multiple attention-related networks. PMID- 26011485 TI - Validation of the Intrinsic Spirituality Scale (ISS) with Muslims. AB - This study validates an existing spirituality measure--the intrinsic spirituality scale (ISS)--for use with Muslims in the United States. A confirmatory factor analysis was conducted with a diverse sample of self-identified Muslims (N = 281). Validity and reliability were assessed along with criterion and concurrent validity. The measurement model fit the data well, normed chi2 = 2.50, CFI = 0.99, RMSEA = 0.07, and SRMR = 0.02. All 6 items that comprise the ISS demonstrated satisfactory levels of validity (lambda > .70) and reliability (R2 > .50). The Cronbach's alpha obtained with the present sample was .93. Appropriate correlations with theoretically linked constructs demonstrated criterion and concurrent validity. The results suggest the ISS is a valid measure of spirituality in clinical settings with the rapidly growing Muslim population. The ISS may, for instance, provide an efficient screening tool to identify Muslims that are particularly likely to benefit from spiritually accommodative treatments. PMID- 26011486 TI - Gynaecological cancer: Biomarker potential of CA-125 enhanced. PMID- 26011487 TI - Targeted therapies: Notching up dormant tumour-cell deaths to avoid recurrence. PMID- 26011488 TI - Adolescent and young adult patients with cancer: a milieu of unique features. AB - Adolescent and young adult (AYA) patients with cancer are a unique category of patients who, depending on age at time of diagnosis, might receive treatment from oncologists specializing either in the treatment of children or adults. In the USA, AYA oncology generally encompasses patients 15-39 years of age. AYA patients with cancer typically present with diseases that span the spectrum from 'paediatric' cancers (such as acute lymphoblastic leukaemia [ALL] and brain tumours) to 'adult' tumours (such as breast cancer and melanoma), as well as cancers that are largely unique to their age group (such as testicular cancer and bone tumours). Research indicates that outcomes of AYA patients with cancer are influenced not only by the treatment provided, but also by factors related to 'host' biology. In addition to the potential biological and cancer-specific differences between AYAs and other patients with cancer, AYA patients also often have disparate access to clinical trials and suffer from a lack of age appropriate psychosocial support services and health services, which might influence survival as well as overall quality of life. In this Review, these issues are discussed, with a focus on two types of AYA cancer--ALL and melanoma- highlighting findings arising from the use of emerging technologies, such as whole-genome sequencing. PMID- 26011490 TI - Surgery: green light given for laparoscopic surgery for rectal cancer. PMID- 26011489 TI - Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. AB - Hormone-receptor-positive breast cancer accounts for the majority-up to 80%-of all breast cancers. The evolution of breast cancer from early stage to the metastatic setting leads to increased heterogeneity, the occurrence of new mutations, and the development of treatment resistance representing a great challenge for management decisions. Unfortunately, little data exist to offer guidance in this context, and a reliance on traditional clinical parameters remains when deciding on optimal treatment. In advanced-stage oestrogen receptor positive (ER+) disease, ongoing issues include the choice between endocrine therapy and chemotherapy, the appropriate sequence of treatment agents, and the incorporation of biological agents, such as everolimus, into the treatment armamentarium. In metastatic disease, repeated biopsies can help to reassess the receptor or genetic mutational status; however, the evidence to support this approach is limited. In this Review, we examine the current evidence that can guide treatment decisions in patients with advanced-stage ER+ breast cancer, discuss how to tackle these therapeutic challenges and provide suggestions for the optimal management of this patient population. PMID- 26011491 TI - Haematological cancer: Bortezomib in MCL--new standard of care or just another option? PMID- 26011492 TI - Tollip is a critical mediator of cerebral ischaemia-reperfusion injury. AB - Toll-like receptor (TLR) signalling plays an important role in regulating cerebral ischaemia-reperfusion (I/R) injury. Toll-interacting protein (Tollip) is an endogenous negative modulator of TLR signalling that is involved in several inflammatory diseases. Our previous study showed that Tollip inhibits overload induced cardiac remodelling. However, the role of Tollip in neurological disease remains unknown. In the present study, we proposed that Tollip might contribute to the progression of stroke and confirmed this hypothesis. We found that Tollip expression was significantly increased in I/R-challenged brain tissue of humans, mice and rats in vivo and in primary neurons subjected to oxygen and glucose deprivation in vitro, indicating the involvement of Tollip in I/R injury. Next, using genetic approaches, we revealed that Tollip deficiency protects mice against I/R injury by attenuating neuronal apoptosis and inflammation, as demonstrated by the decreased expression of pro-apoptotic and pro-inflammatory genes and the increased expression of anti-apoptotic genes. By contrast, neuron specific Tollip over-expression exerted the opposite effect. Mechanistically, the detrimental effects of Tollip on neuronal apoptosis and inflammation following I/R injury were largely mediated by the suppression of Akt signalling. Additionally, to further support our findings, a Tollip knockout rat strain was generated via CRISPR-Cas9-mediated gene inactivation. The Tollip-deficient rats were also protected from I/R injury, based on dramatic decreases in neuronal apoptosis and ischaemic inflammation through Akt activation. Taken together, our findings demonstrate that Tollip acts as a novel modulator of I/R injury by promoting neuronal apoptosis and ischaemic inflammation, which are largely mediated by suppression of Akt signalling. PMID- 26011494 TI - Determining Dosimetric Properties and Lowest Detectable Dose of Fingernail Clippings from their Electron Paramagnetic Resonance Signal. AB - The purpose of this study was to investigate the dosimetric properties and the lowest detectable dose of fingernails from their electron paramagnetic resonance signal. Fingernail clippings from 50 healthy individuals were collected, rinsed in water, and irradiated with (137)Cs gamma rays. Next, their electron paramagnetic resonance spectra were measured before and after exposure. The radiation-induced signal from the irradiated fingernails was relatively stable even after 68 d. Further, the intensity of the radiation-induced signal increased with progressive increases in the dose until saturation, while the background signal from the irradiated fingernails increased only gradually with time. The lowest detectable dose of the irradiated fingernails was 2 Gy. On the basis of these results, it can be concluded that the effect of the intrinsic signal must be taken into account during dose reconstruction. This electron paramagnetic resonance assessment method should be useful for the rapid screening of irradiated populations after nuclear accidents. PMID- 26011493 TI - The Effect of Flattening Filter Free on Three-dimensional Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT) Plans for Metastatic Brain Tumors from Non-small Cell Lung Cancer. AB - Flattening filter free (FFF) may affect outcome measures of radiotherapy. The objective of this study is to compare the dosimetric parameters in three types of radiotherapy plans, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), with or without the flattening filter (FF), developed for the treatment of metastatic brain tumors from non-small cell lung cancer (NSCLC). From July 2013 to October 2013, 3D-CRT, IMRT, and VMAT treatment plans were designed using 6 MV and 10 MV, with and without FF, for 10 patients with brain metastasis from NSCLC. The evaluation of the treatment plans included homogeneity index (HI), conformity index (CI), monitor units (MU), mean dose (Dmean), treatment time, and the influence of FFF on volumes. There was no difference in CI or HI between FFF and FF models with 3D-CRT, IMRT, and VMAT plans. At 6 MV, a lower Dmean was seen in the FFF model of 3D-CRT and in the VMAT plan at 10 MV. In the IMRT 6 MV, IMRT 10 MV, and VMAT 10 MV plans, higher MUs were seen in the FFF models. FFF treatments are similar in quality to FF plans, generally lead to more monitor units, and are associated with shorter treatment times. FFF plans ranked by the order of superiority in terms of a time advantage are VMAT, 3D-CRT, and IMRT. PMID- 26011495 TI - Radiation dose response estimation with emphasis on low dose range using restricted cubic splines: application to all solid cancer mortality data, 1950 2003, in atomic bomb survivors. AB - Using the all solid cancer mortality data set of the Life Span Study (LSS) cohort from 1950 to 2003 (LSS Report 14) data among atomic bomb survivors, excess relative risk (ERR) statistical analyses were performed using the second degree polynomial and the threshold and restricted cubic spline (RCS) dose response models. For the RCS models with 3 to 7 knots of equally spaced percentiles with margins in the dose range greater than 50 mGy, the dose response was assumed to be linear at less than 70 to 90 mGy. Due to the skewed dose distribution of atomic bomb survivors, the current knot system for the RCS analysis results in a detailed depiction of the dose response as less than approximately 0.5 Gy. The 6 knot RCS models for the all-solid cancer mortality dose response of the whole dose or less than 2 Gy were selected with the AIC model selection criterion and fit significantly better (p < 0.05) than the linear (L) model. The usual RCS includes the L-global model but not the quadratic (Q) nor linear-quadratic (LQ) global models. The authors extended the RCS to include L or LQ global models by putting L or LQ constraints on the cubic spline in the lower and upper tails, and the best RCS model selected with AIC criterion was the usual RCS with L constraints in both the lower and upper tails. The selected RCS had a linear dose response model in the lower dose range (i.e., < 0.2-0.3 Gy) and was compatible with the linear no-threshold (LNT) model in this dose range. The proposed method is also useful in describing the dose response of a specific cancer or non-cancer disease incidence/mortality. PMID- 26011496 TI - Discussion on one algorithm for mapping the radiation distribution on contaminated ground. AB - Recently, due to progressions in radiation detection systems, the capability to monitor radiation on the ground by employing detection systems high above the ground has been developed. Therefore, how to map radiation distributions on the ground based upon measured data in air is an important question. One kind of reconstructing algorithm for solving this problem is introduced in this paper. This algorithm reconstructs the radiological contamination distribution through solving the detection response factors equation set (DRFES). The study shows that the reconstructing algorithm performs well when the detection height is lower than 50 m. Through this algorithm, the ability to reconstruct the scope of contamination magnitude on the ground by using the measurement data obtained in the air has been established. The algorithm discussed in the paper has the potential to be used in emergency monitoring and nuclear decontamination. PMID- 26011497 TI - Simultaneous Source Detection and Analysis Using a Zero-inflated Count Rate Model. AB - This paper proposes a novel Bayesian technique that allows for simultaneous source detection and count rate analysis. The technique involves using priors, which include a finite probability that the source count rate is exactly zero. Such priors are called "zero-inflated." Solving the posterior distribution of a zero-inflated count rate model provides the probability that the sample contains a source and a probability distribution for the source count rate if the source exists, without the need to perform redundant computations. Sampling from zero inflated distributions is straightforward and can be accomplished with easily accessible open source software. In addition, zero-inflated priors lead to finite posterior probabilities of "no source," which is an easy-to-understand and satisfying result. PMID- 26011498 TI - HEMODOSE: A Biodosimetry Tool Based on Multi-type Blood Cell Counts. AB - Peripheral blood cell counts are important biomarkers of radiation exposure. In this work, a simplified compartmental modeling approach is applied to simulate the perturbation of the hematopoiesis system in humans after radiation exposure, and HemoDose software is reported to estimate individuals' absorbed doses based on multi-type blood cell counts. Testing with patient data in some historical accidents indicates that either single or serial granulocyte, lymphocyte, leukocyte, and platelet counts after exposure can be robust indicators of the absorbed doses. In addition, such correlation exists not only in the early time window (1 or 2 d) but also in the late phase (up to 4 wk) after exposure, when the four types of cell counts are combined for analysis. These demonstrate the capability of HemoDose as a rapid point-of-care diagnostic or centralized high throughput assay system for personnel exposed to unintended high doses of radiation, especially in large-scale nuclear/radiological disaster scenarios involving mass casualties. PMID- 26011499 TI - Comparing dose rates near a radioactive patient evaluated using various source models: point, line, cylinder, and anthropomorphic phantoms. AB - This study investigated radiation exposures from nuclear medicine patients by systematically comparing the dose rates calculated using various source models, ranging from simplified point, line, and cylinder sources to high-quality anthropomorphic phantoms. Three widely used radionuclides, (99m)Tc, (18)F, and I(131), were considered in these source models with uniform or organ-dependent distributions. Conducting Monte Carlo simulations with anthropomorphic phantoms is a realistic but time-consuming approach. The point source model is simple but too conservative, overestimating dose rates by approximately a factor of 2 at a distance of 30 cm and by 30-40% at 1 m. Both the line and cylinder source models provided improved estimates, reducing the overestimation of dose rates to 10-20% at distances of interest. The line source model was comparable to the cylinder source model because of the offset of two competing effects (i.e., attenuation and buildup) caused by the source volume. The influence of various photon energies and cylinder sizes on the result of compensating errors was examined to evaluate the effective range of the line source model. The line source model, which is relatively easy to implement and predicts slightly conservative dose rates, is considered the most practical method for calculating dose rates near radioactive patients. An application of the line source model to 51 post thyroidectomy patients in Taiwan was demonstrated. The consistency between calculations and measurements was satisfactory after considering the room scattering effect. PMID- 26011500 TI - Signal Processing and Its Effect on Scanning Efficiencies for a Field Instrument for Detecting Low-energy Radiation. AB - Signal processing within a radiation detector affects detection efficiency. Currently, organizations such as private industry, the U.S. Navy, Army, and Air Force are coupling some detector systems with data collection devices to survey large land areas for radioactive contamination. As detector technology has advanced and analog data collection has turned to digital, signal processing is becoming prevalent in some instruments. Using a NIST traceable (241)Am source, detection efficiency for a field instrument for detecting low-energy radiation (FIDLER) was examined for both a static and scanning mode. Experimental results were compared to Monte Carlo-generated efficiencies. Stationary data compared nicely to the theoretical results. Conversely, scanning detection efficiencies were considerably different from their theoretical counterparts. As speed increased, differences in detection efficiency approached two orders of magnitude. To account for these differences, a quasi time-dependent Monte Carlo simulation was created mimicking the signal processing undertaken by the FIDLER detection system. By including signal processing, experimental results fell within the bounds of the Monte Carlo-generated efficiencies, thus demonstrating the negative effects of such processing on detection efficiencies. PMID- 26011501 TI - Could Magnetic Fields Affect the Circadian Clock Function of Cryptochromes? Testing the Basic Premise of the Cryptochrome Hypothesis (ELF Magnetic Fields). AB - It has been suggested that weak 50/60 Hz [extremely low frequency (ELF)] magnetic fields (MF) could affect circadian biorhythms by disrupting the clock function of cryptochromes (the "cryptochrome hypothesis," currently under study). That hypothesis is based on the premise that weak (Earth strength) static magnetic fields affect the redox balance of cryptochromes, thus possibly their signaling state as well. An appropriate method for testing this postulate could be real time or short-term study of the circadian clock function of retinal cryptochromes under exposure to the static field intensities that elicit the largest redox changes (maximal "low field" and "high field" effects, respectively) compared to zero field. Positive results might encourage further study of the cryptochrome hypothesis itself. However, they would indicate the need for performing a similar study, this time comparing the effects of only slight intensity changes (low field range) in order to explore the possible role of the proximity of metal structures and furniture as a confounder under the cryptochrome hypothesis. PMID- 26011505 TI - Medicare Fee Cuts and Hospital- vs Office-Based Cardiovascular Imaging Services. PMID- 26011506 TI - All-optical single-nanoparticle ratiometric thermometry with a noise floor of 0.3 K Hz(-1/2). AB - We demonstrate a temperature noise floor of 0.3 K Hz(-1/2) and a long-term stability better than 0.6 K (peak-to-peak value) using a single crystal of diamond smaller than 50 nm across and containing about 100 nitrogen-vacancy centres as a temperature sensor. We compare the achieved characteristics to other single-particle sensors and show that it is one of the best ratiometric all optical nano-probes of temperature to date. PMID- 26011507 TI - Effects of intermittent theta burst stimulation on spasticity after stroke. AB - Spasticity is a common cause of long-term disability in poststroke hemiplegic patients. We investigated whether intermittent theta burst stimulation (iTBS) could reduce upper-limb spasticity after a stroke. Fifteen hemiplegic stroke patients were recruited for a double-blind sham-controlled cross-over design study. A single session of iTBS or sham stimulation was delivered on the motor hotspot of the affected flexor carpi radialis muscle in a random and counterbalanced order with a 1-week interval. Modified Ashworth scale (MAS), modified Tardieu scale (MTS), H-wave/M-wave amplitude ratio, peak torque (PT), peak torque angle (PTA), work of affected wrist flexor, and rectified integrated electromyographic activity of the flexor carpi radialis muscle were measured before, immediately after, 30 min after, and 1 week after iTBS or sham stimulation. Repeated-measures analysis of variance showed a significant interaction between time and intervention for the MAS, MTS, PT, PTA, and rectified integrated electromyographic activity (P<0.05), indicating that these parameters were significantly improved by iTBS compared with sham stimulation. However, the H-wave/M-wave amplitude ratio and work were not affected. MAS and MTS significantly improved for at least 30 min after iTBS, but the other parameters only improved immediately after iTBS (P<0.05). In conclusion, iTBS on the affected hemisphere may help to reduce poststroke spasticity transiently. PMID- 26011508 TI - Can cannabis use be prevented by targeting personality risk in schools? Twenty four-month outcome of the adventure trial on cannabis use: a cluster-randomized controlled trial. AB - AIMS: To examine the effectiveness of a personality-targeted intervention program (Adventure trial) delivered by trained teachers to high-risk (HR) high-school students on reducing marijuana use and frequency of use. DESIGN: A cluster randomized controlled trial. SETTING: Secondary schools in London, UK. PARTICIPANTS: Twenty-one secondary schools were randomized to intervention (n = 12) or control (n = 9) conditions, encompassing a total of 1038 HR students in the ninth grade [mean (standard deviation) age = 13.7 (0.33) years]. INTERVENTIONS: Brief personality-targeted interventions to students with one of four HR profiles: anxiety sensitivity, hopelessness, impulsivity and sensation seeking. MEASUREMENTS: PRIMARY OUTCOME: marijuana use. Secondary outcome: frequency of use. Assessed using the Reckless Behaviour Questionnaire at intervals of 6 months for 2 years. Personality risk was measured with the Substance Use Risk Profile Scale. FINDINGS: Logistic regression analysis revealed significant intervention effects on cannabis use rates at the 6-month follow-up in the intent-to-treat sample [odds ratio (OR) = 0.67, P = 0.05, 95% confidence interval (CI) = 0.45-1.0] and significant reductions in frequency of use at 12- and 18-month follow-up (beta = -0.14, P <= 0.05, 95% CI = -0.6 to -0.01; beta = 0.12, P <= 0.05, 95% CI = -0.54 to 0.0), but this was not supported in two-part latent growth models. Subgroup analyses (both logistic and two-part models) reveal that the sensation-seeking intervention delayed the onset of cannabis use among sensation seekers (OR = 0.25, beta = -0.833, standard error = 0.342, P = 0.015). CONCLUSIONS: Personality-targeted interventions can be delivered effectively by trained school staff to delay marijuana use onset among a subset of high-risk teenagers: sensation-seekers. PMID- 26011509 TI - Clinical characteristics and outcomes of patients with and without diabetes in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. AB - AIMS: Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of <=35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. METHODS AND RESULTS: The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73-1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63-1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. CONCLUSIONS: Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM. PMID- 26011511 TI - Structural and physical properties of collagen extracted from moon jellyfish under neutral pH conditions. AB - We extracted collagen from moon jellyfish under neutral pH conditions and analyzed its amino acid composition, secondary structure, and thermal stability. The content of hydroxyproline was 4.3%, which is lower than that of other collagens. Secondary structure analysis using circular dichroism (CD) showed a typical collagen helix. The thermal stability of this collagen at pH 3.0 was lower than those from fish scale and pig skin, which also correlates closely with jellyfish collagen having lower hydroxyproline content. Because the solubility of jellyfish collagen used in this study at neutral pH was quite high, it was possible to analyze its structural and physical properties under physiological conditions. Thermodynamic analysis using CD and differential scanning calorimetry showed that the thermal stability at pH 7.5 was higher than at pH 3.0, possibly due to electrostatic interactions. During the process of unfolding, fibrillation would occur only at neutral pH. PMID- 26011512 TI - Editorial Comment from Dr Izumi to Clinical outcomes of prostate cancer patients in Yokosuka City, Japan: A comparative study between cases detected by prostate specific antigen-based screening in Yokosuka and those detected by other means. PMID- 26011510 TI - Pharmacokinetics of eupalinolide A, eupalinolide B and hyperoside from Eupatorium lindleyanum in rats by LC/MS/MS. AB - A simple, selective, and sensitive LC/MS/MS method was developed and validated for simultaneous determination of eupalinolide A, eupalinolide B, and hyperoside in rat plasma. Plasma samples were processed by protein precipitation with acetonitrile. The three analytes, together with internal standard (IS, lysionotin), were separated on a Venusil MP-C18 column (50mm*2.1mm, 3MUm) using a mobile phase of methanol and 10mM ammonium acetate (45:55, v/v) with isocratic elution. Mass spectrometric detection was performed by multiple-reaction monitoring mode via electrospray ionization source. Linear calibration curves were obtained for the following concentration range: 1.28-640ng/mL for EA; 1.98 990ng/mL for EB; and 2.00-1000ng/mL for HYP. The intra- and inter-day precision was less than 10.25%, and the accuracy was between 89.16% and 110.63%. The extraction recovery of the analytes and IS from rat plasma was above 88.75%. The validated method has been successfully applied to pharmacokinetic studies of the three analytes following intragastric administration of Eupatorium lindleyanum extract at a single dose of 100, 250, and 625mg/kg to Sprague-Dawley rats, respectively. The pharmacokinetic results may help to better understand the pharmacological actions of the herb E. lindleyanum. PMID- 26011513 TI - Hedonic sensitivity to natural rewards is affected by prenatal stress in a sex dependent manner. AB - Palatable food is a strong activator of the reward circuitry and may cause addictive behavior leading to eating disorders. How early life events and sex interact in shaping hedonic sensitivity to palatable food is largely unknown. We used prenatally restraint stressed (PRS) rats, which show abnormalities in the reward system and anxious/depressive-like behavior. Some of the hallmarks of PRS rats are known to be sex-dependent. We report that PRS enhanced and reduced milk chocolate-induced conditioned place preference in males and females, respectively. Male PRS rats also show increases in plasma dihydrotestosterone (DHT) levels and dopamine (DA) levels in the nucleus accumbens (NAc), and reductions in 5-hydroxytryptamine (5-HT) levels in the NAc and prefrontal cortex (PFC). In male rats, systemic treatment with the DHT-lowering drug finasteride reduced both milk chocolate preference and NAc DA levels. Female PRS rats showed lower plasma estradiol (E2 ) levels and lower DA levels in the NAc, and 5-HT levels in the NAc and PFC. E2 supplementation reversed the reduction in milk chocolate preference and PFC 5-HT levels. In the hypothalamus, PRS increased ERalpha and ERbeta estrogen receptor and CARTP (cocaine-and-amphetamine receptor transcript peptide) mRNA levels in males, and 5-HT2C receptor mRNA levels in females. Changes were corrected by treatments with finasteride and E2 , respectively. These new findings show that early life stress has a profound impact on hedonic sensitivity to high-palatable food via long-lasting changes in gonadal hormones. This paves the way to the development of hormonal strategies aimed at correcting abnormalities in the response to natural rewards. PMID- 26011515 TI - An Integrated Model of Posttraumatic Stress and Growth. AB - A number of recent models have examined cognitive predictors of posttraumatic stress and posttraumatic growth (S. Barton, A. Boals, & L. Knowles, 2013; J. Groleau, L. Calhoun, A. Cann, & G. Tedeschi, 2013; K. N. Triplett, R. G. Tedeschi, A. Cann, L. G. Calhoun, & C. L. Reeve, 2012). The current study examined an integrated model of predictors of distress and perceived growth in 194 college undergraduates. Domains covered included the roles of core belief challenge, event centrality, posttrauma cognitions, and event-related rumination. Negative cognitions about the self and the centrality of the event directly predicted both growth and distress, although intrusive rumination predicted only posttraumatic stress disorder symptoms, and deliberate rumination predicted only posttraumatic growth. Future research should continue to examine the shared and unique predictors of postevent growth and distress. PMID- 26011514 TI - Safety of ferric carboxymaltose immediately after infliximab administration, in a single session, in inflammatory bowel disease patients with iron deficiency: a pilot study. AB - AIM: To obtain preliminary safety and efficacy data on intravenous (IV) administration of infliximab (IFX) and ferric carboxymaltose (FCM) to inflammatory bowel disease (IBD) patients in a single treatment session. METHODS: A two-phase non-interventional, observational, prospective pilot study was performed to evaluate safety and efficacy of FCM given immediately after IFX. IBD patients were recruited consecutively in the outpatient clinic in two groups. Control group patients (n = 12) received FCM on a separate day from IFX. Subsequently, single-session group patients (n = 33) received FCM after IFX on the same day. All patients received 5mg/kg IFX and 1000mg FCM for iron-restricted anemia (IRA) or 500mg FCM for iron deficiency without anemia. Safety assessment was performed by recording adverse events (AEs) during and immediately after infusion, 30 minutes afterwards, and via follow-up at 7 days and 8 weeks. For efficacy assessment, hematological parameters were assessed prior to FCM infusion (pre-FCM) and after 8 weeks. Economic impact of FCM given immediately after IFX was assessed. RESULTS: All 45 patients (35 Crohn's disease, 10 ulcerative colitis) received IFX 5mg/kg. 21 patients received 500mg FCM and 24 received 1000mg. FCM administration immediately after IFX corrected iron deficiency or IRA as shown by increases in hematological parameters. No AEs were reported during the safety evaluation at the end of FCM or IFX administration, 30 minutes, 7 days and 8 weeks afterwards, in either control or single-session groups. Total cost per patient for single-session administration was 354.63?; for patients receiving IFX and FCM on separate days, it was 531.94?, giving a 177.31? per-patient cost saving. CONCLUSION: Single-session administration of FCM after IFX was safe and effective in IBD patients and can offer a good cost-benefit ratio and improve treatment adherence. To our knowledge, this study is the first to evaluate FCM and IFX administration in a single treatment session. PMID- 26011516 TI - From Soft Self-Healing Gels to Stiff Films in Suckerin-Based Materials Through Modulation of Crosslink Density and beta-Sheet Content. AB - Suckerins are block-copolymer-like structural proteins constituting the building blocks of the strong squid sucker-ring teeth. Here, recombinant suckerin-19 is processed into biomaterials spanning a wide range of elasticity, from very soft hydrogels to stiff films with elastic modulus in the gigapascal range. The elasticity is controlled by the interplay between the beta-sheet content and induced di-tyrosine crosslinking. PMID- 26011517 TI - Oxidation of Olefins with Benzeneseleninic Anhydride in the Presence of TMSOTf. AB - A new oxidizing system for olefins, consisting of benzeneseleninic anhydride and trimethylsilyl triflate, was studied. The highly reactive benzeneseleninyl cation is presumably formed under these conditions. It has been shown that different products are formed with this species depending on the specific structure of olefin. The 1,1-disubstituted olefins afforded mostly alpha,beta-unsaturated carbonyl compounds. The sterically encumbered tri- or tetrasubstituted olefins yielded 1,2- or 1,4-dihydroxylated products, presumably via four-membered cyclic intermediates. PMID- 26011518 TI - Subcutaneous self-injections of C1 inhibitor: an effective and safe treatment in a patient with hereditary angio-oedema. AB - A 25-year-old woman presented to our clinic with a history of recurrent swelling and abdominal symptoms for > 20 years. The patient's father was similarly affected. The patient was diagnosed with hereditary angio-oedema (HAE) due to C1 inhibitor deficiency. This was initially managed with systemic androgens, but the symptoms of hyperandrogenism eventually became intolerable. Treatment with icatibant (an antagonist of bradykinin B2 receptors) was partially successful. We changed the therapy to prophylactic treatment with C1 inhibitor. Although the patient became completely symptom-free under this regimen, she found the repeated intravenous injections unacceptable. Therefore, we changed the route of administration to subcutaneous injections of C1 inhibitor 1000 U in 10 mL twice weekly, using a subcutaneous infusion kit. Since that time (December 2013), she has remained completely free of symptoms under this regimen. To our knowledge, this is the first report documenting the efficacy and safety of subcutaneous injections of C1 inhibitor in a patient with HAE. PMID- 26011519 TI - Assembly of near infra-red emitting upconverting nanoparticles and multiple Gd(III)-chelates as a potential bimodal contrast agent for MRI and optical imaging. AB - Linking multiple paramagnetic gadolinium(III)-chelates based on the 2-[4,7,10 tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate (DOTA) ligand to the surface of NaGdF4:Yb(3+),Tm(3+) upconverting nanoparticles with an average particle size of 20 nm resulted in an assembly that has favorable properties for bimodal Magnetic Resonance Imaging (MRI) and Optical Imaging (OI). An improved synthetic pathway was used to couple the paramagnetic precursor to the nanoparticles. The nanoparticles were rendered water dispersible via citrate capping, leaving one acid group free for amide coupling with the mono-amino precursor of the DOTA ligand. Luminescence spectroscopy measurements have shown that the excitation of the nanoconstruct at 980 nm resulted in intense upconverted emission of thulium(III) at 800 nm. The assembly of several paramagnetic centers on the nanoparticle scaffold reduces the overall tumbling rate, resulting in enhanced longitudinal relaxation times and improved relaxivity. The proton NMRD profiles show a characteristic hump at higher frequencies, which is caused by the slow rotation of the nanoconstruct, resulting in r1 values of 25 mM(-1) s(-1) per gadolinium(III)-ion at 60 MHz and 310 K. This is a significant improvement compared to the Gd-DO3A-ethylamine precursor (4) for which a value of r1 of 3.23 mM(-1) s(-1) was observed under the same conditions. Theoretical fitting by two different approaches showed an increase of tauR from 57.3 ps for the Gd-DO3A-ethylamine precursor (4) to 392.0 ps for the nanoconstruct, which is responsible for the overall substantial increase in relaxivity. PMID- 26011520 TI - Evaluation of small-volume tubes for venous and capillary PT (INR) samples. AB - INTRODUCTION: Frequent PT (INR) testing may represent a problem for patients on warfarin treatment, and capillary or small-volume tubes may be more appropriate for such patients. A demand for small-volume tubes also comes from pediatric wards. Yet, while various small-volume tubes are available, they have not been properly evaluated. METHODS: Three small-volume tubes were tested (MiniCollect 3.8% citrate, MiniCollect 3.2% citrate and Microvette EDTA) and compared with a standard 4.5-mL 3.2% citrated tube. Samples were taken by venipuncture from the back of the hand and by capillary sampling from the tip of the finger. The measures were compared with those after standard venipuncture of the arm fold. A total of 180 samples, using different combinations of tubes and sampling sites, were collected from 30 volunteers. RESULTS: There were no differences in the results obtained using citrate tubes for venous samples in comparison with those obtained by standard sampling, while the results when using EDTA tubes were not comparable to those obtained by standard sampling (P < 0.001), expressing systematically lower values (by about 10%). The results observed after capillary sampling were significantly different to those obtained after standard sampling. CONCLUSIONS: The MiniCollect 3.2% tube may be used for PT (INR) venipuncture samples when withdrawal of a small amount of blood is preferable, while EDTA tubes should not be used for PT (INR) testing. PMID- 26011521 TI - Meta-analysis of rate ratios with differential follow-up by treatment arm: inferring comparative effectiveness of medical devices. AB - Modeling events requires accounting for differential follow-up duration, especially when combining randomized and observational studies. Although events occur at any point over a follow-up period and censoring occurs throughout, most applied researchers use odds ratios as association measures, assuming follow-up duration is similar across treatment groups. We derive the bias of the rate ratio when incorrectly assuming equal follow-up duration in the single study binary treatment setting. Simulations illustrate bias, efficiency, and coverage and demonstrate that bias and coverage worsen rapidly as the ratio of follow-up duration between arms moves away from one. Combining study rate ratios with hierarchical Poisson regression models, we examine bias and coverage for the overall rate ratio via simulation in three cases: when average arm-specific follow-up duration is available for all studies, some studies, and no study. In the null case, bias and coverage are poor when the study average follow-up is used and improve even if some arm-specific follow-up information is available. As the rate ratio gets further from the null, bias and coverage remain poor. We investigate the effectiveness of cardiac resynchronization therapy devices compared with those with cardioverter-defibrillator capacity where three of eight studies report arm-specific follow-up duration. PMID- 26011522 TI - Quantitative on-line concentration for capillary electrophoresis with inkjet sample introduction technique. AB - A quantitative sample introduction method based upon inkjet injection was applied to capillary electrophoresis coupled with stacking and sweeping on-line concentration techniques. Methylxanthines were used as model compounds for the proof-of-concept of the method. The volume of injected sample could be easily manipulated by controlling the number of ejected droplets in the injection procedure. Under optimized conditions, a linear relationship between the ejected droplet number and peak area was obtained when the droplet number introduced into the capillary was less than 100. Under optimized quantitative on-line concentration conditions, the limits of detection for theobromine, caffeine, and theophylline were 1.0, 2.0, and 1.0 MUM, respectively. The inkjet injection system was evaluated by comparing it with conventional injection methods. The electropherogram of the inkjet injection mode was the same as that for hydrodynamic injection mode, and no sample discrimination was observed compared with the electrokinetic injection mode. The established method was applied to the determination of methylxanthines in bottled green tea. The recoveries of theobromine, caffeine, and theophylline were 94.1, 110.6, and 86.8%, respectively. We conclude that proposed method can be used for quantitative concentration for capillary electrophoresis, thus resulting in an improved accuracy. PMID- 26011523 TI - Inventory of Personal Factors Influencing Conditioned Pain Modulation in Healthy People: A Systematic Literature Review. AB - BACKGROUND: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. METHODS: This systematic review follows the PRISMA guidelines. "Pubmed" and "Web of Science" were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. RESULTS: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. CONCLUSION: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required. PMID- 26011524 TI - Performing T-tests to Compare Autocorrelated Time Series Data Collected from Direct-Reading Instruments. AB - Industrial hygienists now commonly use direct-reading instruments to evaluate hazards in the workplace. The stored values over time from these instruments constitute a time series of measurements that are often autocorrelated. Given the need to statistically compare two occupational scenarios using values from a direct-reading instrument, a t-test must consider measurement autocorrelation or the resulting test will have a largely inflated type-1 error probability (false rejection of the null hypothesis). A method is described for both the one-sample and two-sample cases which properly adjusts for autocorrelation. This method involves the computation of an "equivalent sample size" that effectively decreases the actual sample size when determining the standard error of the mean for the time series. An example is provided for the one-sample case, and an example is given where a two-sample t-test is conducted for two autocorrelated time series comprised of lognormally distributed measurements. PMID- 26011525 TI - Chest Compression Synchronized Ventilation versus Intermitted Positive Pressure Ventilation during Cardiopulmonary Resuscitation in a Pig Model. AB - BACKGROUND: Guidelines recommend mechanical ventilation with Intermitted Positive Pressure Ventilation (IPPV) during resuscitation. The influence of the novel ventilator mode Chest Compression Synchronized Ventilation (CCSV) on gas exchange and arterial blood pressure compared with IPPV was investigated in a pig model. METHODS: In 12 pigs (general anaesthesia/intubation) ventricular fibrillation was induced and continuous chest compressions were started after 3 min. Pigs were mechanically ventilated in a cross-over setting with 5 ventilation periods of 4 min each: Ventilation modes were during the first and last period IPPV (100% O2, tidal volumes = 7 ml/kgKG, respiratory rate = 10/min), during the 2nd, 3rd and 4th period CCSV (100% O2), a pressure-controlled and with each chest compression synchronized breathing pattern with three different presets in randomized order. Presets: CCSVA: P insp = 60 mbar, inspiratory time = 205 ms; CCSVB: P insp = 60 mbar, inspiratory time = 265 ms; CCSVC: P insp = 45 mbar, inspiratory time = 265 ms. Blood gas samples were drawn for each period, mean arterial (MAP) and central venous (CVP) blood pressures were continuously recorded. Results as median (25%/75%percentiles). RESULTS: Ventilation with each CCSV mode resulted in higher PaO2 than IPPV: PaO2: IPPV first: 19.6(13.9/36.2)kPa, IPPV last: 22.7(5.4/36.9)kPa (p = 0.77 vs IPPV first), CCSVA: 48.9(29.0/58.2)kPa (p = 0.028 vs IPPV first, p = 0.0001 vs IPPV last), CCSVB: 54.0 (43.8/64.1) (p = 0.001 vs IPPV first, p = 0.0001 vs IPPV last), CCSVC: 46.0 (20.2/58.4) (p = 0.006 vs IPPV first, p = 0.0001 vs IPPV last). Both the MAP and the difference MAP-CVP did not decrease during twelve minutes CPR with all three presets of CCSV and were higher than the pressures of the last IPPV period. CONCLUSIONS: All patterns of CCSV lead to a higher PaO2 and avoid an arterial blood pressure drop during resuscitation compared to IPPV in this pig model of cardiac arrest. PMID- 26011526 TI - Association between Self-Reported Smoking and Hemoglobin A1c in a Korean Population without Diabetes: The 2011-2012 Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Several Western studies have revealed that among non-diabetics, glycosylated hemoglobin A1c (HbA1c) levels are higher in smokers than non smokers. While studies conducted in Western populations consistently support this association, a recent meta-analysis reported that studies carried out in non Western populations, including studies of Chinese, Egyptian, and Japanese Americans, did not detect any significant differences in HbA1c levels between smokers and non-smokers. OBJECTIVES: We assessed the association between smoking habits and HbA1c levels in the general Korean adult population using data from the Korean National Health and Nutrition Examination Survey (KNHANES) performed in 2011-2012. METHODS: A total of 10,241 participants (weighted n=33,946,561 including 16,769,320 men and 17,177,241 women) without diabetes were divided into four categories according to their smoking habits: never smokers (unweighted n/ weighted n=6,349/19,105,564), ex-smokers (unweighted n/ weighted n= 1,912/6,207,144), current light smokers (<15 cigarettes per day, unweighted n/ weighted n=1,205/5,130,073), and current heavy smokers (>=15 cigarettes per day, unweighted n/ weighted n=775/3,503,781). RESULTS: In age- and gender-adjusted comparisons, the HbA1c levels of each group were 5.52 +/- 0.01% in non-smokers, 5.49 +/- 0.01% in ex-smokers, 5.53 +/- 0.01% in light smokers, and 5.61 +/- 0.02% in heavy smokers. HbA1c levels were significantly higher in light smokers than in ex-smokers (p = 0.033), and in heavy smokers compared with light smokers (p < 0.001). The significant differences remained after adjusting for age, gender, fasting plasma glucose, heavy alcohol drinking, hematocrit, college graduation, and waist circumference. Linear regression analyses for HbA1c using the above mentioned variables as covariates revealed that a significant association between current smoking and HbA1c (coefficient 0.021, 95% CI 0.003-0.039, p = 0.019). CONCLUSIONS: Current smoking was independently associated with higher HbA1c levels in a cigarette exposure-dependent manner in a representative population of Korean non-diabetic adults. In this study, we have observed an association between smoking status and HbA1c levels in non-diabetics drawn from a non-Western population, consistent with previous findings in Western populations. PMID- 26011527 TI - Combinations of susceptibility genes are associated with higher risk for multiple sclerosis and imply disease course specificity. AB - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by a genome wide association study (GWAS) conducted by the International Multiple Sclerosis Genetic Consortium in a multinational cohort prompting the discovery of 57 non-MHC MS-associated common genetic variants. Hitherto, few of these newly reported variants have been replicated in larger independent patient cohorts. We genotyped a cohort of 1033 MS patients and 644 healthy controls with a consistent genetic background for the 57 non-MHC variants reported to be associated with MS by the first large GWAS as well as the HLA DRB1*1501 tagging SNP rs3135388. We robustly replicated three of the 57 non-MHC reported MS-associated single nucleotide polymorphisms (SNPs). In addition, our study revealed several genotype-genotype combinations with an evidently higher degree of disease association than the genotypes of the single SNPs. We further correlated well-defined clinical phenotypes, i.e. ataxia, visual impairment due to optic neuritis and paresis with single SNPs and genotype combinations, and identified several associations. The results may open new avenues for clinical implications of the MS associated genetic variants reported from large GWAS. PMID- 26011528 TI - Metathesis of 1-Butene to Propene over Mo/Al2O3@SBA-15: Influence of Alumina Introduction Methods on Catalytic Performance. AB - A series of Mo-based catalysts for 1-butene metathesis to propene were prepared by supporting Mo species on SBA-15 premodified with alumina. The effects of the method of introduction of the alumina guest to the host SBA-15 on the location of the Mo species and the corresponding metathesis activity were studied. As revealed by N2 adsorption isotherms and TEM results, well-dispersed alumina was formed on the pore walls of SBA-15 if the ammonia/water vapor induced hydrolysis (NIH) method was employed. The Mo species preferentially interacted with alumina instead of SBA-15, as evidenced by X-ray photoelectron spectroscopy, time-of flight secondary-ion mass spectrometry, and IR spectroscopy of adsorbed pyridine. Furthermore, new Bronsted acid sites favorable for the dispersion of the Mo species and low-temperature metathesis activity were generated as a result of the effective synergy between the alumina and SBA-15. The Mo/Al2O3@SBA-15 catalyst prepared by the NIH method showed higher metathesis activity and stability under the conditions of 120 degrees C, 0.1 MPa, and 1.5 h(-1) than catalysts prepared by other methods. PMID- 26011529 TI - Quantum mechanical/molecular mechanical calculated reactivity networks reveal how cytochrome P450cam and Its T252A mutant select their oxidation pathways. AB - Quantum mechanical/molecular mechanical calculations address the longstanding question of a "second oxidant" in P450 enzymes wherein the proton-shuttle, which leads to formation of the "primary-oxidant" Compound I (Cpd I), was severed by mutating the crucial residue (in P450cam: Threonine-252-to-Alanine, hence T252A). Investigating the oxidant candidates Cpd I, ferric hydroperoxide, and ferric hydrogen peroxide (Fe(III)(O2H2)), and their reactions, generates reactivity networks which enable us to rule out a "second oxidant" and at the same time identify an additional coupling pathway that is responsible for the epoxidation of 5-methylenylcamphor by the T252A mutant. In this "second-coupling pathway", the reaction starts with the Fe(III)(O2H2) intermediate, which transforms to Cpd I via a O-O homolysis/H-abstraction mechanism. The persistence of Fe(III)(O2H2) and its oxidative reactivity are shown to be determined by interplay of substrate and protein. The substrate 5-methylenylcamphor prevents H2O2 release, while the protein controls the Fe(III)(O2H2) conversion to Cpd I by nailing-through hydrogen-bonding interactions-the conformation of the HO(*) radical produced during O-O homolysis. This conformation prevents HO(*) attack on the porphyrin's meso position, as in heme oxygenase, and prefers H-abstraction from Fe(IV)OH thereby generating H2O + Cpd I. Cpd I then performs substrate oxidations. Camphor cannot prevent H2O2 release and hence the T252A mutant does not oxidize camphor. This "second pathway" transpires also during H2O2 shunting of the cycle of wild type P450cam, where the additional hydrogen-bonding with Thr252 prevents H2O2 release, and contributes to a successful Cpd I formation. The present results lead to a revised catalytic cycle of Cytochrome P450cam. PMID- 26011530 TI - Evidence in obese children: contribution of hyperlipidemia, obesity-inflammation, and insulin sensitivity. AB - BACKGROUND: Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children. METHODS: We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-alpha, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits. RESULTS: Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-alpha and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%). CONCLUSIONS: Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future. PMID- 26011531 TI - Evaluation of the Becton Dickinson Rapid Influenza Diagnostic Tests in Outpatients in Germany during Seven Influenza Seasons. AB - BACKGROUND: An extensive retrospective study spanning several seasons was undertaken to evaluate the diagnostic performance of the BD rapid influenza diagnostic test (RIDT) in comparison with the RT-PCR assay. METHODS: A total of 2,179 respiratory samples were tested in parallel by in-house RT-PCR and the RIDT. During the 2003-2004, 2006-2007, 2007-2008, and 2008-2009 (n=1671) seasons, the BD Directigen Flu A+B test was used, and during the 2010-2011, 2011-2012 and 2012-2013 (n=508) seasons, the BD Directigen EZ Flu A+B test b was used. RESULTS: The sensitivity, specificity, PPV and NPV for the BD Directigen Flu A+B test calculated for types A and B together were 39%, 99%, 98%, and 56%, respectively. For the BD Directigen EZ Flu A+B test, these values were 47%, 100%, 100%, 55%, respectively. The sensitivity of the BD Directigen Flu A+B test did not differ significantly from season to season or between types A (44%) and B (37%). The sensitivity of the BD Directigen EZ Flu A+B test calculated for type A only was 59%, which was considerably higher than the sensitivity of this test for type B (23%). The sensitivity of the RIDT was approximately 40-50% in children and teenagers, but it was only 18.% in adults aged 20 years and older. The specificity of both RIDTs was very high (>99%) during all seasons. CONCLUSIONS: Due to their rapid turnaround time, RIDTs can help guide decisions about the clinical management of influenza. Because of the high specificity, a positive result can be interpreted as a true positive, and antiviral therapy as well as appropriate measures to prevent the transmission of influenza can be initiated. The best sensitivity of the RIDT is achieved in children. However, even in this group, the RIDT will only recognize influenza infection in approximately half of the cases, and influenza should still be considered in patients with negative results; negative RIDT results must be confirmed by PCR. PMID- 26011532 TI - The fitness consequences of aneuploidy are driven by condition-dependent gene effects. AB - Aneuploidy is a hallmark of tumor cells, and yet the precise relationship between aneuploidy and a cell's proliferative ability, or cellular fitness, has remained elusive. In this study, we have combined a detailed analysis of aneuploid clones isolated from laboratory-evolved populations of Saccharomyces cerevisiae with a systematic, genome-wide screen for the fitness effects of telomeric amplifications to address the relationship between aneuploidy and cellular fitness. We found that aneuploid clones rise to high population frequencies in nutrient-limited evolution experiments and show increased fitness relative to wild type. Direct competition experiments confirmed that three out of four aneuploid events isolated from evolved populations were themselves sufficient to improve fitness. To expand the scope beyond this small number of exemplars, we created a genome-wide collection of >1,800 diploid yeast strains, each containing a different telomeric amplicon (Tamp), ranging in size from 0.4 to 1,000 kb. Using pooled competition experiments in nutrient-limited chemostats followed by high-throughput sequencing of strain-identifying barcodes, we determined the fitness effects of these >1,800 Tamps under three different conditions. Our data revealed that the fitness landscape explored by telomeric amplifications is much broader than that explored by single-gene amplifications. As also observed in the evolved clones, we found the fitness effects of most Tamps to be condition specific, with a minority showing common effects in all three conditions. By integrating our data with previous work that examined the fitness effects of single-gene amplifications genome-wide, we found that a small number of genes within each Tamp are centrally responsible for each Tamp's fitness effects. Our genome-wide Tamp screen confirmed that telomeric amplifications identified in laboratory-evolved populations generally increased fitness. Our results show that Tamps are mutations that produce large, typically condition-dependent changes in fitness that are important drivers of increased fitness in asexually evolving populations. PMID- 26011533 TI - Optimizing cross-sectional prediction of social functioning in youth referred for neuropsychological testing. AB - The current study aimed to establish a fine-grained, efficient characterization of the concurrent neuropsychological contributions to social functioning in neuropsychologically-referred youth. A secondary aim was to demonstrate a useful statistic approach for such investigations (Partial Least Squares Regression; PLSR), which is underutilized in this field. Forty-five participants (70 - 164 months; Mage = 110.89; 34 male) were recruited from a large neuropsychological assessment clinic. Participants completed subtests from the NEPSY-II focusing on neuropsychological constructs that have been linked to social functioning (affect decoding, social memory, motor skills, visuomotor skills, response inhibition, attention and set-shifting, and verbal comprehension). Mothers completed the BASC 2, from which Atypicality and Social Skills scales were analyzed. PLSR revealed that difficulty with social memory, sensorimotor integration, and the ability to attend to and accurately discriminate auditory stimuli combine to best predict atypical or "odd" behavior. In terms of social skills, two factors emerged. The first factor indicated that, counterintuitively, greater emotional perception, visuospatial perception, ability to attend to and accurately discriminate auditory stimuli, and understand instructions was related to poorer social skills. The second factor indicated that a pattern of better facial memory, and sensorimotor ability (execution & integration) characterized a distinct profile of greater social ability. PLSR results were compared to traditional OLS and Backwards Stepwise regression approaches to demonstrate utility. Results also suggested that these findings were consistent across age, gender, and diagnostic group, indicating common neuropsychological substrates of social functioning in this sample of referred youth. Overall, this study provides the first characterization of optimized combinations of neuropsychological variables in predicting social functioning in assessment clinic-referred youth, and introduces to this literature a valuable statistical approach for obtaining such characterizations. PMID- 26011536 TI - Characterization of Plasmodium vivax Early Transcribed Membrane Protein 11.2 and Exported Protein 1. AB - In Plasmodium, the membrane of intracellular parasites is initially formed during invasion as an invagination of the red blood cell surface, which forms a barrier between the parasite and infected red blood cells in asexual blood stage parasites. The membrane proteins of intracellular parasites of Plasmodium species have been identified such as early-transcribed membrane proteins (ETRAMPs) and exported proteins (EXPs). However, there is little or no information regarding the intracellular parasite membrane in Plasmodium vivax. In the present study, recombinant PvETRAMP11.2 (PVX_003565) and PvEXP1 (PVX_091700) were expressed and evaluated antigenicity tests using sera from P. vivax-infected patients. A large proportion of infected individuals presented with IgG antibody responses against PvETRAMP11.2 (76.8%) and PvEXP1 (69.6%). Both of the recombinant proteins elicited high antibody titers capable of recognizing parasites of vivax malaria patients. PvETRAMP11.2 partially co-localized with PvEXP1 on the intracellular membranes of immature schizont. Moreover, they were also detected at the apical organelles of newly formed merozoites of mature schizont. We first proposed that these proteins might be synthesized in the preceding schizont stage, localized on the parasite membranes and apical organelles of infected erythrocytes, and induced high IgG antibody responses in patients. PMID- 26011538 TI - Walking to the beat of their own drum: how children and adults meet timing constraints. AB - Walking requires adapting to meet task constraints. Between 5- and 7-years old, children's walking approximates adult walking without constraints. To examine how children and adults adapt to meet timing constraints, 57 5- to 7-year olds and 20 adults walked to slow and fast audio metronome paces. Both children and adults modified their walking. However, at the slow pace, children had more trouble matching the metronome compared to adults. The youngest children's walking patterns deviated most from the slow metronome pace, and practice improved their performance. Five-year olds were the only group that did not display carryover effects to the metronome paces. Findings are discussed in relation to what contributes to the development of adaptation in children. PMID- 26011539 TI - Patients presenting with fractures are likely to be vitamin D deficient: are we getting enough sun? AB - BACKGROUND: 25-Hydroxyvitamin D serves a crucial role in bone metabolism through its role on osteoclast and osteoblastic function. To assess the implication of vitamin D and its relationship to bone fracture and fracture force, we have examined vitamin D levels in patients requiring inpatient fracture management. METHODS: We performed serological testing of vitamin D levels, calcium, parathyroid hormone and liver function tests on patients admitted to our rural institution in southeastern Australia for inpatient fracture management. All participants completed a questionnaire designed to screen for potential contributing factors to bony fragility. Demographic data were also obtained including age, gender and body mass index. Fracture location and the type of inpatient management as well as the force of injury were included in our analysis. RESULTS: We recruited 100 patients to the study, with a median age of 72 (range 22-98) of whom 66 were women. Most had low-energy fractures (79%), treated by internal fixation (73%) or arthroplasty (9%) with 18 treated non operatively. The majority of the patients were at best vitamin D insufficient, <75 nmol/L (77%), and 38% were vitamin D deficient (<50 nmol/L). Only 14 patients had a formal diagnosis of osteoporosis at presentation, with 63 patients claiming daily sun exposure in line with recommendations for vitamin D sufficiency. CONCLUSIONS: Our data suggest that the prevalence of vitamin D insufficiency and deficiency is common in patients presenting with fractures in southeastern Australia and is not confined to elderly patients. All patients with fractures should be assessed for vitamin D levels and treated in accordance with vitamin D deficiency guidelines. PMID- 26011540 TI - Correction: molecular and morphological analyses reveal phylogenetic relationships of stingrays focusing on the family dasyatidae (myliobatiformes). PMID- 26011541 TI - Investigation of IRES Insertion into the Genome of Recombinant MVA as a Translation Enhancer in the Context of Transcript Decapping. AB - Recombinant modified vaccinia virus Ankara (MVA) has been used to deliver vaccine candidate antigens against infectious diseases and cancer. MVA is a potent viral vector for inducing high magnitudes of antigen-specific CD8+ T cells; however the cellular immune responses to a recombinant antigen in MVA could be further enhanced by increasing transgene expression. Previous reports showed the importance of utilizing an early poxviral promoter for increasing transgene expression and therefore enhancing cellular immune responses. However, the vaccinia D10 decapping enzyme is reported to target and decap vaccinia virus early transcripts - a mechanism that could limit the usefulness of early promoters in MVA viral vectors if this enzyme shows the same activity in this closely related virus. Therefore, we attempted to increase transgene expression in recombinant MVA by inserting the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) upstream of a transgene sequence that is controlled by the B8R early promoter, and assessed D10 enzyme decapping activity in MVA. The aim of the IRES element was to initiate translation of the transgene transcript (after the removal of the cap structure by the D10 decapping protein) in a cap independent manner. Here, we report that overexpression of the D10 decapping protein, in trans, in MVA reduced growth and transgene expression; however, the IRES element was not able to compensate for the negative effect of the D10 decapping protein. Recombinant MVA with EMCV IRES induced levels of both gene expression and transcription that were similar to the control recombinant MVA, encoding the same transgene but without the IRES element. Both viruses were tested in BALB/c mice and induced similar magnitudes of epitope-specific CD8+ T cells. This work indicates that the MVA version of the D10 decapping enzyme, overexpressed using a plasmid, is functional, but its negative effect on transgene expression by recombinant MVA cannot be overcome by the use of the EMCV IRES inserted upstream of the transgene initiation codon. PMID- 26011542 TI - 53BP1 suppresses epithelial-mesenchymal transition by downregulating ZEB1 through microRNA-200b/429 in breast cancer. AB - Epithelial-mesenchymal transition (EMT) is an important mechanism of cancer invasion and metastasis. Although p53 binding protein 1 (53BP1) has been implicated in several biological processes, its function in EMT of human cancers has not yet been reported. Here, we show that 53BP1 negatively regulated EMT by modulating ZEB1 through targeting microRNA (miR)-200b and miR-429. Furthermore, 53BP1 promoted ZEB1-mediated upregulation of E-cadherin and also inhibited the expressions of mesenchymal markers, leading to increased migration and invasion in MDA-MB-231 breast cancer cells. Consistently, in MCF-7 breast cancer cells, low 53BP1 expression reduced E-cadherin expression, resulting in increased migration and invasion. These effects were reversed by miR-200b and miR-429 inhibition or overexpression. Sections of tumor xenograft model showed increased ZEB1 expression and decreased E-cadherin expression with the downregulation of 53BP1. In 18 clinical tissue samples, expression of 53BP1 was positively correlated with miR-200b and mir-429 and negatively correlated with ZEB1. It was also found that 53BP1 was associated with lymph node metastasis. Taken together, these results suggest that 53BP1 functioned as a tumor suppressor gene by its novel negative control of EMT through regulating the expression of miR-200b/429 and their target gene ZEB1. PMID- 26011537 TI - Mitochondrial mutations in subjects with psychiatric disorders. AB - A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA. PMID- 26011543 TI - Amperometric bioaffinity sensing platform for avian influenza virus proteins with aptamer modified gold nanoparticles on carbon chips. AB - A sandwich assay platform involving a surface formed aptamer-protein-antibody complex was developed to obtain the highly selective and sensitive amperometric detection of H5N1 viral proteins using a gold nanoparticle (NP) modified electrode. This is the first aptamer-antibody pairing reported for the selective detection of H5N1. Nanoparticle deposited screen-printed carbon electrodes were first functionalized by the covalent immobilization of a DNA aptamer specific to H5N1 followed by the adsorption of H5N1 protein. Alkaline phosphatase (ALP) conjugated monoclonal antibody was then adsorbed to form a surface bound Au NPs aptamer/H5N1/antiH5N1-ALP sandwich complex which was further reacted with the enzyme substrate, 4-amino phenyl phosphate (APP). The current associated with the electrocatalytic reaction of the surface bound ALP with APP increased as the H5N1 concentration increased. A lowest detectable concentration of 100 fM was obtained with a linear dynamic range of 100 fM to 10 pM using differential pulse voltammetry. As an example, the biosensor was applied to the detection of H5N1 protein in diluted human serum samples spiked with different concentrations of the viral protein target. PMID- 26011544 TI - Thermostabilization of Aspergillus oryzae beta-d-galactosidase. AB - The thermal stability of the Aspergillus oryzae beta-d-galactosidase (beta-gal) was evaluated at 60 degrees C. The stability of beta-gal was dependent on the pH, buffer, and additives. The beta-gal exhibited its highest thermal stability in a 0.02 M phosphate buffer pH 6. Among all the tested additives, galactose, a competitive inhibitor of beta-gal, was the upmost thermal stabilizer. A 0.15 M galactose solution caused beta-gal to retain a whole of 98.65% of its initial activity after incubation at 60 degrees C for 2 H. The second best thermal stabilizer of beta-gal was raffinose. A 0.15 M raffinose-beta-gal mixture retained 84.41% of its initial activity after incubation at 60 degrees C for 2 H, whereas the control retained only 61.02%. The results of this study also revealed that all the tested positively charged polymers (diethylaminoethyl [DEAE] dextran and polyethyleneimine [PEI] 800, 2,000, 750,000 Da) significantly destabilized beta-gal. However, these positively charged polymers exerted different effects on the beta-gal's activity. PEI 750,000 significantly activated the enzyme, while DEAE dextran and PEI 800 did not exert any significant effects on the beta-gal's activity. Nevertheless, PEI 2,000 significantly activated the enzyme. PMID- 26011545 TI - RNA sequencing provides insights into the toxicogenomic response of ZF4 cells to methyl methanesulfonate. AB - Whole genome transcriptomic studies are powerful for characterizing the molecular mechanisms underlying the physiological effects of chemicals, and are informative for environmental health risk assessment. Alkylating agents are an abundant class of chemicals that can damage DNA in the environment, and are used for anticancer treatments. Currently, little is known regarding the molecular mechanisms of toxic alkylating agents in zebrafish cell lines. In this study, RNA-sequencing was used to investigate the transcriptomic responses of zebrafish ZF4 cells following exposure to the model genotoxicant methyl methanesulfonate (MMS). The half-maximal inhibitory concentration (IC50 ) of MMS was 639.16 +/- 61.8 um, and apoptosis was induced within 24 h of exposure. RNA sequencing identified 3601 differentially expressed genes (DEGs) that were upregulated and 3037 that were downregulated. Gene ontology enrichment analysis revealed that most DEGs belonged to synthesis and metabolism categories. RNA-associated processes were the most upregulated, while cell cycle and adhesion were the most repressed processes, and neuron-related processes were the most downregulated developmental process. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified DNA damage repair, cell cycle, apoptosis and spliceosome as overrepresented terms. Six types of alternative splicing were detected. In total, 1156 alternative splicing DEGs were specifically expressed following MMS treatment, many of which belonged to metabolism and catabolic process categories. Cluster analysis of orthologs was able to extrapolate toxicotranscriptomic data between zebrafish and yeast. These results provide insight into the genome-wide response of ZF4 cells following exposure to MMS, and this knowledge will inform future toxicogenomic data analysis and environmental health risk assessment. PMID- 26011546 TI - Health care resource utilization and costs associated with nonfatal major adverse cardiovascular events. AB - BACKGROUND: Risk of recurrent cardiovascular events following an initial cardiovascular-related hospitalization remains high despite available interventions. Rates of cardiovascular events as well as associated health care resource utilization and costs are needed to assess the value of treatments. OBJECTIVE: To quantify, in patients with previous hospitalization for acute coronary syndrome (ACS), rates of nonfatal major adverse cardiovascular events (MACE) and secondary coronary events (SCE), as well as health care utilization and costs associated with a first MACE. METHODS: Administrative data from a large population of commercial managed care and managed Medicare enrollees in the United States were retrospectively analyzed. Patients with an ACS-related hospitalization from 2006 to 2011 were followed for 12 months to assess subsequent MACE and SCE rates. Patients were aged >= 18 years at initial ACS hospitalization (the index episode) and had >= 12 months of continuous health plan enrollment before and after the end of the index episode. Resource utilization and costs during a first MACE were assessed. Multivariable analyses were used to assess the associations between cardiovascular risk factors and the occurrence of a MACE, as well as the costs incurred during a first MACE. RESULTS: Of 75,231 study patients identified, 3.3% had a MACE and 8.3% had an SCE during the 12-month follow-up. Median time to first MACE and SCE from end of the index episode was 4.6 and 3.7 months, respectively. Mean MACE-related cost incurred during the first MACE was $19,642. Logistic analyses showed that age and diabetes were associated with increased odds of a MACE, while index ACS episodes involving ST-elevation myocardial infarction were associated with reduced odds. Findings from generalized linear models indicated that statin use and age were associated with lower episode-related costs and that MACE occurrence within 3 months of ACS hospitalization was associated with increased episode-related costs. CONCLUSIONS: MACEs and SCEs represent a common and costly burden in the year following ACS hospitalization. Our findings may inform future economic assessments of new therapies aimed at prevention of MACEs and SCEs. PMID- 26011547 TI - The effect of a diabetes collaborative care management program on clinical and economic outcomes in patients with type 2 diabetes. AB - BACKGROUND: Clinical pharmacy services (CPS) in the primary care setting have been shown to help patients attain treatment goals and improve outcomes. However, the availability of CPS in community-based primary care is not widespread. One reason is that current fee-for-service models offer limited reimbursement opportunities for CPS in the community setting. Furthermore, data demonstrating the value of CPS in this setting are limited, making it difficult for providers to determine the feasibility and sustainability of incorporating CPS into primary care practice. OBJECTIVES: To (a) evaluate the association between a pharmacist led, diabetes collaborative drug therapy management program and patient outcomes, including glycemic control and health care costs, and (b) assess short-term economic outcomes in a primary care setting. METHODS: A retrospective cohort analysis was conducted using medical record data. This study was conducted using patients with uncontrolled type 2 diabetes (T2DM), defined as HbA1c >= 7.0%. Outcomes were compared between patients referred to a diabetes collaborative care management (DCCM) intervention from 2009-2012 and patients who did not participate in the DCCM program. To illustrate the difference in HbA1c between the 2 cohorts over the follow-up period, mean time adjusted HbA1c values were estimated using a panel-type random effects regression model, with results plotted at 90-day intervals from index date through the end of the study period. To help control for confounding by other factors, multivariate regression models were run. A difference-in-difference model was employed to estimate the effect of the program on resource utilization and all-cause charges. RESULTS: A total of 303 DCCM and 394 comparison patients were included. Mean (95% CI) age was 57.4 years (55.963, 58.902) versus 59.9 years (58.613, 61.276; P < 0.001) with 48% and 44% female for DCCM and comparison patients, respectively (P = 0.49). Mean baseline HbA1c was higher for DCCM (10.3%; 10.10, 10.53) than comparison patients (8.4%; 8.26, 8.61; P < 0.001). The greatest reduction in HbA1c was seen for both groups at 9 and 12 months post-index date. At these time points, the mean time adjusted difference in HbA1c between groups was no longer significant. Multivariate modeling identified that the DCCM program was associated with a 0.44% (-0.64, -0.25; P < 0.001) lower HbA1c at follow-up relative to the comparison group controlling for potential confounders, including baseline HbA1c. Change in resource utilization from pre- to post-index date did not differ between groups. However, in the difference-in-difference multivariate analysis the difference in mean all-cause charges from the 12-month pre- to post-index periods DCCM patients experienced a smaller average increase in charges ($250) than comparison patients ($1,341; coefficient = -0.423; 95% CI = -0.779, -0.068). CONCLUSIONS: A pharmacist-led diabetes collaborative care management program in a patient-centered primary care setting was associated with significantly better follow-up glycemic control relative to comparison patients. Further, the data suggest that the DCCM program was associated with a less substantial increase in all-cause total costs in patients with uncontrolled T2DM relative to comparison patients, which could translate into reduced costs and improved outcomes to managed care payers. PMID- 26011549 TI - Patient-reported medication adherence barriers among patients with cardiovascular risk factors. AB - BACKGROUND: Many patients experience barriers that make it difficult to take cardiovascular disease (CVD)-related medications as prescribed. The Cardiovascular Intervention Improvement Telemedicine Study (CITIES) was a tailored behavioral pharmacist-administered and telephone-based intervention for reducing CVD risk. OBJECTIVES: To (a) describe patient-reported barriers to taking their medication as prescribed and (b) evaluate patient-level characteristics associated with reporting medication barriers. METHODS: We recruited patients receiving care at primary care clinics affiliated with Durham Veterans Affairs Medical Center. Eligible patients were diagnosed with hypertension and/or hyperlipidemia that were poorly controlled (blood pressure of > 150/100 mmHg and/or low-density lipoprotein value > 130 mg/dL). At the time of enrollment, patients completed an interview with 7 questions derived from a validated medication barriers measure. Patient characteristics and individual medication treatment barriers are described. Multivariable linear regression was used to examine the association between a medication barrier score and patient characteristics. RESULTS: Most patients (n = 428) were married or living with their partners (57%) and were men (85%) who were diagnosed with hypertension and hyperlipidemia (64%). The most commonly reported barriers were having too much medication to take (31%) and forgetting whether medication was taken at a particular time (24%). In adjusted analysis, those who were not employed (1.32, 95% CI = 0.50-2.14) or did not have someone to help with tasks, if needed (1.66, 95% CI = 0.42-2.89), reported higher medication barrier scores. Compared with those diagnosed with hypertension and hyperlipidemia, those with only hypertension (0.91, 95% CI = 0.04-1.79) reported higher medication barrier scores. CONCLUSIONS: Barriers to medication adherence are common. Evaluating and addressing barriers may increase medication adherence. PMID- 26011548 TI - Clinical outcomes and medication adherence in acute coronary syndrome patients with and without type 2 diabetes mellitus: a longitudinal analysis 2006-2011. AB - BACKGROUND: The presence of type 2 diabetes mellitus magnifies the risks associated with acute coronary syndrome (ACS), increasing the risk of recurrent cardiovascular events (CVEs) and doubling the risk of death. Managing cardiovascular risk factors has little effect on lowering the mortality risk in patients with type 2 diabetes. OBJECTIVE: To evaluate the relationship between type 2 diabetes mellitus and subsequent CVEs and medication adherence following ACS hospitalization. METHODS: Patients with ACS were identified using ICD-9-CM codes for acute myocardial infarction or unstable angina. The risk of subsequent CVEs was assessed at 1 and 3 years after the index ACS event based on type 2 diabetes status, adjusting for baseline demographic characteristics, comorbidities, medication use, and index ACS characteristics. RESULTS: Of 140,903 patients with ACS (mean age 66.8 years, 58.6% male), 27.4% had type 2 diabetes. During follow-up, 22.0% had subsequent CVEs (26.2% type 2 diabetes, 19.0% nondiabetes). After adjusting for other covariates, type 2 diabetes was associated with increased risk of subsequent CVEs by 9.7% at 1 year and 10.2% at 3 years (both P < 0.001). Most patients were not revascularized at first recurrence after index ACS discharge (79.2% type 2 diabetes, 77.5% nondiabetes). Patients with type 2 diabetes had statistically significant higher adherence rates for antiplatelet agents at 1 year and antihypertensives at 1 and 3 years versus nondiabetes patients. Persistence was higher in the type 2 diabetes group for antihypertensives and in the nondiabetes group for antiplatelet agents and statins. CONCLUSIONS: This analysis demonstrates that patients with type 2 diabetes have a higher risk of subsequent CVEs following an initial event versus those without diabetes, despite evidence of higher treatment persistence for certain medications. Adherence rates remained suboptimal, suggesting a continuing need for patient education. PMID- 26011550 TI - Predictors of concomitant use of antipsychotics and stimulants and its impact on stimulant persistence in pediatric attention deficit hyperactivity disorder. AB - BACKGROUND: Concomitant use of stimulants and atypical antipsychotics is common in pediatric attention deficit hyperactivity disorder (ADHD). However, little is known about the determinants of concomitant use and its utility in the management of pediatric ADHD. OBJECTIVES: To (a) examine predictors of concomitant stimulant and atypical antipsychotic use and (b) evaluate the impact of concomitant atypical antipsychotic use on the persistence of stimulants in children and adolescents diagnosed with ADHD. METHODS: The retrospective cohort study was conducted using 4 years (January 2004-December 2007) of IMS LifeLink claims data. The study population included children and adolescents aged 6-16 years with a diagnosis of ADHD and those who initiated long-acting stimulants (LAS) from July 2004 to December 2006. Patients were followed for 1 year after index stimulant use. Concomitant use was defined as the concurrent prescription for LAS and atypical antipsychotic agents with at least 14 days overlap after the index LAS claim. Persistence was measured by summing the total number of days a patient remained on the index LAS from the index prescription date with an allowable gap of no more than 30 days. Multiple logistic regression within the conceptual framework of the Andersen Behavioral Model was performed to determine the predictors of concomitant stimulant and atypical antipsychotic use. Multivariate Cox proportional hazards regression within the conceptual framework of the Andersen Behavioral Model was used to examine the impact of concomitant atypical antipsychotic use on persistence of stimulants. RESULTS: The study cohort consisted of 39,981 children who initiated LAS treatment. Most (96.10%) received LAS monotherapy, and 3.90% received LAS and atypical antipsychotic concomitantly. The multiple logistic regression analysis found that gender, health insurance, region, year of cohort entry, season, physician specialty, coexisting mental health conditions, and general mental health status influenced the concomitant use of LAS and atypical antipsychotic agents. Bivariate analyses revealed that concomitant users had longer persistence (by 71 days) than the stimulant-alone users. Cox proportional hazards regression revealed that concomitant atypical antipsychotic was associated with improvement in LAS persistence by 15% (HR = 0.85, 95% CI = 0.76-0.94) in comparison with the LAS recipients who did not use atypical antipsychotic concomitantly. Other factors such as age, region, season, coexisting mental health conditions, use of comedications, and general mental health status influenced the LAS treatment persistence among children and adolescents. CONCLUSIONS: Various predisposing, enabling, and need factors were associated with the concomitant stimulant and atypical antipsychotic use. Concomitant use of atypical antipsychotics was associated with improved LAS treatment persistence in children and adolescents with ADHD. PMID- 26011551 TI - Association between gastrointestinal events and persistence with osteoporosis therapy: analysis of administrative claims of a U.S. managed care population. AB - BACKGROUND: A large proportion of patients do not persist with osteoporosis (OP) therapy. Gastrointestinal (GI) events (e.g., gastroesophageal reflux disease and nausea/vomiting) are common among OP patients receiving OP therapy and may impact persistence with treatment. OBJECTIVE: To examine the association of GI events and persistence with OP therapy. METHODS: Using a large U.S. administrative claims database, we studied women aged >= 55 years who received oral bisphosphonate (BIS) as their first OP therapy from 2002-2009. The index date was the first pharmacy claim date recorded for oral BIS therapy; the baseline period was 12 months pre-index, and follow-up was 12 months post-index. Patients were considered persistent with therapy if they had continuous refills of the index drug class without additional drug therapy from a different drug class from the index date until the end of the follow-up period with no gaps in supply greater than 45 days. Discontinuation was defined as the first gap greater than 45 days during which there was no evidence of refills of OP medication. The association between post-treatment GI events and the risk of discontinuation or switching was modeled with Cox regression stratified by presence of baseline GI events and adjusted for baseline clinical and demographic characteristics. RESULTS: Of the 75,593 women who met eligibility criteria, 59.9% discontinued BIS; 39.3% were persistent; and 0.5% switched to non-BIS. GI events were diagnosed in 20,073 patients (26.6%) during baseline and in 21,142 (28.0%) in the post-treatment period (12-month follow-up post-index). Patients with post-treatment GI diagnosis were 35.6% more likely to discontinue or switch treatment (HR = 1.356, 95% CI = 1.318-1.396) during the 12-month follow-up compared with those without post treatment GI diagnosis. GI events that occurred closer to treatment discontinuation or switching were associated with a greater risk of discontinuation or switching: 37.9% (HR = 1.379, 95% CI = 1.338-1.421) for GI events within 6 months of discontinuation or switching and 45.6% (HR = 1.456, 95% CI = 1.408-1.505) for GI events within 3 months of discontinuation or switching. CONCLUSIONS: Among women aged 55 years or older in a U.S. managed care population, post-treatment GI events were associated with a higher risk of discontinuation of oral BIS or switching to non-BIS. PMID- 26011552 TI - Managing oral phosphate binder medication expenditures within the Medicare bundled end-stage renal disease prospective payment system: economic implications for large U.S. dialysis organizations. AB - BACKGROUND: From January 2016, payment for oral-only renal medications (including phosphate binders and cinacalcet) was expected to be included in the new Medicare bundled end-stage renal disease (ESRD) prospective payment system (PPS). The implementation of the ESRD PPS has generated concern within the nephrology community because of the potential for inadequate funding and the impact on patient quality of care. OBJECTIVE: To estimate the potential economic impact of the new Medicare bundled ESRD PPS reimbursement from the perspective of a large dialysis organization in the United States. METHODS: We developed an interactive budget impact model to evaluate the potential economic implications of Medicare payment changes to large dialysis organizations treating patients with ESRD who are receiving phosphate binders. In this analysis, we focused on the budget impact of the intended 2016 integration of oral renal drugs, specifically oral phosphate binders, into the PPS. We also utilized the model to explore the budgetary impact of a variety of potential shifts in phosphate binder market shares under the bundled PPS from 2013 to 2016. RESULTS: The base model predicts that phosphate binder costs will increase to $34.48 per dialysis session in 2016, with estimated U.S. total costs for phosphate binders of over $682 million. Based on these estimates, a projected Medicare PPS $33.44 reimbursement rate for coverage of all oral-only renal medications (i.e., phosphate binders and cinacalcet) would be insufficient to cover these costs. A potential renal drugs and services budget shortfall for large dialysis organizations of almost $346 million was projected. CONCLUSIONS: Our findings suggest that large dialysis organizations will be challenged to manage phosphate binder expenditures within the planned Medicare bundled rate structure. As a result, large dialysis organizations may have to make treatment choices in light of potential inadequate funding, which could have important implications for the quality of care for patients with ESRD. PMID- 26011553 TI - Persistence and compliance among U.S. patients receiving pazopanib or sunitinib as first-line therapy for advanced renal cell carcinoma: a retrospective claims analysis. AB - BACKGROUND: For first-line therapy options for advanced renal cell carcinoma (RCC), clinical trials have demonstrated similar efficacy for pazopanib and sunitinib as well as differing side-effect profiles, which may affect patient persistence in self-administration of these oral medications. However, the treatment patterns of each drug in real-world clinical practice, as opposed to the controlled environment of a trial, have not been directly compared. OBJECTIVE: To compare persistence and compliance (adherence) with pazopanib versus sunitinib in a real-world setting. METHODS: This was a retrospective claims analysis using 2 databases: Optum Research Database and Impact National Benchmark Database. Eligible patients included adult patients (aged >= 18 years) with >= 2 RCC diagnoses and evidence of first-line therapy with >= 1 subsequent pharmacy claim for pazopanib or sunitinib between October 2009 and July 2012. The date of the first pazopanib or sunitinib claim was defined as the index date. Additional requirements included continuous enrollment in the health plan for 2 months prior (baseline period) through 6 months after (follow-up period) the index date and no cancers other than those associated with RCC. Propensity score matching was used to minimize selection bias. Persistence with the index drug was compared using days to discontinuation, estimated level of persistence (ELPT) at 180 days, and proportion of days covered (PDC). PDC was defined by dividing the number of days covered with the index drug by the number of follow-up days. Compliance was estimated using medication possession ratio (MPR). For matched cohort pairs with > 1 fill, MPR was defined by dividing the number of days covered with the index drug by the number of days between the first and last index medication fill. RESULTS: We identified 84 matched pairs among 97 patients prescribed pazopanib and 349 prescribed sunitinib. Among the matched population, mean comorbidity index score was 5.8 (95% CI = 1.8-6.0) for pazopanib, and 6.1 (95% CI =1.8-6.0) for sunitinib (P = 0.133). Evidence of any radiation therapy during the baseline period was significantly higher among the sunitinib cohort prior to matching (9% vs. 18%, P = 0.043), and evidence of surgery was higher in the pazopanib cohort after matching (12% vs. 7%, P = 0.046). Cohorts were balanced according to demographic and clinical characteristics with mean (SD) age of 63.0 (9.0) years and 77.4% male. During the 6-month period after drug initiation, there was no significant difference (P > 0.05) by drug cohort in the duration of index drug therapy or the percentage of patients who discontinued their index drugs. The mean (SD) time to discontinuation was 133.4 (62.8) days and 139.9 (55.6) days among the matched pazopanib and sunitinib cohorts, respectively (P = 0.445). In both cohorts, more than 40% of patients discontinued their index drugs (46.4% pazopanib and 44.1% sunitinib, P = 0.732). In addition, there was no significant difference by drug cohort in the ELPT at any time examined between 30 and 180 days after initiation of therapy. PDC with the index drug during the fixed 6-month follow-up was also examined. Although the mean PDC was significantly higher among the sunitinib cohort (0.77 vs. 0.68 for pazopanib, P = 0.037), there was no difference by cohort in the percentage of patients with high PDC (defined as >= 80%): 52.4% versus 56.0% for pazopanib and sunitinib, respectively (P = 0.622). Mean MPR among matched pairs with at least 2 fills for the index drug was significantly higher among the sunitinib cohort, although there was no difference by cohort in the percentage of patients with high MPR (defined as >= 80%): 81.4% versus 93.2% for pazopanib and sunitinib, respectively (P > 0.071). CONCLUSIONS: In the first 6 months of treatment, persistence and compliance to pazopanib and sunitinib were similar. Future studies are needed, including those assessing larger cohorts and longer follow-up periods. PMID- 26011554 TI - Venobiliary fistula related to umbilical venous catheter in a newborn. AB - We present a case of venobiliary fistula due to umbilical venous catheter (UVC). UVC was inserted the day before surgery in a newborn who was scheduled for type IIIB jejunal atresia surgery. The UVC was superimposed on the liver. It was noted that the gastric drainage became chylous and increased to 790 and then 1977 mL daily. I.v. contrast tomography with 650 mL contrast showed that the opaque substance was dispersed around the catheter and a venobiliary fistula formed, with the administered fluid accumulating in the duodenum. Rapid improvement was seen in the clinical picture after the UVC was removed. Venobiliary fistula may develop in patients with UVC that is not placed appropriately, and can direct the fluid administered from the UVC to the gastrointestinal system through the choledochal duct. The importance of contrast computed tomography in the diagnosis of venobiliary fistula in the newborn is also emphasized. PMID- 26011555 TI - Quantitative tracking of protein trafficking to the nucleus using cytosolic protein delivery by nanoparticle-stabilized nanocapsules. AB - We describe a method for quantitative monitoring of subcellular protein trafficking using nanoparticle-stabilized nanocapsules for protein delivery. This method provides rapid delivery of the protein into the cytosol, eliminating complications from protein homeostasis processes found with cellularly expressed proteins. After delivery, nuclear protein trafficking was followed by real time microscopic imaging. Quantitative analyses of the accumulation percentage and the import dynamics of the nuclear protein trafficking, demonstrate the utility of this method for studying intracellular trafficking systems. PMID- 26011556 TI - Arabidopsis Lectin Receptor Kinases LecRK-IX.1 and LecRK-IX.2 Are Functional Analogs in Regulating Phytophthora Resistance and Plant Cell Death. AB - L-type lectin receptor kinases (LecRK) are potential immune receptors. Here, we characterized two closely-related Arabidopsis LecRK, LecRK-IX.1 and LecRK-IX.2, of which T-DNA insertion mutants showed compromised resistance to Phytophthora brassicae and Phytophthora capsici, with double mutants showing additive susceptibility. Overexpression of LecRK-IX.1 or LecRK-IX.2 in Arabidopsis and transient expression in Nicotiana benthamiana increased Phytophthora resistance but also induced cell death. Phytophthora resistance required both the lectin domain and kinase activity, but for cell death, the lectin domain was not needed. Silencing of the two closely related mitogen-activated protein kinase genes NbSIPK and NbNTF4 in N. benthamiana completely abolished LecRK-IX.1-induced cell death but not Phytophthora resistance. Liquid chromatography-mass spectrometry analysis of protein complexes coimmunoprecipitated in planta with LecRK-IX.1 or LecRK-IX.2 as bait, resulted in the identification of the N. benthamiana ABC transporter NbPDR1 as a potential interactor of both LecRK. The closest homolog of NbPDR1 in Arabidopsis is ABCG40, and coimmunoprecipitation experiments showed that ABCG40 associates with LecRK-IX.1 and LecRK-IX.2 in planta. Similar to the LecRK mutants, ABCG40 mutants showed compromised Phytophthora resistance. This study shows that LecRK-IX.1 and LecRK-IX.2 are Phytophthora resistance components that function independent of each other and independent of the cell-death phenotype. They both interact with the same ABC transporter, suggesting that they exploit similar signal transduction pathways. PMID- 26011557 TI - Cyclic Lipopeptides of Bacillus amyloliquefaciens subsp. plantarum Colonizing the Lettuce Rhizosphere Enhance Plant Defense Responses Toward the Bottom Rot Pathogen Rhizoctonia solani. AB - The commercially available inoculant Bacillus amyloliquefaciens FZB42 is able to considerably reduce lettuce bottom rot caused by Rhizoctonia solani. To understand the interaction between FZB42 and R. solani in the rhizosphere of lettuce, we used an axenic system with lettuce bacterized with FZB42 and inoculated with R. solani. Confocal laser scanning microscopy showed that FZB42 could delay the initial establishment of R. solani on the plants. To show which secondary metabolites of FZB42 are produced under these in-situ conditions, we developed an ultra-high performance liquid chromatography coupled to time of flight mass spectrometry-based method and identified surfactin, fengycin, and bacillomycin D in the lettuce rhizosphere. We hypothesized that lipopeptides and polyketides play a role in enhancing the plant defense responses in addition to the direct antagonistic effect toward R. solani and used a quantitative real-time polymerase chain reaction-based assay for marker genes involved in defense signaling pathways in lettuce. A significant higher expression of PDF 1.2 observed in the bacterized plants in response to subsequent pathogen challenge showed that FZB42 could enhance the lettuce defense response toward the fungal pathogen. To identify if surfactin or other nonribosomally synthesized secondary metabolites could elicit the observed enhanced defense gene expression, we examined two mutants of FZB42 deficient in production of surfactin and the lipopetides and polyketides, by expression analysis and pot experiments. In the absence of surfactin and other nonribosomally synthesized secondary metabolites, there was no enhanced PDF 1.2-mediated response to the pathogen challenge. Pot experiment results showed that the mutants failed to reduce disease incidence in lettuce as compared with the FZB42 wild type, indicating, that surfactin as well as other nonribosomally synthesized secondary metabolites play a role in the actual disease suppression and on lettuce health. In conclusion, our study showed that nonribosomally synthesized secondary metabolites of FZB42 are actually produced in the lettuce rhizosphere and contribute to the disease suppression by mediating plant defense gene expression toward the pathogen R. solani. PMID- 26011559 TI - HLA-DRB1 and HLA-DQB1 Are Associated with Adult-Onset Immunodeficiency with Acquired Anti-Interferon-Gamma Autoantibodies. AB - Recently a newly identified clinical syndrome of disseminated non-tuberculous mycobacterial diseases (with or without other opportunistic infections in adult patients who were previously healthy, has been recognized in association with an acquired autoantibody to interferon-gamma. This syndrome is emerging as an important cause of morbidity and mortality, especially among people of Asian descent. Trigger for the production of this autoantibody remains unknown, but genetic factors are strongly suspected to be involved. We compared HLA genotyping between 32 patients with this clinical syndrome, and 38 controls. We found that this clinical syndrome was associated with very limited allele polymorphism, with HLA-DRB1 and DQB1 alleles, especially HLA-DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02. Odds ratio of DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02 were 7.03 (95% CI, 2.18-22.69, P<0.0001, 9.06 (95% CI, 2.79-29.46, P<0.0001), 6.68 (95% CI, 2.29-19.52, P = 0.0004), and 6.64 (95% CI, 2.30-19.20, P = 0.0004), respectively. Further investigation is warranted to provide better understanding on pathogenesis of this association. PMID- 26011558 TI - TRAF3IP3, a novel autophagy up-regulated gene, is involved in marginal zone B lymphocyte development and survival. AB - Tumour necrosis factor receptor-associated factor 3 (TRAF3) interacting protein 3 (TRAF3IP3; also known as T3JAM) is expressed specifically in immune organs and tissues. To investigate the impact of TRAF3IP3 on immunity, we generated Traf3ip3 knock-out (KO) mice. Interestingly, these mice exhibited a significant reduction in the number of common lymphoid progenitors (CLPs) and inhibition of B cell development in the bone marrow. Furthermore, Traf3ip3 KO mice lacked marginal zone (MZ) B cells in the spleen. Traf3ip3 KO mice also exhibited a reduced amount of serum natural antibodies and impaired T cell-independent type II (TI-II) responses to trinitrophenol (TNP)-Ficoll antigen. Additionally, our results showed that Traf3ip3 promotes autophagy via an ATG16L1-binding motif, and MZ B cells isolated from mutant mice showed a diminished level of autophagy and a high rate of apoptosis. These results suggest that TRAF3IP3 contributes to MZ B cell survival by up-regulating autophagy, thereby promoting the TI-II immune response. PMID- 26011561 TI - High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry. AB - OBJECTIVES: The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate. METHODS: Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus. RESULTS: The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values. CONCLUSION: These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients. PMID- 26011560 TI - Achievable radiation reduction during pediatric cardiac catheterization: How low can we go? AB - OBJECTIVES: To assess the effectiveness of radiation-reduction measures implemented during pediatric catheterization, and provide data on the radiation doses for common interventional and diagnostic procedures, indexed to body weight. BACKGROUND: Ionizing radiation exposure must be minimized to "as low as reasonably achievable," by instituting radiation-limiting techniques and knowledge of expected radiation exposure. METHODS: Radiation-reduction measures included pulsed-fluoroscopy at 7.5 pulses/second (0.032-0.045 uGy/pulse), an air gap magnification technique for children<20 kg, operator awareness, and additional exposure reduction techniques through projection optimization. Radiation doses for procedures performed between 2007 through 2014 were retrospectively reviewed, including dose area product (DAP) and DAP/kg of body weight for 25 procedural types. Median doses were compared with those previously published from other large centers and multi-institutional databases and assessed for changes over time. RESULTS: Reviewed were 5,196 cases, which included 2,819 interventional, 710 endomyocardial biopsies and 1,667 diagnostic studies, documenting a significant difference in exposure between various procedures and body weights. The absolute exposure was significantly greater in larger children (e.g., for ductal closure median DAP/kg: 17 uGy*m2/kg 10-20 kg children vs. 37 uGy*m2 /kg for those>30 kg, P<0.001). Dose exposure using radiation-reduction techniques were the lowest reported in the literature for all procedure types compared (e.g. median DAP for pulmonary valvuloplasty 163 uGy*m2 vs. 405 to 1,230 uGy*m2 reported by 3 large centers). Reduction of fluoroscopy acquisition to 7.5 pulses/second nearly halved radiation exposure (P<0.001). CONCLUSIONS: Implementing a radiation dose reduction and awareness program can lead to documented reduction in exposure, across a variety of procedures performed by multiple operators. PMID- 26011562 TI - Effects of two calculolytic diets on parameters of feline mineral metabolism. AB - OBJECTIVES: To evaluate the influence of two feline calculolytic diets on selected parameters of mineral metabolism. MATERIALS AND METHODS: Two dry commercial diets designed for struvite urolith dissolution were evaluated in 14 cats. The study was designed as a two-sequence, four-period crossover protocol with a baseline period, two 60-day "run-in" periods in which calculolytic diets (Diet 1 and Diet 2) were fed and one 30-day "wash-out" period. Data are expressed as median (range). RESULTS: Feeding the calculolytic diets for two months did not alter plasma concentrations of calcium, phosphorus, magnesium and parathyroid hormone. A significant (P < 0.05 in each case) decline in calcitriol was observed after administering both diets from 236.4 (122.4-429.6) to 170.4 (108.0-394.3) pmol/L (Diet 1) and from 278.4 (153.6-492.0) to 177.1 (87.6-392.4) pmol/L (Diet 2). Cats fed Diet 1 showed a significant increase in urine calcium concentration (from 0.3 (0.2-0.5) to 0.4 (0.3-0.7) mmol/L). Magnesium concentration in urine was significantly increased with both diets, from 1.4 (0.1-1.7) to 1.5 (1.3-2.4) mmol/L (Diet 1) and from 1.1 (0.4-1.9) to 2.0 (0.1-3.1) mmol/L (Diet 2). CLINICAL SIGNIFICANCE: Both diets resulted in an increased urinary concentration of magnesium, through different mechanisms: urine acidification (Diet 1) and increased sodium load (Diet 2). PMID- 26011563 TI - Apheresis research-more abstracts should be published as full manuscripts to provide more evidence for clinical practice guidelines. AB - High-quality evidence to support clinical practice is lacking in apheresis medicine compared to other therapeutic modalities. A potential source of evidence comes from the abstracts submitted to the Annual Meetings of the American Society for Apheresis (ASFA). Therefore, the goal of this study is to determine the proportion of abstracts from the 2005 to 2012 ASFA Annual Meetings that subsequently became PubMed-indexed publications. Furthermore, we sought to determine the factor(s) that were associated with the likelihood of abstracts to be published as full manuscripts. During the 8-year study period, 684 abstracts were available for analysis (median: 82/year, range: 64-118). Most abstracts (74%) were from US institutions, and 67% of first authors were affiliated with academic centers. There were more abstracts (64%) on therapeutic versus donor apheresis (20%) and cellular therapy (16%). Overall, 16% of the abstracts have been published in PubMed-indexed journals, with a median time of 17 months from the ASFA Annual Meeting (range: 1-96 months). Abstracts whose first authors were affiliated with academic institutions were 3.14 times more likely to have been published than abstracts with ones affiliated with an apheresis organization and/or a community hospital. However, neither the first author's location nor the type of apheresis procedure significantly affected the publication rate after adjusting for other covariates. In conclusion, the rate of publication is low and authors should be encouraged to follow their presentations at the meeting with peer-reviewed manuscripts. This change is essential to provide more published evidence for future apheresis practice guidelines. J. Clin. Apheresis 31:353-358, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26011565 TI - Enzymatic isolation of viable human odontoblasts. AB - AIM: To improve an enzymatic method previously used for isolation of rat odontoblasts to isolate viable mature human odontoblasts. METHODOLOGY: Collagenase I, collagenase I/hyaluronidase mixture and hyaluronidase were used to extract mature human odontoblasts from the pulp chamber. Detachment of odontoblasts from dentine was determined with field emission scanning electron microscopy (FESEM) and to analyse the significance of differences in tubular diameter, and the t-test was used. MTT-reaction was used to analyse cell viability, and nonparametric Kruskal-Wallis and Mann-Whitney post hoc tests were used to analyse the data. Immunofluorescent staining of dentine sialoprotein (DSP), aquaporin-4 (AQP4) and matrix metalloproteinase-20 (MMP-20) and quantitative PCR (qPCR) of dentine sialophosphoprotein (DSPP) were used to confirm the odontoblastic nature of the cells. RESULTS: MTT-reaction and FESEM demonstrated collagenase I/hyaluronidase resulted in more effective detachment and higher viability than collagenase I alone. Hyaluronidase alone was not able to detach odontoblasts. Immunofluorescence revealed the typical odontoblastic morphology with one process, and DSP, AQP4 and MMP-20 were detected. Quantitative PCR of DSPP confirmed that the isolated cells expressed this odontoblast-specific gene. CONCLUSION: The isolation of viable human odontoblasts was successful. The cells demonstrated morphology typical for odontoblasts and expressed characteristic odontoblast-type genes and proteins. This method will enable new approaches, such as apoptosis analysis, for studies using fully differentiated odontoblasts. PMID- 26011564 TI - Systematic review and meta-analysis: full- vs. half-dose anti-microbials in clarithromycin-based regimens for Helicobacter pylori eradication. AB - BACKGROUND: Half-dose regimens may be equally effective but associated with diminished adverse events (AE) than standard-dose regimens. AIM: To assess efficacy and safety of full- vs. half-dose clarithromycin in the treatment of H. pylori. METHODS: Medline, EMBASE and PubMed databases were searched for randomised controlled trials (RCTs) that meet eligibility criteria. Only parallel group RCTs with >= 2 arms were eligible. Studies comparing triple, quadruple or sequential therapy for 7-14 days were selected. Regimens had to contain the same drug combination, differing only in dosage; the comparison of full- vs. half-dose clarithromycin was required, regardless if other drugs were dose-reduced or not. Data extraction was performed for primary outcome [eradication by intent-to-treat (ITT) and per-protocol (PP) analyses] and secondary outcome (AE). RESULTS: A total of 1622 articles were identified, of which 19 studies were eligible. Overall, eradication was achieved in 82.5% of half-dose (n = 2115) vs. 83.4% of full-dose recipients (n = 2109) on ITT (87.1% vs. 88.4% on PP respectively). Pooled relative risk in the half- vs. full-dose regimen was 0.98 (95% CI: 0.95 1.02) on ITT and 0.99 (95% CI: 0.97-1.01) on PP by the random effects model. Heterogeneity was significant (chi-squared statistic P = 0.05, I(2) = 37%). AE were reported in 29.3% of half- vs. 44.0% of full-dose recipients [pooled RR 0.67 (95% CI: 0.60-0.75)]. Pre-planned subgroup analyses of dose modification, sample size, study origin and treatment duration, as well as sensitivity analysis showed no significant differences between arms. CONCLUSION: A half-dose clarithromycin based regimen is equally effective yet better tolerated than its full-dose counterpart in the treatment of H. pylori. PMID- 26011566 TI - L-arginine supplementation of reduced-protein diets improves pulmonary hypertensive response in broiler chickens reared at high altitude. AB - This study was conducted at high altitude (2100 m above sea level). A total of 208 d-old male broilers (Ross 308) were randomised across 16 floor pens and reared up to 42 d. A normal-protein diet (NPD) was formulated according to the National Research Council. A reduced-protein diet (RPD) was prepared with dietary protein reduced by 30 g/kg relative to that of the NPD. Two additional diets were prepared by adding 2 and 4 g L-arginine (ARG)/kg to the RPD. At the end of trial (42 d), blood sampling was done and carcass characteristics were recorded. ARG supplementation of the RPD at 4 g improved feed:gain in the growing stage and throughout the trial compared with the RPD. The right-to-total ventricular weight ratio was significantly increased in birds fed on RPD compared with those fed on NPD or ARG-supplemented RPD. Feeding RPD caused a significant decrease in plasma concentrations of nitric oxide (NO) and uric acid. Plasma NO level, however, was restored by ARG supplementation of RPD. ARG supplementation of RPD, however, significantly reduced the rate of pulmonary hypertension syndrome mortality compared to the negative control fed on RPD. PMID- 26011567 TI - Some See It, Some Don't: Exploring the Relation between Inattentional Blindness and Personality Factors. AB - Human awareness is highly limited, which is vividly demonstrated by the phenomenon that unexpected objects go unnoticed when attention is focused elsewhere (inattentional blindness). Typically, some people fail to notice unexpected objects while others detect them instantaneously. Whether this pattern reflects stable individual differences is unclear to date. In particular, hardly anything is known about the influence of personality on the likelihood of inattentional blindness. To fill this empirical gap, we examined the role of multiple personality factors, namely the Big Five, BIS/BAS, absorption, achievement motivation, and schizotypy, in these failures of awareness. In a large-scale sample (N = 554), susceptibility to inattentional blindness was associated with a low level of openness to experience and marginally with a low level of achievement motivation. However, in a multiple regression analysis, only openness emerged as an independent, negative predictor. This suggests that the general tendency to be open to experience extends to the domain of perception. Our results complement earlier work on the possible link between inattentional blindness and personality by demonstrating, for the first time, that failures to consciously perceive unexpected objects reflect individual differences on a fundamental dimension of personality. PMID- 26011568 TI - Lithium-induced Clock Gene Expression in Lymphoblastoid Cells of Bipolar Affective Patients. AB - INTRODUCTION: Disturbances of circadian rhythms occur in all episodes of bipolar disorder (BD). Lithium, as gold-standard in the maintenance treatment of BD, is known to influence circadian processes. METHODS: In a pilot study lymphoblastoid cell lines (LCLs) were generated from 8 BD patients and 6 healthy controls. The LCLs were treated with lithiumchloride (LiCl) for 3 weeks. Cell cycles were then synchronized and expressional analysis by quantitative Real Time PCR was done. RESULTS: BD and controls differed in the period length regarding DBP (albumin D box binding protein) expression and DBP expression was also influenced by lithium treatment. Furthermore, baseline DBP expression was significantly different between non-treated BD and healthy controls. None of the other analyzed circadian genes showed to be influenced by chronic lithium treatment or to be differentially regulated due to the diagnosis. DISCUSSION: We here show that chronic lithium treatment of LCLs leads to decreased expression of the clock gene DBP, rendering DBP a lithium-regulated gene. We could confirm the role of the circadian clock as well in lithium mode of action as in the pathomechanisms of BD although future studies with a greater number of participants and cell lines are needed. PMID- 26011569 TI - Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re Analysis of Data from a Randomized Clinical Trial. AB - OBJECTIVE: The aim of this study was to examine whether gender differences may have affected treatment response to S-adenosyl methionine (SAMe) in a recent failed randomized clinical trial (RCT) for adults with major depressive disorder. METHODS: Data from a 2-site, 12-week, double-blind RCT (n=189) assessing the efficacy of SAMe vs. placebo and a comparator selective serotonin reuptake inhibitor (escitalopram) were subjected to post-hoc analyses to evaluate effects of patient gender on treatment response. RESULTS: When assessing the efficacy outcomes within each gender separately, SAMe was superior to placebo among males (n=51), but not among females (n=62). Males showed a significant reduction of depression severity from baseline to study endpoint on the 17-item Hamilton Depression Rating Scale (4.3 point difference; p=0.034; d=0.95), while females did not show significant change. This finding emerged despite equivalence on baseline measures of depression severity between the gender groups. CONCLUSION: RESULTS of this secondary data analysis suggest that gender might impact the antidepressant efficacy of SAMe, with greater therapeutic effect found in males. The underlying mechanism is still relatively unknown. Further work is needed to replicate this observation in independent samples.Clinicaltrials.gov identifier: NCT00101452. PMID- 26011571 TI - Discrepant diagnostic results using two genotyping methods in a chronic hepatitis C patient in serogroup 1. AB - We present the case of a chronic hepatitis C (CHC) patient who was originally diagnosed with genotype 2a on serogroup 1 CHC genotype testing, but who was subsequently confirmed to have genotype 1b when using the hepatitis C virus (HCV) monitor genotype assay. The genotype 2a diagnosis was attributed to the fact that the type 2a-specific primer used in Okamoto et al.'s method (HCV genotype primer kit) has relatively high homology, which caused the amplification reaction to proceed, rendering a HCV RNA genotype test result of 2a. Genotype testing is important in determining whether a patient is indicated for concomitant dual oral therapy; however, the potential for different diagnoses such as described in this report highlights the importance of serogroup confirmation. PMID- 26011570 TI - The repertoire of somatic genetic alterations of acinic cell carcinomas of the breast: an exploratory, hypothesis-generating study. AB - Acinic cell carcinoma (ACC) of the breast is a rare form of triple-negative (that is, oestrogen receptor-negative, progesterone receptor-negative, HER2-negative) salivary gland-type tumour displaying serous acinar differentiation. Despite its triple-negative phenotype, breast ACCs are reported to have an indolent clinical behaviour. Here, we sought to define whether ACCs have a mutational repertoire distinct from that of other triple-negative breast cancers (TNBCs). DNA was extracted from microdissected formalin-fixed, paraffin-embedded sections of tumour and normal tissue from two pure and six mixed breast ACCs. Each tumour component of the mixed cases was microdissected separately. Tumour and normal samples were subjected to targeted capture massively parallel sequencing targeting all exons of 254 genes, including genes most frequently mutated in breast cancer and related to DNA repair. Selected somatic mutations were validated by targeted amplicon resequencing and Sanger sequencing. Akin to other forms of TNBC, the most frequently mutated gene found in breast ACCs was TP53 (one pure and six mixed cases). Additional somatic mutations affecting breast cancer-related genes found in ACCs included PIK3CA, MTOR, CTNNB1, BRCA1, ERBB4, ERBB3, INPP4B, and FGFR2. Copy number alteration analysis revealed complex patterns of gains and losses similar to those of common forms of TNBCs. Of the mixed cases analysed, identical somatic mutations were found in the acinic and the high-grade non-acinic components in two out of four cases analysed, providing evidence of their clonal relatedness. In conclusion, breast ACCs display the hallmark somatic genetic alterations found in high-grade forms of TNBC, including complex patterns of gene copy number alterations and recurrent TP53 mutations. Furthermore, we provide circumstantial genetic evidence to suggest that ACCs may constitute the substrate for the development of more aggressive forms of triple negative disease. PMID- 26011574 TI - Determination of material constants of vertically aligned carbon nanotube structures in compressions. AB - Different chemical vapour deposition (CVD) fabrication conditions lead to a wide range of variation in the microstructure and morphologies of carbon nanotubes (CNTs), which actually determine the compressive mechanical properties of CNTs. However, the underlying relationship between the structure/morphology and mechanical properties of CNTs is not fully understood. In this study, we characterized and compared the structural and morphological properties of three kinds of vertically aligned carbon nanotube (VACNT) arrays from different CVD fabrication methods and performed monotonic compressive tests for each VACNT array. The compressive stress-strain responses and plastic deformation were first compared and analyzed with nanotube buckling behaviours. To quantify the compressive properties of the VACNT arrays, a strain density energy function was used to determine their intrinsic material constants. Then, the structural and morphological effects on the quantified material constants of the VACNTs were statistically investigated and analogized to cellular materials with an open-cell model. The statistical analysis shows that density, defect degree, and the moment of inertia of the CNTs are key factors in the improvement of the compressive mechanical properties of VACNT arrays. This approach could allow a model-driven CNT synthesis for engineering their mechanical behaviours. PMID- 26011573 TI - Test ordering in an evidence free zone: Rates and associations of Australian general practice trainees' vitamin D test ordering. AB - RATIONALE, AIMS AND OBJECTIVES: Indiscriminate health screening is increasingly seen as being problematic. In particular, vitamin D testing rates are increasing rapidly despite recommendations against population screening. The purpose of this study was to determine the level of vitamin D testing among family practice/general practitioner (GP) trainees and to establish associations of this testing. METHODS: Cross-sectional analysis of data from the ReCEnT (Registrars Clinical Encounters in Training) cohort study. The setting was GP practices in four Australian states. Data from 60 consecutive consultations per trainee were recorded each 6-month training term (up to four terms). RESULTS: Vitamin D tests were ordered in 726 (1.0%) of encounters (n = 69 412). Vitamin D test ordering was significantly associated with patients being older, female and non-English speaking. Trainees were more likely to test if they worked in a completely bulk billing practice (i.e. a practice without any patient payment), if more problems were dealt with, more pathology tests were ordered in the consultation and if a lipid profile was ordered. They were less likely to test if they sought in consultation advice or information. The most common reasons for testing were 'check-up' and 'health maintenance'. CONCLUSIONS: In this first report of associations of vitamin D testing in the GP setting, we found that non-targeted vitamin D testing (testing inconsistent with current guidelines) is widespread in GP trainees' practice. Adoption of more rational testing approaches is needed. PMID- 26011575 TI - Relation of borderline personality features to preincarceration HIV risk behaviors of jail inmates: Evidence for gender differences? AB - The present study explored the relationship between borderline personality disorder (BPD) features and preincarceration HIV risk behaviors in a sample of 499 (70% male) jail inmates, as well as gender differences in these associations. Elevated levels of BPD symptomatology were present among male and female participants, though there was considerable variance observed in participants' BPD symptoms and HIV risk behaviors. In the full sample, BPD features were positively associated with a variety of HIV risk behaviors, including injection drug use and frequency of unprotected sex with high risk partners and under high risk circumstances. Gender moderated only 2 relationships between BPD features and HIV risk behaviors, with a stronger association between BPD features and number of sexual partners, and BPD features and frequency of unprotected sex while under the influence of alcohol or drugs for women, relative to men. Taken together, these findings suggest that programs targeting HIV risk within correctional populations may benefit from considering the role of BPD features, particularly emotion regulation difficulties and impulsivity, in influencing HIV risk behaviors among both women and men. PMID- 26011576 TI - Mapping the association of global executive functioning onto diverse measures of psychopathic traits. AB - Psychopathic individuals display a callous-coldhearted approach to interpersonal and affective situations and engage in impulsive and antisocial behaviors. Despite early conceptualizations suggesting that psychopathy is related to enhanced cognitive functioning, research examining executive functioning (EF) in psychopathy has yielded few such findings. It is possible that some psychopathic trait dimensions are more related to EF than others. Research using a 2-factor or 4-facet model of psychopathy highlights some dimension-specific differences in EF, but this research is limited in scope. Another complicating factor in teasing apart the EF-psychopathy relationship is the tendency to use different psychopathy assessments for incarcerated versus community samples. In this study, an EF battery and multiple measures of psychopathic dimensions were administered to a sample of male prisoners (N = 377). Results indicate that using the Psychopathy Checklist-Revised (PCL-R), the independent effect of Factor 2 was related to worse EF, but neither the independent effect of Factor 1 nor the unique variance of the Factors (1 or 2) were related to EF. Using a 4-facet model, the independent effects of Facet2 (Affect) and Facet4 (Antisocial) were related to worse EF, but when examining the unique effects, only Facet2 remained significant. Finally, the questionnaire-based measure, Multidimensional Personality Questionnaire-Brief, of Fearless Dominance was related to better EF performance, whereas PCL-R Factor 1 was unrelated to EF. Overall, the results reveal the complex relationship among EF and behaviors characteristic of psychopathy-related dimensions. Moreover, they demonstrate the interpersonal and affective traits measured by these distinct assessments are differentially related to EF. PMID- 26011578 TI - Does allergy begin in utero? AB - It has been recognized for centuries that allergic disease runs in families, implying a role for genetic factors in determining individual susceptibility. More recently, a range of evidence shows that many of these genetic factors, together with in utero environmental exposures, lead to the development of allergic disease through altered immune and organ development. Environmental exposures during pregnancy including diet, nutrient intake and toxin exposures can alter the epigenome and interact with inherited genetic and epigenetic risk factors to directly and indirectly influence organ development and immune programming. Understanding of these factors will be essential in identifying at risk individuals and possible development of therapeutic interventions for the primary prevention of allergic disease. In this review, we summarize the evidence that suggests allergic disease begins in utero, together with possible mechanisms for the effect of environmental exposures during pregnancy on allergic disease risk, including epigenetics. PMID- 26011579 TI - Dermatitis artefacta in an adolescent female. PMID- 26011577 TI - Self-other disturbance in borderline personality disorder: Neural, self-report, and performance-based evidence. AB - Individuals with borderline personality disorder (BPD) display an impoverished sense of self and representations of self and others that shift between positive and negative poles. However, little research has investigated the nature of representational disturbance in BPD. The present study takes a multimodal approach. A card sort task was used to investigate complexity, integration, and valence of self-representation in BPD. Impairment in maintenance of self and other representations was assessed using a personality representational maintenance task. Finally, functional MRI (fMRI) was used to assess whether individuals with BPD show neural abnormalities related specifically to the self and what brain areas may be related to poor representational maintenance. Individuals with BPD sorted self-aspects suggesting more complexity of self representation, but also less integration and more negative valence overall. On the representational maintenance task, individuals with BPD showed less consistency in their representations of self and others over the 3-hr period, but only for abstract, personality-based representations. Performance on this measure mediated between-groups brain activation in several areas supporting social cognition. We found no evidence for social-cognitive disturbance specific to the self. Additionally, the BPD group showed main effects, insensitive to condition, of hyperactivation in the medial prefrontal cortex, temporal parietal junction, several regions of the frontal pole, the precuneus and middle temporal gyrus, all areas crucial social cognition. In contrast, controls evidenced greater activation in visual, sensory, motor, and mirror neuron regions. These findings are discussed in relation to research regarding hypermentalization and the overlap between self- and other-disturbance. PMID- 26011580 TI - Overactivation of Complement Alternative Pathway in Postpartum Atypical Hemolytic Uremic Syndrome Patients with Renal Involvement. AB - PROBLEM: Postpartum atypical hemolytic uremic syndrome (aHUS) is a life threatening syndrome with unclear pathogenesis. The current study aimed to investigate the clinical and pathological features, complement activation status, and the genetic variations in a Chinese cohort of patients with renal biopsy proven postpartum aHUS. METHOD OF STUDY: Five patients with postpartum aHUS were recruited. Renal biopsy specimens were examined and scored. Plasma levels of complements were detected, and coding sequences of complement regulators were screened. Anti-CFH/CFI autoantibodies were further detected. RESULTS: Patients with postpartum aHUS patients presented with severe clinical manifestations and renal involvement. The renal biopsies of the five patients showed typical features of thrombotic microangiopathies. The levels of the following complement components, C4d, Bb, C3a, C5a, and SC5b-9, were significantly elevated in patients with postpartum aHUS compared with normal non-pregnant controls. The plasma levels of CFH and CFI significantly decreased in patients with postpartum aHUS compared with normal pregnant women. Three CFH single nucleotide polymorphisms (SNPs) were identified in the five patients. Two patients presented with CFH autoantibodies. CONCLUSION: Postpartum aHUS is a clinical syndrome with severe renal damage. Genetic deficiencies and autoantibodies of CFH may lead to alternative pathway overactivation and participated in the pathogenesis of postpartum aHUS. PMID- 26011581 TI - Non-Chemotherapy-Induced Agranulocytosis Detected by a Prospective Pharmacovigilance Program in a Tertiary Hospital. AB - We conducted a prospective evaluation of non-chemotherapy-induced agranulocytosis (NIA) in a tertiary hospital in Spain. Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital, we detected agranulocytosis cases over a period of 42 consecutive months. This report estimates incidence, drug causality, clinical features and outcomes of NIA cases and assesses laboratory differences with respect to non-NIA. We detected 1349 cases of agranulocytosis in 538 adult patients; of these, 43 cases in 40 patients were caused by non chemotherapy drugs. The incidence rate for 10,000 patients during the study period was 2.75 [Poisson confidence interval (CI)-95%: 0.62-7.22]. The mean (S.D.) age was 48 (21) years. All cases were categorized as serious, because they required hospitalization (28 cases) or prolongation of hospitalization (15 cases). The outcome was recovery without sequela (39 cases), recovery with sequela (one case of toe amputation) or death (three cases, 7%). The most frequent cause of NIA was antimicrobial drugs (19 cases). The highest incidence rate per 10,000 defined daily doses was for cefepime (83.85; Poisson-CI 95%: 67 102.89). Automatic linear modelling (n = 75, R(2) = 77.9%) showed a significant inverse association with platelets, alkaline phosphatase, C-reactive protein, fibrinogen, lactate dehydrogenase; and direct association with mean corpuscular haemoglobin, and haematocrit. A generalized linear model retained platelets, total serum proteins, creatinine and haemoglobin. The findings suggest an immune mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure. There might be additional contributing factors, such as nutritional deficiencies or chronic diseases, to develop NIA after exposure to a potentially causative drug. PMID- 26011582 TI - A dietary intervention for chronic diabetic neuropathy pain: a randomized controlled pilot study. AB - BACKGROUND: Diabetic neuropathy is a common and often debilitating condition for which available treatments are limited. Because a low-fat plant-based diet has been shown to improve glycemic control in individuals with type 2 diabetes, we hypothesized that such a diet would reduce painful symptoms of diabetic neuropathy. METHODS: In this 20-week pilot study, individuals with type 2 diabetes and painful diabetic neuropathy were randomly assigned to two groups. The intervention group was asked to follow a low-fat, plant-based diet, with weekly classes for support in following the prescribed diet, and to take a vitamin B12 supplement. The control group was asked to take the same vitamin B12 supplement, but received no other intervention. At baseline, midpoint and 20 weeks, clinical, laboratory and questionnaire data were collected. Questionnaires included an analog 'worst pain' scale, Michigan Neuropathy Screening Instrument, global impression scale, Short Form McGill Pain Questionnaire, Neuropathy Total Symptom Score, a weekly pain diary and Norfolk Quality of Life Questionnaire. RESULTS: After 20 weeks, body weight change with the intervention was -6.4 kg (95% confidence interval (CI) -9.4 to -3.4, P<0.001) in an effect size analysis. Electrochemical skin conductance in the foot improved by an average of 12.4 microseimens (95% CI 1.2-23.6, P=0.03) with the intervention in an effect size analysis. The between-group difference in change in pain, as measured by the McGill pain questionnaire, was -8.2 points (95% CI -16.1 to -0.3, P=0.04). Michigan Neuropathy Screening Instrument questionnaire score change was -1.6 points (95% CI -3.0 to -0.2, P=0.03). CONCLUSIONS: Improvements were seen in some clinical and pain measures. This pilot study suggests the potential value of a plant-based diet intervention, including weekly support classes, for treating painful diabetic neuropathy. PMID- 26011583 TI - An experimental investigation of reactivity to ecological momentary assessment frequency among adults trying to quit smoking. AB - AIMS: Ecological Momentary Assessment (EMA) captures real-time reports in subjects' natural environments. This experiment manipulated EMA frequency to estimate effects on abstinence and peri-cessation subjective experiences. DESIGN: In this randomized trial, subjects had an equal chance of being assigned to low frequency (once) or high-frequency (six times) daily EMA for 4 weeks (1 week pre- and 3 weeks post-cessation). Participants completed six office visits over 5 weeks and 6- and 12-week follow-up telephone interviews. SETTING: Community participants were recruited from central New Jersey, USA. PARTICIPANTS: One hundred and ten adult daily smokers seeking to quit smoking were included in intent-to-treat analyses of tobacco abstinence; 94 were available for secondary analyses of peri-cessation subjective ratings. MEASUREMENTS: Primary outcomes were cessation (abstaining at least 24 hours within 2 weeks of attempting to quit) and prolonged abstinence (no relapse between weeks 2 and 12 post-quit). Secondary outcomes were mean levels and growth in ratings of cigarette craving, affect and quitting motivation and self-efficacy. FINDINGS: EMA frequency was unrelated to cessation (odds ratio = 1.367, 95% confidence interval = 0.603 3.098) or prolonged abstinence (odds ratio = 1.040, 95% confidence interval = 0.453-2.388) in intent-to-treat analyses. High-frequency EMA was associated with lower craving (B = -0.544, standard error (SE) = 0.183, P = 0.004, anxiety (B = 0.424, SE = 0.170, P = 0.015), anger (B = -0.474, SE = 0.139, P = 0.001), hunger (B = -0.388, SE = 0.170, P = 0.025) and positive affect (B = -0.430, SE = 0.196, P = 0.03). CONCLUSIONS: In smokers trying to quit, more frequent ecological momentary assessment self-monitoring results in lower craving, anxiety, anger, hunger and positive affect. It is not clear whether this translates into higher rates of smoking abstinence. PMID- 26011584 TI - Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties. AB - Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202. PMID- 26011585 TI - Childhood Traumatic Experiences, Dissociative Symptoms, and Dissociative Disorder Comorbidity Among Patients With Panic Disorder: A Preliminary Study. AB - This study assessed childhood trauma history, dissociative symptoms, and dissociative disorder comorbidity in patients with panic disorder (PD). A total of 92 psychotropic drug-naive patients with PD, recruited from outpatient clinics in the psychiatry department of a Turkish hospital, were involved in the study. Participants were assessed using the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D), Dissociation Questionnaire, Panic and Agoraphobia Scale, Panic Disorder Severity Scale, and Childhood Trauma Questionnaire. Of the patients with PD, 18 (19%) had a comorbid dissociative disorder diagnosis on screening with the SCID-D. The most prevalent disorders were dissociative disorder not otherwise specified, dissociative amnesia, and depersonalization disorders. Patients with a high degree of dissociation symptoms and dissociative disorder comorbidity had more severe PD than those without (p < .05). All of the childhood trauma subscales used were correlated with the severity of symptoms of dissociation and PD. Among all of the subscales, the strongest relationship was with childhood emotional abuse. Logistic regression analysis showed that emotional abuse and severity of PD were independently associated with dissociative disorder. In our study, a significant proportion of the patients with PD had concurrent diagnoses of dissociative disorder. We conclude that the predominance of PD symptoms at admission should not lead the clinician to overlook the underlying dissociative process and associated traumatic experiences among these patients. PMID- 26011586 TI - Technetium-99m methoxyisobutylisonitrile scintimammography for monitoring and early prediction of breast cancer response to neoadjuvant chemotherapy. AB - PURPOSE: The aim of the study was to evaluate the clinical value of scintimammography (SMG) with technetium-99m methoxyisobutylisonitrile (Tc-MIBI) for evaluating the efficacy of neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: A total of 65 patients with advanced breast cancer (BC) were included in the study. Planar SMG with 740 MBq of Tc-MIBI was performed before the start and after two to three and four to six cycles of NAC. NAC efficacy was estimated as progression (grade I), stabilization (grade II), partial effect (grade III), prominent efficacy (grade IV), and complete response (grade V). In 59 women, histopathologic verification of BC response to NAC was performed according to the Miller-Payne classification with the same scores as were used in the evaluation of scintigraphic response. RESULTS: After two to three cycles of NAC, disease progression was detected in five of 65 (7.7%) patients. In 27 (41.5%) patients SMG detected early stabilization of BC. Only one of these patients achieved prominent (grade IV) response after the end of NAC. Partial (grade III) response after two to three cycles of NAC was seen in 24 (36.9%) patients. One-third of them had grades IV-V response at the end of treatment. The most promising was the group of nine (13.8%) patients with early-grades IV-V response, all of which transformed to complete response at the end of NAC. As per histopathologic verification, early SMG had 85.7% sensitivity, 94.2% specificity, and 93.2% accuracy in predicting complete pathologic response to four to six cycles of NAC. CONCLUSION: After two to three cycles of NAC, SMG with Tc-MIBI can determine patients with low, intermediate, and high probability of complete response to five to six cycles of NAC Video Abstract: http://links.lww.com/NMC/A43. PMID- 26011587 TI - Investigation of attenuation correction in SPECT using textural features, Monte Carlo simulations, and computational anthropomorphic models. AB - PURPOSE: To present and evaluate a new methodology to investigate the effect of attenuation correction (AC) in single-photon emission computed tomography (SPECT) using textural features analysis, Monte Carlo techniques, and a computational anthropomorphic model. MATERIALS AND METHODS: The GATE Monte Carlo toolkit was used to simulate SPECT experiments using the XCAT computational anthropomorphic model, filled with a realistic biodistribution of (99m)Tc-N-DBODC. The simulated gamma camera was the Siemens ECAM Dual-Head, equipped with a parallel hole lead collimator, with an image resolution of 3.54 * 3.54 mm(2). Thirty-six equispaced camera positions, spanning a full 360 degrees arc, were simulated. Projections were calculated after applying a +/- 20% energy window or after eliminating all scattered photons. The activity of the radioisotope was reconstructed using the MLEM algorithm. Photon attenuation was accounted for by calculating the radiological pathlength in a perpendicular line from the center of each voxel to the gamma camera. Twenty-two textural features were calculated on each slice, with and without AC, using 16 and 64 gray levels. A mask was used to identify only those pixels that belonged to each organ. RESULTS: Twelve of the 22 features showed almost no dependence on AC, irrespective of the organ involved. In both the heart and the liver, the mean and SD were the features most affected by AC. In the liver, six features were affected by AC only on some slices. Depending on the slice, skewness decreased by 22-34% with AC, kurtosis by 35-50%, long-run emphasis mean by 71-91%, and long-run emphasis range by 62-95%. In contrast, gray level non-uniformity mean increased by 78-218% compared with the value without AC and run percentage mean by 51-159%. These results were not affected by the number of gray levels (16 vs. 64) or the data used for reconstruction: with the energy window or without scattered photons. CONCLUSION: The mean and SD were the main features affected by AC. In the heart, no other feature was affected. In the liver, other features were affected, but the effect was slice dependent. The number of gray levels did not affect the results. PMID- 26011588 TI - Factors related to self-reported social anxiety symptoms among incoming university students. AB - AIM: The aim of this study was to explore the lifestyle/social, personality trait and mental factors among incoming university students with higher self-reported social anxiety symptoms (SAS). METHODS: A total of 5126 incoming university students were recruited. The test battery included a self-administered questionnaire that examined personal lifestyle, the Measurement of Support Functions, the Chinese Internet Addiction Scale-Revision, the Organizational Citizenship Behaviour Scale, the Social Phobia Inventory, the suicide ideation from the Brief Symptoms Rating Scale and the Pittsburgh Sleep Questionnaire. RESULTS: SAS (23.7%) were prevalent. Using logistic regression analysis, we found that the significant predictors of higher levels of SAS were being an undergraduate student and a non-smoker, having lower Measurement of Support Functions score (poorer social support), having higher Chinese Internet Addiction Scale-Revision score (Internet addiction), having lower Organizational Citizenship Behaviour Scale score (less altruistic behaviour), having suicide ideation and having higher Pittsburgh Sleep Questionnaire score (poorer sleeper). CONCLUSIONS: Given the high prevalence of SAS among university students, it is necessary to build a better strategy to detect students with potential social anxiety-related problems/disorders or other mental problems early on. PMID- 26011590 TI - Habitual physical activity is associated with circulating irisin in healthy controls but not in subjects with diabetes mellitus type 2. AB - BACKGROUND: Irisin, a novel myokine, has been shown to increase following vigorous exercise, with studies suggesting that it mediates some of the beneficial effects of exercise. Irisin might play a role in 'browning' of white adipocytes, thus increasing energy expenditure. The role of irisin in exercise and energy expenditure in subjects with diabetes mellitus type 2 (DMT2) remains largely unknown. We aimed to investigate the association between circulating irisin and habitual physical activity in subjects with and without DMT2. MATERIAL AND METHODS: In this cross-sectional study, 164 Saudi adults: 81 non-DMT2 controls [age: (mean +/- SD) 51.6 +/- 10.9; BMI: 29.6 +/- 4.3 kg/m(2) ] and 83 DMT2 subjects [age: 54.3 +/- 10.3 year; BMI: 29.4 +/- 4.7 kg/m(2) ] were studied. Anthropometric and fasting serum biochemical data were collected. Circulating irisin was measured using an enzyme-linked immunosorbent assay (ELISA). Frequency intensity time (FIT) index was used to assess the level of habitual physical activity. RESULTS: We observed significantly higher levels of irisin in DMT2 subjects than in controls (P < 0.001). FIT index was positively associated (r = 0.20, P = 0.03) with circulating irisin in controls only. Additionally, irisin levels were significantly higher in tertile 3 (0.75 +/- 0.07 MUg/mL) than tertile 1 (0.49 +/- 0.06 MUg/mL) of the FIT index in healthy controls, whilst no such relation with physical activity was observed in DMT2 subjects. CONCLUSION: This cross-sectional study has shown a weak association of irisin with physical activity levels in healthy controls but not in DMT2 subjects, suggesting the possibility of discordant regulation in the condition of DMT2. PMID- 26011589 TI - IRF-1 inhibits NF-kappaB activity, suppresses TRAF2 and cIAP1 and induces breast cancer cell specific growth inhibition. AB - Interferon Regulatory Factor (IRF)-1, originally identified as a transcription factor of the human interferon (IFN)-beta gene, mediates tumor suppression and may inhibit oncogenesis. We have shown that IRF-1 in human breast cancer cells results in the down-regulation of survivin, tumor cell death, and the inhibition of tumor growth in vivo in xenogeneic mouse models. In this current report, we initiate studies comparing the effect of IRF-1 in human nonmalignant breast cell and breast cancer cell lines. While IRF-1 in breast cancer cells results in growth inhibition and cell death, profound growth inhibition and cell death are not observed in nonmalignant human breast cells. We show that TNF-alpha or IFN gamma induces IRF-1 in breast cancer cells and results in enhanced cell death. Abrogation of IRF-1 diminishes TNF-alpha and IFN-gamma-induced apoptosis. We test the hypothesis that IRF-1 augments TNF-alpha-induced apoptosis in breast cancer cells. Potential signaling networks elicited by IRF-1 are investigated by evaluating the NF-kappaB pathway. TNF-alpha and/or IFN-gamma results in decreased presence of NF-kappaB p65 in the nucleus of breast cancer cells. While TNF-alpha and/or IFN-gamma can induce IRF-1 in nonmalignant breast cells, a marked change in NF-kappaB p65 is not observed. Moreover, the ectopic expression of IRF-1 in breast cancer cells results in caspase-3, -7, -8 cleavage, inhibits NF-kappaB activity, and suppresses the expression of molecules involved in the NF-kappaB pathway. These data show that IRF-1 in human breast cancer cells elicits multiple signaling networks including intrinsic and extrinsic cell death and down regulates molecules involved in the NF-kappaB pathway. PMID- 26011591 TI - The Course of Functional Impairment in Older Homeless Adults: Disabled on the Street. PMID- 26011592 TI - Computational Metabolomics Operations at BioCyc.org. AB - BioCyc.org is a genome and metabolic pathway web portal covering 5500 organisms, including Homo sapiens, Arabidopsis thaliana, Saccharomyces cerevisiae and Escherichia coli. These organism-specific databases have undergone variable degrees of curation. The EcoCyc (Escherichia coli Encyclopedia) database is the most highly curated; its contents have been derived from 27,000 publications. The MetaCyc (Metabolic Encyclopedia) database within BioCyc is a "universal" metabolic database that describes pathways, reactions, enzymes and metabolites from all domains of life. Metabolic pathways provide an organizing framework for analyzing metabolomics data, and the BioCyc website provides computational operations for metabolomics data that include metabolite search and translation of metabolite identifiers across multiple metabolite databases. The site allows researchers to store and manipulate metabolite lists using a facility called SmartTables, which supports metabolite enrichment analysis. That analysis operation identifies metabolite sets that are statistically over-represented for the substrates of specific metabolic pathways. BioCyc also enables visualization of metabolomics data on individual pathway diagrams and on the organism-specific metabolic map diagrams that are available for every BioCyc organism. Most of these operations are available both interactively and as programmatic web services. PMID- 26011594 TI - Editorial Comment from Dr Stamatiou to Clinical outcomes of prostate cancer patients in Yokosuka City, Japan: A comparative study between cases detected by prostate-specific antigen-based screening in Yokosuka and those detected by other means. PMID- 26011593 TI - Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. AB - AIMS: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Carotid baroreceptor stimulation (baroreflex activation therapy, BAT) results in centrally mediated reduction of sympathetic and increase in parasympathetic activity. Because patients treated with cardiac resynchronization therapy (CRT) may have less sympathetic/parasympathetic imbalance, we hypothesized that there would be differences in the response to BAT in patients with CRT vs. those without CRT. METHODS AND RESULTS: New York Heart Association (NYHA) Class III patients with an ejection fraction (EF) <=35% were randomized (1 : 1) to ongoing guideline directed medical and device therapy (GDMT, control) or ongoing GDMT plus BAT. Safety endpoint was system-/procedure-related major adverse neurological and cardiovascular events (MANCE). Efficacy endpoints were Minnesota Living with Heart Failure Quality of Life (QoL), 6-min hall walk distance (6MHWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and HF hospitalization rate. In this sample, 146 patients were randomized (70 control; 76 BAT) and were 140 activated (45 with CRT and 95 without CRT). MANCE-free rate at 6 months was 100% in CRT and 96% in no-CRT group. At 6 months, in the no-CRT group, QoL score, 6MHWD, LVEF, NT-proBNP and HF hospitalizations were significantly improved in BAT patients compared with controls. Changes in efficacy endpoints in the CRT group favoured BAT; however, the improvements were less than in the no-CRT group and were not statistically different from control. CONCLUSIONS: BAT is safe and significantly improved QoL, exercise capacity, NTpro BNP, EF, and rate of HF hospitalizations in GDMT-treated NYHA Class III HF patients. These effects were most pronounced in patients not treated with CRT. PMID- 26011595 TI - Epidemiology and risk factors of childhood acne in Korea: a cross-sectional community based study. AB - BACKGROUND: The epidemiology of acne vulgaris appears to be evolving, with an increasingly earlier onset seen in childhood. Relevant studies have been rarely performed in Asia. AIM: We sought to estimate the prevalence and clinical characteristics of acne among schoolchildren, and its association with treatment seeking behaviour, body mass index (BMI), nutritional habits and other lifestyle elements. METHODS: A cross-sectional study was conducted with elementary schoolchildren aged 7-12 years. Children were interviewed by self-administered questionnaires, and were subsequently evaluated by dermatologists. RESULTS: Of 693 children enrolled, 36.2% were diagnosed with acne, and the prevalence increased with age. Additionally, clinical characteristics including severity, duration of disease and lesion distribution were significantly different between the lower (aged 7-9 years) and the higher (aged 10-12 years) grades. Subjective features including recognition about acne and treatment-seeking behaviours were also different between the two groups. Overweight or obesity (BMI >= 25 kg/m(2) at 18 years of age; OR = 2.7) and consumption of chocolates/sweets (OR = 1.6) were significant risk factors for acne. CONCLUSIONS: In the current study, the prevalence of acne among elementary schoolchildren was high, but only a few children had received treatment. Physicians should be attentive to childhood acne, and educate patients and their parents about the need to treat it. PMID- 26011596 TI - An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics. AB - Edoxaban, a once-daily, oral, direct factor Xa inhibitor, is approved for stroke prevention in nonvalvular atrial fibrillation and venous thromboembolism treatment. This study examined the effects of mild or moderate hepatic impairment on the pharmacokinetics of edoxaban and its metabolite M4. Thirty-three subjects enrolled in 4 treatment cohorts-mild hepatic impairment (n = 8), moderate hepatic impairment (n = 9), and 2 cohorts of healthy controls matched for age, sex, and weight (each n = 8)-and received a single 15-mg dose of edoxaban. Plasma pharmacokinetics for edoxaban and M4, prothrombin time (PT), activated partial thromboplastin time (aPTT), and safety data were measured over 72 hours. Edoxaban and M4 exposures were similar in subjects with mild or moderate hepatic impairment compared with matched controls. Higher PT and aPTT values were observed at baseline and after edoxaban dosing in the hepatic impairment groups compared with healthy controls. Edoxaban 15 mg was well tolerated in all cohorts. These results suggest that edoxaban exposure does not significantly increase in patients with mild or moderate hepatic impairment. However, because of the potential for underlying coagulopathy, edoxaban is not recommended for use in patients with moderate or severe hepatic impairment. No dose reduction is recommended for patients with mild hepatic impairment. PMID- 26011597 TI - Tunable Optical Properties and Charge Separation in CH3NH3Sn(x)Pb(1-x)I3/TiO2 Based Planar Perovskites Cells. AB - A sharp potential drop across the interface of the Pb-rich halide perovskites/TiO2 heterostructure is predicted from first-principles calculations, suggesting enhanced separation of photoinduced charge carriers in the perovskite based photovoltaic solar cells. The potential drop appears to be associated with the charge accumulation at the polar interface. More importantly, on account of both the beta phase structure of CH3NH3Sn(x)Pb(1-x)I3 for x < 0.5 and the alpha phase structure of CH3NH3Sn(x)Pb(1-x)I3 for x >= 0.5, the computed optical absorption spectra from time-dependent density functional theory (TD-DFT) are in very good agreement with the measured spectra from previous experiments. Our TD DFT computation also confirms the experimental structures of the mixed Pb-Sn organometal halide perovskites. These computation results provide a highly sought answer to the question why the lead-based halide perovskites possess much higher power conversion efficiencies than the tin-based counterparts for solar-cell applications. PMID- 26011598 TI - Effectiveness of a load-imposing device for cyclic stretching of isolated human bronchi: a validation study. AB - BACKGROUND: Mechanical ventilation may induce harmful effects in the airways of critically ill patients. Nevertheless, the effects of cyclic stretching caused by repetitive inflation-deflation of the bronchial compartment have not been well characterized in humans. The objective of the present study was to assess the effectiveness of a load-imposing device for the cyclic stretching of human bronchi. METHODS: Intact bronchial segments were removed from 128 thoracic surgery patients. After preparation and equilibration in an organ bath, bronchi were stretched repetitively and cyclically with a motorized transducer. The peak force imposed on the bronchi was set to 80% of each individual maximum contraction in response to acetylcholine and the minimal force corresponded to the initial basal tone before stretching. A 1-min cycle (stretching for 15 sec, relaxing for 15 sec and resting for 30 sec) was applied over a time period ranging from 5 to 60 min. The device's performance level was assessed and the properties of the stretched bronchi were compared with those of paired, non stretched bronchi. RESULTS: Despite the intrinsic capacities of the device, the targets of the tension adjustments remained variable for minimal tension (156 178%) while the peak force set point was unchanged (87-115%). In the stretched bronchi, a time-dependent rise in basal tone (P < .05 vs. non-stretched) was apparent after as little as 5 min of cyclic stretching. The stretch-induced rise in basal tone continued to increase (P < .01) after the stretching had ended. Only 60 min of cyclic stretching was associated with a significant (P < .05) increase in responsiveness to acetylcholine, relative to non-stretched bronchi. CONCLUSIONS: Low-frequency, low-force, cyclic loading of human bronchi is associated with elevated basal tone and acetylcholine responsiveness. The present experimental model is likely to be a useful tool for future investigations of the bronchial response to repetitive stress during mechanical ventilation. PMID- 26011599 TI - Penalization, bias reduction, and default priors in logistic and related categorical and survival regressions. AB - Penalization is a very general method of stabilizing or regularizing estimates, which has both frequentist and Bayesian rationales. We consider some questions that arise when considering alternative penalties for logistic regression and related models. The most widely programmed penalty appears to be the Firth small sample bias-reduction method (albeit with small differences among implementations and the results they provide), which corresponds to using the log density of the Jeffreys invariant prior distribution as a penalty function. The latter representation raises some serious contextual objections to the Firth reduction, which also apply to alternative penalties based on t-distributions (including Cauchy priors). Taking simplicity of implementation and interpretation as our chief criteria, we propose that the log-F(1,1) prior provides a better default penalty than other proposals. Penalization based on more general log-F priors is trivial to implement and facilitates mean-squared error reduction and sensitivity analyses of penalty strength by varying the number of prior degrees of freedom. We caution however against penalization of intercepts, which are unduly sensitive to covariate coding and design idiosyncrasies. PMID- 26011600 TI - Quantifying strain variability in modeling growth of Listeria monocytogenes. AB - Prediction of microbial growth kinetics can differ from the actual behavior of the target microorganisms. In the present study, the impact of strain variability on maximum specific growth rate (MUmax) (h(-1)) was quantified using twenty Listeria monocytogenes strains. The MUmax was determined as function of four different variables, namely pH, water activity (aw)/NaCl concentration [NaCl], undissociated lactic acid concentration ([HA]), and temperature (T). The strain variability was compared to biological and experimental variabilities to determine their importance. The experiment was done in duplicate at the same time to quantify experimental variability and reproduced at least twice on different experimental days to quantify biological (reproduction) variability. For all variables, experimental variability was clearly lower than biological variability and strain variability; and remarkably, biological variability was similar to strain variability. Strain variability in cardinal growth parameters, namely pHmin, [NaCl]max, [HA]max, and Tmin was further investigated by fitting secondary growth models to the MUmax data, including a modified secondary pH model. The fitting results showed that L. monocytogenes had an average pHmin of 4.5 (5-95% prediction interval (PI) 4.4-4.7), [NaCl]max of 2.0mM (PI 1.8-2.1), [HA]max of 5.1mM (PI 4.2-5.9), and Tmin of -2.2 degrees C (PI (-3.3)-(-1.1)). The strain variability in cardinal growth parameters was benchmarked to available literature data, showing that the effect of strain variability explained around 1/3 or less of the variability found in literature. The cardinal growth parameters and their prediction intervals were used as input to illustrate the effect of strain variability on the growth of L. monocytogenes in food products with various characteristics, resulting in 2-4 logCFU/ml(g) difference in growth prediction between the most and least robust strains, depending on the type of food product. This underlined the importance to obtain quantitative knowledge on variability factors to realistically predict the microbial growth kinetics. PMID- 26011601 TI - Guided Growth of Horizontal ZnSe Nanowires and their Integration into High Performance Blue-UV Photodetectors. AB - Perfectly aligned horizontal ZnSe nano-wires are obtained by guided growth, and easily integrated into high-performance blue-UV photodetectors. Their crystal phase and crystallographic orientation are controlled by the epitaxial relations with six different sapphire planes. Guided growth paves the way for the large scale integration of nanowires into optoelectronic devices. PMID- 26011602 TI - Manganese Fractionation Using a Sequential Extraction Method to Evaluate Welders' Shielded Metal Arc Welding Exposures During Construction Projects in Oil Refineries. AB - The National Institute for Occupational Safety and Health has conducted an occupational exposure assessment study of manganese (Mn) in welding fume of construction workers rebuilding tanks, piping, and process equipment at two oil refineries. The objective of this study was to evaluate exposures to different Mn fractions using a sequential extraction procedure. Seventy-two worker-days were monitored for either total or respirable Mn during stick welding and associated activities both within and outside of confined spaces. The samples were analyzed using an experimental method to separate different Mn fractions by valence states based on selective chemical solubility. The full-shift total particulate Mn time weighted average (TWA) breathing zone concentrations ranged from 0.013-29 for soluble Mn in a mild ammonium acetate solution; from 0.26-250 for Mn(0,2+) in acetic acid; from non-detectable (ND) - 350 for Mn(3+,4+) in hydroxylamine hydrochloride; and from ND - 39 micrograms per cubic meter (MUg/m(3)) for insoluble Mn fractions in hydrochloric and nitric acid. The summation of all Mn fractions in total particulate TWA ranged from 0.52-470 MUg/m(3). The range of respirable particulate Mn TWA concentrations were from 0.20-28 for soluble Mn; from 1.4-270 for Mn(0,2+); from 0.49-150 for Mn(3+,4+); from ND - 100 for insoluble Mn; and from 2.0-490 MUg/m(3) for Mn (sum of fractions). For all jobs combined, total particulate TWA GM concentrations of the Mn(sum) were 99 (GSD = 3.35) and 8.7 (GSD = 3.54) MUg/m(3) for workers inside and outside of confined spaces; respirable Mn also showed much higher levels for welders within confined spaces. Regardless of particle size and confined space work status, Mn(0,2+) fraction was the most abundant followed by Mn(3+,4+) fraction, typically >50% and ~30-40% of Mn(sum), respectively. Eighteen welders' exposures exceeded the ACGIH Threshold Limit Values for total Mn (100 MUg/m(3)) and 25 exceeded the recently adopted respirable Mn TLV (20 MUg/m(3)). This study shows that a welding fume exposure control and management program is warranted, especially for welding jobs in confined spaces. PMID- 26011604 TI - Investigation on the Cyclability of Lithium-Oxygen Cells in a Confined Potential Window using Cathodes with Pre-filled Discharge Products. AB - With new chemistry and advantageous configuration, the lithium-oxygen (Li-O2) battery promises a much higher specific energy than traditional lithium-ion batteries. The limited understanding on the complicated battery reactions therein, however, has become a major bottleneck of its development for applications requiring a high energy efficiency and long cycle-life. Herein, in a confined potential window with negligible electrolyte degradation, we studied the rechargeability of Li-O2 cathodes with pre-filled well-defined discharge products of Li2O2, Li2CO3, LiOH, or their combinations. Our results suggest Li2CO3 as the most difficult species to be electrochemically decomposed among the three lithium compounds, whereas the presence of LiOH notably increases the initial charge potential. The clearly visible difference in the charge behavior and cycling stability of these artificially "discharged" electrodes provides a guideline for the development of future high-performance Li-O2 batteries. PMID- 26011603 TI - Ice Core Perspective on Mercury Pollution during the Past 600 Years. AB - Past emissions of the toxic metal mercury (Hg) persist in the global environment, yet these emissions remain poorly constrained by existing data. Ice cores are high-resolution archives of atmospheric deposition that may provide crucial insight into past atmospheric Hg levels during recent and historical time. Here we present a record of total Hg (HgT) in an ice core from the pristine summit plateau (5340 m asl) of Mount Logan, Yukon, Canada, representing atmospheric deposition from AD 1410 to 1998. The Colonial Period (~1603-1850) and North American "Gold Rush" (1850-1900) represent minor fractions (8% and 14%, respectively) of total anthropogenic Hg deposition in the record, with the majority (78%) occurring during the 20th Century. A period of maximum HgT fluxes from 1940 to 1975 coincides with estimates of enhanced anthropogenic Hg emissions from commercial sources, as well as with industrial emissions of other toxic metals. Rapid declines in HgT fluxes following peaks during the Gold Rush and the mid-20th Century indicate that atmospheric Hg deposition responds quickly to reductions in emissions. Increasing HgT fluxes from 1993 until the youngest samples in 1998 may reflect the resurgence of Hg emissions from unregulated coal burning and small-scale gold mining. PMID- 26011605 TI - Analytical accuracy of hydrogen measurement using gas chromatography with thermal conductivity detection. AB - Gas chromatography employing a thermal conductivity detector with a nitrogen carrier gas and a molecular sieve 5 A column is commonly used for the analysis of widely varying hydrogen concentrations. Flow variation of the column, caused by carrier gas adsorption, affects the peak shape and impacts the analytical accuracy. The mechanism and factors affecting the adsorption effect are explored, errors caused by the deviation from the linearity of the detector's response are considered, and practical advice is given for improving the analytical accuracy. PMID- 26011606 TI - Impact of Threat Level, Task Instruction, and Individual Characteristics on Cold Pressor Pain and Fear among Children and Their Parents. AB - The cold pressor task (CPT) is increasingly used to induce experimental pain in children, but the specific methodology of the CPT is quite variable across pediatric studies. This study examined how subtle variations in CPT methodology (eg. provision of low- or high-threat information regarding the task; provision or omission of maximum immersion time) may influence children's and parents' perceptions of the pain experience. Forty-eight children (8 to 14 years) and their parents were randomly assigned to receive information about the CPT that varied on 2 dimensions, prior to completing the task: (i) threat level: high threat (task described as very painful, high pain expressions depicted) or low threat (standard CPT instructions provided, low pain expressions depicted); (ii) ceiling: informed (provided maximum immersion time) or uninformed (information about maximum immersion time omitted). Parents and children in the high-threat condition expected greater child pain, and these children reported higher perceived threat of pain and state pain catastrophizing. For children in the low threat condition, an informed ceiling was associated with less state pain catastrophizing during the CPT. Pain intensity, tolerance, and fear during the CPT did not differ by experimental group, but were predicted by child characteristics. Findings suggest that provision of threatening information may impact anticipatory outcomes, but experienced pain was better explained by individual child variables. PMID- 26011608 TI - Stumpless chronic total occlusion with no retrograde option: Multidetector computed tomography-guided intervention via bi-radial approach utilizing bioresorbable vascular scaffold. AB - When dealing with flush ostial chronic total occlusion (CTO) and no viable retrograde option, the only way to perform recanalization is through an antegrade approach. Such a procedure can be extremely difficult considering the ambiguity of the proximal cap. We demonstrate how we solved ambiguity of the proximal cap of an ostial obtuse marginal CTO with the help of cardiac multidetector computed tomography (MDCT). We also discuss several techniques including bilateral radial approach with home-made sheathless large-bore catheters, IVUS-guided cap puncture, ping-pong guide catheters engagement in the left main, and bioresorbable vascular scaffold (BVS) for an ostial left circumflex disease that we all used in our CTO case. PMID- 26011607 TI - The clinical performance of an office-based risk scoring system for fatal cardiovascular diseases in North-East of Iran. AB - BACKGROUND: Cardiovascular diseases (CVD) are becoming major causes of death in developing countries. Risk scoring systems for CVD are needed to prioritize allocation of limited resources. Most of these risk score algorithms have been based on a long array of risk factors including blood markers of lipids. However, risk scoring systems that solely use office-based data, not including laboratory markers, may be advantageous. In the current analysis, we validated the office based Framingham risk scoring system in Iran. METHODS: The study used data from the Golestan Cohort in North-East of Iran. The following risk factors were used in the development of the risk scoring method: sex, age, body mass index, systolic blood pressure, hypertension treatment, current smoking, and diabetes. Cardiovascular risk functions for prediction of 10-year risk of fatal CVDs were developed. RESULTS: A total of 46,674 participants free of CVD at baseline were included. Predictive value of estimated risks was examined. The resulting Area Under the ROC Curve (AUC) was 0.774 (95% CI: 0.762-0.787) in all participants, 0.772 (95% CI: 0.753-0.791) in women, and 0.763 (95% CI: 0.747-0.779) in men. AUC was higher in urban areas (0.790, 95% CI: 0.766-0.815). The predicted and observed risks of fatal CVD were similar in women. However, in men, predicted probabilities were higher than observed. CONCLUSION: The AUC in the current study is comparable to results of previous studies while lipid profile was replaced by body mass index to develop an office-based scoring system. This scoring algorithm is capable of discriminating individuals at high risk versus low risk of fatal CVD. PMID- 26011609 TI - Childhood adversity as a predictor of non-adherence to statin therapy in adulthood. AB - PURPOSE: To investigate whether adverse experiences in childhood predict non adherence to statin therapy in adulthood. METHODS: A cohort of 1378 women and 538 men who initiated statin therapy during 2008-2010 after responding to a survey on childhood adversities, was followed for non-adherence during the first treatment year. Log-binomial regression was used to estimate predictors of non-adherence, defined as the proportion of days covered by dispensed statin tablets <80%. In fully adjusted models including age, education, marital status, current smoking, heavy alcohol use, physical inactivity, obesity, presence of depression and cardiovascular comorbidity, the number of women ranged from 1172 to 1299 and that of men from 473 to 516, because of missing data on specific adversities and covariates. RESULTS: Two in three respondents reported at least one of the following six adversities in the family: divorce/separation of the parents, long term financial difficulties, severe conflicts, frequent fear, severe illness, or alcohol problem of a family member. 51% of women and 44% of men were non adherent. In men, the number of childhood adversities predicted an increased risk of non-adherence (risk ratio [RR] per adversity 1.11, 95% confidence interval [CI] 1.01-1.21], P for linear trend 0.013). Compared with those reporting no adversities, men reporting 3-6 adversities had a 1.44-fold risk of non-adherence (95% CI 1.12-1.85). Experiencing severe conflicts in the family (RR 1.27, 95% CI 1.03-1.57]) and frequent fear of a family member (RR 1.27, 95% CI 1.00-1.62]) in particular, predicted an increased risk of non-adherence. In women, neither the number of adversities nor any specific type of adversity predicted non-adherence. CONCLUSIONS: Exposure to childhood adversity may predict non-adherence to preventive cardiovascular medication in men. Usefulness of information on childhood adversities in identification of adults at high risk of non-adherence deserves further research. PMID- 26011610 TI - A WUSCHEL-Independent Stem Cell Specification Pathway Is Repressed by PHB, PHV and CNA in Arabidopsis. AB - The homeostatic maintenance of stem cells that carry out continuous organogenesis at the shoot meristem is crucial for plant development. Key known factors act to signal between the stem cells and an underlying group of cells thought to act as the stem cell niche. In Arabidopsis thaliana the homeodomain transcription factor WUSCHEL (WUS) is essential for stem cell initiation and maintenance at shoot and flower meristems. Recent data suggest that the WUS protein may move from the niche cells directly into the stem cells to maintain stem cell identity. Here we provide evidence for a second, previously unknown, pathway for stem cell specification at shoot and flower meristems that bypasses the requirement for WUS. We demonstrate that this novel stem cell specification pathway is normally repressed by the activity of the HD-zip III transcription factors PHABULOSA (PHB), PHAVOLUTA (PHV) and CORONA (CNA). When de-repressed, this second stem cell pathway leads to an accumulation of stem cells and an enlargement of the stem cell niche. When de-repressed in a wus mutant background, this second stem cell pathway leads to functional meristems with largely normal cell layering and meristem morphology, activation of WUS cis regulatory elements, and extensive, but not indeterminate, organogenesis. Thus, WUS is largely dispensable for stem cell specification and meristem function, suggesting a set of key stem cell specification factors, competitively regulated by WUS and PHB/PHV/CNA, remain unidentified. PMID- 26011612 TI - Mitigating yield-scaled greenhouse gas emissions through combined application of soil amendments: A comparative study between temperate and subtropical rice paddy soils. AB - Effects of different soil amendments were investigated on methane (CH4) and nitrous oxide (N2O) emissions, global warming potential (GWP) and yield scaled GWPs in paddy soils of Republic of Korea, Japan and Bangladesh. The experimental treatments were NPK only, NPK+fly ash, NPK+silicate slag, NPK+phosphogypsum(PG), NPK+blast furnace slag (BFS), NPK+revolving furnace slag (RFS), NPK+silicate slag (50%)+RFS (50%), NPK+biochar, NPK+biochar+Azolla-cyanobacteria, NPK+silicate slag+Azolla-cyanobacteria, NPK+phosphogypsum (PG)+Azolla-cyanobacteria. The maximum decrease in cumulative seasonal CH4 emissions was recorded 29.7% and 32.6% with Azolla-cyanobacteria plus phospho-gypsum amendments in paddy soils of Japan and Bangladesh respectively, followed by 22.4% and 26.8% reduction with silicate slag plus Azolla-cyanobacteria application. Biochar amendments in paddy soils of Japan and Bangladesh decreased seasonal cumulative N2O emissions by 31.8% and 20.0% respectively, followed by 26.3% and 25.0% reduction with biochar plus Azolla-cyanobacteria amendments. Although seasonal cumulative CH4 emissions were significantly increased by 9.5-14.0% with biochar amendments, however, global warming potentials were decreased by 8.0-12.0% with cyanobacterial inoculation plus biochar amendments. The maximum decrease in GWP was calculated 22.0-30.0% with Azolla-cyanobacteria plus silicate slag amendments. The evolution of greenhouse gases per unit grain yield (yield scaled GWP) was highest in the NPK treatment, which was decreased by 43-50% from the silicate slag and phosphogypsum amendments along with Azolla-cyanobacteria inoculated rice planted soils. Conclusively, it is recommended to incorporate Azolla-cyanobacteria with inorganic and organic amendments for reducing GWP and yield scaled GWP from the rice planted paddy soils of temperate and subtropical countries. PMID- 26011611 TI - New insights into trace elements deposition in the snow packs at remote alpine glaciers in the northern Tibetan Plateau, China. AB - Trace element pollution resulting from anthropogenic emissions is evident throughout most of the atmosphere and has the potential to create environmental and health risks. In this study we investigated trace element deposition in the snowpacks at two different locations in the northern Tibetan Plateau, including the Laohugou (LHG) and the Tanggula (TGL) glacier basins, and its related atmospheric pollution information in these glacier areas, mainly focusing on 18 trace elements (Li, Be, V, Cr, Co, Ni, Cu, Zn, Ga, Rb, Nb, Mo, Cd, Sb, Cs, Ba, Tl, and Pb). The results clearly demonstrate that pronounced increases of both concentrations and crustal enrichment factors (EFs) are observed in the snowpack at the TGL glacier basin compared to that of the LHG glacier basin, with the highest EFs for Sb and Zn in the TGL basin, whereas with the highest EFs for Sb and Cd in the LHG basin. Compared with other studies in the Tibetan Plateau and surrounding regions, trace element concentration showed gradually decreasing trend from Himalayan regions (southern Tibetan Plateau) to the TGL basin (central Tibetan Plateau), and to the LHG basin (northern Tibetan Plateau), which probably implied the significant influence of atmospheric trace element transport from south Asia to the central Tibetan Plateau. Moreover, EF calculations at two sites showed that most of the heavy metals (e.g., Cu, Zn, Mo, Cd, Sb, and Pb) were from anthropogenic sources and some other elements (e.g., Li, Rb, and Ba) were mainly originated from crustal sources. MODIS atmospheric optical depth (AOD) fields derived using the Deep Blue algorithm and CALIOP/CALIPSO transect showed significant influence of atmospheric pollutant transport from south Asia to the Tibetan Plateau, which probably caused the increased concentrations and EFs of trace element deposition in the snowpack on the TGL glacier basin. PMID- 26011613 TI - Effects of climate change and agricultural adaptation on nutrient loading from Finnish catchments to the Baltic Sea. AB - Climate change is expected to increase annual and especially winter runoff, shorten the snow cover period and therefore increase both nutrient leaching from agricultural areas and natural background leaching in the Baltic Sea catchment. We estimated the effects of climate change and possible future scenarios of agricultural changes on the phosphorus and nitrogen loading to the Baltic Sea from Finnish catchments. In the agricultural scenarios we assumed that the prices of agricultural products are among the primary drivers in the adaptation to climate change, as they affect the level of fertilization and the production intensity and volume and, hence, the modeled changes in gross nutrient loading from agricultural land. Optimal adaptation may increase production while supporting appropriate use of fertilization, resulting in low nutrient balance in the fields. However, a less optimal adaptation may result in higher nutrient balance and increased leaching. The changes in nutrient loading to the Baltic Sea were predicted by taking into account the agricultural scenarios in a nutrient loading model for Finnish catchments (VEMALA), which simulates runoff, nutrient processes, leaching and transport on land, in rivers and in lakes. We thus integrated the effects of climate change in the agricultural sector, nutrient loading in fields, natural background loading, hydrology and nutrient transport and retention processes. PMID- 26011614 TI - Organic matter induced mobilization of polymer-coated silver nanoparticles from water-saturated sand. AB - Mobilization of polymer-coated silver nanoparticles (AgNPs) by anionic surfactant (sodium dodecylbenzenesulphonate: SDBS), amino acid derivative (N-acetylcysteine: NAC), and chelate (ethylenediaminetetraacetic acid: EDTA) in water-saturated sand medium was explored based on carefully designed column tests. Exposure experiments monitoring the size evolution of polyvinylpyrrolidone (PVP) coated AgNPs in organic solutions confirm the capacity of SDBS, NAC and EDTA to partly displace PVP. Single Pulse Column Experiment (SPCE) results show both the PVP polymer and the silver core controlled AgNP deposition while the effect of the PVP was dominant. Results of Co-injected Pulse Column Experiments (CPCEs) where AgNP and SDBS or NAC were co-injected into the column following a very short mixing (<1 s) disprove our hypothesis that coating-alternation by particle associated organic would mobilize irreversibly deposited particles from the uncoated sand, while surface charge modification by adsorbed NAC was identified as a potential mobilizing mechanism for AgNP from the iron-oxide-coated sand. Triple Pulse Column Experiment (TPCE) results confirm that such a charging effect of the adsorbed organic molecules may enable SDBS and NAC to mobilize AgNPs from the iron-oxide-coated sands. TPCE results with five distinct levels of SDBS indicate that concentration-stimulated change in the SDBS format from an individual to a micelle significantly increased the mobilizing efficiency and site blockage of SDBS. Although being an electrolyte, EDTA did not mobilize AgNPs, as the case with SDBS or NAC, as it dissolved the iron oxides which in turn prevented EDTA adsorption on sand. The findings have implications for better understanding the behavior of polymer-coated nanoparticles in organic-presented groundwater systems, i.e., detachment-associated uncertainty in exposure prediction of the nanomaterials. PMID- 26011615 TI - Food consumption and waste and the embedded carbon, water and ecological footprints of households in China. AB - Strategies for reducing food waste and developing sustainable diets require information about the impacts of consumption behavior and waste generation on climatic, water, and land resources. We quantified the carbon, water, and ecological footprints of 17,110 family members of Chinese households, covering 1935 types of foods, by combining survey data with available life-cycle assessment data sets. We also summarized the patterns of both food consumption and waste generation and analyzed the factors influencing the observed trends. The average person wasted (consumed) 16 (415) kg of food at home annually, equivalent to 40 (1080) kg CO2e, 18 (673) m(3), and 173 (4956) gm(2) for the carbon, water and ecological footprints, respectively. The generation of food waste was highly correlated with consumption for various food groups. For example, vegetables, rice, and wheat were consumed the most and accounted for the most waste. In addition to the three plant-derived food groups, pork and aquatic products also contributed greatly to embedded footprints. The data obtained in this study could be used for assessing national food security or the carrying capacity of resources. PMID- 26011616 TI - Food intake and serum persistent organic pollutants in the Greenlandic pregnant women: The ACCEPT sub-study. AB - The Greenlandic Inuit have high blood concentrations of environmental persistent organic pollutants (POPs). High POP concentrations have been associated with age, smoking and consumption of marine mammals. Studies have indicated that exposure to POPs during pregnancy may adversely affect fetal and child development. To assess geographical differences in diet, lifestyle and environmental contaminant exposure among pregnant women in Greenland, blood samples and questionnaire data were collected from 207 pregnant women in five Greenlandic regions (North, Disco Bay, West, South and East). Blood samples were analyzed for 11 organochlorine pesticides (OCPs), 14 polychlorinated biphenyls (PCBs), 5 polybrominated diphenyl ethers (PBDEs), 15 perfluoroalkylated substances (PFASs) and 63 metals. A trend of higher intake of marine mammals in the East and North regions was reflected by a higher n-3/n-6 fatty acid ratio. Participants in the East region tended also to have higher intake of terrestrial species. A significant higher seabird intake was seen for pregnant women in the West region. Significant regional differences were found for blood concentrations of PCBs, OCPs, PFASs and mercury, with higher levels in the North and East regions. PFASs were significantly associated with PCBs and OCPs in most of the regions. In the North region, PFASs were associated with both selenium and mercury. No significant regional difference was observed for PBDEs. The regional differences of blood levels of POPs and mercury were related to differences in intake of the traditional food. Compared to earlier reports, decreased levels of legacy POPs, Hg and Pb and perfluorooctane sulfonate and perfluorooctanoic acid were observed, but the levels of PFAS congeners perfluorohexane sulfonate and perfluorononanoic acid were sustained. The detection of POPs and heavy metals in maternal blood indicates fetal exposure to these compounds possibly influencing fetal development. PMID- 26011617 TI - Mobility of antimony, arsenic and lead at a former antimony mine, Glendinning, Scotland. AB - Elevated concentrations of antimony (Sb), arsenic (As) and lead (Pb) in upland organic-rich soils have resulted from past Sb mining activities at Glendinning, southern Scotland. Transfer of these elements into soil porewaters was linked to the production and leaching of dissolved organic matter and to leaching of spoil material. Sb was predominantly present in truly dissolved (<3 kDa) forms whilst As and Pb were more commonly associated with large Fe-rich/organic colloids. The distinctive porewater behaviour of Sb accounts for its loss from deeper sections of certain cores and its transport over greater distances down steeper sections of the catchment. Although Sb and As concentrations decreased with increasing distance down a steep gully from the main spoil heap, elevated concentrations (~6 8 and 13-20 MUg L(-1), respectively) were detected in receiving streamwaters. Thus, only partial attenuation occurs in steeply sloping sections of mining impacted upland organic-rich soils and so spoil-derived contamination of surface waters may continue over time periods of decades to centuries. CAPSULE ABSTRACT: Production and leaching of dissolved organic matter led to the concomitant transfer of truly dissolved Sb to soil porewaters. Leaching of spoil-derived Sb impacted on the quality of receiving stream waters. PMID- 26011618 TI - A BHR Composite Network-Based Visualization Method for Deformation Risk Level of Underground Space. AB - This study proposes a visualization processing method for the deformation risk level of underground space. The proposed method is based on a BP-Hopfield-RGB (BHR) composite network. Complex environmental factors are integrated in the BP neural network. Dynamic monitoring data are then automatically classified in the Hopfield network. The deformation risk level is combined with the RGB color space model and is displayed visually in real time, after which experiments are conducted with the use of an ultrasonic omnidirectional sensor device for structural deformation monitoring. The proposed method is also compared with some typical methods using a benchmark dataset. Results show that the BHR composite network visualizes the deformation monitoring process in real time and can dynamically indicate dangerous zones. PMID- 26011624 TI - Giant necrotic lymph node metastases from testicular tumour with streptococcus pyogenes sepsis. PMID- 26011623 TI - Notch is required in adult Drosophila sensory neurons for morphological and functional plasticity of the olfactory circuit. AB - Olfactory receptor neurons (ORNs) convey odor information to the central brain, but like other sensory neurons were thought to play a passive role in memory formation and storage. Here we show that Notch, part of an evolutionarily conserved intercellular signaling pathway, is required in adult Drosophila ORNs for the structural and functional plasticity of olfactory glomeruli that is induced by chronic odor exposure. Specifically, we show that Notch activity in ORNs is necessary for the odor specific increase in the volume of glomeruli that occurs as a consequence of prolonged odor exposure. Calcium imaging experiments indicate that Notch in ORNs is also required for the chronic odor induced changes in the physiology of ORNs and the ensuing changes in the physiological response of their second order projection neurons (PNs). We further show that Notch in ORNs acts by both canonical cleavage-dependent and non-canonical cleavage independent pathways. The Notch ligand Delta (Dl) in PNs switches the balance between the pathways. These data define a circuit whereby, in conjunction with odor, N activity in the periphery regulates the activity of neurons in the central brain and Dl in the central brain regulates N activity in the periphery. Our work highlights the importance of experience dependent plasticity at the first olfactory synapse. PMID- 26011625 TI - Differential reactivation of fetal/neonatal genes in mouse liver tumors induced in cirrhotic and non-cirrhotic conditions. AB - Hepatocellular carcinoma develops in either chronically injured or seemingly intact livers. To explore the tumorigenic mechanisms underlying these different conditions, we compared the mRNA expression profiles of mouse hepatocellular tumors induced by the repeated injection of CCl4 or a single diethylnitrosamine (DEN) injection using a cDNA microarray. We identified tumor-associated genes that were expressed differentially in the cirrhotic CCl4 model (H19, Igf2, Cbr3, and Krt20) and the non-cirrhotic DEN model (Tff3, Akr1c18, Gpc3, Afp, and Abcd2) as well as genes that were expressed comparably in both models (Ly6d, Slpi, Spink3, Scd2, and Cpe). The levels and patterns of mRNA expression of these genes were validated by quantitative RT-PCR analyses. Most of these genes were highly expressed in mouse livers during the fetal/neonatal periods. We also examined the mRNA expression of these genes in mouse tumors induced by thioacetamide, another cirrhotic inducer, and those that developed spontaneously in non-cirrhotic livers and found that they shared a similar expression profile as that observed in CCl4 induced and DEN-induced tumors, respectively. There was a close relationship between the expression levels of Igf2 and H19 mRNA, which were activated in the cirrhotic models. Our results show that mouse liver tumors reactivate fetal/neonatal genes, some of which are specific to cirrhotic or non-cirrhotic modes of pathogenesis. PMID- 26011626 TI - The impact of coping flexibility on the risk of depressive symptoms. AB - OBJECTIVE: According to the dual-process theory, coping flexibility is defined as the ability to produce and implement a new coping strategy in place of an ineffective coping strategy. Specifically, coping flexibility includes two processes: evaluation coping and adaptive coping. Evaluation coping refers to sensitivity to feedback about the efficacy of a coping strategy, and adaptive coping involves the willingness to implement alternative coping strategies. The coping flexibility hypothesis (CFH) postulates that more flexible coping will be associated with more adaptive outcomes; importantly, there are numerous theories and studies that support the CFH. The main purpose of this study was to test the CFH based on dual-process theory. METHODS: A total of 1,770 Japanese college students participated and, completed a set of questionnaires that measured coping flexibility (evaluation coping and adaptive coping) and depressive symptoms. Depressive symptoms were measured via the Center for Epidemiologic Studies Depression Scale. RESULTS: The proportions of women and men who reported depressive symptoms were 58.69% (95% CIs [55.74, 61.66]) and 54.17% (95% CIs [50.37, 57.95]), respectively when a cut-off score of 16 on the CES-D was used. A multivariable logistic regression analysis revealed that evaluation coping (OR = 0.86, 95% CIs [0.83, 0.0.89]) and adaptive coping (OR = 0.91, 95% CIs [0.88, 0.93]) were significantly associated with lower levels of depressive symptoms. CONCLUSION: The results of the present study indicated that the CFH based on dual process theory was supported in a Japanese sample. PMID- 26011627 TI - Hippocampal sharp-wave ripples in waking and sleeping states. AB - Waking and sleeping states are privileged periods for distinct mnemonic processes. In waking behavior, rapid retrieval of previous experience aids memory guided decision making. In sleep, a gradual series of reactivated associations supports consolidation of episodes into memory networks. Synchronized bursts of hippocampal place cells during events called sharp-wave ripples communicate associated neural patterns across distributed circuits in both waking and sleeping states. Differences between sleep and awake sharp-wave ripples, and in particular the accuracy of recapitulated experience, highlight their state dependent roles in memory processes. PMID- 26011629 TI - Enzymatic transformation of ginseng leaf saponin by recombinant beta-glucosidase (bgp1) and its efficacy in an adipocyte cell line. AB - The major ginseng leaf saponins are transformed into the more pharmacologically active minor ginsenosides by recombinant beta-glucosidase enzyme bgp1. Ginseng leaves contain six major ginsenosides: Rg1, Re, Rb1, Rb2, Rc, and Rd. Among these Rg1, Re and Rd are the most abundant. Within 3 H of incubation, all dominant major ginsenosides found in ginseng leaf had decomposed and been converted into the more active minor ginsenosides (i.e., 100% of Rg1, Re, and Rd were decomposed and converted into Rh1, Rg2, and Rg3, respectively). The recombinant beta glucosidase enzyme (bgp1) hydrolyzed all glucose moieties attached to the C-20 position of the ginsenosides Rg1, Re, Rb1, Rd, and F1. The transformed product contains pharmacologically active minor ginsenosides Rh1, Rg2, Rg3, F1, and protopanaxatriol. This transformed product was used to investigate the effects on the 3T3-L1 adipocyte cell line. The cytotoxicity assay did not show any toxicity, even when used at a concentration of 100 MUg/mL. Adipogenesis was shown to decrease in response to bioconverted leaf saponin in a dose-dependent manner. PMID- 26011630 TI - Floral Reversion in Arabidopsis suecica Is Correlated with the Onset of Flowering and Meristem Transitioning. AB - Angiosperm flowers are usually determinate structures that may produce seeds. In some species, flowers can revert from committed flower development back to an earlier developmental phase in a process called floral reversion. The allopolyploid Arabidopsis suecica displays photoperiod-dependent floral reversion in a subset of its flowers, yet little is known about the environmental conditions enhancing this phenotype, or the morphological processes leading to reversion. We have used light and electron microscopy to further describe this phenomenon. Additionally, we have further studied the phenology of flowering and floral reversion in A. suecica. In this study we confirm and expand upon our previous findings that floral reversion in the allopolyploid A. suecica is photoperiod-dependent, and show that its frequency is correlated with the timing for the onset of flowering. Our results also suggest that floral reversion in A. suecica displays natural variation in its penetrance between geographic populations of A. suecica. PMID- 26011628 TI - CEMP1 Induces Transformation in Human Gingival Fibroblasts. AB - Cementum Protein 1 (CEMP1) is a key regulator of cementogenesis. CEMP1 promotes cell attachment, differentiation, deposition rate, composition, and morphology of hydroxyapatite crystals formed by human cementoblastic cells. Its expression is restricted to cementoblasts and progenitor cell subpopulations present in the periodontal ligament. CEMP1 transfection into non-osteogenic cells such as adult human gingival fibroblasts results in differentiation of these cells into a "mineralizing" cell phenotype. Other studies have shown evidence that CEMP1 could have a therapeutic potential for the treatment of bone defects and regeneration of other mineralized tissues. To better understand CEMP1's biological effects in vitro we investigated the consequences of its expression in human gingival fibroblasts (HGF) growing in non-mineralizing media by comparing gene expression profiles. We identified several mRNAs whose expression is modified by CEMP1 induction in HGF cells. Enrichment analysis showed that several of these newly expressed genes are involved in oncogenesis. Our results suggest that CEMP1 causes the transformation of HGF and NIH3T3 cells. CEMP1 is overexpressed in cancer cell lines. We also determined that the region spanning the CEMP1 locus is commonly amplified in a variety of cancers, and finally we found significant overexpression of CEMP1 in leukemia, cervix, breast, prostate and lung cancer. Our findings suggest that CEMP1 exerts modulation of a number of cellular genes, cellular development, cellular growth, cell death, and cell cycle, and molecules associated with cancer. PMID- 26011632 TI - Correction: discovery of molecular markers to discriminate corneal endothelial cells in the human body. PMID- 26011631 TI - Zearalenone mycotoxin affects immune mediators, MAPK signalling molecules, nuclear receptors and genome-wide gene expression in pig spleen. AB - The toxicity of zearalenone (ZEA) was evaluated in swine spleen, a key organ for the innate and adaptative immune response. Weaned pigs were fed for 18 days with a control or a ZEA contaminated diet. The effect of ZEA was assessed on wide genome expression, pro- (TNF-alpha, IL-8, IL-6, IL-1beta, IFN-gamma) and anti inflammatory (IL-10, IL-4) cytokines, other molecules involved in inflammatory processes (MMPs/TIMPs), as well as signaling molecules, (p38/JNK1/JNK2-MAPKs) and nuclear receptors (PPARgamma/NFkB/AP-1/STAT3/c-JUN). Microarray analysis showed that 46% of total number of differentially expressed genes was involved in cellular signaling pathway, 13% in cytokine network and 10% in the inflammatory response. ZEA increased expression and synthesis of pro- inflammatory (TNF-alpha, IL-8, IL-6, IL-1beta) and had no effect on IFN-gamma, IL-4 and IL-10 cytokines in spleen. The inflammatory stimulation might be a consequence of JNK pathway activation rather than of p-38MAPK and NF-kB involvement whose gene and protein expression were suppressed by ZEA action. In summary, our findings indicated the role of ZEA as an immune disruptor at spleen level. PMID- 26011633 TI - Gender and Personality Differences in Response to Social Stressors in Great Tits (Parus major). AB - In response to stressors, animals can increase the activity of the hypothalamic pituitary-adrenocortical axis, resulting in elevated glucocorticoid concentrations. An increase in glucocorticoids results in an increase in heterophils and a decrease in lymphocytes, which ratio (H/L-ratio) is an indicator of stress in birds. The physiological response to a stressor can depend on individual characteristics, like dominance rank, sex and personality. Although the isolated effects of these characteristics on the response to a stressor have been well studied, little is known about the response in relation to a combination of these characteristics. In this study we investigate the relationship between social stress, dominance rank, sex and exploratory behaviour as a validated operational measure of personality in great tits (Parus major). Great tits show consistent individual differences in behaviour and physiology in response to stressors, and exploratory behaviour can be classified as fast or slow exploring. We group-housed four birds, two fast and two slow explorers, of the same sex that were previously singly housed, in an aviary and compared the H/L-ratio, lymphocyte and heterophil count before and after group housing. After experiencing the social context all birds increased their H/L-ratio and heterophil count. Females showed a stronger increase in H/L-ratio and heterophil count than males, which seemed to be related to a higher number of agonistic interactions compared to males. Dominance rank and exploration type did not affect the H/L-ratio or heterophil count. Contrary to our expectations, all birds increased their lymphocyte count. However, this increase was slower for fast than for slow explorers. Our study suggests that personality and sex related differences, but not dominance rank, are associated with changes in an individual's physiological response due to a social context. PMID- 26011634 TI - Onset of hepatocarcinogen-specific cell proliferation and cell cycle aberration during the early stage of repeated hepatocarcinogen administration in rats. AB - We have previously reported that a 28-day treatment of carcinogens evoking target cell proliferation activates G1 /S checkpoint function and apoptosis, as well as induction of aberrant ubiquitin D (Ubd) expression, suggesting disruptive spindle checkpoint function, in rats. The present study aimed to determine the onset time of rat liver cells to undergo carcinogen-specific cell cycle aberration and proliferation. Animals were treated orally with a hepatocarcinogenic dose of methyleugenol or thioacetamide for 3, 7 or 28 days. For comparison, some animals were subjected to partial hepatectomy or treated with noncarcinogenic hepatotoxicants (acetaminophen, alpha-naphthyl isothiocyanate or promethazine). Carcinogen-specific liver cell kinetics appeared at day 28 as evident by increases of cell proliferation, p21(Cip1+) cells, phosphorylated-Mdm2(+) cells and cleaved caspase 3(+) cells, and upregulation of DNA damage-related genes. Hepatocarcinogens also downregulated Rbl2 and upregulated Cdkn1a and Mdm2, and decreased Ubd(+) cells co-expressing phosphorylated-histone H3 (p-Histone H3) and p-Histone H3(+) cell ratio within the Ki-67(+) proliferating population. These results suggest that it takes 28 days to induce hepatocarcinogen-specific early withdrawal of proliferating cells from M phase due to disruptive spindle checkpoint function as evidenced by reduction of Ubd(+) cells staying at M phase. Disruption of G1 /S checkpoint function reflected by downregulation of Rbl2 as well as upregulation of Mdm2 suggestive of sequestration of retinoblastoma protein is responsible for the facilitation of carcinogen-induced cell proliferation at day 28. Accumulation of DNA damage probably in association with facilitation of p53 degradation by activation of Mdm2 may be a prerequisite for aberrant p21(Cip1) activation, which is responsible for apoptosis. PMID- 26011636 TI - Occult vs. overt upper gastrointestinal bleeding - inverse relationship and the use of mucosal damaging and protective drugs. AB - BACKGROUND: While efforts have focused on the prevention of overt upper gastrointestinal bleeding (UGIB), little is known about occult GIB, which might also originate from sites not protected by acid inhibition. AIM: To measure the incidence and outcomes of both overt and occult GIB over a 6-year period (2007 2012), and to assess the use of NSAIDs, anti-thrombotic therapy (ATT), proton pump inhibitors (PPIs), and iron therapy. METHODS: A sample of 300 patients (100 from each of three index years) with occult GIB was randomly selected and their outcomes were compared with those of patients with overt UGIB (N = 869). RESULTS: The incidence of overt UGIB fell from 140.1 per 100 000 population per annum in 2007 to 106.8 in 2010 and to 88.0 in 2012 (P < 0.001); while that of occult GIB rose from 243.1 to 263.6 and to 292.8 (P < 0.001) over the same period. The incidence of occult GIB was highly correlated with the number of prescriptions of PPIs per 1000 population (chi(2) trend = 11.80; P < 0.001). In the overt UGIB group, the median haemoglobin level on presentation was lowest (10.3) in patients taking NSAIDs/ATT plus PPIs compared with those taking PPIs alone (11.5), NSAIDs/ATT alone (10.4) or none of these drugs (12.7 g/dL) (P < 0.001, Kruskal Wallis). CONCLUSIONS: An inverse trend seems to have formed in the incidence of overt vs. occult gastrointestinal bleeding in association with the wider use of PPIs and NSAIDs. An alternative approach to acid inhibition is needed to prevent gastrointestinal bleeding. PMID- 26011635 TI - Different timing features in brain processing of core and moral disgust pictures: an event-related potentials study. AB - Disgust, an emotion motivating withdrawal from offensive stimuli, protects us from the risk of biological pathogens and sociomoral violations. Homogeneity of its two types, namely, core and moral disgust has been under intensive debate. To examine the dynamic relationship between them, we recorded event-related potentials (ERPs) for core disgust, moral disgust and neutral pictures while participants performed a modified oddball task. ERP analysis revealed that N1 and P2 amplitudes were largest for the core disgust pictures, indicating automatic processing of the core disgust-evoking pictures. N2 amplitudes were higher for pictures evoking moral disgust relative to core disgust and neutral pictures, reflecting a violation of social norms. The core disgust pictures elicited larger P3 and late positive potential (LPP) amplitudes in comparison with the moral disgust pictures which, in turn, elicited larger P3 and LPP amplitudes when compared to the neutral pictures. Taken together, these findings indicated that core and moral disgust pictures elicited different neural activities at various stages of information processing, which provided supporting evidence for the heterogeneity of disgust. PMID- 26011638 TI - Outcomes after multivessel or culprit-Vessel intervention for ST-elevation myocardial infarction in patients with multivessel coronary disease: a Bayesian cross-design meta-analysis. AB - INTRODUCTION: During primary percutaneous coronary intervention (PCI), patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary disease can undergo either multivessel intervention (MVI) or culprit-vessel intervention (CVI) only. BACKGROUND: Randomized controlled trials (RCTs) support the use of MVI, but cohort studies support the use of CVI. METHODS: We developed Bayesian models that incorporated parameters for study type and study outcome after MVI or CVI. RESULTS: A total of 18 studies (4 RCTs, 3 matched cohort studies, and 11 unmatched observational studies) enrolled 48,398 patients with STEMI and multivessel CAD and reported outcomes after MVI or CVI-only at the time of primary PCI. Using a Bayesian hierarchical model, we found that the point estimates replicated previously reported trends, but the wide Bayesian credible intervals (BCI) excluded any plausible mortality difference between MVI versus CVI in all three study types: RCTs (odds ratio [OR] 0.60, 95% BCI 0.31-1.20), matched cohort studies (OR 1.37, 95% BCI 0.86-2.24), or unmatched cohort studies (OR 1.16, 95% BCI 0.70-1.89). Both the global summary (OR 1.10, 95% BCI 0.74 1.51) and a sensitivity analysis that weighted the RCTs 1-5 times as much as observational studies revealed no credible advantage of one PCI strategy over the other (OR 1.05, 95% BCI 0.64-1.48). CONCLUSIONS: Bayesian approaches contextualize the comparison of different strategies by study type and suggest that neither MVI nor CVI emerges as a preferred strategy in an analysis that accounts mortality differences. PMID- 26011637 TI - Community structure analysis of transcriptional networks reveals distinct molecular pathways for early- and late-onset temporal lobe epilepsy with childhood febrile seizures. AB - Age at epilepsy onset has a broad impact on brain plasticity and epilepsy pathomechanisms. Prolonged febrile seizures in early childhood (FS) constitute an initial precipitating insult (IPI) commonly associated with mesial temporal lobe epilepsy (MTLE). FS-MTLE patients may have early disease onset, i.e. just after the IPI, in early childhood, or late-onset, ranging from mid-adolescence to early adult life. The mechanisms governing early (E) or late (L) disease onset are largely unknown. In order to unveil the molecular pathways underlying E and L subtypes of FS-MTLE we investigated global gene expression in hippocampal CA3 explants of FS-MTLE patients submitted to hippocampectomy. Gene coexpression networks (GCNs) were obtained for the E and L patient groups. A network-based approach for GCN analysis was employed allowing: i) the visualization and analysis of differentially expressed (DE) and complete (CO) - all valid GO annotated transcripts - GCNs for the E and L groups; ii) the study of interactions between all the system's constituents based on community detection and coarse-grained community structure methods. We found that the E-DE communities with strongest connection weights harbor highly connected genes mainly related to neural excitability and febrile seizures, whereas in L-DE communities these genes are not only involved in network excitability but also playing roles in other epilepsy-related processes. Inversely, in E-CO the strongly connected communities are related to compensatory pathways (seizure inhibition, neuronal survival and responses to stress conditions) while in L-CO these communities harbor several genes related to pro-epileptic effects, seizure related mechanisms and vulnerability to epilepsy. These results fit the concept, based on fMRI and behavioral studies, that early onset epilepsies, although impacting more severely the hippocampus, are associated to compensatory mechanisms, while in late MTLE development the brain is less able to generate adaptive mechanisms, what has implications for epilepsy management and drug discovery. PMID- 26011639 TI - A new splice of life for the MU-opioid receptor. AB - MU-Opioid agonists mediate their analgesic effect through GPCRs that are generated via alternate splicing of the Oprm1 transcript. While the majority of MU-opioids interact with receptors comprising the canonical 7 transmembrane (7TM) domain, a recently identified class of MU-opioids appears to require a 6TM domain variant. In this issue of the JCI, Lu and colleagues provide an in vivo proof-of concept demonstration that a 6TM isoform of the MU-opioid receptor can support functional analgesia in Oprm1-deficent animals. The 6TM isoform was pharmacologically distinct from the canonical 7TM MU-opioid receptor, and 6TM agonists had a reduced side effect profile, which confers a strong therapeutic advantage over standard opioid analgesics. The observations of Lu et al. extend the reach of opioid-receptor neurobiology and pharmacology into a new era of analgesic discovery. This advance emerges from a series of fundamental research analyses in which elements of the endogenous opioid system were frequently in the vanguard. PMID- 26011640 TI - Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase 1. AB - Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms. PMID- 26011641 TI - Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. AB - The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the MU-opioid receptor. MU-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) MU opioid receptors that mediate the actions of the traditional MU-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6beta-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM MU-opioid receptors but has no activity in mice lacking a set of 6TM truncated MU-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative MU-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a MU-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating MU-opioid activity in these animals. Intrathecal administration of lentivirus containing the 6TM variant mMOR-1G restored IBNtxA, but not morphine, analgesia in Oprm1-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia. PMID- 26011643 TI - Focused antibody response to influenza linked to antigenic drift. AB - The selective pressure that drives antigenic changes in influenza viruses is thought to originate from the human immune response. Here, we have characterized the B cell repertoire from a previously vaccinated donor whose serum had reduced neutralizing activity against the recently evolved clade 6B H1N1pdm09 viruses. While the response was markedly polyclonal, 88% of clones failed to recognize clade 6B viruses; however, the ability to neutralize A/USSR/90/1977 influenza, to which the donor would have been exposed in childhood, was retained. In vitro selection of virus variants with representative monoclonal antibodies revealed that a single amino acid replacement at residue K163 in the Sa antigenic site, which is characteristic of the clade 6B viruses, was responsible for resistance to neutralization by multiple monoclonal antibodies and the donor serum. The K163 residue lies in a part of a conserved surface that is common to the hemagglutinins of the 1977 and 2009 H1N1 viruses. Vaccination with the 2009 hemagglutinin induced an antibody response tightly focused on this common surface that is capable of selecting current antigenic drift variants in H1N1pdm09 influenza viruses. Moreover, amino acid replacement at K163 was not highlighted by standard ferret antisera. Human monoclonal antibodies may be a useful adjunct to ferret antisera for detecting antigenic drift in influenza viruses. PMID- 26011645 TI - Acute toxicity of silver and carbon nanoaerosols to normal and cystic fibrosis human bronchial epithelial cells. AB - Inhalation of engineered nanoparticles (NP) poses a still unknown risk. Individuals with chronic lung diseases are expected to be more vulnerable to adverse effects of NP than normal subjects, due to altered respiratory structures and functions. Realistic and dose-controlled aerosol exposures were performed using the deposition chamber NACIVT. Well-differentiated normal and cystic fibrosis (CF) human bronchial epithelia (HBE) with established air-liquid interface and the human bronchial epithelial cell line BEAS-2B were exposed to spark-generated silver and carbon nanoaerosols (20 nm diameter) at three different doses. Necrotic and apoptotic cell death, pro-inflammatory response, epithelial function and morphology were assessed within 24 h after aerosol exposure. NP exposure resulted in significantly higher necrosis in CF than normal HBE and BEAS-2B cells. Before and after NP treatment, CF HBE had higher caspase-3 activity and secreted more IL-6 and MCP-1 than normal HBE. Differentiated HBE had higher baseline secretion of IL-8 and less caspase-3 activity and MCP-1 secretion compared to BEAS-2B cells. These biomarkers increased moderately in response to NP exposure, except for MCP-1, which was reduced in HBE after AgNP treatment. No functional and structural alterations of the epithelia were observed in response to NP exposure. Significant differences between cell models suggest that more than one and fully differentiated HBE should be used in future toxicity studies of NP in vitro. Our findings support epidemiologic evidence that subjects with chronic airway diseases are more vulnerable to adverse effects of particulate air pollution. Thus, this sub-population needs to be included in nano-toxicity studies. PMID- 26011644 TI - IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell-derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33 expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs. PMID- 26011642 TI - ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. AB - The integrated stress response (ISR) is a critical mediator of cancer cell survival, and targeting the ISR inhibits tumor progression. Here, we have shown that activating transcription factor 4 (ATF4), a master transcriptional effector of the ISR, protects transformed cells against anoikis - a specialized form of apoptosis - following matrix detachment and also contributes to tumor metastatic properties. Upon loss of attachment, ATF4 activated a coordinated program of cytoprotective autophagy and antioxidant responses, including induced expression of the major antioxidant enzyme heme oxygenase 1 (HO-1). HO-1 upregulation was the result of simultaneous activation of ATF4 and the transcription factor NRF2, which converged on the HO1 promoter. Increased levels of HO-1 ameliorated oxidative stress and cell death. ATF4-deficient human fibrosarcoma cells were unable to colonize the lungs in a murine model, and reconstitution of ATF4 or HO 1 expression in ATF4-deficient cells blocked anoikis and rescued tumor lung colonization. HO-1 expression was higher in human primary and metastatic tumors compared with noncancerous tissue. Moreover, HO-1 expression correlated with reduced overall survival of patients with lung adenocarcinoma and glioblastoma. These results establish HO-1 as a mediator of ATF4-dependent anoikis resistance and tumor metastasis and suggest ATF4 and HO-1 as potential targets for therapeutic intervention in solid tumors. PMID- 26011646 TI - DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics. AB - Increasing attention has been directed toward assessing mutational fallout of stereocilin (STRC), the gene underlying DFNB16. A major challenge is due to a closely linked pseudogene with 99.6% coding sequence identity. In 94 GJB2/GJB6 mutation negative individuals with non-syndromic sensorineural hearing loss (NSHL), we identified two homozygous and six heterozygous deletions, encompassing the STRC region by microarray and/or quantitative polymerase chain reaction (qPCR) analysis. To detect smaller mutations, we developed a Sanger sequencing method for pseudogene exclusion. Three heterozygous deletion carriers exhibited hemizygous mutations predicted as negatively impacting the protein. In 30 NSHL individuals without deletion, we detected one with compound heterozygous and two with heterozygous pathogenic mutations. Of 36 total patients undergoing STRC sequencing, two showed the c.3893A>G variant in conjunction with a heterozygous deletion or mutation and three exhibited the variant in a heterozygous state. Although this variant affects a highly conserved amino acid and is predicted as deleterious, comparable minor allele frequencies (MAFs) (around 10%) in NSHL individuals and controls and homozygous variant carriers without NSHL argue against its pathogenicity. Collectively, six (6%) of 94 NSHL individuals were diagnosed with homozygous or compound heterozygous mutations causing DFNB16 and five (5%) as heterozygous mutation carriers. Besides GJB2/GJB6 (DFNB1), STRC is a major contributor to congenital hearing impairment. PMID- 26011649 TI - Taming power: Generative historical consciousness. AB - Power is a necessary dimension of all human enterprises. It can inspire and illuminate, but it can also corrupt, oppress, and destroy. Therefore, taming power has been a central moral and political question for most of human history. Writers, theorists, and researchers have suggested many methods and mechanisms for taming power: through affiliation and love, intellect and reason, responsibility, religion and values, democratic political structures, and separation of powers. Historical examples and social science research suggest that each has some success, but also that each is vulnerable to being hijacked by power itself. I therefore introduce generative historical consciousness (GHC) as a concept and measure that might help to secure the benefits of power while protecting against its outrages and excesses. I conclude by discussing the role that GHC may have played in the peaceful resolution of the Cuban Missile Crisis of 1962. PMID- 26011647 TI - Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact. AB - BACKGROUND: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma. METHODS: Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells. RESULTS: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 * 10(-6) ) and ORMDL2 (P = 4.9 * 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1. CONCLUSIONS: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness. PMID- 26011648 TI - Comparison of two low-density lipoprotein apheresis systems in patients with homozygous familial hypercholesterolemia. AB - Low-density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin-induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (-63.3% vs. -59.9%; P = 0.05), LDL-C (-70.5% vs. -63.0%; P = 0.02), CRP (-75.3% vs. -48.8%; P < 0.0001), and TNF-alpha (-23.7% vs. +14.7%; P = 0.003). Reductions in the plasma levels of PCSK9 (-45.3% vs. -63.4%; P = 0.31), lipoprotein (a) (-70.6% vs. -65.0%; P = 0.30), E-selectin (-16.6% vs. -18.3%; P = 0.65), ICAM-1 (-4.0 vs. 5.6%; P = 0.56), and VCAM-1 (8.3% vs. -1.8%; P = 0.08) were not different between the two systems. For the same volume of filtered plasma (3,000 mL), however, HELP led to greater reductions in plasma apoB (-63.1% vs. -58.3%; P = 0.04), HDL-C (-20.6% vs. -6.5%; P = 0.003), and PCSK9 (-63.4% vs. -28.5%; P = 0.02) levels. These results suggest that both LA systems are effective in reducing plasma lipids and inflammatory markers in HoFH. Compared with HELP, greater reductions in lipid levels and inflammatory markers were achieved with DS, most likely because this method allows for a larger plasma volume to be filtered. J. Clin. Apheresis 31:359-367, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26011650 TI - Serotonin: A New Hope in Alzheimer's Disease? AB - Alzheimer's disease (AD) is the most common form of dementia affecting 35 million individuals worldwide. Current AD treatments provide only brief symptomatic relief. It is therefore urgent to replace this symptomatic approach with a curative one. Increasing serotonin signaling as well as developing molecules that enhance serotonin concentration in the synaptic cleft have been debated as possible therapeutic strategies to slow the progression of AD. In this Viewpoint, we discuss exciting new insights regarding the modulation of serotonin signaling for AD prevention and therapy. PMID- 26011651 TI - Epigenetic down-regulation of integrin alpha7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin alpha7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM. PMID- 26011652 TI - Application of systems thinking: 12-month postintervention evaluation of a complex health system intervention in Zambia: the case of the BHOMA. AB - RATIONALE, AIMS AND OBJECTIVES: Strong health systems are said to be paramount to achieving effective and equitable health care. The World Health Organization has been advocating for using system-wide approaches such as 'systems thinking' to guide intervention design and evaluation. In this paper we report the system-wide effects of a complex health system intervention in Zambia known as Better Health Outcome through Mentorship and Assessment (BHOMA) that aimed to improve service quality. METHODS: We conducted a qualitative study in three target districts. We used a systems thinking conceptual framework to guide the analysis focusing on intended and unintended consequences of the intervention. NVivo version 10 was used for data analysis. RESULTS: The addressed community responded positively to the BHOMA intervention. The indications were that in the short term there was increased demand for services but the health worker capacity was not severely affected. This means that the prediction that service demand would increase with implementation of BHOMA was correct and the workload also increased, but the help of clinic lay supporters meant that some of the work of clinicians was transferred to these lay workers. However, from a systems perspective, unintended consequences also occurred during the implementation of the BHOMA. CONCLUSIONS: We applied an innovative approach to evaluate a complex intervention in low income settings, exploring empirically how systems thinking can be applied in the context of health system strengthening. Although the intervention had some positive outcomes by employing system-wide approaches, we also noted unintended consequences. PMID- 26011653 TI - A Bamboo-Inspired Nanostructure Design for Flexible, Foldable, and Twistable Energy Storage Devices. AB - Flexible energy storage devices are critical components for emerging flexible electronics. Electrode design is key in the development of all-solid-state supercapacitors with superior electrochemical performances and mechanical durability. Herein, we propose a bamboo-like graphitic carbon nanofiber with a well-balanced macro-, meso-, and microporosity, enabling excellent mechanical flexibility, foldability, and electrochemical performances. Our design is inspired by the structure of bamboos, where a periodic distribution of interior holes along the length and graded pore structure at the cross section not only enhance their stability under different mechanical deformation conditions but also provide a high surface area accessible to the electrolyte and low ion transport resistance. The prepared nanofiber network electrode recovers its initial state easily after 3-folded manipulation. The mechanically robust membrane is explored as a free-standing electrode for a flexible all-solid-state supercapacitor. Without the need for extra support, the volumetric energy and power densities based on the whole device are greatly improved compared to the state-of-the-art devices. Even under continuous dynamic operations of forceful bending (90 degrees ) and twisting (180 degrees ), the as-designed device still exhibits stable electrochemical performances with 100% capacitance retention. Such a unique supercapacitor holds great promise for high-performance flexible electronics. PMID- 26011654 TI - Efficient Synthesis and Biological Evaluation of 5'-GalNAc Conjugated Antisense Oligonucleotides. AB - Conjugation of triantennary N-acetyl galactosamine (GalNAc) to oligonucleotide therapeutics results in marked improvement in potency for reducing gene targets expressed in hepatocytes. In this report we describe a robust and efficient solution-phase conjugation strategy to attach triantennary GalNAc clusters (mol. wt. ~2000) activated as PFP (pentafluorophenyl) esters onto 5'-hexylamino modified antisense oligonucleotides (5'-HA ASOs, mol. wt. ~8000 Da). The conjugation reaction is efficient and was used to prepare GalNAc conjugated ASOs from milligram to multigram scale. The solution phase method avoids loading of GalNAc clusters onto solid-support for automated synthesis and will facilitate evaluation of GalNAc clusters for structure activity relationship (SAR) studies. Furthermore, we show that transfer of the GalNAc cluster from the 3'-end of an ASO to the 5'-end results in improved potency in cells and animals. PMID- 26011655 TI - Collagen-like peptide sequences inhibit bacterial invasion of root dentine. AB - AIM: To investigate the effects of peptides derived from the sequence of collagen to inhibit penetration of human or bovine dentine by species of streptococci and enterococci. METHODOLOGY: Blocks of human or bovine root dentine were infected for 14 days with bacterial cultures, in the presence or absence of various collagen-like peptide sequences. Invasion of dentinal tubules was determined from microscopic images of histochemically stained dentine thin sections. Extent of invasion was expressed as tubule invasion index (TI), or tubule invasion factor (TIF) which, in addition to the density of invasion, took into account the depth of invasion. Data were analysed by two-way anova. RESULTS: Streptococcus gordonii, Streptococcus mutans and Enterococcus faecalis were associated with heavy invasion (TI >2.5, TIF >4) of human or bovine root dentinal tubules, with E. faecalis being the most penetrative. Incorporation of peptides Gly-Pro-Ala or Gly-Pro-Hyp into the in vitro model system significantly reduced (P < 0.05) dentine invasion by the three species of highly invasive organisms. Inhibition of bacterial invasion by the peptides was dose dependent, and the peptides did not inhibit bacterial growth in culture. CONCLUSION: Specific collagen-like peptide sequences inhibited the invasion of dentine in vitro by a range of oral bacteria. The peptides likely act as competitive inhibitors blocking bacterial collagen receptors and could potentially allow for target-specific control of dentine infections. PMID- 26011656 TI - Layer-dependent wall properties of abdominal aortic aneurysms: Experimental study and material characterization. AB - Mechanical testing and in-depth characterization of the abdominal aortic aneurysm wall from fifteen patients undergoing open surgery was performed to establish the layer-dependent tissue properties that are non-available in the literature. Quantitative microscopic evaluation was performed to identify the spatial organization of collagen-fiber network. Among a number of candidate models, the four-fiber family (microstructure-motivated) model, especially that including dispersions of fiber angles about the main directions, was superior to the Fung- and Gasser-type models in the fitting quality allowed, though it presented a practical difficulty in parameter estimation, so that an analysis was conducted aiding the identification of a more specific diagonal- and circumferential-fiber family model for all three layers. The adventitia was stiffer and stronger than the other layers, owing to its increased collagen content, and its contribution to the response of the intact wall was augmented being under greater residual tension than the media, whereas the intima was under residual compression. All layers were stiffer circumferentially than longitudinally, due to preferential collagen arrangement along that axis. The histologically-guided material characterization of layered wall presented herein is expected to assist clinical decision, by developing reliable criteria to predict the rupture risk of abdominal aortic aneurysms, and optimize endovascular interventions. PMID- 26011657 TI - Understanding access and use of technology among youth with first-episode psychosis to inform the development of technology-enabled therapeutic interventions. AB - AIM: Computers, video games and technological devices are part of young people's everyday lives. However, their use in first-episode psychosis (FEP) treatment is rare. The purpose of this study was to better understand the access and use of technology among individuals with FEP, including gaming activities, to inform future development of technology-enabled therapeutic applications. METHODS: Self administered survey on use of technological tools in 71 FEP individuals. RESULTS: PCs/laptops were used by all participants; cellphones/smartphones by 92%, consoles by 83% (mainly male and younger participants). Women texted and used social networks more frequently; men played games (mainly action) more often. The younger individuals reported playing games frequently (32% daily) with less use of the Web and social networks (favourite: Facebook). CONCLUSIONS: These data will be useful for developing Web-based psychoeducation tools and cognitive remediation video games for youth with FEP. PMID- 26011658 TI - Vitamin D levels and vitamin D receptor gene polymorphisms in asthmatic children: a case-control study. AB - BACKGROUND: Vitamin D deficiency and single nucleotide polymorphisms (SNP) in the gene encoding vitamin D receptor (VDR) have been associated with asthma. OBJECTIVE: To compare 25-hydroxyvitamin D (25OHD) levels and the frequency of 3 SNPs in the VDR gene between asthmatic and healthy children. METHODS: In persistent asthmatic and healthy control children, the 25OHD levels were measured using radioimmunoassay and SNPs (FokI, ApaI, and TaqI) were analyzed by a PCR RFLP assay. Relevant medical history was collected. RESULTS: About 75 asthmatic (median age: 9.1 years) and 227 healthy children (10.3 years) were studied. In the whole population, the proportion of sufficient, insufficient, and deficient levels of 25OHD were 14.9%, 44%, and 41.1%, respectively. 25OHD sufficiency status was similar in asthmatic and healthy children (p = 0.57). However, the proportion of 25OHD sufficient levels among asthmatics according to the Global Initiative for Asthma treatment steps 2, 3, and 4 was significantly different (8.6%, 16.6%, and 43.7%, respectively, p = 0.046). All patients on step 4 of the treatment (16/16) were heterozygous for the C allele (FokI VDR SNP). There was a lower presence of the C allele among asthmatics in step 2 (30/33), step 3 (16/24), and controls (45/50), p = 0.007, but this significance did not persist after logistic regression. No significant differences in ApaI and TaqI were found. CONCLUSIONS: We found a possible association of vitamin D sufficiency status and FokI C allele with higher requirement of therapy to reach asthma control, suggesting that it may be involved in treatment response. Variations in VDR might also play a role in the 25OHD levels. PMID- 26011659 TI - Cynical beliefs about human nature and income: Longitudinal and cross-cultural analyses. AB - Based on the existing literature on worldview beliefs, cynical hostility, and Machiavellian cynicism, we suggest that holding cynical beliefs about human nature can be detrimental for individuals' income. Cynical individuals are more likely to avoid cooperation and trust or to overinvest in monitoring, control, and other means of protection from potential exploitation. As a result, they are more likely to forgo valuable opportunities for cooperation and consequently less likely to reap the benefits of joint efforts and mutual help compared with their less cynical counterparts. Studies 1 and 2, using nationally representative longitudinal surveys of the American population, show that individuals who endorsed cynical beliefs about human nature at baseline earned comparatively lower incomes 9 (Study 1) and 2 (Study 2) years later. In Study 3, applying a multilevel model of change to a nationally representative panel study of the German population, we show that cynical beliefs at baseline undermined an income increase in the course of the following 9 years. In Study 4, the negative effect of cynical beliefs on income proved to be independent of individual differences in the Big Five personality dimensions. Study 5 provided the first tentative evidence of the hypothesized mechanism underlying this effect. Using survey data from 41 countries, it revealed that the negative effect of cynical beliefs on income is alleviated in sociocultural contexts with low levels of prosocial behavior, high homicide rates and high overall societal cynicism levels. Holding cynical beliefs about others has negative economic outcomes unless such beliefs hold true. PMID- 26011661 TI - Self-esteem, narcissism, and stressful life events: Testing for selection and socialization. AB - We examined whether self-esteem and narcissism predict the occurrence of stressful life events (i.e., selection) and whether stressful life events predict change in self-esteem and narcissism (i.e., socialization). The analyses were based on longitudinal data from 2 studies, including samples of 328 young adults (Study 1) and 371 adults (Study 2). The effects of self-esteem and narcissism were mutually controlled for each other and, moreover, controlled for effects of depression. After conducting the study-level analyses, we meta-analytically aggregated the findings. Self-esteem had a selection effect, suggesting that low self-esteem led to the occurrence of stressful life events; however, this effect became nonsignificant when depression was controlled for. Regardless of whether depression was controlled for or not, narcissism had a selection effect, suggesting that high narcissism led to the occurrence of stressful life events. Moreover, stressful life events had a socialization effect on self-esteem, but not on narcissism, suggesting that the occurrence of stressful life events decreased self-esteem. Analyses of trait-state models indicated that narcissism consisted almost exclusively of perfectly stable trait variance, providing a possible explanation for the absence of socialization effects on narcissism. The findings have significant implications because they suggest that a person's level of narcissism influences whether stressful life events occur, and that self esteem is shaped by the occurrence of stressful life events. Moreover, we discuss the possibility that depression mediates the selection effect of low self-esteem on stressful life events. (PsycINFO Database Record PMID- 26011660 TI - Adolescent emotionality and effortful control: Core latent constructs and links to psychopathology and functioning. AB - Temperament is associated with important outcomes in adolescence, including academic and interpersonal functioning and psychopathology. Rothbart's temperament model is among the most well-studied and supported approaches to adolescent temperament, and contains 3 main components: positive emotionality (PE), negative emotionality (NE), and effortful control (EC). However, the latent factor structure of Rothbart's temperament measure for adolescents, the Early Adolescent Temperament Questionnaire Revised (EATQ-R; Ellis & Rothbart, 2001) has not been definitively established. To address this problem and investigate links between adolescent temperament and functioning, we used confirmatory factor analysis to examine the latent constructs of the EATQ-R in a large combined sample. For EC and NE, bifactor models consisting of a common factor plus specific factors for some subfacets of each component fit best, providing a more nuanced understanding of these temperament dimensions. The nature of the PE construct in the EATQ-R is less clear. Models replicated in a hold-out dataset. The common components of high NE and low EC where broadly associated with increased psychopathology symptoms, and poor interpersonal and school functioning, while specific components of NE were further associated with corresponding specific components of psychopathology. Further questioning the construct validity of PE as measured by the EATQ-R, PE factors did not correlate with construct validity measures in a way consistent with theories of PE. Bringing consistency to the way the EATQ-R is modeled and using purer latent variables has the potential to advance the field in understanding links between dimensions of temperament and important outcomes of adolescent development. PMID- 26011663 TI - Effects of high-fidelity patient simulation led clinical reasoning course: Focused on nursing core competencies, problem solving, and academic self efficacy. AB - AIM: To examine the effects of high-fidelity patient simulation (HFPS) led clinical reasoning course among undergraduate nursing students. METHODS: A quasi experimental study of non-equivalent control group pretest-post test design was applied. A total of 49 senior nursing students participated in this study. The experimental group consisted of the students who took the "clinical reasoning" course (n = 23) while the control group consisted of students who did not (n = 26). Self-administered scales including the nursing core competencies, problem solving, academic self-efficacy, and Kolb learning style inventory were analyzed quantitatively using SPSS version 20.0. Data analysis was conducted using one-way ancova due to a significant difference in nursing core competencies between the experimental group and control group. RESULTS: There was a significant improvement in nursing core competencies in the experimental group (F = 7.747, P = 0.008). The scores of problem solving and academic self-efficacy were higher in the experimental group after the HFPS led clinical reasoning course without statistical difference. CONCLUSION: There is a need for the development of effective instructional methods to improve learning outcomes in nursing education. Future research is needed related to simulation education as well as management strategies so that learning outcomes can be achieved within different students' learning style. PMID- 26011662 TI - Anger perceptually and conceptually narrows cognitive scope. AB - For the last 50 years, research investigating the effect of emotions on scope of cognitive processing was based on models proposing that affective valence determined cognitive scope. More recently, our motivational intensity model suggests that this past work had confounded valence with motivational intensity. Research derived from this model supports the idea that motivational intensity, rather than affective valence, explains much of the variance emotions have on cognitive scope. However, the motivational intensity model is limited in that the empirical work has examined only positive affects high in approach and negative affects high in avoidance motivation. Thus, perhaps only approach-positive and avoidance-negative states narrow cognitive scope. The present research was designed to clarify these conceptual issues by examining the effect of anger, a negatively valenced approach-motivated state, on cognitive scope. Results revealed that anger narrowed attentional scope relative to a neutral state and that attentional narrowing to anger was similar to the attentional narrowing caused by high approach-motivated positive affects (Study 1). This narrowing of attention was related to trait approach motivation (Studies 2 and Study 3). Anger also narrowed conceptual cognitive categorization (Study 4). Narrowing of categorization related to participants' approach motivation toward anger stimuli. Together, these results suggest that anger, an approach-motivated negative affect, narrows perceptual and conceptual cognitive scope. More broadly, these results support the conceptual model that motivational intensity per se, rather than approach-positive and avoidance-negative states, causes a narrowing of cognitive scope. PMID- 26011664 TI - Vitamin D insufficiency and deficiency in pediatric renal transplant recipients. AB - Vitamin D deficiency is prevalent in the pediatric CKD population. Recognizing that renal transplant recipients have CKD, we assessed the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients, compared to a healthy pediatric population. We prospectively studied 25(OH)D levels in 29 pediatric renal transplant recipients and 45 control patients over one yr. The overall prevalence of vitamin D insufficiency and deficiency was common in both populations, at 76% (95% CI: 61, 87%) in the pediatric renal transplant recipients and 91% (95% CI: 80, 98%) in the control group. In the paired renal transplant samples, the mean 25(OH)D level was 52.3 +/- 17.9 nmol/L in the winter and 65.6 +/- 18.8 nmol/L in the summer (95% CI diff.: 3.9, 22.7), in keeping with a significant seasonal difference. The mean dietary intake of vitamin D in the renal transplant recipients, assessed by three-day dietary record, was 5.7 MUg/day, with a vitamin D intake below the EAR in the majority. We did not find an association between vitamin D intake and 25(OH)D levels in this study, likely due to the low dietary intake of vitamin D within the transplant population, identifying a potential area for intervention and improvement. PMID- 26011665 TI - Transvaginal ultrasound for preoperative assessment of myometrial invasion in patients with endometrial cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To review the diagnostic accuracy of transvaginal ultrasound (TVS) in the preoperative detection of deep myometrial infiltration in patients with endometrial cancer, comparing subjective and objective methods. METHODS: An extensive search was performed in MEDLINE (PubMed) and EMBASE for studies published between January 1989 and December 2014. The eligibility criterion was use of TVS for preoperative assessment of myometrial infiltration by subjective evaluation and/or objective measurements. Objective measurements included, specifically, the approaches of Gordon (ratio of the distance between endometrium myometrium interface and maximum tumor depth to the total myometrial thickness) and Karlsson (endometrial tumor thickness/anteroposterior uterine diameter ratio), in women with endometrial cancer, using the surgical pathological data as a reference standard. Study quality was assessed using the QUADAS-2 tool. RESULTS: Our extended search identified a total of 184 citations, among which we examined the full text of 24 articles. Overall pooled sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) of TVS for detecting deep myometrial infiltration were 82% (95% CI, 76-87%), 81% (95% CI, 76 85%), 4.3 (95% CI, 3.6-5.3) and 0.22 (95% CI, 0.16-0.30), respectively. We did not observe differences among the three methods in terms of diagnostic performance. Significant heterogeneity was found for sensitivity and specificity of all three methods (I(2) range, 60.6-95.0). The main limitation was that very few studies compared different approaches in the same set of patients. CONCLUSION: Diagnostic performance of TVS for detecting deep myometrial infiltration in women with endometrial cancer is moderate. PMID- 26011666 TI - Medicare Fee Cuts and Cardiologist-Hospital Integration. PMID- 26011667 TI - Rethinking primary cutaneous marginal zone lymphoma: shifting the focus to the cause of the infiltrate. PMID- 26011668 TI - Feces of feedlot cattle contain a diversity of bacteriophages that lyse non-O157 Shiga toxin-producing Escherichia coli. AB - This study aimed to isolate and characterize bacteriophages that lyse non-O157 Shiga toxin-producing Escherichia coli (STEC) from cattle feces. Of 37 non-O157 STEC-infecting phages isolated, those targeting O26 (AXO26A, AYO26A, AYO26B), O103 (AXO103A, AYO103A), O111 (AXO111A, AYO111A), O121 (AXO121A, AXO121B), and O145 (AYO145A, AYO145B) were further characterized. Transmission electron microscopy showed that the 11 isolates belonged to 3 families and 6 genera: the families Myoviridae (types rV5, T4, ViI, O1), Siphoviridae (type T5), and Podoviridae (type T7). Genome size of the phages as determined by pulsed-field gel electrophoresis ranged from 38 to 177 kb. Excluding phages AXO26A, AYO103A, AYO145A, and AYO145B, all other phages were capable of lysing more than 1 clinically important strain from serogroups of O26, O91, O103, O111, O113, O121, and O128, but none exhibited infectivity across all serogroups. Moreover, phages AYO26A, AXO121A, and AXO121B were also able to lyse 4 common phage types of STEC O157:H7. Our findings show that a diversity of non-O157 STEC-infecting phages are harbored in bovine feces. Phages AYO26A, AYO26B, AXO103A, AXO111A, AYO111A, AXO121A, and AXO121B exhibited a broad host range against a number of serogroups of STEC and have potential for the biocontrol of STEC in the environment. PMID- 26011670 TI - Evaluation of the ventro 20 degrees rostral-dorsocaudal oblique radiographic projection for the investigation of canine nasal disease. AB - OBJECTIVE: To assess the ventro 20 degrees rostral-dorsocaudal oblique projection for canine nasal disease as an alternative to the dorsoventral intra oral view. MATERIALS AND METHODS: Thirty-one dogs with nasal disease underwent radiography and computed tomography with a final diagnosis of underlying cause achieved through rhinoscopy, biopsy or cytology. Three independent observers, blinded to diagnosis, reviewed the nasal radiographs on two separate occasions. Intra- and inter-observer agreement and level of confidence on radiographic diagnosis were evaluated and radiographic diagnosis was compared with computed tomography and definitive diagnosis. RESULTS: The ventro 20 degrees rostral dorsocaudal oblique projection of canine nasal cavities was feasible in anaesthetised dogs and gave diagnostic quality images in most dogs. Assessment of this view showed moderate to substantial agreement with computed tomography diagnosis but gave lower confidence in diagnosis. Interpretation of this radiographic projection had substantial to almost perfect repeatability but moderate reproducibility. CLINICAL SIGNIFICANCE: The ventro 20 degrees rostral dorsocaudal oblique projection may be used as a valuable initial screening tool for canine nasal pathology in practices without access to advanced imaging, although computed tomography is still likely to provide greater diagnostic information. PMID- 26011669 TI - Evolution of host specialization in gut microbes: the bee gut as a model. AB - Bacterial symbionts of eukaryotes often give up generalist lifestyles to specialize to particular hosts. The eusocial honey bees and bumble bees harbor two such specialized gut symbionts, Snodgrassella alvi and Gilliamella apicola. Not only are these microorganisms specific to bees, but different strains of these bacteria tend to assort according to host species. By using in-vivo microbial transplant experiments, we show that the observed specificity is, at least in part, due to evolved physiological barriers that limit compatibility between a host and a potential gut colonizer. How and why such specialization occurs is largely unstudied for gut microbes, despite strong evidence that it is a general feature in many gut communities. Here, we discuss the potential factors that favor the evolution of host specialization, and the parallels that can be drawn with parasites and other symbiont systems. We also address the potential of the bee gut as a model for exploring gut community evolution. PMID- 26011671 TI - Deficits in Metacognitive Capacity Are Related to Subjective Distress and Heightened Levels of Hyperarousal Symptoms in Adults With Posttraumatic Stress Disorder. AB - Among persons with posttraumatic stress disorder (PTSD), the severity of symptoms and concurrent distress are not fully explained by trauma severity. Interest has consequently arisen in the psychological processes that cause distress and heighten PTSD symptoms. This study accordingly sought to examine whether differences in metacognitive capacity are related to levels of emotional distress, avoidance/numbing, and hyperarousal. Participants were 48 adults with a confirmed diagnosis of PTSD. Comparison groups included 51 adults with HIV and 183 with schizophrenia. Metacognition, emotion recognition, depression, and emotional distress and levels of avoidance/numbing and hyperarousal were assessed concurrently using the Metacognition Assessment Scale-Abbreviated, the Bell Lysaker Emotion Recognition Test, the Beck Depression Inventory, and the Clinician-Administered PTSD Scale. Results revealed that the PTSD group had better ratings of overall metacognitive capacity than the schizophrenia group and specifically poorer levels of metacognitive mastery, or the ability to use metacognitive knowledge to respond to challenges, than the HIV group. Within the PTSD group, poorer metacognitive mastery was linked with greater distress and higher hyperarousal when depression was controlled for statistically. Emotion recognition was not linked with distress or symptom severity. Results are consistent with models in which symptom severity in PTSD is related to the extent to which persons can use knowledge of themselves and others to find ways to respond to distress that match their own unique needs. PMID- 26011672 TI - Improved Recharge Estimation from Portable, Low-Cost Weather Stations. AB - Groundwater recharge estimation is a critical quantity for sustainable groundwater management. The feasibility and robustness of recharge estimation was evaluated using physical-based modeling procedures, and data from a low-cost weather station with remote sensor techniques in Southern Abbotsford, British Columbia, Canada. Recharge was determined using the Richards-based vadose zone hydrological model, HYDRUS-1D. The required meteorological data were recorded with a HOBO(TM) weather station for a short observation period (about 1 year) and an existing weather station (Abbotsford A) for long-term study purpose (27 years). Undisturbed soil cores were taken at two locations in the vicinity of the HOBO(TM) weather station. The derived soil hydraulic parameters were used to characterize the soil in the numerical model. Model performance was evaluated using observed soil moisture and soil temperature data obtained from subsurface remote sensors. A rigorous sensitivity analysis was used to test the robustness of the model. Recharge during the short observation period was estimated at 863 and 816 mm. The mean annual recharge was estimated at 848 and 859 mm/year based on a time series of 27 years. The relative ratio of annual recharge-precipitation varied from 43% to 69%. From a monthly recharge perspective, the majority (80%) of recharge due to precipitation occurred during the hydrologic winter period. The comparison of the recharge estimates with other studies indicates a good agreement. Furthermore, this method is able to predict transient recharge estimates, and can provide a reasonable tool for estimates on nutrient leaching that is often controlled by strong precipitation events and rapid infiltration of water and nitrate into the soil. PMID- 26011673 TI - Urinary incontinence: where to now? PMID- 26011674 TI - Indirect Neuromonitoring of the Spinal Cord by Near-Infrared Spectroscopy of the Paraspinous Thoracic and Lumbar Muscles in Aortic Surgery. AB - Paraplegia remains the most devastating complication of open and endovascular thoracic/thoracoabdominal aortic aneurysm (TAA/A) repair. However, the assessment of currently available neuromonitoring modalities remains challenging and difficult to interpret. Near-infrared spectroscopy (NIRS) has been introduced as a strategy for noninvasive, real-time monitoring of the paraspinous collateral network (CN) to detect potential spinal cord ischemia at our institution. Prior to TAA/A repair, a cerebrospinal fluid catheter is placed and four NIRS optodes are bilaterally positioned on the patient's back to transcutaneously monitor regional muscle oxygenation at the thoracic and lumbar levels. Indirect surveillance of the spinal cord by NIRS seems to be a tempting option with increasing evidence supporting the CN concept. PMID- 26011675 TI - Cardiac Surgery in Germany during 2014: A Report on Behalf of the German Society for Thoracic and Cardiovascular Surgery. AB - Based on a voluntary registry of the German Society for Thoracic and Cardiovascular Surgery (GSTCVS), data of all heart surgery procedures performed in 78 German cardiac surgical units during the year 2014 are presented. In 2014, a total of 100,398 cardiac surgical procedures (implantable cardioverter defibrillator and pacemaker procedures excluded) were submitted to the registry. More than 14.2% of the patients were older than 80 years, describing an increase of 0.4% compared with the previous year. The unadjusted in-hospital mortality for 40,006 isolated coronary artery bypass grafting procedures (84.7% on-pump, 15.3% off-pump) was 2.6%. In 31,359 isolated valve procedures (including 9,194 catheter based procedures), an in-hospital mortality of 4.4% was observed. This annual updated registry of the GSTCVS is published since 1989. It is an important tool for quality assurance and voluntary public reporting by illustrating current standards and actual developments for nearly all cardiac surgical procedures in Germany. PMID- 26011676 TI - Cost-effective and morphology controllable PVP based highly efficient CuS counter electrodes for high-efficiency quantum dot-sensitized solar cells. AB - Currently, copper sulfide (CuS) is the most commonly used counter electrode (CE) in high-efficiency quantum dot-sensitized solar cells (QDSSCs) because of its superior electrocatalytic activity in the presence of polysulfide electrolyte. For the first time, CuS thin films were prepared by a facile chemical bath deposition method with different concentrations of polyvinylpyrrolidone (PVP) and directly used as CEs in QDSSCs without any further post treatment. The quantum dot photoanode with the optimized 0.25 mM PVP-based CuS CE exhibits higher short circuit current density (Jsc), open circuit voltage (Voc), fill factor (FF), and power conversion efficiency (PCE) of 17.57 mA cm(-2), 0.578 V, 0.514, and 5.22%, respectively, which are much higher values than those of a bare CuS CE (Jsc: 12.36 mA cm(-2); Voc: 0.591 V; FF: 0.436; PCE: 3.18%) and Pt CE (Jsc: 11.25 mA cm(-2); Voc: 0.464 V; FF: 0.296; PCE: 1.54%) under one-sun illumination (AM 1.5 G, 100 mW cm(-2)). Moreover, the 0.25 mM PVP-based CuS CE produces a charge transfer resistance of only 4.39 Omega with the aqueous polysulfide electrolyte commonly applied in QDSSCs. This value is several orders of magnitude lower than that of a typical Pt electrode (69.75 Omega) and bare CuS electrode (9.27 Omega). This enhancement is mainly attributed to the improved morphology of the 0.25 mM CuS CE with high catalytic activity, which plays a main role in the reduction processes of the oxidized polysulfide electrolyte, as well as the increased sulfur atomic percentage with Cu vacancies. Cyclic voltammetry, electrochemical impedance spectroscopy, and Tafel polarization were performed to study the underlying reasons behind the efficient CE performance. PMID- 26011678 TI - Establishment and characterization of a novel murine model for pollen allergy. AB - Although there have been many studies revealing the mechanism and establishing the therapeutical method for allergic rhinitis, no suitable animal models for allergic rhinitis, especially for pollen allergy, are currently available. We therefore aimed in this study to develop a murine model producing IgE in response to an inhaled antigen without using any adjuvants. Ovalbumin (OVA)-specific T cell receptor transgenic mice (DO11.10) inhaled an OVA solution for one h, twice a week, for six weeks. The resulting increase of OVA-specific IgE in the serum was observed depending on the times of inhalation. Spleen cells from mice that had inhaled the antigen produced more IL-4 and less IFN-gamma than those from the control mice in vitro. These results indicate that inhaled antigen enhanced the Th2-type responses and induced IgE production in a T cell-mediated manner. Our findings would contribute to studies on prevention and treatment of pollen allergy. PMID- 26011679 TI - Usefulness of sonourethrography for penile abscess as a result of xanthogranulomatous granuloma in the corpus cavernosum of an adult: A case report. AB - A 75-year-old man presented with a 4-month history of a swollen and painful penis. Computed tomography showed a round-shaped mass measuring 3 * 2 cm in the corpus cavernosum. Percutaneous drainage of the penile mass was carried out and a course of antibiotics was prescribed. Viral, fungal and selective bacterial cultures were negative. Total penectomy and urethroperineal fistula formation were carried out because of penile pain. Histopathological diagnosis was xanthogranulomatous granuloma of the corpus cavernosum. Before surgery, sonourethrography was carried out under general anesthesia. Sonourethrography is an infrequently used modality to observe the male urethra under urinary micturition or injection of saline. We previously reported modified sonourethrography with retrograde jelly injection. In the present case, sonourethrography successfully showed the damaged and deformed urethra including the abscess cavity and fistula. Although xanthogranulomatous granuloma is rare, the findings reported here showed the usefulness of sonourethrography for morphological evaluation of the male urethra. PMID- 26011682 TI - Scalable Bromide-Triggered Synthesis of Pd@Pt Core-Shell Ultrathin Nanowires with Enhanced Electrocatalytic Performance toward Oxygen Reduction Reaction. AB - This article reports a novel scalable method to prepare ultrathin and uniform Pd@Pt nanowires (NWs) with controllable composition and shell thickness, high aspect ratio, and smooth surface, triggered by bromide ions via a galvanic replacement reaction between PtCl6(2-) and Pd NWs. It was found that bromide ions played a vital role in initiating and promoting the galvanic reaction. The bromide ions served as capping and oxidized etching agents, counterbalancing the Pt deposition and Pd etching on the surface to give final Pd@Pt core-shell nanostructures. Such a counterbalance and the formation PtBr6(2-) with lower redox potential could lower the reaction rate and be responsible for full coverage of a smooth Pt shell. The full coverage of Pt deposited on Pd NWs is important for the enhancement of the activity and stability, which depend strongly on the Pt content and Pt shell thickness. Significantly, the Pd@Pt NWs with Pt content of 21.2% (atomic ratio) exhibited the highest mass activity (810 mA mg(-1)(Pt)) and specific activity (0.4 mA cm(-2)). Interestingly, the mass activity (1560 mA mg(-1)(Pt)) and specific activity (0.98 mA cm(-2)) of Pd@Pt (21.2%) NWs increased to 2.45 and 1.95 times the initial values after 60k cycles tests, 8.5 and 9.0 times greater than those of Pt/C catalysts. In addition, these ultrathin NW electrocatalysts with large aspect ratio are easy to form into a freestanding film, which improves the mass transport, electrical conductivity, and structure stability. PMID- 26011677 TI - Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo controlled trial. AB - AIMS: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies. METHODS AND RESULTS: Heart failure patients with evidence of hyperkalaemia (serum potassium >=5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population. CONCLUSION: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population. PMID- 26011683 TI - Study of the morphology of ZnS thin films deposited on different substrates via chemical bath deposition. AB - In this work, the influence of substrate on the morphology of ZnS thin films by chemical bath deposition is studied. The materials used were zinc acetate, tri sodium citrate, thiourea, and ammonium hydroxide/ammonium chloride solution. The growth of ZnS thin films on different substrates showed a large variation on the surface, presenting a poor growth on SiO2 and HfO2 substrates. The thin films on ITO substrate presented a uniform and compact growth without pinholes. The optical properties showed a transmittance of about 85% in the visible range of 300-800 nm with band gap of 3.7 eV. PMID- 26011684 TI - Correction to "Surface enhanced Raman scattering of amino acids assisted by gold nanoparticles and Gd(3+) ions". PMID- 26011685 TI - Implantation of a 29 mm Sapien XT valve in a pediatric patient with an unstented right ventricular outflow tract. AB - We describe a 29 mm Sapien XT valve implantation in a 10-year-old girl with repaired Tetralogy of Fallot, severe pulmonary regurgitation, and right ventricular dilatation, using the NovaFlex+ delivery system and the expandable introducer eSheath, without pre-stenting of the right ventricular outflow tract. PMID- 26011686 TI - Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans. AB - Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker. PMID- 26011687 TI - Relationship between Extracellular Low-Molecular-Weight Thiols and Mercury Species in Natural Lake Periphytic Biofilms. AB - The uptake of mercury by microorganisms is a key step in the production of methylmercury, a biomagnifiable toxin. Mercury complexation by low-molecular weight (LMW) thiols can affect its bioavailability and thus the production of methylmercury. Freshwater biofilms were sampled in the summer using artificial Teflon substrates submerged for over a year to allow natural community colonization in the littoral zone of a Boreal Shield lake. Inside biofilms, concentrations of different extracellular thiol species (thioglycolic acid, l cysteine-l-glycine, cysteine, and glutathione) were up to 3 orders of magnitude greater than in the surrounding water column, potentially more readily controlling mercury speciation than in the water column. All biofilm thiols except thioglycolic acid were highly correlated to chlorophyll a, likely indicating an algal origin. Extracellular total mercury represented 3 +/- 1% of all biofilm mercury and was preferentially found in the capsular fraction. Levels of LMW thiols of presumed algal origins were highly correlated with total mercury in the mobile colloidal fraction of biofilms. We propose that periphytic phototrophic microorganisms such as algae likely affect the bioavailability of mercury through the exudation of LMW thiols, and thus they may play a key role in the production of methylmercury in biofilms. PMID- 26011688 TI - Two cases of atretic cephalocele, and histological evaluation of skin appendages in the surrounding skin. AB - Atretic cephalocele is a small skin-covered lesion, usually located at or near the mid-line of the scalp. Histologically, it is composed of syncytial cells expressing neurone-specific enolase and epithelial membrane antigen. The syncytial cells form capillary-like structures *(pseudovascular areas) and collagenic fibrosis with densely packed collagen bundles (fibrous areas). Such findings suggest that the atretic cephalocele is a mild form of cephalocele, with its pathogenesis lying in the spectrum of neural tube closure abnormalities. However, few descriptions of abnormalities of the skin overlying and surrounding atretic cephalocele are available. We report two cases of atretic cephalocele that showed hamartomatous change in the surrounding cutaneous appendages. These findings suggest that atretic cephalocele is associated with abnormalities not only of the neural tube, but also of the surrounding skin. PMID- 26011689 TI - Low anterior resection adjacent to a pancake kidney: case report. PMID- 26011690 TI - Pretreatment of forest residues of Douglas fir by wet explosion for enhanced enzymatic saccharification. AB - The logging and lumbering industry in the Pacific Northwest region generates huge amount of forest residues, offering an inexpensive raw material for biorefineries. Wet explosion (WEx) pretreatment was applied to the recalcitrant biomass to optimize process conditions including temperature (170-190 degrees C), time (10-30 min), and oxygen loading (0.5-7.5% of DM) through an experimental design. Optimal pH for enzymatic hydrolysis of the optimized samples and a complete mass balance have been evaluated. Results indicated that cellulose digestibility improved in all conditions tested with maximum digestibility achieved at 190 degrees C, time 30 min, and oxygen loading of 7.5%. Glucose yield at optimal pH of 5.5 was 63.3% with an excellent recovery of cellulose and lignin of 99.9% and 96.3%, respectively. Hemicellulose sugars recovery for xylose and mannose was found to be 69.2% and 76.0%, respectively, indicating that WEx is capable of producing relative high sugar yield even from the recalcitrant forest residues. PMID- 26011691 TI - Conversion of crude Jatropha curcas seed oil into biodiesel using liquid recombinant Candida rugosa lipase isozymes. AB - The versatile Candida rugosa lipase (CRL) has been widely used in biotechnological applications. However, there have not been feasibility reports on the transesterification of non-edible oils to produce biodiesel using the commercial CRL preparations, mixtures of isozymes. In the present study, four liquid recombinant CRL isozymes (CRL1-CRL4) were investigated to convert various non-edible oils into biodiesel. The results showed that recombinant CRL2 and CRL4 exhibited superior catalytic efficiencies for producing fatty acid methyl ester (FAME) from Jatropha curcas seed oil. A maximum 95.3% FAME yield was achieved using CRL2 under the optimal conditions (50 wt% water, an initial 1 equivalent of methanol feeding, and an additional 0.5 equivalents of methanol feeding at 24h for a total reaction time of 48 h at 37 degrees C). We concluded that specific recombinant CRL isozymes could be excellent biocatalysts for the biodiesel production from low-cost crude Jatropha oil. PMID- 26011692 TI - Direct degradation of cellulosic biomass to bio-hydrogen from a newly isolated strain Clostridium sartagoforme FZ11. AB - A mesophilic hydrogen-producing strain, Clostridium sartagoforme FZ11, had been newly isolated from cow dung compost acclimated using microcrystalline cellulose (MCC) for at least 30 rounds in an anaerobic bioreactor, and identified by the 16S rDNA gene sequencing, which could directly utilized various carbon sources, especially cellulosic biomass, to produce hydrogen. The maximum hydrogen yields from MCC (10 g/l) and carboxymethyl cellulose (CMC, 10 g/l) were 77.2 and 64.6 ml/g, separately. Furthermore, some key parameters of affecting hydrogen production from raw corn stalk were also optimized. The maximal hydrogen yield and substrate degradation rate from raw corn stalk were 87.2 ml/g and 41.2% under the optimized conditions with substrate concentration of 15 g/l, phosphate buffer of 0.15 M, urea of 6 g/l and initial pH of 6.47 at 35 degrees C. The result showed that the strain FZ11 would be an ideal candidate to directly convert cellulosic biomass into bio-hydrogen without substrate pretreatment. PMID- 26011693 TI - Catalytic pyrolysis of black-liquor lignin by co-feeding with different plastics in a fluidized bed reactor. AB - Catalytic co-pyrolysis of black-liquor lignin and waste plastics (polyethylene, PE; polypropylene PP; polystyrene, PS) was conducted in a fluidized bed. The effects of temperature, plastic to lignin ratio, catalyst and plastic types on product distributions were studied. Both aromatic and olefin yields increased with increasing PE proportion. Petrochemical yield of co-pyrolysis of PE and lignin was LOSA-1 > spent FCC > Gamma-Al2O3 > sand. The petrochemical yield with LOSA-1 is 43.9% which is more than two times of that without catalyst. The feedstock for co-pyrolysis with lignin is polystyrene > polyethylene > polypropylene. Catalytic co-pyrolysis of black-liquor lignin with PS produced the maximum aromatic yield (55.3%), while co-pyrolysis with PE produced the maximum olefin yield (13%). PMID- 26011694 TI - Improved chalcopyrite bioleaching by Acidithiobacillus sp. via direct step-wise regulation of microbial community structure. AB - A direct step-wise regulation strategy of microbial community structure was developed for improving chalcopyrite bioleaching by Acidithiobacillus sp. Specially, the initial microbial proportion between Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans was controlled at 3:1 with additional 2 g/L Fe(2+) for faster initiating iron metabolism. A. thiooxidans biomass was fed via a step-wise strategy (8-12th d) with the microbial proportion 1:1 for balancing community structure and promoting sulfur metabolism in the stationary phase. A. thiooxidans proportion was further improved via another step wise feeding strategy (14-18th d) with the microbial proportion 1:2 for enhancing sulfur metabolism and weakening jarosite passivation in the later phase. With the community structure-shift control strategy, biochemical reaction was directly regulated for creating a better balance in different phases. Moreover, the final copper ion was increased from 57.1 to 93.2 mg/L, with the productivity 2.33 mg/(Ld). The novel strategy may be valuable in optimization of similar bioleaching process. PMID- 26011695 TI - Rotation-misfit-free heteroepitaxial stacking and stitching growth of hexagonal transition-metal dichalcogenide monolayers by nucleation kinetics controls. AB - 2D vertical stacking and lateral stitching growth of monolayer (ML) hexagonal transition-metal dichalcogenides are reported. The 2D heteroepitaxial manipulation of MoS2 and WS2 MLs is achieved by control of the 2D nucleation kinetics during the sequential vapor-phase growth. It enables the creation of hexagon-on-hexagon unit-cell stacking and hexagon-by-hexagon stitching without interlayer rotation misfits. PMID- 26011696 TI - Pain Management in Four-Limb Amputation: A Case Report. AB - Acute pain following amputation can be challenging to treat due to multiple underlying mechanisms and variable clinical responses to treatment. Furthermore, poorly controlled preoperative pain is a risk factor for developing chronic pain. Evidence suggests that epidural analgesia and peripheral nerve blockade may decrease the severity of residual limb pain and the prevalence of phantom pain after lower extremity amputation. We present the perioperative analgesic management of a patient with gangrene of the bilateral upper and lower extremities as a result of septic shock and prolonged vasopressor administration who underwent four-limb amputation in a single procedure. A multimodal analgesic regimen was utilized, including titration of preoperative opioid and neuropathic pain agents, perioperative intravenous, epidural and peripheral nerve catheter infusions, and postoperative oral medication titration. More than 8 months postoperatively, the patient has satisfactory pain control with no evidence for phantom limb pain. To our knowledge, there have been no publications to date concerning analgesic regimens in four-limb amputation. PMID- 26011697 TI - Assessment of Exposure to Perchloroethylene and its Clinical Repercussions for 50 Dry-Cleaning Employees. AB - The purpose of this article is the assessment of occupational exposure to perchloroethylene (PCE) and its clinical repercussions for dry-cleaning employees. The authors measured atmospheric levels of PCE and blood levels in a population of 50 exposed employees then conducted a study of clinical symptomatology in exposed and non-exposed subjects linked with this solvent. Fifty employees and 95 controls were studied. The median value of atmospheric PCE was 7 ppm (0.22-33), and the median blood level of PCE was 73.6 MUg/l (11.8-144). These levels were correlated statistically to the action of sludge scraping and to the existence of automatic scrapers (p < 0.01). Eight percent of PCE blood levels were higher than the biological levels recently set in France. The exposed population did not show excessive signs of drowsiness nor of pre-narcotic syndrome or other symptoms studied. Dry-cleaning employees were exposed to PCE at atmospheric levels lower than the French and American chronic recommended exposure levels but some results were higher than recommended values. For PCE blood levels for the general working population, results were respectively lower than French and American national recommended levels in 92% and 94% cases. Risk should be considered, however, carefully in women of childbearing age, as 64% exceeded the recommended blood levels for pregnant women. This exposure did not generate any studied neurobehavioral symptomatology. PMID- 26011698 TI - A three-dimensional point process model for the spatial distribution of disease occurrence in relation to an exposure source. AB - We study methods for how to include the spatial distribution of tumours when investigating the relation between brain tumours and the exposure from radio frequency electromagnetic fields caused by mobile phone use. Our suggested point process model is adapted from studies investigating spatial aggregation of a disease around a source of potential hazard in environmental epidemiology, where now the source is the preferred ear of each phone user. In this context, the spatial distribution is a distribution over a sample of patients rather than over multiple disease cases within one geographical area. We show how the distance relation between tumour and phone can be modelled nonparametrically and, with various parametric functions, how covariates can be included in the model and how to test for the effect of distance. To illustrate the models, we apply them to a subset of the data from the Interphone Study, a large multinational case-control study on the association between brain tumours and mobile phone use. PMID- 26011699 TI - Hydrophilic interaction liquid chromatography for the separation, purification, and quantification of raffinose family oligosaccharides from Lycopus lucidus Turcz. AB - A systematic strategy based on hydrophilic interaction liquid chromatography was developed for the separation, purification and quantification of raffinose family oligosaccharides from Lycopus lucidus Turcz. Methods with enough hydrophilicity and selectivity were utilized to resolve the problems encountered in the separation of oligosaccharides such as low retention, low resolution and poor solubility. The raffinose family oligosaccharides in L. lucidus Turcz. were isolated using solid-phase extraction followed by hydrophilic interaction liquid chromatography at semi-preparative scale to obtain standards of stachyose, verbascose and ajugose. Utilizing the obtained oligosaccharides as standards, a quantitative determination method was developed, validated and applied for the content determination of raffinose family oligosaccharides both in the aerial and root parts of L. lucidus Turcz. There were no oligosaccharides in the aerial parts, while in the root parts, the total content was 686.5 mg/g with the average distribution: raffinose 66.5 mg/g, stachyose 289.0 mg/g, verbascose 212.4 mg/g, and ajugose 118.6 mg/g. The result provided the potential of roots of L. lucidus Turcz. as new raffinose family oligosaccharides sources for functional food. Moreover, since the present systematic strategy is efficient, sensitive and robust, separation, purification and quantification of oligosaccharides by hydrophilic interaction liquid chromatography seems to be possible. PMID- 26011700 TI - Regulatory role of B-cell maturation antigen on the toxic effect of chromium ions on human SaOS-2 osteoblasts. AB - Metal prostheses of artificial joints undergo wear, producing numerous metal particles and ions, such as Cr3+ . Cr3+ is considered a key factor leading to aseptic loosening. Many studies focus on the effect of Cr3+ on osteoblasts; however, little is known about the effect of Cr3+ on the B-cell maturation antigen (BCMA) in the osteoblasts. In this study, we first demonstrated the BCMA expressed in human SaOS-2 osteoblasts through reverse transcriptase-PCR, Western blot, and immunocytochemical analyses. Cr3+ decreased alkaline phosphatase (ALP), osteocalcin (OC), cell mineralization, and collagen type I mRNA and protein expression. Moreover, Cr3+ has an inhibitive effect on the expression of the BCMA in human SaOS-2 osteoblasts. However, after we upregulated the expression of the BCMA, ALP, OC, cell mineralization, and collagen type I mRNA and protein expression were increased. Overall, this study demonstrates that the BCMA is involved in human SaOS-2 osteoblast osteogenetic metabolism and plays a regulatory role on the toxic effect of chromium ions on human SaOS-2 osteoblasts. PMID- 26011701 TI - The role of Rhipicephalus sanguineus sensu lato saliva in the dissemination of Rickettsia conorii in C3H/HeJ mice. AB - Animal models have been developed for the study of rickettsial pathogenesis. However, to understand what occurs during the natural route of rickettsial transmission via the tick bite, the role of tick saliva should be considered in these models. To address this, we analysed the role of tick saliva in the transmission of Rickettsia conorii (Rickettsiales: Rickettsiaceae) in a murine host by intradermally (i.d.) inoculating two groups of susceptible C3H/HeJ mice with this Rickettsia, and infesting one group with nymphal Rhipicephalus sanguineus sensu lato (Ixodida: Ixodidae) ticks. Quantification of bacterial loads and mRNA levels of interleukin-1beta (IL-1beta), IL-10 and NF-kappaB was performed in C3H/HeJ lung samples by real-time quantitative polymerase chain reaction (PCR) and real-time reverse transcriptase PCR, respectively. Lung histology was examined to evaluate the pathological manifestations of infection. No statistically significant difference in bacterial load in the lungs of mice was observed between these two groups; however, a statistically significant difference was observed in levels of IL-1beta and NF-kappaB, both of which were higher in the group inoculated with rickettsiae but not infected with ticks. Lung histology in both groups of animals revealed infiltration of inflammatory cells. Overall, this study showed that i.d. inoculation of R. conorii caused infection in the lungs of C3H/HeJ mice and tick saliva inhibited proinflammatory effects. PMID- 26011702 TI - Short-term, low-dose cadmium exposure induces hyperpermeability in human renal glomerular endothelial cells. AB - The kidney is the principal organ targeted by exposure to cadmium (Cd), a well known toxic metal. Even at a low level, Cd damages glomerular filtration. However, little is known about the effects of Cd on the glomerular endothelium, which performs the filtration function and directly interacts with Cd in blood plasma. In this study, we cultured human renal glomerular endothelial cells (HRGECs) in the presence of serum with treatment of a short term (1 h) and low concentration (1 MUm) of Cd, which mimics the pattern of glomerular endothelium exposure to Cd in vivo. We found that this short-term, low-dose Cd exposure does not induce cytotoxicity, but increases permeability in HRGECs monolayers and redistributes adherens junction proteins vascular endothelial-cadherin and beta catenin. Though short-term, low-dose Cd exposure activates all three major mitogen activated protein kinases, only the inhibitor of p38 mitogen activated protein kinase partially prevents Cd-induced hyperpermeability in HRGECs. Our data indicate that the presence of Cd in blood circulation might directly disrupt the glomerular endothelial cell barrier and contribute to the development of clinical symptoms of glomerular diseases. PMID- 26011703 TI - Novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor as treatment for hepatocellular carcinoma. AB - We previously identified Aurora B kinase as the only independent factor predictive of the aggressive recurrence of hepatocellular carcinoma (HCC). In this preclinical study, JNJ-28841072, a novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor, was evaluated for treatment of HCC. In vitro and in vivo effects of JNJ-28841072 were analyzed using human HCC cell cultures and xenograft models. An orthotopic liver xenograft model was used for the pharmacobiological effects on Aurora kinase and vascularization in hepatic tumors. JNJ-28841072 suppressed in vitro phosphorylation of histone H3 with induction of cell polyploidy and death in a dose-dependent manner (IC50 = 0.8 1.2 MUM). In s.c. human HCC xenografts, remarkable inhibition of tumor growth was observed after JNJ-28841072 treatment (P = 0.0005). In orthotopic liver xenografts, the treatment with JNJ-28841072 significantly suppressed in vivo phosphorylation of histone H3 (P = 0.0008), vessel formation (P = 0.018), normoxic area (P = 0.0001), and hepatoma growth (P = 0.038). Our preclinical studies indicate that JNJ-28841072 is a promising novel therapeutic approach for the treatment of HCC. It might be worthy of evaluation in further studies. PMID- 26011704 TI - Impact of bacterial vaginosis, as assessed by nugent criteria and hormonal status on glycosidases and lectin binding in cervicovaginal lavage samples. AB - The objective of this study was to evaluate the impact of hormonal status and bacterial vaginosis (BV) on the glycosidases present and glycosylation changes as assessed by lectin binding to cervicovaginal lavage constituents. Frozen cervicovaginal lavage samples from a completed study examining the impact of reproductive hormones on the physicochemical properties of vaginal fluid were utilized for the present study. In the parent study, 165 women were characterized as having BV, intermediate or normal microflora using the Nugent criteria. The presence of glycosidases in the samples was determined using quantitative 4 methyl-umbelliferone based assays, and glycosylation was assessed using enzyme linked lectin assays (ELLA). Women with BV had elevated sialidase, alpha galactosidase, beta-galactosidase and alpha-glucosidase activities compared to intermediate or normal women (P<0.001, 0.003, 0.006 and 0.042 respectively). The amount of sialic acid (Sambucus nigra, P = 0.003) and high mannose (griffithsin, P<0.001) were reduced, as evaluated by lectin binding, in women with BV. When the data were stratified according to hormonal status, alpha-glucosidase and griffithsin binding were decreased among postmenopausal women (P<0.02) when compared to premenopausal groups. These data suggest that both hormonal status and BV impact the glycosidases and lectin binding sites present in vaginal fluid. The sialidases present at increased levels in women with BV likely reduce the number of sialic acid binding sites. Other enzymes likely reduce griffithsin binding. The alterations in the glycosidase content, high mannose and sialic acid binding sites in the cervicovaginal fluid associated with bacterial vaginosis may impact susceptibility to viruses, such as HIV, that utilize glycans as a portal of entry. PMID- 26011705 TI - Efficient and Stable MoS2 /CdSe/NiO Photocathode for Photoelectrochemical Hydrogen Generation from Water. AB - A novel CdSe/NiO heteroarchitecture was designed, prepared, and used as a photocathode for hydrogen generation from water. The composite films were structurally, optically, and photoelectrochemically characterized. The deposition of CdSe on the NiO film enhanced light harvesting in the visible-light region and photoelectrochemical properties. Moreover, the CdSe/NiO photoelectrode showed superior stability both in nitrogen-saturated and air-saturated neutral environments. The CdSe/NiO photoelectrode after MoS2 modification retained the stability of the CdSe/NiO electrode and exhibited higher photocatalytic and photoelectrochemical performances than the unmodified CdSe/NiO electrode. In pH 6 buffer solution, an average hydrogen-evolution rate of 0.52 MUmol h(-1) cm(-2) at -0.131 V (versus reversible hydrogen electrode, RHE) was achieved on a MoS2 /CdSe/NiO photocathode, with almost 100 % faradaic efficiency. PMID- 26011706 TI - Trends and Determinants of Prescription Drug Use during Pregnancy and Postpartum in British Columbia, 2002-2011: A Population-Based Cohort Study. AB - PURPOSE: To describe trends, patterns, and determinants of prescription drug use during pregnancy and postpartum. METHODS: This is a retrospective, population based study of all women who gave birth between January 2002 and 31 December 2011 in British Columbia, Canada. Study population consisted of 225,973 women who had 322,219 pregnancies. We examined administrative datasets containing person specific information on filled prescriptions, hospitalizations, and medical services. Main outcome measures were filled prescriptions during pregnancy and postpartum. We used logistic regressions to examine associations between prescription drug use and maternal characteristics. RESULTS: Approximately two thirds of women filled a prescription during pregnancy, increasing from 60% in 2002 to 66% in 2011. The proportion of pregnant women using medicines in all three trimesters of pregnancy increased from 20% in 2002 to 27% in 2011. Use of four or more different types of prescription drug during at least one trimester increased from 8.4% in 2002 to 11.7% in 2011. Higher BMI, smoking during pregnancy, age under 25, carrying multiples, and being diagnosed with a chronic condition all significantly increased the odds of prescription drug use during pregnancy. CONCLUSIONS: The observed increase in the number of prescriptions and number of different drugs being dispensed suggests a trend in prescribing practices with potentially important implications for mothers, their neonates, and caregivers. Monitoring of prescribing practices and further research into the safety of most commonly prescribed medications is crucial in better understanding risks and benefits to the fetus and the mother. PMID- 26011708 TI - EGR1 Functions as a Potent Repressor of MEF2 Transcriptional Activity. AB - The myocyte enhancer factor 2 (MEF2) transcription factor requires interactions with co-factors for precise regulation of its target genes. Our lab previously reported that the mammalian MEF2A isoform regulates the cardiomyocyte costamere, a critical muscle-specific focal adhesion complex involved in contractility, through its transcriptional control of genes encoding proteins localized to this cytoskeletal structure. To further dissect the transcriptional mechanisms of costamere gene regulation and identify potential co-regulators of MEF2A, a bioinformatics analysis of transcription factor binding sites was performed using the proximal promoter regions of selected costamere genes. One of these predicted sites belongs to the early growth response (EGR) transcription factor family. The EGR1 isoform has been shown to be involved in a number of pathways in cardiovascular homeostasis and disease, making it an intriguing candidate MEF2 coregulator to further characterize. Here, we demonstrate that EGR1 interacts with MEF2A and is a potent and specific repressor of MEF2 transcriptional activity. Furthermore, we show that costamere gene expression in cardiomyocytes is dependent on EGR1 transcriptional activity. This study identifies a mechanism by which MEF2 activity can be modulated to ensure that costamere gene expression is maintained at levels commensurate with cardiomyocyte contractile activity. PMID- 26011707 TI - Analysis of a Panel of 48 Cytokines in BAL Fluids Specifically Identifies IL-8 Levels as the Only Cytokine that Distinguishes Controlled Asthma from Uncontrolled Asthma, and Correlates Inversely with FEV1. AB - We sought to identify cells and cytokines in bronchoalveolar lavage (BAL) fluids that distinguish asthma from healthy control subjects and those that distinguish controlled asthma from uncontrolled asthma. Following informed consent, 36 human subjects were recruited for this study. These included 11 healthy control subjects, 15 subjects with controlled asthma with FEV1>=80% predicted and 10 subjects with uncontrolled asthma with FEV1 <80% predicted. BAL fluid was obtained from all subjects. The numbers of different cell types and the levels of 48 cytokines were measured in these fluids. Compared to healthy control subjects, patients with asthma had significantly more percentages of eosinophils and neutrophils, IL-1RA, IL-1alpha, IL-1beta, IL-2Ralpha, IL-5, IL-6, IL-7, IL-8, G CSF, GROalpha (CXCL1), MIP-1beta (CCL4), MIG (CXCL9), RANTES (CCL5) and TRAIL in their BAL fluids. The only inflammatory markers that distinguished controlled asthma from uncontrolled asthma were neutrophil percentage and IL-8 levels, and both were inversely correlated with FEV1. We examined whether grouping asthma subjects on the basis of BAL eosinophil % or neutrophil % could identify specific cytokine profiles. The only differences between neutrophil-normal asthma (neutrophil<=2.4%) and neutrophil-high asthma (neutrophils%>2.4%) were a higher BAL fluid IL-8 levels, and a lower FEV1 in the latter group. By contrast, compared to eosinophil-normal asthma (eosinophils<=0.3%), eosinophil-high asthma (eosinophils>0.3%) had higher levels of IL-5, IL-13, IL-16, and PDGF-bb, but same neutrophil percentage, IL-8, and FEV1. Our results identify neutrophils and IL-8 are the only inflammatory components in BAL fluids that distinguish controlled asthma from uncontrolled asthma, and both correlate inversely with FEV1. PMID- 26011710 TI - The treatment of mild cognitive impairment associated with Parkinson's disease. PMID- 26011709 TI - Inhibition of T-Type Voltage Sensitive Calcium Channel Reduces Load-Induced OA in Mice and Suppresses the Catabolic Effect of Bone Mechanical Stress on Chondrocytes. AB - Voltage-sensitive calcium channels (VSCC) regulate cellular calcium influx, one of the earliest responses to mechanical stimulation in osteoblasts. Here, we postulate that T-type VSCCs play an essential role in bone mechanical response to load and participate in events leading to the pathology of load-induced OA. Repetitive mechanical insult was used to induce OA in Cav3.2 T-VSCC null and wild type control mouse knees. Osteoblasts (MC3T3-E1) and chondrocytes were treated with a selective T-VSCC inhibitor and subjected to fluid shear stress to determine how blocking of T-VSCCs alters the expression profile of each cell type upon mechanical stimulation. Conditioned-media (CM) obtained from static and sheared MC3T3-E1 was used to assess the effect of osteoblast-derived factors on the chondrocyte phenotype. T-VSCC null knees exhibited significantly lower focal articular cartilage damage than age-matched controls. In vitro inhibition of T VSCC significantly reduced the expression of both early and late mechanoresponsive genes in osteoblasts but had no effect on gene expression in chondrocytes. Furthermore, treatment of chondrocytes with CM obtained from sheared osteoblasts induced expression of markers of hypertrophy in chondrocytes and this was nearly abolished when osteoblasts were pre-treated with the T-VSCC specific inhibitor. These results indicate that T-VSCC plays a role in signaling events associated with induction of OA and is essential to the release of osteoblast-derived factors that promote an early OA phenotype in chondrocytes. Further, these findings suggest that local inhibition of T-VSCC may serve as a therapy for blocking load-induced bone formation that results in cartilage degeneration. PMID- 26011711 TI - Working memory binding and episodic memory formation in aging, mild cognitive impairment, and Alzheimer's dementia. AB - INTRODUCTION: Recent studies indicate that in both normal and pathological aging working memory (WM) performance deteriorates, especially when associations have to be maintained. However, most studies typically do not assess the relationship between WM and episodic memory formation. In the present study, we examined WM and episodic memory formation in normal aging and in patients with early Alzheimer's disease (mild cognitive impairment, MCI; and Alzheimer's dementia, AD). METHOD: In the first study, 26 young adults (mean age 29.6 years) were compared to 18 middle-aged adults (mean age 52.2 years) and 25 older adults (mean age 72.8 years). We used an associative delayed-match-to-sample WM task, which requires participants to maintain two pairs of faces and houses presented on a computer screen for short (3 s) or long (6 s) maintenance intervals. After the WM task, an unexpected subsequent associative memory task was administered (two alternative forced choice). In the second study, 27 patients with AD and 19 patients with MCI were compared to 25 older controls, using the same paradigm as that in Experiment 1. RESULTS: Older adults performed worse than both middle-aged and young adults. No effect of delay was observed in the healthy adults, and pairs that were processed during long maintenance intervals were not better remembered in the subsequent memory task. In the MCI and AD patients, longer maintenance intervals hampered the task performance. Also, both patient groups performed significantly worse than controls on the episodic memory task as well as the associative WM task. CONCLUSIONS: Aging and AD present with a decline in WM binding, a finding that extends similar results in episodic memory. Longer delays in the WM task did not affect episodic memory formation. We conclude that WM deficits are found when WM capacity is exceeded, which may occur during associative processing. PMID- 26011712 TI - Seasonal influenza vaccination for children in Thailand: a cost-effectiveness analysis. AB - BACKGROUND: Seasonal influenza is a major cause of mortality worldwide. Routine immunization of children has the potential to reduce this mortality through both direct and indirect protection, but has not been adopted by any low- or middle income countries. We developed a framework to evaluate the cost-effectiveness of influenza vaccination policies in developing countries and used it to consider annual vaccination of school- and preschool-aged children with either trivalent inactivated influenza vaccine (TIV) or trivalent live-attenuated influenza vaccine (LAIV) in Thailand. We also compared these approaches with a policy of expanding TIV coverage in the elderly. METHODS AND FINDINGS: We developed an age structured model to evaluate the cost-effectiveness of eight vaccination policies parameterized using country-level data from Thailand. For policies using LAIV, we considered five different age groups of children to vaccinate. We adopted a Bayesian evidence-synthesis framework, expressing uncertainty in parameters through probability distributions derived by fitting the model to prospectively collected laboratory-confirmed influenza data from 2005-2009, by meta-analysis of clinical trial data, and by using prior probability distributions derived from literature review and elicitation of expert opinion. We performed sensitivity analyses using alternative assumptions about prior immunity, contact patterns between age groups, the proportion of infections that are symptomatic, cost per unit vaccine, and vaccine effectiveness. Vaccination of children with LAIV was found to be highly cost-effective, with incremental cost-effectiveness ratios between about 2,000 and 5,000 international dollars per disability-adjusted life year averted, and was consistently preferred to TIV-based policies. These findings were robust to extensive sensitivity analyses. The optimal age group to vaccinate with LAIV, however, was sensitive both to the willingness to pay for health benefits and to assumptions about contact patterns between age groups. CONCLUSIONS: Vaccinating school-aged children with LAIV is likely to be cost effective in Thailand in the short term, though the long-term consequences of such a policy cannot be reliably predicted given current knowledge of influenza epidemiology and immunology. Our work provides a coherent framework that can be used for similar analyses in other low- and middle-income countries. PMID- 26011713 TI - In-frame amber stop codon replacement mutagenesis for the directed evolution of proteins containing non-canonical amino acids: identification of residues open to bio-orthogonal modification. AB - Expanded genetic code approaches are a powerful means to add new and useful chemistry to proteins at defined residues positions. One such use is the introduction of non-biological reactive chemical handles for site-specific biocompatible orthogonal conjugation of proteins. Due to our currently limited information on the impact of non-canonical amino acids (nAAs) on the protein structure-function relationship, rational protein engineering is a "hit and miss" approach to selecting suitable sites. Furthermore, dogma suggests surface exposed native residues should be the primary focus for introducing new conjugation chemistry. Here we describe a directed evolution approach to introduce and select for in-frame codon replacement to facilitate engineering proteins with nAAs. To demonstrate the approach, the commonly reprogrammed amber stop codon (TAG) was randomly introduced in-frame in two different proteins: the bionanotechnologically important cyt b(562) and therapeutic protein KGF. The target protein is linked at the gene level to sfGFP via a TEV protease site. In absence of a nAA, an in-frame TAG will terminate translation resulting in a non fluorescent cell phenotype. In the presence of a nAA, TAG will encode for nAA incorporation so instilling a green fluorescence phenotype on E. coli. The presence of endogenously expressed TEV proteases separates in vivo target protein from its fusion to sfGFP if expressed as a soluble fusion product. Using this approach, we incorporated an azide reactive handle and identified residue positions amenable to conjugation with a fluorescence dye via strain-promoted azide-alkyne cycloaddition (SPAAC). Interestingly, best positions for efficient conjugation via SPAAC were residues whose native side chain were buried through analysis of their determined 3D structures and thus may not have been chosen through rational protein engineering. Molecular modeling suggests these buried native residues could become partially exposed on substitution to the azide containing nAA. PMID- 26011715 TI - The wedding cake solution: A percutaneous correction of a form fruste superior sinus venosus atrial septal defect. AB - We present the case of a patient with a superior sinus venosus defect (SSVD), with the atypical finding of an intact atrial septum and posterior atrial wall, which underwent percutaneous closure in the cardiac catheterization laboratory for repair. SSVDs are rare congenital cardiac anomalies, but when the anatomy is amenable to percutaneous strategies, a collaborative and creative approach can result in a safe and effective result. PMID- 26011716 TI - Collagenous gastroduodenitis with recurrent gastric ulcer in 12-year-old girl. AB - This report describes a rare case of collagenous gastroduodenitis found in a 12 year-old Japanese girl who had recurrent hematemesis. Gastrointestinal endoscopy showed many lotus leaf-like lesions on the gastric mucosa surrounded by atrophic gastric mucosa in the antrum, with a cobblestone appearance and a scarred duodenal ulcer in the duodenal bulb. A biopsy of the gastric mucosa indicated subepithelial collagen band. The patient was treated with H2-blockers for her symptoms for 4 years following the endoscopic findings. Follow-up endoscopy showed the same appearance as before. The pathology, however, showed a more prominent subepithelial collagen deposition. To make the correct diagnosis, it is critical to know from which part the pathological biopsy specimens were taken because there were numerous collagen bands in the atrophic membrane. It is important to monitor the patient regularly for evaluation of the etiology, pathogenesis and prognosis of this rare disease. PMID- 26011714 TI - A Quantitative Analysis of Growth and Size Regulation in Manduca sexta: The Physiological Basis of Variation in Size and Age at Metamorphosis. AB - Body size and development time are important life history traits because they are often highly correlated with fitness. Although the developmental mechanisms that control growth have been well studied, the mechanisms that control how a species characteristic body size is achieved remain poorly understood. In insects adult body size is determined by the number of larval molts, the size increment at each molt, and the mechanism that determines during which instar larval growth will stop. Adult insects do not grow, so the size at which a larva stops growing determines adult body size. Here we develop a quantitative understanding of the kinetics of growth throughout larval life of Manduca sexta, under different conditions of nutrition and temperature, and for genetic strains with different adult body sizes. We show that the generally accepted view that the size increment at each molt is constant (Dyar's Rule) is systematically violated: there is actually a progressive increase in the size increment from instar to instar that is independent of temperature. In addition, the mass-specific growth rate declines throughout the growth phase in a temperature-dependent manner. We show that growth within an instar follows a truncated Gompertz trajectory. The critical weight, which determines when in an instar a molt will occur, and the threshold size, which determines which instar is the last, are different in genetic strains with different adult body sizes. Under nutrient and temperature stress Manduca has a variable number of larval instars and we show that this is due to the fact that more molts at smaller increments are taken before threshold size is reached. We test whether the new insight into the kinetics of growth and size determination are sufficient to explain body size and development time through a mathematical model that incorporates our quantitative findings. PMID- 26011717 TI - Exposure to grass pollen--but not birch pollen--affects lung function in Swedish children. AB - Allergic response to pollen is increasing worldwide, leading to high medical and social costs. However, the effect of pollen exposure on lung function has rarely been investigated. Over 1800 children in the Swedish birth cohort BAMSE were lung function- and IgE-tested at the age of 8 and 16 years old. Daily concentrations for 9 pollen types together with measurements for ozone, NO2 , PM10 , PM2.5 were estimated for the index day as well as up to 6 days before the testing. Exposure to grass pollen during the preceding day was associated with a reduced forced expiratory volume in 8-yr-olds; -32.4 ml; 95% CI: -50.6 to -14.2, for an increase in three pollen counts/m3. Associations appeared stronger in children sensitized to pollen allergens. As the grass species flower late in the pollen season, the allergy care routines might be weakened during this period. Therefore, allergy information may need to be updated to increase awareness among grass pollen sensitized individuals. PMID- 26011718 TI - Mental skills training with basic combat training soldiers: A group-randomized trial. AB - Cognitive skills training has been linked to greater skills, self-efficacy, and performance. Although research in a variety of organizational settings has demonstrated training efficacy, few studies have assessed cognitive skills training using rigorous, longitudinal, randomized trials with active controls. The present study examined cognitive skills training in a high-risk occupation by randomizing 48 platoons (N = 2,432 soldiers) in basic combat training to either (a) mental skills training or (b) an active comparison condition (military history). Surveys were conducted at baseline and 3 times across the 10-week course. Multilevel mixed-effects models revealed that soldiers in the mental skills training condition reported greater use of a range of cognitive skills and increased confidence relative to those in the control condition. Soldiers in the mental skills training condition also performed better on obstacle course events, rappelling, physical fitness, and initial weapons qualification scores, although effects were generally moderated by gender and previous experience. Overall, effects were small; however, given the rigor of the design, the findings clearly contribute to the broader literature by providing supporting evidence that cognitive training skills can enhance performance in occupational and sports settings. Future research should address gender and experience to determine the need for targeting such training appropriately. PMID- 26011719 TI - Understanding cycles of abuse: A multimotive approach. AB - Fundamental to the definition of abusive supervision is the notion that subordinates are often victims of a pattern of mistreatment (Tepper, 2000). However, little research has examined the processes through which such destructive relational patterns emerge. In this study, we draw from and extend the multimotive model of reactions to interpersonal threat (Smart Richman & Leary, 2009) to formulate and test hypotheses about how employees' emotional and behavioral responses may ameliorate or worsen supervisors' abuse. To test this model, we collected 6 waves of data from a sample of 244 employees. Results revealed reciprocal relationships between abusive supervision and both supervisor directed counterproductive behavior and supervisor-directed avoidance. Whereas the abusive supervision--counterproductive behavior relationship was partially driven by anger, the abusive supervision--avoidance relationship was partially mediated by fear. These findings suggest that some may find themselves in abusive relationships, in part, because their own reactions to mistreatment can, perhaps unknowingly, reinforce abusive behavior. PMID- 26011720 TI - An item analysis of the Conditional Reasoning Test of Aggression. AB - This manuscript uses item response theory (IRT) to estimate item characteristics of the Conditional Reasoning Test of Aggression (CRT-A). Using a sample size of 5,511 respondents, the present analysis provides an accurate assessment of the capability of the CRT-A to measure latent aggression. The one-parameter logistic (1PL) model, two-parameter logistic (2PL) model, and three-parameter logistic (3PL) model are compared before the item analysis. Results suggest that the 2PL model is the most appropriate dichotomous IRT model for describing the item characteristics of the CRT-A. Potential multdimensionality in the CRT-A is also examined. Results suggest that CRT-A items work as theoretically intended, with the probability of selecting an aggressive response increasing with latent trait levels. Information curves indicate that the CRT-A is best suited for use with individuals who are high on latent aggression. Exploratory analyses include an examination of polytomous IRT models and DIF comparing student and employee respondents. The results have implications for future research using the CRT-A as well as the identification of populations appropriate for measurement using this assessment tool. PMID- 26011721 TI - Negative core affect and employee silence: How differences in activation, cognitive rumination, and problem-solving demands matter. AB - Employees can help to improve organizational performance by sharing ideas, suggestions, or concerns about practices, but sometimes they keep silent because of the experience of negative affect. Drawing and expanding on this stream of research, this article builds a theoretical rationale based on core affect and cognitive appraisal theories to describe how differences in affect activation and boundary conditions associated with cognitive rumination and cognitive problem solving demands can explain employee silence. Results of a diary study conducted with professionals from diverse organizations indicated that within-person low activated negative core affect increased employee silence when, as an invariant factor, cognitive rumination was high. Furthermore, within-person high-activated negative core affect decreased employee silence when, as an invariant factor, cognitive problem-solving demand was high. Thus, organizations should manage conditions to reduce experiences of low-activated negative core affect because these feelings increase silence in individuals high in rumination. In turn, effective management of experiences of high-activated negative core affect can reduce silence for individuals working under high problem-solving demand situations. PMID- 26011722 TI - Line manager implementation perceptions as a mediator of relations between high performance work practices and employee outcomes. AB - Strategic human resources management (SHRM) scholars recently have suggested that high-performance work practices (HPWP) implementation might serve as a critical mediator between HPWP and workplace outcomes. This study proposes and tests a model that positions line managers' perceptions regarding the extent to which they implement their organization's HPWP as a mediator of relations between HPWP and employee attitudes (i.e., turnover intentions and participative decision making perceptions) and behavior (i.e., job performance). Using data from 507 line managers and 109 matched line manager-subordinate response sets, the results suggest that line managers' HPWP implementation perceptions fully mediate relations between HPWP and employee outcomes. The authors also found that line managers' human resources competency and political skill affect their HPWP implementation perceptions. Overall, these findings contribute to a more informed understanding of relationships between HPWP and work outcomes and suggest that additional SHRM research is needed to better understand whether and how HPWP are implemented. PMID- 26011723 TI - Outperforming whom? A multilevel study of performance-prove goal orientation, performance, and the moderating role of shared team identification. AB - Performance-prove goal orientation affects performance because it drives people to try to outperform others. A proper understanding of the performance-motivating potential of performance-prove goal orientation requires, however, that we consider the question of whom people desire to outperform. In a multilevel analysis of this issue, we propose that the shared team identification of a team plays an important moderating role here, directing the performance-motivating influence of performance-prove goal orientation to either the team level or the individual level of performance. A multilevel study of salespeople nested in teams supports this proposition, showing that performance-prove goal orientation motivates team performance more with higher shared team identification, whereas performance-prove goal orientation motivates individual performance more with lower shared team identification. Establishing the robustness of these findings, a second study replicates them with individual and team performance in an educational context. PMID- 26011725 TI - Agreement on intrapartum cardiotocogram recordings between expert obstetricians. AB - RATIONALE, AIMS AND OBJECTIVES: To evaluate obstetricians' inter- and intra observer agreement on intrapartum cardiotocogram (CTG) recordings and to examine obstetricians' evaluations with respect to umbilical artery pH and base deficit. METHODS: Nine experienced obstetricians annotated 634 intrapartum CTG recordings. The evaluation of each recording was divided into four steps: evaluation of two 30-minute windows in the first stage of labour, evaluation of one window in the second stage of labour and labour outcome prediction. The complete set of evaluations used for this experiment is available online. The inter- and intra observer agreement was evaluated using proportion of agreement and kappa coefficient. Clinicians' sensitivity and specificity was computed with respect to umbilical artery pH, base deficit and to Apgar score at the fifth minute. RESULTS: The overall proportion of agreement between clinicians reached 48% with 95% confidence intervals (CI) (CI: 47-50). Regarding the different classes, proportion of agreement ranged from 57% (CI: 54-60) for normal to 41% (CI: 36-46) for pathological class. The sensitivity of clinicians' majority vote to objective outcome was 39% (CI: 16-63) for the umbilical artery base deficit and 27% (CI: 16 42) for pH. The specificity was 89% (CI: 86-92) for both types of objective outcome. CONCLUSIONS: The reported inter-/intra-observer variability is large and this holds irrespective of clinicians' experience or work place. The results support the need of modernized guidelines for CTG evaluation and/or objectivization and repeatability by introduction of a computerized approach that could standardize the process of CTG evaluation within the delivery ward. PMID- 26011724 TI - Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. AB - Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2--thioredoxin 2 (TRX2)--peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers. Due to the fact that activity of the PRX3 catalytic cycle dictates the rate of adduction by TS, immortalized and primary human mesothelial cells are significantly less sensitive to both compounds. Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS. Expression of catalase in shPRX3 mesothelioma cells restores defects in cell proliferation but not sensitivity to TS. In a SCID mouse xenograft model of human mesothelioma, administration of TS and GV together reduced tumor burden more effectively than either agent alone. Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies. PMID- 26011726 TI - Complex regional pain syndrome and dysautonomia in a 14-year-old girl responsive to therapeutic plasma exchange. AB - Reflex sympathetic dystrophy, also known as complex regional pain syndrome (CRPS), has recently been shown to be associated with autoantibodies against beta2-adrenergic and muscarinic M2 receptors. In addition to pain and sudomotor/vasomotor symptoms, dysautonomia is also observed in a subset of CRPS patients. Despite its severity, there are few effective therapies for CRPS described to date. We report a case of a 14-year-old girl with CRPS of her right leg and dysautonomia (gastroparesis, postural tachycardia) refractory to multiple therapies, successfully treated with therapeutic plasma exchange (TPE) with albumin replacement. The patient, who has serum anti beta2-adrenergic and muscarinic M2 receptor autoantibodies in addition to nicotinic acetylcholine receptor ganglionic autoantibodies, underwent an initial course of five TPEs over a 2-week period. She demonstrated a clinical response to TPE as manifested by a rapid improvement in her fatigue and gastroparesis, with a gradual yet significant improvement in her leg pain and sudomotor/vasomotor flares. Following the loading procedures, the patient was treated with rituximab. She continues to require periodic TPE to maintain a remission, with additional immunosuppression being considered long term. Although further studies are needed, TPE (in combination with immunosuppression) may be an appropriate therapy for CRPS patients with detectable autoantibodies, as it is for better characterized diseases with autoantibodies against neuronal surface receptors such as myasthenia gravis or Lambert Eaton myasthenic syndrome. J. Clin. Apheresis 31:368 374, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26011729 TI - Our senior editorial reviewers: a centerpiece. PMID- 26011728 TI - Accuracy of Clinical Diagnosis of Dengue Episodes in the RV144 HIV Vaccine Efficacy Trial in Thailand. AB - RV144 was a community-based HIV vaccine efficacy trial conducted in HIV uninfected adults in Thailand, where dengue virus continues to cause a large number of infections every year. We attempted to document the accuracy of clinically diagnosed dengue episodes reported as serious adverse events (SAEs) and adverse events (AEs) and examine whether dengue serology would support the clinical diagnosis. Subjects without a clinical dengue diagnosis but with an infection or idiopathic fever were selected as a control population. Dengue serology was performed by hemagglutination inhibition on plasma samples. A total of 124 clinical dengue episodes were reported (103 SAEs and 21 AEs). Overall 82.6% of the clinically diagnosed dengue episodes were supported by a positive dengue serology: 71.4% of the AEs and 85.0% of the SAEs. Of the 100 subjects with both clinical dengue and positive serology, all presented with fever, 83% with leucopenia, 54% with thrombocytopenia, and 27% with hemorrhagic symptoms. All episodes resolved spontaneously without sequellae. Only two of 15 subjects with a negative serology presented with fever. The sensitivity and specificity of clinical dengue diagnosis were 90.9% and 74.4%, respectively, when compared to the control population, and with a positive predictive value of 82.6% and negative predictive value of 84.7% when compared to dengue serology. Clinical diagnosis of dengue is an accurate method of dengue diagnosis in adults in Thailand. Large-scale clinical trials offer the opportunity to systematically study infectious diseases such as dengue and other infections that may occur during the trial. PMID- 26011727 TI - Healthy Eating and Risks of Total and Cause-Specific Death among Low-Income Populations of African-Americans and Other Adults in the Southeastern United States: A Prospective Cohort Study. AB - BACKGROUND: A healthy diet, as defined by the US Dietary Guidelines for Americans (DGA), has been associated with lower morbidity and mortality from major chronic diseases in studies conducted in predominantly non-Hispanic white individuals. It is unknown whether this association can be extrapolated to African-Americans and low-income populations. METHODS AND FINDINGS: We examined the associations of adherence to the DGA with total and cause-specific mortality in the Southern Community Cohort Study, a prospective study that recruited 84,735 American adults, aged 40-79 y, from 12 southeastern US states during 2002-2009, mostly through community health centers that serve low-income populations. The present analysis included 50,434 African-Americans, 24,054 white individuals, and 3,084 individuals of other racial/ethnic groups, among whom 42,759 participants had an annual household income less than US$15,000. Usual dietary intakes were assessed using a validated food frequency questionnaire at baseline. Adherence to the DGA was measured by the Healthy Eating Index (HEI), 2010 and 2005 editions (HEI-2010 and HEI-2005, respectively). During a mean follow-up of 6.2 y, 6,906 deaths were identified, including 2,244 from cardiovascular disease, 1,794 from cancer, and 2,550 from other diseases. A higher HEI-2010 score was associated with lower risks of disease death, with adjusted hazard ratios (HRs) of 0.80 (95% CI, 0.73 0.86) for all-disease mortality, 0.81 (95% CI, 0.70-0.94) for cardiovascular disease mortality, 0.81 (95% CI, 0.69-0.95) for cancer mortality, and 0.77 (95% CI, 0.67-0.88) for other disease mortality, when comparing the highest quintile with the lowest (all p-values for trend < 0.05). Similar inverse associations between HEI-2010 score and mortality were observed regardless of sex, race, and income (all p-values for interaction > 0.50). Several component scores in the HEI 2010, including whole grains, dairy, seafood and plant proteins, and ratio of unsaturated to saturated fatty acids, showed significant inverse associations with total mortality. HEI-2005 score was also associated with lower disease mortality, with a HR of 0.86 (95% CI, 0.79-0.93) when comparing extreme quintiles. Given the observational study design, however, residual confounding cannot be completely ruled out. In addition, future studies are needed to evaluate the generalizability of these findings to African-Americans of other socioeconomic status. CONCLUSIONS: Our results showed, to our knowledge for the first time, that adherence to the DGA was associated with lower total and cause specific mortality in a low-income population, including a large proportion of African-Americans, living in the southeastern US. PMID- 26011730 TI - An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models. AB - Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5 FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders. PMID- 26011732 TI - Sexual antagonism in the pistil varies among populations of a hermaphroditic mixed-mating plant. AB - Sexual conflicts and their evolutionary outcomes may be influenced by population specific features such as mating system and ecological context; however, very few studies have investigated the link between sexual conflict and mating system. The self-compatible, mixed-mating hermaphrodite Collinsia heterophylla (Plantaginaceae) is thought to exhibit a sexual conflict over timing of stigma receptivity. This conflict involves (i) delayed stigma receptivity, which intensifies pollen competition, and (ii) early fertilization forced by pollen, which reduces seed set. We investigated the potential for the conflict to occur under field conditions and performed glasshouse crosses within eight populations to assess its consistency across populations. Flowers were visited, and produced seeds after pollination, at all developmental stages, suggesting that the conflict can be of significance under natural conditions. In the glasshouse, early pollination imposed costs in all populations. Overall, the timing of first seed set was most strongly affected by the maternal parent, denoting stronger female than male ability to influence the onset of stigma receptivity. Crosses also revealed a negative relationship between donor- and recipient-related onset of receptivity within individuals, a novel result hinting at trade-offs in sex allocation or a history of antagonistic selection. Neither timing of stigma receptivity, timing of first seed set, nor pollen competitive ability covaried with population outcrossing rate. In conclusion, these results indicate that sexually antagonistic selection may be present in varying degrees in different populations of C. heterophylla, but this variation does not appear to be directly related to mating system variation. PMID- 26011731 TI - Post-Activation Brain Warming: A 1-H MRS Thermometry Study. AB - PURPOSE: Temperature plays a fundamental role for the proper functioning of the brain. However, there are only fragmentary data on brain temperature (T(br)) and its regulation under different physiological conditions. METHODS: We studied T(br) in the visual cortex of 20 normal subjects serially with a wide temporal window under different states including rest, activation and recovery by a visual stimulation-Magnetic Resonance Spectroscopy Thermometry combined approach. We also studied T(br) in a control region, the centrum semiovale, under the same conditions. RESULTS: Visual cortex mean baseline T(br) was higher than mean body temperature (37.38 vs 36.60, P<0.001). During activation Tbr remained unchanged at first and then showed a small decrease (-0.20 C degrees ) around the baseline value. After the end of activation T(br) increased consistently (+0.60 C degrees ) and then returned to baseline values after some minutes. Centrum semiovale T(br) remained unchanged through rest, visual stimulation and recovery. CONCLUSION: These findings have several implications, among them that neuronal firing itself is not a major source of heat release in the brain and that there is an aftermath of brain activation that lasts minutes before returning to baseline conditions. PMID- 26011733 TI - Single Versus Double Dose Praziquantel Comparison on Efficacy and Schistosoma mansoni Re-Infection in Preschool-Age Children in Uganda: A Randomized Controlled Trial. AB - BACKGROUND: Schistosoma mansoni infection is proven to be a major health problem of preschool-age children in sub-Saharan Africa, yet this age category is not part of the schistosomiasis control program. The objective of this study was to compare the impact of single and double dose praziquantel (PZQ) treatment on cure rates (CRs), egg reduction rates (ERRs) and re-infection rates 8 months later, in children aged 1-5 years living along Lake Victoria, Uganda. METHODOLOGY/PRINCIPAL FINDINGS: Infected children (n= 1017) were randomized to receive either a single or double dose of PZQ. Initially all children were treated with a single standard oral dose 40 mg/kg body weight of PZQ. Two weeks later a second dose was administered to children in the double dose treatment arm. Side effects were monitored at 30 minutes to 24 hours after each treatment. Efficacy in terms of CRs and ERRs for the two treatments was assessed and compared 1 month after the second treatment. Re-infection with S. mansoni was assessed in the same children 8 months following the second treatment. CRs were non-significantly higher in children treated with two 40 mg/kg PZQ doses (85.5%; 290/339) compared to a single dose (83.2%; 297/357). ERRs were significantly higher in the double dose with 99.3 (95%CI: 99.2-99.5) compared with 98.9 (95%CI: 98.7-99.1) using a single dose, (P = 0.01). Side effects occurred more frequently during the first round of drug administration and were mild and short-lived; these included vomiting, abdominal pain and bloody diarrhea. Overall re-infection rate 8 months post treatment was 44.5%. CONCLUSIONS: PZQ is efficacious and relatively safe to use in preschool-age children but there is still an unmet need to improve its formulation to suit small children. Two PZQ doses lead to significant reduction in egg excretion compared to a single dose. Re-infection rates with S. mansoni 8 months post treatment is the same among children irrespective of the treatment regimen. PMID- 26011736 TI - Adapting Family-Based Treatment for Adolescent Anorexia Nervosa Across Higher Levels of Patient Care. AB - An increasing body of evidence supports the use of family-based treatment (FBT) in medically stable outpatient presentations of adolescent anorexia nervosa, although there is relatively less research on adapting evidence-based treatment approaches in more intensive levels of patient care. The integration of FBT, which centrally leverages parental involvement in more intensive levels of care which typically require greater clinical management, requires careful consideration. We provide an overview of several key practical and theoretical considerations when adjusting the delivery of FBT across more intensive levels of patient care, providing clinical guidelines for the delivery of FBT while ensuring fidelity to the core theoretical tenets. Implications for clinical practice and future research are discussed. PMID- 26011737 TI - Isolation of a germanium(II) cation and a germylene iron carbonyl complex utilizing an imidazolin-2-iminato ligand. AB - The novel amino(imino)germylene 1 was prepared by the conversion of HNIPr (NIPr = bis(2,6-diisopropylphenyl)imidazolin-2-imino) with 1 equiv. of Ge[N(SiMe3)2]2. Germylene 1 reacts with B(C6F5)3 to afford the borate salt 2(+)[MeB(C6F5)3](-) in a methyl-abstraction and ring-closing reaction. The conversion of 2 with Fe2(CO)9 furnishes the germylene iron carbonyl complex 3 with a trigonal planar-coordinate germanium atom. PMID- 26011734 TI - miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways. AB - The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system. PMID- 26011735 TI - Seroepidemiology of Coxsackievirus A6, Coxsackievirus A16, and Enterovirus 71 Infections among Children and Adolescents in Singapore, 2008-2010. AB - Coxsackieviruses A6 (CV-A6) and A16 (CV-A16) and Enterovirus 71 (EV-A71) have caused periodic epidemics of hand, foot and mouth disease (HFMD) among children in Singapore. We conducted a cross-sectional study to estimate the seroprevalence of these enteroviruses among Singapore children and adolescents. The study was conducted between August 2008 and July 2010. It involved 700 Singapore residents aged 1-17 years whose residual sera were obtained following the completion of routine biochemical investigations in two public acute-care hospitals. The levels of neutralizing antibodies (NtAb) against CV-A6, CV-A16 and EV-A71 were analyzed by the microneutralization test. The age-specific geometric mean titer (GMT) of antibodies against each of the three enteroviruses and the 95% confidence intervals (CI) were calculated. The seroprevalence of CV-A6 and CV-A16 was high at 62.7% (95% CI: 59.1-66.2%) and 60.6% (95% CI: 56.9-64.1%), respectively. However, the seroprevalence of EV-A71 was significantly lower at 29.3% (95% CI: 26.0-32.8%). About 89.7% of the children and adolescents had been infected by at least one of the three enteroviruses by 13-17 years of age. About half (52.3%) were seropositive for two or all three enteroviruses, while only 16.1% had no NtAb against any of the three enteroviruses. High NtAb levels were observed in the younger age groups. CV-A6 and CV-A16 infections are very common among Singapore children and adolescents, while EV-A71 infections are less common. Infection is continually acquired from early childhood to adolescent age. PMID- 26011738 TI - Tumor accumulation of protein kinase-responsive gene carrier/DNA polyplex stabilized by alkanethiol for intravenous injection. AB - We synthesized polymeric gene carriers consisting of poly-L-lysine (PLL) main chain modified both with substrate peptide for protein kinase Calpha (PKCalpha) and alkanethiol (pentadecanethiol). Due to the grafted substrate peptide, the polyplex prepared from these carriers is expected to show gene expression triggered by the phosphorylation of the peptide by intracellular PKCalpha. The modified alkanethiol on the main chain stabilized the polyplex both via disulfide crosslinking and hydrophobic interaction. The polyplex found to show gene expression in vitro when the alkanethiol content in the main chain was enough low (4-mol%-modification of PLL's epsilon-amine group) to minimize cytotoxic effect. Even though the content of alkanethiol is low, the polyplex had significant stability in a model serum solution and showed longer blood circulation in vivo. The polyplex clearly accumulated in tumor after intravenous injection. PMID- 26011740 TI - Editorial Comment to Laparoscopic off-clamp partial nephrectomy using soft coagulation. PMID- 26011741 TI - Constructing the Japanese version of the Maslach Burnout Inventory-Student Survey: Confirmatory factor analysis. AB - AIM: To examine the factorial validity of the Maslach Burnout Inventory-Student Survey, using a sample of 2061 Japanese university students majoring in the medical and natural sciences (67.9% male, 31.8% female; Mage = 19.6 years, standard deviation = 1.5). The back-translated scale used unreversed items to assess inefficacy. METHODS: The inventory's descriptive properties and Cronbach's alphas were calculated using SPSS software. The present authors compared fit indices of the null, one factor, and default three factor models via confirmatory factor analysis with maximum-likelihood estimation using AMOS software, version 21.0. RESULTS: Intercorrelations between exhaustion, cynicism, and inefficacy were relatively higher than in prior studies. Cronbach's alphas were 0.76, 0.85, and 0.78, respectively. Although fit indices of the hypothesized three factor model did not meet the respective criteria, the model demonstrated better fit than did the null and one factor models. The present authors added four paths between error variables within items, but the modified model did not show satisfactory fit. Subsequent analysis revealed that a bi-factor model fit the data better than did the hypothesized or modified three factor models. CONCLUSION: The Japanese version of the Maslach Burnout Inventory-Student Survey needs minor changes to improve the fit of its three factor model, but the scale as a whole can be used to adequately assess overall academic burnout in Japanese university students. Although the scale was back-translated, two items measuring exhaustion whose expressions overlapped should be modified, and all items measuring inefficacy should be reversed in order to statistically clarify the factorial difference between the scale's three factors. PMID- 26011739 TI - Allergic multimorbidity of asthma, rhinitis and eczema over 20 years in the German birth cohort MAS. AB - BACKGROUND: The occurrence of allergic multimorbidity (coexistence of asthma, allergic rhinitis and eczema) has not been evaluated longitudinally from early childhood up to adulthood in a population-based study sample. We aimed to determine the prevalence of allergic multimorbidity up to age 20 stratified by parental allergies and sex/gender using extensive prospective follow-up data from two decades of a birth cohort study. METHODS: In 1990, we recruited 1314 healthy newborns from 6 maternity wards across Germany for the population-based MAS birth cohort study. The sample was purposely risk-enriched by increasing the proportion of children at high allergy risk (i.e. at least 2 allergic family members among parents and siblings) from 19% in the source population to 38% in the final sample. The remaining 62% of all MAS children had a low or no allergy risk. Symptoms, medication and doctor's diagnoses of allergic diseases have been assessed using standardized questionnaires including validated ISAAC questions in 19 follow-up assessments up to age 20. Allergic multimorbidity at each time point was defined as the coexistence of at least 2 of the following diseases in one participant: asthma, allergic rhinitis and eczema. RESULTS: Response at age 20 was 72% (n = 942) of all recruited participants. At age 20, 18.5% (95% CI, 15.0 22.5%) of all participants with allergic parents had 2 or 3 concurrent allergies as compared to only 6.3% (95% CI, 4.3-9.0%) of those with non-allergic parents. At this age, allergic multimorbidity was similar in women and men (12.7% (95% CI, 9.7-16.2%) vs. 11.6% (95% CI, 8.9-14.8%)), whereas single allergic diseases were slightly more common in women than men (24.2% (95% CI, 20.2-28.5%) vs. 20.1% (95% CI, 16.6-24.0%)). Asthma occurred more frequently with coexisting allergic rhinitis and/or eczema than as a single entity from pre-puberty to adulthood. CONCLUSION: Having parents with allergies is not only a strong predictor to develop any allergy, but it strongly increases the risk of developing allergic multimorbidity. In males and females alike, coexisting allergies were increasingly common throughout adolescence up to adulthood. Particularly asthma occurred in both sexes more frequently with coexisting allergies than as a single entity. PMID- 26011742 TI - Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users. AB - ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2 h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2 h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2 h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research. PMID- 26011743 TI - Crop rotational diversity enhances belowground communities and functions in an agroecosystem. AB - Biodiversity loss, an important consequence of agricultural intensification, can lead to reductions in agroecosystem functions and services. Increasing crop diversity through rotation may alleviate these negative consequences by restoring positive aboveground-belowground interactions. Positive impacts of aboveground biodiversity on belowground communities and processes have primarily been observed in natural systems. Here, we test for the effects of increased diversity in an agroecosystem, where plant diversity is increased over time through crop rotation. As crop diversity increased from one to five species, distinct soil microbial communities were related to increases in soil aggregation, organic carbon, total nitrogen, microbial activity and decreases in the carbon-to nitrogen acquiring enzyme activity ratio. This study indicates positive biodiversity-function relationships in agroecosystems, driven by interactions between rotational and microbial diversity. By increasing the quantity, quality and chemical diversity of residues, high diversity rotations can sustain soil biological communities, with positive effects on soil organic matter and soil fertility. PMID- 26011744 TI - Right unilateral spatial neglect in aphasic patients. AB - To investigate spatial responses by aphasic patients during language tasks, 63 aphasics (21 severe, 21 moderate, and 21 mild) were administered two kinds of auditory pointing tasks-word tasks and sentence tasks-in which the spatial conditions of the stimuli were controlled. There were significantly fewer correct responses on the right side of a space than on the left side in both the word and sentence tasks, but the left deviation of correct responses was more prominent in the sentence task than in the word task. Additionally, the severe aphasics exhibited a prominent leftward deviation that may have been the result of deficits in rightward attention controlled by the left hemisphere. This phenomenon also seems to reflect the directional attention that is subserved by the right hemisphere, which attends to the left side of a space and, less predominantly, the right side of a space. PMID- 26011745 TI - Semantic brain areas are involved in gesture comprehension: An electrical neuroimaging study. AB - While the mechanism of sign language comprehension in deaf people has been widely investigated, little is known about the neural underpinnings of spontaneous gesture comprehension in healthy speakers. Bioelectrical responses to 800 pictures of actors showing common Italian gestures (e.g., emblems, deictic or iconic gestures) were recorded in 14 persons. Stimuli were selected from a wider corpus of 1122 gestures. Half of the pictures were preceded by an incongruent description. ERPs were recorded from 128 sites while participants decided whether the stimulus was congruent. Congruent pictures elicited a posterior P300 followed by late positivity, while incongruent gestures elicited an anterior N400 response. N400 generators were investigated with swLORETA reconstruction. Processing of congruent gestures activated face- and body-related visual areas (e.g., BA19, BA37, BA22), the left angular gyrus, mirror fronto/parietal areas. The incongruent-congruent contrast particularly stimulated linguistic and semantic brain areas, such as the left medial and the superior temporal lobe. PMID- 26011746 TI - New approaches for the standardization and validation of a real-time qPCR assay using TaqMan probes for quantification of yellow fever virus on clinical samples with high quality parameters. AB - The development and production of viral vaccines, in general, involve several steps that need the monitoring of viral load throughout the entire process. Applying a 2-step quantitative reverse transcription real time PCR assay (RT qPCR), viral load can be measured and monitored in a few hours. In this context, the development, standardization and validation of a RT-qPCR test to quickly and efficiently quantify yellow fever virus (YFV) in all stages of vaccine production are extremely important. To serve this purpose we used a plasmid construction containing the NS5 region from 17DD YFV to generate the standard curve and to evaluate parameters such as linearity, precision and specificity against other flavivirus. Furthermore, we defined the limits of detection as 25 copies/reaction, and quantification as 100 copies/reaction for the test. To ensure the quality of the method, reference controls were established in order to avoid false negative results. The qRT-PCR technique based on the use of TaqMan probes herein standardized proved to be effective for determining yellow fever viral load both in vivo and in vitro, thus becoming a very important tool to assure the quality control for vaccine production and evaluation of viremia after vaccination or YF disease. PMID- 26011747 TI - The interpersonal context of client motivational language in cognitive-behavioral therapy. AB - Previous research has found that client motivational language (especially arguments against change or counterchange talk; CCT) in early therapy sessions is a reliable predictor of therapy process and outcomes across a broad range of treatments including cognitive-behavioral therapy (CBT). Existing studies have considered the general occurrence of CCT, but the present study differentiated 2 types of CCT in early CBT sessions for 37 clients with generalized anxiety disorder: (a) statements that are uttered to express ambivalence regarding change versus (b) statements that are intended to oppose the therapist or therapy. Two process coding systems were used to accomplish this differentiation. Findings indicated that a higher number of CCT statements that occurred in the presence of resistance (opposition to the therapist or therapy) were a substantive and consistent predictor of lower homework compliance and poorer outcomes, up to 1 year posttreatment. Moreover, when both types of CCT were considered together, only opposition CCT was related to outcomes, and ambivalent CCT was not significantly predictive of proximal and distal outcomes. These findings suggest that the interpersonal context in which CCT statements occur may be critically important to their predictive capacity. More broadly, the findings of this study have implications for the future study of client motivational language and underscore the clinical importance of detecting opposition CCT. PMID- 26011748 TI - Diffuse idiopathic skeletal hyperostosis of the spine in a nine-year-old cat. AB - A nine-year-old intact female domestic shorthair cat was evaluated for paraparesis, ataxia and severe spinal hyperaesthesia. Neurological examination indicated a T3-L3 spinal cord segment lesion. Computed tomography of the thoracolumbar and lumbosacral vertebral column was performed. This showed contiguous smooth new bone formation ventral and lateral to the vertebrae extending from the cranial thoracic area to the lumbosacral junction and appearing similar to canine diffuse idiopathic skeletal hyperostosis. There was also marked dorsolateral stenosis of the vertebral canal at the level of T4-T5 because of degenerative changes of the facet joints. To the authors' knowledge, this is the first published report of feline diffuse idiopathic skeletal hyperostosis. PMID- 26011749 TI - The expression of RUNDC3B is associated with promoter methylation in lymphoid malignancies. AB - DNA methylation is an epigenetic modification that plays an important role in the regulation of gene expression. The function of RUNDC3B has yet to be determined, although its dysregulated expression has been associated with malignant potential of both breast and lung carcinoma. To elucidate the potential of using DNA methylation in RUNDC3B as a biomarker in lymphoid malignancies, the methylation status of six regions spanning the CpG island in the promoter region of RUNDC3B was determined in cancer cell lines. Lymphoid malignancies were found to have more prominent methylation and did not express RUNDC3B compared with myeloid malignancies and solid tumours, supporting the potential use of DNA methylation in this region as a biomarker for lymphoid malignancies. RUNDC3B contains a RUN domain in its N-terminal region that mediates interaction with Rap2, an important component of the mitogen-activated protein kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. The protein sequence of RUNDC3B also contains characteristic binding sites for MAPK intermediates. Therefore, it is possible that RUNDC3B serves as a mediator between Rap2 and the MAPK signalling cascade. Three genes with MAPK-inducible expression were downregulated in a methylated leukaemia cell line (HSPA5, Jun and Fos). Jun and Fos combine to form the activating protein 1 transcription factor, and loss of this factor is associated with the dysregulation of genes involved in differentiation and proliferation. We hypothesize that the loss of RUNDC3B secondary to aberrant hypermethylation of the early growth response 3 transcription factor binding site results in dysregulated MAPK signalling and carcinogenesis in lymphoid malignancies. (c) 2015 The Authors. Hematological Oncology published by John Wiley & Sons Ltd. PMID- 26011750 TI - The direct segment of the arcuate fasciculus is predictive of longitudinal reading change. AB - Structural coherence across the arcuate fasciculus has previously been related to reading skill, but the arcuate may be divisible into distinct subtracts which support different functions. Here, we examine longitudinal data from 30 children between the ages of 8 and 14 to determine whether initial coherence in any of the arcuate's subsections is predictive of changes in reading across a longitudinal interval of approximately three years. The arcuate was divided using probabilistic tractography; mean fractional anisotropy across each subtract was extracted for each participant. Time 1 to Time 2 change in reading skill (identification, fluency score average) was significantly and uniquely predicted by only direct fronto-temporal arcuate segment coherence. Participants with lower direct segment FA demonstrated decreases in reading scores, potentially reflecting lessened improvements due to continued inefficient processing. These results were consistent in the older and younger halves of the sample. As such, we demonstrate that it is specifically the direct segment of the arcuate that may support and be predictive of reading skill both initially and longitudinally across development. PMID- 26011751 TI - Trait-level temporal lobe hypoactivation to social exclusion in unaffected siblings of children and adolescents with autism spectrum disorders. AB - Social exclusion elicits powerful feelings of negative affect associated with rejection. Additionally, experiencing social exclusion reliably recruits neural circuitry associated with emotion processing. Recent work has demonstrated abnormal neural responses to social exclusion in children and adolescents with autism spectrum disorders (ASD). However, it remains unknown to what extent these abnormalities are due to atypical social experiences versus genetic predispositions to atypical neural processing. To address this question, the current study investigated brain responses to social exclusion compared to a baseline condition of fair play in unaffected siblings of youth with ASD using functional magnetic resonance imaging. We identified common deviations between unaffected siblings and ASD probands that might represent trait-level abnormalities in processing Social Exclusion vs. Fair Play, specifically in the right anterior temporoparietal junction extending into posterior superior temporal sulcus. Thus, hypoactivation to Social Exclusion vs. Fair Play in this region may represent a shared genetic vulnerability to developing autism. In addition, we present evidence supporting the idea that one's status as an unaffected sibling moderates the relationship between IQ and neural activation to Social Exclusion vs. Fair Play in anterior cingulate cortex. These results are discussed in the context of previous literature on neural endophenotypes of autism. PMID- 26011752 TI - Percutaneous tricuspid valve-In-ring replacement for the treatment of recurrent severe tricuspid regurgitation. AB - Percutaneous tricuspid valve-in-ring replacement can be an alternative to surgery for high-risk patients with symptomatic severe tricuspid regurgitation that recurs after surgical ring repair. Practitioners must pay attention to the specific technical details associated with this procedure that include: using the ring as a fluoroscopic landmark, sizing the valve area with multi-modality imaging, choosing the appropriate device based on the patients anatomy, and dealing with the inevitable paravalvular leak (created by the ring deformation in the absence of valve-specific devices). Our case demonstrates that percutaneous tricuspid valve-in-ring replacement is a feasible treatment that can result in both hemodynamic and symptomatic improvement. PMID- 26011753 TI - Controlled Slow-Release Drug-Eluting Stents for the Prevention of Coronary Restenosis: Recent Progress and Future Prospects. AB - Drug-eluting stents (DES) have become more widely used by cardiologists than bare metal stents (BMS) because of their better ability to control restenosis. However, recognized negative events, particularly including delayed or incomplete endothelialization and late stent thrombosis, have caused concerns over the long term safety of DES. Although stent-based drug delivery can facilitate a drug's release directly to the restenosis site, a burst of drug release can seriously affect the pharmacological action and is a major factor accounting for adverse effects. Therefore, the drug release rate has become an important criterion in evaluating DES. The factors affecting the drug release rate include the drug carrier, drug, coating methods, drug storage, elution direction, coating thickness, pore size in the coating, release conditions (release medium, pH value, temperature), and hemodynamics after the stent implantation. A better understanding of how these factors influence drug release is particularly important for the reasonable use of efficient control strategies for drug release. This review summarizes the factors influencing the drug release from DES and presents strategies for enhancing the control of the drug's release, including the stent design, the application of absorbable stents, the development of new polymers, and the application of nanocarriers and improvements in the coating technology. Therefore, this paper provides a reference for the preparation of novel controlled slow-release DES. PMID- 26011754 TI - Effect of Pregnancy Upon Facial Anthropometrics and Respirator Fit Testing. AB - Workers required to wear respirators must undergo additional respirator fit testing if a significant change in body weight occurs. Approximately 10% of working women of reproductive age will be pregnant and experience a significant change in weight, yet the effect of pregnancy-associated weight gain on respirator fit is unknown. Cephalo-facial anthropometric measurements and quantitative fit testing of N95 filtering facepiece respirators (N95 FFR) of 15 pregnant women and 15 matched, non-pregnant women were undertaken for comparisons between the groups. There were no significant differences between pregnant and non-pregnant women with respect to cephalo-facial anthropometric measurements or N95 FFR quantitative fit tests. Healthy pregnant workers, who adhere to the recommended weight gain limits of pregnancy, are unlikely to experience an increase in cephalo-facial dimensions that would mandate additional N95 FFR fit testing above that which is normally required on an annual basis. PMID- 26011755 TI - Hexyl-5-aminolaevulinate 0.2% vs. methyl-5-aminolaevulinate 16% daylight photodynamic therapy for treatment of actinic keratoses: results of a randomized double-blinded pilot trial. PMID- 26011758 TI - Type 1 diabetes exacerbates blood-brain barrier alterations during experimental epileptic seizures in an animal model. AB - The aim of this study was to perform the effects of diabetes on the permeability of the blood-brain barrier (BBB) during pentylenetetrazole (PTZ)-induced epileptic attacks. For this propose, the animals were divided into four groups. These groups contained were intact, PTZ-treated, diabetic and PTZ-treated diabetic individuals, respectively. To evaluate the functioning of the BBB, Evans blue was used as a BBB permeability indicator, and the expressions of zonula occludens-1 and glial fibrillary acidic protein involving the functioning of the BBB were determined immunohistochemically. Also, the changes in the release of serum tumour necrosis factor-alpha and interleukin-10 and interleukin-12 were studied by using enzyme-linked immunosorbent assay method. BBB permeability in the seizures under diabetic conditions showed a considerable increase (p < 0.01) in all of the brain we studied. The immunoreactive staining intensity of zonula occludens-1 and glial fibrillary acidic protein was found reduced in the brain regions of diabetic rats (p < 0.01). However, the serum level of tumour necrosis factor-alpha increased in diabetes and diabetes + PTZ groups, and the serum level of interleukin-12 increased significantly in all experimental groups (p < 0.05). In conclusion, diabetes dramatically increases BBB damage during epileptic seizures, and it may be derived from an elevation of paracellular passage. PMID- 26011757 TI - MRI Texture Analysis Reveals Deep Gray Nuclei Damage in Amyotrophic Lateral Sclerosis. AB - BACKGROUND AND PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is characterized by extensive corticospinal damage, but extrapyramidal involvement is suggested in pathological studies. Texture analysis (TA) is an image processing technique that evaluates the distribution of gray levels between pixels in a given region of interest (ROI). It provides quantitative data and has been employed in several neurodegenerative disorders. Here, we used TA to investigate possible deep gray nuclei (DGN) abnormalities in a cohort of ALS patients. METHODS: Thirty-two ALS patients and 32 healthy controls underwent MRI in a 3T scanner. The T1 volumetric sequence was used for DGN segmentation and extraction of 11 texture parameters using the MaZda software. Statistical analyses were performed using the Mann Whitney non-parametric test, with a significance level set at alpha = 0.025 (FDR corrected) for TA. RESULTS: Patients had significantly higher values for the parameter correlation (CO) in both thalami and in the right caudate nucleus compared to healthy controls. Also, the parameter Inverse Difference Moment or Homogeneity (IDM) presented significantly smaller values in the ALS group in both thalami. CONCLUSIONS: TA of T1 weighted images revealed DGN alterations in patients with ALS, namely in the thalami and caudate nuclei. PMID- 26011759 TI - Epigenetic modulation of dental pulp stem cells: implications for regenerative endodontics. AB - Dental pulp stem cells (DPSCs) offer significant potential for use in regenerative endodontics, and therefore, identifying cellular regulators that control stem cell fate is critical to devising novel treatment strategies. Stem cell lineage commitment and differentiation are regulated by an intricate range of host and environmental factors of which epigenetic influence is considered vital. Epigenetic modification of DNA and DNA-associated histone proteins has been demonstrated to control cell phenotype and regulate the renewal and pluripotency of stem cell populations. The activities of the nuclear enzymes, histone deacetylases, are increasingly being recognized as potential targets for pharmacologically inducing stem cell differentiation and dedifferentiation. Depending on cell maturity and niche in vitro, low concentration histone deacetylase inhibitor (HDACi) application can promote dedifferentiation of several post-natal and mouse embryonic stem cell populations and conversely increase differentiation and accelerate mineralization in DPSC populations, whilst animal studies have shown an HDACi-induced increase in stem cell marker expression during organ regeneration. Notably, both HDAC and DNA methyltransferase inhibitors have also been demonstrated to dramatically increase the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) for use in regenerative therapeutic procedures. As the regulation of cell fate will likely remain the subject of intense future research activity, this review aims to describe the current knowledge relating to stem cell epigenetic modification, focusing on the role of HDACi on alteration of DPSC phenotype, whilst presenting the potential for therapeutic application as part of regenerative endodontic regimens. PMID- 26011760 TI - Identification of a novel HLA-C*15 allele, HLA-C*15:02:21. AB - HLA-C*15:02:21 differs from C*15:02:01:01 by a single nucleotide substitution at position 105 of exon 2. PMID- 26011761 TI - Assessment method influences the severity and type of symptoms reported after self-reported mild traumatic brain injury. AB - OBJECTIVE: To investigate the influence of assessment method (spontaneous report versus checklist) on the report of postconcussive syndrome (PCS) symptoms after mild traumatic brain injury (mTBI). SETTING: Community. PARTICIPANTS: Thirty-six participants (58% female) with postacute self-reported mTBI (i.e., sustained 1-6 months prior to participation) and 36 age-, gender-, and ethnicity-matched controls with no history of mTBI. DESIGN: Cross-sectional. MAIN MEASURES: Spontaneous symptom report from open-ended questions and checklist endorsed symptoms from the Neurobehavioral Symptom Inventory (both measures administered online). RESULTS: Assessment method significantly affected individual symptom item frequencies (small to large effects), the number of symptoms reported, the total severity score, domain severity scores (i.e., somatic/sensory, cognitive, and affective symptom domains), and the number of participants who met a PCS caseness criterion (large effects; checklist > spontaneous report). The types of symptoms that were different between the groups differed for the assessment methods: Compared to controls, the nonclinical mTBI group spontaneously reported significantly greater somatic/sensory and cognitive domain severity scores, whilst no domain severity scores differed between groups when endorsed on a checklist. CONCLUSIONS: Assessment method can alter the number, severity, and types of symptoms reported by individuals who have sustained an mTBI and could potentially influence clinical decisions. PMID- 26011763 TI - Antibiotic Prescribing for Acute Respiratory Infections in Direct-to-Consumer Telemedicine Visits. PMID- 26011762 TI - Taxonomy and distribution of freshwater pearl mussels (Unionoida: Margaritiferidae) of the Russian Far East. AB - The freshwater pearl mussel family Margaritiferidae includes 13 extant species, which are all listed by IUCN as endangered or vulnerable taxa. In this study, an extensive spatial sampling of Margaritifera spp. across the Russian Far East (Amur Basin, Kamchatka Peninsula, Kurile Archipelago and Sakhalin Island) was conducted for a revision of their taxonomy and distribution ranges. Based on their DNA sequences, shell and soft tissue morphology, three valid species were identified: Margaritifera dahurica (Middendorff, 1850), M. laevis (Haas, 1910) and M. middendorffi (Rosen, 1926). M. dahurica ranges across the Amur basin and some of the nearest river systems. M. laevis is distributed in Japan, Sakhalin Island and the Kurile Archipelago. M. middendorffi was previously considered an endemic species of the Kamchatka. However, it is widespread in the rivers of Kamchatka, Sakhalin Island, the Kurile Islands (across the Bussol Strait, which is the most significant biogeographical boundary within the archipelago), and, likely, in Japan. The Japanese species M. togakushiensis Kondo & Kobayashi, 2005 seems to be conspecific with M. middendorffi because of similar morphological patterns, small shell size (<100 mm long) and overlapped ranges, but it is in need of a separate revision. Phylogenetic analysis reveals that two NW Pacific margaritiferid species, M. laevis and M. middendorffi, formed a monophyletic 18S rDNA clade together with the North American species M. marrianae and M. falcata. The patterns that were found in these Margaritifera spp. are similar to those of freshwater fishes, indicating multiple colonizations of Eastern Asia by different mitochondrial lineages, including an ancient Beringian exchange between freshwater faunas across the Pacific. PMID- 26011764 TI - Hemophagocytic lymphohistiocytosis following dengue hemorrhagic fever in Hb H/Hb Constant Spring patient. AB - Infection-associated hemophagocytic syndrome (IAHS), a secondary form of hemophagocytic lymphohistiocytosis (HLH), has been found following several types of infections and can be fatal. We report herein a case of IAHS following dengue infection in a 14-year-old patient with underlying alpha-thalassemia syndrome (non-deletional Hb H/Hb Constant Spring disease). He developed prolonged fever, thrombocytopenia, and progressive splenomegaly. Further investigations indicated hyperferritinemia, and increased reactive histiocytes with hemophagocytic activity in the bone marrow. He responded promptly to dexamethasone and i.v. immune globulin. Physicians should be aware of this condition, especially in countries where both dengue hemorrhagic fever and thalassemia are prevalent. The fatal outcome of IAHS can be prevented with prompt appropriate treatment. PMID- 26011765 TI - Risk stratification in extramammary Paget disease. AB - Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of > 1 mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki-67, cyclin D1, Mucin 5AC and E cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research. PMID- 26011767 TI - Highly Oxidized Multifunctional Organic Compounds Observed in Tropospheric Particles: A Field and Laboratory Study. AB - Very recent studies have reported the existence of highly oxidized multifunctional organic compounds (HOMs) with O/C ratios greater than 0.7. Because of their low vapor pressure, these compounds are often referred as extremely low-volatile organic compounds (ELVOCs), and thus, they are able to contribute significantly to organic mass in tropospheric particles. While HOMs have been successfully detected in the gas phase, their fate after uptake into particles remains unclear to date. Hence, the present study was designed to detect HOMs and related oxidation products in the particle phase and, thus, to shed light on their fate after phase transfer. To this end, aerosol chamber investigations of alpha-pinene ozonolysis were conducted under near environmental precursor concentrations (2.4 ppb) in a continuous flow reactor. The chemical characterization shows three classes of particle constituents: (1) intact HOMs that contain a carbonyl group, (2) particle-phase decomposition products, and (3) highly oxidized organosulfates (suggested to be addressed as HOOS). Besides chamber studies, HOM formation was also investigated during a measurement campaign conducted in summer 2013 at the TROPOS research station Melpitz. During this field campaign, gas-phase HOM formation was found to be correlated with an increase in the oxidation state of the organic aerosol. PMID- 26011769 TI - Air-persistent monomeric (amino)(carboxy) radicals derived from cyclic (alkyl)(amino) carbenes. AB - A series of monomeric (amino)(carboxy) radicals featuring carbonyl substituents with increasing electron-withdrawing properties (3a, phenyl; 3b, 3,5 bis(trifluoromethyl)phenyl; 3c, perfluorophenyl; 3d, heptafluoropropyl; 3e, 2H pyrroliumyl) were synthesized in two or three steps from stable cyclic (alky)(amino)carbenes (CAACs). Although (amino)(carboxy) radicals had been previously considered as highly air-sensitive, some of these compounds feature half-lives of hours (3d), and even days (3c and 3e) in well-aerated solutions. DFT calculations show that (amino)(carboxy) radicals evolve from C-centered radical to ambidentate C,O-radicals when increasing the electron-withdrawing properties of the carbonyl substituent. This is paralleled with a destabilization of the peroxide resulting from the addition of dioxygen to the radical. This latter reaction is even predicted to be endothermic for substituents with Hammett constant sigmap > 0.2. PMID- 26011768 TI - Differences in the serum nonesterified Fatty Acid profile of young women associated with a recent history of gestational diabetes and overweight/obesity. AB - BACKGROUND: Nonesterified fatty acids (NEFA) play pathophysiological roles in metabolic syndrome and type 2 diabetes (T2D). In this study, we analyzed the fasting NEFA profiles of normoglycemic individuals at risk for T2D (women with a recent history of gestational diabetes (GDM)) in comparison to controls (women after a normoglycemic pregnancy). We also examined the associations of NEFA species with overweight/obesity, body fat distribution and insulin sensitivity. SUBJECTS AND METHODS: Using LC-MS/MS, we analyzed 41 NEFA species in the fasting sera of 111 women (62 post-GDM, 49 controls). Clinical characterization included a five-point oral glucose tolerance test (OGTT), biomarkers and anthropometrics, magnetic resonance imaging (n = 62) and a food frequency questionnaire. Nonparametric tests with Bonferroni correction, binary logistic regression analyses and rank correlations were used for statistical analysis. RESULTS: Women after GDM had a lower molar percentage of total saturated fatty acids (SFA; 38.55% vs. 40.32%, p = 0.0002) than controls. At an explorative level of significance several NEFA species were associated with post-GDM status (with and without adjustment for body mass index (BMI) and HbA1c): The molar percentages of 14:0, 16:0, 18:0 and 18:4 were reduced, whereas those of 18:1, 18:2, 20:2, 24:4, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and total n-6 NEFA were increased. BMI and the amount of body fat correlated inversely with several SFA and MUFA and positively with various PUFA species over the whole study cohort (abs(rho)>=0.3 for all). 14:0 was inversely and BMI-independently associated with abdominal visceral adiposity. We saw no correlations of NEFA species with insulin sensitivity and the total NEFA concentration was similar in the post-GDM and the control group. CONCLUSION: In conclusion, we found alterations in the fasting NEFA profile associated with a recent history of gestational diabetes, a risk marker for T2D. NEFA composition also varied with overweight/obesity and with body fat distribution, but not with insulin sensitivity. PMID- 26011770 TI - Influence of the charge distribution on the stationary phases zeta potential. AB - A set of seven home-made silica based bonded phases with different functional groups was investigated. Their zeta potential data in methanol and acetonitrile as well as in methanol/water and acetonitrile/water solution were obtained by using a Zetasizer. The influence of polar functional groups on a zeta potential was investigated. The results show that the amines incorporated in the structure of chemically bonded phases of reversed-phase materials are protonated during chromatographic analysis, resulting in changes of the zeta potential from negative to positive values. Acetonitrile causes more negative values and methanol provides positive (or less negative) values of the zeta potential. PMID- 26011771 TI - Identification and characterization of near-fatal asthma phenotypes by cluster analysis. AB - BACKGROUND: Near-fatal asthma (NFA) is a heterogeneous clinical entity and several profiles of patients have been described according to different clinical, pathophysiological and histological features. However, there are no previous studies that identify in a unbiased way--using statistical methods such as clusters analysis--different phenotypes of NFA. Therefore, the aim of the present study was to identify and to characterize phenotypes of near fatal asthma using a cluster analysis. METHODS: Over a period of 2 years, 33 Spanish hospitals enrolled 179 asthmatics admitted for an episode of NFA. A cluster analysis using two-steps algorithm was performed from data of 84 of these cases. RESULTS: The analysis defined three clusters of patients with NFA: cluster 1, the largest, including older patients with clinical and therapeutic criteria of severe asthma; cluster 2, with an high proportion of respiratory arrest (68%), impaired consciousness level (82%) and mechanical ventilation (93%); and cluster 3, which included younger patients, characterized by an insufficient anti-inflammatory treatment and frequent sensitization to Alternaria alternata and soybean. CONCLUSIONS: These results identify specific asthma phenotypes involved in NFA, confirming in part previous findings observed in studies with a clinical approach. The identification of patients with a specific NFA phenotype could suggest interventions to prevent future severe asthma exacerbations. PMID- 26011772 TI - A New Method for Sham-Controlled Acupuncture in Experimental Visceral Pain - a Randomized, Single-Blinded Study. AB - OBJECTIVE: Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions. To study the effect of acupuncture in experimental and clinical studies, a control condition with sham acupuncture is needed. However, as such models have not been established in assessment of acupunctures effect against visceral pain, this study aimed to validate a new method for blinded sham acupuncture in experimental rectal pain. METHODS: Fifteen subjects underwent a sequence of either sham or real acupuncture in randomized order. In the sham arm, a hollow inner tube with a sharp tip was fitted into an outer tube and subjects were blinded to the stimulations. Before and after the intervention, pain was induced by rectal stimulation with an inflatable balloon distended until the subjects' pain threshold was reached. The resting electroencephalogram (EEG) was quantified by spectral power analysis to explore the central nervous system effects objectively. Additionally, after the second study day, the subject was asked to indicate the sequence of interventions. RESULTS: A significant increase in rectal balloon volume was observed after sham 12 +/- 21 mL (P = 0.049) and acupuncture 17 +/- 30 mL (P = 0.046). However, the change in volume was not different between groups (P = 0.6). No differences in EEG spectral power distributions between sham and acupuncture were seen (all P > 0.6). The correct sequence of sham and acupuncture was indicated by 36% of the subjects (P = 0.4). CONCLUSIONS: The presented sham procedure provides a valid method for blinding of "sham acupuncture" and may be used in future blinded controlled trials of acupuncture for visceral pain. PMID- 26011773 TI - Brain alterations with deep brain stimulation: New insight from a neuropathological case series. AB - BACKGROUND: Previous studies on human brain tissue alterations caused by deep brain stimulation described glial and reactive inflammatory changes. In the current pathoanatomical study, we extended the analysis to signs of axonal changes and the influence of concomitant disease. METHODS: Brains of 10 patients with Parkinson's disease or essential tremor and a total of 18 electrodes were systematically examined up to 7.5 y after surgery. RESULTS: In general, tissue that had long-term contact with the electrode material exhibited astrogliosis in all, T-lymphocytes in 93%, and multinucleated giant cells in 68% of patients. Immunohistochemistry showed an increase in amyloid precursor protein immunoreactive axonal swellings in the brain at the electrically active parts of the electrodes. Patients who died of septicemia showed a more severe astrogliosis and giant cell reaction than patients who died of cardiovascular events. Parkinson's disease or essential tremor did not differentially produce histopathological changes around the electrodes. CONCLUSION: Long-term electrical stimulation by deep brain stimulation causes minor axonal changes. The cause of death, but not the underlying neurological disease, affects the histopathological changes around the electrode. The findings need to be reproduced by examining larger patient subgroups. PMID- 26011774 TI - Chromosomal variation and perinatal mortality in San Diego zoo Soemmerring's gazelles. AB - Chromosomal translocations play a fundamental role in the evolution and speciation of antelopes (Antilopinae, Bovidae), with several species exhibiting polymorphism for centric fusions. For the past 35 years, the San Diego Zoo Global (SDZG) captive population of Soemmerring's gazelles has revealed complex karyotypes resulting from chromosomal translocations with diploid numbers ranging from 34 to 39. Poor reproductive performance of this species in captivity and elevated mortality the first month of life (perinatal) has been attributed to this chromosomal dynamism. We have extended the studies of karyotypic variation in the SDZG Soemmerring's gazelle population and analyzed the effect of chromosomal and genetic variation upon perinatal mortality. Karyotypes from 149 captive Soemmerring's gazelles were evaluated revealing two unreported autosomal combinations, now constituting a total of 15 distinct karyotypes for the 3 Robertsonian centric fusions originally described for this population. Among SDZG founders, distinct chromosomal variation and nuclear and mitochondrial genetic structure were detected corresponding to the institution of origin of the founders. Low levels of genetic distance and nucleotide diversity among individuals, in addition to high relatedness values, suggested that outbreeding is less of a concern than inbreeding for maintaining a sustainable captive population. Finally, analysis of karyotypes of offspring born into the SDZG Soemmerring's gazelle herds, in conjunction with the maternal karyotype showed association of chromosomal makeup with perinatal mortality. This supports the importance of continuing cytogenetic screening efforts, particularly to evaluate the presence of deleterious chromosomal rearrangements in stillborns. PMID- 26011776 TI - Silica-based mesoporous nanobiomaterials as promoter of bone regeneration process. AB - Silica-based mesostructured nanomaterials have emerged as a full family of biomaterials with tremendous potential to address the requirements for the bone regeneration process. This review focuses on more recent advances in bone regeneration process based on silica-based mesoporous biomaterials during 2012 to January 2015. In this review, we describe application of silica-based mesoporous mesostructured nanomaterials (possessing pore sizes in the range 2-50 nm) for the bone regeneration process. We summarize the preparation methods, the effect of mesopore templates and composition on the mesopore-structure characteristics, and different forms of these materials, including particles, fibers, spheres, scaffolds, and composites. The effect of structural and textural properties of mesoporous materials on the development of new biomaterials for treatment of different bone pathologies such as infection, osteoporosis, cancer, and so forth is discussed. In addition, silica-based mesoporous bioactive glass, as a potential drug/growth factor carrier, is reviewed, which includes the composition structure-drug delivery relationship and the functional effect on the antibacteria and tissue-stimulation properties. Also, application of different mesoporous materials on construction of 3D macroporous scaffolds for bone tissue engineering was disused. Finally, this review discusses the possibility of covalently grafting different osteoinductive agents to the silica-based mesoporous scaffold surface that act as attracting signals for bone cells to promote the bone regeneration process. PMID- 26011775 TI - Propensity score matching and persistence correction to reduce bias in comparative effectiveness: the effect of cinacalcet use on all-cause mortality. AB - PURPOSE: The generalisability of randomised controlled trials (RCTs) may be limited by restrictive entry criteria or by their experimental nature. Observational research can provide complementary findings but is prone to bias. Employing propensity score matching, to reduce such bias, we compared the real life effect of cinacalcet use on all-cause mortality (ACM) with findings from the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) RCT in chronic haemodialysis patients. METHODS: Incident adult haemodialysis patients receiving cinacalcet, recruited in a prospective observational cohort from 2007 2009 (AROii; n = 10,488), were matched to non-exposed patients regardless of future exposure status. The effect of treatment crossover was investigated with inverse probability of censoring weighted and lag-censored analyses. EVOLVE ACM data were analysed largely as described for the primary composite endpoint. RESULTS: AROii patients receiving cinacalcet (n = 532) were matched to 1790 non exposed patients. The treatment effect of cinacalcet on ACM in the main AROii analysis (hazard ratio 1.03 [95% confidence interval (CI) 0.78-1.35]) was closer to the null than for the Intention to Treat (ITT) analysis of EVOLVE (0.94 [95%CI 0.85-1.04]). Adjusting for non-persistence by 0- and 6-month lag-censoring and by inverse probability of censoring weight, the hazard ratios in AROii (0.76 [95%CI 0.51-1.15], 0.84 [95%CI 0.60-1.18] and 0.79 [95%CI 0.56-1.11], respectively) were comparable with those of EVOLVE (0.82 [95%CI 0.67-1.01], 0.83 [95%CI 0.73-0.96] and 0.87 [95%CI 0.71-1.06], respectively). CONCLUSIONS: Correcting for treatment crossover, we observed results in the 'real-life' setting of the AROii observational cohort that closely mirrored the results of the EVOLVE RCT. Persistence-corrected analyses revealed a trend towards reduced ACM in haemodialysis patients receiving cinacalcet therapy. PMID- 26011777 TI - Impact of a Swiss adverse drug event prevention collaborative. AB - RATIONALE, AIMS AND OBJECTIVES: The Hospital Federation of Vaud (Switzerland) used a Breakthrough Collaborative with the aim of reducing adverse drug events (ADEs) by 20% in 10 participating hospitals. METHODS: A set of interventions (covering patient identification, high-alert medication and medication preparation in the ward) was deployed over 18 months starting in October 2010. All hospitals monitored discrepancies between drugs prescribed and those prepared for administration, as well as the occurrence of ADEs using the ADE Trigger Tool for 18 months (cohort 1). A subset of five hospitals continued this monitoring for 12 additional months (cohort 2). RESULTS: In cohort 1, pill box discrepancies were present in 5.9% of doses (n = 9772) in 2011 and in 5.8% (n = 2251) in the first 3 months of 2012 (no statistical significance). There were no significant differences in the rate of ADEs/1000 doses across time (1.2 in 2010, 1.0 in 2011 and 1.0 in 2012). In cohort 2, pill box discrepancies were reduced from 6.5% (n = 4846 doses) in 2011 to 4.4% (n = 7355) in 2012 (P < 0.001) to 3.0% for the first 3 months of 2013 (n = 2251; P = 0.004). The rate of ADEs/1000 doses decreased (1.8 in 2010, 1.1 in 2011 and 0.6 in 2012/13 (P = 0.008 for 2010-2011, and P < 0.001 for 2011-2012/2013). CONCLUSIONS: Reductions in drug discrepancies and ADEs occurred in the cohort with the longer monitoring duration. Factors contributing to success may include the strategic status of the project, executive support, perseverance in post-intervention measurement, and institution-wide rather than partial deployment. PMID- 26011778 TI - Mixed-element Octree: a meshing technique toward fast and real-time simulations in biomedical applications. AB - This article introduces a meshing technique focused on fast and real-time simulation in a biomedical context. We describe in details our algorithm, which starts from a basic Octree regarding the constraints imposed by the simulation, and then, mixed-element patterns are applied over transitions between coarse and fine regions. The use of surface patterns, also composed by mixed elements, allows us to better represent curved domains decreasing the odds of creating invalid elements by adding as few nodes as possible. In contrast with other meshing techniques, we let the user define regions of greater refinement, and as a consequence of that refinement, we add as few nodes as possible to produce a mesh that is topologically correct. Therefore, our meshing technique gives more control on the number of nodes of the final mesh. We show several examples where the quality of the final mesh is acceptable, even without using quality filters. We believe that this new meshing technique is in the correct direction toward real-time simulation in the biomedical field. PMID- 26011779 TI - Armodafinil in binge eating disorder: a randomized, placebo-controlled trial. AB - This study evaluated the efficacy, tolerability, and safety of armodafinil in the treatment of binge eating disorder (BED). Sixty participants with BED were randomized to receive armodafinil (150-250 mg/day) (N = 30) or placebo (N = 30) in a 10-week, prospective, parallel-group, double-blind, flexible-dose, single center trial. In the primary longitudinal analysis, armodafinil and placebo produced similar rates of improvement in binge eating day frequency (the primary outcome measure); however, armodafinil was associated with a statistically significantly higher rate of decrease in binge eating episode frequency. In the secondary baseline-to-endpoint analyses, armodafinil was associated with statistically significant reductions in obsessive-compulsive features of binge eating and BMI. The mean (SD) armodafinil daily dose at endpoint evaluation was 216.7 (43.9) mg. There were no serious adverse events, although one armodafinil recipient developed markedly increased blood pressure that resolved upon drug discontinuation. The small sample size may have limited the detection of important drug-placebo differences. As some of the observed effect sizes appeared clinically meaningful, larger studies of armodafinil in the treatment of BED are warranted. PMID- 26011780 TI - Long-term use of benzodiazepines and related drugs among community-dwelling individuals with and without Alzheimer's disease. AB - The aim of this study was to investigate the prevalence of benzodiazepine and related drug (BZDR) use, especially long-term use, and associated factors among community-dwelling individuals with and without Alzheimer's disease (AD). We utilized data from the MEDALZ-2005 cohort, which includes all community-dwelling individuals diagnosed with AD in Finland at the end of 2005 and matched comparison individuals without AD. Register-based data included prescription drug purchases, comorbidities, and hospital discharge diagnoses. In this study, 24,966 individuals with AD and 24,985 individuals without AD were included. During the 4 year follow-up, we found that 45% (N = 11,312) of individuals with AD and 38% (N = 9534) of individuals without AD used BZDRs. The prevalence of long-term (>= 180 days) BZDR use was more common among individuals with AD (30%) than individuals without AD (26%). The median durations of the first long-term use periods of BZDRs were 1.5 and 2 years for individuals with and without AD, respectively. Factors associated with long-term BZDR use included female sex, AD, schizophrenia, bipolar disorder, depression, coronary artery disease, and asthma/chronic obstructive pulmonary disease. The high prevalence of long-term BZDR use among individuals with AD is especially a cause for concern because long term use may further impair cognition and may be associated with serious adverse events. PMID- 26011781 TI - Cerebroradial issue: Not so much. AB - Cerebral events are quite uncommon around the time of any cardiac catheterization procedure. No significant difference seen in cerebral events between radial and femoral approaches was evident in this large prospective registry. Still hard to find a reason not go radial. Go radial. PMID- 26011783 TI - Rapid balloon distension as a tool to study cortical processing of visceral sensations and pain. AB - BACKGROUND: The processing of discomfort and pain in the central nervous system is normally studied with experimental methods, but it is mandatory that they are reliable over time to ensure that any interventions will result in valid results. We investigated reliability of rapid balloon distension in the rectum to elicit cortical evoked potentials (CEPs) to study the reliability of central processing of visceral sensation and discomfort/pain. METHODS: Eighteen healthy volunteers had two series of rectal balloon distensions performed on two separate days. Individualized balloon pressure, corresponding to pain detection threshold or to the maximum possible distension (30 psi), was used. Within- and between days reliability was measured in terms of amplitudes and latencies of the CEP global field power, topography and underlying brain networks. KEY RESULTS: There were two prominent peaks in the CEP recordings at mean latencies of 157 and 322 ms. There were no differences in latencies or amplitudes (p = 0.3) and they passed the Bland-Altman test for reproducibility. There were no differences in topographies (p > 0.7). Brain source connectivity revealed the cingulate operculum network as the most consistent network within and between subjects. There were no differences in the location of brain sources in this network (p = 0.9) and the source coordinates were reproducible. Finally, the cingulate source generally had higher strength than operculum source (p < 0.001). CONCLUSIONS & INFERENCES: A reliable method to study central mechanisms underlying visceral sensation and pain was established. The method may improve our understanding of visceral pain and could be an objective method for studying efficacy of analgesics on visceral pain. PMID- 26011782 TI - The contribution of mast cells to postoperative ileus in experimental and clinical studies. AB - The persistent phase of postoperative ileus (POI) is mediated by inflammatory activation of the resident myeloid immune cell population in the gut wall, likely elicited by neurogenic activation. Mast cells are thought to play a critical role in this inflammatory response and involvement of mast cells in POI has been investigated and described thoroughly in experimental studies. Intestinal manipulation (IM) leads to degranulation of mast cells, resulting in an increase in mast cell proteases in peritoneal fluid and gut tissue. The inflammatory infiltrate formed in the intestinal wall thereby impairs gastrointestinal motility. In the clinical study by Berdun et al., the experimentally known association between mast cell degranulation and delayed motility is shown in a clinical setting. These findings are important and open up therapeutic opportunities to reduce or prevent POI. In this mini-review, the role of mast cells in POI is discussed. Furthermore, an update is given on the involvement of the inflammatory response in POI and potential therapeutic strategies. PMID- 26011784 TI - The First Organic-Inorganic Hybrid Luminescent Multiferroic: (Pyrrolidinium)MnBr3. AB - A hybrid organic-inorganic compound, (pyrrolidinium)MnBr3 , distinguished from rare earth (RE)-doped inorganic perovskites, is discovered as a new member of the ferroelectrics family, having excellent luminescent properties and relatively large spontaneous polarization of 6 MUC cm(-2) , as well as a weak ferromagnetism at about 2.4 K. With a quantum yield of >28% and emission lifetime >0.1 ms, such multiferroic photoluminescence is a suitable candidate for future applications in luminescence materials, photovoltaics, and magneto-optoelectronic devices. PMID- 26011787 TI - Intravenous dexketoprofen induces less injection pain than racemic ketoprofen. AB - WHAT IS KNOWN AND OBJECTIVE: Ketoprofen has high analgesic efficacy against inflammatory and nociceptive pain. Additionally, when ketoprofen is administered in conjunction with an opioid during pain management, it prevents the development of opioid-induced hyperalgesia. The main limitation for racemic ketoprofen IV administration is venous irritation. Dexketoprofen is the active enantiomer of racemic ketoprofen and has a similar analgesic efficacy in a dose proportion of 1 : 2, but it causes fewer adverse effects than racemic ketoprofen. It has been claimed that dexketoprofen may cause less frequent and less severe injection pain than racemic ketoprofen. In this study, we compared the injection pain of IV administered racemic ketoprofen and dexketoprofen in elective surgical patients. METHODS: The ethics committee of our institution approved this randomized, double blinded, two-treatment, two-period, crossover clinical comparison of ketoprofen and dexketoprofen. A total of 221 ASA I-III adult patients, aged 20-75 years, were initially IV administered either 0.5 mg/kg racemic ketoprofen followed 2 h later with 0.25 mg/kg dexketoprofen (group 1) or vice versa (group 2). Both compounds were diluted in 20 mL of normal saline and were injected over 6 min. Patients reported injection pain on an 11-point numerical rating scale (NRS) (0 = no pain, 10 = most pain). RESULTS AND DISCUSSION: Significantly less injection pain was reported after dexketoprofen administration. A total of 201 of 209 patients reported pain during racemic ketoprofen injection, and 157 of 210 patients reported pain during dexketoprofen injection, respectively. Moderate or severe pain was reported by 90 (41%) patients during racemic ketoprofen administration and by 43 (20%) during dexketoprofen injection (P = 0.001). The mean of injection pain during racemic ketoprofen injection was 4.2 (SD 2.5) and was 2.5 (2.4) during dexketoprofen injection (P = 0.001). No serious or unexpected adverse events were reported. WHAT IS NEW AND CONCLUSION: Dexketoprofen causes significantly less injection pain than racemic ketoprofen; therefore, it may be a more suitable IV non-steroidal anti-inflammatory than the racemate. PMID- 26011788 TI - Eyewitness identification across the life span: A meta-analysis of age differences. AB - Lineup identifications are often a critical component of criminal investigations. Over the past 35 years, researchers have been conducting empirical studies to assess the impact of witness age on identification accuracy. A previous meta analysis indicated that children are less likely than adults to correctly reject a lineup that does not contain the culprit, but children 5 years and older are as likely as adults to make a correct identification if the culprit is in the lineup (Pozzulo & Lindsay, 1998). We report an updated meta-analysis of age differences in eyewitness identification, summarizing data from 20,244 participants across 91 studies. Contrary to extant reviews, we adopt a life span approach and examine witnesses from early childhood to late adulthood. Children's increased tendency to erroneously select a culprit-absent lineup member was replicated. Children were also less likely than young adults to correctly identify the culprit. Group data from culprit-absent and culprit-present lineups were used to produce signal detection measures, which indicated young adults were better able than children to discriminate between guilty and innocent suspects. A strikingly similar pattern emerged for older adults, who had even stronger deficits in discriminability than children, relative to adults. Although identifications by young adults were the most reliable, identifications by all witnesses had probative value. PMID- 26011790 TI - Age and reemployment success after job loss: An integrative model and meta analysis. AB - Despite widespread popular concern about what it means to be over 40 and unemployed, little attention has been paid in the literature to clarifying the role of age within the job seeking experience. Extending theory, we propose mechanisms by which chronological age affects job search and reemployment outcomes after job loss. Through a meta-analysis and examination of 2 supplemental datasets, we examine 5 questions: (a) How strong is the relationship between age and reemployment speed? (b) Does age disadvantage individuals with respect to other reemployment outcomes? (c) Is the relationship between age and reemployment outcomes mediated by job search activities? (d) Are these relationships generalizable? and (e) Are these relationships linear or curvilinear? Our findings provide evidence for a negative relationship between age and reemployment status and speed across job search decade, world region, and unemployment rate, with the strength of the negative relationship becoming stronger over age 50. Job search self-efficacy and job search intensity partially mediate the relationship between age and both reemployment status and speed. (PsycINFO Database Record PMID- 26011791 TI - A Multimodal Theory of Affect Diffusion. AB - There is broad consensus in the literature that affect diffuses through social networks (such that a person may "acquire" or "catch" an affective state from his or her social contacts). It is further assumed that affect diffusion primarily occurs as the result of people's tendencies to synchronize their affective actions (such as smiles and frowns). However, as we show, there is a lack of clarity in the literature about the substrate and scope of affect diffusion. One consequence of this is a difficulty in distinguishing between affect diffusion and several other affective influence phenomena that look similar but have very different consequences. There is also a growing body of evidence that action synchrony is unlikely to be the only, or indeed the most important, pathway for affect diffusion. This paper has 2 key aims: (a) to craft a formal definition of affect diffusion that does justice to the core of the phenomenon while distinguishing it from other phenomena with which it is frequently confounded and (b) to advance a theory of the mechanisms of affect diffusion. This theory, which we call the multimodal theory of affect diffusion, identifies 3 parallel multimodal mechanisms that may act as routes for affect diffusion. It also provides a basis for novel predictions about the conditions under which affect is most likely to diffuse. PMID- 26011789 TI - Inner Speech: Development, Cognitive Functions, Phenomenology, and Neurobiology. AB - Inner speech-also known as covert speech or verbal thinking-has been implicated in theories of cognitive development, speech monitoring, executive function, and psychopathology. Despite a growing body of knowledge on its phenomenology, development, and function, approaches to the scientific study of inner speech have remained diffuse and largely unintegrated. This review examines prominent theoretical approaches to inner speech and methodological challenges in its study, before reviewing current evidence on inner speech in children and adults from both typical and atypical populations. We conclude by considering prospects for an integrated cognitive science of inner speech, and present a multicomponent model of the phenomenon informed by developmental, cognitive, and psycholinguistic considerations. Despite its variability among individuals and across the life span, inner speech appears to perform significant functions in human cognition, which in some cases reflect its developmental origins and its sharing of resources with other cognitive processes. PMID- 26011792 TI - An economic evaluation of outpatient versus inpatient polyp treatment for abnormal uterine bleeding. AB - OBJECTIVES: To undertake a cost-effectiveness analysis of outpatient uterine polypectomy compared with standard inpatient treatment under general anaesthesia. DESIGN: Economic evaluation carried out alongside the multi-centre, pragmatic, non-inferiority, randomised controlled Outpatient Polyp Treatment (OPT) trial. The UK National Health Service (NHS) perspective was used in the estimation of costs and the interpretation of results. SETTING: Thirty-one secondary care UK NHS hospitals between April 2008 and July 2011. PARTICIPANTS: Five hundred and seven women with abnormal uterine bleeding and hysteroscopically diagnosed endometrial polyps. INTERVENTIONS: Outpatient uterine polypectomy versus standard inpatient treatment. Clinicians were free to choose the technique for polypectomy within the allocated setting. MAIN OUTCOME MEASURES: Patient-reported effectiveness of the procedure determined by the women's self-assessment of bleeding at 6 months, and QALY gains at 6 and 12 months. RESULTS: Inpatient treatment was slightly more effective but more expensive than outpatient treatment, resulting in relatively high incremental cost-effectiveness ratios. Intention-to-treat analysis of the base case at 6 months revealed that it cost an additional L9421 per successfully treated patient in the inpatient group and L 1,099,167 per additional QALY gained, when compared with outpatient treatment. At 12 months, these costs were L22,293 per additional effectively treated patient and L445,867 per additional QALY gained, respectively. CONCLUSIONS: Outpatient treatment of uterine polyps associated with abnormal uterine bleeding appears to be more cost-effective than inpatient treatment at willingness-to-pay thresholds acceptable to the NHS. TWEETABLE ABSTRACT: HTA-funded OPT trial concluded that outpatient uterine polypectomy is cost-effective compared with inpatient polypectomy. PMID- 26011793 TI - Social monogamy vs. polyandry: ecological factors associated with sex roles in two closely related birds within the same habitat. AB - Why mainly males compete and females take a larger share in parental care remains an exciting question in evolutionary biology. Role-reversed species are of particular interest, because such 'exceptions' help to test the rule. Using mating systems theory as a framework, we compared the reproductive ecology of the two most contrasting coucals with regard to sexual dimorphism and parental care: the black coucal with male-only care and the biparental white-browed coucal. Both species occur in the same lush habitat and face similar ecological conditions, but drastically differ in mating system and sexual dimorphism. Black coucals were migratory and occurred at high breeding densities. With females being obligatory polyandrous and almost twice as heavy as males, black coucals belong to the most extreme vertebrates with reversed sexual dimorphism. Higher variance in reproductive success in fiercely competing females suggests that sexual selection is stronger in females than in males. In contrast, resident white-browed coucals bred at low densities and invariably in pairs. They were almost monomorphic and the variance in reproductive success was similar between the sexes. Black coucals were more likely to lose nests than white-browed coucals, probably facilitating female emancipation of parental care in black coucals. We propose that a combination of high food abundance, high population density, high degree of nest loss and male bias in the adult sex ratio represent ecological conditions that facilitate role reversal and polyandry in coucals and terrestrial vertebrates in general. PMID- 26011794 TI - Parent Coaching Model for Adolescents With Emotional Eating. AB - A significant proportion of both healthy and treatment-seeking youth report eating for emotional reasons. Emotional eating (EE) is associated with medical and psychological sequelae including overeating and eating disorder symptoms. Youth with EE are thought to have a predisposition toward a high level of emotional sensitivity, with a tendency to experience emotions intensely, and for a long duration. Interventions are needed to address emotion dysregulation associated with EE. Parent-focused interventions that emphasize training parents to respond to emotion dysregulation in their children have the potential to reduce the incidence of EE. This article describes an emotion-focused parent training intervention for youth who engage in EE. PMID- 26011796 TI - Grape seed proanthocyanidins prevent DOCA-salt hypertension-induced renal injury and its mechanisms in rats. AB - Renal dysfunction is one of the major effects of DOCA (deoxycorticosterone acetate)-salt hypertension and there is an increasing amount of evidence that oxidative stress damages the function of the kidney. Grape seed proanthocyanidins (GSPE) have been reported to be potent anti-oxidants and free radical scavengers. The present study sought to investigate the ability of GSPE to prevent renal injury in DOCA-salt hypertensive rats and to explore the molecular mechanisms underlying its protective effects. A total of 54 Sprague Dawley (SD) rats were randomly divided into 7 groups: Sham group (n = 7), UnX-sham group (n = 8), DOCA salt group (n = 8), GSPE150 group (150 mg kg(-1), n = 7), GSPE240 group (240 mg kg(-1), n = 8), GSPE384 group (384 mg kg(-1), n = 8) and ALM (amlodipine besylate tablets) group (5 mg kg(-1), n = 8), and treated for 4 weeks. Compared to sham group rats, renal injury was observed in DOCA-salt hypertensive group rats as the urine protein, KW/BW (kidney weight/body weight), degree of renal fibrosis, renal MDA (malondialdehyde) and Hyp (hydroxyproline) contents significantly increased (P < 0.01). Moreover, SOD (Superoxide Dismutase) activities decreased in the model group (P < 0.01). In contrast, DOCA-salt hypertensive rats treated with different dose of GSPE or ALM showed a significant improvement of renal injury with decreased urine protein, KW/BW, degree of renal fibrosis, renal total MDA and Hyp contents compared to the untreated group. In addition, SOD activities increased in the treatment group. Since the experimental modeling time was short, kidney damage occurs to a lesser extent. BUN (Blood Urea Nitrogen), Scr (Serum Creatinine) and UA (Uric Acid) contents did not appear significantly changed in all groups. Finally, the activation of JNK and p38 kinases in the kidney was suppressed in rats treated with GSPEs or ALM compared to the untreated group, suggesting that the inhibition of these kinase pathways by GSPE contributes to the improvement of renal function. Taking these results together, we conclude that the anti-hypertensive and anti-oxidative stress beneficial effects of GSPE on renal injury in rats with DOCA-salt hypertension occur via the attenuation of JNK and p38 activity. PMID- 26011795 TI - An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of alpha1 -antitrypsin upon ligand binding. AB - Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein (alpha1 -antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z alpha1 -antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on alpha1 -antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native alpha1 -antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest. PMID- 26011797 TI - Clustering and visualizing similarity networks of membrane proteins. AB - We proposed a fast and unsupervised clustering method, minimum span clustering (MSC), for analyzing the sequence-structure-function relationship of biological networks, and demonstrated its validity in clustering the sequence/structure similarity networks (SSN) of 682 membrane protein (MP) chains. The MSC clustering of MPs based on their sequence information was found to be consistent with their tertiary structures and functions. For the largest seven clusters predicted by MSC, the consistency in chain function within the same cluster is found to be 100%. From analyzing the edge distribution of SSN for MPs, we found a characteristic threshold distance for the boundary between clusters, over which SSN of MPs could be properly clustered by an unsupervised sparsification of the network distance matrix. The clustering results of MPs from both MSC and the unsupervised sparsification methods are consistent with each other, and have high intracluster similarity and low intercluster similarity in sequence, structure, and function. Our study showed a strong sequence-structure-function relationship of MPs. We discussed evidence of convergent evolution of MPs and suggested applications in finding structural similarities and predicting biological functions of MP chains based on their sequence information. PMID- 26011799 TI - Weighing the adverse cardiac effects of fluoroquinolones: A risk perspective. AB - A rare side effect of fluoroquinolone (FQ) antibiotics is QT prolongation, which may result in serious arrhythmias. Most published comparative trials describe the relative risks among the drug class but do not focus on the incidence of serious arrhythmias. It is important for the prescriber to have a sense not only of relative risk but also of incidence to balance the risks against the other attributes of the individual members of the drug class. A review of English language literature was performed to identify trials that provide data on the relative risk and, when able to be calculated, the incidence of adverse cardiac events among the commonly used FQs. Moxifloxacin had a several-fold higher risk of cardiac arrhythmias than levofloxacin or ciprofloxacin in randomized trials. However, the actual event rate was low in 2 of 3 studies. Given inconsistencies among the studies and the relative rarity of the events, the clinician need not base the choice of drug primarily on concern for a cardiac arrhythmia except in patients at the highest risk of such an event. PMID- 26011800 TI - Stability and pH-independence of nano-zero-valent iron intercalated montmorillonite and its application on Cr(VI) removal. AB - Composite of nano-zero-valent iron and montmorillonite (NZVI/MMT) was prepared by inserting NZVI into the interlayer of montmorillonite. The unique structure montmorillonite with isolated exchangeable Fe(III) cations residing near the sites of structural negative charges inhibited the agglomeration of ZVI and result in the formation of ZVI particles in the montmorillonite interlayer regions. NZVI/MMT was demonstrated to possess large specific surface area and outstanding reducibility that encourage rapid and stable reaction with Cr (VI). Besides, the intercalation also makes NZVI well dispersed and more stable in the interlayer, thereby improving the reaction capacity by 16 times. The effects of pH value, initial concentration of Cr (VI) and reaction time on Cr (VI) removal have also been investigated in detail. According to PXRD and XPS characterization, NZVI/Cr (VI) redox reaction occurred in the interlayer of MMT. The study of NZVI/MMT is instrumental to the development of remediation technologies for persistent environmental contaminants. PMID- 26011798 TI - Sodium Channel Inhibitors Reduce DMPK mRNA and Protein. AB - Myotonic dystrophy type 1 (DM1) is caused by an expanded trinucleotide (CTG)n tract in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. This results in the aggregation of an expanded mRNA forming toxic intranuclear foci which sequester splicing factors. We believe down regulation of DMPK mRNA represents a potential, and as yet unexplored, DM1 therapeutic avenue. Consequently, a computational screen for agents which down regulate DMPK mRNA was undertaken, unexpectedly identifying the sodium channel blockers mexiletine, prilocaine, procainamide, and sparteine as effective suppressors of DMPK mRNA. Analysis of DMPK mRNA in C2C12 myoblasts following treatment with these agents revealed a reduction in the mRNA levels. In vivo analysis of CD1 mice also showed DMPK mRNA and protein down-regulation. The role of DMPK mRNA suppression in the documented efficacy of this class of compounds in DM1 is worthy of further investigation. PMID- 26011801 TI - Aggressive aneurysmal bone cyst in association with polyostotic fibrous dysplasia: A case report. AB - INTRODUCTION: Aneurysmal bone cyst occurring in the setting of previously diagnosed fibrous dysplasia is rare. While both are benign processes, pain, compression of nearby structures and risk of fracture can require treatment. PRESENTATION OF CASE: In this report, we describe a 56 year old male who developed an aggressive aneurysmal bone cyst secondary to fibrous dysplasia in the proximal tibia over a period of 8 months. He required an above knee amputation for disease and symptom control due to the aggressive nature of disease and medical comorbidities. DISCUSSION: The diagnosis of a secondary lesion can prove difficult. It is important to exclude a malignant disease process, particularly when imaging demonstrates an aggressive appearance. In this case, repeat imaging, CT guided biopsies and an open biopsy were performed to exclude malignancy prior to definitive surgical management. CONCLUSION: In order to exclude secondary lesions, we suggest further investigation for new onset pain in the setting of a benign lesion. PMID- 26011802 TI - A closed loop obstruction caused by entrapment of the fallopian tube and herniation through the broad ligament. AB - A 49-year-old female presented with one week history of severe abdominal pain, vomiting and constipation. Pertinent past surgical history consisted of caesarean section, laparoscopic right fallopian tube cystectomy and myomectomy. There was also recent left mastectomy and adjuvant chemotherapy for breast carcinoma. Clinical examination established a tensely distended abdomen with scanty bowel sounds but no clinical peritonism. Blood tests showed severe acute kidney injury and raised inflammatory markers. Computed tomography without intravenous contrast demonstrated small bowel obstruction of uncertain aetiology but with likely calibre change in the pelvis. At operation, the left fallopian tube had wrapped itself around ischemic bowel. A left salpingo-oophorectomy was performed to release the bowel. On closer inspection, an internal hernia caused by a defect in the broad ligament was diagnosed. This case report describes a differential of atypical small bowel obstruction to be considered when faced with a female acute abdomen. PMID- 26011803 TI - Calculus-related ureteral intussusception: A case report and literature review. AB - INTRODUCTION: Ureteral intussusception is a rarely reported condition, primarily as a complication of ureteric tumours. Fewer than 30 case reports have been made. This case represents the first reported case, to our knowledge, of ureteral intussusception caused by a ureteric calculus. PRESENTATION OF CASE: We present the case of a 70 year old man with a history of conservatively managed renal calculi, in whom obstructive ureterolithiasis was incidentally detected. Retrograde pyelography and ureteroscopy revealed intussusception of the ureter around a calculus. Extensive biopsies revealed no evidence of tumour, and the intussusception resolved following stone clearance. DISCUSSION: Literature review of previously reported cases of ureteral intussusception revealed 26 cases, of which 22 were secondary to tumour and 4 were secondary to surgical procedures. We propose a mechanism by which calculus-related ureteral intussusception may occur, and suggest treatment for this condition. CONCLUSION: Calculus-related ureteral intussusception is a rare condition, of which this represents the only case report. Management of the condition should involve excluding the presence of tumour, and then clearing the stone, avoiding the use of a basket for retrieval of fragments. PMID- 26011805 TI - Pseudomamma of the inguinal region in a female patient: A case report. AB - INTRODUCTION: Supernumerary breasts are relative common benign congenital anomalies. General population occurrence rates vary up to 6% according to ethnicity and gender. Higher incidence is recorded in Asian individuals, especially Japanese. Embryonic breast development of the mammary ridge (milk line) is explained and supernumerary breast tissue resulting from involution failure of any portion of the embryonic mammary folds is described. PRESENTATION OF CASE: We report a case of supernumerary breast (pseudomamma) in a female occupying her right inguinal region that was treated in the breast unit of our hospital. Differential diagnosis, imaging methods, operative approach, surgical treatment and histological verification are specified. DISCUSSION: Classification system for supernumerary breast tissue is presented, high risk population is identified and congenital malformations linked to it are outlined. Evaluation of diagnostic workup and limitations are stated. Cancerous degeneration and justification for surgical removal of the accessory gland is discussed. CONCLUSION: Differential diagnosis of lesions along the milk line should always be inclusive of developmental abnormalities such as any type of supernumerary breast, often overlooked due to small size, although carrying a malignant potential equal to normally positioned breasts. Surgical correction is a sensible approach, often encouraged by the patients. Additional evaluation is recommended due to the frequent accompanying urinary tract and cardiac anomalies. PMID- 26011804 TI - Horizontal maxillary sinus septa: An uncommon entity. AB - INTRODUCTION: Maxillary sinus septas are barriers of cortical bone that arise from the floor or from the walls of sinus and may even divide the sinus into two or more cavities. Morphologically maxillary sinus septa are generally oriented in buccopalatinal orientation horizontal or sagittal orientation of the sinus septa is a rare condition. PRESENTATION OF CASE: This report presents two sinus lift case, in which observed septa in a horizontal orientation was presented. Both cases were fixed by an implant supported prosthethic restoration. DISCUSSION: Surgeons must know detailed knowledge about maxillary sinus anatomy for successful sinus augmentation. Computed tomography (CT) is useful for examining the maxillary sinus. CONCLUSION: Horizontal-type sinus septa are rarely seen. Surgeons must be aware of septa types and orientations. PMID- 26011806 TI - Preliminary Development of a Performance Assessment Tool for Documentation of History Taking in Child Physical Abuse. AB - OBJECTIVES: This study aimed to develop a performance assessment tool for the history-taking components of the medical evaluation of physical abuse in young children by (1) determining the consensus-based injury history and social components for documentation, (2) identifying preliminary performance standards, (3) assessing current level-specific performance using the created tools, and (4) evaluating reliability and validity of the created tools. METHODS: The Physical Abuse Assessment Tool (PHAAT) was developed in 2 steps: (1) a modified Delphi survey was used to identify the injury history and social components for documentation in a medical evaluation for physical abuse, and (2) level-specific ("novice," "competent," "expert") practice standards (minimum passing scores) were created using the identified components via the Angoff method. To evaluate validity, reliability, and level-specific performance of the PHAAT, a chart review of 50 consecutive cases from each of the 3 levels was performed. RESULTS: Seventy-one child abuse pediatricians and 39 social workers participated in the modified Delphi survey, and 67 child abuse pediatricians and 27 social workers participated in the Angoff method. The resulting PHAAT included 2 checklists for use based on presence or absence of a history of an injurious event. One-way analysis of variance shows significant differences in performance based on team level (P < 0.001), indicating construct validity. Intrarater and interrater reliability evaluations showed strong (rs = 0.64-0.92) and moderate to strong (intraclass correlation coefficient = 0.81-0.98) correlations, respectively. CONCLUSIONS: Initial evaluation suggests the PHAAT may be a reliable and valid practice assessment tool for the medical evaluation of physical abuse. PMID- 26011807 TI - Neuropsychological Evaluation of Children and Adolescents With Acute Carbon Monoxide Poisoning. AB - OBJECTIVES: Carbon monoxide (CO) poisoning is a worldwide health problem. We have limited information regarding psychological adversities of CO poisoning in children and adolescents. The aim of this study was (1) to investigate the effects of severe CO poisoning on cognitive functions, mood, and behaviors in children and adolescents and (2) to identify factors related to occurrence of neuropsychological symptoms. METHODS: This study included pediatric patients, who were evaluated after CO poisoning at the Department of Child and Adolescent Psychiatry between January 2012 and April 2013. The patients were evaluated at 2 time points. The first evaluation was done when they were discharged from emergency department, and the second evaluation was done 1 month after CO poisoning. Turkish versions of internationally recognized tests were used to evaluate anxiety, depressive symptoms, attention, visual-spatial skills, memory, and behaviors of patients. RESULTS: Twenty-seven patients were analyzed. The mean age of the patients was 11.8 +/- 2.7 years (range, 6-18 years). The mean carboxyhemoglobin level was 31.5% +/- 7.8% (range, 19%-51%) dir. Delayed neurological sequel was observed in only 1 patient, who had headache and tinnitus. We found that carboxyhemoglobin level was not correlated with later neuropsychiatric test scores. However, we found a correlation between history of loss of consciousness and anxiety symptom level, hyperbaric oxygen (HBO) therapy session and behavioral problems, and time to HBO therapy and attention problems. CONCLUSIONS: We suggest that CO exposure duration, history of loss of consciousness, time to HBO therapy, and the number of HBO therapy session affect neuropsychological symptom levels and occurrence of attention and behavioral problems. PMID- 26011808 TI - Potential Dermal Exposure to Flonicamid and Risk Assessment of Applicators During Treatment in Apple Orchards. AB - Exposure and risk assessments of flonicamid for applicators were performed in apple orchards in Korea. Fifteen experiments were done with two experienced applicators under typical field conditions using a speed sprayer. In this study, cotton gloves, socks, masks, and dermal patches were used to monitor potential dermal exposure to flonicamid, and personal air samplers with XAD-2 resin and glass fiber filter were used to monitor potential inhalation exposure. The analytical methods were validated for the limit of detection, limit of quantitation, reproducibility, linearity of the calibration curve, and recovery of flonicamid from various exposure matrices. The results were encouraging and acceptable for an exposure study. The applicability of XAD-2 resin was evaluated via a trapping efficiency and breakthrough test. During the mixing/loading, the average total dermal exposure was 22.6 MUg of flonicamid, corresponding to 4.5*10(-5)% of the prepared amount. For the spraying, the potential dermal exposure was 9.32 mg, and the ratio to applied amount was 1.9 * 10(-2%). The primary exposed body parts were the thigh (2.90 mg), upper arm (1.75 mg), and lower leg (1.66 mg). By comparison, absorbable quantity of exposure was small, only 1.62 MUg (3.2*10(-6)%). The margin of safety (MOS) were calculated for risk assessment, in all sets of trials, MOS > 1, indicating the exposure level of flonicamid was considered to be safe in apple orchards. Although this was a limited study, it provided a good estimate of flonicamid exposure for orchard applicators. PMID- 26011810 TI - Preface. PMID- 26011809 TI - Proton MR Spectroscopy in Patients with Structural MRI-Negative Temporal Lobe Epilepsy. AB - BACKGROUND AND PURPOSE: With conventional magnetic resonance imaging (MRI), 20 30% of patients with temporal lobe epilepsy (TLE) have negative pathological MRI findings. Further investigations of the role of magnetic resonance spectroscopy (MRS) in the pre-surgical evaluation of patients with MRI-negative TLE are important to avoid intracranial EEG recording and to better understand the mechanism of the epileptogenic process. This study aimed to compare the measurements of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) in the hippocampi of MRI-negative TLE patients and normal subjects. METHODS: Twenty patients with MRI-negative TLE and 10 age-matched healthy control subjects underwent MRI and MRS. The concentrations of NAA, Cr, and Cho and the ratios of NAA/Cr and NAA/(Cr+Cho) were measured. Seven of these 20 patients also underwent surgical treatment for TLE. Their pathological results and surgical outcomes were evaluated. RESULTS: In the hippocampi ipsilateral to the seizure side, the NAA/Cr and NAA/(Cr+Cho) ratios were significantly decreased compared with the ratios of the hippocampi contralateral to the seizure side and the normal control hippocampi. There was no significant difference between the hippocampi contralateral to the seizure side and the normal control hippocampi. The pathological results from the patients who underwent temporal lobe resection indicated mild to moderate gliosis and minimal loss of neurons. Five patients were seizure-free during the follow-up period of 9- 47 months (mean 27.7 months). CONCLUSIONS: In MRI-negative TLE, significant reductions in the NAA/Cr and NAA/(Cr+Cho) ratios ipsilateral to the seizure side may help lateralize and localize the epileptogenic zone. PMID- 26011811 TI - Cancer incidence in Canada: trends and projections (1983-2032). AB - PURPOSE AND INTENDED AUDIENCE: Each year, the Canadian Cancer Statistics publication provides an estimate of expected case counts and rates for common cancer sites for the current year in Canada as a whole and in the provinces and territories. This monograph expands on the Canadian Cancer Statistics publication by providing historical and projected cancer incidence frequencies and rates at national and regional levels from 1983 to 2032. The aim is that this monograph will be an important resource for health researchers and planners. Most importantly, it is hoped the monograph will: - provide evidence-based input for the development of public health policy priorities at the regional and national levels; and - guide public health officials in planning strategy including designing and evaluating preventive interventions and planning resources (treatment requirements) and infrastructure for future cancer control and care intended to reduce the burden of cancer in Canada. PMID- 26011812 TI - A case of giant saphenous vein graft aneurysm successfully treated with catheter intervention. AB - The patient was a 67-year-old man who had undergone coronary artery bypass graft surgery using a saphenous vein graft (SVG) 22 years before. Computed tomography angiogram revealed a large aneurysm of the SVG (38 * 42 mm in diameter; 80-mm long) and total occlusion of the left anterior descending artery (LAD). We first performed percutaneous coronary intervention for chronic total occlusion of the native LAD with bi-directional approach via the SVG. One month later, we performed the trans-catheter embolization of the SVG and occluded the SVG using multiple coils. This case demonstrates that trans-catheter embolization after recanalization of native coronary artery is an effective strategy to treat an SVG aneurysm. (c) 2015 Wiley Periodicals, Inc. PMID- 26011813 TI - High-resolution transmission electron microscopy study on reversion of Al2CuMg precipitates in Al-Cu-Mg alloys under irradiation. AB - Image deconvolution analyses showed that reversion of S-Al2CuMg precipitates occurred in an Al-Cu-Mg alloy during high-resolution transmission electron microscopy observations. A fraction of Mg and Cu atoms in the precipitates diffused into Al matrix due to electron beam irradiation at 300kV, resulting in structural/chemical reversion of the precipitates. The structural reversion of the S-Al2CuMg precipitates is closely related with irradiation-induced displacement of atoms. The strong attraction between Cu and Mg atoms might assist the sub-threshold displacement of Cu atoms. One transitional structure is determined to be S''-Al10Cu3Mg3, a precursor of S-Al2CuMg. Two other transitional structures, Al3CuMg and Al18Cu5Mg5 which have the same lattice parameters of a=c=0.405nm as that of S''-Al10Cu3Mg3, but different b values, are suggested. PMID- 26011814 TI - Cytotoxic Potential and Molecular Characterization of Fungal Endophytes from Selected High Value Medicinal Plants of the Kashmir Valley - India. AB - The present study explores the fungal endophytes from selected high value medicinal plants to check their activities at in-vitro and in-vivo level. The in vitro cytotoxicity of selected endophytes revealed potent growth inhibition against human cancer cell lines of leukemia (THP-1), lung (A549), prostate (PC 3), colon (Caco-2), neuroblastoma (IMR-32) and breast (MCF-7) at a concentration of 100 ug/ml. Among them the endophytic strains I. e., IIIM2, IIIM3, IIIM7 and IIIM8 showed most significant growth inhibition against colon (Caco-2), prostate (PC-3), lung (A549) and leukemia (THP-1) cancer cell lines. At the in-vivo level maximum (58.95%) tumor growth inhibition was documented with the extract of IIIM2 against Ehrlich Ascites Carcinoma mouse modal. All the potent fungal endophytic strains were characterized using ITS 4 and ITS 5 region sequencing and phylogenetic analysis was ascertained among them. This paper confirms the 2 elite endophytic fungal strains, IIIM2 and IIIM8, have the potential to act as a source of new anticancer compounds. PMID- 26011815 TI - Limited Sampling Strategy for the Prediction of Area Under the Curve (AUC) of Statins: Reliability of a Single Time Point for AUC Prediction for Pravastatin and Simvastatin. AB - Statins are widely prescribed medicines and are also available in fixed dose combinations with other drugs to treat several chronic ailments. Given the safety issues associated with statins it may be important to assess feasibility of a single time concentration strategy for prediction of exposure (area under the curve; AUC). The peak concentration (Cmax) was used to establish relationship with AUC separately for pravastatin and simvastatin using published pharmacokinetic data. The regression equations generated for statins were used to predict the AUC values from various literature references. The fold difference of the observed divided by predicted values along with correlation coefficient (r) were used to judge the feasibility of the single time point approach. Both pravastatin and simvastatin showed excellent correlation of Cmax vs. AUC values with r value >= 0.9638 (p<0.001). The fold difference was within 0.5-fold to 2 fold for 220 out of 227 AUC predictions and >81% of the predicted values were in a narrower range of >0.75-fold but <1.5-fold difference. Predicted vs. observed AUC values showed excellent correlation for pravastatin (r=0.9708, n=115; p<0.001) and simvastatin (r=0.9810; n=117; p<0.001) suggesting the utility of Cmax for AUC predictions. On the basis of the present work, it is feasible to develop a single concentration time point strategy that coincides with Cmax occurrence for both pravastatin and simvastatin from a therapeutic drug monitoring perspective. PMID- 26011816 TI - Differences between Mitiglinide/Voglibose Fixed-dose Combination and Glimepiride in Modifying Low-density Lipoprotein Heterogeneity in Japanese Type-2 Diabetic Patients: A Pilot Study. AB - PURPOSE: The purpose of this study was to compare the effects of mitiglinide/voglibose fixed-dose combination and glimepiride on low-density lipoprotein (LDL)-heterogeneity in type-2 diabetic patients with unstable glycemic control after treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: This was an open-label pilot study in which type-2 diabetic patients were randomly assigned to the mitiglinide/voglibose (fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg, n=14) or glimepiride (0.5 mg, n=16). RESULTS: In the glimepiride group, serum LDL cholesterol (LDL-C) and small-dense (sd) LDL levels decreased significantly (-8.5% and -9.0%), while sd-LDL/LDL-C and an indicator of LDL-particle size, LDL-C/apoB, did not change significantly. In the mitiglinide/voglibose group, serum LDL-C levels did not change, while sd-LDL levels and sd-LDL/LDL-C decreased significantly (-8.6% and -7.9%) and LDL-C/apoB increased significantly (5.8%). Fasting blood glucose levels tended to be reduced to a greater extent in the glimepiride group than in the mitiglinide/voglibose group (-13.9% vs. -8.4%, p=0.08), while the rate of reduction of HbA1c levels tended to be higher in the mitiglinide/voglibose group than in the glimepiride group (-6.9% vs. -3.4%, p=0.09), suggesting differences in fluctuating blood glucose levels between the 2 groups. CONCLUSION: There were differences in the effects of mitiglinide/voglibose fixed-dose combination and glimepiride in addition to DPP-4 inhibitors on LDL-metabolism, and this may be related to fluctuations in blood glucose levels after treatment with these agents. PMID- 26011818 TI - A Reversible Crystallinity-Preserving Phase Transition in Metal-Organic Frameworks: Discovery, Mechanistic Studies, and Potential Applications. AB - A quenching-triggered reversible single-crystal-to-single-crystal (SC-SC) phase transition was discovered in a metal-organic framework (MOF) PCN-526. During the phase transition, the one-dimensional channel of PCN-526 distorts from square to rectangular in shape while maintaining single crystallinity. Although SC-SC transformations have been frequently observed in MOFs, most reports have focused on describing the resulting structural alterations without shedding light on the mechanism for the transformation. Interestingly, modifying the occupancy or species of metal ions in the extra-framework sites, which provides mechanistic insight into the causes for the transformation, can forbid this phase transition. Moreover, as a host scaffold, PCN-526 presents a platform for modulation of the photoluminescence properties by encapsulation of luminescent guest molecules. Through judicious choice of these guest molecules, responsive luminescence caused by SC-SC transformations can be detected, introducing a new strategy for the design of novel luminescent MOF materials. PMID- 26011817 TI - Solid Manure As a Source of Fecal Indicator Microorganisms: Release under Simulated Rainfall. AB - Understanding and quantifying microbial release from manure is a precondition to estimation and management of microbial water quality. The objectives of this work were to determine the effects of rainfall intensity and surface slope on the release of Escherichia coli, enterococci, total coliforms, and dissolved chloride from solid dairy manure and to assess the performance of the one-parametric exponential model and the two-parametric Bradford-Schijven model when simulating the observed release. A controlled-intensity rainfall simulator induced 1 h of release in runoff/leachate partitioning boxes at three rainfall intensities (30, 60, and 90 mm h(-1)) and two surface slopes (5% and 20%). Bacterial concentrations in initial release were more than 1 order of magnitude lower than their starting concentrations in manure. As bacteria were released, they were partitioned into runoff and leachate at similar concentrations, but in different volumes, depending on slope. Bacterial release occurred in two stages that corresponded to mechanisms associated with release of manure liquid- and solid phases. Parameters of the two models fitted to the bacterial release dependencies on rainfall depth were not significantly affected by rainfall intensity or slope. Based on model performance tests, the Bradford-Schijven model is recommended for simulating bacterial release from solid manure. PMID- 26011819 TI - Characterization and simultaneous quantification of biological aporphine alkaloids in Litsea cubeba by HPLC with hybrid ion trap time-of-flight mass spectrometry and HPLC with diode array detection. AB - The root and rhizome of Litsea cubeba (Lour) Pers., named 'Dou-chi-jiang' in Chinese, has been traditionally used for treatment of cardiovascular and cerebrovascular diseases, rheumatic arthralgia, and other diseases in China. Aporphine alkaloids are its characteristic ingredients and responsible for its bioactivities, especially anti-inflammatory and analgesic effects. A sensitive and reliable high-performance liquid chromatography with diode array detection tandem mass spectrometry method was developed for characterization and simultaneous determination of biological aporphine alkaloids in 'Dou-chi-jiang'. The optimized chromatographic conditions were performed on an Eclipse XDB C18 column with a gradient of acetonitrile/water containing 0.1% formic acid as the mass spectrometry mobile phase and acetonitrile/water containing 0.2% diethylamine (pH 3.10, adjusted by acetic acid) as the liquid chromatography mobile phase. The fragmentation pathways by loss of CO, .CH3 , .NH3 , and .NH2 CH3 were detected as characteristic for aporphine alkaloids. Based on these characteristics, total 12 analogues were identified. The quantification method was validated in terms of linearity, precision, and accuracy for six major aporphine alkaloids, which was successfully applied for simultaneous determination in ten batches of samples. The established method is simple, rapid, and specific for characterization and quantitation of aporphine alkaloids in 'Dou chi-jiang' and other traditional Chinese medicines rich in this kind of ingredient. PMID- 26011820 TI - Effect of zoledronic acid on spinal fusion outcomes in an ovariectomized rat model of osteoporosis. AB - To evaluate the effect of zoledronic acid (ZA) on spinal fusion in ovariectomized (OVX) rats. Female SD rats (n = 50) were OVX or sham-operated and randomized into five groups: Sham, OVX control, ZOL-20 (20 ug/kg), ZOL-100 (100 ug/kg), and ZOL 500 (500 ug/kg). Eight weeks after OVX, bilateral lumbar spinal fusion was performed using autologous iliac bone with ZA or saline according to the grouping. The lumbar spines were harvested at 8 weeks and subjected to radiographic, manual palpation, micro-computed tomographic (micro-CT), and histological analysis. The manual palpation result differed significantly only between the ZOL-500 (fused: partially fused: not fused, 9:0:0) and OVX control (4:2:3) (p < 0.05). The radiographic scales were also differed significantly only between these two groups. According to the micro-CT results, the bone volume fraction (BV/TV) were significantly higher in all ZA-treated groups (54.2%, 65.9%, and 73.6%) than OVX control (43.7%) (p < 0.01). At clinical dose or lower, ZA didn't alter the spinal fusion, but a higher dose increased the spinal fusion rate significantly. This study suggests ZA may have a positive effect on spinal fusion in the presence of osteoporosis, and spinal fusion surgery outcome is not likely to be altered by ZA at clinical dose. PMID- 26011821 TI - Technology for deep brain stimulation at a gallop. PMID- 26011822 TI - Applying comprehensive environmental assessment to research planning for multiwalled carbon nanotubes: Refinements to inform future stakeholder engagement. AB - Risk assessments and risk management efforts to protect human health and the environment can benefit from early, coordinated research planning by researchers, risk assessors, and risk managers. However, approaches for engaging these and other stakeholders in research planning have not received much attention in the environmental scientific literature. The Comprehensive Environmental Assessment (CEA) approach under development by the United States Environmental Protection Agency (USEPA) is a means to manage complex information and input from diverse stakeholder perspectives on research planning that will ultimately support environmental and human health decision making. The objectives of this article are to 1) describe the outcomes of applying lessons learned from previous CEA applications to planning research on engineered nanomaterial, multiwalled carbon nanotubes (MWCNTs) and 2) discuss new insights and refinements for future efforts to engage stakeholders in research planning for risk assessment and risk management of environmental issues. Although framed in terms of MWCNTs, this discussion is intended to enhance research planning to support assessments for other environmental issues as well. Key insights for research planning include the potential benefits of 1) ensuring that participants have research, risk assessment, and risk management expertise in addition to diverse disciplinary backgrounds; 2) including an early scoping step before rounds of formal ratings; 3) using a familiar numeric scale (e.g., US dollars) versus ordinal rating scales of "importance"; 4) applying virtual communication tools to supplement face-to face interaction between participants; and 5) refining criteria to guide development of specific, actionable research questions. PMID- 26011823 TI - Radiation exposure of digital breast tomosynthesis using an antiscatter grid compared with full-field digital mammography. AB - OBJECTIVES: Our study aim was to assess the radiation dose of digital breast tomosynthesis (DBT) in comparison to full-field digital mammography (FFDM) in a clinical setting. MATERIALS AND METHODS: Two-hundred four patients were consecutively included, of which 236 complementary DBT and FFDM examinations were available. All acquisitions were performed on a single commercially available mammography system capable of FFDM and DBT acquisitions using an antiscatter grid. The average glandular dose (AGD) was calculated for each examination using the Dance method. For this, tube output and half-value layer were measured, and the required exposure parameters (target/filter material, tube voltage, tube load, compressed breast thickness) were retrieved from the DICOM metadata. The DBT and FFDM AGD values were pairwise tested, and a subanalysis with respect to breast thickness was performed. RESULTS: The mean (SD) AGD values for a single view DBT and FFDM were 1.49 (0.36) mGy and 1.62 (0.55) mGy, respectively, which are small but statistically significant differences. This difference may be partially attributed to the small difference in the mean breast thickness between FFDM and DBT (3 mm). In this patient population, the AGD was lower for DBT than for FFDM in 61% of the patients. When patients were categorized according to breast thickness, the AGD of DBT was only significantly smaller than the AGD of FFDM for breast thickness categories larger than 50 mm, indicating that the dose reduction for DBT compared with FFDM was more pronounced in thick breasts. CONCLUSIONS: The radiation dose of patients undergoing a single-view DBT was comparable to a single-view FFDM. For patients with thicker breasts, the radiation dose of DBT was slightly lower than FFDM. PMID- 26011825 TI - Duration of ruptured membranes and mother-to-child HIV transmission: a prospective population-based surveillance study. AB - OBJECTIVE: To investigate the association between duration of rupture of membranes (ROM) and mother-to-child HIV transmission (MTCT) rates in the era of combination antiretroviral therapy (cART). DESIGN: The National Study of HIV in Pregnancy and Childhood (NSHPC) undertakes comprehensive population-based surveillance of HIV in pregnant women and children. SETTING: UK and Ireland. POPULATION: A cohort of 2398 singleton pregnancies delivered vaginally, or by emergency caesarean section, in women on cART in pregnancy during the period 2007 2012 with information on duration of ROM; HIV infection status was available for 1898 infants. METHODS: Descriptive analysis of NSHPC data. MAIN OUTCOME MEASURES: Rates of MTCT. RESULTS: In 2116 pregnancies delivered at term, the median duration of ROM was 3 hours 30 minutes (interquartile range, IQR 1-8 hours). The overall MTCT rate for women delivering at term with duration of ROM >=4 hours was 0.64% compared with 0.34% for ROM <4 hours, with no significant difference between the groups (OR 1.90, 95% CI 0.45-7.97). In women delivering at term with a viral load of <50 copies/ml, there was no evidence of a difference in MTCT rates with duration of ROM >=4 hours, compared with <4 hours (0.14% for >=4 hours versus 0.12% for <4 hour; OR 1.14, 95% CI 0.07-18.27). Among infants born preterm with infection status available, there were no transmissions in 163 deliveries where the maternal viral load was <50 copies/ml. CONCLUSIONS: No association was found between duration of ROM and MTCT in women taking cART. TWEETABLE ABSTRACT: Rupture of membranes of more than 4 hours is not associated with MTCT of HIV in women on effective ART delivering at term. PMID- 26011824 TI - HIF3A association with adiposity: the story begins before birth. AB - AIM: Determine if the association of HIF3A DNA methylation with weight and adiposity is detectable early in life. MATERIAL & METHODS: We determined HIF3A genotype and DNA methylation patterns (on hybridization arrays) in DNA extracted from umbilical cords of 991 infants. Methylation levels at three CpGs in the HIF3A first intron were related to neonatal and infant anthropometry and to genotype at nearby polymorphic sites. RESULTS & CONCLUSION: Higher methylation levels at three previously described HIF3A CpGs were associated with greater infant weight and adiposity. The effect sizes were slightly smaller than those reported for adult BMI. There was also an interaction within cis-genotype. The association between higher DNA methylation at HIF3A and increased adiposity is present in neonates. In this study, no particular prenatal factor strongly influenced HIF3A hypermethylation. Our data nonetheless suggest shared prenatal influences on HIF3A methylation and adiposity. PMID- 26011826 TI - Human hemorrhagic Fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. AB - Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV) to highly virulent hemorrhagic fever (HF) causing viruses such as Lassa (LASV), Junin (JUNV), Machupo (MACV), Lujo (LUJV), Sabia (SABV), Guanarito (GTOV), and Chapare (CHPV), for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens. PMID- 26011828 TI - Quantitative assessment of the differential impacts of arbuscular and ectomycorrhiza on soil carbon cycling. AB - A significant fraction of carbon stored in the Earth's soil moves through arbuscular mycorrhiza (AM) and ectomycorrhiza (EM). The impacts of AM and EM on the soil carbon budget are poorly understood. We propose a method to quantify the mycorrhizal contribution to carbon cycling, explicitly accounting for the abundance of plant-associated and extraradical mycorrhizal mycelium. We discuss the need to acquire additional data to use our method, and present our new global database holding information on plant species-by-site intensity of root colonization by mycorrhizas. We demonstrate that the degree of mycorrhizal fungal colonization has globally consistent patterns across plant species. This suggests that the level of plant species-specific root colonization can be used as a plant trait. To exemplify our method, we assessed the differential impacts of AM : EM ratio and EM shrub encroachment on carbon stocks in sub-arctic tundra. AM and EM affect tundra carbon stocks at different magnitudes, and via partly distinct dominant pathways: via extraradical mycelium (both EM and AM) and via mycorrhizal impacts on above- and belowground biomass carbon (mostly AM). Our method provides a powerful tool for the quantitative assessment of mycorrhizal impact on local and global carbon cycling processes, paving the way towards an improved understanding of the role of mycorrhizas in the Earth's carbon cycle. PMID- 26011827 TI - Waterborne pathogens: detection methods and challenges. AB - Waterborne pathogens and related diseases are a major public health concern worldwide, not only by the morbidity and mortality that they cause, but by the high cost that represents their prevention and treatment. These diseases are directly related to environmental deterioration and pollution. Despite the continued efforts to maintain water safety, waterborne outbreaks are still reported globally. Proper assessment of pathogens on water and water quality monitoring are key factors for decision-making regarding water distribution systems' infrastructure, the choice of best water treatment and prevention waterborne outbreaks. Powerful, sensitive and reproducible diagnostic tools are developed to monitor pathogen contamination in water and be able to detect not only cultivable pathogens but also to detect the occurrence of viable but non culturable microorganisms as well as the presence of pathogens on biofilms. Quantitative microbial risk assessment (QMRA) is a helpful tool to evaluate the scenarios for pathogen contamination that involve surveillance, detection methods, analysis and decision-making. This review aims to present a research outlook on waterborne outbreaks that have occurred in recent years. This review also focuses in the main molecular techniques for detection of waterborne pathogens and the use of QMRA approach to protect public health. PMID- 26011829 TI - Water infusion versus air insufflation for colonoscopy. AB - BACKGROUND: Colonoscopy is a widely used diagnostic and therapeutic modality. A large proportion of the population is likely to undergo colonoscopy for diagnosis and treatment of colorectal diseases, or when participating in colorectal cancer screening programs. To reduce pain, water infusion instead of traditional air insufflation during the insertion phase of the colonoscopy has been proposed, thereby improving patients' acceptance of the procedure. Moreover, the water infusion method may improve early detection of precancerous neoplasms. OBJECTIVES: To compare water infusion techniques with standard air insufflation, specifically evaluating technical quality and screening efficacy, as well as patients' acceptance of the water infusion procedure. SEARCH METHODS: We searched the Cochrane Colorectal Cancer Group Specialized Register (February 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 1), Ovid MEDLINE (1950 to February 2014), Ovid EMBASE (1974 to February 2014), and ClinicalTrials.gov (1999 to February 2014) for eligible randomised controlled trials. SELECTION CRITERIA: We included randomised controlled trials comparing water infusion (water exchange or water immersion methods) against standard air insufflation during the insertion phase of the colonoscopy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion and extracted data from eligible studies. We performed analysis using Review Manager software (RevMan 5). MAIN RESULTS: We included 16 randomised controlled trials consisting of 2933 colonoscopies. Primary outcome measures were cecal intubation rate and adenoma detection; secondary outcomes were time needed to reach the cecum, pain experienced by participants during the procedure, completion of cecal intubation without sedation/analgesia, and adverse events. Completeness of colonoscopy, that is cecal intubation rate, was similar between water infusion and standard air insufflation (risk ratio 1.00, 95% confidence interval (CI) 0.97 to 1.03, P = 0.93). Adenoma detection rate, that is number of participants with at least one detected adenoma, was slightly improved with water infusion (risk ratio 1.16, 95% CI 1.04 to 1.30, P = 0.007). Assuming the fraction of patients undergoing screening colonoscopy who had one or more adenomas detected was 20 per 100 with standard colonoscopy, the use of water colonoscopy may increase the fraction to 23 per 100 individuals. From our findings, it is possible that up to 68,000 more of the 1.7 million outpatient screening colonoscopies performed annually in the United States, could detect adenomas if water infusion colonoscopy was used. In addition, with water infusion participants experienced significantly less pain (mean difference in pain score on a 0 to 10 scale: -1.57, 95% CI -2.00 to -1.14, P < 0.00001) and a significantly lower proportion of participants requested on-demand sedation or analgesia, or both (risk ratio 1.20, 95% CI 1.14 to 1.27, P < 0.00001). Qualitative analysis suggests that water infusion colonoscopy was not associated with a markedly increased rate of adverse events compared with the standard procedure. AUTHORS' CONCLUSIONS: Completeness of colonoscopy, that is cecal intubation rate, was not improved by water infusion compared with standard air insufflation colonoscopy. However, adenoma detection, assessed with two different measures (that is adenoma detection rate and number of detected adenomas per procedure), was slightly augmented by the water infusion colonoscopy. Improved adenoma detection might be due to the cleansing effects of water infusions on the mucosa. Detection of premalignant lesions during standard colonoscopy is suboptimal, and so improvements in adenoma detection by water infusion colonoscopy, although small, may help to reduce the risk of interval colorectal carcinoma. The most obvious benefit of water infusion colonoscopy was reduction of procedure-related abdominal pain, which may enhance the acceptance of screening/surveillance colonoscopy. PMID- 26011830 TI - Minimally invasive esophagectomy for esophageal cancer: techniques and outcomes. AB - Despite recent improvements in diagnosis, surgical treatment and neo-adjuvant therapy, patients with esophageal cancer have poor prognosis with overall 5-year survival rates of 5-15%.Esophagectomy is the standard treatment for resectable esophageal cancer, but only one third of patients are considered candidates for cure. Minimally invasive techniques have been attempted to improve the postoperative outcomes in such a surgical procedure with high postoperative morbidity and mortality. The purpose of this review is to analyze the minimally invasive esophagectomy (MIE) techniques in the early-stage esophageal carcinoma. MIE is still crowed with heterogeneous studies with several different techniques. MIE comparing to open esophagectomy procedures have less morbidity with less overall in-hospital incidence of pulmonary infections and shorter duration of ICU admission. In addition,MIE techniques preserve the quality of life better than the open procedures, with faster postoperative recovery. PMID- 26011831 TI - Postoperative functional result and quality of life after oesophageal reconstruction based on the type of cervical anastomosis. AB - INTRODUCTION: The keystone of the rate of postoperative complications and functional outcome in oesophageal reconstruction is the technique method of performing cervical anastomosis.Despite new technologies and improved technique in specialized centres, post-anastomosis complications have not significantly improved. PURPOSE: The goal of our study is to analyse the causes that make anastomosis with the oesophagus hypopharynx a particular case. If anatomical and morphological aspects cannot be adjusted (poor histological structure and vascularity etc.), some important elements for performing a good anastomosis can be identified and corrected. MATERIAL AND METHOD: Between 1981-2014, 195 oesophageal reconstructions were performed in our clinic. Our study involved an analysis of 72 cases (2000-2014), based on a statistical evaluation by Kaplan Meier method that considered as eries of factors (oesophagus hypopharynx as anastomotic partner, stomach, jejuno-ileum, colon as visceral partner,pharyngotomy type, T-L, T-T, L-L, L-T type anastomosis,number of anastomotic layers). RESULTS were compared with those obtained by standard clinical and laboratory investigation,analysing the post-therapeutic outcome using three criteria (clinical aspects of swallowing, barium swallow and endoscopy) and by subjective assessment by each patient of his her state and complaints, with effects on long-term functional outcome (dysphagia, reflux, pain, asthenia, weight loss, hoarseness). RESULTS: Statistical analysis determined that only some of the analysed factors proved to be valuable. The higher the level of the anastomosis, the more intense the impairment of the digestive function. The jejunum and left colon proved to bemost effective anastomotic partners. The best method for implantation seems to be T-T or T-L and the number of anastomosis layers has no influence on postoperative outcome. CONCLUSIONS: Acquired data can influence to some extent the operatory technique, with a lower complication rate.Unfortunately, laborious technical aspects and specific anatomical limitations make this goal difficult to achieve. PMID- 26011832 TI - Impact of allyl disulfide on oxidative damage and liver regeneration in an experimental hepatectomy model. AB - BACKGROUND: We investigated the effects of allyl disulfide (agarlic extract) on tissue damage, regeneration, proliferation and oxidative damage in an experimental liver resection model. MATERIALS AND METHODS: In the study, 24 female Wistar albinorats weighing approximately 200-250 g were used. Group 1:The rats in the experimental group all received a 70%hepatectomy and were fed an Allyl disulfide (30 I1/4g kg day,Allyl disulfide, Sigma-Aldrich, formula: C6H10S2, CASNumber: 2179-57-9, formula weight: 146.27 g mol) in supplement to a regular diet for 1 week both preoperatively and postoperatively. Group 2: The rats in the control group also underwent a 70% hepatectomy and were given regular food and water for 1 week both preop and postop. Group 3: In the sham group, all rats were sacrificed 7 days after surgery. Forbiochemical evaluation, SGOT, SGPT, bilirubin, CRP and MDA were studied. In a histopathological examination, the fattening of the liver tissue, existence of (macro-micro vesicular),fibrosis, pleomorphism at hepatocyte nuclei, portal inflammation, existence of intralobular inflammatory cells,dilation at sinusoids, congestion, congestion at the central vein, regeneration, existence of Kupffer cells in the sinu soidallumen and ki-67 proliferation index at hepatocytes were examined. RESULTS: A significant difference between group 1 and group2 was observed regarding the existence of regeneration,(p:0.06), the occurrence of nuclear pleomorphisms (p:0,001)and the fibroblast activity status (p:0.001). Significant differences were found between the experimental groups in regard to Kupffer cell increase and dilation and the hyperemiastatus in the sinusoid lumens (p:0.013 and p:0.001,respectively). In the Allyl disulfide group, the proliferation index was significantly higher than that of the other groups(p:0,001), while the average plasma MDA value was lower than that of the other groups (p: 0,042). No significant differences were found among the groups with respect to tissue MDA values (p:0,720). No significant difference was found for SGPT (ALT) and SGOT (AST) levels between Group 1 and the other groups (p:0.247 and p:0.539, respectively).The average total bilirubin (T. Bili) values were 0,12,0,08 and 0,04 in the allyl disulfide group, control group andSham group, respectively. This difference among the groups is statistically significant (p:0.001). The average direct bilirubin (D. Bili) values were 0,06, 0,02 and 0,02 in the allyl disulfide group, control group and Sham group, respectively.This variation among the groups is also statistically significant (0.001). CONCLUSION: We observed that the use of Allyl disulfide supplementation after major hepatectomy has a positive impact on liver regeneration, proliferation and oxidative damage. ABBREVIATIONS: Postop: post-operative, Preop: pre-operative,SGOT(AST): serum glutamic oxaloacetic transaminase,SGPT(ALT): serum glutamate-pyruvate transaminase, CRP:C- Reactive protein, MDA: Malondialdehyde, DAS: Garlicextract diallyl sulfide, AGE: aged garlic extract. PMID- 26011833 TI - Can the Principles of Oncological Surgery be Complied with in Haemorrhagic Gastric Cancer? AB - AIM: To discover if in the case of bleeding gastric cancer the principles of oncological surgery could be applied to gastric cancer. METHODS: We studied two groups of patients, one with haemorrhagic gastric cancer and the second with uncomplicated gastric cancer. We took into account gender, age, number of days from admission to surgery, tumour location, type of intervention,haemoglobin on admission, haemorrhage externalization pathway, comorbidities, intervention type, extension of lymphadenectomy, stage, tumour type degree of differentiation there of, number of excised lymph nodes, perineural and vascular invasion, preoperative transfusion, postoperative complications, deaths. RESULTS: The rate of postoperative complications is higher for patients in group 1 who presented upper gastrointestinal bleeding, an increase in the number of days of hospitalization and care, with a higher risk of surgical re-intervention and a higher mortality for these patients. CONCLUSIONS: in the case of haemorrhagic gastric cancer surgery,we can apply the principles of malignant stomach cancer surgery, but with a higher rate of postoperative complications,more hospitalization days and higher mortality. PMID- 26011834 TI - Prophylactic Percutaneous Endoscopic Gastrostomy (PEG) - The Importance of Nutritonal Support in Patients with Head and Neck Cancers (HNCs) or Neurogenic Dysphagia (ND). AB - BACKGROUND: We evaluated the effectiveness and safety of prophylactic PEG performed for the enteral nutrition support during the oncological treatment of patients with HNCs and as a part of the management of neurological patients experiencing neurogenic dysphagia. METHODS: In 2013 we followed up on a group of 23 HNC patients subjected to prophylactic PEG. We assessed the duration of the procedure, intraprocedural incidents and their causes, time to tube-refeeding and discharge after intervention, post interventional analgesia, early and late complications,toleration, costs and postoperative course of these patients after radical surgery maintaining PEG in place. In parallel we followed up on a group of 10 neurological patients who have undergone a PEG placement to improve the nutrional status and to prevent recurrent chest infections due to ND related silent aspiration. RESULTS: The procedures were performed under sedation with Midazolam and the mean duration was about 7 minutes.Postoperative analgesia was minimal. Refeeding through the tube was initiated 2-4h hours later and the patients were discharged 12-24h after the procedure. Early complications were not observed and later we noted 2 cases of peristomal infections, succesfully managed conservatively. After oncologic surgery we noted 2 (8.69%) pharyngocutaneous fistulas.Conservative care obliterated the fistulas at 6 weeks, maintaining the feeding tube in place. We also compared the results with a group of 27 patients fed through the naso-gastric tube and a group of 20 cases with open gastrotomy tube prophylactically inserted. The 10 neurological patients had varied conditions but degenerative diseases like motor neuron disease (3 cases" 30%) and multiple sclerosis (2 cases -20%) took the lead we encountered one case of peristomal infection and one case of tube blockage resolved by replacement. We evaluated the nutritional status by controling the weight of these patients before and after PEG placement. A mean weight gain of 3.1 kg(range 1.2 a?" 7) was documented. CONCLUSIONS: PEG is a simple minimmaly invasive procedure performed safely under sedation. It takes a very short time and is virtually free of major complications. The requirements of analgesics are minimal. The refeeding is started early and the tube is well tolerated by the patient. PEG has an important role in the conservative healing of pharyngocutaneous fistula.PEG is the procedure of choice for the neurological patients.It prevents weight loss and aspiration pneumonia in patients with neurogenic dysphagia with a low rate of complications. PMID- 26011835 TI - Robotically performed total mesorectal excision for rectal cancer. AB - BACKGROUND: Rectal cancer is an important health problem, due to the increasing number of new cases and the quality of life issues brought forth by surgical treatment in these patients. AIM: The aim of the study was to analyse the results of robotic surgery in the treatment of lower and middle rectal cancer,locations in which TME is performed. MATERIAL AND METHOD: Patients diagnosed with and operated on for rectal cancer by the means of robotic surgery between 2008-2012 at the Fundeni Clinical Institute were retrospectively analysed. RESULTS: A number of 117 patients with rectal cancer were operated on by robotic surgery, of which 79 (67.52%) were submitted to total mesorectal excision (TME). The most frequently performed surgery was low anterior resection, followed by rectal amputation through abdominoperineal approach.Anastomosis fistula was observed in 9 (11.39%) patients. Local recurrence was encountered in 2 (2.53%) of the robotically performed surgeries. CONCLUSIONS: 1. Robotically assisted total mesorectal excision is feasible, safe and can be performed with a small number of complications and a low local recurrence rate; 2. The main advantages are oncological safety and quality of life; 3.Conversion to open surgery is rarely encountered; 4. Protection loop ileostomy existence allows avoiding reintervention in case anastomotic fistula occurs in patients with low anterior resection. 5. Robotic surgery may become gold standard in the surgical treatment of rectal cancer. PMID- 26011836 TI - The configuration of biomolecular markers in cancer of the uterine cervix. Personalized therapy. Monitoring and prognosis. AB - INTRODUCTION: The paper deals with the diagnosis of some aggressive forms of uterine cervix cancers, resistant to radio chemotherapy, using biomolecular markers.For this study, the destruction of tumours in stages II-IIIBis carried out by hyperthermia induced by different sources of energy. The aimed targets are toembed a quick and simple technique of haemostas isused in bleeding uterine cervix tumours associated with acute an aemiain the treatment protocols and to identify biomolecular criteria revealing tumour aggressiveness and treatment response. METHOD: The proposed method consists in radio frequency ablation (RFA) applied touterine cervix bleeding tumours with acute secondary anaemia. Studying 16 patients displaying aggressive cancer forms resistant to radio chemotherapy treated by the above mentioned method, we assessed that the commonly present markers: Ki67, p53 and Bcl-2, may be a substantial indication of such cases. Aggressiveness and treatment resistance was defined based on clinical and paraclinical investigations. RESULTS: RFA haemostasis achieved in approximately 20 m inproved the efficiency of this method. A secondary important effect was local tumour volume decrease, resulting in the improvement of radio-chemotherapy responsiveness. CONCLUSIONS: Once an aggressive and radio-chemotherapy resistant cancer is diagnosed,the quantitative, qualitative and associative presence of the biomolecular markers mentioned herein before, could influence the personalised treatment attitude (radiofrequency, neoadjuvant chemotherapy), which onthe long term, may increase patient survival and life quality improvement. PMID- 26011838 TI - The Influence of NBI Vision Over the First Follow-up Cystoscopy Outcomes in Newly Diagnosed NMIBC Patients. AB - BACKGROUND: A retrospective study was aimed to establish the eventual impact of narrow band imaging (NBI) cystos copy over the short term residual tumorsa?? rate determined during the first follow-up endoscopic control in newly determined non muscle invasive bladder cancer (NMIBC) cases. METHODS: 68 patients were found with NMIBC by means of both white light cystoscopy (WLC) and NBI. A follow-up using both investigation modalities was performed at 3 months from the initial procedure in 67 cases (one was lost from follow-up). RESULTS concerning the short termer currences were retrospectively compared to those obtain ending a similar series of 67 patients previously diagnosed and treated by means of classical WLC and resection only. RESULTS: The short term residual tumorsa?? rate established during the first follow-up cystoscopy was lower in the study group initially benefiting from the NBI mode by comparison to the WLC control series (4.5% versus 11.9%). When drawing a parallel with the tumor map location outlined during the initial procedure, the most important differences were emphasized concerning other site recurrences (3%versus 8.95%). CONCLUSIONS: NBI cystoscopy and resection displayed a substantially favorable influence over the short termoncologic outcome in newly diagnosed NMIBC cases when compared to the standard protocol. ABBREVIATIONS: NBI a?" narrow band imaging; NMIBC a?"non muscle invasive bladder cancer; WLC a?" white light cystoscopy; TURBT a?" transurethral resection of bladdertumors; CIS a?" carcinoma in situ. PMID- 26011837 TI - Birth Weight, Compromised Bowel and Sepsis are the Main Variables Significantly Influencing Outcome in Gastroschisis. AB - BACKGROUND: The survival rate for gastroschisis has improved to more than 90% in the developed countries, but increased mortality, morbidity, consequent long hospitalisation and high costs are the rule in Romania. METHODS: Analytic retrospective study of all patients with gastroschisis treated at our department between 1990 and 2012. The study protocol included: demographic data, antenatal diagnosis, prematurity, mode of delivery, birth weight,associated anomalies, time to surgery, presence of compromised bowel, type of repair, post-operative complications, time to full enteral feeding, length of hospitalisation, mortality. RESULTS: 115 newborns with gastroschisis were treated during 23 years. Antenatal diagnosis was made only in 13 cases ata mean gestational age of 25 weeks. Delivery was vaginal in 80.8%. Associated malformations were present in 47 patients. Twenty-four patients had complex gastroschisis.Primary repair was done in 90 cases (79%) and in 24 patients a silo was used. Overall survival was only 29.8%, the main cause of death being severe sepsis with multiple organ failure(61.4%) and bronchopneumonia (52.6%). The rate of complications associated with closure, needing reintervention was 19.3%. CONCLUSIONS: Analysis of risk factors by logistic regression showed that low birth weight increased the risk of postoperative complications 17.4 times, sepsis increased the risk of complicated postoperative course 12.2 times, and the presence of compromised intestinal loops (complex gastroschisis) 5.5 times. PMID- 26011839 TI - A posterior approach pancreaticoduodenectomy with portal vein resection in a large adenocarcinoma of the uncinate process of the pancreas - case report. AB - A portal vein invasion is no longer a contraindication for resection in pancreatic cancer, but increased morbidity and mortality rates can be encountered. Hereby it is presented the case of a patient diagnosed with a large adenocarcinoma of the uncinate process of the pancreas, who underwent aposterior approach pancreaticoduodenectomy, with en bloctang ential resection of the portal vein, and total mesopan creasexcision. A posterior approach allows a negative resection margins pancreaticoduodenectomy, with a good local control of the disease, despite the in creas. PMID- 26011840 TI - Massive intraoperative bleeding after laparoscopic assisted abdominoperineal resection: a case report and systematic review of the literature. AB - INTRODUCTION: The laparoscopic-assisted abdominoperineal resection (LAPR) has been proved to be associated with a shorter postoperative recovery, with equivalent oncological results and similar survival when compared with conventional open surgery, for patients with low rectal cancer. METHOD: Case report of a massive intraoperative bleeding during LAPR and systematic review of the English language literature, using PubMed Medline, ISI Thopmson, OVID and EMBASE databases. RESULTS: 58 years old patient admitted in emergency setting or rectal bleeding. Rectal examination revealed a protruding,frail tumor, located 2 cm from the anal verge. Total colono scopy revealed an infiltrative, protruding tumor, situated at 2 cm from the anal verge, with a 5 cm cranial extension,without any additional colonic lesions. Computed Tomography showed a 4,5 cm circumferential rectal wall thickening, without any enlarged mesorectal or abdominal lymph nodes. The patient was transported to operating room for a LAPR. During final hemostasis, at the level of perineal surgical wound, an acute massive bleeding occurred from the presacral vessels with severe blood loss. This bleeding couldnot be managed laparo scopicaly and conversion to laparotomywas decided, with pelvic packing. At 48 hours after the initial surgical approach, the tamponing packs were removed, without signs of active bleeding. There were applied haemostatic agents and the perineal wound was sutured, without further rbleeding during in-hospital stay. CONCLUSIONS: A rapid and effective control of the presacral bleeding is mandatory to prevent a fatal outcome. Pelvic packing remains a life-saving procedure and the treatment of choice in severe cases. PMID- 26011841 TI - Carcinoid tumor of the cecum presenting with acute appendicitis: a case report. AB - BACKGROUND: Acute appendicitis is the most common cause of acute abdomen. Carcinoid tumor of the appendix is a rare incidental finding that can present with the clinical picture of acute appendicitis. CASE REPORT: During open surgery for acute appendicitis, a 3 cm solid mass, not noticed externally, was palpated at the base of the appendix. The mass and the appendix were excised by en-bloc wedge resection. The histopathological examination of the lesion revealed carcinoid tumor. CONCLUSION: The aim of this presentation is to remind that neoplasms of the appendix may, although rarely, present the clinical picture of acute appendicitis, and to highlight that they, particularly those located at the base of the appendix and in cecum, may be overlooked during laparoscopy. The importance of preoperative computerized tomography ins uch cases has to be underlined. PMID- 26011842 TI - Colonic stenosis post-necrotizing enterocolitis in term newborn with acquired cytomegalovirus infection. AB - Necrotizing enterocolitis is a gastrointestinal emergency typical of premature infants. Intestinal strictures infrequently complicate medical or surgical treatment of necrotizing enterocolitis. Postnatal cytomegalovirus infection with gastrointestinal linvolvement has occasionally been described in subjects with necrotizing enterocolitis. We report the case of a full term infant presenting necrotizing enterocolitis, acquired cytomegalovirus infection and post necrotizing enterocolitis colonic stricture.List of abbreviations: necrotizing enterocolitis = NEC,cytomegalovirus = CMV. PMID- 26011843 TI - Surgical Difficulties in a Case of Left Ophthalmic Artery Ruptured Aneurysm Associated with Right ICA hypoplasia - Case Report. AB - The authors present a rare case of a ruptured left ophthalmic artery aneurysm associated with right ICA hypoplasia in a 49 year old female. The particularity of the case lies in the fact that the patient had a hypoplastic right ICA which was associated with an intracranial aneurysm. In this case we present,surgery was mandatory as it represented the patient'??s only chance for a favorable outcome, given the lack of an adequate team specialized in endovascular coiling. Unlike many neurosurgical centers in Western Europe and the US where endovascular approaches have overtaken microsurgery, in Romania open microsurgery is frequently performed as it allows neurosurgeons to perfectly control the environment in which they operate and minimizes possible complications of coiling or stenting which become more and more frequent in other countries. PMID- 26011844 TI - Thromboangiitis obliterans - case report. AB - Thromboangiitis obliterans (Buerger'??s disease) represents an inflammatory disease of limbs'?? small arteries and veins causing vascular thrombosis, and partial or total obstruction. It affects mostly male gender aged 40 years old. The peculiarity of our case is underlined by presenting a 62 years, chronic tobacco user and not compliant female patient known with thromb oangiitisobliterans for almost 15 years. The arteriographic and clinical features with concomitant and sever affected upper and lower limbs are highly suggestive, emphasizing the possibility of Buerger'??s disease development even in female patients. PMID- 26011845 TI - CREDVW-Linked Polymeric Micelles As a Targeting Gene Transfer Vector for Selective Transfection and Proliferation of Endothelial Cells. AB - Nowadays, gene transfer technology has been widely used to promote endothelialization of artificial vascular grafts. However, the lack of gene vectors with low cytotoxicity and targeting function still remains a pressing challenge. Herein, polyethylenimine (PEI, 1.8 kDa or 10 kDa) was conjugated to an amphiphilic and biodegradable diblock copolymer poly(ethylene glycol)-b poly(lactide-co-glycolide) (mPEG-b-PLGA) to prepare mPEG-b-PLGA-g-PEI copolymers with the aim to develop gene vectors with low cytotoxicity while high transfection efficiency. The micelles were prepared from mPEG-b-PLGA-g-PEI copolymers by self-assembly method. Furthermore, Cys-Arg-Glu-Asp-Val-Trp (CREDVW) peptide was linked to micelle surface to enable the micelles with special recognition for endothelial cells (ECs). In addition, pEGFP-ZNF580 plasmids were condensed into these CREDVW-linked micelles to enhance the proliferation of ECs. These CREDVW-linked micelle/pEGFP-ZNF580 complexes exhibited low cytotoxicity by MTT assay. The cell transfection results demonstrated that pEGFP-ZNF580 could be transferred into ECs efficiently by these micelles. The results of Western blot analysis showed that the relative ZNF580 protein level in transfected ECs increased to 76.9%. The rapid migration of transfected ECs can be verified by wound healing assay. These results indicated that CREDVW-linked micelles could be a suitable gene transfer vector with low cytotoxicity and high transfection efficiency, which has great potential for rapid endothelialization of artificial blood vessels. PMID- 26011846 TI - Surgical innovation: When do I see it in my operating room? PMID- 26011848 TI - Endoscopy training in Canadian general surgery residency programs. AB - Currently, general surgeons provide about 50% of endoscopy services across Canada and an even greater proportion outside large urban centres. It is essential that endoscopy remain a core component of general surgery practice and a core competency of general surgery residency training. The Canadian Association of General Surgeons Residents Committee supports the position that quality endoscopy training for all Canadian general surgery residents is in the best interest of the Canadian public. However, the means by which quality endoscopy training is achieved has not been defined at a national level. Endoscopy training in Canadian general surgery residency programs requires standardization across the country and improved measurement to ensure that competency and basic credentialing requirements are met. PMID- 26011849 TI - A tribute to Dr. Normand Belliveau. PMID- 26011850 TI - To CT or not to CT? The influence of computed tomography on the diagnosis of appendicitis in obese pediatric patients. AB - BACKGROUND: Appendicitis is a common pediatric query. However, obesity often results in nondiagnostic ultrasounds and increased likelihood of abdominal computed tomography (CT). Concern regarding radiation exposure led the Canadian Association of Radiologists to recommend foregoing CT when ultrasounds are nondiagnostic and clinical suspicion is high. We evaluated this recommendation by quantifying the influence of CT on the diagnosis of pediatric appendicitis. METHODS: We performed a 2-year retrospective case series of children presenting with suspected appendicitis. We stratified patients by weight (obese v. nonobese) and pediatric appendicitis score (PAS) and examined how often they received abdominal CT, why they received it, and its influence on diagnosis. RESULTS: Of 223 patients (84 obese, 139 nonobese), 54 received CT. Obese patients received CTs more frequently than nonobese patients (29% v. 22%). The most common reason for CT was a nondiagnostic ultrasound (75% in obese, 80% in nonobese patients). Sixty-five percent of CTs obtained after nondiagnostic ultrasounds confirmed the initial diagnosis, but the rates were 80% and 50%, respectively, when only obese and only nonobese patients were considered. Obese patients were 4 times more likely to have a CT confirming their initial appendicitis diagnosis. CONCLUSION: Because obese patients are more likely than nonobese patients to have a CT that confirms appendicitis, when treating an obese pediatric patient with suspected appendicitis and a nondiagnostic ultrasound, surgeons with a high clinical suspicion should strongly consider foregoing CT and proceeding with treatment. PMID- 26011851 TI - Evaluation of pilot experience with robotic-assisted proctectomy and coloanal anastomosis for rectal cancer. AB - BACKGROUND: Robotic-assisted proctectomy with coloanal anastomosis (RPCA) is an innovative technique of pelvic dissection for low rectal cancer. Our objective was to evaluate our pilot experience with this procedure compared with open proctectomy with coloanal anastomosis (OPCA). METHODS: We performed a retrospective 5-year review of all consecutive cases of RPCA and OPCA performed at our institute. We focused on tumour characteristics, quality of surgery, analgesic requirements, average length of hospital stay (LOS), complications and long-term outcomes. RESULTS: Three patients underwent RPCA and 25 had OPCA. The average duration of surgery was similar (288 min for RPCA v. 285 min for OPCA). Four patients in the OPCA group had positive or very close margins, and 2 had a mesorectal defect less than 5 mm. The average LOS was 6.66 and 9.29 days in the RPCA and OPCA groups, respectively, and the average duration of epidural or patient-controlled anesthesia was 2.67 and 5.16 days, respectively. We did not perform a statistical comparison because of the discordant size and sex distribution between the groups. There were no perioperative complications in the RPCA group, and all patients had negative margins and adequate lymph node retrievals with no long-term complications or recurrence recorded so far. CONCLUSION: Our very early experience with RPCA is quite encouraging, suggesting that it is a safe alternative to OPCA with a similar duration and the added benefits of a minimally invasive procedure, including decreased LOS and reduced postoperative analgesic requirements. PMID- 26011852 TI - Long-term results of cruciate-retaining total knee replacement in patients with rheumatoid arthritis: a minimum 15-year review. AB - BACKGROUND: There is controversy about whether to retain or excise the posterior cruciate ligament in rheumatoid knees because attenuation of the ligament is often present in this subgroup of patients. We reviewed more than 15 years of results of cruciate-retaining total knee replacements (TKRs) in patients with rheumatoid arthritis. METHODS: We reviewed patients' charts and radiographs to evaluate knee range of motion and flexion contractures, component loosening and osteolysis at the bone-cement interface. Our primary outcome was revision of a femoral or tibial component for any reason, and the secondary outcome was revision for any reason and periprosthetic fracture during the follow-up period. RESULTS: Our study included 112 patients (7 men, 105 women, 176 knees). Their mean age was 49.3 (range 33-64) years. Twenty-one patients died and 16 were lost to follow-up, leaving 75 patients (119 knees) with a minimum follow-up of 15 (mean 16.1) years for our analysis. Of these, 61 patients (101 knees) were available for clinical and radiological evaluation at the final follow-up assessment. At a mean of 12.2 (range 6-16) years, revision was necessary in 14 patients (19 knees), including 1 patient with an infection. Eleven patients (11 knees) had periprosthetic fractures at a mean of 11.4 (range 5-14) years after the index operation. The survival rate, with the end point being revision of the femoral or tibial component for any reason, was 98.7% at 10 years and 83.6% at 17 years. The survival rate of revision and periprosthetic fracture was 97.6% at 10 years and 76.9% at 17 years. CONCLUSION: Special attention should be paid to component loosening or periprosthetic fracture after more than 10 years of follow up in this subgroup of patients. PMID- 26011853 TI - Treatment with acetylsalicylic acid prevents short to mid-term radiographic progression of nontraumatic osteonecrosis of the femoral head: a pilot study. AB - BACKGROUND: Nontraumatic osteonecrosis of the femoral head (ONFH) is a progressive disease in young adults producing substantial morbidity and frequently resulting in total hip arthroplasty. Although hip-preserving surgical procedures represent the current mainstay of treatment for early disease, medical therapies targeting specific pathways in the ONFH pathogenesis could help prevent disease progression while producing less morbidity. Acetylsalicylic acid (ASA) is a promising alternative to other therapies for ONFH owing to its anti inflammatory and antithrombotic mechanisms of action and its relatively benign side effect profile. METHODS: We followed a prospective cohort of 10 patients (12 hips) with precollapse ONFH who were given ASA to prevent disease progression. Their outcomes were compared with those of a historic control group taken from the literature. RESULTS: Progression occurred in 1 of 12 (8%) patients taking ASA compared with 30 of 45 (66.6%) controls (p = 0.002) at a mean follow-up of 3.7 years. Patients taking ASA also tended to exhibit decreased femoral head involvement at the end of therapy. CONCLUSION: This hypothesis-generating study leads us to believe that ASA may be a simple and effective treatment option for delaying disease progression in patients with early-stage ONFH. PMID- 26011854 TI - Hair epilation versus surgical excision as primary management of pilonidal disease in the pediatric population. AB - Pilonidal disease is a chronic, acquired inflammatory process of the skin due to entrapped hair at the natal cleft. Reported recurrence rates are as high as 30%, and recurrence has been attributed to persistent hair near the surgical site. Although conservative measures, such as meticulous hair control and improved perineal hygiene, have been shown to be effective, these techniques typically require much effort on behalf of the patient. Laser hair epilation (LE) might solve this issue of poor patient compliance while helping patients to avoid surgical excision. In this article, we discuss recurrence rates of pilonidal disease in children treated with LE versus surgical excision in relation to findings from our institution between 2005 and 2013 as well as patient satisfaction with the treatment method. PMID- 26011856 TI - Canadian spine society 15th annual scientific conference. PMID- 26011855 TI - Hepato-pancreato-biliary surgery workforce in Canada. AB - This article characterizes the Canadian hepato-pancreato-biliary (HPB) surgery workforce (demographics, practice patterns, career satisfaction, education and recruitment plans). This information will serve as a baseline for future national comparisons, allow informed workforce planning and facilitate mathematical modelling of the HPB workforce in Canada. PMID- 26011857 TI - Canadian society of surgical oncology annual general meeting. PMID- 26011859 TI - pH-Responsive Shape Memory Poly(ethylene glycol)-Poly(epsilon-caprolactone)-based Polyurethane/Cellulose Nanocrystals Nanocomposite. AB - In this study, we developed a pH-responsive shape-memory polymer nanocomposite by blending poly(ethylene glycol)-poly(epsilon-caprolactone)-based polyurethane (PECU) with functionalized cellulose nanocrystals (CNCs). CNCs were functionalized with pyridine moieties (CNC-C6H4NO2) through hydroxyl substitution of CNCs with pyridine-4-carbonyl chloride and with carboxyl groups (CNC-CO2H) via 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) mediated surface oxidation, respectively. At a high pH value, the CNC-C6H4NO2 had attractive interactions from the hydrogen bonding between pyridine groups and hydroxyl moieties; at a low pH value, the interactions reduced or disappeared due to the protonation of pyridine groups, which are a Lewis base. The CNC-CO2H responded to pH variation in an opposite manner. The hydrogen bonding interactions of both CNC-C6H4NO2 and CNC-CO2H can be readily disassociated by altering pH values, endowing the pH responsiveness of CNCs. When these functionalized CNCs were added in PECU polymer matrix to form nanocomposite network which was confirmed with rheological measurements, the mechanical properties of PECU were not only obviously improved but also the pH-responsiveness of CNCs could be transferred to the nanocomposite network. The pH-sensitive CNC percolation network in polymer matrix served as the switch units of shape-memory polymers (SMPs). Furthermore, the modified CNC percolation network and polymer molecular chains also had strong hydrogen bonding interactions among hydroxyl, carboxyl, pyridine moieties, and isocyanate groups, which could be formed or destroyed through changing pH value. The shape memory function of the nanocomposite network was only dependent on the pH variation of the environment. Therefore, this pH-responsive shape-memory nancomposite could be potentially developed into a new smart polymer material. PMID- 26011860 TI - Optical and Exciton Dynamical Properties of a Screw-Dislocation-Driven ZnO:Sn Microstructure. AB - Screw dislocation plays a critical role in crystal growth and significantly affects the carrier dynamics process of luminescent semiconductor materials. In this paper, we report a novel screw-dislocation-induced ZnO:Sn hillock microstructure. The detailed growth process and possible formation mechanism of screw dislocation are demonstrated. The temperature-dependent photoluminescence reveals the free exciton recombination emission mechanism of the ZnO:Sn hillock microstructure. By comparing time-resolved photoluminescence spectra with those of two other samples without screw dislocations, it is found that the screw dislocation in the ZnO:Sn microstructures effectively decreases the carrier lifetime. In addition, UV Fabry-Perot lasing action is observed from the ZnO:Sn hillock microstructure, and the numerical simulation of the standing wave pattern and light intensity distribution further confirm the Fabry-Perot lasing mechanism. Therefore, ZnO:Sn can be utilized as a UV laser gain medium, and its optical properties can be modulated by screw dislocation. PMID- 26011858 TI - ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins. AB - The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations. PMID- 26011861 TI - Accelerating Submovement Decomposition With Search-Space Reduction Heuristics. AB - OBJECTIVE: Movements made by healthy individuals can be characterized as superpositions of smooth bell-shaped velocity curves. Decomposing complex movements into these simpler "submovement" building blocks is useful for studying the neural control of movement as well as measuring motor impairment due to neurological injury. APPROACH: One prevalent strategy to submovement decomposition is to formulate it as an optimization problem. This optimization problem is nonconvex and finding an exact solution is computationally burdensome. We build on previous literature that generated approximate solutions to the submovement optimization problem. RESULTS: First, we demonstrate broad conditions on the submovement building block functions that enable the optimization variables to be partitioned into disjoint subsets, allowing for a faster alternating minimization solution. Specifically, the amplitude parameters of a submovement can typically be fit independently of its shape parameters. Second, we develop a method to concentrate the search in regions of high error to make more efficient use of optimization routine iterations. CONCLUSION: Both innovations result in substantial reductions in computation time across multiple nonhuman primate subjects and diverse task conditions. SIGNIFICANCE: These innovations may accelerate analysis of submovements for basic neuroscience and enable real-time applications of submovement decomposition. PMID- 26011862 TI - Flexible 16 Antenna Array for Microwave Breast Cancer Detection. AB - Radar-based microwave imaging has been widely studied for breast cancer detection in recent times. Sensing dielectric property differences of tissues has been studied over a wide frequency band for this application. We design single- and dual-polarization antennas for wireless ultrawideband breast cancer detection systems using an inhomogeneous multilayer model of the human breast. Antennas made from flexible materials are more easily adapted to wearable applications. Miniaturized flexible monopole and spiral antennas on a 50-MUm Kapton polyimide are designed, using a high-frequency structure simulator, to be in contact with biological breast tissues. The proposed antennas are designed to operate in a frequency range of 2-4 GHz (with reflection coefficient (S11) below -10 dB). Measurements show that the flexible antennas have good impedance matching when in different positions with different curvature around the breast. Our miniaturized flexible antennas are 20 mm * 20 mm. Furthermore, two flexible conformal 4 * 4 ultrawideband antenna arrays (single and dual polarization), in a format similar to that of a bra, were developed for a radar-based breast cancer detection system. By using a reflector for the arrays, the penetration of the propagated electromagnetic waves from the antennas into the breast can be improved by factors of 3.3 and 2.6, respectively. PMID- 26011864 TI - Polyp Detection via Imbalanced Learning and Discriminative Feature Learning. AB - Recent achievement of the learning-based classification leads to the noticeable performance improvement in automatic polyp detection. Here, building large good datasets is very crucial for learning a reliable detector. However, it is practically challenging due to the diversity of polyp types, expensive inspection, and labor-intensive labeling tasks. For this reason, the polyp datasets usually tend to be imbalanced, i.e., the number of non-polyp samples is much larger than that of polyp samples, and learning with those imbalanced datasets results in a detector biased toward a non-polyp class. In this paper, we propose a data sampling-based boosting framework to learn an unbiased polyp detector from the imbalanced datasets. In our learning scheme, we learn multiple weak classifiers with the datasets rebalanced by up/down sampling, and generate a polyp detector by combining them. In addition, for enhancing discriminability between polyps and non-polyps that have similar appearances, we propose an effective feature learning method using partial least square analysis, and use it for learning compact and discriminative features. Experimental results using challenging datasets show obvious performance improvement over other detectors. We further prove effectiveness and usefulness of the proposed methods with extensive evaluation. PMID- 26011863 TI - A 3-D Level Set Method for Microwave Breast Imaging. AB - OBJECTIVE: Conventional inverse-scattering algorithms for microwave breast imaging result in moderate resolution images with blurred boundaries between tissues. Recent 2-D numerical microwave imaging studies demonstrate that the use of a level set method preserves dielectric boundaries, resulting in a more accurate, higher resolution reconstruction of the dielectric properties distribution. Previously proposed level set algorithms are computationally expensive, and thus, impractical in 3-D. In this paper, we present a computationally tractable 3-D microwave imaging algorithm based on level sets. METHODS: We reduce the computational cost of the level set method using a Jacobian matrix, rather than an adjoint method, to calculate Frechet derivatives. We demonstrate the feasibility of 3-D imaging using simulated array measurements from 3-D numerical breast phantoms. We evaluate performance by comparing full 3-D reconstructions to those from a conventional microwave imaging technique. We also quantitatively assess the efficacy of our algorithm in evaluating breast density. RESULTS: Our reconstructions of 3-D numerical breast phantoms improve upon those of a conventional microwave imaging technique. The density estimates from our level set algorithm are more accurate than those of the conventional microwave imaging, and the accuracy is greater than that reported for mammographic density estimation. CONCLUSION: Our level set method leads to a feasible level of computational complexity for full 3-D imaging, and reconstructs the heterogeneous dielectric properties distribution of the breast more accurately than conventional microwave imaging methods. SIGNIFICANCE: 3-D microwave breast imaging using a level set method is a promising low-cost, nonionizing alternative to current breast imaging techniques. PMID- 26011865 TI - A Self-Calibrating Radar Sensor System for Measuring Vital Signs. AB - Vital signs (i.e., heartbeat and respiration) are crucial physiological signals that are useful in numerous medical applications. The process of measuring these signals should be simple, reliable, and comfortable for patients. In this paper, a noncontact self-calibrating vital signs monitoring system based on the Doppler radar is presented. The system hardware and software were designed with a four tiered layer structure. To enable accurate vital signs measurement, baseband signals in the radar sensor were modeled and a framework for signal demodulation was proposed. Specifically, a signal model identification method was formulated into a quadratically constrained l1 minimization problem and solved using the upper bound and linear matrix inequality (LMI) relaxations. The performance of the proposed system was comprehensively evaluated using three experimental sets, and the results indicated that this system can be used to effectively measure human vital signs. PMID- 26011866 TI - A Smart Cage With Uniform Wireless Power Distribution in 3D for Enabling Long Term Experiments With Freely Moving Animals. AB - This paper presents a novel experimental chamber with uniform wireless power distribution in 3D for enabling long-term biomedical experiments with small freely moving animal subjects. The implemented power transmission chamber prototype is based on arrays of parallel resonators and multicoil inductive links, to form a novel and highly efficient wireless power transmission system. The power transmitter unit includes several identical resonators enclosed in a scalable array of overlapping square coils which are connected in parallel to provide uniform power distribution along x and y. Moreover, the proposed chamber uses two arrays of primary resonators, facing each other, and connected in parallel to achieve uniform power distribution along the z axis. Each surface includes 9 overlapped coils connected in parallel and implemented into two layers of FR4 printed circuit board. The chamber features a natural power localization mechanism, which simplifies its implementation and ease its operation by avoiding the need for active detection and control mechanisms. A single power surface based on the proposed approach can provide a power transfer efficiency (PTE) of 69% and a power delivered to the load (PDL) of 120 mW, for a separation distance of 4 cm, whereas the complete chamber prototype provides a uniform PTE of 59% and a PDL of 100 mW in 3D, everywhere inside the chamber with a size of 27*27*16 cm(3). PMID- 26011867 TI - On Integration and Validation of a Very Low Complexity ATC UWB System for Muscle Force Transmission. AB - The thresholding of Surface ElectroMyoGraphic (sEMG) signals, i.e., Average Threshold Crossing (ATC) technique, reduces the amount of data to be processed enabling circuit complexity reduction and low power consumption. This paper investigates the lowest level of complexity reachable by an ATC system through measurements and in-vivo experiments with an embedded prototype for wireless force transmission, based on asynchronous Impulse-Radio Ultra Wide Band (IR-UWB). The prototype is composed by the acquisition unit, a wearable PCB 23 * 34 mm, which includes a full custom IC integrating a UWB transmitter (chip active silicon area 0.016 mm(2), 1 mW power consumption), and the receiver. The system is completely asynchronous, it acquires a differential sEMG signal, generates the ATC events and triggers a 3.3 GHz IR-UWB transmission. ATC robustness relaxes filters constraints: two passive first order filters have been implemented, bandwidth from 10 Hz up to 1 kHz. Energy needed for the single pulse generation is 30 pJ while the whole PCB consumes 5.65 mW. The pulses radiated by the acquisition unit TX are received by a short-range and low complexity threshold based 130 nm CMOS IR-UWB receiver with an Ultra Low Power (ULP) baseband unit capable of robustly receiving generic quasi-digital pulse sequences. The acquisition unit have been tested with 10 series of in vivo isometric and isotonic contractions, while the transmission channel with over-the-air and cable measurements obtained with a couple of planar monopole antennas and an integrated 0.004 mm(2) transmitter, the same used for the acquisition unit, with realistic channel conditions. The entire system, acquisition unit and receiver, consumes 15.49 mW. PMID- 26011868 TI - Digital Handwriting with a Finger or a Stylus: A Biomechanical Comparison. AB - In this paper, we present a study concerning the human hand during digital handwriting on a tablet. Two different cases are considered: writing with the finger, and writing with the stylus. We chose an approach based on the biomechanics of the human hand to compare the two different input methods. Performance is evaluated using metrics originally introduced and developed in robotics, such as the manipulability indexes. Analytical results assess that writing with the finger is more suitable for performing large, but not very accurate motions, while writing with the stylus leads to a higher precision and more isotropic motion performance. We then carried out two experiments of digital handwriting to support the approach and contextualize the results. PMID- 26011869 TI - Embedded Hardware-Efficient Real-Time Classification With Cascade Support Vector Machines. AB - Cascade support vector machines (SVMs) are optimized to efficiently handle problems, where the majority of the data belong to one of the two classes, such as image object classification, and hence can provide speedups over monolithic (single) SVM classifiers. However, SVM classification is a computationally demanding task and existing hardware architectures for SVMs only consider monolithic classifiers. This paper proposes the acceleration of cascade SVMs through a hybrid processing hardware architecture optimized for the cascade SVM classification flow, accompanied by a method to reduce the required hardware resources for its implementation, and a method to improve the classification speed utilizing cascade information to further discard data samples. The proposed SVM cascade architecture is implemented on a Spartan-6 field-programmable gate array (FPGA) platform and evaluated for object detection on 800*600 (Super Video Graphics Array) resolution images. The proposed architecture, boosted by a neural network that processes cascade information, achieves a real-time processing rate of 40 frames/s for the benchmark face detection application. Furthermore, the hardware-reduction method results in the utilization of 25% less FPGA custom logic resources and 20% peak power reduction compared with a baseline implementation. PMID- 26011870 TI - Posture and activity recognition and energy expenditure estimation in a wearable platform. AB - The use of wearable sensors coupled with the processing power of mobile phones may be an attractive way to provide real-time feedback about physical activity and energy expenditure (EE). Here, we describe the use of a shoe-based wearable sensor system (SmartShoe) with a mobile phone for real-time recognition of various postures/physical activities and the resulting EE. To deal with processing power and memory limitations of the phone, we compare the use of support vector machines (SVM), multinomial logistic discrimination (MLD), and multilayer perceptrons (MLP) for posture and activity classification followed by activity-branched EE estimation. The algorithms were validated using data from 15 subjects who performed up to 15 different activities of daily living during a 4-h stay in a room calorimeter. MLD and MLP demonstrated activity classification accuracy virtually identical to SVM (~ 95%) while reducing the running time and the memory requirements by a factor of >10 3. Comparison of per-minute EE estimation using activity-branched models resulted in accurate EE prediction (RMSE = 0.78 kcal/min for SVM and MLD activity classification, 0.77 kcal/min for MLP versus RMSE of 0.75 kcal/min for manual annotation). These results suggest that low-power computational algorithms can be successfully used for real-time physical activity monitoring and EE estimation on a wearable platform. PMID- 26011872 TI - Mahalanobis-Taguchi System to Identify Preindicators of Delirium in the ICU. AB - This paper was designed to determine if the Mahalanobis-Taguchi System (MTS) applied to the delirium-evidence-based bundle could detect medical patterns in retrospective datasets. The methodology defined the evidence-based bundle as a multidimensional system that conformed to a parameter diagram. The Mahalanobis distance (MD) was calculated for the retrospective healthy observations and the retrospective unhealthy observations. Signal-to-noise ratios were calculated to determine the relative strength of detection of 23 delirium preindicators. This study discovered that the sufficient variation in the CAM-ICU assessment, the standard for delirium assessment, would benefit from knowledge of how different the MD is from the healthy average. The sensitivity of the detection system was 0.89 with a 95% confidence interval of between 0.84 and 0.92. The specificity of the detection system was 0.93 with a 95% confidence interval between 0.90 and 0.95. The MTS applied to the delirium-evidence-based bundle could detect medical patterns in retrospective datasets. The implication of this paper to a biomedical research is an automated decision support tool for the delirium-evidence-based bundle providing an early detection capability needed today. PMID- 26011871 TI - The effects of cell asynchrony on gene expression levels: analysis and application to Plasmodium falciparum. AB - To investigate the intraerythrocytic developmental cycle of Plasmodium falciparum, time-series gene expression data is commonly measured of infected red blood cells. However, the observed data are usually blurred due to cell asynchrony during experiments. In this paper, the effect of cell asynchrony is investigated by conducting numerical experiments. The simulation results suggest that cell asynchrony has varying effects on different intrinsic expression patterns. Specifically, the intrinsic patterns with high expression around the late life stage are more likely to be affected by cell asynchrony. It is also investigated how the effect of cell asynchrony depends on the experimental conditions. From this analysis, the burst rate r% in infection period and the standard deviation sigma of growth rate are identified to have a strong impact on the blurring due to cell asynchrony. Consequently, it is important to measure these two parameters during biological experiments in order to deblur time-series gene expression data. PMID- 26011873 TI - Plane Localization in 3-D Fetal Neurosonography for Longitudinal Analysis of the Developing Brain. AB - The parasagittal (PS) plane is a 2-D diagnostic plane used routinely in cranial ultrasonography of the neonatal brain. This paper develops a novel approach to find the PS plane in a 3-D fetal ultrasound scan to allow image-based biomarkers to be tracked from prebirth through the first weeks of postbirth life. We propose an accurate plane-finding solution based on regression forests (RF). The method initially localizes the fetal brain and its midline automatically. The midline on several axial slices is used to detect the midsagittal plane, which is used as a constraint in the proposed RF framework to detect the PS plane. The proposed learning algorithm guides the RF learning method in a novel way by: 1) using informative voxels and voxel informative strength as a weighting within the training stage objective function, and 2) introducing regularization of the RF by proposing a geometrical feature within the training stage. Results on clinical data indicate that the new automated method is more reproducible than manual plane finding obtained by two clinicians. PMID- 26011874 TI - Learning With l1 -Regularizer Based on Markov Resampling. AB - Learning with l1 -regularizer has brought about a great deal of research in learning theory community. Previous known results for the learning with l1 regularizer are based on the assumption that samples are independent and identically distributed (i.i.d.), and the best obtained learning rate for the l1 regularization type algorithms is O(1/?m) , where m is the samples size. This paper goes beyond the classic i.i.d. framework and investigates the generalization performance of least square regression with l1 -regularizer ( l1 LSR) based on uniformly ergodic Markov chain (u.e.M.c) samples. On the theoretical side, we prove that the learning rate of l1 -LSR for u.e.M.c samples l1 -LSR(M) is with the order of O(1/m) , which is faster than O(1/?m) for the i.i.d. counterpart. On the practical side, we propose an algorithm based on resampling scheme to generate u.e.M.c samples. We show that the proposed l1 LSR(M) improves on the l1 -LSR(i.i.d.) in generalization error at the low cost of u.e.M.c resampling. PMID- 26011875 TI - System Identification in Presence of Outliers. AB - The outlier detection problem for dynamic systems is formulated as a matrix decomposition problem with low rank and sparse matrices, and further recast as a semidefinite programming problem. A fast algorithm is presented to solve the resulting problem while keeping the solution matrix structure and it can greatly reduce the computational cost over the standard interior-point method. The computational burden is further reduced by proper construction of subsets of the raw data without violating low-rank property of the involved matrix. The proposed method can make exact detection of outliers in case of no or little noise in output observations. In case of significant noise, a novel approach based on under-sampling with averaging is developed to denoise while retaining the saliency of outliers, and so-filtered data enables successful outlier detection with the proposed method while the existing filtering methods fail. Use of recovered "clean" data from the proposed method can give much better parameter estimation compared with that based on the raw data. PMID- 26011876 TI - Robotic Online Path Planning on Point Cloud. AB - This paper deals with the path-planning problem for mobile wheeled- or tracked robot which drive in 2.5-D environments, where the traversable surface is usually considered as a 2-D-manifold embedded in a 3-D ambient space. Specially, we aim at solving the 2.5-D navigation problem using raw point cloud as input. The proposed method is independent of traditional surface parametrization or reconstruction methods, such as a meshing process, which generally has high computational complexity. Instead, we utilize the output of 3-D tensor voting framework on the raw point clouds. The computation of tensor voting is accelerated by optimized implementation on graphics computation unit. Based on the tensor voting results, a novel local Riemannian metric is defined using the saliency components, which helps the modeling of the latent traversable surface. Using the proposed metric, we prove that the geodesic in the 3-D tensor space leads to rational path-planning results by experiments. Compared to traditional methods, the results reveal the advantages of the proposed method in terms of smoothing the robot maneuver while considering the minimum travel distance. PMID- 26011877 TI - Closed-Loop Optogenetic Brain Interface. AB - This paper presents a new approach for implementation of closed-loop brain machine interface algorithms by combining optogenetic neural stimulation with electrocorticography and fluorescence microscopy. We used a new generation of microfabricated electrocorticography (micro-ECoG) devices in which electrode arrays are embedded within an optically transparent biocompatible substrate that provides optical access to the brain tissue during electrophysiology recording. An optical setup was designed capable of projecting arbitrary patterns of light for optogenetic stimulation and performing fluorescence microscopy through the implant. For realization of a closed-loop system using this platform, the feedback can be taken from electrophysiology data or fluorescence imaging. In the closed-loop systems discussed in this paper, the feedback signal was taken from the micro-ECoG. In these algorithms, the electrophysiology data are continuously transferred to a computer and compared with some predefined spatial-temporal patterns of neural activity. The computer which processes the data also readjusts the duration and distribution of optogenetic stimulating pulses to minimize the difference between the recorded activity and the predefined set points so that after a limited period of transient response the recorded activity follows the set points. Details of the system design and implementation of typical closed loop paradigms are discussed in this paper. PMID- 26011878 TI - Tissue-Dependent and Spatially-Variant Positron Range Correction in 3D PET. AB - Positron range (PR) is a significant factor that limits PET image resolution, especially with some radionuclides currently used in clinical and preclinical studies such as (82)Rb, (124)I and (68)Ga. The use of an accurate model of the PR in the image reconstruction may minimize its impact on the image quality. Nevertheless, PR distributions are difficult to model, as they may be different at each voxel and direction, depending on the materials that the positron flies through. Several approximated methods have been proposed, considering only one or several propagating media without taking into account boundaries effects. In some regions, like lungs or trachea, these methods may not be accurate enough and yield artifacts. In this work, we present an efficient method to accurately incorporate spatially-variant PR corrections. The method is based on pre computing voxel-dependent PR kernels using a CT or a manually segmented image, and a model of the dependence of the PR on each material derived from Monte Carlo simulations. The images are convoluted with these kernels in the forward projection step of the iterative reconstruction algorithm. This implementation of the algorithm adds a modest overhead to the overall reconstruction time and it obtains artifact-free PR-corrected images, even when the activity is concentrated at tissue boundaries with extreme changes of density. We verified the method with the preclinical Argus PET/CT scanner, but it can be also applied to other scanners and improve the image quality in clinical PET studies using isotopes with large PR. PMID- 26011879 TI - Automatic Segmentation of the Spinal Cord and Spinal Canal Coupled With Vertebral Labeling. AB - Quantifying spinal cord (SC) atrophy in neurodegenerative and traumatic diseases brings important diagnosis and prognosis information for the clinician. We recently developed the PropSeg method, which allows for fast, accurate and automatic segmentation of the SC on different types of MRI contrast (e.g., T1-, T2- and T2(*) -weighted sequences) and any field of view. However, comparing measurements from the SC between subjects is hindered by the lack of a generic coordinate system for the SC. In this paper, we present a new framework combining PropSeg and a vertebral level identification method, thereby enabling direct inter- and intra-subject comparison of SC measurements for large cohort studies as well as for longitudinal studies. Our segmentation method is based on the multi-resolution propagation of tubular deformable models. Coupled with an automatic intervertebral disk identification method, our segmentation pipeline provides quantitative metrics of the SC and spinal canal such as cross-sectional areas and volumes in a generic coordinate system based on vertebral levels. This framework was validated on 17 healthy subjects and on one patient with SC injury against manual segmentation. Results have been compared with an existing active surface method and show high local and global accuracy for both SC and spinal canal (Dice coefficients =0.91 +/- 0.02) segmentation. Having a robust and automatic framework for SC segmentation and vertebral-based normalization opens the door to bias-free measurement of SC atrophy in large cohorts. PMID- 26011880 TI - Full-reference quality assessment of stereoscopic images by learning binocular receptive field properties. AB - Quality assessment of 3D images encounters more challenges than its 2D counterparts. Directly applying 2D image quality metrics is not the solution. In this paper, we propose a new full-reference quality assessment for stereoscopic images by learning binocular receptive field properties to be more in line with human visual perception. To be more specific, in the training phase, we learn a multiscale dictionary from the training database, so that the latent structure of images can be represented as a set of basis vectors. In the quality estimation phase, we compute sparse feature similarity index based on the estimated sparse coefficient vectors by considering their phase difference and amplitude difference, and compute global luminance similarity index by considering luminance changes. The final quality score is obtained by incorporating binocular combination based on sparse energy and sparse complexity. Experimental results on five public 3D image quality assessment databases demonstrate that in comparison with the most related existing methods, the devised algorithm achieves high consistency with subjective assessment. PMID- 26011881 TI - High dynamic range image compression by optimizing tone mapped image quality index. AB - Tone mapping operators (TMOs) aim to compress high dynamic range (HDR) images to low dynamic range (LDR) ones so as to visualize HDR images on standard displays. Most existing TMOs were demonstrated on specific examples without being thoroughly evaluated using well-designed and subject-validated image quality assessment models. A recently proposed tone mapped image quality index (TMQI) made one of the first attempts on objective quality assessment of tone mapped images. Here, we propose a substantially different approach to design TMO. Instead of using any predefined systematic computational structure for tone mapping (such as analytic image transformations and/or explicit contrast/edge enhancement), we directly navigate in the space of all images, searching for the image that optimizes an improved TMQI. In particular, we first improve the two building blocks in TMQI-structural fidelity and statistical naturalness components-leading to a TMQI-II metric. We then propose an iterative algorithm that alternatively improves the structural fidelity and statistical naturalness of the resulting image. Numerical and subjective experiments demonstrate that the proposed algorithm consistently produces better quality tone mapped images even when the initial images of the iteration are created by the most competitive TMOs. Meanwhile, these results also validate the superiority of TMQI-II over TMQI. PMID- 26011882 TI - A practical one-shot multispectral imaging system using a single image sensor. AB - Single-sensor imaging using the Bayer color filter array (CFA) and demosaicking is well established for current compact and low-cost color digital cameras. An extension from the CFA to a multispectral filter array (MSFA) enables us to acquire a multispectral image in one shot without increased size or cost. However, multispectral demosaicking for the MSFA has been a challenging problem because of very sparse sampling of each spectral band in the MSFA. In this paper, we propose a high-performance multispectral demosaicking algorithm, and at the same time, a novel MSFA pattern that is suitable for our proposed algorithm. Our key idea is the use of the guided filter to interpolate each spectral band. To generate an effective guide image, in our proposed MSFA pattern, we maintain the sampling density of the G -band as high as the Bayer CFA, and we array each spectral band so that an adaptive kernel can be estimated directly from raw MSFA data. Given these two advantages, we effectively generate the guide image from the most densely sampled G -band using the adaptive kernel. In the experiments, we demonstrate that our proposed algorithm with our proposed MSFA pattern outperforms existing algorithms and provides better color fidelity compared with a conventional color imaging system with the Bayer CFA. We also show some real applications using a multispectral camera prototype we built. PMID- 26011884 TI - Video inpainting with short-term windows: application to object removal and error concealment. AB - In this paper, we propose a new video inpainting method which applies to both static or free-moving camera videos. The method can be used for object removal, error concealment, and background reconstruction applications. To limit the computational time, a frame is inpainted by considering a small number of neighboring pictures which are grouped into a group of pictures (GoP). More specifically, to inpaint a frame, the method starts by aligning all the frames of the GoP. This is achieved by a region-based homography computation method which allows us to strengthen the spatial consistency of aligned frames. Then, from the stack of aligned frames, an energy function based on both spatial and temporal coherency terms is globally minimized. This energy function is efficient enough to provide high quality results even when the number of pictures in the GoP is rather small, e.g. 20 neighboring frames. This drastically reduces the algorithm complexity and makes the approach well suited for near real-time video editing applications as well as for loss concealment applications. Experiments with several challenging video sequences show that the proposed method provides visually pleasing results for object removal, error concealment, and background reconstruction context. PMID- 26011883 TI - Template-free wavelet-based detection of local symmetries. AB - Our goal is to detect and group different kinds of local symmetries in images in a scale- and rotation-invariant way. We propose an efficient wavelet-based method to determine the order of local symmetry at each location. Our algorithm relies on circular harmonic wavelets which are used to generate steerable wavelet channels corresponding to different symmetry orders. To give a measure of local symmetry, we use the F-test to examine the distribution of the energy across different channels. We provide experimental results on synthetic images, biological micrographs, and electron-microscopy images to demonstrate the performance of the algorithm. PMID- 26011885 TI - Relevance Preserving Projection and Ranking for Web Image Search Reranking. AB - An image search reranking (ISR) technique aims at refining text-based search results by mining images' visual content. Feature extraction and ranking function design are two key steps in ISR. Inspired by the idea of hypersphere in one-class classification, this paper proposes a feature extraction algorithm named hypersphere-based relevance preserving projection (HRPP) and a ranking function called hypersphere-based rank (H-Rank). Specifically, an HRPP is a spectral embedding algorithm to transform an original high-dimensional feature space into an intrinsically low-dimensional hypersphere space by preserving the manifold structure and a relevance relationship among the images. An H-Rank is a simple but effective ranking algorithm to sort the images by their distances to the hypersphere center. Moreover, to capture the user's intent with minimum human interaction, a reversed k-nearest neighbor (KNN) algorithm is proposed, which harvests enough pseudorelevant images by requiring that the user gives only one click on the initially searched images. The HRPP method with reversed KNN is named one-click-based HRPP (OC-HRPP). Finally, an OC-HRPP algorithm and the H Rank algorithm form a new ISR method, H-reranking. Extensive experimental results on three large real-world data sets show that the proposed algorithms are effective. Moreover, the fact that only one relevant image is required to be labeled makes it has a strong practical significance. PMID- 26011887 TI - Clinical Documents Clustering Based on Medication/Symptom Names Using Multi-View Nonnegative Matrix Factorization. AB - Clinical documents are rich free-text data sources containing valuable medication and symptom information, which have a great potential to improve health care. In this paper, we build an integrating system for extracting medication names and symptom names from clinical notes. Then we apply nonnegative matrix factorization (NMF) and multi-view NMF to cluster clinical notes into meaningful clusters based on sample-feature matrices. Our experimental results show that multi-view NMF is a preferable method for clinical document clustering. Moreover, we find that using extracted medication/symptom names to cluster clinical documents outperforms just using words. PMID- 26011888 TI - The Classification of HEp-2 Cell Patterns Using Fractal Descriptor. AB - Indirect immunofluorescence (IIF) with HEp-2 cells is considered as a powerful, sensitive and comprehensive technique for analyzing antinuclear autoantibodies (ANAs). The automatic classification of the HEp-2 cell images from IIF has played an important role in diagnosis. Fractal dimension can be used on the analysis of image representing and also on the property quantification like texture complexity and spatial occupation. In this study, we apply the fractal theory in the application of HEp-2 cell staining pattern classification, utilizing fractal descriptor firstly in the HEp-2 cell pattern classification with the help of morphological descriptor and pixel difference descriptor. The method is applied to the data set of MIVIA and uses the support vector machine (SVM) classifier. Experimental results show that the fractal descriptor combining with morphological descriptor and pixel difference descriptor makes the precisions of six patterns more stable, all above 50%, achieving 67.17% overall accuracy at best with relatively simple feature vectors. PMID- 26011886 TI - A Correlation-Based Framework for Evaluating Postural Control Stochastic Dynamics. AB - The inability to maintain balance during varying postural control conditions can lead to falls, a significant cause of mortality and serious injury among older adults. However, our understanding of the underlying dynamical and stochastic processes in human postural control have not been fully explored. To further our understanding of the underlying dynamical processes, we examine a novel conceptual framework for studying human postural control using the center of pressure (COP) velocity autocorrelation function (COP-VAF) and compare its results to Stabilogram Diffusion Analysis (SDA). Eleven healthy young participants were studied under quiet unipedal or bipedal standing conditions with eyes either opened or closed. COP trajectories were analyzed using both the traditional posturographic measure SDA and the proposed COP-VAF. It is shown that the COP-VAF leads to repeatable, physiologically meaningful measures that distinguish postural control differences in unipedal versus bipedal stance trials with and without vision in healthy individuals. More specifically, both a unipedal stance and lack of visual feedback increased initial values of the COP VAF, magnitude of the first minimum, and diffusion coefficient, particularly in contrast to bipedal stance trials with open eyes. Use of a stochastic postural control model, based on an Ornstein-Uhlenbeck process that accounts for natural weight-shifts, suggests an increase in spring constant and decreased damping coefficient when fitted to experimental data. This work suggests that we can further extend our understanding of the underlying mechanisms behind postural control in quiet stance under varying stance conditions using the COP-VAF and provides a tool for quantifying future neurorehabilitative interventions. PMID- 26011889 TI - Discovering Variable-Length Patterns in Protein Sequences for Protein-Protein Interaction Prediction. AB - To predict Protein-Protein Interactions (PPIs), there have recently been some attempts to use computational approaches and among them, sequence-based approaches are often preferred over other kinds of approaches as they do not require prior knowledge about proteins to perform their tasks. However, in deciding if two proteins may interact with each other, existing sequence-based approaches consider only fixed-length segments. We believe that if segments of variable-length can also be considered, interactions between proteins can be more accurately predicted. To consider variable-length segments for PPI predictions, we have developed a VLASPD algorithm. Given a database of protein sequences, VLASPD performs its tasks in several steps. The protein database is first searched to identify frequent sequence segments (FSSs) of different length. The different combinations of the presence and absence of these FSSs are then used to form different associative sequential patterns (ASPs). Based on a statistical measure, the ASPs that occur significantly frequently among proteins in the training set are then identified as significant associative sequential patterns (SASPs). If an SASP is found in a protein pair, it can be considered as providing some evidence to support or refute the existence of an interaction relationship between the protein pairs. The amount of evidence provided are then quantified with an information theoretic measure. How likely two proteins may interact with each other are then decided by the total amount of evidence provided by the SASPs found in the protein pairs. To test the effectiveness of VLASPD, we used several sets of real data. The experimental results show that VLASPD can be a promising approach for PPI prediction. The VLASPD is made available for use and testing at http://www.comp.polyu.edu.hk/~cslhu/resources/vlaspd/. PMID- 26011890 TI - Numerical Study of Pillar Shapes in Deterministic Lateral Displacement Microfluidic Arrays for Spherical Particle Separation. AB - Deterministic lateral displacement (DLD) arrays containing shaped pillars have been found to be more effective in biomedical sample separation. This study aims to numerically investigate the interplay between particles and microfluidic arrays, and to find out the key factors in determining the critical size of a DLD device with shaped pillars. A new formula is thus proposed to estimate the critical size for spherical particle separation in this kind of new DLD microfluidic arrays. The simulation results show that both rectangular and I shaped arrays have considerably smaller critical sizes. The ratio of sub-channel widths is also found to play an important role in reducing the critical sizes. This paves a valuable way toward designing high-performance DLD microfluidic arrays. PMID- 26011891 TI - Investigation of Various Types of Nanorods as Sensitive Surface-Enhanced Raman Scattering Substrates. AB - Core-shell-isolated nanorods can be used to amplify the signals of target cancer antigen molecules. Recent research has suggested that these nanorods feature surface-enhanced Raman scattering (SERS) signals superior to those of nanoparticles. In this study, nanorod geometrical models based on core-shell isolated nanocapsule morphology were employed to analyze the scattered power density in three-dimensional spaces. Superior to the conventional cross-section field analysis method, the average scattered power density based method in this presentation could verify the enhancement effects from all possible positions on the nanorod surface. The numerical results in this study were also compared with the experimental results described in the literature. The resonance scattering power reached the maximal value when the radius of the Au/SiO2 and Ag/SiO2 nanorods was 20 nm. At an incident wavelength of 751 nm, the Au/SiO2 and Au/Al2O3 nanorods achieved maximal scattered power density when spacing d=30 nm. Conversely, the Au/TiO2 nanorods achieved maximum scattered power density when spacing d=40 nm. When the core was Au, nanorods with shell thickness h of 1 nm produced a resonant scattering intensity same as it by the nanorods without shells. The numerical results also indicated a stronger resonance peak when the incident ray illuminated the major-axis plane of the Au/SiO2 nanorods. When the incident ray illuminated the curvature plane of the nanorods, the resonance wavelength clearly shifted toward the UV wavelength range. The four Au/SiO2 nanorods with symmetric arrangement achieved the highest resonance peak when the nanorod spacing was 30 nm. This presentation can serve as a key reference for the design of core-shell-isolated nanorods as highly sensitive SERS substrates. PMID- 26011892 TI - A Review of Wavelet Transform Time-Frequency Methods for NIRS-Based Analysis of Cerebral Autoregulation. AB - Near-infrared spectroscopy (NIRS) has been proposed as a suitable technique for the analysis of cerebral autoregulation as it provides a simpler acquisition methodology and more artifact-free signal. A number of sophisticated wavelet transform methods have recently emerged to quantify the cerebral autoregulation mechanism using NIRS and blood pressure signals. These provide an enhanced partitioning of signal information via the time-frequency plane, which facilitates improved extraction of the components of interest. This area is reviewed, and enhancements to this form of analysis are suggested. PMID- 26011893 TI - A Nonnegative Latent Factor Model for Large-Scale Sparse Matrices in Recommender Systems via Alternating Direction Method. AB - Nonnegative matrix factorization (NMF)-based models possess fine representativeness of a target matrix, which is critically important in collaborative filtering (CF)-based recommender systems. However, current NMF based CF recommenders suffer from the problem of high computational and storage complexity, as well as slow convergence rate, which prevents them from industrial usage in context of big data. To address these issues, this paper proposes an alternating direction method (ADM)-based nonnegative latent factor (ANLF) model. The main idea is to implement the ADM-based optimization with regard to each single feature, to obtain high convergence rate as well as low complexity. Both computational and storage costs of ANLF are linear with the size of given data in the target matrix, which ensures high efficiency when dealing with extremely sparse matrices usually seen in CF problems. As demonstrated by the experiments on large, real data sets, ANLF also ensures fast convergence and high prediction accuracy, as well as the maintenance of nonnegativity constraints. Moreover, it is simple and easy to implement for real applications of learning systems. PMID- 26011894 TI - A Simple Method for Solving the SVM Regularization Path for Semidefinite Kernels. AB - The support vector machine (SVM) remains a popular classifier for its excellent generalization performance and applicability of kernel methods; however, it still requires tuning of a regularization parameter, C , to achieve optimal performance. Regularization path-following algorithms efficiently solve the solution at all possible values of the regularization parameter relying on the fact that the SVM solution is piece-wise linear in C . The SVMPath originally introduced by Hastie et al., while representing a significant theoretical contribution, does not work with semidefinite kernels. Ong et al. introduce a method improved SVMPath (ISVMP) algorithm, which addresses the semidefinite kernel; however, Singular Value Decomposition or QR factorizations are required, and a linear programming solver is required to find the next C value at each iteration. We introduce a simple implementation of the path-following algorithm that automatically handles semidefinite kernels without requiring a method to detect singular matrices nor requiring specialized factorizations or an external solver. We provide theoretical results showing how this method resolves issues associated with the semidefinite kernel as well as discuss, in detail, the potential sources of degeneracy and cycling and how cycling is resolved. Moreover, we introduce an initialization method for unequal class sizes based upon artificial variables that work within the context of the existing path following algorithm and do not require an external solver. Experiments compare performance with the ISVMP algorithm introduced by Ong et al. and show that the proposed method is competitive in terms of training time while also maintaining high accuracy. PMID- 26011895 TI - Storage Free Smart Energy Management for Frequency Control in a Diesel-PV-Fuel Cell-Based Hybrid AC Microgrid. AB - This paper proposes a novel, smart energy management scheme for a microgrid, consisting of a diesel generator and power electronic converter interfaced renewable energy-based generators, such as photovoltaic (PV) and fuel cell, for frequency regulation without any storage. In the proposed strategy, output of the PV is controlled in coordination with other generators using neurofuzzy controller, either only for transient frequency regulation or for both transient and steady-state frequency regulation, depending on the load demand, thereby eliminating the huge storage requirements. The option of demand response control is also explored along with the generation control. For accurate and quick tracking of maximum power point and its associated reserve power from the PV generator, this paper also proposes a novel adaptive-predictor-corrector-based tracking mechanism. PMID- 26011896 TI - Data Generators for Learning Systems Based on RBF Networks. AB - There are plenty of problems where the data available is scarce and expensive. We propose a generator of semiartificial data with similar properties to the original data, which enables the development and testing of different data mining algorithms and the optimization of their parameters. The generated data allow large-scale experimentation and simulations without danger of overfitting. The proposed generator is based on radial basis function networks, which learn sets of Gaussian kernels. These Gaussian kernels can be used in a generative mode to generate new data from the same distributions. To assess the quality of the generated data, we evaluated the statistical properties of the generated data, structural similarity, and predictive similarity using supervised and unsupervised learning techniques. To determine usability of the proposed generator we conducted a large scale evaluation using 51 data sets. The results show a considerable similarity between the original and generated data and indicate that the method can be useful in several development and simulation scenarios. We analyze possible improvements in the classification performance by adding different amounts of the generated data to the training set, performance on high-dimensional data sets, and conditions when the proposed approach is successful. PMID- 26011897 TI - Tree Ensembles on the Induced Discrete Space. AB - Decision trees are widely used predictive models in machine learning. Recently, K -tree is proposed, where the original discrete feature space is expanded by generating all orderings of values of k discrete attributes and these orderings are used as the new attributes in decision tree induction. Although K -tree performs significantly better than the proper one, their exponential time complexity can prohibit their use. In this brief, we propose K -forest, an extension of random forest, where a subset of features is selected randomly from the induced discrete space. Simulation results on 17 data sets show that the novel ensemble classifier has significantly lower error rate compared with the random forest based on the original feature space. PMID- 26011898 TI - Application of the Kalman Filter for Faster Strong Coupling of Cardiovascular Simulations. AB - In this paper, we propose a method for reducing the computational cost of strong coupling for multiscale cardiovascular simulation models. In such a model, individual model modules of myocardial cell, left ventricular structural dynamics, and circulatory hemodynamics are coupled. The strong coupling method enables stable and accurate calculation, but requires iterative calculations which are computationally expensive. The iterative calculations can be reduced, if accurate initial approximations are made available by predictors. The proposed method uses the Kalman filter to estimate accurate predictions by filtering out noise included in past values. The performance of the proposed method was assessed with an application to a previously published multiscale cardiovascular model. The proposed method reduced the number of iterations by 90% and 62% compared with no prediction and Lagrange extrapolation, respectively. Even when the parameters were varied and number of elements of the left ventricular finite element model increased, the number of iterations required by the proposed method was significantly lower than that without prediction. These results indicate the robustness, scalability, and validity of the proposed method. PMID- 26011899 TI - A Fully Automatic Method for Gridding Bright Field Images of Bead-Based Microarrays. AB - In this paper, a fully automatic method for gridding bright field images of bead based microarrays is proposed. There have been numerous techniques developed for gridding fluorescence images of traditional spotted microarrays but to our best knowledge, no algorithm has yet been developed for gridding bright field images of bead-based microarrays. The proposed gridding method is designed for automatic quality control during fabrication and assembly of bead-based microarrays. The method begins by estimating the grid parameters using an evolutionary algorithm. This is followed by a grid-fitting step that rigidly aligns an ideal grid with the image. Finally, a grid refinement step deforms the ideal grid to better fit the image. The grid fitting and refinement are performed locally and the final grid is a nonlinear (piecewise affine) grid. To deal with extreme corruptions in the image, the initial grid parameter estimation and grid-fitting steps employ robust search techniques. The proposed method does not have any free parameters that need tuning. The method is capable of identifying the grid structure even in the presence of extreme amounts of artifacts and distortions. Evaluation results on a variety of images are presented. PMID- 26011901 TI - Effect of cheese consumption on blood lipids: a systematic review and meta analysis of randomized controlled trials. AB - CONTEXT: Cheese may affect lipids and lipoproteins differently than other high fat dairy foods. OBJECTIVE: The present systematic review and meta-analysis was performed to evaluate randomized controlled trials that examined the effect of cheese consumption compared with another food product on blood lipids and lipoproteins. DATA SOURCES: A systematic literature search of the MEDLINE, Embase, Scopus, CAB Abstracts, the Cochrane Controlled Trials Register, and the clinicaltrials.gov website was performed. STUDY SELECTION: A total of 12 randomized controlled trials (RCTs) were identified that examined the effect of cheese consumption on blood lipids and lipoproteins in healthy adults. DATA EXTRACTION: A meta-analysis of 5 RCTs that compared the effects of hard cheese and butter, both of which had a similar ratio of polyunsaturated fatty acids to saturated fatty acids (P/S ratio), was performed. DATA SYNTHESIS: Compared with butter intake, cheese intake (weighted mean difference: 145.0 g/d) reduced low density lipoprotein cholesterol (LDL-C) by 6.5% (-0.22 mmol/l; 95%CI: -0.29 to 0.14) and high-density lipoprotein cholesterol (HDL-C) by 3.9% (-0.05 mmol/l; 95%CI: -0.09 to -0.02) but had no effect on triglycerides. Compared with intake of tofu or fat-modified cheese, cheese intake increased total cholesterol or LDL C, as was expected on the basis of the P/S ratio of the diets. There was insufficient data to compare intake of cheese with intake of other foods. CONCLUSION: Despite the similar P/S ratios of hard cheese and butter, consumption of hard cheese lowers LDL-C and HDL-C when compared with consumption of butter. Whether these findings can be attributed to calcium, specific types of saturated fatty acids, or the food matrix of cheese warrants further research. . PMID- 26011902 TI - Effects of pediatric cancer and its treatment on nutritional status: a systematic review. AB - CONTEXT: Malnutrition in pediatric cancer is common worldwide, yet its prevalence and effects on clinical outcomes remain unclear. OBJECTIVE: The aim of this review was to evaluate primary research reporting the prevalence of malnutrition in pediatric cancer patients and to assess the effects of pediatric cancer and its treatment on nutritional status. DATA SOURCES: Electronic databases of MEDLINE, CINHAL, and PubMed were searched (January 1990-February 2013). STUDY SELECTION: Studies of patients aged <18 years who were diagnosed with and treated for cancer and for whom measurements of anthropometry were reported and included. The primary outcome was the prevalence of malnutrition (undernutrition and overnutrition), expressed as body mass index (BMI), in children diagnosed with and treated for cancer. DATA EXTRACTION: Evidence was appraised critically by employing the Critical Appraisal Skills Program tool, and data was extracted from original articles. DATA SYNTHESIS: A total of 46 studies were included, most of which were considered to be of low quality on the basis of heterogeneity in both the criteria and the measurements used to define malnutrition. Undernutrition was identified by measuring BMI, weight loss, mid-upper arm circumference, and triceps skinfold thickness, while overnutrition was assessed using BMI. Overall, the prevalence of undernutrition ranged from 0% to 65% and overnutrition from 8% to 78%. Finally, undernutrition in pediatric cancer at diagnosis was associated with poor clinical outcomes in 6 of 9 studies. CONCLUSION: The possibility of a high prevalence of malnutrition in childhood cancer, indicated by the studies reviewed, highlights the need for high-quality, population-based, longitudinal studies using standard criteria to identify malnutrition. PMID- 26011900 TI - Clinical applications of bioactive milk components. AB - Milk represents a unique resource for translational medicine: It contains a rich pool of biologically active molecules with demonstrated clinical benefits. The ongoing characterization of the mechanistic process through which milk components promote development and immunity has revealed numerous milk-derived compounds with potential applications as clinical therapies in infectious and inflammatory disease, cancer, and other conditions. Lactoferrin is an effective antimicrobial and antiviral agent in high-risk patient populations and a potentially potent adjuvant to chemotherapy in lung cancer. Enteric nutrition formulas supplemented with transforming growth factor beta, a milk cytokine, have been shown to promote remission in pediatric Crohn's disease. A number of milk glycans, including human milk oligosaccharides, show promise in preclinical studies as antimicrobial and anti-inflammatory agents. While active preclinical investigations of human milk may soon result in large-scale production of human milk molecules, bovine milk components in many instances represent a practical source of bioactive milk compounds for use in clinical trials. This review summarizes current efforts to translate the compounds derived from human and bovine milk into effective clinical therapies. These efforts suggest a common pathway for the translation of milk-derived compounds into clinical applications. PMID- 26011904 TI - Iron and colorectal cancer: evidence from in vitro and animal studies. AB - Iron is a vital trace element essential for mammalian life. It is involved in numerous biological and cellular processes such as oxygen transport, oxidative phosphorylation, and DNA synthesis, as well as cell cycle progression and growth. Normal and neoplastic cells have similar qualitative requirements for iron. In addition, research shows that iron promotes cancer cell growth. An adequate balance of iron is, therefore, critical for health. In states of iron deficiency, anemia can develop, whereas iron excess increases oxidative stress in body tissues, leading to lipid, protein, and DNA damage via the Fenton reaction, which results in the synthesis of hydroxyl radicals and other oxidants. It is thought that some of these processes are implicated in the pathogenesis of colorectal cancer. This review provides the clinician with an up-to-date summary of the recent advances in this field using established in vitro and animal models. PMID- 26011905 TI - Oral and intestinal sweet and fat tasting: impact of receptor polymorphisms and dietary modulation for metabolic disease. AB - The human body has evolved with a disposition for nutrient storage, allowing for periods of irregular food availability and famine. In contrast, the modern diet is characterized by excessive consumption of fats and sugars, resulting in a surge in the rates of obesity and type 2 diabetes. Although these metabolic disorders arise from a complex interaction of genetic, social, and environmental factors, evidence now points to fundamental changes in nutrient metabolism at the cellular level contributing to the underlying pathology. Taste receptors detect nutrients in the oral cavity and gastrointestinal tract and can influence the hormonal response to nutrients; they may also become maladaptive in conditions of excess fat or sugar consumption. Precise links between taste receptor activity, and downstream effects on energy intake and glycemia are not well defined. This review outlines the candidate taste receptors for carbohydrates and fats in the oral cavity and within the small intestine, highlighting the contributions of underlying genetics (polymorphisms) and sensory challenges (e.g., a high-fat diet) to the development of obesity and type 2 diabetes. PMID- 26011903 TI - Food reward system: current perspectives and future research needs. AB - This article reviews current research and cross-disciplinary perspectives on the neuroscience of food reward in animals and humans, examines the scientific hypothesis of food addiction, discusses methodological and terminology challenges, and identifies knowledge gaps and future research needs. Topics addressed herein include the role of reward and hedonic aspects in the regulation of food intake, neuroanatomy and neurobiology of the reward system in animals and humans, responsivity of the brain reward system to palatable foods and drugs, translation of craving versus addiction, and cognitive control of food reward. The content is based on a workshop held in 2013 by the North American Branch of the International Life Sciences Institute. PMID- 26011909 TI - Nuts and legume seeds for cardiovascular risk reduction: scientific evidence and mechanisms of action. AB - Consumption of tree nuts and legume seeds is associated with a reduction in cardiovascular risk. The reduction in blood lipids and in inflammatory and oxidative processes exhibited by bioactive compounds such as monounsaturated and polyunsaturated fatty acids, fibers, phenolic compounds, tocopherols, phospholipids, carotenoids, some minerals, and arginine, has stimulated research on the mechanisms of action of these substances through distinct experimental approaches. It is, therefore, important to know the metabolic effect of each nut and legume seed or the mixture of them to choose the most suitable nutritional interventions in clinical practice. The aim of this narrative bibliographic review was to investigate the effects of tree nuts and legume seeds on biomarkers of cardiovascular risk, as well as their mechanisms of action with regard to lipid profiles, insulin resistance, arterial pressure, oxidative stress, and inflammation. The findings indicate that a mixture of nuts and legume seeds optimizes the protective effect against cardiovascular risk. PMID- 26011910 TI - Anti-inflammatory effect of anthocyanins via modulation of nuclear factor-kappaB and mitogen-activated protein kinase signaling cascades. AB - Anthocyanins are a group of bioactive compounds present in plant foods. Although they have consistently shown an anti-inflammatory effect both in vitro and in vivo, their mechanisms of action are not fully understood and have only recently begun to be elucidated. The aim of this review is to highlight the anti inflammatory activity of anthocyanins, including their effect on the expression of several genes involved in inflammation. The available evidence suggests that their anti-inflammatory action can be attributed primarily to their antioxidant properties, which result in downregulation of the redox-sensitive nuclear factor kappaB signaling pathway. Other pathways at least partly involved in the inflammatory response, particularly the mitogen-activated protein kinase pathways, also appear to play a role. A discussion is presented on the most effective dose of anthocyanins, the differential contribution of specific compounds, the comparative effects of anthocyanins versus other anti-inflammatory phenolic compounds, and the extent to which the observed biological activities are exerted by anthocyanins themselves or their metabolites. PMID- 26011911 TI - The intestinal glycome and its modulation by diet and nutrition. AB - The human gastrointestinal epithelium is responsible for adequate digestion and absorption of nutrients. It is an immunological interface and highly selective environment that facilitates colonization by commensal bacteria and prohibits adhesion and invasion of pathogenic agents. The epithelial barrier is reinforced by the intestinal glycome, which consists of the vast array of sugar structures and glycoconjugates expressed by cells of the gastrointestinal tract. Aberrant glycosylation is associated with altered responses to enteric infections as well as immune dysregulation. Intestinal glycosylation is susceptible to alteration by genetic, physiological, and pathological states, in addition to modification by nutritional and environmental stimuli. The effects of nutritional influences upon glycan assembly and topology are of particular importance in intestinal barrier reinforcement and homeostasis. For instance, milk contains factors that can alter intestinal glycosylation, which in turn contributes to early immune development and maturation of the newborn intestinal tract. This review focuses on the glycosylation status of intestinal cells and the means by which nutritional factors modulate the expression and presentation of intestinal glycans. PMID- 26011912 TI - Obesity and the gastrointestinal microbiota: a review of associations and mechanisms. AB - The two-way obesity model that considers only the interplay between humans and their environment has been revised to include the gastrointestinal microbiota. Notable perturbations in the bacterial communities in obese individuals have been uncovered. Research is helping to distinguish between the obesogenic mechanisms attributable to diet and those that may be associated with the microbiota. Examples include studies in which transplant of the microbiota from murine models of weight loss (gastric bypass) into germ-free mice resulted in significant weight loss. Several mechanisms have been identified that suggest the microbiota may play a role in obesity development and propagation. There is some evidence from animal and human studies that the microbiota in the obese harvests energy more effectively and may manipulate host gene function leading to increased adiposity, aggravation of inflammatory mechanisms, metabolic endotoxemia, and metabolic dysfunction. Research findings highlight the potential of the microbiota to influence body weight and they allude to its potential therapeutic use in tackling the costly global epidemic of obesity. PMID- 26011913 TI - Who's calling for weight loss? A systematic review of mobile phone weight loss programs for adolescents. AB - CONTEXT: Adolescent overweight and obesity are ongoing public health concerns, and innovative weight loss interventions are needed to reach this age group. OBJECTIVE: The objective of this systematic review was to assess and synthesize the literature on adolescent weight loss programs that utilize cell phones as an intervention component to reduce weight, as measured by body mass index or body mass index z-score. DATA SOURCES: A systematic review of the literature, consistent with PRISMA guidelines, was undertaken using 11 databases. STUDY SELECTION: Studies of weight loss interventions published in peer-reviewed journals in English during the last 10 years were eligible for inclusion if they examined an adolescent population, used validated measures for pre- and post-test weight, identified weight loss as a primary or secondary outcome, and specified use of cell phones to deliver a component of the program. DATA SYNTHESIS: While within-group weight loss results were noted, no significant between-group differences were found across the majority of studies reviewed. Cell phone components were embedded within larger weight loss programs, making it difficult to determine their true effect. CONCLUSIONS: Cell phone use is ubiquitous and, as such, may offer an interesting addition or alternative to current weight loss programs, particularly for adolescents who are considered digital natives. Future research in this area should be systematic in design so that the true effect of the individual components (i.e., cell phones) can be detected. PMID- 26011918 TI - Validation of Bioelectrical Impedance Spectroscopy to Measure Total Body Water in Resistance-Trained Males. AB - The three-compartment (3-C) model of physique assessment (fat mass, fat-free mass, water) incorporates total body water (TBW) whereas the two-compartment model (2-C) assumes a TBW of 73.72%. Deuterium dilution (D2O) is the reference method for measuring TBW but is expensive and time consuming. Multifrequency bioelectrical impedance spectroscopy (BIS SFB7) estimates TBW instantaneously and claims high precision. Our aim was to compare SFB7 with D2O for estimating TBW in resistance trained males (BMI >25kg/m2). We included TBWBIS estimates in a 3-C model and contrasted this and the 2-C model against the reference 3-C model using TBWD2O. TBW of 29 males (32.4 +/- 8.5 years; 183.4 +/- 7.2 cm; 92.5 +/- 9.9 kg; 27.5 +/- 2.6 kg/m2) was measured using SFB7 and D2O. Body density was measured by BODPOD, with body composition calculated using the Siri equation. TBWBIS values were consistent with TBWD2O (SEE = 2.65L; TE = 2.6L) as were %BF values from the 3-C model (BODPOD + TBWBIS) with the 3-C reference model (SEE = 2.20%; TE = 2.20%). For subjects with TBW more than 1% from the assumed 73.72% (n = 16), %BF from the 2-C model differed significantly from the reference 3-C model (Slope 0.6888; Intercept 5.093). The BIS SFB7 measured TBW accurately compared with D2O. The 2C model with an assumed TBW of 73.72% introduces error in the estimation of body composition. We recommend TBW should be measured, either via the traditional D2O method or when resources are limited, with BIS, so that body composition estimates are enhanced. The BIS can be accurately used in 3C equations to better predict TBW and BF% in resistance trained males compared with a 2C model. PMID- 26011914 TI - Obesity, diet, physical activity, and health-related quality of life in endometrial cancer survivors. AB - Obesity, low-quality diet, and inactivity are all prevalent among survivors of endometrial cancer. The present review was conducted to assess whether these characteristics are associated with health-related quality of life (HRQoL). Electronic databases, conference abstracts, and reference lists were searched, and researchers were contacted for preliminary results of ongoing studies. The quality of the methodology and reporting was evaluated using appropriate checklists. Standardized mean differences were calculated, and data were synthesized narratively. Eight of the 4385 reports retrieved from the literature were included in the analysis. Four of the 8 studies were cross-sectional, 1 was retrospective, 1 was prospective, and 2 were randomized controlled trials. Obesity was negatively associated with overall HRQoL in 4 of 4 studies and with physical well-being in 6 of 6 studies, while it was positively associated with fatigue in 2 of 4 studies. Meeting the recommendations for being physically active, eating a diet high in fruit and vegetables, and abstaining from smoking were positively associated with overall HRQoL in 2 of 2 studies, with physical well-being in 2 of 3 studies, and with fatigue in 1 of 3 studies. Improvements in fatigue and physical well-being were evident after lifestyle interventions. The findings indicate a healthy lifestyle is positively associated with HRQoL in this population, but the number of studies is limited. Additional randomized controlled trials to test effective and practical interventions promoting a healthy lifestyle in survivors of endometrial cancer are warranted. PMID- 26011919 TI - Exercise-Induced Weight Loss is More Effective than Dieting for Improving Adipokine Profile, Insulin Resistance, and Inflammation in Obese Men. AB - The adipokines chemerin and adiponectin are reciprocally related in the pathogenesis of insulin resistance and inflammation in obesity. Weight loss increases adiponectin and reduces chemerin, insulin resistance, and inflammation, but the effects of caloric restriction and physical activity are difficult to separate in combined lifestyle modification. We compared effects of diet- or exercise-induced weight loss on chemerin, adiponectin, insulin resistance, and inflammation in obese men. Eighty abdominally obese Asian men (body mass index [BMI] >= 30 kg/m(2), waist circumference [WC] >= 90 cm, mean age 42.6 years) were randomized to reduce daily intake by ~500 kilocalories (n = 40) or perform moderate-intensity aerobic and resistance exercise (200-300 min/week) (n = 40) to increase energy expenditure by a similar amount for 24 weeks. The diet and exercise groups had similar decreases in energy deficit (-456 +/- 338 vs. -455 +/ 315 kcal/day), weight (-3.6 +/- 3.4 vs. -3.3 +/- 4.6 kg), and WC (-3.4 +/- 4.4 vs. -3.6 +/- 3.2 cm). The exercise group demonstrated greater reductions in fat mass (-3.9 +/- 3.5 vs. -2.7 +/- 5.3 kg), serum chemerin (-9.7 +/- 11.1 vs. -4.3 +/- 12.4 ng/ml), the inflammatory marker high-sensitivity C-reactive protein ( 2.11 +/- 3.13 vs. -1.49 +/- 3.08 mg/L), and insulin resistance as measured by homeostatic model assessment (-2.45 +/- 1.88 vs. -1.38 +/- 3.77). Serum adiponectin increased only in the exercise group. Exercise-induced fat mass loss was more effective than dieting for improving adipokine profile, insulin resistance, and systemic inflammation in obese men, underscoring metabolic benefits of increased physical activity. PMID- 26011920 TI - Examining Impulse-Variability in Kicking. AB - This study examined variability in kicking speed and spatial accuracy to test the impulse-variability theory prediction of an inverted-U function and the speed accuracy trade-off. Twenty-eight 18- to 25-year-old adults kicked a playground ball at various percentages (50-100%) of their maximum speed at a wall target. Speed variability and spatial error were analyzed using repeated-measures ANOVA with built-in polynomial contrasts. Results indicated a significant inverse linear trajectory for speed variability (p < .001, eta2= .345) where 50% and 60% maximum speed had significantly higher variability than the 100% condition. A significant quadratic fit was found for spatial error scores of mean radial error (p < .0001, eta2 = .474) and subject-centroid radial error (p < .0001, eta2 = .453). Findings suggest variability and accuracy of multijoint, ballistic skill performance may not follow the general principles of impulse-variability theory or the speed-accuracy trade-off. PMID- 26011921 TI - Syllable Repetition vs. Finger Tapping: Aspects of Motor Timing in 100 Healthy Adults. AB - In this study we systematically compared syllable repetition and finger tapping in healthy adults, and explored possible impacts of tempi, metronome, musical experience, and age on motor timing ability. One hundred healthy adults used finger-tapping and syllable repetition to perform an isochronous pulse in three different tempi, with and without a metronome. Results showed that the motor timing was more accurate with finger tapping than with syllable repetition in the slowest tempo, and the motor timing ability was better with the metronome than without. Persons with musical experience showed better motor timing accuracy than persons without such experience, and the timing asynchrony increased with increasing age. The slowest tempo 90 bpm posed extra challenges to the participants. We speculate that this pattern reflects the fact that the slow tempo lies outside the 3-8 Hz syllable rate of natural speech, which in turn has been linked to theta-based oscillations in the brain. PMID- 26011923 TI - Diagnostic accuracy of cervical elastography in predicting labor induction success: a systematic review and meta-analysis. AB - AIM: To determine the accuracy of cervical elastography in predicting labor induction success. MATERIALS AND METHODS: A systematic search, review, and meta analysis of observational studies published in English language between January 2000 and October 2014 was performed. It included studies considering cervix sonoelastography as the index test and successful labor or vaginal delivery as the reference standard. As cervix length and Bishop score were considered comparator tests, the quality of the included studies was assessed using quality assessment tool for diagnostic accuracy studies (QUADAS) tool. RESULTS: A total of four studies assessing 323 women before medical induction of labor were included. Cervical elastography, cervical length, and Bishop score showed a diagnostic odds ratio (DOR) with 95% confidence interval (CI) for successful labor prediction of 3.50 (1.93-6.35), 3.35 (1.94-5.77), and 1.45 (0.33-6.41), respectively. In addition, cervical elastography, cervical length, and Bishop score showed a DOR with 95% CI for successful vaginal delivery prediction of 5.24 (3.23-8.50), 4.94 (2.72-8.98), and 4.62 (0.69-30.94), respectively. Considering the summary of receiver operating characteristic curves we show that cervical elastography or length are similarly reliable, and both are more reliable to predict successful labor than the Bishop score. Two studies were excluded because it was not possible to retrieve data for the meta-analysis. Among the excluded studies, one found no significant contribution from elastography for prediction of successful labor induction. CONCLUSIONS: Even though there is a limited number of studies included and the heterogeneity of the methods used, cervical elastography seems to be a promising tool for predicting successful labor induction and vaginal delivery in women treated by medical induction of labor. PMID- 26011924 TI - Harmonization of results has not been fully achieved for serum immunoglobulin measurements. PMID- 26011922 TI - Screening of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) enzyme expression and activity in preterm prelabor rupture of fetal membranes. AB - OBJECTIVE: Lysyl oxidase (LOX) and LOX like enzymes (LOXL1-4) physiologically remodel extracellular matrix and pathologically contribute to cellular senescence under oxidative stress (OS). We characterized LOX and LOXL expressions and activity in human fetal membranes. METHODS: Human fetal membranes from women with uncomplicated pregnancies at term, preterm birth with intact membranes (PTB) or preterm prelabor rupture of membranes (pPROM), and in vitro fetal membranes stimulated with water-soluble cigarette smoke extract (CSE), an OS inducer, were analyzed by real-time PCR and immunohistochemistry for LOX and LOXL (1-4) expression and localization. LOX activity was measured by fluorometric assay. RESULTS: LOX gene expression was ~2.5-fold higher in fetal membranes from pPROM compared to PTB and term (P=0.02). LOX and LOXL1, 2 and 4 were localized to both amniotic and chorionic cells, whereas LOXL3 was limited to chorion. LOX and LOXL isoform expressions were not different between CSE treated and untreated groups, while LOX activity was increased in the presence of an antioxidant (P=0.02). CONCLUSIONS: Increase of LOX expression in pPROM, an OS-related disease, and the apparent inhibition of LOX activity by CSE restored by antioxidant treatment suggest that reactive oxygen species might influence LOX-mediated tissue remodeling in fetal membranes. Balanced antioxidant supplementation during pregnancy may reduce the risk of pPROM by increasing LOX activity. PMID- 26011925 TI - Acute effects of conventional and extended hemodialysis and hemodiafiltration on high-sensitivity cardiac troponins. PMID- 26011926 TI - Analytical performances of the D-100TM hemoglobin testing system (Bio-Rad) for HbA1c assay. AB - BACKGROUND: Glycated hemoglobin (HbA1c) is widely used for the monitoring of glycemic balance in diabetic patients and has also been proposed as a tool for the diagnostic of diabetes mellitus. Accordingly, HbA1c quantification must be performed using robust, reliable and efficient methods. Here are reported the results of the evaluation of a new high performance liquid chromatography (HPLC) system for HbA1c quantification, the D-100TM system from Bio-Rad Laboratories. METHODS: The analytical performances of the method as well as the influence of the most frequent interferences regarding HbA1c assays (e.g., labile HbA1c, carbamylated hemoglobin, high HbF) have been tested. RESULTS: Intra- and between assay CVs were respectively lower than 0.93% and 1.46% (HbA1c results expressed in NGSP units) and lower than 1.67% and 2.27% (HbA1c results expressed in IFCC units). The linearity proved to be excellent from 15 mmol/mol (3.5%) to 184 mmol/mol (19.0%) (r=0.999). The results were well correlated with those obtained by another HPLC method (VARIANTTM II Hemoglobin A1c Program reorder pack 270 2101NU-Bio-Rad): HbA1c[VARIANTTM II, mmol/mol]=1.013*HbA1c[D-100TM, mmol/mol]+0.637 (r=0.993, n=2000). The D-100TM system provided results consistent with IFCC-assigned external quality control samples and the presence of labile HbA1c, carbamylated hemoglobin and HbF did not interfere with HbA1c measurement. CONCLUSIONS: The D-100 TM system proved to be a robust and reliable method for HbA1c measurement suitable for routine practice in clinical chemistry laboratories. PMID- 26011927 TI - Comparison of measured venous carbon dioxide and calculated arterial bicarbonates according to the PaCO2 and PaO2 cut-off values of obesity hypoventilation syndrome. PMID- 26011928 TI - Virosome, a hybrid vehicle for efficient and safe drug delivery and its emerging application in cancer treatment. AB - A virosome is an innovative hybrid drug delivery system with advantages of both viral and non-viral vectors. Studies have shown that a virosome can carry various biologically active molecules, such as nucleic acids, peptides, proteins and small organic molecules. Targeted drug delivery using virosome-based systems can be achieved through surface modifications of virosomes. A number of virosome based prophylactic and therapeutic products with high safety profiles are currently available in the market. Cancer treatment is a big battlefield for virosome-based drug delivery systems. This review provides an overview of the general concept, preparation procedures, working mechanisms, preclinical studies and clinical applications of virosomes in cancer treatment. PMID- 26011929 TI - Synthesis and characterization of some novel 1,2,4-triazoles, 1,3,4-thiadiazoles and Schiff bases incorporating imidazole moiety as potential antimicrobial agents. AB - (1,4,5-Triphenylimidazol-2-yl-thio)butyric acid hydrazide (3) was obtained via alkylation of 1,4,5-triphenylimidazol-2- thiol (1) with ethylbromobutyrate, followed by addition of hydrazine hydrate. Treatment of acid hydrazide 3 with carbon disulfide in an ethanolic potassium hydroxide solution gave the intermediate potassium dithiocarbazinate salt, which was cyclized to 4-amino-5 [(1,4,5-triphenylimidazol- -2-yl)thiopropyl]-2H-1,2,4-triazole-3-thione (4) in the presence of hydrazine hydrate. Condensation of compound 3 with alkyl/arylisothiocyanate afforded the corresponding 1-[4-(1,4,5-triphenylimidazol 2-ylthio)butanoyl]-4-alkyl/arylthiosemicarbazides (5-7), which upon refluxing with sodium hydroxide, yielded the corresponding 1,2,4-triazole - -3-thiols 8-10. Under acidic conditions, compounds 4-6 were converted to aminothiadiazoles 11-13. Moreover, the series of Schiff bases 14-18 were synthesized from the condensation of compound 3 with different aromatic aldehydes. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral analyses. They were also preliminarily screened for their antimicrobial activity. PMID- 26011930 TI - Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation. AB - This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (>95% in 20 minutes) compared to pure crystalline CZ (56%). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism. PMID- 26011931 TI - Rational application of fructose-1,6-diphosphate: From the perspective of pharmacokinetics. AB - Fructose-1,6-diphosphate (FDP), a glycolytic metabolite, has been reported to protect susceptible organs during hypoxia or ischemia. However, there is paucity of human data on its pharmacokinetics after being exogenously administered. In the current study, the preliminary pharmacokinetics of FDP given orally to humans was investigated, and no typical peak was observed in the serum drug-time curve. Then, the pharmacokinetic studies were performed following multiple doses of FDP in rats, and the Caco-2 monolayer model was used to study the absorption of FDP in vitro. The results suggested that plasma FDP concentration was significantly increased after oral multiple doses of 180 mg kg(-1) but not 90 mg kg(-1) of FDP, and FDP was partly depleted during the absorption, which was supposed to be consumed by the intestinal epithelium cells. Thus, we conclude that a high dose of FDP should be orally administered in order to get an effective plasma level. PMID- 26011932 TI - Determination of ramipril in human plasma and its fragmentation by UPLC-Q-TOF-MS with positive electrospray ionization. AB - This report presents the application of ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry with positive electrospray ionization, to determine ramipril in human plasma. First, the proteins in human plasma were precipitated using acetonitrile, then the supernatant was extracted by ethyl acetate at pH 3 and finally, the extract was analyzed using a UPLC-QTOF- MS system. The method was validated and the coefficient of determination (R2) was >0.999, the lower limit of quantification (LLOQ) was 0.5 ng mL(-1). Precision, recovery and stability were determined for three different concentrations of ramipril. RSD for this method ranged from 3.3 to 8.6%. The intra-day mean recovery was from 65.3 to 97.3%. In addition, the fragmentation of ramipril was studied. Due to high resolution of the spectrometer, it was possible to measure fragment masses accurately and determine their molecular and chemical formulas with high accuracy. PMID- 26011933 TI - Immunomodulatory effects of inosine pranobex on cytokine production by human lymphocytes. AB - Inosine pranobex (inosine dimepranol acedoben, isoprinosine) (Inos) is an immunomodulatory and antiviral drug used in some viral infections, especially in patients with weakened immunity. In the present study, effects of Inos on the production of cytokines attributable to Th1 (IL-2, IFN-g, and TNF-a) or Th2 cells (IL-4, IL-5, and IL-10) were tested in human peripheral blood lymphocyte cultures stimulated with phytohemagglutinin (PHA). Inos enhanced TNF-a secretion significantly (in short-term--24-hour, and prolonged term--72-hour cultures) and IFN-g (in 72-hour cultures). Surprisingly, production of IL-10 by PHA-stimulated lymphocytes was suppressed by Inos in a dose-dependent manner in both 24-hour and 72-hour cultures. These results shed some light on immunomodulatory properties of Inos and suggest applicability of this agent in patients with a depressed function of the immune system. PMID- 26011934 TI - In vitro permeation studies of phenolics from horse chestnut seed gels prepared with different polyacrylic acid polymer derivatives. AB - The aim of this study was to investigate the effects of polyacrylic acid polymers (Ultrez 10, Ultrez 20, Carbopol 980, and Carbopol 940) on the viscosity and the in vitro permeation of phenolic compounds from the gel prepared from natural horse chestnut seed extract. Experiments were performed in the presence and in the absence of peppermint oil (Mentha piperita). Our results showed that peppermint oil decreased the viscosity of the gels and permeation of phenolic compounds from all gel samples. Results show that the highest content of phenolic compounds (1.758 MUg cm(-2)) permeated in vitro from gel based on Carbopol Ultrez 20 without peppermint oil added (p<0.05 vs. other tested polymers). PMID- 26011935 TI - The role of phosphodiesterase 4B in IL-8/LTB4-induced human neutrophil chemotaxis evaluated with a phosphodiesterase 4B inhibitor. AB - PDE4B was previously shown to be a dominant PDE4 subtype of neutrophils. However, its physiological role in the neutrophil function has not been evaluated. In this study, the inhibitory effects of a phosphodiesterase 4B (PDE4B)- selective inhibitor (compound A) and subtype non-selective PDE4 inhibitors (roflumilast and cilomilast) were evaluated in human peripheral blood cells. Compound A, roflumilast and cilomilast in a similar manner inhibited TNF-alpha production by LPS-stimulated human mononuclear cells. However, the inhibitory effect of compound A on IL-8 or LTB4-induced chemotactic response of neutrophils was modest even at the highest concentration (10 MUmol L(-1)), whereas roflumilast and cilomilast inhibited IL-8 or LTB4-induced neutrophil chemotaxis. Our results suggest that PDE4B does not play an important role during the chemotactic response of human neutrophils. PMID- 26011937 TI - Thermal analysis of N-carbamoyl benzotriazole derivatives. AB - Thermal properties of N-carbamoyl benzotriazole derivatives and N,N',N'' tribenzyloxyisocyanuric acid were investigated using thermogravimetric analysis and differential scanning calorimetry. The results revealed a difference between structural analogs of N-carbamoyl benzotriazole derivatives. They seem to be in agreement with the previously proposed formation of N,N',N'' tribenzyloxyisocyanuric acid from 1-(N-benzyloxycarbamoyl) benzotriazole, via an intermediary N-benzyloxyisocyanate acid, during heating. Substantially different thermal properties were observed for structural analogues, 1-(N-methoxycarbamoyl) benzotriazole and 1-(N-ethoxycarbamoyl) benzotriazole. In contrast to N benzyloxyisocyanate, no corresponding reactions were observed for their decomposition products, i.e., methoxyisocyanate and ethoxyisocyanate. PMID- 26011936 TI - Release of rosmarinic acid from semisolid formulations and its penetration through human skin ex vivo. AB - The aim of this study was to evaluate the release of rosmarinic acid (RA) from the experimental topical formulations with the Melissa officinalis L. extract and to evaluate its penetration through undamaged human skin ex vivo. The results of the in vitro release study showed that higher amounts of RA were released from the emulsion vehicle when lemon balm extract was added in its dry form. An inverse correlation was detected between the released amount of RA and the consistency index of the formulation. Different penetration of RA into the skin may be influenced by the characteristics of the vehicle as well as by the form of the extract. The results of penetration assessment showed that the intensity of RA penetration was influenced by its lipophilic properties: RA was accumulating in the epidermis, while the dermis served as a barrier, impeding its deeper penetration. PMID- 26011938 TI - Preface to special issue on: Adiposopathy in cancer and (cardio)metabolic diseases: an endocrine approach - Part 3. PMID- 26011940 TI - Influence of age on predictiveness of genetic risk score for prostate cancer in a Chinese hospital-based biopsy cohort. AB - BACKGROUND: We investigated whether age influences the predictiveness of genetic risk score (GRS) for prostate cancer (PCa) in a Chinese hospital-based biopsy cohort. METHODS: We included consecutive patients who underwent prostate biopsies in two tertiary centers between 2012 and 2014. GRS was calculated using 24 PCa associated genetic variants and its predictiveness was assessed by area under curve (AUC). RESULTS: Of 1120 men tested, 724 with prostate-specific antigen (PSA) < 20 ng/ml were selected for further analysis. Patients were divided into 3 groups by age cutoffs at 60 and 70 years. GRS significantly predicted PCa for all patients (AUC: 0.561; 95% CI: 0.514-0.609) and was an independent predictor in multivariate analysis for the 60-70 year-olds (AUC: 0.612, 95% CI: 0.541-0.684), but not for patients aged < 60 years or >= 70 years. For PCa with Gleason score >= 7, GRS discriminative ability was 0.582 (95% CI=0.527-0.637) for all patients, and 0.647 (95% CI: 0.541-0.684) for the 60-70 year-old group. CONCLUSION: GRS significantly increased clinical prediction of PCa and high-grade disease in Chinese men aged 60-70 years, which implies that men in this age group would benefit most from genetic testing. PMID- 26011942 TI - What does better births look lke for you? PMID- 26011941 TI - Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells. AB - The triple-negative breast cancer (TNBC) subtype is enriched in cancer stem cells (CSCs) and clinically correlated with the highest rate of recurrence. Several studies implicate the RSK pathway as being pivotal for the growth and proliferation of CSCs, which are postulated to drive tumor relapse. We now address the potential for the newly developed RSK inhibitor LJI308 to target the CSC population and repress TNBC growth and dissemination. Overexpression of the Y box binding protein-1 (YB-1) oncogene in human mammary epithelial cells (HMECs) drove TNBC tumor formation characterized by a multi-drug resistance phenotype, yet these cells were sensitive to LJI308 in addition to the classic RSK inhibitors BI-D1870 and luteolin. Notably, LJI308 specifically targeted transformed cells as it had little effect on the non-tumorigenic parental HMECs. Loss of cell growth, both in 2D and 3D culture, was attributed to LJI308-induced apoptosis. We discovered CD44+/CD49f+ TNBC cells to be less sensitive to chemotherapy compared to the isogenic CD44-/CD49f- cells. However, inhibition of RSK using LJI308, BI-D1870, or luteolin was sufficient to eradicate the CSC population. We conclude that targeting RSK using specific and potent inhibitors, such as LJI308, delivers the promise of inhibiting the growth of TNBC. PMID- 26011943 TI - Methods in cilia & flagella. Preface. PMID- 26011939 TI - PC-1/PrLZ confers resistance to rapamycin in prostate cancer cells through increased 4E-BP1 stability. AB - An important strategy for improving advanced PCa treatment is targeted therapies combined with chemotherapy. PC-1, a prostate Leucine Zipper gene (PrLZ), is specifically expressed in prostate tissue as an androgen-induced gene and is up regulated in advanced PCa. Recent work confirmed that PC-1 expression promotes PCa growth and androgen-independent progression. However, how this occurs and whether this can be used as a biomarker is uncertain. Here, we report that PC-1 overexpression confers PCa cells resistance to rapamycin treatment by antagonizing rapamycin-induced cytostasis and autophagy (rapamycin-sensitivity was observed in PC-1-deficient (shPC-1) C4-2 cells). Analysis of the mTOR pathway in PCa cells with PC-1 overexpressed and depressed revealed that eukaryotic initiation factor 4E-binding protein 1(4E-BP1) was highly regulated by PC-1. Immunohistochemistry assays indicated that 4E-BP1 up-regulation correlates with increased PC-1 expression in human prostate tumors and in PCa cells. Furthermore, PC-1 interacts directly with 4E-BP1 and stabilizes 4E-BP1 protein via inhibition of its ubiquitination and proteasomal degradation. Thus, PC-1 is a novel regulator of 4E-BP1 and our work suggests a potential mechanism through which PC 1 enhances PCa cell survival and malignant progression and increases chemoresistance. Thus, the PC-1-4E-BP1 interaction may represent a therapeutic target for treating advanced PCa. PMID- 26011944 TI - USDA wants dog breeder accreditation. PMID- 26011945 TI - Senators, academics, others embrace one-health approach. PMID- 26011946 TI - Large animal practitioners grapple with fluid shortage. PMID- 26011947 TI - Contributions of veterinary medicine to health research. PMID- 26011948 TI - The author responds. PMID- 26011949 TI - Affective states of animals. PMID- 26011950 TI - Public trust in the accreditation process. PMID- 26011951 TI - Dr. Matushek responds. PMID- 26011952 TI - Optimizing emergency management to reduce morbidity and mortality in pediatric burn patients. AB - Burns in patients aged < 14 years are consistently among the top causes of injury induced mortality in pediatric patients. Pediatric burn victims with large body surface area involvement have a multisystem physiologic response that differs from that of adult patients. The spectrum of management is vast and relies heavily on both the classification of the burn and the anatomy involved. Immediate goals for emergency clinicians include resuscitation and stabilization, fluid management, and pain control. Additional goals include decreasing the risk of infection along with improving healing and cosmetic outcomes. Discharge care and appropriate follow-up instructions need to be carefully constructed in order to avoid long-standing complications. This article reviews methods for accurate classification and management of the full range of burns seen in pediatric patients. PMID- 26011953 TI - Traumatic vitreous hemorrhage in children-clinical features and outcomes. AB - PURPOSE: To determine the clinical profile, causes, and outcomes of traumatic vitreous hemorrhage (TVH) in children (< 18 years of age). METHODS: Retrospective computer assisted chart review. 501 eyes of 464 children (103 females; 361 males) who presented with TVH between 2001 and 2012 were included. All children underwent a complete ocular and systemic examination and investigation. The etiology, visual, and anatomic results of pediatric TVH were the outcome measures. RESULTS: Median age: 12.27 +/- 4.51 years. 37 patients had bilateral VH; 43.24% of these were firecracker injuries. Commonest complaint was diminished vision (96.45%). Mean BCVA(logMAR) at presentation was 2.64 +/- 1.11 logMAR. Sticks (43.43%) and cricket balls (13.24%) were the commonest causes. Treatment included medical therapy (topical and/or systemic; 56 eyes), laser photocoagulation (34 eyes), and/ or surgery (387 eyes). Mean final BCVA was significantly better (1.01 +/- 0.58 logMAR; P = 0.011, Z test). Mean follow up in the closed and open globe trauma was 47 +/- 12.47 and 36.24 +/- 9.72 months, respectively. CONCLUSION: TVH has significant implications in children. Firecracker injuries are notorious for bilateral VH. PMID- 26011954 TI - Relationship between corneal thickness, corneal curvature, and intraocular pressure before and after laser treatment for simple myopia. AB - PURPOSE: To determine the relationship of central corneal thickness (CCT), curvature (CC), and intraocular pressure (IOP) as determinative factors for corneal biomechanics and in refractive surgery. METHODS: The study investigated 48 eyes from subjects who visited the Excimer Laser Surgery Clinic at the Department of Ophthalmology. The refractive error, IOP, CCT, and CC were measured in all participants. After 3 months, all examinations were repeated. RESULTS: Linear regression demonstrated a significant positive relationship between pre- and postoperative CCT, CC, and IOP values. The IOP showed a significant correlation with CCT (P = 0.033) for pre-PRK, but no significant relationship was seen post-PRK. The CCT also correlated significantly with CC both pre- and post PRK (P < 0.05). CONCLUSION: The IOP was significantly correlated with CCT before PRK, but its behavior differed after surgery. Nearly the same correlation was seen between CCT and CC before and after the PRK; nevertheless, IOP measurements should be calculated or estimated more precisely after PRK based on CCT corrections. PMID- 26011955 TI - Influence of psychological intervention before emergent ocular trauma surgery on patients' negative emotions. AB - PURPOSE: To investigate the effect of preoperative psychological intervention on alleviating negative emotions in patients undergoing emergent ocular trauma surgery. METHODS: A total of 100 patients undergoing emergent ocular trauma surgery were selected using convenience sampling and randomly divided into control (n = 49) and experimental (n = 51) groups. Patients in the control group received conventional nursing and their counterparts in the observation group were treated with individualized psychological interventions including psychological support, relaxation training, and humanistic care based on conventional nursing care. Self-rating anxiety scale (SAS), self-rating depression scale (SDS), and fear visual analog scale (FVAS) scores were statistically compared between the two groups. RESULTS: The scores of SAS, SDS, and FAVS were significantly lower in the experimental group than in the control group (all P < 0.001). CONCLUSION: Comprehensive psychological intervention effectively eliminates negative emotions in patients undergoing emergent ocular trauma surgery and accelerates their physical and mental recovery. PMID- 26011957 TI - Clinical analysis of early and mid-late elevated intraocular pressure after silicone oil injection. AB - PURPOSE: To discuss the incidence and clinical features of early and mid-late elevated intraocular pressure after pars plana vitrectomy and silicone oil injection, and to evaluate the clinical management of eyes with secondary glaucoma. METHODS: This was an observational consecutive case series of 691 eyes in 679 patients who were treated with pars plana vitrectomy and silicone injection. The diagnostic criteria of early elevated intraocular pressure after silicone oil injection was >= 21 mmHg two weeks after surgery, while mid-late elevated intraocular pressure was >= 21 mmHg after two weeks. The incidence and clinical management of elevated intraocular pressure were analyzed. RESULTS: In total, 211 of 691 eyes (30.54%) developed elevated intraocular pressure two weeks after pars plana vitrecto my and silicone injection. Of the 211 eyes, 101 eyes (47.87%) had ocular inflammation, 64 eyes (30.33%) showed hyphema, 35 eyes (16.59%) had silicone oil in the anterior chamber, 6 eyes (2.84% ) had excess silicone oil injected, and 5 eyes (2.37%) had rubeosis irides. Eighty three of 691 eyes (12.01%) developed elevated intraocular pressure after two weeks. Of these 83 eyes, 25 eyes (30.12%) had rubeosis irides, 16 eyes (19.27%) had issues related to topic steroid therapy, 13 eyes (15.66%) had a papillary block, silicone oil in the anterior chamber, 10 eyes (12.05%) had a silicone emulsion, 10 eyes (12.05%) had peripheral anterior synchiae, and 9 eyes (10.84%) had silicone oil in the anterior chamber. All eyes with elevated intraocular pressure were treated with antiglaucoma medications and surgeries. CONCLUSION: The reasons for elevated intraocular pressure differed between early and mid-late after pars plana vitrectomy and silicone oil injection. The elevated intraocular pressure can be controlled effectively by immediate diagnosis and proper treatment with medicine and operation. PMID- 26011956 TI - An association between corneal inflammation and corneal lymphangiogenesis after keratoplasty. AB - PURPOSE: To examine the relationship between corneal inflammation and corneal lymphangiogenesis after keratoplasty. METHODS: Rat corneal lymphangiogenesis was examined by lymphatic vessel endothelial receptor (LYVE-1) immunohistochemistry and whole mount immunofluorescence at 1, 3, 7, 10, and 14 days after corneal transplantation. Corneal inflammation was evaluated by inflammation index (IF) grading and NF-kappaB immunohistochemistry at the same time points. The association between lymphatic vessel counting (LVC) and the IF scores was then examined. RESULTS: LYVE-1 positive lymphatic vessels occurred in the corneal stroma on day 3, developed throughout days 7 and 10, and peaked in number at day 14 after keratoplasty. Corneal inflammation was strong on day 3, and then resolved gradually, but increased again from days 7 to 14 after the transplantation. LVC was strongly and positively correlated with IF after keratoplasty (r = 0.41; P < 0.05). However, changes in IF scores and LVC were not parallel. CONCLUSION: A close, but not parallel, relationship was found between corneal lymphangiogenesis and corneal inflammation after corneal transplantation. PMID- 26011958 TI - Comparison of applicability of different visual acuity charts for pediatric outpatient visual tests. AB - PURPOSE: To evaluate the applicability of different visual acuity charts for outpatient pediatric visual tests. METHODS: Fifty-three children (53 eyes) aged 4 8 years undergoing visual acuity tests as outpatients were randomly selected for this study. The best corrected visual acuity (BCVA) of the eye with better visual acuity was measured for each child using the digital LogMAR visual chart, the ETDRS visual chart, and a new standard logarithm visual chart; all measurements were repeated twice and the BCVA was recorded. Paired comparisons were made between the LogMAR visual acuity chart and ETDRS chart measurements or between the ETDRS chart and logarithm visual acuity chart measurements for statistical analysis of the differences in measurement of visual acuity. The results of different measurements by the same chart were compared to evaluate the consistency of the measurement results. Bland-Altman analysis was employed to evaluate the most suitable chart for outpatient measurement of visual acuity in children. RESULTS: Bland-Altman analysis revealed that the mean visual acuity measured was (0.447 +/- 0.017 LogMAR) by the digital LogMAR chart, (0.301 +/- 0.024 LogMAR) by the standard logarithm visual acuity chart, and (0.309 +/- 0.018 LogMAR) by the ETDRS visual acuity chart. The BCVA was significantly lower when measured by the LogMAR visual acuity chart than by the ETDRS chart (P < 0.01). The BCVA was slightly higher when measured by the logarithm visual acuity chart than by the ETDRS chart, but the difference was not statistically significant (P > 0.05). The Bland-Altman plot showed that the highest consistency was obtained with the digital LogMAR chart, with a difference between two repeated measurements of 0.068 LogMAR, compared to 0.090 and 0.072 LogMAR for the logarithm and ETDRS visual acuity charts, respectively. CONCLUSION: All three types of visual acuity charts are applicable for outpatient measurement of pediatric visual acuity. The ETDRS and logarithm visual acuity charts have a higher consistency, but the LogMAR visual acuity chart shows better reproducibility. Consequently, it is difficult to identify and distinguish which acuity chart is most suitable for cooperative children. PMID- 26011959 TI - Comparison of visual function after multifocal and accommodative IOL implantation. AB - PURPOSE: To compare early visual function between patients undergoing phacoemulsification combined with multifocal and accommodative intraocular lens implantation. METHODS: A total of 112 patients with age-related cataract undergoing phacoemulsification in our hospital were recruited for this study and randomly assigned into multifocal (56 eyes; ZAM00 group) and accommodative (56 eyes; FLEX group) intraocular lens groups. Visual acuity and contrast sensitivity were statistically compared between the two groups. RESULTS: No significant difference was found in uncorrected distant visual acuity between the ZMA00 and FLEX groups at 1 week, or 1, 3, and 6 months after operation (all P > 0.05). At postoperative 6 months, no statistical significance was noted in distant and intermediate best-corrected visual acuity or in contrast sensitivity between the two groups (all P > 0.05). Patients in the ZMA00 group were superior to their counterparts in the FLEX group regarding near best corrected visual acuity, reading speed, and spectacle independence (all P < 0.05). CONCLUSION: ZMA00 and FLEX IOL implantation can provide excellent distant and intermediate visual acuity for patients with age-related cataract. ZMA00 IOL is superior to FLEX in terms of near visual acuity. PMID- 26011960 TI - Ultrasonographic feature of persistent hyperplastic primary vitreous. AB - PURPOSE: To observe the ultrasonographic features of patients with persistent hyperplastic primary vitreous (PHPV). METHODS: Thirty-two subjects (34 eyes) diagnosed with PHPV were evaluated by ultrasonography. RESULTS: The ultrasonography demonstrated a retrolental mass extending from the optic disc to the posterior lens capsule, manifested as band, regular triangle, or inverted triangle shapes. The band-shaped echo was characterized as a linear band extended from the optic disc to the posterior lens capsule. The regular triangle-shaped echo was manifested as a membranous septum with a wide base extended from the optic disc to the posterior lens capsule, and the anterior part became narrower. The inverted triangle echo was characterized as a membranous septum with a narrow base extended from the optic disc to the posterior lens capsule, and the anterior part become wider. CONCLUSION: Ultrasonography is noninvasive and safe, and can offer real-time display of intraocular structures. This is especially important in individuals who are uncooperative or unsuitable for fundus examination due to media opacity. Combined with clinical feature, ultrasonography provides vital evidence for the diagnosis of PHPV. Thought observing ultrasonographic feature, clinicians could evaluate the size, position and severity of lesions in PHPV patients, and which would be helpful to determine the surgical approach and clinical prognosis. PMID- 26011961 TI - Utilization of gene mapping and candidate gene mutation screening for diagnosing clinically equivocal conditions: a Norrie disease case study. AB - Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members. Mapping of the X chromosome and candidate gene mutation screening identified a c.C267A[p.F89L] mutation in NPD previously described as possibly causing Norrie disease. The detection of the c.C267A[p.F89L] variant in another unrelated family confirms the pathogenic nature of the mutation for the Norrie disease phenotype. Gene mapping, haplotype analysis, and candidate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information. The clinical diagnosis and mutation identification were critical for providing proper genetic counseling and prenatal diagnosis for this family. PMID- 26011962 TI - The cause is blooming like Phoenix tree flowers--a feature report on the second generation ophthalmologists of Eugene Chan's family. PMID- 26011963 TI - Exploration of management workflow of cataract surgery in an impoverished population in urban China. AB - PURPOSE: To explore and establish a rational management workflow for a free cataract surgery program for the poor population in urban China, aiming to improve surgical efficiency. METHODS: Establishment of a management workflow mainly includes system design and an auxiliary facility. System design procedures consist of outpatient screening, outpatient physical examination, surgical procedures, and postoperative clinic visits. After establishing the management workflow of cataract surgery, a free cataract surgery program was conducted for 15 months. RESULTS: Based upon the established management mode, 9003 patients received preoperative screening and 2358 underwent cataract surgery. During the 15-month investigation, each procedure was successfully conducted, the efficiency of screening and operation attained the highest standards in China, and no surgical malpractice occurred intraoperatively. CONCLUSION: In this study, a management workflow for cataract surgery was designed for a poverty relief project in urban China. During the 15-month project, the degree of patient satisfaction was enhanced without disrupting the normal practice and safety of the sponsor hospital. PMID- 26011964 TI - Nursing care of the laryngeal mask airway in pediatric cataract surgery. AB - PURPOSE: To investigate the important experience of nursing care of the laryngeal mask airway (LMA) in children undergoing cataract surgery. METHODS: Fifty-five children undergoing cataract surgery were anesthetized by inhaling sevoflurane through a LMA and received perioperative nursing care. The safety of perioperative nursing for these children was also evaluated. RESULTS: Through perioperative nursing care and psychological counseling for children with LMA, all patients were anesthetized without complications and underwent successful surgeries. No severe postoperative complications were observed. CONCLUSION: Nursing care specific for LMA is a vital part of the success of anesthesia and pediatric cataract surgery. PMID- 26011965 TI - Research progress in corneal cross-linking agents. AB - Corneal collagen cross-linking with UVA-riboflavin is currently the only method for preventing the progression of keratoconus from the pathological perspective. Topical application of a direct cross-linking agent is now attracting widespread attention in clinical settings. This article reviews the research progress in the application of indirect or direct cross-linking agents (e.g., riboflavin, glucose, ribose, glutaraldehyde, formaldehyde, glyceraldehyde, short chain aliphatic beta-nitro alcohol, and genipin) in the treatment of corneal diseases and analyzes the cross-linking efficacy, toxicity, and merits and disadvantages of each cross-linking agent, providing clinical information for further studies. PMID- 26011966 TI - Relationship between refractive error and ocular biometrics in twin children: the Guangzhou Twin Eye Study. AB - PURPOSE: A cross-sectional study was conducted to explore the relationship between refractive error and ocular biometrics in children from the Guangzhou twin eye study. METHODS: Twin participants aged 7-15 years were selected from Guangzhou Twin Eye Study. Ocular examinations included visual acuity measurement, ocular motility evaluation, autorefraction under cycloplegia, and anterior segment, media, and fundus examination. Axial length (AL), anterior chamber depth (ACD), and corneal curvature radius were measured using partial coherence laser interferometry. A multivariate linear regression model was used for statistical analysis. RESULTS: Twin children from Guangzhou city showed a decreased spherical equivalent with age, whereas both AL and ACD were increased and corneal curvature radius remained unchanged. When adjusted by age and gender, the data from 77% of twins presenting with spherical equivalent changes indicated that these were caused by predictable variables (R2 = 0.77, P < 0.001). Primary factors affecting children's refraction included axial length (beta = -0.97,P < 0.001), ACD (beta = 0.33, P < 0.001), and curvature radius (beta = 2.10, P < 0.001). Girls had a higher tendency for myopic status than did boys (beta = -0.26, P < 0.001). Age exerted no effect upon the changes in refraction (beta = -0.01, P = 0.25). CONCLUSION: Refraction is correlated with ocular biometrics. Refractive status is largely determined by axial length as the major factor. PMID- 26011967 TI - Ophthalmic evaluation of children from the Tibet plateau with congenital heart disease. AB - PURPOSE: To perform ophthalmic examinations to evaluate the ocular characteristics of children living in the Tibet plateau and diagnosed with congenital heart disease. METHODS: Children with congenital heart disease underwent a conventional ocular examination including distant acuity test, slit lamp examination, fundus examination, non-contact intraocular pressure measurement, measurement of corneal thickness, and fundus photography. RESULTS: Forty-two Tibetan children, aged between 4 and 18 years and diagnosed with congenital heart disease, were enrolled in this study. The percentage of low visual acuity was 4.76%, mean intraocular pressure was (13.67 +/- 2.15) mmHg, average corneal thickness was (492.55 +/- 33.79) MUm, 96.43% had an anterior chamber depth of 1/2 corneal thickness (CT), and 35.7% had an obvious fundus vascular tortuosity. CONCLUSION: This study adds to the understanding of the ocular status of the population living in the Tibet plateau, thereby offering clinical evidence for the prevention and treatment of eye diseases in this area. PMID- 26011968 TI - Ten-year etiologic review of Chinese children hospitalized for pediatric cataracts. AB - PURPOSE: Our aim was to obtain a better understanding of the etiologies and characteristics of pediatric cataracts treated at a single facility in China. METHODS: Medical records accrued over a 10-year period (from August, 2003 to July, 2013) at Shengjing Hospital of China Medical University were reviewed retrospectively, identifying all patients treated for various subtypes of pediatric cataract. A database with 367 subjects under 14 years of age (598, including second-round surgeries) was generated. RESULTS: Of this cohort (n = 367; males: 232, 63.2%; females: 135, 36.8%), 200 patients (54.5%) had bilateral cataracts, and 258 (70.3%) were under 3 years of age. In all age groups and in all subtypes of pediatric cataract, males were most commonly affected. Congenital cataract was the most prevalent subtype, accounting for 296 patients (80.7%). Most congenital cataracts were associated with other ocular or systemic abnormalities; and in 48 patients (16.22%), they were hereditary. Traumatic cataract was the most common subtype (85.92%) of acquired cataract. The few instances of cataracts due to steroids (n = 3) or to metabolic disorders (n = 2) occurred in males and involved both eyes. CONCLUSION: The majority of pediatric cataracts in this patient population were congenital in nature. A significant lag in ophthalmologic evaluation of Chinese infants was evident and should be addressed by educating both children and parents on risk factors for cataract development. Regular assessments are especially important in children subjected to long-term systemic steroid treatments. PMID- 26011969 TI - Clinical features and differential diagnosis of acute idiopathic blind spot enlargement syndrome. AB - PURPOSE: To study the clinical manifestations and the diagnostic and differential diagnostic characteristics of acute idiopathic blind spot enlargement syndrome (AIBSES). METHODS: Six patients diagnosed with AIBSES underwent complete eye examinations including fundus photography, fundus fluorescein angiography(FFA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), electroretinogram (ERG), and visual field examinations. RESULTS: All patients had enlarged blind spots of variable sizes and densities. Three eyes had mild swelling of the optic disc and one eye had peripapillary scarring that corresponded to the permanent field defect. Two patients who underwent FFA had fluorescein leakage of blood vessels around the optic disc and ICGA highlighted diffuse, small hypofluorescent spots scattering throughout the posterior pole. OCT showed that the inner and outer segment (IS/OS) line were absent in five patients and the middle cone outer segment tip line was absent in the nasal macular area in one eye. CONCLUSION: AIBSES is a rare outer retinopathy. Visual field examination and OCT are the most important means of detection. ICGA and FAF can determine the range of lesions earlier, and the progress of the disease should be taken into account when making a diagnosis. PMID- 26011970 TI - Relationship between Foxp3-3279 (rs376158) polymorphism and dust mite allergic conjunctivitis. AB - PURPOSE: To investigate the genotyping of Foxp3-3279 (A/Crs376158) genes in patients with dust mite-induced allergic conjunctivitis from Guangdong province and to explore the association between these genes and the susceptibility to dust mite allergic conjunctivitis. METHODS: In total, 80 patients with dust mite allergic conjunctivitis and 103 healthy Han Chinese were enrolled in the study and received genotyping of Foxp3-3279 (A/C,rs376158) by PCR-SSP technique. RESULTS: Genotype frequency of Foxp3-3279 AA, CA, and CC in patients with dust mite allergic conjunctivitis were 1.25%, 25.00% and 73.75%,respectively. Gene frequency of C and A in patients with dust mite allergic conjunctivitis were 86.25% and 13.75% with no significant difference from healthy counterparts (both P > 0.05). CONCLUSION: Foxp3-3279 polymorphisms did not significantly differ between patients with dust mite allergic conjunctivitis and healthy controls, implying that this genetic locus is probably not an independent risk factor of the underlying pathogenesis of dust mite allergic conjunctivitis. PMID- 26011971 TI - Comparison of postoperative pain following laser-assisted subepithelial keratectomy and transepithelial photorefractive keratectomy: a prospective, random paired bilateral eye study. AB - PURPOSE: To compare postoperative pain following laser-assisted subepithelial keratectomy (LASEK) and transepithelial photorefractive keratectomy (T-PRK, two step surgery) and alleviate postoperative subjective pain. METHODS: Thirty patients (60 eyes) with myopia or myopic astigmatism were consecutively recruited into this prospective, randomized paired study. Patients underwent LASEK in one eye, and T-PRK in the other. The degree of pain was rated on a scale of 0-10 on postoperative days 1, 2 and 3. Uncorrected visual acuity (UCVA) and subepithelial corneal haze were assessed at postoperative 1 and 3 months. RESULTS: The pain was relieved on the 4th postoperative day in all patients, healing of corneal epithelium was observed at 4-5 days after surgery and contact lenses were removed promptly. At postoperative 1 day, the mean subjective pain score in the LASEK group was 3.2 +/- 1.88 and 4.43 +/- 1.61 in T-PRK group (P = 0.008). No significant difference was found between two groups on postoperative 2 and 3 days. At postoperative 3 months, the percentage of UCVA >= 0.8 in the LASEK group was 100% and 96.7% in the T-PRK group (P = 0.24), 93.3% of patients in the LASEK with UCVA >= 1.0 and 90% in the T-PRK group (P = 0.64). In the LASEK group, the value of corneal haze was 0.26 +/- 0.21 and 0.27 +/- 0.25 in the T-PRK group (P = 0.877). CONCLUSION: Good visual acuity was obtained in both groups at postoperative 3 months. Compared with those in the T-PRK group, patients undergoing had less discomfort in the LASEK group, which may be associated with corneal epithelial activity. The changing curve of subjective pain in the T-PRK group was relatively flat and stable at postoperative 3 days. PMID- 26011972 TI - Clinical observation of transepithelial corneal collagen cross-linking by lontophoresis of riboflavin in treatment of keratoconus. AB - PURPOSE: To evaluate the efficacy and safety of transepithelial collagen cross linking by iontophoretic delivery of riboflavin in treatment of progressive keratoconus. METHODS: Eleven patients (15 eyes) with progressive keratoconus were enrolled. After 0.1% riboflavin-distilled water solution was deliveried via transepithelial iontophpresis for 5 min with 1 mA current, and ultraviolet radiation (370 nm, 3 mW/cm2) was performed at a 1.5 cm distance for 30 min. The follow up were 6 months in all eyes. The uncorrected visual acuity, corrected visual acuity, endothelial cell counting, corneal thickness, intraocular pressure, corneal curvature, corneal topography, OCT and corneal opacity before and 6-month after surgery were analyzed. RESULTS: At 6 month postoperatively, mean uncorrected visual acuity and corrected visual acuity changed from 0.36 to 0.30 and from 0.42 to 0.57 without statistical significance. The mean value of each index of corneal curvature declined without statistical significance.Kmax value dereased from 60.91 to 59.91, and the astigmatism declined from 3.86 to 3.19. Central corneal thickness decreased from 460.93 MUm to 455.40 MUm, and thinnest corneal thickness declined from 450.87 MUm to 440.60 MUm with no statistical significance. Intraocular pressure was significantly elevated from 10.85 mmHg to 12.62 mmHg. Endothelial cell count did not change significantly. No corneal haze occurred. Mean depth of corneal demarcation line was 288.46 MUm at 1 month postoperatively. CONCLUSION: Transepithelial corneal collagen cross-linking by iontophoresis is effective and safe in the treatment of progressive keratoconus, and yields stable clinical outcomes during 6-month follow up. However, long-term follow up is urgently required. PMID- 26011973 TI - Follow-up of a case of vitelliform macular dystrophy over an 8-year period. AB - PURPOSE: To show the follow-up of a case of vitelliform macular dystrophy with morphological and visual functional tests over an 8-year period. METHODS: Retrospective review of medical records. The morphological examination included color photography, fluorescein angiography, and ocular coherence tomography (OCT). The visual functional tests included visual acuity, electro-oculogram (EOG) and multifocal electroretinography (mfERG). The patient was observed for 8 years, from 2003 to 2011. RESULTS: During the follow-up, the improvement of sensory retinal detachment and reduction of yellow-white deposit were observed with color photography and fluorescein angiography. OCT revealed a decrease in sensory retinal detachment and subretinal hyper-reflective deposits; both of these morphological changes were correspondent. Visual acuity was maintained throughout the follow-up. The Arden ratio of EOG was decreased. The amplitudes of mfERG were decreased but slightly increased during the follow-up. CONCLUSION: The retinal morphological changes and visual function slightly improved in this case of vitelliform maculopathy. The prognosis is good. PMID- 26011974 TI - Favorable outcome in open globe injuries with low OTS score. AB - PURPOSE: Open globe eye injuries can have profound social and economic consequences. Here, we describe two cases of war and outdoor activity open globe eye injury where, despite a low OTS score, current microsurgical technology allowed for a favorable outcome. CASE REPORT 1: A 33-year-old Libyan soldier had been treated for an open-globe grenade blast trauma to his left eye, which showed light perception and OTS score 2. He had undergone a lensectomy and PPV with silicone oil tamponade. Surgical treatment included scleral buckling, cornea trephination, temporary Eckardt keratoprosthesis, PPV revision, intraocular lens (IOL) implantation, and corneal grafting. Six months later, his VA was improved to 20/70. CASE REPORT 2: A 35-year-old man presented with a corneal laceration in his left eye from a meat skewer, with marked hypotony and LP. After primary corneal wound closure, B-scan ultrasonography revealed massive vitreous hemorrhage (OTS score 2). The patient underwent open cataract extraction with IOL implantation, 23 gauge PPV, laser photocoagulation of the retinochoroidal laceration, and a gas tamponade. After three weeks, the patient underwent a 2nd 23G PPV due to a fibrinous reaction. Six month later, the patients exhibited 20/25 VA. CONCLUSION: These cases confirm that even for patients with a low OTS and poor visual prognosis, an up-to-date surgery protocol may achieve visual results adequate for leading an autonomous daily life. PMID- 26011975 TI - Herniation of the retina in the central macula in an adult after iridocyclitis. AB - PURPOSE: To report an unusual case of retinal hernia in the central macula in an adult after iridocyclitis. CASE REPORT: We report a case of a 46-year-old male who presented with blurred vision 2 weeks after complete resolution of acute iridocyclitis. Anterior segment and vitreous body examinations were unremarkable. Yellowish spots in the macular area were observed. Spectral domain optical coherence tomography (SD-OCT) imaging of the macula showed loss of the inner segment/outer segment (IS/OS) photoreceptor junction, with irregularity of the retinal pigment epithelium (RPE), and a V-shaped hernia of the retina into the choroid. The macular lesions emerged as mild window defects on fluorescein angiography and were visualized as hypofluorescent patches on all-phase indocyanine green angiography. At a one month follow-up, the best-corrected visual acuity improved to 20/20, which was followed by partial restoration of the IS/OS line, but a V-shaped hernia of the retina remained unchanged on SD-OCT. CONCLUSION: Ophthalmologists should be alert to the changes in OCT of the macula in patients after iridocyclitis and further research on the cause and possible predisposing factors for retinal herniation is warranted. PMID- 26011976 TI - Mantle cell lymphoma in a lacrimal gland in a female and a review of the literature. AB - PURPOSE: To report a rare case of Mantle cell lymphoma in lacrimal gland and review of the literature CASE REPORT: We report a case of a 59-year-old female who presented with an upper eyelid mass in the right eye for 3 months, without pain and irrigation. A computerized tomography (CT) scan showed a mass in the bilateral lacrimal gland region, more significant in right eye. The patient underwent a lacrimal gland mass excision surgery and diagnosis of mantle cell lymphoma by histopathology. Immunochemistry for CD20, CD79a, CD5, and CyclinD1 was positive. She was recommended to the Shantou cancer hospital for chemotherapy. CONCLUSION: Mantle cell lymphoma is a rare type of malignant lymphoma, over expressing CD5 and cyclin D1 antigens, which distinguishes it from other B cell lymphomas. PMID- 26011977 TI - Prevention and control of perioperative incision infection in patients undergoing day cataract surgery. AB - PURPOSE: To explore the effects of the prevention and control of perioperative incision infection on the quality of day cataract surgery. METHODS: The nursing care and efficacy of 5087 patients undergoing day cataract surgery between October 2012 and October 2013 were retrospectively reviewed. The disinfection and isolation guidance was established for perioperative prevention and control of infection, topical administration of ocular agents, reexamination and healthcare instruction, and alternative measures were taken. RESULTS: All 5087 patients successfully underwent day surgery of phacoemulsification combined with intraocular lens implantation. All cases recovered without incision infection. CONCLUSION: Preoperative preparation, and intraoperative and postoperative prevention and control of infection serve as vital measures for effectively avoiding the incidence of incision infection in patients undergoing day cataract surgery. PMID- 26011978 TI - Progress of application of sedation technique in pediatric ocular examination. AB - Pediatric ophthalmic test requires meticulous observation and precise measurement. However, children are unable to actively cooperate with the test. If they were forced to receive the examinations, it is difficult to deliver accurate diagnosis and treatment, and cause negative influence upon physical and mental health. Consequently, sedation technique plays an extremely vital role in pediatric eye examinations. This study was designed to summarize the application of chloral hydrate in pediatric eye examination and propose different methods of medicine administration for children of varying ages, aiming to improve the effect of sedation. In addition, the feasibility of use of dexmedetomidine, which had been proven to be effective in pediatric sedation examination, into pediatric ophthalmic sedation examination was evaluated, thereby offering more options for the development of pediatric ocular sedation test. PMID- 26011979 TI - Expression of GPI anchored human recombinant erythropoietin in CHO cells is devoid of glycosylation heterogeneity. AB - Erythropoietin is a glycohormone involved in the regulation of the blood cell levels. It is a 166 amino acid protein having 3 N-glycosylation and one O-linked glycosylation sites, and is used to treat anaemia related illness. Though human recombinant erythropoietin (rEPO) is produced in CHO cells, the loss in quality control is 80% due to incomplete glycosylation of the rEPO with low levels of fully glycosylated active rEPO. Here, we describe the expression from CHO cells of fully glycosylated human rEPO when expressed as a GPI anchored molecule (rEPO g). The results demonstrated the production of a homogenous completely glycosylated human rEPO-g as a 42 kD band without any low molecular weight glycoform variants as shown by affinity chromatography followed by SDS-PAGE and anti-human EPO specific western blot. The western blot using specific monoclonal antibody is the available biochemical technique to prove the presence of homogeneity in the expressed recombinant protein. The GPI anchor can be removed during the purification process to yield a therapeutically relevant recombinant erythropoietin molecule cells with a higher in vivo biological activity due to its high molecular weight of 40 kD. This is possibly the first report on the production of a homogenous and completely glycosylated human rEPO from CHO cells for efficient therapy. PMID- 26011980 TI - Pathology of a H5N1, highly pathogenic avian influenza virus, in two Indian native chicken breeds and a synthetic broiler line. AB - In this study, susceptibility to H5N1 virus infection was studied in two Indian native chicken breeds viz. Kadaknath and Aseel (Peela) and an Indian synthetic broiler strain (Synthetic dam line (SDL-IC). Fifty birds from each genetic group were infected intra-nasally with 1000 EID50 of a highly pathogenic avian influenza virus (HPAIV) strain A/chicken/Navapur/India/7972/ 06 (H5N1) and observed for a period of 10 days. Significant differences in severity of clinical signs, gross lesions and time for onset of symptoms were observed. The overall severity of clinical signs and gross lesions was less in SDL-IC broilers as compared to the other two genetic groups. The mortality percentages were 100, 98 and 92% with Mean Death Time (MDT) of 3.12, 5.92 and 6.96 days, respectively for the two native breeds Kadaknath and Aseel (Peela), the and SDL-IC broiler strain. Comparison of histological lesions revealed differences in disease progression among the genetic groups. Vascular lesions such as disseminated intravascular coagulopathy (DIC) were predominant on 3 days post infection (dpi) in Kadaknath, and on 5 and 6 dpi in Aseel (Peela) and SDL-IC broiler. The mean log2 HA titres of the re-isolated virus from various organs of H5N1 AIV infected birds of the three genetic groups ranged from 2.32 (lung, trachea and bursa) to 5.04 (spleen) in Kadaknath; 2.32 (lung) to 6.68 (brain) in Aseel (Peela); and 2.06 (liver) to 7.01 (lungs and kidney) in SDL-IC broiler. These results suggest that the susceptibility to H5N1 highly pathogenic avian influenza virus infection differed among the three breeds; Kadaknath being highest followed by Aseel (Peela) and synthetic SDL-IC broiler. This is possibly the first report on the differences in the susceptibility of the India native breeds to H5N1 virus infection and its severity. PMID- 26011981 TI - Flavonoid profile and antioxidant activities of methanolic extract of Hyparrhenia hirta (L.) Stapf. AB - In this study, we report isolation of flavonoids, viz., 3-O-methylquercetin, tangeritin, luteolin-7-O-glucoside, luteolin, apigenin-7-O-glucoside, apigenin-8 C-glucoside, luteolin-8-C-glucoside, luteolin-6-C-glucoside, diosmetin and catechin from the methanolic extract of Hyparrhenia hirta employing high performance liquid chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry. The total phenolic content of H. hirta extract was 105.58 +/- 0.1 mg gallic acid equivalents/g of plant extract while the total flavonoid content was 45.20 +/- 0.2 mg quercetin equivalents/g of plant extract and the total condensed tannin were 72.35 +/- 0.7 mg catechin equivalents/g of plant extract by reference to standard curve. The antioxidant activity was assayed through the antioxidant capacity by phosphomolybdenum assay, the reducing power assay and the radical scavenging activity using 2,2-diphenyl-1 picrylhydrazyl method. The extract showed dose dependant activity in all the three assays. PMID- 26011982 TI - Anticancer and anti-inflammatory activities of some dietary cucurbits. AB - In this study, we investigated few dietary cucurbits for anticancer activity by monitoring cytotoxic (MTT and LDH assays), apoptotic (caspase-3 and annexin-V assays), and also their anti-inflammatory effects by IL-8 cytokine assay. Aqua alcoholic (50:50) whole extracts of cucurbits [Lagenaria siceraria (Ls), Luffa cylindrica (Lc) and Cucurbita pepo (Cp)] were evaluated in colon cancer cells (HT 29 and HCT-15) and were compared with isolated biomolecule, cucurbitacin-B (Cbit B). MTT and LDH assays revealed that the cucurbit extracts and Cbit-B, in a concentration dependent manner, decreased the viability of HT-29 and HCT-15 cells substantially. The viability of lymphocytes was, however, only marginally decreased, yielding a potential advantage over the tumor cells. Caspase-3 assay revealed maximum apoptosis with Ls while annexin V assay demonstrated maximum efficacy of Lc in this context. These cucurbits have also shown decreased secretion of IL-8, thereby revealing their anti-inflammatory capability. The results have demonstrated the therapeutic potential of dietary cucurbits in inhibiting cancer and inflammatory cytokine. PMID- 26011983 TI - Impact of marine pollution in green mussel Perna viridis from four coastal sites in Karachi, Pakistan, North Arabian Sea: histopathological observations. AB - Pathological changes are regarded as a standard technique to monitor the effects of pollutants in marine animals. Histopathological examination of the population of green mussel Perna viridis (L.) from four sites in Pakistan, namely, Manora Channel, Rehri Creek, Sandspit Backwaters and Bhanbore was conducted. The first three sites are on the Karachi coast, whereas the fourth one, Bhanbore is situated outside Karachi, and is considered to be less polluted. Two types of parasites, Rickettsia-like organisms and metacestode were found in the mussels studied. In the present study, we observed various pathological lesions, such as inflammatory responses, granulocytomas, lipofuscin pigments, vacuolation in the digestive gland and gonads, lamellar fusion and dilated hemolymphatic sinus in the gills of P. viridis. These observations indicate the extent of environmental pollution in the studied areas. Although, Bhanbore is considered to be relatively less polluted compared to other three sites, the present results have revealed that the waters of Bhanbore are also polluted as evidenced by the pathological changes observed in the mussels collected from there. PMID- 26011984 TI - Sclerotiorin is non-mutagenic and inhibits human PMNL 5-lipoxygenase and platelet aggregation. AB - Sclerotiorin, isolated from the fermented broth of Penicillium frequentans, exhibited potent inhibition against human polymorphonuclear leukocytes 5 lipoxygenase and human platelet aggregation with a half maximal value 36 MUM and 250 MUM, respectively. Further, the Ames test has demonstrated the sclerotiorin to be non-mutagenic. PMID- 26011985 TI - Antimicrobial activity and identification of potential antimicrobial compounds from aquatic pteridophyte, Azolla microphylla Kaulf. AB - Azolla microphylla Kaulf. is an aquatic nitrogen fixing pteridophyte commonly found in aquatic habitats including paddy fields. Methanolic extract of the fronds of A. microphylla was subjected to partial purification by solvent partitioning with diethyl ether and ethyl acetate followed by hydrolysis, and further partitioning with ethyl acetate. The two fractions, thus obtained were tested for antibacterial activity. It was observed that the ethyl acetate fraction inhibited the growth of the pathogenic bacterium Xanthomonas oryzae. The GC-MS analysis of the ethyl acetate fraction showed several prominent peaks with retention time ranging from 8.83 to 45.54 min. A comparison of these peaks with the GC-MS libraries revealed that it could be eicosenes and heptadecanes with potential of antimicrobial activity. PMID- 26011986 TI - Microevolutionary trends of dengue virus-3 in Kerala, India. AB - Envelope gene is of great evolutionary significance and had been targeted as the vaccine candidate for dengue virus. We analyzed partial sequences of this gene to understand its genetic variability among viral isolates from Kerala state, India, if any. The current study focused on the evolutionary trends of this phylogenetically important gene among DENV-3 isolates through 2008 to 2010 outbreaks. The results gave an insight into the microevolutionary trends of the dengue viral genome. A unique mutation was recorded in the Domain II of the Envelope gene (EDII) of the viral genome at the amino acid position 219 (A219T). The evolutionary implication of this non-synonymous mutation near the EDI/EDII hinge remains to be explored. The study also provided knowledge on the genetic ancestral history of the viral isolates. Two variants of different phylogenetic origin were recorded in Kerala State. The findings in the study have significant implications on the development of dengue vaccines based on the Envelope gene of the virus. PMID- 26011987 TI - [How to assess and manage the acute phase of an asthma episode in children]. AB - Asthma is the most common chronic respiratory disease in childhood. An acute crisis can occur during an episode of exacerbation or may be the onset of the disease in a non-asthmatic child. Acute asthma is most often manifested by signs of respiratory distress that will lead the child to the doctor. Regardless of the context, the crisis has to be quickly and efficiently handled. The assessment of the crisis severity, immediate care, treatment and monitoring will be discussed in this article. PMID- 26011988 TI - [Intra-cystic renal calcium milk]. AB - Intra-cystic renal calcium milk is a rare entity. The authors report a clinical case, and describe the radiographic and tomodensitometric appearances. This 50 year old patient has been followed up for more than ten years for urinary lithiasis with recurrent pain. PMID- 26011990 TI - [Hair and their environment]. AB - Hair is influenced by the effects of the daily environment. Some toxic xenobiotics slow down or block the cell renewal of the hair matrix, thus inhibiting hair growth. The ultraviolet light obviously influences the physical structure and physiology of the hair follicle. Tobacco is similarly responsible for negative influences on the evolution of various alopecias. Several cosmetic procedures for maintaining and making hair more attractive are not always harmless, and they occasionally represent a possible origin for alopecia. PMID- 26011989 TI - [Acute disseminated encephalomyelitis: a pediatric case report]. AB - Acute disseminated encephalomyelitis (ADEM) is a disease of the central nervous system (CNS) mainly affecting children. It usually occurs within 2 days to 4 weeks following a triggering factor such a viral infection or an immunization. Clinical presentation is characterized by an acute encephalopathy and by multifocal neurologic abnormalities. In the absence of specific biologic marker, the diagnosis of ADEM is based on clinical, biological and radiological data including cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI). Brain MRI typically shows multifocal lesions predominantly involving the white matter. Treatment is based on high doses of steroids. Intravenous immunoglobulins or plasmapheresis are sometimes required. The prognosis is usually favorable but neurological sequellae can occur. PMID- 26011991 TI - [Comparison between chylothorax and pseudochylothorax]. AB - We report two cases of lipidic pleural effusion: an arthritis-associated pseudochylothorax and a chylous pleural effusion in a HIV seropositive patient. The incidence of lipidic pleural effusions is low, especially for pseudochylothorax. We review their clinical characteristics and management. PMID- 26011992 TI - [When rhinosinusitis reveals a systemic disease]. AB - This retrospective analysis is concerned with 10 patients suffering from granulomatosis with polyangitis (GPA, Wegener's disease), who were followed up in a tertiary care Ear, Nose, and Throat (ENT) department. The inaugural events took place in the ENT field (8 patients), the lung (2 patients), the vestibule (1 patient), or the oral cavity (1 patient). The ENT manifestations during the disease evolution involved the rhinologic (osetocartilaginous--6 cases; mucosal- 9 cases), the otologic (3 cases), or the laryngeal area (2 cases). Facial pain was noted in 6 cases and residual hyposmia in 5. We observed 5 cases of lung involvement, 3 cases of renal involvement, and 4 cases of ocular involvement. An aseptic meningitis was seen in 1 case and the muscles were affected in 6 cases. The average delay between symptom onset and diagnosis was 26 months. Endoscopy, imaging techniques, and determination of antineutrophil antibodies (ANCA) were used to reach the diagnosis. Sinus biopsies were contributive in 6 cases. The patients were treated with immunosuppressive drugs and/or surgery. After treatment, remission was obtained in 6 patients. PMID- 26011993 TI - [Cirrhotic cardiomyopathy: a brief overview]. AB - Even though cardiac disorders were described in alcoholic cirrhosis more than fifty years ago, cirrhotic cardiomyopathy was not defined until the end of the eighties. The term is used to describe all the cardiac structural and functional abnormalities observed in cirrhotic patients without any underlying cardiac disease. This cardiomyopathy is characterized by impaired systolic function, often unmasked during stress, diastolic dysfunction, and electrophysiological abnormalities. It can be detected by the electrocardiogram, transthoracic echocardiography and measurements of cardiac biomarkers (BNP). The pathophysiological mechanisms underlying this disease are complex: anomalies of adrenergic transduction pathways, alterations of myocyte membrane fluidity, fibrosis, cardiac hypertrophy, hormonal disturbances, and various ion channels derangements. To date, there is no specific treatment. Liver transplantation may be curative. The possibility of such a condition must be taken into account, when a TIPS or a liver transplantation are considered. PMID- 26011995 TI - "We want to know why you are #proud2nurse". PMID- 26011994 TI - [Rituximab (MabThera): a new therapy for ANCA vasculitis]. AB - Three recently published randomized studies have demonstrated the efficacy of rituximab in the induction and maintenance therapy of ANCA vasculitis. This is a major advance since these types of vasculitis entail a high morbity and mortality. PMID- 26011996 TI - Peer decries lack of leadership. PMID- 26011997 TI - Nursing Times #proud2nurse campaign aims to restore pride. PMID- 26011998 TI - Self-care slashes asthma admissions. PMID- 26011999 TI - NHS England senior nurse posts to be cut. PMID- 26012000 TI - NICE issues ectopic pregnancy guidance. PMID- 26012001 TI - Post-herpetic pain can last for years. PMID- 26012002 TI - British ebola nurse's African colleague dies of the virus. PMID- 26012003 TI - Royal hoax nurse blamed herself, inquest hears. PMID- 26012004 TI - Anger fuels nurse to challenge minister. PMID- 26012005 TI - NMC deemed to have made "substantial improvements". PMID- 26012006 TI - MPs back split of midwife supervisory role. PMID- 26012008 TI - "Scotland debate shows NHS is of value, not a privatised play area". PMID- 26012007 TI - "Nurses recognise their own health can affect care quality". PMID- 26012009 TI - "Private patient wards are a great source of revenue for the NHS". PMID- 26012010 TI - Using music to maintain the correct rhythm during CPR. AB - BACKGROUND: Cardiopulmonary resuscitation is a competency required of all health professionals, but they do not always meet chest compression standards. METHOD: Nurses received a traditional chest compression demonstration or one with music. Their compression rates were measured and compared. RESULTS: After instruction, 66% of nurses who had received demonstration with music performed chest compressions within the recommended range, compared with 41% of those receiving traditional demonstration. CONCLUSION: Using music when teaching CPR can improve nurses' performance of chest compressions at the recommended rate. PMID- 26012011 TI - Safe administration of blood components. AB - The transfusion process has many stages, each involving different members of staff in different locations. This gives rise to a significant potential for errors. Nurses are involved in many of these stages and therefore require knowledge, skills and competence in the process to ensure the safety of patients. This third article in our five-part series on blood transfusion discusses the safe administration of blood components and the key principles to which nurses must adhere. PMID- 26012012 TI - Opening up placement opportunities for students. AB - Student nurses need a variety of high-quality practice placements to prepare them for qualification yet, in reality, this can be difficult to achieve. A practice placement allocation model has enabled one university and its partner healthcare organisations to shift from a traditional, process-led system to a robust, proactive, student-focused approach. The model is based on partnership concepts including advance planning of student placements and clear lines of communication. It has resulted in 100% of first-year students taking part in a new fundamentals of care placement and received positive feedback from students and mentors. PMID- 26012013 TI - 60 seconds with Janice Stevens. PMID- 26012014 TI - Promoting self wound care. PMID- 26012015 TI - Get ahead, don't lose your way. PMID- 26012016 TI - "A guidance void is worst outcome for the dying". PMID- 26012017 TI - LCP "still in use" despite abolition. PMID- 26012018 TI - NMC poised to agree 20% fee hike. PMID- 26012019 TI - Unions vote to strike and work to rule this month. PMID- 26012020 TI - Nurses say 12-hour shifts are linked to poorer quality care. PMID- 26012021 TI - Scotland's chief nurse announces departure. PMID- 26012023 TI - Cancer patients highlight lack of hospital nurses. PMID- 26012022 TI - Hospital deaths fall "with use of mobile technology by nurses". PMID- 26012024 TI - Labour staff pledge needs university cash. PMID- 26012025 TI - Staff remain unsupported after whistleblowing, warns report. PMID- 26012026 TI - Nurses replaced with HCAs in district teams. PMID- 26012027 TI - "We have a new approach to tackle lack of choice in end-of-life care". PMID- 26012028 TI - "Have your say on research priorities for end-of-life care". PMID- 26012029 TI - Using subcutaneous fluids in end-of-life care. AB - There are currently no universally accepted medical or nursing guidelines for the administration of subcutaneous fluids at the end of life. Each case must be considered individually as it is unclear whether giving parenteral fluids to people who are dying causes, rather than alleviates, symptoms. This article discusses how to give fluids safely and suggests that relatives, who often feel very strongly about giving parenteral fluids, should be supported and involved in the decision making and care of their family member at the end of life. PMID- 26012030 TI - How to administer eye drops and ointments. AB - Eye drops and eye ointments are the main treatment for most eye conditions and after eye surgery or surgery to the periocular structures. This article outlines the role nurses play in ensuring the safe administration of topical eye medication and that patients adhere to their treatment regimens. PMID- 26012031 TI - An ethical defence of the Liverpool Care Pathway. AB - Palliative care in the UK has been ranked as the best in the world. However, the Liverpool Care Pathway was criticised and phased out. This article looks at the LCP's aims, assesses the problems and how these should be tackled. Many of these problems stemmed not from the LCP itself, but its improper use. Better training on the pathway and on communication with patients and relatives could ensure it is used correctly. PMID- 26012032 TI - Strategies to avoid unnecessary transfusions. AB - The Patient Blood Management initiative is an evidence-based, multidisciplinary approach to improve the care of patients who might need a transfusion of blood or blood components. It is an international initiative in best practice for transfusion medicine. This final article in our five-part series on blood transfusion outlines the origin and implementation of the Patient Blood Management initiative in England, why it matters, how it works, how it can be put into practice and nurses' role in supporting it. PMID- 26012033 TI - 60 seconds with Angela Parry. PMID- 26012034 TI - Ask nurse X. Sharing concerns. PMID- 26012035 TI - How to be the strongest link. PMID- 26012036 TI - "Chance to modernise NMC was squandered". PMID- 26012037 TI - NMC to monitor fee rise impact. PMID- 26012038 TI - Nurses and midwives prepare for pay strike. PMID- 26012039 TI - Review at Barts finds bullying and gossip rife. PMID- 26012041 TI - Francis effect stalls as nurse numbers start to fall. PMID- 26012040 TI - Overseas recruits take flight as trust loses half its new nurses. PMID- 26012043 TI - CQC identifies district nursing shortages. PMID- 26012042 TI - Crisis in family doctor retention threatens practice nurse posts. PMID- 26012044 TI - UK survivor of ebola praised for "courage". PMID- 26012045 TI - MP pledges support for inquiry into Worcestershire nurse case. PMID- 26012046 TI - IBD nurses too few to ensure "robust" service. PMID- 26012047 TI - "Train nurses to improve care for people with learning disabilities". PMID- 26012048 TI - "It's never been easier to return to the nursing profession". PMID- 26012049 TI - The transition from staff nurse to ward leader. AB - Moving from the staff nurse to ward sister role involves acquiring a range of skills to lead and motivate a team and ensure standards of care are high. Recognising new ward sisters' need for support, a trust developed a training programme to enable them to develop the necessary skills and provide mutual support. This article discusses the development of the programme and offers the reflections of three ward sisters who participated in it. PMID- 26012050 TI - Should practitioners override patient choices? AB - Patients sometimes decline health interventions, even if this puts them at risk of illness or injury. In such situations, health professionals must decide whether it is ethical to deny the patient's choice. This article presents a case scenario in which a patient declines hospital admission, and key arguments in favour of accepting or denying this choice. PMID- 26012051 TI - Individualised homeopathy after cancer treatment. AB - BACKGROUND: Increasingly, patients are surviving cancer and presenting with new health challenges, and there is greater demand for self-help and complementary and alternative medicine (CAM). AIM: To explore the benefits of a three-month course of individualised homeopathy (IH) for survivors of cancer. DESIGN: Small, community-based study. SETTING: Hampshire, UK. METHOD: Fifteen survivors of any type of cancer were recruited by a walk-in cancer support centre. Conventional treatment had to have taken place within the last three years. Patients scored their total, physical and emotional wellbeing using the Functional Assessment of Chronic Illness Therapy for Cancer (FACIT-G) before and after receiving four IH sessions. RESULTS: Eleven women had statistically positive results for emotional, physical and total wellbeing based on FACIT-G scores. CONCLUSION: Findings support previous research, suggesting CAM or IH could be beneficial for survivors of cancer. PMID- 26012052 TI - Supportive care after breast cancer surgery. AB - Routine follow-up after treatment for breast cancer aims to monitor for recurrence, manage late effects of treatment and give patients information, support and reassurance. However, most symptoms of local recurrence are first identified by patients so time spent following up women who are essentially well may not be clinically beneficial or cost effective. To better use its resources, Calderdale and Huddersfield Foundation Trust developed a follow-up education programme for patients at low-to-moderate risk; after two years an audit showed it reduced overall patient anxiety and routine hospital appointments, maintained standards of care and provided patient with an effective support network. PMID- 26012053 TI - 60 seconds with Tony Clapham. PMID- 26012054 TI - From law to long-term care. PMID- 26012056 TI - "A year of pay restraint and public support". PMID- 26012055 TI - Recognition is a powerful motivator. PMID- 26012057 TI - Overseas nurse influx on rise. PMID- 26012058 TI - Prior experience for students is the "bottom line", says Willis. PMID- 26012059 TI - London nursing shortage is at "critical" level, warns college. PMID- 26012060 TI - Francis investigating fate of whistleblowers. PMID- 26012061 TI - NHS leaders pledge to protect health and wellbeing of staff. PMID- 26012062 TI - Posture training slashes back injuries by 92%. PMID- 26012063 TI - Bloodborne virus exposure from sharps injuries on the rise. PMID- 26012064 TI - Government seeks views on FGM reporting. PMID- 26012065 TI - "Decent pay would show nurses the government values them". PMID- 26012066 TI - "Think spiritual and be alert to the needs of each patient". PMID- 26012067 TI - How to use personal protective equipment. AB - This article offers a refresher on what personal protective equipment (PPE) is, how to choose the right PPE and how to wear and remove it safely. PPE aims to improve staff and patient safety, but self-contamination commonly occurs during its removal; failure to remove PPE carefully can lead to contamination of the user's skin, own clothes, uniform or scrubs, hair, face and hands. The importance of correct PPE use has been highlighted by the ebola crisis and NHS preparations to deal with patients who are infected. PMID- 26012068 TI - Advising on lifestyle can improve nurses' health. AB - Many nurses are trained in brief health promotion interventions to ensure patients' lifestyles are assessed in relation to their overall health. Staff evaluations of health promotion training provided at Bolton Foundation Trust showed how it may prompt nurses to evaluate their own lifestyles. It could benefit healthcare organisations, as it may mean staff are supported to be healthier, happier and more productive. PMID- 26012069 TI - Support for mentors in clinical education. AB - Mentorship of student nurses within the clinical environment is a well established aspect of nurse training. With theory and practice being given equal weighting in the assessment of students' fitness to practise, effective mentorship in clinical settings is essential. While there have been calls for improvements to the clinical learning environment, the demands of daily practice mean it can be difficult to achieve effective mentorship. This article outlines one trust's initiative to improve mentorship support by introducing a clinical education mentorship support team. PMID- 26012070 TI - 60 seconds with Bernadette O'Gorman. PMID- 26012071 TI - "Nurse goodwill vital as winter pressures hit". PMID- 26012072 TI - Hike in assaults on NHS nurses. PMID- 26012073 TI - Critics blast NMC for senior team's "extravagant" pay rise. PMID- 26012074 TI - Morecambe Bay midwives face fitness to practise case. PMID- 26012075 TI - Crash in mental health nursing workforce branded a "tragedy". PMID- 26012076 TI - Hypertension plan depreciates PN role. PMID- 26012077 TI - GOSH staff told to work extra hours to rectify payment error. PMID- 26012078 TI - Stress cause of nurse suicide, rules coroner. PMID- 26012079 TI - Unions agree to new Wales only pay deal. PMID- 26012080 TI - Fall in access to COPD nurses sparks specialist care warning. PMID- 26012081 TI - New palliative care guidelines for Scotland. PMID- 26012082 TI - "We can learn from sharing our experiences and successes". PMID- 26012083 TI - "Why we're recruiting for the right values, as well as skills". PMID- 26012084 TI - Support for nurses returning to practice. AB - There are many benefits of nurses returning to practice: most are very experienced, likely to remain in practice until retirement, and RTP courses have low attrition rates and are more cost effective than pre-registration training. A review of RTP courses found differences in clinical placements, information on courses, funding and the availability of good mentorship. Health Education England has been working with stakeholders to improve the consistency and effectiveness of RTP courses to make it easier for nurses who want to come back to nursing. PMID- 26012085 TI - Role of the CCG nurse in commissioning services. AB - This article explores the changing landscape of commissioning, the commissioning nurse role within clinical commissioning groups and how the role has evolved as a result of the NHS organisational changes. It uses the results from two surveys undertaken by the Commissioning Nurse Leaders network, run by NHS England, to gauge the confidence of nurses in commissioning and leadership roles. PMID- 26012086 TI - How patient and staff experiences affect outcomes. AB - Exploring patient and staff experiences is a new discipline but is providing key insights into the quality of care patients receive. This article explores how patient and staff experiences are measured and how this information is used to change practice. PMID- 26012087 TI - Gaining evidence on the value of health visiting. AB - Health visitors are leading the development of the Healthy Child Programme. Indicators of effective delivery of the programme include parental satisfaction and public health outcomes such as breastfeeding. Proxy measures include delivery of universal HCP assessments. PMID- 26012089 TI - 60 seconds with Christopher Nicholson. PMID- 26012088 TI - Nursing at the centre of community services. AB - This article sets out how changes to the health and social care landscape puts community and primary care nursing centre-stage. PMID- 26012090 TI - "Sorry needn't be the hardest word to say". PMID- 26012091 TI - Unions warn on pension switch. PMID- 26012092 TI - Minister "confident" of hitting health visitor recruitment target. PMID- 26012093 TI - Badge device used to monitor hand hygiene. PMID- 26012094 TI - Cosmetic nurse practitioners to take part in revalidation pilot. PMID- 26012095 TI - "Red book" child records to go digital. PMID- 26012096 TI - It's "OK" to apologise to patients with valid complaints, says RCN. PMID- 26012097 TI - Midwives' leader claims pay decision is "political". PMID- 26012098 TI - Nurse cleared by NMC highlights "shame" of being suspended. PMID- 26012099 TI - "Whistleblower reprisals are costing the NHS trained talent". PMID- 26012100 TI - "Nursing is a social responsibility that can't be replaced with charity". PMID- 26012101 TI - "Holding on to Nightingale myths will damage her legacy". PMID- 26012102 TI - Preventing unintentional injuries in children. AB - Parents and carers try to keep children safe but accidents do occur, particularly in children aged under five years, and many take place in the home. Although it is rare, some of these may even result in death. In an effort to reduce the incidence of these injuries and deaths, Public Health England published a report earlier this year that identifies who is at risk and how professionals involved in children's early years care can help tackle the issue. This article summarises the key findings of that report. PMID- 26012103 TI - Using placements to teach on children's development. AB - Student children's nurses have limited opportunities to gain practical knowledge in normal child development. An initiative involving local non-healthcare organisations that provide care and education to the under-fives was introduced at a London university. This allowed student children's nurses to gain practical experience in meeting the needs of the well child, and to understand normal developmental milestones. Feedback from students and the organisations involved showed positive benefit. Plans are under way to extend the initiative to older children and young people. PMID- 26012104 TI - Treatment to target in rheumatoid arthritis. AB - Treating to target in rheumatoid arthritis means setting defined treatment goals, regularly measuring disease activity and working with, and informing, the patient of these targets at each step. This article discusses the role of the specialist nurse in developing and delivering treatment to target in RA, its impact on patient care and the development of a nurse-led clinic. PMID- 26012106 TI - 60 seconds with David Widdas. PMID- 26012105 TI - Assessing and supporting patients who have IBD. AB - This two-part series gives general nurses information about inflammatory bowel disease. Part 1 explored the aetiology, pathophysiology, signs and symptoms. This second part looks at how patients are assessed and treated, and the nurse's role. Although treatment of this condition may be complex, nurses can embed the 6Cs into practice to ensure they provide care and support of a high quality. PMID- 26012107 TI - [Role of sympatho-adrenomedullar system in adaptation to cold]. AB - It was persuasively shown that norepinephrine released from sympathetic nervous endings plays an important role in the adaptation to cold and epinephrine secreted by adrenal medulla. After acclimatization calorigenic effect of norepinephrine is enhanced. Catecholamines stimulate nonshivering thermogenesis in brown adipose tissue and apparently in white adipose tissue and in skeletal muscles. Adrenergic enhancement of tolerance to cold is depended upon an increase in UCP expression in tissues. In realization of calorigenic effect of catecholamines during long-term cold exposures it is participated following signaling pathway: catecholamines --> beta-adrenergic receptors (AR) --> adenylyl cyclase --> cAMP --> protein kinase A --> p38 kinase --> transcription factors - > enhancement of UCP expression. At acute cold exposure it was realized catecholamines --> beta-AR --> adenylyl cyclase --> cAMP --> protein kinase A --> hormone sensitive lipase --> free fatty acids --> UCP --> uncoupling oxidative phosphorylation. Calorigenic effect of alpha1--AR stimulation is realized by following mechanism: norepinephrine --> alpha1-AR --> phospolipase C --> inositol 1,4,5-triphosphate -->[Ca2+]i --> enhancement of calorigenic effect of catecholamines. PMID- 26012108 TI - [Unpredictable chronic mild stress effects on antidepressants activities in forced swim test]. AB - The experiments has been designed to study unpredictable chronic mild stress effect on anti-depressive activities of amitriptyline (10 mg/kg) and fluoxetine (20 mg/kg) in forced swim test in male outbred mice. It is shown that acute treatment with fluoxetine does not produce any antidepressant effects in mice following stress of 14 days while the sub-chronic injections of fluoxetine result in more deep depressive-like behavior. In 28 daily stressed mice, antidepressant effect of fluoxetine is observed independently of the injection rates. Amitriptyline demonstrates the antidepressant activity regardless of the duration of stress or administration scheduling, but at the same time the severity of anti immobilization effect of amitriptyline in stressed mice is weaker in compare to non-stressed trails. Thus, the injection rates and duration of unpredictable mild chronic stress are the parameters that determine the efficiency of antidepressants in the mouse forced swimming test. PMID- 26012109 TI - [The effect of peptide ACTH4-7-PGP on functional hepatocyte state in rats in acute and chronic foot-shock stress]. AB - The effect of ACTH4-7-PGP (Semax) intraperitoneal injection at the doses of 5, 50, 150 and 450 MUg/kg b. w. on lipid peroxidation and functional hepatocytes state in Wistar male rats subjected to acute and chronic electrical foot-shock stress was investigated. It was observed that peptide at the doses of 50 and 450 MUg/kg normalized malondialdehyde (MDA) level elevation in the liver homogenate caused by acute foot-shock stress. On the contrary, at the doses of 5 and 150 MUg/kg Semax significantly increased MDA content without essential changes of antioxidant defense activity (catalase, superoxide dismutase, common antioxidative activity). In serum peptide at the all doses decreased stress induced asparate aminotransferase activity elevation. In chronic stress peptide provided the normalization of protein synthetic hepatocytes function and the serum alanine aminotransferase activity with less effect on lipid peroxidation. PMID- 26012110 TI - [Influence of nitric oxide inhalations on oxidative and energy metabolism of blood in rats]. AB - The aim of this work was the investigation of nitric oxide (NO) inhalations action on some parameters of energy and oxidative metabolism of healthy rats blood. Wistar rats were randomly divided into two groups: control group (without any manipulations; n = 10) and main group (n = 10) with inhalations by NO containing gas flow (20 ppm). Activity of pro- and antioxidant systems, superoxide dismutase, lactate dehydrogenase and lactate level were estimated in rats blood samples. We observed stimulation of adaptive reserves of rats organism after course of NO (20 ppm) inhalations. First component of these changes was a modulation of pro- and antioxidant systems, including intensification of lipid peroxidation with prevalent activation of superoxide dismutase. Second component was a positive modification of lactate dehydrogenase functioning. PMID- 26012111 TI - [Age-dependent peculiarities of the rat's heart cholinergic regulation]. AB - In vitro and in vivo studies were performed to investigate the effects of M1-, M2 , M3-cholinoreceptors (M-AChR) blockade on the chronotropic and inotropic cardiac function in the rats of 1, 3, 6, 8 and 20 weeks old. These age groups were selected according to the development level of the autonomic regulation of the heart. It was found that the prior blockade of all three subtypes M-AChR did not prevent inhibitory effect of carbacholin on contractility of the atria and ventricles the animals of all studied age groups. The presence of the positive chronotropic response was found after blockade of M3-cholinoreceptor in 20 weeks old rats. The absence of cardiac chronotropic response to the blockade of M2 receptor was revealed. In 3, 6, 8 weeks-old rats the selective blockade of M-AChR does not change of the heart chronotrope. At the same time, the effect of the M1- and M2-AChR blockade on myocardial contractility was revealed. PMID- 26012112 TI - [Mathematical model of the hindlimbs control during cat locomotion with balance]. AB - The musculoskeletal model of cat's hind limbs, capable to step while maintaining balance, was developed using the MatLab. The skeletal part of the model (spine, pelvis, hips, shanks, foots) was created at SimMechanics. The joint in the spine attachment to the support and hip joint have three degrees of freedom. Knee and ankle joints have one degree of freedom. The pelvis is rigidly connected to the spine. The control of the skeleton's segments is done by six groups of muscles (flexors and extensors of hips, knees and ankles), modeled using the package VirtualMuscle. The generalized lateral force exerted on the spine was introduced to compensate insecure lateral deviations. Experimental verification of the model realness have shown that its locomotor characteristics (e. g., muscles activation patterns, oscillation period of pelvis, correlation between step length and maximal lateral shift of pelvis) do not significantly differ from the locomotion of decerebrate cats. The simulation confirms the key role of lateral force evolved by paravertebral and abductor-adductor muscles in the control of lateral stability during locomotion. PMID- 26012113 TI - [Thyroid status and antioxidant vitamins in the girls of different ethnic groups]. AB - In our work it was studied the metabolic reactions in adolescent girls representatives the two small nationalities (Tofalars and Evenki) and alien (Caucasians) of the population living in different areas of the Irkutsk region. It is found the hypothalamo-thyroid adaptive response development (increase in free T3 concentration, and decrease of TSH in Tofalars; and higher levels of total T4 and T3 in Evenki) in comparison with Caucasians. The study of antioxidant defense system demonstrated the increased content of a-tocopherol and retinol in Tofalars and only retinol in Evenki. The analysis of these two systems relationships revealed the correlation between the thyroid status and antioxidants (T3-alpha-tocopherol axis) in Evenki and Tofalars. This data proposed that indicated metabolic changes revealed in Tofalars and Evenki may be the result of genetically-determined long-term adaptation to the region environment conditions. PMID- 26012114 TI - [Identification of biological processes on the composition of the urine proteome in cosmonauts on the first day after long space flights]. AB - There are several difficulties that impede medical support of space missions. We can assume that the long-term space missions will be accompanied by functional changes in the organism. These changes will be a natural reaction to the factors of space flight. Complex action of factors can lead to the development of both non-specific changes (general adaptation syndrome), and specific changes. We analyzed the physiological changes after long space flights and carried out the correlation of these changes with previously identified proteins in the urine. It is possible to determine the mechanisms of adaptation of the human organism to the conditions of life on Earth after a long stay in Earth orbit. PMID- 26012115 TI - [Analysis of cardiorespiratory coupling in athletes and non-athletes at paced rate of breathing]. AB - The aims of the work were the study of cardiorespiratory coupling by method of paced breathing and the analysis of heart rate variability in men. Heart rhythm of 14 athletes and 12 non-athletes, 21 +/- 1.4 years old, was registered in 3 minute sessions during spontaneous and paced breathing 14, 10, 9, 8, 7, 6, 5, 4 times/minute. The subjects were following breathing rate from a display. Initial heart rate being more slow in athletes (p < 0.05) was retained during episodes of controlled breathing. The power of FFT spectra peaks of RR-intervals was growing quasilinearly during reduction of breathing rate, reaching its peak value at 5-4 breaths/minute in athletes. More pronounced modulations of RR intervals were observed in HF spectral band (p < 0.05) of athletes breathing 14-10 times/minute compared to non-athletes. The power of LF band of the spectrum in athletes breathing 8-4 times/minute was 2 times higher: variability of RR-intervals "shrinked" accordingly to paced breathing rate. The dominant role in slow oscillations of heart rate manifested by paced respirations with involvement of vagus baroreflex afferentations of lungs and chest is hypothesized to be the consequence of breathing under attentional control. PMID- 26012116 TI - Medicare ACO results: down, but not out. PMID- 26012117 TI - The status of advanced practitioners in nephrology: the 2014 report. PMID- 26012118 TI - The PD solution crisis. Incremental peritoneal dialysis may be of particular value--right now. PMID- 26012119 TI - ESRD special needs plans: a proof of concept for integrated care. AB - Since the completion of the Centers for Medicare and Medicaid Services' end-stage renal disease (ESRD) demonstration projects, passage of the Affordable Care Act, and announcement of ESRD Seamless Care Organizations (ESCOs) by CMS' Innovation Center, it seems that ESRD-centered accountable care organizations will be the future model for kidney care of Medicare beneficiaries. Regardless of what you call it--managed care organization, special needs plan, ESCO--balancing quality of health care with costs of health care will continue to be the primary directive for physicians and institutions using integrated care management (ICM) strategies to manage their ESRD patients' health. The renal community has had previous success with ICM, and these experiences could help to guide our way. PMID- 26012120 TI - The correlation between pain perception among patients with six different orthodontic archwires and the degree of dental crowding. AB - INTRODUCTION: Forces generated in orthodontic treatment with fixed appliances create tension and compression zones in the periodontal ligament resulting in a painful experience for patients. In the first phase of orthodontic treatment, when leveling of teeth is needed, nickel-titanium (NiTi) archwires can be completely engaged in brackets, even in the cases of extreme crowding, exerting small forces. There is a great individual variation in the pain perception related to the application of orthodontic forces. OBJECTIVE: The aim of this study was to investigate the pain perception among patients with dental crowding after insertion of six different NiTi orthodontic archwires as a part of fixed appliances in the first stage of orthodontic treatment. METHODS: The study was conducted on a sample of 189 orthodontic patients receiving one of six different either superelastic or heat activated NiTi archwires, in the first phase of orthodontic treatment. Pain perception was evaluated in groups of patients with different degree of crowding. The modified McGill Pain Questionnaire with Visual Analogue Scale was used to evaluate the quality and intensity of pain. Statistical analysis was performed using simple descriptive statistics, and Pearson's chi-square test with statistical significance of p<0.05. RESULTS: Majority of patients reported pain as discomfort or pressure of moderate intensity caused by chewing or biting, started within 12 hours, carried on for 3 4 days, and decreased over time without self-medication. CONCLUSION: No correlation was found between pain perception among patients with different types of NiTi archwires and the degree of crowdinq. PMID- 26012121 TI - Regional reference values of thyroid gland volume in Turkish Adults. AB - INTRODUCTION: It is important to know the size of the thyroid gland, and its normal value may vary among different geographic regions. OBJECTIVE: In this study, we aimed to establish reference ranges for thyroid volume in euthyroid adults and to compare these results with the literature data. METHODS: Between June 2011 and June 2012,461 patients with normal laboratory results (serum TSH, anti-TG, anti-TPO antibodies and urine iodine level) that underwent thyroid gland ultrasound examination were retrospectively analyzed.Two hundred and 92 patients were females and 169 were males; the age range was 18-61 years with mean age 30.84+/-9.97 years. Length, breadth and thickness were measured, and the volume of each lobe was estimated using the ellipsoid formula. RESULTS: The overall mean thyroid volume in all patients who were examined was 12.98+/-2.53 mL. The mean thyroid volume in females and males was 12.09+/-2.05 mL and 14.53+/-2.55, respectively (p<0.05). The right thyroid lobe volume was greater than the left in all patients of both sexes. In addition, the study establishes a significant correlation between the thyroid volume and height, weight and body surface area of the subjects of both sexes (p<0.05). In the light of our findings we can provide reference values in order to evaluate patients who have thyroid hyperplasia or who are considered as normal. CONCLUSION: We consider that further studies are necessary to establish national references thyroid volume for each country. PMID- 26012122 TI - Risk factors for the development of metabolic syndrome in obese children and adolescents. AB - INTRODUCTION: High prevalence of metabolic syndrome (MetS) in children and adolescents is a great concern of the modern society. OBJECTIVE: bjective: Our aim was to determine the influence of previously investigated, but also and potentially novel risk factors for the development of metabolic syndrome in children and adolescents. METHODS: Observational case-control clinical study was conducted involving children and adolescents with obesity/metabolic syndrome, treated on inpatient basis from January 2008 to January 2012 at the Pediatric Clinic of the Clinical Centre Kragujevac, Kragujevac, Serbia. The group of"cases"(n=28) included patients aged 10-16 years with the diagnosis of metabolic syndrome according to the International Diabetes Federation (IDF) criteria, while the control group included twice as many obese patients (n=56) matched to the compared group. RESULTS: Presence of maternal gestational diabates (ORadjusted: 39.426; 95% Cl: 1.822-853.271; p=0.019), and/or lack of breastfeeding in the first six months of life (ORadjusted: 0.079; 95% CI: 0.009 0.716; p=0.024) were significant predictors for developing MetS. Also, microalbuminuria is associated with MetS in obese children and adolescants (ORadjusted: 1.686; 95% Cl: 1.188-2.393; p=0.003) CONCLUSION: Presence of maternal gestational diabetes and/or lack of infant breastfeeding are considered as relevant factors that may contribute to the increased risk of developing MetS syndrome, while microalbuminuria is frequently associated with MetS in obese children and adolescents. PMID- 26012123 TI - Myocardial bridges: a prospective forensic autopsy study. AB - INTRODUCTION: When the coronary artery, located subepicardially, submerges into the myocardium and appears again subepicardially after a short intramural course, it represents an embedded coronary artery, while the part of the myocardium above is a myocardial bridge. OBJECTIVE: We investigated the frequency of the embedded left coronary artery (LAD) in the autopsy material considering the descending branch of the LAD to be the most important one in the nourishment of the myocardium and myocardial bridges to be the most frequent in its area, as well as clinically important. METHODS: A prospective autopsy study of 975 cases was performed, including both, natural (21.33%) and violent (78.67%) deaths. The sample consisted of 74.56% males and 25.44%females. In order to discover myocardyal bridges and their characteristics, the hearts were examined by both transverse cuts and longitudinal openings of the LAD. RESULTS: Myocardial bridge was found in 78 cases (8.00%), more commonly in males (9.35%) than females (4.03%).The average length of the myocardial bridge was 21.85+/-16.10mm and thickness 3.744+/-1.48 mm. The common localization of the myocardial bridge was the proximal half of the LAD (89.74%).The upper part of the artery, proximal to the bridge, was a common site of atherosclerotic changes. Myocardial bridge was found in 12.50% of natural deaths, but in 13.38% out of all cases of sudden cardiac deaths. CONCLUSION: Therefore, the presence of the myocardial bridge by itself is not predominant, but it is certainly a contributing factor to a sudden cardiac death. PMID- 26012124 TI - Comparison of functional outcome of colonic J-pouch and latero-terminal anastomosis in low anterior resection for rectal cancer. AB - INTRODUCTION: Functional results after low anterior resection for rectal cancer are an issue of increasing attention among colorectal surgeons and others interested in this subject. The consensus on ideal reconstruction type has not been achieved to date, although the number of papers on this subject has been published in recent years. OBJECTIVE: We conducted a prospective, parallel group study comparing latero-terminal with colonic J-pouch anastomosis in terms of defecatory function in patients undergoing stapled low colorectal/ coloanal anastomosis. METHODS: A total of 80 patients were included in this study with either latero-terminal or colonic J-pouch anastomosis. Defecatory function was evaluated using the modified version of MSKCC questionnaire 6, 12 and 24 months after the operation. Fecal continence was evaluated using the Wexner continence score. RESULTS: In both groups, trend towards improvement was registered in all measured variables in all three control intervals. This can apply to bowel frequency, urgency, night soiling, fragmentation and incomplete evacuation. However, the difference was not statistically significant, and when reviewing the trend of results we can note that in the J-pouch group steady state has not been reached even after 24 month control. CONCLUSION: This trial did not reveal any significant differences in defecatory function 6, 12 and 24 months after low anterior resection (LAR) between patients with a latero-terminal anastomosis and those with colonic J-pouch anastomosis. Our results did not confirm superiority of colonic J-pouch over the latero-terminal anastomosis PMID- 26012125 TI - Iatrogenic ureteral trauma: a 16-year single tertiary centre experience. AB - INTRODUCTION: lItrogenic ureteral injuries can occur during various abdominopelvic and retroperitoneal surgical procedures including gynecological, urological, colorectal and vascular. OBJECTIVE: The aim of our study was to examine the incidence and types of iatrogenic ureteral injuries occurred over the period of 16 years, as well as to evaluate the values of applied diagnostic and therapeutic procedures. METHODS: A retrospective analysis of clinical data (medical records and operative reports) of 55 patients (11 male and 44 female; mean age 54.5 years) with verified iatrogenic ureteral injury from 1998 to 2014, was performed. RESULTS: latrogenic ureteral injuries occurred during gynecological procedures in 55%, urological in 25%, colorectal in 15% and vascular in 5% of cases. Mechanisms of injury were incomplete transection (n=23), complete transection (n=1), ligation (n=7), partial perforation (mucosal abrasion) (n=1 3) and total perforation (n=1). The most frequent diagnostic procedures for postoperative identification of ureteral injuries were abdominal ultrasonography, excretory urography, antegrade pyeloureterography and retrograde ureteropyelography. Early therapeutic procedures were applied in 35 (64%), while delayed in 20 cases (36%). Early (<30 days) or late (>30 days) postoperative complications were verified in 14 cases (25%). CONCLUSION: Among different surgeries that may lead to the development of iatrogenic ureteral injury, gynecological procedures represent the most common cause. Rapid diagnosis enables immediate ureteral repair and is associated with low morbidity rates, representing a major factor contributing to the treatment success and ultimately preserving the renal function. PMID- 26012126 TI - The impact of demographic and socio-economic conditions on the prevalence of speech disorders in preschool children in Bitola. AB - INTRODUCTION: Speech development in preschool children should be consistent with a child's overall development. However, disorders of speech in childhood are not uncommon. OBJECTIVE: The purpose of the study was to determine the impact of demographic and socio-economic conditions on the prevalence of speech disorders in preschool children in Bitola. METHODS: The study is observational and prospective with two years duration. During the period from May 2009 to June 2011, 1607 children aged 3 and 5 years, who came for regular examinations, were observed. The following research methods were applied: pediatric examination, psychological testing (Test of Chuturik), interviews with parents and a questionnaire for behavior of children (Child Behavior Checklist - CBCL). RESULTS: 1,607 children were analyzed, 772 aged three years, 835 aged five years, 51.65% male and 49.35% female.The prevalence of speech disorders was 37.65%. Statistical analysis showed that these disorders were more frequent in three years old children, males living in rural areas and in larger families.They did not have their own rooms at home, they were using mobile phones and were spending many hours per day watching television, (p<0.01). Also, children whose parents had lower levels of education and were engaged in agriculture, often had significant speech disorders, (p<0.01). CONCLUSION: Speech disorders in preschool children in Bitola have a high prevalence. Because of their influence on later cognitive development of children, the process requires cooperation among parents, children, speech and the audiologist with the significant role in prevention, early detection and treatment. PMID- 26012127 TI - Impact of educational intervention on prescribing inappropriate medication to elderly nursing homes residents. AB - INTRODUCTION: Problems with polypharmacy, adverse drug reactions and non adherence are especially frequent among elderly nursing home residents. OBJECTIVE: The aim of our study was to evaluate effectiveness of a specific form of staff education on appropriateness of prescribing in a cluster of nursing homes for the elderly. METHODS: The study was designed as before-and-after trial of educational intervention on appropriateness of prescribing in nursing homes for the elderly. In total 20 nursing homes located in Belgrade, Serbia were included in the study with 104 elderly residents and 27 caring physicians. Appropriateness of prescribing was checked against Beers, START and STOPP criteria, before and 6 months after the intervention. RESULTS: There were 349 inappropriately prescribed drugs according to Beers criteria before the intervention and 37 drugs six months after the intervention. According to STOPP criteria there were 70 drugs inappropriately prescribed before the intervention, and 20 drugs 6 months after. When both criteria are taken together, there is a significant difference between the average number of inappropriate drugs per patient before (3.4+/-0.5) and after (0.6+/-0.7) educational intervention (t=38.902; p<0.001). Finally, before the intervention 143 appropriate drugs were omitted according to START criteria, while 6 months after the intervention there were only 67 omissions. CONCLUSION: Simple, but well targeted educational interventions may improve polypharmacy and decrease inappropriate prescribing rate, contributing to a better care of elderly patients in nursing homes. PMID- 26012128 TI - Social support, self-perceived health and mental status of general population of Republic of Srpska. AB - INTRODUCTION: Social support is defined as perception of how other people take care of us, how they understand our needs and give us support. Social support has positive influence on health, adoption of healthy lifestyles and recovery from illness. OBJECTIVE: The aim of this paper is to detect the level of social support across different socio-demographic groups and to analyze relationship between social support, self-perceived health and mental well-being. METHODS: Data from the 2010 Household Survey (National Health Survey) for the Republic of Srpska were used. A specially designed questionnaire was used, developed on the basis of internationally recognized and accepted instruments. Representative sample of 4,178 persons aged 18 and older were interviewed. RESULTS: The obtained results showed that the level of social support was the lowest among the oldest population, persons with the lowest level of education unemployed and unmarried.There was present relationship between social support, self-perceived health and mental health (distress/stress and vitality). It was detected that males mostly lived alone relying on help from neighbors, while females mostly lived with other household members and relied more on persons close to them. CONCLUSION: Social support appears to be related to mental status and self perceived health.The results are intertwined with different age groups and they can provide baseline for further analysis of causal relationship between social support and mental and physical health among different age categories. Detecting a link among social support, mental and physical health could provide insight into the mechanisms of social support influencing health status and behaviour. PMID- 26012129 TI - Giant destructive sinonasal polyposis. AB - INTRODUCTION: Authors report their clinical experience in managing a 46-year-old male patient with long lasting nose breathing difficulties caused by nasal obstruction due to a large bilateral tumor masses in both nasal cavities. CASE OUTLINE: Physical examination, laboratory and biochemistry analyses, as well as computed tomography showed an inhomogeneous soft-tissue tumor mass completely filling both nasal cavities, maxillary, ethmoidal, sphenoidal, and frontal sinuses on both sides, accompanied by destruction of bony walls of all sinuses. Preoperative histopathology analysis showed a polyp with squamous metaplasia.The gigantic polypoid mass was removed by bicoronal approach to the frontal and ethmoidal sinuses and by direct approach to the maxillary sinuses and nasal cavity. Definite histopathology analysis confirmed the initial diagnosis, but the presence of fungal hyphae in allergic mucus was also observed. CONCLUSION: Polypoid growth in the nose rarely grow to such gigantic dimensions that it causes destruction of all walls of paranasal sinuses. Considering so far published reports from the literature, the presented case is among the biggest nasal polyps reported until now. PMID- 26012130 TI - Ameloblastic fibroma: a rare case report with 7-year follow-up. AB - INTRODUCTION: Ameloblastic fibroma (AF) is a rare benign odontogenic tumor that usually occurs in the fi two decades of life. It affects adolescents and young adults and is found in the mandible and with a high frequency in the posterior region of this segment. There are rare case reports with a long-term follow-up. CASE OUTLINE: We report the case of a 6-year-old boy with extensive ameloblastic fibroma in the man ble. Treatment consisted of enucleation and bone curettage, with the preservation of permanent teE adjacent to the tumor. Clinical and radiographic follow-up of the patient over a period of 7 years show no signs of recurrence or malignant transformation. CONCLUSION: Patients with AF should be under follow-up for prolonged periods of time, even in ca! exhibiting a low proliferation index, because of the potential for recurrence and malignant transformation of this tumor. PMID- 26012131 TI - Laparoscopic distal pancreatectomy for intrapancreatic accessory spleen: case report. AB - INTRODUCTION: Accessory spleens can be found in up to 10% of the population, and their intrapancreatic occurrence is considered uncommon. When present, the intrapancreatic accessory spleen is usually found in the tail of the pancreas in about 1.7% of adult individuals. The infrequent presence of the accessory spleen in the pancreatic tissue could lead to inappropriate diagnosis and hence therapeutic approach, as they are commonly presented as a hypervascular node in the tail of the pancreas on abdominal CT and MRI, mimicking a well differentiated tumor of the pancreas or non-functioning pancreatic neuroendocrine tumor. CASE OUTLINE: We present a 70-year-old female in whom a preoperative evaluation finding was highly suggestive of a non-functioning neuroendocrine tumor of the pancreatic tail. We performed spleen preserving laparoscopic distal pancreatectomy, and histopathological examination revealed the intrapancreatic accessory spleen. CONCLUSION: Although infrequent, the presence of the intrapancreatic accessory spleen must be considered in the differential diagnosis of pancreatic tail tumors. PMID- 26012132 TI - Extragenital malignant mixed Mullerian tumor in the incisional hernia - primary carcinosarcoma in the abdominal wall: case report. AB - INTRODUCTION: This report presents a primary Mullerian carcinosarcoma localized in the incisional hernia i.e. anterior abdominal wall.There is no data in the literature about this localization of extragenital Mullerian carcinosarcoma. CASE OUTLINE: The patient had previous medical history of right-sided ovarian cystadenocarcinoma managed by hysterectomy, bilateral ovariectomy and chemotherapy. An incisional hernia occurred 1 year after the operation and Mullerian carcinosarcoma at the right border of the incisional hernia 16 years later. There was no tumor spreading into the abdominal cavity and pelvis. Full thickness of the abdominal wall resection and coexisting incisional hernia resulted in a large 25x20 cm abdominal wall defect managed by the modified components separation technique and implanting meshes. CONCLUSION: Major abdominal wall resection and abdominal wall reconstruction using the modified components separation technique reinforced with meshes could be one of possible solutions in the surgical treatment of primary malignant mixed Mullerian tumor localized in the abdominal wall. PMID- 26012133 TI - Management of brain metastasis in a patient with advanced epithelial ovarian carcinoma by gamma-knife radiosurgery. AB - INTRODUCTION: Brain metastases from epithelial ovarian cancer (EOC) are rare events. We present a rare case of single ovarian cancer metastasis to the brain treated with gamma-knife radiosurgery (GKRS). CASE OUTLINE: A 65-year-old woman with advanced EOC presented with severe neurologic symptoms. A single brain metastasis of 3.2 cm with surrounding edema in the left parietal lobe was detected by brain magnetic resonance imaging (MRI) scan during the work-up. The decision to perform GKRS was due to a surgical inaccessibility of intracranial lesion. Twelve weeks after the procedure, the MRI scan showed reduction in the diameter of brain metastasis and surrounding edema and the patient returned to good mental and motor performance.The patient survived for 22 months following treatment and died from a progressive intra-abdominal disease. Prognosis of ovarian cancer patients with brain metastases is generally poor regardless of treatment. CONCLUSION: Our case shows that GKRS as primary treatment modality for the control of ovarian cancer metastases to the brain was effective and can be considered as a treatment of choice if international selection criteria are followed. PMID- 26012134 TI - First successful pregnancy outcome after intrauterine insemination in a woman with primary infertility and essential thrombocythemia treated with interferon alpha and aspirin. AB - INTRODUCTION: The management of pregnancy in young women with essential thrombocythemia is complex and may present a difficult problem. An adverse pregnancy outcome due to thrombosis or bleeding is a common complication. in addition, little is known about fertility in these women prior to the disease. CASE OUTLINE: We present the first case of a young woman with primary infertility and essential thrombocythemia who had uneventfully delivered a healthy boy in the fortieth week of pregnancy. Her platelet count was normalized during treatment with interferon-alfa. The patient failed to become pregnant in the natural way and after three attempts of programmed intercourse. She conceived only following intrauterine insemination. During pregnancy, the patient was carefully controlled by a hematologist and gynecologist. CONCLUSION: Natural course and prognosis of essential thrombocythemia is not adversely affected by pregnancy. In these women, the pregnancy should be planned only after normalization of platelet count. The interferon-alpha should be administered before the pregnancy to regulate and maintain the platelet count within the normal range. Intrauterine insemination with minimal hormonal stimulation due to the risk of thrombosis could be recommended as the safest treatment option of infertility in women with essential thrombocythemia. PMID- 26012135 TI - [Complete androgen insensitivity syndrome]. AB - SUMMARY INTRODUCTION: Androgen insensitivity syndrome (AIS) belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY) with normally developed testes and age-appropriate for males of serum testosterone concentration. CASE OUTLINE: A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years.The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multi-sliced computed tomography (MSCT) showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia. CONCLUSION: The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina. PMID- 26012136 TI - [Develooment of the lower urinary tract and its functional disorders]. AB - A normal development of lower urinary tract function control evolves from involuntary bladder empting (incontinence) during infancy to daytime urinary continence, and finally a successful day and night continence that is generally achieved by the 5th to 7th year of age.This gradual process primarily depends on the progressive maturation of the neural control of the lower urinary tract, but it is also influenced by behavioral training that evolves through social support. Functional voiding disorders (bladder dysfunction) are common problems during childhood. They are present in 5-15 % of general pediatric population, and in one fifth of school-age children or in over one-third of patients of the pediatric urologist or nephrologist. More than half of children with bladder dysfunction have vesicoureteral reflux, and more than two-thirds have recurrent urinary tract infections. There is also a frequent association of bladder dysfunction with constipation and encopresis (dysfunctional elimination syndrome). Bladder dysfunction may cause a permanent damage to the upper urinary tract and kidneys. In addition, urinary incontinence, as the most common manifestation of bladder dysfunction can be the cause of major stress in school- age children and have a negative effect on the child's feeling of self-esteem. Thus, a timely detection and treatment of this group of disorders in children is highly significant. PMID- 26012137 TI - [High rate of native arteriovenous fistulas: how to reach this goal?]. AB - The types of vascular accesses for hemodialysis (HD) include the native arteriovenous fistula (AVF), arteriovenous graft (AVG) and central venous catheter (CVC). Adequately matured native AVF is the best choice for HD patients and a high percentage of its presence is the goal of every nephrologist and vascular surgeon. This paper analyses the number and type of vascular accesses for HD performed over a 10-year period at the Clinical Center of Serbia, and presents the factors of importance for the creation of such a high number of successful native AVF (over 80%). Such a result is, inter alia, the consequence of the appointment of the Vascular Access Coordinator, whose task was to improve the quality of care of blood vessels in the predialysis period as well as of functional vascular accesses, and to promote the cooperation among different specialists within the field. Vascular access is the "lifeline"for HD patients. Thus, its successful planning, creation and monitoring of vascular access is a continuous process that requires the collaboration and cooperation of the patient, nephrologist, vascular surgeon, radiologist and medical personnel. PMID- 26012138 TI - [Contribution of novel anticoagulants fondaparinux and dabigatran to venous thromboembolism prevention]. AB - The data that episodes and sequels of venous thromboembolism (VTE) are recorded in a significant percentage of patients receiving standard anticoagulants as VTE prophylaxis (unfractionated, low-molecular-weight heparin and vitamin K inhibitors) as well as the fact that these drugs have significant limitations and that they may cause serious side-effects in some patients indicate the need for the introduction of new anticoagulant drugs. Fondaparinux, a selective inhibitor of Factor Xa, administered following major orthopedic surgeries having a high risk for the development of VTE, is more efficient than enoxaparin sodium used in European and North-American approved doses. The increased incidence of major bleeding (excluding fatal) due to fondaparinux could be perhaps lowered by dosage reduction in patients with a mildly decreased creatinine clearance. Dabigatran, a peroral direct thrombin inhibitor, administered for VIE prophylaxis in elective hip and knee surgery, showed in to date studies the efficacv comparable (if dabiqatran is given in both dosage regimes of 150 mg and 220 mg daily) or superior (if dabigatran is given at a dose of 220 mg daily) to enoxaparin administered in European-approved doses, while North American-approved doses of enoxaparin were superior than dabigatran in VTE reduction. No significant differences in bleeding rates were determined in any of the study groups. We consider that the introduction of new anticoagulants, including fondaparinux and dabigatran, will contribute to the establishment of a better safety profile and efficacy, and will also enable adequate therapy individualization for each patient depending on his/hers clinical characteristics. The introduction of novel peroral anticoagulants will, inter alia, significantly contribute to improvement in the quality of life, release the patient from numerous limitations in nutrition, interreaction, frequent laboratory monitoring, and also significantly improve therapeutic predictability. PMID- 26012140 TI - Professor Yukio Fukuyama (1928-2014). PMID- 26012139 TI - Learning medical English: a prerequisite for successful academic and professional education. AB - The aim of this paper is to present specificities of the English language teaching necessary for successful education and professional training of medical students. In contemporary globalized world the English language has become the basic language of communication in all scientific fields including the field of medical science. It is well established that Medical English teaching should primarily focus on stable linguistic competence in English that is created by means of content and context based curriculum, thus preparing students for active use of English upon graduation. In order to achieve this it is very important that English language teaching be based on specific real situations in which the language is to be used. In addition, students should be encouraged to adapt practical skills applicable in specific future professional setting. Medical English teaching represents constant challenge for teachers because they need to be flexible, open to new approaches and methods, make decisions and adapt themselves to constant changes. In addition, long-term learning is at the core of higher education, and being equal partners, both students and teachers should be aware that education is a two-way process. PMID- 26012141 TI - [What do we know about chronic kidney disease at the beginning of the 21st century?]. AB - Data are presented on the number of chronic kidney disease (CKD) patients and on the most common causes of the disease, with special reference to data collected at the Registry of Renal Replacement Therapy by Dialysis and Kidney Transplantation in the Republic of Croatia. Emphasis is put on the very high cost of managing patients with end-stage CKD. As currently there is no drug able to halt progression of kidney damage in CKD, attention is focused on early detection of renal disease, screening of CKD patients, specific therapy, slowing down disease progression, and treatment of complications and comorbidities. The role of general practitioners and compliance of patients who have to decide on the mode of renal replacement therapy, as well as of continuous education of nephrologists and public awareness of renal diseases is underlined. PMID- 26012142 TI - [The effect of intradialytic exercise program on the quality of life and physical performance in hemodialysis patients]. AB - AIM: To determine the effect of a 16-week intradialytic exercise program consisting of 30 minutes of exercise during the first two hours of dialysis with three times a week frequency, on the quality of life (QoL), level of depression/anxiety and physical perfor- mance in hemodialysis (HD) patients. METHODS: The clinical, longitudinal, prospective study with one-group repeated measures design was conducted during a 16-week period. A convenience sample of 52 HD patients, who had been on HD for a minimum of 6 months, were included. QoL, level of depression and anxiety (questionnaires: SF-36, Back Depression Inventory (BDI) and Back Anxiety Inventory (BAI)) and physical performance (modifying Visual Analogue Scale (VAS) and Manual Muscle Testing (MMT)) were assessed at baseline and after 4-month exercise program. RESULTS: The following scales of SF 36 questionnaire were improved after 16-week exercise program: role functioning/emotional (P=0.01 8), energy/fatigue (P = 0.002) and social functi- oning (P = 0.030). Level of depression and anxiety were significantly decreased in males (P = 0.007 and P = 0.022, respectively) and females (P = 0.001 and P = 0.000, respectively). VAS scale and MMT were significantly increased in males (P = 0.000 and P = 0.001, respectively) and females (P = 0.01 9 and P = 0.001, respectively) after 16-week exercise program. CONCLUSION: Exercise program improves some aspects of QoL and physical performance, and decreases the level of depression and anxiety in HD patients. PMID- 26012143 TI - [Acid-base status in patients treated with peritoneal dialysis]. AB - When compared to hemodialysis, peritoneal dialysis is very simple yet low cost method of renal replacement therapy. Series of studies have shown its superiority in preserving residual renal function, postponing uremic complications, maintaining the acid-base balance and achieving better post-transplant outcome in patients treated with this method. Despite obvious advantages, its role in the treatment of chronic kidney disease is still not as important as it should be. Metabolic acidosis is an inevitable complication associated with progressive loss of kidney function. Its impact on mineral and muscle metabolism, residual renal function, allograft function and anemia is very complex but can be successfully managed. The aim of our study was to evaluate the efficiency in preserving the acid-base balance in patients undergoing peritoneal dialysis at Zagreb University Hospital Center. Twenty-eight patients were enrolled in the study. The mean time spent on the treatment was 32.39 +/- 43.43 months. Only lactate-buffered peritoneal dialysis fluids were used in the treatment. Acid-base balance was completely maintained in 73.07% of patients; 11.54% of patients were found in the state of mild metabolic acidosis, and the same percentage of patients were in the state of mild metabolic alkalosis. In one patient, mixed alkalosis with respiratory and metabolic component was present. The results of this study showed that acid-base balance could be maintained successfully in patients undergoing peritoneal dialysis, even only with lactate-buffered solutions included in the treatment, although they were continuously proclaimed as inferior in comparison with bicarbonate-buffered ones. In well educated and informed patients who carefully use this method, accompanied by the attentive and thorough care of their physicians, this method can provide quality continuous replacement of lost renal function as well as better quality of life. PMID- 26012144 TI - [Assisted peritoneal dialysis]. AB - According to the National Registry of Renal Replacement Therapy (RRT), the incidence of chronic kidney disease (end-stage renal disease) and the need of RRT have declined in the last decade renal. One of the reasons for this tendency certainly is transplantation as the best choice. However, transplant procedure has limitations in elderly patients due to the number of comorbidities. This study was designed as retrospective analysis of outcomes in patients treated with peritoneal dialysis for a period of eleven years. Patients were divided into those who had been assisted or unassisted. Out of 100 patients treated with peritoneal dialysis (PD), 77 completed the treatment, including 26 assisted and 51 unassisted patients. Peritonitis was recorded in 20 assisted and 26 unassisted patients. Peritonitis was more common in unassisted patients, who were more frequently lost from PD. Assisted PD could be a good and safe choice of RRT in this special group of patients. PMID- 26012145 TI - [Assessment of nutritional status in patients with chronic kidney disease on maintance hemodialysis]. AB - INTRODUCTION: It is well established that nutritional status is an important factor affecting the outcome and recovery from disease or injury. Assessment of nutritional status is an integral part of care for patients with chronic kidney disease, especially for those treated with dialysis procedures. According to available literature, 18%-80% of patients on dialysis have some form of nutritional deficiency. Furthermore, in patients treated with dialysis procedures there is a rule called 'reverse epidemiology', according which patients with better nutritional status have better survival rate. Therefore, nutritional assessment should detect malnutrition and rate the overall nutritional status of each patient through clinical data categories: medical history, physical examination, nutrition physical examination, psychosocial history, demographics, physical activity, and current medical/surgical issues. Consequently, the main aim of our study was to analyze the nutritional status of our patients treated with hemodialysis procedures. Another aim was to analyze the applicability of measuring skinfold by caliper as a method of nutritional status assessment. SUBJECTS AND METHODS: During a six-month period, we analyzed 129 patients (57.4% of men and 42.6% of women), mean age 68.1 +/- 12.4 years, treated with hemodialysis procedures (24.8% of patients were treated with online hemodiafiltration and 75.2% with standard, conventional hemodialysis) as the method of choice of renal replacement therapy (RRT) for more than 6 months. All patients were dialyzed three times a week for four hours on biocompatible synthetic membranes. The patients treated with online hemodiafiltration were dialyzed on high-flux helixone membranes, while those treated with standard, conventional hemodialysis were dialyzed on polysulfone membranes and helixone low flux membranes. The mean time of RRT was 71.2 +/- 56.7 months. During the study period, in each patient we followed medical history, and clinical and laboratory parameters of nutritional status at 3 and 6 months. To assess the nutritional status, we used dry weight (DW), body mass index (BMI), skinfold caliper measurement (result is correlated with total body fat, FAT), and common laboratory indicators of nutritional status (serum albumin and cholesterol). RE- SULTS: Analyzing the efficiency of skinfold thickness measurement with caliper, we found that the FAT obtained by caliper showed a statistically significant positive correlation with clinical indicators of nutritional status, and with BMI (r = 0.364, p < 0.0001), DW (r = 0.206, p = 0.005) and volume of muscle circumference (r = 0.399, p < 0.0001). Also, FAT showed statistically significant positive correlation with laboratory indicators of nutritional status, including serum albumin (r = 0.299, p = 0.01) and cholesterol (r = 0.225, p = 0.002). There was no statistically significant correlation between the duration of RRT and FAT (p = NS). CONCLUSION: In clinical practice, as well as for regular evaluation of nutritional status, it is important that the method we used proved efficient, precise, relatively fast and posing less economic burden. From our experience, the measurement of skinfold with caliper is an applicable, relatively quick and inexpensive method for regular assessment of nutritional status in patients treated with hemodialysis proce- dures. Therefore, all patients treated with RRT should undergo nutritional screening and expert help should be available from dietitians or nutritional support teams in order to identify this problem properly in its early stage and to reduce its high prevalence. PMID- 26012146 TI - [Analysis of patients with acute renal failure hospitalized at department of nephrology and dialysis, Rijeka University Hospital, during the five-year period]. AB - INTRODUCTION: Acute renal failure (ARF) is a serious complication that occurs in 5%-18% of hospitalized patients and in up to 30% of patients admitted to Intensive Care Unit. The hospital mortality rate of patients with ARF is between 28% and 90%. The incidence of ARF is proportional to patient age. Therefore, despite all improvements in modern medicine, the annual incidence of ARF has not changed over the two past decades. The aim of our study was to analyze the incidence and causes of ARF in our Center during the five-year period, to analyze the characteristics of patients and their comorbid conditions, variations in laboratory parameters during hospitalization, and therapy administered. Also, we analyzed the outcome and length of hospitalization. SUBJECTS AND METHODS: During the five-year period (from January 2008 till December 2012), we analyzed 316 patients treated for ARF at Department of Nephrology and Dialysis, Rijeka University Hospital Center. Data were obtained by searching medical records. ARF was defined according to the KDIGO recommendations: increase in serum creatinine (sCR) > 26 MUmol/L within 48 h, or increase in sCR by 1.5 times compared to the reference values, which is known or assumed to have appeared within a week of hospitalization, or diuresis < 0.5 mL/kg/h for >= 6 hours. RESULTS: Out of 316 ARF patients analyzed, 57 were hospitalized at our Department in 2008 (50.9% of men and 49.1% of women), 56 in 2009 (39.3% of men and 60.7% of women), 66 in 2010 (55.3% of men and 44.7% of women) and 76 in 2011 (55.3% of men and 44.7% of women). In 2012, we analyzed 61 ARF patients (42.6% of men and 53.4% of women). There were no statistically significant age and gender differences, although we noticed an increasing tendency in the number of elderly patients hospitalized for ARF. Furthermore, analyzing the frequency of patient arrival from home, nursing home or transfer from other departments we recorded an increase in the arrival of patients from nursing homes during the study period. Analysis of the proportion of patients hospitalized for ARF in our Department in relation to the total number of hospitalized patients revealed that ARF was the cause of hospitalization in 8.2%-9.9% of all patients. There was no significant change in the number of patients hospitalized for ARF during the period observed. Analyzing the frequency of hospitalization due to ARF by months, we noticed that the largest number of patients were hospitalized during summer months (from June to September). The most common form of ARF was prerenal (56.1%-67.9%). The largest number of patients were treated by parenteral rehydration and antibiotics (52.6% 71.4%). Renal replacement therapy was performed in 12.5%- 21.1% of all patients. The mortality rate throughout the period of observation ranged from 21.2%-30.4%. Furthermore, complete recovery of renal function was achieved in 30.5%-40.4% of all patients. The mean length of hospital stay ranged from 11.8 to 15.1 days. CONCLUSION: Acute renal failure is a significant cause of hospitalization, especially in elderly patients. Therefore, early identification along with appropriate and early treatment of patients with ARF is needed to improve survival and recovery of renal function in these patients. PMID- 26012147 TI - [Importance of standardized stepwise screening in patients with resistant hypertension]. AB - Resistant hypertension (RH) is a condition that confers a high cardiovascular risk to the patient due to both persistent blood pressure elevation and the high prevalence of comorbidities and organ damage. Hypertension is defined as resistant (RH) to treatment when a therapeutic strategy that includes appropriate lifestyle measures plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses fails to lower blood pressure (BP) values to < 140 and 90 mm Hg, respectively. Prior to diagnosing a patient as having RH, it is important to document adherence and exclude white-coat hypertension, inaccurate measurement of BP, and secondary causes. Ambulatory BP monitoring (ABPM) has become an important tool in the diagnosis and follow-up of hypertensive patient, and it is even more important in the evaluation of those with resistant RH. Among patients with RH, it is very important to select patients with standardized stepwise screening: ABPM of resistant hypertensives has a circadian profile with a high proportion of nondipping. The possible reasons for the absence of dipping are sleep disturbance, obstructive sleep apnea, obesity, high salt intake in salt-sensitive subjects, orthostatic hypotension, autonomic dysfunction, chronic kidney disease, diabetic neuropathy, and old age. It seems reasonable to routinely use ABPM in the initial evaluation of all resistant hypertensive patients. In a significant number of these patients, ABPM will also be an essential tool in follow-up, especially regarding the possible effects of all therapeutic maneuvers that are devoted to bringing BP into the target ranges. The potential success of other therapeutic options such as renal denervation depends on the ability to select patients most likely to benefit. PMID- 26012148 TI - [Resistant hypertension and reasons for excluding patients from treatment with renal denervation]. AB - Increased activation of the sympathetic nervous system is identified as an important factor in the development and progression of hypertension. In this context, a catheter-based approach has been developed to disrupt the renal sympathetic nerves, i.e. renal denervation. Among patients with resistant hypertension, it is very important to select patients using standardized stepwise screening. The potential success of renal denervation depends on the ability to select patients most likely to benefit. A multidisciplinary meeting in necessary. In this work, we describe the potential reasons for excluding patients from treatment with renal denervation. PMID- 26012149 TI - [Infections during the first posttransplant year--experience at Sibenik General Hospital]. AB - AIM: The aim of this study was to assess the frequency and type of infective complications in kidney recipients during the first year after transplantation. PATIENTS AND METHODS: We retrospectively analyzed data on the diagnosis and treatment of infective complications in 36 patients transplanted from 2004 until September 2012 (22 men and 14 women), age at the time of transplantation 19-73 years. We recorded the incidence of urinary tract infections, clinical variants (asymptomatic bacteriuria, acute pyelonephritis, sepsis) and etiology, i.e. causes, pneumonia, viral infections and cytomegalovirus infections (CMV) (with special reference to the use or no use of prophylactic valganciclovir), polyoma virus infection, BKV, JC, Epstein-Barr virus, and herpes zoster virus. RESULTS: The most common infective complication, uroinfection, was recorded in 69% of patients, of which 68% had one or more relapses. The most common clinical form of the infection was acute tubulointerstitial nephritis, caused by Klebsiella pneumoniae (of which 4 cases of ESBL Klebsiella pneumoniae). Pneumonia occurred in 4 transplant patients, one CMV pneumonia, other of bacterial origin. CMV infection and BKV occurred in 17% and herpes zoster infection in 11% of patients. One patient was diagnosed with EBV meningoencephalitis. One-year graft survival was 100% in patients without urinary tract infections in the first year after transplantation (31% of all patients) and 96% in patients with infections (69% of all patients).Three-year graft survival rate was 100% in patients without infection and 96% in patients with infections in the first year after transplantation. One- and three-year graft survival in patients with chronic hepatitis C was 100%. It was a small group of patients (5/36, 14%); the incidence of urinary tract infections amounted to 60%, and of CMV and BK virus to 20%. CONCLUSION: Infections are a common problem after kidney transplantation, which can be treated in a secondary care hospital. PMID- 26012150 TI - [Anesthesiological approach to patients with chronic kidney disease]. AB - Anesthesia in patients with chronic kidney disease (CKD) represents a challenge for anesthesiologists and other specialists in the perioperative team. There is a high incidence of CKD among patients preoperatively, especially in elderly population. For anesthesiologists, it is an imperative to understand the pathophysiology of CKD, prevention of further kidney damage and its complications. This requires experienced anesthesiologist, careful preoperative patient assessment, recognition and modification of the potential risk factors in order to improve patient outcome. Priorities for successful prevention of kidney damage are appropriate fluid distribution peri- and intraoperatively, maintenance of euvolemia, and avoiding hypotension. PMID- 26012151 TI - [Pathophysiological factors in the development of diabetic nephropathy--new insights]. AB - Diabetic nephropathy (DN), also known as Kimmelstiel-Wilson syndrome, is a progressive kidney disease characterized by nephrotic syndrome and diffuse glomerulosclerosis. It affects about 30% of patients with diabetes mellitus and is a prime indication for dialysis in many Western countries as well as in Croatia. Moreover, it takes a high fourth place in total disease cost, thus it is a very important public health problem. Hyperglycemia, dyslipidemia and hypertension are well established risk factors for the disease development and progression. However, nowadays, the knowledge about the pathophysiology of the disease is expanded and recently focused on the role of growth factors. Well balanced local and plasma concentration of growth factors is important for achievement and maintenance of glomerular integrity and function, so any disturbances could be a contributing factor to the development of DN. There is a growing body of literature suggesting that bone morphogenic protein 7 (BMP7), fibroblast growth factor 23 (FGF23) and fibroblast growth factor 21(FGF21) may play an important role in the DN development and progression. BMP7 possesses antifibrotic and proteolytic activity, so it could diminish the action of profibrotic factors and play an inhibitory role in the disease pathogenesis. It has been demonstrated that plasma concentration of BMP7 is decreasing in parallel to the drop in glomerular filtration rate (GFR) and albumin excretion increase. The plasma concentration of FGF21 and FGF23 has been shown to increase in parallel to DN progression. Moreover, they are linked with hyperinsulinemia and insulin resistance as well as with other diabetic complications such as cardiovascular events and endothelial dysfunction and retinopathy conditions closely related to DN. However, the background of the disturbances is not well established; it is not clarified whether GFR lowering causes increase of FGF21 and FGF23 or the increase in FGF21 and FGF23 concentration causes GFR lowering. The loop is yet to be clarified in order to develop a possible novel therapeutic approach in the treatment of this disease with serious consequences for the individual as well as for the entire population. PMID- 26012152 TI - [Dyslipidemia and stroke in patients with chronic kidney disease]. AB - Altered lipid and lipoprotein metabolism occurs in patients with chronic kidney disease (CKD). Dyslipidemia persists in patients on chronic hemodialysis orperitoneal dialysis and even in renal transplant recipients, and contributes to accelerated atherosclerosis but may also contribute to the progression of kidney disease as well. The etiologies of altered lipid profile in patients with CKD, dialysis, and renal transplant recipients are complex because there are profound changes in the structure and function of lipoprotein and lipid molecules, which lead to accelerated atherosclerosis, cardiovascular disease and stroke. Cardiovascular disease and stroke are the major cause of morbidity and mortality in patients with impaired renal function. In this review, the pathogenesis and treatment of CKD-induced dyslipidemia are discussed. Studies on lipid abnormalities in predialysis, hemodialysis and peritoneal dialysis patients are analyzed. In addition, results of the studies that tested the effects of hypolipidemic drugs on stroke morbidity and mortality in patients with CKD are reported. PMID- 26012154 TI - [Cardiorenal syndrome type 2--literature review]. AB - We performed literature search in the Pubmed database in July 2013. The key word used for search was cardiorenal syndrome type 2, limited to English language and humans. Over the last decade, a significant advance in the understanding of the cardiorenal syndrome has been achieved. However, precise pathogenesis remains to be clarified. Current treatment in postponing progression of cardiorenal syndrome type 2 is not efficient, although novel drugs like levosimendan and tezosentan seem promising. Future research is necessary to determine their role in the treatment of cardiorenal syndrome type 2. PMID- 26012153 TI - [Evaluation of viral hepatitis in solid organ transplantation]. AB - Renal transplantation has significantly improved survival of patients with end stage renal disease (ESRD). Transplantation is the best treatment in this population of patients. Despite the introduction of various preventive measures, viral hepatitis, i.e. hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, are still a major problem because they are common in patients on renal replacement therapy as well as in allograft recipients. They are a significant cause of morbidity and mortality in this patient population. In recent years, hepatitis E virus (HEV) infection has been added as an emergent cause of chronic hepatitis in solid organ transplantation, mainly in renal and liver allograft recipients. Most studies show higher mortality in renal transplant recipients (RTRs) infected with HBV, compared with RTRs without HBV infection, although this topic is still under debate. Furthermore, HCV infection in RTRs is associated with a significant reduction in patient and graft survival due to liver disease and septic complications related to cirrhosis and immunosuppressive therapy. The immunosuppressive therapy prescribed after transplantation modifies the natural history of chronic HCV infection. Given the high prevalence of HCV and HBV infections in RTRs, a growing incidence of hepatocellular carcinoma and the possible contribution of immunosuppression might be expected in these patients. Therefore, after renal transplantation, early screening with abdominal ultrasound (every 3 months in cirrhotic patients and every 6-12 months in non-cirrhotic RTRs) is necessary when the risk factors such as HBV and HCV are present. The European Association for the Study of the Liver (EASL) recommends that all HbsAg-positive patients who are candidates for solid organ transplantation should be treated with nucleoside analogs. The KDIGO guidelines recommend that all HbsAg-positive RTRs receive prophylaxis with tenofovir, entecavir or lamivudine; however, tenofovir and entecavir are preferable to lamivudin. Viral suppression by inhibiting necro-inflammation may result in reduced fibrosis, thereby improving transplant survival. Active HCV infection in a dialysis patient requires evaluation of liver fibrosis. Antiviral therapy should be given to all HCV-infected dialysis patients in order to achieve a sustained virologic response (SVR) not only to avoid subsequent hepatic deterioration but also to limit the risks of HCV-related posttransplant de novo glomerulonephritis. Systematic vaccination of all HbsAg-negative patients is the best preventive treatment of HBV infection. HbsAg positive donors are only used occasionally, whereas the use of hepatitis B core antibody (HbcAb)+, HbsAg negative donors is more common but remains somewhat controversial. The presence of antibody to HCV is indicative of HCV infection because antibody to HCV appears in peripheral blood within two months of HCV exposure. However, it is important to emphasize that detection of antibody to HCV by serologic screening of the donor is not predictive of HCV transmission. Approximately 50% of patients positive for antibody to HCV have detectable hepatitis C viremia by PCR analysis of peripheral blood. Therefore, all organ donors with PCR analysis positive for HCV will transmit HCV to RTRs. On the other hand, the risk of transmission from an organ donor with negative PCR analysis is unclear. Another problem in the evaluation of the potential donors of solid organs is the fact that antibody testing by enzyme-linked immunosorbent assays (ELISAs) will not detect recent infections. The use of nucleid acid testing (NAT) could be useful because it involves amplification of viral gene products and thus is not dependent on antibody formation. Therefore, by using this method the period between the infection and detectability, which is known as the window period, could be reduced. However, this method is expensive and time consuming. PMID- 26012155 TI - [Temporary and permanent central venous catheters for hemodialysis]. AB - The usage of temporary and permanent dialysis catheters for hemodialysis vascular access has been on continual increase. The reason for this increase is aging population on hemodialysis with blood vessels inappropriate for arteriovenous fistula creation. Complications may occur during catheter insertion as well as in the already inserted catheters, e.g., thrombosis and infections. The severity of complications is determined by experience of the operator as well as the quality and localization of blood vessels. Monitoring of dialysis catheter function, choice of the site of catheter insertion and methods of salvaging catheters from thrombosis and treating catheter-related local and systemic infections are described in this paper. Constant evaluation, proper care and hygiene of dialysis catheters are highly recommended. PMID- 26012156 TI - [Liver damage caused by atorvastatin and cyclosporine in patients with renal transplant]. AB - Kidney transplantation is the preferred method of treatment of end-stage renal disease, which significantly improves the quality of life, but also increases survival when compared to dialysis. Prevention of acute or chronic rejection demands the use of immunosuppression. However, nephrotoxicity, hepatotoxicity, cardiovascular disease, post-transplantation diabetes mellitus, chronic graft dysfunction and dyslipidemia may all occur as complications of immunosuppressive therapy. Dyslipidemia is a significant problem in renal transplant recipients due to the fact that it increases the risk of cardiovascular mortality in patients in whom the risk is already higher than in the general population. Very often, there is an interaction between immunosuppressive drugs, especially cyclosporine, and drugs that are used in the treatment of dyslipidemia. We present a case of a patient who developed severe hepatotoxicity after the introduction of atorvastatin in a cyclosporine-based immunosuppressive regimen. After discontinuation of atorvastatin and replacement of cyclosporine with everolimus, liver chemistries returned to normal values. PMID- 26012157 TI - [Disseminated intravascular coagulation and acute kidney injury requiring renal replacement therapy after diagnostic amniocentesis]. AB - Disseminated intravascular coagulation (DIC) is a very rare complication of amniocentesis. We present a case of a 33-year-old patient who developed DIC with acute respiratory distress syndrome and acute kidney injury after diagnostic amniocentesis. The patient required replacement of renal function for 59 days with continuous venovenous hemodiafiltration and later with hemodialysis. She was treated with heparin, fresh frozen plasma, platelets and cryoprecipitate. Her condition was further complicated with the development of intracranial hematoma. After 67 days of hospitalization, she was discharged from the hospital with serum creatinine 337 MUmol/L. Three years later, her serum creatinine was 102 MUmol/L, and she is currently in the 7th month of pregnancy. PMID- 26012158 TI - [Kidney function in a patient with thrombotic thrombocytopenic purpura]. AB - Thrombotic thrombocytopenic purpura is a systemic disorder with high mortality rate if not treated with plasma exchange. We present a case of severe thrombotic thrombocytopenic purpura diagnosed and treated at Montenegro Clinical Center, with spe- cial reference to the follow-up of renal function. PMID- 26012159 TI - [How to prevent protein-energy wasting in patients with chronic kidney disease- position statement of the Croatian Society of Nephrology, Dialysis and Transplantation]. AB - Protein-energy wasting (PEW) is a frequent problem in patients with end-stage renal disease, which is associated with adverse outcome. Risk factors for development of PEW in dialysis patients include anorexia, limitations in food intake due to problems with mineral metabolism (hyperphosphatemia, hyperkalemia). Prevention of PEW in dialysis population demands different therapeutic measures to correct abnormalities and to prevent loss of energy and proteins. Therapeutic approach should be individualized based on the specific problems of each patient in order to correct metabolic problems and to optimize food intake. In patients with inability to maintain nutritional status with standard oral feeding, other measures which include oral nutrition supplements and intradialytic parenteral feeding should be applied. Anabolic steroids, growth hormone and adequate oral nutritional supplements, together with physical activity may prevent further catabolism and correct abnormalities. Appetite stimulators, antiinflammatory interventions and anabolic drugs seem promising; however, their efficacy should be investigated in future clinical trials. PMID- 26012160 TI - [What doctors need to know about biosimilar medicinal products?]. AB - Biological drug is a drug containing one or more active substances produced or secreted from a biological source. Some of them may be previously present in the human body, and examples include proteins such as insulin, growth hormone or erythropoetin. Biosimilar drug is a medical product that is a copy of the original approved drug whose patent has expired. Strict rules apply to similar biological medicines: 1) it is unable to support extrapolation of data on safety and efficacy between individual indications, except in the case of appropriate, science-based evidence; 2) biosimilar drugs must meet the requirements associated with testing the immunogenicity and safety monitoring afterthe introduction of the drug in clinical practice, including the risk management program; 3) each biosimilar drug has to be labeled under its own name in order to allow clear traceability of all medications; and 4) the principle of automatic substitution cannot apply to biosimilar drugs because they are not interchangeable. PMID- 26012161 TI - [Transplantation and retransplantation--impact on emotional state]. AB - In our clinical practice, we are often faced with emotional difficulties of transplanted patients. Most are due to anxiety, difficulty in integrating newly recruited organ as its own, feeling of guilt, and difficulties with personal experience of self. Despite common presence of emotional difficulties, many studies describe improvement in the quality of life of transplant patients. However, the quality of life is deteriorating again in case of transplant rejection. In such situations, restlessness develops along with losing control over their own lives, a sense of failure, hopelessness and lack of prosperity ideas. Complex emotional experiencing is very important in strengthening the patient's psychological health and personality, thus achieving better treatment compliance in general. PMID- 26012162 TI - [Consensus statement of the Croatian Society for Nephrology, Dialysis and Transplantation regarding the use of generic immunosuppressive drugs]. AB - The use of generic immunosuppressive drugs may decrease the cost of immunosuppressive medication, although total cost sav- ings are still a matter of debate since patients need close monitoring after conversion from original to the generic formulation. A working group of the Croatian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in renal transplant recipients based on a review of the available data. Immunosuppressive drugs belong to the 'narrow therapeutic index' drugs, with huge pharmacokinetic variations secondary to the impact of food, other drugs, as well as of kidney and liver function. Failure to maintain an appropriate balance of immunosuppression seriously influences graft and patient survival. Published evidence supporting therapeutic equivalence of generic formulations is scarce or completely lacking. Different generic formulations may expose patients to uncontrolled product switching by pharmacists or general practitioners, which is very dangerous for patients, since generic preparations are not required to demonstrate bioequivalence with each other. The Croatian Society for Nephrology, Dialysis and Transplantation is not against the use of generic immunosuppressive drugs, but it requires close supervision of nephrologists and respecting the strict rules of their use. More efforts should be invested in education of primary care physicians as well as of patients to be aware of differences between the original and generic, as well as between different generic formulations. PMID- 26012163 TI - [Treatment of anemia in chronic kidney disease--position statement of the Croatian Society for Nephrology, Dialysis and Transplantation and review of the KDIGO and ERPB guidelines]. AB - Renal anemia is the result of chronic kidney disease (CKD) and deteriorates with disease progression. Anemia may be the first sign of kidney disease. In all patients with anemia and CKD, diagnostic evaluation is required. Prior to diagnosing renal anemia, it is necessary to eliminate the other possible causes. Direct correlation between the concentration of hemoglobin and the stage of renal failure is well known. Early development of anemia is common in diabetic patients. Correction of anemia may slow the progression of CKD. Anemia is an independent risk factor for developing cardiovascular disease in patients with CKD. Treatment of anemia in patients with CKD is based on current guidelines. Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group has produced comprehensive clinical practice guidelines for the management of anemia in CKD patients and ERBP (European Renal Best Practice) group its position statement and comments on the KDIGO guidelines. The Croatian Society of Nephrology, Dialysis and Transplantation (HDNDT) has already published its own guidelines based on the recommendations and positive experience of European and international professional societies, as well as on own experience. The latest version of Croatian guidelines was published in 2008. Since then, on the basis of research and clinical practice, there have been numerous changes in the modern understanding of the treatment of anemia in CKD. Consequently, HDNDT hereby publishes a review of the recent recommendations of international professional societies, expressing the attitude about treating anemia in CKD as a basis for new guidelines tailored to the present time. PMID- 26012165 TI - [Proteomics in nephrology]. PMID- 26012164 TI - [Guidelines for diagnosis, therapy and follow up of Anderson-Fabry disease]. AB - Fabry disease (Anderson-Fabry disease) is one of the most common lysosomal storage diseases (after Gaucher disease) caused by deficient activity of the alpha-galactosidase A (alpha-Gal A) enzyme, which leads to progressive accumulation of globotriaosylceramide in various cells, predominantly in endothelium and vascular smooth muscles, with multisystem clinical manifestations. Estimates of the incidence range from one per 40,000 to 60,000 in males, and 1:117,000 in the general population. Pain is usually the first symptom and is present in 60%-80% of affected children, as well as gastrointestinal disturbances, ophthalmologic abnormalities and hearing loss. Renal failure, hypertrophic cardiomyopathy, or stroke as the presenting symptom may also be found even as isolated symptoms of the disease. Life expectancy is reduced by approximately 20 years in males and 10-15 years in females, therefore enzyme replacement therapy should be introduced in patients of any age and either sex, who meet treatment criteria for Anderson-Fabry disease. PMID- 26012166 TI - In praise of doubt and systematic inquiry: conclusion. PMID- 26012167 TI - Deaf scholars on reading: a historical review of 40 years of dissertation research (1973-2013): implications for research and practice. AB - Taking a historical view, the authors reviewed 40 years of dissertation research by deaf scholars (1973-2013) related to reading. Using a qualitative interpretive analysis approach (J. Smith & Osborn, 2003), the authors selected 31 dissertations as primary texts, reviewing them for themes over five time periods. The first finding was a trend of themes on communication methodology in the 1970s (first period), to English reading skills in the 1980s (second period), to American Sign Language/English bilingualism to support acquisition of English literacy during the third, fourth and fifth periods (1990-2013). The second finding was that most of the dissertations used a combination of qualitatively similar and qualitatively different epistemologies in their research. These two findings are related to (a) the role of the deaf reading researcher, (b) historical and current trends in reading research, and (c) the qualitative similarity hypothesis (Paul, Wang, & Williams, 2013). PMID- 26012168 TI - Reading among diverse DHH learners: what, how, and for whom? AB - Students whO are deaf and hard of hearing (DHH) face challenges in learning to read. Much has been written about the relative importance of the different factors associated with success in reading, but these factors are disputed within the literature on DHH readers. The Center on Literacy and Deafness, funded by the Institute of Education Sciences, is engaged in a nationwide project to identify child-by-instruction interactions related to instructional factors that are malleable within the classroom context. In the present article, the authors describe the project, present the conceptual model on which it is based, explain the processes and procedures used to choose assessment tools, and discuss their theoretical view of how reading and instruction might differ based on an individual student's language and level of functional hearing. PMID- 26012169 TI - Effects of SES on literacy development of deaf signing bilinguals. AB - Research on spoken-language monolinguals and bilinguals has shown that socioeconomic status significantly affects literacy outcomes. One explanation for this effect is that children in higher-SES homes have better oral proficiency in the language of literacy instruction (Hoff, 2013; Zhang et al., 2013). American Sign Language-English deaf bilingual children exhibit a unique profile because they achieve L2 literacy without prior development of spoken L2 proficiency. This provides an opportunity to evaluate the role of SES in literacy development without the confounding effect of the influence of spoken-language proficiency. The present study evaluated effects of SES and ASL proficiency on 135 deaf signing bilinguals' English reading proficiency. Although SES and ASL proficiency were not correlated in this sample, both factors were significant predictors of reading proficiency. The implications of these findings for educational reform in schools with deaf students are discussed. PMID- 26012170 TI - Reading for deaf and hearing readers: qualitatively and/or quantitatively similar or different? A nature versus nurture issue. AB - The authors discuss whether the covert reading process differs qualitatively and/or quantitatively for hearing and deaf peers and whether formal reading instruction should be different for deaf and hearing students. The authors argue that hearing status (deaf, hearing) is less important in learning to read than environmental factors, including: (a) the richness of the early linguistic environment leading to an age-appropriate L1 prior to formal reading instruction and (b) clear, complete visual access to the instructional language (e.g., English, Spanish, American Sign Language) used to deliver curriculum via conventional or English Language Learner methods. In U.S. schools attended by 89% of deaf students, English is "regularly" used as the language of instruction (Gallaudet Research Institute, 2013, p. 11). Of the available communication systems for conveying English conversationally (oral-aural methods, Manually Coded English sign systems, Cued Speech), only Cued Speech is structurally capable of affording clear, complete visual access to English. PMID- 26012172 TI - An honour and a pleasure. PMID- 26012171 TI - The qualitative similarity hypothesis: research synthesis and future directions. AB - In the penultimate article of a two-part special issue of the American Annals of the Deaf examining the qualitative similarity hypothesis (QSH), findings of nine research teams with articles in the special issue are summarized. The teams addressed three questions: (a) For students who are d/Deaf or hard of hearing (d/Dhh), is reading qualitatively similar to the reading process of hearing students (per the QSH)? (b) Is it, rather, qualitatively different (per the qualitative difference hypothesis [QDH])? (c) Or is reading qualitatively similar and qualitatively different? All nine teams recognized that aspects of the reading acquisition process of d/Dhh children resemble those of hearing children and that the QSH is tenable if it is independent of a child's language modality. Two teams concluded that there is research supporting both the QSH and the QDH. Implications for teacher education, future research, and language policymaking are discussed. PMID- 26012173 TI - Don't panic! PMID- 26012174 TI - A contentious subject. PMID- 26012175 TI - Consultation on termination of pregnancy legal changes. PMID- 26012176 TI - An unusual finding at laryngoscopy: remember all is not always what it seems! PMID- 26012177 TI - ... its about the journey! AB - The aim of this article is to discuss: the importance of effective communication, the importance of maintaining confidentiality and equality for all individuals, the importance of maintaining a secure, safe and hygienic environment within the operating department, the principles of maintaining sterility and controlling infection, and the resulting hazards if these are not maintained. A paediatric patient was followed through her perioperative journey to find out if routinely, at the author's trust, the values of the NHS constitution--the six Cs--are being upheld. PMID- 26012178 TI - Surgical efficacy of the ankle tourniquet for forefoot surgery. AB - For precise, safe and proficient procedures haemostasis is critical. For forefoot surgery, the customary thigh tourniquet is commonly accepted for this role as the additional muscle mass and minimal bony prominences in the thigh avert neuromuscular and skin injury. However, for patients with pathophysiological issues that may be exacerbated by a thigh tourniquet, application of an ankle tourniquet may decrease the risks and increase cuff tolerance as the volume of ischaemic tissue is reduced. PMID- 26012179 TI - The right skin preparation technique: a literature review. AB - Recent debates and guidelines are suggesting back and forth motion to be the optimal preoperative technique for skin preparation. There is a lack of conclusive evidence showing this to be the case, but it may be reasonable to follow this technique, in preference to the widely used concentric circles motion, as the antiseptic agent will reach deeper cell layers of the skin where most of the microbes are found. PMID- 26012180 TI - Admiral Nelson's above elbow amputation. AB - The loss of Horatio Nelson's right arm is undoubtedly the best known amputation in this country's history and the story is well worth the telling. In 1797, the 38 year old Nelson, then a Rear Admiral, devised a plan for a surprise night attack to seize treasure ships, which he believed were sheltering at Santa Cruz on Tenerife, (one of the Canary Islands). On the night of July 24th, Nelson led an armada of rowing boats from his fleet, anchored below the horizon. The plan was to land on the harbour mole and then rush the main square of the town. Unfortunately, the Spaniards were ready for them. As the little boats approached the harbour, the Spaniards opened fire with cannon and muskets and the British losses were heavy. As Nelson scrambled off his boat his right arm was shattered with grapeshot; "I am shot through the arm, I am a dead man" he exclaimed. PMID- 26012181 TI - Are you invisible? PMID- 26012182 TI - I could never do research. AB - My recent career move into allied health education has served as a reminder of the importance of research in healthcare. Whether we, as perioperative practitioners, perform a clinical audit, evaluate a service, explore a patient's experience or undertake a large-scale research project, the results from all types of studies shape what we do in practice and also what we teach in both pre- and post-graduate education. This month's Journal of Perioperative Practice recognises the importance of perioperative research by bringing together a collection of papers detailing the results from a variety of studies carried out by perioperative practitioners. PMID- 26012183 TI - Who are physicians' assistants (anaesthesia) and where do they work? AB - Physicians' Assistants (Anaesthesia) (PA(A) s) were introduced in the UK almost a decade ago, and are now established within many NHS hospitals. PA(A)s are highly trained and skilled practitioners that work within an anaesthetic team under the direction and supervision of a consultant anaesthetist. These professionals are involved in all aspects of general anaesthesia delivery and some organisations have trained PA(A)s to additionally perform regional and local anaesthesia procedures. PMID- 26012184 TI - What's in a name? An evaluation of public perceptions around job role titles within the modern anaesthesia team. AB - The aim of this study was to examine the association made by members of the public between a healthcare professional's title and the function they actually perform within the anaesthesia team. It was also the intention of this research to establish whether the public felt that the title 'anaesthesia practitioner' or 'physicians' assistant (anaesthesia)' was more synonymous with a member of the non-medical team trained to administer anaesthesia. The study population evaluated was 55 members of the public who were randomly selected from the outpatient department at Good Hope Hospital, part of Heart of England NHS Foundation Trust. Results demonstrated that the titles the general public felt were most synonymous with healthcare professionals who administer anaesthesia were 'consultant anaesthetist' and 'anaesthesia practitioner'. Less than a third of those evaluated felt that an anaesthetic would be given by a 'physicians' assistant (anaesthesia)'. PMID- 26012185 TI - Patient evaluation of outpatient venous thromboembolism prophylaxis service following lower limb injuries using a developed validated questionnaire. AB - This paper explores patients' perceptions of a new service and protocol for managing outpatient venous thromboembolism (VTE) prophylaxis, using either subcutaneous Dalteparin or oral off-license Dabigatran in patients with lower limb injury requiring immobilisation. Establishing a patient's perspective is part of good practice as, when this is positive, it aids patient compliance and protocol dissemination. A questionnaire consisting of fifty questions was given at random to one hundred patients over a six month period when they attended the trauma clinic. Each question was scored on a five point Likert scale (1 = poor, 5 = excellent) by the patient. The internal consistency of the questionnaire (Cronbach's alpha reliability coefficient) was more than 0.9 in all domains. Qualitative analysis was done for open-ended questions. One hundred respondents completed the questionnaire, two were void due to significant amounts of incomplete data. The gender split was 54 females, 43 males, and one did not answer the question. The average age was 43 (range 18-72). Sixty seven respondents were first-time attenders, 22 were follow-up patients and nine did not complete this section. The overall average score was 4.26 (range 1-5), with 90% of the patients recommending the service. The overall patient satisfaction for a VTE prophylaxis service is high although there is room for improvement as demonstrated by the range of the scores. PMID- 26012187 TI - The shocking stocking audit: an audit on the use of thromboembolic deterrent stockings (TEDS) for patients having surgery at Sligo regional hospital. AB - A concurrent audit was conducted over a four week period to determine if patients coming for surgery and wearing thromboembolic deterrent stockings (TEDS) adhered to local policy and recommended guidelines. Data was collected on 30 surgical procedures. The audit highlighted failings in the application of TEDS, identifying poor compliance with correct measurement, application and documentation. It also recognised poor communication between care givers and surgical patients regarding TEDS use. There needs to be an increased awareness about local policy, national and international guidelines regarding the use of TEDS for patients having surgery. PMID- 26012186 TI - Part one: An introduction to the research process. AB - Research modules have become a common inclusion to graduate healthcare programmes. To the novice researcher, undertaking a study or dissertation can appear daunting. This article is the first of a series of four that aims to help perioperative practitioners feel more positive about undertaking a project by examining the research process and the theoretical frameworks of qualitative and quantitative approaches. The final of the four articles provides advice on writing a dissertation. PMID- 26012188 TI - The first 'antiseptic' operation. AB - On August 12th 1865, 150 years ago, the Professor of Surgery at the University of Glasgow, Joseph Lister, performed a relatively minor operation in a side ward at the Royal Infirmary, the dressing and splintage of a compound fracture of the left leg. Yet this operation must be regarded as the watershed between two eras of surgery--the primitive and the modern--since it was the first to be performed as an antiseptic procedure. PMID- 26012189 TI - Do you know the new recognition and requirements for education, training and job descriptions for your CSSD staff? PMID- 26012190 TI - Work-life balance. PMID- 26012191 TI - Never happen? It could just be a matter of time. PMID- 26012192 TI - A sticky situation! PMID- 26012193 TI - Chief Inspector of Hospitals, professor Sir Mike Richards announces his findings following an inspection at Mid Staffordshire NHS Foundation Trust. PMID- 26012194 TI - The productive operating theatre and lean thinking systems. AB - The concept of 'lean thinking' first originated in the manufacturing industry as a means of improving productivity whilst maintaining quality through eliminating wasteful processes. The purpose of this article is to demonstrate how the principles of 'lean thinking' are relevant to healthcare and the operating theatre, with reference to our own institutional experience. PMID- 26012195 TI - The challenge of change: not everyone's cup of tea. AB - This article explains how the authors adapted The Productive Operating Theatre (TPOT) programme for a large theatre department. The multidisciplinary theatre teams identified barriers at each launch. At subsequent programme workshops they learned to collate information and to work together to challenge and change practices. PMID- 26012196 TI - Reflective case study on end of life care in post anaesthesia. AB - Operating department practitioners (ODPs) are well known for their technical abilities within the perioperative environment and are passionate about the care they deliver. This article will critically reflect on the post anaesthetic care of a dying patient, the challenges of having relatives present, the importance of having a good student/mentor relationship, and will show that student ODPs can deliver compassionate and personalised care. PMID- 26012197 TI - Patients' willingness to drink carbohydrate liquids two hours before surgery. AB - Carbohydrate loading is an important component of enhanced recovery pathways. Some practitioners argue that patients' low acceptance for drinking such solutions could hamper the implementation of a full protocol. The aim of this study was to assess patients' actual acceptance of drinking carbohydrate solutions. Thirty patients scheduled to undergo digestive surgery participated in a survey which asked them to evaluate the taste of a carbohydrate loading drink mix (Clinutren Preload). They were asked whether they took all the solution, experienced nausea or vomiting, and whether they would be willing to take the solution again. Twenty two patients (73%) took all the solution, 27 (90%) judged the solution easy or quite easy to drink, 25 (83%) found the taste good or quite good, and 23 experienced (76%) no nausea. Finally 16 patients (54%) responded that they would be willing to take it again if indicated. We concluded that patient-related factors were not sufficient to hamper the implementation of carbohydrate loading before major surgery. The lack of implementation is probably related more to the attitude of the practitioner. PMID- 26012198 TI - The strangulated umbilical hernia of Queen Caroline. AB - One of the lessons we learn from medical history is how great the improvement has been in the management of commonplace surgical emergencies. Less than three hundred years ago, the Queen of England, in her healthy middle age, died of a straightforward strangulated umbilical hernia. PMID- 26012199 TI - Different strokes. PMID- 26012200 TI - Is the NHS safe in their hands? PMID- 26012201 TI - 'We need to put children at the heart of services'. PMID- 26012203 TI - Best practice in infancy: moving onto cups. PMID- 26012202 TI - The healing power of love. PMID- 26012204 TI - Type-i diabetes: are children getting the care they need? PMID- 26012205 TI - Wound care for children. Part 1. PMID- 26012206 TI - Protecting family health. PMID- 26012207 TI - MMP inhibitors and cancer treatment trials, limitations and hopes for the future. AB - Matrix metalloproteinases (MMPs) are a family of enzymes that have been recognized as promising therapeutic and diagnostic targets for the treatment and detection of human cancers. This rises from their unique ability to degrade all components of the extracellular matrix and their overexpression at different stages of tumor progression. The specific involvement of MMPs in the oncogenic processes has speeded up the efforts that have been made for the past 20 years to develop and evaluate MMP inhibitors (MMPIs) as potential anti-cancer agents. However, bringing an MMPI to the point of clinical approval is still a challenge. In this review, we provide an overview of the structure and function of MMPs along with their implication in cancer development. Furthermore, we focus on the literature concerning the development of broad spectrum natural and synthetic MMPIs, with emphasis on their limitations and the disappointing results of most clinical trials. The failure of broad spectrum MMPIs highlighted the need for the development of selective inhibitors that fully discriminate between different members of the MMP family. As a future perspective on the development of potent MMPIs, we also report in this review a novel structure-based strategy developed in our group to design new mini-protein ligands for MMP inhibition by functional motif grafting. PMID- 26012208 TI - [Snake venom proteins related to "vascular endothelial growth factor": new tools for therapeutic angiogenesis]. AB - The Vascular Endothelial Growth Factor "VEGF" plays a pivotal role in the stimulation of angiogenesis. The VEGF isoforms (A-D) and PlGF act in a coordinate fashion to develop the vascular network. Numerous proteins closely related in structure and function to VEGF-A have been reported and were grouped in the VEGF family. Some predators make use of VEGF-like molecules with devastating results for their prey. VEGF-E, investigated in 1994, is encoded by the parapoxvirus (Orf virus). VEGF-F is a common term designating molecules which were isolated from snake venom (also known as svVEGF). These proteins are disulphide-linked homodimers of 110 amino acids each and have a molecular weight of approximately 25 kDa. Their primary structures show approximately 50% identity to VEGF-A. However, unlike VEGF-A, they do not contain any N-linked glycosylation sites. They interact with heparin but have a different binding domain from that of VEGF A. Among species, these svVEGFs vary extensively in amino acid sequences and in receptor-binding specificities towards endogenous VEGF receptors. Understanding the properties that determine the specificity of these interactions could improve our knowledge of the VEGF-receptor interactions. This knowledge is essential to the development of new drugs in angiogenesis. This knowledge is essential to the development of new drugs in angiogenesis. PMID- 26012209 TI - In vitro antifungal activity of the essential oil and the methanolic extract of Ruta chalepensis. AB - Ruta chalepensis L. (Rutaceae), is an ancient aromatic medicinal plant still used in the traditional medicine of many countries as a laxative, antiinflammatory, analgesic, antispasmodic, abortifacient, antiepileptic, emmenagogue and for dermatopathy treatment. Regarding increasing prevalence of mycotoxins and inefficiency of methods used to decrease them, it is possible to use plants metabolites to decrease mycotoxins. This study was carried out to evaluate chemical composition, antifungal and anticandidal activities of R. chalepensis extracts. The chemical composition of its essential oil was analyzed by gas chromatography coupled with mass spectrometry (GCMS). The major components of R. chalepensis essential oil were menthol (49.92%), linalool (31.1%) and 2-hexanal (5.2%). The antifungal and anticandidal effects of the essential oil and methanolic extract of R. chalepensis leaves were studied by disc diffusion assay and broth dilution method. The obtained results showed that R. chalepensis extracts had a significant fungicidal effect against Aspergillus niger, Aspergillus flavus and Candida albicans. The inhibition zones diameters and the minimum inhibitory concentration values for tested microorganisms were in the range of 11-17 mm and 3.25-6.25% (v/v), respectively. The methanolic extract showed much better antimicrobial activity than the essential oil against three tested micro-organisms PMID- 26012210 TI - [Comparative study of survival Vibrio parahaemolyticus with Escherichia coli and Salmonella typhimurium in seawater]. AB - In this work, survival tests are conducted in oligotrophic seawater using pathogenic bacterial strains: Escherichia coli enteroagregative, Salmonella Typhimurium and Vibrio parahaemolyticus. After 26 days of incubation in seawater, the three bacterial strains are exposed to sunlight for nine hours. Bacterial cells of the three strains, recovered at the end of the experiment by centrifugation were tested for their sensitivity to antibiotics and their enzymatic and metabolic profile (API 20E and 20NE). The results showed a decline in the culturability of ascending chronological order: first enteroaggregative Escherichia coli (T90 = 7 days), followed by Salmonella Typhimurium (T90 = 12 days) and finally Vibrio parahaemolyticus (T90 = 43 days). Vibrio parahaemolyticus strain showed better survival under seawater conditions before and after exposure to sunlight compared to other strains tested. On the other hand, the most reduced survival time is observed for Escherichia coli, which then becomes inadequate to predict halophilic pathogenic bacteria. Also, we noted that the solar radiation in this study would be the most important factor affecting the survival of three bacterial strains incubated in oligotrophic seawater. Changes of the enzymatic and metabolic profile are more pronounced in Escherichia coli and Salmonella, which reflect a form of resistance and a response to the passage in a hostile environment. However, the rate of antibiotic susceptibility is more apparent in Vibrio (100%) compared to the wild type Escherichia coli (60%) although the latter has completely lost its power to cultivate. This result underlines the relationship between the antibiotics resistance power of VNC cells and the history of the bacterial strain. PMID- 26012211 TI - Coinfection with Mycobacterium tuberculosis and Pneumocystis Jirovecii in immunocompetent young woman. AB - Pneumocystis pneumonia is a severe opportunistic infection in immunocompromised patients, caused by Pneumocystis jirovecii (P. jirovecii). The co-infection with community-acquired P. jirovecii and Mycobacterium tuberculosis (M. tuberculosis) is exceptionally described in non immunocompromised patients. We herein report the case of a young woman, with no medical history, who developed an acute respiratory failure due to P. jirovecii pneumonia associated with miliary tuberculosis. An extensive immunological investigation ruled out any acquired or primary immunodeficiency, suggesting that she was most likely immunocompetent. This report shows that such infections are not restricted to immunocompromised hosts. Moreover, it is tempting to speculate that the development of M. tuberculosis infection in this patient could be a risk factor for transition from colonization status of respiratory tract by P. jirovecii to pneumocystosis. PMID- 26012212 TI - [Significance and contribution to the diagnosis of multiple myeloma according to the IGF1-R gene expression profile]. AB - Multiple myeloma (MM) is a still incurable adult's severe hematologic malignancy. It is characterized by deregulation of several cytokines and their receptors. Among these cytokines, Insulin growth factor 1 (IGF1) and its receptor (IGF1-R) are well documented as major factor of malignant plasma cells growth and survival in multiple myeloma. The objective of this study was to analyze the expression of IGF1-R in multiple myeloma at diagnosis in correlation with clinical and biological data. IGF1-R gene plasma cells expression was studied in 47 patients and 17 controls by Taqman technology RT-PCR. IGF1-R gene was down expressed in the malignant plasma cells of MM patients at diagnosis compared to normal plasma cells, isolated from healthy donors (p = 0.01). Expression decrease was accentuated in the disease advanced stage IIIB. A negative correlation was found between IGF1-R malignant plasma cells expression and the percentage of bone marrow invasion (p = 0.03). Bone marrow infiltration greater than 30% was significantly associated with a low level of IGF1-R gene expression (p = 0.04). Our results suggest that the decreased expression of IGF1-R by malignant plasma cells is a prognostic factor associated with severe disease. Understanding of mechanisms involved in IGF1-R expression negative regulation may contribute to the discovery of new targets therapy in myeloma. the discovery of new targets therapy in myeloma. PMID- 26012213 TI - Efficacy of certain insecticides against rat flea (Xenopsylla cheopis) among rodent species in Cairo Governorate, Egypt. AB - The efficacy of malathion, chlorpyrifos and deltamethrine to oriental rat flea, Xenopsylla cheopis associated different rodent species was carried out in Cairo Governorates. The results indicated that the LC50 values were 1.972, 1.023 and 0.185 % for Malathion, Chlorpyrifos and Deltamethrine, respectively. The values of Lc90 were 4.452, 2.269 & 0.456% for the three insecticides respectively. Data also indicated that deltamethrine was effective on fleas than malathion and chlorpyrifos. The slope function was 3.625, 3.70 & 3.267, respectively. PMID- 26012214 TI - Interplay between vitamin D status and antiviral therapy among chronic hepatitis C Egyptian patients. AB - Vitamin D has been shown to play an important immunomodulatory role; deficiency of vitamin D has been recently associated to the lack of response to antiviral therapy in chronic hepatitis C patients. This study evaluated the interrelationship between serum level of vitamin D and early response to antiviral therapy in Egyptian patients with chronic HCV infection. A total of 45 patients with chronic HCV infection who received antiviral treatment (Pegylated interferon and Ribavirin), their vitamin D serum level was assessed once at the start of treatment and 12 weeks later, when the EVR was determine by Quantitative HCV-RNA by PCR. The results showed that vitamin D status has no correlation with viral load and hepatitis activity by biopsy and without significant association between vitamin D deficiency and the antiviral therapy response. However, there was significance improvement in level of vitamin D after 12 weeks of receiving the antiviral therapy of HCV. PMID- 26012215 TI - Light and scanning electron microscopy on Serrasentis sagittifer Linton, 1889 (Acanthocephala): Palaeacanthocephala: Rhadinorhynchidae) infecting the common sea bream in Egypt. AB - Serrasentis sagittifer is one of the most important acanthocephalan parasites parasitizing fish. This species attach to the intestinal wall via their armed proboscis which is anchored by rows of recurved spines. In the present study, Twenty two out of 50 fish specimens (44.0%) were found to be naturally infected by adult worms of Serrasentis Sagittifer Linton, 1889 (Acanthocephala: Rhadinorhynchidae) which were collected from the stomach and intestine of the common sea bream Pagrus pagrus (family: Sparidae) from locations along the Red Sea at Hurghada City, Egypt. The light and scanning microscopic study revealed that the adult worm possessed a proboscis which was long, cylindrical with a uniform width measured 0.81 +/- 0.020 (0.77-0.84) mm in length and 0.48 +/- 0.020 (0.33-0.69) mm in width. Claviform, armed with 25 (23-28) longitudinal rows of hooks which show a distinct dorsoventral asymmetry, with ventral hooks stouter, larger. Proboscis receptacle was 2.12 +/- 0.30 (2.10-2.14) long, double-walled, with ganglion at mid-level; two unequal, long and thin lemnisci 2.9 +/- 0.30(2.41 3.33) length, arised from the base of the neck, and extend up to the med-level of the trunk. The present species is compared morphologically and morphometrically with some of the previously recorded species isolated from different host species, which revealed that the present species should be classified as Serrasentis sagittifer with a new host record in Egypt. PMID- 26012216 TI - Beyond immunization: travelers' infectious diseases. 1--Diarrhea. AB - Travelers' diarrhea is the most common illness in persons traveling from resource rich to resource-poor regions of the world. The fear of developing diarrhea while traveling is common among travelers to any part of the developing world. This concern is realistic; 40 to 60% of travelers to these countries may develop diarrhea. Diarrheal diseases represent one of the five leading causes of death worldwide. Morbidity and mortality are significant even in the United States where diarrhea is more often than not a "nuisance disease" in the normally healthy individual. PMID- 26012217 TI - Illness anxiety disorder related to filariasis: a case report. AB - Lymphatic filariasis is a parasitic disease which is associated with anxiety and depression and may also result in social isolation. We present here a case of illness anxiety disorder where the patient developed a morbid fear that he will develop filariasis. PMID- 26012218 TI - Studies on the role of tumor necrosis factor- alpha (TNF-alpha) in hepatocytes induced apoptosis in vaccinated, Schistosoma mansoni-challenged mice. AB - Tumour Necrosis Factor-alpha (TNF-alpha) plays a complex role in pathophysiological changes caused by schistosomiasis in the liver cells as induced apoptosis. So, The highlighted experimentally the role of TNF-alpha in hepatocytes apoptosis, using that as an assessment of the efficacy of antischistosomal vaccination by mixed crude antigens preparations [Cercarial antigen preparation (CAP) + soluble worm antigen preparation (SWAP) + soluble egg antigen(SEA)] by parasitological, histo-pathological and histochemical studies using Feulgen stain of hepatoytes DNA, a serological study also of serum TNF alpha level by ELISA. Fifty two laboratory bred Albino male mice, were used in this study. They were classified into four groups (13 mice in each group), G1: normal control, G2 as infected control while G3 supported by Freund's Adjuvant (F. Adj) then infected and G4 vaccinated with combined antigens (CAP, SWAP and SEA) + F. Adj, then infected. Mice were sacrificed by cervical dislocation 9 weeks post infection, parasitological (Kato-Katz thick smear for egg count), histopathologial {haematoxylin and eosin (H&E) staining of hepatic sections}, histochemical (feulgen staining of hepatocytes DNA) and ELISA to estimate serum TNF-alpha level were performed. The data showed that vaccination with combined antigens showed protective effect on vaccinated then Schistosoma challenged mice, hepatocytes induced apoptosis was directly proportional with the TNF-alpha serum level, and the protection degree of potential combined vaccine was inversely proportional with serum TNF-alpha level and induced apoptosis. PMID- 26012220 TI - Study on parasites from farm animals in Kuwait. AB - No doubt, farm animals are essential as a source of milk, protein, and leather and wool ... etc. But, they are always exposed to ecto- and endo-parasites, which cause diseases conditions that may end in death. This study evaluated farm animal parasitosis. Thus, different animal farms were visited to collect fecal samples and data to determine the infection rates with parasites and the relationship between animal management and parasitism in Kuwait. Out of 86, 17, 20, 96 & 52 cattle, sheep, goats, horses and camels examined, 5.5, 17.5, 10, 9.3 and 2.5% respectively were infected with different parasites. These parasites were Ascarids in cattle and horses, Strongylids in cattle, horses and camels, and Eimeriids in cattle and small ruminants. Eimeria spp. were the most prevalent parasite particularly in small ruminants. The relationship between Eimeria infection and management in small ruminant farms was discussed. PMID- 26012219 TI - Lassa fever or lassa hemorrhagic fever risk to humans from rodent-borne zoonoses. AB - Viral hemorrhagic fevers (VHFs) typically manifest as rapidly progressing acute febrile syndromes with profound hemorrhagic manifestations and very high fatality rates. Lassa fever, an acute hemorrhagic fever characterized by fever, muscle aches, sore throat, nausea, vomiting, diarrhea and chest and abdominal pain. Rodents are important reservoirs of rodent-borne zoonosis worldwide. Transmission rodents to humans occur by aerosol spread, either from the genus Mastomys rodents' excreta (multimammate rat) or through the close contact with infected patients (nosocomial infection). Other rodents of the genera Rattus, Mus, Lemniscomys, and Praomys are incriminated rodents hosts. Now one may ask do the rodents' ectoparasites play a role in Lassa virus zoonotic transmission. This paper summarized the update knowledge on LHV; hopping it might be useful to the clinicians, nursing staff, laboratories' personals as well as those concerned zoonoses from rodents and rodent control. PMID- 26012221 TI - Redescription of Pseudolepidapedon balistis Manter, 1940 and a biological variant (Trematoda: Acanthocolpidae) from the Red Sea fishes; Balistoides viridescens and Rhinecanthus assasi. AB - During a survey of Red Sea fish parasites, two trematodes belonging to the genus Pseudolepidapedon Yamaguti, 1938 were encountered: P. balistis Manter, 1940 was found in the small intestine of the fish Balistoides viridescens and was redescribed for the first time from Egypt; adding many detailed morphological and ultrastructural characters. The second trematode was found in the small intestine of the fish Rhinecanthus assasi and found to represent a biological variant of the previous species as it differs from it in its generally smaller dimensions, shape of suckers and pharynx and the testes. SEM details of the first species were described for the first time illustrating the differences in the spination and papillae on different parts of the body; which may be of taxonomic importance in recognizing future different species of the genus. PMID- 26012222 TI - Efficiency of Colocasia esculenta leaves extract and histopathological effects on Culex pipiens (Diptera: Culicidae). AB - This study evaluated the toxicity of Colocasia esculenta leaves extract on 3rd, 4th instars larvae and pupae of Culex pipiens. Bioassays showed that the 3rd instar larvae was the most susceptible to the different concentrations of extract, where the LC50 after 48 hr. post-exposure was 79.41, 109.65 & 141.25 for the 3rd, 4th instars larvae and pupal stage respectively. The histo-pathological effects of C. esculenta leaves extract on midgut regions and gastric caeca of the 3rd instar larvae were studied. When larvae were treated with 100 ppm of C. esculenta extract, all larvae developed dramatic pathological lesions especially Malpighian tubules were extensively affected. The midgut cells showed morphological deviation from normal ones, through slightly apical degenerated (lysis) of epithelial cells. The epithelial cells with extensive cellular microvilli were shrinkage, the nuclei showed pyknotic characteristic and the peritrophic membrane was appeared discontinuation in compared to control. When the 3rd larval instar was exposed to extract 400 ppm, the epithelial cells, adipose fabric and muscles were extensively affected. Also, the gastric caeca was affected obviously. These observation and alterations in cells of Cx. pipiens larvae are related to the dangerous effect of C. esculent leaves extract. PMID- 26012223 TI - In vitro effect of some Egyptian herbal extracts against Blastocystis hominis. AB - Blastocystis hominis is an enteric parasite that inhabits the gastrointestinal tract of humans and many animals. This emerging parasite has a worldwide distribution. It is often identified as the most common eukaryotic organism reported in human fecal samples that showed a dramatic increase in recent years. Metronidazole is the main therapy for blastocystosis. However, frequent reports of treatment failure suggesting isolates resistance to metronidazole. This study determined the growth pattern and in vitro susceptibility of B. hominis to nitazoxanide (NTZ), garlic, ginger, onion and turmeric. Fecal samples positive for Blastocystis were collected from patients with irritable bowel syndrome (IBS), and processed for culture. Cultured samples were subjected to examination by light microscopy. Herbs' extracts was freshly prepared. Drug susceptibility assays was done using 0.1 mg/ml of NTZ, garlic, ginger, onion and turmeric. Effects assessed on parasite culture after 24 hr. and 48 hr. Cultured fecal samples of B. hominis have identified several forms of the organism; vacuolar, granular, amoeboid and cyst forms within 24 hr. Nitazoxanide treatment significantly (P < 0.001) lowered the parasite number after 48 hr. (mean, 337.5 +/- 17.67) /ml. The reduction rate after 48 hr. compared to PBS was 93.33%. Ginger treatment significantly (P < 0.002) lowered the number of the parasite after 48 hr. (mean, 335 +/- 7.07)/ml. Moreover, garlic treatment also significantly (P < 0.002) lowered the number of the parasite after 48 hr. (mean, 382.5 +/- 10.60)/ml. The reduction rates after 48 hr. in these treated samples compared to PBS were 92.98% and 92.44% respectively. However, onion, and turmeric treatments insignificantly lowered the number of the parasite after 48 hr. (P < 0.15 & < 0.22 respectively). PMID- 26012224 TI - Prevalence of Helicobacter pylori infection among adult patients with different gastrointestinal parasites in Tanta City district. AB - This study determined the prevalence of Helicobacter pylori infection in patients with different gastrointestinal symptoms. Two hundred and six patients were collected from outpatient clinic of medical department from March to June 2014. The age was ranged between 15 years old up to 60 years old. 76 males with mean age (33.2 +/- 13.5) and 130 females with mean age (32.8 +/- 14.9). All patients were submitted to full clinical examination and stool examination was performed to detect Helicobacter pylori antigen and other intestinal parasites. After getting a full history, the patient was asked specifically for history of taking non-steroidal anti-inflammatory drugs, presence of heart burn, epigastric pain, flatulence, nausea or vomiting passing black stool hematemesis and presence of other diseases. The results showed that 69.4% of the patients were positive for Helicobacter pylori antigen (143/206). The prevalence among males and females was the same (69.7%-69.2%). The prevalence among different age groups was not significant but; some-how high among age group of 15 up to 25 years old (70%). 72 patients out of 140 were associated with Co-infection with Entamaeba histolytica mainly or Giardia lamblia (51.4%). Epigastric pain and heart burn were representing about 90% of symptoms in patients with positive Helicobacter pylori antigen. Consequently, the prevalence of H. pylori infection is high in and around Tanta City in the Nile Delta (about 70%). PMID- 26012225 TI - Study of the role of insulin resistance as a risk factor in HCV related hepatocellular carcinoma. AB - Chronic HCV infection causes hepatic cirrhosis and approximately 10%-20% of cirrhotic patients may develop hepatocellular carcinoma within 5 years. Diabetes mellitus is associated with a 2-4-fold increase in the risk of HCC. Insulin resistance (IR) emerged as a risk factor for a variety of cancers, including endometrial and breast and various gastrointestinal cancers The role of IR in the development of HCC associated with chronic HCV infection has not, been established. This study elucidated the role of insulin resistance assessed by the homeostasis model (HOMA-IR) in development of hepatocellular carcinoma associated with chronic hepatitis C infection. The study included 3 groups: GI: 100 newly diagnosed cases of HCV related hepatocellular carcinoma GII: 60 patients with HCV related chronic liver disease. Forty healthy persons as a control group (GIII). All groups were subjected to full history taking, physical examination, laboratory investigations abdominal ultrasonography and Triphasic C.T examination. In addition to Calculation of Body mass Index, Measurement of fasting blood insulin and glucose, Calculation of insulin resistance using HOMA IR. The results showed that fasting insulin and HOMA-IR were significantly higher among HCC group than HCV group & control group. Also, fasting insulin and HOMA-IR were significantly higher in HCV group than control group. HOMA-IR above 3.7, insulin above 9MUU/L & DM were considered independent predictors of HCC. PMID- 26012226 TI - Some studies on spontaneous Hymenolepis diminuta infection in laboratory rats. AB - Hymenolepis diminuta is a tapeworm that occurs worldwide. It is known to be found commonly in areas where large amounts of food grains or other dry feed products, which are the favorite foods for rats. Transmission of disease to human is uncommon; however, it may be a serious threat for population who are living in rural areas which are suffering from excessive rodents. Here, this study had done on spontaneous H. diminuta infection in laboratory rats as a model. Out of thirty five adult laboratory rats investigated for parasitic diseases only nine (25.71%) were diagnosed positive for spontaneous H. diminuta infection. Four of them (44.44%) were found losing of weight and lacking of motility, while the others were normal. On microscopic examination, H. diminuta eggs had been found in their stool. On autopsy, small intestines were found to contain from 5-6 multi segmented tapeworms in each rat. Histopathologically, intestinal lumen showed varying sections of H. diminuta segments with serrated borders. H. diminuta infection caused multiple mucosal ulcers with absence of intestinal villi from the surface epithelium and excessive mucin. Moreover, inflammatory cells infiltration in the connective tissue core of the villi. Furthermore, the Toluidine blue stain showed that there are Mastiocytosis. Additionally, there were goblet cells hyperplasia on using PAS. Moreover, there were high expression of cyclooxygenase 2 (COX-2), tumor necrosis factor-alpha (TNF-alpha) and inducible Nitric-Oxide Synthase (iNOs). This implicate, strong correlation between COX-2, TNF-alpha and iNOs expression and inflammation induced by H. diminuta. PMID- 26012227 TI - Cryptosporidium parvum infection among Egyptian school children. AB - The present study determined cryptosporidiosis among 120 randomly chosen school children aged 4-16 years. Medical sheets were filled out on each child. The fresh stool samples were examined by using Sheather's sugar flotation stained with modified Ziehl Neelsen stain. Blood samples were examined by ELISA and IFA techniques. The results revealed that, the prevalence rate was 13.51% with a peak among the age group (5-10) and. significant relation between males and females. There was a significant relation between infection and low socio-economic level in rural area. Also, a significant relation was obtained between the infection and the presence of animal contact. Watery and loose diarrhea was more significant among infected children. Positive stool samples were among 37 (30.8 %), while ELISA and IFA detected 30 (25%) and 33 (27.5%) respectively. The validity test of ELISA declared sensitivity and specificity with 93.3% and 90% while IFA declared 90.9% and 91.1% respectively. PMID- 26012228 TI - Studies on the molluscicidal activity of Agave angustifolia and Pittosporum tobira on schistosomiasis transmitting snails. AB - In the search for new molluscicidal plants for controlling the snail vectors of schistosomiasis, laboratory evaluation was made to assess the molluscicidal activity of Agave angustifolia and Pittosporum tobira plants against Biomphalaria alexandrina snails. Results indicated that both plants have promising molluscicidal activity as the LC90 of the dry powder of both plants was 120 ppm. Both plants showed marked cercaricidal and miracidicidal potencies against S. mansoni larvae. The LC90 of both plants (120 ppm) killed most B. alexandrina eggs within 24 h of exposure. The sub-lethal concentrations of both plants markedly suppressed the survival rate of B. alexandrina snails and the mortality increased with increasing the concentrations and the exposure period up to 10 successive weeks. The accumulative toxic effect of these concentrations was continuous during the recovery period. Also, the reproductive rates of exposed snails were greatly affected even through the recovery period. This depression in reproductive ability of snails was accompanied by histological damage in the hermaphrodite glands of exposed snails. Meanwhile, the growth of snails was estimated weekly and it showed great inhibition in exposed snails comparing with the control ones. PMID- 26012229 TI - Surface topography of two trematodes parasites infecting grey heron Ardea cinerea Jouyi (Aves, Ciconiiformes) in Qena, Egypt. AB - Apharyngostrigea ardeolina and Echinoparyphium recurvatum are two important digenean parasites that were recovered from small intestine of grey heron with an infection rate (16.2%) and (8.8%) respectively. The surface topography of two species was redescribed by both light and scanning electron microscopy. Using SEM studies showed that the body surface of two trematodes were covered by contact receptors, several types of sensory tegumental papillae which may have useful function in orientation and feeding through increasing the surface area of absorption, could also play a role in sensation or in selection of the materials for ingestion by the fluke. The head collar of E. recurvatum is reniform in shape, bearing uninterrupted double row of 41 collar finger-like spines, a total including 4 end group ones on both ventral corners., tegumental spines were tongue-shaped without a terminal tip. PMID- 26012230 TI - Studies on the effect of pollution on Lake Manzala ecosystem in Port-Said, Damietta and Dakahlia Governorates Egypt. AB - This work studied how pollution impacts the ecosystem of Lake Manzala by determination of physicochemical parameters, studying biodiversity of aquatic plants and macroinvertebrates, and determining bioaccumulation of Pb, Cu, Cd & Zn in some major organisms, Biomphalaria alexandrina and Melanoides tuberculata snails and Oreochromis niloticus fish. The more near to Mediterranean Sea and to the industrial area, Port-Said and Damietta sites showed higher dissolved oxygen and conductivity than Dakahlia sites. Distribution percentage of Eichhornia crassipes is high among Port-Said and Dakahlia sites of 100 and 88%, respectively, while Lemna giba is the most abundant among Damietta sites of 60%. The maximum macroinvertebrate taxa richness was obtained at Gammalya, Dakahlia of 16 species while the maximum abundance was registered at Annanya, Damietta of 591 organisms. Gastropoda are the most distributed organisms in Lake Manzala followed by Hemiptera and Plecoptera then shrimps and scud. All the medically important snails, B. alexandrina, B. truncatus and L. natalensis were recorded in Dakahlia, but only B. alexandrina was in Damietta and Port-Said sites. The collected water samples from Damietta sites showed the highest significant Cu & Cd concentration while Port-Said samples showed the highest Pb concentration and Dakahlia showed the highest Zn concentration. The metals concentrations were higher in snail tissue and in fish liver, kidney and most of muscle samples as compared in surface water. The higher metal bioaccumulation was determined in snails collected from sites showed higher water metals concentrations. Fish muscle showed the least residues than liver and kidney for all the measured metals. Pb and Cd were more accumulated in kidneys, Cu was more accumulated in liver and Zn was accumulated in all examined fish parts in descending order as follows Kidney > liver > muscle. PMID- 26012231 TI - Partial portal vein arterialization maintains regeneration after critical major hepatectomy: experimental study. AB - Portal vein arterialization (PVA) is often referred to as a salvage procedure for insufficient arterial or portal inflow. Its main role focuses on two domains, liver transplantation and extensive surgery for malignancies of liver, biliary tract and pancreas. It ha been applied in treatment of fulminant hepatic failure due to intoxications and as a bridging procedure for transplantation or re transplant. Radical resections with arterial reconstruction are a major challenge for surgeons especially in prolonging survival in advanced malignancies of the liver or biliary tract. This study revisited the benefits of this procedure to test the hypothesis of supporting a failing liver during critical period of regeneration following major hepatectomy with insufficient arterial inflow. The endpoints were to identify the histopathological and biochemical evidence of regeneration. The experimental design: 24 adult dogs of both sexes were included. They were divided into 3 groups: G1 (n = 7): animals subjected to 65% hepatectomy (control), G2 (n = 8): animals subjected to 65% hepatectomy & hepatic artery ligation, G3 (n = 8): animals subjected to 65% hepatectomy & partial portal vein arterialization (PPVA). Blood samples were taken for assessment of liver functions and blood gas analysis. Liver biopsy was assessed for morphological and histopathological changes of regeneration. Gross specimens were used to calculate the liver regeneration rate. Results showed the presence of mitotic activity and regeneration in groups with PPVA comparable to controls. No evidence of regeneration observed in G2. Shunt patency was confirmed by increase in PO2 levels of arterialized portal vein. A significant increase in the regeneration rate in groups with arterialized portal vein 1 week post procedure was noted. PMID- 26012232 TI - Randomized clinical trial comparing two different techniques of local anesthesia (subcutaneous versus subcutaneous & deep infiltration) for postoperative pain in patients undergoing open appendecectomy. AB - This study compared the postoperative analgesic effect of local anesthetic (LA) injected subcutaneous (SC) alone versus local anesthetic injected both SC and deep in patients undergoing open appendecectomy operations. Sixty patients ASA class I-II undergoing open appendecectomy for presumed acute appendicitis will be randomly assigned into three groups. After routine monitoring, anesthesia induction was performed with propofol, fentanyl and, cis-atracurium; later, maintenance was continued with isoflurane. GA received local infiltration of the skin prior to incision with bupivacaine 0.25% (10 ml), GB received received half the bupivacaine infiltrated into the skin and other half deep-to external oblique prior to incision to create a local nerve field blockade & GC received half dose of saline subcutaneous & half deep to external oblique muscle prior to incision. Postoperative pain was assessed using visual analogue score (VAS) at 1, 4, 8, & 24 hours post extubation. Pethidine 1 mg/kg was given if VAS is >= 4. All patients in GA (SC) and Control required postoperative analgesics, compared to only 60% of the patients in GB (SC+deep). Time for the first analgesic requirement was prolonged in GB compared to other groups (P < 0.01). VAS scores were significantly lower in patients of GB in the first 8 hr. postoperative compared to GA &GC (P < 0.01). PMID- 26012233 TI - Toxicity of some plant extracts against vector of lymphatic filariasis, Culex pipiens. AB - Many insecticides are generally used as larvicides to control Culex pipiens, vector of lymphatic filariasis. This study was undertaken to evaluate the larvicidal activity of some potential larvicidal plants extracts against C. pipiens larvae. The toxic effects of both ethanolic and petroleum ether plant extracts were evaluated under laboratory conditions against 3rd instar larvae of C. pipiens. Forty ethanolic and petroleum ether extracts of 10 plants namely Echinochloa stagninum, Phragmites australis, Eichhornia crassipes, Rhizophora mucronata, Cichorium intybus, Ocimum basilicum, Origanum majorana, Azadirachta indica, Rosmarinus officinalis and Nigella sativa. On the basis of LC50, the toxic effect of the plant extracts tested varied depending on the plant species, part, solvent used in extraction and the extract concentrations. The petroleum ether extraction was more effective against mosquito as compared with ethanolic extraction. The most effective plant extract was A. indica followed by Ph. australis, N. sativa, C. intybus, R. officinalis, O. basilicum, O. majorana, E. stagninum, Rh. Mucronata and E. crassipes. PMID- 26012234 TI - Monitoring of the antiviral potential of bee venom and wax extracts against Adeno 7 (DNA) and Rift Valley fever virus (RNA) viruses models. AB - This study monitored the antiviral potential of bee venom and four wax extracts, ethanol white and black beeswax (EWW/EBW) and acetone white and black beeswax (AWW/ABW) extracts. Two different virus models namely Adeno-7 as DNA model and RVFV as RNA virus models. End point calculation assay was used to calculate virus depletion titer. The depletion of viral infectivity titer of ABW to Adeno-7 virus showed strong antiviral activity recorded a depletion of viral infectivity titer (1.66 log (10)/ ml) that gave equal action with bee venom and more than interferon IFN (1 log (10)/ ml). On the other hand, antiviral activity of EBW showed a moderate potential, while AWW showed no antiviral activity. Finally EWW showed synergetic activity against Adeno-7 virus activity. Thus, activity of wax extracts to RVFV was arranged in order of IFN bee venom > AWW & EBW > EWW and ABW recorded 3.34, 0.65, 0.5, 0.34 respectively. It is the first time to study the beeswax effect against DNA and RNA virus' models; acetone black beeswax recorded a depletion titer 1.66 log (10)/ml. PMID- 26012236 TI - Study of depression among a sample of hypertensive patients. AB - Hypertension is one of the commonest diseases worldwide. Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition, which elevated blood pressure in the arteries. This forces the heart to work harder than normal to circulate blood via the blood vessels. Blood pressure is summarized by two measurements, systolic and diastolic, which depend on between beats (diastole). Normal blood pressure at rest is within the range of 100-140 mmHg systolic (top reading) high blood pressure is said to be present if it is persistently at or above 140/90 mmHg of cases are categorized as primary hypertension that means high blood pressure with no obvious underlying medical cause. Updated studies reported associations between depressive symptoms and hypertensive patients. Depression may be an independent diagnosis, it is also possible that depressive symptoms are secondary to chronic illnesses and their associated complex medication regimens, regardless of the diagnosis being primary or secondary, prior reports have demonstrated that depressive symptoms are associated with inadequate blood pressure control and complications of hypertension. PMID- 26012235 TI - Genetic diversity in the msp-1 and msp-2 alleles among Plasmodium falciparum field isolates from Jazan, Saudi Arabia. AB - The genetic diversity of Plasmodium falciparum infections in human is associated with the pathogenesis of malaria. It is commonly determined through amplification of the polymorphic regions of the merozoite surface proteins -1 (msp-1) and -2 (msp-2) genes. This study aimed to (1) determine the prevalence of the msp-1 and msp-2 allelic familiesand (2) identify the multiplicity of infection (MOI) in P. falciparum field isolates from the Jazan region in the Kingdom of Saudi Arabia (KSA). Blood samples from patients with microscopically confirmed malaria infections (N = 48), collected in 2010, were analysed for msp-1 and msp-2 polymorphisms.K1, MAD20 and RO33 allelic types of the msp-1 gene and 3D7 and FC27 alleles of the msp-2 gene were analysed via nested polymerase chain reaction (PCR) according to band size. The MOI was then calculated. In msp-1, 16 different alleles were identified by examining size differences in the agarose gels. These alleles-representing 5, 5 & 6 alleles-belong to K1 (120bp-420bp), RO22 (180bp 420bp) and MAD 20 (150 bp-410bp), respectively. For msp-2, a larger range of amplicon sizes was detected. A total of 13 different alleles were identified: the FC27 family had 6 alleles (380- bp1280bp), while the 3D7 family had 7 alleles (110 bp-1200bp.MOI was 1.81 for MSP-1 & 2.17 for MSP-2, with overall mean MOI of 1.99). Considerable genetic diversity was evident in the P. falciparum field isolates from the Jazan region of KSA. This diversity represents an essential step in developing effective measures to prevent malaria in KSA, as well as in assessing vaccines derived from these genes. PMID- 26012237 TI - Possible factors of success in teaching esophageal speech. AB - INTRODUCTION: Well-established esophageal voice and speech is the most human-like form of communication of laryngectomized patients. MATERIAL AND METHODS: The study sample consisted of 28 patients of the Department of Ear. Nose and Throat, Clinical Center of Vojvodina in Novi Sad. All patients underwent total laryngectomy because of laryngeal cancer previously confirmed. The patients were divided into two groups based on the success of mastering esophageal voice and speech, group I being successful and group 2 being unsuccessful. Results. All patients were subjected to total laryngectomy and had their hyoid bone removed (100%). Esophageal speech was rated excellent afid good in 71% and 29% of patients from group 1, respectively. There was no significant difference between the successful (group 1) and unsuccessful group (group 2) in time when teaching began (chi2=5.14, p=0.023). Neither was there a statistically significant difference between these two groups regarding the methods applied in teaching esophageal. speech (chi2 = 2.02, p=0.155, which is greater than 0.05). CONCLUSION: The effectiveness of teaching esophageal speech depends significantly on the motivatidn of the patients. It was found that the patients who mastered esophageal speech successfully had'been learning it longer than those who did not master it. The success in mastering esophageal speech did not depend on whether the patients were trained individually or collectively, whereas neither method of training was successful in group 2. PMID- 26012238 TI - Micromorphological characterization of adhesive interface of sound dentin and total-etch and self-etch adhesives. AB - INTRODUCTION: The ultimate goal in restorative dentistry has always been to achieve strong and permanent bond between the dental tissues and filling materials. It is not easy to achieve this task because the bonding process is different for enamel and dentin-dentin is more humid and more organic than enamel. It is moisture and organic nature of dentin that make this hard tissue very complex to achieve adhesive bond. One of the first and most widely used tools for examining the adhesive bond between hard dental tissues and composite restorative materials is scanning electron microscopy. The aim of this study was scanning electron microscopy analyzes the interfacial micro morphology of total etch and self-etch adhesives. MATERIAL AND METHODS: Micro morphological characteristics of interface between total-etch adhesive (Prime & Bond NT) in combination with the corresponding composite (Ceram X Mono) were compared with those of self-etching adhesive (AdheSE One) in, combination with the corresponding composite (Tetric EvoCeram). The specimens were observed under 1000 x magnification of scanning electron microscopy (JEOL, JSM-6460 Low Vacuum). Measurement of the thickness of the hybrid layer of the examined com posite systems was performed with the software of the device used (NIH Image Analyser). RESULTS: Micromorphological analysis of interface showed that the hybrid layer in sound dentin was well formed, its average thickness being 2.68 microm, with a large number of resin tags and a large amount of lateral branches for specimens with a composite system Prime & Bond NT-Ceram X Mono. However, the specimens' with composite systems Adhese One-Tetric EvoCeram did not show the presence of hybrid layer and the resin tags were poorly represented. CONCLUSION: The results of this study suggest that total-etch adhesives bond better with sound dentin than self-etch adhesive. PMID- 26012239 TI - Risk factors of the first stroke. AB - INTRODUCTION: This study was aimed at investigating the vascular risk factors associated with the first stroke. It highlighted unfavorable trends in stroke mortality in the region gravitating towards the general hospital in Doboj. MATERIAL AND METHODS: The study included all patients hospitalized with the diagnosis of first stroke and their main vascular risk factors were explored, both in terms of their importance in the occurrence of stroke, and in terms of gender and age lines. The research results were statistically processed, analyzed and commented on. RESULTS: The most common risk factor for the first stroke included hypertension (70%), smoking (35%), heart diseases (28%), diabetes mellitus (28%), hyperlipoproteinemia (26%), atrial fibrillation (18.5%) and immoderate consumption of alcohol (17%). CONCLUSION: The presence of vascular risk factors in the majority of patients is important, and at least one of them was present in 80% of patients. Alcohol consumption, smoking and hyperlipoproteinemia were significantly more frequent in men, and atrial fibrillation was more frequent in women. Arterial hypertension, heart disease and diabetes mellitus were present PMID- 26012240 TI - Patellar tendon rupture--treatment results. AB - INTRODUCTION: Patellar tendon rupture is a rare injury which, if missed, leads to delayed surgical treatment and may result in the loss of the knee joint function. The aim of this study was to report our results of operative treatment of the patellar tendon rupture and point out the significance of timely diagnosis and surgical procedure. MATERIAL AND METHODS: This retrospective ten-year study included 20 patients, 15 males and 5 females, their mean age being 42 (20-84) years. Seven participants had an injury on the right side and 13 had an injury on the left side. Thirteen participants had the diagnosis set in the first seven days after the injury. The applied techniques were surgical suture of the tendon, bone-tendon-bone ligamentoplasty using allograft from a bone bank and bone-tendon bone ligamentoplasty using contralateral autograft, and they were performed in 12, 5 and 3 patients, respectively. The treatment results were assessed by using the Lysholm score, measuring the range of movement in the knee joint and measuring the girth of the thigh 10 cm above the patella. RESULTS: The follow-up period after the surgery was 4 years on average (1-10 years) and the average value of the Lysholm score was 83 (27-100). The result was found to be excellent in 11 cases, satisfactory in 5 cases and unsatisfactory in 4. A statistically significant difference (p=0.0197 p<0.05) was found in the average values of the Lysholm score between the group of patients with risk factors (71.78) and the subjects without risk factors (92.18). A statistically significant difference (p=0.008 p<0.01) was found in the Lysholm score between the patients with timely diagnosis (91.62) and cases of chronic tendon tear (67). CONCLUSION: Timely diagnosis and early surgical reparation are the basic imperatives in the treatment of this injury. Comorbidity and risk factors are related to a poorer postoperative Lysholm score. The method of choice is early surgical treatment. PMID- 26012241 TI - Psychological aspects of pediatric anesthesia. AB - Surgery and anesthesia cause a significant emotional stress in both parents and children. Since the consequences of this stress develop immediately after surgery and can last even when the hospital treatment is over, the role of the anesthesiologist is to ensure psychological as well as physiological well-being of the patient. In order to reduce emotional stress induced by anesthesia and operation, the anesthesiologist has to understand certain developmental phases that children go through and to identify situations which a child could potentially see as a danger or a threat. This can usually be achieved by careful preoperative assessment and by administering preoperative sedation. During the preoperative visit to the patient, the anesthesiologist can evaluate the levels of anxiety of both parents and children as well as assess the child's medical condition. PMID- 26012242 TI - Reasons for and frequency of off-label drug use. AB - INTRODUCTION: The application of drugs in accordance with the marketing authorization issued by the regulatory authority is considered on-label use, while off-label drug use frequently occurs in medical practice. It includes the application of drugs beyond approved indications; for unapproved age group, with different dosage regimens or different administration route. Medical specialists frequently prescribe an off-label drug in pediatrics, neonatology, geriatrics, psychiatry and oncology. Some countries have established registers of off-label drugs and guidelines for their prescribing and administration. The aim of the paper is to review practices in off-label drug use in order to satisfy the attitude of regulatory bodies and professional associations regarding the off label use of drugs. MATERIAL AND METHODS: The sources of information used are articles published in scientific journals and information from the official websites of regulatory agencies. RESULTS AND DISCUSSION: The most common reasons why physicians decide to prescribe off-label drugs are primarily the absence of drugs for a particular indication or those for a particular age group. In their daily work, doctors prescribe drugs for an off-label use based on their own or other colleague's experience. There is no general agreement on off-label use of drugs at the national or international level, but more and more doctors' associations and regulatory bodies approve off-label drug use in compliance with certain scientific and legal requirements. CONCLUSION: Off-label drug use has its place in practice and it has been widely accepted by the medical community and by itself it is not a violation of the standards of healthcare. Off-label use is common in our country and worldwide, and it is necessary to establish a registry for off-label drug use. PMID- 26012243 TI - 18F-fluorideoxyglucose positron emission tomography/computed tomography imaging: artifacts and pitfalls. AB - "F-fluorodeoxyglucose, being a radiolabeled glucose analogue, is a marker of glucose metabolism indicator. Since glucose uptake is increased in malignant tumors, its major application is in oncology. However, an increased 18F fluorodeoxyglucose uptake is found in various benign tumors, granulomatous diseases, tuberculosis, inflammation, infection. A healing process may be interpreted as a false positive finding. In contrast, some types of renal cell cancers and lymphomas, neuroendocrine tumors, colonic mucinous adenocarcinomata, hepatocellular carcinomas, prostate cancer, and carcinoid tumors have low "F fluorodeoxyglucose avidity which may give a misleading false negative result. In addition, an increased "F-fluorodeoxyglucose uptake in the bone marrow may be seen in oncologycal patients following various types of therapy. Besides the advantages of hybrid positron emission tomography-computed tomography imaging, this dual-modality scanning may produce their own specific artifacts due to different causes, such as metallic implants, respiratory motion, contrast medium and truncation. Proper patient preparation is required to minimize the potential artifactual uptake patterns that make reporting difficult. It is important to learn about proper quality control, imaging and reconstruction and to be familiar with potential artifacts and, pitfalls for the accurate interpretation of "F fluorodeoxyglucose positron emission tomography-computed tomography. PMID- 26012245 TI - Posterior reversible encephalopathy syndrome in eclamptic patients: neuroradiological manifestation, pathogenesis and management. AB - INTRODUCTION: Eclampsia is one of the most serious complications of hypertensive disorders of pregnancy, defined as the occurrence of one or more convulsions superimposed on preeclampsia. Besides the ordinary course of the disease, ranging from a mild to a severe form, with culmination in eclamptic seizures, there is a significant percent of cases where eclampsia starts unexpectedly, without typical premonitory symptoms and signs, which makes it difficult to prevent. NEURORADIOLOGICAL CHARACTERISTICS AND PATHOGENESIS OF ECLAMPSIA. Neuroradiological signs of eclampsia are described as posterior reversible encephalopathy syndrome, and are manifested by nausea, vomiting, headache, visual disturbances, altered mental status, convulsions and coma, together with characteristic findings on computed tomography or magnetic resonance imaging scan of the head, indicating the presence of vasogenic brain edema. The topic of this article are possible mechanisms of the development of posterior reversible encephalopathy syndrome in pregnancy and modalities of acute treatment of this emergency state. MANAGEMENT OF ECLAMPSIA: Magnesium sulphate is nowadays the drug of choice for the treatment and prevention of eclamptic seizures. Labetalol is considered to be the agent of choice in the treatment of hypertensive emergencies of pregnancy, followed by hydralazine, nifedipine, nicardipine, urapidil, nitroglycerin and sodium nitroprusside (in most refractory cases). Angiotensin converting enzyme inhibitors and angiotensin blocking drugs are contraindicated in pregnancy. Captopril and enalapril are allowed during lactation. CONCLUSION: Posterior reversible encephalopathy syndrome in eclamptic patients is completely reversible if adequate diagnosis is promptly made and intensive treatment immediately administered. PMID- 26012244 TI - Solitary synovial chondromatosis as a cause of Hoffa's fat pad impingement. AB - INTRODUCTION: Synovial chondromatosis is a benign disease of synovial membrane usually affecting knee, elbow and shoulder joints. It rarely appears as a solitary formation and exceptionally within Hoffa's fat pad. CASE REPORT: We report a case of solitary synovial chondromatosis within Hoffa's fat pad as a cause of its impingement in a female patient aged 63. At first, the patient had anterior knee pain with limited extension of the knee. Standard radiogram showed only mild patellofemoral osteoarthritic changes. Magnetic resonance of the knee showed ovoid solitary formation within Hoffa's fat pad repressing its superior part between the kneecap and distal femur. Histopathological examination confirmed a case of extra-articular synovial chondromatosis. The tumorous mass was extracted surgically en bloc. CONCLUSIONS: Solitary synovial chondromatosis is an uncommon cause of Hoffa's fat pad impingement and anterior knee pain in elderly female patients and can easily be misinterpreted as a different diagnosis. PMID- 26012246 TI - History of sports medicine in East European countries. AB - The purpose of this article is to provide a historical background of medicine, science and sports with the focus on the development of modern sports medicine in European countries, with an accent on Eastern European countries that have a long sports medicine tradition. The development of modern sports medicine began at the end of 19th and the beginning of 20th century, and it has been associated with social and cultural changes in the world of medicine, science and sports. Advanced medical knowledge, skills and practices, and the progress of scientific achievements enabled sports people to improve their performance level. Increased popularisation and commercialisation of sports have resulted from urbanization and city lifestyle, leading to the lack of physical activity and increased psychological pressure. In addition, the growing need and interest in sports and successes in professional sports have become a symbol of international recognition and PMID- 26012247 TI - Dr. Igor Bitenc--a great man has gone. PMID- 26012249 TI - Design, synthesis and in vitro NO-releasing activities of ocotillol-type furoxans. AB - A series of novel ocotillol-type furoxan derivatives was synthesized by coupling various furoxans to 3-OH of 6-deoxy ocotillol, and their in vitro nitric oxide (NO) releasing capability was studied. The discharge of NO was examined after 30 min at two different concentrations, the results showed that all of the compounds tested could release NO in a dose-dependent manner. All of the synthesized compounds released similar amounts of NO at 100 MUM, whereas at 500 MUM these compounds showed more difference, in which compound II1, II3, II4, III2 displayed higher potency in releasing NO at this concentration. Analysis of the in vitro data showed that the derivatives bearing the same furoxan group on different ocotillol cores possessed various NO releasing capacity, suggesting that the structure of carrier of NO releasing groups may affect the NO release. Indeed, except compound II2, 24(S)-6-deoxy ocotillol derivatives from compound 6 with different furoxan substitutions at 3-OH and III2 displayed enhanced NO releasing capacity, compared to other compounds derived from compounds 5 and 9. The results illustrated that the functional group and the stereochemistry on the ocotillol structure may affect the NO release of furoxans. PMID- 26012250 TI - Development of a LC-MS/MS method for the estimation of clinofibrate in human urine. AB - A highly sensitive and rapid liquid chromatography-tandem mass spectrometry method was developed for the determination of clinofibrate in human urine. The analyte and IS were extracted through a simple protein precipitation by the mixture of acetonitrile and 1 mol/L hydrochloric acid (95:5, v/v) and separated on an Inspire C18 (150 mm x 4.6 mm I.D., 5 MUm particle size) column using isocratic elution with methanol and water containing 0.1% formic acid and 10 mM ammonium acetate (90:10, v/v). Mass spectrometric detection was performed in electrospray positive ionization MRM mode. The mass transition was m/z 486.3- >175.0 for clinofibrate and m/z 361.1-->233.1 for IS, respectively. The flow rate was 0.6 mL/min and the column oven temperature was set at 35 degrees C. The total run time was 6.5 min. Good linear relationships were obtained for all analytes over the concentrations ranging of 0.1002-10.02 MUg/mL (r2 = 0.9991) and the limit of quantification was 0.1002 MUg/mL. The extraction recovery was larger than 87.4% and intra- and inter-batch precision and accuracy with RSD were all less than 6.5%. The total amount of unchanged clinofibrate excreted in urine was less than 0.34%. This method was successfully applied to the pharmacokinetic study of clinofibrate in human urine. PMID- 26012251 TI - Bilirubin degradation in methanol induced by continuous UV-B irradiation: a UHPLC -ESI-MS study. AB - Degradation of bilirubin in aerobic methanol solution by continuous UV-B irradiation has been investigated in this work. The purpose of this study was to shed more light on bilirubin interaction with the UV-B component of natural sunlight, since bilirubin is a very efficient UV-B absorber located in the skin epidermis. The degradation products have been detected and studied by a combined method of Ultra High Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry (UHPLC-ESI-MS). Bilirubin, a toxic pigment which itself is a product of (hemoglobin) degradation in organisms, undergoes its own degradation under aerobic conditions of UV-B continuous irradiation (e.g. photooxidation) that can be partly self-sensitized. Two dipyrrolic structures have been identified as a result of the bilirubin degradation, not including the bilirubin derivative biliverdin whose increase in the irradiated system is synchronous with a time dynamics of bilirubin degradation. It appears that one of dipyrrolic products originates directly from bilirubin and biliverdin molecules, while the other one is probably connected to bilirubin self-sensitized degradation. The precursor role of biliverdin in the degradation process--related to the detected dipyrroles--has not been confirmed. PMID- 26012252 TI - Hepatoprotective effects of a self-micro emulsifying drug delivery system containing Silybum marianum native seed oil against experimentally induced liver injury. AB - The main purpose of this study was to certify the effect of native silymarin oil (SM-oil) formulated in a self-microemulsifying drug delivery system (SMEDDS). The optimal formulation was 25% of SM-oil, 33.3 % of Cremophor RH40, 20% of Transcutol HP, 16.6% of Labrasol and 5% of Capryol 90. In this novel formulation the SM-oil was the active substance and the lipid part. The in vivo study examined the preventive effects of SMEDDS containing SM native seeds oil against carbon tetrachloride (CC14) induced hepatotoxicity in mice. Determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and also liver histology investigations have been done. The liver antioxidant status was determined with the concentrations of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), and glutathione (GSH) hepatic lipid peroxidation was examined and expressed in terms of malondialdehyde (MDA) content. The plasma levels of AST and ALT significantly diminished by pre treatment with 500 mg/kg and 1000 mg/kg SMEDDS. The pre-treatment with 500 mg/kg and 1000 mg/kg SMEDDS increased GSH level by about 6% respectively 24% compared to the CC14 group. Due to preventive administration of 500 mg/kg and 1000 mg/kg of SMEDDS in the intoxicated animals, MDA levels were reduced by 22% respectively 58%. Also, an insignificant rise by almost 17% and 19% in the animals treated with the both doses of SMEDDS could be noticed. It can be concluded that hepatotoxicity may be avoided by the oral application of our formulation. PMID- 26012253 TI - Structure-inhibition relationship of podophyllotoxin (PT) analogues towards UDP glucuronosyltransferase (UGT) isoforms. AB - UDP-glucuronosyltransferases (UGTs) are involved in the clearance of many important drugs and endogenous substances, and inhibition of UGTs' activity by herbal components might induce severe herb-drug interactions or metabolic disturbances of endogenous substances. The present study aims to determine the inhibition of UGTs' activity by podophyllotoxin derivatives, trying to indicate the potential herb-drug interaction or metabolic influence towards endogenous substances' metabolism. Recombinant UGT isoforms (except UGT1A4)-catalyzed 4 methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the podophyllotoxin derivatives' inhibition potential. Structure-dependent inhibition behavior of podophyllotoxin derivatives towards UGT isoforms was detected. Inhibition kinetic type and parameter (Ki) were determined for the inhi- bition of podophyllotoxin towards UGT1A1, and competitive inhibition of podophyllotoxin towards UGT1A1 was observed with the inhibition kinetic parameter (Ki) to be 4.0 MUM. Furthermore, podophyllotoxin was demonstrated to exert medium and weak inhibition potential towards human liver microsomes (HLMs)-catalyzed SN-38 glucuronidation and estradiol-3-glucuronidation. In conclusion, podophyllotoxin inhibited UGT1A1 activity, indicating potential herb-drug interactions between podophyllotoxin-containing herbs and drugs mainly undergoing UGT1A1-mediated metabolism. PMID- 26012254 TI - Triptolide alleviates isoprenaline-induced cardiac remodeling in rats via TGF beta1/Smad3 and p38 MAPK signaling pathway. AB - Triptolide (TPL) is a diterpene triepoxide with potent immunosuppressive and anti inflammatory properties. It is the main effective component of the traditional Chinese herb Tripterygium wilfordii Hook F and has been used in China for centuries to treat immune-related disorders. The present study was conducted to investigate the effects of TPL on cardiac remodeling in rats. Age matched male Wistar rats were used in this study. Cardiac remodeling rat model was established by hypodermic injection of isoprenaline for ten days. The rats were treated with TPL (20 or 100 MUg/kg/d) for six consecutive weeks. At the end of the study, the cardiac function, collagen volume fraction, perivascular collagen area and hydroxyproline concentration were studied. Echocardiography, Masson staining, immunohistochemistry, western blot and real-time polymerase chain reaction were performed. The protein and mRNA expression of transforming growth factor-beta1 (TGF-beta1), drosophila mothers against decapentaplegic protein 3 (Smad3) and p38 mitogen activated protein kinase (p38 MAPK) were analyzed. The results indicated that TPL treatment significantly reduced the collagen volume fraction, perivascular collagen area, ventricular weight/body weight ratio and hydroxyproline concentration in myocardial tissue compared with the model group. In addition, it also improved the cardiac function. TPL attenuated cardiac remodeling in rats by down-regulating the p38 MAPK and TGF-beta1/Smad3 signaling pathways. TPL treatment significantly attenuated cardiac fibrosis and improved cardiac function through suppressing the p38 MAPK and TGF-beta1/Smad3 signaling pathway in isoprenaline-induced cardiac remodeling rats. Our findings suggested that TPL might be a novel complementary medicine in the treatment of chronic heart failure. PMID- 26012255 TI - The role of 8-OH-DPAT on the rat neuronal apoptosis after diffuse brain injury coupled with secondary brain injury. AB - The potential role of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on rat neuronal apoptosis after diffuse brain injury (DBI) coupled with secondary brain injury (SBI) was investigated. One hundred and twelve adult male Wister rats weighing 305-355 g were randomly divided into four groups and received an intraperitoneal injection of 8-OH-DPAT (0.5 mg/kg) or an equal volume of normal saline. Neurological severity score (NSS) was recorded and the injured extent was observed after hematoxylin-eosin (HE) staining. The neuronal cell apoptosis index and the expression of Bax and Bcl-2 were detected by TUNEL method and immunohistochemistry respectively. We found a higher NSS value for rats in the DBI + SBI groups compared with those in normal control and sham-operated control groups (P < 0.01). HE staining showed that 8-OH-DPAT treatment could alleviate the occurrence of injury in rats CA3 hippocampus and PFC. The neuronal apoptosis index decreased in the 8-OH-DPAT treatment group compared with the NS group (P< 0.05) and gradually increased at 6 h, reached the peak level at 72 h and still had a high performance at 168 h in not only CA3 hippocampus but also PFC. Expression of Bax and Bcl-2 increased after DBI + SBI, however, with 8-OH-DPAT treatment Bcl-2 expression increased while Bax expression decreased. 8-OH-DPAT had an inhibitory effect on the rat neuronal apoptosis in CA3 hippocampus and PFC after DBI coupled with SBI. PMID- 26012256 TI - Nobiletin inhibited hypoxia-induced epithelial-mesenchymal transition of lung cancer cells by inactivating of Notch-1 signaling and switching on miR-200b. AB - Epithelial-mesenchymal transition (EMT) is an early step in the process of tumor metastasis. It is well known that tumor microenvironment affects malignancy in various carcinomas; in particular, that hypoxia induces EMT. Deregulated notch signaling also contributes a lot to the development of EMT in lung cancer. In this study, we investigated the use of Notch-1-inhibiting compound as novel therapeutic candidates to regulate hypoxia-induced EMT in lung cancer cells. According to previous screening, nobiletin was selected as a Notch-1 inhibitor. Hypoxia-induced EMT was characteristic of increased N-cadherin & vimentin expressions and decreased E-cadherin expressions. Treatment with nobiletin notably attenuated hypoxia-induced EMT, invasion and migration in H1299 cells, accompanied with reduced Notch-1, Jagged1/2 expressions and its downstream genes Hey-1 and Hes-1. Nobiletin treatment also promoted tumorsuppressive miR-200b level. Moreover, notch-1 siRNA prevented hypoxia-mediated cell migration and decreased Twist1, Snail1, and ZEB1/2 expressions, which are key EMT markers. Re expression of miR-200b blocked hypoxia-induced EMT and cell invasion. Our findings suggest that downregulation of Notch-1 and reexpression of miR-200b by nobiletin might be a novel remedy for the therapy of lung cancer. PMID- 26012257 TI - Apoptosis induced by weisiensin B isolated from Rabdosia weisiensis C.Y. Wu in K562. AB - The ent-kaurane diterpenoid weisinensis B shows significant cytotoxicity to human chronic myeloid leukemia K562 cells. It inhibits cell growth at low concentration and kills cells at high concentration. The compound induced cell apoptosis and necrosis mainly associated with G2/M phase cell cycle arrest and the ROS generation is the early event in weisiensin B induced cell apoptosis. PMID- 26012258 TI - Clinical effect of a polysaccharide-rich extract of Acanthopanax senticosus on alcohol hangover. AB - The present study aimed to examine the effects polysaccharide-rich extract of Acanthopanax senticosus (PEA) on blood alcohol concentration (BAC) and hangover as well as blood lab parameters. A randomized, placebo-controlled, double-blind crossover trial was conducted. The PEA was orally administered before and after consuming alcohol 1.75 g/kg of pure alcohol. After alcohol consumption, BAC was measured for evaluation of alcohol pharmacokinetics. In the second day morning, subjects were asked to complete the Acute Hangover Scale (AHS) questionnarie. BAC results showed little difference between placebo and PEA groups, indicating that PEA does not have an effect on the pharmacokinetics of alcohol. However, several AHS items (i.e., tired, headache, dizziness, stomachache and nausea) and AHS total score were significantly improved by PEA. Blood lab parameters were significantly altered by alcohol in the placebo group. The alteration by alcohol of glucose and C-reactive protein (CRP) level was significantly attenuated by PEA. Therefore, PEA may have potential to reduce the severity of the alcohol hangover by inhibiting the alcohol-induced hypoglycemia and inflammatory response. PMID- 26012259 TI - [Derogating victims and dehumanizing perpetrators: functions of two types of beliefs in a just world]. AB - This study defined Belief in Just World (BJW) multidimensionally and investigated the effects of Belief in Immanent Justice (BIJ) and Belief in Ultimate Justice (BUJ) on victim derogation and draconian punishment of perpetrators. Study 1 tested the validity of the multidimensional structure of BJW and demonstrated relationships between BJW and other psychological variables. In Study 2, we measured the reactions to the victim and perpetrator in an injury case reported in a news.article, and evaluated the relationships of these reactions to BIJ and BUJ. The results revealed that BIJ was associated with a preference in draconian punishment of the perpetrator, while BUJ was associated with dissociation from the victim (a type of victim derogation). In addition, as hypothesized, we found that dehumanization of the perpetrator partially mediated the relationship between BIJ and victim derogation. We discussed relationships between the two types of BJW and just-world maintenance strategies in the situation where a victim and a perpetrator are both recognized. PMID- 26012260 TI - [Examination of the effects of stress coping on later affect using daily diary methods]. AB - In response to recent calls in the literature for within-person examination of coping processes over time, this study used daily diary methods to investigate the relationships between daily events, coping, and daily affects. Every day for two weeks, 62 undergraduates recorded their perceived interpersonal stress, most troublesome events, how they coped, positive events, and positive and negative affect. A hierarchical linear model was used to examine the relations between these variables. The results suggested that both positive and negative events made significantly influenced current-day positive and negative affect. In addition, avoidance thinking was associated with within-level adjustment, while emotional sharing with others, distancing and positive reappraisal were associated with within-level maladjustment. PMID- 26012261 TI - [The effects of charity advertising on donations and donors' explicit and implicit evaluations of recipients]. AB - Advertisements for charity generally employ one of two advertising strategies. The first appeals to the efficacy of support, while the second appeals to the necessity of support. Two experiments investigated the effect of each type of charity advertising on donations and on donors' explicit and implicit evaluations of the recipients. The results indicated that although participants' explicit evaluations of charity recipients were not changed by efficacy-based advertising, they were negatively influenced by necessity-based advertising. Furthermore, Experiment 1 detected moderating effects of empathic concern. The explicit evaluations of participants in the necessity-based advertising group were negatively correlated with their empathic concern. Implicit evaluations were consistently negative in both groups. Both advertising strategies were more effective at securing donations than the control group, which did not use any strategies. These findings suggest practical implications for charity advertising. PMID- 26012262 TI - [Development of free will and determinism scale in Japanese]. AB - We developed a free will and determinism scale in Japanese (FAD-J) to assess lay beliefs in free will, scientific determinism, fatalistic determinism, and unpredictability. In Study 1, we translated a free will and determinism scale (FAD-Plus) into Japanese and verified its reliability and validity. In Study 2, we examined the relationship between the FAD-J and eight other scales. Results suggested that lay beliefs in free will and determinism were related to self regulation, critical thinking, other-oriented empathy, self-esteem, and regret and maximization in decision makings. We discuss the usefulness of the FAD-J for studying the psychological functions of lay beliefs in free will and determinism. PMID- 26012263 TI - [Reliability and validity of a marital commitment scale in middle-aged and elderly couples]. AB - A marital commitment scale was created to study marital relationships of middle aged and elderly couples. This study examined the scale's reliability, and validity. A total of 840 middle-aged and elderly married participants ranged from 37 to 89 years completed the marital commitment questionnaire and answered questions regarding marital love, perception of the balance of power between spouses, and the concept of gender roles. The results showed that marital commitment consisted of personal commitment, resigned and instrumental commitment and normative commitment. Personal commitment was highly correlated with marital love. Resigned and instrumental commitment was correlated with perception of poorly balanced of power between spouses. Normative commitment was correlated with the concept of traditional gender roles. Thus the internal consistency as well as the construct and criterion-related validity of the marital commitment scale were confirmed. Gender differences were also identified. Men scored higher on,personal and normative commitment, and women, scored higher on resigned and instrumental commitment. The results are discussed in terms of gender. PMID- 26012264 TI - [Effect of goal activation on goal management]. AB - Studies of goal management have examined how to manage multiple goals. Previous research (Finkelstein & Fislibach, 2010) showed that healthy eating made one hungrier. This study hypothesized that participants were hungrier when a health goal was not activated than when it was activated. It is expected that in such cases, goal shifting might be more likely to occur because goal progress had been perceived. Two experiments were conducted and their results were in line with this hypothesis. Participants reported being hungrier when their health goal were not activated than when these goals were activated. We consider the effect of goal activation on goal management and its implications for future research. PMID- 26012265 TI - [Career exploration as related to self-efficacy and the motivation based on self determination theory]. AB - The purpose of the present study was to examine the multivariate relations between career exploration and its predictors. University sophomores and seniors completed a questionnaire about career exploration, career decision-making self efficacy, career decision-making outcome expectations, and career motivation. Canonical correlation analysis showed that combining all predictors, i.e., career decision-making self-efficacy, career decision-making outcome expectations, and career motivations, accounted for a large portion of the career exploration variance. Of subfactors of career motivation, only "integrated and identified regulation" was significantly related to career exploration. This result suggests that career exploration is predicted by self-efficacy as well as a highly self determinated extrinsic motivation. PMID- 26012266 TI - [A negative meta-cognitive belief about thought suppression induces intrusive thoughts]. AB - The purpose of the present study was to investigate the causal relationship between meta-cognitive beliefs about thought suppression and intrusive thoughts. We conducted structural equation modeling using a cross-lagged effect model and a synchronous effect model. Results revealed that the Paradoxical Effect subscale score synchronously increased the frequency of intrusive thoughts. On the other hand, the frequency of intrusive thoughts did not affect the degree of confidence in meta-cognitive beliefs. These results demonstrate a causal relationship between meta-cognitive beliefs about thought suppression and intrusive thoughts. The cognitive processes underlying this causal relationship and future directions of research about thought suppression are discussed. PMID- 26012267 TI - [Job performance in work organizations: the effects of management by group goals and job interdependence]. AB - cThis study examined the interactive effect of management by group goals and job interdependence on employee's activities in terms of task and contextual performance. A survey was conducted among 140 Japanese employees. Results indicated that management by group goals was related only to contextual performance. Job interdependence, however, had a direct effect on both task and contextual performance. Moreover, moderated regression analyses revealed that for work groups requiring higher interdependence among employees, management by group goals had a positive relation to contextual performance but not to task performance. When interdependence was not necessarily required, however, management by group goals had no relation to contextual performance and even negatively impacted task performance, respectively. These results show that management by group goals affects task and contextual performance, and that this effect is moderated by job interdependence. This provides a theoretical extension as well as a practical application to the setting and management of group goals. PMID- 26012268 TI - [The role of dispensarization in decreasing of morbidity of population]. AB - During recent years positive shifts occurred in demographic development of the Russian Federation. The number of births increased and number of deceased decreased. In spite of that, mortality of vascular pathology, external causes, tuberculosis remains high. The tasks of health care and health promotion require scientific comprehension both dispensarization and disease prevention. Such kind of approach is necessary to effectively implement this work and to restore prevalent in history of national health care traditions concerning active implementation of dispensarization of population as the most important mode of prevention activities. The prerequisites of development of dispensarization are changing and a corresponding research systematic support is needed. The conceptual maintenance of dispensarization of population is founded on a set of theoretical notions and new paradigm of population health enhancement. The actual state of affairs in the area of dispensarization of population is analyzed in a number of dissertation studies. The study has particular significance for residents of rural territories due to characteristics of life and medical care support. Hence, the necessity to revise organization of dispensarization of rural population. In urban conditions, volume, character and time-frame of dispensarization and shortcomings of functioning ofmunicipal polyclinic are determined. The effect ofmass dispensarization is substantiated by decreasing of temporary disability in dispensarization patients. The dispensarization of population is an example of successful periodic preventive examination of population. PMID- 26012270 TI - [The priority diet factor of rural population of the Republic of Tatarstan]. AB - The four risk factors of 60% of disease burden in Europe are closely related to diet. The results of random study of rural population substantiated that diet factors interact with other factors of life activity of rural population. Therefore, to control diet factors is possible only through other factors of life activity. The management of rural population health requires considering regional and gender characteristics offormation of population life-style. PMID- 26012269 TI - [The complex study of road traumatism at the territory of the Cheliabinskaia oblast]. AB - The article presents analysis of prevalence of road traumatism in territory of region. The degree of coverage of population with specialized medical care in conditions of traumatological centers of I, II and III levels is examined The evaluation of effectiveness of these centers is given. The received data testify the high-repeatability indicators of road traumatism and corresponding mortality. The issues related to functioning of traumatological centers as a comprehensive system are established Hence, necessity to implement operative monitoring of their functioning. The management actions targeted to optimize process of interrelationship between traumatological centers and medical organizations having no traumatological centers are needed. PMID- 26012271 TI - [The evaluation of medicinal therapy under treatment of arterial hypertension in hospital]. AB - The article presents the analysis of data of "Study on Global AGEing and Adult Health, 2007-2010" (SAGE) concerning subjective judging of health, prevalence of ischemic heart disease under different levels of arterial pressure in similar age groups. An attempt is made to evaluate spectrum of pharmaceuticals applied in treatment of patients with arterial pressure in hospital at the level of oblast hospital. According official statistics of Minzdrav of Russia, in 20102 prevalence of diseases characterized by higher arterial pressure amounted to 10.5% in adult population and to 22.3% in population older than able-bodied age. At the same time, according SAGE data, prevalence of various forms of hypertension disease in population older than 50 years amounted to 52.8%. That is, this pathology is often missed in conditions of mass medical network. Thereafter, patients receive no necessary medicinal therapy. The one or another treatment was provided to almost 94% of patients with hypertension disease diagnosed by physician. At that, among patients received treatment the normal levels of both systolic and diastolic pressure were established in less than 20% of patients with hypertension. Therefore, the issue of effectiveness of applied methods of correction of arterial hypertension become a matter of interest. The appropriate treatment of hypertension is a mean to decrease complications and as a result to diminish mortality of diseases of circulatory system. PMID- 26012272 TI - [The opinions of district physicians-therapists concerning expedience of distant counseling of patients at the ambulatory level]. AB - The sociological survey of 91 district physician-therapists was carried out to evaluate degree of implementation by patients of prescribed treatment. At the same time, most of the respondents assume that untimely decision of issues appeared in patients during treatment process decrease effectiveness of prescribed treatment. Besides, these issues very often can be resolved using Internet. The remote counseling, as an element of system of medical information support in out-patient medical organization is a method of development of organization of ambulatory care of population. PMID- 26012273 TI - [The multi-factorial model of satisfaction of medical care by hospital patients suffering from borderline psychic disorders]. AB - The satisfaction of patients with medical care determines their consumer behavior. The factors of satisfaction with medical care vary depending on level of its provision and profile of medical specialty. At that, there are only sporadic studies dedicated to factors of satisfaction with psychiatric care. The study was carried out to examine factors of satisfaction with hospital psychiatric care by patients suffering from depressive and neurotic disorders. The sampling consisted of 356 hospital patients suffering from depressive and neurotic disorders. The survey in written form was carried out using originally developed questionnaire. The statistical analysis was implemented by compiling equation of multiple regression. It is established that key factors of satisfaction include functioning of medical nurses of department, functioning of attending physician, comfort of wards, proportions and quality of psychiatric care capability of physician to empathic listening. The developed mathematical model explains 81% of variation of satisfaction with treatment. PMID- 26012274 TI - [The responsiveness of health care system and its characteristics]. AB - The responsiveness of health care system is an indicator proposed by the World Health Organization to evaluate reaction of health care system to non-medical expectations of patient. The article presents results of analysis of responsiveness of health care system according the data of sociological survey of population of the Arkhangelskaia oblast. The sampling included 1416 respondents. According results of survey, such criteria as participation ofpatient in course of treatment, communicability and confidentiality received the least ofpositive values. The analysis of main components revealed two factors explaining 53% of dispersion of responsiveness of system. PMID- 26012275 TI - [The organizational aspects of medical support of convicts in the Republic of Sakha (Yakutia)]. AB - The organization of medical care in the Central hospital of the department of Federal penitentiary service of Russia of the Republic of Sakha (Yakutia) was examined The analysis of morbidity of convicts was carried out. The activities concerning enhancement of quality of organization of medical care considering tendencies in health care are proposed. PMID- 26012276 TI - [The efficiency of psychological educational programs under depressive disorders]. AB - The psychological educational programs make possible to increase level of awareness of depression in patients with depressive conditions and to enhance coping of patients with symptoms of disease. In scientific publications, the experience of application of both full-time group and individual and nonresident psychological educational programs is exposed The result of implementation of these programs consists in decreasing of expression depression symptoms, increasing of number of remissions, increasing of commitment to pharmaceutical treatment and decreasing of rate of refusals of treatment and increasing of rate of seeking of professional medical care in case of exacerbation of disease. The psychological educational programs ameliorate socialfunctioning, work capacity, quality of life and life satisfaction in patients. PMID- 26012277 TI - [The expert evaluation of enhancement of organization of functioning of territorial polyclinic]. AB - The planning of optimizing activities of out-patient service is appropriate to carry out examination of opinions of administrators of ambulatory medical organizations. The expertise of 70 head physicians and their deputies of treatment activities of ambulatory medical organizations of Novosibirsk determined directions of optimization of functioning of territorial polyclinic. The applied activities resulted in decreasing of indicators of period of visiting, and level of social deadaptation of patients. The number of treated patients increased both in polyclinic and day-stay hospital. The average duration of treatment in day-stay hospital and numbers of calls of emergency care ambulance on the territory ofpolyclinic attendance decreased PMID- 26012278 TI - [The regularities and tendencies of infant and children mortality in the Russian Federation]. AB - The article presents dynamics and causes of infant and children mortality in the Russian Federation during post-soviet period (1990-2012) in conditions of implementation of demographic policy and reforming of health care system. The data of official statistics of Rosstat (1990-2012) is analyzed. The comparative analysis with similar indicators in countries of European Union was made. The significant decreasing of infant mortality more than twice at the expense of all its components (early neonatal, neonatal, post-neonatal mortality) and because ofalmost all causes (conditions of perinatal period, infectious diseases, respiratory organs diseases, malformations, accidents) is established In the Russian. Federation, the characteristic of this indicator is decreasing of neonatal mortality and mortality and increasing of post-neonatal mortality in contrast with countries of European Union where its decreasing occurs just at the expense of late losses. It is demonstrated that this particularity is conditioned by under-registration of infants died in early neonatal period. The higher level of infant mortality in rural territories is established. However, the gap between urban and rural indicators shortens. In the Russian Federation infant mortality has regional characteristics and the Siberian and Far-East region are the most unfavorable ones. The mortality of children aged before 5 decreases. However, its level is still higher than in countries of European Union. Among causes of death of children in this age group the first places are for external factors and significance of malignant neoplasms increases. Therefore, development of system of mother and child health care in the Russian Federation made it possible to significantly decrease infant and children mortality. PMID- 26012279 TI - [The children health centers: first results of functioning and perspectives of development]. AB - The article presents analysis of functioning of children health centers organized in allsubjects of the Russian Federation. For the first time, according data of report form 68, the information are received concerning visits of children in following age groups: 0-4 years, 5-9 years, 10-14 years, 15 and 16-17 years. The average Russian indicators of visits of children health centers are calculated that can be applied in territories as markers of their effectiveness. The main flows of arrival of children population to health centers and determining factors are established. The particular attention is paid to analysis of repeated visits. The regional experience of their payments in the system of mandatory medical insurance is presented. The experience of implementation of Internet resources in propaganda of healthy life-style in adolescents and young parents is examined. The results of the carried out study were used as a basis to establish in n prevention activities of children health centers problem zones of medical organizational, technological and informational character. The proposals are given concerning enhancement of children health centers functioning. PMID- 26012280 TI - [The main principles of concept of development of palliative care to children and adolescents]. AB - The article substantiates actuality of elaboration of the concept of development of palliative care of children and adolescents. The analysis of legislative and normative legal base, international documents, scientific studies related to this issue are analyzed. The situation in the regions ofthe Russian Federation is examined concerning organization of palliative care of children and its forms, provision of pharmaceuticals and specialized equipment and professional training of specialists. The demand of children population in palliative care in Russia is calculated according data of 2012. The results of carried out study are used as a basis of determining measures of development of system of palliative care of children and adolescents in the Russian Federation to propose as a foundation for the National concept as a necessary condition for organization of effective and efficient service. PMID- 26012281 TI - [The business game as a form of organization of competent approach in teaching of history of medicine]. AB - The article considers issue of implementation of competent approach in teaching of course of history of medicine in medical universities. The such methods of active training as imitation role business games are proposed as a mean of developing common cultural and professional competences offuture medical personnel. The business games promote development of motivation basis or education and require activities related to practical implementation of acquired knowledge and skills (analysis of historical event, work with map, reading of historical documents, participation in scientific discussion, etc.). As a result, students acquire sufficiently large notion concerning world of medicine, relationship of historical epochs and occurrences and unity of medical systems. PMID- 26012282 TI - [The scientific revolution in medicine of the last quarter of XIX-first half of XX centuries. Report I. The causes and mechanisms of scientific revolution]. AB - The article describes the system of conceptions about subject of investigation in medicine and methods of research activities of physicians well-established by early 70s of XIX century. It is postulated that in the middle of 1870s in medicine occurred an objective need of entirely different from before vision of investigated reality, development and implementation of fundamentally new methodological approaches to its studying that by-turn initiated global scientific revolution in medicine of the last quarter of XIX-first half of XX centuries. It is substantiated that need of new vision of investigated reality became first of all a consequence of profound intra-disciplinary crisis related to awareness of fallibility of existed ideas of human organism and its vital activity. The second cause is two "paradigm inoculations" from biology which resulted in forced acceptance by physicians the extreme incompleteness and fallacy of their previous views concerning environment and essence of its effect on human organism. PMID- 26012283 TI - [The standards of Russian industrial law regulating regimen of working time of personnel of medical organizations]. AB - The article presents history of becoming in Russia on standards of low regulating regimen of working time of medical personnel. The normative legal acts of the USSR and the RSFSR having juridical empower nowadays are presented. PMID- 26012284 TI - [The activities of hospitals of Narkomat of public health system for special contingent during the Great Patriotic War]. AB - The period of the Great Patriotic War from autumn 1942 to summer 1945 is marked by process of becoming ofsystem of hospitals for special contingent. The special hospitals were marked out in common system of medical care in war time by specificity of its treatment activities, every day and technical commodities and schemes of management and provision. The organization of treatment of prisoners of war encountered difficulties in transportation and diagnostic of diseases, health conditions of arrived contingent, provision with medical documentation and specificity of psychological aspects of work of military medical personnel in hospitals for special contingent. PMID- 26012285 TI - [Sublingual specific immunotherapy for allergic rhinitis]. PMID- 26012286 TI - [Diagnosis and treatment of allergic rhinitis in children]. PMID- 26012288 TI - [Leukotriene receptor antagonist as add-on therapy to intranasal corticosteroids in the treatment of allergic rhinitis: a systematic review]. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of leukotriene receptor antagonist (LTRA) combined intranasal corticosteroids in the treatment of allergic rhinitis (AR). METHOD: The randomized controlled trials (RCT) about the combined therapy of LTRA and nasal corticosteroids from January 1985 to May 2014 were searched in OVID, PubMed, EMBASE, CNKI, WanFang Data, and Cochrane Library. Two reviewers independently screened the literatures, extracted the data, and evaluated the methodological quality. Then meta-ana- lyses were conducted by using RevMan 5.1 software. RESULT: A total of 5 RCTs were included upon literature search. The results of meta-analyses showed that the efficacy of nasal corticosteroids plus LTRA was superior to nasal corticosteroids alone in total nasal symptom scores and individual nasal symptom scores (rhinorrhea, sneezing) [WMD = -4.49, 95% CI (-4.95(-)-4.03)-, P < 0.01; WMD = -0.43, 95% CI ( 0.78(-)-0.07), P < 0.05; WMD = -0.10, 95% CI (-0.6(-)-0. 04), P < 0.01], with significant differences. However, compa- ring the subgroup treated with nasal corticosteroids combined LTRA against the subgroup treated with nasal corti- costeroids alone, we found no significant differences for RQLQ score and for individual nasal symptom scores (nasal blockage, nasal itching) [WMD = -15.19, 95% CI (-55.37(-)-25. 00), P > 0.05; WMD = 0.01, 95% CI(-) 0.06-0.08), P > 0. 05; WMD = -0.15,95% CI (-0.43(-)-0.13), P > 0.05]. CONCLUSION: Based on limited evidence, we preliminary concluded the combined therapy of nasal corticosteroids and LTRA was more effective than nasal corticosteroids alone in the management of AR. Further large-scale, well-designed RCTs were still required to validate the add-on efficacy of LTRA for AR patients. PMID- 26012287 TI - [Recent advances in allergic rhinitis]. AB - Allergic rhinitis (AR) clinically expressed by sneezing, rhinorrhea, nasal itching and congestion is an allergen-driven mucosal inflammatory disease which is modulated by immunoglobulin E. Epidemiological studies have indicated that prevalence of AR continues to increase, and it has been a worldwide health problem that places a significant healthcare burden on individuals and society. Given the evolving understanding of the process by which an allergen is recognized and the roles of mediators which account for AR progress, the pathogenesis of AR has become clearer. Current studies have demonstrated local allergic rhinitis (LAR) that patients with both sug- gestive symptoms of AR and a negative diagnostic test for atopy may have local allergic inflammation is a prevalent entity in patients evaluated with rhinitis, but further research remains needed. Management of AR includes aller- gen avoidance, pharmacological treatment and allergen-specific immunotherapy. Recently montelukast has exhibited previously undocumented anti-inflammatory properties, leukotriene receptor antagonists therefore may serve a more important role in the treatment of AR. Not only has immunotherapy proved its efficacy, but also been able to alter disease course and thereby mitigate progression to asthma. Thus immunotherapy can be initiated while receiving pharmacotherapy, especially in children with AR. As clinical guidelines, the ARIA (Allergic Rhinitis and its Impact on Asthma) provides basic principles of effective treatment of AR. Besides, choosing an appropriate treatment strategy should be based on the severity and chronicity of patient's symptom. The aim of this review was to provide an update mainly on the pathophysiology, epidemiology, and management of AR. PMID- 26012289 TI - [The effection of environmental and health message forecasting service offer to the allergic rhinitis in children]. AB - OBJECTIVE: To investigate the impact of environment and message information for the treatment efficacy of children with allergic rhinitis (AR). METHOD: To choose 100 cases of children diagnosed with AR. The parents of children record daily symptom scores of AR of children everyday. While the doctors send the short message to the parents by using meteorological environment warning forecast technology to tell the parents the risk of AR attacks. We observe the morbidity of AR of the children and the treatment efficacy of children for 1 year. The 100 cases control group children diagnosed AR, their parents do not record daily symptom scores of AR and the doctors do not give the short message. We also observe the morbidity of AR of the control group children and the treatment efficacy of the children for 1 year. RESULT: The 100 cases intervention group children with AR, there are 11 cases refused to participate the group. We included a total 89 cases, 74 cases of children did a full year of intervention, 15 cases of children gave up. The control group 100 cases, nine cases refused to participate, 91 cases were included. The average episodes in the intervention group was 4. 67 times, the control group was 8. 12 times,--there were significant differences between the groups statistically. The execution rate on the prescribed clinic date in the intervention group visits was 91. 5%, while in the control. group, was only 67%. The compliance of parents of children to complete course of medication in the intervention group was 95. 6%, while the control group was 74.1%. Both sets of data are statistically significant differences. The children with sinusitis in intervention group was 26.97%, significantly lower than the 64.04% in the control group. The incidence in the intervention group and the control group of secretory otitis media was 8.99% and 6.60%, there was no statistically significant differences. CONCLUSION: It can significantly increase the degree of attention of parents of children with AR that the parents of children record daily symptom scores of AR of children everyday, while the doctors send the short message to the parents by using meteorological environment warning forecast technology to tell the parents the risk of AR attacks. It can also improve the execution rate on the prescribed clinic date and improve compliance of parents of children to complete course of medication. It can significantly reduce seizure frequency and severity of episodes of AR, thereby improving the quality of life of children with AR, reduce the economic burden on families and society. PMID- 26012290 TI - [Study on influential factors associated with the long-term effect of allergic rhinitis specific immunotherapy]. AB - OBJECTIVE: To investigate the influential factors associated with the long-term effect of allergic rhinitis (AR) specific immunotherapy (SIT). METHOD: Retrospective analyzed the following visual analog scale(VAS) before and after the specific immunotherapy of 219 patients with allergic rhinitis. Logistic regression and pair t-test were used to explore the key factors influencing the prognosis. RESULT: (1) The gender and the VAS before specific immunotherapy (P < 0.05) were associated with the long-term effect of allergic rhinitis specific immunotherapy, while family history, the age of specific immunotherapy, number of allergens and stitches and with other allergic diseases (P > 0.05) were not associated with the long-term effect of specific immunotherapy; (2) Compared VAS of different endpoints with VAS before the treatment,there were significant differences. The primary endpoints were the time following no more than half a year (total effective rate: 50.0%), half a year to 1 year (total effective rate: 51.7%), 1 to 2 year (total effective rate: 47.1%), 2 to 3 year (total effective rate: 54.5%) and over 3 year (total effective rate: 40.7%). CONCLUSION: Apart from the gender and the VAS before specific immunotherapy,genetic and other factors can not significant influence the long-term effect of specific immunotherapy. The effect of specific im- munotherapy seems to last for 3 years at least. Increasing stitches can not improve long-term effect of SIT,but it can consolidate the effect. The long-term effect of specific immunotherapy tends to drop off with fluctuations over time and the higher of VAS before SIT,the better effect of long-term SIT. Further more, the long-term effect of SIT of male is worse than female. In consequences, we speculate epigenetics related to the interaction between environmental factors and genetic factors plays an important role in the long-term effect of allergic rhinitis specific immunotherapy. PMID- 26012291 TI - [Effects of nasal symptoms on the psychological statuses of adults with moderate to-severe persistent allergic rhinitis]. AB - OBJECTIVE: To investigate the psychological statuses of Chinese adults with moderate-to-severe persistent allergic rhinitis, and evaluate the effects of nasal symptoms on their psychological statuseses. METHOD: The Symptom Checklist 90 (SCL-90) or self-reporting Inventory was employed to analyze the psychological statuses of 539 adults with moderate-to-severe persistent allergic rhinitis. RESULT: The SCL-90 scores of the adults with moderate-to-severe persistent allergic rhinitis were statistically higher than those of non-allergic adults in terms of somatization, depression, anxiety and hostility. No statistical discrepancies existed in gender or age. The course of disease contributed to somatization and compulsion. The effects of nasal symptoms included two aspects: nasal obstruction had a conspicuous impact on somatization, compulsion, interpersonal sensitivity, depression, anxiety and psychosis, while nasal itching contributed to somatization, depression and anxiety. CONCLUSION: The psychological statuses of adults with moderate-to-severe persistent allergic rhinitis is evidently worse than that of non-allergic adults. Symptoms such as nasal obstruction and itching had an obvious impact on outpatients' psychological statuses. PMID- 26012292 TI - [Efficacy of sublingual immunotherapy with Dermatophagoides farinae drops on patients with allergic rhinitis of different symptom severity]. AB - OBJECTIVE: To evaluate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides farinae drops for allergic rhinitis (AR) of different symptom severity. METHOD: This retrospective analysis to receive SLIT treatment of 143 cases of patients with allergic rhinitis, according to the severity of disease symptoms divid- ed into two groups, moderate group (62 patients) and severe group (81 patients). Before SLIT and after SLIT for half year, 1 year and 1. 5-2.0 years, the TNSS, TMS and sign scores of patients with allergic rhinitis were evaluated. RESULT: The TNSS, TMS and sign scores had continuously improved significantly after SLIT for half year, 1 year and 1.5-2.0 years in two groups as compared with baseline (P < 0.05). Before SLIT, TNSS and sign scores of severe group had a significantly higher level than moderate group (Z = 10.40, 2.40, P < 0.05), while TMS of two groups had no significant differences (Z = 0.00, P > 0.05). Half year after SLIT treatment, in two groups for sign scores, there were significant differences (Z = 3.32, P < 0.05), and there were no significant differences for TNSS (Z = 1.58, P > 0.05) and TMS (Z = 0.37, P > 0.05). 1 and 1.5 2.0 years after SLIT, there were no significant differences in two groups for TNSS, TMS and sign scores (P > 0.05). CONCLUSION: SLIT with Dermatophagoides farinae drops for 1.5-2.0 years is effective in the patients with allergic rhinitis of different symptom severity. And equivalent efficacy could be achieved for different symptom severity. PMID- 26012293 TI - [Quality of life in 164 allergic rhinitis patients caused by different aeroallergens]. AB - OBJECTIVE: We aimed to analyze the quality of life (QOL) in adults with allergic rhinitis according to the sensitization profile for relevant aeroallergens in Northern China, investigate the proportion of patients with coexisting asthma, and explore the correlation between QOL of rhinitis patients and the specific IgE level to the causative allergen. METHOD: One hundred and sixty-four allergic rhinitis patients participated in this study, whose clinical history, results of intradermal skin test and serum specific IgE levels to common aeroallergens in North China were collected. QOL was evaluated using the rhinoconjunctivitis quality of life questionnaire (RQLQ). RESULT: QOL of rhinitis patients was worse in those sensitized to tree pollens or weed pollens than those sensitized to house dust mites in Northern China. The proportion of patients with co-existing asthma was lower in tree pollen group than in house dust mite group or weed pollen group, and there was no significant difference between house dust mite group and weed pollen group. There was no significant correlation between QOL of rhinitis patients and the specific IgE level to the causative allergen. CONCLUSION: In our study group, QOL of patients with allergic rhinitis varied with the allergen responsible for symptoms, but was not influenced by the specific IgE level to relevant allergen. The proportion of patients with co existing asthma also varied with different pollen allergens. Rhinitis patients sensitized to weed pollens might be more likely to suffer from asthma than those sensitized to tree pollens. PMID- 26012294 TI - [The recurrent rate of nasal endoscopic microsurgical skills for the treatment of nasal inverted papilloma: a meta-analysis]. AB - OBJECTIVE: To investigate the recurrence rate of nasal inverted papilloma treating by endoscopic and non-endoscopic approach. METHOD: A search on Pubmed, Medline, Springer and Elsevier databases was done to collect the reports (2001 2013) concerning different surgery treating nasal inverted papillomas, and meta analysis was performed with RevMan 5.0 software. RESULT: Twelve papers (2001 2013) concerning the different surgery approach treating nasal inverted papillomas were retrieved. The heterogeneity test indicated that the 12 studies were consistent statistically (Q = 14.64, df = 11, P = 0.20), the data from these 12 studies could be analyzed by fixed effect model. After combination of these data, those of 1012 subjects accepted endoscopic surgical intervention and 359 subjects treating by non-endoscopic surgical intervention were collected. Test of overall effect by fixed effect model showed that the recurrence rate of inverted papilloma was significantly lower in endoscopic group than in non-endoscopic group (OR = 0.49, 95% CI was 0.35-0.69, P < 0.01). Funnel plot implied that publication bias was not obvious. CONCLUSION: The recurrence rate of inverted papilloma was significantly lower in endoscopic group than in non-endoscopic group. PMID- 26012295 TI - [Study of the relationship among expression of Survivin and MRP and the drug resistance in human nasopharyngeal carcinoma]. AB - OBJECTIVE: This study aimed to explore the relationship among expression of Survivin and MRP and drug resistance in NPC. METHOD: Expression of Survivin were detected by immunohistochemistry method in 45 cases of NPC and 24 cases of normal mucous membrane of nasopharynx (NMMN). The relationship between expression of Survivin and pathological factors in NPC were analysized. Expression of Survivin and MRP were detected in 31 patients of NPC with paclitaxel resistance and 20 patients of NPC without paclitaxel resistance. The relation- ship among the expression of Survivin or MRP and paclitaxel resistance in NPC were analysized. The paclitaxel resistance cell line, 5-8F-PTX(+); was established by a step increased method. The expression of Survivin and MRP were detected by western blot in 5-8F-PTX(+) and 5-8F. RESULT: The positive were 71. 1% (32/45) in NPC and 8.33% (2/24) in NMMN. And there were significantly differences between them (P < .05). There were relationship among expression of Survivin and differentiation degree, lymph node metastasis, distant metastasis, and clinic stages of NPC. The positive were 75.9% (31/39) in moderately differentiated NPC and 16.7% (1/6) in lowly differentiated NPC, respectively. There were significantly differences between them (P < 0.05). The positive of Survivin were 83.9% (26/31) in NPC patients with paclitaxel resistance and 45.0% (9/20) in NPC patients without Paclitaxel resistance, respectively. There were significantly differences between them (P < 0.05). The positive of MRP were 87.1% (27/31) in NPC patients with paclitaxel resistance and 40.0% (8/20) in NPC patients without paclitaxel resistance, respectively. There were significantly differences between them (P < 0.05). There were positive correlation between the expression of Survivin and MRP in NPC patients with Paclitaxel resistance. The expression of Survivin and MRP were higher in 5-8F-PTX(+) than in 5-8F. The IC50 of paclitaxel, cDDP, 5-FU and Vincristine were significantly higher in 5-8F-PTX(+) than in 5-8F. CONCLUSION: There were relationship among the expression of Survivin and difference, metastasis and TNM stages of NPC. Survivin may serves as a molecular marker for development and progress in NPC. There were relationship among the high expression of Survivin and MRP and increasing of drug resistance in NPC. PMID- 26012296 TI - [A comparison between adults and children tonsillectomy with monopolar electrocautery]. AB - OBJECTIVE: Tonsillectomy is one of the most frequently applied operations in the ENT practice. This prospective study compared intraoperative records and postoperative clinical outcomes between adults and children patients following monopolar electrocautery tonsillectomy. METHOD: Forty adult patients and Forty children patients with histories of recurrent tonsillitis or hypertrophic tonsillitis were enrolled. Intraoperative parameters and postoperative outcomes were compared. RESULT: Children tonsillectomy with monopolar electrocautery was significantly faster to perform (P < 0.05), and produced significantly less intraoperative blood loss (P < 0.05), and faster to return to commencement of a regular diet (P < 0.05) than adults. Children tonsillectomy endured less postopera- tive pain within a week (P > 0.05) than adults, but there was no significant difference in pain on the 14th postoperative day in two groups. There was no obvious postoperative hemorrhage in two groups. There was no significant difference in postoperative tonsillar fossa healing and postoperative temperature between the groups. CONCLUSION: Children and adults tonsillectomy with monopolar electrocautery had clinical characteristics respectively. Monopolar electrocautery tonsillectomy was safe and operated easily in both two groups. PMID- 26012297 TI - [Clinical study of the combination therapy with intranasal antihistamine and nasal corticosteroids in the treatment of nasal obstruction of persistent non allergic rhinitis]. AB - OBJECTIVE: To determine if greater efficacy could be achieved with the intranasal antihistamine azelastine and the intranasal corticosteroid fluticasone propionate used concurrently in the treatment of nasal obstruction of persistent non allergic rhinitis. METHOD: A total of 162 persistent non-allergic rhinitis cases with moderate to severe nasal obstruction were randomized to treatment with the following: the combination therapy or nasal corticosteroids monotherapy. Efficacy was assessed by change from baseline in nasal obstruction score at week 2 and week 6 visits. The perceptions of global treatment satisfaction(convenience, side effects, cost and effectiveness) in both groups were analyzed. RESULT: In both groups, the nasal obstruction score assessment descended significantly at week 2 and week 6 visits versus at baseline (all P < 0.01). At week 2 and week 6 visits, the nasal obstruction score in the combination therapy groups were significantly improved than that in nasal corticosteroids monotherapy groups (all P < 0.01). The perceptions of global treatment satisfaction in the combination therapy groups were significantly better (P < 0.05). CONCLUSION: Azelastine nasal spray and intranasal corticosteroid in combination may provide a substantial therapeutic benefit for patients with persistent non-allergic rhinitis, especially nasal obstruction. The combination therapy was well tolerated and safety. PMID- 26012298 TI - [Application of an image navigation system in nasal endoscopic surgery in treatment of basicranial tumor]. AB - OBJECTIVE: To investigate the therapeutic effects of the image navigation system in nasal endoscopic surgery in treatment of basicranial tumor. METHOD: Retrospective analysis was carried out in 17 patients with basicranial tumor who underwent nasal endoscopic resection via image navigation system. The accuracy of image navigation system, operation procedure time, curative effect and complications were analyzed and summarized to evaluate the effect. RESULT: The image navigation system provided an accurate anatomical localization 0.5-2.0 mm localization error (mean 1.2 mm). The operation procedure time was 1.5-3.0 h. Postoperative complications occurred in 3 of 17 patients including cerebrospinal fluid rhinorrhea and injury of sieve plate. Two patients recrudesce within half a year. CONCLUSION: The image navigation system in combination with a nasal endoscope is helpful in the resection of basicranial tumor with minimal trauma, increasing the curative effect and avoiding complications. PMID- 26012299 TI - [To investigate the diagnosis and treatment of children with subglottic area tumor]. AB - OBJECTIVE: To discuss the diagnosis and treatment method in children with mass in subglottic. METHOD: There were totally 35 patients with subglottic mass who complained with dyspnea in our department. All the patients got electronic laryngoscopy examination in order to get the preliminary judgment of the mass' property. Then they accepted ultrasound and CT scan to make the definite diagnosis. The patients with subglottic hemangioma accepted oral propranolol or intralesional Pingyangmycin injection. The other type of masses got the laryngoscope CO2 laser tumor resection. RESULT: There were 31 patients with subglottic hemangiomas, 2 patients with subglottic cysts, 1 patient with subglottic fibroma, 1 patient with subglottic granuloma. The substantial follow up time was from 1 month to 3 years. 25 patients with subglottic hemangiomas were cured, 6 patients got improvement. The patients with non-hemangiomas were all cured. CONCLUSION: There was a high incidence of hemangioma in children with subglottic mass. We suggested making a diagnosis by doing electronic laryngoscopy, ultrasound and CT scan step by step. Oral propranolol was a safe and effective method in treating subglottic hemangioma. For the patients with non hemangiomas, we considered the laryngoscope CO2 laser tumor resection as the first choice of treatment. PMID- 26012300 TI - [Clinical and diagnosis analysis of malignant lymphoma in nasal cavity and paranasal sinus]. AB - OBJECTIVE: To investigate the clinical features, imaging characteristics, pathological types, the misdiagnosis causes and the early diagnosis method of malignant lymphoma in nasal cavity and paranasal sinuses. METHOD: Clinicopathological data of 34 patients with malignant lymphoma in nasal cavity and paranasal sinuses were retrospectively analyzed. RESULT: Most of patients were middle aged man, the incidence of malignant lymphoma of nasal cavity and paranasal sinuses accounted for 21.7% of nasal malignant tumor over the same period, nasal malignant lymphoma incidence rate was higher than the sinus malignant lymphoma (76.5% VS. 17.6%). The main symptoms were presented as snuffle, epistaxis, purulent nasal discharge, fever and so on. Nasal neoplasm, nasal mucosa hyperemia, erosion, necrosis are the main signs of the disease. CT features were summarized as the lesions located in the anterior-middle area in nasal cavity, homogeneous in density, soft tissue swelling in some cases and less bone destruction. The majority pathological type of nasal malignant lymphoma was NK/T cell lymphoma, but the common pathological type of paranasal sinus malignant lymphoma was B-cell lymphoma. The misdiagnosis rate of malignant lymphoma in nasal cavity and paranasal sinus was 21.2%. CONCLUSION: Malignant lymphoma in nasal cavity and paranasal sinuses without specific clinical characteristics, but has some certain CT characteristics. Combined with the clinical, imaging and pathological features, can improve the cognition and diagnosis of the disease. PMID- 26012301 TI - [Clinical analysis of 49 cases of special airway foreign bodies in children]. AB - OBJECTIVE: To explore the clinical characteristics and treatment skills of children with respiratory special foreign body. METHOD: To retrospectively analyze the clinical characteristics of 49 cases of special airway foreign bodies in children during 2013. 5.1-2014. 5.1 in our hospital, and the treatment methods were summarized. RESULT: Fourty-seven cases with rigid bronchoscopy foreign body cured, 1 case turned Department of thoracic sur- gery chest to remove foreign body, 1 case of death. CONCLUSION: The clinical characteristics of special airway foreign bodies in children is different from ordinary foreign body, treatment of preoperative, intraoperative and postoperative is not fully equivalent to the ordinary foreign body. PMID- 26012303 TI - [Expression of AMCase mRNA in nasal mucosa of allergic rhinitis in SD rats]. AB - OBJECTIVE: To examine AMCase mRNA expression levels in nasal mucosa of allergic rhinitis SD rats. METHOD: Thirty SD rats were chosen and randomly divided into the experimental group and the control group. 20 in experimental group and 10 in the control group. AR model rats were established through repeated intraperitoneal shot of ovalbumin (OVA) for 2 weeks and consequently confirmed by local challenge with OVA for 1 week. The control group was treated by the same method with Physiological saline water instead of OVA. After the last excitation allergic rhinitis was diagnosed according to the accumulation score about nasal symptom. The septal mucosa of all rats were used to diagnose pathologically by HE dyeing. AMCase mRNA in nasal mucosa, obtained from the bilateral nasal mucosa in two groups, were used to do reverse transcriptive polymerase chain reaction. Real time polymerase chain reaction was used to examine AMCase mRNA expression levels. RESULT: (1) The results showed definitely that there were positive expression of AMCase mRNA in normal nasal mucosa. This expression increase significantly during nasal allergy (P < 0.05). (2) The increased expression of AMCase mRNA in allergic rhinitis are related with the nasal symptoms score (r = 0.411, P < 0.05). CONCLUSION: Increased expression of AMCase mRNA in nasal mucosa in allergic rhinitis model might play roles in the pathogenesis of AR, and Restrain the enzyme activity could become new treatment targets of allergic rhinitis. PMID- 26012302 TI - [Analysis the epidemiological features of 3,258 patients with allergic rhinitis in Yichang City]. AB - OBJECTIVE: To investigate the epidemiological features in patients with allergic rhinitis (AR) in Yichang city, and put forward effective prevention and control measures. METHOD: Collecting the data of allergic rhinitis in city proper from 2010 to 2013, input the data into the database and used statistical analysis. RESULT: In recent years, the AR patients in this area increased year by year. The spring and the winter were the peak season of onset. The patients was constituted by young men. There was statistically significant difference between the age, the area,and the gender (P < 0.01). The history of allergy and the diseases related to the gender composition had statistical significance difference (P < 0.05). The allergens and the positive degree in gender, age structure had statistically significant difference (P < 0.01). CONCLUSION: Need to conduct the healthy propaganda and education, optimizing the environment, change the bad habits, timely medical treatment, standard treatment. PMID- 26012305 TI - [Application of rigid bronchoscopy combined with flexible bronchoscope in multiple bronchial foreign body operation]. PMID- 26012304 TI - [Effect of budesonide on the expression of IL-12 in animal model of minimal persistent inflammation of allergic rhinitis in rats]. AB - OBJECTIVE: To investigate the influence of budesonide on animal model of minimal persistent inflammation (MPI) of allergic rhinitis in rats and to investigate the changes of interleukin-12 (IL-12) in nasal mucosa. METHOD: Sixty Sprague-Dawley (SD) rats were randomly divided into four groups: group A (allergic rhinitis group), B (experimental group), C (MPI model group) and D (bland group) respectively, with fifteen animals in each group. Rats from group A,B and C were sensitized intraperitoneally by injection of suspension of ovalbumin (OVA) and aluminum hydroxide in 0.9% physiological saline. Then, repeated local booster sensitization with different concentration of OVA suspension (1% and 0.01%) or physiological saline into the nasal cavity of those rats were performed. For group D, physiological saline was used only. From 36th day, group B were given budesonide treatment for three weeks. A, C and D group were given normal saline nasal spray. Symptoms (sneezing) of rats after antigen challenge were observed and the infiltration of eosinophils (EOS) together with the expression of intercellular adhesion molecule 1 (ICAM-1) and IL-12 in the nasal epithelial cells were also examined. RESULT: When challenged with 1% OVA, the sneezing number of rats in group B was increased markedly than that in group D (P < 0.05). However, there was no difference between group B, A and C (P > 0.05). When challenged with 0.01% OVA and given budesonide, the symptom of sneezing almost disappeared in group B just like that in group D and there was no difference between the two groups (P > 0.05). Besides, there was still more EOS infiltrated in the nasal mucosa of rats in group C than that in group D (P < 0.05). There was no expression of ICAM-1 in nasal epithelium of rats in group D, nevertheless, ICAM-1 was found mildly expressed in group C. IL-12 expression was significantly increased compared with group A and group C, and was no significantly difference compared with bland group (P > 0.05). CONCLUSION: Budesonide significantly inhibited the late reaction of animal model of minimal persistent inflammation (MPI) of allergic rhinitis in rats and increase the expression of IL-12 in MPI model. PMID- 26012306 TI - [One case report of primary sphenoid sinus tuberculosis]. AB - We report a case of primary sinonasal tuberculosis in a 23-year old man. He had a half-year history of headache and eye pain on the left side, and found the neoplasm of nasopharynx 15 days ago. Previously denied history of tuberculosis and contact history. After be admitted to hospital, twice biopsy from neoplasm of na- sopharynx were both of chronic inflammation. Coronal CT scan of the lesion when admission found the left parasellar region and the left sphenoid sinus soft tissue density increased, about 20 mm X 32 mm X 34 mm, left inferior wall between sella bone defects, and bone sclerosis, plain CT value was about 34 HU, the lesion protruded downward left the nasopharynx. Eight days after he was admissioned in hospital of sphenoid sinus biopsy showed granulomatous inflammation and tuberculosis diagnosis was considered. Review of the lesion is partial absorbed after 11 months of anti-tuberculosis treatment and now is still in follow-up. PMID- 26012307 TI - [Oncocytic papilloma in nasal cavity and paranasal sinuses: 3 of cases]. AB - Oncocytic papilloma (OP) of nasal cavity and paranasal sinuses are uncommon. We report 3 cases of oncocytic papilloma arising in the nasal cavity and paranasal sinuses, and review the relevant literatures. Unilateral sinonasal lesions are the main clinical manifestation. Pathological feature is multiple layers of epithelial cells. The cytoplasm contains abundant eosinophilic granular and microcapsules filling with mucus. The neutrophils aggregate in the microcapsules which form microabscess. The tendence of recurrence and malignant transformation are the biological character. The best treatment choice is surgical excision completely, and long-term postoperative follow-up is necessary to prevent relapse. PMID- 26012308 TI - [One case of papillary adenocarcinoma located in the back-end of nasal septum]. AB - Patients with nasopharyngeal foreign body sensation for 3 years, and had nasal obstruction in the past six months. electric nasopharyngoscopy: a irregular ellipse shape mass occupied in the nasopharynx, the mass surface is not smooth, with erosion ulcer and filthy secretions, the mass had a root in the back-end of nasal septum, and was adjacent to the bilateral round pillow. Sinus CT showed an irregular soft tissue shadow connected to the nasal septum backend in the nasopharynx, the size is about 2.8 cm X 3.5 cm, CT value is about 43 HU. Pathological examination: papillary adenocarcinoma. PMID- 26012309 TI - [Allergic inflammation in respiratory system]. AB - The pathophysiology of allergic disease such as asthma and allergic rhinitis tell the similar story: when the endogenous and exogenous inflammatory mechanisms occur disorder, the body may begin with inflammatory cell activation, namely through the release of cytokine and inflammatory mediator role in the corresponding target cells, activate the sensory nerve fiber, acting on the cell organ specificity effect, clinical symptoms. This article is divided into the following five parts focused on the research progress of allergic inflammatory diseases: (1) inflammatory cells; (2) staphylococcus aureus superantigen; (3) small molecules (cytokines, inflammatory mediators, lipid classes medium); (4) nerve fibers and effect cells; (5) genetic and epigenetic factors. PMID- 26012310 TI - [The research progress of maxillary sinusitis surgery]. AB - Maxillary sinusitis is a common condition in nose section. Traditional operations are always have more complications and easy to relapse, seriously affectting the quality of patient's life. The application of functional endoscopic sinus surgery (FESS) makes a qualitative progress on surgical treatment of maxillary sinusitis. In re- cent years, the researchs found that there are still unsatisfactories to long-term curative effect of some patients With the development of minimally invasive, people begin doubting its "functional". Recently, some new treat- merits have emerged in the world, but their safety and effectiveness needs further research. To seek for a better treatment, this article reviews the development and the existential problems of maxillary sinusitis surgery. PMID- 26012311 TI - Historical note on subjective refraction, trial lens sets, and phoropters. PMID- 26012312 TI - Half a century ago: optometric education in the United States in the 1960s. PMID- 26012313 TI - Authors of the first contact lens textbooks: Beacher, Feinbloom, and Obrig. PMID- 26012314 TI - Biographical notes on Benjamin Pike, Sr. (1777-1863) and Benjamin Pike, Jr. (1809 1864). PMID- 26012316 TI - The exposome in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC), is an immunologically mediated chronic disease. The key underlying pathology is a deregulated immune response to commensal flora in a genetically susceptible host. Advances in genomics, epigenomics and understanding of the microbiome have brought forth the role of these spheres in the pathogenesis of IBD. Yet these factors explain only a small fraction of disease risk and our ability to predict relapses and response to treatment remains dismal. The external environment plays an important role in modifying the risk of IBD and in precipitating relapses in patients with established disease. The term 'exposome' was proposed to reflect a life-course of environmental influences beginning in utero and proceeding right through childhood to adulthood. While the exposome is still a concept which needs practical perspective to enable better patient care, this review examines the gaps in our understanding that the IBD exposome helps explain. We further highlight the definition and parameters of this metric which can be incorporated for its application in research and clinical practice. PMID- 26012317 TI - Role of contrast enhanced ultrasound in hepatic imaging. AB - Grey scale ultrasound (US) is the first line imaging modality used for the evaluation of liver by the radiologists and clinicians worldwide. It is a simple, inexpensive, safe and an easily available technique. US has the ability to delineate the hepatic parenchyma and differentiate the cystic from solid hepatic lesions. However, it has limited accuracy in the detection and characterization of focal liver lesions (FLL). CEUS is a major breakthrough in ultrasound imaging which evolved with the aim of overcoming these limitations of US. With the use of ultrasound contrast agents (UCAs), CEUS has the ability to detect the intranodular hemodynamics and thereby provide information of the enhancement pattern of the lesion resulting in reliable characterization of the FLL. This capability brings it at par with the cross sectional contrast enhanced imaging techniques of computed tomography and magnetic resonance imaging. UCAs are safe, non-nephrotoxic and thus can be used to evaluate patients with renal failure as well. The technique of CEUS is simple, requires few minutes to perform, portable, lacks ionising radiation and above all is a cost-effective modality. These advantages have made CEUS an established modality for hepatic imaging. Besides detection and characterization of FLL, it also plays a vital role in the management and repeated follow up of treated patients of FLL. Newer clinical applications of CEUS with promising results are also being unravelled . This review highlights the multifaceted role of CEUS in hepatic imaging and its upcoming clinical applications. PMID- 26012318 TI - Correlation of age and hepatitis B virus DNA levels with histological activity in HBeAg negative chronic hepatitis B patients. AB - BACKGROUND: The relationship between age and serum HBV DNA levels with histological activity in chronic hepatitis B inactive carriers is still unclear. We evaluated the correlation between age and hepatitis B viral DNA levels with Metavir score in inactive chronic HBV carriers. METHODS: 50 patients (30 males and 20 females) were enrolled in the study after informed consent. Their blood samples were taken for routine investigations and specific tests for the study. Serum HBV DNA levels were quantified by real-time PCR. Metavir score was used for histologic grading. RESULTS: A1F0, A1F1, A1F2, A2F2 and A2F3 metavir scores were found in 41 (82%), 4 (8%), 1 (2%), 3 (6%), and 1 (2%) patients, respectively. There was significant correlation between age > 40 years and Metavir scores (p < 0.001). However there was no significant correlation between HBV DNA level with Metavir score (p = 0.074). CONCLUSION: Inactive carriers of 40 years of age or more should undergo liver biopsy to look for presence of significant histological findings despite having low HBV DNA level and normal SGPT level. PMID- 26012319 TI - QT interval prolongation: a risk factor for development of hepatorenal syndrome in cirrhotic patients with acute variceal bleeding. AB - BACKGROUND: This study aimed to assess whether QT interval prolongation is an independent risk factor for development of hepatorenal syndrome (HRS) in cirrhotic patients with acute variceal bleeding. METHODS: 78 consecutive cirrhotic patients with acute variceal bleeding were included in the study. All patients were evaluated before bleeding (T0), during bleeding (T1) and 6 weeks later (T2). RESULTS: HRS developed in 14 (17.9%) patients. QT corrected by heart rate (QTc) prolonged at T1, returning towards baseline at T2 (mean +/- SD; from 424.0 +/- 10.2 to 461.2 +/- 17.6 to 426.1 +/- 8.8ms, P < 0.001). At T1, patients who developed HRS had longer QTc (P = 0.017) and lower serum sodium (P = 0.039). QTc and serum sodium independently predicted HRS; the best cut-off values were QTc > 468 ms and sodium < 120 mEq/L. Patients on beta-blocker were found to have significant risk for developing HRS (p = 0.040). Based on these three factors, the risk for HRS was nil for patients without risk factors; 6.1%, 11.1%, and 83.3% for those with one, two or three risk factors, respectively (p < 0.001). CONCLUSIONS: Acute variceal bleeding causes further prolongation of QTc in cirrhosis. The combination of beta-blocker, QTc interval and serum sodium can aid in early detection of patients at increased risk of developing bleed-precipitated HRS, thus improving their outcome. PMID- 26012320 TI - Time trends in the etiology of chronic pancreatitis in South India. AB - BACKGROUND: Recent reports indicate a decline in prevalence of classical tropical chronic pancreatitis (TCP). We studied the etiologies and risk factors over a 14 year period at a tertiary care university hospital. METHODS: We compared the etiology in chronic pancreatitis (CP) patients presenting and followed-up in our Pancreas Clinic over two time periods (2000-06 and 2007-13). RESULTS: Idiopathic chronic pancreatitis (ICP) was the predominant etiology seen over the two time periods. However an increase in prevalence of alcoholic chronic pancreatitis (ACP) during the latter time period suggests that it may be emerging as a dominant etiology over recent years. Hypertriglyceridemia and hyperparathyroidism were uncommon causes of non-alcoholic CP. Autoimmune pancreatitis was noted only during 2007-13, but remains a rare cause of CP. There are multiple risk factors for CP in our population. CONCLUSIONS: The high prevalence of ICP indicates need closer examination of risk factors and ICP pathogenesis. ACP appears to be emerging as a dominant cause of CP which suggests a need to reorient preventive strategies. PMID- 26012322 TI - Combination of non-endoscopic parameters as predictors of large esophageal varices. AB - BACKGROUND AND AIM: Bleeding from gastroesophageal varices is a life-threatening complication of cirrhosis. Prophylactic therapy for large varices considerably reduces such bleeding. Current guidelines recommend upper GI endoscopy as the gold standard for detecting high-grade varices. However, in peripheral centers, this is often unfeasible or inaccessible thus requiring non-endoscopic predictors of large oesophageal varices. METHODS: This prospective study involved 100 newly diagnosed cirrhosis patients without any history of variceal bleeding. Demographic, clinical, bio-chemical and ultrasonographic parameters were recorded. Esophageal varices were classified endoscopically as small and large. Multivariate logistic regression was performed to identify predictors of variceal size and presence. Cut-offs of significant indicators were determined by ROC analysis. RESULTS: 69% patients had small and 31% had large varices. Univariate analysis revealed significant differences between the grade of spleen, blood parameters, platelet count, international normalized ratio, serum albumin, spleen size, portal vein diameter (PVD) and platelet count to spleen diameter ratio in the two groups. Multivariate analysis revealed that INR [OR: 2.432(95% CI: 1.192 4.958)], splenomegaly at USG [OR: 2.138 (95% CI: 0.662 - 6.911)] and PVD [OR: 1.318 (95% CI: 0.937 - 1.853)] were the most significant predictors for large varices. CONCLUSIONS: Multivariate prediction of large varices based on a combination of non-endoscopic parameters can be utilized in place of single parameter based predictions. PMID- 26012321 TI - Gastroesophageal reflux disease in pregnancy: a longitudinal study. AB - BACKGROUND: Gastroesophageal reflux (GER) symptoms are common in pregnancy. It often manifests for the first time in pregnancy during the first three months and ceases after delivery. AIM: To study the prevalence of gastroesophageal reflux in each of the three trimesters by follow-up of pregnant women. To examine the association between dietary factors and GER in pregnancy. METHODS: This was a prospective hospital-based study. Sixty four pregnant women in their first trimester attending an antenatal clinic were interviewed for symptoms of GER and for dietary details and followed up until term and delivery. RESULTS: Fifty women (83.4%) experienced either heartburn or regurgitation during pregnancy. GER was commoner in primi-gravida (69.3%) and 50% remained symptomatic until term. Regurgitation was more common than heartburn and was often associated with nausea/vomiting. Women with an antenatal history of GERD had 3.79 times the odds of developing symptoms in the third trimester. There was no difference in weight gain in those with and without GER. Spicy food significantly increased the risk of heartburn and green vegetables were protective. CONCLUSIONS: The incidence of GERD decreased over three trimesters. Weight gain did not increase the prevalence of GERD. Spicy food aggravated while green vegetables protected against GERD. PMID- 26012323 TI - Macronodular tuberculosis of the liver: a tumour masquerade. PMID- 26012324 TI - Lymphoepithelioma-like carcinoma: an unusual gall bladder tumour. PMID- 26012326 TI - Retrieval of an impacted foreign body in the oesophagus by combined endoscopic surgical approach. PMID- 26012325 TI - Ultrasound-guided glue injection of ileocolic artery aneurysm. PMID- 26012327 TI - Esophageal ulcers: an uncommon manifestation of Behcet's disease. PMID- 26012328 TI - Accessory hepatic lobe: a rare cause of extra-hepatic portal vein obstruction. PMID- 26012329 TI - Bleeding lingual varix in a patient with cirrhosis. PMID- 26012330 TI - Diagnosis of an early stage IPSID using Syndecan 1. PMID- 26012331 TI - A rare case of multiple inflammatory fibroid polyps in a young woman with family history of inflammatory fibroid polyps. PMID- 26012332 TI - Squamous cell carcinoma of the stomach. PMID- 26012333 TI - Recurrent acute pancreatitis secondary to pancreatic neuroendocrine tumor: role of endoscopic ultrasound. PMID- 26012334 TI - The historiography of psychoanalysis in Brazil: the case of Rio de Janeiro. AB - The objective of this article is to analyze the background of the historiography of psychoanalysis in Rio de Janeiro. Three different phases and approaches are analyzed, based on the viewpoints of different groups of authors. The first group features authors who displayed an early interest in the subject, in the 1920's 1930's. The second refers to psychiatrists/psychoanalysts who worked with mental health institutes and societies between the 1940's and 1970's, while the third perspective comes from the academic/university environment, from the end of the 70's to the present. This distinction was made not only to better define the timeframe of the arrival and dissemination of psychoanalysis in Rio de Janeiro, but also to provide a better understanding of the relation between the specific professional and intellectual interests of each group and the respective historical context. PMID- 26012335 TI - [The assimilation of the books on animals of Aristotle in the medicine of Arnau de Vilanova (c. 1240-1311)]. AB - The Latin translation of Aristotle's books on animals, which was carried out during the middle ages, lead to the dissemination of new theories in the field of biology and zoology in the western culture. From the second half of the 13th century, this group of books contributed to the development of a new medical practice based on the recovery of classical authorities and natural philosophy. On different occasions, Arnau de Vilanova (c. 1240-1311)--one of the most preeminent physicians of the Latin middle ages--used the books on animals to describe biological and physiological processes, and also to formulate a new medical discipline within the framework of discussions between natural philosophy and medicine in Montpellier; this took place at the end of the 13th century and early 14h century. PMID- 26012336 TI - [Suicide and cultural criticism in 19th century Spanish medicine]. AB - This paper explores the major role of suicide in the cultural criticism deployed by 19th century Spanish doctors by analysing the most important theoretical models that inspired their contributions to its aetiology. In the first half of the century, the most commonly debated causal factor was the passions, which were thought to stand in a permanent tension with a free, reflexive and conscious self, in accordance with the spiritualist doctrine that was then dominant. In the context of a growing somatisation of moral and intellectual phenomena, the notion of suicide as an act of free will was later modified, and it became considered the consequence of certain organic disturbances. However, this process did not alter the central role of suicidal behaviour within 19th-century cultural criticism, because the advent of degeneration theory meant that doctors finally had a doctrine that allowed them to combine biological determinism with the extended perception of a moral and social crisis threatening the stability and achievements of bourgeois society. PMID- 26012337 TI - [The marvels of the incarnated man. Victor Melcior and the redefinition of mediumship (1901)]. AB - Towards the end of the 19th century, new medico-psychological approaches were applied to mediumship through the scientific study of spiritualist phenomena. The spiritualist idea of the medium was replaced with the notion of the medium as an unstable human being capable of emanating psychic forces unconsciously. This paper analyses the redefinition of mediumship through the polemical articles of the Catalan physician Victor Melcior. On one hand, this microhistory allows the local debate to be placed within the scientific international context, describing the relationships among spiritualism, medicine and psychopathology at that time. On the other hand, it permits analysis of the reactions of some spiritualists to Melcior's theories and of the consequences of this debate for spiritualism in general. PMID- 26012338 TI - ?Que pasa en La Inclusa? The role of press scandals, doctors and public authorities in the evolution of La Inclusa de Madrid, 1890-1935. AB - Traditionally, infants abandoned at foundling hospitals were identified as "bastards" and "children of vice" whose health, to all intents and purposes, reflected the moral sins of their parents and thus, led to unavoidable mortality. By late 19th century, several changes challenged that consideration: a growing emphasis on the importance of fighting infant mortality, the appearance of a new, medicalized, ideal of motherhood, the spread of new medical theories, the appearance of disciplines like Child Health, the construction of pediatric wards, and maternity hospitals. The consequences of these changes had their greatest impact at La Inclusa due to its location in the capital city, close to the decision-making centres and as focus of the interest of the national media. This article examines the role of the press and the medical profession in successively denouncing La Inclusa's excess mortality during the period 1890-1935. By looking at daily press and medical publications, it sheds light on the uneven consequences of the press scandals denouncing foundlings' extreme mortality in the period. The first scandal (1899-1900) faded without acknowledging any excess foundling mortality; the second (1918) was initiated by the doctors in charge but only produced some changes. The third scandal (1927) was instrumental in bringing about the changes that would turn a century-old institution in a state-of-the art medicalized centre and the change from debris of society to healthy children of foundlings. The effects of the press coverage were not restricted locally to foundlings in Madrid, and had a wider impact: by making the public aware of the dire situation of foundlings, they contributed to the development of legislation related to the fight against infant mortality and the control of mercenary breastfeeding. PMID- 26012339 TI - The role of the media in influencing public attitudes to penicillin during World War II. AB - Penicillin's trajectory towards becoming an effective antibacterial chemotherapeutic agent took place during World War II. Its strategic military value was immediately recognised by the Allies, and mass production was undertaken with the prime objective of meeting the needs of the armed forces. News of its development came to be widely reported on in the media and is examined here. These reports frequently combined accounts of penicillin's prodigious clinical effectiveness with the fact that it was to remain unavailable to the civilian population essentially until the war had ended. More penicillin was to be made available to the civilian population in the United States than in Britain, but the sense that it was severely rationed remained as high. It was in response to this that the idea of "homemade penicillin" was hatched. News of this was also widely promulgated by both the British and American media. Although the numbers treated with penicillin produced in this way was never to be significant, knowledge of the existence of such endeavours may have served to assuage in some measure the feelings of frustration felt by the civilian population at penicillin's non-availability. PMID- 26012340 TI - [Embryology and "official science": the contribution of the anatomical school of Jose Escolar to embryology during the first Francoism (1939-1959)]. AB - In this paper, we analyse the contribution of the anatomical school of Jose Escolar (1913-1998) to embryology during the first two decades of the Francoist dictatorship. Special attention is paid to the process by which the Spanish group, with the support of the new Superior National Research Council, made contact with the German morphology being developed by Hugo Spatz (1888-1979) at the Max Planck-Institut fur Hirnforschung. Our study reveals the numerous influences that finally led to the anatomy and embryology of Escolar. In Spain, we found a direct influence of the Gegenbaurian morphology of Gumersindo Sanchez Guisande (1894-1976) and the neuroanatomy of Juan Jose Barcia Goyanes (1901 2003), full of references to studies by Braus. International contacts of the "Escolarian group", first with North America and then with Germany, created a homogeneous group with a single anatomy (functional and ontophylogenetic) but with so many research interests that subspecialisations had to be developed. An important embryological work resulted from an intense relationship with the German anatomical community during the 1950s. Escolar worked in this field on the development of the amygdala and allocortex, Fernando Reinoso studied the embryology of the diencephalon and Smith Victor Agreda, along with the German scientist Rudolf Diepen, made some important discoveries on the development of the hypothalamic-pituitary system. PMID- 26012341 TI - ["Influence of epidermal friction and wear on papillary patterns": unpublished fingerprinting experiments by Federico Oloriz Aguilera (1855-1912)]. AB - Federico Oloriz introduced in Spain a method of identification based on fingerprints that is now used in various other countries. Among the numerous studies he performed for this purpose is a hitherto unpublished experiment reported in this paper. The objective was to test whether fleshy parts of fingers that undergo manipulation can maintain their dermal folds in a manner that permits their correct identification. Oloriz found that dermal folds produced by a simple ligation did not pose serious identification problems, while alterations resulting from sharp elements generated greater but in some way surmountable difficulties. A brief biography of Oloriz is first provided, with a summary of his studies on Anthropology and, in greater detail, his dedication to Forensic Anthropology, which led to the development of the so-called "Oloriz Method" of identification by means of fingerprints. PMID- 26012342 TI - John Victor Pickstone, or "JVP". PMID- 26012343 TI - John Pickstone: a personal tribute. PMID- 26012344 TI - The youngest of the senior scholars: a tribute to John V. Pickstone. PMID- 26012345 TI - Appropriate dose of dexmedetomidine for the prevention of emergence agitation after desflurane anesthesia for tonsillectomy or adenoidectomy in children: up and down sequential allocation. AB - BACKGROUND: Dexmedetomidine can be used for the prevention of emergence agitation (EA) in children. However, an inadequate dose of dexmedetomidine can induce prolonged sedation and cardiovascular complications. The aim of this study was to evaluate the effective dose of dexmedetomidine for the prevention of EA after desflurane anesthesia for patients undergoing a tonsillectomy or adenoidectomy. METHODS: We enrolled 21 unpremedicated children, between 2 and 12 years, undergoing either a tonsillectomy or an adenoidectomy. General anesthesia was induced using sevoflurane and oxygen, and dexmedetomidine was administered before surgery. Anesthesia was maintained using desflurane resulting in a BIS range of 40-60. In the postanesthetic care unit (PACU), EA (agitation measured at level 4 or more at least once) was assessed on arrival in the PACU,15 min later, and 30 min later. The dose of dexmedetomidine for consecutive patients was determined by the response of the previous patient, using an increment or decrement of 0.1 MUg/kg. RESULTS: The 50% effective dose of dexmedetomidine for prevention of EA was 0.25 MUg/kg (95% confidence limits, 0.17-0.33 MUg/kg), and the 95% effective dose was 0.38 MUg/kg (95% confidence limits, 0.29-0.39 MUg/kg). CONCLUSIONS: For prevention of EA after desflurane anesthesia for 50% and 95% of children undergoing tonsillectomies or adenoidectomies, 0.25 MUg/kg or 0.38 MUg/kg of dexmedetomidine is suggested. Further study is needed to validate the suggested dose of dexmedetomidine to prevent the EA that was identified in the present study. TRIAL REGISTRATION: Clinical Research Information Service KCT0000126 . PMID- 26012347 TI - Carbon dioxide activation and reaction induced by electron transfer at an oxide metal interface. AB - A model system has been created to shuttle electrons through a metal-insulator metal (MIM) structure to induce the formation of a CO2 anion radical from adsorbed gas-phase carbon dioxide that subsequently reacts to form an oxalate species. The process is completely reversible, and thus allows the elementary steps involved to be studied at the atomic level. The oxalate species at the MIM interface have been identified locally by scanning tunneling microscopy, chemically by IR spectroscopy, and their formation verified by density functional calculations. PMID- 26012346 TI - Effect of genetic ancestry on leukocyte global DNA methylation in cancer patients. AB - BACKGROUND: The study of genetic variants alone is not enough to explain a complex disease like cancer. Alterations in DNA methylation patterns have been associated with different types of tumor. In order to detect markers of susceptibility for the development of cutaneous melanoma and breast cancer in the Uruguayan population, we integrated genetic and epigenetic information of patients and controls. METHODS: We performed two case-control studies that included 49 individuals with sporadic cutaneous melanoma and 73 unaffected controls, and 179 women with sporadic breast cancer and 209 women controls. We determined the level of global leukocyte DNA methylation using relative quantification of 5mdC by HPLC, and we compared methylation levels between cases and controls with nonparametric statistical tests. Since the Uruguayan population is admixed and both melanoma and breast cancer have very high incidences in Uruguay compared to other populations, we examined whether individual ancestry influences global leucocyte DNA methylation status. We carried out a correlation analysis between the percentage of African, European and Native American individual ancestries, determined using 59 ancestry informative markers, and global DNA methylation in all participants. RESULTS: We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001). Additionally, we found a negative correlation between African ancestry and global DNA methylation in cancer patients (p <0.005). CONCLUSIONS: These results support the potential use of global DNA methylation as a biomarker for cancer risk. In addition, our findings suggest that the ancestral genome structure generated by the admixture process influences DNA methylation patterns, and underscore the importance of considering genetic ancestry as a modifying factor in epigenetic association studies in admixed populations such as Latino ones. PMID- 26012348 TI - Alternative preparation of propolis extracts: comparison of their composition and biological activities. AB - BACKGROUND: Propolis is the bee product noted for multiple biological effects, and therefore it is widely used for the prevention and treatment of a variety of diseases. The active substances of propolis are easily soluble in ethanol. However ethanolic extracts cannot be used in treatment of certain diseases encountered in ophthalmology, pediatrics, etc. Unfortunately, the main biologically active substances of propolis are scarcely soluble in water, oil and other solvents usually used in pharmaceutical industry. The aim of this study was to investigate chemical composition, radical scavenging and antimicrobial activity of propolis extracts differently made in nonethanolic solvents. METHODS: Total content of phenolic compounds in extracts was determined using Folin Ciocalteu method. Chemical composition and radical scavenging activity of extracts were determined using HPLC system with free radical reaction detector. Antimicrobial activity of examined preparations was evaluated using the agar-well diffusion assay. RESULTS: Total amount of phenolic compounds in extracts made in polyethylene glycol 400 (PEG) and water mixture or in PEG, olive oil and water mixture at 70 degrees C was comparable to that of ethanolic extract. Predominantly identified compounds were phenolic acids, which contribute ca. 40 % of total radical scavenging activity. Investigated nonethanolic extracts inhibited the growth and reproduction of all tested microrganisms. Antimicrobial activity of some extracts was equal or exceeded the antimicrobial effect of ethanolic extract. Extracts made in pure water or oil only at room temperature, contained more than 5 - 10-fold lower amount of phenolic compounds, and demonstrated no antimicrobial activity. CONCLUSIONS: Nonethanolic solvent complex and the effect of higher temperature allows more effective extraction of active compounds from propolis. Concentration of total phenolic compounds in these extracts does not differ significantly from the concentration found in ethanolic extract. Propolis nonethanolic extracts have radical scavenging and antimicrobial activity. PMID- 26012349 TI - Authors' reply to responses. PMID- 26012351 TI - The role of the NLRP3 inflammasome in pulmonary diseases. AB - Respiratory diseases and lung injuries are one of the leading causes of death in the world. One critical component of these diseases is exaggerated inflammatory response. The recently discovered inflammasome is believed to play a key role in inflammation. The inflammasome is an oligomer of intracellular proteins that, once activated by an insult or damage signal, produces mature cytokines from the interleukin-1 family that mediate an inflammatory response. Previous research has provided evidence that suggests the role of the inflammasome in the pathogenesis of many chronic respiratory diseases and acute lung injuries, such as transfusion related acute lung injury, ventilator-induced lung injury, asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. This article summarizes recent research on the inflammasome and reviews proposed molecular models of the role of the inflammasome in several prominent lung diseases and injuries. PMID- 26012350 TI - Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis. AB - BACKGROUND: Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD). METHODS: Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review. RESULTS: All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250-350 mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250-350 mg daily). CONCLUSIONS: All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects. PMID- 26012353 TI - Model selection for marginal regression analysis of longitudinal data with missing observations and covariate measurement error. AB - Missing observations and covariate measurement error commonly arise in longitudinal data. However, existing methods for model selection in marginal regression analysis of longitudinal data fail to address the potential bias resulting from these issues. To tackle this problem, we propose a new model selection criterion, the Generalized Longitudinal Information Criterion, which is based on an approximately unbiased estimator for the expected quadratic error of a considered marginal model accounting for both data missingness and covariate measurement error. The simulation results reveal that the proposed method performs quite well in the presence of missing data and covariate measurement error. On the contrary, the naive procedures without taking care of such complexity in data may perform quite poorly. The proposed method is applied to data from the Taiwan Longitudinal Study on Aging to assess the relationship of depression with health and social status in the elderly, accommodating measurement error in the covariate as well as missing observations. PMID- 26012352 TI - The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation. AB - Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The blockade of transcription factors has been a central part of T cell-depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein-1 (AP-1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP-1 inhibition are available. In this study, we investigated the immunosuppressive effects of T-5224, a c-Fos/AP-1-selective inhibitor, on murine T cells activated by alphaCD3+alphaCD28 mAbs. T-5224 inhibited proliferation, CD25 up-regulation, and the production of IL-2 and interferon-gamma. In addition, T-5224 blocked the nuclear translocation of c Fos/AP-1 in activated murine T cells. In BALB/c (H-2(d) )-to-C57BL/6J (H-2(b) ) mouse PIT, the 2-week administration of T-5224 prolonged survival of 600 islet allografts in a dose-dependent manner. When combined with a 2-week low-dose tacrolimus, the T-5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c-Fos/AP-1 inhibition by T-5224 is a potentially attractive strategy for allogeneic PIT. PMID- 26012355 TI - Differences in parental bonding between schizophrenia and bipolar disorder: Evidence of prodromal symptoms? AB - BACKGROUND: The Parental Bonding Instrument (PBI) examines parent-child bonds and attachment during the first 16 years. Our study aims to compare PBI scores between patients with schizophrenia and bipolar disorder (BD). METHODS: We analyzed PBI scores in 59 patients with schizophrenia, 36 with BD and 52 healthy controls using ANCOVA, with age, gender and years of education as covariates. Bonferroni correction was used to adjust for multiple comparisons. PBI has maternal and paternal scores, each one with two domains: care and overprotection. RESULTS: In PBI maternal and paternal care domains, patients with schizophrenia showed significantly higher scores when compared with BD patients (p<0.001). However, when compared with healthy controls, patients with schizophrenia only showed significantly higher scores of PBI maternal care domain (p=0.037). BD patients showed significantly lower PBI care scores compared with healthy controls (maternal score: p=0.016; paternal score: p<0.001). In PBI maternal and paternal overprotection domain, BD patients showed significantly higher scores compared with patients with schizophrenia (p=0.004; p=0.021) and healthy controls (p=0.014; p=0.008); while no significant difference was observed between patients with schizophrenia and healthy controls. "P values" are according to Bonferroni correction. CONCLUSION: There are significant differences in the perception of attachment between schizophrenia and BD. This finding may shed some light to better understand the prodromal symptoms of each disorder. PMID- 26012354 TI - Evaluation of emulsion electrospun polycaprolactone/hyaluronan/epidermal growth factor nanofibrous scaffolds for wound healing. AB - Wound healing scaffolds provide cells with structural integrity and can also deliver biological agents to establish a skin tissue-specific microenvironment to regulate cell functions and to accelerate the healing process. In this study, we fabricated biodegradable nanofibrous scaffolds with an emulsion electrospinning technique. The scaffolds were composed of polycaprolactone, hyaluronan and encapsulating epidermal growth factor. The morphology and core-sheath structure of the nanofibers were characterized by scanning electron microscopy and transmission electron microscopy. The scaffolds were also characterized for chemical composition and hydrophilicity with a Fourier-transform infrared analysis, energy dispersive spectroscopy and the water contact angle. An in vitro model protein bovine serum albumin and epidermal growth factor release study was conducted to evaluate the sustained release potential of the core-sheath structured nanofibers with and without the hyaluronan component. Additionally, an in vitro cultivation of human skin keratinocytes (HaCaT) and fibroblasts on polycaprolactone/hyaluronan and polycaprolactone/hyaluronan-epidermal growth factor scaffolds showed a significant synergistic effect of hyaluronan and epidermal growth factor on cell proliferation and infiltration. Furthermore, there was an up-regulation of the wound-healing-related genes collagen I, collagen III and TGF-beta in polycaprolactone/hyaluronan/epidermal growth factor scaffolds compared with control groups. In the full-thickness wound model, the enhanced regeneration of fully functional skin was facilitated by epidermal regeneration in the polycaprolactone/hyaluronan/epidermal growth factor treatment group. Our findings suggest that bioactivity and hemostasis of the hyaluronan based nanofibrous scaffolds have the capability to encapsulate and control the release of growth factors that can serve as skin tissue engineering scaffolds for wound healing. PMID- 26012356 TI - Precordial skin burns after endoscopic submucosal dissection for gastric tube cancer. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is useful as a minimally invasive treatment option for early gastric cancer. ESD is also used in the management of postoperative remnant gastric cancers in the stomach and gastric tube cancers. Perforation and delayed bleeding have been the main complications of ESD reported in the management of gastric tube cancer. However, in the current literature, there is no description of precordial skin burns caused by electrical coagulation. METHODS: While we treated 22 patients with gastric tube cancers by ESD from 2005 to 2014, we experienced five skin burns in four patients after ESD. We retrospectively analyzed clinical characteristics of precordial skin burn as a complication of ESD. RESULTS: All skin burns occurred in patients reconstructed using a presternal route, whose incidence of precordial skin burn was 55.6%. In all cases, lesions were located in the upper or middle third of gastric tubes irrespective of their direction. Skin burn developed on postoperative day (POD) 1 or POD 2, taking 4-7 days to heal and was accompanied by high fever in 60% of cases. CONCLUSION: The present study suggests that when carrying out ESD for gastric tube cancer using the presternal route, it is necessary to consider the occurrence of a precordial skin burn as a possible complication. PMID- 26012357 TI - Phylogenetic eigenvectors and nonstationarity in the evolution of theropod dinosaur skulls. AB - Despite the long-standing interest in nonstationarity of both phenotypic evolution and diversification rates, only recently have methods been developed to study this property. Here, we propose a methodological expansion of the phylogenetic signal-representation (PSR) curve based on phylogenetic eigenvectors to test for nonstationarity. The PSR curve is built by plotting the coefficients of determination R(2) from phylogenetic eigenvector regression (PVR) models increasing the number of phylogenetic eigenvectors against the accumulated eigenvalues. The PSR curve is linear under a stationary model of trait evolution (i.e. the Brownian motion model). Here we describe the distribution of shifts in the models R(2) and used a randomization procedure to compare observed and simulated shifts along the PSR curve, which allowed detecting nonstationarity in trait evolution. As an applied example, we show that the main evolutionary pattern of variation in the theropod dinosaur skull was nonstationary, with a significant shift in evolutionary rates in derived oviraptorosaurs, an aberrant group of mostly toothless, crested, birdlike theropods. This result is also supported by a recently proposed Bayesian-based method (AUTEUR). A significant deviation between Ceratosaurus and Limusaurus terminal branches was also detected. We purport that our new approach is a valuable tool for evolutionary biologists, owing to its simplicity, flexibility and comprehensiveness. PMID- 26012358 TI - Dose escalation with over-dose and under-dose controls in Phase I/II clinical trials. AB - To save valuable time and resources in new drug development, Phase I/II clinical trials with toxicity control and drug efficacy as dual primary endpoints have become increasingly popular. Escalation with over-dose control (the EWOC) is a Bayesian adaptive Phase I clinical trial design that can accurately estimate the maximum tolerated dose (MTD) level and control the probability of overdosing patients during the dose allocation phase. In this paper, we extend EWOC to Phase I/II clinical trials by controlling for under-dosing with a Gumbel Copula model to provide patients with at least minimum drug efficacy. We propose a utility function to measure the composite effect of toxicity and efficacy and select the optimal dose. To deal with the common issue that the efficacy endpoint often cannot be quickly ascertained, we employ Bayesian data augmentation to handle delayed efficacy and allow for flexible patient accrual without a waiting period. Extensive simulations demonstrate that the proposed new design not only provides better therapeutic effect by reducing the probability of treating patients at under-dose levels while protecting patients from being overdosed, but also improves trial efficiency and increases the accuracy of dose recommendation for subsequent clinical trials. We apply the proposed design to a Phase I/II solid tumor trial. PMID- 26012359 TI - Antimicrobial effect of 4-hydroxybenzoic acid ester with glycerol. AB - WHAT IS KNOWN AND OBJECTIVES: Parabens have been commonly used as preservatives in pharmaceutical and cosmetics industries for almost 50 years. These compounds are thermostable, pH-stable and inexpensive and have a wide antimicrobial effect. The antimicrobial activity of parabens in emulsion system is limited by their poor solubility in water phase, which is increasing with the length of their alkyl chain. The aim of this work was preparation of 1-O-(4-hydroxybenzoyl) glycerol, more hydrophilic and naturally occurring analogue of parabens, and comparison of its antimicrobial activity with commercially used parabens (4 hydroxybenzoic acid, methylparaben, ethylparaben, propylparaben). METHODS: 1-O-(4 Hydroxybenzoyl)-glycerol was obtained by the transesterification reaction of methyl paraben with glycerol. Purity was confirmed by determination of melting point and by GC/MSD. Antimicrobial activity of 1-O-(4-hydroxybenzoyl)-glycerol and commercially used parabens was determined by spectrophotometrical monitoring of microbial growth in media containing the testing substances, using spectrophotometers PowerWave XS and Cary 50 Conc. RESULTS AND DISCUSSION: 1-O-(4 Hydroxybenzoyl)-glycerol was prepared with purity >99%. This compound showed antimicrobial activity against all tested microorganisms (Staphylococcus aureus, Escherichia coli, Saccharomyces cerevisiae and Fusarium culmorum). In comparison with other tested substances, 1-O-(4-hydroxybenzoyl)-glycerol showed less inhibitory activity at the highest concentration of 20 mmol/L, with the maximum inhibitory activity ca. 70%. On the other hand, antimicrobial activity of 1-O-(4 hydroxybenzoyl)-glycerol at the lower concentrations (2.5 mmol/L, 1.25 mmol/L) was the same or, in some cases, even higher (S. aureus) in comparison with commercially used parabens. WHAT IS NEW AND CONCLUSION: A novel hydrophilic analogue of parabens was synthetized and tested for its antimicrobial activity against selected microorganisms in model system. This study confirms antimicrobial potential of 1-O-(4-hydroxybenzoyl)-glycerol, which is comparable with other commercially used parabens. Unlike commercial parabens, it is possible to expect more significant antimicrobial activity of 1-O-(4-hydroxybenzoyl) glycerol in real emulsion systems due to the increased solubility of this substance in water phase and also the lower skin irritation. PMID- 26012360 TI - Aging, Practice Effects, and Genetic Risk in the Wisconsin Registry for Alzheimer's Prevention. AB - BACKGROUND: In the last five years, a consensus has developed that Alzheimer's disease (AD) may begin years before overt cognitive impairment. Accordingly, the focus has shifted to identifying preclinical disease in order to match treatments to those most likely to benefit. Subtle cognitive changes, including reduced benefit from practice, may be one such preclinical sign. In this study, we explore cognitive aging trajectories within a large cohort of clinically intact late middle-aged adults. METHOD: Longitudinal cognitive data were analyzed from 594 participants in the Wisconsin Registry for Alzheimer's Prevention. Mixed models were used to examine trajectories, adjusting for prior exposure, and the moderation thereof by markers of dementia risk, APOE-epsilon4 status, and family history of AD. RESULTS: Practice effects were observed for Verbal Learning & Memory, Working Memory, Speed & Flexibility, and Visual Learning. However, for Working Memory and Speed & Flexibility, these effects were attenuated for FH + subjects. CONCLUSION: Reduced practice effects have previously been observed in clinical groups. These results in middle-aged adults suggest that they may also indicate preclinical changes on the path to AD. PMID- 26012361 TI - Combined assessment of WT1 and BAALC gene expression at diagnosis may improve leukemia-free survival prediction in patients with myelodysplastic syndromes. AB - Several genes with relevant pathogenetic and prognostic value have been identified in patients with myelodysplastic syndromes. Overexpression of WT1 at diagnosis has been associated with increased progression to acute myeloid leukemia and reduced leukemia free survival. Conversely, few data are available on the prognostic value of BAALC gene overexpression in AML and MDS patients. We evaluated the prognostic value of the combined expression of WT1 and BAALC genes at diagnosis in 86 MDS patients who had been stratified according to IPSS and R IPSS scoring systems. Our results suggest that in the whole group of patients, low levels of both WT1 and BAALC were associated with a favorable outcome (3-year LFS 74.5%, median not reached), whereas patients presenting high expression levels of both genes had the worst prognosis (3-year LFS 0%, median 12 months, p<0.001). More specifically, molecular profiling was especially useful for intermediate 1 and intermediate-2/high risk groups. This study suggests that evaluating WT1 and BAALC gene expression at diagnosis may improve standard risk stratification and possibly refine the therapeutic approach for MDS patients. PMID- 26012362 TI - Association of lymphoid malignancies and Philadelphia-chromosome negative myeloproliferative neoplasms: Clinical characteristics, therapy and outcome. AB - The co-occurrence of myeloproliferative and lymphoproliferative neoplasms (MPN/LPN) has been reported, mostly in case reports. The aim of this study was to assess the characteristics and clinical course of the coexistent diseases. Among 9866 patients who presented to our institution from 1960 to 2014, 34 (0.3%) were diagnosed with MPN/LPN. LPN was diagnosed first in 16 patients, second in 15, and at the same time in 3. The time to secondary malignancy was longer when LPN was diagnosed first (119 vs 98 months). Myelofibrosis (41%), polycythemia vera (24%), and essential thrombocythemia (18%) were the most common MPNs, and non-Hodgkin lymphoma (50%) and chronic lymphocytic leukemia (32%) were the most common LPNs. Seventy-three percent of patients treated for MPN and 72% of those treated for LPN achieved a complete response. After a median follow-up from MPN diagnosis of 84 months, 16 patients are alive and 18 died (4 related to MPN and 2 LPN). Coexistent MPN/LPN is a rare event that does not appear to predict worse outcomes. Treatment choice is generally oriented towards controlling the prevalent disease; the other malignancy may influence treatment strategies in selected cases. PMID- 26012363 TI - Association of HLA-B*27 with ankylosing spondylitis in Kurdish patients. AB - OBJECTIVE: To investigate the prevalence of human leukocyte antigen (HLA)-B*27 among a healthy Kurdish population and in patients with ankylosing spondylitis. METHODS: The prevalence of HLA-B*27 was investigated in 209 healthy donors recruited from the Kurdistan Region of Iraq, and in 41 diagnosed ankylosing spondylitis patients. The HLA statuses for the patients and healthy donors were determined by using the low-resolution Olerup SSP(r) HLA typing kits. RESULTS: We observed that the prevalence of HLA-B*27 in healthy Kurdish donors was 3.8% (8/209). While the prevalence of HLA-B*27 in patients with ankylosing spondylitis was 65.9% (27/41 studied) with a P-value of < 0.01. The relative risk of having the disease is 12 times higher in individuals with HLA-B*27 compared to those who do not have it. The male-to-female ratio was 5.8 : 1 in HLA-B*27 positive patients. The disease onset is earlier in HLA-B*27-positive patients. CONCLUSION: From this study, we can conclude that the prevalence of HLA-B*27 among the Kurdish healthy population is 3.8% and there is a strong association between HLA B*27 and ankylosing spondylitis patients in the Kurdistan Region of Iraq. PMID- 26012364 TI - How Does a Patient's Primary Renal Disease Impact Chronic Dialysis Management?: Patients with Autosomal Dominant Polycystic Kidney Disease. PMID- 26012365 TI - The Role of Wnt/beta-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target? AB - Temporal lobe epilepsy is one of the most common clinical neurological disorders. One of the major pathological findings in temporal lobe epilepsy is hippocampal sclerosis, characterized by massive neuronal loss and severe gliosis. The epileptogenesis process of temporal lobe epilepsy usually starts with initial precipitating insults, followed by neurodegeneration, abnormal hippocampus circuitry reorganization, and the formation of hypersynchronicity. Experimental and clinical evidence strongly suggests that dysfunctional neurogenesis is involved in the epileptogenesis. Recent data demonstrate that neurogenesis is induced by acute seizures or precipitating insults, whereas the capacity of neuronal recruitment and proliferation substantially decreases in the chronic phase of epilepsy. Participation of the Wnt/beta-catenin signaling pathway in neurogenesis reveals its importance in epileptogenesis; its dysfunction contributes to the structural and functional abnormality of temporal lobe epilepsy, while rescuing this pathway exerts neuroprotective effects. Here, we summarize data supporting the involvement of Wnt/beta-catenin signaling in the epileptogenesis of temporal lobe epilepsy. We also propose that the Wnt/beta catenin signaling pathway may serve as a promising therapeutic target for temporal lobe epilepsy treatment. PMID- 26012366 TI - Unsaturated Analogues of the Neurotransmitter GABA: trans-4-Aminocrotonic, cis-4 Aminocrotonic and 4-Aminotetrolic Acids. AB - Analogues of the neurotransmitter GABA containing unsaturated bonds are restricted in the conformations they can attain. This review traces three such analogues from their synthesis to their use as neurochemicals. trans-4 Aminocrotonic acid was the first conformationally restricted analogue to be extensively studied. It acts like GABA across a range of macromolecules from receptors to transporters. It acts similarly to GABA on ionotropic receptors. cis 4-Aminocrotonic acid selectively activates bicuculline-insensitive GABAC receptors. 4-Aminotetrolic acid, containing a triple bond, activates bicuculline sensitive GABAA receptors. These findings indicate that GABA activates GABAA receptors in extended conformations and GABAC receptors in folded conformations. These and related analogues are important for the molecular modelling of ionotropic GABA receptors and to the development of new agents acting selectively on these receptors. PMID- 26012368 TI - Tanshinone IIA Rescued the Impairments of Primary Hippocampal Neurons Induced by BV2 Microglial Over-Activation. AB - Activated microglia plays an important role in monitoring the microenvironment and prune neural process in healthy neural tissue, in order to maintain synaptic homeostasis. However, hyperactive microglia may release various cytotoxic factors and induce neuroinflammation, which cause neuronal damages leading to neurodegenerative diseases. Tanshinone IIA (TSA), an extract from traditional Chinese medicine, features potent anti-apoptotic and anti-inflammatory effects both in vitro and in vivo. But little is known on the effects of TSA on microglial-over-activation-induced neural impairments. In this study, by employing murine BV2 cell lines as well as the combinations of ELISA assay, immunostaining, western blotting analysis and RT-PCR, we found that TSA has the potential to exhibit anti-inflammatory effects. We hereby demonstrated that TSA rescued neural growth and development in the primary cultured hippocampal neurons from impairments caused by BV2 microglial over-activation insult. The results show that TSA attenuated the BV2 cell activation by lipopolysaccharide (LPS) stimulation through suppressing the NF-kB signal pathway. Also, conditioned mediums (CM) from TSA treated and activated BV2 cells protected against LPS-CM induced neuronal death. Furthermore, TSA treatment could recover the inhibitory effects of LPS-CM on growth cone extension, neurite sprouting and outgrowth, as well as spinogenesis. Our findings support that TSA is capable of inhibiting BV2 cell over-activation thus has potential protective effects in the cultured hippocampal neurons. This study may lay a foundation for using TSA to restore cerebral injuries after severe neuroinflammation. PMID- 26012369 TI - Electronic Band Structure and Sub-band-gap Absorption of Nitrogen Hyperdoped Silicon. AB - We investigated the atomic geometry, electronic band structure, and optical absorption of nitrogen hyperdoped silicon based on first-principles calculations. The results show that all the paired nitrogen defects we studied do not introduce intermediate band, while most of single nitrogen defects can introduce intermediate band in the gap. Considering the stability of the single defects and the rapid resolidification following the laser melting process in our sample preparation method, we conclude that the substitutional nitrogen defect, whose fraction was tiny and could be neglected before, should have considerable fraction in the hyperdoped silicon and results in the visible sub-band-gap absorption as observed in the experiment. Furthermore, our calculations show that the substitutional nitrogen defect has good stability, which could be one of the reasons why the sub-band-gap absorptance remains almost unchanged after annealing. PMID- 26012370 TI - Association of B-cell activating factor receptor deficiency with the P21R polymorphism and common variable immunodeficiency. PMID- 26012371 TI - Process boundaries of irreversible scCO2 -assisted phase separation in biphasic whole-cell biocatalysis. AB - The formation of stable emulsions in biphasic biotransformations catalyzed by microbial cells turned out to be a major hurdle for industrial implementation. Recently, a cost-effective and efficient downstream processing approach, using supercritical carbon dioxide (scCO2 ) for both irreversible emulsion destabilization (enabling complete phase separation within minutes of emulsion treatment) and product purification via extraction has been proposed by Brandenbusch et al. (2010). One of the key factors for a further development and scale-up of the approach is the understanding of the mechanism underlying scCO2 assisted phase separation. A systematic approach was applied within this work to investigate the various factors influencing phase separation during scCO2 treatment (that is pressure, exposure of the cells to CO2 , and changes of cell surface properties). It was shown that cell toxification and cell disrupture are not responsible for emulsion destabilization. Proteins from the aqueous phase partially adsorb to cells present at the aqueous-organic interface, causing hydrophobic cell surface characteristics, and thus contribute to emulsion stabilization. By investigating the change in cell-surface hydrophobicity of these cells during CO2 treatment, it was found that a combination of catastrophic phase inversion and desorption of proteins from the cell surface is responsible for irreversible scCO2 mediated phase separation. These findings are essential for the definition of process windows for scCO2 -assisted phase separation in biphasic whole-cell biocatalysis. PMID- 26012367 TI - Glutamate Release. AB - Our aim was to review the processes of glutamate release from both biochemical and neurophysiological points of view. A large body of evidence now indicates that glutamate is specifically accumulated into synaptic vesicles, which provides strong support for the concept that glutamate is released from synaptic vesicles and is the major excitatory neurotransmitter. Evidence suggests the notion that synaptic vesicles, in order to sustain the neurotransmitter pool of glutamate, are endowed with an efficient mechanism for vesicular filling of glutamate. Glutamate-loaded vesicles undergo removal of Synapsin I by CaM kinase II-mediated phosphorylation, transforming to the release-ready pool. Vesicle docking to and fusion with the presynaptic plasma membrane are thought to be mediated by the SNARE complex. The Ca(2+)-dependent step in exocytosis is proposed to be mediated by synaptotagmin. PMID- 26012372 TI - Perspectives of US Direct Care Workers on the Grief Process of Persons with Intellectual and Developmental Disabilities: Implications for Practice. AB - BACKGROUND: The study explored the grief process of persons with intellectual and developmental disabilities (PWIDDs) as perceived by direct care workers (DCWs) and how such workers can guide and support PWIDDs experiencing grief. MATERIALS AND METHODS: A thematic analysis approach was used to examine data from nine focus groups with 60 DCWs from five community-based organizations. RESULTS: Findings were supported in the context of seminal grief and bereavement theories. Three themes (i.e. reactions to loss, processing the loss and incorporating the loss) and related subthemes emerged from the data. CONCLUSIONS: PWIDDs are susceptible to traumatic grief, and DCWs are often key witnesses to such experiences. DCWs' perspectives can guide the development of grief and bereavement training which can lead to more tailored support systems. PMID- 26012373 TI - Development of fluorescent probes that bind and stain amyloid plaques in Alzheimer's disease. AB - beta-amyloid (Abeta) plaques in the brain are composed of Abeta40 and Abeta42 peptides, and are the defining pathological feature of Alzheimer's disease (AD). Fluorescent probes that can detect Abeta plaques have gained increasing interest as potential tools for in vitro and in vivo monitoring of the progression of AD. In this study, chalcone-mimic fluorescent probe 5 was designed and prepared. Probe 5 exhibited an approximately 50-fold increase in emission intensity after mixing with Abeta42 aggregates, a high affinity for Abeta42 aggregates (K D = 1.59 MUM), and reasonable lipophilicity (log P value = 2.55). Probe 5 also exhibited specific staining of Abeta plaques in the transgenic mice (APP/PS1) brain sections. Ex vivo fluorescence imaging of the brain from normal and TG mice revealed that probe 5 was able to penetrate the BBB and stain the Abeta plaques. These results suggest that chalcone-mimic probe 5 possessed the requirements of a fluorescent probe for Abeta plaques and may be useful in AD research. PMID- 26012374 TI - Beneficial Effects of Supplementation of the Rare Sugar "D-allulose" Against Hepatic Steatosis and Severe Obesity in Lep(ob)/Lep(ob) Mice. AB - A rare sugar, D-allulose (also called D-psicose), has recently been applied as a food supplement in view of controlling diabetes and obesity in Japan. D-allulose has been proven to have unique effects against hyperglycemia and hyperlipidemia in a number of studies using several species of rats and mice. However, the antiobesity effects of D-allulose have not yet been assessed in Lep(ob)/Lep(ob) (ob/ob) mice. Therefore, this study explored the dietary supplemental effects of this sugar in leptin-deficient ob/ob mice. Consequently, the subchronic ingestion of D-allulose in ob/ob mice for 15 wk significantly decreased the body and liver weights, and the loss of body weight was involved in the reduction of the total fat mass, including abdominal visceral fat, and not fat-free body mass, including muscle. Furthermore, D-allulose improved hepatic steatosis, as evaluated using hepatic histological studies and MRI. In the normal mice, none of these parameters were influenced by the single or long-term ingestion of D-allulose. These results indicate that dietary supplementation of D-allulose especially influences postprandial hyperglycemia and obesity-related hepatic steatosis, without exercise therapy or dietary restriction. Therefore, D-allulose may be useful as a supplement for preventing and improving obesity and obesity-related disorders. PMID- 26012375 TI - TADs as modular and dynamic units for gene regulation by hormones. AB - During cell differentiation epigenetic processes permit the establishment of a cell type specific transcriptome by limiting the fraction of the genome that will be expressed. Based upon steady-state requirements and transcription factor expression, differentiated cells respond transiently to external cues by modulating the expression levels of subsets of genes. Increasing evidence demonstrates that the genome is organized non-randomly in a hierarchy of structures within the nuclear space, where chromosome territories are segmented into Topologically Associating Domains (TADs) and sub-domains. It remains poorly understood how this three-dimensional organization of the genome participates in the acquisition of a cell-specific program of gene expression. Furthermore, it is unknown whether this spatial framework influences the dynamic changes of gene expression that accompany alterations in the cell environment. In this review, we will discuss the impact of genome topology on the response of breast cancer cells to steroid hormones. We will cover steroid nuclear receptor mechanisms of action and discuss how topological organization of the genome, including segmentation into TADs, acts as a combinatorial platform to integrate signals whilst ultimately ensuring coordinate regulation of gene expression. PMID- 26012376 TI - Luminescence-Functionalized Metal-Organic Frameworks Based on a Ruthenium(II) Complex: A Signal Amplification Strategy for Electrogenerated Chemiluminescence Immunosensors. AB - Novel luminescence-functionalized metal-organic frameworks (MOFs) with superior electrogenerated chemiluminescence (ECL) properties were synthesized based on zinc ions as the central ions and tris(4,4'-dicarboxylicacid-2,2' bipyridyl)ruthenium(II) dichloride ([Ru(dcbpy)3](2+)) as the ligands. For potential applications, the synthesized MOFs were used to fabricate a "signal-on" ECL immunosensor for the detection of N-terminal pro-B-type natriuretic peptide (NT-proBNP). As expected, enhanced ECL signals were obtained through a simple fabrication strategy because luminescence-functionalized MOFs not only effectively increased the loading of [Ru(dcbpy)3](2+), but also served as a loading platform in the ECL immunosensor. Furthermore, the proposed ECL immunosensor had a wide linear range from 5 pg mL(-1) to 25 ng mL(-1) and a relatively low detection limit of 1.67 pg mL(-1) (signal/noise=3). The results indicated that luminescence-functionalized MOFs provided a novel amplification strategy in the construction of ECL immunosensors and might have great prospects for application in bioanalysis. PMID- 26012377 TI - Feeding time. AB - A hormone released from the gut after a meal can reset clock gene activity in the liver. PMID- 26012378 TI - Erratum to: Physical exercise programs in CKD: lights, shades and perspectives. PMID- 26012379 TI - The impact of fluid balance on diagnosis, staging and prediction of mortality in critically ill patients with acute kidney injury. AB - BACKGROUND: Fluid accumulation may delay recognition of acute kidney injury (AKI) in intensive care unit (ICU) patients. This study aims to evaluate the impact of fluid balance on the incidence, time of AKI diagnosis and predictive performance for outcomes of critically ill patients. METHODS: This study included a cohort of 7696 adult ICU patients at Mayo Clinic Hospital in year 2011 with at least one serum creatinine (SCr) measured in ICU. AKI was defined based on SCr criterion for stage I of KDIGO definition. The AKI incidence and predictive performance for 60-day mortality was compared before and after SCr adjustment for fluid balance. RESULTS: AKI was detected in 1860 (24.2 %) before and 1947 (25.3 %) after fluid balance adjustment (P < 0.001). Patients with AKI both before and after SCr adjustment had significantly higher 60-day mortality in comparison with patients who did not develop AKI (OR 3.38; 95 % CI 2.84-4.02). The risk of 60-day mortality in patients who met AKI criteria after but not before SCr adjustment was significantly higher than patients without AKI (OR 2.00; 95 % CI 1.25-3.11). In contrast, the risk of 60-day mortality in patients who met AKI criteria before but not after SCr adjustment was similar to patients without AKI (OR 1.19; 95 % CI 0.48-2.50). The C-statistic for unadjusted and adjusted SCr to predict 60-day mortality were 0.68 and 0.70, respectively (P = 0.001). CONCLUSION: Our study found that SCr adjustment for fluid balance could result in a more accurate detection of AKI cases. We suggest using fluid balance adjustment for volume overload critically ill patients. PMID- 26012381 TI - Polyvinylidene fluoride sensor-based method for unconstrained snoring detection. AB - We established and tested a snoring detection method using a polyvinylidene fluoride (PVDF) sensor for accurate, fast, and motion-artifact-robust monitoring of snoring events during sleep. Twenty patients with obstructive sleep apnea participated in this study. The PVDF sensor was located between a mattress cover and mattress, and the patients' snoring signals were unconstrainedly measured with the sensor during polysomnography. The power ratio and peak frequency from the short-time Fourier transform were used to extract spectral features from the PVDF data. A support vector machine was applied to the spectral features to classify the data into either the snore or non-snore class. The performance of the method was assessed using manual labelling by three human observers as a reference. For event-by-event snoring detection, PVDF data that contained 'snoring' (SN), 'snoring with movement' (SM), and 'normal breathing' epochs were selected for each subject. As a result, the overall sensitivity and the positive predictive values were 94.6% and 97.5%, respectively, and there was no significant difference between the SN and SM results. The proposed method can be applied in both residential and ambulatory snoring monitoring systems. PMID- 26012380 TI - Peritoneal Cell-free DNA: an innovative method for determining acute cell damage in peritoneal membrane and for monitoring the recovery process after peritonitis. AB - BACKGROUND: Cell-free DNA (cfDNA) is present in the peritoneal effluent of stable peritoneal dialysis (PD) patients, but there are no data on cfDNA in PD patients with peritonitis. We investigated the variation of peritoneal cfDNA levels subsequent to peritonitis in PD patients. METHODS: We enrolled 53 PD patients: 30 without any history of systemic inflammation or peritonitis in the last 3 months (group A) and 23 with acute peritonitis (group B). CfDNA was quantified in the peritoneal effluent. Peritoneal samples on days 1, 3, 10, 30 and until day 120 from the start of peritonitis were collected for white blood cells (WBC) count and cfDNA evaluation in group B. RESULTS: Quantitative analysis of cfDNA showed significantly higher levels in group B on day 1, 3, 10 and 30 compared with group A (p < 0.05). A significant positive correlation was observed between cfDNA concentration and WBC on day 1 (rho = 0.89) and day 3 (rho = 0.5) (both, p < 0.05). However, no significant correlation was observed between cfDNA and WBC on days 10 and 30. In group B, peritoneal cfDNA levels tended to progressively decline during follow-up of peritonitis. From this decreasing curve, we estimated that 49 days are necessary to reach the value of 51 genome equivalents (GE)/ml (75th percentile in controls) and 63 days to reach 31 GE/ml (median). CONCLUSION: Our results demonstrate that cfDNA increases in peritoneal effluent of PD patients with peritonitis and tends to progressively decline in step with peritonitis resolution and membrane repair process. Peritoneal cfDNA quantification could be an innovative method to determine acute damage and an inverse index of the repair process. PMID- 26012382 TI - Dissociating the Influence of Affective Word Content and Cognitive Processing Demands on the Late Positive Potential. AB - The late positive potential (LPP) elicited by affective stimuli in the event related brain potential (ERP) is often assumed to be a member of the P3 family. The present study addresses the relationship of the LPP to the classic P3b in a published data set, using a non-parametric permutation test for topographical comparisons, and residue iteration decomposition to assess the temporal features of the LPP and the P3b by decomposing the ERP into several component clusters according to their latency variability. The experiment orthogonally manipulated arousal and valence of words, which were either read or judged for lexicality. High-arousing and positive valenced words induced a larger LPP than low-arousing and negative valenced words, respectively, and the LDT elicited a larger P3b than reading. The experimental manipulation of arousal, valence, and task yielded main effects without any interactions on ERP amplitude in the LPP/P3b time range. The arousal and valence effects partially differed from the task effect in scalp topography; in addition, whereas the late positive component elicited by affective stimuli, defined as LPP, was stimulus-locked, the late positive component elicited by task demand, defined as P3b, was mainly latency-variable. Therefore LPP and P3b manifest different subcomponents. PMID- 26012383 TI - Blue Light: A Fascinating Journey (Nobel Lecture). PMID- 26012384 TI - Influenza virus infection in pregnancy: a review. AB - BACKGROUND: Influenza virus infection is very common and a significant cause of morbidity and mortality in specific populations like pregnant women. Following the 2009 pandemic, several reports on the effects of influenza virus infection on maternal health and pregnancy outcome have been published. Also the safety and efficacy of antiviral treatment and vaccination of pregnant women have been studied. In this review, we have analyzed and summarized these data. OBJECTIVE: To provide information on the influence of influenza virus infection during pregnancy on maternal health and pregnancy outcome and on the effect of treatment and vaccination. DATA SOURCES: We have searched Medline, Embase and the Cochrane Library. We used influenza, influenz*, pregnancy and pregnan* as search terms. STUDY SELECTION: In total, 294 reports were reviewed and judged according to the STROBE guidelines or CONSORT statement. In all, 100 studies, published between 1961 and 2015, were included. RESULTS: Compared to the general population, pregnant women are more often hospitalized and admitted to an intensive care unit due to influenza virus infection. For hospitalized patients, increased rates of preterm birth and fetal/neonatal death are reported. Early treatment with oseltamivir is associated with a reduced risk of severe disease. Vaccination of pregnant women is safe and reduces maternal and neonatal morbidity. CONCLUSIONS: There is level 2b evidence that maternal health and pregnancy outcome can be severely affected by influenza virus infection. Antiviral treatment may diminish these effects and vaccination protects pregnant women and neonates from infection (level of evidence 2b and 1b, respectively). PMID- 26012418 TI - Structure elucidation of the designer drug N-(1-amino-3,3-dimethyl-1-oxobutan-2 yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide and the relevance of predicted (13) C NMR shifts - a case study. AB - The detailed structure elucidation process of the new cannabimimetic designer drug, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4 fluorophenyl)-pyrazole-5-carboxamide, with a highly substituted pyrazole skeleton, using nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric (MS) techniques is described. After a first analysis of the NMR spectra and comparison with 48 possible pyrazole and imidazole structures, a subset of six positional isomeric pyrazoles and six imidazoles remained conceivable. Four substituents of the heterocyclic skeleton were identified: a proton bound to a pyrazole ring carbon atom; a 5-fluoropentyl group; a 4 fluorophenyl substituent; and a carbamoyl group, which is N-substituted with a methyl residue carrying a tert.-butyl and a carbamoyl substituent. The 5 fluoropentyl residue is situated at the nitrogen ring atom. Additional NMR experiments like the (1) H,(13) C HMBC were performed, but due to the small number of signals based on long-range couplings, the comparison of predicted and observed (13) C chemical shifts became necessary. The open access Internet shift prediction programs NMRDB, NMRSHIFTDB2, and CSEARCH were employed for the prediction of (13) C shift values which allowed an efficient and unambiguous structure determination. For the identified N-(1-amino-3,3-dimethyl-1-oxobutan-2 yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide, the best agreement between predicted (13) C shifts and the observed chemical shifts and long-range couplings for the pyrazole ring carbon atoms, with a standard error of about 2 ppm, was found with each of the predictions. For the comparison of measured and predicted chemical shifts model compounds with simple substituents proved helpful. The identified compound is a homologue of AZ-037 which is offered by Internet suppliers. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26012419 TI - Combining voice therapy and physical therapy: A novel approach to treating muscle tension dysphonia. AB - OBJECTIVE: This study investigated the role of a specialized physical therapy program for muscle tension dysphonia patients as an adjunct to standard of care voice therapy. STUDY DESIGN: Retrospective Cohort Study Methods Adult MTD patients seen between 2007 and 2012 were identified from the clinical database. They were prescribed voice therapy and, if concomitant neck pain, adjunctive physical therapy. In a pragmatic observational cohort design, patients underwent one of four potential treatment approaches: voice therapy alone (VT), voice therapy and physical therapy (VT+PT), physical therapy alone (PT), or incomplete/no treatment. Voice handicap outcomes were compared between treatment approaches. RESULTS: Of 153 patients meeting criteria (Median age 48 years, 68% female, and 30% had fibromyalgia, chronic pain, chronic fatigue, depression, and/or anxiety), there was a similar distribution of patients with moderate or severe pre-treatment VHI scores across treatment groups (VT 45.5%, VT+PT 43.8%, PT 50%, no treatment 59.1%; p=0.45). Patients treated with VT alone had significantly greater median improvement in VHI than those not treated: 10-point vs. 2-point (p=0.02). Interestingly, median VHI improvement in patients with baseline moderate-severe VHI scores was no different between VT (10), VT+PT (8) and PT alone (10; p=0.99). CONCLUSIONS: Findings show voice therapy to be an effective approach to treating MTD. Importantly, other treatment modalities incorporating physical therapy had a similar, albeit not significant, improvement in VHI. This preliminary study suggests that physical therapy techniques may have a role in the treatment of a subset of MTD patients. Larger, comparative studies are needed to better characterize the role of physical therapy in this population. LEARNING OUTCOMES: The reader will describe symptoms associated with muscle tension dysphonia and current treatment. The reader will describe the systematic adjunctive physical therapy approach and understand the rationale to consider incorporation of physical therapy into the current treatment regimen. PMID- 26012420 TI - Synthetic dendrimeric peptide active against biofilm and persister cells of Pseudomonas aeruginosa. AB - Antimicrobial dendrimeric peptides (AMDP) are a relatively new class of agents displaying repetitive functional groups on a branched core. Previously, we have investigated the length requirement for antimicrobial activity of peptides consisting of repeated arginine (R) and tryptophan (W) side chains and found that even short linear RW repeats are active, providing a starting point for a de novo design of multivalent structures. In this study, we synthesized and tested a new synthetic dendrimer, 2D-24, for its antimicrobial activity against Pseudomonas aeruginosa, including the wild-type PAO1 and its mucoid mutant PDO300. This synthetic AMDP was found to kill planktonic cells of both PAO1 and PDO300 in a dose-dependent manner, with nearly complete killing of both strains observed when treated with 50 MUM of this agent. In addition to planktonic cells, 2D-24 was also found to kill biofilm cells of both strains in a dose-dependent manner. For example, treatment with 30 MUM 2D-24 led to 94.4 +/- 1.4 and 93.9 +/- 4.2 % killing of PAO1 and PDO300 biofilm cells, respectively. Furthermore, 2D-24 was effective in killing multidrug-tolerant persister cells of PAO1 and PDO300. While higher concentrations of 2D-24 were required to kill persister cells, combinations of 2D-24 with ciprofloxacin, tobramycin, or carbenicillin showed synergistic effects on killing persister cells of both strains. Based on hemolysis assays using sheep erythrocytes and a coculture model of PAO1 and human epithelial cells, 2D-24 was found to kill P. aeruginosa cells at concentrations that are not toxic to mammalian cells. PMID- 26012421 TI - Spectral domain and swept source optical coherence tomography findings in acute retinal necrosis. PMID- 26012422 TI - Spectral domain optical coherence tomography imaging of mucopolysaccharidoses I, II, IV A, and VI. PMID- 26012423 TI - Cooperative Effect of Erythropoietin and TGF-beta Inhibition on Erythroid Development in Human Pluripotent Stem Cells. AB - Patient-specific human induced-pluripotent stem cells (hiPSCs) represent important cell sources to treat patients with acquired blood disorders. To realize the therapeutic potential of hiPSCs, it is crucial to understand signals that direct hiPSC differentiation to a hematopoietic lineage fate. Our previous study demonstrated that CD34(+)CD31(+) cells derived from human pluripotent stem cells (hPSCs) contain hemato-endothelial progenitors (HEPs) that give rise to hematopoietic cells and endothelial cells. Here, we established a serum-free and feeder-free system to induce the differentiation of hPSC-derived CD34(+)CD31(+) progenitor cells to erythroid cells. We show that extracellular matrix (ECM) proteins promote the differentiation of CD34(+)CD31(+) progenitor cells into CD235a(+) erythroid cells through CD41(+)CD235a(+) megakaryocyte-erythroid progenitors (MEP). Erythropoietin (EPO) is a predominant factor for CD34(+)CD31(+) progenitor differentiation to erythroid cells, whereas transforming growth factor beta (TGF-beta) inhibits the development of CD34(+)CD31(+) progenitor cells. Apoptosis of progenitor cells is induced by TGF beta in early erythroid differentiation. Suppression of TGF-beta signaling by SB431542 at early stage of CD34(+)CD31(+) progenitor differentiation induces the erythroid cell generation. Together, these findings suggest that TGF-beta suppression and EPO stimulation promote erythropoiesis of CD34(+)CD31(+) progenitor cells derived from hPSCs. PMID- 26012424 TI - Magnetic resonance tagging for diagnosis of focal hypertrophic cardiomyopathy in a child. AB - Magnetic resonance imaging has become an important diagnostic tool in the differential diagnosis of lesions for evaluation of cardiovascular disorders. In magnetic resonance tagging (MRt), tissue elements are magnetically labeled so that their positions can be tracked as a function of time. Thus, MRt evaluates heart wall motion both qualitatively and quantitatively. We present herein the case of a 12-year-old boy who had chest pain, dyspnea on effort and murmur. On cardiac computed tomography, there was focal thickening of the left ventricular posterior wall, similar to a mass. MRt indicated active displacement and deformation of the tags at the level of the hypertrophic myocardium during systole, as with normal myocardium. Thus, the tagged images supported the diagnosis of focal hypertrophic cardiomyopathy (HCM). In view of these results, MRt should be considered as a useful technique for differentiating between a mass like focal lesion such as neoplasm and HCM. PMID- 26012428 TI - [And this two days before the wedding! Esophageal ulceration]. PMID- 26012425 TI - Biomonitoring using dried blood spots: detection of ochratoxin A and its degradation product 2'R-ochratoxin A in blood from coffee drinkers. AB - SCOPE: In this study, human exposure to the mycotoxin ochratoxin A (OTA) and its thermal degradation product 2'R-ochratoxin A (2'R-OTA, previously named as 14R Ochratoxin A [22]) through coffee consumption was assessed. LC-MS/MS and the dried blood spot (DBS) technique were used for the analysis of blood samples from coffee and noncoffee drinkers (n = 50), and food frequency questionnaires were used to document coffee consumption. METHODS AND RESULTS: For the detection of OTA and 2'R-OTA in blood, a new sensitive and efficient sample preparation method based on DBS was established and validated. Using this technique 2'R-OTA was for the first time detected in biological samples. Comparison between coffee drinkers and noncoffee drinkers showed for the first time that 2'R-OTA was only present in blood from the first group while OTA could be found in both groups in a mean concentration of 0.21 MUg/L. 2'R-OTA mean concentration was 0.11 MUg/L with a maximum concentration of 0.414 MUg/L. Thus, in average 2'R-OTA was approx. half the concentration of OTA but in some cases even exceeded OTA levels. No correlation between the amounts of coffee consumption and OTA or 2'R-OTA levels was observed. CONCLUSION: The results of this study revealed for the first time a high exposure of coffee consumers to 2'R-OTA, a compound formed from OTA during coffee roasting. Since little information is available regarding toxicity and possible carcinogenicity of this compound, further OTA monitoring in blood including 2'R-OTA is advisable. PMID- 26012429 TI - [Traveler's diarrhea: immediate antibiotic not always necessary]. PMID- 26012430 TI - [Dog bite: who needs preventive antibiotics?]. PMID- 26012431 TI - ["Many infected patients have no idea that they are carriers":]. PMID- 26012432 TI - [The railroad physician is not allowed to know!]. PMID- 26012434 TI - [Do old listeners still do this?]. PMID- 26012433 TI - [A traffic accident of the slippery kind]. PMID- 26012435 TI - [Expert testimony for accident insurance are paid significantly more]. PMID- 26012436 TI - [The fiasco in remuneration of emergency care continues]. PMID- 26012437 TI - [General palliative care is expanded]. PMID- 26012438 TI - [Without patient control the system hits the wall]. PMID- 26012439 TI - [Is the clock test reimbursable?]. PMID- 26012440 TI - [Solving the goiter nodule]. PMID- 26012441 TI - [Symptoms of hypo- and hyperfunction]. PMID- 26012442 TI - [Incidental finding in pneumonia investigation]. PMID- 26012443 TI - [Are targeted therapies better tolerated?]. PMID- 26012444 TI - [Spring time fatigue or iron deficiency?]. PMID- 26012445 TI - [Managing every iron deficiency]. PMID- 26012446 TI - [Shrinking the lung with an endoscope]. PMID- 26012447 TI - [Anticoagulants in special situations]. PMID- 26012448 TI - [Tired, tired, constantly and always tired]. PMID- 26012449 TI - [Oat fiber lowers cholesterol]. PMID- 26012450 TI - [Special foot padding to prevent recurrent ulcers]. PMID- 26012451 TI - [Genital hygiene can also be overdone]. PMID- 26012452 TI - [Yogurt to control antibiotic-induced diarrhea in children?]. PMID- 26012453 TI - [Why there are so many overdiagnoses in clinics]. PMID- 26012455 TI - [Addictions in general practice. Don't look away!]. PMID- 26012454 TI - [Do not shake hands anymore!]. PMID- 26012456 TI - [Treatment of a silent addiction- current treatment recommendations to drug dependence]. PMID- 26012457 TI - [Nicotine addiction- a treatable addiction]. PMID- 26012458 TI - [New psychoactive drugs - perhaps legal but not safe]. PMID- 26012459 TI - [Proctological basics]. PMID- 26012460 TI - [Pseudozanthoma elasticum]. PMID- 26012461 TI - [Emergency checklist: acute cholecystitis]. PMID- 26012462 TI - [Long-acting insulins in the treatment of type 2 diabetes: a hard choice]. PMID- 26012463 TI - [Good evidence for phytotherapy drugs]. PMID- 26012464 TI - [Prevention and emergency measures]. PMID- 26012465 TI - [Insulin pump therapy: from eleven to one]. PMID- 26012466 TI - [Start of the salt reduction campaign]. PMID- 26012467 TI - [A new method in biotechnology]. PMID- 26012468 TI - [What therapy for which patient?]. PMID- 26012471 TI - Cosmetics: the medicine of beauty. PMID- 26012470 TI - Partially purified components of Uncaria sinensis attenuate blood brain barrier disruption after ischemic brain injury in mice. AB - BACKGROUND: Uncaria sinensis (US) has long been used in traditional Korean medicine to relieve various nervous-related symptoms and cardiovascular disease. We recently showed the neuroprotective and cerebrovascular protective effects of US on cerebral ischemia; however, its effects on the blood-brain barrier (BBB) are poorly understood. In this study, the effects of partially purified components of US (PPUS) on BBB disruption were investigated in mice subjected to ischemic brain injury. METHODS: Focal cerebral ischemia was induced in C57BL/6J mice by photothrombotic cortical ischemia. PPUS was injected intraperitoneally 30 min before ischemic insults. Infarct volume, neurological score, wire-grip test, Evans blue leakage and brain water content were then examined 24 h after ischemic brain injury. RESULTS: Infarct volume was significantly reduced and neurological deficit and motor deficit were greatly improved in PPUS-pretreated mice relative to those treated with vehicle following photothrombotic cortical ischemia. Brain edema-induced change of Evans blue extravasation and water content in the ipsilateral hemisphere were alleviated by treatment with PPUS. In addition, PPUS significantly reduced ischemic brain injury-induced degradation of tight junction proteins and elevation of matrix metalloproteinase-9 (MMP-9). CONCLUSIONS: PPUS prevents cerebral ischemic damage by BBB protection, and these effects were associated with inhibition of tight junction degradation and MMP-9 induction. PMID- 26012472 TI - Challenges associated with tracking resources allocation for reproductive health in sub-Saharan African countries: the UNFPA/NIDI resource flows project experience. AB - Universal access to reproductive health services entails strengthening health systems, but requires significant resource commitments as well as efficient and effective use of those resources. A number of international organizations and governments in developing countries are putting efforts into tracking the flow of health resources in order to inform resource mobilization and allocation, strategic planning, priority setting, advocacy and general policy making. The UNFPA/NIDI-led Resource Flows Project ("The UNFPA/NIDI RF Project") has conducted annual surveys since 1997 to monitor progress achieved by developing countries in implementing reproductive health financial targets. This commentary summarizes the Project experiences and challenges in gathering data on allocation of resources for reproductive health at the domestic level in sub-Saharan African countries. One key lesson learnt from the Project experience is the need for strengthening tracking mechanisms in sub-Saharan African countries and making information on reproductive health resources and expenditures available, in particular the private sector resources. PMID- 26012473 TI - Dispositions and tissue depletion of melamine in ducks. AB - To evaluate the toxicokinetics and persistence of residues of melamine (MEL) in ducks, MEL was administered intravenously (i.v.) or orally (p.o.) to ducks at a dosage of 5.5 mg/kg body weight. The concentration of MEL in the plasma and various tissues was detected using HPLC equipped with an ultraviolet detector. The plasma concentration of MEL in ducks was determined up to 12 h after both i.v. and p.o. administrations. The average value of elimination half-life (t1/2beta) of MEL was 2.16 +/- 0.37 and 2.01 +/- 0.56 h after i.v. and p.o. administration, respectively. The absolute p.o. bioavailability was 90.79%. MEL was measurable in the liver and kidney after p.o. administration with maximum levels of 15.80 +/- 1.81 and 15.49 +/- 2.12 MUg/g at 6 h, respectively. The results suggest that most of the administered MEL is efficiently absorbed from the gastro intestinal tract, and it has the ability to distribute into various tissues of the duck. PMID- 26012474 TI - The effects of nicorandil on microvascular function in patients with ST segment elevation myocardial infarction undergoing primary PCI. AB - BACKGROUND: Nicorandil, as a selective potassium channel opener, has dual action including coronary and peripheral vasodilatation and cardioprotective effect through ischemic preconditioning. Considering those characteristics, nicorandil was suggested to reduce the degree of microvascular dysfunction. METHODS: Thirty two patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (pPCI) were included in the study. Index of microvascular resistance (IMR) was measured in all patients immediatelly after pPCI before the after administration of Nicorandil. ST segment resolution was monitored before intervention and 60 min after terminating the procedure. Echocardiographic evaluation of myocardial function and transthoracic Doppler derived Coronary flow reserve (CFR) of infarct related artery (IRA) was performed during hospitalization and 3 months later. RESULTS: IMR was significantly lower after administration of Nicorandil (9.9 +/- 3.7 vs. 14.1 +/- 5.1, p < 0.001). There was significant difference in ST segment elevation before and after primary PCI with administration of Nicorandil (6.9 +/- 3.7 mm vs. 1.6 +/- 1.6 mm, p < 0.001). Transthoracic Doppler CFR measurement improved after 3 months (2.69 +/- 0.38 vs. 2.92 +/- 0.54, p = 0.021), as well as WMSI (1.14 +/- 0.17 vs. 1.07 +/- 0.09, p = 0.004). CONCLUSION: Intracoronary Nicorandil administration after primary PCI significantly decreases IMR, resulting in improved CFR and ventricular function in patients with STEMI undergoing primary PCI. PMID- 26012475 TI - The Effects of miR-20a on p21: Two Mechanisms Blocking Growth Arrest in TGF-beta Responsive Colon Carcinoma. AB - Loss of response to TGF-beta is a central event in the genesis of colorectal cancer (CRC), a disease that, in the majority cases, is refractory to growth inhibition induced by this cytokine. However, inactivating mutations at receptors and transducers from the TGF-beta cascade occur only in approximately half of CRCs, suggesting the involvement of additional mechanisms altering the response to the cytokine. We have recently described the amplification of the 13q31 locus, where the miR-17-92 cluster maps, associated with overexpression of its members. In this study, we address the potential role of miR-20a, from the miR-17-92 cluster, in the suppression of TGF-beta cytostatic response in CRC. Using the poorly tumorigenic and TGF-beta-sensitive FET cell line that expresses low miR 20a levels, we first confirmed that miR-20a downmodulated CDKN1A expression, both at mRNA and protein level, through direct binding to its 3'-UTR. We demonstrated that miR-20a significantly diminished cell response to TGF-beta by preventing its delay of G1/S transition and promoting progression into cell cycle. Moreover, besides modulating CDKN1A, miR-20a blocked TGF-beta-induced transactivation of its promoter without affecting the post-receptor activation of Smad3/4 effectors directly. Finally, miR-20a abrogated the TGF-beta-mediated c-Myc repression, a direct inhibitor of the CDKN1A promoter activation, most likely by reducing the expression of specific MYC-regulating genes from the Smad/E2F-based core repressor complex. Our experiments indicate that miR-20a interferes with the colonic epithelium homeostasis by disrupting the regulation of Myc/p21 by TGF beta, which is essential for its malignant transformation. PMID- 26012476 TI - Arterial hypotension and prerenal failure in an extremely preterm infant associated with oral sildenafil. AB - We report significant hypotension and prerenal failure in an extremely preterm infant following two doses of oral sildenafil that warranted discontinuation of the drug and treatment with inotropes. Blood pressure and urine output normalized after 24 h of withdrawal of the oral drug. Sildenafil should be used cautiously in extremely preterm infants early in the neonatal course, where there is limited data on its efficacy and safety. PMID- 26012477 TI - Acute paraplegia in a preterm infant with cerebral sinovenous thrombosis. AB - We report the case of a 1-month old, 28-week gestational age infant who presented with acute paraplegia after cardiopulmonary arrest. Later imaging confirms cerebral sinovenous thrombosis (CSVT) and a suspected infarction in the conus medullaris of the spinal cord. A prothrombotic state may explain the numerous areas of infarction visualized on neuroimaging. To our knowledge this is the first case report of acute and persistent paraplegia in an infant with CSVT and conus medullaris injury, which may be due to venous infarction of the spinal cord. PMID- 26012478 TI - Transfer of care and offload delay: continued resistance or integrative thinking? AB - The disciplines of paramedicine and emergency medicine have evolved synchronously over the past four decades, linked by emergency physicians with expertise in prehospital care. Ambulance offload delay (OD) is an inevitable consequence of emergency department overcrowding (EDOC) and compromises the care of the patient on the ambulance stretcher in the emergency department (ED), as well as paramedic emergency medical service response in the community. Efforts to define transfer of care from paramedics to ED staff with a view to reducing offload time have met with resistance from both sides with different agendas. These include the need to return paramedics to serve the community versus the lack of ED capacity to manage the patient. Innovative solutions to other system issues, such as rapid access to trauma teams, reducing door-to-needle time, and improving throughput in the ED to reduce EDOC, have been achieved by involving all stakeholders in an integrative thinking process. Only by addressing this issue in a similar integrative process will solutions to OD be realized. PMID- 26012479 TI - Donor/Acceptor Dihydroindeno[1,2-a]fluorene and Dihydroindeno[2,1-b]fluorene: Towards New Families of Organic Semiconductors. AB - New families of donor/acceptor semiconductors based on dihydroindeno[1,2 a]fluorene and dihydroindeno[2,1-b]fluorene are reported. Due to the spiro bridges, this new generation of dihydroindenofluorenes allows a spatial separation of HOMO and LUMO, which retains the high ET value of the dihydroindenofluorene backbone and excellent physical properties. This control of the electronic and physical properties has allowed a second generation of dihydroindeno[1,2-a]fluorene to be obtained with strongly enhanced performance in green and sky-blue phosphorescent organic light-emitting diodes (PhOLEDs) relative to the first generation of materials. To date, this is the highest performance ever reported for a blue PhOLED by using a dihydroindenofluorene derivative. Through this structure-property relationship study, a remarkable difference of performance between syn and anti isomers has also been highlighted. This surprising behaviour has been attributed to the different symmetry of the two molecules, and highlights the importance of the geometry profiles in the design of host materials for PhOLEDs. PMID- 26012480 TI - Glyceroglycolipids Affect Uptake of Carotenoids Solubilized in Mixed Micelles by Human Intestinal Caco-2 Cells. AB - We previously reported that phospholipids markedly affected the uptake of carotenoids solubilized in mixed micelles by human intestinal Caco-2 cells. In the present study, we found that two classes of dietary glyceroglycolipids and the corresponding lysoglyceroglycolipids affected uptake of beta-carotene and lutein by differentiated Caco-2 cells. The levels of carotenoid uptake from micelles containing digalactosyldiacylglycerol or sulfoquinovosyldiacylglycerol were significantly lower than that from control micelles. On the other hand, the uptakes from micelles containing digalactosylmonoacylglycerol or sulfoquinovosylmonoacylglycerol were significantly higher than that from control micelles. In dispersed cells and Caco-2 cells with poor cell-to-cell adhesion, however, the levels of uptake from micelles containing these lyso-lipids were much lower than that from control micelles. The uptake levels from control micelles were markedly decreased depending on the development of cell-to cell/cell-matrix adhesion in Caco-2 cells, but the uptake levels from the micelles containing these lyso-lipids were not substantially changed, suggesting that the intercellular barrier formed by cell-to-cell/cell-matrix adhesion inhibited the uptake from control micelles, but not from the lyso-lipid containing micelles. The lyso-lipids appeared to enhance carotenoid uptake by decreasing the intercellular barrier integrity. The results showed that some types of glyceroglycolipids have the potential to modify the intestinal uptake of carotenoids. PMID- 26012481 TI - Salt stains from evaporating droplets. AB - The study of the behavior of sessile droplets on solid substrates is not only associated with common everyday phenomena, such as the coffee stain effect, limescale deposits on our bathroom walls , but also very important in many applications such as purification of pharmaceuticals, de-icing of airplanes, inkjet printing and coating applications. In many of these processes, a phase change happens within the drop because of solvent evaporation, temperature changes or chemical reactions, which consequently lead to liquid to solid transitions in the droplets. Here we show that crystallization patterns of evaporating of water drops containing dissolved salts are different from the stains reported for evaporating colloidal suspensions. This happens because during the solvent evaporation, the salts crystallize and grow during the drying. Our results show that the patterns of the resulting salt crystal stains are mainly governed by wetting properties of the emerging crystal as well as the pathway of nucleation and growth, and are independent of the evaporation rate and thermal conductivity of the substrates. PMID- 26012483 TI - Establishment of 6- to 7-MeV high-energy gamma-ray calibration fields produced using the 4-MV Van de Graaff accelerator at the Facility of Radiation Standards, Japan Atomic Energy Agency. AB - A 6- to 7-MeV high-energy gamma-ray field, produced by the nuclear reaction of (19)F(p, alphagamma)(16)O, has been established at the Facility of Radiation Standards (FRS) in Japan Atomic Energy Agency for calibration purposes. Basic dosimetric quantities (i.e. averaged gamma-ray energy, air-kerma-to-dose equivalent conversion coefficients and air kerma rates at the point of test) have been precisely determined through a series of measurements using the NaI(Tl) spectrometer and an ionisation chamber coupled with an appropriate build-up material. The measurements obtained comply with values recommended by the International Organization for Standardization for an 'R-F field'. The neutron contamination component for the field has also been measured by means of a conventional neutron dose equivalent meter (the so-called neutron rem-counter) and determined to be ~ 0.5 % of the total dose equivalent. PMID- 26012482 TI - Statin use and risk of prostate cancer: Results from the Southern Community Cohort Study. AB - BACKGROUND: Epidemiologic studies suggest that statin use may be inversely associated with risk of prostate cancer, but prior studies have focused predominantly on non-Hispanic white populations. METHODS: We evaluated the association between statin use and prostate cancer risk in the Southern Community Cohort Study (SCCS). Study participants were 32,091 men aged 40-79 at baseline, 67% of whom were non-Hispanic black. Between study enrollment (2002-2009) and December 31, 2010, 570 prostate cancer cases were diagnosed, including 324 low grade cancers (Gleason score <7 or Gleason pattern 3 + 4) and 107 high-grade cancers (Gleason score >7 or Gleason pattern 4 + 3). Analyses of overall prostate cancer were conducted using Cox regression and analyses of grade-specific cancer were conducted using competing risks models. RESULTS: Ten percent of non-Hispanic black men and 22% of non-Hispanic white men reported use of statins at study enrollment. As compared to non-use, statin use was associated with a non significant 14% lower risk of prostate cancer in multivariable models (Hazard Ratio [HR]:0.86; 95% Confidence Interval [CI]: 0.63-1.18). This association was stronger for high-grade cancer (HR: 0.62; 95%CI: 0.30, 1.28) than low-grade cancer (HR:0.98; 95%CI: 0.65-1.48). Results were similar by race/ethnicity (p interaction: 0.41) and did not vary by history of prostate-specific antigen [PSA] screening (p-interaction: 0.65). CONCLUSIONS: Results suggest no strong association between statin use and prostate cancer risk overall, and further suggest that if a modest protective effect does exist, it does not vary by race/ethnicity and may be restricted to high-grade tumors, although power to detect differences by subgroup was limited. PMID- 26012484 TI - The contribution of interventional cardiology procedures to the population radiation dose in a 'health-care level I' representative region. AB - This study evaluates per-procedure, collective and per capita effective dose to the population by interventional cardiology (IC) procedures performed during 2002 11 at the main hospital of Aosta Valley Region that can be considered as representative of the health-care level I countries, as defined by the UNSCEAR, based on its socio-demographic characteristics. IC procedures investigated were often multiple procedures in patients older than 60 y. The median extreme dose area product values of 300 and 22 908 cGycm(2) were found for standard pacemaker implantation and coronary angioplasty, respectively, while the relative mean per procedure effective dose ranged from 0.7 to 47 mSv. A 3-fold increase in frequency has been observed together with a correlated increase in the delivered per capita dose (0.05-0.27 mSv y(-1)) and the collective dose (5.8-35 man Sv y( 1)). Doses increased particularly from 2008 onwards mainly because of the introduction of coronary angioplasty procedures in the authors' institution. IC practice contributed remarkably in terms of effective dose to the population, delivering ~10% of the total dose by medical ionising radiation examination categories. PMID- 26012485 TI - Germinoma with an extensive rhabdoid cell component centered at the corpus callosum. AB - Intracranial germinomas comprise 0.5-2.0 % of all central nervous system (CNS) tumors and 50-60 % of CNS germ cell tumors. They most frequently originate in the pineal gland and the suprasellar region. The corpus callosum is an extremely uncommon location for germinoma formation. Herein, we report about a 20-year-old man with a germinoma centered at the corpus callosum and that extended to both cerebral hemispheres. In addition to its location, this case is unique in that the amount of tumor cells with rhabdoid morphology exceeded that of tumor cells with typical morphology. The rhabdoid cell component showed an immunophenotype compatible with germinoma. While the presence of rhabdoid cells is generally regarded as a sign of aggressive behavior, the patient has been doing well for at least 4 years since undergoing radiation therapy and chemotherapy. The cellular composition of germinoma might not critically affect prognosis with adequate treatment. PMID- 26012486 TI - Balloon mitral valvotomy in youngest documented rheumatic mitral stenosis patient. AB - Juvenile rheumatic mitral stenosis (MS) is common in the Indian subcontinent. Early recognition and management is essential. Rarely rheumatic MS may occur in <5 years of age, wherein rapid hemodynamic progression and cardiac morbidity and mortality occurs. Severe/symptomatic MS in preschool age requires urgent and meticulous decision making. Condition of valve and wishes of parents may complicate management decisions. Percutaneous transmitral commissurotomy (PTMC) may, therefore, become the only life-saving intervention in these cases unless contraindicated, although the procedure entails considerable technical issues in this age group. Herein, we report a successful balloon mitral valvotomy in a 4 year-old child with severe rheumatic MS (documented since 2 years 6 months of age) presenting with repeated pulmonary edema. To the best of our knowledge, this child is the youngest documented case of established rheumatic heart disease and also one of the youngest PTMC procedure performed. This report supports the clinical usefulness of PTMC in childhood MS; however, pertinent technical issues are raised, which needs a proper consensus. PMID- 26012487 TI - The Magic Au60 Nanocluster: A New Cluster-Assembled Material with Five Au13 Building Blocks. AB - Herein, we report the synthesis and atomic structure of the cluster-assembled [Au60Se2(Ph3P)10(SeR)15](+) material. Five icosahedral Au13 building blocks from a closed gold ring with Au-Se-Au linkages. Interestingly, two Se atoms (without the phenyl tail) locate in the center of the cluster, stabilized by the Se-(Au)5 interactions. The ring-like nanocluster is unprecedented in previous experimental and theoretical studies of gold nanocluster structures. In addition, our optical and electrochemical studies show that the electronic properties of the icosahedral Au13 units still remain unchanged in the penta-twinned Au60 nanocluster, and this new material might be a promising in optical limiting material. This work offers a basis for deep understanding on controlling the cluster-assembled materials for tailoring their functionalities. PMID- 26012488 TI - Broad family of carbon nanoallotropes: classification, chemistry, and applications of fullerenes, carbon dots, nanotubes, graphene, nanodiamonds, and combined superstructures. PMID- 26012489 TI - Noradrenergic modulation of glutamate-induced excitatory responses in single neurons of the red nucleus: an electrophysiological study. AB - The effect induced by noradrenaline (NA) on the spiking activity evoked by glutamate (Glu) on single neurons of the mesencephalic red nucleus (RN) of the rat was studied extracellularly. Long-lasting microiontophoretic applications of the amine induced a significant and reversible depression of the responsiveness of RN neurons to Glu. This effect was mediated by noradrenergic alpha2 receptors since it was mimicked by application of clonidine, an alpha2 adrenoceptor agonist, and blocked or at least reduced by application of yohimbine, an antagonist of NA for the same receptors. The effect appears homogeneously throughout the nucleus and is independent of the effect of NA on baseline firing rate. Application of isoproterenol, a beta adrenoceptor agonist, either enhanced or depressed neuronal responses to Glu in a high percentage (86%) of the tested neurons. Moreover, application of timolol, a beta adrenoceptor antagonist, was able to strengthen the depressive effects induced by NA application on neuronal responsiveness to Glu. Although these data suggest some involvement of beta adrenergic receptors in the modulation of neuronal responsiveness to Glu, the overall results indicate a short-term depressive action of NA, mediated by alpha2 receptors, on the responsiveness of RN neurons and suggest that stress initially leads to an attenuation of the relay function of the RN. PMID- 26012490 TI - A novel SDS-stable dimer of a heterogeneous nuclear ribonucleoprotein at presynaptic terminals of squid neurons. AB - The presence of mRNAs in synaptic terminals and their regulated translation are important factors in neuronal communication and plasticity. Heterogeneous nuclear ribonucleoprotein (hnRNP) complexes are involved in the translocation, stability, and subcellular localization of mRNA and the regulation of its translation. Defects in these processes and mutations in components of the hnRNP complexes have been related to the formation of cytoplasmic inclusion bodies and neurodegenerative diseases. Despite much data on mRNA localization and evidence for protein synthesis, as well as the presence of translation machinery, in axons and presynaptic terminals, the identity of RNA-binding proteins involved in RNA transport and function in presynaptic regions is lacking. We previously characterized a strongly basic RNA-binding protein (p65), member of the hnRNPA/B subfamily, in squid presynaptic terminals. Intriguingly, in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), p65 migrated as a 65-kDa protein, whereas members of the hnRNPA/B family typically have molecular masses ranging from 35 to 42kDa. In this report we present further biochemical and molecular characterization that shows endogenous p65 to be an SDS-stable dimer composed of ~37-kDa hnRNPA/B-like subunits. We cloned and expressed a recombinant protein corresponding to squid hnRNPA/B-like protein and showed its propensity to aggregate and form SDS-stable dimers in vitro. Our data suggest that this unique hnRNPA/B-like protein co-localizes with synaptic vesicle protein 2 and RNA binding protein ELAV and thus may serve as a link between local mRNA processing and presynaptic function and regulation. PMID- 26012491 TI - Voxel-based morphometry of the marmoset brain: In vivo detection of volume loss in the substantia nigra of the MPTP-treated Parkinson's disease model. AB - Movement dysfunction in Parkinson's disease (PD) is caused by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Here, we established a method for voxel-based morphometry (VBM) and automatic tissue segmentation of the marmoset monkey brain using a 7-T animal scanner and applied the method to assess DA degeneration in a PD model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animals, with tyrosine-hydroxylase staining. The most significant decreases of local tissue volume were detected in the bilateral SN of MPTP treated marmoset brains (-53.0% in right and -46.5% in left) and corresponded with the location of DA neurodegeneration found in histology (-65.4% in right). In addition to the SN, the decreases were also confirmed in the locus coeruleus, and lateral hypothalamus. VBM using 7-T MRI was effective in detecting volume loss in the SN of the PD-model marmoset. This study provides a potential basis for the application of VBM with ultra-high field MRI in the clinical diagnosis of PD. The developed method may also offer value in automatic whole-brain evaluation of structural changes for the marmoset monkey. PMID- 26012492 TI - Imaging of autoimmune encephalitis--Relevance for clinical practice and hippocampal function. AB - The field of autoimmune encephalitides associated with antibodies targeting cell surface antigens is rapidly expanding and new antibodies are discovered frequently. Typical clinical presentations include cognitive deficits, psychiatric symptoms, movement disorders and seizures and the majority of patients respond well to immunotherapy. Pathophysiological mechanisms and clinical features are increasingly recognized and indicate hippocampal dysfunction in most of these syndromes. Here, we review the neuroimaging characteristics of autoimmune encephalitides, including N-methyl-d-aspartate (NMDA) receptor, leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) encephalitis as well as more recently discovered and less frequent forms such as dipeptidyl-peptidase-like protein 6 (DPPX) or glycine receptor encephalitis. We summarize findings of routine magnetic resonance imaging (MRI) investigations as well as (18)F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) and single photon emission tomography (SPECT) imaging and relate these observations to clinical features and disease outcome. We furthermore review results of advanced imaging analyses such as diffusion tensor imaging, volumetric analyses and resting-state functional MRI. Finally, we discuss contributions of these neuroimaging observations to the understanding of the pathophysiology of autoimmune encephalitides. PMID- 26012493 TI - Subcutaneous infection caused by Blastoschizomyces capitatus post allogeneic hematopoietic transplant and its successful treatment with voriconazole. AB - We describe a 33-year-old man with relapsed acute myelogenous leukemia who developed subcutaneous nodules >6 months after allogeneic hematopoietic stem cell transplant. These nodules were caused by Blastoschizomyces capitatus. The lesions progressed after treatment with a posaconazole suspension. The lesions resolved after switching to voriconazole, which was given for 21 weeks. B. capitatus is a rare infection affecting immunocompromised patients, which responds to azoles. PMID- 26012494 TI - Cytoplasmic-genetic male sterility gene provides direct evidence for some hybrid rice recently evolving into weedy rice. AB - Weedy rice infests paddy fields worldwide at an alarmingly increasing rate. There is substantial evidence indicating that many weedy rice forms originated from or are closely related to cultivated rice. There is suspicion that the outbreak of weedy rice in China may be related to widely grown hybrid rice due to its heterosis and the diversity of its progeny, but this notion remains unsupported by direct evidence. We screened weedy rice accessions by both genetic and molecular marker tests for the cytoplasmic male sterility (CMS) genes (Wild abortive, WA, and Boro type, BT) most widely used in the production of indica and japonica three-line hybrid rice as a diagnostic trait of direct parenthood. Sixteen weedy rice accessions of the 358 tested (4.5%) contained the CMS-WA gene; none contained the CMS-BT gene. These 16 accessions represent weedy rices recently evolved from maternal hybrid rice derivatives, given the primarily maternal inheritance of this trait. Our results provide key direct evidence that hybrid rice can be involved in the evolution of some weedy rice accessions, but is not a primary factor in the recent outbreak of weedy rice in China. PMID- 26012495 TI - Rapid Cationization of Gold Nanoparticles by Two-Step Phase Transfer. AB - Cationic gold nanoparticles offer intriguing opportunities as drug carriers and building blocks for self-assembled systems. Despite major progress on gold nanoparticle research in general, the synthesis of cationic gold particles larger than 5 nm remains a major challenge, although these species would give a significantly larger plasmonic response compared to smaller cationic gold nanoparticles. Herein we present the first reported synthesis of cationic gold nanoparticles with tunable sizes between 8-20 nm, prepared by a rapid two-step phase-transfer protocol starting from simple citrate-capped particles. These cationic particles form ordered self-assembled structures with negatively charged biological components through electrostatic interactions. PMID- 26012496 TI - Neutral amine based alcohol-soluble interface materials for inverted polymer solar cells: realizing high performance and overcoming solvent erosion. AB - Three amino-functionalized fluorene oligomers with different solubility were developed as cathode interfacial materials for inverted polymer solar cells (I PSCs). By side chain design, we solved the interface layer erosion problem for I PSCs, and the devices exhibit a power conversion efficiency as high as 8.94%. PMID- 26012497 TI - Molecular methods (digital PCR and real-time PCR) for the quantification of low copy DNA of Phytophthora nicotianae in environmental samples. AB - BACKGROUND: Currently, real-time polymerase chain reaction (qPCR) is the technique most often used to quantify pathogen presence. Digital PCR (dPCR) is a new technique with the potential to have a substantial impact on plant pathology research owing to its reproducibility, sensitivity and low susceptibility to inhibitors. In this study, we evaluated the feasibility of using dPCR and qPCR to quantify Phytophthora nicotianae in several background matrices, including host tissues (stems and roots) and soil samples. RESULTS: In spite of the low dynamic range of dPCR (3 logs compared with 7 logs for qPCR), this technique proved to have very high precision applicable at very low copy numbers. The dPCR was able to detect accurately the pathogen in all type of samples in a broad concentration range. Moreover, dPCR seems to be less susceptible to inhibitors than qPCR in plant samples. Linear regression analysis showed a high correlation between the results obtained with the two techniques in soil, stem and root samples, with R(2) = 0.873, 0.999 and 0.995 respectively. CONCLUSIONS: These results suggest that dPCR is a promising alternative for quantifying soil-borne pathogens in environmental samples, even in early stages of the disease. PMID- 26012498 TI - Tetrazepam Allergy: A Case Series of Cutaneous Adverse Events. PMID- 26012502 TI - A Comprehensive Structural Overview of p38alpha MAPK in Complex with Type I Inhibitors. AB - p38alpha mitogen-activated protein kinase (MAPK) is a well-recognized therapeutic target for the treatment of autoimmune and inflammatory diseases. Over the past two decades, tremendous efforts have been focused on the discovery and development of small-molecule p38alpha MAPK inhibitors, although currently no drugs targeting this protein are clinically available. Therefore, the identification of novel chemotypes that are able to inhibit p38alpha MAPK function is still of great therapeutic significance. With the objective to support drug discovery programs aimed at identifying new immunomodulators acting on p38alpha MAPK, herein we present a complete overview of the available crystal structures of this protein in complex with ATP-site type I inhibitors. The 85 available complexes are classified by chemotype and experimental binding mode, and the ligand-protein interactions are discussed using the most representative inhibitors. The type and frequency of key inhibitor features are analyzed to give a final summary of the chemical requirements of promising p38alpha MAPK inhibitors. The proposed pharmacophore can be exploited to enhance the opportunities to identify novel type I inhibitors of p38alpha MAPK. PMID- 26012503 TI - Identifying fasciculation potentials in motor neuron disease: A matter of probability. AB - INTRODUCTION: Fasciculations, the spontaneous activity of single motor units (MUs) are characteristic, but nonspecific for motor neuron disease (MND). We aimed to identify MU discharge properties to optimally differentiate MND patients from healthy controls. METHODS: High-density surface electromyography recordings were performed in the thenar muscles during 10 min of rest. MU discharges were classified as "isolated" when the interspike intervals (ISIs) before and after were > 250 ms, "continual" when both ISIs were <= 250 ms, or as "other". RESULTS: In patients (n = 30) compared with controls (n = 14), more MUs were active (9 vs. 3, P < 0.001) and generated relatively more isolated discharges (35% vs. 10%, P = 0.01). Two or more MUs with isolated discharges occurred more frequently in patients compared with controls (24% vs. <1% of 10-s windows, P < 0.001). CONCLUSIONS: More frequent occurrence of multiple MUs showing isolated discharges may improve identification of patients with MND. PMID- 26012499 TI - Incidence of severe hypoglycaemic episodes in patients with type 2 diabetes in the Basque country: impact on healthcare costs. AB - BACKGROUND: Hypoglycaemia is an acute complication of diabetes mellitus which poses a serious threat. This study aims to describe the annual rate of people suffering episodes of severe hypoglycaemia and to estimate the healthcare costs for individuals who have suffered such events. METHODS: A descriptive study involving all patients with type 2 diabetes (T2DM) from the Basque Country (period: 1/09/2010 to 31/08/2011) aged >=35 years (N = 134,413). The rate of hypoglycaemic episodes treated in hospitals (Accident and Emergency and in patient services) was calculated using an algorithm based on diagnostics and laboratory tests. The variables recorded included demographic, comorbidity (diagnoses categorised using the Adjusted Clinical Groups case-mix system) and socioeconomic variables (deprivation index of the area of residence). The annual healthcare cost for people with T2DM who suffered those episodes was compared with those who did not by regression analysis. RESULTS: The incidence of hypoglycaemia in the Basque Country was 0.56 %. This percentage was higher among women and people with a lower socioeconomic status. These episodes were associated with age and high values of glycosylated haemoglobin (HbA1c) > 7 %. Adjusting for the other variables, on average, people who suffered hypoglycaemia accounted for an additional ?2509 in annual healthcare costs. CONCLUSIONS: Hypoglycaemia has high morbi-mortality and a major economic impact. As such, health services must monitor its appearance and promote specific actions, especially in the higher risk sub-populations. PMID- 26012504 TI - Antioxidants and K+ channel agonists versus hydrogen therapy during ex vivo lung perfusion?. PMID- 26012505 TI - The need to regulate non-clinical hospital managers. PMID- 26012506 TI - School Performance and Neurodevelopment of Very Low Birth Weight Preterm Infants: First Report From Turkey. AB - Very low birth weight preterm infants are under significant risk of neurologic, developmental, and somatic problems. In this study, 90 infants born with a birth weight <1500 g and/or with a gestational age <32 weeks were evaluated after the first year of elementary school to assess neurodevelopment. The Wechsler Intelligence Scale for Children-Revised (WISC-R) test, Pediatric Symptom Checklist, and Parent Evaluation of Developmental Status were performed. Mental retardation, cerebral palsy, blindness, epilepsy, and posthemorrhagic hydrocephaly incidences were 14%, 7%, 2%, 5%, and 2%, respectively. The WISC-R score of 32 patients (35.5%) were below 85. Perinatal asphyxia, abnormal neurologic examination, and delayed or impaired speech correlated significantly with low WISC-R scores. Education and income of the father had positive impact on WISC-R scores (P = .042 and P = .026). Parents' concern and presence of cognitive problems were correlated (P = .026). Environmental factors, as well as the prevention of morbidity, affected school performance positively. PMID- 26012507 TI - Intracranial Hypertension Without Papilledema in Children. AB - This study aims to determine the frequency of intracranial hypertension without papilledema in children. Charts of patients evaluated in a pediatric intracranial hypertension clinic at our institution were retrospectively reviewed. The patients were divided into 2 groups depending on whether they had presence or absence of optic nerve edema at the time of presentation. Age, body mass index, and opening cerebrospinal fluid pressures were considered continuous variables and compared by Wilcoxon rank sum test because of non-normality. A P-value of 0.05 was considered significant. A total of 228 charts were reviewed; 152 patients met the criteria for intracranial hypertension, and 27 patients (17.8%) met the criteria of headache without optic nerve edema. There was no clinically significant difference in age, body mass index, opening pressure, and modified opening pressure between the 2 groups. PMID- 26012508 TI - Psychiatric considerations in the oncology setting. AB - An aging population and advances in diagnostics and treatment have resulted in a rapidly growing population of people impacted by cancer. People live longer after a cancer diagnosis and tolerate more aggressive treatments than in the past. Younger patients struggle with diversions from the normal developmental milestones in career and relationships, while older patients deal with the dual challenges of aging and cancer. Cancer's transition from likely death to survival has increased interest in its impact on psychosocial issues and quality of life, rather than just longevity. In this article, the authors review the psychiatric diagnosis and management of the mental health issues most often encountered in oncology. Oncology treatment teams, including oncologists, nurses, social workers, and other ancillary staff, are often on the front lines of addressing psychiatric distress and clinical syndromes when psychiatrists are not easily available. The purpose of this review article is to highlight opportunities for nonpsychiatrists to improve identification and treatment of psychosocial distress and psychiatric syndromes and to request formal psychiatric consultation in appropriate situations. Psychotherapeutic, psychopharmacologic, cognitive, and behavioral-oriented interventions, as well as supportive interventions, are discussed for treating patients who are facing challenges during active cancer treatment, survivorship, and at the end of life. This review is not exhaustive but highlights the more common psychosomatic medicine and palliative care scenarios that impact cancer patient care. The importance of recognizing and addressing burnout and compassion fatigue in multidisciplinary professionals who care for those treated for cancer is also discussed given the secondary impact this can have on patient care. PMID- 26012509 TI - Determination of pseudoprotodioscin in rat plasma by UPLC-MS/MS: Assay development and application to pharmacokinetic study. AB - An original and sensitive ultraperformance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method for the determination of pseudoprotodioscin (PPD) in rat plasma was developed and validated. Digitoxin was applied as an internal standard. Plasma samples were processed by acetonitrile-mediated plasma protein precipitation and chromatographed using a step gradient program on a C18 column (2.1*50mm i.d., 1.7MUm). The mobile phase was comprised of acetonitrile and 0.1mmolL(-1) aqueous lithium acetate mixed with 0.03% formic acid at the flow rate of 0.2mLmin(-1). Multiple reaction monitoring (MRM) transitions were performed for detection and lithium adduct ions were employed with a significant improvement of the response of the analytes in electrospray positive ionization mode. The concentration range of calibration curve was linear over the range 2 5000ngmL(-1). The intra- and inter-day precisions were all less than 11.5% and accuracies were within the range of 94.1-103.5%, and the analytes exhibited no severe matrix effect. The validated method was successfully applied in the pharmacokinetics of PPD after intragastric (50mgkg(-1)) and intravenous (4mgkg( 1)) administration in rats. PPD showed rapid excretion and with bioavailability of simply about 5.7% in rats. PMID- 26012511 TI - Quantifying the dynamics of light tolerance in Arabidopsis plants during ontogenesis. AB - The amount of light plants can tolerate during different phases of ontogenesis remains largely unknown. This was addressed here employing a novel methodology that uses the coefficient of photochemical quenching (qP) to assess the intactness of photosystem II reaction centres. Fluorescence quenching coefficients, total chlorophyll content and concentration of anthocyanins were determined weekly during the juvenile, adult, reproductive and senescent phases of plant ontogenesis. This enabled quantification of the protective effectiveness of non-photochemical fluorescence quenching (NPQ) and determination of light tolerance. The light intensity that caused photoinhibition in 50% of leaf population increased from ~70 MUmol m(-2) s(-1) , for 1-week-old seedlings, to a maximum of 1385 MUmol m(-2) s(-1) for 8-week-old plants. After 8 weeks, the tolerated light intensity started to gradually decline, becoming only 332 MUmol m(-2) s(-1) for 13-week-old plants. The dependency of light tolerance on plant age was well-related to the amplitude of protective NPQ (pNPQ) and the electron transport rates (ETRs). Light tolerance did not, however, show a similar trend to chlorophyll a/b ratios and content of anthocyanins. Our data suggest that pNPQ is crucial in defining the capability of high light tolerance by Arabidopsis plants during ontogenesis. PMID- 26012510 TI - Mechanism of regulation of stem cell differentiation by matrix stiffness. AB - Stem cell behaviors are regulated by multiple microenvironmental cues. As an external signal, mechanical stiffness of the extracellular matrix is capable of governing stem cell fate determination, but how this biophysical cue is translated into intracellular signaling remains elusive. Here, we elucidate mechanisms by which stem cells respond to microenvironmental stiffness through the dynamics of the cytoskeletal network, leading to changes in gene expression via biophysical transduction signaling pathways in two-dimensional culture. Furthermore, a putative rapid shift from original mechanosensing to de novo cell derived matrix sensing in more physiologically relevant three-dimensional culture is pointed out. A comprehensive understanding of stem cell responses to this stimulus is essential for designing biomaterials that mimic the physiological environment and advancing stem cell-based clinical applications for tissue engineering. PMID- 26012512 TI - Influence of Xanthan-Curdlan Hydrogel Complex on Freeze-Thaw Stability and Rheological Properties of Whey Protein Isolate Gel over Multiple Freeze-Thaw Cycle. AB - The effect of adding xanthan-curdlan hydrogel complex (XCHC) at 2 concentrations (0.25 and 0.5% w/w) on the freeze-thaw stability of heat-induced whey protein isolate (WPI) gel was investigated. Samples were stored at 4 degrees C for 24 h before subjected to 5 freeze-thaw cycles alternating between -16 degrees C (18 h) and 25 degrees C (6 h). Adding XCHC to the WPI solution resulted in the reduction of a significant amount of syneresis up to 5 repeated freeze-thaw cycles. Addition of XCHC decreased the amount of syneresis from 45% in the control sample (pure WPI gel) to 31.82% and 5.44% in the samples containing 0.25% and 0.5% gum, respectively, after the 5th freeze-thaw cycle. XCHC increased the storage modulus (G') of the gels and minimized the changes of the G' values over the 5 freeze-thaw cycles, indicating improvement of the stability of the system. Furthermore, the minimum protein concentration for gel formation decreased in the presence of the XCHC. Scanning electron microscopy (SEM) images showed that addition of XCHC resulted in the formation of a well-structured gel with numerous small pores in the network, which consequently improved the water retention ability during the temperature abuses up to 5 freeze-thaw cycles. These results have important implications for using XCHC in the formulation of the frozen WPI based products with improved freeze-thaw stability and rheological properties. PRACTICAL APPLICATION: Application of XCHC in the formulation of frozen dairy based food products has the potential to enhance freeze-thaw stability and minimize moisture migration caused by temperature abuses of the products during distribution and consumer application. PMID- 26012513 TI - Sexual rest and post-meiotic sperm ageing in house mice. AB - Fertilization by aged sperm can result in adverse fitness consequences for both males and females. Sperm storage during male sexual rest could provide an environment for post-meiotic sperm senescence causing a deterioration in the quality of stored sperm, possibly impacting on both sperm performance (e.g. swimming ability) and DNA quality. Here, we compared the proportion of sperm with fragmented DNA, an indicator of structural damage of DNA within the sperm cell, among males that had been sexually rested for approximately 2 months, to that of males that had mated recently. We found no evidence of intra-epididymal sperm DNA damage or any impairment in sperm performance, and consequently no evidence of post-meiotic sperm senescence. Our results suggest that male house mice are likely to possess mechanisms that function to ensure that their sperm reserves remain stocked with 'young', viable sperm during periods of sexual inactivity. We also discuss the possibility that our experimental design leads to no difference in the age of sperm among males from the two mating treatments. Post-meiotic sperm senescence is especially relevant under sperm competition. Thus, we sourced mice from populations that differed in their levels of post-copulatory sexual selection, enabling us to gain insight into how selection for higher sperm production influences the rate of sperm ageing and levels of DNA fragmentation. We found that males from the population that produced the highest number of sperm also had the smallest proportion of DNA-fragmented sperm and discuss this outcome in relation to selection acting upon males to ensure that they produce ejaculates with high-quality sperm that are successful in achieving fertilizations under competitive conditions. PMID- 26012514 TI - The history of trying to fix liver allocation: why a consensus approach will never work. PMID- 26012515 TI - The Effects of an Academic--Workplace Partnership Intervention to Promote Physical Activity in Sedentary Office Workers. AB - This study was designed to determine the effect of an academic-workplace partnership intervention, "3,000 more steps," on improving physical activity (PA) and body composition of workers, and compare the characteristics of those workers who completed and did not complete the program. Participants were 70 sedentary office workers from an airline company. Pedometers determined their daily steps, and body composition was compared before and after the 8-week intervention; 39 of 70 (55.7%) participants completed the program. Daily steps increased from 5,811 to 9,240, and fat mass, waist-hip ratio, and body mass index (BMI) decreased for the completers. Non-completers had lower average PA and higher average fat mass at baseline than did completers. Overall, a workplace PA program could be successfully undertaken by occupational health nurses and a research team in partnership. However, to implement a cost-effective intervention program for inactive workers, further research is needed to ascertain why some workers do not complete the program. PMID- 26012516 TI - Awareness and Utilization of Welders' Personal Protective Eye Devices and Associated Factors: Findings and Lessons From a Nigerian Population. AB - This study assessed commercial welders' awareness and utilization of personal protective eye devices (PPEDs), and their associations, in Enugu, Nigeria, between January and March, 2011. The participants included 343 males, age 33.9 years+/-10.0 SD years. The participants reported high awareness of welding associated ocular hazards (99.4%) and PPEDs (75.2%-98.3%), but low PPED possession and utilization rates. Cost and "presumed lack of utility" were the leading barriers to PPED possession; non-utilization was mainly attributed to "user inconvenience" and "presumed lack of protective benefit." PPED utilization was significantly associated with lower educational status (p=.030) and electric welding (p<.0001). The underlying causes are amenable to preventive occupational eye health education, enhanced ergonomics and affordability of PPEDs, and legislative enforcement of their use. PMID- 26012517 TI - Exploring Physical Health in a Sample of Firefighters. AB - Firefighters' work responsibilities involve strenuous physical activity and exposure to extremely stressful situations. The purpose of this research study was to describe the physical activity, stress, and culture promoting or inhibiting a healthy work environment. A descriptive qualitative study design was used with a convenience sample of firefighters from an urban Midwestern public fire service. Respondents participated in focus groups from which data were audio recorded, transcribed verbatim, and analyzed using Colaizzi's phenomenological method. Themes derived from the data were Stressors Affecting Physical Health, Barriers to Physical Health, Facilitators of Physical Health, and Motivators for Physical Health. Future research is needed to test interventions based on the study findings. PMID- 26012518 TI - Two siblings with cortical dysplasia: Clinico-electroencephalographic features. AB - The older of two siblings began to have spasms and partial seizures at 1 month of age. Head magnetic resonance imaging showed an abnormal area in the left temporo parieto-occipital region. Interictal electroencephalogram (EEG) showed a suppression-burst pattern. Adrenocorticotropic hormone stopped the spasms, but the seizures continued. Clonazepam, carbamazepine, zonisamide, and clobazam were ineffective. She underwent focal resection at age 8 months. Postoperatively, the seizures disappeared. Histopathologically, the lesion appeared to be focal cortical dysplasia type IIa. The younger sibling had spasms from birth. Head magnetic resonance imaging showed left hemi-megalencephaly. Interictal EEG showed a suppression-burst pattern. Phenobarbital, valproic acid, and zonisamide were ineffective. He underwent hemispherotomy at age 2 months and became seizure free. The histopathological features were consistent with those of hemi-megalencephaly. The siblings' EEG and clinical courses had some similarities. These siblings' conditions may have the same genetic background. PMID- 26012519 TI - Frequency-Specific Neural Signatures of Spontaneous Low-Frequency Resting State Fluctuations in Psychosis: Evidence From Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Consortium. AB - BACKGROUND: We quantified frequency-specific, absolute, and fractional amplitude of low-frequency fluctuations (ALFF/fALFF) across the schizophrenia (SZ) psychotic bipolar disorder (PBP) psychosis spectrum using resting functional magnetic resonance imaging data from the large BSNIP family study. METHODS: We assessed 242 healthy controls (HC), 547 probands (180 PBP, 220 SZ, and 147 schizoaffective disorder-SAD), and 410 of their first-degree relatives (134 PBPR, 150SZR, and 126 SADR). Following standard preprocessing in statistical parametric mapping (SPM8), we computed absolute and fractional power (ALFF/fALFF) in 2 low frequency bands: slow-5 (0.01-0.027 Hz) and slow-4 (0.027-0.073 Hz). We evaluated voxelwise post hoc differences across traditional Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic categories. RESULTS: Across ALFF/fALFF, in contrast to HC, BP/SAD showed hypoactivation in frontal/anterior brain regions in the slow-5 band and hypoactivation in posterior brain regions in the slow-4 band. SZ showed consistent hypoactivation in precuneus/cuneus and posterior cingulate across both bands and indices. Increased ALFF/fALFF was noted predominantly in deep subcortical and temporal structures across probands in both bands and indices. Across probands, spatial ALFF/fALFF differences in SAD resembled PBP more than SZ. None of these ALFF/fALFF differences were detected in relatives. CONCLUSIONS: Results suggest ALFF/fALFF is a putative biomarker rather than a familial endophenotype. Overall sensitivity to discriminate proband brain alteration was stronger for fALFF than ALFF. Patterns of differences noted in SAD were more similar to those observed in PBP. Differential effects were noted across the 2 frequency bands, more prominently for BP/SAD compared with SZ, suggesting frequency-sensitive physiologic mechanisms for the former. PMID- 26012520 TI - Reduced SP1-mediated transcriptional activation decreases expression of intestinal folate transporters in response to ethanol exposure. AB - SCOPE: The study was designed to identify the regulatory mechanisms underlying the effects of ethanol exposure on intestinal folate transport and to investigate the reversibility of such effects. METHODS AND RESULTS: Caco-2 cells were grown in control and ethanol containing medium for 96 h. Thereafter, one subgroup of cells was shifted on ethanol free medium and grown for next 72 h. For in vivo studies, rats were given 1g ethanol/kg body weight/day either for 3 or 5 months and after 3 months of ethanol treatment, one group of rats received no ethanol for 2 months. A significant decrease in folic acid transport as well as expression of folate transporters was observed on ethanol treatment and the effects were reversible upon removal of ethanol. Ethanol exposure had no impact on CpG island methylation of the folate transporters however, an increase in their mRNA half-life was observed that seems to be a homeostatic mechanism. Chromatin immunoprecipitation assay revealed a decrease in binding of SP1 transcription factor to the promoter regions of folate transporters. CONCLUSION: Reduced binding of SP1 to the promoter region of folate transporters may be a part of the regulatory mechanism resulting in decreased expression of folate transporters on ethanol exposure. PMID- 26012521 TI - MicroRNA-155 Regulates ROS Production, NO Generation, Apoptosis and Multiple Functions of Human Brain Microvessel Endothelial Cells Under Physiological and Pathological Conditions. AB - The microRNA-155 (miR155) regulates various functions of cells. Dysfunction or injury of endothelial cells (ECs) plays an important role in the pathogenesis of various vascular diseases. In this study, we investigated the role and potential mechanisms of miR155 in human brain microvessel endothelial cells (HBMECs) under physiological and pathological conditions. We detected the effects of miR155 silencing on ROS production, NO generation, apoptosis and functions of HBMECs at basal and in response to oxidized low density lipoprotein (ox-LDL). Western blot and q-PCR were used for analyzing the gene expression of epidermal growth factor receptor (EGFR)/extracellular regulated protein kinases (ERK)/p38 mitogen activated protein kinase (p38 MAPK), phosphatidylinositol-3-kinase (PI3K) and serine/threonine kinase(Akt), activated caspase-3, and intercellular adhesion molecule-1 (ICAM-1). Results showed that under both basal and challenge situations: (1) Silencing of miR155 decreased apoptosis and reactive oxygen species (ROS) production of HBMECs, whereas, promoted nitric oxide (NO) generation. (2) Silencing of miR155 increased the proliferation, migration, and tube formation ability of HBMECs, while decreased cell adhesion ability. (3) Gene expression analyses showed that EGFR/ERK/p38 MAPK and PI3K/Akt were increased and that activated caspase-3 and ICAM-1 mRNA were decreased after knockdown of miR155. In conclusion, knockdown of miR155 could modulate ROS production, NO generation, apoptosis and function of HBMECs via regulating diverse gene expression, such as caspase-3, ICAM-1 and EGFR/ERK/p38 MAPK and PI3K/Akt pathways. PMID- 26012522 TI - Copper-Catalyzed Oxy-Alkenylation of Homoallylic Alcohols to Generate Functional syn-1,3-Diol Derivatives. AB - A novel method for the synthesis of a wide range of functionalized 1,3-diol derivatives is reported. Employing a copper-catalyzed oxy-alkenylation strategy, a range of readily available, substituted homoallylic alcohol derivatives and alkenyl(aryl) iodonium salts combine to form syn-1,3-carbonates in excellent yield and with high selectivity. Furthermore, the products formed are amenable to an iterative reaction sequence, thus affording highly complex polyketide-like fragments. PMID- 26012523 TI - Financial conflicts of interest and their association with outcome and quality of fibromyalgia drug therapy randomized controlled trials. AB - AIMS: To evaluate the association of financial conflicts of interest (FCOI) with the characteristics, outcome and reported methodological quality of fibromyalgia drug therapy randomized controlled trials (FM-RCTs). METHODS: A cross-sectional study of original, parallel-group, drug therapy FM-RCTs published between 1997 and 2011 from Medline and Cochrane Central Register of Controlled Trials was conducted. Two reviewers independently assessed each RCT for funding source, authors' FCOI(s), study characteristics, reporting of methodological measures important for internal validity and outcome (positive [statistically significant result favoring experimental drug for the primary outcome] or non-positive). RESULTS: Forty-seven RCTs were eligible with funding source as: 26 (55.3%) industry; eight (17%) non-profit source(s); five (10.6%) mixed; and eight (17%) unspecified. Industry-funded RCTs were more likely to be multicenter and enroll greater number of patients. Reporting of key methodological measures was suboptimal; however, industry and non-profit funded RCTs did not differ in their reporting. Thirty (63.8%) RCTs had >= one author who disclosed an FCOI (receipt of research grant [21, 44.7%], industry sponsor employee [20, 42.6%], receipt of consultancy fee/honorarium [16, 34%] and stock ownership [11, 23.4%]). Although industry funding and certain authors' FCOIs (employment and receipt of consultancy fee/honorarium) were univariately associated with positive outcome, such association was not observed after adjusting for study sample size. CONCLUSIONS: The majority of FM-RCTs were industry-sponsored, and had at least one author with an FCOI. Reporting of key methodological measures was suboptimal. After adjusting for study sample size, no association of industry funding or author's FCOI with study outcome was seen. PMID- 26012524 TI - Halogen-Bond-Assisted Guest Inclusion in a Synthetic Cavity. AB - The confined space inside a self-assembled cage enhanced halogen bonding (XB) between iodoperfluorocarbons (XB donors) and NO3(-) anions or H2O molecules (XB acceptors), as confirmed by NMR spectroscopy in solution and by X-ray crystallography in the solid state. The cavity also bound an XB donor-acceptor pair, C6F3I3 and C6H5NMe2, in a selective pairwise fashion. PMID- 26012525 TI - Structured illumination microscopy reveals focal adhesions are composed of linear subunits. AB - The ability to mechanically interact with the extracellular matrix is a fundamental feature of adherent eukaryotic cells. Cell-matrix adhesion in many cell types is mediated by protein complexes called focal adhesions (FAs). Recent progress in super resolution microscopy revealed FAs possess an internal organization, yet such methods do not enable observation of the formation and dynamics of their internal structure in living cells. Here, we combine structured illumination microscopy (SIM) with total internal reflection fluorescence microscopy (TIRF) to show that the proteins inside FA patches are distributed along elongated subunits, typically 300 +/- 100 nm wide, separated by 400 +/- 100 nm, and individually connected to actin cables. We further show that the formation and dynamics of these linear subunits are intimately linked to radial actin fiber formation and actomyosin contractility. We found FA growth to be the result of nucleation of new linear subunits and their coordinated elongation. Taken together, this study reveals that the basic units of mature focal adhesion are 300-nm-wide elongated, dynamic structures. We anticipate this ultrastructure to be relevant to investigation of the function of FAs and their behavior in response to mechanical stress. PMID- 26012526 TI - Quantification of periodic breathing in premature infants. AB - Periodic breathing (PB), regular cycles of short apneic pauses and breaths, is common in newborn infants. To characterize normal and potentially pathologic PB, we used our automated apnea detection system and developed a novel method for quantifying PB. We identified a preterm infant who died of sudden infant death syndrome (SIDS) and who, on review of her breathing pattern while in the neonatal intensive care unit (NICU), had exaggerated PB.We analyzed the chest impedance signal for short apneic pauses and developed a wavelet transform method to identify repetitive 10-40 second cycles of apnea/breathing. Clinical validation was performed to distinguish PB from apnea clusters and determine the wavelet coefficient cutoff having optimum diagnostic utility. We applied this method to analyze the chest impedance signals throughout the entire NICU stays of all 70 infants born at 32 weeks' gestation admitted over a two-and-a-half year period. This group includes an infant who died of SIDS and her twin.For infants of 32 weeks' gestation, the fraction of time spent in PB peaks 7-14 d after birth at 6.5%. During that time the infant that died of SIDS spent 40% of each day in PB and her twin spent 15% of each day in PB.This wavelet transform method allows quantification of normal and potentially pathologic PB in NICU patients. PMID- 26012527 TI - Comparison of postoperative estimated glomerular filtration rate between kidney donors and radical nephrectomy patients, and risk factors for postoperative chronic kidney disease. AB - OBJECTIVES: To compare post-nephrectomy renal function between kidney donors and renal cell carcinoma patients, to evaluate trends in recovery, and to identify factors relevant to renal failure. METHODS: Patients who had radical or donor nephrectomy from four different institutions between 2003 and 2012 were reviewed. Propensity score matching was carried out and 79 patients were selected for each group. The estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula preoperatively and postoperatively at 1, 3, 6, 12, 24 and 36 months. Mean estimated glomerular filtration rate was compared, and the difference between preoperative values and each preceding date was calculated. A multivariate logistic regression was used to determine independent factors for a decrease in estimated glomerular filtration rate to <60 mL/min/1.73 m(2) . RESULTS: The donor nephrectomy group showed a trend of improved estimated glomerular filtration rate recovery at 24 months and 36 months compared with the radical nephrectomy group, which was statistically significant (P = 0.028, P = 0.012). Multivariate logistic regression showed that renal cell carcinoma (odds ratio 4.605, 95% confidence interval 1.626-13.040, P = 0.004), a baseline estimated glomerular filtration rate lower than 110 (odds ratio 4.477, 95% confidence interval 1.360-14.742, P = 0.014) and age older than 40 years (odds ratio 21.616, 95% confidence interval 2.761-169.222, P = 0.003) were predictive factors for a decrease in renal function. CONCLUSIONS: Renal cell carcinoma is an independent risk factor for chronic kidney disease after nephrectomy. In addition, age older than 40 years and a baseline estimated glomerular filtration rate of 110 mL/min/1.73 m(2) or less seem to represent risk factors associated with chronic kidney disease after nephrectomy. PMID- 26012528 TI - Ni-Catalyzed Asymmetric Cycloisomerization of Dienes by Using TADDOL Phosphoramidites. AB - A library of alpha,alpha,alpha,alpha-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites has been synthesized and applied in the Ni catalyzed cycloisomerization of different dienes. Through the systematic variation of the three structural motifs of the lead structure, that is, the amine moiety, the protecting group, and the aryl substituents, the ligand features could be optimized for the asymmetric cycloisomerization of the model substrate diethyl diallylmalonate. The substrate scope of the new catalytic system was extended to other diallylic substrates, including unsymmetrical dienes. Overall remarkably high activities of up to approximately 13 500 h(-1) , very high selectivities toward five-membered exo-methylenecyclopentanes, and enantioselectivities of up to 92 % ee have been achieved. PMID- 26012529 TI - A large-scale field trial of thin-layer capping of PCDD/F-contaminated sediments: Sediment-to-water fluxes up to 5 years post-amendment. AB - The longer-term effect (3-5 y) of thin-layer capping on in situ sediment-to surface water fluxes was monitored in a large-scale field experiment in the polychlorinated dibenzodioxin and dibenzofuran (PCDD/F) contaminated Grenlandfjords, Norway (4 trial plots of 10,000 to 40,000 m(2) at 30 to 100 m water depth). Active caps (designed thickness 2.5 cm) were established in 2 fjords, consisting of dredged clean clay amended with powdered activated carbon (PAC) from anthracite. These active caps were compared to 2 nonactive caps in one of the fjords (designed thickness 5 cm) consisting of either clay only (i.e., without PAC) or crushed limestone. Sediment-to-water PCDD/F fluxes were measured in situ using diffusion chambers. An earlier study showed that during the first 2 years after thin-layer capping, flux reductions relative to noncapped reference fields were more extensive at the fields capped with nonactive caps (70%-90%) than at the ones with PAC-containing caps (50%-60%). However, the present work shows that between 3 and 5 years after thin-layer capping, this trend was reversed and cap effectiveness in reducing fluxes was increasing to 80% to 90% for the PAC caps, whereas cap effectiveness of the nonactive caps decreased to 20% to 60%. The increasing effectiveness over time of PAC-containing "active" caps is explained by a combination of slow sediment-to-PAC mass transfer of PCDD/Fs and bioturbation by benthic organisms. The decreasing effectiveness of "nonactive" limestone and clay caps is explained by deposition of contaminated particles on top of the caps. The present field data indicate that the capping efficiency of thin active caps (i.e., enriched with PAC) can improve over time as a result of slow diffusive PCDD/F transfer from sediment to PAC particles and better mixing of the PAC by bioturbation. PMID- 26012530 TI - TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting. AB - We hypothesised that the genetic effect of single nucleotide polymorphisms in the TACR1 gene, which encodes NK1 receptors, could influence the sex difference in postoperative nausea and vomiting. Thirty-two selected single nucleotide polymorphisms were genotyped by the Sanger sequencing method in 200 patients who underwent lower abdominal surgery. The incidence and severity of postoperative nausea and vomiting were evaluated after surgery. The rs3755468-SNP showed significant association with the incidence and severity of postoperative nausea and vomiting (p = 0.016). The TT haplotype defined by two single nucleotide polymorphisms, including the rs3755468-SNP, was associated with reduced incidence and severity of postoperative nausea and vomiting in female patients (p = 0.03). The rs3755468-SNP is located within the predicted oestrogen response element and a DNase I hypersensitive site. The single nucleotide polymorphisms in the TACR1 gene are associated with sex differences in postoperative nausea and vomiting and may help to elucidate the mechanisms underlying these differences. PMID- 26012531 TI - Amphiphilic Organic-Inorganic Hybrid Zeotype Aluminosilicate like a Nanoporous Crystallized Langmuir-Blodgett Film. AB - A new organic-inorganic hybrid zeotype compound with amphiphilic one-dimensional nanopore and aluminosilicate composition was developed. The framework structure is composed of double aluminosilicate layers and 12-ring nanopores; a hydrophilic layer pillared by Q(2) silicon atom species and a lipophilic layer pillared by phenylene groups are alternately stacked, and 12-ring nanopores perpendicularly penetrate the layers. The framework topology looks similar to that of an AFI-type zeolite but possesses a quasi-multidimensional pore structure consisting of a 12 ring channel and intersecting small pores equivalent to 8-rings. The hybrid material with alternately laminated lipophilic and hydrophilic nanospaces can be assumed as a crystallized Langmuir-Blodgett film. It demonstrates microporous adsorption for both hydrophilic and lipophilic adsorptives, and its outer surface tightly adsorbs lysozyme whose molecular size is much larger than its micropore opening. Our results suggest the possibility of designing porous adsorbent with high amphipathicity. PMID- 26012532 TI - Heterogeneous copper concentrations in cancerous human prostate tissues. AB - BACKGROUND: Therapeutics that target copper for the treatment of prostate cancer are being evaluated in human clinical trials. Elevated intracellular copper is considered to sensitize prostate cancer cells to certain copper-coordination compounds, especially those with ionophoric properties. While there is compelling in vitro evidence that prostate cancer cells accumulate intracellular copper, a corresponding status for copper in patient tissues has not been corroborated. We therefore established whether copper concentrations increase in cancerous prostate tissues, and in sera, in patients throughout disease progression. METHODS: Human prostate tissue samples were obtained from patient prostatectomies (n = 28), and together with patient-matched sera, were analyzed for copper content by inductively coupled plasma mass spectrometry. RESULTS: When grouped together, cancerous prostate tissues exhibiting moderate disease severity (Gleason Score 7) (n = 10) had 1.6-fold more copper than age-matched normal tissues (n = 10) (P < 0.05). Those with more aggressive disease (Gleason Score 9) (n = 8) had 1.8-fold more copper (P < 0.05). In both disease stages however, the copper concentrations between individual samples were rather variable (0.55-3.02 MUg/g), with many clearly within the normal range (0.52-1.28 MUg/g). Additionally, we found that there was no change in serum copper concentrations in patients with either moderate or aggressive prostate cancer (Gleason Score 7 or 9), compared with reference intervals and to age-matched controls. CONCLUSIONS: The heterogeneous nature of copper concentrations in cancerous prostate tissues, suggest that a small subset of patients may respond to treatments that target elevated intratumoral copper. Therefore, such approaches would likely require personalized treatment strategies. PMID- 26012533 TI - The Incorporation of an Advanced Donation Program Into Kidney Paired Exchange: Initial Experience of the National Kidney Registry. AB - The continued growth of kidney paired donation (KPD) to facilitate transplantation for otherwise incompatible or suboptimal living kidney donors and recipients has depended on a balance between the logistics required for patients and the collaborating transplant centers. The formation of chains for KPD and the shipping of kidneys have permitted networks such as the National Kidney Registry (NKR) to offer KPD to patients over a transcontinental area. However, over the last 3 years, we have encountered patient requests for a more flexible experience in KPD to meet their individual needs often due to rigid time constraints. To accommodate these requests, we have developed an Advanced Donation Program (ADP) in which the donor desires to donate by a specific date, but their paired recipient has not yet been matched to a specific donor or scheduled for surgery. After obtaining careful informed consent from both the donor and paired recipient, 10 KPD chains were constructed using an ADP donor. These 10 ADP donors have facilitated 47 transplants, and thus far eight of their paired recipients have received a kidney within a mean of 178 (range 10-562) days. The ADP is a viable method to support time limited donors in a KPD network. PMID- 26012534 TI - Hydrodynamic and Thermophoretic Effects on the Supramolecular Chirality of Pyrene Derived Nanosheets. AB - Chiroptical properties of two-dimensional (2D) supramolecular assemblies (nanosheets) of achiral, charged pyrene trimers (Py3 ) are rendered chiral by asymmetric physical perturbations. Chiral stimuli in a cuvette can originate either from controlled temperature gradients or by very gentle stirring. The chiroptical activity strongly depends on the degree of supramolecular order of the nanosheets, which is easily controlled by the method of preparation. The high degree of structural order ensures strong cooperative effects within the aggregates, rendering them more susceptible to external stimuli. The samples prepared by using slow thermal annealing protocols are both CD and LD active (in stagnant and stirred solutions), whereas for isothermally aged samples chiroptical activity was in all cases undetectable. In the case of temperature gradients, the optical activity of 2D assemblies could be recorded for a stagnant solution due to migration of the aggregates from the hottest to the coldest regions of the system. However, a considerably stronger exciton coupling, coinciding with the J-band of the interacting pyrenes, is developed upon subtle vortexing (0.5 Hz, 30 rpm) of the aqueous solution of the nanosheets. The sign of the exciton coupling is inverted upon switching between clockwise and counter clockwise rotation. The supramolecular chirality is evidenced by the appearance of CD activity. To exclude artefacts from proper CD spectra, the contribution from LD to the observed CD was determined. The data suggest that the aggregates experience asymmetrical deformation and alignment effects because of the presence of chiral flows. PMID- 26012535 TI - Plant growth-promoting effects of native Pseudomonas strains on Mentha piperita (peppermint): an in vitro study. AB - Plant growth-promoting rhizobacteria (PGPR) affect growth of host plants through various direct and indirect mechanisms. Three native PGPR (Pseudomonas putida) strains isolated from rhizospheric soil of a Mentha piperita (peppermint) crop field near Cordoba, Argentina, were characterised and screened in vitro for plant growth-promoting characteristics, such as indole-3-acetic acid (IAA) production, phosphate solubilisation and siderophore production, effects of direct inoculation on plant growth parameters (shoot fresh weight, root dry weight, leaf number, node number) and accumulation and composition of essential oils. Each of the three native strains was capable of phosphate solubilisation and IAA production. Only strain SJ04 produced siderophores. Plants directly inoculated with the native PGPR strains showed increased shoot fresh weight, glandular trichome number, ramification number and root dry weight in comparison with controls. The inoculated plants had increased essential oil yield (without alteration of essential oil composition) and biosynthesis of major essential oil components. Native strains of P. putida and other PGPR have clear potential as bio-inoculants for improving productivity of aromatic crop plants. There have been no comparative studies on the role of inoculation with native strains on plant growth and secondary metabolite production (specially monoterpenes). Native bacterial isolates are generally preferable for inoculation of crop plants because they are already adapted to the environment and have a competitive advantage over non-native strains. PMID- 26012536 TI - Risk assessment by client and case manager for shared decision making in outpatient forensic psychiatry. AB - BACKGROUND: In outpatient forensic psychiatry, assessment of re-offending risk and treatment needs by case managers may be hampered by an incomplete view of client functioning. The client's appreciation of his own problem behaviour is not systematically used for these purposes. The current study tests whether using a new client self-appraisal risk assessment instrument, based on the Short Term Assessment of Risk and Treatability (START), improves the assessment of re offending risk and can support shared decision making in care planning. METHODS: In a sample of 201 outpatient forensic psychiatric clients, feasibility of client risk assessment, concordance with clinician assessment, and predictive validity of both assessments for violent or criminal behaviour were studied. RESULTS: Almost all clients (98 %) were able to fill in the instrument. Agreement between client and case manager on the key risk and protective factors of the client was poor (mean kappa for selection as key factor was 0.15 and 0.09, respectively, and mean correlation on scoring -0.18 and 0.20). The optimal prediction model for violent or criminal behaviour consisted of the case manager's structured professional risk estimate for violence in combination with the client's self appraisal on key risk and protective factors (AUC = 0.70; 95%CI: 0.60-0.80). CONCLUSIONS: In outpatient forensic psychiatry, self-assessment of risk by the client is feasible and improves the prediction of re-offending. Clients and their case managers differ in their appraisal of key risk and protective factors. These differences should be addressed in shared care planning. The new Client Self Appraisal based on START (CSA) risk assessment instrument can be a useful tool to facilitate such shared care planning in forensic psychiatry. PMID- 26012537 TI - One-year clinical outcomes after sirolimus-eluting coronary stent implantation in diabetics enrolled in the worldwide e-SELECT registry. AB - BACKGROUND: Diabetes mellitus has worse outcome after percutaneous coronary intervention. AIM: We assessed stent thrombosis (ST), major adverse cardiac events (MACE), and major bleeding rates at 1 year after implantation of sirolimus eluting stents (SES) in patients with diabetes mellitus in a large multicenter registry. METHODS: From May 2006 to April 2008, 15,147 unselected consecutive patients were enrolled at 320 centers in 56 countries in a prospective, observational registry after implantation of >= 1 SES. Source data were verified in 20% randomly chosen patients at > 100 sites. Adverse events were adjudicated by an independent Clinical Event Committee. RESULTS: Complete follow-up at 1 year was obtained in 13,693 (92%) patients, 4,577 (30%) of whom were diabetics. Within diabetics, 1,238 (9%) were insulin-treated diabetics (ITD). Diabetics were older (64 vs. 62 years, P < 0.001), with higher incidence of major coronary risk factors, co-morbidities, and triple-vessel coronary artery disease. Coronary lesions had smaller reference vessel diameter (2.88 +/- 0.46 vs. 2.93 +/- 0.45 mm, P < 0.001) and were more often heavily calcified (26.1% vs. 22.6%, P < 0.001). At 1 year, diabetics had higher MACE rate (6.8% vs. 3.9%, P < 0.001) driven by ITD (10.6% vs. 5.5%, P < 0.001). Finally, diabetics had significant increase in ST (1.7% vs. 0.7%, P < 0.001), principally owing to ITD (3.4% vs. 1.1%, P < 0.001). There was an overall low risk of major bleeding during follow up, without significant difference among subgroups. CONCLUSIONS: In the e-SELECT registry, diabetics represented 30% of patients undergoing SES implantation and had significantly more co-morbidities and complex coronary lesions. Although 1 year follow-up documented good overall outcome in diabetics, higher ST and MACE rates were observed, mainly driven by ITD. (c) 2015 Wiley Periodicals, Inc. PMID- 26012538 TI - Multistimuli-Responsive, Moldable Supramolecular Hydrogels Cross-Linked by Ultrafast Complexation of Metal Ions and Biopolymers. AB - A new type of multistimuli-responsive hydrogels cross-linked by metal ions and biopolymers is reported. By mixing the biopolymer chitosan (CS) with a variety of metal ions at the appropriate pH values, we obtained a series of transparent and stable hydrogels within a few seconds through supramolecular complexation. In particular, the CS-Ag hydrogel was chosen as the model and the gelation mechanism was revealed by various measurements. It was found that the facile association of Ag(+) ions with amino and hydroxy groups in CS chains promoted rapid gel-network formation. Interestingly, the CS-Ag hydrogel exhibits sharp phase transitions in response to multiple external stimuli, including pH value, chemical redox reactions, cations, anions, and neutral species. Furthermore, this soft matter showed a remarkable moldability to form shape-persistent, free-standing objects by a fast in situ gelation procedure. PMID- 26012539 TI - Correction: Membranes linked by trans-SNARE complexes require lipids prone to non bilayer structure for progression to fusion. PMID- 26012540 TI - Evaluation of the expression pattern of rAAV2/1, 2/5, 2/7, 2/8, and 2/9 serotypes with different promoters in the mouse visual cortex. AB - This study compared the expression pattern, laminar distribution, and cell specificity of several rAAV serotypes (2/1, 2/5, 2/7, 2/8, and 2/9) injected in the primary visual cortex (V1) of adult C57Bl/6J mice. In order to obtain specific expression in certain neuron subtypes, different promoter sequences were evaluated for excitatory cell specificity: a universal cytomegalovirus (CMV) promoter, and two versions of the excitatory neuron-specific Ca(2+) /calmodulin dependent kinase subunit alpha (CaMKIIalpha) promoter, CaMKIIalpha 0.4 and CaMKIIalpha 1.3. The spatial distribution as well as the cell type specificity was immunohistochemically verified. Depending on the rAAV serotype used, the transduced volume expressing reporter protein differed substantially (rAAV2/5 ? 2/7 ~ 2/9 ~ 2/8 ? 2/1). Excitatory neuron-specific targeting was promoter dependent, with a surprising difference between the 1.3 kb and 0.4 kb CaMKIIalpha promoters. While CaMKIIalpha 1.3 and CMV carrying vectors were comparable, with 78% of the transduced neurons being excitatory for CMV and 82% for CaMKIIalpha 1.3, the shorter CaMKIIalpha 0.4 version resulted in 95% excitatory specificity. This study therefore puts forward the CaMKIIalpha 0.4 promoter as the best choice to target excitatory neurons with rAAVs. Together, these results can be used as an aid to select the most optimal vector system to deliver transgenes into specific rodent neocortical circuits, allowing further elucidation of their functions. PMID- 26012541 TI - Tricycloundecane Derivatives as Potential N-Methyl-D-aspartate (NMDA) Receptor and Voltage-Gated Calcium Channel Modulators. AB - Neurodegenerative disorders are debilitating conditions characterised by progressive dysfunction and death of neuronal cells. Amidst the proposed mechanisms of neurodegeneration, the effects of excitotoxicity via N-methyl-D aspartate (NMDA) receptor stimulation and activation of voltage-gated calcium channels (VGCC) on neuronal cells are prominent. This has led to the development of polycyclic cage molecules such as NGP1-01, which exhibit neuroprotective properties through NMDA receptor and VGCC modulation. The medicinal potential of structurally related tricycloundecanes that are open-cage or rearranged polycyclic moieties has not been explored. This study is therefore focused on the synthesis of a series of novel tricycloundecane derivatives and their ability to inhibit NMDA receptors and VGCC. Significant NMDA receptor inhibition was observed for tricyclo[6.2.1.0(2,7) ]undec-9-ene-3,6-dione (4, 78%) and 6 hydroxytricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (5, >95%) at a concentration of 100 MUM. The highest inhibitory activity was observed for 6 (benzylimino)tricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (9, >95%), which is in the same range as the inhibitory activity of MK-801 (dizocilpine). In the VGCC inhibition assay, 6-(benzylamino)tricyclo[6.2.1.0(2,7) ]undeca-4,9-dien-3-one (8, 34%), 9 (38%) and 2-(benzylamino)-3,6-epoxytricyclo[6.2.1.0(5,10) ]undecan-9-ol (12, 40%) showed statistically significant (p<0.05) VGCC inhibition. PMID- 26012542 TI - Corrigendum. PMID- 26012543 TI - Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion. AB - INTRODUCTION: We describe a 6-year-old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2-p12) resulting in a severe sensorimotor polyneuropathy. METHODS: This study is a case report in which the relevant mutations are described. RESULTS: Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found when the patient was age 6 years. Nerve conduction studies showed evidence of a sensorimotor polyneuropathy and compressive mononeuropathies of bilateral median nerves at the wrist and ulnar nerves at the elbow. Genetic testing revealed deletion of a PMP22 allele and T118M PMP22 mutation in the remaining allele. CONCLUSIONS: The severe sensorimotor polyneuropathy and hereditary neuropathy with liability to pressure palsies (HNPP) in this patient was likely a consequence of both decreased expression of PMP22 causing features consistent with HNPP and unopposed expression of the T118M mutant form of PMP22 that is relatively benign in the heterozygous state. The T118M mutant form of PMP22 can be disease-modifying in the appropriate circumstances. PMID- 26012544 TI - Does Diet-Induced Weight Loss Lead to Bone Loss in Overweight or Obese Adults? A Systematic Review and Meta-Analysis of Clinical Trials. AB - Diet-induced weight loss has been suggested to be harmful to bone health. We conducted a systematic review and meta-analysis (using a random-effects model) to quantify the effect of diet-induced weight loss on bone. We included 41 publications involving overweight or obese but otherwise healthy adults who followed a dietary weight-loss intervention. The primary outcomes examined were changes from baseline in total hip, lumbar spine, and total body bone mineral density (BMD), as assessed by dual-energy X-ray absorptiometry (DXA). Secondary outcomes were markers of bone turnover. Diet-induced weight loss was associated with significant decreases of 0.010 to 0.015 g/cm(2) in total hip BMD for interventions of 6, 12, or 24 (but not 3) months' duration (95% confidence intervals [CIs], -0.014 to -0.005, -0.021 to -0.008, and -0.024 to -0.000 g/cm(2), at 6, 12, and 24 months, respectively). There was, however, no statistically significant effect of diet-induced weight loss on lumbar spine or whole-body BMD for interventions of 3 to 24 months' duration, except for a significant decrease in total body BMD (-0.011 g/cm(2); 95% CI, -0.018 to -0.003 g/cm(2)) after 6 months. Although no statistically significant changes occurred in serum concentrations of N-terminal propeptide of type I procollagen (P1NP), interventions of 2 or 3 months in duration (but not of 6, 12, or 24 months' duration) induced significant increases in serum concentrations of osteocalcin (0.26 nmol/L; 95% CI, 0.13 to 0.39 nmol/L), C-terminal telopeptide of type I collagen (CTX) (4.72 nmol/L; 95% CI, 2.12 to 7.30 nmol/L) or N-terminal telopeptide of type I collagen (NTX) (3.70 nmol/L; 95% CI, 0.90 to 6.50 nmol/L bone collagen equivalents [BCEs]), indicating an early effect of diet-induced weight loss to promote bone breakdown. These data show that in overweight and obese individuals, a single diet-induced weight-loss intervention induces a small decrease in total hip BMD, but not lumbar spine BMD. This decrease is small in comparison to known metabolic benefits of losing excess weight. PMID- 26012545 TI - Open reduction and internal fixation aided by intraoperative 3-dimensional imaging improved the articular reduction in 72 displaced acetabular fractures. AB - BACKGROUND AND PURPOSE: During acetabular fracture surgery, the acetabular roof is difficult to visualize with 2-dimensional fluoroscopic views. We assessed whether intraoperative 3-dimensional (3D) imaging can aid the surgeon to achieve better articular reduction and improve implant fixation. PATIENTS AND METHODS: We operated on 72 acetabular fractures using intraoperative 3D imaging and compared the operative results, duration of surgery, and complications with those for 42 consecutive acetabular fracture operations conducted using conventional fluoroscopic imaging. Postoperative reduction was evaluated on reconstructed coronal and sagittal images of the acetabulum. RESULTS: The fracture severity and patient characteristics were similar in the 2 groups. In the 3D group, 46 of 72 patients (0.6) had a perfect result after open reduction and internal fixation, and in the control group, 17 of 42 (0.4) had a perfect result. The mean difference in postoperative articular incongruity was 0.5 mm (95% CI: 0.4-0.7). In 29 of 72 operations, the intraoperative 3D scans led to intraoperative correction of the reduction and an improved result. The duration of surgery and infection rate were similar in the 2 groups. INTERPRETATION: Intraoperative 3D imaging, which is not time-consuming, allowed the surgeon to correct malreductions and screw placement in 29 of 72 operations, leading to better articular reduction and more precise screw placement than in operations where conventional fluoroscopic imaging was used to control the reduction. PMID- 26012546 TI - Precision of radiostereometric analysis (RSA) of acetabular cup stability and polyethylene wear improved by adding tantalum beads to the liner. AB - BACKGROUND AND PURPOSE: In traditional radiostereometric analysis (RSA), 1 segment defines both the acetabular shell and the polyethylene liner. However, inserting beads into the polyethylene liner permits employment of the shell and liner as 2 separate segments, enabling distinct analysis of the precision of 3 measurement methods in determining femoral head penetration and shell migration. PATIENTS AND METHODS: The UmRSA program was used to analyze the double examinations of 51 hips to determine if there was a difference in using the shell only segment, the liner-only segment, or the shell + liner segment to measure wear and acetabular cup stability. The standard deviation multiplied by the critical value (from a t distribution) established the precision of each method. RESULTS: Due to the imprecision of the automated edge detection, the shell-only method was least desirable. The shell + liner and liner-only methods had a precision of 0.115 mm and 0.086 mm, respectively, when measuring head penetration. For shell migration, the shell + liner had a precision of 0.108 mm, which was better than the precision of the shell-only method. In both the penetration and migration analyses, the shell + liner condition number was statistically significantly lower and the bead count was significantly higher than for the other methods. INTERPRETATION: Insertion of beads in the polyethylene improves the precision of femoral head penetration and shell migration measurements. A greater dispersion and number of beads when combining the liner with the shell generated more reliable results in both analyses, by engaging a larger portion of the radiograph. PMID- 26012547 TI - Knee arthroscopies: who gets them, what does the radiologist report, and what does the surgeon find? An evaluation from southern Sweden. AB - BACKGROUND AND PURPOSE: Several randomized controlled trials have not shown any added benefit of arthroscopy over placebo surgery or physiotherapy in middle-aged patients with knee symptoms without trauma. We studied the characteristics of the knee arthroscopies performed in southern Sweden. PATIENTS AND METHODS: From the orthopedic surgical records from 2007-2009 in the Skane region of Sweden (with a population of 1.2 million), we retrieved ICD-10 diagnostic codes and selected all 4,096 arthroscopies that were diagnosed peroperatively with code M23.2 (derangement of meniscus due to old tear or injury) or code M17 (knee osteoarthritis). We extracted information on cartilage and meniscus status at arthroscopy, and we also randomly sampled 502 of these patients from the regional archive of radiology and analyzed the preoperative prevalence of radiographic or magnetic resonance imaging (MRI)-defined osteoarthritis. RESULTS: 2,165 (53%) of the 4,096 arthroscopies had the diagnostic code M23.2 or M17. In this subgroup, 1,375 cases (64%) had typical findings consistent with degenerative meniscal tear (i.e. that correspond to a degenerative meniscal tear in at least a third of all arthroscopies). Of the randomly sampled patients, the preoperative prevalence of radiological knee osteoarthritis was 46%. INTERPRETATION: There is a discrepancy between evidence-based medicine treatment guidelines and clinical practice regarding the amount of knee arthroscopies performed in patients with symptoms of degenerative knee disease. PMID- 26012548 TI - Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62 Triggered Keap1 Degradation. AB - Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway. PMID- 26012549 TI - Bimodal Interaction of Mammalian Polo-Like Kinase 1 and a Centrosomal Scaffold, Cep192, in the Regulation of Bipolar Spindle Formation. AB - Serving as microtubule-organizing centers, centrosomes play a key role in forming bipolar spindles. The mechanism of how centrosomes promote bipolar spindle assembly in various organisms remains largely unknown. A recent study with Xenopus laevis egg extracts suggested that the Plk1 ortholog Plx1 interacts with the phospho-T46 (p-T46) motif of Xenopus Cep192 (xCep192) to form an xCep192 mediated xAurA-Plx1 cascade that is critical for bipolar spindle formation. Here, we demonstrated that in cultured human cells, Cep192 recruits AurA and Plk1 in a cooperative manner, and this event is important for the reciprocal activation of AurA and Plk1. Strikingly, Plk1 interacted with Cep192 through either the p-T44 (analogous to Xenopus p-T46) or the newly identified p-S995 motif via its C terminal noncatalytic polo-box domain. The interaction between Plk1 and the p-T44 motif was prevalent in the presence of Cep192-bound AurA, whereas the interaction of Plk1 with the p-T995 motif was preferred in the absence of AurA binding. Notably, the loss of p-T44- and p-S995-dependent Cep192-Plk1 interactions induced an additive defect in recruiting Plk1 and gamma-tubulin to centrosomes, which ultimately led to a failure in proper bipolar spindle formation and mitotic progression. Thus, we propose that Plk1 promotes centrosome-based bipolar spindle formation by forming two functionally nonredundant complexes with Cep192. PMID- 26012550 TI - Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells. AB - We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression. PMID- 26012553 TI - Increased risk of melanoma in organ transplant recipients: systematic review and meta-analysis of cohort studies. AB - Transplant recipients have a raised risk of melanoma but the relative magnitude is uncertain. We undertook a systematic review by searching major databases for relevant publications to June 2014. Cohort studies quantifying the association between transplantation and melanoma were included and data were pooled using the weighted average method. Among 20 eligible studies the pooled relative risk (pRR) of melanoma was 2.71 (95% confidence interval (CI), 2.23-3.30) with significant heterogeneity (p < 0.001). There was no indication of publication bias. Sub-group analyses by study design, follow-up period, adjustment for confounding and quality score did not materially alter results. Among liver and heart transplant patients pRR for melanoma was 5.27 (95% CI 4.50-6.62), higher than the pRR of 2.54 (95% CI 2.18-2.96) among kidney transplant patients. Transplant recipients are at more than double the risk of melanoma overall compared with the general population. PMID- 26012551 TI - Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes. AB - Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1alpha and HIF2alpha under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2alpha or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2alpha activation. HIF2alpha also induces the expression of HIF3alpha, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2alpha-EpoHE cascade in vivo. PMID- 26012552 TI - The Lineage-Specific Transcription Factor PU.1 Prevents Polycomb-Mediated Heterochromatin Formation at Macrophage-Specific Genes. AB - Lineage-specific transcription factors (TFs) are important determinants of cellular identity, but their exact mode of action has remained unclear. Here we show using a macrophage differentiation system that the lineage-specific TF PU.1 keeps macrophage-specific genes accessible during differentiation by preventing Polycomb repressive complex 2 (PRC2) binding to transcriptional regulatory elements. We demonstrate that the distal enhancer of a gene becomes bound by PRC2 as cells differentiate in the absence of PU.1 binding and that the gene is wrapped into heterochromatin, which is characterized by increased nucleosome occupancy and H3K27 trimethylation. This renders the gene inaccessible to the transcriptional machinery and prevents induction of the gene in response to an external signal in mature cells. In contrast, if PU.1 is bound at the transcriptional regulatory region of a gene during differentiation, PRC2 is not recruited, nucleosome occupancy is kept low, and the gene can be induced in mature macrophages. Similar results were obtained at the enhancers of other macrophage-specific genes that fail to bind PU.1 as an estrogen receptor fusion (PUER) in this system. These results show that one role of PU.1 is to exclude PRC2 and to prevent heterochromatin formation at macrophage-specific genes. PMID- 26012554 TI - Role of Chemistry in Earth's Climate. PMID- 26012555 TI - The real obstacles to collaborative and affordable healthcare in the UK. PMID- 26012556 TI - Cascading costs of reproduction in female house wrens induced to lay larger clutches. AB - In many species, females produce fewer offspring than they are capable of rearing, possibly because increases in current reproductive effort come at the expense of a female's own survival and future reproduction. To test this, we induced female house wrens (Troglodytes aedon) to lay more eggs than they normally would and assessed the potential costs of increasing cumulative investment in the three main components of the avian breeding cycle - egg laying, incubation and nestling provisioning. Females with increased clutch sizes reared more offspring in the first brood than controls, but fledged a lower proportion of nestlings. Moreover, nestlings of experimental females were lighter than those of control females as brood size and prefledging mass were negatively correlated. In second broods of the season, when females were not manipulated, experimental females laid the same number of eggs as controls, but experienced an intraseasonal cost through reduced hatchling survival and a lower number of young fledged. Offspring of control and experimental females were equally likely to recruit to the breeding population, although control females produced more recruits per egg laid. The reproductive success of recruits from broods of experimental and control females did not differ. The manipulation also induced interseasonal costs to future reproduction, as experimental females had lower fecundity than controls when breeding at least 2 years after having their reproductive effort experimentally increased. Finally, females producing the modal clutch size of seven eggs in their first broods had the highest lifetime number of fledglings. PMID- 26012558 TI - Subunits B'gamma and B'zeta of protein phosphatase 2A regulate photo-oxidative stress responses and growth in Arabidopsis thaliana. AB - Plants survive periods of unfavourable conditions with the help of sensory mechanisms that respond to reactive oxygen species (ROS) as signalling molecules in different cellular compartments. We have previously demonstrated that protein phosphatase 2A (PP2A) impacts on organellar cross-talk and associated pathogenesis responses in Arabidopsis thaliana. This was evidenced by drastically enhanced pathogenesis responses and cell death in cat2 pp2a-b'gamma double mutants, deficient in the main peroxisomal antioxidant enzyme CATALASE 2 and PP2A regulatory subunit B'gamma (PP2A-B'gamma). In the present paper, we explored the impacts of PP2A-B'gamma and a highly similar regulatory subunit PP2A-B'zeta in growth regulation and light stress tolerance in Arabidopsis. PP2A-B'gamma and PP2A-B'zeta display high promoter activities in rapidly growing tissues and are required for optimal growth under favourable conditions. Upon acclimation to a combination of high light, elevated temperature and reduced availability of water, however, pp2a-b'gammazeta double mutants grow similarly to the wild type and show enhanced tolerance against photo-oxidative stress. We conclude that by controlling ROS homeostasis and signalling, PP2A-B'gamma and PP2A-B'zeta may direct acclimation strategies upon environmental perturbations, hence acting as important determinants of defence responses and light acclimation in plants. PMID- 26012557 TI - Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage. AB - BACKGROUND: Rett syndrome (RTT) is one of the most prevalent neurodevelopmental disorders in females, caused by de novo mutations in the X-linked methyl CpG binding protein 2 gene, MECP2. Although abnormal regulation of neuronal genes due to mutant MeCP2 is thought to induce autistic behavior and impaired development in RTT patients, precise cellular mechanisms underlying the aberrant neural progression remain unclear. RESULTS: Two sets of isogenic pairs of either wild type or mutant MECP2-expressing human induced pluripotent stem cell (hiPSC) lines were generated from a single pair of 10-year-old RTT-monozygotic (MZ) female twins. Mutant MeCP2-expressing hiPSC lines did not express detectable MeCP2 protein during any stage of differentiation. The lack of MeCP2 reflected altered gene expression patterns in differentiated neural cells rather than in undifferentiated hiPSCs, as assessed by microarray analysis. Furthermore, MeCP2 deficiency in the neural cell lineage increased astrocyte-specific differentiation from multipotent neural stem cells. Additionally, chromatin immunoprecipitation (ChIP) and bisulfite sequencing assays indicated that anomalous glial fibrillary acidic protein gene (GFAP) expression in the MeCP2 negative, differentiated neural cells resulted from the absence of MeCP2 binding to the GFAP gene. CONCLUSIONS: An isogenic RTT-hiPSC model demonstrated that MeCP2 participates in the differentiation of neural cells. Moreover, MeCP2 deficiency triggers perturbation of astrocytic gene expression, yielding accelerated astrocyte formation from RTT-hiPSC-derived neural stem cells. These findings are likely to shed new light on astrocytic abnormalities in RTT, and suggest that astrocytes, which are required for neuronal homeostasis and function, might be a new target of RTT therapy. PMID- 26012559 TI - Association of parental education with tooth loss among Korean Elders. AB - OBJECTIVE: There are few reports showing an association between childhood socioeconomic circumstances and tooth loss among the elderly. The purpose of this study was (i) to examine the association between early childhood socioeconomic position (parental education level) and tooth loss and (ii) to determine the relative effects of the subjects' education level, occupation, and income on tooth loss in Korean elders. MATERIAL AND METHODS: Data from the fourth and fifth Korea National Health and Nutritional Examination Survey on 8814 Korean elders (age >=65 years) were analyzed. Demographic factors (age, survey year, marital status, and residence area), health behaviors (dental check-up during the past year and cigarette smoking), and the presence of a somatic health problem (diabetes) were included in our gender-specific analyses. Tooth loss was defined as edentulism or severe tooth loss (<20 teeth). For our analyses, chi-square test and Student's t-tests and multiple logistic regressions were performed. RESULTS: A low parental education level was associated with elevated odds of edentulism (OR = 1.87 for father's education and 1.52 for mother's education among male elders and OR = 1.73 for father's education and 1.55 for mother's education among female elders) and with severe tooth loss (OR = 1.58 for father's education and 1.53 for mother's education among male elders and OR = 1.25 for father's education and 1.48 for mother's education among female elders). The association between parental education level and tooth loss was attenuated after adjusting for the subject's education level, occupation, and income. Relative magnitude of attenuation varied with personal factors (education > income > occupation). In a fully adjusted model, father's education level was significantly associated with edentate status (OR = 1.96 for male elders and 1.46 for female elders), but not with severe tooth loss. CONCLUSION: Our results indicate that early life socioeconomic circumstances measured by the father's education level were independently associated with the edentate status of Korean elders. PMID- 26012560 TI - Virus-templated FRET platform for the rational design of ratiometric fluorescent nanosensors. AB - We report here the construction of a bacteriophage M13-templated supramolecular nanosystem, i.e. M13-beta-CD/Ada-FITC/Ada-RhB, which can be used as effective ratiometric fluorescent sensors for intracellular sensing. PMID- 26012561 TI - Extracorporeal cardiopulmonary resuscitation for breath-holding spells followed by cardiac arrest due to left main coronary artery stenosis. AB - Non-syndromic congenital supravalvular aortic stenosis (SVAS) leads to ventricular hypertrophy and increased oxygen consumption, and when combined with other factors reduces coronary blood flow, potentially resulting in myocardial ischemia and sudden cardiac death. While the anatomic obstruction of coronary circulation is as common in non-syndromic SVAS as in Williams syndrome, it often remains unacknowledged. Extracorporeal membrane oxygenation (ECMO) is an elective procedure that can be used to support patients with cardiac arrest during diagnosis as a way to reduce cardiopulmonary load in preparation for surgery or further treatment. In this report, we describe the rare case of an infant with severe SVAS and mild valvular pulmonary and left main coronary artery stenosis, as well as breath-holding spells. After multiple cardiac arrests, the infant underwent diagnostic catheter angiography on ECMO and had the pathology surgically corrected. PMID- 26012562 TI - Is photodynamic diagnostic flexible ureterorenoscopy suitable for a patient presenting with chronic actinic dermatitis? PMID- 26012563 TI - Health-related quality of life and tuberculosis: a longitudinal cohort study. AB - BACKGROUND: Active tuberculosis (TB) disease can impose substantial morbidity, while treatment for latent TB infection (LTBI) has frequent side effects. We compared health-related quality of life (HRQOL) between persons diagnosed and treated for TB disease, persons treated for LTBI, and persons screened but not treated for TB disease or LTBI, over one year following diagnosis/initial assessment. METHODS: Participants were recruited at two hospitals in Montreal (2008-2011), and completed the Short Form-36 version 2 (SF-36) at baseline, and at 1, 2, 4, 6, 9, and 12 months thereafter. Eight domain scores and physical and mental component summary (PCS and MCS, respectively) scores were calculated from responses. Linear mixed models were used to compare mean scores at each evaluation and changes in scores over consecutive evaluations, among participants treated for TB disease and those treated for LTBI, each compared to the control group. RESULTS: Of the 263 participants, 48 were treated for TB disease, 105 for LTBI, and 110 were control participants. Fifty-four percent were women, mean age was 35 years, and 90% were foreign-born. Participants treated for TB disease reported significantly worse mean scores at baseline compared to control participants (mean PCS scores: 50.0 vs. 50.7; mean MCS scores: 46.4 vs. 51.1), with improvement in mean MCS scores throughout the study period. Scores reported by participants treated for LTBI and control participants were comparable throughout the study. CONCLUSION: TB disease is associated with decrements in HRQOL as measured by the SF-36. This is most pronounced during the weeks after diagnosis and treatment initiation, but is no longer evident after two months. PMID- 26012567 TI - Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation induced intestinal cell death and reduces GVHD. AB - Inhibition of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) system reduces intestinal cell death and disease development in several models of colitis. In view of the crucial role of TNF and intestinal cell death in graft-versus-host disease (GVHD) and the ability of TWEAK to enhance TNF-induced cell death, we tested here the therapeutic potential of Fn14 blockade on allogeneic hematopoietic cell transplantation (allo-HCT)-induced intestinal GVHD. An Fn14-specific blocking human immunoglobulin G1 antibody variant with compromised antibody-dependent cellular cytotoxicity (ADCC) activity strongly inhibited the severity of murine allo-HCT-induced GVHD. Treatment of the allo-HCT recipients with this monoclonal antibody reduced cell death of gastrointestinal cells but neither affected organ infiltration by donor T cells nor cytokine production. Fn14 blockade also inhibited intestinal cell death in mice challenged with TNF. This suggests that the protective effect of Fn14 blockade in allo-HCT is based on the protection of intestinal cells from TNF-induced apoptosis and not due to immune suppression. Importantly, Fn14 blockade showed no negative effect on graft-versus leukemia/lymphoma (GVL) activity. Thus, ADCC-defective Fn14-blocking antibodies are not only possible novel GVL effect-sparing therapeutics for the treatment of GVHD but might also be useful for the treatment of other inflammatory bowel diseases where TNF-induced cell death is of relevance. PMID- 26012569 TI - The human microbiome in hematopoiesis and hematologic disorders. AB - Humans are now understood to be in complex symbiosis with a diverse ecosystem of microbial organisms, including bacteria, viruses, and fungi. Efforts to characterize the role of these microorganisms, commonly referred as the microbiota, in human health have sought to answer the fundamental questions of what organisms are present, how are they functioning to interact with human cells, and by what mechanism are these interactions occurring. In this review, we describe recent efforts to describe the microbiota in healthy and diseased individuals, summarize the role of various molecular technologies (ranging from 16S ribosomal RNA to shotgun metagenomic sequencing) in enumerating the community structure of the microbiota, and explore known interactions between the microbiota and humans, with a focus on the microbiota's role in hematopoiesis and hematologic diseases. PMID- 26012568 TI - Phosphatase Wip1 controls antigen-independent B-cell development in a p53 dependent manner. AB - Wild-type p53-induced phosphatase 1 (Wip1), a phosphatase previously considered as an oncogene, has been implicated in the regulation of thymus homeostasis and neutrophil maturation. However, the role of Wip1 in B-cell development is unknown. We show that Wip1-deficient mice exhibit a significant reduction of B cell numbers in the bone marrow, peripheral blood, and spleen. A reciprocal transplantation approach revealed a cell-intrinsic defect in early B-cell precursors caused by Wip1 deficiency. Further experiments revealed that Wip1 deficiency led to a sustained activation of p53 in B cells, which led to increased level of apoptosis in the pre-B-cell compartment. Notably, the impairment of B-cell development in Wip1-deficient mice was completely rescued by genetic ablation of p53, but not p21. Therefore, loss of Wip1 phosphatase induces a p53-dependent, but p21-independent, mechanism that impairs B-cell development by enhancing apoptosis in early B-cell precursors. Moreover, Wip1 deficiency exacerbated a decline in B-cell development caused by aging as evidenced in mice with aging and mouse models with serial competitive bone marrow transplantation, respectively. Our present data indicate that Wip1 plays a critical role in maintaining antigen-independent B-cell development in the bone marrow and preventing an aging-related decline in B-cell development. PMID- 26012571 TI - An Endovascular-First Approach to the Treatment of Critical Limb Ischemia Results in Superior Limb Salvage Rates. AB - PURPOSE: To evaluate the effect of a shift to a primary endovascular revascularization (ER) strategy for patients presenting with critical limb ischemia (CLI) after a change in staff at our center in 2008 altered our revascularization strategy. METHODS: Between 2004 and 2012, 344 critically ischemic limbs were treated in 279 patients (mean age 74.0+/-11.4 years; 179 men) during 546 separate hospital admissions. Limbs were analyzed according to (1) their principal revascularization strategy and (2) their date of presentation [early (2004-2008) or late (2008-2012)]. RESULTS: Compared with the open revascularization (OR) and no revascularization (NR) groups, the ER group had an increased freedom from major amputation (92.3% vs 80.0% OR vs 69.3% NR, p<0.001), reduced hospital stay (15.2 vs OR 31.6 vs NR 25.9 days, p<0.001), intensive care unit (ICU) stay (2.3 vs OR 23.7 vs NR 7.2 hours, p=0.033), and operating time for ER vs OR (157.9 vs 316.8 minutes, respectively; p<0.0001). There was also a significant decrease in limbs requiring minor amputations (23.2% vs OR 29.3% vs NR 37.6%, p=0.041) and mean number of admissions/limb compared to OR (1.5 vs OR 1.9 vs NR 1.5, p=0.007). The late era saw the treatment of a larger number of limbs (223 vs 121) compared with the earlier time period. This institutional shift resulted in increased freedom from major amputation (87.4% vs 74.4%, p<0.01), reduced ICU stay (3.45 vs 16.98 hours, p<0.01), and shorter length of stay (20.9 vs 31.5 days, p<0.01) between the 2 eras, respectively. CONCLUSION: A shift to an endovascular-first treatment strategy is associated with fewer major amputations and shorter length of stay. PMID- 26012570 TI - Hematopoietic stem cell transplantation for infantile osteopetrosis. AB - We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty four percent of transplants used grafts from HLA-matched siblings, 13% from HLA mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5- and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P = .01 and P = .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA matched sibling and 61% after alternative donor transplantation (P = .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed. PMID- 26012572 TI - Assessment of serum asymmetric dimethylarginine levels and left ventricular diastolic function in patients with ankylosing spondylitis. AB - AIM: To assess left ventricular diastolic functions and serum dimethylarginine (ADMA) concentrations, as well as the effect of different treatment strategies on ADMA concentrations and diastolic function parameters, in patients with ankylosing spondylitis (AS). METHOD: Sixty AS patients and 40 control subjects without classical cardiovascular (CV) risk factors were included in the study. Baseline clinical and echocardiographic variables were obtained. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and ADMA levels were measured. Spinal mobility, disease activity and functional status were assessed using Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index. RESULTS: CRP, ESR and ADMA levels were significantly higher in the AS group as compared to the control group. Two (5%) control subjects and six (10%) AS patients met the criteria for left ventricular diastolic dysfunction (DD) on conventional Doppler echocardiography, but the difference was not statistically significant (P = 0.36). However, using tissue Doppler imaging, 12 (20%) patients in the AS group and three (8%) subjects in the control group were diagnosed with left ventricular DD (P = 0.08). The anti-tumor necrosis factor (TNF)-alpha group, conventional therapy group and control group were compared in terms of ADMA, CRP, ESR levels and echocardiographic parameters. ADMA levels were significantly lower in anti TNF-alpha group as compared to the conventional therapy group (P < 0.001). In the control group, ADMA levels were significantly lower than both treatment groups (P < 0.001). CONCLUSION: Increased ADMA levels reveal impaired nitric oxide metabolism in a relatively young group of patients with AS, who have no classical CV risk factors. Anti-TNF-alpha may have beneficial effect on endothelial function in AS patients by reducing ADMA levels. PMID- 26012576 TI - Platelet-Rich Plasma Increases Growth and Motility of Adipose Tissue-Derived Mesenchymal Stem Cells and Controls Adipocyte Secretory Function. AB - Adipose tissue-derived mesenchymal stem cells (Ad-MSC) and platelet derivatives have been used alone or in combination to achieve regeneration of injured tissues. We have tested the effect of platelet-rich plasma (PRP) on Ad-MSC and adipocyte function. PRP increased Ad-MSC viability, proliferation rate and G1-S cell cycle progression, by at least 7-, 2-, and 2.2-fold, respectively, and reduced caspase 3 cleavage. Higher PRP concentrations or PRPs derived from individuals with higher platelet counts were more effective in increasing Ad-MSC growth. PRP also accelerated cell migration by at least 1.5-fold. However, PRP did not significantly affect mature adipocyte viability, differentiation and expression levels of PPAR-gamma and AP-2 mRNAs, while it increased leptin production by 3.5-fold. Interestingly, PRP treatment of mature adipocytes also enhanced the release of Interleukin (IL)-6, IL-8, IL-10, Interferon-gamma, and Vascular Endothelial Growth Factor. Thus, data are consistent with a stimulatory effect of platelet derivatives on Ad-MSC growth and motility. Moreover, PRP did not reduce mature adipocyte survival and increased the release of pro-angiogenic factors, which may facilitate tissue regeneration processes. PMID- 26012577 TI - Electroacupuncture for older adults with mild cognitive impairment: study protocol for a randomized controlled trial. AB - BACKGROUND: Mild cognitive impairment is an intermediary state between normal aging and clinical Alzheimer's disease. Early intervention of mild cognitive impairment may be an important strategy in the management of Alzheimer's disease. The proposal aims to evaluate if electroacupuncture would optimize cognitive function in subjects with mild cognitive impairment and understand the role of electroacupuncture in the treatment of Alzheimer's disease. METHODS/DESIGN: A randomised patient- and assessor-blind sham-controlled trial is designed to assess whether electroacupuncture intervention decreases the rate of cognitive decline amongst older adults with mild cognitive impairment. One hundred and fifty subjects aged 65 years of age or over with a diagnosis of mild cognitive impairment are recruited from the community and elderly centre in Hong Kong. All subjects are randomly allocated into two groups (75 subjects each group): the electroacupuncture group and sham control. Participants in the electroacupuncture group receive electroacupuncture stimulation by sterile, disposable acupuncture needles inserted to the acupoints with a depth of 1 to 3 cm. The acupuncture needles are subjected to 2 Hz electroacupuncture with an intensity of 5 to 10 mA. Each participant receives electroacupuncture for 8 weeks (once a day, 3 days a week) and the treatment lasts for 30 minutes each time. For sham electroacupuncture, needles are inserted to a depth of 1 to 2 mm, and connected to the electroacupuncture device without any current passing through. Outcome measures (including primary and secondary outcome measures) are collected at baseline, at the end day of intervention, and months 4 and 6 after intervention. The primary outcome is measured by the Alzheimer Disease Assessment Scale Cognitive subscale. Secondary outcomes are measured by the mini-mental state examination, category fluency text and the Short Form 12. DISCUSSION: The study will provide evidence for evaluating and understanding the role of electroacupuncture in the treatment of Alzheimer's disease. TRIAL REGISTRATION: This trial is registered with chictr.org (registration number: ChiCTR-TRC 12002414 . Registration date: 11 August 2012. PMID- 26012579 TI - Streptococcus pharyngis sp. nov., a novel streptococcal species isolated from the respiratory tract of wild rabbits. AB - Four isolates of an unknown Gram-stain-positive, catalase-negative coccus-shaped organism, isolated from the pharynx of four wild rabbits, were characterized by phenotypic and molecular genetic methods. The micro-organisms were tentatively assigned to the genus Streptococcus based on cellular morphological and biochemical criteria, although the organisms did not appear to correspond to any species with a validly published name. Comparative 16S rRNA gene sequencing confirmed their identification as members of the genus Streptococcus, being most closely related phylogenetically to Streptococcus porcorum 682-03(T) (96.9% 16S rRNA gene sequence similarity). Analysis of rpoB and sodA gene sequences showed divergence values between the novel species and S. porcorum 682-03(T) (the closest phylogenetic relative determined from 16S rRNA gene sequences) of 18.1 and 23.9%, respectively. The novel bacterial isolate could be distinguished from the type strain of S. porcorum by several biochemical characteristics, such as the production of glycyl-tryptophan arylamidase and alpha-chymotrypsin, and the non-acidification of different sugars. Based on both phenotypic and phylogenetic findings, it is proposed that the unknown bacterium be assigned to a novel species of the genus Streptococcus, and named Streptococcus pharyngis sp. nov. The type strain is DICM10-00796B(T) ( = CECT 8754(T) = CCUG 66496(T)). PMID- 26012578 TI - Full UPF3B function is critical for neuronal differentiation of neural stem cells. AB - BACKGROUND: Mutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins. RESULTS: Here we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets. CONCLUSIONS: Together our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation. PMID- 26012580 TI - Pontivivens insulae gen. nov., sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, non-motile and coccoid, ovoid or rod-shaped bacterial strain, designated GYSW-23(T), was isolated from seawater off Geoje island in the South Sea, South Korea. Strain GYSW-23(T) grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of approximately 2.0-3.0% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain GYSW-23(T) forms a distinct evolutionary lineage independent of other taxa of the family Rhodobacteraceae. It exhibited 16S rRNA gene sequence similarity values of 94.0, 93.5, 93.4 and 93.4% to the type strains of Roseovarius aestuarii, Ruegeria marina, Roseovarius pacificus and Oceanicola litoreus, respectively, and 93.6% to 'Actibacterium atlanticum' 22II-S11-z10. Strain GYSW-23(T) contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids of strain GYSW-23(T) were phosphatidylcholine, phosphatidylglycerol and one unidentified aminolipid. The fatty acid and polar lipid profiles of strain GYSW-23(T) were distinguishable from those of the phylogenetically related taxa. The DNA G+C content of strain GYSW-23(T) was 60.6 mol%. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain GYSW-23(T) is considered to represent a novel species of a new genus in the family Rhodobacteraceae, for which the name Pontivivens insulae gen. nov., sp. nov. is proposed. The type strain of Pontivivens insulae is GYSW-23(T) ( = KCTC 42458(T) = CECT 8812(T)). PMID- 26012581 TI - Mariniphaga sediminis sp. nov., isolated from coastal sediment. AB - A Gram-stain-negative and facultatively anaerobic bacterium, SY21(T), was isolated from marine sediments of the coastal area in Weihai, China (122 degrees 0' 37" E 37 degrees 31' 33" N). Cells of strain SY21(T) were 0.3-0.5 MUm wide and 1.5-2.5 MUm long, catalase- and oxidase-positive. Colonies on 2216E agar were transparent, beige- to pale-brown-pigmented, and approximately 0.5 mm in diameter. Growth occurred optimally at 33-37 degrees C, pH 7.0-7.5 and in the presence of 2-3% (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene indicated that strain SY21(T) was a member of the genus Mariniphaga within the family Prolixibacteraceae. The closest described neighbour in terms of 16S rRNA gene sequences identity was Mariniphaga anaerophila Fu11-5(T) (94.7%). The major respiratory quinone of strain SY21(T) was MK-7, and the dominant fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and anteiso-C15 : 0. The major polar lipids were phosphatidylethanolamine, aminolipid and an unidentified lipid, and the DNA G+C content was 37.9 mol%. The distinct phylogenetic position and phenotypic traits distinguished the novel isolate from M. anaerophila Fu11-5(T). Phenotypic and genotypic analysis indicated that strain SY21(T) could be assigned to the genus Mariniphaga. The name Mariniphaga sediminis sp. nov. is proposed, with the type strain SY21(T) ( = KCTC 42260(T) = MCCC 1H00107(T)). PMID- 26012582 TI - Diaphorobacter polyhydroxybutyrativorans sp. nov., a novel poly(3-hydroxybutyrate co-3-hydroxyvalerate)-degrading bacterium isolated from biofilms. AB - A novel Gram-stain-negative, facultatively aerobic and rod-shaped strain, designated SL-205(T), was isolated from the biofilms of a denitrifying reactor using poly(3-hydoxybutyrate-co-3-hydroxyvalerate) as the sole carbon source in Beijing, PR China. A polyphasic taxonomic characterization was performed on the novel isolate. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that strain SL-205(T) is a member of the genus Diaphorobacter. High levels of 16S rRNA gene sequence similarity were found between strain SL-205(T) and Diaphorobacter nitroreducens NA10B(T) (99.4%) and Diaphorobacter oryzae RF3(T) (98.5%), respectively. However, the DNA-DNA relatedness values between strain SL 205(T) and D. nitroreducens NA10B(T) and D. oryzae RF3(T) were 57 +/- 1% and 45 +/- 1.5%, respectively. The G+C content of the genomic DNA of strain SL-205(T) was 66.8 mol%. The major fatty acids consisted of summed feature 3 (including C16 : 1omega7c and/or iso-C15 : 0 2-OH), C16 : 0 and C18 : 1omega7c. Ubiquinone Q-8 was the only respiratory quinone; the polar lipid profile comprised phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and one uncharacterized phospholipid. We conclude that strain SL-205(T) represents a novel species of the genus Diaphorobacter for which the name Diaphorobacter polyhydroxybutyrativorans is proposed; the type strain is SL-205(T) ( = ACCC 19739(T) = DSM 29460(T)). PMID- 26012583 TI - Sphingobium barthaii sp. nov., a high molecular weight polycyclic aromatic hydrocarbon-degrading bacterium isolated from cattle pasture soil. AB - A Gram-stain-negative, yellow, rod-shaped bacterium, designated strain KK22(T), was isolated from a microbial consortium that grew on diesel fuel originally recovered from cattle pasture soil. Strain KK22(T) has been studied for its ability to biotransform high molecular weight polycyclic aromatic hydrocarbons. On the basis of 16S rRNA gene sequence phylogeny, strain KK22(T) was affiliated with the genus Sphingobium in the phylum Proteobacteria and was most closely related to Sphingobium fuliginis TKP(T) (99.8%) and less closely related to Sphingobium quisquiliarum P25(T) (97.5%). Results of DNA-DNA hybridization (DDH) revealed relatedness values between strain KK22(T) and strain TKP(T) and between strain KK22(T) and strain P25(T) of 21 +/- 4% (reciprocal hybridization, 27 +/- 2%) and 15 +/- 2% (reciprocal hybridization, 17 +/- 1%), respectively. Chemotaxonomic analyses of strain KK22(T) showed that the major respiratory quinone was ubiquinone Q-10, that the polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidyl N-methylethylethanolamine and sphingoglycolipid, and that C18 : 1omega7c and C14 : 0 2-OH were the main fatty acid and hydroxylated fatty acids, respectively. This strain was unable to reduce nitrate and the genomic DNA G+C content was 64.7 mol%. Based upon the results of the DDH analyses, the fact that strain KK22(T) was motile, and its biochemical and physiological characteristics, strain KK22(T) could be separated from recognized species of the genus Sphingobium. We conclude that strain KK22(T) represents a novel species of this genus for which the name Sphingobium barthaii sp. nov. is proposed; the type strain is KK22(T) ( = DSM 29313(T) = JCM 30309(T)). PMID- 26012586 TI - Eighth international congress on peer review in biomedical publication. PMID- 26012584 TI - Transplantation of mesenchymal stem cells ameliorates secondary osteoporosis through interleukin-17-impaired functions of recipient bone marrow mesenchymal stem cells in MRL/lpr mice. AB - INTRODUCTION: Secondary osteoporosis is common in systemic lupus erythematosus and leads to a reduction in quality of life due to fragility fractures, even in patients with improvement of the primary disorder. Systemic transplantation of mesenchymal stem cells could ameliorate bone loss and autoimmune disorders in a MRL/lpr mouse systemic lupus erythematosus model, but the detailed therapeutic mechanism of bone regeneration is not fully understood. In this study, we transplanted human bone marrow mesenchymal stem cells (BMMSCs) and stem cells from exfoliated deciduous teeth (SHED) into MRL/lpr mice and explored their therapeutic mechanisms in secondary osteoporotic disorders of the systemic lupus erythematosus model mice. METHODS: The effects of systemic human mesenchymal stem cell transplantation on bone loss of MRL/lpr mice were analyzed in vivo and ex vivo. After systemic human mesenchymal stem cell transplantation, recipient BMMSC functions of MRL/lpr mice were assessed for aspects of stemness, osteogenesis and osteoclastogenesis, and a series of co-culture experiments under osteogenic or osteoclastogenic inductions were performed to examine the efficacy of interleukin (IL)-17-impaired recipient BMMSCs in the bone marrow of MRL/lpr mice. RESULTS: Systemic transplantation of human BMMSCs and SHED recovered the reduction in bone density and structure in MRL/lpr mice. To explore the mechanism, we found that impaired recipient BMMSCs mediated the negative bone metabolic turnover by enhanced osteoclastogenesis and suppressed osteoblastogenesis in secondary osteoporosis of MRL/lpr mice. Moreover, IL-17-dependent hyperimmune conditions in the recipient bone marrow of MRL/lpr mice damaged recipient BMMSCs to suppress osteoblast capacity and accelerate osteoclast induction. To overcome the abnormal bone metabolism, systemic transplantation of human BMMSCs and SHED into MRL/lpr mice improved the functionally impaired recipient BMMSCs through IL-17 suppression in the recipient bone marrow and then maintained a regular positive bone metabolism via the balance of osteoblasts and osteoclasts. CONCLUSIONS: These findings indicate that IL-17 and recipient BMMSCs might be a therapeutic target for secondary osteoporosis in systemic lupus erythematosus. PMID- 26012585 TI - A mother-child intervention program in adolescent mothers and their children to improve maternal sensitivity, child responsiveness and child development (the TeeMo study): study protocol for a randomized controlled trial. AB - BACKGROUND: Children of adolescent mothers present a high-risk group for child neglect and maltreatment. Previous findings suggest that early interventions can reduce maltreatment by improving the quality of mother-child interaction, particularly maternal sensitivity. The aim of the current study is to evaluate the effects of a mother-child intervention program using home visits and video feedback regarding mother-child interaction (STEEP-b) plus psychiatric treatment of the mother in cases where mental illness is present compared with TAU (treatment as usual, that is, standardized support by the child welfare system) on enhancing maternal sensitivity and child responsiveness in adolescent, high risk mothers. The second aim of the current project is to investigate behavioral and neural differences between adolescent and adult mothers at baseline and postintervention. METHODS/DESIGN: This is a randomized controlled trial (RCT) with 120 high-risk adolescent mothers (<21 years old) and their 3- to 6-month-old children. Half of the participants will be randomized to receive STEEP-b in addition to their standard treatment for up to 12 to 18 sessions over 9 months. The other half will continue with treatment as usual. For further comparisons, 40 adult mothers with positive and negative rearing experiences (>25 years) will additionally be recruited to investigate behavioral and neural differences between the adolescent and adult group. Blind assessments will take place at T1 (pre-intervention), at the end of the 9-month intervention (T2, postintervention) and 6 months postintervention (T3, follow-up). Moderators of treatment outcomes and sociodemographic data will be assessed at T1. The primary outcome hypothesis is that STEEP-b added to treatment as usual will improve maternal sensitivity and child responsiveness compared with treatment as usual alone in high-risk adolescent mothers. The primary hypothesis will be evaluated at the end of the 9 month follow-up assessment based on the intention-to-treat principle. The trial is funded by the German Ministry for Research and Education (BMBF). Data collection started in October 2012. DISCUSSION: This is a randomized controlled trial that evaluates the effects of an early intervention program (STEEP-b) on the quality of mother-child interaction and child development in adolescent, high risk mothers. TRIAL REGISTRATION: DRKS00004409 (27 September 2012). PMID- 26012587 TI - Breast cancer risk in hyperprolactinemia: a population-based cohort study and meta-analysis of the literature. AB - OBJECTIVE: To enhance the precision of the risk estimate for breast cancer in hyperprolactinemia patients by collecting more data and pooling our results with available data from former studies in a meta-analysis. DESIGN: Population-based cohort study and meta-analysis of the literature. METHODS: Using nationwide registries, we identified all patients with a first-time diagnosis of hyperprolactinemia during 1994-2012 including those with a new breast cancer diagnoses after the start of follow-up. We calculated standardised incidence ratios (SIRs) as a measure of relative risk (RR) using national cancer incidence rates. We performed a meta-analysis, combining data from our study with data in the existing literature. RESULTS: We identified 2457 patients with hyperprolactinemia and 20 breast cancer cases during 19,411 person-years of follow-up, yielding a SIR of 0.99 (95% CI 0.60-1.52). Data from two additional cohort studies were retrieved and analyzed. When the three risk estimates were pooled, the combined RR was 1.04 (95% CI 0.75-1.43). CONCLUSIONS: We found no increased risk of breast cancer among patients with hyperprolactinemia. PMID- 26012588 TI - Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. AB - Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis. PMID- 26012589 TI - Prevalence and risk factors of gestational diabetes in Punjab, North India: results from a population screening program. AB - OBJECTIVE: The World Health Organization (WHO) has in 2013 changed the diagnostic criteria for gestational diabetes mellitus (GDM) to acknowledge the putative effect of mildly elevated fasting plasma glucose (FPG) levels on pregnancy outcomes. We aimed to determine the prevalence and risk factors of GDM comparing the previous WHO 1999 criteria to the WHO 2013 criteria in North India. METHODS: In a population-based screening programme, 5100 randomly selected North Indian women were studied using a cross-sectional design with a questionnaire, venous FPG and 2-h capillary plasma glucose (PG) after a 75 g oral glucose tolerance test performed between 24 and 28 weeks of pregnancy. RESULTS: The prevalence of GDM was 35% using WHO 2013 criteria vs 9% using WHO 1999 criteria. FPG measurements identified 94% of WHO 2013 GDM cases as opposed to 11% of WHO 1999 GDM cases. In contrast, 2-h PG measurements identified only 13% of WHO 2013 GDM cases compared with 96% of the WHO 1999 GDM cases. Using logistic regression with backward elimination, urban habitat, illiteracy, non-vegetarianism, increased BMI, Hindu religion and low adult height were all independent risk factors of GDM using the 1999 criteria, whereas only urban habitat, low adult height and increased age were independent risk factors of GDM using the 2013 criteria. CONCLUSIONS: Intervention studies are needed to justify the WHO 2013 GDM criteria increasing the prevalence four fold to include more than one third of North Indian pregnant women. PMID- 26012590 TI - Novel expression pattern of neuropeptide Y immunoreactivity in the peripheral nervous system in a rat model of neuropathic pain. AB - BACKGROUND: Neuropeptide Y (NPY) has been implicated in the modulation of pain. Under normal conditions, NPY is found in interneurons in the dorsal horn of the spinal cord and in sympathetic postganglionic neurons but is absent from the cell bodies of sensory neurons. Following peripheral nerve injury NPY is dramatically upregulated in the sensory ganglia. How NPY expression is altered in the peripheral nervous system, distal to a site of nerve lesion, remains unknown. To address this question, NPY expression was investigated using immunohistochemistry at the level of the trigeminal ganglion, the mental nerve and in the skin of the lower lip in relation to markers of sensory and sympathetic fibers in a rat model of trigeminal neuropathic pain. RESULTS: At 2 and 6 weeks after chronic constriction injury (CCI) of the mental nerve, de novo expression of NPY was seen in the trigeminal ganglia, in axons in the mental nerve, and in fibers in the upper dermis of the skin. In lesioned animals, NPY immunoreactivity was expressed primarily by large diameter mental nerve sensory neurons retrogradely labelled with Fluorogold. Many axons transported this de novo NPY to the periphery as NPY immunoreactive (IR) fibers were seen in the mental nerve both proximal and distal to the CCI. Some of these NPY-IR axons co-expressed Neurofilament 200 (NF200), a marker for myelinated sensory fibers, and occasionally colocalization was seen in their terminals in the skin. Peptidergic and non-peptidergic C fibers expressing calcitonin gene-related peptide (CGRP) or binding isolectin B4 (IB4), respectively, never expressed NPY. CCI caused a significant de novo sprouting of sympathetic fibers into the upper dermis of the skin, and most, but not all of these fibers, expressed NPY. CONCLUSIONS: This is the first study to provide a comprehensive description of changes in NPY expression in the periphery after nerve injury. Novel expression of NPY in the skin comes mostly from sprouted sympathetic fibers. This information is fundamental in order to understand where endogenous NPY is expressed, and how it might be acting to modulate pain in the periphery. PMID- 26012591 TI - Polymicrogyria in a 10-month-old boy with Mowat-Wilson syndrome. AB - Mowat-Wilson syndrome (MWS, OMIM# 235730) is a multiple congenital anomaly disorder characterized by intellectual disability, seizures, microcephaly, and distinct facial features. Additional findings include structural brain abnormalities, eye defects, congenital heart defects, Hirschsprung disease (HSCR), and genitourinary anomalies. It is caused by de novo heterozygous mutations or deletions of the ZEB2 gene on chromosome 2q21-q23. We report here on a 10-month-old boy with typical features of MWS who presented with the novel finding of polymicrogyria on brain magnetic resonance imaging. We also review the current literature regarding central nervous system anomalies in MWS. PMID- 26012592 TI - Public should have been warned of risk of contracting Ebola at healthcare facilities. PMID- 26012593 TI - Valve reconstruction for congenital mitral valve disease. AB - The surgical treatment of mitral valve disease in children is a challenging problem. Mitral stenosis and regurgitation may occur in isolation or together. Mitral valve repair is almost always preferable to replacement. Mitral valve replacement is not an ideal alternative to repair due to limitations of size, growth, structural valve degeneration, anticoagulation and poor survival. Surgical repair of congenital mitral stenosis must address the multiple levels of obstruction, including resection of the supramitral ring, thinning of leaflets and mobilization of the subvalvular apparatus. Sometimes leaflet augmentation is required. Repair of mitral regurgitation in children may involve simple cleft closures, edge-to-edge repairs, triangular resections and annuloplasties. Techniques used in adults, such as annuloplasty bands or artificial chords, may not be appropriate for children. Overall, an imperfect mitral valve repair may be more acceptable than the negative consequences of a replacement in a child. PMID- 26012629 TI - Editorial Comment to Role of cytoreductive nephrectomy for Japanese patients with primary renal cell carcinoma in the cytokine and targeted therapy era. PMID- 26012630 TI - Xenopus TACC1 is a microtubule plus-end tracking protein that can regulate microtubule dynamics during embryonic development. AB - Microtubule plus-end dynamics are regulated by a family of proteins called plus end tracking proteins (+TIPs). We recently demonstrated that the transforming acidic coiled-coil (TACC) domain family member, TACC3, can function as a +TIP to regulate microtubule dynamics in Xenopus laevis embryonic cells. Although it has been previously reported that TACC3 is the only TACC family member that exists in Xenopus, our examination of its genome determined that Xenopus, like all other vertebrates, contains three TACC family members. Here, we investigate the localization and function of Xenopus TACC1, the founding member of the TACC family. We demonstrate that it can act as a +TIP to regulate microtubule dynamics, and that the conserved C-terminal TACC domain is required for its localization to plus-ends. We also show that, in Xenopus embryonic mesenchymal cells, TACC1 and TACC3 are each required for maintaining normal microtubule growth speed but exhibit some functional redundancy in the regulation of microtubule growth lifetime. Given the conservation of TACC1 in Xenopus and other vertebrates, we propose that Xenopus laevis is a useful system to investigate unexplored cell biological functions of TACC1 and other TACC family members in the regulation of microtubule dynamics. PMID- 26012631 TI - Morphometry of the hard palate in Down's syndrome through CBCT-image analysis. AB - OBJECTIVES: To define the morphometry of the hard palate in Down's syndrome (DS) on cone beam computed tomography (CBCT) images. SETTING AND SAMPLE POPULATION: Santiago de Compostela University (Spain). The study group included 40 white DS individuals aged 10 to 40 years (mean = 18.8 +/- 7.3 years), 25 males and 15 females. The control group consisted of 40 individuals matched for age and sex were selected. MATERIAL & METHODS: Nine measurements were taken on the CBCT images. Axial plane: anteroposterior length (aAPL) and arch length (aARL); sagittal plane: anteroposterior length (sAPL), maximum height (sMH) and sagittal arch (sAR); coronal plane: interdental width (cIDW), height (cHE), skeletal width (cSW) and coronal arch (cAR). RESULTS: aAPL, aARL, sAPL, sMH, sAR, cMH and cAR were comparable in the two groups. cIDW and cSW were greater in controls than in DS. We found no statistically significant differences between males and females with DS. In the controls, sAPL and sAR were greater in males than females. In DS, age only had a statistically significantly increasing effect on aAPL and sAPL. In the controls, age significantly affected sAR and cHE. CONCLUSION: The hard palate is narrower in DS than in controls, but the anteroposterior measurements and the height of the vault are comparable in both groups. PMID- 26012632 TI - A new strategy to ERADicate HER2-positive breast tumors? AB - HER2-positive breast cancers that have become resistant to HER2-targeting agents, such as trastuzumab (also known as Herceptin), have limited treatment options. In this issue of Science Signaling, Singh et al. have identified a characteristic increase in the endoplasmic reticulum (ER)-associated degradation (ERAD) system in HER2-positive tumors as a mechanism of relieving proteotoxic stress. Synthetic lethality arising from targeted disruption of ERAD signaling in conjunction with other HER2-dependent signaling may improve therapeutic management of this difficult class of breast tumors. PMID- 26012635 TI - HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive. AB - Targeting non-oncogenic vulnerabilities may provide additional therapeutic approaches in tumors that are resistant to oncogene-targeted therapy. Using a computational pathway-based approach, we interrogated clinical breast cancer genomic data sets for candidate non-oncogenic vulnerabilities in breast cancers that have genomic amplification of ERBB2, which encodes human epidermal growth factor 2 (HER2). HER2-positive (HER2(+)) breast cancers showed increased expression of genes encoding proteins in the endoplasmic reticulum (ER) associated degradation (ERAD) pathway. Genetic ablation or pharmacological inhibition of ERAD led to irrecoverable ER stress and selectively killed HER2(+) breast cancer cells. Cell death caused by ERAD inhibition partially depended on increased HER2-mTOR signaling, which imposed an increased proteotoxic burden on the ER. Cell death in response to ER stress required the IRE1alpha-JNK pathway, which was selectively suppressed in HER2(+) breast cancers by phosphatases that inactivate JNK. Accordingly, the cytotoxicity of inhibiting ERAD as well as JNK phosphatases was synergistic in HER2(+) but not in HER2-negative breast cancer cells. Therefore, our study suggests that reactivation of oncogene-induced stress by targeting stress-adaptive pathways may be a beneficial approach for therapy resistant breast cancers. PMID- 26012633 TI - A large-scale screen reveals genes that mediate electrotaxis in Dictyostelium discoideum. AB - Directional cell migration in an electric field, a phenomenon called galvanotaxis or electrotaxis, occurs in many types of cells, and may play an important role in wound healing and development. Small extracellular electric fields can guide the migration of amoeboid cells, and we established a large-scale screening approach to search for mutants with electrotaxis phenotypes from a collection of 563 Dictyostelium discoideum strains with morphological defects. We identified 28 strains that were defective in electrotaxis and 10 strains with a slightly higher directional response. Using plasmid rescue followed by gene disruption, we identified some of the mutated genes, including some previously implicated in chemotaxis. Among these, we studied PiaA, which encodes a critical component of TORC2, a kinase protein complex that transduces changes in motility by activating the kinase PKB (also known as Akt). Furthermore, we found that electrotaxis was decreased in mutants lacking gefA, rasC, rip3, lst8, or pkbR1, genes that encode other components of the TORC2-PKB pathway. Thus, we have developed a high throughput screening technique that will be a useful tool to elucidate the molecular mechanisms of electrotaxis. PMID- 26012636 TI - Aggregation and asymptotic analysis of an SI-epidemic model for heterogeneous populations. AB - The paper investigates a version of a simple epidemiological model involving only susceptible and infected individuals, where the heterogeneity of the population with respect to susceptibility/infectiousness is taken into account. A comprehensive analysis of the asymptotic behaviour of the disease is given, based on an explicit aggregation of the model. The results are compared with those of a homogeneous version of the model to highlight the influence of the heterogeneity on the asymptotics. Moreover, the performed analysis reveals in which cases incomplete information about the heterogeneity of the population is sufficient in order to determine the long-run outcome of the disease. Numerical simulation is used to emphasize that, for a given level of prevalence, the evolution of the disease under the influence of heterogeneity may in the long run qualitatively differ from the one 'predicted' by the homogeneous model. Furthermore, it is shown that, in a closed population, the indicator for the survival of the population is in the presence of heterogeneity distinct from the basic reproduction number. PMID- 26012634 TI - Tandem phosphorylation within an intrinsically disordered region regulates ACTN4 function. AB - Phosphorylated residues occur preferentially in the intrinsically disordered regions of eukaryotic proteins. In the disordered amino-terminal region of human alpha-actinin-4 (ACTN4), Tyr(4) and Tyr(31) are phosphorylated in cells stimulated with epidermal growth factor (EGF), and a mutant with phosphorylation mimicking mutations of both tyrosines exhibits reduced interaction with actin in vitro. Cleavage of ACTN4 by m-calpain, a protease that in motile cells is predominantly activated at the rear, removes the Tyr(4) site. We found that introducing a phosphomimetic mutation at only Tyr(31) was sufficient to inhibit the interaction with actin in vitro. However, molecular dynamics simulations predicted that Tyr(31) is mostly buried and that phosphorylation of Tyr(4) would increase the solvent exposure and thus kinase accessibility of Tyr(31). In fibroblast cells, EGF stimulation increased tyrosine phosphorylation of a mutant form of ACTN4 with a phosphorylation-mimicking residue at Tyr(4), whereas a truncated mutant representing the product of m-calpain cleavage exhibited EGF stimulated tyrosine phosphorylation at a background amount similar to that observed for a double phosphomimetic mutant of Tyr(4) and Tyr(31). We also found that inhibition of the receptor tyrosine kinases of the TAM family, such as AXL, blocked EGF-stimulated tyrosine phosphorylation of ACTN4. Mathematical modeling predicted that the kinetics of phosphorylation at Tyr(31) can be dictated by the kinase affinity for Tyr(4). This study suggests that tandem-site phosphorylation within intrinsically disordered regions provides a mechanism for a site to function as a switch to reveal a nearby function-regulating site. PMID- 26012637 TI - Lower Coated-Platelet Levels Are Associated With Increased Mortality After Spontaneous Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Coated-platelets are highly procoagulant platelets observed on dual-agonist stimulation with collagen and thrombin. Coated-platelet levels are decreased in patients with spontaneous intracerebral hemorrhage when compared with controls and inversely correlated with bleed volume. We sought to investigate whether coated-platelets are associated with increased mortality at 30 days after spontaneous intracerebral hemorrhage. METHODS: Coated-platelet levels were assayed in 95 consecutive patients with spontaneous intracerebral hemorrhage. The main outcome was mortality at 30 days according to coated platelet levels at enrollment. Subjects were grouped into tertiles of the observed coated-platelet level distribution. Groups defined by tertile of coated platelet level were compared using either ANOVA or a Kruskal-Wallis test for small group size for continuous measures and an exact Cochrane-Armitage trend test for categorical measures. Logistic regression was used to estimate the adjusted odds of death within 30 days associated with coated-platelet levels. RESULTS: Cumulative mortality at 30 days was 23% (22 subjects). Mortality at 30 days differed among the coated-platelet tertiles: 44% for the first tertile (lowest coated-platelet levels), 19% for the second tertile, and 6% for the third tertile (trend test; P=0.0004). Logistic regression examining the association between mortality and coated-platelet levels showed that the odds of death at 30 days in those with levels <27% (n=47) were 6.83* the odds for patients with levels >=27% (95% confidence interval, 2.10-22.23). CONCLUSIONS: These results support a link between impaired coated-platelet potential and outcome in intracerebral hemorrhage. PMID- 26012638 TI - Aerobic, Resistance, and Cognitive Exercise Training Poststroke. PMID- 26012640 TI - Soluble CD40L Is a Useful Marker to Predict Future Strokes in Patients With Minor Stroke and Transient Ischemic Attack. AB - BACKGROUND AND PURPOSE: Elevated soluble CD40 ligand (sCD40L) was shown to be related to cardiovascular events, but the role of sCD40L in predicting recurrent stroke remains unclear. METHODS: Baseline sCD40L levels were measured in 3044 consecutive patients with acute minor stroke and transient ischemic attack, who had previously been enrolled in the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Cox proportional-hazards model was used to assess the association of sCD40L with recurrent stroke. RESULTS: Patients in the top tertile of sCD40L levels had increased risk of recurrent stroke comparing with those in the bottom tertile, after adjusted for conventional confounding factors (hazard ratio, 1.49; 95% confidence interval, 1.11-2.00; P=0.008). The patients with elevated levels of both sCD40L and high sensitive C-reactive protein also had increased risk of recurrent stroke (hazard ratio, 1.81; 95% confidence interval, 1.23-2.68; P=0.003). CONCLUSIONS: Elevated sCD40L levels independently predict recurrent stroke in patients with minor stroke and transient ischemic attack. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589. PMID- 26012639 TI - Cost-Effectiveness of Intra-Arterial Treatment as an Adjunct to Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: The objective of this study was to determine the cost effectiveness of intra-arterial treatment within the 0- to 6-hour window after intravenous tissue-type plasminogen activator within 0- to 4.5-hour compared with intravenous tissue-type plasminogen activator alone, in the US setting and from a social perspective. METHODS: A decision analytic model estimated the lifetime costs and outcomes associated with the additional benefit of intra-arterial therapy compared with standard treatment with intravenous tissue-type plasminogen activator alone. Model inputs were obtained from published literature, the Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study, and claims databases in the United States. Health outcomes were measured in quality-adjusted life years (QALYs). Treatment benefit was assessed by calculating the cost per QALY gained. One-way and probabilistic sensitivity analyses were performed to estimate the overall uncertainty of model results. RESULTS: The addition of intra-arterial therapy compared with standard treatment alone yielded a lifetime gain of 0.7 QALY for an additional cost of $9911, which resulted in a cost of $14 137 per QALY. Multivariable sensitivity analysis predicted cost-effectiveness (<=$50 000 per QALY) in 97.6% of simulation runs. CONCLUSIONS: Intra-arterial treatment after intravenous tissue-type plasminogen activator for patients with anterior circulation strokes within the 6-hour window is likely cost-effective. From a societal perspective, increased investment in access to intra-arterial treatment for acute stroke may be justified. PMID- 26012641 TI - Donor mesenchymal stem cell-derived neural-like cells transdifferentiate into myelin-forming cells and promote axon regeneration in rat spinal cord transection. AB - INTRODUCTION: Severe spinal cord injury often causes temporary or permanent damages in strength, sensation, or autonomic functions below the site of the injury. So far, there is still no effective treatment for spinal cord injury. Mesenchymal stem cells (MSCs) have been used to repair injured spinal cord as an effective strategy. However, the low neural differentiation frequency of MSCs has limited its application. The present study attempted to explore whether the grafted MSC-derived neural-like cells in a gelatin sponge (GS) scaffold could maintain neural features or transdifferentiate into myelin-forming cells in the transected spinal cord. METHODS: We constructed an engineered tissue by co seeding of MSCs with genetically enhanced expression of neurotrophin-3 (NT-3) and its high-affinity receptor tropomyosin receptor kinase C (TrkC) separately into a three-dimensional GS scaffold to promote the MSCs differentiating into neural like cells and transplanted it into the gap of a completely transected rat spinal cord. The rats received extensive post-operation care, including cyclosporin A administrated once daily for 2 months. RESULTS: MSCs modified genetically could differentiate into neural-like cells in the MN + MT (NT-3-MSCs + TrKC-MSCs) group 14 days after culture in the GS scaffold. However, after the MSC-derived neural like cells were transplanted into the injury site of spinal cord, some of them appeared to lose the neural phenotypes and instead transdifferentiated into myelin-forming cells at 8 weeks. In the latter, the MSC-derived myelin-forming cells established myelin sheaths associated with the host regenerating axons. And the injured host neurons were rescued, and axon regeneration was induced by grafted MSCs modified genetically. In addition, the cortical motor evoked potential and hindlimb locomotion were significantly ameliorated in the rat spinal cord transected in the MN + MT group compared with the GS and MSC groups. CONCLUSION: Grafted MSC-derived neural-like cells in the GS scaffold can transdifferentiate into myelin-forming cells in the completely transected rat spinal cord. PMID- 26012642 TI - Comparison of the diagnostic accuracies of very low stress-dose with standard dose myocardial perfusion imaging: Automated quantification of one-day, stress first SPECT using a CZT camera. AB - BACKGROUND: Previous studies have demonstrated accurate diagnosis of reduced dose myocardial perfusion imaging (MPI) using Cadmium-Zinc-Telluride (CZT) technology. We compared the diagnostic performances of very low stress-dose (<2 mSv) with standard-dose stress-first, quantitative MPI using a CZT camera. METHODS: Patients without known coronary artery- disease who underwent a stress-first Tc 99 m sestamibi CZT-MPI and invasive coronary angiography (ICA), and low-risk patients without ICA were included. A stress-rest standard-dose (10/30 mCi) MPI and a low-dose (5/15 mCi) MPI were compared. Normal limits for quantification were developed from 40 (20 males) low-risk patients, and total perfusion deficit (TPD) was derived. RESULTS: 208 patients who underwent MPI and ICA, and 76 low risk patients were included. Of these, 128 had a standard-dose MPI and 156 had a low-dose MPI. Stress-doses in low-dose and standard-dose groups were 5.9 +/- 1.2 vs 10.2 +/- 0.5 mCi (1.7 +/- 0.3 vs 3.0 +/- 0.1 mSv), respectively, P < 0.001, and stress-rest effective radiation was 6.9 +/- 1.1 vs 11.7 +/- 0.4 mSv, respectively, P < 0.001. Sensitivity, specificity, and accuracy values in the low dose and standard-dose groups were 86.1%, 76.6%, and 81.4%; and 90.6%, 78.1%, and 84.4%, respectively, P = ns. Using TPD prone, specificity values were 84.9% and 80.3%, respectively, P = ns. CONCLUSION: One-day stress-first MPI with 50% radiation reduction and a very low stress-dose (<2 mSv) using CZT technology and quantitative supine and prone analysis provided a high diagnostic value, similar to standard-dose MPI. PMID- 26012643 TI - Assessing absolute changes in breast cancer risk due to modifiable risk factors. AB - Clinical risk assessment involves absolute risk measures, but information on modifying risk and preventing cancer is often communicated in relative terms. To illustrate the potential impact of risk factor modification in model-based risk assessment, we evaluated the performance of the IBIS Breast Cancer Risk Evaluation Tool, with and without current body mass index (BMI), for predicting future breast cancer occurrence in a prospective cohort of 665 postmenopausal women. Overall, IBIS's accuracy (overall agreement between observed and assigned risks) and discrimination (AUC concordance between assigned risks and outcomes) were similar with and without the BMI information. However, in women with BMI > 25 kg/m(2), adding BMI information improved discrimination (AUC = 63.9 % and 61.4 % with and without BMI, P < 0.001). The model-assigned 10-year risk difference for a woman with high (27 kg/m(2)) versus low (21 kg/m(2)) BMI was only 0.3 % for a woman with neither affected first-degree relatives nor BRCA1 mutation, compared to 4.5 % for a mutation carrier with three such relatives. This contrast illustrates the value of using information on modifiable risk factors in risk assessment and in sharing information with patients of their absolute risks with and without modifiable risk factors. PMID- 26012644 TI - Efficacy of endocrine therapy in relation to progesterone receptor and Ki67 expression in advanced breast cancer. AB - We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002-2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series (P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors (P = 0.026) or metastases (P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response. PMID- 26012646 TI - Detection and prevalence of disseminated tumor cells from the bone marrow of early stage male breast cancer patients. AB - Male breast cancer (mBC) is a rare entity. As detection of disseminated tumor cells (DTCs) in the bone marrow of females with early stage breast cancer is a promising prognostic marker, we aimed to determine the prevalence and prognostic value of DTCs in mBC. Bone marrow aspirates were collected from male patients undergoing primary surgery for early stage breast cancer (T1-4, N0-2, M0) at Tuebingen University, Germany, between January 2001 and April 2015. DTCs were identified by immunocytochemistry (pancytokeratin antibody A45/B-B3) and cytomorphology. 24 patients with mBC were included into the analysis. DTCs were detected in four of these (17 %). There was no significant association between the DTC status and any other clinicopathological parameter. Also, no significant impact of the DTC status on DFS or OS could be observed. DTCs are detectable in patients with early stage mBC. The detection rate is comparable to that in women. No associations between DTCs and clinicopathological features or prognosis were observed, which is most likely due to the small sample size. The detection of DTCs in male patients with early stage breast cancer emphasizes the transmission of future clinical applications for DTCs from women to men. PMID- 26012645 TI - Racial and ethnic differences in risk of second primary cancers among breast cancer survivors. AB - Disparities exist in breast cancer (BC) outcomes between racial and ethnic groups in the United States. Reasons for these disparities are multifactorial including differences in genetics, stage at presentation, access to care, and socioeconomic factors. Less is documented on racial/ethnic differences in subsequent risk of second primary cancers (SPC). The purpose of this study is to evaluate the risk of SPC among different racial/ethnic groups of women with BC. We conducted a retrospective cohort study of 134,868 Non-Hispanic White, 17,484 Black, 18,034 Hispanic, and 19,802 Asian/Pacific Islander (API) women with stages I-III BC in twelve Surveillance, Epidemiology and End Results Program registries between 2001 and 2010. Standardized incidence ratios (SIR), 95 % confidence intervals (CI), and absolute excess risks were calculated by comparing incidence of SPC in the cohort to incidence in the general population for specific cancer sites by race/ethnicity and stratified by index BC characteristics. All women were at increased risks of second primary BC and acute myeloid leukemia (AML), with higher risk among more advanced stage index BC. Black and API women had higher SIRs for AML [4.86 (95 % CI 3.05-7.36) and 5.00 (95 % CI 3.26-7.32)], respectively] which remained elevated among early-stage (I) BC cases. Women with a history of invasive BC have increased risk of SPC, most notable for second primary BC and AML. These risks for secondary cancers differ by race/ethnicity. Studies evaluating possible genetic and biobehavioral mechanisms underlying these differences are warranted. Strategies for BC adjuvant treatment and survivorship care may require further individualization with consideration given to race/ethnicity. PMID- 26012650 TI - [Why is the exanthema so extremely painful? Impetigo contagiosa]. PMID- 26012651 TI - ["One can only advise against a pregnancy at this age"]. PMID- 26012647 TI - Characterization of the psbH precursor RNAs reveals a precise endoribonuclease cleavage site in the psbT/psbH intergenic region that is dependent on psbN gene expression. AB - The plastid psbB operon harbours 5 genes, psbB, psbT, psbH, petB and petD. A sixth gene, the psbN gene, is located on the opposite DNA strand in the psbT/psbH intergenic region. Its transcription produces antisense RNA to a large part of the psbB pentacistronic mRNA. We have investigated whether transcription of the psbN gene, i.e. production of antisense RNA, influences psbT/psbH intergenic processing. Results reveal the existence of four different psbH precursor RNAs. Three of them result from processing and one is produced by transcription initiation. One of the processed RNAs is probably created by site-specific RNA cleavage. This RNA is absent in plants where the psbN gene is not transcribed suggesting that cleavage at this site is dependent on the formation of sense/antisense double-stranded RNA. In order to characterize the nuclease that might be responsible for double-stranded RNA cleavage, we analysed csp41a and csp41b knock-out mutants and the corresponding double mutant. Both CSP41 proteins are known to interact physically and CSP41a had been shown to cleave within 3' untranslated region stem-loop structures, which contain double-stranded RNA, in vitro. We demonstrate that the psbH RNA, that is absent in plants where the psbN gene is not transcribed, is also strongly diminished in all csp41 plants. Altogether, results reveal a site-specific endoribonuclease cleavage event that seems to depend on antisense RNA and might implicate endoribonuclease activity of CSP41a. PMID- 26012652 TI - [Inquire about genital symptoms in psoriasis patients!]. PMID- 26012653 TI - [All outside data are immediately available]. PMID- 26012660 TI - [A change in software must be really worthwhile]. PMID- 26012661 TI - [We should pull together rather than perpetuating conflict]. PMID- 26012664 TI - [Polycythemia vera: the disadvantages of overproduction]. PMID- 26012666 TI - [Axillary perspiration, facial acne]. PMID- 26012667 TI - [Naturopathy consultation. Plants and light to combat depressed mood]. PMID- 26012668 TI - [Treatments you should not recommend]. PMID- 26012670 TI - [Suspected sexual abuse: what should be done now - and what not]. PMID- 26012674 TI - [Ischemic hair loss]. PMID- 26012675 TI - [Completely filled up with own hair]. PMID- 26012676 TI - [Quadrivalent HPV vaccination does not increase MS risk]. PMID- 26012677 TI - [The microbiome - the unsuspected etiological scope!]. PMID- 26012678 TI - [Automatic defibrillators are lifesavers]. PMID- 26012679 TI - [Too violent during sex]. PMID- 26012680 TI - [Focusing on elderly patients and concomitant drug therapy - Diabetology for the general practitioner]. PMID- 26012681 TI - [Therapy of diabetes mellitus in old age]. PMID- 26012682 TI - [Aspirin and statins for every diabetic?]. PMID- 26012683 TI - [Urinary tract infection]. PMID- 26012684 TI - [Destructive chondrolysis following intraarticular application of lavasorb (polihexanid) for treatment of knee empyema]. PMID- 26012685 TI - [Emergency checklist: hyperventilation tetany]. PMID- 26012686 TI - [Masses of the neck - a potpourri of various diagnoses]. PMID- 26012687 TI - [Direct-acting antiviral treatment of chronic hepatitis C infection]. PMID- 26012694 TI - Positive and Negative Contributions in the Solvation Enthalpy due to Specific Interactions in Binary Mixtures of C1-C4 n-Alkanols and Chloroform with Butan-2 one. AB - In the paper, results of calorimetric measurements, IR spectra, and calculated ab initio stabilization energies of dimers are reported for binary systems butan-2 one + (methanol, ethanol, propan-1-ol, butan-1-ol, and chloroform). Changes in the total enthalpy of specific interactions due to dissolution of butan-2-one in the alcohols, calculated using equations derived in previous works, are positive. That results from the endothermic breaking of the O-H...O-H bonds not completely compensated by the exothermic effects of formation of the O-H...O?C ones. Moreover, the concentration of nonbonded molecules of butan-2-one is significant even in dilute solutions, as is evidenced by the shape of the C?O stretching vibrations band in the IR spectra. Apart from that, the spectra do not confirm 1:2 complexes in spite of two lone electron pairs in the carbonyl group of butan 2-one capable of forming the hydrogen bonds. The changes in enthalpy of specific interactions are negative for dilute solutions of alcohols and chloroform in butan-2-one and of butan-2-one in chloroform, because no hydrogen bonds occur in pure butan-2-one. The experimental results are positively correlated with the enthalpies estimated from the ab initio energies using a simple "chemical reaction" approach. PMID- 26012695 TI - Which environmental factors are associated with lived health when controlling for biological health? - a multilevel analysis. AB - BACKGROUND: Lived health and biological health are two different perspectives of health introduced by the International Classification of Functioning, Disability and Health (ICF). Since in the concept of lived health the impact of the environment on biological health is inherently included, it seems intuitive that when identifying the environmental determinants of health, lived health is the appropriate outcome. The Multilevel Item Response Theory (MLIRT) model has proven to be a successful method when dealing with the relation between a latent variable and observed variables. The objective of this study was to identify environmental factors associated with lived health when controlling for biological health by using the MLIRT framework. METHODS: We performed a psychometric study using cross-sectional data from the Spanish Survey on Disability, Independence and Dependency Situation. Data were collected from 17,303 adults living in 15,263 dwellings. The MLIRT model was used for each of the two steps of the analysis to: (1) calculate people's biological health abilities and (2) estimate the association between lived health and environmental factors when controlling for biological health. The hierarchical structure of individuals in dwellings was considered in both models. RESULTS: Social support, being able to maintain one's job, the extent to which one's health needs are addressed and being discriminated against due to one's health problems were the environmental factors identified as associated with lived health. Biological health also had a strong positive association with lived health. CONCLUSIONS: This study identified environmental factors associated with people's lived health differences within and between dwellings according to the MLIRT-model approach. This study paves the way for the future implementation of the MLIRT model when analysing ICF-based data. PMID- 26012697 TI - Non-invasive measurement of tibialis anterior muscle temperature during rest, cycling exercise and post-exercise recovery. AB - We introduce a non-invasive and accurate method to assess tibialis anterior muscle temperature (Tm) during rest, cycling exercise, and post-exercise recovery using the insulation disk (INDISK) technique. Twenty-six healthy males (23.6 +/- 6.2 years; 24.1 +/- 3.1 body mass index) were randomly allocated into the 'model' (n = 16) and the 'validation' (n = 10) groups. Participants underwent 20 min supine rest, 20 min cycling exercise at 60% of age-predicted maximum heart rate, and 20 min supine post-exercise recovery. In the model group, Tm (34.55 +/ 1.02 degrees C) was greater than INDISK temperature (Tid; 32.44 +/- 1.23 degrees C; p < 0.001) and skin surface temperature (Tsk; 29.84 +/- 1.47 degrees C; p < 0.001) throughout the experimental protocol. The strongest prediction model (R(2) = 0.646) incorporated Tid and the difference between the current Tid temperature and that recorded four minutes before. No mean difference (p > 0.05) and a strong correlation (r = 0.804; p < 0.001) were observed between Tm and predicted Tm (predTm) in the model group. Cross-validation analyses in the validation group demonstrated no mean difference (p > 0.05), a strong correlation (r = 0.644; p < 0.001), narrow 95% limits of agreement (-0.06 +/- 1.51), and low percent coefficient of variation (2.24%) between Tm (34.39 +/- 1.00 degrees C) and predTm (34.45 +/- 0.73 degrees C). We conclude that the novel technique accurately predicts Tm during rest, cycling exercise, and post-exercise recovery, providing a valid and cost-efficient alternative when direct Tm measurement is not feasible. PMID- 26012698 TI - Polyethylene glycol/graphene oxide coated solid-phase microextraction fiber for analysis of phenols and phthalate esters coupled with gas chromatography. AB - A new polyethylene glycol/graphene oxide composite material bonded on the surface of a stainless-steel wire was used for solid-phase microextraction. The layer-by layer structure increased the adsorption sites of the novel fiber, which could facilitate the extraction of trace compounds. The polyethylene glycol/graphene oxide was characterized by Fourier transform infrared spectroscopy and elemental analysis, which verified that polyethylene glycol was successfully grafted onto the surface of graphene oxide. The performance of the polyethylene glycol/graphene oxide coated fiber was investigated for phenols and phthalate esters coupled with gas chromatography with flame ionization detection under the optimal extraction and desorption conditions, and the proposed method exhibited an excellent extraction capacity and high thermal stability. Wide linear ranges were obtained for the analytes with good correlation coefficients in the range of 0.9966-0.9994, and the detection limits of model compounds ranged from 0.003 to 0.025 MUg/L. Furthermore, the as-prepared fiber was used to determine the model compounds in the water and soil samples and satisfactory results were obtained. PMID- 26012696 TI - Two independently folding units of Plasmodium profilin suggest evolution via gene fusion. AB - Gene fusion is a common mechanism of protein evolution that has mainly been discussed in the context of multidomain or symmetric proteins. Less is known about fusion of ancestral genes to produce small single-domain proteins. Here, we show with a domain-swapped mutant Plasmodium profilin that this small, globular, apparently single-domain protein consists of two foldons. The separation of binding sites for different protein ligands in the two halves suggests evolution via an ancient gene fusion event, analogous to the formation of multidomain proteins. Finally, the two fragments can be assembled together after expression as two separate gene products. The possibility to engineer both domain-swapped dimers and half-profilins that can be assembled back to a full profilin provides perspectives for engineering of novel protein folds, e.g., with different scaffolding functions. PMID- 26012699 TI - Erratum: MicroRNAs expression profiling of eutopic proliferative endometrium in women with ovarian endometriosis. PMID- 26012702 TI - Industry-sponsored research: how to eliminate bias? PMID- 26012704 TI - Serum amyloid A and inflammation in diabetic kidney disease and podocytes. PMID- 26012701 TI - A liquidus tracking approach to the cryopreservation of human cartilage allografts. AB - In the "liquidus tracking" (LT) approach to cryopreservation both the temperature and the concentration of cryoprotectant (CPA) are controlled such that solution composition "tracks" the liquidus (melting point) line for that system. Ice crystal formation is prevented but the tissue is not exposed to CPA concentrations exceeding those experienced by cells during conventional cryopreservation. This approach is particularly appropriate for articular cartilage because chondrocytes in situ are exquisitely susceptible to damage by the crystallisation of ice. This project aimed to develop a suitable process for tissue to be used in the surgical repair of damaged human knee joints. A high proportion of the chondrocytes should be alive. Human articular cartilage was obtained from deceased donors and dimethyl sulphoxide (DMSO) was used as the CPA, cooling was at 0.14 degrees C/min and warming at 0.42 degrees C/min. The vehicle solution was CPTes2. A program of increasing DMSO concentration was developed for cooling and this gave satisfactory tissue concentrations but reduction of DMSO concentration during warming was inadequate, resulting in higher tissue concentrations than required. Biomechanical testing indicated a compressive modulus of 9.5+/-1.3 MPa in LT-processed cartilage, with control values of 11.6+/ 0.8 MPa (p>0.05, Student's t-test). Measurement of GAG synthesis sometimes approached 65% or 85% of control, but the variability of replicate data prevented firm conclusions. Ideally allograft tissue should score 1A or above on the Noyes scale and the donor age should be less than 46 years but the cartilage used in this study did not meet these standards. PMID- 26012700 TI - Impact of a web-based treatment decision aid for early-stage prostate cancer on shared decision-making and health outcomes: study protocol for a randomized controlled trial. AB - BACKGROUND: At an early stage, prostate cancer patients are often eligible for more than one treatment option, or may choose to defer curative treatment. Without a pre-existing superior option, a patient has to weigh his personal preferences against the risks and benefits of each alternative to select the most appropriate treatment. Given this context, in prostate cancer treatment decision making, it is particularly suitable to follow the principles of shared decision making (SDM), especially with the support of specific instruments like decision aids (DAs). Although several alternatives are available, present tools are not sufficiently compatible with routine clinical practice. To overcome existing barriers and to stimulate structural implementation of DAs and SDM in clinical practice, a web-based prostate cancer treatment DA was developed to fit clinical workflow. Following the structure of an existing DA, Dutch content was developed, and values clarification methods (VCMs) were added. The aim of this study is to investigate the effect of this DA on (shared) treatment choice and patient reported outcomes. METHODS/DESIGN: Nineteen Dutch hospitals are included in a pragmatic, cluster randomized controlled trial, with an intervention and a control arm. In the intervention group, the DA will be offered after diagnosis, and a summary of the patients' preferences, which were identified with the DA, can be discussed by the patient and his clinician during later consultation. Patients in the control group will receive information and decisional support as usual. Results from both groups on decisional conflict, treatment choice and the experience with involvement in the decision-making process are compared. Patients are requested to fill in questionnaires after treatment decision-making but before treatment is started, and 6 and 12 months later. This will allow the development of treatment satisfaction, decisional regret, and quality of life to be monitored. Clinicians from both groups will evaluate their practice of information provision and decisional support. DISCUSSION: This study will describe a web-based prostate cancer treatment DA with VCMs. The effect of this DA on the decision-making process and subsequent patient reported outcomes will be evaluated. TRIAL REGISTRATION: The Netherlands National Trial Register: NTR4554, registration date 1 May 2014. PMID- 26012705 TI - Classification of malignant and benign tumors of the lung by infrared spectral histopathology (SHP). PMID- 26012706 TI - Eye closure enhances dark night perceptions. AB - We often close our eyes when we explore objects with our fingers to reduce the dominance of the visual system over our other senses. Here we show that eye closure, even in complete darkness, results in improved somatosensory perception due to a switch from visual predominance towards a somatosensory processing mode. Using a tactile discrimination task and functional neuroimaging (fMRI) data were acquired from healthy subjects with their eyes opened and closed in two environments: under ambient light and in complete darkness. Under both conditions the perception threshold decreased when subjects closed their eyes, and their fingers became more sensitive. In complete darkness, eye closure significantly increased occipital blood-oxygen-level-dependent (BOLD) activity in the somatosensory and secondary visual processing areas. This change in brain activity was associated with enhanced coupling between the sensory thalamus and somatosensory cortex; connectivity between the visual and somatosensory areas decreased. The present study demonstrates that eye closure improves somatosensory perception not merely due to the lack of visual signals; instead, the act of closing the eyes itself alters the processing mode in the brain: with eye closure the brain switches from thalamo-cortical networks with visual dominance to a non visually dominated processing mode. PMID- 26012708 TI - Experimental evidence of contagious yawning in budgerigars (Melopsittacus undulatus). AB - Experimental evidence of contagious yawning has only been documented in four mammalian species. Here, we report the results from two separate experimental studies designed to investigate the presence of contagious yawning in a social parrot, the budgerigar (Melopsittacus undulatus). In Study 1, birds were paired in adjacent cages with and without visual barriers, and the temporal association of yawning was assessed between visual conditions. In Study 2, the same birds were exposed to video stimuli of both conspecific yawns and control behavior, and yawning frequency was compared between conditions. Results from both studies demonstrate that yawning is contagious. To date, this is the first experimental evidence of contagious yawning in a non-mammalian species. We propose that future research could use budgerigars to explore questions related to basic forms of empathic processing. PMID- 26012709 TI - Use of coloured overlays and lenses are unlikely to help children with dyslexia, study finds. PMID- 26012710 TI - Survival and Functional Stability in Chronic Kidney Disease Due to Surgical Removal of Nephrons: Importance of the New Baseline Glomerular Filtration Rate. AB - BACKGROUND: Chronic kidney disease (CKD) can be associated with a higher risk of progression to end-stage renal disease and mortality, but the etiology of nephron loss may modify this. Previous studies suggested that CKD primarily due to surgical removal of nephrons (CKD-S) may be more stable and associated with better survival than CKD due to medical causes (CKD-M). OBJECTIVE: We addressed limitations of our previous work with comprehensive control for confounding factors, differentiation of non-renal cancer-related mortality, and longer follow up for more discriminatory assessment of the impact of CKD-S. DESIGN, SETTING, AND PARTICIPANTS: From 1999 to 2008, 4299 patients underwent surgery for renal cancer at a single institution. The median follow-up was 9.4 yr (7.3-11.0). The new baseline glomerular filtration rate (GFR) was defined as the highest GFR between the nadir and 42 d after surgery. Three cohorts were retrospectively evaluated: no CKD (new baseline GFR >60 ml/min/1.73 m(2)); CKD-S (new baseline GFR<60 but preoperative >60 ml/min/1.73 m(2)); and CKD-M/S (new baseline and preoperative GFR both <60 ml/min/1.73 m(2)). Cohort status was permanently set at 42 d after surgery. INTERVENTION: Renal surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Decline in renal function (50% reduction in GFR or dialysis), all-cause mortality, and non-renal cancer mortality were examined using a multivariable Cox proportional hazards model. RESULTS AND LIMITATIONS: CKD-M/S had a higher incidence of relevant comorbidities and the new baseline GFR was lower. On multivariable analysis (controlling for age, gender, race, diabetes, hypertension, and cardiac disease), CKD-M/S had higher rates of progressive decline in renal function, all-cause mortality, and non-renal cancer mortality when compared to CKD-S and no CKD (hazard ratio [HR] 1.69-2.33, all p<0.05). All-cause mortality was modestly higher for CKD-S than for no CKD (HR 1.19, p=0.030), but renal stability and non-renal cancer mortality were similar for these groups. New baseline GFR of <45 ml/min/1.73 m(2) significantly predicted adverse outcomes. The main limitation is the retrospective design. CONCLUSIONS: CKD-S is more stable than CKD-M/S and has better survival, approximating that for no CKD. However, if the new baseline GFR is <45 ml/min/1.73 m(2), the risks of functional decline and mortality increase. These findings may influence counseling for patients with localized renal cell carcinoma and higher oncologic potential when a normal contralateral kidney is present. PATIENT SUMMARY: Survival is better for surgically induced chronic kidney disease (CKD) than for medically induced CKD, particularly if the postoperative glomerular filtration rate is >=45 ml/min/1.73 m(2). Patients with preexisting CKD are at risk of a significant decline in kidney function after surgery, and kidney-preserving treatment should be strongly considered in such cases. PMID- 26012711 TI - Suprachiasmatic nucleus as the site of androgen action on circadian rhythms. AB - Androgens act widely in the body in both central and peripheral sites. Prior studies indicate that in the mouse, suprachiasmatic nucleus (SCN) cells bear androgen receptors (ARs). The SCN of the hypothalamus in mammals is the locus of a brain clock that regulates circadian rhythms in physiology and behavior. Gonadectomy results in reduced AR expression in the SCN and in marked lengthening of the period of free-running activity rhythms. Both responses are restored by systemic administration of androgens, but the site of action remains unknown. Our goal was to determine whether intracranial androgen implants targeted to the SCN are sufficient to restore the characteristic free-running period in gonadectomized male mice. The results indicate that hypothalamic implants of testosterone propionate in or very near the SCN produce both anatomical and behavioral effects, namely increased AR expression in the SCN and restored period of free-running locomotor activity. The effect of the implant on the period of the free-running locomotor rhythm is positively correlated with the amount of AR expression in the SCN. There is no such correlation of period change with amount of AR expression in other brain regions examined, namely the preoptic area, bed nucleus of the stria terminalis and premammillary nucleus. We conclude that the SCN is the site of action of androgen effects on the period of circadian activity rhythmicity. PMID- 26012712 TI - Early bi-parental separation or neonatal paternal deprivation in mandarin voles reduces adult offspring paternal behavior and alters serum corticosterone levels and neurochemistry. AB - Although the effect of early social environments on maternal care in adulthood has been examined in detail, few studies have addressed the long-term effect on paternal care and its underlying neuroendocrine mechanisms. Here, using monogamous mandarin voles (Microtus mandarinus) that show high levels of paternal care, the effects of early bi-parental separation (EBPS) or neonatal paternal deprivation (NPD) on adult paternal behavior, serum corticosterone levels, and receptor mRNA expression in the nucleus accumbens (NAcc) and medial preoptic area (MPOA) were investigated. Compared to the parental care group (PC), we found that EBPS reduced crouching behavior and increased inactivity, self-grooming, and serum corticosterone levels in adult offspring; and NPD significantly reduced retrieval behavior and increased self-grooming behavior of offspring at adulthood. EBPS displayed more dopamine type I receptor (D1R) mRNA expression in the NAcc, but less oxytocin receptor (OTR) mRNA expression than PC in the MPOA. Both EBPS and NPD exhibited more mRNA expression of estrogen receptor alpha (ERalpha) than PC in the MPOA. In the EBPS group, increased serum corticosterone concentration was closely associated with reduced crouching behavior, and reduced expression of OTR was closely associated with altered crouching behavior and increased D1R expression. Our results provide substantial evidence that EBPS or NPD has long-term consequences and reduces paternal behavior in adult animals. Importantly the oxytocin system in the MPOA might interact with NAcc dopamine systems to regulate paternal behavior and EBPS may affect interactions between the MPOA and NAcc. PMID- 26012714 TI - Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions. AB - Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with alpha-benzylidene and alpha-alkylidene beta dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C-C bonds and one C O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported. PMID- 26012713 TI - Structure-function-behavior relationship in estrogen-induced synaptic plasticity. AB - This article is part of a Special Issue "Estradiol and Cognition". In estrogen induced synaptic plasticity, a correlation of structure, function and behavior in the hippocampus has been widely established. 17beta-estradiol has been shown to increase dendritic spine density on hippocampal neurons and is accompanied by enhanced long-term potentiation and improved performance of animals in hippocampus-dependent memory tests. After inhibition of aromatase, the final enzyme of estradiol synthesis, with letrozole we consistently found a strong and significant impairment of long-term potentiation (LTP) in female mice as early as after six hours of treatment. LTP impairment was followed by loss of hippocampal spine synapses in the hippocampal CA1 area. Interestingly, these effects were not found in male animals. In the Morris water maze test, chronic administration of letrozole did not alter spatial learning and memory in either female or male mice. In humans, analogous effects of estradiol on hippocampal morphology and physiology were observed using neuroimaging techniques. However, similar to our findings in mice, an effect of estradiol on memory performance has not been consistently observed. PMID- 26012715 TI - Child behaviors as a moderator: Examining the relationship between foster parent supports, satisfaction, and intent to continue fostering. AB - Foster parents need access to supports and resources in order to be satisfied with their caregiving role and continue providing foster care services. However, they often experience multiple demands in their role as a substitute caregiver that could lead to stress. Child behaviors especially may be a significant factor when considering sources of strain and may be a potential risk factor for negative outcomes such as dissatisfaction or the decision to discontinue providing foster care. The purpose of this study was to examine whether child disruptive behaviors moderated or influenced the nature or strength of the relationship between foster parent supports and satisfaction as a caregiver as well as intent to continue fostering. The sample consisted of 155 licensed foster caregivers from across the United States. Child behaviors served as a significant moderator between some types of supports and satisfaction. Implications for future research, practice, and policy are discussed. PMID- 26012716 TI - Detection of composite communities in multiplex biological networks. AB - The detection of community structure is a widely accepted means of investigating the principles governing biological systems. Recent efforts are exploring ways in which multiple data sources can be integrated to generate a more comprehensive model of cellular interactions, leading to the detection of more biologically relevant communities. In this work, we propose a mathematical programming model to cluster multiplex biological networks, i.e. multiple network slices, each with a different interaction type, to determine a single representative partition of composite communities. Our method, known as SimMod, is evaluated through its application to yeast networks of physical, genetic and co-expression interactions. A comparative analysis involving partitions of the individual networks, partitions of aggregated networks and partitions generated by similar methods from the literature highlights the ability of SimMod to identify functionally enriched modules. It is further shown that SimMod offers enhanced results when compared to existing approaches without the need to train on known cellular interactions. PMID- 26012718 TI - Pregnancy Outcomes and Risk Factors for Uterine Rupture After Laparoscopic Myomectomy: A Single-Center Experience and Literature Review. AB - STUDY OBJECTIVE: To evaluate pregnancy outcomes after laparoscopic myomectomy (LSM), focusing on the risk of uterine rupture. DESIGN: Retrospective cohort study (Canadian Task Force classification III). SETTING: University hospital. PATIENTS: Of 676 women who visited the obstetrics department for a pregnancy after undergoing LSM performed at the same center between 1994 and 2012, we included the 523 women who had follow-up through the end of pregnancy. INTERVENTIONS: All patients underwent LSM, and their medical charts were retrospectively reviewed. MEASUREMENTS AND MAIN RESULTS: Multiple myomas were removed in 35.2% of cases, intramural-type lesions occurred in 46.5% of cases, and the mean myoma diameter was 4.9 cm. Pregnancy outcomes after LSM included 400 (76.5%) full-term deliveries and 100 (19.1%) vaginal deliveries, with other adverse outcomes being no different than the general population. The mean interval between LSM and pregnancy was 14 months, and only 3 (0.6%) cases of uterine rupture occurred during pregnancy. In analysis, by reviewing the published cases of uterine rupture, we found that the mean diameter, myoma number and type, and the rate of uterine suture were similar between the ruptured cases and all of our cases of LSM. CONCLUSION: LSM can be safely used in women of reproductive age who want to become pregnant. Uterine rupture occurs in rare cases, regardless of myoma features, but further large-scale studies are required to ascertain the detailed effects of various surgical techniques. PMID- 26012719 TI - 3,6,7-Triamino-[1,2,4]triazolo[4,3-b][1,2,4]triazole: A Non-toxic, High Performance Energetic Building Block with Excellent Stability. AB - A novel strategy for the design of energetic materials that uses fused amino substituted triazoles as energetic building blocks is presented. The 3,6,7 triamino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazolium (TATOT) motif can be incorporated into many ionic, nitrogen-rich materials to form salts with advantages such as remarkably high stability towards physical or mechanical stimuli, excellent calculated detonation velocity, and toxicity low enough to qualify them as "green explosives". Neutral TATOT can be synthesized in a convenient and inexpensive two-step protocol in high yield. To demonstrate the superior properties of TATOT, 13 ionic derivatives were synthesized and their chemical- and physicochemical properties (e.g., sensitivities towards impact, friction and electrostatic discharge) were investigated extensively. Low toxicity was demonstrated for neutral TATOT and its nitrate salt. Both are insensitive towards impact and friction and the nitrate salt combines outstanding thermal stability (decomposition temperature=280 degrees C) with promising calculated energetic values. PMID- 26012717 TI - Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCepsilon-Dependent ERK Activation and TRBP Phosphorylation. AB - Previously we have shown that morphine regulates adult neurogenesis by modulating miR-181a maturation and subsequent hippocampal neural progenitor cell (NPC) lineages. Using NPCs cultured from PKCepsilon or beta-arrestin2 knockout mice and the MAPK/ERK kinase inhibitor U0126, we demonstrate that regulation of NPC differentiation via the miR-181a/Prox1/Notch1 pathway exhibits ligand-dependent selectivity. In NPCs, morphine and fentanyl activate ERK via the PKCepsilon- and beta-arrestin-dependent pathways, respectively. After fentanyl exposure, the activated phospho-ERK translocates to the nucleus. Conversely, after morphine treatment, phospho-ERK remains in the cytosol and is capable of phosphorylating TAR RNA-binding protein (TRBP), a cofactor of Dicer. This augments Dicer activity and promotes the maturation of miR-181a. Furthermore, using NPCs transfected with wild-type TRBP, SDeltaA, and SDeltaD TRBP mutants, we confirmed the crucial role of TRBP phosphorylation in Dicer activity, miR-181a maturation, and finally the morphine-induced astrocyte-preferential differentiation of NPCs. Thus, morphine modulates the lineage-specific differentiation of NPCs by PKCepsilon-dependent ERK activation with subsequent TRBP phosphorylation and miR-181a maturation. PMID- 26012720 TI - Regional anisotropy of airspace orientation in the lung as assessed with hyperpolarized helium-3 diffusion MRI. AB - PURPOSE: To evaluate regional anisotropy of lung-airspace orientation by assessing the dependence of helium-3 ((3) He) apparent diffusion coefficient (ADC) values on the direction of diffusion sensitization at two field strengths. MATERIALS AND METHODS: Hyperpolarized (3) He diffusion-weighted magnetic resonance imaging (MRI) of the lung was performed at 0.43T and 1.5T in 12 healthy volunteers. A gradient-echo pulse sequence was used with a bipolar diffusion sensitization gradient applied separately along three orthogonal directions. ADC maps, median ADC values, and signal-to-noise ratios were calculated from the diffusion-weighted images. Two readers scored the ADC maps for increased values at lung margins, major fissures, or within focal central regions. RESULTS: ADC values were found to depend on the direction of diffusion sensitization (P < 0.01, except for craniocaudal vs. anteroposterior directions at 1.5T) and were increased at the lateral and medial surfaces for left-right diffusion sensitization (12 of 12 subjects); at the apex and base (9 of 12), and along the major fissure (8 of 12), for craniocaudal diffusion sensitization; and at the most anterior and posterior lung (10 of 12) for anteroposterior diffusion sensitization. Median ADC values at 0.43T (0.201 +/- 0.017, left-right; 0.193 +/- 0.019, craniocaudal; and 0.187 +/- 0.017 cm(2) /s, anteroposterior) were slightly lower than those at 1.5T (0.205 +/- 0.017, 0.197 +/- 0.017 and 0.194 +/- 0.016 cm(2) /s, respectively; P < 0.05). CONCLUSION: These findings indicate that diffusion-weighted hyperpolarized (3) He MRI can detect regional anisotropy of lung-airspace orientation, including that associated with preferential orientation of terminal airways near pleural surfaces. PMID- 26012721 TI - Emergency medicine as a primary specialty-French emergency medicine residents' attitudes. AB - Emergency medicine (EM) has been a fellowship program (supra-specialty) in France since 2004. Even though the program can be accessed after completion of one of several primary specialties, the vast majority (97%) of its residents enter the program after having completed training in family medicine. A change to develop a primary EM specialty is being discussed. Our objective was to assess French residents and young EM physicians' attitudes toward EM as a primary specialty. We conducted a brief cross-sectional online survey among young EM physicians and trainees in November and December 2012. There were 288 respondents to the survey. Forty-nine percent (n=142) of respondents would have chosen EM if it was a primary specialty, but 73% (n=209) prefer maintaining the status quo, offering EM training as a supra-specialty fellowship program. Work-related quality of life was the main reason for those not choosing EM as a primary specialty. PMID- 26012722 TI - Suppression of the swallowing reflex by stimulation of the red nucleus. AB - We study whether the red nucleus is involved in control of swallowing. The swallowing reflex was induced in anesthetized rats by repetitive electrical stimulation of the superior laryngeal nerve. The electromyographic activities of the mylohyoid and thyrohyoid muscles were recorded in order to identify the swallowing reflex. Repetitive electrical stimulation applied to the red nucleus reduced the number of swallows. The onset latency of the first swallow was increased during repetitive electrical stimulation applied to the magnocellular part of the red nucleus. Microinjection of monosodium glutamate into the red nucleus also reduced the number of swallows. The onset latency of the first swallow was increased after microinjection of monosodium glutamate into the magnocellular part of the red nucleus. These results imply that the red nucleus is involved in the control of swallowing. PMID- 26012723 TI - Quantitative trait loci * environment interactions for plant morphology vary over ontogeny in Brassica rapa. AB - Growth in plants occurs via the addition of repeating modules, suggesting that the genetic architecture of similar subunits may vary between earlier- and later developing modules. These complex environment * ontogeny interactions are not well elucidated, as studies examining quantitative trait loci (QTLs) expression over ontogeny have not included multiple environments. Here, we characterized the genetic architecture of vegetative traits and onset of reproduction over ontogeny in recombinant inbred lines of Brassica rapa in the field and glasshouse. The magnitude of genetic variation in plasticity of seedling internodes was greater than in those produced later in ontogeny. We correspondingly detected that QTLs for seedling internode length were environment-specific, whereas later in ontogeny the majority of QTLs affected internode lengths in all treatments. The relationship between internode traits and onset of reproduction varied with environment and ontogenetic stage. This relationship was observed only in the glasshouse environment and was largely attributable to one environment-specific QTL. Our results provide the first evidence of a QTL * environment * ontogeny interaction, and provide QTL resolution for differences between early- and later stage plasticity for stem elongation. These results also suggest potential constraints on morphological evolution in early vs later modules as a result of associations with reproductive timing. PMID- 26012724 TI - Progression of drug exanthemas to serious drug eruptions: A retrospective review identifying early determinants. AB - BACKGROUND/OBJECTIVES: Maculo-papular drug exanthema (MPE) is the most common type of cutaneous adverse drug reaction (CAR). Exanthematous macules and papules may also be the initial presentation of severe CAR (SCAR). We aimed to identify characteristics associated with the diagnosis of SCAR in CAR-hospitalised patients. METHODS: This cross-sectional study was performed in a tertiary hospital in Chile. All CAR patients who were initially evaluated for exanthematous macules and papules were assessed for clinical, laboratory and pathological variables and these were contrasted with MPE or SCAR diagnosis at discharge. RESULTS: We enrolled 86 patients, of whom 25 (29%) had an at-discharge diagnosis of SCAR. SCAR patients were younger and the latency (time from starting drug to development of first skin lesions) was longer than in MPE patients: 43.6 +/- 18.7 years versus 54.0 +/- 21.8 years (P = 0.039) and 14 days; range 1 to 35, versus 7 days; range 1 to 45 (P = 0.001). The presence of cutaneous pain (OR 7.4 95% CI 1.3-41), mucosal involvement (OR 9.5 CI 95% 2.6- 34.5) and anticonvulsant use (OR 6.11 95% CI 1.91-19.53) were significantly associated with SCAR at discharge. Antibiotics use was significantly associated with MPE diagnosis (OR 2.8 95% CI 1.1-7.6). These six variables together explain 45% of the risk of having SCAR (R2 = 0.449). None of the early laboratory or pathological variables was associated with SCAR. CONCLUSIONS: In hospitalised patients assessed for exanthematous macules and papules, the evaluation of these clinical features may aid in the early identification of SCAR cases. PMID- 26012725 TI - When is rotational angiography superior to conventional single-plane angiography for planning coronary angioplasty? AB - OBJECTIVES: To investigate the value of rotational coronary angiography (RoCA) in the context of percutaneous coronary intervention (PCI) planning. BACKGROUND: As a diagnostic tool, RoCA is associated with decreased patient irradiation and contrast use compared with conventional coronary angiography (CA) and provides superior appreciation of three-dimensional anatomy. However, its value in PCI remains unknown. METHODS: We studied stable coronary artery disease assessment and PCI planning by interventional cardiologists. Patients underwent either RoCA or conventional CA pre-PCI for planning. These were compared with the referral CA (all conventional) in terms of quantitative lesion assessment and operator confidence. An independent panel reanalyzed all parameters. RESULTS: Six operators performed 127 procedures (60 RoCA, 60 conventional CA, and 7 crossed over) and assessed 212 lesions. RoCA was associated with a reduction in the number of lesions judged to involve a bifurcation (23 vs. 30 lesions, P < 0.05) and a reduction in the assessment of vessel caliber (2.8 vs. 3.0 mm, P < 0.05). RoCA improved confidence assessing lesion length (P = 0.01), percentage stenosis (P = 0.02), tortuosity (P < 0.04), and proximity to a bifurcation (P = 0.03), particularly in left coronary artery cases. X-ray dose, contrast agent volume, and procedure duration were not significantly different. CONCLUSIONS: Compared with conventional CA, RoCA augments quantitative lesion assessment, enhances confidence in the assessment of coronary artery disease and the precise details of the proposed procedure, but does not affect X-ray dose, contrast agent volume, or procedure duration. PMID- 26012726 TI - Arylamino Esters As P-Glycoprotein Modulators: SAR Studies to Establish Requirements for Potency and Selectivity. AB - A set of basic aryl-group-containing compounds was synthesized with the aim of developing potent and selective P-glycoprotein (P-gp) modulators that are able to reverse multidrug resistance (MDR). The natures of the spacer (dicyclohexylamine or dialkylamine) and the aryl moieties were modified to investigate selectivity and the mechanism of P-gp interaction. The inhibitory activities of the compounds toward P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), the most relevant ATP binding cassette (ABC) transporters for MDR, were evaluated. The mechanism of P-gp interaction for each compound was investigated with three biological assays: apparent permeability (Papp ) determination (B->A/A->B) in Caco-2 cell monolayers, ATP cell depletion, and inhibition of Calcein-AM transport in MDCK-MDR1 cells. These assays allowed us to estimate the selectivity of the compounds for the three efflux pumps and to identify the structural requirements that define the P-gp-interaction profile. All dicyclohexylamine derivatives were found to be P-gp substrates, whereas one dialkylamine derivative was shown to be a P-gp inhibitor. The good MRP1 activity of one cis/cis isomer highlighted this as a lead candidate for the development of MRP1 ligands. PMID- 26012729 TI - ANCA-positive crescentic glomerulonephritis in a patient with rheumatoid arthritis treated with anti-tumor necrosis factor alpha. PMID- 26012727 TI - 11p15 duplication and 13q34 deletion with Beckwith-Wiedemann syndrome and factor VII deficiency. AB - Here we report a patient with 11p15.4p15.5 duplication and 13q34 deletion presenting with Beckwith-Wiedemann syndrome (BWS) and moderate deficiency of factor VII (FVII). The duplication was initially diagnosed on methylation sensitive multiplex ligation-dependent probe amplification. Array comparative genome hybridization confirmed its presence and indicated a 13q34 distal deletion. The patient's clinical symptoms, including developmental delay and facial dysmorphism, were typical of BWS with paternal 11p15 trisomy. Partial 13q monosomy in this patient is associated with moderate deficiency of FVII and may also overlap with a few symptoms of paternal 11p15 trisomy such as developmental delay and some facial features. To our knowledge this is the first report of 11p15.4p15.5 duplication associated with deletion of 13q34 and FVII deficiency. Moreover, this report emphasizes the importance of detailed clinical as well as molecular examinations in patients with BWS features and developmental delay. PMID- 26012728 TI - A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination. AB - BACKGROUND: New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. METHODS: In the phase I portion of this phase I/II study, non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals. Inc., Clemmons, NC) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary endpoint was the recommended phase II dosing regimen. RESULTS: The cohort (n = 14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2 29.7) months, median age of 61 years, and median Gleason score of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (five metastatic, one rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose-limiting toxicities led to the selection of 4,000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, P = 0.17). No patients experienced a maintained decline in serum PSA from baseline. CONCLUSION: These data suggest that 4,000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low-dose (500 mg) and high-dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial. PMID- 26012730 TI - Pyogenic liver abscess in patients with inflammatory bowel disease: a nationwide cohort study. AB - BACKGROUND & AIMS: Pyogenic liver abscess (PLA) is a rare and severe extraintestinal complication in patients with inflammatory bowel disease (IBD). However, the incidence of PLA in patients with IBD remains unknown. METHODS: A nationwide cohort study was conducted by analysing data from the National Health Insurance Research Database in Taiwan. Patients with IBD (N = 11 504) from 2000 to 2010 and control participants without IBD (N = 46 016) were included in this study. We analysed the risks of PLA by using competing-risks (death) regression models. RESULTS: The incidence of PLA was higher in the IBD cohort than in the control cohort (6.72 vs 4.06 per 10 000 person-years), with an adjusted subhazard ratio (SHR) of 1.46 (95% confidence interval [CI], 1.01-2.12). Patients with IBD who required two or more hospitalizations per year and underwent laparotomy had an increased risk of PLA. Patients with ulcerative colitis were more likely to develop PLA than were those with Crohn's disease (incidence, 8.56 vs 5.45 per 10 000 person-years; adjusted SHR, 1.65 vs 1.32). Among the IBD cohort, age and gender did not affect PLA risk. Patients with diabetes mellitus or percutaneous aspiration of the gallbladder and biliary tract and who underwent endoscopic insertion of a biliary drainage tube exhibited a significantly increased risk of PLA. CONCLUSIONS: Patients with IBD exhibited an increased risk of developing PLA, particularly those with ulcerative colitis. Knowledge of the expected frequency and potential risk for this severe extraintestinal infection may minimize the serious consequences. PMID- 26012731 TI - Diagnosing and treating neurogenic orthostatic hypotension in primary care. AB - In response to a change in posture from supine or sitting to standing, autonomic reflexes normally maintain blood pressure (BP) by selective increases in arteriovenous resistance and by increased cardiac output, ensuring continued perfusion of the central nervous system. In neurogenic orthostatic hypotension (NOH), inadequate vasoconstriction and cardiac output cause BP to drop excessively, resulting in inadequate perfusion, with predictable symptoms such as dizziness, lightheadedness and falls. The condition may represent a central failure of baroreceptor signals to modulate cardiovascular function, a peripheral failure of norepinephrine release from cardiovascular sympathetic nerve endings, or both. Symptomatic patients may benefit from both non-pharmacologic and pharmacologic interventions. Among the latter, two pressor agents have been approved by the US Food and Drug Administration: the sympathomimetic prodrug midodrine, approved in 1996 for symptomatic orthostatic hypotension, and the norepinephrine prodrug droxidopa, approved in 2014, which is indicated for the treatment of symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure). A wide variety of off-label options also have been described (e.g. the synthetic mineralocorticoid fludrocortisone). Because pressor agents may promote supine hypertension, NOH management requires monitoring of supine BP and also lifestyle measures to minimize supine BP increases (e.g. head-of-bed elevation). However, NOH has been associated with cognitive impairment and increases a patient's risk of syncope and falls, with the potential for serious consequences. Hence, concerns about supine hypertension - for which the long-term prognosis in patients with NOH is yet to be established - must sometimes be balanced by the need to address a patient's immediate risks. PMID- 26012732 TI - Analysis of the nicotinamide phosphoribosyltransferase family provides insight into vertebrate adaptation to different oxygen levels during the water-to-land transition. AB - One of the most important events in vertebrate evolutionary history is the water to-land transition, during which some morphological and physiological changes occurred in concert with the loss of specific genes in tetrapods. However, the molecular mechanisms underlying this transition have not been well explored. To explore vertebrate adaptation to different oxygen levels during the water-to-land transition, we performed comprehensive bioinformatics and experimental analysis aiming to investigate the NAMPT family in vertebrates. NAMPT, a rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, is critical for cell survival in a hypoxic environment, and a high level of NAMPT significantly augments oxidative stress in normoxic environments. Phylogenetic analysis showed that NAMPT duplicates arose from a second round whole-genome duplication event. NAMPTA existed in all classes of vertebrates, whereas NAMPTB was only found in fishes and not tetrapods. Asymmetric evolutionary rates and purifying selection were the main evolutionary forces involved. Although functional analysis identified several functionally divergent sites during NAMPT family evolution, in vitro experimental data demonstrated that NAMPTA and NAMPTB were functionally conserved for NAMPT enzymatic function in the NAD+ salvage pathway. In situ hybridization revealed broad NAMPTA and NAMPTB expression patterns, implying regulatory functions over a wide range of developmental processes. The morpholino-mediated knockdown data demonstrated that NAMPTA was more essential than NAMPTB for vertebrate embryo development. We propose that the retention of NAMPTB in water breathing fishes and its loss in air-breathing tetrapods resulted from vertebrate adaptation to different oxygen levels during the water-to-land transition. PMID- 26012737 TI - Bond breaking dynamics in semiflexible networks under load. AB - We examine the bond-breaking dynamics of transiently cross-linked semiflexible networks using a single filament model in which that filament is peeled from an array of cross-linkers. We examine the effect of quenched disorder in the placement of the linkers along the filament and the effect of stochastic bond breaking (assuming Bell model unbinding kinetics) on the dynamics of filament cross-linker dissociation and the statistics of ripping events. We find that bond forces decay exponentially away from the point of loading and that bond breaking proceeds sequentially down the linker array from the point of loading in a series of stochastic ripping events. We compare these theoretical predictions to the observed trajectories of large beads in a cross-linked microtubule network and identify the observed jumps of the bead with the linker rupture events predicted by the single filament model. PMID- 26012738 TI - Comparison between 200 mg QD and 100 mg BID oral celecoxib in the treatment of knee or hip osteoarthritis. AB - This network meta-analysis aimed to investigate the effectiveness and safety of 100 mg BID and 200 mg QD oral celecoxib in the treatment of OA of the knee or hip. PubMed, Embase and Cochrane Library were searched through from inception to August 2014. Bayesian network meta-analysis was used to combine direct and indirect evidences on treatment effectiveness and safety. A total of 24 RCTs covering 11696 patients were included. For the comparison in between the two dosage regimens, 100 mg BID oral celecoxib exhibited a greater probability to be the preferred one either in terms of pain intensity or function at the last follow-up time point. For total gastrointestinal (GI) adverse effects (AEs), both of the two dosage regimens demonstrated a higher incidence compared to the placebo group. Further analyses of GI AEs revealed that only 200 mg QD was associated with a significantly higher risk of abdominal pain when compared with placebo. Furthermore, 100 mg BID showed a significantly lower incidence of skin AEs when compared with 200 mg QD and placebo. Maybe 100 mg BID should be considered as the preferred dosage regimen in the treatment of knee or hip OA. PMID- 26012739 TI - Atrx promotes heterochromatin formation at retrotransposons. AB - More than 50% of mammalian genomes consist of retrotransposon sequences. Silencing of retrotransposons by heterochromatin is essential to ensure genomic stability and transcriptional integrity. Here, we identified a short sequence element in intracisternal A particle (IAP) retrotransposons that is sufficient to trigger heterochromatin formation. We used this sequence in a genome-wide shRNA screen and identified the chromatin remodeler Atrx as a novel regulator of IAP silencing. Atrx binds to IAP elements and is necessary for efficient heterochromatin formation. In addition, Atrx facilitates a robust and largely inaccessible heterochromatin structure as Atrx knockout cells display increased chromatin accessibility at retrotransposons and non-repetitive heterochromatic loci. In summary, we demonstrate a direct role of Atrx in the establishment and robust maintenance of heterochromatin. PMID- 26012742 TI - Asymmetric cell divisions constructing Arabidopsis stem cell niches: the emerging role of protein phosphatases. AB - Plant stem cell niches (SCNs) can be maintained in time through asymmetric cell divisions (ACDs) that allow the production of new cell types while constantly renewing the pools of stem cells (SCs). ACDs in plants require the asymmetric distribution of molecular components inside the cells as well as external asymmetric positional information. These two types of asymmetric information are controlled by inter- and intracellular signalling events. Phosphorylation of proteins is a major intermediate step in these signalling events, serving either as an activator or repressor of signalling, via fast auto- and trans phosphorylation mechanisms. Whereas protein kinases, which phosphorylate proteins on serine, threonine or tyrosine residues, have been thoroughly studied, less attention has been given to protein phosphatases, which de-phosphorylate their protein targets on these same residues. Phosphatases modulate the activity of signalling pathways by balancing the action of kinases, and are therefore critical in the regulation of ACDs in plants. In this review, we first present the different types of ACDs that operate during Arabidopsis embryonic and post embryonic development and participate in the construction and maintenance of its root and shoot SCNs; we then give a brief description of the main protein phosphatases so far described in the Arabidopsis genome; and finally discuss their functions toward the regulation of the ACDs introduced in the first part of the paper. PMID- 26012741 TI - Histological changes of the unligated vein wall adjacent to the central venous catheter after open cutdown in rats. AB - BACKGROUND: The sequelae of a central venous cutdown usually include venous deformity causing venous stenosis or stricture. However, the cellular mechanisms causing these deformities have not been elucidated. METHODS: Silicone 2.7-Fr catheters were placed via the right external jugular vein of 16 rats with the cutdown method. After fixation with formalin at scheduled intervals (1week, 2weeks, 4weeks, and 8weeks; 4 rats in each group), the vein segment with the catheter in situ was harvested. Histological changes in the vein wall were studied and serially compared with light microscopy; standard hematoxylin-eosin staining, Masson's trichrome staining, van Gieson's elastin stain, and immunohistochemical stain against alpha-actin. RESULTS: Pericatheter sleeve formation, circumferential smooth muscle cell proliferation and infiltration into the pericatheter sleeve by direct contact were noted in all 4 rats of 1-week model; this indicated the initiation of neointimal hyperplasia. The neointimal hyperplasia was located inside the elastin layer. At 2weeks, the SMCs stained faintly but the components of the vein wall were largely replaced by collagen. The proliferation and infiltration of SMCs stabilized at 4weeks and no SMCs were stained around the catheter. At 8weeks, luminal narrowing was noted and the venous wall was composed mainly of collagen. CONCLUSIONS: Circumferential neointimal hyperplasia occurred after surgical cutdown of the external jugular vein in a rat model and was caused by SMC activation, proliferation, and infiltration into the pericatheter sleeve. PMID- 26012740 TI - Pregnant women with HIV in rural Nigeria have higher rates of antiretroviral treatment initiation, but similar loss to follow-up as non-pregnant women and men. AB - BACKGROUND: We examined antiretroviral therapy (ART) initiation and retention by sex and pregnancy status in rural Nigeria. METHODS: We studied HIV-infected ART naive patients aged >=15 years entering care from June 2009 to September 2013. We calculated the probability of early ART initiation and cumulative incidence of loss to follow-up (LTFU) during the first year of ART, and examined the association between LTFU and sex/pregnancy using Cox regression. RESULTS: The cohort included 3813 ART-naive HIV-infected adults (2594 women [68.0%], 273 [11.8%] of them pregnant). The proportion of pregnant clients initiating ART within 90 days of enrollment (78.0%, 213/273) was higher than among non-pregnant women (54.3%,1261/2321) or men (53.0%, 650/1219), both p<0.001. Pregnant women initiated ART sooner than non-pregnant women and men (median [IQR] days from enrollment to ART initiation for pregnant women=7 days [0-21] vs 14 days [7-49] for non-pregnant women and 14 days [7-42] for men; p<0.001). Cumulative incidence of LTFU during the first year post-ART initiation was high and did not differ by sex and pregnancy status. Persons who were unemployed, bedridden, had higher CD4+ counts, and/or in earlier WHO clinical stages were more likely to be LTFU. CONCLUSIONS: Pregnant women with HIV in rural Nigeria were more likely to initiate ART but were no more likely to be retained in care. Our findings underscore the importance of effective retention strategies across all patient groups, regardless of sex and pregnancy status. PMID- 26012743 TI - TC-2559, an alpha4beta2 nicotinic acetylcholine receptor agonist, suppresses the expression of CCL3 and IL-1beta through STAT3 inhibition in cultured murine macrophages. AB - The anti-inflammatory properties of TC-2559, an alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonist, on cultured murine macrophages was investigated. TC-2559 suppressed the upregulation of CC-chemokine ligand 3 (CCL3) and interleukin-1beta (IL-1beta) following lipopolysaccharide (LPS) treatment in J774A.1 cells. TC-2559 inhibited the phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) but not nuclear factor-kappaB p65 after LPS. Blockade of pSTAT3 by AG490 inhibited the upregulation of CCL3 and IL-1beta after LPS. In conclusion, TC-2559-driven alpha4beta2 nAChR signaling suppressed the upregulation of CCL3 and IL-1beta by inhibiting pSTAT3 in inflammatory macrophages, resulting in the suppression of neuropathic pain. PMID- 26012744 TI - OsWS1 involved in cuticular wax biosynthesis is regulated by osa-miR1848. AB - Cuticular wax forms a hydrophobic layer covering aerial plant organs and acting as a protective barrier against biotic and abiotic stresses. Compared with well known wax biosynthetic pathway, molecular regulation of wax biosynthesis is less known. Here, we show that rice OsWS1, a member of the membrane-bound O-acyl transferase gene family, involved in wax biosynthesis and was regulated by an osa miR1848. OsWS1-tagged green fluorescent protein localized to the endoplasmic reticulum (ER). Compared with wild-type rice, OsWS1 overexpression plants displayed a 3% increase in total wax, especially a 35% increase in very long chain fatty acids, denser wax papillae around the stoma, more cuticular wax crystals formed on leaf and stem surfaces, pollen coats were thicker and more seedlings survived after water-deficit treatment. In contrast, OsWS1-RNAi and osa miR1848 overexpression plants exhibited opposing changes. Gene expression analysis showed that overexpression of osa-miR1848 down-regulated OsWS1 transcripts; furthermore, expression profiles of OsWS1 and osa-miR1848 were inversely correlated in the leaf, panicle and stem, and upon water-deficit treatment. These results suggest that OsWS1 is regulated by osa-miR1848 and participates in cuticular wax formation. PMID- 26012746 TI - Reversible piezochromism in a molecular wine-rack. AB - The highly-polymorphic, strongly-coloured 'ROY' system exhibits a yellow -> orange -> red piezochromic response under hydrostatic compression. The 'Y' (yellow) polymorph accommodates the effect of pressure via a wine-rack-type mechanism, made accessible by the conformational flexibility of the molecule, while retaining the crystal symmetry of the parent Y form. Decompression from 1.49 GPa demonstrates reversibility of this behaviour. PMID- 26012745 TI - Visual system evolution and the nature of the ancestral snake. AB - The dominant hypothesis for the evolutionary origin of snakes from 'lizards' (non snake squamates) is that stem snakes acquired many snake features while passing through a profound burrowing (fossorial) phase. To investigate this, we examined the visual pigments and their encoding opsin genes in a range of squamate reptiles, focusing on fossorial lizards and snakes. We sequenced opsin transcripts isolated from retinal cDNA and used microspectrophotometry to measure directly the spectral absorbance of the photoreceptor visual pigments in a subset of samples. In snakes, but not lizards, dedicated fossoriality (as in Scolecophidia and the alethinophidian Anilius scytale) corresponds with loss of all visual opsins other than RH1 (lambdamax 490-497 nm); all other snakes (including less dedicated burrowers) also have functional sws1 and lws opsin genes. In contrast, the retinas of all lizards sampled, even highly fossorial amphisbaenians with reduced eyes, express functional lws, sws1, sws2 and rh1 genes, and most also express rh2 (i.e. they express all five of the visual opsin genes present in the ancestral vertebrate). Our evidence of visual pigment complements suggests that the visual system of stem snakes was partly reduced, with two (RH2 and SWS2) of the ancestral vertebrate visual pigments being eliminated, but that this did not extend to the extreme additional loss of SWS1 and LWS that subsequently occurred (probably independently) in highly fossorial extant scolecophidians and A. scytale. We therefore consider it unlikely that the ancestral snake was as fossorial as extant scolecophidians, whether or not the latter are para- or monophyletic. PMID- 26012776 TI - Evaluation of cell sorting aerosols and containment by an optical airborne particle counter. AB - Understanding aerosols produced by cell sorting is critical to biosafety risk assessment and validation of containment efficiency. In this study an Optical Airborne Particle Counter was used to analyze aerosols produced by the BD FACSAria and to assess the effectiveness of its aerosol containment. The suitability of using this device to validate containment was directly compared to the Glo-Germ method put forth by the International Society for Advancement of Cytometry (ISAC) as a standard for testing. It was found that high concentrations of aerosols ranging from 0.3 um to 10 um can be detected in failure mode, with most less than 5 um. In most cases, while numerous aerosols smaller than 5 um were detected by the Optical Airborne Particle Counter, no Glo-Germ particles were detected, indicating that small aerosols are under-evaluated by the Glo-Germ method. The results demonstrate that the Optical Airborne Particle Counter offers a rapid, economic, and quantitative analysis of cell sorter aerosols and represents an improved method over Glo-Germ for the task of routine validation and monitoring of aerosol containment for cell sorting. PMID- 26012777 TI - Remembrance of time series past: simple chromatic method for visualizing trends in biomedical signals. AB - Analysis of biomedical time series plays an essential role in clinical management and basic investigation. However, conventional monitors streaming data in real time show only the most recent values, not referenced to past dynamics. We describe a chromatic approach to bring the 'memory' of the physiologic system's past behavior into the current display window.The method employs the estimated probability density function of a time series segment to colorize subsequent data points.For illustrative purposes, we selected open-access recordings of continuous: (1) fetal heart rate during the pre-partum period, and (2) heart rate and systemic blood pressure from a critical care patient during a spontaneous breathing trial. The colorized outputs highlight changes from the 'baseline' reference state, the latter defined as the mode value assumed by the signal, i.e. the maximum of its probability density function.A colorization method may facilitate the recognition of relevant features of time series, especially shifts in baseline dynamics and other trends (including transient and longer-term deviation from baseline values) which may not be as readily noticed using traditional displays. This method may be applicable in clinical monitoring (real time or off-line) and in research settings. Prospective studies are needed to assess the utility of this approach. PMID- 26012778 TI - Functional in situ assessment of muscle contraction in wild-type and mdx mice. AB - INTRODUCTION: Reports of muscle testing are frequently limited to maximal force alone. The experiments reported here show that force generation and relaxation rates can be obtained from the same experiments and provide a more complete functional characterization. METHODS: Partial in situ testing was performed on the tibialis anterior of young wild-type (WT) mice, young mdx mice, and old mdx mice. Force, force generation rate, and relaxation rates were measured during a fatigue test, 2 frequency-force tests, and a passive tension test. RESULTS: We measured increased force but decreased force generation rate in WT compared with mdx muscles, and increased force but decreased relaxation rate of old compared with young mdx muscles. Young mdx muscles were the most sensitive to increases in passive tension. CONCLUSIONS: These measurements offer an improved understanding of muscle capability and are readily acquired by further analysis of the same tests used to obtain force measurements. PMID- 26012779 TI - Fractional carbon dioxide laser-assisted photodynamic therapy for patients with actinic keratosis. AB - BACKGROUND/PURPOSE: A relatively long incubation time is needed for photosensitizer absorption in conventional photodynamic therapy (PDT) for actinic keratosis (AK). The use of ablative CO2 fractional lasers (AFXLs) to increase drug delivery could shorten the incubation time. Here, we aimed to compare the efficacy between AFXL-assisted PDT with a short incubation time and conventional PDT for AK. METHODS: Patients with histopathologically confirmed facial AK were randomly divided into two groups. The lesions were histopathologically classified into grades I-III. In the AFXL-assisted PDT group, an ablative fractional laser was used for pretreatment, prior to the application of methyl aminolevulinate, with an incubation time of 90 min. Irradiation was performed with a 630-nm light emitting diode. In the conventional PDT group, the incubation time was 180 min. All the patients received two rounds of PDT at 2-week intervals and underwent clinical or histological evaluation at 10 weeks after the first PDT course. RESULTS: Twenty-two patients underwent conventional PDT and 24 patients underwent AFXL-assisted PDT. Thirty-four AKs were included in the conventional PDT group, and 35 AKs were included in the AFXL-assisted PDT group. The clearance rate was 64.7% in the conventional PDT and 71.4% in the AFXL-assisted PDT group; no significant differences in the clearance rate were noted between the groups (P = 0.55). The clearance rates for each grade also did not significantly differ between the two groups. CONCLUSIONS: The use of AFXL before PDT reduced the incubation time, but yielded similar treatment efficacy as compared to conventional PDT. PMID- 26012780 TI - Pilot study on novel skin care method by augmentation with Staphylococcus epidermidis, an autologous skin microbe--A blinded randomized clinical trial. AB - BACKGROUND AND OBJECTIVE: Staphylococcus epidermidis is an autologous bacterium that is beneficial to skin health. Our goal was to develop a novel, personalized basic cosmetic that exploits this characteristic. METHODS: We conducted a double blinded, randomized clinical trial on augmentation with S. epidermidis as a pilot study, in which S. epidermidis was collected from the subject, cultured for proliferation, and then continuously applied to the subject's own face before sleep twice per week for four weeks in order to increase colonization levels. RESULTS: The results showed that this treatment increased the lipid content of the skin and suppressed water evaporation, thereby markedly improving skin moisture retention. Moreover, augmentation with S. epidermidis maintained a low acidic condition on the skin surface. The low risk of undesirable effects induced by augmentation with S. epidermidis was also confirmed by measuring erythema and melanin levels. CONCLUSIONS: These results may serve as a driving force to accelerate the development of novel, personalized basic cosmetics. PMID- 26012781 TI - MiR-218 Inhibited Growth and Metabolism of Human Glioblastoma Cells by Directly Targeting E2F2. AB - In recent years, microRNA has become a hotspot in research on diseases, especially in the initiation and progression of different types of cancer. In this study, we found that miR-218 could inhibit growth and metabolism in gliomas by directly targeting E2F2. First, we obtained data from the Chinese Glioma Genome Atlas (CGGA) database to analyze miR-218 expression in different grades of gliomas. The effects of miR-218 on cell cycle progression and cell proliferation in U87 and U251 cell lines were investigated by flow cytometry, specifically CCK8 assay and tablet cloning, respectively. Glucose consumption and lactate production of glioma cell lines were measured by correlative test kits. Furthermore, we used Western blot analysis and luciferase reporter assay to identify the direct and functional target of miR-218. Data from the CGGA database and real-time quantitative reverse transcription-PCR demonstrated that miR-218 was obviously reduced in human glioblastoma tissues, as well as in the cell lines. When miR-218 level was elevated in vitro, cell cycle progression was arrested in the G1 phase, and cell proliferation was dramatically inhibited. Both glucose consumption and lactate production of glioma cells were significantly reduced. Western blot analysis and luciferase reporter assay revealed that E2F2 was a direct target of miR-218 in glioma cells. This investigation demonstrated that elevated E2F2 expression could partly weaken the effect of miR-218 in vitro. This study also showed that miR-218 may be a repressor in glioma by directly targeting E2F2, as well as a potential therapeutic target in gliomas. PMID- 26012782 TI - A Novel Monoclonal Antibody Against Neuroepithelial and Ependymal Cells and Characteristics of Its Positive Cells in Neurospheres. AB - There are still few useful cell membrane surface antigens suitable for identification and isolation of neural stem cells (NSCs). We generated a novel monoclonal antibody (mAb), designated as mAb against immature neural cell antigens (INCA mAb), which reacted with the areas around a lateral ventricle of a fetal cerebrum. INCA mAb specifically reacted with neuroepithelial cells in fetal cerebrums and ependymal cells in adult cerebrums. The recognition molecules were O-linked 40 and 42 kDa glycoproteins on the cell membrane surface (gp40 INCA and gp42 INCA). Based on expression pattern analysis of the recognition molecules in developing cerebrums, it was concluded that gp42 INCA was a stage-specific antigen expressed on undifferentiated neuroepithelial cells, while gp40 INCA was a cell lineage-specific antigen expressed at the stages of differentiation from neuroepithelial cells to ependymal cells. A flow cytometric analysis showed that fetal and young adult neurospheres were divided into INCA mAb(-) CD133 polyclonal antibody (pAb)(-), INCA mAb(+) CD133 pAb(-), and INCA mAb(+) CD133 pAb(+) cell populations based on the reactivity against INCA mAb and CD133 pAb. The proportion of cells having the neurosphere formation capability in the INCA mAb(+) CD133 pAb(+) cell population was significantly larger than that of undivided neurospheres. Neurospheres formed by clonal expansion of INCA mAb(+) CD133 pAb(+) cells gave rise to neurons and glial cells. INCA mAb will be a useful immunological probe in the study of NSCs. PMID- 26012783 TI - Using new technologies to promote weight management: a randomised controlled trial study protocol. AB - BACKGROUND: Over the last three decades, overweight and obesity and the associated health consequences have become global public health priorities. Methods that have been tried to address this problem have not had the desired impact, suggesting that other approaches need to be considered. One of the lessons learned throughout these attempts is that permanent weight loss requires sustained dietary and lifestyle changes, yet adherence to weight management programs has often been noted as one of the biggest challenges. This trial aims to address this issue by examining whether social media, as a potential health promotion tool, will improve adherence to a weight management program. To test the effectiveness of this measure, the designated program will be delivered via the popular social networking site Facebook, and compared to a standard delivery method that provides exactly the same content but which is communicated through a pamphlet. The trial will be conducted over a period of twelve weeks, with a twelve week follow-up. Although weight loss is expected, this study will specifically investigate the effectiveness of social media as a program delivery method. The program utilised will be one that has already been proven to achieve weight loss, namely The CSIRO Total Wellbeing Diet. METHODS/DESIGN: This project will be conducted as a 3-arm randomised controlled trial. One hundred and twenty participants will be recruited from the Perth community, and will be randomly assigned to one of the following three groups: the Facebook group, the pamphlet group, or a control group. The Facebook Group will receive the weight management program delivered via a closed group in Facebook, the Pamphlet Group will be given the same weight management program presented in a booklet, and the Control Group will follow the Australian Dietary Guidelines and the National Physical Activity Guidelines for Adults as usual care. Change in weight, body composition and waist circumference will be initial indicators of adherence to the program. Secondary outcome measures will be blood glucose, insulin, blood pressure, arterial stiffness, physical activity, eating behaviour, mental well-being (stress, anxiety, and depression), social support, self-control, self-efficacy, Facebook activity, and program evaluation. DISCUSSION: It is expected that this trial will support the use of social media - a source of social support and information sharing - as a delivery method for weight management programs, enhancing the reduction in weight expected from dietary and physical activity changes. Facebook is a popular, easy to access and cost-effective online platform that can be used to assist the formation of social groups, and could be translated into health promotion practice relatively easily. It is anticipated in the context of the predicted findings that social media will provide an invaluable resource for health professionals and patients alike. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register (ANZCTR): ACTRN12614000536662. Date registered: 21 May 2014. PMID- 26012784 TI - Proximal caries lesion detection using the Canary Caries Detection System: an in vitro study. AB - OBJECTIVE: This study investigated the accuracy of the Canary System (CS) to detect proximal caries lesions in vitro, and compared it with conventional methods: International Caries Detection and Assessment System (ICDAS) II and bitewing radiography (BW). METHODS: Visible proximal surfaces of extracted human teeth were assessed by ICDAS-II before setting them in five manikin mouth models. Then contacting proximal surfaces in mouth models were assessed by BW and CS. Histological validation with polarized-light microscopy served as a gold standard. Pairwise comparisons were performed on area under the curve (AUC), sensitivity, and specificity of the three methods, and corrected using Bonferroni's method. Sensitivities and specificities were compared using a test of proportions and AUC values were compared using DeLong's method. RESULTS: The CS presented significantly higher sensitivity (0.933) than ICDAS-II (0.733, P = 0.01) and BW (0.267, P < 0.001), and ICDAS-II higher sensitivity than BW (P < 0.001). There were no significant differences between their specificity values: 0.825 (CS), 0.65 (ICDAS-II), and 0.875 (BW). The AUC of CS (0.862) was significantly higher than of ICDAS-II (0.681, P < 0.001) and BW (0.577, P < 0.001). CONCLUSION: The CS demonstrated greater accuracy in detecting proximal lesions than ICDAS-II and BW, although without significantly higher specificity. PMID- 26012785 TI - GTP cyclohydrolase 1 mutations and Parkinson's disease: new insights beyond DOPA responsive dystonia. PMID- 26012787 TI - Effect of specialization on genetic parameters of studbook-entry inspection in Dutch Warmblood horses. AB - Recent studies on data from the Dutch Warmblood Studbook (KWPN) have shown that the ongoing specialization of horses for either dressage (DH) or show jumping (JH) has led to a decreasing genetic relationship between the two subpopulations. The aim of this study was to analyse the effect of the specialization process on the genetic parameters of traits measured in the studbook-entry inspection of KWPN during the last fifteen years. Data from 18,125 DH and 23,800 JH recorded from 1998 until 2013 were used to analyse 13 traits scored in both DH and JH. Analyses were performed in a Bayesian framework. Firstly, variance components were estimated based on the whole data set. Secondly, genetic correlations between traits measured in DH or JH were estimated using bivariate analyses. Thirdly, three time periods were defined and genetic correlations between subpopulations were estimated within each period. Heritability was moderate (0.17 0.39) for both DH and JH. Genetic correlations between traits measured in DH or JH were not different from one considering the posterior standard deviation of the estimation; however, in most of the traits, a clear trend in reduction of the genetic correlation for traits expressed in DH and JH and an increase in their posterior standard deviation for recent years was observed. These results suggest that specialization could lead to differences in traits measured in DH and JH in the recent years. PMID- 26012789 TI - Dielectric Relaxations of (Acetamide + Electrolyte) Deep Eutectic Solvents in the Frequency Window, 0.2 <= nu/GHz <= 50: Anion and Cation Dependence. AB - Dielectric relaxation (DR) measurements in the frequency range 0.2 <= nu/GHz <= 50 have been carried out for neat molten acetamide and six different (acetamide + electrolyte) deep eutectic solvents (DESs) for investigating ion effects on DR dynamics in these ionic DESs. Electrolytes used are lithium salts of bromide (LiBr), nitrate (LiNO3), and perchlorate (LiClO4); sodium salts of perchlorate (NaClO4) and thiocyante (NaSCN); and potassium thiocyanate (KSCN). With these electrolytes acetamide forms DESs approximately at an 80:20 mol ratio. Simultaneous fits to the measured permittivity (epsilon') and loss (epsilon") spectra of these DESs at ~293 K require a sum of four Debye (4-D) processes with relaxation times spread over picosecond to nanosecond regime. In contrast, DR spectra for neat molten acetamide (~354 K) depict 2-D relaxation with time constants ~50 ps and ~5 ps. For both the neat and ionic systems, the undetected dispersion, epsiloninfinity - n(D)2, remains to be ~3-4. Upon comparison, measured DR dynamics reveal pronounced anion and cation effects. Estimated static dielectric constants (epsilon0) from fits for these DESs cover the range 12 < epsilon0 < 30 and are remarkably lower than that (epsilon0 ~ 64) measured for molten acetamide at ~354 K. Hydrodynamic effective rotation volumes (Veff) estimated from the slowest DR relaxation time constants vary with ion identity and are much smaller than the molecular volume of acetamide. This decrease of epsilon0 and Veff is attributed respectively to the pinning of acetamide molecules by ions and orientation jumps and undetected portion to the limited frequency coverage employed in these measurements PMID- 26012788 TI - CON-COUR study: Interferential therapy in the treatment of chronic constipation in adults: study protocol for a randomized controlled trial. AB - BACKGROUND: The prevalence of chronic constipation is about 15 % in Western countries with a significant impact on quality of life and health care costs. The first-line therapy, based on medical treatment combined with laxatives and dietary rules, is often disappointing. Interferential therapy is a new treatment that has demonstrated its efficiency in the treatment of chronic constipation in children and encouraging results in adults. The primary objective of this study is to assess the efficacy of interferential therapy during 8 weeks in adult patients. The secondary objectives are to assess this new and noninvasive therapy in terms of persistence of the clinical efficacy, colonic transit time, ano rectal manometry, patient satisfaction and quality of life (QoL), and tolerance. METHODS/DESIGN: DESIGN: multicenter, prospective, randomized, placebo controlled, double blind, two-parallel groups study. SETTING: nine French adult gastroenterology centers. INCLUSION CRITERIA: adult patients with a history of chronic constipation refractory to medical treatment for at least 3 months. Treatment groups: (1) interferential-experimental group (effective stimulation); (2) placebo-control group (sham stimulation). RANDOMIZATION: 1:1 allocation ratio. Evaluation times: inclusion (T0, randomization), baseline assessment (T1), start of stimulation (T2), intermediary assessment (T3, 4 weeks), end of stimulation (T4, 8 weeks), follow-up (T5 and T6, 1- and 6-month). ENDPOINTS: (1) primary: short-term efficacy at T4 (treatment response defined as three or more spontaneous, complete bowel movements per week); (2) secondary: efficacy at T5 and T6, symptoms (Patient Assessment of Constipation Symptoms questionnaire), colonic transit time, anorectal manometry, patient satisfaction (analogical visual scale), patient QoL (Patient Assessment of Constipation Quality of Life Questionnaire), side/unexpected effects. SAMPLE SIZE: 200 individuals to obtain 80 % power to detect a 20 % difference in treatment response at T4 between the two groups (15 % of lost to follow-up patients expected). DISCUSSION: The randomized, double-blind, placebo-controlled design is the most appropriate to demonstrate the efficacy of a new experimental therapeutic (Evidence-Based Medicine Working Group classification). National and international recommendations could be updated based on the findings of this study. TRIAL REGISTRATION: Current controlled trials NCT02381665 (registration date: February 13, 2015). PMID- 26012790 TI - Five-headed biceps brachii muscle with a rare origin from the tendon of pectoralis major muscle. AB - We found a five-headed biceps brachii (BB) muscle associated with the pectoralis major muscle in a 43-year-old Korean male cadaver during a routine dissection course. A supernumerary head originated from the anterior surface of the distal tendinous part of the pectoralis major muscle, lay in the sulcus between the short and long heads of BB muscle, and terminated at their point of union. The additional two accessory heads originated from the body of the humerus between the insertion site of the coracobrachialis muscle and the origin site of the brachialis muscle and inserted into the distal part of the united muscle belly of the BB muscle. The additional accessory heads were supplied by branches of the musculocutaneous nerve. Although a supernumerary head of BB muscle originated from the pectoralis major is a peculiar finding, morphological details on the presence of another combined variation might be essential for clinicians as well as anatomists. PMID- 26012794 TI - [Globus sensation and progressive hoarseness in esophageal cancer]. PMID- 26012795 TI - [Your experiences with autopsy]. PMID- 26012791 TI - Comparative pharmacokinetics and bioavailability of albendazole sulfoxide in sheep and goats, and dose-dependent plasma disposition in goats. AB - BACKGROUND: The aims of this study were to compare the pharmacokinetics of albendazole sulfoxide (ABZ-SO, ricobendazole) in goats and sheep at a dose of 5 g/kg bodyweight (BW), after intravenous (IV) and subcutaneous (SC) administrations, and to investigate the effects of increased doses (10 and 15 mg/kg BW) on the plasma disposition of ABZ-SO in goats following SC administration. A total of 16 goats (Capra aegagrus hircus, eight males and eight females) and 8 sheep (Ovis aries, four males and four females) 12-16 months old and weighing 20-32 kg, were used. The study was designed according to two-phase crossover study protocol. In Phase-1, eight sheep were assigned as Group I and 16 goats were allocated into two groups (Group II and Group III). ABZ-SO was applied to Group I (sheep) and Group II (goats) animals subcutaneously, and to Group III (goats) animals intravenously, all at a dose rate of 5 mg/kg BW. In Phase-2, the sheep in the Group I received ABZ-SO intravenously in a dose of 5 mg/kg BW; the goats in Group II and Group III received ABZ-SO subcutaneously at a dose of 10 mg/kg and 15 mg/kg BW, respectively. Blood samples were collected from the jugular vein at different times between 1 and 120 h after drug administrations. The plasma concentrations of ABZ-SO and its metabolites were analysed by high performance liquid chromatography. RESULTS: In goats, the area under the curve, terminal half-life and plasma persistence of ABZ-SO were significantly smaller and shorter, respectively, compared with those observed in sheep following both IV and SC administrations at a dose of 5 mg/kg BW. On the other side, dose dependent plasma dispositions of ABZ-SO were observed following SC administration at increased doses (10 and 15 mg/kg) in goats. CONCLUSIONS: Consequently, ABZ-SO might be used at higher doses to provide higher plasma concentration and thus to achieve greater efficacy against the target parasites. PMID- 26012797 TI - [Empathy to the last breath]. PMID- 26012796 TI - ["No evidence that the benefits outweight the damage"]. PMID- 26012806 TI - [More public attorneys in the jungle of health care!]. PMID- 26012807 TI - [Prescribe sports - but in the proper dosage!]. PMID- 26012808 TI - [Almost every 4th stroke patient has atrial fibrillation]. PMID- 26012810 TI - [Even now smoking cessation is worthwhile]. PMID- 26012811 TI - [Do you recognize the signs of hyponatremia?]. PMID- 26012812 TI - [Helpful information for pets]. PMID- 26012814 TI - [Should gays undergo regular tests?]. PMID- 26012818 TI - [A free floating egg in the abdomen]. PMID- 26012819 TI - [Brain doping becomes more popular]. PMID- 26012821 TI - [What caused the death of Richard III of England]. PMID- 26012822 TI - [Counseling intervention helps little in obesity]. PMID- 26012823 TI - [Nodular band of the body surface]. PMID- 26012824 TI - [HPV-associated diseases: ignorance is fatal]. PMID- 26012825 TI - [HPV associated diseases: More than warts and cervical carcinoma]. PMID- 26012827 TI - [Elbow joint dislocation - important considerations for closed reduction]. PMID- 26012826 TI - [HPV-vaccination - not just for girls]. PMID- 26012828 TI - [I constantly feel full and bloated]. PMID- 26012829 TI - [Diagnosis of cognitive disorders in general practice]. PMID- 26012831 TI - [Remembering, recognizing early and treating]. PMID- 26012830 TI - [Use of behavioral therapies in hypertention]. PMID- 26012835 TI - [Advantages of NOAKs validated in clinical routine]. PMID- 26012840 TI - An Involvement of PI3-K/Akt Activation and Inhibition of AIF Translocation in Neuroprotective Effects of Undecylenic Acid (UDA) Against Pro-Apoptotic Factors Induced Cell Death in Human Neuroblastoma SH-SY5Y Cells. AB - Undecylenic acid (UDA), a naturally occurring 11-carbon unsaturated fatty acid, has been used for several years as an economical antifungal agent and a nutritional supplement. Recently, the potential usefulness of UDA as a neuroprotective drug has been suggested based on the ability of this agent to inhibit MU-calpain activity. In order to verify neuroprotective potential of UDA, we tested protective efficacy of this compound against cell damage evoked by pro apoptotic factors (staurosporine and doxorubicin) and oxidative stress (hydrogen peroxide) in human neuroblastoma SH-SY5Y cells. We showed that UDA partially protected SH-SY5Y cells against the staurosporine- and doxorubicin-evoked cell death; however, this effect was not connected with its influence on caspase-3 activity. UDA decreased the St-induced changes in mitochondrial and cytosolic AIF level, whereas in Dox-model it affected only the cytosolic AIF content. Moreover, UDA (1-40 MUM) decreased the hydrogen peroxide-induced cell damage which was connected with attenuation of hydrogen peroxide-mediated necrotic (PI staining, ADP/ATP ratio) and apoptotic (mitochondrial membrane potential, caspase-3 activation, AIF translocation) changes. Finally, we demonstrated that an inhibitor of PI3-K/Akt (LY294002) but not MAPK/ERK1/2 (U0126) pathway blocked the protection mediated by UDA in all tested models of SH-SY5Y cell injury. These in vitro data point to UDA as potentially effective neuroprotectant the utility of which should be further validated in animal studies. PMID- 26012839 TI - Communicating patient-reported outcome scores using graphic formats: results from a mixed-methods evaluation. AB - BACKGROUND: Patient-reported outcomes (PROs) promote patient-centered care by using PRO research results ("group-level data") to inform decision making and by monitoring individual patient's PROs ("individual-level data") to inform care. We investigated the interpretability of current PRO data presentation formats. METHOD: This cross-sectional mixed-methods study randomized purposively sampled cancer patients and clinicians to evaluate six group-data or four individual-data formats. A self-directed exercise assessed participants' interpretation accuracy and ratings of ease-of-understanding and usefulness (0 = least to 10 = most) of each format. Semi-structured qualitative interviews explored helpful and confusing format attributes. RESULTS: We reached thematic saturation with 50 patients (44 % < college graduate) and 20 clinicians. For group-level data, patients rated simple line graphs highest for ease-of-understanding and usefulness (median 8.0; 33 % selected for easiest to understand/most useful) and clinicians rated simple line graphs highest for ease-of-understanding and usefulness (median 9.0, 8.5) but most often selected line graphs with confidence limits or norms (30 % for each format for easiest to understand/most useful). Qualitative results support that clinicians value confidence intervals, norms, and p values, but patients find them confusing. For individual-level data, both patients and clinicians rated line graphs highest for ease-of-understanding (median 8.0 patients, 8.5 clinicians) and usefulness (median 8.0, 9.0) and selected them as easiest to understand (50, 70 %) and most useful (62, 80 %). The qualitative interviews supported highlighting scores requiring clinical attention and providing reference values. CONCLUSIONS: This study has identified preferences and opportunities for improving on current formats for PRO presentation and will inform development of best practices for PRO presentation. Both patients and clinicians prefer line graphs across group-level data and individual-level data formats, but clinicians prefer greater detail (e.g., statistical details) for group-level data. PMID- 26012841 TI - Hyperbranched Hybridization Chain Reaction for Triggered Signal Amplification and Concatenated Logic Circuits. AB - A hyper-branched hybridization chain reaction (HB-HCR) is presented herein, which consists of only six species that can metastably coexist until the introduction of an initiator DNA to trigger a cascade of hybridization events, leading to the self-sustained assembly of hyper-branched and nicked double-stranded DNA structures. The system can readily achieve ultrasensitive detection of target DNA. Moreover, the HB-HCR principle is successfully applied to construct three input concatenated logic circuits with excellent specificity and extended to design a security-mimicking keypad lock system. Significantly, the HB-HCR-based keypad lock can alarm immediately if the "password" is incorrect. Overall, the proposed HB-HCR with high amplification efficiency is simple, homogeneous, fast, robust, and low-cost, and holds great promise in the development of biosensing, in the programmable assembly of DNA architectures, and in molecular logic operations. PMID- 26012842 TI - Rare FLT3 deletion mutants may provide additional treatment options to patients with AML: an approach to individualized medicine. PMID- 26012844 TI - Family Disruption and Intergenerational Reproduction: Comparing the Influences of Married Parents, Divorced Parents, and Stepparents. AB - The transmission of individual characteristics and behaviors across generations has frequently been studied in the social sciences. For a growing number of children, however, the biological father was present in the household for only part of the time; and for many children, stepfathers were present. What are the implications of these changes for the process of intergenerational transmission? To answer this question, this article compares intergenerational transmission among married, divorced, and stepparents. Two forms of reproduction are studied: educational attainment and church attendance. For education, divorced fathers were as influential as married fathers, whereas stepfathers were less influential. For church attendance, married fathers were most influential, divorced fathers were least influential, and stepfathers were in between. Divorced mothers, in contrast, appeared to be more influential than married mothers. These findings lend negative support for the social capital hypothesis and positive support for notions of value socialization. The strong role of the divorced father for educational transmission is consistent with genetic processes and hypotheses about early advantages. PMID- 26012843 TI - Emerging drugs for the treatment of anxiety. AB - INTRODUCTION: Anxiety disorders are among the most prevalent and disabling psychiatric disorders in the United States and worldwide. Basic research has provided critical insights into the mechanism regulating fear behavior in animals and a host of animal models have been developed in order to screen compounds for anxiolytic properties. Despite this progress, no mechanistically novel agents for the treatment of anxiety have come to market in more than two decades. AREAS COVERED: The current review will provide a critical summary of current pharmacological approaches to the treatment of anxiety and will examine the pharmacotherapeutic pipeline for treatments in development. Anxiety and related disorders considered herein include panic disorder, social anxiety disorder, generalized anxiety disorder and post-traumatic stress disorder. The glutamate, neuropeptide and endocannabinoid systems show particular promise as future targets for novel drug development. EXPERT OPINION: In the face of an ever growing understanding of fear-related behavior, the field awaits the translation of this research into mechanistically novel treatments. Obstacles will be overcome through close collaboration between basic and clinical researchers with the goal of aligning valid endophenotypes of human anxiety disorders with improved animal models. Novel approaches are needed to move basic discoveries into new, more effective treatments for our patients. PMID- 26012845 TI - Disentangling the Effects of Racial Self-identification and Classification by Others: The Case of Arrest. AB - Scholars of race have stressed the importance of thinking about race as a multidimensional construct, yet research on racial inequality does not routinely take this multidimensionality into account. We draw on data from the U.S. National Longitudinal Study of Adolescent Health to disentangle the effects of self-identifying as black and being classified by others as black on subsequently being arrested. Results reveal that the odds of arrest are nearly three times higher for people who were classified by others as black, even if they did not identify themselves as black. By contrast, we find no effect of self-identifying as black among people who were not seen by others as black. These results suggest that racial perceptions play an important role in racial disparities in arrest rates and provide a useful analytical approach for disentangling the effects of race on other outcomes. PMID- 26012846 TI - Motives underlying food consumption in the Western Balkans: consumers' profiles and public health strategies. AB - OBJECTIVES: This study aims to identify subgroups of consumers based on the health motives underlying their food choice in Western Balkan Countries. METHODS: The survey (n = 2943) was based on the Food Choice Questionnaire (FCQ) and elicited information on socio-demographic characteristics, consumption frequency of healthy food products, nutrition knowledge and impulsiveness. Analysis of the FCQ data focused on items of "health and natural content" and "weight control" factors to identify clusters. RESULTS: The biggest group of the sample was weight control and health-concerned individuals (34 %), mainly urban women older than 50. The second group of respondents (31 %) was moderately motivated about health and weight. A third group was health concerned but paid less attention to weight control (21 %), mainly comprising men and people living with children. The last group consisted of unconcerned young men (14 %) eating less fruit and showing higher impulsiveness. CONCLUSIONS: Western Balkan consumers differ in the importance they attach to health and natural content and weight control. This insight is needed to target interventions. PMID- 26012847 TI - An integrative review of coping related to problematic computer use in adolescence. AB - OBJECTIVES: Problematic computer use is the use of computer technology that may be health-endangering and may cause immediate or later negative physical or psychological health outcomes or disturb well-being in users. The main purpose of this study was to review current empirical research on coping strategies which adolescents apply in the context of problematic computer use and the coping relevant impacts of problematic computer use. METHODS: An integrative review of empirical studies using the Web of Science, Google Scholar, reference lists and forward tracking was conducted. Of the 404 articles identified, 28 peer-reviewed, full-text articles that directly addressed coping in relation to problematic Internet use, computer overuse and cyberbullying were included in the review. RESULTS: This review identified the structure of specific coping strategies related to problematic computer use as well as the general patterns of relationships between reviewed instances of problematic computer use, situational coping and dispositional coping. CONCLUSIONS: Instrumental action and talking with others were the most frequent strategies used by adolescents to cope with cyberbullying. The structure of the coping strategies related to problematic Internet use and computer overuse is highly differentiated, revealing a new and promising area for future research. PMID- 26012848 TI - School satisfaction and social relations: Swedish schoolchildren's improvement suggestions. AB - OBJECTIVES: The aim was to explore schoolchildren's views on how to increase school satisfaction and improve social relations among peers at school. METHOD: Improvement suggestions were collected from school children aged 10-12 years with the help of a feedback model developed for the purpose. Qualitative content analysis was used. RESULTS: Two categories emerged from the analysis: 'psychosocial climate', which included the subcategories 'adults' roles and responsibilities' and 'classmates' norms and values'; 'influence', which included the subcategories 'changes in the physical environment' and 'flexible learning'. The categories are seen as important to increase school satisfaction and improve social relations among peers at school. CONCLUSION: Examining children's opinions is requested and promoted by the UN convention on the Rights of the Child. The findings contribute to the field by showing how school satisfaction and social relations might be improved, if the child perspective is considered in the planning of health promotion activities in school. PMID- 26012850 TI - Evaluation of two molecularly imprinted polymers for the solid-phase extraction of natural, synthetic and mycoestrogens from environmental water samples before liquid chromatography with mass spectrometry. AB - In this work, we have compared the selectivity of two commercial molecularly imprinted polymers (AFFINIMIP(r)SPE Estrogens and AFFINIMIP(r)SPE Zearalenone) for the extraction of 12 estrogenic compounds of interest (i.e. 17alpha estradiol, 17beta-estradiol, estrone, hexestrol, 17alpha-ethynylestradiol, diethylstibestrol, dienestrol, zearalenone, alpha-zearalanol, beta-zearalanol, alpha-zearalenol and beta-zearalenol) from different water samples. High performance liquid chromatography coupled with ion trap mass spectrometry with electrospray ionization was used for their determination. Results showed that although both molecularly imprinted polymeric cartridges were specifically designed for different groups of analytes (natural estrogens like estradiol in the first case and zearalenone derivatives in the second) they nearly have the same extraction performance (with recovery values in the range 65-101%) for the same analytes in Milli-Q water because of the cross-reactivity of the polymer. However, when more complex water samples were analyzed, it was clear that the behavior was different and that the AFFINIMIP(r)SPE Estrogens showed less cross reactivity than the other cartridge. Validation of the proposed methodology with both cartridges revealed that the extraction was reproducible and that the final limits of detection of the proposed method were in the low ng/L range. PMID- 26012851 TI - Sociolinguistic reflection on neuropsychological assessment: an insight into selected culturally adapted battery of Lebanese Arabic cognitive testing. AB - Neuropsychological tests (NPTs) are highly dependent on education, culture differences as well as age and sex. It is therefore essential to take these factors into consideration when translating NPTs to be used in screening for cognitive impairment. Translations into Arabic must respect the principles of linguistic relativity and cultural specificity of the population under study. The objective is to assess feasibility and outcome of translating neuropsychological tests to Arabic. A team of Lebanese professionals selected a battery of screening NPTs. These tests were translated into Arabic and independently back translated by a team of sociolinguists and cultural specialists. The translations were adapted to suit the Lebanese culture. The final NPT translated versions were reached by consensus of an expert panel and tested on a group of independently living community-dwelling elderly. Translated items had to be modified when: (1) terms could not be translated using one word as required by the test; (2) Concepts were foreign to the culture; (3) Translated words carried multiple meanings; (4) Words were rarely used in Lebanon; (5) Sentences did not have an equivalent; and (6) Words had letters pronounced differently by subgroups in Lebanon. Despite all measures to maintain cultural sensitivity in translations, non-linguistic challenges remained. A battery of cognitive screening tests were translated into Arabic and adapted for the Lebanese population. These adaptations allow for a better assessment of cognitive abilities since they reflect the thought patterns of the population. The challenge is to establish local normative data. PMID- 26012849 TI - Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir. AB - Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80's) loop residues (mainly I50-I84' and I50'-I84) play an important role in maintaining the closed conformation of HIV-1 protease. The double mutation in Act variant weakens the hydrophobic interactions, leading to the transition from closed to semi-open conformation of apo Act. APV or DRV binds with HIV-1 protease via both hydrophobic and hydrogen bonding interactions. The hydrophobic interactions from the inhibitor is aimed to the residues of I50 (I50'), I84 (I84'), and V82 (V82') which create hydrophobic core clusters to further stabilize the closed conformation of flaps, and the hydrogen bonding interactions are mainly focused with the active site of HIV-1 protease. The combined change in the two kinds of protease-inhibitor interactions is correlated with the observed resistance mutations. The present study sheds light on the microscopic mechanism underlying the mutation effects on the dynamics of HIV-1 protease and the inhibition by APV and DRV, providing useful information to the design of more potent and effective HIV-1 protease inhibitors. PMID- 26012852 TI - Retinol-binding protein-4 and hs-CRP levels in patients with migraine. AB - Retinol-binding protein-4 (RBP4) and high-sensitivity C-reactive protein (hs-CRP) levels are associated with inflammation in patients with migraine. The release of proinflammatory cytokines during migraine results in recurrent sterile neurogenic inflammation. This study aimed to determine the correlation between RBP4 and hs CRP levels, and migraine, which is considered an inflammatory disease. The study included 48 migraine patients and 40 age- and gender-matched controls. Migraine was diagnosed according to International Classification of Headache Disorders-II. The serum RBP4 level was measured using a commercial ELISA kit and hs-CRP was measured using an enzyme immunoassay test kit. The serum RBP4 level was significantly lower in the migraine patients than in the controls (P < 0.001), whereas the hs-CRP level was significantly higher in the migraine patients (P < 0.001). RBP4 and hs-CRP levels did not differ between the migraine patients with and without aura (P > 0.05). Migraine headache severity, frequency and duration were not correlated with serum RBP or hs-CRP levels (P > 0.05). The observed high hs-CRP level and low RBP4 level in migraine patients suggest that vitamin A might play a major role in the pathogenesis of migraine. It is known that inflammation is a key factor in many diseases. Additional research might result in a better understanding of the anti-inflammatory effects of vitamin A. PMID- 26012853 TI - Peptide Bioconjugates of Electron-Poor Metallocenes: Synthesis, Characterization, and Anti-Proliferative Activity. AB - We report the synthesis of metallocene compounds Cp2 M with two different electron-withdrawing substituents on both cyclopentadienyl rings (hexafluoroacetone (HFA) and chlorobenzoyl (1-5); HFA and COOH (6 and 7), M=Fe or Ru). The COOH-containing derivatives were used to synthesize peptide bioconjugates with enkephalin (8 and 9) and neurotensin (10 and 11) as well as fluorescein-labeled neurotensin (12). All the molecules were fully characterized, including X-ray structures for 6 and 7. The physicochemical properties (lipophilicity and electrochemistry) and cytotoxicity on MCF-7, HT-29, and PT-45 cancer cells were evaluated for selected compounds. Electrochemical investigation by cyclic voltammetry revealed that all bis-substituted metallocenes are up to 300 mV harder to oxidize compared to the monosubstituted 2 ferrocenylhexafluoropropan-2-ol (FcHFA: Delta${E{{{?rm f}?hfill ?atop 0?hfill}}}$=214 mV; disubstituted derivatives: up to Delta${E{{{?rm f}?hfill ?atop 0?hfill}}}$=512 mV; both vs. FcH(0/+) ). For the bis-substituted compounds, log P determinations by RP-HPLC showed increased lipophilicity in comparison to the monosubstituted FcHFA and RcHFA. Cellular uptake was investigated by fluorescence microcopy, and this revealed endosomal entrapment for 12. PMID- 26012854 TI - Thioredoxin of Litopenaeus vannamei facilitated white spot syndrome virus infection. AB - Thioredoxin (TRX), a major intracellular antioxidant, has a wide range of biological functions. It was up-regulated and targeted by WSSV. However, the relevance of TRX with WSSV infection and signaling pathway remains largely unknown. Sequence analysis indicated that TRX might interact with the WSSV030 (VP362) and WSSV454 (thymidine kinase-thymidylate kinase, TK-TMK) of WSSV. In this study, TRX, VP362 and TK-TMK were expressed and the interaction of TRX with VP362 or TK-TMK was investigated. Furthermore, how TRX affect the process of WSSV infection and the gene transcription of inhibitor of nuclear factor kappa-B kinase (IKK), a p38 mitogen-activated protein kinase (LvP38) and signal transducer and activator of transcription (STAT) in the hemocytes and hepatopancreas was explored. Far-western blot and enzyme-linked immuno assay (ELISA) results showed that TRX interacted with VP362 and TK-TMK. The mRNA expressions of IKK, LvP38 and STAT were significantly affected by the over presence of TRX of Litopenaeus vannamei. Neutralization experiment in vivo indicated that TRX induced the transcription expression of VP28 and increased the viral copy numbers in the early stage of WSSV infection and it may attribute to the death of shrimps infected by WSSV. PMID- 26012855 TI - The occurrence and genetic characterization of Cryptosporidium and Giardia species in foals in Belgium, The Netherlands, Germany and Greece. AB - Faecal samples were collected from foals between the age of 1 week and 6 months in Belgium, The Netherlands, Germany and Greece. A quantitative direct immunofluorescence assay based on the commercial MERIFLUOR Cryptosporidium/Giardia kit was performed to evaluate the presence of (oo) cysts. Parasite positive samples were genotyped, based on the 18S ribosomal DNA gene and the heat shock protein (HSP70) gene for Cryptosporidium and on the beta-giardin gene and the triose phosphate isomerase (TPI) gene for Giardia. In total, 134 foals from Belgium, 44 foals from The Netherlands, 30 foals from Germany and 190 foals from Greece were examined. No Cryptosporidium oocysts were identified in faecal samples from foals in Germany and The Netherlands. In Belgium and Greece, 4.5% and 1.1% of the foals examined were Cryptosporidium positive, respectively, all with a low oocyst excretion ranging from 100 to 2450 oocysts per gram of faeces. For Giardia, 14.2%, 11.4%, 10.0% and 11.6% of the foals in Belgium, The Netherlands, Germany and Greece, respectively, were found to excrete cysts, with a range of 50 up to 4,000,000 cysts per gram of faeces. Younger animals secreted significantly more Giardia cysts than older horses (p<0.05), but no significant correlation between Giardia infection and diarrhoea was observed. Most Giardia positive samples belonged to assemblage AI and/or BIV, but also assemblage E was detected in two samples. Together with the identification of Cryptosporidium horse genotype, this suggests only a low risk for zoonotic transmission. PMID- 26012856 TI - Dissemination of parasites by animal movements in small ruminant farms. AB - The present paper discusses the spread of parasites by animal movements in small ruminant farms; it focuses in dissemination of parasitic forms that would lead to subsequent infection of sheep or goats. Systems of small ruminant production involve a component of animal movement (e.g., grazing) as part of routine husbandry, which favors spread of parasitic forms; that refers mainly to parasites of the digestive system (nematodes, trematodes, cestodes, protozoa), as well as helminthes of the respiratory system, although dissemination of the various parasitic forms in the environment would not always result to subsequent infection; external parasites may also be disseminated during movements, e.g., to inhabit wooden poles used in fencing. New livestock into a farm constitutes a biosecurity hazard and the most common means to introducing new parasitic pathogens into a farm; in contemporary small ruminant health management, this contributes in dissemination of anthelmintic resistant parasitic strains; other parasitic disease agents (e.g., mange mites, ticks) may also be spread into a farm that way. Often, especially in small scale farming, visits of rams or bucks take place from one farm to another during the mating season; in such cases, ectoparasites (e.g., mange mites) can be disseminated through direct contact of animals, as well other pathogens (e.g., Toxoplasma gondii, Neospora caninum) via the semen. During transportation of sheep/goats, parasitic forms can also spread, as well as during movement of sheep or goats to slaughterhouses, in which case dogs present in these places would contribute to their dissemination. Spread of life forms of various parasites can also occur from animal species present in the environment of sheep or goats; these include animals present within a farm, stray dogs roaming around a farm (e.g., for spread of Multiceps multiceps, Echinococcus granulosus, Taenia hydatigena, N. caninum), cats commanding the environment of a farm (e.g., for spread of T. gondii), cats or rats responsible for dissemination of fleas, which may also be spread by humans as well, and, finally, wildlife animals. Finally, life forms of parasites of small ruminants may be also spread indirectly, by material associated with sheep or goats (e.g., materials of humans visiting farms, animal feeds) that had been contaminated by faecal material of animals. PMID- 26012857 TI - Surra Sero K-SeT, a new immunochromatographic test for serodiagnosis of Trypanosoma evansi infection in domestic animals. AB - Trypanosoma evansi, the causative agent of surra, infects different domestic and wild animals and has a wide geographical distribution. It is mechanically transmitted mainly by haematophagous flies. Parasitological techniques are commonly used for the diagnosis of surra but have limited sensitivity. Therefore, serodiagnosis based on the detection of T. evansi specific antibodies is recommended by the World Organisation for Animal Health (OIE). Recently, we developed a new antibody detection test for the serodiagnosis of T. evansi infection, the Surra Sero K-SeT. Surra Sero K-SeT is an immunochromatographic test (ICT) that makes use of recombinant variant surface glycoprotein rVSG RoTat 1.2, produced in the yeast Pichia pastoris. In this study, we compared the diagnostic accuracy of the Surra Sero K-SeT and the Card Agglutination Test for T. evansi Trypanosomososis (CATT/T. evansi) with immune trypanolysis (TL) as reference test on a total of 806 sera from camels, water buffaloes, horses, bovines, sheep, dogs and alpacas. Test agreement was highest between Surra Sero K SeT and TL (kappa=0.91, 95% CI 0.841-0.979) and somewhat lower between CATT/T. evansi and TL (kappa=0.85, 95% CI 0.785-0.922) and Surra Sero K-SeT and CATT/T. evansi (kappa=0.81, 95% CI 0.742-0.878). The Surra Sero K-SeT displayed a somewhat lower overall specificity than CATT/T. evansi (94.8% versus 98.3%, chi(2)=13.37, p<0.001) but a considerably higher sensitivity (98.1% versus 84.4%, chi(2)=33.39, p<0.001). We conclude that the Surra Sero K-SeT may become an alternative for the CATT/T. evansi for sensitive detection of antibodies against T. evansi in domestic animals. PMID- 26012858 TI - A multiplex PCR for the detection of Fasciola hepatica in the intermediate snail host Galba cubensis. AB - Fasciolosis is a snail-borne trematode infection that has re-emerged as a human disease, and is considered a significant problem for veterinary medicine worldwide. The evaluation of the transmission risk of fasciolosis as well as the efficacy of the strategies for its control could be carried out through epidemiological surveillance of the snails that act as intermediate hosts of the parasites. The present study aimed to develop the first multiplex PCR to detect Fasciola hepatica in Galba cubensis, an important intermediate host of the parasite in the Americas and especially in the Caribbean basin. The multiplex PCR was optimized for the amplification of a 340 bp fragment of the second internal transcribed spacer (ITS-2) of F. hepatica rDNA, while another set of primers was designed and used to amplify a conserved segment of the nuclear 18S rDNA of the snail (451 bp), as an internal control of the reaction. The assay was able to detect up to 100 pg of the parasite even at high concentrations of snail DNA, an analytical sensitivity that allows the detection of less than a single miracidium, which is the minimal biological infestation unit. A controlled laboratory-reared G. cubensis - F. hepatica system was used for the evaluation of the developed multiplex PCR, and 100% sensitivity and specificity was achieved. This assay constitutes a novel, useful and suitable technique for the survey of fasciolosis transmission through one of the main intermediate hosts in the Western hemisphere. PMID- 26012859 TI - Acute-phase protein behavior in dairy cattle herd naturally infected with Trypanosoma vivax. AB - Trypanosoma vivax is a hemoprotozoon that causes disease in cattle and is difficult to diagnose. The host-parasite relationship in cattle that are infected by T. vivax has only been poorly studied. In the present study, a total of 429 serum proteinograms were produced from naturally infected animals (NIF) and were compared with 50 samples from control animals (C). The total protein, IgA band, complement C3 beta chain band, albumin band, antitrypsin band, IgG band, haptoglobin band, complement C3c alpha chain band and protein HP-20 band presented higher levels in the serum proteinograms of the NIF group. Inter-alpha trypsin inhibitor heavy chain H4, alpha2-macroglobulin, complement C6, ceruloplasmin, transferrin band and apolipoprotein A1 band presented lower levels in this group. There was no significant difference (p<0.05) in acid glycoprotein serum concentration between the NIF and C groups. Acute phase proteins may be useful for understanding the host-parasite relationship, since the antitrypsin band was only present in the NIF group. This can be used as an indicator for infection in cattle that are naturally infected by T. vivax. PMID- 26012860 TI - Characterization of the Eimeria maxima sporozoite surface protein IMP1. AB - The purpose of this study was to characterize Eimeria maxima immune-mapped protein 1 (IMP1) that is hypothesized to play a role in eliciting protective immunity against E. maxima infection in chickens. RT-PCR analysis of RNA from unsporulated and sporulating E. maxima oocysts revealed highest transcription levels at 6-12h of sporulation with a considerable downregulation thereafter. Alignment of IMP1 coding sequence from Houghton, Weybridge, and APU-1 strains of E. maxima revealed single nucleotide polymorphisms that in some instances led to amino acid changes in the encoded protein sequence. The E. maxima (APU-1) IMP1 cDNA sequence was cloned and expressed in 2 different polyHis Escherichia coli expression vectors. Regardless of expression vector, recombinant E. maxima IMP1 (rEmaxIMP1) was fairly unstable in non-denaturing buffer, which is consistent with stability analysis of the primary amino acid sequence. Antisera specific for rEmaxIMP1 identified a single 72 kDa protein or a 61 kDa protein by non-reducing or reducing SDS-PAGE/immunoblotting. Immunofluorescence staining with anti rEmaxIMP1, revealed intense surface staining of E. maxima sporozoites, with negligible staining of merozoite stages. Immuno-histochemical staining of E. maxima-infected chicken intestinal tissue revealed staining of E. maxima developmental stages in the lamnia propia and crypts at both 24 and 48 h post infection, and negligible staining thereafter. The expression of IMP1 during early stages of in vivo development and its location on the sporozoite surface may explain in part the immunoprotective effect of this protein against E. maxima infection. PMID- 26012861 TI - Spirocercosis in dogs in Israel: A retrospective case-control study (2004-2009). AB - This case-control retrospective study (years 2004-2009) investigated the epidemiological, clinical, and diagnostic test findings of dogs with esophageal spirocercosis (ES) presented to the Hebrew University Veterinary Teaching Hospital (HUVTH) and coproscopy-positive dogs at the Kimron Veterinary Institute (KVI), Israel. It included 133 dogs with ES and 133 negative controls diagnosed at the hospital, and 343 dogs diagnosed at the KVI. The average incidence of ES at the HUVTH was 22.5/year, and the percentage of spirocercosis cases was stable at both institutions (HUVTH, 0.67-1.23%; KVI, 5-8%). Dogs aged > 5 years old had 100-fold likelihood to be infected compared to dogs aged <= 1 year of age (P < 0.001). Mean body weight (P = 0.0004), proportion of Retrievers (P = 0.002) and sporting breed dogs (P = 0.006) were higher, while proportion of toy breeds (P = 0.004) was lower in the ES group compared to the control group. The proportion of cases from Greater Tel-Aviv decreased (P = 0.002), while that of those from Judea and Jerusalem increased (P = 0.01) compared to the 1990 s. Spirocercosis occurred in 22 dogs despite past prophylactic avermectin treatment. Vomiting and regurgitation were the most common clinical signs of ES. Coproscopy was S. lupi positive in 33/60 dogs (55.0%). The median number of esophageal nodules was two (range 1-8), with a median diameter of 3.5 cm (range 1.0-11.0). Malignant esophageal lesion transformation was confirmed in 29 dogs (22%). Despite preventive attempts, spirocercosis has spread in Israel over time, compared to previous findings, raising questions about the efficacy of the currently accepted prophylactic protocol is incompletely effective. PMID- 26012862 TI - A Facile Synthesis of High-Surface-Area Sulfur-Carbon Composites for Li/S Batteries. AB - Small-grained elemental sulfur is precipitated from sodium thiosulfate (Na2 S2 O3 ) in a carbon-containing oxalic acid (HOOC-COOH) solution through a novel spray precipitation method. Surface area analysis, elemental mapping, and transmission electron micrographs revealed that the spray-precipitated sulfur particles feature 11 times higher surface area compared to conventional precipitated sulfur, with homogeneous distribution in the carbon. Moreover, the scanning electron micrographs show that these high-surface-area sulfur particles are firmly adhered to and covered by carbon. This precipitated S-C composite exhibits high discharge capacity with about 75 % capacity retention. The initial discharge capacity was further improved to 1444 mA h g(-1) by inserting a free-standing single-walled carbon nanotube layer in between the cathode and the separator. Moreover, with the help of the fixed capacity charging technique, 91.6 % capacity retention was achieved. PMID- 26012863 TI - Universal dependence of the spin wave band structure on the geometrical characteristics of two-dimensional magnonic crystals. AB - In the emerging field of magnon-spintronics, spin waves are exploited to encode, carry and process information in materials with periodic modulation of their magnetic properties, named magnonic crystals. These enable the redesign of the spin wave dispersion, thanks to its dependence on the geometric and magnetic parameters, resulting in the appearance of allowed and forbidden band gaps for specific propagation directions. In this work, we analyze the spin waves band structure of two-dimensional magnonic crystals consisting of permalloy square antidot lattices with different geometrical parameters. We show that the frequency of the most intense spin-wave modes, measured by Brillouin light scattering, exhibits a universal dependence on the aspect ratio (thickness over width) of the effective nanowire enclosed between adjacent rows of holes. A similar dependence also applies to both the frequency position and the width of the main band gap of the fundamental (dispersive) mode at the edge of the first Brillouin zone. These experimental findings are successfully explained by calculations based on the plane-wave method. Therefore, a unified vision of the spin-waves characteristics in two-dimensional antidot lattices is provided, paving the way to the design of tailored nanoscale devices, such as tunable magnonic filters and phase-shifters, with predicted functionalities. PMID- 26012864 TI - Diagnostic Cytologic Features of Uveal Melanoma. AB - PURPOSE: To report the cytologic characteristics of uveal melanoma. DESIGN: This is a prospective, single-center study of consecutive patients. SUBJECTS: All patients with a clinical diagnosis of uveal melanoma from May 2009 to July 2013 who underwent prognostication fine-needle aspiration biopsy (FNAB) were included. METHODS: The cytologic characteristics of uveal melanoma were analyzed for 150 consecutive patients with a clinical diagnosis of uveal melanoma who were treated at the Cleveland Clinic Cole Eye Institute between May 2009 and August 2012. MAIN OUTCOME MEASURES: Cellular features of all cases were analyzed for cell type, presence of melanin, nuclear grade, tumor-infiltrating lymphocytes, and necrosis. Cytology was then correlated with histopathology in enucleated eyes. RESULTS: A total of 150 patients were included. Seven samples of tumor resections were excluded from the study because they were studied by impression smears. A total of 143 FNAB samples of 143 patients formed the basis for analysis. Fifty-three percent of the patients were male, and the average age for all patients was 60 years. Transcorneal (n = 8), transscleral (n = 71), and transvitreal (n = 64) approaches were used. Of 143 samples, 131 were adequate. Among these, spindle cells were observed in 98% (63% mixed and 35% spindle only), whereas only epithelioid cells were observed in 2 samples. Melanin granules were observed in 80% of samples. Tumor nuclear grade (atypia) increased with tumor height and by tumor location (least atypia with iris tumors). CONCLUSIONS: Cytologic features such as spindle cells and melanin granules, present in 98% and 80% of samples, respectively, are important cytologic diagnostic features. Tumor nuclear grade (atypia) increased with tumor height. Iris melanoma has bland features compared with ciliary and choroidal melanoma. PMID- 26012865 TI - CD38 Is Required for Neural Differentiation of Mouse Embryonic Stem Cells by Modulating Reactive Oxygen Species. AB - CD38 is a multifunctional membrane enzyme and the main mammalian ADP-ribosyl cyclase, which catalyzes the synthesis and hydrolysis of cADPR, a potent endogenous Ca(2+) mobilizing messenger. Here, we explored the role of CD38 in the neural differentiation of mouse embryonic stem cells (ESCs). We found that the expression of CD38 was decreased during the differentiation of mouse ESCs initiated by adherent monoculture. Perturbing the CD38/cADPR signaling by either CD38 knockdown or treatment of cADPR antagonists inhibited the neural commitment of mouse ESCs, whereas overexpression of CD38 promoted it. Moreover, CD38 knockdown dampened reactive oxygen species (ROS) production during neural differentiation of ESCs by inhibiting NADPH oxidase activity, while CD38 overexpression enhanced it. Similarly, application of hydrogen peroxide mitigated the inhibitory effects of CD38 knockdown on neural differentiation of ESCs. Taken together, our data indicate that the CD38 signaling pathway is required for neural differentiation of mouse ESCs by modulating ROS production. PMID- 26012866 TI - Resistive index for kidney evaluation in normal and diseased cats. AB - OBJECTIVES: The objectives were to determine the resistive index (RI) in normal cats and in cats with various renal diseases, and to evaluate the effect of age on RI. METHODS: The subjects were cats that had ultrasonography (US) of the urinary tract and RI measurement at our centre between January 2003 and April 2014. Based on clinical evaluation, biochemical and haematological tests, urinalysis and US, the cats were classified as healthy or diseased. RI measurements were made from the interlobar or arcuate arteries. Data were analysed for differences between the right and the left kidney, the two sexes, different age groups in healthy cats, and between healthy and diseased cats. RESULTS: A total of 116 cats (68 males, 48 females) were included: 24 healthy and 92 diseased. In the healthy cats, RI (mean +/- SD) differed significantly (P = 0.02) between the right kidney (0.54 +/- 0.07) and the left kidney (0.59 +/- 0.08). For the left kidney, RI was significantly higher in cats with chronic kidney disease (0.73 +/- 0.12) and acute kidney injury (0.72 +/- 0.08) (P = 0.0008). For the right kidney, RI was significantly higher in cats with chronic kidney disease (0.72 +/- 0.11), acute kidney injury (0.74 +/- 0.08), polycystic kidney disease (0.77 +/- 0.11) and renal tumour (0.74 +/- 0.001) (P <0.0001). There was no significant effect on RI value in either kidney in terms of age or sex. CONCLUSIONS AND RELEVANCE: RI could be considered a valuable diagnostic tool in cats, useful in the differential diagnosis of diffuse renal diseases. While it does not change with the age of the cat, ultrasonographers should be aware that RI may differ between the two kidneys. PMID- 26012867 TI - Mathematical equation for prediction of cat mandibular canal height dimension based on canine tooth width measurement. AB - OBJECTIVES: The present study was performed in a sample of 33 cats and aimed (1) to characterise the mandible height (Mh), mandibular canal height (MCh) and the distance between the interdental alveolar margin and the mandibular canal (dIAM MC); and (2) to develop a mathematical model for dimension prediction of MCh using the patient's age, weight (Wg) and canine tooth width at the free gingival margin level (wCGM) that was easily accessible during the oral examination. METHODS: Age, sex, breed, weight, skull type and the wCGM were the recorded variables for each patient. Right and left lateral view skull radiographs were made followed by measurements of the mandible anatomical structures, taken between the third premolar distal root and the fourth premolar proximal root. Results were considered statistically significant for P values <0.05, and statistical analysis was performed using SPSS software. RESULTS: We observed a strong correlation only between wCGM and MCh, and a prediction mathematical model was developed to calculate the MCh, with a standard error of only 0.4 mm. CONCLUSIONS AND RELEVANCE: Our study allows a surgeon to establish relationships between a physical parameter, such as wCGM, evaluated in an oral examination, and the mandibular canal, which is a very important anatomical structure to consider in surgical procedures. Ideally, surgeons should always plan their mandible work only after obtaining a final diagnosis achieved through the use of complementary imaging exams, such as intra- and extra-oral radiographs. Thus, this mathematical equation offers an additional tool, providing more information on the relationships between oral anatomical structures, reducing the risk of iatrogenic lesions and promoting patient safety. PMID- 26012868 TI - Decontamination of laundry exposed to Microsporum canis hairs and spores. AB - OBJECTIVES: The objective of this study was to determine the efficacy of decontamination of fabric exposed to Microsporum canis hairs and spores by mechanical washing using hot or cold water with or without a sodium hypochlorite additive, and to field test a washing protocol for terry cloth and denim exposed to M canis via direct contact with infected cats. METHODS: Cotton, terry cloth and denim fabric swatches were contaminated with isolated infective spores and hairs and then washed in water at temperatures of 30 degrees C and 60 degrees C, with and without a sodium hypochlorite additive, and with and without mechanical drying. Terry cloth and denim were contaminated by direct contact with infected kittens and washed at 30 degrees C until culture-negative. RESULTS: All prelaundering samples had >300 colony forming units (cfu)/plate. Experimentally contaminated fabrics were culture-negative, regardless of fabric type, water temperature, the presence or absence of sodium hypochlorite, or tumble drying after one wash. After one wash, 22/34 (65%) of terry cloth towels and 12/20 (60%) denim fabric squares were culture-positive, but the infective load was minimal (1 5 cfu/plate). After two washes in cold water there was no detectable contamination of fabric. The rinse water was not contaminated with spores. The laundry tub was easily decontaminated via mechanical cleaning followed by use of a disinfectant. CONCLUSIONS AND RELEVANCE: Washable textiles exposed to M canis can be decontaminated via mechanical washes in cold water without the addition of bleach. Two washes are recommended to ensure removal of spores. Laundry can be effectively decontaminated by washing twice in cold water on a long wash cycle (for ?14 mins). It is important to ensure maximal agitation (ie, the machine should not be overloaded). PMID- 26012869 TI - Structural and functional analysis of botulinum neurotoxin subunits for pH dependent membrane channel formation and translocation. AB - The structure-function relationship of Botulinum Neurotoxin (BoNT) proteins is greatly influenced by pH. While the low pH of endosome favors membrane interaction of the heavy chain (HC) for the formation of a membrane channel and translocation of the light chain (LC), the catalytic activity of the LC requires a neutral pH for cleavage of the soluble NSF attachment protein receptor (SNARE) complex in the cytosol. In this study, we monitored secondary structural characteristics of LC, HC and holotoxin at individual pHs 4.5 and 7.2 and at the transition pH4.5 to 7.2 to identify the structural signatures underlying their function. The HC showed higher thermal stability at pH4.5 with a melting temperature (Tm) of 60.4 degrees C. The structural analysis of HC in the presence of liposomes showed no difference in ellipticity with that of HC at pH7.2 at 208 and 222 nm but a 25.2% decrease in ellipticity at 208 nm at acidic pH, indicating low pH-induced structural changes that might facilitate interaction with the membrane. Further, HC showed 18% release of K+ ions from liposomes at pH4.5 as against 6% at neutral pH, reinforcing its role in membrane channel formation. LC on the other hand, showed maximum ellipticity at pH7.2, a condition that is relevant to its endopeptidase activity in the cytosol of the neurons. Also, the similarity in the structures at pH7.2 and transition pH4.5 to 7.2 suggested that the flexibility acquired by the protein at low pH was reversible upon exposure to neutral pH for cleavage of SNARE proteins. PMID- 26012870 TI - Asymmetric processing of mutant factor X Arg386Cys reveals differences between intrinsic and extrinsic pathway activation. AB - Alterations in coagulation factor X (FX) activation, mediated by the extrinsic VIIa/tissue factor (FVIIa/TF) or the intrinsic factor IXa/factor VIIIa (FIXa/FVIIIa) complexes, can result in hemorrhagic/prothrombotic tendencies. However, the molecular determinants involved in substrate recognition by these enzymes are poorly defined. Here, we investigated the role of arginine 386 (chymotrypsin numbering c202), a surface-exposed residue on the FX catalytic domain. The naturally occurring FX386Cys mutant and FX386Ala variant were characterized. Despite the unpaired cysteine, recombinant (r)FX386Cys was efficiently secreted (88.6+/-21.3% of rFXwt) and possessed normal clearance in mice. rFX386Cys was also normally activated by FVIIa/TF and displayed intact amidolytic activity. In contrast, rFX386Cys activation by the FIXa/FVIIIa complex was 4.5-fold reduced, which was driven by a decrease in the kcat (1.6*10(-4) s( 1) vs 5.8*10(-4) s(-1), rFXwt). The virtually unaltered Km (70.6 nM vs 55.6nM, rFXwt) suggested no major alterations in the FX substrate exosite. Functional assays in plasma supplemented with rFX386Cys indicated a remarkable reduction in the thrombin generation rate and thus in coagulation efficiency. Consistently, the rFX386Ala variant displayed similar biochemical features suggesting that global changes at position 386 impact the intrinsic pathway activation. These data indicate that the FXArg386 is involved in FIXa/FVIIIa-mediated FX activation and help in elucidating the bleeding tendency associated with the FX386Cys in a rare FX deficiency case. Taking advantage of the unpaired cysteine, the rFX386Cys mutant may be efficiently targeted by thiol-specific ligands and represent a valuable tool to study FX structure-function relationships both in vitro and in vivo. PMID- 26012871 TI - Monte Carlo Strategies for Selecting Parameter Values in Simulation Experiments. AB - Simulation experiments are used widely throughout evolutionary biology and bioinformatics to compare models, promote methods, and test hypotheses. The biggest practical constraint on simulation experiments is the computational demand, particularly as the number of parameters increases. Given the extraordinary success of Monte Carlo methods for conducting inference in phylogenetics, and indeed throughout the sciences, we investigate ways in which Monte Carlo framework can be used to carry out simulation experiments more efficiently. The key idea is to sample parameter values for the experiments, rather than iterate through them exhaustively. Exhaustive analyses become completely infeasible when the number of parameters gets too large, whereas sampled approaches can fare better in higher dimensions. We illustrate the framework with applications to phylogenetics and genetic archaeology. PMID- 26012872 TI - Incompatible Ages for Clearwing Butterflies Based on Alternative Secondary Calibrations. AB - The recent publication of a time-tree for the plant family Solanaceae (nightshades) provides the opportunity to use independent calibrations to test divergence times previously inferred for the diverse Neotropical butterfly tribe Ithomiini. Ithomiini includes clades that are obligate herbivores of Solanaceae, with some genera feeding on only one genus. We used 8 calibrations extracted from the plant tree in a new relaxed molecular-clock analysis to produce an alternative temporal framework for the diversification of ithomiines. We compared the resulting age estimates to: (i) a time-tree obtained using 7 secondary calibrations from the Nymphalidae tree of Wahlberg et al. (2009), and (ii) Wahlberg et al.'s (2009) original age estimates for the same clades. We found that Bayesian clock estimates were rather sensitive to a variety of analytical parameters, including taxon sampling. Regardless of this sensitivity however, ithomiine divergence times calibrated with the ages of nightshades were always on average half the age of previous estimates. Younger dates for ithomiine clades appear to fit better with factors long suggested to have promoted diversification of the group such as the uplifting of the Andes, in the case of montane genera. Alternatively, if ithomiines are as old as previous estimates suggest, the recent ages inferred for the diversification of Solanaceae seem likely to be seriously underestimated. Our study exemplifies the difficulty of testing hypotheses of divergence times and of choosing between alternative dating scenarios, and shows that age estimates based on seemingly plausible calibrations may be grossly incongruent. PMID- 26012873 TI - Development of a general-purpose method for cell purification using Cre/loxP mediated recombination. AB - A mammalian body is composed of more than 200 different types of cells. The purification of a certain cell type from tissues/organs enables a wide variety of studies. One popular cell purification method is immunological isolation, using antibodies against specific cell surface antigens. However, this is not a general purpose method, since suitable antigens have not been found in certain cell types, including embryonic gonadal somatic cells and Sertoli cells. To address this issue, we established a knock-in mouse line, named R26 KI, designed to express the human cell surface antigen hCD271 through Cre/loxP-mediated recombination. First, we used the R26 Kl mouse line to purify embryonic gonadal somatic cells. Gonadal somatic cells were purified from the R26 KI; Nr5a1-Cre transgenic (tg) embryos almost equally as efficiently as from Nr5a1-hCD271-tg embryos. Second, we used the R26 KI mouse line to purify Sertoli cells successfully from R26 KI; Amh-Cre-tg testes. In summary, we propose that the R26 KI mouse line is a powerful tool for the purification of various cell types. PMID- 26012874 TI - Liquid-Phase Synthesis of 2'-Methyl-RNA on a Homostar Support through Organic Solvent Nanofiltration. AB - Due to the discovery of RNAi, oligonucleotides (oligos) have re-emerged as a major pharmaceutical target that may soon be required in ton quantities. However, it is questionable whether solid-phase oligo synthesis (SPOS) methods can provide a scalable synthesis. Liquid-phase oligo synthesis (LPOS) is intrinsically scalable and amenable to standard industrial batch synthesis techniques. However, most reported LPOS strategies rely upon at least one precipitation per chain extension cycle to separate the growing oligonucleotide from reaction debris. Precipitation can be difficult to develop and control on an industrial scale and, because many precipitations would be required to prepare a therapeutic oligonucleotide, we contend that this approach is not viable for large-scale industrial preparation. We are developing an LPOS synthetic strategy for 2' methyl RNA phosphorothioate that is more amenable to standard batch production techniques, using organic solvent nanofiltration (OSN) as the critical scalable separation technology. We report the first LPOS-OSN preparation of a 2'-Me RNA phosphorothioate 9-mer, using commercial phosphoramidite monomers, and monitoring all reactions by HPLC, (31)P NMR spectroscopy and MS. PMID- 26012875 TI - Whole-body vibration and occupational physical performance: a review. AB - INTRODUCTION: In the occupational environment, there are a considerable number of stressors that can affect physical performance in job tasks. Whole-body vibration (WBV), which arises from vehicle transit, is one such stressor that has been demonstrated to alter human function in several ways. This study identifies the known physical changes to human function which result from WBV, to comment on changes which may translate to performance in physically demanding occupational tasks. METHODS: A systematic review is performed on the literature relating to changes in the neuromuscular, physiological and biomechanical properties of the human body, when exposed to WBV. Selection criteria are constructed to synthesise articles which strictly relate to in-vehicle WBV and physical responses. RESULTS: In total, 29 articles were identified which satisfied the criteria for inclusion. A range of physical responses produced from WBV are presented; however, little consistency exists in study design and the responses reported. DISCUSSION: Given the inconsistency in the reported responses, the precise changes to human function remain unknown. However, there is sufficient evidence to warrant the design of studies which investigate occupationally relevant physical performance changes following WBV. PMID- 26012877 TI - No blood pressure lowering agents prolong survival in diabetes and kidney disease, review shows. PMID- 26012876 TI - Apparent diffusion coefficient is highly reproducible on preclinical imaging systems: Evidence from a seven-center multivendor study. AB - PURPOSE: To evaluate between-site agreement of apparent diffusion coefficient (ADC) measurements in preclinical magnetic resonance imaging (MRI) systems. MATERIALS AND METHODS: A miniaturized thermally stable ice-water phantom was devised. ADC (mean and interquartile range) was measured over several days, on 4.7T, 7T, and 9.4T Bruker, Agilent, and Magnex small-animal MRI systems using a common protocol across seven sites. Day-to-day repeatability was expressed as percent variation of mean ADC between acquisitions. Cross-site reproducibility was expressed as 1.96 * standard deviation of percent deviation of ADC values. RESULTS: ADC measurements were equivalent across all seven sites with a cross site ADC reproducibility of 6.3%. Mean day-to-day repeatability of ADC measurements was 2.3%, and no site was identified as presenting different measurements than others (analysis of variance [ANOVA] P = 0.02, post-hoc test n.s.). Between-slice ADC variability was negligible and similar between sites (P = 0.15). Mean within-region-of-interest ADC variability was 5.5%, with one site presenting a significantly greater variation than the others (P = 0.0013). CONCLUSION: Absolute ADC values in preclinical studies are comparable between sites and equipment, provided standardized protocols are employed. PMID- 26012878 TI - Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. AB - Article chosen Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 2014;311(16):1622-31. Clinical question Does prehospital thrombolysis in specialized ambulances reduce delay to thrombolysis in acute ischemic stroke? OBJECTIVE: To determine the effect of prehospital thrombolysis for acute ischemic stroke administered in specialized ambulances on delay in thrombolytic administration, thrombolysis rate, post-thrombolysis intracerebral hemorrhage, and 7-day mortality. PMID- 26012879 TI - Petals of Crocus sativus L. as a potential source of the antioxidants crocin and kaempferol. AB - Saffron from the province of L'Aquila, in the Abruzzo region of Italy, is highly prized and has been awarded a formal recognition by the European Union with EU Protected Designation of Origin (PDO) status. Despite this, the saffron regions are abandoned by the younger generations because the traditional cultivation of saffron (Crocus sativus L.) is labour intensive and yields only one crop of valuable saffron stamens per year. Petals of the saffron Crocus have had additional uses in traditional medicine and may add value to the crops for local farmers. This is especially important because the plant only flowers between October and November, and farmers will need to make the best use of the flowers harvested in this period. Recently, the petals of C. sativus L., which are considered a waste material in the production of saffron spice, were identified as a potential source of natural antioxidants. The antioxidants crocin and kaempferol were purified by flash column chromatography, and identified by thin layer chromatography (TLC), HPLC-DAD, infrared (IR), and nuclear magnetic resonance ((1)H &(13)C NMR) spectroscopy. The antioxidant activity was determined with the ABTS and DPPH tests. The antioxidant activities are mainly attributed to carotenoid and flavonoid compounds, notably glycosides of crocin and kaempferol. We found in dried petals 0.6% (w/w) and 12.6 (w/w) of crocin and kaempferol, respectively. Petals of C. sativus L. have commercial potential as a source for kaempferol and crocetin glycosides, natural compounds with antioxidant activity that are considered to be the active ingredients in saffron-based herbal medicine. PMID- 26012880 TI - Adaptation of flower and fruit colours to multiple, distinct mutualists. AB - Communication in plant-animal mutualisms frequently involves multiple perceivers. A fundamental uncertainty is whether and how species adapt to communicate with groups of mutualists having distinct sensory abilities. We quantified the colour conspicuousness of flowers and fruits originating from one European and two South American plant communities, using visual models of pollinators (bee and fly) and seed dispersers (bird, primate and marten). We show that flowers are more conspicuous than fruits to pollinators, and the reverse to seed dispersers. In addition, flowers are more conspicuous to pollinators than to seed dispersers and the reverse for fruits. Thus, despite marked differences in the visual systems of mutualists, flower and fruit colours have evolved to attract multiple, distinct mutualists but not unintended perceivers. We show that this adaptation is facilitated by a limited correlation between flower and fruit colours, and by the fact that colour signals as coded at the photoreceptor level are more similar within than between functional groups (pollinators and seed dispersers). Overall, these results provide the first quantitative demonstration that flower and fruit colours are adaptations allowing plants to communicate simultaneously with distinct groups of mutualists. PMID- 26012881 TI - Multiple testing for neuroimaging via hidden Markov random field. AB - Traditional voxel-level multiple testing procedures in neuroimaging, mostly p value based, often ignore the spatial correlations among neighboring voxels and thus suffer from substantial loss of power. We extend the local-significance index based procedure originally developed for the hidden Markov chain models, which aims to minimize the false nondiscovery rate subject to a constraint on the false discovery rate, to three-dimensional neuroimaging data using a hidden Markov random field model. A generalized expectation-maximization algorithm for maximizing the penalized likelihood is proposed for estimating the model parameters. Extensive simulations show that the proposed approach is more powerful than conventional false discovery rate procedures. We apply the method to the comparison between mild cognitive impairment, a disease status with increased risk of developing Alzheimer's or another dementia, and normal controls in the FDG-PET imaging study of the Alzheimer's Disease Neuroimaging Initiative. PMID- 26012882 TI - Modulation of Retinoic Acid Receptor Subtypes by 5- and 8-Substituted (Naphthalen 2-yl)-based Arotinoids. AB - Retinoid receptors (RARs and RXRs) transduce the signals of their natural and synthetic ligands (retinoids and rexinoids) to cellular transcriptional machinery to induce gene programs that control diverse biological and physiological effects on organisms. All-trans-retinoic acid, the natural ligand for RARs, is used therapeutically for the treatment of acute promyelocytic leukemia (APL), whereas the synthetic rexinoid bexarotene (a representative member of the aromatic retinoids or arotinoids) is approved for the treatment of cutaneous T-cell lymphoma (CTCL). Other retinoids have found applications in the topical treatment of skin disorders. In continuation of previous work on the naphthalene-based arotinoid scaffold, we synthesized a new series of (3-halo)benzoic acids connected to C5- or C8-substituted naphthyl rings via (E)-ethenyl and amide and, for the C5 series, (E)-chalcone linkers. These compounds were evaluated as RAR modulators in comparison with previously described dihydronaphthalene arotinoids with the same substitution pattern. Transactivation studies in this series revealed an absence of synergy between small halogen atoms (F, Cl) at C3 and the groups at C5 or C8, as had been observed on some of the dihydronaphthalene analogues. Instead, non-halogenated 4-(2-naphthamido)benzoic acid derivatives transactivated toward the RARbeta subtype in preference to the paralogues. The derivatives with bulkier substituents at C8 were characterized as dual RARbeta/RARalpha antagonists, and (E)-4-[(8-(phenylethynyl)naphthalene-2 yl)ethenyl]benzoic acid (11 c), with an ethenyl connector, was shown to be a potent antagonist of RARalpha. PMID- 26012883 TI - Post mortem study of the depth and circumferential location of sympathetic nerves in human renal arteries--implications for renal denervation catheter design. AB - OBJECTIVES: The aims of this study were to examine human renal arteries and to accurately characterize their sympathetic innervation and location using CD-56 immunohistochemistry stains to highlight Neural Cell Adhesion Molecules (N-CAM). BACKGROUND: Porcine models have often formed the basis for design of denervation technology, with only a limited number of human studies available to detail the complex microarray of renal sympathetic nerves. METHODS: Post-mortem renal arteries (N = 14) were harvested and prepared into three sections (proximal, mid, and distal), and then stained using Hematoxylin and Eosin, followed by immunohistochemistry to characterize the expression of CD-56 renal neural tissue. Digital micro calipers were then used to measure the nerve distances and locations within the vessels. RESULTS: (i) Approximately 77% of nerves are located between 0.5 and 2.5 mm from the tunica intima layer, with 22.5% occurring in the 2.5-5.0 mm range, (ii) nerve bundles occur in 3-dimensional arborized arrays, (iii) the nerve bundles are evenly distributed throughout the proximal and distal vessel in this human study. Thickness of vessel wall correlated with proximity of the nerve bundles (r = 0.74, P < 0.01), and nerve bundle thickness (r = 0.62, P = 0.04). The larger the internal and external diameters and areas of the vessel were, the further the distance to the nearest nerve bundles were (r = 0.752, P =<0.01). CONCLUSIONS: In human renal arteries with larger diameters and thicker vessel parenchyma, the innervation is found further from the lumen, and the nerves increase in thickness. This has implications for catheter and system design, as well as depth and duration of energy required for effective ablations. Effective percutaneous transluminal denervation procedures in this population would need to be circumferential rather than interrupted, and to mediate tissue damage to depths beyond 2.5 mm from the tunica intima. PMID- 26012884 TI - Transcriptional regulation of BNIP3 by Sp3 in prostate cancer. AB - BACKGROUND: The transcription factors Sp3/Sp1 are expressed in a various types of cancers and BNIP3 is overexpressed in prostate cancer. Although it has been demonstrated that BNIP3 is transcriptionally regulated by HIF-1alpha and is post transcriptionally regulated by miR145, our previous data indicated that there might be some other transcription factors regulating BNIP3 in prostate cancer. This study is conducted to investigate whether BNIP3 expression is directly regulated by Sp3/Sp1 or not. MATERIALS AND METHODS: Bioinformatics analysis shows that BNIP3 promoter contains several potential Sp3/Sp1 binding sites. And then it is demonstrated that SP3 could regulate the BNIP3 transcriptionally by binding to the predicted sites by dual reporter gene assays, ChIP, and EMSA. The biological effects of SP3 regulating BNIP3 on prostate cancer cells proliferation are measured by MTT, TUNEL, and flow cytometry. RESULTS: Our data show that Sp3 but not Sp1, is positively related to BNIP3 overexpression in prostate cancer. Sp3 can directly regulate BNIP3 transcription by mainly binding to the Sp3 binding sites (-624~-615 and -350~-343) of BNIP3 promoter. Knockdown of Sp3 by RNA interference could reduce cells growth and lead to cells apoptosis in PC-3 and DU145. Sp3-dependent BNIP3 overexpression might be an important mechanism to promote prostate cancer cells proliferation. CONCLUSION: This is the first study to provide direct evidence of Sp3-dependent BNIP3 expression. Sp3 might be the major transcriptional regulator of BNIP3 in prostate cancer and it is worthy to further study. The regulation of BNIP3 by Sp3 may be a new cancer-specific therapeutic target in prostate cancer. PMID- 26012885 TI - Bile duct-ligated mice exhibit multiple phenotypic similarities to acute decompensation patients despite histological differences. AB - BACKGROUND & AIMS: Patients with decompensated cirrhosis are susceptible to infection. Innate immune dysfunction and development of organ failure are considered to underlie this. A rodent model of liver disease sharing these phenotypic features would assist in vivo study of underlying mechanisms and testing of therapeutics. We evaluated three models to identify which demonstrated the greatest clinical and immunological phenotypic similarity to patients with acutely decompensated (AD) cirrhosis. METHODS: We selected Bile Duct Ligation (BDL) rats at 4 weeks, BDL mice at 14 days and Carbon tetrachloride (CCl4 ) mice at 10 weeks (with studies performed 7 days after final CCl4 infection). We examined organ dysfunction, inflammatory response to carrageenan-in-paw, plasma eicosanoid concentrations, macrophage cytokine production and responses to peritoneal infection. RESULTS: Bile duct ligation caused sarcopenia, liver, cardiovascular and renal dysfunction whereas CCl4 mice demonstrated no clinical abnormalities. BDL rodents exhibited depressed response to carrageenan-in-paw unlike CCl4 mice. BDL rats have slightly elevated plasma eicosanoid levels and plasma showed partial PGE2 -mediated immune suppression whereas CCl4 mice did not. Plasma NOx was elevated in patients with acute or chronic liver failure (AoCLF) compared to healthy volunteers and BDL rodents but not CCl4 mice. Elevated nitric oxide (NO) via inducible nitric oxide synthase (iNOS) mediates defective leucocyte trafficking in BDL rodent models. CONCLUSIONS: We conclude that BDL mice and rats are not simply models of cholestatic liver injury but may be used to study mechanisms underlying poor outcome from infection in AD and have identified elevated NO as a potential mediator of depressed leucocyte trafficking. PMID- 26012886 TI - Polyarteritis nodosa complicated with chronic interstitial nephritis. PMID- 26012887 TI - Does Australia need credentialed emergency nurse specialists? PMID- 26012888 TI - Partnered medication review and charting between the pharmacist and medical officer in the Emergency Short Stay and General Medicine Unit. AB - OBJECTIVE: A partnered medication review and charting model involving a pharmacist and medical officer was implemented in the Emergency Short Stay Unit and General Medicine Unit of a major tertiary hospital. The aim of the study was to describe the safety and effectiveness of partnered medication charting in this setting. METHODS: A partnered medication review and charting model was developed. Credentialed pharmacists charted pre-admission medications and venous thromboembolism prophylaxis in collaboration with the admitting medical officer. The pharmacist subsequently had a clinical discussion with the treating nurse regarding the medication management plan for the patient. A prospective audit was undertaken of all patients from the initiation of the service. RESULTS: A total of 549 patients had medications charted by a pharmacist from the 14th of November 2012 to the 30th of April 2013. A total of 4765 medications were charted by pharmacists with 7 identified errors, corresponding to an error rate of 1.47 per 1000 medications charted. CONCLUSIONS: Partnered medication review and charting by a pharmacist in the Emergency Short Stay and General Medicine unit is achievable, safe and effective. Benefits from the model extend beyond the pharmacist charting the medications, with clinical value added to the admission process through early collaboration with the medical officer. Further research is required to provide evidence to further support this collaborative model. PMID- 26012889 TI - Nurses' attitudes towards the reporting of violence in the emergency department. AB - BACKGROUND: The incidence of workplace violence against nurses in emergency departments is underreported. Thus, the true nature and frequency of violent incidents remains unknown. It is therefore difficult to address the problem. AIM: To identify the attitudes, barriers and enablers of emergency nurses to the reporting of workplace violence. METHOD: Using a phenomenological approach, two focus groups were conducted at a tertiary emergency department. The data were audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Violent incidents in this emergency department were underreported. Nurses accepted violence as part of their normal working day, and therefore were less likely to report it. Violent incidents were not defined as 'violence' if no physical injury was sustained, therefore it was not reported. Nurses were also motivated to report formally in order to protect themselves from any possible future complaints made by perpetrators. The current formal reporting system was a major barrier to reporting because it was difficult and time consuming to use. Nurses reported violence using methods other than the designated reporting system. CONCLUSION: While emergency nurses do report violence, they do not use the formal reporting system. When they did use the formal reporting system they were motivated to do so in order to protect themselves. As a consequence of underreporting, the nature and extent of workplace violence remains unknown. PMID- 26012890 TI - Sleep-Related Safety Behaviors and Dysfunctional Beliefs Mediate the Efficacy of Online CBT for Insomnia: A Randomized Controlled Trial. AB - Several trials have demonstrated the efficacy of online cognitive behavioral therapy (CBT) for insomnia. However, few studies have examined putative mechanisms of change based on the cognitive model of insomnia. Identification of modifiable mechanisms by which the treatment works may guide efforts to further improve the efficacy of insomnia treatment. The current study therefore has two aims: (1) to replicate the finding that online CBT is effective for insomnia and (2) to test putative mechanism of change (i.e., safety behaviors and dysfunctional beliefs). Accordingly, we conducted a randomized controlled trial in which individuals with insomnia were randomized to either online CBT for insomnia (n = 36) or a waiting-list control group (n = 27). Baseline and posttest assessments included questionnaires assessing insomnia severity, safety behaviors, dysfunctional beliefs, anxiety and depression, and a sleep diary. Three- and six-month assessments were administered to the CBT group only. Results show moderate to large statistically significant effects of the online treatment compared to the waiting list on insomnia severity, sleep measures, sleep safety behaviors, and dysfunctional beliefs. Furthermore, dysfunctional beliefs and safety behaviors mediated the effects of treatment on insomnia severity and sleep efficiency. Together, these findings corroborate the efficacy of online CBT for insomnia, and suggest that these effects were produced by changing maladaptive beliefs, as well as safety behaviors. Treatment protocols for insomnia may specifically be enhanced by more focused attention on the comprehensive fading of sleep safety behaviors, for instance through behavioral experiments. PMID- 26012891 TI - Matrix metalloproteinases and risk stratification in patients undergoing surgical revascularisation for critical limb ischaemia. AB - Critical limb ischaemia (CLI) is the most advanced form of peripheral artery disease (PAD) and it is often associated with foot gangrene, which may lead to major amputation of lower limbs, and also with a higher risk of death due to fatal cardiovascular events. Matrix metalloproteinases (MMPs) seem to be involved in atherosclerosis, PAD and CLI. Aim of this study was to evaluate variations in MMP serum levels in patients affected by CLI, before and after lower limb surgical revascularisation through prosthetic or venous bypass. A total of 29 patients (7 females and 22 males, mean age 73.4 years, range 65-83 years) suffering from CLI and submitted to lower extremity bypass (LEB) in our Institution were recruited. Seven patients (group I) underwent LEB using synthetic polytetrafluoroethylene (PTFE) graft material and 22 patients (group II) underwent LEB using autogenous veins. Moreover, 30 healthy age-sex-matched subjects were also enrolled as controls (group III). We documented significantly higher serum MMPs levels (P < 0.01) in patients with CLI (groups I and II) with respect to control group (group III). Finally, five patients with CLI (17.2%) showed poor outcomes (major amputations or death), and enzyme-linked immunosorbent assay (ELISA) test showed very high levels of MMP-1 and MMP-8. MMP serum levels seem to be able to predict the clinical outcomes of patients with CLI. PMID- 26012892 TI - Spin Polarization Inversion at Benzene-Absorbed Fe4N Surface. AB - We report a first-principle study on electronic structure and simulation of the spin-polarized scanning tunneling microscopy graphic of a benzene/Fe(4)N interface. Fe(4)N is a compound ferromagnet suitable for many spintronic applications. We found that, depending on the particular termination schemes and interface configurations, the spin polarization on the benzene surface shows a rich variety of properties ranging from cosine-type oscillation to polarization inversion. Spin-polarization inversion above benzene is resulting from the hybridizations between C p(z) and the out-of-plane d orbitals of Fe atom. PMID- 26012894 TI - Disruption of the 'disease triangle' by chemical and physical environmental change. AB - The physical and chemical environment of the Earth has changed rapidly over the last 100 years and is predicted to continue to change into the foreseeable future. One of the main concerns with potential alterations in climate is the propensity for increases in the magnitude and frequency of extremes to occur. Even though precipitation is predicted to increase in some locations, in others precipitation is expected to decrease and evapotranspiration increase with air temperature, resulting in exacerbated drought in the future. Chemical [ozone (O3 ) and other air contaminants] and subsequent physical alterations in the environment will have a profound effect on the 'disease triangle' (a favourable environment, a susceptible host and a virulent pathogen) and should be included in any analysis of biological response to climate change. The chemical and physical environment affects plant health and alters plant susceptibility to insect and pathogen attack through increased frequency, duration and severity of drought and reduction in host vigour. The potential effects of climate change and O3 on tree diseases with emphasis on the western United States are discussed. We describe a generalised modelling approach to incorporate the complexities of the 'disease triangle' into dynamic vegetation models. PMID- 26012893 TI - Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life. AB - OBJECTIVE: To describe the administration of sedatives and analgesics at the end of life in a large cohort of infants in North American neonatal intensive care units. STUDY DESIGN: Data on mortality and sedative and analgesic administration were from infants who died from 1997-2012 in 348 neonatal intensive care units managed by the Pediatrix Medical Group. Sedatives and analgesics of interest included opioids (fentanyl, methadone, morphine), benzodiazepines (clonazepam, diazepam, lorazepam, midazolam), central alpha-2 agonists (clonidine, dexmedetomidine), ketamine, and pentobarbital. We used multivariable logistic regression to evaluate the association between administration of these drugs on the day of death and infant demographics and illness severity. RESULTS: We identified 19 726 infants who died. Of these, 6188 (31%) received a sedative or analgesic on the day of death; opioids were most frequently administered, 5366/19 726 (27%). Administration of opioids and benzodiazepines increased during the study period, from 16/283 (6%) for both in 1997 to 523/1465 (36%) and 295/1465 (20%) in 2012, respectively. Increasing gestational age, increasing postnatal age, invasive procedure within 2 days of death, more recent year of death, mechanical ventilation, inotropic support, and antibiotics on the day of death were associated with exposure to sedatives or analgesics. CONCLUSIONS: Administration of sedatives and analgesics increased over time. Infants of older gestational age and those more critically ill were more likely to receive these drugs on the day of death. These findings suggest that drug administration may be driven by severity of illness. PMID- 26012896 TI - Interview with Marc Van Montagu. PMID- 26012895 TI - Microfluidic Formation of Membrane-Free Aqueous Coacervate Droplets in Water. AB - We report on the formation of coacervate droplets from poly(diallyldimethylammonium chloride) with either adenosine triphosphate or carboxymethyl-dextran using a microfluidic flow-focusing system. The formed droplets exhibit improved stability and narrower size distributions for both coacervate compositions when compared to the conventional vortex dispersion techniques. We also demonstrate the use of two parallel flow-focusing channels for the simultaneous formation and co-location of two distinct populations of coacervate droplets containing different DNA oligonucleotides, and that the populations can coexist in close proximity up to 48 h without detectable exchange of genetic information. Our results show that the observed improvements in droplet stability and size distribution may be scaled with ease. In addition, the ability to encapsulate different materials into coacervate droplets using a microfluidic channel structure allows for their use as cell-mimicking compartments. PMID- 26012897 TI - Chemical Synthesis of O-Glycosylated Human Interleukin-2 by the Reverse Polarity Protection Strategy. AB - The chemical synthesis of human interleukin-2 (IL-2) , having a core 1 sugar, by a ligation method is reported. Although IL-2 is a globular glycoprotein, its C terminal region, in particular (99-133), is extremely insoluble when synthesized by solid-phase method. To overcome this problem, the side-chain carboxylic acid of the Glu residues was protected by a picolyl ester, thus reversing its polarity from negative to positive. This reverse polarity protection significantly increased the isoelectric point of the peptide segment and made it positive under acidic conditions and facilitated the purification. An efficient method to prepare the prolyl peptide thioester required for the synthesis of the (28-65) segment was also developed. These efforts resulted in the total synthesis of the glycosylated IL-2 having full biological activity. PMID- 26012898 TI - Inoculation with an enhanced N2 -fixing Bradyrhizobium japonicum strain (USDA110) does not alter soybean (Glycine max Merr.) response to elevated [CO2 ]. AB - This study tested the hypothesis that inoculation of soybean (Glycine max Merr.) with a Bradyrhizobium japonicum strain (USDA110) with greater N2 fixation rates would enhance soybean response to elevated [CO2 ]. In field experiments at the Soybean Free Air CO2 Enrichment facility, inoculation of soybean with USDA110 increased nodule occupancy from 5% in native soil to 54% in elevated [CO2 ] and 34% at ambient [CO2 ]. Despite this success, inoculation with USDA110 did not result in greater photosynthesis, growth or seed yield at ambient or elevated [CO2 ] in the field, presumably due to competition from native rhizobia. In a growth chamber experiment designed to study the effects of inoculation in the absence of competition, inoculation with USDA110 in sterilized soil resulted in nodule occupation of >90%, significantly greater (15) N2 fixation, photosynthetic capacity, leaf N and total plant biomass compared with plants grown with native soil bacteria. However, there was no interaction of rhizobium fertilization with elevated [CO2 ]; inoculation with USDA110 was equally beneficial at ambient and elevated [CO2 ]. These results suggest that selected rhizobia could potentially stimulate soybean yield in soils with little or no history of prior soybean production, but that better quality rhizobia do not enhance soybean responses to elevated [CO2 ]. PMID- 26012899 TI - Gold-Catalyzed Cascade Cyclization of 2-Alkynyl-N-Propargylanilines by Rearrangement of a Propargyl Group. AB - Gold catalysis enables direct construction of tetracyclic fused indolines through the migration of a propargyl substituent from an aniline nitrogen atom to the C3 position of an indole from 2-alkynyl-N-propargylanilines. This reaction provides rapid access to fused three-dimensional indolines in a single operation with the formation of four bonds and three rings. PMID- 26012900 TI - 111In-anti-F4/80-A3-1 antibody: a novel tracer to image macrophages. AB - PURPOSE: Here, the expression of F4/80 on the cell surface of murine macrophages was exploited to develop a novel imaging tracer that could visualize macrophages in vivo. METHODS: The immunoreactive fraction and IC50 of anti-F4/80-A3-1, conjugated with diethylenetriaminepentaacetic acid (DTPA) and radiolabelled with (111)In, were determined in vitro using murine bone marrow-derived macrophages. In vivo biodistribution studies were performed with (111)In-anti-F4/80-A3-1 and isotype-matched control antibody (111)In-rat IgG2b at 24 and 72 h post-injection (p.i.) in SCID/Beige mice bearing orthotopic MDA-MB-231 xenografts. In some studies mice were also treated with liposomal clodronate. Macrophage content in tissues was determined immunohistochemically. Micro-single photon emission computed tomography (SPECT)/CT images were also acquired. RESULTS: In vitro binding assays showed that (111)In-anti-F4/80-A3-1 specifically binds F4/80 receptor-positive macrophages. The immunoreactivity of anti-F4/80-A3-1 was 75 % and IC50 was 0.58 nM. In vivo, injection of 10 or 100 MUg (111)In-anti-F4/80-A3-1 resulted in splenic uptake of 78 %ID/g and 31 %ID/g, respectively, and tumour uptake of 1.38 %ID/g and 4.08 %ID/g, respectively (72 h p.i.). Liposomal clodronate treatment reduced splenic uptake of 10 MUg (111)In-anti-F4/80-A3-1 from 248 %ID/g to 114 %ID/g and reduced (111)In-anti-F4/80-A3-1 uptake in the liver and femur (24 h p.i.). Tracer retention in the blood and tumour uptake increased (24 h p.i.). Tumour uptake of (111)In-anti-F4/80-A3-1 was visualized by microSPECT/CT. Macrophage density in the spleen and liver decreased in mice treated with liposomal clodronate. Uptake of (111)In-rat IgG2b was lower in the spleen, liver and femur when compared to (111)In-anti-F4/80-A3-1. CONCLUSION: Radiolabelled anti-F4/80-A3-1 antibodies specifically localize in tissues infiltrated by macrophages in mice and can be used to visualize tumours. The liver and spleen act as antigen sink organs for macrophage-specific tracers. PMID- 26012902 TI - Reduction in broad-spectrum Gram-negative agents by diverse prescribing of aztreonam within NHS Tayside. PMID- 26012901 TI - Left atrial enlargement increases the risk of major adverse cardiac events independent of coronary vasodilator capacity. AB - PURPOSE: Longstanding uncontrolled atherogenic risk factors may contribute to left atrial (LA) hypertension, LA enlargement (LAE) and coronary vascular dysfunction. Together they may better identify risk of major adverse cardiac events (MACE). The aim of this study was to test the hypothesis that chronic LA hypertension as assessed by LAE modifies the relationship between coronary vascular function and MACE. METHODS: In 508 unselected subjects with a normal clinical (82)Rb PET/CT, ejection fraction >=40 %, no prior coronary artery disease, valve disease or atrial fibrillation, LAE was determined based on LA volumes estimated from the hybrid perfusion and CT transmission scan images and indexed to body surface area. Absolute myocardial blood flow and global coronary flow reserve (CFR) were calculated. Subjects were systematically followed-up for the primary end-point - MACE - a composite of all-cause death, myocardial infarction, hospitalization for heart failure, stroke, coronary artery disease progression or revascularization. RESULTS: During a median follow-up of 862 days, 65 of the subjects experienced a composite event. Compared with subjects with normal LA size, subjects with LAE showed significantly lower CFR (2.25 +/- 0.83 vs. 1.95 +/- 0.80, p = 0.01). LAE independently and incrementally predicted MACE even after accounting for clinical risk factors, medication use, stress left ventricular ejection fraction, stress left ventricular end-diastolic volume index and CFR (chi-squared statistic increased from 30.9 to 48.3; p = 0.001). Among subjects with normal CFR, those with LAE had significantly worse event-free survival (risk adjusted HR 5.4, 95 % CI 2.3 - 12.8, p < 0.0001). CONCLUSION: LAE and reduced CFR are related but distinct cardiovascular adaptations to atherogenic risk factors. LAE is a risk marker for MACE independent of clinical factors and left ventricular volumes; individuals with LAE may be at risk of MACE despite normal coronary vascular function. PMID- 26012903 TI - Reversible thermo-sensitivity induced from varying the hydrogen bonding between the side residues of rationally designed polypeptides. AB - Rationally designed polypeptides with similar molecular structures but varying patterns of hydrogen bonding between the side groups have been synthesized and demonstrated to possess distinct solubility and thermal behaviors. Further balancing the ratio of both isopropylamine and ethylenediamine side groups endows the random copolymer with reversible thermo-sensitivity. PMID- 26012904 TI - Evolution Is an Experiment: Assessing Parallelism in Crop Domestication and Experimental Evolution: (Nei Lecture, SMBE 2014, Puerto Rico). AB - In this commentary, I make inferences about the level of repeatability and constraint in the evolutionary process, based on two sets of replicated experiments. The first experiment is crop domestication, which has been replicated across many different species. I focus on results of whole-genome scans for genes selected during domestication and ask whether genes are, in fact, selected in parallel across different domestication events. If genes are selected in parallel, it implies that the number of genetic solutions to the challenge of domestication is constrained. However, I find no evidence for parallel selection events either between species (maize vs. rice) or within species (two domestication events within beans). These results suggest that there are few constraints on genetic adaptation, but conclusions must be tempered by several complicating factors, particularly the lack of explicit design standards for selection screens. The second experiment involves the evolution of Escherichia coli to thermal stress. Unlike domestication, this highly replicated experiment detected a limited set of genes that appear prone to modification during adaptation to thermal stress. However, the number of potentially beneficial mutations within these genes is large, such that adaptation is constrained at the genic level but much less so at the nucleotide level. Based on these two experiments, I make the general conclusion that evolution is remarkably flexible, despite the presence of epistatic interactions that constrain evolutionary trajectories. I also posit that evolution is so rapid that we should establish a Speciation Prize, to be awarded to the first researcher who demonstrates speciation with a sexual organism in the laboratory. PMID- 26012905 TI - GPU MrBayes V3.1: MrBayes on Graphics Processing Units for Protein Sequence Data. AB - We present a modified GPU (graphics processing unit) version of MrBayes, called ta(MC)(3) (GPU MrBayes V3.1), for Bayesian phylogenetic inference on protein data sets. Our main contributions are 1) utilizing 64-bit variables, thereby enabling ta(MC)(3) to process larger data sets than MrBayes; and 2) to use Kahan summation to improve accuracy, convergence rates, and consequently runtime. Versus the current fastest software, we achieve a speedup of up to around 2.5 (and up to around 90 vs. serial MrBayes), and more on multi-GPU hardware. GPU MrBayes V3.1 is available from http://sourceforge.net/projects/mrbayes-gpu/. PMID- 26012928 TI - Hypoxia Induced by Upconversion-Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors. AB - Local hypoxia in tumors is an undesirable consequence of photodynamic therapy (PDT), which will lead to greatly reduced effectiveness of this therapy. Bioreductive pro-drugs that can be activated at low-oxygen conditions will be highly cytotoxic under hypoxia in tumors. Based on this principle, double silica shelled upconversion nanoparticles (UCNPs) nanostructure capable of co-delivering photosensitizer (PS) molecules and a bioreductive pro-drug (tirapazamine, TPZ) were designed (TPZ-UC/PS), with which a synergetic tumor therapeutic effect has been achieved first by UC-based (UC-) PDT under normal oxygen environment, immediately followed by the induced cytotoxicity of activated TPZ when oxygen is depleted by UC-PDT. Treatment with TPZ-UC/PS plus NIR laser resulted in a remarkably suppressed tumor growth as compared to UC-PDT alone, implying that the delivered TPZ has a profound effect on treatment outcomes for the much-enhanced cytotoxicity of TPZ under PDT-induced hypoxia. PMID- 26012929 TI - Probability state modeling theory. AB - As the technology of cytometry matures, there is mounting pressure to address two major issues with data analyses. The first issue is to develop new analysis methods for high-dimensional data that can directly reveal and quantify important characteristics associated with complex cellular biology. The other issue is to replace subjective and inaccurate gating with automated methods that objectively define subpopulations and account for population overlap due to measurement uncertainty. Probability state modeling (PSM) is a technique that addresses both of these issues. The theory and important algorithms associated with PSM are presented along with simple examples and general strategies for autonomous analyses. PSM is leveraged to better understand B-cell ontogeny in bone marrow in a companion Cytometry Part B manuscript. Three short relevant videos are available in the online supporting information for both of these papers. PSM avoids the dimensionality barrier normally associated with high-dimensionality modeling by using broadened quantile functions instead of frequency functions to represent the modulation of cellular epitopes as cells differentiate. Since modeling programs ultimately minimize or maximize one or more objective functions, they are particularly amenable to automation and, therefore, represent a viable alternative to subjective and inaccurate gating approaches. PMID- 26012930 TI - A novel technique for full anatomic restoration of volar tilt in distal radius fracture. AB - OBJECTIVE: The aim of this study was to present a technique that allows the surgeon to easily and reliably achieve volar tilt in dorsally displaced distal radius fractures treated with variable-angle volar locking plates. The study introduced this technique using 2.4 mm variable angle locking screws as reduction tools, and investigated the radiological outcomes of this technique. METHODS: A total of 42 patients (30 female and 12 male; mean age: 58 years, range, 25 to 84 years) with unstable distal radius fractures were treated with this technique. All were patients with insufficient volar tilt in spite of primary fracture reduction through classic reduction techniques such as traction, manipulation, and direct fragment manipulation. Postoperatively, the patients were instructed to perform wrist active and passive motion exercises at home for minimum 30 minutes a day, and were allowed to perform activities of daily living after removal of splint. The patients were evaluated radiographically at minimum twelve months after surgery. RESULTS: Mean follow-up period was 15.1 months (range: 12 to 24 months). Volar tilt of the distal radius before surgery was -11.9+/-10.4 (minus value means dorsal angulation), and after screw leverage was 11.5+/-4.3 degrees (uninjured side: 11.7+/-2.3 degrees ). Mean radiological outcomes at final visit were as follows: volar tilt; 10.8+/-4.5 degrees , radial inclination; 24+/-3.2 degrees , radial height; 12.2+/-1.7 mm, and ulnar variance; 0.2+/-1.7 mm. CONCLUSION: We describe a simple, reliable technique to fine-tune volar tilt in dorsally displaced distal radius fractures fixed with variable-angle volar locking plates. This technique is especially useful when volar tilt remains insufficient in spite of primary fracture reduction through classic techniques. PMID- 26012931 TI - Validity and reliability of the Turkish "Patient-Rated Wrist Evaluation" questionnaire. AB - OBJECTIVE: The Patient-Rated Wrist Evaluation (PRWE) scale is a self-administered outcome questionnaire used to determine level of pain and disability in wrist problems. The scale includes pain (PRWE-P) and function (PRWE-F) subscales, the latter consisting of specific function (PRWE-SF) and usual (PRWE-UF) function. This study aimed to evaluate the validity and reliability of the Turkish versionof the PRWE scale. METHODS: Permission was sought and received from the original author of the PRWE for a Turkish translation for use in the study. The study included 110 patients (85 female and 25 male; mean age: 50.8+/-1.53 years; range: 18 to 85) with distal radius fracture, carpal tunnel syndrome, wrist ganglion cyst, De Quervain syndrome, Kienbock disease, and connective lesions affecting the wrist, all of whom completed the Turkish version of both the PRWE (PRWE-T) and the Disabilities of the Arm Shoulder and Hand scale (DASH). Reliability and validity of the PRWE-T scale were evaluated via an internal consistency analysis and a factor analysis respectively. The level of correlation between PRWE-T and DASH scores was also examined. RESULTS: Cronbach's alpha coefficient was calculated as 0.86, 0.82 and 0.88 for PRWE-P, PRWE-F and PRWE-T respectively for the scale and all subscales. The PRWE-T scale was found to be highly reliable. A statistically significant correlation was found between PRWE-T and DASH in the criterion-related validity analysis (Spearman's rho=0.9). CONCLUSION: The PRWE-T was found to be valid and reliable. It is therefore suggested for use in evaluating patient-based pain and disability levels in routine clinical practice. PMID- 26012932 TI - Correlations between ultrasonography findings and surgical findings in patients with refractory symptoms after primary surgical release for carpal tunnel syndrome. AB - OBJECTIVE: Surgical carpal tunnel release is very effective for symptom relief in carpal tunnel syndrome, and it remains the preferred choice of treatment. However, refractory symptoms following surgical release are not uncommon. We aimed to assess the usefulness of ultrasonography for determining the potential causes of ongoing symptoms following surgical release. METHODS: This retrospective study included 34 patients (32 women; mean age, 54.7+/-16.65 years; range: 30 to 81 years) with carpal tunnel syndrome who underwent surgical carpal tunnel release. RESULTS: A pathology related to the cause of the ongoing symptoms was detected by ultrasonography in 25 (74.5%) patients. The most common pathological findings were median nerve swelling (70.6%), incomplete transection of the transverse carpal ligament (23.5%) and perineural fibrosis (17.6%). CONCLUSION: In the majority of the patients the pathology related to the ongoing symptoms was detected by ultrasonography, suggesting that ultrasonography could be used as a complementary imaging method for identifying the causes of failure following surgical carpal tunnel release. Detection of an ongoing pathology might help clinicians in managing persistent disease cases and aid in planning an exploration. PMID- 26012933 TI - Predictive factors for postoperative deformity in thoracolumbar burst fractures: a statistical approach. AB - OBJECTIVE: To assess, using statistical analysis, if and to what extent the final outcome of surgical treatment for burst fractures depends on operation type, fracture level and initial deformity severity. METHODS: A database of 287 patients with single-vertebral-level thoracic and lumbar spine fractures analysed using simple and multiple linear regression analyses models. The dependent variable was last follow-up (LFU) kyphotic angle and the predictor variables were operation type [anterior approach (AA), posterior short-segment fixation (PSSF) and posterior monosegmental fixation (PMF)], fracture level (T11-L1, L2-L3 and L4 L5) and preoperative kyphotic angle. The models were applied on either the whole sample or on the operation type subgroups. RESULTS: In simple linear regression analysis models, fracture level accounted for 32% and 18% of the variation in LFU kyphotic angle in the AA and PMF subgroups, respectively. In the multiple linear regression models for the same subgroups, up to 40% of the variation in LFU kyphotic angle was accounted for by fracture level. Surgical treatment, as predictor variable, indicated that patients treated by PSSF developed a post surgical kyphotic angle 8.51 degrees more severe than those treated by AA. However, the model accounted for only 2% of the variation in LFU kyphotic angle. Simple linear regressions performed on each subgroup with preoperative kyphotic angle as the independent variable revealed that the variable accounted for 15% (PSSF subgroup), 17% (AA subgroup) and 34% (PMF subgroup) of the variation in LFU kyphotic angle. CONCLUSION: All valid regression models displayed modest explanatory power, suggesting that factors other than those taken into consideration are involved. PMID- 26012934 TI - Surgical excision of peripheral nerve schwannomas: analysis of 11 patients. AB - OBJECTIVE: Benign schwannomas are the most common tumour of the peripheral nerves. Symptomatic schwannomas are treated by surgical excision, but new neurological deficits may develop. We performed a retrospective review of cases of schwannomas in the extremities and reviewed the relevant literature. METHODS: We retrospectively reviewed the demographic characteristics of 11 patients with schwannomas treated at our institution. We also reviewed the clinical characteristics and postoperative results of these cases, determined the possible risk factors influencing the development of complications and compared the risk factors with those reported in the literature. RESULTS: There were five males and six females with a mean age of 37.6 (range: 17-62) years. The mean postoperative follow-up was 54.6 (range: 26-88) months. Three tumours were located in the forearm and the rest were localized in the lower extremity. No recurrences were observed during the follow-up period. New motor and sensory deficits were observed in only one patient. CONCLUSION: Schwannomas in the extremities can be excised with acceptable risk of neurological deficits. Meticulous dissection is required during surgery. PMID- 26012935 TI - Long-term follow-up of long and flat bone eosinophilic granulomas managed only with biopsy. AB - OBJECTIVE: We evaluated long-term clinical and radiological follow-up results of patients with long and flat bone eosinophilic granulomas managed only with biopsy. METHODS: Seventeen patients [11 male, 6 female; average age 8.5 years (range: 3.5 to 14 years)] with long and flat bone eosinophilic granulomas were followed after biopsy. Involved bones were femur (5), tibia (3), humerus (2), ulna (1), pelvis (3), scapula (1) and clavicle (1). After confirmation of diagnosis by biopsy, no further surgical intervention was performed. Clinical follow-up was done with preoperative and postoperative MSTS and VAS scores. The healing process was followed with periodic radiographs. Limb-length discrepancy, deformity, and lesion progression or recurrence were recorded. Average follow-up was 65 months (range: 28 to 115 months). RESULTS: Average preoperative MSTS score was 45% (range: 30 to 56.6%), while postoperative 6, 12 and 24 months scores were measured as 76% (range: 70 to 83.3%), 88% (range: 73.3 to 93.3%) and 94% (range: 86.6 to 100%) respectively. Average VAS score, which was 8.4 (range: 6 to 10) preoperatively, had a tendency to decrease postoperatively, and was measured as 3.5 (range: 2 to 5), 2.2 (range: 1 to 3.5) and 1.1 (range: 0 to 2) at 3, 6, and 12 months. Even though the majority of lesions demonstrated complete radiographic healing at 12 months, the healing process extended to 24 months for flat bones. No patients experienced limb-length discrepancy or deformity. All lesions regressed following biopsy and no recurrence was seen. CONCLUSION: Eosinophilic granuloma has a spontaneous healing potential, and confirming the diagnosis by biopsy is sufficient to obtain good functional and radiological results without any further intervention. PMID- 26012936 TI - A comparison of results of 3-dimensional gait analysis and observational gait analysis in patients with knee osteoarthritis. AB - OBJECTIVE: This study aimed to investigate levels of validity, and inter- and intra-observer reliability of observational gait analysis (OGA) in clinical usage, done by the physical therapists with varying clinical experience, in subjects with knee osteoarthritis. METHODS: The study included 33 subjects (22 female, 11 male; mean age: 58.24+/-9.14 years range: 46 to 81) clinically and radiographically diagnosed with bilateral knee osteoarthritis, and 4 physical therapists to observe the subjects' gaits. The physical therapists were separated into two groups according to their professional experience: those with 10 or more years, and those with fewer than 10 years. Video recordings were made of the subjects undergoing three-dimensional gait analysis (3DGA). These recordings were then observationally assessed twice by the participating physical therapists with at least a 6-week interval between observations. OGA was done via a form comprising 11 kinematic and 5 temporo-spatial parameters. RESULTS: Lowest levels of agreement in both validity (r=0.06, p>0.05), and inter- (ICC:-0.12-0.06) and intra-observer (ICC:0.30-0.45) reliability were found in the parameters of ankle dorsiflexion in initial contact phase and pelvic rotation in midstance phase. Highest inter- and intra-observer agreement was found in the temporo-spatial parameters of step width, double step length, cadence and velocity (ICC:0.61 0.80). Highest validity was found in pelvic tilt in stance phase (r=0.74-0.78, p<0.001). With the exception of stance phase, moderate or good agreement (r=0.52 0.69, p<0.05) was found in the temporo-spatial parameters. CONCLUSION: This study found that OGA assessment of temporo-spatial parameters had moderate or good validity and reliability. Assessment of the majority of kinematic parameters had fair or moderate validity and inter-observer reliabilty, and moderate or good intra-observer reliability. PMID- 26012937 TI - Effects of salmon calcitonin treatment on serum and synovial fluid bone formation and resorption markers in osteoporosis patients. AB - OBJECTIVE: This study aimed to evaluate the effects of salmon calcitonin, and calcium and vitamin D treatment on bone mineral density, serum and synovial fluid bone formation and resorption markers in patients with osteoporosis. METHODS: The study was completed with twenty-five osteoporosis patients divided into two groups: The 15 patients comprising Group I (1 male and 14 females; mean age: 67.0+/-12.0) were administered calcitonin treatment in addition to calcium and vitamin D. The 10 patients in Group II (3 males and 7 females; mean age 68.0+/ 16.0) were administered calcium and vitamin D only. Serum and synovial fluid calcium phosphorus, alkaline phosphatase, calcitonin, C-telopeptide (CTx), N telopeptide (NTx) and sialoprotein levels, and bone densitometries were determined at the beginning and at the end of one year of treatment. RESULTS: In the calcitonin and calcium and vitamin D treatment group (Group I), femoral neck density scores were decreased and vertebrae scores were increased after one-year treatment. Both scores were increased in the non-calcitonin group (Group II). In Group I, synovial fluid levels of calcitonin, sialoprotein and NTx were decreased, and synovial fluid CTx levels showed no change. The only decrease that was statistically significant was that in calcitonin levels. In Group II, synovial fluid calcitonin levels were decreased, synovial fluid CTx levels were increased and synovial fluid NTx and sialoprotein level were unchanged. These changes were not statistically significant. Serum changes in the parameters were not statistically significant in either group. CONCLUSION: In osteoporosis, salmon calcitonin treatment affects synovial fluid bone formation and absorption marker levels. Advanced studies are needed to evaluate the mechanisms by which this takes place, and to explain the relationship between osteoporosis and articular cartilage metabolism. PMID- 26012938 TI - The effect of postural stabilization exercises on pain and function in females with patellofemoral pain syndrome. AB - OBJECTIVE: This study aimed to investigate the effect of postural stabilization exercises on pain, muscle strength and function in females with patellofemoral pain. METHODS: Forty-two volunteers with patellofemoral pain syndrome (PFPS) were included in this study. The subjects were randomly divided into two groups: Group 1 performed therapeutic knee and postural stabilization exercises (n=22); Group 2 performed therapeutic knee exercises only (n=20). All patients were evaluated for pain, hamstring flexibility, function, lower extremity strength and postural control before and after treatment and at the 12th week. A two-way ANOVA was done within each group before and after treatment and at the 12th week. The level of significance was set at p<0.05, and when this was observed, the Tukey test was used to determine which group had caused the significance. RESULTS: The results were statistically significant between the groups in terms of pain, flexibility, function, strength, endurance, postural control and the parameters of the Kujala patellofemoral pain scale (p<0.05). For all parameters, Group 1 achieved the greater success after treatment (p<0.05). CONCLUSION: The implementation of physiotherapy and rehabilitation programs including postural stabilization exercises may improve strength and function and reduce pain in patients with PFPS. PMID- 26012939 TI - Medium-term results of single-stage posteromedial release and triple arthrodesis in treatment of neglected clubfoot deformity in adults. AB - OBJECTIVE: This study aimed to evaluate the implementation, in a single session, of both massive posteromedial release and triple arthrodesis for rigid neglected clubfoot deformities in adult patients, and its effects on clinical and radiological results. METHODS: The procedures were performed in one session on 15 feet of 11 patients [7 male, 4 female; mean age 26 (range: 15 to 50)]. Staples were used for fixation in all patients. For clinical assessment, the AOFAS (American Orthopaedic Foot and Ankle Society) ankle- hindfoot scale was used. Anteroposterior/lateral side talocalcaneal and talus-1st metatarsal angles were used as radiographic parameters. The mean follow-up was 7.5 years (range: 6 to 11). RESULTS: The mean AOFAS score rose from a preoperative 39 (range: 15 to 52) to 88 (range: 76 to 94) in the final follow up (p<0.0001). Among the 15 feet, 9 were evaluated as excellent, 5 as good, and 1 as fair. Significant clinical improvement was obtained between preoperative and postoperative surgical periods (p<0.05). Significant improvements were observed in radiographic parameters (p<0.0001). At final follow-up, radiographic values were within normal physiological limits. Average union time was 12.4 (range: 7 to 36) weeks. While pseudoarthrosis was not observed in any patients, delayed union developed in 2 cases, and talus avascular necrosis in 1. In the preoperative period, 5 patients had various degrees of degenerative changes. Nine patients developed degenerative changes in different joints and of different degrees. CONCLUSION: The authors believe that massive soft tissue release and triple arthrodesis performed in a single session yields satisfactory results cosmetically and functionally in neglected clubfoot cases with severe deformities. PMID- 26012940 TI - Utilization of the bicipital groove axis for confirming alignment of the humerus with transepicondylar and ulnar shaft axes during intramedullary nailing. AB - OBJECTIVE: Intramedullary nailing is the preferred surgical treatment of humerus shaft fractures. The purpose of this study was to investigate the relationship between the bicipital groove and specific anatomical landmarks in achieving correct alignment of the humerus during intramedullary nailing, and to describe these anatomical landmarks. METHODS: Thirty (15 right; 15 left) total upper cadaver extremities were used in this study. After the anatomical landmarks were identified and marked, humeral head axis, transepicondylar axis, ulnar shaft axis, bicipital groove axis, and angular measurements of these were obtained. RESULTS: The mean angle between the bicipital groove axis and transepicondylar axis was 48.17 degrees +/-12.35o (range: 20.10o to 74.6o). The mean angle between the bicipital groove axis and ulna diaphysis axis was 41.82o+/-11.56 o (range: 17.91o to 68.27o). The mean angle between the humeral head axis and bicipital groove axis was 20.53 degrees +/-3.90o (range: 11.85o to 31.81o). The mean retroversion angle between the humeral head axis and transepicondylar axis was 27.52+/-11.37o (range: 4.26o to 49.36o). The mean angle between the humeral head axis and ulna diaphysis axis was 61.73o+/-12.08o (range: 33.97o to 86.37o). The mean torsion angle was 62.58o+/-11.28 o (range: 40.74o to 85.74o). CONCLUSION: Measurement and utilization of the relationship between the bicipital groove, ulna diaphysis and transepicondylar axes may be used for restoring humeral rotation. PMID- 26012941 TI - Modified tension band wiring technique for olecranon fractures: where and how should the K-wires be inserted to avoid articular penetration? AB - OBJECTIVE: Articular penetration of K-wires is a possible complication of the modified tension band wiring technique. However, there is no clear information or evidence regarding the entry point or introduction angle for K-wires to avoid this complication. The aim of this experimental study was to evaluate the effect of varying K-wire insertion points and angles on the risk for articular penetration during modified tension band wiring for olecranon fractures. METHODS: All anatomical measurements were made on 50 cadaveric ulnas, and all other measurements were performed on exact foam replications of the 50 cadaveric ulnas. Morphometric measurements, including olecranon height and heights of the central, radial and ulnar facets of the semilunar notch, were taken. In the sagittal plane, articular angle and tubercle angle were measured. Two 1.6-mm parallel K wires were inserted from 0, 5 and 8 mm anterior to the dorsal cortex of the olecranon process at angles of 20 degrees and 30 degrees . K-wire articular penetration was evaluated both visually and radiographically. RESULTS: The mean central, radial and ulnar heights of the semilunar notch were 17.3 mm (14.7 20.0), 16.2 mm (12.0-21.0) and 15.8 mm (13.30-20.5), respectively. We observed no articular penetration at the 0-mm level at 20 degrees and 30 degrees (0 mm 20 degrees and 0 mm 30 degrees , respectively) or at 5 mm 20 degrees . At 8 mm 30 degrees wire introduction, more than 64% articular penetration was observed on either facet. The sequence from least to most likely to cause articular penetration was: 0 mm = 5 mm 20 degrees > 5 mm 30 degrees = 8 mm 20 degrees > 8 mm 30 degrees . The radial height of the semilunar notch was negatively correlated to the risk of articular penetration, when the wire was introduced at 8 mm 30 degrees , 8 mm 20 degrees and 5 mm 30 degrees (all p<0.047). There were poor correlations between radiological and direct observational assessments, particularly for 8 mm 20 degrees and 5 mm 30 degrees . The frequency of intra articular positioning for those observed to be radiologically extra-articular was 4/28 (14.3%) for 8 mm 30 degrees , 4/7 (57.1%) for 8 mm 20 degrees and 5/6 (83.3%) for 5 mm 30 degrees . CONCLUSION: When applying the modified tension band wiring technique to prevent articular penetration, K-wires should be inserted in the first 5 mm from dorsal cortex of the olecranon process at a maximum angle of 20 degrees . Moreover, if the wires are required to be inserted more anteriorly because of the anatomical configuration of the fracture, they should be inserted at a shallow angle in the sagittal plane in relation to the proximal cortex of the ulna. PMID- 26012942 TI - A new small-animal model for the study of acquired heterotopic ossification after hip surgery. AB - OBJECTIVE: Heterotopic ossification (HO)--the formation of bone in soft tissues- is a frequent problem after surgery of the hip and pelvis, but little is known about its underlying pathogenic mechanisms. It is vital to study the underlying pathogenesis in animal models to develop and evaluate new prophylactic regimens directed against HO. However, previously developed small-animal models for the study of HO imitate neither surgery nor trauma-mechanisms that potentially cause HO. Hence, the goal of this study was to develop a novel small-animal model imitating hip surgery that can reliably produce HO. METHODS: Twenty male Wistar rats were subjected to surgery of the right hip during which the femoral canal was reamed in three steps up to 2 mm, and a muscle lesion was made. Twelve weeks after surgery, the amount of heterotopic bone was assessed using micro-computed tomography. RESULTS: Eighteen of 20 animals showed HO around the hip 12 weeks after surgery. The amount of heterotopic bone varied from very small particles up to near ankylosis. CONCLUSION: A rat model of hip/pelvic surgery that does not use exogenous osteogenic stimulus and can reliably produce HO was developed. PMID- 26012943 TI - Biomechanical effect of medial cortical support and medial screw support on locking plate fixation in proximal humeral fractures with a medial gap: a finite element analysis. AB - OBJECTIVE: This finite element analysis aimed to examine the effect of medial cortical support and medial screw support on loads at the implant-bone interface of locking plate fixation of proximal humeral fractures with a medial gap. METHODS: An intact humerus from a healthy volunteer was used as the basis for a 3 dimensional (3D) computer-aided design (CAD) model. The 3D CAD model of the locking plate system was based on information in the manufacturer's catalogue. The proximal part of the humerus was osteotomized to create standard three-part fractures, which were then divided into a -MSC group (which lacked medial cortical support, and in which fractures with a 5-mm medial bone gap simulated this lack) and +MCS group (which had medial cortical support, and in which fractures with medial cortical-to-cortical contact simulated this). Both fracture groups were respectively fixed with either +MSS (in which medial screw support was simulated by the addition of two calcar screws to the locking plate system), or with -MSS (in which the lack of medial screw support was simulated by absence of the two additional calcar screws to the locking plate system). All the modeling was conducted to represent 90 degrees arm abduction. RESULTS: On the screw-bone interface, medial screw support and medial cortical support decreased maximum shear stress by 17% and 23% respectively. On the locking plate, medial screw support and medial cortical support decreased maximum von Mises stress by 11% and 22% respectively. However, a combination of these two appeared to decrease maximum shear stress by 56% for the screw-bone interface, and maximum von Mises stress by 54% for the locking plate. CONCLUSION: Placement of calcar screws combined with good medial cortical contact in varus in locking plate fixation of proximal humeral fractures with a medial gap may provide optimal stability for the fixation. PMID- 26012944 TI - Osteofibrous dysplasia-like adamantinoma in a 3-month-old male infant: a case report. AB - We report a case of a very rarely seen osteofibrous dysplasia-like adamantinoma (OFDLA) of the lower leg in a 3-month-old male infant, making it the youngest case in the literature. OFDLA is typically regarded as a benign lesion; however, due to its convertibility into classical adamantinoma, it is recommended to evaluate it as a pre-malignant lesion. After OFDLA diagnosis with biopsy, our case underwent surgical resection and reconstruction with a large allograft. Patient experienced good outcomes and did not experience any local relapse in the 3-year follow-up. PMID- 26012945 TI - Apophyseal avulsion fracture of the anterior inferior iliac spine due to a simple bone cyst. AB - Apophyseal avulsion fractures of the anterior inferior iliac spine are rare; they are usually seen in adolescents as a result of sudden contraction of the rectus femoris muscle. Treatment is usually conservative, but surgical management may be necessary in certain circumstances. We present an unusual case of a 14-year-old male who was referred to our department for a suspicious pathological fracture of his right anterior inferior iliac spine; he was found to have an avulsion fracture of the anterior inferior iliac spine due to simple bone cyst. We discuss the treatment of this rare injury caused by a benign osseous tumour. PMID- 26012946 TI - Removal of a femoral intramedullary nail with impacted nail end cap using a broken screw extraction set: a case report and literature review. AB - We report the technique we used in extraction of a femoral intramedullary nail with impacted nail cap. The extraction was done using a damaged screw extraction device and a bone hook, with no additional bone or soft tissue damage. This technique has not been reported before in the literature. We also review the cases reported for difficult nail extractions due to impacted nail end caps. PMID- 26012947 TI - Venous thromboembolism after shoulder arthroplasty: a report of three cases. AB - Venous thromboembolism after shoulder arthroplasty is considered a rare phenomenon, but can be a dangerous and life-threatening condition. We report three cases of venous thromboembolism sustained after shoulder arthroplasty. One of the patients had a non-fatal pulmonary embolism. The other two had deep vein thrombosis, one in the operated upper extremity, and the other in a lower extremity. The cases are described in detail and discussed to reveal the possible contributing risk factors. The purpose of this case series is to increase awareness of this relatively rare, but potentially serious complication. PMID- 26012948 TI - What if the silent disease comes with the reality? Comment on: Prevalence of bone mineral density testing and osteoporosis management following low-and high-energy fractures. PMID- 26012949 TI - Comment on: Locking knee after intra-articular migration of broken patella tension band wire: an extraordinary intra-articular migration via pseudarthrosis line. PMID- 26012951 TI - Management of pediatric chronic spontaneous and physical urticaria patients with omalizumab: case series. PMID- 26012950 TI - Job Demand and Job Satisfaction in Latent Groups of Turnover Intention Among Licensed Nurses in Taiwan Nursing Homes. AB - Nurses' turnover intention is not dichotomous; it may reflect intent to leave the profession, intent to leave a type of facility, or intent to leave a specific workplace. In a latent class analysis (LCA) of data from 186 licensed nurses (RNs and LPNs) recruited from 25 nursing homes (NHs) in Taiwan, we classified nurses into turnover intention subgroups based on seven questionnaire items and used a multilevel contrast analysis to characterize the subgroups according to demographic and facility factors, job demand, and job satisfaction. A multilevel probit model was used to examine how job demand and job satisfaction influenced subgroup membership. Three turnover subgroups were identified: high turnover intention (12%), middle turnover intention (57%), and low turnover intention (31%). The high turnover intention subgroup comprised the youngest nurses and had the lowest percentage of registered nurses (RNs); nurses in this subgroup had worked the longest at the current NH and had the greatest likelihood of working at a for-profit facility. Nurses in the middle turnover intention subgroup had the lowest likelihood of working at a for-profit facility. Nurses in the low turnover intention subgroup were primarily RNs and had the shortest work experience in the current facility. Nurses in the high and middle turnover intention subgroups reported lower intrinsic job satisfaction than those with low turnover intention. Extrinsic job satisfaction mediated the relationship between job demand and turnover intention subgroup assignment. The results of this LCA can help target interventions to address heterogeneity of turnover intention and ultimately lessen turnover. PMID- 26012952 TI - Semi-online patient scheduling in pathology laboratories. AB - OBJECTIVE: Nowadays, effective scheduling of patients in clinics, laboratories, and emergency rooms is becoming increasingly important. Hospitals are required to maximize the level of patient satisfaction, while they are faced with lack of space and facilities. An effective scheduling of patients in existing conditions is vital for improving healthcare delivery. The shorter waiting time of patients improves healthcare service quality and efficiency. Focusing on real settings, this paper addresses a semi-online patient scheduling problem in a pathology laboratory located in Tehran, Iran, as a case study. METHODS AND MATERIAL: Due to partial precedence constraints of laboratory tests, the problem is formulated as a semi-online hybrid shop scheduling problem and a mixed integer linear programming model is proposed. A genetic algorithm (GA) is developed for solving the problem and response surface methodology is used for setting GA parameters. A lower bound is also calculated for the problem, and several experiments are conducted to estimate the validity of the proposed algorithm. RESULTS: Based on the empirical data collected from the pathology laboratory, comparison between the current condition of the laboratory and the results obtained by the proposed approach is performed through simulation experiments. The results indicate that the proposed approach can significantly reduce waiting time of the patients and improve operations efficiency. CONCLUSION: The proposed approach has been successfully applied to scheduling patients in a pathology laboratory considering the real-world settings including precedence constraints of tests, constraint on the number of sites or operators for taking tests (i.e. multi-machine problem), and semi-online nature of the problem. PMID- 26012953 TI - Effects of infliximab on sister chromatid exchanges and chromosomal aberration in patients with rheumatoid arthritis. AB - The aim of this study was to evaluate in a 24-weeks the effect of anti-TNF-alpha, infliximab, on cytogenetic biomarkers in peripheral lymphocytes of patients with rheumatoid arthritis (RA). A total of 40 patients with RA met the criteria to be treated with methotrexate (15 mg/week) were evaluated. Twenty patients, randomly selected, were treated with infliximab in addition to methotrexate (group I), whereas the other 20 patients continued with only methotrexate treatment (group M). Twenty healthy volunteers matched for age, gender and smoking habits served as control group (group C). At baseline, sister chromatid exchange rate was 7.20 +/- 2.21 in group I, 7.40 +/- 1.60 in group M and 4.97 +/- 1.32 in group C (P < 0.01 vs group I and M). After 24-weeks, sister chromatid exchange rate was 7.87 +/- 2.54 in group I and 7.81 +/- 1.95 in group M (P = ns). High frequency cells count was 4.9 % and 4.7 % in the groups I and M, respectively, at the end of the study (P = ns). The basal chromosomal aberration frequency was 4.90 % in group I and 5.20 % in groups M; after 24-weeks, this was 5.10 % in group I and 5.10 % in groups M (P = ns). Infliximab treatment, for 24 weeks, did not increase the cytogenetic biomarkers in patients with RA. Our data show that the use of infliximab has not a genotoxic effect in patients with RA. PMID- 26012957 TI - Time Scales of Conformational Gating in a Lipid-Binding Protein. AB - Lipid-binding proteins sequester amphiphilic molecules in a large internal cavity occupied by ~30 water molecules, some of which are displaced by the ligand. The role of these internal water molecules in lipid binding and release is not understood. We use magnetic relaxation dispersion (MRD) to directly monitor internal-water dynamics in apo and palmitate-bound rat intestinal fatty acid binding protein (rIFABP). Specifically, we record the water (2)H and (17)O MRD profiles of the apo and holo forms of rIFABP in solution or immobilized by covalent cross-links. A global analysis of this extensive data set identifies three internal-water classes with mean survival times of ~1 ns, ~100 ns, and ~6 MUs. We associate the two longer time scales with conformational fluctuations of the gap between beta-strands D and E (~6 MUs) and of the portal at the helix capped end of the beta-barrel (~100 ns). These fluctuations limit the exchange rates of a few highly ordered structural water molecules but not the dissociation rate of the fatty acid. The remaining 90% (apo) or 70% (holo) of cavity waters exchange among internal hydration sites on a time scale of ~1 ns but exhibit substantial orientational order, particularly in the holo form. PMID- 26012956 TI - Pneumococcal lower respiratory tract infections in adults: an observational case control study in primary care in Belgium. AB - BACKGROUND: Serious lower respiratory tract infections (SLRTIs), especially Streptococcus pneumoniae (SP)-related pneumonia cause considerable morbidity and mortality. Chest imaging, sputum and blood culture are not routinely obtained by general practitioners (GPs). Antibiotic therapy is usually started empirically. The BinaxNOW(r) and Urine Antigen Detection (UAD) assays have been developed respectively to detect a common antigen from all pneumococcal strains and the 13 pneumococcal serotypes present in the vaccine Prevenar 13(r) (PCV13). METHODS: OPUS-B was a multicentre, prospective, case-control, observational study of patients with SLRTI in primary care in Belgium, conducted during two winter seasons (2011-2013). A urine sample was collected at baseline for the urine assays. GPs were blinded to the results. All patients with a positive BinaxNOW(r) test and twice as much randomly selected BinaxNOW(r) negative patients were followed up. Recorded data included: socio-demographics, medical history, vaccination history, clinical symptoms, CRB-65 score, treatments, hospitalization, blood cultures, healthcare use, EQ-5D score. The objectives were to evaluate the percentage of SP SLRTI within the total number of SLRTIs, to assess the percentage of SP serotypes and to compare the burden of disease between pneumococcal and non-pneumococcal SLRTIs. RESULTS: There were 26 patients with a BinaxNOW(r) positive test and 518 patients with a BinaxNOW(r) negative test. The proportion of pneumococcal SLRTI was 4.8 % (95 % CI: 3.1 %-7.2 %). Sixty-eight percent of positive cases showed serotypes represented in PCV13. In the BinaxNOW-positive patients, women were more numerous, there was less exposure to young children, seasonal influenza vaccination was less frequent, COPD was more frequent, the body temperature and the number of breaths per minute were higher, the systolic blood pressure was lower, the frequency of sputum, infiltrate, chest pain, muscle ache, confusion/disorientation, diarrhoea, pneumonia and exacerbations of COPD was more frequent, EQ-5D index and VAS scale were lower, the number of visits to the GP, of working days lost and of days patients needed assistance were higher. CONCLUSIONS: SP was responsible for approximately 5 % of SLRTIs observed in primary care in Belgium. Pneumococcal infection was associated with a significant increase in morbidity. Sixty-eight percent of serotypes causing SLRTI were potentially preventable by PCV13. PMID- 26012959 TI - Immunolocalization of G protein-coupled estrogen receptor in the rat epididymis. AB - BACKGROUND: Estrogen plays an important role in male reproduction, and males lacking estrogen signaling in the reproductive tissues are infertile. Estrogen signaling is mediated via two nuclear receptors, ERalpha and ERbeta, but it was recently found that a G protein-coupled estrogen receptor (GPER) is present in the testis. It is believed that GPER is a membrane form of the estrogen receptor and mediates non-classical estrogen signaling. However, the cellular localization of GPER in the epididymis is unknown. Therefore, the objective of this study was to determine the cellular and regional expression of GPER in the rat epididymis. FINDINGS: To localize expression, immunohistochemistry (IHC) was performed using fixed epididymal tissue. Three strains and ages of rats were used to identify whether GPER expression is strain or age specific. Our results are the first to demonstrate immunostaining of GPER in epididymal epithelial cells. Expression was highest near the apical membrane followed by the cytoplasm, consistent with a membrane bound receptor. The highest expression in adult rats was observed in corpus followed by cauda. Western blotting analysis of epididymal tissues from Sprague Dawley rats confirmed specificity of the antibody and regional expression. CONCLUSIONS: Expression of GPER in the corpus and cauda suggests a role for non-classical estrogen signaling in sperm maturation in the corpus, and sperm protection/storage in the cauda. GPER expression pre-pubertally suggests that estrogen may have a role in epithelial cell development in addition to regulation of adult function. PMID- 26012962 TI - [What is the origin of bright red blood in stool? Angiodysplasia]. PMID- 26012963 TI - ["The problem of over-extended fathers is still not well recognized"]. PMID- 26012958 TI - Pre-ischemic exercise reduces apoptosis in hippocampal CA3 cells after cerebral ischemia by modulation of the Bax/Bcl-2 proteins ratio and prevention of caspase 3 activation. AB - Ischemia induces physiological alterations in neurons that lead to cell death. This study investigated the effects of pre-ischemic exercise on CA3 neurons. Rats were divided into three groups. Animals in the exercise group were trained 5 days a week for 4 weeks. Ischemia was induced by occlusion of both common carotid arteries (CCAs) for 20 min. Apoptotic cell death was detected by TUNEL assay. Furthermore, expression of different proteins was determined by immunohistochemical staining. The number of TUNEL-positive cells was significantly increased in the ischemia group, but pre-ischemic exercise significantly reduced apoptotic cell death (P < 0.001). In addition, our results showed a significant increase in the Bax/Bcl-2 ratio in the ischemia group. Pre ischemic exercise attenuated this ratio (P < 0.05). Furthermore, the number of active caspase-3-positive neurons was significantly increased in the ischemia group, which was reduced markedly by exercise preconditioning (P < 0.05). This study showed that pre-ischemic exercise can exert neuroprotective effects against ischemia in CA3 neurons. PMID- 26012964 TI - [With a substantial breakfast to control hyperglycemia]. PMID- 26012965 TI - [Stress in adolescence paves the way for later coronary heart disease]. PMID- 26012966 TI - [Less anxiety and pain in surgery by simple distraction maneuvers]. PMID- 26012967 TI - [Charges for autopsy unnecessarily tricky]. PMID- 26012968 TI - [Ministry stops retroactive fee reconciliation: chaos in reimbursement of emergency service is complete]. PMID- 26012969 TI - [A real man, a jealous wife]. PMID- 26012970 TI - [Addiction is a matter of opinion]. PMID- 26012971 TI - [Infusions are generally not separately remunerated]. PMID- 26012972 TI - [IGeL should not be primarily a sales center for physician practices]. PMID- 26012973 TI - [Above all, the steam must be comfortable]. PMID- 26012974 TI - [What helps adolescent binge drinkers]. PMID- 26012975 TI - [How may a physician help the dying patient?]. PMID- 26012977 TI - [A novelty: patient centered guidelines]. PMID- 26012976 TI - [What is enough, what is too much?]. PMID- 26012978 TI - [Learning from shaman]. PMID- 26012979 TI - [Masked healers in the operating room]. PMID- 26012980 TI - [Discontinuing antirheumatic medication]. PMID- 26012981 TI - [Every second obese teenager at risk for coronary heart disease]. PMID- 26012982 TI - [Sleep apnea: RR lowering drugs need to be administered in the evening]. PMID- 26012983 TI - [Donor stool now available in capsules]. PMID- 26012984 TI - [Decreased sense of smell predicts imminent death]. PMID- 26012985 TI - [Dupilumab effective in atopic dermatitis]. PMID- 26012986 TI - [Penile ulcers are not always syphilis]. PMID- 26012987 TI - [Practice guidance for the rational use of diagnostic tests for borreliosis]. PMID- 26012988 TI - [Recommended adult immunization schedule]. PMID- 26012989 TI - [Rheumatoid arthritis - look at the patients fingers]. PMID- 26012990 TI - [Asthma, a contemporary review]. PMID- 26012991 TI - [Why does your patient look so pale? Efficient diagnostic work-up in anaemia]. PMID- 26012992 TI - [Modern management with oral antihyperglycemic agents in type 2 diabetes]. PMID- 26012993 TI - [Liver cirrhosis and the most common complications: diagnosis and treatment]. PMID- 26012994 TI - [Driving safety and pain therapy]. PMID- 26012995 TI - ["Entry inhibitors" prevent virus access to the cell]]. PMID- 26012996 TI - [Prerequisites for sound sleep]. PMID- 26012997 TI - [Injection time flexibility when needed]. PMID- 26012998 TI - [Awards for superior hemophilia projects]. PMID- 26012999 TI - [Two times daily to manage daily life]. PMID- 26013000 TI - [First biosimilar infliximab approved]. PMID- 26013001 TI - Mesenchymal Stem Cells Repress Osteoblast Differentiation Under Osteogenic Inducing Conditions. AB - This study was designed to investigate the influence of mesenchymal stem cells (MSCs) on osteoblast (OB) differentiation. Rat bone marrow MSCs were cultured either in growth medium that maintained a MSC phenotype or in osteogenic medium that induced differentiation into OBs. Then, cells were grown in two different culture conditions: indirect co-culture of MSCs and OBs and OBs cultured in MSC conditioned medium. As a control culture condition, OBs were grown in osteogenic medium without the influence of MSCs. We evaluated cell proliferation, the gene expression of key bone markers, alkaline phosphatase (ALP) activity, bone sialoprotein (BSP) expression, and extracellular matrix mineralization. The results showed that, regardless of whether OBs were indirectly co-cultured with MSCs or cultured in MSC-conditioned medium, MSCs repressed OB differentiation, as evidenced by the downregulation of all evaluated bone marker genes, decreased ALP activity, inhibition of BSP protein expression, and reduced extracellular matrix mineralization. Taken together, these results indicate that despite the key role of both MSCs and OBs in the osteogenic process, the repressive effect of MSCs on OB differentiation in an osteogenic environment may represent a barrier to the strategy of using them together in cell-based therapies to induce bone repair. PMID- 26013002 TI - Multifunctional Nano-Bioprobes Based on Rattle-Structured Upconverting Luminescent Nanoparticles. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) have shown great promise in versatile bioapplications. For the first time, organosilica-shelled beta NaLuF4:Gd/Yb/Er nanoprobes with a rattle structure have been designed for dual modal imaging and photodynamic therapy (PDT). Benefiting from the unique rattle structure and aromatic framework, these nanoprobes are endowed with a high loading capacity and the disaggregation effect of photosensitizers. After loading of beta-carboxyphthalocyanine zinc or rose Bengal into the nanoprobes, we achieved higher energy transfer efficiency from UCNPs to photosensitizers as compared to those with conventional core-shell structure or with pure-silica shell, which facilitates a large production of singlet oxygen and thus an enhanced PDT efficacy. We demonstrated the use of these nanoprobes in proof-of concept X-ray computed tomography (CT) and UC imaging, thus revealing the great potential of this multifunctional material as an excellent nanoplatform for cancer theranostics. PMID- 26013004 TI - Finding the positive feedback loops underlying multi-stationarity. AB - BACKGROUND: Bistability is ubiquitous in biological systems. For example, bistability is found in many reaction networks that involve the control and execution of important biological functions, such as signaling processes. Positive feedback loops, composed of species and reactions, are necessary for bistability, and generally for multi-stationarity, to occur. These loops are therefore often used to illustrate and pinpoint the parts of a multi-stationary network that are relevant ('responsible') for the observed multi-stationarity. However positive feedback loops are generally abundant in reaction networks but not all of them are important for understanding the network's dynamics. RESULTS: We present an automated procedure to determine the relevant positive feedback loops of a multi-stationary reaction network. The procedure only reports the loops that are relevant for multi-stationarity (that is, when broken multi stationarity disappears) and not all positive feedback loops of the network. We show that the relevant positive feedback loops must be understood in the context of the network (one loop might be relevant for one network, but cannot create multi-stationarity in another). Finally, we demonstrate the procedure by applying it to several examples of signaling processes, including a ubiquitination and an apoptosis network, and to models extracted from the Biomodels database. The procedure is implemented in Maple. CONCLUSIONS: We have developed and implemented an automated procedure to find relevant positive feedback loops in reaction networks. The results of the procedure are useful for interpretation and summary of the network's dynamics. PMID- 26013003 TI - Antimicrobial photodynamic therapy combined with periodontal treatment for metabolic control in patients with type 2 diabetes mellitus: study protocol for a randomized controlled trial. AB - BACKGROUND: The relationship between diabetes mellitus (DM) and periodontal disease is bidirectional. DM is a predisposing and modifying factor of periodontitis, which, in turn, worsens glycemic control and increases proteins found in the acute phase of inflammation, such as C-reactive protein. The gold standard for the treatment of periodontal disease is oral hygiene orientation, scaling and planing. Moreover, systemic antibiotic therapy may be employed in some cases. In an effort to minimize the prescription of antibiotics, photodynamic therapy (PDT) has been studied as an antimicrobial technique and has demonstrated promising results. The aim of the proposed study is to determine whether PDT as a complement to periodontal therapy (PT) is helpful in the metabolic control of individuals with type 2 diabetes and the reduction of acute phase inflammatory markers. METHODS/DESIGN: The patients will be randomized using a proper software program into two groups: 1) PT + placebo PDT or 2) PT + active PDT. All patients will first be examined by a specialist, followed by PT performed by two other healthcare professionals. At the end of each session, PDT (active or placebo) will be administered by a fourth healthcare professional. The following will be the PDT parameters: diode laser (660 nm); power output = 110 mW; exposure time = 90 s per point (9 J/point); and energy density = 22 J/cm(2). The photosensitizer will be methylene blue (50 MUg/mL). The patients will be re evaluated 15, 30, 90 and 180 days after treatment. Serological examinations with complete blood count, fasting glucose, glycated hemoglobin and salivary examinations to screen for tumor necrosis factor alpha, interleukin 1, interleukin 6, ostelocalcin, and osteoprotegerin/RANKL will be performed at each evaluation. The data will be statistically evaluated using the most appropriate tests. DISCUSSION: The results of this study will determine the efficacy of photodynamic therapy as an adjuvant to periodontal treatment in diabetic patients. TRIAL REGISTRATION: The protocol for this trial was registered with Clinical Trials registration number NCT01964833 on 14 October 2013. PMID- 26013005 TI - Supportive medical care for children with acute lymphoblastic leukemia in low- and middle-income countries. AB - In the last two decades, remarkable progress in the treatment of children with acute lymphoblastic leukemia has been achieved in many low- and middle-income countries (LMIC), but survival rates remain significantly lower than those in high-income countries. Inadequate supportive care and consequent excess mortality from toxicity are important causes of treatment failure for children with acute lymphoblastic leukemia in LMIC. This article summarizes practical supportive care recommendations for healthcare providers practicing in LMIC, starting with core approaches in oncology nursing care, management of tumor lysis syndrome and mediastinal masses, nutritional support, use of blood products for anemia and thrombocytopenia, and palliative care. Prevention and treatment of infectious diseases are described in a parallel paper. PMID- 26013008 TI - Inferring sex and caste seasonality patterns in three species of bumblebees from southern Brazil using biological collections. AB - Biological collections may often be an important source of information about natural history, behavioral habits, and ecology as they contain samples of organisms collected in different places and moments in times. In here, we used museum specimens to examine how populations of three species of Bombus-Bombus bellicosus Smith, Bombus morio (Swederus), and Bombus pauloensis Friese-vary over time with respect to abundance and biomass of each sex and caste. The study included all specimens of these three bumblebee species deposited in the insect collection of the Federal University of Parana that were collected in eastern Parana, in southern Brazil. Seasonality is most noticeable in the peak of queen activity (number of individuals in collections) in early spring, after dormancy during the winter. Queens then founded nests, and workers and males began to become more abundant during spring and summer. Worker abundance peaked at the end of summer and beginning of fall and may correspond to increasing activity for production of new males and gynes. Male abundance peaks are during the reproductive period. Thus, we show with these data and analyses that museum collections can be very useful tools to examine temporal and ecological processes. We recommend greater use of museum accessions to explore these kinds of patterns that may otherwise go unnoticed. PMID- 26013007 TI - Absence of Transovarial Transmission of 'Candidatus Phytoplasma ulmi' in the Vector Amplicephalus curtulus Linnavuori & DeLong (Hemiptera: Cicadellidae): Is It a Rule More Than an Exception? AB - 'Candidatus Phytoplasma ulmi' (Elm yellows, 16SrV-A), transmitted by Amplicephalus curtulus Linnavuori & DeLong (Hemiptera: Cicadellidae), has been found in native Chilean plants, and transovarial transmission has been considered as a possible form of transmission. An analysis to detect the presence of 'Ca. Phytoplasma ulmi' and other phytoplasmas in A. curtulus eggs, nymphs of the first and fifth instars were carried out in two experiments using nested PCR and DNA sequencing. The first experiment showed the natural acquisition of phytoplasma by adult females, and the second demonstrated the acquisition of phytoplasma in controlled conditions. Results showed that eggs and the first and fifth instars were not positive for phytoplasmas in nested PCR. 'Candidatus Phytoplasma ulmi' was detected and identified on average 10 and 47% of the adult females used in experiments 1 and 2, respectively. Other phytoplasma (X-disease group) was also found in adult females used in the experiment 1. We demonstrate that although gravid females contain phytoplasmas, they are not able to transmit them to their progeny, confirming that transovarial transmission of 'Ca. Phytoplasma ulmi' does not occur in A. curtulus. PMID- 26013006 TI - An IL-27/Lag3 axis enhances Foxp3+ regulatory T cell-suppressive function and therapeutic efficacy. AB - Foxp3-expressing regulatory T cells (Tregs) are central regulators of immune homeostasis and tolerance. As it has been suggested that proper Treg function is compromised under inflammatory conditions, seeking for a pathway that enhances or stabilizes Treg function is a subject of considerable interest. We report that interleukin (IL)-27, an IL-12 family cytokine known to have both pro- and anti inflammatory roles in T cells, plays a pivotal role in enhancing Treg function to control T cell-induced colitis, a model for inflammatory bowel disease (IBD) in humans. Unlike wild-type (WT) Tregs capable of inhibiting colitogenic T-cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T-cell responses. Tregs stimulated with IL-27 expressed substantially improved suppressive function in vitro and in vivo. IL-27 stimulation of Tregs induced expression of Lag3, a surface molecule implicated in negatively regulating immune responses. Lag3 expression in Tregs was critical to mediate Treg function in suppressing colitogenic responses. Human Tregs also displayed enhanced suppressive function and Lag3 expression following IL-27 stimulation. Collectively, these results highlight a novel function for the IL 27/Lag3 axis in modulating Treg regulation of inflammatory responses in the intestine. PMID- 26013009 TI - Pollinators of Richardia grandiflora (Rubiaceae): an Important Ruderal Species for Bees. AB - Ruderal species may provide pollen and nectar to maintain the pollinators of crops in periods of floral resource shortage. The knowledge about the floral biology of these plant species and their interaction with insects is important for management strategies of agricultural systems. The study was carried out at an experimental research station in two different periods (August 2010-April 2011 and August 2012-January 2013). Floral biology was studied, and the reproductive system and reproductive efficacy (RE) were analyzed using controlled pollination experiments. Furthermore, floral visitors and pollination were identified and quantified. Reproductive success obtained in the open pollination and cross pollination experiments was higher than those obtained in spontaneous self, hand self, and wind pollination. Richardia grandiflora bloomed throughout the experimental period, and flowers were visited by Coleoptera, Diptera, Hymenoptera, and Lepidoptera, which were observed foraging for pollen and/or nectar. Among the floral visitors, bees were the richest and most frequent group and often contacted anthers and stigmas during visits. Africanized honeybees touched the floral reproductive structures in all visits, and their frequency may be related to changes in the reproductive efficacy between the study periods. Pollinator species of crops cultivated at the experimental research station were frequent bee visitors of R. grandiflora. We demonstrated that R. grandiflora requires cross-pollination and biotic pollen vectors. Among floral visitors, bees are the main pollinators, especially the Africanized honeybees. R. grandiflora can be considered an important ruderal species for maintaining bee pollinator populations at the study site, providing resources during the period that crops are not blooming. PMID- 26013010 TI - Spatial and temporal variation of dung beetle assemblages in a fragmented landscape at eastern humid Chaco. AB - The aims of this study were to characterize the fauna of dung beetles and analyze their spatial and temporal diversity in a cattle ranch in the province of Chaco. Seven surveys were conducted in three environmental units: a forest fragment, a cattle pasture, and an open grassland. The efficiency of the sampling was assessed with non-parametric richness estimators, and attributes of the assemblage were evaluated. The species composition and the abundance distribution in each of the environmental units studied were compared using rank-abundance curves. The indicator value of each species was measured with the IndVal method. The relationship between richness, abundance, and environmental variables (temperature, precipitation, and relative humidity) was calculated by multivariate multiple regression analysis. A total of 3,356 adult individuals belonging to 29 species of the subfamily Scarabaeinae and to five species of Aphodiinae were captured. Dichotomius nisus (Olivier), Trichillum externepunctatum (Preudhomme), Canthon podagricus (Harold), Onthophagus hirculus (Mannerheim), Pseudocanthon aff. perplexus, Ontherus sulcator (Fabricius), and Ataenius platensis (Blanchard) were the most abundant. Diversity, species richness, and abundance were highest in the forest fragment and in spring and summer captures. Between 94% and 97% of the species present in the entire landscape were recorded. According to the analysis of similarity, the composition of the assemblage was different among habitats. Eurysternus caribaeus (Herbst), Eurysternus aeneus (Genier), and O. sulcator were indicators of the forest. In the three units, the coprophagous species represented more than 60% of the total species number. The rainfall regime, the temperature, and the heterogeneous use of the environmental units influenced the structure of dung beetle assemblages. PMID- 26013011 TI - Structure of dung beetle communities in an altitudinal gradient of neotropical dry forest. AB - To understand the effects of global warming in tropical insect communities, it is necessary to comprehend how such communities respond to different abiotic factors that covariate with altitude. In this study, we partially answer this question applied to dung beetle communities distributed along an altitudinal gradient. The sampling was conducted in seven stations 100 m apart each in altitude in a dry mountain scrub in southern Ecuador. A total of 7422 individuals belonging to six species were captured. Canthon balteatus Boheman was the most abundant with 6502 individuals, and Onoreidium ohausi (Arrow) was the least abundant with 20 individuals. We found significant changes in the structure of the dung beetle communities with altitude. Two abiotic factors showed a relationship with the abundance pattern for all species (altitude, Z = 0.011, p < 0.01, and temperature, Z = 0.859, p < 0.01). Canthon balteatus Boheman showed a positive relationship with altitude (Z = 1.422, p < 0.001) and temperature (Z = 1.121, p < 0.001), Dichotomius problematicus (Luederwaldt) a positive relationship with precipitation (Z = 0.113, p < 0.001), and Malagoniella cupreicollis (Waterhouse) a positive relationship with temperature (Z = 0.668, p < 0.001) and negative with precipitation (Z = -0.189, p < 0.001). Phanaeus achilles Boheman, Onthophagus sp., and O. ohausi (Arrow) did not show any relationship with the studied variables, nor was the richness correlated with the studied variables. These results suggest that the effects of global warming over dung beetle communities will be difficult to predict because of species-specific responses to global warming. PMID- 26013012 TI - Review of the longipalpus-Group of Chrysotus Meigen (Diptera: Dolichopodidae), with Description of Four New Species. AB - The longipalpus-group of Chrysotus Meigen is reviewed and comprises eight species: Chrysotus coquitos n. sp. (Mexico), Chrysotus crosbyi Van Duzee (Eastern US, Bermuda, Cuba, Puerto Rico and Brazil; introduced in Australasian Region), Chrysotus longipalpus Aldrich (=Chrysotus sagittarius Van Duzee, n. syn.; Eastern US, Saint Vincent, Grenadas and Brazil; introduced in the Afrotropical, Australasian, Oriental and Palaearctic regions), Chrysotus miripalpus Parent (Costa Rica and Brazil), Chrysotus neopedionomus n. sp. (Brazil), Chrysotus pachystoma n. sp. (Belize), Chrysotus xiphostoma Robinson (Dominica and Saint Lucia), and Chrysotus zumbadoi n. sp. (Costa Rica). Lectotype and paralectotypes are designated for Chrysotus pallidipalpus Van Duzee, and a neotype for C. miripalpus. Illustrations of the hypopygium and ovipositor, photos of the male palpus and a key to species of the group are provided. PMID- 26013013 TI - First record of mites of the genus Anoplocheylus (Acari: Pseudocheylidae) in South America with description of a new species from Brazil. AB - The genus Anoplocheylus Berlese is recorded for the first time in South America. A new species, Anoplocheylus brasiliensis n. sp., is described based on material from Rio de Janeiro, Brazil. A key to the world species of the genus Anoplocheylus is provided. PMID- 26013014 TI - Sensilla on the Antennae and Ovipositor of the Sea Buckthorn Carpenter Moth, Holcocerus hippophaecolus Hua et al (Lepidoptera: Cossidae). AB - Holcocerus hippophaecolus Hua et al (Lepidoptera: Cossidae) is an important boring pest that damages the sea buckthorn Hippophae rhamnoides. Larvae of H. hippophaecolus cause major losses of this shrub in Northern China, with severe economic and ecological consequences. In this study, we used scanning electron microscopy to investigate the typology, morphology, and distribution of sensilla on the antennae and ovipositor of H. hippophaecolus. In total, seven subtypes of sensilla were found on the antennae, i.e., chaetica, trichodea (two subtypes), basiconica (two subtypes), coeloconica, and Bohm bristles. In addition, three types of sensilla were detected on the ovipositor, i.e., chaetica, trichodea, and basiconica. The identification of these sensilla types could provide morphological evidence to facilitate a better understanding of the host location, mate finding, and oviposition processes of this important species. PMID- 26013015 TI - The Effect of Protease Inhibitors on Digestive Proteolytic Activity in the Raspberry Weevil, Aegorhinus superciliosus (Guerin) (Coleoptera: Curculionidae). AB - The raspberry weevil, Aegorhinus superciliosus (Guerin) (Coleoptera: Curculionidae), is an economically important pest of blueberry in southern Chile. The digestive protease activity of adult insects was investigated using general and specific substrates and inhibitors. Enzymatic assays demonstrated the presence of trypsin- and chymotrypsin-like serine proteinases. Furthermore, in vitro assays using phenylmethylsulfonyl fluoride (PMSF) and soybean trypsin inhibitor (SBTI) at 0.01 and 0.1 mM showed percentages of enzymatic inhibition between 0 and 16% for PMSF and 67 to 76% for SBTI, whereas in vivo assays indicated that SBTI caused between 50 and 90% mortality in males and between 80 and 100% in females. Our data indicate the presence of serine proteases and suggest that digestive proteases could be a target for the design and development of strategies to control the raspberry weevil. PMID- 26013016 TI - Toxic Effects of Couroupita guianensis Against Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae). AB - Laboratory experiments were conducted to find out the efficacy of different crude extracts and fractions of Couroupita guianensis (Lecythidaceae) against Spodoptera litura (Fabricius). Results revealed that hexane, chloroform and ethyl acetate extracts of C. guianensis showed larvicidal and pupicidal activities against S. litura. Maximum larvicidal activity (68.66%) was observed in hexane extract at 5.0% concentration followed by chloroform and ethyl acetate extracts, and least LC50 value of 2.64% was observed in hexane extract. A 100% pupicidal activity was observed in hexane extract. Based on the efficacy of crude extracts, the effective crude extract (hexane extract) was further fractionated and subjected to screening for biological activities against S. litura. Among the eight fractions isolated from the hexane extract, fraction 8 showed maximum antifeedant activity (81. 8%) and larvicidal activity (76.9%) at 1000-ppm concentration; this fraction showed least LC50 value of 375.92 ppm for larvicidal activity. Cent per cent pupicidal activity was recorded. Reduced midgut and hemolymph protein contents were observed at 1000 ppm of fraction 8. Histopathological studies revealed that fraction 8 severely damaged the midgut cells of S. litura. This fraction could be used to develop botanical formulation to control agricultural pests. PMID- 26013018 TI - Hylax bahiensis Bechyne (Chrysomelidae: Eumolpinae): a New Potential Pest of Eucalyptus and Species Used for Atlantic Rainforest Restoration. AB - Hylax bahiensis Bechyne (Coleoptera: Chrysomelidae), a new pest of forest species, including eucalyptus (hybrid Eucalyptus urophylla x Eucalyptus grandis), Joannesia princeps, Mimosa artemisiana, Croton urucurana, Croton floribundus, and Senna multijuga is recorded. The insect attack in clonal eucalyptus plantations and in forest restoration areas between 2010 and 2013 in the states of Espirito Santo, Bahia and Minas Gerais, Brasil, was observed for the first time. The outbreaks generally occurred from September to March. This new potential pest can affect the growth, productivity, and quality of the trees. We recommended monitoring this leaf-eating beetle especially during the critical period of its occurrence. PMID- 26013017 TI - The relationship between ovarioles number and female size in blackflies of the high Andes of Colombia. AB - Fitness of a single species is often measured in terms of the number of viable offspring produced. We explore the relationship between the number of ovarioles and the size of females in five species of Simuliidae in two paramo regions of Colombia. Individuals of seven species of female blackflies that landed on animals were collected from mules in the Ucumari Regional Park (RPNU) and from cattle in the Chingaza Natural National Park (ChNNP). The ovarioles of the five most abundant species were dissected out and counted, and a one-factor ANOVA was performed to explore differences in the mean number of ovarioles produced by different female size categories. Simulium ignescens Roubaud and S. ignescens like species were collected in RPNU and S. ignescens, Simulium muiscorum Bueno et al, Simulium cormonsi Wygodzinsky and Simulium pautense Coscaron & Takaoka, in ChNNP. In addition, we also analyzed the Pearson product-moment correlation between the mean number of ovarioles per blackfly and female size within species using those which more than 20 individuals were collected. Ovarioles were meroistic-polytrophic type. A multiple range test (least significant difference) indicated that the largest size group had the largest mean number of ovarioles per female. In the other size groups, there were approximately equal numbers of ovarioles per female. Pearson's correlation coefficient was separately measured and indicated a 50% correlation between female size and ovariole number in S. ignescens. Although ovariole number is probably a genetically driven feature, other environmental and physiological conditions, including infections, can influence the number of eggs. PMID- 26013019 TI - Epidermal consumption in benign and malignant melanocytic neoplasms. AB - Consumption of the epidermis associated with effacement of the rete ridge pattern has been cited as a useful criterion in the diagnosis of melanoma, but the significance of consumption in the absence of rete ridge effacement is unknown. We evaluated 701 melanocytic neoplasms for presence and 'grade' of consumption by melanocytic nests relative to diagnosis, body location, gender and age. We defined 1+ consumption as collections of melanocytes occupying greater than two thirds of the viable epidermis, with or without loss of the rete ridge pattern. Nests extending to the bottom of, within, and through the granular layer were graded 2+, 3+ and 4+, respectively. Consumption was more frequent and higher grades were found in melanomas followed by Spitz nevi compared with conventional melanocytic nevi (p < 0.001). Melanomas with higher Breslow thickness showed higher grades (p < 0.05). In conventional nevi, consumption occurred most frequently in back (13.7%), acral (11.9%) and scalp (9.8%) locations. Consumption without the requirement for rete ridge effacement occurs more frequently and at higher grades in melanoma. Higher grades correlate with higher Breslow thickness. Consumption is also common in Spitz nevi and occurs at lower grades in conventional (non-Spitz) nevi, especially on the back, the scalp and at acral sites. PMID- 26013020 TI - [Ultrasound-guided intermediate cervical plexus block. Anatomical study]. AB - BACKGROUND AND OBJECTIVES: The innervation of the human cervical region is complex and subject to relevant anatomical variability involving sections of the cervical plexus, brachial plexus and cranial nerves. AIM: The objective was to demonstrate the dissemination of injected dye solution by anatomical preparation and to define a suitable target compartment for an ultrasound-guided block technique. MATERIAL AND METHODS: Own anatomical preparations are compared to recent review articles on the subject. The focus is on clinically relevant conclusions for performing cervical plexus blocks. In three non-embalmed cadavers six intermediate ultrasound-guided blocks of the cervical plexus were carried out, each with 20 ml methylene blue. Following preparation of the cervical plexus photographic documentation of the spread of the injected marker was performed. RESULTS: In five cases the target compartment was correctly identified. In these cases, a cranio-caudal spread of the injectate within the double layer of the cervical fascia was observed. In addition, the superficial layer was permeable to the injected methylene blue. The injection solution disseminated with the sensitive terminal branches of the cervical plexus below the platysma. In all cases an anastomosis (superficial cervical ansa) between the facial nerve (ramus colli) and the cervical plexus (transverse cervical nerve) could be demonstrated. The prevertebral lamina proved to be impermeable to injected methylene blue and no evidence of a porous structure of the prevertebral lamina was found. CONCLUSION: The compartment between the superficial and the prevertebral layer of the cervical fascia is a suitable target for cervical plexus blocks. This injection site describes an intermediate cervical plexus block. As the compartment contains the sensory terminal branches of the spinal nerves C2-4, it may be referred to as C2-C4 compartment. The cranio-caudal spread of the injectate allows lateromedial needle guidance in the horizontal plane. As the superficial lamina is not a barrier to the injectate an additional subcutaneous infiltration of the nerve area appears dispensable. The prevertebral lamina proved to be impermeable to injected methylene blue. Whether phrenic nerve blocks are preventable with more distal intermediate cervical plexus blocks (selective block of the supraclavicular nerves, e.g. for surgery of the clavicle) must be investigated in clinical trials. The permanent anastomosis (superficial cervical ansa) between the cervical plexus and the ramus colli of the facial nerve provides an anatomically reasonable explanation for inadequate cervical plexus blocks. PMID- 26013022 TI - Ferumoxytol as an intraprostatic MR contrast agent for lymph node mapping of the prostate: a feasibility study in non-human primates. AB - Background A variety of magnetic resonance (MR) lymphographic agents have been proposed for mapping the lymph nodes draining the prostate. Purpose To investigate the feasibility of using ferumoxytol (an FDA-approved iron oxide agent) for lymph node mapping of the prostate on imaging (MRI) in a non-human primate (NHP) Macaque model. Material and Methods Four NHPs weighing 5-13 kg underwent injection of ferumoxytol after a needle was introduced transrectally under MRI guidance into the prostate using a commercially available intrarectal MRI biopsy guide. Ferumoxytol was administered at dosage in the range of 0.15 0.75 mg Fe/kg in a fixed injection volume of 0.2 mL. T1-weighted MRI was performed at 3 T starting immediately and extending at least 45 min post injection. Two readers evaluated the images in consensus. The NHPs tolerated the ferumoxytol injections at all doses with no evident side effects. Results It was determined that the lowest dose of 0.15 mg Fe/kg produced the best outcome in terms of lymph node visualization and draining nodes were reliably visualized at this dose and volume. Conclusion Thus, MRI with intraprostatic injection of ferumoxytol may be considered an effective T1 contrast agent for prospective mapping of lymph nodes draining the prostate and, thus, for attempted sentinel lymph node identification in prostate cancer. Large clinical trials to determine safety and efficacy are needed. PMID- 26013021 TI - [Anesthesia in children and adolescents with congenital heart defects]. AB - The incidence of congenital heart defects (CHD) has remained constant over many years; however, due to improved therapeutic options an increasing number of children and adolescents even with complex heart defects now reach adulthood. The increasing prevalence of adults with persisting or surgically corrected CHD as well as age-dependent non-cardiac comorbidities will increase the need for medical and non-cardiac surgical treatment in this population. Although elective medical care for these patients should be reserved for highly specialized centers, emergency treatment might become necessary in a non-specialized hospital setting as well. Due to the variety and complexity of CHD it is difficult to provide standardized guidelines for the anesthetic management. The treatment of patients with complex CHD requires a profound understanding of the underlying CHD and the current state of the hemodynamics by the anesthesiologist. Furthermore, typical comorbidities, such as chronic heart failure, altered coagulation and arrhythmia also have to be taken into account to ensure successful perioperative treatment. Especially in patients with shunt lesions or passive pulmonary blood flow the anesthetic management often substantially affects the hemodynamics and may be the starting point of severe decompensation. Awareness of anesthesia induced changes of pulmonary and/or systemic vascular resistance as well as of preload alterations are the basis for successful anesthetic management. Finally, a multidisciplinary approach including cardiologists and radiologists in the planning is absolutely essential to achieve an optimal postoperative result for the patient. PMID- 26013023 TI - The inability of an early post-transplantation intrarenal resistive index to predict renal allograft function at 12 weeks after engraftment in young adults. AB - Background The intrarenal resistive index (RI) is a promising tool for predicting renal graft outcomes. Due to the complexity of graft function and the presence of diverse contributing factors, however, the available data are inconclusive. Purpose To examine the performance of the RI 1 week after transplant in predicting allograft function at week 12, with an emphasis on the type of intrarenal artery used in the examination. Material and Methods A total of 58 first-time living-donor kidney-allograft-transplantation patients aged less than 50 years underwent Doppler ultrasonography (US) of the intrarenal arteries 1 week after engraftment. The RI was calculated for both the segmental (RI-C) and interlobar-arcuate (RI-P) arteries. Serum creatinine level and the creatinine reduction ratio (CRR) were determined at weeks 1 and 12 post transplantation. Results While the RI did not correlate with serum creatinine level and CRR at week 1, significant correlations were present between the RI and serum creatinine level (r = 0.28, P = 0.03 for both RI-C and RI-P) and CRR (r = -0.25, P = 0.05 for both RI-C and RI-P) at week 12. The sensitivity, specificity, positive predictive value, and negative predictive value of using RI-C in predicting abnormal 12-week serum creatinine level were 51.2%, 52.9%, 72.4%, and 31.3%, respectively; and 53.7%, 47.1%, 70.9%, and 29.6% for RI-P, respectively ( P > 0.99 for all comparisons). Conclusion Early post-transplantation RI correlates significantly with both serum creatinine level and creatinine reduction ratio 12 weeks after engraftment with intermediate predictive accuracy. PMID- 26013024 TI - Squamous cell carcinoma of the oral cavity and oropharynx: what does the apparent diffusion coefficient tell us about its histology? AB - Background Diffusion-weighted imaging obtained with magnetic resonance (DW-MRI) is a non-invasive imaging tool potentially able to provide information about microstructural tumor characteristics. Purpose To prospectively analyze the correlation between the apparent diffusion coefficient (ADC) and clinical histologic characteristics of squamous cell carcinoma (SCCA) of the oral cavity and oropharynx. Material and Methods Sixty-seven patients with untreated, histologically proven SCCA of the oral cavity and oropharynx underwent conventional and diffusion-weighted (b-values 0, 50, 250, 500, and 900 s/mm2) MRI. Tumor ADC was calculated from regions of interest drawn manually on the highest b-value images using ImageJ (ImageJ, NIH) and fsl (fsl 4, University of Oxford) image processing packages. ADC was calculated in two ways: standard ADC using all b-values; and ADCHigh using only b-values >= 250 s/mm2. We assessed the correlations between both ADC and ADCHigh and the clinical-histological characteristics of SCCA. Results Fifty-two patients (36 men, 16 women; mean age, 55 +/- 13 years) were suitable for ADC calculation. Mean ADC was 1136.0 +/- 108.5 * 10-6 mm2/s. Mean tumor ADCHigh was 991.2 +/- 152.1 * 10-6 mm2/s. Mean tumor size was 32.3 +/- 13.4 mm (range, 14.0-69.0 mm). We observed no correlation of either ADC or ADCHigh values with any of the clinical-histological tumor characteristics. Undifferentiated tumors (G3) showed lower apparent diffusion coefficient values compared to differentiated ones (G1-G2), without reaching statistical significance. Conclusion We did not observe any statistically significant correlation between ADC values and clinical-histological characteristics of SCCA of the oral cavity and oropharynx. PMID- 26013025 TI - Is there an additive value of 18 F-FDG PET-CT to CT/MRI for detecting nodal metastasis in oropharyngeal squamous cell carcinoma patients with palpably negative neck? AB - Background Cervical node metastasis is one of the most significant prognostic factors in patients with oropharyngeal squamous cell carcinoma (SCC). There is little information regarding the comparison of histopathologic analysis following neck dissection with imaging results in oropharyngeal SCC. Purpose To investigate the clinical utility of PET-CT compared with computed tomography (CT) or magnetic resonance imaging (MRI) for detecting nodal metastasis in oropharyngeal SCC patients with palpably negative neck and to investigate whether pretreatment imaging modalities support the rationale for elective neck treatment. Material and Methods A total of 49 oropharyngeal SCC patients with palpably negative neck (42 men, 7 women; average age, 59.1 years) underwent primary tumor resection and neck dissection as a primary treatment. All patients were preoperatively evaluated with PET-CT and CT/MRI, and the diagnostic accuracy of each imaging modality was assessed by comparison with histopathologic results of the surgical specimen. Results Twenty-five (51.0%) of our 49 patients had neck metastases. On a level-by-level analysis, the sensitivity of PET-CT, CT/MRI, and a combination of PET-CT and CT/MRI was 54.6%, 54.6%, and 60.6%, respectively, at all neck levels. The area under the ROC showed that the diagnostic performance of the combined interpretation was not significantly different from that of CT/MRI alone (0.780 vs. 0.750, respectively; P = 0.158) and PET-CT alone (0.780 vs. 0.765, respectively; P = 0.501). Conclusion Addition of PET-CT to CT/MRI did not provide better diagnostic accuracy for detecting nodal metastasis in preoperative evaluation of oropharyngeal SCC patients with palpably negative neck, suggesting that current imaging studies might not replace elective neck dissection. PMID- 26013026 TI - MDCT of complications and common postoperative findings following penetrating torso trauma. AB - Victims of penetrating torso trauma often present with findings that necessitate emergent exploratory laparotomy, precluding scanning with multidetector computed tomography (MDCT) until the postoperative period. This article reviews the wide range of complications as well as expected findings that may be encountered at MDCT performed postoperatively. Little has been written to guide the radiologist in interpreting these often complex and potentially confusing studies. PMID- 26013027 TI - Value of the CT "capsular sign" as a potential indicator of acute adrenal ischemia. AB - Acute adrenal ischemia represents a rare cause of adrenal insufficiency which should be promptly diagnosed in order to preserve adrenal vitality and function. Our study aims to retrospectively evaluate the diagnostic accuracy of the CT capsular sign as an indicator of adrenal ischemia and its association with vascular involvement. Between January 2013 and January 2014, 69 consecutive patients (47 men, 22 women; mean age 46; range 22-67) with suspected adrenal insufficiency based on clinical and biochemical data underwent 320-row CT examination in our Emergency Department. Written informed consent was obtained for the CT examinations, and the institutional review board approval was obtained for our retrospective study. CT multi-planar images were retrospectively and independently analyzed by two radiologists searching for the patency of adrenal vessels, enlarged adrenals, the presence of the "capsular sign" represented by a peripheral subtle hyperdense line around a hypodense enlarged adrenal, and the presence of any periadrenal inflammatory changes. All CT findings were then compared with the surgical findings (n = 5), follow-up examinations (n = 20), or autopsy (n = 4). Sensitivity, specificity, diagnostic accuracy (DA), positive predictive value (PPV), and negative predictive value (NPV) were calculated for the "capsular sign" and were further evaluated by ROC analysis. Acute adrenal ischemia occurred in 29/69 patients (42 %), unilateral in 20, and bilateral in 9. Forty of sixty-nine patients (58 %) had no evidence of adrenal disease on CT. Thrombosis of the main adrenal vein was found in 20/29 (69 %) and non-venous ischemia in 9/29 (31 %). The capsular sign was found in 24/29 patients (83 %). Sensitivity, specificity, DA, PPV, and NPV values of 83, 100, 93, 100, and 89 %, respectively, were obtained. The capsular sign represents a CT indicator of acute adrenal ischemia, with a specificity of 100 % and leading to a prompt diagnosis in the early phase of the disease. PMID- 26013028 TI - Treating Burkitt Lymphoma in Adults. AB - Burkitt lymphoma is an uncommon form of aggressive lymphoma affecting approximately 1200 patients per year in the USA. It is characterized by a translocation involving the MYC oncogene. Three subtypes of Burkitt lymphoma are recognized: the endemic form, occurring primarily in Africa and associated with the Epstein-Barr virus (EBV); the sporadic form, representing less than 3 % of all non-Hodgkin lymphomas (NHL); and the immunodeficiency-associated form, occurring primarily in HIV-infected patients. Burkitt lymphoma appears histologically with a diffuse pattern of intermediate-sized monomorphic B cells, multiple nucleoli, a very high proliferative rate, and frequent mitotic figures. Recent advances in transcriptional profiling have improved the current molecular understanding of Burkitt lymphoma and have better characterized its mutational landscape. Most Burkitt lymphoma patients are cured with intensive treatment; however, prognosis is poor in elderly patients and those with relapsed disease. PMID- 26013029 TI - Enthalpy-entropy compensation at play in human copper ion transfer. AB - Copper (Cu) is an essential trace element but toxic in free form. After cell uptake, Cu is transferred, via direct protein-protein interactions, from the chaperone Atox1 to the Wilson disease protein (WD) for incorporation into Cu dependent enzymes. Cu binds to a conserved C(1)XXC(2) motif in the chaperone as well as in each of the cytoplasmic metal-binding domains of WD. Here, we dissect mechanism and thermodynamics of Cu transfer from Atox1 to the fourth metal binding domain of WD. Using chromatography and calorimetry together with single Cys-to-Ala variants, we demonstrate that Cu-dependent protein heterocomplexes require the presence of C(1) but not C(2). Comparison of thermodynamic parameters for mutant versus wild type reactions reveals that the wild type reaction involves strong entropy-enthalpy compensation. This property is explained by a dynamic inter-conversion of Cu-Cys coordinations in the wild type ensemble and may provide functional advantage by protecting against Cu mis-ligation and bypassing enthalpic traps. PMID- 26013030 TI - Rapid quick, easy, cheap, effective, rugged, and safe extraction with novel phospholipid cleanup: A streamlined ultra high performance liquid chromatography with ultraviolet detection approach for screening polycyclic aromatic hydrocarbons in avian blood cells and plasma. AB - A streamlined method has been developed for the isolation and analysis of polycyclic aromatic hydrocarbons in avian blood cells and plasma utilizing quick, easy, cheap, effective, rugged, and safe extraction in combination with novel phospholipid cleanup technology. A variety of traditional extraction and cleanup techniques have been employed in the preparation and analysis of polycyclic aromatic hydrocarbonsin a variety of matrices; liquid-liquid partitioning, solid phase extractions, gel permeation chromatography, and column chromatography are all effective techniques, however they are laborious and time consuming processes that require large amounts of solvent. Using quick, easy, cheap, effective, rugged, and safe extraction coupled with phospholipid cleanup, samples can be quickly screened while maintaining high throughput and sensitivity. With a liquid chromatography approach, analysis times may be kept short at 16 min while maintaining high analyte recovery. Recoveries in quality control samples ranged from 70 to 109%, with average surrogate recoveries of 80.6 +/- 1.10%. The result of using a quick, easy, cheap, effective, rugged, and safe extraction approach in conjunction with phospholipid cleanup is a methodology that significantly reduces sample preparation time and solvent use while maintaining high sensitivity and reproducibility. PMID- 26013031 TI - Centromeric Alpha-Satellite DNA Adopts Dimeric i-Motif Structures Capped by AT Hoogsteen Base Pairs. AB - Human centromeric alpha-satellite DNA is composed of tandem arrays of two types of 171 bp monomers; type A and type B. The differences between these types are concentrated in a 17 bp region of the monomer called the A/B box. Here, we have determined the solution structure of the C-rich strand of the two main variants of the human alpha-satellite A box. We show that, under acidic conditions, the C rich strands of two A boxes self-recognize and form a head-to-tail dimeric i motif stabilized by four intercalated hemi-protonated C:C(+) base pairs. Interestingly, the stack of C:C(+) base pairs is capped by T:T and Hoogsteen A:T base pairs. The two main variants of the A box adopt a similar three-dimensional structure, although the residues involved in the formation of the i-motif core are different in each case. Together with previous studies showing that the B box (known as the CENP-B box) also forms dimeric i-motif structures, our finding of this non-canonical structure in the A box shows that centromeric alpha satellites in all human chromosomes are able to form i-motifs, which consequently raises the possibility that these structures may play a role in the structural organization of the centromere. PMID- 26013032 TI - Could brown fat be good for the heart? PMID- 26013033 TI - A base-independent repair mechanism for DNA glycosylase--no discrimination within the active site. AB - The ubiquitous occurrence of DNA damages renders its repair machinery a crucial requirement for the genomic stability and the survival of living organisms. Deficiencies in DNA repair can lead to carcinogenesis, Alzheimer, or Diabetes II, where increased amounts of oxidized DNA bases have been found in patients. Despite the highest mutation frequency among oxidized DNA bases, the base excision repair process of oxidized and ring-opened guanine, FapydG (2,6-diamino 4-hydroxy-5-formamidopyrimidine), remained unclear since it is difficult to study experimentally. We use newly-developed linear-scaling quantum-chemical methods (QM) allowing us to include up to 700 QM-atoms and achieving size convergence. Instead of the widely assumed base-protonated pathway we find a ribose-protonated repair mechanism which explains experimental observations and shows strong evidence for a base-independent repair process. Our results also imply that discrimination must occur during recognition, prior to the binding within the active site. PMID- 26013034 TI - Muscle Satellite Cell Protein Teneurin-4 Regulates Differentiation During Muscle Regeneration. AB - Satellite cells are maintained in an undifferentiated quiescent state, but during muscle regeneration they acquire an activated stage, and initiate to proliferate and differentiate as myoblasts. The transmembrane protein teneurin-4 (Ten-4) is specifically expressed in the quiescent satellite cells; however, its cellular and molecular functions remain unknown. We therefore aimed to elucidate the function of Ten-4 in muscle satellite cells. In the tibialis anterior (TA) muscle of Ten-4-deficient mice, the number and the size of myofibers, as well as the population of satellite cells, were reduced with/without induction of muscle regeneration. Furthermore, we found an accelerated activation of satellite cells in the regenerated Ten-4-deficient TA muscle. The cell culture analysis using primary satellite cells showed that Ten-4 suppressed the progression of myogenic differentiation. Together, our findings revealed that Ten-4 functions as a crucial player in maintaining the quiescence of muscle satellite cells. PMID- 26013036 TI - Copper-Catalyzed gamma-Selective and Stereospecific Allylic Cross-Coupling with Secondary Alkylboranes. AB - The scope of the copper-catalyzed coupling reactions between organoboron compounds and allylic phosphates is expanded significantly by employing triphenylphosphine as a ligand for copper, allowing the use of secondary alkylboron compounds. The reaction proceeds with complete gamma-E-selectivity and preferential 1,3-syn stereoselectivity. The reaction of gamma-silicon-substituted allylic phosphates affords enantioenriched alpha-stereogenic allylsilanes. PMID- 26013035 TI - HDAC8: a multifaceted target for therapeutic interventions. AB - Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions. PMID- 26013037 TI - Antivitamins for Medicinal Applications. AB - Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin-based drugs are still nowadays limited to antagonists of vitamins B9 and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin-based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B9 and B12 . PMID- 26013038 TI - Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH responsive polymeric micelles. AB - Cyclic RGDyK (cRGDyK)-conjugated pH-sensitive polymeric micelles were fabricated for targeted delivery of paclitaxel to prostate cancer cells based on pH sensitive copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and cRGDyK-PEOz-PLA to enhance antitumor efficacy. The prepared micelles with an average diameter of about 28nm exhibited rapid release behavior at endo/lysosome pH, effectively enhanced the cytotoxicity of paclitaxel to PC-3 cells by increasing the cellular uptake, which was correlated with integrin alphavbeta3 expression in tumor cells. The active targeting activity of the micelles was further confirmed by in vivo real time near-infrared fluorescence imaging in PC-3 tumor-bearing nude mice. Moreover, the active targeting and pH-sensitivity endowed cRGDyK-conjugated micelles with a higher antitumor effect in PC-3 xenograft-bearing nude mice compared with unmodified micelles and Taxol with negligible systemic toxicity. Therefore, these results suggested that cRGDyK conjugated pH-sensitive polymeric micelles may be a promising delivery system for efficient delivery of anticancer drugs to treat integrin alphavbeta3-rich prostate cancers. PMID- 26013039 TI - Spatial distribution and antitumor activities after intratumoral injection of fragmented fibers with loaded hydroxycamptothecin. AB - There was only a small percentage of drug delivered to tumors after systemic administration, and solid tumors also have many barriers to prevent drug penetration within tumors. In the current study, intratumoral injection of drug loaded fiber fragments was proposed to overcome these barriers, allowing drug accumulation at the target site to realize the therapeutic efficacy. Fragmented fibers with hydroxycamptothecin (HCPT) loaded were constructed by cryocutting of aligned electrospun fibers, and the fiber lengths of 5 (FF-5), 20 (FF-20), and 50MUm (FF-50) could be easily controlled by adjusting the slice thickness. Fragmented fibers were homogeneously dispersed into 2% sodium alginate solution, and could be smoothly injected through 26G1/2 syringe needles. FF-5, FF-20 and FF 50 fiber fragments indicated similar release profiles except a lower burst release from FF-50. In vitro viability tests showed that FF-5 and FF-20 fiber fragments caused higher cytotoxicity and apoptosis rates than FF-50. After intratumoral injection into murine H22 subcutaneous tumors, fragmented fibers with longer lengths indicated a higher accumulation into tumors and a better retention at the injection site, but showed less apparent diffusion within tumor tissues. In addition to the elimination of invasive surgery, HCPT-loaded fiber fragments showed superior in vivo antitumor activities and fewer side effects than intratumoral implantation of drug-loaded fiber mats. Compared with FF-5 and FF-50, FF-20 fiber fragments indicated optimal spatial distribution of HCPT within tumors and achieved the most significant effects on the animal survival, tumor growth inhibition and tumor cell apoptosis induction. It is suggested that the intratumoral injection of drug-loaded fiber fragments provided an efficient strategy to improve patient compliance, allow the retention of fragmented fibers and spatial distribution of drugs within tumor tissues to achieve a low systemic toxicity and an optimal therapeutic efficacy. PMID- 26013040 TI - An interferon-gamma-delivery system based on chitosan/poly(gamma-glutamic acid) polyelectrolyte complexes modulates macrophage-derived stimulation of cancer cell invasion in vitro. AB - Macrophages represent a large component of the tumour microenvironment and are described to establish interactions with cancer cells, playing crucial roles in several stages of cancer progression. The functional plasticity of macrophages upon stimulation from the environment makes them susceptible to the influence of cancer cells and also renders them as promising therapeutic targets. In this work, we describe a drug delivery system to modulate the phenotype of macrophages, converting them from the pro-tumour M2 phenotype to the anti-tumour M1 phenotype, based on the incorporation of a pro-inflammatory cytokine (interferon-gamma) in chitosan (Ch)/poly(gamma-glutamic acid) (gamma-PGA) complexes. Ch is a biocompatible cationic polysaccharide extensively studied and gamma-PGA is a biodegradable, hydrophilic and negatively charged poly-amino acid. These components interact electrostatically, due to opposite charges, resulting in self-assembled structures that can be designed to deliver active molecules such as drugs and proteins. Ch and gamma-PGA were self-assembled into polyelectrolyte multilayer films (PEMs) of 371nm thickness, using the layer-by layer method. Interferon-gamma (IFN-gamma) was incorporated within the Ch layers at 100 and 500ng/mL. Ch/gamma-PGA PEMs with IFN-gamma were able to modulate the phenotype of IL-10-treated macrophages at the cell cytoskeleton and cytokine profile levels, inducing an increase of IL-6 and a decrease of IL-10 production. More interestingly, the pro-invasive role of IL-10-treated macrophages was hindered, as their stimulation of gastric cancer cell invasion in vitro decreased from 4 to 2-fold, upon modulation by Ch/gamma-PGA PEMs with IFN-gamma. This is the first report proposing Ch/gamma-PGA PEMs as a suitable strategy to incorporate and release bioactive IFN-gamma with the aim of modulating macrophage phenotype, counteracting their stimulating role on gastric cancer cell invasion. PMID- 26013042 TI - Animal welfare towards sustainability in pork meat production. AB - Animal welfare is an important pillar of sustainability in meat production and is associated with other aspects of this concept, such as animal health, productivity, food safety, food quality and efficiency from a cost of production perspective. These interactions are present at all stages of the production cycle, from the beginning of the animals' farm life until their slaughter. On farm, some of the main welfare issues are related to neonatal mortality and low level of sensory input, which are likely to engender stereotypes and injurious behaviours, such as tail-biting. Pre-slaughter handling refers to the interaction between humans and animals prior to and during transport and at slaughter. Strategies to reduce pre-slaughter stress will benefit carcass and meat quality, being the training of stockpeople one of the most cost-effective policies to improve animal welfare. These strategies include also the implementation of standard monitoring procedures to detect signs of consciousness after stunning, before sticking and during bleeding until death occurs. PMID- 26013041 TI - Cationic, amphiphilic dextran nanomicellar clusters as an excipient for dry powder inhaler formulation. AB - Effective delivery of drugs to alveoli in a controlled manner using hydrophobic polymers as carriers has already been reported. Preclinical studies revealed that toxicity and hydrophobicity are related to each other in pulmonary delivery. Here, we are reporting a chemically modified dextran having amphiphilicity and cationicity achieved by controlled grafting of stearyl amine. Two proportions of lipopolymers were synthesized and physico-chemical characterization was carried out. In vivo evaluation of sub-acute toxicity of the synthesized lipopolymer in Sprague-Dawley rats was carried out for three months. This was followed by a histological evaluation of the sacrificed animal's lung. Further, the synthesized lipopolymer was formulated with drug (Rifampicin) loaded inhalable microparticles through spray drying. The final drug formulation was tested for toxicity and proinflammatory responses in human cell lines. Dose deposition efficiency of the formulation was determined using Anderson Cascade Impactor. PMID- 26013044 TI - C-reactive protein gene variants associated with recurrent pregnancy loss independent of CRP serum levels: a case-control study. AB - The aim of this study is to investigate the association of recurrent pregnancy loss (RPL) with altered C-reactive protein (CRP) serum levels, and genetic variation in CRP gene. This was a retrospective case-control study, involving 275 women with three or more consecutive pregnancy losses, and 290 age-matched control women, who were recruited from outpatient obstetrics/gynecology clinics. CRP serum levels (hs-CRP) were determined by latex-enhanced nephelometry, and CRP genotyping was done by allelic discrimination. Mean serum CRP levels were higher in RPL cases than in control women, and carriage of the (minor) T allele of rs2794520 was associated with significant increase in CRP levels (P=0.017). Minor allele frequency (MAF) of rs7553007 was significantly different between RPL cases and control women, and was associated with reduced risk of RPL after adjusting for BMI and menarche. There was a significant enrichment of minor allele-carrying genotypes of rs1130864 and rs1417938 SNPs, and reduced frequency of minor allele carrying genotypes of rs876537, rs2794520, and rs7553007 in RPL cases, thus assigning RPL-susceptible and -protective nature to these genotypes, respectively. Carriage of (minor) T allele of only rs2794520 was associated with significant increase in CRP levels. CRP variants that influenced circulating CRP levels in chronic inflammatory conditions are also associated with RPL, pointing to CRP as RPL candidate gene. PMID- 26013043 TI - Quality assurance multicenter comparison of different MR scanners for quantitative diffusion-weighted imaging. AB - PURPOSE: To propose a magnetic resonance imaging (MRI) quality assurance procedure that can be used for multicenter comparison of different MR scanners for quantitative diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Twenty six centers (35 MR scanners with field strengths: 1T, 1.5T, and 3T) were enrolled in the study. Two different DWI acquisition series (b-value ranges 0-1000 and 0 3000 s/mm(2) , respectively) were performed for each MR scanner. All DWI acquisitions were performed by using a cylindrical doped water phantom. Mean apparent diffusion coefficient (ADC) values as well as ADC values along each of the three main orthogonal directions of the diffusion gradients (x, y, and z) were calculated. Short-term repeatability of ADC measurement was evaluated for 26 MR scanners. RESULTS: A good agreement was found between the nominal and measured mean ADC over all the centers. More than 80% of mean ADC measurements were within 5% from the nominal value, and the highest deviation and overall standard deviation were 9.3% and 3.5%, respectively. Short-term repeatability of ADC measurement was found <2.5% for all MR scanners. CONCLUSION: A specific and widely accepted protocol for quality controls in DWI is still lacking. The DWI quality assurance protocol proposed in this study can be applied in order to assess the reliability of DWI-derived indices before tackling single- as well as multicenter studies. PMID- 26013045 TI - Lack of association between cytotoxic T-lymphocyte antigen-4+49A/G polymorphism and psoriasis and vitiligo: A meta-analysis of case-control studies. AB - BACKGROUND: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical negative regulator of T-cell activation and proliferation. Several studies have assessed the association between CTLA-4+49A/G polymorphism and psoriasis and vitiligo, but the results are inconsistent. AIMS: This study was conducted to examine the association between CTLA-4+49A/G polymorphism and psoriasis and vitiligo susceptibility. METHODS: The PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched according to predefined criteria for all relevant studies published prior to July 3, 2014. Odds ratios (ORs) with 95% confidence intervals (CIs), and heterogeneity and publication bias tests were performed to estimate the strength of the association. RESULTS: Fourteen studies comprising six on psoriasis (700 cases, 781 controls) and eight on vitiligo (1514 cases, 2049 controls) were included. Overall, no significant association was detected between CTLA-4+49A/G polymorphism and psoriasis. There was still no significant relationship when the studies were limited to ethnicity (Asian and Caucasian), HWE or heterogeneity, except the limitation to heterogeneity in the dominant (OR=0.69, 95% CI=0.51-0.93, I(2)=0.0%) and additive (OR=0.69, 95% CI=0.48-0.98, I(2)=0.0%) models, and the limitation to both heterogeneity and HWE in the dominant model (OR=0.68, 95% CI=0.48-0.98, I(2)=0.0%). Both overall and subgroup analyses based on ethnicity, genotype frequencies, and heterogeneity also failed to demonstrate an association between CTLA-4+49A/G polymorphism and vitiligo. CONCLUSION: CTLA-4+49A/G polymorphism may not contribute to psoriasis and vitiligo susceptibility, but further well-designed studies with large sample size are warranted to confirm this conclusion. PMID- 26013046 TI - Genome-wide identification of microRNAs associated with taproot development in radish (Raphanus sativus L.). AB - MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that play vital regulatory roles in plant growth and development. To identify the miRNAs associated with taproot development at the whole genome level, we sequenced five RNA libraries constructed from radish taproots at different developmental stages and generated a total of 148M clean reads. Using an integrative bioinformatics analysis, 494 known miRNAs belonging to 434 families and 220 putative novel miRNAs were identified. Combining the differential expression analysis and target prediction, we found that 77 miRNAs were potentially associated with taproot development. Target transcripts generated significant GO terms relating to cell proliferation, root development and hormone-mediated signaling. The KEGG analyses revealed that plant hormone signal transduction, zeatin biosynthesis, biosynthesis of secondary metabolites, cell cycle, MAPK signaling and p53 signaling were closely associated with taproot development. These findings will provide valuable information for further functional verification of miRNAs and their targets in radish taproot development. PMID- 26013048 TI - Hammer time: penetrating trauma from sledgehammer use. PMID- 26013049 TI - New insights into vegetation patterns and processes. PMID- 26013047 TI - A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors. AB - The interaction between the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E binding proteins (4E-BP) is a promising template for the inhibition of eIF4E and the treatment of diseases such as cancer and a spectrum of autism disorders, including the Fragile X syndrome (FXS). Here, we report an atomically detailed model of the complex between eIF4E and a peptide fragment of a 4E-BP, the cytoplasmic Fragile X interacting protein (CYFIP1). This model was generated using computer simulations with enhanced sampling from an alchemical replica exchange approach and validated using long molecular dynamics simulations. 4E-BP proteins act as post-transcriptional regulators by binding to eIF4E and preventing mRNA translation. Dysregulation of eIF4E activity has been linked to cancer, FXS, and autism spectrum disorders. Therefore, the study of the mechanism of inhibition of eIF4E by 4E-BPs is key to the development of drug therapies targeting this regulatory pathways. The results obtained in this work indicate that CYFIP1 interacts with eIF4E by an unique mode not shared by other 4E-BP proteins and elucidate the mechanism by which CYFIP1 interacts with eIF4E despite having a sequence binding motif significantly different from most 4E-BPs. Our study suggests an alternative strategy for the design of eIF4E inhibitor peptides with superior potency and specificity than currently available. PMID- 26013050 TI - The proportional odds cumulative incidence model for competing risks. AB - We suggest an estimator for the proportional odds cumulative incidence model for competing risks data. The key advantage of this model is that the regression parameters have the simple and useful odds ratio interpretation. The model has been considered by many authors, but it is rarely used in practice due to the lack of reliable estimation procedures. We suggest such procedures and show that their performance improve considerably on existing methods. We also suggest a goodness-of-fit test for the proportional odds assumption. We derive the large sample properties and provide estimators of the asymptotic variance. The method is illustrated by an application in a bone marrow transplant study and the finite sample properties are assessed by simulations. PMID- 26013051 TI - The effects of high intensity interval training in women with rheumatic disease: a pilot study. AB - PURPOSE: Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are inflammatory diseases which involve increased risk of cardiovascular disease (CVD). High intensity interval training (HIIT) is known to be effective in improving cardiovascular health. The aim of this study was to investigate whether 10 weeks of HIIT at 85-95% of HRmax would improve important risk factors of CVD in rheumatic patients, and if these patients would tolerate exercise intensities above today's recommendations. METHODS: Seven women with RA and eleven with adult JIA, 20-50 years, were recruited to this cross-over study. Participants performed HIIT, consisting of 4 * 4 min intervals at 85-95% of HRmax twice a week for 10 weeks on spinning bikes. Maximal oxygen uptake (VO2max), heart rate recovery, blood pressure, body composition, and blood variables were measured before and after the exercise and control period. Disease activity was determined and questionnaire data were collected. RESULTS: HIIT resulted in 12.2% increase in VO2max and 2.9% improvement in heart rate recovery (p < 0.05). BMI, body fat, and waist circumference decreased 1.2, 1.0, and 1.6%, respectively, whereas muscle mass increased 0.6% (p < 0.05). A trend toward decreased CRP was detected after HIIT (p = 0.08). No changes were detected in disease activity or pain. CONCLUSION: Despite rigorous high intensity exercise, no increase was detected in disease activity or pain, indicating that HIIT was well tolerated by these patients. Furthermore, HIIT had positive effects on several CVD risk factors. In light of this pilot study, HIIT seems like a promising non-pharmacological treatment strategy for patients with RA and adult-JIA. PMID- 26013052 TI - Transarterial embolization for pediatric hepatocellular carcinoma with cardiac cirrhosis. AB - We describe the case of a 15-year-old boy with a history of Fontan operation and multiple intrahepatic tumors. Computed tomography showed multiple hepatic nodules with arterial enhancement. Because hepatocellular carcinoma (HCC) was not detected on biopsies and tumor markers were normal, progress was monitored on imaging. One hepatic tumor increased greatly in size during follow up. At 15 years of age, tumor markers rose rapidly, and he had upper abdominal swelling. Therefore, transarterial embolization (TAE) was performed for the largest tumor, suspected to be a HCC due to cardiac cirrhosis. This tumor had not increased at follow up 4 months later. The patient died from hepatic failure at the age of 17 years, and HCC was diagnosed at autopsy. Although pediatric HCC is rare, its incidence is likely to increase. TAE, with or without anticancer agents, is a therapeutic option for unresectable pediatric HCC, as it is for adult HCC. PMID- 26013054 TI - Paradoxes in studies of liver regeneration: Relevance of the parable of the blind men and the elephant. PMID- 26013053 TI - Transcarotid balloon valvuloplasty in neonates and small infants with critical aortic valve stenosis utilizing continuous transesophageal echocardiographic guidance: A 22 year single center experience from the cath lab to the bedside. AB - OBJECTIVE: Utilization of continuous transesophageal echocardiographic guidance (cTEE) during transcarotid balloon valvuloplasty (TCBV) in neonates and small infants with critical aortic valve stenosis (AS) allows for continuous hemodynamic assessment and improved outcomes. BACKGROUND: Preferred method of intervention for critical AS remains controversial due to conflicting results. METHODS: Since 1992, 30 neonates and small infants with critical AS and adequate left ventricular (LV) volumes underwent TCBV with cTEE. Critical AS was defined as ductal dependent systemic circulation, LV systolic dysfunction, or an echo gradient>=100 mm Hg with evidence of hypoperfusion. RESULTS: The median age at intervention was 4 days (range 1-54 days). Nineteen (63%) patients required PGE1 and 25 (85%) had LV dysfunction. All procedures were performed with cTEE guidance. The initial 15 patients were performed in the cath lab whereas the subsequent 15 patients were performed at the bedside without fluoroscopy. The peak systolic gradient decreased from 70 to 24 mm Hg (P<0.001). Four (13%) early deaths were secondary to associated cardiac anomalies although one patient developed severe aortic valve insufficiency (AI) immediately post intervention. At discharge, two patients (8%) had >=moderate AI. At a mean follow-up of 9 years (range: 2.2-20 years), there were 15 additional aortic valve interventions. Freedom from aortic valve reintervention at 10 years was 55% and actuarial survival rate at 10 and 15 years was 82%. CONCLUSION: Bedsides TCBV with cTEE guidance is effective palliation for neonates and small infants with critical AS and allows for continuous hemodynamic assessment without the use of ionizing radiation. Our early and late results appear comparable to surgical valvotomy. PMID- 26013055 TI - Increased Pygo2 expression in liver of patients with hepatitis B virus-related fibrosis. AB - BACKGROUND & AIMS: It has been reported that Wnt/beta-catenin signalling pathway played a key role in liver fibrosis and that Pygo2 was an important mediator in beta-catenin induced pathway. However, the role of Pygo2 in liver fibrogenesis was unknown. Our study was to investigate the expression of Pygo2 and its diagnostic value in patients with HBV-related liver fibrosis. METHODS: Hundred and sixty-four patients with HBV infection underwent liver biopsy and liver stiffness measurement (LSM) by transient elastography (Fibroscan((r)) ; Echosens). Liver function was tested by routine biochemical examinations. Liver condition was assessed by haematoxylin and eosin (H&E) and Masson's trichrome staining. The expression of Pygo2 in liver tissue was measured by Real-time PCR and immunohistochemistry, respectively, while the serum levels of Pygo2 were detected by ELISA. The relationship between degree of liver fibrosis and Pygo2 expression was assessed by correlation analysis. Receiver operating characteristics (ROC) analysis was used to evaluate diagnostic accuracy of serum Pygo2, LSM and their combination. RESULTS: The mRNA and protein levels of Pygo2 in HBV-infected patients were all higher than in normal persons (P < 0.05 respectively). Moreover, Pygo2 expression increased along with the progression of liver fibrosis (P < 0.05 respectively). The trend of serum Pygo2 agreed with its expression in liver tissue. The combination of serum Pygo2 and LSM had a significantly higher area under the curve than Pygo2 or LSM alone (P < 0.05 respectively). CONCLUSIONS: This study suggested that Pygo2 was involved in HBV induced liver fibrogenesis. Pygo2 is a valuable biomarker for the evaluation of fibrosis in HBV-infected patients. PMID- 26013056 TI - Cross-cultural adaptation of the Revised Korean version of the Fibromyalgia Impact Questionnaire: its association with physical function and quality of life. AB - AIM: Despite its shortcomings, the Fibromyalgia Impact Questionnaire (FIQ) is widely used to assess clinical symptoms and measure therapeutic changes in patients with fibromyalgia (FM). Recently, the revised version of the FIQ (FIQR) was released. In this study, we validated the Korean version of the FIQR and evaluated whether the revised version is superior to the original version in reflecting the physical function and quality of life of these patients. METHODS: Seventy-nine patients with FM were invited to complete a questionnaire that included the original FIQ, FIQR, Multidimensional Health Assessment Questionnaire (MDHAQ), Rheumatology Attitudes Index (RAI), and Medical Outcome Study Short-Form 36 (SF-36). RESULTS: The test-retest reliability was assessed in 55 patients after 1 week, and the Spearman coefficients were 0.604-0.825 and Cronbach's alpha was 0.948 (95% confidence interval 0.930-0.964). The FIQR was significantly correlated with the pain visual analogue scale (VAS), fatigue VAS, RAI, MDHAQ, and physical and mental component summary scores of the SF-36. The FIQR was more strongly associated with the MDHAQ and SF-36 scores than with the original FIQ. CONCLUSION: Our study showed that the FIQR is a reliable, valid instrument for assessing patients with FM and performs better in the prediction of physical function and health status than the original version. PMID- 26013057 TI - Non-central nervous system fetal magnetic resonance imaging. AB - Fetal magnetic resonance imaging (MRI) is currently offered in a limited number of centers but is predominantly used for suspected fetal central nervous system abnormalities. This article concentrates on the role of the different imaging sequences and their value to clinical practice. It also discusses the future of fetal MRI. PMID- 26013058 TI - Assessment of the banana pseudostem as a low-cost biosorbent for the removal of reactive blue 5G dye. AB - In this work, the removal of reactive blue 5G (RB5G) dye using the drying biomass of banana pseudostem (BPS) was investigated. The characterization of BPS particles was performed. Improvement in the RB5G dye removal performance at the following sorption conditions was evidenced: pH 1, 30 degrees C sorption temperature and 40 rpm shaking, regardless of the particle size range. Kinetic RB5G dye sorption data obtained at better conditions fit well in an Elovich model. A combined Langmuir-BET isotherm model provides a good representation of the RB5G dye equilibrium sorption data, which shows the evidence of a physical sorption process on the BPS surface. Based on the results, the removal of RB5G dye molecules by BPS is based on a physical sorption process. PMID- 26013059 TI - Stimulation of Suicidal Erythrocyte Death by Naphthazarin. AB - The 1,4-naphthoquinone derivative naphthazarin may trigger apoptosis and is thus considered for the treatment of malignancy. On the other hand, naphthazarin decreases neurotoxicity. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with translocation of phosphatidylserine to the erythrocyte surface. Signalling leading to triggering of eryptosis include increase in cytosolic Ca(2+)-activity ([Ca(2+)]i), ceramide and oxidative stress. The present study explored whether naphthazarin impacts on eryptosis and, if so, to unravel underlying mechanisms. To this end, erythrocyte volume was estimated from forward scatter, phosphatidylserine abundance at the erythrocyte surface from FITC-annexin-V-binding, [Ca(2+)]i from Fluo3 fluorescence, reactive oxidant species (ROS) from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance at the erythrocyte surface from binding of fluorescent antibodies in flow cytometry. As a result, a 24-hr exposure of human erythrocytes to naphthazarin (10 MUM) significantly decreased erythrocyte forward scatter, significantly increased the percentage of annexin-V-binding cells, significantly increased ceramide abundance at the erythrocyte surface and significantly increased ROS. The effect of naphthazarin on annexin-V-binding was not significantly blunted by removal of extracellular Ca(2+). In conclusion, naphthazarin stimulates eryptosis, an effect at least in part due to oxidative stress and enhanced ceramide abundance at the erythrocyte surface. PMID- 26013060 TI - Tracking Global Fund HIV/AIDS resources used for sexual and reproductive health service integration: case study from Ethiopia. AB - OBJECTIVE/BACKGROUND: The Global Fund to Fight AIDS, Tuberculosis & Malaria (GF) strives for high value for money, encouraging countries to integrate synergistic services and systems strengthening to maximize investments. The GF needs to show how, and how much, its grants support more than just HIV/AIDS, TB and malaria. Sexual and Reproductive Health (SRH) has been part of HIV/AIDS grants since 2007. Previous studies showed the GF PBF system does not allow resource tracking for SRH integration within HIV/AIDS grants. We present findings from a resource tracking case study using primary data collected at country level. METHODS: Ethiopia was the study site. We reviewed data from four HIV/AIDS grants from January 2009-June 2011 and categorized SDAs and activities as directly, indirectly, or not related to SRH integration. Data included: GF PBF data; financial, performance, in-depth interview and facility observation data from Ethiopia. RESULTS: All HIV/AIDS grants in Ethiopia support SRH integration activities (12-100%). Using activities within SDAs, expenditures directly supporting SRH integration increased from 25% to 66% for the largest HIV/AIDS grant, and from 21% to 34% for the smaller PMTCT-focused grant. Using SDAs to categorize expenditures underestimated direct investments in SRH integration; activity-based categorization is more accurate. The important finding is that primary data collection could not resolve the limitations in using GF GPR data for resource tracking. The remedy is to require existing activity-based budgets and expenditure reports as part of PBF reporting requirements, and make them available in the grant portfolio database. The GF should do this quickly, as it is a serious shortfall in the GF guiding principle of transparency. CONCLUSIONS: Showing high value for money is important for maximizing impact and replenishments. The Global Fund should routinely track HIV/AIDs grant expenditures to disease control, service integration, and overall health systems strengthening. The current PBF system will not allow this. Real-time expenditure analysis could be achieved by integrating existing activity-based financial data into the routine PBF system. The GF's New Funding Model and the 2012-2016 strategy present good opportunities for over-hauling the PBF system to improve transparency and allow the GF to monitor and maximize value for money. PMID- 26013061 TI - Online Continuing Education for Expanding Clinicians' Roles in Breastfeeding Support. AB - Lack of health professional support is an important variable affecting mothers' achievement of breastfeeding goals. Online continuing education is a recognized pathway for disseminating content for improving clinicians' knowledge and supporting efforts to change practices. At the time we developed our project, free, accredited continuing education for physicians related to breastfeeding management that could be easily accessed using portable devices (via tablets/smartphones) was not available. Such resources were in demand, especially for facilities pursuing designation through the Baby-Friendly Hospital Initiative. We assembled a government, academic, health care provider, and professional society partnership to create such a tutorial that would address the diverse content needed for supporting breastfeeding mothers postdischarge in the United States. Our 1.5-hour-long continuing medical and nursing education was completed by 1606 clinicians (1172 nurses [73%] and 434 physicians [27%]) within 1 year. More than 90% of nurses and over 98% of physicians said the tutorial achieved its 7 learning objectives related to breastfeeding physiology, broader factors in infant feeding decisions and practices, the American Academy of Pediatrics' policy statement, and breastfeeding management/troubleshooting. Feedback received from the tutorial led to the creation of a second tutorial consisting of another 1.5 hours of continuing medical and nursing education related to breast examination and assessment prior to delivery, provision of anticipatory guidance to pregnant women interested in breastfeeding, maternity care practices that influence breastfeeding outcomes, breastfeeding preterm infants, breastfeeding's role in helping address disparities, and dispelling common myths. The tutorials contribute to achievement of 8 Healthy People 2020 Maternal, Infant and Child Health objectives. PMID- 26013063 TI - Complexities in responding to the Ebola epidemic. PMID- 26013064 TI - Direct Detection of the Superoxide Anion as a Stable Intermediate in the Electroreduction of Oxygen in a Non-Aqueous Electrolyte Containing Phenol as a Proton Source. AB - The non-aqueous Li-air (O2 ) battery has attracted intensive interest because it can potentially store far more energy than today's batteries. Presently Li-O2 batteries suffer from parasitic reactions owing to impurities, found in almost all non-aqueous electrolytes. Impurities include residual protons and protic compounds that can react with oxygen species, such as the superoxide (O2 (-) ), a reactive, one-electron reduction product of oxygen. To avoid the parasitic reactions, it is crucial to have a fundamental understanding of the conditions under which reactive oxygen species are generated in non-aqueous electrolytes. Herein we report an in situ spectroscopic study of oxygen reduction on gold in a dimethyl sulfoxide electrolyte containing phenol as a proton source. It is shown directly that O2 (-) , not HO2 , is the first stable intermediate during the oxygen reduction process to hydrogen peroxide. The unusual stability of O2 (-) is explained using density functional theory (DFT) calculations. PMID- 26013062 TI - Tumor invasion optimization by mesenchymal-amoeboid heterogeneity. AB - Metastasizing tumor cells migrate through the surrounding tissue and extracellular matrix toward the blood vessels, in order to colonize distant organs. They typically move in a dense environment, filled with other cells. In this work we study cooperative effects between neighboring cells of different types, migrating in a maze-like environment with directional cue. Using a computerized model, we measure the percentage of cells that arrive to the defined target, for different mesenchymal/amoeboid ratios. Wall degradation of mesenchymal cells, as well as motility of both types of cells, are coupled to metabolic energy-like resource level. We find that indirect cooperation emerges in mid-level energy, as mesenchymal cells create paths that are used by amoeboids. Therefore, we expect to see a small population of mesenchymals kept in a mostly-amoeboid population. We also study different forms of direct interaction between the cells, and show that energy-dependent interaction strength is optimal for the migration of both mesenchymals and amoeboids. The obtained characteristics of cellular cluster size are in agreement with experimental results. We therefore predict that hybrid states, e.g. epithelial-mesenchymal, should be utilized as a stress-response mechanism. PMID- 26013066 TI - Clinical outcomes and success rates of quartz fiber post restorations: A retrospective study. AB - STATEMENT OF PROBLEM: Cast metal posts and dowels are inherently dark and, when metal-free restorations are used, could impair the definitive esthetic appearance. Quartz fiber posts could represent a reliable choice for restoring abutment teeth. PURPOSE: The purpose of this study was to evaluate the long-term success rate of teeth restored with quartz fiber posts and fixed dental prostheses (FDPs). MATERIAL AND METHODS: Ninety-nine teeth restored with 114 quartz fiber posts and FDPs were evaluated. The evaluation time ranged from 7 months to 9.25 years. The Kaplan-Meier method was used to obtain success curves. The influence of the tooth location, definitive restoration, and failure pattern upon the success function was analyzed with the log-rank test. The Cox regression test was used to evaluate possible predictors among the interactions of the observed parameters. RESULTS: The success rate of the restorations was 85.86% in a mean period of 5.88 +/-1.37 years, with an estimated success probability of 85% at 6.17 years. The statistical analysis identified the factors related to the arch (P=.045) and type of definitive restoration (P=.021) as significantly associated with success. Post debonding was the most frequent failure mode, followed by endodontic failure, with the latter not necessarily being related to the post itself. No root fractures were recorded. Twelve teeth out of the 14 that failed were restored again, bringing the overall survival rate of the teeth to 98%. CONCLUSIONS: The rehabilitation of abutment teeth with quartz fiber posts can be considered a reliable procedure; however, adhesive techniques and luting materials require improvement. PMID- 26013067 TI - CAD/CAM-fabricated template for locating implant abutment screws in cement retained anatomic zirconia restorations. AB - Currently, appropriate access to the abutment screw within cement-retained implant restorations is determined using labor-intensive techniques. The introduction of computer-aided design/computer-aided manufacture technology has facilitated a digitized fabrication process to yield a template that can enhance the accuracy of drilling a screw channel. This article describes the method used to create these guide templates by using advanced dental design programs and machining. PMID- 26013068 TI - Computer-guided implant surgery and immediate loading with a modifiable radiographic template in a patient with partial edentulism: A clinical report. AB - Computer-guided implant surgery in fresh extraction sites is an underdeveloped procedure. The presence of teeth that will be extracted makes the creation of an appropriate radiographic template for virtual simulation of the rehabilitation impossible. A modified radiographic template is presented to define a digital restorative simulation for the maxillary rehabilitation of a patient with partial edentulism. This modification enables 3-dimensional prosthetic virtual information in regions where teeth will be extracted. PMID- 26013065 TI - Pre-treatment with dual antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention. AB - BACKGROUND: Although dual antiplatelet therapy is the standard of care in non-ST segment elevation acute coronary syndromes (NSTEACS), it remains unclear when a second antiplatelet agent should be initiated. We sought to assess the safety and efficacy of pre-treatment with clopidogrel in patients with NSTEACS undergoing percutaneous coronary intervention (PCI). METHODS: We analysed baseline clinical and procedural characteristics of 6817 patients with NSTEACS who underwent PCI from the Melbourne Interventional Group registry from 2005 to 2012. Patients were included in the pre-treatment group if clopidogrel was administered prior to cardiac catheterisation. We assessed 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events. The safety endpoint was in-hospital bleeding. RESULTS: Of the 6817 patients, only 2951 (43%) received pre-treatment with clopidogrel. Patients in the pre-treatment group were more likely to present with unstable angina (70.8% vs 68.2%, P = 0.02) and have a history of MI (35.6% vs 23.6%, P < 0.01) but were less likely to have PCI within 24 h of admission (17.2% vs 25.2%, P < 0.01). There was no difference between the groups in 30-day mortality (0.9% vs 1.4%, P = 0.06), MI (2.0% vs 2.2%, P = 0.52) or major adverse cardiovascular event (3.7% vs 4.2%, P = 0.25). There was no difference in bleeding complications (1.9% vs 1.9%, P = 0.94). CONCLUSIONS: Pre-treatment with dual antiplatelet therapy in NSTEACS is not routine clinical practice in Australia. Pre-treatment appears safe but is not associated with improved short term clinical outcomes. PMID- 26013069 TI - Comparison of mechanical properties of three machinable ceramics with an experimental fluorophlogopite glass ceramic. AB - STATEMENT OF PROBLEM: Fluorophlogopite glass ceramic (FGC) is a biocompatible, etchable, and millable ceramic with fluoride releasing property. However, its mechanical properties and reliability compared with other machinable ceramics remain undetermined. PURPOSE: The purpose of this in vitro study was to compare the mechanical properties of 3 commercially available millable ceramic materials, IPS e.max CAD, Vitablocs Mark II, and Vita Enamic, with an experimental FGC. MATERIAL AND METHODS: Each type of ceramic block was sectioned into beams (n=15) of standard dimensions of 2*2*15 mm. Before mechanical testing, specimens of the IPS e.max CAD group were further fired for final crystallization. Flexural strength was determined by the 3-point bend test with a universal loading machine at a cross head speed of 1 mm/min. Hardness was determined with a hardness tester with 5 Vickers hardness indentations (n=5) using a 1.96 N load and a dwell time of 15 seconds. Selected surfaces were examined by scanning electron microscopy and energy-dispersive x-ray spectroscopy. Data were analyzed by the 1-way ANOVA test and Weibull analysis (alpha=.05). Weibull parameters, including the Weibull modulus (m) as well as the characteristic strength at 63.2% (eta) and 10.0% (B10), were obtained. RESULTS: A significant difference in flexural strength (P<.001) was found among groups, with IPS e.max CAD (341.88 +/-40.25 MPa)>Vita Enamic (145.95 +/-12.65 MPa)>Vitablocs Mark II (106.67 +/-18.50 MPa), and FGC (117.61 +/-7.62 MPa). The Weibull modulus ranged from 6.93 to 18.34, with FGC showing the highest Weibull modulus among the 4 materials. The Weibull plot revealed that IPS e.max CAD>Vita Enamic>FGC>Vitablocs Mark II for the characteristic strength at both 63.2% (eta) and 10.0% (B10). Significant difference in Vickers hardness among groups (P<.001) was found with IPS e.max CAD (731.63 +/-30.64 H(V))>Vitablocs Mark II (594.74 +/-25.22 H(V))>Vita Enamic (372.29 +/-51.23 H(V))>FGC (153.74 +/-23.62 H(V)). CONCLUSIONS: The flexural strength and Vickers hardness of IPS e.max CAD were significantly higher than those of the 3 materials tested. The FGC's flexural strength was comparable with Vitablocs Mark II. The FGC's Weibull modulus was the highest, while its Vickers hardness was the lowest among the materials tested. PMID- 26013070 TI - Alternative antireflection substance for a digital impression. PMID- 26013071 TI - Using a guide template with a handpiece sleeve to locate the abutment screw position of a cement-retained implant restoration. AB - The existing techniques for drilling a screw access hole in cement-retained restorations are limited by inaccurate drill guidance and ineffective cooling of the drilling area. An approach for fabricating a guide template to provide screw retrievability using computer-aided design and computer-aided manufacturing (CAD/CAM) is described. A handpiece sleeve was made by 3-dimensional printing and incorporating it into a vacuum-formed template. The handpiece sleeve not only guides the head of the handpiece accurately but also enables the cooling water to reach the area of drilling directly. PMID- 26013072 TI - Using a thermoplastic sheet to add palatal rugae to a complete removable dental prosthesis. PMID- 26013073 TI - Custom total occlusal convergence angle sticker fabrication. AB - This article describes a method of fabricating a custom total occlusal convergence angle sticker with photo editing software and label stickers. The custom total occlusal convergence angle sticker can help clinicians achieve an accurate degree of taper during axial wall reduction of tooth preparation. PMID- 26013075 TI - Using Shrub Clearing, Draining, and Herbivory to Control Bramble Invasion in Mediterranean Dry Grasslands. AB - For centuries, the dry grassland of the plain of La Crau (south-eastern France) has been subjected to numerous disturbances resulting in the destruction and the fragmentation of this emblematic rangeland ecosystem of the Mediterranean. Today, this ecosystem is facing a new threat from a proliferating native species, the bramble (Rubus ulmifolius Schott), which preferentially colonizes areas that were formerly cultivated and/or exposed to water infiltration. To identify a strategy for effective control of this colonization, in situ experiments testing disturbance regimes (shrub clearing and/or mixed grazing by sheep and goats) combined with the control of access to water resources (with or without drainage trenches) were undertaken between 2010 and 2013. Only clearing and grazing combined over 3 years led to significant changes in vegetation height and bramble cover as well as modifications in the floristic composition, diversity, similarity, and richness of the plant community. Neither a clearing operation carried out in 2010 alone, nor grazing alone, reduced bramble cover, and neither treatment increased the species richness of the plant community. Similarly, digging drainage trenches had no significant impact either on the plant community or on bramble cover. Our study suggests that only annual mechanical clearing coupled with sheep and goats grazing can significantly reduce bramble cover. This combined restoration treatment needs to be applied for at least 3 consecutive years to induce significant changes and enable this ecosystem to return to the dry grassland succession. PMID- 26013076 TI - Enantioselective synthesis of 3-fluoro-3-allyl-oxindoles via phosphine-catalyzed asymmetric gamma-addition of 3-fluoro-oxindoles to 2,3-butadienoates. AB - The first phosphine-catalyzed enantioselective gamma-addition of 3-fluoro oxindoles to 2,3-butadienoates has been developed. A range of 3-fluoro substituted oxindole substrates were employed, and oxindoles containing a 3 fluoro quaternary center were constructed in high yields and with excellent enantioselectivities. The gamma-addition products could be converted readily to optically enriched 3-fluoro-3-allyl oxindole derivatives. PMID- 26013074 TI - Evidence for ACD5 ceramide kinase activity involvement in Arabidopsis response to cold stress. AB - Although sphingolipids emerged as important signals for plant response to low temperature, investigations have been limited so far to the function of long chain base intermediates. The formation and function of ceramide phosphates (Cer Ps) in chilled Arabidopsis were explored. Cer-Ps were analysed by thin layer chromatography (TLC) following in vivo metabolic radiolabelling. Ceramide kinase activity, gene expression and growth phenotype were determined in unstressed and cold-stressed wild type (WT) and Arabidopsis ceramide kinase mutant acd5. A rapid and transient formation of Cer-P occurs in cold-stressed WT Arabidopsis plantlets and cultured cells, which is strongly impaired in acd5 mutant. Although concomitant, Cer-P formation is independent of long-chain base phosphate (LCB-P) formation. No variation of ceramide kinase activity was measured in vitro in WT plantlets upon cold stress but the activity in acd5 mutant was further reduced by cold stress. At the seedling stage, acd5 response to cold was similar to that of WT. Nevertheless, acd5 seed germination was hypersensitive to cold and abscisic acid (ABA), and ABA-dependent gene expression was modified in acd5 seeds when germinated at low temperature. Our data involve for the first time Cer-P and ACD5 in low temperature response and further underline the complexity of sphingolipid signalling operating during cold stress. PMID- 26013077 TI - An Isolable Radical Anion of an Organosilicon Cluster Containing Only sigma Bonds. AB - The radical anion of octa-tert-butyloctasilacubane was generated and isolated. The EPR spectrum showed the satellites due to the tertiary (13)C nuclei of the eight tert-butyl groups. The X-ray crystallographic analysis showed that the Si Si bonds are shortened and the Si-C bonds are elongated compared with those of octa-tert-butyloctasilacubane. These results are well explained by the distribution of an unpaired electron in the singly occupied molecular orbital (SOMO). PMID- 26013098 TI - Nanobarcoded superparamagnetic iron oxide nanoparticles for nanomedicine: Quantitative studies of cell-nanoparticle interactions by scanning image cytometry. AB - Oligonucleotide-functionalized nanoparticles (NPs) are promising agents for nanomedicine, but the potential in vitro nanotoxicity that may arise from such conjugates has yet to be evaluated in a dose response manner. Since nanomedicine functions on the single-cell level, measurements of nanotoxicity should also be performed as such. In vitro single-cell nanotoxicity assays based on scanning image cytometry are used to study a specific type of oligo-functionalized NP, "nanobarcoded" superparamagnetic iron oxide NPs (NB-SPIONs). The selected panel of single-cell assays measures well-known modes of nanotoxicity--apoptosis, necrosis, generation of reactive oxygen species (ROS), and cell number. Using these assays, the cytotoxicity of two sizes of NB-SPIONs (10 nm and 30 nm core size) was compared to the parent NP, carboxylated SPIONs (COOH-SPIONs). The results suggest that the conjugated NB confers a biocompatible coating that protects against cytotoxicity at very high SPION doses, but both NB- and COOH SPIONs of either size generally have low in vitro cytotoxicity at physiologically relevant doses. PMID- 26013099 TI - Characterization of electrode alignment for optimal droplet charging and actuation in droplet-based microfluidic system. AB - The actuation method using electric force as a driving force is utilized widely in droplet-based microfluidic systems. In this work, the effects of charging electrode alignment on direct charging of a droplet on electrified electrodes and a subsequent electrophoretic control of the droplet are investigated. The charging characteristics of a droplet according to different electrode alignments are quantitatively examined through experiments and systematic numerical simulations with varying distances and angles between the two electrodes. The droplet charge acquired from the electrified electrode is directly proportional to the distance and barely affected by the angle between the two electrodes. This implies that the primary consideration of electrode alignment in microfluidic devices is the distance between electrodes and the insignificant effect of angle provides a great degree of freedom in designing such devices. Not only the droplet charge acquired from the electrode but also the force exerted on the droplet is analyzed. Finally, the implications and design guidance for microfluidic systems are discussed with an electrophoresis of a charged droplet method-based digital microfluidic device. PMID- 26013100 TI - Hindlimb muscle anatomical mechanical advantage differs among joints and stride phases in basilisk lizards. AB - The vertebrate musculoskeletal system is composed of skeletal levers powered by muscles. Effective mechanical advantage (EMA) and muscle properties influence organismal performance at various tasks. Anatomical mechanical advantage (AMA) is a proxy for EMA that facilitates the study of preserved specimens when many muscles or many species are of interest. AMA is the quotient of in-lever to out lever length, and quantifies the force-velocity trade-off of a lever, where high AMAs translate into high force, low velocity levers. We studied AMAs, physiological cross-sectional areas (PCSAs), fiber lengths, and fiber widths for 20 hindlimb muscles of the lizard Basiliscus vittatus, moving the hip, knee, and ankle during both the stance and swing phases of the stride. We tested the hypotheses that muscles moving proximal limb joints, and those active during stance, would have characteristics that maximize force. We also tested whether adults had more force-optimized levers than juveniles to compensate for higher body mass. We found no differences between adults and juveniles, but found differences among joints and between stride phases. AMAs were lowest and PCSAs highest for the knee, and PCSA was higher for stance than swing muscles. Fiber width decreased distally, but did not differ between stride phases. Fiber length of stance muscles decreased distally and was highest for swing muscles of the knee. Our findings show that different muscle and lever characteristics allow the knee to be both force- and velocity-optimized, indicating its important role in locomotion. PMID- 26013101 TI - Spatial variations of bacterial community and its relationship with water chemistry in Sanya Bay, South China Sea as determined by DGGE fingerprinting and multivariate analysis. AB - Bacteria play important roles in the structure and function of marine food webs by utilizing nutrients and degrading the pollutants, and their distribution are determined by surrounding water chemistry to a certain extent. It is vital to investigate the bacterial community's structure and identifying the significant factors by controlling the bacterial distribution in the paper. Flow cytometry showed that the total bacterial abundance ranged from 5.27 * 10(5) to 3.77 * 10(6) cells/mL. Molecular fingerprinting technique, denaturing gradient gel electrophoresis (DGGE) followed by DNA sequencing has been employed to investigate the bacterial community composition. The results were then interpreted through multivariate statistical analysis and tended to explain its relationship to the environmental factors. A total of 270 bands at 83 different positions were detected in DGGE profiles and 29 distinct DGGE bands were sequenced. The predominant bacteria were related to Phyla Protebacteria species (31 %, nine sequences), Cyanobacteria (37.9 %, eleven sequences) and Actinobacteria (17.2 %, five sequences). Other phylogenetic groups identified including Firmicutes (6.9 %, two sequences), Bacteroidetes (3.5 %, one sequences) and Verrucomicrobia (3.5 %, one sequences). Conical correspondence analysis was used to elucidate the relationships between the bacterial community compositions and environmental factors. The results showed that the spatial variations in the bacterial community composition was significantly related to phosphate (P = 0.002, P < 0.01), dissolved organic carbon (P = 0.004, P < 0.01), chemical oxygen demand (P = 0.010, P < 0.05) and nitrite (P = 0.016, P < 0.05). This study revealed the spatial variations of bacterial community and significant environmental factors driving the bacterial composition shift. These results may be valuable for further investigation on the functional microbial structure and expression quantitatively under the polluted environments in the world. PMID- 26013104 TI - Lessons learned in andrology: physicians and animal scientists can learn from each other. PMID- 26013102 TI - A Preliminary Study of Biomonitoring for Bisphenol-A in Human Sweat. AB - Measurement of human exposure to the endocrine disruptor bisphenol-A (BPA) is hampered by the ubiquitous but transient exposure for most individuals, coupled with a short metabolic half-life which leads to high inter- and intra-individual variability. We investigated the possibility of measuring multiday exposure to BPA in human sweat among volunteer participants with the goal of identifying an exposure assessment method less affected by temporal variability. We recruited 50 participants to wear a sweat collection patch (PharmChek((r))) for 7 days with concurrent collection of daily first-morning urine. Urines and sweat patch extracts were analyzed with quantitative LC-MS-MS using a method we previously validated. In addition, a human volunteer consumed one can of commercially available soup (16 oz, 473 cm(3)) daily for 3 days and collected urine. Sweat patches (n = 2, 1 per arm) were worn for the 3 days of the study. BPA was detected in quality control specimens prepared by fortification of BPA to sweat patches, but was only detected at 5* above average background on three participant patches. Although the highest measured urine BPA concentration was 195 ng/mL for an individual with deliberate exposure, no BPA was detected above background in the corresponding sweat patches. In this preliminary investigation, the use of sweat patches primarily worn on the upper-outer arm did not detect BPA exposures that were documented by urine monitoring. The absence of BPA in sweat patches may be due to several factors, including insufficient quantity of specimen per patch, or extremely low concentrations of BPA in naturally occurring sweat, among others. PMID- 26013103 TI - Oxidative stress, telomere shortening, and DNA methylation in relation to low-to moderate occupational exposure to welding fumes. AB - Evidence suggests that exposure to welding fumes is a risk factor for lung cancer. We examined relationships between low-to-moderate occupational exposure to particles from welding fumes and cancer-related biomarkers for oxidative stress, changes in telomere length, and alterations in DNA methylation. We enrolled 101 welders and 127 controls (all currently nonsmoking men) from southern Sweden. We performed personal sampling of respirable dust and measured 8 oxodG concentrations in urine using a simplified liquid chromatography tandem mass spectrometry method. Telomere length in peripheral blood was measured by quantitative polymerase chain reaction. Methylation status of 10 tumor suppressor genes was determined by methylation-sensitive high-resolution melting analysis. All analyses were adjusted for age, body mass index, previous smoking, passive smoking, current residence, and wood burning stove/boiler at home. Welders were exposed to respirable dust at 1.2 mg/m(3) (standard deviation, 3.3 mg/m(3); range, 0.1-19.3), whereas control exposures did not exceed 0.1 mg/m(3) (P < 0.001). Welders and controls did not differ in 8-oxodG levels (beta = 1.2, P = 0.17) or relative telomere length (beta = -0.053, P = 0.083) in adjusted models. Welders showed higher probability of adenomatous polyposis coli (APC) methylation in the unadjusted model (odds ratio = 14, P = 0.014), but this was not significant in the fully adjusted model (P = 0.052). Every working year as a welder was associated with 0.0066 units shorter telomeres (95% confidence interval -0.013 to -0.00053, P = 0.033). Although there were no clear associations between concentrations of respirable dust and the biomarkers, there were modest signs of associations between oxidative stress, telomere alterations, DNA methylation, and occupational exposure to low-to-moderate levels of particles. PMID- 26013105 TI - Assessment of the optimal vitrification protocol for pre-pubertal mice testes leading to successful in vitro production of flagellated spermatozoa. AB - Testicular tissue cryopreservation offers the hope of preserved future fertility to pre-pubertal boys with cancer before exposition to gonadotoxic treatments. The objective of this study was to compare controlled slow freezing (CSF) with five vitrification techniques for cryopreservation of murine pre-pubertal testicular tissue and to evaluate the best protocol that could provide a successful completion of spermatogenesis after in vitro maturation. Testicular tissue from 24 mice at 6.5 days post-partum (dpp) was used to compare several vitrification protocols with one another, as well as with a CSF protocol. Toxicity test using additional 12 mice was performed for all cryopreservation solutions. Fresh tissue (FT) from six mice was used as a control. Once the optimal vitrification protocol was selected [the modified solid surface vitrification No. 1 (mSSV1 )], testes from 18 mice were cultured in vitro for 30 days with (i) fresh, (ii) slow frozen/thawed and (iii) vitrified/warmed tissues. Testes from six mice at 36.5 dpp were used as controls. At day 30 of in vitro culture, germ cells of the seminiferous tubules showed a high ability to proliferate and elongated spermatids were observed after both freezing techniques, confirming the successful completion of in vitro spermatogenesis. However, after mSSV1 , the morphological alterations and the percentage of pyknotic seminiferous tubules were lower than CSF (4.67 +/- 0.53 vs. 10.1 +/- 1.12 and 22.7 +/- 2.83% vs. 37.3 +/- 4.24% respectively). Moreover, the number of flagellated spermatozoa produced per mg of tissue was higher for mSSV1 than for CSF (35 +/- 3 vs. 9 +/- 4 cells), with amounts of secreted testosterone during the culture close to those of FT. The mSSV1 protocol resulted in success rates better than CSF in maintaining testicular tissue structure, tubular morphology and tissue functions not solely for immediate frozen/thawed tissues but also after a long-term in vitro culture. PMID- 26013106 TI - How is delayed ejaculation defined and treated in North America? AB - Delayed ejaculation (DE) is an uncommon disorder that is difficult to treat because it is poorly understood. The aim was to evaluate the current opinion and clinical management of DE by practitioners in sexual medicine. Members of the Sexual Medicine Society of North America (SMSNA) were invited by email to participate in a web-based survey. The questionnaire consisted of eight questions pertaining to DE. Questions addressed patient volume, qualification of patient bother, ranking of etiologies, perceived success, treatments used, quantification of symptom resolution, and broad characterization of practitioner type. A total of 94 respondents completed the survey with 73% of those being urologists. Fifty nine percent of the respondents saw <= 2 patients a month with DE and 89% of practitioners felt that DE was moderately or severely bothersome to the patients. Etiology was felt to be from medications and psychological factors primarily. Despite treatment modality, 'seldom' success was obtained for 49% of the time and 'never' for 11%. Carbergoline was the most common selected medication for DE. Academic and private urologists reported 'never' or 'seldom' success with sexual counseling compared to other practitioners, respectively (p = 0.008 and p = 0.001). Respondents who saw <= 2 patients per month often reported normalization of hypogonadism 'never' or 'seldom' corrected DE (p = 0.047). Delayed ejaculation is still a poorly understood disorder with inconsistent practice patterns seen among members of the SMSNA. A better understanding of this vexing disorder is needed with efforts placed on research and practitioner education. PMID- 26013107 TI - Acute penile trauma and associated morbidity: 9-year experience at a tertiary care center. AB - Penile fracture is an uncommon urologic emergency, defined as traumatic rupture of the tunica albuginea of the corpus cavernosum. It occurs mainly in young adults during sexual activity. In the United States, urethral injury is associated with 10-38% of all penile fractures. Diagnosis can be made clinically with the classic triad of an audible crack, detumescence, and appearance of hematoma. We sought to identify characteristics associated with true penile fracture vs. other diagnoses, and determine associated morbidity and risk factors for complications. Retrospective operative chart review identified 39 patients (mean age 39.4 years) with clinical features of penile fracture presenting to Boston Medical Center from June 2004 to May 2013. Average time from injury to presentation was 76 h (range 0.5 h-9 days) and the mechanism of injury was coital in 32 (82%) patients. Thirty-two patients (82%) had confirmed penile fracture, 7 (18%) had isolated vascular injury. Of confirmed fractures, 4 (13%) had bilateral corporal injury and associated urethral injury. Imaging was utilized in a total of 21 cases, penoscrotal ultrasound (US) in 17 cases, retrograde urethrogram (RUG) in 3 cases, and magnetic resonance imaging (MRI) in 1 case. Penile exploration was carried out via degloving (n = 5, 13%) or penoscrotal (n = 34, 87%) incisions. At follow-up, six patients (15%) had complications: 2 wound infections, 2 new-onset erectile dysfunction (ED), 1 urethral stricture, 1 fistula and 1 wound dehiscence. Urethral injury increased the risk of post operative complications (p = 0.015). Penile fracture is primarily a clinical diagnosis, however imaging may be helpful if diagnosis is uncertain. Urethral injury should be suspected in cases of bilateral corporal injury and may be associated with increased morbidity. Surgical approach does not affect morbidity, but may facilitate surgical repair. PMID- 26013109 TI - Efficacy and safety of dendritic cells co-cultured with cytokine-induced killer cells immunotherapy for non-small-cell lung cancer. AB - Dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been widely studied and might be a new therapeutic strategy for non-small-cell lung cancer (NSCLC). We aimed to comprehensively and quantitatively evaluate the efficacy and safety of DC-CIK immunotherapy in NSCLC. Pubmed, Embase, Cochrane Library, and Web of Science were searched for randomized controlled trials comparing DC-CIK immunotherapy with control therapies in NSCLC. A total of 505 patients from 6 trials were enrolled. Compared with control therapies, DC-CIK immunotherapy significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.528, 95% confidence interval (CI): 0.390-0.715, P<0.001], overall survival (OS) (HR: 0.619, 95% CI: 0.487-0.786, P<0.001), and disease control rates (DCR) [relative risk (RR): 1.250, 95% CI: 1.058-1.477, P=0.009], but objective response rates (ORR) (RR: 1.190, 95% CI: 0.561-2.526, P=0.650) was not improved for DC-CIK immunotherapy. The risks of all-grade anemia, leukopenia, dermatosis, diarrhea, nausea, acratia, and chest distress in patients receiving DC-CIK immunotherapy were comparable to those receiving control therapies. This meta-analysis demonstrates DC-CIK immunotherapy has superiority in PFS, OS, and DCR for NSCLC patients, and no more serious adverse events appeared. Further studies to provide solid evidence for the routine clinical use of DC-CIK immunotherapy are urgently needed. PMID- 26013110 TI - Impact of ambulatory surgery day of the week on postoperative outcomes: a population-based cohort study. AB - PURPOSE: Ambulatory surgery is generally considered safe; however, as many as 3% of patients require unplanned acute postoperative care. The purpose of this study was to measure the impact of the day of the week of surgery on the outcomes of ambulatory surgery. METHODS: Using population-based health administrative data, we conducted a historical cohort analysis by identifying patients who underwent ambulatory surgery from 2002-2012. Multivariable regression was used to measure the association between the day of the week of surgery and the primary outcomes of 30-day emergency department (ED) visit or hospital readmission after successful discharge on the day of surgery. The secondary outcome that was similarly compared was unsuccessful discharge on the day of surgery. RESULTS: Of 296,497 patients identified, 32,100 (10.5%) returned to the ED or were readmitted to hospital within 30 days. Adjusting for demographics, comorbidities, and preoperative use of health resources, Friday surgery was most associated with the primary outcome (adjusted hazard ratio, 1.07; 95% confidence interval, 1.03 to 1.11) when compared with Monday surgery. This association was stronger in certain surgery types. There were 9,197 (3.1%) patients who were not discharged on the day of surgery; no association between day of the week and unsuccessful discharge was identified. CONCLUSION: On a population level, there was a small effect of the day of the week of ambulatory surgery on outcomes; however, the clinical impact is likely not relevant. Certain surgical types may be more susceptible to a day of the week effect, but more research is needed to elucidate this notion. PMID- 26013111 TI - History of the national licensing examination for the health professions under the Japanese Government-General of Korea (1910-1945). AB - During the reign of Japanese Government-General of Korea (Joseon) from 1910 to 1945, the main health professionals who were educated about modern medicine were categorized into physicians, dentists, pharmacists, midwives, and nurses. They were clearly distinguished from traditional health professionals. The regulations on new health professionals were enacted, and the licensing system was enforced in earnest. There were two kinds of licensing systems: the license without examination through an educational institution and the license with the national examination. The Japanese Government-General of Korea (Joseon) combined education with a national examination system to produce a large number of health professionals rapidly; however, it was insufficient to fulfill the increasing demand for health services. Therefore, the government eased the examination several times and focused on quantitative expansion of the health professions. The proportion of professionals licensed through national examination had increased. This system had produced the maximum number of available professionals at low cost. Furthermore, this system was significant in three respects: first, the establishment of the framework of the national licensing examination still used today for health professionals; second, the protection of people from the poor practices of unqualified practitioners; and third, the standardization of the quality of health. PMID- 26013112 TI - [Concept of an additional physical education lesson in English ("moving words") per week in a secondary school: Results of controlled investigation]. AB - BACKGROUND: Physical exercise improves physical fitness of children and pupils may also benefit from sports with regard to cognitive competence. However, timetable and syllabus often give little scope so that alternatives such as combined lessons in English and sports may be suited to integrate the desire for exercise and leaning. METHOD: Parallel classes of a secondary school (form V; 39 pupils) were determined by random as control group (CG: age 10.5 ys, m 11, f 10) or intervention group (IG: age 10.7 ys, m 7, f 11). All pupils got regular physical education of 3 hours per week. In the IG one English lesson was relocated into the sports hall according to the "moving words" concept for one year. Both physical fitness (Munich fitness test) and concentration (d2-test) were assessed before and 3 times with intervals of 3 months. Moreover, 6-month marks were documented. All data were analyzed descriptively in addition to confirmative statistics (Repeated Measures ANOVA). RESULTS: Neither physical fitness nor concentration showed significant differences between the two groups. Both groups improved both criteria within one year, girls of the IG tended to work exacter with fewer mistakes (d2-Test), but dropped behind with regard to physical fitness. Otherwise, boys in the IG ameliorated rate of mistakes, tempo and exactness in the d2-test (p < 0.05) including a positive trend in physical fitness. Whereas English marks in the reports of the IG improved (0.4 versus 0.1), in both groups marks in sports did not change substantially. CONCLUSIONS: Particularly, boys benefit from the "moving-words" concept improving both their physical fitness as well as concentration. Why girls aged 10 to 11 years, on the contrary, do not benefit from the combined learning to the same degree is an interesting issue for further studies. PMID- 26013113 TI - [Clinical efficacy of a herbal drug combination in acute viral rhinosinusitis]. AB - BACKGROUND: Acute rhinosinusitis is a frequent inflammatory disease of the mucosa of the nose and paranasal sinuses, usually associated with substantial morbidity having considerable socioeconomic impact. A new herbal drug based on a dry extract of a combination of 5 medicinal drugs (Sinupret(r) extract Dragees) was tested in a confirmatory trial in patients with acute viral rhinosinusitis. METHODS: 386 patients with symptomatic acute viral rhinosinusitis have been treated with the herbal drug combination (daily dosage 3 * 160 mg) or placebo in a double-blind, randomised, placebo-controlled clinical trial for 15 days. Primary efficacy endpoint was the investigator assessed symptom score at the end of therapy (Major Symptom Score, MSSINV). RESULTS: Treatment with verum lead to a statistically significant, clinically relevant improvement of the symptom score (2.07 +/- 0.18 [SEM] vs. 3.47 +/- 0.28 score points, p = 0.0001; PP: N = 300) compared to placebo at visit 5. The Number Needed to Treat (NNT) was 7 (PP). Adverse events occurred in 9.8% of the patients treated with verum and 14.1% of the patients treated with placebo. No serious adverse event was observed. The investigators assessed the tolerability of the herbal drug combination predominantly as good and very good (96.4% verum, 95.3% placebo). CONCLUSION: The results prove the efficacy and tolerability of the herbal drug in the indication acute viral rhinosinusitis. Especially due to the favorable benefit-risk ratio the drug represents a suitable treatment alternative. PMID- 26013114 TI - [Clinical practice data regarding tapentadol prolonged release treatment for severe chronic pain - improvement of analgesia, functional competence and quality of life in particular under tapentadol monotherapy]. AB - STUDY OBJECTIVE: To assess effectiveness and tolerability of tapentadol prolonged release (PR, Palexia(r) retard) for the treatment of severe chronic pain under routine clinical practice conditions in Germany. METHODS: In this prospective non interventional study, data regarding previous and concomitant analgesic treatment, tapentadol dosage, pain intensity, functionality, quality of life, and tolerability of tapentadol PR were collected over a 3-month observation period. A total of 5,002 patients were included in the effectiveness analysis; a subgroup analysis assessed effectiveness for all patients receiving tapentadol monotherapy (n = 1476). RESULTS: Nearly all patients of the total study population (95.9%) had already received analgesic long-term treatment (31.7% strong opioids) prior to the start of the study. Treatment with tapentadol PR (mean daily dose 216 +/- 103 mg at end of observation) resulted in a reduction in pain intensity of 3.9 points from 7.2 +/- 1.4 at baseline (95%CI -3.93; -3.83; p <= 0.001; NRS-11); clinically relevant pain relief >= 50% was documented for 65.1% of the patients. All 4 evaluated aspects regarding pain-related functionality, and quality of life of the patients also improved significantly. Compared to the total patient population, pain relief was greater in the subgroup receiving tapentadol monotherapy; baseline pain intensity was comparable between the groups. Pain related functional impairment also declined to a slightly greater extent, and quality of life was rated more positively at end of observation. CONCLUSIONS: Analgesic treatment with tapentadol PR in routine clinical practice resulted in a marked reduction of severe chronic pain with significant improvements of functionality and quality of life. On the basis of these results and the favourable safety profile, tapentadol PR can thus be considered an alternative to classical opioids in the treatment of severe chronic pain. PMID- 26013115 TI - [Dialysis care in Germany - demand, outpatient care and challenges]. AB - BACKGROUND: Dialysis is the mostly used renal replacement therapy in patients with end-stage renal disease. The aim of the study was to analyze the present dialysis care system and to scrutinize future changes regarding the need of dialysis as well as the system of care. METHODS: The study is based on a structured literature search in Pubmed; selecting relevant studies by predefined criteria. Prevalence of ESRD and the share of nephrologists in outpatient care were modeled until 2020. Guideline-based interviews with experts including a two round Delphi survey were conducted to identify options for action. RESULTS: The number of dialysis-dependent patients will increase by one fifth from 83,000 in 2013 to 100,000 in 2020 while the share of nephrologists in outpatient care will decrease by 8% simultaneously. Therefore, young nephrologists and team-building in dialysis care need to be promoted. Home therapy should be used more often to cover the increasing need of dialysis in the future. Besides changes in the structures of care, shared-decision-making needs to be strengthened. CONCLUSIONS: The study offers concrete options to strengthen outpatient care by nephrologists (a) and to use home therapy more often (b) in order to provide adequate and appropriate dialysis care until 2020. PMID- 26013117 TI - An environmental problem hidden in plain sight? Small human-made ponds, emergent insects, and mercury contamination of biota in the Great Plains. AB - Mercury (Hg) contamination of small human-made ponds and surrounding terrestrial communities may be 1 of the largest unstudied Hg-pollution problems in the United States. Humans have built millions of small ponds in the Great Plains of the United States, and these ponds have become contaminated with atmospherically deposited mercury. In aquatic ecosystems, less toxic forms of Hg deposited from the atmosphere are converted to highly toxic methylmercury (MeHg). Methylmercury is incorporated into the aquatic food web and then can be transferred to terrestrial food webs via emergent aquatic insects. The authors present a conceptual model that describes the movement of MeHg produced in aquatic ecosystems to terrestrial consumers via insects emerging from small human-made ponds. The authors hypothesize that pond permanence and the level of Hg contamination of the food web control this emergent insect-mediated flux of MeHg. The highest insect-mediated flux of MeHg is predicted to be from fishless semipermanent ponds with food webs that are highly contaminated with MeHg. Further development and testing of the conceptual model presented in the present column, particularly in the context of a changing climate, will require research at the regional, watershed, and pond scales. PMID- 26013118 TI - In response: Viewpoint on chemicals and multiple stresses: An industry perspective. PMID- 26013116 TI - A possible role of Drosophila CTCF in mitotic bookmarking and maintaining chromatin domains during the cell cycle. AB - BACKGROUND: The CCCTC-binding factor (CTCF) is a highly conserved insulator protein that plays various roles in many cellular processes. CTCF is one of the main architecture proteins in higher eukaryotes, and in combination with other architecture proteins and regulators, also shapes the three-dimensional organization of a genome. Experiments show CTCF partially remains associated with chromatin during mitosis. However, the role of CTCF in the maintenance and propagation of genome architectures throughout the cell cycle remains elusive. RESULTS: We performed a comprehensive bioinformatics analysis on public datasets of Drosophila CTCF (dCTCF). We characterized dCTCF-binding sites according to their occupancy status during the cell cycle, and identified three classes: interphase-mitosis-common (IM), interphase-only (IO) and mitosis-only (MO) sites. Integrated function analysis showed dCTCF-binding sites of different classes might be involved in different biological processes, and IM sites were more conserved and more intensely bound. dCTCF-binding sites of the same class preferentially localized closer to each other, and were highly enriched at chromatin syntenic and topologically associating domains boundaries. CONCLUSIONS: Our results revealed different functions of dCTCF during the cell cycle and suggested that dCTCF might contribute to the establishment of the three dimensional architecture of the Drosophila genome by maintaining local chromatin compartments throughout the whole cell cycle. PMID- 26013119 TI - The Challenge: Assessing the effects of chemicals in freshwaters under multiple stress. PMID- 26013121 TI - In response: Assessing the effects of chemicals in freshwaters under multiple stress: A regulatory science perspective. PMID- 26013120 TI - In response: The evidence--What actions are needed to effectively transfer from science to policy? An academic perspective. PMID- 26013124 TI - Current developments for improving efficacy of allergy vaccines. AB - Allergic diseases are prevalent worldwide. Allergen immunotherapy (AIT) is a current treatment for allergy, leading to modification of the natural course of disease. Mechanisms of efficacy include Treg through release of IL-10 and TGF beta and specific IgG4 blocking antibodies. Subcutaneous and sublingual routes are popular, but uptake is limited by inconvenience and safety concerns. Inclusion criteria limit application to a small proportion of allergic patients. New forms of immunotherapy are being investigated for more efficacious, convenient and safer options with promising advances in recent years. The rationale of reducing vaccine allergenicity to increase safety while improving immunogenicity led to investigation of T-cell epitope-based peptides and recombinant allergen derivatives. Additionally, different routes of administration and adjuvants and adjunct therapies are being explored. This review discusses the current status of AIT and recent advances to improve clinical efficacy, safety and long-term immune tolerance. PMID- 26013126 TI - Linking pollination effectiveness and interspecific displacement success in bees. AB - Pollen deposition, a surrogate for bee efficiency, becomes increasingly important during their interspecific interactions. We conducted field experiments on highly cross-pollinated melon (Cucumis melo) and watermelon (Citrullus lanatus) in order to understand how bee species with different pollination efficiencies displace each other from floral resources. We observed significant displacement of less abundant but more efficient bees by the more abundant but less efficient bees in both crops, which may lead to deficient pollination. We did not find significant relationship of the bee displacement success and body size or abundance. Apis florea (Fabricius) and Nomia sp.2 (Latreille) had significantly more winner events in melon, while the former also had significantly more winner events in watermelon. A. florea was the only bee species that foraged mostly within the 1 m(2) virtual area after their displacement, which may indicate its behavior of geitinogamous pollination. The two bee species, Ceratina sexmaculata (Smith) and Lasioglossum sp. (Curtis), were more sensitive to displacement as their proportion of leaving the 1-m(2) virtual area was higher. PMID- 26013123 TI - Hepatic stellate cells: central modulators of hepatic carcinogenesis. AB - Hepatocellular carcinoma (HCC) represents the second most common cause of cancer related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90% of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC. PMID- 26013125 TI - Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression. AB - Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy. PMID- 26013127 TI - Stay out (almost) all night: contrasting responses in flight activity among tropical moth assemblages. AB - Variations in diel activity among hyperdiverse tropical communities of moths, despite representing a key component of niche partitioning between species, have barely been studied so far. Using light trapping from dawn to sunset over a 1 year period in French Guiana, we investigated these variations within and between two families of moths (Sphingidae and Saturniidae). Our results revealed contrasting patterns in flight activity at night between Sphingidae and Saturniidae. Sphingidae reached their peak in species richness and abundance between 7:00 and 8:00 p.m., followed by a decrease around 11:00 p.m. to midnight, whereas Saturniidae were continuously present throughout the night, with a peak around midnight. In addition, we found changes in diel activity among some of the most common genera in each family, highlighting distinct behavioral, physiological, and functional traits among taxa. Given differences in flight activity at different taxonomic levels, it is strongly recommended to monitor by light trapping throughout the night to effectively sample saturniid and sphingid assemblages, even though the activity of Sphingidae sharply declines after midnight. These results improve the general natural history information of tropical moths and reinforce the need of further research on the ecological and taxonomic consequences of differences in diel activity. PMID- 26013128 TI - Body Size, Fecundity, and Sexual Size Dimorphism in the Neotropical Cricket Macroanaxipha macilenta (Saussure) (Orthoptera: Gryllidae). AB - Body size is directly or indirectly correlated with fitness. Body size, which conveys maximal fitness, often differs between sexes. Sexual size dimorphism (SSD) evolves because body size tends to be related to reproductive success through different pathways in males and females. In general, female insects are larger than males, suggesting that natural selection for high female fecundity could be stronger than sexual selection in males. I assessed the role of body size and fecundity in SSD in the Neotropical cricket Macroanaxipha macilenta (Saussure). This species shows a SSD bias toward males. Females did not present a correlation between number of eggs and body size. Nonetheless, there were fluctuations in the number of eggs carried by females during the sampling period, and the size of females that were collected carrying eggs was larger than that of females collected with no eggs. Since mating induces vitellogenesis in some cricket species, differences in female body size might suggest male mate choice. Sexual selection in the body size of males of M. macilenta may possibly be stronger than the selection of female fecundity. Even so, no mating behavior was observed during the field observations, including audible male calling or courtship songs, yet males may produce ultrasonic calls due to their size. If female body size in M. macilenta is not directly related to fecundity, the lack of a correlated response to selection on female body size could represent an alternate evolutionary pathway in the evolution of body size and SSD in insects. PMID- 26013129 TI - Spatially Heterogeneous Nest-Clearing Behavior Coincides with Rain Event in the Leaf-Cutting Ant Atta cephalotes (L.) (Hymenoptera: Formicidae). AB - Leaf-cutting ants of the genus Atta construct the probably largest nests among ants and are ecosystem engineers because they alter light and nutrient availability at nest sites. Besides creating canopy gaps in the forest, workers remove all vegetation from atop their nest mounds. Here, we examined the extent and spatial distribution of this nest-clearing behavior by transplanting Licania tomentosa seedlings on Atta cephalotes (Linnaeus) nest mounds in the Atlantic forest in northeast Brazil and documented defoliation patterns by the workers. Within 9 days, workers removed around 53% of the total leaf area planted per colony. All colonies showed a synchronized start of defoliation after a rain event in the fifth night after the seedlings had been transplanted. Defoliation increased with time elapsed since transplanting and with the number of entrances surrounding each seedling. In addition, workers started defoliation on the top of the mound. In contrast, the distance to the next entrance and the size of the seedling did not affect the defoliation pattern. Defoliation was not part of the colony foraging activities but was identified as an element of nest maintenance. Possible cues triggering nest-clearing behavior and the potential link between nest-clearing activities and the control of microclimate of ant nests are discussed. PMID- 26013131 TI - Effects of white grubs on soil water infiltration. AB - Water infiltration rates k were measured in mesocosms with soil and "white grubs" of Ancognatha falsa (Arrow) (Coleoptera: Melolonthidae). Three third instars of A. falsa and three adult earthworms Pontoscolex corethrurus were selected, weighted, and introduced into the mesocosms setting three treatments: soil + A. falsa, soil + P. corethrurus, and control (soil without any macroorganism). The experiment had a completely random design with four replicates per treatment (n = 4). The infiltration rates of soil matrix were assessed in each mesocosms with a minidisk tension infiltrometer. Six measurements were made along the experiment. Results showed that larvae of A. falsa promoted a higher water infiltration in the soil, compared to the control. On day 7, k values were similar among treatments, but k values after 28 days and up to 100 days were much higher in the A. falsa treatment (k = 0.00025 cm s(-1)) if compared to control (k = 0.00011 cm s(-1)) and P. corethrurus (k = 0.00008 cm s(-1)) treatments. The k values were significantly higher in the presence of larvae of A. falsa compared to the control and P. corethrurus treatments. The larvae of A. falsa are potential candidates for new assays on soil water infiltration with different tensions to evaluate the role of pores and holes created by the larvae on soils. PMID- 26013130 TI - Identification of Grapholita molesta (Busk) (Lepidoptera: Tortricidae) Biotypes Using Infrared Spectroscopy. AB - The aim of this study was to determine the differences between two Grapholita molesta (Busk) populations by applying infrared spectroscopy. Grapholita molesta populations were collected from different regions within Porto Amazonas, Brazil, and Emilia Romagna, Italy. Eggs, fifth instars, pupae, and adults were examined. Pupae and adults were sexed. A spectrophotometer that was set between 400 and 4000 cm(-1) range was used to perform 32 scans. The spectra obtained were analyzed using partial least squares (PLS), and external validation of the model was conducted with Unscrambler(TM) software, Version 9.1 (CAMO Software AS, Oslo, Norway). The results showed the differences between the populations in all of the analyzed stages of maturation. The pupal stage was the most viable stage for reading the beam spectrum, and it was concluded that IR can separate G. molesta biotypes. PMID- 26013132 TI - Environmental determinants on the assemblage structure of Drosophilidae flies in a temperate-subtropical region. AB - The species composition and the relative abundance of species in an insect community can vary in time and space for many reasons, including climatic variables and habitat preferences. Drosophilids were collected each quarter from April 2011 to April 2012 (five collections in all) in a natural area of the Pampa biome, considering three environments: open field, forest edge and the interior of forest patches. Kruskal-Wallis and chi-square tests were used to examine the effects of temporal and spatial components on the drosophilid assemblage. Four diversity measures: S obs , S rar , H' and E var were used to evaluate the community structure. A total of 7164 drosophilids belonging to 51 species were collected. The interaction of species in each environment varied among sampling periods. The abundance of both Neotropical and exotic species was affected by temporal and spatial components. The species of the D. repleta group were predominantly more abundant in the open field, but they migrated to the forest patches during periods of thermal stress. Generally, diversity was greatest in the interior of forest patches. Nevertheless, temporal components appear to be the predominant environmental determinant of the characteristics of the drosophilid community of the Pampas. Furthermore, the forest patches appear to act as a center of recolonization, reinforcing their importance in the maintenance of biodiversity in the Pampas; this function will be even more important in the future, when the temperatures will, most likely, be higher. PMID- 26013133 TI - Are Horn Morphological Patterns Able to Differentiate the Two Closely Related Species Copris klugi Harold and Copris sierrensis Matthews? AB - Several thousand species of beetles evolved impressive, exaggerated horns or horn like structures. The horn phenotypic patterns and the developmental mechanisms are well documented especially in the Scarabaeidae, the family most predominated by species with horns. The regulation of horn expression appears to be extremely evolutionary labile to the extent that horn allometric patterns have been seen to rapidly diverge between closely related species. For this reason, it has been suggested that horn morphological pattern may be able to differentiate closely related and sibling species even when other traits fail. In this study, we used horn morphological pattern (shape and allometric variation) as a "tool" to evaluate the differentiation of two closely related scarab species, Copris klugi Harold and Copris sierrensis Matthews whose full species status has long been debated due to their high similarity. Combining traditional and geometric morphometric methods, we evidenced that male head horn phenotypic pattern is able to clearly differentiate C. klugi from C. sierrensis, supporting the hypothesis that they are two true species. PMID- 26013134 TI - Influence of Constant Temperature on Development and Reproduction of Encarsia guadeloupae Viggiani (Hymenoptera: Aphelinidae), a Parasitoid of the Spiraling Whitefly Aleurodicus dispersus Russell (Hemiptera: Aleyrodidae). AB - Encarsia guadeloupae Viggiani is an important parasitoid of Aleurodicus dispersus Russell. The effects of temperature (16, 20, 24, 28, and 32 degrees C) on development and reproduction of this parasitoid on A. dispersus were studied in laboratory experiments. The developmental duration of E. guadeloupae varied from 14.9 (32 degrees C) to 54.4 days (16 degrees C). The developmental threshold and thermal constant for an entire generation were 10.52 degrees C and 308.85 degree days, respectively. The highest survival rate (63.8%) of immature E. guadeloupae was recorded at 28 degrees C. The average adult longevity ranged from 6.0 (32 degrees C) to 15.1 days (16 degrees C). The highest fecundity was observed at 28 degrees C. The intrinsic rate of increase (r m ), net reproduction rate (R o ), and finite rate of increase (lambda) were the highest at 28 degrees C, which were 0.18, 54.25 and 1.21, respectively. We concluded that 28 degrees C is the most suitable temperature for development and reproduction of E. guadeloupae. PMID- 26013135 TI - Foraging Allocation in the Honey Bee, Apis mellifera L. (Hymenoptera, Apidae), Tuned by the Presence of the Spinosad-Based Pesticide GF-120. AB - Agroecosystem management commonly involves the use of pesticides. As a result, a heterogeneous landscape is created, in which suitable and unsuitable spaces are defined by the absence/presence of pesticides. In this study, we explored how foragers of the honey bee, Apis mellifera L., adapt to such context. We specifically evaluated the effect of GF-120, a spinosad-based fruit fly toxic bait, on the allocation of foragers between food sources under the hypothesis that foragers will move from food sources with GF-120 to food sources without it. We thus carried out three experiments: in experiment 1, a group of foragers was trained to collect honey solution from a feeder; next, this feeder offered a GF 120/honey solution. A minority of foragers continued collecting the GF-120/honey solution. In experiment 2, we trained two groups of foragers from a colony to two food sources equally rewarding. Next, GF-120 was added to one of the food sources. We found that the majority of foragers moved from the GF-120-treated feeder to the feeder without GF-120 and that the minority that continued visiting the GF-120-treated feeder did not collect the GF-120/honey solution. In a third experiment, we wanted to know if foragers in an experimental setup as in experiment 1 would perform waggle dances: none of the foragers that collected GF 120/honey were observed dancing. Our results emphasize the importance of "food refuges" for non-target species, since they minimize the impact of agrochemicals upon them. PMID- 26013136 TI - Formulations of Melia azedarach to Control Diabrotica speciosa (Germar) (Coleoptera: Chrysomelidae) Larvae in Corn and Plant Enhancement. AB - We evaluated oil and powder formulations of Melia azedarach for controlling larvae of Diabrotica speciosa (Germar) in corn and plant enhancement. Five concentrations of each formulation were evaluated and compared to fipronil (negative control) and distilled water (positive control). After treatment, the number of surviving insects (larvae, pupae, and adults), the adult body weight, the sex ratio, and the longevity were recorded, while the height, dry weight of aerial part and roots, and number of leaves of plants were measured. The oil formulation at 4.0 mL reduced the larvae population of D. speciosa similarly to the insecticide fipronil, which resulted in greater height, dry weight of the root system, and number of leaves. Powder formulation at concentrations of 40, 80, and 160 mg caused larval mortality above 80%; however, these concentrations did not prevent reduction of plant height and dry weight of aerial part. Further studies assessing the residual period of M. azedarach control against D. speciosa larvae and its phytotoxicity, which are common traits associated with azadirachtin application, are necessary to subsidize the next steps of this alternative control strategy. PMID- 26013137 TI - Subterranean termites in urban forestry: tree preference and management. AB - Urban tree deterioration is a common problem all over the world. Inappropriate plant species choice and inadequate planting may lead to micro and macro organism attacks, such as pests and diseases. Subterranean termite damage is common and may promote tree falls. In order to help urban forestry planning, this work was carried out for 9 years on 1477 street trees in a neighborhood in the city of Sao Paulo, Brazil. Plants were identified to species, grouped as native, exotic plants, and palm trees, and their measures of circumference at breast height (CBH) were taken, in order to evaluate if subterranean termite damages are related to tree size and plant group. Four subterranean termite species were identified infesting up to 27% of the plants, with Coptotermes gestroi (Wasmann) being the most common. Palm trees were not damaged by subterranean termites, while native plants are the most susceptible, especially Caesalpinia pluviosa var. peltophoroides (Fabaceae). Among the native plants monitored C. pluviosa var. peltophoroides, Caesalpinia ferrea var. leiostachya, Erythrina speciosa, Piptadenia gonoacantha (Fabaceae), Gochnatia polymorpha (Asteraceae), Tibouchina granulosa (Melastomataceae), and Handroanthus spp. (Bignoniaceae), the latter was the least damaged. Exotic plants were also susceptible with the exception of Lagerstroemia indica (Lythraceae) and Platanus acerifolia (Platanaceae). Correlation analysis showed that the higher the CBH value, the higher the percentage of internal damage by C. gestroi. Infested trees were treated with imidacloprid and thiamethoxam, and subterranean termites were effectively controlled during the 9-year study. PMID- 26013139 TI - New Records Reveal the Actual Distribution of Cratomelus meritus Gorochov (Orthoptera: Anostostomatidae), a Giant Red Cricket from Chile. AB - The geographic distribution of the red cricket Cratomelus meritus Gorochov had remained unknown until now due to mislabeling and lack of new records. The aim of this short communication is to uncover and establish the actual distribution of the species on the basis of new records and discuss potential biogeographic hypotheses about its distribution. PMID- 26013138 TI - Are Members of the Triatoma brasiliensis (Hemiptera, Reduviidae) Species Complex Able to Alter the Biology and Virulence of a Trypanosoma cruzi Strain? AB - Trypanosoma cruzi is the causative agent of Chagas disease, transmitted to humans and mammals by blood-sucking hemipteran insects belonging to the Triatominae subfamily. The two main genotypes of T. cruzi (TcI and TcII) differ in many characteristics concerning their genetic profile. Despite the extensive literature on vectors and the etiologic agent, several interactive aspects between these two elements of Chagas disease are still waiting to be further clarified. Here, biological and histological features resulting from the interaction between Albino Swiss mice and T. cruzi isolate PB913 after passages through vectors of the Triatoma brasiliensis species complex were evaluated. Comparing the four members of the T. brasiliensis species complex-Triatoma brasiliensis brasiliensis Neiva, Triatoma brasiliensis macromelasoma Galvao, Triatoma melanica Neiva & Lent, and Triatoma juazeirensis Costa & Felix-no significant differences in parasitemia of the infected mice were observed. At 20 days post-infection, the highest number of parasites was observed in the group of mice that were infected with parasites obtained from T. b. macromelasoma. Tropism of the parasites to different organs such as heart, bladder, and skeletal muscles followed by inflammatory cell infiltrates was observed with quantitative and qualitative differences. Even though the four members of the T. brasiliensis species complex differ in their geographical distribution, morphology, biology, ecology, and genetics, no significant influence on the parasitemia of the T. cruzi PB913 isolate was detected. After evaluation of the tissue samples, a higher pathogenicity of parasites obtained from T. b. brasiliensis was noticeable. PMID- 26013140 TI - Questionable effect of lavage for treatment of painful jaw movements at disc displacement without reduction: a 3-year randomised controlled follow-up. AB - The present randomised controlled study compared the 3-year outcome of local anaesthetics with anaesthetics and lavage in patients suffering from painful temporomandibular joint (TMJ) locking. The study included 45 patients referred for treatment of temporomandibular disorders (TMD) to the Department of Orofacial Pain and Jaw Function, Faculty of Odontology, Malmo University, Malmo, Sweden. All patients received a history questionnaire and clinical examination according to the Research Diagnostic Criteria for TMD, panoramic radiographs and magnetic resonance imaging at baseline. Twenty-five patients were randomised to anaesthetics alone and 20 patients to anaesthetics and lavage. Three years after treatment, we sent the 37 patients who were available for follow-up a questionnaire that evaluated pain intensity, physical and emotional functioning, and global improvement. Thirty-four patients responded. The primary outcome was defined as >= 30% pain relief. In an intention-to-treat analysis, 28 of 45 patients (62%) reported >= 30% pain relief at the follow-up. At 3 years, improvement in pain relief, physical functioning, emotional functioning and global improvement differed non-significantly between local anaesthetics and anaesthetics and lavage. Compared with baseline, significant improvements (P < 0.05) in pain intensity, physical functioning, emotional functioning and global changes had occurred in both groups after 3 years. Because outcome measurements in the local anaesthetics and lavage and the local anaesthetics groups differed non-significantly 3 years after treatment of painful TMJ disc displacement without reduction, use of lavage (50 mL saline) has an equivalent effect as local anaesthetics. PMID- 26013141 TI - Survival and prognostic factors for adrenocortical carcinoma: a single institution experience. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is aggressive, but rare tumours that have not been sufficiently studied. The aim of our study was to present the demographic and clinical characteristics of patients with ACC, to determine the overall survival rates, analyse the effect of prognostic factors on survival, as well as to identify favorable and unfavourable predictors of survival. METHOD: The study included 72 patients (42 women and 30 men) with ACC. We analysed the prognostic value of the demographic and clinical characteristics of the patients, tumour characteristics, therapy administered and survival rates. Kaplan-Meier survival curves and the log-rank test were used to estimate the overall and specific survival probabilities and the Cox regression model was used to identify independent prognostic factors for survival. RESULTS: The patients had mean age of 50 years. The 1-, 5-, and 10-year probabilities of survival in patients with ACC were 52.5 %, 41.1 %, and 16.4 %, respectively. The median survival time was 36 months. The results of multivariate Cox regression analysis showed that the presence of lymphatic metastases (HR = 7.37, 95 % CI = 2.31-23.48, p = 0.001) and therapy with mitotane (HR = 0.11, 95 % CI = 0.04-0.27, p = 0.001) were independent prognostic factors for survival. CONCLUSION: The presence of lymphatic metastasis is an unfavourable prognostic factor, while postoperative therapy with mitotane is a favorable prognostic factor for survival in patients with ACC. PMID- 26013142 TI - Effect of manual versus mechanically assisted manipulations of the thoracic spine in neck pain patients: study protocol of a randomized controlled trial. AB - BACKGROUND: Neck pain is a common musculoskeletal condition with a point prevalence of around 15% in males and 23% in females that often presents in physiotherapy practice. Physical therapy and/or manipulation therapy is generally the first management option for patients with mechanical neck pain. Physical therapists treat mechanical neck pain with a number of interventions including joint mobilization and/or manipulation, therapeutic exercises or education. However, manipulation of the cervical spine carries some risks. Treating the thoracic spine for neck pain is an alternative approach. Emerging evidence suggests that it may be effective for treating neck pain without the risks associated with cervical spine manipulation. A new electromechanical device has recently been developed and tested for delivering multiple high velocity, low amplitude thrust manipulations to the spine. This device incorporates both auditory and visual systems that provide real time feedback on the applied treatment. The objective of this study is to compare the short- and long-term effects of manual versus mechanically assisted manipulations of the thoracic spine for neck pain patients. METHODS/DESIGN: A 6-month, randomized controlled trial consisting of 54 patients with acute or chronic neck pain patients will be conducted. Patients with no signs of major pathology and with little or no interference with daily activities will be recruited. Three treatment sessions with 4-day intervals will be carried out. The patients will be randomly assigned to receive either manually performed manipulations or electromechanical manipulations at the thoracic spine. The primary outcome is pain intensity as measured by the Visual Analogue Pain Rating Scale. The secondary outcome measures are neck physical disability using the Neck Disability Index, quality of life measured by the European Quality of Life 5 Dimensions 5 Levels and patients' improvement using the Patient's Global Impression of Change Scale. DISCUSSION: It is expected that both interventions will improve neck pain. This would be a significant finding, as thoracic spine manipulation for neck pain does not carry the same risk of injury as cervical spine manipulation. In addition, the results may provide useful information about therapeutic options for health care providers and patients for the problem of neck pain. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88585962, registered January 2013. PMID- 26013143 TI - miR-375 gene dosage in pancreatic beta-cells: implications for regulation of beta cell mass and biomarker development. AB - MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased beta-cell and increased alpha-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal beta-cell mass and function. Selective re-expression of miR-375 in beta-cells of miR-375KO mice normalizes both, alpha- and beta-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of beta cells to the total plasma miR-375 levels. Only a small proportion (~1 %) of circulating miR-375 originates from beta-cells. Furthermore, acute and profound beta-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of beta-cell mass and provide in vivo evidence for release of miRNAs from pancreatic beta-cells. The small contribution of beta-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for beta-cell function but suggests a utility for the detection of acute beta-cell death for autoimmune diabetes. KEY MESSAGES: * Overexpression of miR-375 in beta-cells does not influence beta-cell mass and function. * Increased alpha-cell mass in miR-375KO arises secondarily to loss of miR-375 in beta-cells. * Only a small proportion of circulating miR-375 levels originates from beta-cells. * Acute beta-cell destruction results in measurable increases of miR-375 in the blood. Circulating miR-375 levels are not a biomarker for pancreatic beta-cell function. PMID- 26013144 TI - Second harmonic generation microscopy reveals altered collagen microstructure in usual interstitial pneumonia versus healthy lung. AB - BACKGROUND: It is not understood why some pulmonary fibroses such as cryptogenic organizing pneumonia (COP) respond well to treatment, while others like usual interstitial pneumonia (UIP) do not. Increased understanding of the structure and function of the matrix in this area is critical to improving our understanding of the biology of these diseases and developing novel therapies. The objectives herein are to provide new insights into the underlying collagen- and matrix related biological mechanisms driving COP versus UIP. METHODS: Two-photon second harmonic generation (SHG) and excitation fluorescence microscopies were used to interrogate and quantify differences between intrinsic fibrillar collagen and elastin matrix signals in healthy, COP, and UIP lung. RESULTS: Collagen microstructure was different in UIP versus healthy lung, but not in COP versus healthy, as indicated by the ratio of forward-to-backward propagating SHG signal (FSHG/BSHG). This collagen microstructure as assessed by FSHG/BSHG was also different in areas with preserved alveolar architecture adjacent to UIP fibroblastic foci or honeycomb areas versus healthy lung. Fibrosis was evidenced by increased col1 and col3 content in COP and UIP versus healthy, with highest col1:col3 ratio in UIP. Evidence of elastin breakdown (i.e. reduced mature elastin fiber content), and increased collagen:mature elastin ratios, were seen in COP and UIP versus healthy. CONCLUSIONS: Fibrillar collagen's subresolution structure (i.e. "microstructure") is altered in UIP versus COP and healthy lung, which may provide novel insights into the biological reasons why unlike COP, UIP is resistant to therapies, and demonstrates the ability of SHG microscopy to potentially distinguish treatable versus intractable pulmonary fibroses. PMID- 26013145 TI - Differential expression of four soybean bZIP genes during Phakopsora pachyrhizi infection. AB - Asian soybean rust (ASR), caused by the obligate biotrophic fungus Phakopsora pachyrhizi, is one of most important diseases in the soybean (Glycine max (L.) Merr.) agribusiness. The identification and characterization of genes related to plant defense responses to fungal infection are essential to develop ASR resistant plants. In this work, we describe four soybean genes, GmbZIP62, GmbZIP105, GmbZIPE1, and GmbZIPE2, which encode transcription factors containing a basic leucine zipper (bZIP) domain from two divergent classes, and that are responsive to P. pachyrhizi infection. Molecular phylogenetic analyses demonstrated that these genes encode proteins similar to bZIP factors responsive to pathogens. Yeast transactivation assays showed that only GmbZIP62 has strong transactivation activity in yeast. In addition, three of the bZIP transcription factors analyzed were also differentially expressed by plant defense hormones, and all were differentially expressed by fungal attack, indicating that these proteins might participate in response to ASR infection. The results suggested that these bZIP proteins are part of the plant defense response to P. pachyrhizi infection, by regulating the gene expression related to ASR infection responses. These bZIP genes are potential targets to obtain new soybean genotypes resistant to ASR. PMID- 26013146 TI - CORR Insights((r)): Time-driven Activity-based Costing More Accurately Reflects Costs in Arthroplasty Surgery. PMID- 26013147 TI - Knee Society Award Papers Are Highly Cited Works. AB - BACKGROUND: Since 1993, The Knee Society has presented three annual awards recognizing the best research papers presented at the annual meetings. To date, no quantitative evaluation has determined whether the selection process identifies the most meritorious papers based on subsequent citations. In the absence of validation of this process, it is unclear whether the journal readership should view the award-winning papers as those with potentially greater impact for the specialty. QUESTIONS/PURPOSES: (1) Are award papers cited both more than nonaward papers published in the same Knee Society proceedings issue of CORR((r)) and more than all other knee research papers published in all issues of CORR((r)) during any given year? (2) Does the award selection process identify potentially highly influential knee research? METHODS: Subsequent citations for each award and nonaward paper published in The Knee Society proceedings issue for 2002 to 2008 were determined using the SCOPUS citation index. The citations for all papers on knee surgery published in CORR((r)) during the same years were also determined. RESULTS: Mean citations for an award paper were statistically greater than for a nonaward paper: 86 (SD 95; median 55; 95% confidence interval [CI] of the mean, 44-128) versus 33 (SD 30; median 24; 95% CI of the mean, 28-37; p < 0.001). Mean number of citations for award papers was also higher than for all other knee research papers published in nonproceedings issues of CORR((r)): 86 (SD 95; median 55; 95% CI of the mean, 44-128) versus 30 (SD 31; median 20; 95% CI for the mean, 25-35; p < 0.001). Twelve of the 22 (54.6%) award papers were in the top five cited papers from the proceedings issue for the respective year versus 24 of the 190 (12.6%) of the nonaward papers (difference in the percentages is 41.9% and the 95% CI for the risk difference is 20.6%-63.3%; p < 0.001). In 3 of 7 years, an award paper was the most cited knee paper published in CORR((r)). CONCLUSIONS: The selection process for The Knee Society scientific awards identifies potentially influential papers that are likely to be highly cited in future research articles about the knee. CLINICAL RELEVANCE: The selection process for Knee Society Award Papers appears to identify papers that are potentially influential in the field of knee surgery and are likely to be highly cited in future published articles. As such, these award papers deserve special attention from the readership. PMID- 26013148 TI - CORR Insights(r): Does Combined Intra- and Extraarticular ACL Reconstruction Improve Function and Stability? A Meta-analysis. PMID- 26013149 TI - Intraoperative synovial C-reactive protein is as useful as frozen section to detect periprosthetic hip infection. AB - BACKGROUND: Synovial quantification of C-reactive protein (SCRP) has been recently published with high sensitivity and specificity in the diagnosis of periprosthetic joint infection. However, to our knowledge, no studies have compared the use of this test with intraoperative frozen section, which is considered by many to be the best intraoperative test now available. QUESTIONS/PURPOSES: We asked whether intraoperative SCRP could lead to comparable sensitivity, specificity, and predictive values as intraoperative frozen section in revision total hip arthroplasty. METHODS: A prospective study was performed including 76 patients who underwent hip revision for any cause. SCRP quantification (using 9.5 mg/L as denoting infection) and the analysis of frozen section of intraoperative samples (five or more polymorphonuclear leukocytes under high magnification in 10 fields) were performed in all the patients. The definitive diagnosis of an infection was determined according to the Musculoskeletal Infection Society (MSIS). In this group, 30% of the patients were diagnosed with infection using the MSIS criteria (23 of 76 patients). RESULTS: With the numbers available, there were no differences between SCRP and frozen section in terms of their ability to diagnose infection. The sensitivity of SCRP was 90% (95% confidence interval [CI], 70.8%-98.6%), the specificity was 94% (95% CI, 84.5%-98.7%), the positive predictive value was 87% (95% CI, 66.3%-97%), and the negative predictive value was 96% (95% CI, 87%-99.4%); the sensitivity, specificity, positive predictive value, and negative predictive value were the same using frozen sections to diagnose infection. The positive likelihood ratio was 16.36 (95% CI, 5.4-49.5), indicating a low probability of an individual without the condition having a positive test, and the negative likelihood ratio was 0.10 (95% CI, 0.03-0.36), indicating low probability of an individual without the condition having a negative test. CONCLUSIONS: We found that quantitative SCRP had similar diagnostic value as intraoperative frozen section with comparable sensitivity, specificity, and predictive value in a group of patients undergoing revision total hip arthroplasty. In our institution, SCRP is easier to obtain, less expensive, and less dependent on the technique of obtaining and interpreting a frozen section. If our findings are confirmed by other groups, we suggest that quantitative SCRP be considered as a viable alternative to frozen section. LEVEL OF EVIDENCE: Level I, diagnostic study. PMID- 26013150 TI - What Risk Factors Are Associated With Musculoskeletal Injury in US Army Rangers? A Prospective Prognostic Study. AB - BACKGROUND: Musculoskeletal injury is the most common reason that soldiers are medically not ready to deploy. Understanding intrinsic risk factors that may place an elite soldier at risk of musculoskeletal injury may be beneficial in preventing musculoskeletal injury and maintaining operational military readiness. Findings from this population may also be useful as hypothesis-generating work for particular civilian settings such as law enforcement officers (SWAT teams), firefighters (smoke jumpers), or others in physically demanding professions. QUESTIONS/PURPOSES: The purposes of this study were (1) to examine whether using baseline measures of self-report and physical performance can identify musculoskeletal injury risk; and (2) to determine whether a combination of predictors would enhance the accuracy for determining future musculoskeletal injury risk in US Army Rangers. METHODS: Our study was a planned secondary analysis from a prospective cohort examining how baseline factors predict musculoskeletal injury. Baseline predictors associated with musculoskeletal injury were collected using surveys and physical performance measures. Survey data included demographic variables, injury history, and biopsychosocial questions. Physical performance measures included ankle dorsiflexion, Functional Movement Screen, lower and upper quarter Y-balance test, hop testing, pain provocation, and the Army Physical Fitness Test (consisting of a 2-mile run and 2 minutes of sit-ups and push-ups). A total of 320 Rangers were invited to enroll and 211 participated (66%). Occurrence of musculoskeletal injury was tracked for 1 year using monthly injury surveillance surveys, medical record reviews, and a query of the Department of Defense healthcare utilization database. Injury surveillance data were available on 100% of the subjects. Receiver operator characteristic curves and accuracy statistics were calculated to identify predictors of interest. A logistic regression equation was then calculated to find the most pertinent set of predictors. Of the 188 Rangers (age, 23.3 +/- 3.7 years; body mass index, 26.0 +/- 2.4 kg/m(2)) remaining in the cohort, 85 (45.2%) sustained a musculoskeletal injury of interest. RESULTS: Smoking, prior surgery, recurrent prior musculoskeletal injury, limited-duty days in the prior year for musculoskeletal injury, asymmetrical ankle dorsiflexion, pain with Functional Movement Screen clearing tests, and decreased performance on the 2-mile run and 2 minute sit-up test were associated with increased injury risk. Presenting with one or fewer predictors resulted in a sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.95), and having three or more predictors resulted in a specificity of 0.98 (95% CI, 0.93-0.99). The combined factors that contribute to the final multivariable logistic regression equation yielded an odds ratio of 4.3 (95% CI, 2.0-9.2), relative risk of 1.9 (95% CI, 1.4-2.6), and an area under the curve of 0.64. CONCLUSIONS: Multiple factors (musculoskeletal injury history, smoking, pain provocation, movement tests, and lower scores on physical performance measures) were associated with individuals at risk for musculoskeletal injury. The summation of the number of risk factors produced a highly sensitive (one or less factor) and specific (three or more factors) model that could potentially be used to effectively identify and intervene in those persons with elevated risk for musculoskeletal injury. Future research should establish if screening and intervening can improve musculoskeletal health and if our findings among US Army Rangers translate to other occupations or athletes. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 26013151 TI - A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis. AB - BACKGROUND: Because immunity against Staphylococcus aureus has not been fully elucidated, there is no diagnostic test to gauge how robust a patient's host response is likely to be. Therefore, we aimed to develop a test for specific antibodies in serum with diagnostic and prognostic potential. QUESTIONS/PURPOSES: We describe the development and validation of a multiplex immunoassay for characterizing a patient's immune response against 14 known S aureus antigens, which we then used to answer four questions: (1) Do certain antigens predominate in the immune response against S aureus? (2) Is there a predominant pattern of antigens recognized by patients and mice with infections? (3) Is the immunoglobulin G (IgG) response to any single antigen a useful predictor of ongoing S aureus infection? (4) Does measurement of the combined response against all 14 antigens provide a better predictor of ongoing infection? METHODS: A case control study was performed. Sera were collected from 35 consecutive patients with S aureus culture-confirmed (methicillin-sensitive S aureus or methicillin resistant S aureus) musculoskeletal infections (deep implant-associated, osteomyelitis, and cases of established septic arthritis). Patients were excluded only if they did not give informed consent for participation. Twenty-four patients had implant infections after total joint replacements, five had fracture implant infections, four had native knee infections, and two had chronic osteomyelitis without an implant. Control patients were chosen from a group of healthy, medically optimized patients scheduled to undergo elective arthroplasty. Control patients were matched for age (+/- 3 years), BMI (+/- 3 kg/m(2)), and sex as closely as possible to patients with infections. Sera from patients with S aureus infections and murine S aureus tibial implant infections were used to evaluate a multiplex immunoassay for immunoglobulin titers against 14 recombinant S aureus antigens. All patients were treated with organism-targeted antibiotic therapy and appropriate, timely surgery. Treatment response was monitored with clinical examination, erythrocyte sedimentation rate, C-reactive protein, and resampling of the infection site for the pathogen as needed. Elevated inflammatory markers or persistent positive culture results were considered evidence of ongoing infection. Treatment provided was considered standard-of-care therapy in our medical center and all patients were treated jointly with a board certified infectious disease specialist. RESULTS: Four antigens elicited more than 65% of the measurable IgG, the most dominant being against iron-regulated surface determinant protein B (IsdB). Patients with infections had different patterns of elevated IgG titers, so that no single titer was elevated in more than 50% of patients with infections (area under the curve [AUC] <= 0.80). Multivariate analysis of IgG titers yielded greater predictive power of S aureus infection (AUC = 0.896). Patients with infections who had high titers against IsdB (median of survivors, 7.28 [25%-75% range, 2.22-21.26] vs median of patients with infection-related death, 40.41 [25%-75% range, 23.57-51.37], difference of medians, 33.13; p = 0.043) and iron-regulated surface determinant protein A (IsdA) median of survivors, 2.21 [25%-75% range, 0.79-9.11] vs median of patients with infection-related death, 12.24 [25%-75% range, 8.85-15.95], difference of medians, 10.03; p = 0.043) were more likely to die from infections than those who did not have high titers of IsdB. CONCLUSIONS: Measurement of the host antibody response is a predictor of ongoing infection that may prove to have prognostic value. Future studies will seek to enlarge the patient population with infections to allow us to reduce the number of antigens required to achieve a stronger predictive power. CLINICAL RELEVANCE: Measurement of the immune response against S aureus with this diagnostic tool may help guide future studies on prophylaxis and therapy in an era of personalized medicine and pathogen-specific therapies. PMID- 26013152 TI - High Survivorship With Cementless Stems and Cortical Strut Allografts for Large Femoral Bone Defects in Revision THA. AB - BACKGROUND: Numerous studies have investigated the clinical and radiographic results of revision THAs with use of cementless stems and cortical strut allografts. However, to our knowledge, no long-term followup studies have evaluated patients undergoing revision THA with use of cortical strut allografts where the allografts provided the primary stability for extensively coated femoral stems in the presence of extensive femoral diaphyseal bone defects. QUESTION/PURPOSES: We performed this study to determine (1) validated outcomes scores; (2) radiographic signs of fixation and allograft healing; (3) frequency of complications; and (4) survivorship of the components after use of cortical strut onlay allografts in Types IIIB and IV femoral diaphyseal bone defects. METHODS: Between 1994 and 2003, we performed 140 revision THAs in 130 patients with Paprosky Types IIIB and IV femoral diaphyseal defects. The patients were treated using extensively coated femoral stems and cortical strut allografts because primary axial or rotational stability could not be achieved without grafting. Ten of the patients (10 hips; 7.7%) were lost to followup or died before 10 years; the remaining 120 patients (130 hips) represent the study group in this retrospective study. There were 66 men and 54 women. Their mean age at the time of index surgery was 59 +/- 18 years (range, 36-67 years). The primary diagnosis was predominantly osteonecrosis of the femoral head (53%). The most common reason for revision was aseptic loosening (97%), followed by periprosthetic fracture (3%). The mean time from primary to revision THA was 12 years (range, 8-27 years). The mean duration of followup was 16.1 years (range, 12-20 years). RESULTS: The mean Harris hip score was 39 +/- 10 points before revision and improved to 86 +/- 14 points at 16 years followup (p = 0.02). The mean preoperative WOMAC score was 62 +/- 29 (41-91) points and improved to 22 +/- 19 (11-51) points at 16 years followup (p = 0.003). Of the 130 stems, 113 (87%) had bone ingrowth, five (4%) had stable fibrous ingrowth, and 12 (9%) were unstable. All allografts were incorporated. Four hips (3%) had a displaced femoral shaft fracture at the stem tip; four (3%) had a postoperative dislocation; and six (5%) had early postoperative infection. Kaplan-Meier survivorship analysis, with revision or radiographic failure as the endpoint, revealed that the 16-year rate of survival of the components was 91% (95% CI, 0.88%-0.96%). CONCLUSION: Supportive cortical strut onlay allografts provided high survivorship beyond 12 years of followup in revision THAs. Future studies might compare this approach with allograft-prosthesis composites, proximal femoral replacement, or modular fluted, tapered stems. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26013153 TI - Do Surgical Margins Affect Local Recurrence and Survival in Extremity, Nonmetastatic, High-grade Osteosarcoma? AB - BACKGROUND: Long-term survival for all patients with osteosarcoma using current aggressive adjuvant chemotherapy and surgical resection is between 60% and 70%. In patients who present with nonmetastatic, high-grade extremity osteosarcoma of bone, limb salvage surgery is favored, when appropriate, over amputation to preserve the limb, because limb salvage may lead to a superior quality of life compared with amputation. However, concern remains that in the attempt to preserve the limb, close or microscopically positive surgical margins may have an adverse effect on event-free survival. QUESTIONS/PURPOSES: (1) Does a positive or close surgical margin increase the likelihood of a local recurrence? (2) Does a positive or close surgical margin adversely affect the development of metastatic disease? (3) What is the relationship of surgical margin on overall survival? METHODS: With institutional review board approval, we retrospectively evaluated 241 patients treated at our institution between 1999 and 2011. Exclusion criteria included nonextremity locations, metastatic disease at initial presentation, low- or intermediate-grade osteosarcoma, treatment regimens that did not follow National Comprehensive Cancer Network (NCCN) guidelines, incomplete medical records, and any part of treatment performed outside of Moffitt Cancer Center or All Children's Hospital. Fifty-one patients were included in the final analysis, of whom 31 (61%) had followup data at a minimum of 2 years or whose clinical status was known but had died before 2 years of followup. Margin status was defined as (1) microscopically positive; (2) negative <= 1 mm; and (3) negative > 1 mm. Margin status, histologic response (tumor percent necrosis), type of osteosarcoma, type of surgery, presence of local recurrence, metastatic disease, and overall survival were recorded for each patient. The mean age was 22 years (range, 12-74 years) and the mean followup was 3 years (range, 0.1-14 years). Margin status was positive in 10% (five of 51), negative <= 1 mm 26% (13 of 51), and negative > 1 mm 65% (33 of 51). RESULTS: Local recurrence was noted to be 14% (seven of 51) at 3.4 years. After controlling for relevant confounding variables, the presence of a positive margin compared with a negative margin > 1 mm was the only independent predictor of local recurrence (hazard ratio [HR], 8.006; 95% confidence interval [CI], 1.314-48.781; p = 0.0241). At a mean of 3.4 years, 29% (15 of 51) of the patients developed metastatic disease with no difference with the numbers available in the probability of developing metastatic disease among the three margin groups (p = 0.614). Overall survival at 3.8 years was 75% (38 of 51). After controlling for relevant confounding variables, we found that patients with positive margins were more likely to die from disease than those with negative margins (HR, 6.26; 95% CI, 1.50-26.14; p = 0.0119); no other independent predictors of survival were identified. CONCLUSIONS: With the numbers of patients we had, we observed that patients with extremity, nonmetastatic, high-grade osteosarcoma who had positive margins showed a higher probability of local recurrence in comparison to those with negative surgical margins. Given that positive margins appear to be associated with poorer survival in patients with high-grade osteosarcoma of the extremities, surgeons should strive to achieve negative margins, but larger studies are needed to confirm these findings. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26013154 TI - CORR Insights((r)): acetate templating on digital images is more accurate than computer-based templating for total hip arthroplasty. PMID- 26013156 TI - Ion adsorption-induced wetting transition in oil-water-mineral systems. AB - The relative wettability of oil and water on solid surfaces is generally governed by a complex competition of molecular interaction forces acting in such three phase systems. Herein, we experimentally demonstrate how the adsorption of in nature abundant divalent Ca(2+) cations to solid-liquid interfaces induces a macroscopic wetting transition from finite contact angles (~ 10 degrees ) with to near-zero contact angles without divalent cations. We developed a quantitative model based on DLVO theory to demonstrate that this transition, which is observed on model clay surfaces, mica, but not on silica surfaces nor for monovalent K(+) and Na(+) cations is driven by charge reversal of the solid-liquid interface. Small amounts of a polar hydrocarbon, stearic acid, added to the ambient decane synergistically enhance the effect and lead to water contact angles up to 70 degrees in the presence of Ca(2+). Our results imply that it is the removal of divalent cations that makes reservoir rocks more hydrophilic, suggesting a generalizable strategy to control wettability and an explanation for the success of so-called low salinity water flooding, a recent enhanced oil recovery technology. PMID- 26013155 TI - How Does the Level of Sacral Resection for Primary Malignant Bone Tumors Affect Physical and Mental Health, Pain, Mobility, Incontinence, and Sexual Function? AB - BACKGROUND: En bloc resection for treatment of sacral tumors is the approach of choice for patients with resectable tumors who are well enough to undergo surgery, and studies describe patient survival, postoperative complications, and recurrence rates associated with this treatment. However, most of these studies do not provide patient-reported functional outcomes other than binary metrics for bowel and bladder function postresection. QUESTIONS/PURPOSES: The purpose of this study was to use validated patient-reported outcomes tools to compare quality of life based on level of sacral resection in terms of (1) physical and mental health; (2) pain; (3) mobility; and (4) incontinence and sexual function. METHODS: Our analysis included 33 patients (19 men, 14 women) who had a mean age of 53 years (range, 22-72 years) with a quality-of-life survey administered at a mean postoperative followup of 41 months (range, 6-123 months). The majority of patient-reported quality-of-life outcome surveys for this study were taken from the National Institute of Health's Patient Reported Outcome Measurement Information System (PROMIS) system. To assess physical and mental health, the PROMIS Global Items Survey with physical and mental subscores, Anxiety, and Depression scores were used. Pain outcomes were assessed using PROMIS Pain Intensity and Pain Interference surveys. Patient-reported lower extremity function was assessed using the PROMIS Mobility Survey. Patient-reported quality of life for sexual function was assessed using the PROMIS Sex Interest and Orgasm survey, whereas incontinence was measured using the International Continence Society Voiding and Incontinence scores and the Modified Obstruction and Defecation Score. Surveys were collected prospectively during clinic visits in the postoperative period. Patients were grouped by the level of osteotomy as determined by review of postoperative MRI or CT and half levels were grouped with the more cephalad level. This resulted in the inclusion of total sacrectomy (N = 6), S1 (N = 8), S2 (N = 10), S3 (N = 5), and S4 (N = 4). One-way analysis of variance tests on means or ranks were used to conduct statistical analysis between levels. RESULTS: Patients with more caudal resections had higher physical health (95% confidence interval [CI] total sacrectomy 36-42 versus S4 50-64, p < 0.001), less intense pain (95% CI total sacrectomy 47-60 versus S4 28-37, p < 0.001), less interference resulting from pain (95% CI total sacrectomy 58-69 versus S4 36-51, p = 0.004), higher mobility (95% CI total sacrectomy 24-46 versus S4 59-59, p = 0.002), and were more functionally able to achieve orgasm (95% CI S1 1-1 versus S4 2.2-5.3, p = 0.043). No difference was found for PROMIS Global Item Mental Health Subscore, Sex Interest, Sex Satisfaction, modified obstruction and defecation score, and International Continence Society Voiding and Incontinence although this could be the result of an inadequate sample size. CONCLUSIONS: Our analysis on patient-reported quality of life based on the level of bony resection in patients who underwent resection for primary sacral tumor indicates that patients with higher resections have more pain and loss of physical function in comparison to patients with lower resections. Additionally, use of the PROMIS outcomes allows for comparisons to normative data. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26013157 TI - Appropriateness of ICNP in Korean home care nursing. AB - OBJECTIVES: There are several hospitals in Korea that introduced the ICNP (International Classification for Nursing Practice) as the standard terminology for clinical and home care nursing. This research attempted to determine the appropriateness of ICNP in Korean, hospital based, home care nursing. METHODS: The data was collected from a home care nursing center from January 1, 2009 to September 21, 2012. The center is operated by a Korean teaching hospital equipped with an ICNP based electronic nursing record (ENR) system. Via a refining process, 40,082 simplified sentences of nursing intervention were acquired from 41,158 nursing records. Among them, 545 preferred nursing statements were extracted, then mapped, to ICNP 2011 at both axis and sentence levels. RESULTS: The mapping results were classified into three categories based on the axis of concept origin and the level of hierarchy. These categories were titled: complete, incomplete and no mapping. Out of 45 unique concepts in the action axis, 42 (93.33%) concepts were completely mapped. However, only 38 (15.08%), out of 252 unique concepts, were completely mapped in the focus axis. At the statement level, only 19.63% of statements were completely mapped. CONCLUSIONS: The ICNP is not useful as a tool for home care nursing in its present form. The granularity of ICNP has to be improved and more concepts, specific to home care nursing, need to be added in the focus and action axes. Also, a new measure needs to be introduced to prevent information loss during mapping. PMID- 26013158 TI - Enrichment of protein N-termini by charge reversal of internal peptides. AB - Protein N-termini provide useful information for the understanding of posttranslational processing of proteins. The majority of proteins undergo N terminal processing, such as proteolytic truncation or modifications like acetylation. Multiple methods currently exist for the enrichment of N-terminal peptides for proteomic analyses. Here, we report a novel, simple, and straightforward N-terminomic strategy, based on charge reversal of internal peptides followed by their removal through strong cation exchange chromatography. Our initial proof-of-concept study shows the feasibility of this technique, yielding over 3000 identifications of protein N-termini. We further show the application of this strategy in investigating the N-terminome of mouse embryonic fibroblasts cells deficient for both cathepsin B and L in comparison to wild type) control cells. Finally, we demonstrate that this workflow can be used in combination with a gel-based strategy, allowing preseparation of proteins and thus providing an estimate of the molecular weight of the identified cleavage products. PMID- 26013159 TI - The amount effect and marginal value. AB - The amount effect of delay discounting (by which the value of larger reward amounts is discounted by delay at a lower rate than that of smaller amounts) strictly implies that value functions (value as a function of amount) are steeper at greater delays than they are at lesser delays. That is, the amount effect and the difference in value functions at different delays are actually a single empirical finding. Amount effects of delay discounting are typically found with choice experiments. Value functions for immediate rewards have been empirically obtained by direct judgment. (Value functions for delayed rewards have not been previously obtained.) The present experiment obtained value functions for both immediate and delayed rewards by direct judgment and found them to be steeper when the rewards were delayed--hence, finding an amount effect with delay discounting. PMID- 26013160 TI - Ligand Symmetry Modulation for Designing a Mesoporous Metal-Organic Framework: Dual Reactivity to Transition and Lanthanide Metals for Enhanced Functionalization. AB - A promising alternative strategy for designing mesoporous metal-organic frameworks (MOFs) has been proposed, by modifying the symmetry rather than expanding the length of organic linkers. By means of this approach, a unique MOF material based on the target [Zn8(ad)4] (ad = adeninate) clusters and C3 symmetric organic linkers can be obtained, with trigonal microporous (ca., 0.8 nm) and hexagonal mesoporous (ca., 3.0 nm) 1D channels. Moreover, the resulting 446-MOF shows distinct reactivity to transition and lanthanide metal ions. Significantly, the transmetalation of Co(II) or Ni(II) on the Zn(II) centers in 446-MOF can enhance the sorption capacities of CO2 and CH4 (16-21%), whereas the impregnation of Eu(III) and Tb(III) in the channels of 446-MOF will result in adjustable light-emitting behaviors. PMID- 26013161 TI - Refugial isolation and range expansions drive the genetic structure of Oxyria sinensis (Polygonaceae) in the Himalaya-Hengduan Mountains. AB - The formation of the Mekong-Salween Divide and climatic oscillations in Pleistocene were the main drivers for the contemporary diversity and genetic structure of plants in the Himalaya-Hengduan Mountains (HHM). To identify the relative roles of the two historical events in shaping population history of plants in HHM, we investigated the phylogeographic pattern of Oxyria sinensis, a perennial plant endemic to the HHM. Sixteen chloroplast haplotypes were identified and were clustered into three phylogenetic clades. The age of the major clades was estimated to be in the Pleistocene, falling into several Pleistocene glacial stages and postdating the formation of the Mekong-Salween Divide. Range expansions occurred at least twice in the early and middle Pleistocene, but the spatial genetic distribution rarely changed since the Last Glacial Maximum. Our results suggest that temporary mountain glaciers may act as barriers in promoting the lineage divergence in O. sinensis and that subsequential range expansions and secondary contacts might reshape the genetic distribution in geography and blur the boundary of population differentiation created in the earlier glacial stages. This study demonstrates that Pleistocene climatic change and mountain glaciers, rather than the Mekong-Salween Divide, play the primary role in shaping the spatial genetic structure of O. sinensis. PMID- 26013162 TI - SRY and OCT4 Are Required for the Acquisition of Cancer Stem Cell-Like Properties and Are Potential Differentiation Therapy Targets. AB - The acquisition of stemness is a hallmark of aggressive human hepatocellular carcinoma (hHCC). The stem cell marker OCT4 is frequently expressed in HCCs, and its expression correlates with those of putative cancer stem cell (CSC) markers and CSC properties. Here, we describe a novel mechanism of CSC maintenance by SRY through OCT4. We previously reported that Sry is involved in tumor malignancy in rodent HCCs. However, the oncogenic function of SRY in hHCCs is poorly understood. Ectopic expression of SRY increased multiple stem cell factors, including OCT4 and CD13. The OCT4 promoter contained SRY-binding sites that were directly activated by SRY. In HCC-derived cells, SRY knockdown decreased OCT4 expression and cancer stem-like phenotypes such as self-renewal, chemoresistance, and tumorigenicity. Conversely, OCT4 and SRY overexpression promoted cancer stem like phenotypes. OCT4 knockdown in SRY clones downregulated the self-renewal capacity and chemoresistance. These data suggest that SRY is involved in the maintenance of cancer stem-like characteristics through OCT4. Moreover, CSCs of HCC-derived cells differentiated into Tuj1-positive neuron-like cells by retinoic acid. Noteworthily, SRY was highly expressed in some hHCC patients. Taken together, our findings imply a novel therapeutic strategy against CSCs of hHCCs. PMID- 26013163 TI - Robust Antibody-Antigen Complexes Prediction Generated by Combining Sequence Analyses, Mutagenesis, In Vitro Evolution, X-ray Crystallography and In Silico Docking. AB - Hu 15C1 is a potent anti-human Toll-like receptor 4 (TLR4) neutralizing antibody. To better understand the molecular basis of its biological activity, we used a multidisciplinary approach to generate an accurate model of the Hu 15C1-TLR4 complex. By combining site-directed mutagenesis, in vitro antibody evolution, affinity measurements and X-ray crystallography of Fab fragments, we identified key interactions across the Hu 15C1-TLR4 interface. These contact points were used as restraints to predict the structure of the Fab region of Hu 15C1 bound to TLR4 using computational molecular docking. This model was further evaluated and validated by additional site-directed mutagenesis studies. The predicted structure of the Hu 15C1-TLR4 complex indicates that the antibody antagonizes the receptor dimerization necessary for its activation. This study exemplifies how iterative cycles of antibody engineering can facilitate the discovery of components of antibody-target interactions. PMID- 26013164 TI - Structure and Mechanism of Dimer-Monomer Transition of a Plant Poly(A)-Binding Protein upon RNA Interaction: Insights into Its Poly(A) Tail Assembly. AB - Poly(A)-binding proteins (PABPs) play crucial roles in mRNA biogenesis, stability, transport and translational control in most eukaryotic cells. Although animal PABPs are well-studied proteins, the biological role, three-dimensional structure and RNA-binding mode of plant PABPs remain largely uncharacterized. Here, we report the structural features and RNA-binding mode of a Citrus sinensis PABP (CsPABPN1). CsPABPN1 has a domain architecture of nuclear PABPs (PABPNs) with a single RNA recognition motif (RRM) flanked by an acidic N-terminus and a GRPF-rich C-terminus. The RRM domain of CsPABPN1 displays virtually the same three-dimensional structure and poly(A)-binding mode of animal PABPNs. However, while the CsPABPN1 RRM domain specifically binds poly(A), the full-length protein also binds poly(U). CsPABPN1 localizes to the nucleus of plant cells and undergoes a dimer-monomer transition upon poly(A) interaction. We show that poly(A) binding by CsPABPN1 begins with the recognition of the RNA-binding sites RNP1 and RNP2, followed by interactions with residues of the beta2 strands, which stabilize the dimer, thus leading to dimer dissociation. Like human PABPN1, CsPABPN1 also seems to form filaments in the presence of poly(A). Based on these data, we propose a structural model in which contiguous CsPABPN1 RRM monomers wrap around the RNA molecule creating a superhelical structure that could not only shield the poly(A) tail but also serve as a scaffold for the assembly of additional mRNA processing factors. PMID- 26013165 TI - Interventions to Improve the Quality of Outpatient Specialty Referral Requests: A Systematic Review. AB - Requests for outpatient specialty consultations occur frequently but often are of poor quality because of incompleteness. The authors searched bibliographic databases, trial registries, and references during October 2014 for studies evaluating interventions to improve the quality of outpatient specialty referral requests compared to usual practice. Two reviewers independently extracted data and assessed quality. Findings were qualitatively summarized for completeness of information relayed in a referral request within naturally emerging intervention categories. Of 3495 articles screened, 11 were eligible. All 3 studies evaluating software-based interventions found statistically significant improvements. Among 4 studies evaluating template/pro forma interventions, completeness was uniformly improved but with variable or unreported statistical significance. Of 4 studies evaluating educational interventions, 2 favored the intervention and 2 found no difference. One study evaluating referral management was negative. Current evidence for improving referral request quality is strongest for software-based interventions and templates, although methodological quality varied and findings may be setting specific. PMID- 26013166 TI - Psychometric properties of the Balance Computerized Adaptive Test in residents in long-term care facilities. AB - PURPOSE: To validate the psychometric properties and efficiency of the Balance Computerized Adaptive Testing (Balance CAT) when applied to residents in long term care (LTC) facilities. DESIGN AND METHODS: A cohort study was conducted in central Taiwan. The Balance CAT, the Berg Balance Scale (BBS), and the Barthel Index (BI) were administered to each participant with the ability to follow simple instructions by a trained rater in two days. The Pearson's correlation coefficient (r) was used to determine the concurrent validity of the Balance CAT. ANOVA and post hoc analysis were employed to investigate the discriminative ability of the Balance CAT. The paired t test was used to validate the efficiency. RESULTS: A total of 120 participants completed assessments of the Balance CAT, the BBS, and the Barthel Index (BI). The Pearson's r between the scores of the Balance CAT and the BBS was 0.90. Groups with different levels of dependence had significantly different mean scores of the Balance CAT. The mean IRT reliability of the Balance CAT scores was 0.93. The mean administration time of the Balance CAT was about 28% of that of the BBS, and the mean number of items used in the Balance CAT was 3.4. CONCLUSIONS: The Balance CAT had excellent concurrent and discriminative validity, reliability, and efficiency in residents of LTC facilities. These results indicate that the Balance CAT is a sound and practical measure for assessing the balance function of residents of LTC facilities. PMID- 26013167 TI - Group 9 Metal Complexes of meso-Aryl-Substituted Rubyrin. AB - The metalation of meso-tetrakis(pentafluorophenyl)-substituted [26]rubyrin has been explored with Group 9 metal salts (Rh(I) , Co(II) , Ir(III) ), affording a Huckel aromatic [26]rubyrin-bis-Rh(I) complex with a highly curved gable-like structure, a Huckel antiaromatic [24]rubyrin-bis-Co(II) complex that displays intramolecular antiferromagnetic coupling between the two Co(II) ions (J=-4.5 cm( 1) ), and two Cp*-capped Ir(III) complexes; in one, the iridium metal sits on the [26]rubyrin frame with two Ir?N bonds, whereas the other has an additional Ir?C bond, although both Ir(III) complexes display moderate aromatic character. This work demonstrates characteristic metalation abilities of this [26]rubyrin toward Group 9 metals. PMID- 26013168 TI - PTK6 Potentiates Gemcitabine-Induced Apoptosis by Prolonging S-phase and Enhancing DNA Damage in Pancreatic Cancer. AB - Protein Tyrosine Kinase 6 (PTK6) is a non-receptor-type tyrosine kinase known to be expressed in various cancers, including pancreatic cancer. The role of PTK6 in cancer chemoresistance remains unclear. Therefore, it was hypothesized that PTK6 mechanistically regulates gemcitabine resistance in pancreatic cancer. Gemcitabine treatment stimulated endogenous PTK6 overexpression in MIAPaCa2 and Panc1 cells. PTK6 gene silencing increased cell survival after gemcitabine treatment and decreased apoptosis, whereas PTK6 overexpression decreased cell survival and increased apoptosis. Selection for gemcitabine resistance revealed substantially lower PTK6 expression in the gemcitabine-resistant subclones compared with the parental lines, while restoring PTK6 rescued gemcitabine sensitivity. Gemcitabine induced phosphorylation of H2AX (gamma-H2AX) and ataxia telangiectasia mutated kinase (pATM), specific markers for DNA double-strand breaks. Both gemcitabine-induced phosphorylation of H2AX and ATM were reduced by PTK6 knockdown and increased by PTK6 overexpression. PTK6 overexpression also increased the S-phase fraction 48 hours after gemcitabine treatment. Although gemcitabine activated both caspase-8 (CASP8) and caspase-9 (CASP9), the effect of PTK6 on gemcitabine-induced apoptosis required CASP8 but not CASP9. In mouse xenografts, PTK6 overexpression in subcutaneous tumors attenuated tumor growth after gemcitabine treatment. In conclusion, PTK6 prolongs S-phase and increases the ability of gemcitabine to cause DNA damage in vitro and in vivo. IMPLICATIONS: PTK6 affects cell cycle and DNA damage, thus making it an important therapeutic target to improve the outcomes of patients with pancreatic cancer. PMID- 26013171 TI - Urinary reconstruction after kidney transplantation: Pyeloureterostomy versus ureteroneocystostomy. AB - A best evidence topic in transplant surgery was written according to a structured protocol. The question addressed was: In adults undergoing renal transplantation, does pyeloureterostomy, as compared to ureteroneocystostomy, improve clinical outcomes? A total of 235 articles were identified using the search protocol described, of which six represented the best evidence available to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. These included one prospective cohort study, three retrospective cohort studies and two case series. The largest of the five cohort studies demonstrated significantly reduced levels of complications with pyeloureterostomy as compared to ureteroneocystostomy. The consensus from the remaining trials was that pyeloureterostomy is a safe but underused technique. However, the majority of the evidence pertaining to pyeloureterostomy and ureteroneocystostomy was archaic, with four of the six dating from pre-1990. Furthermore, the most recent articles (reported in 2010 and 2013) provide only level three and four evidence respectively, and contain important flaws with regard to patient-cohort allocation inherent to the study design. For these reasons we are cautious in recommending pyeloureterostomy over ureteroneocystostomy with the current evidence base, but would like to emphasise that pyeloureterostomy remains a safe surgical option which should form part of the modern transplant surgeon's reconstructive repertoire, particularly when managing patients in which multiple complications are anticipated, or when there is fear of ureteral vascular compromise, such as with cadaveric kidneys. We call for larger scale prospective trials to aid clarification of the roles of pyeloureterostomy and ureteroneocystostomy in renal transplant surgery and to enrich this prescient field with much needed 21st century evidence. PMID- 26013170 TI - miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis. AB - Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. IMPLICATIONS: Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. PMID- 26013172 TI - Sac ligation in inguinal hernia repair: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Traditionally, hernia sac ligation during inguinal hernia repair is considered mandatory to prevent postoperative development of hernia. However, ligation may induce postoperative pain. The aim of this study was to evaluate the outcomes of hernia sac ligation after inguinal hernia repair. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials to investigate the outcomes of hernia sac ligation for open or laparoscopic inguinal hernia repair. Incidence of hernia recurrence was assessed following the surgery. The secondary outcomes included pain scores and postoperative complications. RESULTS: Five trials were selected and their results were summarized. These 5 trials were published between 1984 and 2014, and the sample sizes ranged from 50 to 467 patients. Four trials had recruited patients with inguinal hernia who underwent open repair, and one study enrolled patients who underwent laparoscopic procedures. We observed no difference in the incidence of hernia recurrence and postoperative complications between the sac ligation and nonligation groups. Postoperatively, the intensity of pain was significantly higher in the ligation group than in the nonligation group at Day 7 (Weight mean difference 1.46; 95% confident interval: 0.98-1.95). CONCLUSION: Hernia sac ligation was associated with higher postoperative pain, and did not show any benefit over sac nonligation regarding the incidence of recurrence and postoperative complications in patients undergoing open tension-free mesh repair or laparoscopic procedures. PMID- 26013173 TI - The clinical features and management of women with ductal carcinoma in situ with microinvasion: A retrospective Cohort study. AB - OBJECTIVE: The purpose of our study is to demonstrate the clinical features and management of patients with Ductal Carcinoma in situ with microinvasion (DCISM) in a single Chinese cancer center. METHODS: Retrospectively analysis of cases between 2003 and 2009 was performed in our institution. The type of treatments, pathological results, and axillary lymph nodes status, hormonal receptor statues (estrogen receptor (ER), progesterone receptor (PR) and Her2) were collected. The disease-free survival rate was calculated from the date of initial diagnosis using the Kaplan-Meier method. RESULTS: Five hundred and sixty-seven cases were enrolled in our study, 474 pure Ductal Carcinoma in situ (DCIS) and 93 DCISM were included. Among these, 168 (35.4%) was diagnosed with the grade I and 26(5.5%) with grade III in pure DCIS group, compared with 3 (3.2%) and 11(11.8%) with grade I and III in DCISM (p < .0001). We also found that DCISM was associated with comadonecrosis histologic subtype (p < .0001) and presence of luminal B type (ER/PR positive and Her-2 positive) (p < .0032). There were more positive axillary lymph nodes involvement in patients with DCISM than those with DCIS after performing ALND(p = .0284). Patients with DCISM underwent more axillary lymph node dissection (ALND) in Chinese cancer center than those did in US centers (1.1% VS 47.8-68% and 86.1% VS 3.6-6.9%, respectively). No significantly difference was found in the overall survival rate between patients with DCIS and DCISM during median 100 months follow-up. CONCLUSIONS: In a Chinese cancer hospital, the majority of cases underwent mastectomy and ALDN after the diagnosis of DCISM.The optimal treatments of patients with DCISM should be further investigated. PMID- 26013174 TI - Juvenile animal testing of hydroxypropyl-beta-cyclodextrin in support of pediatric drug development. AB - Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) is being explored as excipient for administration of poorly soluble NCE's in pediatrics. In support of pharmaceutical development, non-clinical studies were performed to investigate whether oral and intravenous administration of HP-beta-CD showed a different response in juvenile rats versus adult rats. Juvenile rats received HP-beta-CD via the intravenous route at dose levels of 50, 200 and 400mg/kg/day from postnatal day 16 to 44, or via oral gavage at 500, 1000 and 2000mg/kg/day from postnatal day 4 to 46. In addition to in vivo parameters, toxicokinetics and post mortem evaluations were conducted. The main findings were related to the renal excretion of intact HP-beta-CD and were regarded as non-adverse transient adaptive responses. The pathogenesis of the osmotic nephrosis-like changes are discussed. With increasing age a more effective renal clearance of HP-beta-CD is present in line with the postnatal functional maturation of the kidney. In addition, following oral administration an increase in soft stools was seen which was related to osmotic water retention in the large intestine. The findings in the juvenile studies are very similar to those observed in previously performed adult rat studies at similar dose levels, same routes and similar or longer dose duration. No novel toxicity was seen in the juvenile studies. PMID- 26013169 TI - When Cancer Fights Back: Multiple Myeloma, Proteasome Inhibition, and the Heat Shock Response. AB - Multiple myeloma is a plasma cell malignancy with an estimated 26,850 new cases and 11,240 deaths in 2015 in the United States. Two main classes of agents are the mainstays of therapy-proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Other new targets are emerging rapidly, including monoclonal antibodies and histone deacetylase (HDAC) inhibitors. These therapeutic options have greatly improved overall survival, but currently only 15% to 20% of patients experience long-term progression-free survival or are cured. Therefore, improvement in treatment options is needed. One potential means of improving clinical options is to target resistance mechanisms for current agents. For example, eliminating the cytoprotective heat-shock response that protects myeloma cells from proteasome inhibition may enhance PI-based therapies. The transcription factor heat-shock factor 1 (HSF1) is the master regulator of the heat-shock response. HSF1 is vital in the proteotoxic stress response, and its activation is controlled by posttranslational modifications (PTM). This review details the mechanisms of HSF1 regulation and discusses leveraging that regulation to enhance PI activity. PMID- 26013175 TI - Are ECG monitoring recommendations before prescription of QT-prolonging drugs applied in daily practice? The example of haloperidol. AB - PURPOSE: Monitoring of the QT duration by electrocardiography (ECG) prior to treatment is frequently recommended in the label of QT-prolonging drugs. It is, however, unknown how often general practitioners in daily clinical practice are adhering to these risk-minimization measures. We assessed the frequency of ECG measurements in patients where haloperidol was initiated in primary care. METHODS: Patients (>=18 years) with a first prescription of haloperidol in the UK Clinical Practice Research Datalink (2009-2013) were included. The proportion of ECGs made was determined in two blocks of 4 weeks: during the exposure period when haloperidol was initiated, and during the control period, 1 year before. Conditional logistic regression analysis was applied to calculate the relative risk of having an ECG in the exposure period compared with the control period. Subgroup analyses were performed to assess the proportion of ECG measurements in patients with one or more additional risk factors for QT prolongation. RESULTS: In total, 3420 patients were prescribed haloperidol during the exposure period, and 1.8% of them had an ECG at treatment initiation, compared with 0.8% during the control period (relative risk [RR] 2.4 [1.5-3.8]). Of the patients with additional risk factors for QT prolongation, 1.9% of the patients had an ECG at initiation of the prescription, compared with 1.0% during the control period (RR 2.1 [1.2-3.5]). CONCLUSIONS: Compliance with recommendations to perform an electrocardiogram when starting a new QT-prolonging drug is extremely low, when haloperidol is taken as an example. PMID- 26013176 TI - Protonation states and catalysis: Molecular dynamics studies of intermediates in tryptophan synthase. AB - The importance of protonation states and proton transfer in pyridoxal 5' phosphate (PLP)-chemistry can hardly be overstated. Although experimental approaches to investigate pKa values can provide general guidance for assigning proton locations, only static pictures of the chemical species are available. To obtain the overall protein dynamics for the interpretation of detailed enzyme catalysis in this study, guided by information from solid-state NMR, we performed molecular dynamics (MD) simulations for the PLP-dependent enzyme tryptophan synthase (TRPS), whose catalytic mechanism features multiple quasi-stable intermediates. The primary objective of this work is to elucidate how the position of a single proton on the reacting substrate affects local and global protein dynamics during the catalytic cycle. In general, proteins create a chemical environment and an ensemble of conformational motions to recognize different substrates with different protonations. The study of these interactions in TRPS shows that functional groups on the reacting substrate, such as the phosphoryl group, pyridine nitrogen, phenolic oxygen and carboxyl group, of each PLP-bound intermediate play a crucial role in constructing an appropriate molecular interface with TRPS. In particular, the protonation states of the ionizable groups on the PLP cofactor may enhance or weaken the attractions between the enzyme and substrate. In addition, remodulation of the charge distribution for the intermediates may help generate a suitable environment for chemical reactions. The results of our study enhance knowledge of protonation states for several PLP intermediates and help to elucidate their effects on protein dynamics in the function of TRPS and other PLP-dependent enzymes. PMID- 26013177 TI - Diagnostic and prognostic biomarkers of a sellar melanocytic tumor mimicking pituitary adenoma: Case report and literature review. AB - Primary or metastatic melanocytic tumors in the sellar region are rare and can pose a diagnostic challenge. Here we describe a case of a 74-year-old man who underwent radiological investigations for a transient episode of blurred vision. Based on the clinical and endocrinological findings and MRI results, the patient was assumed to have a clinically non-functioning pituitary macroadenoma, which was followed-up over a 2-year period. He did not have any endocrine symptoms or progressive visual deterioration, and no history of past malignancy, including melanoma. Endocrinological investigation was unremarkable; blood hormone levels were within the normal ranges except for low serum total testosterone and bioavailable testosterone levels without symptoms of hypogonadism. The longitudinal MRI follow-up demonstrated a gradual increase in the size of the tumor over the course of 11 months. For this reason, the patient underwent surgery. Pathologic examination including histology, immunohistochemistry and electron microscopy achieved the correct diagnosis of melanocytic tumor of the sellar region morphologic examination is essential in the diagnosis of melanocytic tumors. Hmb-45 is an important diagnostic biomarker in melanocytic lesions. The use and exploration of miRNA, Ki67 and osteopontin are important in understanding the genesis, progression, and prognosis in treatment of patients with melanocytic tumors. PMID- 26013178 TI - Outcomes of pregnancy following liver transplantation: The King's College Hospital experience. AB - Reports of pregnancy in liver transplantation (LT) patients have largely favorable outcomes. Concerns remain with regards to maternal and graft risk, optimal immunosuppression (IS), and fetal outcomes. We review all post-LT pregnancies at our center with regard to the outcomes and safety for the patient, graft, and fetus. A total of 117 conceptions occurred in 79 patients. Median age at conception was 29 years. Maternal complications included graft loss (2%), acute cellular rejection (ACR; 15%), pre-eclampsia/eclampsia (15%), gestational diabetes (7%), and bacterial sepsis (5%). ACR was significantly more common in those women who conceived within 12 months of LT (P = 0.001). The live birth rate was 73%. Prematurity occurred in 26 (31%) neonates, and 24 (29%) neonates were of low or very low birth weight. IS choice (cyclosporine versus tacrolimus) had no significant effect on pregnancy outcomes and complications. No congenital abnormalities occurred, and only 1 child born at 24 weeks had delayed developmental milestones. In conclusion, pregnancy following LT has a favorable outcome in the majority, but severe maternal risks remain. Patients should be counseled with regard to the above information so informed decisions can be made, and pregnancy must be considered high risk with regular monitoring by transplant clinicians and specialist obstetricians. PMID- 26013179 TI - Delayed onset diplopia following head trauma. PMID- 26013180 TI - A Catalyst Platform for Unique Cationic (Co)Polymerization in Aqueous Emulsion. AB - Sodium dodecyl benzene sulfonate (DBSNa) surfactants, with a polydisperse and hyperbranched structure, combined with different rare earth metal salts generate highly water-dispersible Lewis acid surfactant combined catalysts (LASCs). This platform of new complexes promotes fast, efficient cationic polymerization of industrially relevant monomers in direct emulsion at moderate temperature. The process described here does not require high shearing, long polymerization time, or large catalyst content. It allows the reproducible generation of high-molar mass homopolymers of pMOS, styrene, and isoprene, as well as random or multiblock copolymers of the latter two, in a simple and straightforward one-pot reaction. PMID- 26013181 TI - Are reports of the death of taxonomy an exaggeration? PMID- 26013183 TI - MSLT-I: it's all about the lymph nodes.... PMID- 26013182 TI - ZD958 is a low-nitrogen-efficient maize hybrid at the seedling stage among five maize and two teosinte lines. AB - MAIN CONCLUSION: ZD958 was the most low-N-efficient line among five maize and two teosinte lines. Zea parviglumis and Zea diploperennis were insensitive to N limitation. Maize and teosinte genetically and evolutionarily diverged in gene regulation. GDH2, ASN2, and T4 were consistently down-regulated across seven lines. Maternal asymmetric inheritance and heterosis vigor made ZD958 low-N efficient. Nitrogen (N) deficiency remains a serious limiting factor for maize production in many developing countries. It is particularly important to better understand how hybrid maize responds to N limitation. ZD958, a dominant high yield hybrid in North China, was comparatively analyzed with four other maize and two teosinte lines at physiological and transcriptional levels. ZD958 was the most low-N-efficient line among five maize and two teosinte lines due to its largest biomass accumulation at a lowest N concentration under N limitation; while Zea parviglumis and Zea diploperennis had large root systems and were insensitive to N limitation. In anti-parallel with down-regulation of N metabolic genes in the ZD958 root, carbon allocation towards the root was enhanced for the significant increase in the root length. Variations in expression patterns of ten genes mediating N uptake, transport, and metabolism indicated large genetic and evolutionary divergence among seven lines under N limitation. Notably, GDH2, ASN2, and VAAT5 were consistently down-regulated under N limitation across these maize and teosinte lines, suggesting essential evolutionary conservation of gene regulation in response to N limitation and providing molecular markers for N nutritional diagnosis. Asymmetric inheritance, mostly from its maternal donor Z58, and heterosis vigor made ZD958 low-N-efficient at the seedling stage. The superior traits in crown roots in ZD958 may be derived from its paternal donor Chang7-2. Thus, Z58, Chang7-2, and two wild maize lines (Z. parviglumis and Z. diploperennis) provide valuable germplasms for N-efficient and large-root maize breeding. PMID- 26013184 TI - Rebuttal. PMID- 26013185 TI - Risk for self-reported anorexia or bulimia nervosa based on drive for thinness and negative affect clusters/dimensions during adolescence: A three-year prospective study of the TChAD cohort. AB - OBJECTIVE: This study explored the cross-sectional and predictive effect of drive for thinness and/or negative affect scores on the development of self-reported anorexia nervosa (AN) and bulimia nervosa (BN). METHOD: K-means were used to cluster the Eating Disorder Inventory-Drive for Thinness (DT) and Child Behavior Checklist Anxious/Depressed (A/D) scores from 615 unrelated female twins at age 16-17. Logistic regressions were used to assess the effect of these clusters on self-reported eating disorder diagnosis at ages 16-17 (n = 565) and 19-20 (n = 451). RESULTS: DT and A/D scores were grouped into four clusters: Mild (scores lower than 90th percentile on both scales), DT (higher scores only on DT), A/D (higher scores only on A/D), and DT-A/D (higher scores on both the DT and A/D scales). DT and DT-A/D clusters at age 16-17 were associated cross-sectionally with AN and both cross-sectionally and longitudinally with BN. The DT-A/D cluster had the highest prevalence of AN at follow-up compared with all other clusters. Similarly, an interaction was observed between DT and A/D that predicted risk for AN. DISCUSSION: Having elevated DT and A/D scores may increase risk for eating disorder symptomatology above and beyond a high score on either alone. Findings suggest that cluster modeling based on DT and A/D may be useful to inform novel and useful intervention strategies for AN and BN in adolescents. PMID- 26013186 TI - Addition of tumor multiplicity improves the prognostic performance of the hepatoma arterial-embolization prognostic score. AB - BACKGROUND & AIMS: The hepatoma arterial-embolization prognostic (HAP) score predicts survival outcome in patients with hepatocellular carcinoma (HCC) treated with trans-arterial chemoembolization (TACE). We validated the HAP score in Korean subjects with HCC and investigated whether its prognostic performance is improved with additional parameters. METHODS: A total of 280 patients with HCC treated with TACE between 2003 and 2009 were included. Validation and modification of HAP score were performed based on multivariate Cox regression models. RESULTS: The median age of the study population (211 men, 69 women) was 60 years. Viral etiology of HCC accounted for 80.4% (n = 181 for hepatitis B, 44 for hepatitis C). The median overall survival (OS) was 40.5 months. On multivariate analysis, together with the original components of the HAP score (serum albumin <3.6 g/dl, total bilirubin >0.9 mg/dl, alpha-foetoprotein >400 ng/ml, and tumor size >7 cm), tumor number >=2 was selected as an independent unfavorable prognostic factor for OS (hazard ratio 2.3; P < 0.001). Accordingly, a modified HAP-II (mHAP-II) score was established by adding tumor number >=2. Although both HAP and mHAP-II scores discriminated the four different risk groups (log-rank test, all P < 0.001), the mHAP-II score performed significantly better than the HAP score, as per the areas under receiver-operating curves predicting OS at 3 years (0.717 vs. 0.658) and 5 years (0.728 vs. 0.645), respectively (all P < 0.05). CONCLUSIONS: Although the HAP score predicted OS for Korean subjects with HCC undergoing TACE, the addition of tumor number significantly improved the prognostic performance. The mHAP-II score can be used for accurate prognostication and selection of optimal candidates for TACE. PMID- 26013188 TI - Confessions of a clinical teaching fellow. PMID- 26013187 TI - A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia. AB - AIM: To compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia. METHODS: The trial which was conducted at 13 centers in China during 2011-2013 included a 2-week run-in and a 24-week treatment period. A total of 504 eligible participants with gout and with serum urate >= 480 MUmol/L were randomly assigned 1 : 1 : 1 to febuxostat 40 mg/day, febuxostat 80 mg/day and allopurinol 300 mg/day groups. The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 MUmol/L. RESULTS: The primary efficacy endpoint was reached by 33.5% of subjects taking febuxostat 80 mg/day, 22.5% of those taking febuxostat 40 mg/day and 17.0% of those taking allopurinol 300 mg/day (P < 0.001 for the comparison between febuxostat 80 mg/day and allopurinol 300 mg/day groups; P = 0.216 for the comparison between febuxostat 40 mg/day and allopurinol 300 mg/day groups). The incidence of gout flare was relatively high in each group during the first 8 weeks and gradually decreased thereafter. There was no statistically significant difference between the three groups (P > 0.05). The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities. CONCLUSIONS: Febuxostat 80 mg/day had superior urate-lowering efficacy to that of febuxostat 40 mg/day or allopurinol 300 mg/day, which was comparable in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated. PMID- 26013189 TI - Transnasal tendon suspension for the paralyzed lower eyelid. AB - BACKGROUND: Paralytic ectropion is a significantly functional and esthetic problem leading to problems with lacrimation, corneal exposure, and poor palpebral closure. Limitations with traditional corrective procedures include poor apposition of the lid to the globe, suboptimal medial canthal position, and high recurrence rates. OBJECTIVE: The objective of this study was to develop a technique of lower-lid suspension using transnasal wiring for the long-term maintenance of lid position. METHODS: Twenty-three consecutive patients with complete unilateral facial nerve paralysis underwent the procedure, and they were followed up for a median of 27 months (1-73 months). RESULTS: Fifteen of 18 patients maintained their intraoperative lower-lid position beyond the 12-month follow-up. Three patients had a minimal scleral show at 3 months. One of these patients also developed lid laxity seen on the snap test. No perioperative complications were experienced. CONCLUSIONS: Transnasal wiring of the lower-lid tendon suspension provides consistent results that are maintained over time. PMID- 26013190 TI - Crossroads between nature and culture: an introduction. PMID- 26013191 TI - Preparations, models, and simulations. AB - This paper proposes an outline for a typology of the different forms that scientific objects can take in the life sciences. The first section discusses preparations (or specimens)--a form of scientific object that accompanied the development of modern biology in different guises from the seventeenth century to the present: as anatomical-morphological specimens, as microscopic cuts, and as biochemical preparations. In the second section, the characteristics of models in biology are discussed. They became prominent from the end of the nineteenth century onwards. Some remarks on the role of simulations--characterising the life sciences of the turn from the twentieth to the twenty-first century--conclude the paper. PMID- 26013192 TI - Succession of functions, from Darwin to Dohrn. AB - By formulating in 1875 his major theoretical achievement, the "principle of succession of functions", Dohrn was consciously entering the controversy between Darwin and Mivart. Dohrn's principle enjoyed the approval of Darwin, but not his enthusiasm. The paper examines the evolution of Darwin's original idea of 'conversion of functions' in the 6th edition of his Origin, following Mivart's criticism, and contrasts the overtly functionalist interpretation entailed in Dohrn's formulation with Darwin's increasing structuralist hesitations as to the origin of evolutionary novelty. A more accurate analysis of Dohrn's principle, however, appears to corroborate the thesis that Dohrn was equally receptive to Darwin's argument as to Mivart's criticism. PMID- 26013193 TI - Music and biology at the Naples Zoological Station. AB - Anton Dohrn projected the Stazione Zoologica as composed of two complementary halves: nature and culture. This attitude was not only expression of the general cultural background of the nineteenth century cultural elite, for Dohrn both formed a coherent and organized whole. In my essay I will analyse the different levels of the relationship between music and biology. In particular, I will demonstrate that both share similar "styles of thought". In the last part I will show that Dohrn's most important scientific contribution, the concept or "principle" of Functionswechsel, provides evidence for the link he had established between music and biology. PMID- 26013194 TI - Alexei Sewertzoff and Adolf Naef: revising Haeckel's biogenetic law. AB - Ernst Haeckel formulated his biogenetic law, famously stating that ontogeny recapitulates phylogeny, in 1872. The Russian evolutionist Alexei Sewertzoff, and the Swiss-born zoologist Adolf Naef were among those who revised Haeckel's law, thus changing the course of evolutionary theory and of developmental biology. Although Sewertzoff and Naef approached the problem in a similar way and formulated similar hypotheses at a purely descriptive level, their theoretical viewpoints were crucially different. While Sewertzoff laid the foundations for a Darwinian evolutionary morphology and is regarded as a forerunner of the modern synthesis, Naef was one of the most important figures in "idealistic morphology", which is usually seen as a type of anti-Darwinism. Both Naef and Sewertzoff aimed to revise Haeckel's biogenetic law and came to comparable conclusions at the empirical level. This paper is an attempt to explain how their fundamentally different theoretical backgrounds influenced their views on the relationship between ontogeny and phylogeny. PMID- 26013196 TI - Of germ-plasm and zymoplasm: August Weismann, Carlo Emery and the debate about the transmission of acquired characteristics. AB - In this essay I discuss the contents and the context of Italian zoologist and entomologist Carlo Emery's discussion of the germ-plasm theory. August Weismann considered him one of his very few creditable supporters, and encouraged him to publish his theoretical reflections. In his Gedanken zur Descendenz- und Vererbungstheorie, which appeared between 1893 and 1903 as a series of five essays in the journal Biologisches Zentralblatt, Emery developed a very personal account, applying the concept of determinants to problems like atavism, sexual dimorphism, speciation, geographical isolation, transmission of characters, and putting forward, as early as 1903, the idea of a genetic program. PMID- 26013195 TI - The cult of amphioxus in German Darwinism; or, our gelatinous ancestors in Naples' blue and balmy bay. AB - Biologists having rediscovered amphioxus, also known as the lancelet or Branchiostoma, it is time to reassess its place in early Darwinist debates over vertebrate origins. While the advent of the ascidian-amphioxus theory and challenges from various competitors have been, documented, this article offers a richer account of the public appeal of amphioxus as a primitive ancestor. The focus is on how the 'German Darwin' Ernst Haeckel persuaded general magazine and newspaper readers to revere this "flesh of our flesh and blood of our blood", and especially on Das neue Laienbrevier des Haeckelismus (The new lay breviary of Haeckelism) by Moritz Reymond with cartoons by Fritz Steub. From the late 1870s these successful little books of verse introduced the Neapolitan discoveries that made the animal's name and satirized Haeckel's rise as high priest of its cult. One song is reproduced and translated here, with a contemporary "imitation" by the Canadian palaeontologist Edward John Chapman, and extracts from others. Predating the American "It's a long way from amphioxus" by decades, these rhymes dramatize neglected 'species politics' of Darwinism and highlight the roles of humour in negotiating evolution. PMID- 26013197 TI - Chromosomenindividualitat or Entmischung? The debate between Paolo Della Valle and Edmund B. Wilson. AB - At the beginning of the twentieth century, the Italian cytologist Paolo Della Valle developed a theory of instable chromosomes (teoria dei cromosomi labili). He radically criticized the so-called Sutton-Boveri hypothesis (Martins and Martins, Genetics and Molecular Biology, 22:261-271, 1999), focusing on numerical constancy in the species and individuality. On the basis of bibliographical review and personal observations, he maintained that the chromosomes were neither stable bodies, nor permanent structures, but transitory cellular materials, resulting from the periodical rearrangement of the chromatin during the cell division. German and English-speaking biologists reacted. The paper shows some content of the argumentations used by Thomas H. Montgomery and especially Edmund B. Wilson. The discussion was characterized by the same data which is interpretedby different scholars in different ways. And the point is that no one of them had the decisive test to demonstrate his own point of view. Wilson simply invoked on his behalf a certain 'common sense', defending at least a 'high degree of constancy'. The debate waned along with the reception of Morgan's chromosome theory of heredity, but only the advent of molecular biology definitively stated the nature of chromosomes as permanent structures of the cell. PMID- 26013198 TI - [Benedetto Croce and the Stazione Zoologica Anton Dohrn]. AB - The relationship between the family of Benedetto Croce and that of Anton Dohrn were always characterized by cordiality and mutual respect. Both houses were international meeting places of artists, intellectuals and scientists. The narrowest and most lasting relationship was that between the philosopher and Reinhard Dohrn, from 1909 to 1965 director of the Zoological Station, a long period, marked, among other things, by the two World Wars. Both events caused major problems in the life of the institution. Starting in the twenties, their relationship continued until 1952, the year of Croce's death. In the years immediately following World War I Croce strove, with his prestige and authority, to preserve the Zoological Station's nature as a private entity, directed by Dohrn. As Minister of Education, on 30 September, 1920, he issued a decree-law which repealed that of 26 May, 1918, which had aimed at the 'Italianisation' of the Zoological Station. Croce instead transformed the Station into a "non-profit organization under the supervision of the Ministry of Education". The new decree sparked a lively debate in the Parliament and in the press, between supporters and opponents of the measure. On 9 December, a major discussion took place in the Senate, published in the same year under the title On the Zoological Station in Naples. The discussion revolved around two fundamental political concepts: is it legitimate to take, for reasons of culture, civilization and the law of war, possession of the "the fruit of the talent of others"? is it legitimate "to replace with a state organization'' what had been created as a private activity, and was the result of the enthusiasm and interest of individuals? Croce's victory, however, was not lasting. During the Fascist era, with the decree of 21 October 1923, the Zoological Station was again transformed into an Italian state body. PMID- 26013199 TI - An appreciation of Christiane Groehen: the correspondence between Charles Darwin and Anton Dohrn. AB - Anton Dohrn was introduced to Darwinism by Ernst Haeckel during his student years at Jena, and became an eager disciple of Charles Darwin's work. He founded the Stazione Zoologica in 1872. Darwin became a patron of Dohrn's Stazione, and the two naturalists corresponded regularly. This article discusses their relationship and the contributions of Christiane Groeben to its elucidation. PMID- 26013200 TI - Science, evolution and natural selection: in praise of Darwin at the Stazione Zoologica Anton Dohrn of Naples. AB - Copernicus, Galileo, Newton and other physical scientists ushered in a conception of the universe as matter in motion governed by natural laws. Their discoveries brought about a fundamental revolution, namely a commitment to the postulate that the universe obeys immanent laws that can account for natural phenomena. The workings of the universe were brought into the realm of science: explanation through natural laws. Darwin completed the Copernican revolution by extending it to the living world. Darwin demonstrated the evolution of organisms. More important yet is that he discovered natural selection, the process that explains the 'design' of organisms. The adaptations and diversity of organisms, the origin of novel and complex species, even the origin of mankind, could now be explained by an orderly process of change governed by natural laws. The origin of species and the exquisite features of organisms had previously been explained as special creations of an omniscient God. Darwin brought them into the domain of science. PMID- 26013202 TI - To follow or not? How animals in fusion-fission societies handle conflicting information during group decision-making. AB - When group members possess differing information about the environment, they may disagree on the best movement decision. Such conflicts result in group break-ups, and are therefore a fundamental driver of fusion-fission group dynamics. Yet, a paucity of empirical work hampers our understanding of how adaptive evolution has shaped plasticity in collective behaviours that promote and maintain fusion fission dynamics. Using movement data from GPS-collared bison, we found that individuals constantly associated with other animals possessing different spatial knowledge, and both personal and conspecific information influenced an individual's patch choice decisions. During conflict situations, bison used group familiarity coupled with their knowledge of local foraging options and recently sampled resource quality when deciding to follow or leave a group - a tactic that led to energy-rewarding movements. Natural selection has shaped collective behaviours for coping with social conflicts and resource heterogeneity, which maintain fusion-fission dynamics and play an essential role in animal distribution. PMID- 26013201 TI - Depsipeptide Intermediates Interrogate Proposed Biosynthesis of Cereulide, the Emetic Toxin of Bacillus cereus. AB - Cereulide and isocereulides A-G are biosynthesized as emetic toxins by Bacillus cereus via a non-ribosomal peptide synthetase (NRPS) called Ces. Although a thiotemplate mechanisms involving cyclo-trimerization of ready-made D-O-Leu-D-Ala L-O-Val-L-Val via a thioesterase (TE) domain is proposed for cereulide biosynthesis, the exact mechanism is far from being understood. UPLC-TOF MS analysis of B. cereus strains in combination with (13)C-labeling experiments now revealed tetra-, octa-, and dodecapeptides of a different sequence, namely (L-O Val-L-Val-D-O-Leu-D-Ala)1-3, as intermediates of cereulide biosynthesis. Surprisingly, also di-, hexa-, and decadepsipeptides were identified which, together with the structures of the previously reported isocereulides E, F, and G, do not correlate to the currently proposed mechanism for cereulide biosynthesis and violate the canonical NRPS biosynthetic logic. UPLC-TOF MS metabolite analysis and bioinformatic gene cluster analysis highlighted dipeptides rather than single amino or hydroxy acids as the basic modules in tetradepsipeptide assembly and proposed the CesA C-terminal C* domain and the CesB C-terminal TE domain to function as a cooperative esterification and depsipeptide elongation center repeatedly recruiting the action of the C* domain to oligomerize tetradepsipeptides prior to the release of cereulide from the TE domain by macrocyclization. PMID- 26013203 TI - Aripiprazole augmentation versus antidepressant switching for patients with major depressive disorder: A 6-week, randomized, rater-blinded, prospective study. AB - No study has directly compared the efficacy and tolerability of aripiprazole augmentation (AA) and antidepressant switching (SW) in patients with major depressive disorder (MDD). This is the first 6-week, randomized, rater-blinded, direct comparison study between AA and SW in outpatients. An inadequate response to antidepressants was defined as a total score >= 14 on the Hamilton Depression Rating Scale-item 17 (HDRS-17) despite adequate antidepressant dosage for at least 6 weeks in the current depressive episode. The primary endpoint was change in the total score of the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to the end of treatment. Secondary efficacy measures included the response and remission rates as priori defined at the end of treatment: changes in total scores of the HDRS-17, Iowa Fatigue Scale (IFS), and Sheehan Disability Scale (SDS) from baseline to the end of treatment and the proportion of patients who scored 1 or 2 on the Clinical Global Impression-Improvement Score (CGI-I) at the end of treatment. Tolerability was assessed with the Barnes Akathisia Rating Scale (BARS) and Arizona Sexual dysfunction scale (ASEX), and the numbers of adverse events were compared between the two groups. A total of 101 patients were randomized to either AA (n = 52) or SW (n = 49). The mean change in the MADRS score from baseline was significantly higher in the AA, with a difference in magnitude of -8.7 (p < 0.0001). The intergroup difference was first evident in week 2. The numbers of responders (p = 0.0086) and remitters (p = 0.0005) were also significantly higher in the AA (60% and 54%, respectively) compared with the SW (32.6% and 19.6%, respectively). On most secondary endpoints, AA showed better clinical outcomes compared to SW. The tolerability profiles were comparable between the two groups. Overall, AA yielded potentially beneficial clinical outcomes compared to SW. Given the methodological shortcomings of the present study, adequately powered, more rigorously controlled clinical trials are strongly warranted to confirm the present findings. PMID- 26013204 TI - Hydrogen isotope response to changing salinity and rainfall in Australian mangroves. AB - Hydrogen isotope ratios ((2) H/(1) H, delta(2) H) of leaf waxes covary with those in precipitation and are therefore a useful paleohydrologic proxy. Mangroves are an exception to this relationship because their delta(2) H values are also influenced by salinity. The mechanisms underlying this response were investigated by measuring leaf lipid delta(2) H and leaf and xylem water delta(2) H and delta(18) O values from three mangrove species over 9.5 months in a subtropical Australian estuary. Net (2) H/(1) H fractionation between surface water and leaf lipids decreased by 0.5-1.00/00 ppt(-1) for n-alkanes and 0.4-0.80/00 ppt(-1) for isoprenoids. Xylem water was (2) H depleted relative to surface water, reflecting (2) H discrimination of 4-100/00 during water uptake at all salinities and opportunistic uptake of freshwater at high salinity. However, leaf water (2) H enrichment relative to estuary water was insensitive to salinity and identical for all species. Therefore, variations in leaf and xylem water delta(2) H values cannot explain the salinity-dependent (2) H depletion in leaf lipids, nor the 300/00 range in leaf lipid delta(2) H values among species. Biochemical changes in direct response to salt stress, such as increased compatible solute production or preferential use of stored carbohydrates, and/or the timing of lipid production and subsequent turnover rates, are more likely causes. PMID- 26013205 TI - The Correlation Between RhoA Expression and Clinicopathological Characteristics in Gastric Cancer Patients After Curative Surgery. AB - BACKGROUND: The expression of RhoA, a member of the ras homologue family, is reported to be involved in tumorigenesis in some cancers; however, its prognostic value in gastric cancer is controversial. METHODS: Between April 1988 and January 2005, a total of 206 gastric cancer patients receiving curative surgery were enrolled in this study. Immunohistochemical staining of the RhoA protein was performed, and the clinicopathological characteristics and initial recurrence patterns were compared between low RhoA expression (n = 55) and high RhoA expression (n = 151) gastric cancer patients. RESULTS: For intestinal-type (n = 134) gastric cancer, there is no significant difference between the clinicopathological characteristics and RhoA expression. However, for diffuse type (n = 82) gastric cancer, high RhoA expression was associated with more advanced pathological N category compared to low RhoA expression. A multivariate analysis revealed that age, pathological T and N categories, and RhoA expression were independent prognostic factors for overall survival after curative surgery. For all patients, the five-year overall survival rates and disease-free survival rates were higher in patients with low RhoA expression compared to those with high RhoA expression, which was observed in diffuse-type gastric cancer, not in intestinal-type gastric cancer. With regard to the initial recurrence pattern, patients with high RhoA expression had more distant metastasis compared to those with low RhoA expression, especially more liver metastasis. CONCLUSIONS: RhoA expression is an independent prognostic factor for gastric cancer, especially for diffuse-type. We should be aware of liver metastasis during the follow-up of gastric cancer with high RhoA expression. PMID- 26013207 TI - Incidence and Risk Factors of Abdominal Complications After Lung Transplantation. AB - BACKGROUND: Due to the underlying diseases and the need for immunosuppression, patients after lung transplantation are particularly at risk for gastrointestinal (GI) complications that may negatively influence long-term outcome. The present study assessed the incidences and impact of GI complications after lung transplantation and aimed to identify risk factors. METHODS: Retrospective analysis of all 227 consecutively performed single- and double-lung transplantations at the University hospitals of Lausanne and Geneva was performed between January 1993 and December 2010. Logistic regressions were used to test the effect of potentially influencing variables on the binary outcomes overall, severe, and surgery-requiring complications, followed by a multiple logistic regression model. RESULTS: Final analysis included 205 patients for the purpose of the present study, and 22 patients were excluded due to re-transplantation, multiorgan transplantation, or incomplete datasets. GI complications were observed in 127 patients (62%). Gastro-esophageal reflux disease was the most commonly observed complication (22.9%), followed by inflammatory or infectious colitis (20.5%) and gastroparesis (10.7%). Major GI complications (Dindo/Clavien III-V) were observed in 83 (40.5%) patients and were fatal in 4 patients (2.0%). Multivariate analysis identified double-lung transplantation (p = 0.012) and early (1993-1998) transplantation period (p = 0.008) as independent risk factors for developing major GI complications. Forty-three (21%) patients required surgery such as colectomy, cholecystectomy, and fundoplication in 6.8, 6.3, and 3.9% of the patients, respectively. Multivariate analysis identified Charlson comorbidity index of >=3 as an independent risk factor for developing GI complications requiring surgery (p = 0.015). CONCLUSION: GI complications after lung transplantation are common. Outcome was rather encouraging in the setting of our transplant center. PMID- 26013209 TI - Strong electronic polarization of the C60 fullerene by imidazolium-based ionic liquids: accurate insights from Born-Oppenheimer molecular dynamic simulations. AB - Fullerenes are known to be polarizable due to their strained carbon-carbon bonds and high surface curvature. The electronic polarization of fullerenes is steadily of practical importance because it leads to non-additive interactions and, therefore, to unexpected phenomena. For the first time, hybrid density functional theory (HDFT) powered Born-Oppenheimer molecular dynamics (BOMD) simulations have been conducted to observe electronic polarization and charge transfer phenomena in the C60 fullerene at finite temperature (350 K). The non-additive phenomena are fostered by the three selected imidazolium-based room-temperature ionic liquids (RTILs). We conclude that although charge transfer appears nearly negligible in these systems, electronic polarization is indeed significant, leading to a systematically positive effective electrostatic charge on the C60 fullerene: +0.14e in [MMIM][Cl], +0.21e in [MMIM][NO3], and +0.17e in [MMIM][PF6]. These results are, to a certain extent, unexpected and provide a motivation for considering novel C60-RTILs systems. HDFT BOMD is a powerful tool for investigating electronic effects in RTIL and fullerene containing nuclear electronic systems. PMID- 26013206 TI - National Comprehensive Cancer Network Resectability Status for Pancreatic Carcinoma Predicts Overall Survival. AB - BACKGROUND: The aim of this study was to evaluate the validity of preoperative resectability status, as defined by the National Comprehensive Cancer Network (NCCN), from the viewpoint of overall survival. METHODS: A total of consecutive 704 patients with pancreatic head carcinoma who underwent pancreatoduodenectomy with upfront surgery at seven Japanese hospitals between 2001 and 2012 were evaluated retrospectively. According to the NCCN definition of preoperative resectability status, tumors were divided into resectable tumors without vascular contact (R group), resectable tumors with portal or superior mesenteric vein (PV/SMV) contact of ?180 degrees (R-PV group), borderline resectable(BR) tumors with PV/SMV contact of >180 degrees (BR-PV group), and BR tumors with arterial contact (BR-A group). The relationship between the NCCN definition of preoperative resectability status and overall survival was analyzed. RESULTS: Of the 704 patients, 389, 114, 145, and 56 were classified into the R group, the R PV group, the BR-PV group, and the BR-A group, respectively. Overall survival of the BR-PV and BR-A groups was significantly worse than that of the R group and R PV groups (P < 0.05), although there was no significant difference in overall survival between the R group and the R-PV group (P = 0.310). Multivariate analysis revealed that PV/SMV contact of >180 degrees (P = 0.008) and arterial contact (P < 0.001) were independent prognostic factors of overall survival. CONCLUSION: From the viewpoint of overall survival, the NCCN definition of preoperative resectability status was valid. PMID- 26013208 TI - Raising the Alarm: A Cross-Sectional Study Exploring the Factors Affecting Patients' Willingness to Escalate Care on Surgical Wards. AB - BACKGROUND: Delays in escalation of care for patients may contribute to poor outcome. The factors that influence surgical patients' willingness to call for help on wards are currently unknown. This study explored the factors that affect patients' willingness to call for help on surgical wards; how patients call for help and to whom; how to encourage patients to call for help, and the barriers to patients calling for help. METHODS: A cross-sectional study was conducted in three London hospitals using a questionnaire designed through expert opinion and the published literature. A total of 155 surgical patients (83% response rate) participated. RESULTS: Patients were more willing to call for help using the bedside buzzer or by calling a nurse compared to a doctor (p < 0.001). The prompts to calling for help patients were most likely to act on were bleeding and pain. Patients were more willing to call for help if encouraged by a healthcare professional than a relative or fellow patient (p < 0.01). Patients were more likely to worry about taking up too much time when calling for help than being perceived as difficult (p < 0.001). For some prompts, male patients were more willing to call for help (p < 0.05). CONCLUSIONS: This is the first study to identify factors affecting patients' willingness to call for help on surgical wards. Interventions that take these factors into account can be developed to encourage patients to call for help and may avoid delays in treatment. PMID- 26013241 TI - Treatment of peri-implantitis: clinical outcome of chloramine as an adjunctive to non-surgical therapy, a randomized clinical trial. AB - PURPOSE: To evaluate the adjunctive clinical effects of a chloramine to non surgical treatment of peri-implantitis. MATERIAL AND METHODS: Eighteen individuals diagnosed with peri-implantitis (clinical signs of inflammation and progressive bone loss) on at least two implants were included. Clinical variables; plaque accumulation (Pl), probing depth (PD), clinical attachment level (CAL) and bleeding on probing (BoP), were recorded at baseline and at 3 month follow-up. Primary clinical efficacy variable was the change in the number of sites with BoP. The implants were randomized into two different treatment groups: test and control. Both implants received supra- and submucosal debridement by ultrasonic instrumentation supplemented with hand instruments. The implants assigned to the test group first received local applications of a chloramine gel (PerisolvTM ; RLS Global AB, Gothenburg, Sweden) followed by mechanical instrumentation. The oral hygiene was checked at 6 weeks. RESULTS: After 3 months, implants of both groups showed statistically significant reduction (P < 0.001) in the number of BoP-positive sites compared with baseline. The reduction of BoP-positive sites in the test group changed from 0.97 (SD +/- 0.12) to 0.38 (SD +/- 0.46), and in the control group from 0.97 (SD +/- 0.12) to 0.31 (SD +/- 0.42). Between-group comparisons revealed no statistically significant differences at baseline and after 3 months, for BoP or any of the other variables. CONCLUSION: In the present randomized clinical trial of peri implantitis therapy; non-surgical mechanical debridement with adjunctive use of a chloramine is equally effective in the reduction of mucosal inflammation as conventional non-surgical mechanical debridement up to 3 months. PMID- 26013242 TI - Failed airway management with the GlideScope: it is not the same tool in infants. PMID- 26013243 TI - Oligodendrocyte generation during mouse development. AB - Oligodendrocytes (OLs) are glial cells, which generate myelin in the central nervous system. Their interesting developmental features attract many neurobiologists eager to study cell differentiation, gene expression regulation, or dynamic morphogenesis. Their primary role in protecting the axons has major impacts in the medical research field: in multiple sclerosis, a demyelinating disease in which remyelination is blocked. Oligodendrogenesis is involved in higher brain function including motor skill learning and cognitive function. Here, we review advances in the research on OL development and highlight areas where questions remain to be answered in both developmental biology and neurobiology related aspects. PMID- 26013245 TI - Errors relating to study controls and criteria naming in the editorial by Wolfe (Arthritis Rheumatol, February 2015). PMID- 26013244 TI - Surgical training and clinical trial involvement--the trainees' view. PMID- 26013247 TI - Inhibitory short-term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro. AB - The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input-output transformation we performed whole-cell and perforated-patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short-term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short-term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter-spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low-frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high-frequency pallidal output may continuously modulate EP firing. PMID- 26013248 TI - Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy. AB - Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes. We describe the case of a man with a long history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who developed AHA while on stable antiretroviral therapy and then presented with new onset bleeding and hypotension. We treated our patient with incrementally increasing doses of cyclophosphamide resulting in resolution of coagulopathy. We review the medical literature for additional cases of HIV-associated AHA and discuss the challenges in the care of our patient, since the immunosuppression needed to eradicate the FVIII inhibitor had the potential to cause recrudescence of his PML. PMID- 26013249 TI - Prevalence and Pattern of Chronic Kidney Disease in Antiretroviral-Naive Patients with HIV/AIDS. AB - BACKGROUND: Chronic renal failure and HIV/AIDS are both prevalent in Nigeria. We performed a cross-sectional analysis of renal function in newly diagnosed, treatment-naive HIV-infected patients before initiating highly active antiretroviral therapy. METHODS: Treatment-inexperienced individuals were recruited. Patients with diabetes mellitus and hypertension were excluded. Plasma creatinine level was used to measure the estimated glomerular filtration rate ([eGFR] by Modification of Diet in Renal Disease equation). Predictors of creatinine and eGFR were determined by univariate and multivariate analyses. RESULTS: We evaluated 183 patients. In all, 44 (24%) patients had a GFR <60 mL/min/1.73 m(2), implying moderate chronic kidney disease (CKD). Considering the eGFR, 22 (12%) patients had stage 1, 117 (63.9%) stage 2, 13 (7.1%) stage 3, 27 (14.8%) stage 4, and 4 (2.2%) stage 5 CKD. Creatinine inversely correlated with CD4 (r = -.228, P = .025). CD4 predicts creatinine (odds ratio 1.6, 95% confidence interval 1.0-1.8, P = .003). CONCLUSION: In ART-naive patients, CKD is common, and low eGFR was associated with lower CD4 counts. PMID- 26013251 TI - [A boy with pupil asymmetry]. AB - A 4-year-old boy presented with an enlarged pupil and anterior uveitis of his left eye. He had a recent history of a chickenpox infection. Contrary to previous cases presented in literature, over time partial recovery of the enlarged pupil took place. PMID- 26013250 TI - Evaluation of Skin Fibroblasts from Amyotrophic Lateral Sclerosis Patients for the Rapid Study of Pathological Features. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive degeneration of brain and spinal cord motor neurons. Ubiquitin-proteasome system (UPS) dysfunction and oxidative stress have been implicated in ALS pathogenesis. However, it is unknown whether the defects in these pathways extend to non-neuronal tissues such as fibroblasts. Fibroblasts, unlike neuronal tissue, are readily available and may hold potential for short-term, rapid diagnostic and prognostic purposes. We investigated whether primary skin fibroblasts from ALS patients share, or can be manipulated to develop, functional and pathological abnormalities seen in affected neuronal cells. We inhibited UPS function and induced oxidative stress in the fibroblasts and found that ALS-related cellular changes, such as aggregate formation and ubiquitination of ALS-associated proteins (TDP-43 and ubiquilin 2), can be reproduced in these cells. Higher levels of TDP-43 ubiquitination, as evident by colocalization between TDP-43 and ubiquitin, were found in all six ALS cases compared to controls following extracellular insults. In contrast, colocalization between ubiquilin 2 and ubiquitin was not markedly different between ALS cases and control. A UPS reporter assay revealed UPS abnormalities in patient fibroblasts. Despite the presence of ALS-related cellular changes in the patient fibroblasts, no elevated toxicity was observed. This suggests that aggregate formation and colocalization of ALS-associated proteins may be insufficient alone to confer toxicity in fibroblasts used in the present study. Chronic exposure to ALS-linked stresses and the ALS-linked cellular pathologies may be necessary to breach an unknown threshold that triggers cell death. PMID- 26013252 TI - [Ethical aspects of clinical drug research in critically ill children]. AB - All critically ill children admitted to a paediatric intensive care unit (PICU) receive drug treatment. However, the majority of these drugs has never been tested in these children, and their safety and efficacy have not been proven. Clinical drug research is therefore required in this patient group. While doing this research we need to balance between the advancement of knowledge--and thereby potential improvements in clinical care--and protection of a vulnerable population against harm and exploitation. The PICU environment and the vulnerable population raise specific ethical challenges and mean that the research should be designed and conducted with care. The ethical challenges are related to 4 areas: a) study design and conduct; b) informed consent from parents and children; c) burden and risk for the child; and d) research or experimental treatment. These challenges and possible solutions will be discussed in this article. PMID- 26013253 TI - [Familial hypercholesterolemia: why screening, counselling and treatment should be integrated]. AB - Familial hypercholesterolemia (FH) is a monogenic autosomal dominant disorder. FH is the most common hereditary cause of raised serum cholesterol levels and is associated with an increased risk of premature cardiovascular disease (CVD). This disorder is known to have a genetic cause, and effective drug therapies exist for patients with FH. Successful cascade screening, within the framework of a national screening programme, gave the Netherlands an international role as model and pioneer as far as FH detection is concerned. With the ending of this screening programme as of 1 January 2014 the care for FH patients, including screening and counselling has had to be incorporated within the basic Dutch healthcare insurance system. It is essential that detection of FH should continue in as efficient and cost-effective a manner as possible. Our proposal is that this detection should be performed and co-ordinated by those treating patients with FH so that FH screening, counselling and treatment are integrated. PMID- 26013254 TI - [Carpal tunnel syndrome and Down's syndrome]. AB - BACKGROUND: Carpal tunnel syndrome is caused by entrapment of the median nerve in the wrist, leading to pain, paraesthesia and numbness in the hand, especially at night. It is relatively common in adults but rare in children. CASE DESCRIPTION: We describe a 13-year-old girl with Down's syndrome who was experiencing increased tiredness. Her sleep was disrupted by pain and tingling in her hands. Electrophysiological examination revealed a bilateral absence of median nerve conduction, confirming the diagnosis of carpal tunnel syndrome. The diagnosis had not been made before, probably because the patient could not describe her symptoms and because carpal tunnel syndrome is not readily identified by doctors who mainly treat children. CONCLUSION: Carpal tunnel syndrome can be a cause of tiredness. The literature suggests that individuals with Down's syndrome are at greater risk of developing carpal tunnel syndrome. PMID- 26013255 TI - Roles of Crystal Surface in Pt-Loaded Titania for Photocatalytic Conversion of Organic Pollutants: A First-Principle Theoretical Calculation. AB - Titania modified with nanosized metallic clusters is found to substantially enhance its photocatalytic capacity for renewable energy generation and environmental purification, but the underlying mechanism, especially the roles of crystal surface in noble-metal-loaded TiO2, remain unclear. In this work, such roles in the Pt-loaded anatase TiO2 for the photocatalytic conversion of nitrobenzene (NB), a model pollutant, are explored by first-principle calculations. The theoretical calculations reveal that the Pt-TiO2 complex has a higher catalytic activity toward NB conversion than pure Pt clusters, and the (001) facets of TiO2 in this complex tend to accumulate more positively charged holes and thus have a higher photocatalytic activity than the (101) facets. Furthermore, the thermodynamic and kinetic results also show that the Pt cluster loaded on the (001) surface of anatase TiO2 is favored for NB conversion in the photooxidation pathway. This work deepens our fundamental understanding on the evolution of molecule-photocatalyst interface and provides implications for designing and preparing photocatalysts. PMID- 26013256 TI - Phage display for identifying peptides that bind the spike protein of transmissible gastroenteritis virus and possess diagnostic potential. AB - The spike (S) protein of porcine transmissible gastroenteritis virus (TGEV) is located within the viral envelope and is the only structural protein that possesses epitopes capable of inducing virus-neutralizing antibodies. Among the four N-terminal antigenic sites A, B, C, and D, site A and to a lesser extent site D (S-AD) induce key neutralizing antibodies. Recently, we expressed S-AD (rS AD) in recombinant form. In the current study, we used the rS-AD as an immobilized target to identify peptides from a phage-display library with application for diagnosis. Among the 9 phages selected that specifically bound to rS-AD, the phage bearing the peptide TLNMHLFPFHTG bound with the highest affinity and was subsequently used to develop a phage-based ELISA for TGEV. When compared with conventional antibody-based ELISA, phage-mediated ELISA was more sensitive; however, it did not perform better than semi-quantitative RT-PCR, though phage mediated ELISA was quicker and easier to set up. PMID- 26013257 TI - A new gyrovirus in human feces. AB - A novel gyrovirus genome found in the feces of an adult with diarrhea is described. The genome shows the three expected main ORFs encoding a structural protein (VP1), nonstructural protein (VP2), and Apoptin protein (VP3), which shared identities of 41, 42, and 38 % with those of the most closely related gyrovirus proteins, respectively. Given the high divergence in its genome, this gyrovirus may be considered the prototype for a new viral species (GyV9) in the Gyrovirus genus. Because the closest relatives of this gyrovirus infect chicken, a possible dietary origin for the presence of this virus in human feces is discussed. PMID- 26013259 TI - Structure of the tripartite multidrug efflux pump AcrAB-TolC suggests an alternative assembly mode. AB - Escherichia coli AcrAB-TolC is a multidrug efflux pump that expels a wide range of toxic substrates. The dynamic nature of the binding or low affinity between the components has impeded elucidation of how the three components assemble in the functional state. Here, we created fusion proteins composed of AcrB, a transmembrane linker, and two copies of AcrA. The fusion protein exhibited acridine pumping activity, suggesting that the protein reflects the functional structure in vivo. To discern the assembling mode with TolC, the AcrBA fusion protein was incubated with TolC or a chimeric protein containing the TolC aperture tip region. Three-dimensional structures of the complex proteins were determined through transmission electron microscopy. The overall structure exemplifies the adaptor bridging model, wherein the funnel-like AcrA hexamer forms an intermeshing cogwheel interaction with the alpha-barrel tip region of TolC, and a direct interaction between AcrB and TolC is not allowed. These observations provide a structural blueprint for understanding multidrug resistance in pathogenic Gram-negative bacteria. PMID- 26013260 TI - A cytosolic thioredoxin acts as a molecular chaperone for peroxisome matrix proteins as well as antioxidant in peroxisome. AB - Thioredoxin (TRX) is a disulfide reductase present ubiquitously in all taxa and plays an important role as a regulator of cellular redox state. Recently, a redox independent, chaperone function has also been reported for some thioredoxins. We previously identified nodulin-35, the subunit of soybean uricase, as an interacting target of a cytosolic soybean thioredoxin, GmTRX. Here we report the further characterization of the interaction, which turns out to be independent of the disulfide reductase function and results in the co-localization of GmTRX and nodulin-35 in peroxisomes, suggesting a possible function of GmTRX in peroxisomes. In addition, the chaperone function of GmTRX was demonstrated in in vitro molecular chaperone activity assays including the thermal denaturation assay and malate dehydrogenase aggregation assay. Our results demonstrate that the target of GmTRX is not only confined to the nodulin-35, but many other peroxisomal proteins, including catalase (AtCAT), transthyretin-like protein 1 (AtTTL1), and acyl-coenzyme A oxidase 4 (AtACX4), also interact with the GmTRX. Together with an increased uricase activity of nodulin-35 and reduced ROS accumulation observed in the presence of GmTRX in our results, especially under heat shock and oxidative stress conditions, it appears that GmTRX represents a novel thioredoxin that is co-localized to the peroxisomes, possibly providing functional integrity to peroxisomal proteins. PMID- 26013261 TI - Defining exacerbations in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease is a very common disease often punctuated by intermittent episodes of exacerbation. These exacerbations affect the natural history of the disease, accelerating a decline in lung function. They affect the individual in many ways and affect the health service caring for these patients. The definition of exacerbation varies and lacks clarity. The definitions used most are either symptom based, for example, breathlessness, sputum production and sputum purulence, or event driven, for example, an event causing a patient to seek healthcare input or change to medications. In this article, we discuss the importance of exacerbations, the clinical definitions, clinical trial definitions, physiological and biomarker evidence of exacerbations and the challenges associated with each of these. Application of a practical definition would aid in our clinical management of patients with chronic obstructive pulmonary disease and facilitate developments in future therapeutic advances through clinical trials. PMID- 26013262 TI - Epigenetic genome mining of an endophytic fungus leads to the pleiotropic biosynthesis of natural products. AB - The small-molecule biosynthetic potential of most filamentous fungi has remained largely unexplored and represents an attractive source for the discovery of new compounds. Genome sequencing of Calcarisporium arbuscula, a mushroom-endophytic fungus, revealed 68 core genes that are involved in natural product biosynthesis. This is in sharp contrast to the predominant production of the ATPase inhibitors aurovertin B and D in the wild-type fungus. Inactivation of a histone H3 deacetylase led to pleiotropic activation and overexpression of more than 75 % of the biosynthetic genes. Sampling of the overproduced compounds led to the isolation of ten compounds of which four contained new structures, including the cyclic peptides arbumycin and arbumelin, the diterpenoid arbuscullic acid A, and the meroterpenoid arbuscullic acid B. Such epigenetic modifications therefore provide a rapid and global approach to mine the chemical diversity of endophytic fungi. PMID- 26013263 TI - Resonance shifts and spill-out effects in self-consistent hydrodynamic nanoplasmonics. AB - The standard hydrodynamic Drude model with hard-wall boundary conditions can give accurate quantitative predictions for the optical response of noble-metal nanoparticles. However, it is less accurate for other metallic nanosystems, where surface effects due to electron density spill-out in free space cannot be neglected. Here we address the fundamental question whether the description of surface effects in plasmonics necessarily requires a fully quantum-mechanical ab initio approach. We present a self-consistent hydrodynamic model (SC-HDM), where both the ground state and the excited state properties of an inhomogeneous electron gas can be determined. With this method we are able to explain the size dependent surface resonance shifts of Na and Ag nanowires and nanospheres. The results we obtain are in good agreement with experiments and more advanced quantum methods. The SC-HDM gives accurate results with modest computational effort, and can be applied to arbitrary nanoplasmonic systems of much larger sizes than accessible with ab initio methods. PMID- 26013264 TI - RNAi Technology for Insect Management and Protection of Beneficial Insects from Diseases: Lessons, Challenges and Risk Assessments. AB - The time has passed for us to wonder whether RNA interference (RNAi) effectively controls pest insects or protects beneficial insects from diseases. The RNAi era in insect science began with studies of gene function and genetics that paved the way for the development of novel and highly specific approaches for the management of pest insects and, more recently, for the treatment and prevention of diseases in beneficial insects. The slight differences in components of RNAi pathways are sufficient to provide a high degree of variation in responsiveness among insects. The current framework to assess the negative effects of genetically modified (GM) plants on human health is adequate for RNAi-based GM plants. Because of the mode of action of RNAi and the lack of genomic data for most exposed non-target organisms, it becomes difficult to determine the environmental risks posed by RNAi-based technologies and the benefits provided for the protection of crops. A better understanding of the mechanisms that determine the variability in the sensitivity of insects would accelerate the worldwide release of commercial RNAi-based approaches. PMID- 26013266 TI - Structure and dynamics of the taxocenoses of Pimplinae, Poemeniinae, Rhyssinae, Anomaloninae and Metopiinae in an urban secondary semideciduous montane forest. AB - Ichneumonidae (Hymenoptera) is one of the largest families of Insecta, but information on family diversity and distribution in Brazil is limited. The aim of the study was to assess the abundance, richness and seasonal distribution of Ichneumonidae in an urban secondary semideciduous montane forest. Insect specimens were captured in a Malaise trap placed within a restored sub-evergreen forest and sampling was performed every week during three non-consecutive 12 month periods. Of the 507 specimens collected, 338 were captured between May 1991 and May 1992, 95 between May 2000 and May 2001, and 74 between May 2007 and May 2008. Specimens were distributed among the subfamilies Pimplinae (n = 444), Anomaloninae (n = 42), Metopiinae (n = 16), Poemeniinae (n = 3) and Rhyssinae (n = 2). Species richness was highest in 1991-1992 with 33 rare and eight common species captured, followed by 2000-2001 with 31 rare and one common species captured, and 2007-2008 with 24 rare and one common species captured. The Shannon Wiener diversity index (H') and Jackknife 1 species richness (S) values for the respective periods were 2.75/59.6, 3.15/35.8 and 2.83/35.8. In the 1991-1992 and 2000-2001 periods, parasitoid abundance was higher during the rainy season, while in 2007-2008 abundance was higher during the dry season. Colpotrochia mexicana (Cresson), Colpotrochia neblina Gauld & Sithole and Exochus izbus Gauld & Sithole were recorded for the first time in Brazil. PMID- 26013265 TI - Effect of biotic and abiotic factors on diversity patterns of anthophyllous insect communities in a tropical mountain forest. AB - The determinants of diversity are a central issue in ecology, particularly in Andean forests that are known to be a major diversity hotspot for several taxa. We examined the effect of abiotic (elevation and precipitation) and biotic (flowering plant diversity) factors considered to be decisive causal factors of diversity patterns on anthophyllous insect communities on mountain forest. Sampling was carried out in 100-m transects at eight elevational levels and during a period of 8 months. All flowering plants in the understory and their flowering visitors were recorded. Species richness and diversity were estimated for each elevation and month. Diversity of flowering plants, elevation, and precipitation were used as independent variables in multiple regressions against insect diversity. The evaluated abiotic and biotic factors had contrasting effects on insect diversity: a significant decrease on insect diversity occurred at high elevation and dry months (i.e., threshold effect), while it showed a positive relationship with flowering plant diversity through time (i.e., linear effect), but not along elevation. Rapid turnover of species of both interacting guilds was observed every 100-m altitude and month. Local insect communities were also divided functionally depending on the plant family they visit. These results indicate that each insect community is distinctive among elevations and months and that diversity of flowering plants, precipitation, and elevation influence their structure and composition. Thus, conservation strategies should involve protection of forest cover at the whole elevation gradient, in order to preserve common and exclusive components of diversity and consequently, the mosaic of plant-pollinator interactions. PMID- 26013267 TI - Honeybee Foraging, Nectar Secretion, and Honey Potential of Wild Jujube Trees, Ziziphus nummularia. AB - Ziziphus trees are of economic importance due to their aggregated value (source of fruits and timber) and are the most important melliferous plants in the Arabian Peninsula. Interaction between honeybees and Ziziphus nummularia was investigated by assessing foraging, flower phenology, nectar secretion, and honey potential. It is demonstrate that both the native Apis mellifera jemenitica Ruttner and the exotic Apis mellifera carnica Pollmann foraged on Z. nummularia flowers. Bee foraging for nectar and pollen was low (2 +/- 0.7 workers/200 flowers/3 min) during early morning and increased to a peak in the afternoon (100 +/- 15 workers/200 flowers/3 min). Remarkable foraging activity was recorded during high temperature (35 degrees C) and low humidity (20%) conditions. Foraging for nectar collection was more distinct than that for pollen. The flowering of Z. nummularia was gradual, and was characterized by some flowers that opened and secreted nectar early before sunrise, whereas other flowers remained opened until sunrise. The flowers lasted 2 days, with 83% of nectar secreted in the first day. The peak of nectar secretion was recorded at noon under hot and dry conditions. The lowest amount of nectar was secreted during sunrise under mild temperature (24 degrees C) and humidity (31%) conditions. Under optimum conditions, it is assumed that the average sugar mass was 0.321 +/- 0.03 mg TSS/flower, while the total sugar mass was 27.65 +/- 11 g/tree. The average honey production potential of tested Z. nummularia was approximately 2.998 kg/tree and 749.475 kg/ha in the main flowering season. PMID- 26013268 TI - Leaf beetle (Chrysomelidae: Coleoptera) assemblages in a mosaic of natural and altered areas in the Brazilian cerrado. AB - In landscape mosaics, species may use different vegetation types or be restricted to a single vegetation type or land-use feature highlighting the importance of the interaction of species requirements and environmental heterogeneity. In these systems, the determination of the overall pattern of beta-diversity can indicate the importance of the environmental heterogeneity on diversity patterns. Here, we evaluate leaf beetles (Coleoptera: Chrysomelidae) as habitat quality bioindicators in a system with varying intensities of human impacts and different phyto-physiognomies (from open field to forests). We collected 1117 leaf beetles belonging to 245 species, of which 12 species and 5 genus were considered possible bioindicators based on IndVal measures. Higher species richness was observed in forests and regenerating fields, and habitats with lower species richness included pastures, mines, and veredas. Natural fields, regenerating fields, natural cerrado, and forest had higher values of beta-diversity. Bioindicator systems that include not only species richness and abundance but also assemblage composition are needed to allow for a better understanding of Chrysomelidae response to environmental disturbance. PMID- 26013269 TI - Spatial distribution, temporal variation and specificity of microhabitat of Tropisternus species (Coleoptera: Hydrophilidae) in permanent ponds. AB - The spatial distribution and temporal variation of 11 species of Tropisternus were analyzed in two permanent ponds located in the province of Corrientes, Argentina. Samples were collected every 15 days, between October 2010 and March 2011. The species recorded were Tropisternus collaris (Fabricius), Tropisternus ovalis Castelnau, Tropisternus laevis (Sturm), Tropisternus lateralis limbatus (Brulle), Tropisternus longispina Fernandez & Bachmann, Tropisternus carinispina Orchymont, Tropisternus bourmeisteri Fernandez & Bachmann, Tropisternus apicipalpis (Chevrolat), Tropisternus dilatatus Bruch, Tropisternus obesus Bruch, and Tropisternus ignoratus Knisch. The first four were present in higher proportions than the remaining during most of the study period. The spatial distribution of individuals was mostly related to the homogeneity or heterogeneity of the ecosystem in relation to microhabitats with aquatic vegetation: In ponds with different microhabitats, individuals were mainly aggregated, whereas in ponds with homogenous features, individuals were randomly distributed. However, when species were analyzed individually, the spatial distribution and the use of microhabitat by each species were different with respect to preference and behavior. PMID- 26013270 TI - A New Species of Austrocarabodes (Austrocarabodes) from Brazil, Including Keys to Known Species of the Subgenus from the Neotropical Region and to the agressor Group (Acari: Oribatida: Carabodidae). AB - A new species of oribatid mites, Austrocarabodes (Austrocarabodes) brasiliensis Ermilov & Tolstikov n. sp., is described from soil litter of the Atlantic forest of Rio de Janeiro, Brazil. It is most similar morphologically to Austrocarabodes (A.) armatus Mahunka. However, the new species differs from the latter by the morphology of bothridial and adanal setae. Identification keys to known species of Austrocarabodes (Austrocarabodes) from the Neotropical region and the agressor group are provided. PMID- 26013271 TI - Assessing the Total Mortality Caused by Two Species of Trichogramma on Its Natural Host Plutella xylostella (L.) at Different Temperatures. AB - Trichogramma pretiosum Riley and Trichogramma atopovirilia Oatman & Platner are natural enemies of Plutella xylostella (L.) in Southern Brazil. Laboratory studies to evaluate parasitoids performance under different conditions, such as temperature regimes, are necessary to assess their potential as biocontrol agents of P. xylostella. In most studies involving Trichogramma, parasitism rate is the main parameter used to evaluate parasitoid performance, ignoring that parasitoids can cause egg mortality by feeding on the host content and/or to multiple drilling without laying eggs. This study was conducted to investigate three main issues: how temperature affects T. pretiosum and T.atopovirilia development on eggs of P. xylostella, whether or not these species respond differently to temperature, and how important is the mortality they cause besides parasitism on P. xylostella. Temperature effects (from 10 to 30 degrees C) on development, survival, parasitism rate, mortality, and total mortality caused by T. pretiosum and T. atopovirilia on eggs of P. xylostella were evaluated. Temperature affected the development time, female longevity, parasitism rate, mortality not directly related to parasitoid larval development, and total mortality caused on the host. No significant differences were recorded for the estimated thermal requirements for T. pretiosum and T. atopovirilia. However, the higher mortality caused by T. pretiosum indicates that this parasitoid is the most suitable to be used against P. xylostella. Also, the results suggest that the use of parasitism rate as the only parameter to evaluate the performance of T. pretiosum and T. atopovirilia may underestimate the potential of these parasitoids in regulating pest populations. PMID- 26013272 TI - Erratum to: Assessing the Total Mortality Caused by Two Species of Trichogramma on Its Natural Host Plutella xylostella (L.) at Different Temperatures. PMID- 26013274 TI - Associations of wheat with pea can reduce aphid infestations. AB - Increasing plant diversity within crops can be beneficial for pest control. In this field study, the effects of two wheat and pea associations (mixed cropping and strip cropping) on aphid populations were compared with pure stands of both crops by observations on tillers and plants. Pea was more susceptible to infestations than wheat. As expected, the density of aphid colonies was significantly higher in pure stands during the main occurrence periods, compared with associations. Additionally, flying beneficials, such as not only aphidophagous adult ladybirds but also parasitoid, hoverfly and lacewing species that feed on aphids at the larval stage, were monitored using yellow pan traps. At specific times of the sampling season, ladybirds and hoverflies were significantly more abundant in the pure stand of pea and wheat, respectively, compared with associations. Few parasitoids and lacewings were trapped. This study showed that increasing plant diversity within crops by associating cultivated species can reduce aphid infestations, since host plants are more difficult to locate. However, additional methods are needed to attract more efficiently adult beneficials into wheat and pea associations. PMID- 26013275 TI - Population Growth and Characterization of Plant Injuries of Steneotarsonemus spinki Smiley (Acari: Tarsonemidae) on Rice. AB - Rice is attacked by Steneotarsonemus spinki Smiley, a mite that has dispersed throughout many countries causing important loss on rice production. Rice plants of the variety Morelos A-92 were infested with S. spinki, and its population growth was estimated along plant development. Further, the morphological and histological injuries associated to the mite attack were characterized. The highest infestation level was obtained 13 weeks after plant infestation, with an average of 58.5 mites per plant, predominantly females. Morphological injuries were categorized from level 0 (no injuries from uninfested plants) to level 3, characterized by the highest injuries represented by blotches on the adaxial epidermis of the leaf sheath and on panicles and grains. Plants ranked within levels 0, 1, and 2 for morphological injury did not exhibit clear histological injuries, while those at level 3 exhibited histological injury characterized by destruction of cells of the adaxial epidermis, disorder, color change, and hypertrophy in the mesophyll cells, as well as color change in the abaxial epidermis. Thus, it presented a significant correlation between morphological injuries and mite density level, which can be further adopted to help the control decision-making process for this mite on rice. PMID- 26013273 TI - Repellent Effect and Metabolite Volatile Profile of the Essential Oil of Achillea millefolium Against Aegorhinus nodipennis (Hope) (Coleoptera: Curculionidae). AB - Aegorhinus nodipennis (Hope) (Coleoptera: Curculionidae) is an important native pest in fruit crops that is mainly found in European hazelnut fields in the south of Chile. We investigated the behavioral response of A. nodipennis to volatile compounds released from the essential oil of Achillea millefolium and its main constituent using olfactometric bioassays. Gas chromatographic and mass spectral analysis of the A. millefolium essential oil revealed the presence of 11 compounds. Monoterpene beta-thujone (96.2%) was the main component of the oil. Other compounds identified were alpha-thujone, 1,8-cineole, p-cymene, and 4 terpineol, all with percentages below 1%. Both A. millefolium essential oil and thujone exhibited a repellent activity against this insect at the higher doses tested (285.7 ng/cm(2)), demonstrating their potential as repellents for this species. PMID- 26013276 TI - Rehydration After Water Stress in Forager Workers of Coptotermes gestroi (Wasmann) (Blattaria: Rhinotermitidae). AB - Water maintenance is vital for termite survival under dry conditions, hence environment humidity is one of the most important factors that controls the distribution of Isoptera. To understand the dynamics of termite rehydration after water loss, two bioassays were performed with forager workers of Coptotermes gestroi (Wasmann) submitted to water stress. Insects were weighed and placed into Petri dishes without water and food for periods of 3, 15, and 30 h. For each period of water stress, 10 replicates were performed in the treatment and control groups, totalling 120 experimental units. Forager workers lost body mass across all periods of water stress and tested with the highest reduction for the 30 h exposure period. Subsequent access to water resulted in termite rehydration, and final weight values were near to initial body mass values. These results demonstrate that workers of C. gestroi experienced large reductions of body mass under water stress, but these reductions were not severe enough to cause mortality. Additionally, termites were able to rehydrate after water stress conditions. This is a potential risk factor to be considered in cases of new infestations because C. gestroi workers will be able to cause economic damage in their new locations even when deprived of water during their transportation by humans. PMID- 26013277 TI - Effortful swallow enhances vertical hyolaryngeal movement and prolongs duration after maximal excursion. AB - Effortful swallowing (EFS) is a common compensatory swallowing manoeuver for dysphagia patients. We investigated the influence of EFS on temporal and spatial characteristics of the movements of the hyoid bone, larynx and epiglottis in healthy subjects. A total of 41 volunteers swallowed 10 mL of diluted barium solution using two swallowing strategies: usual and effortful swallowing (USS and EFS). The motions of the hyoid bone, larynx and epiglottis were tracked using frame-by-frame kinematic motion analysis of videofluoroscopic images. Maximal velocities and maximal displacements of hyoid and larynx, the maximal angle of the epiglottic tilt, and the durations of hyoid excursion, laryngeal elevation and epiglottic tilt were measured. Compared to USS, EFS was associated with significantly greater vertical displacement of the hyoid (P < 0.001), vertical and horizontal displacement of the larynx (P = 0.003, P = 0.019), and maximal angle of the epiglottic tilt (P = 0.001). In addition, the durations of the vertical and horizontal excursions of the hyoid, vertical excursion of the larynx and the epiglottic tilt were greater in EFS, compared with USS. Effortful swallowing was also associated with significantly greater maximum velocities of the hyoid and larynx during swallowing. In conclusion, the EFS manoeuver facilitates vertical speed and distance of hyolaryngeal excursion and epiglottic tilt and extends the duration of excursion and the epiglottic tilt, especially after reaching maximal excursion in healthy subjects. These results confirm the temporal and kinematic benefits of airway protection induced by the EFS manoeuver. PMID- 26013278 TI - Diplomatic advantages and threats in global health program selection, design, delivery and implementation: development and application of the Kevany Riposte. AB - BACKGROUND: Global health programs, as supported by organizations such as the Global Fund to Fight AIDS, Tuberculosis and Malaria and the President's Emergency Plan for AIDS Relief (PEPFAR), stand to make significant contributions to international medical outcomes. Traditional systems of monitoring and evaluation, however, fail to capture downstream, indirect, or collateral advantages (and threats) of intervention selection, design, and implementation from broader donor perspectives, including those of the diplomatic and foreign policy communities, which these programs also generate. This paper describes the development a new metier under which assessment systems designed to consider the diplomatic value of global health initiatives are described and applied based on previously identified "Top Ten" criteria. METHODS: The "Kevany Riposte" and the "K-Score" were conceptualized based on a retrospective and collective assessment of the author's participation in the design, implementation and delivery of a range of global health interventions related to the HIV/AIDS epidemic. Responses and associated scores reframe intervention worth or value in terms of global health diplomacy criteria such as "adaptability", "interdependence", "training," and "neutrality". Response options ranged from "highly advantageous" to "significant potential threat". RESULTS: Global health initiatives under review were found to generate significant advantages from the diplomatic perspective. These included (1) intervention visibility and associations with donor altruism and prestige, (2) development of international non-health collaborations and partnerships, (3) adaptability and responsiveness of service delivery to local needs, and (4) advancement of broader strategic goals of the international community. Corresponding threats included (1) an absence of formal training of project staff on broader political and international relations roles and responsibilities, (2) challenges to recipient cultural and religious practices, (3) intervention related environmental concerns, and (4) a lack of prima facie consideration of intervention diplomatic and foreign policy consequences. CONCLUSIONS: Global health interventions stand to generate significant diplomatic advantages for donor and recipient countries and organizations when appropriately selected, designed, targeted, and delivered. Conversely, in the absence of the application of standards such as those developed under the Kevany Riposte, threats to diplomacy and international relations may occur. With the application of related systems to other global health programmes and settings, comparative results on the relative worth of alternate approaches from the diplomatic perspective may be generated to better inform political, strategic, and global health policy and programmatic decisions. PMID- 26013280 TI - Gallotannins and Tannic Acid: First Chemical Syntheses and In Vitro Inhibitory Activity on Alzheimer's Amyloid beta-Peptide Aggregation. AB - The screening of natural products in the search for new lead compounds against Alzheimer's disease has unveiled several plant polyphenols that are capable of inhibiting the formation of toxic beta-amyloid fibrils. Gallic acid based gallotannins are among these polyphenols, but their antifibrillogenic activity has thus far been examined using "tannic acid", a commercial mixture of gallotannins and other galloylated glucopyranoses. The first total syntheses of two true gallotannins, a hexagalloylglucopyranose and a decagalloylated compound whose structure is commonly used to depict "tannic acid", are now described. These depsidic gallotannins and simpler galloylated glucose derivatives all inhibit amyloid beta-peptide (Abeta) aggregation in vitro, and monogalloylated alpha-glucogallin and a natural beta-hexagalloylglucose are shown to be the strongest inhibitors. PMID- 26013279 TI - Attitudes of Germans towards distributive issues in the German health system. AB - Social health care systems are inevitably confronted with the scarcity of resources and the resulting distributional challenges. Since prioritization implies distributional effects, decisions regarding respective rules should take citizens' preferences into account. In this study we concentrate on two distributive issues in the German health system: firstly, we analyze the acceptance of prioritizing decisions concerning the treatment of certain patient groups, in this case patients who all need a heart operation. We focus on the patient criteria smoking behavior, age and whether the patient has or does not have young children. Secondly, we investigate Germans' opinions towards income dependent health services. The results reveal the strong effects of individuals' attitudes regarding general aspects of the health system on priorities, e.g. that individuals with an unhealthy lifestyle should not be prioritized. In addition, experience of limited access to health services is found to have a strong influence on citizens' attitudes, too. Finally, decisions on different prioritization criteria are found to be not independent. PMID- 26013281 TI - IgG4-related kidney disease from the renal pelvis that mimicked urothelial carcinoma: a case report. AB - BACKGROUND: IgG4-related kidney disease is a comprehensive term for renal lesions associated with IgG4-related disease, which mainly manifests as plasma cell-rich tubulointerstitial nephritis with increased IgG4+ plasma cells and fibrosis. IgG4 related kidney disease in the renal pelvis is rare. CASE PRESENTATION: We describe a 53-year-old Asian woman who was referred to our hospital with a space occupying renal lesion discovered by medical examination. A physical examination and laboratory evaluation revealed no significant abnormalities. Computed tomography scans showed a soft-tissue mass with an irregular border and mild homogeneous enhancement in the right renal pelvis and calyces. A positron emission tomography/computed tomography scan revealed soft-tissue density shadows with increased radionuclide uptake. To investigate a suspected pelvic carcinoma, a right ureteronephrectomy was performed. A pathologic examination of the renal sections showed a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, with fibrosis beneath the urothelial epithelium of the renal pelvis. Postoperatively, the serum IgG4 level was significantly elevated. The patient was diagnosed with IgG4-related kidney disease. CONCLUSION: We present a case of IgG4 related kidney disease mimicking urothelial carcinoma in the renal pelvis. When a buried and solitary hypovascular tumor is detected in the kidney, we must consider IgG4-related kidney disease as a differential diagnosis. Accordingly, elevated serum IgG4, radiologic findings, and pathologic examination may improve the diagnosis. PMID- 26013282 TI - Cyanobacterial Sunscreen Scytonemin: Role in Photoprotection and Biomedical Research. AB - Cyanobacteria are the most promising group of photosynthetic microorganisms capable of producing an array of natural products of industrial importance. Scytonemin is a small hydrophobic alkaloid pigment molecules present in the extracellular sheath of several cyanobacteria as a protective mechanism against short wavelength solar ultraviolet (UV) radiation. It has great efficacy to minimize the production of reactive oxygen species and formation of DNA lesions. The biosynthesis of scytonemin is regulated by different physico-chemical stressors. Scytonemin display multiple roles, functioning as a potent UV sunscreen and antioxidant molecules, and can be exploited in cosmetic and other industries for the development of new cosmeceuticals. Herein, we review the occurrence, biosynthesis, and potential application of scytonemin in photoprotection, pharmaceuticals, and biomedical research. PMID- 26013283 TI - Parasite prevalence in fecal samples from shelter dogs and cats across the Canadian provinces. AB - BACKGROUND: In Canada, surveys of enteric parasites in dogs and cats have been reported sporadically over the past 40 years, mostly focusing on a specific region. The present work was performed to determine the current prevalence of various parasites in fecal samples from shelter dogs and cats across the Canadian provinces. METHODS: A total of 1086 dog and 636 cat fecal samples from 26 shelters were analysed using a sugar solution double centrifugal flotation technique. Prevalences (national, regional, provincial, age and parasite specific), were calculated and compared using the Fisher-Exact test. A multiplex PCR was performed to distinguish Taenia spp, Echinococcus granulosus and E. multilocularis on samples positive for taeniid eggs. RESULTS: Overall, 33.9% of dogs and 31.8% of cats were positive for at least one parasite. Toxocara canis and T. cati were the most prevalent parasite present in fecal samples followed by Cystoisospora spp. Prevalence in dogs was similar across the Atlantic, East, West and Pacific regions, while prevalence in cats varied regionally. Eggs of E. granulosus/E. canadensis were detected in samples from dogs from BC, AB, and ON. CONCLUSIONS: Data from this study will help in the development of strategies, based on the level of risk per geographic location for the prevention and response to these parasites in pets and free-roaming and shelter animals in Canada. PMID- 26013285 TI - Attachment of Poly(l-lactide) Nanoparticles to Plasma-Treated Non-Woven Polymer Fabrics Using Inkjet Printing. AB - Active dressings that based on fabric materials are an area of interest for the treatment of wounds. Poly(l-lactide) nanoparticles containing the antimicrobial agent octenidine can be controllably lysed by toxins released by pathogenic bacteria thus releasing antimicrobial material in response to the presence of the bacterial toxins and so counteracting the infection. We developed an integrated engineering solution that allows for the stable immobilisation of nanoparticles on non-woven fabrics. The process involves coating nanoparticles on non-woven polymer surfaces by using an inkjet printing process. In order to improve the adhesion and retention of the nanoparticles on the fabric, surface pretreatment of the non-woven fabric using plasma jet treatment can be applied to increase its surface energy. PMID- 26013284 TI - Cooperative transmembrane penetration of nanoparticles. AB - Physical penetration of lipid bilayer membranes presents an alternative pathway for cellular delivery of nanoparticles (NPs) besides endocytosis. NPs delivered through this pathway could reach the cytoplasm, thereby opening the possibility of organelle-specific targeting. Herein we perform dissipative particle dynamics simulations to elucidate the transmembrane penetration mechanisms of multiple NPs. Our simulations demonstrate that NPs' translocation proceeds in a cooperative manner, where the interplay of the quantity and surface chemistry of the NPs regulates the translocation efficiency. For NPs with hydrophilic surfaces, the increase of particle quantity facilitates penetration, while for NPs with partly or totally hydrophobic surfaces, the opposite highly possibly holds. Moreover, a set of interesting cooperative ways, such as aggregation, aggregation-dispersion, and aggregation-dispersion-reaggregation of the NPs, are observed during the penetration process. We find that the penetration behaviors of multiple NPs are mostly dominated by the changes of the NP-membrane force components in the membrane plane direction, in addition to that in the penetration direction, suggesting a different interaction mechanism between the multiple NPs and the membrane compared with the one-NP case. These results provide a fundamental understanding in the underlying mechanisms of cooperative penetration of NPs, and shed light on the NP-based drug and gene delivery. PMID- 26013286 TI - Relative sparing of the second lumbrical muscle in carpal tunnel syndrome is not associated with regional differences in axonal membrane potential. AB - OBJECTIVE: Regional differences in nerve resting membrane potential have been associated with susceptibility to entrapment neuropathy. The aim of this study was to test whether the different susceptibilities to carpal tunnel syndrome (CTS) of median nerve motor axons supplying the second lumbrical (L2) and abductor pollicis brevis (APB) muscles could be explained in this way. METHODS: Computerized nerve-excitability testing was used to examine the excitability properties of the median motor axons of both L2 and APB in 24 healthy volunteers. RESULTS: Although some excitability measurements differed between the L2 and APB motor axons, estimates of resting membrane potential (RMP) by model fitting indicated no significant difference between the two groups. CONCLUSION: Differences in RMP cannot account for the relative sparing of L2 axons in severe CTS. SIGNIFICANCE: L2 sparing in CTS most likely has an anatomical rather than a biophysical basis. PMID- 26013287 TI - A Triphenylamine with Two Phenoxy Radicals Having Unusual Bonding Patterns and a Closed-Shell Electronic State. AB - Reported herein is the structure and the electronic properties of a novel triphenylamine derivative having two phenoxy radicals appended to the amino nitrogen atom. X-ray single crystal analysis and the magnetic resonance measurements demonstrates the unexpected closed-shell electronic structure, even at room temperature, of the molecule and two unusual C-N bonds with multiple-bond character. The theoretical calculations support the experimentally determined molecular geometry with the closed-shell electronic structure, and predicted a small HOMO-LUMO gap originating from the nonbonding character of the HOMO. The optical and electrochemical measurements show that the molecule has a remarkably small HOMO-LUMO gap compared with its triphenylamine precursor. PMID- 26013288 TI - Conformational Tuning of the Intramolecular Electronic Coupling in Molecular-Wire Biruthenium Complexes Bridged by Biphenyl Derivatives. AB - The synthesis and characterization of a series of biphenyl-derived binuclear ruthenium complexes with terminal {RuCl(CO)(PMe3)3} moieties and different structural arrangements of the phenyl rings are reported. Electrochemical studies revealed that the two metal centers of the binuclear ruthenium complexes interact with each other through the biphenyl bridge, and the redox splittings DeltaE1/2 show a strong linear correlation with cos(2) phi, where phi is the torsion angle between the two phenyl rings. A combination of electrochemical, UV/Vis/NIR, and in situ IR differential spectroelectrochemical analysis clearly showed that: 1) the intramolecular electronic couplings in the binuclear ruthenium complexes could be modulated by changing phi; 2) the electronic ground state of the mixed valent cations changes from delocalized to localized through the biphenyl bridge with increasing torsion angle phi, that is, the redox processes of these complexes change from significant involvement of the bridging ligand to an oxidation behavior with less participation of the bridge. PMID- 26013291 TI - On the final size of epidemics in random environment. AB - This paper extends the final size result of the classical SIR epidemic model in constant and periodic environments to random environment. Conditionally on the basic reproduction number R0 recently defined for random environment and the initial infected population fraction, we prove a final size result of an epidemic governed by the SIR model with time-depending parameters. The parameters are driven by an ergodic inhomogeneous time-periodic Markov process with finite state space. We also analyze the classical SEIR epidemic model in random environment. PMID- 26013289 TI - SOXE transcription factors form selective dimers on non-compact DNA motifs through multifaceted interactions between dimerization and high-mobility group domains. AB - The SOXE transcription factors SOX8, SOX9 and SOX10 are master regulators of mammalian development directing sex determination, gliogenesis, pancreas specification and neural crest development. We identified a set of palindromic SOX binding sites specifically enriched in regulatory regions of melanoma cells. SOXE proteins homodimerize on these sequences with high cooperativity. In contrast to other transcription factor dimers, which are typically rigidly spaced, SOXE group proteins can bind cooperatively at a wide range of dimer spacings. Using truncated forms of SOXE proteins, we show that a single dimerization (DIM) domain, that precedes the DNA binding high mobility group (HMG) domain, is sufficient for dimer formation, suggesting that DIM : HMG rather than DIM:DIM interactions mediate the dimerization. All SOXE members can also heterodimerize in this fashion, whereas SOXE heterodimers with SOX2, SOX4, SOX6 and SOX18 are not supported. We propose a structural model where SOXE-specific intramolecular DIM:HMG interactions are allosterically communicated to the HMG of juxtaposed molecules. Collectively, SOXE factors evolved a unique mode to combinatorially regulate their target genes that relies on a multifaceted interplay between the HMG and DIM domains. This property potentially extends further the diversity of target genes and cell-specific functions that are regulated by SOXE proteins. PMID- 26013290 TI - Stability and backward bifurcation in a malaria transmission model with applications to the control of malaria in China. AB - In this paper, we consider a deterministic malaria transmission model with standard incidence rate and treatment. Human population is divided into susceptible, infectious and recovered subclasses, and mosquito population is split into susceptible and infectious classes. It is assumed that, among individuals with malaria who are treated or recovered spontaneously, a proportion moves to the recovered class with temporary immunity and the other proportion returns to the susceptible class. Firstly, it is shown that two endemic equilibria may exist when the basic reproduction number R0<1 and a unique endemic equilibrium exists if R0>1. The presence of a backward bifurcation implies that it is possible for malaria to persist even if R0<1. Secondly, using geometric method, some sufficient conditions for global stability of the unique endemic equilibrium are obtained when R0>1. To deal with this problem, the estimate of the Lozinskii measure of a 6 * 6 matrix is discussed. Finally, numerical simulations are provided to support our theoretical results. The model is also used to simulate the human malaria data reported by the Chinese Ministry of Health from 2002 to 2013. It is estimated that the basic reproduction number R0~0.0161 for the malaria transmission in China and it is found that the plan of eliminating malaria in China is practical under the current control strategies. PMID- 26013292 TI - Time to treatment as a quality metric in lung cancer: Staging studies, time to treatment, and patient survival. AB - PURPOSE: Prompt staging and treatment are crucial for non-small cell lung cancer (NSCLC). We determined if predictors of treatment delay after diagnosis were associated with prognosis. MATERIALS AND METHODS: Medicare claims from 28,732 patients diagnosed with NSCLC in 2004-2007 were used to establish the diagnosis to-treatment interval (ideally ?35days) and identify staging studies during that interval. Factors associated with delay were identified with multivariate logistic regression, and associations between delay and survival by stage were tested with Cox proportional hazard regression. RESULTS: Median diagnosis-to treatment interval was 27days. Receipt of PET was associated with delays (57.4% of patients with PET delayed [n=6646/11,583] versus 22.8% of those without [n=3908/17,149]; adjusted OR=4.48, 95% CI 4.23-4.74, p<0.001). Median diagnosis to-PET interval was 15days; PET-to-clinic, 5days; and clinic-to-treatment, 12days. Diagnosis-to-treatment intervals <35days were associated with improved survival for patients with localized disease and those with distant disease surviving ?1year but not for patients with distant disease surviving <1year. CONCLUSION: Delays between diagnosing and treating NSCLC are common and associated with use of PET for staging. Reducing time to treatment may improve survival for patients with manageable disease at diagnosis. PMID- 26013294 TI - Priority review drugs approved by the FDA and the EMA: time for international regulatory harmonization of pharmaceuticals? AB - INTRODUCTION: The US Food and Drug Administration (FDA) priority review process applies to a drug that is considered a significant improvement over the available alternatives. The European Medicines Agency (EMA) accelerated approval applies to a product that is of major public health interest. This study assessed differences in the characteristics of priority review new molecular entities and new therapeutic biologic products approved by the FDA and the EMA. METHODS: This study includes regulatory information on drug applications, approvals, indications, and orphan designations of all priority review drugs approved by the FDA and the EMA in the period 1999-2011. Descriptive statistics, t-tests, and chi squared and Wilcoxon tests were performed. RESULTS: Overall, 100 FDA priority review new molecular entities and new therapeutic biologics were approved by both agencies; 87.0% of the products were first approved by the FDA. The average FDA review time (9.2 +/- 8.4 months) was significantly lower than the EMA average review time (14.6 +/- 4.0 months) (p < 0.0001). The FDA and the EMA granted orphan designation to 43.0% and 33.0%, respectively, of the applications. There were differences in the administration route (1.0% of all products), dosage (8.0%), strength (23%), posology (51.0%), indications (30.0%), restrictions of use (52.0%), limitations of use (19.0%), and outcomes limitations (28.0%) approved by both regulatory agencies. CONCLUSION: Significant differences exist in the characteristics of the priority review drugs approved by the FDA and the EMA. Harmonization of the US and European regulatory frameworks may facilitate timely approval of pharmaceutical products. PMID- 26013295 TI - Viability-qPCR for detecting Legionella: Comparison of two assays based on different amplicon lengths. AB - Two different real-time quantitative PCR (PMA-qPCR) assays were applied for quantification of Legionella spp. by targeting a long amplicon (approx 400 bp) of 16S rRNA gene and a short amplicon (approx. 100 bp) of 5S rRNA gene. Purified DNA extracts from pure cultures of Legionella spp. and from environmental water samples were quantified. Application of the two assays to quantify Legionella in artificially contaminated water achieved that both assays were able to detect Legionella over a linear range of 10 to 10(5) cells ml(-1). A statistical analysis of the standard curves showed that both assays were linear with a good correlation coefficient (R(2) = 0.99) between the Ct and the copy number. Amplification with the reference assay was the most effective for detecting low copy numbers (1 bacterium per PCR mixture). Using selective quantification of viable Legionella by the PMA-qPCR method we obtained a greater inhibition of the amplification of the 400-bp 16S gene fragment (Deltalog(10) = 3.74 +/- 0.39 log(10) GU ml(-1)). A complete inhibition of the PCR signal was obtained when heat-killed cells in a concentration below 1 * 10(5) cells ml(-1) were pretreated with PMA. Analysing short amplicon sizes led to only 2.08 log reductions in the Legionella dead-cell signal. When we tested environmental water samples, the two qPCR assays were in good agreement according to the kappa index (0.741). Applying qPCR combined with PMA treatment, we also obtained a good agreement (kappa index 0.615). The comparison of quantitative results shows that both assays yielded the same quantification sensitivity (mean log = 4.59 vs mean log = 4.31). PMID- 26013296 TI - Preparation and characterization of a stable BHK-21 cell line constitutively expressing the Schmallenberg virus nucleocapsid protein. AB - Schmallenberg virus (SBV) is a newly emerged orthobunyavirus that predominantly infects livestock such as cattle, sheep, and goats. Its nucleocapsid (N) protein is an ideal target antigen for SBV diagnosis. In this study, a stable BHK-21 cell line, BHK-21-EGFP-SBV-N, constitutively expressing the SBV N protein was obtained using a lentivector-mediated gene transfer system combined with puromycin selection. To facilitate the purification of recombinant SBV N protein, the coding sequence for a hexa-histidine tag was introduced into the C-terminus of the SBV N gene during construction of the recombinant lentivirus vector pLV-EGFP SBV-N. The BHK-21-EGFP-SBV-N cell line was demonstrated to spontaneously emit strong enhanced green fluorescent protein (EGFP) signals that exhibited a discrete punctate distribution throughout the cytoplasm. SBV N mRNA and protein expression in this cell line were detected by real-time RT-PCR and western blot, respectively. The expressed recombinant SBV N protein carried an N-terminal EGFP tag, and was successfully purified using Ni-NTA agarose by means of its C terminal His tag. The purified SBV N protein could be recognized by SBV antisera and an anti-SBV monoclonal antibody (mAb) 2C8 in an indirect enzyme-linked immunosorbent assay and western blot analyses. Indirect immunofluorescence assays further demonstrated that the stable cell line reacts with SBV antisera and mAb 2C8. These results suggest that the generated cell line has the potential to be used in the serological diagnosis of SBV. PMID- 26013297 TI - Metabolic profiling of hematopoietic stem and progenitor cells during proliferation and differentiation into red blood cells. AB - An understanding of the metabolic profile of cell proliferation and differentiation should support the optimization of culture conditions for hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and maturation into red blood cells. We have evaluated the key metabolic parameters during each phase of HSPC culture for red blood cell production in serum supplemented (SS) and serum-free (SF) conditions. A simultaneous decrease in growth rate, total protein content, cell size, and the percentage of cells in the S/G2 phase of cell cycle, as well as an increase in the percentage of cells with a CD71(-)/GpA(+) surface marker profile, indicates HSPC differentiation into red blood cells. Compared with proliferating HSPCs, differentiating HSPCs showed significantly lower glucose and glutamine consumption rates, lactate and ammonia production rates, and amino acid consumption and production rates in both SS and SF conditions. Furthermore, extracellular acidification was associated with late proliferation phase, suggesting a reduced cellular metabolic rate during the transition from proliferation to differentiation. Under both SS and SF conditions, cells demonstrated a high metabolic rate with a mixed metabolism of both glycolysis and oxidative phosphorylation (OXPHOS) in early and late proliferation, an increased dependence on OXPHOS activity during differentiation, and a shift to glycolytic metabolism only during maturation phase. These changes indicate that cell metabolism may have an important impact on the ability of HSPCs to proliferate and differentiate into red blood cells. PMID- 26013293 TI - Novel Xylene-Linked Maltoside Amphiphiles (XMAs) for Membrane Protein Stabilisation. AB - Membrane proteins are key functional players in biological systems. These biomacromolecules contain both hydrophilic and hydrophobic regions and thus amphipathic molecules are necessary to extract membrane proteins from their native lipid environments and stabilise them in aqueous solutions. Conventional detergents are commonly used for membrane protein manipulation, but membrane proteins surrounded by these agents often undergo denaturation and aggregation. In this study, a novel class of maltoside-bearing amphiphiles, with a xylene linker in the central region, designated xylene-linked maltoside amphiphiles (XMAs) was developed. When these novel agents were evaluated with a number of membrane proteins, it was found that XMA-4 and XMA-5 have particularly favourable efficacy with respect to membrane protein stabilisation, indicating that these agents hold significant potential for membrane protein structural study. PMID- 26013299 TI - A Ruthenium(II)-Copper(II) Dyad for the Photocatalytic Oxygenation of Organic Substrates Mediated by Dioxygen Activation. AB - Dioxygen activation by copper complexes is a valuable method to achieve oxidation reactions for sustainable chemistry. The development of a catalytic system requires regeneration of the Cu(I) active redox state from Cu(II). This is usually achieved using extra reducers that can compete with the Cu(II)(O2) oxidizing species, causing a loss of efficiency. An alternative would consist of using a photosensitizer to control the reduction process. Association of a Ru(II) photosensitizing subunit with a Cu(II) pre-catalytic moiety assembled within a unique entity is shown to fulfill these requirements. In presence of a sacrificial electron donor and light, electron transfer occurs from the Ru(II) center to Cu(II). In presence of dioxygen, this dyad proved to be efficient for sulfide, phosphine, and alkene catalytic oxygenation. Mechanistic investigations gave evidence about a predominant (3)O2 activation pathway by the Cu(I) moiety. PMID- 26013298 TI - Peptide folding driven by Van der Waals interactions. AB - Contrary to the widespread view that hydrogen bonding and its entropy effect play a dominant role in protein folding, folding into helical and hairpin-like structures is observed in molecular dynamics (MD) simulations without hydrogen bonding in the peptide-solvent system. In the widely used point charge model, hydrogen bonding is calculated as part of the interaction between atomic partial charges. It is removed from these simulations by setting atomic charges of the peptide and water to zero. Because of the structural difference between the peptide and water, van der Waals (VDW) interactions favor peptide intramolecular interactions and are a major contributing factor to the structural compactness. These compact structures are amino acid sequence dependent and closely resemble standard secondary structures, as a consequence of VDW interactions and covalent bonding constraints. Hydrogen bonding is a short range interaction and it locks the approximate structure into the specific secondary structure when it is included in the simulation. In contrast to standard molecular simulations where the total energy is dominated by charge-charge interactions, these simulation results will give us a new view of the folding mechanism. PMID- 26013300 TI - Transfusion strategy for acute upper gastrointestinal bleeding. AB - Clinical question Does a hemoglobin transfusion threshold of 70 g/L yield better patient outcomes than a threshold of 90 g/L in patients with acute upper gastrointestinal bleeding? Article chosen Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368(1):11-21. Study objectives The authors of this study measured mortality, from any cause, within the first 45 days, in patients with acute upper gastrointestinal bleeding, who were managed with a hemoglobin threshold for red cell transfusion of either 70 g/L or 90 g/L. The secondary outcome measures included rate of further bleeding and rate of adverse events. PMID- 26013301 TI - Redox and rice blast: new tools for dissecting molecular fungal-plant interactions. PMID- 26013302 TI - Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures. AB - Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to alpha2 adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to alpha2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence. PMID- 26013303 TI - Variation in homotopic areas' activity and inter-hemispheric intrinsic connectivity with type of language lateralization: an FMRI study of covert sentence generation in 297 healthy volunteers. AB - We investigated the regional correlates of differences in hemispheric lateralization in 297 healthy volunteers [including 153 left-handers (LH)] previously classified into three types of language lateralization according to their hemispheric functional lateralization index measured with fMRI during covert sentence production versus word list production (PRODSENT-LIST): 250 leftward asymmetrical Typicals, 10 rightward asymmetrical Strong-atypicals (only LH), and 37 Ambilaterals with weak lateralization. Using a functionally driven homotopic atlas (AICHA), we compared patterns of regional asymmetry during PRODSENT-LIST in these three groups. Among the 192 homotopic regions of interest (hROIs) of the AICHA atlas, 58 exhibited a significant effect of the type of lateralization on their BOLD signal variation during PRODSENT-LIST. The analyses of patterns of asymmetry of these 58 hROIs showed that (1) hROIs asymmetries in Strong-atypicals were significantly negatively correlated with those observed in Typicals, which indicates that their regional pattern of rightward asymmetries was comparable to the regional pattern of leftward language asymmetries of Typicals; (2) right- and left-handed Typicals had identical profiles, whereas left-handed Ambilaterals exhibited reduced leftward asymmetry as compared either to right-handed Ambilaterals or to Typicals. Moreover, left-handed Ambilaterals pattern of hROIs asymmetries significantly positively correlated with those of both Typicals and Strong-atypicals. In 291 of the participants, we tested the hypothesis that differences in language lateralization were associated with differences in inter-hemispheric connectivity during resting state by measuring their regional homotopic inter-hemispheric intrinsic connectivity coefficient (rHIICC) in 36 of the 58 hROIs known to be connected via the corpus callosum. Mean rHIICCs were negatively correlated with task-induced functional asymmetries, suggesting that enhanced inter-hemispheric cooperation at rest translates into increased inter-hemispheric cooperation during language production. In addition, the left-handed Ambilaterals exhibited a significantly larger rHIICC compared with right-handed Ambilaterals and Typicals, confirming a difference in inter hemispheric organization in this group. PMID- 26013306 TI - European Journal of Orthodontics: Editor's Report 2014. PMID- 26013305 TI - National survey of fibrinogen concentrate usage for post-partum hemorrhage in Japan: investigated by the Perinatology Committee, Japan Society of Obstetrics and Gynecology. AB - AIM: The aim of this study was to provide basic documents applicable to studying the usefulness of administering fibrinogen concentrate to patients with massive post-partum hemorrhage. We investigated the usage of fibrinogen concentrate at training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology. MATERIAL AND METHODS: The subjects were women who required fibrinogen concentrate for hemostasis of post-partum hemorrhage during the period between April 2008 and March 2013. The underlying diseases, obstetric disseminated intravascular coagulation scores, blood loss, amount of blood transfusion, dose of fibrinogen concentrate administered, and plasma fibrinogen levels before and after the administration of fibrinogen concentrate were retrospectively investigated. RESULTS: Ninety-nine (98.0%) patients survived and two died after taking fibrinogen concentrate. Of the surviving 99 cases, the average amount of blood loss at the time of initial fibrinogen administration and total blood loss was 3559 +/- 2103 mL and 4562 +/- 3198 mL, respectively. The dose per administration was 3 g, and the plasma fibrinogen level before the initial administration of fibrinogen concentrate was 70.5 mg/dL, thereafter increasing to 187.0 mg/dL. The increase in the fibrinogen level was 32.9 mg/dL/g of fibrinogen concentrate. It was less than 150 mg/dL after the first administration of fibrinogen concentrate only in patients with amniotic fluid embolism and patients with atonic bleeding showed the smallest increase in fibrinogen per gram of fibrinogen concentrate. No adverse events, including thromboembolism, were reported. CONCLUSION: The results indicated the increase in blood fibrinogen levels to, on occasion, be insufficient even with fibrinogen concentrate use; however, this survey may support the safety and usefulness of fibrinogen concentrate for PPH. PMID- 26013304 TI - Whole body diffusion weighted MRI--a new view of myeloma. AB - The recent consensus statement from the International Myeloma Working Group has introduced the role of whole body (WB) magnetic resonance imaging (MRI) into the management pathway for patients with multiple myeloma. The speed, coverage and high sensitivity of WB diffusion weighted (DW)-MRI and the unique capability to quantify both burden of disease and response to treatment has led to increasing implementation at leading centres worldwide for imaging malignant marrow disease, both primary and metastatic. WB DW-MRI is likely to have a significant impact on management decisions and pathways for patients with multiple myeloma. This review will introduce the basic principles of DW-MRI, present current evidence for patients with myeloma and will discuss practicalities and exciting future applications. PMID- 26013308 TI - Estimation of causal effects of binary treatments in unconfounded studies. AB - Estimation of causal effects in non-randomized studies comprises two distinct phases: design, without outcome data, and analysis of the outcome data according to a specified protocol. Recently, Gutman and Rubin (2013) proposed a new analysis-phase method for estimating treatment effects when the outcome is binary and there is only one covariate, which viewed causal effect estimation explicitly as a missing data problem. Here, we extend this method to situations with continuous outcomes and multiple covariates and compare it with other commonly used methods (such as matching, subclassification, weighting, and covariance adjustment). We show, using an extensive simulation, that of all methods considered, and in many of the experimental conditions examined, our new 'multiple-imputation using two subclassification splines' method appears to be the most efficient and has coverage levels that are closest to nominal. In addition, it can estimate finite population average causal effects as well as non linear causal estimands. This type of analysis also allows the identification of subgroups of units for which the effect appears to be especially beneficial or harmful. PMID- 26013307 TI - Transcatheter, inflatable, and fully repositionable aortic valve: Preliminary results using a modified implantation technique. AB - OBJECTIVES: We present our experience with an inflatable, non-metallic, fully retrievable, and repositionable transcatheter aortic valve [Direct Flow(r) Medical (DFM)] focusing on technical features adopted during implantation. BACKGROUND: Implantation techniques of new generation percutaneous aortic valves are still developing and with experience implementations are described. METHODS: The "low pressure" (initial valve inflation at 4 ATM, lower than the recommended 12 ATM) and the "alternate aortic curve" techniques (initial valve pulling either from the wire running on the side of the inner or from the one on the outer aortic curve) are part of our modified protocol for DFM(r) implantation. RESULTS: Forty-two consecutive patients underwent TAVI with DFM. The "low pressure" technique was used in all patients. In 27 (64.3%) patients the bulkiest calcifications were on the inner aortic curve side, and an inner curve technique was used to initiate valve pulling toward the annular hinge point. In the remaining 15 (35.7%) patients, an outer curve technique was used. Neither pull through nor re-valving was reported. Valve performance showed mean gradient of 8.9 mm Hg. Mild paravalvular leak was reported in seven (16%) patients. No one experienced moderate or severe aortic insufficiency. Thirty-day mortality was 9.5% (4/42). CONCLUSION: The "low pressure technique" and the "alternate curve technique" guarantee an anatomy and patient tailored approach to achieve controlled and finely tuned valve seating. PMID- 26013309 TI - Acetaminophen (paracetamol) oral absorption and clinical influences. AB - Acetaminophen (paracetamol) is a widely used nonopioid, non-NSAID analgesic that is effective against a variety of pain types, but the consequences of overdose can be severe. Because acetaminophen is so widely available as a single agent and is increasingly being formulated in fixed-ratio combination analgesic products for the potential additive or synergistic analgesic effect and/or reduced adverse effects, accidental cumulative overdose is an emergent concern. This has rekindled interest in the sites, processes, and pharmacokinetics of acetaminophen oral absorption and the clinical factors that can influence these. The absorption of oral acetaminophen occurs primarily along the small intestine by passive diffusion. Therefore, the rate-limiting step is the rate of gastric emptying into the intestines. Several clinical factors can affect absorption per se or the rate of gastric emptying, such as diet, concomitant medication, surgery, pregnancy, and others. Although acetaminophen does not have the abuse potential of opioids or the gastrointestinal bleeding or organ adverse effects of NSAIDs, excess amounts can produce serious hepatic injury. Thus, an understanding of the sites and features of acetaminophen absorption--and how they might be influenced by factors encountered in clinical practice--is important for pain management using this agent. It can also provide insight for design of formulations that would be less susceptible to clinical variables. PMID- 26013310 TI - Comparison of the DAS28-CRP and DAS28-ESR in patients with rheumatoid arthritis. AB - AIM: To compare the Disease Activity Score with 28 joint (DAS28) using erythrocyte sedimentation rate (ESR) (DAS28-ESR) and DAS28 using C-reactive protein (CRP) (DAS28-CRP) with thresholds validated for DAS28-ESR in Turkish patients with rheumatoid arthritis. METHOD: The DAS28 data of 112 patients with rheumatoid arthritis followed in a local outpatient clinic were used. First, the correlation between DAS28-CRP and DAS28-ESR and the correlation between their unique components ([0.36 * In (CRP + 1) + 0.96] and [0.70 * In (ESR)]) were analyzed. Second, a Bland-Altman plot was constructed for the evaluation of the level of agreement between DAS28-CRP and DAS28-ESR. Lastly, the agreement between these two methods was analyzed by kappa coefficient. RESULTS: Although there was a strong correlation between DAS28-CRP and DAS28-ESR, the correlation between their unique components was fair. Although more than 95% of the point data fall between the upper and lower bounds of the limit of agreement, the percentage error (46%) was higher than the acceptable proportion of 30%. The kappa coefficient of agreement between DAS28- ESR and DAS28-CRP with validated thresholds for DAS28-ESR was 0.42, which was close to the lower boundary for moderate agreement. CONCLUSION: The results of this study demonstrated that there is discordance between DAS28-ESR and DAS28-CRP with the validated thresholds for DAS28-ESR. Using the DAS28-CRP with threshold values validated for DAS28-ESR may lead to errors in the determination of disease activity and therefore may lead to errors in the management of patients with rheumatoid arthritis. PMID- 26013311 TI - Initial experiences of a student assistantship. AB - BACKGROUND: Evidence suggests that medical graduates are underprepared to work as junior doctors. To ease transition in the UK, the General Medical Council (GMC) recommended the introduction of a student 'assistantship'. This is a period of training where final-year students take on duties of a foundation doctor under supervision. This study explored the experiences of the first cohort of students and junior doctors participating in the assistantship in one UK medical school in 2012. METHODS: All 248 students and their supervisors were asked to complete an online feedback questionnaire. All students who went on to work locally were also invited to participate in focus groups as recent graduates. Evidence suggests that medical graduates are underprepared to work as junior doctors RESULTS: Questionnaire response rates were 49 per cent for students and 43 per cent for supervisors. Fifteen new graduates participated in focus groups. Aspects of the assistantship considered important to participants frequently mapped to areas specified by the GMC and the locally identified learning outcomes. Additional themes identified included the importance of having meaningful responsibility for patient care, a placement in a general medical or surgical ward and receiving effective feedback. DISCUSSION: The assistantship seems to have been highly valued by students, but could be improved by ensuring that all students are given relevant placements and clinical responsibility. PMID- 26013312 TI - Forensic genetic analysis of bio-geographical ancestry. AB - With the great strides made in the last ten years in the understanding of human population variation and the detailed characterization of the genome, it is now possible to identify sets of ancestry informative markers suitable for relatively small-scale PCR-based assays and use them to analyze the ancestry of an individual from forensic DNA. This review outlines some of the current understanding of past human population structure and how it may have influenced the complex distribution of contemporary human diversity. A simplified description of human diversity can provide a suitable basis for choosing the best ancestry-informative markers, which is important given the constraints of multiplex sizes in forensic DNA tests. It is also important to decide the level of geographic resolution that is realistic to ensure the balance between informativeness and an over-simplification of complex human diversity patterns. A detailed comparison is made of the most informative ancestry markers suitable for forensic use and assessments are made of the data analysis regimes that can provide statistical inferences of a DNA donor's bio-geographical ancestry. PMID- 26013313 TI - Pedigrees of madness: the study of heredity in nineteenth and early twentieth century psychiatry. AB - This article discusses the development of the statistical methods employed by psychiatrists to study heredity as a causative factor of mental diseases. It argues that psychiatric asylums and clinics were the first institutions in which human heredity became the object of systematic research. It also highlights the different concepts of heredity prevalent in the psychiatric community. The first of four parts traces how heredity became a central category of asylum statistics in the first half of the nineteenth century. The second part deals with attempts to introduce new methods of surveying in order to generate more precise data about psychopathological inheritance in the 1860s and 1870s. The third part discusses how, by the end of the nineteenth century, a widespread discontent with the results of asylum statistics led to an increasing interest in the use of family studies. Finally, the fourth part examines the impact of Mendelian theory on psychiatric statistics in the early twentieth century. PMID- 26013314 TI - That 70s show: regulation, evolution and development beyond molecular genetics. AB - This paper argues that the "long 1970s" (1969-1983) is an important though often overlooked period in the development of a rich landscape in the research of metabolism, development, and evolution. The period is marked by: shrinking public funding of basic science, shifting research agendas in molecular biology, the incorporation of new phenomena and experimental tools from previous biological research at the molecular level, and the development of recombinant DNA techniques. Research was reoriented towards eukaryotic cells and development, and in particular towards "giant" RNA processing and transcription. We will here focus on three different models of developmental regulation published in that period: the two models of eukaryotic genetic regulation at the transcriptional level that were developed by Georgii P. Georgiev on the one hand, and by Roy Britten and Eric Davidson on the other; and the model of genetic sufficiency and evolution of regulatory genes proposed by Emile Zuckerkandl. These three bases illustrate the range of exploratory hypotheses that characterised the challenging landscape of gene regulation in the 1970s, a period that in hindsight can be labelled as transitional, between the biology at the laboratory bench of the preceding period, and the biology of genetic engineering and intensive data driven research that followed. PMID- 26013315 TI - Advice for a young psychiatrist researcher. PMID- 26013316 TI - Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide. AB - OBJECTIVES: In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls. METHOD: We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls. RESULTS: Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex ( 17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p < 0.01) and GRIN2C mRNA (laminae I-VI; -27%, p < 0.05) were lower in the anterior cingulate cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral prefrontal cortex (-19%, p < 0.01). In major depressive disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower (-35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex. CONCLUSION: These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine. PMID- 26013317 TI - Fast immuno-labeling by electrophoretically driven infiltration for intact tissue imaging. AB - Recently developed tissue clearing techniques, where the tissue is embedded within a hydrogel, have revolutionized our ability to resolve fine cellular structures in nearly intact tissues. However, the slow rate of penetration of antibodies within this hydrogel-tissue matrix has become a significantly limiting factor in many experiments, as thick tissues often require weeks to months to be adequately labeled. Increasing the pore size of this matrix has been investigated as a possible solution, but with only modest success. Here, we have systematically examined the diffusional behavior of antibodies and other typically used immuno-labels within this hydrogel-tissue matrix and, surprisingly, found that infiltration occurs at rates similar to those of diffusion in free solution. Therefore, changing the pore size of the matrix would be expected to afford only limited improvement and, instead, some means of active transport is necessary. We show that an electrophoretically-driven approach decreases the delivery time of antibodies by more than 800-fold over simple diffusion, without incurring structural damage. These results, together with the high quality of the images obtained with this method, demonstrate the advantage of this approach, thus significantly broadening the practical range of samples that can now be investigated by whole-mount tissue clearing methods. PMID- 26013318 TI - Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations. AB - A prominent role in the pathogenesis of squamous cell carcinoma of the lung (SQCLC) has been attributed to the aberrant activation of the PI3K signaling pathway, due to amplification or mutations of the p110alpha subunit of class I phosphatidylinositol 3-kinase (PIK3CA) gene. The aim of our study was to determine whether different genetic alterations of PIK3CA affect the biologic properties of SQCLC and to evaluate the response to specific targeting agents in vitro and in vivo. The effects of NVP-BEZ235, NVP-BKM120, and NVP-BYL719 on two dimensional/three-dimensional (2D/3D) cellular growth, epithelial-to-mesenchymal transition, and invasiveness were evaluated in E545K or H1047R PIK3CA-mutated SQCLC cells and in newly generated clones carrying PIK3CA alterations, as well as in a xenograft model. PIK3CA mutated/amplified cells showed increased growth rate and enhanced migration and invasiveness, associated with an increased activity of RhoA family proteins and the acquisition of a mesenchymal phenotype. PI3K inhibitors reverted this aggressive phenotype by reducing metalloproteinase production, RhoA activity, and the expression of mesenchymal markers, with the specific PI3K inhibitors NVP-BKM120 and NVP-BYL719 being more effective than the dual PI3K/mTOR inhibitor NVP-BEZ235. A xenograft model of SQCLC confirmed that PIK3CA mutation promotes the acquisition of a mesenchymal phenotype in vivo and proved the efficacy of its specific targeting drug NVP-BYL719 in reducing the growth and the expression of mesenchymal markers in xenotransplanted tumors. These data indicate that PIK3CA mutation/amplification may represent a good predictive feature for the clinical application of specific PI3K inhibitors in SQCLC patients. PMID- 26013319 TI - MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor. AB - Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and subsequently determine the mechanism of apoptosis mediated by the MCL-1 selective inhibitor A-1210477. We demonstrate that apoptosis resulting from a loss in MCL-1 function requires expression of the proapoptotic protein BAK. However, expression of BCL-XL can limit apoptosis resulting from loss in MCL-1 function through sequestration of free BIM. Finally, we demonstrate substantial synergy between navitoclax and MCL-1 siRNA, the direct MCL-1 inhibitor A-1210477, or the indirect MCL-1 inhibitor flavopiridol, highlighting the therapeutic potential for inhibiting BCL-XL and MCL-1 in breast cancer. PMID- 26013320 TI - Somatic concerns, depressive traits, atherosclerosis and the incidence of cardiovascular disease in ageing Finnish men. AB - OBJECTIVE: To examine the impact of somatic concerns and depressive traits on carotid artery intima-media thickness (IMT) and on the incidence of cardiovascular disease (CVD). METHODS: In the cross-sectional study of 2682 Finnish men aged 42 to 61years, a subsample of 1333 men had their carotid artery IMT recorded. In the prospective part of the study participants (n=1453) were followed up for an average of 20years. Data on incident CVD (n=766) were obtained from the National Population Register. For both subsamples, the Minnesota Multiphasic Personality Inventory (MMPI) was used to measure depressive traits and somatic concerns. In addition, composite scales of general ill-being, sleep and pain problems, psychological well-being, energy level, and cheerfulness were formed. RESULTS: In the final corrected models there were no significant associations between somatic concerns or depressive traits and IMT. Both somatic concerns and depressive traits predicted a higher CVD incidence after adjustments for age and risk factors. The association between depressive traits and CVD incidence was highest among the subgroup of men with the highest levels of hsCRP, but this result did not reach statistical significance. Of the composite scales, general ill-being predicted a higher CVD incidence in the fully adjusted model, even when all the composite scales were entered into the model simultaneously. CONCLUSION: Somatic concerns and depressive traits predict a higher CVD incidence. In particular, general ill-being contributes to this association. The association between depressive traits and CVD may be moderated by low-grade inflammation. PMID- 26013321 TI - Sleep deprivation affects reactivity to positive but not negative stimuli. AB - OBJECTIVE: The current study examined the effects of partial and total sleep deprivation on emotional reactivity. METHODS: Twenty-eight partially sleep deprived participants and 31 totally sleep-deprived participants rated their valence and arousal responses to positive and negative pictures across four testing sessions during the day following partial sleep deprivation or during the night under total sleep deprivation. RESULTS: The results suggest that valence and arousal ratings decreased under both sleep deprivation conditions. In addition, partial and total sleep deprivation had a greater negative effect on positive events than negative events. CONCLUSION: These results suggest that sleep-deprived persons are more likely to respond less to positive events than negative events. One explanation for the current findings is that negative events could elicit more attentive behavior and thus stable responding under sleep deprivation conditions. As such, sleep deprivation could impact reactivity to emotional stimuli through automated attentional and self-regulatory processes. PMID- 26013322 TI - The magnitude of placebo analgesia effects depends on how they are conceptualized. AB - OBJECTIVE: Placebo effects are usually calculated as the difference between placebo treatments and no treatments. Recently, placebo-like effects have been investigated using open and hidden administrations of active treatments. The aim of the study was to directly compare the two types of placebo effects and examine how they are influenced by personality traits. METHODS: In a within-subject, randomized, blinded, balanced placebo trial design study with 48 healthy volunteers, we compared placebo and placebo-like effects and tested if expectancy, absorption and suggestibility correlated with these effects. Subjects completed the Tellegen Absorption Scale and the Sensory Suggestibility Scale, and pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections of hypertonic saline with lidocaine or matching placebo in randomized order: open treatment, hidden treatment, placebo and control. The placebo effect was defined as the difference in pain between the placebo and the control condition and the placebo-like effect as the difference in pain between the open and hidden condition. RESULTS: Placebo effects were significant both in the traditional paradigm: mean placebo effect AUC 1626 mm(2) (95% CI 958-2293) and the open-hidden paradigm: mean placebo-like effect AUC 801 mm(2) (95% CI 134-1469), but there was a significant difference between the magnitude of the two effects (p=0.049). Absorption and suggestibility did not predict the placebo or the placebo-like effect. Estimated expected pain relief correlated with placebo effects but not placebo-like effects. CONCLUSION: The magnitude of placebo effects differs depending on how they are conceptualized and calculated. PMID- 26013323 TI - New prenyllipid metabolites identified in Arabidopsis during photo-oxidative stress. AB - In the present study, we have identified new prenyllipid metabolites formed during high light stress in Arabidopsis thaliana, whose origin and function remained unknown so far. It was found that plastoquinone-C accumulates mainly in the reduced form under high light conditions, as well as during short-term excess light illumination both in the wild-type and tocopherol biosynthetic vte1 mutant, suggesting that plastoquinone-C, a singlet oxygen-derived prenyllipid, is reduced in chloroplasts by photosystem II or enzymatically, outside thylakoids. Plastoquinone-B, a fatty acid ester of plastoquinone-C, was identified for the first time in Arabidopsis in high light grown wild-type plants and during short time, excess light illumination of the wild-type plants and the vte1 mutant. The gene expression analysis showed that vte2 gene is most pronouncedly up-regulated among the prenyllipid biosynthetic genes under high light and induction of its expression is mainly caused by an increased level of singlet oxygen, as was demonstrated in experiments with D2 O-treated plants under excess light conditions. PMID- 26013325 TI - Geometry controls the stability of FeSi14. AB - First-principles theoretical studies have been carried out to investigate the stability of Sin cages impregnated with a Fe atom. It is shown that FeSi9, FeSi11, and FeSi14 clusters exhibit enhanced local stability as seen through an increase in Si binding energy, Fe embedding energy, the gap between the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO), and the Ionization Potential (IP). The conventional picture for the stability of such species combines an assumption of electron precise bonding with the 18-electron rule; however, we find this to be inadequate to explain the enhanced stability in FeSi11 and FeSi14 because the d-band is filled for all FeSin clusters for n>= 9. FeSi14 is shown to be the most stable due to a compact and highly symmetric Si14 cage with octahedral symmetry that allows better mixing between Fe 3d- and Si 3p-electronic states. PMID- 26013324 TI - A phase II study of biweekly S-1 and paclitaxel (SPA) as first-line chemotherapy in patients with metastatic or advanced gastric cancer. AB - PURPOSE: Paclitaxel and S-1 are both effective antitumor chemotherapeutic agents for advanced gastric cancer. However, the continuous administration of S-1 for 3 weeks or more can result in unacceptable toxicities, particularly hematological toxicities. Therefore, an alternative treatment schedule (1-week administration followed by 1-week rest) is warrant for testing in order to allow continuation of the therapy. We evaluate the efficacy and safety of biweekly S-1 and paclitaxel (SPA) as first-line chemotherapy in patients with metastatic or advanced gastric cancer. METHODS: Patients with previously untreated advanced or relapsed gastric cancer who had measurable lesion(s) were enrolled. Paclitaxel was administered intravenously at a dose of 120 mg/m(2) on day 1 and oral S-1 was given twice daily (BSA < 1.25 m(2), 80 mg/day; 1.25 <= BSA < 1.50 m(2), 100 mg/day; 1.50 m(2) <= BSA, 120 mg/day) on days 1-7 followed by a drug-free interval of 1 week every 14-day cycle. RESULTS: Forty-four patients (M/F = 33/11) were enrolled. A total of 277 chemotherapy cycles were administered, with a median of six cycles per patient (range 1-12), and 19 (43.2 %) patients received up to seven cycles. The assessed overall response rate was 38.6 with 38.6 % partial response in 17 patients, 45.4 % stable disease in 20 patients, and 13.6 % progressive disease in six patients. Thirty-four patients (77.3 %) received second-line chemotherapy. The estimated median progression-free survival and median overall survival times were, respectively, 5.2 months (95 % CI 4.08-6.39 months) and 12.2 months (95 % CI 8.81-15.60 months). The major hematological toxicities were included grade 3 leucocytopenia in two patients (4.5 %), grade 3 neutropenia in 14 patients (40.9 %), and grade 4 neutropenia in four patients (9.0 %). Two patients (4.5 %) suffered grade 1 febrile neutropenia. All grade of the non-hematological toxicities, such as nausea, vomiting, alopecia, and diarrhea, held the proportion of 54.5 % (grade 3/4, 4.5 %), 31.8, 95.4, and 18.1 % (grade 3/4, 2.2 %), respectively. CONCLUSIONS: Biweekly S-1 and paclitaxel (SPA regimen) combination therapy had promising activity with acceptable adverse toxicities. SPA regimen was easily implemented, and more patients received second-line chemotherapy. It deserved to conduct a well-designed randomized phase III study to compare this regimen with S-1-based combination treatment. PMID- 26013326 TI - Anti-Inflammatory Activity of Polysaccharide Fraction of Curcuma longa Extract (NR-INF-02). AB - The aim of the study was to investigate the safety and anti-inflammatory effects of polysaccharide fraction (F1) of Curcuma longa extract (NR-INF-02) in classical rodent models of inflammation. F1 was evaluated for its acute oral toxicity and found to be safe upto 5000 mg/kg body weight in rats. The anti-inflammatory activity of F1 was evaluated in acute (carrageenan - induced paw edema; xylene - induced ear edema) and chronic (cotton pellet - induced granuloma) models of inflammation. The results of the study demonstrated that F1 significantly (p <= 0.05) inhibited carrageenan-induced paw edema at 1 h and 3 h at doses of 11.25, 22.5 and 45 mg/kg body weight in rats. Also, F1 at doses of 15.75, 31.5 and 63 mg/kg significantly inhibited the xylene induced ear edema in mice. In a chronic model, F1 at 11.25, 22.5 and 45 mg/kg doses produced significant reduction of wet and dry weights of cotton pellets in rats. Overall results indicated that F1 of NR-INF-02 significantly attenuated acute and chronic inflammation in rodent models. This study emphasizes on the importance of Curcuma longa polysaccharide's role in acute and chronic inflammation. PMID- 26013358 TI - Characterization of 2D colloid aggregations created by optically induced electrohydrodynamics. AB - Rapid electrokinetic patterning (REP) is a technique for creating self-assembled monolayers (SAMs) of spherical particles in a liquid medium, and dynamically controlling them though the simultaneous application of an electric field and optically induced temperature gradients. Previous work has investigated and characterized REP axisymmetric aggregations generated from a focus laser within a uniform electric field; work herein characterizes line-shaped particle assemblies derived from the application of a linearly scanned laser. The resulting aggregations of spherical polystyrene particles (1 MUm) suspended in low conductivity aqueous potassium chloride solution (KCl, 2.5 mS/m) resembled elliptical-shaped crystalline geometries. The mean particle-to-particle spacing within the aggregation remained greater than 1.5 diameters for experiments herein (6.5 Vrms , 30 kHz) due to dipole-dipole repulsive forces. Interparticle spacing demonstrated a linear relationship (1.6-2.1 MUm) with increasing scanning lengths (up to 83 MUm), decreased from 1.9 to 1.7 MUm with increasing scanning frequency (0.38-16 Hz) for a 53 MUm scan length, and decreased from 2.0 to 1.6 MUm with increasing laser power (11.9-18.8 mW) for a 59 MUm, 16 Hz laser scan. PMID- 26013357 TI - Platelet-Derived Growth Factor BB Enhances Osteogenesis of Adipose-Derived But Not Bone Marrow-Derived Mesenchymal Stromal/Stem Cells. AB - Tissue engineering using mesenchymal stem cells (MSCs) holds great promise for regenerating critically sized bone defects. While the bone marrow-derived MSC is the most widely studied stromal/stem cell type for this application, its rarity within bone marrow and painful isolation procedure have motivated investigation of alternative cell sources. Adipose-derived stromal/stem cells (ASCs) are more abundant and more easily procured; furthermore, they also possess robust osteogenic potency. While these two cell types are widely considered very similar, there is a growing appreciation of possible innate differences in their biology and response to growth factors. In particular, reports indicate that their osteogenic response to platelet-derived growth factor BB (PDGF-BB) is markedly different: MSCs responded negatively or not at all to PDGF-BB while ASCs exhibited enhanced mineralization in response to physiological concentrations of PDGF-BB. In this study, we directly tested whether a fundamental difference existed between the osteogenic responses of MSCs and ASCs to PDGF-BB. MSCs and ASCs cultured under identical osteogenic conditions responded disparately to 20 ng/ml of PDGF-BB: MSCs exhibited no difference in mineralization while ASCs produced more calcium per cell. siRNA-mediated knockdown of PDGFRbeta within ASCs abolished their ability to respond to PDGF-BB. Gene expression was also different; MSCs generally downregulated and ASCs generally upregulated osteogenic genes in response to PDGF-BB. ASCs transduced to produce PDGF-BB resulted in more regenerated bone within a critically sized murine calvarial defect compared to control ASCs, indicating PDGF-BB used specifically in conjunction with ASCs might enhance tissue engineering approaches for bone regeneration. PMID- 26013360 TI - Erratum to: Quantifying the health benefits of chronic disease prevention: a fresh approach using cardiovascular disease as an example. PMID- 26013359 TI - Asthma prevalence in Olympic summer athletes and the general population: An analysis of three European countries. AB - BACKGROUND: Some studies have shown a higher prevalence of asthma in elite athletes as compared to the general population. It is inconclusive to what extent certain sport categories are especially affected. The present study offered a unique opportunity to assess these differences in asthma prevalence in the general population and elite summer athletes from a wide range of sport disciplines across various geographical areas. METHODS: Cross-sectional data for 1568 general population participants from the European Community Respiratory Health Survey II and 546 elite athletes from the Global Allergy and Asthma European Network Olympic study from three European countries were analyzed. Using logistic regression, the asthma risks associated with athlete sport practice, endurance level and aquatic sport practice, respectively, were investigated. RESULTS: Athletes in the highest endurance category had increased risk of doctor diagnosed asthma (OR 3.5; 95% CI 1.7-7.5), asthma symptoms (OR 3.0; CI 1.5-6.0) and asthma symptoms or medication use (OR 3.5; CI 1.8-6.7) compared to the general population. Aquatic athletes were at increased risk of doctor-diagnosed asthma (OR 2.0; CI 1.1-3.9), asthma symptoms (OR 2.6; CI 1.3-5.0) and asthma symptoms or medication use (OR 2.3; CI 1.2-4.4) when compared to individuals not involved in aquatic sports. Regarding the entire athlete population, no increase in asthma was found when compared to the general population. CONCLUSIONS: Practice of very high endurance and aquatic sports may be associated with increased asthma risks. Athlete participation as such showed no association with asthma risk. PMID- 26013361 TI - In memoriam: Uwe-Karsten Hanisch (May 6, 1961 to April 18, 2015). PMID- 26013362 TI - Management of bleeding with oral anticoagulants in patients with atrial fibrillation. AB - Fear of bleeding is a common barrier to the use of anticoagulants. Warfarin has been the only oral anticoagulant for more than 60 years and warfarin-related bleeding is reported to be the most common drug-related cause of emergency hospitalization in elderly Americans. Non-vitamin K oral antagonists were introduced five years ago and compared with warfarin are associated with lower risk of intracranial bleeding, and similar or lower case fatality after major bleeding. Despite their superior safety profile, serious bleeding can occur. Most bleeding can be managed with holding the drug, local measures to control the bleeding and transfusion support as required because the NOACs have a relatively short half life and their anticoagulant effect rapidly dissipates. In patients with ongoing bleeding despite supportive measures and in those with life threatening bleeding, consideration may be given to the use of general hemostatic agents. Experimental and animal evidence suggests that 3 and 4 factor prothrombin complex concentrates can improve hemostasis in the presence of a NOAC and this is reinforced by anecdotal evidence in humans. Specific antidotes are currently in phase 3 trials and could become available in the near future. PMID- 26013363 TI - A Biodegradation Study of SBA-15 Microparticles in Simulated Body Fluid and in Vivo. AB - Mesoporous silica has received considerable attention as a drug delivery vehicle because of its large surface area and large pore volume for loading drugs and large biomolecules. Recently, mesoporous silica microparticles have shown potential as a three-dimensional vaccine platform for modulating dendritic cells via spontaneous assembly of microparticles in a specific region after subcutaneous injection. For further in vivo applications, the biodegradation behavior of mesoporous silica microparticles must be studied and known. Until now, most biodegradation studies have focused on mesoporous silica nanoparticles (MSNs); here, we report the biodegradation of hexagonally ordered mesoporous silica, SBA-15, with micrometer-sized lengths (~32 MUm with a high aspect ratio). The degradation of SBA-15 microparticles was investigated in simulated body fluid (SBF) and in mice by analyzing the structural change over time. SBA-15 microparticles were found to degrade in SBF and in vivo. The erosion of SBA-15 under biological conditions led to a loss of the hysteresis loop in the nitrogen adsorption/desorption isotherm and fingerprint peaks in small-angle X-ray scattering, specifically indicating a degradation of ordered mesoporous structure. Via comparison to previous results of degradation of MSNs in SBF, SBA 15 microparticles degraded faster than MCM-41 nanoparticles presumably because SBA-15 microparticles have a pore size (~8 nm) and a pore volume larger than those of MCM-41 mesoporous silica. The surface functional groups, the residual amounts of organic templates, and the hydrothermal treatment during the synthesis could affect the rate of degradation of SBA-15. In in vivo testing, previous studies focused on the evaluation of toxicity of mesoporous silica particles in various organs. In contrast, we studied the change in the physical properties of SBA-15 microparticles depending on the duration after subcutaneous injection. The pristine SBA-15 microparticles injected into mice subcutaneously slowly degraded over time and lost ordered structure after 3 days. These findings represent the possible in vivo use of microsized mesoporous silica for drug delivery or vaccine platform after local injection. PMID- 26013364 TI - Percutaneous stenting of the portal vein prior to biliary bypass in a patient with chronic pancreatitis and portal biliopathy. AB - Chronic pancreatitis (CP) often leads to obstruction of one or all the components of the spleno-mesenterico-portal (SMP) axis. This is often due to the ongoing inflammatory process which may lead to thrombosis of the surrounding veins. However, the inflammation also leads to progressive fibrosis and occlusion of the veins without thrombosis. This fibrosis is also responsible for the duodenal obstruction and biliary strictures associated with CP. These patients, with simple occlusion or encasement of one or a combination of components of the SMP axis, can be treated with venous stenting. Here, we present the case of a 58-year old gentleman with portal vein occlusion and portal biliopathy secondary to CP. This patient was successfully treated with percutaneous transhepatic portal vein stenting and a subsequent surgical biliary bypass. In conclusion, portal venous obstruction in CP may be just due to local fibrosis and is amenable to treatment with a percutaneously placed portal venous stent. PMID- 26013365 TI - Controlling Conjugation and Solubility of Donor-Acceptor Semiconducting Copolymers for High-Performance Organic Field-Effect Transistors. AB - Diketopyrrolopyrrole (DPP)-based copolymers, including poly[2,5-bis(2 octyldodecyl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione-(E)-1,2-di([2,2'-bithiophen] 5-yl)ethene] (PDDBE) and poly[2,5-bis(2-octyldodecyl)pyrrolo[3,4-c]pyrrole 1,4(2H,5H)-dione-(E)-1,2-bis(6-hexylthieno[3,2-b]thiophen-2-yl)ethene] (PDTTE), were synthesized by alternating a DPP-derivative acceptor (A) block with different donor (D) blocks, such as (E)-1,2-di([2,2'-bithiophen]-5-yl)ethene (DBE) and (E)-1,2-bis(6-hexylthieno[3,2-b]thiophen-2-yl)ethene (TTE). As solution processed semiconducting channel layers in organic field-effect transistors (OFETs), PDDBE and PDTTE copolymers had drastically different ordered structures on polymer-grafted SiO2 dielectrics. Multiple-layered domains of PDDBE had a long range, pi-conjugated extension but a wide pi-stacking distance, d(010), of 3.90 A. One-dimensional nanorod-percolated agglomerates of PDTTE had a much shorter d(010) of 3.71 A, originating from the alternating A-D structures of the DPP derivative with different D blocks. The corresponding ordered domains yielded a wide range of field-effect mobilities from 0.01 to 1.40 cm2 V(-1) s(-1) in the OFETs. PMID- 26013366 TI - Exposure to the androgenic brominated flame retardant 1,2-dibromo-4-(1,2 dibromoethyl)-cyclohexane alters reproductive and aggressive behaviors in birds. AB - Detected in environmental samples, 1,2-dibromo-4-(1,2-dibromoethyl) cyclohexane (DBE-DBCH) is a bioaccumulative isomer of a current-use brominated flame retardant. All 4 structural isomers are androgen agonists; however, little toxicological information exists for this compound. The objective of the present study was to determine if beta-DBE-DBCH, the isomer found most prominently in animal tissue, affects androgen-dependent behavior of breeding American kestrels (Falco sparverius). The authors hypothesized that if beta-DBE-DBCH acts as an androgen agonist in kestrels, androgen-dependent behaviors (i.e., copulation, courtship, aggression) would increase and behaviors inhibited by androgens (i.e., parental care behaviors) would decrease. Sixteen captive experimental kestrel pairs were exposed to 0.239 ng beta-DBE-DBCH/g kestrel/d by diet from 4 wk prior to pairing until their nestlings hatched (mean 82 d) and compared with vehicle only-exposed control pairs (n = 15). Androgen-dependent behaviors were significantly increased in beta-DBE-DBCH-exposed birds, consistent with the authors' hypothesis. These behavioral changes included copulation and other sexual behaviors in males and females and aggression in males, suggesting that beta-DBE-DBCH may have acted like an androgen agonist in these birds. Parental behaviors were not reduced in exposed birds as predicted, although dietary exposure had ceased before chicks hatched. Further assessment of beta-DBE-DBCH is recommended given these behavioral changes and the previously reported reproductive changes in the same birds. PMID- 26013367 TI - Targeted temperature management: It is not yet time to change your target temperature. AB - Clinical question In unconscious patients of out-of-hospital cardiac arrest, does targeted temperature management to 36 degrees C (96.8 degrees F) improve outcomes compared to the standard target of 32 degrees C-34 degrees C (89.6 degrees F-93.2 degrees F)? Article chosen Nielson N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013;369:2197-2206. OBJECTIVE: To determine which temperature, 33 degrees C (91.4 degrees F) or 36 degrees C (96.8 degrees F), is associated with lower mortality and better neurologic function after cardiac arrest. PMID- 26013369 TI - Tackling imported malaria: an elimination endgame. AB - As countries move toward malaria elimination, imported infections become increasingly significant as they often represent the majority of cases, can sustain transmission, cause resurgences, and lead to mortality. Here we review and critique current methods to prevent malaria importation in countries pursuing elimination and explore methods applied in other transmission settings and to other diseases that could be transferred to support malaria elimination. To improve intervention targeting we need a better understanding of the characteristics of populations importing infections and their patterns of migration, improved methods to reliably classify infections as imported or acquired locally, and ensure early and accurate diagnosis. The potential for onward transmission in the most receptive and vulnerable locations can be predicted through high-resolution risk mapping that can help malaria elimination or prevention of reintroduction programs target resources. Cross border and regional initiatives can be highly effective when based on an understanding of human and parasite movement. Ultimately, determining the optimal combinations of approaches to address malaria importation will require an evaluation of their impact, cost effectiveness, and operational feasibility. PMID- 26013368 TI - The Influence of Mining and Human Immunodeficiency Virus Infection Among Patients Admitted for Retreatment of Tuberculosis in Northern Tanzania. AB - In tuberculosis (TB)-prevalent settings, patients admitted for retreatment of TB may account for a high burden of poor treatment outcome. We performed a retrospective cohort study to characterize retreatment patients and outcomes at a TB referral hospital in northern Tanzania. From 2009 to 2013, 185 patients began a retreatment regimen, the majority for relapse after prior treatment completion. Men accounted for an unexpected majority (88%), 36 (20%) were human immunodeficiency virus (HIV) infected and for 45 (24%) mining was their primary occupation. A poor outcome (death, default, or persistent smear positivity after 7 months of treatment) was found in 37 (23%). HIV infection was the only significant predictor of poor outcome (adjusted odds ratio [aOR] = 2.50, 95% confidence interval [CI] = 1.07-5.83, P = 0.034). Interventions to minimize need for retreatment or improve retreatment success may be regionally specific. In our setting, community-based diagnosis and management among at-risk subpopulations such as miners and those HIV infected appear of highest yield. PMID- 26013371 TI - Review of mass drug administration for malaria and its operational challenges. AB - Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings. PMID- 26013370 TI - Matrix metalloproteinase-9 polymorphism 1562 C > T (rs3918242) associated with protection against placental malaria. AB - Phagocytosis of malaria pigment (hemozoin) induces increased activity of matrix metalloproteinase (MMP)-9, an endopeptidase involved in cytokine regulation. In this study, we examined whether a common functional MMP-9 promoter polymorphism (rs3918242) affects Plasmodium falciparum infection in pregnancy. Eighteen percent of Ghanaian primiparae carried the minor T allele. It was associated with reduced odds of placental hemozoin and of placental as well as peripheral blood parasitemia. The results indicate that a common MMP-9 polymorphism protects against placental malaria indicating that this endopeptidase is involved in susceptibility to P. falciparum. PMID- 26013372 TI - Effective program management: a cornerstone of malaria elimination. AB - Effective program management is essential for successful elimination of malaria. In this perspective article, evidence surrounding malaria program management is reviewed by management science and malaria experts through a literature search of published and unpublished gray documents and key informant interviews. Program management in a malaria elimination setting differs from that in a malaria control setting in a number of ways, although knowledge and understanding of these distinctions are lacking. Several core features of successful health program management are critical to achieve elimination, including effective leadership and supervision at all levels, sustained political and financial commitment, reliable supply and control of physical resources, effective management of data and information, appropriate incentives, and consistent accountability. Adding to the complexity, the requirements of an elimination program may conflict with those of a control regimen. Thus, an additional challenge is successfully managing program transitions along the continuum from control to elimination to prevention of reintroduction. This article identifies potential solutions to these challenges by exploring managerial approaches that are flexible, relevant, and sustainable in various cultural and health system contexts. PMID- 26013373 TI - Prospective cohort study with active surveillance for fever in four dengue endemic countries in Latin America. AB - To prepare for a Phase III dengue vaccine efficacy trial, 20 investigational sites were selected for this observational study to identify dengue infections in a closed cohort (N = 3,000 children 9-16 years of age). Of 255 acute febrile episodes experienced by 235 children, 50 (21.3%) were considered serologically probable dengue, and 18 (7.7%) were considered virologically confirmed (i.e., dengue NS1 antigen positive) dengue cases. Considering the disease-free and at risk period from study start to onset of symptoms, the overall incidence density of acute febrile episodes was 17.7 per 100 person-years of follow-up, ranging from 15.3 in Colombia to 22.0 in Puerto Rico. This study showed that all sites were capable of capturing and following up acute febrile episodes within a specific timeframe among the established cohort and to detect dengue cases. PMID- 26013374 TI - Introduction of Monkeypox into a Community and Household: Risk Factors and Zoonotic Reservoirs in the Democratic Republic of the Congo. AB - An increased incidence of monkeypox (MPX) infections in the Democratic Republic of the Congo was noted by the regional surveillance system in October 2013. Little information exists regarding how MPX is introduced into the community and the factors associated with transmission within the household. Sixty-eight wild animals were collected and tested for Orthopoxvirus. Two of three rope squirrels (Funisciurus sp.) were positive for antibodies to Orthopoxviruses; however, no increased risk was associated with the consumption or preparation of rope squirrels. A retrospective cohort investigation and a case-control investigation were performed to identify risk factors affecting the introduction of monkeypox virus (MPXV) into the community and transmission within the home. School-age males were the individuals most frequently identified as the first person infected in the household and were the group most frequently affected overall. Risk factors of acquiring MPXV in a household included sleeping in the same room or bed, or using the same plate or cup as the primary case. There was no significant risk associated with eating or processing of wild animals. Activities associated with an increased risk of MPXV transmission all have potential for virus exposure to the mucosa. PMID- 26013375 TI - Case-Control Study of Posttreatment Regression of Urinary Tract Morbidity Among Adults in Schistosoma haematobium-Endemic Communities in Kwale County, Kenya. AB - Previous population-based studies have examined treatment impact on Schistosoma associated urinary tract disease among children, but much less is known about longer-term treatment benefits for affected adult populations in areas where risk of recurrent infection is high. In communities in Msambweni, along the Kenya coast, we identified, using a portable ultrasound, 77 adults (aged 17-85) with moderate-to-severe obstructive uropathy or bladder disease due to Schistosoma haematobium. Treatment response was assessed by repeat ultrasound 1-2 years after praziquantel (PZQ) therapy and compared with interval changes among age- and sex matched infected/treated control subjects who did not have urinary tract abnormalities at the time of initial examination. Of the 77 affected adults, 62 (81%) had improvement in bladder and/or kidney scores after treatment, 14 (18%) had no change, and one (1.3%) had progression of disease. Of the 77 controls, 75 (97%) remained disease free by ultrasound, while two (3%) had apparent progression with abnormal findings on follow-up examination. We conclude that PZQ therapy for S. haematobium is effective in significantly reducing urinary tract morbidity from urogenital schistosomiasis among adult age groups, and affected adults stand to benefit from inclusion in mass treatment campaigns. PMID- 26013376 TI - Dengue seroprevalence of healthy adults in Singapore: serosurvey among blood donors, 2009. AB - Routine national notifications of dengue cases typically do not reflect the true dengue situation due to large proportion of unreported cases. Serosurveys, when conducted periodically, could shed light on the true dengue infections in the population. To determine the magnitude of dengue infections of the adult population in Singapore following the outbreak in 2007, we performed a cross sectional study on blood donor samples from December 2009 to February 2010. The residual blood of 3,995 donors (aged 16-60 years) was screened for the presence of dengue-specific immunoglobulin G (IgG) and IgM using enzyme-linked immunosorbent assay (ELISA) kits. The age-weighted IgG prevalence of residents was 50.8% (N = 3,627, 95% confidence interval [CI] = 49.4-52.3%). Dengue IgG prevalence increased with age, with the lowest in 16-20 years age group (16.1%) and the highest in 56-60 years age group (86.6%). Plaque reduction neutralization test (PRNT) on samples of young resident adults (aged 16-30 years) revealed lower prevalence of neutralizing antibodies to each serotype, ranging from 5.4% to 20.3% compared with the older age groups. The level of exposure to dengue among the young adults is relatively low despite the endemicity of the disease in Singapore. It partially explains the population's susceptibility to explosive outbreaks and the high incidence rate among young adults. PMID- 26013377 TI - Assessment of antibody responses in local and immigrant residents of areas with autochthonous malaria transmission in Greece. AB - Greece has been officially malaria free since 1974. However, from 2009 to 2012, several locally acquired, cases of Plasmodium vivax malaria were detected, in immigrants and in Greek citizens. In this study, the antibody (Ab) response of Greeks and immigrants with documented malaria was initially assessed, followed by an Ab screening of Greeks and immigrant residents of local transmission areas. Of the 38 patients tested, 10.5% of Greeks and 15.7% of immigrants were positive 5-7 months after infection. Of the 1,019 individuals from various areas of Greece, including those of autochthonous transmission, 85 of the 721 (11.8%) immigrants were positive, whereas all 298 Greeks were negative. The rapid Ab titer decline observed is reasonable, given the non-endemic epidemiological setting. The seroepidemiological findings indicate that the local Greek population remains malaria naive and that at this point Greeks are unlikely to serve as reservoir for the infection of local mosquitoes. PMID- 26013378 TI - Information systems to support surveillance for malaria elimination. AB - Robust and responsive surveillance systems are critical for malaria elimination. The ideal information system that supports malaria elimination includes: rapid and complete case reporting, incorporation of related data, such as census or health survey information, central data storage and management, automated and expert data analysis, and customized outputs and feedback that lead to timely and targeted responses. Spatial information enhances such a system, ensuring cases are tracked and mapped over time. Data sharing and coordination across borders are vital and new technologies can improve data speed, accuracy, and quality. Parts of this ideal information system exist and are in use, but have yet to be linked together coherently. Malaria elimination programs should support the implementation and refinement of information systems to support surveillance and response and ensure political and financial commitment to maintain the systems and the human resources needed to run them. National malaria programs should strive to improve the access and utility of these information systems and establish cross-border data sharing mechanisms through the use of standard indicators for malaria surveillance. Ultimately, investment in the information technologies that support a timely and targeted surveillance and response system is essential for malaria elimination. PMID- 26013379 TI - It doesn't "come with the job": violence against doctors at work must stop. PMID- 26013380 TI - Use of angiotensin-converting enzyme inhibitors in the prophylaxis of anthracycline or trastuzumab-related cardiac dysfunction: preclinical and clinical considerations. AB - Cardiac toxicity is one of the most important long-term toxicities experienced by cancer survivors so that survival rate due to anticancer therapy may be negatively affected due to cardiac complications. Thus, the search for novel methods to lower the incidence of treatment-related cardiotoxicity is a priority for all cancer-related disciplines. In this review, we provide an overview of the available preclinical and clinical data evaluating the role of angiotensin converting enzyme inhibitors in the prophylaxis of cardiac dysfunction secondary to anthracyclines and trastuzumab use. The available clinical data suggest some degree of protective utility for the use of some angiotensin-converting enzyme inhibitors against anthracycline-related cardiotoxicity while the data are scarce with regard to a similar role for patients receiving trastuzumab. PMID- 26013381 TI - Activating MET kinase rearrangements in melanoma and Spitz tumours. AB - Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCgamma1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist. PMID- 26013382 TI - The Histone Methyltransferase Inhibitor BIX01294 Inhibits HIF-1alpha Stability and Angiogenesis. AB - Hypoxia-inducible factor (HIF) is a key regulator of tumor growth and angiogenesis. Recent studies have shown that, BIX01294, a G9a histone methyltransferase (HMT)-specific inhibitor, induces apoptosis and inhibits the proliferation, migration, and invasion of cancer cells. However, not many studies have investigated whether inhibition of G9a HMT can modulate HIF-1alpha stability and angiogenesis. Here, we show that BIX01294 dose-dependently decreases levels of HIF-1alpha in HepG2 human hepatocellular carcinoma cells. The half-life of HIF 1alpha, expression of proline hydroxylase 2 (PHD2), hydroxylated HIF-1alpha and von Hippel-Lindau protein (pVHL) under hypoxic conditions were decreased by BIX01294. The mRNA expression and secretion of vascular endothelial growth factor (VEGF) were also significantly reduced by BIX01294 under hypoxic conditions in HepG2 cells. BIX01294 remarkably decreased angiogenic activity induced by VEGF in vitro, ex vivo, and in vivo, as demonstrated by assays using human umbilical vein endothelial cells (HUVECs), mouse aortic rings, and chick chorioallantoic membranes (CAMs), respectively. Furthermore, BIX01294 suppressed VEGF-induced matrix metalloproteinase 2 (MMP2) activity and inhibited VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), focal adhesion kinase (FAK), and paxillin in HUVECs. In addition, BIX01294 inhibited VEGF-induced formation of actin cytoskeletal stress fibers. In conclusion, we demonstrated that BIX01294 inhibits HIF-1alpha stability and VEGF-induced angiogenesis through the VEGFR-2 signaling pathway and actin cytoskeletal remodeling, indicating a promising approach for developing novel therapeutics to stop tumor progression. PMID- 26013383 TI - Expression Analyses Revealed Thymic Stromal Co-Transporter/Slc46A2 Is in Stem Cell Populations and Is a Putative Tumor Suppressor. AB - By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the CD31(+) endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca 1(+) fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation. PMID- 26013384 TI - Structural Identification of a Non-Glycosylated Variant at Ser126 for O Glycosylation Site from EPO BRP, Human Recombinant Erythropoietin by LC/MS Analysis. AB - A variant peak was detected in the analysis of RP-HPLC of rHu-EPO, which has about 7% relative content. Fractions of the main and the variant peaks were pooled separately and further analyzed to identify the molecular structure of the variant peak. Total mass analysis for each peak fraction using ESI-TOF MS shows differences in molecular mass. The fraction of the main peak tends to result in higher molecular masses than the fraction of the variant. The detected masses for the variant are about 600-1000 Da smaller than those for the main peak. Peptide mapping analysis for each peak fraction using Asp-N and Glu-C shows differences in O-glycopeptide profiles at Ser126. The O-glycopeptides were not detected in the fraction of the variant. It is concluded that the variant peak is non-O glycosylated rHu-EPO and the main peak is fully O-glycosylated rHu-EPO at Ser126. PMID- 26013386 TI - Rhombencephalosynapsis: a rare congenital anomaly presenting with seizure and developmental delay. PMID- 26013385 TI - The Signaling Mechanism of Contraction Induced by ATP and UTP in Feline Esophageal Smooth Muscle Cells. AB - P2 receptors are membrane-bound receptors for extracellular nucleotides such as ATP and UTP. P2 receptors have been classified as ligand-gated ion channels or P2X receptors and G protein-coupled P2Y receptors. Recently, purinergic signaling has begun to attract attention as a potential therapeutic target for a variety of diseases especially associated with gastroenterology. This study determined the ATP and UTP-induced receptor signaling mechanism in feline esophageal contraction. Contraction of dispersed feline esophageal smooth muscle cells was measured by scanning micrometry. Phosphorylation of MLC20 was determined by western blot analysis. ATP and UTP elicited maximum esophageal contraction at 30 s and 10 MUM concentration. Contraction of dispersed cells treated with 10 MUM ATP was inhibited by nifedipine. However, contraction induced by 0.1 MUM ATP, 0.1 MUM UTP and 10 MUM UTP was decreased by U73122, chelerythrine, ML-9, PTX and GDPbetaS. Contraction induced by 0.1 MUM ATP and UTP was inhibited by Galphai3 or Galphaq antibodies and by PLCbeta1 or PLCbeta3 antibodies. Phosphorylated MLC20 was increased by ATP and UTP treatment. In conclusion, esophageal contraction induced by ATP and UTP was preferentially mediated by P2Y receptors coupled to Galphai3 and G q proteins, which activate PLCbeta1 and PLCbeta3. Subsequently, increased intracellular Ca(2+) and activated PKC triggered stimulation of MLC kinase and inhibition of MLC phosphatase. Finally, increased pMLC20 generated esophageal contraction. PMID- 26013388 TI - [Trend sports]. AB - BACKGROUND: Popular trend sports are characterized by intensive and high speed performance. Due to the high energy mechanism in falls, typical injury distributions and patterns result. OBJECTIVES: In a retrospective study the injury patterns and frequencies in mountain bike athletes were analyzed and pathophysiological, diagnostic and therapeutic options in the treatment of high energy injuries to the carpal bones are shown. MATERIAL AND METHODS: Based on a retrospective survey over 2 successive years, active mountain bike athletes (World Cup Series) were interviewed using a standardized questionnaire. Injury patterns and frequencies were analyzed. The pathophysiology, diagnostics and therapy of high energy carpal injuries are discussed. RESULTS: In this study 107 World Cup mountain bike athletes were enrolled. Injuries of the extremities were found in more than 75% of athletes with a higher prevalence in the upper extremities (40.7%) than the lower extremities (34.84%), followed by injuries of the head and face (13.3%, of which 10.6% were traumatic brain injuries) and the trunk (10.6%). Fractures and dislocations of the hand and wrist were found in approximately half of the athletes (50.9%). CONCLUSION: In popular trend sports injuries of the extremities are common, especially of the carpal bones and ligaments. It is important to distinguish stable from destabilizing injuries in order to provide adequate therapeutic options. PMID- 26013387 TI - Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity. AB - Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE. PMID- 26013389 TI - [Hand injuries from combat sports]. AB - BACKGROUND: Each year 3.1% of German adults suffer from accidents related to sports and 75% of the injured athletes are male between 20 and 29 years old. The upper limbs are affected in more than 20% of cases and one third of these injuries involve the hands and fingers. OBJECTIVES: More than half a million athletes are organized in combat sport associations in Germany with an increasing trend. Combat sports are commonly said to have a high risk of injuries to the hand. The aim of this study was to test this hypothesis as well as to describe typical hand injuries associated with combat sports. MATERIAL AND METHODS: A systematic review of literature (up to January 2015) in PubMed/Medline and The Cochrane Library as well as a secondary search in the reference lists were carried out. CONCLUSION: Conclusive comparative studies on the incidence and severity of hand injuries directly related to combat sports action could not be found in the currently available literature. The overall risk of suffering from a sports injury seems to be relatively low in combat sports compared to other sports. Boxing, however, seems to be the most dangerous sport for injuries to the upper extremities and especially the hand. The injury pattern after punching (emergency patients and professional boxers) shows that more than half of these fractures affect the 5th metacarpal and 25% of these are the classical boxer's fracture. This differs significantly from the fracture distribution generally associated with sports, where fractures of the phalanges are the most common. Two rare conditions that may occur as a result of repeated punching are referred to as carpal bossing and boxer's knuckle and excellent results are described for both injury forms after surgical therapy. PMID- 26013390 TI - [Amputation and prosthesis attachment of the lower extremities]. AB - Approximately 61,000 amputations are performed in Germany per year. In most cases the lower limbs are affected. The reasons for amputations are arteriosclerosis, diabetes mellitus, severe infections, tumors and complex trauma to the extremities. A decision must be made concerning whether a salvage procedure or amputation is appropriate, specially after trauma. In cases where the need for amputation is clear, the site of amputation needs to be planned in advance with the aim of creating a stump which allows sufficient prosthetic attachment. Adjuvant pain therapy is mandatory, especially in order to avoid subsequent phantom pain. The type of prosthetic restoration is influenced by the grade of mobility and personal requirements of patients. Moreover, aftercare and adjusted rehabilitation are recommended. PMID- 26013391 TI - [Air rescue missions at night: Data analysis of primary and secondary missions by the DRF air rescue service in 2014]. AB - The advantages that are inherent to the air ambulance service are shown in a reduction in mortality of critically ill or injured patients. The air ambulance service ensures quick and efficient medical care to a patient as well as the immediate transport of patients to a suitable hospital. In addition, primary air rescue has proved to be effective as a support for the standard ground-based ambulance services in some regions of Germany during the night. Under certain conditions, such as the strict adherence to established, practiced and coordinated procedures, air rescue at night does not have a significantly higher risk compared to operations in daytime. Particular requirements should be imposed for air rescue operations at night: a strict indication system for alerting, 4 man helicopter crews solely during the night as well as pilots (and copilots) with the correct qualifications and experience in dealing with night vision devices on a regular basis. Moreover, the helicopters need to be suitable and approved for night flying including cabin upgrades and the appropriate medical technology equipment. To increase the benefits of air rescue for specific diseases and injuries, a nationwide review of the processes is needed to further develop the primary air rescue service. PMID- 26013392 TI - [Posttraumatic arthrosis of the glenohumeral joint. From partial resurfacing to reverse shoulder arthroplasty]. AB - BACKGROUND: Arthroplasty of symptomatic sequelae after fractures of the proximal humerus is a demanding procedure for surgeons. Exact preoperative planning is crucial in order to achieve acceptable functional results. OBJECTIVE: Discussion of preoperative considerations in planning the procedure and choosing the appropriate implant taking the osseous anatomy and surrounding soft tissue situation into consideration. METHODS: Selective literature review and description of personal experience. RESULTS: The geometry and consolidation status of bone fragments as well as the conditions of the surrounding soft tissue have to be taken into account and influence the choice of implant used. Insufficient planning will not only cause intraoperative technical problems but can also greatly influence the subjective patient assessment of the postoperative outcome. Unequal strain distribution can cause early loosening of components resulting in malfunctioning of the implant. In this respect, knowledge of the position and consolidation status of fractured tuberosities with respect to the humeral shaft is essential and allows an approximate estimation of the achievable outcome. This is taken into account by the classification of Boileau which can also help to decide on which type of implant to use. Because such cases are scarce, reported results in the literature are heterogeneous, which is discussed in this article. CONCLUSION: Each case needs a thorough and individualized preoperative assessment along with exact planning and should therefore be reserved for experienced shoulder surgeons only. PMID- 26013393 TI - The ideal adjuvant treatment in node positive vulvar cancer is (fill in your best guess here). PMID- 26013394 TI - Caseload midwifery as organisational change: the interplay between professional and organisational projects in Denmark. AB - BACKGROUND: The large obstetric units typical of industrialised countries have come under criticism for fragmented and depersonalised care and heavy bureaucracy. Interest in midwife-led continuity models of care is growing, but knowledge about the accompanying processes of organisational change is scarce. This study focuses on midwives' role in introducing and developing caseload midwifery. Sociological studies of midwifery and organisational studies of professional groups were used to capture the strong interests of midwives in caseload midwifery and their key role together with management in negotiating organisational change. METHODS: We studied three hospitals in Denmark as arenas for negotiating the introduction and development of caseload midwifery and the processes, interests and resources involved. A qualitative multi-case design was used and the selection of hospitals aimed at maximising variance. Ten individual and 14 group interviews were conducted in spring 2013. Staff were represented by caseload midwives, ward midwives, obstetricians and health visitors, management by chief midwives and their deputies. Participants were recruited to maximise the diversity of experience. The data analysis adopted a thematic approach, using within- and across-case analysis. RESULTS: The analysis revealed a highly interdependent interplay between organisational and professional projects in the change processes involved in the introduction and development of caseload midwifery. This was reflected in three ways: first, in the key role of negotiations in all phases; second, in midwives' and management's engagement in both types of projects (as evident from their interests and resources); and third in a high capacity for resolving tensions between the two projects. The ward midwives' role as a third party in organisational change further complicated the process. CONCLUSIONS: For managers tasked with the introduction and development of caseload midwifery, our study underscores the importance of understanding the complexity of the underlying change processes and of activating midwives' and managers' interests and resources in addressing the challenges. Further studies of female-dominated professions such as midwifery should offer good opportunities for detailed analysis of the deep-seated interdependence of professional and organisational projects and for identifying the key dimensions of this interdependence. PMID- 26013395 TI - Chromium Supplements in the Feed for Lactating Murrah Buffaloes (Bubalus bubalis): Influence on Nutrient Utilization, Lactation Performance, and Metabolic Responses. AB - This study was conducted to evaluate the effect of different levels of inorganic chromium (Cr) on nutrient intake, nutrient utilization, milk mineral contents, and blood biochemical in lactating Murrah buffaloes. Twenty-four multifarious Murrah buffaloes were blocked into four groups having six animals in each group and fed for 150 days post-partum. Feeding regimen was same in all the groups except that treatment groups were supplemented with 0.0, 0.5, 1.0, and 1.5 mg inorganic Cr/kg dry matter (DM) in the four respective groups. Group fed on basal diet supplemented with 0.0 mg Cr/kg DM served as a control. Adding inorganic Cr to the diet of lactating buffaloes increased feed intake, milk yield, and nutrient digestibility. Nitrogen (N) and Cr balance were significantly increased (P<0.05) by adding Cr. Milk and plasma Cr concentration could be increased by adding Cr (P<0.001), while no significant differences were found between the four treatments in milk and plasma concentration of calcium (Ca), copper (Cu), and zinc (Zn). Feeding of diet supplemented with inorganic Cr decreased plasma insulin concentration (P=0.016). Concentration of blood glucose and the ratio of blood glucose to insulin were increased by adding Cr (P=0.037 and P=0.011, respectively). Adding Cr to the diet of lactating buffaloes did not show any effect on blood hemoglobin (Hb), while plasma concentration of progesterone and antioxidant status was increased (P<0.05). It could be concluded that adding Cr to the diet of lactating buffaloes improved nutrient intake, nutrient utilization, and lactation performance. PMID- 26013396 TI - Exposure to Violence and Children's Desensitization Attitudes in Lebanon. AB - Children exposed to multiple sources of violence may become desensitized, increasing the possibility of them imitating the aggressive behaviors they watch and considering such behavior as normal. The purpose of this article is to assess the association between exposure to various types of violence (including war) and desensitization in Lebanese children. A cross-sectional design with 207 school aged children assessed exposure to violence using three surveys: (a) violence in the media (the Media Preference survey), (b) exposure to violence (the KID-SAVE survey), and (c) desensitization attitudes (the Attitude Toward Violence-Child Version). Children were between 8 and 12 years old, 56% were males, and 70%were from middle socioeconomic status (SES) backgrounds. Seventy-six percent of children reported being exposed to violence, with more exposure in males and in the lower SES group. Impact, however, was greater on girls. The predictors of attitude toward violence were "Frequency" of exposure, "Impact" of exposure, and the amount of violence viewed on television. Children are massively exposed to violence in Lebanon resulting in desensitization, which may habituate them to accept violence as normal and put them at risk for imitating violent behaviors. PMID- 26013397 TI - Measuring Adolescent Violent Behavior Across Groups: Assessing Measurement Invariance of the Violent Behavior Checklist-Modified. AB - Measures of violent behavior are often assumed to function identically across different groups (e.g., gender, race/ethnicity). However, failure to verify measurement invariance can lead to biased cross-group comparisons. The current study examines the measurement invariance of the Violent Behavior Checklist Modified across genders and race/ethnicities. Using multiple group confirmatory factor analysis, configural and metric invariance are assessed in a sample of racially/ethnically diverse middle and high school students ( N = 4,128) in two rural counties. Results indicate that the Violent Behavior Checklist-Modified has partial measurement invariance across genders and race/ethnicities. Specifically, four out of six items were non-invariant across genders, while one out of six items was non-invariant across race/ethnicities. Findings suggest that the latent factor of violence may be qualitatively different across males and females. Implications are discussed. PMID- 26013398 TI - Cyanamide is biosynthesized from L-canavanine in plants. AB - Cyanamide had long been recognized as a synthetic compound but more recently has been found as a natural product from several leguminous plants. This compound's biosynthetic pathway, as yet unelaborated, has attracted attention because of its utility in many domains, such as agriculture, chemistry, and medicine. We noticed that the distribution of L-canavanine in the plant kingdom appeared to include that of cyanamide and that the guanidino group structure in L-canavanine contained the cyanamide skeleton. Here, quantification of these compounds in Vicia species suggested that cyanamide was biosynthesized from L-canavanine. Subsequent experiments involving L-[guanidineimino-(15)N2]canavanine addition to young Vicia villosa seedlings resulted in significant incorporation of (15)N label into cyanamide, verifying its presumed biosynthetic pathway. PMID- 26013400 TI - Bacteria abundance and diversity of different life stages of Plutella xylostella (Lepidoptera: Plutellidae), revealed by bacteria culture-dependent and PCR-DGGE methods. AB - Microbial abundance and diversity of different life stages (fourth instar larvae, pupae and adults) of the diamondback moth, Plutella xylostella L., collected from field and reared in laboratory, were investigated using bacteria culture dependent method and PCR-DGGE analysis based on the sequence of bacteria 16S rRNA V3 region gene. A large quantity of bacteria was found in all life stages of P. xylostella. Field population had higher quantity of bacteria than laboratory population, and larval gut had higher quantity than pupae and adults. Culturable bacteria differed in different life stages of P. xylostella. Twenty-five different bacterial strains were identified in total, among them 20 strains were presented in larval gut, only 8 strains in pupae and 14 strains in adults were detected. Firmicutes bacteria, Bacillus sp., were the most dominant species in every life stage. 15 distinct bands were obtained from DGGE electrophoresis gel. The sequences blasted in GenBank database showed these bacteria belonged to six different genera. Phylogenetic analysis showed the sequences of the bacteria belonged to the Actinobacteri, Proteobacteria and Firmicutes. Serratia sp. in Proteobacteria was the most abundant species in larval gut. In pupae, unculturable bacteria were the most dominant species, and unculturable bacteria and Serratia sp. were the most dominant species in adults. Our study suggested that a combination of molecular and traditional culturing methods can be effectively used to analyze and to determine the diversity of gut microflora. These known bacteria may play important roles in development of P. xylostella. PMID- 26013399 TI - Uterine NDRG2 expression is increased at implantation sites during early pregnancy in mice, and its down-regulation inhibits decidualization of mouse endometrial stromal cells. AB - BACKGROUND: N-myc down-regulated gene 2 (NDRG2) is a tumor suppressor involved in cell proliferation and differentiation. The aim of this study was to determine the uterine expression pattern of this gene during early pregnancy in mice. METHODS: Uterine NDRG2 mRNA and protein expression levels were determined by RT PCR and Western blot analyses, respectively, during the peri-implantation period in mice. Immunohistochemical (IHC) analysis was performed to examine the spatial localization of NDRG2 expression in mouse uterine tissues. The in vitro decidualization model of mouse endometrial stromal cells (ESCs) was used to evaluate decidualization of ESCs following NDRG2 knock down by small interfering RNA (siRNA). Statistical significance was analyzed by one-way ANOVA using SPSS 19.0 software. RESULTS: Uterine NDRG2 gene expression was significantly up regulated and was predominantly localized to the secondary decidual zone on days 5 and 8 of pregnancy in mice. Its increased expression was associated with artificial decidualization as well as the activation of delayed implantation. Furthermore, uterine NDRG2 expression was induced by estrogen and progesterone treatments. The in vitro decidualization of mouse ESCs was accompanied by up regulation of NDRG2 expression, and knock down of its expression in these cells by siRNA inhibited the decidualization process. CONCLUSIONS: These results suggest that NDRG2 might play an important role in the process of decidualization during early pregnancy. PMID- 26013401 TI - Associations between short-term exposure to particulate matter and ultrafine particles and myocardial infarction in Augsburg, Germany. AB - BACKGROUND: Short-term exposure to increased particulate matter (PM) concentration has been reported to trigger myocardial infarction (MI). However, the association with ultrafine particles remains unclear. OBJECTIVES: We aimed to assess the effects of short-term air pollution and especially ultrafine particles on registry-based MI events and coronary deaths in the area of Augsburg, Germany. METHODS: Between 1995 and 2009, the MONICA/KORA myocardial infarction registry recorded 15,417 cases of MI and coronary deaths. Concentrations of PM<10MUm (PM10), PM<2.5MUm (PM2.5), particle number concentration (PNC) as indicator for ultrafine particles, and meteorological parameters were measured in the study region. Quasi-Poisson regression adjusting for time trend, temperature, season, and weekday was used to estimate immediate, delayed and cumulative effects of air pollutants on the occurrence of MI. The daily numbers of total MI, nonfatal and fatal events as well as incident and recurrent events were analysed. RESULTS: We observed a 1.3% risk increase (95%-confidence interval: [-0.9%; 3.6%]) for all events and a 4.4% [-0.4%; 9.4%] risk increase for recurrent events per 24.3MUg/m(3) increase in same day PM10 concentrations. Nonfatal events indicated a risk increase of 3.1% [-0.1%; 6.5%] with previous day PM10. No association was seen for PM2.5 which was only available from 1999 on. PNC showed a risk increase of 6.0% [0.6%; 11.7%] for recurrent events per 5529 particles/cm(3) increase in 5 day average PNC. CONCLUSIONS: Our results suggested an association between short term PM10 concentration and numbers of MI, especially for nonfatal and recurrent events. For ultrafine particles, risk increases were notably high for recurrent events. Thus, persons who already suffered a MI seemed to be more susceptible to air pollution. PMID- 26013402 TI - Barium-mediated cross-dehydrocoupling of hydrosilanes with amines: a theoretical and experimental approach. AB - Alkaline-earth (most prominently barium) complexes of the type [Ae{N(SiMe3 )2 }2 ?(THF)x ] and [{N^N}Ae{N(SiMe3 )2 }?(THF)x ] are very active and productive precatalysts (TON=396, TOF up to 3600 h(-1) ; Ca17 %) with a kex value of 509+/-51 s(-1) , whereas in the glucose-bound form these exchange processes were quenched. This exchange behavior directly competes with the enzymatic turnover rate at physiological glucose concentrations, thereby generating the sigmoidal rate dependence that defines kinetic cooperativity. PMID- 26013421 TI - International Federation for emergency medicine model curriculum for continuing professional development. PMID- 26013422 TI - The ADH gene cluster SNP rs1789891 and temperamental dimensions in patients with alcohol dependence and affective disorders. AB - This study had three objectives: (1) to assess the relationship between the single nucleotide polymorphism (SNP) rs1789891 in the alcohol dehydrogenase gene cluster and alcohol dependence and affective disorders; (2) to assess the differences in the Regulative Theory of Temperament (RTT) traits between an alcohol dependent group, an affective disorders group, and a healthy group; and (3) to assess the relationship between rs1789891 and temperament traits in a healthy group, taking into account the interaction of genotype and sex. The SNP rs1789891 was genotyped in a group of 194 alcohol dependent men, aged 21 to 71 years; 137 patients with affective disorders, including 51 males and 86 females, aged 19 to 85 years; and a group of 207 healthy individuals, including 89 males and 118 females, aged 18 to 71 years. Temperament traits (briskness, perseveration, sensory sensitivity, emotional reactivity, endurance, and activity) were assessed in all groups using the Formal Characteristics of Behaviour-Temperament Inventory. The comparative analysis of genotypic frequencies showed no significant differences between patients with alcoholism or affective disorders and those in the control group. Alcohol dependent men and the affective disorder group were characterised by higher levels of emotional reactivity (p-value 1.4e-5 and 9.84e-7, respectively) and lower levels of briskness, sensory sensitivity, endurance, and activity (p-value from 3.76e-8 to 0.012) when compared to the healthy group. The rs1789891 polymorphism was associated with briskness (p = 0.02), sensory sensitivity (p = 0.036), and activity (p = 0.049). None of the results were statistically significant after Bonferroni correction. PMID- 26013423 TI - Acute kidney injury from tumour lysis syndrome and urate crystalluria. PMID- 26013425 TI - Experience with recombinant activated factor VII for severe post-partum hemorrhage in Japan, investigated by Perinatology Committee, Japan Society of Obstetrics and Gynecology. AB - AIM: To investigate the utility of recombinant activated Factor VII (rFVIIa) for severe post-partum hemorrhage (PPH) in Japan. METHODS: We studied 69 patients treated with rFVIIa for severe PPH; 44 patients were from the registry of Japan Society of Obstetrical, Gynecological and Neonatal Hematology, and 25 were identified by a survey of the Japan Society of Obstetrics and Gynecology. RESULTS: Overall, the mean and median blood loss were 11 835 mL and 8639 mL, respectively. Treatment before rFVIIa included transarterial embolization in 23 patients and hysterectomy in 38. Forty-two patients had a single dose, 17 had two doses, and four had three doses. The mean (+/- SD) single dose was 81.60 +/- 16.25 ug/kg. Sixty-five patients survived, and four died. The cause of PPH in patients who died was uterine rupture plus amniotic fluid embolism in two patients, uterine cervical laceration in one, and placental abruption in one. The amount of blood loss in cases of death was 6428-43 810 mL. This suggested that whether a patient survives or not was more dependent on her general condition before and after rFVIIa treatment than on the amount of blood loss. Four patients had thromboembolic events after rFVIIa treatment (deep vein thrombosis; deep vein thrombosis plus pulmonary embolism; acute myocardial infarction; and pulmonary embolism); all of these patients recovered. CONCLUSION: The present promising results may support the utility of rFVIIa for severe PPH in Japan. PMID- 26013424 TI - The use of targeted MR-guided prostate biopsy reduces the risk of Gleason upgrading on radical prostatectomy. AB - PURPOSE: Gleason grading is the strongest predictor of prostate cancer outcome and commonly used to decide for or against the different treatment options. However, Gleason upgrading between systematic transrectal ultrasound-guided prostate biopsy (TRUS-GB) and radical prostatectomy (RPE) has frequently been observed. With respect to the high accuracy of multiparametric MRI (mpMRI) for high-grade cancers and the higher percentage of cancer involvement per biopsy core in targeted MR-guided prostate biopsy (MR-GB), we hypothesized that MR-GB reduces the risk of Gleason upgrading on RPE as compared to the gold standard. The purpose of this study was to compare the rate of Gleason upgrading on RPE for MR-GB, TRUS-GB, and the combination of both biopsy modalities. METHODS: Overall, 52 consecutive patients with RPE had received an mpMRI of the prostate and subsequently underwent targeted MR-GB prior to surgery. All patients underwent an additional TRUS-GB during the same biopsy session. Gleason grading was measured by two different methods: the conventional Gleason score (cGS = primary + secondary pattern) and the highest Gleason pattern (hGP). RESULTS: In relation to TRUS-GB, MR-GB alone showed lower rates of upgrading when comparing the cGS (40.4 vs. 50.0 %) and the hGP (21.2 vs. 32.7 %). The combination of MR-GB and TRUS-GB showed the lowest rates of upgrading (cGS: 28.8 %; hGP: 11.5 %), and compared to TRUS-GB, significantly reduced the risk of upgrading for both measurements of Gleason grading (cGS: OR 0.41, 95 % CL 0.18-0.91, p = 0.0289; hGP: OR 0.27, 95 % CL 0.10-0.75, p = 0.0123). CONCLUSION: MpMRI and targeted MR-GB are useful tools to better characterize and stage the extent of disease, and therefore enable the urologist to better risk-stratify and counsel the patient. The combined use of targeted MR-GB and TRUS-GB presents the least risk of Gleason underestimation. PMID- 26013426 TI - Emergent transcatheter mitral valve-in-valve implantation in a patient with cardiogenic shock secondary to a failed mitral bioprosthesis. AB - Transcatheter valve-in-valve (VIV) implantation is emerging as a therapeutic option for treatment of failed bioprosthesis in patients that are deemed high risk or inoperable for redo-valve replacement. It can be carried out in suitable bioprosthetic valves in any position and usually performed as an elective or semi elective procedure. Here, we report a case of emergent transcatheter VIV implantation in a failed mitral bioprosthesis in a critically ill patient with cardiogenic shock. We conclude that transcatheter VIV implantation may also be an option for critically ill patients with failing bioprosthesis. (c) 2015 Wiley Periodicals, Inc. PMID- 26013427 TI - Rapid model exploration for complex hierarchical data: application to pharmacokinetics of insulin aspart. AB - We consider situations, which are common in medical statistics, where we have a number of sets of response data, from different individuals, say, potentially under different conditions. A parametric model is defined for each set of data, giving rise to a set of random effects. Our goal here is to efficiently explore a range of possible 'population' models for the random effects, to select the most appropriate model. The range of possible models is potentially vast, because the random effects may depend on observed covariates, and there may be multiple credible ways of partitioning their variability. Here, we consider pharmacokinetic (PK) data on insulin aspart, a fast acting insulin analogue used in the treatment of diabetes. PK models are typically nonlinear (in their parameters), often complex and sometimes only available as a set of differential equations, with no closed-form solution. Fitting such a model for just a single individual can be a challenging task. Fitting a joint model for all individuals can be even harder, even without the complication of an overarching model selection objective. We describe a two-stage approach that decouples the population model for the random effects from the PK model applied to the response data but nevertheless fits the full, joint, hierarchical model, accounting fully for uncertainty. This allows us to repeatedly reuse results from a single analysis of the response data to explore various population models for the random effects. This greatly expedites not only model exploration but also cross validation for the purposes of model criticism. (c) 2015 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. PMID- 26013428 TI - Hierarchically Structured Hole Transport Layers of Spiro-OMeTAD and Multiwalled Carbon Nanotubes for Perovskite Solar Cells. AB - The low electrical conductivity of spiro-OMeTAD hole transport layers impedes further enhancements of the power conversion efficiency (PCE) of perovskite solar cells. We embedded multiwalled carbon nanotubes (MWNTs) in spiro-OMeTAD (spiro OMeTAD/MWNTs) to increase carrier mobility and conductivity. However, direct electrical contact between CH3 NH3 PbI3 and the MWNTs created pathways for undesirable back-electron transfer, owing to the large work function of MWNTs, limiting enhancements of the PCE. A hierarchical structure of pure spiro-OMeTAD and spiro-OMeTAD/MWNTs was designed to block back-electron transfer and fully exploit the enhanced charge transport of spiro-OMeTAD/MWNTs. The enhanced fill factor, short-circuit current density, open-circuit voltage, and PCE (15.1 %) were achieved by using this hierarchical hole transport layer structure (MWNT concentration=2 wt %). The perovskite solar cells were fabricated by a low temperature solution process, further decreasing their per-Watt cost. PMID- 26013430 TI - The Impact of Lumbosacral Transitional Vertebrae on Therapeutic Outcomes of Transforaminal Epidural Injection in Patients with Lumbar Disc Herniation. AB - BACKGROUND: Although some studies have evaluated the clinical impact of lumbosacral transitional vertebrae (LSTV), few have attempted to determine an effective conservative treatment method for lumbar disc herniation (LDH) presenting concurrently with LSTV. METHODS: We prospectively enrolled 291 consecutive patients who were followed-up for at least one year after transforaminal epidural injection (TFEI) for LDH. We confirmed the presence of LSTV with Paik et al.'s method, the Castellvi classification, and the Southworth and Bersack method. Clinical outcomes were evaluated with a visual analogue scale (VAS) for pain intensity and the Oswestry Disability Index (ODI) for functional status. RESULTS: Of the 291 patients, 47 (16.2%) had LSTV, including 33 with sacralization and 14 with lumbarization, while 244 (83.8%) did not have LSTV. Patients in both groups improved significantly after TFEI in terms of the VAS (P < 0.001) and ODI (P < 0.001) scores. However, LDH patients with LSTV had a worse clinical outcome after six months of TFEI than did those without LSTV, with a significant difference between groups for both the VAS (P < 0.01) and ODI (P = 0.01) scores. LDH patients with sacralization had worse post-treatment clinical outcomes than LDH patients with lumbarization (P < 0.001) or LDH patients without LSTV (P < 0.001). CONCLUSIONS: Sacralization can reduce the improvement after TFEI among LDH patients, while lumbarization appears to have no direct effect on TFEI outcomes. The presence of sacralization should be identified before TFEI, and if present, patients should be informed that the outcomes of TFEI may not be as good as they would be if sacralization was not present. PMID- 26013431 TI - Educating medical students: introducing a journal club. PMID- 26013432 TI - Temporalities of reproduction: practices and concepts from the eighteenth to the early twenty-first century. PMID- 26013433 TI - Folding into being: early embryology and the epistemology of rhythm. AB - Historians have often described embryology and concepts of development in the period around 1800 in terms of "temporalization" or "dynamization". This paper, in contrast, argues that a central epistemological category in the period was "rhythm", which played a major role in the establishment of the emerging discipline of biology. I show that Caspar Friedrich Wolff's epigenetic theory of development was based on a rhythmical notion, namely the hypothesis that organic development occurs as a series of ordered rhythmical repetitions and variations. Presenting Christian Heinrich Pander's and Karl Ernst von Baer's theory of germ layers, I argue that Pander and Baer regarded folding as an organizing principle of ontogenesis, and that the principle's explanatory power stems from their understanding of folding as a rhythmical figuration. In a brief discussion of the notion of rhythm in contemporary music theory, I identify an underlying physiological epistemology in the new musical concept of rhythm around 1800. The paper closes with a more general discussion of the relationship between the rhythmic episteme, conceptions of life, and aesthetic theory at the end of the eighteenth century. PMID- 26013434 TI - Seeking the constant in what is transient: Karl Ernst von Baer's vision of organic formation. AB - A well-established narrative in the history of science has it that the years around 1800 saw the end of a purely descriptive, classificatory and static natural history. The emergence of a temporal understanding of nature and the new developmental-history approach, it is thought, permitted the formation of modern biology. This paper questions that historical narrative by closely analysing the concepts of development, history and time set out in Karl Ernst von Baer's study of the mammalian egg (1827). I show that Baer's research on embryogenesis aimed not simply to explain temporal changes, but to inscribe the formation of new individual organisms into a continuous, unending organic process. I confront Baer's views with other explanations of embryogenesis arising in the 1820s and 1830s, especially those of Jean-Baptiste Dumas and Jean-Louis Prevost and of Theodor Schwann. By highlighting divergences between these scientists, especially as to their view of the role of gender differences in reproduction, I argue that biology evolved not from a homogeneous concept of developmental history but out of various, even opposing, views and research programmes. Thus, the birth of biology did not imply the end of all natural history's thought models. PMID- 26013435 TI - Traversing birth: continuity and contingency in research on development in nineteenth-century life and human sciences. AB - In the history of life sciences, it has often been argued that the individual organism emerged, around 1800, as a four-dimensional entity--a temporalized entity. Against this backdrop, the article asks how research on development contributed to structuring the time of the organism in terms of a historical process, that is, by understanding a given phenomenon as brought forth by what preceded it and as establishing conditions for what will follow, thus relating the past, the present and the future in a specific way. To shed light on this conceptualization, we must take into account not only embryological research on morphogenesis but also physiological research on the genesis of vital functions and the causation of congenital anomalies. Three layers of structuring time in such research may be discerned: the making of a trans-natal continuity of the developing organism; a conceptualization of birth as a threshold of past and future that paradigmatically reveals the historical understanding of such developmental continuity; and an approach to intergenerational transmission that confronts developmental continuity with historical contingency. My contribution focuses on the work of William T. Preyer and Charles Fere but, in a genealogical vein, situates their work in the larger context of nineteenth-century research on development. PMID- 26013436 TI - Times of danger: embryos, sperm and precarious reproduction ca. 1870s-1910s. AB - This paper discusses the rise and fall of the theory of paternal transmission, drawing attention to the hitherto underresearched debates about the importance and impact of male-mediated harm to the embryo in reproduction that peaked around the turn of the twentieth century. The focus is on the implications of the twin "great social evils," syphilis and alcohol, which converged at the time of a general transformation of medicine into experimental science and a concomitant rise in new concepts of heredity. Looking at the way in which the issue of time added to profound changes which were linked to particular visions of society and changes in the politics of gender at the turn of the century, I examine the asymmetrical relationship of sociopolitical and epistemological dimensions of time and reproduction. The paper shows how these debates were positioned within the wider context of eugenics and in relation to concepts of male reproduction that involved fundamental political, social and moral dimensions. PMID- 26013437 TI - Observing temporal order in living processes: on the role of time in embryology on the cell level in the 1870s and post-2000. AB - The article analyses the role of time in the visual culture of two phases in embryological research: at the end of the nineteenth century, and in the years around 2000. The first case study involves microscopical cytology, the second reproductive genetics. In the 1870s we observe the first of a series of abstractions in research methodology on conception and development, moving from a method propagated as the observation of the "real" living object to the production of stained and fixated objects that are then aligned in temporal order. This process of abstraction ultimately fosters a dissociation between space and time in the research phenomenon, which after 2000 is problematized and explicitly tackled in embryology. Mass data computing made it possible partially to re-include temporal complexity in reproductive genetics in certain, though not all, fields of reproductive genetics. Here research question, instrument and modelling interact in ways that produce very different temporal relationships. Specifically, this article suggests that the different techniques in the late nineteenth century and around 2000 were employed in order to align the time of the researcher with that of the phenomenon and to economize the researcher's work in interaction with the research material's own temporal challenges. PMID- 26013438 TI - Obstetrical care as a matter of time: ultrasound screening, temporality and prevention. AB - This article explores the ways in which ultrasound screening influences the temporal dimensions of prevention in the obstetrical management of pregnancy. Drawing on praxeographic perspectives and empirically based on participant observation of ultrasound examinations in obstetricians' offices, it asks how ultrasound scanning facilitates anticipatory modes of pregnancy management, and investigates the entanglement of different notions of time and temporality in the highly risk-oriented modes of prenatal care in Germany. Arguing that the paradoxical temporality of prevention--acting now in the name of the future--is intensified by ultrasound screening, I show how the attribution of risk regarding foetal growth in prenatal check-ups is based on the fragmentation of procreative time and ask how time standards come into play, how pregnancy is located in calendrical time, and how notions of foetal time and the everyday life times of pregnant women clash during negotiations between obstetricians and pregnant women about the determination of the due date. By analysing temporality as a practical accomplishment via technological devices such as ultrasound, the paper contributes to debates in feminist STS studies on the role of time in reproduction technologies and the management of pregnancy and birth in contemporary societies. PMID- 26013439 TI - The prognostic factors and multiple biomarkers in young patients with colorectal cancer. AB - The incidence of colorectal cancer (CRC) in young patients (<= 50 years of age) appears to be increasing. However, their clinicopathological characteristics and survival are controversial. Likewise, the biomarkers are unclear. We used the West China (2008-2013, China), Surveillance, Epidemiology, and End Results program (1973-2011, United States) and Linkoping Cancer (1972-2009, Sweden) databases to analyse clinicopathological characteristics, survival and multiple biomarkers of young CRC patients. A total of 509,934 CRC patients were included from the three databases. The young CRC patients tended to have more distal location tumours, fewer tumour numbers, later stage, more mucinous carcinoma and poorer differentiation. The cancer-specific survival (CSS) of young patients was significantly better. The PRL (HR = 12.341, 95% CI = 1.615-94.276, P = 0.010), RBM3 (HR = 0.093, 95% CI = 0.012-0.712, P = 0.018), Wrap53 (HR = 1.952, 95% CI = 0.452-6.342, P = 0.031), p53 (HR = 5.549, 95% CI = 1.176-26.178, P = 0.045) and DNA status (HR = 17.602, 95% CI = 2.551-121.448, P = 0.001) were associated with CSS of the young patients. In conclusion, this study suggests that young CRC patients present advanced tumours and more malignant pathological features, while they have a better prognosis. The PRL, RBM3, Wrap53, p53 and DNA status are potential prognostic biomarkers for the young CRC patients. PMID- 26013441 TI - Anti-inflammatory effects of flap and lymph node transfer. AB - BACKGROUND: Transfer of healthy tissue is commonly used in the treatment of complicated wounds and in reconstruction of tissue defects. Recently, microvascular lymph node transfer (LN) has been used to improve the lymphatic function in lymphedema patients. To elucidate the biological effects of flap transfer (with and without lymph nodes), we have studied the postoperative production of proinflammatory, anti-inflammatory, prolymphangiogenic and antilymphangiogenic cytokines, and growth factors (interleukin 1alpha [IL 1alpha], IL-1beta, tumor necrosis factor alpha [TNF-alpha], IL-10, transforming growth factor beta1 [TGF-beta1], IL-4 and IL-13, and vascular endothelial growth factor C [VEGF-C] and VEGF-D) in postoperative wound exudate samples. METHODS: Axillary wound exudate samples were analyzed from four patient groups: axillary lymph node dissection (ALND), microvascular breast reconstruction (BR), LN, and combined LN and BR (LN-BR). RESULTS: The concentration of proinflammatory cytokines was low in all the flap transfer groups as opposed to the ALND group, which showed an extensive proinflammatory response. The level of anti inflammatory and antifibrotic cytokine IL-10 was increased in the LN-BR group samples compared with the ALND and BR groups. In the LN and LN-BR groups, the cytokine profile showed an anti-inflammatory response. CONCLUSIONS: Transfer of healthy tissue hinders the proinflammatory response after surgery, which may explain the beneficial effects of flap transfer in various patient groups. In addition, flap transfer with lymph nodes seems to also promote an antifibrotic effect. The clinical effects of LN in lymphedema patients may be mediated by the increased production of prolymphangiogenic growth factor (VEGF-C) and antifibrotic cytokine (IL-10). PMID- 26013440 TI - Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743. AB - Ecteinascidin 743 (ET-743, Yondelis) is a clinically approved chemotherapeutic natural product isolated from the Caribbean mangrove tunicate Ecteinascidia turbinata. Researchers have long suspected that a microorganism may be the true producer of the anticancer drug, but its genome has remained elusive due to our inability to culture the bacterium in the laboratory using standard techniques. Here, we sequenced and assembled the complete genome of the ET-743 producer, Candidatus Endoecteinascidia frumentensis, directly from metagenomic DNA isolated from the tunicate. Analysis of the ~ 631 kb microbial genome revealed strong evidence of an endosymbiotic lifestyle and extreme genome reduction. Phylogenetic analysis suggested that the producer of the anti-cancer drug is taxonomically distinct from other sequenced microorganisms and could represent a new family of Gammaproteobacteria. The complete genome has also greatly expanded our understanding of ET-743 production and revealed new biosynthetic genes dispersed across more than 173 kb of the small genome. The gene cluster's architecture and its preservation demonstrate that the drug is likely essential to the interactions of the microorganism with its mangrove tunicate host. Taken together, these studies elucidate the lifestyle of a unique, and pharmaceutically important microorganism and highlight the wide diversity of bacteria capable of making potent natural products. PMID- 26013442 TI - Utilization and costs associated with robotic surgery in children. AB - BACKGROUND: To evaluate utilization and costs associated with robotic surgery in children. MATERIALS AND METHODS: We identified patients in the Pediatric Health Information System database who underwent robotic surgery between October 2008 and December 2013. After determining the six most frequently performed surgeries in this group, we identified patients who underwent equivalent nonrobotic surgeries at the same hospitals. Equivalent surgeries were defined as open procedures for urology and laparoscopic procedures for general surgery. We examined trends in the numbers of surgeries performed and compared hospitalization costs between patients undergoing elective robotic and nonrobotic surgery for each procedure. RESULTS: The number of robotic surgeries performed increased by 19.8% per year (P < 0.001). The most common robotic surgeries performed were pyeloplasty (n = 760), ureteral reimplantation (n = 351), nephrectomy (n = 145), partial nephrectomy (n = 56), gastrointestinal antireflux procedure (n = 61), and cholecystectomy (n = 46). Total increase over time was primarily driven by increases in urologic surgeries (17.4% per year, P < 0.001). Postoperative length of stay was shorter after robotic surgeries than equivalent open urologic surgeries but not equivalent laparoscopic general surgery procedures. Total hospitalization costs were higher for robotic surgeries than equivalent urologic or general surgery procedures. CONCLUSIONS: Use of robotic surgery in pediatrics is increasing especially in the management of urologic conditions. Costs of robotic surgery-associated hospitalizations were higher than nonrobotic surgery-associated hospitalizations. PMID- 26013443 TI - Surgical follow-up costs disproportionately impact low-income patients. AB - BACKGROUND: Surgical procedures have significant costs at the national level, but the financial burden on patients is equally important. Patients' out-of-pocket costs for surgery and surgical care include not only direct medical costs but also the indirect cost of lost wages and direct nonmedical costs including transportation and childcare. We hypothesized that the nonmedical costs of routine postoperative clinic visits disproportionately impact low-income patients. MATERIALS AND METHODS: This was a cross-sectional study performed in the postoperative acute care surgery clinic at a large, urban county hospital. A survey containing items about social, demographic, and financial data was collected from ambulatory patients. Nonmedical costs were calculated as the sum of transportation, childcare, and lost wages. Costs and cost to income ratios were compared between income strata. RESULTS: Ninety-seven patients responded to the survey of which 59 reported all items needed for cost calculations. The median calculated cost of a clinic visit was $27 (interquartile range $18-59). Components of this cost were $16 ($14-$20) for travel, $22 ($17-$50) for childcare among patients requiring childcare, and $0 ($0-$30) in lost wages. Low income patients had significantly higher (P = 0.0001) calculated cost to income ratios, spending nearly 10% of their monthly income on these costs. CONCLUSIONS: The financial burden of routine postoperative clinic visits is significant. Consistent with our hypothesis, the lowest income patients are disproportionately impacted, spending nearly 10% of their monthly income on costs associated with the clinic visit. Future cost-containment efforts should examine alternative, lower cost methods of follow-up, which reduce financial burden. PMID- 26013444 TI - Cell Surface Display and Characterization of Rhizopus oryzae Lipase in Pichia pastoris Using Sed1p as an Anchor Protein. AB - It has been investigated to conduct the surface displaying of lipase from Rhizopus oryzae onto the cells of Pichia pastoris yeast using Sed1p as an anchor protein. A yeast cell surface display plasmid pPICZalphaA-rol-histag-sed1p was constructed by fusing rol and sed1p gene fragments into the plasmid pPICZalphaA, followed by introducing recombinant plasmid into P. pastoris cells. Surface display levels were monitored by Western Blot and immunofluorescence microscopy. The activity of displaying lipase obtained from recombinant mutS reached at 60 U/g-dry cell. In addition, the displaying lipase was stable in broad ranges of temperatures and pH, with the optimum temperature at 40 degrees C and pH 7.5. These results indicate that the P. pastoris displaying lipase may have potential in whole-cell biocatalyst. PMID- 26013466 TI - Polarizable coarse-grained models for molecular dynamics simulation of liquid cyclohexane. AB - Force field parameters for polarizable coarse-grained (CG) supra-atomic models of liquid cyclohexane are proposed. Two different bead sizes were investigated, one representing two fine-grained (FG) CH(2)r united atoms of the cyclohexane ring, and one representing three FG CH(2)r united atoms. Electronic polarizability is represented by a massless charge-on-spring particle connected to each CG bead. The model parameters were calibrated against the experimental density and heat of vaporization of liquid cyclohexane, and the free energy of cyclohexane hydration. Both models show good agreement with thermodynamic properties of cyclohexane, yet overestimate the self-diffusion. The dielectric properties of the polarizable models agree very well with experiment. PMID- 26013468 TI - Posttraumatic Growth in Breast Cancer Survivors: Constructive and Illusory Aspects. AB - This study investigated the impact of a building-resilience intervention on coping and posttraumatic growth (PTG) in a convenience sample of 94 breast cancer survivors. PTG was divided into constructive and illusory components, based on the two-sided Janus face model (Maercker & Zoellner, 2004). We operationalized constructive PTG as an improvement in both PTG and coping, and illusory PTG as an improvement in PTG only. An 8-session group intervention was delivered to 49 women (mean age = 51.5 years, SD = 10.7) who completed self-report questionnaires at baseline and at 6 months follow-up; a control group of 45 women only completed questionnaires. More than half the participants (n = 53; 56.38%) reported increased PTG at 6 months (mean change = 0.56, SD = 0.48, eta(2) = .58). The increase in both PTG and positive coping was significantly greater in the intervention group than the control group (B = 0.23 for PTG, and B = 0.35 for positive coping). Further, a higher proportion of constructive PTG (vs. illusory PTG) was reported by the participants in the intervention group (89.3%), as compared to the control group (56.3%; z = 2.57). The distinction between constructive and illusory PTG has clinical implications for interventions promoting coping and growth among cancer survivors. PMID- 26013465 TI - The GIPC1-Akt1 Pathway Is Required for the Specification of the Eye Field in Mouse Embryonic Stem Cells. AB - During early patterning of the neural plate, a single region of the embryonic forebrain, the eye field, becomes competent for eye development. The hallmark of eye field specification is the expression of the eye field transcription factors (EFTFs). Experiments in fish, amphibians, birds, and mammals have demonstrated largely conserved roles for the EFTFs. Although some of the key signaling events that direct the synchronized expression of these factors to the eye field have been elucidated in fish and frogs, it has been more difficult to study these mechanisms in mammalian embryos. In this study, we have used two different methods for directed differentiation of mouse embryonic stem cells (mESCs) to generate eye field cells and retina in vitro to test for a role of the PDZ domain containing protein GIPC1 in the specification of the mammalian eye primordia. We find that the overexpression of a dominant-negative form of GIPC1 (dnGIPC1), as well as the downregulation of endogenous GIPC1, is sufficient to inhibit the development of eye field cells from mESCs. GIPC1 interacts directly with IGFR and participates in Akt1 activation, and pharmacological inhibition of Akt1 phosphorylation mimics the dnGIPC1 phenotype. Our data, together with previous studies in Xenopus, support the hypothesis that the GIPC1-PI3K-Akt1 pathway plays a key role in eye field specification in vertebrates. PMID- 26013469 TI - Platelet-activating factor modulates fat storage in the liver induced by a high refined carbohydrate-containing diet. AB - Hepatic diseases are comorbidities caused by obesity and are influenced by diet composition. The aim of this study was to evaluate the kinetics of metabolic and inflammatory liver dysfunction induced by a high-refined carbohydrate-containing (HC) diet and to determine how platelet-activating factor (PAF) modulates the liver lipid content of mice. BALB/c mice were fed a chow or HC diet for the following experimental periods: 1 and 3 days, 1, 2, 4, 6, 8, 10 and 12 weeks. Wild-type (WT) and PAF receptor-deficient (PAFR(-/-)) mice were fed the same diets for 8 weeks. Mice fed with HC diet showed higher triglycerides and cholesterol levels, fibrosis and inflammation in the liver. The number of neutrophils migrating into the liver was also increased in mice fed with HC diet. However, transaminase levels did not change. PAFR(-/-) mice fed with HC diet showed more steatosis, oxidative stress and higher transaminases levels associated with lower inflammation than WT mice. The consumption of HC diet altered the metabolic and inflammatory response in the liver and was worse in PAFR(-/-) mice. We suggest that PAF regulates liver lipid content and dyslipidemia, protecting the mice from lipotoxicity and liver damage. PMID- 26013470 TI - Guideline on the clinical use of apheresis procedures for the treatment of patients and collection of cellular therapy products. British Committee for Standards in Haematology. PMID- 26013471 TI - [New drugs for horses and production animals in 2014]. AB - In 2014, no new active pharmaceutical ingredients were released on the German market for horses and food producing animals. One established veterinary active pharmaceutical ingredient is avaibable for an additional species. The analgetic buprenorphine (Buprenodale(r) Multidose) has additionally been authorized for horses. Furthermore, four new preparations with a new pharmaceutical form, one drug with a new formulation, new galenics and a new indication, respectively, have recently been released to the market. Furthermore, the prostaglandin F2alpha analoque luprostiol is available again. PMID- 26013472 TI - Plasma cell leukemia mimicking hairy cell leukemia. PMID- 26013473 TI - Biocompatible Polymeric Nanoparticles as Promising Candidates for Drug Delivery. AB - The use of polymeric nanoparticles (NPs) in pharmacology provides many benefits because this approach can increase the efficacy and selectivity of active compounds. However, development of new nanocarriers requires better understanding of the interactions between NPs and the immune system, allowing for the optimization of NP properties for effective drug delivery. Therefore, in the present study, we focused on the investigation of the interactions between biocompatible polymeric NPs and a murine macrophage cell line (RAW 264.7) and a human monocytic leukemia cell line (THP-1). NPs based on a liquid core with polyelectrolyte shells were prepared by sequential adsorption of polyelectrolytes (LbL) using AOT (docusate sodium salt) as the emulsifier and the biocompatible polyelectrolytes polyanion PGA (poly-l-glutamic acid sodium salt) and polycation PLL (poly l-lysine). The average size of the obtained NPs was 80 nm. Pegylated external layers were prepared using PGA-g-PEG (PGA grafted by PEG poly(ethylene glycol)). The influence of the physicochemical properties of the NPs (charge, size, surface modification) on viability, phagocytosis potential, and endocytosis was studied. Internalization of NPs was determined by flow cytometry and confocal microscopy. Moreover, we evaluated whether addition of PEG chains downregulates particle uptake by phagocytic cells. The presented results confirm that the obtained PEG-grafted NPs are promising candidates for drug delivery. PMID- 26013474 TI - Editorial: current perspectives in diabetes and transplantation. PMID- 26013476 TI - Photoluminescent SBA-16 Rhombic Dodecahedral Particles: Assembly, Characterization, and ab Initio Modeling. AB - Nowadays, the use of polyhedral instead of spherical particles as building blocks of engineering new materials has become an area of particular effort in the scientific community. Therefore, fabricating in a reproducible manner large amounts of uniform crystal-like particles is a huge challenge. In this work we report a low reagent-consuming binary surfactant templated method mediated by a hydrothermal treatment as a facile and controllable route for the synthesis of crystal-like rombdodecahedral particles exhibiting SBA-16 mesoporosity. It was determined that the hydrothermal treatment conditions were a key point upon the final material morphology, surface area, microporosity, wall thickness, and mesopore width. As a consequence of their internal mesoporosity order, rhombic dodecahedral synthesized particles exhibited highly efficient ultraviolet absorptions and photoluminescence emissions at room temperature. Conducting experimental and theoretical comparative studies allowed us to infer that the presence of intrinsic defects confined into an ordered mesoporous structure plays a very important role in semiconductor materials. The information presented here is expected to be useful, giving new, accurate information, for the construction of novel technological devices. PMID- 26013475 TI - Long-term renal effects of tenofovir-disoproxil-fumarate in vertically HIV infected children, adolescents, and young adults: a 132-month follow-up study. AB - BACKGROUND AND OBJECTIVES: The introduction of highly active anti-retroviral therapy has led to a significant decline in morbidity and mortality. Although several studies in adult populations have shown that tenofovir-disoproxil fumarate (TDF) use is associated with a significant loss of renal function, there is still uncertainty on the long-term TDF safety profile in pediatric HIV populations, mostly in vertically HIV-infected patients. The aim of this study was to evaluate the long-term TDF renal safety profile, during a ten-year follow up. METHODS: Twenty-six vertically HIV-infected patients were evaluated for a total of 132 months of follow up, monitoring anthropometric parameters, renal function, viral load and CD4+ count. Generalized estimating equations were used to evaluate the changes in anthropometric and laboratory variables. Multivariable fractional polynomials were used to test for the existence of non-linear relationships of outcomes with time and other continuous covariates. In all patients, weight, height and body mass index increased linearly with time. CD4+ count and glomerular filtration rate decreased linearly with time (p < 0.01). RESULTS: No significant increase of serum creatinine was registered. An inverse linear relationship between time and plasma phosphate was found. Hypophosphatemia was detected in 17 patients, mostly mild. In 14 out of 17 we also genotyped single nucleotide polymorphisms rs717620 mapping in ABCC2, a gene encoding for a renal transporter. CONCLUSIONS: Our study demonstrates the relative safety of prolonged use of TDF in vertically HIV-infected children and young adults. The most relevant alteration that emerged was hypophosphatemia, appearing after 72 months of TDF therapy, mostly mild and without clinical significance. PMID- 26013477 TI - Mercury and selenium concentrations in skeletal muscle, liver, and regions of the heart and kidney in bearded seals from Alaska, USA. AB - Mean concentrations of total mercury ([THg]) and selenium ([TSe]) (mass and molar based) were determined for 5 regions of the heart and 2 regions of the kidney of bearded seals (Erignathus barbatus) harvested in Alaska, USA, in 2010 and 2011. Mean [THg] and [TSe] of bearded seal liver and skeletal muscle tissues were used for intertissular comparison. The Se:Hg molar ratios were used to investigate elemental associations and potential antioxidant protection against Hg toxicosis. Age was an important factor in [THg] and Se:Hg molar ratios in heart and kidney. Small but statistically significant differences in mean [THg] occurred among some of the 5 heart regions (p < 0.05). Mean [THg] was highest in liver, 3.057 ug/g, and lowest in heart left ventricle, 0.017 ug/g. Mean [THg] ranked: liver > kidney cortex > kidney medulla > skeletal muscle > heart left ventricle (p < 0.001). Mean [TSe] was highest in liver, 3.848 ug/g, and lowest in heart left ventricle, 0.632 ug/g. Mean [TSe] ranked: liver > kidney cortex > kidney medulla > skeletal muscle > heart left ventricle (p < 0.001). The Se:Hg molar ratios were significantly greater than 1.0 in all tissues (p < 0.001) and represented baselines for normal [TSe] under relatively low [THg]. Mean Se:Hg molar ratios ranked: heart left ventricle > kidney medulla > kidney cortex (p < 0.001). PMID- 26013478 TI - In Vivo Evaluation of Radiofluorinated Caspase-3/7 Inhibitors as Radiotracers for Apoptosis Imaging and Comparison with [18F]ML-10 in a Stroke Model in the Rat. AB - PURPOSE: The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis. PROCEDURES: In vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by MUPET to previously described 1-[4-(2 [(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model. RESULTS: [(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In MUPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10. CONCLUSIONS: Radiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration. PMID- 26013479 TI - Comparison of [(18)F]DCFPyL and [ (68)Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with Relapsed Prostate Cancer. AB - PURPOSE: Gallium-68 (Ga-68)-labeled tracers for imaging expression of the prostate-specific membrane antigen (PSMA) such as the [(68)Ga]Ga-PSMA-HBED-CC have already demonstrated high potential for the detection of recurrent prostate cancer. However, compared to Ga-68, a labeling with fluorine-18 (F-18) would offer advantages with respect to availability, production amount, and image resolution. [(18)F]DCFPyL is a promising F-18-labeled candidate for PSMA-positron emission tomography (PET) imaging that has been recently introduced. In the current study, we aimed to compare [(68)Ga]Ga-PSMA-HBED-CC and [(18)F]DCFPyL for clinical use in biochemically relapsed prostate cancer. PROCEDURES: In 14 selected patients with PSA relapse of prostate cancer, [(18)F]DCFPyL PET/X-ray computed tomography (CT) was performed in addition to [(68)Ga]Ga-PSMA-HBED-CC PET/CT. A systematic comparison was carried out between results obtained with both tracers with regard to the number of detected PSMA-positive lesions, the standardized uptake value (SUV)max and the lesion to background ratios. RESULTS: All suspicious lesions identified by [(68)Ga]Ga-PSMA-HBED-CC were also detected with [(18)F]DCFPyL. In three patients, additional lesions were observed using [(18)F]DCFPyL PET/CT. The mean SUVmax in the concordant [(18)F]DCFPyL PSMA positive lesions was significantly higher as compared to [(68)Ga]Ga-PSMA-HBED-CC (14.5 vs. 12.2, p = 0.028, n = 15). The mean tumor to background ratios (n = 15) were significantly higher for [(18)F]DCFPyL compared to [(68)Ga]Ga-PSMA-HBED-CC using kidney, spleen, or parotid as reference organs (p = 0.006, p = 0.002, p = 0.008), but no significant differences were found using the liver (p = 0.167) or the mediastinum (p = 0.363) as reference organs. CONCLUSION: [(18)F]DCFPyL PET/CT provided a high image quality and visualized small prostate lesions with excellent sensitivity. [(18)F]DCFPyL represents a highly promising alternative to [(68)Ga]Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer. PMID- 26013480 TI - An accelerated diagnostic protocol for the early, safe discharge of low-risk chest pain patients. AB - CLINICAL QUESTION: Can an accelerated 2-hour diagnostic protocol using the cardiac troponin I (cTnI) measurement as the only biomarker be implemented to allow an earlier and safe discharge of low-risk chest pain patients? ARTICLE CHOSEN: Than M, Cullen L, Aldous S, et al. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol 2012;59(23):2091-8. OBJECTIVE: To determine whether an accelerated diagnostic protocol (ADP) for possible cardiac chest pain could identify low-risk patients suitable for early discharge using cTnI as the sole biomarker. PMID- 26013481 TI - Phase-Variable Control of Multiple Phenotypes in Acinetobacter baumannii Strain AB5075. AB - Acinetobacter baumannii strain AB5075 produces colonies with two opacity phenotypes, designated opaque and translucent. These phenotypes were unstable and opaque and translucent colony variants were observed to interconvert at high frequency, suggesting that a phase-variable mechanism was responsible. The frequency of phase variation both within colonies and in broth cultures increased in a cell density-dependent manner and was mediated by the accumulation of an extracellular factor. This factor was distinct from the known A. baumannii signaling molecule 3-OH C12-homoserine lactone. Opaque and translucent colony variants exhibited a number of phenotypic differences, including cell morphology, surface motility, biofilm formation, antibiotic resistance, and virulence in a Galleria mellonella model. Additional clinical isolates exhibited a similar phase variable control of colony opacity, suggesting that this may be a common feature of A. baumannii. IMPORTANCE: A novel phase-variable mechanism has been identified in Acinetobacter baumannii that results in an interconversion between opaque and translucent colony phenotypes. This phase variation also coordinately regulates motility, cell shape, biofilm formation, antibiotic resistance, and virulence. The frequency of phase variation is increased at high cell density via a diffusible extracellular signal. To our knowledge, this report presents the first example of phase variation in A. baumannii and also the first example of quorum sensing-mediated control of phase variation in a bacterium. The findings are important, as this phase-variable mechanism can be identified only via changes in colony opacity using oblique light; therefore, many researchers studying A. baumannii may unknowingly be working with different colony variants. PMID- 26013482 TI - Functional Analysis of Porphyromonas gingivalis W83 CRISPR-Cas Systems. AB - The CRISPR-Cas (clustered regularly interspaced short palindromic repeats/CRISPR associated genes) system provides prokaryotic cells with an adaptive and heritable immune response to foreign genetic elements, such as viruses, plasmids, and transposons. It is present in the majority of Archaea and almost half of species of Bacteria. Porphyromonas gingivalis is an important human pathogen that has been proven to be an etiological agent of periodontitis and has been linked to systemic conditions, such as rheumatoid arthritis and cardiovascular disease. At least 95% of clinical strains of P. gingivalis carry CRISPR arrays, suggesting that these arrays play an important function in vivo. Here we show that all four CRISPR arrays present in the P. gingivalis W83 genome are transcribed. For one of the arrays, we demonstrate in vivo activity against double-stranded DNA constructs containing protospacer sequences accompanied at the 3' end by an NGG protospacer-adjacent motif (PAM). Most of the 44 spacers present in the genome of P. gingivalis W83 share no significant similarity with any known sequences, although 4 spacers are similar to sequences from bacteria found in the oral cavity and the gastrointestinal tract. Four spacers match genomic sequences of the host; however, none of these is flanked at its 3' terminus by the appropriate PAM element. IMPORTANCE: The CRISPR-Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated genes) system is a unique system that provides prokaryotic cells with an adaptive and heritable immunity. In this report, we show that the CRISPR-Cas system of P. gingivalis, an important human pathogen associated with periodontitis and possibly also other conditions, such as rheumatoid arthritis and cardiovascular disease, is active and provides protection from foreign genetic elements. Importantly, the data presented here may be useful for better understanding the communication between cells in larger bacterial communities and, consequently, the process of disease development and progression. PMID- 26013483 TI - A Mutant Chaperonin That Is Functional at Lower Temperatures Enables Hyperthermophilic Archaea To Grow under Cold-Stress Conditions. AB - Thermococcus kodakarensis grows optimally at 85 degrees C and possesses two chaperonins, cold-inducible CpkA and heat-inducible CpkB, which are involved in adaptation to low and high temperatures, respectively. The two chaperonins share a high sequence identity (77%), except in their C-terminal regions. CpkA, which contains tandem repeats of a GGM motif, shows its highest ATPase activity at 60 degrees C to 70 degrees C, whereas CpkB shows its highest activity at temperatures higher than 90 degrees C. To clarify the effects of changes in ATPase activity on chaperonin function at lower temperatures, various CpkA variants were constructed by introducing single point mutations into the C terminal region. A CpkA variant in which Glu530 was replaced with Gly (CpkA E530G) showed increased ATPase activity, with its highest activity at 50 degrees C. The efficacy of the CpkA variants against denatured indole-3-glycerol phosphate synthase of T. kodakarensis (TrpCTk), which is a CpkA target, was then examined in vitro. CpkA-E530G was more effective than wild-type CpkA at facilitating the refolding of chemically unfolded TrpCTk at 50 degrees C. The effect of cpkA-E530G on cell growth was then examined by introducing cpkA-E530G into the genome of T. kodakarensis KU216 (pyrF). The mutant strain, DA4 (pyrF cpkA-E530G), grew as well as the parental KU216 strain at 60 degrees C. In contrast, DA4 grew more vigorously than KU216 at 50 degrees C. These results suggested that the CpkA-E530G mutation prevented cold denaturation of proteins under cold-stress conditions, thereby enabling cells to grow in cooler environments. Thus, a single base pair substitution in a chaperonin gene allows cells to grow vigorously in a new environment. IMPORTANCE: Thermococcus kodakarensis possesses two group II chaperonins, cold-inducible CpkA and heat inducible CpkB, which are involved in adaptation to low and high temperatures, respectively. CpkA might act as an "adaptive allele" to adapt to cooler environments. In this study, we compared the last 20 amino acids within the C termini of the chaperonins and found a clear correlation between the CpkA-type chaperonin gene copy number and growth temperature. Furthermore, we introduced single mutations into the CpkA C-terminal region to clarify its role in cold adaptation, and we showed that a single base substitution allowed the organism to adapt to a lower temperature. The present data suggest that hyperthermophiles have evolved by obtaining mutations in chaperonins that allow them to adapt to a colder environment. PMID- 26013485 TI - Secreted Cyclic Di-GMP Induces Stalk Cell Differentiation in the Eukaryote Dictyostelium discoideum. AB - Cyclic di-GMP (c-di-GMP) is currently recognized as the most widely used intracellular signal molecule in prokaryotes, but roles in eukaryotes were only recently discovered. In the social amoeba Dictyostelium discoideum, c-di-GMP, produced by a prokaryote-type diguanylate cyclase, induces the differentiation of stalk cells, thereby enabling the formation of spore-bearing fruiting bodies. In this review, we summarize the currently known mechanisms that control the major life cycle transitions of Dictyostelium and focus particularly on the role of c di-GMP in stalk formation. Stalk cell differentiation has characteristics of autophagic cell death, a process that also occurs in higher eukaryotes. We discuss the respective roles of c-di-GMP and of another signal molecule, differentiation-inducing factor 1, in autophagic cell death in vitro and in stalk formation in vivo. PMID- 26013486 TI - Critical Components of the Conjugation Machinery of the Integrative and Conjugative Element ICEBs1 of Bacillus subtilis. AB - Conjugation, or mating, plays a profound role in bacterial evolution by spreading genes that allow bacteria to adapt to and colonize new niches. ICEBs1, an integrative and conjugative element of Bacillus subtilis, can transfer itself and mobilize resident plasmids. DNA transfer is mediated by a type IV secretion system (T4SS). Characterized components of the ICEBs1 T4SS include the conserved VirB4-like ATPase ConE, the bifunctional cell wall hydrolase CwlT, and the presumed VirD4-like coupling protein ConQ. A fusion of ConE to green fluorescent protein (GFP) localizes to the membrane preferentially at the cell poles. One or more ICEBs1 proteins are required for ConE's localization at the membrane, as ConE lacks predicted transmembrane segments and ConE-GFP is found dispersed throughout the cytoplasm in cells lacking ICEBs1. Here, we analyzed five ICEBs1 genes to determine if they are required for DNA transfer and/or ConE-GFP localization. We found that conB, conC, conD, and conG, but not yddF, are required for both ICEBs1 transfer and plasmid mobilization. All four required genes encode predicted integral membrane proteins. conB and, to some extent, conD were required for localization of ConE-GFP to the membrane. Using an adenylate cyclase-based bacterial two-hybrid system, we found that ConE interacts with ConB. We propose a model in which the ICEBs1 conjugation machinery is composed of ConB, ConC, ConD, ConE, ConG, CwlT, ConQ, and possibly other ICEBs1 proteins, and that ConB interacts with ConE, helping to recruit and/or maintain ConE at the membrane. IMPORTANCE: Conjugation is a major form of horizontal gene transfer and has played a profound role in bacterial evolution by moving genes, including those involved in antibiotic resistance, metabolism, symbiosis, and infectious disease. During conjugation, DNA is transferred from cell to cell through the conjugation machinery, a type of secretion system. Relatively little is known about the conjugation machinery of Gram-positive bacteria. Here, we analyzed five genes of the integrative and conjugative element ICEBs1 of Bacillus subtilis. Our research identifies four new components of the ICEBs1 conjugation machinery (ConB, ConC, ConD, and ConG) and shows an interaction between ConB and ConE that is required for ConE to associate with the cell membrane. PMID- 26013487 TI - Observations on the Role of TcdE Isoforms in Clostridium difficile Toxin Secretion. AB - Clostridium difficile is a major nosocomial pathogen and the principal causative agent of antibiotic-associated diarrhea. The toxigenic C. difficile strains that cause disease secrete virulence factors, toxin A and toxin B, that cause colonic injury and inflammation. C. difficile toxins have no export signature and are secreted by an unusual mechanism that involves TcdE, a holin-like protein. We isolated a TcdE mutant of the epidemic R20291 strain with impaired toxin secretion, which was restored by complementation with functional TcdE. In the TcdE open reading frame (ORF), we identified three possible translation start sites; each translated isoform may play a specific role in TcdE-controlled toxin release. We created plasmid constructs that express only one of the three TcdE isoforms and complemented the TcdE mutant with these isoforms. Western blot analysis of the complemented strains demonstrated that TcdE is translated efficiently from the start codon at the 25th and 27th positions in the predicted ORF, producing proteins with 142 amino acids (TcdE142) and 140 amino acids (TcdE140), respectively. TcdE166 was not detected when expressed from its own ribosomal binding site (RBS). The effects of all three TcdE isoforms on C. difficile cell viability and toxin release were determined. Among the three isoforms, overexpression of TcdE166 and TcdE142 had a profound effect on cell viability compared to the TcdE140 isoform. Similarly, TcdE166 and TcdE142 facilitated toxin release more efficiently than did TcdE140. The importance of these variations among TcdE isoforms and their role in toxin release are discussed. IMPORTANCE: C. difficile is a nosocomial pathogen that has become the most prevalent cause of antibiotic-associated diarrhea in North America and in several countries in Europe. Most strains of C. difficile produce two high molecular-weight toxins that are regarded as the primary virulence factors. The mechanism by which these large toxins are secreted from bacterial cells is not yet clear but involves TcdE, a holin-like protein. In this work, we show that TcdE could be translated from three different start codons, resulting in the production of three TcdE isoforms. Furthermore, we investigated the role of these isoforms in toxin release and cell lysis in C. difficile. An understanding of TcdE-dependent toxin secretion may be helpful for the development of strategies for preventing and treating C. difficile infections. PMID- 26013484 TI - The copYAZ Operon Functions in Copper Efflux, Biofilm Formation, Genetic Transformation, and Stress Tolerance in Streptococcus mutans. AB - In bacteria, copper homeostasis is closely monitored to ensure proper cellular functions while avoiding cell damage. Most Gram-positive bacteria utilize the copYABZ operon for copper homeostasis, where copA and copB encode copper transporting P-type ATPases, whereas copY and copZ regulate the expression of the cop operon. Streptococcus mutans is a biofilm-forming oral pathogen that harbors a putative copper-transporting copYAZ operon. Here, we characterized the role of copYAZ operon in the physiology of S. mutans and delineated the mechanisms of copper-induced toxicity in this bacterium. We observed that copper induced toxicity in S. mutans cells by generating oxidative stress and disrupting their membrane potential. Deletion of the copYAZ operon in S. mutans strain UA159 resulted in reduced cell viability under copper, acid, and oxidative stress relative to the viability of the wild type under these conditions. Furthermore, the ability of S. mutans to form biofilms and develop genetic competence was impaired under copper stress. Briefly, copper stress significantly reduced cell adherence and total biofilm biomass, concomitantly repressing the transcription of the gtfB, gtfC, gtfD, gbpB, and gbpC genes, whose products have roles in maintaining the structural and/or functional integrity of the S. mutans biofilm. Furthermore, supplementation with copper or loss of copYAZ resulted in significant reductions in transformability and in the transcription of competence associated genes. Copper transport assays revealed that the DeltacopYAZ strain accrued significantly large amounts of intracellular copper compared with the amount of copper accumulation in the wild-type strain, thereby demonstrating a role for CopYAZ in the copper efflux of S. mutans. The complementation of the CopYAZ system restored copper expulsion, membrane potential, and stress tolerance in the copYAZ-null mutant. Taking these results collectively, we have established the function of the S. mutans CopYAZ system in copper export and have further expanded knowledge on the importance of copper homeostasis and the CopYAZ system in modulating streptococcal physiology, including stress tolerance, membrane potential, genetic competence, and biofilm formation. IMPORTANCE: S. mutans is best known for its role in the initiation and progression of human dental caries, one of the most common chronic diseases worldwide. S. mutans is also implicated in bacterial endocarditis, a life-threatening inflammation of the heart valve. The core virulence factors of S. mutans include its ability to produce and sustain acidic conditions and to form a polysaccharide-encased biofilm that provides protection against environmental insults. Here, we demonstrate that the addition of copper and/or deletion of copYAZ (the copper homeostasis system) have serious implications in modulating biofilm formation, stress tolerance, and genetic transformation in S. mutans. Manipulating the pathways affected by copper and the copYAZ system may help to develop potential therapeutics to prevent S. mutans infection in and beyond the oral cavity. PMID- 26013488 TI - Every Site Counts: Submitting Transcription Factor-Binding Site Information through the CollecTF Portal. AB - Experimentally verified transcription factor-binding sites represent an information-rich and highly applicable data type that aptly summarizes the results of time-consuming experiments and inference processes. Currently, there is no centralized repository for this type of data, which is routinely embedded in articles and extremely hard to mine. CollecTF provides the first standardized resource for submission and deposition of these data into the NCBI RefSeq database, maximizing its accessibility and prompting the community to adopt direct submission policies. PMID- 26013489 TI - Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ, in an M1T1 Clinical Strain of Streptococcus pyogenes. AB - Infection with Streptococcus pyogenes is associated with a breadth of clinical manifestations ranging from mild pharyngitis to severe necrotizing fasciitis. Elevated levels of intracellular copper are highly toxic to this bacterium, and thus, the microbe must tightly regulate the level of this metal ion by one or more mechanisms, which have, to date, not been clearly defined. In this study, we have identified two virulence mechanisms by which S. pyogenes protects itself against copper toxicity. We defined a set of putative genes, copY (for a regulator), copA (for a P1-type ATPase), and copZ (for a copper chaperone), whose expression is regulated by copper. Our results indicate that these genes are highly conserved among a range of clinical S. pyogenes isolates. The copY, copA, and copZ genes are induced by copper and are transcribed as a single unit. Heterologous expression assays revealed that S. pyogenes CopA can confer copper tolerance in a copper-sensitive Escherichia coli mutant by preventing the accumulation of toxic levels of copper, a finding that is consistent with a role for CopA in copper export. Evaluation of the effect of copper stress on S. pyogenes in a planktonic or biofilm state revealed that biofilms may aid in protection during initial exposure to copper. However, copper stress appears to prevent the shift from the planktonic to the biofilm state. Therefore, our results indicate that S. pyogenes may use several virulence mechanisms, including altered gene expression and a transition to and from planktonic and biofilm states, to promote survival during copper stress. IMPORTANCE: Bacterial pathogens encounter multiple stressors at the host-pathogen interface. This study evaluates a virulence mechanism(s) utilized by S. pyogenes to combat copper at sites of infection. A better understanding of pathogen tolerance to stressors such as copper is necessary to determine how host-pathogen interactions impact bacterial survival during infections. These insights may lead to the identification of novel therapeutic targets that can be used to address antibiotic resistance. PMID- 26013490 TI - A Trigger Residue for Transmembrane Signaling in the Escherichia coli Serine Chemoreceptor. AB - The transmembrane Tsr protein of Escherichia coli mediates chemotactic responses to environmental serine gradients. Serine binds to the periplasmic domain of the homodimeric Tsr molecule, promoting a small inward displacement of one transmembrane helix (TM2). TM2 piston displacements, in turn, modulate the structural stability of the Tsr-HAMP domain on the cytoplasmic side of the membrane to control the autophosphorylation activity of the signaling CheA kinase bound to the membrane-distal cytoplasmic tip of Tsr. A five-residue control cable segment connects TM2 to the AS1 helix of HAMP and transmits stimulus and sensory adaptation signals between them. To explore the possible role of control cable helicity in transmembrane signaling by Tsr, we characterized the signaling properties of mutant receptors with various control cable alterations. An all alanine control cable shifted Tsr output toward the kinase-on state, whereas an all-glycine control cable prevented Tsr from reaching either a fully on or fully off output state. Restoration of the native isoleucine (I214) in these synthetic control cables largely alleviated their signaling defects. Single amino acid replacements at Tsr-I214 shifted output toward the kinase-off (L, N, H, and R) or kinase-on (A and G) states, whereas other control cable residues tolerated most amino acid replacements with little change in signaling behavior. These findings indicate that changes in control cable helicity might mediate transitions between the kinase-on and kinase-off states during transmembrane signaling by chemoreceptors. Moreover, the Tsr-I214 side chain plays a key role, possibly through interaction with the membrane interfacial environment, in triggering signaling changes in response to TM2 piston displacements. IMPORTANCE: The Tsr protein of E. coli mediates chemotactic responses to environmental serine gradients. Stimulus signals from the Tsr periplasmic sensing domain reach its cytoplasmic kinase control domain through piston displacements of a membrane spanning helix and an adjoining five-residue control cable segment. We characterized the signaling properties of Tsr variants to elucidate the transmembrane signaling role of the control cable, an element present in many microbial sensory proteins. Both the kinase-on and kinase-off output states of Tsr depended on control cable helicity, but only one residue, I214, was critical for triggering responses to attractant inputs. These findings suggest that signal transmission in Tsr involves modulation of control cable helicity through interaction of the I214 side chain with the cytoplasmic membrane. PMID- 26013492 TI - Cofactor Specificity of the Bifunctional Alcohol and Aldehyde Dehydrogenase (AdhE) in Wild-Type and Mutant Clostridium thermocellum and Thermoanaerobacterium saccharolyticum. AB - Clostridium thermocellum and Thermoanaerobacterium saccharolyticum are thermophilic bacteria that have been engineered to produce ethanol from the cellulose and hemicellulose fractions of biomass, respectively. Although engineered strains of T. saccharolyticum produce ethanol with a yield of 90% of the theoretical maximum, engineered strains of C. thermocellum produce ethanol at lower yields (~50% of the theoretical maximum). In the course of engineering these strains, a number of mutations have been discovered in their adhE genes, which encode both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes. To understand the effects of these mutations, the adhE genes from six strains of C. thermocellum and T. saccharolyticum were cloned and expressed in Escherichia coli, the enzymes produced were purified by affinity chromatography, and enzyme activity was measured. In wild-type strains of both organisms, NADH was the preferred cofactor for both ALDH and ADH activities. In high-ethanol producing (ethanologen) strains of T. saccharolyticum, both ALDH and ADH activities showed increased NADPH-linked activity. Interestingly, the AdhE protein of the ethanologenic strain of C. thermocellum has acquired high NADPH linked ADH activity while maintaining NADH-linked ALDH and ADH activities at wild type levels. When single amino acid mutations in AdhE that caused increased NADPH linked ADH activity were introduced into C. thermocellum and T. saccharolyticum, ethanol production increased in both organisms. Structural analysis of the wild type and mutant AdhE proteins was performed to provide explanations for the cofactor specificity change on a molecular level. IMPORTANCE: This work describes the characterization of the AdhE enzyme from different strains of C. thermocellum and T. saccharolyticum. C. thermocellum and T. saccharolyticum are thermophilic anaerobes that have been engineered to make high yields of ethanol and can solubilize components of plant biomass and ferment the sugars to ethanol. In the course of engineering these strains, several mutations arose in the bifunctional ADH/ALDH protein AdhE, changing both enzyme activity and cofactor specificity. We show that changing AdhE cofactor specificity from mostly NADH linked to mostly NADPH linked resulted in higher ethanol production by C. thermocellum and T. saccharolyticum. PMID- 26013491 TI - The Crystal Structure of Nitrosomonas europaea Sucrose Synthase Reveals Critical Conformational Changes and Insights into Sucrose Metabolism in Prokaryotes. AB - In this paper we report the first crystal structure of a prokaryotic sucrose synthase from the nonphotosynthetic bacterium Nitrosomonas europaea. The obtained structure was in an open form, whereas the only other available structure, from the plant Arabidopsis thaliana, was in a closed conformation. Comparative structural analysis revealed a "hinge-latch" combination, which is critical to transition between the open and closed forms of the enzyme. The N. europaea sucrose synthase shares the same fold as the GT-B family of the retaining glycosyltransferases. In addition, a triad of conserved homologous catalytic residues in the family was shown to be functionally critical in the N. europaea sucrose synthase (Arg567, Lys572, and Glu663). This implies that sucrose synthase shares not only a common origin with the GT-B family but also a similar catalytic mechanism. The enzyme preferred transferring glucose from ADP-glucose rather than UDP-glucose like the eukaryotic counterparts. This predicts that these prokaryotic organisms have a different sucrose metabolic scenario from plants. Nucleotide preference determines where the glucose moiety is targeted after sucrose is degraded. IMPORTANCE: We obtained biochemical and structural evidence of sucrose metabolism in nonphotosynthetic bacteria. Until now, only sucrose synthases from photosynthetic organisms have been characterized. Here, we provide the crystal structure of the sucrose synthase from the chemolithoautotroph N. europaea. The structure supported that the enzyme functions with an open/close induced fit mechanism. The enzyme prefers as the substrate adenine-based nucleotides rather than uridine-based like the eukaryotic counterparts, implying a strong connection between sucrose and glycogen metabolism in these bacteria. Mutagenesis data showed that the catalytic mechanism must be conserved not only in sucrose synthases but also in all other retaining GT-B glycosyltransferases. PMID- 26013494 TI - Chloroquine-containing compounds: a patent review (2010 - 2014). AB - INTRODUCTION: Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented. AREAS COVERED: In this review, patents describing CQ and its derivatives/compositions over the last 5 years are analyzed. The review highlights the rationale, chemical structures, biological evaluation and potential therapeutic application of CQ, its derivatives and compositions. EXPERT OPINION: Repurposing efforts have dominantly focused on racemic CQ with no studies exploring the effect of the (R) and (S) enantiomers, which might potentially have additional benefits in other diseases. Additionally, evaluating other similarly acting antimalarials in clinical use and structural analogs could help maximize the intrinsic value of the 4-aminoquinolines. With regard to cancer therapy, successful repurposing of CQ-containing compounds will require linking the mode of action of these antimalarials with the signaling pathways that drive cancer cell proliferation to facilitate the development of a 4-amino-7 chloroquinoline that can be used as a synergistic partner in anticancer combination chemotherapy. PMID- 26013495 TI - Tetrabenzoperipentacene: Stable Five-Electron Donating Ability and a Discrete Triple-Layered beta-Graphite Form in the Solid State. AB - An oxidative ring-closure reaction of a tetranaphthylpyrene derivative led to the synthesis of a 56 all-carbon conjugated tetrabenzoperipentacene. In the single crystal X-ray structure, three molecules make a triple-layered cluster by pi stacking, wherein each layer rotates by 120 degrees , and is thus considered a petit beta-graphite. As for the optical properties, the Stokes shift is extremely small (10 cm(-1) ), thus indicating its remarkably rigid framework. The tetrabenzoperipentacene exhibits reversible five-electron oxidation waves in cyclic voltammetry, and is regarded as a counterpart to the fullerene C60 in terms of stable multicharge-storage nanocarbon materials. PMID- 26013493 TI - Databases for Microbiologists. AB - Databases play an increasingly important role in biology. They archive, store, maintain, and share information on genes, genomes, expression data, protein sequences and structures, metabolites and reactions, interactions, and pathways. All these data are critically important to microbiologists. Furthermore, microbiology has its own databases that deal with model microorganisms, microbial diversity, physiology, and pathogenesis. Thousands of biological databases are currently available, and it becomes increasingly difficult to keep up with their development. The purpose of this minireview is to provide a brief survey of current databases that are of interest to microbiologists. PMID- 26013496 TI - Continuous renal replacement therapy for safe and adequate voriconazole intravenous treatment: enough reason to be confident? PMID- 26013531 TI - Building from a conceptual model of the resilience process during ageing, towards the Groningen Aging Resilience Inventory. AB - AIM: To develop and psychometrically test the Groningen Ageing Resilience Inventory. BACKGROUND: Ageing is a process that is often accompanied by functional limitation, disabilities and losses. Instead of focusing on these negative events of ageing, there are opportunities in focusing on adaptation mechanisms, like resilience, that are helpful to cope with those adversities. DESIGN: Cross-sectional study. METHOD: The study was conducted from 2011-2012. First, a conceptual model of resilience during the ageing process was constructed. Next, items were formulated that made up a comprehensive template questionnaire reflecting the model. Finally, a cross-sectional study was performed to evaluate the construct validity and internal consistency of this template 16-item questionnaire. FINDINGS: Participants (N = 229) with a mean age of 71.5 years, completed the template 16-item Groningen Ageing Resilience Inventory, and performance based tests and psychological questionnaires. Exploratory factor analysis resulted in a two factor solution of internal and external resources of resilience. Three items did not discriminate well between the two factors and were deleted, remaining a final 13-item questionnaire that shows evidence of good internal consistency. The direction and magnitude of the correlations with other measures support the construct validity. CONCLUSION: The Groningen Ageing Resilience Inventory is a useful instrument that can help nurses, other healthcare workers, researchers and providers of informal care to identify the internal and external resources of resilience in individuals and groups. In a multidisciplinary biopsychosocial approach this knowledge provides tools for empowering older patients in performing health promoting behaviors and self-care tasks. PMID- 26013497 TI - AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation. AB - Lipid droplets (LDs) are intracellular organelles that provide fatty acids (FAs) to cellular processes including synthesis of membranes and production of metabolic energy. While known to move bidirectionally along microtubules (MTs), the role of LD motion and whether it facilitates interaction with other organelles are unclear. Here we show that during nutrient starvation, LDs and mitochondria relocate on detyrosinated MT from the cell centre to adopt a dispersed distribution. In the cell periphery, LD-mitochondria interactions increase and LDs efficiently supply FAs for mitochondrial beta-oxidation. This cellular adaptation requires the activation of the energy sensor AMPK, which in response to starvation simultaneously increases LD motion, reorganizes the network of detyrosinated MTs and activates mitochondria. In conclusion, we describe the existence of a specialized cellular network connecting the cellular energetic status and MT dynamics to coordinate the functioning of LDs and mitochondria during nutrient scarcity. PMID- 26013532 TI - UDP-D-galactose synthesis by UDP-glucose 4-epimerase 4 is required for organization of the trans-Golgi network/early endosome in Arabidopsis thaliana root epidermal cells. AB - Endomembrane organization is essential for cell physiology. We previously identified an Arabidopsis thaliana mutant in which a plasma membrane (PM) marker GFP-NIP5;1 and trans-Golgi network/early endosome (TGN/EE) markers were accumulated in intracellular aggregates in epidermal cells of the root elongation zone. The mutant was identified as an allele of UDP-glucose epimerase 4 (UGE4)/root hair defective 1/root epidermal bulgar 1, which was previously described as a mutant with swollen root epidermal cells and has an altered sugar composition in cell wall polysaccharides. Importantly, these defects including aggregate formation were restored by supplementation of D-galactose in the medium. These results suggested that UDP-D-galactose synthesis by UGE4 is important for endomembrane organization in addition to cell wall structure. Here, we further investigated the nature of the aggregates using various markers of endomembrane compartments and BOR1-GFP, which traffics from PM to vacuole in response to high-B supply. The markers of multi-vesicular bodies/late endosomes (MVB/LEs) and BOR1-GFP were strongly accumulated in the intracellular aggregates, while those of the endoplasmic reticulum (ER), the vacuolar membrane, and the Golgi were only slightly affected in the uge4 mutant. The abnormal localizations of these markers in the uge4 mutant differed from the effects of inhibitors of actin and microtubule polymerization, although they also affected endomembrane organization. Furthermore, electron microscopy analysis revealed accumulation of abnormal high-electron-density vesicles in elongating epidermal cells. The abnormal vesicles were often associated or interconnected with TGN/EEs and contained ADP-ribosylation factor 1, which is usually localized to the Golgi and the TGN/EEs. On the other hand, structures of the ER, Golgi apparatus, and MVB/LEs were apparently normal in uge4 cells. Together, our data indicate the importance of UDP-D-galactose synthesis by UGE4 for the organization and function of endomembranes, especially TGN/EEs, which are a sorting station of the secretory and vacuolar pathways. PMID- 26013533 TI - Construction of an Internally B3 N3 -Doped Nanographene Molecule. AB - The synthesis of a hexa-peri-hexabenzocoronene (HBC) with a central borazine core is described. The solid-state structure of this BN-doped HBC (BN-HBC) is isotypic with that of the parent HBC. Scanning tunneling microscopy shows that BN-HBC lies flat on Au(111) in a two-dimensional pattern. PMID- 26013534 TI - [Primary CNS lymphoma. Progress in the diagnostics and therapy]. AB - BACKGROUND: Some important knowledge has recently been gained on primary central nervous system lymphomas (PCNSL) despite its rarity. GOAL: This article summarizes the most relevant progress in the diagnostics and therapy of PCNSL and discusses future directions. MATERIAL AND METHODS: Reference articles in the English language literature were studied with respect to future approaches in PCNSL. RESULTS: New diagnostic methods in cerebrospinal fluid have been developed to facilitate lymphoma diagnosis; however, their value still has to be validated. A better immunohistological and molecular characterization of PCNSL will probably result in identification of new therapeutic targets. The only phase III trial for PCNSL completed so far did not demonstrate a survival advantage with whole brain irradiation after high-dose methotrexate (HDMTX)-based chemotherapy as compared to chemotherapy alone. The optimal primary chemotherapy has not yet been established due to a lack of results from randomized trials. Non-comparative studies suggest a superiority of combined polychemotherapy over HDMTX monotherapy. Future therapeutic developments are directed towards consolidation of HDMTX-based induction chemotherapy with noncross-resistant conventional chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. An important goal of all therapies for PCNSL is to avoid delayed neurotoxicity. DISCUSSION: Further improvement of diagnostics and well-designed comparative studies, including new drugs when possible are still needed to define the optimal management of this still frequently prognostically unfavorable disease. PMID- 26013535 TI - [Mechanical thrombectomy in acute ischemic stroke. What is the position after the latest study results?]. AB - Mechanical devices for the recanalization of vessel occlusions in severe acute ischemic stroke have been developed for more than a decade. Several devices have been approved for clinical use on the basis of uncontrolled case series. Many neurologists have asked for randomized clinical trials comparing the new devices with standard treatment, e.g. thrombolytic therapy within a 4.5 h time window. The first 3 investigator initiated randomized trials published in 2013 failed to show superiority of mechanical thrombectomy over standard treatment. In the aftermath of these negative results several new trials with changes in design (e.g. shorter time window and only proximal vessel occlusions) and the use of modern devices with proven higher recanalization rates, so called stent retrievers, have been launched. In October 2014 the first of these new trials was presented and showed a clear superiority of thrombectomy. Based on this result interim analyses of five other studies were performed and most were prematurely terminated because of overwhelming efficacy. Only one trial testing another type of recanalization device failed to reach a statistically significant result. Currently five studies have already been published and two more studies have been presented at scientific conferences. This article provides an overview of the study protocols and the results of the individual studies, their common features and the characteristics of patients who benefit from this treatment. Finally, the consequences that these results may have for the treatment of patients with severe stroke caused by proximal vessel occlusion are discussed. PMID- 26013536 TI - Overdiagnosis of bone fragility in the quest to prevent hip fracture. PMID- 26013538 TI - Graphene oxide-Li(+)@C60 donor-acceptor composites for photoenergy conversion. AB - An ionic endohedral metallofullerene (Li(+)@C60) with mild hydrophilic nature was combined with graphene oxide (GO) to construct a donor-acceptor composite in neat water. The resulting composite was characterised by UV-Vis and Raman spectroscopy, powder X-ray diffraction, dynamic light scattering measurements and transmission electron microscopy. Theoretical calculations (DFT at the B3LYP/6 31(d) level) were also utilized to gain further insight into the composite formation. As detected by electron paramagnetic resonance spectroscopy, photoexcitation of the GO-Li(+)@C60 composite results in electron transfer from GO to the triplet excited state of Li(+)@C60, leading to photocurrent generation at the OTE/SnO2 electrode. PMID- 26013537 TI - Screening and concurrent brief intervention of conjoint hazardous or harmful alcohol and tobacco use in hospital out-patients in Thailand: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to conduct a cluster randomized control trial to assess the efficacy of screening and brief intervention (SBI) for conjoint alcohol and tobacco use among hospital out-patients. METHOD: In all 620 hospital out-patients who screened positive for both tobacco and alcohol moderate risk in four hospitals were randomized into 2 control and 1 intervention condition using the hospital as a unit of randomization (2 intervention and 2 control hospitals) to 405 patients in the two control groups (tobacco only intervention, n=199, and alcohol only intervention, n=206) and 215 in the intervention group. The intervention or control consisted of three counselling sessions. RESULTS: Results of the interaction (Group * Time) effects using GEE indicated that there were statistically significant differences between the three study groups over the 6-month follow-up on the ASSIST tobacco score (Wald chi(2) = 8.43, P=0.004), and past week tobacco use abstinence (Wald chi(2)=7.34, P=0.007). Although there were no significant interaction effects on the other outcomes (Alcohol ASSIST score, low alcohol risk score, past week tobacco abstinence or low alcohol risk score, and past week tobacco abstinence and low alcohol risk score), the scores in all of the six outcome measures showed consistent improvements. For past week tobacco abstinence the tobacco only intervention was more effective than the alcohol only intervention and the integrated alcohol and tobacco intervention. For the outcome of low alcohol risk, the alcohol only intervention and the integrated alcohol and tobacco intervention was more effective than the tobacco only or alcohol only intervention. CONCLUSIONS: The study found that for past week tobacco abstinence the tobacco only intervention was more effective than the alcohol only intervention and the polydrug use (alcohol and tobacco) integrated intervention. PMID- 26013539 TI - Severe fetal acidemia in cases of clinical chorioamnionitis in which the infant later developed cerebral palsy. AB - BACKGROUND: The umbilical arterial pH (UApH) in cases of clinically apparent chorioamnionitis (CAM) in which the infant later develop severe cerebral palsy (CP) has not yet been fully investigated. The objective of this study was to determine the UApH in CAM cases in which the infant later develop severe CP. METHODS: A review was conducted unti1 April 2014 among 324 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions, as determined by the Japan Council for Quality Health Care. Eighty-six infants born at over 34 weeks of gestation with an abnormal FHR pattern during labor were selected. The subjects were divided into the following two groups: cases with (Group I, n = 19) and those without (Group II, n = 67) clinical CAM. Severe fetal acidemia was defined as a pH of less than 7.0. RESULTS: The frequency of severe acidemia in Groups 1 and II was 26.3 and 74.6 %, respectively. In addition, the frequency of severe acidemia was significantly less in Group I (odds ratio (OR) 0.12, 95 % confidence interval (CI) 0.03-0.53) than in Group II, while the frequency of fetal tachycardia was greater in Group I (OR 7.61, 95 % CI 1.82-31.7) than in Group II, after adjusting for confounding effects. CONCLUSIONS: The frequency of severe acidemia was lower in the cases of clinical CAM in which the infant later developed severe cerebral palsy than in the cases without clinical CAM. The relation of fetal tachycardia to CP with clinical CAM, but not to acidemia, should be reevaluated in such cases. PMID- 26013540 TI - Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen Activated Protein Kinase Signaling Pathway. AB - Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) 1/2 significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, protein kinase B (Akt), ERK, and cAMP responsive element-binding protein (CREB). These effects were markedly reduced by addition of the corresponding inhibitors. We also found that ABG-001-induced neurite outgrowth was reduced by protein kinase C inhibitor as well as small-interfering RNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose nerve growth factor augmented the observed effects of ABG-001 on neurite outgrowth. These results suggest that ABG-001 targets the IGF-1 receptor and activates PI3K, mitogen-activated protein kinase, and their downstream signaling cascades to induce neurite outgrowth. PMID- 26013541 TI - Biased Agonism of Endogenous Opioid Peptides at the MU-Opioid Receptor. AB - Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein-coupled receptor (GPCR) ligands to activate different cell signaling pathways, and to result in different physiologic outcomes. To date, most studies of biased agonism have focused on synthetic molecules targeting various GPCRs; however, many of these receptors have multiple endogenous ligands, suggesting that "natural" bias may be an unappreciated feature of these GPCRs. The MU-opioid receptor (MOP) is activated by numerous endogenous opioid peptides, remains an attractive therapeutic target for the treatment of pain, and exhibits biased agonism in response to synthetic opiates. The aim of this study was to rigorously assess the potential for biased agonism in the actions of endogenous opioids at the MOP in a common cellular background, and compare these to the effects of the agonist d-Ala2-N-MePhe4-Gly-ol enkephalin (DAMGO). We investigated activation of G proteins, inhibition of cAMP production, extracellular signal-regulated kinase 1 and 2 phosphorylation, beta-arrestin 1/2 recruitment, and MOP trafficking, and applied a novel analytical method to quantify biased agonism. Although many endogenous opioids displayed signaling profiles similar to that of DAMGO, alpha-neoendorphin, Met-enkephalin-Arg-Phe, and the putatively endogenous peptide endomorphin-1 displayed particularly distinct bias profiles. These may represent examples of natural bias if it can be shown that they have different signaling properties and physiologic effects in vivo compared with other endogenous opioids. Understanding how endogenous opioids control physiologic processes through biased agonism can reveal vital information required to enable the design of biased opioids with improved pharmacological profiles and treat diseases involving dysfunction of the endogenous opioid system. PMID- 26013542 TI - Role of G Protein-Coupled Receptor Kinases 2 and 3 in MU-Opioid Receptor Desensitization and Internalization. AB - There is ongoing debate about the role of G protein-coupled receptor kinases (GRKs) in agonist-induced desensitization of the MU-opioid receptor (MOPr) in brain neurons. In the present paper, we have used a novel membrane-permeable, small-molecule inhibitor of GRK2 and GRK3, Takeda compound 101 (Cmpd101; 3-[[[4 methyl-5-(4-pyridyl)-4H-1,2,4-triazole-3-yl] methyl] amino]-N-[2-(trifuoromethyl) benzyl] benzamidehydrochloride), to study the involvement of GRK2/3 in acute agonist-induced MOPr desensitization. We observed that Cmpd101 inhibits the desensitization of the G protein-activated inwardly-rectifying potassium current evoked by receptor-saturating concentrations of methionine-enkephalin (Met-Enk), [d-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO), endomorphin-2, and morphine in rat and mouse locus coeruleus (LC) neurons. In LC neurons from GRK3 knockout mice, Met-Enk-induced desensitization was unaffected, implying a role for GRK2 in MOPr desensitization. Quantitative analysis of the loss of functional MOPrs following acute agonist exposure revealed that Cmpd101 only partially reversed MOPr desensitization. Inhibition of extracellular signal-regulated kinase 1/2, protein kinase C, c-Jun N-terminal kinase, or GRK5 did not inhibit the Cmpd101 insensitive component of desensitization. In HEK 293 cells, Cmpd101 produced almost complete inhibition of DAMGO-induced MOPr phosphorylation at Ser(375), arrestin translocation, and MOPr internalization. Our data demonstrate a role for GRK2 (and potentially also GRK3) in agonist-induced MOPr desensitization in the LC, but leave open the possibility that another, as yet unidentified, mechanism of desensitization also exists. PMID- 26013544 TI - Halogen bonding molecular capsules. AB - Molecular capsules based solely on the interaction of halogen bonding (XB) are presented along with their host-guest binding properties in solution. The first example of a well-defined four-point XB supramolecular system is realized by decorating resorcin[4]arene cavitands with polarized halogen atoms for dimerization with tetra(4-pyridyl) resorcin[4]arene cavitands. NMR binding data for the F, Cl, Br, and I cavitands as the XB donor show association constants (Ka ) of up to 5370 M(-1) (DeltaG283 K =-4.85 kcal mol(-1) , for I), even in XB competitive solvent, such as deuterated benzene/acetone/methanol (70:30:1) at 283 K, where comparable monodentate model systems show no association. The XB capsular geometry is evidenced by two-dimensional HOESY NMR, and the thermodynamic profile shows that capsule formation is enthalpically driven. Either 1,4-dioxane or 1,4-dithiane are encapsulated within each of the two separate cavities within the XB capsule, with of up to Ka =9.0 10(8) M(-2) (DeltaG283 K =-11.6 kcal mol(-1) ). PMID- 26013543 TI - Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3 Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists. AB - 6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain-penetrant compound 14G: [5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2R)-2-hydroxy-cyclohexyl] 3-pyridinecarboxamide] and its peripherally restricted analog 14H: [5-(4 chlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-6-(2-methoxyethoxy)-3 pyridinecarboxamide], have been recently introduced as selective, high-affinity antagonists of the human cannabinoid-1 receptor (hCB1R). Binding analyses revealed two orders of magnitude lower affinity of these compounds for mouse and rat versus human CB1R, whereas the affinity of rimonabant is comparable for all three CB1Rs. Modeling of ligand binding to CB1R and binding assays with native and mutant (Ile105Met) hCB1Rs indicate that the Ile105 to Met mutation in rodent CB1Rs accounts for the species-dependent affinity of 14G: and 14H: . Our work identifies Ile105 as a new pharmacophore component for developing better hCB1R antagonists and invalidates rodent models for assessing the antiobesity efficacy of 14G: and 14H: . PMID- 26013545 TI - Alpha-L-fucosidase isoenzyme iso2 from Paenibacillus thiaminolyticus. AB - BACKGROUND: alpha-L-Fucosidases are enzymes involved in metabolism of alpha-L fucosylated molecules, compounds with a fundamental role in different life essential processes including immune response, fertilization and development, but also in some serious pathological events. According to the CAZy database, these enzymes belong to families 29 and 95. Some of them are also reported to be able to catalyze transglycosylation reactions, during which alpha-L-fucosylated molecules, representing compounds of interest especially for pharmaceutical industry, are formed. METHODS: Activity-based screening of a genomic library was used to isolate the gene encoding a novel alpha-L-fucosidase. The enzyme was expressed in E.coli and affinity chromatography was used for purification of His tagged alpha-L-fucosidase. Standard activity assay was used for enzyme characterization. Thin layer chromatography and mass spectrometry were used for transglycosylation reactions evaluation. RESULTS: Using a genomic library of Paenibacillus thiaminolyticus, constructed in E.coli DH5alpha cells, nucleotide sequence of a new alpha-L-fucosidase isoenzyme was determined and submitted to the EMBL database (HE654122). However, no similarity with enzymes from CAZy database families 29 and 95 was detected. This enzyme was produced in form of histidine-tagged protein in E.coli BL21 (DE3) cells and purified by metaloaffinity chromatography. Hydrolytic and transglycosylation abilities of alpha-L-fucosidase iso2 were tested using different acceptor molecules. CONCLUSIONS: In this study, new enzyme alpha-L-fucosidase iso2 originating from Paenibacillus thiaminolyticus was described and prepared in recombinant form and its hydrolytic and transglycosylation properties were characterized. As a very low amino acid sequence similarity with known alpha-L-fucosidases was found, following study could be important for different biochemical disciplines involving molecular modelling. PMID- 26013546 TI - Fitness and physiology of Adelges tsugae (Hemiptera: Adelgidae) in relation to the health of the eastern hemlock. AB - The hemlock woolly adelgid, Adelges tsugae Annand is an invasive insect that frequently causes hemlock (Tsuga spp.) mortality in the eastern United States. Studies have shown that once healthy hemlocks become infested by the adelgid, nutrients are depleted from the tree, leading to both tree decline and a reduction of the adelgid population. Since A. tsugae is dependent on hemlock for nutrients, feeding on trees in poor health may affect the ability of the insect to obtain necessary nutrients and may consequently affect their physiological and population health. Trees were categorized as lightly or moderately impacted by A. tsugae based on quantitative and qualitative tree health measurements. Population health of A. tsugae on each tree was determined by measuring insect density and peak mean fecundity; A. tsugae physiological health was determined by measuring insect biomass, total carbon, carbohydrate, total nitrogen, and amino nitrogen levels. Adelges tsugae from moderately impacted trees exhibited significantly greater fecundity than from lightly impacted trees. However, A. tsugae from lightly impacted hemlocks contained significantly greater levels of carbohydrates, total nitrogen, and amino nitrogen. While the results of the physiological analysis generally support our hypothesis that A. tsugae on lightly impacted trees are healthier than those on moderately impacted trees, this was not reflected in the population health measurements. Adelges tsugae egg health in response to tree health should be verified. This study provides the first examination of A. tsugae physiological health in relation to standard A. tsugae population health measures on hemlocks of different health levels. PMID- 26013547 TI - Live Cell Characterization of DNA Aggregation Delivered through Lipofection. AB - DNA trafficking phenomena, such as information on where and to what extent DNA aggregation occurs, have yet to be fully characterised in the live cell. Here we characterise the aggregation of DNA when delivered through lipofection by applying the Number and Brightness (N&B) approach. The N&B analysis demonstrates extensive aggregation throughout the live cell with DNA clusters in the extremity of the cell and peri-nuclear areas. Once within the nucleus aggregation had decreased 3-fold. In addition, we show that increasing serum concentration of cell media results in greater cytoplasmic aggregation. Further, the effects of the DNA fragment size on aggregation was explored, where larger DNA constructs exhibited less aggregation. This study demonstrates the first quantification of DNA aggregation when delivered through lipofection in live cells. In addition, this study has presents a model for alternative uses of this imaging approach, which was originally developed to study protein oligomerization and aggregation. PMID- 26013548 TI - Following the Reaction of Heteroanions inside a {W18O56} Polyoxometalate Nanocage by NMR Spectroscopy and Mass Spectrometry. AB - By incorporating phosphorus(III)-based anions into a polyoxometalate cage, a new type of tungsten-based unconventional Dawson-like cluster, [W18O56(HP(III)O3)2(H2O)2](8-), was isolated, in which the reaction of the two phosphite anions [HPO3](2-) within the {W18O56} cage could be followed spectroscopically. As well as full X-ray crystallographic analysis, we studied the reactivity of the cluster using both solution-state NMR spectroscopy and mass spectrometry. These techniques show that the cluster undergoes a structural rearrangement in solution whereby the {HPO3} moieties dimerize to form a weakly interacting (O3PH???HPO3) moiety. In the crystalline state the cluster exhibits a thermally triggered oxidation of the two P(III) template moieties to form P(V) centers (phosphite to phosphate), commensurate with the transformation of the cage into a Wells-Dawson {W18O54} cluster. PMID- 26013549 TI - Spontaneous Self-Assembly of gamma-Cyclodextrins in Dilute Solutions with Tunable Sizes and Thermodynamic Stability. AB - The behavior in dilute solution of phosphate-functionalized gamma-cyclodextrin macroanions with eight charges on the rim was explored. The hydrophilic macroions in mixed solvents show strong attraction between each other, mediated by the counterions, and consequently self-assemble into blackberry-type hollow spherical structures. Time-resolved laser light scattering (LLS) measurements at high temperature ruled out the possibility of hydrogen bonding as the main driving force in the self-assembly and indicated the good thermodynamic stability of assemblies regulated by the charge. The transition from single macroions to blackberries can be tuned by adjusting the content of organic solvent. The sizes of blackberries vary with the charge density of gamma-cyclodextrin by adjusting pH. It is the first report that pure cyclodextrins can generate supramolecular structures by themselves in dilute solution. The unique solution behavior of macroions provides a new opportunity to assemble cyclodextrin into functional materials and devices. PMID- 26013555 TI - Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis. AB - Intestinal fungi are increasingly believed to greatly influence gut health. However, the effects of fungi on intestinal inflammation and on gut bacterial constitution are not clear. Here, based on pyrosequencing method, we reveal that fungal compositions vary in different intestinal segments (ileum, cecum, and colon), prefer different colonization locations (mucosa and feces), and are remarkably changed during intestinal inflammation in dextran sulfate sodium (DSS) colitis mouse models compare to normal controls: Penicillium, Wickerhamomyces, Alternaria, and Candida are increased while Cryptococcus, Phialemonium, Wallemia and an unidentified Saccharomycetales genus are decreased in the guts of DSS colitis mice. Fungi-depleted mice exhibited aggravated acute DSS-colitis associated with gain of Hallella, Barnesiella, Bacteroides, Alistipes, and Lactobacillus and loss of butyrate-producing Clostridium XIVa, and Anaerostipes compare with normal control. In contrast, bacteria-depleted mice show attenuated acute DSS-colitis. Mice with severely chronic recurrent DSS-colitis show increased plasma (1,3)-beta-D-glucan level and fungal translocation into the colonic mucosa, mesenteric lymph nodes and spleen. This work demonstrate the different roles of fungi in acute and chronic recurrent colitis: They are important counterbalance to bacteria in maintaining intestinal micro-ecological homeostasis and health in acutely inflamed intestines, but can harmfully translocate into abnormal sites and could aggravate disease severity in chronic recurrent colitis. PMID- 26013556 TI - Encapsulation of Ln(III) Ions/Dyes within a Microporous Anionic MOF by Post synthetic Ionic Exchange Serving as a Ln(III) Ion Probe and Two-Color Luminescent Sensors. AB - A new anionic framework {[Me2NH2]0.125[In0.125(H2L)0.25]?xDMF}n (1) with one dimensional (1D) channels along the c axis of about 13.06*13.06 A(2), was solvothermally synthesized and well characterized. Post-synthetic cation exchange of 1 with Eu(3+), Tb(3+), Dy(3+), Sm(3+) afforded lanthanide(III)-loaded materials, Ln(3+)@1, with different luminescent behavior, indicating that compound 1 could be used as a potential luminescent probe toward different lanthanide(III) ions. Additionally, compound 1 exhibits selective adsorption ability toward cationic dyes. Moreover, the RhB@1 realized the probing of different organic solvent molecules by tuning the energy transfer efficiency between two different emissions, especially for sensing DMF. This work highlights the practical application of luminescent guest@MOFs as sensors, and it paves the way toward other one/multi-color luminescent host-guest systems by rational selection of MOF hosts and guest chromophores with suitable emissive colors and energy levels. PMID- 26013558 TI - Osteoblast-derived microvesicles: A novel mechanism for communication between osteoblasts and osteoclasts. AB - The maintenance of bone homeostasis is largely dependent upon cellular communication between osteoclasts and osteoblasts. Microvesicles (MVs) have received a good deal of attention and are increasingly considered as mediators of intercellular communication due to their capacity to merge with and transfer a repertoire of bioactive molecular content (cargo) to recipient cells, triggering a variety of biologic responses. Here, we demonstrated that MVs shed from osteoblasts contain RANKL protein and can transfer it to osteoclast precursors through receptor ligand (RANKL-RANK), leading to stimulation of RANKL-RANK signaling to facilitate osteoclast formation. Such MV-mediated intercellular communication between osteoblasts and osteoclasts may represent a novel mechanism of bone modeling and remodeling. It may be worthwhile to further explore MVs as tools to modify the biological responses of bone cells or develop an alternative drug to treat bone diseases. PMID- 26013559 TI - Editorial overview: Respiratory: Cough: a burning issue. PMID- 26013557 TI - Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. AB - OBJECTIVE: To investigate the association between use of combined oral contraceptives and risk of venous thromboembolism, taking the type of progestogen into account. DESIGN: Two nested case-control studies. SETTING: General practices in the United Kingdom contributing to the Clinical Practice Research Datalink (CPRD; 618 practices) and QResearch primary care database (722 practices). PARTICIPANTS: Women aged 15-49 years with a first diagnosis of venous thromboembolism in 2001-13, each matched with up to five controls by age, practice, and calendar year. MAIN OUTCOME MEASURES: Odds ratios for incident venous thromboembolism and use of combined oral contraceptives in the previous year, adjusted for smoking status, alcohol consumption, ethnic group, body mass index, comorbidities, and other contraceptive drugs. Results were combined across the two datasets. RESULTS: 5062 cases of venous thromboembolism from CPRD and 5500 from QResearch were analysed. Current exposure to any combined oral contraceptive was associated with an increased risk of venous thromboembolism (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives levonorgestrel (2.38, 2.18 to 2.59) and norethisterone (2.56, 2.15 to 3.06), and for norgestimate (2.53, 2.17 to 2.96). The number of extra cases of venous thromboembolism per year per 10,000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17). CONCLUSIONS: In these population based, case-control studies using two large primary care databases, risks of venous thromboembolism associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs. PMID- 26013560 TI - The association of parent's outcome expectations for child TV viewing with parenting practices and child TV viewing: an examination using path analysis. AB - BACKGROUND: Television (TV) viewing has been associated with many undesirable outcomes for children, such as increased risk of obesity, but TV viewing can also have benefits. Although restrictive parenting practices are effective in reducing children's TV viewing, not all parents use them and it is currently unclear why. The current study examined parenting practices related to TV viewing in the context of social- cognitive theory. Specifically, we hypothesized that positive and negative Parental Outcome Expectations for child's TV Viewing (POETV) would be associated with social co-viewing and restrictive parenting practices, and that POETV and parenting practices influence the amount of TV viewed by child. METHOD: Data were collected from an internet survey of 287 multi-ethnic parents and their 6-12 year old children on participants' sociodemographic information, parenting practices related to TV use, POETV, and parent and child TV viewing. Path analysis was used to examine the relationship amongst variables in separate models for weekday and weekend TV viewing. controlling for child age, household education, and parental TV viewing. RESULTS: The results provided partial support for the hypotheses, with notable differences between weekday and weekend viewing. The models explained 13.6% and 23.4% of the variance in children's TV viewing on weekdays and weekends respectively. Neither positive nor negative POETV were associated with restrictive TV parenting in either model. One subscale each from positive and negative POETV were associated with social co-viewing parenting on both weekends and weekdays in the expected direction. Restrictive parenting practices were directly negatively associated with children's TV viewing on weekdays, but not weekends. Social co-viewing parenting was directly positively associated with children's TV viewing on weekends, but not weekdays. The strongest influence on children's TV viewing was having a TV in the child's bedroom. Negative POETV was weakly associated with having a TV in the child's room. CONCLUSIONS: These findings suggest that POETV and parenting may have a greater impact on weekend TV viewing, when children tend to watch more TV, than weekday. The models suggest that POETV, parenting and especially removing the TV from children's rooms may be promising targets for interventions. PMID- 26013561 TI - Development of genetic tools for Myceliophthora thermophila. AB - BACKGROUND: The thermophilic filamentous fungus Myceliophthora thermophila has many suitable characteristics for industrial biotechnology and could be a promising new chassis system for synthetic biology, particularly the ATCC 42464 strain, whose genome was sequenced in 2011. However, metabolic engineering of this strain using genetic approaches has not been reported owing to a lack of genetic tools for this organism. RESULTS: In the present study, we developed a high efficiency Agrobacterium tumefaciens mediated transformation system for M. thermophila, including an approach for targeted gene deletion using green fluorescence protein (GFP) as a marker for selection. Up to 145 transformants per 10(5) conidia were obtained in one transformation plate. Moreover, a ku70 deletion mutant was constructed in the ATCC 42464 background using the tools developed in present study and subsequently characterized. The ku70 deletion construct was designed using resistance to phosphinothricin as the selection marker. Additionally, a GFP-encoding cassette was incorporated that allowed for the selection of site-specific (no fluorescence) or ectopic (fluorescence) integration of the ku70 construct. Transformants with ectopically integrated ku70 deletion constructs were therefore identified using the fluorescent signal of GFP. PCR and Southern blotting analyses of non-fluorescent putative ku70 deletion transformants revealed all 11 tested transformants to be correct deletions. The deletion frequency in a pool of 116 transformants analyzed was 58 %. Moreover, the homologous rate improved about 3 folds under ku70 mutant using the pyrG as a test gene to disrupt in M. thermophila. CONCLUSIONS: We successfully developed an efficient transformation and target gene disruption approach for M. thermophila ATCC 42464 mediated by A. tumefaciens. The tools and the ku70 deletion strain developed here should advance the development of M. thermophila as an industrial host through metabolic engineering and accelerate the elucidation of the mechanism of rapid cellulose degradation in this thermophilic fungus. PMID- 26013562 TI - Screening and identification of potential sex-associated sequences in Danio rerio. AB - Current knowledge on zebrafish (Danio rerio) suggests that sex determination has a polygenic genetic basis in this species, although environmental factors may also be involved. This study aimed to identify sex-associated genomic regions using two different marker systems: inter-simple sequence repeats (ISSRs) and random-amplified polymorphic DNA (RAPDs). Two bulks were constructed: one with DNA from zebrafish females and the other from males; then, a total of 100 ISSR and 280 RAPD primers were tested. Three DNA fragments presenting sexual dimorphism (female-linked: OPA17436 and OPQ191027 ; male-linked: OPQ19951 ) were determined from sequential analysis of the bulks followed by assessment in individuals. These fragments were cloned and convert into the following sequenced characterized amplified regions (SCAR): DrSM_F1, DrSM_F2, and DrSM_M, which share identities with sequences located in chromosomes 2, 3, and 11 (Zv9), respectively. Using these potential markers in zebrafish samples it was possible to correctly identify 80% of the males (DrSM_M) and 100% of the females (DrSM_F1 + DrSM_F2) in the analyzed population. PMID- 26013563 TI - Growth of the atrial septum after Amplatzer device closure of atrial septal defects in young children. AB - BACKGROUND: Trans-catheter closure of atrial septal defects (ASD) with the Amplatzer Septal Occluder (ASO) device is safe and effective, but concern over erosions has increased. Devices are placed in growing children but septal growth after ASOs is ill-defined. Understanding the device relationship to cardiac structures as a child grows may help us understand erosions. OBJECTIVE: To define (1) how preprocedural septal measurements change after ASO and (2) the effect of somatic growth on these dimensions. METHODS: Data were collected retrospectively. Echocardiograms were reviewed and rims measured prior to ASO, immediately after ASO, and at follow-up. Demographic, procedural and device data were collected. RESULTS: Thirty-three patients were enrolled; mean age 5.2 +/- 3.2 years with 4.0 +/- 2.2 years follow-up. All septal measurements decreased after ASO. Thirty-one of 33 devices (94%) contacted the aortic root after ASO; all remained in contact at follow-up with only the IVC rim growing significantly over time. Change in BSA predicted an asymmetric septal growth with increases in superior (P = 0.01) and IVC (P = 0.005) rims and no increase in aortic or AVV rims. No episodes of erosion occurred. CONCLUSIONS: ASDs in young children are not central in the septum, but proximate to the aorta. After ASO, the device remains in close proximity to the aorta. With somatic growth, the septum grows asymmetrically, and device position relative to the aorta is constant. Our study was not powered to detect rare serious adverse events such as erosion, but aortic rims were consistently zero and yet no events occurred. PMID- 26013564 TI - Correlates of male involvement in maternal and newborn health: a cross-sectional study of men in a peri-urban region of Myanmar. AB - BACKGROUND: Evidence suggests that increasing male involvement in maternal and newborn health (MNH) may improve MNH outcomes. However, male involvement is difficult to measure, and further research is necessary to understand the barriers and enablers for men to engage in MNH, and to define target groups for interventions. Using data from a peri-urban township in Myanmar, this study aimed to construct appropriate indicators of male involvement in MNH, and assess sociodemographic, knowledge and attitude correlates of involvement. METHODS: A cross-sectional study of married men with one or more children aged up to one year was conducted in 2012. Structured questionnaires measured participants' involvement in MNH, and their sociodemographic characteristics, knowledge and attitudes. An ordinal measure of male involvement was constructed describing the subject's participation across five areas of MNH, giving a score of 1-4. Proportional-odds regression models were developed to determine correlates of male involvement. RESULTS: A total of 210 men participated in the survey, of which 203 provided complete data. Most men reported involvement level scores of either 2 or 3 (64 %), with 13 % reporting the highest level (score of 4). Involvement in MNH was positively associated with wives' level of education (AOR = 3.4; 95 % CI: 1.9-6.2; p < 0.001) and men's level of knowledge of MNH (AOR = 1.2; 95 % CI: 1.1-1.3; p < 0.001), and negatively correlated with number of children (AOR = 0.78; 95 % CI: 0.63-0.95; p = 0.016). CONCLUSIONS: These findings can inform the design of programs aiming to increase male involvement, for example by targeting less educated couples and addressing their knowledge of MNH. The composite index proved a useful summary measure of involvement; however, it may have masked differential determinants of the summed indicators. There is a need for greater understanding of the influence of gender attitudes on male involvement in Myanmar and more robust indicators that capture these gender dynamics for use both in Myanmar and globally. PMID- 26013565 TI - Listeriolysin O mediates cytotoxicity against human brain microvascular endothelial cells. AB - Penetration of the brain microvascular endothelial layer is one of the routes Listeria monocytogenes use to breach the blood-brain barrier. Because host factors in the blood severely limit direct invasion of human brain microvascular endothelial cells (HBMECs) by L. monocytogenes, alternative mechanisms might be used by this bacterium to penetrate the endothelial cell layer. In this study, we evaluated the cytotoxicity of proteins secreted by L. monocytogenes against HBEMCs using a live/dead staining method. Interestingly, the integrity of the plasma membrane of HBMECs was impaired by proteins secreted by the EGD wild-type strain but not proteins secreted by the isogenic DeltaprfA strain. Therefore, we investigated the cytotoxicity of proteins secreted by several isogenic mutant strains (DeltaplcA, Deltampl and Deltahly) incapable of producing the prfA regulated bacterial products PlcA, Mpl and LLO, respectively. Results from both fluorescent microscopy and flow cytometry analyses showed that proteins secreted by the Deltahly strain were not cytotoxic to HBMECs, whereas those secreted by the DeltaplcA and Deltampl strains were cytotoxic. These results suggest that LLO mediated cytotoxicity against brain microvascular endothelial cells enables L. monocytogenes to effectively penetrate the brain microvascular endothelial layer. PMID- 26013566 TI - Early experience of a virtual journal club. AB - BACKGROUND: Traditional journal club models based on didactic presentation sessions followed by group discussion have many limitations. To overcome some of these shortcomings, a virtual journal club (VJC) using social media and e-mail was developed. The aim of this study was to report the initial experience of this novel multimodal e-learning platform to facilitate journal club discussion and promote the development of critical appraisal skills. METHODS: Journal articles were discussed monthly via e-mail and social media. After a 3-week period of discussion, all comments were collated and group-generated critical appraisal summaries were fed back to participants. In addition, letters to the journal editors based on the group appraisal were submitted. A questionnaire survey to evaluate the VJC concept was also conducted. FINDINGS: After eight cycles of the VJC, the mean trainee participation rate was 29.6 per cent (range 21.1-42.1%). Senior trainees (>=4 years of postgraduate experience) were more likely to participate than more junior trainees (75.0 versus 21.1%; p = 0.005). The majority of participants thought that the VJC was educationally valuable, easy to participate in, helpful in keeping up to date with recent papers and useful in developing critical appraisal skills. Barriers to participation were lack of time, motivation and lack of experience in critical appraisal. In addition, the group-generated critical appraisal summaries derived from VJC discussions led to eight published 'letters to the editor'. Traditional journal club models based on didactic presentation sessions followed by group discussion have many limitations CONCLUSION: This novel VJC model is a feasible and popular method of delivering a journal club in the postgraduate setting. PMID- 26013567 TI - Diabetes and quality of life: Comparing results from utility instruments and Diabetes-39. AB - OBJECTIVE: To compare the Diabetes-39 (D-39) with six multi-attribute utility (MAU) instruments (15D, AQoL-8D, EQ-5D, HUI3, QWB, and SF-6D), and to develop mapping algorithms which could be used to transform the D-39 scores into the MAU scores. RESEARCH DESIGN AND METHODS: Self-reported diabetes sufferers (N=924) and members of the healthy public (N=1760), aged 18 years and over, were recruited from 6 countries (Australia 18%, USA 18%, UK 17%, Canada 16%, Norway 16%, and Germany 15%). Apart from the QWB which was distributed normally, non-parametric rank tests were used to compare subgroup utilities and D-39 scores. Mapping algorithms were estimated using ordinary least squares (OLS) and generalised linear models (GLM). RESULTS: MAU instruments discriminated between diabetes patients and the healthy public; however, utilities varied between instruments. The 15D, SF-6D, AQoL-8D had the strongest correlations with the D-39. Except for the HUI3, there were significant differences by gender. Mapping algorithms based on the OLS estimator consistently gave better goodness-of-fit results. The mean absolute error (MAE) values ranged from 0.061 to 0.147, the root mean square error (RMSE) values 0.083 to 0.198, and the R-square statistics 0.428 and 0.610. Based on MAE and RMSE values the preferred mapping is D-39 into 15D. R-square statistics and the range of predicted utilities indicate the preferred mapping is D-39 into AQoL-8D. CONCLUSIONS: Utilities estimated from different MAU instruments differ significantly and the outcome of a study could depend upon the instrument used. The algorithms reported in this paper enable D-39 data to be mapped into utilities predicted from any of six instruments. This provides choice for those conducting cost-utility analyses. PMID- 26013568 TI - Hepatic and intramyocellular glycogen stores in adults with type 1 diabetes and healthy controls. AB - Glycogen levels in liver and skeletal muscle assessed non-invasively using magnetic resonance spectroscopy after a 48-h pre-study period including a standardized diet and withdrawal from exercise did not differ between individuals with well-controlled Type 1 DM and matched healthy controls. PMID- 26013569 TI - Post-marketing monitoring of intussusception after rotavirus vaccination in Japan. AB - PURPOSE: Rotarix(TM) was launched in November 2011 in Japan to prevent rotavirus gastroenteritis. Some studies suggest that Rotarix(TM) may have a temporal association with a risk of intussusception (IS). We assessed a possible association between IS and Rotarix(TM) vaccination in Japan. METHODS: All IS cases spontaneously reported post-vaccination (Brighton collaboration levels 1, 2, and 3) were extracted from the GlaxoSmithKline spontaneous report database on the 11th of January 2013. Expected numbers of IS cases were estimated using the number of vaccine doses distributed and the Japanese incidence rate of IS stratified by month of age. The observed versus expected analysis considered the IS cases for each risk period (7 and 30 days post-vaccination) and for each vaccine dose (two doses). RESULTS: Before January 2013, approximately 601 000 Rotarix(TM) doses were distributed in Japan. For a risk period of 7 days post dose 1 and post-dose 2, 10 and five IS cases were observed, whereas 3.4 and 7.6 were expected, providing an observed-to-expected ratio of 2.96 (95% confidence interval [CI]: 1.42; 5.45) and 0.66 (95% CI: 0.21; 1.53), respectively. For a risk period of 30 days post-dose 1 and post-dose 2, 14 and eight cases were observed, whereas 14.5 and 32.7 were expected, providing an observed-to-expected ratio of 0.97 (95% CI: 0.53; 1.62) and 0.24 (95% CI: 0.11; 0.48), respectively. CONCLUSION: A statistically significant excess of IS cases was observed within 7 days post-dose 1, but not post-dose 2. These results are consistent with previous observations in large post-marketing safety studies in other world regions. PMID- 26013570 TI - Convenient and Efficient Method for Quality Control Analysis of 18F Fluorocholine: For a Small Scale GMP-based Radiopharmaceuticals Laboratory Set up. AB - BACKGROUND AND OBJECTIVE: Prostate cancer continues to be the most prevalent cancer in men in Malaysia. As time progresses, the prospect of PET imaging modality in diagnosis of prostate cancer is promising, with on-going improvement on novel tracers. Among all tracers, 18F-Fluorocholine is reported to be a reputable tracer and reliable diagnostic technique for prostate imaging. Nonetheless, only 18F-Fluorodeoxyglucose (18F-FDG) is available and used in most oncology cases in Malaysia. With a small scale GMP-based radiopharmaceuticals laboratory set-up, initial efforts have been taken to put Malaysia on 18F Fluorocholine map. This article presents a convenient, efficient and reliable method for quality control analysis of 18F-Fluorocholine. Besides, the aim of this research work is to assist local GMP radiopharmaceuticals laboratories and local authority in Malaysia for quality control analysis of 18F-Fluorocholine guideline. METHODS: In this study, prior to synthesis, quality control analysis method for 18F-Fluorocholine was developed and validated, by adapting the equipment set-up used in 18F-Fluorodeoxyglucose (18FFDG) routine production. Quality control on the 18F-Fluorocholine was performed by means of pH, radionuclidic identity, radio-high performance liquid chromatography equipped with ultraviolet, radio- thin layer chromatography, gas chromatography and filter integrity test. RESULTS: Post-synthesis; the pH of 18F-Fluorocholine was 6.42 +/- 0.04, with half-life of 109.5 minutes (n = 12). The radiochemical purity was consistently higher than 99%, both in radio-high performance liquid chromatography equipped with ultraviolet (r-HPLC; SCX column, 0.25 M NaH2PO4: acetonitrile) and radio-thin layer chromatography method (r-TLC). The calculated relative retention time (RRT) in r-HPLC was 1.02, whereas the retention factor (Rf) in r-TLC was 0.64. Potential impurities from 18F-Fluorocholine synthesis such as ethanol, acetonitrile, dimethylethanolamine and dibromomethane were determined in gas chromatography. Using our parameters, (capillary column: DB 200, 30 m x 0.53 mm x 1 um) and oven temperature of 35 degrees C (isothermal), all compounds were well resolved and eluted within 3 minutes. Level of ethanol and acetonitrile in 18F-Fluorocholine were detected below threshold limit; less than 5 mg/ml and 0.41 mg/ml respectively. Meanwhile, dimethylethanolamine and dibromomethane were undetectable. CONCLUSION: A convenient, efficient and reliable quality control analysis work-up procedure for 18FFluorocholine has been established and validated to comply all the release criteria. The convenient method of quality control analysis may provide a guideline to local GMP radiopharmaceutical laboratories to start producing 18F-Fluorocholine as a tracer for prostate cancer imaging. PMID- 26013571 TI - Therapeutic potential of manipulating suicidal erythrocyte death. AB - INTRODUCTION: Eryptosis, the suicidal erythrocyte death, is characterized by erythrocyte shrinkage and phosphatidylserine translocation to the erythrocyte surface. Eryptosis is triggered by cell stress such as energy depletion and oxidative stress, by Ca(2+)-entry, ceramide, caspases, calpain and/or altered activity of several kinases. Phosphatidylserine-exposing erythrocytes adhere to the vascular wall and may thus impede microcirculation. Eryptotic cells are further engulfed by phagocytes and thus rapidly cleared from circulation. AREAS COVERED: Stimulation of eryptosis contributes to anemia of several clinical conditions such as metabolic syndrome, diabetes, malignancy, hepatic failure, heart failure, uremia, hemolytic uremic syndrome, sepsis, fever, dehydration, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency and Wilson's disease. On the other hand, eryptosis with subsequent clearance of infected erythrocytes in malaria may counteract parasitemia. EXPERT OPINION: In theory, anemia due to excessive eryptosis could be alleviated by treatment with small molecules inhibiting eryptosis. In malaria, stimulators of eryptosis may accelerate death of infected erythrocytes and thus favorably influence the clinical course of the disease. Many small molecules inhibit or stimulate eryptosis. Several stimulators favorably influence murine malaria. Further preclinical and subsequent clinical studies are required to elucidate the therapeutic potential of stimulators or inhibitors of eryptosis. PMID- 26013573 TI - Starvation-induced collective behavior in C. elegans. AB - We describe a new type of collective behavior in C. elegans nematodes, aggregation of starved L1 larvae. Shortly after hatching in the absence of food, L1 larvae arrest their development and disperse in search for food. In contrast, after two or more days without food, the worms change their behavior--they start to aggregate. The aggregation requires a small amount of ethanol or acetate in the environment. In the case of ethanol, it has to be metabolized, which requires functional alcohol dehydrogenase sodh-1. The resulting acetate is used in de novo fatty acid synthesis, and some of the newly made fatty acids are then derivatized to glycerophosphoethanolamides and released into the surrounding medium. We examined several other Caenorhabditis species and found an apparent correlation between propensity of starved L1s to aggregate and density dependence of their survival in starvation. Aggregation locally concentrates worms and may help the larvae to survive long starvation. This work demonstrates how presence of ethanol or acetate, relatively abundant small molecules in the environment, induces collective behavior in C. elegans associated with different survival strategies. PMID- 26013572 TI - Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures. AB - INTRODUCTION: Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology. METHODS: In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology. RESULTS: The tumor-to-normal relative ratio of Ki67 positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = -0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments. CONCLUSIONS: Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information. PMID- 26013574 TI - The main factors influencing canine demodicosis treatment outcome and determination of optimal therapy. AB - The main idea of this research was to evaluate the efficacy of canine demodicosis conventional treatments using mathematical analyses. All available papers published between 1980 and 2014 were used in this study. One hundred six clinical trials enrolling 3414 cases of generalized demodicosis in dogs are studied. Dogs entered in the analysis were only the ones in which the disease occurred naturally, excluding the studies in which transplantation of Demodex canis mites was done from other animals. In conventional acaricide treatments, sorted according to active substances (moxidectin, amitraz, doramectin, ivermectin, and milbemycin oxime), the way of application (spot-on, dips, orally, or subcutaneous), concentration, and interval of application were used as input parameters in mathematical modeling. Data of interest were the treatment outcome, the number of dogs that went into remission, the number of animals not responding to treatment microscopically, the average duration of therapy, the follow-up period, the number of patients with disease recurrence, the number of adverse effects, and the number of animals with side effects. Dogs lost to follow-up or when the treatment was discontinued, due to various reasons not in connection with the therapy protocol, were not considered. Statistical and mathematical analyses were applied for prediction of the drugs' effectiveness. Developed mathematical models showed satisfactorily r (2), higher than 0.87. Good evidence for recommending the use of milbemycin oxime PO (0.5 mg/kg, daily) and moxidectin spot-on (Advocate(r), Bayer) weekly is found. A bit less effective therapies were based on ivermectin PO (0.5 mg/kg, daily), moxidectin PO (0.35 mg/kg, daily), and amitraz dips (0.05 % solution, weekly), respectively. It is important to keep in mind that Advocate(r) is recommended by the manufacturer for use in milder cases. PMID- 26013575 TI - Modelling ventricular fibrillation coarseness during cardiopulmonary resuscitation by mixed effects stochastic differential equations. AB - For patients undergoing cardiopulmonary resuscitation (CPR) and being in a shockable rhythm, the coarseness of the electrocardiogram (ECG) signal is an indicator of the state of the patient. In the current work, we show how mixed effects stochastic differential equations (SDE) models, commonly used in pharmacokinetic and pharmacodynamic modelling, can be used to model the relationship between CPR quality measurements and ECG coarseness. This is a novel application of mixed effects SDE models to a setting quite different from previous applications of such models and where using such models nicely solves many of the challenges involved in analysing the available data. PMID- 26013576 TI - Head-to-head running race simulation alters pacing strategy, performance, and mood state. AB - The objective of this study was to analyze the influence of the presence and absence of competitors on pacing, overall running performance, and mood state during a self-paced 3-km run. Nine recreational runners participated in this study. They performed the following tests: a) an incremental test to exhaustion to measure the respiratory compensation point (RCP), maximal oxygen uptake, and peak treadmill speed; b) a submaximal speed constant test to measure running economy; and c) two 3-km running time trials performed collectively (COL, head-to head competition) or individually (IND, performed alone) to establish pacing and running performance. The COL condition was formed of a group of four runners or five runners. Runners were grouped by matched performance times and to retain head-to-head characteristics.A mood state profile questionnaire was completed before and after the 3-km running time trial. The overall performance was better in the COL than in the IND (11.75 +/- 0.05 min vs. 12.25 +/- 0.06 min, respectively; p = 0.04). The running speeds during the first 500 m were significantly greater in COL (16.8 +/- 2.16 km.h-1) than in IND (15.3 +/- 2.45 km.h-1) (p = 0.03).The gain in running speed from IND to COL during the first 400 m (i.e. running speed in COL less running speed in IND) was significantly correlated with the RCP (r = 0.88; p = 0.05). The vigor score significantly decreased from pre- to post-running in COL (p=0.05), but not in IND (p=0.20). Additionally, the post running vigor was significantly higher in IND compared to COL (p = 0.03).These findings suggested that the presence of competitors induces a fast start, which results in an improved overall performance and reduced post exercise vigor scores, compared to an individual run. PMID- 26013578 TI - Pre-conditioned place preference treatment of chloral hydrate interrupts the rewarding effect of morphine. AB - The medical use of morphine as a pain killer is hindered by its side effects including dependence and further addiction. As the prototypical MU receptor agonist, morphine's rewarding effect can be measured by conditioned place preference (CPP) paradigms in animals. Chloral hydrate is a clinical sedative. Using a morphine CPP paradigm that mainly contains somatosensory cues, we found that pre-CPP treatment in rats using chloral hydrate for 6 consecutive days could disrupt the establishment of CPP in a U shape. Chloral hydrate had no effect on the body weight of rats. Our results indicate that prior treatment with chloral hydrate can interrupt the rewarding effect of morphine. PMID- 26013579 TI - Protracted alcohol abstinence induces analgesia in rats: Possible relationships with BDNF and interleukin-10. AB - Exposure to ethanol alters the expression of brain-derived neurotrophic factor (BDNF) in central regions such as, the hippocampus, cortex and striatum. Moreover, chronic alcohol intake is known to induce selective neuronal damage associated with an increase in the inflammatory cascade, resulting in neuronal apoptosis and neurodegeneration. In the present study, we investigated the nociceptive response after 24h of protracted alcohol abstinence. Rats were submitted to a model of alcohol withdrawal syndrome and the nociceptive response was assessed by the tail-flick and the hot plate tests. In addition, we evaluated BDNF and interleukin-10 (IL-10) in the cerebral prefrontal cortex, brainstem and hippocampus of rats after protracted alcohol abstinence. Male adult Wistar rats were divided into three groups: non-treated group (control group), treated with water (water group), and alcohol (alcohol group). The water and alcohol administrations were done by oral gavage and were performed over three periods of five days of treatment with two intervals of two days between them. Alcohol (20%w/v) was given at 4g/kg of body weight. There was a significant effect of treatment in the tail-flick and hot plate latencies with greater latencies in alcohol-treated rats after 10days of abstinence. There was a significant increase in the prefrontal cortex BDNF levels in the alcohol group in relation to the water group, after 11days of alcohol abstinence. In addition, alcohol withdrawal induced a significant increase in the hippocampus, prefrontal cortex and brainstem IL-10 levels compared with control group. Thus, the present study demonstrates that protracted alcohol withdrawal produced an analgesic effect indexed via increased nociceptive threshold. We suggest that these effects could be related to the increased levels of BDNF and IL-10 observed in the central nervous system. PMID- 26013580 TI - An Efficient Halogen-Free Electrolyte for Use in Rechargeable Magnesium Batteries. AB - Unlocking the full potential of rechargeable magnesium batteries has been partially hindered by the reliance on chloride-based complex systems. Despite the high anodic stability of these electrolytes, they are corrosive toward metallic battery components, which reduce their practical electrochemical window. Following on our new design concept involving boron cluster anions, monocarborane CB11H12(-) produced the first halogen-free, simple-type Mg salt that is compatible with Mg metal and displays an oxidative stability surpassing that of ether solvents. Owing to its inertness and non-corrosive nature, the Mg(CB11H12)2/tetraglyme (MMC/G4) electrolyte system permits standardized methods of high-voltage cathode testing that uses a typical coin cell. This achievement is a turning point in the research and development of Mg electrolytes that has deep implications on realizing practical rechargeable Mg batteries. PMID- 26013577 TI - Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans. AB - The fact that more than 78 million adults in the US are considered overweight or obese highlights the need to develop new, effective strategies to treat obesity and its associated complications, including type 2 diabetes, kidney disease and cardiovascular disease. While the neurohypophyseal peptide oxytocin (OT) is well recognized for its peripheral effects to stimulate uterine contraction during parturition and milk ejection during lactation, release of OT within the brain is implicated in prosocial behaviors and in the regulation of energy balance. Previous findings indicate that chronic administration of OT decreases food intake and weight gain or elicits weight loss in diet-induced obese (DIO) mice and rats. Furthermore, chronic systemic treatment with OT largely reproduces the effects of central administration to reduce weight gain in DIO and genetically obese rodents at doses that do not appear to result in tolerance. These findings have now been recently extended to more translational models of obesity showing that chronic subcutaneous or intranasal OT treatment is sufficient to elicit body weight loss in DIO nonhuman primates and pre-diabetic obese humans. This review assesses the potential use of OT as a therapeutic strategy for treatment of obesity in rodents, nonhuman primates, and humans, and identifies potential mechanisms that mediate this effect. PMID- 26013582 TI - Rapid exchange ultra-thin microcatheter using fibre-optic sensing technology for measurement of intracoronary fractional flow reserve. AB - AIMS: The present report describes a novel coronary fractional flow reserve (FFR) system which allows FFR assessment using a rapid exchange microcatheter (RXi). METHODS AND RESULTS: The RXi microcatheter is compatible with standard 0.014" coronary guidewires facilitating lesion negotiation and FFR assessment in a wide range of coronary anatomies. In case of serial lesions, a microcatheter would have the important advantage of allowing multiple pullbacks while maintaining wire access to the vessel. The RXi is a fibre-optic sensor technology-based device. This technology might allow reduction in signal drift. The RXi microcatheter's fibre-optic sensor is located 5 mm from the distal tip. The microcatheter profile at the sensor site is 0.027"0.036". The segment of the catheter which is intended to reside within the target lesion is proximal to the sensor and has dimensions decreased to 0.020"0.025"; these dimensions are comparable to a 0.022" circular-shaped wire. CONCLUSIONS: The RXi microcatheter FFR system represents a novel technology that could allow easier lesion negotiation, maintaining guidewire position, facilitating pullbacks for assessment of serial lesions and simplifying the obtainment of post-intervention FFR measurements. The optical sensing technology could additionally result in less signal drift. Further investigations are required to evaluate the clinical value of this technology fully. PMID- 26013581 TI - Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson's disease. AB - BACKGROUND: Compelling evidence suggests that inhibition of the complex I of the electron transport chain and elevated oxidative stress are the earliest events during the pathogenesis of Parkinson's disease (PD). Therefore, anti-oxidants, especially those from natural sources, hold good promise in treating PD as demonstrated mostly by the studies in rodent models. RESULTS: Herein, we determined if polydatin (piceid), a natural polyphenol, could exert anti oxidative activity and attenuate dopaminergic neurodegeneration in three commonly used rodent models of PD. Male Sprague Dawley rats given rotenone subcutaneously for 5 weeks developed all the essential features of PD, including a strong increase in catalepsy score and a decrease in motor coordination activity, starting at 4 weeks. Selective increase in oxidative damage was found in the striatal region as compared to the hippocampus and cortex, accompanied by massive degeneration of dopaminergic neurons in the substantia nigra (SNc). Co administration of piceid orally was able to attenuate rotenone-induced motor defects in a dose dependent manner, with 80 mg/kg dosage showing even better effect than L-levodopa (L-dopa). Piceid treatment significantly prevented the rotenone-induced changes in the levels of glutathione, thioredoxin, ATP, malondialdehyde (MDA) and the manganese superoxide dismutases (SOD) in striatum. Furthermore, piceid treatment rescued rotenone-induced dopaminergic neurodegeneration in the SNc region. Similar protective effect of piceid was also observed in two additional models of PD, MPTP in mice and 6-OHDA in rats, showing corrected motor functions, SOD and MDA activities as well as p-Akt and activated caspase-3 levels. CONCLUSION: In three rodent models of PD, piceid preserves and corrects several major anti-oxidant pathways/parameters selectively in the affected SNc region. This implies its potent anti-oxidant activity as one major underscoring mechanism for protecting the vulnerable SNc neurodegeneration in these models. Taken together, these findings strongly suggest a therapeutic potential of piceid in treating PD. PMID- 26013583 TI - Myocardial injury during transfemoral transcatheter aortic valve implantation: an intracoronary Doppler and cardiac magnetic resonance imaging study. AB - AIMS: Myocardial injury reflected by a post-procedural increase of serum troponin I (TnI) occurs frequently during transcatheter aortic valve implantation (TAVI). It is potentially caused by intraprocedural hypotension, periprocedural coronary microembolisation and post-procedural (para)valvular leakages (PVLs). We invasively assessed coronary flow dynamics including coronary flow velocity reserve (CFVR), embolic high-intensity transient signals (HITS) as well as rapid pacing induced hypotension and post-procedural PVLs to determine their contribution to post-procedural TnI increases. METHODS AND RESULTS: In 15 transfemoral TAVI patients, TnI was measured serially, and cardiac MRIs with late gadolinium enhancement (LGE) were performed pre- and post-interventionally. There were no significant correlations between coronary flow dynamics, CFVR and the area under the curve (AUC) of TnI over 72 hours. Despite the detection of HITS in all patients and during all procedural steps, there was also no correlation between the amount of HITS and the AUC of TnI. However, there were positive correlations between the duration of rapid pacing as well as the time of subsequent blood pressure recovery and the AUC of TnI. Both LGE and more than mild PVL were observed in a single case only. CONCLUSIONS: Myocardial injury after TAVI appears to be related more to hypoperfusion-induced ischaemia than to periprocedural microembolisation. PMID- 26013584 TI - A subset of N-substituted phenothiazines inhibits NADPH oxidases. AB - NADPH oxidases (NOXs) constitute a family of enzymes generating reactive oxygen species (ROS) and are increasingly recognized as interesting drug targets. Here we investigated the effects of 10 phenothiazine compounds on NOX activity using an extensive panel of assays to measure production of ROS (Amplex red, WST-1, MCLA) and oxygen consumption. Striking differences between highly similar phenothiazines were observed. Two phenothiazines without N-substitution, including ML171, did not inhibit NOX enzymes, but showed assay interference. Introduction of an aliphatic amine chain on the N atom of the phenothiazine B ring (promazine) conferred inhibitory activity toward NOX2, NOX4, and NOX5 but not NOX1 and NOX3. Addition of an electron-attracting substituent in position 2 of the C ring extended the inhibitory activity to NOX1 and NOX3, with thioridazine being the most potent inhibitor. In contrast, the presence of a methylsulfoxide group at the same position (mesoridazine) entirely abolished NOX inhibitory activity. A cell-free NOX2 assay suggested that inhibition by N substituted phenothiazines was not due to competition with NADPH. A functional implication of NOX-inhibitory activity of thioridazine was demonstrated by its ability to block redox-dependent myofibroblast differentiation. Our results demonstrate that NOX-inhibitory activity is not a common feature of all antipsychotic phenothiazines and that substitution on the B-ring nitrogen is crucial for the activity, whereas that on the second position of the C ring modulates it. Our findings contribute to a better understanding of NOX pharmacology and might pave the path to discovery of more potent and selective NOX inhibitors. PMID- 26013586 TI - Ultrasonography Leads to Accurate Diagnosis and Management of Painful Acromioclavicular Joint Cyst. AB - BACKGROUND: Acromioclavicular joint (ACJ) cysts are uncommon causes of shoulder pain. Type 1 ACJ cysts are limited to the ACJ and form in the presence of intact rotator cuff musculature, while type 2 cysts form secondary to biomechanical instability following rotator cuff tear or rupture. CASE PRESENTATION: A 36-year old overweight male with history of chronic left grade 2 (Rockwood classification) ACJ separation presented with intermittent pain at the distal superoanterior left clavicle. Physical examination revealed small step off at the ACJ and multiple subcutaneous cysts surrounding the ACJ. Ultrasound examination revealed a mild separation of the left ACJ, mild distension of the joint capsule, and a small, well-circumscribed, compressible hypo-echoic cyst overlying the clavicle. Palpation of the cyst against the clavicle reproduced the patient's symptoms of intermittent pain. He opted for ultrasound-guided aspiration and subsequently had full resolution of his symptoms. DISCUSSION: Musculoskeletal ultrasound is useful for diagnosis and management of refractory musculoskeletal conditions that are commonly misdiagnosed on physical examination and translucent to radiographic imaging. Musculoskeletal ultrasound allowed us to exclude rotator cuff pathology, identify ACJ cyst as the pain generator, classify it as a type 1 ACJ cyst, and aid in needle guidance for successful aspiration leading to full resolution of our patient's pain. PMID- 26013587 TI - Rates of renal transplantations in the elderly-data from Europe and the US. AB - The demography in most part of the world is changing with an increasing proportion of elderly persons. This is expected to reflect demography of patients accepted for renal replacement therapy both in the form of dialysis and transplantation. Based on this, the intention of the present review is to collect and describe available data on rates of transplantation with focus on the elderly patients in both Europe and the US. Data were collected from available sources including activity reports from national and supranational registries on uremia, organ procurement, waiting lists, and transplantations. Since 1990 both absolute numbers and proportions of elderly patients starting renal replacement therapy have increased dramatically in both Europe and the US. Although the pattern of changes is similar in Europe and the US, the incidence and prevalence rates for renal replacement therapy in the elderly are 3-4 times higher in the US. In the same period, the rates of renal transplantations in the elderly patient group have increased in both Europe and the US with increased access to the waiting list and to transplantation. Data from the United States Renal Data System on incidence of transplantation document a substantial increase in proportion of elderly transplant recipients (65+ years) from 4.2% in 1990 to 17.2% in 2012 and an increase in proportion of prevalent elderly renal transplant patients from 3.8% in 1992 to 23.3% in 2012. Similar changes have been seen in Europe. Due to these alterations in the demography of the transplant patients in both Europe and the US it is concluded that the elderly transplant patient from being a rare patient has now become a common patient necessitating increased focus on this group in order to optimize treatment results. PMID- 26013588 TI - How we provide thawed plasma for trauma patients. AB - Almost 50% of trauma-related fatalities within the first 24 hours of injury are related to hemorrhage. Improved survival in severely injured patients has been demonstrated when massive transfusion protocols are rapidly invoked as part of a therapeutic approach known as damage control resuscitation (DCR). DCR incorporates the early use of plasma to prevent or correct trauma-induced coagulopathy. DCR often requires the transfusion of plasma before determination of the recipient's ABO group. Historically, group AB plasma has been considered the "universal donor" plasma product. At our facility, the number of AB plasma products produced on an annual basis was found to be inadequate to support the trauma service's DCR program. A joint decision was made by the transfusion medicine and trauma services to provide group A thawed plasma (TP) for in hospital and prehospital DCR protocols. A description of the implementation of group A TP into the DCR program is provided as well as outcome data pertaining to the use of TP in trauma patients. PMID- 26013585 TI - COPD and squamous cell lung cancer: aberrant inflammation and immunity is the common link. AB - Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Squamous cell lung cancer is commonly detected in heavy smokers, where the risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking related squamous cell lung cancer. Since COPD is characterized by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumourigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumour suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumour promoting serum amyloid A (SAA) and IL-17A is discussed. SAA is also an endogenous allosteric modifier of FPR2 expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD-lung cancer overlap. PMID- 26013589 TI - Ingested microplastics (>100 MUm) are translocated to organs of the tropical fiddler crab Uca rapax. AB - Microplastics, which are accumulating in marine sediments, are assumed to pose a risk for deposit feeding invertebrates. We tested whether the fiddler crab Uca rapax ingests and retains microplastics in its body. Furthermore, we investigated whether retention rates depend on (a) the quality of the marine environment in which the plastics were pre-weathered and on (b) their abundance. For this, polystyrene pellets were submersed at a polluted and a pristine site near Niteroi, Brazil, for 2 weeks. Then specimens of U. rapax were, in laboratory experiments, exposed to fragments (180-250 MUm) derived from these pellets for 2 months. After this period, microplastics were observed in the gills, stomach and hepatopancreas of the animals. However, fragment retention was not influenced by the two factors that we manipulated. The presence of microplastics in different organs of the crab supports the assumption that these particles have the potential to harm marine invertebrates. PMID- 26013590 TI - Determining the footprint of sewage discharges in a coastal lagoon in South Western Europe. AB - Ria Formosa is a highly productive lagoon in South-Western Europe, supporting 90% of Portuguese clam production. Decreases in shellfish production have been ascribed to deterioration of water quality due to sewage discharges. Nevertheless, a thorough study considering their impact on the whole lagoon system has been missing. This work determined the sewage footprint from the major sewage treatment plants (STP) regarding eutrophication and microbial contamination within a two-year monitoring program. This focused on salinity, oxygen, nutrients, chlorophyll-a and faecal coliforms. Areas closer to sewage discharges showed an evident impact with maximum effects detected at the major STP. However, globally, the Ria Formosa did not show clear eutrophication problems due to high tidal flushing. Ammonium, oxygen, chlorophyll-a and faecal coliforms, unlike the other parameters, showed no seasonality. Microbiological contamination was of great concern and public health issues could be avoided by settling shellfish beds at least 500 m away from discharge points. PMID- 26013592 TI - Copper- and Vanadium-Catalyzed Oxidative Cleavage of Lignin using Dioxygen. AB - Transition-metal-containing hydrotalcites (HTc) and V(acac)3 /Cu(NO3 )2 ?3 H2 O (acac=acetylacetonate) mixtures were tested for their catalytic activity in the cleavage of the lignin model compound erythro-1-(3,4-dimethoxyphenyl)-2-(2 methoxyphenoxy)-l,3-propanediol (1) with molecular oxygen as oxidant. Both catalytic systems displayed high activity and good selectivity and afforded veratric acid as the main product. The catalyst behavior was studied by EPR spectroscopy, XRD, and Raman spectroscopy. After the catalysts were established for the model system, lignin depolymerization studies were performed with various organsolv and kraft lignin sources. The oxidative depolymerization and lignin bond cleavage were monitored by gel permeation chromatography (GPC), MALDI MS, and 2D-NMR (HSQC). Irrespective of the lignin pretreatment, both HTc-Cu-V and V(acac)3 /Cu(NO3 )2 ?3 H2 O were able to cleave the beta-O-4 linkages and the resinol structures to form dimeric and trimeric products. PMID- 26013591 TI - Mercury speciation in the Adriatic Sea. AB - Mercury and its speciation were studied in surface and deep waters of the Adriatic Sea. Several mercury species (i.e. DGM - dissolved gaseous Hg, RHg - reactive Hg, THg - total Hg, MeHg - monomethyl Hg and DMeHg - dimethylmercury) together with other water parameters were measured in coastal and open sea deep water profiles. THg concentrations in the water column, as well as in sediments and pore waters, were the highest in the northern, most polluted part of the Adriatic Sea as the consequence of Hg mining in Idrija and the heavy industry of northern Italy. Certain profiles in the South Adriatic Pit exhibit an increase of DGM just over the bottom due to its diffusion from sediment as a consequence of microbial and/or tectonic activity. Furthermore, a Hg mass balance for the Adriatic Sea was calculated based on measurements and literature data. PMID- 26013593 TI - Consistent, multi-instrument single tube quantification of CD20 in antibody bound per cell based on CD4 reference. AB - Detecting changes in the expression levels of cell antigens could provide critical information for the diagnosis of many diseases, for example, leukemia, lymphoma, and immunodeficiency diseases, detecting minimal residual disease, monitoring immunotherapies and discovery of meaningful clinical disease markers. One of the most significant challenges in flow cytometry is how to best ensure measurement quality and generate consistent and reproducible inter-laboratory and intra-laboratory results across multiple cytometer platforms and locations longitudinally over time. In a previous study, we developed a procedure for instrument standardization across four different flow cytometer platforms from the same manufacturer. CD19 quantification was performed on three of the standardized instruments relative to CD4 expression on T lymphocytes with a known amount of antibody bound per cell (ABC) as a quantification standard. Consistent and reliable measures of CD19 expression were obtained independent of fluorochrome used demonstrating the utility of this approach. In the present investigation, quantification of CD20 relative to CD4 reference marker was implemented within a single tube containing both antibodies. Relative quantification of CD20 was performed using anti-CD20 antibody (clone L27) in three different fluorochromes relative to anti-CD4 antibody (clone SK3). Our results demonstrated that cell surface marker quantification can be performed robustly using the single tube assay format with novel gating strategies. The ABC values obtained for CD20 expression levels using PE, APC, or PerCP Cy5.5 are consistent over the five different instrument platforms for any given apparently healthy donor independent of the fluorochrome used. PMID- 26013594 TI - The Role of Drug Exposure in Clinical Development: To What Extent Is Pharmacokinetic Assessment Needed in a Drug Development Programme? PMID- 26013595 TI - Organocatalytic asymmetric intramolecular aza-Henry reaction: facile synthesis of trans-2,3-disubstituted tetrahydroquinolines. AB - An enantio- and diastereoselective organocatalytic intramolecular aza-Henry (nitro-Mannich) reaction has been developed. The trans-2-aryl-3-nitro tetrahydroquinoline products are obtained in high yields and in good enantioselectivities with a bifunctional tertiary amine-thiourea catalyst. Excellent enantioselectivities were obtained after single recrystallization of some products. PMID- 26013596 TI - Computer-Aided Design of Ionic Liquids as CO2 Absorbents. AB - Ionic liquids (ILs), vary strongly in their interaction with CO2. We suggest simple theoretical approach to predict the CO2 absorption behavior of ILs. Strong interaction of the CO2 with the IL anions corresponds to chemical absorption whereas weak interaction indicates physical absorption. A predictive estimate with a clear distinction between physical and chemical absorption can be simply obtained according to geometries optimized in the presence of a solvation model instead of optimizing it only in gas phase as has been done to date. The resulting Gibbs free energies compare very well with experimental values and the energies were correlated with experimental capacities. Promising anions, for ionic liquids with reversible CO2 absorption properties can be defined by a reaction Gibbs free energy of absorption in the range of -30 to 16 kJ mol(-1). PMID- 26013597 TI - Role of Halides in the Ordered Structure Transitions of Heated Gold Nanocrystal Superlattices. AB - Dodecanethiol-capped gold (Au) nanocrystal superlattices can undergo a surprisingly diverse series of ordered structure transitions when heated (Goodfellow, B. W.; Rasch, M. R.; Hessel, C. M.; Patel, R. N.; Smilgies, D.-M.; Korgel, B. A. Nano Lett. 2013, 13, 5710-5714). These are the result of highly uniform changes in nanocrystal size, which subsequently force a spontaneous rearrangement of superlattice structure. Here, we show that halide-containing surfactants play an essential role in these transitions. In the absence of any halide-containing surfactant, superlattices of dodecanethiol-capped (1.9-nm diameter) Au nanocrystals do not change size until reaching about 190-205 degrees C, at which point the gold cores coalesce. In the presence of halide containing surfactant, such as tetraoctylphosphonium bromide (TOPB) or tetraoctylammounium bromide (TOAB), the nanocrystals ripen at much lower temperature and superlattices undergo various ordered structure transitions upon heating. Chloride- and iodide-containing surfactants induce similar behavior, destabilizing the Au-thiol bond and reducing the thermal stability of the nanocrystals. PMID- 26013598 TI - Collaborating With Police in the Emergency Department While Maintaining Patient Confidentiality: How Can We Improve? PMID- 26013600 TI - Focal humero-ulnar impingement following subtotal coronoid ostectomy in six dogs with fragmented medial coronoid process. AB - OBJECTIVE: To report acute eburnation of joint cartilage at the humeral trochlea following subtotal coronoid ostectomy (SCO) in a clinical case series of six elbows. MATERIAL AND METHODS: Six dogs (median BW 27.1 kg; median age 7.5 months) with fragmented medial coronoid process (FCP) and varying degree of radio-ulnar incongruence (RUI) (mean 2 mm) were treated with SCO using an arthroscopic burr. Second look arthroscopy 4-12 weeks later was performed either because of recurrent or persistent lameness in three dogs. In the others, second-look arthroscopy was scheduled prospectively because of RUI, which was thought to be a risk factor for the observed humero-ulnar impingement. RESULTS: All six elbows had a 1-2 mm wide line of focal full-thickness cartilage loss along the edge of the SCO, while the opposing trochlea had diffuse cartilage damage of Outerbridge grade III-IV, indicating focal humero-ulnar impingement. None of the elbows showed repeated FCP. CONCLUSION: In some cases SCO might lead to focal humero ulnar impingement along the osteotomy line. CLINICAL SIGNIFICANCE: Whether this relays to variations in respect the amount of resected bone (too much vs. too less) or concomitant joint pathologies like RUI or joint instability remains unknown and warrants further studies. PMID- 26013599 TI - Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus. AB - Recent genome-wide association studies have identified variations in the recombination repair gene, RAD52, that are associated with increased lung cancer risk, and particularly with the development of lung squamous cell carcinomas (LUSC). As LUSC development is strongly associated with smoking, DNA repair is increased in the lung tissues of smokers, presumably because of ongoing DNA damage from exposure to tobacco smoke. A key player in the DNA damage response, RAD52 plays a role in DNA strand exchange and annealing during homologous recombination (HR) in mammalian cells. In this study, we discovered two cis expression quantitative trait loci (eQTL) SNPs in the RAD52 gene that are associated with its expression and are also associated with LUSC risk. In addition, we report that amplification of the genomic region 12p13.33, which contains the RAD52 gene, is significantly associated with the development of LUSC in the TCGA database and that somatic overexpression of RAD52 was confirmed to be significant in LUSC tumors from our own patient cohort. Consistent with these genetic findings, we demonstrate that blockade of Rad52 slows cell growth and induces senescence in mouse bronchial epithelial cells. In contrast, overexpression of Rad52 leads to an increased rate of cell proliferation. We show that depletion of Rad52 in mouse lung tumor cells alters cell cycle distribution and increases DNA damage accumulation associated with increased tumor cell death. Our genetic and functional data implicate RAD52 as a significant determinant of risk in the development of LUSC. PMID- 26013601 TI - Patients' experiences of safety during haemodialysis treatment--a qualitative study. AB - AIM: To explore the experiences of safety of adult patients during their haemodialysis treatment. BACKGROUND: Haemodialysis is a complex treatment with a risk for harm that causes anxiety among many patients. To date, no in-depth study of haemodialysis patients' emotional responses to conditions of their treatment exists. DESIGN: A descriptive exploratory qualitative study using content analysis was conducted. METHODS: Outpatients (>=18 years old) (n = 12) who were treated with haemodialysis for more than half a year were purposefully selected from two haemodialysis units (one in an academic hospital and one in a top clinical hospital) in the Netherlands. Data were collected through in-depth individual interviews from January-April 2013. Analysis of the transcribed interviews consisted of open coding, creating categories and synthesis. RESULTS: Patients defined 'safety' as feeling safe from physical or emotional threats. Four main categories were identified in the descriptions of haemodialysis patients' experiences of safety: (a) insecurity; (b) trust in the nurse; (c) presence of the nurse; and (d) patients' need to control their situation. CONCLUSION: Although haemodialysis patients perceived multiple risks, most patients reported feeling safe during their treatment. The nurse had a pivotal role in promoting patients' feelings of safety. Nurses should take into account patients' coping strategies because these coping strategies may cause some patients to feel anxious, especially when patients say that they leave everything to the nurse, yet they still desire control over their treatment. PMID- 26013603 TI - A too-early lesson. PMID- 26013602 TI - CD49f Acts as an Inflammation Sensor to Regulate Differentiation, Adhesion, and Migration of Human Mesenchymal Stem Cells. AB - The advent of mesenchymal stem cell (MSC)-based therapies has been an exciting innovation for the treatment of degenerative and inflammatory diseases. However, the surface markers that accurately reflect the self-renewal and differentiation potential of MSCs and their sensitivity to environmental cues remain poorly defined. Here, we studied the role of CD49f in bone marrow MSCs (BMSCs) and the mechanism by which it regulates the behavior of BMSCs under inflammatory conditions. We found that CD49f is preferentially expressed in fetal cells rather than adult cells, CD49f-positive BMSCs possess higher CFU-F formation ability and differentiation potential than CD49f negative cells, and the CD49f expression of BMSCs gradually decreases during in vitro passaging. CD49f knockdown dramatically decreased the differentiation of BMSCs and isoform A was demonstrated to be the main functional form that enhanced the differentiation ability of BMSCs. The influences of inflammatory cytokines on BMSCs revealed that TNF-alpha downregulated CD49f in BMSCs with impaired differentiation, decreased adhesion to laminins, and increased migration. Moreover, tissue transglutaminase was found to work together with CD49f to regulate the behavior of BMSCs. Finally, we showed that mTOR signaling rather than NF-kappaB activation mediated CD49f downregulation induced by TNF-alpha and maintained CD49f homeostasis in BMSCs. Our findings suggest that CD49f is a stemness marker of BMSCs and is tightly correlated with the behavioral changes of BMSCs under inflammatory conditions. These data demonstrate a novel role for CD49f in sensing inflammation through mTOR pathway to further modulate the behavior of MSCs to fulfill the requirements of the body. PMID- 26013604 TI - Intriguing emission properties of triphenylamine-carborane systems. AB - Electron donor-acceptor (D-A) systems with a triphenylamino moiety (D) and ortho carborane (A) show three kinds of intriguing emissions that can be attributed to the local excited state, the intramolecular charge-transfer state, and the aggregation-induced emission state. The emission behaviors depend on which positions of the carborane are substituted. PMID- 26013634 TI - Anatomical characteristics of catathrenia (nocturnal groaning) in upper airway and orofacial structures. AB - BACKGROUND: Catathrenia is a rare sleep disorder characterized by repeated groaning in a protracted expiration preceded by a deep inspiration. This study aimed to explore whether anatomy is one of pathophysiology of catathrenia by investigating the anatomical features associated with catathrenia in the upper airway, craniofacial structures, and dental patterns. MATERIAL AND METHODS: Twenty-two patients with catathrenia (7 males, 15 females; age 22 to 69 years) were recruited as well as 66 patients matched by age and gender (matching proportion 1:3) with obstructive sleep apnea syndrome (OSAS). Both groups underwent cephalograms and dental casting, and cephalometric measurements and the Peer Assessment Rating (PAR) index was applied. Differences between the two groups were evaluated and cephalometric measurements in catathrenia group were compared with control values of Chinese patients from previous studies. RESULTS: As for airway-related measurements, increased PNS-R, PNS-UPW, and H-FH and decreased SPT and TGL were found in catathrenia group compared to normal values. Such trends were found even more evident when compared with the OSAS Group. As for craniofacial parameters, values of U1/NA and U1/SN were found increased in the catathrenia group compared with normal values and values of MP/FH and Y decreased. The differences were more distinct from the OSAS Group. Increased arch lengths and upper inter-first molar widths, and decreased overbite and PAR index, were found in catathrenia group compared with the OSAS Group. CONCLUSION: Catathrenia patients present with a broad upper airway, yet protrusive upper incisors and flat mandibular angles. Anatomical characteristics of catathrenia are different from those associated with OSAS, namely a wide airway, large skeleton, and good occlusion. PMID- 26013635 TI - A new theory on the pathogenesis of acquired cholesteatoma: Mucosal traction. AB - OBJECTIVES/HYPOTHESIS: Although the migration of its squamous outer surface of the tympanic membrane has been well characterized, there is a paucity of data available concerning the migratory behavior of its medial mucosal surface. Existing theories of primary acquired cholesteatoma pathogenesis do not adequately explain the observed characteristics of the disease. We propose a new hypothesis, based upon a conjecture that mucosal membrane interactions are the driving force in cholesteatoma. STUDY DESIGN: A retrospective chart review and a prospective observational cohort study in rats. METHODS: After developing the new theory, it was tested through both clinical and experimental observations. To evaluate whether impairment of middle ear mucociliary migration would influence cholesteatoma formation, a retrospective chart review evaluating cholesteatoma occurrence in a sizable population of patients with either primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) was performed. To study mucosal migration on the medial aspect of the tympanic membrane, ink tattoos were monitored over time in a rat model. RESULTS: No cholesteatomas were identified in either PCD patients (470) or in CF patients (1,910). In the rat model, mucosa of the posterior pars tensa migrated toward the posterior superior quadrant, whereas the mucosa of the anterior pars tensa migrated radially toward the annulus. CONCLUSION: Mucosal coupling with traction generated by interaction of migrating opposing surfaces provides the first comprehensive theory that explains the observed characteristics of primary acquired cholesteatoma. The somewhat counterintuitive hypothesis that cholesteatoma is fundamentally a mucosal disease has numerous therapeutic implications. PMID- 26013636 TI - Sonographic features of congenital infantile fibrosarcoma that appeared as a sacrococcygeal teratoma during pregnancy. AB - We experienced an extremely rare case of congenital infantile fibrosarcoma originating from the fetal sacrococcygeal region in pregnancy. At first, we suspected fetal sacrococcygeal teratoma; however, the following ultrasonography findings of the tumor complicated this diagnosis: (i) laterality; (ii) no cystic component; (iii) hypervascularity, with the feeding vessels not derived from the middle sacral artery; and (iv) a skin covering. The pathological findings indicated that the tumor was an infantile fibrosarcoma, not a teratoma. Thus, we believe that these sonographic features may aid the prenatal diagnosis of congenital infantile fibrosarcoma, which, in turn, may contribute to a better prognosis and may be useful for parental counseling. PMID- 26013637 TI - Normalizing Heterogeneous Medical Imaging Data to Measure the Impact of Radiation Dose. AB - The production of medical imaging is a continuing trend in healthcare institutions. Quality assurance for planned radiation exposure situations (e.g. X ray, computer tomography) requires examination-specific set-ups according to several parameters, such as patient's age and weight, body region and clinical indication. These data are normally stored in several formats and with different nomenclatures, which hinder the continuous and automatic monitoring of these indicators and the comparison between several institutions and equipment. This article proposes a framework that aggregates, normalizes and provides different views over collected indicators. The developed tool can be used to improve the quality of radiologic procedures and also for benchmarking and auditing purposes. Finally, a case study and several experimental results related to radiation exposure and productivity are presented and discussed. PMID- 26013638 TI - Protease inhibitors in Bombyx mori silk might participate in protecting the pupating larva from microbial infection. AB - Pupae inside cocoons rarely suffer from disease. It is apparent that some factors in the cocoon exert antimicrobial effects whereby the pupae inside can be protected from microbial infection. In the present study, we investigated the expression of cocoon protease inhibitors using immunoblotting and activity staining. Enzymatic hydrolysis of cocoon proteins in vitro was performed to characterize their roles in protecting the cocoon from microbial proteases. We found that some protease inhibitors, particularly trypsin inhibitor-like (TIL) type protease inhibitors, can be secreted into the cocoon layer during the spinning process, thereby providing effective protection to the cocoon and pupa by inhibiting the extracellular proteases that can be secreted by pathogens. PMID- 26013639 TI - Neurogenetics in Peru: clinical, scientific and ethical perspectives. AB - Neurogenetics, the science that studies the genetic basis of the development and function of the nervous system, is a discipline of recent development in Peru, an emerging Latin American country. Herein, we review the clinical, scientific and ethical aspects regarding the development of this discipline, starting with the first molecular diagnosis of neurogenetic diseases, to family and population based genetic association studies. Neurogenetics in Peru aims to better explain the epidemiology of monogenic and complex neurodegenerative disorders that will help in implementing public health policies for these disorders. The characterization of Peru and its health system, legal issues regarding rare diseases and the historical milestones in neurogenetics are also discussed. PMID- 26013640 TI - Being reasonable during coronary revascularization. AB - The SYNTAX score is an angiographically based tool useful for clinical decision making prior to coronary revascularization. The residual SYNTAX score (after angioplasty) is an independent predictor of clinical long-term outcome in patients with complex coronary artery disease. Both scores require functional lesion assessment. Adding clinical risk factors to both scores enhances their performance. PMID- 26013641 TI - [Not Available]. PMID- 26013642 TI - Carbon Nanodots: Supramolecular Electron Donor-Acceptor Hybrids Featuring Perylenediimides. AB - We describe the formation of charge-transfer complexes that feature electron donating carbon nanodots (CND) and electron-accepting perylenediimides (PDI). The functionalities of PDIs have been selected to complement those of CNDs in terms of electrostatic and pi-stacking interactions based on oppositely charged ionic head groups and extended pi-systems, respectively. Importantly, the contributions from electrostatic interactions were confirmed in reference experiments, in which stronger interactions were found for PDIs that feature positively rather than negatively charged head groups. The electronic interactions between the components in the ground and excited state were characterized in complementary absorption and fluorescence titration assays that suggest charge-transfer interactions in both states with binding constants on the order of 8*10(4) M(-1) (25 L g(-1) ). Selective excitation of the two components in ultrafast pump probe experiments gave a 210 ps lived charge-separated state. PMID- 26013643 TI - Levels of selection in Darwin's Origin of Species. AB - References in Darwin's Origin of Species to competition between units of selection at and above the level of individual organisms are enumerated. In many cases these references clearly speak of natural selection and do not support the view that Darwin thought selection only occurred at the level of the individual organism. Darwin did see organismal selection as the main process by which varieties were created but he also espoused what is here termed community and varietal selection. He saw no essential difference between varieties and species and the references show that he also believed that selection could operate at the species level. PMID- 26013644 TI - William Keith Brooks and the naturalist's defense of Darwinism in the late nineteenth century. AB - William Keith Brooks was an American zoologist at Johns Hopkins University from 1876 until his death in 1908. Over the course of his career, Brooks staunchly defended Darwinism, arguing for the centrality of natural selection in evolutionary theory at a time when alternative theories, such as neo-Lamarckism, grew prominent in American biology. In his book The Law of Heredity (1883), Brooks addressed problems raised by Darwin's theory of pangenesis. In modifying and developing Darwin's pangenesis, Brooks proposed a new theory of heredity that sought to avoid the pitfalls of Darwin's hypothesis. In so doing he strengthened Darwin's theory of natural selection by undermining arguments for the inheritance of acquired characteristics. In later attacks on neo-Lamarckism, Brooks consistently defended Darwin's theory of natural selection on logical grounds, continued to challenge the idea of the inheritance of acquired characteristics, and argued that natural selection best explained a wide range of adaptations. Finally, he critiqued Galton's statistical view of heredity and argued that Galton had resurrected an outmoded typological concept of species, one which Darwin and other naturalists had shown to be incorrect. Brooks's ideas resemble the "biological species concept" of the twentieth century, as developed by evolutionary biologist Ernst Mayr and others. The late-nineteenth century was not a period of total "eclipse" of Darwinism, as biologists and historians have hitherto seen it. Although the "Modern Synthesis" refers to the reconciliation of post-Mendelian genetics with evolution by natural selection, we might adjust our understanding of how the synthesis developed by seeing it as the culmination of a longer discussion that extends back to the late-nineteenth century. PMID- 26013645 TI - Discovery of causal mechanisms: Oxidative phosphorylation and the Calvin-Benson cycle. AB - We investigate the context of discovery of two significant achievements of twentieth century biochemistry: the chemiosmotic mechanism of oxidative phosphorylation (proposed in 1961 by Peter Mitchell) and the dark reaction of photosynthesis (elucidated from 1946 to 1954 by Melvin Calvin and Andrew A. Benson). The pursuit of these problems involved discovery strategies such as the transfer, recombination and reversal of previous causal and mechanistic knowledge in biochemistry. We study the operation and scope of these strategies by careful historical analysis, reaching a number of systematic conclusions: (1) even basic strategies can illuminate "hard cases" of scientific discovery that go far beyond simple extrapolation or analogy; (2) the causal-mechanistic approach to discovery permits a middle course between the extremes of a completely substrate-neutral and a completely domain-specific view of scientific discovery; (3) the existing literature on mechanism discovery underemphasizes the role of combinatorial approaches in defining and exploring search spaces of possible problem solutions; (4) there is a subtle interplay between a fine-grained mechanistic and a more coarse-grained causal level of analysis, and both are needed to make discovery processes intelligible. PMID- 26013646 TI - Conference report "Stoffwechsel. Histories of metabolism", workshop organized by Mathias Grote at Technische Universitat Berlin, November 28-29th, 2014. AB - Historical analyses of what metabolism has been conceived of, how concepts of metabolism were related to disciplines such as nineteenth-century nutritional physiology or twentieth-century biochemistry, and how their genealogies relate to the current developments may be helpful to understand the various, at times polemic, ways in which the boundaries between metabolism and heredity have been re-drawn. Against this background, a small number of scholars gathered in Berlin for a workshop that equally aimed at bringing new stories to the fore, and at considering seemingly known ones in a new light. Some aspects of the discussions are summarized in this paper. PMID- 26013647 TI - MERFISHing for spatial context. AB - A new paper in Science by Zhuang and colleagues introduces multiplexed error robust FISH (MERFISH). MERFISH extends single-molecule imaging techniques to profile the copy number and localization patterns of thousands of genes, representing a major advance for spatial transcriptomics, with exciting potential applications in immunology. PMID- 26013648 TI - Start of cheaper technique for breast cancer is delayed in UK despite adoption elsewhere. PMID- 26013654 TI - Assessment of heavy metal pollution in vegetables and relationships with soil heavy metal distribution in Zhejiang province, China. AB - There are increasing concerns on heavy metal contaminant in soils and vegetables. In this study, we investigated heavy metal pollution in vegetables and the corresponding soils in the main vegetable production regions of Zhejiang province, China. A total of 97 vegetable samples and 202 agricultural soil samples were analyzed for the concentrations of Cd, Pb, As, Hg, and Cr. The average levels of Cd, Pb, and Cr in vegetable samples [Chinese cabbage (Brassica campestris spp. Pekinensis), pakchoi (Brassica chinensis L.), celery (Apium graveolens), tomato (Lycopersicon esculentum), cucumber (Colletotrichum lagenarium), cowpea (Vigna unguiculata), pumpkin (Cucurbita pepo L.), and eggplant (Solanum melongena)] were 0.020, 0.048, and 0.043 mg kg(-1), respectively. The Pb and Cr concentrations in all vegetable samples were below the threshold levels of the Food Quality Standard (0.3 and 0.5 mg kg(-1), respectively), except that two eggplant samples exceeded the threshold levels for Cd concentrations (0.05 mg kg(-1)). As and Hg contents in vegetables were below the detection level (0.005 and 0.002 mg kg(-1), respectively). Soil pollution conditions were assessed in accordance with the Chinese Soil Quality Criterion (GB15618-1995, Grade II); 50 and 68 soil samples from the investigated area exceeded the maximum allowable contents for Cd and Hg, respectively. Simple correlation analysis revealed that there were significantly positive correlations between the metal concentrations in vegetables and the corresponding soils, especially for the leafy and stem vegetables such as pakchoi, cabbage, and celery. Bio-concentration factor values for Cd are higher than those for Pb and Cr, which indicates that Cd is more readily absorbed by vegetables than Pb and Cr. Therefore, more attention should be paid to the possible pollution of heavy metals in vegetables, especially Cd. PMID- 26013655 TI - Validation of atmospheric aerosols parallel sampling in a multifold device. AB - In this work, particulate matter was collected using an active sampling system consisting of a PM10 (<10 MUm) inlet coupled to a multifold device containing six channels, connected to a vacuum pump. Each channel was equipped with a filter holder fitted with adequately chosen filters. The system was fixed on a metallic structure, which was placed on the roof of the laboratory building, at the Faculty of Sciences, in Lisbon. Sampling took place under flow-controlled conditions. Aerosols were extracted from the filters with water, in defined conditions, and the water-soluble fraction was quantified by ion chromatography (IC) for the determination of inorganic anions (Cl(-), NO3 (-) and SO4 (2-)). Equivalent sampling through the various channels was validated. Validation was based on the metrological compatibility of the content results for the various filters. Ion masses are metrologically equivalent when their absolute difference is smaller than the respective expanded uncertainty. When this condition is verified, the studied multifold device produces equivalent samples. PMID- 26013656 TI - Characterizing ozone pollution in a petrochemical industrial area in Beijing, China: a case study using a chemical reaction model. AB - This study selected a petrochemical industrial complex in Beijing, China, to understand the characteristics of surface ozone (O3) in this industrial area through the on-site measurement campaign during the July-August of 2010 and 2011, and to reveal the response of local O3 to its precursors' emissions through the NCAR-Master Mechanism model (NCAR-MM) simulation. Measurement results showed that the O3 concentration in this industrial area was significantly higher, with the mean daily average of 124.6 MUg/m(3) and mean daily maximum of 236.8 MUg/m(3), which are, respectively, 90.9 and 50.6 % higher than those in Beijing urban area. Moreover, the diurnal O3 peak generally started up early in 11:00-12:00 and usually remained for 5-6 h, greatly different with the normal diurnal pattern of urban O3. Then, we used NCAR-MM to simulate the average diurnal variation of photochemical O3 in sunny days of August 2010 in both industrial and urban areas. A good agreement in O3 diurnal variation pattern and in O3 relative level was obtained for both areas. For example of O3 daily maximum, the calculated value in the industrial area was about 51 % higher than in the urban area, while measured value in the industrial area was approximately 60 % higher than in the urban area. Finally, the sensitivity analysis of photochemical O3 to its precursors was conducted based on a set of VOCs/NOx emissions cases. Simulation results implied that in the industrial area, the response of O3 to VOCs was negative and to NOx was positive under the current conditions, with the sensitivity coefficients of 0.16~-0.43 and +0.04~+0.06, respectively. By contrast, the urban area was within the VOCs-limitation regime, where ozone enhancement in response to increasing VOCs emissions and to decreasing NOx emission. So, we think that the VOCs emissions control for this petrochemical industrial complex will increase the potential risk of local ozone pollution aggravation, but will be helpful to inhibit the ozone formation in Beijing urban area through reducing the VOCs transport from the industrial area to the urban area. PMID- 26013657 TI - Detection of hormones in surface and drinking water in Brazil by LC-ESI-MS/MS and ecotoxicological assessment with Daphnia magna. AB - The growing use of pharmaceutical drug is mainly due to several diseases in human and in animal husbandry. As these drugs are discharged into waterways via wastewater, they cause a major impact on the environment. Many of these drugs are hormones; in which even at low concentrations can alter metabolic and physiological functions in many organisms. Hormones were found in surface water, groundwater, soil, and sediment at concentrations from nanograms to milligrams per liter of volume--quantities known to cause changes in the endocrine system of aquatic organisms. This study aimed to develop a methodology for hormone detection (estriol, estrone, 17beta-estradiol, 17alpha-ethinylestradiol, progesterone, and testosterone) on surface and treated water samples. Sample toxicity was assessed by ecotoxicology tests using Daphnia magna. A liquid chromatograph coupled to a mass spectrometer with an electrospray ionization source (LC-ESI-MS/MS) was used for the analysis. The results showed that samples were contaminated by the hormones estriol, estrone, progesterone, 17beta estradiol, and 17alpha-ethinylestradiol during the sampling period, and the highest concentrations measured were 90, 28, 26, 137, and 194 ng . L(-1), respectively. This indicates the inflow of sewage containing these hormones at some points in the Piracicaba River in the State of Sao Paulo-Brazil. Results indicated little toxicity of the hormone estriol in D. magna, indicating that chronic studies with this microcrustacean are necessary. PMID- 26013658 TI - Experiences with a clinical reasoning and evidence-based medicine course. AB - BACKGROUND: Although clinical reasoning (CR) and evidence-based medicine (EBM) are taught in some medical schools, the curricular details and students' clinical use of these skills are unknown. A detailed description of, and student experiences with, a practical CR and EBM curriculum delivering recommended content and pedagogy in an emerging academic environment may be broadly informative. PURPOSE: To describe and characterise student experiences with a CR and EBM curriculum at a newly formed Academic Medical Centre (AMC). METHODS: Applying expert recommended content and pedagogy, we developed a CR and EBM curriculum for final-year medical students delivered by existing clinical faculty members. We evaluated the course content by delineating the CR elements and EBM steps taught, and characterised student CR and EBM classroom and clinical experiences using a self-reported survey (1, strongly disagree; 5, strongly agree). RESULTS: Clinical faculty members, presenting real cases using active learning techniques, delivered all six recommended CR elements and three EBM steps throughout the course. Thirty-nine (89%) students completed a survey and agreed that the course added value to their clinical practice (3.90). Students agreed that they practised CR in the classroom (3.93) and in the clinical setting (3.78) similarly (p = 0.21). Their agreement differed for EBM practice (classroom 3.78, clinical 3.35; p = 0.002). Exploring factors that inhibit the application of EBM in a clinical setting [is] important CONCLUSIONS: Our curriculum addressed recommended CR and EBM elements, used clinical faculty members efficiently and was valued by students. Although our students practised these skills in the classroom and the clinical setting, exploring factors that inhibit the application of EBM in a clinical setting will be important in optimising both student learning and patient care. PMID- 26013659 TI - Effect of 10 different TiO2 and ZrO2 (nano)materials on the soil invertebrate Enchytraeus crypticus. AB - Nearly 80% of all the nano-powders produced worldwide are metal oxides, and among these materials titanium dioxide (TiO2 ) is one of the most produced. Titanium dioxide's toxicity is estimated as low to soil organisms, but some studies have shown that TiO2 nanoparticles can cause oxidative stress. Additionally, it is known that TiO2 is activated by ultraviolet (UV) radiation, which can promote photocatalytic generation of reactive oxygen species, which is seldom taken into account in toxicity testing. In the present study, the authors investigated the effects of different TiO2 and zirconium materials on the soil oligochaete Enchytraeus crypticus, using exposure via soil, water, and soil:water extracts, and studied the effects combined with UV radiation. The results showed that zirconium dioxide (bulk and nano) was not toxic, whereas zirconium tetrachloride reduced enchytraeid reproduction in soil (50% effect concentration = 502 mg/kg). The TiO2 materials were also not toxic via soil exposure or under UV radiation. However, pre-exposure to TiO2 and UV radiation via aqueous media caused a lower reproductive output post-exposure in clean soil (20-50% less but only observed at the lowest concentration tested, 1 mg/L); that is, the effect of TiO2 in water was potentiated by the UV radiation and measurable as a decrease in reproduction in soil media. PMID- 26013660 TI - Synthesis and Mechanistic Study of Cyclic Oxoguanidines via Zn(OTf)2 -Catalyzed Guanylation/Amidation from Readily Available Amino Acid Esters and Carbodiimides. AB - The Zn(OTf)2 -catalyzed guanylation/amidation from readily available amino acid esters and carbodiimides is achieved to provide efficiently various cyclic oxoguanidines, including 2-amino-1H-imidazol-5(4H)-ones and 2-aminoquinazolin 4(3H)-ones in medium-to-high yields. It is the first time that an ammonium salt has been used in a guanylation reaction. The application of cyclic oxoguanidines to provide the conjugated heterocyclic compounds via oxidative C-N formation or aldol reaction is explored. The reaction mechanism is well elucidated by the isolation and characterization of three important intermediates. PMID- 26013661 TI - MiR-133 is Involved in Estrogen Deficiency-Induced Osteoporosis through Modulating Osteogenic Differentiation of Mesenchymal Stem Cells. AB - BACKGROUND: MiR-133 expression is dysregulated in postmenopausal osteoporosis. However, its role in postmenopausal osteoporosis is still not well understood. In the current study, we explore how estrogen deficiency affects miR-133 expression and how miR-133 is involved in osteogenic differentiation of mesenchymal stem cells (MSCs). MATERIAL AND METHODS: qRT-PCR analysis was performed to assess miR 133 expression in MSCs isolated from bone marrow of an ovariectomized (OVX) animal model and postmenopausal osteoporosis patients (PMOP) and their corresponding controls. The binding between miR-133 and predicted target SLC39A1 was verified using dual luciferase assay and Western blot analysis. The effect of miR-133 and SLC39A1 on osteogenic differentiation of MSCs was assessed through measuring alkaline phosphatase (ALP), mineralization nodules, and osteoblast specific genes Runx2 and Osterix expression. RESULTS: miR-133 expression is significantly enhanced as a result of estrogen deficiency. Its overexpression is negatively correlated to osteogenic differentiation of hMSCs. SLC39A1 showed an inverse expression trend to miR-133 during the differentiation. miR-133 can directly target 3'UTR of SLC39A1 and thereby modulate its expression in hMSCs. The miR-133-SLC39A1 axis might play an important role in osteogenic differentiation of hMSCs. SLC39A1 can promote ALP activity and formation of mineralization nodules. In addition, SLC39A1 expression level is also positively correlated with RUNX2 and Osterix. CONCLUSIONS: Estrogen deficiency is associated with miR-133 overexpression. MiR-133 can induce postmenopausal osteoporosis by weakening osteogenic differentiation of hMSCs, at least partly through repressing SLC39A1 expression. PMID- 26013663 TI - Validating the British Columbia Perinatal Data Registry: a chart re-abstraction study. AB - BACKGROUND: The British Columbia Perinatal Data Registry (BCPDR) contains individual-level obstetrical and neonatal medical chart data for virtually all births occurring in British Columbia, Canada. The objective of this study was to assess the validity of information in the BCPDR by performing a provincial chart re-abstraction study. METHODS: A two-stage stratified clustered sampling design was employed. Obstetrical facilities were stratified based on geographic location and obstetrical volume. Charts of mothers and newborns with a length of stay of five or more days or transfer to another facility following the delivery were oversampled. A total of 85 maternal and 32 newborn variables were assessed for completeness (percent completion) and validity (sensitivity and specificity for categorical variables, intra-class correlation coefficient [ICC] for continuous variables). RESULTS: 1,084 maternal and 1,142 newborn charts were abstracted. Mandatory variables such as primary indication for induction and primary indication for cesarean delivery were 100 % complete. Some variables such as pre pregnancy weight were relatively more complete in the re-abstraction as compared with the BCPDR (83.0 % vs 76.8 %; p < 0.001). The validity of key surveillance variables was high (e.g., HIV screening completed [sensitivity 98.0 %, 95 % confidence interval (CI) 97.0-98.8 %; specificity 72.3 %, 95 % CI 60.8-81.9 %], induction of labour [sensitivity 93.9 %, 95 % CI 90.2-96.5 %; specificity 98.7 %, 95 % CI 97.7-99.3 %], primary elective cesarean delivery [sensitivity 96.0 %, 95 % CI 83.8-99.7 %; specificity 99.8 %, 95 % CI 99.4-100.0 %], gestational age from newborn examination [ICC 0.99, 95 % CI 0.99-0.99]). Examples of variables with lower validity included total admissions prior to delivery episode, maternal smoking status, and timing of breastfeeding initiation. CONCLUSION: Many important clinical and population health variables in the BCPDR had excellent validity. Some key variables warrant strengthening through improved definitions, system changes, and abstractor training. PMID- 26013662 TI - Nonautophagic cytoplasmic vacuolation death induction in human PC-3M prostate cancer by curcumin through reactive oxygen species -mediated endoplasmic reticulum stress. AB - The antiapoptotic and antiautophagic abilities of cancer cells constitute a major challenge for anticancer drug treatment. Strategies for triggering nonapoptotic or nonautophagic cell death may improve therapeutic efficacy against cancer. Curcumin has been reported to exhibit cancer chemopreventive properties. Herein, we report that curcumin induced apoptosis in LNCaP, DU145, and PC-3 cells but triggered extensive cytoplasmic vacuolation in PC-3M cells. Electron microscopic images showed that the vacuoles lacked intracellular organelles and were derived from the endoplasmic reticulum (ER). Moreover, curcumin-induced vacuolation was not reversed by an apoptosis- or autophagy-related inhibitor, suggesting that vacuolation-mediated cell death differs from classical apoptotic and autophagic cell death. Mechanistic investigations revealed that curcumin treatment upregulated the ER stress markers CHOP and Bip/GRP78 and the autophagic marker LC3-II. In addition, curcumin induced ER stress by triggering ROS generation, which was supported by the finding that treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death. An in vivo PC-3M orthotopic prostate cancer model revealed that curcumin reduced tumor growth by inducing ROS production followed by vacuolation-mediated cell death. Overall, our results indicated that curcumin acts as an inducer of ROS production, which leads to nonapoptotic and nonautophagic cell death via increased ER stress. PMID- 26013664 TI - Antagonistic interactions between endophytic cultivable bacterial communities isolated from the medicinal plant Echinacea purpurea. AB - In this work we have studied the antagonistic interactions existing among cultivable bacteria isolated from three ecological niches (rhizospheric soil, roots and stem/leaves) of the traditional natural medicinal plant Echinacea purpurea. The three compartments harboured different taxonomic assemblages of strains, which were previously reported to display different antibiotic resistance patterns, suggesting the presence of differential selective pressure due to antagonistic molecules in the three compartments. Antagonistic interactions were assayed by the cross-streak method and interpreted using a network-based analysis. In particular 'within-niche inhibition' and 'cross-niche inhibition' were evaluated among isolates associated with each compartment as well as between isolates retrieved from the three different compartments respectively. Data obtained indicated that bacteria isolated from the stem/leaves compartment were much more sensitive to the antagonistic activity than bacteria from roots and rhizospheric soil. Moreover, both the taxonomical position and the ecological niche might influence the antagonistic ability/sensitivity of different strains. Antagonism could play a significant role in contributing to the differentiation and structuring of plant-associated bacterial communities. PMID- 26013666 TI - Zinc-Catalyzed Functionalization of Si-H Bonds with 2-Furyl Carbenoids through Three-Component Coupling. AB - A three-component coupling of alk-2-ynals, 1,3-dicarbonyls and silanes is reported. ZnCl2 serves as an inexpensive and low-toxic catalyst for the overall transformation, which involves Knoevenagel condensation, cyclization, and carbene Si-H bond insertion. The process takes place with high atom economy in the absence of organic solvents and shows a broad scope. This reaction is also applicable to the functionalization of oligomeric siloxanes. PMID- 26013665 TI - Mining geographic variations of Plasmodium vivax for active surveillance: a case study in China. AB - BACKGROUND: Geographic variations of an infectious disease characterize the spatial differentiation of disease incidences caused by various impact factors, such as environmental, demographic, and socioeconomic factors. Some factors may directly determine the force of infection of the disease (namely, explicit factors), while many other factors may indirectly affect the number of disease incidences via certain unmeasurable processes (namely, implicit factors). In this study, the impact of heterogeneous factors on geographic variations of Plasmodium vivax incidences is systematically investigate in Tengchong, Yunnan province, China. METHODS: A space-time model that resembles a P. vivax transmission model and a hidden time-dependent process, is presented by taking into consideration both explicit and implicit factors. Specifically, the transmission model is built upon relevant demographic, environmental, and biophysical factors to describe the local infections of P. vivax. While the hidden time-dependent process is assessed by several socioeconomic factors to account for the imported cases of P. vivax. To quantitatively assess the impact of heterogeneous factors on geographic variations of P. vivax infections, a Markov chain Monte Carlo (MCMC) simulation method is developed to estimate the model parameters by fitting the space-time model to the reported spatial-temporal disease incidences. RESULTS: Since there is no ground-truth information available, the performance of the MCMC method is first evaluated against a synthetic dataset. The results show that the model parameters can be well estimated using the proposed MCMC method. Then, the proposed model is applied to investigate the geographic variations of P. vivax incidences among all 18 towns in Tengchong, Yunnan province, China. Based on the geographic variations, the 18 towns can be further classify into five groups with similar socioeconomic causality for P. vivax incidences. CONCLUSIONS: Although this study focuses mainly on the transmission of P. vivax, the proposed space time model is general and can readily be extended to investigate geographic variations of other diseases. Practically, such a computational model will offer new insights into active surveillance and strategic planning for disease surveillance and control. PMID- 26013668 TI - Corrigendum: Freely orbiting magnetic tweezers to directly monitor changes in the twist of nucleic acids. PMID- 26013667 TI - Cameriere's third molar maturity index in assessing age of majority. AB - Estimation of chronological age of an individual is one of the main challenges in forensic science. Legally to be able to treat a person as a minor or an adult, it is necessary to determine whether their age of majority (if they are older or younger than 18, in most countries). Methods for estimating age are especially important when an individual in question lacks personal documents or other means of identification. As the dental age differs in various populations, the aim of this study was to evaluate applicability of third molar method for assessing age of majority in Croatia. Cameriere's third molar maturity index (I3M) value of 0.08, measured by the open apices of the teeth, was verified in sample of 1336 panoramic images aged between 14 and 23 years. Chronological age gradually decreased as I3M increased in both genders. Males showed statistically significant advanced maturation when I3M was between 0.0 and 0.3 value. The results indicate that the sensitivity of the test for 0.08 value was 84.3% (95%CI 80.6%, 87.5%) for females and 91.2% (95%CI 88.7%, 93.1) for males. Specificity was 95.4% (95%CI 92.5%, 97.5%) and 91.9% (95%CI 88.8%, 94.3%). The proportions of accurately classified males were 88.8% and that of females 91.5%. The estimated post-test probabilities, of individuals, in other word the probability that a Croatian individual with an I3M<0.08 is 18 years or older is 94.5% for females, and 96.5% for males. With high accuracy, the third molar maturity index should be used as a determinant of the age of majority in Croatia. PMID- 26013669 TI - Evaluating the effect of risperidone on speech: A cross-sectional study. AB - Speech subsystems are susceptible to the effects of several factors including medications. The atypical antipsychotics can also adversely affect the speech because of its action on serotonin and dopamine neurotransmitters. The present study aims to analyze the speech characteristics associated with atypical antipsychotic risperidone. Speech of 92 patients on risperidone with or without trihexyphenidyl and/or clonazepam were compared with that of 31 persons who were not on any psychotropic medicines. Compared to control group, maximum phonation duration, sequential motion rate of diadochokinesia was reduced by about 3s and 1syllable/s respectively and s/z ratio was increased by 0.16 in patients with risperidone. Performance of larynx, lips and tongue sub-system and intelligibility of speech were also significantly reduced in risperidone group. Risperidone did impact the phonation and articulation sub-systems of speech mildly, which was independent of tardive dyskinesia and extrapyramidal symptoms. Randomized controlled prospective study looking into impact on speech and related effect on drug adherence, functioning and quality of life needs to be conducted with risperidone and other atypical antipsychotics. PMID- 26013670 TI - GHQ-12 as a predictor of burnout with emotional exhaustion in resident doctors. PMID- 26013671 TI - Relationship of obsessive compulsive symptoms/disorder with clozapine: A retrospective study from a multispeciality tertiary care centre. AB - OBJECTIVE: To study the prevalence, phenomenology and course of OCS/OCD in patients receiving clozapine. METHODOLOGY: Case records of 220 patients who received clozapine for at least 3 months were reviewed. RESULTS: One fifth (N=42; 19.1%) of patients had OCS/OCD, of which majority (13.2%) had onset of OCS/OCD prior to starting of clozapine and remaining 5.9% developed OCS/OCD after starting of clozapine. About one fourth of the patients with pre-existing OCS/OCD had worsening with clozapine while the remaining maintained at the same level (55.17%) or improved (20.7%). Majority of the patients who developed de novo OCS/OCD on clozapine were females and OCS/OCD emerged within 12 months (69.2%) of starting of clozapine. In those who developed OCS/OCD with clozapine, among obsessions, pathological doubts were most common, followed by obsessions with sexual content; among compulsions repetitive checking was the most common. SSRIs were required for management in half the patients, while the remaining improved spontaneously or with reduction in clozapine dose. CONCLUSION: Clozapine can lead to aggravation or de novo presentation of OCS/OCD but these can be managed with reduction in dose or addition of SSRIs. PMID- 26013672 TI - Commentary on 'Predictors of Failure of Closure in Percutaneous EVAR Using the Prostar XL Percutaneous Vascular Surgery Device'. PMID- 26013673 TI - Influence of green tea extract on oxidative damage and apoptosis induced by deltamethrin in rat brain. AB - In the present study, we investigated the protective effect of an aqueous extract of green tea leaves (GTE) against neurotoxicity and oxidative damage induced by deltamethrin (DM) in male rats. Four different groups of rats were used: the 1st group was the vehicle treated control group, the 2nd group received DM (0.6 mg/kg BW), the 3rd group received DM plus GTE, and the 4th received GTE alone (25 mg/kg BW). The brain tissues were collected at the end of the experimental regimen for subsequent investigation. Rats that were given DM had a highly significant elevation in MDA content, nitric oxide concentration, DNA fragmentation and expression level of apoptotic genes, TP53 and COX2. Additionally, a significant reduction in the total antioxidant capacity in the second group was detected. The findings for the 3rd group highlight the efficacy of GTE as a neuro-protectant in DM-induced neurotoxicity through improving the oxidative status and DNA fragmentation as well as suppressing the expression of the TP53 and COX2 genes. In conclusion, GTE, at a concentration of 25mg/kg/day, protected against DM induced neurotoxicity through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product against DM-induced neurotoxicity. PMID- 26013674 TI - Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery. AB - Cognitive dysfunction has been found in epidemiological studies to be among the most sensitive impairments associated with developmental exposure to a variety of environmental contaminants from heavy metals to polyhalogenated hydrocarbons and pesticides. These chemicals have been also shown to impair cognitive function after developmental exposure in experimental animal models. The radial-arm maze (RAM) has proven to be a sensitive and reliable way to assess both learning and memory in a variety of species, most often in rats and mice. The RAM is a very adaptable test method that takes advantage of rodents' instinct to explore new places in the environment to forage. That is, rodents do not need to be trained to run through the maze; they will normally do this from the initial session of testing. Training with differential reinforcement for arm choices provides a more rigorous test of learning and memory. The RAM is quite adaptable for assessing various aspects of cognition. Although the RAM has been mostly used to assess spatial learning and memory, it can be configured to assess non-spatial memory as well. Both working and reference memory can be easily distinguished. The RAM can be run with both appetitive (food reinforced) and aversive (water escape) motivators. The RAM has been found to be sensitive to a wide variety of developmental toxicants including heavy metals such as mercury and pesticides such as chlorpyrifos. There is an extremely rich literature especially with rats showing the effects of many types of brain lesions and drug effects so that the participation of a wide variety of neural systems in RAM performance is known. These systems, notably the hippocampus and frontal cortex, and acetylcholine and glutamate neurotransmitter systems, are the same neural systems that have been shown in humans to be critical for learning and memory. This considerably aids the interpretation of neurobehavioral toxicity studies. PMID- 26013675 TI - Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases. AB - PURPOSE: Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics. METHODS: We have analyzed the role of various antidiabetic drugs on HCC in a nested case-control study using the healthcare utilization databases of the Lombardy Region in Italy. This included 190 diabetic subjects with a hospital discharge reporting a diagnosis of malignant HCC and 3772 diabetic control subjects matched to each case on sex, age, date at cohort entry, and duration of follow-up. RESULTS: Increased risks of HCC were found for use of insulin (odds ratio [OR] = 3.73, 95% confidence interval [CI] 2.52-5.51), sulfonylureas (OR = 1.39, 95%CI 0.98-1.99), and repaglinide (OR = 2.12, 95%CI 1.38-3.26), while a reduced risk was found for use of metformin (OR = 0.57, 95%CI 0.41-0.79). The risk of HCC increased with increasing duration of insulin use (OR = 2.52 for <1 year, 5.41 for 1-2 years, and 6.01 for >=2 years; p for trend < 0.001), while no clear pattern with duration was observed for sulfonylureas, repaglinide, and metformin. CONCLUSION: Our study supports the evidence that patients with diabetes using metformin, and possibly other antidiabetic drugs that increase insulin sensibility, have a reduced risk of HCC, while those using insulin or drugs that increase circulating insulin, such as insulin secretagogues, have an increased risk. Whether these associations are causal, or influenced by different severity of diabetes and/or possible residual bias or misclassification, is still open to discussion. PMID- 26013677 TI - The origins of mutational robustness. AB - Biological systems are resistant to genetic changes; a property known as mutational robustness, the origin of which remains an open question. In recent years, researchers have explored emergent properties of biological systems and mechanisms of genetic redundancy to reveal how mutational robustness emerges and persists. Several mechanisms have been proposed to explain the origin of mutational robustness, including molecular chaperones and gene duplication. The latter has received much attention, but its role in robustness remains controversial. Here, I examine recent findings linking genetic redundancy through gene duplication and mutational robustness. Experimental evolution and genome resequencing have made it possible to test the role of gene duplication in tolerating mutations at both the coding and regulatory levels. This evidence as well as previous findings on regulatory reprogramming of duplicates support the role of gene duplication in the origin of robustness. PMID- 26013676 TI - Cellular microRNA miR-26a suppresses replication of porcine reproductive and respiratory syndrome virus by activating innate antiviral immunity. AB - Porcine reproductive and respiratory syndrome (PRRS) has caused large economic losses in the swine industry in recent years. Current PRRS vaccines fail to effectively prevent and control this disease. Consequently, there is a need to develop new antiviral strategies. MicroRNAs play critical roles in intricate host pathogen interaction networks, but the involvement of miRNAs during PRRS virus (PRRSV) infection is not well understood. In this study, pretreatment with miR 26a induced a significant inhibition of PRRSV replication and remission of the cytopathic effect in MARC-145 cells, and this antiviral effect was sustained for at least 120 h. Luciferase reporter analysis showed that the PRRSV genome was not the target of miRNA-26a. Instead, RNA-seq analysis demonstrated that miR-26a significantly up-regulated innate anti-viral responses, including activating the type I interferon (IFN) signaling pathway and promoting the production of IFN stimulated genes. These findings suggest that delivery of miR-26a may provide a potential strategy for anti-PRRSV therapies. PMID- 26013678 TI - Dentures in dementia: a two-edged sword. PMID- 26013679 TI - Median estimation of chemical constituents for sampling on two occasions under a log-normal model. AB - Sampling from a finite population on multiple occasions introduces dependencies between the successive samples when overlap is designed. Such sampling designs lead to efficient statistical estimates, while they allow estimating changes over time for the targeted outcomes. This makes them very popular in real-world statistical practice. Sampling with partial replacement can also be very efficient in biological and environmental studies where estimation of toxicants and its trends over time is the main interest. Sampling with partial replacement is designed here on two occasions in order to estimate the median concentration of chemical constituents quantified by means of liquid chromatography coupled with tandem mass spectrometry. Such data represent relative peak areas resulting from the chromatographic analysis. They are therefore positive-valued and skewed data, and are commonly fitted very well by the log-normal model. A log-normal model is assumed here for chemical constituents quantified in mainstream cigarette smoke in a real case study. Combining design-based and model-based approaches for statistical inference, we seek for the median estimation of chemical constituents by sampling with partial replacement on two time occasions. We also discuss the limitations of extending the proposed approach to other skewed population models. The latter is investigated by means of a Monte Carlo simulation study. PMID- 26013681 TI - Diabetologia at 50: celebrating half a century of progress in diabetes research and care. PMID- 26013682 TI - Cereal fibre and type 2 diabetes: time now for randomised controlled trials? AB - Diet and nutrition are strongly implicated in the aetiology of type 2 diabetes; low dietary fibre intake could be an important factor. Evidence from prospective observational studies has suggested that it may be low cereal fibre intake, rather than low fruit and vegetable fibre intake, which is particularly important. In this issue of Diabetologia (DOI 10.1007/s00125-015-3585-9 ) Kuijsten et al report on the prospective associations between different dietary fibre sources and type 2 diabetes risk in the European Prospective Investigation of Cancer and Nutrition (EPIC)-Interact study and set their findings in context with a meta-analysis of relevant published prospective studies. The results presented strengthen the evidence implicating cereal fibre as an important determinant of type 2 diabetes risk and suggest that randomised controlled trials examining the effect of cereal fibre supplementation on type 2 diabetes risk are now needed. PMID- 26013683 TI - Disease detection or public opinion reflection? Content analysis of tweets, other social media, and online newspapers during the measles outbreak in The Netherlands in 2013. AB - BACKGROUND: In May 2013, a measles outbreak began in the Netherlands among Orthodox Protestants who often refuse vaccination for religious reasons. OBJECTIVE: Our aim was to compare the number of messages expressed on Twitter and other social media during the measles outbreak with the number of online news articles and the number of reported measles cases to answer the question if and when social media reflect public opinion patterns versus disease patterns. METHODS: We analyzed measles-related tweets, other social media messages, and online newspaper articles over a 7-month period (April 15 to November 11, 2013) with regard to topic and sentiment. Thematic analysis was used to structure and analyze the topics. RESULTS: There was a stronger correlation between the weekly number of social media messages and the weekly number of online news articles (P<.001 for both tweets and other social media messages) than between the weekly number of social media messages and the weekly number of reported measles cases (P=.003 and P=.048 for tweets and other social media messages, respectively), especially after the summer break. All data sources showed 3 large peaks, possibly triggered by announcements about the measles outbreak by the Dutch National Institute for Public Health and the Environment and statements made by well-known politicians. Most messages informed the public about the measles outbreak (ie, about the number of measles cases) (93/165, 56.4%) followed by messages about preventive measures taken to control the measles spread (47/132, 35.6%). The leading opinion expressed was frustration regarding people who do not vaccinate because of religious reasons (42/88, 48%). CONCLUSIONS: The monitoring of online (social) media might be useful for improving communication policies aiming to preserve vaccination acceptability among the general public. Data extracted from online (social) media provide insight into the opinions that are at a certain moment salient among the public, which enables public health institutes to respond immediately and appropriately to those public concerns. More research is required to develop an automatic coding system that captures content and user's characteristics that are most relevant to the diseases within the National Immunization Program and related public health events and can inform official responses. PMID- 26013684 TI - Transcriptional control of late differentiation in human keratinocytes by TAp63 and Notch. AB - We previously showed that in cervical carcinoma cells, the TAp63beta isoform of the p63 transcription factor is negatively interfering with the carcinogenic pathways promoting anchorage-independent growth. In this study, we have defined the mechanisms underlying the effects of TAp63beta through a transcriptome analysis of human keratinocytes overexpressing this protein. TAp63beta modulated expression of 1203 genes (944 activated and 259 repressed; P-value <0.05), notably genes involved in epithelial development and keratinocyte differentiation. In comparison, while TAp63gamma acts similarly to TAp63beta to transactivate a selected panel of target genes, other p63 isoforms, including DeltaNp63alpha, which is highly expressed in keratinocytes, are inactive. Upon induction of differentiation of primary human keratinocytes, we observed endogenous expression of TAp63beta and gamma isoforms, along with transcriptional activation of selected target genes. Intriguingly, our data also indicated that TAp63beta activates transcription of members of the Notch pathway, which is known to promote keratinocyte differentiation. By inhibiting and activating the Notch pathway, we revealed a subset of TAp63beta-activated genes that were co-dependent on Notch for their expression. Our work demonstrates that the shorter TAp63 isoforms (TAp63beta/gamma) are specifically induced in human keratinocytes and cooperate with Notch signalling to activate transcription of late differentiation genes supporting their role as putative tumor suppressors in HPV-associated tumorigenesis. PMID- 26013685 TI - Special characteristics of the transcription and splicing machinery in photoreceptor cells of the mammalian retina. AB - Chromatin organization and the management of transcription and splicing are fundamental to the correct functioning of every cell but, in particular, for highly active cells such as photoreceptors, the sensory neurons of the retina. Rod photoreceptor cells of nocturnal animals have recently been shown to have an inverted chromatin architecture compared with rod photoreceptor cells of diurnal animals. The heterochromatin is concentrated in the center of the nucleus, whereas the genetically active euchromatin is positioned close to the nuclear membrane. This unique chromatin architecture suggests that the transcription and splicing machinery is also subject to specific adaptations in these cells. Recently, we described the protein Simiate, which is enriched in nuclear speckles and seems to be involved in transcription and splicing processes. Here, we examine the distribution of Simiate and nuclear speckles in neurons of mouse retinae. In retinal neurons of the inner nuclear and ganglion cell layer, Simiate is concentrated in a clustered pattern in the nuclear interior, whereas in rod and cone photoreceptor cells, Simiate is present at the nuclear periphery. Further staining with markers for the transcription and splicing machinery has confirmed the localization of nuclear speckle components at the periphery. Comparing the distribution of nuclear speckles in retinae of the nocturnal mouse with the diurnal degu, we found no differences in the arrangement of the transcription and splicing machinery in their photoreceptor cells, thus suggesting that the organization of these machineries is not related to the animal's lifestyle but rather represents a general characteristic of photoreceptor organization and function. PMID- 26013690 TI - Rapid Screening of Immobilized Amine CO2 Sorbents for Steam Stability by Their Direct Contact with Liquid H2 O. AB - Rapid testing of hydrophilic and hydrophobic basic immobilized amine sorbents (BIAS) for CO2 capture stability under practical conditions was achieved by direct contact of the sorbents with flowing liquid water. Losses in both CO2 capture capacity and amine content of sorbents after exposure to 0.5 mL min(-1) of H2 O at 25 degrees C for 40 min followed similar trends as losses observed after exposure to N2 /steam (105 degrees C, 7 % H2 O) for 10 h. We also found that hydrophobic TMPED helped stabilize sorbents to H2 O, which was confirmed by DRIFTS and combined TGA-DSC. PMID- 26013691 TI - Evaluation of the effectiveness of a pathogen inactivation technology against clinically relevant transfusion-transmitted bacterial strains. AB - BACKGROUND: To increase blood safety, various procedures are currently implemented, including donor selection, optimized donor arm disinfection, and diversion. In addition, pathogen inactivation (PI) techniques can be used for platelets (PLTs) and plasma concentrates. STUDY DESIGN AND METHODS: This study investigated the clinical efficacy of an inactivation technique for different blood components at two time points (12 and 35.5 hr). Eight transfusion-relevant bacterial strains were spiked at two different concentrations (100 and 1000 colony-forming units [CFUs]/bag) into whole blood (WB), apheresis PLTs (APs), and buffy coat (BC)-derived minipool PLTs. RESULTS: The bacterial concentrations were higher than 10(6) CFUs/mL within 24 hours after spiking depending on the particular bacterial strain. PI was absolute for all of the APs performed 12 hours after inoculation, but the bacterial strains of Klebsiella pneumoniae and Bacillus cereus were not completely inactivated in WB or BC PLTs, performed 35.5 and 12 hours after inoculation, respectively. CONCLUSION: The INTERCEPT PI system was not 100% effective for high concentrations of certain K. pneumoniae strains or spore-forming B. cereus. A critical observation was that the period between blood donation and inactivation needs to be minimal to enable efficient PI. In the case where PI cannot be performed immediately after preparation, a combination of a PI technology after the production of blood components with a rapid bacterial screen test on Day 4 or 5 after donation may offer a solution to further prevent the risk of bacterial transmission by transfusion. PMID- 26013692 TI - Alkaline hydrothermal liquefaction of swine carcasses to bio-oil. AB - It is imperative that swine carcasses are disposed of safely, practically and economically. Alkaline hydrothermal liquefaction of swine carcasses to bio-oil was performed. Firstly, the effects of temperature, reaction time and pH value on the yield of each liquefaction product were determined. Secondly, liquefaction products, including bio-oil and solid residue, were characterized. Finally, the energy recovery ratio (ERR), which was defined as the energy of the resultant products compared to the energy input of the material, was investigated. Our experiment shows that reaction time had certain influence on the yield of liquefaction products, but temperature and pH value had bigger influence on the yield of liquefaction products. Yields of 62.2wt% bio-oil, having a high heating value of 32.35MJ/kg and a viscosity of 305cp, and 22wt% solid residue were realized at a liquefaction temperature of 250 degrees C, a reaction time of 60min and a pH value of 9.0. The bio-oil contained up to hundreds of different chemical components that may be classified according to functional groups. Typical compound classes in the bio-oil were hydrocarbons, organic acids, esters, ketones and heterocyclics. The energy recovery ratio (ERR) reached 93.63%. The bio-oil is expected to contribute to fossil fuel replacement in stationary applications, including boilers and furnaces, and upgrading processes for the bio-oil may be used to obtain liquid transport fuels. PMID- 26013693 TI - Biological pre-treatment: Enhancing biogas production using the highly cellulolytic fungus Trichoderma viride. AB - With regard to renewable sources of energy, bioconversion of lignocellulosic biomass has long been recognized as a desirable endeavor. However, the highly heterogeneous structure of lignocellulose restricts the exploitation of its promising potential in biogas plants. Hence, effective pre-treatment methods are decisive prerequisites to overcome these challenges in order to improve the utilization ratio of (ligno) cellulosic substrates during fermentation. In the present study, the application of Trichoderma viride in an aerobic upstream process prior to anaerobic digestion led up to a threefold increase in the yield of methane and total gas in a lab-scale investigation. Due to its highly efficient cellulolytic activities, T. viride seemed to be responsible for an improved nutrient availability that positively influenced the anaerobic microbiocenosis. Aerobic pre-treatment of organic matter with T. viride is therefore a promising solution to achieve higher methane yields and degradation performances without any additional energy demand, nor undesired by-product inhibition. PMID- 26013694 TI - Thermal degradation of paper industry wastes from a recovered paper mill using TGA. Characterization and gasification test. AB - In this survey, a refuse derived fuel (RDF) was produced from paper industry wastes through a mechanical treatment (MT). The two main wastes generated from a recovered paper mill were rejects and de-inking sludge, which were produced principally in the pulping and de-inking processes, respectively. This work presents raw wastes characterization, fuel preparation and gasification tests performed in a circulating fluidized bed (CFB) gasifier pilot plant. The characterization was carried out by proximate and ultimate analysis. Several blends of pre-conditioned rejects and de-inking sludge were densified by means of pelletizing, studying the energy consumption and its quality properties. Besides, thermal degradation of blends was studied under thermogravimetric analysis (TGA). The experimental runs were made from 30 to 900 degrees C in nitrogen atmosphere at three heating ranges, beta=5, 10 and 20 degrees C/min. Two thermal stages were identified during the thermal degradation, which are linked to cellulose and plastic degradation. In addition, kinetics parameters were estimated by the application of non-isothermal methods: Kissinger-Akahira-Sunose (KAS), Flynn Ozawa-Wall (FOW) and Coats and Redfern. The activation energy values were about 140-160 kJ/mol and 60-80 kJ/mol for plastic and cellulosic materials, respectively. Regarding waste valorisation, a blend composed of 95% of rejects and 5% of de-inking sludge was selected for gasification tests. The energy consumption during the preparation was recorded and a gasification tests were done to prove the usability of these pellets in a CFB gasifier. The main results were a net calorific value (NCV) of 5 MJ/Nm(3) and a total tar content of 11.44 g/Nm(3) at an equivalence ratio (ER) of 0.3. PMID- 26013695 TI - Low-dose fractionated radiation and chemotherapy prior to definitive chemoradiation in locally advanced carcinoma of the uterine cervix: Results of a prospective phase II clinical trial. AB - BACKGROUND: We investigated the feasibility of neoadjuvant low-dose radiation and chemotherapy with paclitaxel and carboplatin (LDCRT) before radical chemoradiation (CRT) and assessed the feasibility, efficacy, and response rate to such a regimen. METHODS: This is a single-arm phase II trial of 24 patients, with locally advanced squamous cell carcinoma of the cervix (stage IIB-IIIB). Patients received low-dose fractionated radiotherapy, carboplatin (AUC*5) and paclitaxel (175 mg/m(2)), three weekly for two cycles followed by CRT. The primary end point was overall and disease-free survival. RESULTS: Mean age of the patients at diagnosis was 50 years; Radiological complete or partial response rate was 40% and 60%, respectively, post-LDCRT. The median follow-up was 30 months (24-36 months). Both overall and progression-free survivals at 2.5 years were 84%. Grade 3/4 toxicities were 24% hematological toxicity during LDCRT and 46% during CRT (hematological: 42%, non-hematological: 4%). CONCLUSION: A good response rate is achieved by low-dose radiation and chemotherapy with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible and effective as evidenced by the acceptable toxicity and 84% local control at 2.5 years. PMID- 26013696 TI - Women at extreme risk for obesity-related carcinogenesis: Baseline endometrial pathology and impact of bariatric surgery on weight, metabolic profiles and quality of life. AB - OBJECTIVES: The study objectives were to determine baseline endometrial histology in morbidly obese women undergoing bariatric surgery and to assess the surgical intervention's impact on serum metabolic parameters, quality of life (QOL), and weight. METHODS: Women undergoing bariatric surgery were enrolled. Demographic and clinicopathologic data, serum, and endometrium (if no prior hysterectomy) were collected preoperatively and serum collected postoperatively. Serum global biochemical data were assessed pre/postoperatively. Welch's two sample t-tests and paired t-tests were used to identify significant differences. RESULTS: Mean age of the 71 women enrolled was 44.2 years, mean body mass index (BMI) was 50.9 kg/m(2), and mean weight loss was 45.7 kg. Endometrial biopsy results: proliferative (13/30; 43%), insufficient (8/30; 27%), secretory (6/30; 20%) and hyperplasia (3/30; 10%-1 complex atypical, 2 simple). QOL data showed significant improvement in physical component scores (PCS means 33.9 vs. 47.2 before/after surgery; p<0.001). Twenty women underwent metabolic analysis which demonstrated significantly improved glucose homeostasis, improved insulin responsiveness, and free fatty acid levels. Significant perturbations in tryptophan, phenylalanine and heme metabolism suggested decreased inflammation and alterations in the intestinal microbiome. Most steroid hormones were not significantly impacted with the exception of decreased DHEAS and 4-androsten metabolites. CONCLUSIONS: Bariatric surgery is accompanied by an improved physical quality of life as well as beneficial changes in glucose homeostasis, insulin responsiveness, and inflammation to a greater extent than the hormonal milieu. The potential cancer protective effects of bariatric surgery may be due to other mechanisms other than simply hormonal changes. PMID- 26013697 TI - Minority participation in Gynecologic Oncology Group (GOG) Studies. AB - OBJECTIVE: Participation of minority populations in clinical trials is paramount to understanding and overcoming cancer racial disparities. The goal of this project is to evaluate minority participation in published GOG clinical trials. METHODS: GOG publications from 1985 to 2013 were reviewed. Minority enrollment was stratified by tumor site, type of study, and year published. Based on Centers of Disease Control and Prevention (CDC) age-adjusted incidence for race, expected and observed ratios of racial participation were calculated. RESULTS: A total of 445 GOG publications involving 67,568 patients were reviewed. Racial breakdown was provided in 170 studies (38%) for a total of 45,259 patients: 83% White (n=37,617); 8% Black (n=3,686), and 9% Other (n=3,956). The majority of studies were Ovarian (n=202) and Phase 2 (n=290). When evaluating the quartiles of publication year, a steady decline in the proportion of Black patients enrolled was seen. Race was not reported in any publication prior to 1994. Compared to years 1994-2002, a 2.8-fold lower proportion of black enrollment was noted in years 2009-2013 (16% and 5.8%, respectively; p<0.01). Utilizing CDC age-adjusted incidence, observed enrollment of Black patients onto GOG clinical trials was significantly less than expected enrollment. Observed Black enrollment was 15 fold lower than expected for ovarian trials, 10-fold lower for endometrial, 4.5 fold for cervix, and 5.2-fold for sarcoma (each p<0.001). CONCLUSIONS: Based on age-adjusted incidence, observed enrollment of Black patients was lower than expected enrollment onto GOG studies. Despite national emphasis on minority enrollment on clinical trials, fewer Black patients were enrolled over time. PMID- 26013698 TI - Significance of monocyte counts on tumor characteristics and survival outcome of women with endometrial cancer. AB - OBJECTIVE: Tumor-associated macrophages are known to be associated with decreased survival of patients with endometrial cancer. Given the physiological link of circulating monocytes as a progenitor of tumor-associated macrophages, monocyte counts were examined for tumor characteristics and survival in endometrial cancer. METHODS: A retrospective study was conducted to examine consecutive patients with endometrial cancer with all histologic types who underwent hysterectomy-based surgical staging between 2003 and 2013 (n=541). Preoperative monocyte counts were correlated to patient demographics, pathological findings, complete blood count results, and survival outcomes. RESULTS: Median monocyte counts were 0.5*10(9)/L. Monocyte counts significantly correlated with all other complete blood count components, with neutrophil counts having the most significant association (r=0.52, p<0.001). Elevated monocyte counts (defined as >0.7*10(9)/L) when compared to lower counts were significantly associated with an increased risk of >50% myometrial tumor invasion (29.2% versus 22.0%, odds ratio [OR] 1.59, 95% confidence interval [CI] 1.01-2.45, p=0.045), pelvic lymph node metastasis (39.0% versus 18.8%, OR 2.76, 95%CI 1.35-5.62, p=0.007), and advanced stage (stage I through IV, 18.5%, 24.6%, 32.5%, and 41.5%, p=0.001). In survival analysis, elevated monocyte counts were associated with decreased disease-free survival (5-year rates, 71.0% versus 84.5%, p=0.001) and overall survival (77.2% versus 89.3%, p<0.001). In multivariate analysis, elevated monocyte counts remained an independent prognostic factor for decreased disease-free (hazard ratio [HR] 1.74, 95% CI 1.02-2.96, p=0.041) and overall (HR 2.63, 95% CI 1.37 5.05, p=0.004) survival. CONCLUSIONS: Elevated monocyte counts were associated with aggressive tumor features and poor survival outcomes of patients with endometrial cancer. PMID- 26013699 TI - Three-dimensional cage-like microscaffolds for cell invasion studies. AB - Cancer cell motility is one of the major events involved in metastatic process. Tumor cells that disseminate from a primary tumor can migrate into the vascular system and, being carried by the bloodstream, transmigrate across the endothelium, giving rise to a new tumor site. However, during the invasive process, tumor cells must pass through the extracellular matrix, whose structural and mechanical properties define the parameters of the migration process. Here, we propose 3D-complex cage-like microstructures, realized by two-photon (TP) direct laser writing (DLW), to analyze cell migration through pores significantly smaller than the cell nucleus. We found that the ability to traverse differently sized pores depends on the metastatic potential and on the invasiveness of the cell lines, allowing to establish a pore-area threshold value able to discriminate between non-tumorigenic and tumorigenic human breast cells. PMID- 26013700 TI - Aberrant NK cell associated marker (CD56 and CD57) expression in chronic lymphocytic leukemia. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the commonest leukemias that has been reported extensively throughout the literature. The characteristic phenotype includes co-expression of CD5 and CD23, along with dim expression of light chain and CD22/CD79b, with lack of FMC7. The immunophenotypic scoring system given by Matutes has been used to differentiate CLL from non-CLL chronic lymphoproliferative disorders. Various aberrancies have been described in CLL cases, including abnormal (dim or bright) expression of B cell markers and lineage infidel T cell, myelomonocytic, or rarely Natural killer (NK) cells markers. However, the aberrant co-expression of CD56 and CD57 has not yet been reported. METHOD AND RESULTS: We hereby report a case of 62-year female with a typical CLL phenotype and Matutes score of 5, showing the expression of CD56 and CD57. CONCLUSION: This entity may represent a rare subtype of CLL which needs to be studied more extensively for its prognostic implications. This is the first report of CLL with aberrant CD56 and CD57 expression. PMID- 26013702 TI - Frenkel-Defect-Mediated Chemical Ordering Transition in a Li-Mn-Ni Spinel Oxide. AB - Using spinel-type Li(Mn(1.5)Ni(0.5) )O4 with two different cations, Mn and Ni, in the oxygen octahedra as a model system, we show that a cation ordering transition takes place through the formation of Frenkel-type point defects. A series of experimental results based on atomic-scale observations and in situ powder diffractions along with ab initio calculations consistently support such defect mediated transition behavior. In addition to providing a precise suggestion of the intermediate transient states and the resulting kinetic pathway during the transition between two phases, our findings emphasize the significant role of point defects in ordering transformation of complex oxides. PMID- 26013701 TI - Endothelin ETA receptor/lipid peroxides/COX-2/TGF-beta1 signalling underlies aggravated nephrotoxicity caused by cyclosporine plus indomethacin in rats. AB - BACKGROUND AND PURPOSE: Cyclosporine (CSA) and non-steroidal anti-inflammatory drugs (NSAIDs) are co-prescribed for some arthritic conditions. We tested the hypothesis that this combined regimen elicits exaggerated nephrotoxicity in rats via the up-regulation of endothelin (ET) receptor signalling. EXPERIMENTAL APPROACH: The effects of a 10 day treatment with CSA (20 mg . kg(-1) . day(-1)), indomethacin (5 mg . kg(-1) . day(-1)) or their combination on renal biochemical, inflammatory, oxidative and structural profiles were assessed. The roles of ETA receptor and COX-2 pathways in the interaction were evaluated. KEY RESULTS: Oral treatment with CSA or indomethacin elevated serum urea and creatinine, caused renal tubular atrophy and interstitial fibrosis, increased renal TGF-beta1, and reduced immunohistochemical expressions of ETA receptors and COX-2. CSA, but not indomethacin, increased renal ET-1, the lipid peroxidation product malondialdehyde (MDA) and GSH activity. Compared with individual treatments, simultaneous CSA/indomethacin exposure caused: (i) greater elevations in serum creatinine and renal MDA; (ii) loss of the compensatory increase in GSH; (iii) renal infiltration of inflammatory cells and worsening of fibrotic and necrotic profiles; and (iv) increased renal ET-1 and decreased ETA receptor and COX-2 expressions. Blockade of ETA receptors by atrasentan ameliorated the biochemical, structural, inflammatory and oxidative abnormalities caused by the CSA/indomethacin regimen. Furthermore, atrasentan partly reversed the CSA/indomethacin-evoked reductions in the expression of ETA receptor and COX-2 protein. CONCLUSIONS AND IMPLICATIONS: The exaggerated oxidative insult and associated dysregulation of the ETA receptor/COX-2/TGF-beta1 signalling might account for the aggravated nephrotoxicity caused by the CSA/indomethacin regimen. The potential renoprotective effect of ETA receptor antagonism might be exploited therapeutically. PMID- 26013704 TI - Apoptotic and autophagic pathways with relevant small-molecule compounds, in cancer stem cells. AB - Accumulating evidence demonstrates existence of cancer stem cells (CSCs), which are suspected of contributing to cancer cell self-renewal capacity and resistance to radiation and/or chemotherapy. Including evasion of apoptosis and autophagic cell death, CSCs have revealed abilities to resist cell death, making them appealing targets for cancer therapy. Recently, molecular mechanisms of apoptosis and of autophagy in CSCs have been gradually explored, comparing them in stem cells and in cancer cells; distinct expression of these systems in CSCs may elucidate how these cells exert their capacity of unlimited self-renewal and hierarchical differentiation. Due to their proposed ability to drive tumour initiation and progression, CSCs may be considered to be potentially useful pharmacological targets. Further, multiple compounds have been verified as triggering apoptosis and/or autophagy, suppressing tumour growth, thus providing new strategies for cancer therapy. In this review, we summarized regulation of apoptosis and autophagy in CSCs to elucidate how key proteins participate in control of survival and death; in addition, currently well-studied compounds that target CSC apoptosis and autophagy are selectively presented. With increasing attention to CSCs in cancer therapy, researchers are now trying to find responses to unsolved questions as unambiguous as possible, which may provide novel insight into future anti-cancer regimes. PMID- 26013703 TI - Levetiracetam Monotherapy in Children with Epilepsy: A Systematic Review. AB - BACKGROUND: Levetiracetam, a second-generation anti-epileptic drug (AED) with a good efficacy and safety profile, is licensed as monotherapy for adults and children older than 16 years with focal seizures with or without secondary generalization. However, it is increasingly being used off-label in younger children. OBJECTIVES: We critically reviewed the available evidence and discuss the present status of levetiracetam monotherapy in children 0-16 years old. DATA SOURCES: We systematically searched the literature using PubMed, Web of Science and Embase up to August 2014 for articles on levetiracetam monotherapy in children. Keywords were levetiracetam, monotherapy and child*. The titles and abstracts of 532 articles were evaluated by AW, of which 480 were excluded. The full texts of the other 52 articles were assessed for relevance. RESULTS: We covered one review, one opinion statement and 32 studies in this review, including four randomized controlled trials, ten open-label prospective studies, eight retrospective studies, and ten case reports. The formal evidence for levetiracetam monotherapy in children is minimal: it is potentially efficacious or effective as initial monotherapy in children with benign epilepsy with centrotemporal spikes. In all of the published studies, however, efficacy and tolerability of levetiracetam seemed to be good and comparable to other AEDs. CONCLUSION: The data of 32 studies on levetiracetam monotherapy in children were insufficient to confirm that levetiracetam is effective as initial monotherapy for different types of seizures and/or epilepsy syndromes. There is still an urgent need for well designed trials to justify the widespread use of levetiracetam monotherapy in children of all ages. PMID- 26013705 TI - Prehospital initiation of mild therapeutic hypothermia for out-of-hospital cardiac arrest (OHCA): where are we now? PMID- 26013706 TI - Novel species interactions: American black bears respond to Pacific herring spawn. AB - BACKGROUND: In addition to the decline and extinction of the world's species, the decline and eventual loss of species interactions is one of the major consequences of the biodiversity crisis. On the Pacific coast of North America, diminished runs of salmon (Oncorhynchus spp.) drive numerous marine-terrestrial interactions, many of which have been intensively studied, but marine-terrestrial interactions driven by other species remain relatively unknown. Bears (Ursus spp.) are major vectors of salmon into terrestrial ecosystems, but their participation in other cross-ecosystem interactions is similarly poorly described. Pacific herring (Clupea pallasii), a migratory forage fish in coastal marine ecosystems of the North Pacific Ocean and the dominant forage fish in British Columbia (BC), spawn in nearshore subtidal and intertidal zones. Spawn resources (eggs, milt, and spawning adults) at these events are available to coastal predators and scavengers, including terrestrial species. In this study, we investigated the interaction between American black bears (Ursus americanus) and Pacific herring at spawn events in Quatsino Sound, BC, Canada. RESULTS: Using remote cameras to monitor bear activity (1,467 camera days, 29 sites, years 2010 2012) in supratidal and intertidal zones and a machine learning approach, we determined that the quantity of Pacific herring eggs in supratidal and intertidal zones was a leading predictor of black bear activity, with bears positively responding to increasing herring egg masses. Other important predictors included day of the year and Talitrid amphipod (Traskorchestia spp.) mass. A complementary analysis of black bear scats indicated that Pacific herring egg mass was the highest ranked predictor of egg consumption by bears. Pacific herring eggs constituted a substantial yet variable component of the early springtime diet of black bears in Quatsino Sound (frequency of occurrence 0-34%; estimated dietary content 0-63%). Other major dietary items included graminoids (grasses and sedges), Phaeophyta (brown algae), Zosteraceae (seagrasses), and Talitrid amphipods. CONCLUSION: This research represents the first scientific evidence of a cross-ecosystem interaction between Pacific herring and American black bears. Our findings also expand knowledge of the ecological roles of both species. Combined, evidence of anthropogenic constraints on both black bears and Pacific herring suggests that bear-herring interactions were potentially stronger and more widespread in the past. PMID- 26013707 TI - Prior Innominate Vein Occlusion Does Not Preclude Successful Bidirectional Superior Cavopulmonary Connection. AB - BACKGROUND: Low superior vena cava (SVC) blood flow has recently been identified as a marker for bidirectional superior cavopulmonary connection (SCPC) failure and death. Prior innominate vein occlusion is considered a significant anatomic risk factor for SCPC failure. We therefore evaluated the outcomes of infants who underwent SCPC with known upper-body venous obstruction. METHODS: Between February 1995 and June 2014, SCPC was carried out in 8 patients who had either a single SVC with known prior occlusion of the innominate vein (n = 6) or bilateral SVCs without a bridging vein with occlusion of one SVC (n = 2). The cause of the occlusion was an indwelling catheter in 5 patients. These patients were compared with 8 patients with normal upper-body venous drainage who underwent SCPC. Patients were evaluated for preoperative risk factors (including SVC size, pulmonary artery size, Nakata index, pulmonary vascular resistance), operative factors, and clinical outcomes to determine the impact of prior upper-body venous occlusion on SCPC failure or death. RESULTS: There were no significant differences in preoperative risk factors between the two groups, except for a significantly lower Nakata index in the study group with a trend toward smaller pulmonary artery branch size. There were no SCPC takedowns or mortalities. There was no significant difference in postoperative length of stay (median of 7 days [range, 5 to 32 days] versus 5 days [range, 4 to 32 days]; p = 0.17. Study patients had a lower mean systemic oxygen saturation at discharge, 81% versus 85% (p = 0.05). In the study group, at a median follow-up of 42 months, 3 patients underwent successful Fontan completion and 5 are still awaiting Fontan completion. CONCLUSIONS: Although patients with prior upper-body venous obstruction may have lower systemic oxygen saturations at hospital discharge, they do not demonstrate an increased SCPC failure or mortality rate. Innominate vein occlusion or its equivalent in patients with bilateral SVCs should not preclude the performance of SCPC. Physiologic rather than anatomic evaluation of preoperative systemic venous return may be more useful to predict outcome after SCPC. PMID- 26013708 TI - Outcomes of Treatment of Nonagenarians With Severe Aortic Stenosis. AB - BACKGROUND: Because nonagenarians with aortic stenosis (AS) often present as frail with more comorbid conditions, long-term outcomes and quality of life are important treatment considerations. The aim of this report is to describe survival and functional outcomes of nonagenarians undergoing treatment for AS by surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). METHODS: This is a retrospective analysis of all patients aged 90 years or more undergoing treatment for AS between 2007 and 2013 at two centers. Outcomes were compared between SAVR and TAVR. Long-term survival was compared with an age- and sex-matched population from the Social Security Actuarial Life Table. RESULTS: In all, 110 patients underwent treatment for isolated AS (20 SAVR and 90 TAVR). Mean age was 91.85 +/- 1.80 years, and 50.9% were female. The Society of Thoracic Surgeons mean predicted risk of mortality was 11.11% +/- 5.74%. Operative mortality was 10.9% (10.0% SAVR; 11.1% TAVR); 2.7% of patients had a stroke. The TAVR patients were more likely to be discharged home (75.9% versus 55.6% for SAVR, p = 0.032). Mean follow-up was 1.8 +/- 1.5 years, with a 1-year and 5-year survival of 78.7% and 45.3%, respectively, which approximated the US actuarial survival. There was a significant improvement in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire at 1 year compared with baseline. CONCLUSIONS: Treatment of AS approximates natural life expectancy in select nonagenarians, with no significant difference in long-term survival between SAVR and TAVR. Importantly, patient quality of life improved at 1 year. With appropriate selection, nonagenarians with severe AS can benefit from treatment. PMID- 26013709 TI - [New drugs for small animals in 2014]. AB - In 2014, six active pharmaceutical ingredients were released on the German market for small animals. Those are the ektoparasiticide of the isoxazoline group afoxolaner (NexGard(r)) and fluralaner (Bravecto(r)) and the neonicotinoid dinotefuran (Vectra 3D, Vectra Felis), the antidiabetic protamine zinc insulin of human origin (ProZinc(r)), the antifungal agent ketoconazole (Fugazid(r)) as well as the cytostatic drug oclacitinib (Apoquel(r)). Two substances were authorized for an additional species. The antiparasiticide eprinomectin and the antibiotic clindamycin were also authorized for use in cats. In addition, two active pharmaceutical ingredients, which were approved 2014 for use in human medicine and are of potential interest to veterinary medicine, are discussed. These are the antihypertensive drug riociguat and the urological substance mirabegron. PMID- 26013712 TI - Retroperitoneal Fibrosis. PMID- 26013711 TI - Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study. AB - OBJECTIVES: The objective was to determine the efficacy of coadministration of subcutaneous (SQ) insulin glargine in combination with intravenous (IV) insulin for treating diabetic ketoacidosis (DKA). METHODS: This was a prospective, randomized, controlled trial comparing coadministration of insulin glargine and IV insulin (experimental) with IV insulin (standard care control). The setting was emergency departments (EDs) in two hospitals in Houston, Texas. Patients presenting with blood sugar >= 200 mg/dL, pH <= 7.3, bicarbonate (HCO3 ) <= 18 mg/dL, ketonemia or ketonuria, and anion gap >= 16 between November 2012 and April 2013 were enrolled. All patients received IV insulin. Additionally, the experimental group was given SQ insulin glargine within 2 hours of diagnosis. Upon closure of anion gap, patients in the control group were subsequently transitioned to long-acting insulin. In the study group, IV insulin was discontinued and long-acting SQ insulin was reinstituted 24 hours after initial introduction. The primary outcome of time to closure of anion gap (TCAG) was compared between groups using a general linear model (GLM), adjusting for initial anion gap, etiology, and presence of comorbidities. Similarly, the secondary outcome hospital length of stay (LOS) was adjusted for age, etiology, and hospital site in the GLM. Rate of hypoglycemia and intensive care unit (ICU) admission was compared using Fisher's exact test while ICU LOS was compared using Wilcoxon's two-sample test. RESULTS: A total of 40 patients were enrolled in this pilot trial. The estimated mean TCAG was 10.2 hours (SE +/- 6.8 hours) in the experimental group and 11.6 hours (SE +/- 6.4 hours) in the control group (p = 0.63). The estimated mean hospital LOS was 3.9 days (SE +/- 3.4 days) in the experimental group and 4.8 days (SE +/- 3.6 days) in the control group (p = 0.66). Incidents of hypoglycemia, rates of ICU admission, and ICU LOS were similar between the groups. CONCLUSIONS: Coadministration of glargine in combination with an insulin infusion in the acute management of DKA is feasible. Further study is needed to determine the true efficacy in terms of TCAG and hospital LOS. PMID- 26013710 TI - Twist1 regulates keratinocyte proliferation and skin tumor promotion. AB - In the present study, we evaluated the effect of deleting Twist1 on keratinocyte proliferation and on skin tumor development using the two-stage chemical carcinogenesis model. BK5.Cre * Twist1(flox/flox) mice, which have a keratinocyte specific Twist1 knockout (Twist1 KO), developed significantly reduced numbers of papilloma (70% reduction) and squamous cell carcinoma (75% reduction) as well as delayed tumor latency compared to wild-type (WT) mice. Interestingly, knockdown of Twist1 in primary keratinocytes impeded cell cycle progression at the G1/S transition that coincided with reduced levels of the cell cycle proteins c-Myc, Cyclin E1, and E2F1 and increased levels of p53 and p21. Furthermore, ChIP analyses revealed that Twist1 bound to the promoter regions of Cyclin E1, E2F1, and c-Myc at the canonical E-box binding motif suggesting a direct transcriptional regulation. Further analyses of Twist1 KO mice revealed a significant reduction in the number of label-retaining cells as well as the number of alpha6-integrin(+) /CD34(+) cells in the hair follicles of untreated mice compared to WT mice. These mice also exhibited significantly reduced epidermal proliferation in response to TPA treatment that again correlated with reduced levels of cell cycle regulators and increased levels of p53 and p21. Finally, Twist1 deficiency in keratinocytes led to an upregulation of p53 via its stabilization and nuclear localization, which is responsible for the increased expression of p21 in these cells. Collectively, these findings indicate that Twist1 has a novel role in epithelial carcinogenesis by regulating proliferation of keratinocytes, including keratinocyte stem cells during tumor promotion. PMID- 26013732 TI - A Niche for GFRalpha1-Positive Spermatogonia in the Terminal Segments of the Seminiferous Tubules in Hamster Testes. AB - In invertebrate species such as flies and nematodes, germline stem cells are maintained in a niche environment, which is restricted to the terminal end of the tubular structure in the gonads. In mice, spermatogonial stem cells (SSCs), a subpopulation of Asingle GFRalpha1 (glial cell line-derived neurotrophic factor [GDNF] family receptor-alpha1)-positive spermatogonia, are widely distributed along the longitudinal axis in the convoluted seminiferous tubules, preferentially juxtaposed to the interstitial vasculature. However, whether this area is the only SSC niche is not known. In this study, we identified a valve like terminal segment of the seminiferous tubules, the Sertoli valve (SV), adjacent to the rete testis as another niche for GFRalpha1-positive spermatogonia in hamsters. Here, we show that the SV epithelium is composed of the modified Sertoli cells that are still capable of proliferation and missing most spermatogenic activities in the adult stage. The SV epithelium constitutively expresses GDNF, a major niche factor for SSCs, and supports the stable proliferation and selective maintenance of an Asingle subpopulation of GFRalpha1 positive spermatogonia in hamsters. The SV region of hamster seminiferous tubules has features that are similar to the stem cell niche in invertebrate gonads. Therefore, we propose that the SV may be a novel niche for Asingle GFRa1-positive spermatogonia potentially including a SSC population, at the terminal segments of the seminiferous tubules in hamsters. PMID- 26013733 TI - Protective effect of melatonin-supported adipose-derived mesenchymal stem cells against small bowel ischemia-reperfusion injury in rat. AB - We tested the hypothesis that combined melatonin and autologous adipose-derived mesenchymal stem cells (ADMSC) was superior to either alone against small bowel ischemia-reperfusion (SBIR) injury induced by superior mesenteric artery clamping for 30 min followed by reperfusion for 72 hr. Male adult Sprague Dawley rats (n = 50) were equally categorized into sham-operated controls SC, SBIR, SBIR-ADMSC (1.0 * 10(6) intravenous and 1.0 * 10(6) intrajejunal injection), SBIR-melatonin (intraperitoneal 20 mg/kg at 30 min after SI ischemia and 50 mg/kg at 6 and 18 hr after SI reperfusion), and SBIR-ADMSC-melatonin groups. The results demonstrated that the circulating levels of TNF-alpha, MPO, LyG6+ cells, CD68+ cells, WBC count, and gut permeability were highest in SBIR and lowest in SC, significantly higher in SBIR-ADMSC group and further increased in SBIR-melatonin group than in the combined therapy group (all P < 0.001). The ischemic mucosal damage score, the protein expressions of inflammation (TNF-alpha, NF-kappaB, MMP-9, MPO, and iNOS), oxidative stress (NOX-1, NOX-2, and oxidized protein), apoptosis (APAF-1, mitochondrial Bax, cleaved caspase-3 and PARP), mitochondrial damage (cytosolic cytochrome C) and DNA damage (gamma-H2AX) markers, as well as cellular expressions of proliferation (PCNA), apoptosis (caspase-3, TUNEL assay), and DNA damage (gamma-H2AX) showed an identical pattern, whereas mitochondrial cytochrome C exhibited an opposite pattern compared to that of inflammation among all groups (all P < 0.001). Besides, antioxidant expressions at protein (NQO-1, GR, and GPx) and cellular (HO-1) levels progressively increased from SC to the combined treatment group (all P < 0.001). In conclusion, combined melatonin-ADMSC treatment offered additive beneficial effect against SBIR injury. PMID- 26013734 TI - Combined use of GAP and AOX1 promoters and optimization of culture conditions to enhance expression of Rhizomucor miehei lipase. AB - Rhizo mucor miehei lipase (RML) is an industrially important enzyme, but its application is limited due to its high cost. In this study, a series of measures such as codon optimization, propeptide addition, combined use of GAP and AOX1 promoters, and optimization of culture conditions were employed to increase the expression of RML. Three transformants of the constitutive-inducible combined Pichia pastoris strains were generated by transforming the pGAPZalphaA-rml vector into the pPIC9K-rml/GS115 strain, which resulted in high-expression yields of RML. Using the shake flask method, highest enzyme activity corresponding to 140 U/mL was observed in the strain 3-17, which was about sixfold higher than that of pPIC9K-rml/GS115 or pGAPZalphaA-rml/GS115. After optimization of culture conditions by response surface methodology, the lipolytic activity of strain 3-17 reached 175 U/mL in shake flasks. An increase in the copy number simultaneously with the synergistic effect provided by two promoters led to enhanced degree of protein expression. PMID- 26013735 TI - Simultaneous ion and neutral evaporation in aqueous nanodrops: experiment, theory, and molecular dynamics simulations. AB - We use a combination of tandem ion mobility spectrometry (IMS-IMS, with differential mobility analyzers), molecular dynamics (MD) simulations, and analytical models to examine both neutral solvent (H2O) and ion (solvated Na(+)) evaporation from aqueous sodium chloride nanodrops. For experiments, nanodrops were produced via electrospray ionization (ESI) of an aqueous sodium chloride solution. Two nanodrops were examined in MD simulations: a 2500 water molecule nanodrop with 68 Na(+) and 60 Cl(-) ions (an initial net charge of z = +8), and (2) a 1000 water molecule nanodrop with 65 Na(+) and 60 Cl(-) ions (an initial net charge of z = +5). Specifically, we used MD simulations to examine the validity of a model for the neutral evaporation rate incorporating both the Kelvin (surface curvature) and Thomson (electrostatic) influences, while both MD simulations and experimental measurements were compared to predictions of the ion evaporation rate equation of Labowsky et al. [Anal. Chim. Acta, 2000, 406, 105 118]. Within a single fit parameter, we find excellent agreement between simulated and modeled neutral evaporation rates for nanodrops with solute volume fractions below 0.30. Similarly, MD simulation inferred ion evaporation rates are in excellent agreement with predictions based on the Labowsky et al. equation. Measurements of the sizes and charge states of ESI generated NaCl clusters suggest that the charge states of these clusters are governed by ion evaporation, however, ion evaporation appears to have occurred with lower activation energies in experiments than was anticipated based on analytical calculations as well as MD simulations. Several possible reasons for this discrepancy are discussed. PMID- 26013736 TI - Feasibility study on the effectiveness of Goreisan-based Kampo therapy for lower abdominal lymphedema after retroperitoneal lymphadenectomy via extraperitoneal approach. AB - AIM: To evaluate the efficacy and safety of Kampo therapy based on Goreisan for lower abdominal lymphedema after surgical treatment of endometrial cancer or cervical cancer. METHODS: Radical surgery, including retroperitoneal lymphadenectomy, was performed for endometrial cancer and cervical cancer. After surgery, Kampo therapy based on Goreisan and integrated physical therapy were provided for patients with lower abdominal lymphedema, especially lymphedema affecting the pubic-inguinal-vulval region. Goreisan (7.5 g/day) was given orally three times a day (tds). If a significant response was not observed, Saireito (9 g/day; 3 g tds) or Gosyajinkigan (7.5 g/day; 2.5 g tds) was administered concomitantly. RESULTS: A total of 21 patients received treatment. The response rate to Goreisan monotherapy was 78%, with 22% being non-responders. Median reduction of abdominal circumference was 2.1cm (95% CI 1.3-2.85). When Goreisan was combined with another Kampo agent, the response rate was 92% and the non response rate was 8%. The median reduction of the abdominal circumference was 2.85 cm (95% CI: 2.25-3.3). In particular, concomitant Goreisan and Saireito therapy achieved satisfactory results. No severe adverse reactions occurred. CONCLUSIONS: Goreisan-based Kampo therapy might be effective and safe for lower abdominal lymphedema after retroperitoneal lymphadenectomy. We will perform a prospective control study in the near future. PMID- 26013737 TI - Stabilization of As-, Pb-, and Cu-contaminated soil using calcined oyster shells and steel slag. AB - In this study, As-, Pb-, and Cu-contaminated soil was stabilized using calcined oyster shells (COS) and steel slag (SS). The As-contaminated soil was obtained from a timber mill site where chromate copper arsenate (CCA) was used as a preservative. On the other hand, Pb- and Cu-contaminated soil was obtained from a firing range. These two soils were thoroughly mixed to represent As-, Pb-, and Cu contaminated soil. Calcined oyster shells were obtained by treating waste oyster shells at a high temperature using the calcination process. The effectiveness of stabilization was evaluated by 1-N HCl extraction for As and 0.1-N HCl extraction for Pb and Cu. The treatment results showed that As, Pb, and Cu leachability were significantly reduced upon the combination treatment of COS and SS. The sole treatment of SS (10 wt%) did not show effective stabilization. However, the combination treatment of COS and SS showed a significant reduction in As, Pb, and Cu leachability. The best stabilization results were obtained from the combination treatment of 15 wt% COS and 10 wt% SS. The SEM-EDX results suggested that the effective stabilization of As was most probably achieved by the formation of Ca-As and Fe-As precipitates. In the case of Pb and Cu, stabilization was most probably associated with the formation of pozzolanic reaction products such as CSHs and CAHs. PMID- 26013738 TI - Biodegradation of bisphenol A by an algal-bacterial system. AB - The degradation of bisphenol A (BPA) by Chlorella sorokiniana and BPA-degrading bacteria was investigated. The results show that BPA was partially removed by a monoculture of C. sorokiniana, but the remaining BPA accounted for 50.2, 56.1, and 60.5 % of the initial BPA concentrations of 10, 20, and 50 mg L(-1), respectively. The total algal BPA adsorption and accumulation were less than 1 %. C. sorokiniana-bacterial system effectively removed BPA with photosynthetic oxygen provided by the algae irrespective of the initial BPA concentration. The growth of C. sorokiniana in the algal system was inhibited by BPA concentrations of 20 and 50 mg L(-1), but not in the algal-bacterial system. This observation indicates that bacterial growth in the algal-bacterial system reduced the BPA inhibiting effect on algae. A total of ten BPA biodegradation intermediates were identified by GC-MS. The concentrations of the biodegradation intermediates decreased to a low level at the end of the experiment. The hypothetical carbon mass balance analysis showed that the amounts of oxygen demanded by the bacteria are insufficient for effective BPA degradation. However, adding an external carbon source could compensate for the oxygen shortage. This study demonstrates that the algal-bacterial system has the potential to remove BPA and its biodegradation intermediates. PMID- 26013739 TI - Effects of chitin and its derivatives on human cancer cells lines. AB - The present study is focused on the effect of chitin derivatives against human cancer cell lines RD and Hep2. As an outcome from this research, chitin was cytotoxic at IC50 = 400 MUg/ml and 200 MUg/ml against Hep2 cells and RD cells lines, respectively. Irradiated chitin had an IC50 value of 450 MUg/ml for Hep2 and an IC50 of 200 MUg/ml for RD. The lowest IC50 is attributed to chitosan, 300 MUg/ml in Hep2 and 190 MUg/ml in RD. PMID- 26013741 TI - Comment on "Performance of ANFIS versus MLP-NN dissolved oxygen prediction models in water quality monitoring A. Najah & A. El-Shafie & O. A. Karim & Amr H. El Shafie. Environ Sci Pollut Res (2014) 21:1658-1670". PMID- 26013740 TI - An integrated study on Gammarus elvirae (Crustacea, Amphipoda): perspectives for toxicology of arsenic-contaminated freshwater. AB - The Italian region Latium is characterized by extensive quaternary volcanic systems that contribute greatly to arsenic (As) contamination of freshwater, including drinking water supplies. However, knowledge of the possible toxic effects in these aquatic environments is, despite being highly relevant to public health, still limited. In this paper, we approach this issue using Gammarus elvirae, an amphipod species that inhabits rivers and streams in central Italy, including Latium. We explored the possibility of using G. elvirae in the toxicology of freshwater by addressing the most relevant issues. First, we tested the usefulness of hemocytes from G. elvirae in determining non-specific DNA damage by means of the Comet assay after exposure (24 h and 7 days) to different river water samples in Latium; second, we provided an interpretative overview of the usefulness of hepatopancreatic epithelial cells of G. elvirae as a means of assessing toxicity after long-term exposure to As and other pollutants; third, the LC (50-240 h) value for G. elvirae was estimated for arsenate, which is usually the dominant arsenic species in surface waters. Our study sheds light on G. elvirae at different levels, providing a background for future toxicological research of freshwater. PMID- 26013742 TI - Assessment of cytotoxicity and oxidative stress induced by titanium oxide nanoparticles on Chinook salmon cells. AB - Titanium oxide nanoparticles (TiO2 NPs) have received wide attention in diverse application, but the potential impact of these nanomaterials on the environment, aquatic life and especially on fish cell lines is lacking. The present study aimed to investigate the cytotoxicity and oxidative stress induced by TiO2 NPs on Chinook salmon cells derived from Oncorhynchus tshawytscha embryos (CHSE-214). The The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] and neutral red (NR) assays in CHSE-214 cells exposed to TiO2 NPs revealed concentration-dependent cytotoxic effect in the range of 10 to 60 MUg/ml for 24 h. CHSE-214 cells exposed to TiO2 NPs (10-60 MUg/ml) exhibited significant decline in superoxide dismutase (SOD), catalase (CAT) glutathione (GSH) content and increased lipid peroxidation (LPO) in a concentration-dependent manner. TiO2 NPs induced cytotoxicity and oxidative stress in CHSE-214 cells which serve as a base line studies for future studies. PMID- 26013743 TI - Phytoremediation of cadmium by the facultative halophyte plant Bolboschoenus maritimus (L.) Palla, at different salinities. AB - The cadmium phytoremediation capacity of the halophyte plant Bolboschoenus maritimus (L.) Palla and the influence of water salinity were assessed in a greenhouse experiment, in order to better understand the bioremediation capacity of this plant. Three concentrations of cadmium (0, 50 and 100 MUg l(-1)) and four salinity conditions (0, 5, 10 and 20) were chosen to evaluate the cadmium accumulation, in order to test these plants as a potential phytoremediation tool in brackish environments. The cadmium content in water and plants (underground organs, stems and leaves) was analysed with graphite furnace atomic absorption spectrometry. All the plants submitted to salinity 20 and in the three cadmium treatments died. The plants' survival was highest in the lowest salinities, where highest growth and biomasses were also obtained. The plants presented more cadmium content in the rhizomes, followed by stems and even less in leaves. The salt stress of the plants interfered with their cadmium accumulation capacity. The highest cadmium accumulation in the rhizomes occurred at salinity 0, while the salinities 0 and 5 were the most adequate for stems and leaves. The experiment pointed out that B. maritimus represents a good possible intervenient for cadmium bioremediation in freshwater and low salinity brackish water environments, but its use is limited in the habitats of higher salinity. PMID- 26013744 TI - Ozonation and ultrafiltration for the treatment of olive mill wastewaters: effect of key operating conditions and integration schemes. AB - With the objective of reaching suitable techniques for olive mill wastewater treatment, ozonation and ultrafiltration were studied individually and combined. A continuous reactor was run for the treatment of a phenolic mixture mimicking an actual olive mill wastewater (OMW) by ozonation. The effect of the main operating parameters was analysed (pH, liquid flow rate and ozone inlet concentration). The increase of pH and ozone dose improved ozonation efficiency. As expected, the highest residence time led to higher steady-state degradation (35 % of chemical oxygen demand (COD) abatement). Even if the rise on ozone inlet gas concentration was able to remove COD in a higher extent, it should be taken into consideration that with the lowest oxidant load (15 g O3/m(3)), the maximum steady-state biochemical oxygen demand (BOD5)/COD ratio was reached which would reduce the process costs. These operating conditions (pH 9, 1 mL/min of liquid flow rate and 15 g O3/m(3)) were applied to an actual OMW leading to 80 % of phenolic content abatement and 12 % of COD removal at the steady state. Regarding ultrafiltration, it was concluded that the best total phenolic content (TPh) and COD abatement results (55 and 15 %) are attained for pH 9 and using a transmembrane pressure drop of 1 bar. Among the integration schemes that were tested, ultrafiltration followed by ozonation was able to reach 93 and 20 % of TPh and COD depletion, respectively. Moreover, this sequence led to an effluent with a BOD5/COD ratio of about 0.55 which means that it likely can be posteriorly refined in a municipal wastewater treatment plant. PMID- 26013745 TI - Supracricoid laryngectomy and dysphagia: A systematic literature review. AB - OBJECTIVES/HYPOTHESIS: Perform a systematic literature search to provide an overview of today's literature regarding the different aspects that can cause dysphagia after supracricoid laryngectomy. STUDY DESIGN: A systematic literature review. REVIEW METHODS: The inclusion criteria were laryngeal cancer, supracricoid laryngectomy, and swallowing. Thirty-one qualifying articles were included and analyzed describing swallowing after supracricoid laryngectomy. RESULTS: Included studies examined the incidence of dysphagia and discussed various factors that will or will not contribute to dysphagia after supracricoid laryngectomy, type of reconstruction, swallow training, radiation, arytenoid cartilage resection, extended procedures, and age. CONCLUSION: A high incidence of dysphagia was reported after supracricoid laryngectomy. However, good recovery rates were observed with low incidence of severe complications. The included studies used different methods and standards to start oral intake, remove the nasogastric feeding tube, and observe swallow function. Homogenous study population and standardized guidelines on how to handle the pre- and postoperative course after supracricoid laryngectomy and how to measure swallow function could improve further research. PMID- 26013747 TI - Medical Toxicology Education in a World of Limited Resources. PMID- 26013748 TI - Clinical outcomes following bioresorbable scaffold implantation for bifurcation lesions: Overall outcomes and comparison between provisional and planned double stenting strategy. AB - The aim of this study was to investigate clinical outcomes of patients treated with a provisional stenting (PS) versus a double stenting (DS) strategy for coronary bifurcation lesions with bioresorbable scaffolds (BRS). There are limited data available with regards to outcomes following BRS implantation for bifurcation lesions. A total of 132 bifurcation lesions treated with BRS between 2012 and 2014 were analyzed. Of the total of 132 bifurcation lesions, 10 lesions were treated without crossover stenting. 99 lesions (81%) were treated with a PS strategy and 23 lesions (19%) with a DS strategy. The DS group consisted of patients with a greater number of true bifurcation lesions (PS 52.0% vs. DS 91.3%: P < 0.001). In the PS group, seven lesions (7.1%) were crossed-over to T stenting. In the DS group, 13 lesions (57%) were treated with BRS to the side branch (SB). A hybrid stenting technique [BRS to the main branch, and metallic drug-eluting stent (DES) to the SB] was utilized in 10 (43%) lesions. Target lesion revascularization (TLR) rates were 5.5% for PS and 11.2% for DS (P = 0.49) at 1-year follow-up. Definite scaffold thrombosis did not occur at the site of any bifurcation lesion. These findings suggest that BRS implantation for bifurcation lesions is technically feasible. The rates of TLR tended to be higher in the DS group compared to when a PS strategy was employed. Larger studies are eagerly awaited to determine longer-term follow-up of this treatment strategy. PMID- 26013749 TI - Erratum to: Glutaric Acidemia Type 1-Clinico-Molecular Profile and Novel Mutations in GCDH Gene in Indian Patients. PMID- 26013746 TI - Extracorporeal Membrane Oxygenation (ECMO) for Severe Toxicological Exposures: Review of the Toxicology Investigators Consortium (ToxIC). AB - Although there have been many developments related to specific strategies for treating patients after poisoning exposures, the mainstay of therapy remains symptomatic and supportive care. One of the most aggressive supportive modalities is extracorporeal membrane oxygenation (ECMO). Our goal was to describe the use of ECMO for toxicological exposures reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC). We performed a retrospective review of the ACMT ToxIC Registry from January 1, 2010 to December 31, 2013. Inclusion criteria included patients aged 0 to 89 years, evaluated between January 2010 through December 2013, and received ECMO for toxicological exposure. There were 26,271 exposures (60 % female) reported to the ToxIC Registry, 10 (0.0004 %) received ECMO: 4 pediatric (< 12 years), 2 adolescent (12 18 years), and 4 adults (>18 years). Time of initiation of ECMO ranged from 4 h to 4 days, with duration from 15 h to 12 days. Exposures included carbon monoxide/smoke inhalation (2), bitter almonds, methanol, and several medications including antihistamines (2), antipsychotic/antidepressant (2), cardiovascular drugs (2), analgesics (2), sedative/hypnotics (2), and antidiabetics (2). Four ECMO patients received cardiopulmonary resuscitation (CPR) during their hospital course, and the overall survival rate was 80 %. ECMO was rarely used for poisoning exposures in the ACMT ToxIC Registry. ECMO was utilized for a variety of ages and for pharmaceutical and non-pharmaceutical exposures. In most cases, ECMO was administered prior to cardiovascular failure, and survival rate was high. If available, ECMO may be a valid treatment modality. PMID- 26013750 TI - Re-thinking prevention and treatment of travelers' diarrhea--Time for a change? PMID- 26013751 TI - Dissemination of 'misleading' information on social media during the 2014 Ebola epidemic: An area of concern. PMID- 26013757 TI - Optimal duration of dual antiplatelet therapy after drug eluting stent remains unclear. PMID- 26013759 TI - From the N-Heterocyclic Carbene-Catalyzed Conjugate Addition of Alcohols to the Controlled Polymerization of (Meth)acrylates. AB - Among various N-heterocyclic carbenes (NHCs) tested, only 1,3-bis(tert butyl)imidazol-2-ylidene (NHC(tBu) ) proved to selectively promote the catalytic conjugate addition of alcohols onto (meth)acrylate substrates. This rather rare example of NHC-catalyzed 1,4-addition of alcohols was investigated as a simple means to trigger the polymerization of both methyl methacrylate and methyl acrylate (MMA and MA, respectively). Well-defined alpha-alkoxy poly(methyl (meth)acrylate) (PM(M)A) chains, the molar masses of which could be controlled by the initial [(meth)acrylate]0/[ROH]0 molar ratio, were ultimately obtained in N,N dimethylformamide at 25 degrees C. A hydroxyl-terminated poly(ethylene oxide) (PEO-OH) macro-initiator was also employed to directly access PEO-b-PMMA amphiphilic block copolymers. Investigations into the reaction mechanism by DFT calculations revealed the occurrence of two competitive concerted pathways, involving either the activation of the alcohol or that of the monomer by NHC(tBu) . PMID- 26013758 TI - Intradiscal application of rhBMP-7 does not induce regeneration in a canine model of spontaneous intervertebral disc degeneration. AB - INTRODUCTION: Strategies for biological repair and regeneration of the intervertebral disc (IVD) by cell and tissue engineering are promising, but few have made it into a clinical setting. Recombinant human bone morphogenetic protein 7 (rhBMP-7) has been shown to stimulate matrix production by IVD cells in vitro and in vivo in animal models of induced IVD degeneration. The aim of this study was to determine the most effective dose of an intradiscal injection of rhBMP-7 in a spontaneous canine IVD degeneration model for translation into clinical application for patients with low back pain. METHODS: Canine nucleus pulposus cells (NPCs) were cultured with rhBMP-7 to assess the anabolic effect of rhBMP-7 in vitro, and samples were evaluated for glycosaminoglycan (GAG) and DNA content, histology, and matrix-related gene expression. Three different dosages of rhBMP-7 (2.5 MUg, 25 MUg, and 250 MUg) were injected in vivo into early degenerated IVDs of canines, which were followed up for six months by magnetic resonance imaging (T2-weighted images, T1rho and T2 maps). Post-mortem, the effects of rhBMP-7 were determined by radiography, computed tomography, and macroscopy, and by histological, biochemical (GAG, DNA, and collagen), and biomolecular analyses of IVD tissue. RESULTS: In vitro, rhBMP-7 stimulated matrix production of canine NPCs as GAG deposition was enhanced, DNA content was maintained, and gene expression levels of ACAN and COL2A1 were significantly upregulated. Despite the wide dose range of rhBMP-7 (2.5 to 250 MUg) administered in vivo, no regenerative effects were observed at the IVD level. Instead, extensive extradiscal bone formation was noticed after intradiscal injection of 25 MUg and 250 MUg of rhBMP-7. CONCLUSIONS: An intradiscal bolus injection of 2.5 MUg, 25 MUg, and 250 MUg rhBMP-7 showed no regenerative effects in a spontaneous canine IVD degeneration model. In contrast, intradiscal injection of 250 MUg rhBMP-7, and to a lesser extent 25 MUg rhBMP-7, resulted in extensive extradiscal bone formation, indicating that a bolus injection of rhBMP-7 alone cannot be used for treatment of IVD degeneration in human or canine patients. PMID- 26013760 TI - Type 2 Diabetes: Progress Made but Still a Long Road to Travel to Reduce Disease Burden. PMID- 26013761 TI - The two-step assemblies of basic-amino-Acid-rich Peptide with a highly charged polyoxometalate. AB - Two-step assembly of a peptide from HPV16 L1 with a highly charged europium substituted polyoxometalate (POM) cluster, accompanying a great luminescence enhancement of the inorganic polyanions, is reported. The mechanism is discussed in detail by analyzing the thermodynamic parameters from isothermal titration calorimetry (ITC), time-resolved fluorescent and NMR spectra. By comparing the actions of the peptide analogues, a binding process and model are proposed accordingly. The driving forces in each binding step are clarified, and the initial POM aggregation, basic-sequence and hydrophobic C termini of peptide are revealed to contribute essentially to the two-step assembly. The present study demonstrates both a meaningful preparation for bioinorganic materials and a strategy using POMs to modulate the assembly of peptides and even proteins, which could be extended to other proteins and/or viruses by using peptides and POMs with similar properties. PMID- 26013762 TI - Topical application of LEVORAG(r) as first-line treatment for chronic anal fissures: a preliminary multicentric study. AB - AIM: The aim of the present study was to assess the safety and efficacy of this new topical agent as a first line treatment in patients with chronic anal fissures. METHODS: Nine centres were involved in the study. Patients with chronic anal fissures were recruited and received Levorag(r) for 40 days. Follow-up visits were conducted at 10, 20 and 40 days from the recruitment. Primary outcome was the healing rate, secondary outcome the reduction of pain at the end of the treatment measured with a VAS scale. RESULTS: Fifty patients completed the treatment. No adverse events were recorded. 60% of patients healed completely at the end of the treatment. In those that did not heal the reduction of mean VAS values was 60%. CONCLUSION: The use of Levorag(r) on patients affected by chronic anal fissures achieved in the short term results similar to those experienced by more classic local treatments without any side effect. PMID- 26013763 TI - Bevacizumab in combination with first-line chemotherapy in patients with metastatic colorectal cancer: a meta-analysis. AB - Bevacizumab plays an important role in the treatment of patients with metastatic colorectal cancer (mCRC). The aim of this study is to assemble current RCTs to analyze efficacy of adding bevacizumab to the most used combination first-line chemotherapy in mCRC patients. PubMed, Web of Science, the Cochrane Library and Embase were systematically searched. Our primary endpoint was overall survival (OS), progression-free survival (PFS) and secondary endpoint was overall response rate (ORR). Hazard ratios (HRs) for PFS and OS and risk ratio (RR) for ORR were extracted from each trial. All these above were performed using a random-effects model and statistics was performed in StataSE 12.0. Seven randomized controlled studies aggregating 3264 patients were enrolled in our meta-analysis. OS, PFS and ORR were performed using a random-effects model. A therapeutic effect advantage was showed in Bevacizumab added to first-line chemotherapy with higher OS (HR=0.67; 95% CI=0.61-0.72; P=0.000), PFS (HR=0.67; 95% CI=0.61-0.72; P=0.000) compared with chemotherapy alone. Chemotherapy plus bevacizumab increased ORR (38.42% vs. 33.44%), showing statistically difference (RR=1.17, 95% CI=1.06-1.28, P=0.001). Our meta-analysis shows that the addition of bevacizumab to first-line regimens can be beneficial in terms of OS, PFS and ORR compared with chemotherapy alone. PMID- 26013765 TI - A detailed report of the resource use and costs associated with implementation of a short stay programme for breast cancer surgery. AB - BACKGROUND: Despite the increased attention for assessing the effectiveness of implementation strategies, most implementation studies provide little or no information on its associated costs. The focus of the current study was to provide a detailed report of the resource use and costs associated with implementation of a short stay programme for breast cancer surgery in four Dutch hospitals. METHODS: The analysis was performed alongside a multi-centre implementation study. The process of identification, measurement and valuation of the implementation activities was based on recommendations for the design, analysis and reporting of health technology assessments. A scoring form was developed to prospectively determine the implementation activities at professional and implementation expert level. A time horizon of 5 years was used to calculate the implementation costs per patient. RESULTS: Identified activities were consisted of development and execution of the implementation strategy during the implementation project. Total implementation costs over the four hospitals were ?83.293. Mean implementation costs, calculated for 660 patients treated over a period of 5 years, were ?25 per patient. Subgroup analyses showed that the implementation costs ranged from ?3.942 to ?32.000 on hospital level. From a local hospital perspective, overall implementation costs were ?21 per patient, after exclusion of the costs made by the expert centre. CONCLUSIONS: We provided a detailed case description of how implementation costs can be determined. Notable differences in implementation costs between hospitals were observed. TRIAL REGISTRATION: ISRCTN: ISRCTN77253391. PMID- 26013764 TI - Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. AB - Human PIWI-interacting RNAs (piRNAs) are known to be expressed in germline cells, functionally silencing LINEs and SINEs. Their expression patterns in somatic tissues are largely uncharted. We analyzed 6,260 human piRNA transcriptomes derived from non-malignant and tumour tissues from 11 organs. We discovered that only 273 of the 20,831 known piRNAs are expressed in somatic non-malignant tissues. However, expression patterns of these piRNAs were able to distinguish tissue-of-origin. A total of 522 piRNAs are expressed in corresponding tumour tissues, largely distinguishing tumour from non-malignant tissues in a cancer type specific manner. Most expressed piRNAs mapped to known transcripts, contrary to "piRNA clusters" reported in germline cells. We showed that piRNA expression can delineate clinical features, such as histological subgroups, disease stages, and survival. PiRNAs common to many cancer types might represent a core gene-set that facilitates cancer growth, while piRNAs unique to individual cancer types likely contribute to cancer-specific biology. PMID- 26013767 TI - Predictive value of neutrophil to lymphocyte ratio in first-time and recurrent idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: To determine if the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients with recurrent idiopathic sudden sensorineural hearing loss (ISSNHL) differ from those in healthy people and non recurrent ISSNHL patients. METHODS: A retrospective review of 16 patients with recurrent ISSNHL was performed with strict exclusion criteria. Independent variables were NLR and PLR, which yielded four groups (control, non-recurrent, recurrent-first attack, and recurrent-second attack groups). RESULTS: Compared with the control group, non-recurrent and recurrent attack groups showed significantly higher NLR values (p<0.001, respectively). The NLR (odds ratio [OR] 2.178, 95% confidence interval [CI] 1.587-2.988; p<0.001) and PLR (OR, 1.013, 95% CI, 1.006-1.020; p<0.001) were found to be independent risk factors only between the control and recurrent-first attack groups. CONCLUSION: Evidence of increased NLR and PLR is shown in recurrent ISSNHL and non-recurrent ISSNHL, and these increased levels are shown in the second attack of recurrent ISSNHL. Clinicians are advised to monitor the NLR and PLR at the clinic to predict recurrent ISSNHL even after hearing is restored. PMID- 26013766 TI - Use of carbon monoxide and hydrogen by a bacteria-animal symbiosis from seagrass sediments. AB - The gutless marine worm Olavius algarvensis lives in symbiosis with chemosynthetic bacteria that provide nutrition by fixing carbon dioxide (CO2 ) into biomass using reduced sulfur compounds as energy sources. A recent metaproteomic analysis of the O. algarvensis symbiosis indicated that carbon monoxide (CO) and hydrogen (H2 ) might also be used as energy sources. We provide direct evidence that the O. algarvensis symbiosis consumes CO and H2 . Single cell imaging using nanoscale secondary ion mass spectrometry revealed that one of the symbionts, the gamma3-symbiont, uses the energy from CO oxidation to fix CO2 . Pore water analysis revealed considerable in-situ concentrations of CO and H2 in the O. algarvensis environment, Mediterranean seagrass sediments. Pore water H2 concentrations (89-2147 nM) were up to two orders of magnitude higher than in seawater, and up to 36-fold higher than previously known from shallow-water marine sediments. Pore water CO concentrations (17-51 nM) were twice as high as in the overlying seawater (no literature data from other shallow-water sediments are available for comparison). Ex-situ incubation experiments showed that dead seagrass rhizomes produced large amounts of CO. CO production from decaying plant material could thus be a significant energy source for microbial primary production in seagrass sediments. PMID- 26013772 TI - Melanoidin Removal Mechanism in An Aqueous Adsorption System: An Equilibrium, Kinetic and Thermodynamic Study. AB - Melanoidins are colored products that can be found in food and drinks, formed by Maillard reactions. Sometimes these compounds are considered undesirable in certain food products, because they impart a brownish color and must be removed. An overview of recent patents related to melanoidin removal indicates that it can be performed by chemical/biological degradation or by adsorption processes. Therefore, in the present study, the adsorption mechanism for synthetic melanoidin removal from aqueous solutions was studied using different Raphanus sativus press-cake sorbents, with the precursor material being carbonized in a microwave oven, either with direct heating or after a chemical activation process with phosphoric acid, nitric acid or potassium hydroxide. Physical and chemical modifications were evaluated by FTIR, pHPZC, thermogravimetry and BET. The adsorption kinetics was better described by a pseudo-second order model for all activated carbons (ACs). Evaluation of the diffusion process showed dependence on the initial melanoidin concentration due to the wide range of sizes of the adsorbed molecules. The equilibrium data were best fitted by the Langmuir model for the acid-treated AC and by the Freundlich model for the base-treated and non chemically treated ACs. Melanoidin adsorption was characterized as a spontaneous, favorable and endothermic process involving hydrogen bonds and pi-pi interactions between the adsorbents surfaces and the adsorbed molecules. PMID- 26013771 TI - Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization. AB - BACKGROUND: Interphase chromosomes adopt a hierarchical structure, and recent data have characterized their chromatin organization at very different scales, from sub-genic regions associated with DNA-binding proteins at the order of tens or hundreds of bases, through larger regions with active or repressed chromatin states, up to multi-megabase-scale domains associated with nuclear positioning, replication timing and other qualities. However, we have lacked detailed, quantitative models to understand the interactions between these different strata. RESULTS: Here we collate large collections of matched locus-level chromatin features and Hi-C interaction data, representing higher-order organization, across three human cell types. We use quantitative modeling approaches to assess whether locus-level features are sufficient to explain higher-order structure, and identify the most influential underlying features. We identify structurally variable domains between cell types and examine the underlying features to discover a general association with cell-type-specific enhancer activity. We also identify the most prominent features marking the boundaries of two types of higher-order domains at different scales: topologically associating domains and nuclear compartments. We find parallel enrichments of particular chromatin features for both types, including features associated with active promoters and the architectural proteins CTCF and YY1. CONCLUSIONS: We show that integrative modeling of large chromatin dataset collections using random forests can generate useful insights into chromosome structure. The models produced recapitulate known biological features of the cell types involved, allow exploration of the antecedents of higher-order structures and generate testable hypotheses for further experimental studies. PMID- 26013768 TI - Comparison of cumulative false-positive risk of screening mammography in the United States and Denmark. AB - INTRODUCTION: In the United States (US), about one-half of women screened with annual mammography have at least one false-positive test after ten screens. The estimate for European women screened ten times biennially is much lower. We evaluate to what extent screening interval, mammogram type, and statistical methods, can explain the reported differences. METHODS: We included all screens from women first screened at age 50-69 years in the US Breast Cancer Surveillance Consortium (BCSC) (n=99,455) between 1996-2010, and from two population-based mammography screening programs in Denmark (n=230,452 and n=400,204), between 1991 2012 and 1993-2013, respectively. Model-based cumulative false-positive risks were computed for the entire sample, using two statistical methods (Hubbard Njor) previously used to estimate false-positive risks in the US and Europe. RESULTS: Empirical cumulative risk of at least one false-positive test after eight (annual or biennial) screens was 41.9% in BCSC, 16.1% in Copenhagen, and 7.4% in Funen. Variation in screening interval and mammogram type did not explain the differences by country. Using the Hubbard method, the model-based cumulative risks after eight screens was 45.1% in BCSC, 9.6% in Copenhagen, and 8.8% in Funen. Using the Njor method, these risks were estimated to be 43.6, 10.9 and 8.0%. CONCLUSION: Choice of statistical method, screening interval and mammogram type does not explain the substantial differences in cumulative false-positive risk between the US and Europe. PMID- 26013770 TI - Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide induced acute kidney injury. AB - Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 MUg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3 pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes. PMID- 26013773 TI - The Impact of Waiting Time on Health Gains from Surgery: Evidence from a National Patient-reported Outcome Dataset. AB - Reducing waiting times has been a major focus of the English National Health Service for many years, but little is known about the impact on health outcomes. The collection of data on patient-reported outcome measures for all patients undergoing four large-volume procedures facilitates analysis of the impact of waiting times on patient outcomes. The availability of patient-reported outcome measures before and after surgery allows us to estimate the impact of waiting times on the effectiveness of treatment, controlling for pre-surgery health and the endogeneity of waiting times caused by prioritisation with respect to pre intervention health. We find that waiting time has a negative and statistically significant impact on the health gain from hip and knee replacement surgery and no impact on the effectiveness of varicose vein and hernia surgery. The magnitude of this effect at patient level is small, 0.1% of the outcome measure range for each additional week of waiting. However, the value of this effect is substantially larger than existing estimates of the disutility experienced during the waiting period. The health losses associated with an additional week of waiting for annual populations of hip and knee replacement patients are worth L11.1m and L11.5m, respectively. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26013775 TI - Diabetes care in Ramadan: An exemplar of person centered care. PMID- 26013774 TI - A Versatile Room-Temperature Route to Di- and Trisubstituted Allenes Using Flow Generated Diazo Compounds. AB - A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups. PMID- 26013776 TI - Basic rules of Ramadan: A medico-religious perspective. AB - Fasting during the month of Ramadan is obligatory for all adult Muslims with few exceptions. The person observing a fast does not eat, drink, and smoke from dawn to dusk. Google and Medline search was undertaken for the articles related to basic rules of fasting-religious and medical perspectives in the previous 24 years using following key words: Islamic fasting, fasting and diabetes, fasting and endocrine system. There are clear cut guidelines regarding fasting in healthy people and exemptions have been emphasized. Some alterations in pulmonary, cardiac, gastrointestinal and neuropsychiatric systems are observed which do not harm a normal person. A risk strategy has been devised for people with diabetes regarding management during Ramadan fasting. Rules regarding adherence to fasting and concessions during the month of Ramadan are clear. Minor alterations in different body systems are observed in normal people during Ramadan. PMID- 26013777 TI - Risk stratification of Ramadan fasting in person with diabetes. AB - The world population comprises of 23% Muslims. Ramadan is the holy month of the Islamic year during which all healthy Muslims observe fasts. Although children and sick people are exempted from fasting but many of this group, want to observe fasts despite the medical advice against it. This includes a subset of people with diabetes which carries a considerable risk. Hypoglycaemia and hyperglycaemia are among the main hazards. Majority of Muslims with diabetes can fast safely during Ramadan; However some are placed at a greater risk. Pre-Ramadan risk assessment, structured education and selection of appropriate medication has shown to minimize the risks associated with fasting among people with diabetes. PMID- 26013778 TI - Fasting Ramadan in diabetic patients: When is fasting not advisable in a person with diabetes? AB - Ramadan Fasting is one of the five pillars of Islam, but there is a clear exemption in holy Qur'an for those who are temporarily or permanently ill. Diabetes Mellitus is one of the most prevalent chronic illnesses globally; it is associated with metabolic risks that might be augmented with fasting. In spite of this risk many Muslims prefer to fast considering not fasting is a great sin and shameful. Defining the situations when fasting is not advisable in a diabetic patient is an important issue which has to be clearly determined on bases of solid evidence whenever possible. The recommendations have to be agreed between experts of physicians and Islamic Religion scientists. The advances in diabetes management necessitate continuous updating of the recommendations to match with Islamic legitimacy. The role of healthcare providers is neither recommending nor preventing a patient from fasting, their role is just to explore risks and provide medical advice for safe fasting. This review summarizes previous trials for risk stratifications and recommendations for fasting in diabetic patients. PMID- 26013780 TI - Ramadan Fasting in people with Diabetes. PMID- 26013779 TI - Should Type 1 diabetics fast in Ramadan. AB - Fasting during the holy month of Ramadan is obligatory for all healthy adult and adolescent Muslims from the age of 12 years. This involves abstaining from eating or drinking from early dawn (Suhur/Sehri) till sunset (Iftar).Fasting is not meant to create excessive hardships or impart any adverse effect to the Muslim individual. As such, Islam has exempted certain categories of people from fasting including young children, travelers, the sick, the elderly,and pregnant and lactating women. According to expert opinion, people with type 1 diabetes who fast during Ramadan are at very high risk of metabolic deterioration. However, some recent studies have demonstrated that individuals with type 1 diabetes who are otherwise healthy and stable, can fast during Ramadan provided they comply with the Ramadan focused management plan and are under close professional supervision. This article discusses how to assess, counsel, monitor and manage people with type 1 diabetes who wish to fast during Ramadan. PMID- 26013781 TI - Pregnancy and fasting in women with diabetes mellitus. AB - Fasting during the Holy month of Ramadan is one of the obligatory prayer for all normal healthy Muslims. There are a few special situations as pregnant and breastfeeding women, who are exempted from fasting. Different surveys observed that 70-90% pregnant women prefer not to accept this fiqh. A complex series of metabolic and hormonal changes occur in pregnancy and this is augmented from fed to starvation stage during fasting from dawn to sunset. Adaptive metabolism is established by balance of insulin and other counter- regulatory hormones. This adaptive metabolism is decompensated by relative or absolute lack of insulin and exaggerated insulin resistance (IR) on preexisting defect altered by foeto placental hormones. Thus in both fasting and fed states high blood glucose, triglycerides, free fatty acids and ketones are encountered. Unregulated fat catabolism with increased FFA and ketones can alter embryonic and foetal development. There is no definite consensus guideline on how to manage blood glucose during fasting in pregnant women with diabetes. Most authors advocate insulin therapy to manage diabetes. Pregnant women with diabetes who wish to fast during Ramadan must be aware of symptoms and signs of foetal and maternal distress, and must terminate the fast if these occur. More practical approach, with empathy, might be helpful instead of imposing absolute ban on fasting in women with pregnancy and diabetes. PMID- 26013782 TI - Diabetes mellitus and Ramadan in elderly patients. AB - Worldwide, the proportion of people above 60 years old represents 15% of the whole population. Diabetes mellitus is more frequent in this age group, and is associated with increased risk of morbidities and premature mortality. Aged Muslim people with diabetes insist on fasting during Ramadan, for many reasons. Elderly people, especially frail patients, who fast are at increased risk for many complications such as hypoglycaemia, hyperglycaemia and metabolic decompensation including hyperosmolar coma, diabetic ketoacidosis, dehydration and thrombosis. Therefore it is important to assess functional capacity, cognition, mental health and comorbidities in elderly people with diabetes in order to evaluate the risk of fasting, individualize the therapy, and adapt care to their needs. PMID- 26013783 TI - Oral anti-diabetics in Ramadan. AB - A large proportion of Muslim patients with type 2 diabetes fast during the month of Ramadan worldwide. Hypoglycaemia is one of the major complications associated with long periods without food during the fasting hours. There is also a risk of hyperglycaemia due to over indulgence in food during the two main meals of Suhur and Iftar. Healthcare providers need to be cognizant of the risk of fasting and be competent to provide Ramadan adjusted diabetes care particularly adjustment of oral anti diabetics. This review article has taken into consideration observational studies, randomized trial data, pathophysiology and practical experience in recommending adjustment in oral anti-diabetics during fasting in type-2 diabetics. Metformin and Thiazolidinediones (TZD'S) being insulin sensitizers need minimum adjustment with low risk of hypoglycaemia. Older generation Sulphonylureas (SU) pose a high risk of hypoglycaemia but the newer generations of Sulphonylureas have a reasonable safety profile. Alpha- Glucosidase inhibitors are safe during fasting but their use is limited due to the side effects. PMID- 26013784 TI - Newer antidiabetic drugs in Ramadan. AB - The management of diabetes in the month of Ramadan can be very challenging. On one hand there is the issue of fasting associated hypoglycaemia, and on the other, fasting as well as post prandial hyperglycaemia. Under such circumstances, a planned regimen needs to be followed to keep the blood glucose levels under control. The same oral antidiabetic agents that were used prior to the fast are used during Ramadan with modification in dosage and timing. With the advent of newer anti-diabetic agents, there is a good scope for better control and reduced complications. PMID- 26013785 TI - Insulin in ramadan. AB - Many people with diabetes, both type 1 and type 2, require insulin for maintainance of glycaemic control and health. Most of these people can observe the Ramadan fast, provided appropriate dosage adjustments are made, and basic rules of safety followed. This article describes modifications and precautions that are needed while prescribing insulin during Ramadan. PMID- 26013786 TI - Fasting in Ramadan with an insulin pump. AB - A good majority of subjects with diabetes on insulin therapies observe fasting during Ramadan. The challenge for the physician and the patient is to manage diabetes without an interruption to fasting by avoiding hypoglycaemia and simultaneously ensuring that blood glucose remain at acceptable safe levels. Insulin Pumps differ from syringes and insulin pens in that it offers a variable basal rate, different type of boluses and associated calculators. The technological advances that pumps offer, help educated subjects pre-programme a reduced basal rate throughout the day. Pumps ensure avoidance of hypoglycaemia and hyperglycaemia and preserve quality of life and enhance confidence in patients during fasting. Due to multiple benefits, insulin pumps are considered the best delivery systems for insulin during the holy month of Ramadan, despite the prerequisites for its optimal output and cost concerns. PMID- 26013788 TI - Glucose monitoring during Ramadan. AB - In patients with diabetes who intend to fast during Ramadan, self-monitoring of blood glucose (SMBG) is an important tool. During this month, a long established treatment regimen, including medications, physical activity and diet plan, is changed to achieve concordance with the rules of fasting. Without proper glucose monitoring, it is not possible to achieve good glycaemic control. PMID- 26013789 TI - Weight management in Ramadan. AB - Ramadan fasting is associated with significant weight loss in both men and women. Reduction in blood pressure, lipids, blood glucose, body mass index and waist and hip circumference may also occur. However, benefits accrued during this month often reverse within a few weeks of cessation of fasting, with most people returning back to their pre-Ramadan body weights and body composition. To ensure maintenance of this fasting induced weight loss, health care professionals should encourage continuation of healthy dietary habits, moderate physical activity and behaviour modification, even after conclusion of fasting. It should be realized that Ramadan is an ideal platform to target year long lifestyle modification, to ensure that whatever health care benefits have been gained during this month, are perpetuated. PMID- 26013787 TI - Ramadan and diabetes mellitus. PMID- 26013790 TI - Lipid management in ramadan. AB - During Ramadan fast, Muslims must refrain from smoking, eating, drinking, having sexual activity, and consuming oral medications from sunrise to sunset. It has been previously shown that Ramadan fasting induces favourable changes on metabolic parameters, reduces oxidative stress and inflammation and promotes cardiovascular benefits. Although ill people are exempted from fasting, most patients with chronic diseases are keen on performing this Islamic-ritual. During recent years, Risk stratification and treatment adjustment during Ramadan are well known and structured in several guidelines for patients with diabetes mellitus. Data related to the effect of Ramadan fast on lipid profiles are less known and several controversies have been reported. Here, we focus on lipid profile and lipid management during Ramadan taking into account comorbidities and cardiovascular risk. PMID- 26013791 TI - Physiological changes during fasting in Ramadan. AB - Fasting during Ramadan is one of the five fundamental pillars of Islam and mandatory for all healthy adult Muslims to fast from sunrise to sunset for a period of a month. During fasting, Muslims are required to refrain from all intakes of food, water, beverages, smoking and from sexual intercourse. Ramadan fasting causes many physiological, biochemical, metabolic and spiritual changes in the body. Ramadan Fasting increases the Red Blood Cells (RBCs), White Blood Cells (WBCs), platelet (PLT) count, High Density Lipoprotein Cholesterol (HDL-c), and decreases the blood cholesterol, triglycerides, Low Density Lipoprotein Cholesterol (LDL-c) and Very Low Density Lipoprotein Cholesterol (VLDL-c). Moreover, it reduces body weight, waist circumference, body mass index, body fat, blood glucose, systolic and diastolic blood pressure and anxiety levels. Furthermore, Ramadan fasting decreases the inflammation, pro-inflammatory cytokines IL-1b, IL-6, tumour necrosis factor a and cancer promotion. Among healthy adults, there are no adverse effects of Ramadan fasting on the brain, heart, lung, liver, kidney, haematologic, endocrine profile and cognitive functions. Ramadan fasting is a healthy non pharmacological means for minimizing the risk factors and improving health. Although Ramadan fasting is safe for all healthy individuals, but those with various illnesses such as diabetes mellitus, coronary artery disease, renal and eye illness should consult their physicians and firmly follow the scientific recommendations. PMID- 26013792 TI - Coronary artery disease and diabetes - Management during Ramadan. AB - Ramadan is the Islamic holy month of fasting and practiced by all adult Muslims all over the world at the same time simultaneously. Although people who are ill or diabetics with coronary heart disease are exempted from fasting, they still desire to fast and this is a challenge to themselves and the treating physician. We performed a systematic review of the available Medline English literature on the subject from January 1982 to December 2014 so as to help guide physicians in managing these patients. The results revealed that although the metabolic parameters change during Ramadan fasting, but this does not lead to any significant increase in the incidence of acute coronary events. Most adults with stable coronary artery disease can fast without significant complications, but those with unstable disease or recent or pending revascularization procedures should generally refrain from fasting. Regular monitoring by the physician is mandatory along with adjustment of the dosages. PMID- 26013793 TI - How to avoid infections in Ramadan, especially urinary tract infections. AB - Prolonged and poor control of diabetes has detrimental effects on the immune system by reducing both B and T cell function, causing neutrophilic dysfunction and less production of inflammatory cytokines. This makes people with diabetes vulnerable to various bacterial, viral and fungal infections in all body organs. The commonest cause of chronic renal disease is uncontrolled diabetes, placing patients, particularly women, at high risk for recurrent and complicated urinary tract infections. Diabetic patients who opt to fast during Ramadan must be clearly counseled about keeping themselves hydrated between non-fasting hours and maintaining good glycaemic control through diet and antidiabetic drugs. PMID- 26013794 TI - Gastrointestinal health in Ramadan with special reference to diabetes. AB - Fasting in the month of Ramadan can improve a person's health, but if the correct diet is not followed, one is prone to acquire some ailments related to the digestive health. Dyspeptic symptoms are frequently encountered during Ramadan, with indigestion, bloating and heartburns being more common, particularly after eating too much at lftar or Suhur meals. Eating in moderation and elimination of foods that can trigger gastroesophageal reflux are helpful. Empiric therapy with a proton pump inhibitor (PPI) is recommended in this setting. Duodenal ulcers and duodenitis are more common during Ramadan and the frequency of complications of peptic ulcer is higher. Patients with duodenal ulcer treated with PPI may fast without any symptoms. Ramadan fasting does not impose serious risks on patients with inflammatory bowel disease. Chronic hepatitis patients show non-significant changes in the liver function tests. However, patients with advanced liver disease may decompensate. As gastrointestinal and liver ailments tend to be more common and severe in diabetics compared with the normal individuals, extra vigilance is needed for the people with diabetes who are allowed to fast by their physicians. PMID- 26013795 TI - Diabetes and diet in Ramadan. AB - Ramadan, the month of fasting, is observed by Muslims all over the world. Fasting is obligatory for all healthy adult Muslims which amounts to refraining from eating and drinking from predawn to sunset. The dietary patterns therefore totally change. For people with diabetes, instead of taking 5-6 meals, it is reduced to 2 or 3 meals in 24 hours. Good glycaemic control can be accomplished by people with diabetes, maintaining appropriate diets. It is suggested that during Ramadan similar general dietary guidelines should be followed as those throughout the year. The pre dawn meal should be taken as late as possible, before the start of the fast and should have a high proportion of carbohydrates with fibre. The traditional sugar drinks and foods rich in fat taken at iftar should be avoided. The evening meal or dinner should be consumed as early as possible at iftar and contain whole wheat flour chapattis, vegetables and a meat dish. Salads increase the fiber intake. A glass of milk or fruit at bedtime will maintain normoglycaemia till suhur. PMID- 26013796 TI - Ramadan focused diabetes education; a much needed approach. AB - Ramadan Fasting is passionately practiced by millions of Muslims with diabetes across the globe. Structured education is recommended by the various diabetes societies to empower the person with diabetes to better self manage their condition. Indeed, Ramadan focused diabetes education has been shown to be beneficial to Muslim persons with diabetes wishing to fast in the Holy month of Ramadan. Hence, many national and international guidelines stress the importance of Ramadan focused structured education. Such education is targeted at the general public including the religious authorities to raise their awareness about diabetes and Ramadan, healthcare professionals to improve their clinical skills on managing diabetes during Ramadan and most importantly for the person with diabetes to help them to sail through the month of Ramadan safely. Consequently, any educational programme needs to be simple, clear and in the person with diabetes own language. Studies have shown that such a practice whether in a group session or one to one can help to reduce risk of hypoglycaemia and indeed other possible complications. Self-monitoring of blood glucose is a crucial element of Ramadan focused diabetes education to empower the person with the information and help in behaviour change for safer fast during Ramadan. PMID- 26013797 TI - Ramadan and diabetes management - The 5 R's. PMID- 26013800 TI - 'What if...': a simple, creative tool for reflective practice. PMID- 26013799 TI - A density-based clustering approach for identifying overlapping protein complexes with functional preferences. AB - BACKGROUND: Identifying protein complexes is an essential task for understanding the mechanisms of proteins in cells. Many computational approaches have thus been developed to identify protein complexes in protein-protein interaction (PPI) networks. Regarding the information that can be adopted by computational approaches to identify protein complexes, in addition to the graph topology of PPI network, the consideration of functional information of proteins has been becoming popular recently. Relevant approaches perform their tasks by relying on the idea that proteins in the same protein complex may be associated with similar functional information. However, we note from our previous researches that for most protein complexes their proteins are only similar in specific subsets of categories of functional information instead of the entire set. Hence, if the preference of each functional category can also be taken into account when identifying protein complexes, the accuracy will be improved. RESULTS: To implement the idea, we first introduce a preference vector for each of proteins to quantitatively indicate the preference of each functional category when deciding the protein complex this protein belongs to. Integrating functional preferences of proteins and the graph topology of PPI network, we formulate the problem of identifying protein complexes into a constrained optimization problem, and we propose the approach DCAFP to address it. For performance evaluation, we have conducted extensive experiments with several PPI networks from the species of Saccharomyces cerevisiae and Human and also compared DCAFP with state-of-the art approaches in the identification of protein complexes. The experimental results show that considering the integration of functional preferences and dense structures improved the performance of identifying protein complexes, as DCAFP outperformed the other approaches for most of PPI networks based on the assessments of independent measures of f-measure, Accuracy and Maximum Matching Rate. Furthermore, the function enrichment experiments indicated that DCAFP identified more protein complexes with functional significance when compared with approaches, such as PCIA, that also utilize the functional information. CONCLUSIONS: According to the promising performance of DCAFP, the integration of functional preferences and dense structures has made it possible to identify protein complexes more accurately and significantly. PMID- 26013798 TI - Practical NK cell phenotyping and variability in healthy adults. AB - Human natural killer (NK) cells display a wide array of surface and intracellular markers that indicate various states of differentiation and/or levels of effector function. These NK cell subsets exist simultaneously in peripheral blood and may vary among individuals. We examined variety among selected NK cell receptors expressed by NK cells from normal donors, as well as the distribution of select NK cell subsets and NK cell receptor expression over time in several individual donors. Peripheral blood mononuclear cells were evaluated using flow cytometry via fluorochrome-conjugated antibodies against a number of NK cell receptors. Results were analyzed for both mean fluorescence intensity (MFI) and the percent positive cells for each receptor. CD56(bright) and CD56(dim) NK cell subsets were also considered separately, as was variation in receptor expression in NK cell subsets over time in selected individuals. Through this effort, we provide ranges of NK cell surface receptor expression for a local adult population as well as provide insight into intra-individual variation. PMID- 26013802 TI - Biomedicine is plagued by failure of replication. PMID- 26013803 TI - Intraneuronal amyloid-beta accumulation in basal forebrain cholinergic neurons: a marker of vulnerability, yet inversely related to neurodegeneration. PMID- 26013804 TI - The enlarging spectrum of focal cortical dysplasias. PMID- 26013805 TI - ExPLAining early synucleinopathies. PMID- 26013806 TI - Nuclear-mitochondrial proteins: too much to process? PMID- 26013807 TI - Absence of aryl hydrocarbon receptors increases endogenous kynurenic acid levels and protects mouse brain against excitotoxic insult and oxidative stress. AB - L-kynurenine (Kyn) is a key element of tryptophan metabolism; it is enzymatically converted by kynurenine aminotransferase II (KAT II) to kynurenic acid (KYNA), which acts as an antagonist to the NMDA receptor-glycine site. Kyn is also an endogenous ligand of the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of a diverse set of genes. KYNA levels are reduced in several regions of the brain of Huntington's disease (HD) patients. The present work uses an AhR-null mouse and age-matched wild-type mice to determine the effect of the absence of AhR on KYNA availability. We found that, in AhR-null mice, there is an increase of KYNA levels in specific brain areas associated with higher expression of KAT II. Moreover, we induced an excitotoxic insult by intrastriatal administration of quinolinic acid, a biochemical model of HD, in both AhR-null and wild-type mice to evaluate the neurological damage as well as the oxidative stress caused by the lesion. The present work demonstrates that, in specific brain regions of AhR-null mice, the levels of KYNA are increased and that this induces a neuroprotective effect against neurotoxic insults. Moreover, AhR-null mice also show improved motor performance in the rotarod test, indicating a constitutive protection of striatal tissue. PMID- 26013808 TI - A mass spectrometry-based method for comprehensive quantitative determination of post-transcriptional RNA modifications: the complete chemical structure of Schizosaccharomyces pombe ribosomal RNAs. AB - We present a liquid chromatography-mass spectrometry (LC-MS)-based method for comprehensive quantitative identification of post-transcriptional modifications (PTMs) of RNA. We incorporated an in vitro-transcribed, heavy isotope-labeled reference RNA into a sample RNA solution, digested the mixture with a number of RNases and detected the post-transcriptionally modified oligonucleotides quantitatively based on shifts in retention time and the MS signal in subsequent LC-MS. This allowed the determination and quantitation of all PTMs in Schizosaccharomyces pombe ribosomal (r)RNAs and generated the first complete PTM maps of eukaryotic rRNAs at single-nucleotide resolution. There were 122 modified sites, most of which appear to locate at the interface of ribosomal subunits where translation takes place. We also identified PTMs at specific locations in rRNAs that were altered in response to growth conditions of yeast cells, suggesting that the cells coordinately regulate the modification levels of RNA. PMID- 26013809 TI - A novel hybrid single molecule approach reveals spontaneous DNA motion in the nucleosome. AB - Structural dynamics of nucleic acid and protein is an important physical basis of their functions. These motions are often very difficult to synchronize and too fast to be clearly resolved with the currently available single molecule methods. Here we demonstrate a novel hybrid single molecule approach combining stochastic data analysis with fluorescence correlation that enables investigations of sub-ms unsynchronized structural dynamics of macromolecules. Based on the method, we report the first direct evidence of spontaneous DNA motions at the nucleosome termini. The nucleosome, comprising DNA and a histone core, is the fundamental packing unit of eukaryotic genes that must be accessed during various genome transactions. Spontaneous DNA opening at the nucleosome termini has long been hypothesized to enable gene access in the nucleosome, but has yet to be directly observed. Our approach reveals that DNA termini in the nucleosome open and close repeatedly at 0.1-1 ms(-1). The kinetics depends on salt concentration and DNA histone interactions but not much on DNA sequence, suggesting that this dynamics is universal and imposes the kinetic limit to gene access. These results clearly demonstrate that our method provides an efficient and robust means to investigate unsynchronized structural changes of DNA at a sub-ms time resolution. PMID- 26013810 TI - PatternQuery: web application for fast detection of biomacromolecular structural patterns in the entire Protein Data Bank. AB - Well defined biomacromolecular patterns such as binding sites, catalytic sites, specific protein or nucleic acid sequences, etc. precisely modulate many important biological phenomena. We introduce PatternQuery, a web-based application designed for detection and fast extraction of such patterns. The application uses a unique query language with Python-like syntax to define the patterns that will be extracted from datasets provided by the user, or from the entire Protein Data Bank (PDB). Moreover, the database-wide search can be restricted using a variety of criteria, such as PDB ID, resolution, and organism of origin, to provide only relevant data. The extraction generally takes a few seconds for several hundreds of entries, up to approximately one hour for the whole PDB. The detected patterns are made available for download to enable further processing, as well as presented in a clear tabular and graphical form directly in the browser. The unique design of the language and the provided service could pave the way towards novel PDB-wide analyses, which were either difficult or unfeasible in the past. The application is available free of charge at http://ncbr.muni.cz/PatternQuery. PMID- 26013811 TI - DeAnnCNV: a tool for online detection and annotation of copy number variations from whole-exome sequencing data. AB - With the decrease in costs, whole-exome sequencing (WES) has become a very popular and powerful tool for the identification of genetic variants underlying human diseases. However, integrated tools to precisely detect and systematically annotate copy number variations (CNVs) from WES data are still in great demand. Here, we present an online tool, DeAnnCNV (Detection and Annotation of Copy Number Variations from WES data), to meet the current demands of WES users. Upon submitting the file generated from WES data by an in-house tool that can be downloaded from our server, DeAnnCNV can detect CNVs in each sample and extract the shared CNVs among multiple samples. DeAnnCNV also provides additional useful supporting information for the detected CNVs and associated genes to help users to find the potential candidates for further experimental study. The web server is implemented in PHP + Perl + MATLAB and is online available to all users for free at http://mcg.ustc.edu.cn/db/cnv/. PMID- 26013812 TI - Nucleotidyl transferase assisted DNA labeling with different click chemistries. AB - Here, we present a simple, modular and efficient strategy that allows the 3' terminal labeling of DNA, regardless of whether it has been chemically or enzymatically synthesized or isolated from natural sources. We first incorporate a range of modified nucleotides at the 3'-terminus, using terminal deoxynucleotidyl transferase. In the second step, we convert the incorporated nucleotides, using either of four highly efficient click chemistry-type reactions, namely copper-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, Staudinger ligation or Diels-Alder reaction with inverse electron demand. Moreover, we create internal modifications, making use of either ligation or primer extension, after the nucleotidyl transferase step, prior to the click reaction. We further study the influence of linker variants on the reactivity of azides in different click reactions. We find that different click reactions exhibit distinct substrate preferences, a fact that is often overlooked, but should be considered when labeling oligonucleotides or other biomolecules with click chemistry. Finally, our findings allowed us to extend our previously published RNA labeling strategy to the use of a different copper-free click chemistry, namely the Staudinger ligation. PMID- 26013813 TI - Quantitative characterization of protein-protein complexes involved in base excision DNA repair. AB - Base Excision Repair (BER) efficiently corrects the most common types of DNA damage in mammalian cells. Step-by-step coordination of BER is facilitated by multiple interactions between enzymes and accessory proteins involved. Here we characterize quantitatively a number of complexes formed by DNA polymerase beta (Polbeta), apurinic/apyrimidinic endonuclease 1 (APE1), poly(ADP-ribose) polymerase 1 (PARP1), X-ray repair cross-complementing protein 1 (XRCC1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), using fluorescence- and light scattering based techniques. Direct physical interactions between the APE1-Polbeta, APE1 TDP1, APE1-PARP1 and Polbeta-TDP1 pairs have been detected and characterized for the first time. The combined results provide strong evidence that the most stable complex is formed between XRCC1 and Polbeta. Model DNA intermediates of BER are shown to induce significant rearrangement of the Polbeta complexes with XRCC1 and PARP1, while having no detectable influence on the protein-protein binding affinities. The strength of APE1 interaction with Polbeta, XRCC1 and PARP1 is revealed to be modulated by BER intermediates to different extents, depending on the type of DNA damage. The affinity of APE1 for Polbeta is higher in the complex with abasic site-containing DNA than after the APE1-catalyzed incision. Our findings advance understanding of the molecular mechanisms underlying coordination and regulation of the BER process. PMID- 26013814 TI - The Cas6e ribonuclease is not required for interference and adaptation by the E. coli type I-E CRISPR-Cas system. AB - CRISPR-Cas are small RNA-based adaptive prokaryotic immunity systems protecting cells from foreign DNA or RNA. Type I CRISPR-Cas systems are composed of a multiprotein complex (Cascade) that, when bound to CRISPR RNA (crRNA), can recognize double-stranded DNA targets and recruit the Cas3 nuclease to destroy target-containing DNA. In the Escherichia coli type I-E CRISPR-Cas system, crRNAs are generated upon transcription of CRISPR arrays consisting of multiple palindromic repeats and intervening spacers through the function of Cas6e endoribonuclease, which cleaves at specific positions of repeat sequences of the CRISPR array transcript. Cas6e is also a component of Cascade. Here, we show that when mature unit-sized crRNAs are provided in a Cas6e-independent manner by transcription termination, the CRISPR-Cas system can function without Cas6e. The results should allow facile interrogation of various targets by type I-E CRISPR Cas system in E. coli using unit-sized crRNAs generated by transcription. PMID- 26013815 TI - Synthesis and triplex-forming properties of oligonucleotides capable of recognizing corresponding DNA duplexes containing four base pairs. AB - A triplex-forming oligonucleotide (TFO) could be a useful molecular tool for gene therapy and specific gene modification. However, unmodified TFOs have two serious drawbacks: low binding affinities and high sequence-dependencies. In this paper, we propose a new strategy that uses a new set of modified nucleobases for four base recognition of TFOs, and thereby overcome these two drawbacks. TFOs containing a 2'-deoxy-4N-(2-guanidoethyl)-5-methylcytidine (d(g)C) residue for a C-G base pair have higher binding and base recognition abilities than those containing 2'-OMe-4N-(2-guanidoethyl)-5-methylcytidine (2'-OMe (g)C), 2'-OMe-4N (2-guanidoethyl)-5-methyl-2-thiocytidine (2'-OMe (g)Cs), d(g)C and 4S-(2 guanidoethyl)-4-thiothymidine ((gs)T). Further, we observed that N-acetyl-2,7 diamino-1,8-naphtyridine ((DA)Nac) has a higher binding and base recognition abilities for a T-A base pair compared with that of dG and the other DNA derivatives. On the basis of this knowledge, we successfully synthesized a fully modified TFO containing (DA)Nac, d(g)C, 2'-OMe-2-thiothymidine (2'-OMe (s)T) and 2'-OMe-8-thioxoadenosine (2'-OMe (s)A) with high binding and base recognition abilities. To the best of our knowledge, this is the first report in which a fully modified TFO accurately recognizes a complementary DNA duplex having a mixed sequence under neutral conditions. PMID- 26013816 TI - Real-time single-molecule studies of the motions of DNA polymerase fingers illuminate DNA synthesis mechanisms. AB - DNA polymerases maintain genomic integrity by copying DNA with high fidelity. A conformational change important for fidelity is the motion of the polymerase fingers subdomain from an open to a closed conformation upon binding of a complementary nucleotide. We previously employed intra-protein single-molecule FRET on diffusing molecules to observe fingers conformations in polymerase-DNA complexes. Here, we used the same FRET ruler on surface-immobilized complexes to observe fingers-opening and closing of individual polymerase molecules in real time. Our results revealed the presence of intrinsic dynamics in the binary complex, characterized by slow fingers-closing and fast fingers-opening. When binary complexes were incubated with increasing concentrations of complementary nucleotide, the fingers-closing rate increased, strongly supporting an induced fit model for nucleotide recognition. Meanwhile, the opening rate in ternary complexes with complementary nucleotide was 6 s(-1), much slower than either fingers closing or the rate-limiting step in the forward direction; this rate balance ensures that, after nucleotide binding and fingers-closing, nucleotide incorporation is overwhelmingly likely to occur. Our results for ternary complexes with a non-complementary dNTP confirmed the presence of a state corresponding to partially closed fingers and suggested a radically different rate balance regarding fingers transitions, which allows polymerase to achieve high fidelity. PMID- 26013817 TI - A field test of the effect of spiked ivermectin concentrations on the biodiversity of coprophagous dung insects in Switzerland. AB - Veterinary medical product residues can cause severe damage in the dung ecosystem. Depending on the manner of application and the time after treatment, the excreted concentration of a given pharmaceutical varies. The popular anthelmintic drug ivermectin can be applied to livestock in several different ways and is fecally excreted over a period of days to months after application. In a field experiment replicated in summer and autumn, the authors mixed 6 ivermectin concentrations plus a null control into fresh cow dung to assess the reaction of the dung insect community. Taxon richness of the insect dung fauna emerging from the dung, but not Hill diversity ((1) D) or the total number of individuals (abundance), decreased as ivermectin concentration increased. Corresponding declines in the number of emerging insects were found for most larger brachyceran flies and hymenopteran parasitoids, but not for most smaller nematoceran flies or beetles (except Hydrophilidae). Parallel pitfall traps recovered all major dung organism groups that emerged from the experimental dung, although at times in vastly different numbers. Ivermectin generally did not change the attractiveness of dung: differences in emergence therefore reflect differences in survival of coprophagous offspring of colonizing insects. Because sample size was limited to 6 replicates, the authors generally recommend more than 10 (seasonal) replicates and also testing higher concentrations than used in the present study as positive controls in future studies. Results accord with parallel experiments in which the substance was applied and passed through the cow's digestive system. In principle, therefore, the authors' experimental design is suitable for such higher-tier field tests of the response of the entire dung community to pharmaceutical residues, at least for ivermectin. Environ Toxicol Chem 2016;35:1947-1952. (c) 2015 SETAC. PMID- 26013818 TI - Development and manufacturability assessment of chemically-defined medium for the production of protein therapeutics in CHO cells. AB - Advantages of using internally developed chemically-defined (CD) media for cell culture-based therapeutic protein production over commercial media include better raw material control and medium vendor options, and most importantly, flexibility for process development and subsequent optimization needed for therapeutic protein production. Through several rounds of design of experiment (DOE) screening, and medium component supplementation and optimization studies, we successfully developed a CD basal medium (CDM) for CHO cell culture. The internally prepared liquid CDM demonstrated comparable cell culture performance to that from a commercially available control medium. However, when the same CDM formulation was transferred to two major commercial medium suppliers for manufacturing, cell culture performance utilizing these newly prepared media was significantly reduced compared with the in-house prepared counterpart. An investigation was launched to assess whether key medium components were sensitive to large-scale preparation of the final bulk media by the vendors. Further work necessitated the reformulation of the original CDM formulation into a core medium that was suitable for large-scale media manufacturing. The modified preparation of the core medium with two separate supplements to generate the final CDM was able to recover the expected cell culture performance and monoclonal antibody (mAb) productivity. Confirmation of cell culture robustness in cell growth and production was corroborated in two additional mAb-expressing cell lines. This work demonstrates that a robust CD medium is not only one that performs during the development stage, but also one that must be reproducible by commercial media vendors. PMID- 26013819 TI - 4-Hydroxybenzyl-substituted glutathione derivatives from Gastrodia elata. AB - Seven new 4-hydroxybenzyl-substituted glutathione derivatives (2-8), together with a known analogue (1), were isolated from the aqueous extract of Gastrodia elata Blume rhizomes. Their structures were determined by using spectroscopic and chemical methods. The absolute configurations of 1-8 were assigned by using Marfey's method, combined with comparing the NMR and CD spectroscopic data of sulfoxide moieties in 3-6 with those of S-(4-hydroxybenzyl)cysteine sulfoxide stereoisomers (9-12) synthesized as authentic samples. The configurations of 9-12 were confirmed by electronic CD calculations based on the quantum-mechanical time dependent density functional theory. Furthermore, the structures of 1, 3, 5, 7, and 8 were verified by synthesis. Compound 3 was active against serum deprivation induced PC12 cell damage and synthetic 9-14 exhibited activity against Fe(2+) cysteine induced rat liver microsomal lipid peroxidation. PMID- 26013820 TI - Physiological and Antioxidant Responses in Wheat (Triticum aestivum) to HHCB in Soil. AB - Seedlings of wheat (Triticum aestivum) were exposed in soil to the polycyclic musk chemical, 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2 benzopyran (HHCB) for 21 days, to evaluate its effect upon chlorophyll (CHL), lipid peroxidation and the antioxidant system. The content of CHL in leaves was inhibited significantly after 14- and 21-days exposures, whereas it was significantly induced by a low level of HHCB after a 7-days exposure. The content of malondialdehyde (MDA) in wheat leaves increased with an increase in the concentration of HHCB in soil, indicating that oxidative stress could be induced by HHCB. Moreover, HHCB exposure induced significant antioxidant responses in wheat. The activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) in wheat leaves were induced by HHCB after 14 and 21 days of exposure. However, the changing trend of the antioxidant enzymes in wheat roots was different from that in leaves. The results suggested that the assayed parameters of T. aestivum could be used as responsive biomarkers for oxidative stress in the soil environment. PMID- 26013821 TI - Interference of quorum sensing in urinary pathogen Serratia marcescens by Anethum graveolens. AB - Serratia marcescens is an opportunistic turned obligate pathogen frequently associated with urinary tract infections (UTI) and are multidrug resistant at most instances. Quorum sensing (QS) system, a population-dependent global regulatory system, controls the pathogenesis machinery of S. marcescens as it does in other pathogens. In the present study, methanol extract of a common herb and spice, Anethum graveolens (AGME) was assessed for its anti-QS potential against the clinical isolate of S. marcescens. AGME notably reduced the biofilm formation and QS-dependent virulence factors production in a concentration dependent manner (64-1024 MUg mL(-1)). The light and confocal microscopic images clearly evidenced the antibiofilm activity of AGME (256 MUg mL(-1)) at its minimal biofilm inhibitory concentration. Besides, in support of biochemical assays, the expression analysis of QS-regulated genes fimC, bsmA and flhD which are crucial for initial adhesion and motility confirmed their downregulation upon exposure to AGME. LC-MS analysis of AGME revealed 3-O-methyl ellagic acid (3-O ME) as one of its active principles having nearly similar antibiofilm activity and a reduced inhibition of prodigiosin (27%) and protease (15%) compared to AGME [prodigiosin (47%) and protease (50%)]. UFLC analysis revealed that 0.355 mg g( 1) of 3-O-ME was present in the AGME. AGME and the 3-O-ME significantly interfered the QS system of a QS model strain S. marcescens MG1 and its mutant S. marcescens MG44 which in turn corroborates the anti-QS mechanism of AGME. PMID- 26013822 TI - Generation of a Potent Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Antagonist by Engineering a Stable Form of the Receptor-associated Protein (RAP) D3 Domain. AB - The low density lipoprotein receptor-related protein 1 (LRP1) is a member of the low density lipoprotein receptor family and plays important roles in a number of physiological and pathological processes. Expression of LRP1 requires the receptor-associated protein (RAP), a molecular chaperone that binds LRP1 and other low density lipoprotein receptor family members in the endoplasmic reticulum and traffics with them to the Golgi where the acidic environment causes its dissociation. Exogenously added RAP is a potent LRP1 antagonist and binds to LRP1 on the cell surface, preventing ligands from binding. Following endocytosis, RAP dissociates in the acidic endosome, allowing LRP1 to recycle back to the cell surface. The acid-induced dissociation of RAP is mediated by its D3 domain, a relatively unstable three-helical bundle that denatures at pH <6.2 due to protonation of key histidine residues on helices 2 and 3. To develop an LRP1 inhibitor that does not dissociate at low pH, we introduced a disulfide bond between the second and third helices in the RAP D3 domain. By combining this disulfide bond with elimination of key histidine residues, we generated a stable RAP molecule that is resistant to both pH- and heat-induced denaturation. This molecule bound to LRP1 with high affinity at both neutral and acidic pH and proved to be a potent inhibitor of LRP1 function both in vitro and in vivo, suggesting that our stable RAP molecule may be useful in multiple pathological settings where LRP1 blockade has been shown to be effective. PMID- 26013823 TI - Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism. AB - Cathelicidins are a family of gene-encoded peptide effectors of innate immunity found exclusively in vertebrates. They play pivotal roles in host immune defense against microbial invasions. Dozens of cathelicidins have been identified from several vertebrate species. However, no cathelicidin from marine reptiles has been characterized previously. Here we report the identification and characterization of a novel cathelicidin (Hc-CATH) from the sea snake Hydrophis cyanocinctus. Hc-CATH is composed of 30 amino acids, and the sequence is KFFKRLLKSVRRAVKKFRKKPRLIGLSTLL. Circular dichroism spectroscopy and structure modeling analysis indicated that Hc-CATH mainly assumes an amphipathic alpha helical conformation in bacterial membrane-mimetic solutions. It possesses potent broad-spectrum and rapid antimicrobial activity. Meanwhile, it is highly stable and shows low cytotoxicity toward mammalian cells. The microbial killing activity of Hc-CATH is executed through the disruption of cell membrane and lysis of bacterial cells. In addition, Hc-CATH exhibited potent anti-inflammatory activity by inhibiting the LPS-induced production of nitric oxide (NO) and pro inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. Hc-CATH directly binds with LPS to neutralize its toxicity, and it also binds to Toll-like receptor 4 (TLR4/MD2 complex), which therefore inhibits the binding of LPS to TLR4/MD2 complex and the subsequent activation of LPS-induced inflammatory response pathways. Taken together, our study demonstrates that Hc-CATH, the first cathelicidin from sea snake discovered to have both antimicrobial and anti inflammatory activity, is a potent candidate for the development of peptide antibiotics. PMID- 26013824 TI - Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis. AB - Human chymotrypsin C (CTRC) protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intra-pancreatic trypsinogen activation. Loss-of-function mutations in CTRC increase the risk for chronic pancreatitis. Here we describe functional analysis of eight previously uncharacterized natural CTRC variants tested for potential defects in secretion, proteolytic stability, and catalytic activity. We found that all variants were secreted from transfected cells normally, and none suffered proteolytic degradation by trypsin. Five variants had normal enzymatic activity, whereas variant p.R29Q was catalytically inactive due to loss of activation by trypsin and variant p.S239C exhibited impaired activity possibly caused by disulfide mispairing. Surprisingly, variant p.G214R had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovine beta casein or the natural CTRC substrates human cationic trypsinogen and procarboxypeptidase A1. Mutation p.G214R is analogous to the evolutionary mutation in human mesotrypsin, which rendered this trypsin isoform resistant to proteinaceous inhibitors and conferred its ability to cleave these inhibitors. Similarly to the mesotrypsin phenotype, CTRC variant p.G214R was inhibited poorly by eglin C, ecotin, or a CTRC-specific variant of SGPI-2, and it readily cleaved the reactive-site peptide bonds in eglin C and ecotin. We conclude that CTRC variants p.R29Q, p.G214R, and p.S239C are risk factors for chronic pancreatitis. Furthermore, the mesotrypsin-like CTRC variant highlights how the same natural mutation in homologous pancreatic serine proteases can evolve a new physiological role or lead to pathology, determined by the biological context of protease function. PMID- 26013825 TI - Human gamma-Glutamyl Transpeptidase 1: STRUCTURES OF THE FREE ENZYME, INHIBITOR BOUND TETRAHEDRAL TRANSITION STATES, AND GLUTAMATE-BOUND ENZYME REVEAL NOVEL MOVEMENT WITHIN THE ACTIVE SITE DURING CATALYSIS. AB - gamma-Glutamyl transpeptidase 1 (GGT1) is a cell surface, N-terminal nucleophile hydrolase that cleaves glutathione and other gamma-glutamyl compounds. GGT1 expression is essential in cysteine homeostasis, and its induction has been implicated in the pathology of asthma, reperfusion injury, and cancer. In this study, we report four new crystal structures of human GGT1 (hGGT1) that show conformational changes within the active site as the enzyme progresses from the free enzyme to inhibitor-bound tetrahedral transition states and finally to the glutamate-bound structure prior to the release of this final product of the reaction. The structure of the apoenzyme shows flexibility within the active site. The serine-borate-bound hGGT1 crystal structure demonstrates that serine borate occupies the active site of the enzyme, resulting in an enzyme-inhibitor complex that replicates the enzyme's tetrahedral intermediate/transition state. The structure of GGsTop-bound hGGT1 reveals its interactions with the enzyme and why neutral phosphonate diesters are more potent inhibitors than monoanionic phosphonates. These structures are the first structures for any eukaryotic GGT that include a molecule in the active site covalently bound to the catalytic Thr 381. The glutamate-bound structure shows the conformation of the enzyme prior to release of the final product and reveals novel information regarding the displacement of the main chain atoms that form the oxyanion hole and movement of the lid loop region when the active site is occupied. These data provide new insights into the mechanism of hGGT1-catalyzed reactions and will be invaluable in the development of new classes of hGGT1 inhibitors for therapeutic use. PMID- 26013826 TI - Small C-terminal Domain Phosphatase 3 Dephosphorylates the Linker Sites of Receptor-regulated Smads (R-Smads) to Ensure Transforming Growth Factor beta (TGFbeta)-mediated Germ Layer Induction in Xenopus Embryos. AB - Germ layer induction is one of the earliest events shortly after fertilization that initiates body formation of vertebrate embryos. In Xenopus, the maternally deposited transcriptional factor VegT promotes the expression of zygotic Nodal/Activin ligands that further form a morphogen gradient along the vegetal animal axis and trigger the induction of the three germ layers. Here we found that SCP3 (small C-terminal domain phosphatase 3) is maternally expressed and vegetally enriched in Xenopus embryos and is essential for the timely induction of germ layers. SCP3 is required for the full activation of Nodal/Activin and bone morphogenetic protein signals and functions via dephosphorylation in the linker regions of receptor-regulated Smads. Consistently, the linker regions of receptor-regulated Smads are heavily phosphorylated in fertilized eggs, and this phosphorylation is gradually removed when embryos approach the midblastula transition. Knockdown of maternal SCP3 attenuates these dephosphorylation events and the activation of Nodal/Activin and bone morphogenetic protein signals after midblastula transition. This study thus suggested that the maternal SCP3 serves as a vegetally enriched, intrinsic factor to ensure a prepared status of Smads for their activation by the upcoming ligands during germ layer induction of Xenopus embryos. PMID- 26013827 TI - Identification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel. AB - The aquaporin family of integral membrane proteins is composed of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system and facilitates the osmotically driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves PKA activation, influx of extracellular calcium, and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain edema. PMID- 26013828 TI - Isolation and Characterization of a Thionin Proprotein-processing Enzyme from Barley. AB - Thionins are plant-specific antimicrobial peptides that have been isolated from the endosperm and leaves of cereals, from the leaves of mistletoes, and from several other plant species. They are generally basic peptides with three or four disulfide bridges and a molecular mass of ~5 kDa. Thionins are produced as preproproteins consisting of a signal peptide, the thionin domain, and an acidic domain. Previously, only mature thionin peptides have been isolated from plants, and in addition to removal of the signal peptide, at least one cleavage processing step between the thionin and the acidic domain is necessary to release the mature thionin. In this work, we identified a thionin proprotein-processing enzyme (TPPE) from barley. Purification of the enzyme was guided by an assay that used a quenched fluorogenic peptide comprising the amino acid sequence between the thionin and the acidic domain of barley leaf-specific thionin. The barley TPPE was identified as a serine protease (BAJ93208) and expressed in Escherichia coli as a strep tag-labeled protein. The barley BTH6 thionin proprotein was produced in E. coli using the vector pETtrx1a and used as a substrate. We isolated and sequenced the BTH6 thionin from barley to confirm the N and C terminus of the peptide in planta. Using an in vitro enzymatic assay, the recombinant TPPE was able to process the quenched fluorogenic peptide and to cleave the acidic domain at least at six sites releasing the mature thionin from the proprotein. Moreover, it was found that the intrinsic three-dimensional structure of the BTH6 thionin domain prevents cleavage of the mature BTH6 thionin by the TPPE. PMID- 26013829 TI - Intra-domain Cross-talk Regulates Serine-arginine Protein Kinase 1-dependent Phosphorylation and Splicing Function of Transformer 2beta1. AB - Transformer 2beta1 (Tra2beta1) is a splicing effector protein composed of a core RNA recognition motif flanked by two arginine-serine-rich (RS) domains, RS1 and RS2. Although Tra2beta1-dependent splicing is regulated by phosphorylation, very little is known about how protein kinases phosphorylate these two RS domains. We now show that the serine-arginine protein kinase-1 (SRPK1) is a regulator of Tra2beta1 and promotes exon inclusion in the survival motor neuron gene 2 (SMN2). To understand how SRPK1 phosphorylates this splicing factor, we performed mass spectrometric and kinetic experiments. We found that SRPK1 specifically phosphorylates 21 serines in RS1, a process facilitated by a docking groove in the kinase domain. Although SRPK1 readily phosphorylates RS2 in a splice variant lacking the N-terminal RS domain (Tra2beta3), RS1 blocks phosphorylation of these serines in the full-length Tra2beta1. Thus, RS2 serves two new functions. First, RS2 positively regulates binding of the central RNA recognition motif to an exonic splicing enhancer sequence, a phenomenon reversed by SRPK1 phosphorylation on RS1. Second, RS2 enhances ligand exchange in the SRPK1 active site allowing highly efficient Tra2beta1 phosphorylation. These studies demonstrate that SRPK1 is a regulator of Tra2beta1 splicing function and that the individual RS domains engage in considerable cross-talk, assuming novel functions with regard to RNA binding, splicing, and SRPK1 catalysis. PMID- 26013830 TI - Human CLC-K Channels Require Palmitoylation of Their Accessory Subunit Barttin to Be Functional. AB - CLC-K/barttin chloride channels are essential for NaCl re-absorption in Henle's loop and for potassium secretion by the stria vascularis in the inner ear. Here, we studied the posttranslational modification of such channels by palmitoylation of their accessory subunit barttin. We found that barttin is palmitoylated in vivo and in vitro and identified two conserved cysteine residues at positions 54 and 56 as palmitoylation sites. Point mutations at these two residues reduce the macroscopic current amplitudes in cells expressing CLC-K/barttin channels proportionally to the relative reduction in palmitoylated barttin. CLC-K/barttin expression, plasma membrane insertion, and single channel properties remain unaffected, indicating that these mutations decrease the number of active channels. R8W and G47R, two naturally occurring barttin mutations identified in patients with Bartter syndrome type IV, reduce barttin palmitoylation and CLC K/barttin channel activity. Palmitoylation of the accessory subunit barttin might thus play a role in chloride channel dysfunction in certain variants of Bartter syndrome. We did not observe pronounced alteration of barttin palmitoylation upon increased salt and water intake or water deprivation, indicating that this posttranslational modification does not contribute to long term adaptation to variable water intake. Our results identify barttin palmitoylation as a novel posttranslational modification of CLC-K/barttin chloride channels. PMID- 26013831 TI - Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-kappaB Signaling Pathway. AB - Inflammation is widely distributed in patients with Duchenne muscular dystrophy and ultimately leads to progressive deterioration of muscle function with chronic muscle damage, oxidative stress, and reduced oxidative capacity. NF-E2-related factor 2 (Nrf2) plays a critical role in defending against inflammation in different tissues via activation of phase II enzyme heme oxygenase-1 and inhibition of the NF-kappaB signaling pathway. However, the role of Nrf2 in the inflammation of dystrophic muscle remains unknown. To determine whether Nrf2 may counteract inflammation in dystrophic muscle, we treated 4-week-old male mdx mice with the Nrf2 activator sulforaphane (SFN) by gavage (2 mg/kg of body weight/day) for 4 weeks. The experimental results demonstrated that SFN treatment increased the expression of muscle phase II enzyme heme oxygenase-1 in an Nrf2-dependent manner. Inflammation in mice was reduced by SFN treatment as indicated by decreased infiltration of immune cells and expression of the inflammatory cytokine CD45 and proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in the skeletal muscles of mdx mice. In addition, SFN treatment also decreased the expression of NF-kappaB(p65) and phosphorylated IkappaB kinase-alpha as well as increased inhibitor of kappaB alpha expression in mdx mice in an Nrf2-dependent manner. Collectively, these results show that SFN-induced Nrf2 can alleviate muscle inflammation in mdx mice by inhibiting the NF-kappaB signaling pathway. PMID- 26013833 TI - HEFFICON: HIV Effectiveness Italian Conference. AB - Since the first acquired immunodeficiency syndrome cases were reported in 1981, more than 1.5 million people have been diagnosed with Human Immunodeficiency Virus-1 in Europe, including more than 136,000 new HIV cases in 2013. Recent epidemiological data estimate an incidence of 5-10 newly diagnosed HIV infections per 100,000 population per year in Europe and an average prevalence of infection of 5.7 cases per 100,000 population. In the absence of an effective curative strategy for HIV, optimization of prevention policies and clinical management of HIV positive patients is fundamental to reduce the impact of the HIV pandemic on public health. Clinical trials represent an essential tool for translating research findings into routine clinical practice. Careful evaluation and planning of clinical trials are therefore mandatory in order to provide relevant information to clinicians. The HEFFICON Project was conceived to investigate and pinpoint methodological issues and critical points that need to be addressed in future clinical studies to increase the translation of experimental results to the real life environment. PMID- 26013832 TI - Osteonecrosis of the Jaw Developed in Mice: DISEASE VARIANTS REGULATED BY gammadelta T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY. AB - Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier gammadelta T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 MUg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. gammadelta T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL treated gammadelta T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of gammadelta T cells from human peripheral blood (h gammadelta T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-gammadelta T cells exhibited rapid expansion and robust IFN-gamma secretion. When h-gammadelta T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that gammadelta T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ. PMID- 26013834 TI - Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors. AB - Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in DMSO at 130 degrees C provides rapid access to 3 aminobenzo[b]thiophenes in 58-96% yield. This transformation has been applied in the synthesis of the thieno[2,3-b]pyridine core motif of LIMK1 inhibitors, the benzo[4,5]thieno[3,2-e][1,4]diazepin-5(2H)-one scaffold of MK2 inhibitors and a benzo[4,5]thieno[3,2-d]pyrimidin-4-one inhibitor of the PIM kinases. PMID- 26013836 TI - Spectroelectrochemical Studies on Quinacridone by Using Poly(vinyl alcohol) Coating as Protection Layer. AB - Spectroscopic measurements in the infrared range combined with electrochemistry are a powerful technique for investigation of organic semiconductors to track changes during oxidation and reduction (p- and n-doping) processes. For these measurements it is important that the studied material, mostly deposited as a thin film on an internal reflection element, does not dissolve during this characterization. In this study we introduce a technique that allows infrared spectroelectrochemical characterization of films of these materials for the first time. In many cases so far this has been impossible, due to solubility in the oxidized and/or reduced form. This novel technique is shown on thin films of quinacridone by adding a protection layer of poly(vinyl alcohol) (PVA). PMID- 26013835 TI - Landscape of the lipidome and transcriptome under heat stress in Arabidopsis thaliana. AB - Environmental stress causes membrane damage in plants. Lipid studies are required to understand the adaptation of plants to climate change. Here, LC-MS-based lipidomic and microarray transcriptome analyses were carried out to elucidate the effect of short-term heat stress on the Arabidopsis thaliana leaf membrane. Vegetative plants were subjected to high temperatures for one day, and then grown under normal conditions. Sixty-six detected glycerolipid species were classified according to patterns of compositional change by Spearman's correlation coefficient. Triacylglycerols, 36:4- and 36:5-monogalactosyldiacylglycerol, 34:2- and 36:2-digalactosyldiacylglycerol, 34:1-, 36:1- and 36:6-phosphatidylcholine, and 34:1-phosphatidylethanolamine increased by the stress and immediately decreased during recovery. The relative amount of one triacylglycerol species (54:9) containing alpha-linolenic acid (18:3) increased under heat stress. These results suggest that heat stress in Arabidopsis leaves induces an increase in triacylglycerol levels, which functions as an intermediate of lipid turnover, and results in a decrease in membrane polyunsaturated fatty acids. Microarray data revealed candidate genes responsible for the observed metabolic changes. PMID- 26013837 TI - bmj.com at 20 years. PMID- 26013838 TI - Size-dependent ligand layer dynamics in semiconductor nanocrystals probed by anisotropy measurements. AB - Colloidal semiconductor nanocrystals (NC) have reached a high level of synthetic control allowing the tuning of their properties, and their use in various applications. However, the surface of NCs and in particular their size-dependent capping organic ligand behavior, which play an important role in the NC synthesis, dispersibility, and optoelectronic properties, is still not well understood. We study the size-dependent properties of the ligand shell on the surface of NCs, by embedding surface bound dyes as a probe within the ligand shell. The reorientation times for these dyes show a linear dependence on the NC surface curvature indicating size-dependent change in viscosity, which is related to a change in the density of the ligand layer because of the geometry of the surface, a unique feature of NCs. Understanding the properties of the ligand shell will allow rational design of the surface to achieve the desired properties, providing an additional important knob for tuning their functionality. PMID- 26013839 TI - Interleukin-6 enhances the activity of in vivo long-term reconstituting hematopoietic stem cells in "hypoxic-like" expansion cultures ex vivo. AB - BACKGROUND: Since interleukin (IL)-6 synergizes with the physiologically relevant O2 concentration in the maintenance of primitive hematopoietic stem cell (HSC) subpopulations, we hypothesized that its addition to our hypoxic response mimicking cultures (HRMCs), composed of an antioxidant-supplied serum-free xeno free medium supplemented with the cytokines stabilizing hypoxia-inducible factor 1alpha and balancing HSC self-renewal and commitment, will result in a similar effect even if they are exposed to 20% O2 . STUDY DESIGN AND METHODS: HRMCs were exposed to 20 and 5% O2 with and without IL-6. Functional committed progenitors (colony-forming cells [CFCs]: CFU-GM, BFU-E, CFU-Mix, and CFU-Mk) were evaluated as well as the short- and long-term repopulating HSCs using in vivo NSG mice model (primary and secondary recipients, respectively). RESULTS: The addition of IL-6 to HRMCs exposed to 20% O2 did not significantly impact either the CFCs or in vivo short-term repopulating cells. However, it enhanced both the frequency and the individual proliferative capacity of the most primitive long-term repopulating cell population evidenced by the generation of human CFCs in the marrow of secondary recipient mice. The exposure of HRMCs to 5% O2 negatively affected the amplification of CFCs, which was not changed by the addition of IL-6 and exhibited a partial enhancing effect on the long-term repopulating cells. CONCLUSION: The addition of IL-6 to the cytokine cocktail further improves our expansion procedure based on atmospheric O2 concentration-exposed HRMCs by enhancing the maintenance of the most primitive HSCs without a negative impact on the less primitive HSC populations and CFCs. PMID- 26013841 TI - Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations. AB - The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 degrees C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ~70% RH (25 degrees C). Our results highlight the outcome of inadvertent drug excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development. PMID- 26013840 TI - Development of the OnTrack Diabetes Program. AB - BACKGROUND: Type 2 diabetes affects an estimated 347 million people worldwide and often leads to serious complications including blindness, kidney disease, and limb amputation. Comorbid dysphoria is common and is an independent risk factor for poor glycaemic control. Professional support for diabetes self-management and dysphoria has limited availability and involves high costs, especially after regular hours, and in rural and remote areas. Web-based cognitive behavior therapy offers highly accessible, acceptable, and cost-effective support for people with diabetes. This paper describes the development of OnTrack Diabetes, a self-guided, Web-based program to promote improved physical and emotional self management in people with Type 2 diabetes. OBJECTIVE: The objective of the study is to describe the development of the OnTrack Diabetes program, which is a self guided, Web-based program aimed to promote euthymia and improved disease self management in people with Type 2 diabetes. METHODS: Semistructured interviews with 12 general practitioners and 13 patients with Type 2 diabetes identified enablers of and barriers to effective diabetes self-management, requirements for additional support, and potential program elements. Existing resources and research data informed the development of content, and consultants from relevant disciplines provided feedback on draft segments and reviewed the program before release. Using a self-guided delivery format contained costs, in addition to adapting program features and modules from an existing OnTrack program. RESULTS: A separate paper describes the protocol for a randomized controlled trial to provide this required evaluation. CONCLUSIONS: Development of the OnTrack Diabetes program demonstrates strategies that help ensure that a program is acceptable to users. The next stages involve testing users' experiences and examining the program's effectiveness and cost-effectiveness in randomized controlled trials. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ACTRN): 12614001126606; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261400112660 (Archived by WebCite at http://www.webcitation.org/6U0Fh3vOj). PMID- 26013842 TI - Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor. AB - Skin is in daily contact with potentially harmful molecules from the environment such as cigarette smoke, automobile emissions, industrial soot and groundwater. Pregnane X receptor (PXR) is a transcription factor expressed in liver and intestine that is activated by xenobiotic chemicals including drugs and environmental pollutants. Topical application of the tumor initiator 7,12 dimethylbenz(a)anthracene (DMBA) enhances Pxr, Cyp1a1, Cyp1b1 and Cyp3a11, but not Ahr expression in the skin. Surprisingly, DMBA-induced Pxr upregulation is largely impaired in Langerin(+) cell-depleted skin, suggesting that DMBA mainly triggers Pxr in Langerin(+) cells. Furthermore, PXR deficiency protects from DNA damage in epidermal cells but to a lesser extent than aryl hydrocarbon receptor (AHR) deficiency. Interestingly, skin exposure to low doses of DMBA induces migration of PXR-deficient but not of wild-type and AHR-deficient Langerhans cells (LCs). PXR-humanized mice show a marked increase in DNA damage to epidermal cells after topical application of DMBA, demonstrating relevance of these findings in human tissue. This is the first report suggesting that carcinogens might trigger PXR in epidermal cells, particularly in LCs, thus leading to DNA damage. Further studies are required to better delineate the role of PXR in cutaneous carcinogenesis. PMID- 26013843 TI - Spanning a Decade of Physician Boundary Violations: Are We Improving? AB - Sexual boundary violations can negatively impact the culture of safety within a medical practice or healthcare institution and severely compromise the covenant of care and physician objectivity. Lack of education and training is one factor associated with physician misconduct that leads to high financial and personal cost. This paper presents a follow-up study of physicians referred to a professional development course in 2001 and presents demographic data from 2001 to present. The paper focuses on the education and remediation progress regarding sexual misconduct by physicians. PMID- 26013844 TI - The opportunities and challenges for shared decision-making in the rural United States. AB - The ethical standard for informed consent is fostered within a shared decision making (SDM) process. SDM has become a recognized and needed approach in health care decision-making. Based on an ethical foundation, the approach fosters the active engagement of patients, where the clinician presents evidence-based treatment information and options and openly elicits the patient's values and preferences. The SDM process is affected by the context in which the information exchange occurs. Rural settings are one context that impacts the delivery of health care and SDM. Rural health care is significantly influenced by economic, geographical and social characteristics. Several specific distinctive features influence rural health care decision-making-poverty, access to health care, isolation, over-lapping relationships, and a shared culture. The rural context creates challenges as well as fosters opportunities for the application of SDM as a natural dynamic within the rural provider-patient relationship. To fulfill the ethical requirements of informed consent through SDM, it is necessary to understand its inherent challenges and opportunities. Therefore, rural clinicians and ethicists need to be cognizant of the impact of the rural setting on SDM and use the insights as an opportunity to achieve SDM. PMID- 26013845 TI - Effects of iron oxide nanoparticles on biological responses and MR imaging properties in human mammary healthy and breast cancer epithelial cells. AB - Superparamagnetic iron oxide nanoparticles (SPIONs, diameters >50 nm) have received great attention due to their promising use as magnetic resonance imaging (MRI) contrast agents. In this study, we evaluated the cellular uptake and biological responses in vitro of ultrasmall SPIONs (USPIONs, diameters < 50 nm). We compared the cellular responses between breast epithelia isolated from healthy and breast cancer donors after exposure to carboxy-terminated USPIONs (10 and 30 nm PEG-coated, 10 and 30 nm non-PEG-coated). The particles were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS) and gel electrophoresis. Cellular interactions with USPIONs were assessed by confocal microscopy and TEM. Cellular uptake of USPIONs was quantified using ICP-MS. Cell viability was measured by MTT and neutral red uptake assays. T2* weighted MRI scans were performed using a 7T scanner. Results demonstrated that cell association/internalization of USPIONs was size- and surface coating-dependent (PEG vs. non-PEG), and higher cellular uptake of 10 and 30 nm non-coated particles was observed in both cell types compared with PEG-coated particles. Cell uptake for 10 and 30 nm non-coated particles was higher in cancer cells from two of three tested donors compared to healthy cells from three donors. There was no significant cytotoxicity observed for all tested particles. Significantly enhanced MRI contrast was observed following exposure to 10 and 30 nm non-coated particles compared to PEG-coated particles in both cell types. In comparison, cancer cells showed more enhanced MRI signals when compared to normal cells. The data indicate that cell responses following exposure to USPIONs are dependent on particle properties. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1032-1042, 2016. PMID- 26013846 TI - Liquid-Phase Catalytic Transfer Hydrogenation of Furfural over Homogeneous Lewis Acid-Ru/C Catalysts. AB - The catalytic performance of homogeneous Lewis acid catalysts and their interaction with Ru/C catalyst are studied in the catalytic transfer hydrogenation of furfural by using 2-propanol as a solvent and hydrogen donor. We find that Lewis acid catalysts hydrogenate the furfural to furfuryl alcohol, which is then etherified with 2-propanol. The catalytic activity is correlated with an empirical scale of Lewis acid strength and exhibits a volcano behavior. Lanthanides are the most active, with DyCl3 giving complete furfural conversion and a 97 % yield of furfuryl alcohol at 180 degrees C after 3 h. The combination of Lewis acid and Ru/C catalysts results in synergy for the stronger Lewis acid catalysts, with a significant increase in the furfural conversion and methyl furan yield. Optimum results are obtained by using Ru/C combined with VCl3 , AlCl3 , SnCl4 , YbCl3 , and RuCl3 . Our results indicate that the combination of Lewis acid/metal catalysts is a general strategy for performing tandem reactions in the upgrade of furans. PMID- 26013848 TI - Synthesis and antifungal activity of ethers, alcohols, and iodohydrin derivatives of sclareol against phytopathogenic fungi in vitro. AB - This study synthesized 20 sclareol derivatives. The antifungal activities of these derivatives were evaluated in vitro against five phytopathogenic fungi using the mycelium growth rate method. Among all the tested compounds, compound 16 with one iodine atom and three hydroxyl groups displayed higher fungicidal activities against all the tested phytopathogenic fungi than precursor sclareol. Compound 16 also showed more pronounced antifungal activities against Curvularia lunata (IC50=12.09 MUg/mL) and Alternaria brassicae (IC50=14.47 MUg/mL) than the positive control, a commercial agricultural fungicide thiabendazole. PMID- 26013849 TI - Unusual airway injury following a motor vehicle collision. AB - A 16-year-old male presented to the emergency department following a single-truck motor vehicle collision. The patient was the driver of an older model pickup truck that he lost control of while driving and went off of the road. He was restrained with a lap belt only, given the age of the vehicle. His only complaint at the presenting hospital was left-sided neck pain and hoarseness. PMID- 26013847 TI - Small molecule inhibitors of HIVgp41 N-heptad repeat trimer formation. AB - Identification of mechanistically novel anti-HIV fusion inhibitors was accomplished using a computer-aided structure-based design approach with the goal of blocking the formation of the N-heptad repeat (NHR) trimer of the viral protein gp41. A virtual screening strategy that included per-residue interaction patterns (footprints) was employed to identify small molecules compatible with putative binding pockets at the internal interface of the NHR helices at the core native viral six-helix bundle. From a screen of ~2.8 million compounds using the DOCK program, 120 with favorable energetic and footprint overlap characteristics were purchased and experimentally tested leading to two compounds with favorable cell-cell fusion (IC50) and cytotoxicity profiles. Importantly, both hits were identified on the basis of scores containing footprint overlap terms and would not have been identified using the standard DOCK energy function alone. To our knowledge, these compounds represent the first reported small molecules that inhibit viral entry via the proposed NHR-trimer obstruction mechanism. PMID- 26013850 TI - Post-occlusion administration of sodium butyrate attenuates cognitive impairment in a rat model of chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) has been commonly associated with Alzheimer's disease and other types of dementia, but therapies that can improve cerebral blood flow displayed little effect on impaired cognition. Epigenetic intervention with histone deacetylase inhibitors, such as sodium butyrate (SB), on the other hand has been shown to improve cognition in several animal models of dementia. To investigate the effect of SB on cognitive impairment induced by CCH in rats, adult male SD rats were given intraperitoneal injections of SB at a daily dose of 840mg/kg for 4weeks, from the 29th day after permanent occlusion of bilateral common carotid arteries (2VO). Learning and memory were assessed by Morris water maze and novel object recognition. Following behavioral tests, western blotting of histone acetylation, of transcription factors, of neuronal/synaptic proteins, were performed using rat hippocampus and cortex. The data showed that SB treatment alleviated hippocampal dependent spatial learning disability in 2VO rats, and altered HDAC1/2 mRNA level, histone H4 acetylation and Nrf2 transcriptional activation in rat hippocampus. Accordingly, cognition protective effect of SB appeared to be partially mediated by enhancing histone acetylation and hence by facilitating the transcription of Nrf2 downstream genes in the hippocampus. Thus, SB might be considered for putative treatment for CCH related cognitive impairment. PMID- 26013852 TI - [Present conditions and problems of transanal total mesorectal excision in rectal cancer]. AB - Transanal total mesorectal excision (taTME) is a very innovative approach for the treatment of rectal cancer. This technique comes from some concepts such as natural-orifice transluminal endoscopic surgery (NOTES), transanal endoscopic microsurgery(TEM), transanal transabdominal operation(TATA), transanal minimally invasive surgery(TAMIS) and total mesorectum excision (TME). It has emerged in a dozen countries throughout the world in recent years. We have performed taTME in patients after a series of animal and human cadaver operations, and the technique approved by Ethics committee of the Six Affiliated Hospital of Sun Yat-sen University. The initial results seem to be advantageous in terms of distal margin and circumferential margins especially in obese and narrow pelvis, minimally invasiveness, reduced complications of anastomosis. There are no results on the long term functional and oncological outcomes by multiple center RCT clinical trials with taTME until now. This novel approach must be governed by skills acquisition and mentorship; it could become a valid alternative for patients with middle and low rectal cancer after experience accumulation and optimized operation equipment. PMID- 26013853 TI - [Current status and prospect of transanal total mesorectal excision]. AB - In the last 30 years, the treatment of rectal cancer has changed extensively including the emerge of total mesorectal excision, multidisciplinary approach, and laparoscopy. Transanal total mesorectal excision (taTME) has been a hot topic in the past several years. It was reported that taTME was safe and feasible, and had a satisfactory short-term outcomes. But at this stage it may be premature to compare a new technique, such as taTME, which is still evolving and developing instrumentation to well-established standard procedures like laparoscopic TME. What is possibly needed is selective cases, high quality operation, and more cohort studies with larger sample sizes addressing the safety, feasibility and efficiency. PMID- 26013851 TI - Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells. AB - BACKGROUND AND PURPOSE: NF-kappaB-driven inflammation is negatively regulated by the zinc finger protein A20. Gibberellic acid (GA3 ) is a plant-derived diterpenoid with documented anti-inflammatory activity, which is reported to induce A20-like zinc finger proteins in plants. Here, we sought to investigate the anti-inflammatory effect of GA3 in airway epithelial cells and determine if the anti-inflammatory action relates to A20 induction. EXPERIMENTAL APPROACH: Primary nasal epithelial cells and a human bronchial epithelial cell line (16HBE14o-) were used. Cells were pre-incubated with GA3 , stimulated with Pseudomonas aeruginosa LPS; IL-6 and IL-8 release, A20, NF-kappaB and IkappaBalpha expression were then evaluated. To determine if any observed anti inflammatory effect occurred via an A20-dependent mechanism, A20 was silenced using siRNA. KEY RESULTS: Cells pre-incubated with GA3 had significantly increased levels of A20 mRNA (4 h) and protein (24 h), resulting in a significant reduction in IL-6 and IL-8 release. This effect was mediated via reduced IkappaBalpha degradation and reduced NF-kappaB (p65) expression. Furthermore, the anti-inflammatory action of GA3 was abolished in A20-silenced cells. CONCLUSIONS AND IMPLICATIONS: We showed that A20 induction by GA3 attenuates inflammation in airway epithelial cells, at least in part through its effect on NF-kappaB and IkappaBalpha. GA3 or gibberellin-derived derivatives could potentially be developed into anti-inflammatory drugs for the treatment of chronic inflammatory diseases associated with A20 dysfunction. PMID- 26013854 TI - [Prospect of transanal minimally invasive surgery for rectal neoplasm]. AB - Transanal minimally invasive surgery (TAMIS) is a kind of minimally invasive surgery that local resection or total mesorectal excision for rectal neoplasm is performed through the use of multichannel port(single port) transanally. Compared to transanal endoscopic microsurgery(TEM) approach, TAMIS offers an alternative to TEM for rectal neoplasm, and shows the advantage of lower cost and shorter learning curve. TAMIS approach has been used not only in the local resection of rectal neoplasm but also in transanal total mesorectal excision (transanal TME), which is also called TAMIS-TME, in recent four years. The safety and efficacy of TAMIS approach has been shown in the currently published literatures. However, TAMIS approach has to wait for more evidence-based data with larger-scale and longer follow-up to get its validation. PMID- 26013855 TI - [Application of transanal endoscopic microsurgery in anorectal diseases]. AB - Transanal endoscopic microsurgery(TEM) is a safe and effective procedure for the treatment of local tumors, especially for the rectal villous adenoma (pT0), polyps with severe dysplasia and in situ carcinoma(pTis). It can also be applied as salvage surgery for incidental carcinoma after colonoscopy as well as in cases of giant villous adenoma. With the introduction of screening colonoscopy, more early polyps will be detected. We should be able to customize our treatment accordingly. On one hand, we want to prevent overkill and on the other hand to avoid under-treatment. This article is aimed to review the development of TEM and discuss its various indications. PMID- 26013856 TI - [Patient selection and operation standard of transanal endoscopic microsurgery]. AB - The development of transanal endoscopic microsurgery (TEM) during the last 30 years has led to the evolution of the treatment in rectal neoplasms. TEM has revolutionized the technique and outcomes of transanal surgery. To our knowledge, this technique is currently the only one-port system in endoscopic surgery by which a direct endoluminal approach to the target organ by using a natural opening of the body become available. TEM affords the advantage of a less invasive transanal approach with low recurrence rates secondary to a more precise dissection due to enhanced visualization of the surgical field. Currently, TEM represents the standard treatment modality for large rectal adenomas and a surgical option in selected early rectal cancers. Its potential role in the treatment of more invasive cancer in combination with neoadjuvant therapies, and other rectal localized tumors are currently under evaluation. The current trend of TEM is favorable in China. TEM has also been increasingly used in the treatment of rectal neoplasms, but there are many problems in the development of TEM, for example, preoperative assessment is inadequate, patient selection is not precise enough, the surgical procedure is not standardized, etc. These problems require the majority of surgical colleagues to work together to make the standards scientifically and objectively in accordance with the actual situation of our country, so as to promote the healthy development and popularity of TEM in China. PMID- 26013857 TI - [Transanal total mesorectal excision: the operative platform and potential issues]. AB - In recent 20 years, the most important advancement of rectal cancer surgery is the total mesorectal excision(TME) and laparoscopic minimal invasive surgery. However, visualization of the distal rectum is still troublesome because of narrow pelvic, bulky tumor, and especially obese male patients. A possible solution for this situation is distal rectal mobilization by transanal minimally invasive surgery (TAMIS), or even pure transanal total mesorectal excision (taTME). When people applaud a new era of rectal cancer surgery is coming, we must also concern about the patients selection, the long-term follow up results and even the operative safety. PMID- 26013858 TI - [A new beta-shaped intracorporeal Billroth II anastomosis technique after totally laparoscopic distal gastrectomy]. AB - OBJECTIVE: To investigate the feasibility and safety of the new beta-shaped intracorporeal Billroth II( gastrojejunostomy using laparoscopic linear stapler after totally laparoscopic distal gastrectomy. METHODS: Clinical data of 17 patients with distal gastric cancer who underwent beta-shape intracorporeal Billroth II( reconstruction after totally laparoscopic distal gastrectomy in our department from January 2012 to September 2014 were analyzed retrospectively. Laparoscopic linear stapler was used in intracorporeal beta-shaped Billroth II( side-to-side gastrojejunostomy for reconstruction. RESULTS: All the 17 patients underwent beta-shape intracorporeal Billroth II( reconstruction after totally laparoscopic distal gastrectomy successfully. There were no conversions and perioperative deaths. The average operative time was (207.3+/-11.3) min and the average anastomosis time was (41.2+/-2.5) min. The average number of harvested lymph node was 25.5+/-2.0 and estimated blood loss was (160.0+/-10.0) ml. The mean number of stapler was 6.5+/-0.2. The mean time to first flatus was (2.6+/ 0.2) d and the mean hospital stay was (10.0+/-0.4) d. No anastomotic stenosis, leakage or other complications were found during 6 to 14 month follow-up. CONCLUSIONS: The beta-shaped intracorporeal Billroth II( anastomosis technique after totally laparoscopic distal gastrectomy is safe and feasible. Anastomotic stenosis can be avoided using this new anastomosis method. PMID- 26013859 TI - [Application of modified double tracks anastomosis in patients with Siewert II III adenocarcinoma of the esophagogastric junction treated with radical gastrectomy]. AB - OBJECTIVE: To discuss the effect of modified double tracks anastomosis in patients with type Siewert II-III( adenocarcinoma of the esophagogastric junction(AEG) treated with radical gastrectomy. METHODS: Clinical data of 763 patients with type Siewert II-III AEG undergoing radical operation in our department from January 2004 to December 2008 were analyzed retrospectively. Patients were randomized into 3 groups according to the different procedures modes: radical proximal gastrectomy with modified double tracks anastomosis(266 cases), radical proximal gastrectomy with esophageal gastric stump end-to-side anastomosis(252 cases), and radical total gastrectomy with esophageal jejunum Roux-en-Y anastomosis(245 cases). There were no significant differences in general information and biological characteristics among the 3 groups(all P>0.05). Radical degree, safety, quality of life and prognosis were compared among 3 groups. RESULTS: There were no significant differences in postoperative complications among the three groups(P>0.05). Six months after operation, in modified double tracks anastomosis group, food intake recovery percentage was superior to the other two groups, and the Visick scores and endoscopic grading were better than esophageal gastric stump end-to-side anastomosis group(all P<0.05). There was no significant difference in recurrent rate of gastric stump between modified double tracks anastomosis group and esophageal gastric stump end to-side anastomosis group(P>0.05). The 5-year overall survival rate of these 3 groups was 48.7%, 46.3% and 50.2% respectively, and no significant difference was found(all P>0.05). CONCLUSION: Modified double tracks anastomosis is an ideal surgical method for type II-III AEG. PMID- 26013860 TI - [Comparison of postoperative outcomes between hand-assisted laparoscopic and conventional sigmoidectomy: a prospective non-randomized controlled trial]. AB - OBJECTIVE: To compare the perioperative safety and efficacy between hand-assisted laparoscopic surgery(HALS) and conventional open sigmoidectomy. METHODS: A total of 291 patients with sigmoid colon cancer who underwent surgery in our hospital from January 2010 to June 2013 were seperated into (HALS) group (n=200) and conventional open surgery (COS) group (n=91) with a non-randomized method. The perioperative safety and efficacy of two groups and perioperative outcomes were compared. RESULTS: These two groups were comparable in operative time, lymph node harvest, and postoperative complications. However, HALS group had less intraoperative bleeding [(57.9+/-28.3) ml vs. (82.5+/-47.6) ml, P=0.000], shorter time to flatus [(3.0+/-1.4) d vs. (3.3+/-0.9) d, P=0.000], and shorter hospital stay [(7.3+/-4.2) d vs. (8.9+/-4.4) d, P=0.004]. There werer no significant differences in overall survival time and disease-free survival time between the two groups during 6 months to 3 years follow-up. CONCLUSIONS: HALS results in similar outcomes of conventional open surgery for sigmoidectomy with the advantage of minimal invasiveness. PMID- 26013861 TI - [Efficacy analysis of laparoscopic adjustable gastric placation for obesity]. AB - OBJECTIVE: To analyze the efficacy and safety of laparoscopic adjustable gastric placation (LAGBP), a new procedure for surgical treatment of obesity. METHODS: Clinical and 1-year follow-up data of 10 patients who underwent LAGBP in our department between September and November 2011 were analyzed retrospectively. RESULTS: The mean operative time was (93.0+/-13.4) min, while the mean intraoperative blood loss was (15.5+/-4.7) ml. The mean excessive body weight loss rate(%EWL) at 3, 6, 9 and 12 months after the operation was 25.1%, 40.6%, 45.3% and 50.8% respectively. There were no severe post operative complications. CONCLUSIONS: LAGBP is associated with high safety and good short-term efficacy. PMID- 26013862 TI - [Feasibility of terminal intestinal exteriorization in laparoscopic anterior resection for anterior cancer]. AB - OBJECTIVE: To discuss the feasibility of terminal intestinal exteriorization (exteriorization without ileostomy) in laparoscopic anterior resection for rectal cancer. METHODS: Clinicopathological data of 77 patients undergoing laparoscopic anterior resection for low rectal cancer in our department from January 2011 to December 2013 were retrospectively analyzed. After laparoscopic rectal resection, 32 patients received terminal intestinal exteriorization (exteriorization group) and 45 patients received preventive ileostomy (ileostomy group). Anastomosis related, stoma-related and intestinal stoma closure-related morbidity was compared between the two groups. RESULTS: There were no significant differences in operative time, blood loss and overall hospital stay between the two groups (all P>0.05). The total hospital cost was (5.39+/-1.74)*10(4) yuan in the exteriorization group, and (6.98+/-1.37)*10(4) yuan in the ileostomy group(P<0.01). The incidences of postoperative anastomotic fistula was not significantly different between the two groups(P>0.05). Three patients(9.4%) developed anastomotic leak in the exteriorization group and 2(4.4%) in the ileostomy group. The anastomotic leak was managed by opening the external intestinal wall and maturating an ileostomy under local anaesthesia. All these 5 patients were cured with nutritional support, antibiotics, continuous local drainage. In the exteriorization group, 5 patients had complications related to stoma and intestinal stoma closure operation(15.6%), which was lower than(42.2%) in the ileostomy group(P=0.013). CONCLUSION: Terminal intestinal exteriorization in laparoscopic anterior resection is a safe and feasible surgical procedure with little trauma and less hospital cost, which can be an alternative as a prophylactic treatment for patients with high risk of anastomotic leak. PMID- 26013863 TI - [Influence of length of preserved ileocecum on the efficacy of laparoscopic subtotal colectomy antiperistaltic cecorectal anastomosis in the treatment of slow transit constipation]. AB - OBJECTIVE: To investigate the influence of length of preserved ileocecum on the efficacy of laparoscopic subtotal colectomy antiperistaltic cecorectal anastomosis (LSCACRA) in treating slow transit constipation (STC). METHODS: Clinical data of 81 STC patients who received LSCACRA between April 2007 And December 2011 in the 150th Center Hospital of PLA were continuously collected. Patients were divided into two groups: 10 cm to 15 cm ascending colon preserved above ileocecal junction(10-15 cm group, n=41), and 2 cm to 3 cm ascending colon preserved above ileocecal junction (2-3 cm group, n=40). The Wexner constipation scale (WCS), Wexner incontinence scale(WIS), gastrointestinal quality of life index(GIQLI), abdominal pain intensity scale(NRS), abdominal pain frequency scale and abdominal bloating frequency scale in the two groups were determined and compared before and 6, 12, 24 months after operation. RESULTS: No postoperative incontinence was found in all the patients. There were no significant differences in evacuation frequency between two groups at 6th and 12th month after surgery (all P>0.05). Two years after operation, barium enema emptying time examination revealed 2-3 cm group was (17.7+/-9.5) h, which was remarkably shorter than (21.2+/-20.7) h in 10-15 cm group (P=0.011). The WCS, GIQLI, NRS and abdominal pain frequency scale of two groups were improved obviously at 6th, 12th and 24th month after surgery (all P<0.01). Above parameters in 2-3 cm group were superior to 10-15 cm group (all P<0.01), but abdominal bloating frequency scale was not significantly different between the two groups (P>0.05). As compared with before operation, NRS in 2-3 cm group 6, 12, 24 months after operation reduced remarkably (all P<0.01), but did not improve obviously in 10-15 cm group (P>0.05). CONCLUSION: The shorter length of ascending colon preserved above ileocecal junction can improve the efficacy of LSCACRA in the treatment of STC and the prognosis of patients. Two to three cm length of ascending colon preserved above the ileocecal junction should be recommended. PMID- 26013864 TI - [Complication analysis of endorectal pull-through radical operation for Hirschsprung disease]. AB - OBJECTIVE: To summarize the complications after endorectal pull-through radical operation, Soave procedure, for Hirschsprung disease. METHODS: Clinical data of 286 cases with Hirschsprung disease who received Soave procedure and were proved by postoperative pathology in our hospital from February 2003 to February 2010 were analyzed retrospectively. All the patients were diagnosed with barium enema and anorectal manometry. Among them, 233 cases(81.5%) were identified during neonatal period. All the patients underwent cleansing enema and anus dilation immediately after definite diagnosis. Radical operation with Soave endorectal pull-through procedure, including simple transanal endorectal pull-through in 251 cases(87.8%), transabdominal approach in 17 cases (5.9%), laparoscopy-assisted endorectal pull-through in 18 cases (6.3%). The operations were performed in 54 cases (18.9%) within 3 months of age, in 183 cases (64.1%) between 3 and 6 months, in 38 cases(13.3%) between 6 months and one year, in 10 cases (3.5%) older than 1 year. The rectosigmoid was resected in 259 cases. Subtotal colectomy was performed in 25 cases, and total colectomy in 2 cases. Postoperative regular anal dilation lasted for 6 months. A total of 286 cases (male:250, female:36) were followed up for 2 to 5 years. RESULTS: There was wound infection in 1 case, ileus in 1 cases, anastomotic stricture in 1 case, which was cured by continuous anal dilation. Two cases had constipation and received re-operation because of refractory to conservative therapy for 6 months. Perianal erosion was found in 63 cases(22.0%) and was healed within 3 months, except 2 children undergoing total colectomy. During follow-up, enterocolitis occurred in 11 cases(3.8%), including healing in 8 cases with conservative therapy, death in 1 case, and recurrent attacks in 2 cases. Soiling occurred in 45 cases(15.7%), among them, 5 cases presented in kindergarten and primary school. Morbidities of perianal erosion, enterocolitis and soiling were higher in infants undergoing operation within 3 months as compared to those more than 3 months [90.7%(49/63) vs. 6.0%(14/63), P=0.000; 9.3%(5/54) vs. 2.6%(6/232), P=0.022; 25.9%(14/54) vs. 13.4%(31/232), P=0.022]. Morbidity of perianal erosion enterocolitis was higher in infants undergoing subtotal or total colectomy as compared to those partial colon resection[51.9%(14/27) vs. 18.9%(49/259), P=0.000; 18.5%(5/27) vs. 2.3%(6/259), P=0.000]. CONCLUSIONS: Primary transanal endorental pull-through procedure can be performed in most children with Hirschsprung disease. Postoperative short-term complications are mainly perianal erosion and long-term ones are enterocolitis and soiling. Early diagnosis, colon irrigation, avoiding premature operation and anal dilation can decrease the morbidities of enterocolitis and soiling. PMID- 26013865 TI - [Meta-analysis comparing robotic right colectomy with laparoscopic right colectomy on clinical short-term outcomes]. AB - OBJECTIVE: To compare the clinical short-term safety and efficacy between robotic right colectomy (RRC) and laparoscopic right colectomy(LRC) with meta-analysis. METHODS: A search of the Medline, Embase, Ovid, CNKI and WANFANG databases was performed for studies comparing clinical or oncologic outcomes of RRC with LRC before July 2014. The RevMan 5.2 software was used for meta-analysis. The operative time, estimated blood loss, length of hospital stay, conversion rate to open surgery, postoperative complications and related outcomes were evaluated. RESULTS: Six studies including 217 RRC cases and 400 conventional LRC cases were enrolled and analyzed. The meta-analysis showed that RRC had longer operative time (MD=48.05, 95% CI: 26.52 to 69.57, P<0.01), less estimated blood loss (MD= 17.74, 95% CI: -28.32 to -7.16, P=0.01), faster postoperative intestinal peristalsis recovery (MD=-0.79, 95% CI: -1.10 to -0.48, P<0.01), lower postoperative overall complications (OR=0.63, 95% CI: 0.42 to 0.93, P=0.02). Conversion rate and postoperative hospital stay between the two groups were not significantly different (all P>0.05). CONCLUSION: Compared to LRC, RRC is associated with less estimated blood loss, faster postoperative intestinal peristalsis recovery, lower postoperative overall complications, and longer operative time. PMID- 26013866 TI - [Investigation of quality of life in rectal cancer patients after anterior resection and expression of 5-hydroxytryptamine in rectal mucosa before and after operation]. AB - OBJECTIVE: To investigate the quality of life of rectal cancer patients after anterior resection and the role of 5-hydroxytryptamine(5-HT) in the pathogenesis of anterior resection syndrome (ARS). METHODS: Between November 2012 and October 2014, 90 rectal cancer patients who underwent Dixon procedure in the Institute of Surgery Research, Daping Hospital, Third Military Medical University, and developed ARS postoperatively were enrolled in the study. By clinic interview and telephone follow-up, they were investigated according to the 4 questionnaires, including gastrointestinal quality of life index(GIQLI), Wexner constipation and incontinence score(WCS, WIS), and 36-item short form health survey(SF-36). Associated clinical data and above parameters were compared between postoperative 0-6 months and 7-24 months. Expression of 5-HT in rectal mucosa was determined by immunohistochemistry preoperatively and postoperatively. RESULTS: The GIQLI, WCS and WIS were significantly improved in 7-24 months group compared with those in 0 6 months group(all P<0.05). Furthermore, the SF-36 test result also showed significant improvement in the terms of physical function, physical role, vitality, social function, emotional role and health changes spheres in 7-24 months group(P<0.05). 5-HT expression in rectal mucosa(upper anastomosis 3402.95+/-1876.24, lower anastomosis 3045.35+/-1373.59 of ARS patients was significantly down-regulated compared with the preoperative expression(rectal margin mucosa 7176.60+/-3927.61)(P<0.05). CONCLUSIONS: Patients with ARS experience a significant trend toward recovery in their whole long-term quality of life. The down-regulation of 5-HT expression in rectal mucosa after surgery may be related with the pathogenesis of ARS. PMID- 26013867 TI - [Predictive value of preoperative imaging and postoperative pathology on clinical complete response after neoadjuvant chemoradiation for locally advanced rectal cancer]. AB - OBJECTIVE: To evaluate the accuracy and clinical significance of clinical complete response (cCR) after neoadjuvant themoradiotherapy for locally advanced rectal cancer. METHODS: Locally advanced rectal cancer patients who received neoadjuvant chemoradiotherapy following radical resection were retrospectively assessed for tumor response during 2005 to 2014 from the database of colorectal cancer. The concomitant preoperative chemoradiation consisted of 50 Gy radiation, fractionated within 5 weeks and 5-FU combined with oxaliplatin. Endorectal ultrasound and MRI were applied to preoperative staging, and postoperative gross pathologic inspection was retrospectively employed to evaluate the status of clinical complete response(cCR). RESULTS: A total of 227 patients undergoing radical surgery were enrolled in the study. Complete pathological response (ypT0N0, pCR) was found in 40 patients(17.6%) by postoperative pathologic examination while the rate of node involved in ypT0 patients was 11.1%. The preoperative rectal MRI was more sensitive to correlate ypT0 than endorectal ultrasound and gross pathologic inspection(60.0% vs 19.4% and 17.8%), but the accuracy and specificity showed no significant differences among these three tests. Multivariate Logistic regression analysis revealed preoperative MRI evaluation of cT0 might predict ypT0 independently(OR=4.975, 95% CI: 1.073 to 23.067, P=0.040). CONCLUSION: It is difficult to diagnose the primary tumor to be a cCR status based on preoperative MRI, EUS, or ulceration of rectal mucosa, and further to predict pCR. Preoperative MRI is more sensitive. The strategy of "wait and see" for cCR patients after neoadjuvant chemoradiation should be seriously considered in the decision-making before surgery. PMID- 26013868 TI - [Submucosal tunneling endoscopic resection in the treatment of esophageal submucosal tumors originating from muscularis propria layer]. AB - OBJECTIVE: To evaluate the short-term outcomes and complication management of submucosal tunneling endoscopic resection(STER) for esophageal submucosal tumors (SMTs) originating from the muscularis propria(MP) layer. METHODS: Clinical data of 48 patients with esophageal SMTs from MP layer undergoing STER in the Department of Gastroenterology, the First People's Hospital of Xiangshan, Zhejiang, and the Endoscopy Center of Zhongshan Hospital, Fudan University, Shanghai between September 2013 and August 2014 were retrospectively analyzed. The clinicopathological features, complication management, and short-term outcomes were evaluated. RESULTS: All the patients underwent STER successfully. The complete resection rate was 100%. The mean maximum diameter of the lesions was (22.9+/-12.1) mm (range 9.0-60.0 mm), and the mean operation time 41.8 min (range 15.0-140.0 min). Intraoperative mucosal injury occurred in 5 patients (10.4%), which was successfully clipped, pneumoperitoneum in 2 patients (4.2%) and subcutaneous emphysema in 3 patients(6.3%), which were successfully controlled with conservative treatments. Five patients (10.4%) had postoperative severe chest pain. Seven patients (14.6%) developed fever, among them, 5 were managed by conservative therapy, and 2 were submucosal tunnel infection, who were successfully treated after reclosing the ruptured tunnel entry with clips. All the removed tumors had tumor-free resection margins. The average length of postoperative hospital stay was 2.4 days (range 1-13 days). Local recurrence and distant metastasis did not occur during mean 6.8 months (range 2-12 months) follow up. CONCLUSIONS: STER appears to be a safe and effective option for esophageal SMTs originating from MP layer. Common complications related to STER often can be successfully controlled with conservative treatments. PMID- 26013869 TI - [Risk factors of unplanned reoperation after colorectal cancer surgery: a case control study]. AB - OBJECTIVE: To explore the risk factors of unplanned reoperation after radical resection for colorectal cancer. METHODS: A retrospective analysis of 60 patients (within 14 to 24 days after the initial surgery) receiving unplanned reoperation after colorectal cancer surgery in the First Affiliated Hospital of Xinjiang Medical University from January 2010 to January 2014 was carried out, comparing with 120 randomly paired patients without reoperation during the same period. Univariate and multivariate Logistic regression analysis was performed to investigate the clinicopathologic characteristics of patients in both groups. RESULTS: Univariate logistic regression analysis showed that male, massive blood loss, diabetes, high BMI, hypertension and poorer tumor staging were selected as possible risk factors, and surgeon and laparoscopic surgery as conservative factors (all P<0.05). Multivariate logistic regression analysis revealed that massive blood loss (OR=12.935, 95% CI: 2.267 to 73.806, P=0.004), diabetes (OR=1.747, 95% CI: 1.098 to 2.777, P=0.018) and male (OR=1.805, 95% CI: 1.074 to 3.034, P=0.026) were the independent risk factors of unplanned reoperation after radical resection for colorectal cancer. CONCLUSION: For heavy bleeding, diabetes and male gender in patients with colorectal cancer, surgeon should pay attention to prevent the risk of postoperative unplanned reoperation. PMID- 26013870 TI - [Accuracy of endoscopic ultrasound in the preoperative staging and the guidance of transanal endoscopic microsurgery for rectal cancer]. AB - OBJECTIVE: To explore the accuracy of endoscopic ultrasound (EUS) in preoperative staging of rectal cancer and to guide the treatment of transanal endoscopic microsurgery (TEM) in early rectal cancer. METHODS: Clinical data of 80 patients with rectal cancer receiving EUS examination for preoperative staging in our department between June and December 2012 were retrospectively analyzed. Consistence comparison of EUS preoperative staging and pathological staging was performed to identify the accuracy of EUS preoperative staging. All the patients underwent operation within 1 week after EUS examination. According to preoperative staging, early rectal cancer(Tis or T1N0M0) patients with lesions less 20 cm to anus underwent TEM. RESULTS: The overall accuracy of EUS for preoperative T stage was 68.8%(55/80), and for T1, T2, T3, T4 was 91.3%(73/80), 83.8%(68/80), 77.5%(62/80), 85.0%(67/80), which had a good consistence with postoperative pathological T staging(Kappa=0.562). The overall accuracy of EUS for preoperative N stage was 52.7%(39/74), and for N0, N1, N2 stage was 64.9%(48/74), 55.4%(41/74), 85.1%(63/74), which had a poor consistence with postoperative pathological N staging(Kappa=0.235). Six patients underwent TEM successfully, with mean operation time 99(65 to 123) min, without intraoperative and postoperative complication, and were discharged 2-3 days after operation. Enteroscope showed good recovery 1 month later. Pathology confirmed that all the lesions were early rectal cancer. During postoperative follow-up of 14.8 (11 to 19) months, there was no local recurrence and distant metastasis. CONCLUSION: Preoperative EUS has a good accuracy with pathologic T stage, and can guide TEM in early rectal cancer. PMID- 26013871 TI - [Establishment of rat slow transit constipation model by selective chemical ablation of the enteric plexus]. AB - OBJECTIVE: To establish an innovative rat model of slow transit constipation by selective chemical ablation of the colon enteric plexus. METHODS: Sprague Dawley rats, 5-6 weeks old, were randomly divided into normal control group, sham operation group, treatment group I, II, III, IIII. The normal control group did not receive treatment. Rats in the sham operation group and the treatment groups received abdominal operation under anesthesia, and the gauze containing 0.9% normal saline, 0.05%, 0.1%, 0.25%, 0.5% benzalkonium chloride (BAC) was applied into colon for 30 minutes. Two weeks after operation, the number of feces, fecal dry weight in 24 h and gastrointestinal transit time were recorded, then hematoxylin-eosin (HE) staining, immunohistochemistry, ELISA were used for the evaluation of colonic pathology, enteric plexus, Interstitial cells of Cajal and neurotransmitters 5-hydroxytryptamine(5-HT). RESULTS: Compared to the normal control group and the sham operation group, the gastrointestinal transit time was significantly prolonged and fecal dry weight was lower in the treatment group II, III (all P<0.05). HE and immunohistochemical staining showed varying degrees of pathological changes in the treatment groups and in line with the pathological changes of slow transit constipation. 5-HT concentration reduced significantly in treatment group III compared to other groups (P<0.01). CONCLUSION: The animal model of STC is successfully established by applying 0.25% BAC selective chemical ablation of the colon enteric plexus. This model is simple, stable, and is more in line with pathological changes of slow transit constipation. PMID- 26013872 TI - [Recent advances of anastomosis techniques of esophagojejunostomy after laparoscopic totally gastrectomy in gastric tumor]. AB - The esophageal jejunum anastomosis of the digestive tract reconstruction techniques in laparoscopic total gastrectomy includes two categories: circular stapler anastomosis techniques and linear stapler anastomosis techniques. Circular stapler anastomosis techniques include manual anastomosis method, purse string instrument method, Hiki improved special anvil anastomosis technique, the transorally inserted anvil(OrVil(TM)) and reverse puncture device technique. Linear stapler anastomosis techniques include side to side anastomosis technique and Overlap side to side anastomosis technique. Esophageal jejunum anastomosis technique has a wide selection of different technologies with different strengths and the corresponding limitations. This article will introduce research progress of laparoscopic total gastrectomy esophagus jejunum anastomosis from both sides of the development of anastomosis technology and the selection of anastomosis technology. PMID- 26013873 TI - [Bile acids and bariatric surgery]. AB - As an essential metabolic molecule, bile acids regulate triglyceride, cholesterol, energy metabolism. Bariatric surgery offers a treatment that can reduce weight and induce metabolic syndrome, but the mechanism is still unclear. New researches reveal that serum bile acids are elevated after surgery, as well as the improvement of metabolic disease. The surgery changes gastrointestinal tract, resulting in a short circuiting of the enterohepatic circulation of bile acids. Here we review the bile acids metabolism and their effect after bariatric surgery. PMID- 26013874 TI - Effects of precipitation regime and soil nitrogen on leaf traits in seasonally dry tropical forests of the Yucatan Peninsula, Mexico. AB - Leaf traits are closely associated with nutrient use by plants and can be utilized as a proxy for nutrient cycling processes. However, open questions remain, in particular regarding the variability of leaf traits within and across seasonally dry tropical forests. To address this, we considered six leaf traits (specific area, thickness, dry matter content, N content, P content and natural abundance (15)N) of four co-occurring tree species (two that are not associated with N2-fixing bacteria and two that are associated with N2-fixing bacteria) and net N mineralization rates and inorganic N concentrations along a precipitation gradient (537-1036 mm per year) in the Yucatan Peninsula, Mexico. Specifically we sought to test the hypothesis that leaf traits of dominant plant species shift along a precipitation gradient, but are affected by soil N cycling. Although variation among different species within each site explains some leaf trait variation, there is also a high level of variability across sites, suggesting that factors other than precipitation regime more strongly influence leaf traits. Principal component analyses indicated that across sites and tree species, covariation in leaf traits is an indicator of soil N availability. Patterns of natural abundance (15)N in foliage and foliage minus soil suggest that variation in precipitation regime drives a shift in plant N acquisition and the openness of the N cycle. Overall, our study shows that both plant species and site are important determinants of leaf traits, and that the leaf trait spectrum is correlated with soil N cycling. PMID- 26013875 TI - Age-dependent survival of island vs. mainland populations of two avian scavengers: delving into migration costs. AB - Large terrestrial long-lived birds (including raptors) are typically sedentary on islands, even when they are migratory on the mainland. Density-dependent variation in the age at first breeding has been described as responsible for the long-term persistence of long-lived bird populations on islands. However, sedentary island populations may also benefit from higher survival rates derived from the absence of migration costs, especially for young individuals. Thus, sedentary island populations can mimic a natural experiment to study migration costs. We estimated the age-dependent survival of two sedentary raptors on the island of Menorca (Egyptian vultures Neophron percnopterus and red kites Milvus milvus) and compared these estimates with those reported for other migratory and sedentary populations. In Menorca, Egyptian vultures, but not red kites, showed low levels of human-related mortality resulting in extremely high survival probabilities, probably due to different diet choices and behavioral patterns. Juvenile Egyptian vultures and red kites in the studied population had lower survival probabilities than adults. This difference, however, was smaller than those reported for mainland migrant populations, which showed a lower juvenile survival rate. In fact, between-population comparisons suggested that survival of the young in migrant populations may be triggered by mortality factors in wintering areas. In contrast, adult survival may respond to mortality factors in breeding areas. Our results suggest that raptor species that become sedentary on islands may benefit from higher pre-breeder survival prospects in comparison with their mainland migrant counterparts. This fact, in combination with an earlier age at first reproduction, may facilitate their persistence. PMID- 26013877 TI - Evaluate the subjective experience of the disease and its treatment in the partners of young women with non-metastatic breast cancer. AB - The impact of the disease experience on the quality of life of the relatives of patients with cancer is now well documented. However, few scales specifically address the partners' subjective quality of life. This study aims to validate a questionnaire assessing the impact of cancer on the quality of life of the partners of young women with breast cancer. Partners (n = 499) of women aged <45 when diagnosed with a non-metastatic breast cancer completed a self-reported questionnaire generated from non-directive interviews led in an initial study. The structure of the scale was examined by exploratory and confirmatory factor analyses. Internal consistency, test-retest reliability and concurrent validity were assessed. The final Partner-YW-BCI contained 36 items and assessed eight dimensions of the subjective experience of partners: (1) feeling of couple cohesion, (2) negative affectivity and apprehension about the future, (3) body image and sexuality, (4) career management, (5) deterioration of the relationships with close relatives, (6) management of child(ren) and of everyday life, (7) financial difficulties, and (8) sharing and support from close relatives. The scale showed adequate psychometric properties, and will help clinicians to identify the problems of partners and to respond to them by an optimal care management. PMID- 26013878 TI - PI3K target based novel cyano derivative of betulinic acid induces its signalling inhibition by down-regulation of pGSK3beta and cyclin D1 and potentially checks cancer cell proliferation. AB - In spite of the Betulinic acid (BA) being recognized as anticancerous source; its further use in clinical development is greatly hampered because of its poor pharmacokinetic properties. To circumvent these limitations, we synthesized a PI3K target based library of 18 triazole based derivatives and we identified a C 3 cyano analog of betulinic acid (CBA) with significant cell death effects with 5 7 fold higher potency than BA in various cancers. Importantly, no such report is available demonstrating the involvement of BA or its structural analogs in the modulation of PI3K pathway. Using, human leukemia HL-60 cells as a model, we for the first time report that CBA decreased expression of PI3K p110alpha, p85alpha, and pAKT in HL-60. Furthermore, we could find significant depletion of pGSK3beta, cyclin D1 and increased expression of p21/cip, p27/Kip proteins. CBA induced G0/G1 cell cycle arrest, increased sub-G0 DNA fraction and annexin V binding of the cells besides imparting the typical surface features of cell death. Also, this target specific inhibition was associated with mitochondrial apoptosis as was reflected by expression studies of various proteins together with reactive oxygen species generation and decline in mitochondrial trans membrane potential. The apoptotic effectors i.e., caspase 8 and caspase 9 were found to get upregulated besides PI3K associated DNA repair enzyme i.e., PARP cleavage was observed. Thus, our results elucidated that CBA or other BA based small molecules inhibit PI3K/AKT pathway with induction of subsequent cancer cell death which may be useful therapeutic strategy against leukemias and possibly other cancers. PMID- 26013879 TI - Innate and virtual memory T cells in man. AB - A hallmark of the antigen-specific B and T lymphocytes of the adaptive immune system is their capacity to "remember" pathogens long after they are first encountered, a property that forms the basis for effective vaccine development. However, studies in mice have provided strong evidence that some naive T cells can develop characteristics of memory T cells in the absence of foreign antigen encounters. Such innate memory T cells may develop in response to lymphopenia or the presence of high levels of the cytokine IL-4, and have also been identified in unmanipulated animals, a phenomenal referred to as "virtual memory." While the presence of innate memory T cells in mice is now widely accepted, their presence in humans has not yet been fully validated. In this issue of the European Journal of Immunology, Jacomet et al. [Eur. J. Immunol. 2015. 45:1926-1933] provide the best evidence to date for innate memory T cells in humans. These findings may contribute significantly to our understanding of human immunity to microbial pathogens and tumors. PMID- 26013880 TI - Hysteroscopy and contraception. AB - The Essure method is the only available hysteroscopic sterilisation method. A 4 cm device is placed in the fallopian tubes, which then induces an inflammatory reaction that causes occlusion. The method has a high successful placement rate and high effectiveness, and it can be performed in an office setting without anaesthesia. Three months after the procedure, a confirmation test has to be conducted to assure a correct position of the micro-inserts and tubal occlusion. This test can be performed by hysterosalpingography (HSG), plain X-ray or ultrasound. Pregnancies reported after Essure sterilisation are, in a majority, related to non-adherence to the follow-up protocol or misreading of the confirmation test. A majority of the pregnancies occurred after HSGs that were determined to have been misinterpreted, including missed expulsion or perforation of the micro-insert. Other complications such as ectopic pregnancy and allergic reaction to the micro-inserts seem to have been described to be of low incidence. PMID- 26013882 TI - Carboxylate Assisted Ni-Catalyzed C-H Bond Allylation of Benzamides. AB - A one-step synthetic method was developed for allylation of benzamides using Ni(COD)2/RCO2 H and [Ni(MU-H2O)(OOCCMe3)2 (HOOCCMe3)2]2 (A') catalytic system. Efficient, well-defined, air and moisture-stable Ni-pivalate complex was isolated and employed in catalytic allylation. The influence of solvent on product selectivity was also investigated. PMID- 26013883 TI - Nucleophilic beta-Carbon Activation of Propionic Acid as a 3-Carbon Synthon by Carbene Organocatalysis. AB - Direct beta-carbon activation of propionic acid (C2H5CO2H) by carbene organocatalysis has been developed. This activation affords the smallest azolium homoenolate intermediate (without any substituent) as a 3-carbon nucleophile for enantioselective reactions. Propionic acid is an excellent raw material because it is cheap, stable, and safe. This approach provides a much better solution to azolium homoenolate synthesis than the previously established use of acrolein (enal without any substituent), which is expensive, unstable, and toxic. PMID- 26013908 TI - Mitochondrial Ca(2+) in neurodegenerative disorders. AB - Functional mitochondria are vital to accomplish their key role in the cell, by maintaining the energy metabolism, buffering of the Ca(2+) signal and directing the cell death mechanism. Mitochondrial Ca(2+) can stimulate ATP production or trigger the opening of mitochondrial permeability transition pore and activating the cell death cascade. Mitochondrial Ca(2+) uptake play a crucial role in neurons by buffering excessive Ca(2+) from the cytosol at the time of the transmission of the signal. Changes in the maintenance of mitochondrial Ca(2+) may trigger neuronal cell death. Abnormality in mitochondrial Ca(2+) handling has been detected in a range of neurodegenerative diseases, and emerging evidence from disease models suggests that mitochondrial Ca(2+) may play a role in disease pathogenesis. In this review, we assess how mitochondrial Ca(2+) imbalance may be a trigger in common neurodegenerative disease. PMID- 26013909 TI - Preventability of Voluntarily Reported or Trigger Tool-Identified Medication Errors in a Pediatric Institution by Information Technology: A Retrospective Cohort Study. AB - INTRODUCTION: Information technology (IT) has the potential to prevent medication errors. While many studies have analyzed specific IT technologies and preventable adverse drug events, no studies have identified risk factors for errors still occurring that are not preventable by IT. OBJECTIVES: The objective of this study was to categorize reported or trigger tool-identified errors and adverse events (AEs) at a pediatric tertiary care institution. Also, we sought to identify medication errors preventable by IT, determine why IT-preventable errors occurred, and to identify risk factors for errors that were not preventable by IT. METHODS: This was a retrospective analysis of voluntarily reported or trigger tool-identified errors and AEs occurring from 1 July 2011 to 30 June 2012. Medication errors reaching the patients were categorized based on the origin, severity, and location of the error, the month in which they occurred, and the age of the patient involved. Error characteristics were included in a multivariable logistic regression model to determine independent risk factors for errors occurring that were not preventable by IT. A medication error was defined as a medication-related failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim. An IT-preventable error was defined as having an IT system in place to aid in prevention of the error at the phase and location of its origin. RESULTS: There were 936 medication errors (identified by voluntarily reporting or a trigger tool system) included and analyzed. Drug administration errors were identified most frequently (53.4% ), but prescribing errors most frequently caused harm (47.2 % of harmful errors). There were 470 (50.2 %) errors that were IT preventable at their origin, including 155 due to IT system bypasses, 103 due to insensitivity of IT alerting systems, and 47 with IT alert overrides. Dispensing, administration, and documentation errors had higher odds than prescribing errors for being not preventable by IT [odds ratio (OR) 8.0, 95 % CI 4.4-14.6; OR 2.4, 95 % CI 1.7-3.7; and OR 6.7, 95 % CI 3.3-14.5, respectively; all p < 0.001). Errors occurring in the operating room and in the outpatient setting had higher odds than intensive care units for being not preventable by IT (OR 10.4, 95 % CI 4.0-27.2, and OR 2.6, 95 % CI 1.3-5.0, respectively; all p <= 0.004). CONCLUSIONS: Despite extensive IT implementation at the studied institution, approximately one-half of the medication errors identified by voluntarily reporting or a trigger tool system were not preventable by the utilized IT systems. Inappropriate use of IT systems was a common cause of errors. The identified risk factors represent areas where IT safety features were lacking. PMID- 26013910 TI - Enhanced training in emergency medicine: the search and application process. PMID- 26013911 TI - Light availability affects stream biofilm bacterial community composition and function, but not diversity. AB - Changes in riparian vegetation or water turbidity and browning in streams alter the local light regime with potential implications for stream biofilms and ecosystem functioning. We experimented with biofilms in microcosms grown under a gradient of light intensities (range: 5-152 MUmole photons s(-1) m(-2) ) and combined 454-pyrosequencing and enzymatic activity assays to evaluate the effects of light on biofilm structure and function. We observed a shift in bacterial community composition along the light gradient, whereas there was no apparent change in alpha diversity. Multifunctionality, based on extracellular enzymes, was highest under high light conditions and decoupled from bacterial diversity. Phenol oxidase activity, involved in the degradation of polyphenolic compounds, was twice as high on average under the lowest compared with the highest light condition. This suggests a shift in reliance of microbial heterotrophs on biofilm phototroph-derived organic matter under high light availability to more complex organic matter under low light. Furthermore, extracellular enzyme activities correlated with nutrient cycling and community respiration, supporting the link between biofilm structure-function and biogeochemical fluxes in streams. Our findings demonstrate that changes in light availability are likely to have significant impacts on biofilm structure and function, potentially affecting stream ecosystem processes. PMID- 26013913 TI - Midtrimester spontaneous torsion of unruptured gravid rudimentary horn: Presurgical diagnosis on magnetic resonance imaging. AB - Unicornuate uterus with rudimentary horn occurs due to failure of complete development and partial fusion of one of the Mullerian ducts. Pregnancy in a non communicating rudimentary horn is extremely rare, with a reported incidence of 1 in 76 000-150 000 pregnancies, and usually terminates in rupture during the first or second trimester. Clinical diagnosis of rudimentary horn pregnancy in a woman with history of normal vaginal delivery in prior gestations is difficult. The role of sonography, and more recently, magnetic resonance imaging, in the presurgical diagnosis of rudimentary horn pregnancy is established. We present a case of magnetic resonance imaging diagnosis of 20-week pregnancy in the unruptured non-communicating rudimentary horn in a patient with previous history of two full-term normal vaginal deliveries. The novelty of the case lies in the fact that there was associated torsion of the gravid rudimentary horn and ipsilateral ovary, which has not been reported previously. PMID- 26013914 TI - Illness representations and psychological distress in Indian patients with cancer: does being aware of one's cancer diagnosis make a difference? AB - BACKGROUND: This study applied the Common Sense Model of illness representations to understand the psychological reactions of Indian patients with cancer who report being aware or unaware of their cancer diagnosis. METHODS: Adult Indian patients with cancer (N = 329) were asked about their understanding of their illness (to assess awareness of a cancer diagnosis), and then completed the Brief Illness Perception Questionnaire and the Hospital Anxiety Depression Scale. RESULTS: Patients who reported being unaware of their cancer diagnosis (54.1%) experienced higher levels of anxiety and depression. After controlling for awareness, education, income, cancer symptoms, and cancer stage, illness perceptions accounted for significant amounts of variance in anxiety (?R(2) = 0.42) and depression (?R(2) = 0.33). Illness coherence mediated the relationship between awareness of a cancer diagnosis and anxiety. Moderated regression analyses indicated that several relationships between illness perceptions and anxiety/depression were stronger among patients who reported being unaware of their cancer diagnosis. CONCLUSIONS: The Common Sense Model provides a useful framework for explaining the psychological reactions of Indian patients with cancer to their illness, particularly for those who report being unaware of their cancer diagnosis. PMID- 26013912 TI - Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial. AB - Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (<35 years) and 20 elderly (50-80 year) healthy, male non-smokers consumed either a CF-containing drink (450 mg CF) or nutrient-matched, CF-free control drink bi-daily for 14 days. The primary endpoint was endothelial function as measured by flow-mediated vasodilation (FMD). Secondary endpoints included cardiac output, vascular stiffness, conductance of conduit and resistance arteries, and perfusion in the microcirculation. Following 2 weeks of CF intake, FMD improved in young (6.1 +/- 0.7 vs. 7.6 +/- 0.7 %, p < 0.001) and elderly (4.9 +/- 0.6 vs. 6.3 +/- 0.9 %, p < 0.001). Secondary outcomes demonstrated in both groups that CF intake decreased pulse wave velocity and lowered total peripheral resistance, and increased arteriolar and microvascular vasodilator capacity, red cell deformability, and diastolic blood pressure, while cardiac output remained affected. In the elderly, baseline systolic blood pressure was elevated, driven by an arterial-stiffness related augmentation. CF intake decreased aortic augmentation index (-9 %) and thus systolic blood pressure (-7 mmHg; Clinicaltrials.gov: NCT01639781). CF intake reverses age-related burden of cardiovascular risk in healthy elderly, highlighting the potential of dietary flavanols to maintain cardiovascular health. PMID- 26013915 TI - Ticks on passerines from the Archipelago of the Azores as hosts of borreliae and rickettsiae. AB - We examined the presence of borreliae and rickettsiae bacteria in ticks from wild passerine birds on three islands of the Archipelago of the Azores, the westernmost region of Palearctic. A total of 266 birds belonging to eight species from seven families were examined on Sao Miguel, Santa Maria and Graciosa islands in 2013. Ticks collected from these birds consisted of 55 Ixodes frontalis (22 larvae, 32 nymphs, 1 adult female) and 16 Haemaphysalis punctata nymphs. Turdus merula and Erithacus rubecula were the birds most infested with both tick species. Three T. merula in Santa Maria were infested with 4 I. frontalis infected with Borrelia turdi. No rickettsiae were found in the ticks. We report for the first time the presence of I. frontalis and B. turdi on the Azores islands and we showed that the spatial distribution reaches further west than previously thought. PMID- 26013916 TI - Impact of laryngologist and speech pathologist coassessment on outcomes and billing revenue. AB - OBJECTIVES/HYPOTHESIS: This study investigated financial and treatment implications of a speech-language pathologist (SLP) performing a voice evaluation at the initial laryngologic visit. STUDY DESIGN: Retrospective chart review. METHODS: Medical records from 75 consecutive adult voice therapy patients during a 3-month period were categorized into two groups: group 1 (n = 37) represented patients who underwent a medical speech evaluation (MSE) at the initial voice assessment with the laryngologist (+SLP), and group 2 (n = 38) represented patients who did not receive an MSE (-SLP). Data collected included age, gender, voice diagnosis, number of therapy sessions attended and cancelled, reason for discharge, and pre- and post-voice therapy Voice Handicap Index-10 (VHI-10) scores. RESULTS: Patients in the +SLP group had fewer cancellations (P = 0.001), greater change in VHI-10 from pre- to post-therapy (P = .001), and were more likely to be discharged from therapy having met therapeutic goals (P = .007) than patients in the -SLP group. In addition, lost revenue over 3 months due to cancellations/no-shows was $2,260 in the +SLP group compared to $7,030 in the SLP group (P < .001). CONCLUSIONS: Concurrent voice evaluation by an SLP and laryngologist at initial diagnostic visit affects therapy attendance, voice therapy outcomes, and ultimately SLP and departmental billing revenue. Results may be due to more appropriate therapy referrals from SLP assessment of patients in conjunction with a laryngologist. LEVEL OF EVIDENCE: 4. PMID- 26013917 TI - Can Dyscalculics Estimate the Results of Arithmetic Problems? AB - The present study is the first to examine the computation estimation skills of dyscalculics versus controls using the estimation comparison task. In this task, participants judged whether an estimated answer to a multidigit multiplication problem was larger or smaller than a given reference number. While dyscalculics were less accurate than controls, their performance was well above chance level. The performance of controls but not of those with developmental dyscalculia (DD) improved consistently for smaller problem sizes. The performance of both groups was superior when the reference number was smaller (vs. larger) than the exact answer and when it was far (vs. close) from it, both of which are considered to be the markers of the approximate number system (ANS). Strategy analysis distinguished between an approximated calculation strategy and a sense of magnitude strategy, which does not involve any calculation but relies entirely on the ANS. Dyscalculics used the latter more often than controls. The present results suggest that there is little, if any, impairment in the ANS of adults with DD and that their main deficiency is with performing operations on magnitudes rather than with the representations of the magnitudes themselves. PMID- 26013918 TI - Deletion of phospholipase A2 group IVc induces apoptosis in rat mammary tumour cells by the nuclear factor-kappaB/lipocalin 2 pathway. AB - Although some forms of phospholipase A2, the initiator of the arachidonic acid cascade, contribute to carcinogenesis in many organs, the contribution of phospholipase A2 group IVc (Pla2g4c) remains to be clarified and the function of the enzyme in cancer development is unknown. The Hirosaki hairless rat (HHR), a mutant rat strain with autosomal recessive inheritance, derived spontaneously from the Sprague-Dawley rat (SDR). The HHRs showed a lower incidence and much smaller volume of mammary tumours induced by 7,12-dimethylbenz[a]anthracene, and a markedly increased number of TUNEL (terminal deoxynucleotidyltransferase mediated dUTP nick-end labelling)-positive apoptotic cells was detected. Array comparative genomic hybridization and PCR analyses revealed the deletion of 50-kb genomic DNA on 1q21, including Pla2g4c, in HHRs. The Pla2g4c gene was expressed in the ductal carcinoma cells and myoepithelial cells in SDRs, but not in HHRs. The direct involvement of Pla2g4c in the prevention of cell death was demonstrated through the inhibition of its expression in rat mammary tumour RMT-1 cells using siRNA. This treatment also induced expression of lipocalin 2 (Lcn2) and other NF-kappaB (nuclear factor kappaB)-related genes. siRNA-induced apoptosis was inhibited by Lcn2 repression or NF-kappaB inhibitors. This is the first report on Pla2g4c gene-deficient rats and their low susceptibility to mammary carcinogenesis by enhancing NF-kappaB/Lcn2-induced apoptosis. PMID- 26013919 TI - NIG_MoG: a mouse genome navigator for exploring intersubspecific genetic polymorphisms. AB - The National Institute of Genetics Mouse Genome database (NIG_MoG; http://molossinus.lab.nig.ac.jp/msmdb/) primarily comprises the whole-genome sequence data of two inbred mouse strains, MSM/Ms and JF1/Ms. These strains were established at NIG and originated from the Japanese subspecies Mus musculus molossinus. NIG_MoG provides visualized genome polymorphism information, browsing single-nucleotide polymorphisms and short insertions and deletions in the genomes of MSM/Ms and JF1/Ms with respect to C57BL/6J (whose genome is predominantly derived from the West European subspecies M. m. domesticus). This allows users, especially wet-lab biologists, to intuitively recognize intersubspecific genome divergence in these mouse strains using visual data. The database also supports the in silico screening of bacterial artificial chromosome (BAC) clones that contain genomic DNA from MSM/Ms and the standard classical laboratory strain C57BL/6N. NIG_MoG is thus a valuable navigator for exploring mouse genome polymorphisms and BAC clones that are useful for studies of gene function and regulation based on intersubspecific genome divergence. PMID- 26013920 TI - Cation-assisted interactions between N-heterocycles and CO2. AB - Cation-assisted interactions between N-containing heterocycles (NHCs) and CO2 have been systematically studied by using density functional theory (DFT). For neutral and anionic (non-carbenoid) NHCs, the effects of monovalent cations (i.e., alkali metal ions) are moderate to small (the NHC-CO2 binding energy change, DeltaBE usually < 25 kJ mol(-1)). However, for NHC carbenes, due to their strong basicity, the effects are strong (DeltaBE > 60 kJ mol(-1)) and the monovalent cations play a critical role in the single carboxylation of dicarbenes with CO2. In comparison, divalent alkali earth metal cations, due to both their smaller sizes and higher formal charges, exhibit a much stronger influence (DeltaBE > 100 kJ mol(-1)). Divalent cations should be incorporated into next generation CO2 capture reagents. Other aspects including the reaction potential energy surface (PES), orbital-based analyses of interactions, substitution effects, and the reactivity descriptors (cation size, reacting N lone pair orbital energy, etc.) have been discussed in detail as well. PMID- 26013921 TI - Response Rates to Anticonvulsant Trials in Patients with Triphasic-Wave EEG Patterns of Uncertain Significance. AB - BACKGROUND: Generalized triphasic waves (TPWs) occur in both metabolic encephalopathies and non-convulsive status epilepticus (NCSE). Empiric trials of benzodiazepines (BZDs) or non-sedating AED (NSAEDs) are commonly used to differentiate the two, but the utility of such trials is debated. The goal of this study was to assess response rates of such trials and investigate whether metabolic profile differences affect the likelihood of a response. METHODS: Three institutions within the Critical Care EEG Monitoring Research Consortium retrospectively identified patients with unexplained encephalopathy and TPWs who had undergone a trial of BZD and/or NSAEDs to differentiate between ictal and non ictal patterns. We assessed responder rates and compared metabolic profiles of responders and non-responders. Response was defined as resolution of the EEG pattern and either unequivocal improvement in encephalopathy or appearance of previously absent normal EEG patterns, and further categorized as immediate (within <2 h of trial initiation) or delayed (>2 h from trial initiation). RESULTS: We identified 64 patients with TPWs who had an empiric trial of BZD and/or NSAED. Most patients (71.9%) were admitted with metabolic derangements and/or infection. Positive clinical responses occurred in 10/53 (18.9%) treated with BZDs. Responses to NSAEDs occurred in 19/45 (42.2%), being immediate in 6.7%, delayed but definite in 20.0%, and delayed but equivocal in 15.6%. Overall, 22/64 (34.4%) showed a definite response to either BZDs or NSAEDs, and 7/64 (10.9%) showed a possible response. Metabolic differences of responders versus non-responders were statistically insignificant, except that the 48-h low value of albumin in the BZD responder group was lower than in the non-responder group. CONCLUSIONS: Similar metabolic profiles in patients with encephalopathy and TPWs between responders and non-responders to anticonvulsants suggest that predicting responders a priori is difficult. The high responder rate suggests that empiric trials of anticonvulsants indeed provide useful clinical information. The more than twofold higher response rate to NSAEDs suggests that this strategy may be preferable to BZDs. Further prospective investigation is warranted. PMID- 26013946 TI - Percutaneous closure of the patent foramen ovale, easy does it. AB - Closure of the patent foramen ovale does not benefit from echocardiographic guidance in the majority of cases. Guiding these procedures with fluoroscopy only reduces procedure time, radiation exposure, and amount of contrast medium. There is a clear trend to abandon echocardiographic guidance for this procedure over time and with growing experience. PMID- 26013922 TI - Morphological and molecular characterization of a sexually reproducing colony of the booklouse Liposcelis bostrychophila (Psocodea: Liposcelididae) found in Arizona. AB - The booklouse, Liposcelis bostrychophila, is a worldwide pest of stored products. For decades, only thelytokous parthenogenetic reproduction was documented in L. bostrychophila. Male L. bostrychophila were first found in Hawaii in 2002. In 2009, a sexual strain was found in Arizona. We examined the morphology of both males and females of the Arizona strain and compared the Arizona sexual strain with the Hawaii sexual strain and the parthenogenetic strains of L. bostrychophila. The sexual and parthenogenetic strains show some differences in eye morphology. To examine the relationship between sexual and asexual lineages, we sequenced the mitochondrial 12S and 16S ribosomal RNA genes of males and females from the Arizona strain. Phylogenetic analyses of L. bostrychophila individuals revealed that: 1) the sexually reproducing colony found in Arizona contains two closely related mitochondrial DNA haplotypes--one present in only females and the other in both males and females; and 2) the Arizona sexual strain was most closely related to a parthenogenetic strain in Illinois. We detected Rickettsia in all of the parthenogenetic individuals we checked but not in any Arizona sexual individuals. Further evidence is required to establish whether the presence of Rickettsia is linked to asexual reproduction in Liposcelis. PMID- 26013947 TI - Bedside teaching: specialists versus non-specialists. AB - BACKGROUND: Bedside teaching (BT) is a valuable learning experience for medical students. In 2010, the BT curriculum at the University of Dundee was revised so that clinical specialist doctors facilitated these sessions. The aim of this study was to compare student opinion of BT delivered by specialist and non specialist doctors. METHODS: A retrospective survey was sent to two medical student year groups who received teaching delivered by either specialist or non specialist doctors during year 2. RESULTS: The response rate was 24.5 per cent, of which 49.4 per cent were taught by specialists. Responses indicated that specialist doctors improved communication skills (p = 0.034), were less intimidating (p = 0.01) and gave greater opportunity to ask questions (p = 0.028) than their non-specialist counterparts. Overall, students taught by specialty doctors rated BT as more valuable (p < 0.001). A positive correlation was noted between the frequency of patient interaction and the overall value of BT (p < 0.0121); however, there was no significant association between the main teaching location and the overall value of BT. DISCUSSION: Findings indicate that specialist doctors provide students with a better understanding of disease processes. Several students from the specialist group noted that their tutors linked theory to practice. No significant difference was found between the two groups regarding whether teaching was at an appropriate level. Specialist doctors therefore allow a number of improvements over the use of non-specialist doctors for BT. Overall, students taught by specialty doctors rated bedside teaching as more valuable. PMID- 26013948 TI - Miscanthus as cellulosic biomass for bioethanol production. AB - The members of the genus Miscanthus are potential feedstocks for biofuels because of the promising high yields of biomass per unit of planted area. This review addresses species, cultivation, and lignocellulose composition of Miscanthus, as well as pretreatment and enzyme saccharification of Miscanthus biomass for ethanol fermentation. The average cellulose contents in dried biomass of Miscanthus floridulus, Miscanthus sinensis, Miscanthus sacchariflorus, and Miscanthus * giganteus (M * G) are 37.2, 37.6, 38.9, and 41.1% wt/wt, respectively. A number of pretreatment methods have been applied in order to enhance digestibility of Miscanthus biomass for enzymatic saccharification. Pretreatment of Miscanthus using liquid hot water or alkaline results in a significant release of glucose; while glucose yields can be 90% or higher if a pretreatment like AFEX that combines both chemical and physical processes is used. As ethanol is produced by yeast fermentation of the hydrolysate from enzymatic hydrolysis of residual solids (pulp) after pretreatment, theoretical ethanol yields are 0.211-0.233 g/g-raw biomass if only cellulose is taken into account. Simultaneous saccharification and fermentation of pretreated M * G and M. lutarioriparius results in experimental ethanol yields of 0.13 and 0.15 g/g raw biomass, respectively. Co-production of value-added products can reduce the overall production cost of bioethanol. PMID- 26013949 TI - Association between asymptomatic inflammatory prostatitis NIH category IV and prostatic calcification in patients with obstructive benign prostatic hyperplasia. AB - BACKGROUND: The aim of this study was to evaluate the incidence of prostatic calcification and prostatitis NIH category IV in patients with obstructive BPH. METHODS: Ninety-six patients with obstructive BPH who had undergone transurethral electroresection of the prostate gland were evaluated. In accordance with a preoperative transrectal ultrasound examination, patients were divided into one group with prostatic calcification (N.=31) and one without (N.=65). Prostatitis NIH category IV was classified according to the grading system by Irani. Correlations between the incidence of prostatic calcification, histological prostatitis, PSA, uric acid, cholesterol, triglycerides, CRP, IPSS, IIEF-25, and NIC-CPSI were analyzed. A stone analysis of prostatic calcification was performed using X-ray powder diffraction. RESULTS: Sixty-nine (71.9%) patients had NIH category IV prostatitis, accounting for 83.9% of those with prostatic calcification versus 66.1% of those without (P<0.04). Significant correlations were found between prostatic calcification and the severity of inflammation (P<0.02) as well as the NIH-CPSI subdomain of urinary symptoms (P<0.02). The only predictor for prostatic calcifications were elevated levels of uric acid. Such patients were 1.4times more likely of having calcifications in the prostate gland (OR=1.4, P<0.047). Stone analysis revealed the following: apatite in 41.7%, whewellite in 29.2%, weddellite and brushite in 8.7% each, whitlockite, apatite/whewellite and organic substances in 4.2%. CONCLUSIONS: On ultrasound examination, one third of patients who were treated with TURP for obstructive BPH had prostatic calcification. These were significantly more common in patients with NIH category IV prostatitis. PMID- 26013950 TI - Stapling for prostate pedicle management during robot-assisted radical prostatectomy. AB - BACKGROUND: Prostate pedicle management is a crucial step during robot-assisted radical prostatectomy (RARP). Wide excision of prostate pedicle may be required to avoid positive surgical margins (PSMs) whereas preservation of neurovascular bundles requires resection close on the prostate. We studied Endo GIATM stapling of prostate pedicle during RARP. METHODS: Retrospectively the outcome of 55 men who underwent RARP with Endo GIATM stapling (45-mm Echelon Ethicon; group A) of the pedicle were compared with 100 men where another method for prostate pedicle management (mono- and bipolar electrocautery, Hem-o-Lock clips or titanium 10-mm clips; group B) was used. Both groups were matched for age, prostate size, clinical T-stage, Gleason Score and fascia preservation (FP) score (as a measure of nerve sparing). Surgical, oncological, functional outcome factors and costs were compared. RESULTS: The overall PSM rate was 33% in group A and 42% in group B (P=0.251). None of the cases had PSMs at the location of staples. PSMs with Endo GIATM stapler at the periphery of the prostate were less frequent than in control group (4.1% vs. 11.5%; P=0.021). Median pedicle dissection time (7.8 [3.1 15.1] min vs. 10.5 [5.8-28.3] min; P=0.0001) and median operative time for RARP combined with lymphadenectomy (114 [70-129] min vs. 120 [67-200] min; P=0.043) tended to be shorter compared to group B. Erectile function and continence recovery at 12 months were comparable for both groups. Material costs for stapling (?730) were higher compared to variable costs in control group. CONCLUSIONS: Pedicle stapling during RARP reduced peripheral PSMs. It did not compromise functional results, provided a modest operation time gain for pedicle dissection, but is more expensive. PMID- 26013951 TI - A prospective comparative study of channel photoselective vaporization of prostate vs. channel transurethral resection of prostate in patients with advanced carcinoma prostate. AB - OBJECTIVE: To compare short term efficacy and safety of channel photoselective vaporization of prostate (PVP) and channel transurethral resection of prostate (TURP) in patients with bladder outlet obstruction (BOO) secondary to advanced carcinoma prostate. METHODS: This prospective, non-randomized comparative study was conducted between April 2012 and December 2014. Patients with locally advanced/metastatic carcinoma prostate, who underwent either channel PVP or channel TURP for troublesome LUTS/ acute retention of urine were included in the study. Preoperative, intraoperative, postoperative and follow up data at 1,3 and 6 months was recorded for analysis. RESULTS: Data analysis of 34 and 37 patients, who underwent channel PVP and channel TURP respectively, were done. Baseline characteristics of the two groups were similar with no statistical difference noted between them. Though the operative duration was significantly higher in channel PVP group; perioperative blood loss, need for postoperative irrigation, duration of postoperative irrigation and catheterization were significantly lesser compared to channel TURP group. Clot retention rates were significantly higher in channel TURP group. The efficacy parameters were comparable between the two groups at 6 month follow up. CONCLUSION: Channel KTP-PVP is an efficacious alternative to channel TURP in the management of BOO secondary to advanced carcinoma prostate with the added advantages of significantly less perioperative blood loss, no requirement for blood transfusion and a short catheterization time. PMID- 26013952 TI - MRI/TRUS fusion software-based targeted biopsy: the new standard of care? AB - The advent of multiparametric MRI has made it possible to change the way in which prostate biopsy is done, allowing to direct biopsies to suspicious lesions rather than randomly. The subject of this review relates to a computer-assisted strategy, the MRI/US fusion software-based targeted biopsy, and to its performance compared to the other sampling methods. Different devices with different methods to register MR images to live TRUS are currently in use to allow software-based targeted biopsy. Main clinical indications of MRI/US fusion software-based targeted biopsy are re-biopsy in men with persistent suspicious of prostate cancer after first negative standard biopsy and the follow-up of patients under active surveillance. Some studies have compared MRI/US fusion software-based targeted versus standard biopsy. In men at risk with MRI suspicious lesion, targeted biopsy consistently detects more men with clinically significant disease as compared to standard biopsy; some studies have also shown decreased detection of insignificant disease. Only two studies directly compared MRI/US fusion software-based targeted biopsy with MRI/US fusion visual targeted biopsy, and the diagnostic ability seems to be in favor of the software approach. To date, no study comparing software-based targeted biopsy against in-bore MRI biopsy is available. The new software-based targeted approach seems to have the characteristics to be added in the standard pathway for achieving accurate risk stratification. Once reproducibility and cost-effectiveness will be verified, the actual issue will be to determine whether MRI/TRUS fusion software-based targeted biopsy represents anadd-on test or a replacement to standard TRUS biopsy. PMID- 26013953 TI - Focal therapy for prostate cancer: current status and future perspectives. AB - Focal therapy is a relatively new and extremely attractive option of treatment for prostate cancer. It has been described as the "middle approach" between active surveillance and radical treatment, aiming to destroy the tumor itself or the region containing the tumor in order to preserve surrounding non-cancerous tissue. The goal is to maintain disease control at acceptable levels, while preserving erectile, urinary, and rectal function. While a lot of technologies have been described for delivering targeted therapy to the prostate, such as cryoablation, high intensity focused ultrasound, photodynamic therapy, irreversible electroporation and laser, the key point is the patient selection. Recent advances in mpMRI and the introduction of new biopsy techniques that use MR images as a guidance, have significantly improved localization of the tumor lesions and the detection rate, evolving prostate biopsy toward targeted rather than systematic biopsies. The future challenge to clinicians is to precisely risk stratify patients to differentiate between those who would profit from focal treatment and who would not. Forthcoming research efforts should pursue to identify molecular, genetic, and imaging characteristics that distinguish aggressive prostate tumors from indolent lesions. PMID- 26013954 TI - Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma. AB - OBJECTIVES: In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined. MATERIALS AND METHODS: Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR. RESULTS: Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p<0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p<0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p<0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p<0.0001 and p<0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p<0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p<0.0001), but only miR519 correlated inversely to HuR expression (p=0.01). CONCLUSION: While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC. PMID- 26013955 TI - GluN2B-containing N-methyl-D-aspartate receptors compensate for the inhibitory control of synaptic plasticity during the early critical period in the rat visual cortex. AB - In the visual cortex, synaptic plasticity is very high during the early developmental stage known as the critical period and declines with development after the critical period. Changes in the properties of N-methyl-D-aspartate receptor (NMDAR) and gamma-aminobutyric acid type A receptor (GABAA R) have been suggested to underlie the changes in the characteristics of plasticity. However, it is largely unknown how the changes in the two receptors interact to regulate synaptic plasticity. The present study investigates the changes in the properties of NMDAR and GABAA R from 3 to 5 weeks of age in layer 2/3 pyramidal neurons of the rat visual cortex. The impact of these changes on the characteristics of long term potentiation (LTP) is also investigated. The amplitude and decay time constant of GABAA R-mediated currents increased during this period. However, the decay time constant of NMDAR-mediated currents decreased as a result of the decrease in the proportion of the GluN2B subunit-mediated component. Induction of NMDAR-dependent LTP at 3 weeks depended on the GluN2B subunit, but LTP at 5 weeks did not. Enhancement of GABAA R-mediated inhibition suppressed the induction of LTP only at 5 weeks. However, partial inhibition of the GluN2B subunit with a low concentration of ifenprodil allowed the GABAA R-mediated suppression of LTP at 3 weeks. These results suggest that changes in the properties of NMDAR- and GABAA R mediated synaptic transmission interact to determine the characteristics of synaptic plasticity during the critical period in the visual cortex. PMID- 26013957 TI - Noncovalent Lone Pair???(No-pi!)-Heteroarene Interactions: The Janus-Faced Hydroxy Group. AB - A comparative study using NMR spectroscopy and designed top-pan molecular balances demonstrates that the noncovalent interaction of a hydroxy group with pi deficient pyrazine and quinoxaline units involves a lone pair-heteroarene interaction which is much stronger and solvent independent when measured relative to the classical pi-facial hydrogen bond to a benzene ring. Alkyl fluorides also prefer the heteroarene rings over the benzene ring. The attractive interaction between a quinoxaline and a terminal alkyne is also stronger than the intramolecular hydrogen bond to an arene. PMID- 26013958 TI - Inverted Fuel Cell: Room-Temperature Hydrogen Separation from an Exhaust Gas by Using a Commercial Short-Circuited PEM Fuel Cell without Applying any Electrical Voltage. AB - A short-circuited PEM fuel cell with a Nafion membrane has been evaluated in the room-temperature separation of hydrogen from exhaust gas streams. The separated hydrogen can be recovered or consumed in an in situ olefin hydrogenation when the fuel cell is operated as catalytic membrane reactor. Without applying an outer electrical voltage, there is a continuous hydrogen flux from the higher to the lower hydrogen partial pressure side through the Nafion membrane. On the feed side of the Nafion membrane, hydrogen is catalytically split into protons and electrons by the Pt/C electrocatalyst. The protons diffuse through the Nafion membrane, the electrons follow the short-circuit between the two brass current collectors. On the cathode side, protons and electrons recombine, and hydrogen is released. PMID- 26013956 TI - Atomic Force Microscopy Mechanical Mapping of Micropatterned Cells Shows Adhesion Geometry-Dependent Mechanical Response on Local and Global Scales. AB - In multicellular organisms, cell shape and organization are dictated by cell-cell or cell-extracellular matrix adhesion interactions. Adhesion complexes crosstalk with the cytoskeleton enabling cells to sense their mechanical environment. Unfortunately, most of cell biology studies, and cell mechanics studies in particular, are conducted on cultured cells adhering to a hard, homogeneous, and unconstrained substrate with nonspecific adhesion sites, thus far from physiological and reproducible conditions. Here, we grew cells on three different fibronectin patterns with identical overall dimensions but different geometries (?, T, and Y), and investigated their topography and mechanics by atomic force microscopy (AFM). The obtained mechanical maps were reproducible for cells grown on patterns of the same geometry, revealing pattern-specific subcellular differences. We found that local Young's moduli variations are related to the cell adhesion geometry. Additionally, we detected local changes of cell mechanical properties induced by cytoskeletal drugs. We thus provide a method to quantitatively and systematically investigate cell mechanics and their variations, and present further evidence for a tight relation between cell adhesion and mechanics. PMID- 26013959 TI - Differential diagnosis of ventriculomegaly and brainstem kinking on fetal MRI. AB - BACKGROUND: Fetal ventriculomegaly is a common and frequently leading neuroimaging finding in complex brain malformations. Here we report on pre- and postnatal neuroimaging findings in three fetuses with prenatal ventriculomegaly and brainstem kinking. We aim to identify key neuroimaging features that may allow the prenatal differentiation between diseases associated with fetal ventriculomegaly and brainstem kinking. METHODS: All pre- and postnatal magnetic resonance imaging (MRI) data were qualitatively evaluated for infra- and supratentorial abnormalities. Data about clinical features and genetic findings were collected from clinical histories. RESULTS: In all three patients, fetal MRI showed ventriculomegaly and brainstem kinking. In two patients, postnatal MRI also showed supratentorial migration abnormalities and eye abnormalities were found. In these children, the diagnosis of alpha-dystroglycanopathy was genetically confirmed. In the third patient, basal ganglia had an abnormal shape on MRI suggesting a tubulinopathy. CONCLUSION: The differential diagnosis of prenatal ventriculomegaly and brainstem kinking includes alpha dystroglycanopathies, X-linked hydrocephalus due to mutations in L1CAM, and tubulinopathies. The prenatal differentiation between these diseases may be difficult. The presence of ocular abnormalities on prenatal neuroimaging may favor alpha-dystroglycanopathies, while dysplastic basal ganglia may suggest a tubulinopathy. However, in some patients the final differentiation between these diseases is possible only postnatally. PMID- 26013961 TI - Cancer stem cell marker-expressing cell-rich spheroid fabrication from PANC-1 cells using alginate microcapsules with spherical cavities templated by gelatin microparticles. AB - Cancer stem-like cells (CSCs) are rare subpopulations of cancer cells. The development of three-dimensional tissues abundant in CSCs is important to both the understanding and establishment of novel therapeutics targeting them. Here, we describe the fabrication of multicellular tumor spheroids (MTSs) abundant in CSCs by employing alginate microcapsules with spherical cavities templated by cell-enclosing gelatin microparticles. Encapsulated human pancreatic cancer cell line PANC-1 cells grew for 14 days until they filled the cavities. The percentage of cells expressing reported CSC markers CD24, CD44, and epithelial-specific antigen (ESA), increased during this growth period. The percentage at 24 days of incubation, 22%, was 1.6 times higher than that of MTSs formed on a nonadherent surface in the same period of incubation. The MTSs in microcapsules could be cryopreserved in liquid nitrogen using a conventional method. No significant difference in the content of CSC marker-expressing cells was detected at 3 days of incubation when thawed after cryopreservation for 2 weeks, compared with cells incubated without prior cryopreservation. PMID- 26013960 TI - Cell seeding density is a critical determinant for copolymer scaffolds-induced bone regeneration. AB - Constructs intended for bone tissue engineering (TE) are influenced by the initial cell seeding density. Therefore, the objective of this study was to determine the effect of bone marrow stromal stem cells (BMSCs) density loaded onto copolymer scaffolds on bone regeneration. BMSCs were harvested from rat's bone marrow and cultured in media with or without osteogenic supplements. Cells were seeded onto poly(l-lactide-co-epsilon-caprolactone) [poly(LLA-co-CL)] scaffolds at two different densities: low density (1 * 10(6) cells/scaffold) or high density (2 * 10(6) cells/scaffold) using spinner modified flasks and examined after 1 and 3 weeks. Initial attachment and spread of BMSC onto the scaffolds was recorded by scanning electron microscopy. Cell proliferation was assessed by DNA quantification and cell differentiation by quantitative real-time reverse transcriptase-polymerized chain reaction analysis (qRT-PCR). Five millimeter rat calvarial defects (24 defects in 12 rats) were implanted with scaffolds seeded with either low or high density expanded with or without osteogenic supplements. Osteogenic supplements significantly increased cell proliferation (p < 0.001). Scaffolds seeded at high cell density exhibited higher mRNA expressions of Runx2 p = 0.001, Col1 p = 0.001, BMP2 p < 0.001, BSP p < 0.001, and OC p = 0.013. More bone was formed in response to high cell seeding density (p = 0.023) and high seeding density with osteogenic medium (p = 0.038). Poly (LLA-co-CL) scaffolds could be appropriate candidates for bone TE. The optimal number of cells to be loaded onto scaffolds is critical for promoting Extracellular matrix synthesis and bone formation. Cell seeding density and osteogenic supplements may have a synergistic effect on the induction of new bone. PMID- 26013962 TI - Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users. AB - Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase 2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene * environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5 HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene * environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5 HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence. PMID- 26013963 TI - Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects. AB - There is growing interest in anxiolytic and pro-social effects of the neuropeptide oxytocin (OXT), but the underlying intraneuronal mechanisms are largely unknown. Here we examined OXT-mediated anxiolysis in the hypothalamic paraventricular nucleus (PVN) of rats and effects of OXT administration on signaling events in hypothalamic primary and immortalized cells. In vivo, the application of SKF96365 prevented the anxiolytic activity of OXT in the PVN, suggesting that changes in intracellular Ca(2+) mediate the acute OXT behavioral effects. In vitro, mainly in the neurons with autonomous Ca(2+) oscillations, OXT increased intracellular Ca(2+) concentration and oscillation amplitude. Pharmacological intervention revealed OXT-dependent changes in Ca(2+) signaling that required activation of transient receptor potential vanilloid type-2 channel (TRPV2), mediated by phosphoinositide 3-kinase. TRPV2 induced the activation of the anxiolytic mitogen-activated protein kinase kinase (MEK1/2). In situ, immunohistochemistry revealed co-localization of TRPV2 and OXT in the PVN. Thus, functional and pharmacological analyses identified TRPV2 as a mediator of anxiolytic effects of OXT, conveying the OXT signal to MEK1/2 via modulation of intracellular Ca(2+). PMID- 26013964 TI - Factors affecting levels of circulating cell-free fetal DNA in maternal plasma and their implications for noninvasive prenatal testing. AB - OBJECTIVE: Sufficient fetal DNA in a maternal plasma sample is required for accurate aneuploidy detection via noninvasive prenatal testing, thus highlighting a need to understand the factors affecting fetal fraction. METHOD: The MaterniT21TM PLUS test uses massively parallel sequencing to analyze cell-free fetal DNA in maternal plasma and detect chromosomal abnormalities. We assess the impact of a variety of factors, both maternal and fetal, on the fetal fraction across a large number of samples processed by Sequenom Laboratories. RESULTS: The rate of increase in fetal fraction with increasing gestational age varies across the duration of the testing period and is also influenced by fetal aneuploidy status. Maternal weight trends inversely with fetal fraction, and we find no added benefit from analyzing body mass index or blood volume instead of weight. Strong correlations exist between fetal fractions from aliquots taken from the same patient at the same blood draw and also at different blood draws. CONCLUSION: While a number of factors trend with fetal fraction across the cohort as a whole, they are not the sole determinants of fetal fraction. In this study, the variability for any one patient does not appear large enough to justify postponing testing to a later gestational age. PMID- 26013965 TI - Peptide 2-formylthiophenol esters do not proceed through a Ser/Thr ligation pathway, but participate in a peptide aminolysis to enable peptide condensation and cyclization. AB - Peptide thiol salicylaldehyde (SAL) esters unexpectedly do not follow a Ser/Thr ligation pathway to react with peptides containing N-terminal Ser/Thr, but proceed towards a peptide aminolysis in DMSO. The reaction takes place even at a low substrate concentration (1 mM). The method has been successfully used to synthesize several natural cyclic peptides, with a high ratio of monocyclic to dimeric products. PMID- 26013966 TI - Habitat stability, predation risk and 'memory syndromes'. AB - Habitat stability and predation pressure are thought to be major drivers in the evolutionary maintenance of behavioural syndromes, with trait covariance only occurring within specific habitats. However, animals also exhibit behavioural plasticity, often through memory formation. Memory formation across traits may be linked, with covariance in memory traits (memory syndromes) selected under particular environmental conditions. This study tests whether the pond snail, Lymnaea stagnalis, demonstrates consistency among memory traits ('memory syndrome') related to threat avoidance and foraging. We used eight populations originating from three different habitat types: i) laboratory populations (stable habitat, predator-free); ii) river populations (fairly stable habitat, fish predation); and iii) ditch populations (unstable habitat, invertebrate predation). At a population level, there was a negative relationship between memories related to threat avoidance and food selectivity, but no consistency within habitat type. At an individual level, covariance between memory traits was dependent on habitat. Laboratory populations showed no covariance among memory traits, whereas river populations showed a positive correlation between food memories, and ditch populations demonstrated a negative relationship between threat memory and food memories. Therefore, selection pressures among habitats appear to act independently on memory trait covariation at an individual level and the average response within a population. PMID- 26013967 TI - Cubic C8 : An Observable Allotrope of Carbon? AB - Ab initio and DFT calculations are used to investigate the structure, electronic properties, spectra and reactivity of cubic C8 , which is predicted to be aromatic according to Hirsch's rule. Although highly strained and with a small amount of diradical character, the carbon cube represents a surprisingly deep minimum and should therefore be observable as an isolated molecule. It is, however, predicted to be very reactive, both with itself and triplet oxygen. Calculated IR, Raman, and UV/Vis spectra are provided to aid identification of cubic C8 should it be synthesized. PMID- 26013968 TI - Extra-slow-growing Tardiphaga strains isolated from nodules of Vavilovia formosa (Stev.) Fed. AB - Eleven extra-slow-growing strains were isolated from nodules of the relict legume Vavilovia formosa growing in North Ossetia (Caucasus) and Armenia. All isolates formed a single rrs cluster together with the type strain Tardiphaga robiniae LMG 26467(T), while the sequencing of the 16S-23S rDNA intergenic region (ITS) and housekeeping genes glnII, atpD, dnaK, gyrB, recA and rpoB divided them into three groups. North Ossetian isolates (in contrast to the Armenian ones) were clustered separately from the type strain LMG 26467(T). However, all isolates were classified as T. robiniae because the DNA-DNA relatedness between them and the type strain LMG 26467(T) was 69.6% minimum. Two symbiosis-related genes (nodM and nodT) were amplified in all isolated Tardiphaga strains. It was shown that the nodM gene phylogeny is similar to that of ITS and housekeeping genes. The presence of the other symbiosis-related genes in described Tardiphaga strains, which is recently described genus of rhizobia, as well as their ability to form nodules on any plants are under investigation. PMID- 26013969 TI - Psychometric properties of the Posttraumatic Cognition Inventory within a Northern Ireland adolescent sample. AB - OBJECTIVES: This study sought to investigate the psychometric properties of the Posttraumatic Cognitions Inventory (PTCI; Foa et al., 1999, Psychol. Assess., 11, 303) among a cohort of older adolescents and to determine the relationship between post-traumatic cognitions and a variety of psychological outcomes including depression, anxiety, stress, and loneliness. METHODS: The PTCI was investigated among a large sample (N = 785) of Northern Irish adolescents. Confirmatory factor analysis and composite reliability analysis were conducted to assess the psychometric properties of the scale. RESULTS: The familiar three factor solution of negative cognitions of self, negative cognitions of the world and others, and self-blame was supported; however, it was necessary to remove eight items from the original 33-item scale. The three-factor structure was subsequently demonstrated to be factorially invariant across gender and to possess satisfactory internal reliability. The three PTCI factors were found to correlate with depression, anxiety, stress, and three dimensions of loneliness. CONCLUSION: These results provide the first piece of evidence that older adolescents cognitively respond to trauma in a similar manner to adults, that the PTCI is factorially invariant between genders, and that trauma cognitions are correlated with feelings of loneliness. The contextual dependent nature of the structure of the PTCI factors is discussed in relation to future research efforts. PRACTITIONER POINTS: The PTCI is a valid and reliable measure of trauma related cognitions among adolescents and works equally well for male adolescents and female adolescents. Trauma cognitions are associated with a range of mental health problems beyond post-traumatic stress disorder including depression, anxiety, stress, and various aspects of loneliness. Reductions in trauma cognitions in survivors of trauma will have wide-scale clinical benefits to patient well-being. The exact structure and make-up of items in the PTCI may well be dependent on culture, context, and the nature of the trauma. The study is limited due to the fact that the authors could not assess the severity of the trauma experienced by the adolescent sample. PMID- 26013971 TI - Bronsted Acid Catalyzed Asymmetric Hydroamination of Alkenes: Synthesis of Pyrrolidines Bearing a Tetrasubstituted Carbon Stereocenter. AB - The first highly enantioselective Bronsted acid catalyzed intramolecular hydroamination of alkenes enables the efficient construction of a series of chiral (spirocyclic) pyrrolidines with an alpha-tetrasubstituted carbon stereocenter with excellent functional group tolerance. A unique feature of this strategy is the use of a thiourea group acting as both the activating and the directing group through cooperative multiple hydrogen bonding with a Bronsted acid and the double bond. The utility of this method is highlighted by the facile construction of chiral synthetic intermediates and important structural motifs that are widely found in organic synthesis. PMID- 26013970 TI - Sensitivity of hepatitis C virus core antigen and antibody combination assays in a global panel of window period samples. AB - BACKGROUND: Hepatitis C virus (HCV) antigen and antibody combination assays have been launched as a cost-effective alternative to nucleic acid testing (NAT) for reducing the antibody-negative window period (WP). Later, a HCV antigen chemiluminescence immunoassay (CLIA) became available. STUDY DESIGN AND METHODS: A panel composed of 337 HCV NAT-yield samples that were characterized for viral load (VL) and genotype was used to compare the sensitivity of two combination enzyme-linked immunosorbent assays (Monolisa, Bio-Rad; and Murex, formerly Abbott) and a HCV antigen CLIA (Abbott). Analytic sensitivity was compared with HCV RNA detection using Ultrio (Grifols) by testing serial dilutions of 10 genotype (gt)1 to gt4 samples. RESULTS: HCV antigen CLIA detected 92.4% of samples, whereas Monolisa and Murex detected 38.3 and 47.5%, respectively. In the HCV RNA VL range of 10(5) to 10(7) IU/mL, Monolisa and Murex detected 38% to 56% of gt1, 85% to 78% of gt2, and 21% to 37% of gt3. The overall geometric mean 50% limit of detection (range) of Ultrio on gt1 to gt4 dilution series was 3.5 (1.2 7.7) copies/mL, compared to 3.3 * 10(6) (4.4 * 10(5) -2.7 * 10(7) ), 3.4 * 10(6) (2.2 * 10(5) -4.2 * 10(7) ), and 2728 (415-7243) copies/mL for Monolisa, Murex, and HCV antigen CLIA, respectively. CONCLUSION: Analytical sensitivity of NAT was on average 1 million- and 780-fold higher than combination assays and HCV antigen CLIA, respectively. Relative sensitivities of combination assays differed for genotypes with Murex being more sensitive for gt1 and gt3 and Monolisa more sensitive for gt2. Although being less sensitive than NAT, combination assays could be considered in resource-limited settings since they detect 38% to 47% of seronegative WP donations. PMID- 26013972 TI - Dynamics of Membrane Proteins within Synthetic Polymer Membranes with Large Hydrophobic Mismatch. AB - The functioning of biological membrane proteins (MPs) within synthetic block copolymer membranes is an intriguing phenomenon that is believed to offer great potential for applications in life and medical sciences and engineering. The question why biological MPs are able to function in this completely artificial environment is still unresolved by any experimental data. Here, we have analyzed the lateral diffusion properties of different sized MPs within poly(dimethylsiloxane) (PDMS)-containing amphiphilic block copolymer membranes of membrane thicknesses between 9 and 13 nm, which results in a hydrophobic mismatch between the membrane thickness and the size of the proteins of 3.3-7.1 nm (3.5-5 times). We show that the high flexibility of PDMS, which provides membrane fluidities similar to phospholipid bilayers, is the key-factor for MP incorporation. PMID- 26013974 TI - Fresh evidence confirms links between newer contraceptive pills and higher risk of venous thromboembolism. PMID- 26013973 TI - Evaluation of 3D multi-contrast joint intra- and extracranial vessel wall cardiovascular magnetic resonance. AB - BACKGROUND: Multi-contrast vessel wall cardiovascular magnetic resonance (CMR) has demonstrated its capability for atherosclerotic plaque morphology measurement and component characterization in different vasculatures. However, limited coverage and partial volume effect with conventional two-dimensional (2D) techniques might cause lesion underestimation. The aim of this work is to evaluate the performance in a) blood suppression and b) vessel wall delineation of three-dimensional (3D) multi-contrast joint intra- and extracranial vessel wall imaging at 3T. METHODS: Three multi-contrast 3D black blood (BB) sequences with T1, T2 and heavy T1 weighting and a custom designed 36-channel neurovascular coil covering the entire intra- and extracranial vasculature have been used and investigated in this study. Two healthy subjects were recruited for sequence parameter optimization and twenty-five patients were consecutively scanned for image quality and blood suppression assessment. Qualitative image scores of vessel wall delineation as well as quantitative Signal-to-Noise Ratio (SNR) and Contrast-to-Noise Ratio (CNR) were evaluated at five typical locations ranging from common carotid arteries to middle cerebral arteries. RESULTS: The 3D multi contrast images acquired within 15mins allowed the vessel wall visualization with 0.8 mm isotropic spatial resolution covering intra- and extracranial segments. Quantitative wall and lumen SNR measurements for each sequence showed effective blood suppression at all selected locations (P < 0.0001). Although the wall-lumen CNR varied across measured locations, each sequence provided good or adequate image quality in both intra- and extracranial segments. CONCLUSIONS: The proposed 3D multi-contrast vessel wall technique provides isotropic resolution and time efficient solution for joint intra- and extracranial vessel wall CMR. PMID- 26013975 TI - A Single-Use Paper-Shaped Microbial Fuel Cell for Rapid Aqueous Biosensing. AB - The traditional chamber-based microbial fuel cell (MFC) often has the disadvantages of high ohmic resistance, large volume requirements, and delayed start-up. In this study, paper-shaped MFCs utilizing a porous carbon anode, a solid Ag2 O-coated carbon cathode, and a micrometer-thin porous polyvinylidene fluoride (PVDF) separator are investigated to address the classical MFC issues. The Ag2 O-coated cathode has a low overpotential of 0.06 V at a reducing current of 1 mA compared to a Pt-air cathode. Rapid inoculation by filtration results in an instantaneous power density of 92 mW m(-2) with an internal resistance of 162 Omega. Integrated current over the first 30 min of operation has a linear relation with microbial concentration. PMID- 26013976 TI - Global DNA hypomethylation and hypoxia-induced expression of the ten eleven translocation (TET) family, TET1, in scleroderma fibroblasts. AB - The precise mechanisms of tissue fibrosis have not yet been elucidated in systemic sclerosis (SSc). However, studies of the regulation of DNA methylation, the most widely studied epigenetic mechanism, have confirmed the involvement of the TET family proteins, recently identified DNA demethylases, in the pathogenesis of SSc. The mRNA levels of TET family members were compared in normal and SSc fibroblasts. The effects of hypoxia and siRNA specific to HIF 1alpha on TET expression were also examined. Global methylation status was analysed by LUMA. The presence of 5-hydroxymethylcytosine (5hmC) in SSc was examined by immunohistochemistry. The level of TET1 mRNA in SSc fibroblasts was elevated by 1.68 fold compared with that of normal fibroblasts, but the expression levels of TET2 and TET3 were comparable between both cell types. The expression levels of DNMT1 and DNMT3B mRNA have a tendency to elevate in SSc fibroblasts. Among TET family members, the expression of TET1 was exclusively induced by hypoxia via HIF-1alpha-independent pathways in SSc fibroblasts, but not in normal fibroblasts. The methylation level was decreased in SSc fibroblasts relative to normal fibroblasts, and 5hmC was present in dermal fibroblasts of skin sections from patients with SSc. TET1 expression in SSc fibroblasts was abnormally regulated in the hypoxic environment and accompanied by global DNA hypomethylation, suggesting the involvement of aberrant DNA methylation in the pathogenesis of SSc. PMID- 26013977 TI - Bottom-up topography assembly into 3D porous scaffold to mediate cell activities. AB - Native cells live in a three-dimensional (3D) extracellular matrix (ECM) capable of regulating cell activities through various physical and chemical factors. Designed topographies have been well proven to trigger significant difference in cell behaviours. However, present topographies are almost all constructed on two dimensional (2D) substrates like discs and films, which are far from features like 3D and porosity required in application like bone repair. Here we bottom-up assembled poly(lactic-co-glycolic acid)/calcium carbonate (PLGA/CC) microspheres with superficial porous topography intactly into a 3D porous scaffold. Because the scaffold was obtained through a mild technique, the bioactivity of released BMP-2 was well retained. Mouse bone marrow mesenchymal stem cells (mMSCs) were cultured on produced scaffolds having different 3D topographies. It turned out that osteogenic differentiation of mMSCs did respond to the 3D topographies, while proliferation didn't. Gene expression of alphav and beta1 integrins revealed that adhesion was supposed to be the underlying mechanism for osteogenic response. The study provides insight into enhancing function of practical scaffolds by elaborate topography design. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1056-1063, 2016. PMID- 26013978 TI - Ultrasound evaluation of the radial artery for arterial catheterization in healthy anesthetized patients. AB - The purpose of this study was to assess the anatomy of the radial artery using ultrasound in anesthetized patients, and to correlate its anatomical data with patients' characteristics. The success rate of radial artery cannulation using ultrasound was also evaluated to analyze the relationship between the anatomical data and the success rate. Study 1 One hundred ninety-five patients scheduled for general anesthesia were enrolled. Ultrasound measurements were obtained when the vital signs were stable after anesthesia induction. The wrist joint of patients were extended to 30 degrees . The diameter and depth of the radial artery, and the angle between the radial artery and skin surface were measured using ultrasound. Anatomical data were correlated with patients' characteristics. Study 2 Arterial cannulation was performed in 125 patients using long-axis in-plane technique to evaluate the success rate using ultrasound. Study 1 The diameter of the radial artery was mean value of 2.2 +/- 0.4 mm and larger than 0.9 mm in all patients. It had significant correlation with body surface area (BSA) (Pearson correlation 0.292, P < 0.001). The incidence of abnormal angle between the radial artery and skin surface was significantly higher in elderly patients (>=65 years) than young patients (P = 0.017). Study 2 The first attempt success rate of arterial catheterization using ultrasound was 92.5 % using long-axis in-plane technique, regardless of patient's characteristics. For small sized adult patients, a 22G angio-catheter should be used during radial artery cannulation, because the radial artery diameter significantly correlated with BSA in healthy anesthetized patients. In addition, ultrasound-guided catheterization is recommended in elderly patients because the incidence of abnormal angle between the radial artery and skin surface was high. PMID- 26013979 TI - Assessment of the time-dependent need for stay in a high dependency unit (HDU) after major surgery by using data from an anesthesia information management system. AB - Admittance to a high dependency unit (HDU) is expensive. Patients who receive surgical treatment with 'low anterior resection of the rectum' (LAR) or 'abdominoperineal resection of the rectum' (APR) at our hospital are routinely treated in an HDU the first 16-24 h of the postoperative (PO) period. The aim of this study was to describe the extent of HDU-specific interventions given. We included patients treated with LAR or APR at the St. Olav University Hospital (Trondheim, Norway) over a 1-year period. Physiologic data and HDU-interventions recorded during the PO-period were obtained from the anesthesia information management system (AIMS). HDU-specific interventions were defined as the need for respiratory support, fluid replacement therapy >500 ml/h, vasoactive medications, or a need for high dose opioids (morphine >7.5 mg/h i.v.). Sixty-two patients were included. Most patients needed HDU-specific interventions during the first 6 h of the PO period. After this, one-third of the patients needed one or more of the HDU-specific interventions for shorter periods of time. Another one-third of the patients had a need for HDU-specific therapies for more than ten consecutive hours, primarily an infusion of nor-epinephrine. Most patients treated with LAR or APR was in need of an HDU-specific intervention during the first 6 h of the PO period, with a marked decline after this time period. The applied methodology, using an AIMS, demonstrates that there is great variability in individual patients' postoperative needs after major surgery, and that these needs are dynamic in their nature. PMID- 26013980 TI - Is mouse embryonic stem cell technology obsolete? AB - Injection of recombinant Cas9 protein and synthetic guide RNAs into mouse zygotes has been shown to facilitate gene disruption and knock-ins using the CRISPR system. These technologies may soon displace genetic modification using embryonic stem cells. PMID- 26013981 TI - Fostering synergy between cell biology and systems biology. AB - In the shared pursuit of elucidating detailed mechanisms of cell function, systems biology presents a natural complement to ongoing efforts in cell biology. Systems biology aims to characterize biological systems through integrated and quantitative modeling of cellular information. The process of model building and analysis provides value through synthesizing and cataloging information about cells and molecules, predicting mechanisms and identifying generalizable themes, generating hypotheses and guiding experimental design, and highlighting knowledge gaps and refining understanding. In turn, incorporating domain expertise and experimental data is crucial for building towards whole cell models. An iterative cycle of interaction between cell and systems biologists advances the goals of both fields and establishes a framework for mechanistic understanding of the genome-to-phenome relationship. PMID- 26013982 TI - Expanding simulation-based education through institution-wide initiatives: A blueprint for success. AB - BACKGROUND: The Consortium of American College of Surgeons Accredited Education Institutes (ACS-AEIs) was created to promote patient safety through the use of simulation, develop innovative education and training, advance technologies, identify best practices, and encourage research and collaboration. METHODS: During the seventh annual meeting of the consortium, leaders from across the consortium who have developed institution-wide simulation centers were invited to participate in a panel to discuss their experiences and the lessons learned. CONCLUSION: These discussions resulted in definition of 5 key areas that need to be addressed effectively to support efforts of the ACS-AEIs. PMID- 26013983 TI - The "weekend effect" in urgent general operative procedures. AB - BACKGROUND: There is growing concern that the quality of inpatient care may differ on weekends versus weekdays. We assessed the "weekend effect" in common urgent general operative procedures. METHODS: The Healthcare Cost and Utilization Project Florida State Inpatient Database (2007-2010) was queried to identify inpatient stays with urgent or emergent admissions and surgery on the same day. Included were patients undergoing appendectomy, cholecystectomy for acute cholecystitis, and hernia repair for obstructed/gangrenous hernia. Outcomes included duration of stay, inpatient mortality, hospital-adjusted charges, and postoperative complications. Controlling for hospital and patient characteristics and type of surgery, we used multilevel mixed-effects regression modeling to examine associations between patient outcomes and admissions day (weekend vs weekday). RESULTS: A total of 80,861 same-day surgeries were identified, of which 19,078 (23.6%) occurred during the weekend. Patients operated on during the weekend had greater charges by $185 (P < .05), rates of wound complications (odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.05-1.58; P < .05), and urinary tract infection (OR 1.39, 95% CI 1.05-1.85; P < .05). Patients undergoing appendectomy had greater rates of transfusion (OR 1.43, 95% CI 1.09-1.87; P = .01), wound complications (OR 1.32, 95% CI 1.04-1.68; P < .05), urinary tract infection (OR 1.76, 95% CI 1.17-2.67; P < .01), and pneumonia (OR 1.41, 95% CI 1.05-1.88; P < .05). Patients undergoing cholecystectomy had a greater duration of stay (P = .001) and greater charges (P = .003). CONCLUSION: Patients undergoing weekend surgery for common, urgent general operations are at risk for increased postoperative complications, duration of stay, and hospital charges. Because the cause of the "weekend effect" is still unknown, future studies should focus on elucidating the characteristics that may overcome this disparity. PMID- 26013984 TI - Hospital-level resource use by the oldest-old for pancreaticoduodenectomy at high volume hospitals. AB - INTRODUCTION: Owing to limited data on hospital resources consumed in caring for the oldest-old, we examined the use of pancreaticoduodenectomy (PD)-relevant hospital resources in patients of increasing age treated in high-volume hospitals participating in the University HealthSystem Consortium. METHODS: Perioperative outcomes, resource use, and direct costs were compared across increasing age groups in 12,766 PDs (<70 years, n = 8,564; 70-79 years, n = 3,302; >=80 years, n = 900) performed in 79 high-volume hospitals between 2010 and 2014. Linear regression models with and without covariate adjustments were used to assess the impact of older age. RESULTS: The oldest-old experienced fewer readmissions and had equivalent intensive care unit use and mortality rates compared with both younger cohorts. However, those >=80 years experienced more complications, blood transfusions, greater total parenteral nutrition (TPN) use, longer duration of stay, and higher direct hospital costs compared with those <70 years No differences were found between patients >=80 years and those 70-79 years with respect to the administration of blood products, TPN, or the direct cost of PD. CONCLUSION: Our findings suggest the ability to deliver quality pancreatic surgical care to an aging population without strong associations to increased resource utilization. As the number of octogenarians undergoing PD continues to grow, the impact of this technically complex procedure on other important cancer care metrics, including patient-reported outcomes and quality of life, requires further assessment. PMID- 26013985 TI - Factors associated with failure-to-rescue in patients undergoing trauma laparotomy. AB - INTRODUCTION: Quality improvement initiatives have focused primarily on preventing in-hospital complications. Patients developing complications are at a greater risk of mortality; however, factors associated with failure-to-rescue (death after major complication) in trauma patients remain undefined. The aim of this study was to identify risk factors associated with failure-to-rescue in patients undergoing trauma laparotomy. METHODS: An -8-year, retrospective analysis of patients undergoing trauma laparotomy was performed. Patients who developed major in-hospital complications were included. Major complications were defined as respiratory, infectious, cardiac, renal, or development of compartment syndrome. Regression analysis was performed to identify independent factors associated with failure-to-rescue after we adjusted for demographics, mechanism of injury, abdominal abbreviated injury scale, initial vital signs, damage control laparotomy, and volume of crystalloids and blood products administered. RESULTS: A total of 1,029 patients were reviewed, of which 21% (n = 217) patients who developed major complications were included. The mean age was 39 +/- 18 years, 82% were male, 61% had blunt trauma, and median abdominal abbreviated injury scale was 25 [16-34, interquartile range]. Respiratory complications (n = 77) followed by infectious complications (n = 75) were the most common complications. The failure-to-rescue rate was 15.7% (n = 34/217). Age, blunt trauma, severe head injury, uninsured status, and blood products administered on the second day were independent predictor for failure-to-rescue. CONCLUSION: When major complications develop, age, uninsured status, severity of head injury, and prolonged resuscitation are associated independently with failure-to-rescue, whereas initial resuscitation, coagulopathy, and acidosis did not predict failure to rescue. Quality-of-care programs focus in patient level should be on improving the patient's insurance status, preventing secondary brain injury, and further development of resuscitation guidelines. PMID- 26013986 TI - Increasing incidence of duodenal neuroendocrine tumors: Incidental discovery of indolent disease? AB - BACKGROUND: There has been a marked increase in the recognized incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Studies have often combined duodenal neuroendocrine tumors (D-NETs) with other small bowel GEP-NETs. As a result, the natural history and clinical ramifications of these D-NETs is poorly understood. METHODS: Patients diagnosed with duodenal "carcinoid" tumors from 1983 to 2010 were identified in the Surveillance Epidemiology and End Results tumor registry. RESULTS: A total of 1,258 patients were identified. The mean age was 64 years. The majority of patients were male (55.6%), white (55.6%), and had stage I disease (66.2%). Patients meeting inclusion criteria were divided into 2 cohorts: (i) era 1 patients diagnosed with GEP-NETs from 1983 to 2005, and (ii) era 2 those diagnosed from 2005 to 2010. There was a clear increase in the incidence rate of D-NETs from 0.27 per 100,000 in 1983 to 1.1 per 100,000 in 2010 (P < .001). Comparison of patients from the different eras revealed that those in era 2 were more likely than era 1 to present with stage I disease (69.9 vs 57.5%; P < .01) and less likely to present with late-stage disease. The 5-year, disease specific survival improved for era 2 patients compared with era 1 (89.3 vs 85.2%; P = .05); however, multivariate analysis demonstrated that stage but not era was associated with disease-specific survival. CONCLUSION: Prognosis for D-NETs, in contrast with other small bowel NETs, is excellent. There has been a steady increase in the recognized incidence of D-NETs, coincident with the migration to earlier disease stage and improved disease-specific survival. PMID- 26013987 TI - Gearing up for milestones in surgery: Will simulation play a role? AB - BACKGROUND: The Consortium of American College of Surgeons-Accredited Education Institutes was created to promote patient safety through the use of simulation, develop new education and technologies, identify best practices, and encourage research and collaboration. METHODS: During the 7th Annual Meeting of the Consortium, leaders from a variety of specialties discussed how simulation is playing a role in the assessment of resident performance within the context of the Milestones of the Accreditation Council for Graduate Medical Education as part of the Next Accreditation System. CONCLUSION: This report presents experiences from several viewpoints and supports the utility of simulation for this purpose. PMID- 26013988 TI - Prognostic relevance of lymph node ratio and total lymph node count for small bowel adenocarcinoma. AB - BACKGROUND: Nodal metastasis is a known prognostic factor for small bowel adenocarcinoma. The goals of this study were to evaluate the number of lymph nodes (LNs) that should be retrieved and the impact of lymph node ratio (LNR) on survival. METHODS: Surveillance, Epidemiology, and End Results was queried to identify patients with small bowel adenocarcinoma who underwent resection from 1988 to 2010. Survival was calculated with the Kaplan-Meier method. Multivariate analysis identified predictors of survival. RESULTS: A total of 2,772 patients underwent resection with at least one node retrieved, and this sample included equal numbers of duodenal (n = 1,387) and jejunoileal (n = 1,386) adenocarcinomas. There were 1,371 patients with no nodal metastasis (N0, 49.4%), 928 N1 (33.5%), and 474 N2 (17.1%). The median numbers of LNs examined for duodenal and jejunoileal cancers were 9 and 8, respectively. Cut-point analysis demonstrated that harvesting at least 9 for jejunoileal and 5 LN for duodenal cancers resulted in the greatest survival difference. Increasing LNR at both sites was associated with decreased overall median survival (LNR = 0, 71 months; LNR 0-0.02, 35 months; LNR 0.21-0.4, 25 months; and LNR >0.4, 16 months; P < .001). Multivariate analysis confirmed number of LNs examined, T-stage, LN positivity, and LNR were independent predictors of survival. CONCLUSION: LNR has a profound impact on survival in patients with small bowel adenocarcinoma. To achieve adequate staging, we recommend retrieving a minimum of 5 LN for duodenal and 9 LN for jejunoileal adenocarcinomas. PMID- 26013989 TI - The role of adjunctive antibiotics in the treatment of skin and soft tissue abscesses: a systematic review and meta-analysis. AB - OBJECTIVE: To perform a review and meta-analysis on the effect of antibiotics on treatment of skin and soft tissue abscesses (SSTAs) after incision and drainage. METHODS: We searched MEDLINE, EMBASE, Web of Knowledge, and Google Scholar databases to identify randomized controlled trials (RCTs) and observational studies. For RCTs, we included studies comparing any antibiotic (treatment) to placebo (control). For observational studies, treatment was the use of appropriate antibiotics effective against bacterial isolate, and control was the use of inappropriate (ineffective) or no antibiotics. Outcome was treatment success during follow-up. Two investigators reviewed records, assessed quality (according to Cochrane and Newcastle-Ottawa tools), and extracted treatment success rates. Primary analysis was the effect of treatment among RCTs. Secondary analyses included the effect of treatment in 1) observational studies of confirmed methicillin-resistant Staphylococcus aureus (MRSA) infection (MRSA only) and 2) all studies after 1998 (MRSA-era). We used random effects modelling, except when no heterogeneity was present when we used fixed effects. RESULTS: We screened 1,968 records. Twelve were included (five RCTs, seven observational studies), representing 1,969 subjects. Seven enrolled from emergency departments, two from surgical clinics, and three from ambulatory clinics. Three enrolled children only. Pooled relative risk (RR) of treatment success among RCTs was 1.03 (95% confidence interval [CI] 0.97-1.08). Pooled RR in the secondary analyses was 1.05 (95% CI 0.96-1.15) in MRSA-only and 0.99 (95% CI 0.98-1.01) in MRSA-era. CONCLUSION: Despite limitations in pooling available data, there is no clear evidence to support antibiotic use in treating uncomplicated SSTAs. PMID- 26013990 TI - Genetic rescue: a safe or risky bet? AB - Small and isolated populations face threats from genetic drift and inbreeding. To rescue populations from these threats, conservation biologists can augment gene flow into small populations to increase variation and reduce inbreeding depression. Spectacular success stories include greater prairie chickens in Illinois (Westermeier et al. ), adders in Sweden (Madsen et al. ) and panthers in Florida (Johnson et al. ). However, we also know that performing such crosses risks introducing genes that may be poorly adapted to local conditions or genetic backgrounds. A classic example of such 'outbreeding depression' occurred when different subspecies of ibex from Turkey and the Sinai were introduced to assist recovery of an ibex population in Czechoslovakia (Templeton ). Despite being fertile, the hybrids birthed calves too early, causing the whole population to disappear. In the face of uncertainty, conservation biologists have tended to respect genetic identity, shying away from routinely crossing populations. In this issue of Molecular Ecology, Frankham () compiles empirical data from experimental studies to assess the costs and benefits of between-population crosses (Fig. ). Crosses screened to exclude those involving highly divergent populations or distinct habitats show large heterosis with few apparent risks of outbreeding depression. This leads Frankham to advocate for using assisted gene flow more widely. But do the studies analysed in this meta-analysis adequately test for latent outcrossing depression? PMID- 26013991 TI - Population genomic analyses reveal possible drivers of population divergence. AB - Recent advances in sequencing technology and efficiency enable new and improved methods to investigate how populations diverge and species evolve. Fungi have relatively small and simple genomes and can often be cultured in the laboratory. Fungal populations can thus be sequenced for a relatively low cost, which makes them ideal for population genomic analyses. In several recent population genomic studies, wild populations of fungal model organisms and human pathogens have been analysed, for example Neurospora crassa (Ellison et al. ), Saccharomyces uvarum (Almeida et al. ), Coccidioides spp. (Neafsey et al. ) and Cryptococcus gatti (Engelthaler et al. ). In this issue of Molecular Ecology, Branco et al. () apply population genomic tools to understand population divergence and adaptation in a symbiotic (mycorrhizal) fungus. This study exemplifies the possibilities of diving deeper into the genomic features involved in population divergence and speciation, also for nonmodel organisms, and how molecular and analytical tools will improve our understanding of the patterns and mechanisms that underlie adaptation to habitats, population divergence and dispersal limitation of fungi. PMID- 26013992 TI - A novel approach to recycle bacterial culture waste for fermentation reuse via a microbial fuel cell-membrane bioreactor system. AB - Biochemical production processes require water and nutrient resources for culture media preparation, but aqueous waste is generated after the target products are extracted. In this study, culture waste (including cells) produced from a lab scale fermenter was fed into a microbial fuel cell-membrane bioreactor (MFC-MBR) system. Electrical energy was generated via the interaction between the microbial consortia and the solid electrode in the MFC. The treated wastewater was reclaimed in this process which was reused as a solvent and a nutrient source in subsequent fermentation. Polarization testing showed that the MFC produced a maximum current density of 37.53 A m(-3) with a maximum power density of 5.49 W m(-3). The MFC was able to generate 0.04 kWh of energy per cubic meter of culture waste treated. The lab-scale fermenters containing pure cultures of an engineered Pseudomonas spp. were used to generate 2-pyrone-4,6-dicarboxylic acid (PDC), a high value platform chemical. When the MFC-MBR-treated wastewater was used for the fermenter culture medium, a specific bacterial growth rate of 1.00 +/- 0.05 h(-1) was obtained with a PDC production rate of 708.11 +/- 64.70 mg PDC L(-1) h( 1). Comparable values for controls using pure water were 0.95 +/- 0.06 h(-1) and 621.01 +/- 22.09 mg PDC L(-1) h(-1) (P > 0.05), respectively. The results provide insight on a new approach for more sustainable bio-material production while at the same time generating energy, and suggest that the treated wastewater can be used as a solvent and a nutrient source for the fermentation production of high value platform chemicals. PMID- 26013993 TI - Effect of a Novel Interdisciplinary Teaching Program in the Care-continuum on Medical Student Knowledge and Self-Efficacy. AB - OBJECTIVES: Medical students report that they receive inadequate training in different levels of care, including care transitions to and from post-acute (PA) and long-term care (LTC). The authors implemented the Medical Students as Teachers in Extended Care (MedTEC) program as an educational innovation at the Cleveland Clinic to address training in the care-continuum, as well as the new medical student and physician competencies in PA/LTC. DESIGN: MedTEC is a 7-hour interactive program that supplements standard geriatric didactics during the medical student primary care rotation. This study evaluated the performance of the program in improving medical student knowledge and attitudes on levels and transitions of care. SETTING: The program occurs in a community facility that includes subacute/skilled nursing, assisted living, and nursing home care. PARTICIPANTS: Five to 8 students completing their primary care rotation at the Cleveland Clinic are required to participate in the MedTEC program each month. INTERVENTION: The program includes up to 3 hours of interactive discussion and opportunities to meet facility staff, residents, and patients. The highlight of the program is a student-led in-service for facility staff. MEASUREMENTS: With institutional review board approval as an exempt educational research project, pre- and postactivity surveys assessed self-efficacy and knowledge regarding levels of care for students who participated in the program and a student comparison group. The post-program knowledge test also was administered to hospital medicine staff, and test performance was compared with medical students who participated in the MedTEC program. RESULTS: Between October 2011 and December 2013, approximately 100 students participated in 20 sessions of MedTEC. All students reported improved self-efficacy and attitudes regarding care of older adults and care transition management. Mean percentage correct on the knowledge test increased significantly from 59.8% to 71.2% (P = .004) for the MedTEC participants but not for the comparison group students (63.1%-58.3%, P = .47). There was no significant difference in mean percentage correct on the post program knowledge test between MedTEC medical students and hospitalists (71.0% versus 70.3%, P = .86). Students led 8 in-service sessions for facility staff on various topics relating to the care of older adults in PA/LTC. CONCLUSION: The MedTEC program appears to be a successful innovation in medical student education on levels of care. It could serve as a model for building competency of health professionals on managing care transitions and determining appropriate levels of care for older adults. PMID- 26013994 TI - Objectively measured and self-reported leisure-time sedentary behavior and academic performance in youth: The UP&DOWN Study. AB - OBJECTIVE: To examine the associations of (i) objectively measured and self reported sedentary behavior during leisure time with academic performance and (ii) patterns of sedentary behavior with academic performance. METHODS: This study was conducted with 1146 youth aged 12.5+/-2.5years in Spain during 2011 2012. Leisure-time sedentary behavior during out-of-school hours was assessed by accelerometry and self-report. Academic performance was assessed through school grades. RESULTS: Objectively measured sedentary leisure-time was not significantly associated with academic performance. Time spent in Internet surfing, listening to music, and sitting without doing anything were negatively associated with all academic performance indicators (beta ranging from -0.066 to 0.144; all p<0.05). However, time spent in doing homework/study without computer and reading for fun were positively associated (beta ranging from 0.058 to 0.154; all p<0.05). Five major sedentary patterns were identified. The "high social-low TV/video" and the "low studying-high TV/video" patterns were negatively associated with all academic indicators (beta ranging from -0.085 to -0.148; all p<0.05). The "educational" pattern was positively associated with all academic indicators (beta ranging from 0.063 to 0.105; all p<0.05). CONCLUSIONS: Specific domains of self-reported sedentary behavior during leisure-time, but not objectively measured sedentary leisure time, may influence academic performance. PMID- 26013995 TI - New selective inhibitors of calcium-activated chloride channels - T16A(inh) -A01, CaCC(inh) -A01 and MONNA - what do they inhibit? AB - BACKGROUND AND PURPOSE: T16A(inh)-A01, CaCC(inh)-A01 and MONNA are identified as selective inhibitors of the TMEM16A calcium-activated chloride channel (CaCC). The aim of this study was to examine the chloride-specificity of these compounds on isolated resistance arteries in the presence and absence (+/-) of extracellular chloride. EXPERIMENTAL APPROACH: Isolated resistance arteries were maintained in a myograph and tension recorded, in some instances combined with microelectrode impalement for membrane potential measurements or intracellular calcium monitoring using fura-2. Voltage-dependent calcium currents (VDCC) were measured in A7r5 cells with voltage-clamp electrophysiology using barium as a charge carrier. KEY RESULTS: Rodent arteries preconstricted with noradrenaline or U46619 were concentration-dependently relaxed by T16A(inh) -A01 (0.1-10 MUM): IC50 and maximum relaxation were equivalent in +/-chloride (30 min aspartate substitution) and the T16A(inh) -A01-induced vasorelaxation +/-chloride were accompanied by membrane hyperpolarization and lowering of intracellular calcium. However, agonist concentration-response curves +/-chloride, with 10 MUM T16A(inh) -A01 present, achieved similar maximum constrictions although agonist-sensitivity decreased. Contractions induced by elevated extracellular potassium were concentration-dependently relaxed by T16A(inh)-A01 +/-chloride. Moreover, T16A(inh) -A01 inhibited VDCCs in A7r5 cells in a concentration-dependent manner. CaCC(inh) -A01 and MONNA (0.1-10 MUM) induced vasorelaxation +/-chloride and both compounds lowered maximum contractility. MONNA, 10 MUM, induced substantial membrane hyperpolarization under resting conditions. CONCLUSIONS AND IMPLICATIONS: T16A(inh) -A01, CaCC(inh) -A01 and MONNA concentration-dependently relax rodent resistance arteries, but an equivalent vasorelaxation occurs when the transmembrane chloride gradient is abolished with an impermeant anion. These compounds therefore display poor selectivity for TMEM16A and inhibition of CaCC in vascular tissue in the concentration range that inhibits the isolated conductance. PMID- 26013998 TI - Zinc-Catalyzed Alkyne Oxidation/C-H Functionalization: Highly Site-Selective Synthesis of Versatile Isoquinolones and beta-Carbolines. AB - An efficient zinc(II)-catalyzed alkyne oxidation/C-H functionalization sequence was developed, thus leading to highly site-selective synthesis of a variety of isoquinolones and beta-carbolines. Importantly, in contrast to the well established gold-catalyzed intermolecular alkyne oxidation, over-oxidation can be completely suppressed in this system and the reaction most likely proceeds by a Friedel-Crafts-type pathway. Mechanistic studies and theoretical calculations are described. PMID- 26013999 TI - f-Block Ansa Complexes in the Solid State: [3]Thoro- and [3]Uranocenophanes. AB - The preparation of [3]thoro- and [3]uranocenophanes, the first structurally authenticated ansa-bridged complexes of actinocenes, is reported. Following a flytrap route, 1,2-bis(cyclooctatetraenyldimethylsilyl)methane was synthesized, reduced to its tetraanion, and subsequently converted into bridged uranocene and thorocene complexes by salt metathesis with the corresponding actinide tetrachlorides. In addition, their electronic structures have been investigated by experimental (UV/Vis spectroscopy, cyclic voltammetry) and theoretical (DFT) methods. PMID- 26014000 TI - UNESCO world cultural heritage of Edirne: Selimiye Mosque Complex. PMID- 26013997 TI - Regulation of NANOG in cancer cells. AB - As one of the key pluripotency transcription factors, NANOG plays a critical role in maintaining the self-renewal and pluripotency in normal embryonic stem cells. Recent data indicate that NANOG is expressed in a variety of cancers and its expression correlates with poor survival in cancer patients. Of interest, many studies suggest that NANOG enhances the defined characteristics of cancer stem cells and may thus function as an oncogene to promote carcinogenesis. Therefore, NANOG expression determines the cell fate not only in pluripotent cells but also in cancer cells. Although the regulation of NANOG in normal embryonic stem cells is reasonably well understood, the regulation of NANOG in cancer cells has only emerged recently. The current review provides a most updated summary on how NANOG expression is regulated during tumor development and progression. PMID- 26014001 TI - Primary pineal malignant melanoma - illustrated review. AB - AIM: Primary pineal melanoma is a rare tumor. We herein review the histogenesis, pathology, radiology and therapeutic options of this rare tumor. MATERIAL AND METHODS: We conducted a PUBMED search using a combination of keywords such as "primary pineal melanoma", "CNS melanoma", and "pineal tumor" and identified 16 cases of primary pineal melanoma. Clinical features, pathologic characteristics and treatment details of these patients were noted from respective case reports. We also describe a case of a 45-year-old Indian woman with primary pineal melanoma treated with a combination of surgery and post-op radiation. RESULTS: The median age at presentation is 50 years. Median duration of symptoms is 6 weeks. Common symptoms at presentation include headache (58.8%), personality changes (41.2%), gait disturbance (35.3%) and Parinaud's syndrome (29.4%). Surgery, radiotherapy and chemotherapy have been used in 29.4%, 47.1% and 23.5% of patients respectively. Median overall survival is 56 weeks. Leptomeningeal dissemination and ventricular ependymal spread were noted in 70.6% and 35.3% patients, respectively. CONCLUSION: Combined modality treatment comprising maximal safe surgery and post-operative radiation should be preferred in patients with localized pineal melanoma without leptomeningeal dissemination. Taking a cue from other subsites of melanoma, chemotherapy can perhaps be deferred until recurrence. PMID- 26014003 TI - Three-dimensional anatomical landmarks of the sphenoid ostium for a safer transsphenoidal approach. AB - AIM: The sphenoid ostium (SO) is an anatomical reference in transsphenoidal approach surgery. MATERIAL AND METHODS: The morphological features of the SO were studied in 352 skull base by 3D-Doctor Demo version. RESULTS: The mean diameters of the SO were measured as 5.8 +/- 1.3 mm (right) and 5.9 +/- 1.2 mm (left), respectively. The mean distance from the SO to the midline was measured as 2.3 +/ 1.1 mm (right) and 1.8 +/- 0.9 mm (left), respectively. 8 bones had SO on one side, whilst 4 bones had no SO. In 5 bones there was a double SO structure on one side. 74.4% of ovoid SO specimens have the largest perimeter, therefore, allow the highest degree of surgical success. It was noted that they were not symmetrical (21.8%). Openings were found to be at different distances from the midline, some at different distances from the floor; in addition, differently shaped openings, as well as those with an opening absent on one side or with double openings, were observed. CONCLUSION: Separate coordinates and safe routes must be calculated for right and left openings. The SO analysis could eliminate some of standardization measurements of an exposed surgical area. PMID- 26014002 TI - Surgical and anesthesiological considerations of awake craniotomy: Cerrahpasa experience. AB - AIM: Awake craniotomy (AC) with electrical cortical stimulation has become popular during the last ten years although the basic principles were introduced almost 50 years ago. The aim of this paper is to share with the readers our experience in 25 patients who underwent AC with electrical stimulation. MATERIAL AND METHODS: Twenty-five patients who underwent AC between 2010 and 2013 are the subjects of this paper. All patients were diagnosed with intraaxial lesions involving the functional area itself or very close to it by preoperative imaging. During surgery, the functional area was demonstrated by cortical electrical stimulation and resection aimed to preserve it in order to avoid an irreversible functional deficit. RESULTS: Total resection was possible in 80% while in 20% subtotal resection had to be performed because of involvement of the functional area itself. The neurological complication rate was found to be 16% (4 patients) and all were transient. No complication regarding anesthesia was noted. CONCLUSION: Awake craniotomy in selected patients is very effective, safe and practical for supratentorial lesions close to the eloquent area. Complications related to the surgery itself are uncommon and general anesthesia is avoided. The hospital stay including the intensive care unit is short which makes it very economical surgical procedure. PMID- 26014004 TI - Increased osseous thickening of the inner surface of the frontal bone. AB - AIM: Increased thickening of the internal surface of the frontal bone (ISFB) was investigated, regarding possible pressure application to the brain tissue and the changes in bone marrow structure. MATERIAL AND METHODS: Morphological analysis of the ISFB was carried out in a total of 300 adult skulls. RESULTS: Type A, defined as normal appearance, has been detected in 243 cranium. In 57 cranium (19%), increased osseous thickening cases with different appearance were observed. The most frequent examples of osseous thickening were present in nodular types (Types B, C) and diffuse types (Types D, E), (29.8%). In fact, an irregular osseous thickening, which is in the form of plaques, was situated on both sides of the origin of sagittal sulcus. Types B and C were seen as small isolated nodules on the ISFB. In the histological analysis of ISFB, it is determined that the endocranium, normally present in a compact bone structure, changed its lamellar and had a nonwoven immature bone structure, in the areas with the characteristic of increased osseous thickening. The thickening of the diploe gap and increasing lamellar bone tissue in the endocranium revealed an increase in vascularization. CONCLUSION: The nodular and widespread form of increased osseous thickening could apply pressure on to dura mater and the brain tissue. PMID- 26014005 TI - Microsurgery with or without Neuroendoscopy in Petroclival Meningiomas. AB - AIM: This study aimed to investigate the operative procedure for neuroendoscope assisted microscopic resection of petroclival meningioma to improve prognosis. MATERIAL AND METHODS: Twelve patients with petroclival meningioma who had undergone neuroendoscope-assisted microscopic resection at the Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University were selected. In addition, 12 patients with petroclival meningioma who had undergone microscopic surgery were used as control. Clinical data from the 24 cases of petroclival meningioma were analyzed. RESULTS: For the neuroendoscope-assisted group, six, five, and one cases were respectively subjected to total resection, subtotal resection, and most resection. For the microscopic surgery group, two, three, and seven cases were respectively subjected to total resection, subtotal resection, and most resection. Both the total and subtotal resection rates of petroclival meningioma in the neuroendoscope-assisted group were significantly higher than those in the microscopic surgery group (p < 0.05). No difference was observed for short-term and long-term complications (p > 0.05) between the two groups. CONCLUSION: Neuroendoscope-assisted microscopic resection for petroclival meningioma can improve the total and subtotal resection rates of the tumor. Moreover, this method does not increase postoperative short-term and long-term complications. PMID- 26014006 TI - A Comparison of Bilateral Decompression via Unilateral Approach and Classic Laminectomy in Patients with Lumbar Spinal Stenosis: A retrospective Clinical Study. AB - AIM: Bilateral decompression via unilateral approach is one of the minimally invasive methods used for degenerative spinal stenosis. The aim of this retrospective study was to observe the clinical and radiological results of classic laminectomy and bilateral decompression via unilateral approach applied for lumbar stenosis. MATERIAL AND METHODS: The data of 40 patients who underwent surgical treatment for lumbar spinal stenosis with different techniques was reviewed retrospectively. The patients were divided into 2 groups according to the surgical technique. In the first group, patients underwent classic laminectomy, while in the second group patients underwent bilateral decompression via unilateral approach. Preoperative and postoperative computed tomography section areas of both groups were examined. Visual analogue scale (VAS) was used to evaluate low back and leg pain in preoperative and postoperative 1, 6, and 12 months. The two groups were compared in respect of surgery time and bleeding. RESULTS: In both groups, postoperative low back and leg pain VAS scores declined compared to the preoperative condition. Low back pain VAS scores were lower at postoperartive 1, 6, and 12 months. The bleeding was higher in the 1st group, whereas the surgery time was higher in the 2nd group. CONCLUSION: Bilateral decompression through unilateral approach is an effective method without instability effect, which provides sufficient decompression in the degenerative stenosis and increases patient comfort in the postoperative period. PMID- 26014007 TI - Superior medullary velum: anatomical-histological study in the sheep brain and a preliminary tractographic study in the human brain. AB - AIM: To study the anatomy, histology and fiber relations of the superior medullary velum. MATERIAL AND METHODS: Ten previously frozen and formalin-fixed sheep brains were used. The fiber dissection was done using the operating microscope at the Rhoton Anatomy Laboratory of Marmara Faculty of Medicine. A tractographic study was conducted on five volunteer patients to see the fiber anatomy of the superior medullary velum. RESULTS: The average thickness and length was found to be 0.296 mm (range 0.09-1 mm) and 4.25 mm (range 3.25-4.5 mm) respectively. Histologically, the superior medullary velum consisted of cuboidal layer of ependymal cells on the anterior surface related to fourth ventricle. The subependymal layer contained hypocellular fibrillary zone with few glial cells, and the outer layer consisted of thin layer of fibroblasts. Under the hypocellular fibrillary zone, abundant axons and organized structures were observed. Tractographically, only a few fibers were identified on diffusion tensor imaging (DTI). CONCLUSION: We could not identify a distinct tract anatomically and neuron cells histologically. Neuron-like cells and organized structures were observed on immunohistochemical analysis. Also a few tracts were observed on DTI study as an ascending pathway from spinal tracts to the superior medullary velum. Further studies including human cadaveric, histologic and fiber tractographic investigations are needed to say that it is harmless to divide this anatomical structure. PMID- 26014008 TI - Local application of corticosteroids combined with surgery for the treatment of chronic subdural hematoma. AB - AIM: Combination treatment consisting of surgery and pre-or post-operative corticosteroids for chronic subdural hematoma (CSH) tend to have better outcomes than surgery only. However, there are many complications after long-term use of corticosteroids. In this study, we evaluated the clinical outcomes of local application of corticosteroids combined with surgery for CSH. MATERIAL AND METHODS: We retrospectively analysed the data of the patients undergoing surgery and local application of Methylprednisolone Sodium Succinate for Injection (MPSS) into the hematoma cavity. Neurological status was assessed by Markwalder's Grading Scale (MGS). Recurrence was defined as deteriorating neurological status with radiological evidence of reaccumulation. RESULTS: A total of 26 patients were enrolled in this study. During the follow-up period, all patients made excellent neurological recovery. 24 (92.3%) patients' MGS was grade 0 at 12 months after the surgery. There was no mortality or recurrence. 5 patients (19.2%) suffered postoperative complications, of which 2 developed some subdural air collection, 2 had a partial seizure attack and 1 developed an acute epidural hemorrhage. CONCLUSION: The results suggest that local application of MPSS combined with surgery is a safe and effective method in the management of CSH. It may reduce hematoma recurrence. PMID- 26014009 TI - Diagnosis of brain death by orbital Doppler ultrasound: a comparative research study. AB - AIM: It remains unknown whether orbital Doppler-ultrasound (ODUS) could be an alternative to other established ancillary tests for the diagnosis of brain death. We investigated the effectiveness of ODUS in the diagnosis of brain death and compared data obtained from ODUS with transcranial Doppler-ultrasound (TDUS) and carotid Doppler-ultrasound (CDUS) findings. MATERIAL AND METHODS: ODUS, CDUS and TDUS examinations were performed on 22 consecutive patients who had clinical examination and confirmatory test findings consistent with brain death. The compatibility of resistive indices (RI) from ODUS, TDUS and CDUS examinations were analyzed. RESULTS: In ODUS examinations, the RI values were equal to or greater than one in 15 patients (68%). In the remaining 7 patients, the RI values were >=0.75. RI values were >= 1 in 16 (72%) and 18 (82%) patients in CDUS and TDUS examinations, respectively. RI values of CDUS and TDUS were >=0.76 in the remaining patients. CONCLUSION: ODUS is an easily applicable technique that is safer, cheaper and faster when compared with the other confirmatory tests. False results could be prevented by evaluating patients with an ODUS RI value of < 1 together with the TDUS and/or CDUS results. PMID- 26014010 TI - A combined bilateral approach to anterior communicating artery aneurysm. AB - AIM: To discuss the features, feasibility, and safety of a combined bilateral approach in the endovascular treatment of intracranial anterior communicating artery (ACoA) aneurysm. MATERIAL AND METHODS: We performed a retrospective analysis of the clinical data of patients with ACoA aneurysm treated with a combined bilateral approach. RESULTS: We successfully embolized aneurysms in nine patients with intracranial ACoA aneurysm using a combined bilateral approach. All treated patients had an open ACoA connecting with the bilateral anterior cerebral arteries. CONCLUSION: Because the ACoA connects the intracranial arteries in both hemispheres, patients with ACoA aneurysm can be endovascularly treated with a combined bilateral approach. Notably, surgeon experience and dexterity play important roles in the success of this procedure. PMID- 26014011 TI - Management of Type II Odontoid Fracture for Osteoporotic Bone Structure: Preliminary Report. AB - AIM: Anterior transodontoid screw fixation technique is generally chosen for the management of type II odontoid fractures. The nonunion of type II odontoid fractures is still a major problem especially in elderly and osteoporotic patients. Eleven osteoporotic type II odontoid fracured patients were presented in this article. MATERIAL AND METHODS: We have divided 11 patients in two groups as classical and Ozer's technique. We have also compared (radiologically and clinically) the classical anterior transodontoid screw fixation (group II: 6 cases) and Ozer's transodontoid screw fixation technique (group I: 5 cases) retrospectively. RESULTS: There was no difference regaring the clinical features of the groups. However, the radiological results showed 100% fusion for Ozer's screw fixation technique and 83% fusion for the classical screw fixation technique. CONCLUSION: In conclusion, we suggest that Ozer's technique may help to increase the fusion capacity for osteoporotic type II odontoid fractures. PMID- 26014012 TI - The role of vagal nerve root injury on respiration disturbances in subarachnoid hemorrhage. AB - AIM: We examined whether there is a relationship between vagal nerve root injury and the severity of respiration disorders associated with subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: This study was conducted on 20 rabbits. Experimental SAH was induced by injecting homologous blood into the cisterna magna. During the experiment, electrocardiography and respiratory rhythms were measured daily. After the experiment, any axonal injury or changes to the arterial nervorums of the vagal nerves were examined. All respiratory irregularities and vagal nerve degenerations were statistically analyzed. RESULTS: Normal respiration rate, as measured in the control group, was 30 +/- 6 bpm. In the SAH-induced group, respiration rates were initially 20 +/- 4 bpm, increasing to 40 +/- 9/min approximately ten hours later, with severe tachypneic and apneic variation. In histopathological examinations, axon density of vagal nerves was 28,500 +/- 5,500 in both control and sham animals, whereas axon density was 22,250 +/- 3,500 in survivors and 16,450 +/- 2,750 in dead SAH animals. The severity of axonal degeneration of vagal nerves was greater in the six dead animals than in the survivors. CONCLUSION: If vagal nerves are lesioned, the muscles of respiration are paralyzed and respiratory reflexes are disrupted. That the ischemic and mechanical factors created by SAH cause vagal nerve root injury and respiration disorders may be inevitable and fatal. PMID- 26014013 TI - X-Stop(r) Implantation Effectively Limits Segmental Lumbar Extension in-vivo without Altering the Kinematics of the Adjacent Levels. AB - AIM: To evaluate the in-vivo three-dimensional (3D) vertebral kinematics of the implanted and adjacent segments after implantation of the interspinous process distracting (ISP) device during various functional activities. MATERIAL AND METHODS: Eight patients with lumbar spinal stenosis (LSS) scheduled for X-Stop(r) surgery were recruited. Prior to surgery, patients were scanned with computed tomography/ magnetic resonance imaging (CT/MRI) in order to construct 3D L2 to S1 vertebral models. The lumbar spines of the patients were then imaged using two fluoroscopes while they performed seven functional activities before and after X Stop(r) surgeries. The in-vivo 3D vertebral positions were determined in the dual fluoroscopic images using an established 2D-3D matching method. The vertebral 3D ranges of motion (ROM) of the implanted and cranial-caudal adjacent levels were then measured. RESULTS: Primary ROMs of the implanted segments were significantly decreased (p < 0.05) by 50.2% only at torso extension, from preoperative 2.5 +/- 1.4 degrees to postoperative 1.1 +/- 0.5 degrees , but not significantly (p > 0.05) at flexion, twisting and lateral bending. Primary ROM and the coupled translations and rotations of the implanted and the adjacent levels were not significantly changed during each posture. CONCLUSION: X-Stop(r) implantation reduced the in-vivo range of extension by 50.2% at the implanted segment without disturbing 3D kinematics at the adjacent segments. PMID- 26014014 TI - The evaluation of three-dimensional anatomy of the superficial temporal artery using the volume rendering technique. AB - AIM: The superficial temporal artery (STA) is the one of the terminal branches of the external carotid artery. Three-dimensional anatomical structure of the STA can be evaluated by using three dimensional volume rendering technique (3D-VRT) from acquired two-dimensional contrast-enhanced computerized tomographic images. MATERIAL AND METHODS: The raw data of the Three-dimensional Computerized Tomography Angiography (3D-CTA) was transferred to computer and recorded in a software program. This software program created the three-dimensional images of STA using these transferred raw data with the volume rendering technique. These images were evaluated in terms of the location of the STA bifurcation, the distance from the some anatomical landmarks, the inner diameter of the artery, and the type of the variations. RESULTS: The total number of patients consists of 53 (27 female and 26 male) patients. The mean age of the patients was estimated as 57.9 +/- 9.7 years. It was found that the location of the STA bifurcation was over the posterior third of the zygomatic arch in 58% of the cases. In 40% of the cases the location of the bifurcation was above the zygomatic arch. The location of the bifurcation was below the zygomatic arch in the remaining part of the cases (2%). CONCLUSION: The STA images created using the volume rendering technique were evaluated in terms of the bifurcation point of the artery, the length of the bifurcation from some anatomical structures, the inner diameter of the artery and arterial variations. The results of this study showed that this technique might be helpful for the three-dimensional microsurgical anatomy of the STA in daily neurosurgical practice. PMID- 26014015 TI - The anatomical variations in the neurovascular relations of the sphenoid sinus: an evaluation by coronal computed tomography. AB - AIM: The sphenoid sinus is deeply situated in the skull and is the least accessible paranasal sinus. The sphenoid sinus is surrounded by vital structures such as the optic nerve and internal carotid artery, and therefore additional radiological assessment of the sphenoid sinus and the related neurovascular structures is inevitable before surgery. The aim of this study was to note the anatomic variations in the relationship of these structures with the sphenoid sinus by analyzing the coronal computed tomography (CT) scans. MATERIAL AND METHODS: The consecutive coronal CT scans of 100 patients that included 43 males and 57 females were evaluated. RESULTS: Variations in the neurovascular boundaries of the sphenoid sinus were a common finding in the present study and were seen in as many as 66% of the cases. Variations involving the Vidian canal were the commonest in our study and were seen in around 42%, followed by those involving the bony canal for internal carotid artery, 33%; maxillary nerve, 21 % and optic nerve, 9%. CONCLUSION: These variations do not represent disease as such, but may increase the risk of endoscopic mishaps. CT of the paranasal sinus region is therefore an essential prerequisite prior to sinonasal and trans sphenoidal surgeries. PMID- 26014016 TI - Effects of the popular food additive sodium benzoate on neural tube development in the chicken embryo. AB - AIM: Many more additives have been introduced with the development of processed foods. Neural tube defects are congenital malformations of the central nervous system. More than 300 000 children are born with neural tube defects every year and surviving children remain disabled for life. Sodium benzoate is used intensively in our daily lives. We therefore aimed to evaluate the effects of sodium benzoate on neural tube defects in chicken embryos. MATERIAL AND METHODS: Fertile, specific pathogen-free eggs were used. The study was conducted on five groups. After 30 hours of incubation, the eggs were opened under 4x optical magnification. The embryonic disc was identified and sodium benzoate solution was injected. Eggs were closed with sterile adhesive strips and incubation was continued till the end of the 72nd hour. All eggs were then reopened and embryos were dissected from embryonic membranes and evaluated histopathologically. RESULTS: We found that the development of all embryos was consistent with the stage. We detected neural tube obstruction in one embryo. Neural tube defects were not detected in any embryos. CONCLUSION: This study showed that sodium benzoate as one of the widely used food preservatives has no effect to neural tube defect development in chicken embryos even at high doses. PMID- 26014017 TI - Increase in folate receptor alpha expression in nonfunctional pituitary adenomas. AB - AIM: Human pituitary adenomas account for 10% of intracranial tumours and occur in about 20% of the population. They cause hypopituitarism or the compression of adjacent regional structures. However, little is known about the molecular pathogenesis that contributes to the development of these tumours. MATERIAL AND METHODS: In this study, we investigated the relationship between the expression level of folate receptor alpha and some clinical factors (endocrine, age, gender, repeated operation or not, mean diameter of tumour and invasiveness) of pituitary adenomas. Realtime fluorescent quantitative reverse transcriptase polymerase chain reaction was used to determine the expression of folate receptor alpha mRNA in pituitary adenomas and normal pituitaries. Folate receptor alpha protein levels were quantified using Western blot analysis and Immunohistochemistry. RESULTS: We found folate receptor alpha mRNA and protein were significantly upregulated in clinically nonfunctional pituitary adenomas compared to functional tumours. For nonfunctional tumours, folate receptor alpha expression was much higher in the invasive group than in non-invasive group. CONCLUSION: These results suggest that the overexpression of folate receptor alpha mRNA and protein by nonfunctional pituitary adenomas may facilitate the growth of these tumours. Potentially, this finding could be exploited to develop innovative molecular targeted diagnosis and treatment for human nonfunctional pituitary adenomas. PMID- 26014018 TI - Treatment of Supraclinoid Internal Carotid Artery Iatrogenic Pseudoaneurym with Extracranial-to- Intracranial Bypass and Trapping: Demonstration of Technique with Video Presentation. AB - Intracranial pseudoaneurysms (IP) represent about 1% of all patients presenting with an intracranial aneurysm. In true intracranial aneurysms, the intima, internal elastic lamina, and media are disrupted, but the adventitia is intact. In pseudoaneurysms, there is disruption of all three layers of the arterial wall, thus resulting in higher rates of re-hemorrhage and thrombus formation. Patients with IP commonly present with subarachnoid hemorrhage or thromboembolic complications. Until now, no specific guidelines have been established for the ideal treatment of pseudoaneurysms. Although IP have higher rates of morbidity and mortality compared to true intracranial aneurysms, surgical treatment can prevent catastrophic hemorrhagic and thrombotic complications. Despite recent advances in endovascular techniques that allow safe approaches to complicated intracranial vascular pathologies, vascular trapping and bypass remains the definitive and safe treatment for IP. Based on our experience and related literature, we consider the latter treatment in experienced hands as an effective and decisive treatment modality to prevent the devastating complications of IP. In this article, we discuss the surgical management of iatrogenic intracranial internal carotid artery pseudoaneurysms by trapping, and extracranial intracranial bypass through a case illustration in which the technique is demonstrated via a video presentation. PMID- 26014019 TI - Management of consecutive development of ruptured intracranial mycotic aneurysms: case report. AB - Intracranial mycotic aneurysm (MA), also known as intracranial infectious aneurysm, is a rare type of intracranial aneurysm. However, it carries a high mortality rate of 80% when ruptured and 30% even when unruptured. Here we report a 22-year-old male patient who consecutively developed two ruptured intracranial MAs related to infective endocarditis. The time interval between the two attacks was approximately seven months. The second aneurysm formed and ruptured regardless of long-term antibiotic therapy and cardiac surgery to replace the dysfunctional aortic valve. This case indicates that intracranial MAs may develop even after successful treatment of the underlying cardiac disorders, and hence close angiographic follow-ups may be warranted following the cardiac surgery. PMID- 26014020 TI - Total Resolution of Large Scalp Swelling due to Calvarial Tuberculosis with Medical Management Only: Case Report and Review of the Literature. AB - Calvarial tuberculosis is rare. It presents with single or multiple discharging sinus or a localized focal scalp swelling with overlying skin discoloration. Usually subgaleal collection is associated with evolution of sinus formation in different stages. However, extensive scalp swelling spreading across bifrontal area and overlying healthy scalp is not reported. Pathologically it causes significant destruction of calvarium including erosion of both the tables with concurrent significant epidural granulation tissue deposits as dura acts as barrier to trans-dural spread. Concurrent surgical management and antitubercular medication is the standard treatment modality. Authors report a unique presentation of calvarial tuberculosis in 17-year- female presented with complaint of large painless scalp swelling extensively spreading over both frontal area from supraorbital margin to coronal suture without discoloration, puckering of overlying scalp or sinus formation, and neuroimaging showed absence of extradural granulation tissue deposits with very subtle bony architecture changes of adjacent calvarium. The swelling completely subsided with medical therapy alone. To the best of knowledge of authors such case of calvarial tuberculosis having large scalp swelling in western literature has not been reported. Clinical presentation, imaging, management and pertinent literature are reviewed. PMID- 26014021 TI - Skull base fracture involving the foramen spinosum - an indirect sign of middle meningeal artery lesion: case report and literature review. AB - Skull base fractures comprise a relatively common finding among trauma patients. Before the widespread use of computed tomography (CT), these lesions used to be misdiagnosed. Currently, with improved imaging technology, diagnosis of skull base fractures is no longer cumbersome. On the other hand, cranial fractures involving the foramen spinosum are rarely described in the literature. In this present article, we report on a patient affected by head trauma, who suffered from a vault fracture towards the foramen spinosum and acute epidural hematoma (EH) due to middle meningeal artery injury. We further discuss the clinical consequences of foramen spinosum fracture. PMID- 26014022 TI - Thoracic epidural blood patch for spontaneous intracranial hypotension: case report and review of the literature. AB - Spontaneous intracranial hypotension (SIH) is caused by spinal leakage of cerebrospinal fluid (CSF). Treatment is directed at sealing the site of leak, which is often difficult to localize. We present a case of near fatal SIH that was treated with thoracic epidural blood patching. A 47-year old male presented with orthostatic headache and bilateral cranial nerve VI palsies progressing over several weeks. Brain magnetic resonance (MR) imaging showed features typical of SIH and identified an epidural collection stretching from spinal levels C6 to T4, but further imaging with MR myelography and radionuclide cisternography failed to identify a precise site of leak. The patient worsened in the hospital requiring craniotomy for evacuation of an evolving subdural hematoma (SDH). Epidural blood patch was performed at the T1-2 level, the presumed location of the leak due to presence of a bone spur on computed tomography and the large corresponding CSF collection. This quickly led to resolution of the headache and cranial nerve palsies, and later to the complete resolution of his SDH. Through this case and review of the literature, we aim to demonstrate that directed cervical or thoracic blood patching should be considered for SIH as an alternative to the conventional lumbar blood patch. PMID- 26014023 TI - Subdural extramedullary melanotic schwannoma of the thoracic spinal cord: a case report. AB - Melanotic schwannoma is a rare "Schwann" cell tumor characterized by the deposition of melanin in the cell cytoplasm. Melanotic schwannoma varies greatly in terms of morphology and clinical manifestations. Here, we describe a patient with subdural extramedullary melanotic schwannoma of the thoracic spinal cord. The 47-year-old man presented with pain in his chest and back that had lasted a year, numbness and weakness in both his lower extremities for 20 days, and urinary retention for 4 days. Magnetic resonance imaging (MRI) revealed a subdural extramedullary lesion at the level of the T2-T4 thoracic spinal cord. A total resection of the mass was performed. A diagnosis of melanotic schwannoma was made based on the histopathological examination. During the six-month follow up period, no recurrence of the tumor was observed. A long-term follow-up will be necessary to fully evaluate this case. PMID- 26014024 TI - Pure Lymphocytic Infundibuloneurohypophysitis Caused by the Rupture of Rathke's Cleft Cyst: Report of 2 Cases and Review of the Literature. AB - The major symptoms that are caused by Rathke's cleft cysts (RCCs) are visual disturbances, headaches, and endocrine insufficiencies. Among these symptoms, the endocrine insufficiencies are thought to result from the spreading of inflammation that is induced by the cyst contents onto the pituitary gland or the compression of the gland and the pituitary stalk by RCCs. Here, we present 2 rare cases with lymphocytic infundibulohypophysitis with the sudden onset of headaches and subsequent diabetes insipidus (DI). Magnetic resonance imaging revealed remarkable swelling of the pituitary gland with a small mass that was located between the anterior and the posterior lobe of the pituitary gland. Transsphenoidal surgery was performed to remove the mass, and pathological examinations of the cyst wall demonstrated that the epithelial tissue of the RCC and the posterior lobe were affected by massive lymphocytic infiltration. The clinical courses and pathological results of these patients strongly suggested that the rupture of the RCC onto the posterior lobe caused the lymphocytic hypophysitis. Postoperatively, the DI could be controlled with a smaller amount of anti-diuretic hormone replacement compared to that required preoperatively. PMID- 26014025 TI - Intracranial giant tuberculoma mimicking brain tumor: a case report. AB - Tuberculomas are small tumor-like lumps that can be seen, usually in large numbers, in central nervous system involvement of tuberculosis. Giant tuberculomas that are big enough to cause symptoms of compression are also encountered, though rarely. When they are really large, tuberculomas may result in increased intracranial compression, neurologic deficits, or epileptic attacks. Giant tuberculomas may be confused with brain tumors on cranial magnetic resonance imaging. Cranial magnetic resonance imaging and histopathology examinations are used for diagnosis. Although magnetic resonance imaging is useful for diagnosing tuberculoma, histopathology examination is the gold standard for a final diagnosis. This paper presents a case involving a 66-year old patient who complained of headache, imbalance and dizziness, and underwent an operation in the neurosurgery clinic with a pre-diagnosis of brain tumor, and was then diagnosed with intracranial giant tuberculoma. PMID- 26014026 TI - Multi-level, bilateral pedicle fractures: case report. AB - Bilateral pedicle fracture is an extremely rare entity and few cases have been reported in literature. A case of bilateral multi-level pedicle fractures involving four lumbar vertebrae is being presented. Bilateral pedicle stress fracture at L1 - L4 was observed in a 61-year-old woman presented with low back pain. There was no any predisposing factor like trauma, spinal surgery, smoking or alcohol consumption except mild osteoporosis and bisphosphonate usage in the patient's medical history. We are unable to determine whether the fractures are related to osteoporosis or bisphosphonate therapy but these are the only remaining suspected reasons in the present case. Further studies are required to define the effect of bisphosphonates usage on vertebral segments. PMID- 26014027 TI - Minimally Invasive Treatment of Biventricular Hydrocephalus Caused by a Giant Basilar Apex Aneurysm via a Staged Combination of Endoscopy and Endovascular Embolization: A Case Report. AB - Biventricular hydrocephalus caused by a Giant Basilar Apex Aneurysm (GBAA) is a rare finding that presents unique and challenging treatment decisions. We report a case of GBAA causing a life-threatening biventricular hydrocephalus in which both the aneurysm and hydrocephalus were given definitive treatment through a staged, minimally invasive approach. An obtunded 82-year-old male was found to have biventricular hydrocephalus caused by an unruptured GBAA obstructing the foramina of Monro. The patient was treated via staged, minimally invasive technique that first involved endoscopic fenestration of the septum pellucidum to create communication between the lateral ventricles. A programmable ventriculo peritoneal shunt was then placed with a high-pressure setting. The patient was then loaded with dual anti-platelet therapy prior to undergoing endovascular coiling of the GBAA with adjacent stenting of the Posterior Cerebral Artery. He remained on dual anti-platelet therapy and the shunt setting was lowered at the bedside to treat the hydrocephalus. At 6-month follow up, the patient had returned to his cognitive baseline, speaking fluently and appropriately. Biventricular hydrocephalus caused by a GBAA can successfully be treated in a minimally invasive fashion utilizing a combination of endoscopy and endovascular therapy, even when a stent-assisted coiling is needed. PMID- 26014028 TI - Application of three-dimentional computerized tomographic angiography in the planning of pterional scalp incision to preserve the superficial temporal artery. AB - A standard pterional scalp incision is commonly used in the surgical treatment of lesions located at the cranial base. There is a close relationship between the superficial temporal artery and a pterional scalp incision. Standard pterional scalp incision is widely used in the aneurysm surgery of the basal cerebral arteries. Three-dimensional computerized tomographic angiography (3D CT Angiography) using the three-dimensional (3D) volume rendering technique is commonly used in the neuroradiological diagnosis of intracranial aneurysms. 3D CT Angiography produced for the mentioned purpose may concomitantly be used without any additional investigation for the imagination of superficial temporal artery. Virtual skin incision may be done in the computer software under the illumination of data obtained from the 3D CT Angiography. In this study, we investigated the applicability of this technique using 3D CT Angiography. In conclusion, using this technique in cases undergoing surgery with standard pterional scalp incision may preserve the superficial temporal artery leading to the prevention of the skin problems originating from insufficient blood supply, and allowing the use of the preserved superficial temporal artery for cranial anastomosis surgery in the future. PMID- 26014030 TI - Is it time for emergency medicine to develop a digital health presence? PMID- 26014029 TI - Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of alpha-Oxo Acids. AB - The direct decarboxylative arylation of alpha-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple alpha-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate. PMID- 26014031 TI - Probing the Catalytic Activity of Reduced Graphene Oxide Decorated with Au Nanoparticles Triggered by Visible Light. AB - Hybrid materials in which reduced graphene oxide (rGO) is decorated with Au nanoparticles (rGO-Au NPs) were obtained by the in situ reduction of GO and AuCl4(-)(aq) by ascorbic acid. On laser excitation, rGO could be oxidized as a result of the surface plasmon resonance (SPR) excitation in the Au NPs, which generates activated O2 through the transfer of SPR-excited hot electrons to O2 molecules adsorbed from air. The SPR-mediated catalytic oxidation of p aminothiophenol (PATP) to p,p'-dimercaptoazobenzene (DMAB) was then employed as a model reaction to probe the effect of rGO as a support for Au NPs on their SPR mediated catalytic activities. The increased conversion of PATP to DMAB relative to individual Au NPs indicated that charge-transfer processes from rGO to Au took place and contributed to improved SPR-mediated activity. Since the transfer of electrons from Au to adsorbed O2 molecules is the crucial step for PATP oxidation, in addition to the SPR-excited hot electrons of Au NPs, the transfer of electrons from rGO to Au contributed to increasing the electron density of Au above the Fermi level and thus the Au-to-O2 charge-transfer process. PMID- 26014037 TI - TGF-beta downregulates KLRG1 expression in mouse and human CD8(+) T cells. AB - The inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the integrin alphaE (CD103) are expressed by CD8(+) T cells and both are specific for E-cadherin. However, KLRG1 ligation by E-cadherin inhibits effector T-cell function, whereas binding of CD103 to E-cadherin enhances cell-cell interaction and promotes target cell lysis. Here, we demonstrate that KLRG1 and CD103 expression in CD8(+) T cells from untreated and virus-infected mice are mutually exclusive. Inverse correlation of KLRG1 and CD103 expression was also found in human CD8(+) T cells-infiltrating hepatocellular carcinomas. As TGF-beta is known to induce CD103 expression in CD8(+) T cells, we examined whether this cytokine also regulates KLRG1 expression. Indeed, our data further reveal that TGF-beta signaling in mouse as well as in human CD8(+) T cells downregulates KLRG1 expression. This finding provides a rationale for the reciprocal expression of KLRG1 and CD103 in different CD8(+) T-cell subsets. In addition, it points to the limitation of KLRG1 as a marker for terminally differentiated CD8(+) T cells if lymphocytes from tissues expressing high levels of TGF-beta are analyzed. PMID- 26014038 TI - Computer vision for image-based transcriptomics. AB - Single-cell transcriptomics has recently emerged as one of the most promising tools for understanding the diversity of the transcriptome among single cells. Image-based transcriptomics is unique compared to other methods as it does not require conversion of RNA to cDNA prior to signal amplification and transcript quantification. Thus, its efficiency in transcript detection is unmatched by other methods. In addition, image-based transcriptomics allows the study of the spatial organization of the transcriptome in single cells at single-molecule, and, when combined with superresolution microscopy, nanometer resolution. However, in order to unlock the full power of image-based transcriptomics, robust computer vision of single molecules and cells is required. Here, we shortly discuss the setup of the experimental pipeline for image-based transcriptomics, and then describe in detail the algorithms that we developed to extract, at high throughput, robust multivariate feature sets of transcript molecule abundance, localization and patterning in tens of thousands of single cells across the transcriptome. These computer vision algorithms and pipelines can be downloaded from: https://github.com/pelkmanslab/ImageBasedTranscriptomics. PMID- 26014039 TI - Characterization of top-down ETD in a travelling-wave ion guide. AB - Top-down sequencing methods are becoming increasingly relevant for protein characterization, in particular electron capture (ECD) and electron transfer dissociation (ETD) which allow for extensive backbone cleavage with minimal side reactions. The ability to obtain sequence-specific fragments while maintaining aspects of the higher-order structure, as well as the position of deuterium labels in H/D exchange, has attracted interest from scientists in the field of structural proteomics. Recently, ETD has also been combined with ion mobility on commercially available quadrupole/time-of-flight instruments, and this implementation paves the way to novel structural studies and investigation of the ETD process itself. In the current work, we investigate the use of ETD for fragmentation of standard peptides and proteins and provide a detailed description of the effect of the parameters controlling the time and efficiency of the reaction. We also highlight how the combination with ion mobility separation after electron transfer provides extended analytical benefits, such as assignment of fragments to a specific charge-reduced state of the precursor. PMID- 26014040 TI - Erythema annulare centrifugum associated with ovarian cancer. PMID- 26014042 TI - Comparative proteomics reveals highly and differentially expressed proteins in field-collected and laboratory-cultured blooming cells of the diatom Skeletonema costatum. AB - Diatoms are a major phytoplankton group causing extensive blooms in the ocean. However, little is known about the intracellular biological processes occurring during the blooming period. This study compared the protein profiles of field collected and laboratory-cultured blooming cells of Skeletonema costatum, and identified highly and differentially expressed proteins using the shotgun proteomic approach. A total of 1372 proteins were confidently identified with two or more peptides. Among them, 222 and 311 proteins were unique to the laboratory and field samples respectively. Proteins involved in photosynthesis, translation, nucleosome assembly, carbohydrate and energy metabolism dominated the protein profiles in both samples. However, different features of specific proteins were also found: proteins participated in light harvesting, photosynthetic pigment biosynthesis, photoprotection, cell division and redox homeostasis were highly detected in the field sample, whereas proteins involved in translation, amino acid and protein metabolic processes, and nitrogen and carbon assimilation presented high detection rates in the laboratory sample. ATP synthase cf1 subunit beta and light harvest complex protein were the most abundant protein in the laboratory and field samples respectively. These results indicated that S. costatum had evolved adaptive mechanisms to the changing environment, and integrating field and laboratory proteomic data should provide comprehensive understanding of bloom mechanisms. PMID- 26014044 TI - Neutrophil-to-lymphocyte ratio and platelet distribution in patients with endometrial cancer. PMID- 26014043 TI - Patient-reported assessment of self-management strategies of health in cancer patients: development and validation of the Smart Management Strategy for Health Assessment Tool (SAT). AB - OBJECTIVE: The objective of this study was to evaluate the psychometric properties of the Smart Management Strategy for Health Assessment Tool (SAT), which we developed to enable cancer patients to assess their self-management (SM) strategies of health by themselves. PATIENTS AND METHODS: The development of the questionnaire included four phases: item generation, construction, pilot testing, and field testing. To assess the instrument's sensitivity and validity, we recruited 300 cancer patients from three Korean hospitals who were 18 or more years old and accustomed to using the Internet or email. Using the appropriate and priority criteria for pilot and field testing, we tightened the content and constructed the first version of the SAT. RESULTS: We developed the core strategies with 28 items, preparation strategies with 30 items, and implementation strategies with 33 items. Factor analysis of data from 300 patients resulted in core strategies with four factors, preparation strategies with five factors, and implementation strategies with six factors. All the SAT subscales demonstrated a high reliability with good internal consistency. The total scores of the three SAT sets differentiated participant groups well according to their stage of goal implementation and proportions of action of the 10 Rules for Highly Effective Health Behavior. Each factor of the three SAT sets correlated positively with the scores for additional assessment tool. CONCLUSION: The SAT is a three-set, 16-factor, 91-item tool that assesses the SM strategies of health that patients use to overcome a crisis. Patients can use the SAT to assess their SM strategies of health and obtain feedback from clinicians in the practice setting. PMID- 26014045 TI - Phenolic compounds from the bark of Oroxylum indicum activate the Ngn2 promoter. AB - A reporter gene assay that detects neurogenin 2 (Ngn2) promoter activity was utilized to identify compounds that induce neuronal differentiation. Ngn2 is a basic helix-loop-helix transcription factor that activates transcription of pro neural genes. Using this assay system and an activity-guided approach, seven phenolic compounds were isolated from the methanol extract of Oroxylum indicum: 1 oroxylin A, 2 chrysin, 3 hispidulin, 4 baicalein, 5 apigenin, 6 baicalin, and 7 isoverbascoside. Compounds 1 and 2 induced an estimated 2.7-fold increase in Ngn2 promoter activity, whereas 3 increased the activity by 2.5-fold. Furthermore, 1 and 2 enhanced neuronal differentiation of C17.2 cells, which are multipotent stem cells. PMID- 26014046 TI - Ninjin'yoeito and ginseng extract prevent oxaliplatin-induced neurodegeneration in PC12 cells. AB - Ninjin'yoeito (NYT) is a formula of Japanese traditional kampo medicine composed of 12 crude drugs, and is designed to improve the decline in constitution after recovery from disease, fatigue, anemia, anorexia, perspiration during sleep, cold limbs, slight fever, chills, persistent cough, malaise, mental disequilibrium, insomnia, and constipation. Oxaliplatin (L-OHP) is a platinum-based anticancer drug used to treat colorectal, pancreatic, and stomach cancers. However, it often causes acute and chronic peripheral neuropathies including cold allodynia and mechanical hyperalgesia. In this study, we investigated the preventive effects of NYT on neuronal degeneration caused by L-OHP using PC12 cells, which are derived from the rat adrenal medulla and differentiate into nerve-like cells after exposure to nerve growth factor. L-OHP treatment decreased the elongation of neurite-like projection outgrowths in differentiated PC12 cells. When PC12 cells were treated with NYT hot water extract, neurodegeneration caused by L-OHP was significantly prevented in a concentration-dependent manner. Among the 12 crude drugs composing NYT, the extract of Ginseng (the root of Panax ginseng) exhibited the strongest preventive effects on neurodegeneration in differentiated PC12 cells. By activity-guided fractionation, we found that the fraction containing ginsenosides displayed preventive activity and, among several ginsenosides, ginsenoside F2 exhibited significant preventive effects on L-OHP-induced decreases in neurite-like outgrowths in differentiated PC12 cells. These results suggest that NYT and ginseng are promising agents for preventing L-OHP-induced neuropathies and present ginsenoside F2 as one of the active ingredients in ginseng. PMID- 26014041 TI - The CODATwins Project: The Cohort Description of Collaborative Project of Development of Anthropometrical Measures in Twins to Study Macro-Environmental Variation in Genetic and Environmental Effects on Anthropometric Traits. AB - For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes. PMID- 26014047 TI - CSF neopterin level as a diagnostic marker in primary central nervous system lymphoma. AB - BACKGROUND: The diagnosis of primary central nervous system lymphoma (PCNSL) can be challenging. PCNSL lesions are frequently located deep within the brain, and performing a cerebral biopsy is not always feasible. The aim of this study was to investigate the diagnostic value of CSF neopterin, a marker of neuroinflammation, in immunocompetent patients with suspected PCNSL. METHODS: We retrospectively reviewed the characteristics of 124 patients with brain tumor (n = 82) or an inflammatory CNS disorder (n = 42) in whom CSF neopterin levels were assessed. Twenty-eight patients had PCNSL, 54 patients had another type of brain tumor (glioma n = 36, metastasis n = 13, other n = 5), and 13 patients had a pseudotumoral inflammatory brain lesion. RESULTS: CSF neopterin levels were significantly higher in the patients with PCNSL than in those with other brain tumors (41.8 vs 5.1 nmol/L, P < .001), those with pseudotumoral inflammatory brain lesions (41.8 vs 4.3 nmol/L, P < .001), and those with nontumefactive inflammatory CNS disorders (41.8 vs 3.8 nmol/L, P < .001). In the 95 patients with space-occupying brain lesions, at a cutoff of 10 nmol/L, the sensitivity of this approach was 96% and the specificity was 93% for the diagnosis of PCNSL. The positive and negative predictive values were 84% and 98%, respectively. CONCLUSION: Assessing CSF neopterin levels in patients with a suspected brain tumor might be helpful for the positive and differential diagnosis of PCNSL. A prospective study is warranted to confirm these results. PMID- 26014048 TI - Transcriptional upregulation of microtubule-associated protein 2 is involved in the protein kinase A-induced decrease in the invasiveness of glioma cells. AB - BACKGROUND: Malignant glioma is the most lethal primary tumor of the central nervous system, with notable cell invasion causing significant recurrence. Suppression of glioma invasion is very important for improving clinical outcomes. Drugs that directly disrupt the cytoskeleton have been developed for this purpose; however, drug resistance and unsatisfactory selectivity have limited their clinical use. Previously, we reported that protein kinase A (PKA, also known as cyclic-AMP dependent protein kinase) activation induced the differentiation of glioma cells. METHODS: We used several small molecular inhibitors and RNA interference, combined with wound healing assays, Matrigel transwell assay, and microscopic observation, to determine whether activation of the PKA pathway could inhibit the invasion of human glioma cells. RESULTS: Activation of PKA decreased the invasion of glioma cells. The mechanism operated via transcriptional upregulation of microtubule-associated protein 2 (MAP2), which was activated by the PKA pathway and led to ossification of microtubule dynamics via polymerization of tubulin. This resulted in morphological changes and a reduction in glioma cell invasion. Furthermore, chromosome immunoprecipitation and quantitative real-time polymerase chain reaction showed that signal transducer and activator of transcription 3 (STAT3) is involved in the transcriptional upregulation of MAP2. CONCLUSION: Our findings suggested that PKA may represent a potential target for anti-invasion glioma therapy and that the downstream modulators (eg, STAT3/MAP2) partially mediate the effects of PKA. PMID- 26014049 TI - Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases. AB - Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM. PMID- 26014051 TI - Surgical margins and oncologic results after carcinoma of the external auditory canal. AB - OBJECTIVES/HYPOTHESIS: External auditory canal cancer is rare and carries a poor prognosis. To date, only a few studies provide evidence for clinical decision making in multimodal treatment. METHODS: Retrospective chart review of 36 cases in three tertiary referral centers. RESULTS: Thirteen patients were treated by surgery alone, 18 by surgery with adjuvant chemoradiotherapy (CRT) and five by primary CRT. Clear surgical margins (R0) were obtained in 19 patients and positive margins (R1) in 12. The 5-year overall survival and local control rates were 59.4% and 74.2% with R0 status versus 56.6% and 26.3% with R1 status. The 5 year overall survival and local control rates were 46.2% and 70.7% with surgery alone, 78.1% and 43.2% with surgery and adjuvant CRT, and 25.0% and 80.0% with primary CRT. CONCLUSION: Surgery is integral to the management of external auditory canal cancer, whereas CRT is necessary as an adjuvant or primary treatment, depending on tumor stage. LEVEL OF EVIDENCE: 4. PMID- 26014052 TI - [The situation of residents in ophthalmology in Germany: Results of an online survey]. AB - PURPOSE: The main purpose of the present survey was to describe the situation of residents in ophthalmology in Germany, including professional aims and plans for the future. By evaluating the current conditions, potential deficits should be identified which could lead to demand-oriented approaches for improvement. METHODS: The online questionnaire was sent out per e-mail to 1100 German residents. The rate of received answers was 30.1 % (334 completed questionnaires). RESULTS: Of the participants 68 % were female,32 % were male (mean age 31.8 years), one third of the participants had children, 44.6 % worked at university institutions, 54.4 % at non-university institutions and 45.5 % considered themselves as well-trained. Deficits during residency training were seen in the field of neuro-ophthalmology and ophthalmic surgery. The evaluation of the residency in total revealed an overall average grade of 2.9 ("satisfactory"). Of the physicians 35.5 % reported to be actively involved in research projects and 21.9 % reported pursuing an academic career. Almost 50 % of the participant residents aimed to work in a private practice after residency and 15 % aimed to work at an university hospital. CONCLUSION: The present survey revealed representative data because of the acceptable return rate and participating residents from all different educational levels (1st to 5th year). The survey can therefore help to characterize the current situation of residents in ophthalmology in Germany and to develop demand-oriented possibilities for improvement. PMID- 26014050 TI - Telomere maintenance and the etiology of adult glioma. AB - A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length. PMID- 26014053 TI - Summary of the European Directive 2013/59/Euratom: essentials for health professionals in radiology. AB - The aspects of the new European Directive 2013/59/Euratom most relevant to diagnostic imaging and intervention are summarised. The Directive, laying down basic safety standards for protection against the dangers from exposure to ionising radiation, emphasises the need for justification of medical exposure (including asymptomatic individuals), introduces requirements concerning patient information and strengthens those for recording and reporting doses from radiological procedures, the use of diagnostic reference levels, the availability of dose-indicating devices and the improved role and support of the Medical Physics Experts in imaging. Relevant changes include new definitions, a new dose limit for the eye lens, non-medical imaging exposures, procedures in asymptomatic individuals, the use and regular review of diagnostic reference levels (including interventional procedures), dosimetric information in imaging systems and its transfer to the examination report, new requirements on responsibilities, the registry and analysis of accidental or unintended exposure and population dose evaluation (based on age and gender distribution). These changes will require Member States, the radiology community and the industry to adapt regulations, practices and equipment for a high standard of radiation safety. By 6 February 2018, the Directive has to be transposed into the national legislation of the Member States of the European Union. Main messages * The new European Basic Safety Standards Directive impacts radiology departments * Changes in justification, patient information, responsibilities and dose reporting are most significant * Diagnostic reference levels and the role of medical physics experts are clarified * Dose limits to the eye lens are lower than in the previous directive * Responsibilities in radiation safety have been defined. PMID- 26014054 TI - Recent advances in employing homoenolates generated by N-heterocyclic carbene (NHC) catalysis in carbon-carbon bond-forming reactions. AB - The use of NHCs for generating homoenolate species has gained widespread popularity in recent years. A number of highly stereoselective processes of NHC homoenolates have emerged. Homoenolate reactions have also been employed as key steps in the total synthesis of a number of natural products. The use of compatible co-catalysts, improved NHC-catalyst design and the use of novel precursors for homoenolate generation are among the major developments in this area that were disclosed recently. This tutorial review organises and presents the advancements in this rapidly growing area of catalysis and in the process updates a previous account published in 2011 in this journal. PMID- 26014055 TI - Structural analysis of the diadenylate cyclase reaction of DNA-integrity scanning protein A (DisA) and its inhibition by 3'-dATP. AB - The identification of the essential bacterial second messenger cyclic-di-AMP (c di-AMP) synthesized by the DNA-integrity scanning protein A (DisA) has opened up a new and emerging field in bacterial signalling. To further analyse the diadenylate cyclase (DAC) reaction catalysed by the DAC domains of DisA, we crystallized Thermotoga maritima DisA in the presence of different ATP analogues and metal ions to identify the metal-binding site and trap the enzyme in pre- and post-reaction states. Through structural and biochemical assays we identified important residues essential for the reaction in the active site of the DAC domains. Our structures resolve the metal-binding site and thus explain the activation of ATP for the DAC reaction. Moreover, we were able to identify a potent inhibitor of the DAC domain. Based on the available structures and homology to annotated DAC domains we propose a common mechanism for c-di-AMP synthesis by DAC domains in c-di-AMP-producing species and a possible approach for its effective inhibition. PMID- 26014056 TI - Topological nature and the multiple Dirac cones hidden in Bismuth high-Tc superconductors. AB - Recent theoretical studies employing density-functional theory have predicted BaBiO3 (when doped with electrons) and YBiO3 to become a topological insulator (TI) with a large topological gap (~0.7 eV). This, together with the natural stability against surface oxidation, makes the Bismuth-Oxide family of special interest for possible applications in quantum information and spintronics. The central question, we study here, is whether the hole-doped Bismuth Oxides, i.e. Ba(1-x)K(x)BiO3 and BaPb(1-x)Bi(x)O3, which are "high-Tc" bulk superconducting near 30 K, additionally display in the further vicinity of their Fermi energy EF a topological gap with a Dirac-type of topological surface state. Our electronic structure calculations predict the K-doped family to emerge as a TI, with a topological gap above EF. Thus, these compounds can become superconductors with hole-doping and potential TIs with additional electron doping. Furthermore, we predict the Bismuth-Oxide family to contain an additional Dirac cone below EF for further hole doping, which manifests these systems to be candidates for both electron- and hole-doped topological insulators. PMID- 26014089 TI - Eliminate the sheath and maximize the working space: Sheathless transradial guiding catheters. AB - Use of a sheathless 6.5-F guide may provide an option for transradial access in patients with smaller radial arteries or in need of a larger diameter guide. This sheathless system avoids many of the problems inherent in home-made systems as it is hydrophilic coated and has a tight interface between components reducing vascular trauma on insertion. Advantages of this system need to be weighed against its relative thermal instability for support, while its low-resistance from hydrophilic coatings gives a different. PMID- 26014090 TI - The relationship between the heart rate deflection point test and maximal lactate steady state. AB - BACKGROUND: The aim of this study was to investigate the use of the Heart Rate Deflection Point Test (HRDP) in the determination of the velocity at the Maximal Lactate Steady State (MLSS). METHODS: Fifteen untrained male participants took part in a 3000-m running performance on a 400-m track. The volunteers performed an incremental test for HRDP determination. The third test was constant velocity, which lasted around 30 minutes and was based around HRDP for MLSS determination. RESULTS: Performance velocity at HRDP was strongly correlated with the MLSS running velocity (r=0.84; R2=0.71; P<0.0001). HRDP running velocity (mean+/-SD 9.0+/-1.3-km.h-1) was not significantly different (P>0.05) from MLSS velocity (9.3+/-1.3km.h-1). A high agreement was observed between methods (Bland and Altman analysis) with a mean error of 0.47 km.h-1. CONCLUSIONS: We can conclude that the HRDP was able to predict MLSS velocity. PMID- 26014091 TI - Neuromuscular changes associated with superior fatigue resistance in African runners. AB - BACKGROUND: An enhanced ability to resist fatigue has been proposed as one of African runners' performance superiority sources, although their fatigue resistance during sustained non-running-specific activities remain unclear. This study aimed to compare fatigue resistance during sustained isometric exercise between performance-matched African and European runners. METHODS: Thirty long distance runners (16 African, 14 European) performed submaximal fatiguing sustained isometric knee extensions. Rectus femoris electromyographic (EMG) activity was measured, and the muscle was electrically stimulated to contract at the beginning and end of the test. RESULTS: Time to task failure was greater for African than European runners (269+/-115 vs. 193+/-52 s, P=0.002; effect size [ES]=0.85, large effect). During the test, EMG amplitude increased less over time (P=0.031), and the left shift in the EMG frequency spectrum was less over time for the African runners (P<0.001). In addition, there was a lower relative reduction in stimulated force output from the first to the second stimulation in African runners (17.75+/-14.95 vs. 37.89+/-14.78%, P=0.006; ES=1.35; large effect). CONCLUSIONS: These findings of greater fatigue resistance during non running-specific activity and the associated muscle recruitment profile may contribute to the understanding of the physiology underlying endurance performance in African runners. PMID- 26014092 TI - Diclofenac patch for the treatment of acute pain caused by soft tissue injuries of limbs: a randomized, placebo-controlled clinical trial. AB - BACKGROUND: This study aimed to assess the efficacy and the safety of a newly developed patch containing diclofenac sodium 140 mg in patients affected by acute soft tissue sport injuries, such as contusion, strain and sprain with a randomised, double-blind, placebo-controlled trial. METHODS: One hundred and sixty-four subjects were recruited within 3 hours of a soft-tissue sport injury and were equally assigned to receive diclofenac or placebo patch applied twice a day for 7 days. The primary study endpoint was reduction in severity of pain on movement from baseline to 48 hours measured by Visual Analogue Scale. Secondary outcomes were reduction of pain on movement and at rest, reduction of pain on pressure, time to efficacy onset, global efficacy assessment and use of rescue analgesics. RESULTS: The reduction of pain on movement from baseline to day 2 was markedly greater in the diclofenac group compared with placebo (treatment effect: -24.25 mm, P<0.001 between groups). Statistically significant improvements were also observed in the diclofenac group compared to placebo for the secondary variables of pain on movement and at rest, pain on pressure, time to efficacy onset and global patient and investigator efficacy assessment. Local adverse reactions at the application site were reported in comparable rates in the two groups. CONCLUSIONS: The diclofenac patch could be a safe and effective alternative to the oral administration of non-steroidal anti-inflammatory drugs in the treatment of minor sport injuries. PMID- 26014093 TI - Post-molecular systematics and the future of phylogenetics. AB - The time is past when a research program in systematics should be based on only a few genes, extant taxa, and ultrametric trees. Cheap genome sequencing, powerful statistical methods, and new fossil discoveries promise to reinvigorate research programs in evolutionary biology. Population genetics, phylogeography, and species delimitation all benefit from genomic data, not just tree building alone. Null-hypothesis testing and power analysis via simulation can increase the confidence and robustness of phylogenetic comparative methods. Merging morphological and molecular datasets for fossil and extant taxa gives a more complete view of the Tree of Life. Combined, these developments can foster a post molecular systematics, integrating phylogenetic signal from the population up based on DNA and through time based on direct observation rather than inference. PMID- 26014094 TI - Hypercoagulability in adolescent girls on oral contraceptives-global coagulation profile and estrogen receptor polymorphisms. AB - Oral contraceptive (OCP) induced changes on coagulation are complex with high inter-individual variability. The precise reason for differences in this variability is unknown. We hypothesized that global coagulation assays better delineate these changes and variability in hypercoagulability may be the result of differences in estrogen metabolism and thrombophilia. Fifty-two adolescents initiating OCPs were prospectively enrolled; 33 subjects completed the study. Samples were analyzed prior to and after OCPs for procoagulant and anticoagulant factor activities and thrombin generation (TG) +/-thrombomodulin. Participants were genotyped for common thrombophilia and estrogen receptor-alpha (ESR-alpha) single nucleotide polymorphisms (SNPs). SNP genotypes were compared to coagulation parameters; TG parameters and differences pre and post OCPs were examined. At baseline, a striking finding was elevated FVIII levels. FVL was absent in all and F2 G20210A was present in one participant. The ESR-alpha polymorphism was present in heterozygous state in 59% and homozygous state in 21% participants. There were no differences in VWF levels and FVIII: C after being on OCPs. Protein S levels decreased with OCPs. Sixty percent of participants showed evidence of hypercoagulability on TG testing on OCPs. Higher thrombin peak and endogenous thrombin potential (ETP) were seen on TG after OCPs. With thrombomodulin, ETP and thrombin peak did not decrease after OCPs, signifying 'thrombomodulin resistance'. We demonstrated that OCPs induce a state of "variable" hypercoagulability in adolescents, predominantly through the protein S pathway. Genetic and nongenetic factors may account for the variable increase in hypercoagulability. Further research is needed to understand this. PMID- 26014095 TI - Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear Cell Renal Cell Carcinoma. AB - PD-L1 expression in primary clear-cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11 of 53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (P = 0.51). Tumor cell PD-L1 positivity was associated with higher T stage (P = 0.03) and higher Fuhrman nuclear grade (P < 0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (P < 0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (P = 0.82). The heterogeneity of PD L1 expression in ccRCC suggests that its assessment as a predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, because PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false negative results, these areas should be specifically selected for assessment. PMID- 26014096 TI - Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation. AB - PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. PMID- 26014099 TI - A case of catastrophic antiphospholipid syndrome: first report with advanced cardiac imaging using MRI. AB - This present case pertains to a 48-year-old woman with a history of antiphospholipid syndrome, who presented with progressive fatigue, generalized weakness, and orthopnea acutely. She had a prior diagnosis of antiphospholipid syndrome with recurrent deep vein thromboses (DVTs) and repeated demonstration of lupus anticoagulants. She presented in cardiogenic shock with markedly elevated troponin and global myocardial dysfunction on echocardiography, and cardiac catheterization revealed minimal disease. Cardiac magnetic resonance imaging was performed, which revealed findings of perfusion defects and microvascular obstruction, consistent with the pathophysiology of catastrophic antiphospholipid syndrome (CAPS). Diagnosis was made based on supportive imaging, including head magnetic resonance imaging (MRI) revealing multifocal, acute strokes; microvascular thrombosis in the dermis; and subacute renal infarctions. The patient was anticoagulated with intravenous unfractionated heparin and received high-dose methylprednisolone, plasmapheresis, intravenous immunoglobulin, and one dose each of rituximab and cyclophosphamide. She convalesced with eventual myocardial recovery after a complicated course. The diagnosis of CAPS relies on the presence of (1) antiphospholipid antibodies and (2) involvement of multiple organs in a microangiopathic thrombotic process with a close temporal association. The myocardium is frequently affected, and heart failure, either as the presenting symptom or cause of death, is common. Despite echocardiographic evidence of myocardial dysfunction in such patients, MRIs of CAPS have not previously been reported. This case highlights the utility in assessing the involvement of the myocardium by the microangiopathic process with MRI. Because the diagnosis of CAPS requires involvement in multiple organ systems, cardiac MRI is likely an underused tool that not only reaffirms the pathophysiology of CAPS, but could also clue clinicians in to the possibility of a diffuse thrombotic process. PMID- 26014098 TI - Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. AB - Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD 1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNgamma can enhance tumor cell PD L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. PMID- 26014097 TI - Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy-treated RCC primary tumors showed increased infiltration of CD4(+) and CD8(+) T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4(+)FOXP3(+) regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1-blocking agents. PMID- 26014100 TI - Nanoporous Cathodes for High-Energy Li-S Batteries from Gyroid Block Copolymer Templates. AB - This study reports on a facile approach to the fabrication of nanoporous carbon cathodes for lithium sulfur batteries using gyroid carbon replicas based on use of polystyrene-poly-4-vinylpyridine (PS-P4VP) block copolymers as sacrificial templates. The free-standing gyroid carbon network with a highly ordered and interconnected porous structure has been fabricated by impregnating the carbon precursor solution into the gyroid block copolymer nanotemplates and subsequently carbonizing them. A wide range of analytical tools have been employed to characterize fabricated porous carbon material. Prepared nanostructures are envisioned to have a great potential in myriad areas such as energy storage/conversion devices owing to their fascinating morphology exhibiting high surface area and uniform porosity with interconnected three-dimensional networks. The resulting carbon nanoporous structures infused with elemental sulfur have been found to work as a promising electrode for lithium sulfur batteries demonstrating a high cycling stability over more than 200 cycles. PMID- 26014101 TI - Thin-Layer Chemical Modulations by a Combined Selective Proton Pump and pH Probe for Direct Alkalinity Detection. AB - We report a general concept based on a selective electrochemical ion pump used for creating concentration perturbations in thin layer samples (~40 MUL). As a first example, hydrogen ions are released from a selective polymeric membrane (proton pump) and the resulting pH is assessed potentiometrically with a second membrane placed directly opposite. By applying a constant potential modulation for 30 s, an induced proton concentration of up to 350 mM may be realized. This concept may become an attractive tool for in situ titrations without the need for sampling, because the thin layer eventually re-equilibrates with the contacting bulk sample. Acid-base titrations of NaOH and Na2 CO3 are demonstrated. The determination of total alkalinity in a river water sample is carried out, giving levels (23.1 mM) comparable to that obtained by standard methods (23.6 mM). The concept may be easily extended to other ions (cations, anions, polyions) and may become attractive for environmental and clinical applications. PMID- 26014102 TI - Growing indications for CEUS: The kidney, testis, lymph nodes, thyroid, prostate, and small bowel. AB - Contrast enhanced ultrasonography (CEUS) is increasingly used for non-hepatic applications as well, so that nearly all organs have been investigated. Among them, there is a growing clinical use for a variety of pathologies of the kidney, testis, and small bowel. The possibility to differentiate benign from malignant nodes in cancer patients has been investigated. A new application is in the detection of sentinel nodes after intradermal microbubble injection. The need to distinguish thyroid nodules eligible for fine needle aspiration cytology has led to the use of CEUS in thyroid examinations as well. The potential of CEUS for prostate cancer detection has been extensively investigated, with encouraging initial results. Early promise, however, has not been fulfilled. New perspective regards evaluation of the extent of prostate tissue devascularization following ablative treatments. PMID- 26014103 TI - Biomimetic fiber assembled gradient hydrogel to engineer glycosaminoglycan enriched and mineralized cartilage: An in vitro study. AB - The study investigated the potential of electrospun fiber assembled hydrogel, with physical gradients of chondroitin sulfate (CS) and sol-gel-derived bioactive glass (BG), to engineer hyaline and mineralized cartilage in a single 3D system. Electrospun poly(caprolactone) (PCL) fibers incorporated with 0.1% w/w of CS (CSL) and 0.5% w/w of CS (CSH), 2.4% w/w of BG (BGL) and 12.5% w/w of BG (BGH) were fabricated. The CS showed a sustained release up to 3 days from CSL and 14 days from CSH fibers. Chondrocytes secreted hyaline like matrix with higher sulfated glycosaminoglycans (sGAG), collagen type II and aggrecan on CSL and CSH fibers. Mineralization was observed on BGL and BGH fibers when incubated in simulated body fluid for 14 days. Chondrocytes cultured on these fibers secreted a mineralized matrix that consisted of sGAG, hypertrophic proteins, collagen type X, and osteocalcin. The CS and BG incorporated PCL fiber mats were assembled in an agarose-gelatin hydrogel to generate a 3D hybrid scaffold. The signals in the fibers diffused and generated continuous opposing gradients of CS (chondrogenic signal) and BG (mineralization) in the hydrogel. The chondrocytes were encapsulated in hybrid scaffolds; live dead assay at 48 h showed viable cells. Cells maintained their phenotype and secreted specific extracellular matrix (ECM) in response to signals within the hydrogel. Continuous opposing gradients of sGAG enriched and mineralized ECM were observed surrounding each cell clusters on gradient hydrogel after 14 days of culture in response to the physical gradients of raw materials CS and BG. A construct with gradient mineralization might accelerate integration to subchondral bone during in vivo regeneration. PMID- 26014105 TI - Formation of As-As Interlayer Bonding in the collapsed tetragonal phase of NaFe2As2 under pressure. AB - NaFe2As2 is investigated experimentally using powder x-ray diffraction and Raman spectroscopy at pressures up to 23 GPa at room temperature and using ab-initio calculations. The results reveal a pressure-induced structural modification at 4 GPa from the starting tetragonal to a collapsed tetragonal phase. We determined the changes in interatomic distances under pressure that allowed us to connect the structural changes and superconductivity. The transition is related to the formation of interlayer As-As bonds at the expense of weakening of Fe-As bonds in agreement with recent theoretical predictions. PMID- 26014104 TI - Biogenesis, characterization, and the effect of vicenin-gold nanoparticles on glucose utilization in 3T3-L1 adipocytes: a bioinformatic approach to illuminate its interaction with PTP 1B and AMPK. AB - This study reported the synthesis of Vicenin-2 gold nanoparticles (VN-AuNPs) and evaluated their effect on the glucose utilization efficiency of 3T3-L1 adipocytes. The VN-AuNPs were characterized by microscopic, DLS and spectral analysis. The bio-reducing efficiency of Vicenin-2 (VN) was computed and confirmed by HPLC analysis. The stability of VN-AuNPs in various physiological media was explored. The cytotoxicity and glucose uptake assays were performed in 3T3-L1 adipocytes. The docking of VN with PTP1B and AMPK was also performed. The color change and UV absorption at 537 nm preliminarily confirmed the VN reduced gold nanoparticles. The VN-AuNPs appeared as spherical particles (57 nm) and face centered cubic crystals under TEM and XRD analysis, respectively. Its zeta potential was found to be -6.53 mV. The FT-IR spectra of VN and its AuNPs confirmed its stability. The computed reducing potential of VN was similar to the extent of VN utilized during the synthesis of VN-AuNPs. The VN-AuNPs showed a remarkable stability in different physiological media. At 100 uM concentration, VN-AuNPs displayed 78.21% cell viability. A concentration dependent increase in glucose uptake was noted in 3T3-L1 adipocytes when incubated with VN-AuNPs. The docking data revealed a strong interaction of VN with the binding pockets of PTP1B and AMPK. This demonstrates that the fabricated VN-AuNPs might enhance the intracellular VN availability mediated cellular glucose utilization and this would serve as a novel nanodrug for the management of diabetes. PMID- 26014106 TI - Diagnostic value of ultrasonographic combining biochemical markers for Down syndrome screening in first trimester: a meta-analysis. AB - OBJECTIVE: The meta-analysis was to determine the diagnostic value of the combining tests for Down syndrome and to evaluate their utilities in the Down syndrome screening. METHOD: Through comprehensive literature search, 24 studies met the inclusion criteria and were included in the databases (PubMed, Wed of knowledge, Chinese National Knowledge Infrastructure (CNKI)). Summary estimates for sensitivity and specificity were calculated by using the bivariate random effect model. The summary receiver operating characteristic curve was also undertaken. RESULTS: The overall sensitivity and specificity of the combination of NT and free beta-hCG and PAPP-A for Down syndrome were 0.86(95%CI 0.75-0.92) and 0.96(95%CI 0.95-0.97), respectively. The summary positive likelihood ratio and negative likelihood ratio were 23.3 (95%CI 16.7-32.5) and 0.15(95%CI 0.08 0.26), respectively. The pooled diagnostic odds ratio was 156 (95%CI 75-326). CONCLUSION: The meta-analysis shows the accumulative evidence for the clinician that the performance of the combined test of MA and NB and NT and PAPP-A and free beta-hCG is the most effective test in the four different combined tests, while, the combination of NT and PAPP-A and free beta-hCG is a cost-effective screening tool for Down syndrome. PMID- 26014107 TI - Fractal features of soil particle size distribution in newly formed wetlands in the Yellow River Delta. AB - The characteristic of particle size distribution (PSD) in the newly formed wetlands in coast has seldom been studied. We applied fractal-scaling theory in assessing soil particle size distribution (PSD) features of newly formed wetlands in the Yellow River Delta (YRD), China. The singular fractal dimensions (D) values ranged from 1.82 to 1.90, the capacity dimension (D0) values ranged from 0.84 to 0.93, and the entropy dimension (D1) values ranged from 0.66 to 0.84. Constrained corresponding analysis revealed that 43.5% of the variance in soil PSD can be explained by environmental factors, including 14.7% by seasonal variation, 8.6% by soil depth, and 8.0% by vegetation type. The fractal dimensions D and D1 were sensitive with fine particles with size ranging less than 126 MUm, and D0 was sensitive with coarse particles with size ranging between 126 MUm to 2000 MUm. Fractal analysis makes full use of soil PSD information, and offers a useful approach to quantify and assess the soil physical attributes in the newly formed wetland. PMID- 26014108 TI - Synthesis of tetraarylpyridines by chemo-selective Suzuki-Miyaura reactions of 3,5-dibromo-2,6-dichloropyridine. AB - Chemoselective Suzuki-Miyaura reactions on 3,5-dibromo-2,6-dichloropyridine were studied. The optimized reaction conditions allow for the facile access of 3-aryl- and 3,5-diarylpyridines in good yields. Suzuki-Miyaura reactions of the selectively synthesized 2,6-dichloro-3,5-diarylpyridines gave the corresponding 2,3,5,6-tetraarylpyridines, containing two different aryl moieties. PMID- 26014109 TI - Opposing effects of glutamatergic and GABAergic pharmacological manipulations on a visual perception task with relevance to schizophrenia. AB - RATIONALE: Numerous psychiatric disorders and neurodegenerative diseases have been associated with differences in visual perception, and it has been proposed that the treatment of these differences may represent a novel means to treat disorders like schizophrenia. Unfortunately, few methods exist to study visual perception in pre-clinical species. OBJECTIVE: The purpose of the present study was to adapt a task of visual integration by proximity with relevance to schizophrenia to a rodent touchscreen environment to determine the effects of glutamatergic and GABAergic compounds. In this way, we could evaluate the effects of common models of cognitive impairment, as well as the effects of net excitation versus inhibition, on a task of visual integration. METHOD: Rats were trained to perform a visual discrimination where the stimuli were composed of rows of dots differing only in there horizontal and vertical proximity. Once stable performance had been achieved, animals were tested under the influence of glutamatergic or GABAergic drugs (ketamine, MK-801, PCP, memantine, chlordiazepoxide, or diazepam) while attempting to perform a visual discrimination with altered stimuli. RESULTS: Ketamine appeared to impair perceptual grouping in this paradigm, while the GABA agonist chlordiazepoxide enhanced grouping even in the presence of non-selective effects. CONCLUSIONS: In general, these findings support the theory that NMDA antagonists may disrupt visual grouping by proximity and highlight a potential beneficial effect of enhanced GABA activity in perception. However, additional research will be required to confirm the stimulus selectivity of this effect, and the clinical significance of this approach. PMID- 26014110 TI - The role of machine learning in neuroimaging for drug discovery and development. AB - Neuroimaging has been identified as a potentially powerful probe for the in vivo study of drug effects on the brain with utility across several phases of drug development spanning preclinical and clinical investigations. Specifically, neuroimaging can provide insight into drug penetration and distribution, target engagement, pharmacodynamics, mechanistic action and potential indicators of clinical efficacy. In this review, we focus on machine learning approaches for neuroimaging which enable us to make predictions at the individual level based on the distributed effects across the whole brain. Crucially, these approaches can be trained on data from one study and applied to an independent study and, unlike group-level statistics, can be readily use to assess the generalisability to unseen data. In this review, we present examples and suggestions for how machine learning could help answer fundamental questions spanning the drug discovery pipeline: (1) Who should I recruit for this study? (2) What should I measure and when should I measure it? (3) How does the pharmacological agent behave using an experimental medicine model?, and (4) How does a compound differ from and/or resemble existing compounds? Specifically, we present studies from the literature and we suggest areas for the focus of future development. Further refinement and tailoring of machine learning techniques may help realise their tremendous potential for drug discovery and drug validation. PMID- 26014111 TI - Alcohol attention bias in adolescent social drinkers: an eye tracking study. AB - RATIONALE: Previous research on attention bias in nondependent social drinkers has focused on adult samples with limited focus on the presence of attention bias for alcohol cues in adolescent social drinkers. OBJECTIVES: The aim of this study was to examine the presence of alcohol attention bias in adolescents and the relationship of this cognitive bias to alcohol use and alcohol-related expectancies. METHODS: Attention bias in adolescent social drinkers and abstainers was measured using an eye tracker during exposure to alcohol and neutral cues. Questionnaires measured alcohol use and explicit alcohol expectancies. RESULTS: Adolescent social drinkers spent significantly more time fixating to alcohol stimuli compared to controls. Total fixation time to alcohol stimuli varied in accordance with level of alcohol consumption and was significantly associated with more positive alcohol expectancies. No evidence for automatic orienting to alcohol stimuli was found in adolescent social drinkers. CONCLUSION: Attention bias in adolescent social drinkers appears to be underpinned by controlled attention suggesting that whilst participants in this study displayed alcohol attention bias comparable to that reported in adult studies, the bias has not developed to the point of automaticity. Initial fixations appeared to be driven by alternative attentional processes which are discussed further. PMID- 26014112 TI - Impaired capacity for prospection in the dementias--Theoretical and clinical implications. AB - OBJECTIVES: Prospection, or future thinking, refers to the ability to mentally simulate plausible events at a future point in time and draws heavily upon the capacity to retrieve autobiographical details from the past. This review examines the extent to which prospection is compromised in neurodegenerative disorders with a view to identifying (1) underlying mechanisms of future thinking disruption and (2) the impact of future thinking deficits on everyday adaptive functioning. METHODS: PubMed and MEDLINE were searched for peer-reviewed articles published or in press up to 14 October 2014. The key criterion for inclusion was that the primary outcome measure concerned the envisaging of episodic events at a future time point. Search terms of 'future thinking', 'prospection', and 'future simulation' were used in combination with the following terms: 'dementia', 'Mild Cognitive Impairment', 'Alzheimer's disease', 'semantic dementia', 'frontotemporal dementia', 'Parkinson's disease', 'Motor Neuron disease', 'Vascular dementia', and 'Dementia with Lewy bodies' (e.g., 'future thinking' AND 'Alzheimer's disease'). Searches were limited to articles published in English. RESULTS: A total of nine unique papers were identified in which prospection was the main outcome measure in dementia. Collectively, these studies reveal marked impairments in the ability to simulate personally relevant events at a future time point in dementia syndromes. CONCLUSIONS: Future research investigating the real-world implications of prospection deficits in dementia is crucial to elucidate the interplay between future-oriented thought and everyday adaptive functions such as prospective memory, decision-making, and maintaining a coherent sense of self over time. PMID- 26014113 TI - Bimodal distribution of Trypanosoma cruzi antibody levels in blood donors from a highly endemic area of Argentina: what is the significance of low-reactive samples? AB - BACKGROUND: Low-level seroreactive donor samples that are inconsistently detected by different Trypanosoma cruzi immunoassays are common, but the population distribution has not been reported in an endemic region. The objective was to understand the distribution of low-level reactive samples using highly sensitive immunoassays and the relationship with epidemiologic evidence of exposure to T. cruzi. STUDY DESIGN AND METHODS: Blood donors (BDs) were recruited in two blood banks located in Chaco province, in northeastern Argentina, from June 2006 to March 2007. Donors completed a Chagas exposure questionnaire and provided blood samples. All samples were tested in parallel with five contemporary and commercially available enzyme immunoassays for T. cruzi and a subgroup by a chemiluminescent assay. RESULTS: Of the 1423 enrolled donors, 304 (21.4%) tested positive on all assays while 93 (6.5%) were reactive on at least one assay (inconclusive). Epidemiologic evidence of exposure to T. cruzi was significantly higher among positive and inconclusive donors compared to seronegative BD (p values range from 0.01 to <0.001 depending on the exposure). Histograms of the signal-to-cutoff values from all positive samples showed clear bimodal distributions for the whole parasite lysate assays, but not for the one recombinant antigen-based assay. Low antibody level responses were present in 30% to 40% of the reactives, depending on the assay. CONCLUSION: The population of individuals exposed to T. cruzi in highly endemic regions has a bimodal distribution of antibody response to the parasite. Although the clinical significance of low-level reactivity is not fully established, these results may reflect evolving seroreversions after spontaneously resolved infections. PMID- 26014114 TI - Nonencapsulated Streptococcus pneumoniae causes otitis media during single species infection and during polymicrobial infection with nontypeable Haemophilus influenzae. AB - Streptococcus pneumoniae strains lacking capsular polysaccharide have been increasingly reported in carriage and disease contexts. Since most cases of otitis media involve more than one bacterial species, we aimed to determine the capacity of a nonencapsulated S. pneumoniae clinical isolate to induce disease in the context of a single-species infection and as a polymicrobial infection with nontypeable Haemophilus influenzae. Using the chinchilla model of otitis media, we found that nonencapsulated S. pneumoniae colonizes the nasopharynx following intranasal inoculation, but does not readily ascend into the middle ear. However, when we inoculated nonencapsulated S. pneumoniae directly into the middle ear, the bacteria persisted for two weeks post-inoculation and induced symptoms consistent with chronic otitis media. During coinfection with nontypeable H. influenzae, both species persisted for one week and induced polymicrobial otitis media. We also observed that nontypeable H. influenzae conferred passive protection from killing by amoxicillin upon S. pneumoniae from within polymicrobial biofilms in vitro. Therefore, based on these results, we conclude that nonencapsulated pneumococci are a potential causative agent of chronic/recurrent otitis media, and can also cause mutualistic infection with other opportunists, which could complicate treatment outcomes. PMID- 26014116 TI - DNA-Encoded Dynamic Combinatorial Chemical Libraries. AB - Dynamic combinatorial chemistry (DCC) explores the thermodynamic equilibrium of reversible reactions. Its application in the discovery of protein binders is largely limited by difficulties in the analysis of complex reaction mixtures. DNA encoded chemical library (DECL) technology allows the selection of binders from a mixture of up to billions of different compounds; however, experimental results often show low a signal-to-noise ratio and poor correlation between enrichment factor and binding affinity. Herein we describe the design and application of DNA encoded dynamic combinatorial chemical libraries (EDCCLs). Our experiments have shown that the EDCCL approach can be used not only to convert monovalent binders into high-affinity bivalent binders, but also to cause remarkably enhanced enrichment of potent bivalent binders by driving their in situ synthesis. We also demonstrate the application of EDCCLs in DNA-templated chemical reactions. PMID- 26014115 TI - The anti-inflammatory and antioxidant activity of 25 plant species used traditionally to treat pain in southern African. AB - BACKGROUND: Inflammation is a common risk factor in the pathogenesis of conditions such as infections, arthritis, type 2 diabetes mellitus, obesity and cancer. An ethnobotanical survey of medicinal plants used traditionally to treat inflammation and related disorders such as pain, arthritis and stomach aches in southern Africa led to the selection of 25 plant species used in this study. METHODS: The antioxidant activities of acetone extracts were determined by measuring the free radical scavenging activity and ferric reducing ability, respectively. The anti-inflammatory activities of the extracts were determined by measuring the inhibitory effect of the extracts on the activities of the pro inflammatory enzyme, lipoxygenase and inducible nitric oxide synthase. RESULTS: Extracts of Peltophorum africanum had good antioxidant activity with IC50 values of 4.67 +/- 0.31 MUg/mL and 7.71 +/- 0.36 MUg/mL compared to that of the positive control ascorbic acid (2.92 +/- 0.14 MUg/mL and 13.57 +/- 0.44 MUg/mL), using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging and 2,2'-azinobis (3 ethylbenzthiazoline-6-sulphonic acid (ABTS) methods, respectively. The metabolism of linoleic acid to leukotriene derivatives by 15-lipoxygenase (15-LOX) was also inhibited by the crude acetone extracts of Peltophorum africanum (IC50 = 12.42 MUg/mL), Zanthoxylum capense (IC50 = 14.92 MUg/mL) compared to the positive control quercetin (IC50 = 8.75 MUg/mL). There was a poor correlation between the flavonoid content and 15-LOX inhibition by the extracts (R(2) = 0.05), indicating that flavonoids are not involved in LOX inhibition. Extracts of Clausena anisata, at a concentration of 6.25 MUg/mL inhibited nitric oxide production by RAW 264.7 macrophage cell lines in vitro by 96 %. The extracts of Zanthoxylum capense were the least cytotoxic (IC50 > 1000 MUg/mL) when the extract toxicity was determined against Vero (African green Monkey) kidney cell lines. CONCLUSION: Some plant species used traditionally to treat pain have reasonable anti-inflammatory activity and flavonoids are probably not involved in this process. PMID- 26014117 TI - Measurement of Large Dipolar Couplings of a Liquid Crystal with Terminal Phenyl Rings and Estimation of the Order Parameters. AB - NMR spectroscopy is a powerful means of studying liquid-crystalline systems at atomic resolutions. Of the many parameters that can provide information on the dynamics and order of the systems, (1) H-(13) C dipolar couplings are an important means of obtaining such information. Depending on the details of the molecular structure and the magnitude of the order parameters, the dipolar couplings can vary over a wide range of values. Thus the method employed to estimate the dipolar couplings should be capable of estimating both large and small dipolar couplings at the same time. For this purpose, we consider here a two-dimensional NMR experiment that works similar to the insensitive nuclei enhanced by polarization transfer (INEPT) experiment in solution. With the incorporation of a modification proposed earlier for experiments with low radio frequency power, the scheme is observed to enable a wide range of dipolar couplings to be estimated at the same time. We utilized this approach to obtain dipolar couplings in a liquid crystal with phenyl rings attached to either end of the molecule, and estimated its local order parameters. PMID- 26014118 TI - All is balanced: inter-alpha-trypsin inhibitors as unseen extracellular matrix proteins in epidermal morphology and differentiation. PMID- 26014119 TI - Self-Assembled 3D Graphene-Based Aerogel with Co3 O4 Nanoparticles as High Performance Asymmetric Supercapacitor Electrode. AB - Using graphene oxide and a cobalt salt as precursor, a three-dimensional graphene aerogel with embedded Co3 O4 nanoparticles (3D Co3 O4 -RGO aerogel) is prepared by means of a solvothermal approach and subsequent freeze-drying and thermal reduction. The obtained 3D Co3 O4 -RGO aerogel has a high specific capacitance of 660 F g(-1) at 0.5 A g(-1) and a high rate capability of 65.1 % retention at 50 A g(-1) in a three-electrode system. Furthermore, the material is used as cathode to fabricate an asymmetric supercapacitor utilizing a hierarchical porous carbon (HPC) as anode and 6 M KOH aqueous solution as electrolyte. In a voltage range of 0.0 to 1.5 V, the device exhibits a high energy density of 40.65 Wh kg(-1) and a power density of 340 W kg(-1) and shows a high cycling stability (92.92 % capacitance retention after 2000 cycles). After charging for only 30 s, three CR2032 coin-type asymmetric supercapacitors in series can drive a light-emitting diode (LED) bulb brightly for 30 min, which remains effective even after 1 h. PMID- 26014120 TI - In Vitro and In Vivo Studies of the Biological Effects of Bioceramic (a Material of Emitting High Performance Far-Infrared Ray) Irradiation. AB - Bioceramic is a material that emits high performance far-infrared ray, and possess physical, chemical and biological characteristics on irradiation of water, particularly to in reducing the size of water clusters, weakening of the hydrogen bonds of water molecules and other effects on physical and chemical properties of water. In this review paper, we summarized the in vivo and in vitro biological effects of Biocermaic, and included previous published data on nitric oxide, calmodulin induction on cells, effects of bioceramic on intracellular heat shock protein and intracellular nitric oxide contents of melanoma cells, antioxidant effects of Bioceramic on cells and plants under H2O2-mediated oxidative stress, effects on anti-oxidative stress of myoblast cells and on preventing fatigue of amphibian skeletal muscle during exercise, anti inflammatory and pain relief mechanism, effects on the chondrosarcoma cell line with prostaglandin E2 production, effects on the rabbit with inflammatory arthritis by injection of lipopolysaccharides under monitoring by positron emission tomography scan, effects on psychological stress-conditioned elevated heart rate, blood pressure and oxidative stress-suppressed cardiac contractility, and protective effects of non-ionized radiation against oxidative stress on human breast epithelial cell. We anticipate that the present work will benefit medical applications. PMID- 26014121 TI - Effects of Lu-Do-Huang Extract (LDHE) on Apoptosis Induction in Human Hep3B Cells. AB - Lu-Do-Huang (Pracparatum mungo) is a fermented mung bean [corrected] (Vigna radiata) and has long been used as a traditional and functional food in Traditional Chinese Medicine, especially for treating a variety of liver disorders. The present study aimed to evaluate the apoptotic effects of Lu-Do Huang ethanol extract (LDHE) on Hep3B cells, a human hepatoma cell line. A variety of cellular assays, flow cytometry and immunoblotting were used. Our results showed that LDHE significantly inhibited Hep3B cells growth. Additionally, the cell cycle assay showed that LDHE prevented Hep3B cell entry into S phase and led to an arrest of Hep3B cells in the G0/G1 phase. LDHE induced Hep3B cells to undergo apoptosis as determined through Hep3B cell morphology changes, increase of apoptotic bodies, apoptotic cells, DNA fragmentations and caspase activity. We further examined the protein expression of TRADD, FADD, and Bax to verify the possible apoptotic pathways. The results indicated that LDHE induced apoptosis in Hep3B cells might be mediated [corrected] by an extrinsic signaling pathway leading to an induction of apoptosis in Hep3B cells. In conclusion, LDHE induced apoptosis and cell cycle arrest in Hep3B cells. Our data provide the evidences regarding the anti-hepatoma potential of LDHE in Hep3B cells. PMID- 26014122 TI - A New Type of Signaling Pathways as Pilomotor Lines along Skin for Transmitting Acupuncture Signals to Produce Acupuncture Effects. AB - In our previous study, we observed a linear system consisted of sympathetic endings in the arrector pili muscles (AP muscles) along the rat skin termed sympathetic substance lines, or SSLs. After shaving the hair of the rats, the first wave of hair re-growth was not evenly distributed, but followed specific hair loop lines (HLLs). The patterns of HLL and SSL correspond with each other and also with the "Meridians" described in Chinese traditional medicine (CTM). Here I investigated in rabbits and rats whether the acupuncture signals are transmitted via the SSL/HLL, and whether the acupuncture analgesia (AA) is dependent on any peripheral mechanism. Firstly, when acupuncture was operated or phenylephrine, an agonist for alpha receptor, was injected into the dermis at an acupoint, a pilomotor line occurred. The course of the pilomotor line coincided with the SSL/HLL. When the skin was incised or regitin, an antagonist for alpha receptor, was injected into the dermis, the pilomotor line did not cross the site of incision or injection. These results directly demonstrated the process of transmission of acupuncture signals involving the pilomotor line and the sympathetic. Secondly, AA produced by acupuncture at an acupoint was significantly blocked when the skin was incised or regitin was injected into the dermis along the SSL/HLL or the Meridians. [corrected]. These results suggest that the factor that blocked the pilomotor line also blocked the AA and the pilomotor line related to the AA. Lastly, noradrenaline was shown to be released from the skin along the Meridian line after acupuncture; when phenylephrine was injected into an acupoint, AA was strongly simulated. All these results indicate that: 1. the transmission pathway of acupuncture signals exists in the skin, just as the Meridians described in the CTM; 2. these pathways are the SSLs/HLLs and the pilomotor lines; and 3. the pilomotor line is just for the transmission of acupuncture signals and the transmission is dependent on the alpha receptor in the AP muscles, specifically the contraction of the AP muscles. Moreover, these findings suggest a new system and a new type of signal transmission in the physiology. PMID- 26014123 TI - Effect of Antidepressant Doxepin on Ca2+ Homeostasis and Viability in PC3 Human Prostate Cancer Cells. AB - The effect of the antidepressant doxepin on cytosolic Ca2+ concentrations ([Ca2+](i)) and viability in PC3 human prostate cancer cells was explored. The Ca2+-sensitive fluorescent dye fura-2 was applied to measure [Ca2+](i). Doxepin at concentrations of 500-1000 MUM induced a [Ca2+](i) rise in a concentration dependent manner. The response was reduced partly by removing Ca2+. Doxepin evoked Ca2+ entry was suppressed by Ca2+ entry blockers (nifedipine, econazole, SK&F96365), and protein kinase C (PKC) modulators. In the absence of extracellular Ca2+, incubation with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) partly inhibit doxepin induced [Ca2+](i) rise. Incubation with doxepin nearly inhibited thapsigargin or BHQ-induced [Ca2+](i) rise. Inhibition of phospholipase C (PLC) with U73122 failed to alter doxepin-induced [Ca2+](i) rise. At concentrations of 200-250 MUM, doxepin killed cells in a concentration-dependent manner. This cytotoxic effect was not reversed by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane N,N,N',N'- tetraacetic acid/acetoxy methyl (BAPTA/AM). Annexin V/PI staining data implied that doxepin (200 and 250 MUM) did not induce apoptosis. Collectively, in PC3 cells, doxepin induced a [Ca2+](i) rise by evoking PLC-independent Ca2+ release from stores including the endoplasmic reticulum and Ca2+ entry via PKC sensitive store-operated Ca2+ channels. Doxepin caused cell death that was independent of [Ca2+](i) rises. PMID- 26014124 TI - Cardio Protective Effects of Lumbrokinase and Dilong on Second-Hand Smoke-Induced Apoptotic Signaling in the Heart of a Rat Model. AB - Exposure to second-hand tobacco smoke (SHS) has been epidemiologically linked to heart disease among non-smokers. However, the molecular mechanism behind SHS induced cardiac disease is not well known. This study found that SD rats exposed to cigarette smoke at a dose of 10 cigarettes for 30 min twice a day for 1 month had a reduced left ventricle-to-tibia length ratio (mg/mm), increased cardiomyocyte apoptosis by TUNEL assay and a wider interstitial space by H&E staining. However, lumbrokinase and dilong both reversed the effects of SHS. Western blotting demonstrated significantly increased expression of the pro apoptotic protein caspase-3 in the hearts of the rats exposed to SHS. Elevated protein expression levels of Fas, FADD and the apoptotic initiator activated caspase-8, a molecule in the death-receptor-dependent pathway, coupled with increased t-Bid and apoptotic initiator activated caspase-9 were found. Molecules in the mitochondria-dependent pathway, which disrupts mitochondrial membrane potential, were also found in rats exposed to SHS. These factors indicate myocardial apoptosis. However, treatment with lumbrokinase and dilong inhibited SHS-induced apoptosis. Regarding regulation of the survival pathway, we found in western blot analysis that cardiac protein expression of pAkt, Bcl2, and Bcl-xL was significantly down-regulated in rats exposed to SHS. These effects were reversed with lumbrokinase and dilong treatment. The effects of SHS on cardiomyocytes were also found to be mediated by the Fas death receptor-dependent apoptotic pathway, an unbalanced mitochondria membrane potential and decreased survival signaling. However, treatment with both lumbrokinase and dilong inhibited the effects of SHS. Our data suggest that lumbrokinase and dilong may prevent heart disease in SHS-exposed non-smokers. PMID- 26014125 TI - Attenuated Effects of Deep-Sea Water on Hepatic Apoptosis in STZ-Induced Diabetic Rats. AB - Diabetes mellitus (DM) is a metabolic disorder and increasing evidences have indicated a connection between DM and hepatic abnormality. Deep-sea water (DSW) has been applied in many fields, especially in medicine; herein, we investigated the influence of DSW on hepatic apoptosis in streptozocin (STZ)-induced diabetes rats. Our experimental results firstly demonstrated the beneficial effects of 1*DSW, 2*DSW and 3*DSW in alleviating hepatic apoptosis in STZ-induced diabetic rats. We demonstrated that 1*DSW, 2*DSW and 3*DSW significantly suppressed the caspase-3 activity and TUNEL-positive cells in livers of STZ-induced diabetic rats. Significant reductions of both Fas-dependent and mitochondrial-dependent apoptotic molecules were also detected in livers of STZ-induced diabetic rats receiving DSW. Additionally, apoptotic signaling molecules such as phosphorylated IkappaB-alpha and NF-kappaB were significantly reduced in livers of DSW-treated STZ-induced diabetic rats. These findings indicate hepatic protective effects of DSW on DM and suggest DSW as a possible ingredient for health food. PMID- 26014126 TI - Inhibitory effect of direct electric field and HA-ZnO composites on S. aureus biofilm formation. AB - In addressing the issue of prosthetic infection, we demonstrate herein how direct electric field (DC EF) stimulation can effectively inhibit biofilm formation, when pathogenic Staphylococcus aureus (MRSA, USA 300) are grown on HA-xZnO (x = 0, 5, 7.5, and 10 wt %) biocomposites in vitro. After bacterial preincubation for 4 h, a low intensity DC EF (1V/cm) was applied for different time periods (t = 6, 12, 18, and 24 h). The bacterial viability and biofilm maturation were evaluated by a combination of biochemical assays, fluorescence/confocal microscopy, and flow cytometry. The results confirm a time-dependent and composition-independent decrease in bacterial viability and biofilm formation on HA-xZnO composites w.r.t EF-treated HA. Flow cytometry analysis indicated that 12 h EF application resulted in membrane depolarization of ~35% of S. aureus populations on HA-xZnO composites. The live/dead assay results revealed ~60% decline in viable bacterial numbers with a concomitant 3.5-fold increase in the production of reactive oxygen species (ROS) after 18 h of EF. The loss in bacterial viability and biofilm instability is due to the synergistic bactericidal action of ZnO and EF. Taken together, the use of engineered biomaterial substrate with antimicrobial reinforcement coupled with continuous low intensity EF application can be adopted to treat prosthetic implant associated infection. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1064-1075, 2016. PMID- 26014127 TI - Swiss medical centres vary significantly when it comes to outcomes of neonates with a very low gestational age. AB - AIM: This study quantified the impact of perinatal predictors and medical centre on the outcome of very low-gestational-age neonates (VLGANs) born at <32 completed weeks in Switzerland. METHODS: Using prospectively collected data from a 10-year cohort of VLGANs, we developed logistic regression models for three different time points: delivery, NICU admission and seven days of age. The data predicted survival to discharge without severe neonatal morbidity, such as major brain injury, moderate or severe bronchopulmonary dysplasia, retinopathy of prematurity (>=stage three) or necrotising enterocolitis (>=stage three). RESULTS: From 2002 to 2011, 6892 VLGANs were identified: 5854 (85%) of the live born infants survived and 84% of the survivors did not have severe neonatal complications. Predictors for adverse outcome at delivery and on NICU admission were low gestational age, low birthweight, male sex, multiple birth, birth defects and lack of antenatal corticosteroids. Proven sepsis was an additional risk factor on day seven of life. The medical centre remained a statistically significant factor at all three time points after adjusting for perinatal predictors. CONCLUSION: After adjusting for perinatal factors, the survival of Swiss VLGANs without severe neonatal morbidity was strongly influenced by the medical centre that treated them. PMID- 26014128 TI - Pheromone Production by an Invasive Bark Beetle Varies with Monoterpene Composition of its Naive Host. AB - The secondary chemistry of host plants can have cascading impacts on the establishment of new insect herbivore populations, their long-term population dynamics, and their invasion potential in novel habitats. Mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae) has recently expanded its range into forests of jack pine, Pinus banksiana Lamb., in western Canada. We investigated whether variations in jack pine monoterpenes affect beetle pheromone production, as the primary components of the beetle's aggregation pheromone, (-) trans-verbenol and anti-aggregation pheromone (-)-verbenone, are biosynthesized from the host monoterpene alpha-pinene. Jack pine bolts were collected from five Canadian provinces east of the beetle's current range, live D. ponderosae were introduced into them, and their monoterpene compositions were characterized. Production of (-)-trans-verbenol and (-)-verbenone emitted by beetles was measured to determine whether pheromone production varies with monoterpene composition of jack pines. Depending on particular ratios of major monoterpenes in host phloem, jack pine could be classified into three monoterpenoid groups characterized by high amounts of (+)-alpha-pinene, 3-carene, or a more moderate blend of monoterpenes, and beetle pheromone production varied among these groups. Specifically, beetles reared in trees characterized by high (+)-alpha-pinene produced the most (-)-trans-verbenol and (-)-verbenone, while beetles in trees characterized by high 3-carene produced the least. Our results indicate that pheromone production by D. ponderosae will remain a significant aspect and important predictor of its survival and persistence in the boreal forest. PMID- 26014129 TI - BCG+MMC trial: adding mitomycin C to BCG as adjuvant intravesical therapy for high-risk, non-muscle-invasive bladder cancer: a randomised phase III trial (ANZUP 1301). AB - BACKGROUND: Despite adequate trans-urethral resection of the bladder tumour (TURBT), non-muscle-invasive bladder cancer (NMIBC) is associated with high rates of recurrence and progression. Instillation of Bacillus Calmette-Guerin (BCG) into the urinary bladder after TURBT (adjuvant intravesical administration) reduces the risk of both recurrence and progression, and this is therefore the standard of care for high-risk tumours. However, over 30 % of people still recur or progress despite optimal delivery of BCG. Our meta-analysis suggests that outcomes might be improved further by using an adjuvant intravesical regimen that includes both mitomycin and BCG. These promising findings require corroboration in a definitive, large scale, randomised phase III trial using standard techniques for intravesical administration. METHODS AND DESIGN: The BCG + MMC trial (ANZUP 1301) is an open-label, randomised, stratified, two-arm multi-centre phase III trial comparing the efficacy and safety of standard intravesical therapy (BCG alone) against experimental intravesical therapy (BCG and mitomycin) in the treatment of adults with resected, high-risk NMIBC. Participants in the control group receive standard treatment with induction (weekly BCG for six weeks) followed by maintenance (four-weekly BCG for ten months). Participants in the experimental group receive induction (BCG weeks 1, 2, 4, 5, 7, and 8; mitomycin weeks 3, 6, and 9) followed by four-weekly maintenance (mitomycin weeks 13, 17, 25, 29, 37, and 41; BCG weeks 21, 33, and 45). The trial aims to include 500 participants who will be centrally randomised to one of the two treatment groups in a 1:1 ratio stratified by T-stage, presence of CIS, and study site. The primary endpoint is disease-free survival; secondary endpoints are disease activity, time to recurrence, time to progression, safety, health-related quality of life, overall survival, feasibility, and resource use. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12613000513718 ). PMID- 26014130 TI - The influence of the donor on dental apical papilla stem cell properties. AB - Stem cells from the human dental apical papilla (SCAP) can be obtained from almost all extracted wisdom teeth with an immature tooth root. Although different stem cell lines are used for studies, it remains elusive whether specific characteristics of the dental stem cell cultures such as proliferation rates or the cell differentiation potential are related to the cell source, e.g. the donor tissue of the dental apical papilla. To answer this question, we compared two independent SCAP cell lines from the same donor and compared them with a third cell line from another donor. We investigated the expression of stem cell markers, the efficiency of colony forming units, cell proliferation and the differentiation potential. Results showed particular differences for typical stem cell attributes such as stem cell marker expression, cell proliferation and the adipogenic differentiation. These differences were regardless of the donor of the cell lines. In conclusion, we suppose that stem cell characteristics of SCAP cell cultures are independent from the donor. PMID- 26014132 TI - Crowdsourcing: an instructional method at an emergency medicine continuing education course. PMID- 26014134 TI - Doctors online: "Like flies to honey". PMID- 26014133 TI - Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) with brain metastasis (BM) harboring an epidermal growth factor receptor (EGFR) mutation shows good response to tyrosine kinase inhibitors (TKIs). This study is to assess the appropriate timing of brain radiotherapy (RT) for asymptomatic BM in EGFR mutant NSCLC patients. METHODS: There were 628 patients diagnosed with EGFR mutant NSCLC between October 2005 and December 2011. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT. RESULTS: With a median follow up of 26 months, the 2-year OS was 40.6 %. Univariate analyses revealed that ECOG performance status (p = 0.006), other distant metastases (p = 0.002) and first line systemic treatment (p = 0.032) were significantly associated with overall survival (OS). Multivariate analyses revealed that other sites of distant metastases (p = 0.030) were prognostic factor. The timing of brain RT was not significantly related to OS (p = 0.246). The 2-year BM progression-free survival (PFS) was 26.9 %. Brain RT as first-line therapy failed to demonstrate a significant association with BM PFS (p = 0.643). CONCLUSIONS: First-line brain RT failed to improve long-term survival in TKI-naive EGFR mutant NSCLC patients with asymptomatic BM. Prospective studies are needed to validate these clinical findings. PMID- 26014131 TI - A novel hypothesis for atherosclerosis as a cholesterol sulfate deficiency syndrome. AB - BACKGROUND: Despite a vast literature, atherosclerosis and the associated ischemia/reperfusion injuries remain today in many ways a mystery. Why do atheromatous plaques make and store a supply of cholesterol and sulfate within the major arteries supplying the heart? Why are treatment programs aimed to suppress certain myocardial infarction risk factors, such as elevated serum homocysteine and inflammation, generally counterproductive? METHODS: Our methods are based on an extensive search of the literature in atherosclerotic cardiovascular disease as well as in the area of the unique properties of water, the role of biosulfates in the vascular wall, and the role of electromagnetic fields in vascular flow. Our investigation reveals a novel pathology linked to atherosclerosis that better explains the observed facts than the currently held popular view. RESULTS: We propose a novel theory that atherosclerosis can best be explained as being due to cholesterol sulfate deficiency. Furthermore, atheromatous plaques replenish the supply of cholesterol and sulfate to the microvasculature, by exploiting the inflammatory agent superoxide to derive sulfate from homocysteine and other sulfur sources. We argue that the sulfate anions attached to the glycosaminoglycans in the glycocalyx are essential in maintaining the structured water that is crucial for vascular endothelial health and erythrocyte mobility through capillaries. Sulfate depletion leads to cholesterol accumulation in atheromas, because its transport through water-based media depends on sulfurylation. We show that streaming potential induces nitric oxide (NO) release, and NO derivatives break down the extracellular matrix, redistributing sulfate to the microvasculature. We argue that low (less negative) zeta potential due to insufficient sulfate anions leads to hypertension and thrombosis, because these responses can increase streaming potential and induce nitric-oxide mediated vascular relaxation, promoting oxygen delivery. Our hypothesis is a parsimonious explanation of multiple features of atherosclerotic cardiovascular disease. CONCLUSIONS: If our interpretation is correct, then it would have a significant impact on how atherosclerosis is treated. We recommend a high intake of sulfur-containing foods as well as an avoidance of exposure to toxicants that may impair sulfate synthesis. PMID- 26014135 TI - The public health impact of economic fluctuations in a Latin American country: mortality and the business cycle in Colombia in the period 1980-2010. AB - INTRODUCTION: Studies in high-income countries suggest that mortality is related to economic cycles, but few studies have examined how fluctuations in the economy influence mortality in low- and middle-income countries. We exploit regional variations in gross domestic product per capita (GDPpc) over the period 1980-2010 in Colombia to examine how changes in economic output relate to adult mortality. METHODS: Data on the number of annual deaths at ages 20 years and older (n = 3,506,600) from mortality registries, disaggregated by age groups, sex and region, were linked to population counts for the period 1980-2010. We used region fixed effect models to examine whether changes in regional GDPpc were associated with changes in mortality. We carried out separate analyses for the periods 1980 1995 and 2000-2010 as well as by sex, distinguishing three age groups: 20-44 (predominantly young working adults), 45-64 (middle aged working adults), and 65+ (senior, predominantly retired individuals). RESULTS: The association between regional economic conditions and mortality varied by period and age groups. From 1980 to 1995, increases in GDPpc were unrelated to mortality at ages 20 to 64, but they were associated with reductions in mortality for senior men. In contrast, from 2000 to 2010, changes in GDPpc were not associated with old age mortality, while an increase in GDPpc was associated with a decline in mortality at ages 20-44 years. Analyses restricted to regions with high registration coverage yielded similar albeit less precise estimates for most sub-groups. CONCLUSIONS: The relationship between business cycles and mortality varied by period and age in Colombia. Most notably, mortality shifted from being acyclical to being countercyclical for males aged 20-44, while it shifted from being countercyclical to being acyclical for males aged 65+. PMID- 26014137 TI - A Dynamic Image Quality Evaluation of Videofluoroscopy Images: Considerations for Telepractice Applications. AB - High-quality fluoroscopy images are required for accurate interpretation of videofluoroscopic swallow studies (VFSS) by speech pathologists and radiologists. Consequently, integral to developing any system to conduct VFSS remotely via telepractice is ensuring that the quality of the VFSS images transferred via the telepractice system is optimized. This study evaluates the extent of change observed in image quality when videofluoroscopic images are transmitted from a digital fluoroscopy system to (a) current clinical equipment (KayPentax Digital Swallowing Workstation, and b) four different telepractice system configurations. The telepractice system configurations consisted of either a local C20 or C60 Cisco TelePresence System (codec unit) connected to the digital fluoroscopy system and linked to a second remote C20 or C60 Cisco TelePresence System via a network running at speeds of either 2, 4 or 6 megabits per second (Mbit/s). Image quality was tested using the NEMA XR 21 Phantom, and results demonstrated some loss in spatial resolution, low contrast detectability and temporal resolution for all transferred images when compared to the fluoroscopy source. When using higher capacity codec units and/or the highest bandwidths to support data transmission, image quality transmitted through the telepractice system was found to be comparable if not better than the current clinical system. This study confirms that telepractice systems can be designed to support fluoroscopy image transfer and highlights important considerations when developing telepractice systems for VFSS analysis to ensure high-quality radiological image reproduction. PMID- 26014136 TI - Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity. AB - Mia40 participates in oxidative protein folding within the mitochondrial intermembrane space (IMS) by mediating the transfer of reducing equivalents from client proteins to FAD-linked oxidoreductases of the Erv1 family (lfALR in mammals). Here we investigate the specificity of the human Mia40/lfALR system towards non-cognate unfolded protein substrates to assess whether the efficient introduction of disulfides requires a particular amino acid sequence context or the presence of an IMS targeting signal. Reduced pancreatic ribonuclease A (rRNase), avian lysozyme, and riboflavin binding protein are all competent substrates of the Mia40/lfALR system, although they lack those sequence features previously thought to direct disulfide bond formation in cognate IMS substrates. The oxidation of rRNase by Mia40 does not limit overall turnover of unfolded substrate by the Mia40/lfALR system. Mia40 is an ineffective protein disulfide isomerase when its ability to restore enzymatic activity from scrambled RNase is compared to that of protein disulfide isomerase. Mia40's ability to bind amphipathic peptides is evident by avid binding to the isolated B-chain during the insulin reductase assay. In aggregate these data suggest that the Mia40/lfALR system has a broad sequence specificity and that potential substrates may be protected from adventitious oxidation by kinetic sequestration within the mitochondrial IMS. PMID- 26014138 TI - Modulation of collagen by addition of Hofmeister salts. AB - Collagen can be modified by addition of chaotropic or kosmotropic salts of the reversed Hofmeister series. Hence, telopeptide-poor collagen type I was suspended in H2SO4 (pH 2) and 0.05-0.5 M KCl and KNO3 (chaotropes), as well as KI and KSCN (kosmotropes). Rheological parameters, including storage and loss modulus, intrinsic viscosity, and critical overlap concentration, were assessed and the microstructure was characterized by applying confocal laser scanning microscopy and scanning electron microscopy. The addition of up to 0.1 M KCl and 0.05 M KNO3 increased the intrinsic viscosity from 1.22 to 1.51 L/g without salt to a maximal value of 1.74 L/g and decreased the critical overlap concentration from 0.66 to 0.82 g/L to a minimal value of 0.57 g/L. Higher salt concentrations increased the collagen-collagen interactions due to ions withdrawing the water from the collagen molecules. Hence, 0.1 M KSCN delivered the largest structures with the highest structure factor, area value and the highest critical overlap concentration with 17.6 L/g. Overall, 0.5 M salt led to salting out, with chaotropes forming fine precipitates and kosmotropes leading to elastic three dimensional networks. The study demonstrated that collagen entanglement and microstructure depend strongly on the ionic strength and type of salt. PMID- 26014139 TI - In vivo immunological activity of carboxymethylated-sulfated (1->3)-beta-D-glucan from sclerotium of Poria cocos. AB - beta-Glucans are one of the polysaccharides known as biological response modifiers extracted from the sclerotium of Poria cocos which has been used for several decades as Traditional Chinese Medicine. Due to its ability to activate immune system, it can be applied in chemotherapy after being chemically modified. In this study, sulfated (1->3)-beta-D-glucan (S-P), carboxymethyl (1->3)-beta-D glucan (CMP), and carboxymethylated-sulfated (1->3)-beta-D-glucan (S-CMP), which are (1->3)-beta-D-glucan derivatives were synthesized. The current study was aimed to investigate in vivo potential immunological activity of S-CMP in mice. In addition, mice were separately treated with S-P, CMP and S-CMP to evaluate the relationship between single and multiple functional groups. Interestingly, S-CMP exhibited the best in vivo immunological activities and the highest inhibition rate against the implanted HepG2 tumor in BALB/c mice, with significant increase in serum hemolysin antibody titer, spleen antibody production as well as delayed type hypersensitivity compared with S-P and CMP. Furthermore, it was assumed that simultaneous introduction of carboxymethyl and sulfate groups also had great potential effect on antioxidant activity, as substantial decrease in malondialdehyde (MDA) content was remarked. Therefore, it may suggest that S-CMP has better immunological and anti-tumor effects on mice in vivo. PMID- 26014140 TI - Influence of molecular weight on structure and rheological properties of microcrystalline chitosan mixtures. AB - In the present work, the atomic force microscopy (AFM) studies and rheological properties of aqueous solutions of microcrystalline chitosan (MCCh), polyacrylamide (PAM) and their mixtures at different weight ratios have been investigated. Flow measurements were carried out using on solutions of native polymers and their mixtures with various weight fractions of components. It has been observed that the polymer solutions and their mixtures exhibited the non Newtonian behavior with shear-thinning and/or shear-thickening areas. Rheological parameters from power law and activation energy of viscous flow are determined and discussed. The AFM images showed difference in surface properties films for the native polymers and their mixtures. The roughness of the mixtures increases with the increase of MCCh content. This may indicate a strong interaction between the polymeric components. PMID- 26014141 TI - Versatile particles from water-soluble chitosan and sodium alginate for loading toxic or bioactive substance. AB - Versatile hydrogel particles were obtained by cross-linking of water-soluble chitosan (WSC) with sodium alginate (SA) in an acid-free medium. The structure of the particles was investigated with Fourier transform infrared spectra, differential scanning calorimetry and thermogravimetric analysis. These characterization results confirmed that the product was physically cross-linked hydrogel consisted of WSC and SA. It was found that the swelling ratio of the particles depended on the formation time, which indicated that their cross linking degrees were easily modulated. The particles showed high capability to bind heavy metal ions, acidic gas and basic gas. The adsorption capacities of the particles could reach 88.2 and 66.0 mg/g for Cu(2+) and Pb(2+), 33.8 and 30.3 mg/g for NH3 and H2S, respectively. Especially, the existence of water significantly enhanced the adsorption capacities for NH3 and H2S. In addition, the mild formation condition made the particles suitable for encapsulating bioactive substance. The loading efficiency of the beads for hemoglobin (HB) reached close to 100%. Moreover, the release behavior of the HB-loaded particles was pH-sensitive. In contrast, HB was deactivated during encapsulating it with chitosan and sodium alginate. Obviously, such a kind of particles was an attractive adsorbent or carrier. PMID- 26014142 TI - SjAPI-2 is the first member of a new neurotoxin family with Ascaris-type fold and KCNQ1 inhibitory activity. AB - Peptides with Ascaris-type fold are a new kind of toxins founded from venomous animals recently. Functionally, these unique toxin peptides had been identified as potent protease inhibitors, which was similar to other known Ascaris-type peptides from non-venomous animals. Whether Ascaris-type peptides from venom animals have neurotoxin activities remains unclear. Here, a scorpion toxin SjAPI 2 with Ascaris-type fold was characterized to have a neurotoxin activity, which can selectively inhibit KCNQ1 potassium channel. SjAPI-2 had 62 amino acid residues, including 10 cysteine residues. Charged residue analyses showed that two acidic residues of SjAPI-2 were regionally distributed, and 10 basic residues were distributed widely throughout the whole peptide, which was similar to classical potassium channel toxins. Pharmacological studies confirmed that SjAPI 2 was a selective KCNQ1 potassium channel inhibitor with weak effects on other potassium channels, such as Kv1.1, Kv1.2, Kv1.3, SKCa2, SKCa3, and IKCa channels. Concentration-dependent studies showed that SjAPI-2 inhibited the KCNQ1 potassium channel with an IC50 of 771.5+/-169.9 nM. To the best of our knowledge, SjAPI-2 is the first neurotoxin with a unique Ascaris-type fold, providing novel insights into the divergent evolution of neurotoxins from venomous animals. PMID- 26014143 TI - Rheological studies of the fucose-rich exopolysaccharide FucoPol. AB - In this work, the solution properties of the bacterial fucose-rich polysaccharide, FucoPol, were studied. The effect of pH (3.5-10.0) and ionic strength (0.02-1.0 M NaCl) on the intrinsic viscosity and steady shear flow were evaluated using a central composite rotatable design of experiments and surface response methodology. FucoPol's intrinsic and apparent viscosities presented a quite low variation under a wide range of pH (3.5-8.0) and ionic strength (0.05 0.50 M NaCl) values. FucoPol produced viscous solutions with shear-thinning behavior at different polymer concentrations (0.2-1.2 wt.%). Flow curves were successfully described by the Cross model. The viscosity of the first Newtonian plateau varied from 0.01 to 2.47 Pas for polymer concentrations from 0.2 to 1.2 wt.%, and the dependence of the estimated relaxation time with polymer concentration suggests a large degree of interaction between FucoPol molecules. Given the results obtained, FucoPol is proposed as thickening agent for applications in which stability of the apparent viscosity under pH and ionic strength variations is required. PMID- 26014144 TI - Optimization of extraction and antioxidant activity of polysaccharides from Salvia miltiorrhiza Bunge residue. AB - In this study, the process of extracting polysaccharides from Salvia miltiorrhiza Bunge residue was optimized by using a Box-Behnken design. Statistical analysis of the results showed that the linear and quadratic terms of the three variables of the extraction process had significant effects. The optimal conditions are as follows: extracting time of 2.6 h, extraction temperature of 89 degrees C, and ratio of water to raw material of 32 mL/g. Moreover, a new polysaccharide with antioxidant activity [i.e., SMWP-1 (~5.27*10(5) Da)] was isolated from S. miltiorrhiza residue. The carbohydrate, uronic acid, and protein contents of SMWP 1 were 90.11%, 0.13%, and 0.53%, respectively. The SMWP-1 is composed of glucose, xylose, mannose, and galactose. The preliminary structural characterization of SMWP-1 was determined via Fourier transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM) analyses. This polysaccharide exhibited strong reducing power and free-radical scavenging activities in vitro against 2,2 diphenyl-1-picrylhydrazyl, superoxide anion, and hydroxyl. Therefore, SMWP-1 can be investigated further as a novel natural antioxidant. PMID- 26014145 TI - Graft copolymerization of cellulose acetate for removal and recovery of lead ions from wastewater. AB - In this study, cellulose acetate (CA) was modified by grafting with an equimolar binary mixture of acrylic acid (AA) and acrylamide (AAm) via radical polymerization technique using benzoyl peroxide as an initiator. Comparative studies between CA powder and modified CA [CA-g-(AA-co-AAm)] were investigated for Pb(II) ions removal and recovery from wastewater. The main operating conditions such as pH, concentration of Pb(II) ions and sorbent dose were also studied. Kinetic modeling has been studied and lead uptake capacity was calculated using the Langmuir, Freundlich and Dubinin-Kaganer-Radushkevich (DKR) models. The maximum sorption capacity (qemax) for Pb ions was only 9.4 mg/g for unmodified CA, while, it was reached to 66.67 mg/g by using modified CA. Spectroscopic analysis (FTIR), SEM, EDX and XRD analysis were investigated for CA and modified CA before and after recovery of lead ions from wastewater. PMID- 26014146 TI - Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches. AB - BACKGROUND AND PURPOSE: 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4 ) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH4 restores vascular function in patients. Unfortunately, oral BH4 has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH4 synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo. EXPERIMENTAL APPROACH: Detailed characterization of GCH1-GFRP protein-protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH4 biosynthesis in vivo were investigated following L-phe treatment (100 mg.kg(-1) , p.o.). KEY RESULTS: GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH4 , an effect absent in GCH1(fl/fl)-Tie2Cre mice. CONCLUSIONS AND IMPLICATIONS: Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH4 in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1-GFRP complex have the potential to elevate endothelial BH4 biosynthesis for numerous cardiovascular disorders. PMID- 26014147 TI - In silico ribozyme evolution in a metabolically coupled RNA population. AB - BACKGROUND: The RNA World hypothesis offers a plausible bridge from no-life to life on prebiotic Earth, by assuming that RNA, the only known molecule type capable of playing genetic and catalytic roles at the same time, could have been the first evolvable entity on the evolutionary path to the first living cell. We have developed the Metabolically Coupled Replicator System (MCRS), a spatially explicit simulation modelling approach to prebiotic RNA-World evolution on mineral surfaces, in which we incorporate the most important experimental facts and theoretical considerations to comply with recent knowledge on RNA and prebiotic evolution. In this paper the MCRS model framework has been extended in order to investigate the dynamical and evolutionary consequences of adding an important physico-chemical detail, namely explicit replicator structure - nucleotide sequence and 2D folding calculated from thermodynamical criteria - and their possible mutational changes, to the assumptions of a previously less detailed toy model. RESULTS: For each mutable nucleotide sequence the corresponding 2D folded structure with minimum free energy is calculated, which in turn is used to determine the fitness components (degradation rate, replicability and metabolic enzyme activity) of the replicator. We show that the community of such replicators providing the monomer supply for their own replication by evolving metabolic enzyme activities features an improved propensity for stable coexistence and structural adaptation. These evolutionary advantages are due to the emergent uniformity of metabolic replicator fitnesses imposed on the community by local group selection and attained through replicator trait convergence, i.e., the tendency of replicator lengths, ribozyme activities and population sizes to become similar between the coevolving replicator species that are otherwise both structurally and functionally different. CONCLUSIONS: In the most general terms it is the surprisingly high extra viability of the metabolic replicator system that the present model adds to the MCRS concept of the origin of life. Surface-bound, metabolically coupled RNA replicators tend to evolve different, enzymatically active sites within thermodynamically stable secondary structures, and the system as a whole evolves towards the robust coexistence of a complete set of such ribozymes driving the metabolism producing monomers for their own replication. PMID- 26014148 TI - Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells. AB - Epidemiological studies demonstrate that alcohol consumption is associated with an increased risk of colorectal cancer (CRC). In addition to promoting carcinogenesis, alcohol may also accelerate the progression of existing CRC. We hypothesized that alcohol may enhance the aggressiveness of CRC. In this study, we investigated the effect of alcohol on the migration/invasion and metastasis of CRC. Alcohol increased the migration/invasion of colorectal cancer cells (DLD1, HCT116, HT29, and SW480) in a concentration-dependent manner. Among these colon cancer cell lines, HCT116 cells were most responsive while HT29 cells were the least responsive to ethanol-stimulated cell migration/invasion. These in vitro results were supported by animal studies which demonstrated that ethanol enhanced the metastasis of colorectal cancer cells to the liver and lung. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays an important role in regulating tumor microenvironment and metastasis. Alcohol increased the expression of MCP-1 and its receptor CCR2 at both protein and mRNA levels. The pattern of alcohol-induced alterations in MCP-1 expression was consistent with its effect on migration/invasion; HCT116 cells displayed the highest up regulation of MCP-1/CCR2 in response to alcohol exposure. An antagonist of CCR2 blocked alcohol-stimulated migration. Alcohol caused an initial cytosolic accumulation of beta-catenin and its subsequent nuclear translocation by inhibiting GSK3beta activity. Alcohol stimulated the activity of MCP-1 gene promoter in a beta-catenin-dependent manner. Furthermore, knock-down of MCP 1/CCR2 or beta-catenin was sufficient to inhibit alcohol-induced cell migration/invasion. Together, these results suggested that alcohol may promote the metastasis of CRC through modulating GSK3beta/beta-catenin/MCP-1 pathway. PMID- 26014150 TI - Risk Factors for Positive Deep Pelvic Nodal Involvement in Patients with Palpable Groin Melanoma Metastases: Can the Extent of Surgery be Safely Minimized? : A Retrospective, Multicenter Cohort Study. AB - BACKGROUND: Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient. AIM: The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future. METHODS: This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992-2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] +/- positron emission tomography [PET], or PET low-dose CT). RESULTS: Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11-46 months). Median Breslow thickness was 2.10 mm (IQR 1.40-3.40 mm), and 26 % of all primary melanomas were ulcerated. Positive deep pelvic nodes occurred in 35 % of CGDs. Significantly fewer inguinal nodes were positive in case of negative deep pelvic nodes (median 1 [IQR 1-2] vs. 3 [IQR 1-4] for positive deep pelvic nodes; p < 0.001), and LNR was significantly lower for negative versus positive deep pelvic nodes [median 0.15 (IQR 0.10-0.25) vs. 0.33 (IQR 0.14-0.54); p < 0.001]. A combination of negative imaging, low LNR, low number of positive inguinal nodes, and no extracapsular extension (ECE) could accurately predict the absence of pelvic nodal involvement in 84 % of patients. CONCLUSIONS: Patients with negative imaging, few positive inguinal nodes, no ECE, and low LNR have a low risk of positive deep pelvic nodes and may safely undergo SGD alone. PMID- 26014151 TI - Impact of Preoperative Biliary Drainage on Long-Term Survival in Resected Pancreatic Ductal Adenocarcinoma: A Multicenter Observational Study. AB - BACKGROUND: This study aimed to evaluate the impact of preoperative biliary drainage (PBD) on the long-term survival of patients with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreaticoduodenectomy (PD). METHODS: A multicenter observational study was performed using a common database of patients with resected PDAC from seven high-volume surgical institutions in Japan. RESULTS: Of 932 patients who underwent PD for PDAC, 573 (62 %) underwent PBD, including 407 (44 %) who underwent endoscopic biliary drainage (EBD) and 166 (18 %) who underwent percutaneous transhepatic biliary drainage (PTBD). The patients who did not undergo PBD and those who underwent EBD had a significantly better overall survival than those who underwent PTBD, with median survival times of 25.7 months (P < 0.001), 22.3 months (P = 0.001), and 16.7 months, respectively. Multivariate analysis showed that seven clinicopathologic factors, including the use of PTBD but not EBD, were independently associated with poorer overall survival. Furthermore, patients who underwent PTBD more frequently experienced peritoneal recurrence (23 %) than those who underwent EBD (10 %; P < 0.001) and those who did not undergo PBD (11 %; P = 0.001). Multivariate analysis demonstrated that the independent risk factors for peritoneal recurrence included surgical margin status (P < 0.001) and use of PTBD (P = 0.004). CONCLUSIONS: Use of PTBD, but not EBD, was associated with a poorer prognosis, with an increased rate of peritoneal recurrence among patients who underwent PD for PDAC. PMID- 26014152 TI - Predictive Factors of Recurrence in Patients with Pathological Complete Response After Esophagectomy Following Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Multicenter Study. AB - BACKGROUND: Minimal data have previously emerged from studies regarding the factors associated with recurrence in patients with ypT0N0M0 status. The purpose of the study was to predict survival and recurrence in patients with pathological complete response (pCR) following chemoradiotherapy (CRT) and surgery for esophageal cancer (EC). METHODS: Among 2944 consecutive patients with EC operations in 30 centers between 2000 and 2010, patients treated with neoadjuvant CRT followed by surgery who achieved pCR (n = 191) were analyzed. The factors associated with survival and recurrence were analyzed using a Cox proportional hazard regression analysis. RESULTS: Among 593 patients who underwent neoadjuvant CRT followed by esophagectomy, pCR was observed in 191 patients (32.2 %). Recurrence occurred in 56 (29.3 %) patients. The median time to recurrence was 12 months. The factors associated with recurrence were postoperative complications grade 3-4 [odds ratio (OR): 2.100; 95 % confidence interval (CI) 1.008-4.366; p = 0.048) and adenocarcinoma histologic subtype (OR 2.008; 95 % CI 0.1.06-0.3.80; p = 0.032). The median overall survival was 63 months (95 % CI 39.3-87.1), and the median disease-free survival was 48 months (95 % CI 18.3-77.4). Age (>65 years) [hazard ratio (HR): 2.166; 95 % CI 1.170-4.010; p = 0.014), postoperative complications grades 3-4 [HR 2.099; 95 % CI 1.137-3.878; p = 0.018], and radiation dose (<40 Gy) (HR 0.361; 95 % CI 0.159-0.820; p = 0.015) were identified as factors associated with survival. CONCLUSIONS: An intensive follow up may be beneficial for patients with EC who achieve pCR and who develop major postoperative complications or the adenocarcinoma histologic subtype. PMID- 26014153 TI - Surgical Management of Small Bowel Neuroendocrine Tumors: Specific Requirements and Their Impact on Staging and Prognosis. AB - BACKGROUND: Small bowel neuroendocrine tumors (SB-NETs) are characterized by two main features: they usually are metastatic at diagnosis and multiple in 30 % of cases. As such, SB-NETs require specific surgical management. This retrospective study examined local recurrence, survival, and prognosis of SB-NETs after adapted surgery. METHODS: All consecutive patients with SB-NETs who underwent resection of at least one primary tumor between 1 January 2000 and 1 January 2013 were analyzed. The preoperative morphologic workup, histologic classification, and metastatic lymph node (LN) ratio (LNs involved/removed) were recorded. RESULTS: The study enrolled 107 patients, 35 (33 %) of whom had multiple SB-NETs (range 1 44; mean 3.1). Preoperative imaging and perioperative surgical examination missed 61 and 33 % of SB-NETs, respectively, in contrast to pathologic examination. Of the 107 patients, 43 % had carcinoid syndrome, 70 % had metastatic disease, and 90 % had LN involvement. The median number of LNs retrieved was 12 (range 1-69). The LN ratio (LNs involved/removed) was 0.25. The highest tumoral grades were G1 (in 61 % of patients) and G2 (in 37 % of patients). Of the 107 patients, 13 (12 %) had local LN recurrence. The rate of LN recurrence-free survival at 5 years was 88 %. The median overall survival (OS) time was 128 months (range 91-165 months). In the multivariate analysis, high chromogranin A (CgA) levels and peritoneal carcinomatosis were significantly associated with shorter OS. CONCLUSIONS: Systematic palpation of the entire small bowel detects more multiple NETs than preoperative imaging. Systematic surgery with extensive LN resection is associated with low local recurrence. High CgA levels and carcinomatosis are linked with shorter survival. PMID- 26014154 TI - Postoperative Radiotherapy Improves Survival in Stage pT2N0M0 Esophageal Squamous Cell Carcinoma with High Risk of Poor Prognosis. AB - PURPOSE: Clinically, some patients with stage pT2N0M0 esophageal squamous cell carcinoma (ESCC) might have poor survival outcomes after Ivor-Lewis esophagectomy. We explored whether adjuvant radiotherapy could improve the prognosis for the patients with high risk of poor clinical outcomes. METHODS: We screened 326 pT2N0M0 ESCC patients who had complete resection with Ivor-Lewis esophagectomy. The expression profile of Ku80 was examined by immunohistochemistry and validated by Western blotting. Patients with high expression of Ku80 were divided randomly into the adjuvant radiotherapy group and control group. Patients with low expression of Ku80 were enrolled into the negative group. The overall survival (OS) and disease-free survival (DFS) was determined by Kaplan-Meier and log-rank analysis. RESULTS: According to receiver operating characteristics curve analysis of Ku80 expression, 124 patients were enrolled into the negative group, 106 patients into the radiotherapy group, and 106 patients into the control group. Log-rank analysis showed that patients in the control group had worse OS and DFS than those in the negative group (P < 0.001, P < 0.001). There is no difference in OS and DFS of patients between radiotherapy group and negative group (P = 0.166, P = 0.648). Patients in the radiotherapy group had significantly better OS and DFS than those in the control group (P = 0.007, P < 0.001). Multivariate analysis further suggested that adjuvant radiotherapy was an independent prognostic indicator for patients with Ku80 overexpression. CONCLUSIONS: In stage pT2N0M0 ESCC, Ku80 can be exploited as a predictor to identify patients with high risk of poor prognosis. Adjuvant radiotherapy could significantly improve survival for the patients with Ku80 overexpression. PMID- 26014155 TI - Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery and the Risk of Platinum Resistance in Epithelial Ovarian Cancer. AB - BACKGROUND: Interval debulking surgery (IDS) is an option for treating patients with advanced ovarian carcinoma. Two randomized trials have shown similar survival rates for primary debulking surgery (PDS) and IDS. One of the concerns with IDS is the potentially higher risk of inducing platinum resistance when treating patients with greater disease volume. METHODS: A retrospective review of data on 237 patients with stage IIIC and IV ovarian carcinoma who were treated at a single institution from 2000 to 2013. We analyzed the association of IDS with time to first platinum resistant relapse (TTPR); platinum-resistant disease at first relapse, defined as a platinum-free interval (PFI) after first-line chemotherapy of <6 months; and overall response rate (ORR) to chemotherapy at first platinum-sensitive relapse. RESULTS: The TTPR was 60 months, and the median TTPR was longer for the PDS (80.8 months) versus IDS group (39.3 months; p = 0.012) and for patients with residual disease (RD) <=10 mm (80.8 months) compared with those with RD >10 mm (26.1 months; p < 0.001). In the multivariate analysis, IDS [hazard ratio (HR) 1.92; p = 0.009] and RD >10 mm (HR 1.65; p < 0.001) retained an increased risk of developing platinum-resistant disease. IDS was not associated with a greater risk of PFI <6 months at first relapse, and the ORR to platinum-based chemotherapy at first platinum-sensitive relapse was 87.2 % for patients who were treated with PDS compared with 68.0 % for those who underwent IDS (p = 0.051). CONCLUSIONS: IDS correlates with a higher risk of the development of platinum resistance. PMID- 26014156 TI - Age-Related Morbidity and Mortality with Cytoreductive Surgery. AB - INTRODUCTION: Cytoreduction and intraperitoneal chemotherapy (IPC) are increasingly considered in older patients. We sought to better characterize the influence of age on 30-day outcomes following this procedure. METHODS: The ACS NSQIP database was queried for patients who underwent IPC and a concurrent intra abdominal operation (2005-2012). Thirty-day death and serious morbidity (DSM) was the primary outcome. Trends in DSM by age were defined using Joinpoint regression. Univariate and multivariate logistic regression identified factors associated with DSM. RESULTS: In 1085 patients, DSM increased at a significant rate after age 50 (0.6 %/year, p = 0.001). Patients >=60 (n = 376) represented 35 % of the study population. Age >=60 years was independently associated with DSM (odds ratio [OR] 1.6, p = 0.001). The older patient population (>=60 years) experienced 44 % morbidity and 3.2 % mortality. In these patients, preoperative weight loss, low preoperative albumin, splenectomy, intraoperative transfusion, contaminated or dirty wound classification, and prolonged operative time were all independently significantly associated with increased DSM. In the absence of these factors (n = 45), the DSM rate was 11 %. Rates of DSM increased to 33, 63, and 100 % in patients with 1 factor, 2-3 factors, and 4 or more factors (n = 14; p < 0.001), respectively. Venous thromboembolism, sepsis, postoperative bleeding, and respiratory complications were significantly more common among those aged 60 years and older (p < 0.05 each). CONCLUSIONS: The risk of DSM increases with age in patients undergoing cytoreduction and IPC. Risk can be stratified using a limited number of patient and operative characteristics. PMID- 26014157 TI - Identification, clinical significance, and management of very small melanoma metastases in sentinel lymph nodes. PMID- 26014158 TI - Linear Relationship of Peritoneal Cancer Index and Survival in Patients with Peritoneal Metastases from Colorectal Cancer. AB - BACKGROUND: The peritoneal cancer index (PCI) is the main prognostic factor for establishing potentially resectable peritoneal metastases from colorectal cancer. Attempts have been made to set a PCI cutoff on which to base indications of complete cytoreductive surgery (CCRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), but none have reached consensus. The aim of this study was to investigate the relation between the PCI and overall survival (OS). METHODS: We included all consecutive patients homogeneously treated with CCRS and HIPEC between 2003 and 2012. The PCI was calculated at the end of the surgical procedure. The correlation between the PCI and OS was studied using statistical modeling from the simplest to the most complex methods (including linear, quadratic, cubic, and spline cubic). These models were compared by Akaike's information criteria (AIC). RESULTS: For the 173 treated patients, 5-year OS reached 41 %. The mean PCI was 10.2 (+/-6.8). The linear model was the most appropriate to relate the PCI to OS as confirmed with the AIC scoring system. In multivariate analysis, the PCI was confirmed as being the most important prognostic factor (hazard ratio = 1.1 for each supplementary point, p < 0.0001). CONCLUSIONS: There is a perfect linear correlation between the PCI and OS, which precludes setting a unique PCI cutoff for CCRS + HIPEC. Overall, CCRS + HIPEC is generally indicated for PCI < 12 and contraindicated for PCI > 17. Between 12 and 17, other parameters have to be taken into account, such as the presence of extraperitoneal metastases, general performance status, and chemosensitivity. PMID- 26014159 TI - Directional Dynamic Covalent Motion of a Carbonyl Walker on a Polyamine Track. AB - Invited for the cover of this issue is the group of Jean-Marie Lehn at the Universite de Strasbourg (France). The image depicts the trend of the research activities pursued in our laboratory in Strasbourg over 50 years towards chemical systems, entities and processes, of increasing complexity. Read the full text of the article at 10.1002/chem.201500987. PMID- 26014161 TI - What U.S. emergency care value transformation can learn from Canadian efforts to improve emergency department throughput. PMID- 26014162 TI - Attenuated Organomagnesium Activation of White Phosphorus. AB - Sequential reactions between a 2,6-diisopropylphenyl-substituted beta diketiminato magnesium n-butyl derivative and P4 allow the highly discriminating synthesis of unusual [nBu2P4](2-) and [nBu2P8](2-) cluster dianions. PMID- 26014163 TI - Carboxylate-Driven Supramolecular Assemblies of Protonated meso-Aryl-Substituted Dipyrrolylpyrazoles. AB - Dipyrrolylpyrazole (dpp) derivatives possessing an aryl ring at the pyrazole 4 position were synthesized. Upon protonation, modified dpp derivatives formed a variety of assembled structures through complexation with carboxylates, as observed by single-crystal X-ray and synchrotron XRD analyses. In particular, the complexation of protonated dpp species possessing long alkyl chains with dicarboxylates resulted in highly ordered assembled structures, the packing modes of which as lamellar structures were controlled by the lengths of the spacer units between two carboxylate moieties. The charge-carrier transporting properties of the solid materials were also controlled by bound anions, including dicarboxylates. PMID- 26014160 TI - Oral protein calorie supplementation for children with chronic disease. AB - BACKGROUND: Poor growth and nutritional status are common in children with chronic diseases. Oral protein calorie supplements are used to improve nutritional status in these children. These expensive products may be associated with some adverse effects, e.g. the development of inappropriate eating behaviour patterns. This is a new update of a Cochrane review last updated in 2009. OBJECTIVES: To examine evidence that in children with chronic disease, oral protein calorie supplements alter daily nutrient intake, nutritional indices, survival and quality of life and are associated with adverse effects, e.g. diarrhoea, vomiting, reduced appetite, glucose intolerance, bloating and eating behaviour problems. SEARCH METHODS: Trials of oral protein calorie supplements in children with chronic diseases were identified through comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. Companies marketing these products were also contacted.Most recent search of the Group's Trials Register: 24 February 2015. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing oral protein calorie supplements for at least one month to increase calorie intake with existing conventional therapy (including advice on improving nutritional intake from food or no specific intervention) in children with chronic disease. DATA COLLECTION AND ANALYSIS: We independently assessed the outcomes: indices of nutrition and growth; anthropometric measures of body composition; calorie and nutrient intake (total from oral protein calorie supplements and food); eating behaviour; compliance; quality of life; specific adverse effects; disease severity scores; and mortality; we also assessed the risk of bias in the included trials. MAIN RESULTS: Four studies (187 children) met the inclusion criteria. Three studies were carried out in children with cystic fibrosis and one study included children with paediatric malignant disease. Overall there was a low risk of bias for blinding and incomplete outcome data.Two studies had a high risk of bias for allocation concealment. Few statistical differences were found in the outcomes we assessed between treatment and control groups, except change in total energy intake at six and 12 months, mean difference 304.86 kcal per day (95% confidence interval 5.62 to 604.10) and mean difference 265.70 kcal per day (95% confidence interval 42.94 to 485.46), respectively. However, these were based on the analysis of just 58 children in only one study. Only two chronic diseases were included in these analyses, cystic fibrosis and paediatric malignant disease. No other studies were identified which assessed the effectiveness of oral protein calorie supplements in children with other chronic diseases. AUTHORS' CONCLUSIONS: Oral protein calorie supplements are widely used to improve the nutritional status of children with a number of chronic diseases. We identified a small number of studies assessing these products in children with cystic fibrosis and paediatric malignant disease, but were unable to draw any conclusions based on the limited data extracted. We recommend a series of large, randomised controlled trials be undertaken investigating the use of these products in children with different chronic diseases. Until further data are available, we suggest these products are used with caution. PMID- 26014205 TI - Secondary Cutaneous Diffuse Large B-cell Lymphoma has a Higher International Prognostic Index Score and Worse Prognosis Than Diffuse Large B-cell Lymphoma, Leg Type. AB - Diffuse large B-cell lymphoma (DLBCL) can be separated into 2 groups: nodal and extranodal disease. The aim of this study was to analyse the clinical features of skin lesions and survival outcomes of cutaneous DLBCL according to the primary tumour site. A total of 44 patients with cutaneous DLBCL were classified as primary cutaneous DLBCL, leg type or cutaneous DLBCL secondary to primary disease. Although skin lesion characteristics did not differ significantly between groups, extensive cutaneous lesions were more often observed in secondary cutaneous DLBCL compared with DLBCL, leg type. Secondary cutaneous DLBCL was more commonly associated with an advanced stage and higher International Prognostic Index score than DLBCL, leg type. DLBCL, leg type demonstrated a better survival outcome than secondary cutaneous DLBCL. The multiplicity of skin lesions and time point of cutaneous involvement were associated with prognosis in secondary cutaneous DLBCL. Survival outcomes and prognostic factors differ depending on the primary tumour site of cutaneous DLBCL. PMID- 26014206 TI - Revisiting the age, evolutionary history and species level diversity of the genus Hydra (Cnidaria: Hydrozoa). AB - The genus Hydra has long served as a model system in comparative immunology, developmental and evolutionary biology. Despite its relevance for fundamental research, Hydra's evolutionary origins and species level diversity are not well understood. Detailed previous studies using molecular techniques identified several clades within Hydra, but how these are related to described species remained largely an open question. In the present study, we compiled all published sequence data for three mitochondrial and nuclear genes (COI, 16S and ITS), complemented these with some new sequence data and delimited main genetic lineages (=hypothetical species) objectively by employing two DNA barcoding approaches. Conclusions on the species status of these main lineages were based on inferences of reproductive isolation. Relevant divergence times within Hydra were estimated based on relaxed molecular clock analyses with four genes (COI, 16S, EF1alpha and 28S) and four cnidarians fossil calibration points All in all, 28 main lineages could be delimited, many more than anticipated from earlier studies. Because allopatric distributions were common, inferences of reproductive isolation often remained ambiguous but reproductive isolation was rarely refuted. Our results support three major conclusions which are central for Hydra research: (1) species level diversity was underestimated by molecular studies; (2) species affiliations of several crucial 'workhorses' of Hydra evolutionary research were wrong and (3) crown group Hydra originated ~200mya. Our results demonstrate that the taxonomy of Hydra requires a thorough revision and that evolutionary studies need to take this into account when interspecific comparisons are made. Hydra originated on Pangea. Three of four extant groups evolved ~70mya ago, possibly on the northern landmass of Laurasia. Consequently, Hydra's cosmopolitan distribution is the result of transcontinental and transoceanic dispersal. PMID- 26014208 TI - Mechanistic Investigations of the AuCl3-Catalyzed Nitrene Insertion into an Aromatic C-H Bond of Mesitylene. AB - The AuCl3-catalyzed nitrene insertion into an aromatic C-H bond of mesitylene demonstrates a unique activity and chemoselectivity in direct C-H aminations. Mechanisms for catalytic nitrene insertion are examined here using theory. The AuCl3 catalyst favors formation of a complex with the PhI?NNs (Ns = p nitrobenzenesulfonyl) substrate, followed by the appearance of the key (N-chloro 4-nitrophenylsulfonamido)gold(III) chloride intermediate (INT5). However, the putative gold(III)-nitrene analogue (AuCl3-NNs complex) is thermodynamically unfavorable compared with INT5. Therefore, INT5 is suggested to play a critical role in the AuCl3-promoted aromatic C-H bond amination, a prediction in contrast to the previously reported crucial metal-nitrene intermediates. The activation of a C(sp(2))-H bond of mesitylene via sigma-bond metathesis is proposed based on INT5, and the subsequent detailed pathways for the aromatic C-H bond amination are computationally explored. A chemoselective nitrene insertion into a mesitylene aromatic C-H bond, instead of a benzylic C-H bond, is rationalized for the AuCl3-catalyzed amination. PMID- 26014207 TI - A novel protein quality control mechanism contributes to heat shock resistance of worldwide-distributed Pseudomonas aeruginosa clone C strains. AB - Pseudomonas aeruginosa is a highly successful nosocomial pathogen capable of causing a wide variety of infections with clone C strains most prevalent worldwide. In this study, we initially characterize a molecular mechanism of survival unique to clone C strains. We identified a P. aeruginosa clone C specific genomic island (PACGI-1) that contains the highly expressed small heat shock protein sHsp20c, the founding member of a novel subclass of class B bacterial small heat shock proteins. sHsp20c and adjacent gene products are involved in resistance against heat shock. Heat stable sHsp20c is unconventionally expressed in stationary phase in a wide temperature range from 20 to 42 degrees C. Purified sHsp20c has characteristic features of small heat shock protein class B as it is monodisperse, forms sphere-like 24-meric oligomers and exhibits significant chaperone activity. As the P. aeruginosa clone C population is significantly more heat shock resistant than genetically unrelated P. aeruginosa strains without sHsp20c, the horizontally acquired shsp20c operon might contribute to the survival of worldwide-distributed clone C strains. PMID- 26014210 TI - Aspartate aminotransferase and free thyroid hormones in vaginal washing fluid as markers for preterm pre-labor rupture of membranes. AB - AIM: To evaluate the diagnostic value of vaginal fluid aspartate aminotransferase (AST), free triiodothyronine (T3) and free thyroxine (T4 ) in women with preterm pre-labor rupture of membranes (PPROM). METHODS: A case-control study was carried out of 100 women: 50 with PPROM (study group) and 50 age-, gestational age- and weight-matched women with intact membranes (control group). All women underwent sterile speculum vaginal examination. The vaginal posterior fornix was irrigated and the retrieved fluid was sent for AST, free T3 and free T4 assays. RESULTS: Median vaginal fluid free T3, free T4 and AST were significantly higher in the PPROM group compared with the control group, with vaginal fluid free T4 having the largest area under the curve on receiver operating characteristic curve analysis (P<0.001). Sensitivity, specificity, positive and negative predictive values for free T3 (cut-off, 1.06 pg/mL) were 88%, 70%, 74.6% and 85.4%, respectively, while those for free T4 (cut-off 0.063 ng/dL) were 86%, 72%, 75.4% and 83.7%, and those for AST (4.5 IU/L) were 56%, 70%, 65.1% and 61.4%, respectively. Vaginal fluid AST had less diagnostic accuracy when compared with either free T3 or free T4. CONCLUSIONS: Vaginal fluid AST, free T3 and free T4 seem to be useful and simple markers in diagnosis of PPROM. PMID- 26014211 TI - Temporal Variation in Rates of Multiple Maternities in Denmark, 1850-2012. AB - In this study, the temporal trends in the rates of multiple maternities in Denmark were analyzed and an association between the rates of multiple maternities and the socioeconomic variations in Denmark was obtained. The findings are compared with the results obtained in studies of Swedish rates. Obtained temporal differences in the twinning rates (TWRs) were similar to the results presented by Fellman and Eriksson (2014). Temporal variation in rates of multiple maternities in Sweden (1751-2000). JP Journal of Biostatistics, 11, 2, 143-156. PMID- 26014209 TI - Post-traumatic stress disorder symptoms in family caregivers of adult patients with acute leukemia from a dyadic perspective. AB - BACKGROUND: Acute leukemia is a fatal disease in adults that not only affects the patients who suffer from it but also their family caregivers. No studies have investigated post-traumatic stress disorder symptoms (PTSS) in family caregivers of adult patients with acute leukemia using a matched sample. The current study examined PTSS in adult patients with acute leukemia and their family caregivers and investigated the factors associated with caregivers' PTSS. METHODS: A total of 163 patient-caregiver dyads completed questionnaires assessing their PTSS, psychological resilience, and perceived social support. Hierarchical linear regression was used to explore the related factors of caregivers' PTSS. RESULTS: More caregivers than patients met caseness criteria for PTSS (36.8% vs. 18.4%, p < 0.001). Among caregivers, being more closely related to the patients (e.g., spouses and parents), having patients with higher PTSS and having lower psychological resilience were independently associated with more severe PTSS. CONCLUSIONS: Caregivers of acute leukemia patients had significantly more severe PTSS than did their patients. This study is the first to investigate PTSS among family caregivers of adult patients with acute leukemia and its related factors in a matched sample. More attention should be paid to the caregivers of patients with acute leukemia to minimize their PTSS and thus improve mental health of caregivers and reduce potential negative consequences for the patients themselves. PMID- 26014212 TI - Construction and evaluation of nitric oxide generating vascular graft material loaded with organoselenium catalyst via layer-by-layer self-assembly. AB - A new biomimetic material for artificial blood vessel with in situ catalytic generation of nitric oxide (NO) was prepared in this study. Organoselenium immobilized polyethyleneimine as NO donor catalyst and sodium alginate were alternately loaded onto the surface of electrospun polycaprolactone matrix via electrostatic layer-by-layer self-assembly. This material revealed significant NO generation when contacting NO donor S-nitrosoglutathione (GSNO). Adhesion and spreading of smooth muscle cells were inhibited on this material in the presence of GSNO, while proliferation of endothelial cells was promoted. In vitro platelet adhesion and arteriovenous shunt experiments demonstrated good antithrombotic properties of this material, with inhibited platelet activation and aggregation, and prevention of acute thrombosis. This study may provide a new method of improving cellular function and antithrombotic property of vascular grafts. PMID- 26014213 TI - Phosphorylation regulates the disassembly of cilia. PMID- 26014214 TI - Efficacy and Time Course of Theta Burst Stimulation in Healthy Humans. AB - BACKGROUND: In the past decade research has shown that continuous (cTBS) and intermittent theta burst stimulation (iTBS) alter neuronal excitability levels in the primary motor cortex. OBJECTIVE: Quantitatively review the magnitude and time course on cortical excitability of cTBS and iTBS. METHODS: Sixty-four TBS studies published between January 2005 and October 2014 were retrieved from the scientific search engine PubMED and included for analyses. The main inclusion criteria involved stimulation of the primary motor cortex in healthy volunteers with no motor practice prior to intervention and motor evoked potentials as primary outcome measure. RESULTS: ITBS applied for 190 s significantly increases cortical excitability up to 60 min with a mean maximum potentiation of 35.54 +/- 3.32%. CTBS applied for 40 s decreases cortical excitability up to 50 min with a mean maximum depression of -22.81 +/- 2.86%, while cTBS applied for 20 s decreases cortical excitability (mean maximum -27.84 +/- 4.15%) for 20 min. CONCLUSION: The present findings offer normative insights into the magnitude and time course of TBS-induced changes in cortical excitability levels. PMID- 26014215 TI - Images in emergency medicine. Young man with pain in right eye. Traumatic intraocular foreign body. PMID- 26014216 TI - Use safety glasses, save an eye...enough said. PMID- 26014217 TI - Change of shift. And now, this.... PMID- 26014218 TI - Laboring under the stone: answers to the January 2015 Annals of Emergency Medicine Journal Club. PMID- 26014219 TI - Images in emergency medicine. Elderly woman with shortness of breath. Endobronchial tuberculosis. PMID- 26014220 TI - Images in emergency medicine. Man with pain in left eye. Ophthalmomyiasis from the sheep nasal bot fly, Oestrus ovis. PMID- 26014221 TI - Subjective visual vertical testing in children and adolescents. AB - OBJECTIVES/HYPOTHESIS: Subjective visual vertical (SVV) is a vestibular test commonly used in adults that has not been well studied in children. In this test, the patient aligns a projected line with the perceived true vertical. Deviation of >2 degrees is usually associated with utricular dysfunction and may also be seen with central vestibular lesions. The goal of this study was to determine the efficacy of SVV in children. STUDY DESIGN: Prospective, controlled study. METHODS: Thirty-three children aged 7 to 18 years with (n = 21) and without (n = 12) dizziness underwent static SVV. History, exam, rotary chair, and caloric testing were used to categorize subjects with dizziness into groups with peripheral vestibular loss (PVL), benign paroxysmal positioning vertigo (BPPV), central vertigo (CV), and nonvestibular dizziness (NVD). RESULTS: Mean SVV deviation was significantly higher in the peripheral vestibular loss group (n = 4; 2.1 +/- 1.5) compared to BPPV (n = 5; 0.5 +/- 0.3), CV (n = 7; 0.4 +/- 0.3), NVD (n = 5; 0.6 +/- 0.4), and control (n = 12; 0.7 +/- 0.5) groups by one-way analysis of variance (P = .002). SVV deviation >2 degrees demonstrated a sensitivity of 100%, specificity of 75%, positive predictive value of 100%, and negative predictive value of 97% for PVL. CONCLUSIONS: SVV is a simple, noninvasive test that provides a valuable contribution to the assessment of peripheral vestibular function in children. LEVEL OF EVIDENCE: 3b Laryngoscope, 126:727-731, 2016. PMID- 26014222 TI - Molecular pathways in protecting the liver from ischaemia/reperfusion injury: a 2015 update. AB - Ischaemia/reperfusion injury is an important cause of liver damage during surgical procedures such as hepatic resection and liver transplantation, and represents the main cause of graft dysfunction post-transplantation. Molecular processes occurring during hepatic ischaemia/reperfusion are diverse, and continuously include new and complex mechanisms. The present review aims to summarize the newest concepts and hypotheses regarding the pathophysiology of liver ischaemia/reperfusion, making clear distinction between situations of cold and warm ischaemia. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field are described. PMID- 26014223 TI - Enhanced magneto-dielectric coupling in multiferroic Fe and Gd codoped PbTiO3 nanorods synthesized via microwave assisted technique. AB - The quest for new multiferroic materials is on the rise due to their potential application in spintronics and futuristic multiple state memory devices. Here we report the microwave synthesis of iron/gadolinium co-doped PbTiO3 nanorods, which display multiferroic behavior. Both the undoped and doped PbTiO3 samples have been characterized using powder X-ray diffraction, energy dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) techniques. The morphology of the samples has been studied using transmission electron microscopy (TEM) and high resolution transmission electron microscopy (HRTEM), which confirmed the formation of nanorods. The substitution of Fe ions for Ti and Gd ions for Pb enhances the ferromagnetic and ferroelectric properties of this system. The reasons for this observation have been explored in detail. The ferroelectric, magnetic and magneto-capacitive measurements at room temperature substantiate the multiferroic nature of the codoped samples with significant magnetoelectric coupling observed in case of nano PbTiO3:Gd(3+)(0.5%):Fe(3+)(5%). PMID- 26014224 TI - Cage-Like B41 (+) and B42 (2+) : New Chiral Members of the Borospherene Family. AB - The newly discovered borospherenes B40 (-/0) and B39 (-) mark the onset of a new class of boron nanostructures. Based on extensive first-principles calculations, we introduce herein two new chiral members to the borospherene family: the cage like C1 B41 (+) (1) and C2 B42 (2+) (2), both of which are the global minima of the systems with degenerate enantiomers. These chiral borospherene cations are composed of twelve interwoven boron double chains with six hexagonal and heptagonal faces and may be viewed as the cuborenes analogous to cubane (C8 H8 ). Chemical bonding analyses show that there exists a three-center two-electron sigma bond on each B3 triangle and twelve multicenter two-electron pi bonds over the sigma skeleton. Molecular dynamics simulations indicate that C1 B41 (+) (1) fluctuates above 300 K, whereas C2 B42 (2+) (2) remains dynamically stable. The infrared and Raman spectra of these borospherene cations are predicted to facilitate their experimental characterizations. PMID- 26014225 TI - A Lentiviral Vector Expressing Desired Gene Only in Transduced Cells: An Approach for Suicide Gene Therapy. AB - Suicide gene therapy is a therapeutic strategy, in which cell suicide inducing transgenes are introduced into target cells. Inserting a toxin-encoding gene into a lentiviral vector leads to decreased efficiency of virus production due to lethal effect of toxin on packaging cells. In this study, we designed and constructed a transfer vector to express the toxin in transduced cells but not in packaging cells. Plasmid pLenti-F/GFP was constructed by cutting out R 5'LTR-R 3'LTR fragment with the AflII restriction endonuclease from a plasmid pLenti4 GW/H1/TO-laminshRNA, followed by ligating R 5'LTR-R 3'LTR fragment, constructed by three PCR stages. The promoter and GFP CDS were inserted in opposite strand. For lentiviral production, the HEK293T cell line was co-transfected with the PMD2G, psPAX2, and pLenti-F/GFP plasmids (envelope, packaging, and transfer plasmids).Viral vector titers were assayed. The HEK293T cell line was transduced with this virus. PCR was performed to confirm the presence of the promoter fragment between the R and U5 in 3'LTR. The lentivirus titers were approximately 2 * 10(5). The GFP expression was seen in 51 % of the HEK293T cells transduced with lentivirus. The PCR product size was 1440 bp confirming the promoter fragment position between the R and U5 in 3'LTR. The strategy enables us to use a broad spectrum of toxin genes in gene therapy and helps avoid the death of the packaging cells with lentiviral vectors carrying a toxin-encoding gene, thereby increasing the efficiency of viral production in packaging cells. PMID- 26014226 TI - Circulating miR-497 and miR-663b in plasma are potential novel biomarkers for bladder cancer. AB - MicroRNAs (miRNAs), abundant and highly stable in the plasma, have been widely reported. This greatly pursued us to investigate whether plasma miRNAs could be considered as powerful biomarkers for diagnosing bladder cancer (BC). We performed a plasma miRNAs profile with the TaqMan Low Density Array, and a two phase validation to detect the candidate miRNAs expression by quantitative PCR. The receiver operating characteristic curve (ROC) and the area under curve (AUC) were used to evaluate diagnostic accuracy. A total of eight plasma miRNAs abnormally expressed between BC patients and healthy controls in microarray analysis (i.e., elevated miRNAs for miR-505, miR-363 and miR-663b, and decreased for miR-99a, miR-194, miR-100, miR-497 and miR-1 in BC plasma). In further independent cohorts, miR-497 and miR-663b with significantly differential expression were confirmed. Moreover, the AUC, sensitivity and specificity were raised to 0.711 (95% CI = 0.641-0.780), 69.7% and 69.6%, respectively, when miR 497 and miR-663b were integrated. This is the first study systematically exploring the existence of specific plasma miRNAs as early diagnostic biomarkers for BC in Chinese population; and these findings supported that plasma miR-497 and miR-663b could be promising novel circulating biomarkers in clinical detection of BC. PMID- 26014262 TI - Generation and characterization of a novel shoulder contracture mouse model. AB - Frozen shoulder is a relatively common disorder that leads to severe pain and stiffness in the shoulder joint. Although this disorder is self-limiting in nature, the symptoms often persist for years, resulting in severe disability. Recent studies using human specimens and animal models have shown distinct changes in the gene expression patterns in frozen shoulder tissue, indicating that novel therapeutic intervention could be achieved by controlling the genes that are potentially involved in the development of frozen shoulder. To achieve this goal, it is imperative to develop a reliable animal joint contracture model in which gene expression can be manipulated by gene targeting and transgenic technologies. Here, we describe a novel shoulder contracture mouse model. We found that this model mimics the clinical presentation of human frozen shoulder and recapitulates the changes in the gene expression pattern and the histology of frozen shoulder and joint contracture in humans and other larger animal models. The model is highly reproducible, without any major complications. Therefore, the present model may serve as a useful tool for investigating frozen shoulder etiology and for identifying its potential target genes. PMID- 26014263 TI - Mediterranean diet: the missing link between gut microbiota and inflammatory diseases. PMID- 26014264 TI - Changes in weight, body composition and physical fitness after 1.5 years at university. AB - BACKGROUND/OBJECTIVES: This study examined changes in Belgian students' weight, body composition and physical fitness after 1.5 years at university. Furthermore, this study investigated whether these changes differed by gender and weight status. SUBJECTS/METHODS: In this longitudinal study, 172 students' weight, body mass index (BMI) and waist circumference (WC) were objectively measured, whereas fat%, fat mass, fat-free mass, dynamic leg strength, handgrip strength, hamstring flexibility and cardiorespiratory fitness were estimated using validated instruments. Measurements were conducted at the start of the first semester (T0), after the first semester (T1) and after 1.5 years (T2) at university. RESULTS: Female students' weight and BMI did not change, whereas male students gained 2.7 kg of weight and showed a 0.7 kg/m(2) BMI increase after 1.5 years. After the first semester, an increase in fat% was observed in the total group of students, whereas this time effect did not remain significant when comparing T0 and T2. In contrast to females, increases in 2.1 kg of fat-free mass and 1.8 cm of WC were found in males after 1.5 years. Higher baseline BMI and WC predicted greater BMI and fat% increases in males. Handgrip strength improved for both sexes, whereas no changes in other physical fitness components were found across the 1.5-year period. CONCLUSIONS: The greatest weight and BMI gains as well as unfavourable changes in body composition were found in male students with higher baseline BMI and WC. The observed changes in body composition did not cohere with changes in physical fitness. PMID- 26014265 TI - Investigating the effects of arctic dietary intake on lung health. AB - BACKGROUND/OBJECTIVE: Preservation of lung health requires understanding the modifiable risk factors of airflow limitation. This study investigates the association between diet and lung function in a population of Greenland Inuit residing in the Arctic (Greenland) or Western Europe (Denmark). SUBJECTS/METHODS: Two unselected Inuit populations were recruited, one living in Greenland (Urban (Nuuk) n=358; Rural (Uummannaq) n=207) and the other in Denmark (n=539). Lung function was measured using spirometry and diet by a food frequency questionnaire. Factors associated with airflow limitation were assessed using multiple linear regression models. RESULTS: The dietary composition differed significantly in the two regions, with higher whale, seal and wild meat intake and lower fruit and vegetable intake in the Arctic regions compared with Denmark. Consumption of vegetables (P=0.004) and whale and/or seal (P<0.0001) was significantly and positively associated with FEV1, as well as with FVC (vegetables: P=0.001, whale and/or seal: P=0.002). Regular fruit intake was included in the statistical models; however, it did not reach statistical significance (FEV1: P=0.053; FVC: P=0.055). CONCLUSIONS: High dietary intake of vegetables as well as intake of arctic marine mammals had independent positive associations with lung function in this cohort of Greenlandic Inuit. These findings suggest an additive role of dietary intake of antioxidants and unsaturated fatty acids in lung health, which warrants prospective evaluation. PMID- 26014266 TI - Fruit and vegetable consumption and hypertriglyceridemia: Korean National Health and Nutrition Examination Surveys (KNHANES) 2007-2009. AB - BACKGROUND: Limited research has been conducted on the association between intake of fruits and vegetables and hypertriglyceridemia, especially in Asian populations. This study aimed to investigate the association between total fruit and vegetable intake, as well as subgroups of fruit and vegetable intake, with hypertriglyceridemia among Korean adults. METHODS: We conducted a cross-sectional study of 7934 adults aged 19-64 years from the fourth Korean Health and Nutrition Examination Survey. Fruit and vegetable intake was estimated from a food frequency questionnaire. Subgroups of fruits and vegetables included citrus, non citrus and carotene-rich fruits and cruciferous, green leafy and carotene-rich vegetables. Hypertriglyceridemia (plasma triglyceride ?150 mg/dl) was diagnosed using a blood sample drawn after 12+ hours of fasting. RESULTS: There were 2001 (25.2%) cases of hypertriglyceridemia among the participants. Total fruit intake was significantly inversely associated with the prevalence of hypertriglyceridemia; the multivariate odds ratios (95% confidence intervals) of hypertriglyceridemia across increasing quintiles were 1.00 (ref), 0.76 (0.62, 0.92), 0.72 (0.58, 0.90), 0.68 (0.54, 0.85) and 0.64 (0.49, 0.82; Ptrend=0.001) after controlling for survey year, body mass index, waist circumference, smoking, alcohol drinking, physical activity, education and income. Similar inverse associations were found for all fruit subgroups. However, we found no significant association between intakes of total or subgroups of vegetable and hypertriglyceridemia; the odds ratio for top vs bottom quintile was 1.00 (0.81 1.24) for total vegetable intake. CONCLUSIONS: Our findings support a potential beneficial role of fruit consumption to reduce blood triglyceride levels in Asian populations. PMID- 26014267 TI - Longitudinal association of measures of adiposity with serum antioxidant concentrations in postmenopausal women. AB - BACKGROUND/OBJECTIVES: The relationship between obesity and circulating levels of antioxidants is poorly understood. Most studies that have examined the association of adiposity with blood or tissue concentrations of antioxidant micronutrients have been cross-sectional, and few have compared the associations for indices of overall obesity and central obesity. Our aim was to prospectively examine the longitudinal association of body mass index (BMI), waist circumference (WC), waist circumference-height ratio (WCHtR) and waist-hip ratio (WHR) with major serum antioxidants in a population of postmenopausal women. SUBJECTS/METHODS: We used a subsample of participants in the Women's Health Initiative aged 50-79 years at entry with available fasting blood samples and anthropometric measurements obtained at multiple time points over 12.8 years of follow-up (N=2672). Blood samples were used to measure alpha-carotene, beta carotene, beta-cryptoxanthin, lutein+zeaxanthin, alpha-tocopherol, gamma tocopherol and retinol at baseline, and at years 1, 3 and 6. We used mixed effects linear regression analyses to examine associations between anthropometric measures and serum antioxidants at baseline and over time, controlling for covariates. RESULTS: In longitudinal analyses, carotenoids, and particularly beta carotene, were strongly and inversely associated with BMI, WC and WCHtR and less so with WHR. alpha-Tocopherol showed a strong positive association with WHR but not with other anthropometric measures, whereas gamma-tocopherol was positively and strongly associated with BMI, WC, WCHtR and less so with WHR. Retinol was positively associated with WHR. The inverse association of several carotenoids with anthropometric measures was stronger in never and former smokers compared with current smokers and in women without the metabolic syndrome. The inverse association of carotenoids with obesity measures may reflect reduced micronutrient concentrations owing to inflammation associated with obesity. CONCLUSIONS: In the present study, the strongest observed associations between anthropometric variables and micronutrients were an inverse association of WC with serum beta-carotene and a positive association of WC with gamma-tocopherol. PMID- 26014269 TI - A perspective perception on the applications of light-emitting diodes. AB - Light-emitting diodes (LEDs) continue to penetrate the global market; their pervasiveness clearly being felt in such diverse fields as technological, socio economic and commercial interests. The multi-billion dollar LED market is shared by various segments, including office and household lighting, street lighting, the automobile industry, traffic signals, backlighting for hand-held devices, indoor and outdoor signs and indicators, medicine, communication systems, crop cultivation using artificial light and many more. The technological development of LEDs has undergone many phases in different parts of the world. From the early discovery of luminescence to the invention of highly efficient organic LEDs, researchers have worked with the prime purpose of improving the performance of luminaires. The need to infuse the market with more efficient and cheaper products has been prevalent from the start. LEDs are a result of this uncontrolled desire of researchers to develop superior products that would displace existing products in the market. To understand what led to the current prominence of LEDs, we give a brief historical overview of the field followed by a thorough discussion of the positive features of LEDs. This work includes the basic requirements, advantages and disadvantages of LEDs in a variety of applications. A brief description of the diverse applications of LED in fields such as lighting, indicators and displays, farming, medicine and communication is given. Considerable importance is placed on discussing the possible difficulties that must be overcome before using LEDs in commercial applications. PMID- 26014268 TI - Taste genetics and gastrointestinal symptoms experienced in chronic kidney disease. AB - BACKGROUND/OBJECTIVES: It is unknown what causes uraemic symptoms in renal disease. Chronic kidney disease (CKD) patients are known to have increased levels of urea, sodium, potassium and phosphate in their saliva compared with those without renal disease. The present cross-sectional study investigated associations between known genetic traits of taste and self-reported upper gastrointestinal (GI) symptoms experienced in CKD patients with the changes in saliva composition found in renal failure. SUBJECTS/METHODS: Fifty-six CKD patients (35 males, 21 females, age 67+/-14 years), with stages 4 and 5 renal failure, selected from a tertiary hospital renal outpatient clinic participated in this study. Subjects answered a questionnaire to assess upper GI symptoms and tested for the genetic taste recognition thresholds of thiourea, phenylthiocarbamide and sodium benzoate. Saliva samples were collected to determine biochemical composition. Possible associations between genetic taste variations, saliva composition and upper GI symptoms were investigated. RESULTS: Of the 56 patients enroled, 29 (52%) reported major upper GI uraemic symptoms, whereas 27 (48%) had no symptoms or only minor complaints of dry mouth. There was a strong association between the symptomatic burden a patient experienced and the genetic ability to taste thiourea (P<0.0003). Uraemic symptoms of taste changes (P<0.004) and nausea (P<0.002) were found to be related to a patient's genetic ability to taste thiourea. CONCLUSIONS: This study provides evidence that the genetic ability to taste thiourea as bitter, in combination with the increase in active compounds found in CKD patient's saliva, impacts on the uraemic upper GI symptoms experienced. PMID- 26014270 TI - Inadvertent Perianesthetic Hypothermia in Small Animal Patients. AB - Inadvertent perianesthetic hypothermia is one of the most common complications in anesthesia of dogs and cats. Hypothermia during anesthesia can lead to altered pharmacokinetics of anesthetic and analgesic drugs, dysfunction of organ systems, increased patient susceptibility to infection, reduced wound healing, altered coagulation, hypotension, and delayed recovery. An understanding of the pathophysiology, complications, and techniques to minimize hypothermia during anesthesia can help veterinarians optimize care of patients. This article provides an overview of inadvertent perianesthetic hypothermia. PMID- 26014271 TI - 'Language of the past' - Exploring past tense disruption during autobiographical narration in neurodegenerative disorders. AB - Compromised retrieval of autobiographical memory (ABM) is well established in neurodegenerative disorders. The recounting of autobiographical events is inextricably linked to linguistic knowledge, yet no study to date has investigated whether tense use during autobiographical narration is disrupted in dementia syndromes. This study investigated the incidence of correct past tense use during ABM narration in patients with Alzheimer's disease (AD, n = 10) and semantic dementia (SD, n = 10) in comparison with healthy older Controls (n = 10). Autobiographical narratives were analysed for episodic content (internal/external) and classified according to tense use (past/present). Across both patient groups, use of the past tense was significantly compromised relative to Controls, with increased levels of off-target present tense verbs observed. Voxel-based morphometry analyses based on structural MRI revealed differential associations between past tense use and regions of grey matter intensity in the brain. Bilateral temporal cortices were implicated in the SD group, whereas frontal, lateral, and medial temporal regions including the right hippocampus emerged in AD. This preliminary study provides the first demonstration of the disruption of specific linguistic constructs during autobiographical narration in AD and SD. Future studies are warranted to clarify at what point in the disease trajectory such deficits in tense use emerge, and whether these deficits are a product or contributing factor in memory disruption in these syndromes. PMID- 26014272 TI - Reply to Adams and Kwee. PMID- 26014273 TI - Harnessing Quantum Interference in Molecular Dielectric Materials. AB - We investigate the relationship between dielectric response and charge transport in molecule-based materials operating in the quantum coherent regime. We find that quantum interference affects these observables differently, for instance, allowing current passing through certain materials to be reduced by orders of magnitude without affecting dielectric behavior (or band gap). As an example, we utilize ab initio electronic structure theory to calculate conductance and dielectric constants of cross-conjugated anthraquinone (AQ)-based and linearly conjugated anthracene (AC)-based materials. In spite of having nearly equal fundamental gaps, electrode bonding configurations, and molecular dimensions, we find a ~1.7 order of magnitude (~50-fold) reduction in the conductance of the AQ based material relative to the AC-based material, a value in close agreement with recent measurements, while the calculated dielectric constants of both materials are nearly identical. From these findings, we propose two molecular materials in which quantum interference is used to reduce leakage currents across a ~25 A monolayer gap with dielectric constants larger than 4.5. PMID- 26014274 TI - Antifungal prophylaxis with Amphotericin B deoxycholate emulsified in lipids for acute myeloid leukemia patients treated in low economy countries. PMID- 26014275 TI - Control of relapsed or refractory acute myeloid leukemia by clofarabine in preparation for allogeneic stem cell transplant. AB - Allogeneic stem cell transplant is indicated for patients with refractory or relapsed acute myeloid leukemia (AML). Since elimination of the leukemic load is thought to be a prerequisite for treatment success, we here investigate toxicity and anti-leukemic activity of a clofarabine-AraC salvage protocol preceding transplant. In this retrospective analysis, we observed induction of objective remissions in 86% of patients receiving clofarabine-AraC as compared to 83% with sequential high dose AraC/mitoxantrone (S-HAM) and 50% after mitoxantrone/topotecane/AraC (MTC) salvage strategies. In addition, clofarabine conferred anti-leukemic activity to some patients who failed initial MTC or S-HAM therapy. For overall and leukemia-free survival, we identified cytogenetically defined adverse risk markers but not response to therapy to be a strong predictor. In summary, the clofarabine-AraC salvage strategy combines pronounced anti-leukemic activity with an acceptable toxicity profile and allows the majority of patients with relapsed or refractory AML to proceed to allo-SCT, even in cytogenetically defined high risk situations. PMID- 26014276 TI - Taxonomic update on proposed nomenclature and classification changes for bacteria of medical importance, 2013-2014. AB - A key aspect of medical, public health, and diagnostic microbiology laboratories is the accurate and rapid reporting and communications regarding infectious agents of clinical significance. Microbial taxonomy in the age of molecular diagnostics and phylogenetics causes changes in this taxonomy at a rapid rate further complicating this process. This review focuses on the description of new species and classification changes proposed over the past 2 years. PMID- 26014277 TI - Unambiguous Diagnosis of Photoinduced Charge Carrier Signatures in a Stoichiometrically Controlled Semiconducting Polymer-Wrapped Carbon Nanotube Assembly. AB - Single-walled carbon nanotube (SWNT)-based nanohybrid compositions based on (6,5) chirality-enriched SWNTs ([(6,5) SWNTs]) and a chiral n-type polymer (S-PBN(b) Ph4 PDI) that exploits a perylenediimide (PDI)-containing repeat unit are reported; S-PBN(b)-Ph4 PDI-[(6,5) SWNT] superstructures feature a PDI electron acceptor unit positioned at 3 nm intervals along the nanotube surface, thus controlling rigorously SWNT-electron acceptor stoichiometry and organization. Potentiometric studies and redox-titration experiments determine driving forces for photoinduced charge separation (CS) and thermal charge recombination (CR) reactions, as well as spectroscopic signatures of SWNT hole polaron and PDI radical anion (PDI(-.) ) states. Time-resolved pump-probe spectroscopic studies demonstrate that S-PBN(b)-Ph4 PDI-[(6,5) SWNT] electronic excitation generates PDI(-.) via a photoinduced CS reaction (tauCS ~0.4 ps, PhiCS ~0.97). These experiments highlight the concomitant rise and decay of transient absorption spectroscopic signatures characteristic of the SWNT hole polaron and PDI(-.) states. Multiwavelength global analysis of these data provide two charge recombination time constants (tauCR ~31.8 and 250 ps) that likely reflect CR dynamics involving both an intimately associated SWNT hole polaron and PDI(-.) charge-separated state, and a related charge-separated state involving PDI(-.) and a hole polaron site produced via hole migration along the SWNT backbone that occurs over this timescale. PMID- 26014278 TI - Development of advanced host cell protein enrichment and detection strategies to enable process relevant spike challenge studies. AB - An orthogonal chromatography methodology for the enrichment of host cell protein (HCP) species relative to monoclonal antibody (mAb) products was developed and applied for the successful enrichment of HCP from post-Protein A process pools for seven different mAb products. An advanced two-dimensional liquid chromatography/mass spectrometry platform (2D-LC/MS(E) ) was utilized to demonstrate that the HCP enriched material was representative, in terms of species content, to pre-enriched process pools. The HCP enrichment methodology was scaled up for two different mAb products, and this process relevant enriched HCP material was used to conduct advanced spike challenge studies to demonstrate the utility of the approach for the understanding of (1) quantitative HCP clearance, (2) individual species clearance, and (3) species clearance redundancy across polishing chromatography steps. The combined ability to enrich process relevant HCP, detect individual HCP species with 2D-LC/MS(E) technology, and conduct advanced challenge studies with process relevant material surmounts prior limitations to high integrity process challenge study implementation, and facilitates significant process understanding for development of risk-based control strategies and strategic process design. This also demonstrates implementation of a foundational strategy for conducting spike-challenge studies using process-relevant impurities isolated from processes of interest using orthogonal approaches. PMID- 26014279 TI - Culture of hESC-derived pancreatic progenitors in alginate-based scaffolds. AB - The effect of alginate-based scaffolds with added basement membrane proteins on the in vitro development of hESC-derived pancreatic progenitors was investigated. Cell clusters were encapsulated in scaffolds containing the basement membrane proteins collagen IV, laminin, fibronectin, or extracellular matrix-derived peptides, and maintained in culture for up to 46 days. The cells remained viable throughout the experiment with no signs of central necrosis. Whereas nonencapsulated cells aggregated into larger clusters, some of which showed signs of morphological changes and tissue organization, the alginate matrix stabilized the cluster size and displayed more homogeneous cell morphologies, allowing culture for long periods of time. For all conditions tested, a stable or declining expression of insulin and PDX1 and an increase in glucagon and somatostatin over time indicated a progressive reduction in beta cell-related gene expression. Alginate scaffolds can provide a chemically defined, xeno-free and easily scalable alternative for culture of pancreatic progenitors. Although no increase in insulin and PDX1 gene expression after alginate-immobilized cell culture was seen in this study, further optimization of the matrix physicochemical and biological properties and of the medium composition may still be a relevant strategy to promote the stabilization or maturation of stem cell derived beta cells. PMID- 26014280 TI - When do high and low status group members support confrontation? The role of perceived pervasiveness of prejudice. AB - This paper examines how perceived pervasiveness of prejudice differentially affects high and low status group members' support for a low status group member who confronts. In Experiment 1 (N = 228), men and women read a text describing sexism as rare or as pervasive and subsequently indicated their support for a woman who confronted or did not confront a sexist remark. Experiment 2 (N = 324) specified the underlying process using a self-affirmation manipulation. Results show that men were more supportive of confrontation when sexism was perceived to be rare than when it was pervasive. By contrast, women tended to prefer confrontation when sexism was pervasive relative to when it was rare. Personal self-affirmation decreased men's and increased women's support for confrontation when prejudice was rare, suggesting that men's and women's support for confrontation when prejudice is rare is driven by personal impression management considerations. Implications for understanding how members of low and high status groups respond to prejudice are discussed. PMID- 26014281 TI - Toxicogenomic responses of human liver HepG2 cells to silver nanoparticles. AB - The increased use of silver nanoparticles (AgNPs) in foods and cosmetics has raised public safety concerns. However, only limited knowledge exists on the effect of AgNPs on the cellular transcriptome. This study evaluated global gene expression profiles of human liver HepG2 cells exposed to 20 and 50 nm AgNPs for 4 and 24 h at 2.5 ug ml(-1) . Exposure to 20 nm AgNPs resulted in 811 altered genes after 4 h, but much less after 24 h. Exposure to 50 nm AgNPs showed minimal altered genes at both exposure times. The HepG2 cells responded to the toxic insult of AgNPs by transiently upregulating stress response genes such as metallothioneins and heat shock proteins. Functional analysis of the altered genes showed more than 20 major biological processes were affected, of which metabolism, development, cell differentiation and cell death were the most dominant categories. Several cellular pathways were also impacted by AgNP exposure, including the p53 signaling pathway and the NRF2-mediated oxidative stress response pathway, which may lead to increased oxidative stress and DNA damage in the cell and potentially result in genotoxicity and carcinogenicity. Together, these results indicate that HepG2 cells underwent a multitude of cellular processes in response to the toxic insult of AgNP exposure, and suggest that toxicogenomic characterization of human HepG2 cells could serve as an alternative model for assessing toxicities of NPs. PMID- 26014282 TI - Collaborative study for the characterization of a chikungunya virus RNA reference reagent for use in nucleic acid testing. AB - BACKGROUND AND OBJECTIVES: Infections with the mosquito-borne chikungunya virus (CHIKV) can cause febrile illness or be asymptomatic. Laboratory diagnosis of CHIKV is often made with laboratory-developed nucleic acid amplification technology (NAT) assays because there are no U.S. Food and Drug Administration (FDA)-approved diagnostic or blood screening assays. We aimed to produce a well characterized CHIKV RNA reference reagent (CHIKV-RR) for use in NAT assays. MATERIALS AND METHODS: A CHIKV RNA-RR consisting of cell culture-grown, heat inactivated CHIKV diluted in human plasma was assessed by 8 laboratories in a collaborative study. The participants were asked to test the CHIKV-RR using their NAT assay(s) by qualitative testing (determination of RNA end-point by testing log and half-log dilutions followed by calculation of estimated NAT-detectable units/ml, after adjustment for the sample volume used for testing), and by quantitative testing, when available. RESULTS: Results from the testing showed that the CHIKV-RR had an estimated overall mean of 7.56 log10 detectable units/ml, ranging from 6.2 log10 to 8.6 log10. CONCLUSIONS: The Center for Biologics for Evaluation and Research/FDA CHIKV RNA-RR for NAT was established with a concentration of 7.56 log10 detectable units/ml. PMID- 26014283 TI - In vitro Phase I and Phase II metabolism of alpha-pyrrolidinovalerophenone (alpha PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol. AB - The aim of the present study was to identify the in vitro Phase I and Phase II metabolites of three new psychoactive substances: alpha-pyrrolidinovalerophenone (alpha-PVP), methylenedioxypyrovalerone (MDPV), and methedrone, using human liver microsomes and human liver cytosol. Accurate-mass spectra of metabolites were obtained using liquid chromatography-quadrupole time-of-flight mass spectrometry. Six Phase I metabolites of alpha-PVP were identified, which were formed involving reduction, hydroxylation, and pyrrolidine ring opening reactions. The lactam compound was the major metabolite observed for alpha-PVP. Two glucuronidated metabolites of alpha-PVP, not reported in previous in vitro studies, were further identified. MDPV was transformed into 10 Phase I metabolites involving reduction, hydroxylation, and loss of the pyrrolidine ring. Also, six glucuronidated and two sulphated metabolites were detected. The major metabolite of MDPV was the catechol metabolite. Methedrone was transformed into five Phase I metabolites, involving N- and O-demethylation, hydroxylation, and reduction of the ketone group. Three metabolites of methedrone are reported for the first time. In addition, the contribution of individual human CYP enzymes in the formation of the detected metabolites was investigated. PMID- 26014284 TI - Metabolomic analysis of wild and transgenic Nicotiana langsdorffii plants exposed to abiotic stresses: unraveling metabolic responses. AB - Nicotiana langsdorffii plants, wild and transgenic for the Agrobacterium rhizogenes rol C gene and the rat glucocorticoid receptor (GR) gene, were exposed to different abiotic stresses (high temperature, water deficit, and high chromium concentrations). An untargeted metabolomic analysis was carried out in order to investigate the metabolic effects of the inserted genes in response to the applied stresses and to obtain a comprehensive profiling of metabolites induced during abiotic stresses. High-performance liquid chromatography separation (HPLC) coupled to high-resolution mass spectrometry (HRMS) enabled the identification of more than 200 metabolites, and statistical analysis highlighted the most relevant compounds for each plant treatment. The plants exposed to heat stress showed a unique set of induced secondary metabolites, some of which were known while others were not previously reported for this kind of stress; significant changes were observed especially in lipid composition. The role of trichome, as a protection against heat stress, is here suggested by the induction of both acylsugars and glykoalkaloids. Water deficit and Cr(VI) stresses resulted mainly in enhanced antioxidant (HCAs, polyamine) levels and in the damage of lipids, probably as a consequence of reactive oxygen species (ROS) production. Moreover, the ability of rol C expression to prevent oxidative burst was confirmed. The results highlighted a clear influence of GR modification on plant stress response, especially to water deficiency-a phenomenon whose applications should be further investigated. This study provides new insights into the field of system biology and demonstrates the importance of metabolomics in the study of plant functioning. Graphical Abstract Untargeted metabolomic analysis was applied to wild type, GR and RolC modified Nicotiana Langsdorffii plants exposed to heat, water and Cr(VI) stresses. The key metabolites, highly affected by stress application, were identified, allowing to outline the main metabolic responses to stress in each plant genotype. PMID- 26014285 TI - Determination of ketosteroid hormones in meat by liquid chromatography tandem mass spectrometry and derivatization chemistry. AB - A method for the determination and quantification of ketosteroid hormones in meat by mass spectrometry, based on the derivatization of the carbonyl moiety of steroids by O-methylhydroxylamine, is presented. The quantitative assay is performed by means of multiple-reaction-monitoring (MRM) scan mode and using the corresponding labelled species, obtained by reaction with d 3-methoxylamine, as internal standard. The accuracy of the method was established by evaluating artificially spiked samples, obtaining values in the range 90-110%. Recovery tests were performed on blank matrix samples spiked with non-natural steroids including trenbolone and melengestrol acetate. The latter experiment revealed that the yield of the extraction processes was approximately 60%. Good values of LOQ and LOD were achieved, making this method competitive with current hormone assay methods. PMID- 26014288 TI - Reply to L'Huillier et al. PMID- 26014286 TI - Novel insights into the pathogenicity of epidemic Aeromonas hydrophila ST251 clones from comparative genomics. AB - Outbreaks in fish of motile Aeromonad septicemia (MAS) caused by Aeromonas hydrophila have caused a great concern worldwide. Here, for the first time, we provide two complete genomes of epidemic A. hydrophila strains isolated in China. To gain an insight into the pathogenicity of epidemic A. hydrophila, we performed comparative genomic analyses of five epidemic strains belonging to sequence type (ST) 251, together with the environmental strain ATCC 7966(T). We found that the known virulence factors, including a type III secretion system, a type VI secretion system and lateral flagella, are not required for the high virulence of the ST251 clonal group. Additionally, our work identifies three utilization pathways for myo-inositol, sialic acid and L-fucose providing clues regarding the factors that underlie the epidemic and virulent nature of ST251 A. hydrophila. Based on the geographical distribution and biological resources of the ST251 clonal group, we conclude that ST251 is a high-risk clonal group of A. hydrophila which may be responsible for the MAS outbreaks in China and the southeastern United States. PMID- 26014289 TI - Multiple MoS2 Transistors for Sensing Molecule Interaction Kinetics. AB - Atomically layered transition metal dichalcogenides (TMDCs) exhibit a significant potential to enable next-generation low-cost transistor biosensors that permit single-molecule-level quantification of biomolecules. To realize such potential biosensing capability, device-oriented research is needed for calibrating the sensor responses to enable the quantification of the affinities/kinetics of biomolecule interactions. In this work, we demonstrated MoS2-based transistor biosensors capable of detecting tumor necrosis factor--alpha (TNF-alpha) with a detection limit as low as 60 fM. Such a detection limit was achieved in both linear and subthreshold regimes of MoS2 transistors. In both regimes, all sets of transistors exhibited consistent calibrated responses with respect to TNF-alpha concentration, and they resulted in a standard curve, from which the equilibrium constant of the antibody-(TNF-alpha) pair was extracted to be KD = 369 +/- 48 fM. Based on this calibrated sensor model, the time-dependent binding kinetics was also measured and the association/dissociation rates of the antibody-(TNF-alpha) pair were extracted to be (5.03 +/- 0.16) * 10(8) M(-1) s(-1) and (1.97 +/- 0.08) * 10(-4) s(-1), respectively. This work advanced the critical device physics for leveraging the excellent electronic/structural properties of TMDCs in biosensing applications as well as the research capability in analyzing the biomolecule interactions with fM-level sensitivities. PMID- 26014290 TI - Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. AB - PURPOSE: The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. PATIENTS AND METHODS: From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. RESULTS: The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. CONCLUSION: The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation. PMID- 26014291 TI - Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials. AB - PURPOSE: We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment. PATIENTS AND METHODS: Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies. RESULTS: Seven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotype-matched trials targeting these alterations. Of 230 patients with PIK3CA/AKT1/PTEN/BRAF mutations that returned for therapy, 116 (50%) received a genotype-matched drug. Forty patients (17%) were treated on a genotype-selected trial requiring a mutation for eligibility, 16 (7%) were treated on a genotype-relevant trial targeting a genomic alteration without biomarker selection, and 40 (17%) received a genotype-relevant drug off trial. Challenges to trial accrual included patient preference of noninvestigational treatment or local treatment, poor performance status or other reasons for trial ineligibility, lack of trials/slots, and insurance denial. CONCLUSION: Broad implementation of multiplex hotspot testing is feasible; however, only a small portion of patients with actionable alterations were actually enrolled onto genotype-matched trials. Increased awareness of therapeutic implications and access to novel therapeutics are needed to optimally leverage results from broad-based genomic testing. PMID- 26014292 TI - Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group. AB - PURPOSE: Given concerns that dexrazoxane may reduce treatment efficacy, induce second cancers, and thus compromise overall survival among children, we examined long-term overall and cause-specific mortality and disease relapse rates from three randomized clinical trials. PATIENTS AND METHODS: Children's Oncology Group trials P9404 (T-cell acute lymphoblastic leukemia/lymphoma; n = 537), P9425 (intermediate/high-risk Hodgkin lymphoma; n = 216), and P9426 (low-risk Hodgkin lymphoma; n = 255) were conducted between 1996 and 2001. Each trial randomly assigned patients to doxorubicin with or without dexrazoxane. The dexrazoxane:doxorubicin dose ratio was 10:1, and the cumulative protocol specified doxorubicin dose was 100 to 360 mg/m(2). Dexrazoxane was given as an intravenous bolus before each doxorubicin dose. Data from all three trials were linked with the National Death Index to determine overall and cause-specific mortality by dexrazoxane status. RESULTS: Among 1,008 patients (507 received dexrazoxane) with a median follow-up of 12.6 years (range, 0 to 15.5 years), 132 died (67 received dexrazoxane). Overall mortality did not vary by dexrazoxane status (12.8% with dexrazoxane at 10 years v 12.2% without; hazard ratio [HR], 1.03; 95% CI, 0.73 to 1.45). Findings were similar when each trial was examined separately. Dexrazoxane also was not significantly associated with differential causes of death. The original cancer caused 76.5% of all deaths (HR, 0.90; 95% CI, 0.61 to 1.32) followed by second cancers (13.6% of deaths; HR, 1.24; 95% CI, 0.49 to 3.15). Specifically, dexrazoxane was not associated with deaths from acute myeloid leukemia/myelodysplasia or cardiovascular events. CONCLUSION: Among pediatric patients with leukemia or lymphoma, after extended follow-up, dexrazoxane use did not seem to compromise long-term survival. PMID- 26014293 TI - Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. AB - PURPOSE: Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1 derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. PATIENTS AND METHODS: Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously >= 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. RESULTS: Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in >= 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred. CONCLUSION: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma. PMID- 26014294 TI - BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non-Small-Cell Lung Cancer. AB - PURPOSE: The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. PATIENTS AND METHODS: Patients age >= 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non-small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m(2)) intravenously (CP) on day 1 of each 3-week cycle, for <= six cycles, plus placebo (Pl+CP) or bevacizumab (B+CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. RESULTS: A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B+CP versus Pl+CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P < .001). Objective response rate was improved with B+CP compared with Pl+CP (54% v 26%, respectively). Overall survival was also prolonged with B+CP compared with Pl+CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P = .0154). Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation-positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B+CP in NSCLC; no new safety signals were observed. CONCLUSION: The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC. PMID- 26014295 TI - Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial. AB - PURPOSE: The NCIC CTG PR3/MRC PR07 randomized phase III trial compared androgen deprivation therapy (ADT) alone versus ADT with radiotherapy (RT) for patients with locally advanced prostate cancer. This article reports the health-related quality-of-life (HRQOL) outcomes of this trial. PATIENTS AND METHODS: A total of 1,205 patients were randomly allocated to either ADT alone or ADT with RT. HRQOL was assessed at baseline and every 6 months thereafter using the European Organisation for Research and Treatment of Cancer Core Questionnaire and a prostate cancer-specific checklist or the Functional Assessment of Cancer Therapy Prostate questionnaire. Mean changes from baseline scores for five function domains and nine symptom domains were analyzed as those most relevant to ADT and RT. The proportions of patients with improved, stable, or worsened HRQOL scores according to instrument-specific minimal important differences were calculated. RESULTS: Baseline questionnaires were completed by 1,028 patients (88%). At 6 months, RT had a statistically significant impact on mean score for bowel symptoms (P = .02), diarrhea (P < .001), urinary function (P = .003), and erectile dysfunction (P = .008); by 3 years, however, there were no significant between-group differences in any domain. Generalized linear mixed modeling revealed no significant between-arm differences in any of the function scales but showed significant deterioration in both arms over time for Functional Assessment of Cancer Therapy-Prostate total score, treatment outcome index, and physical and functional well-being. CONCLUSION: The addition of RT to ADT for patients with locally advanced prostate cancer significantly improved overall survival and had only modest and transient negative impact on relevant domains of HRQOL. PMID- 26014296 TI - Economic Evaluation of Bevacizumab for the First-Line Treatment of Newly Diagnosed Glioblastoma Multiforme. AB - PURPOSE: The Avastin in Glioblastoma trial has shown that patients newly diagnosed with glioblastoma multiforme (GBM) treated with bevacizumab plus radiotherapy and temozolomide versus radiotherapy and temozolomide alone showed improvement in progression-free survival, possibly leading to a new indication for first-line use of bevacizumab in GBM. The cost-utility of this new intervention remains unknown; therefore, we developed a Markov model estimating the incremental cost-utility ratio (ICUR) from a Canadian public payer perspective. METHODS: We incorporated trial data for state transitions and treatment effects from the Avastin in Glioblastoma trial, costs and resource use data from Canadian published studies and databases, and utility parameters from published literature. We addressed uncertainty through one-way deterministic and probabilistic sensitivity analyses, extended the model to lifetime horizon and by another arm to compare first-line versus second-line use of bevacizumab on progression, performed value of information analysis, and performed US costing sensitivity analysis. RESULTS: Adding bevacizumab to radiotherapy and temozolomide resulted in increases of 0.13 quality-adjusted life-years (QALYs) and $80,000 per patient over 2-year time horizon at the base case analysis. The ICUR was $607,966/QALY (95% CI, $305,000/QALY to $2,550,000/QALY), with 0% chance of being cost effective at the $100,000/QALY willingness-to-pay threshold and never going below $450,000/QALY in the one-way sensitivity analysis. The ICUR using the US costing data was $787,519/QALY. The lifetime ICUR was $439,764/QALY (95% CI, $235,000/QALY to $1,520,000/QALY), never going below $350,000/QALY in the sensitivity analysis. Second-line use of bevacizumab on progression is more effective and less expensive than its first-line use. Value of information analysis revealed that future research is unwarranted. CONCLUSION: Bevacizumab has only limited effectiveness and is therefore not likely to be cost effective in treating adult patients with newly diagnosed GBM. PMID- 26014297 TI - Reply to G.J. Weiss. PMID- 26014299 TI - Influence of Robotic-Assisted Surgery on Readmission Burden. PMID- 26014298 TI - Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma. AB - PURPOSE: As glioblastoma progresses, patients experience a decline in health related quality of life (HRQoL). Delaying this decline is an important treatment goal. In newly diagnosed glioblastoma, progression-free survival was prolonged when bevacizumab was added to radiotherapy plus temozolomide (RT/TMZ) versus placebo plus RT/TMZ (phase III AVAglio study; hazard ratio, 0.64; 95% CI, 0.55 to 0.74; P < .001). To ensure that addition of bevacizumab to standard-of-care therapy was not associated with HRQoL detriment, HRQoL assessment was a secondary objective. PATIENTS AND METHODS: Patients completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BN20 at each tumor assessment (Appendix Table A1, online only). Raw scores were converted to a 100-point scale and mean changes from baseline scores were evaluated (stable: < 10-point change; clinically relevant deterioration/improvement: >= 10 point change). Deterioration-free survival was the time to deterioration/progression/death; time to deterioration was the time to deterioration/death. RESULTS: Most evaluable patients who had not progressed (> 74%) completed all HRQoL assessments for at least 1 year of treatment, and almost all completed at least one HRQoL assessment at baseline (98.3% and 97.6%, bevacizumab and placebo arms, respectively). Mean changes from baseline did not reach a clinically relevant difference between arms for most items. HRQoL declined at progression in both arms. The addition of bevacizumab to RT/TMZ resulted in statistically longer (P < .001) deterioration-free survival across all items. Time to deterioration was not statistically longer in the placebo plus RT/TMZ arm (v bevacizumab) for any HRQoL item. CONCLUSION: The addition of bevacizumab to standard-of-care treatment for newly diagnosed glioblastoma had no impact on HRQoL during the progression-free period. PMID- 26014300 TI - Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies. AB - PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined. PMID- 26014301 TI - Study of sedative activity of different extracts of Kaempferia galanga in Swiss albino mice. AB - BACKGROUND: Kaempferia galanga is an important medicinal plant and has been traditionally used to help restlessness, stress, anxiety, depression etc. in tropics and subtropics of Asia including Bangladesh, India, China, Japan and Indochina. Literature survey revealed that there are very less reports on neuropharmacological activity of this plant. Therefore, the present study investigated the sedative activity of different extracts of rhizome and leaf of Kaempferia galanga. METHODS: The sedative activity was evaluated by using thiopental sodium induced sleeping time, hole cross and open field tests in Swiss albino mice at the doses of 100 and 200 mg/kg body weight per oral (p.o). The acetone extract of rhizome (ACR), as well as petroleum ether fraction (PEF), chloroform fraction (CHF), methanol fraction (MEF) and acetone extract of leaf (ACL) were examined for sedative activity. RESULTS: In the sedative activity study, all the extracts exhibited significant (p < 0.05 and p < 0.001) reduction of onset and duration of thiopental sodium induced sleeping time, reduction of locomotor and exploratory activities in the hole cross and open field tests. In thiopental sodium induced sleeping time test, the chloroform extract of rhizome (200 mg/kg) showed maximum 358.55 % effect in duration of loss of righting reflex, whereas the standard drug Diazepam (2 mg/kg) produced 231.42 % effect. In hole cross and open field tests, maximum 95.09 % and 95.58 % suppression of locomotor activity were observed with the acetonic leaf extract (200 mg/kg) whereas suppression of locomotor activity of the standard drug Diazepam were 71.70 % and 70.58 % respectively. CONCLUSION: The present study indicates that the acetone extracts of rhizome and leaf of Kaempferia galanga including fractions possess central nervous system (CNS) depressant properties which supports its use in traditional medicine. So, the plant may be further investigated to find out for its pharmacological active natural products. PMID- 26014302 TI - On the Importance of C-H/pi and C-H???H-C Interactions in the Solid State Structure of 15-Lipoxygenase Inhibitors Based on Eugenol Derivatives. AB - In this manuscript the X-ray structures of two potent and known inhibitors of 15 lipoxygenase, that is, 4-allyl-2-methoxyphenyl-1-admantanecarboxylate (1) and allyl-2-methoxyphenyl-1-cyclohexanecarboxylate (2), are reported. Their solid state architectures show that they have a strong ability to establish C-H/pi and C-H???H-C interactions. For the former interaction, the adamantane or cyclohexane moieties are the C-H donors and the electron-rich methoxyphenyl ring is the pi system. For the latter, the C-H bonds belong to the aliphatic rings of the inhibitors. Interestingly, the active site of lipoxygenase enzyme family is rich in isoleucine and leucine amino acids that participate in the binding of the unsaturated fatty acid substrate by means of multiple hydrophobic C-H???H-C interactions. By means of theoretical calculations, we analyze the ability of compounds 1 and 2 to establish C-H/pi and C-H???H-C interactions in the solid state. PMID- 26014303 TI - Stress and Personality Development Among US-Immigrating Youth. PMID- 26014304 TI - The prevalence of acute kidney injury in neonates with birth asphyxia is higher in the Democratic Republic of Congo than in Western countries. AB - AIM: There is very little data on acute kidney injury in neonates in Africa. The aim of this study was to describe the frequency of acute kidney injury and the outcome in neonates admitted to hospital for asphyxia in the Democratic Republic of Congo. METHODS: A descriptive study was conducted in the country's capital Kinshasa. Acute kidney injury was diagnosed within three days of life when the creatinine clearance was <=16 mL/min/1.73 m2. RESULTS: Acute kidney injury occurred in 54.3% of the 35 neonates with severe perinatal asphyxia and 31.4% of the 35 neonates with moderate perinatal asphyxia, and this rate was higher than the prevalence reported in Western countries. Prerenal acute kidney injury occurred in 12 (40%) of the 30 neonates with acute kidney injury. The frequency of oliguria was significantly higher in neonates with severe perinatal asphyxia than moderate perinatal asphyxia (73.7% vs. 45.5%), and mortality was also higher in neonates with severe rather than moderate perinatal asphyxia (57.9% vs. 36.4%). CONCLUSION: The prevalence of acute kidney injury was higher in asphyxiated patients in the Democratic Republic of Congo than in Western countries. It was also higher in neonates with severe rather than moderate perinatal asphyxia. PMID- 26014305 TI - Strategy for a transparent, accessible, and sustainable national claims database. AB - The article outlines the strategy employed by FAIR Health, Inc, an independent nonprofit, to maintain a national database of over 18 billion private health insurance claims to support consumer education, payer and provider operations, policy makers, and researchers with standard and customized data sets on an economically self-sufficient basis. It explains how FAIR Health conducts all operations in-house, including data collection, security, validation, information organization, product creation, and transmission, with a commitment to objectivity and reliability in data and data products. It also describes the data elements available to researchers and the diverse studies that FAIR Health data facilitate. PMID- 26014306 TI - Cost differential by site of service for cancer patients receiving chemotherapy. AB - OBJECTIVES: To compare the costs of: 1) chemotherapy treatment across clinical, demographic, and geographic variables; and 2) various cancer care-related cost categories between patients receiving chemotherapy in a community oncology versus a hospital outpatient setting. STUDY DESIGN: Data from the calendar years 2008 to 2010 from the Truven Health Analytics MarketScan Commercial Claims and Encounters Database were analyzed. During 2010, the data set contained approximately 45 million unique commercially insured patients with 70,984 cancer patients receiving chemotherapy. These patients were assigned to cohorts depending on whether they received chemotherapy at a community oncology or hospital outpatient setting. METHODS: Cost data for 9 common cancer types were extracted from the database and analyzed on a per member per month basis to normalize costs; costs included amounts paid by the payer and patient payment. Community oncology and hospital outpatient setting chemotherapy treatment costs were categorized and examined according to cancer diagnosis, patient demographics, and geographic location. RESULTS: Patients receiving chemotherapy treatment in the community oncology clinic had a 20% to 39% lower mean per member per month cost of care, depending on diagnosis, compared with those receiving chemotherapy in the hospital outpatient setting. This cost differential was consistent across cancer type, geographic location, patient age, and number of chemotherapy sessions. Various cost categories examined were also higher for those treated in the hospital outpatient setting. CONCLUSIONS: The cost of care for patients receiving chemotherapy was consistently lower in the community oncology clinic compared with the hospital outpatient setting, controlling for the clinical, demographic, and geographic variables analyzed. PMID- 26014307 TI - Factors affecting medication adherence trajectories for patients with heart failure. AB - OBJECTIVES: To examine the relationship between patient characteristics and medication adherence trajectories for patients with congestive heart failure (CHF). STUDY DESIGN: Historical prospective study. METHODS: We conducted a secondary analysis of data assembled for the Practice Variation and Care Outcomes (PRAVCO) study, which examined patterns of cardiovascular care. We used group based trajectory modeling to define medication adherence trajectories, and then modeled factors associated with belonging to a trajectory group during the 6year period from 2005 to 2010 (n = 10,986). We focused on the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for secondary prevention of CHF. RESULTS: Four trajectory groups were optimal in characterizing adherence level patterns: 1) low adherence group, with an initial average adherence rate of 62% that dropped to between 40% and 50%; 2) increasing adherence group, with an initial average adherence rate of 55% that increased to 90%; 3) decreasing adherence group, with an initial average adherence rate above 90% that decreased to 60%; 4) high adherence group, with an average adherence rate consistently above 90%. Age, region, education, smoking, and race were all significantly associated with the likelihood of belonging to a particular trajectory. Nonwhites were less likely to be in the high adherence group, and smoking was more common in the low adherence group (22%) than in the high group (10%); increasing body mass index and Charlson Comorbidity Index (CCI) scores were also associated with being in the low adherence group. CONCLUSIONS: Population characteristics associated with sustained low adherence might be used to target interventions and improve vulnerable patients' prospects of heart health. PMID- 26014308 TI - Trends in mortality following hip fracture in older women. AB - OBJECTIVES: To examine contemporary trends in mortality following hip fracture among older postmenopausal women in an integrated healthcare delivery system. STUDY DESIGN: Retrospective cohort study of 13,550 women aged >=65 years with hip fracture during 2000 to 2010. METHODS: Demographic factors, comorbidity index score, fracture history, early rehospitalization, and all-cause mortality within 1 year following hip fracture were examined using health plan databases and records. Temporal trends, risk factors, and the association of race/ethnicity and mortality within 1 year post fracture were examined using multivariable logistic regression. RESULTS: Among 13,550 women with hip fracture, 84.6% were aged >=75 years: 83.6% were white, 2.8% black, 5.6% Hispanic, 4.5% Asian, and 3.5% of other/unknown race. Following hip fracture, 2.4% died during the index hospitalization, while 12.3% were rehospitalized within 30 days of discharge. Infection, pneumonia, and cardiovascular conditions were the most common nonorthopedic indications for readmission. Mortality rates at 6 months (17%) and 1 year (22.8%) following hip fracture were high and increased with age. Greater comorbidity and early rehospitalization were associated with increased mortality risk, while Asian and Hispanic race/ethnicity were associated with lower mortality risk (vs white). Temporal trends demonstrated a small but significant reduction in mortality risk during 2004 to 2010. CONCLUSIONS: While hip fracture morbidity and mortality remain high, temporal trends suggest recent declines in mortality risk, with risk of death following hip fracture lower for Asian and Hispanic women. Future studies should examine potential benefits of targeted interventions within integrated healthcare settings and factors contributing to observed racial/ethnic differences in post fracture survival. PMID- 26014309 TI - The combined effect of the electronic health record and hospitalist care on length of stay. AB - OBJECTIVES: To assess the combined impact of electronic health record (EHR) adoption and hospitalist care on length of stay (LOS). STUDY DESIGN: Retrospective cohort study using data from the Healthcare Information and Management Systems Society and a 5% national sample of Medicare beneficiaries. Patients included 20,862 admissions for respiratory disease cared for by hospitalists, and 28,714 admissions for respiratory disease cared for by nonhospitalists in 2985 general and surgical hospitals in the United States. METHODS: The interaction effect of EHR and hospitalist care on LOS was evaluated using generalized linear models with log-link normal distribution after controlling for patient and hospital characteristics. RESULTS: In multivariable analyses controlling for patient and hospital characteristics, we found that the reduced LOS associated with complete EHR was 0.166 days and was statistically significant in the hospitals in which 50% or less of patients were cared for by hospitalists. Moreover, we found that reductions in LOS associated with hospitalist care were greater in hospitals that had not adopted a complete EHR. LOS was 0.599 days shorter for patients cared for by hospitalists versus nonhospitalists in hospitals with incomplete EHR adoption; in hospitals with complete EHR adoption, the stay was 0.433 days shorter. CONCLUSIONS: The reduced LOS associated with hospitalist care is greater than that associated with EHR adoption. However, the combined reduction in LOS with both EHR adoption and hospitalist care may be substantial. PMID- 26014310 TI - Treatment patterns, healthcare utilization, and costs of chronic opioid treatment for non-cancer pain in the United States. AB - OBJECTIVES: To evaluate treatment patterns, healthcare resource utilization, and costs among patients within a large managed care population chronically using opioids for non-cancer pain. STUDY DESIGN: Retrospective cohort study. METHODS: Patients aged >=18 years with >=1 prescription initiating opioids between January 1, 2007, and December 31, 2011, who also had 12 months of continuous pre-index health plan enrollment, were identified. Patients with pre-index opioid use or cancer diagnosis were excluded. Opioid exposure was stratified by treatment duration-short-term (30-182 days) versus chronic (>=183 days)-and by index opioid type (weak vs strong). RESULTS: A total of 2.9 million patients initiating opioids were identified, of which 257,602 had at least 30 days of continuous use and were included in the study. The mean age was 51 years and 52% were female. Overall, 239,998 (93%) patients had short-term opioid use, and 17,604 (7%) had chronic use; 215,424 (84%) initiated treatment with a weak opioid, and 44,712 (17%) with a strong opioid. The specialty most associated with the use of less potent opioids was general/family practice (28%), and for more potent opioids it was surgery (22%). Large increases in health-care utilization were reported between the pre-index and first 6-month post initiation periods for chronic users. Utilization rates decreased after the first 6 months but never reverted to baseline levels. Costs mirrored utilization trends, more than doubling between baseline and the first 6 months of treatment for pharmacy ($2029 vs $4331) and all-cause medical ($11,430 vs $27,365). Costs declined after the first 6 months of opioid use but remained above pre-index levels. CONCLUSIONS: These results demonstrated that healthcare resource utilization and costs increased during the first 6 months following clinical scenarios that necessitated opioid initiation and subsequently declined, suggesting the need to monitor patients beyond the acute care period. PMID- 26014312 TI - Systematic evaluation of women with suspected endometriosis using a 5-domain sonographically based approach. AB - In recent years, knowledge has evolved regarding the role of transvaginal sonography in the assessment of the pouch of Douglas status and the preoperative prediction of extraovarian endometriosis in specific locations. Despite these advances in transvaginal sonography, the challenge of developing a comprehensive, cost-effective, and reproducible preoperative classification system for endometriosis remains. Critical to this classification system should be a sonographically based evaluation protocol that is systematic, evidence based, and reproducible with clearly defined end points. To date, no structured evaluation protocol exists for the assessment of the pelvis in women with suspected endometriosis. In this article, we propose a domain-based evaluation protocol for the assessment of women with suspected endometriosis using transvaginal sonography. PMID- 26014311 TI - Long-term outcomes of analogue insulin compared with NPH for patients with type 2 diabetes mellitus. AB - BACKGROUND: Long-acting insulin analogues (eg, insulin glargine and insulin detemir) are an alternative to neutral protamine Hagedorn (NPH) insulin for maintaining glycemic control in patients with diabetes. Clinical trials comparing analogue insulin and NPH have neither been adequately powered nor had sufficient follow-up to examine long-term health outcomes. OBJECTIVES: To compare the effects of NPH and long-acting insulin analogues on long-term outcomes. STUDY DESIGN: This retrospective observational study relied on administrative data from the Veterans Health Administration and Medicare from 2000 to 2010. Local variations in analogue insulin prescribing rates were used in instrumental variable models to control for confounding. Outcomes were assessed using survival models. METHODS: The study population included US veterans dually enrolled in Medicare who received at least 1 prescription for oral diabetes medication and then initiated long-acting insulin between 2001 and 2009. Outcomes included ambulatory care-sensitive condition (ACSC) hospitalizations and mortality. RESULTS: There was no significant relationship between type of insulin and ACSC hospitalization or mortality. The hazard ratio for mortality of individuals starting a long-acting analogue insulin was 0.97 (95% CI, 0.85-1.11), and was 1.05 (95% CI, 0.95-1.16) for ACSC hospitalization. Differences in risk remained insignificant when predicting diabetes-specific ACSC hospitalizations, but starting on long-acting analogue insulin significantly increased the risk of a cardiovascular-specific ACSC hospitalization. CONCLUSIONS: We found no consistent difference in long-term health outcomes when comparing use of long-acting insulin analogues and NPH insulin. The higher cost of analogue insulin without demonstrable clinical benefit raises questions of its cost-effectiveness in the treatment of patients with diabetes. PMID- 26014313 TI - Unusual ectopic pregnancies: sonographic findings and implications for management. AB - Ectopic pregnancy is a considerable source of morbidity and mortality for women of childbearing age. Improved detection and increased risk factors have led to a dramatic rise in the incidence of ectopic pregnancy in recent years. Early diagnosis is critical for the health of the patient as well as the success rate of future pregnancies. Besides laparoscopy, sonography is the mainstay for evaluating ectopic pregnancy. It is important to understand the sonographic features of ectopic pregnancies, including unusual cases that occur outside the fallopian tube. PMID- 26014314 TI - First-trimester 3-dimensional power Doppler placental vascularization indices from the whole placenta versus the placental bed to predict preeclampsia: does pregnancy-associated plasma protein a or uterine artery Doppler sonography help? AB - OBJECTIVES: The purpose of this study was to compare the use of vascular indices derived from the whole placenta to those from the placental bed only for predicting preeclampsia and to determine whether the addition of pregnancy associated plasma protein A (PAPP-A) and mean uterine artery Doppler values improves prediction. METHODS: We conducted a secondary analysis of a prospective cohort of women with singletons between 11 and 14 weeks' gestation undergoing sonography for aneuploidy screening. Placental vascularization indices from the whole placenta versus the placental bed were combined with first-trimester maternal serum PAPP-A levels, mean uterine artery Doppler values, or the combination of both to predict the development of preeclampsia or early preeclampsia (delivery <34 weeks). The predictive ability of each vascular index was calculated by using areas under receiver operating characteristic curves. The sensitivity of the model for predicting preeclampsia and early preeclampsia at fixed false-positive rates of 10% and 20% was calculated. RESULTS: Of 570 women, 48 (8.4%) had preeclampsia, and 10 (1.7%) had early preeclampsia. The area under the curve and sensitivity values for the prediction of preeclampsia or early preeclampsia were not different when evaluating the whole placenta versus the placental bed. Additionally, there was no significant improvement when adding PAPP-A, uterine artery Doppler values, or both. The variables in the model were more sensitive for the prediction of early preeclampsia than preeclampsia. CONCLUSIONS: Although placental bed vascular indices are modestly predictive of preeclampsia, the addition of PAPP-A and uterine artery Doppler values to vascularization indices in the whole placenta or the placental bed did not significantly improve their predictive ability. PMID- 26014315 TI - Fetal weight estimation in diabetic pregnancies using the gestation-adjusted projection method: comparison of two timing strategies for third-trimester sonography. AB - OBJECTIVES: The gestation-adjusted projection method extrapolates birth weight using third-trimester sonography. This technique is shown to be more accurate for sonographic examinations from 34 weeks to 36 weeks 6 days than 37 weeks to 38 weeks 6 days. Our objective was to determine whether even earlier sonographic examinations (31 weeks-33 weeks 6 days) further improves birth weight prediction in patients with diabetes. METHODS: We conducted a retrospective cohort analysis of 388 pregnant women with pregestational or gestational diabetes who delivered at 37 weeks or later and had a sonographic examination performed between 31 weeks and 36 weeks 6 days. Sonographic examinations were categorized as "early" if performed at 31 weeks to 33 weeks 6 days or "late" if performed at 34 weeks to 36 weeks 6 days. We estimated birth weight using the gestation-adjusted projection method, compared errors in prediction of birth weight using the t test and Mann Whitney U test, and performed a 2-sample test of proportions to compare prediction of macrosomia (birth weight >4000 g). RESULTS: The early and late groups had similar mean gestational ages at birth (38 weeks 4 days versus 38 weeks 5 days; P = .13) and rates of macrosomia (10.7% versus 12.4%; P = .63). The early group had a greater mean absolute error (336 versus 297 g; P = .03) and percent error (9.9% versus 7.9%; P = .01) in birth weight prediction but a lower mean birth weight (3303 versus 3426 g; P = .02). Sensitivity for prediction of macrosomia was 19% in the early group versus 45% in the late group (P = .07), whereas specificity was similar (98% versus 96%; P = .27). CONCLUSIONS: Using the gestation-adjusted projection method in our patients with diabetes, we found that sonographic examinations performed at 34 weeks to 36 weeks 6 days better predicted birth weight than those performed at 31 weeks to 33 weeks 6 days. PMID- 26014316 TI - Gestational age at cervical length and fetal fibronectin assessment and the incidence of spontaneous preterm birth in twins. AB - OBJECTIVES: To estimate the risk of spontaneous preterm birth in twin pregnancies based on transvaginal sonographic cervical length, fetal fibronectin (fFN) testing, and the gestational age at which these tests were performed. METHODS: Women with twin pregnancies, cervical length assessment, and fFN testing between 22 weeks and 31 weeks 6 days in a single maternal-fetal medicine practice from 2005 to 2013 were included. All testing was done on asymptomatic women on an out patient basis. Women with monochorionic monoamniotic twins and twin-twin transfusion were excluded. Logistic regression analysis was used to estimate the risk of spontaneous preterm birth before 35, 32, and 28 weeks. RESULTS: Six hundred eleven patients were included and underwent a total of 2406 cervical length measurements and 2279 fFN tests over the course of the study period. The likelihood values for spontaneous preterm birth before 35, 32, and 28 weeks were 19.1%, 6.3%, and 2.3%, respectively. The risk of spontaneous preterm birth before 35 weeks increased with a decreasing cervical length (coefficient for the log of the odds ratio [OR coefficient], -0.13; P < .01; 95% confidence interval [CI], 0.22 to -0.037), a positive fFN result (OR coefficient, 1.04; P < .01; 95% CI, 0.45 to 1.64), as well as earlier gestational ages at testing (OR coefficient, 0.214; P < .01; 95% CI, -0.33 to -0.10). Similar results were seen for spontaneous preterm birth before 32 and 28 weeks. CONCLUSIONS: In asymptomatic patients with twin pregnancies, the cervical length, fFN, and gestational age are all significantly associated with spontaneous preterm birth. PMID- 26014317 TI - Ultrasound-guided aspiration of adnexal cysts with a low risk of malignancy: is it a recommendable option? AB - OBJECTIVES: The purpose of this study was to establish the viability of ultrasound (US)-guided adnexal cyst aspiration and identify a target group in which this procedure would be advisable. METHODS: A prospective cohort of 96 women with a low risk of malignant adnexal cysts was studied between 2002 and 2009, using recurrence after the procedure as the primary outcome measure. All procedures were performed on an outpatient basis without anesthesia. Patients were followed by US imaging at 6, 12, 24, 48, and 72 months. Potential risk factors for recurrence (menopausal status, previous hysterectomy, symptoms, US pattern, cyst diameter, and aspirated fluid volume and color) were analyzed by multivariate logistic regression. The association between recurrence and cyst size was calculated by Kaplan-Meier curves. RESULTS: The median diameter of the cysts was 61 (range, 30-150) mm. Multivariate logistic regression analysis showed that an increased risk of recurrence was associated with a cyst diameter of greater than 70 mm (odds ratio, 4.2; 95% confidence interval, 1.2-14.1) and the presence of symptoms (odds ratio, 5.03; 95% confidence interval, 1.02-24.6). The median follow-up time was 24 (range, 2-78) months. Surgery was avoided in 64 patients (73.6%). Full cyst recurrence was observed in 34 patients (39.0%). CONCLUSIONS: Ultrasound-guided aspiration is a viable alternative to surgery for treatment of adnexal cysts with a low risk of malignancy, especially when the cyst diameter is less than 70 mm. PMID- 26014318 TI - Initial experience with the New York State breast density inform law at a community-based breast center. AB - OBJECTIVES: The purpose of this study was to review our initial experience with the New York State breast density inform law (New York public health law, S2404 C) at our outpatient breast center. We sought to review the findings in patients returning for screening breast sonography after a screening mammogram revealed heterogeneously dense or extremely dense breast tissue. METHODS: From January 1, 2013, through May 31, 2014, 102,841 patients who underwent screening mammography were seen at our institution. Of these, 35,153 were determined to have heterogeneously dense breast tissue, and 11,864 were determined to have extremely dense breast tissue. Due to the New York State breast density inform law, these 47,017 patients were notified of their breast density, with 935 patients (2%) returning for 971 screening breast sonographic examinations. RESULTS: Heterogeneously dense breast tissue was noted in 66% of the patients (619), and extremely dense breast tissue was noted in 34% (316). Thirty-one percent of the patients (290) reported no additional risk factors; 68% (635) presented with 1 or more additional risk factors; and 1% (10) were adopted, and the risk status could not be assessed. Twenty-five procedures (2.6%) were performed after screening breast sonography, resulting in 22 benign findings, 1 atypical finding, and 2 malignancies. The overall positive predictive value was 8% (2 of 25), and the overall cancer detection rate was 2.1 per 1000 (2 of 935). CONCLUSIONS: Handheld screening breast sonography performed in women with dense breast tissue can aid in the detection of otherwise occult breast cancer, as we found 2 cancers in the study population, with an overall positive predictive value of 8%. The addition of screening sonography in this cohort did lead to an increase in minimally invasive procedures in 2.6%. PMID- 26014319 TI - Sonographic features of medullary thyroid carcinomas according to tumor size: comparison with papillary thyroid carcinomas. AB - OBJECTIVES: The aim of this study was to evaluate the differences in sonographic features of medullary thyroid carcinomas according to nodule size and compared with findings for papillary thyroid carcinomas. METHODS: This study included 38 medullary thyroid carcinoma nodules and 91 papillary thyroid carcinoma nodules, which were confirmed by pathologic examination between May 2008 and September 2013. Nodules were divided into those that were greater than 10 mm (large nodules) and 10 mm or less (small nodules). The differences in sonographic features (composition, echogenicity, margin, calcifications, and shape) between groups were analyzed with a chi(2) test. RESULTS: Large medullary thyroid carcinomas more frequently showed an ovoid-to-round shape and a smooth margin; small medullary thyroid carcinomas more frequently showed a taller-than-wide shape and a spiculated margin; the differences were statistically significant between the groups (P < .05). Compared with papillary thyroid carcinomas, large medullary thyroid carcinomas tended to have an ovoid-to-round shape, a smooth margin, and macrocalcifications and were more frequently diagnosed as indeterminate nodules (P < .05); however, there were no significant differences in the internal composition, calcifications, echogenicity, margin, and shape between small medullary thyroid carcinomas and small papillary thyroid carcinomas (P > .05). CONCLUSIONS: Our data indicate that the sonographic features of medullary thyroid carcinomas are associated with tumor size; furthermore, the sonographic features of medullary thyroid carcinomas are similar to those of small papillary thyroid carcinomas but greatly different from those of large papillary thyroid carcinomas. Large medullary thyroid carcinomas are more commonly diagnosed as indeterminate nodules by sonography than large papillary thyroid carcinomas, and fine-needle aspiration biopsy or serum calcitonin measurement may be helpful. PMID- 26014320 TI - Shooting with sound: optimizing an affordable ballistic gelatin recipe in a graded ultrasound phantom education program. AB - OBJECTIVES: The goal of this study was to investigate the durability and longevity of gelatin formulas for the production of staged ultrasound phantoms for education. METHODS: Gelatin phantoms were prepared from Knox gelatin (Kraft Foods, Northfield, IL) and a standard 10%-by-mass ordinance gelatin solution. Phantoms were durability tested by compressing to a 2-cm depth until cracking was visible. Additionally, 16 containers with varying combinations of phenol, container type, and storage location were tested for longevity against desiccation and molding. Once formulation was determined, 4 stages of phantoms from novice to clinically relevant were poured, and clinicians with ultrasound training ranked them on a 7-point Likert scale based on task difficulty, phantom suitability, and fidelity. RESULTS: On durability testing, the ballistic gelatin outperformed the Knox gelatin by more than 200 compressions. On longevity testing, gelatin with a 0.5% phenol concentration stored with a lid and refrigeration lasted longest, whereas containers without a lid had desiccation within 1 month, and those without phenol became moldy within 6 weeks. Ballistic gelatin was more expensive when buying in small quantities but was 7.4% less expensive when buying in bulk. The staged phantoms were deemed suitable for training, but clinicians did not consistently rank the phantoms in the intended order of 1 to 4 (44%). CONCLUSIONS: Refrigerated and sealed ballistic gelatin with phenol was a cost-effective method for creating in-house staged ultrasound phantoms suitable for large-scale ultrasound educational training needs. Clinician ranking of phantoms may be influenced by current training methods that favor biological tissue scanning as easier. PMID- 26014321 TI - A Randomized Controlled Trial Evaluating the See, Tilt, Align, and Rotate (STAR) Maneuver on Skill Acquisition for Simulated Ultrasound-Guided Interventional Procedures. AB - OBJECTIVES: Achieving the best view of the needle and target anatomy when performing ultrasound-guided interventional procedures requires technical skill, which novices may find difficult to learn. We hypothesized that teaching novice performers to use 4 sequential steps (see, tilt, align, and rotate [STAR] method) to identify the needle under ultrasound guidance is more efficient than training with the commonly described probe movements of align, rotate, and tilt (ART). METHODS: This study compared 2 instructional methods for transducer manipulation including alignment of a probe and needle by novices during a simulated ultrasound-guided nerve block. Right-handed volunteers between the ages of 18 and 55 years who had no previous ultrasound experience were recruited and randomized to 1 of 2 groups; one group was trained to troubleshoot misalignment with the ART method, and the other was trained with the new STAR maneuver. Participants performed the task, consisting of directing a needle in plane to 3 targets in a standardized gelatin phantom 3 times. The performance assessor and data analyst were blinded to group assignment. RESULTS: Thirty-five participants were recruited. The STAR group was able to complete the task more quickly (P < .001) and visualized the needle in a greater proportion of the procedure time (P = .004) compared to the ART group. All STAR participants were able to complete the task, whereas 41% of ART participants abandoned the task (P = .003). CONCLUSIONS: Novices are able to complete a simulated ultrasound-guided nerve block more quickly and efficiently when trained with the 4-step STAR maneuver compared to the ART method. PMID- 26014322 TI - Sonographic findings in the ulnar nerve according to the electrophysiologic stage of carpal tunnel syndrome. AB - OBJECTIVES: Involvement of the ulnar nerve in patients with carpal tunnel syndrome is controversial. The aim of our study was to evaluate sonographic findings in the ulnar nerve in patients with carpal tunnel syndrome. METHODS: We performed median and ulnar nerve conduction studies with sonography in 109 hands of 60 patients with clinically suspected carpal tunnel syndrome. Sonographic findings were analyzed with regard to electrophysiologic stages of carpal tunnel syndrome. RESULTS: We found that the sensory conduction velocity of the ulnar nerve decreased as the electrophysiologic stage of carpal tunnel syndrome increased (P = .038), but there was no change in the cross-sectional area of the ulnar nerve at the wrist. The median-to-ulnar nerve cross-sectional area ratio at the wrist showed a significant correlation with the electrophysiologic stage of carpal tunnel syndrome (Spearman r = 0.431; P < .0001), in addition to the median nerve cross-sectional area at the wrist and the wrist-to- forearm median nerve cross-sectional area ratio. CONCLUSIONS: In our study, ulnar nerve involvement in patients with carpal tunnel syndrome was shown electrophysiologically but not sonographically. These results suggest that morphologic changes in the ulnar nerve do not occur in carpal tunnel syndrome, although functional changes may occur. PMID- 26014323 TI - Dedicated training program for shoulder sonography: the results of a quality program reverberate with everyone. AB - OBJECTIVES: The purpose of this study was to define and report on the effect of a comprehensive musculoskeletal sonography training program to improve accuracy (sensitivity and specificity) for the diagnosis of rotator cuff tears in relatively inexperienced operators. METHODS: Before the training program was implemented, radiologists (n = 12) had a mean of 2 years (range, <1-12 years) of experience performing and interpreting musculoskeletal sonography. Pre- and post training shoulder sonographic results were compared to surgical reports or, in their absence, to shoulder magnetic resonance imaging or computed tomographic arthrographic results if within 2 months of the sonographic examination. A total of 82 patients were included in the pre-training group (January 2010-December 2011), and 50 patients were included in the post-training group (January 2012 June 2013). The accuracy, sensitivity, specificity, and positive and negative predictive values were determined for the presence or absence of supraspinatus and infraspinatus tendon tears. RESULTS: After implementation of the training program, the sensitivity of sonography for detecting full-thickness rotator cuff tears increased by 14%, and the sensitivity for detecting partial-thickness rotator cuff tears increased by 3%. CONCLUSIONS: Quality improvement programs and acquisition standardization along with ongoing, focused case conferences for the entire care team increased the sensitivity of shoulder sonography for diagnosing both full- and partial-thickness rotator cuff tears, independent of the years of operator experience. PMID- 26014324 TI - Effects of low-intensity pulsed ultrasound on spinal pseudarthrosis created by nicotine administration: a model of lumbar posterolateral pseudarthrosis in rabbits. AB - OBJECTIVES: Low-intensity pulsed ultrasound (US) can enhance spinal fusion and fracture healing; however, its effect on spinal pseudarthrosis has not been reported in the literature. We hypothesized that low-intensity pulsed US could overcome spinal pseudarthrosis created by nicotine administration. METHODS: Thirty-two rabbits underwent posterolateral fusion with an iliac bone graft and nicotine administration. At 5 weeks, the spines were examined by computed tomography (CT) to determine the presence of pseudarthrosis. All rabbits with pseudarthrosis were randomly divided into groups A, B, C, and D according to treatment: no second graft, iliac autograft only, low-intensity pulsed US only, and iliac autograft and low-intensity pulsed US, respectively. At 10 weeks, the rabbits were euthanized, and the specimens were assessed with radiography, CT, manual palpation, and histologic analysis. RESULTS: One rabbit was lost because of severe infection. Twenty-seven (87%) had pseudarthrosis on CT at 5 weeks. On manual palpation at 10 weeks, the fusion rates were 0%, 29%, 0%, and 57% in groups A, B, C, and D, respectively. Group D had highest radiographic scores (mean +/- SD, 2.87 +/- 0.92), and the difference was statistically significant compared to the other groups (P < .001). Computed tomography confirmed that group D had the most fused segments at 10 weeks. Histologic specimens from group D also showed the most mature bone formation inside the fusion mass. CONCLUSIONS: Low intensity pulsed US can enhance spinal fusion but cannot overcome spinal pseudarthrosis created by nicotine administration. Stopping nicotine consumption or administering a more powerful bone substitute might be an alternative method for overcoming spinal pseudarthrosis. PMID- 26014325 TI - Improved method for calculating hepatic steatosis using the hepatorenal index. AB - OBJECTIVES: Marshall et al (AJR Am J Roentgenol 2012; 199:997-1002) initially demonstrated that the hepatorenal index is an effective and noninvasive tool to screen patients for hepatic steatosis. The aim of this study was to determine whether the hepatorenal index can be accurately calculated directly from a picture archiving and communication system (PACS) quickly and efficiently without the need for the multiple steps and specialized software used to calculate hepatorenal index in the study by Marshall et al. METHODS: We evaluated 99 of the 101 patients included in the study by Marshall et al: patients being followed by hepatologists with plans for liver biopsy. The hepatorenal index was calculated by using Digital Imaging and Communications in Medicine (DICOM) images from a PACS and a markup region-of-interest tool. We compared this value to the value that Marshall et al derived by using specialized software and to standard histologic estimates. We created similar subgroups: patients with steatosis based on histologically estimated intracellular fat exceeding 5% and patients without steatosis. RESULTS: The mean hepatorenal index +/- SD for those with steatosis according to histologic findings was 1.87 +/- 0.6, and for those without, it was 1.14 +/- 0.2. A hepatorenal index of 1.34 or higher had 92% sensitivity for identifying fat exceeding 5%, 85% specificity, a 94% negative predictive value, and a 79% positive predictive value. Substantial agreement was found between the hepatorenal index calculated from DICOM images and macrovesicular fat categorized at the cut point of 1.34 or higher (kappa = 0.76; 95% confidence interval, 0.62 0.88; P < .001). CONCLUSIONS: The hepatorenal index can be quickly and accurately calculated from DICOM images directly on a PACS without supplementary software. PMID- 26014326 TI - Differential diagnosis of polypoid lesions of the gallbladder using contrast enhanced sonography. AB - OBJECTIVES: The purpose of this study was to evaluate the usefulness of real-time contrast-enhanced sonography and microvascular imaging for differential diagnosis of neoplastic and non-neoplastic polypoid lesions of the gallbladder. METHODS: Real-time contrast-enhanced sonography and microvascular imaging were performed in 128 patients with polypoid lesions of the gallbladder larger than 6 mm in diameter. The enhancement patterns, microvascular imaging types, and kinetic parameters were analyzed on contrast-enhanced sonography. The maximum diameters of the lesions measured by conventional and contrast-enhanced sonography were also recorded and subjected to a comparative analysis. RESULTS: Among the 128 patients, histologic diagnoses were obtained in 83 (27 neoplastic lesions and 56 non-neoplastic lesions), which constituted the study group. On contrast-enhanced sonography, mild enhancement and absence of contrast were more easily found in non-neoplastic lesions (12 [21.4%]), whereas all neoplastic lesions showed marked enhancement (27 [100%]; P = .006). Of the 27 neoplastic lesions, 6 malignant tumors showed a perfusion defect on contrast-enhanced sonography, whereas none of the non-neoplastic lesions showed a perfusion defect (P = .003). The microvascular architecture of the lesions was categorized into 4 types: spotty, linear, branched, and spinous, and there were significant differences between the groups (P< .001). In a kinetic evaluation, none of the parameters reached statistical significance (all P> .05). There was a discrepancy in maximum diameters between conventional and contrast-enhanced sonography in both groups but the discrepancy was significantly greater in the non-neoplastic group (P = .026). CONCLUSIONS: Contrast-enhanced sonography is a useful imaging technique and an adjunct to conventional sonography for differential diagnosis of neoplastic and non-neoplastic polypoid lesions of the gallbladder. PMID- 26014327 TI - Identification of implanted mesh after incisional hernia repair using an automated breast volume scanner. AB - OBJECTIVES: This study aimed to evaluate the utility of an automated breast volume scanner (ABVS) versus handheld ultrasound (US) for identifying implanted mesh after incisional hernia repair. METHODS: In vitro, the appearances of 3 samples of different flat mesh and a mesh plug on both ABVS and handheld US examinations were evaluated. In vivo, 97 patients received both ABVS and handheld US examinations in the incisional region. The frequency used for handheld US was 11 MHz. The presence of the previously implanted mesh in the incisional region was evaluated and compared between the US modalities. The identified results were confirmed by surgical findings. RESULTS: In the in vitro study, the ABVS had more visualized and efficient imaging results for implanted mesh than handheld US. In the in vivo study, among 97 cases, 39 and 32 were identified as regions with mesh by the ABVS and handheld US, respectively. The ABVS had better identification performance than handheld US in terms of accuracy (94.8% versus 83.5%), sensitivity (90.5% versus 69.0%), and specificity (98.2% versus 94.5%). The kappa values showed that handheld US had substantial agreement with surgical findings (kappa = 0.78; 95% confidence interval, 0.66-0.90), whereas the ABVS had almost perfect agreement with surgical findings (kappa = 0.93; 95% confidence interval, 0.86-1.00). More importantly, the ABVS could display the texture of lightweight mesh in the coronal plane. The specificity and sensitivity for mesh texture were 100.0% (55 of 55) and 94.4% (17 of 18), respectively. CONCLUSIONS: The use of an ABVS may help identify the presence of implanted mesh after incisional hernia repair in some cases in which the implant is difficult to appreciate on handheld US imaging with an 11-MHz transducer. PMID- 26014328 TI - Distribution of Epididymal Involvement in Mumps Epididymo-orchitis. AB - OBJECTIVES: To evaluate characteristic sonographic findings for mumps orchitis with epididymal involvement. METHODS: This study included 18 patients (aged 12-18 years) with mumps orchitis. We assessed the volume, echogenicity, and vascularity of the testes and the transverse diameter, echogenicity, and vascularity of the epididymal head, body, and tail. We classified 4 types of epididymal involvement: 1A, focal swelling of the epididymal head with hypervascularity only on the swollen head; 1B, focal swelling of the epididymal head with hypervascularity on the entire epididymis; 1C, diffuse swelling of the entire epididymis with hypervascularity; and 2, no epididymal involvement. The Student t test was used to evaluate the significance of the size of each part of the epididymis and the epididymal head-to-tail diameter ratio. RESULTS: Orchitis was unilateral in 13 patients and bilateral in 5. Of 23 affected hemiscrotums, 7 (30.4%) were type 1A, 4 (17.4%) type 1B, 2 (8.7%) type 1C, and 10 (43.5%) type 2. In 11 patients with unilateral epididymal involvement, the mean diameters +/- SDs of the epididymal heads on the affected and contralateral sides were 1.11 +/- 0.19 (range, 0.7-1.7) and 0.65 +/- 0.14 (0.3-0.9) cm (significantly different, P <.001). The diameters of the epididymal tails on the affected and contralateral sides were 0.51 +/- 0.41 (0.2-0.8) and 0.46 +/- 0.21 (0.3-0.6) cm (not statistically different, P = .106). The mean head-to-tail ratios on the affected and contralateral sides were 2.28 +/- 0.49 (1.29-3.00) and 1.41 +/- 0.22 (1.00-1.75; significantly different, P < .001). In all types 1A and 1B, the ratio was higher than 2.00; in 22 of 23 unaffected epididymides, the ratio was lower than 2.00. CONCLUSIONS: Focal swelling of epididymal heads was a characteristic sonographic finding of mumps epididymo-orchitis, and a head-to-tail ratio higher than 2.00 can be a useful diagnostic finding. PMID- 26014329 TI - The baseline diameter of the inferior vena cava measured by sonography increases with age in normovolemic children. AB - OBJECTIVES: To evaluate normative sonographic measurements of the inferior vena cava (IVC) diameter in healthy pediatric patients. METHODS: We performed a prospective observational study of a convenience sample of healthy patients between the ages of 0 and 22 years presenting to a pediatric emergency department. Exclusion criteria included abnormal vital signs, pregnancy, or illnesses thought to influence volume status. During quiet respiration, the maximum and minimum IVC diameters were measured in the sagittal plane distal to the hepatic vein-IVC junction. As second measurements, the maximum diameters of the IVC and aorta were measured in the transverse plane distal to the insertion of the left renal vein into the IVC. RESULTS: From February 2013 through April 2014, 63 children (51% female; mean age, 11 years) were enrolled. There were 20 children in each age group of 2 to 7, 7 to 12, and 12 to 22 years. The correlations between IVC and aortic diameters as a function of age were calculated using the Spearman rank correlation coefficient. The correlation coefficients were all statistically significant (P < .001): sagittal maximum IVC diameter (0.81), sagittal minimum IVC diameter (0.79), transverse maximum IVC diameter (0.79), and transverse maximum aortic diameter (0.81). CONCLUSIONS: This pilot study of sonographic measurements of the IVC diameter in normovolemic children suggests a statistically significant positive correlation between age and IVC diameter. Future studies should focus on multicenter enrollment, children in the youngest age group, and the development of normative growth curves for the IVC by age, sex, and body mass index. PMID- 26014330 TI - Chronic cerebrospinal venous insufficiency: pitfalls and perils of sonographic assessment. AB - OBJECTIVES: Duplex sonography has been proposed as a diagnostic modality for detection of chronic cerebrovascular venous insufficiency, a recently proposed hypothesis of multiple sclerosis (MS) pathogenesis. We reviewed potential challenges of duplex sonography for diagnosis of chronic cerebrovascular venous insufficiency and used interim pooled data from a study aimed to apply cerebrovascular venous insufficiency criteria to a group of patients with MS and control patients without MS. METHODS: Duplex sonography for chronic cerebrovascular venous insufficiency was performed in patients with MS and controls. Extracranial and deep cerebral veins were studied by using a published chronic cerebrovascular venous insufficiency protocol and criteria. Comparative imaging was performed to explore how physiologic factors and imaging techniques could affect key parameters. The effects of varying definitions on fulfilling chronic cerebrovascular venous insufficiency diagnostic criteria were also explored. RESULTS: Forty-two patients were enrolled. Twenty-five (60%) had a reduction in internal jugular vein cross-sectional area by 50% or more, cross sectional area of 0.3 cm(2) or less, and/or a B-mode abnormality. No patients had reflux longer than 0.88 seconds in both sitting and supine positions, the presence of duplex sonographic reflux on transcranial Doppler imaging, or a larger internal jugular vein cross-sectional area in the sitting versus supine position. Fourteen patients (33.3%) had either a flap or septum, and 1 had a web. Collateral veins to the vertebral veins were identified in 14 of 42 patients (33.3%). The use of transcranial Doppler imaging versus quality Doppler profiles resulted in fewer patients meeting criteria for chronic cerebrovascular venous insufficiency. CONCLUSIONS: There are several important variables, including physiologic, technical, and criterion definitions, in the application of sonographic assessment of chronic cerebrovascular venous insufficiency that may affect diagnostic accuracy. PMID- 26014331 TI - Comparative sonographic study of cerebral hemodynamic differences and changes after oxygen therapy in healthy youths of different ethnicities in Tibet. AB - OBJECTIVES: The purpose of this study was to sonographically assess the cerebral hemodynamic differences and changes after oxygen therapy in healthy youths of different ethnicities in Tibet. METHODS: Sixty-six healthy young Han visitors and 29 healthy young Tibetan residents were divided into 4 groups. Basic information was collected. Pulsed Doppler sonography was used to record the cerebral hemodynamic parameters for the internal carotid, vertebral, and middle cerebral arteries. The participants were then instructed to inhale oxygen, and basic information and cerebral hemodynamic parameters were recorded at 1, 2, 4, and 8 minutes, respectively. Differences in these parameters between groups were analyzed. RESULTS: In comparisons of the flow parameters between sex-matched groups, the mean resistive index values for the internal carotid, vertebral, and middle cerebral arteries in the Han groups were significantly lower than those in the Tibetan groups (P <. 05). The mean peak systolic velocity, end-diastolic velocity, and mean velocity values for the middle cerebral artery in the Han groups were significantly higher than those in the Tibetan groups (P < .05). After oxygen uptake, there were no significant differences in the mean arterial oxygen saturation, heart rate, mean velocity, and resistive index values between the male groups, and similar changes were found for the arterial oxygen saturation and peak systolic velocity values between female groups after 8 minutes of oxygen uptake (P > .05). CONCLUSIONS: Sonography is a useful modality for noninvasive and real-time detection of changes in cerebral hemodynamics and can provide reference values for the prevention and treatment of cerebrovascular diseases. PMID- 26014332 TI - Contrast Ultrasound Imaging of the Aorta Does Not Affect Progression of Atherosclerosis or Cardiovascular Biomarkers in ApoE-/- Mice. AB - OBJECTIVES: Ultrasound contrast agents (UCAs) enhance cardiovascular ultrasound imaging. Adverse biological effects have occurred after administration of UCAs, and more research is needed for a comprehensive understanding of the risks involved. We used the ApoE(-/-) mouse model of atherosclerosis to characterize the effects of ultrasound and UCAs on atherosclerosis and plasma biomarkers. METHODS: Male ApoE(-/-) mice (8 weeks old; n = 24) were intravenously infused with a UCA (2 * 10(10) Definity microbubbles per hour; Lantheus Medical Imaging, North Billerica, MA) and exposed to 2.8-MHz center frequency ultrasound (10 Hz pulse repetition frequency, 1.4 microseconds pulse duration, 2 minutes exposure duration, and 2 sites) at 1 of 3 derated peak rarefactional pressure amplitudes (0, 1.9, or 3.8 MPa), and then consumed either a chow or Western diet for 4 weeks (n = 4 per group). Blood plasma samples were collected before ultrasound exposure and at 2 and 4 weeks after exposure and assayed for total cholesterol and von Willebrand Factor (vWF). A pathologist measured atheroma thickness in formalin fixed, hematoxylin-eosin-stained transverse aorta sections and scored them for severity of atherosclerosis. RESULTS: Plasma total cholesterol initially averaged 286 mg/dL in the Western diet group and increased to 861 mg/dL after 4 weeks on the diet (P < .0001). Total cholesterol did not increase significantly in the chow diet group. Plasma vWF increased after 2 weeks on the Western diet (P < .0001). Atheroma thickness was greater in animals consuming the Western diet than in chow-fed animals (P < .05). Ultrasound had no significant effect on plasma total cholesterol, plasma vWF, or atheroma thickness. CONCLUSIONS: Contrast ultrasound did not increase the severity of atherosclerosis or alter cardiovascular biomarkers in the ApoE(-/-) mouse model. PMID- 26014333 TI - Shear wave dispersion in lean versus steatotic rat livers. AB - OBJECTIVES: The precise measurement of fat accumulation in the liver, or steatosis, is an important clinical goal. Our previous studies in phantoms and mouse livers support the hypothesis that, starting with a normal liver, increasing accumulations of microsteatosis and macrosteatosis will increase the lossy viscoelastic properties of shear waves in a medium. This increase results in an increased dispersion (or slope) of the shear wave speed in the steatotic livers. METHODS: In this study, we moved to a larger animal model, lean versus obese rat livers ex vivo, and a higher-frequency imaging system to estimate the shear wave speed from crawling waves. RESULTS: The results showed elevated dispersion in the obese rats and a separation of the lean versus obese liver parameters in a 2-dimensional parameter space of the dispersion (slope) and shear wave speed at a reference frequency of 150 Hz. CONCLUSIONS: We have confirmed in 3 separate studies the validity of our dispersion hypothesis in animal models. PMID- 26014334 TI - Five cases of axillary lymph node metastatic breast cancer on contrast-enhanced sonography. AB - This study was performed to determine the importance of contrast-enhanced sonography for axillary lymph node metastatic breast cancer. Contrast-enhanced sonographic findings in 5 patients with breast cancer and axillary lymph node metastasis are discussed, and imaging-pathologic correlations are also presented in 3 cases. In all 5 cases, lymph nodes showed a perfusion defect in the late phase. Rapid arterial enhancement and wash-out were observed in 2 cases in which we performed second injections. Contrast-enhanced sonography may be effective for identifying metastatic lesions in lymph nodes, especially in the early stages. PMID- 26014336 TI - The irregular diaphragmatic pleural interface: a novel sonographic sign facilitating the diagnosis of pneumonia. AB - Pneumonia, a disease that has been reported to be the sixth leading cause of death in the United States, has worsening mortality with delays in diagnosis. As the history and physical examination are excessively inaccurate in the diagnosis of pneumonia, we often rely on chest radiography to rule in or out disease. However, it is found to lack sufficient accuracy when computed tomography is used as the reference standard. Sonography has emerged as a viable alternative to chest radiography in the diagnosis of pneumonia. Here, we describe a novel sonographic sign that can be used to assist in the diagnosis of pneumonia. PMID- 26014335 TI - Grayscale and color Doppler features of testicular lymphoma. AB - Pooled data from 16 radiology centers were retrospectively analyzed to seek patients with pathologically proven testicular lymphoma and grayscale and color Doppler images available for review. Forty-three cases were found: 36 (84%) primary and 7 (16%) secondary testicular lymphoma. With unilateral primary lymphoma, involvement was unifocal (n = 10), multifocal (n = 11), or diffuse (n = 11). Synchronous bilateral involvement occurred in 6 patients. Color Doppler sonography showed normal testicular vessels within the tumor in 31 of 43 lymphomas (72%). Testicular lymphoma infiltrates through the tubules, preserving the normal vascular architecture of the testis. Depiction of normal testicular vessels crossing the lesion is a useful adjunctive diagnostic criterion. PMID- 26014337 TI - Calibration of the Dutch-Flemish PROMIS Pain Behavior item bank in patients with chronic pain. AB - BACKGROUND: The aims of the current study were to calibrate the item parameters of the Dutch-Flemish PROMIS Pain Behavior item bank using a sample of Dutch patients with chronic pain and to evaluate cross-cultural validity between the Dutch-Flemish and the US PROMIS Pain Behavior item banks. Furthermore, reliability and construct validity of the Dutch-Flemish PROMIS Pain Behavior item bank were evaluated. METHODS: The 39 items in the bank were completed by 1042 Dutch patients with chronic pain. To evaluate unidimensionality, a one-factor confirmatory factor analysis (CFA) was performed. A graded response model (GRM) was used to calibrate the items. To evaluate cross-cultural validity, Differential item functioning (DIF) for language (Dutch vs. English) was evaluated. Reliability of the item bank was also examined and construct validity was studied using several legacy instruments, e.g. the Roland Morris Disability Questionnaire. RESULTS: CFA supported the unidimensionality of the Dutch-Flemish PROMIS Pain Behavior item bank (CFI = 0.960, TLI = 0.958), the data also fit the GRM, and demonstrated good coverage across the pain behavior construct (threshold parameters range: -3.42 to 3.54). Analysis showed good cross-cultural validity (only six DIF items), reliability (Cronbach's alpha = 0.95) and construct validity (all correlations >=0.53). CONCLUSIONS: The Dutch-Flemish PROMIS Pain Behavior item bank was found to have good cross-cultural validity, reliability and construct validity. The development of the Dutch-Flemish PROMIS Pain Behavior item bank will serve as the basis for Dutch-Flemish PROMIS short forms and computer adaptive testing (CAT). PMID- 26014338 TI - The mitochondrion is a common target of disease pathophysiology in pemphigus and pemphigoid. PMID- 26014339 TI - Improving patient satisfaction through physician education, feedback, and incentives. AB - BACKGROUND: Patient satisfaction has been associated with improved outcomes and become a focus of reimbursement. OBJECTIVE: Evaluate an intervention to improve patient satisfaction. DESIGN: Nonrandomized, pre-post study that took place from 2011 to 2012. SETTING: Large tertiary academic medical center. PARTICIPANTS: Internal medicine (IM) resident physicians, non-IM resident physicians, and adult patients of the resident physicians. INTERVENTION: IM resident physicians were provided with patient satisfaction education through a conference, real-time individualized patient satisfaction score feedback, monthly recognition, and incentives for high patient-satisfaction scores. MAIN MEASURES: Patient satisfaction on physician-related and overall satisfaction questions on the HCAHPS survey. We conducted a difference-in-differences regression analysis comparing IM and non-IM patient responses, adjusting for differences in patient characteristics. KEY RESULTS: In our regression analysis, the percentage of patients who responded positively to all 3 physician-related Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) questions increased by 8.1% in the IM and 1.5% in the control cohorts (absolute difference 6.6%, P = 0.04). The percentage of patients who would definitely recommend this hospital to friends and family increased by 7.1% in the IM and 1.5% in the control cohorts (absolute difference 5.6%, P = 0.02). The national average for the HCAHPS outcomes studied improved by no more than 3.1%. LIMITATIONS: This study was nonrandomized and was conducted at a single site. CONCLUSION: To our knowledge, this is the first intervention associated with a significant improvement in HCAHPS scores. This may serve as a model to increase patient satisfaction, hospital revenue, and train resident physicians. PMID- 26014340 TI - Editorial: green chemistry and the environment. PMID- 26014341 TI - Return to activity among athletes with a symptomatic bipartite patella: a systematic review. AB - BACKGROUND: A bipartite patella is typically rare, but can become symptomatic during overuse activities such as those performed during athletic events. Therefore, this anomaly typically presents in the young, athletic population, often inhibiting athletic activities. Multiple treatment options exist, with nonsurgical management frequently adopted as the initial treatment of choice. PURPOSE: To determine the most effective intervention in returning athletes with symptomatic bipartite patella to their prior activity levels. METHODS: A systematic review of the literature was performed using PRISMA guidelines to identify studies reporting outcomes of athletes' ability to return to activity following treatment for a symptomatic bipartite patella. The type of intervention, type of bipartite classification, outcomes, and complications were recorded. RESULTS: Twenty articles with a total of 125 patients and 130 knees were identified and included in this review. A total of 105 athletes made a full return to athletic activity following treatment for their painful bipartite patella. One hundred athletes (85.5%) that underwent surgical treatment were able to make a full return to their sport without symptoms, although this varied by surgical procedure performed. Excision of the painful fragment produced the best results in returning athletes to sport, with 91% returning without symptoms and nine percent returning but with residual symptoms. CONCLUSION: Surgical treatments for symptomatic bipartite patellae are successful at returning athletes to their same level of play, and best outcomes are with excision of the fragment. These results are limited, however, due to the poor quality of original data given the rarity of the anomaly and the underrepresented conservative treatment group. PMID- 26014342 TI - Intraoperative joint gaps and mediolateral balance affect postoperative knee kinematics in posterior-stabilized total knee arthroplasty. AB - BACKGROUND: Adjusting joint gaps and establishing mediolateral (ML) soft tissue balance are considered essential interventions for better outcomes in total knee arthroplasty (TKA). However, the relationship between intraoperative laxity measurements and weightbearing knee kinematics has not been well explored. This study aimed to quantify the effect of intraoperative joint gaps and ML soft tissue balance on postoperative knee kinematics in posterior-stabilized (PS)-TKA. METHODS: We investigated 44 knees in 34 patients who underwent primary PS-TKA by a single surgeon. The central joint gaps and ML tilting angles at 0 degrees , 10 degrees , 30 degrees , 60 degrees , 90 degrees , 120 degrees and 135 degrees flexion were measured during surgery. At a minimum of two year follow-up, we analyzed in vivo kinematics of these knees and examined the influence of intraoperative measurements on postoperative kinematics. RESULTS: Gap difference of knee flexion at 135 degrees minus 0 degrees was correlated with the total posterior translation of lateral femoral condyle (r=0.336, p=0.042) and femoral external rotation (r=0.488, p=0.002) during squatting, anteroposterior position of lateral femoral condyle (r=-0.510, p=0.001) and maximum knee flexion (r=0.355, p=0.031) in kneeling. Similar correlations were observed between deep flexion gap differences with respect to the 90 degrees reference and postoperative knee kinematics. Well-balanced knees showed less anterior translation of medial femoral condyle in mid- to deep flexion, consistent femoral external rotation, and the most neutral valgus/varus rotation compared with unbalanced knees. CONCLUSION: These findings indicate the importance of adequate intraoperative joint gaps in deep flexion and ML soft tissue balance throughout the range of motion. PMID- 26014343 TI - Introducing the CJEM emergency medical services (EMS) series. PMID- 26014344 TI - Slow oscillating transcranial direct current stimulation during sleep has a sleep stabilizing effect in chronic insomnia: a pilot study. AB - Recent evidence suggests that lack of slow-wave activity may play a fundamental role in the pathogenesis of insomnia. Pharmacological approaches and brain stimulation techniques have recently offered solutions for increasing slow-wave activity during sleep. We used slow (0.75 Hz) oscillatory transcranial direct current stimulation during stage 2 of non-rapid eye movement sleeping insomnia patients for resonating their brain waves to the frequency of sleep slow-wave. Six patients diagnosed with either sleep maintenance or non-restorative sleep insomnia entered the study. After 1 night of adaptation and 1 night of baseline polysomnography, patients randomly received sham or real stimulation on the third and fourth night of the experiment. Our preliminary results show that after termination of stimulations (sham or real), slow oscillatory transcranial direct current stimulation increased the duration of stage 3 of non-rapid eye movement sleep by 33 +/- 26 min (P = 0.026), and decreased stage 1 of non-rapid eye movement sleep duration by 22 +/- 17.7 min (P = 0.028), compared with sham. Slow oscillatory transcranial direct current stimulation decreased stage 1 of non rapid eye movement sleep and wake time after sleep-onset durations, together, by 55.4 +/- 51 min (P = 0.045). Slow oscillatory transcranial direct current stimulation also increased sleep efficiency by 9 +/- 7% (P = 0.026), and probability of transition from stage 2 to stage 3 of non-rapid eye movement sleep by 20 +/- 17.8% (P = 0.04). Meanwhile, slow oscillatory transcranial direct current stimulation decreased transitions from stage 2 of non-rapid eye movement sleep to wake by 12 +/- 6.7% (P = 0.007). Our preliminary results suggest a sleep stabilizing role for the intervention, which may mimic the effect of sleep slow wave-enhancing drugs. PMID- 26014345 TI - Mitochondrial DNA mutations in neurodegeneration. AB - Mitochondrial dysfunction is observed in both the aging brain, and as a core feature of several neurodegenerative diseases. A central mechanism mediating this dysfunction is acquired molecular damage to mitochondrial DNA (mtDNA). In addition, inherited stable mtDNA variation (mitochondrial haplogroups), and inherited low level variants (heteroplasmy) have also been associated with the development of neurodegenerative disease and premature neural aging respectively. Herein we review the evidence for both inherited and acquired mtDNA mutations contributing to neural aging and neurodegenerative disease. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID- 26014346 TI - Different faces of mitochondrial DNA mutators. AB - A number of studies have shown that ageing is associated with increased amounts of mtDNA deletions and/or point mutations in a variety of species as diverse as Caenorhabditis elegans, Drosophila melanogaster, mice, rats, dogs, primates and humans. This detected vulnerability of mtDNA has led to the suggestion that the accumulation of somatic mtDNA mutations might arise from increased oxidative damage and could play an important role in the ageing process by producing cells with a decreased oxidative capacity. However, the vast majority of DNA polymorphisms and disease-causing base-substitution mutations and age-associated mutations that have been detected in human mtDNA are transition mutations. They are likely arising from the slight infidelity of the mitochondrial DNA polymerase. Indeed, transition mutations are also the predominant type of mutation found in mtDNA mutator mice, a model for premature ageing caused by increased mutation load due to the error prone mitochondrial DNA synthesis. These particular misincorporation events could also be exacerbated by dNTP pool imbalances. The role of different repair, replication and maintenance mechanisms that contribute to mtDNA integrity and mutagenesis will be discussed in details in this article. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID- 26014347 TI - Stem cells, mitochondria and aging. AB - Decline in metabolism and regenerative potential of tissues are common characteristics of aging. Regeneration is maintained by somatic stem cells (SSCs), which require tightly controlled energy metabolism and genomic integrity for their homeostasis. Recent data indicate that mitochondrial dysfunction may compromise this homeostasis, and thereby contribute to tissue degeneration and aging. Progeroid Mutator mouse, accumulating random mtDNA point mutations in their SSCs, showed disturbed SSC homeostasis, emphasizing the importance of mtDNA integrity for stem cells. The mechanism involved changes in cellular redox environment, including subtle increase in reactive oxygen species (H2O2and superoxide anion), which did not cause oxidative damage, but disrupted SSC function. Mitochondrial metabolism appears therefore to be an important regulator of SSC fate determination, and defects in it in SSCs may underlie premature aging. Here we review the current knowledge of mitochondrial contribution to SSC dysfunction and aging. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID- 26014349 TI - Bipolar disorder and antibodies against the N-methyl-d-aspartate receptor: A gate to the involvement of autoimmunity in the pathophysiology of bipolar illness. AB - The high prevalence of comorbidity between bipolar disorder (BD) and other medical conditions, including autoimmune diseases, supports the hypothesis of the nature of BD as a biological illness category. Hence, an immune dysregulation process may play an important role in the development of at least certain subtypes of BD. Increasing evidence also suggests that the N-methyl-d-aspartate receptor (NMDAR) may be relevant in the pathophysiology of BD. A possible key mechanism underlying the physiopathology of certain autoimmune diseases that may present with affective symptoms might be the production of anti-NMDAR auto antibodies (auto-Abs). The best characterized autoimmune anti-NMDAR disease is the anti-NMDAR encephalitis. It has been found that 4% of these patients present isolated, mostly affective, psychiatric manifestations during their illness. An interesting suggestion emerged from this overview is that the same mechanisms that trigger affective symptoms in patients with increased anti-NMDAR auto-Abs levels could be involved in the physiopathology of at least a subgroup of BD. Future studies are needed to characterize the relationship between anti-NMDAR auto-Abs and BD. PMID- 26014348 TI - Low expression levels of hepsin and TMPRSS3 are associated with poor breast cancer survival. AB - BACKGROUND: Hepsin, (also called TMPRSS1) and TMPRSS3 are type II transmembrane serine proteases (TTSPs) that are involved in cancer progression. TTSPs can remodel extracellular matrix (ECM) and, when dysregulated, promote tumor progression and metastasis by inducing defects in basement membrane and ECM molecules. This study investigated whether the gene and protein expression levels of these TTSPs were associated with breast cancer characteristics or survival. METHODS: Immunohistochemical staining was used to evaluate hepsin levels in 372 breast cancer samples and TMPRSS3 levels in 373 samples. TMPRSS1 mRNA expression was determined in 125 invasive and 16 benign breast tumor samples, and TMPRSS3 mRNA expression was determined in 167 invasive and 23 benign breast tumor samples. The gene and protein expression levels were analyzed for associations with breast cancer-specific survival and clinicopathological parameters. RESULTS: Low TMPRSS1 and TMPRSS3 mRNA expression levels were independent prognostic factors for poor breast cancer survival during the 20-year follow-up (TMPRSS1, P = 0.023; HR, 2.065; 95 % CI, 1.106-3.856; TMPRSS3, P = 0.013; HR, 2.106; 95 % CI, 1.167-3.800). Low expression of the two genes at the mRNA and protein levels associated with poorer survival compared to high levels (log rank P-values 0.015 0.042). Low TMPRSS1 mRNA expression was also an independent marker of poor breast cancer prognosis in patients treated with radiotherapy (P = 0.034; HR, 2.344; 95 % CI, 1.065-5.160). Grade III tumors, large tumor size, and metastasis were associated with low mRNA and protein expression levels. CONCLUSIONS: The results suggest that the TTSPs hepsin and TMPRSS3 may have similar biological functions in the molecular pathology of breast cancer. Low mRNA and protein expression levels of the studied TTSPs were prognostic markers of poor survival in breast cancer. PMID- 26014350 TI - Regional recurrence of oropharyngeal cancer after definitive radiotherapy: a case control study. AB - BACKGROUND: Elective treatment of lymph nodes in oropharyngeal cancer (OPC) has impact on both regional recurrences (RR) and risk of late side effects. This study was performed to quantify the dose-dependent impact on RR and overall survival (OS) in a prospectively collected cohort of OPC from the ARTSCAN study with emphasis on elective treatment. METHODS: ARTSCAN is a previously published prospective, randomized, multicentre study of altered radiotherapy (RT) fractionation in head and neck cancer. In ARTSCAN the elective treatment volume for node positive OPC varied significantly between centres due to local treatment principles. All patients with OPC in complete response after primary treatment were eligible for the present case-control study. Cases were patients with RR during five years follow-up. Patients with no recurrence were eligible as controls. Four controls per case were matched according to T- and N-stage. Mean (D mean) and median (D 50%) dose for the lymph node level (LNL) of RR in the cases and the corresponding LNL in the controls were analysed with conditional logistic regression. OS was estimated with the Kaplan-Meier method and evaluated by multivariate Cox regression analysis. RESULTS: There was a dose-dependent risk reduction for D 50% in the interval that represented elective treatment (40-50 Gy) (OR = 0.18, p < 0.05) and a trend in the same dose interval for D mean (OR = 0.19, p = 0.07). OS rates at five years were 0.39 (0.24-0.65) for cases and 0.70 (0.62-0.81) for controls (p < 0.001). The Kaplan-Meier and the Cox regression analysis for cases categorised by delivered dose showed an inverse relationship between dose and survival. The cases with RR in a LNL outside planning target volume (PTV) (D mean < 40 Gy) had an OS rate comparable to that of all patients, and those with RR in a LNL in PTVelective (D mean 40-60 Gy) or PTVtumour (D mean >60 Gy) did significantly worse (p < 0.05). The same inverse relationship was also shown for a small subset of patient with known HPV-status, defined by over expression of p16 (p < 0.05). CONCLUSIONS: There was a significant risk reduction for RR of elective treatment. However the OS for patients with RR outside target volumes was not affected, with similar results for patients with HPV-positive OPC. This could be an argument for a prospective randomized study on limited elective target volumes in OPC. PMID- 26014351 TI - Early Behavioral Inhibition and Emotion Regulation: Pathways Toward Social Competence in Middle Childhood. AB - This study examined emotion regulation (ER) as a mediator in the relation between early behavioral inhibition (BI) and later social competence (N = 257), and whether this mediation varied depending on BI levels. Maternal report and observational measures were used to assess BI (ages 2 and 3). Children's ER strategies (age 5) and social competence with an unfamiliar peer (age 7) were measured using observational measures. Results showed that BI predicted less engaged ER strategies during a disappointment task, and engaged ER predicted higher social competence. Engaged ER mediated the effect of BI on social competence, but only for highly inhibited children. Findings elucidate developmental trajectories of risk and resilience, and suggest targeting regulatory strategies in early prevention efforts with highly inhibited children. PMID- 26014352 TI - The geography of maternal and newborn health: the state of the art. AB - As the deadline for the millennium development goals approaches, it has become clear that the goals linked to maternal and newborn health are the least likely to be achieved by 2015. It is therefore critical to ensure that all possible data, tools and methods are fully exploited to help address this gap. Among the methods that are under-used, mapping has always represented a powerful way to 'tell the story' of a health problem in an easily understood way. In addition to this, the advanced analytical methods and models now being embedded into Geographic Information Systems allow a more in-depth analysis of the causes behind adverse maternal and newborn health (MNH) outcomes. This paper examines the current state of the art in mapping the geography of MNH as a starting point to unleashing the potential of these under-used approaches. Using a rapid literature review and the description of the work currently in progress, this paper allows the identification of methods in use and describes a framework for methodological approaches to inform improved decision-making. The paper is aimed at health metrics and geography of health specialists, the MNH community, as well as policy-makers in developing countries and international donor agencies. PMID- 26014353 TI - Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome. AB - Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted. PMID- 26014354 TI - CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility. AB - The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p trend = 0.022, p trend = 0.042, p trend = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p trend = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p trend = 0.009, p trend = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways. PMID- 26014355 TI - Diaminothiazoles evade multidrug resistance in cancer cells and xenograft tumour models and develop transient specific resistance: understanding the basis of broad-spectrum versus specific resistance. AB - Acquired drug resistance poses a challenge in cancer therapy. Drug efflux is the most common mechanism of resistance displayed by hydrophobic drugs beyond a certain size. However, target specific changes and imbalance between the pro- and anti-apoptotic proteins are also found quite often in many tumours. A number of small antimitotic agents show high potential for multidrug resistant tumours, mainly because they are able to evade the efflux pumps. However, these compounds are also likely to suffer from resistance upon prolonged treatment. Thus, it is important to find out agents that are sensitive to resistant tumours and to know the resistance mechanisms against small molecules so that proper combinations can be planned. In this report, we have studied the efficiency of diaminothiazoles, a novel class of tubulin targeting potential anticancer compounds of small size, in multidrug resistant cancer. Studies in model cell lines raised against taxol and the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole], and the xenograft tumours derived from them, show that diaminothiazoles are highly promising against multidrug resistant cancers. They were able to overcome the expression of efflux protein MDR1 and certain tubulin isotypes, could sensitize improper apoptotic machinery and ablated checkpoint proteins Bub1 and Mad2. Further, we have found that the resistance against microtubule binding compounds with higher size is broad-spectrum and emerges due to multiple factors including overexpression of transmembrane pumps. However, resistance against small molecules is transient, specific and is contributed by target specific changes and variations in apoptotic factors. PMID- 26014356 TI - Effective antidotes for new anticoagulants. PMID- 26014359 TI - 3D Reconstruction of Chick Embryo Vascular Geometries Using Non-invasive High Frequency Ultrasound for Computational Fluid Dynamics Studies. AB - Recent animal studies have provided evidence that prenatal blood flow fluid mechanics may play a role in the pathogenesis of congenital cardiovascular malformations. To further these researches, it is important to have an imaging technique for small animal embryos with sufficient resolution to support computational fluid dynamics studies, and that is also non-invasive and non destructive to allow for subject-specific, longitudinal studies. In the current study, we developed such a technique, based on ultrasound biomicroscopy scans on chick embryos. Our technique included a motion cancelation algorithm to negate embryonic body motion, a temporal averaging algorithm to differentiate blood spaces from tissue spaces, and 3D reconstruction of blood volumes in the embryo. The accuracy of the reconstructed models was validated with direct stereoscopic measurements. A computational fluid dynamics simulation was performed to model fluid flow in the generated construct of a Hamburger-Hamilton (HH) stage 27 embryo. Simulation results showed that there were divergent streamlines and a low shear region at the carotid duct, which may be linked to the carotid duct's eventual regression and disappearance by HH stage 34. We show that our technique has sufficient resolution to produce accurate geometries for computational fluid dynamics simulations to quantify embryonic cardiovascular fluid mechanics. PMID- 26014360 TI - The effect of head rotation on the geometry and hemodynamics of healthy vertebral arteries. AB - The geometric and hemodynamic characteristics of the left and right vertebral arteries (LVA, RVA) of six healthy volunteers were investigated for the supine (S) and the prone position (P) a common sleeping posture with head rotation. MRI images were used to reconstruct the subject specific three-dimensional solid models of the LVA and RVA from the level of the carotid bifurcation to the vertebrobasilar junction (VJ). Geometric parameters such as cross sectional area ratio, curvature, tortuosity and branch angle were estimated. MR-PCA was used to obtain the blood flow waveforms for the two positions and computational fluid dynamics (CFD) were used to assess the flow field in terms of wall shear stress (WSS) relative residence times (RRT) and localized normalized helicity (LNH). Significant geometric changes but moderate flow changes were observed for both vertebral arteries with head rotation. The CFD results at the VJ show that head rotation causes changes in the WSS distribution, RRT and LNH. Further studies are warranted to assess the clinical significance of the results in terms of atherosclerosis development at the VJ and how the observed geometric changes may affect blood flow to the brain in healthy subjects and vertebral artery stenosis patients, and in terms of increased rapture susceptibility in vertebrobasilar aneurysm patients. PMID- 26014357 TI - Modeling of interaction between cytochrome c and the WD domains of Apaf-1: bifurcated salt bridges underlying apoptosome assembly. AB - BACKGROUND: Binding of cytochrome c, released from the damaged mitochondria, to the apoptotic protease activating factor 1 (Apaf-1) is a key event in the apoptotic signaling cascade. The binding triggers a major domain rearrangement in Apaf-1, which leads to oligomerization of Apaf-1/cytochrome c complexes into an apoptosome. Despite the availability of crystal structures of cytochrome c and Apaf-1 and cryo-electron microscopy models of the entire apoptosome, the binding mode of cytochrome c to Apaf-1, as well as the nature of the amino acid residues of Apaf-1 involved remain obscure. RESULTS: We investigated the interaction between cytochrome c and Apaf-1 by combining several modeling approaches. We have applied protein-protein docking and energy minimization, evaluated the resulting models of the Apaf-1/cytochrome c complex, and carried out a further analysis by means of molecular dynamics simulations. We ended up with a single model structure where all the lysine residues of cytochrome c that are known as functionally-relevant were involved in forming salt bridges with acidic residues of Apaf-1. This model has revealed three distinctive bifurcated salt bridges, each involving a single lysine residue of cytochrome c and two neighboring acidic resides of Apaf-1. Salt bridge-forming amino acids of Apaf-1 showed a clear evolutionary pattern within Metazoa, with pairs of acidic residues of Apaf-1, involved in bifurcated salt bridges, reaching their highest numbers in the sequences of vertebrates, in which the cytochrome c-mediated mechanism of apoptosome formation seems to be typical. CONCLUSIONS: The reported model of an Apaf-1/cytochrome c complex provides insights in the nature of protein-protein interactions which are hard to observe in crystallographic or electron microscopy studies. Bifurcated salt bridges can be expected to be stronger than simple salt bridges, and their formation might promote the conformational change of Apaf-1, leading to the formation of an apoptosome. Combination of structural and sequence analyses provides hints on the evolution of the cytochrome c-mediated apoptosis. PMID- 26014361 TI - Oxidative Stress and Plasma Membrane Repair in Single Myoblasts After Femtosecond Laser Photoporation. AB - Cell membranes are susceptible to biophysical damages. These biophysical damages often present themselves in challenging oxidative environments, such as in chronic inflammation. Here we report the damage evolution after single myoblasts were individually subjected to femtosecond (fs) laser photoporation on their plasma membranes under normal and oxidative conditions. A well-characterized tunable fs laser was coupled with a laser scanning confocal microscope. The post damage wound evolution was documented by real-time imaging. The fs laser could generate a highly focused hole at a targeted site of the myoblast plasma membrane. The initial hole size depended on the laser dosage in terms of power and exposure duration. With the same laser power and irradiation duration, photoporation invoked bigger holes in the oxidative groups than in the control. Myoblasts showed difficulty in repairing holes with initial size beyond certain threshold. Within the threshold, holes could apparently be resealed within 100 s under the normal condition; while in oxidative condition, the resealing process could take 100-300 s. The hole-resealing capacity of myoblasts was compromised under oxidative stress particularly when the oxidative exposure was chronic. It is interesting to note that brief exposure to oxidative stress apparently could promote resealing in myoblasts after photoporation. PMID- 26014362 TI - Cartilage Oligomeric Matrix Protein Angiopoeitin-1 Provides Benefits During Nerve Regeneration In Vivo and In Vitro. AB - Our group pioneered the study of nerve regeneration in China and has successfully developed human "acellular nerve grafts (ACNGs)". However, our clinical studies revealed that the effects of ACNGs for long and large nerve defects are far from satisfactory. To improve the efficacy of ACNGs, we combined Cartilage oligomeric matrix protein angiopoietin-1 (COMP-Ang1) with ACNGs in rat sciatic nerve injury models and observed the outcomes via angiographic, morphological, and functional analyses. Co-cultures of endothelial cells (ECs) and dorsal root ganglion neurons (DRGs) were also used to characterize the relationship between neovascularization and nerve regeneration. The results showed significant improvements in early neovascularization, nerve regeneration, and functional outcomes in vivo in the ACNG + COMP-Ang1 group. In vitro, neurite length, and density as well as the expression levels of neurofilament 68 (NF68) and phosphorylated-Tie-2 (p-Tie-2) significantly increased when ECs were co-cultured with DRGs using COMP-Ang1. p Tie-2 expression dramatically decreased after treatment with a Tie-2 kinase inhibitor (S157701), which consequently decreased the level of NF68. COMP-Ang1 can be concluded to promote early neovascularization followed by brisk nerve regeneration, and the mechanism of this regeneration may involve the modulation of the p-Tie-2 and Tie-2 receptors on ECs. These findings demonstrate that ACNGs can be modified using COMP-Ang1 to improve their efficacy in repairing peripheral nerve defects in clinical trials. PMID- 26014363 TI - Fibroblast Migration in 3D is Controlled by Haptotaxis in a Non-muscle Myosin II Dependent Manner. AB - Cell migration in 3D is a key process in many physiological and pathological processes. Although valuable knowledge has been accumulated through analysis of various 2D models, some of these insights are not directly applicable to migration in 3D. In this study, we have confined biomimetic hydrogels within microfluidic platforms in the presence of a chemoattractant (platelet-derived growth factor-BB). We have characterized the migratory responses of human fibroblasts within them, particularly focusing on the role of non-muscle myosin II. Our results indicate a prominent role for myosin II in the integration of chemotactic and haptotactic migratory responses of fibroblasts in 3D confined environments. PMID- 26014364 TI - Computational Analysis of the Mechanical Behaviors of Hemiarch and Total Arch Replacements. AB - Surgery for aortic dissections or aneurysms can be extended into the aortic arch by hemiarch replacement (HAR) or total arch replacement (TAR). Although cardiovascular surgeons have been performing HAR and TAR for decades, the mechanical properties of HAR and TAR are not well understood. This study investigates the mechanical behaviors and stress distributions in HAR and TAR using a hybrid fluid-structure interaction analysis that combines computational fluid dynamics and structural static analysis. Geometrical information on the aortas of 11 subjects was extracted from contrast-enhanced computed tomography (CT) scan data. The CT images were imported into medical image processing software to reconstruct 3D models of the aortas. A 3D finite element model was employed to simulate aortas that receive HAR or TAR. The deformation of the great vessels and the stress distributions at both the vessels and the aortic grafts were calculated. The numerical results revealed that the aortas following TAR exhibited a lower level of stress than those following HAR. Higher stresses may cause arterial wall injury and increase the risk of rupture. Finite element analysis of the aortas and the aortic grafts provides useful information that helps physicians better understand the potential problems that may arise after various surgical procedures. PMID- 26014366 TI - Dopamine agonists for the treatment of cocaine dependence. AB - BACKGROUND: Cocaine misuse is a disorder for which no pharmacological treatment of proven efficacy exists. Advances in neurobiology could guide future medication development. OBJECTIVES: To investigate the efficacy and acceptability of dopamine agonists alone or in combination with any psychosocial intervention for the treatment of of people who misuse cocaine. SEARCH METHODS: We run the search on 12 January 2015. We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE, CINAHL, PsycINFO, ICTRP, clinicaltrials.gov and screened reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing dopamine agonists alone or associated with psychosocial intervention with placebo, no treatment or other pharmacological interventions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: Twenty four studies, including 2147 participants, met the inclusion criteria. Comparing any dopamine agonist versus placebo, we found no differences for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). This was also observed when single dopamine agonists were compared against placebo. Comparing amantadine versus antidepressants, we found low quality of evidence that antidepressants performed better for abstinence (RR 0.25, 95% CI 0.12 to 0.53) based on two studies with 44 participants. No differences were found for dropout or adverse events, for both moderate quality of evidence.The major flaws of the included studies concerned selection bias because most studies did not report information about sequence generation (80%) and allocation concealment methods (86%): half of the included studies were judged at unclear risk of performance bias and 62.5% at unclear risk of detection bias for what concerns subjective outcomes. AUTHORS' CONCLUSIONS: Current evidence from RCTs does not support the use of dopamine agonists for treating cocaine misuse. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Even the potential benefit of combining a dopamine agonist with a more potent psychosocial intervention, which was suggested by the previous Cochrane Review (Soares 2003), is not supported by the results of this Cochrane Review update. PMID- 26014367 TI - The Donor-Base-Free Aggregation of Lithium Diisopropyl Amide in Hydrocarbons Revealed by a DOSY Method. AB - Lithium diisopropyl amide (LDA) is a very prominent reagent that plays a key role in organic synthesis, serving as a base par excellence for a broad range of deprotonation reactions. However, the state of aggregation in solution in the absence of donor bases was unclear. In this paper we solved this problem by employing DOSY NMR experiments based on a newly elaborated external calibration curve (ECC) approach with normalized diffusion coefficients. PMID- 26014365 TI - Consensus statement on advancing research in emergency department operations and its impact on patient care. AB - The consensus conference on "Advancing Research in Emergency Department (ED) Operations and Its Impact on Patient Care," hosted by The ED Operations Study Group (EDOSG), convened to craft a framework for future investigations in this important but understudied area. The EDOSG is a research consortium dedicated to promoting evidence-based clinical practice in emergency medicine. The consensus process format was a modified version of the NIH Model for Consensus Conference Development. Recommendations provide an action plan for how to improve ED operations study design, create a facilitating research environment, identify data measures of value for process and outcomes research, and disseminate new knowledge in this area. Specifically, we call for eight key initiatives: 1) the development of universal measures for ED patient care processes; 2) attention to patient outcomes, in addition to process efficiency and best practice compliance; 3) the promotion of multisite clinical operations studies to create more generalizable knowledge; 4) encouraging the use of mixed methods to understand the social community and human behavior factors that influence ED operations; 5) the creation of robust ED operations research registries to drive stronger evidence-based research; 6) prioritizing key clinical questions with the input of patients, clinicians, medical leadership, emergency medicine organizations, payers, and other government stakeholders; 7) more consistently defining the functional components of the ED care system, including observation units, fast tracks, waiting rooms, laboratories, and radiology subunits; and 8) maximizing multidisciplinary knowledge dissemination via emergency medicine, public health, general medicine, operations research, and nontraditional publications. PMID- 26014368 TI - Prevalence of Chronic Metoclopramide Use and Associated Diagnoses in the US Pediatric Population. AB - OBJECTIVE: Metoclopramide is the only medication widely used to promote gastrointestinal motility in the USA. Despite its appreciable risk of central nervous system complications, it continues to be prescribed to children for chronic use. We sought to estimate the prevalence of chronic metoclopramide use among US children and identify the diagnoses that may have prompted this use. The US metoclopramide label lists only two indications in adults: symptomatic gastroesophageal reflux (GERD) and diabetic gastroparesis. The latter is rare in children so, in examining the indications likely to have prompted chronic metoclopramide use, we focused on GERD. METHODS: From two health services databases representing privately and publically insured children, respectively, we estimated the number of US children who used metoclopramide chronically and identified the diagnoses recorded at approximately the time when the chronic use began. We defined chronic use liberally as >= 35 days' supply, or conservatively as >= 130 days' supply in a 6-month period. For each chronic-use definition, insurance type, and age group, we estimated the proportion of children using metoclopramide chronically. We applied these proportions to US population estimates. RESULTS: Under the liberal and conservative definitions, respectively, 89,020 and 28,222 US children used metoclopramide chronically. CONCLUSION: In spite of its risk, substantial numbers of US children use metoclopramide chronically for symptoms suggestive of GERD. PMID- 26014369 TI - In situ hydrogen, acetone, butanol, ethanol and microdiesel production by Clostridium acetobutylicum ATCC 824 from oleaginous fungal biomass. AB - An in situ batch fermentation technique was employed for biohydrogen, acetone, butanol, ethanol and microdiesel production from oleaginous fungal biomass using the anaerobic fermentative bacterium Clostridium acetobutylicum ATCC 824. Oleaginous fungal Cunninghamella echinulata biomass which has ability to accumulate up to 71% cellular lipid was used as the substrate carbon source. The maximum cumulative hydrogen by C. acetobutylicum ATCC 824 from crude C. echinulata biomass was 260 ml H2 l(-1), hydrogen production efficiency was 0.32 mol H2 mole(-1) glucose and the hydrogen production rate was 5.2 ml H2 h(-1). Subsequently, the produced acids (acetic and butyric acids) during acidogenesis phase are re-utilized by ABE-producing clostridia and converted into acetone, butanol, and ethanol. The total ABE produced by C. acetobutylicum ATCC 824 during batch fermentation was 3.6 g l(-1) from crude fungal biomass including acetone (1.05 g l(-1)), butanol (2.19 g l(-1)) and ethanol (0.36 g l(-1)). C. acetobutylicum ATCC 824 has ability to produce lipolytic enzymes with a specific activity 5.59 U/mg protein to hydrolyze ester containing substrates. The lipolytic potential of C. acetobutylicum ATCC 824 was used as a biocatalyst for a lipase transesterification process using the produced ethanol from ABE fermentation for microdiesel production. The fatty acid ethyl esters (microdiesel) generated from the lipase transesterification of crude C. echinulata dry mass was analyzed by GC/MS as 15.4% of total FAEEs. The gross energy content of biohydrogen, acetone, butanol, ethanol and biodiesel generated through C. acetobutylicum fermentation from crude C. echinulata dry mass was 3113.14 kJ mol(-1). These results suggest a possibility of integrating biohydrogen, acetone, butanol and ethanol production technology by C. acetobutylicum with microdiesel production from crude C. echinulata dry mass and therefore improve the feasibility and commercialization of bioenergy production. PMID- 26014370 TI - Prometabolites of 5-Diphospho-myo-inositol Pentakisphosphate. AB - Diphospho-myo-inositol phosphates (PP-InsP(y)) are an important class of cellular messengers. Thus far, no method for the transport of PP-InsP(y) into living cells is available. Owing to their high negative charge density, PP-InsP(y) will not cross the cell membrane. A strategy to circumvent this issue involves the generation of precursors in which the negative charges are masked with biolabile groups. A PP-InsP(y) prometabolite would require twelve to thirteen biolabile groups, which need to be cleaved by cellular enzymes to release the parent molecules. Such densely modified prometabolites of phosphate esters and anhydrides have never been reported to date. This study discloses the synthesis of such agents and an analysis of their metabolism in tissue homogenates by gel electrophoresis. The acetoxybenzyl-protected system is capable of releasing 5-PP InsP5 in mammalian cell/tissue homogenates within a few minutes and can be used to release 5-PP-InsP5 inside cells. These molecules will serve as a platform for the development of fundamental tools required to study PP-InsP(y) physiology. PMID- 26014371 TI - Accuracy of visual inspection with acetic acid and with Lugol's iodine for cervical cancer screening: Meta-analysis. AB - The aim of this review was to provide an updated summary estimation of the accuracy of visual inspection with acetic acid (VIA) and with Lugol's iodine (VILI) in detecting cervical cancer and precancer. Studies on VIA/VILI accuracy were eligible in which VIA/VILI was performed on asymptomatic women who all underwent confirmatory testing of histology, combination of colposcopy and histology, or combination of multiple screening tests, colposcopy and histology, to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+ or CIN3+). A bivariate model was fitted to estimate the accuracy of VIA/VILI and provide estimates of heterogeneity. Subgroup analysis was used to investigate the source of heterogeneity. A total of 29 studies on VIA and 19 studies on VILI were included finally in the meta-analysis. The summary sensitivity and specificity of VIA for CIN2+ were 73.2% (95%CI: 66.5-80.0%) and 86.7% (95%CI: 82.9-90.4%), respectively, and those for VILI were 88.1% (95%CI: 81.5-94.7%) and 85.9% (95%CI: 81.7-90.0%), respectively. VIA and VILI were both more sensitive in detecting more severe outcome, although there was a slight loss in specificity. Apparent heterogeneity existed in sensitivity and specificity for both VIA and VILI. High sensitivity of both VIA and VILI for CIN2+ was found when a combination of colposcopy and histology was used as disease confirmation. VIA, VILI, even a combination of them in parallel, could be good options for cervical screening in low-resource settings. Significant differences in sensitivity between different gold standards might provide a proxy for optimization of ongoing cervical cancer screening programs. PMID- 26014372 TI - Reductive Alkylation of alpha-Keto Imines Catalyzed by PTSA/FeCl3: Synthesis of Indoles and 2,3'-Biindoles. AB - A simple and efficient method for the synthesis of highly functionalized indoles and biindoles was developed. In the reaction protocol, three components were used in one pot and products were obtained in high yield in an easy workup procedure. The reaction occurred via initial reductive alkylation of alpha-keto imines, followed by a cyclization process in the presence of PTSA/FeCl3 as catalyst. PMID- 26014373 TI - No major effect of cyclosporin A in patients with severe solar urticaria: a french retrospective case series. PMID- 26014374 TI - Asymmetric Total Synthesis of ent-Pyripyropene A. AB - An asymmetric total synthesis of ent-pyripyropene A was achieved by a convergent synthetic route. We used our originally developed Ti(III) -catalyzed radical cyclization to construct an AB-ring portion that consisted of a trans-decalin skeleton with five contiguous stereogenic centers. The coupling between the AB ring and the DE-ring portions, and a subsequent C-ring cyclization, led to the total synthesis of ent-pyripyropene A. An evaluation of the insecticidal activity of ent-pyripyropene A against two aphid species revealed that ent-pyripyropene A was 35-175 times less active than naturally occurring pyripyropene A. This result indicated that the biological target of pyripyropene A recognizes the absolute configuration of pyripyropene A. PMID- 26014376 TI - Plenary oral presentations. PMID- 26014375 TI - Socioeconomic determinants of overnight and weekend emergency department use for acute rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: Prior work has shown Medicaid and self-pay insurance status is associated with emergency department (ED), rather than outpatient clinic, presentation for uncomplicated acute rhinosinusitis (ARS). We investigate whether the disparate use of ED resources for this nonemergent condition by patients with Medicaid and self-pay insurance can be attributed to presentation overnight or on weekends. STUDY DESIGN: Cross-sectional survey of 990,849 patients from the 2009 and 2010 National Hospital Ambulatory Medical Care Survey presenting to EDs with uncomplicated ARS. Patients with orbital and intracranial complications of ARS were excluded. METHODS: Univariate and multivariate associations identified demographic and socioeconomic characteristics, including insurance status, which were independently associated with overnight (between 5 pm and 7 am) or daytime weekend ED presentation for uncomplicated ARS. RESULTS: Medicaid or self-pay insurance status was associated with evening/overnight ED presentation (odds ratio=1.88, P=.018) in comparison to private or Medicare insurance. However, weekend daytime ED presentation was not associated with Medicaid or self-pay insurance statuses (P=.144). Income and education levels of patients' zip codes, taken as markers of socioeconomic status, were not associated with either evening/overnight or daytime weekend ED presentation for uncomplicated ARS (P>.05). CONCLUSIONS: ARS patients with Medicaid or self-pay status, previously shown to preferentially use EDs for uncomplicated ARS, were more likely to present for overnight ED care compared to patients with private insurance or Medicare. These findings suggest a potential lack of access to extended-hours primary care during evenings and nights for Medicaid patients. LEVEL OF EVIDENCE: 4. PMID- 26014377 TI - Inhibition of Myeloid Cell Leukemia 1 and Activation of Caspases Are Critically Involved in Gallotannin-induced Apoptosis in Prostate Cancer Cells. AB - Although gallotannin contained in several medicinal plants was known to have multi-biological activities, such as antioxidant, antiinflammatory, antimicrobial, immunomodulatory, and antitumor effects, the underlying apoptotic mechanism of gallotannin is not fully understood so far. Thus, in the present study, the apoptotic mechanism of gallotannin was elucidated in DU145, PC-3, and M2182 prostate cancer cells in association with myeloid cell leukemia 1 (Mcl-1) signaling. Gallotannin exerted dose-dependent cytotoxicity in DU145, PC-3, and M2182 prostate cancer cells. Also, gallotannin showed apoptotic morphological features and increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells and sub-G1 accumulation in three prostate cancer cell lines. Consistently, gallotannin cleaved poly (ADP-ribose) polymerase (PARP) and attenuated the expression of procaspases 9 and 3 in three prostate cancer cell lines. Furthermore, gallotannin attenuated the expression of survival genes such as Mcl-1, B-cell lymphoma 2, and B-cell lymphoma 2 extra large in three prostate cancer cell lines. Interestingly, overexpression of Mcl-1 reversed the ability of gallotannin to cleave PARP and increase sub-G1 population in three prostate cancer cell lines. Conversely, silencing of Mcl-1 enhanced apoptosis by gallotannin in three prostate cancer cell lines by FACSCalibur (Becton Dickinson, Franklin Lakes, NJ, USA). Taken together, our findings demonstrate that inhibition of Mcl-1 and activation of caspases are critically involved in gallotannin-induced apoptosis in prostate cancer cells. PMID- 26014378 TI - Robust liquid-infused surfaces through patterned wettability. AB - Liquid-infused surfaces display advantageous properties that are normally associated with conventional gas-cushioned superhydrophobic surfaces. However, the surfaces can lose their novel properties if the infused liquid drains from the surface. We explore how drainage due to gravity or due to an external flow can be prevented through the use of chemical patterning. A small area of the overall surface is chemically treated to be preferentially wetted by the external fluid rather than the infused liquid. These sacrificial regions disrupt the continuity of the infused liquid, thereby preventing the liquid from draining from the texture. If the regions are patterned with the correct periodicity, drainage can be prevented entirely. The chemical patterns are created using spray coating or deep-UV exposure, two facile techniques that are scalable to generate large-scale failure-resistant surfaces. PMID- 26014379 TI - Betaproteobacteria Limnohabitans strains increase fecundity in the crustacean Daphnia magna: symbiotic relationship between major bacterioplankton and zooplankton in freshwater ecosystem. AB - How symbioses between bacteria and aquatic animals influence food webs in freshwater ecosystems is a fundamental question in ecology. We investigated symbiosis between a crustacean zooplankton Daphnia magna and its dominant bacterial symbiont Limnohabitans, an abundant and globally distributed freshwater Betaproteobacteria. Aposymbiotic juvenile Daphnia were prepared and exposed to any of four Limnohabitans sp. - Limnohabitans strains DM1, 2KL-3, 2KL-7 and Limnohabitans planktonicus strain II-D5, all previously found in D. magna digestive tract or culture. Re-infected Daphnia were cultured until they produced the first clutch of juveniles. Limnohabitans strain DM1 and L. planktonicus strain II-D5 successfully re-infected Daphnia through single exposure at the first instar juvenile stage. In contrast to aposymbiotic Daphnia that produced non-viable juveniles, re-infected Daphnia produced viable juveniles and increased fecundity to levels of that of symbiotic Daphnia. Re-infected Daphnia did not increase their number of eggs nor growth rates. Limnohabitans strains 2KL-7 and 2KL-3 could not recover fecundity even in multiple exposures during culture. This study shows the functional evidence demonstrating that a single bacterium Limnohabitans regulates fecundity of the consumer Daphnia through symbiosis. Our results indicated that symbiotic relationship between major bacterioplankton and zooplankton is important for maintaining the population of zooplankton in freshwater ecosystems. PMID- 26014382 TI - Depressive Symptomology and Hostile Affect among Latinos Using Housing Rental Assistance: the AHOME Study. AB - Studies show that those residing in households subsidized with federal housing vouchers exhibit fewer mental health problems than residents of public housing. The role of housing conditions and neighborhood quality in this relationship is unclear. This study investigated the relationship between rental assistance, housing and neighborhood conditions, and the risk of depressive symptomology and hostile affect among low-income Latino adults living in the Bronx, NY. Latino adults participating in the Affordable Housing as an Obesity Mediating Environment (AHOME) study were used for analysis. All AHOME participants were eligible for federal low-income housing rental assistance (n = 385) and living in the Bronx, New York (2010-2012). Housing (crowding and structural deficiencies) and neighborhood (physical disorder and social cohesion) were measured by questionnaire during in-home interview. Depressive symptomology was measured using the Center for Epidemiologic Studies Depression Scale Short Form, CES-D 10 (score >=10). Hostile affect was measured using items from the Cook-Medley Hostility Scale (score >= 4). Results suggest residents of Section 8 housing have similar levels of depressive symptomology and hostility compared to residents in public housing or those receiving no federal housing assistance. However, depressive symptomology was significantly associated with maintenance deficiencies [OR = 1.17; CI 1.02, 1.35] and social cohesion [OR = 0.71; CI 0.55, 0.93]. Hostility was significantly associated with perceived crowding [OR = 1.18; CI 1.16, 2.85], neighborhood physical disorder [OR = 1.94; CI 1.12, 3.40], and social cohesion [OR = 0.70; CI 0.50, 0.98]. Low-income housing assistance did not have an independent effect on mental health outcomes. However, characteristics of the housing and neighborhood environments were associated with depressive symptomology and hostility. PMID- 26014383 TI - Alkyne substituted mononuclear photocatalysts based on [RuCl(bpy)(tpy)]+. AB - The ethynyl-phenylene substituted 2,2':6',2''-terpyridine (tpy) derivatives, 4 (phenyl-ethynyl)-2,2':6',2''-terpyridine (L(1)), 4-(methoxyphenyl-ethynyl) 2,2':6',2''-terpyridine (L(2)), 4-(tolyl-ethynyl)-2,2':6',2''-terpyridine (L(3)) and 4-(nitrophenyl-ethynyl)-2,2':6',2''-terpyridine (L(4)) have been used to synthesize four new [RuCl(2,2'-bipyridine)(L(n))]PF6 based complexes. Electronic absorption, resonance Raman, cyclic voltammetry and spectroelectrochemistry aided by DFT calculations were used to explore the influence of the alkynyl substituents on the electronic structures, photochemical and redox properties of the complexes. Furthermore, it is shown that the addition of ethynyl phenyl moieties to the 4-position of the tpy ligand does not have a detrimental effect on these complexes, or the analogous aqua complexes, with respect to their ability to photocatalyse the oxidation of 4-methoxybenzyl alcohol to the corresponding benzaldehyde. PMID- 26014381 TI - Stroke: a Hidden Danger of Margin Trading in Stock Markets. AB - Using 10-year population data from 2000 through 2009 in Taiwan, this is the first paper to analyze the relationship between margin trading in stock markets and stroke hospitalizations. The results show that 3 and 6 days after an increase of margin trading in the Taiwan stock markets are associated with greater stoke hospitalizations. In general, a 1 % increase in total margin trading positions is associated with an increment of 2.5 in the total number of stroke hospitalizations, where the mean number of hospital admissions is 233 cases a day. We further examine the effects of margin trading by gender and age groups and find that the effects of margin trading are significant for males and those who are 45-74 years old only. In summary, buying stocks with money you do not have is quite risky, especially if the prices of those stocks fall past a certain level or if there is a sudden and severe drop in the stock market. There is also a hidden danger to one's health from margin trading. A person should be cautious before conducting margin trading, because while it can be quite profitable, danger always lurks just around the corner. PMID- 26014384 TI - CSF tau correlates with CJD disease severity and cognitive decline. AB - BACKGROUND: Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans. The clinical diagnosis of CJD is supported by a combination of electroencephalogram, MRI, and the presence in the CSF of biomarkers. CSF tau is a marker for neuronal damage and tangle pathology, and is correlated with cognitive status in Alzheimer's disease (AD). OBJECTIVES: The aim of this study was to test whether tau levels in the CSF also correlate with the degree of the neurological deficit and cognitive decline in patients with CJD as reflected by various clinical scales that assess disease severity and cognitive performance. METHODS: Consecutive patients with familial CJD (fCJD) were examined by a neurologist who performed several tests including minimental status examination (MMSE), frontal assessment battery (FAB), NIH stroke scale (NIHSS), CJD neurological scale (CJD-NS), and the expanded disability status scale (EDSS). CSF tau was tested as part of the workout, and the correlation was tested using Pearson correlation. RESULTS: Fifty-two patients with fCJD were recruited to the study (35 males, mean age 59.4 +/- 5.7, range 48-75 years). A significant negative correlation was found between CSF tau levels and the cognitive performance of the patients as reflected by their MMSE and FAB scores. In addition, a significant positive correlation was found between tau levels and the clinical disease severity scales of CJD-NS, NIHSS, and EDSS. CONCLUSION: The correlation between tau levels and the disease severity and degree of cognitive decline in patients with fCJD suggests that tau can be a biomarker reflecting the extent of neuronal damage. PMID- 26014385 TI - LRRK2 Promotes Tau Accumulation, Aggregation and Release. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer's disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2 mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD. PMID- 26014386 TI - Environmental Enrichment Improves Behavior, Cognition, and Brain Functional Markers in Young Senescence-Accelerated Prone Mice (SAMP8). AB - The environment in which organisms live can greatly influence their development. Consequently, environmental enrichment (EE) is progressively recognized as an important component in the improvement of brain function and development. It has been demonstrated that rodents raised under EE conditions exhibit favorable neuroanatomical effects that improve their learning, spatial memory, and behavioral performance. Here, by using senescence-accelerated prone mice (SAMP8) and these as a model of adverse genetic conditions for brain development, we determined the effect of EE by raising these mice during early life under favorable conditions. We found a better generalized performance of SAMP8 under EE in the results of four behavioral and learning tests. In addition, we demonstrated broad molecular correlation in the hippocampus by an increase in NeuN and Ki67 expression, as well as an increase in the expression of neurotrophic factors, such as pleiotrophin (PTN) and brain-derived neurotrophic factor (BDNF), with a parallel decrease in neurodegenerative markers such as GSK3, amyloid-beta precursor protein, and phosphorylated beta-catenin, and a reduction of SBDP120, Bax, GFAP, and interleukin-6 (IL-6), resulting in a neuroprotective panorama. Globally, it can be concluded that EE applied to SAMP8 at young ages resulted in epigenetic regulatory mechanisms that give rise to significant beneficial effects at the molecular, cellular, and behavioral levels during brain development, particularly in the hippocampus. PMID- 26014387 TI - Acute porcine renal metabolic effect of endogastric soft drink administration assessed with hyperpolarized [1-(13)C]pyruvate. AB - PURPOSE: Our aim was to determine the quantitative reproducibility of metabolic breakdown products in the kidney following intravenous injection of hyperpolarized [1-(13)C]pyruvate and secondly to investigate the metabolic effect on the pyruvate metabolism of oral sucrose load using dissolution dynamic nuclear polarization. By this technique, metabolic alterations in several different metabolic related diseases and their metabolic treatment responses can be accessed. METHODS: In four healthy pigs the lactate-to-pyruvate, alanine-to pyruvate and bicarbonate-to-pyruvate ratio was measured following administration of regular cola and consecutive injections of hyperpolarized [1-(13)C]pyruvate four times within an hour. RESULTS: The overall lactate-to-pyruvate metabolic profile changed significantly over one hour following an acute sucrose load leading to a significant rise in blood glucose. CONCLUSION: The reproducibility of hyperpolarized magnetic resonance spectroscopy in the healthy pig kidney demonstrated a repeatability of more than 94% for all metabolites and, furthermore, that the pyruvate to lactate conversion and the blood glucose level is elevated following endogastric sucrose administration. PMID- 26014423 TI - Pure rhombohedral Bi1-x EuxPO4 nano-/micro-structures: fast synthesis, shape evolution and luminescence properties. AB - BiPO4 and Eu-doped BiPO4 crystals were synthesized via a simple precipitation route at room temperature, employing Bi(NO3)3 and (NH4)2HPO4 as the reactants, Eu2O3 as the dopant and citric acid as a template. X-ray powder diffraction analyses showed that pure rhombohedral BiPO4 form was obtained, and was the preferential orientation growth of the crystal. Field emission scanning electron microscope observations showed that the concentration of Bi(3+) obviously changed the products' morphologies from nanosphere, hollow sphere to hexagonal prism. The acidity of the solution and the contents of citric acid and Eu(3+) ion tailored the size of the final crystals. Effects of concentration of Eu(3+) ion on the luminescence emission intensity were also investigated. PMID- 26014388 TI - Exercise intolerance and developmental delay associated with a novel mitochondrial ND5 mutation. AB - The aim of this study was to evaluate the contribution of mitochondrial DNA (mtDNA) mutations in oxidative phosphorylation (OXPHOS) deficiency. The complete mitochondrial genomes of 41 families with OXPHOS deficiency were screened for mutations. Mitochondrial functional analysis was then performed in primary and cybrid cells containing candidate mutations identified during the screening. A novel mitochondrial NADH dehydrogenase 5 (ND5) m.12955A > G mutation was identified in a patient with exercise intolerance and developmental delay. A biochemical analysis revealed deficiencies in the activity of complex I (NADH:quinone oxidoreductase) and IV (cytochrome c oxidase) of this patient. Defects in complexes I and IV were confirmed in transmitochondrial cybrid cells containing the m.12955A > G mutation, suggesting that this mutation impairs complex I assembly, resulting in reduced stability of complex IV. Further functional investigations revealed that mitochondria with the m.12955A > G mutation exhibited lower OXPHOS coupling respiration and adenosine triphosphate (ATP) generation. In addition, the cytotoxic effects, determined as reactive oxygen species (ROS) and lactate levels in the present study, increased in the cells carrying a higher m.12955A > G mutant load. In conclusion, we identified m.12955A > G as a mitochondrial disease-related mutation. Therefore, screening of m.12955A > G is advised for the diagnosis of patients with mitochondrial disease. PMID- 26014424 TI - Attitudes of women of advanced maternal age undergoing invasive prenatal diagnosis and the impact of genetic counselling. AB - Despite the increasing availability and effectiveness of non-invasive screening for foetal aneuploidies, most women of advanced maternal age (AMA) still opt for invasive tests. A retrospective cross-sectional survey was performed on women of AMA undergoing prenatal invasive procedures, in order to explore their motivations and the outcome of preliminary genetic counselling according to the approach (individual or group) adopted. Of 687 eligible women, 221 (32.2%) participated: 117 had received individual counselling, while 104 had attended group sessions. The two groups did not differ by socio-demographic features. The commonest reported reason to undergo invasive tests was AMA itself (67.4%), while only 10.4% of women mentioned the opportunity of making informed choices. The majority perceived as clear and helpful the information received at counselling, and only 12.7% had doubts left that, however, often concerned non-pertinent issues. The impact of counselling on risk perception and decisions was limited: a minority stated their perceived risk of foetal abnormalities had either increased (6.8%) or reduced (3.6%), and only one eventually declined invasive test. The 52.6% of women expressed a preference toward individual counselling, which also had a stronger impact on perceived risk reduction (P=0.003). Nevertheless, group counselling had a more favourable impact on both clarity of understanding and helpfulness (P=0.0497 and P=0.035, respectively). The idea that AMA represents an absolute indication for invasive tests appears deeply rooted; promotion of non invasive techniques may require extensive educational efforts targeted to both the general population and health professionals. PMID- 26014427 TI - A qualitative study to explore how professionals in the United Kingdom make decisions to test children for a sickle cell carrier status. AB - European guidelines recommend that, unless there are clear benefits of autosomal recessive carrier testing in childhood, it should be deferred to protect children's autonomous decision making. Although it is believed that children receive testing in the United Kingdom, it is unclear how or why professionals make decisions to provide tests. Semi-structured interviews were conducted with 25 professionals in the United Kingdom who advise about, and undertake, childhood sickle cell trait testing. Data were analysed using thematic analysis. Few professionals were aware of, or used, guidelines to inform testing decisions and instead, considered the reproductive and clinical relevance of testing, and autonomous rights of parents. Many professionals believed testing was important and readily offered it to parents. Professionals who discouraged testing were met with parental resistance and often provided testing when conflict was difficult to manage. Children were rarely considered to be capable of making decisions and few were engaged in discussions. When consulted, older children demonstrated interest, but younger children usually declined testing. Wide variation in testing advice emerged because of opposing beliefs about children's best interests and potential benefits or harms of testing. An explanation of how children's best interests should be determined in light of conflicting evidence regarding the psychosocial and clinical implications of carrier status is needed. Improved awareness of guidelines might encourage professionals to support the role of children in testing decisions. Strategies are also required to help professionals determine children's cognitive capacity and to protect children's future autonomy during discussions with persistent parents. PMID- 26014425 TI - The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus. AB - Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized here, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented. PMID- 26014428 TI - Genetic counsellors in Sweden: their role and added value in the clinical setting. AB - Genetic testing is becoming more commonplace in general and specialist health care and should always be accompanied by genetic counselling, according to Swedish law. Genetic counsellors are members of the multi-disciplinary team providing genetic counselling. This study examined the role and added value of genetic counsellors in Sweden, using a cross-sectional on-line survey. The findings showed that the genetic counsellors added value in the clinical setting by acting as the 'spider-in-the-web' regarding case management, having a more holistic, ethical and psychological perspective, being able to offer continuous support and build a relationship with the patient, and being more accessible than medical geneticists. The main difference between a genetic counsellor and medical geneticist was that the doctor had the main medical responsibility. Thus genetic counsellors in Sweden contribute substantially to the care of patients in the clinical genetic setting. PMID- 26014426 TI - Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. AB - Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 * 10(-8)), with minor allele frequencies of 1.3 23.9%. Novel signals included variants for progesterone (P=7.68 * 10(-12)), oestradiol (P=1.63 * 10(-8)) and FAI (P=1.50 * 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 * 10(-8)) and LH (P=3.94 * 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 * 10(-14)) and progesterone (P=6.09 * 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation. PMID- 26014429 TI - Reanalysis of mGWAS results and in vitro validation show that lactate dehydrogenase interacts with branched-chain amino acid metabolism. AB - The assignment of causative genes to noncoding variants identified in genome-wide association studies (GWASs) is challenging. We show how combination of knowledge from gene and pathway databases and chromatin interaction data leads to reinterpretation of published quantitative trait loci for blood metabolites. We describe a previously unidentified link between the rs2403254 locus, which is associated with the ratio of 3-methyl-2-oxobutanoate and alpha-hydroxyisovalerate levels, and the distal LDHA gene. We confirmed that lactate dehydrogenase can catalyze the conversion between these metabolites in vitro, suggesting that it has a role in branched-chain amino acid metabolism. Examining datasets from the ENCODE project we found evidence that the locus and LDHA promoter physically interact, showing that LDHA expression is likely under control of distal regulatory elements. Importantly, this discovery demonstrates that bioinformatic workflows for data integration can have a vital role in the interpretation of GWAS results. PMID- 26014430 TI - A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field. AB - The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 *), NKX2-5 (6 *), ZIC3 (3 *), MLPA (2 *) and ELN (4 *). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era. PMID- 26014431 TI - Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content. AB - Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders. PMID- 26014432 TI - High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing. AB - Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c.4183C>T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C>T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region. PMID- 26014433 TI - Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. AB - X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, alpha5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of >=50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population. PMID- 26014435 TI - Comparison of Mortality and Costs at Trauma and Nontrauma Centers for Minor and Moderately Severe Injuries in California. AB - STUDY OBJECTIVE: We examine differences in inpatient mortality and hospitalization costs at trauma and nontrauma centers for injuries of minor and moderate severity. METHODS: Inpatient data sets from the California Office of Statewide Health Planning and Development were analyzed for 2009 to 2011. The study population included patients younger than 85 years and admitted to general, acute care hospitals with a primary diagnosis of a minor or moderate injury. Minor injuries were defined as having a New Injury Severity Score less than 5 and moderate injuries as having a score of 5 to 15. Multivariate logistic regression and generalized linear model with log-link and gamma distribution were used to estimate differences in adjusted inpatient mortality and costs. RESULTS: A total of 126,103 admissions with minor or moderate injury were included in the study population. The unadjusted mortality rate was 6.4 per 1,000 admissions (95% confidence interval [CI] 5.9 to 6.8). There was no significant difference found in mortality between trauma and nontrauma centers in unadjusted (odds ratio 1.2; 95% CI 0.97 to 1.48) or adjusted models (odds ratio 1.1; 95% CI 0.79 to 1.57). The average cost of a hospitalization was $13,465 (95% CI $12,733 to $14,198) and, after adjustment, was 33.1% higher at trauma centers compared with nontrauma centers (95% CI 16.9% to 51.6%). CONCLUSION: For patients admitted to hospitals for minor and moderate injuries, hospitalization costs in this study population were higher at trauma centers than nontrauma centers, after adjustments for patient clinical-, demographic-, and hospital-level characteristics. Mortality was a rare event in the study population and did not significantly differ between trauma and nontrauma centers. PMID- 26014434 TI - Myelination-related genes are associated with decreased white matter integrity in schizophrenia. AB - Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity--as measured by fractional anisotropy (FA)--is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA. PMID- 26014436 TI - At the Crossroads of the HIV Care Continuum: Emergency Departments and the HIV Epidemic. PMID- 26014437 TI - Ventilator Strategies and Rescue Therapies for Management of Acute Respiratory Failure in the Emergency Department. AB - Acute respiratory failure is commonly encountered in the emergency department (ED), and early treatment can have effects on long-term outcome. Noninvasive ventilation is commonly used for patients with respiratory failure and has been demonstrated to improve outcomes in acute exacerbations of chronic obstructive lung disease and congestive heart failure, but should be used carefully, if at all, in the management of asthma, pneumonia, and acute respiratory distress syndrome. Lung-protective tidal volumes should be used for all patients receiving mechanical ventilation, and FiO2 should be reduced after intubation to achieve a goal of less than 60%. For refractory hypoxemia, new rescue therapies have emerged to help improve the oxygenation, and in some cases mortality, and should be considered in ED patients when necessary, as deferring until ICU admission may be deleterious. This review article summarizes the pathophysiology of acute respiratory failure, management options, and rescue therapies including airway pressure release ventilation, continuous neuromuscular blockade, inhaled nitric oxide, and extracorporeal membrane oxygenation. PMID- 26014438 TI - NMR-based approach to the analysis of radiopharmaceuticals: radiochemical purity, specific activity, and radioactive concentration values by proton and tritium NMR spectroscopy. AB - Compounds containing tritium are widely used across the drug discovery and development landscape. These materials are widely utilized because they can be efficiently synthesized and produced at high specific activity. Results from internally calibrated (3)H and (1)H nuclear magnetic resonance (NMR) spectroscopy suggests that at least in some cases, this calibrated approach could supplement or potentially replace radio-high-performance liquid chromatography for radiochemical purity, dilution and scintillation counting for the measurement of radioactivity per volume, and liquid chromatography/mass spectrometry analysis for the determination of specific activity. In summary, the NMR-derived values agreed with those from the standard approaches to within 1% to 9% for solution count and specific activity. Additionally, the NMR-derived values for radiochemical purity deviated by less than 5%. A benefit of this method is that these values may be calculated at the same time that (3)H NMR analysis provides the location and distribution of tritium atoms within the molecule. Presented and discussed here is the application of this method, advantages and disadvantages of the approach, and a rationale for utilizing internally calibrated (1)H and (3)H NMR spectroscopy for specific activity, radioactive concentration, and radiochemical purity whenever acquiring (3)H NMR for tritium location. PMID- 26014439 TI - Scalable Synthesis of Defect Abundant Si Nanorods for High-Performance Li-Ion Battery Anodes. AB - Microsized nanostructured silicon-carbon composite is a promising anode material for high energy Li-ion batteries. However, large-scale synthesis of high performance nano-Si materials at a low cost still remains a significant challenge. We report a scalable low cost method to synthesize Al/Na-doped and defect-abundant Si nanorods that have excellent electrochemical performance with high first-cycle Coulombic efficiency (90%). The unique Si nanorods are synthesized by acid etching the refined and rapidly solidified eutectic Al-Si ingot. To maintain the high electronic conductivity, a thin layer of carbon is then coated on the Si nanorods by carbonization of self-polymerized polydopamine (PDA) at 800 degrees C. The carbon coated Si nanorods (Si@C) electrode at 0.9 mg cm(-2) loading (corresponding to area-specific-capacity of ~2.0 mAh cm(-2)) exhibits a reversible capacity of ~2200 mAh g(-1) at 100 mA g(-1) current, and maintains ~700 mAh g(-1) over 1000 cycles at 1000 mA g(-1) with a capacity decay rate of 0.02% per cycle. High Coulombic efficiencies of 87% in the first cycle and ~99.7% after 5 cycles are achieved due to the formation of an artificial Al2O3 solid electrolyte interphase (SEI) on the Si surface, and the low surface area (31 m(2) g(-1)), which has never been reported before for nano-Si anodes. The excellent electrochemical performance results from the massive defects (twins, stacking faults, dislocations) and Al/Na doping in Si nanorods induced by rapid solidification and Na salt modifications; this greatly enhances the robustness of Si from the volume changes and alleviates the mechanical stress/strain of the Si nanorods during the lithium insertion/extraction process. Introducing massive defects and Al/Na doping in eutectic Si nanorods for Li-ion battery anodes is unexplored territory. We venture this uncharted territory to commercialize this nanostructured Si anode for the next generation of Li-ion batteries. PMID- 26014440 TI - Study of the S427G polymorphism and of MYBL2 variants in patients with acute myeloid leukemia. AB - Dysregulation of MYBL2 has been associated to tumorigenesis and the S427G polymorphism could induce partial inactivation of MYBL2, associating it with cancer risk. It has previously been shown that MYBL2 was over-expressed in some acute myeloid leukemias (AML), portending poor prognosis. However, to date no studies have investigated the S427G or other genetic variants of MYBL2 in AML. This study analyzed the S427G in 197 AML patients and 179 controls and screened the MYBL2 sequence in patients. In contrast to other studies in solid tumors, the S427G was not associated with the incidence of AML. This study detected four unannotated genetic alterations, of which the Q67X could be involved in MYBL2 dysfunction. Eight polymorphisms were identified, among which the rs73116571, located in a splicing region, was associated with higher incidence in AML and weaker MYBL2 expression, suggesting pre-disposition to AML. Additional functional studies should be performed to verify these genetic variations as possible targets in AML. PMID- 26014441 TI - Biocatalytic Pathway Selection in Transient Tripeptide Nanostructures. AB - Structural adaption in living systems is achieved by competing catalytic pathways that drive assembly and disassembly of molecular components under the influence of chemical fuels. We report on a simple mimic of such a system that displays transient, sequence-dependent formation of supramolecular nanostructures based on biocatalytic formation and hydrolysis of self-assembling tripeptides. The systems are catalyzed by alpha-chymotrypsin and driven by hydrolysis of dipeptide aspartyl-phenylalanine-methyl ester (the sweetener aspartame, DF-OMe). We observed switch-like pathway selection, with the kinetics and consequent lifetime of transient nanostructures controlled by the peptide sequence. In direct competition, kinetic (rather than thermodynamic) component selection is observed. PMID- 26014442 TI - Multivalent Polymer Nanocomplex Targeting Endosomal Receptor of Immune Cells for Enhanced Antitumor and Systemic Memory Response. AB - We have designed and synthesized linear polymer-based nanoconjugates and nanocomplexes bearing multivalent immunostimulatory ligands and also demonstrated that the synthetic multivalent nanocomplexes led to an enhanced stimulation of immune cells in vitro and antitumor and systemic immune memory response in vivo. We have developed hyaluronic acid (HA)-based multivalent nanoconjugates and nanocomplexes for enhanced immunostimulation through the combination of multivalent immune adjuvants with CpG ODNs (as a TLR9 ligand) and cationic poly(L lysine) (PLL; for the enhancement of cellular uptake). The multivalent HA-CpG nanoconjugate efficiently stimulated the antigen-presenting cells and the multivalent PLL/HA-CpG nanocomplex also led to an enhanced cellular uptake as well as continuous stimulation of endosomal TLR9. The mice vaccinated with dendritic cells treated with the multivalent nanocomplex exhibited tumor growth inhibition as well as a strong antitumor memory response. PMID- 26014443 TI - Mesoporous calcium phosphate bionanomaterials with controlled morphology by an energy-efficient microwave method. AB - Calcium phosphate nanomaterials with controllable morphology and mesostructure were synthesized via a rapid and energy efficient microwave method. An increase in aspect ratio from nanoplates to nanorods was achieved by increasing the solvent chain length, accompanied by a subsequent about 23% increase in surface area and porosity. Control of mesoporosity was also achieved by varying the synthesis time and quantity of H2 O in the reaction solvent. Comparative studies were carried out using conventional heating (CON) and room temperature co precipitation (RT) methods. It was found that microwave synthesis produces nanomaterials with about 50% higher yields, 7.5/1.7 times higher surface area and 3/5 times higher pore volume than RT/CON materials respectively, as well as having a lower distribution of particle size/shape (lower standard deviation values of their dimensions). Furthermore, in vitro protein loading tests of microwave synthesized mesoporous calcium phosphate materials showed an enhanced loading efficiency of bovine serum albumin (3-7 times), as compared with non mesostructured products from room temperature precipitation, in accordance with their larger surface area and porosity. PMID- 26014444 TI - Short-Term Heparin Kinetics during Catheter Ablation of Atrial Fibrillation. AB - BACKGROUND: Percutaneous catheter ablation of atrial fibrillation (CA-AF) is a treatment option for symptomatic drug-refractory atrial fibrillation (AF). CA-AF carries a risk for thromboembolic complications that has been minimized by the use of intraprocedural intravenous unfractionated heparin (UFH). The optimal administration of UFH as well as its kinetics are not well established and need to be precisely determined. METHODS AND RESULTS: A total 102 of consecutive patients suffering from symptomatic drug-refractory AF underwent CA-AF. The mean age was 61 +/- 10 years old. After transseptal puncture of the fossa ovalis, weight-adjusted UFH bolus (100 U/kg) was infused. A significant increase in activated clotting time (ACT) was observed from an average value of 100 +/- 27 seconds at baseline, to 355 +/- 94 seconds at 10 min (T10), to 375 +/- 90 seconds at 20 min (T20). Twenty-four patients failed to reach the targeted ACT value of >=300 seconds at T10 and more than half of these remained with subtherapeutic ACT values at T20. This subset of patients showed similar clinical characteristics and amount of UFH but were more frequently prescribed preprocedural vitamin K1 than the rest of the study population. CONCLUSIONS: In a typical intervention setting, UFH displays unexpected slow anticoagulation kinetics in a significant proportion of procedures up to 20 minutes after infusion. These findings support the infusion of UFH before transseptal puncture or any left-sided catheterization with early ACT measurements to identify patients with delayed kinetics. They are in line with recent guidelines to perform CA-AF under therapeutic anticoagulation. PMID- 26014445 TI - A sensitive and efficient method for trace analysis of some phenolic compounds using simultaneous derivatization and air-assisted liquid-liquid microextraction from human urine and plasma samples followed by gas chromatography-nitrogen phosphorous detection. AB - In present study, a simultaneous derivatization and air-assisted liquid-liquid microextraction method combined with gas chromatography-nitrogen phosphorous detection has been developed for the determination of some phenolic compounds in biological samples. The analytes are derivatized and extracted simultaneously by a fast reaction with 1-flouro-2,4-dinitrobenzene under mild conditions. Under optimal conditions low limits of detection in the range of 0.05-0.34 ng mL(-1) are achievable. The obtained extraction recoveries are between 84 and 97% and the relative standard deviations are less than 7.2% for intraday (n = 6) and interday (n = 4) precisions. The proposed method was demonstrated to be a simple and efficient method for the analysis of phenols in biological samples. PMID- 26014446 TI - Giant Electroresistive Ferroelectric Diode on 2DEG. AB - Manipulation of electrons in a solid through transmitting, storing, and switching is the fundamental basis for the microelectronic devices. Recently, the electroresistance effect in the ferroelectric capacitors has provided a novel way to modulate the electron transport by polarization reversal. Here, we demonstrate a giant electroresistive ferroelectric diode integrating a ferroelectric capacitor into two-dimensional electron gas (2DEG) at oxide interface. As a model system, we fabricate an epitaxial Au/Pb(Zr(0.2)Ti(0.8))O3/LaAlO3/SrTiO3 heterostructure, where 2DEG is formed at LaAlO3/SrTiO3 interface. This device functions as a two-terminal, non-volatile memory of 1 diode-1 resistor with a large I+/I- ratio (>10(8) at +/- 6 V) and I(on)/I(off) ratio (>10(7)). This is attributed to not only Schottky barrier modulation at metal/ferroelectric interface by polarization reversal but also the field-effect metal-insulator transition of 2DEG. Moreover, using this heterostructure, we can demonstrate a memristive behavior for an artificial synapse memory, where the resistance can be continuously tuned by partial polarization switching, and the electrons are only unidirectionally transmitted. Beyond non-volatile memory and logic devices, our results will provide new opportunities to emerging electronic devices such as multifunctional nanoelectronics and neuromorphic electronics. PMID- 26014448 TI - Corrigendum for ann. N.y. Acad. Sci. 1048: 363-365. PMID- 26014447 TI - Perspectives on depression--past, present, future(a). AB - Depression presents a wide canvas for considering some approaches, issues, and problems in the study of major categories of mental illness in the context of current behavioral and molecular neurobiology. The study of depression encompasses multiple interactions among psychiatry, neurology, and neuroscience, as well as interactions with a host of other disciplines. This paper considers issues from an American perspective and discusses topics including historical aspects of the ways humanity has struggled with depression; the growth of approaches, and the "wars" in psychiatry in the middle of the 20th century between different ideologies; the development of psychiatry as a behavioral science inclusive of many disciplines; current diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association, and the ICD-10 Classification of Mental and Behavioral Disorders of the World Health Organization; the efforts to delineate subtypes of depression; the search for new neurobiological and behavioral targets in the context of the National Institute of Mental Health's Research Domain Criteria framework; and examples of potential future discoveries and disciplines that may ultimately improve treatment. PMID- 26014449 TI - Introduction for affective disorders and traumatic brain injury: Qatar clinical neuroscience conference. PMID- 26014450 TI - Are Partial Workplace Smoking Bans as Effective as Complete Smoking Bans? A National Population-Based Study of Smoke-Free Policy Among Japanese Employees. AB - INTRODUCTION: Although complete workplace smoking bans are generally recommended rather than partial bans, the latter are widespread in many countries, especially Japan. Our objective was to compare complete workplace smoking bans and partial bans for associations with employee smoking and secondhand smoke (SHS)-related discomfort/ill-health. We also evaluated complete bans versus no ban and partial bans versus no ban. METHODS: Eleven thousand ninety eligible employees (weighted number: 34 353 241) aged 20-64 years in 2011 (response rate: 62.5%) were analyzed using a nationally-representative, population-based cross-sectional study. Adjusted prevalence ratios for self-reported current smoking and SHS-related discomfort/ill-health according to workplace smoke-free policies were calculated, using conventional regression and propensity score (PS) weighting (targeting population of average treatment effect among both treated [TET] and untreated [TEU]). RESULTS: Both conventional regressions and PS weighting analyses showed complete bans were significantly associated with lower prevalence of current smoking and perceived SHS-related discomfort/ill-health among nonsmokers than partial or no ban. In contrast, partial bans were not significantly associated with either outcome compared with no ban. Using several PS trimming levels, we found interesting differences between TET and TEU in a comparison between partial and no ban: that is, significant associations in TET estimations, but none in TEU estimations. CONCLUSIONS: Although complete smoking bans were associated with lower levels of employee smoking and SHS-related discomfort/ill-health compared with no smoking ban, partial bans were not. Findings from PS weighting of TEU suggest that partial workplace bans may not be any more effective for Japanese employees than no ban. Therefore, complete bans may be strongly recommended for future implementation, but careful interpretation of the data is necessary because of the cross-sectional study design. PMID- 26014452 TI - The Social Patterning of Tobacco Use Among Women in Jordan: The Protective Effect of Education on Cigarette Smoking and the Deleterious Effect of Wealth on Cigarette and Waterpipe Smoking. AB - INTRODUCTION: The presence of social inequalities in tobacco-use has been fully recognized in the international literature. Even though cigarette and waterpipe tobacco smoking (WTS) are prevalent in the Arab region, the literature has not addressed the social determinants of the impending tobacco epidemic. This study examined the socioeconomic patterning of cigarette and WTS among Jordanian women. METHODS: We analyzed pooled data from four waves of the Jordan Demographic and Health Surveys: 2002 (N = 5851); 2007 (N = 10 654); 2009 (N = 9879), and 2012 (N = 11 113). We specified logistic regression models to test the association between education and household wealth and the two outcome measures, cigarette and WTS, adjusting for other covariates. For each outcome, we ran time-unadjusted and time-adjusted logistic models. RESULTS: Cigarette smoking prevalence among Jordanian women remained almost constant (around 10%) between 2002 and 2012. WTS prevalence steadily increased from 4.1% in 2002 to 10.2% in 2012. Increasing education predicted lower odds of cigarette smoking, whereas increasing household wealth weakly predicted higher odds. As to WTS, increasing household wealth strongly predicted higher odds of use. CONCLUSIONS: Among Jordanian women, increasing education is protective against cigarette smoking. Household wealth, on the other hand, exerts a deleterious effect on both forms of tobacco consumption, particularly WTS. This pattern shows that Jordan has not fully undergone the socioeconomic crossover in tobacco prevalence which characterizes high-income countries. Future control policies should aim to decrease prevalence but also preempt increasing social inequalities in tobacco use. PMID- 26014451 TI - Psychometric Characteristics of the Brief Wisconsin Inventory of Smoking Dependence Motives Among a Nonclinical Sample of Smokers. AB - INTRODUCTION: Attempts to validate the Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM) have produced mixed results. The objectives for the current research were to (1) evaluate the test-retest reliability, internal consistency, and concurrent validity for each of the motive scales (2) evaluate three models to determine fit based on previous research: (i) 11-factor model, (ii) 11-factor model with four error covariances specified by previous research, and (iii) 11-factor model with two higher order primary and secondary dependence motive factors, and (3) evaluate the discriminant and convergent validity of the Brief WISDM scales. METHODS: Smoking adults aged 18-65 completed a survey about their smoking behaviors and nicotine dependence with a web-based instrument that was administered at a 3-month test-retest interval. Psychometric properties and test-retest reliability were evaluated for each instrument. The 11-factor Brief WISDM was evaluated with confirmatory factor analyses; the scales were evaluated for convergent and discriminant validity. RESULTS: The Brief WISDM demonstrated good to excellent test-retest reliability. Confirmatory factor analysis showed the model with the second order primary and secondary dependence motive factors demonstrated the best fit for the data at both administrations. Discriminant validity issues were present for most of the primary dependence motive scales. CONCLUSIONS: To date, the theoretically derived smoking motives for the Brief WISDM have demonstrated mixed support when submitted to confirmatory factor analysis. While these scales tap critical motives of nicotine dependence, further refinement of primary dependence motives is necessary to ensure each latent variable assesses a unique construct. PMID- 26014453 TI - Exploration of Incarcerated Men's and Women's Attitudes of Smoking in the Presence of Children and Pregnant Women: Is There a Disparity Between Smoking Attitudes and Smoking Behavior? AB - INTRODUCTION: A major health challenge facing persons who are incarcerated is tobacco smoking. Upon reentry to the community, concerns regarding smoking cessation may be less likely to receive needed attention. Many individuals have partners who are pregnant and/or reside in households where children and pregnant women live. We explored incarcerated adults' attitudes of smoking in the presence of children and pregnant women and how post-release smoking behaviors are influenced by their attitudes. METHODS: Two hundred forty-seven incarcerated adults participated in a smoking cessation randomized clinical trial in a tobacco free prison. An instrument was developed to examine smoking attitudes and behaviors around children and pregnant women. Moderating effects of smoking factors on post-release abstinence were examined by evaluating interactions between smoking factors and treatment group. RESULTS: Four factors were defined using factor analysis: smoking around children; impact of smoking on child's health; awareness of environmental tobacco smoke (ETS) risk for pregnant women; and importance of smoking avoidance during pregnancy. We found moderation effects of smoking factors on smoking outcomes which included: treatment group by smoking behavior around children (beta = 0.8085; standard error [SE] = 0.4002; P = .04); treatment group by impact of smoking on child's health (beta = 1.2390; SE = 0.5632; P = .03) and for those smoking 50% fewer cigarettes post-release, treatment group by smoking impact on child's health (beta = 1.2356; SE = 0.4436; P < .01). CONCLUSIONS: Concern for smoking around children and pregnant women and awareness of ETS risk for pregnant women was not found to be significantly associated with smoking outcomes and requires additional investigation. Among individuals who continue to smoke post-release, effective ETS interventions are needed aimed at protecting children and pregnant women with whom they live. PMID- 26014454 TI - The Impact of Cigarette Packaging Design Among Young Females in Canada: Findings From a Discrete Choice Experiment. AB - INTRODUCTION: The tobacco industry uses various aspects of cigarette packaging design to market to specific groups. The current study examined the relative importance of five cigarette packaging attributes--pack structure (eg, "slims"), brand, branding, warning label size, and price--on perceptions of product taste, harm, and interest in trying, among young females in Canada. METHODS: A discrete choice experiment was conducted with smoking and nonsmoking females, aged 16 to 24 (N = 448). Respondents were shown 10 choice sets, each containing four packs with different combinations of the attributes: pack structure (slim, lipstick, booklet, traditional); brand ("Vogue," "du Maurier"); branding (branded, plain); warning label size (50%, 75%); and price ($8.45, $10.45). For each choice set, respondents chose the brand that they: (1) would rather try, (2) would taste better, and (3) would be less harmful, or "none." For each outcome, the attributes' impact on consumer choice was analyzed using a multinomial logit model. RESULTS: The multinomial logit analyses revealed that young females weighted pack structure to be most important to their intention to try (46%), judgment of product taste (52%), and judgment of product harm (48%). Price and branding were weighted important in trial intent decisions (23% and 18%, respectively) and product taste judgments (29% and 15%, respectively). Whereas warning label size and brand were weighted important when judging product harm (23% and 17%, respectively). CONCLUSION: The findings suggest that standardized cigarette packaging may decrease demand and reduce misleading perceptions about product harm among young females. PMID- 26014455 TI - Smoking Cessation Awareness and Utilization Among Lesbian, Gay, Bisexual, and Transgender Adults: An Analysis of the 2009-2010 National Adult Tobacco Survey. AB - INTRODUCTION: Each year, there are more than 480 000 deaths in the United States attributed to smoking. Lesbian, gay, bisexual and transgender (LGBT) adults are a vulnerable population that smokes at higher rates than heterosexuals. METHODS: We used data collected from the National Adult Tobacco Survey 2009-2010, a large, nationally representative study using a randomized, national sample of US landline and cellular telephone listings, (N = 118 590). We compared LGBT adults to their heterosexual counterparts with regard to exposure to advertisements promoting smoking cessation, and awareness and use of tobacco treatment services, including quitlines, smoking cessation classes, health professional counseling, nicotine replacement therapy, and medications. RESULTS: Fewer GBT men, compared to heterosexual men, were aware of the quitline. However, LGBT individuals have similar exposure to tobacco cessation advertising, as well as similar awareness of and use of evidence based cessation methods as compared to heterosexual peers. CONCLUSIONS: The similarly of awareness and use of cessation support indicates a need for LGBT-specific efforts to reduce smoking disparities. Potential interventions would include: improving awareness of, access to and acceptability of current cessation methods for LGBT patients, developing tailored cessation interventions, and denormalizing smoking in LGBT community spaces. PMID- 26014456 TI - Smoking Behaviors and Attitudes Among Clients and Staff at New York Addiction Treatment Programs Following a Smoking Ban: Findings After 5 Years. AB - INTRODUCTION: Addiction treatment clients are more likely to die of tobacco related diseases than of alcohol or illicit drug-related causes. We aimed to assess smoking behavior, and smoking-related attitudes and services, in New York addiction treatment programs before a statewide smoking ban in treatment facilities was implemented (2008), 1 year (2009) and 5 years after implementation (2013). METHODS: We conducted surveys at each time point with clients (N = 329, 341, and 353, respectively) and staff (N = 202, 203, and 166, respectively) from five residential and two methadone maintenance programs in New York State. At each data collection wave, questionnaires measured smoking behavior as well as smoking-related knowledge, attitudes, and experiences with tobacco cessation services as part of addiction treatment. RESULTS: Staff smoking prevalence decreased from 35.2% in 2008 to 21.8% in 2013 (P = .005) while client smoking prevalence over the same period was unchanged (68.1% vs. 66.0%, P = .564). Among clients who smoked, mean cigarettes per day decreased from 13.7 (SD = 8.38) to 10.2 (SD = 4.44; P < .001). There were significant time-by-treatment-type interactions for client tobacco-related attitudes and cessation services received; and for staff self-efficacy and cessation services provided. In residential programs, scores for most items decreased (became less positive) in 2009 followed by a partial rebound in 2013. Methadone program scores tended to rise (become more positive) throughout the study period. CONCLUSIONS: Staff and clients may respond differentially to tobacco-free policies depending on type of treatment program, and this finding may help to inform the implementation of tobacco-free policies in other statewide addiction treatment systems. PMID- 26014457 TI - Hepatitis B Virus Immunization Before and After Pediatric Liver Transplantation: Check, Catch-Up, and Check Again! PMID- 26014458 TI - Dzyaloshinskii-Moriya Interaction and Spiral Order in Spin-orbit Coupled Optical Lattices. AB - We show that the recent experimental realization of spin-orbit coupling in ultracold atomic gases can be used to study different types of spin spiral order and resulting multiferroic effects. Spin-orbit coupling in optical lattices can give rise to the Dzyaloshinskii-Moriya (DM) spin interaction which is essential for spin spiral order. By taking into account spin-orbit coupling and an external Zeeman field, we derive an effective spin model in the Mott insulator regime at half filling and demonstrate that the DM interaction in optical lattices can be made extremely strong with realistic experimental parameters. The rich finite temperature phase diagrams of the effective spin models for fermions and bosons are obtained via classical Monte Carlo simulations. PMID- 26014459 TI - Inter-hemispheric desynchronization of the human MT+ during visually induced motion sickness. AB - Visually induced motion sickness (VIMS) is triggered in susceptible individuals by stationary viewing of moving visual scenes. VIMS is often preceded by an illusion of self-motion (vection) and/or by inappropriate optokinetic nystagmus (OKN) responses associated with increased activity in the human motion-sensitive middle temporal area (MT+). Neuroimaging studies have reported predominant right hemispheric activation in MT+ during both vection and OKN, suggesting that VIMS may result from desynchronization of activity between left and right MT+ cortices. However, this possibility has not been directly tested. To this end, we presented VIMS-free and VIMS-inducing movies in that order while measuring the temporal correlations between corresponding left and right visual cortices (including MT+) using functional magnetic resonance imaging. The inter hemispheric correlation was reduced significantly during the viewing of the VIMS inducing movie compared to the control VIMS-free movie in the MT+ of subjects reporting VIMS, but not in insusceptible subjects. In contrast, there were no significant inter-hemispheric differences within VIMS-free or VIMS-inducing movie exposure for visual area V1, V2, V3, V3A or V7. Our findings provide the first evidence for an association between asynchronous bilateral MT+ activation and VIMS. Desynchronization of left and right MT+ regions may reflect hemispheric asymmetry in the activities of functional networks involved in eye movement control, vection perception and/or postural control. PMID- 26014461 TI - Promoting Health and Wellness in Congregations Through Lay Health Educators: A Case Study of Two Churches. AB - Religious institutions are in regular contact with people who need education about and support with health issues. Creating lay health educators to serve in these communities can promote health initiatives centered on education and accessing resources. This paper is a prospective observational report of the impact of trained lay health community congregation members in two faith communities based on an urban setting. We describe health efforts made in an African-American Methodist church and in a Latino Spanish-speaking Catholic church. We review the intricacies in establishing trust with the community, the training of lay health educators, and the implementation strategies and outcomes of health initiatives for these communities. PMID- 26014462 TI - Transitional Metal/Chalcogen Dependant Interactions of Hairpin DNA with Transition Metal Dichalcogenides, MX2. AB - Owing to the attractive properties that transition metal dichalcogenides (TMDs) display, they have found recent application in the fabrication of biosensing devices. These devices involve the immobilization of a recognition element such as DNA onto the surface of TMDs. Therefore, it is imperative to examine the interactions between TMDs and DNA. Herein, we explore the effect of different transition metals (Mo and W) and chalcogens (S and Se) on the interactions between hairpin DNA and TMDs of both bulk and t-BuLi exfoliated forms. We discovered that the interactions are strongly dependent on the metal/chalcogen composition in TMDs. PMID- 26014463 TI - Inflammatory pain memory facilitates occlusal interference-induced masticatory muscle hyperalgesia in rats. AB - BACKGROUND: Patients with an orofacial pain history appear to be more susceptible to occlusal interference pain in dental practice for unknown reasons. Pain memory has a critical function in subsequent pain perception. This study aims to explore whether orofacial pain memory could affect the masticatory muscle pain perception for occlusal interference. METHODS: Cross-injection of 2% carrageenan into bilateral masseters in male rats was carried out to establish the inflammatory pain memory model. The effects of pain memory on masseter muscle nociception were tested by applying crowns with heights beyond the occlusal plane by 0.2 or 0.4 mm onto a maxillary molar 2 weeks after inflammation in the right masseter. The 0.4 mm crowns were removed on day 2 or day 4 after application to further confirm the effects of pain memory. Moreover, memory impairment was established using ibotenic acid (IBO) infusion into the bilateral hippocampus, followed by behaviour tests, including the Morris water maze test and the locomotor activity test. The relationship between pain memory and occlusal interference-induced masseter muscle pain perception was subsequently re-examined. The head withdrawal thresholds of masseters on both sides were measured to reflect the perception. RESULTS: Inflammatory pain memory aggravated the 0.2-mm crown-induced mechanical hyperalgesia of the masseters, but not in the 0.4-mm crown group. However, the recovery of the 0.4-mm crown-induced mechanical hyperalgesia was postponed. The effects of pain memory were reversed in rats with impaired mnemonic function of the hippocampus. CONCLUSIONS: Inflammatory pain memory facilitated occlusal interference-induced masseter muscle pain. PMID- 26014464 TI - Dutch neonatologists have adopted a more interventionist approach to neonatal care. AB - AIM: This study investigated whether continuous improvements to neonatal care and the legalisation of newborn euthanasia in 2005 had changed end-of-life decisions by Dutch neonatologists. METHODS: We carried out a retrospective study of foetuses and neonates of more than 22 weeks' gestation that died in the delivery room or in the neonatal intensive care unit (NICU) of a tertiary referral hospital in the Netherlands, comparing end-of-life decisions and mortality in 2001-2003 and 2008-2010, before and after euthanasia legislation was introduced. RESULTS: In 2008-2010, there were more deaths in the delivery room due to termination of pregnancy than in 2001-2003 (17% versus 29%, p = 0.031), and fewer infants received comfort medication (12% versus 20%, p = 0.078). The main mode of death in the NICU was the withdrawal of life-sustaining therapy. The number of days that infants lived increased significantly between 2001-2003 (11.5 days) and 2008-2010 (18.4 days, p < 0.006). Most infants received comfort medication, and neuromuscular blocking agents were administered incidentally. CONCLUSION: Terminations increased after changes in healthcare regulations. Modes of death in the NICU remained similar over 10 years. The increased duration of NICU treatment before dying suggests a more interventionist approach to treatment in 2008-2010. PMID- 26014465 TI - Optimizing the use of telephone nursing advice for upper respiratory infection symptoms. AB - OBJECTIVES: To describe efforts to optimize telephone self-care advice for upper respiratory infection (URI) symptoms by registered nurses in Kaiser Permanente Northern California's Appointment and Advice Call Center, and to assess the sufficiency of this advice. STUDY DESIGN: Retrospective observational study. METHODS: The study sample included 279,625 calls from adults 18 years and older that resulted in self-care advice for URI symptoms in 2009. Utilizing electronic medical records of these calls and follow-ups, we determined the rate of return calls within 7 days and the clinical outcomes associated with these. Advice for self-care at home was considered sufficient if no return calls received within 7 days of the original call were associated with the need for a "higher" level of care, such as an appointment. RESULTS: Self-care advice was sufficient for 88% of index advice calls, with either no follow-up calls within 7 days associated with a higher level of care, or follow-up calls only for additional advice or nonmedical information. CONCLUSIONS: Telephone advice for self-care by registered nurses can effectively manage URI symptoms for most otherwise healthy adults. PMID- 26014466 TI - Clinical provider perceptions of proactive medication discontinuation. AB - OBJECTIVES: Polypharmacy and adverse drug events lead to considerable healthcare costs and morbidity, yet there is little to guide clinical providers in the area of discontinuing medications that may not be necessary. We sought to understand providers' beliefs and attitudes about polypharmacy and medication discontinuation. STUDY DESIGN: Qualitative study using semi-structured interviews of 20 providers with prescribing privileges at 2 US Veterans Affairs Medical Centers, from April 2012 to October 2012. METHODS: Transcribed interviews were analyzed using grounded thematic analysis, a systematic approach to deriving qualitative themes from textual data. RESULTS: We identified 10 themes within 4 domains of medication discontinuation. Within the first domain (medication factors), we identified 2 themes: 1) medication characteristics, and 2) uncertainties of why a patient was taking a particular drug. Within the second domain (patient factors), we identified 3 themes: 3) clinical picture of the patient, 4) clinicians' understanding of the patients' knowledge and beliefs, and 5) patients' adherence. Within the third domain (clinical provider factors), we identified 2 themes: 6) professional identity, and 7) providers' decisions related to their own beliefs about medications. Within the fourth domain (system factors), we identified 3 themes: 8) multiple providers, 9) workload, and 10) external directives and policies such as structural components of a healthcare system. CONCLUSIONS: Provider decisions to discontinue medications are affected by factors at all levels of the clinical encounter. Our findings have implications for development and implementation of interventions to improve appropriate medication discontinuation via enhanced medication reviews, enriched patient-provider communication, and better system-level structures. This, in turn, may reduce the continued prescribing of potentially inappropriate medications that can lead to adverse outcomes or increased healthcare costs. PMID- 26014467 TI - Managing specialty care in an era of heightened accountability: emphasizing quality and accelerating savings. AB - OBJECTIVES: Engaging specialists in accountable care organizations (ACOs) may make them more responsive to pressures to lower costs and raise quality. This paper introduces a novel accountable care design in cardiology. STUDY DESIGN: Preliminary study using baseline data. METHODS: The Accelerating Clinical Transformation for Creating Value and Controlling Cost in Cardiology concept study involved providers employed by the Providence Medical Group, Oregon. First, using claims data from 2009 through 2011, we created a historic budget to capture cardiovascular disease (CVD)-related costs for attributed patients on a per patient per year basis. Second, we introduced a validated quality metric, the Clinical Performance and Value vignette, to a sample of cardiology providers to examine clinical practice variation in treating coronary heart disease (CHD), coronary heart failure (CHF), and atrial fibrillation (AF). Lastly, we analyzed reimbursement claims paid for CHD, CHF, and AF, and forecasted potential cost savings from reductions in clinical variation. RESULTS: Examining historic costs, we found they were stable over time, but variable by provider and disease. Quality scores, measured against evidence-based cardiology guidelines, ranged from 48.9% to 85.4% (mean=66.8%; SD=5.4%), and the prevalence of unnecessary testing was 46% in CHD, 71% in CHF, and 30% in AF. We project that reducing unnecessary care by 15% to 25% would yield $200,000 to $498,000 in savings ($50 $83 per patient visit) annually. And, if the top 10% of providers as determined by CVD-related costs reduced their costs by 25%, savings would be an additional $283,512 per year. CONCLUSIONS: This accountable care design framework is timely for cardiology and could be applied for other specialty conditions, such as cancer. PMID- 26014468 TI - Antibiotic prescribing for respiratory infections at retail clinics, physician practices, and emergency departments. AB - OBJECTIVES: To compare antibiotic prescribing among retail clinics, primary care practices, and emergency departments (EDs) for acute respiratory infections (ARIs): antibiotics-may-be-appropriate ARIs (eg, sinusitis) and antibiotics-never appropriate ARIs (eg, acute bronchitis). STUDY DESIGN: We analyzed retail clinic data from the electronic health records of the 3 largest retail clinic chains in the United States, and data on visits to primary care practices and EDs from the nationally representative National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. METHODS: Using multivariate models, we estimated an adjusted antibiotic prescribing rate for each site of care, controlling for differences in patient characteristics and diagnosis. RESULTS: From 2007 to 2009 in the United States, there were 3 million, 167 million, and 29 million ARI visits at retail clinics, primary care practices, and EDs, respectively. For all ARI visits, the adjusted antibiotic prescribing rate at retail clinics (58%) was similar to the rate at primary care practices (62%; P=.09) and EDs (59%; P=.48). For antibiotics-may-be-appropriate ARI visits, the adjusted antibiotic prescribing rate (95%) at retail clinics was higher than at primary care practices (85%; P<.01) and EDs (83%; P<.01). For antibiotics-never appropriate ARI visits, the adjusted antibiotic prescribing rate (34%) at retail clinics was lower than at primary care practices (51%; P<.01) and EDs (48%; P<.01). CONCLUSIONS: Compared with primary care practices and EDs, there was no difference at retail clinics in overall ARI antibiotic prescribing. At retail clinics, antibiotic prescribing was more diagnosis-appropriate. PMID- 26014469 TI - Persistent high utilization in a privately insured population. AB - OBJECTIVES: To describe individuals characterized as persistent high users--that is, individuals who are in the top 10% of users every year over the 3-year study period. STUDY DESIGN: Retrospective cohort study of 4 groups in a privately insured population. Groups were defined by the number of years an enrollee was in the top 10% of the spending group (top decile) for the period from 2009 to 2011: persistent high-user group (3 out of 3 years in the top decile spending group); frequent high-user group (2 out of 3 years in top decile); incidental high-user group (1 out of 3 years in top decile); and never high user group (0 out of 3 years in top decile). METHODS: This study used insurance claims data to examine enrollees with persistently high health service utilization. Data for the year 2008 were utilized to assess baseline individual characteristics. Annual data for 2009 to 2011 were used to examine healthcare expenditures, utilization patterns, and specific clinical conditions among the 4 groups of the study sample. RESULTS: Among 42,038 enrollees, 1216 (2.9%) met the criteria as persistent high users. Over a 3-year period, this group accounted for 21% of total healthcare expenditure. Compared with the other groups, persistent high users had higher overall disease burden due to multiple chronic conditions and incurred significantly higher expenses in medication and professional services (including primary and specialty care). CONCLUSIONS: This study highlights the need to proactively engage employees and their dependents for primary and secondary prevention of common chronic diseases before an individual's health status, healthcare utilization, and medical cost become difficult to manage. PMID- 26014470 TI - Redefining and reaffirming managed care for the 21st century. PMID- 26014471 TI - Variation in printed handoff documents: Results and recommendations from a multicenter needs assessment. AB - BACKGROUND: Handoffs of patient care are a leading root cause of medical errors. Standardized techniques exist to minimize miscommunications during verbal handoffs, but studies to guide standardization of printed handoff documents are lacking. OBJECTIVE: To determine whether variability exists in the content of printed handoff documents and to identify key data elements that should be uniformly included in these documents. SETTING: Pediatric hospitalist services at 9 institutions in the United States and Canada. METHODS: Sample handoff documents from each institution were reviewed, and structured group interviews were conducted to understand each institution's priorities for written handoffs. An expert panel reviewed all handoff documents and structured group-interview findings, and subsequently made consensus-based recommendations for data elements that were either essential or recommended, including best overall printed handoff practices. RESULTS: Nine sites completed structured group interviews and submitted data. We identified substantial variation in both the structure and content of printed handoff documents. Only 4 of 23 possible data elements (17%) were uniformly present in all sites' handoff documents. The expert panel recommended the following as essential for all printed handoffs: assessment of illness severity, patient summary, action items, situation awareness and contingency plans, allergies, medications, age, weight, date of admission, and patient and hospital service identifiers. Code status and several other elements were also recommended. CONCLUSIONS: Wide variation exists in the content of printed handoff documents. Standardizing printed handoff documents has the potential to decrease omissions of key data during patient care transitions, which may decrease the risk of downstream medical errors. PMID- 26014472 TI - Eccrine sweat gland development and sweat secretion. AB - Eccrine sweat glands help to maintain homoeostasis, primarily by stabilizing body temperature. Derived from embryonic ectoderm, millions of eccrine glands are distributed across human skin and secrete litres of sweat per day. Their easy accessibility has facilitated the start of analyses of their development and function. Mouse genetic models find sweat gland development regulated sequentially by Wnt, Eda and Shh pathways, although precise subpathways and additional regulators require further elucidation. Mature glands have two secretory cell types, clear and dark cells, whose comparative development and functional interactions remain largely unknown. Clear cells have long been known as the major secretory cells, but recent studies suggest that dark cells are also indispensable for sweat secretion. Dark cell-specific Foxa1 expression was shown to regulate a Ca(2+) -dependent Best2 anion channel that is the candidate driver for the required ion currents. Overall, it was shown that cholinergic impulses trigger sweat secretion in mature glands through second messengers - for example InsP3 and Ca(2+) - and downstream ion channels/transporters in the framework of a Na(+) -K(+) -Cl(-) cotransporter model. Notably, the microenvironment surrounding secretory cells, including acid-base balance, was implicated to be important for proper sweat secretion, which requires further clarification. Furthermore, multiple ion channels have been shown to be expressed in clear and dark cells, but the degree to which various ion channels function redundantly or indispensably also remains to be determined. PMID- 26014474 TI - BRAF mutations in pediatric metanephric tumors. AB - Metanephric neoplasms of the kidney are uncommon, and some cases are associated with papillary carcinoma. Most cases of metanephric adenoma occur in adults, with fewer than 25 cases reported in children, and metanephric adenofibroma is even less common. The few metanephric tumors studied at the genetic level have not shown the gains of chromosomes 7 and 17 commonly seen in renal cell carcinoma, suggesting that the carcinoma arising in this setting has a separate genetic origin from the adenoma. However, the assumption that this carcinoma has the same chromosome gains as sporadic renal cell carcinoma has never been validated. We studied 4 cases of metanephric tumors in children, including 1 metanephric adenofibroma with papillary carcinoma. The composite tumor was studied by single nucleotide polymorphism array and fluorescence in situ hybridization, with the adenoma and carcinoma components analyzed separately. No copy number alterations were detected in either component. A BRAF V600E mutation has been reported in most cases of metanephric adenoma in adults. We performed BRAF V600E immunostaining and sequencing in our 4 pediatric cases. Three cases had a BRAF V600E mutation including the composite tumor, with both the adenoma and carcinoma components showing the same mutation. This finding provides the first genetic evidence that these 2 tumors are biologically linked. Ten cases each of pediatric renal cell carcinoma and Wilms tumor were immunonegative. Thus, BRAF V600E immunostaining is a helpful marker for pediatric metanephric adenoma, and additional research is required on the possible role of this mutation in the development of renal carcinoma. PMID- 26014473 TI - Temporal patterns of gene expression during calyx of held development. AB - Relating changes in gene expression to discrete developmental events remains an elusive challenge in neuroscience, in part because most neural territories are comprised of multiple cell types that mature over extended periods of time. The medial nucleus of the trapezoid body (MNTB) is an attractive vertebrate model system that contains a nearly homogeneous population of neurons, which are innervated by large glutamatergic nerve terminals called calyces of Held (CH). Key steps in maturation of CHs and MNTB neurons, including CH growth and competition, occur very quickly for most cells between postnatal days (P)2 and P6. Therefore, we characterized genome-wide changes in this system, with dense temporal sampling during the first postnatal week. We identified 541 genes whose expression changed significantly between P0-6 and clustered them into eight groups based on temporal expression profiles. Candidate genes from each of the eight profile groups were validated in separate samples by qPCR. Our tissue sample permitted comparison of known glial and neuronal transcripts and revealed that monotonically increasing or decreasing expression profiles tended to be associated with glia and neurons, respectively. Gene ontology revealed enrichment of genes involved in axon pathfinding, cell differentiation, cell adhesion and extracellular matrix. The latter category included elements of perineuronal nets, a prominent feature of MNTB neurons that is morphologically distinct by P6, when CH growth and competition are resolved onto nearly all MNTB neurons. These results provide a genetic framework for investigation of general mechanisms responsible for nerve terminal growth and maturation. PMID- 26014475 TI - Alteration of Delta-like ligand 1 and Notch 1 receptor in various placental disorders with special reference to early onset preeclampsia. AB - Notch signaling pathway has been shown to be dysregulated in placentas with preeclampsia, but there has been a lack of studies on methylation of Notch family genes in this disorder. We therefore executed methylation-specific polymerase chain reaction and immunostaining for Notch 1 receptor and the activating ligand, Delta-like (DLL) 1, with placental tissues from cases of preeclampsia (early onset, n = 18; late-onset, n = 19) and other placental disorders, including maternal complications such as diabetes mellitus and collagen disease (n = 10), fetal growth restriction (n = 17), fetal anomaly (n = 23), preterm birth (n = 15), miscarriage (n = 25), and hydatidiform moles (n = 9) as well as term births (n = 12). The frequency of DLL1 methylation was higher in early onset preeclamptic placentas (61%) than the other subjects (0%-36%; P <= .016). Appreciable samples (36%) of miscarriage also represented DLL1 methylation. None of the samples studied showed Notch 1 methylation. On gestational period-matched analysis, the rate of DLL1 methylation was higher in early onset preeclampsia (83.3%) than preterm birth (13.3%; P < .001), with no significant differences in clinical backgrounds between the two. In this analysis, increase of syncytial knots and accelerated villous maturation were most prominent in DLL1-methylated placentas with early onset preeclampsia. Notch 1 and DLL1 expressions in villous trophoblasts and endothelial cells were significantly lower in early onset preeclamptic placentas as compared with preterm birth controls. In conclusion, altered Notch signaling via methylation of DLL1 is likely involved in possible disease-related mechanisms of early onset preeclampsia. Alternatively, DLL1 methylation in early onset preeclampsia could be a manifestation of a lack of placental maturation, similar to miscarriage. PMID- 26014476 TI - Feeding Strategies Derived from Behavioral Economics and Psychology Can Increase Vegetable Intake in Children as Part of a Home-Based Intervention: Results of a Pilot Study. AB - BACKGROUND: Behavioral economics and psychology have been applied to altering food choice, but most studies have not measured food intake under free-living conditions. OBJECTIVES: To test the effects of a strategy that pairs positive stimuli (ie, stickers and cartoon packaging) with vegetables and presents them as the default snack. DESIGN: A randomized controlled trial was conducted with children who reported consumption of fewer than two servings of vegetables daily. Children (aged 3 to 5 years) in both control (n=12) and treatment (n=12) groups received a week's supply of plainly packaged (ie, generic) vegetables, presented by parents as a free choice with an alternative snack (granola bar), during baseline (Week 1) and follow-up (Week 4). During Weeks 2 and 3, the control group continued to receive generic packages of vegetables presented as a free choice, but the treatment group received vegetables packaged in containers with favorite cartoon characters and stickers inside, presented by parents as the default choice. Children in the treatment group were allowed to opt out of the vegetables and request the granola bar after an imposed 5-minute wait. STATISTICAL ANALYSIS: General Linear Model repeated measures analysis of variance was conducted to compare vegetable and granola bar intake between control and treatment groups across the 4-week study. Both within- and between-subjects models were tested. RESULTS: A time*treatment interaction on vegetable intake was significant. The treatment group increased vegetable intake from baseline to Week 2 relative to control (P<0.01), but the effects were not sustained at Week 4 when the treatment was removed. Granola bar intake decreased in the treatment group at Week 2 (P<=0.001) and Week 3 (P<=0.005) relative to baseline. CONCLUSIONS: Parents were able to administer feeding practices derived from behavioral economics and psychology in the home to increase children's vegetable intake and decrease intake of a high-energy-density snack. Additional studies are needed to test the long-term sustainability of these practices. PMID- 26014477 TI - [Aging Brain Care Program from Indianapolis: Transferability to the German healthcare system]. AB - BACKGROUND: New and innovative concepts of care management have been developed to improve the health of older adults with dementia and depression. AIM: This article describes the American aging brain care (ABC) program and the possible transfer to the German healthcare system is discussed. MATERIAL AND METHODS: The ABC medical home model in Indianapolis incorporates a specialized geriatric healthcare center which is affiliated to the Eskenazi Hospital as well as a program involving home-based domestic visits by healthcare personnel to affected people. The diagnoses are made in the geriatric center where therapy and treatment are also planned. These stages are carried out in a multiprofessional team, which identifies the individual needs of the patients and relatives and discusses these in family conferences as well as in close consultation with the primary care center of the hospital. The care, diagnosis and therapy are coordinated using a self-developed software for the program and via predetermined pathways and procedural instructions on the approach in the healthcare center and in the domestic visit program. RESULTS AND CONCLUSION: From the perspective of the authors the core elements of the program include not only the use of a home based care model but also the selection and training of a new type of front-line care provider. Models like the program presented here show great promise for meeting the demands of a rapidly expanding population of vulnerable older adults. PMID- 26014478 TI - Adult Hirschsprung's disease. PMID- 26014479 TI - Yi Qi Qing Re Gao formula ameliorates puromycin aminonucleoside-induced nephrosis by suppressing inflammation and apoptosis. AB - BACKGROUND: Yi Qi Qing Re Gao (YQQRG) formula is a traditional Chinese herbal medicine used to treat chronic nephritis. This study was designed to evaluate the underlying mechanism in the use of YQQRG formula to treat nephrosis induced by puromycin aminonucleoside (PAN). METHODS: Thirty-six male Wistar rats were randomly divided into 3 groups of 12 rats each: a sham group, a vehicle-treated PAN model group (PAN), and a group treated with YQQRG (PAN + YQQRG). The PAN model was established by a single intravenous injection of PAN at a dose of 40 mg/kg body weight; rats in the sham group received the same volume of saline. Twenty-four hour urinary protein was measured 0, 3, 5, 10, and 15 days after the injection. The rats were sacrificed on day 10 and day 15 and the serum lipid profile examined. The renal cortex of each rat was stained with periodic acid Schiff reagent and the pathologic alterations and ultrastructural changes were examined by transmission electron microscopy. In situ cell apoptosis was detected by a terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate biotin nick end-labeling (TUNEL) assay. Transcriptive levels of inflammatory markers and molecules associated with apoptosis were detected by a real-time polymerase chain reaction and expression of proteins was examined by either immunohistochemistry or Western blot analysis. RESULTS: YQQRG significantly decreased urinary protein level, and lowered serum lipid level. YQQRG also attenuated histologic lesions in the rat kidneys. Activation of inflammatory markers was largely restored by the administration of YQQRG. TUNEL assay showed that YQQRG decreased the number of apoptotic cells. Both mRNA and protein levels of caspase-3 were significantly reduced in the group treated with YQQRG, whereas expression of the Bcl-2 protein increased in the YQQRG group. CONCLUSIONS: YQQRG alleviated kidney injury in PAN-treated rats, possibly through anti-inflammatory and anti-apoptotic effects. PMID- 26014480 TI - Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: discovery and computational modeling of a new series of ligands with nanomolar affinity. AB - Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors. PMID- 26014481 TI - Anti-arthritic agents: progress and potential. AB - Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents. PMID- 26014483 TI - New developments in antiinfectives research for tropical infectious diseases. PMID- 26014484 TI - Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaffold as a hydrophobic core structure. AB - Molecular structure calculations indicated that the dibenzosilole skeleton could be well superposed on phenanthridinone, which is a structural component of ligands of retinoic acid receptor-related orphan receptors (RORs). Therefore, we designed, synthesized and biologically evaluated a series of novel ROR ligands based on the dibenzosilole scaffold as a hydrophobic core structure. Dibenzosilole derivatives bearing a hexafluoro-2-hydroxypropyl group on the benzene ring exhibited significant ROR-inhibitory activity, comparable to that of the lead phenanthridinone derivative 5. Our results indicate that the dibenzosilole skeleton would be a useful scaffold for developing novel biologically active compounds, and that cis-amide structure can be replaced by an alkylsilyl functionality. PMID- 26014482 TI - Cloning, characterization and anion inhibition study of a beta-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans. AB - The oral pathogenic bacterium involved in human dental caries formation Streptococcus mutans, encodes for two carbonic anhydrase (CA, EC 4.2.1.1) one belonging to the alpha- and the other one to the beta-class. This last enzyme (SmuCA) has been cloned, characterized and investigated for its inhibition profile with a major class of CA inhibitors, the inorganic anions. Here we show that SmuCA has a good catalytic activity for the CO2 hydration reaction, with kcat 4.2*10(5)s(-1) and kcat/Km of 5.8*10(7)M(-1)*s(-1), being inhibited by cyanate, carbonate, stannate, divannadate and diethyldithiocarbamate in the submillimolar range (KIs of 0.30-0.64mM) and more efficiently by sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid (KIs of 15-46MUM). The anion inhibition profile of the S. mutans enzyme is very different from other alpha- and beta-CAs investigated earlier. Identification of effective inhibitors of this new enzyme may lead to pharmacological tools useful for understanding the role of S. mutans CAs in dental caries formation, and eventually the development of pharmacological agents with a new mechanism of antibacterial action. PMID- 26014485 TI - A rare case of infectious colitis. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for numerous infectious processes. Gastrointestinal tract involvement is rather rare and only a handful of cases of MRSA colitis have been reported in North America. We present a case of MRSA colitis in an adult without apparent risk factors. Abdominal computed tomography (CT) showed thickening of the sigmoid colon, indicative of colitis, and empiric therapy with ciprofloxacin and metronidazole was started. Initial work-up for infection-including blood and stool cultures, and stool Clostridium difficile toxin assay-was negative. The patient's clinical status improved but his diarrhea did not abate. Repetition of stool culture demonstrated luxuriant growth of MRSA sensitive to vancomycin. Oral vancomycin was administered and the patient's symptoms promptly ceased. PMID- 26014486 TI - Functional and histopathological changes induced by intraparenchymal injection of kainic acid in the rat cervical spinal cord. AB - Kainic acid (KA) is an analog of the neurotransmitter glutamate and is widely used as an excitotoxic agent to lesion spinal cord networks, thus, providing an interesting model to learn basic mechanisms of spinal cord injury. The present work was aimed to evaluate motor and sensory performance of rats and analyze morphometric parameters of spinal cord neurons after KA injection. Animals were injected either with 0.75, 1 or 1.25 mM of KA at the C5 segment of the cervical spinal cord. Motor and sensory performance of the rats were evaluate at day 0 (before injection) and at days 1, 2, 3 and 7 post-injection (pi) and compared with those of saline-treated and non-operated animals. Animals were sacrificed at each time point for morphometric and histopathological analysis and compared among groups. All KA-treated animals showed a significant impairment at the motor and sensory tests for the ipsilateral forelimb in a concentration-dependent manner in comparison to saline-treated and non-operated animals. Neuronal cell count showed a significant loss of neurons at C4, C5 and C6 cervical segments when compared with those of saline-treated and non-operated animals. The contralateral side of the cervical segments in KA-treated rats remained unchanged. Some improvement at the motor and sensory tests was observed in animals injected with 0.75 and 1mM KA. Moreover, a mild increase in the neuronal count of the damaged segments was also recorded. The improvement recorded in the motor and sensory tests by day 7 pi may be a consequence of a neuron repairing mechanism triggered soon after the KA excitotoxic effect. PMID- 26014487 TI - Decreased work ability associated to indoor air problems--An intervention (RCT) to promote health behavior. AB - INTRODUCTION: Indoor air problems may induce respiratory irritation and inflammation. In occupational settings, long-lasting non-specific building related symptomatology, not fully medically explained, is encountered. The symptomatology may lead to illness, avoidance behavior and decreased work ability. In Finland, investigations of workers suspected of occupational asthma have revealed excess disability. There are no well-established clinical practices for the condition. OBJECTIVE: The aim was to develop a clinical intervention for patients with non-specific indoor air-related symptoms and decreased work ability. METHODS: A randomized controlled trial including psychoeducation and promotion of health behavior was carried out in 55 patients investigated for causal relationship between work-related respiratory symptoms and moisture damaged workplaces. Inclusion criteria for disability was the work ability score (WAS)<=7 (scale 0-10) and indoor air-related sick leave >=14 days the preceding year. After medical evaluation and the 3-session counseling intervention, follow up at 6-months was assessed using self-evaluated work-ability, sick leave days, quality of life, and illness worries as outcome measures. RESULTS: The mean symptom history was 55.5 months. 82% (45 out of 55) had asthma with normal lung function tests in most cases, although reporting abundant asthma symptoms. 81% of patients (39/48) had symptomatology from multiple organ systems without biomedical explanation, despite environmental improvements at work place. At the psychological counseling sessions, 15 (60%) patients of the intervention (INT, n=25) group showed concerns of a serious disease and in 5 (20%), concerns and fears had led to avoidance and restricted personal life. In the 6-month follow up, the outcomes in the INT group did not differ from the treatment as usual group. CONCLUSION: No intervention effects were found. Patients shared features with medically unexplained symptoms and sick building syndrome or idiopathic environmental intolerance. Long environment-attributed non-specific symptom history and disability may require more intensive interventions. There is a need for improved recognition and early measures to prevent indoor-associated disability. TRIAL REGISTRATION NUMBER: Single-center randomized controlled trial (ISRCTN33165676). PMID- 26014489 TI - Structural and dynamic changes adopted by EmrE, multidrug transporter protein- Studies by molecular dynamics simulation. AB - EmrE protein transports positively charged aromatic drugs (xenobiotics) in exchange for two protons and thus provides bacteria resistance to variety of drugs. In order to understand how this protein may recognize ligands, the monomer and asymmetric apo-form of the EmrE dimer embedded in a heterogeneous phospholipid (POPE+POPG) membrane were studied by molecular dynamics simulations. Dimer is regarded as a functional form of the transporter, but to understand molecular aspects of its mode of action, a monomer was also included in our work. We analyzed hydrogen bonds which include inter- and intra-molecular interactions. Analyzing the long-lasting H-bond interactions, we found that water access to the internal transmembrane segments is regulated by residues with aromatic or basic side chains and fluctuating transmembrane helices. Our finding supports that GLU14 in EmrE apo-form is ready to interact or bind with substrate molecule. The analysis of distance center of masses and water entrance area indicate the feasibility of the dimer to undergo induced fit in order to accommodate a ligand. The results indicate that a binding pattern can be formed in the EmrE in such a way that GLU14 binds to the positively charged fragment of a substrate molecule, and other aromatic residues (i.e., TRP63 and TYR40) located in vicinity may accommodate other non-polar parts of substrate molecule. The results of our simulation also allow us to support experimentally testable hypotheses concerning functional inward-outward conformational changes of the protein. PMID- 26014488 TI - Effect of surface-potential modulators on the opening of lipid pores in liposomal and mitochondrial inner membranes induced by palmitate and calcium ions. AB - The effect of surface-potential modulators on palmitate/Ca2+-induced formation of lipid pores was studied in liposomal and inner mitochondrial membranes. Pore formation was monitored by sulforhodamine B release from liposomes and swelling of mitochondria. zeta-potential in liposomes was determined from electrophoretic mobility. Replacement of sucrose as the osmotic agent with KCl decreased negative zeta-potential in liposomes and increased resistance of both mitochondria and liposomes to the pore inducers, palmitic acid, and Ca2+. Micromolar Mg2+ also inhibited palmitate/Ca2+-induced permeabilization of liposomes. The rate of palmitate/Ca2+-induced, cyclosporin A-insensitive swelling of mitochondria increased 22% upon increasing pH from 7.0 to 7.8. At below the critical micelle concentration, the cationic detergent cetyltrimethylammonium bromide (10 MUM) and the anionic surfactant sodium dodecylsulfate (10-50 MUM) made the zeta-potential less and more negative, respectively, and inhibited and stimulated opening of mitochondrial palmitate/Ca2+-induced lipid pores. Taken together, the findings indicate that surface potential regulates palmitate/Ca2+-induced lipid pore opening. PMID- 26014490 TI - Erratum to: Diagnostic and prognostic value of sCD14-ST--presepsin for patients admitted to hospital intensive care unit (ICU). PMID- 26014491 TI - A public health strategy for e-cigarettes. AB - The e-cigarette may present a new and significant Public Health problem: Studies published so far do not seem to indicate that e-cigarette use is just a passing trend. If e-cigarette use is less harmless than it is portrayed in many advertisements, Public Health would do well to start a serious discussion about a suitable prevention policy as soon as possible.The aim of this short paper is to discuss a range of measures designed to prevent e-cigarette consumption.Concretely, we suggest to monitor e-cigarette use, the e-cigarette industry and prevention policies, to implement a vapor-free policy, to develop help to quit e-cigarette use, to inform about the health risks of e-cigarette use, to establish regulations on e-cigarette advertising, promotion and sponsorship, and to introduce taxes on e-cigarettes. PMID- 26014492 TI - New findings on the function and potential applications of the trimeric autotransporter adhesin. AB - Trimeric autotransporter adhesins (TAAs) are located on the surface of many pathogenic Gram-negative bacteria. TAAs belong to the autotransporter protein family and consist of three identical monomers. These obligate homotrimeric proteins are secreted through the bacterial type Vc secretion system and share a common molecular organization that each monomer consists of a N-terminal "passenger" domain and a C-terminal translocation domain. TAAs are important virulence factors that are involved in bacterial life cycle and participate in mediating infection, invasion, dissemination and evasion of host immune responses. TAAs have also proved to be useful for many applications, such as vaccines and disease biomarkers. We here mainly focused on new findings on bio function and application of TAAs in addition to their common structure and secretion mechanisms. PMID- 26014493 TI - Spatial distribution and abundance of ammonia-oxidizing microorganisms in deep sea sediments of the Pacific Ocean. AB - Nitrification, the aerobic oxidation of ammonia to nitrate via nitrite, is performed by nitrifying microbes including ammonia-oxidizing bacteria (AOB) and archaea (AOA). In the current study, the phylogenetic diversity and abundance of AOB and AOA in deep-sea sediments of the Pacific Ocean were investigated using ammonia monooxygenase subunit A (amoA) coding genes as molecular markers. The study uncovered 3 AOB unique operational taxonomic units (OTUs, defined at sequence groups that differ by <=5 %), which indicates lower diversity than AOA (13 OTUs obtained). All AOB amoA gene sequences were phylogenetically related to amoA sequences similar to those found in marine Nitrosospira species, and all AOA amoA gene sequences were affiliated with the marine sediment clade. Quantitative PCR revealed similar archaeal amoA gene abundances [1.68 * 10(5)-1.89 * 10(6) copies/g sediment (wet weight)] among different sites. Bacterial amoA gene abundances ranged from 5.28 * 10(3) to 2.29 * 10(6) copies/g sediment (wet weight). The AOA/AOB amoA gene abundance ratios ranged from 0.012 to 162 and were negatively correlated with total C and C/N ratio. These results suggest that organic loading may be a key factor regulating the relative abundance of AOA and AOB in deep-sea environments of the Pacific Ocean. PMID- 26014494 TI - Surface refraction of sound waves affects calibration of three-dimensional ultrasound. AB - BACKGROUND: Three-dimensional ultrasound (3D-US) is used in planning and treatment during external beam radiotherapy. The accuracy of the technique depends not only on the achievable image quality in clinical routine, but also on technical limitations of achievable precision during calibration. Refraction of ultrasound waves is a known source for geometric distortion, but such an effect was not expected in homogenous calibration phantoms. However, in this paper we demonstrate that the discontinuity of the refraction index at the phantom surface may affect the calibration unless the ultrasound probe is perfectly perpendicular to the phantom. METHODS: A calibration phantom was repeatedly scanned with a 3D US system (Elekta Clarity) by three independent observers. The ultrasound probe was moved horizontally at a fixed angle in the sagittal plane. The resulting wedge shaped volume between probe and phantom was filled with water to couple in the ultrasound waves. Because the speed of sound in water was smaller than the speed of sound in Zerdine, the main component of the phantom, the angle of the ultrasound waves inside the phantom increased. This caused an apparent shift in the calibration features which was recorded as a function of the impeding angle. To confirm the magnitude and temperature dependence, the experiment was repeated by two of the observers with a mixture of ice and water at 0 degrees C and with thermalized tap water at 21 degrees C room temperature. RESULTS: During the first series of measurements, a linear dependency of the displacements dx of the calibration features on the angle alpha of the ultrasound probe was observed. The three observers recorded significantly nonzero (p < 0.0001) and very consistent slopes of dx/dalpha of 0.12, 0.12, and 0.13 mm/ degrees , respectively.. At 0 degrees C water temperature, the slope increased to 0.18 +/- 0.04 mm/ degrees . This matched the prediction of Snell's law of 0.185 mm/ degrees for a speed of sound of 1,402 m/s at the melting point of ice. At 21 degrees C, slopes of 0.11 and 0.12 mm/ degrees were recorded in agreement with the first experiment at about room temperature. The difference to the theoretical expectation of 0.07 mm/ degrees was not significant (p = 0.09). CONCLUSIONS: The surface refraction of sound waves my affect the calibration of three-dimensional ultrasound. The temperature dependence of the effect rules out alternative explanations for the observed shifts in calibration. At room temperature and for a structure that is 10 cm below the water-phantom interface, a tilt of the ultrasound probe of 10 degrees may result in a position reading that is off by more than half a millimeter. Such errors are of the order of other relevant errors typically encountered during the calibration of a 3D-US system. Hence, care must be taken not to tilt the ultrasound probe during calibration. PMID- 26014495 TI - Parents' Talk About Letters With Their Young Children. AB - A literacy-related activity that occurs in children's homes-talk about letters in everyday conversations-was examined using data from 50 children who were visited every 4 months between 14 and 50 months. Parents talked about some letters, including those that are common in English words and the first letter of their children's names, especially often. Parents' focus on the child's initial was especially strong in families of higher socioeconomic status, and the extent to which parents talked about the child's initial during the later sessions of the study was related to the children's kindergarten reading skill. Conversations that included the child's initial were longer than those that did not, and parents presented a variety of information about this letter. PMID- 26014498 TI - Polymorphisms and plasma levels of IL-27: impact on genetic susceptibility and clinical outcome of bladder cancer. AB - BACKGROUND: Interleukin-27 (IL-27) has been recognized as a pleiotropic cytokine with both pro- and anti-inflammatory properties. Few studies have investigated polymorphisms and serum/plasma levels of IL-27 in diseases including cancers. This study has analyzed the associations of IL-27 gene polymorphisms, as well as plasma levels of IL-27, with susceptibility to bladder cancer and clinical outcome. METHODS: Three hundred and thirty-two patients (nonmuscle-invasive bladder cancer (NMIBC)/muscle-invasive bladder cancer (MIBC): 176/156) included in a 60-month follow-up program and 499 controls were enrolled. Two single nucleotide polymorphisms (SNPs), rs153109 and rs17855750, were genotyped by polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) method. Plasma concentration of IL-27 was determined by ELISA in 124 patients (NMIBC/MIBC: 50/74) and 151 controls. RESULTS: Significantly increased risk for bladder cancer was associated with AG/GG genotypes of rs153109 (P = 0.029). No GG genotype of rs17855750 was observed in controls, while 4 patients were found to be GG homozygotes, suggesting GG genotype may be associated with bladder cancer risk (P = 0.006). For bladder cancer patients, SNP rs17855750 was also associated with increased risk for MIBC. For MIBC patients, but not NMIBC, TG/GG genotypes of rs17855750 turned out to be a protective factor for overall survival (P = 0.035). Significantly reduced plasma levels of IL-27 were observed in both NMIBC and MIBC patients compared with controls (P < 0.0001). CONCLUSION: Our data suggest that polymorphisms and reduced plasma levels of IL-27 may predict the susceptibility to bladder cancer, and rs17855750 may be a useful marker to distinguish patients with high risk of death. PMID- 26014500 TI - Chronic disease management programmes for adults with asthma. AB - BACKGROUND: The burden of asthma on patients and healthcare systems is substantial. Interventions have been developed to overcome difficulties in asthma management. These include chronic disease management programmes, which are more than simple patient education, encompassing a set of coherent interventions that centre on the patients' needs, encouraging the co-ordination and integration of health services provided by a variety of healthcare professionals, and emphasising patient self-management as well as patient education. OBJECTIVES: To evaluate the effectiveness of chronic disease management programmes for adults with asthma. SEARCH METHODS: Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register, MEDLINE (MEDLINE In-Process and Other Non-Indexed Citations), EMBASE, CINAHL, and PsycINFO were searched up to June 2014. We also handsearched selected journals from 2000 to 2012 and scanned reference lists of relevant reviews. SELECTION CRITERIA: We included individual or cluster randomised controlled trials, non-randomised controlled trials, and controlled before-after studies comparing chronic disease management programmes with usual care in adults over 16 years of age with a diagnosis of asthma. The chronic disease management programmes had to satisfy at least the following five criteria: an organisational component targeting patients; an organisational component targeting healthcare professionals or the healthcare system, or both; patient education or self-management support, or both; active involvement of two or more healthcare professionals in patient care; a minimum duration of three months. DATA COLLECTION AND ANALYSIS: After an initial screen of the titles, two review authors working independently assessed the studies for eligibility and study quality; they also extracted the data. We contacted authors to obtain missing information and additional data, where necessary. We pooled results using the random-effects model and reported the pooled mean or standardised mean differences (SMDs). MAIN RESULTS: A total of 20 studies including 81,746 patients (median 129.5) were included in this review, with a follow-up ranging from 3 to more than 12 months. Patients' mean age was 42.5 years, 60% were female, and their asthma was mostly rated as moderate to severe. Overall the studies were of moderate to low methodological quality, because of limitations in their design and the wide confidence intervals for certain results.Compared with usual care, chronic disease management programmes resulted in improvements in asthma-specific quality of life (SMD 0.22, 95% confidence interval (CI) 0.08 to 0.37), asthma severity scores (SMD 0.18, 95% CI 0.05 to 0.30), and lung function tests (SMD 0.19, 95% CI 0.09 to 0.30). The data for improvement in self-efficacy scores were inconclusive (SMD 0.51, 95% CI -0.08 to 1.11). Results on hospitalisations and emergency department or unscheduled visits could not be combined in a meta analysis because the data were too heterogeneous; results from the individual studies were inconclusive overall. Only a few studies reported results on asthma exacerbations, days off work or school, use of an action plan, and patient satisfaction. Meta-analyses could not be performed for these outcomes. AUTHORS' CONCLUSIONS: There is moderate to low quality evidence that chronic disease management programmes for adults with asthma can improve asthma-specific quality of life, asthma severity, and lung function tests. Overall, these results provide encouraging evidence of the potential effectiveness of these programmes in adults with asthma when compared with usual care. However, the optimal composition of asthma chronic disease management programmes and their added value, compared with education or self-management alone that is usually offered to patients with asthma, need further investigation. PMID- 26014499 TI - Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability. AB - OBJECTIVE: Chronic presentation of the MS is associated with an increased likelihood for stroke and poor stroke outcomes following occlusive cerebrovascular events. However, the physiological mechanisms contributing to compromised outcomes remain unclear, and the degree of cerebral cortical MVD may represent a central determinant of stroke outcomes. METHODS: This study used the OZR model of MS and clinically relevant, chronic interventions to determine the impact on cerebral cortical microvascular rarefaction via immunohistochemistry with a parallel determination of cerebrovascular function to identify putative mechanistic contributors. RESULTS: OZR exhibited a progressive rarefaction (to ~80% control MVD) of the cortical microvascular networks vs. lean Zucker rats. Chronic treatment with antihypertensive agents (captopril/hydralazine) had limited effectiveness in blunting rarefaction, although treatments improving glycemic control (metformin/rosiglitazone) were superior, maintaining ~94% control MVD. Chronic treatment with the antioxidant TEMPOL severely blunted rarefaction in OZR, although this ameliorative effect was prevented by concurrent NOS inhibition. CONCLUSIONS: Further analyses revealed that the maintenance of glycemic control and vascular NO bioavailability were stronger predictors of cerebral cortical MVD in OZR than was prevention of hypertension, and this may have implications for chronic treatment of CVD risk under stroke-prone conditions. PMID- 26014506 TI - Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential. PMID- 26014501 TI - Transcriptome and venom proteome of the box jellyfish Chironex fleckeri. AB - BACKGROUND: The box jellyfish, Chironex fleckeri, is the largest and most dangerous cubozoan jellyfish to humans. It produces potent and rapid-acting venom and its sting causes severe localized and systemic effects that are potentially life-threatening. In this study, a combined transcriptomic and proteomic approach was used to identify C. fleckeri proteins that elicit toxic effects in envenoming. RESULTS: More than 40,000,000 Illumina reads were used to de novo assemble ~ 34,000 contiguous cDNA sequences and ~ 20,000 proteins were predicted based on homology searches, protein motifs, gene ontology and biological pathway mapping. More than 170 potential toxin proteins were identified from the transcriptome on the basis of homology to known toxins in publicly available sequence databases. MS/MS analysis of C. fleckeri venom identified over 250 proteins, including a subset of the toxins predicted from analysis of the transcriptome. Potential toxins identified using MS/MS included metalloproteinases, an alpha-macroglobulin domain containing protein, two CRISP proteins and a turripeptide-like protease inhibitor. Nine novel examples of a taxonomically restricted family of potent cnidarian pore-forming toxins were also identified. Members of this toxin family are potently haemolytic and cause pain, inflammation, dermonecrosis, cardiovascular collapse and death in experimental animals, suggesting that these toxins are responsible for many of the symptoms of C. fleckeri envenomation. CONCLUSIONS: This study provides the first overview of a box jellyfish transcriptome which, coupled with venom proteomics data, enhances our current understanding of box jellyfish venom composition and the molecular structure and function of cnidarian toxins. The generated data represent a useful resource to guide future comparative studies, novel protein/peptide discovery and the development of more effective treatments for jellyfish stings in humans. (Length: 300). PMID- 26014508 TI - Osmotic water permeability diversification in primary trophoblast cultures from aquaporin 1-deficient pregnant mice. AB - AIM: Aquaporins (AQP) are water channel proteins, and some play an important role in maternal-fetal fluid exchange. The present study aimed to measure the osmotic water permeability in primary cultures of trophoblast cells from AQP1-deficient (AQP1(-/-) ) pregnant mice and to define the quantitative role of AQP1 in water transport across the trophoblast plasma membrane. MATERIAL AND METHODS: Trophoblast cells were obtained from placental tissue cell culture of AQP1(-/-) pregnant mice and were characterized by cytokeratin 7 immunostaining. The expression of the AQP1 gene in trophoblast cells of wild-type (AQP1(+/+) ) mice was confirmed by immunofluorescence. The osmotic water permeability of trophoblast plasma membranes was measured by a calcein fluorescence quenching method in response to osmotic gradients. RESULTS: A primary cell culture system for trophoblasts was successfully established. Immunofluorescence showed the expression of AQP1 in the trophoblast cell membrane of AQP1(+/+) mice. The osmotic water permeability of AQP1(-/-) trophoblast cells was significantly lower than that in AQP1(+/+) trophoblast cells, in response to both hypotonic and hypertonic challenges. CONCLUSION: The results suggest an important role of AQP1 mediated plasma membrane water permeability in maternal-fetal fluid balance and also provide a potential direction for the identification of therapeutic targets for the treatment of abnormalities in amniotic fluid volume. PMID- 26014509 TI - Catalytic Enantioselective Reaction of alpha-Aminoacetonitriles Using Chiral Bis(imidazoline) Palladium Catalysts. AB - The catalytic enantioselective reaction of diphenylmethylidene-protected alpha aminoacetonitriles with imines has been developed. Good yields and diastereo- and enantioselectivities were observed for the reaction of various imines using chiral bis(imidazoline)/Pd catalysts. The reaction of alpha-aminonitriles with di tert-butyl azodicarboxylate afforded chiral alpha,alpha-diaminonitriles in high yields with high enantioselectivities. PMID- 26014510 TI - Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma. AB - Orally inhaled agents are a key therapeutic class for treatment of asthma. Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma thus representing the first-line therapy and bronchodilators complement the effects of ICSs. A significant body of evidence indicates that addition of a beta2-agonist to ICS therapy is more effective than increasing the dose of ICS monotherapy. In this paper, pharmacological features of available ICSs and bronchodilators will be reviewed with a focus on fluticasone propionate/formoterol fumarate combination which represents the one of the most powerful ICS acting together with the most rapid active LABA. PMID- 26014511 TI - Vulvovaginal-gingival Lichen Planus: Association with Lichen Planopilaris and Stratified Epithelium-specific Antinuclear Antibodies. AB - Vulvovaginal-gingival lichen planus (VVG-LP) consists of a triad of symptoms: vulval, vaginal and gingival lichen planus lesions. The aim of this study was to analyse the prevalence of lesions in various anatomical locations in patients with VVG-LP. The study included 126 consecutive patients with lichen planus. Sixteen (12.7%) patients fulfilled the criteria of VVG-LP. In 12/16 (75%) patients with VVG-LP scalp lesions were also observed. Stratified epithelium specific antinuclear antibodies (SES-ANA) and anti-DeltaNp.3alpha antibodies were detected in 10/16 (75%) patients with VVG-LP and in 15/110 (13.6%) patients with other forms of lichen planus (p < 0.05). In conclusion, VVG-LP is frequently associated with lichen planopilaris. The new entity may be termed "vulvovaginal gingival-pilar lichen planus" and our study indicates that SES-ANA is a marker of this type of lichen planus with extensive, severe and refractory-to-therapy involvement of the mucous membranes, skin and scalp. PMID- 26014512 TI - Heteroatom-Guided, Palladium-Catalyzed, Site-Selective C-H Arylation of 4H Chromenes: Diastereoselective Assembly of the Core Structure of Myristinin B through Dual C-H Functionalization. AB - A highly site-selective, heteroatom-guided, palladium-catalyzed direct arylation of 4H-chromenes is reported. The C-H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C-H functionalization strategy for regioselective direct arylation. PMID- 26014513 TI - Transcriptomic Analysis Reveals Wound Healing of Morus alba Root Extract by Up Regulating Keratin Filament and CXCL12/CXCR4 Signaling. AB - Facilitation of the wound healing process is important because a prolonged wound site increases pain and the risk of infection. In oriental medicine, an extract of Morus alba root (MA) has usually been prescribed as traditional treatment for accelerating wound healing, and it has been proven to be safe for centuries. To study the molecular mechanism of MA-mediated skin wound healing, we performed a primary cell culture and a skin explant culture and observed significant difference between the groups with and without MA extract. In the cellular system, a real-time cell analysis and real-time quantitative PCR were performed. It was found that MA extract enhanced proliferation in a dose-dependent manner on Kera-308 cell line, and up-regulated keratin expression including wound-induced Krt6a. In skin explant culture, the mRNA level derived from cell outgrowth displayed a tendency toward more up-regulated mRNA associated keratin filaments and toward a more up-regulated mRNA level of C-X-C motif chemokine 12 (CXCL12) and a chemokine receptor 4 (CXCR4) axis signaling pathway downstream. In this process, we concluded that MA extract had a scientific possibility of wound repair by increasing intracellular and extracellular supports and by inducing a CXCL12/CXCR4 signaling pathway. PMID- 26014514 TI - The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein. AB - Congenital disorder of glycosylation type Ia (PMM2-CDG), the most common form of CDG, is caused by mutations in the PMM2 gene that reduce phosphomannomutase 2 (PMM2) activity. No curative treatment is available. The present work describes the functional analysis of nine human PMM2 mutant proteins frequently found in PMM2-CDG patients and also two murine Pmm2 mutations carried by the unique PMM2 CDG mouse model described to overcome embryonic lethality. The effects of the mutations on PMM2/Pmm2 stability, oligomerization, and enzyme activity were explored in an optimized bacterial system. The mutant proteins were associated with an enzymatic activity of up to 47.3% as compared with wild type (WT). Stability analysis performed using differential scanning fluorimetry and a bacterial transcription-translation-coupled system allowed the identification of several destabilizing mutations (p.V44A, p.D65Y, p.R123Q, p.R141H, p.R162W, p.F207S, p.T237M, p.C241S). Exclusion chromatography identified one mutation, p.P113L, that affected dimer interaction. Expression analysis of the p.V44A, p.D65Y, p.R162W, and p.T237M mutations in a eukaryotic expression system under permissive folding conditions showed the possibility of recovering their associated PMM2 activity. Together, the results suggest that some loss-of function mutations detected in PMM2-CDG patients could be destabilizing, and therefore PMM2 activity could be, in certain cases, rescuable via the use of synergetic proteostasis modulators and/or chaperones. PMID- 26014515 TI - Risk factors and prediction-score model for distant metastasis in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. AB - The objective of this study is to identify the risk factors and construct a prediction-score model for distant metastasis (DM) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). A total of 520 nonmetastatic NPC patients were analysed retrospectively. The independent risk factors for DM were tested by multivariate Cox regression analysis. The prediction-score model was established according to the regression coefficient. The median follow-up was 88.4 months. The 5-year DM rate was 15.1%. N2-3, primary tumour volume of nasopharynx (GTVnx) >24.56 cm(3), haemoglobin change after treatment (DeltaHGB) >25.8 g/L, albumin-globulin ratio (AGR) <=1.34, pretreatment neutrophil-lymphocyte ratio (NLR) >2.81 and pretreatment serum lactate dehydrogenase (LDH) >245 U/L were significantly adverse independent predictive factors for DM. Three subgroups were defined based on the prediction-score model: low risk (0-2), intermediate risk (3-4) and high risk (5-8). The 5-year DM rates were 4.6, 21.8 and 50.8%, respectively (P < 0.001). The areas under the curve for DM in the prediction-score model and the UICC/AJCC staging system seventh edition were 0.748 and 0.627, respectively (P < 0.001). The scoring model is useful in evaluating the risk of DM in IMRT-treated NPC patients and guiding future therapeutic trials. Further prospective study is needed. PMID- 26014516 TI - Andrographolide radiosensitizes human ovarian cancer SKOV3 xenografts due to an enhanced apoptosis and autophagy. AB - Andrographolide (AND), a diterpenoid lactone isolated from Andrographis paniculata, has been shown to have radiosensitivity in several types of cancer. Whether AND can radiosensitize ovarian cancer remains unknown. The present study investigated the radiosensitizing effects of AND in human ovarian SKOV3 xenografts and examined the molecular mechanisms of AND-mediated radiosensitization. Nude mice bearing human ovarian SKOV3 were treated with AND to investigate the effects of drug administration on tumor growth, radiosensitivity, apoptosis, and autophagy. Subsequent Western blot analysis and monodansylcadaverine (MDC) staining (autophagy analysis) were used to determine the role of AND. Finally, the pathway of apoptosis was characterized by caspase-3 activity assay as well as TUNEL analysis. AND potently sensitized SKOV3 xenografts to radiation. Moreover, apoptosis and autophagy in radiation combined with drug-treated xenografts increased significantly compared with the simple drug or single radiation treatment. This result was associated with an increase in the Bax/Bcl-2 protein ratio and p-p53 expression after exposure to combination treatment. Meanwhile, the level of Beclin 1 and Atg5 and the conversion from LC3 I to LC3-II, three important proteins involved in autophagy, were increased. AND acts as a strong radiosensitizer in human ovarian SKOV3 xenografts in vivo by increasing the Bax/Bcl-2 protein ratio and promoting the activation of caspase-3, leading to enhanced apoptosis as well as autophagy. PMID- 26014517 TI - SEMA6A is a prognostic biomarker in glioblastoma. AB - Glioblastoma multiforme (GBM) is one of the most aggressive tumors in the central nervous system. SEMA6A, the first identified class 6 semaphorin, is contributed to regulate vascular development and adult angiogenesis. However, the function of SEMA6A in GBM is still undefined. In the present study, we investigated the expression of SEMA6A protein in 200 GBM tissues using immunohistochemistry (IHC). SEMA6A expression was associated with time to progression (P = 0.001) and mean tumor diameter (P = 0.038). Kaplan-Meier analysis revealed that patients expressing high SEMA6A protein levels had a significantly longer overall survival (OS, P = 0.013) and progression-free survival (PFS, P = 0.005) compared to those with low SEMA6A expression level. Cox multivariate regression analysis confirmed that low SEMA6A expression was an independent unfavorable prognostic factors for PFS (HR, 1.896; 95% CI, 1.147-2.768; P = 0.009) and OS (HR, 1.712; 95% CI, 1.011 2.657; P = 0.012). Furthermore, in vitro experiments showed that SEMA6A could inhibit proliferation, migration, and invasion in different glioma cell lines. In conclusion, our findings indicated that SEMA6A may be a potential prognostic biomarker in the treatment of GBM. PMID- 26014518 TI - Gab1 regulates proliferation and migration through the PI3K/Akt signaling pathway in intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma is the second most common primary malignant tumor of the liver, and it originates from the intrahepatic biliary duct epithelium. Prognosis is poor due to lack of effective comprehensive treatments. In this study, we assessed the expression of Gab1, VEGFR-2, and MMP-9 in intrahepatic cholangiocarcinoma solid tumors by immunohistochemistry and determined whether their expression was associated with clinical and pathological features. We found that expression of Gab1, VEGFR-2, and MMP-9 was highly and positively correlated with each other and with lymph node metastasis and TNM stage in intrahepatic cholangiocarcinoma tissues. Interference of Gab1 and VEGFR-2 expression via siRNA in the intrahepatic cholangiocarcinoma cell line RBE resulted in decreased PI3K/Akt pathway activity. Inhibition of Gab1 and VEGFR-2 expression also caused decreased cell proliferation, cell cycle arrested in G1 phase, increased apoptosis, and decreased invasion in RBE cells. These results suggest that Gab1, VEGFR-2, and MMP-9 contribute significantly to the highly malignant behavior of intrahepatic cholangiocarcinoma. The regulation of growth, apoptosis, and invasion by Gab1 through the VEGFR-2/Gab1/PI3K/Akt signaling pathway may represent potential targets for improving the treatment of intrahepatic cholangiocarcinoma. PMID- 26014520 TI - Fabrication of C-doped WO3 nanoparticle cluster arrays from PS-b-P4VP for room temperature H2 sensing. AB - C-doped WO3 based room temperature hydrogen sensors including nanoparticle cluster arrays and nanorods were successfully prepared by a PS-b-P4VP template based method. AFM, TEM and XPS are used to characterize the structure and composition of the samples. Analyses indicate that the C-doped WO3 nanoparticle cluster arrays are arranged in a beautiful hexagonal configuration and they are interconnected by a superthin carbon film. The cluster with sizes in the range of 12-15 nm is composed of several 4-6 nm nanocrystallites. An improved room temperature hydrogen response is found on C doped WO3 nanoparticle cluster arrays, whose response sensitivity (S), response time and recovery time are 114, 162 s and 108 s, respectively. Three aspects are used to analyze the reasons for the improved room temperature hydrogen response; the study indicates the great potential of the block copolymer based method to prepare excellent WO3 based room temperature H2 sensors. PMID- 26014519 TI - Prognostic value of age in neurological cancer: an analysis of 22,393 cases from the SEER database. AB - Although the risk of neurological cancer (NC) is age-dependent, few studies have evaluated the prognostic value of age in determining NC survival in a large population. The aim of this retrospective study was to compare the long-term survival of young and elderly NC patients. We searched the Surveillance, Epidemiology, and End-Results database and identified 22,393 patients who were diagnosed with NC between 1988 and 2003 and were treated with surgery. Patients were categorized as young (<=40 years old) or elderly (>40 years old), and 5-year NC-specific survival (NCSS) data were obtained for each patient. A Kaplan-Meier survival analysis and the Cox proportional hazards model were used to analyze long-term survival outcomes and risk factors. The two groups differed significantly in terms of pathological grade, histological type, stage, and tumor size (P < 0.001). A difference in 5-year NCSS rates (63.8 and 19.0% in young and elderly patients, respectively) was detected by uni- and multivariate analyses. A stratified analysis of age on cancer survival revealed significant differences at T1-T4 stages. Age has prognostic value for determining NC risk. NCSS is higher in young than in elderly NC patients. PMID- 26014521 TI - Suppression of creep-regime dynamics in epitaxial ferroelectric BiFeO3 films. AB - Switching dynamics of ferroelectric materials are governed by the response of domain walls to applied electric field. In epitaxial ferroelectric films, thermally-activated 'creep' motion plays a significant role in domain wall dynamics, and accordingly, detailed understanding of the system's switching properties requires that this creep motion be taken into account. Despite this importance, few studies have investigated creep motion in ferroelectric films under ac-driven force. Here, we explore ac hysteretic dynamics in epitaxial BiFeO3 thin films, through ferroelectric hysteresis measurements, and stroboscopic piezoresponse force microscopy. We reveal that identically fabricated BiFeO3 films on SrRuO3 or La0.67Sr0.33MnO3 bottom electrodes exhibit markedly different switching behaviour, with BiFeO3/SrRuO3 presenting essentially creep-free dynamics. This unprecedented result arises from the distinctive spatial inhomogeneities of the internal fields, these being influenced by the bottom electrode's surface morphology. Our findings further highlight the importance of controlling interface and defect characteristics, to engineer ferroelectric devices with optimised performance. PMID- 26014522 TI - The business impact of an integrated continuous biomanufacturing platform for recombinant protein production. AB - The biotechnology industry primarily uses batch technologies to manufacture recombinant proteins. The natural evolution of other industries has shown that transitioning from batch to continuous processing can yield significant benefits. A quantitative understanding of these benefits is critical to guide the implementation of continuous processing. In this manuscript, we use process economic modeling and Monte Carlo simulations to evaluate an integrated continuous biomanufacturing (ICB) platform and conduct risk-based valuation to generate a probabilistic range of net-present values (NPVs). For a specific ten year product portfolio, the ICB platform reduces average cost by 55% compared to conventional batch processing, considering both capital and operating expenses. The model predicts that these savings can further increase by an additional 25% in situations with higher-than-expected product demand showing the upward potential of the ICB platform. The ICB platform achieves these savings and corresponding flexibility mainly due to process intensification in both upstream and downstream unit operations. This study demonstrates the promise of continuous bioprocessing while also establishing a novel framework to quantify financial benefits of other platform process technologies. PMID- 26014524 TI - An Accidental Ingestion of Mosquito Repellent Liquid Vapouriser. PMID- 26014523 TI - Term Infant with Fetal Tachyarrhythmia, Hydrops, and Persistent Pulmonary Hypertension. PMID- 26014525 TI - Carnett Sign Revisited- Abdominal Wall Abscess Mimicking Painful Splenomegaly. PMID- 26014526 TI - Z chromosome divergence, polymorphism and relative effective population size in a genus of lekking birds. AB - Sex chromosomes contribute disproportionately to species boundaries as they diverge faster than autosomes and often have reduced diversity. Their hemizygous nature contributes to faster divergence and reduced diversity, as do some types of selection. In birds, other factors (mating system and bottlenecks) can further decrease the effective population size of Z-linked loci and accelerate divergence (Fast-Z). We assessed Z-linked divergence and effective population sizes for two polygynous sage-grouse species and compared them to estimates from birds with various mating systems. We found lower diversity and higher FST for Z-linked loci than for autosomes, as expected. The pi(Z)/pi(A) ratio was 0.38 in Centrocercus minimus, 0.48 in Centrocercus urophasianus and 0.59 in a diverged, parapatric population of C. urophasianus, a broad range given the mating system among these groups is presumably equivalent. The full data set had unequal males and females across groups, so we compared an equally balanced reduced set of C. minimus and individuals pooled from both C. urophasianus subgroups recovering similar estimates: 0.54 for C. urophasianus and 0.38 for C. minimus. We provide further evidence that N(eZ)/N(eA) in birds is often lower than expected under random mating or monogamy. The lower ratio in C. minimus could be a consequence of stronger selection or drift acting on Z loci during speciation, as this species differs strongly from C. urophasianus in sexually selected characters with minimal mitochondrial divergence. As C. minimus also exhibited lower genomic diversity, it is possible that a more severe demographic history may contribute to its lower ratio. PMID- 26014575 TI - B1 and T1 mapping of the breast with a reference tissue method. AB - PURPOSE: To develop a method for mapping the B1 field using a reference signal from a tissue with known T1. METHODS: Flip angle correction factors were calculated in a region with a known "gold standard" T1; by comparing T1 values from a variable flip angle (VFA) sequence to the "gold standard" and correcting the value of the Ernst angle. The resulting partial B1 map was interpolated for all other regions. In the breast, fat is an ideal reference tissue because its T1 is spatially homogeneous and interpatient variability is low. This method was tested with scans of phantoms and patients (n = 4) on a 3T magnet. The performance of the method was evaluated by comparing the results of VFA T1 mapping with and without B1 correction to inversion recovery (IR) T1 maps. RESULTS: Phantom data determined that a linear inverse distance weighted interpolation accurately recovered the full B1 map. Use of interpolated maps to correct the VFA data in vivo, reduced the average difference in the T1 of parenchyma between VFA and IR results from 58% to 8%. CONCLUSION: This proof-of principle study showed that it is possible to recover a full and accurate map of the B1 field in the breast by using a reference tissue (fat) with an accurately measured T1. PMID- 26014576 TI - Linking superinhibitory PLN mutations to CaMKII activation: a new arrhythmogenic mechanism in genetic DCM? PMID- 26014577 TI - Right ventricular suction: an important determinant of cardiac performance. PMID- 26014578 TI - Zn-doped CaTiO3:Eu(3+) red phosphors for enhanced photoluminescence in white LEDs by solid-state reaction. AB - Zn-doped CaTiO3:Eu(3+) red phosphors for enhanced photoluminescence in white light-emitting diodes (LEDs) were synthesized by a solid-state method. The structure and morphology of the obtained phosphor samples were observed by X-ray diffraction (XRD) and scanning electron microscopy (SEM), and the impact of Ca, Zn and Eu content on their photoluminescence properties was studied. The results indicated that Zn not only participates in the formation of defects in suitable lattice matrices but also has a role in flux in the transformation from ZnO to Zn2TiO4, which is beneficial for the enhancement of photoluminescence properties. Photoluminescence test data showed that the Zn-doped phosphor is excited efficiently by near-ultraviolet (NUV) light at wavelengths around 398 nm and emits an intense red light with a broad peak around 616 nm corresponding to the (5) D0 ->(7) F2 transition of Eu(3+). The intensity of this phosphor emission is three times stronger than that without Zn-doping. Furthermore, this phosphor has very good thermal stability, high color purity and a low sintered temperature, all of which suggest its potential as a promising red phosphor for white LEDs. PMID- 26014579 TI - What is quality in medical care? PMID- 26014580 TI - Oxygen plasma surface modification augments poly(L-lactide-co-glycolide) cytocompatibility toward osteoblasts and minimizes immune activation of macrophages. AB - Here, we report on modification of one of the model biomedical polymers, poly L lactide-co-glycolide (PLGA; 85:15), by reactive ion etching (RIE) oxygen plasma treatment. PLGA's major disadvantage is high hydrophobicity which restrains binding of cell-adhesive proteins and host cells. In the current approach, we aimed to answer two questions: (1) will only short (10 s) and moderate (20-200 mTorr, 45-90 W) RIE oxygen plasma treatment, leading to decrease of water contact angle by only up to 10 degrees , sufficiently improve PLGA adherence to cells, and (2) how will this affect osteoblasts and activation of the immune system? All obtained modified PLGAs had improved hydrophilicity but unaltered roughness (as revealed by water contact angle measurements, X-ray photoelectron spectroscopy, and atomic force microscopy) resulting in significantly improved adhesion of osteoblasts (MG-63) and their low activation. Importantly, macrophages (RAW 264.7), one of the key cells initiating inflammation and bone resorption, responded significantly less vigorously to the modified polymers, expressing/releasing lower amounts of nitric oxide, matrix metalloproteinases (MMP-9), and pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12p70, IFN-gamma, IL 10). We conclude that already slight RIE oxygen plasma modification of PLGA is sufficient to improve its surface properties, and enhance cytocompatibility. Most importantly, this type of modification prevents excessive immune response. PMID- 26014581 TI - Iron Carbide Nanoparticles Encapsulated in Mesoporous Fe-N-Doped Carbon Nanofibers for Efficient Electrocatalysis. AB - Exploring low-cost and high-performance nonprecious metal catalysts (NPMCs) for oxygen reduction reaction (ORR) in fuel cells and metal-air batteries is crucial for the commercialization of these energy conversion and storage devices. Here we report a novel NPMC consisting of Fe3 C nanoparticles encapsulated in mesoporous Fe-N-doped carbon nanofibers, which is synthesized by a cost-effective method using carbonaceous nanofibers, pyrrole, and FeCl3 as precursors. The electrocatalyst exhibits outstanding ORR activity (onset potential of -0.02 V and half-wave potential of -0.140 V) closely comparable to the state-of-the-art Pt/C catalyst in alkaline media, and good ORR activity in acidic media, which is among the highest reported activities of NPMCs. PMID- 26014582 TI - The impact of library preparation protocols on the consistency of allele frequency estimates in Pool-Seq data. AB - Sequencing pools of individuals (Pool-Seq) is a cost-effective method to determine genome-wide allele frequency estimates. Given the importance of meta analyses combining data sets, we determined the influence of different genomic library preparation protocols on the consistency of allele frequency estimates. We found that typically no more than 1% of the variation in allele frequency estimates could be attributed to differences in library preparation. Also read length had only a minor effect on the consistency of allele frequency estimates. By far, the most pronounced influence could be attributed to sequence coverage. Increasing the coverage from 30- to 50-fold improved the consistency of allele frequency estimates by at least 27%. We conclude that Pool-Seq data can be easily combined across different library preparation methods, but sufficient sequence coverage is key to reliable results. PMID- 26014583 TI - Is the pulsed xenon ultraviolet light no-touch disinfection system effective on methicillin-resistant Staphylococcus aureus in the absence of manual cleaning? AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has been shown to survive on ambient surfaces for extended periods of time. Leftover MRSA environmental contamination in a hospital room places future patients at risk. Manual disinfection supplemented by pulsed xenon ultraviolet (PX-UV) light disinfection has been shown to greatly decrease the MRSA bioburden in hospital rooms. However, the effect of PX-UV in the absence of manual disinfection has not been evaluated. METHODS: Rooms that were previously occupied by a MRSA-positive patient (current colonization or infection) were selected for the study immediately postdischarge. Five high-touch surfaces were sampled, before and after PX-UV disinfection, in each hospital room. The effectiveness of the PX-UV device on the concentration of MRSA was assessed employing a Wilcoxon signed-rank test for all 70 samples with MRSA in 14 rooms, as well as by surface location. RESULTS: The final analysis included 14 rooms. Before PX-UV disinfection there were a total of 393 MRSA colonies isolated from the 5 high-touch surfaces. There were 100 MRSA colonies after disinfection by the PX-UV device and the overall reduction was statistically significant (P < .01). CONCLUSIONS: Our study results suggest that PX-UV light effectively reduces MRSA colony counts in the absence of manual disinfection. These findings are important for hospital and environmental services supervisors who plan to adapt new technologies as an adjunct to routine manual disinfection. PMID- 26014584 TI - Brain metabolomics in rats after administration of ketamine. AB - In this study, we developed a brain metabolomic method, based on gas chromatography-mass spectrometry (GC/MS), to evaluate the effect of ketamine on rats. Pattern recognition analysis, including both principal component analysis and partial least squares-discriminate analysis revealed that ketamine induced metabolic perturbations. Compared with the control group, the levels of glycerol, uridine, cholesterol in rat brain of the ketamine group (50 mg/kg, 14 days) decreased, while the urea levels increased. Our results indicate that metabolomic methods based on GC/MS may be useful to elucidate ketamine abuse through the exploration of biomarkers. PMID- 26014586 TI - Bronchodilators should be considered for all patients with acute bronchiolitis, but closely monitored for objectively measured clinical benefits. PMID- 26014585 TI - The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth. AB - Recent studies revealed C-type natriuretic peptide (CNP) and its receptor, guanylyl cyclase-B (GC-B) are potent stimulators of endochondral bone growth. As they exist ubiquitously in body, we investigated the physiological role of the local CNP/GC-B in the growth plate on bone growth using cartilage-specific knockout mice. Bones were severely shorter in cartilage-specific CNP or GC-B knockout mice and the extent was almost the same as that in respective systemic knockout mice. Cartilage-specific GC-B knockout mice were shorter than cartilage specific CNP knockout mice. Hypertrophic chondrocyte layer of the growth plate was drastically reduced and proliferative chondrocyte layer, along with the proliferation of chondrocytes there, was moderately reduced in either cartilage specific knockout mice. The survival rate of cartilage-specific CNP knockout mice was comparable to that of systemic CNP knockout mice. The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth and might further affect mortality via unknown mechanisms. PMID- 26014589 TI - Fast ultrasound is fine, but accuracy is everything. PMID- 26014587 TI - Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers. AB - PURPOSE: We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. METHODS: This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. RESULTS: Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. CONCLUSION: A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil. PMID- 26014590 TI - Re: Endogenous and exogenous factors affecting the levels of carboxyhemoglobin. PMID- 26014591 TI - Innovation in metabolomics to improve personalized healthcare. AB - Metabolomics is the systemic study of all small molecules (metabolites) and their concentration as affected by pathological and physiological alterations or environmental or other factors. Metabolic alterations represent a "window" on the complex interactions between genetic expression, enzyme activity, and metabolic reactions. Techniques, including nuclear magnetic resonance spectroscopy, mass spectrometry, Fourier-transform infrared, and Raman spectroscopy, have led to significant advances in metabolomics. The field is shifting from feasibility studies to biological and clinical applications. Fields of application range from cancer biology to stem cell research and assessment of xenobiotics and drugs in tissues and single cells. Cross-validation across high-throughput platforms has allowed findings from expression profiling to be confirmed with metabolomics. Specific genetic alterations appear to drive unique metabolic programs. These, in turn, can be used as biomarkers of genetic subtypes of prostate cancer or as discovery tools for therapeutic targeting of metabolic enzymes. Thus, metabolites in blood may serve as biomarkers of tumor state, including inferring driving oncogenes. Novel applications such as these suggest that metabolic profiling may be utilized in refining personalized medicine. PMID- 26014592 TI - The FDA and genomic tests--getting regulation right. PMID- 26014593 TI - Precision medicine--personalized, problematic, and promising. PMID- 26014594 TI - The FDA and genetic testing. PMID- 26014597 TI - Curating the way to better determinants of genetic risk. PMID- 26014598 TI - Chemical Basis for Qualitative and Quantitative Differences Between ABO Blood Groups and Subgroups: Implications for Organ Transplantation. AB - Blood group ABH(O) carbohydrate antigens are carried by precursor structures denoted type I-IV chains, creating unique antigen epitopes that may differ in expression between circulating erythrocytes and vascular endothelial cells. Characterization of such differences is invaluable in many clinical settings including transplantation. Monoclonal antibodies were generated and epitope specificities were characterized against chemically synthesized type I-IV ABH and related glycans. Antigen expression was detected on endomyocardial biopsies (n = 50) and spleen (n = 11) by immunohistochemical staining and on erythrocytes by flow cytometry. On vascular endothelial cells of heart and spleen, only type II based ABH antigens were expressed; type III/IV structures were not detected. Type II-based ABH were expressed on erythrocytes of all blood groups. Group A1 and A2 erythrocytes additionally expressed type III/IV precursors, whereas group B and O erythrocytes did not. Intensity of A/B antigen expression differed among group A1 , A2 , A1 B, A2 B and B erythrocytes. On group A2 erythrocytes, type III H structures were largely un-glycosylated with the terminal "A" sugar alpha-GalNAc. Together, these studies define qualitative and quantitative differences in ABH antigen expression between erythrocytes and vascular tissues. These expression profiles have important implications that must be considered in clinical settings of ABO-incompatible transplantation when interpreting anti-ABO antibodies measured by hemagglutination assays with reagent erythrocytes. PMID- 26014599 TI - Dynamic near-field optical interaction between oscillating nanomechanical structures. AB - Near-field optical techniques exploit light-matter interactions at small length scales for mechanical sensing and actuation of nanomechanical structures. Here, we study the optical interaction between two mechanical oscillators--a plasmonic nanofocusing probe-tip supported by a low frequency cantilever, and a high frequency nanomechanical resonator--and leverage their interaction for local detection of mechanical vibrations. The plasmonic nanofocusing probe provides a confined optical source to enhance the interaction between the two oscillators. Dynamic perturbation of the optical cavity between the probe-tip and the resonator leads to nonlinear modulation of the scattered light intensity at the sum and difference of their frequencies. This double-frequency demodulation scheme is explored to suppress unwanted background and to detect mechanical vibrations with a minimum detectable displacement sensitivity of 0.45 pm/Hz(1/2), which is limited by shot noise and electrical noise. We explore the demodulation scheme for imaging the bending vibration mode shape of the resonator with a lateral spatial resolution of 20 nm. We also demonstrate the time-resolved aspect of the local optical interaction by recording the ring-down vibrations of the resonator at frequencies of up to 129 MHz. The near-field optical technique is promising for studying dynamic mechanical processes in individual nanostructures. PMID- 26014596 TI - Gene-panel sequencing and the prediction of breast-cancer risk. PMID- 26014600 TI - Neuroenhancement through cognitive training and anodal tDCS in multiple sclerosis. AB - BACKGROUND: Cognitive training has been shown to improve cognitive function and quality of life in multiple sclerosis (MS) patients and is correlated with increased activity in the left dorsolateral prefrontal cortex (DLPFC). OBJECTIVE: This study aims to test whether combining attention training with anodal transcranial direct current stimulation (a-tDCS) over the left DLPFC can improve training efficacy. METHODS: Twenty patients impaired in attention/speed of information processing were randomly assigned to cognitive training during a-tDCS over the left DLPFC or cognitive training during sham tDCS for 10 daily sessions. Neuropsychological evaluations were conducted at baseline, after treatment and six months later. RESULTS: When a-tDCS, rather than sham, was applied during the cognitive training, patients showed a significantly greater improvement in the Symbol Digit Modality Test (SDMT) and Wisconsin Card Sorting Test (WCST) after treatment (p < 0.05) and in the Paced Auditory Serial Addition Test (PASAT) 2" and WCST six months later (p < 0.05). They also had significantly shorter time to reach the most difficult exercise level, compared to sham treatment (6.3 vs. 7.4 sessions; p < 0.05). CONCLUSIONS: These results indicate that a-tDCS on the DLPFC during cognitive training fosters improvements in attention and executive function in MS patients and shortens treatment duration. PMID- 26014601 TI - Educational attainment and cognitive status in MS: Reading, writing, and economics. PMID- 26014602 TI - The occurrence of dystonia in upper-limb multiple sclerosis tremor. AB - BACKGROUND: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available. OBJECTIVE: To investigate whether dystonia contributes to MS tremor and its severity. METHODS: MS patients (n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer's cramp. RESULTS: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe (p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08-0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48-1.6, p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45-1.41, p < 0.001) in tremor severity and 1.5-units (95% CI 0.62-2.41, p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated (p < 0.001). CONCLUSIONS: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo cortical network dysfunction. PMID- 26014603 TI - Removal Notice. PMID- 26014595 TI - ClinGen--the Clinical Genome Resource. AB - On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient's family pursues genetic testing that shows a "likely pathogenic" variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography. Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as "likely benign" by another laboratory that uses more recently derived population-frequency data. A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic. Family members are retested, and one member who previously tested negative is now found to be positive for this new variant. An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death. PMID- 26014604 TI - Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years. AB - BACKGROUND: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. OBJECTIVE: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). METHODS: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. RESULTS: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate 4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. CONCLUSIONS: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression. PMID- 26014606 TI - Antibodies to myelin oligodendrocyte glycoprotein are uncommon in Japanese opticospinal multiple sclerosis. PMID- 26014607 TI - Cardiopulmonary fitness is related to disease severity in multiple sclerosis. AB - BACKGROUND: In persons with MS (pwMS), a lower cardiopulmonary fitness has been associated with a higher risk for secondary disorders, decreased functional capacity, symptom worsening and reduced health-related quality of life. OBJECTIVE: To investigate the association between disease severity and cardiopulmonary fitness. METHODS: Data from cardiopulmonary exercise tests, previously conducted in three different countries, were pooled. The association between disease severity (Expanded Disability Status Scale (EDSS)) and cardiopulmonary fitness (peak oxygen uptake (VO2peak)) was adjusted for age, sex and the country of origin. RESULTS: The combined sample comprised 116 ambulant pwMS having a mean (+/- SD) EDSS score of 2.7 +/- 1.3. There was a significant correlation (r = -0.418, p < .01) between VO2peak and EDSS. A multiple regression model (R(2) = 0.520, p < .01) was constructed to describe VO2peak (mL?kg(-1)?min( 1)); VO2peak = 36.622 - 5.433 (Sex (1=men)) - 0.124 (Age) - 2.082 (EDSS) + 2.737 (Belgium) + 8.674 (Denmark). CONCLUSION: There was a significant association between disease severity and cardiopulmonary fitness. The close relation between cardiopulmonary fitness and chronic conditions associated with physical inactivity, suggest a progressive increase in risk of secondary health conditions in pwMS. PMID- 26014605 TI - Level of education and multiple sclerosis risk after adjustment for known risk factors: The EnvIMS study. AB - BACKGROUND: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education. OBJECTIVE: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size. METHODS: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors. RESULTS: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded. CONCLUSION: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk. PMID- 26014608 TI - Characteristics of lesional and extra-lesional cortical grey matter in relapsing remitting and secondary progressive multiple sclerosis: A magnetisation transfer and diffusion tensor imaging study. AB - BACKGROUND: In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed. OBJECTIVE: To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS. METHODS: Seventy-two people with MS (46 relapsing-remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter. RESULTS: Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability. CONCLUSION: Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability. PMID- 26014610 TI - Commentary on Pique et al.'s paper entitled: Peripheral late reactivation of a previously typical monofocal Balo's concentric sclerosis lesion. PMID- 26014609 TI - Peripheral late reactivation of a previously typical monofocal Balo's concentric sclerosis lesion. AB - We report a 41-year-old woman with rapidly progressive left hemiparesis, revealing an inflammatory reactivation of a previously known parietal Balo's concentric sclerosis lesion. The first attack occurred five years before. After a slow recovery following high-dose steroid infusions the patient stabilized. Because of recurrent ataxia and left hemiparesis a new magnetic resonance imaging was performed showing an extension of the initial lesion with a peripheral gadolinium enhancement on T1-weighted images. Such a reactivation pattern of an isolated Balo's concentric sclerosis lesion, occurring some years later, is described for the first time. PMID- 26014611 TI - Child Welfare and the Transition to Adulthood: Investigating Placement Status and Subsequent Arrests. AB - Studies of the transition to adulthood in child welfare focus almost exclusively on youth in foster care. Yet, research indicates that maltreated children who remain in the home may display similar risks as compared with their peers in formal foster care settings. Utilizing administrative data from child welfare, juvenile justice and adult corrections, the current study fills a gap in the literature by analyzing justice outcomes for older adolescents involved with the child welfare system regardless of their placement status. We focus on both intact family cases and formal foster care placements. The diverse sample (11% Hispanic, 8% African American, 6% Native American, 9% multi-racial, 56% female) included open child welfare cases involving 17 year olds (n = 9874). Twenty-nine percent of adolescents were associated with a long term out of home placement and 62% were associated with an intact family case. Event history models were developed to estimate the risk of subsequent offending. Adolescents associated with long term foster care placement were significantly less likely to experience a subsequent arrest as compared with adolescents associated with a long term intact family case. Males, African Americans and adolescents associated with neglect were also more likely to experience a subsequent arrest. Limited focus on the intact family population in child welfare represents a lost opportunity to support critical developmental gains and facilitate a smooth transition to adulthood. PMID- 26014612 TI - THE IMPACT OF LATE-LIFE ANXIETY AND DEPRESSION ON COGNITIVE FLEXIBILITY AND COGNITIVE RESTRUCTURING SKILL ACQUISITION. AB - BACKGROUND: Studies examining treatment moderators and mediators in late-life anxiety and depression are sparse. Executive functioning skills decrease with age, and are poorer in the context of anxiety and depression. One of the key cognitive behavioral therapy techniques for anxiety and depression is cognitive restructuring (CR), which teaches people to identify and dispute maladaptive thoughts. There is evidence that cognitive flexibility (CF), one aspect of executive functioning, has a negative impact on CR skill acquisition in nonclinical older adults, and this warrants extension in a clinical sample. METHOD: This study assessed CR skill acquisition in a clinical sample of 47 older adults with anxiety and depression and 53 nonclinical controls during an experimental paradigm, and investigated the influence of CF on this relationship. A battery of neuropsychological tests assessing CF were administered and CR was learned during a brief intervention. RESULTS: The clinical sample showed poorer CF on some measures, as well as poorer CR quality and efficacy (reduction in subjective distress). CF partially mediated the relationship between clinical status and CR quality, and between clinical status and CR efficacy. CONCLUSION: These results provide preliminary evidence that older adults with anxiety and depression are worse at learning and benefiting from CR with a brief intervention and this is partially due to having poorer CF skills. These findings warrant further examination in a treatment context to assess whether CR skill acquisition improves over treatment. PMID- 26014614 TI - Sebum, inflammasomes and the skin: current concepts and future perspective. AB - Increasing evidence has identified ultraviolet radiation (UVR) as the skins most potent mutagen as over exposure results in sunburn, inflammation and DNA damage, thus contributing to a photo-ageing phenotype and possibly skin carcinogenesis. The lipid-rich sebum secreted onto the surface of the skin plays an important physiological role in protecting the skin against external challenges. When skin is photosensitised by UVR, the lipid constituents of sebum are easily oxidised, generating several lipid photo-oxidative products (e.g. squalene peroxides). These photo-oxidative products have been shown to exert diverse toxicological, biological and immunological effects in the skin and have therefore been implicated in several detrimental skin alterations including premature skin ageing. The involvement of lipid peroxidation products in UVR-induced inflammatory responses has been inadequately studied and highly controversial. Furthermore, it is unclear to what extent these oxidative products contribute to the underlying mechanisms of skin photo-ageing. Therefore, this viewpoint essay will discuss the current knowledge on the effect of UVR exposure on skin surface lipids and how these may mediate UVR-induced inflammatory responses which may be key contributors to photo-damage in skin. This essay will also examine the potential role of inflammasomes (innate immune complexes) in the inflammatory response associated with UVR-induced lipid peroxidation. Limited evidence is available on the interactions between sebaceous lipids, downstream mediators and concomitant immune response in sun-exposed skin and clearer elucidation may lead to novel biomarkers of photo-ageing and the incorporation of new molecules into current skin therapies which better target oxidised lipids and or downstream mediators/pathways. PMID- 26014613 TI - Targeted Capture of Phylogenetically Informative Ves SINE Insertions in Genus Myotis. AB - Identification of retrotransposon insertions in nonmodel taxa can be technically challenging and costly. This has inhibited progress in understanding retrotransposon insertion dynamics outside of a few well-studied species. To address this problem, we have extended a retrotransposon-based capture and sequence method (ME-Scan [mobile element scanning]) to identify insertions belonging to the Ves family of short interspersed elements (SINEs) across seven species of the bat genus Myotis. We identified between 120,000 and 143,000 SINE insertions in six taxa lacking a draft genome by comparing to the M. lucifugus reference genome. On average, each Ves insertion was sequenced to 129.6 * coverage. When mapped back to the M. lucifugus reference genome, all insertions were confidently assigned within a 10-bp window. Polymorphic Ves insertions were identified in each taxon based on their mapped locations. Using cross-species comparisons and the identified insertion positions, a presence-absence matrix was created for approximately 796,000 insertions. Dollo parsimony analysis of more than 85,000 phylogenetically informative insertions recovered strongly supported, monophyletic clades that correspond with the biogeography of each taxa. This phylogeny is similar to previously published mitochondrial phylogenies, with the exception of the placement of M. vivesi. These results support the utility of our variation on ME-Scan to identify polymorphic retrotransposon insertions in taxa without a reference genome and for large-scale retrotransposon-based phylogenetics. PMID- 26014615 TI - Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer. AB - The epithelium of gastrointestinal tract organizes many innate defense systems against microbial intruders such as integrity of epithelial, rapid eviction of infected cells, quick turnover of epithelial cell, intrinsic immune responses and autophagy. However, Enteropathogenic Escherichia coli (EPEC) are equipped with well developed infectious tricks that evade the host defense systems and utilize the gastrointestinal epithelium as a multiplicative foothold. During multiplication on and within the epithelium, EPEC secrete various toxins that can weaken, usurp, and use many host cellular systems. However, the possible mechanisms of pathogenesis are still poorly elusive. Recent study reveals the existence of EPEC in colorectal cancer patients and their potential role in depletion of DNA mismatch repair (MMR) proteins of host cell in colonic cell lines. The EPEC colonised intracellularly in colon mucosa of colorectal carcinoma whereas extracellular strain was detected in mucosa of normal colon cells. Interestingly, alteration in MutS, MutL complexes and MUTYH of mammalian cells may be involved in development of CRC. These data propose that MMR of E. coli may be potential therapeutic targets and early detection biomarkers for CRC. This article reviews the potential role of E. coli MutS, MutL and MutY protein in CRC aetiology. PMID- 26014616 TI - Fecal ESBL Escherichia coli carriage as a risk factor for bacteremia in patients with hematological malignancies. AB - PURPOSE: The purpose of this study is to evaluate the impact of fecal extended spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) colonization for bloodstream infection (BSI), clinical outcome, and costs in patients with hematologic malignancies (HM) and severe neutropenia. METHODS: This is a cohort study, carried out at a cancer-referral hospital. The study population comprises patients with HM, hospitalized prior to administration of the first chemotherapy cycle. A stool culture was taken during the first 48 h; they were grouped as colonized by ESBL-EC or non-ESBL-EC. Patients were followed upon completion of chemotherapy or death. The sum of the days of antibiotics and the length of stay of all hospitalizations in the different cycles of chemotherapy were recorded. RESULTS: We included 126 patients with a recent diagnosis of HM, grouped as 63 patients colonized by ESBL-EC and 63 colonized by non-ESBL-EC, aged 42 +/- 16 years old, 78 males (62%). BSI by ESBL-EC developed in 14 patients (22.2%) colonized by the same strain and in 5 (7.9%) in the group colonized with non-ESBL EC. BSI by non-ESBL-EC was observed in 3 patients (4.7%) colonized by ESBL-EC and in 17 (26.9%) patients colonized by non-ESBL-EC. Colonization with ESBL-EC increased the risk of BSI by the same strain (relative risk (RR) = 3.4, 95% confidence interval (95% CI) 1.5-7.8, p = 0.001), shorter time to death (74 +/- 62 vs. 95 +/- 83 days, p < 0.001), longer hospital stay (64 +/- 39 vs. 48 +/- 32 days, p = 0.01), and higher infection-related costs ($6528 +/- $4348 vs. $4722 +/ $3173, p = 0.01). There was no difference in overall mortality between both groups. CONCLUSIONS: Fecal colonization by ESBL-EC is associated with increased risk of BSI by this strain, longer hospital stay, and higher related costs. PMID- 26014617 TI - Presurgical symptom profiles predict quality of life 2 years after surgery in women with breast cancer. AB - PURPOSE: Higher symptom burden in oncology patients is associated with poorer quality of life (QOL). However, the long-term predictive relationship between pre treatment symptom profiles and QOL is unknown. The aim of this study was to identify subgroups of breast cancer patients based on their presurgical symptom profiles and to examine the predictive effect of group membership on QOL 2 years after surgery. METHODS: Data were analyzed from a longitudinal study of women's (N = 198) symptoms after breast cancer surgery. Patient subgroups were identified by latent class analysis based on presurgical severity of five symptoms (i.e., attentional and physical fatigue, sleep disturbance, depression, and anxiety). Among these 198 women, quality of life 2 years after surgery was available for 97. Group differences in QOL were examined by general linear models. RESULTS: We identified four distinct patient groups. Group A (All Low) had low levels of all symptoms. Group B (Low Fatigue and Moderate Mood) was characterized by low attentional and physical fatigue but moderate sleep disturbance, depression, and anxiety. Group C (All Moderate) was characterized by moderate levels of all five symptoms. Group D was characterized by moderate attentional and physical fatigue and severe sleep disturbance, depression, and anxiety (Moderate Fatigue and High Mood). Group D had significantly lower overall QOL scores 2 years after surgery than Group A (p = 0.002). CONCLUSIONS: Breast cancer patients' presurgical symptom profile had a long-term predictive effect on QOL. Routine assessment of patients' pre-treatment symptom is suggested to identify high risk group. PMID- 26014618 TI - Two models of nursing practice: a comparative study of motivational characteristics, work satisfaction and stress. AB - AIM: To examine the differences in work-related motivational and stress factors between two nursing allocation models (the primary nursing model and the individual patient allocation model). BACKGROUND: A number of nursing allocation models are applied in hospital settings, but little is known about the potential associations between various models and work-related psychosocial profiles in nurses. METHOD: A cross-sectional study using an electronic questionnaire. The data were collected from nurses (n = 643) working in 22 wards. In total, 317 questionnaires were returned (response rate 49.3%). RESULTS: There were no significant differences in motivational characteristics between the different models. The nurses working according to the individual patient allocation model were more satisfied with their supervisors. The work itself and turnover caused more stress to the nurses working in the primary nursing model, whereas patient related stress was higher in the individual patient allocation model. CONCLUSION: No consistent evidence to support the use of either of these models over the other was found. Both these models have positive and negative features and more comparative research is required on various nursing practice models from different points of view. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing directors and ward managers should be aware of the positive and negative features of the various nursing models. PMID- 26014621 TI - Australian and New Zealand psychiatry and the world psychiatric association. PMID- 26014619 TI - [Austrian nutrition and lifestyle recommendations for gout and hyperuricemia]. AB - BACKGROUND: Gout is the most common inflammatory arthropathy in the Western world. This is mainly due to the high socioeconomic status, sufficient even superfluous nutrition, overweight and alcohol consumption. Despite adequate medication, information and advice on nutrition and lifestyle are one of the cornerstones in the management of these patients. OBJECTIVE: The aim was to provide recommendations on nutrition and lifestyle in cases of gout and hyperuricemia by a group of rheumatologists, based on a review of the most recent literature. MATERIALS AND METHODS: The study group for osteoarthritis and crystal arthropathies of the Austrian Society for Rheumatology and Rehabilitation (OGR) carried out a literature search on this topic. The selected papers were listed according to the level of evidence. RESULTS: Based on this literature search nine recommendations were generated and modified via a Delphi approach: four red "don'ts" concerning nutrition and beverages to be avoided, three green "do's" concerning favorable food as well as two blue general lifestyle recommendations. The format of the recommendations is a two-page leaflet with the list of recommendations, level of evidence, strength of recommendation and literature citations on the front page and a colored icon presentation of food and beverages in a circle, matching the colors of the written recommendations, on the reverse. CONCLUSION: For the first time in Austria, nine recommendations on nutrition, beverages and lifestyle for patients with gout and hyperuricemia were defined for everyday practice, as education material for patients and updated information for physicians. PMID- 26014620 TI - Effects of aging on strategic-based visuomotor learning. AB - There are different kinds of visuomotor learnings. One of the most studied is error-based learning where the information about the sign and magnitude of the error is used to update the motor commands. However, there are other instances where subjects show visuomotor learning even if the use of error sign and magnitude information is precluded. In those instances subjects could be using strategic instead of procedural adaptation mechanisms. Here, we present the results of the effect of aging on visuomotor strategic learning under a reversed error feedback condition, and its contrast with procedural visuomotor learning within the same participants. A number of measures were obtained from a task consisting of throwing clay balls to a target before, during and after wearing lateral displacing or reversing prisms. The displacing prism results show an age dependent decrease on the learning rate that corroborates previous findings. The reversing prism results also show significant adaptation impairment in the aged population. However, decreased reversing learning in the older group was the result of an increase in the number of subjects that could not adapt to the reversing prism, and not on a reduction of the learning capacity of all the individuals of the group. These results suggest a significant deleterious effect of aging on visuomotor strategic learning implementation. PMID- 26014622 TI - An interview with Professor Herrman. PMID- 26014623 TI - Substance use disorders in New Zealand adults with severe mental illness: descriptive study of an acute inpatient population. AB - OBJECTIVE: To elucidate patterns of substance misuse, across diagnoses and demographic variables, in patients with severe mental illness. METHOD: We studied 141 adults admitted to an acute psychiatric unit in Hamilton, New Zealand. Semi structured interviews, including the Alcohol Use Disorders Identification Test (AUDIT) and Cannabis Use Disorders Identification Test - Revised (CUDIT-R), were used to assess substance use. RESULTS: Seventy-six participants were of European origin (56%), 59 were Maori (42%). Tobacco smoking was noted in 81% overall, with a higher frequency (93%) among Maori. A majority of patients had alcohol use disorder, with greater prevalence in bipolar and schizoaffective disorder compared to schizophrenia. By contrast, cannabis use disorder was strikingly associated with schizophrenia. Younger patients and Maori were disproportionately affected by both alcohol and cannabis use. CONCLUSIONS: Substance misuse in New Zealand patients with severe mental illness is common, particularly among younger patients and Maori, and differentially distributed across diagnoses. PMID- 26014624 TI - Vortioxetine. PMID- 26014627 TI - Correspondence with GPs. PMID- 26014628 TI - "Equivalent other" scholarly projects. PMID- 26014629 TI - Smoking ban in psychiatric wards raises safety and ethical issues. PMID- 26014630 TI - Clarifying the diagnosis of myocarditis in a patient on clozapine. PMID- 26014631 TI - Paliperidone depot: another treatment option for delusional parasitosis. PMID- 26014632 TI - The Dynamic Appraisal of Situational Aggression does not predict aggression in young patients. PMID- 26014633 TI - The DASA:YV assists the appraisal of imminent aggression risk in young patients. PMID- 26014643 TI - Microfluidic technology as an emerging clinical tool to evaluate thrombosis and hemostasis. AB - Assessment of platelet function and coagulation under flow conditions can augment traditional static assays used to evaluate patients with suspected hemostatic or thrombotic disorders. Among the available flow-based assays, microfluidic devices require the smallest blood volume and provide multiple output options. These assays are based on the presence of wall shear stress that mimics in vivo interactions between blood components and vessel walls. Microfluidic devices can generate essential information regarding homeostatic regulation of platelet activation and subsequent engagement of the coagulation cascade leading to fibrin deposition and clot formation. Emerging data suggest that microfluidic assays may also reveal consistent patterns of hemostatic or thrombotic pathology, and could aid in assessing and monitoring patient-specific effects of coagulation-modifying therapies. PMID- 26014644 TI - Canonical wnt signaling is required for commissural axon guidance. AB - Morphogens have been identified as guidance cues for postcrossing commissural axons in the spinal cord. Shh has a dual effect on postcrossing commissural axons: a direct repellent effect mediated by Hhip as a receptor, and an indirect effect by shaping a Wnt activity gradient. Wnts were shown to be attractants for postcrossing commissural axons in both chicken and mouse embryos. In mouse, the effects of Wnts on axon guidance were concluded to depend on the planar cell polarity (PCP) pathway. Canonical Wnt signaling was excluded based on the absence of axon guidance defects in mice lacking Lrp6 which is an obligatory coreceptor for Fzd in canonical Wnt signaling. In the loss-of-function studies reported here, we confirmed a role for the PCP pathway in postcrossing commissural axon guidance also in the chicken embryo. However, taking advantage of the precise temporal control of gene silencing provided by in ovo RNAi, we demonstrate that canonical Wnt signaling is also required for proper guidance of postcrossing commissural axons in the developing spinal cord. Thus, axon guidance does not seem to depend on any one of the classical Wnt signaling pathways but rather involve a network of Wnt receptors and downstream components. PMID- 26014645 TI - The fixity of prostate seed implants: The impact of the strand surface on its ability to migrate inside oil and gel medium. AB - PURPOSE: Radioactive seed implants are widely used to treat cancer patients, most commonly those with prostate cancer. However, the seeds have a tendency to migrate after placement in patients, a phenomenon that can result in unfavorable outcomes. The ability of the seed strand to migrate was investigated by examining the impact of the strand surface on the velocity of its movement inside oil and gel media. METHODS AND MATERIALS: We investigated the motion of smooth surface strands and strands with different grooved helical profiles after they were placed in oil and gel media. Three patterns of grooved helices were studied (60, 140, and 300 rotations per meter). The movement of the strands through a tube filled with the medium was recorded by the motion sensor, and the drag forces on the individual strands were calculated and compared for the oil and gel media. RESULTS: The strands with 60, 140, and 300 rotations/meter grooved helical surfaces demonstrated less mobility in both oil and gel than the strands with a smooth surface. The strand with the highest number of helical grooves per meter recorded the largest drag force and moved more slowly in both media. CONCLUSIONS: The differential in the motion of the smooth strand and the strands with grooved surfaces can be attributed to the increased surface area of the grooved strands. This finding is significant since it will impact, theoretically, the design, and thus the migration of seed implants that are used to treat cancer patients, particularly those with prostate cancer. PMID- 26014646 TI - [Salmonella meningitis in an infant due to a pet turtle]. AB - In humans, Salmonella most often causes self-limiting gastroenteritis, but more severe symptoms such as sepsis and meningitis can also occur and can sometimes have a fatal outcome. Even if the meningitis is not fatal, sequelae such as epilepsy, cranial nerve palsies, and hydrocephalus can occur. In the United States, it has been estimated that approximately 6% of the human cases of salmonellosis can be attributed to contact with reptiles or amphibians. The infection may take place by direct contact between reptile and human or indirectly via contact with an environment contaminated with Salmonella from a reptile. Salmonella enterica subsp. enterica serotype Vitkin is a common gut inhabitant of reptiles. Though human cases due to this organism are exceedingly rare, it may infect young infants and immunocompromised individuals with a history of intimate associations with reptiles. Gastroenteritis is the most common presentation ; others include peritonitis, meningitis and bacteremia. We report a case of meningitis caused by S. enterica subsp. enterica serotype Vitkin in a 1-month-old child due to a pet turtle. PMID- 26014647 TI - Development and reproduction of five Tetranychus species (Acari: Tetranychidae): Do they all have the potential to become major pests? AB - The objective of this study was to investigate whether four spider mite species, Tetranychus ludeni, T. phaselus, T. piercei and T. truncatus, currently with insignificant economic impact, have the potential to achieve the same status as T. urticae, which until now has been considered as the most serious tetranychid pest species in orchards and greenhouses. We investigated the effect of temperature on development, survival and oviposition at 11 constant temperatures ranging from 15 to 40 degrees C at intervals of 2.5 degrees C and estimated demographic parameters, such as the intrinsic rate of natural increase (rm), for these five species at five constant temperatures. Developmental time from egg to adult (female and male) decreased with increasing temperature from 15 to 32.5 degrees C in all five species, but increased slightly at 35 degrees C or higher, especially in T. ludeni and T. urticae. Using linear and non-linear developmental rate models, the lower thermal thresholds for egg-to-adult (female and male) and egg-to-egg development were found to range from 9.8 to 11.7 and from 9.8 to 11.4 degrees C, respectively. The intrinsic optimal temperature (TPhi) ranged from 18.0 to 27.4 degrees C for egg-to-female adult and from 23.9 to 27.2 degrees C for egg-to-egg development. The oviposition period and adult longevity were strongly affected by temperature. The rm-values increased with increasing temperature from 15 to 30 or 35 degrees C in all five species. The highest rm values at each temperature were 0.114 day(-1) at 15 degrees C for T. ludeni, 0.199 day(-1) at 20 degrees C for T. urticae, 0.314 day(-1) at 25 degrees C for T. ludeni, 0.451 day(-1) at 30 degrees C for T. ludeni and 0.433 day(-1) at 35 degrees C for T. truncatus. The total fecundity, net reproductive rate (R0) and rm of T. ludeni were higher than those of T. urticae at all temperatures. T. piercei and T. truncatus showed higher rm-values at 30 and 35 degrees C than T. urticae. The results indicate that the former three species are better adapted to hot weather than T. urticae and have a high potential to become serious pests. PMID- 26014648 TI - Dietary effects on body weight of predatory mites (Acari, Phytoseiidae). AB - Pollen is offered as alternative or supplementary food for predacious mites; however, it may vary in its nutritional value. Body weight appears a representative parameter to describe food quality. Thus, we assessed the body weight for adults of the generalist mites Amblyseius swirskii, Amblydromalus limonicus, and Neoseiulus cucumeris reared on 22, 12, and 6 pollen species, respectively. In addition, A. swirskii and A. limonicus was reared on codling moth eggs. In all mite species, female body weight was higher than that of males, ranging between 4.33 and 8.18 ug for A. swirskii, 2.56-6.53 ug for A. limonicus, and 4.66-5.92 ug for N. cucumeris. Male body weight ranged between 1.78 and 3.28 ug, 1.37-3.06 ug, and 2.73-3.03 ug, respectively. Nutritional quality of pollen was neither consistent among the mite species nor among sex, revealing superior quality of Quercus macranthera pollen for females of A. swirskii and Tulipa gesneriana pollen for males, Alnus incana pollen for females of A. limonicus and Aesculus hippocastanum pollen for males, and Ae. hippocastanum pollen for both sexes of N. cucumeris. The results are discussed against the background of known or putative pollen chemistry and mite's nutritional physiology. PMID- 26014651 TI - Prevalence of Stroke in a Rural Population of Bangladesh. PMID- 26014649 TI - Neural transcriptome reveals molecular mechanisms for temporal control of vocalization across multiple timescales. AB - BACKGROUND: Vocalization is a prominent social behavior among vertebrates, including in the midshipman fish, an established model for elucidating the neural basis of acoustic communication. Courtship vocalizations produced by territorial males are essential for reproductive success, vary over daily and seasonal cycles, and last up to hours per call. Vocalizations rely upon extreme synchrony and millisecond precision in the firing of a homogeneous population of motoneurons, the vocal motor nucleus (VMN). Although studies have identified neural mechanisms driving rapid, precise, and stable neuronal firing over long periods of calling, little is known about underlying genetic/molecular mechanisms. RESULTS: We used RNA sequencing-based transcriptome analyses to compare patterns of gene expression in VMN to the surrounding hindbrain across three daily and seasonal time points of high and low sound production to identify candidate genes that underlie VMN's intrinsic and network neuronal properties. Results from gene ontology enrichment, enzyme pathway mapping, and gene category wide expression levels highlighted the importance of cellular respiration in VMN function, consistent with the high energetic demands of sustained vocal behavior. Functionally important candidate genes upregulated in the VMN, including at time points corresponding to high natural vocal activity, encode ion channels and neurotransmitter receptors, hormone receptors and biosynthetic enzymes, neuromodulators, aerobic respiration enzymes, and antioxidants. Quantitative PCR and RNA-seq expression levels for 28 genes were significantly correlated. Many candidate gene products regulate mechanisms of neuronal excitability, including those previously identified in VMN motoneurons, as well as novel ones that remain to be investigated. Supporting evidence from previous studies in midshipman strongly validate the value of transcriptomic analyses for linking genes to neural characters that drive behavior. CONCLUSIONS: Transcriptome analyses highlighted a suite of molecular mechanisms that regulate vocalization over behaviorally relevant timescales, spanning milliseconds to hours and seasons. To our knowledge, this is the first comprehensive characterization of gene expression in a dedicated vocal motor nucleus. Candidate genes identified here may belong to a conserved genetic toolkit for vocal motoneurons facing similar energetic and neurophysiological demands. PMID- 26014650 TI - Stroke in Latin America: Burden of Disease and Opportunities for Prevention. AB - The epidemiological transition in Latin America toward older urban dwelling adults has led to the rise in cardiovascular risk factors and an increase in morbidity and mortality rates related to both stroke and myocardial infarction. As a result, there is an immediate need for effective actions resulting in better detection and control of cardiovascular risk factors that will ultimately reduce cardiovascular disease burden. Data from case-control studies have identified the following risk factors associated with stroke: hypertension; smoking; abdominal obesity; diet; physical activity; diabetes; alcohol intake; psychosocial factors; cardiac causes; and dyslipidemia. In addition to its high mortality, patients who survive after a stroke present quite frequently with marked physical and functional disability. Because stroke is the leading cause of death in most Latin American countries and also because it is a clearly preventable cause of death and disability, simple, affordable, and efficient strategies must be urgently implemented in Latin America. PMID- 26014652 TI - Low Prevalence of AHA-Defined Ideal Cardiovascular Health Factors: A Study of Urban Indian Men and Women. AB - BACKGROUND: Coronary heart disease risk factors are widely prevalent among urban subjects in India but the prevalence of good cardiovascular health is unknown. OBJECTIVES: This multisite study sought to determine the prevalence of American Heart Association-defined ideal cardiovascular health factors. METHODS: The study was performed in 11 cities using cluster sampling. Middle-class urban subjects ages 20 to 75 years (N = 6,198; men: 3,426; women: 2,772, response: 62%) were evaluated for socioeconomic, biophysical, and biochemical factors. Prevalence of ideal cardiovascular health using 7-factor American Heart Association metric (nonsmoking, moderate or greater physical activity, low-fat, high-fruit/vegetable diet, body mass index <25 kg/m2, untreated blood pressure <120/<80 mm Hg, cholesterol <200 mg/dl, and fasting glucose <100 mg/dl) was determined. Descriptive statistics are reported. RESULTS: Age-adjusted prevalences of ideal health factors in men and women, respectively, were non-tobacco use in 72.0% and 89.6%, moderate physical activity in 20.1% and 20.6%, healthy diet in 10.6% and 10.6%, normal body mass index in 57.7% and 52.8%, normotension in 17.1% and 22.4%, normocholesterolemia in 72.4% and 72.7%, and normoglycemia in 57.4% and 59.5%. Prevalence of all the 7 health factors was in <1.0% in both men and women, any 6 in 3.4% and 3.5%, any 5 in 12.7% and 17.8%, any 4 in 36.9% and 44.7%, any 3 in 67.2% and 70.8%, any 2 in 89.1% and 92.4%, and 1 in 98.2% and 99.1%. Cardiovascular health was poor (1 to 3 factors) in 62.4% of men and 54.9% of women, average (4 to 5 factors) in 34.1% and 41.5%, and good (>=6 factors) in 3.5% and 3.6%. With increasing age, the behavioral health factors (tobacco use, physical activity, healthy diet) did not change, whereas others declined (ptrend < 0.01). Clustering of average and good health factors also declined with age (ptrend < 0.01). There were no socioeconomic status-related differences in prevalence of good cardiovascular health. CONCLUSIONS: Good cardiovascular health factors-physical activity, healthy diet, and desirable body mass index, blood pressure, and glucose levels-are low in urban Asian Indians. PMID- 26014654 TI - The Authors' Reply. PMID- 26014653 TI - Heart Disease Is Associated With Anthropometric Indices and Change in Body Size Perception Over the Life Course: The Golestan Cohort Study. AB - BACKGROUND: Cardiovascular disease and obesity are now becoming leading causes of morbidity and mortality in low- and middle-income countries. OBJECTIVES: We investigated the relationship between prevalent heart disease (HD) and current anthropometric indices and body size perception over time from adolescence to adulthood in Iran. METHODS: We present a cross-sectional analysis of baseline data from a prospective study of adults in Golestan Province, Iran. Demographics, cardiac history, and current anthropometric indices-body mass index, waist circumference, and waist to hip ratio-were recorded. Body size perception for ages 15 years, 30 years, and at the time of interview was assessed via pictograms. Associations of these factors and temporal change in perceived body size with HD were evaluated using multivariable logistic regression models. RESULTS: Complete data were available for 50,044 participants; 6.1% of which reported having HD. Higher body mass index, waist circumference, and waist to hip ratio were associated with HD (p < 0.001). Men had a U-shaped relationship between HD and body size perception at younger ages. For change in body size perception, men and women demonstrated a U-shaped relationship with prevalent HD from adolescence to early adulthood, but a J-shaped pattern from early to late adulthood. CONCLUSIONS: HD was associated with anthropometric indices and change in body size perception over time for men and women in Iran. Due to the increasing prevalence of overweight and obesity in low- and middle-income countries, interventions focused on decreasing the cumulative burden of risk factors throughout the life course may be an important component of cardiovascular risk reduction. PMID- 26014655 TI - A Meta-Analysis of Effect of Dietary Salt Restriction on Blood Pressure in Chinese Adults. AB - The aim of this study was to estimate the effects of dietary salt reduction on blood pressure (BP) in Chinese adults and the effects of China-specific cooking salt-reduction strategies (the use of salt substitutes and salt-restriction spoons). The PubMed and China National Knowledge Infrastructure databases were searched for studies satisfying the search criteria. Outcomes extracted from each included study were 24-h urinary sodium excretion, salt (sodium chloride) intake, and BP before and after dietary salt lowering. A random-effects meta-analysis was performed, and results were evaluated for evidence of publication bias and heterogeneity. Because most studies aggregated results for hypertensive and normotensive participants, estimates were made for hypertensive participants only and for hypertensive and normotensive participants combined. Six salt-restriction experiment studies (3,153 participants), 4 cooking salt-restriction spoon studies (3,715 participants), and 4 cooking salt-substitute studies (1,730 participants) were analyzed. In salt-restriction experiment studies, the pooled estimate of mean change in 24-h urinary sodium excretion in hypertensive participants was 163.0 mmol/day (95% confidence interval [CI]: -233.5 to -92.5 mmol/day), which was associated with a mean reduction of -8.9 mm Hg (95% CI: -14.1 to -3.7 mm Hg) in systolic BP. Each 1.00-g dietary salt reduction in hypertensive participants was associated with a reduction of 0.94 mm Hg in systolic BP (95% CI: 0.69 to 1.03 mm Hg). These systolic BP reductions in hypertensive participants were 1.71 times greater compared with the mixed hypertensive and normotensive group. Salt restriction spoon studies demonstrated a 1.46-g decrease in daily salt intake level. The effect of salt-substitute use on systolic BP control was substantial among the hypertensive participants (-4.2 mm Hg; 95% CI: -7.0 to -1.3 mm Hg), but the change did not reach statistical significance in hypertensive and normotensive participants combined (-2.31 mm Hg; 95% CI: -5.57 to 0.94 mm Hg). Salt restriction lowers mean BP in Chinese adults, with the strongest effect among hypertensive participants. Future studies of salt-restriction strategies should be report results stratified by hypertension status and adjust for medication use. PMID- 26014656 TI - Population Study of Urban, Rural, and Semiurban Regions for the Detection of Endovascular Disease and Prevalence of Risk Factors and Holistic Intervention Study: Rationale, Study Design, and Baseline Characteristics of PURSE-HIS. AB - We designed and implemented the PURSE-HIS (Population Study of Urban, Rural and Semiurban Regions for the Detection of Endovascular Disease and Prevalence of Risk Factors and Holistic Intervention Study) to understand the prevalence and progression of subclinical and overt endovascular disease (EVD) and its risk factors in urban, semiurban, and rural communities in South India. The study is also designed to generate clinical evidence for effective, affordable, and sustainable community-specific intervention strategies to control risks factors for EVD. As of June 2012, 8,080 (urban: 2,221; semiurban: 2,821; rural: 3,038) participants >20 years of age were recruited using 2-stage cluster sampling. Baseline measurements included standard cardiovascular disease risk factors, sociodemographic factors, lifestyle habits, psychosocial factors, and nutritional assessment. Fasting blood samples were assayed for putative biochemical risk factors and urine samples for microalbuminuria. All nondiabetic participants underwent oral glucose tolerance test with blood and urine samples collected every 30 min for 2 h. Additional baseline measurements included flow-mediated brachial artery endothelial vasodilation, assessment of carotid intimal medial wall thickness using ultrasonography, screening for peripheral vascular disease using ankle and brachial blood pressures, hemodynamic screening using a high fidelity applanation tonometry to measure central blood pressure parameters, and aortic pulse wave velocity. To assess prevalence of coronary artery disease, all participants underwent surface electrocardiography and documentation of ventricular wall motion abnormality and function using echocardiography imaging. To detect subclinical lesions, all eligible participants completed an exercise treadmill test. Prospectively, the study will assess progression of subclinical and overt EVD, including risk factor-outcome relation differences across communities. The study will also evaluate community-specific EVD prevention using traditional Indian system of medicine versus recognized allopathic (mainstream) systems of medicine. PMID- 26014658 TI - Low 25-Hydroxyvitamin D Concentrations May Explain Atherosclerosis in Ancient and Modern Humans. PMID- 26014657 TI - Biomarkers of Coronary Artery Disease Differ Between Asians and Caucasians in the General Population. AB - Coronary artery disease (CAD) markers have not been thoroughly investigated among Asians. The incidence of CAD, however, is rising rapidly in Asia. In this review, we systematically discuss publications that compare CAD biomarkers between Asians and Caucasians in the general population. A PubMed search yielded 5,570 hits, containing 59 articles describing 47 unique cohorts that directly compare Asians with Caucasians. Ten biomarkers were taken into account for this review: total cholesterol; triglycerides; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; C-reactive protein; glucose; insulin; glycated hemoglobin; fibrinogen; and plasminogen activator inhibitor-1. Triglycerides were 1.13-fold higher in South Asians than in Caucasians, and insulin levels were 1.33 fold higher. In Japanese and Chinese subjects, lower C-reactive protein levels were reported: 0.52 and 0.36-fold, respectively. Ethnicity-specific prognostic measures of CAD biomarkers were rarely reported. CAD biomarker levels differ between Asians and Caucasians and among Asian ethnic groups in population-based cohorts. The ethnicity-specific prognostic value of CAD biomarkers is yet to be determined. PMID- 26014659 TI - World Heart Federation Emerging Leaders Program: An Innovative Capacity Building Program to Facilitate the 25 * 25 Goal. PMID- 26014660 TI - Reversible posterior encephalopathy syndrome in children with nephrotic syndrome. AB - AIM: To investigate the clinical features and prognoses of children who develop reversible posterior encephalopathy syndrome (RPES) during treatment for nephrotic syndrome (NS). METHODS: The clinicoradiological characteristics and prognoses of 51 patients with NS, including 21 with RPES and 30 without, were analyzed. RESULTS: Compared with the controls, the RPES patients exhibited a higher rate of tacrolimus (P = 0.01) and cyclosporine (P = 0.02) treatment; higher-dose prednisolone (P = 0.01) treatment; higher systolic blood pressure (P = 0.04), serum cholesterol (P = 0.03), and proteinuria (P < 0.01); and lower serum albumin levels (P = 0.03). Hypertension was present in 85.7% of RPES patients. The clinical manifestations of RPES included an altered mental status, seizures, headaches, nausea and vomiting, and visual impairment. Electroencephalography findings included slow waves and focal sharp or/and spiked waves; magnetic resonance imaging showed lesions localized in the occipital, parietal, frontal, temporal lobes and the cerebellum and brainstem; and magnetic resonance angiography revealed vertebral artery narrowing. All RPES patients recovered completely with timely and appropriate therapy. CONCLUSION: Hypertension, calcineurin inhibitor and high-dose steroid treatments, high serum cholesterol and proteinuria levels, and low serum albumin levels can predispose children with NS to RPES, although both the clinical and imaging outcomes are satisfactory. PMID- 26014661 TI - Alternatives to Traditional EMS Dispatch and Transport: A Scoping Review of Reported Outcomes. AB - OBJECTIVES: Emergency medical services (EMS) programs, which provide an alternative to traditional EMS dispatch or transport to the emergency department (ED), are becoming widely implemented. This scoping review identified and catalogued all outcomes used to measure such alternative EMS programs. Data Source Broad systematized bibliographic and grey literature searches were conducted. Study Selection Inclusion criteria were 911 callers/EMS patients, reported on alternatives to traditional EMS dispatch OR traditional EMS transport to the ED, and reported an outcome measure. Data Extraction The reports were categorized as either alternative to dispatch or to EMS transport, and outcome measures were categorized and described. Data Synthesis The bibliographic search retrieved 13,215 records, of which 34 articles met the inclusion criteria, with an additional 10 added from reference list hand-searching (n=44 included). In the grey literature search, 31 websites were identified, from which four met criteria and were retrieved (n=4 included). Fifteen reports (16 studies) described alternatives to EMS dispatch, and 33 reports described alternatives to EMS transport. The most common outcomes reported in the alternatives to EMS dispatch reports were service utilization and decision accuracy. Twenty-four different specific outcomes were reported. The most common outcomes reported in the alternatives to EMS transport reports were service utilization and safety, and 50 different specific outcomes were reported. CONCLUSIONS: Numerous outcome measures were identified in reports of alternative EMS programs, which were catalogued and described. Researchers and program leaders should achieve consensus on uniform outcome measures, to allow benchmarking and improve comparison across programs. PMID- 26014663 TI - Sequence detection analysis based on canonical correlation for steady-state visual evoked potential brain computer interfaces. AB - BACKGROUND: Steady-state visual evoked potential (SSVEP) has been widely applied to develop brain computer interface (BCI) systems. The essence of SSVEP recognition is to recognize the frequency component of target stimulus focused by a subject significantly present in EEG spectrum. NEW METHOD: In this paper, a novel statistical approach based on sequence detection (SD) is proposed for improving the performance of SSVEP recognition. This method uses canonical correlation analysis (CCA) coefficients to observe SSVEP signal sequence. And then, a threshold strategy is utilized for SSVEP recognition. RESULTS: The result showed the classification performance with the longer duration of time window achieved the higher accuracy for most subjects. And the average time costing per trial was lower than the predefined recognition time. It was implicated that our approach could improve the speed of BCI system in contrast to other methods. Comparison with existing method(s): In comparison with other resultful algorithms, experimental accuracy of SD approach was better than those using a widely used CCA-based method and two newly proposed algorithms, least absolute shrinkage and selection operator (LASSO) recognition model as well as multivariate synchronization index (MSI) method. Furthermore, the information transfer rate (ITR) obtained by SD approach was higher than those using other three methods for most participants. CONCLUSIONS: These conclusions demonstrated that our proposed method was promising for a high-speed online BCI. PMID- 26014662 TI - Stress-free automatic sleep deprivation using air puffs. AB - BACKGROUND: Sleep deprivation via gentle handling is time-consuming and personnel intensive. NEW METHOD: We present here an automated sleep deprivation system via air puffs. Implanted EMG and EEG electrodes were used to assess sleep/waking states in six male Sprague-Dawley rats. Blood samples were collected from an implanted intravenous catheter every 4h during the 12-h light cycle on baseline, 8h of sleep deprivation via air puffs, and 8h of sleep deprivation by gentle handling days. RESULTS: The automated system was capable of scoring sleep and waking states as accurately as our offline version (~90% for sleep) and with sufficient speed to trigger a feedback response within an acceptable amount of time (1.76s). Manual state scoring confirmed normal sleep on the baseline day and sleep deprivation on the two manipulation days (68% decrease in non-REM, 63% decrease in REM, and 74% increase in waking). No significant differences in levels of ACTH and corticosterone (stress hormones indicative of HPA axis activity) were found at any time point between baseline sleep and sleep deprivation via air puffs. COMPARISON WITH EXISTING METHOD: There were no significant differences in ACTH or corticosterone concentrations between sleep deprivation by air puffs and gentle handling over the 8-h period. CONCLUSIONS: Our system accurately detects sleep and delivers air puffs to acutely deprive rats of sleep with sufficient temporal resolution during the critical 4-5h post learning sleep-dependent memory consolidation period. The system is stress-free and a viable alternative to existing sleep deprivation techniques. PMID- 26014664 TI - Does involvement in clinical trials make trainees better surgeons? PMID- 26014665 TI - Early school outcomes for extremely preterm infants with transient neurological abnormalities. AB - AIM: To determine if transient neurological abnormalities (TNA) at 9 months corrected age predict cognitive, behavioral, and motor outcomes at 6 years of age in extremely preterm infants. METHOD: A cohort of 124 extremely preterm infants (mean gestational age 25.5wks; 55 males, 69 females), admitted to our unit between 2001 and 2003, were classified based on the Amiel-Tison Neurological Assessment at 9 months and 20 months corrected age as having TNA (n=17), normal neurological assessment (n=89), or neurologically abnormal assessment (n=18). The children were assessed at a mean age of 5 years 11 months (SD 4mo) on cognition, academic achievement, motor ability, and behavior. RESULTS: Compared with children with a normal neurological assessment, children with TNA had higher postnatal exposure to steroids (35% vs 9%) and lower adjusted mean scores on spatial relations (84 [standard error {SE} 5] vs 98 [SE 2]), visual matching (79 [SE 5] vs 91 [SE 2]), letter-word identification (97 [SE 4] vs 108 [SE 1]), and spelling (76 [SE 4] vs 96 [SE 2]) (all p<0.05). INTERPRETATION: Despite a normalized neurological assessment, extremely preterm children with a history TNA are at higher risk for lower cognitive and academic skills than those with normal neurological findings during their first year of school. PMID- 26014666 TI - Associations between teaching effectiveness scores and characteristics of presentations in hospital medicine continuing education. AB - BACKGROUND: There is little research regarding characteristics of effective continuing medical education (CME) presentations in hospital medicine (HM). Therefore, we sought to identify associations between validated CME teaching effectiveness scores and characteristics of CME presentations in the field of HM. DESIGN/SETTING: This was a cross-sectional study of participants and didactic presentations from a national HM CME course in 2014. MEASUREMENTS: Participants provided CME teaching effectiveness (CMETE) ratings using an instrument with known validity evidence. Overall CMETE scores (5-point scale: 1 = strongly disagree; 5 = strongly agree) were averaged for each presentation, and associations between scores and presentation characteristics were determined using the Kruskal-Wallis test. The threshold for statistical significance was set at P < 0.05. RESULTS: A total of 277 out of 368 participants (75.3%) completed evaluations for the 32 presentations. CMETE scores (mean [standard deviation]) were significantly associated with the use of audience response (4.64 [0.16]) versus no audience response (4.49 [0.16]; P = 0.01), longer presentations (>=30 minutes: 4.67 [0.13] vs <30 minutes: 4.51 [0.18]; P = 0.02), and larger number of slides (>=50: 4.66 [0.17] vs <50: 4.55 [0.17]; P = 0.04). There were no significant associations between CMETE scores and use of clinical cases, defined goals, or summary slides. CONCLUSIONS: To our knowledge, this is the first study regarding associations between validated teaching effectiveness scores and characteristics of effective CME presentations in HM. Our findings, which support previous research in other fields, indicate that CME presentations may be improved by increasing interactivity through the use of audience response systems and allowing longer presentations. PMID- 26014667 TI - Are we overpathologizing everyday life? A tenable blueprint for behavioral addiction research. AB - Background Behavioral addiction research has been particularly flourishing over the last two decades. However, recent publications have suggested that nearly all daily life activities might lead to a genuine addiction. Methods and aim In this article, we discuss how the use of atheoretical and confirmatory research approaches may result in the identification of an unlimited list of "new" behavioral addictions. Results Both methodological and theoretical shortcomings of these studies were discussed. Conclusions We suggested that studies overpathologizing daily life activities are likely to prompt a dismissive appraisal of behavioral addiction research. Consequently, we proposed several roadmaps for future research in the field, centrally highlighting the need for longer tenable behavioral addiction research that shifts from a mere criteria based approach toward an approach focusing on the psychological processes involved. PMID- 26014668 TI - Study addiction--a new area of psychological study: conceptualization, assessment, and preliminary empirical findings. AB - AIMS: Recent research has suggested that for some individuals, educational studying may become compulsive and excessive and lead to 'study addiction'. The present study conceptualized and assessed study addiction within the framework of workaholism, defining it as compulsive over-involvement in studying that interferes with functioning in other domains and that is detrimental for individuals and/or their environment. METHODS: The Bergen Study Addiction Scale (BStAS) was tested - reflecting seven core addiction symptoms (salience, mood modification, tolerance, withdrawal, conflict, relapse, and problems) - related to studying. The scale was administered via a cross-sectional survey distributed to Norwegian (n = 218) and Polish (n = 993) students with additional questions concerning demographic variables, study-related variables, health, and personality. RESULTS: A one-factor solution had acceptable fit with the data in both samples and the scale demonstrated good reliability. Scores on BStAS converged with scores on learning engagement. Study addiction (BStAS) was significantly related to specific aspects of studying (longer learning time, lower academic performance), personality traits (higher neuroticism and conscientiousness, lower extroversion), and negative health-related factors (impaired general health, decreased quality of life and sleep quality, higher perceived stress). CONCLUSIONS: It is concluded that BStAS has good psychometric properties, making it a promising tool in the assessment of study addiction. Study addiction is related in predictable ways to personality and health variables, as predicted from contemporary workaholism theory and research. PMID- 26014669 TI - Determinants of phubbing, which is the sum of many virtual addictions: a structural equation model. AB - BACKGROUND AND AIMS: Phubbing can be described as an individual looking at his or her mobile phone during a conversation with other individuals, dealing with the mobile phone and escaping from interpersonal communication. In this research, determinants of phubbing behavior were investigated; in addition, the effects of gender, smart phone ownership and social media membership were tested as moderators. METHODS: To examine the cause-effect relations among the variables of the theoretical model, the research employs a correlational design. Participants were 409 university students who were selected via random sampling. Phubbing was obtained via the scales featuring mobile phone addiction, SMS addiction, internet addiction, social media addiction and game addiction. The obtained data were analyzed using a correlation analysis, multiple linear regression analysis and structural equation model. RESULTS: The results showed that the most important determinants of phubbing behavior are mobile phone, SMS, social media and internet addictions. DISCUSSION: Although the findings show that the highest correlation value explaining phubbing is a mobile phone addiction, the other correlation values reflect a dependency on the phone. CONCLUSIONS: There is an increasing tendency towards mobile phone use, and this tendency prepares the basis of phubbing. PMID- 26014671 TI - Compulsive sexual behavior: a review of the literature. AB - BACKGROUND AND AIMS: Compulsive sexual behavior (CSB) is a common disorder featuring repetitive, intrusive and distressing sexual thoughts, urges and behaviors that negatively affect many aspects of an individual's life. This article reviews the clinical characteristics of CSB, cognitive aspects of the behaviors, and treatment options. METHODS: We reviewed the literature regarding the clinical aspects of CSB and treatment approaches. RESULTS: The literature review of the clinical aspects of CSB demonstrates that there is likely a substantial heterogeneity within the disorder. In addition, the treatment literature lacks sufficient evidence-based approaches to develop a clear treatment algorithm. CONCLUSIONS: Although discussed in the psychological literature for years, CSB continues to defy easy categorization within mental health. Further research needs to be completed to understand where CSB falls within the psychiatric nosology. PMID- 26014670 TI - Problematic Internet use, excessive alcohol consumption, their comorbidity and cardiovascular and cortisol reactions to acute psychological stress in a student population. AB - BACKGROUND AND AIMS: Problematic Internet use and excessive alcohol consumption have been associated with a host of maladaptive outcomes. Further, low (blunted) cardiovascular and stress hormone (e.g. cortisol) reactions to acute psychological stress are a feature of individuals with a range of adverse health and behavioural characteristics, including dependencies such as tobacco and alcohol addiction. The present study extended this research by examining whether behavioural dependencies, namely problematic Internet use, excessive alcohol consumption, and their comorbidity would also be associated with blunted stress reactivity. METHODS: A large sample of university students (N = 2313) were screened using Internet and alcohol dependency questionnaires to select four groups for laboratory testing: comorbid Internet and alcohol dependence (N = 17), Internet dependence (N = 17), alcohol dependence (N = 28), and non-dependent controls (N = 26). Cardiovascular activity and salivary cortisol were measured at rest and in response to a psychological stress protocol comprising of mental arithmetic and public speaking tasks. RESULTS: Neither problematic Internet behaviour nor excessive alcohol consumption, either individually or in combination, were associated with blunted cardiovascular or cortisol stress reactions. Discussion It is possible that problematic Internet behaviour and excessive alcohol consumption in a student population were not related to physiological reactivity as they may not reflect ingrained addictions but rather an impulse control disorder and binging tendency. CONCLUSIONS: The present results serve to indicate some of the limits of the developing hypothesis that blunted stress reactivity is a peripheral marker of the central motivational dysregulation in the brain underpinning a wide range of health and behavioural problems. PMID- 26014672 TI - Neurocognitive findings in compulsive sexual behavior: a preliminary study. AB - BACKGROUND AND AIMS :Compulsive sexual behavior (CSB) is a common behavior affecting 3-6% of the population, characterized by repetitive and intrusive sexual urges or behaviors that typically cause negative social and emotional consequences. METHODS: For this small pilot study on neurological data, we compared 13 individuals with CSB and gender- matched healthy controls on diagnostic assessments and computerized neurocognitive testing. RESULTS: No significant differences were found between the groups. CONCLUSIONS: These data contradict a common hypothesis that CSB is cognitively different from those without psychiatric comorbidities as well as previous research on impulse control disorders and alcohol dependence. Further research is needed to better understand and classify CSB based on these findings. PMID- 26014673 TI - Comparing problem gamblers with moderate-risk gamblers in a sample of university students. AB - BACKGROUND AND AIMS: In an effort to provide further empirical evidence of meaningful differences, this study explores, in a student population, the distinctions in gambling behavioral patterns and specific associated problems of two levels of gambling severity by comparing problem gamblers (PG) and moderate risk gamblers (MR) as defined by the score on the Problem Gambling Severity Index (PGSI; MR: 3-7; PG: 8 and more). METHODS: The study sample included 2,139 undergraduate students (male = 800, mean age = 22.6) who completed the PGSI and questionnaires on associated problems. RESULTS: Results show that problem gamblers engage massively and more diversely in gambling activities, more often and in a greater variety of locations, than moderate-risk gamblers. In addition, important differences have been observed between moderate-risk and problem gamblers in terms of expenditures and accumulated debt. In regards to the associated problems, compared to moderate-risk gamblers, problem gamblers had an increased reported psychological distress, daily smoking, and possible alcohol dependence. DISCUSSION AND CONCLUSIONS: The severity of gambling and associated problems found in problem gamblers is significantly different from moderate-risk gamblers, when examined in a student population, to reiterate caution against the amalgamation of these groups in future research. PMID- 26014674 TI - Characteristics and associated factors of non-suicidal self-injury among Italian young people: a survey through a thematic website. AB - BACKGROUND AND AIMS: The aim of this study is to examine the characteristics of non-suicidal self-injury (NSSI) in a group of young Italians who self-injure. In examining the characteristics, specific attention was given to the feelings and personal experiences associated with episodes of NSSI. METHODS: The research involved 362 young people (332 females and 30 males) who completed an online survey hosted on a website specifically geared to supporting young people who self-injure. This methodology enabled involving a diverse population of young people who self-injure, thus going beyond specific groups or clinical samples. RESULTS: Results show that the majority of respondents start injuring themselves between the ages of 12 and 16 years (72.38%, n = 262). Cutting was the most common self-injuring method (81.77%, n = 297). The 79.83% (n = 289) of respondents had not sought professional help for their wounds, preferring to care for their wounds on their own. More than half of the respondents (56.91%, n = 206) claimed to have experienced anxiety-spectrum disorders and almost half of the respondents (41.71%, n = 151) claimed to have experienced some type of eating disorder. DISCUSSION AND CONCLUSIONS: Many similarities have been found between this study and the literature, thus strengthening the hypothesis that NSSI is becoming a universal issue with similar characteristics across countries. PMID- 26014675 TI - Photobiocatalysis: the power of combining photocatalysis and enzymes. AB - Photobiocatalysts are constituted by a semiconductor with or without a light harvester that activates an enzyme. A logical source of inspiration for the development of photobiocatalysts has been natural photosynthetic centers. In photobiocatalysis, the coupling of the semiconductor and the enzyme frequently requires a natural cofactor and a relay transferring charge carriers from the semiconductor. The most widely studied photobiocatalysts so far make use of conduction band electrons of excited semiconductors to promote enzymatic reductions mediated by NAD(+) /NADH and an electron relay. The present review presents the state of the art in the field and has been organized based on the semiconductor and the reaction type including oxidations, hydrogen generation, and CO2 reduction. The possibility of direct enzyme activation by the semiconductor and the influence of the nature of mediator are also discussed as well as the use of mimics of the enzyme active center in combination with the semiconductor. The final section summarizes the state of the art of photobiocatalysis and comments on our view on future developments of the field. PMID- 26014677 TI - A Photoelectrochemical Solar Cell Consisting of a Cadmium Sulfide Photoanode and a Ruthenium-2,2'-Bipyridine Redox Shuttle in a Non-aqueous Electrolyte. AB - A photoelectrochemical (PEC) cell consisting of an n-type CdS single-crystal electrode and a Pt counter electrode with the ruthenium-2,2'-bipyridine complex [Ru(bpy)3](2+/3+) as the redox shuttle in a non-aqueous electrolyte was studied to obtain a higher open-circuit voltage (V(OC)) than the onset voltage for water splitting. A V(OC) of 1.48 V and a short-circuit current (I(SC)) of 3.88 mA cm( 2) were obtained under irradiation by a 300 W Xe lamp with 420-800 nm visible light. This relatively high voltage was presumably due to the difference between the Fermi level of photo-irradiated n-type CdS and the redox potential of the Ru complex at the Pt electrode. The smooth redox reaction of the Ru complex with one electron transfer was thought to have contributed to the high V(OC) and I(SC). The obtained V(OC) was more than the onset voltage of water electrolysis for hydrogen and oxygen generation, suggesting prospects for application in water electrolysis. PMID- 26014676 TI - Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay. AB - Lung cancer is the most prevalent cancer in the world. Few effective and cheap methods are available so far for early detection and screening of lung cancer. Although histological and cytological examinations are gold standards in lung cancer diagnosis, patients are always at late stages when diagnosis is confirmed. Therefore, new diagnostic methods are needed urgently to increase the early diagnostic rate, enhance the confirmed diagnostic rate, and reduce mortality. The SHOX2 gene methylation assay has become a promising option for the above purposes. It has been shown to enhance the confirmed diagnostic rate of lung cancer in several clinical trials when combined with histological or cytological assays, and has the potential to become an early diagnostic tool. This article reviews the outcome of clinical trials using the SHOX2 gene methylation assay alone or in combination with other examinations, and suggests its future applications and research directions. PMID- 26014678 TI - A novel genomic signature reclassifies an oral cancer subtype. AB - Verrucous carcinoma of the oral cavity (OVC) is considered a subtype of classical oral squamous cell carcinoma (OSCC). Diagnosis is problematic, and additional biomarkers are needed to better stratify patients. To investigate their molecular signature, we performed low-coverage copy number (CN) sequencing on 57 OVC and exome and RNA sequencing on a subset of these and compared the data to the same OSCC parameters. CN results showed that OVC lacked any of the classical OSCC patterns such as gain of 3q and loss of 3p and demonstrated considerably fewer genomic rearrangements compared to the OSCC cohort. OVC and OSCC samples could be clearly differentiated. Exome sequencing showed that OVC samples lacked mutations in genes commonly associated with OSCC (TP53, NOTCH1, NOTCH2, CDKN2A and FAT1). RNA sequencing identified genes that were differentially expressed between the groups. In silico functional analysis showed that the mutated and differentially expressed genes in OVC samples were involved in cell adhesion and keratinocyte proliferation, while those in the OSCC cohort were enriched for cell death and apoptosis pathways. This is the largest and most detailed genomic and transcriptomic analysis yet performed on this tumour type, which, as an example of non-metastatic cancer, may shed light on the nature of metastases. These three independent investigations consistently show substantial differences between the cohorts. Taken together, they lead to the conclusion that OVC is not a subtype of OSCC, but should be classified as a distinct entity. PMID- 26014679 TI - Increased expression of caspase-1 and interleukin-18 in peeling skin disease, and a novel mutation of corneodesmosin. PMID- 26014680 TI - Pd-Pb Alloy Nanocrystals with Tailored Composition for Semihydrogenation: Taking Advantage of Catalyst Poisoning. AB - Metallic nanocrystals (NCs) with well-defined sizes and shapes represent a new family of model systems for establishing structure-function relationships in heterogeneous catalysis. Here in this study, we show that catalyst poisoning can be utilized as an efficient strategy for nanocrystals shape and composition control, as well as a way to tune the catalytic activity of catalysts. Lead species, a well-known poison for noble-metal catalysts, was investigated in the growth of Pd NCs. We discovered that Pb atoms can be incorporated into the lattice of Pd NCs and form Pd-Pb alloy NCs with tunable composition and crystal facets. As model catalysts, the alloy NCs with different compositions showed different selectivity in the semihydrogenation of phenylacetylene. Pd-Pb alloy NCs with better selectivity than that of the commercial Lindlar catalyst were discovered. This study exemplified that the poisoning effect in catalysis can be explored as efficient shape-directing reagents in NC growth, and more importantly, as a strategy to tailor the performance of catalysts with high selectivity. PMID- 26014684 TI - To stent or not to stent? A meta-analysis of endonasal congenital bilateral choanal atresia repair. AB - OBJECTIVES: The use of nasal stents as a postoperative adjunct following repair of choanal atresia remains controversial. The study objective was to systematically review the literature regarding the efficacy and safety of stenting following transnasal endoscopic repair of bilateral choanal atresia. STUDY DESIGN: Systematic review with meta-analysis. METHODS: A comprehensive search in PubMed, EMBASE, CINAHL, and the Cochrane Library was conducted. Inclusion criteria included articles written in the English language with five or more subjects and clear intervention data and outcomes. Two independent reviewers screened studies for eligibility, appraised the level of evidence, extracted data, and resolved discrepancies by consensus. Successful surgery was defined as the absence of restenosis. RESULTS: Of 154 identified studies, 15 met inclusion criteria. Levels of evidence varied from level 3 to 4. Mean age at surgery ranged from 5 days to 25 months. Thirteen studies (n = 167 patients) included patients who were stented; the weighted pooled proportion of successful surgery was 65% (95% confidence interval [CI], 49-76%). Mean duration of stenting ranged from 48 hours to 16 weeks. Six studies (n = 42) evaluated patients who were not stented; the weighted pooled proportion of successful surgery was 64% (95% CI, 42-84%). Complications associated with stenting included alar injury, vestibular stenosis, columellar tear, and stent dislodgement or blockage. CONCLUSIONS: Success rates for bilateral choanal atresia repair were similar with and without the use of nasal stents. The use of nasal stents may be associated with more complications. There is insufficient data to determine if mitomycin C is a useful therapeutic adjunct. PMID- 26014685 TI - Functional outcome of macular edema in different retinal disorders. AB - Macular edema accompanies many ocular pathologies, affecting visual function and is an important factor in treatment decisions and disease outcome. Though visual acuity is commonly used to evaluate patient vision it does not always provide a complete estimate of their visual abilities or reflect their own visual perception. Furthermore, different pathologies result in macular edema causing a variable effect on visual function, related to the rate of fluid accumulation and accompanying ocular changes. Use of complementary visual function tests, such as retinal contrast sensitivity on microperimetry and reading speed provide additional information that can be used to evaluate patients and assist in treatment choices. Here we explore the effect of macular edema on visual function in different retinal pathologies, namely diabetic retinopathy, retinal vein occlusion and uveitis, examine its influence on the various vision tests and discuss the factors underlying this variable response. PMID- 26014686 TI - Copper-Carbene Intermediates in the Copper-Catalyzed Functionalization of O-H Bonds. AB - Copper-carbene [Tp(x)Cu=C(Ph)(CO2Et)] and copper-diazo adducts [Tp(x)Cu{eta(1) N2C(Ph)(CO2Et)}] have been detected and characterized in the context of the catalytic functionalization of O-H bonds through carbene insertion by using N2=C(Ph)(CO2Et) as the carbene source. These are the first examples of these type of complexes in which the copper center bears a tridentate ligand and displays a tetrahedral geometry. The relevance of these complexes in the catalytic cycle has been assessed by NMR spectroscopy, and kinetic studies have demonstrated that the N-bound diazo adduct is a dormant species and is not en route to the formation of the copper-carbene intermediate. PMID- 26014687 TI - [Epidemiology of neonatal purulent meningitis in Hebei Province, China: a multicenter study]. AB - OBJECTIVE: To investigate the clinical characteristics, diagnosis and main pathogenic bacteria, and outcomes of neonatal purulent meningitis. METHODS: A prospective epidemiological study was conducted in neonates with purulent meningitis admitted to 23 cooperating hospitals between 2013 and 2014. Clinical data were collected and clinical characteristics and outcomes were analyzed. RESULTS: A total of 301 neonates with purulent meningitis from the 23 cooperating hospitals were included. Neonatal pneumonia was the most common primary disease (167 cases, 55.5%). Fever was the most common manifestation (214 cases, 71.1%). Blood culture findings were positive in 72 patients (23.9%), with Escherichia coli, Klebsiella pneumoniae and Staphylococcus epidermidis as the most common bacteria. Positive cerebrospinal fluid (CSF) culture was found in 36 patients (36/264, 13.6%) , with Escherichia coli and Staphylococcus epidermidis as the most common bacteria. The median of CSF WBC counts was 80/mm(3) (range: 0-9 2500/mm(3)), and 11 cases (3.7%) had CSF WBC counts of <20/mm(3) and 154 cases (51.2%) had CSF WBC counts of >100/mm(3). There were 258 patients (85.7%) who were cured or improved at discharge and 15 deaths (15/298, 5.0%). CONCLUSIONS: The most common primary disease of neonatal purulent meningitis is neonatal pneumonia in this area. The patients with neonatal purulent meningitis most often present with fever. Escherichia coli is the leading pathogenic bacteria causing neonatal purulent meningitis. A normal CSF WBC count can barely be used to exclude the possibility of this diosorder. PMID- 26014688 TI - [Values of C-reactive protein, percentage of neutrophils and mean platelet volume in early diagnosis of neonatal sepsis]. AB - OBJECTIVE: To study the clinical values of C-reactive protein (CRP), the percentage of neutrophils, and mean platelet volume (MPV) in the diagnosis of neonatal sepsis. METHODS: A total of 315 neonates who were confirmed to have sepsis between January 2010 and May 2014 were divided into two groups: proven sepsis (with a positive blood culture; n=207) and clinical sepsis (with a clinical diagnosis; n=108). Within the same period, 132 hospitalized neonates with noninfectious diseases were enrolled as the control group. Serum CRP level, percentage of neutrophils, and MPV were measured. The receiver operating characteristic (ROC) curves were drawn to evaluate the values of the three parameters in the diagnosis of neonatal sepsis. RESULTS: Serum CRP level, percentage of neutrophils, and MPV were significantly higher in the two sepsis groups than in the control group (P<0.05). The optimal cut-off point of CRP for the diagnosis of sepsis was 8.5 mg/L, with the sensitivity and specificity of 74.6% and 92.0%, respectively. The optimal cut-off point of the percentage of neutrophils for the diagnosis of sepsis was 0.53, with the sensitivity and specificity of 64.4% and 83.3%, respectively. The optimal cut-off point of MPV for the diagnosis of sepsis was 11.4 fL, with the sensitivity and specificity of 40.5% and 88.4%, respectively. CONCLUSIONS: The diagnostic accuracy of CRP for neonatal sepsis is superior to those of the percentage of neutrophils and MPV. The measurements of the percentage of neutrophils and MPV hold promise for the early diagnosis of neonatal sepsis. PMID- 26014689 TI - [Clinical study of neonatal twin-twin transfusion syndrome]. AB - OBJECTIVE: To explore the clinical manifestations and short-term prognosis of twin-twin transfusion syndrome (TTTS) in neonates with different disease stages, receiving different intrauterine interventions, or as blood donors and recipients. METHODS: The study retrospectively collected 76 TTTS neonates who were hospitalized in the Neonatal Ward, Peking University Third Hospital. The participants were classified into mild TTTS (n=38) and severe TTTS groups (n=21), or into amnioreduction (n=20), laser surgery (n=21), and expectant therapy groups (n=32), or into donor (n=23) and recipient groups (n=30). RESULTS: The severe TTTS group had higher incidences of brain injury, heart disease, asphyxia, and renal damage and in-hospital mortality rate compared with the mild TTTS group, but the differences had no statistical significance. The laser surgery group displayed decreasing trends in the incidences of brain injury, heart disease, and renal damage and in-hospital mortality rate compared with the amnioreduction and expectant therapy groups. The recipient group had higher incidences of heart diseases and pathological jaundice than the donor group (P<0.05). The donor group had higher incidences of asphyxia and renal damage than the recipient group, but with no significant difference. CONCLUSIONS: The neonates with severe TTTS have higher rates of organ damages and in-hospital mortality. Intrauterine laser surgery seems to lead to a better prognosis compared with the amnioreduction and expectant therapy. The recipients are more susceptible to heart diseases and pathological jaundice, whereas the donors are more susceptible to asphyxia and renal damage. PMID- 26014690 TI - [Diagnostic value and influencing factors for amplitude-integrated EEG in brain injury in preterm infants]. AB - OBJECTIVE: To study the diagnostic value and influencing factors for amplitude integrated EEG (aEEG) in brain injury in preterm infants. METHODS: One hundred and sixteen preterm infants with a gestational age (GA) between 27 weeks and 36(+6) weeks were enrolled as subjects. The aEEG scores of all preterm infants were obtained within 6 hours after birth. According to the diagnostic results, the 116 preterm infants were divided into two groups: brain injury (n=63) and non brain injury (n=53). The risk factors for brain injury were evaluated using logistic regression analysis. According to the aEEG results, the 116 preterm infants were divided into two groups: normal aEEG (n=58) and abnormal aEEG (n=58). The influencing factors for aEEG results in preterm infants were determined using univariate analysis. RESULTS: The brain injury group had a significantly higher rate of abnormal aEEG than the non-brain injury group (83% vs 11%; P<0.05). The infants in the brain injury group from two different GA subgroups (27-33(+6) weeks and 34-36(+6) weeks) had significantly lower aEEG scores than the non-brain injury group from corresponding GA subgroups (P<0.01). Logistic regression analysis showed that low GA (<32 weeks), low birth weight (<1 500 g), abnormal placenta, fetal membranes, and umbilical cord, and hypertension during pregnancy were high-risk factors for brain injury (P<0.05). There were significant differences in GA, birth weight, abnormal placenta, fetal membranes, and umbilical cord, and hypertension during pregnancy between the normal and abnormal aEEG groups (P<0.05). CONCLUSIONS: The risk factors for brain injury are consistent with the influencing factors for aEEG results in preterm infants, suggesting that aEEG contributes to the early diagnosis of brain injury. PMID- 26014691 TI - [Clinical and imaging features of premature infants with different degrees of bronchopulmonary dysplasia]. AB - OBJECTIVE: To study the clinical and imaging features of premature infants with different degrees of bronchopulmonary dysplasia (BPD). METHODS: A prospective study was performed on the clinical data of 59 premature infants (gestational age <32 weeks) with BPD. Among the 59 premature infants, 37 cases had mild BPD and the other 22 cases had moderate to severe BPD. The clinical and imaging data were compared between these premature infants with different degrees of BPD. RESULTS: The durations of mechanical ventilation, oxygen therapy, antibiotic therapy, parenteral nutrition, and hospitalization in the moderate to severe group were significantly longer than those in the mild group (P<0.05). The incidence of nosocomial infection and number of times of red blood cell transfusion in the moderate to severe group were significantly higher than that in the mild group. The rates of X-ray changes, including grade I respiratory distress syndrome (1 day after birth) and hypolucency of lungs (4-10 days and >= 28 days after birth) were significantly higher in the mild group than in the moderate to severe group. The rates of X-ray changes in classical BPD stage III (4-10 days after birth) and IV (>= 28 days after birth) were significantly higher in the moderate to severe group than in the mild group. CONCLUSIONS: The durations of mechanical ventilation, oxygen therapy, and antibiotic therapy and the incidence of nosocomial infection are correlated with the severity of BPD. The premature infants with severer BPD need a longer duration of parenteral nutrition and more times of red blood cell transfusion and have more typical imaging changes of BPD. Imaging examination has a predictive value for the severity of BPD. PMID- 26014692 TI - [Expression profile of TGF-beta1 and BMP-7 in serum of preterm infants with respiratory distress syndrome]. AB - OBJECTIVE: To study the expression profile and significance of serum transforming growth factor-beta 1 (TGF-beta1) and bone morphogenetic protein-7 (BMP-7) in preterm infants with respiratory distress syndrome (RDS). METHODS: Thirty-two preterm infants with RDS who were given pulmonary surfactant (PS) within 12 hours after birth were enrolled as the PS group. Twenty-eight preterm infants with RDS who were not given PS were selected as the non-PS group. Another 30 preterm infants without RDS were used as the control group. Serum levels of TGF-beta1 and BMP-7 in the three groups were measured using enzyme-linked immunosorbent assay at 0, 1, 3, and 7 days after birth. RESULTS: The PS group had higher serum levels of TGF-beta1 than the control group at 1 and 3 days after birth (P<0.05). The non PS group had significantly higher serum levels of TGF-beta1 than the control group at 1, 3, and 7 days after birth (P<0.05), and serum levels of TGF-beta1 in the non-PS group were significantly higher than the PS group at 3 and 7 days after birth (P<0.05). The PS group had higher serum levels of BMP-7 than the control group at 1 and 3 days after birth (P<0.05). The non-PS group had higher serum levels of BMP-7 than the control group at 1, 3, and 7 days after birth (P<0.05). The levels of BMP-7 in the non-PS group at 7 days after birth were reduced than before, but were still higher than in the PS group (P<0.05). CONCLUSIONS: Both serum TGF-beta1 and BMP-7 levels increase in the early stage in preterm infants with RDS, however, in the late stage, the expression of BMP-7 decreases with the increase in TGF-beta1 expression, suggesting that administration of exogenous BMP-7 may reduce the expression of TGF-beta1, which might be a therapeutic approach for RDS in preterm infants. PMID- 26014693 TI - [Measurement of tidal breathing pulmonary function in premature infants with different gestational ages]. AB - OBJECTIVE: To investigate the characteristics of the tidal breathing pulmonary function in premature infants with different gestational ages. METHODS: A total of 75 premature infants were classified into three groups according to their gestational ages: <32 weeks, 32-33(+6) weeks and 34-36(+6) weeks. Fifty-five full term infants (39-40 weeks group) were selected as the control group. All infants were given the tidal breathing pulmonary function test at 3-5 days after birth. Moreover, all infants were given the tidal breathing pulmonary function test again at 40 weeks of the corrected gestational age. RESULTS: At 3-5 days after birth, the three groups of premature infants had significantly lower inspiratory time, time to peak tidal expiratory flow (tPTEF), and ratio of tPTEF to total expiratory time (tPTEF/tE) than the control group (P<0.05). The parameter values of the tidal breathing pulmonary function were lower when the gestational age was lower. Even at 40 weeks of the corrected gestational age, the three groups of premature infants still had significantly lower tPTEF and tPTEF/tE than the control group (P<0.05). CONCLUSIONS: The tidal breathing pulmonary function of neonates is influenced by the gestational age. The tidal breathing pulmonary function of premature infants is obviously impaired, and the lower the gestational age, the more obvious the impairment. PMID- 26014694 TI - [Risk factors for extrauterine growth restriction in preterm infants with gestational age less than 34 weeks]. AB - OBJECTIVE: To investigate the correlated factors contributed to extrauterine growth restriction (EUGR) in preterm infants with the gestational age less than 34 weeks. METHODS: A total of 694 preterm infants with the gestational ages less than 34 weeks were enrolled. They were classified into EUGR and non-EUGR groups by weight on discharge. The perinatal data, growth data, nutritional information and morbidities during hospitalization were compared between the two groups. RESULTS: EUGR on discharge occurred in 284 (40.9%) out of the 694 infants. The incidence of EUGR in intrauterine growth restriction (IUGR) infants was significantly higher than in non-IUGR infants (P<0.01). The very low birth weight (VLBW) infants had a higher incidence of EUGR than non-VLBW infants (P<0.01). The incidence of EUGR increased with the decreases of gestational age at birth and birth weight (P<0.01). Compared with the non-EUGR group, the fasting time, the duration of parenteral nutrition, the time beginning to feed and the age to achieve full enteral feeds were significantly greater in the EUGR group (P<0.01). The cumulative protein deficit and cumulative caloric deficit in the first week of life in the EUGR group were higher than in the non-EUGR group (P<0.05). The incidences of respiratory distress syndrome, apnea, necrotizing enterocolitis and septicemia in the EUGR group were higher than in the non-EUGR group (P<0.05). The logistic regression analysis showed that birth weight, gestational age at birth and IUGR were the independent risk factors for EUGR. CONCLUSIONS: The incidence of EUGR in infants with gestational age less than 34 weeks is high, especially in IUGR or VLBW infants. Early and aggressive nutritional strategy and prevention of apnea and septicemia may facilitate to reduce the occurrence of EUGR. PMID- 26014695 TI - [Molecular diagnosis of children with unexplained intellectual disability/ developmental delay by array-CGH]. AB - OBJECTIVE: To analyze the potential pathogenic genomic imbalance in children with unexplained intellectual disability (ID) and/or developmental delay (DD) and its association with phenotypes, and to investigate the value of array-based comparative genomic hybridization (array-CGH) in clinical molecular genetic diagnosis. METHODS: The whole genome of 16 children with ID/DD was scanned by the array-CGH for detection of genomic copy number variations (CNVs), and the revealed genomic imbalance was confirmed by multiplex ligation-dependent probe amplification. RESULTS: G-band karyotyping of peripheral blood cells showed no abnormalities in the 16 children. The results of the array-CGH revealed that 6 (38%) of the 16 patients had genomic CNVs, and 3 cases of CNVs were normal polymorphic changes; 1 CNV was a microdeletion of 4p16.3, which was the critical region for Wolf-Hirschhorn syndrome, and 1 CNV was a microdeletion of 7q11.23, which was the critical region for Williams-Beuren syndrome. Moreover, a CNV was identified with two duplications at 2q22.2 and 15q21.3 in a boy, which proved to have a clinical significance due to its association with ID, brain DD, unusual facies, cryptorchidism, irregular dentition, etc. CONCLUSIONS: Array-CGH allows for the etiological diagnosis in some of the children with unexplained ID/DD. As a high-throughput and rapid tool, it has a great clinical significance in the etiological diagnosis of ID/DD. PMID- 26014696 TI - [Characteristics of R bone age, C bone age, and T bone age in children with different causes of short stature based on Tanner and Whitehouse skeletal age assessment system 2]. AB - OBJECTIVE: To study the characteristics of R bone age, C bone age, and T bone age in children with different causes of short stature based on the Tanner and Whitehouse skeletal age assessment system 2 (TW2), and to provide a reference for the etiological diagnosis of short stature. METHODS: Three hundred and sixty three children with previously untreated short stature were classified into four groups according to the causes: growth hormone deficiency (GHD; 27 cases), idiopathic short stature (ISS; 280 cases), small for gestational age (SGA; 41 cases), and Turner syndrome (TS; 15 cases). The X-ray films of their left hand wrist bones were taken to determine the bone age. R bone age, C bone age, and T bone age were assessed by the TW2 method and compared with their chronological age (CA). RESULTS: R bone age, C bone age, and T bone age were over 2 years less than CA in both boys and girls from the GHD group. In the ISS group, R bone age, C bone age, and T bone age were about 1 year less than CA in boys, while there were no significant differences between the bone ages and CA in girls. In the SGA group, there were no significant differences between the bone ages and CA in either boys or girls. In the TS group, R bone age and T bone age were significantly lower than CA, while there was no significant difference between C bone age and CA. CONCLUSIONS: The children with different causes of short stature have different characteristics of R bone age, C bone age, and T bone age assessed by the TW2 method. The assessment of R bone age, C bone age, and T bone age by the TW2 method is helpful for the etiological diagnosis of short stature in children. PMID- 26014697 TI - [Association between polymorphism of RAD50 gene and acute lymphoid leukemia in children]. AB - OBJECTIVE: To investigate the association between single nucleotide polymorphism (SNP) (rs17166050) in RAD50 gene and acute lymphoid leukemia (ALL) in children. METHODS: A total of 177 ALL children from Wuhan and surrounding areas and 232 healthy children were selected. The numbers of standard-risk, medium-risk, and high-risk children were 66, 69, and 42, respectively. The genotypes of SNP in RAD50 gene were determined using PCR-RFLP, and the relationship of the RAD50 polymorphism with ALL susceptibility and clinical risk was analyzed. RESULTS: The genotype (AA, GA, and GG) distribution of SNP in RAD50 gene showed significant differences between the ALL and control groups (P=0.038), and G allele was significantly associated with ALL susceptibility (OR=1.459, 95% CI: 1.034-2.057, P=0.031). However, the SNP was not associated with the risk stratification of ALL. CONCLUSIONS: The SNP (rs17166050) in RAD50 gene is associated with the susceptibility to ALL in children, but is not associated with the risk stratification of ALL. PMID- 26014698 TI - [Clinical features and StAR gene mutations in children with congenital lipoid adrenal hyperplasia]. AB - This article reported the clinical manifestations, steroid profiles and adrenal ultrasound findings in two unrelated Chinese girls with lipoid congenital adrenal hyperplasia (LCAH). Direct DNA sequencing and restriction fragment length polymorphism (RFLP) analysis were used to identify the mutations of steroidogenic acute regulatory protein (StAR) gene. The two patients with 46,XX karyotype, presented hyperpigmentation, growth retardation, and hyponatremia. Steroid profiles analysis revealed elevated plasma adrenocorticotrophic hormone levels, decreased or normal serum cortisol levels and low levels of androgens. Ultrasound examinations revealed that enlarged adrenals in patient 1 and normal adrenals in patient 2. Direct DNA sequencing of StAR gene showed a reported homozygous for c.772C>T(p.Q258X) in patient 1. Compound heterozygous for c.367G>A(p.E123K) and IVS4+2T>A (both novel mutations) were found in patient 2, inherited from her mother and father respectively. The amino acid of mutant position of the novel p.E123K was highly conserved in ten different species and was predicted to have impacts on the structure and function of StAR protein by the PolyPhen-2 prediction software. RFLP analysis revealed three bands (670, 423 and 247 bp) in patient 2 and her father and two bands (423 and 247 bp) in her mother and 50 controls. It is concluded that LCAH should be considered in girls with early onset of adrenal insufficiency and that steroid profiles, karyotype analysis, adrenal ultrasound and StAR gene analysis may be helpful for the definite diagnosis of LCAH. PMID- 26014699 TI - [Clinical analysis of 15 pediatric patients with tuberous sclerosis complex complicated by cardiac rhabdomyomas]. AB - OBJECTIVE: To investigate the clinical features in children with tuberous sclerosis complex (TSC)-associated cardiac rhabdomyomas (CRM). METHODS: The clinical data of 15 children with TSC complicated by CRM were collected. The clinical features of the patients were analyzed, and TSC gene mutations were detected. RESULTS: Eleven cases (73%) developed multiple CRM. The majority of the tumors were located in the left and right ventricles. Most tumors presented as a round-like hyperechogenic mass with a clear margin on echocardiography. Arrhythmias occurred in 3 patients and 2 patients experienced heart failure. Gene mutation tests were performed in 2 patients, and pathogenic mutations were detected in both patients, which were TSC1 mutation and TSC2 mutation, respectively. Three patients were followed up for 6 to 38 months, and their CRM shrank or regressed spontaneously. CONCLUSIONS: TSC-associated CRM is generally multiple. Heart failure and arrhythmias may occur in some patients. Echocardiography is important for diagnosis of CRM. TSC-associated CRM has an inclination to spontaneous regression. TSC can be diagnosed at a molecular genetic level by TSC gene mutation detection. PMID- 26014700 TI - [Prevalence of respiratory syncytial virus infection in hospitalized children at a children's hospital and effects of climate change on the prevalence in Suzhou, China]. AB - OBJECTIVE: To investigate the prevalence of respiratory syncytial virus (RSV) infection in hospitalized children and the relationship between the prevalence and the climate change in Suzhou, China. METHODS: A total of 42 664 nasopharyngeal secretions from hospitalized children with acute respiratory infection at the Suzhou Children's Hospital were screened for RSV antigens using direct immunofluorescence. Monthly meteorological data (mean monthly air temperature, monthly relative humidity, monthly rainfall, total monthly sunshine duration, and mean monthly wind velocity) in Suzhou between 2001 and 2011 were collected. The correlations between RSV detection rate and climatic factors were evaluated using correlation and stepwise regression analysis. RESULTS: The annual RSV infection rate in hospitalized children with respiratory infection in the Suzhou Children's Hospital varied between 11.85% and 27.30% from 2001 to 2011. In the 9 epidemic seasons, each spanning from November to April of the next year, from 2001 to 2010, the RSV detection rates were 40.75%, 22.72%, 39.93%, 27.37%, 42.71%, 21.28%, 38.57%, 19.86%, and 29.73%, respectively; there were significant differences in the detection rate between the epidemic seasons. The monthly RSV detection rate was negatively correlated with mean monthly air temperature, total monthly sunshine duration, monthly rainfall, monthly relative humidity, and mean monthly wind velocity (P<0.05). Stepwise regression analysis showed that mean monthly air temperature fitted into a linear model (R(2)=0.64, P<0.01). CONCLUSIONS: From 2001 to 2011, RSV infection in Suzhou was predominantly prevalent between November and April of the next year. As a whole, the infection rate of RSV reached a peak every other year. Air temperature played an important role in the epidemics of RSV infection in Suzhou. PMID- 26014701 TI - [Prognostic judgment of children with Mycoplasma pneumoniae pneumonia associated with airway mucous plug formation]. AB - OBJECTIVE: To investigate the clinical characteristics and treatment defects in slow-to-recover children with Mycoplasma pneumoniae pneumonia (MPP) associated with airway mucous plug formation, and to provide a basis for prognostic judgment and therapeutic guidance. METHODS: A retrospective analysis was performed on the clinical data of 67 children with MPP who were admitted between May 2012 and May 2014 and showed airway mucous plug formation in fiberoptic bronchoscope examinations. Based on the results of re-examinations using imaging methods, all patients were classified into a slow-to-recover group (n=30) and a control group (n=37). Comparisons of clinical outcomes, laboratory indices, imaging findings, and treatment methods were performed between the two groups. The receiver operating characteristic (ROC) curves were drawn to analyze the indices with significant differences. RESULTS: The percentage of neutrophils, levels of C reactive protein (CRP), lactic dehydrogenase (LDH), fibrinogen (FIB), and IgM in peripheral blood, and incidence of pleural effusion were significantly higher in the slow-to-recover group than in the control group (P<0.05). The fever duration and treatment time of azithromycin and fiberoptic bronchoscope for the first time were significantly longer in the slow-to-recover group than in the control group (P<0.05). The results of ROC curve analysis showed that the optimal cut-off points of fever duration, percentage of neutrophils, levels of CRP and FIB, and treatment time of fiberoptic bronchoscope for the first time were 11.5 days, 70.7%, 57 mg/L, 4.7 g/L, and 13.5 days, respectively, with sensitivity and specificity higher than 0.643 and 0.727. CONCLUSIONS: The fever duration, percentage of neutrophils, level of CRP, level of FIB, and treatment time of fiberoptic bronchoscope for the first time can predict a recovery time longer than two months in children with MPP associated with mucous plug formation. PMID- 26014702 TI - [Expression of CD163 in children with Epstein-Barr virus infection]. AB - OBJECTIVE: To study the clinical significance of CD163 in the diagnosis and the evaluation of severity and prognosis of childhood hemophagocytic lymphohistiocytosis (HLH). METHODS: Ninety-four children were classified into Epstein-Barr virus (EBV)-positive (n=55) and EBV-negative groups (n=39; control group). The EBV-positive group was subgrouped into infectious mononucleosis (IM; n=47) and HLH (n=8). Serum levels of soluble CD163 were measured using ELISA. Expression of CD163 on mononuclear cells was detected by flow cytometry. RESULTS: The serum levels of soluble CD163 were>10 000 ng/mL in all eight HLH patients (>30 000 ng/mL in 3 cases). The mean serum levels of soluble CD163 in the HLH group were significantly higher than in the control and IM groups (P<0.05). The serum levels of soluble CD163 in EBV-positive children were positively correlated with EBV-DNA copies and serum levels of ferritin and LDH, but were negatively correlated with white blood cell count, neutrophil count, hemoglobin and platelet count. The follow-up after treatment for three HLH patients showed that serum levels of soluble CD163 were significantly reduced, but the soluble CD163 levels rebounded in one patient who was complicated by fungal pneumonia infection. CONCLUSIONS: The levels of serum soluble CD163 may be related to the severity in children with HLH. The EBV-positive children with soluble CD163 levels >10 000 ng/mL should be considered the possibility of HLH. PMID- 26014703 TI - [Silencing of Pin1 suppresses hyperoxia-induced apoptosis of A549 cells]. AB - OBJECTIVE: To explore the effect of silence of Pin1 expression on hyperoxia induced apoptosis in alveolar epithelial cells A549. METHODS: A549 cells were divided into four groups: control, hyperoxia, negative lentivirus and Pin1-shRNA hyperoxia. The hyperoxia group was exposed to a mixture of 95%O2 and 5%CO2 for 10 minutes. Then cells were cultured in a closed environment. After 24 hours, the changes of morphology were observed under an inverted microscope. Cell apoptosis was detected by flow cytometry (FCM). The expression of X-linked inhibitor of apoptosis protein (XIAP) and Caspase-9 were detected by immunohistochemistry. The production of reactive oxygen species (ROS) and cellular mitochondria membrane potential (?Psim) were determined by fluorescence microscopy. RESULTS: Under the inverted microscope, the A549 cells grew slowly and the changes in morphology of the cells were most obvious in the hyperoxia and negative lentivirus groups. The changes in morphology of A549 cells were obviously improved in the Pin1-shRNA hyperoxia group. The FCM results showed that the apoptosis rate of A549 cells increased, Caspase-9 expression increased, XIAP expression decreased, mitochondrial ROS production increased and mitochondrial membrane potential decreased in the hyperoxia and negative lentivirus groups compared with the control group (P<0.05). Compared with the hyperoxia and negative lentivirus groups, the apoptosis rate of A549 cells decreased, Caspase-9 expression decreased, XIAP expression increased, mitochondrial ROS production decreased and mitochondrial membrane potential increased in the Pin1-shRNA hyperoxia group (P<0.05), although the levels of the indexes did not reach to those of the control group. CONCLUSIONS: Silencing of Pin1 could suppress hyperoxia-induced apoptosis of A549 cells. PMID- 26014704 TI - [Effect of L-alanyl-L-glutamine on expression of insulin-like growth factor-1 in intestinal tissues of low-birth-weight newborn rats with hypoxia/reoxygenation induced intestinal injury]. AB - OBJECTIVE: To study the effect of L-alanyl-L-glutamine (Ala-Gln) on the levels of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) in the intestinal tissues of low-birth-weight (LBW) newborn rats with hypoxia/reoxygenation-induced intestinal injury. METHODS: Pregnant rats were fed with or without smoking. The rats born by those fed without smoking were included in group A; for the rats born by those fed with smoking, normal-birth-weight rats were included in group B, and LBW rats were randomly divided into control group (group C), hypoxia/reoxygenation (H/R) group (group D), and Ala-Gln group (group E). Each group consisted of 24 newborn rats. The rats in groups D and E received H/R treatment twice a day for three consecutive days to establish an intestinal injury model; the rats in group E were intraperitoneally injected with Ala-Gln (10 ml/kg) before daily H/R treatment, while those in groups C and D were given an equal dose of normal saline by intraperitoneal injections. On days 4, 7, and 10 after birth, 8 rats were sacrificed in each group to collect intestinal tissues. The IGF-1 levels in intestinal tissues were measured using ELISA, and IGF-1R levels were measured by immunohistochemistry. RESULTS: There were no significant differences in IGF-1 and IGF-1R levels between groups A and B at all time points. The levels of IGF-1 and IGF-1R in group C kept increasing, were higher than those in other groups on day 7 (P<0.05), and reached a normal level on day 10, without significant differences compared with those in groups A and B. Group D had significantly lower IGF-1 and IGF-1R levels than group C at all time points (P<0.05). The levels of IGF-1 and IGF-1R in group E were lower than those in group C on days 4 and 7 (P<0.05), but they increased to approximately the levels in group C and were significantly higher than those in group D on day 10. CONCLUSIONS: Intrauterine and postnatal hypoxia may induce intestinal injury in LBW newborn rats, and parenteral administration of high-dose Ala-Gln can reduce hypoxia-induced intestinal injury. Therefore, Ala-Gln has a protective effect against hypoxia-induced intestinal injury. PMID- 26014705 TI - [Improvement in cardiac morphology and function in young rats with dilated cardiomyopathy by recombinant human growth hormone]. AB - OBJECTIVE: To investigate the effects of recombinant human growth hormone (rhGH) on the morphology and function of the left cardiac ventricle in young rats with dilated cardiomyopathy (DCM), and to evaluate the efficacy and safety of rhGH in the treatment of DCM. METHODS: Sixty male Sprague-Dawley rats were randomly and equally assigned to control group, DCM group, and rhGH group. Furazolidone (0.25 mg/g) was given by gavage for 12 weeks to prepare the DCM model. Rats in the rhGH group received an intraperitoneal injection of rhGH (0.15 U/kg) once per day for 12 weeks, while rats in the DCM group received an equal volume of normal saline instead. Rats in the control group did not receive any treatment. Cardiac indices, serum biochemical parameters, hemodynamic indices, cardiac histopathological changes, and levels of myocardial collagen fibrils in each group were determined using Doppler echocardiography, enzyme-linked immunosorbent assay, multi-channel physiological recorder, light and electron microscopy, and picrosirius red staining plus polarization microscopy, respectively. RESULTS: Compared with the control group, rats in the DCM group had significantly increased cardiac chamber size, significantly reduced ventricular wall thickness, and significantly decreased fractional shortening (FS) and ejection fraction (EF) (P<0.05). Rats in the rhGH group had significantly improved cardiac chamber size, ventricular wall thickness, FS, and EF compared with the DCM group (P<0.05). Those indices in the rhGH group were similar to those in the control group (P>0.05). There were significant differences in serum biochemical parameters and hemodynamic indices between the DCM and control groups (P<0.05). Compared with the DCM group, the rhGH group had significantly improved serum biochemical parameters and hemodynamic indices (P<0.05). Those indices in the rhGH group were similar to those in the control group (P>0.05), except for the levels of insulin like growth factor-1 and insulin-like growth factor-binding protein-3. The DCM group had a significantly higher collagen type I/collagen type III (Col I/Col III) ratio in the myocardium than the control group (P<0.05), and there was no significant difference in the Col I/Col III ratio between the control and rhGH groups (P>0.05). CONCLUSIONS: rhGH plays a certain role in improvement in the morphology and function of the left cardiac ventricle in young rats with DCM. PMID- 26014706 TI - [Role of transient receptor potential melastatin 8 channels in migraine mechanism in rats]. AB - OBJECTIVE: To investigate the role of transient receptor potential melastatin 8 (TRPM8) channels in migraine mechanism in rats by measuring the changes in expression of TRPM8 in the trigeminal nerve of rats with migraine. METHODS: Twenty male Sprague-Dawley rats were randomly and equally divided into a blank control group and a model group. Nitroglycerin (10 mg/kg) was injected subcutaneously in the back of the neck once a week for 5 weeks, to prepared a rat model of migraine without aura. Normal saline was injected subcutaneously instead of nitroglycerin in the control group. At 4 hours after the final injection, behavior scoring of all rats was performed, and then the trigeminal nerve ganglions of rats in both groups were collected for measurement of expression of N-methyl-D-aspartate receptor (NMDAR), protein kinase A (PKA), and TRPM8 using immunohistochemical staining, immunofluorescence, and Western blot, respectively. RESULTS: The behavior score in each week during the rat model preparing was significantly higher in the model group than in the control group (P<0.05). The expression of NMDAR, PKA, and TRPM8 in the model group was significantly higher than in the control group (P<0.01). Both the behavior score and the expression of NMDAR were positively correlated with the expression of TRPM8 (r=0.822 and 0.794 respectively; P<0.01). CONCLUSIONS: TRPM8 may be involved in migraine mechanism probably by activation of the NMDAR pathway. PMID- 26014707 TI - [Amiodarone as a second-line drug in treating neonatal paroxysmal supraventricular tachycardia]. PMID- 26014708 TI - [Trisomy 22 syndreom: a report of 2 cases]. PMID- 26014709 TI - [Langerhans cell histiocytosis in a neonate]. PMID- 26014710 TI - [Research progress in the relationship between childhood wheezing and bacteria]. AB - Wheezing is one of the most common clinical manifestations of childhood respiratory diseases, mainly associated with virus infection. Recent years, bacteria colonization and its infection are reported to involve in childhood wheezing, especially in infantile wheezing. However, the bacteria flora in the airway is only a phenomenon or a reason to induce some childhood wheezing, and its roles, as well as the mechanism in the development of wheezing remain unknown. This article summarizes the research progress in the relationship between childhood wheezing and bacteria and in the possible mechanisms of childhood wheezing caused by bacteria. PMID- 26014711 TI - [Research advances in diagnosis and therapy of Niemann-Pick disease type C]. AB - Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disease associated with impaired intracellular cholesterol trafficking. A wide spectrum of clinical phenotype has been described, with a possible onset at all ages of life from the neonatal period to adulthood, more often in childhood. Typically, hepatosplenomegaly, dystaxia, dysphagia, dysarthria and dementia are presented in NPC patients. Neurologic symptoms vary according to the onset age, but prolonged neonatal cholestasis, splenomegaly, cataplexy and vertical supranuclear gaze palsy are more specific signs to the diagnosis of the disease. Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all play roles in the physiological processes. The definite diagnosis requires demonstration of unesterified cholesterol accumulated in fibroblasts cultured from skin biopsies or of pathogenic mutation of NPC1/NPC2 genes. Miglustat, the only available treatment approved to date, can alleviate neurological symptoms and slow disease progression when administered earlier. PMID- 26014712 TI - Cation-Anion Dual Sensing of a Fluorescent Quinoxalinone Derivative Using Lactam Lactim Tautomerism. AB - A quinoxalinone derivative capable of lactam-lactim tautomerization was designed as a new fluorescence probe for sensing of cation (M(+) = Li(+) and Na(+)) and anion (X(-) = F(-), Cl(-), Br(-), and CH3COO(-)) in organic solvents. In THF, the minor lactam tautomer exhibited a weak fluorescence band at 425 nm with a typical Stokes shift of ~4400 cm(-1), whereas the major lactim tautomer exhibited an intense fluorescence band at 520 nm with large Stokes shift of ~8900 cm(-1) due to excited-state intramolecular proton transfer (ESIPT). The presence of either cations or anions was found to promote lactim-to-lactam conversion, resulting in the lowering of the ESIPT fluorescence. The lone pairs on the alkylamide oxygen and the quinoxalinone ring nitrogen of the lactam were found to bind Li(+) to form a 1:2 coordination complex, which was confirmed by single crystal X-ray structural analysis and fluorescent titrations. In addition, the N-H bond of the lactam was able to recognize anions via N-H...X hydrogen bonding interactions. Where X = F(-) or CH3COO(-), further addition of these anions caused deprotonation of the lactam to generate an anionic state, consistent with the crystal structure of the anion prepared by mixing tetrabutylammonium fluoride and the quinoxalinone derivative in THF. Dual cation-anion-sensing responses were found to depend on the ion-recognition procedure. The anionic quinoxalinone derivative and its Li(+) complex, which are formed by the addition of CH3COO(-) and Li(+), respectively, displayed different fluorescence enhancement behavior due to the two anions exchanging with each other. PMID- 26014713 TI - Involvement of Renin-Angiotensin System Inhibition, the Potential Risk of Danshen in the Treatment of Pregnancy-Induced Hypertension. PMID- 26014714 TI - On cosmetic vaginal surgery - an anatomical and biomechanical perspective. PMID- 26014715 TI - Extraordinary Supercapacitor Performance of a Multicomponent and Mixed-Valence Oxyhydroxide. AB - We report a novel multicomponent mixed-valence oxyhydroxide-based electrode synthesized by electrochemical polarization of a de-alloyed nanoporous NiCuMn alloy. The multicomponent oxyhydroxide has a high specific capacitance larger than 627 F cm(-3) (1097+/-95 F g(-1) ) at a current density of 0.25 A cm(-3) , originating from multiple redox reactions. More importantly, the oxyhydroxide electrode possesses an extraordinarily wide working-potential window of 1.8 V in an aqueous electrolyte, which far exceeds the theoretically stable window of water. The realization of both high specific capacitance and high working potential windows gives rise to a high energy density, 51 mWh cm(-3) , of the multicomponent oxyhydroxide-based supercapacitor for high-energy and high-power applications. PMID- 26014716 TI - A novel one-dimensional chain built of vanadyl ions and pyrazine-2,5 dicarboxylate. AB - We present a new coordination polymer, {[VO(pzdc)(H2O)2] H2O}n, built from vanadyl and pyrazine-2,5-dicarboxylate (pzdc) ions. It consists of a one dimensional chain of vanadyl ions linked by pzdc ions. The carboxylate groups show monodentate coordination, while the pyrazine ring is present both in non coordinated and coordinated modes. This novel structure is stabilized by an intricate network of hydrogen bonds. The material is highly robust, and thermally stable up to 400 K. It is also antiferromagnetic, with a maximum magnetic susceptibility at ca. 50 K. The orbital shape and population analysis by means of DFT analysis confirm the pi-acceptor role of the aromatic nitrogen function of the ligand, while the oxygen-based moieties (carboxylates from pzdc, the aqua ligands and oxo from V=O group) behave as normal donors. Charting the density flow related with significant transitions computed by time-dependent DFT, we determined the ligand-to-metal charge transfer processes. The topology of the chain complex implies two different types of connecting bridges. Using Broken Symmetry DFT modelling gives evidence for two different exchange coupling mechanisms between the vanadyl ions along each of these two molecular bridges. One is strongly antiferromagnetic, practically reducing the chain to 'vanadyl dimers'. The other is almost uncoupled, due to the large distance between the vanadyl ions. PMID- 26014717 TI - Local Recurrence after Radiofrequency Ablation of Hepatocellular Carcinoma: Treatment Choice and Outcome. AB - BACKGROUND/AIMS: Radiofrequency ablation (RFA) has been proven effective for treating small hepatocellular carcinoma (HCC) nodules. However, post-RFA local recurrence is a major factor limiting prognosis. Up to now, there is no consensus on a standardized treatment strategy for these local recurrences. The aim of this study is to evaluate the outcomes of salvage treatments for RFA-related local recurrence. METHODS: From May 2008 to June 2013, a total of 112 patients with HCC were detected with local recurrence after RFA. Among them, 94 patients received sequential treatments in our hospital, including salvage resection (SR) (n = 24), salvage liver transplantation (n = 2), repeated RFA (n = 62), and transarterial chemoembolization (TACE) (n = 6). We evaluated the treatment outcomes of patients by salvage surgery (SS), RFA, and TACE. RESULTS: The median follow-up time was 32 months. After treatment, local recurrence was eradicated in 82 of 94 patients (87.2%). The complete response (CR) rate in the RFA group was 90.3% (56/62), while it was 100% (26/26) in the SS group (P = 0.175) and 0% (0/6) in the TACE group. When analysis confined to patients with CR, the 1- and 3-year disease-free survival (DFS) rates were 57.7 and 20.2% in the SS group, and 41.7 and 28.6% in the RFA group, respectively (P = 0.640). The 1- and 3-year overall survival (OS) rates were 93.3 and 69.1% in the SS group, and 78.6 and 57.5% in the RFA group, respectively (P = 0.251). CONCLUSION: Repeated RFA is the first treatment choice for patients with post-RFA local recurrence. SS should be considered when RFA failed or is inapplicable. PMID- 26014718 TI - The Impact of Preoperative Radiation Therapy on Locoregional Recurrence in Patients with Stage IV Rectal Cancer Treated with Definitive Surgical Resection and Contemporary Chemotherapy. AB - PURPOSE: Definitive resection of primary rectal cancers is frequently incorporated, with or without preoperative radiotherapy and perioperative chemotherapy, in the management of selected patients with metastatic rectal adenocarcinoma. This study reviews the impact of preoperative radiotherapy and perioperative chemotherapy on locoregional recurrence and overall survival in these patients. METHODS AND MATERIALS: This retrospective study with an Institutional Review Board (IRB) waiver included 109 patients with metastatic rectal adenocarcinoma who underwent definitive primary resection between 1998 and 2011. In addition to resection, 64 patients were treated with preoperative radiotherapy and perioperative chemotherapy and 45 patients were treated with perioperative chemotherapy alone. Radiotherapy dose was typically 50.4 Gy. Baseline variables were compared using chi-square and unpaired t tests. Overall survival was calculated using Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards regression. RESULTS: There were no significant baseline differences between the two groups. There was no significant difference in locoregional recurrence (10.9 vs. 11.1%; p = 0.90) or overall survival (34.5 vs. 34.8 months; p = 0.89) for patients treated with preoperative radiotherapy compared to those treated with perioperative chemotherapy alone, respectively. Patients who underwent radiotherapy were less likely to have a positive margin (10.9 vs. 20.0%; p = 0.19), lymphovascular invasion (32.8 vs. 53.3%; p = 0.03), and pathologic stage N2 disease (25.0 vs. 42.2%; p = 0.02). Grade 2 postoperative complications were more common in the preoperative radiotherapy group (32.8 vs. 15.6%; p = 0.04). Multivariate analysis demonstrated that patients with poorly differentiated tumors (HR 2.19; p = 0.009) and those that did not undergo liver-directed therapy (HR 2.20; p = 0.005) had inferior survival. CONCLUSIONS: Locoregional recurrence is modest in patients with metastatic rectal adenocarcinoma receiving definitive primary resection, irrespective of the use of radiotherapy. Preoperative radiotherapy may enhance pathologic downstaging at the expense of increased grade 2 postoperative complications. Its use should be reserved for patients at high risk for locoregional recurrence. PMID- 26014719 TI - 13-Deoxytetrodecamycin, a new tetronate ring-containing antibiotic that is active against multidrug-resistant Staphylococcus aureus. AB - WAC04657 is a wild-isolate Streptomyces that has antibiotic activities against multidrug-resistant Gram-negative and Gram-positive pathogens. From a solid-agar culture of this organism we isolated 13-deoxytetrodecamycin, a novel antibacterial molecule. It is one of at least three distinct antimicrobial compounds produced by this strain. The molecule has the molecular formula C18H22O5 and is related to the previously discovered compound tetrodecamycin. 13 Deoxytetrodecamycin has potent bioactivity against Gram-positive pathogens including multidrug-resistant Staphylococcus aureus. PMID- 26014720 TI - First total synthesis of (+)-epogymnolactam, a novel autophagy inducer. AB - A novel autophagy inducer, (+)-epogymnolactam (1), was first synthesized from cis 4-benzyloxy-2-butene-1-ol (2) in eight steps. A reliable preparation of optically pure epoxy alcohol (+)-3 from monobenzyl derivative (2) was established by a tandem strategy, Sharpless epoxidation/lipase kinetic resolution. PMID- 26014721 TI - Evaluation of the therapeutic efficacy of a MEK inhibitor (TAK-733) using 18F fluorodeoxyglucose-positron emission tomography in the human lung xenograft model A549. AB - OBJECTIVE: The aim of this study was to evaluate the potential of (18)F fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts. METHODS: TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5% w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose). Tumor size was measured before treatment (day 0), and on days 1, 3, 7, 9, 11, and 14. PET scans were performed pretreatment (day 0), and on days 2, 4, 7, 10, and 14. Tracer accumulations in tumor tissue were quantified as the mean standard uptake value (SUVmean). RESULTS: No deaths or treatment related body weight losses occurred during the study period. TAK-733 showed dose dependent inhibition of tumor growth and (18)F-FDG uptake in tumor tissue. At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05). Tumor growth was inhibited in the 10 mg/kg group with a treated/control value of 31% on day 14. The SUVmean on day 2 in this dosage group was statistically lower than that observed on day 0, and that seen in the vehicle group on day 2 (P < 0.05 for both comparisons). Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time. In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time. CONCLUSIONS: (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment. PMID- 26014747 TI - Peasants, Warriors, and the Streams of Deafness. Language games and etiologies of deafness in Adamorobe, Ghana. AB - Me: Were you born deaf? Kwame Osae: Yes, I was born deaf. Me: How come? You have hearing parents, right? [Being born deaf is usually linked to having deaf parents] Kwame Osae: (slightly confused) I don't know... maybe because of witches. Me: Ama Korkor [Kwame's younger deaf sister] told me that she was born hearing. Kwame Osae: That is not true, we were all born deaf: me, Kofi Pare, Ama Korkor, Yaa Bomo and Yaa Aketewa [i.e. his four younger deaf siblings]. I decided to confront his version with the one of Ama Korkor and I called for her attention. She was sitting a bit further in the compound where they live. I reminded her that she once told me that she was born hearing. Ama Korkor: Yes, I don't know that myself... but my mother told me that I was hearing as a baby... This article is protected by copyright. All rights reserved. PMID- 26014748 TI - Information processing via physical soft body. AB - Soft machines have recently gained prominence due to their inherent softness and the resulting safety and resilience in applications. However, these machines also have disadvantages, as they respond with complex body dynamics when stimulated. These dynamics exhibit a variety of properties, including nonlinearity, memory, and potentially infinitely many degrees of freedom, which are often difficult to control. Here, we demonstrate that these seemingly undesirable properties can in fact be assets that can be exploited for real-time computation. Using body dynamics generated from a soft silicone arm, we show that they can be employed to emulate desired nonlinear dynamical systems. First, by using benchmark tasks, we demonstrate that the nonlinearity and memory within the body dynamics can increase the computational performance. Second, we characterize our system's computational capability by comparing its task performance with a standard machine learning technique and identify its range of validity and limitation. Our results suggest that soft bodies are not only impressive in their deformability and flexibility but can also be potentially used as computational resources on top and for free. PMID- 26014749 TI - Photophysical and electrochemical properties of a dysprosium-zinc tetra(4 sulfonatophenyl)porphyrin complex. AB - A dysprosium-zinc porphyrin, [DyZn(TPPS)H3O]n (1) (TPPS = tetra(4 sulfonatophenyl)porphyrin), was prepared through solvothermal reactions and structurally characterized by single-crystal X-ray diffraction analyses. Complex 1 features a three-dimensional (3-D) porous open framework that is thermally stable up to 400 degrees C. Complex 1 displays a void space of 215 A(3), occupying 9.2% of the unit cell volume. The fluorescence spectra reveal that it shows an emission band in the red region. The fluorescence lifetime is 39 usec and the quantum yield is 1.7%. The cyclic voltammetry (CV) measurement revealed one quasi-reversible wave with E1/2 = 0.30 V. PMID- 26014750 TI - Bioactivity of permselective PVA hydrogels with mixed ECM analogues. AB - The presentation of multiple biological cues, which simulate the natural in vivo cell environment within artificial implants, has recently been identified as crucial for achieving complex cellular functions. The incorporation of two or more biological cues within a largely synthetic network can provide a simplified model of multifunctional ECM presentation to encapsulated cells. Therefore, the aim of this study was to examine the effects of simultaneously and covalently incorporating two dissimilar biological molecules, heparin and gelatin, within a PVA hydrogel. PVA was functionalized with 7 and 20 methacrylate functional groups per chain (FG/c) to tailor the permselectivity of UV photopolymerized hydrogels. Both heparin and gelatin were covalently incorporated into PVA at an equal ratio resulting in a final PVA:heparin:gelatin composition of 19:0.5:0.5. The combination of both heparin and gelatin within a PVA network has proven to be stable over time without compromising the PVA base characteristics including its permselectivity to different proteins. Most importantly, this combination of ECM analogues supplemented PVA with the dual functionalities of promoting cellular adhesion and sequestering growth factors essential for cellular proliferation. Multi-functional PVA hydrogels with synthetically controlled network characteristics and permselectivity show potential in various biomedical applications including artificial cell implants. PMID- 26014751 TI - What enhances the development of emotion understanding in young children? A longitudinal study of interpersonal predictors. AB - We studied potential determinants of the development of children's emotion understanding (EU) from age 4 to 6 in a Norwegian community sample (N = 974) using the Test of Emotion Comprehension. Interpersonal predictors included the accuracy of parental mentalization, parental emotional availability, and teacher reported child social skills. Intrapersonal child factors were child gender and verbal skills. Overall, children's EU increased significantly over time. After adjusting for child gender, age-4 EU, and parental socio-economic status, greater child verbal and social skills and greater parental mentalization each uniquely predicted growth in EU. Results are discussed in terms of theory and research on children's EU and parents' emotion socialization. PMID- 26014752 TI - Calcium-Channel Blockers Attenuate the Antiplatelet Effect of Clopidogrel. AB - AIMS: Dihydropyridine calcium-channel blockers (CCBs) inhibit cytochrome 3A4 and could therefore interfere with the conversion of clopidogrel to its active form. The impact of CCBs on the antiplatelet effect of clopidogrel has not been studied with assays directly capturing platelet activation to adenosine diphosphate (ADP), so far. We therefore sought to investigate platelet activation in response to ADP by flow cytometry in clopidogrel-treated patients without and with CCBs. METHODS: Platelet surface P-selectin expression and activated glycoprotein (GP) IIb/IIIa in response to ADP were determined by flow cytometry in 302 patients on dual antiplatelet therapy with aspirin and clopidogrel after successful angioplasty with stent implantation. RESULTS: Ninety-two patients (30.5%) received CCBs. Patients with concomitant CCB therapy showed significantly higher platelet surface expressions of P-selectin and activated GPIIb/IIIa in response to ADP than patients without CCBs (both P <= 0.03). Moreover, the fold increase of P-selectin and activated GPIIb/IIIa in response to ADP was significantly more pronounced in patients taking CCBs (both P <= 0.03). The associations of ADP inducible activated GPIIb/IIIa and fold increase of activated GPIIb/IIIa after the addition of ADP with CCB therapy remained significant after adjustment for differences in patient characteristics and factors that were previously associated with clopidogrel response by multivariate regression analyses (both P < 0.05). High levels of ADP-inducible P-selectin and activated GPIIb/IIIa were seen significantly more frequent in patients with CCBs than in patients without CCB therapy (both P <= 0.01). CONCLUSION: Dihydropyridine CCBs attenuate the effect of clopidogrel on ADP-inducible platelet activation in patients undergoing angioplasty and stenting for cardiovascular disease. PMID- 26014753 TI - Simultaneous determination of four secoiridoid and iridoid glycosides in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to a comparative pharmacokinetic study. AB - A simple, reliable and rapid ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of four secoiridoid (gentiopicroside, swertiamarin, sweroside) and iridoid glycosides (loganic acid), the bio-active ingredients in rat plasma. After liquid-liquid extraction, chromatographic separation was accomplished on a Shim-pack XR-ODS column with a mobile phase consisting of methanol and 0.1% formic acid in water. A triple quadrupole tandem mass spectrometry equipped with an electrospray ionization source was used as detector operating both in positive and negative ionization mode and operated by multiple-reaction monitoring scanning. The lower limits of quantitation were 0.25-30 ng/mL for all the analytes. Both intra-day and inter-day precision and accuracy of analytes were well within acceptance criteria (+/-15%). The mean extraction recoveries of analytes and internal standard (amygdalin) from rat plasma were all >71.4%. The validated method was successfully applied to a comparative pharmacokinetic study of four analytes in rat plasma between normal and arthritic rats after oral administration of Huo Luo Xiao Ling Dan and Gentiana macrophylla extract, respectively. Results showed significant differences in pharmacokinetic properties of the analytes among the different groups. PMID- 26014754 TI - Nitrilase-catalyzed conversion of (R,S)-mandelonitrile by immobilized recombinant Escherichia coli cells harboring nitrilase. AB - (R)-(-)-Mandelic acid (R-MA) is widely used both as a versatile intermediate for pharmaceuticals and a resolving agent in chiral resolution processes. In the current study, to improve the stability of operation, recombinant Escherichia coli cells expressing nitrilase from Alcaligenes faecalis were immobilized for the enantioselective hydrolysis of (R,S)-mandelonitrile to R-MA. Different immobilization methods including entrapment matrices, entrapment matrices cross linked by cross-linking and polymerization agents, and direct cross-linking cells using glutaraldehyde (GA) or bionic silicon were investigated. To facilitate industrial solid-liquid separation, the direct cross-linking recombinant E. coli cells using diatomite/GA/polyethyleneimine with 135.95% relative activity compared with free cells was chosen using water as the reaction medium. The operational stability of the immobilized cells was obviously superior to that of free cells, without significant activity loss after 28 cycles of batch reaction and the successive production of R-MA could reach 1.88 M. Moreover, the immobilized cells showed good storage stability with about 52% relative activity after storing for 30 days at 4 degrees C. Therefore, the immobilized biocatalyst is very promising for upscale production of optically pure R-MA with high performance and low cost. PMID- 26014755 TI - Hierarchical heteroaggregation of binary metal-organic gels with tunable porosity and mixed valence metal sites for removal of dyes in water. AB - Hierarchical heteronuclear metal-organic gels (MOGs) based on iron (Fe) and aluminium (Al) metal-organic framework (MOF) backbones bridged by tri-carboxylate ligands have firstly been synthesized by simple solvothermal method. Monometallic MOGs based on Fe or Al give homogenous monoliths, which have been tuned by introduction of heterogeneity in the system (mismatched growth). The developed gels demonstrate that surface areas, pore volumes and pore sizes can be readily tuned by optimizing heterogeneity. The work also elaborates effect of heterogeneity on size of MOG particles which increase substantially with increasing heterogeneity as well as obtaining mixed valence sites in the gels. High surface areas (1861 m(2)/g) and pore volumes (9.737 cc/g) were obtained for heterogeneous gels ((0.5)Fe-(0.5)Al). The large uptakes of dye molecules (290 mg/g rhodamine B and 265 mg/g methyl orange) with fast sorption kinetics in both neutral and acidic mediums show good stability and accessibility of MOG channels (micro and meso-/macropores), further demonstrating their potential applications in catalysis and sorption of large molecules. PMID- 26014758 TI - Remote Hydroxylation through Radical Translocation and Polar Crossover. AB - Mild conditions are reported for the hydroxylation of aliphatic C-H bonds through radical translocation, oxidation to carbocation, and nucleophilic trapping with H2O. This remote functionalization employs fac-[Ir(ppy)3] together with Tz(o) sulfonate esters and sulfonamides to facilitate the site-selective replacement of relatively inert C-H bonds with the more synthetically useful C-OH group. The hydroxylation of a range of substrates and the methoxylation of two substrates through 1,6- and 1,7-hydrogen-atom transfer are demonstrated. In addition, a synthesis of the antidepressant fluoxetine using remote hydroxylation as a key step is presented. PMID- 26014757 TI - When Competing Viruses Unify: Evolution, Conservation, and Plasticity of Genetic Identities. AB - In the early 1970s, Manfred Eigen and colleagues developed the quasispecies model (qs) for the population-based origin of RNAs representing the early genetic code. The Eigen idea is basically that a halo of mutants is generated by error-prone replication around the master fittest type which will behave similarly as a biological population. But almost from the start, very interesting and unexpected observations were made regarding competition versus co-operation which suggested more complex interactions. It thus became increasingly clear that although viruses functioned similar to biological species, their behavior was much more complex than the original theory could explain, especially adaptation without changing the consensus involving minority populations. With respect to the origin of natural codes, meaning, and code-use in interactions (communication), it also became clear that individual fittest type-based mechanisms were likewise unable to explain the origin of natural codes such as the genetic code with their context- and consortia-dependence (pragmatic nature). This, instead, required the participation of groups of agents competent in the code and able to edit code because natural codes do not code themselves. Three lines of inquiry, experimental virology, quasispecies theory, and the study of natural codes converged to indicate that consortia of co-operative RNA agents such as viruses must be involved in the fitness of RNA and its involvement in communication, i.e., code-competent interactions. We called this co-operative form quasispecies consortia (qs-c). They are the essential agents that constitute the possibility of evolution of biological group identity. Finally, the basic interactional motifs for the emergence of group identity, communication, and co-operation together with its opposing functions-are explained by the "Gangen" hypothesis. PMID- 26014759 TI - Newly designed and validated impedance spectroscopy setup in microtiter plates successfully monitors viable biomass online. AB - In microtiter plates, conventional online monitoring of biomass concentration based on optical measurements is limited to transparent media: It also cannot differentiate between dead or viable biomass or suspended particles. To address this limitation, this study introduces and validates a new online monitoring setup based on impedance spectroscopy for detecting only viable biomass in 48- and 96-well microtiter plates. The setup was first validated electronically and characterized by determining the cell constants of the measuring geometry. Defined cell suspensions of Ustilago maydis, Hansenula polymorpha, Escherichia coli and Bacillus licheniformis were characterized to find, among other parameters, the most suitable frequency range and the characteristic frequency of beta-dispersion for each organism. Finally, the setup was exemplarily applied to monitor the growth of Hansenula polymorpha online. As reference, three different parallel cultures were performed in established cultivation systems. This new online monitoring setup based on impedance spectroscopy is robust and enables precise measurements of microbial biomass concentration. It is promising for future high-throughput applications. PMID- 26014760 TI - Petroleum Jelly: A Novel Medium for Ocular Ultrasound. AB - BACKGROUND: Ocular ultrasound is a useful emergency department imaging modality for evaluation of many conditions, such as retinal detachment, vitreous detachment, vitreous hemorrhage, and elevated intracranial pressure. Obtaining satisfactory ocular ultrasound images requires the use of a medium that eliminates the air interface between the patient's eye and the transducer. Ultrasound gel is most commonly used; however, the use of a transparent dressing applied to the closed eye prior to the application of gel has also been described as a suitable technique. DISCUSSION: Ocular ultrasound is performed with the high frequency linear array transducer using a medium to eliminate the air interface between the eye and the transducer. Although ultrasound gel is most frequently used, it can cause minor eye irritation. Placing a transparent dressing over a closed eye prior to application of gel can eliminate the eye irritation. However, our experience in training >500 students in ocular ultrasound has shown that air is frequently introduced underneath the dressing, which leads to poor-quality images. This article introduces petroleum jelly as a medium for ocular ultrasound. By applying a layer of petroleum jelly over the closed eye and allowing it to warm via body heat for 30 to 45 s, this medium can both minimize patient discomfort and provide easily obtainable, high-quality ocular ultrasound images. CONCLUSIONS: This article introduces petroleum jelly as a safe, comfortable, and effective medium for ocular ultrasound examination. PMID- 26014762 TI - A Traditional Paradigm vs. an Ultrasound-Supported Paradigm in Emergency and Critical Care Medicine: A Crisis of the Mind Is Needed. PMID- 26014761 TI - Epidemiology of Shortness of Breath in Prehospital Patients in Andhra Pradesh, India. AB - BACKGROUND: Shortness of breath is a frequent reason for patients to request prehospital emergency medical services and is a symptom of many life-threatening conditions. To date, there is limited information on the epidemiology of, and outcomes of patients seeking emergency medical services for, shortness of breath in India. OBJECTIVE: This study describes the characteristics and outcomes of patients with a chief complaint of shortness of breath transported by a public ambulance service in the state of Andhra Pradesh, India. METHODS: This prospective, observational study enrolled patients with a chief complaint of shortness of breath during twenty-eight, 12-h periods. Demographic and clinical data were collected from emergency medical technicians using a standardized questionnaire. Follow-up information was collected at 48-72 h and 30 days. RESULTS: Six hundred and fifty patients were enrolled during the study period. The majority of patients were male (63%), from rural communities (66%), and of lower socioeconomic status (78%). Prehospital interventions utilized included oxygen (76%), physician consultation (40%), i.v. placement (15%), nebulized medications (13%), cardiopulmonary resuscitation (5%), and bag-mask ventilation (4%). Mortality ratios before hospital arrival, at 48-72 h, and 30 days were 12%, 27%, and 35%, respectively. Forty-six percent of patients were confirmed to have survived to 30 days. Predictors of death before hospital arrival were symptoms of chest pain (16% vs. 12%; p < 0.05) recent symptoms of upper respiratory infection (7.5% vs. 4%; p < 0.05), history of heart disease (14% vs. 7%; p < 0.05), and prehospital hypotension, defined as systolic blood pressure <90 mm Hg (6.3% vs. 3.7%; p < 0.05). CONCLUSIONS: Among individuals seeking prehospital emergency medical services in India, the chief complaint of shortness of breath is associated with a substantial early and late mortality, which may be in part due to the underutilization of prehospital interventions. PMID- 26014763 TI - Expect the unexpected. PMID- 26014764 TI - General practice staff asked to complete online QNI survey. PMID- 26014765 TI - Government commits to seven-day NHS. PMID- 26014767 TI - NHS Employers selects 'equality and diversity' partners. PMID- 26014768 TI - Nurses receive inadequate training in duty of candour. PMID- 26014769 TI - 'Carrying the lamp made me feel proud to be a nurse'. PMID- 26014770 TI - Unison conference hears call to retain 12-hour shifts. PMID- 26014771 TI - 'Worrying UK health care' is 28th out of 30 richest countries. PMID- 26014772 TI - Staff shortages threaten move into community care services. PMID- 26014773 TI - Obsession with targets is having a negative impact on health care. PMID- 26014774 TI - Nurse awarded for innovation in care homes. PMID- 26014775 TI - Genetically modified. PMID- 26014776 TI - International outlook--Lessons to be learned from Ebola epidemic. PMID- 26014779 TI - Vantage point--What is the secret of a long, healthy life? PMID- 26014791 TI - Transforming emergency services for frail older people in hospital. AB - Managers of emergency care, acute medicine and geriatric medicine care had a difficult few months over winter managing rising demand for emergency care, and the likelihood is that we will face similar demands in future winters unless we improve services and release capacity. The complexity of this demand is also changing with more frail older people presenting for emergency care. With this in mind, there is an urgent need to improve and streamline emergency services to meet the needs of this patient group. This article focuses on the principles that managers can employ to improve frailty services and the processes that can be adopted to develop effective frailty services in hospitals that deliver better outcomes for patients. PMID- 26014792 TI - Illness prevention in the NHS five year forward view. AB - Illness prevention is a priority for the NHS Mandate and the Five Year Forward View, and offers a means to maintain sustainable health and social care services in the context of an ageing population and the growth of behaviour-related illness. The National Institute for Health and Care Excellence guidance recommends a structured approach to embedding behaviour change interventions into clinical care, and effective implementation requires organisational support. This article describes how nurse leaders, managers and commissioners can ensure this implementation through setting objectives for staff, training and development, as well as supporting staff to adopt healthier lifestyles. PMID- 26014793 TI - Nutritional habits and cognitive performance of older adults. AB - Healthy nutritional habits, including drinking plenty of water and maintaining hydration, are fundamental components for sustaining life, health and wellbeing. Evidence has suggested that certain dietary patterns and lifestyles could help delay the ageing process and reduce the risk of Alzheimer's disease. This article explores the potential association between nutritional habits and the cognitive performance of older adults and identifies research gaps that could be filled by future studies on healthy ageing. PMID- 26014794 TI - Evidence-based development in nurse-led interprofessional teams. AB - Team-based care is often described as the best way to provide health care. However the effective use of teams in primary care is not yet prevalent in the US and nurse-led interprofessional collaborative teams are rare. Over the past three years the US Department of Health and Human Services has put great emphasis on the development of nurse-led interprofessional teams and this article describes the development of one such team in a primary care setting and the evidence base behind it. PMID- 26014795 TI - Inspiring change. PMID- 26014796 TI - Pilot Study Evaluating Regulatory T Cell-Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model. AB - The full potential of islet transplantation will only be realized through the development of tolerogenic regimens that obviate the need for maintenance immunosuppression. Here, we report an immunotherapy regimen that combines 1-ethyl 3-(3'-dimethylaminopropyl)-carbodiimide (ECDI)-treated donor lymphoid cell infusion (ECDI-DLI) with thymoglobulin, anti-interleukin-6 receptor antibody and rapamycin to achieve prolonged allogeneic islet graft survival in a nonhuman primate (NHP) model. Prolonged graft survival is associated with Treg expansion, donor-specific T cell hyporesponsiveness and a transient absence of donor specific alloantibody production during the period of graft survival. This regimen shows promise for clinical translation. PMID- 26014797 TI - Characterizing the size and shape of sea ice floes. AB - Monitoring drift ice in the Arctic and Antarctic regions directly and by remote sensing is important for the study of climate, but a unified modeling framework is lacking. Hence, interpretation of the data, as well as the decision of what to measure, represent a challenge for different fields of science. To address this point, we analyzed, using statistical physics tools, satellite images of sea ice from four different locations in both the northern and southern hemispheres, and measured the size and the elongation of ice floes (floating pieces of ice). We find that (i) floe size follows a distribution that can be characterized with good approximation by a single length scale , which we discuss in the framework of stochastic fragmentation models, and (ii) the deviation of their shape from circularity is reproduced with remarkable precision by a geometric model of coalescence by freezing, based on random Voronoi tessellations, with a single free parameter expressing the shape disorder. Although the physical interpretations remain open, this advocates the parameters and as two independent indicators of the environment in the polar regions, which are easily accessible by remote sensing. PMID- 26014798 TI - PERSONALITY AND DEPRESSIVE SYMPTOMS: INDIVIDUAL PARTICIPANT META-ANALYSIS OF 10 COHORT STUDIES. AB - BACKGROUND: Personality is suggested to be a major risk factor for depression but large-scale individual participant meta-analyses on this topic are lacking. METHOD: Data from 10 prospective community cohort studies with 117,899 participants (mean age 49.0 years; 54.7% women) were pooled for individual participant meta-analysis to determine the association between personality traits of the five-factor model and risk of depressive symptoms. RESULTS: In cross sectional analysis, low extraversion (pooled standardized regression coefficient (B) = -.08; 95% confidence interval = -0.11, -0.04), high neuroticism (B = .39; 0.32, 0.45), and low conscientiousness (B = -.09; -0.10, -0.06) were associated with depressive symptoms. Similar associations were observed in longitudinal analyses adjusted for baseline depressive symptoms (n = 56,735; mean follow-up of 5.0 years): low extraversion (B = -.03; -0.05, -0.01), high neuroticism (B = .12; 0.10, 0.13), and low conscientiousness (B = -.04; -0.06, -0.02) were associated with an increased risk of depressive symptoms at follow-up. In turn, depressive symptoms were associated with personality change in extraversion (B = -.07; 95% CI = -0.12, -0.02), neuroticism (B = .23; 0.09, 0.36), agreeableness (B = -.09; 0.15, -0.04), conscientiousness (B = -.14; -0.21, -0.07), and openness to experience (B = -.04; -0.08, 0.00). CONCLUSIONS: Personality traits are prospectively associated with the development of depressive symptoms. Depressive symptoms, in turn, are associated with changes in personality that may be temporary or persistent. PMID- 26014799 TI - Biomarkers for Tuberculosis Based on Secreted, Species-Specific, Bacterial Small Molecules. AB - Improved biomarkers are needed for tuberculosis. To develop tests based on products secreted by tubercle bacilli that are strictly associated with viability, we evaluated 3 bacterial-derived, species-specific, small molecules as biomarkers: 2 mycobactin siderophores and tuberculosinyladenosine. Using liquid chromatography-tandem mass spectrometry, we demonstrated the presence of 1 or both mycobactins and/or tuberculosinyladenosine in serum and whole lung tissues from infected mice and sputum, cerebrospinal fluid (CSF), or lymph nodes from infected patients but not uninfected controls. Detection of the target molecules distinguished host infection status in 100% of mice with both serum and lung as the target sample. In human subjects, we evaluated detection of the bacterial small molecules (BSMs) in multiple body compartments in 3 patient cohorts corresponding to different forms of tuberculosis. We detected at least 1 of the 3 molecules in 90%, 71%, and 40% of tuberculosis patients' sputum, CSF, and lymph node samples, respectively. In paucibacillary forms of human tuberculosis, which are difficult to diagnose even with culture, detection of 1 or more BSM was rapid and compared favorably to polymerase chain reaction-based detection. Secreted BSMs, detectable in serum, warrant further investigation as a means for diagnosis and therapeutic monitoring in patients with tuberculosis. PMID- 26014800 TI - Persistence of Antibodies to Influenza Hemagglutinin and Neuraminidase Following One or Two Years of Influenza Vaccination. AB - BACKGROUND: Antibody titers to influenza hemagglutinin (HA) and neuraminidase (NA) surface antigens increase in the weeks after infection or vaccination, and decrease over time thereafter. However, the rate of decline has been debated. METHODS: Healthy adults participating in a randomized placebo-controlled trial of inactivated (IIV) and live-attenuated (LAIV) influenza vaccines provided blood specimens immediately prior to vaccination and at 1, 6, 12, and 18 months postvaccination. Approximately half had also been vaccinated in the prior year. Rates of hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titer decline in the absence of infection were estimated. RESULTS: HAI and NAI titers decreased slowly over 18 months; overall, a 2-fold decrease in antibody titer was estimated to take >600 days for all HA and NA targets. Rates of decline were fastest among IIV recipients, explained in part by faster declines with higher peak postvaccination titer. IIV and LAIV recipients vaccinated 2 consecutive years exhibited significantly lower HAI titers following vaccination in the second year, but rates of persistence were similar. CONCLUSIONS: Antibody titers to influenza HA and NA antigens may persist over multiple seasons; however, antigenic drift of circulating viruses may still necessitate annual vaccination. Vaccine seroresponse may be impaired with repeated vaccination. PMID- 26014801 TI - Streptococcus gallolyticus Pil3 Pilus Is Required for Adhesion to Colonic Mucus and for Colonization of Mouse Distal Colon. AB - Streptococcus gallolyticus is an increasing cause of bacteremia and infective endocarditis in the elderly. Several epidemiological studies have associated the presence of this bacterium with colorectal cancer. We have studied the interaction of S. gallolyticus with human colonic cells. S. gallolyticus strain UCN34, adhered better to mucus-producing cells such as HT-29-MTX than to the parental HT-29 cells. Attachment to colonic mucus is dependent on the pil3 pilus operon, which is heterogeneously expressed in the wild-type UCN34 population. We constructed a pil3 deletion mutant in a Pil3 overexpressing variant (Pil3+) and were able to demonstrate the role of Pil3 pilus in binding to colonic mucus. Importantly, we showed that pil3 deletion mutant was unable to colonize mice colon as compared to the isogenic Pil3+ variant. Our findings establish for the first time a murine model of intestinal colonization by S. gallolyticus. PMID- 26014802 TI - A Highly Expressed Human Protein, Apolipoprotein B-100, Serves as an Autoantigen in a Subgroup of Patients With Lyme Disease. AB - To discover novel autoantigens associated with Lyme arthritis (LA), we identified T-cell epitopes presented in vivo by human leukocyte antigen (HLA)-DR molecules in patients' inflamed synovial tissue or joint fluid and tested each epitope for autoreactivity. Using this approach, we identified the highly expressed human protein, apolipoprotein B-100 (apoB-100), as a target of T- and B-cell responses in a subgroup of LA patients. Additionally, the joint fluid of these patients had markedly elevated levels of apoB-100 protein, which may contribute to its autoantigenicity. In patients with antibiotic-refractory LA, the magnitude of apoB-100 antibody responses correlated with increased numbers of plasma cells in synovial tissue, greater numbers and activation of endothelial cells, and more synovial fibroblast proliferation. Thus, a subset of LA patients have high levels of apoB-100 in their joints and autoreactive T- and B-cell responses to the protein, which likely contributes to pathogenic autoimmunity in patients with antibiotic-refractory LA. PMID- 26014803 TI - Integrated genomic analysis suggests MLL3 is a novel candidate susceptibility gene for familial nasopharyngeal carcinoma. AB - BACKGROUND: Little is known about genetic factors associated with nasopharyngeal carcinoma (NPC). To gain insight into NPC etiology, we performed whole exome sequencing on germline and tumor DNA from three closely related family members with NPC. METHODS: The family was ascertained through the Pediatric Familial Cancer Clinic at The University of Chicago (Chicago, IL). The diagnosis of NPC was confirmed pathologically for each individual. For each sample sequenced, 97.3% of the exome was covered at 5*, with an average depth of 44*. Candidate germline and somatic variants associated with NPC were identified and prioritized using a custom pipeline. RESULTS: We discovered 72 rare deleterious germline variants in 56 genes shared by all three individuals. Of these, only three are in previously identified NPC-associated genes, all of which are located within MLL3, a gene known to be somatically altered in NPC. One variant introduces an early stop codon in MLL3, which predicts complete loss-of-function. Tumor DNA analysis revealed somatic mutations and Epstein-Barr virus (EBV) integration events; none, however, were shared among all three individuals. CONCLUSIONS: These data suggest that inherited mutations in MLL3 may have predisposed these three individuals from a single family to develop NPC, and may cooperate with individually acquired somatic mutations or EBV integration events in NPC etiology. IMPACT: Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC. PMID- 26014804 TI - Nicotine metabolite ratio (3-hydroxycotinine/cotinine) in plasma and urine by different analytical methods and laboratories: implications for clinical implementation. AB - BACKGROUND: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. METHODS: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. RESULTS: Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios, 0.82-1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR. CONCLUSIONS: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site. IMPACT: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. PMID- 26014805 TI - Impairment of skin barrier function via cholinergic signal transduction in a dextran sulphate sodium-induced colitis mouse model. AB - Dry skin has been clinically associated with visceral diseases, including liver disease, as well as for our previously reported small intestinal injury mouse model, which have abnormalities in skin barrier function. To clarify this disease induced skin disruption, we used a dextran sulphate sodium (DSS)-induced colitis mouse model. Following treatment with DSS, damage to the colon and skin was monitored using histological and protein analysis methods as well as the detection of inflammatory mediators in the plasma. Notably, transepidermal water loss was higher, and skin hydration was lower in DSS-treated mice compared to controls. Tumor necrosis factor-alpha (TNF-alpha), interleukin 6 and NO2-/NO3- levels were also upregulated in the plasma, and a decrease in body weight and colon length was observed in DSS-treated mice. However, when administered TNF alpha antibody or an iNOS inhibitor, no change in skin condition was observed, indicating that another signalling mechanism is utilized. Interestingly, the number of tryptase-expressing mast cells, known for their role in immune function via cholinergic signal transduction, was elevated. To evaluate the function of cholinergic signalling in this context, atropine (a muscarinic cholinoceptor antagonist) or hexamethonium (a nicotinic cholinergic ganglion-blocking agent) was administered to DSS-treated mice. Our data indicate that muscarinic acetylcholine receptors (mAChRs) are the primary receptors functioning in colon to-skin signal transduction, as DSS-induced skin disruption was suppressed by atropine. Thus, skin disruption is likely associated with DSS-induced colitis, and the activation of mast cells via mAChRs is critical to this association. PMID- 26014806 TI - Bone mineral density (BMD) and vertebral trabecular bone score (TBS) for the identification of elderly women at high risk for fracture: the SEMOF cohort study. AB - PURPOSE: To determine the predictive value of the vertebral trabecular bone score (TBS) alone or in addition to bone mineral density (BMD) with regard to fracture risk. METHODS: Retrospective analysis of the relative contribution of BMD [measured at the femoral neck (FN), total hip (TH), and lumbar spine (LS)] and TBS with regard to the risk of incident clinical fractures in a representative cohort of elderly post-menopausal women previously participating in the Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk study. RESULTS: Complete datasets were available for 556 of 701 women (79 %). Mean age 76.1 years, LS BMD 0.863 g/cm2, and TBS 1.195. LS BMD and LS TBS were moderately correlated (r 2 = 0.25). After a mean of 2.7 +/- 0.8 years of follow-up, the incidence of fragility fractures was 9.4 %. Age- and BMI-adjusted hazard ratios per standard deviation decrease (95 % confidence intervals) were 1.58 (1.16 2.16), 1.77 (1.31-2.39), and 1.59 (1.21-2.09) for LS, FN, and TH BMD, respectively, and 2.01 (1.54-2.63) for TBS. Whereas 58 and 60 % of fragility fractures occurred in women with BMD T score <=-2.5 and a TBS <1.150, respectively, combining these two thresholds identified 77 % of all women with an osteoporotic fracture. CONCLUSIONS: Lumbar spine TBS alone or in combination with BMD predicted incident clinical fracture risk in a representative population based sample of elderly post-menopausal women. PMID- 26014807 TI - The effect of decompressive surgery on lumbar paraspinal and biceps brachii muscle function and movement perception in lumbar spinal stenosis: a 2-year follow-up. AB - PURPOSE: Chronic low back pain and lumbar spinal stenosis (LSS) seem to deteriorate lumbar muscle function and proprioception but the effect of surgery on them remains unclear. This study evaluates the effect of decompressive surgery on lumbar movement perception and paraspinal and biceps brachii (BB) muscle responses during sudden upper limb loading in LSS. METHODS: Low back and radicular pain intensity (VAS) and Oswestry Disability Index (ODI) were measured together with lumbar proprioception and paraspinal and BB muscle responses prior to and 3 and 24 months after surgery in 30 LSS patients. Lumbar proprioception was assessed by a previously validated motorized trunk rotation unit and muscle responses for sudden upper limb loading by surface EMG. RESULTS: Lumbar perception threshold improved after surgery during 3-month follow-up (from 4.6 degrees to 3.1 degrees , P = 0.015) but tend to deteriorate again during 24 months (4.0 degrees , P = 0.227). Preparatory paraspinal and BB muscle responses prior to sudden load as well as paraspinal muscle activation latencies after the load remained unchanged. CONCLUSION: Impaired lumbar proprioception seems to improve shortly after decompressive surgery but tends to deteriorate again with longer follow-up despite the sustaining favorable clinical outcome. The surgery did not affect either the feed-forward or the feed-back muscle function, which indicates that the abnormal muscle activity in LSS is at least partly irreversible. PMID- 26014808 TI - Metastatic thymoma presenting as spontaneous epidural lumbar haematoma. AB - We report the case of a 44-year-old man who was found to have metastatic thymoma to his lumbar spine presenting as a spontaneous epidural haematoma. The man presented with back pain and cauda equina like symptoms in the absence of trauma, antiplatelet or anticoagulant agents. Following a laminectomy and excision of the epidural collection he made a full neurological recovery. Histopathology of the haematoma demonstrated metastatic thymoma. To the best of our knowledge, this is the first such case of metastatic thymoma to the lumbar spine presenting as a spontaneous epidural collection. We believe, in all patients with spontaneous spinal epidural haematoma and a background of malignancy, histopathological analysis should be sought. PMID- 26014810 TI - Fluctuating creatinine in the cardiac unit. AB - BACKGROUND: Inconsistent serum creatinine results were observed in a patient with a history of lambda light-chain (AL) amyloidosis with multiple comorbidities, including renal nephropathy. Throughout admission, serum creatinine concentrations varied and were inconsistent with the patient's clinical presentation. Studies were conducted to elucidate the cause of the observed fluctuations. METHODS: Whole blood plasma and serum samples were assessed using alternate methodologies and confirmed a falsely low creatinine concentration when analyzed using an enzymatic methodology. A review of the patient's chart identified a potential interfering substance, which was verified via spiking studies. A review of the specimen collection practices was also conducted to understand the intermittently low creatinine values. RESULTS: Upon admission, the patient's serum creatinine concentration was 1.7mg/dl. However, creatinine values varied from 0.6 to 1.9mg/dl in the proceeding days, and the low creatinine concentrations were inconsistent with the patient's clinical presentation. To investigate, paired specimens were collected for whole blood plasma analysis via amperometric detection and serum analysis using either enzymatic or Jaffe methodologies. Enzymatic measurement of creatinine resulted in a lower creatinine concentration (0.6mg/dl) as compared to kinetic Jaffe or whole blood testing (1.8mg/dl). Following consultation with the clinical team, the patient had been administered dopamine intravenously in the days following admission. Studies illustrated dopamine concentrations above 6.50*10(5)pg/ml resulted in decreased creatinine concentrations when measured enzymatically. The intermittent low creatinine concentrations observed were due to collection via a peripherally inserted central catheter line. CONCLUSION: Fluctuations in serum creatinine concentrations in a hospitalized patient were due to interference by dopamine. Samples collected from a peripherally inserted central catheter line in which dopamine was administered resulted in the suppression of peroxidase assays that use phenazone as a substrate. PMID- 26014809 TI - Sensitization of estrogen receptor-positive breast cancer cell lines to 4 hydroxytamoxifen by isothiocyanates present in cruciferous plants. AB - PURPOSE: Tamoxifen has been used for the treatment of estrogen receptor (ER) positive breast cancers and in women who are at an increased risk of breast cancer. Acquired resistance to this drug and its toxicity still pose a clinically significant problem, especially in the prevention setting. Isothiocyanates present in cruciferous plants, such as sulforaphane or erucin, have been shown to reduce growth of breast cancer cells in vivo and in vitro. In this study, we explored their ability to sensitize cancer cells to 4-hydroxytamoxifen. METHODS: We used three ER-positive breast cancer cell lines, T47D, MCF-7 and BT-474, as well as the drug-resistant T47D and MCF-7 derivatives. We examined the effect of 4-hydroxytamoxifen, isothiocyanates and their combinations on cell viability by MTT and clonogenic assays. Impact of treatments on the levels of proteins engaged in apoptosis and autophagy was determined by Western blotting. RESULTS: Isothiocyanates act in a synergistic way with 4-hydroxytamoxifen, and co treatment reduces breast cancer cell viability and clonogenic potential more effectively than treatment with any single agent. This is connected with a drop in the Bcl-2/Bax ratio and the level of survivin as well as increased PARP cleavage, and elevation in ADRP, the mitochondrial stress marker. Moreover, isothiocyanates sensitize 4-hydroxytamoxifen-resistant T47D and MCF-7 cells to the drug. CONCLUSION: Isothiocyanates enhance response to 4-hydroxytamoxifen, which allows for reduction of the effective drug concentration. Combinatorial strategy may hold promise in development of therapies and chemoprevention strategies against ER-positive breast tumors, even those with acquired resistance to the drug. PMID- 26014811 TI - Frank Netter's legacy: Interprofessional anatomy instruction. AB - Several medical schools have recently described new innovations in interprofessional interactions in gross anatomy courses. The Frank H. Netter MD School of Medicine at Quinnipiac University in Hamden, CT has developed and implemented two contrasting interprofessional experiences in first-year medical student gross anatomy dissection laboratories: long-term, informal visits by pathologists' assistant students who work with the medical students to identify potential donor pathologies, and a short-term, formal visit by fourth-year dental students who teach craniofacial anatomy during the oral cavity dissection laboratory. A survey of attitudes of participants was analyzed and suggest the interprofessional experiences were mutually beneficial for all involved, and indicate that implementing multiple, contrasting interprofessional interactions with different goals within a single course is feasible. Two multiple regression analyses were conducted to analyze the data. The first analysis examined attitudes of medical students towards a pathologists' assistant role in a health care team. The question addressing a pathologists' assistant involvement in the anatomy laboratory was most significant. The second analysis examined attitudes of medical students towards the importance of a good foundation in craniofacial anatomy for clinical practice. This perceived importance is influenced by the presence of dental students in the anatomy laboratory. In both instances, the peer interprofessional interactions in the anatomy laboratory resulted in an overall positive attitude of medical students towards pathologists' assistant and dental students. The consequences of these interactions led to better understanding, appreciation and respect of the different professionals that contribute to a health care team. PMID- 26014812 TI - Human seroreactivity to gut microbiota antigens. AB - BACKGROUND: Although immune responses directed against antigens from the intestinal microbiota are observed in certain diseases, the normal human adaptive immune response to intestinal microbiota is poorly defined. OBJECTIVE: Our goal was to assess the adaptive immune response to the intestinal microbiota present in 143 healthy adults and compare this response with the response observed in 52 children and their mothers at risk of having allergic disease. METHODS: Human serum was collected from adults and children followed from birth to 7 years of age, and the serum IgG response to a panel of intestinal microbiota antigens was assessed by using a novel protein microarray. RESULTS: Nearly every subject tested, regardless of health status, had serum IgG that recognized a common set of antigens. Seroreactivity to the panel of antigens was significantly lower in atopic adults. Healthy infants expressed the highest level of IgG seroreactivity to intestinal microbiota antigens. This adaptive response developed between 6 and 12 months of age and peaked around 2 years of age. Low IgG responses to certain clusters of microbiota antigens during infancy were associated with allergy development during childhood. CONCLUSIONS: There is an observed perturbation of the adaptive response to antigens from the microbiota in allergic subjects. These perturbations are observable even in childhood, suggesting that optimal stimulation of the adaptive immune system by the microbiota might be needed to prevent certain immune-mediated diseases. PMID- 26014814 TI - The quality of obtaining surgical informed consent. AB - BACKGROUND: Informed consent goes beyond signing a form; it is a process of providing necessary information, helping patients make an informed decision, and actively participate in their treatment. AIM/OBJECTIVE: This study aimed to assess the quality of obtaining surgical informed consent in hospitals affiliated with Tehran University of Medical Sciences. Research design/participants/context: In a cross-sectional, descriptive-analytical study, 300 patients were chosen through stratified sampling from seven hospitals affiliated with Tehran University of Medical Sciences. Data were collected using a questionnaire developed by the researchers and analyzed using descriptive and analytical statistics on SPSS software. Ethical considerations: Ethical approval of this study was granted by Tehran University of Medical Sciences research ethics committee. Written informed consent for participation was obtained. The participants were reassured that their information will be used anonymously and their answers will not affect their treatment and care. FINDINGS: The mean score of quality of acquisition of informed consent was 17.13 out of 35, indicating that the quality falls in the inappropriate category. The results indicate that 48% of the signatories do not even read the form before signing it. Among the 52% who did read the consent form, 61.3% mentioned varying degrees of incomprehensibility of the consent form and 94.2% mentioned the presence of incomprehensible technical, medical and legal vocabulary. Only 12% and 18% of respondents reported that they were not in hurry and they had no fear or anxiety, respectively, when signing the form. The quality of obtaining informed consent was higher in women, younger patients, patients with higher education, and those who had special surgeries. DISCUSSION: This study shows a poor practice in obtaining surgical informed consent in Iran. It seems necessary to consider fundamental changes in the process of acquiring consent based on the temporal and local conditions of the patients. PMID- 26014813 TI - Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine with pleiotropic functions in the immune system. It has been associated with allergic reactions in the skin and lungs but also homeostatic tolerogenic responses in the thymus and gut. OBJECTIVE: In human subjects TSLP is present in 2 isoforms, short and long. Here we wanted to investigate the differential expression of the TSLP isoforms and discern their biological implications under homeostatic or inflammatory conditions. METHODS: We evaluated the expression of TSLPs in tissues from healthy subjects, patients with ulcerative colitis, patients with celiac disease, and patients with atopic dermatitis and on epithelial cells and keratinocytes under steady-state conditions or after stimulation. We then tested the immune activity of TSLP isoforms both in vitro and in vivo. RESULTS: We showed that TSLP isoforms are responsible for 2 opposite immune functions. The short isoform is expressed under steady-state conditions and exerts anti-inflammatory activities by affecting the capacity of PBMCs and dendritic cells to produce inflammatory cytokines. Moreover, the short isoform TSLP ameliorates experimental colitis in mice and prevents endotoxin shock. The long isoform of TSLP is proinflammatory and is only expressed during inflammation. The isoforms are differentially regulated by pathogenic bacteria, such as Salmonella species and adhesive invasive Escherichia coli. CONCLUSIONS: We have solved the dilemma of TSLP being both homeostatic and inflammatory. The TSLP isoform ratio is altered during several inflammatory disorders, with strong implications in disease treatment and prevention. Indeed, targeting of the long isoform of TSLP at the C-terminal portion, which is common to both isoforms, might lead to unwanted side effects caused by neutralization of the homeostatic short isoform. PMID- 26014823 TI - Women Who Use Drugs and Have Sex with Women in a Canadian Setting: Barriers to Treatment Enrollment and Exposure to Violence and Homelessness. AB - Individuals who use illicit drugs and belong to a sexual minority group often contend with elevated risks for adverse health outcomes. However, little is known about women who use drugs and have sex with women. We therefore sought to identify sociodemographic, substance use patterns, and exposures to social structural factors associated with reporting sexual activity among women participating in three open prospective cohort studies of individuals who use illicit drugs in Vancouver, Canada. Generalized estimating equations were used to identify substance use patterns, violence, and other social and structural drivers of health-related harm among women who reported having sex with women (WSW) between December 2005 and May 2012. In multivariate analyses, younger age (adjusted odds ratio [AOR] 2.89; 95 % confidence interval [CI] 1.81, 4.60), violence (AOR 1.78; 95 % CI 1.22, 2.59), and homelessness (AOR 1.42; 95 % CI 1.00, 2.02) were associated with WSW. WSW were also less likely to report enrollment in addiction treatment (AOR 0.68; 95 % CI 0.46, 0.99). In a second model, sexual violence (AOR 3.47; 95 % CI 2.08, 5.78) in the previous 6 months was also found to be positively associated with WSW. These findings indicate a critical need for more thorough understandings of the intersections between sexual relationships, exposure to violence, and enrollment in addiction treatment among women who use illicit drugs, as well as the development of programs to address the unique needs of this population. PMID- 26014824 TI - Emotional Intimacy Among Coupled Heterosexual and Gay/Bisexual Croatian Men: Assessing the Role of Minority Stress. AB - Emotional intimacy cuts across contexts as diverse as sexual motivation and satisfaction, psychological and physical health, and relational well-being. Although the experience of intimacy and its effects on sex life may be gender and sexual orientation-specific, the role of intimacy in personal and sexual relationships has been studied mostly among heterosexual individuals and couples. Using the minority stress framework (Meyer, 2003) to address this gap in knowledge, the present study comparatively explored levels and predictors/correlates of emotional intimacy, and its association with sexual satisfaction among coupled heterosexual and gay/bisexual men sampled online in a predominantly homonegative country (Croatia). Heterosexual participants (n = 860; M age = 36.4, SD = 9.09) were recruited in 2011 and gay/bisexual participants (n = 250; M age = 29.4, SD = 7.13) in 2013. Controlling for age and relationship duration, gay/bisexual men reported higher levels of emotional intimacy than heterosexual men. Suggesting that the role of emotional intimacy in sexual satisfaction is not sexual orientation-specific, the strength of the association between these two constructs was similar in both samples. However, internalized homonegativity, which was negatively associated with emotional intimacy in this study, remains a challenge to creating and maintaining intimacy in male same-sex relationships. PMID- 26014825 TI - The Westermarck Hypothesis and the Israeli Kibbutzim: Reconciling Contrasting Evidence. AB - The case of the communal education system in the Israeli kibbutzim is often considered to provide conclusive support for Westermarck's (1891) assertion regarding the existence of evolutionary inbreeding avoidance mechanisms in humans. However, recent studies that have gone back to the kibbutzim seem to provide contrasting evidence and reopen the discussion regarding the case of the kibbutzim and inbreeding avoidance more generally (Lieberman & Lobel, 2012; Shor & Simchai, 2009). In this article, I reassess the case of the kibbutzim, reevaluating the findings and conclusions of these recent research endeavors. I argue that the differences between recent research reports largely result from conceptual and methodological differences and that, in fact, these studies provide insights that are more similar than first meets the eye. I also suggest that we must reexamine the common assumption that the kibbutzim serve as an ideal natural experiment for examining the sources of incest avoidance and the incest taboo. Finally, I discuss the implications of these studies to the longstanding debate over the Westermarck hypothesis and call for a synthetic theoretical framework that produces more precise predictions and more rigorous empirical research designs. PMID- 26014826 TI - Sex Differences in Neurophysiological Activation Patterns During Phonological Input Processing: An Influencing Factor for Normative Data. AB - In the context of neurophysiological normative data, it has been established that aging has a significant impact on neurophysiological correlates of auditory phonological input processes, such as phoneme discrimination (PD) and word recognition (WR). Besides age, sex is another demographic factor that influences several language processes. We aimed to disentangle whether sex has a similar effect on PD and WR. Event-related potentials (ERPs) were recorded in 20 men and 24 women. During PD, three phonemic contrasts (place and manner of articulation and voicing) were compared using the attentive P300 and pre-attentive Mismatch Negativity. To investigate WR, real words were contrasted with pseudowords in a pre-attentive oddball task. Women demonstrated a larger sensitivity to spectrotemporal differences, as evidenced by larger P300 responses to the place of articulation (PoA) contrast and larger P300 and MMN responses than men in PoA based PD. Men did not display such sensitivity. Attention played an important role, considering that women needed more attentional resources to differentiate between PoA and the other phonemic contrasts. During WR, pseudowords evoked larger amplitudes already 100 ms post-stimulus independent of sex. However, women had decreased P200 latencies, but longer N400 latencies in response to pseudowords, whereas men showed increased N400 latencies compared to women in response to real words. The current results demonstrate significant sex-related influences on phonological input processes. Therefore, existing neurophysiological normative data for age should be complemented for the factor sex. PMID- 26014828 TI - Training and trials--building a future. PMID- 26014829 TI - On reading. PMID- 26014827 TI - Early-Life Intelligence Predicts Midlife Biological Age. AB - OBJECTIVES: Early-life intelligence has been shown to predict multiple causes of death in populations around the world. This finding suggests that intelligence might influence mortality through its effects on a general process of physiological deterioration (i.e., individual variation in "biological age"). We examined whether intelligence could predict measures of aging at midlife before the onset of most age-related disease. METHODS: We tested whether intelligence assessed in early childhood, middle childhood, and midlife predicted midlife biological age in members of the Dunedin Study, a population-representative birth cohort. RESULTS: Lower intelligence predicted more advanced biological age at midlife as captured by perceived facial age, a 10-biomarker algorithm based on data from the National Health and Nutrition Examination Survey (NHANES), and Framingham heart age (r = 0.1-0.2). Correlations between intelligence and telomere length were less consistent. The associations between intelligence and biological age were not explained by differences in childhood health or parental socioeconomic status, and intelligence remained a significant predictor of biological age even when intelligence was assessed before Study members began their formal schooling. DISCUSSION: These results suggest that accelerated aging may serve as one of the factors linking low early-life intelligence to increased rates of morbidity and mortality. PMID- 26014830 TI - Seclusion experienced by mental health professionals. AB - Seclusion in psychiatric inpatient care means confining service users in a locked room. Service users and staff seem to have different opinions on the usefulness of seclusion. This is possibly the first time when two mental health nurses went voluntarily into seclusion and reported their experiences. The nurses felt that the seclusion room was inhumane and proposed improvements to seclusion in general and to the seclusion facilities in particular. Seclusion in psychiatric hospital care refers to isolating a service user from other service users and staff, most often in a locked and unfurnished room. Service users' experiences of seclusion are mostly negative, and although some have seen a rationale for its use, mental health nurses should be encouraged to evaluate current seclusion practices from the service user's perspective. In this small-scale experiment, two mental health nurses were voluntarily secluded for 24 h. The aim was to explore the experience of being secluded, to understand and evaluate the impact of seclusion in greater detail, and to encourage discussion on one of the controversies in mental health nursing. To the best of our knowledge, this is the first attempt to evaluate the impact of seclusion based on mental health nurses' firsthand experiences. The nurses received usual seclusion treatment and described their experiences of this every 6 h. Based on the nurses' experiences, seclusion, even in voluntary, safe and planned circumstances, may increase anxiety and frustration. Seclusion was viewed negatively and the physical environment was considered inhumane. The nurses offered some practical suggestions for updating seclusion practices and re designing seclusion facilities. Mental health nurses, who frequently decide on and invariably implement seclusion, are key to improving seclusion practices. PMID- 26014831 TI - Exploring the compatibility of mental health nursing, recovery-focused practice and the welfare state. AB - Mental health nurses are expected to adhere to a range of professional values. The values of social integration that mental health nurses practise are somewhat at odds with the values of the British welfare state. Alternative systems of welfare support are demonstrated in other countries. Mental health nurses must consider models of practice, such as that described by Clifton et al. (2013b), to manage the disconnection between what is expected and what can be achieved. This discussion paper considers the implications for mental health nursing practice when working alongside individuals in receipt of state benefits. There is arguably a profound impact on an individual's recovery from mental ill health when that individual is also dependent on financial support from the government. Access to welfare benefits can have a significant impact on the recovery journey of that individual. This discussion paper will consider the practice implications for mental health nurses whose professional values include maxims such as 'challenging inequality' and 'respecting diversity', and will seek to examine the implications for practice when such values are divergent from those demonstrated in government policy. The paper will make comparisons with international welfare systems to demonstrate the way in which alternative configurations of state welfare can promote a system of social justice that is in greater equilibrium with the professional values of mental health nurses. Finally, the discussion will focus on the options for mental health nurses to either subscribe to government policy or to find compromise solutions that enable attention to remain focused and active on a strong value base of social justice and recovery-focused practice. PMID- 26014832 TI - Improving access to psychological therapies (IAPT) and treatment outcomes: epistemological assumptions and controversies. AB - Cognitive behaviour therapy (CBT) is recommended as a primary treatment choice in England, for anxiety and depression, by the National Institute for Health and Care Excellence (NICE). It has been argued that CBT has enjoyed political and cultural dominance and this has arguably led to maintained government investment in England for the cognitive and behavioural treatment of mental health problems. The government programme 'Improving Access to Psychological Therapies' (IAPT) aims to improve the availability of CBT. The criticism of the NICE evidence-based guidelines supporting the IAPT programme, has been the dominance of the gold standard randomized controlled trial methodology, with a focus on numerical outcome data, rather than a focus on a recovery narrative. RCT-based research is influenced by a philosophical paradigm called positivism. The IAPT culture is arguably influenced by one research paradigm and such an influence can skew services only towards numerical outcome data as the only truth of 'recovery'. An interpretative paradigm could assist in shaping service-based cultures, alter how services are evaluated and improve the richness of CBT research. This paper explores the theory of knowledge (epistemology) that underpins the evidence-based perspective of CBT and how this influences service delivery. The paper argues that the inclusion of service user narrative (qualitative data) can assist the evaluation of CBT from the user's perspective and can understand the context in which people live and how they access services. A qualitative perspective is discussed as a research strategy, capturing the lived experience of under represented groups, such as sexual, gender and ethnic minorities. Cognitive behaviour therapy (CBT) has enjoyed political and cultural dominance within mental healthcare, with renewed government investment in England for the'Improving Access to Psychological Therapies' (IAPT) programme. The criticism of the evidence-based guidelines, published by the National Institute for Health and Care Excellence (NICE), which supports the IAPT programme has been the dominance of the gold standard randomized controlled trial methodology. The definition of 'recovery' used by IAPT is based on a positivist position, with a focus on numerical outcome data garnered through psychometric measures. An interpretative perspective of recovery, which would include a subjective individual patient/service user narrative and would include a collaborative qualitative dialogue, is arguably absent from the IAPT programme. The challenge inherent in the IAPT programme is the high demand/high turnover culture, and psychometric measures are quick to administer; however, this culture is driven from one research paradigm. An interpretative paradigm may assist in shaping service-based cultures, alter how services are evaluated, and improve the richness of CBT research. PMID- 26014833 TI - Cardiopoietic index predicts heart repair fitness of patient-derived stem cells. AB - BACKGROUND: Stem cell therapy shows promise for regeneration in heart disease, yet interpatient variability challenges implementation into practice. AIM: To establish a biomarker profile, predictive of reparative potential in patient derived progenitors, human mesenchymal stem cells were isolated from patients undergoing coronary artery bypass grafting. MATERIALS & METHODS: Stem cell delivery postinfarction translated into divergent benefit, distinguishing reparative from nonreparative populations. RESULTS: While the nonreparative subtype was characterized by low expression of cardiac transcription factors, reparative human mesenchymal stem cells demonstrated high expression of cardiac transcription factors. CONCLUSION: This index of factors (cardiopoietic index) was found sensitive and specific in predicting impact of stem cell benefit on left ventricular function. The cardiopoietic index thus offers a tool to screen stem cell fitness for heart repair prior to intervention. PMID- 26014834 TI - Cooperative Binding of Divalent Diamides by N-Alkyl Ammonium Resorcinarene Chlorides. AB - N-Alkyl ammonium resorcinarene chlorides, stabilized by an intricate array of hydrogen bonds leading to a cavitand-like structure, bind amides. The molecular recognition occurs through intermolecular hydrogen bonds between the carbonyl oxygen and the amide hydrogen of the guests and the cation-anion circular hydrogen-bonded seam of the hosts, as well as through CH???pi interactions. The N alkyl ammonium resorcinarene chlorides cooperatively bind a series of di acetamides of varying spacer lengths ranging from three to seven carbons. Titration data fit either a 1:1 or 2:1 binding isotherm depending on the spacer lengths. Considering all the guests possess similar binding motifs, the first binding constants were similar (K1:10(2) M(-1)) for each host. The second binding constant was found to depend on the upper rim substituent of the host and the spacer length of the guests, with the optimum binding observed with the six carbon spacer (K2:10(3) M(-2)). Short spacer lengths increase steric hindrance, whereas longer spacer lengths increase flexibility thus reducing cooperativity. The host with the rigid cyclohexyl upper rim showed stronger binding than the host with flexible benzyl arms. The cooperative binding of these divalent guests was studied in solution through (1)H NMR titration studies and supplemented by diffusion-ordered spectroscopy (DOSY), X-ray crystallography, and mass spectrometry. PMID- 26014836 TI - Functional Organ Damage in Cardiovascular Low Risk Patients with High Central Aortic Pressure. AB - BACKGROUND: The loss of the viscoelastic properties of central arteries independently of blood pressure loads could stimulate the development of left ventricular hypertrophy and dysfunction, renal failure, or cerebral vascular injury. OBJECTIVE: The aim of the present study is to determine if an elevated systolic aortic pressure is a marker of more frequent target organ damage (TOD) in hypertensive low cardiovascular risk (CVR) patients. METHODS: Hypertensive non treated consecutive patients (p) assisted at first visit in a specialized center with a CVR according to WHO Americas B area score less than 10 % were included. Left ventricular mass index (LVMI) and tissue Doppler diastolic and systolic function were measured as Lang et al. (J Am Soc Echocardiogr 18:1440-1463, 2005) and Nagueh et al. (J Am Soc Echocardiogr 22:107-133, 2009). Cardiac TOD was considered according to 2013 European Society of Hypertension/European Society of Cardiology. Glomerular filtration rate (GFR) was calculated by MDRD formula, a value <60 ml/min/1.73 m(2) was considered TOD. Systolic aortic pressured (CAoP) was measured by radial tonometry and classified according to criteria proposed by Herbert et al. (Eur Heart J 35:3100-3132, 2014). Continue variables are reported as means with standard deviation and discrete variables as absolute values and percentages. Statistical analysis was performed with Students t test, significant differences were considered with a p value < 0.05 RESULTS: 155 p were included; 23 p (14.8 %) had elevated CAoP while 132 p (85.2 %) had normal CAoP. Sample mean age was 54.1 + 12.9 years; 85 p (54.8 %) were males. Dyslipidemia was detected in 44 p (28.4 %), and 18 p (11.6 %) were smokers. Mean blood pressure was 143.7 + 17.1 mmHg/86.4 + 12.3 mmHg in p with normal (n) CAoP and 140.3 + 12 mmHg/81.9 + 6.8 mmHg in p with CAoP elevated e (p = NS). Mean CAoP in p with normal values was 117.4 + 10.9 mmHg and 116.9 + 10.7 in p with elevated values (p = NS). The average s wave was 7.42 + 1 cm/sec in n CAoP p vs 6.6 + 1 cm/sec in e CAoP p (p < 0.05) while and E/e' ratio >13 was detected in 14.4 % n CAoP p vs 8.7 % e CAoP p (p = NS). Mean GFR was 105.4 + 40.5 ml/min/1.73 m(2) in n CAoP p vs 103.9 + 45.6 ml/min/1.73 m(2) in e CAoP p (p = NS) and GFR <60 ml/min/1.73 m(2) was present in 4.5 % n CAoP p vs 26.1 % e CAoP p (p < 0.0125). CONCLUSIONS: At the same level of CVR according to WHO Americas B score patients with elevated CAoP had lower longitudinal left ventricular systolic function and renal function was more deteriorated. PMID- 26014837 TI - Associations Between Hypertension and Body Mass Index and Waist Circumference in U.S. Adults: A Comparative Analysis by Gender. AB - INTRODUCTION: The body mass index (BMI) and waist circumference (WC) are a risk of hypertension, but their potentially multiplicative effect on hypertension is underexplored. AIM: To examine modifying effects of BMI and WC on hypertension using a nationally representative U.S. adult sample stratified by gender. METHODS: Data were derived from the 2009-2010 NHANES. Overweight and obesity were based on BMI of 25.0-29.9 and >=30 kg/m(2), respectively. High-risk WC was based on >=102.0 and >=88.0 cm for males and females, respectively. Hypertension was determined by systolic/diastolic blood pressure of >=140/>=90 mmHg, or taking prescribed medications. Logistic regression was used to examine the association between hypertension and BMI and WC by gender. Interaction terms were added to examine if BMI modified the effect of WC on hypertension. RESULTS: Both BMI and WC were significant predictors of hypertension in overall population. Gender specific models indicated that BMI played an important role in hypertension risk among males, but WC in females. The interaction effects were present among males implying that the association of WC with hypertension was stronger if subjects were overweight or obese. This effect, however, was not present in females. CONCLUSION: BMI and WC may influence hypertension differently among males and females. PMID- 26014838 TI - Safety and Clinical Outcome of the Delivery of Radiofrequency Nerve Ablation Therapy in a Renal Artery of Unusual Anatomy. AB - INTRODUCTION: Catheter-based renal sympathetic denervation is an emerging therapy for resistant hypertension (RHTN) patients, resulting in a significant blood pressure reduction. The presence of accessory renal arteries and anomalous branching patterns are reported in approximately 20-27 % of patients. However, accessory renal arteries, when smaller than 4 mm in diameter, they are out of the inclusion criteria for renal denervation therapy. For this reason patients with evidence of accessory renal arteries have been excluded in previous clinical trials. Recent data suggest that accessory renal arteries may play an important role in non-response therapy when they do not receive renal denervation treatment. CASE REPORT: In this report, we present the outcome of a patient with resistant hypertension and an anomalous right renal artery, having undergone denervation of both principal and accessory renal arteries. The renal ablation by radiofrequency energy of a distant accessory renal artery resulted in a safe procedure with no clinical complications. CONCLUSION: Consistent with literature the RDN of all, main and accessory renal arteries, was effective in decreasing patient blood pressure while decreasing the need for antihypertensive medication. PMID- 26014839 TI - Is there concordance in attitudes and beliefs between parents and scientists about autism spectrum disorder? AB - There is no reported investigation comparing concordance in attitudes and beliefs about autism spectrum disorder between parents of children with autism spectrum disorder and scientists who research autism spectrum disorder. To investigate the level of concordance between these groups on causes of autism, priorities of research, perceived stigma, and disclosure of genetic test results, telephone interviews were conducted. Parents (n = 502) were recruited from the Simons Simplex Collection, and research scientists (n = 60) were recruited from investigators funded by the Simons Foundation. Response rates were notable (parents 91%, scientists 80%). Parents and scientists differed significantly regarding beliefs of the likely major cause of autism (p = 0.007) and priorities for further research (p < 0.001). Scientists believed in genetic causes while many parents believed in vaccines as the cause of autism. Parents (37%) were more likely to hesitate vaccinating their child (p < 0.001). In contrast, there was strong concordance regarding extent of perceived stigma (95% vs 92%) and preferences for disclosure of genetic test results, including incidental findings. While scientists believed communication important, paradoxically fewer than half reported it important for scientists to communicate directly with parents. Better communication between parents and scientists should improve mutual understanding and ultimately the health and well-being of children with autism spectrum disorder and their families. PMID- 26014840 TI - The broad autism phenotype predicts relationship outcomes in newly formed college roommates. AB - Although previous studies have reported that the broad autism phenotype is associated with reduced relationship quality within established relationships, understanding how this association emerges requires assessment prior to relationship development. In the present longitudinal study, college roommates with minimal familiarity prior to cohabitation (N = 162) completed the broad autism phenotype questionnaire and intermittently reported on their relationship quality and interpersonal behaviors toward their roommate over their first 10 weeks of living together. Actor-Partner Interdependence Models demonstrated that roommates mismatched on aloofness (one high and one low) had lower relationship satisfaction than those matched on it, with the interpersonal behavior of warmth mediating this association. Because relationship satisfaction remained high when both roommates were aloof, satisfaction does not appear predicated upon the presence of aloofness generally but rather reflects a product of dissimilarity in aloof profiles between roommates. In contrast, although participants reported less relationship satisfaction and commitment with roommates higher on pragmatic language abnormalities, mismatches on this broad autism phenotype trait, and on rigid personality, were less consequential. In sum, these findings suggest that complementary profiles of social motivation may facilitate relationship quality during the early course of relationship development. PMID- 26014841 TI - Self and informant reports of mental health difficulties among adults with autism findings from a long-term follow-up study. AB - Data on psychiatric problems in adults with autism are inconsistent, with estimated rates ranging from around 25% to over 75%. We assessed difficulties related to mental health in 58 adults with autism (10 females, 48 males; mean age 44 years) whom we have followed over four decades. All were of average non-verbal intelligence quotient when diagnosed as children. Overall ratings of mental health problems were based on data from the Family History Schedule (Bolton et al., 1994). Informant reports indicated that many of the cohort (44%) had experienced no mental health problems in adulthood; 28% had experienced mild to moderate difficulties, 23% had severe and 5% very severe problems. Depression was the most commonly reported problem. Among those adults (n = 22) able to report on their own mental state, again many (45%) reported no mental health problems, although 27% reported very severe mental health problems related to anxiety, depression and/or obsessive-compulsive symptoms. Informant ratings of poor mental health were not associated with gender, severity of autism in childhood, or child or adult intelligence quotient, but there were small correlations with overall social functioning (rho = 0.34) and current autism severity (rho = 0.37). The findings highlight the difficulties of assessing mental health problems in adults with autism and the need for appropriately validated measures. PMID- 26014842 TI - Skin autofluorescence advanced glycosylation end products as an independent predictor of mortality in high flux haemodialysis and haemodialysis patients. AB - AIM: Haemodialysis (HD) patients have an increased risk of cardiovascular death. In addition to the standard cardiovascular disease (CVD) risk factors, HD patients have additional risk factors including bone mineral disorders, anaemia and uraemic toxins, including advance glycosylation end product (AGEs). AGEs increase in HD patients due to reduced renal clearance and increased production. Tissue AGEs measured by skin autofluorescence (SAF) have been shown to be more reliable and reproducible to asses AGE accumulation in HD patients compared with serum levels. We wished to determine whether increasing SAF due to AGEs was associated with reduced survival in HD patients. METHODS: We measured SAF in the non-fistula arm in a cross-sectional study of 332 thrice weekly HD outpatients who were then followed prospectively for 30 months. RESULTS: Mean patient age was 65.7 +/- 15.1 years, 64.2% male, 41.9% diabetic, mean dialysis vintage 65.1 (range 1-413) months, with an average sessional Kt/Vurea of 1.43 +/- 0.34. A percentage of 61.1 had a history of hypertension, 32.2% had CVD, 16% had peripheral vascular disease (PVD) and 37% was current smokers. The mean SAF was 3.27 +/- 0.96 IU, and patients with SAF above the mean (>3.27 IU) had a higher risk of death, and higher SAF was independently associated with increased mortality: hazard ratio 12.95 (1.60-104.8), P = 0.016. CONCLUSION: Accumulation of AGEs, measured by SAF, was independently associated with higher risk of death in HD patients. Additional studies are required to determine whether a reduction in tissue AGEs in dialysis patients may reduce mortality in this high-risk population. PMID- 26014843 TI - Large deletions in the NSDHL gene in two patients with CHILD syndrome. PMID- 26014844 TI - Comparative Efficacy of Adding Sitagliptin to Metformin, Sulfonylurea or Dual Therapy: A Propensity Score-Weighted Cohort Study. AB - INTRODUCTION: The aim of this study was to assess the efficacy of co administering sitagliptin to patients with inadequate glycemic control following treatment with metformin (MET), sulfonylurea (SU), or MET + SU. METHODS: A cohort of 25,386 patients with type 2 diabetes mellitus (hemoglobin A1c [HbA1C] >53 mmol/mol or 7%), newly treated with sitagliptin between 2007 and 2013, was sourced from UK general practices via The Health Improvement Network database. Among these, eligible patients were segregated into three groups: MET (n = 3364), SU (n = 509), or MET + SU therapy (n = 5929). The relative efficacy of sitagliptin added to SU or MET + SU compared with sitagliptin added to MET monotherapy was assessed with regards to HbA1c and body weight changes from baseline up to 52 weeks. The glycemic efficacy was a measure of average treatment effects obtained from multivariable linear regression models and propensity score matching analysis. RESULTS: A total of 9802 patients were included in the study. Overall, addition of sitagliptin 100 mg once daily resulted in 5.5 mmol/mol (0.5%) HbA1c reduction (P < 0.001) and 0.8 kg weight reduction at 1 year (P < 0.001). Efficacy was similar across the treatment groups, but in patients with baseline HbA1c >=9% adding sitagliptin to MET + SU produced a significantly smaller reduction in HbA1c when compared to the reference group MET (MET + SU vs. MET only: -0.5% vs. -0.7%, P < 0.001). The mean HbA1c reduction from baseline within this subgroup of patients was not significantly different between SU and MET monotherapies (-0.8% vs. -0.7%, respectively, P = 0.4). Across treatment groups, HbA1c reductions with add-on sitagliptin occurred after 24 weeks of treatment with a peak reduction occurring between 36 and 48 weeks, and receded after week 48. CONCLUSION: In a real-world general practice setting, sitagliptin was effective in patients with suboptimal glycemic control with MET, SU or dual therapy, maximum between 36 and 48 weeks, but in patients with HbA1c of >9% receiving MET + SU therapy, adding sitagliptin, as a third agent, conferred minimal benefit. PMID- 26014845 TI - DNA cyclization and looping in the wormlike limit: Normal modes and the validity of the harmonic approximation. AB - For much of the last three decades, Monte Carlo-simulation methods have been the standard approach for accurately calculating the cyclization probability, J, or J factor, for DNA models having sequence-dependent bends or inhomogeneous bending flexibility. Within the last 10 years approaches based on harmonic analysis of semi-flexible polymer models have been introduced, which offer much greater computational efficiency than Monte Carlo techniques. These methods consider the ensemble of molecular conformations in terms of harmonic fluctuations about a well-defined elastic-energy minimum. However, the harmonic approximation is only applicable for small systems, because the accessible conformation space of larger systems is increasingly dominated by anharmonic contributions. In the case of computed values of the J factor, deviations of the harmonic approximation from the exact value of J as a function of DNA length have not been characterized. Using a recent, numerically exact method that accounts for both anharmonic and harmonic contributions to J for wormlike chains of arbitrary size, we report here the apparent error that results from neglecting anharmonic behavior. For wormlike chains having contour lengths less than four times the persistence length, the error in J arising from the harmonic approximation is generally small, amounting to free energies less than the thermal energy, kB T. For larger systems, however, the deviations between harmonic and exact J values increase approximately linearly with size. PMID- 26014846 TI - The Role of Oxygen in the Degradation of Methylammonium Lead Trihalide Perovskite Photoactive Layers. AB - In this paper we report on the influence of light and oxygen on the stability of CH3 NH3 PbI3 perovskite-based photoactive layers. When exposed to both light and dry air the mp-Al2 O3 /CH3 NH3 PbI3 photoactive layers rapidly decompose yielding methylamine, PbI2 , and I2 as products. We show that this degradation is initiated by the reaction of superoxide (O2 (-) ) with the methylammonium moiety of the perovskite absorber. Fluorescent molecular probe studies indicate that the O2 (-) species is generated by the reaction of photoexcited electrons in the perovskite and molecular oxygen. We show that the yield of O2 (-) generation is significantly reduced when the mp-Al2 O3 film is replaced with an mp-TiO2 electron extraction and transport layer. The present findings suggest that replacing the methylammonium component in CH3 NH3 PbI3 to a species without acid protons could improve tolerance to oxygen and enhance stability. PMID- 26014851 TI - Development of highly sensitive sensor system for methane utilizing cataluminescence. AB - A gaseous sensor system was developed for the detection of methane based on its cataluminescence emission. Cataluminescence characteristics and optimal conditions were studied in detail under optimized experimental conditions. Results showed that the methane cataluminescence sensor system could cover a linear detection range from 10 to 5800 ppm (R = 0.9963, n = 7) and the detection limit was about 7 ppm (S/N = 3), which was below the standard permitted concentration. Moreover, a linear discriminant analysis method was used to test the recognizable performance of the methane sensor. It was found that methane, ethane, propane and pentane could be distinguished clearly. Its methane sensing properties, including improved sensitivity, selectivity, stability and recognition demonstrated the TiO2/SnO2 materials to be promising candidates for constructing a cataluminescence-based gas sensor that could be used for detecting explosive gas contaminants. PMID- 26014852 TI - Safety of peripheral intravenous administration of vasoactive medication. AB - BACKGROUND: Central venous access is commonly performed to administer vasoactive medication. The administration of vasoactive medication via peripheral intravenous access is a potential method of reducing the need for central venous access. The aim of this study was to evaluate the safety of vasoactive medication administered through peripheral intravenous access. METHODS: Over a 20-month period starting in September 2012, we monitored the use of vasoactive medication via peripheral intravenous access in an 18-bed medical intensive care unit. Norepinephrine, dopamine, and phenylephrine were all approved for use through peripheral intravenous access. RESULTS: A total of 734 patients (age 72 +/- 15 years, male/female 398/336, SAPS II score 75 +/- 15) received vasoactive medication via peripheral intravenous access 783 times. Vasoactive medication used was norepinephrine (n = 506), dopamine (n = 101), and phenylephrine (n = 176). The duration of vasoactive medication via peripheral intravenous access was 49 +/- 22 hours. Extravasation of the peripheral intravenous access during administration of vasoactive medication occurred in 19 patients (2%) without any tissue injury following treatment, with local phentolamine injection and application of local nitroglycerin paste. There were 95 patients (13%) receiving vasoactive medication through peripheral intravenous access who eventually required central intravenous access. CONCLUSIONS: Administration of norepinephrine, dopamine, or phenylephrine by peripheral intravenous access was feasible and safe in this single-center medical intensive care unit. Extravasation from the peripheral intravenous line was uncommon, and phentolamine with nitroglycerin paste were effective in preventing local ischemic injury. Clinicians should not regard the use of vasoactive medication is an automatic indication for central venous access. PMID- 26014853 TI - Characterisation of Ascaridoid larvae from marine fish off New Caledonia, with description of new Hysterothylacium larval types XIII and XIV. AB - Here we report occurrence of six different morphotypes of ascaridoid type larvae from 28 species of fish collected from New Caledonian waters. The larvae were morphologically identified as Anisakis type I, Hysterothylacium type VI and new larval types XIII and XIV, Raphidascaris larval type and Terranova larval type II. Representatives of each morphotype were subjected to the amplification of the second internal transcribed spacers (ITS-2) of ribosomal DNA (rDNA) and those sequences were compared with ITS-2 sequences of other ascaridoid nematodes previously deposited in GenBank. ITS-2 sequences of Anisakis larval type I were identical to those of A. typica. ITS-2 sequences of Hysterothylacium larval type VI in the present study were identical to those previously found in Eastern Australian waters. No match was found for ITS-2 sequences of Hysterothylacium larval types XIII and XIV; therefore, the specific identities of these larval types remain unclear. ITS-2 sequences of Raphidascaris larval type were identical to those of R. trichiuri, which have previously been reported in Taiwanese waters. Terranova larval type II in the present study had identical ITS-2 sequences with Terranova larval types reported from Australian waters, however, the specific identity is unknown. This taxonomic work is essential if further research on these zoonotic parasites is to be effective. This includes investigations into such aspects as life cycle studies, impacts on human health and risk assessment for their transmission to humans. PMID- 26014854 TI - Controlling the Structure and Length of Self-Synthesizing Supramolecular Polymers through Nucleated Growth and Disassembly. AB - Directing self-assembly processes out-of-equilibrium to yield kinetically trapped materials with well-defined dimensions remains a considerable challenge. Kinetically controlled assembly of self-synthesizing peptide-functionalized macrocycles through a nucleation-growth mechanism is reported. Spontaneous fiber formation in this system is effectively shut down as most of the material is diverted into metastable non-assembling trimeric and tetrameric macrocycles. However, upon adding seeds to this mixture, well-defined fibers with controllable lengths and narrow polydispersities are obtained. This seeded growth strategy also allows access to supramolecular triblock copolymers. The resulting noncovalent assemblies can be further stabilized through covalent capture. Taken together, these results show that self-synthesizing materials, through their interplay between dynamic covalent bonds and noncovalent interactions, are uniquely suited for out-of-equilibrium self-assembly. PMID- 26014855 TI - Broccoli sprout supplementation during pregnancy prevents brain injury in the newborn rat following placental insufficiency. AB - Chronic placental insufficiency and subsequent intrauterine growth restriction (IUGR) increase the risk of hypoxic-ischemic encephalopathy in the newborn by 40 fold. The latter, in turn, increases the risk of cerebral palsy and developmental disabilities. This study seeks to determine the effectiveness of broccoli sprouts (BrSp), a rich source of the isothiocyanate sulforaphane, as a neuroprotectant in a rat model of chronic placental insufficiency and IUGR. Placental insufficiency and IUGR was induced by bilateral uterine artery ligation (BUAL) on day E20 of gestation. Dams were fed standard chow or chow supplemented with 200mg of dried BrSp from E15 - postnatal day 14 (PD14). Controls received Sham surgery and the same dietary regime. Pups underwent neurologic reflex testing and open field testing, following which they were euthanized and their brains frozen for neuropathologic assessment. Compared to Sham, IUGR pups were delayed in attaining early reflexes and performed worse in the open field, both of which were significantly improved by maternal supplementation of BrSp (p<0.05). Neuropathology revealed diminished white matter, ventricular dilation, astrogliosis and reduction in hippocampal neurons in IUGR animals compared to Sham, whereas broccoli sprout supplementation improved outcome in all histological assessments (p<0.05). Maternal dietary supplementation with BrSp prevented the detrimental neurocognitive and neuropathologic effects of chronic intrauterine ischemia. These findings suggest a novel approach for prevention of cerebral palsy and/or developmental disabilities associated with placental insufficiency. PMID- 26014883 TI - Combined unsupervised-supervised classification of multiparametric PET/MRI data: application to prostate cancer. AB - Multiparametric medical imaging data can be large and are often complex. Machine learning algorithms can assist in image interpretation when reliable training data exist. In most cases, however, knowledge about ground truth (e.g. histology) and thus training data is limited, which makes application of machine learning algorithms difficult. The purpose of this study was to design and implement a learning algorithm for classification of multidimensional medical imaging data that is robust and accurate even with limited prior knowledge and that allows for generalization and application to unseen data. Local prostate cancer was chosen as a model for application and validation. 16 patients underwent combined simultaneous [(11) C]-choline positron emission tomography (PET)/MRI. The following imaging parameters were acquired: T2 signal intensities, apparent diffusion coefficients, parameters Ktrans and Kep from dynamic contrast-enhanced MRI, and PET standardized uptake values (SUVs). A spatially constrained fuzzy c means algorithm (sFCM) was applied to the single datasets and the resulting labeled data were used for training of a support vector machine (SVM) classifier. Accuracy and false positive and false negative rates of the proposed algorithm were determined in comparison with manual tumor delineation. For five of the 16 patients rates were also determined in comparison with the histopathological standard of reference. The combined sFCM/SVM algorithm proposed in this study revealed reliable classification results consistent with the histopathological reference standard and comparable to those of manual tumor delineation. sFCM/SVM generally performed better than unsupervised sFCM alone. We observed an improvement in accuracy with increasing number of imaging parameters used for clustering and SVM training. In particular, including PET SUVs as an additional parameter markedly improved classification results. A variety of applications are conceivable, especially for imaging of tissues without easily available histopathological correlation. PMID- 26014856 TI - Identification of several potential chromatin binding sites of HOXB7 and its downstream target genes in breast cancer. AB - HOXB7 encodes a transcription factor that is overexpressed in a number of cancers and encompasses many oncogenic functions. Previous results have shown it to promote cell proliferation, angiogenesis, epithelial-mesenchymal transition, DNA repair and cell survival. Because of its role in many cancers and tumorigenic processes, HOXB7 has been suggested to be a potential drug target. However, HOXB7 binding sites on chromatin and its targets are poorly known. The aim of our study was to identify HOXB7 binding sites on breast cancer cell chromatin and to delineate direct target genes located nearby these binding sites. We found 1,504 HOXB7 chromatin binding sites in BT-474 breast cancer cell line that overexpresses HOXB7. Seventeen selected binding sites were validated by ChIP-qPCR in several breast cancer cell lines. Furthermore, we analyzed expression of a large number of genes located nearby HOXB7 binding sites and found several new direct targets, such as CTNND2 and SCGB1D2. Identification of HOXB7 chromatin binding sites and target genes is essential to understand better the role of HOXB7 in breast cancer and mechanisms by which it regulates tumorigenic processes. PMID- 26014884 TI - Temporoparietal fascia flap "sandwich" technique for repair of near-total traumatic auricle avulsion. PMID- 26014885 TI - Assessment of methods to recover DNA from bacteria, fungi and archaea in complex environmental samples. AB - DNA extraction from environmental samples is a critical step for metagenomic analysis to study microbial communities, including those considered uncultivable. Nevertheless, obtaining good quality DNA in sufficient quantities for downstream methodologies is not always possible, and it depends on the complexity and stability of each ecosystem, which could be more problematic for samples from tropical regions because those ecosystems are less stable and more complex. Three laboratory methods for the extraction of nucleic acids from samples representing unstable (decaying coffee pulp and mangrove sediments) and relatively stable (compost and soil) environments were tested. The results were compared with those obtained using two commercial DNA extraction kits. The quality of the extracted DNA was evaluated by PCR amplification to verify the recovery of bacterial, archaeal, and fungal genetic material. The laboratory method that gave the best results used a lysis procedure combining physical, chemical, and enzymatic steps. PMID- 26014886 TI - Instantaneous room temperature bonding of a wide range of non-silicon substrates with poly(dimethylsiloxane) (PDMS) elastomer mediated by a mercaptosilane. AB - This paper introduces an instantaneous and robust strategy for bonding a variety of non-silicon substrates such as thermoplastics, metals, an alloy, and ceramics to poly(dimethylsiloxane) (PDMS) irreversibly, mediated by one-step chemical modification using a mercaptosilane at room temperature followed by corona treatment to realize heterogeneous assembly also at room temperature. The mercapto functional group is one of the strongest nucleophiles, and it can instantaneously react with electrophiles of substrates, resulting in an alkoxysilane-terminated substrate at room temperature. In this way, prior oxidation of the substrate is dispensed with, and the alkoxysilane-terminated substrate can be readily oxidized and irreversibly bonded with oxidized PDMS at room temperature. A commercially available Tesla coil was used for surface oxidation, replacing a bulky and expensive plasma generator. Surface characterization was conducted by water contact angle measurement and X-ray photoelectron spectroscopy (XPS) analysis. A total of fifteen non-silicon substrates including polycarbonate (PC), two types of poly(vinylchloride) (PVC), poly(methylmethacrylate) (PMMA), polystyrene (PS), polyimide (PI), two types of poly(ethylene terephthalate) (PET), polypropylene (PP), iron (Fe), aluminum (Al), copper (Cu), brass, alumina (Al2O3), and zirconia (ZrO2) were bonded successfully with PDMS using this method, and the bond strengths of PDMS-PMMA, PDMS-PC, PDMS PVC, PDMS-PET, PDMS-Al, and PDMS-Cu assemblies were measured to be approximately 335.9, 511.4, 467.3, 476.4, 282.2, and 236.7 kPa, respectively. The overall processes including surface modification followed by surface oxidation using corona treatment for bonding were realized within 12 to 17 min for most of the substrates tested except for ceramics which required 1 h for the bonding. In addition, large area (10 * 10 cm(2)) bonding was also successfully realized, ensuring the high reliability and stability of the introduced method. PMID- 26014887 TI - Highly sensitive HPLC-DAD method for the assay of gefitinib in patient plasma and cerebrospinal fluid: application to a blood-brain barrier penetration study. AB - The quantification of intracranial gefitinib (GEF) exposure is limited owing to the sensitivity of analytical equipment. Although mass spectrometry (MS) is the preferred method because of its high sensitivity, the equipment is not available in many laboratories, especially in developing Asian countries. In this paper, we developed a highly sensitive high performance liquid chromatography-diode array detector (HPLC-DAD) method for the assay of GEF in human cerebrospinal fluid (CSF) and plasma. GEF was extracted from CSF and plasma by solid-phase extraction and liquid-liquid extraction, respectively. The chromatographic separation was performed on a C18 column with gradient elution of 0.1% triethylamine solution and acetonitrile, then finally detected at 344 nm. This method was validated and proved to be highly sensitive with a lower limit of quantitation value of 0.11 ng/mL in CSF and 11 ng/mL in plasma. The blood-brain barrier penetration ratio of GEF ranged from 1.48 to 2.41%. This method provides a reliable MS-independent solution for the quantitation of GEF in patients' CSF and plasma. PMID- 26014888 TI - [Consumption of drugs in over 65 in Porto (Portugal) and risk of potentially inappropriate medication prescribing]. AB - OBJECTIVE: To determine medication consumption in the older people from a central area of Oporto; determine the prevalence of prescription of Potentially Inappropriate Medication and to analyse the polypharmacy and other important connected factors. DESIGN, SETTING AND PATIENTS: Cross-sectional study with a sample of 747 patients older than 64 years, who were attended in a Primary care health centre: USF Rainha D. Amelia, Oporto, Portugal. MAIN OUTCOME MEASURES: identification of all medication prescribed from electronic registers. Polypharmacy was considered more than 5 medication prescribed and Potential Inappropriate Medication was identified by Beers criteria 2012. The socio demographic factors, diagnosis and health care services use were registered too. Logistic regression analysis was used to determine the association between co variables. RESULTS: There were 89.2% (95%CI: 87.6-92.0) of the studied population with at least one prescription. The polypharmacy was present at 59.2% (95%CI: 55.7-62.7) of people. The Potential Inappropriate Medication was present in 37.0% (95%CI: 33.5-40.5) of the cases. The Potential Inappropriate Medication was related with increasing age [OR=1.02 (95%CI: 1.00-1.05)], polypharmacy [OR=4.45 (95%CI: 3.12-6.36)], and be diagnosed with depression/anxiety [OR=2.18 (95%CI: 1.36-3.51)] and/or arthrosis [OR=1.64 (95%CI: 1.11-2.42)]. CONCLUSION: The rate of medication prescription, polypharmacy and the prescription of Potentially Inappropriate Medication are very high in Portuguese population studied. The polypharmacy is the most important factor related with this potential inappropriate medication. The physician need to have carefully with prescription of the anxiolytic and anti-inflammatory pain drugs. PMID- 26014889 TI - Highly conductive transparent organic electrodes with multilayer structures for rigid and flexible optoelectronics. AB - Transparent electrodes are essential components for optoelectronic devices, such as touch panels, organic light-emitting diodes, and solar cells. Indium tin oxide (ITO) is widely used as transparent electrode in optoelectronic devices. ITO has high transparency and low resistance but contains expensive rare elements, and ITO-based devices have poor mechanical flexibility. Therefore, alternative transparent electrodes with excellent opto-electrical performance and mechanical flexibility will be greatly demanded. Here, organics are introduced into dielectric-metal-dielectric structures to construct the transparent electrodes on rigid and flexible substrates. We show that organic-metal-organic (OMO) electrodes have excellent opto-electrical properties (sheet resistance of below 10 Omega sq(-1) at 85% transmission), mechanical flexibility, thermal and environmental stabilities. The OMO-based polymer photovoltaic cells show performance comparable to that of devices based on ITO electrodes. This OMO multilayer structure can therefore be used to produce transparent electrodes suitable for use in a wide range of optoelectronic devices. PMID- 26014890 TI - Reduced functional connectivity during controlled semantic integration in schizophrenia: A multivariate approach. AB - Impairment in controlled semantic association is a central feature of schizophrenia, and the goal of the current functional magnetic resonance imaging study was to identify the neural correlates of this impairment. Thirty people with schizophrenia and 30 healthy age- and gender-matched control subjects performed a task requiring participants to match word pairs that varied in semantic distance (distant vs. close). A whole-brain multivariate connectivity analysis revealed three functional brain networks of primary interest engaged by the task: two configurations of a multiple demands network, in which brain activity did not differ between groups, and a semantic integration network, in which coordinated activity was reduced in schizophrenia patients relative to healthy controls, for distantly relative to closely related word pairs. The hypoactivity during controlled semantic integration in schizophrenia reported here, combined with hyperactivity in automatic semantic association reported in the literature, suggests an imbalance between controlled integration and automatic association. This provides a biological basis for Bleuler's concept of schizophrenia as a "split mind" arising from an impaired ability to form coherent associations between semantic concepts. PMID- 26014891 TI - The Association Between Sensemaking During Physician Team Rounds and Hospitalized Patients' Outcomes. AB - BACKGROUND: Sensemaking is the social act of assigning meaning to ambiguous events. It is recognized as a means to achieve high reliability. We sought to assess sensemaking in daily patient care through examining how inpatient teams round and discuss patients. OBJECTIVE: Our purpose was to assess the association between inpatient physician team sensemaking and hospitalized patients' outcomes, including length of stay (LOS), unnecessary length of stay (ULOS), and complication rates. DESIGN: Eleven inpatient medicine teams' daily rounds were observed for 2 to 4 weeks. Rounds were audiotaped, and field notes taken. Four patient discussions per team were assessed using a standardized Situation, Task, Intent, Concern, Calibrate (STICC) framework. PARTICIPANTS: Inpatient physician teams at the teaching hospitals affiliated with the University of Texas Health Science Center at San Antonio participated in the study. Outcomes of patients admitted to the teams were included. MAIN MEASURES: Sensemaking was assessed based on the order in which patients were seen, purposeful rounding, patient driven rounding, and individual patient discussions. We assigned teams a score based on the number of STICC elements used in the four patient discussions sampled. The association between sensemaking and outcomes was assessed using Kruskal-Wallis sum rank and Dunn's tests. KEY RESULTS: Teams rounded in several different ways. Five teams rounded purposefully, and four based rounds on patient driven needs. Purposeful and patient-driven rounds were significantly associated with lower complication rates. Varying the order in which patients were seen and purposefully rounding were significantly associated with lower LOS, and purposeful and patient-driven rounds associated with lower ULOS. Use of a greater number of STICC elements was associated with significantly lower LOS (4.6 vs. 5.7, p = 0.01), ULOS (0.3 vs. 0.6, p = 0.02), and complications (0.2 vs. 0.5, p = 0.0001). CONCLUSIONS: Improving sensemaking may be a strategy for improving patient outcomes, fostering a shared understanding of a patient's clinical trajectory, and enabling high reliability. PMID- 26014892 TI - Capsule Commentary on Clair et al., The Effect of Cigarette Smoking on Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis. PMID- 26014893 TI - Industry Collaboration and Primary Guest Authorship of High-Impact Clinical Trials. PMID- 26014895 TI - Capsule Commentary on Gonzalo, et al., Impact of an Overnight Internal Medicine Academic Hospitalist Program on Patient Outcomes. PMID- 26014894 TI - Future Research Prioritization: Implantable Cardioverter-Defibrillator Therapy in Older Patients. AB - BACKGROUND: Although the implantable cardioverter-defibrillator (ICD) is highly effective therapy for preventing sudden cardiac death, there is considerable uncertainty about its benefits and harms in older patients, especially in the presence of factors, other than old age, that increase the risk of death. OBJECTIVE: To develop a prioritized research agenda for the Patient-Centered Outcomes Research Institute as informed by a diverse group of stakeholders on the use and outcomes of the ICD in older patients. DESIGN: The existing literature was reviewed to identify evidence gaps, which were then refined by engaged stakeholders. Using a forced-ranking prioritization method, the stakeholders ranked evidence gaps by importance. For the highest-ranked evidence gaps, relevant recent studies were identified using PubMed, and relevant ongoing trials were identified using ClinicalTrials.gov. PARTICIPANTS: Eighteen stakeholders, including clinical experts and researchers in the prevention of sudden cardiac death and ICD therapy, representatives from federal and non-governmental funding agencies, representatives from relevant professional societies, health care decision-makers and policymakers, and representatives from related consumer and patient advocacy groups KEY RESULTS: The top 12 evidence gaps prioritized by stakeholders were related to the safety and effectiveness of ICDs in older patient subgroups not well represented in clinical trials, predictors of SCD, the impact of the ICD on quality of life, the use of shared decision-making, disparities in ICD use, risk stratification strategies, patient preferences, and distribution of modes of death in older patients. CONCLUSIONS: In this paper, we identify evidence gaps of high priority for current and future investigations of ICD therapy. Addressing these gaps will likely resolve many of the uncertainties surrounding the use and outcomes of the ICD in older patients seen in clinical practice. PMID- 26014896 TI - trans-(Cl)-[Ru(5,5'-diamide-2,2'-bipyridine)(CO)2 Cl2 ]: Synthesis, Structure, and Photocatalytic CO2 Reduction Activity. AB - A series of trans-(Cl)-[Ru(L)(CO)2 Cl2 ]-type complexes, in which the ligands L are 2,2'-bipyridyl derivatives with amide groups at the 5,5'-positions, are synthesized. The C-connected amide group bound to the bipyridyl ligand through the carbonyl carbon atom is twisted with respect to the bipyridyl plane, whereas the N-connected amide group is in the plane. DFT calculations reveal that the twisted structure of the C-connected amide group raises the level of the LUMO, which results in a negative shift of the first reduction potential (Ep ) of the ruthenium complex. The catalytic abilities for CO2 reduction are evaluated in photoreactions (lambda>400 nm) with the ruthenium complexes (the catalyst), [Ru(bpy)3 ](2+) (bpy=2,2'-bipyridine; the photosensitizer), and 1-benzyl-1,4 dihydronicotinamide (the electron donor) in CO2 -saturated N,N dimethylacetamide/water. The logarithm of the turnover frequency increases by shifting Ep a negative value until it reaches the reduction potential of the photosensitizer. PMID- 26014897 TI - C9H8 Pyrolysis. o-Tolylacetylene, Indene, 1-Indenyl, and Biindenyls and the Mechanism of Indene Pyrolysis. AB - o-Tolylacetylene 5 is obtained by flash vacuum pyrolysis (FVP) of the isoxazolone 13a at 800 degrees C/10(-4) hPa. At 900-1000 degrees C the acetylene 5 isomerizes to indene 1, which reacts further by elimination of a hydrogen atom and dimerization of the 1-indenyl radical 9 to 1,1'-biindenyl 10. The latter undergoes partial isomerization to 3,3'-biindenyl 16, and further pyrolysis of the biindenyls yields higher polycyclic aromatic hydrocarbons (PAHs), particularly chrysene 2. C-H bond breakage in indene, which occurs with an activation energy of 80 +/- 5 kcal/mol with formation of the 1-indenyl radical 9, has been the subject of much investigation in relation to hydrocarbon combustion, in particular the formation of chrysene and other PAHs from indene, which itself is formed in the combustion of toluene and other hydrocarbons. However, C-C bond breakage also needs to be considered. Calculations at the B3LYP/6-311+G(d,p) level indicate that key C-C bond breakages in indene have free energies of activation of ca. 80 kcal/mol. Positive entropies of activation make all these reactions more facile at high temperatures relevant to hydrocarbon combustion chemistry. C1-C2 bond breakage results in the formation of o-tolylvinylidene 6 and o-tolylacetylene 5. The reversible 1,2-shift interconverting 5 and 6 (the Roger Brown rearrangement) can lead to carbon scrambling in C3-labeled indene 1a, resulting in indene 1d carrying the label in positions 1, 2, and 3 and explaining the (14)C-labeling pattern observed by Badger et al. in the derived chrysene 2d. o-Tolylacetylene 5 and o-tolylvinylidene 6 should be considered as intermediates in models of the fuel-rich combustion of toluene, indene, and other hydrocarbons. PMID- 26014898 TI - Activation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene expression following DNA demethylation in placental choriocarcinoma and transformed cell lines. AB - We characterised DNA methylation and gene expression of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4, DR5, DcR1 and DcR2 in three choriocarcinoma (JAR, JEG-3, BeWo) and two transformed (HTR-8/SVneo and HPT-8) cell lines. DR4 mRNA was detected in JAR, JEG-3, BeWo and HTR-8/SVneo cells, whereas DR5 was present in all detected cells. DcR1 transcripts were expressed only in JAR, JEG-3 and BeWo cells, whereas DcR2 transcripts were detected only in HTR-8/SVneo and HPT-8 cells. Hypermethylated DR4 promoter was observed in JAR, JEG-3, BeWo and HTR-8/SVneo cells, hypermethylated DcR1 promoter in HTR-8/SVneo and HPT-8 cells and hypermethylated DcR2 promoter in JAR, JEG-3 and BeWo cells. Restoration of DR4, DcR1 and DcR2 expression with decreased DNA methylation of these genes was induced by the DNA demethylation agent 5-aza-2' deoxycytidine (5-aza-CdR) in trophoblast cells, whereas DR5 expression did not exhibit any change. Significant negative correlation between the expression and DNA methylation of these genes was also observed. In all tested cell lines, only HPT-8 demonstrated sensitivity to TRAIL-induced apoptosis. Combined treatment with 5-aza-CdR and TRAIL resulted in apoptosis in JAR, JEG-3, BeWo and HTR 8/SVneo cells but not in HPT-8 cells. The results indicate that DNA methylation is associated with TRAIL receptor expression and might be involved in trophoblast apoptosis. PMID- 26014900 TI - Size of gold nanoparticles driving selective amide synthesis through aerobic condensation of aldehydes and amines. AB - Metal nanoparticles (NPs) have attracted much attention in many fields due to their intrinsic characteristics. It is generally accepted that smaller NPs (1.5-3 nm) are more active than larger NPs, and reverse cases are very rare. We report here the direct aerobic oxidative amide synthesis from aldehydes and amines catalyzed by polymer-incarcerated gold (Au) NPs. A unique correlation between imine/amide selectivity and size of NPs was discovered; Au-NPs of medium size (4.5-11 nm) were found to be optimal. High yields were obtained with a broad range of substrates, including primary amines. Au-NPs of medium size could be recovered and reused several times without loss of activity, and they showed good activity and selectivity in amide formation from alcohols and amines. PMID- 26014901 TI - An Operationally Simple Method for Separating the Rare-Earth Elements Neodymium and Dysprosium. AB - Rare-earth metals are critical components of electronic materials and permanent magnets. Recycling of consumer materials is a promising new source of rare earths. To incentivize recycling there is a clear need for simple methods for targeted separations of mixtures of rare-earth metal salts. Metal complexes of a tripodal nitroxide ligand [{(2-(t) BuNO)C6 H4 CH2 }3 N](3-) (TriNOx(3-) ), feature a size-sensitive aperture formed of its three eta(2) -(N,O) ligand arms. Exposure of metal cations in the aperture induces a self-associative equilibrium comprising [M(TriNOx)thf]/ [M(TriNOx)]2 (M=rare-earth metal). Differences in the equilibrium constants (Keq ) for early and late metals enables simple Nd/Dy separations through leaching with a separation ratio SNd/Dy =359. PMID- 26014899 TI - Design of antimicrobial peptides conjugated biodegradable citric acid derived hydrogels for wound healing. AB - Wound healing is usually facilitated by the use of a wound dressing that can be easily applied to cover the wound bed, maintain moisture, and avoid bacterial infection. In order to meet all of these requirements, we developed an in situ forming biodegradable hydrogel (iFBH) system composed of a newly developed combination of biodegradable poly(ethylene glycol) maleate citrate (PEGMC) and poly(ethylene glycol) diacrylate (PEGDA). The in situ forming hydrogel systems are able to conform to the wound shape in order to cover the wound completely and prevent bacterial invasion. A 2(k) factorial analysis was performed to examine the effects of polymer composition on specific properties, including the curing time, Young's modulus, swelling ratio, and degradation rate. An optimized iFBH formulation was achieved from the systematic factorial analysis. Further, in vitro biocompatibility studies using adult human dermal fibroblasts (HDFs) confirmed that the hydrogels and degradation products are not cytotoxic. The iFBH wound dressing was conjugated and functionalized with antimicrobial peptides as well. Evaluation against bacteria both in vitro and in vivo in rats demonstrated that the peptide-incorporated iFBH wound dressing offered excellent bacteria inhibition and promoted wound healing. These studies indicated that our in situ forming antimicrobial biodegradable hydrogel system is a promising candidate for wound treatment. PMID- 26014902 TI - Deep ultraviolet laser direct write for patterning sol-gel InGaZnO semiconducting micro/nanowires and improving field-effect mobility. AB - Deep-UV (DUV) laser was used to directly write indium-gallium-zinc-oxide (IGZO) precursor solution and form micro and nanoscale patterns. The directional DUV laser beam avoids the substrate heating and suppresses the diffraction effect. A IGZO precursor solution was also developed to fulfill the requirements for direct photopatterning and for achieving semi-conducting properties with thermal annealing at moderate temperature. The DUV-induced crosslinking of the starting material allows direct write of semi-conducting channels in thin-film transistors but also it improves the field-effect mobility and surface roughness. Material analysis has been carried out by XPS, FTIR, spectroscopic ellipsometry and AFM and the effect of DUV on the final material structure is discussed. The DUV irradiation step results in photolysis and a partial condensation of the inorganic network that freezes the sol-gel layer in a homogeneous distribution, lowering possibilities of thermally induced reorganization at the atomic scale. Laser irradiation allows high-resolution photopatterning and high-enough field effect mobility, which enables the easy fabrication of oxide nanowires for applications in solar cell, display, flexible electronics, and biomedical sensors. PMID- 26014903 TI - HLA-DPB1 variant rs3117242 is associated with anti-neutrophil cytoplasmic antibody-associated vasculitides in a Han Chinese population. AB - AIM: The vasculitis diseases granulomatosis with polyangiitis (GPA) and microscopic polyangitis (MPA) are the two major forms of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). A recent genome-wide association study has shown that the genes HLA-DPB1 and HLA-DQ conferred susceptibility to GPA and MPA, respectively. We investigated the linkage between putative AAV-related genes (HLA-DPB1, ARHGAP18, CD226, CTLA-4, MOSPD2 and PRTN3) and AAV in a Han Chinese population. METHOD: A Sequenom MassAarray system (iPLEX assay, Sequenom, San Diego, CA, USA) was used to genotype single nucleotide polymorphisms (SNPs) in 176 Han Chinese patients with AAV (100 with GPA, 76 with MPA) and 485 ethnically matched healthy controls. RESULT: The frequency of the rs3117242 variant T allele (HLA-DPB1) was significantly higher in GPA patients than in the controls (68.0% compared with 50.4%, OR = 2.09, 95% CI: 1.51-2.88, Bonferroni corrected P-value [Pc] = 6.24E-5), but was not significantly different between MPA patients and controls (Pc = 0.14). The same results were obtained via genotype distribution and logistic regression analysis based on three genetic models. The allele and genotype distributions of the other polymorphisms were not significantly associated with AAV patients as a whole or GPA or MPA patients considered separately. CONCLUSION: The rs3117242 of HLA-DPB1 could be considered a genetic risk factor for GPA in Chinese Han people. These findings provide further insights and clues into the etiology of GPA and MPA. PMID- 26014904 TI - Bedside Ultrasonography for Arteriovenous Fistula Cannulation. AB - Difficulty in accessing a new arteriovenous fistula (AVF) is a common technical issue in hemodialysis patients, which often leads to interventional radiology and/or vascular surgery referral. As a consequence, the patient who needs dialysis may require a temporary dialysis catheter with its known potential complications. We present a case where bedside ultrasonography facilitated successful cannulation of a difficult AVF. Ultrasonography (US) training in this procedure may allow early cannulation of new AVFs when the venous diameter is large enough (>0.6 cm) but the fistula is too deep (>0.6 cm). Real-time, US guided AVF cannulation may also decrease the number of failed venous punctures per hemodialysis (HD) session minimizing vessel wall damage and subsequent potential hematoma and aneurysm formation. PMID- 26014905 TI - Fluoroless ureteroscopy: in whom and when? PMID- 26014906 TI - Review article: the efficacy and safety of daclatasvir in the treatment of chronic hepatitis C virus infection. AB - BACKGROUND: The treatment of hepatitis C virus (HCV) has evolved dramatically after the introduction of direct acting anti-virals. NS5A protein plays an important role in HCV replication and is an attractive target for drug development. AIM: To review clinical studies on the efficacy and safety of direct acting anti-virals regimens containing daclastavir, an NS5A inhibitor, in the treatment of chronic hepatitis C. METHODS: A Medline search was undertaken to identify relevant literature using search terms including 'daclatasvir', 'HCV treatment' and 'NS5A inhibitors'. Furthermore, we scanned abstracts presented at the recent international meetings in liver disease, viral hepatitis and infectious disease, as well as the reference lists of the review articles to identify publications not retrieved by electronic searches. RESULTS: Daclatasvir is the first-in-class HCV NS5A inhibitor that has been demonstrated in Phase I III trials to have a potent anti-viral effect and clinical efficacy across multiple HCV genotypes (GT). Daclastavir is generally safe and well tolerated, with a low barrier to resistance and low potential for drug-drug interaction. When Daclastavir is added to PEG-IFN/RBV platform, sustained virological response (SVR) rates are increased significantly compared with PEG-IFN/RBV alone. The all oral combination of Daclastavir/asunaprevir (ASV; protease inhibitor) has high SVR rates against GT1b, but less activity against GT1a. Dual combination of Daclastavir/Sofosbuvir (SOF; nucleotide polymerase inhibitor) and triple combination of Daclastavir/ASV/beclabuvir (BCV; non-nucleoside polymerase inhibitor) have demonstrated >90% SVR rates in both treatment naive and treatment experienced patients with GT1. Furthermore, Daclastavir/SOF combination has also demonstrated up to 90% SVR rates in patients with GT3, and in those with human immunodeficiency virus coinfection, cirrhosis and post-transplant HCV recurrence with any GT. Daclastavir/ASV/BCV has primarily demonstrated near 100% SVR rates in patients with GT4. CONCLUSION: Daclastavir-containing regimens, with or without PEG-IFN, have shown promising results in clinical trials, and present an excellent treatment option for those with chronic HCV and for multiple genotypes. PMID- 26014907 TI - A versatile, non genetically modified organism (GMO)-based strategy for controlling low-producer mutants in Bordetella pertussis cultures using antigenic modulation. AB - The uncontrolled presence of non-producer mutants negatively affects bioprocesses. In Bordetella pertussis cultures, avirulent mutants emerge spontaneously and accumulate. We characterized the dynamics of accumulation using high-throughput growth assays and competition experiments between virulent and avirulent (bvg(-) ) isolates. A fitness advantage of bvg(-) cells was identified as the main driver for bvg(-) accumulation under conditions of high virulence factor production. Conversely, under conditions that reduce their expression (antigenic modulation), bvg(-) takeover could be avoided. A control strategy was derived, which consists in applying modulating conditions whenever virulence factor production is not required. It has a wide range of applications, from routine laboratory operations to vaccine manufacturing, where pertussis toxin yields were increased 1.4-fold by performing early pre-culture steps in modulating conditions. Because it only requires subtle modifications of the culture medium and does not involve genetic modifications, this strategy is applicable to any B. pertussis isolate, and should facilitate regulatory acceptance of process changes for vaccine production. Strategies based on the same concept, could be derived for other industrially relevant micro-organisms. This study illustrates how a sound scientific understanding of physiological principles can be turned into a practical application for the bioprocess industry, in alignment with Quality by Design principles. PMID- 26014908 TI - The optimal number of offspring per gamete donor. AB - Our aim was to create a mathematical basis to calculate the risks for unintended matings of consanguineous half-siblings from a donor in a society with approximately 10 million inhabitants. The Curie-Cohen model for calculation of the risk for consanguineous mating was used. When the number of offspring per donor is limited to 10, then the model gives a yearly risk for consanguineous matings below 1%. Thus 10 offspring gives a risk for consanguineous matings of 0.9% per year, or approximately once in every 100 years. The risk increases exponentially: with 15 offspring it exceeds 2% and with 25 it reaches up above 5%. PMID- 26014909 TI - Superior Sensitivity of Ex Vivo IFN-gamma Release Assays as Compared to Skin Testing in Immunocompromised Patients. AB - Comparative assessment of the tuberculin skin testing (TST) and commercial IFN gamma release-assays (IGRAs) is hampered by the use of different antigens (tuberculin PPD in TST vs. ESAT-6/CFP-10 in IGRAs). Thus, PPD was used as a common stimulus to compare performance of the TST and three IGRAs in 72 controls, 101 hemodialysis patients and 100 renal transplant recipients. Results of the TST were compared with PPD-induced IFN-gamma induction in vitro detected by ELISPOT, ELISA or a flow-cytometric FACS assay. Percentages of positive tests were significantly lower in TST (9.2%) compared to ELISA (55.3%), ELISPOT (45.3%) and FACS (44.9%, p < 0.0001). Agreement between TST and IGRAs was highest for controls (kappa = 0.19-0.32) and poor in immunocompromised patients (kappa = 0 for transplant patients, kappa = 0.06-0.13 for hemodialysis patients). Discrepant results were largely TST negative and IGRA positive. Among IGRAs, agreement was highest between ELISPOT and FACS (kappa = 0.61). Unlike TST, all IGRAs were associated with variables of mycobacterial exposure. Among IGRAs, the FACS assay was least affected by the level of immunosuppression. In conclusion, both the percentage of positive results and between-test-agreement were higher with IGRAs as compared to TST. This indicates superiority of IGRAs in detecting a PPD specific immune response which may also apply for immunity toward Mycobacterium tuberculosis-specific antigens. PMID- 26014910 TI - IDENTIFYING PANIC DISORDER SUBTYPES USING FACTOR MIXTURE MODELING. AB - BACKGROUND: The clinical presentation of panic disorder (PD) is known to be highly heterogeneous, complicating research on its etiology, neurobiological pathways, and treatment. None of the attempts to identify PD subtypes have been independently reproduced, rendering the current literature inconclusive. METHODS: Using a data-driven, case-centered approach (factor mixture modeling) on a broad range of anxiety symptoms assessed with the Beck anxiety inventory, the present study identifies PD disorder subtypes in a large (n = 658), well-documented mixed population sample from the Netherlands Study of Depression and Anxiety (NESDA), with subtypes being validated and detailed using a variety of clinical characteristics. RESULTS: A three-class, one-factor model proved superior to all other possible models (Bayesian information criterion = 13,200; Lo-Mendel-Rubin = 0.0295; bootstrapped likelihood ratio test <= 0.0001), with the first class, a cognitive-autonomic subtype, accounting for 29.8%, the second class, the autonomic subtype, for 29.9%, and a third class, the aspecific subtype, for 40.3% of the population. The cognitive-autonomic and autonomic subtypes showed significant differences compared to the aspecific subtype (e.g., comorbidity and suicide attempts) but on severity differed between themselves only. CONCLUSION: Three qualitatively different PD subtypes were identified: a severe cognitive autonomic subtype, a moderate autonomic subtype, and a mild aspecific subtype. Qualitative and quantitative differences were related to severity and clinical properties such as comorbidity, suicide attempts, sleep, and sense of mastery. PMID- 26014912 TI - The collective nuclear migration of p53 and phosphorylated S473 of Akt during ellipticine-mediated apoptosis in human lung epithelial cancer cells. AB - Topoisomerase II inhibitor ellipticine effectively suppressed the growth of human non-small-cell-lung-cancer (NSCLC) epithelial cells. Previously, we reported the drug activity was consummated through parallel nucleus migration of p53 and Akt in A549 cells. While inducing cell death, the drug activity was proved related to autophagy through phosphorylated Akt at S473. In addition, ellipticine induced cytotoxicity in p53-null H1299 cells with stable expression of ectopic p53. In this work, we further demonstrated that dominant-negative Akt (S473A) or p53 shRNA inhibited ellipticine-mediated translocalization of p53 and Akt and attenuated apoptotic cell death in A549 cells. The presence of p53 predates ellipticine-mediated apoptotic cell death, assists in nucleus translocation of phosphorylated Akt and activation of autophagy pathway. Growth inhibition through collaborating p53 and phosphorylated Akt(473) in lung epithelial cancer cells provided a new perspective of the topoisomerase inhibitor as an effective cancer therapy agent. PMID- 26014913 TI - Centrin-2 (Cetn2) mediated regulation of FGF/FGFR gene expression in Xenopus. AB - Centrins (Cetns) are highly conserved, widely expressed, and multifunctional Ca(2+)-binding eukaryotic signature proteins best known for their roles in ciliogenesis and as critical components of the global genome nucleotide excision repair system. Two distinct Cetn subtypes, Cetn2-like and Cetn3-like, have been recognized and implicated in a range of cellular processes. In the course of morpholino-based loss of function studies in Xenopus laevis, we have identified a previously unreported Cetn2-specific function, namely in fibroblast growth factor (FGF) mediated signaling, specifically through the regulation of FGF and FGF receptor RNA levels. Cetn2 was found associated with the RNA polymerase II binding sites of the Cetn2-regulated FGF8 and FGFR1a genes, but not at the promoter of a gene (BMP4) whose expression was altered indirectly in Cent2 morphant embryos. These observations point to a previously unexpected role of Cetn2 in the regulation of gene expression and embryonic development. PMID- 26014914 TI - A story told by a single nanoparticle in the body fluid: demonstration of dissolution-reprecipitation of nanocrystals in a biological system. AB - AIM: Analysis of the chemical composition of mineral particles found in the body is critical to understand the formation and effects of these entities in vivo. Yet, the possibility that biological fluids may modulate particle composition over time has not been examined. Materials & methods: Mineralo-organic nanoparticles similar to the ones that spontaneously form in human tissues were analyzed using electron microscopy, spectroscopy and proteomic analyses. RESULTS: We show that the mineralo-organic nanoparticles assimilate various ions and minerals during incubation in ionic solutions simulating body fluids. The particles undergo dissolution-reprecipitation reactions that affect the final protein composition of the particles. CONCLUSION: The reactions occurring at the mineral-water interface therefore modulate the ionic and organic composition of mineral nanoparticles formed in biological fluids, producing changes that may alter the effects of mineral particles and stones in vivo. PMID- 26014915 TI - Conjugation of photosensitisers to antimicrobial peptides increases the efficiency of photodynamic therapy in cancer cells. AB - Some antimicrobial peptides (AMPs) have the ability to penetrate and kill not only pathogenic microorganisms but also cancer cells, while they are less active toward normal eukaryotic cells. Here we have investigated the potential of three AMPs, namely apidaecin 1b (Api), magainin 2 (Mag) and buforin II (Buf), as carriers of drugs for cancer cells by using the hydrophobic photosensitiser 5-(4 carboxyphenyl)-10,15,20-triphenylporphyrin (cTPP) as the drug model, conjugated to the N-terminus of the peptides. Flow cytometry measurements demonstrated that conjugation of cTPP increased its rate and efficiency of uptake in A549 human lung adenocarcinoma cells in the order Mag > Buf > Api. In vitro photodynamic therapy (PDT) experiments showed that the increased uptake of the conjugated cTPP determined 100% cell killing at concentrations in the nanomolar range while micromolar concentrations were required for the same killing effect with unconjugated cTPP. Serum proteins interacted with cTPP conjugated to Buf and Api and slightly interfered with the cellular uptake of these conjugates but not with that of Mag. The data suggest electrostatic interactions of the conjugates with sialic acid and ganglioside rich domains, as lipid rafts of the plasma membrane, followed by cell internalization via non-caveolar dynamin-dependent endocytosis as indicated by the effects of inhibitors of specific endocytic pathways. Our study demonstrated that the three AMPs investigated, Mag in particular, have the ability to carry a hydrophobic cargo inside cancer cells and may therefore represent useful carriers of anticancer drugs, especially those with a poor capacity to penetrate inside the target cells. PMID- 26014916 TI - Predictors of Opioid-Related Death During Methadone Therapy. AB - We aimed to examine pharmacologic, demographic and medical comorbidity risk factors for opioid-related mortality among patients currently receiving methadone for an opioid use disorder. We conducted a population-based, nested case-control study linking healthcare and coroner's records in Ontario, Canada, from January 31, 1994 to December 31, 2010. We included social assistance recipients receiving methadone for an opioid use disorder. Within this group, cases were those who died of opioid-related causes. For each case, we identified up to 5 controls matched on calendar quarter. The primary analysis examined the association between use of psychotropic drugs (benzodiazepines, antidepressants or antipsychotics) and opioid-related mortality. Secondary analyses examined the associations between baseline characteristics, health service utilization, comorbidities and opioid-related mortality. Among 43,545 patients receiving methadone for an opioid use disorder, we identified 175 (0.4%) opioid-related deaths, along with 873 matched controls. Psychotropic drug use was associated with a two fold increased risk of opioid-related death (adjusted odds ratio (OR) 2.0; 95% confidence interval (CI) 1.2 to 3.5). Specifically, benzodiazepines (adjusted OR 1.6; 95% CI 1.1 to 2.5) and antipsychotics (adjusted OR 2.3; 95% CI 1.5 to 3.5) were independently associated with opioid-related death. Other associated factors included chronic lung disease (adjusted OR 1.7; 95% CI 1.2 to 2.6), an alcohol use disorder (adjusted OR 1.9; 95% CI 1.2 to 3.2), mood disorders (adjusted OR 1.8; 95% CI 1.0 to 3.2), and a history of heart disease (adjusted OR 5.3; 95% CI 2.0 to 14.0). Psychotropic drug use is associated with opioid-related death in patients receiving methadone. Mindfulness of these factors may reduce the risk of death among methadone recipients. PMID- 26014917 TI - Experimental model for peanut allergy by epicutaneous sensitization in atopic beagle dogs. PMID- 26014918 TI - Effects of the innervation zone on the time and frequency domain parameters of the surface electromyographic signal. AB - The purposes of the present study were to examine the effects of electrode placements over, proximal, and distal to the innervation zone (IZ) on electromyographic (EMG) amplitude (RMS) and frequency (MPF) responses during: (1) a maximal voluntary isometric contraction (MVIC), and; (2) a sustained, submaximal isometric muscle action. A linear array was used to record EMG signals from the vastus lateralis over the IZ, 30mm proximal, and 30mm distal to the IZ during an MVIC and a sustained isometric muscle action of the leg extensors at 50% MVIC. During the MVIC, lower EMG RMS (p>0.05) and greater EMG MPF (p<0.05) values were recorded over the IZ compared to away from the IZ, however, no differences in slope coefficients for the EMG RMS and MPF versus time relationships over, proximal, and distal to the IZ occurred. Thus, the results of the present study indicated that during an MVIC, EMG RMS and MPF values recorded over the IZ are not comparable to those away from the IZ. However, the rates of fatigue-induced changes in EMG RMS and MPF during sustained, submaximal isometric muscle actions of the leg extensors were the same regardless of the electrode placement locations relative to the IZ. PMID- 26014919 TI - Dual Hypervalent Iodine(III) Reagents and Photoredox Catalysis Enable Decarboxylative Ynonylation under Mild Conditions. AB - A combination of hypervalent iodine(III) reagents (HIR) and photoredox catalysis with visible light has enabled chemoselective decarboxylative ynonylation to construct ynones, ynamides, and ynoates. This ynonylation occurs effectively under mild reaction conditions at room temperature and on substrates with various sensitive and reactive functional groups. The reaction represents the first HIR/photoredox dual catalysis to form acyl radicals from alpha-ketoacids, followed by an unprecedented acyl radical addition to HIR-bound alkynes. Its efficient construction of an mGlu5 receptor inhibitor under neutral aqueous conditions suggests future visible-light-induced biological applications. PMID- 26014920 TI - An evolutionary insight into Newcastle disease viruses isolated in Antarctica. AB - The disease caused by Newcastle disease virus (NDV) is a severe threat to the poultry industry worldwide. Recently, NDV has been isolated in the Antarctic region. Detailed studies on the mode of evolution of NDV strains isolated worldwide are relevant for our understanding of the evolutionary history of NDV. For this reason, we have performed Bayesian coalescent analysis of NDV strains isolated in Antarctica to study evolutionary rates, population dynamics, and patterns of evolution. Analysis of F protein cleavage-site sequences of NDV isolates from Antarctica suggested that these strains are lentogenic. Strains isolated in Antarctica and genotype I reference strain Ulster/67 diverged from ancestors that existed around 1958. The time of the most recent common ancestor (MRCA) was established to be around 1883 for all class II viruses. A mean rate of evolution of 1.78 * 10(-3) substitutions per site per year (s/s/y) was obtained for the F gene sequences of NDV strains examined in this study. A Bayesian skyline plot indicated a decline in NDV population size in the last 25 years. The results are discussed in terms of the possible role of Antarctica in emerging or re-emerging viruses and the evolution of NDV populations worldwide. PMID- 26014921 TI - Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice. AB - Acute hyperglycemia during acute myocardial infarction is associated with worse myocardial injury and increased mortality. Using a mouse model of myocardial ischemia/reperfusion injury, we tested the hypothesis that acute hyperglycemia activates splenic leukocytes and subsequently exacerbates myocardial infarct size. We then examined whether the adverse effects of hyperglycemia could be attenuated by a potent anti-inflammatory agent (an agonist of the adenosine A2A receptor) administered immediately prior to reperfusion. C57BL6 (WT) mice underwent 30-min LAD occlusion and 60-min reperfusion with or without prior splenectomy. Acute hyperglycemia before ischemia increased myocardial infarct size (IS) by 43% (p < 0.05). Splenectomy before ischemia did not change IS (vs. control, p = NS) but did serve to prevent the exacerbation of IS by hyperglycemia. Acute hyperglycemia activated splenic leukocytes by increasing formyl peptide receptor expression and reactive oxygen species production before ischemia, and enhanced splenic neutrophil release with resultant peripheral neutrophilia and increased myocardial neutrophil infiltration during reperfusion. Acute adoptive transfer of splenic leukocytes to splenectomized mice before ischemia restored the hyperglycemic exacerbation of infarct size. ATL146e, an adenosine 2A receptor (A2AR) agonist, abolished neutrophilia during reperfusion and reduced IS in hyperglycemic mice. ATL146e also reduced IS in splenectomized hyperglycemic mice with transfer of WT splenic leukocytes, but not with transfer of splenic leukocytes from A2AR knockout mice. Acute hyperglycemia prior to myocardial ischemia and reperfusion exacerbates IS by activating splenic leukocytes. ATL146e administered at reperfusion suffices to abrogate the hyperglycemic exacerbation of IS by acting on A2ARs on splenic leukocytes. PMID- 26014922 TI - The cell as the mechanistic basis for evolution. AB - The First Principles for Physiology originated in and emanate from the unicellular state of life. Viewing physiology as a continuum from unicellular to multicellular organisms provides fundamental insight to ontogeny and phylogeny as a functionally integral whole. Such mechanisms are most evident under conditions of physiologic stress; all of the molecular pathways that evolved in service to the vertebrate water-land transition aided and abetted the evolution of the vertebrate lung, for example. Reduction of evolution to cell biology has an important scientific feature-it is predictive. One implication of this perspective on evolution is the likelihood that it is the unicellular state that is actually the object of selection. By looking at the process of evolution from its unicellular origins, the causal relationships between genotype and phenotype are revealed, as are many other aspects of physiology and medicine that have remained anecdotal and counter-intuitive. Evolutionary development can best be considered as a cyclical, epigenetic, reiterative environmental assessment process, originating from the unicellular state, both forward and backward, to sustain and perpetuate unicellular homeostasis. PMID- 26014923 TI - Positive control radiographs for identifying a suspected retained surgical item. PMID- 26014924 TI - Studies of the CETP TaqIB and ApoE Polymorphisms in Southern Thai Subjects with the Metabolic Syndrome. AB - Several genetic factors have been investigated responsible for metabolic syndrome (MetS). The aim of this study was to investigate the association between cholesteryl ester transfer protein (CETP) TaqIB and apolipoprotein E (ApoE) polymorphisms and MetS in 378 subjects from Southern Thailand. Subjects were divided into MetS+ (n = 121) and MetS- (n = 257) groups according to the criteria of National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII). The CETP TaqIB and ApoE polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Logistic regression analysis revealed no association of CETP TaqIB and ApoE variants with MetS, after adjustment for age and sex. However, epsilon4 allele had a significantly increased odds ratio (OR) of reduced high-density lipoprotein cholesterol (HDL-C) levels when compared with epsilon3 allele (OR 1.91; 95% CI 1.11-3.29, p = 0.020). This suggests that CETP TaqIB and ApoE polymorphisms may not be considered as genetic risk factors for MetS in a Southern Thai population. However, epsilon4 allele which is associated with one metabolic component, low HDL-C levels, might predispose the subjects to develop metabolic disturbances. PMID- 26014925 TI - Relationship of MTHFR and NQO1 Pharmacogenetics and Chemotherapy Clinical Outcomes in Breast Cancer Patients. AB - The study aimed at evaluating the influence of MTHFR 677C>T and NQO1 609C>T polymorphisms in toxicity and response to chemotherapy in breast cancer patients. These two genes are involved in the folate homeostasis and bioactivation of chemotherapeutic drugs, respectively. In this study, 243 patients treated with FEC/FAC/methotrexate chemotherapy regimen were recruited and followed up for toxicity (NCI-CTCAE ver. 3). While out of 243 patients, 115 patients who received neo-adjuvant chemotherapy (NACT) were followed for treatment response. Genetic analysis of MTHFR 677C>T and NQO1 609C>T was done by PCR-restriction fragment length polymorphism. We found significant association of variant genotype (TT) of NQO1 609C>T with grade 2-4 toxicity [OR 0.33 (0.13-0.88), P = 0.027] and with grade 2-4 anemia [OR 0.34 (0.12-0.95), P = 0.041]. However, no association of MTHFR 677C>T was seen with either response to NACT or drug-induced toxicity. The study provides useful information for prediction of clinical outcomes in breast cancer patients in terms of NQO1 609C>T by evaluating its association with chemotherapy-induced toxicity. PMID- 26014926 TI - Effect of early addition of bone morphogenetic protein 5 (BMP5) to embryo culture medium on in vitro development and expression of developmentally important genes in bovine preimplantation embryos. AB - Previous studies have reported that bone morphogenetic protein 5 (BMP5) is differentially expressed in the isthmus of bovine oviducts and it is present in the oviductal fluid. However, the specific action of this factor is unknown. To evaluate whether BMP5 exerts some effect during early bovine embryo development, gene expression of BMP5, BMP receptors, and the effect of exogenous BMP5 on in vitro development and expression of developmentally important genes were assessed. In experiment 1, pools of embryos at two-cell, four-cell, eight-cell, and blastocyst stages, derived from in vitro fertilization, were collected for analysis of BMP5 and BMP receptors (BMPR1A, BMPR1B, and BMPR2) messenger RNA (mRNA) expression. On the basis of previous results, in experiment 2, presumptive zygotes were cultured for the first 48 hours after insemination in CR1aa medium assaying three different treatments: (1) control (CR1aa); (2) vehicle control (CR1aa + 0.04 mM HCl), and (3) BMP5 treatment (CR1aa + 100 ng/mL of BMP5). The cleavage rate was evaluated 48 hours after insemination (Day 2), and then, embryos were transferred to CR1aa + 10% fetal bovine serum. The blastocyst rate was determined on Day 7. In experiment 3, pools of embryos at two-cell, four cell, eight-cell, and blastocyst stages, derived from control and BMP5-treated groups, were collected for analysis of ID2 (BMP target gene), OCT4, NANOG, and SOX2 (pluripotency genes) mRNA expression. BMP5 transcripts were not detectable in any of the embryonic stages examined, whereas the relative mRNA abundance of the three BMP receptors analyzed was greater in early embryo development stages before maternal-embryonic transition, raising the possibility of a direct effect of exogenous BMPs on the embryo during the first developmental period. Although early addition of 100 ng/mL of BMP5 to the embryo culture medium had no effect on the cleavage rate, a significantly higher proportion of cleaved embryos developed to the blastocyst stage in the BMP5 group. Moreover, reverse transcription quantitative real-time polymerase chain reaction analysis showed a significant increase in the relative abundance of SOX2 in two-cell stage embryos, ID2 and OCT4 in eight-cell stage embryos, and NANOG and OCT4 in blastocysts derived from BMP5-treated embryos. In conclusion, our results report that early addition of BMP5 to the embryo culture medium had a positive effect on the blastocyst rate and affected the relative expression of BMP target and pluripotency genes, suggesting that BMP5 could play an important role in the preimplantation development of bovine embryos. PMID- 26014927 TI - First Report of OXA-181-Producing Escherichia coli in China and Characterization of the Isolate Using Whole-Genome Sequencing. AB - We report the first OXA-181-producing strain in China. blaOXA-181 was found in sequence type 410 (ST410) Escherichia coli strain WCHEC14828 from a Chinese patient without recent travel history. Genome sequencing and conjugation experiments were performed. blaOXA-181 was carried on a 51-kb self-transmissible IncX3 plasmid and was linked with qnrS1, a quinolone resistance gene. blaOXA-181 was introduced onto the IncX3 plasmid from a ColE2-type plasmid, and IncX3 plasmids have the potential to mediate the dissemination of blaOXA-181. PMID- 26014928 TI - Comparative Evaluation of Colistin Susceptibility Testing Methods among Carbapenem-Nonsusceptible Klebsiella pneumoniae and Acinetobacter baumannii Clinical Isolates. AB - We compared six colistin susceptibility testing (ST) methods on 61 carbapenem nonsusceptible Klebsiella pneumoniae (n = 41) and Acinetobacter baumannii (n = 20) clinical isolates with provisionally elevated colistin MICs by routine ST. Colistin MICs were determined by broth microdilution (BMD), BMD with 0.002% polysorbate 80 (P80) (BMD-P80), agar dilution (AD), Etest, Vitek2, and MIC test strip (MTS). BMD was used as the reference method for comparison. The EUCAST recommended susceptible and resistant breakpoints of <=2 and >2 MUg/ml, respectively, were applied for both K. pneumoniae and A. baumannii. The proportions of colistin-resistant strains were 95.1, 77, 96.7, 57.4, 65.6, and 98.4% by BMD, BMD-P80, AD, Etest, MTS, and Vitek2, respectively. The Etest and MTS methods produced excessive rates of very major errors (VMEs) (39.3 and 31.1%, respectively), while BMD-P80 produced 18% VMEs, AD produced 3.3% VMEs, and Vitek2 produced no VMEs. Major errors (MEs) were rather limited by all tested methods. These data show that gradient diffusion methods may lead to inappropriate colistin therapy. Clinical laboratories should consider the use of automated systems, such as Vitek2, or dilution methods for colistin ST. PMID- 26014929 TI - Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells. AB - Borrelia burgdorferi is the causative agent of Lyme disease, which affects an estimated 300,000 people annually in the United States. When treated early, the disease usually resolves, but when left untreated, it can result in symptoms such as arthritis and encephalopathy. Treatment of the late-stage disease may require multiple courses of antibiotic therapy. Given that antibiotic resistance has not been observed for B. burgdorferi, the reason for the recalcitrance of late-stage disease to antibiotics is unclear. In other chronic infections, the presence of drug-tolerant persisters has been linked to recalcitrance of the disease. In this study, we examined the ability of B. burgdorferi to form persisters. Killing growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from the exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary-phase cells but not persisters. Mitomycin C, an anticancer agent that forms adducts with DNA, killed persisters and eradicated growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and the antibiotic was added again. Four pulse doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture. PMID- 26014930 TI - In Vitro and In Vivo Efficacy of Amphotericin B Combined with Posaconazole against Experimental Disseminated Sporotrichosis. AB - We evaluated the combination of posaconazole with amphotericin B in vitro and in a murine model of systemic infections caused by Sporothrix brasiliensis and Sporothrix schenckii sensu stricto. In vitro data demonstrated a synergistic effect, and although posaconazole alone was effective against sporotrichosis, efficacy in terms of survival and burden reduction was increased with the combination. This combination might be an option against disseminated sporotrichosis, especially when itraconazole or amphotericin B at optimal doses are contraindicated. PMID- 26014931 TI - Activity of Imipenem with Relebactam against Gram-Negative Pathogens from New York City. AB - Imipenem with relebactam was active against Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp., including K. pneumoniae carbapenemase (KPC) producing isolates. Loss of OmpK36 in KPC-producing K. pneumoniae isolates affected the susceptibility of this combination. Enhanced activity was evident against Pseudomonas aeruginosa, including isolates with depressed oprD and increased ampC expression. However, the addition of relebactam to imipenem did not provide added benefit against Acinetobacter baumannii. The combination of imipenem with relebactam demonstrated activity against KPC-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa. PMID- 26014932 TI - The Monoterpene Carvacrol Generates Endoplasmic Reticulum Stress in the Pathogenic Fungus Candida albicans. AB - The monoterpene carvacrol, the major component of oregano and thyme oils, is known to exert potent antifungal activity against the pathogenic yeast Candida albicans. This monoterpene has been the subject of a considerable number of investigations that uncovered extensive pharmacological properties, including antifungal and antibacterial effects. However, its mechanism of action remains elusive. Here, we used integrative chemogenomic approaches, including genome scale chemical-genetic and transcriptional profiling, to uncover the mechanism of action of carvacrol associated with its antifungal property. Our results clearly demonstrated that fungal cells require the unfolded protein response (UPR) signaling pathway to resist carvacrol. The mutants most sensitive to carvacrol in our genome-wide competitive fitness assay in the yeast Saccharomyces cerevisiae expressed mutations of the transcription factor Hac1 and the endonuclease Ire1, which is required for Hac1 activation by removing a nonconventional intron from the 3' region of HAC1 mRNA. Confocal fluorescence live-cell imaging revealed that carvacrol affects the morphology and the integrity of the endoplasmic reticulum (ER). Transcriptional profiling of pathogenic yeast C. albicans cells treated with carvacrol demonstrated a bona fide UPR transcriptional signature. Ire1 activity detected by the splicing of HAC1 mRNA in C. albicans was activated by carvacrol. Furthermore, carvacrol was found to potentiate antifungal activity of the echinocandin antifungal caspofungin and UPR inducers dithiothreitol and tunicamycin against C. albicans. This comprehensive chemogenomic investigation demonstrated that carvacrol exerts its antifungal activity by altering ER integrity, leading to ER stress and the activation of the UPR to restore protein folding homeostasis. PMID- 26014933 TI - Effects of a Mutation in the gyrA Gene on the Virulence of Uropathogenic Escherichia coli. AB - Fluoroquinolones are among the drugs most extensively used for the treatment of bacterial infections in human and veterinary medicine. Resistance to quinolones can be chromosome or plasmid mediated. The chromosomal mechanism of resistance is associated with mutations in the DNA gyrase- and topoisomerase IV-encoding genes and mutations in regulatory genes affecting different efflux systems, among others. We studied the role of the acquisition of a mutation in the gyrA gene in the virulence and protein expression of uropathogenic Escherichia coli (UPEC). The HC14366M strain carrying a mutation in the gyrA gene (S83L) was found to lose the capacity to cause cystitis and pyelonephritis mainly due to a decrease in the expression of the fimA, papA, papB, and ompA genes. The levels of expression of the fimA, papB, and ompA genes were recovered on complementing the strain with a plasmid containing the gyrA wild-type gene. However, only a slight recovery was observed in the colonization of the bladder in the GyrA complement strain compared to the mutant strain in a murine model of ascending urinary tract infection. In conclusion, a mutation in the gyrA gene of uropathogenic E. coli reduced the virulence of the bacteria, likely in association with the effect of DNA supercoiling on the expression of several virulence factors and proteins, thereby decreasing their capacity to cause cystitis and pyelonephritis. PMID- 26014934 TI - Dissemination of IncI2 Plasmids That Harbor the blaCTX-M Element among Clinical Salmonella Isolates. AB - The extended-spectrum-beta-lactamase (ESBL) determinant CTX-M-55 is increasingly prevalent in Escherichia coli but remains extremely rare in Salmonella. This study reports the isolation of a plasmid harboring the blaCTX-M-55 element in a clinical Salmonella enterica serotype Typhimurium strain resistant to multiple antibiotics. This plasmid is genetically identical to several known IncI2-type elements harbored by E. coli strains recovered from animals. This finding indicates that IncI2 plasmids harboring the blaCTX-M genes may undergo cross species migration among potential bacterial pathogens, with E. coli as the major source of such elements. PMID- 26014935 TI - Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway. AB - Acanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time- and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections. PMID- 26014936 TI - Limited Ability of Posaconazole To Cure both Acute and Chronic Trypanosoma cruzi Infections Revealed by Highly Sensitive In Vivo Imaging. AB - The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo and ex vivo imaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole was found to be significantly inferior to benznidazole as a treatment for both acute and chronic T. cruzi infections. Whereas 20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment of chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with posaconazole in the acute, but not the chronic stage of infection. This in vivo screening model for Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial. PMID- 26014937 TI - Validation of Sensititre Dry-Form Broth Microdilution Panels for Susceptibility Testing of Ceftazidime-Avibactam, a Broad-Spectrum-beta-Lactamase Inhibitor Combination. AB - Ceftazidime-avibactam is a broad-spectrum-beta-lactamase inhibitor combination in late-stage clinical development for the treatment of serious infections. In preparation for clinical microbiology laboratory use, a validation experiment was initiated to evaluate a commercial broth microdilution product (Sensititre dried MIC susceptibility system) compared to reference panels using 525 recent clinical isolates. Among 11 pathogen groups, all had Sensititre MIC/reference MIC ratios predominantly at 1 (47.5% to 97.5%), and automated and manual endpoint results did not differ. Enterobacteriaceae MIC comparisons showed a modest skewing of Sensititre MIC results toward an elevated MIC (33.9%), but the essential agreement was 98.9% with 100.0% reproducibility. In conclusion, Sensititre panels produced accurate ceftazidime-avibactam MIC results, allowing quality MIC guidance for therapy following regulatory approvals. PMID- 26014938 TI - Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. AB - The continuous emergence of multidrug-resistant pathogenic bacteria is compromising the successful treatment of serious microbial infections. GSK1322322, a novel peptide deformylase (PDF) inhibitor, shows good in vitro antibacterial activity and has demonstrated safety and efficacy in human proof-of concept clinical studies. In vitro studies were performed to determine the frequency of resistance (FoR) to this antimicrobial agent in major pathogens that cause respiratory tract and skin infections. Resistance to GSK1322322 occurred at high frequency through loss-of-function mutations in the formyl-methionyl transferase (FMT) protein in Staphylococcus aureus (4/4 strains) and Streptococcus pyogenes (4/4 strains) and via missense mutations in Streptococcus pneumoniae (6/21 strains), but the mutations were associated with severe in vitro and/or in vivo fitness costs. The overall FoR to GSK1322322 was very low in Haemophilus influenzae, with only one PDF mutant being identified in one of four strains. No target-based mutants were identified from S. pyogenes, and only one or no PDF mutants were isolated in three of the four S. aureus strains studied. In S. pneumoniae, PDF mutants were isolated from only six of 21 strains tested; an additional 10 strains did not yield colonies on GSK1322322-containing plates. Most of the PDF mutants characterized from those three organisms (35/37 mutants) carried mutations in residues at or in close proximity to one of three highly conserved motifs that are part of the active site of the PDF protein, with 30 of the 35 mutations occurring at position V71 (using the S. pneumoniae numbering system). PMID- 26014939 TI - Flow Cytometry-Based Method To Detect Persisters in Candida albicans. AB - Candida albicans biofilms contain a subpopulation whose members are defined as persisters, displaying great tolerance of fungicides. To directly observe such persisters, an effective method using green fluorescent protein (GFP) strain labeling by mutation of the gene encoding glyceraldehyde-3-phosphate dehydrogenase (TDH3), combined with propidium iodide (PI) staining, was established. Amphotericin B-tolerant persisters harbor the characteristics of both GFP positivity [GFP (+)] and propidium iodide (PI) negativity [PI (-)], which are easily visualized using a fluorescence microscope and measured by flow cytometry. PMID- 26014940 TI - Effect of Lactobacillus rhamnosus GG Administration on Vancomycin-Resistant Enterococcus Colonization in Adults with Comorbidities. AB - Vancomycin-resistant enterococci (VRE) are endemic in health care settings. These organisms colonize the gastrointestinal tract and can lead to infection which is associated with increased mortality. There is no treatment for VRE colonization. We conducted a randomized, double-blind, placebo-controlled clinical trial to examine the safety and efficacy of administration of the probiotic Lactobacillus rhamnosus GG (LGG) for the reduction or elimination of intestinal colonization by VRE. Colonized adults were randomized to receive LGG or placebo for 14 days. Quantitative stool cultures for LGG and VRE were collected at baseline and days 7, 14, 21, 28, and 56. Day 14 stool samples from some subjects were analyzed by quantitative PCR (qPCR) for LGG. Patients were closely monitored for adverse events. Eleven subjects, of whom 5 received LGG and 6 received placebo, were analyzed. No differences in VRE colony counts were seen at any time points between groups. No decline in colony counts was seen over time in subjects who received LGG. LGG was detected by PCR in all samples tested from subjects who received LGG but was only isolated in culture from 2 of 5 subjects in the LGG group. No treatment-related adverse events were seen. We demonstrated that LGG could be administered safely to patients with comorbidities and is recoverable in some patients' stool cultures. Concomitant administration of antibiotics may have resulted in an inability to recover viable organisms from stool samples, but LGG DNA could still be detected by qPCR. LGG administration did not affect VRE colonization in this study. (This study was registered at Clinicaltrials.gov under registration no. NCT00756262.). PMID- 26014941 TI - Characterization of Poliovirus Neutralization Escape Mutants of Single-Domain Antibody Fragments (VHHs). AB - To complete the eradication of poliovirus and to protect unvaccinated people subsequently, the development of one or more antiviral drugs will be necessary. A set of five single-domain antibody fragments (variable parts of the heavy chain of a heavy-chain antibody [VHHs]) with an in vitro neutralizing activity against poliovirus type 1 was developed previously (B. Thys, L. Schotte, S. Muyldermans, U. Wernery, G. Hassanzadeh-Ghassabeh, and B. Rombaut, Antiviral Res 87:257-264, 2010, http://dx.doi.org/10.1016/j.antiviral.2010.05.012), and their mechanisms of action have been studied (L. Schotte, M. Strauss, B. Thys, H. Halewyck, D. J. Filman, M. Bostina, J. M. Hogle, and B. Rombaut, J Virol 88:4403-4413, 2014, http://dx.doi.org/10.1128/JVI.03402-13). In this study, neutralization escape mutants were selected for each VHH. Sequencing of the P1 region of the genome showed that amino acid substitutions are found in the four viral proteins of the capsid and that they are located both in proximity to the binding sites of the VHHs and in regions further away from the canyon and hidden beneath the surface. Characterization of the mutants demonstrated that they have single-cycle replication kinetics that are similar to those of their parental strain and that they are all drug (VHH) independent. Their resistant phenotypes are stable, as they do not regain full susceptibility to the VHH after passage over HeLa cells in the absence of VHH. They are all at least as stable as the parental strain against heat inactivation at 44 degrees C, and three of them are even significantly (P < 0.05) more resistant to heat inactivation. The resistant variants all still can be neutralized by at least two other VHHs and retain full susceptibility to pirodavir and 35-1F4. PMID- 26014943 TI - In Vitro Triple Combination of Antifungal Drugs against Clinical Scopulariopsis and Microascus Species. AB - Broth microdilution checkerboard techniques based on the methodology of the Clinical and Laboratory Standards Institute (CLSI) were employed to study the triple antifungal combination of caspofungin, posaconazole, and terbinafine against 27 clinical isolates of Scopulariopsis and Microascus species. Synergy was observed for 26 isolates, whereas antagonism was observed for Scopulariopsis candida in this study. PMID- 26014942 TI - Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance. AB - Cambodia's first-line artemisinin combination therapy, dihydroartemisinin piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure. PMID- 26014944 TI - Antibiofilm Activity of Low-Amperage Continuous and Intermittent Direct Electrical Current. AB - Bacterial biofilms are difficult to treat using available antimicrobial agents, so new antibiofilm strategies are needed. We previously showed that 20, 200, and 2,000 MUA of electrical current reduced bacterial biofilms of Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. Here, we tested continuous direct current at lower amperages, intermittent direct current, and combinations of surface materials (Teflon or titanium) and electrode compositions (stainless steel, graphite, titanium, or platinum) against S. aureus, S. epidermidis, and P. aeruginosa biofilms. In addition, we tested 200 or 2,000 MUA for 1 and 4 days against biofilms of 33 strains representing 13 species of microorganisms. The logarithmic reduction factor was used to measure treatment effects. Using continuous current delivery, the lowest active amperage was 2 MUA for 1, 4, or 7 days against P. aeruginosa and 5 MUA for 7 days against S. epidermidis and S. aureus biofilms. Delivery of 200 MUA for 4 h a day over 4 days reduced P. aeruginosa, S. aureus, and S. epidermidis biofilms on Teflon or titanium discs. A reduction of P. aeruginosa, S. aureus, and S. epidermidis biofilms was measured for 23 of 24 combinations of surface materials and electrode compositions tested. Four days of direct current delivery reduced biofilms of 25 of 33 strains studied. In conclusion, low-amperage current or 4 h a day of intermittent current delivered using a variety of electrode compositions reduced P. aeruginosa, S. aureus, and S. epidermidis biofilms on a variety of surface materials. The electricidal effect was observed against a majority of bacterial species studied. PMID- 26014945 TI - Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease. AB - Acetylation of lysine is a major posttranslational modification of proteins and is catalyzed by lysine acetyltransferases, while lysine deacetylases remove acetyl groups. Among the deacetylases, the sirtuins are NAD(+)-dependent enzymes, which modulate gene silencing, DNA damage repair, and several metabolic processes. As sirtuin-specific inhibitors have been proposed as drugs for inhibiting the proliferation of tumor cells, in this study, we investigated the role of these inhibitors in the growth and differentiation of Trypanosoma cruzi, the agent of Chagas disease. We found that the use of salermide during parasite infection prevented growth and initial multiplication after mammalian cell invasion by T. cruzi at concentrations that did not affect host cell viability. In addition, in vivo infection was partially controlled upon administration of salermide. There are two sirtuins in T. cruzi, TcSir2rp1 and TcSir2rp3. By using specific antibodies and cell lines overexpressing the tagged versions of these enzymes, we found that TcSir2rp1 is localized in the cytosol and TcSir2rp3 in the mitochondrion. TcSir2rp1 overexpression acts to impair parasite growth and differentiation, whereas the wild-type version of TcSir2rp3 and not an enzyme mutated in the active site improves both. The effects observed with TcSir2rp3 were fully reverted by adding salermide, which inhibited TcSir2rp3 expressed in Escherichia coli with a 50% inhibitory concentration (IC50) +/- standard error of 1 +/- 0.5 MUM. We concluded that sirtuin inhibitors targeting TcSir2rp3 could be used in Chagas disease chemotherapy. PMID- 26014946 TI - A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients. AB - De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum beta-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum beta-lactam antibiotics and narrower spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure (n = 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics. PMID- 26014947 TI - In Vitro Susceptibility of Leishmania infantum to Artemisinin Derivatives and Selected Trioxolanes. AB - Leishmaniasis is among the world's most neglected diseases. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. A small library of artemisinin-derived trioxanes and synthetic trioxolanes was tested against promastigote and intramacrophage amastigote forms of Leishmania infantum. The trioxolanes LC50 and LC95 presented the best activity and safety profiles, showing potential for further studies in the context of leishmanial therapy. Our results indicate that the compounds tested exhibit peroxide-dependent activity. PMID- 26014948 TI - Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14alpha-Demethylase (CYP51). AB - In this study, we investigate the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. Amebicidal activities of the triazoles were assessed by in vitro minimum inhibition concentration (MIC) determinations using trophozoites of A. castellanii and A. polyphaga. In addition, triazole effectiveness was assessed by ligand binding studies and inhibition of CYP51 activity of purified A. castellanii CYP51 (AcCYP51) that was heterologously expressed in Escherichia coli. Itraconazole and voriconazole bound tightly to AcCYP51 (dissociation constant [Kd] of 10 and 13 nM), whereas fluconazole bound weakly (Kd of 2,137 nM). Both itraconazole and voriconazole were confirmed to be strong inhibitors of AcCYP51 activity (50% inhibitory concentrations [IC50] of 0.23 and 0.39 MUM), whereas inhibition by fluconazole was weak (IC50, 30 MUM). However, itraconazole was 8- to 16-fold less effective (MIC, 16 mg/liter) at inhibiting A. polyphaga and A. castellanii cell proliferation than voriconazole (MIC, 1 to 2 mg/liter), while fluconazole did not inhibit Acanthamoeba cell division (MIC, >64 mg/liter) in vitro. Voriconazole was an effective inhibitor of trophozoite proliferation for A. castellanii and A. polyphaga; therefore, it should be evaluated in trials versus itraconazole for controlling Acanthamoeba infections. PMID- 26014949 TI - Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment. AB - Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA) piperaquine (PP), the latest of the artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine, polymorphisms in the K13 gene, and the copy number of the Pfmdr-1 gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P <10( 3)). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM; P = 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele (odds ratio [OR], 17.5; 95% confidence interval [CI], 1 to 308; P = 0.04). Our data show evidence of P. falciparum resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.). PMID- 26014950 TI - Hsp70 and the Cochaperone StiA (Hop) Orchestrate Hsp90-Mediated Caspofungin Tolerance in Aspergillus fumigatus. AB - Aspergillus fumigatus is the primary etiologic agent of invasive aspergillosis (IA), a major cause of death among immunosuppressed patients. Echinocandins (e.g., caspofungin) are increasingly used as second-line therapy for IA, but their activity is only fungistatic. Heat shock protein 90 (Hsp90) was previously shown to trigger tolerance to caspofungin and the paradoxical effect (i.e., decreased efficacy of caspofungin at higher concentrations). Here, we demonstrate the key role of another molecular chaperone, Hsp70, in governing the stress response to caspofungin via Hsp90 and their cochaperone Hop/Sti1 (StiA in A. fumigatus). Mutation of the StiA-interacting domain of Hsp70 (C-terminal EELD motif) impaired thermal adaptation and caspofungin tolerance with loss of the caspofungin paradoxical effect. Impaired Hsp90 function and increased susceptibility to caspofungin were also observed following pharmacologic inhibition of the C-terminal domain of Hsp70 by pifithrin-MU or after stiA deletion, further supporting the links among Hsp70, StiA, and Hsp90 in governing caspofungin tolerance. StiA was not required for the physical interaction between Hsp70 and Hsp90 but had distinct roles in the regulation of their function in caspofungin and heat stress responses. In conclusion, this study deciphering the physical and functional interactions of the Hsp70-StiA-Hsp90 complex provided new insights into the mechanisms of tolerance to caspofungin in A. fumigatus and revealed a key C-terminal motif of Hsp70, which can be targeted by specific inhibitors, such as pifithrin-MU, to enhance the antifungal activity of caspofungin against A. fumigatus. PMID- 26014951 TI - Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii. AB - Cryptococcus gattii is the main etiological agent of cryptococcosis in immunocompetent individuals. The triazole drug itraconazole is one of the antifungals used to treat patients with cryptococcosis. Heteroresistance is an adaptive mechanism to counteract the stress of increasing drug concentrations, and it can enhance the ability of a microorganism to survive under antifungal pressure. In this study, we evaluated the ability of 11 C. gattii strains to develop itraconazole heteroresistance. Heteroresistant clones were analyzed for drug susceptibility, alterations in cell diameter, capsule properties, and virulence in a murine model. Heteroresistance to itraconazole was intrinsic in all of the strains analyzed, reduced both the capsule size and the cell diameter, induced molecular heterogeneity at the chromosomal level, changed the negatively charged cells, reduced ergosterol content, and improved the antioxidant system. A positive correlation between surface/volume ratio of original cells and the level of heteroresistance to itraconazole (LHI) was observed in addition to a negative correlation between capsule size of heteroresistant clones and LHI. Moreover, heteroresistance to itraconazole increased the engulfment of C. gattii by macrophages and augmented fungal proliferation inside these cells, which probably accounted for the reduced survival of the mice infected with the heteroresistant clones and the higher fungal burden in lungs and brain. Our results indicate that heteroresistance to itraconazole is intrinsic and increases the virulence of C. gattii. This phenomenon may represent an additional mechanism that contributes to relapses of cryptococcosis in patients during itraconazole therapy. PMID- 26014952 TI - RX-P873, a Novel Protein Synthesis Inhibitor, Accumulates in Human THP-1 Monocytes and Is Active against Intracellular Infections by Gram-Positive (Staphylococcus aureus) and Gram-Negative (Pseudomonas aeruginosa) Bacteria. AB - The pyrrolocytosine RX-P873, a new broad-spectrum antibiotic in preclinical development, inhibits protein synthesis at the translation step. The aims of this work were to study RX-P873's ability to accumulate in eukaryotic cells, together with its activity against extracellular and intracellular forms of infection by Staphylococcus aureus and Pseudomonas aeruginosa, using a pharmacodynamic approach allowing the determination of maximal relative efficacies (Emax values) and bacteriostatic concentrations (Cs values) on the basis of Hill equations of the concentration-response curves. RX-P873's apparent concentration in human THP 1 monocytes was about 6-fold higher than the extracellular one. In broth, MICs ranged from 0.125 to 0.5 mg/liter (S. aureus) and 2 to 8 mg/liter (P. aeruginosa), with no significant shift in these values against strains resistant to currently used antibiotics being noted. In concentration-dependent experiments, the pharmacodynamic profile of RX-P873 was not influenced by the resistance phenotype of the strains. Emax values (expressed as the decrease in the number of CFU from that in the initial inoculum) against S. aureus and P. aeruginosa reached more than 4 log units and 5 log units in broth, respectively, and 0.7 log unit and 2.7 log units in infected THP-1 cells, respectively, after 24 h. Cs values remained close to the MIC in all cases, making RX-P873 more potent than antibiotics to which the strains were resistant (moxifloxacin, vancomycin, and daptomycin for S. aureus; ciprofloxacin and ceftazidime for P. aeruginosa). Kill curves in broth showed that RX-P873 was more rapidly bactericidal against P. aeruginosa than against S. aureus. Taken together, these data suggest that RX-P873 may constitute a useful alternative for infections involving intracellular bacteria, especially Gram-negative species. PMID- 26014953 TI - Tailoring a Pediatric Formulation of Artemether-Lumefantrine for Treatment of Plasmodium falciparum Malaria. AB - Specially created pediatric formulations have the potential to improve the acceptability, effectiveness, and accuracy of dosing of artemisinin-based combination therapy (ACT) in young children, a patient group that is inherently vulnerable to malaria. Artemether-lumefantrine (AL) Dispersible is a pediatric formulation of AL that is specifically tailored for the treatment of children with uncomplicated Plasmodium falciparum malaria, offering benefits relating to efficacy, convenience and acceptance, accuracy of dosing, safety, sterility, stability, and a pharmacokinetic profile and bioequivalence similar to those of crushed and intact AL tablets. However, despite being the first pediatric antimalarial to meet World Health Organization (WHO) specifications for use in infants and children who are >=5 kg in body weight and its inclusion in WHO Guidelines, there are few publications that focus on AL Dispersible. Based on a systematic review of the recent literature, this paper provides a comprehensive overview of the clinical experience with AL Dispersible to date. A randomized, phase 3 study that compared the efficacy and safety of AL Dispersible to those of crushed AL tablets in 899 African children reported high PCR-corrected cure rates at day 28 (97.8% and 98.5% for AL Dispersible and crushed tablets, respectively), and the results of several subanalyses of these data indicate that this activity is observed regardless of patient weight, food intake, and maximum plasma concentrations of artemether or its active metabolite, dihydroartemisinin. These and other clinical data support the continued use of pediatric antimalarial formulations in all children <5 years of age with uncomplicated malaria when accompanied by continued monitoring for the emergence of resistance. PMID- 26014954 TI - Unprecedented Silver Resistance in Clinically Isolated Enterobacteriaceae: Major Implications for Burn and Wound Management. AB - Increased utilization of inorganic silver as an adjunctive to many medical devices has raised concerns of emergent silver resistance in clinical bacteria. Although the molecular basis for silver resistance has been previously characterized, to date, significant phenotypic expression of these genes in clinical settings is yet to be observed. Here, we identified the first strains of clinical bacteria expressing silver resistance at a level that could significantly impact wound care and the use of silver-based dressings. Screening of 859 clinical isolates confirmed 31 harbored at least 1 silver resistance gene. Despite the presence of these genes, MIC testing revealed most of the bacteria displayed little or no increase in resistance to ionic silver (200 to 300 MUM Ag(+)). However, 2 isolates (Klebsiella pneumonia and Enterobacter cloacae) were capable of robust growth at exceedingly high silver concentrations, with MIC values reaching 5,500 MUM Ag(+). DNA sequencing of these two strains revealed the presence of genes homologous to known genetic determinants of heavy metal resistance. Darkening of the bacteria's pigment was observed after exposure to high silver concentrations. Scanning electron microscopy images showed the presence of silver nanoparticles embedded in the extracellular polymeric substance of both isolates. This finding suggested that the isolates may neutralize ionic silver via reduction to elemental silver. Antimicrobial testing revealed both organisms to be completely resistant to many commercially available silver-impregnated burn and wound dressings. Taken together, these findings provide the first evidence of clinical bacteria capable of expressing silver resistance at levels that could significantly impact wound management. PMID- 26014955 TI - In Vivo Selection of Paromomycin and Miltefosine Resistance in Leishmania donovani and L. infantum in a Syrian Hamster Model. AB - In 2002 and 2006, respectively, miltefosine (MIL) and paromomycin (PMM) were licensed in the Indian subcontinent for treatment of visceral leishmaniasis; however, their future routine use might become jeopardized by the development of drug resistance. Although experimental selection of resistant strains in vitro has repeatedly been reported using the less relevant promastigote vector stage, the outcome of resistance selection on intracellular amastigotes was reported to be protocol and species dependent. To corroborate these in vitro findings, selection of resistance in Leishmania donovani and Leishmania infantum was achieved by successive treatment/relapse cycles in infected Syrian golden hamsters. For PMM, resistant amastigotes were already obtained within 3 treatment/relapse cycles, while their promastigotes retained full susceptibility, thereby sharing the same phenotypic characteristics as in vitro-generated PMM resistant strains. For MIL, even five treatment/relapse cycles failed to induce significant susceptibility changes in either species, which also corresponds with the in vitro observations where selection of an MIL-resistant phenotype proved to be quite challenging. In conclusion, these results argue for cautious use of PMM in the field to avoid rapid emergence of primary resistance and highlight the need for additional research on the mechanisms and dynamics of MIL resistance selection. PMID- 26014956 TI - Incidence, Predictors, and Impact on Hospital Mortality of Amphotericin B Nephrotoxicity Defined Using Newer Acute Kidney Injury Diagnostic Criteria. AB - Studies on amphotericin B (AmB) nephrotoxicity use diverse definitions of acute kidney injury (AKI). Here, we used the new Kidney Disease Improving Global Outcome (KDIGO) system to describe the incidence, predictors, and impact of AmB induced AKI on hospital mortality in 162 patients treated with AmB (120 with deoxycholate preparation and 42 with liposomal preparation). KDIGO stage 1 requires an absolute increase of >=0.3 mg/dl or >=1.5* over baseline serum creatinine (SCr), while stage 2 requires >=2*, and stage 3 requires >=3*. A binary KDIGO definition (KDIGObin) corresponds to stage >=1. For comparison, we included two definitions of AKI traditionally utilized in nephrotoxicity studies: >=0.5 mg/dl (NT0.5) and >=2* (NT2*) increase in baseline SCr. The overall incidence of AmB-induced AKI by KDIGObin was 58.6% (stage 1, 30.9%; stage 2, 18.5%; stage 3, 9.3%). Predictors of AKI by KDIGObin were older age and use of furosemide and angiotensin-converting enzyme inhibitor (ACE-I). Traditional criteria detected lower incidences of AKI, at 45.1% (NT0.5) and 27.8% (NT2*). Predictors of AKI by traditional criteria were older age and use of vancomycin (NT0.5) and use of vancomycin and vasopressors (NT2*). KDIGObin detected AKI 2 days earlier than the most sensitive traditional criterion. However, only traditional criteria were associated with intensive care unit (ICU) admission, mechanical ventilation, and mortality. In conclusion, the increase in sensitivity of KDIGObin is accompanied by a loss of specificity and ability to predict outcomes. Prospective studies are required to weigh the potential gain from early AKI detection against the potential loss from undue changes in management in patients with subtle elevations in SCr. PMID- 26014958 TI - Association between social capital and health in women of reproductive age: a population-based study. AB - Women's health is a public health priority. The origins of health inequalities are very complex. The present study was conducted to determine the association between social capital and health status in reproductive-age women in Tehran, Iran. In this population-based, cross-sectional study, the Social Capital Integrated Questionnaire, the SF-36 and socio-demographic questionnaires were used. Analysis of data by one-way ANOVA test and stepwise multiple linear regression showed that the manifestation dimensions of social capital (groups and networks, trust and solidarity, collective action and cooperation) can potentially lead to the outcome dimensions of social capital (social cohesion and inclusion, and empowerment and political action), which in turn affect health inequities after controlling for socio-demographic differences. PMID- 26014957 TI - Open-Label Study To Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants Less than 12 Weeks in Chronological Age. AB - Doripenem, a parenteral carbapenem with broad-spectrum activity against aerobic Gram-negative and Gram-positive and anaerobic pathogens, is currently approved for use in adults in the United States and European Union. Single-dose doripenem pharmacokinetics in 52 infants <12 weeks in chronological age were investigated in this phase 1 study. Hospitalized, medically stable infants <12 weeks in chronological age were stratified into 6 groups based on chronological and gestational age designed to reflect increasing renal maturation and decreasing volume of distribution (Vz) for beta-lactam antimicrobials during the first 3 months of life. Subjects received single-dose doripenem (5 mg/kg of body weight for <8 weeks and 8 mg/kg for >=8 weeks in chronological age) administered intravenously over 1 h. Plasma samples were obtained immediately before the end of the infusion and 1.5, 3, and 7 h after the start of the infusion. Urine was obtained by indwelling catheter during the 8 h following infusion. Doripenem showed linear pharmacokinetics across the 6 age groups. Neonates (<4 weeks in chronological age) had increased mean exposure (area under the plasma concentration-time curve from time zero to infinite time [AUCinfinity], 45.7 versus 32.4 MUg . h/ml), longer elimination half-life (2.98 versus 1.79 h), and lower clearance (2.03 versus 3.03 ml/min/kg) compared with infants >4 weeks. Mean Vz was highest in subjects with the earliest gestational age (<32 weeks): 0.564 liter/kg for neonates and 0.548 liter/kg for infants. Single-dose pharmacokinetics of doripenem administered as a 1-hour infusion in term and preterm infants <12 weeks in chronological age were similar to what has been observed in neonates and very young infants with other carbapenems. Single-dose doripenem was generally safe and well tolerated. (This study has been registered with ClinicalTrials.gov under registration no. NCT01381848 and with EudraCT under registration no. 2009-014387-20.). PMID- 26014959 TI - Inverted frontal view method facilitates bile duct cannulation via the intact papilla in patients with Roux-en-Y anastomosis. PMID- 26014960 TI - EUS-guided drainage of pancreatic fluid collections using a novel lumen-apposing metal stent on an electrocautery-enhanced delivery system: a large retrospective study (with video). AB - BACKGROUND AND AIMS: A lumen-apposing, self-expanding metal stent incorporated in an electrocautery-enhanced delivery system for EUS-guided drainage of pancreatic fluid collections (PFCs) recently has become available. The aim of this study was to analyze the safety and clinical effectiveness of this newly developed device in this clinical setting. METHODS: This was a retrospective analysis of all consecutive patients with PFCs who underwent EUS-guided drainage using the study device in 13 European centers. RESULTS: Ninety-three patients with PFCs (80% with complex collections) underwent drainage using the study device. Penetration of the PFC was accomplished directly with the study device in 74.2% of patients, and successful stent placement was accomplished in all but 1 patient, mostly without fluoroscopic assistance. Direct endoscopic necrosectomy (DEN) was carried out in 31 of 52 cases (59.6%) of walled-off necrosis and in 2 of 4 cases (50%) of acute peripancreatic fluid collection. Complete resolution of the PFC was obtained in 86 cases (92.5%), with no recurrence during follow-up. Treatment failure occurred in 6 patients because of persistent infection requiring surgery (n = 3), perforation and massive bleeding caused by the nasocystic drainage catheter (NCDC) (n = 2), and the need for a larger opening to extract large necrotic tissue pieces (n = 1). Major adverse events occurred in 5 patients (perforation and massive bleeding caused by the NCDC in 2 patients, 1 pneumoperitoneum and 1 stent dislodgement during DEN, and 1 postdrainage infection) and were mostly not related to the drainage procedure. CONCLUSIONS: EUS-guided drainage with the electrocautery-enhanced delivery system is a safe, easy to perform, and a highly effective minimally invasive treatment modality for PFCs. PMID- 26014961 TI - HDL-C, ABCA1-mediated cholesterol efflux, and lipoprotein(a): insights into a potential novel physiologic role of lipoprotein(a). PMID- 26014963 TI - Water Level Declines in the High Plains Aquifer: Predevelopment to Resource Senescence. AB - A large imbalance between recharge and water withdrawal has caused vital regions of the High Plains Aquifer (HPA) to experience significant declines in storage. A new predevelopment map coupled with a synthesis of annual water levels demonstrates that aquifer storage has declined by approximately 410 km(3) since the 1930s, a 15% larger decline than previous estimates. If current rates of decline continue, much of the Southern High Plains and parts of the Central High Plains will have insufficient water for irrigation within the next 20 to 30 years, whereas most of the Northern High Plains will experience little change in storage. In the western parts of the Central and northern part of the Southern High Plains, saturated thickness has locally declined by more than 50%, and is currently declining at rates of 10% to 20% of initial thickness per decade. The most agriculturally productive portions of the High Plains will not support irrigated production within a matter of decades without significant changes in management. PMID- 26014962 TI - Sources, metabolism, and regulation of circulating sphingosine-1-phosphate. AB - Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts either as an intracellular messenger or as a ligand for its membrane receptors. S1P is a normal constituent of blood, where it is found both in plasma and blood cells. Compared with other cell types, sphingolipid metabolism in erythrocytes and platelets has unique features that allow the erythrocytes and platelets to accumulate S1P. In plasma, S1P is bound mainly to HDLs and albumin. Of note, metabolism and biological activity of S1P is to a large extent affected by the type of its carrier. Plasma S1P is characterized by a short half-life, indicating rapid clearance by degradative enzymes and the presence of high-capacity sources involved in maintaining its high concentration. These sources include blood cells, vascular endothelium, and hepatocytes. However, the extent to which each of these contributes to the plasma pool of S1P is a matter of debate. Circulating S1P plays a significant physiological role. It was found to be the key regulator of lymphocyte trafficking, endothelial barrier function, and vascular tone. The purpose of this review is to summarize the present state of knowledge on the metabolism, transport, and origin of plasma S1P, and to discuss the mechanisms regulating its homeostasis in blood. PMID- 26014964 TI - LC-MS-MS Characterization of Forced Degradation Products of Fidarestat, a Novel Aldose Reductase Inhibitor: Development and Validation of a Stability-Indicating RP-HPLC Method. AB - An accurate, precise, robust and selective stability-indicating liquid chromatographic (LC) method has been developed for the monitoring of fidarestat in the presence of its forced degradants. The drug was subjected to hydrolysis (acid, alkali and neutral degradation), oxidation, photolysis and thermal stress conditions. The drug degraded significantly under hydrolytic (basic, acidic and neutral) and oxidative stress conditions, whereas it was found to be stable in photolytic and thermal conditions. The chromatographic separation was achieved on a Grace C18, (250 mm * 4.6 mm * 5 MUm) column using gradient mobile phase system consisting of 10 mM of ammonium acetate buffer at pH 4 and acetonitrile at a flow rate of 1 mL/min with UV detection at 283 nm. The developed method was extended to liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC QTOF-MS-MS) for characterization of all the degradation products. A total of five new degradation products were identified and characterized by LC-QTOF-MS-MS. The developed LC method was validated as per ICH guideline Q2 (R1). The proposed method was found to be successively applied for the quality control of fidarestat in bulk drug analysis. PMID- 26014965 TI - Ultra-Performance Liquid Chromatography for the Simultaneous Quantification of Rutin and Chlorogenic Acid in Leaves of Ribes L. Species by Conventional and Chemometric Calibration Approaches. AB - A new ultra-performance liquid chromatography (UPLC) using conventional and chemometric calibrations was improved for the simultaneous estimation of chlorogenic acid (CA) and rutin (RUT) in leaves of Ribes L. species (R. rubrum, R. biebersteinii, R. nigrum, R. uva-crispa, R. alpinum, R. orientale, R. multiflorum and R. anatolica). The UPLC separation for CA and RUT in samples were performed on a Waters UPLC BEH phenyl column (100 mm * 1.0 mm i.d., 1.7 MUm) and mobile phase consisting of acetonitrile and 0.1 M formic acid buffer, pH = 3.77 (15:85, v/v) containing 1.0 mL triethylamine in 1,000 mL mobile phase. Multi wavelength UPLC chromatograms of CA and RUT in calibration and plant samples were obtained by the photodiode array (PDA) detection at the wavelength set from 290 to 360 nm with the interval of Deltalambda = 10 nm. Conventional UPLC-single and chemometric calibrations were subjected to the analysis of the related compounds. By using UPLC data, conventional and chemometric calibrations in the linear concentration range between 2.5 and 40.0 MUg/mL for all compounds were applied for the simultaneous quantitative analysis of CA and RUT in plant samples of seven different Ribes species. PMID- 26014966 TI - Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand. AB - The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm-HPV E6 proteins tested but not to low-risk mucosal or cutaneous HPV E6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase 3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers. PMID- 26014969 TI - Mycetoma Caused by Aspergillus nidulans. PMID- 26014968 TI - Intermedin is upregulated and attenuates renal fibrosis by inhibition of oxidative stress in rats with unilateral ureteral obstruction. AB - AIM: Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in the progression of renal fibrosis. Reactive oxygen species mediate profibrotic action of TGF-beta1. Intermedin (IMD) has been shown to inhibit oxidative stress, but its role in renal fibrosis remains unclear. Here, we investigated the effects of IMD on renal fibrosis in a rat model of unilateral ureteral obstruction (UUO). METHODS: The expression of IMD and its receptors, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP1/2/3), in the obstructed kidney was detected by real-time polymerase chain reaction (PCR), western blotting and immunohistochemistry. To evaluate the effects of IMD on renal fibrosis, we locally overexpressed exogenous IMD in the obstructed kidney using an ultrasound-microbubble-mediated delivery system. Renal fibrosis was determined by Masson trichrome staining. The expression of TGF-beta1, connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA) and fibronectin was measured. Smad2/3 activation and macrophage infiltration were evaluated. We also studied oxidative stress by measuring superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. RESULTS: mRNA and protein expression of IMD increased after UUO. CRLR, RAMP1, RAMP2 and RAMP3 were also induced by ureteral obstruction. IMD overexpression remarkably attenuated UUO induced tubular injury and blunted fibrotic response as shown by decreased interstitial collagen deposition and downregulation of fibronectin. Macrophage infiltration, alpha-SMA and CTGF upregulation caused by UUO were all relieved by IMD, whereas TGF-beta1 upregulation and Smad2/3 activation were not affected. Meanwhile, we noted increased oxidative stress in obstruction, which was also attenuated by IMD gene delivery. CONCLUSIONS: Our results indicate that IMD is upregulated after UUO. IMD plays a protective role in renal fibrosis via its antioxidant effects. PMID- 26014971 TI - MSF Ebola treatment centres were far from perfect. PMID- 26014970 TI - Familial late-onset Alzheimer's disease: description of an Italian family with four affected siblings and one case of early-onset dementia in the preceding generation. AB - We describe a family composed of six siblings, four of which affected by late onset Alzheimer's disease (LOAD). We constructed the family pedigree, evaluated mutations usually associated with early-onset Alzheimer's disease (APP, PSEN1, PSEN2), and assessed polymorphisms in the apolipoprotein E (APOE) gene and in cytokine genes that we had previously found to be associated with a higher risk of LOAD (IL-10, IL-6, TNF-alpha). Results showed that all subjects carried one epsilon4 allele of the APOE gene and those with the earliest age of onset exhibited the AA (-1082) IL-10 and the CC (-174) IL-6 genotypes. The only male had a genetic profile which also included the A (-308) TNF-alpha allele. These data confirm the role of the APOE gene as genetic risk factor in LOAD, and suggest that the risk of developing AD may be governed by a "susceptibility profile" involving polymorphisms in inflammatory genes. PMID- 26014967 TI - Biomaterial-mediated strategies targeting vascularization for bone repair. AB - Repair of non-healing bone defects through tissue engineering strategies remains a challenging feat in the clinic due to the aversive microenvironment surrounding the injured tissue. The vascular damage that occurs following a bone injury causes extreme ischemia and a loss of circulating cells that contribute to regeneration. Tissue-engineered constructs aimed at regenerating the injured bone suffer from complications based on the slow progression of endogenous vascular repair and often fail at bridging the bone defect. To that end, various strategies have been explored to increase blood vessel regeneration within defects to facilitate both tissue-engineered and natural repair processes. Developments that induce robust vascularization will need to consolidate various parameters including optimization of embedded therapeutics, scaffold characteristics, and successful integration between the construct and the biological tissue. This review provides an overview of current strategies as well as new developments in engineering biomaterials to induce reparation of a functional vascular supply in the context of bone repair. PMID- 26014972 TI - A chemiluminescence method to detect hydroquinone with water-soluble sulphonato (salen)manganese(III) complex as catalyst. AB - A water-soluble sulphonato-(salen)manganese(III) complex with excellent catalytic properties was synthesized and demonstrated to greatly enhance the chemiluminescence signal of the hydrogen peroxide - luminol reaction. Coupled with flow-injection technique, a simple and sensitive chemiluminescence method was first developed to detect hydroquinone based on the chemiluminescence system of the hydrogen peroxide-luminol-sulphonato-(salen)manganese(III) complex. Under optimal conditions, the assay exhibited a wide linear range from 0.1 to 10 ng mL( 1) with a detection limit of 0.05 ng mL(-1) for hydroquinone. The method was applied successfully to detect hydroquinone in tap-water and mineral-water, with a sampling frequency of 120 times per hour. The relative standard deviation for determination of hydroquinone was less than 5.6%, and the recoveries ranged from 96.8 to 103.0%. The ultraviolet spectra, chemiluminescence spectra, and the reaction kinetics for the peroxide-luminol-sulphonato-(salen)manganese(III) complex system were employed to study the possible chemiluminescence mechanism. The proposed chemiluminescence analysis technique is rapid and sensitive, with low cost, and could be easily extended and applied to other compounds. PMID- 26014973 TI - Hospitalized patients frequently unaware of their chronic kidney disease. AB - Prior studies have found that outpatients are frequently unaware of their chronic kidney disease (CKD). Little is known about CKD awareness in hospitalized patients. We conducted a retrospective study of general medicine inpatients with CKD, ascertained through International Classification of Diseases, Ninth Revision codes for non-dialysis-dependent CKD (585.0-585.9) in their first 20 admission diagnoses (n = 590). Patient awareness of their CKD, defined as correct patient self-report of "kidney problems" was 32%. Of 161 patients with advanced CKD, 48% of patients with stage 4 (estimated glomerular filtration rate [eGFR] 15-29) and 63% with stage 5 (eGFR <15) reported having CKD. In multivariable analysis, factors significantly associated with patient self-report of CKD included advanced CKD stage, other race (nonwhite, non-African American), and increasing Mini-Mental State Exam score (all P < 0.05). CKD awareness increased, but remained low, in patients with advanced CKD who would benefit from referral to multidisciplinary nephrology care. Hospitalization provides an opportunity to educate patients with CKD and link them to care. PMID- 26014974 TI - Solid-Phase Parallel Synthesis of Functionalised Medium-to-Large Cyclic Peptidomimetics through Three-Component Coupling Driven by Aziridine Aldehyde Dimers. AB - The first solid-phase parallel synthesis of macrocyclic peptides using three component coupling driven by aziridine aldehyde dimers is described. The method supports the synthesis of 9- to 18-membered aziridine-containing macrocycles, which are then functionalized by nucleophilic opening of the aziridine ring. This constitutes a robust approach for the rapid parallel synthesis of macrocyclic peptides. PMID- 26014975 TI - Copulatory courtship by bushcricket genital titillators revealed by functional morphology, MUCT scanning for 3D reconstruction and female sense structures. AB - Genitalia are rapidly evolving morphological structures most likely under sexual selection. Due to their internal nature they are often hidden inside the body, thus morpho-functional studies of animal genitalia are broadly lacking. Males of some bushcricket taxa bear paired genital appendices called titillators, the exact function of which is unknown since they are obscured inside the female body during pairing. To investigate titillator morphology and possible function during copulation, we studied the bushcricket Metrioptera roeselii (Hagenbach, 1822) using a novel combination of independent, yet complementary, techniques. Copulating pairs were snap-frozen and scanned by X-ray micro-computed tomography (MUCT) to visualize the coupling of male and female genitalia in situ. Video recordings of copulating pairs also showed rhythmical insertion of male titillators into the female's genital chamber, where they percuss a softened structure on the female's subgenital plate. Movements did not induce damage to the female's structure, which lacks any sclerotized genital counterparts. Instead, scanning electron microscopy and histological sections show the female subgenital plate to be covered with two different types of sensory receptors at the contact zone between the male's titillator and the female genital chamber. We interpret the non-harmful function of the titillator processes, the lack of a genital counter-structure and the presence of sensory cells on the female's subgenital plate as indicators of a copulatory courtship function of titillators, subject to sexual selection by female choice. PMID- 26014978 TI - [What did she catch in North Africa? Acne aestivalis]. PMID- 26014979 TI - [The wrist watch that calls for help]. PMID- 26014982 TI - [Benefit for patients whose physicians amuse themselves at congresses]. PMID- 26014985 TI - [The limits of veterinary medicine are fluid]. PMID- 26014983 TI - [Software that remembers every vaccination]. PMID- 26014986 TI - [The cardiac pacemaker beeps faithfully every day]. PMID- 26014989 TI - [Varicose ulcer should not be treated by the principal general practitioner]. PMID- 26014990 TI - [Vital care at the onset of disability]. PMID- 26014992 TI - [What does the crime reveal about the criminal?]. PMID- 26014993 TI - [How emotional abuse can cause illness]. PMID- 26014994 TI - [Is cholesterol actually not so unhealthy?]. PMID- 26014995 TI - [Naturopathy consultation. Finally able to breathe again!]. PMID- 26014996 TI - [Recognizing celiac disease]. PMID- 26014997 TI - [Illness caused by electromagnetic fields]. PMID- 26014998 TI - [Supplementation reduces mortality]. PMID- 26015000 TI - [Calming the hyperactive bladder]. PMID- 26015002 TI - [Diabetics are often unimpressed by blood glucose values]. PMID- 26015004 TI - [Carotid stent shows problems during follow-up]. PMID- 26015006 TI - [Return visit to the cataract piercer]. PMID- 26015007 TI - [Mepolizumab can reduce oral steroids]. PMID- 26015008 TI - [Zebra bones after bisphosphonate treatment]. PMID- 26015010 TI - [Ear ache, bullae and facial paralysis]. PMID- 26015011 TI - [Heart failure: the cardiovascular epidemic of the 21th century]. PMID- 26015012 TI - [Heart failure with preserved ejection fraction (HFpEF)]. PMID- 26015013 TI - [The treatment of terminal heart failure with implantable ventricular assist devices]. PMID- 26015014 TI - [Pruritus in elderly: causes, prevention and therapy]. PMID- 26015015 TI - [Emergency checklist: hypertension urgency]. PMID- 26015016 TI - [Cystic tumors of the pancreas: diagnosis and therapy]. PMID- 26015017 TI - [New allergy prevention guidelines - the accurate way to advise your patient]. PMID- 26015018 TI - [Insulin aspartate: well suited for pump therapy]. PMID- 26015026 TI - Drug Pharmacokinetics Determined by Real-Time Analysis of Mouse Breath. AB - Noninvasive, real-time pharmacokinetic (PK) monitoring of ketamine, propofol, and valproic acid, and their metabolites was achieved in mice, using secondary electrospray ionization and high-resolution mass spectrometry. The PK profile of a drug influences its efficacy and toxicity because it determines exposure time and levels. The antidepressant and anaesthetic ketamine (Ket) and four Ket metabolites were studied in detail and their PK was simultaneously determined following application of different sub-anaesthetic doses of Ket. Bioavailability after oral administration vs. intraperitoneal injection was also investigated. In contrast to conventional studies that require many animals to be sacrificed even for low-resolution PK curves, this novel approach yields real-time PK curves with a hitherto unmatched time resolution (10 s), and none of the animals has to be sacrificed. This thus represents a major step forward not only in animal welfare, but also major cost and time savings. PMID- 26015027 TI - Modification of the degree of branching of a beta-(1,3)-glucan affects aggregation behavior and activity in an oxidative burst assay. AB - Scleroglucan is a beta-(1,3)-glucan which is highly branched at the 6-position with a single glucose residue. Acid hydrolysis of a high molecular weight scleroglucan gave a medium molecular weight, freely soluble material. Linkage analysis by the partially methylated alditol acetate method showed that the solubilized material had 30% branching. When the material was subjected to partial Smith degradations, the percent branching was reduced accordingly to 12% or 17%. After the percent branching was reduced, the average molecular weight of the samples increased considerably, indicating the assembly of higher ordered aggregate structures. An aggregate number distribution analysis was applied to confirm the higher aggregated structures. These aggregated structures gave the material significantly enhanced activity in an in vitro oxidative burst assay compared to the highly branched material. PMID- 26015058 TI - Definitive proof of graphene hydrogenation by Clemmensen reduction: use of deuterium labeling. AB - Graphane is one of the most intensively studied derivatives of graphene. Here we demonstrate the evaluation of exact degree of graphene hydrogenation using the Clemmensen reduction reaction and deuterium labeling. The Clemmensen reduction reaction is based on application of zinc in an acid environment. It effectively reduces various functional groups (like ketones) present in graphite oxide. However, the mechanism of reduction is still unknown and elusive. Here we bring a major insight into the mechanisms of the Clemmensen reduction via deuterium labeling and the topochemical approach applied on graphite oxide. The use of deuterated reactants and the exact measurement of deuterium concentration in reduced/hydrogenated graphene by nuclear methods can be used for accurate estimation of C-H bond abundance in graphene. Various topochemical configurations of experiments showed that the reduction of a ketonic group proceeds in contact with the zinc metal by a carbenoid mechanism. Our results showed that the application of nuclear methods of isotope analysis in combination with deuterium labeling represents a very effective tool for investigation of graphene based materials. Our results demonstrate that graphene based materials can also be effectively used for the investigation of organic reaction mechanisms, because the robust structure of graphene allows the use of various spectroscopic techniques which could not be applied on small organic molecules. PMID- 26015063 TI - Uses and limitations of green fluorescent protein as a viability marker in Enterococcus faecalis: An observational investigation. AB - Enterococci are capable of producing biofilms that are notoriously difficult to treat and remove, for instance in root canal infections. The tenacious nature of these organisms makes screening of known and novel antimicrobial compounds necessary. While traditionally growth and fluorescence-based screening methods have proven useful, these methods have their limitations when applied to enterococci (e.g. time consuming, no kinetic data, diffusion properties of the fluorescent dyes). The aim of this study was to develop and validate a GFP-based high-throughput screening system to assess the bactericidal activity of a broad range of antimicrobial agents on Enterococcus faecalis and its biofilms. The effect of antimicrobial compounds on cell viability and GFP fluorescence of enterococcal planktonic and biofilm cells was determined using colony forming unit counts, fluorescence spectrophotometry and real-time imaging devices. There was a linear correlation between cell viability and GFP fluorescence. The intensity of the GFP signal was effected by the extracellular pH. For a range of antimicrobials however, there was no correlation between these two parameters. In contrast, for oxidizing agents such as sodium hypochlorite, the antimicrobial of choice for root canal disinfection, there was a correlation between loss of fluorescence and loss of viability. To conclude, the use of a GFP-based system to monitor the antimicrobial activity of compounds on E. faecalis is possible despite significant limitations. This approach is useful for analysis of susceptibility to oxidizing agents. Using real-time measuring devices to follow GFP fluorescence it should be possible to investigate the mode of action and rate of diffusion of oxidizing agents in E. faecalis biofilm. PMID- 26015064 TI - Helicobacter pylori TlyA Forms Amyloid-like Aggregates with Potent Cytotoxic Activity. AB - Helicobacter pylori is a potent human gastric pathogen. It is known to be associated with several gastroenteric disorders, including gastritis, peptic ulcer, and gastric cancer. The H. pylori genome encodes a gene product TlyA that has been shown to display potent membrane damaging properties and cytotoxic activity. On the basis of such properties, TlyA is considered as a potential virulence factor of H. pylori. In this study, we show that the H. pylori TlyA protein has a strong propensity to convert into the amyloid-like aggregated assemblies, upon exposure to elevated temperatures. Even at the physiological temperature of 37 degrees C, TlyA shows a strong amyloidogenic property. TlyA aggregates that are generated upon exposure at temperatures of >=37 degrees C show prominent binding to dyes like thioflavin T and Nile Red. Transmission electron microscopy also demonstrates the presence of typical amyloid-like fibrils in the TlyA aggregates generated at 37 degrees C. Conversion of TlyA into the amyloid-like aggregates is found to be associated with major alterations in the secondary and tertiary structural organization of the protein. Finally, our study shows that the preformed amyloid-like aggregates of TlyA are capable of exhibiting potent cytotoxic activities against human gastric adenocarcinoma cells. Altogether, such a propensity of H. pylori TlyA to convert into the amyloid-like aggregated assemblies with cytotoxic activity suggests potential implications for the virulence functionality of the protein. PMID- 26015065 TI - Systematic enrichment analysis of potentially functional regions for 103 prostate cancer risk-associated loci. AB - BACKGROUND: More than 100 prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) have been identified by genome wide association studies (GWAS). However, the molecular mechanisms are unclear for most of these SNPs. METHODS: All reported PCa risk-associated SNPs reaching the genome-wide significance level of P < 1 * 10(-7) (index SNPs), as well as SNPs in linkage disequilibrium (LD, r(2) >= 0.5) with them were cataloged. Genomic regions with potentially functional impact were also identified, including UCSC annotated coding regions (exon and snoRNA/miRNA) and regulatory regions, as well as binding regions for transcription factors (TFs), histone modifications (HMs), DNase I hypersensitivity (DHSs), and RNA Polymerase IIA (POLR2A) defined by ChIP-Seq in prostate cell lines and tissues. Enrichment analysis was performed to test whether PCa risk-associated SNPs are located in these functional regions more than expected. RESULTS: A total of 103 PCa risk-associated index SNPs and 7,244 SNPs in LD with these index SNPs were cataloged. Genomic regions with potentially functional impact, grouped in 30 different categories of functionalities, were identified. Enrichment analysis indicated that genomic regions in the following 15 categories were enriched for the PCa risk-associated SNPs: exons, CpG regions, 6 TFs (AR, ERG, FOXA1, HOXB13, CTCF, and NR3C1), 5 HMs (H3K4me1, H3K4me2, H3K4me3, H3K27AC, and H3T11P), DHSs and POLR2A. In contrast, significantly fewer PCa risk SNPs were mapped to binding regions for H3K27me3, a repressive chromatin marker. CONCLUSIONS: The PCa risk-associated SNPs discovered to date may affect PCa risk through multiple different mechanisms, especially by affecting binding regions of TFs/HMs. PMID- 26015066 TI - EGF Inhibits Wnt/beta-Catenin-Induced Osteoblast Differentiation by Promoting beta-Catenin Degradation. AB - Bone morphogenetic protein (BMP) and canonical Wnts are representative developmental signals that enhance osteoblast differentiation and bone formation. Previously, we demonstrated that epidermal growth factor (EGF) inhibits BMP2 induced osteoblast differentiation by inducing Smurf1 expression. However, the regulatory role of EGF in Wnt/beta-catenin-induced osteoblast differentiation has not been elucidated. In this study, we investigated the effect of EGF on Wnt/beta catenin signaling-induced osteoblast differentiation using the C2C12 cell line. EGF significantly suppressed the expression of osteoblast marker genes, which were induced by Wnt3a and a GSK-3beta inhibitor. EGF increased the expression levels of Smurf1 mRNA and protein. Smurf1 knockdown rescued Wnt/beta-catenin induced osteogenic marker gene expression in the presence of EGF. EGF treatment or Smurf1 overexpression did not affect beta-catenin mRNA expression levels, but reduced beta-catenin protein levels and TOP-Flash activity. EGF and Smurf1 promoted beta-catenin ubiquitination. Co-immunoprecipitation and GST pull-down assays showed that Smurf1 associates with beta-catenin. These results suggest that EGF/Smurf1 inhibits Wnt/beta-catenin-induced osteogenic differentiation and that Smurf1 downregulates Wnt/beta-catenin signaling by enhancing proteasomal degradation of beta-catenin. PMID- 26015067 TI - Retrospective study of tolerability and efficacy of linezolid in patients with multidrug-resistant tuberculosis (1998-2014). AB - INTRODUCTION: Although linezolid is known to be effective when used as an adjunct therapy in the treatment of patients with multidrug-resistant tuberculosis (MDR TB), the clinical experience is limited. In this study the efficacy and adverse effects of linezolid treatment were evaluated. METHODS: A retrospective study of tolerability and efficacy of linezolid in MDR-TB patients was performed in Madrid, Spain. Demographic characteristics, microbiological and clinical features and data on treatment tolerability were collected. Regimens were constructed with a target of prescribing, at least, five anti-tuberculosis agents likely to be effective. Linezolid, at a dosage of 1200 or 600 mg daily, was included to complete the treatment if no other sensitive drugs were available. Vitamin B6 was used to reduce toxicity. Treatment outcome and clinical status at last contact were compared between patients with linezolid-containing regimens and with those without linezolid-containing regimens. RESULTS: During the period 1998-2014, 55 patients with MDR-TB received treatment. In 21 of these patients, linezolid was added. The median of linezolid administration was 23.9 months (IQT 13.1-24.7). Patients using linezolid showed a greater resistance to drugs, with a median of 6 (IQR 5-7) compared with those who did not use it, with a median of 4 drugs (IQR 3 5) (p<0.001). The median time to sputum culture conversion of the patients in the linezolid group (73.5 days) did not differ significantly from those in the non linezolid group (61 days) (p=0.29). There were no significant differences in the outcomes of the two patient groups. There were no reported adverse events in 81% of patients assigned to linezolid therapy. Only four patients developed toxicity attributed to linezolid. The most serious adverse event in these patients was anemia observed in the two patients treated with 1200 mg per day. One of them also developed moderate paresthesia. In both cases the dosage was reduced to 600 mg per day, with improvement of the anemia and paresthesias. No patients stopped linezolid therapy. CONCLUSION: A daily dosage of 600 mg of linezolid was well tolerated without stopping treatment in any case. The efficacy of the treatment and the outcomes were similar in both the linezolid and non-linezolid group. PMID- 26015068 TI - Decreased LKB1 predicts poor prognosis in Pancreatic Ductal Adenocarcinoma. AB - Liver kinase B1 (LKB1) has been identified as a critical modulator involved in cell proliferation and polarity. The purpose of the current study was to characterize the expression pattern of LKB1 and assess the clinical significance of LKB1 expression in pancreatic ductal adenocarcinoma (PDAC) patients. LKB1 mRNA expression which was analyzed in 32 PDAC lesions and matched non-tumor tissues, was downregulated in 50% (16/32) of PDAC lesions. Similar results were also obtained by analyzing three independent datasets from Oncomine. Protein expression of LKB1 was significantly reduced in 6 PDAC cell lines and downregulated in 31.3% (10/32) of PDAC lesions compared to matched non-tumorous tissues, as determined by Western blot analysis. Additionally, tissue microarray containing 205 PDAC specimens was evaluated for LKB1 expression by IHC and demonstrated that reduced expression of LKB1 in 17.6% (36/205) of PDAC tissues was significantly correlated with clinical stage, T classification, N classification, liver metastasis and vascular invasion. Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of PDAC and found that LKB1 protein expression was one of the independent prognostic factors for overall survival of PDAC patients. PMID- 26015069 TI - Biological and medicinal significance of benzofuran. AB - This article emphasizes on the importance of benzofuran as a biologically relevant heterocycle. It covers most of the physiologically as well as medicinally important compounds containing benzofuran rings. This article also covers clinically approved drugs containing benzofuran scaffold. PMID- 26015070 TI - Task-related modulation of functional connectivity variability and its behavioral correlations. AB - Two new directions of functional connectivity investigation are emerging to advance studies of the brain's functional organization. First, the identification of task-related dynamics of functional connectivity has elicited a growing interest in characterizing the brain's functional reorganization due to task demands. Second, the nonstationarity of functional connectivity [i.e., functional connectivity variability (FCV)] within a single brain state has been increasingly recognized and studied. However, a combined investigation of these two avenues of research to explore the potential task-modulation of FCV is lacking, which, nevertheless, could both improve our understanding of the potential sources of FCV and also reveal new strategies to study the neural correlates of task performance. In this study, 19 human subjects underwent four functional magnetic resonance imaging (fMRI) scans including both resting and task states to study task-related modulation of FCV. Consistent with the hypothesis that FCV is partly underpinned by unconstrained mind wandering, FCV demonstrated significant task related decreases measured at the regional, network and system levels, which was greater for between-network interactions than within-network connections. Conversely, there remained a significant degree of residual variability during the task scans, suggesting that FCV is not specific to the resting state and likely includes an intrinsic, physiologically driven component. Finally, the degree of task-induced decreases in FCV was significantly correlated with task performance accuracy, supporting its behavior significance. Overall, task modulation of FCV may represent an important direction for future studies, not only to provide insight into normal brain functioning but also to reveal potential biomarkers of various brain disorders. PMID- 26015071 TI - Effects of Interaction Between Dopamine D2 Receptor and Monoamine Oxidase A Genes on Smoking Status in Young Men. AB - Although the effect of gene-gene interaction on nicotine-dopamine metabolism for smoking behavior has been reported, polymorphisms of dopamine D2 receptor (DRD2) and monoamine oxidase A (MAOA) have not been simultaneously examined among smokers. In this study, 481 young Taiwanese men completed a self-report questionnaire on smoking status, and data were obtained on polymorphisms of DRD2 rs1800497, DRD2 rs1079597, MAOA rs309850, and MAOA rs1137070, urinary nicotine, and urinary cotinine. In a comparison of 261 current smokers and 220 never smokers, odds ratios (ORs) for the development of smoking in all genotypes were not statistically significant. Among smokers with DRD2 rs1079597 GG//MAOA rs309850 3-repeat, the OR of heavier smoking was 2.67 times higher (95% confidence interval [CI]: [1.08, 6.59], p = .031) and the score on the Fagerstrom test for nicotine dependence was higher (4.26 vs. 2.83) than in those with DRD2 rs1079597 AA//MAOA rs309850 3-repeat. Adjusted urinary cotinine concentration was significantly different between those two groups (median value: 95.83 ng/MUl vs. 133.24 ng/MUl, respectively, p = .045). These findings suggest that the interaction of DRD2 rs1079597 and MAOA rs309850 3-repeat affects smoking intensity in young Taiwanese men. PMID- 26015072 TI - Comparing Genomic Profiles of Women With and Without Fibromyalgia. AB - BACKGROUND: Fibromyalgia syndrome (FMS), a chronic musculoskeletal condition characterized by diffuse pain, fatigue, sleep impairment, and cognitive dysfunction, is associated with significant functional disability. Its underlying biological mechanisms are unknown. This study investigated differentially expressed genes between women with FMS and healthy volunteers. METHODS: Women who met the 1990 or 2010 American College of Rheumatology fibromyalgia criteria were compared to age- and race-matched pain-free healthy women. Peripheral blood samples were collected, and a full genome microarray gene expression analysis was performed. One-way analysis of variance was used to identify differentially expressed genes using the filtering criterion of 1% false discovery rate. Analysis of canonical pathways associated with these genes was performed. Confirmatory quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay verified microarray results. Independent t-tests compared gene and protein expression between groups. RESULT: Participants were 54 women with FMS and 25 controls. Expression arrays from a subset of women with FMS (n = 29) and controls (n = 20) showed upregulation of 12 genes (>1.8-fold change, p < .05) in the FMS sample. Differentially expressed genes were related to B-cell development, primary immunodeficiency signaling, and mitotic roles of polo-like kinase. CENPK and HSP90AA1 were the most differentially expressed genes (p < .01). CONCLUSION: Activity of interrelated pathways related to immune response, and homeostasis appears to be relevant to the experience of FMS. Replication and exploration of the relationship between gene expression and symptom severity will help determine clinical relevance of these findings. PMID- 26015073 TI - Hydroxysafflor yellow A attenuate lipopolysaccharide-induced endothelium inflammatory injury. AB - OBJECTIVE: This study observed attenuating effect of hydroxysafflor yellow A (HSYA), an effective ingredient of aqueous extract of Carthamus tinctorius L, on lipopolysaccharide (LPS)-induced endothelium inflammatory injury. METHODS: Eahy926 human endothelium cell (EC) line was used; thiazolyl blue tetrazolium bromide (MTT) test was assayed to observe the viability of EC; Luciferase reporter gene assay was applied to measure nuclear factor-kappaB (NF-kappaB) p65 subunit nuclear binding activity in EC; Western blot technology was used to monitor mitogen activated protein kinase (MAPKs) and NF-kappaB activation. Reverse transcription polymerase chain reaction (RT-PCR) method was applied to observe intercellular cell adhesion molecule-1 (ICAM-1) and E-selectin mRNA level; EC surface ICAM-1 expression was measured with flow cytometry and leukocyte adhesion to EC was assayed with Rose Bengal spectrophotometry technology. RESULTS: HSYA protected EC viability against LPS-induced injury (P <0.05). LPS-induced NF-kappaB p65 subunit DNA binding (P <0.01) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) phosphorylation was inhibited by HSYA. HSYA attenuated LPS triggered ICAM-1 and E-selectin mRNA levels elevation and phosphorylation of p38 MAPK or c-Jun N-terminal kinase MAPK. HSYA also inhibited LPS-induced cell surface ICAM-1 protein expression P <0.01) and leukocyte adhesion to EC (P <0.05). CONCLUSION: HSYA is effective to protect LPS-induced high expression of endothelium adhesive molecule and inflammatory signal transduction. PMID- 26015075 TI - Cystic fibrosis-Children and adults Tai Chi study (CF CATS2): Can Tai Chi improve symptoms and quality of life for people with cystic fibrosis? Second phase study protocol. AB - BACKGROUND: Cystic fibrosis (CF) is a genetic disorder affecting respiratory and digestive systems. People with CF experience physical symptoms; cough, poor lung ventilation, recurrent infections, poor weight gain, diarrhoea, and malnutrition, as well as lower quality of life. Tai Chi, a Chinese form of meditative movement, may help with the symptoms of CF and help people with CF to exercise. However, there is very little research in this area. OBJECTIVE: To evaluate the feasibility of studying Tai Chi for CF and to compare the effectiveness of Tai Chi to standard care and face-to-face Tai Chi with online Tai Chi for people with CF. METHODS: This is a comparative effectiveness trial with 72 people with CF over 6 years old and a patient at the Royal Brompton Hospital, London, UK. Participants receive 8 Tai Chi sessions, then home practice with a DVD. Sessions are one-on-one for group A, online for group B. Group B is a no treatment standard care control (first 3 months). At baseline, 3, 6 and 9 months, questionnaires will be used to measure quality of life, mindfulness and sleep, and medical data health and respiratory function. At Tai Chi sessions and at 4 follow-up points, the Borg Scale and healthcare use data will be collected. At 9 months online focus groups will assess participants' experience, Tai Chi feasibility, perceived health impact, and study participation. Recruitment will use adverts in hospital clinics and website, and letter/phone for non-regularly attending patients. Block randomisation will use random number tables. The two groups will be compared for: weeks 1 to 12 (Tai Chi vs. standard care); before and after intervention (differences in delivery method); week 1 (of intervention) to month 9 (long-term impact). Qualitative data will use Framework analysis. DISCUSSION: We believe this is the first trial of Tai Chi for CF. Tai Chi may help with the physiological symptoms of CF and increase levels of exercise by providing a self-management technique and low stress activity. This study will provide data on the feasibility of a randomized controlled trial of Tai Chi for CF, including data for a sample size calculation and will inform future study design. PMID- 26015074 TI - Effect of Tai Chi on muscle strength of the lower extremities in the elderly. AB - OBJECTIVE: Aging is associated with a progressive decline in muscle strength, muscle mass and impaired physical function, which reduces mobility and impairs quality of life in the elderly population. The 6-12 months of exercise can enhance the muscle strength, but these improvements can only be maintained for a short period. In this study, we investigated the effects of long-term Tai Chi (TC) exercise on muscle strength of lower extremities. METHODS: A cross-sectional study was conducted in 205 long-term TC practitioners (age: 60-89 years) and 205 age and gentle matched controls who did not practice TC. Each of the activity group was further divided into three distinct age groups: G1, 60-69 years; G2, 70 79 years; and G3, 80-89 years. Hand-held dynamometery was used to measure the maximum isometric strength of iliopsoas, quadriceps femoris, tibialis anterior and hamstrings in both sides of the participants. Unpaired t tests were performed to compare the difference of strength between the TC and non-Tai Chi (NTC) groups. Multivariate analysis of variance (MANOVA) was used to compare the lower muscle strengths among the different age groups in the TC and NTC groups. Pearson's correlations were used to quantify the linear relationship between the months of TC practice and lower limbs muscle strength. RESULTS: The inter-rater reliabilities of iliopsoas, quadriceps femoris, tibialis anterior and hamstrings were intraclass correlation coeffificient (ICC) (1,1) = 0.895 (0.862-0.920), ICC (2,2) = 0.905 (0.874-0.928), ICC (3,3) = 0.922 (0.898-0.941) and ICC (4,4) = 0.930 (0.908-0.947). The strength of the muscles in the TC group did not differ among different age groups (P>0.05). The strength of iliopsoas, quadriceps femoris, tibialis anterior and hamstrings in TC group was higher than that in the NTC group (P<0.05). A correlation between muscle strength and extension of the exercise period was positive (P<0.05). CONCLUSIONS: Results shed light on the orientation and magnitude of long-term TC in preventing muscle strength loss with aging. TC might be a good form to slow down the trend of age-related decline in muscle strength in community-dwelling population. PMID- 26015076 TI - Effects of climate change on residential infiltration and air pollution exposure. AB - Air exchange through infiltration is driven partly by indoor/outdoor temperature differences, and as climate change increases ambient temperatures, such differences could vary considerably even with small ambient temperature increments, altering patterns of exposures to both indoor and outdoor pollutants. We calculated changes in air fluxes through infiltration for prototypical detached homes in nine metropolitan areas in the United States (Atlanta, Boston, Chicago, Houston, Los Angeles, Minneapolis, New York, Phoenix, and Seattle) from 1970-2000 to 2040-2070. The Lawrence Berkeley National Laboratory model of infiltration was used in combination with climate data from eight regionally downscaled climate models from the North American Regional Climate Change Assessment Program. Averaged over all study locations, seasons, and climate models, air exchange through infiltration would decrease by ~5%. Localized increased infiltration is expected during the summer months, up to 20-30%. Seasonal and daily variability in infiltration are also expected to increase, particularly during the summer months. Diminished infiltration in future climate scenarios may be expected to increase exposure to indoor sources of air pollution, unless these ventilation reductions are otherwise compensated. Exposure to ambient air pollution, conversely, could be mitigated by lower infiltration, although peak exposure increases during summer months should be considered, as well as other mechanisms. PMID- 26015078 TI - Bridging the Gap between the Gas Phase and Solution Phase: Solvent Specific Photochemistry in 4-tert-Butylcatechol. AB - Eumelanin is a naturally synthesized ultraviolet light absorbing biomolecule, possessing both photoprotective and phototoxic properties. We infer insight into these properties of eumelanin using a bottom-up approach, by investigating an ultraviolet absorbing motif of eumelanin, 4-tert-butylcatechol. Utilizing a combination of femtosecond transient electronic absorption spectroscopy and time resolved velocity map ion imaging, our results suggest an environmental-dependent relaxation pathway, following irradiation at 267 nm to populate the S1 ((1)pipi*) state. Gas-phase and nonpolar solution-phase measurements reveal that the S1 state decays primarily through coupling onto the S2 ((1)pisigma*) state which is dissociative along the nonintramolecular hydrogen bonded "free" O-H bond. This process occurs in 4.9 +/- 0.6 ps in the gas-phase and 18 +/- 1 ps in the nonpolar cyclohexane solution. Comparative studies on the deuterated isotopologue of 4 tert-butylcatechol in both the gas- and solution-phase (cyclohexane) reveal kinetic isotope effects of ~19 and ~4, respectively, supportive of O-H dissociation along a barriered pathway, and potentially mediated by quantum tunneling. In contrast, in the polar solvent acetonitrile, the S1 state decays on a much longer time scale of 1.7 +/- 0.1 ns. We propose that the S1 decay is now multicomponent, driven by internal conversion, intersystem crossing, and fluorescence, as well as O-H dissociation. The attribution of conformer-driven excited state dynamics to explain how the S1 state decays in the gas- and nonpolar solution-phase versus the polar solution-phase, demonstrates the influence the environment can have on the ensuing excited state dynamics. PMID- 26015077 TI - Urinary cadmium and estimated dietary cadmium in the Women's Health Initiative. AB - Cadmium, a heavy metal dispersed in the environment as a result of industrial and agricultural applications, has been implicated in several human diseases including renal disease, cancers, and compromised bone health. In the general population, the predominant sources of cadmium exposure are tobacco and diet. Urinary cadmium (uCd) reflects long-term exposure and has been frequently used to assess cadmium exposure in epidemiological studies; estimated dietary intake of cadmium (dCd) has also been used in several studies. The validity of dCd in comparison with uCd is unclear. This study aimed to compare dCd, estimated from food frequency questionnaires, to uCd measured in spot urine samples from 1,002 participants of the Women's Health Initiative. Using linear regression, we found that dCd was not statistically significantly associated with uCd (beta=0.006, P value=0.14). When stratified by smoking status, dCd was not significantly associated with uCd both in never smokers (beta=0.006, P-value=0.09) and in ever smokers (beta=0.003, P-value=0.67). Our results suggest that because of the lack of association between estimated dCd and measured uCd, dietary estimation of cadmium exposure should be used with caution in epidemiologic studies. PMID- 26015079 TI - Phenyl Groups Result in the Highest Benzene Storage and Most Efficient Desulfurization in a Series of Isostructural Metal-Organic Frameworks. AB - A series of isoreticular metal-organic frameworks (MOFs; NENU-511-NENU-514), which all have high surface areas and strong adsorption capacities, have been successfully constructed by using mixed ligands. NENU-513 has the highest benzene capacity of 1687 mg g(-1) at 298 K, which ranks as the top MOF material among those reported up to now. This NENU series has been used for adsorptive desulfurization because of its permanent porosity. The results indicate that this series has a higher adsorptive efficiency in the removal of organosulfur compounds than other MOF materials, especially NENU-511, which has the highest adsorptive efficiency in the ambient atmosphere. This study proves that the design and synthesis of targeted MOFs with higher surface areas and with functional groups present is an efficient method to enhance benzene-storage capacity and the adsorption of organosulfur compounds. PMID- 26015080 TI - Preparation and characterization of (PCL-crosslinked-PEG)/hydroxyapatite as bone tissue engineering scaffolds. AB - In this study, interconnected porous bioactive scaffolds were synthesized for bone tissue engineering. At the first step, poly( E-caprolactone) (PCL) diols were diacrylated with acryloyl chloride. Then, the scaffolds were synthesized by radical crosslinking reaction of PCL and poly(ethyleneglycol) (PEG) diacrylates in the presence of hydroxyapatite (HA) particles. Morphological, swelling, thermal, and mechanical characteristics as well as degradability of the scaffolds were investigated. Results showed that increasing the ratio of PEG to PCL led to significant increase of swelling ratio and degradation rate, and decrease of crystallinity and compressive modulus of the networks, respectively. It was found that the incorporation of HA particles with the polymer matrices resulted in an augmented crystallinity, a decreased swelling ratio, and also a significantly increased compressive modulus of the networks. Cytocompatability and osteoconductivity of the scaffolds were assessed by MTT and alkaline phosphatase (ALP) assays, respectively. The results confirmed the cytocompatible nature of PCL/PEG/HA scaffolds with no toxicity. MG-63 cells attached and spread on the pore walls offered by the scaffolds. PCL/PEG/HA scaffolds compared with PCL/PEG ones showed higher ALP activity. Thus, the results indicated that the PCL/PEG/HA scaffolds have the potential of being used as promising substrates in bone tissue engineering. PMID- 26015081 TI - iMSRC: converting a standard automated microscope into an intelligent screening platform. AB - Microscopy in the context of biomedical research is demanding new tools to automatically detect and capture objects of interest. The few extant packages addressing this need, however, have enjoyed limited uptake due to complexity of use and installation. To overcome these drawbacks, we developed iMSRC, which combines ease of use and installation with high flexibility and enables applications such as rare event detection and high-resolution tissue sample screening, saving time and resources. PMID- 26015083 TI - The organocatalytic asymmetric Prins cyclization. AB - We describe here the design and development of an organocatalytic Prins cyclization. In the presence of a confined chiral imidodiphosphoric acid catalyst, salicylaldehydes react with 3-methyl-3-buten-1-ol to afford highly functionalized 4-methylenetetrahydropyrans in excellent regio- and enantioselectivity. The extreme steric demand of the acid catalyst is key for the success of this transformation. PMID- 26015082 TI - Feasibility of a large cohort study in sub-Saharan Africa assessed through a four country study. AB - BACKGROUND: Large prospective epidemiologic studies are vital in determining disease etiology and forming national health policy. Yet, such studies do not exist in sub-Saharan Africa (SSA) notwithstanding the growing burden of chronic diseases. OBJECTIVE: We explored the feasibility of establishing a large-scale multicountry prospective study at five sites in four sub-Saharan countries. DESIGN: Based on country-specific considerations of feasibility, Nigeria enrolled health care professionals, South Africa and Tanzania enrolled teachers, and Uganda enrolled village residents at one rural and one periurban site each. All sites used a 6-month follow-up period but different approaches for data collection, namely standardized questionnaires filled out by participants or face to-face interviews. RESULTS: We enrolled 1415 participants from five sites (range 200-489) with a median age of 41 years. Approximately half had access to clean burning cooking fuel and 70% to piped drinking water, yet 92% had access to a mobile phone. The prevalence of chronic diseases was 49% among 45- to 54-year olds and was dominated by hypertension (21.7% overall) - ranging from 4.5 to 31.2% across sites - and a serious injury in the past 12 months (12.4% overall). About 80% of participants indicated willingness to provide blood samples. At 6 month follow-up, 68% completed a questionnaire (45 to 96% across sites) with evidence that mobile phones were particularly useful. CONCLUSIONS: Our pilot study indicates that a large-scale prospective study in SSA is feasible, and the burden of chronic disease in SSA may already be substantial necessitating urgent etiologic research and primary prevention. PMID- 26015084 TI - Characteristics of hand involvement in a comparative study of two early RA cohorts from the UK and China. AB - AIM: To compare the characteristics of early hand involvement in rheumatoid arthritis (RA) using two matched populations, from the UK and China. METHODS: A cohort comparison study was conducted. Sixty Chinese patients recruited from Shanghai, China were matched on gender and age with 60 patients from a prospective early RA cohort from the UK (SARAH trial). The procedures of data collection in China followed the standard operating procedures employed in the SARAH trial. Outcome measures including Michigan Hand Outcomes Questionnaire (MHQ), medication history and physical assessments were used to assess functional ability and hand impairment. RESULTS: UK patients reported significantly more hand pain (P = 0.015), less satisfaction with dominant hand performance (P = 0.040), more swollen and tender joints (P = 0.016 and P = 0.001) and greater dexterity of both dominant and non-dominant hands (P < 0.001 and P < 0.001), while Chinese patients had higher disease activity indicated by erythrocyte sedimentation rate and C-reactive protein, more rheumatoid factor, less satisfaction in both dominant and non-dominant hand appearances (P < 0.001 and P < 0.001, respectively) and greater dominant hand deformity (P = 0.003). No statistically significant differences were seen in range of movement and overall hand function as reported by the MHQ. CONCLUSION: The severity of RA is not milder in China than in the UK and the characteristics of hand involvement tend to be different. Clinicians should consider country-specific differences in managing pain and delivering treatment. It would be helpful for a future study to investigate the RA impact characteristics on a wider range of patients both from within China and from other populations. PMID- 26015085 TI - How Does a Patient's Primary Renal Disease Impact Chronic Dialysis Management?: Primary Renal Diseases and Renal Recovery. PMID- 26015086 TI - Utility of a High-Resolution 3D MRI Sequence (3D-SPACE) for Evaluation of Congenital Heart Disease. AB - The purpose of this study was to evaluate the role of a high-resolution 3D dark blood turbo spin echo sequence with variable flip angles (3D-SPACE) in evaluation of congenital heart disease. SPACE sequence was performed in 20 patients (mean age, 17.6 +/- 12.6 years, range 9 months-57 years, M: 13) with either unrepaired (N = 3) or post-repair (n = 17) congenital heart disease. All scans were performed on 1.5 T Aera scanners (Siemens). Two separate observers with expertise in cardiovascular imaging scored the quality of the images for blood suppression and definition of key anatomical structures in a blinded fashion using a 5 grade scoring system. Mean of average overall quality scores for two observers was 4 +/ 0.62. All overall quality scores were greater than 3. None of the studies were deemed nondiagnostic. Mean length of the SPACE acquisition time was 12.7 min (4 21 min). There was no significant correlation between image quality and duration of scans. Lack of blood suppression was the limiting factor in image quality with the most common place being ascending aorta in nine patients. However, overall blood suppression score was very good with score of 3.9 +/- 0.43. There was very good overall agreement between observers in rating the image quality (85.6 % agreement, kappa 0.5, standard error 0.04, p < 0.0001). The 3D-SPACE dark-blood sequence with near-isotropic spatial resolution coupled with respiratory and cardiac gating can be feasibly performed in all age groups with diagnostic image quality in all cases in this study. PMID- 26015088 TI - Preoperative arterial embolization facilitates multivisceral transplantation for portomesenteric thrombosis. AB - Multivisceral transplantation (MvTx) for diffuse venous portomesenteric thrombosis is a surgically and anesthesiologically challenging procedure, partly because of the risk of massive bleeding during visceral exenteration. Preoperative visceral artery embolization might reduce this risk. In three consecutive MvTx, the celiac trunk (CT) and superior mesenteric artery (SMA) were embolized immediately pretransplant. We analyzed demographics, serum D-lactate, pH, base excess, hemoglobin, blood pressure, transfused packed cell (PC) units, intervention time and outcome. Results are reported as median (range). All recipients were male (43, 22, 47 years old). Portomesenteric thrombosis followed antiphospholipid syndrome, neuroendocrine tumor and liver cirrhosis. A peritransplant D-lactate peak of 6.1 (5.1-7.6) mmol/L, lowest pH of 7.24 (7.18 7.36) and lowest base excess level of -9.5 (-7.6 to -11.5) were observed. Values normalized within 3 h posttransplant. Embolization and exenteration times were 80 (70-90) min and 140 (130-165) min, respectively, during which blood pressure remained stable, lowest hemoglobin was 6.1 (6.1-7.6) g/dL and three (2-4) PC were administered. All procedures were uneventful. Follow-up was 7 (4-9) months. The first patient died 4 months post-MvTx after an intracranial bleeding; the other patients are doing well. Our experience suggests that preoperative embolization of CT and SMA facilitates native organ resection in MvTx. PMID- 26015089 TI - Terrestrial and marine perspectives on modeling organic matter degradation pathways. AB - Organic matter (OM) plays a major role in both terrestrial and oceanic biogeochemical cycles. The amount of carbon stored in these systems is far greater than that of carbon dioxide (CO2 ) in the atmosphere, and annual fluxes of CO2 from these pools to the atmosphere exceed those from fossil fuel combustion. Understanding the processes that determine the fate of detrital material is important for predicting the effects that climate change will have on feedbacks to the global carbon cycle. However, Earth System Models (ESMs) typically utilize very simple formulations of processes affecting the mineralization and storage of detrital OM. Recent changes in our view of the nature of this material and the factors controlling its transformation have yet to find their way into models. In this review, we highlight the current understanding of the role and cycling of detrital OM in terrestrial and marine systems and examine how this pool of material is represented in ESMs. We include a discussion of the different mineralization pathways available as organic matter moves from soils, through inland waters to coastal systems and ultimately into open ocean environments. We argue that there is strong commonality between aspects of OM transformation in both terrestrial and marine systems and that our respective scientific communities would benefit from closer collaboration. PMID- 26015087 TI - Programming of Essential Hypertension: What Pediatric Cardiologists Need to Know. AB - Hypertension is recognized as one of the major contributing factors to cardiovascular disease, but its etiology remains incompletely understood. Known genetic and environmental influences can only explain a small part of the variability in cardiovascular disease risk. The missing heritability is currently one of the most important challenges in blood pressure and hypertension genetics. Recently, some promising approaches have emerged that move beyond the DNA sequence and focus on identification of blood pressure genes regulated by epigenetic mechanisms such as DNA methylation, histone modification and microRNAs. This review summarizes information on gene-environmental interactions that lead toward the developmental programming of hypertension with specific reference to epigenetics and provides pediatricians and pediatric cardiologists with a more complete understanding of its pathogenesis. PMID- 26015090 TI - Cost-effectiveness analysis of a low-dose contraceptive levonorgestrel intrauterine system in Sweden. AB - OBJECTIVE: To evaluate the cost-effectiveness of a novel intrauterine system, levonorgestrel intrauterine system 13.5 mg vs. oral contraception, in women at risk of unintended pregnancy. DESIGN: Cost-effectiveness model using efficacy and discontinuation data from published articles. SETTING: Societal perspective including direct and indirect costs. POPULATION: Women at risk of unintended pregnancy using reversible contraception. METHODS: An economic analysis was conducted by modeling the different health states of women using contraception over a 3-year period. Typical use efficacy rates from published articles were used to determine unintended pregnancy events. Discontinuation rates were used to account for method switching. MAIN OUTCOME MEASURES: Cost-effectiveness was evaluated in terms of the incremental cost per unintended pregnancy avoided. In addition, the incremental cost per quality-adjusted life-year was calculated. RESULTS: Levonorgestrel intrauterine system 13.5 mg generated costs savings of ? 311,000 in a cohort of 1000 women aged 15-44 years. In addition, there were fewer unintended pregnancies (55 vs. 294) compared with women using oral contraception. CONCLUSION: Levonorgestrel intrauterine system 13.5 mg is a cost-effective method when compared with oral contraception. A shift in contraceptive use from oral contraception to long-acting reversible contraception methods could result in fewer unintended pregnancies, quality-adjusted life-year gains, as well as cost savings. PMID- 26015091 TI - Systematic interpolation method predicts protein chromatographic elution from batch isotherm data without a detailed mechanistic isotherm model. AB - Predicting protein elution for overloaded ion exchange columns requires models capable of describing protein binding over broad ranges of protein and salt concentrations. Although approximate mechanistic models are available, they do not always have the accuracy needed for precise predictions. The aim of this work is to develop a method to predict protein chromatographic behavior from batch isotherm data without relying on a mechanistic model. The method uses a systematic empirical interpolation (EI) scheme coupled with a lumped kinetic model with rate parameters determined from HETP measurements for non-binding conditions, to numerically predict the column behavior. For two experimental systems considered in this work, predictions based on the EI scheme are in excellent agreement with experimental elution profiles under highly overloaded conditions without using any adjustable parameters. A qualitative study of the sensitivity of predicting protein elution profiles to the precision, granularity, and extent of the batch adsorption data shows that the EI scheme is relatively insensitive to the properties of the dataset used, requiring only that the experimental ranges of protein and salt concentrations overlap those under which the protein actually elutes from the column and possess a +/- 10% measurement precision. PMID- 26015092 TI - Multiple and aggressive pulmonary vein transcatheter interventions as bridge to transplantation in primary diffuse pulmonary vein stenosis. AB - Primary diffuse congenital pulmonary vein stenosis (PDPVS) is a severe condition with poor prognosis. No therapeutic strategy has been found to be effective in its management to date. We report the case of a premature child with severe PDPVS who underwent multiple transcatheter interventions as bridge to heart-lung transplantation. PMID- 26015093 TI - Classical imaging with undetected photons. AB - Barreto Lemos et al. [Nature 512, 409-412 (2014)] reported an experiment in which a non-degenerate parametric downconverter and a non-degenerate optical parametric amplifier--used as a wavelength-converting phase conjugator--were employed to image object transparencies in a manner akin to ghost imaging. Their experiment, however, relied on single-photon detection, rather than the photon-coincidence measurements employed in ghost imaging with a parametric downconverter source. More importantly, their system formed images despite the photons that passed through the object never being detected. Barreto Lemos et al. interpreted their experiment as a quantum imager, as assuredly it is, owing to its downconverter's emitting entangled signal and idler beams. We show, however, that virtually all the features of their setup can be realized in a quantum-mimetic fashion using classical-state light, specifically a pair of bright pseudothermal beams possessing a phase-sensitive cross correlation. Owing to its much higher signal to-noise ratio, our bright-source classical imager could greatly reduce image acquisition time compared to that of Barreto Lemos et al.'s quantum system, while retaining the latter's ability to image with undetected photons. PMID- 26015094 TI - Dissecting Aneurysm of Anterior Inferior Cerebellar Artery Initially Presenting with Nonhemorrhagic Symptom. AB - We report a patient with a probable dissecting aneurysm of the anterior inferior cerebellar artery (AICA) initially presenting with a nonhemorrhagic symptom, which resulted in subarachnoid hemorrhage. A 61-year-old woman suddenly experienced nausea. Computed tomography (CT) on admission showed a high-density mass with a double lumen in the right cerebellopontine angle without subarachnoid hemorrhage. Five days after the onset, she suddenly lost consciousness. CT demonstrated subarachnoid hemorrhage. Emergency angiography revealed a probable dissecting aneurysm at the lateral pontomedullary segment of the right AICA. Although the initial symptom is not hemorrhage, an unruptured dissecting aneurysm of the AICA may have a high risk of rupture. Immediate radical treatment to prevent subsequent rupture is necessary for even an unruptured dissecting aneurysm of the AICA. PMID- 26015095 TI - Improving the Prediction of Spontaneous and Post-thrombolytic Recanalization in Ischemic Stroke Patients. AB - BACKGROUND: Endovascular treatment for acute ischemic stroke patients was recently shown to improve recanalization rates and clinical outcome in a well defined study population. Intravenous thrombolysis (IVT) alone is insufficiently effective to recanalize in certain patients or of little value in others. Accordingly, we aimed at identifying predictors of recanalization in patients treated with or without IVT. METHODS: In the observational Acute Stroke Registry and Analysis of Lausanne (ASTRAL) registry, we selected those stroke patients (1) with an arterial occlusion on computed tomography angiography (CTA) imaging, (2) who had an arterial patency assessment at 24 hours (CTA/magnetic resonance angiography/transcranial Doppler), and (3) who were treated with IVT or had no revascularization treatment. Based on 2 separate logistic regression analyses, predictors of spontaneous and post-thrombolytic recanalization were generated. RESULTS: Partial or complete recanalization was achieved in 121 of 210 (58%) thrombolyzed patients. Recanalization was associated with atrial fibrillation (odds ratio , 1.6; 95% confidence interval, 1.2-3.0) and absence of early ischemic changes on CT (1.1, 1.1-1.2) and inversely correlated with the presence of a significant extracranial (EC) stenosis or occlusion (.6, .3-.9). In nonthrombolyzed patients, partial or complete recanalization was significantly less frequent (37%, P < .01). The recanalization was independently associated with a history of hypercholesterolemia (2.6, 1.2-5.6) and the proximal site of the intracranial occlusion (2.5, 1.2-5.4), and inversely correlated with a decreased level of consciousness (.3, .1-.8), and EC (.3, .1-.6) and basilar artery pathology (.1, .0-.6). CONCLUSIONS: Various clinical findings, cardiovascular risk factors, and arterial pathology on acute CTA-based imaging are moderately associated with spontaneous and post-thrombolytic arterial recanalization at 24 hours. If confirmed in other studies, this information may influence patient selection toward the most appropriate revascularization strategy. PMID- 26015097 TI - This staffing model is great news for nursing. AB - Imagine working in an NHS organisation that enforces a 70:30 split between registered and unregistered staff, and that ensures ward sisters and those in similar roles are wholly supervisory; where hospital managers guarantee there will be between 1.25 and 1.8 nurses per bed. Well, this is exactly what is being promised by the five NHS trusts in Northern Ireland, as you can discover by reading a feature in this week's Nursing Standard. PMID- 26015096 TI - Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation. AB - Kruppel-like transcription factors (Klfs), each of which contains a CACCC-box binding domain, have been investigated in a variety of developmental processes, such as angiogenesis, neurogenesis and somatic-cell reprogramming. However, the function and molecular mechanism by which the Klf family acts during developmental hematopoiesis remain elusive. Here, we report identification of 24 Klf family genes in zebrafish using bioinformatics. Gene expression profiling shows that 6 of these genes are expressed in blood and/or vascular endothelial cells during embryogenesis. Loss of function of 2 factors (klf3 or klf6a) leads to a decreased number of mature erythrocytes. Molecular studies indicate that both Klf3 and Klf6a are essential for erythroid cell differentiation and maturation but that these two proteins function in distinct manners. We find that Klf3 inhibits the expression of ferric-chelate reductase 1b (frrs1b), thereby promoting the maturation of erythroid cells, whereas Klf6a controls the erythroid cell cycle by negatively regulating cdkn1a expression to determine the rate of red blood cell proliferation. Taken together, our study provides a global view of the Klf family members that contribute to hematopoiesis in zebrafish and sheds new light on the function and molecular mechanism by which Klf3 and Klf6a act during erythropoiesis in vertebrates. PMID- 26015098 TI - NI Macmillan nurse wins RCN accolade. AB - Macmillan cancer nurse specialist Cherith Semple has been named RCN Northern Ireland Nurse of the Year. PMID- 26015099 TI - Hospitals must stop being 'ripped off' by staff agencies - NHS chief. AB - Hospitals should cap their spending on agency staff, including nurses, says the chief executive of NHS England. PMID- 26015100 TI - ICN reiterates its call for more Ebola protection. AB - The International Council of Nurses (ICN) has repeated its call for safer working environments for nurses working in countries hit by the Ebola epidemic. PMID- 26015101 TI - Patient concerns over low staffing levels revealed. AB - Staff shortages are negatively affecting patients' experiences of care, RCN general secretary Peter Carter has said in response to findings from the latest national NHS inpatient survey. PMID- 26015102 TI - Regulator to consult on language competency testing for EEA workers. AB - The Nursing and Midwifery Council will hold a 12-week public consultation on new English language competence requirements for European Economic Area (EEA) nurses registering in the UK. PMID- 26015103 TI - Pilot trust introduces new checks to prepare staff for revalidation. AB - A London trust is asking its nurses to reflect on their practice and the Nursing and Midwifery Council's new code for nurses and midwives as part of their annual appraisals to prepare them for revalidation. PMID- 26015104 TI - 'Talk to new recruits about their use of social media'. AB - Senior nurses should be talking to newly qualified nurses about their social media profiles to ensure they are suitable for the workplace, says NHS England's head of patient experience - maternity, newborn, children and young people. PMID- 26015105 TI - Hospital staff caught up in Chua killings offered support by trust. AB - Nurses who unwittingly administered saline contaminated by a colleague to murder two patients and poison 20 others have been given counselling. PMID- 26015107 TI - Trusts set to trial hand-held scanner for pressure ulcers. AB - Twenty-nine UK trusts are in line to trial a hand-held scanner that spots early signs of tissue damage and could help reduce the incidence of pressure ulcers. PMID- 26015108 TI - New guidance for assessing dementia. AB - Guidance for professionals who assess people with dementia for NHS continuing healthcare - a free package of nursing and personal care - has been published by the Alzheimer's Society. PMID- 26015109 TI - Care homes struggle to balance rising costs with fall in funding. AB - Next month at RCN congress members will be asked to vote to lobby governments to recognise the true cost of caring for older people. PMID- 26015115 TI - Progestogen-only pills. AB - Essential facts Oral contraception remains the most popular method of birth control for a majority of women in the UK. According to a 2012/13 report by the Health and Social Care Information Centre, it was chosen by 47% of women attending NHS community contraceptive clinics in England. An Office of National Statistics survey of 2008/09 shows that of the three quarters of UK women aged up to 49 using contraception, a third were prescribed the contraceptive pill. Of these, 6% used progestogen-only pills, also known as the mini-pill or POP. PMID- 26015116 TI - Designing the service around the patient. PMID- 26015117 TI - How to pin down 'butterfly' care. PMID- 26015118 TI - 'A light at the end of the tunnel'. PMID- 26015128 TI - Alzheimer's society. AB - With a vast amount of content ranging from legal and financial information to details of activities in your local area, the Alzheimer's Society website is a valuable resource for patients and carers. PMID- 26015129 TI - Hearing voices. AB - This free app was created to help and empower people who experience the challenge of hearing voices, and to aid their relatives, carers and health professionals in understanding this phenomenon. PMID- 26015131 TI - Our Ebola teams in Sierra Leone are up there with the bravest. AB - I recently had the privilege of attending a symposium at Royal Military Academy Sandhurst, organised by the director of army nursing services Colonel David Bates. PMID- 26015132 TI - Far from a 'fallback' job option, care home nursing is a privilege. AB - How sad to read that care home nursing is seen as 'something people do when they cannot get a job elsewhere' (News, April 29). I chose care home nursing straight out of university. PMID- 26015133 TI - Policies will only increase pressure on nurses and GPs, not improve care. AB - I find it hard to believe that the new Conservative government is pushing ahead with plans to introduce a seven-day NHS by 2020 (News, May 13). Have they not noticed that this already exists, with consultant cover? PMID- 26015136 TI - The past can teach us much about educators in clinical practice. AB - I agree with the remarks made by James Smith about the absence of nurse educators in UK clinical settings (Letters, April 29). PMID- 26015137 TI - The NMC should know spiritual care is as important as ever. AB - I support the campaign to have spirituality included in the Nursing and Midwifery Council's code of conduct (Reflections, April 29). I was disturbed to find that it was not there when the new Code was published in March. PMID- 26015138 TI - Spare a thought for managers stuck in the middle of this crisis. AB - With the NHS - and nursing in particular - under a great deal of strain at the moment, it is easy for healthcare staff to feel stressed, pressured and overwhelmed at times. PMID- 26015140 TI - Brain function, disease and dementia. AB - Dementia is a consequence of brain disease. This article, the second in this series on dementia, discusses normal brain function and how certain functions are localised to different areas of the brain. This is important in determining the symptoms of dementia, depending on which parts of the brain are most directly involved. The most common types of dementia - Alzheimer's disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia - affect the brain in different ways and cause different changes at the microscopic level. Dementia is affected by genetics, and recent advances in molecular techniques have improved our understanding of some of the mechanisms involved, which in turns suggests possibilities for new treatments in the future. PMID- 26015141 TI - Using the Delphi technique in nursing research. AB - The Delphi technique is often used when consensus views of experts are sought in nursing education, management and clinical work. This article discusses the usefulness of the technique for research in nursing, using personal experience, past critiques and examples from contemporary nursing research. PMID- 26015142 TI - Spirituality in nursing practice. AB - Spirituality is an important aspect of holistic care that is frequently overlooked. This is because of difficulties in conceptualising spirituality and confusion about how it should be integrated into nursing care. This article explores what is meant by spirituality and spiritually competent practice. It examines attitudes to spirituality, describes factors that might affect the integration of spirituality into nursing care and offers practical guidance to equip nurses to incorporate spirituality into their practice. PMID- 26015143 TI - Advance care planning. AB - The continuing professional development article on advance care planning prompted reflection on my role as a nurse caring for older people, some of whom have progressive neurological conditions. Progression is often unpredictable and this uncertainty can cause considerable anxiety for patients and their families. Cognitive impairment can also affect the individual's ability to communicate. PMID- 26015144 TI - A community approach. AB - Since extra nurses were recruited for a north east England community children's nursing team and some services reallocated from hospital to the community, it has been possible to care for very sick children at home. PMID- 26015145 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26015146 TI - Recruitment network. AB - An innovative campaign developed on social media has helped an NHS trust to attract and recruit more than 150 qualified nurses. PMID- 26015147 TI - Always think 'always events'. AB - The concept of 'never events' - largely preventable patient safety incidents such as surgery on the wrong body part - has been widely used in managing healthcare quality. The focus is on fixing what is wrong in an institution, although it is not possible to prevent every never event, nor do they always indicate negligence. PMID- 26015148 TI - Student life - Outstanding beginnings. AB - The Cavell nursing student awards are given to recognise exceptional nursing and midwifery students. Each year, five scholarships are offered for placements in the UK or abroad. PMID- 26015149 TI - Prospective analysis of cardiac collapsibility of inferior vena cava using ultrasonography. AB - PURPOSE: The inferior vena cava (IVC) diameter and its respiratory change (respiratory variation) reportedly correlate well with the central venous pressure and response to fluid. However, changes in the IVC diameter are related to the cardiac rhythm (cardiac variation), which can be useful as an indicator for intravascular volume but can affect respiratory variation. We conducted a prospective analysis of this cardiac variation in adult emergency department patients. METHODS: Ultrasonographic IVC images from 190 consecutive adult emergency department patients were collected prospectively. The IVC diameters 2 cm caudal from the middle hepatic vein were tracked automatically and measured. The IVC diameter changes were analyzed using a software program that tracks 2 dimensional motion in B-mode images. Cardiac and respiratory variations were calculated and analyzed. RESULTS: The average IVC cardiac variation was 11.0% (95% confidence interval, 9.8%-12.3%) in these patients, which affects the respiratory variation resulting in 1.68-fold higher overestimation of respiratory variation. The coefficient of correlation between IVC cardiac variations and respiratory variations was 0.34 (P < .05). CONCLUSIONS: The IVC cardiac variation affects our interpretation of ultrasonography IVC imaging. The IVC cardiac variation provides several advantages over other parameters of intravascular volume. Therefore, it can be a novel tool to assess the intravascular volume of the patients. PMID- 26015150 TI - Mean arterial pressure and mean perfusion pressure deficit in septic acute kidney injury. AB - BACKGROUND: Changes in mean perfusion pressure (MPP) from premorbid resting values may contribute to the progression of septic acute kidney injury (AKI). OBJECTIVES: In patients with septic shock, we aimed to investigate the association of changes from premorbid values with AKI severity and progression. METHODS: We obtained premorbid resting mean arterial pressure (MAP), central venous pressure (CVP), and MPP, and then recorded data from intensive care unit admission 2 hourly for the first 24 hours to calculate hemodynamic deficits. We recorded 4-hourly creatinine measurements for 96 hours. The association of hemodynamic variables with progression of AKI by Kidney Disease: Improving Global Outcomes >=2 stages was explored by multivariate logistic regression. RESULTS: Of 107 patients, 55 (51.4%) had severe AKI. Median MAP deficit was similar for patients with or without severe AKI. Median MPP deficit was 29% in patients with severe AKI and 24% in those without (P = .04), a difference determined by greater CVP levels. Central venous pressure was independently associated with worsening AKI (odds ratio, 1.26 [95% confidence interval, 1.01-1.58]; P = .04). CONCLUSIONS: Mean arterial pressure and MPP deficits were substantial in septic shock patients, with patients with severe AKI having a greater MPP deficit. However, only CVP was independently associated with AKI progression. These findings suggest a possible role for venous congestion in septic AKI. PMID- 26015151 TI - Mitigating nonurgent interruptions during high-severity intensive care unit tasks using a task-severity awareness tool: A quasi-controlled observational study. AB - PURPOSE: In a previous study of interruptions to intensive care unit (ICU) nurses, we found that other personnel tend to regulate their interruptions based on nurses' tasks. However, nurses' tasks are not always immediately visible to an interrupter. This article evaluates a task-severity awareness tool (TAT) designed for nurses to inform others when they are performing high-severity tasks. When a nurse engages the tool within an ICU room, a "do not disturb please!" message is displayed outside the room. METHODS: Task-severity awareness tool was installed in a cardiovascular ICU room at a Canadian hospital. Fifteen nurses assigned to the TAT room and 13 nurses assigned to 11 other rooms were observed, approximately 2 hours each, over a 3-week period. Data were collected in real time, using a tablet computer. RESULTS: Interruption rate during high-severity tasks in the TAT room was significantly lower than in other rooms; interruptions with personal content were entirely mitigated during high-severity tasks. Furthermore, interruptions from nurses and medical doctors were also entirely mitigated during high-severity tasks but happened more frequently during non-high severity tasks compared with rooms with no TAT. CONCLUSIONS: Task-severity awareness tool proved to be effective in mitigating unnecessary interruptions to critical tasks. Future research should assess its long-term effectiveness. PMID- 26015152 TI - Inequality in oral health-related quality of life before and after a major subsidization reform. AB - In Finland, a dental subsidization reform, implemented in 2001-2002, abolished age restrictions on subsidized dental care. We investigated income-related inequality in oral health-related quality of life (OHRQoL) and its determinants among adult Finns before and after the reform. Three cross-sectional postal surveys, focusing on perceived oral health and the use of dental services among people born before 1971, were conducted in 2001 (n = 2,046), 2004 (n = 1,728), and 2007 (n = 1,560). Five measures, based on the Oral Health Impact Profile-14, were used as indicators of OHRQoL. Income-related inequality and associated factors were analysed using the concentration index and its decomposition. Prevalence, extent, and severity of oral health impacts were slightly lower in 2007 than in 2001. The oral health impacts were concentrated, at all study time points, among individuals with lower income. Most of the inequality was related to self-perceived general health, tooth loss, and income. Contributions of time since the last dental visit and satisfaction with the last treatment period to the inequality decreased from 2001 to 2007. However, the contributions of these factors were already small (10-20%) in 2001. In general, OHRQoL improved slightly; however, no clear or dramatic change in inequality in OHRQoL was seen after the reform. PMID- 26015153 TI - The Role of Substituent Effects in Tuning Metallophilic Interactions and Emission Energy of Bis-4-(2-pyridyl)-1,2,3-triazolatoplatinum(II) Complexes. AB - The photoluminescence spectra of a series of 5-substituted pyridyl-1,2,3 triazolato Pt(II) homoleptic complexes show weak emission tunability (ranging from lambda=397-408 nm) in dilute (10(-6) M) ethanolic solutions at the monomer level and strong tunability in concentrated solutions (10(-4) M) and thin films (ranging from lambda=487-625 nm) from dimeric excited states (excimers). The results of density functional calculations (PBE0) attribute this "turn-on" sensitivity and intensity in the excimer to strong Pt-Pt metallophilic interactions and a change in the excited-state character from singlet metal-to ligand charge transfer ((1)MLCT) to singlet metal-metal-to-ligand charge transfer ((1)MMLCT) emissions in agreement with lifetime measurements. PMID- 26015154 TI - Sensitivity and specificity of CT- and MRI-scanning in evaluation of occult fracture of the proximal femur. AB - OBJECTIVE: To estimate sensitivity and specificity of CT and MRI examinations in patients with fractures of the proximal femur. To determine the interobserver agreement of the modalities among a senior consulting radiologist, a resident in radiology and a resident in orthopaedics surgery. MATERIALS AND METHODS: 67 patients (27 males, 40 females, mean age 80.5) seen in the emergency room with hip pain after fall, inability to stand and a primary X-ray without fracture were evaluated with both CT and MRI. The images were analysed by a senior consulting musculoskeletal radiologist, a resident in radiology and a resident in orthopaedic surgery. Sensitivity and specificity were estimated with MRI as the golden standard. Kappa value was used to assess level of agreement in both MRI and CT finding. RESULTS: 15 fractures of the proximal femur were found (7 intertrochanteric-, 3 femoral neck and 5 fractures of the greater trochanter). Two fractures were not identified by CT and four changed fracture location. Among those, three patients underwent surgery. Sensitivity of CT was 0.87; 95% CI [0.60; 0.98]. Kappa for interobserver agreement for CT were 0.46; 95% CI [0.23; 0.76] and 0.67; 95% CI [0.42; 0.90]. For MRI 0.67; 95% CI [0.43; 0.91] and 0.69; 95% CI [0.45; 0.92]. CONCLUSION: MRI was observed to have a higher diagnostic accuracy than CT in detecting occult fractures of the hip. Interobserver analysis showed high kappa values corresponding substantial agreement in both CT and MRI. PMID- 26015155 TI - Displaced supracondylar humeral fractures: influence of delay of surgery on the incidence of open reduction, complications and outcome. AB - BACKGROUND: Closed reduction and pinning is the accepted treatment choice for dislocated supracondylar humeral fractures in children (SCHF). Rates of open reduction, complications and outcome are reported to be dependent on delay of surgery. We investigated whether delay of surgery had influence on the incidence of open reduction, complications and outcome of surgical treatment of SCHFs in the authors' institution. METHODS: Three hundred and forty-one children with 343 supracondylar humeral fractures (Gartland II: 144; Gartland III: 199) who underwent surgery between 2000 and 2009 were retrospectively analysed. The group consisted of 194 males and 149 females. The average age was 6.3 years. Mean follow-up was 6.2 months. Time interval between trauma and surgical intervention was determined using our institutional database. Clinical and radiographical data were collected for each group. Influence of delay of treatment on rates of open reduction, complications and outcome was calculated using logistic regression analysis. Furthermore, patients were grouped into 4 groups of delay (<6 h, n = 166; 6-12 h, n = 95; 12-24 h, n = 68; >24 h, n = 14) and the aforementioned variables were compared among these groups. RESULTS: The incidence of open procedures in 343 supracondylar humeral fractures was 2.6 %. Complication rates were similar to the literature (10.8 %) primarily consisting of transient neurological impairments (9.0 %) which all were fully reversible by conservative treatment. Poor outcome was seen in 1.7 % of the patients. Delay of surgical treatment had no influence on rates of open surgery (p = 0.662), complications (p = 0.365) or poor outcome (p = 0.942). CONCLUSIONS: In this retrospective study delay of treatment of SCHF did not have significant influence on the incidence of open reduction, complications, and outcome. Therefore, in SCHF with sufficient blood perfusion and nerve function, elective treatment is reasonable to avoid surgical interventions in the middle of the night which are stressful and wearing both for patients and for surgeons. LEVEL OF EVIDENCE: III (retrospective comparative study). PMID- 26015156 TI - Co-expression of GAD67 and choline acetyltransferase reveals a novel neuronal phenotype in the mouse medulla oblongata. AB - GABAergic and cholinergic systems play an important part in autonomic pathways. To determine the distribution of the enzymes responsible for the production of GABA and acetylcholine in areas involved in autonomic control in the mouse brainstem, we used a transgenic mouse expressing green fluorescent protein (GFP) in glutamate decarboxylase 67 (GAD67) neurones, combined with choline acetyl transferase (ChAT) immunohistochemistry. ChAT-immunoreactive (IR) and GAD67-GFP containing neurones were observed throughout the brainstem. A small number of cells contained both ChAT-IR and GAD67-GFP. Such double labelled cells were observed in the NTS (predominantly in the intermediate and central subnuclei), the area postrema, reticular formation and lateral paragigantocellular nucleus. All ChAT-IR neurones in the area postrema contained GAD67-GFP. Double labelled neurones were not observed in the dorsal vagal motor nucleus, nucleus ambiguus or hypoglossal nucleus. Double labelled ChAT-IR/GAD67-GFP cells in the NTS did not contain neuronal nitric oxide synthase (nNOS) immunoreactivity, whereas those in the reticular formation and lateral paragigantocellular nucleus did. The function of these small populations of double labelled cells is currently unknown, however their location suggests a potential role in integrating signals involved in oromotor behaviours. PMID- 26015157 TI - Correlation between Enterococcus faecalis and Persistent Intraradicular Infection Compared with Primary Intraradicular Infection: A Systematic Review. AB - INTRODUCTION: The relationship between Enterococcus faecalis and pulpal or periradicular diseases has been studied for many years; however, whether E. faecalis is correlated with persistent intraradicular infections (teeth after failed endodontic treatments) compared with primary intraradicular infections remains controversial. The objective of this systematic review was to compare the prevalence of E. faecalis in primary and persistent intraradicular infections. METHODS: An exhaustive literature search combined with specified inclusion criteria was performed to collect all studies comparing the prevalence of E. faecalis in root canals with primary and persistent intraradicular infections. Descriptive statistics were applied first because of the high heterogeneity among studies. Subgroup analysis according to different detecting methods (culture and polymerase chain reaction) and sensitivity analysis was then applied. Meta analysis was conducted with the help of Stata/SE 12.0 (StataCorp, College Station, TX) after excluding studies with uncertain forms of pulpal and periradicular lesions in their primary infection groups. RESULTS: The systematic review included 10 studies covering 972 teeth. Among them, 2 studies used the culture technique, 6 studies used polymerase chain reaction, and the other 2 used both techniques. The detection rate of E. faecalis by both methods was higher in persistent infections compared with untreated chronic periapical periodontitis as primary infections. The difference was statistically significant (odds ratio = 7.247; 95% confidence interval, 4.039-13.002). CONCLUSIONS: E. faecalis is more highly correlated with persistent intraradicular infections compared with untreated chronic periapical periodontitis. PMID- 26015158 TI - Comparative Study of Pulpal Responses to Pulpotomy with ProRoot MTA, RetroMTA, and TheraCal in Dogs' Teeth. AB - INTRODUCTION: This study was conducted to evaluate and compare pulpal responses to ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK), RetroMTA (Meta Biomed Co, Ltd, Seoul, Korea), and TheraCal (Bisco Inc, Schamburg, IL) in dog partial pulpotomy models. METHODS: Partial pulpotomies were performed on 60 beagle teeth. The exposed pulp tissues were randomly capped with either ProRoot MTA (n = 15), RetroMTA (n = 15), TheraCal (n = 15), or interim restorative material as a negative control (n = 15). After 4 weeks, the teeth were extracted and processed for histologic and immunohistochemical examinations using osteocalcin and dentin sialoprotein. Calcific barrier formation, inflammatory reaction, and the odontoblastic layer were evaluated and scored in a blind manner. The areas of newly formed calcific barriers were measured for each group. RESULTS: In most of the ProRoot MTA and RetroMTA specimens, continuous calcific barriers were formed, and the pulps contained palisading patterns in the odontoblastic layer that were free of inflammation. However, the TheraCal specimens had lower quality calcific barrier formation, extensive inflammation, and less favorable odontoblastic layer formation. Overall, areas of newly formed calcific barrier were higher in the ProRoot MTA and RetroMTA specimens than in the TheraCal specimens. Also, immunohistochemistry revealed that osteocalcin and dentin sialoprotein were more clearly visible in the ProRoot MTA and RetroMTA specimens than in the TheraCal specimens. CONCLUSIONS: RetroMTA could provide an alternative to ProRoot MTA. Both materials produced favorable pulpal responses that were similar in nature, whereas TheraCal produced less favorable pulpal responses. PMID- 26015159 TI - General Dentists' Use of Isolation Techniques during Root Canal Treatment: From the National Dental Practice-based Research Network. AB - INTRODUCTION: A preliminary study done by a National Dental Practice-Based Research Network precursor observed that 44% of general dentists (GDs) reported always using a rubber dam (RD) during root canal treatment (RCT). This full-scale study quantified the use of all isolation techniques, including RD use. METHODS: Network practitioners completed a questionnaire about isolation techniques used during RCT. Network enrollment questionnaire data provided practitioner characteristics. RESULTS: One thousand four hundred ninety of 1716 eligible GDs participated (87%); 697 (47%) reported always using an RD. This percentage varied by tooth type. These GDs were more likely to always use an RD, do not own a private practice, perform less than 10 RCTs/month, and have postgraduate training. CONCLUSIONS: Most GDs do not use an RD all the time. Ironically, RDs are used more frequently by GDs who do not perform molar RCT. RD use varies with tooth type and certain dentist, practice, and patient characteristics. PMID- 26015160 TI - Topology, dynamics, and heterogeneity in immune signaling. AB - Development and function of the immune system depends on cells exchanging information between themselves and with their environment. This information is processed and integrated by complex signal transduction and gene regulatory networks with rich temporal dynamics. A growing body of evidence points to a combination of network topology and temporal dynamics as a fundamental link between stimulus and function. Recent findings also bring cellular variability and stochastic events to the forefront as additional determinants of cell population responses to immune cues. In this article, we review examples of how the trinity of network topology, temporal dynamics, and cellular variability together determine the immune function. In particular we focus on Nuclear Factor kappa-B and T-cell receptor signaling networks as they have proven fertile ground for studying how function arises from the combination of topology, dynamics, and variability in a context of great clinical importance. PMID- 26015162 TI - Solar Water Splitting at lambda=600 nm: A Step Closer to Sustainable Hydrogen Production. AB - Overall water splitting with a semiconductor photocatalyst under visible-light irradiation is considered as a "dream reaction" in chemistry. The development of a 600 nm photocatalyst for solar water splitting highlighted here is not only an important milestone towards sustainable hydrogen production, but also a new starting point for artificial photosynthesis. STH=solar-to-hydrogen energy conversion efficiency. PMID- 26015161 TI - Hexavalent chromium-induced differential disruption of cortical microtubules in some Fabaceae species is correlated with acetylation of alpha-tubulin. AB - The effects of hexavalent chromium [Cr(VI)] on the cortical microtubules (MTs) of five species of the Fabaceae family (Vicia faba, Pisum sativum, Vigna sinensis, Vigna angularis, and Medicago sativa) were investigated by confocal laser scanning microscopy after immunolocalization of total tubulin with conventional immunofluorescence techniques and of acetylated alpha-tubulin with the specific 6 11B-1 monoclonal antibody. Moreover, total alpha-tubulin and acetylated alpha tubulin were quantified by Western immunoblotting and scanning densitometry. Results showed the universality of Cr(VI) detrimental effects to cortical MTs, which proved to be a sensitive and reliable subcellular marker for monitoring Cr(VI) toxicity in plant cells. However, a species-specific response was recorded, and a correlation of MT disturbance with the acetylation status of alpha-tubulin was demonstrated. In V. faba, MTs were depolymerized at the gain of cytoplasmic tubulin background and displayed low alpha-tubulin acetylation, while in P. sativum, V. sinensis, V. angularis, and M. sativa, MTs became bundled and changed orientation from perpendicular to oblique or longitudinal. Bundled MTs were highly acetylated as determined by both immunofluorescence and Western immunoblotting. Tubulin acetylation in P. sativum and M. sativa preceded MT bundling; in V. sinensis it followed MT derangement, while in V. angularis the two phenomena coincided. Total alpha-tubulin remained constant in all treatments. Should acetylation be an indicator of MT stabilization, it is deduced that bundled MTs became stabilized, lost their dynamic properties, and were rendered inactive. Results of this report allow the conclusion that Cr(VI) toxicity disrupts MTs and deranges the MT-mediated functions either by depolymerizing or stabilizing them. PMID- 26015163 TI - Antidiabetic and cardiovascular drug utilisation in patients diagnosed with type 2 diabetes mellitus over the age of 80 years: a population-based cohort study. AB - BACKGROUND: there is a lack of evidence to inform treatment recommendations for very old people with type 2 diabetes mellitus (T2DM). OBJECTIVE: to evaluate trends in antidiabetic and cardiovascular drug utilisation for patients developing T2DM over 80 years of age. METHODS: a population-based cohort was sampled from the UK Clinical Practice Research Datalink between 1990 and 2013. Eligible patients were those with T2DM diagnosed after the age of 80 years and prescribed antidiabetic drugs. RESULTS: twelve thousand eight hundred and eighty one patients, with 61% of females, were included. From 1990 to 2013, use of sulphonylureas declined from 94 to 29%, while metformin use increased from 22 to 86%. Prescribing of antihypertensive drugs increased substantially from 46 to 77%, lipid-lowering drugs from 1 to 64%, antiplatelets from 34 to 47% and oral anticoagulants from 5 to 19%. Women were more frequently prescribed antihypertensive drugs (odds ratio 1.26, 95% confidence interval 1.17 to 1.37) but less prescribed antiplatelets (0.83, 0.78 to 0.89). Compared with those diagnosed with T2DM from 80 to 89 years (n = 11,467, 89%), patients diagnosed after the age of 90 years (n = 1,414, 11%) were less likely to be prescribed insulin (0.37, 0.24 to 0.58), metformin (0.67, 0.60 to 0.75), antihypertensive drugs (0.42, 0.38 to 0.48), lipid-lowering drugs (0.26, 0.23 to 0.30) and anticoagulants (0.55, 0.44 to 0.68). CONCLUSIONS: there have been major increases in the intensity of pharmacological management of patients diagnosed with T2DM over 80 years of age, but the effectiveness and safety of these interventions in very old people require further evaluation. PMID- 26015164 TI - Integrated Medicine and Psychiatry Curriculum for Psychiatry Residency Training: a Model Designed to Meet Growing Mental Health Workforce Needs. PMID- 26015165 TI - H syndrome: a multifaceted histiocytic disorder with hyperpigmentation and hypertrichosis. PMID- 26015167 TI - Epigenetic regulation in the acute kidney injury to chronic kidney disease transition. AB - Epigenetic modifications have emerged as a new, important contributor to gene expression regulation in both normal and pathophysiological conditions. Epigenetics have been studied in many diseases and conditions such as acute kidney injury (AKI), a syndrome with a high prevalence that carries a poor prognosis with increased morbidity and mortality. In addition, it has recently been shown that AKI increases the risk for the development of chronic kidney disease (CKD). The specific molecular mechanisms by which AKI increases the risk of CKD and end stage renal disease (ESRD) remain unknown, although there is new evidence supporting a role of epigenetic changes. The most studied epigenetic regulations in AKI are chromatin compaction, DNA methylation, and histone acetylation/deacetylation. These modifications predominantly increase the production of pro-inflammatory and profibrotic cytokines such as: monocyte chemoattractant protein-1 (MCP-1), complement protein 3 (C3), transforming growth factor beta (TGF-beta) that have been shown for perpetuating inflammation, promoting epithelial-to-mesenchymal transition (EMT) and ultimately causing renal fibrosis. A review of epigenetic mechanisms, the pathophysiology of AKI and recent studies that implicate epigenetic modifications in AKI and in the transition to CKD are discussed below. PMID- 26015166 TI - An Optimized Informatics Pipeline for Mass Spectrometry-Based Peptidomics. AB - The comprehensive MS analysis of the peptidome, the intracellular and intercellular products of protein degradation, has the potential to provide novel insights on endogenous proteolytic processing and its utility in disease diagnosis and prognosis. Along with the advances in MS instrumentation and related platforms, a plethora of proteomics data analysis tools have been applied for direct use in peptidomics; however, an evaluation of the currently available informatics pipelines for peptidomics data analysis has yet to be reported. In this study, we began by evaluating the results of several popular MS/MS database search engines, including MS-GF+, SEQUEST, and MS-Align+, for peptidomics data analysis, followed by identification and label-free quantification using the well established accurate mass and time (AMT) tag and newly developed informed quantification (IQ) approaches, both based on direct LC-MS analysis. Our results demonstrated that MS-GF+ outperformed both SEQUEST and MS-Align+ in identifying peptidome peptides. Using a database established from MS-GF+ peptide identifications, both the AMT tag and IQ approaches provided significantly deeper peptidome coverage and less missing data for each individual data set than the MS/MS methods, while achieving robust label-free quantification. Besides having an excellent correlation with the AMT tag quantification results, IQ also provided slightly higher peptidome coverage. Taken together, we propose an optimized informatics pipeline combining MS-GF+ for initial database searching with IQ (or AMT tag) approaches for identification and label-free quantification for high-throughput, comprehensive, and quantitative peptidomics analysis. Graphical Abstract ?. PMID- 26015168 TI - Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It's Been .... AB - BACKGROUND: The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine. Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science. However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research. Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis. Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence. OBJECTIVE: To review the history of medicinal cannabis use, discuss the pharmacology and physiology of the endocannabinoid system and cannabis-derived cannabinoids, perform a comprehensive literature review of the clinical uses of medicinal cannabis and cannabinoids with a focus on migraine and other headache disorders, and outline general clinical practice guidelines. CONCLUSION: The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache. Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research. Cannabis contains an extensive number of pharmacological and biochemical compounds, of which only a minority are understood, so many potential therapeutic uses likely remain undiscovered. Cannabinoids appear to modulate and interact at many pathways inherent to migraine, triptan mechanisms ofaction, and opiate pathways, suggesting potential synergistic or similar benefits. Modulation of the endocannabinoid system through agonism or antagonism of its receptors, targeting its metabolic pathways, or combining cannabinoids with other analgesics for synergistic effects, may provide the foundation for many new classes of medications. Despite the limited evidence and research suggesting a role for cannabis and cannabinoids in some headache disorders, randomized clinical trials are lacking and necessary for confirmation and further evaluation. PMID- 26015169 TI - Thermoluminescence properties of gamma-irradiated nano-structure hydroxyapatite. AB - The suitability of nano-structured hydroxyapatite (HAP) for use as a thermoluminescence dosimeter was investigated. HAP samples were synthesized using a hydrolysis method. The formation of nanoparticles was confirmed by X-ray diffraction and average particle size was estimated to be ~30 nm. The glow curve exhibited a peak centered at around 200 degrees C. The additive dose method was applied and this showed that the thermoluminescence (TL) glow curves follow first order kinetics due to the non-shifting nature of Tm after different doses. The numbers of overlapping peaks and related kinetic parameters were identified from Tm -Tstop through computerized glow curve deconvolution methods. The dependence of the TL responses on radiation dose was studied and a linear dose response up to 1000 Gy was observed for the samples. PMID- 26015170 TI - Resistant starches differentially stimulate Toll-like receptors and attenuate proinflammatory cytokines in dendritic cells by modulation of intestinal epithelial cells. AB - SCOPE: Main objectives of this study were (1) to demonstrate direct signaling of starch on human dendritic cells (DCs), (2) to study whether this is mediated by the pattern recognition receptors such as Toll-like receptors (TLRs) and (3) to study whether intestinal epithelial cells (IECs) are involved in modulating the starch induced immune activation of DCs. METHODS AND RESULTS: Two different types of resistant starch, High-maize(r) 260 (RS2) and Novelose(r) 330 (RS3) were characterized for their starch content and particle size. Human DCs and reporter cells for TLRs were incubated with starches and analyzed for NF-kB/AP-1 activation. Complex coculture systems were applied to study the cross-talk. High maize(r) 260 predominantly binds to TLR2 while Novelose(r) 330 binds to TLR2 and TLR5. The strong immune-stimulating effects of High-maize(r) 260 were attenuated by starch-exposed IECs illustrating the regulatory function of IECs. Despite these attenuating effects, DCs kept producing Th1 cytokines. CONCLUSION: Resistant starch possesses direct signaling capacity on human DCs in a starch type-dependent manner. IECs regulate these responses. High-maize(r) 260 skews toward a more regulatory phenotype in coculture systems of DCs, IEC, and T cells. PMID- 26015171 TI - A Self-Assembled Spherical Complex Displaying a Gangliosidic Glycan Cluster Capable of Interacting with Amyloidogenic Proteins. AB - Physiological and pathological functions of glycans are promoted through their clustering effects as exemplified by a series of gangliosides, sialylated glycosphingolipids, which serve as acceptors for bacterial toxins and viruses. Furthermore, ganglioside GM1 clusters on neuronal cell membranes specifically interact with amyloidogenic proteins, triggering their conformational transitions and leading to neurodegeneration. Here we develop a self-assembled spherical complex that displays a cluster of the GM1 pentasaccharide, and successfully demonstrate its ability to interact with amyloid beta and alpha-synuclein. Due to the lack of hydrophobic lipid moieties, which would stably trap these cohesive proteins or give rise to toxic aggregates, this artificial cluster enabled NMR spectroscopic characterization of the early encounter stage of protein interactions with its outer carbohydrate moieties, which were not observable with previous glycan clusters. PMID- 26015172 TI - One-pot liquid-phase exfoliation from graphite to graphene with carbon quantum dots. AB - Carbon quantum dots (CQDs) are novel carbon nanomaterials and are attracting increasing interest due to their good characteristics such as hydrophilicity, chemical stability, quantum yield, small particle sizes, and low cytotoxicity. Herein, we used CQDs as stabilizers and exfoliation agents to exfoliate graphite to graphene in an aqueous medium for the first time. The functions of CQDs are to reduce the surface tension of water to match that of graphite and to make weak interactions (pi-pi conjugation, hydrophobic force, and the Coulomb attraction) with the graphite surface. Different characterization methods were used to evaluate the presence of layers (<5 layers) of graphene sheets with fewer defects and low oxidation. In the future, CQDs can also be good candidates to exfoliate other two-dimensional materials, such as WS2, BN, MoS2, and g-C3N4, to form two dimensional heterostructures for a range of possible applications. PMID- 26015176 TI - [A painful connection. Urachal fistula]. PMID- 26015177 TI - [Bullying and abuse induce chronic pain]. PMID- 26015178 TI - [Distinguished award for the prokinetic drug prucalopride]. PMID- 26015179 TI - [Systemic dermatitis after Easter egg hunt]. PMID- 26015180 TI - [Physician network paves the way for newcomers]. PMID- 26015181 TI - [A sweat producing April Fool's Day]. PMID- 26015182 TI - [A small, reliable pocket-sized translator]. PMID- 26015183 TI - [CRP infection marker may soon have company]. PMID- 26015185 TI - [Employed, part of the team, in the MVZ and nonetheless a free physician]. PMID- 26015184 TI - [Travel vaccination not without treatment contract!]. PMID- 26015186 TI - [Who may actually offer desensitization?]. PMID- 26015187 TI - [After myocardial infarct: ticagrelor also has a long-term preventive effect]. PMID- 26015188 TI - [No improvement in the prognosis with CT angiography in suspected coronary heart disease]. PMID- 26015189 TI - [No large cost differences]. PMID- 26015190 TI - [Risk of cardiovascular complications cut in half?]. PMID- 26015191 TI - [Sustained weight loss heals atrial fibrillation]. PMID- 26015192 TI - [Heart risk due to testosterone?]. PMID- 26015193 TI - [Irritable bowel and dyspepsia require fingertip sensitivity]. PMID- 26015194 TI - [The pain is not imaginary!]. PMID- 26015195 TI - [When it tingles, burns and is painful]. PMID- 26015196 TI - [Music as co-analgesic]. PMID- 26015197 TI - [Exacerbations complicate the prognosis]. PMID- 26015198 TI - [Targeted against every genotype]. PMID- 26015199 TI - [Decreased blood pressure helps every diabetic patient long term]. PMID- 26015200 TI - [Long working hours lead to alcohol consumption]. PMID- 26015201 TI - [Accidental falls at home - a preventable evil]. PMID- 26015202 TI - [Self injury behavior: an early indication of problems]. PMID- 26015203 TI - [Craniotomy in Sierra Leone?]. PMID- 26015204 TI - [Olive oil also helps control atrial fibrillation]. PMID- 26015205 TI - [Joint soft tissues suddenly become hard]. PMID- 26015206 TI - [The key role of primary care physicians in staging and managing early stages of chronic kidney disease]. PMID- 26015207 TI - [Emergency checklist: acute flank pain]. PMID- 26015208 TI - [Accidental finding: hypertriglyceridemia]. PMID- 26015209 TI - [Incidental findings of blood count]. PMID- 26015210 TI - [Serum uric acid reference values: clinical nonsense as a measure of quality]. PMID- 26015211 TI - [An uncommon way to treat the tophaceous gout]. PMID- 26015212 TI - [How to react to a wish towards hastening death in palliative care?]. PMID- 26015213 TI - [Hypertension education program - recommendations for health behavior management]. PMID- 26015214 TI - [Weight also counts for patients]. PMID- 26015215 TI - [Somatovital therapy receives the IPO Science Award]. PMID- 26015216 TI - [How can recurrences be prevented?]. PMID- 26015217 TI - [Prevention with lower bleeding risk]. PMID- 26015218 TI - [Fixed combination improves compliance]. PMID- 26015219 TI - [The first high concentrate meal time insulin is on the market]. PMID- 26015220 TI - [Insulin glulisin prevents subsequent damage effectively]. PMID- 26015221 TI - [Healing rate after 12 weeks over 90% for the first time]. PMID- 26015222 TI - Preface. PMID- 26015223 TI - Oxygen Evolution Catalyzed by a Mononuclear Ruthenium Complex Bearing Pendant SO3(-) Groups. AB - Rational molecular design of catalytic systems capable of smooth O-O bond formation is critical to the development of efficient catalysts for water oxidation. A new ruthenium complex was developed, which bears pendant SO3(-) groups in the secondary coordination sphere: [Ru(terpy)(bpyms)(OH2)] (terpy=2,2':6',2''-terpyridine, bpyms=2,2'-bipyridine-5,5' bis(methanesulfonate)). Water oxidation driven by a Ce(4+) oxidant is distinctly accelerated upon introduction of the pendant SO3(-) groups in comparisons to the parent catalyst, [Ru(terpy)(bpy)(OH2)](2+) (bpy=2,2'-bipyridine). Spectroscopic, electrochemical, and crystallographic investigations concluded that the pendant SO3(-) groups promote the formation of an O-O bond via the secondary coordination sphere on the catalyst, whereas the influence of the pendant SO3(-) groups on the electronic structure of the [Ru(terpy)(bpy)(OH2)](2+) core is negligible. The results of this work indicate that modification of the secondary coordination sphere is a valuable strategy for the design of water oxidation catalysts. PMID- 26015224 TI - Probing Ionic Crystals by the Invariom Approach: An Electron Density Study of Guanidinium Chloride and Carbonate. AB - A comparative study of two guanidinium salts, chloride and carbonate, is carried out to test the performance of the invariom approach for ionic crystals. Although treating them as formed by isolated ions with no charge transfer between them, the invariom approach provides features of interionic contacts that are amazingly similar to those obtained from conventional charge density analysis of high resolution X-ray diffraction data, thus emerging as an easy way towards reliable description of chemical bonding peculiarities in ionic crystals. PMID- 26015225 TI - Estrogen induces androgen-repressed SOX4 expression to promote progression of prostate cancer cells. AB - BACKGROUND: The sex determing region Y-box 4 (SOX4) gene is a critical developmental transcriptional factor that is overexpressed in prostate cancer (PCa). While we and others have investigated the role of SOX4 overexpression in PCa, the molecular mechanism underlying its aberrant expression remains unclear. METHODS: Immunohistochemistry were utilized to detect SOX4 expression and the correlation between estrogen receptor beta (ERbeta), androgen receptor (AR) and SOX4 in a cohort of 94 clinical specimens. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Immunofluorescence staining and co-immunoprecipitation were performed to assess the interaction and subcellular location of ERbeta and AR. Chromatin immunoprecipitation (ChIP) assays and Luciferase reporter assays were performed to explore the binding and transcriptional activities of ERbeta and AR to the SOX4 promoter. Cellular function was evaluated by MTS, invasion and wound healing assays. RESULTS: SOX4 expression is up-regulated in Castration-Resistant Prostate Cancer (CRPC) tumors compared to hormone-dependent PCa (HDPC) cases. Increased expression was also observed in PCa cells after long-term androgen-deprivation treatment (ADT). In vitro data indicated that SOX4 is an AR transcriptional target and down-regulated by dihydrotestosterone (DHT) via AR. 17beta-estradiol (E2) up-regulates SOX4 expression in the absence of androgen through the formation of a protein complex between ERbeta and AR. Knockdown of AR or ERbeta blocks the E2-induced SOX4 expression. ChIP assays confirmed that both ERbeta and AR bind to the SOX4 promoter in response to E2. Functionally, silencing SOX4 significantly attenuates the proliferative effect, as well as the capacity of migration and invasion of E2 on PCa cells. Clinically, overexpression of SOX4 is significantly associated with ERbeta expression in PCa. In addition, this association is still retained in CRPC patients with poor prognosis. CONCLUSION: These findings suggest that SOX4 is a novel DHT-repressed AR-target gene. E2 could promote proliferation of PCa cells through the up-regulation of SOX4 under androgen-depleted environment. Our data provides a possible molecular basis for the overexpression of SOX4 in CRPC and may facilitate the detection and prevention of the emergence of CRPC. PMID- 26015260 TI - Production of 13S-hydroxy-9(Z)-octadecenoic acid from linoleic acid by whole recombinant cells expressing linoleate 13-hydratase from Lactobacillus acidophilus. AB - Linoleate 13-hydratase from Lactobacillus acidophilus LMG 11470 converted linoleic acid to hydroxyl fatty acid, which was identified as 13S-hydroxy-9(Z) octadecenoic acid (13-HOD) by GC-MS and NMR. The expression of linoleate 13 hydratase gene in Escherichia coli was maximized by using pACYC plasmid and super optimal broth with catabolite repression (SOC) medium containing 40mM Mg(2+). To optimize induction conditions, recombinant cells were cultivated at 37 degrees C, 1mM isopropyl-beta-d-thiogalactopyranoside was added at 2h, and the culture was further incubated at 16 degrees C for 18h. Recombinant cells expressing linoleate 13-hydratase from L. acidophilus were obtained under the optimized expression conditions and used for 13-HOD production from linoleic acid. The optimal reaction conditions were pH 6.0, 40 degrees C, 0.25% (v/v) Tween 40, 25gl(-1) cells, and 100gl(-1) linoleic acid, and under these conditions, whole recombinant cells produced 79gl(-1) 13-HOD for 3h with a conversion yield of 79% (w/w), a volumetric productivity of 26.3gl(-1)h(-1), and a specific productivity of 1.05g g-cells(-1)h(-1). To the best of our knowledge, the recombinant cells produced hydroxy fatty acid with the highest concentration and productivity reported so far. PMID- 26015261 TI - In vivo anti-tumor efficacy of afucosylated anti-CS1 monoclonal antibody produced in glycoengineered Pichia pastoris. AB - Monoclonal antibody (mAb) therapy has been successfully used for the treatment of B-cell lymphomas and is currently extended for the treatment of multiple myeloma (MM). New developments in MM therapeutics have achieved significant survival gains in patients but the disease still remains incurable. Elotuzumab (HuLuc63), an anti-CS1 monoclonal IgG1 antibody, is believed to induce anti-tumor activity and MM cytotoxicity through antibody dependent cellular cytotoxicity (ADCC) and inhibition of MM cell adhesion to bone marrow stromal cells (BMSCs). Modulations of the Fc glycan composition at the N297 site by selective mutations or afucosylation have been explored as strategies to develop bio-better therapeutics with enhanced ADCC activity. Afucosylated therapeutic antibodies with enhanced ADCC activity have been reported to possess greater efficacy in tumor growth inhibition at lower doses when compared to fucosylated therapeutic antibodies. The N-linked glycosylation pathway in Pichia pastoris has been engineered to produce human-like N-linked glycosylation with uniform afucosylated complex type glycans. The purpose of this study was to compare afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris with fucosylated anti-CS1 mAb expressed in mammalian HEK293 cells through in vitro ADCC and in vivo tumor inhibition models. Our results indicate that Fc glycosylation is critical for in vivo efficacy and afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris shows a better in vivo efficacy in tumor regression when compared to fucosylated anti-CS1 mAb expressed in HEK293 cells. Glycoengineered Pichia pastoris could provide an alternative platform for generating homogeneous afucosylated recombinant antibodies where Fc mediated immune effector function is important for efficacy. PMID- 26015262 TI - Cryogel-supported titanate nanotubes for waste treatment: Impact on methane production and bio-fertilizer quality. AB - By reducing the cadmium (Cd(2+)) content in biomass used for bio-based products such as biogas, a less toxic bio-based fertilizer can be obtained. In this work, we demonstrate how a macroporous polymer can support titanate nanotubes, and we take advantage of its known selective adsorption behavior towards Cd(2+) in an adsorption process from real nutrient-rich process water from hydrolysis of seaweed, a pollutant-rich biomass. We show that pretreatment steps involving alteration in area-to-volume ratio performed in aerated and acidic conditions release the most Cd(2+) from the solid material. By integrating an adsorption step between hydrolysis and the biomethane, we show that it was possible to obtain high Cd(2+) removal (ca. 94%) despite molar excess (between 100 and 500) of co-present ions (e.g., Mg(2+), Ca(2+), Na(+), K(+)) and with maintained total phosphorous content. The bio-methane potential did not significantly decrease as compared to a process without cadmium removal and the yielded bio-fertilizer followed Swedish guideline values. This study provides a sound and promising alternative for a novel remediation step, enabling higher use of otherwise tricky and to some extent overlooked biomass sources. PMID- 26015263 TI - Cell size modulates oscillation, positioning and length of mitotic spindles. AB - Mitotic spindle is the main subcellular structure that accomplishes the chromosome segregation between daughter cells during cell division. However, how mitotic spindles sense and control their size, position and movement inside the cell still remains unclear. In this paper, we focus on the size effects of mitotic spindles, i.e., how cell size controls various interesting phenomena in the metaphase, such as oscillation, positioning and size limit of mitotic spindles. We systematically studied the frequency doubling phenomenon during chromosome oscillation and found that cell size can regulate the period and amplitude of chromosome oscillation. We found that the relaxation time of the positioning process increases exponentially with cell size. We also showed that the stabler microtubule-kinetochore attachments alone can directly lead to an upper limit of spindle size. Our work not only explains the existing experimental observations, but also provides some interesting predictions that can be verified or rejected by further experiments. PMID- 26015264 TI - Insulin-Like Growth Factor II (IGF-II) Inhibits IL-1beta-Induced Cartilage Matrix Loss and Promotes Cartilage Integrity in Experimental Osteoarthritis. AB - Osteoarthritis (OA) is a widespread chronic joint disease characterized by articular cartilage destruction and accompanied by pain and disability. In this study, we found that the expression of Insulin-like Growth Factor II (IGF-II) was reduced in articular cartilage in human OA patients as well as in the murine experimental OA model of destabilization of the medial meniscus (DMM). In primary human articular chondrocytes, ectopic expression of lentiviral IGF-II inhibited pro-inflammatory cytokine IL-1beta-induced NF-kappaB activation as well as catabolic gene expression. Interestingly, IGF-II did not significantly alter the phosphorylation states of ERK1/2 or Akt, which are kinases typically activated by IGF-I. Instead, it induced the activity of phospholipase C (PLC) and a PLC inhibitor blocked the inhibitory activity of IGF-II against IL-1beta, suggesting that this activity is mediated through PLC. Furthermore, IGF-II increased cartilage matrix levels and decreased MMP13 protein expression in explanted human OA cartilage cultures in vitro. In the in vivo DMM model, intraarticular injection of lentiviral IGF-II led to enhanced cartilage matrix levels and decreased MMP13 protein expression, as well as reduced osteophyte formation and subchondral bone sclerosis. Therefore, our results suggest that IGF-II can promote cartilage integrity and halt knee joint destruction in OA. PMID- 26015265 TI - The molecular mechanisms of sodium metabisulfite on the expression of K ATP and L Ca2+ channels in rat hearts. AB - Sodium metabisulfite (SMB) is used as an antioxidant and antimicrobial agent in a variety of drugs and foods. However, there are few reported studies about its side effects. This study is to investigate the SMB effects on the expression of ATP-sensitive K(+) (KATP) and L-type calcium (L-Ca(2+)) channels in rat hearts. The results show that the mRNA and protein levels of the KATP channel subunits Kir6.2 and SUR2A were increased by SMB; on the contrary, SMB at 520 mg/kg significantly decreased the expression of the L-Ca(2+) channel subunits Cav1.2 and Cav1.3. This suggests that SMB can activate the expression of KATP channel by increasing the mRNA and protein levels of Kir6.2 and SUR2A, while it inhibits the expression of L-Ca(2+) channels by decreasing the mRNA and protein levels of Cav1.2 and Cav1.3 in rat hearts. Therefore, the molecular mechanism of the SMB effect on rat hearts might be related to the increased expression of KATP channels and the decreased expression of L-Ca(2+) channels. PMID- 26015266 TI - Relationship between alcohol consumption and cardiac structure and function in the elderly: the Atherosclerosis Risk In Communities Study. AB - BACKGROUND: Excessive alcohol consumption is associated with cardiomyopathy, but the influence of moderate alcohol use on cardiac structure and function is largely unknown. METHODS AND RESULTS: We studied 4466 participants from visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (76+/-5 years and 60% women) who underwent transthoracic echocardiography, excluding former drinkers and those with significant valvular disease. Participants were classified into 4 categories based on self-reported alcohol intake: nondrinkers, drinkers of <=7, >=7 to 14, and >=14 drinks per week. We related alcohol intake to measures of cardiac structure and function, stratified by sex, and fully adjusted for covariates. In both genders, increasing alcohol intake was associated with larger left ventricular diastolic and systolic diameters and larger left atrial diameter (P<0.05). In men, increasing alcohol intake was associated with greater left ventricular mass (8.2+/-3.8 g per consumption category; P=0.029) and higher E/E' ratio (0.82+/-0.33 per consumption category; P=0.014). In women, increasing alcohol intake was associated with lower left ventricular ejection fraction ( 1.9+/-0.6% per consumption category; P=0.002) and a tendency for worse left ventricular global longitudinal strain (0.45+/-0.25% per consumption category; P=0.07). CONCLUSIONS: In an elderly community-based population, increasing alcohol intake is associated with subtle alterations in cardiac structure and function, with women appearing more susceptible than men to the cardiotoxic effects of alcohol. PMID- 26015267 TI - Performance of t1 and t2 mapping cardiovascular magnetic resonance to detect active myocarditis in patients with recent-onset heart failure. AB - BACKGROUND: This study evaluated the performance of novel quantitative T1 and T2 mapping cardiovascular magnetic resonance (CMR) techniques to identify active myocarditis in patients with recent-onset heart failure. METHODS AND RESULTS: Thirty-one consecutive patients with recent-onset heart failure, reduced left ventricular function and clinically suspected myocarditis underwent endomyocardial biopsy and CMR at 1.5 Tesla. The CMR protocol included standard Lake-Louise parameters as well as T1 mapping using a modified Look-Locker inversion recovery sequence and T2 mapping using a hybrid gradient and spin-echo sequence. Short-axis maps were generated using an OsiriX plug-in to calculate global myocardial T1, T2, and extracellular volume fraction. Active myocarditis was defined by ongoing inflammation on endomyocardial biopsy. Endomyocardial biopsy revealed active myocarditis in 16 (52%) of 31 patients. Neither clinical characteristics, standard Lake-Louise CMR parameters, global myocardial T1 nor extracellular volume fraction differed significantly between patients with and without active myocarditis. However, median global myocardial T2 was significantly higher in patients with active myocarditis (65 ms [Q1-Q3, 61-70 ms]) than in patients without active myocarditis (59 ms [Q1-Q3, 55-64 ms]; P<0.01). A cutoff value for global myocardial T2 of >=60 ms provided a sensitivity, specificity, accuracy, negative and positive predictive value of 94% (70%-100%), 60% (32%-84%), 77% (60%-89%), 90% (56%-100%), and 71% (48%-89%) for active myocarditis, respectively. CONCLUSIONS: T2 mapping seems to be superior when compared with standard CMR parameters, global myocardial T1, and extracellular volume fraction values for assessing the activity of myocarditis in patients with recent-onset heart failure and reduced left ventricular function. PMID- 26015268 TI - Alcohol consumption and myocardial remodeling in elderly women and men. PMID- 26015269 TI - Brain damage following prophylactic cranial irradiation in lung cancer survivors. AB - Long-term toxic effects of prophylactic cranial irradiation (PCI) on cognition in small cell lung cancer (SCLC) patients have not yet been well-established. The aim of our study was to examine the cognitive toxic effects together with brain structural changes in a group of long-term SCLC survivors treated with PCI. Eleven SCLC patients, who underwent PCI >= 2 years before, were compared with an age and education matched healthy control group. Both groups were evaluated using a neuropsychological battery and multimodal structural magnetic resonance imaging. Voxel-based morphometry and Tract-based Spatial Statistics were used to study gray matter density (GMD) and white matter (WM) microstructural changes. Cognitive deterioration was correlated with GMD and Fractional Anisotropy (FA). Finally, we carried out a single-subject analysis in order to evaluate individual structural brain changes. Nearly half of the SCLC met criteria for cognitive impairment, all exhibiting a global worsening of cognitive functioning. Patients showed significant decreases of GMD in basal ganglia bilaterally (putamen and caudate), bilateral thalamus and right insula, together with WM microstructural changes of the entire corpus callosum. Cognitive deterioration scores correlated positively with mean FA values in the corpus callosum. Single-subject analysis revealed that GMD and WM changes were consistently observed in nearly all patients. This study showed neuropsychological deficits together with brain specific structural differences in long-term SCLC survivors. Our results suggest that PCI therapy, possibly together with platinum-based chemotherapy, was associated to permanent long-term cognitive and structural brain effects in a SCLC population. PMID- 26015270 TI - Molecular Dynamics of Cellulose Amphiphilicity at the Graphene-Water Interface. AB - Molecular dynamics (MD) simulations have been applied to study the interactions between hydrophobic and hydrophilic faces of ordered cellulose chains and a single layer of graphene in explicit aqueous solvent. The hydrophobic cellulose face is predicted to form a stable complex with graphene. This interface remains solvent-excluded over the course of simulations; the cellulose chains contacting graphene in general preserve intra- and interchain hydrogen bonds and a tg orientation of hydroxymethyl groups. Greater flexibility is observed in the more solvent-exposed cellulose chains of the complex. By contrast, the hydrophilic face of cellulose exhibits progressive rearrangement over the course of MD simulations, as it seeks to present its hydrophobic face, with disrupted intra- and interchain hydrogen bonding; residue twisting to form CH-pi interactions with graphene; and partial permeation of water. This transition is also accompanied by a more favorable cellulose-graphene adhesion energy as predicted at the PM6-DH2 level of theory. The stability of the cellulose-graphene hydrophobic interface in water exemplifies the amphiphilicity of cellulose and provides insight into favored interactions within graphene-cellulose materials. Furthermore, partial permeation of water between exterior cellulose chains may indicate potential in addressing cellulose recalcitrance. PMID- 26015271 TI - Brain activity and connectivity during poetry composition: Toward a multidimensional model of the creative process. AB - Creativity, a multifaceted construct, can be studied in various ways, for example, investigating phases of the creative process, quality of the creative product, or the impact of expertise. Previous neuroimaging studies have assessed these individually. Believing that each of these interacting features must be examined simultaneously to develop a comprehensive understanding of creative behavior, we examined poetry composition, assessing process, product, and expertise in a single experiment. Distinct activation patterns were associated with generation and revision, two major phases of the creative process. Medial prefrontal cortex (MPFC) was active during both phases, yet responses in dorsolateral prefrontal and parietal executive systems (DLPFC/IPS) were phase dependent, indicating that while motivation remains unchanged, cognitive control is attenuated during generation and re-engaged during revision. Experts showed significantly stronger deactivation of DLPFC/IPS during generation, suggesting that they may more effectively suspend cognitive control. Importantly however, similar overall patterns were observed in both groups, indicating the same cognitive resources are available to experts and novices alike. Quality of poetry, assessed by an independent panel, was associated with divergent connectivity patterns in experts and novices, centered upon MPFC (for technical facility) and DLPFC/IPS (for innovation), suggesting a mechanism by which experts produce higher quality poetry. Crucially, each of these three key features can be understood in the context of a single neurocognitive model characterized by dynamic interactions between medial prefrontal areas regulating motivation, dorsolateral prefrontal, and parietal areas regulating cognitive control and the association of these regions with language, sensorimotor, limbic, and subcortical areas distributed throughout the brain. PMID- 26015272 TI - The striated MR nephrogram, not a reflection of pathology. AB - BACKGROUND: We have intermittently observed low signal striations in the kidneys on delayed post-contrast MR exams of the spine. While we suspected these striations were due to concentrated gadolinium, the clinical importance of this finding was uncertain. OBJECTIVE: To describe the striated MR nephrogram (low signal striations in the kidney) and assess its clinical relevance. MATERIALS AND METHODS: Retrospective review of delayed post-contrast MRIs of the spine (mean: 45 min after contrast administration). The presence of the striated MR nephrogram was correlated with imaging parameters (field strength, time since contrast), and findings (gadolinium in the bladder, inferior vena cava and aorta diameters) and with clinical factors (history of renal disease, laboratory values). RESULTS: Seven hundred seventy-three exams performed on 229 patients, 8.3 +/- 5.3 years of age, were reviewed. The striated MR nephrogram was observed in 102/773 examinations (13.2%) and was present on at least one study in 54/229 patients (23.6%). The presence of striations was associated with the specific magnet on which the exam was performed (P < 0.01) but not with magnet field strength. Serum creatinine was minimally lower in patients with striations (0.43 +/- 0.12 vs. 0.49 +/- 0.18 mg/dL, P = 0.002), but no other clinical or historical data, including time from contrast administration (P = 0.54), fluid status (P = 0.17) and clinical history of renal disease (P = 0.14), were predictive of the presence of striations. CONCLUSION: The striated MR nephrogram was observed in 13% of delayed post-contrast MR exams of the spine. Precipitating factors are unclear, but the striated nephrogram does not appear to be a marker of clinically apparent renal dysfunction. PMID- 26015273 TI - A statistical framework to predict functional non-coding regions in the human genome through integrated analysis of annotation data. AB - Identifying functional regions in the human genome is a major goal in human genetics. Great efforts have been made to functionally annotate the human genome either through computational predictions, such as genomic conservation, or high throughput experiments, such as the ENCODE project. These efforts have resulted in a rich collection of functional annotation data of diverse types that need to be jointly analyzed for integrated interpretation and annotation. Here we present GenoCanyon, a whole-genome annotation method that performs unsupervised statistical learning using 22 computational and experimental annotations thereby inferring the functional potential of each position in the human genome. With GenoCanyon, we are able to predict many of the known functional regions. The ability of predicting functional regions as well as its generalizable statistical framework makes GenoCanyon a unique and powerful tool for whole-genome annotation. The GenoCanyon web server is available at http://genocanyon.med.yale.edu. PMID- 26015274 TI - Facility Dialysate Calcium Practices and Clinical Outcomes Among Patients Receiving Hemodialysis: A Retrospective Observational Study. AB - BACKGROUND: Some US dialysis facilities have reduced default dialysate calcium concentrations from 2.5 mEq/L to lower levels. There has been no rigorous systematic examination of the effects of such a reduction on clinical and biochemical outcomes. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare-eligible patients who received in-center hemodialysis at a large dialysis organization in January 2008 to December 2010. PREDICTOR: Facility conversion from predominant use (>=75% patients) of 2.50-mEq/L dialysate calcium to predominant use of lower dialysate calcium concentrations versus maintenance of predominant use of 2.50-mEq/L dialysate calcium. OUTCOMES: All-cause and cause specific mortality and hospitalization, laboratory markers of metabolic bone disease, and drug utilization. MEASUREMENTS: Hierarchical mixed linear and Poisson models were fit to compare pre- to postconversion differences in outcomes between converter and matched control facilities. Results, expressed as relative rate ratios (RRRs) and delta-delta (change in mean values), were estimated for early (months 0-2) and late (months 3-12) postconversion to allow for possible latent effects. RESULTS: Facility conversion was associated with greater rates of hospitalization for heart failure exacerbation (late RRR, 1.27 [95% CI, 1.06 1.51]), hypocalcemia (early RRR, 1.19 [95% CI, 1.05-1.35]; late RRR, 1.39 [95% CI, 1.20-1.60]), and intradialytic hypotension (early RRR, 1.07 [95% CI, 1.02 1.11]; late RRR, 1.05 [95% CI, 1.01-1.10]), but no differences were observed for all-cause mortality or hospitalization rates. Facility conversion was also associated with comparative temporal decreases in serum calcium level, increases in serum phosphate and parathyroid hormone levels, and increases in use of phosphate binders, vitamin D, and calcimimetics. LIMITATIONS: Possible residual confounding, generalizability beyond Medicare patients uncertain. CONCLUSIONS: There are potential safety concerns associated with the default use of dialysate calcium concentrations < 2.50 mEq/L, as well as biochemical evidence of poorer disease control despite associated greater medication use. Individualization of dialysate calcium concentration rather than predominant use of dialysate calcium concentrations < 2.50 mEq/L should be considered. PMID- 26015275 TI - Recent Advances in Traditional Chinese Medicine for Kidney Disease. AB - Because current treatment options for chronic kidney disease (CKD) are limited, many patients seek out alternative therapies such as traditional Chinese medicine. However, there is a lack of evidence from large clinical trials to support the use of traditional medicines in patients with CKD. Many active components of traditional medicine formulas are undetermined and their toxicities are unknown. Therefore, there is a need for research to identify active compounds from traditional medicines and understand the mechanisms of action of these compounds, as well as their potential toxicity, and subsequently perform well designed, randomized, controlled, clinical trials to study the efficacy and safety of their use in patients with CKD. Significant progress has been made in this field within the last several years. Many active compounds have been identified by applying sophisticated techniques such as mass spectrometry, and more mechanistic studies of these compounds have been performed using both in vitro and in vivo models. In addition, several well-designed, large, randomized, clinical trials have recently been published. We summarize these recent advances in the field of traditional medicines as they apply to CKD. In addition, current barriers for further research are also discussed. Due to the ongoing research in this field, we believe that stronger evidence to support the use of traditional medicines for CKD will emerge in the near future. PMID- 26015276 TI - Predialysis and Postdialysis pH and Bicarbonate and Risk of All-Cause and Cardiovascular Mortality in Long-term Hemodialysis Patients. AB - BACKGROUND: To date, very few studies have been carried out on the associations of pre- and postdialysis acid-base parameters with mortality in hemodialysis patients. STUDY DESIGN: An observational study including cross-sectional and 1 year analyses. SETTING & PARTICIPANTS: Data from the renal registry of the Japanese Society of Dialysis Therapy (2008-2009), including 15,132 dialysis patients 16 years or older. PREDICTOR: Predialysis pH<7.30, 7.30 to 7.34 (reference), 7.35 to 7.39, or >=7.40 (1,550, 4,802, 6,023, and 2,757 patients, respectively); predialysis bicarbonate level < 18.0, 18.0 to 21.9 (reference), 22.0 to 25.9, or >=26.0 mEq/L (2,724, 7,851, 4,023, and 534 patients, respectively); postdialysis pH<7.40, 7.40 to 7.44, 7.45 to 7.49 (reference), or >=7.50 (2,114, 5,331, 4,975, and 2,712 patients, respectively); and postdialysis bicarbonate level < 24.0, 24.0 to 25.9, 26.0 to 27.9 (reference), or >=28.0 mEq/L (5,087, 4,330, 3,451, and 2,264 patients, respectively). OUTCOMES: All-cause and cardiovascular (CV) mortality during the 1-year follow-up. MEASUREMENTS: HRs were estimated using unadjusted models and models adjusted for age, sex, dialysis vintage, history of CV disease, diabetes, weight gain ratio, body mass index, calcium-phosphorus product, serum albumin level, serum total cholesterol level, blood hemoglobin level, single-pool Kt/V, and normalized protein catabolic rate. RESULTS: Of 15,132 patients, during follow-up, 1,042 died of all causes, including 408 CV deaths. In the adjusted analysis for all-cause mortality, HRs compared to the reference group were significantly higher in patients with predialysis pH>=7.40 (HR, 1.36; 95% CI, 1.13-1.65) and postdialysis pH<7.40 (HR, 1.22; 95% CI, 1.00-1.49). Predialysis pH>=7.40 was also associated with higher risk of CV mortality (HR, 1.34; 95% CI, 1.01-1.79). No association of pre- or postdialysis bicarbonate level with all-cause and CV mortality was observed. LIMITATIONS: Single measurements of acid-base parameters, short duration of follow-up, small number of CV deaths. CONCLUSIONS: Predialysis pH>=7.40 was associated with significantly elevated risk of all-cause and CV mortality. However, pre- and postdialysis bicarbonate levels were not associated with all cause and CV mortality. Predialysis pH may be the most appropriate reference for accurate correction of metabolic acidosis in dialysis patients. PMID- 26015277 TI - Comorbidity ascertainment from the ESRD Medical Evidence Report and Medicare claims around dialysis initiation: a comparison using US Renal Data System data. AB - BACKGROUND: The end-stage renal disease Medical Evidence Report serves as a source of comorbid condition data for risk adjustment of quality metrics. We sought to compare comorbid condition data in the Medical Evidence Report around dialysis therapy initiation with diagnosis codes in Medicare claims. STUDY DESIGN: Observational cohort study using US Renal Data System data. SETTING & PARTICIPANTS: Medicare-enrolled elderly (>=66 years) patients who initiated maintenance dialysis therapy July 1 to December 31, 2007, 2008, or 2009. INDEX TESTS: 12 comorbid conditions ascertained from claims during the 6 months before dialysis therapy initiation, the Medical Evidence Report, and claims during the 3 months after dialysis therapy initiation. REFERENCE TEST: None. RESULTS: Comorbid condition prevalence according to claims before dialysis therapy initiation generally exceeded prevalence according to the Medical Evidence Report. The kappa statistics for comorbid condition designations other than diabetes ranged from 0.06 to 0.43. Discordance of designations was associated with age, race, sex, and end-stage renal disease Network. During 23,930 patient-years of follow-up from 4 to 12 months after dialysis therapy initiation (8,930 deaths), designations from claims during the 3 months after initiation better discriminated risk of death than designations from the Medical Evidence Report (C statistics of 0.674 vs 0.616). Between the Medical Evidence Report and claims, standardized mortality ratios changed by >10% for more than half the dialysis facilities. LIMITATIONS: Neither the Medical Evidence Report nor diagnosis codes in claims constitute a gold standard of comorbid condition data; results may not apply to nonelderly patients or patients without Medicare coverage. CONCLUSIONS: Discordance of comorbid condition designations from the Medical Evidence Report and claims around dialysis therapy initiation was substantial and significantly associated with patient characteristics, including location. These patterns may engender bias in risk-adjusted quality metrics. In lieu of the Medical Evidence Report, claims during the 3 months after dialysis therapy initiation may constitute a useful source of comorbid condition data. PMID- 26015278 TI - Distal Angiopathy and Atypical Hemolytic Uremic Syndrome: Clinical and Functional Properties of an Anti-Factor H IgAlambda Antibody. AB - Abnormal regulation of the alternative pathway of the complement system is a well described trigger of microangiopathy leading to atypical hemolytic uremic syndrome (aHUS). However, the involvement of complement dysregulation in distal angiopathy has not been reported in adults. We describe the clinical course of a patient with severe distal angiopathy (amputation of all fingers and toes) followed 3 years later by aHUS with end-stage renal disease. This course was attributed to a circulating monoclonal immunoglobulin A lambda light chain (IgAlambda) with unusual properties: it bound complement factor H (CFH) and impaired CFH-glycosaminoglycan interaction and cell-surface protection. Local complement activation with distal angiopathy and microvascular injury was suggested by deposition of IgA, C4d, and C5b-9 in limb and preglomerular arteries. We therefore postulated that the monoclonal IgAlambda inhibited activity of endothelial cell-bound CFH, which led to local activation of complement, vasoconstriction (distal angiopathy), and aHUS. While the patient was dependent on dialysis and plasma exchange, treatment with the anti-C5 antibody eculizumab induced remission of distal angiopathy and aHUS. During eculizumab treatment, kidney transplantation was performed. The patient had normal kidney function at the 3-year follow-up. We suggest that the association of distal angiopathy and aHUS in this patient is clearly linked to anti-CFH properties of the monoclonal IgAlambda. PMID- 26015279 TI - Supported lipid bilayers as models for studying membrane domains. AB - Supported lipid bilayers have been in use for over 30 years. They have been employed to study the structure, composition, and dynamics of lipid bilayer phases, the binding and distribution of soluble, integral, and lipidated proteins in membranes, membrane fusion, and interactions of membranes with elements of the cytoskeleton. This review focuses on the unique ability of supported lipid bilayers to study liquid-ordered and liquid-disordered domains in membranes. We highlight methods to produce asymmetric lipid bilayers with lipid compositions that mimic those of the extracellular and cytoplasmic leaflets of cell membranes and the functional reconstitution of membrane proteins into such systems. Questions related to interleaflet domain coupling and membrane protein activation have been addressed and answered using advanced reconstitution and imaging procedures in symmetric and asymmetric supported membranes with and without coexisting lipid phase domains. Previously controversial topics regarding anomalous and anisotropic diffusion in membranes have been resolved by using supported membrane approaches showing that the propensity of certain lipid compositions to form "rafts" are important but overlaid with "picket-fence" interactions that are imposed by a subtended cytoskeletal network. PMID- 26015280 TI - Giant plasma membrane vesicles: models for understanding membrane organization. AB - The organization of eukaryotic membranes into functional domains continues to fascinate and puzzle cell biologists and biophysicists. The lipid raft hypothesis proposes that collective lipid interactions compartmentalize the membrane into coexisting liquid domains that are central to membrane physiology. This hypothesis has proven controversial because such structures cannot be directly visualized in live cells by light microscopy. The recent observations of liquid liquid phase separation in biological membranes are an important validation of the raft hypothesis and enable application of the experimental toolbox of membrane physics to a biologically complex phase-separated membrane. This review addresses the role of giant plasma membrane vesicles (GPMVs) in refining the raft hypothesis and expands on the application of GPMVs as an experimental model to answer some of key outstanding problems in membrane biology. PMID- 26015282 TI - The nanoscale organization of signaling domains at the plasma membrane. AB - In this chapter, we present an overview of the role of the nanoscale organization of signaling domains in regulating key cellular processes. In particular, we illustrate the importance of protein and lipid nanodomains as triggers and mediators of cell signaling. As particular examples, we summarize the state of the art of understanding the role of nanodomains in the mounting of an immune response, cellular adhesion, intercellular communication, and cell proliferation. Thus, this chapter underlines the essential role the nanoscale organization of key signaling proteins and lipid domains. We will also see how nanodomains play an important role in the lifecycle of many pathogens relevant to human disease and therefore illustrate how these structures may become future therapeutic targets. PMID- 26015283 TI - Mechanisms underlying anomalous diffusion in the plasma membrane. AB - The plasma membrane is a complex fluid where lipids and proteins undergo diffusive motion critical to biochemical reactions. Through quantitative imaging analyses such as single-particle tracking, it is observed that diffusion in the cell membrane is usually anomalous in the sense that the mean squared displacement is not linear with time. This chapter describes the different models that are employed to describe anomalous diffusion, paying special attention to the experimental evidence that supports these models in the plasma membrane. We review models based on anticorrelated displacements, such as fractional Brownian motion and obstructed diffusion, and nonstationary models such as continuous time random walks. We also emphasize evidence for the formation of distinct compartments that transiently form on the cell surface. Finally, we overview heterogeneous diffusion processes in the plasma membrane, which have recently attracted considerable interest. PMID- 26015284 TI - N-3 Polyunsaturated Fatty Acids, Lipid Microclusters, and Vitamin E. AB - Increased consumption of long-chain marine n-3 polyunsaturated fatty acids (PUFA) has potential health benefits for the general population and for select clinical populations. However, several key limitations remain in making adequate dietary recommendations on n-3 PUFAs in addition to translating the fatty acids into clinical trials for select diseases. One major constraint is an incomplete understanding of the underlying mechanisms of action of n-3 PUFAs. In this review, we highlight studies to show n-3 PUFA acyl chains reorganize the molecular architecture of plasma membrane sphingolipid-cholesterol-enriched lipid rafts and potentially sphingolipid-rich cholesterol-free domains and cardiolipin protein scaffolds in the inner mitochondrial membrane. We also discuss the possibility that the effects of n-3 PUFAs on membrane organization could be regulated by the presence of vitamin E (alpha-tocopherol), which is necessary to protect highly unsaturated acyl chains from oxidation. Finally, we propose the integrated hypothesis, based predominately on studies in lymphocytes, cancer cells, and model membranes, that the mechanism by which n-3 PUFAs disrupt signaling microclusters is highly dependent on the type of lipid species that incorporate n-3 PUFA acyl chains. The current evidence suggests that n-3 PUFA acyl chains disrupt lipid raft formation by incorporating primarily into phosphatidylethanolamines but can also incorporate into other lipid species of the lipidome. PMID- 26015286 TI - Trafficking and Membrane Organization of GPI-Anchored Proteins in Health and Diseases. AB - Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are a class of lipid-anchored proteins attached to the membranes by a glycolipid anchor that is added, as posttranslation modification, in the endoplasmic reticulum. GPI-APs are expressed at the cell surface of eukaryotes where they play diverse vital functions. Like all plasma membrane proteins, GPI-APs must be correctly sorted along the different steps of the secretory pathway to their final destination. The presence of both a glycolipid anchor and a protein portion confers special trafficking features to GPI-APs. Here, we discuss the recent advances in the field of GPI-AP trafficking, focusing on the mechanisms regulating their biosynthetic pathway and plasma membrane organization. We also discuss how alterations of these mechanisms can result in different diseases. Finally, we will examine the strict relationship between the trafficking and function of GPI APs in epithelial cells. PMID- 26015287 TI - Recent progress in the topology, structure, and oligomerization of caveolin: a building block of caveolae. AB - Caveolae are cholesterol-rich plasma membrane invaginations that are found in a plethora of cell types. They play many roles including signal transduction, endocytosis, and mechanoprotection. The most critical protein in caveolae is the integral membrane protein, caveolin, which has been shown to be necessary for caveolae formation, and governs the major functions attributed to caveolae. Caveolin is postulated to act as a scaffold in the high molecular weight striated coat that surrounds the caveolar bulb, stabilizing it. Caveolin interacts, both directly and indirectly, with a large number of signaling molecules, and presides over the endocytosis of molecular cargo by caveolae. However, many of the key biophysical aspects of the caveolin protein, its structure, topology, and oligomeric behavior, are just beginning to come to light. Herein is an up-to-date summary and critique of the progress that has been made in understanding caveolin on a molecular and atomic level. PMID- 26015281 TI - Dances with Membranes: Breakthroughs from Super-resolution Imaging. AB - Biological membrane organization mediates numerous cellular functions and has also been connected with an immense number of human diseases. However, until recently, experimental methodologies have been unable to directly visualize the nanoscale details of biological membranes, particularly in intact living cells. Numerous models explaining membrane organization have been proposed, but testing those models has required indirect methods; the desire to directly image proteins and lipids in living cell membranes is a strong motivation for the advancement of technology. The development of super-resolution microscopy has provided powerful tools for quantification of membrane organization at the level of individual proteins and lipids, and many of these tools are compatible with living cells. Previously inaccessible questions are now being addressed, and the field of membrane biology is developing rapidly. This chapter discusses how the development of super-resolution microscopy has led to fundamental advances in the field of biological membrane organization. We summarize the history and some models explaining how proteins are organized in cell membranes, and give an overview of various super-resolution techniques and methods of quantifying super resolution data. We discuss the application of super-resolution techniques to membrane biology in general, and also with specific reference to the fields of actin and actin-binding proteins, virus infection, mitochondria, immune cell biology, and phosphoinositide signaling. Finally, we present our hopes and expectations for the future of super-resolution microscopy in the field of membrane biology. PMID- 26015288 TI - Lipid Domains. Preface. PMID- 26015285 TI - Raft-like membrane domains in pathogenic microorganisms. AB - The lipid bilayer of the plasma membrane is thought to be compartmentalized by the presence of lipid-protein microdomains. In eukaryotic cells, microdomains composed of sterols and sphingolipids, commonly known as lipid rafts, are believed to exist, and reports on the presence of sterol- or protein-mediated microdomains in bacterial cell membranes are also appearing. Despite increasing attention, little is known about microdomains in the plasma membrane of pathogenic microorganisms. This review attempts to provide an overview of the current state of knowledge of lipid rafts in pathogenic fungi and bacteria. The current literature on characterization of microdomains in pathogens is reviewed, and their potential role in growth, pathogenesis, and drug resistance is discussed. Better insight into the structure and function of membrane microdomains in pathogenic microorganisms might lead to a better understanding of their pathogenesis and development of raft-mediated approaches for therapy. PMID- 26015289 TI - Synthesis and Characterization of Far-Red/NIR-Fluorescent BODIPY Dyes, Solid State Fluorescence, and Application as Fluorescent Tags Attached to Carbon Nano onions. AB - A series of pi-extended distyryl-substituted boron dipyrromethene (BODIPY) derivatives with intense far-red/near-infrared (NIR) fluorescence was synthesized and characterized, with a view to enhance the dye's performance for fluorescence labeling. An enhanced brightness was achieved by the introduction of two methyl substituents in the meso positions on the phenyl group of the BODIPY molecule; these substituents resulted in increased structural rigidity. Solid-state fluorescence was observed for one of the distyryl-substituted BODIPY derivatives. The introduction of a terminal bromo substituent allows for the subsequent immobilization of the BODIPY fluorophore on the surface of carbon nano-onions (CNOs), which leads to potential imaging agents for biological and biomedical applications. The far-red/NIR-fluorescent CNO nanoparticles were characterized by absorption, fluorescence, and Raman spectroscopies, as well as by thermogravimetric analysis, dynamic light scattering, high-resolution transmission electron microscopy, and confocal microscopy. PMID- 26015290 TI - Mesenchymal stem cell response to topographically modified CoCrMo. AB - Surface roughness on implant materials has been shown to be highly influential on the behavior of osteogenic cells. Four surface topographies were engineered on cobalt chromium molybdenum (CoCrMo) in order to examine this influence on human mesenchymal stem cells (MSC). These treatments were smooth polished (SMO), acid etched (AE) using HCl 7.4% and H2SO4 76% followed by HNO3 30%, sand blasted, and acid etched using either 50 MUm Al2O3 (SLA50) or 250 MUm Al2 O3 grit (SLA250). Characterization of the surfaces included energy dispersive X-ray analysis (EDX), contact angle, and surface roughness analysis. Human MSCs were cultured onto the four CoCrMo substrates and markers of cell attachment, retention, proliferation, cytotoxicity, and osteogenic differentiation were studied. Residual aluminum was observed on both SLA surfaces although this appeared to be more widely spread on SLA50, whilst SLA250 was shown to have the roughest topography with an Ra value greater than 1 MUm. All substrates were shown to be largely non-cytotoxic although both SLA surfaces were shown to reduce cell attachment, whilst SLA50 also delayed cell proliferation. In contrast, SLA250 stimulated a good rate of proliferation resulting in the largest cell population by day 21. In addition, SLA250 stimulated enhanced cell retention, calcium deposition, and hydroxyapatite formation compared to SMO (p < 0.05). The enhanced response stimulated by SLA250 surface modification may prove advantageous for increasing the bioactivity of implants formed of CoCrMo. PMID- 26015291 TI - Historical Matching Strategies in Kidney Paired Donation: The 7-Year Evolution of a Web-Based Virtual Matching System. AB - Failure to convert computer-identified possible kidney paired donation (KPD) exchanges into transplants has prohibited KPD from reaching its full potential. This study analyzes the progress of exchanges in moving from "offers" to completed transplants. Offers were divided into individual segments called 1-way transplants in order to calculate success rates. From 2007 to 2014, the Alliance for Paired Donation performed 243 transplants, 31 in collaboration with other KPD registries and 194 independently. Sixty-one of 194 independent transplants (31.4%) occurred via cycles, while the remaining 133 (68.6%) resulted from nonsimultaneous extended altruistic donor (NEAD) chains. Thirteen of 35 (37.1%) NEAD chains with at least three NEAD segments accounted for 68% of chain transplants (8.6 tx/chain). The "offer" and 1-way success rates were 21.9 and 15.5%, respectively. Three reasons for failure were found that could be prospectively prevented by changes in protocol or software: positive laboratory crossmatch (28%), transplant center declined donor (17%) and pair transplanted outside APD (14%). Performing a root cause analysis on failures in moving from offer to transplant has allowed the APD to improve protocols and software. These changes have improved the success rate and the number of transplants performed per year. PMID- 26015292 TI - Incidence, Time Course and Predictors of Impairments Relating to Caring for the Profoundly Affected arm After Stroke: A Systematic Review. AB - BACKGROUND AND PURPOSE: A significant number of stroke survivors will not recover the use of their affected arm. A proportion will experience pain, stiffness and difficulty with basic care activities. The purpose of the review was to identify predictors of difficulty caring for the profoundly affected arm and establish the incidence and time-course of the related impairments of pain, spasticity and contracture. METHOD: Data sources: Databases (PubMED, MEDLINE, AMED, EMBASE, CINAHL and the Cochrane Controlled Trials Register) were searched from inception to December 2013. Additional studies were identified from citation tracking. REVIEW METHODS: Independent reviewers used pre-defined criteria to identify eligible studies. Quality assessment and risk of bias were assessed using the McMasters Assessment Tool. A narrative evidence synthesis was performed. RESULTS: Thirty-nine articles reporting 34 studies were included. No studies formally measured difficulty caring for the arm, but related impairments were common. Incidence of spasticity in those with weakness ranged from 33% to 78%, shoulder pain affected 22% to 90% and contracture was present in at least 50%. Spasticity and pain appear within 1 week of stroke, and contracture within two weeks. Impairments continued to develop over at least 3-6 months. The most frequent predictors of spasticity and contracture were weakness and reduced motor control, and the risk of pain is most commonly predicted by reduced sensation, shoulder subluxation, weakness and stroke severity. DISCUSSION: There is no published evidence on predicting the likelihood of difficulty caring for the arm following stroke. However, the related impairments of spasticity, pain and contracture are common. Given the time-course of development, clinicians may need not only to intervene early but also be prepared to act over a longer time period. Further research is needed to examine difficulty caring for the arm and the relationship with associated impairments to enable researchers and clinicians to develop targeted interventions. (c) 2015 The Authors. Physiotheraphy Research International Published by John Wiley & Sons Ltd. PMID- 26015293 TI - Exploiting lipopolysaccharide-induced deformation of lipid bilayers to modify membrane composition and generate two-dimensional geometric membrane array patterns. AB - Supported lipid bilayers have proven effective as model membranes for investigating biophysical processes and in development of sensor and array technologies. The ability to modify lipid bilayers after their formation and in situ could greatly advance membrane technologies, but is difficult via current state-of-the-art technologies. Here we demonstrate a novel method that allows the controlled post-formation processing and modification of complex supported lipid bilayer arrangements, under aqueous conditions. We exploit the destabilization effect of lipopolysaccharide, an amphiphilic biomolecule, interacting with lipid bilayers to generate voids that can be backfilled to introduce desired membrane components. We further demonstrate that when used in combination with a single, traditional soft lithography process, it is possible to generate hierarchically organized membrane domains and microscale 2-D array patterns of domains. Significantly, this technique can be used to repeatedly modify membranes allowing iterative control over membrane composition. This approach expands our toolkit for functional membrane design, with potential applications for enhanced materials templating, biosensing and investigating lipid-membrane processes. PMID- 26015294 TI - A 12-month angiographic and optical coherence tomography follow-up after bioresorbable vascular scaffold implantation in patients with ST-segment elevation myocardial infarction. AB - OBJECTIVES: The aim of the study was to evaluate the healing process at 12 months after ABSORBTM bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: There is currently no data on long-term BVS performance in the acute thrombotic setting. The underlying altered plaque pathomorphology may impact the neointima healing pattern, potentially making it different to that observed in stable coronary artery disease (CAD). METHODS: We have performed an angiographic and optical coherence tomography (OCT) 12-month follow-up of 19 STEMI patients who were treated with a BVS implantation (23 scaffolds). An independent core laboratory performed a paired analysis of the corresponding frames at baseline and follow up. RESULTS: At 12 months, the OCT follow-up showed a decrease in the mean lumen area (8.29 +/- 1.53 mm(2) vs. 6.82 +/- 1.57 mm(2) , P < 0.001), but no significant change in the mean scaffold area (8.49 +/- 1.53 mm(2) vs. 8.90 +/- 1.51 mm(2) ). Significant decreases in malapposed strut ratio (4.9 +/- 8.65% vs. 0.4 +/- 1.55%, P < 0.001) and malapposition area (0.29 +/- 0.60 mm(2) 0.08 +/- 0.32 mm(2) , P = 0.002) were observed. A nonhomogenous proliferation of neointima was revealed with a symmetry index of 0.15 (0.08-0.27), a mean neointima thickness of 203 MUm (183-249) and mean neointima area of 2.07 +/- 0.51 mm(2) . The quantitative coronary angiography showed late lumen loss of 0.08 +/- 0.23 mm and no significant change in the minimal lumen diameter (P = 0.11). There were no major adverse cardiovascular events (MACE), except for one nontarget vessel revascularization. CONCLUSIONS: The OCT revealed a favorable healing pattern after BVS implantation in a STEMI population. PMID- 26015295 TI - Systems biology and metabolic modelling unveils limitations to polyhydroxybutyrate accumulation in sugarcane leaves; lessons for C4 engineering. AB - In planta production of the bioplastic polyhydroxybutyrate (PHB) is one important way in which plant biotechnology can address environmental problems and emerging issues related to peak oil. However, high biomass C4 plants such as maize, switch grass and sugarcane develop adverse phenotypes including stunting, chlorosis and reduced biomass as PHB levels in leaves increase. In this study, we explore limitations to PHB accumulation in sugarcane chloroplasts using a systems biology approach, coupled with a metabolic model of C4 photosynthesis. Decreased assimilation was evident in high PHB-producing sugarcane plants, which also showed a dramatic decrease in sucrose and starch content of leaves. A subtle decrease in the C/N ratio was found which was not associated with a decrease in total protein content. An increase in amino acids used for nitrogen recapture was also observed. Based on the accumulation of substrates of ATP-dependent reactions, we hypothesized ATP starvation in bundle sheath chloroplasts. This was supported by mRNA differential expression patterns. The disruption in ATP supply in bundle sheath cells appears to be linked to the physical presence of the PHB polymer which may disrupt photosynthesis by scattering photosynthetically active radiation and/or physically disrupting thylakoid membranes. PMID- 26015296 TI - Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas. AB - Treatment for recurrent and aggressive meningiomas remains an unmet medical need in neuro-oncology, and chemotherapy exhibits limited clinical activity, if any. Merlin expression, encoded by the NF2 gene, is lost in a majority of meningiomas, and merlin is a negative regulator of mTORC1. The sst2 somatostatin receptor, targeted by octreotide, is highly expressed in meningiomas. To investigate new therapeutic strategies, we evaluated the activity of everolimus (mTOR inhibitor), BKM-120 and BEZ-235 (new Pi3K/Akt/mTOR inhibitors), octreotide and a combined treatment (octreotide plus everolimus), on cell proliferation, signaling pathways, and cell cycle proteins, respectively. The in vitro study was conducted on human meningioma primary cells extracted from fresh tumors, allowing the assessment of somatostatin analogs at the concentration levels used in patients. The results were correlated to WHO grades. Further, everolimus decreased cell viability of human meningiomas, but concomitantly, induced Akt activation, reducing the antiproliferative effect of the drug. The new Pi3K inhibitors were not more active than everolimus alone, limiting their clinical relevance. In contrast, a clear cooperative inhibitory effect of octreotide and everolimus was observed on cell proliferation in all tested meningiomas, including WHO grades II III. Octreotide not only reversed everolimus-induced Akt phosphorylation but also displayed additive and complementary effects with everolimus on downstream proteins involved in translation (4EB-P1), and controlling cell cycle (p27Kip1 and cyclin D1). We have demonstrated a co-operative action between everolimus and octreotide on cell proliferation in human meningiomas, including aggressive ones, establishing the basis for a clinical trial. PMID- 26015297 TI - Impact of glycemia on survival of glioblastoma patients treated with radiation and temozolomide. AB - Evidence suggests hyperglycemia is associated with worse outcomes in glioblastoma (GB). This study aims to confirm the association between glycemia during radiotherapy (RT) and temozolomide (TMZ) treatment and overall survival (OS) in patients with newly diagnosed GB. This retrospective study included GB patients treated with RT and TMZ from 2004 to 2011, randomly divided into independent derivation and validation datasets. Time-weighted mean (TWM) glucose and dexamethasone dose were collected from start of RT to 4 weeks after RT. Univariate (UVA) and multivariable (MVA) analyses investigated the association of TWM glucose and other prognostic factors with overall survival (OS). In total, 393 patients with median follow-up of 14 months were analyzed. In the derivation set (n = 196) the median OS was 15 months and median TWM glucose was 6.3 mmol/L. For patients with a TWM glucose <=6.3 and >6.3 mmol/L, median OS was 16 and 13 months, respectively (p = 0.03). On UVA, TWM glucose, TWM dexamethasone, age, extent of surgery, and performance status were associated with OS. On MVA, TWM glucose remained an independent predictor of OS (p = 0.03) along with TWM dexamethasone, age, and surgery. The validation set (n = 197), with similar baseline characteristics, confirmed that TWM glucose <=6.3 mmol/L was independently associated with longer OS (p = 0.005). This study demonstrates and validates that glycemia is an independent predictor for survival in GB patients treated with RT and TMZ. PMID- 26015298 TI - Use of Ilizarov External Fixation Without Soft Tissue Release to Correct Severe, Rigid Equinus Deformity. AB - The purpose of the present retrospective study was to report the correction of severe, rigid equinus deformities using an Ilizarov external fixator alone, without adjunctive open procedures. Ten feet in 10 patients with rigid equinus deformities were enrolled and underwent gradual correction using an Ilizarov external fixator alone, without additional open procedures. The range of ankle joint motion was measured preoperatively and at the last follow-up visit. The radiographic outcome was assessed using the lateral tibiotalar angle on ankle radiographs taken preoperatively, immediately after removal of the Ilizarov fixator, and at the last follow-up visit. The mean duration of external fixator treatment was 40.1 +/- 13.5 days. The preoperative mean ankle range of motion was -55.5 degrees +/- 22.2 degrees of dorsiflexion and 63.0 degrees +/- 20.8 degrees of plantarflexion. At the last follow-up visit, the mean dorsiflexion had increased to -2.5 degrees +/- 6.8 degrees and the mean plantarflexion had decreased to 30.5 degrees +/- 12.6 degrees . The mean lateral tibiotalar angle was 152.9 degrees +/- 19.7 degrees preoperatively, 103.9 degrees +/- 9.4 degrees immediately after removal of the Ilizarov external fixator, and 113.9 degrees +/- 11.6 degrees at the last follow-up visit. Immediately after fixator removal, all the patients had clinical correction of their deformity to a plantigrade foot using the Ilizarov external fixator alone, with a mean correction of 49.0 degrees +/- 17.4 degrees . Some recurrence was noted at the last follow-up examination, with a final mean correction of 39.0 degrees +/- 18.0 degrees . The present study has demonstrated successful correction of severe, rigid equinus deformity with the use of an Ilizarov external fixator without the need for adjunctive soft tissue procedures. This method can be effective for patients with a high risk of complications after open procedures owing to their poor soft tissue envelope. PMID- 26015299 TI - Augmented Repair of Acute Achilles Tendon Rupture Using an Allograft Tendon Weaving Technique. AB - Achilles tendon rupture is a common injury, especially in those who are physically active. Although open surgery is a widely used option for the treatment of acute Achilles tendon rupture, the optimal treatment is still disputed. In our study, 59 patients with unilateral, closed, acute rupture of the Achilles tendon were treated by open surgery using an allograft weave to augment the repair. All the surgeries were performed within 1 to 4 days after injury. The mean American Orthopaedic Foot and Ankle Society ankle-hindfoot score was recorded as 91.20 (range 88 to 95), 95.34 (range 92 to 98), and 98.27 (range 97 to 99) at the 3-, 6-, and 12-month follow-up visit, respectively. At the final follow-up visit, the mean difference between the mid-calf circumference of the injured and uninjured legs was 0.19 (range -0.03 to 1.50) cm (p = .43). At the final follow-up visit, the mean difference between the vertical distances from the plantar surface of the heel to the ground for the injured and uninjured lower extremities was 0.44 (range -0.03 to 0.5) cm (p = .17). Augmented repair using the allograft tendon weaving technique provided satisfactory tendon strength and functional outcomes and a timely return to the patients' activities. PMID- 26015300 TI - Chondroid Syringoma of the Foot: A Rare Diagnosis. AB - Chondroid syringoma is a rare tumor with the potential for malignant transformation and distant metastasis. The site of predilection for benign chondroid syringoma is the head and neck region, and it is less likely to involve the foot. In contrast, malignant chondroid syringoma is more commonly encountered in the extremities and is characterized by rapid growth, local invasion, and distant metastasis. We report an unusual case of benign chondroid syringoma in a 47-year-old female who presented with a 20-year history of a mass in her left foot to bring such cases to the attention of foot and ankle specialists. We highlight the histologic diagnosis and surgical procedures with a 6-month postoperative follow-up period. It is unlikely that a treating physician would anticipate this histologic tumor type, considering the rarity of the condition, the long history of this patient's lesion, and the benign presentation in the extremities. PMID- 26015301 TI - Development of a Radiographic Union Score for Determining Osteotomy Union Rates in Long Bones of the Foot. AB - Determining the status of bone healing after osteotomy can be challenging and has implications ranging from clinical decision-making to standardization of research outcomes without the use of computed tomography. To date, no method has been validated for determining osseous healing of an osteotomy site of the long bones of the foot. The purpose of the present study was to develop a radiographic union scoring system that would enhance the diagnostic healing assessment. We adapted existing orthopedic scales that had been validated for healing in the leg for application in the long bones of the foot. One hundred cases were evaluated by 6 blinded assessors to test the inter- and intrarater reliability of the subjective healing assessment compared with the proposed scoring system. The radiographs were classified by postoperative period: <=4, 5 to 12, and >12 weeks. The proposed scale had a high interrater reliability but was burdensome. Using a priori item reduction protocols, the scale was limited to the 5 items with the best internal consistency, which significantly reduced the burden. The result was excellent interrater reliability (alpha = 0.87) among all assessors compared with acceptable reliability (alpha = 0.66) for the subjective osteotomy healing assessment. The intrarater reliability during the subsequent retest phase demonstrated similar relationships, with low agreement (r = 0.38) for subjective healing. Each of the items included in the final scoring scale had moderate to good agreement across all assessors (r = 0.51 to 0.63). The reliability of this system appeared superior to the subjective assessment of osseous healing alone, even in the absence of clinical correlates after an osteotomy in the foot. PMID- 26015302 TI - Elastic Bandage Traction Technique for Reduction of Distal Tibial Fractures. AB - In the present technique report, we describe a useful noninvasive traction technique that uses a 6-inch elastic bandage that can be obtained in every operating room and can be easily applied around the patient's ankle and the surgeon's waist to offer a stable traction force during minimally invasive plate fixation of distal tibial fractures. This technique frees the surgeon's hands to focus on applying other forces, such as rotational, varus, or valgus forces, to reduce the fracture and stabilize the reduction and alignment during percutaneous insertion and fixation of the plate. This technique, although simplistic and old fashioned, is also useful for the closed reduction of distal tibial physeal injuries in children, because it can provide a significant amount of traction force while allowing the surgeon to apply other forces for fracture reduction. This technique can be used in the emergency room, where an ankle distractor is not usually present, and in some cases could be useful during ankle arthroscopy. PMID- 26015303 TI - Preoperative and Postoperative Range of Motion: A Retrospective Comparison of Two Total Ankle Replacement Systems. AB - The purpose of the present report was to compare the range of motion between a total ankle replacement requiring arched bony resection and a total ankle replacement requiring a flat cut for implantation. We hypothesized that the arched contour would more closely mimic the patient's pre-existing anatomy and increase the range of motion. Pain was evaluated as a secondary outcome. Twenty eight patients (age 55.95 +/- 15.29 years) were included. Of the 28 patients, 14 were treated with an arch cut and 14 with a flat cut. Although no significant difference was found in dorsiflexion between the 2 implant groups (p = .38), preoperative dorsiflexion, body mass index, implant type, and preoperative plantarflexion emerged as significant predictors of postoperative plantarflexion (p = .04). This finding indicates that postoperative plantarflexion was significantly greater in patients treated with an arch cut (30.43 degrees +/- 10.01 degrees ) than a flat cut (21.79 degrees +/- 15.70 degrees , p = .02), when controlling for the other explanatory variables. A statistically significant improvement in pain was observed after total ankle replacement (p < .001). The mean change in pain was similar for the 2 implant groups when statistically controlling for the follow-up duration (p = .09). The findings from the present report suggest that plantarflexion significantly improves after total ankle replacement requiring an arched cut for implantation. Future studies should be designed to control for potentially confounding variables and assess the differences in range of motion after total ankle replacement. PMID- 26015304 TI - Quantification of Subtalar Posterior Facet Involvement During Intramedullary Guidance of Total Ankle Arthroplasty:A Cadaveric Study. AB - Total ankle arthroplasty is an evolving treatment of ankle arthritis. One implant uses intramedullary guidance to enhance accuracy by accessing the tibial canal through the inferior aspect of the foot, potentially placing the subtalar joint articulation at risk. The purpose of the present cadaveric anatomic evaluation was to identify posterior subtalar articular facet joint involvement during intramedullary guidance to the tibial canal. Ten below-the-knee cadaveric specimens were used. After drilling into the tibial medullary canal with a 6-mm drill bit and using the standard targeting jig, the specimens were dissected, and the posterior facet was evaluated. We graded posterior facet involvement according to the location of the drill hole and, if within the facet, the percentage of the facet violated by the drill bit, with 100% representing the full circumference of the 6-mm drill bit. Of the 8 specimens in which the drill bit passed through the subtalar posterior articular facet, the encroachment was peripheral in all cases, with no specimen showing circumferential 6-mm drill bit articular penetration (no cases with 100%). Sinus tarsi penetration occurred in 20% of the cases. The dissections with articular involvement included 3 specimens with >50% of the drill bit penetrating and 5 with <50%. The portion of the posterior facet involved among the specimens that were violated was anterocentral in the joint. A risk of damage to the posterior facet of the subtalar joint exists with intramedullary total ankle systems. Our study has demonstrated that the drill bit will involve the anterocentral and anterolateral portions of the posterior facet of the subtalar joint, with <6 mm articular disruption in all cases. PMID- 26015306 TI - Measles in India: Challenges & recent developments. PMID- 26015305 TI - Tibiotalocalcaneal Arthrodesis Using Retrograde Intramedullary Nail Fixation: Comparison of Patients With and Without Diabetes Mellitus. AB - Retrograde intramedullary nailing for tibiotalocalcaneal arthrodesis is a salvage procedure reserved for severe cases of deformity. The aim of the present study was to compare the outcomes of this technique in patients with and without diabetes mellitus (DM). A total of 61 patients with and 56 without DM underwent retrograde intramedullary nailing and had a minimum follow-up period of 12 months. The overall incidence of complication was 45.2%; however, the overall incidence of complications between those with and without DM was not significantly different (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.38 to 1.65, p = .54). Patients with DM had a significantly greater rate of superficial infections (OR 8.3, 95% CI 1.01 to 68.67, p = .03). However, no difference was seen in the rate of deep infection (OR 0.90, 95% CI 0.34 to 2.46, p = .83) or noninfectious complications (OR 0.50, 95% CI 0.23 to 1.13, p = .09). Successful limb salvage was achieved for 96.8% of the patients with DM and 94.7% of those without DM (p = .66). A femoral head allograft was used in 32 (27.4%) of 117 patients to substitute for an osseous void. Of the 32 patients who required a femoral head allograft, 21 (67.7%) experienced a complication compared with 32 (37.6%) of 85 patients who did not require a femoral head allograft (OR 3.16, 95% CI 1.35 to 7.41, p = .008). The incidence of patient satisfaction was 80% for patients with DM and 72% for those without DM (p = .36). Despite a high incidence of complications, limb salvage was accomplished in approximately 95% of patients with complicated deformities. Four patients (6.56%) with DM experienced a tibia fracture; therefore, we now routinely use a 300-mm-long nail for this reconstruction. PMID- 26015307 TI - Hypoglycemic, antilipidemic and antioxidant effects of valproic acid in alloxan induced diabetic rats. AB - This study was designed to investigate the hypoglycemic, antilipidemic and antioxidant effects of valproic acid (VA) in alloxan-induced diabetic rats. VA (100, 300 and 600mg/kg p.o.) and insulin (17IU/kg s.c.) were administered once daily for 21 days. Fasting blood glucose level was determined at 7 days interval. On day 21, blood samples were collected for assay of serum biochemical parameters (total protein, creatinine, urea, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), and low density lipoprotein (LDL)). Kidneys and livers were harvested for antioxidant indices and histopathological examination. In diabetic rats, VA produced a dose and day dependent reduction in glucose level. Peak effect (52.79% reduction; P<0.001) was produced at the dose of 600mg/kg on day 21. In normoglycemic rats, VA (600mg/kg) caused significant reduction (P<0.05) in blood glucose level on days 1 and 21 with 16.38% and 15.63% reductions respectively. In diabetic rats, VA significantly reduced the level of catalase (CAT) and malondialdehyde (MDA) in the kidney, and increased the level of superoxide dismutase, CAT and glutathione peroxidase with reduction in MDA in the liver compared to diabetic control, especially at the dose of 600mg/kg. VA (600mg/kg) generally increased the level of HDL and reduced the levels of TG, LDL, TC, AST, ALT, ALP, bilirubin, creatinine and urea compared with diabetic control. The findings in this study suggest that VA possess beneficial antidiabetic effects. PMID- 26015308 TI - Following JGES guidelines for patients with antiplatelet agents might increase bleeding after gastric endoscopic submucosal dissection. PMID- 26015309 TI - Cyclic versus continuous medroxyprogesterone acetate for treatment of endometrial hyperplasia without atypia: a 2-year observational study. AB - OBJECTIVE: To assess the efficacy, safety and acceptability of cyclic medroxyprogesterone acetate (MPA) compared to continuous MPA for treatment of endometrial hyperplasia (EH) without atypia. MATERIALS AND METHODS: A prospective observational study conducted on premenopausal women with EH without atypia (n = 80) who were randomly assigned into two groups; 40 patients received cyclic 15 mg MPA and 40 patients received continuous 15 mg MPA. Follow-up endometrial sampling was done after 6 months. Primary outcome measure was regression of hyperplasia. Secondary outcome measures include side effects and patient acceptability. RESULTS: There was no significant difference between the two groups regarding regression of endometrial hyperplasia (90 % in the cyclic MPA group in comparison to 82.5 % in the continuous MPA group with p value >0.05). There was a significant higher women suffering from nausea, acne and menstrual changes in the continuous MPA group (p value <0.05). Cyclic MPA regimen was more acceptable to the patients in comparison to continuous MPA intake. CONCLUSIONS: Cyclic MPA regimen seems a safer and more acceptable therapy in comparison to continuous MPA regimen in patients with endometrial hyperplasia without atypia. Larger studies are warranted to confirm these results. PMID- 26015310 TI - Enhancing reuse of structured eligibility criteria and supporting their relaxation. AB - Patient recruitment is one of the most important barriers to successful completion of clinical trials and thus to obtaining evidence about new methods for prevention, diagnostics and treatment. The reason is that recruitment is effort consuming. It requires the identification of candidate patients for the trial (the population under study), and verifying for each patient whether the eligibility criteria are met. The work we describe in this paper aims to support the comparison of population under study in different trials, and the design of eligibility criteria for new trials. We do this by introducing structured eligibility criteria, that enhance reuse of criteria across trials. We developed a method that allows for automated structuring of criteria from text. Additionally, structured eligibility criteria allow us to propose suggestions for relaxation of criteria to remove potentially unnecessarily restrictive conditions. We thereby increase the recruitment potential and generalizability of a trial. Our method for automated structuring of criteria enables us to identify related conditions and to compare their restrictiveness. The comparison is based on the general meaning of criteria, comprised of commonly occurring contextual patterns, medical concepts and constraining values. These are automatically identified using our pattern detection algorithm, state of the art ontology annotators and semantic taggers. The comparison uses predefined relations between the patterns, concept equivalences defined in medical ontologies, and threshold values. The result is a library of structured eligibility criteria which can be browsed using fine grained queries. Furthermore, we developed visualizations for the library that enable intuitive navigation of relations between trials, criteria and concepts. These visualizations expose interesting co-occurrences and correlations, potentially enhancing meta-research. The method for criteria structuring processes only certain types of criteria, which results in low recall of the method (18%) but a high precision for the relations we identify between the criteria (94%). Analysis of the approach from the medical perspective revealed that the approach can be beneficial for supporting trial design, though more research is needed. PMID- 26015311 TI - beta-Methylphenylethylamines: common fragmentation pathways with amphetamines in electrospray ionization collision-induced dissociation. AB - beta-Methylphenylethylamines are positional isomers of amphetamines and have been discovered in sporting supplements. Although the fragmentation of the beta methylphenylethylamine and N-methyl-beta-methylphenylethylamine in gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) systems is significantly different to their amphetamine and methylamphetamine isomers, under electrospray ionization commonly used in liquid chromatography-mass spectrometry (LC-MS) systems, the fragmentation of each of the isomeric pairs is almost identical. The similarities in fragmentation make it possible for the misidentification of the beta-methylphenylethylamines as the illicit amphetamines. It is proposed that the similarities are due to a fragmentation pathway involving a common phenonium ion intermediate. By careful control of fragmentation energies in liquid chromatography-tandem mass spectrometry (LC MS/MS) systems and/or close examination of the relative abundances of product ions formed by collision-induced dissociation (qualifier ratios), it is possible to distinguish the beta-methylphenylethylamines from the amphetamines, even if significant retention time separation is not achieved. In liquid chromatography electrospray ionization-quadrupole time of flight (LC-ESI-QTOF) systems the mass spectra of the beta-methylphenylethylamines are identical to their amphetamine isomers. In such systems, retention time separation of the isomers is critical to avoid misidentification. During this study beta-methylphenylethylamine and N methyl-beta-methylphenylethylamine have been identified in commercially available sporting supplements and oral fluid samples taken during the course of road-side drugs-in-drivers and workplace testing programmes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26015312 TI - Human surrogate models of histaminergic and non-histaminergic itch. AB - Within the last decade understanding of the mechanistic basis of itch has improved significantly, resulting in the development of several human surrogate models of itch and related dysesthetic states. Well-characterized somatosensory models are useful in basic studies in healthy volunteers, in clinical studies for diagnostic and segmentation purposes, and in pharmacological studies to evaluate the antipruritic efficacy of existing and novel compounds. This review outlines recently introduced histamine-independent human models of itch, their mechanisms, their ability to induce clinically relevant phenomena, such as alloknesis, and the results obtained through their use. The article also introduces recent advances in the understanding of itch and provides an overview of the methods to assess experimentally-induced itch and associated manifestations. Major improvements are warranted in the treatment of chronic pruritus, and reliable human surrogate models are a valuable tool in achieving them, both for basic researchers and for clinicians. PMID- 26015313 TI - Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues. AB - With the wide application of combined antiretroviral therapy, the prognosis of human immunodeficiency virus (HIV)-1 infected patient has been significantly improved. However, long-term administration of antiretroviral drugs can result in various drug-associated toxicities. Among them, nucleoside analogues were confirmed to inhibit DNA polymerase gamma, resulting in mitochondrial toxicity. Our previous study indicated that long-term exposure of mice to nucleoside analogue could induce mitochondria DNA (mtDNA) loss in cortical neurons. Herein, we further identify mitochondrial toxicity of four nucleoside analogues (zidovudine (AZT), stavudine (D4T), lamivudine (3TC), and didanosine (DDI)) by cloning and sequencing mtDNA D-loop region in mice neurons captured with laser capture microdissection. The results showed that mutation of neuronal mtDNA D loop sequences increased in mice treated with each of the four nucleoside analogues for 4 months and D4T and DDI induced more severe D-loop lesion than the other two nucleoside analogues. The major type of D-loop point mutations induced by four nucleoside analogues was transition, in particular of "A->G" and "T->C" transition, but the point transition sites were variable. Our findings suggest that long-term exposure to nucleoside analogue can result in mtDNA D-loop region lesion in mouse cortical neurons. PMID- 26015315 TI - High-performance liquid chromatographic separation of unusual beta(3)-amino acid enantiomers in different chromatographic modes on Cinchona alkaloid-based zwitterionic chiral stationary phases. AB - Polar-ionic and hydro-organic mobile phase mode of high-performance liquid chromatographic separations of 23 sterically constrained primary beta(3)-amino acid enantiomers containing, alkyl, aryl or heteroaryl side-chains were carried out by using newly developed Cinchona alkaloid-based zwitterionic chiral selectors and the stationary phases Chiralpak ZWIX(+)TM and ZWIX(-)TM. In the polar-ionic mode, the effects of the composition of the bulk solvent and the natures of the co- and counter-ions, while in the hydro-organic mode, the effects of the pH, the counter-ion concentration and the structures of the analytes were investigated. The separations of the enantiomers of these 23 primary beta(3) amino acids, which can be classified as a series of quasi- (pseudo-) homologs, were optimized in both chromatographic modes. The elution sequence was determined in most cases and a reversal of elution order on ZWIX(+)TM and ZWIX(-)TM column was observed. On the basis of this intermolecular recognition model between the selectors and the given enantiomers an indirect assignment of the resolved enantiomer via chromatography is proposed. PMID- 26015314 TI - Comparison of optical data from flow cytometry and microscopy of leukocytes after exposure to specific reagents. AB - Flow cytometry and microscopy are equally important in cell analysis. However, few reports have compared the optical data (cell size, internal complexity and fluorescent signal) from flow cytometry and microscopy. In this study, we compared the scattergram from XN-series, a flow cytometry based hematology analyzer with microscopic images of similarly treated leukocytes, and investigated the correlation between the appearance in the scattergram and cell size, internal complexity and fluorescence intensity. Healthy human peripheral blood was analyzed using the XN analyzer. For microscopic comparison, five types of leukocytes (monocytes, lymphocytes, basophils, neutrophils and eosinophils) were isolated from the peripheral blood by centrifugation and magnetic cell sorting, treated with a specific reagent and analyzed using electron microscopy, laser microscopy and confocal laser microscopy. Cell size, residual internal structures and fluorescence intensity correlated with intensity of forward scattering, side scattering and fluorescent light. In this study, optical data from a clinically used hematology analyzer was clarified using microscopic images. PMID- 26015316 TI - Effects of a high-protein/low-carbohydrate versus a standard hypocaloric diet on adipocytokine levels and cardiovascular risk factors during 9 months, role of rs6923761 gene variant of glucagon-like peptide 1 receptor. AB - BACKGROUND: The role of GLP-1 R variants on body weight response after dietary intervention is unclear. OBJECTIVE: The aim was to investigate the role of this polymorphism on cardiovascular risk factors, adipokine levels and weight loss secondary to a high-protein/low-carbohydrate vs. standard hypocaloric diets during 9 months. DESIGN: 211 obese subjects were randomly allocated to one of these two diets for a period of 9 months; diet HP (high protein/low carbohydrate) and diet S (standard). RESULTS: Ninety-four patients (44.5%) had the genotype GG (wild group) and 117 (55.5%) patients had the next genotypes; GA (89 patients, 42.2%) or AA (28 patients, 13.3%) (mutant group). With both diets and in both genotype groups, body mass index, weight, fat mass, waist circumference and systolic blood pressure decreased. Anthropometric parameters were higher in non-A allele carriers than A allele carriers. With diet HP in both genotypes, LDL cholesterol, total cholesterol, leptin, insulin levels and HOMA-R decreased. With the diet S and only in wild genotype, the same parameters decreased, too. CONCLUSION: Our data showed a lack of association of rs6923761 GLP-1 R polymorphism with weight loss. Better anthropometric parameters in obese subjects with the mutant allele (A) of rs6923761 GLP-1 R polymorphism were observed. Total cholesterol, LDL cholesterol, insulin levels and HOMA-R decreased in all patients with both diets, although A allele carriers treated with standard diet did not show these changes. PMID- 26015317 TI - Revaluation of the clinical and metabolic behavior of children with isolated growth hormone deficiency during GH treatment according to newly proposed note 39 of the Italian Medicines Agency (AIFA). AB - PURPOSE: This study aimed at evaluating the clinical and metabolic behavior of children with isolated growth hormone (GH)-deficiency (GHD), grouped according to the new AIFA criteria for the appropriateness of use and reimbursement of GH treatment in children. METHODS: The clinical and metabolic data of 310 prepubertal children (220 M, 90 F; mean age 10.8 years) grouped, according to new AIFA note 39, into Group A (No. 181 with a peak of GH <8 ug/l), Group B (No. 103 with a peak of GH >=8 and <10 ug/l) and Group C (No. 26 with a peak of GH >10 ug/l) were retrospectively analyzed. Group A and B, diagnosed as having GHD, were treated with GH for at least 24 months, while Group C was analyzed only at baseline. RESULTS: At baseline, Group A showed higher waist circumference than B (p = 0.031) and C (p = 0.041), while no difference in metabolic parameters was found between the three groups. After 12 and 24 months of treatment, Group B showed lower height velocity (p < 0.001 and p = 0.049, respectively) than Group A. As regards the metabolic parameters, both after 12 and 24 months of treatment, in Group B we found higher fasting glucose (p < 0.001 and p = 0.020), insulin (p = 0.002 and p = 0.011), Homa-beta (p = 0.020 and p = 0.015) and Homa-IR (both p = 0.001) than Group A, with concomitant lower QUICKI (both p < 0.001) and HDL cholesterol (p = 0.020 and p = 0.011), without difference in other lipid parameters. The HbA1c levels, although always within the normal range, were found higher in Group B than Group A after 12 months (p = 0.015). CONCLUSIONS: According to the new AIFA criteria, the reduction of GH cut-off for GHD diagnosis can be supported by auxological and metabolic data. The real benefits from GH therapy in children with higher stimulated GH levels at diagnosis remains to be better understand. PMID- 26015319 TI - Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study. AB - Conformational preferences for the turn and beta-hairpin structures of Ala-based peptides [Ac-Ala(n)-(R)-Nip-(S)-Nip-Ala(n)-X (n = 0-2; X = NHMe or NMe2)] containing nipecotic acid (Nip) residues were carried out using the density functional M06-2X and the implicit solvation model SMD in CH2Cl2 and/or water. The turn structure of the (R)-Nip-(S)-Nip segment with a C10 H-bond between two terminal groups was found to be most preferred (populated at 98.9%) in CH2Cl2; this structure is consistent with IR and (1)H NMR results. The stabilities of the beta-hairpins containing the (R)-Nip-(S)-Nip segment as a turn motif relative to the extended structures increased with peptide sequence length. The relative strengths of the H-bonds between the carbonyl oxygen and the amide hydrogen appeared to be responsible for stabilizing the turn and beta-hairpin structures in CH2Cl2. In addition, the (R)-Nip-(S)-Nip segment exhibited the capability to be incorporated into one of the two beta-turn motifs of gramicidin S (GS). The structure of this GS derivative (GS-Nip2 ) was generally similar to the native peptide but was less hydrophobic and it is therefore expected to exhibit lower hemolytic activity; however, further experiments are needed to evaluate its antimicrobial activity. The structure of GS-Nip2 was somewhat more flexible than GS in solvents of higher polarity. Thus, our calculated results regarding the turn and beta-hairpin motifs of the (R)-Nip-(S)-Nip segment indicate that this structure might be useful for the design of bioactive macrocyclic peptides containing beta-hairpin mimics as well as binding epitopes in protein-protein and protein-nucleic acid recognitions. PMID- 26015320 TI - Cassava brown streak disease: a threat to food security in Africa. AB - Cassava brown streak disease (CBSD) has emerged as the most important viral disease of cassava (Manihot esculenta) in Africa and is a major threat to food security. CBSD is caused by two distinct species of ipomoviruses, Cassava brown streak virus and Ugandan cassava brown streak virus, belonging to the family Potyviridae. Previously, CBSD was reported only from the coastal lowlands of East Africa, but recently it has begun to spread as an epidemic throughout the Great Lakes region of East and Central Africa. This new spread represents a major threat to the cassava-growing regions of West Africa. CBSD-resistant cassava cultivars are being developed through breeding, and transgenic RNA interference derived field resistance to CBSD has also been demonstrated. This review aims to provide a summary of the most important studies on the aetiology, epidemiology and control of CBSD and to highlight key research areas that need prioritization. PMID- 26015318 TI - Circulating miRNAs as biomarkers for endocrine disorders. AB - Specific, sensitive and non-invasive biomarkers are always needed in endocrine disorders. miRNAs are short, non-coding RNA molecules with well-known role in gene expression regulation. They are frequently dysregulated in metabolic and endocrine diseases. Recently it has been shown that they are secreted into biofluids by nearly all kind of cell types. As they can be taken up by other cells they may have a role in a new kind of paracrine, cell-to-cell communication. Circulating miRNAs are protected by RNA-binding proteins or microvesicles hence they can be attractive candidates as diagnostic or prognostic biomarkers. In this review, we summarize the characteristics of extracellular miRNA's and our knowledge about their origin and potential roles in endocrine and metabolic diseases. Discussions about the technical challenges occurring during identification and measurement of extracellular miRNAs and future perspectives about their roles are also highlighted. PMID- 26015321 TI - Retraction. RNA transcripts of full-length cDNA clones of rabbit hepatitis E virus are infectious in rabbits. PMID- 26015322 TI - Consensus proposals for classification of the family Hepeviridae. PMID- 26015323 TI - From whole exome sequencing to patient-specific therapy: another example of how basic research pays off in patient care. PMID- 26015325 TI - Platelet function tests: why they fail to guide personalized antithrombotic medication. PMID- 26015324 TI - Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy. AB - BACKGROUND: Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment. METHODS AND RESULTS: We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito. CONCLUSIONS: We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams. PMID- 26015326 TI - Orthopaedic shoes along with physical therapy was effective in Charcot-Marie Tooth patient over 10 years. AB - BACKGROUND: The aim was to investigate the effectiveness of custom-made orthopaedic shoes (derby shoes) along with physiotherapy (twice a week) on a person with Charcot-Marie-Tooth over a period of 10 years. CASE DESCRIPTION AND METHODS: A 66-year-old woman with Charcot-Marie-Tooth disease, who did not have other health conditions, complained of pain and frequent falls. Physical examination, including ankle, knee and hip muscle strength; sensory evaluation of foot and joint range of motion; self-reported assessment of pain, frequency of falls and sprains; and gait analyses, including spatial and temporal parameters and motion analyses, were performed in 2001, 2007 and 2011. FINDINGS AND OUTCOMES: During the 10 years of follow-up, the physical examination parameters had stabilized since 2001; falls, sprains and walking distance had improved as compared to 2000; pain had alleviated since 2001 and gait parameters had improved up to 2007 and stabilized between 2007 and 2011. CONCLUSION: Bracing with orthopaedic shoes along with physical therapy was effective in treating pain, improving the gait and enhancing the walking distance (>500 m) without assistive device in a person with Charcot-Marie-Tooth disease. CLINICAL RELEVANCE: Orthopaedic shoes along with physical therapy can be a good option for treating Charcot-Marie-Tooth associated pain, foot drop, falls and sprains, improving the gait abnormalities and also increasing the walking distance. PMID- 26015327 TI - A comparison of different over-the-counter foot orthotic devices on multi-segment foot biomechanics. AB - BACKGROUND: Over-the-counter foot orthoses are a cost-effective alternative to custom-made devices. However, few studies have compared over-the-counter devices and most biomechanical research involving orthoses has focused on rearfoot biomechanics. OBJECTIVES: To determine changes in multi-segment foot biomechanics during shod walking in three commercially available over-the-counter devices: SOLE, SuperFeet and Powerstep when compared to no orthotic. STUDY DESIGN: Repeated measures, cross-sectional study. METHODS: Retroreflective markers were placed on the right limb of 18 participants representing forefoot, midfoot, rearfoot and shank segments. Three-dimensional kinematics were recorded using an eight-camera motion capture system while participants walked on a treadmill and the order of condition was randomized between four conditions: SOLE, SuperFeet, Powerstep and no orthotic. RESULTS: All over-the-counter devices exhibited significant decreases in plantar fascia strain compared to no orthotic and only Powerstep exhibited significant decreases in peak rearfoot eversion. Medial longitudinal arch deformation was not reduced for any over-the-counter device. CONCLUSION: Different over-the-counter devices exhibited specific alterations in rearfoot kinematics and all reduced plantar fascia strain by varying amounts. These over-the-counter-specific kinematic changes should be taken into consideration when recommending these devices as a treatment option. CLINICAL RELEVANCE: Over-the-counter orthoses are a cost-effective alternative to custom made devices. We demonstrated that three commonly used over-the-counter devices influence foot kinematics and plantar fascia strain differently. Clinicians can use these results to provide more tailored treatment options for their patients. PMID- 26015328 TI - Organocatalytic Asymmetric 1,6-Addition/1,4-Addition Sequence to 2,4-Dienals for the Synthesis of Chiral Chromans. AB - A novel asymmetric organocatalytic 1,6-addition/1,4-addition sequence to 2,4 dienals is described. Based on a 1,6-Friedel-Crafts/1,4-oxa-Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94-99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies. PMID- 26015330 TI - Factors That Predict the Development of Hypertension in Women With Pregnancy Induced Hypertension. AB - BACKGROUND: Pregnancy-induced hypertension (PIH) is associated with chronic hypertension (HTN) and cardiovascular complications. We investigated the factors that predict the development of chronic HTN in women with PIH. METHODS: The study population comprised 108 women with PIH and 87 healthy age-matched women control subjects who gave birth during the years 1990-1994 at the Chaim Sheba Medical Center, Israel, and were followed for up to 23 years (average 20.8 +/- 1.4). We analyzed the association between PIH and subsequent HTN and cardiovascular complications, aiming to identify predicting factors for the development of chronic HTN in this subject population. RESULTS: At the time of index pregnancy, women with PIH were more likely to be overweight, had elevated blood pressure (BP) levels, a shorter gestational period, required more cesarean sections, and were more likely to deliver small infants than the control group. Compared to women with normotensive pregnancy, women with PIH had 11-fold higher age-adjusted risk of developing HTN. They also had a higher body mass index (BMI), and were more likely to develop diabetes mellitus (DM) and coronary artery disease, during follow-up. Among women with PIH, those subjects who developed HTN were older during pregnancy, had higher BMI and more deliveries before the index pregnancy. CONCLUSION: Our findings confirm the association between PIH and chronic HTN. In women with PIH, high BMI and more previous pregnancies are risk factors for developing HTN. Thus, obese women with multiple pregnancies who develop PIH should be more closely followed for the development of HTN. PMID- 26015329 TI - Assessment of intensive care unit-acquired weakness in young and old mice: An E. coli septic peritonitis model. AB - INTRODUCTION: There are few reports of in vivo muscle strength measurements in animal models of ICU-acquired weakness (ICU-AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU-AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU-AW is age-dependent in this model. METHODS: Young and old mice were injected intraperitoneally with E. coli and treated with ceftriaxone. Forelimb grip strength was measured at multiple time points, and the myosin/actin ratio in muscle was determined. RESULTS: E. coli administration was not associated with grip strength decrease, neither in young nor in old mice. In old mice, the myosin/actin ratio was lower in E. coli mice at t = 48 h and higher at t = 72 h compared with controls. CONCLUSIONS: This E. coli septic peritonitis mouse model did not induce decreased grip strength. In its current form, it seems unsuitable as a model for ICU-AW. PMID- 26015331 TI - Beyond Sexist Beliefs: How Do People Decide to Use Gender-Inclusive Language? AB - When people use generic masculine language instead of more gender-inclusive forms, they communicate gender stereotypes and sometimes exclusion of women from certain social roles. Past research related gender-inclusive language use to sexist beliefs and attitudes. Given that this aspect of language use may be transparent to users, it is unclear whether people explicitly act on these beliefs when using gender-exclusive language forms or whether these are more implicit, habitual patterns. In two studies with German-speaking participants, we showed that spontaneous use of gender-inclusive personal nouns is guided by explicitly favorable intentions as well as habitual processes involving past use of such language. Further indicating the joint influence of deliberate and habitual processes, Study 2 revealed that language-use intentions are embedded in explicit sexist ideologies. As anticipated in our decision-making model, the effects of sexist beliefs on language emerged through deliberate mechanisms involving attitudes and intentions. PMID- 26015332 TI - Predicting Disability among Community-Dwelling Medicare Beneficiaries Using Claims-Based Indicators. AB - OBJECTIVES: To assess the feasibility of using existing claims-based algorithms to identify community-dwelling Medicare beneficiaries with disability based solely on the conditions for which they are being treated, and improving on these algorithms by combining them in predictive models. DATA SOURCE: Data on 12,415 community-dwelling fee-for-service Medicare beneficiaries who first responded to the Medicare Current Beneficiary Survey (MCBS) in 2003-2006. STUDY DESIGN: Logistic regression models in which six claims-based disability indicators are used to predict self-reported disability. Receiver operating characteristic (ROC) curves were used to assess the performance of the predictive models. PRINCIPAL FINDINGS: The predictive performance of the regression-based models is better than that of the individual claims-based indicators. At a predicted probability threshold chosen to maximize the sum of sensitivity and specificity, sensitivity is 0.72 for beneficiaries age 65 or older and specificity is 0.65. For those under 65, sensitivity is 0.54 and specificity is 0.67. The findings also suggest ways to improve predictive performance for specific disability populations of interest to researchers. CONCLUSIONS: Predictive models that incorporate multiple claims-based indicators provide an improved tool for researchers seeking to identify people with disabilities in claims data. PMID- 26015335 TI - A Survey Study of Pre-Professionals' Understanding of the Canadian Music Therapy Internship Experience. AB - BACKGROUND: There is limited research to date on the clinical music therapy internship experience from the perspective of the pre-professional. Further study is required to advance this significant stage in clinician development, as it is an intense period when pre-professionals apply and integrate theoretical knowledge about music therapy into their clinical practice. OBJECTIVE: This study aimed to: (1) assess the skills, competence, comfort, concerns, issues, challenges, and anxieties of Canadian undergraduate students at two stages in the internship process (pre- and post-internship); and (2) examine whether these perceptions are consistent with published research on internship. METHODS: Thirty five pre-professionals, from a pool of 50 eligible respondents (70% response rate), completed a 57-question survey using a five-point Likert scale ranking pre and post-internship experience and participated in an interview post-study. RESULTS: Survey results indicate a statistically significant increase in pre professionals' perceived clinical, music, and personal skill development from pre to post-internship. Areas of desired skill development included counseling, functional guitar, and clinical improvisation. CONCLUSIONS: Recommendations for educators and supervisors are provided with respect to areas of focus in undergraduate education and during clinical internship. PMID- 26015333 TI - Diffusion tensor imaging in hemorrhagic stroke. AB - Diffusion tensor imaging (DTI) has evolved considerably over the last decade to now be knocking on the doors of wider clinical applications. There have been several efforts over the last decade to seek valuable and reliable application of DTI in different neurological disorders. The role of DTI in predicting outcomes in patients with brain tumors has been extensively studied and has become a fairly established clinical tool in this scenario. More recently DTI has been applied in mild traumatic brain injury to predict clinical outcomes based on DTI of the white matter tracts. The resolution of white matter fiber tractography based on DTI has improved over the years with increased magnet strength and better tractography post-processing. The role of DTI in hemorrhagic stroke has been studied preliminarily in the scientific literature. There is some evidence that DTI may be efficacious in predicting outcomes of motor function in animal models of intracranial hemorrhage. Only a handful of studies of DTI have been performed in subarachnoid hemorrhage or intraventricular hemorrhage scenarios. In this manuscript we will review the evolution of DTI, the existing evidence for its role in hemorrhagic stroke and discuss possible application of this non invasive evaluation technique of human cerebral white matter tracts in the future. PMID- 26015336 TI - Laparoscopic Adjustable Gastric Banded Plication (Lagbp): Standardization of Surgical Technique and Analysis of Surgical Outcomes. AB - BACKGROUND: Laparoscopic adjustable gastric banded plication (LAGBP) is a novel bariatric procedure which is restrictive and reversible. The aim of this study were to compare two LAGBP techniques and analyze its postoperative outcomes, in order to standardize the procedure. METHODS: Eighty patients who underwent LAGBP were enrolled in this study. Forty patients who underwent LAGBP (group 1) from December 2011 to June 2012 were compared with 40 patients (group 2) who underwent a modified LAGBP technique, which included preserving the right gastroepiploic vessels and uniform plication volume between July 2012 and January 2013. Relevant patient's data were collected and analyzed. RESULTS: Both groups were similar in age, gender, preoperative body mass index (BMI), and hospital stay. The median total operative time was shorter in group 2 (100.5 min; range 41-189) compared to group 1 (124 min; range 63-192), p = 0.048. There were two major complications involving gastric fold herniation (GFH) in group 1, while none was seen in group 2, p = 0.07. The minor complications encountered in both groups were similar, p = 0.37. At 6-month follow-up, there was no difference in mean frequency of band adjustments, weight, and BMI reduction in both groups. No mortality was seen in our series. CONCLUSIONS: A standardized LAGBP procedure which includes uniform plication volume and preservation of right gastroepiploic vessels could potentially avoid early GFH. However, larger comparative studies with longer follow-up would be needed to evaluate the late outcomes of this procedure and its efficacy in weight loss. PMID- 26015337 TI - Identification of a novel truncation mutation of EYA4 in moderate degree hearing loss by targeted exome sequencing. AB - The EYA4 gene encodes a 640-amino-acid protein that serves as a transcription factor. This protein contains a highly conserved Eya domain (eya-HR) and a variable domain (eya-VR). Mutations of this gene are known to cause postlingual and progressive sensorineural hearing loss, either as non-syndromic (DFNA10) or syndromic hearing loss, depending on the location of truncation of the mutant protein. Since our previous report, we have recruited 14 families segregating autosomal dominant moderate SNHL. A thorough medical history and physical examination including evaluation of heart problems ruled out any syndromic features in these families. Screening of EYA4 was performed by targeted exome sequencing of 134 known deafness genes (TES-134) from the probands. After basic filtering of the variants, we identified one proband who carried a novel truncation mutation, c.1194delT (p.Met401TrpfsX3) of EYA4, making the frequency of DFNA10 to be 7.14 % (1/14) in Koreans. The variant co-segregated perfectly with a slightly down-sloping, moderate degree of SNHL in the family (SH117), and was not detected in any of the 592 normal control chromosomes. This variant is likely to generate protein products that are truncated just downstream of the eya VR domain. None of the three affected family members showed any syndromic features, including cardiac problems, which was compatible with a previous genotype-phenotype correlation. The identification of a novel EYA4 truncation mutation associated with DFNA10, rather than syndromic hearing loss, supports a previously reported genotype-phenotype correlation in this gene. Considering its detection rate, EYA4 mutations should be suspected in hereditary moderate hearing loss with a corresponding audiologic configuration, and a cardiac examination should be included in the initial evaluation. PMID- 26015367 TI - Probing the role of sequence in the assembly of three-dimensional DNA crystals. AB - DNA is a widely used biopolymer for the construction of nanometer-scale objects due to its programmability and structural predictability. One long-standing goal of the DNA nanotechnology field has been the construction of three-dimensional DNA crystals. We previously determined the X-ray crystal structure of a DNA 13 mer that forms a continuously hydrogen bonded three-dimensional lattice through Watson-Crick and non-canonical base pairs. Our current study sets out to understand how the sequence of the Watson-Crick duplex region influences crystallization of this 13-mer. We screened all possible self-complementary sequences in the hexameric duplex region and found 21 oligonucleotides that crystallized. Sequence analysis showed that one specific Watson-Crick pair influenced the crystallization propensity and the speed of crystal self-assembly. We determined X-ray crystal structures for 13 of these oligonucleotides and found sequence-specific structural changes that suggests that this base pair may serve as a structural anchor during crystal assembly. Finally, we explored the crystal self-assembly and nucleation process. Solution studies indicated that these oligonucleotides do not form base pairs in the absence of cations, but that the addition of divalent cations leads to rapid self-assembly to higher molecular weight complexes. We further demonstrate that crystals grown from mixtures of two different oligonucleotide sequences contain both oligonucleotides. These results suggest that crystal self-assembly is nucleated by the formation of the Watson Crick duplexes initiated by a simple chemical trigger. This study provides new insight into the role of sequence for the assembly of periodic DNA structures. PMID- 26015369 TI - Proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhosis: An undesirable association? PMID- 26015370 TI - Low ascitic fluid protein does not indicate an increased risk for spontaneous bacterial peritonitis in current cohorts. PMID- 26015368 TI - Microbiota prevents cholesterol loss from the body by regulating host gene expression in mice. AB - We have previously observed that knockout of Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol transporter essential for intestinal cholesterol absorption, reduces the output of dry stool in mice. As the food intake remains unaltered in NPC1L1 knockout (L1-KO) mice, we hypothesized that NPC1L1 deficiency may alter the gut microbiome to reduce stool output. Consistently, here we demonstrate that the phyla of fecal microbiota differ substantially between L1-KO mice and their wild type controls. Germ-free (GF) mice have reduced stool output. Inhibition of NPC1L1 by its inhibitor ezetimibe reduces stool output in specific pathogen-free (SPF), but not GF mice. In addition, we show that GF versus SPF mice have reduced intestinal absorption and increased fecal excretion of cholesterol, particularly after treatment with ezetimibe. This negative balance of cholesterol in GF mice is associated with reduced plasma and hepatic cholesterol, and likely caused by reduced expression of NPC1L1 and increased expression of ABCG5 and ABCG8 in small intestine. Expression levels of other genes in intestine and liver largely reflect a state of cholesterol depletion and a decrease in intestinal sensing of bile acids. Altogether, our findings reveal a broad role of microbiota in regulating whole-body cholesterol homeostasis and its response to a cholesterol lowering drug, ezetimibe. PMID- 26015371 TI - The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress. AB - Targeting respiration and ATP synthesis has received strong interest as a new strategy for combatting drug-resistant Mycobacterium tuberculosis. Mycobacteria employ a respiratory chain terminating with two branches. One of the branches includes a cytochrome bc1 complex and an aa3-type cytochrome c oxidase while the other branch terminates with a cytochrome bd-type quinol oxidase. In this communication we show that genetic inactivation of cytochrome bd, but not of cytochrome bc1, enhances the susceptibility of Mycobacterium smegmatis to hydrogen peroxide and antibiotic-induced stress. The type-II NADH dehydrogenase effector clofazimine and the ATP synthase inhibitor bedaquiline were bacteriostatic against wild-type M. smegmatis, but strongly bactericidal against a cytochrome bd mutant. We also demonstrated that the quinone-analog aurachin D inhibited mycobacterial cytochrome bd at sub-micromolar concentrations. Our results identify cytochrome bd as a key survival factor in M. smegmatis during antibiotic stress. Targeting the cytochrome bd respiratory branch therefore appears to be a promising strategy that may enhance the bactericidal activity of existing tuberculosis drugs. PMID- 26015372 TI - Remote Ischemic Preconditioning To Reduce Contrast-Induced Nephropathy: A Randomized Controlled Trial. AB - BACKGROUND: Despite the increasing use of pre- and post-hydration protocols and low osmolar instead of high osmolar iodine containing contrast media, the incidence of contrast induced nephropathy (CIN) is still significant. There is evidence that contrast media cause ischemia reperfusion injury of the renal medulla. Remote ischemic preconditioning (RIPC) is a non-invasive, safe, and low cost method to reduce ischemia reperfusion injury. The aim of this study is to investigate whether RIPC, as an adjunct to standard preventive measures, reduces contrast induced acute kidney injury in patients at risk of CIN. METHODS: The RIPCIN study is a multicenter, single blinded, randomized controlled trial in which 76 patients at risk of CIN received standard hydration combined with RIPC or hydration with sham preconditioning. RIPC was applied by four cycles of 5 min ischemia and 5 min reperfusion of the forearm. The primary outcome measure was the change in serum creatinine from baseline to 48 to 72 hours after contrast administration. RESULTS: With regard to the primary endpoint, no significant effect of RIPC was found. CIN occurred in four patients (2 sham and 2 RIPC). A pre-defined subgroup analysis of patients with a Mehran risk score >=11, showed a significantly reduced change in serum creatinine from baseline to 48 to 72 hours in patients allocated to the RIPC group (Delta creatinine -3.3 +/- 9.8 MUmol/L) compared with the sham group (Delta creatinine +17.8 +/- 20.1 MUmol/L). CONCLUSION: RIPC, as an adjunct to standard preventive measures, does not improve serum creatinine levels after contrast administration in patients at risk of CIN according to the Dutch guideline. However, the present data indicate that RIPC might have beneficial effects in patients at a high or very high risk of CIN (Mehran score >= 11). The RIPCIN study is registered at: http://www.controlled trials.com/ISRCTN76496973. PMID- 26015373 TI - Re: 'why do health systems not fund supervised exercise programmes for intermittent claudication'. PMID- 26015374 TI - Obsessive-compulsive symptoms are associated with psychiatric comorbidities, behavioral and clinical problems: a population-based study of Brazilian school children. AB - Pediatric-onset obsessive-compulsive disorder (OCD) is underdiagnosed, and many affected children are untreated. The present study seeks to evaluate the presence and the clinical impact of OCD and obsessive-compulsive symptoms (OCS) in a large sample of school-age children. In Phase I, we performed an initial screening using the Family History Screen (FHS). In Phase II, we identified an "at-risk" sample, as well as a randomly selected group of children. A total of 2,512 children (6-12 years old) were assessed using the FHS, the Development and Well Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), and the Child Behavior Checklist (CBCL). Data analyses included descriptive and multivariate analytical techniques. 2,512 children (mean age: 8.86 +/- 1.84 years; 55.0% male) were categorized into one of the three diagnostic groups: OCD (n = 77), OCS (n = 488), and unaffected controls (n = 1,947). There were no significant socio-demographic differences (age, gender, socioeconomic status) across groups. The OCS group resembled the OCD on overall impairment, including school problems and delinquent behaviors. However, the OCD group did have significantly higher rates of several comorbid psychiatric disorders, including separation anxiety, generalized anxiety, and major depressive disorder, than OCS or unaffected controls. Moreover, the OCD group also scored higher than the SDQ, as well as on each of CBCL items rated by the parent. Our findings suggest that there is a psychopathological continuum between OCS and OCD in school-aged children. The presence of OCS is associated with functional impairment, which needs further investigation in longitudinal studies. PMID- 26015375 TI - Optogenetic intervention to the vascular endothelium. AB - Endothelium lining the interior of cardiovascular system and most visceral organs plays an important role in vascular function. Its dysfunction occurs in some of the most challenging diseases. An important function of the endothelium is to release vasoactive substances that act on the smooth muscle to change vascular tones. Substance secretion from endocrine cells relies on membrane potentials and firing activity, while it is unclear whether the membrane potential regulates substance release from the ECs. Understanding of this requires selective intervention to membrane potentials of the endothelial cells in situ. Here we show a novel intervention to endothelial cells using the optogenetic approach. A strain of transgenic mice was developed with the Cre-loxP recombination system. These transgenic mice expressed channelrhodopsin (ChR) in endothelial cells driven by the vascular endothelial cadherin or cdh5 promoter. Linked in a tandem with YFP, the ChR expression was detected by YFP fluorescence in various endothelium-lining tissues and organs. The YFP fluorescence was observed in the lumen of blood vessels and pericardium, but not in tissues beneath the endothelium lining. Optostimulation of dissociated endothelial cells evoked inward currents and depolarization. In the isolated and perfused heart, surprisingly, optostimulation of endothelial cells produced fast, robust, reproducible and long-lasting vasoconstriction that was not blocked by either ET 1A or TXA2 receptor antagonist. Similar optical vasoconstriction was found in the isolated and perfused kidney. These results indicate that the optogenetics is an effective intervention to vascular endothelium where optostimulation produces vasoconstriction. PMID- 26015377 TI - [Endoscopic hematoma evacuation for intracerebral hemorrhage]. PMID- 26015378 TI - [Pharmacological treatment and neuromodulation therapy for central neuropathic pain: current trend and issue of spinal cord stimulation]. PMID- 26015376 TI - MnTBAP stimulates angiogenic functions in endothelial cells through mitofusin-1. AB - AIMS: Angiogenesis is defined as the sprouting of capillaries from pre-existing vasculature. It is a complex process that includes endothelial proliferation, migration, and tube formation. Previous data have demonstrated a high expression level of manganese-superoxide dismutase (MnSOD) in endothelial cells and suggested an important role of MnSOD in several cardiovascular diseases. In addition, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) has been shown to mimic some of the effects of MnSOD in various tissues. However, its effect on the vasculature remains unknown. METHODS AND RESULTS: HUVECs were treated with MnTBAP. Migration, tube formation, and capillary sprouting assays were performed to evaluate the pro-angiogenic effect in vitro. Matrigel plug assay was performed to assess capillary ingrowth in vivo. Compared to control, treatment with MnTBAP revealed increased cell migration, tube formation and capillary sprouting along with more capillary ingrowth in the Matrigel plug assay. This effect was mediated through a mitofusin (Mfn)-1-dependent pathway. Expression of Tie-2, Ang-2 and VEGF mRNA was increased in muscle tissues after ligation in MnTBAP treated mice. However, revascularization in the hindlimb ischemia model was not statistically significant at day 10 in MnTBAP treated mice. CONCLUSION: In summary, our data demonstrate a strong pro-angiogenic, but less pro-arteriogenic effect of MnTBAP in HUVECs mediated by Mfn-1. PMID- 26015379 TI - [Perforating Artery Injury during Microsurgery for Internal Carotid Artery Bifurcation Aneurysms]. AB - Internal carotid artery bifurcation aneurysms(ICB-ANs)are relatively rare and are difficult to occlude by direct clipping without perforating artery injury(PAI). We retrospectively analyzed 11 aneurysms in 10 cases. PAI was identified in 5 of 10 cases on postoperative computed tomography(CT)or magnetic resonance imaging(MRI), and 2 of these patients were symptomatic. PAIs were distributed in the caudate nucleus and/or the genu of the internal capsule. PAI occurred in 3 of 5 cases in which indocyanine green videoangiography(ICG-VAG)was performed. ICG VAG is a helpful tool visualizing blood flow of vessels in surgical fields. However, PAI is a potential risk in direct clipping of ICB-ANs even if adjacent perforating arteries were observed using ICG-VAG. PMID- 26015380 TI - [Analysis of Rupture during Follow-up of Unruptured Aneurysm]. AB - OBJECT: To elucidate clinical aspects of ruptured aneurysms, we retrospectively investigated associations between risk factors and ruptured and unruptured cases during conservative management. METHODS: Two hundred and twenty-nine patients with 291 unruptured cerebral aneurysms treated between 2000 and 2012 were analyzed. Mean duration of observation was 62 months (1183.4 person-years). We investigated the following six risk factors: history of subarachnoid hemorrhage;multiplicity;location of aneurysms;aneurysm size <=5mm;bleb or irregular forms;and follow-up period <1 year. RESULTS: Twenty-two aneurysms in 22 patients (19 women;86.4%) ruptured during this study. The annual rate of rupture was 1.86%. In ruptured cases, mean age was 66.7 years. According to univariate analysis, aneurysm size>=5mm(p=0.000), bleb or irregular form(p=0.006)and duration of observation<1 year (p =0.000) were significantly associated with aneurysmal rupture. In multivariate analysis of these factors, aneurysm size>=5mm(p =0.0188;odds ratio(OR), 3.4;95% confidence interval (CI), 1.2-9.7) and duration of observation<1 year (p=0.006;OR, 5.0;95% CI, 1.6-14.9) represented independent risk factors for aneurysm rupture. CONCLUSIONS: The results of this study were almost the same as those of the UCAS Japan study. In addition, duration of observation <1 year was a risk factor for aneurysm rupture. When we decide on surgical treatment after considering factors such as aneurysm size, form, and surgical risk, surgery should be performed as soon as possible. PMID- 26015381 TI - [Case Report of a Suspected Extrapontine Myelinolysis due to Hyperglycemic Hyperosmolar Syndrome]. AB - A 68-year-old female, who suffered from depression, fell down the stairs in her house. She was soon transferred to an accident and emergent ward by an ambulance. Two days later, she was transferred and admitted to our hospital. Next day after admission to our ward, her consciousness level changed for the worse. She developed diabetic ketoacidosis, and was administered insulin during reinfusion. Next day, her diabetic ketoacidosis improved;however, her consciousness level was still poor. Brain magnetic resonance imaging(MRI)showed suspected osmotic myelinolysis lesions in the bilateral cerebellar hemisphere and globus pallidus. After conservative therapy, her lesions almost disappeared in 2 months. We diagnosed the lesions as reversible extrapontine myelinolysis. PMID- 26015382 TI - [Juxta-facet Cyst Associated with Conjoined Nerve Roots:A Case Report]. AB - We report a case of a patient with a juxta-facet cyst and conjoined nerve roots. A 66-year-old man presented with left leg pain from the past 4 months. Neurological examinations revealed L5 and S1 radiculopathy on the left side. Magnetic resonance imaging(MRI)detected a mass lesion located near the left intervertebral joint at the level of L5/S1 and canal stenosis at the level of L3/L4. A juxta-facet cyst was diagnosed by arthrography. We performed a curettage and resection of the mass, posterior lumbar interbody fusion at the level of L5/S1, and laminectomy at the level of L3/L4. Conjoined left L5/S1 nerve roots were observed during surgery. The patient recovered from the symptoms of L5 and S1 radiculopathy immediately after surgery. Postoperative review of the preoperative computed tomography images revealed bony abnormality in the L5/S1 joint. We speculate that the bony abnormality may be associated with the development of conjoined nerve roots and the juxta-facet cyst. PMID- 26015383 TI - [A synovial cyst accompanied by asymptomatic lumbar vertebral fracture requiring differentiation from spinal metastasis]. AB - We experienced a case with a synovial cyst accompanied by asymptomatic lumbar vertebral fracture that required differentiation from spinal metastasis. An 82 year-old man suffered from right leg and anal pain. Computed tomography (CT) showed L5 spondylolysis. Magnetic resonance images (MRI) revealed an intra spinal cyst and acute lumbar vertebral fracture of L5 vertebral body. The surrounding area of the cyst presented contrast enhancement, and the extradural mass compressed the dural sac. Bone scintigraphy with 99m technetium-MDP demonstrated intense uptake on the right first, fourth, fifth, and seventh ribs and L2, L3, and L5 vertebra. The F-18 fluorodeoxyglucose positron emission tomography (FDG PET) image demonstrated an increased radiotracer uptake in the L5 vertebra(standardized uptake value(SUV) max=3.5). Spinal metastasis was suspected. Because of the cauda equina compression syndrome, it was surgically removed. Intraoperatively, a well-demarcated extradural cyst was found and compressed the dural sac markedly. The cyst capsule was thin and contained clear, thin fluid with no signs of bleeding. The histological diagnosis was a synovial cyst. His neurological symptoms improved after the surgery. The synovial cyst may enlarge after asymptomatic vertebral fractures. PMID- 26015384 TI - [Subarachnoid Hemorrhage without Direct Vascular Injury after Transsphenoidal Surgery: 2 Cases Report]. PMID- 26015385 TI - [Required knowledge for stroke specialists (11): Management of Moyamoya disease]. PMID- 26015386 TI - Scoring the correlation of genes by their shared properties using OScal, an improved overlap quantification model. AB - Scoring the correlation between two genes by their shared properties is a common and basic work in biological study. A prospective way to score this correlation is to quantify the overlap between the two sets of homogeneous properties of the two genes. However the proper model has not been decided, here we focused on studying the quantification of overlap and proposed a more effective model after theoretically compared 7 existing models. We defined three characteristic parameters (d, R, r) of an overlap, which highlight essential differences among the 7 models and grouped them into two classes. Then the pros and cons of the two groups of model were fully examined by their solution space in the (d, R, r) coordinate system. Finally we proposed a new model called OScal (Overlap Score calculator), which was modified on Poisson distribution (one of 7 models) to avoid its disadvantages. Tested in assessing gene relation using different data, OScal performs better than existing models. In addition, OScal is a basic mathematic model, with very low computation cost and few restrictive conditions, so it can be used in a wide-range of research areas to measure the overlap or similarity of two entities. PMID- 26015387 TI - Homosexual men in HIV serodiscordant relationships: implications for HIV treatment as prevention research. AB - INTRODUCTION: Studies in heterosexual HIV serodiscordant couples have provided critical evidence on the role of HIV treatments in reducing HIV transmission risk. However, there are limited data regarding the effect of treatment on HIV transmission in homosexual male couples. We examined features of male homosexual HIV serodiscordant relationships that may impact upon the design of HIV treatment and transmission studies. METHODS: Data were from a prospective cohort study of HIV-negative homosexual men in Sydney, Australia. Men were followed up with six monthly interviews and annual testing for HIV. Characteristics of men in HIV serodiscordant and seroconcordant relationships at baseline were compared, and a longitudinal analysis performed of rate of relationship break-up and of HIV incidence. RESULTS: At baseline, 5.5% of participants (n=79) had an HIV-positive partner. Most (80.8%) of these relationships were non-monogamous, and 36.7% of men reported recent unprotected anal intercourse (UAI) with casual partners. The rate of relationship break-up was 29.5 per 100 person-years. Half of men in serodiscordant relationships (49.4%) reported recent UAI with their regular partners. HIV incidence was 2.2 per 100 person-years. It was substantially higher in relationships of less than one year's duration (6.1 per 100 person-years) and in men who reported unprotected receptive anal intercourse with ejaculation with their regular partners (15.5 per 100 person-years). CONCLUSIONS: Levels of HIV transmission risk and incidence were high, particularly in early relationships. Rates of relationship break-up were high. These data suggest that studies of HIV treatments and transmission in homosexual serodiscordant couples should focus on early relationships so as not to underestimate risk, and sample sizes must allow for high rates of relationship break-up. PMID- 26015388 TI - Vitamin D serum levels are associated with handgrip strength but not with muscle mass or length of hospital stay after hip fracture. AB - OBJECTIVES: The aim of this study was to evaluate the association between serum levels of 25(OH) vitamin D3 with midupper arm muscle circumference (MUAMC), handgrip strength and length of hospital stay (LOS) after hip fracture. METHODS: In total, 102 consecutive patients with hip fracture over the age of 65 were admitted to the orthopedic unit and prospectively evaluated. All of the patients were treated according to specific protocols depending on the type of fracture. Anthropometric measurements and handgrip strength were performed, and blood samples were taken for serum biochemistry and 25(OH) vitamin D3 analysis within the first 72 h of admission. All of the patients were followed during their hospital stay, and the length of stay was recorded. RESULTS: Of the patients, two were excluded because of pathologic fractures. In total, 100 patients with a mean age of 80 +/- 7 y were included in the analysis. Among these patients, 73% were female, and 37% had vitamin D deficiency. The median LOS was 7 (5-11) d. Patients with vitamin D deficiency had lower handgrip strength in univariate analysis. In the multiple linear regression analysis with robust standard error, serum vitamin D levels adjusted by age and sex were associated with handgrip strength but not with MUAMC and LOS after hip fracture. CONCLUSIONS: In conclusion, vitamin D serum levels were associated with handgrip strength but not with muscle mass or length of hospital stay after hip fracture. PMID- 26015389 TI - Protective effects of dietary supplementation with natural omega-3 polyunsaturated fatty acids on the visual acuity of school-age children with lower IQ or attention-deficit hyperactivity disorder. AB - OBJECTIVE: Little attention has been paid to the possible protective role of omega-3 polyunsaturated fatty acids (PUFAs) on the visual acuity of school-age children with lower IQs or attention-deficit hyperactivity disorder (ADHD). The aim of this study was to evaluate the effect of dietary omega-3 PUFAs on the visual acuity and red blood cell (RBC) fatty acid compositions of these children. METHODS: We randomly assigned 179 children with lower IQs or ADHD to receive ordinary eggs (control group, n = 90) or eggs rich in C18:3 omega-3, eicosapentaenoic acid (EPA, 20:5 omega-3) and docosahexaenoic acid (DHA, 22:6 omega-3) for 3 mo (study group, n = 89). Before and after the intervention, distance visual acuity was tested using an E chart and the RBC fatty acid composition was determined using capillary gas chromatography. RESULTS: Three months later, 171 children completed the follow-up with the exception of 8 children who were unavailable during follow-up. Both groups of children showed a significant improvement in visual acuity (P < 0.05), however, visual acuity in the study group was significantly better than that of the control group (P = 0.013). The C18:3 omega-3 (P = 0.009), DHA (P = 0.009) and ?omega-3 (P = 0.022) levels of the intervention group were significantly higher than those of the control group, while the C20:4 omega-6 (P = 0.003), C22:4 omega-6 (P = 0.000), ?omega-6 (P = 0.001), ?omega-6/?omega-3 (P = 0.000) and arachidonic acid/DHA (P = 0.000) of the study group were significantly lower than those of the control group. No significant differences in the levels of C18:2 omega-6 (P = 0.723), C20:2 omega-6 (P = 0.249), C20:3 omega-6 (P = 0.258), C20:5 omega-3 (P = 0.051), or C22:5 (P = 0.200) were found between the two groups. CONCLUSIONS: Dietary supplementation with omega-3 PUFAs improves both visual acuity and the RBC fatty acid profile in school-age children with lower IQs or ADHD. PMID- 26015390 TI - European food-based dietary guidelines: a comparison and update. AB - OBJECTIVES: The aim of this study was to review and update information about food based dietary guidelines (FBDGs) used by European countries. METHODS: FBDGs from 34 European countries were collected and their pictorial representations, food groupings, and associated messages of healthy eating and behavior were compared. RESULTS: FBDGs from 34 European countries were collected, representing 64% (34 of 53) of all European countries; 74% (28 of 34) are European Union members. Of these FBDGs, 67% (23 of 34) adopt the pyramid as a food guide illustration, and classify foods into five or six groups. The main food groups are grains, vegetables, fruits, and vegetables and fruits as a unified group. Some differences include the modality of food classification. Despite dietary pattern results from geographic conditions and cultural (ethnic) heritages, most nutritional key points are similar among the different European FBDGs: In particular, the basic message is to consume adequate amounts of grains, vegetables, and fruits with moderate intake of fats, sugars, meats, caloric beverages, and salt. Other healthy behaviors are frequently but not always indicated. CONCLUSIONS: FBDGs still seem insufficient as far as ethnic peculiarities, agreement on how to group foods, and subgroup population nutritional requirements. PMID- 26015392 TI - Why Do People Regulate Their Emotions? A Taxonomy of Motives in Emotion Regulation. AB - Emotion regulation involves the pursuit of desired emotional states (i.e., emotion goals) in the service of superordinate motives. The nature and consequences of emotion regulation, therefore, are likely to depend on the motives it is intended to serve. Nonetheless, limited attention has been devoted to studying what motivates emotion regulation. By mapping the potential benefits of emotion to key human motives, this review identifies key classes of motives in emotion regulation. The proposed taxonomy distinguishes between hedonic motives that target the immediate phenomenology of emotions, and instrumental motives that target other potential benefits of emotions. Instrumental motives include behavioral, epistemic, social, and eudaimonic motives. The proposed taxonomy offers important implications for understanding the mechanism of emotion regulation, variation across individuals and contexts, and psychological function and dysfunction, and points to novel research directions. PMID- 26015391 TI - Regional cerebral blood flow in late-onset schizophrenia: a SPECT study using 99mTc-ECD. AB - Progressive disability in schizophrenia has been considered to be associated with onset-age. The objective of this study was to evaluate age onset-related degeneration in rCBF in patients with schizophrenia. We evaluated characteristic changes in brain perfusion by age, gender, medication and clinical symptoms in medicated patients with early-onset (EOS: developed at younger than 40 years old: n = 44) and late-onset (LOS: developed at older than 40 years old: n = 19) schizophrenia and control subjects matched for age and gender (n = 37) using statistical parametric mapping (SPM8) applied to 99mTc-ECD SPECT. We performed SPECT with 99mTc-ECD on the brains of subjects. A voxel-by-voxel group analysis was performed using SPM 8 and ANOVA. rCBF in EOS was found to be reduced in the precentral and inferior frontal gyri; on the other hand, rCBF was reduced in the bilateral postcentral gyrus in LOS. This study revealed a significant difference in brain perfusion between EOS and LOS. The present study might suggest that the characteristic changes in rCBF are related to onset-age in schizophrenia. PMID- 26015393 TI - The combination of HDAC and aminopeptidase inhibitors is highly synergistic in myeloma and leads to disruption of the NFkappaB signalling pathway. AB - There is a growing body of evidence supporting the use of epigenetic therapies in the treatment of multiple myeloma. We show the novel HDAC inhibitor CHR-3996 induces apoptosis in myeloma cells at concentrations in the nanomolar range and with apoptosis mediated by p53 and caspase pathways. In addition, HDAC inhibitors are highly synergistic, both in vitro and in vivo, with the aminopeptidase inhibitor tosedostat (CHR-2797). We demonstrate that the basis for this synergy is a consequence of changes in the levels of NFkappaB regulators BIRC3/cIAP2, A20, CYLD, and IkappaB, which were markedly affected by the combination. When co administered the HDAC and aminopeptidase inhibitors caused rapid nuclear translocation of NFkappaB family members p65 and p52, following activation of both canonical and non-canonical NFkappaB signalling pathways. The subsequent up regulation of inhibitors of NFkappaB activation (most significantly BIRC3/cIAP2) turned off the cytoprotective effects of the NFkappaB signalling response in a negative feedback loop. These results provide a rationale for combining HDAC and aminopeptidase inhibitors clinically for the treatment of myeloma patients and support the disruption of the NFkappaB signalling pathway as a therapeutic strategy. PMID- 26015394 TI - Inhibition of muscle fibrosis results in increases in both utrophin levels and the number of revertant myofibers in Duchenne muscular dystrophy. AB - Duchenne Muscular Dystrophy is characterized by: near absence of dystrophin in skeletal muscles; low percentage of revertant myofibers; up-regulation of utrophin synthesis; and a high degree of muscle fibrosis. In patient quadriceps femoris biopsies (n = 6, ages between 3-9 years) an inverse correlation was observed between the levels of collagen type I - representing fibrosis - and the levels of utrophin. This correlation was independent of the patient's age and was observed in the entire muscle biopsy sections. In the mdx mice diaphragm (n = 6/group), inhibition of fibrosis by halofuginone resulted in increases in the levels of utrophin. The utrophin/fibrosis relationships were not limited to collagen type I, but also applied to other constituents of the fibrosis machinery. The inverse correlation was found also in old mdx mice with established fibrosis. In addition, inhibition of collagen type I levels was associated with increases in the numbers of revertant myofibers, both as single myofibers and in clusters in the diaphragm and the gastrocnemius. In summary, our results demonstrate an inverse correlation between the level of muscle fibrosis and the level of utrophin and that of the number of revertant myofibers. These findings may reveal common links between the fibrotic and utrophin-synthesis pathways and offer new insights into the regulation of utrophin synthesis. PMID- 26015395 TI - Clinical next generation sequencing to identify actionable aberrations in a phase I program. AB - PURPOSE: We determined the frequency of recurrent hotspot mutations in 46 cancer related genes across tumor histologies in patients with advanced cancer. METHODS: We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA). RESULTS: Of the 500 patients, 362 had at least one reported mutation/variant. The most common likely somatic mutations were within TP53 (36%), KRAS (11%), and PIK3CA (9%) genes. Sarcoma (20%) and kidney (30%) had the lowest proportion of likely somatic mutations detected, while pancreas (100%), colorectal (89%), melanoma (86%), and endometrial (75%) had the highest. There was high concordance in 62 patients with paired primary tumors and metastases analyzed. 151 (30%) patients had alterations in potentially actionable genes. 37 tumor types were enrolled; both rare actionable mutations in common tumor types and actionable mutations in rare tumor types were identified. CONCLUSION: Multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor lineages and identification of novel opportunities for genotype-driven trials. PMID- 26015396 TI - A novel SAHA-bendamustine hybrid induces apoptosis of leukemia cells. AB - Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome the deficiencies of conventional chemotherapy drugs and improve the efficacy. Many studies have revealed that the combination of histone deacetylase inhibitors (HDACi) and alkylating agents have synergistic effects. We reported a novel hybrid NL-101, in which the side chain of bendamustine was replaced with the hydroxamic acid of HDACi vorinostat (SAHA). NL-101 exhibited efficient anti-proliferative activity on myeloid leukemia cells especially Kasumi 1 and NB4 cells, accompanied by S phase arrest and caspase-3 dependent apoptosis. Importantly, it presented both the properties of HDAC inhibition and DNA damaging, as assessed by the acetylation of histone H3 and DNA double-strand breaks marker gamma-H2AX. NL-101 also down-regulated the expression of anti apoptotic protein Bcl-xL which was involved in the mitochondrial death pathway. Meanwhile, NL-101 induced apoptosis and DNA damage in primary cells from acute myeloid leukemia (AML) patients. NL-101 treatment could significantly prolong the survival time of t(8;21) leukemia mice with enhanced efficacy than bendamustine. These data demonstrate that NL-101 could be a potent and selective agent for leukemia treatment. PMID- 26015397 TI - Association of the intermediate filament nestin with cancer stage: a meta analysis based on 223 positive/high nestin cases and 460 negative/low case-free controls. AB - BACKGROUND: Nestin, a member of the intermediate filament protein family, has been reported to be associated with several types of neoplastic transformation. However, questions remain, with studies reporting sometimes inconclusive or conflicting data. Thus, the aim of this study was to evaluate literature reports on the relationship between nestin and cancer stage. METHODS: Relevant articles published as of June 2014 were retrieved from multiple databases. After applying specific inclusion criteria, we chose seven articles relating to nestin expression and cancer stage, which included a total of 223 positive/high nestin cases and 460 negative/low case-free controls. RESULTS: Overall, positive/high nestin was significantly associated with median or advanced stages of several types of cancer (nestin and cancer stage: OR = 1.90, 95% CI = 1.30-2.78; nestin and lymph node: OR = 2.17, 95% CI = 1.26-3.72). Notably, studies relating to lung cancer (three qualifying articles) showed a significant association between nestin and lung cancer stage (OR = 2.00, 95% CI = 1.16-3.44). CONCLUSION: These findings indicate that positive/high nestin may be more strongly linked to median or advanced cancer stage and correlated with malignant characteristics that lead to poor prognosis in different cancers, especially lung cancer. PMID- 26015398 TI - YAP is a critical oncogene in human cholangiocarcinoma. AB - Yes-associated protein (YAP), a transcriptional co-activator, has important regulatory roles in cell signaling and is dysregulated in a number of cancers. However, the role of YAP in cholangiocarcinoma (CCA) progression remains unclear. Here, we demonstrated that YAP was overexpressed in CCA cells and human specimens. High levels of nuclear YAP (nYAP) correlated with histological differentiation, TNM stage, metastasis and poor prognosis in CCA. Silencing YAP increased tumor sensitivity to chemotherapy and inhibited CCA tumorigenesis and metastasis both in vivo and in vitro. YAP overexpression in vivo and in vitro promoted CCA tumorigenesis and metastasis. Additionally, we found that YAP induced epithelial-mesenchymal transition (EMT) and formed a regulatory circuit with miR-29c, IGF1, AKT and gankyrin to promote the progression of CCA. Results of CCA tissue microarray showed positive correlations between nYAP and gankyrin or p-AKT expression. Combination of nYAP and gankyrin or p-AKT exhibited improved prognostic accuracy for CCA patients. In conclusion, YAP promotes carcinogenesis and metastasis by up-regulating gankyrin through activation of the AKT pathway. PMID- 26015399 TI - K-Ras stabilization by estrogen via PKCdelta is involved in endometrial tumorigenesis. AB - Estrogens are considered as a major risk factor of endometrial cancer. In this study, we identified a mechanism of tumorigenesis in which K-Ras protein is stabilized via estrogen signaling through the ER-alpha36 receptor. PKCdelta was shown to stabilize K-Ras specifically via estrogen signaling. Estrogens stabilize K-Ras via inhibition of polyubiquitylation-dependent proteasomal degradation. Estrogen-induced cellular transformation was abolished by either K-Ras or PKCdelta knockdown. The role of PKCdelta in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKCdelta inhibitor. Finally, levels of PKCdelta correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKCdelta up-regulation provides a potential therapeutic approach for treatment of endometrial cancer. PMID- 26015400 TI - Mutated Fanconi anemia pathway in non-Fanconi anemia cancers. AB - An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy. PMID- 26015401 TI - Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR. AB - The mutation of T790M in EGFR is a major mechanism of resistance to treatment with EGFR-TKIs. Only qualitative detection (presence or absence) of T790M has been described to date, however. Digital PCR (dPCR) analysis has recently been applied to the quantitative detection of target molecules in cancer with high sensitivity. In the present study, 25 tumor samples (13 obtained before and 12 after EGFR-TKI treatment) from 18 NSCLC patients with activating EGFR mutations were evaluated for T790M with dPCR. The ratio of the number of T790M alleles to that of activating mutation alleles (T/A) was determined. dPCR detected T790M in all 25 samples. Although T790M was present in all pre-TKI samples from 13 patients, 10 of these patients had a low T/A ratio and manifested substantial tumor shrinkage during treatment with EGFR-TKIs. In six of seven patients for whom both pre- and post-TKI samples were available, the T/A ratio increased markedly during EGFR-TKI treatment. Highly sensitive dPCR thus detected T790M in all NSCLC patients harboring activating EGFR mutations whether or not they had received EGFR-TKI treatment. Not only highly sensitive but also quantitative detection of T790M is important for evaluation of the contribution of T790M to EGFR-TKI resistance. PMID- 26015402 TI - p53-induced autophagy and senescence. PMID- 26015404 TI - Forming ideas about health: a qualitative study of Ontario adolescents. AB - Adolescence is a crucial period of child development during which one's ideas about health are formed. However, little is known about the different contexts, experiences, and potential other factors that contribute to shaping the health ideas of adolescent populations, particularly when they are not seeking out the information for a particular purpose. In this Ontario-based qualitative study, grounded theory methods were used to explore ways that health knowledge is obtained in adolescents (age 10-16). A purposeful, criterion-based sampling strategy was used, and data were collected through seven focus groups (n=40). Findings indicate that while young people get their ideas about health through both didactic and organic learning contexts, the significant impact of organic learning is often overlooked. Categories of organic learning that emerged include self-reflective experience, the experience of close contacts, casually observing others, and common discourse. This study suggests that one central way that young people get their ideas about health is from living life: from the people they watch, the conversations that they have, and the experiences they live. Findings support the development of effective health promotion messages and also contribute to considering the place of some aspects of organic learning in the development of health-related resources that target adolescent populations. PMID- 26015403 TI - DNA methylation and cognitive aging. AB - With ever-increasing elder population, the high incidence of age-related diseases such as neurodegenerative disorders has turned out to be a huge public concern. Especially the elders and their families dreadfully suffer from the learning, behavioral and cognitive impairments. The lack of effective therapies for such a horrible symptom makes a great demanding for biological mechanism study for cognitive aging. Epigenetics is an emerging field that broadens the dimensions of mammalian genome blueprint. It is, unlike genetics, not only inheritable but also reversible. Recent studies suggest that DNA methylation, one of major epigenetic mechanisms, plays a pivotal role in the pathogenesis of age-related neurodegenerations and cognitive defects. In this review, the evolving knowledge of age-related cognitive functions and the potential DNA methylation mechanism of cognitive aging are discussed. That indicates the impairment of DNA methylation may be a crucial but reversible mechanism of behavioral and cognitive related neurodegeneration. The methods to examine the dynamics of DNA methylation patterns at tissue and single cell level and at the representative scale as well as the whole genome single base resolution are also briefly discussed. Importantly, the challenges of DNA methylation mechanism of cognitive aging research are brought up, and the possible solutions to tackle these difficulties are put forward. PMID- 26015405 TI - Adolescent suicide in Ghana: a content analysis of media reports. AB - Adolescent suicide is now a major health concern for many countries. However, there is paucity of systematic studies and lack of official statistics on adolescent suicide in Ghana. Mass media coverage of adolescent suicide (even though crude), at least, may reflect the reality of the phenomenon. With an ecological orientation, this study used qualitative content analysis to analyse the pattern of 44 media reports of adolescent suicide in Ghana from January 2001 through September 2014. Results showed that hanging was the dominant method used. The behaviour usually takes place within or near the adolescent's home environment. The act was often attributed to precursors within the microsystem (family and school) of the deceased. This study serves a seminal function for future empirical studies aimed at deeper examination of the phenomenon in order to inform prevention programmes. PMID- 26015406 TI - Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment. AB - Accumulating evidence has suggested that myristoylated alanine-rich C-kinase substrate (MARCKS) is critical for regulating multiple pathophysiological processes. However, the molecular mechanism underlying increased phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) and its functional consequence in neoplastic disease remain to be established. Herein, we investigated how phospho MARCKS is regulated in breast carcinoma, and its role in the context of chemotherapy. In a screen of patients with breast tumors, we find that the abundance of phospho-MARCKS, not MARCKS protein per se, increased in breast cancers and positively correlated with tumor grade and metastatic status. Among chemotherapeutic agents, mitotic inhibitors, including paclitaxel, vincristine or eribulin, notably promoted phospho-MARCKS accumulation in multiple breast cancer cells. We further show that phospho-MARCKS acted upstream of Src activation upon paclitaxel exposure. Reduction of phospho-MARCKS by knockdown of MARCKS or pharmacological agents increased paclitaxel sensitivity. Particularly, a known phospho-MARCKS inhibitor, MANS peptide, was demonstrated to increase paclitaxel efficacy and attenuate angiogenesis/metastasis of xenografted breast cancer cells by decreasing abundance of phospho-MARCKS and messages of inflammatory mediators. Our data suggest that unresponsiveness of breast cancer to paclitaxel treatment is, at least in part, mediated by phospho-MARCKS and also provide an alternative therapeutic strategy against breast cancer by improving taxanes sensitivity. PMID- 26015407 TI - Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases. AB - Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-beta/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-beta/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-beta/Smad3 cascade and the response of TGF-beta key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination. PMID- 26015409 TI - Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. AB - In this study, we show that the transmembrane glycoprotein Trop-2 is up-regulated in human prostate cancer (PCa) with extracapsular extension (stages pT3/pT4) as compared to organ-confined (stage pT2) PCa. Consistent with this evidence, Trop-2 expression is found to be increased in metastatic prostate tumors of Transgenic Adenocarcinoma of Mouse Prostate mice and to strongly correlate with alpha5beta1 integrin levels. Using PCa cells, we show that Trop-2 specifically associates with the alpha5 integrin subunit, as binding to alpha3 is not observed, and that Trop-2 displaces focal adhesion kinase from focal contacts. In support of the role of Trop-2 as a promoter of PCa metastatic phenotype, we observe high expression of this molecule in exosomes purified from Trop-2-positive PCa cells. These vesicles are then found to promote migration of Trop-2-negative PCa cells on fibronectin, an alpha5beta1 integrin/focal adhesion kinase substrate, thus suggesting that the biological function of Trop-2 may be propagated to recipient cells. In summary, our findings show that Trop-2 promotes an alpha5beta1 integrin dependent pro-metastatic signaling pathway in PCa cells and that the altered expression of Trop-2 may be utilized for early identification of capsule-invading PCa. PMID- 26015410 TI - Snail and serpinA1 promote tumor progression and predict prognosis in colorectal cancer. AB - The role of Snail and serpin peptidase inhibitor clade A member 1 (serpinA1) in tumorigenesis has been previously identified. However, the exact role and mechanism of these proteins in progression of colorectal cancer (CRC) are controversial. In this study, we investigated the role of Snail and serpinA1 in colorectal cancer (CRC) and examined the mechanisms through which these proteins mediate CRC progression. Immunohistochemical analysis of 528 samples from patients with CRC showed that elevated expression of Snail or serpinA1 was correlated with advanced stage, lymph node metastasis, and poor prognosis. Moreover, we detected a correlation between Snail and serpinA1 expression. Functional studies performed using the CRC cell lines DLD-1 and SW-480 showed that overexpression of Snail or serpinA1 significantly increased CRC cell invasion and migration. Conversely, knockdown of Snail or serpinA1 expression suppressed CRC cell invasion and migration. ChIP analysis revealed that Snail regulated serpinA1 by binding to its promoter. In addition, fibronectin mediated Snail and serpinA1 signaling was involved in CRC cell invasion and migration. Taken together, our data showed that Snail and serpinA1 promoted CRC progression through fibronectin. These findings suggested that Snail and serpinA1 were novel prognostic biomarkers and candidate therapeutic targets in CRC. PMID- 26015411 TI - Safety, virology and pharmacokinetics of oseltamivir in infants with laboratory confirmed influenza: a Phase I/II, prospective, open-label, multicentre clinical trial. AB - BACKGROUND: The influenza antiviral oseltamivir is not licensed for infants aged <1 year in most countries outside the United States. More information is needed on oseltamivir safety at different dosing levels in this vulnerable age group. METHODS: In this prospective, observational, non-randomized study, infants aged <1 year with laboratory-confirmed influenza were treated with oral oseltamivir for 5 days. Cohorts 1, 2 and 3 (aged 91-364, 31-90 and 0-30 days, respectively), received twice-daily dosages of 3, 2.5 and 2 mg/kg, respectively. Assessments included pharmacokinetics, on-treatment adverse events, resistance testing and viral shedding. RESULTS: A total of 65 patients were enrolled: 40, 20 and 5 in cohorts 1, 2 and 3, respectively. Systemic exposure to oseltamivir carboxylate (active metabolite) reached therapeutic levels in all patients, with an adequate safety margin. On-treatment adverse events (n=48) were reported by 32 patients (49%). At least one adverse event was reported by 43%, 65% and 40% of infants in cohorts 1, 2 and 3, respectively; most frequently vomiting and diarrhoea. Eight serious adverse events were reported, all of which were considered unrelated to treatment by the investigator. No deaths occurred and no patient had treatment withdrawn. Oseltamivir resistance mutations were detected in eight patients. CONCLUSIONS: Oseltamivir dosages of 2-3 mg/kg were well tolerated in infants aged <1 year and achieved therapeutic exposure levels. The current study supports the adoption of a universal dosing recommendation for infants. Clinicaltrials.gov unique identifier NCT00988325. PMID- 26015408 TI - NF-kappaB drives acquired resistance to a novel mutant-selective EGFR inhibitor. AB - The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase 1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-kappaB1 in driving CNX-2006 acquired resistance and show that NF-kappaB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-kappaB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-kappaB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs. PMID- 26015412 TI - Roots and Benefits of Costly Giving: Children Who Are More Altruistic Have Greater Autonomic Flexibility and Less Family Wealth. AB - Altruism, although costly, may promote well-being for people who give. Costly giving by adults has received considerable attention, but less is known about the possible benefits, as well as biological and environmental correlates, of altruism in early childhood. In the current study, we present evidence that children who forgo self-gain to help other people show greater vagal flexibility and higher subsequent vagal tone than children who do not, and children from less wealthy families behave more altruistically than those from wealthier families. These results suggest that (a) altruism should be viewed through a biopsychosocial lens, (b) the influence of privileged contexts on children's willingness to make personal sacrifices for others emerges early, and (c) altruism and healthy vagal functioning may share reciprocal relations in childhood. When children help others at a cost to themselves, they could be playing an active role in promoting their own well-being as well as the well being of others. PMID- 26015414 TI - Automatic BSS-based filtering of metallic interference in MEG recordings: definition and validation using simulated signals. AB - OBJECTIVE: One of the principal drawbacks of magnetoencephalography (MEG) is its high sensitivity to metallic artifacts, which come from implanted intracranial electrodes and dental ferromagnetic prosthesis and produce a high distortion that masks cerebral activity. The aim of this study was to develop an automatic algorithm based on blind source separation (BSS) techniques to remove metallic artifacts from MEG signals. APPROACH: Three methods were evaluated: AMUSE, a second-order technique; and INFOMAX and FastICA, both based on high-order statistics. Simulated signals consisting of real artifact-free data mixed with real metallic artifacts were generated to objectively evaluate the effectiveness of BSS and the subsequent interference reduction. A completely automatic detection of metallic-related components was proposed, exploiting the known characteristics of the metallic interference: regularity and low frequency content. MAIN RESULTS: The automatic procedure was applied to the simulated datasets and the three methods exhibited different performances. Results indicated that AMUSE preserved and consequently recovered more brain activity than INFOMAX and FastICA. Normalized mean squared error for AMUSE decomposition remained below 2%, allowing an effective removal of artifactual components. SIGNIFICANCE: To date, the performance of automatic artifact reduction has not been evaluated in MEG recordings. The proposed methodology is based on an automatic algorithm that provides an effective interference removal. This approach can be applied to any MEG dataset affected by metallic artifacts as a processing step, allowing further analysis of unusable or poor quality data. PMID- 26015413 TI - Perceived Partner Responsiveness Predicts Diurnal Cortisol Profiles 10 Years Later. AB - Several decades of research have demonstrated that marital relationships have a powerful influence on physical health. However, surprisingly little is known about how marriage affects health--both in terms of psychological processes and biological ones. Over a 10-year period, we investigated the associations between perceived partner responsiveness--the extent to which people feel understood, cared for, and appreciated by their romantic partners--and diurnal cortisol in a large sample of married and cohabitating couples in the United States. Partner responsiveness predicted higher cortisol values at awakening and steeper (i.e., healthier) cortisol slopes at the 10-year follow-up. These associations remained strong after we controlled for demographic factors, depressive symptoms, agreeableness, and other positive and negative relationship factors. Furthermore, declines in negative affect over the 10-year period mediated the prospective association between responsiveness and cortisol slope. These findings suggest that diurnal cortisol may be a key biological pathway through which social relationships affect long-term health. PMID- 26015415 TI - Integrated dialysis care-by chance or design? PMID- 26015416 TI - Peritoneal dialysis: nanoparticles have entered the game. PMID- 26015418 TI - Dr. Alain slingeneyer born in Oran, Algeria, on January 5, 1948; died on November 9, 2014, at his home in Montpellier, France. PMID- 26015417 TI - Development of surgical guidelines for laparoscopic peritoneal dialysis access: down a long and winding road. PMID- 26015419 TI - Re-embedding catheter technique at the discontinuation of peritoneal dialysis. PMID- 26015420 TI - Exit-site infection and acute peritonitis due to peritoneal dialysis catheter rupture. PMID- 26015421 TI - Repair of vagino-peritoneal fistula caused by vaginal cuff fixation of peritoneal dialysis catheter: a case report. PMID- 26015422 TI - Hydrothorax secondary to a malpositioned peritoneal dialysis catheter. PMID- 26015423 TI - Is It Beneficial to Convert to a Neutral-pH Bicarbonate/Lactate-Buffered PD Solution in Long-Term CAPD Patients? A Single-Center Prospective Study. PMID- 26015424 TI - Peritoneal Dialysis-Associated Peritonitis Caused by Mycobacterium abscessus. PMID- 26015425 TI - Successful management of a chest exit site in a psoriasis patient. PMID- 26015426 TI - Decreased circulating klotho levels in patients undergoing dialysis and relationship to oxidative stress and inflammation. PMID- 26015428 TI - Factors Influencing Delayed Health Care Seeking Among Pulmonary Tuberculosis Suspects in Rural Communities in Ntcheu District, Malawi. AB - Delayed diagnosis and treatment of tuberculosis (TB) among individuals suspected of having TB may lead to continued transmission of Mycobacterium tuberculosis in communities, higher mortality rates, and increase in government health expenditure because of prolonged illness due to late diagnosis and treatment initiation. The study explored factors leading to delayed health care seeking among individuals living in Ntcheu District, Malawi. Two key informant interviews, 16 in-depth interviews, and three focus group discussions were conducted. Participants were aged 18 years and older and never had TB. Data were analyzed using content analysis and factors were identified: inadequate knowledge about cause and transmission of TB, low self-awareness of personal risk to TB, cultural and traditional beliefs about sources of TB, stigma, and strong belief in witchcraft as a cause of illness. The TB Control Program needs to invest in social mobilization and education of communities to mitigate early health care seeking. PMID- 26015427 TI - Implications of chronic daily anti-oxidant administration on the inflammatory response to intracortical microelectrodes. AB - OBJECTIVE: Oxidative stress events have been implicated to occur and facilitate multiple failure modes of intracortical microelectrodes. The goal of the present study was to evaluate the ability of a sustained concentration of an anti-oxidant and to reduce oxidative stress-mediated neurodegeneration for the application of intracortical microelectrodes. APPROACH: Non-functional microelectrodes were implanted into the cortex of male Sprague Dawley rats for up to sixteen weeks. Half of the animals received a daily intraperitoneal injection of the natural anti-oxidant resveratrol, at 30 mg kg(-1). The study was designed to investigate the biodistribution of the resveratrol, and the effects on neuroinflammation/neuroprotection following device implantation. MAIN RESULTS: Daily maintenance of a sustained range of resveratrol throughout the implantation period resulted in fewer degenerating neurons in comparison to control animals at both two and sixteen weeks post implantation. Initial and chronic improvements in neuronal viability in resveratrol-dosed animals were correlated with significant reductions in local superoxide anion accumulation around the implanted device at two weeks after implantation. Controls, receiving only saline injections, were also found to have reduced amounts of accumulated superoxide anion locally and less neurodegeneration than controls at sixteen weeks post-implantation. Despite observed benefits, thread-like adhesions were found between the liver and diaphragm in resveratrol-dosed animals. SIGNIFICANCE: Overall, our chronic daily anti-oxidant dosing scheme resulted in improvements in neuronal viability surrounding implanted microelectrodes, which could result in improved device performance. However, due to the discovery of thread-like adhesions, further work is still required to optimize a chronic anti-oxidant dosing regime for the application of intracortical microelectrodes. PMID- 26015429 TI - The fractional viscoelastic response of human breast tissue cells. AB - The mechanical response of a living cell is notoriously complicated. The complex, heterogeneous characteristics of cellular structure introduce difficulties that simple linear models of viscoelasticity cannot overcome, particularly at deep indentation depths. Herein, a nano-scale stress-relaxation analysis performed with an atomic force microscope reveals that isolated human breast cells do not exhibit simple exponential relaxation capable of being modeled by the standard linear solid (SLS) model. Therefore, this work proposes the application of the fractional Zener (FZ) model of viscoelasticity to extract mechanical parameters from the entire relaxation response, improving upon existing physical techniques to probe isolated cells. The FZ model introduces a new parameter that describes the fractional time-derivative dependence of the response. The results show an exceptional increase in conformance to the experimental data compared to that predicted by the SLS model, and the order of the fractional derivative (alpha) is remarkably homogeneous across the populations, with a median value of 0.48 +/- 0.06 for the malignant population and 0.51 +/- 0.07 for the benign. The cells' responses exhibit power-law behavior and complexity not associated with simple relaxation (SLS, alpha = 1) that supports the application of a fractional model. The distributions of some of the FZ parameters also preserve the distinction between the malignant and benign sample populations seen from the linear model and previous results while including the contribution of fast-relaxation behavior. The resulting viscosity, measured by a composite relaxation time, exhibits considerably less dispersion due to residual error than the distribution generated by the linear model and therefore serves as a more powerful marker for cell differentiation. PMID- 26015430 TI - Insulin secretion and signaling in response to dietary restriction and subsequent re-alimentation in cattle. AB - The objectives of this study were to examine systemic insulin response to a glucose tolerance test (GTT) and transcript abundance of genes of the insulin signaling pathway in skeletal muscle, during both dietary restriction and re alimentation-induced compensatory growth. Holstein Friesian bulls were blocked to one of two groups: 1) restricted feed allowance for 125 days (period 1) (RES, n = 15) followed by ad libitum feeding for 55 days (period 2) or 2) ad libitum access to feed throughout (periods 1 and 2) (ADLIB, n = 15). On days 90 and 36 of periods 1 and 2, respectively, a GTT was performed. M. longissimus dorsi biopsies were harvested from all bulls on days 120 and 15 of periods 1 and 2, respectively, and RNA-Seq analysis was performed. RES displayed a lower growth rate during period 1 (RES: 0.6 kg/day, ADLIB: 1.9 kg/day; P < 0.001), subsequently gaining more during re-alimentation (RES: 2.5 kg/day, ADLIB: 1.4 kg/day; P < 0.001). Systemic insulin response to glucose administration was lower in RES in period 1 (P < 0.001) with no difference observed during period 2. The insulin signaling pathway in M. longissimus dorsi was enriched (P < 0.05) in response to dietary restriction but not during re-alimentation (P > 0.05). Genes differentially expressed in the insulin signaling pathway suggested a greater sensitivity to insulin in skeletal muscle, with pleiotropic effects of insulin signaling interrupted during dietary restriction. Collectively, these results indicate increased sensitivity to glucose clearance and skeletal muscle insulin signaling during dietary restriction; however, no overall role for insulin was apparent in expressing compensatory growth. PMID- 26015431 TI - Statistical radii associated with amino acids to determine the contact map: fixing the structure of a type I cohesin domain in the Clostridium thermocellum cellulosome. AB - We propose to improve and simplify protein refinement procedures through consideration of which pairs of amino acid residues should form native contacts. We first consider 11 330 proteins from the CATH database to determine statistical distributions of contacts associated with a given type of amino acid. The distributions are set across the distances between the alpha-C atoms that are in contact. Based on this data, we determine typical radii of effective spheres that can be placed on the alpha-C atoms in order to reconstruct the distribution of the contact lengths. This is done by checking for overlaps with enlarged van der Waals spheres associated with heavy atoms on other amino acids.The resulting contacts can be used to identify non-native contacts that may arise during the time evolution of structure-based models. Here, the radii are used to guide reconstruction of nine missing side chains in a type I cohesin domain with the Protein Data Bank code 1AOH. We first identify the likely missing contacts and then sculpt the corresponding side chains by standard refinement tools to achieve consistency with the expected contact map. One ambiguity in refinement is resolved by determining all-atom conformational energies. PMID- 26015432 TI - Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice. AB - Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1( /-)) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1(-/-) mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1(-/-) mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1(-/ ) mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1(-/-) mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1(-/-) mice and between male Tbc1d1(-/-) mice in different studies due to variations in body composition and nutrient handling. PMID- 26015433 TI - Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance. AB - Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome. PMID- 26015434 TI - Acute effects of hyperinsulinemia and hyperglycemia on vascular inflammatory biomarkers and endothelial function in overweight and obese humans. AB - We investigated the separate and combined effects of hyperglycemia and hyperinsulinemia on markers of endothelial function, proinflammatory and proatherothrombotic responses in overweight/obese nondiabetic humans. Twenty-two individuals (13 F/9 M, BMI 30.1 +/- 4.1 kg/m(2)) were studied during four randomized, single-blind protocols. The pancreatic clamp technique was combined with 4-h glucose clamps consisting of either 1) euinsulinemia-euglycemia, 2) euinsulinemia-hyperglycemia, 3) hyperinsulinemia-hyperglycemia, or 4) hyperinsulinemia-euglycemia. Insulin levels were higher (998 +/- 66 vs. 194 +/- 22 pmol/l) during hyperinsulinemia compared with euinsulinemia. Glucose levels were 11.1 mmol/l during hyperinsulinemia compared with 5.1 +/- 0.1 mmol/l during euglycemia. VCAM, ICAM, P-selectin, E-selectin, IL-6, adiponectin, and PAI-1 responses were all increased (P < 0.01-0.0001), and endothelial function was decreased (P < 0.0005) during euinsulinemia-hyperglycemia compared with other protocols. Hyperinsulinemia in the presence of hyperglycemia prevented the increase in proinflammatory and proatherothrombotic markers while also normalizing vascular endothelial function. We conclude that 4 h of moderate hyperglycemia can result in increases of proinflammatory markers (ICAM, VCAM, IL 6, E-selectin), platelet activation (P-selectin), reduced fibrinolytic balance (increased PAI-1), and disordered endothelial function in a group of obese and overweight individuals. Hyperinsulinemia prevents the actions of moderate hyperglycemia to reduce endothelial function and increase proinflammatory and proatherothrombotic markers. PMID- 26015435 TI - Tracer-based estimates of protein flux in cases of incomplete product renewal: evidence and implications of heterogeneity in collagen turnover. AB - The synthesis of various molecules can be estimated by measuring the incorporation of a labeled precursor into a product of interest. Unfortunately, a central problem in many studies has been an inability to estimate the intracellular dilution of the precursor and therein correctly calculate the synthesis of the product; it is generally assumed that measuring the true product labeling is straightforward. We initiated a study to examine liver collagen synthesis and identified an apparent problem with assumptions regarding measurements of the product labeling. Since it is well known that collagen production is relatively slow, we relied on the use of [(2)H]H2O labeling (analogous to a primed infusion) and sampled animals over the course of 16 days. Although the water labeling (the precursor) remained stable and we observed the incorporation of labeled amino acids into collagen, the asymptotic protein labeling was considerably lower than what would be expected based on the precursor labeling. Although this observation is not necessarily surprising (i.e., one might expect that a substantial fraction of the collagen pool would appear "inert" or turn over at a very slow rate), its implications are of interest in certain areas. Herein, we discuss a novel situation in which tracers are used to quantify rates of flux under conditions where a product may not undergo complete replacement. We demonstrate how heterogeneity in the product pool can lead one to the wrong conclusions regarding estimates of flux, and we outline an approach that may help to minimize errors surrounding data interpretation. PMID- 26015436 TI - The nuclear retinoid-related orphan receptor-alpha regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis. AB - Circadian rhythms have an essential role in feeding behavior and metabolism. RORalpha is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phosphoenolpyruvate carboxykinase c (PEPCKc), whose gene is a RORalpha target in the liver. RORalpha-deficient mice (staggerer, ROR(sg/sg)) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of RORalpha, and we further evaluated the role of RORalpha in hepatocyte gluconeogenesis. In vivo investigations comparing ROR(sg/sg) mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of RORalpha, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the ROR(sg/sg) mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with RORalpha agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not ROR(sg/sg) mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by RORalpha. This study demonstrates the physiological function of RORalpha in regulating both glucose and FFA homeostasis. PMID- 26015437 TI - New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism. AB - Despite significant reduction of cardiovascular events by statin treatment, substantial residual risk persists, driving emerging needs for the development of new therapies. We identified a novel cholesteryl ester transfer protein (CETP) inhibitor, K-312, that raises HDL and lowers LDL cholesterol levels in animals. K 312 also suppresses hepatocyte expression of proprotein convertase subtilisin/kexin 9 (PCSK9), a molecule that increases LDL cholesterol. We explored the underlying mechanism for the reduction of PCSK9 expression by K-312. K-312 inhibited in vitro human plasma CETP activity (IC50; 0.06 MUM). Administration of K-312 to cholesterol-fed New Zealand White rabbits for 18 wk raised HDL cholesterol, decreased LDL cholesterol, and attenuated aortic atherosclerosis. Our search for additional beneficial characteristics of this compound revealed that K-312 decreases PCSK9 expression in human primary hepatocytes and in the human hepatoma cell line HepG2. siRNA silencing of CETP in HepG2 did not compromise the suppression of PCSK9 by K-312, suggesting a mechanism independent of CETP. In HepG2 cells, K-312 treatment decreased the active forms of sterol regulatory element-binding proteins (SREBP-1 and -2) that regulate promoter activity of PCSK9. Chromatin immunoprecipitation assays demonstrated that K-312 decreased the occupancy of SREBP-1 and SREBP-2 on the sterol regulatory element of the PCSK9 promoter. PCSK9 protein levels decreased by K-312 treatment in the circulating blood of cholesterol-fed rabbits, as determined by two independent mass spectrometry approaches, including the recently developed, highly sensitive parallel reaction monitoring method. New CETP inhibitor K-312 decreases LDL cholesterol and PCSK9 levels, serving as a new therapy for dyslipidemia and cardiovascular disease. PMID- 26015439 TI - Stress assessment based on EEG univariate features and functional connectivity measures. AB - The biological response to stress originates in the brain but involves different biochemical and physiological effects. Many common clinical methods to assess stress are based on the presence of specific hormones and on features extracted from different signals, including electrocardiogram, blood pressure, skin temperature, or galvanic skin response. The aim of this paper was to assess stress using EEG-based variables obtained from univariate analysis and functional connectivity evaluation. Two different stressors, the Stroop test and sleep deprivation, were applied to 30 volunteers to find common EEG patterns related to stress effects. Results showed a decrease of the high alpha power (11 to 12 Hz), an increase in the high beta band (23 to 36 Hz, considered a busy brain indicator), and a decrease in the approximate entropy. Moreover, connectivity showed that the high beta coherence and the interhemispheric nonlinear couplings, measured by the cross mutual information function, increased significantly for both stressors, suggesting that useful stress indexes may be obtained from EEG based features. PMID- 26015438 TI - DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-kappaB activation. AB - Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP IV inhibitor, anagliptin (10 MUM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IkappaBalpha and phosphorylations of p65, JNK, and p38, as well as NF-kappaB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF-kappaB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFalpha. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 MUM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-kappaB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events. PMID- 26015441 TI - Residual pulmonary vasodilative reserve predicts outcome in idiopathic pulmonary hypertension. AB - OBJECTIVE: Idiopathic pulmonary arterial hypertension (IPAH) remains a devastating and incurable, albeit treatable condition. Treatment response is not uniform and parameters that help to anticipate a rather benign or a malignant course of the disease are warranted. Acute pulmonary vasoreactivity testing during right heart catheterisation is recommended to identify a minority of patients with IPAH with sustained response to calcium channel blocker therapy. This study aimed to evaluate the prognostic significance of a residual pulmonary vasodilative reserve in patients with IPAH not meeting current vasoresponder criteria. DESIGN: Observational right heart catheter study in 66 (n=66) patients with IPAH not meeting current vasoresponse criteria. Pulmonary vasodilative reserve was assessed by inhalation of 5 ug iloprost-aerosol. RESULTS: Sixty-six (n=66) of 72 (n=72) patients with IPAH did not meet current definition criteria assessed during vasodilator testing to assess pulmonary vasodilatory reserve. In those, iloprost-aerosol caused a reduction of mean pulmonary artery pressure (Delta pulmonary artery pressure-11.4%; p<0.001) and increased cardiac output (Delta cardiac output +16.7%; p<0.001), resulting in a reduction of pulmonary vascular resistance (Delta pulmonary vascular resistance-25%; p<0.001). The magnitude of this response was pronounced in surviving patients. A pulmonary vascular resistance reduction of >=30% turned out to predict outcome in patients with IPAH. CONCLUSIONS: Residual pulmonary vasodilative reserve during acute vasodilator testing is of prognostic relevance in patients with IPAH not meeting current definitions of acute vasoreactivity. Therefore vasoreactivity testing holds more information than currently used. PMID- 26015442 TI - Nutrient depletion and metabolic profiles in breast carcinoma cell lines measured with a label-free platform. AB - The response of two well-characterized human breast cancer cell lines (MCF-7 and MDA-MB-231) to a series of nutrient deficiencies is investigated with a label free cell assay platform. The motivation of the research is to analyze adaptive responses of tumor cell metabolism and to find limiting conditions for cell survival. The platform measures extracellular values of pH and dissolved oxygen saturation to provide data of extracellular acidification rates and oxygen uptake rates. Additional electric cell substrate impedance sensing and bright-field cell imaging supports the data interpretation by providing information about cell morphological parameters. A sequential administration of nutrient depletions does not cause metabolic reprogramming, since the ratios of oxygen uptake to acidification return to their basal values. While the extracellular acidification drops sharply upon reduction of glucose and glutamine, the oxygen uptake is not affected. In contrast to other published data, cell death is not observed when both glucose and glutamine are depleted and cell proliferation is not inhibited, at least in MCF-7 cultures. It is assumed that residual concentrations of nutrients from the serum component are able to maintain cell viability when delivered regularly by active flow like in the cell assay platform, and, in a similar way, under physiological conditions. PMID- 26015443 TI - Platelet-rich plasma for arthroscopic repair of medium to large rotator cuff tears: a randomized controlled trial. AB - BACKGROUND: Two main questions about the use of platelet-rich plasma (PRP) for regeneration purposes are its effect on the speed of healing and the quality of healing. Despite recent numerous studies, evidence is still lacking in this area, especially in a representative patient population with medium to large rotator cuff tears. PURPOSE: To assess the efficacy of PRP augmentation on the speed and quality of healing in patients undergoing arthroscopic repair for medium to large rotator cuff tears. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 74 patients scheduled for arthroscopic repair of medium to large rotator cuff tears were randomly assigned to undergo either PRP-augmented repair (PRP group) or conventional repair (conventional group). In the PRP group, 3 PRP gels (3 * 3 mL) were applied to each patient between the torn end and the greater tuberosity. The primary outcome was the Constant score at 3 months after surgery. Secondary outcome measures included the visual analog scale (VAS) for pain, range of motion (ROM), muscle strength, overall satisfaction and function, functional scores, retear rate, and change in the cross-sectional area (CSA) of the supraspinatus muscle. RESULTS: There was no difference between the 2 groups in the Constant score at 3 months (P > .05). The 2 groups had similar results on the VAS for pain, ROM, muscle strength, overall satisfaction and function, and other functional scores (all P > .05) except for the VAS for worst pain (P = .043). The retear rate of the PRP group (3.0%) was significantly lower than that of the conventional group (20.0%) (P = .032). The change in 1-year postoperative and immediately postoperative CSAs was significantly different between the 2 groups: -36.76 +/- 45.31 mm(2) in the PRP group versus -67.47 +/- 47.26 mm(2) in the conventional group (P = .014). CONCLUSION: Compared with repairs without PRP augmentation, the current PRP preparation and application methods for medium to large rotator cuff repairs significantly improved the quality, as evidenced by a decreased retear rate and increased CSA of the supraspinatus, but not the speed of healing. However, further studies may be needed to investigate the effects of PRP on the speed of healing without risking the quality. PMID- 26015444 TI - Arthroscopic Partial Repair of Irreparable Rotator Cuff Tears: Preoperative Factors Associated With Outcome Deterioration Over 2 Years. AB - BACKGROUND: Arthroscopic partial repair is a treatment option in irreparable large-to-massive rotator cuff tears without arthritic changes. However, there are indications that arthroscopic partial repair does not yield satisfactory outcomes. PURPOSE: To report the clinical and radiographic results of arthroscopic partial repairs in patients with irreparable large-to-massive cuff tears. In addition, an analysis was performed regarding preoperative factors that may influence patient outcomes and patient-rated satisfaction over time. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From 2005 to 2011, a total of 31 patients who underwent arthroscopic partial repair for irreparable large-to massive cuff tears were retrospectively evaluated. Partial repair was defined as posterior cuff tissue repair with or without subscapularis tendon repair to restore the transverse force couple of the cuff. Pain visual analog scale (PVAS), questionnaire results (American Shoulder and Elbow Surgeons [ASES] and Simple Shoulder Test [SST]), and radiographic changes (acromiohumeral distance and degenerative change) were assessed preoperatively, at first follow-up (roughly 1 year postoperatively), and at final follow-up (>2 years postoperatively). Patients rated their satisfaction level at each postoperative follow-up as well. Preoperative factors that might influence outcomes, such as patient demographics, tear size, and fatty infiltration, were investigated. RESULTS: The preoperative, first follow-up, and final follow-up results for mean PVAS (5.13, 2.13, and 3.16, respectively) and questionnaires (ASES: 41.97, 76.37, and 73.78; SST: 3.61, 6.33, and 6.07, respectively) improved significantly (all P < .05). Radiographic evaluation showed no difference compared with preoperative status. Nevertheless, patient-rated satisfaction at final evaluation was inferior: 16 good responses ("very satisfied" and "satisfied") and 15 poor responses ("rather the same" and "dissatisfied"). Despite initial improvements in both groups (P < .05), patients with poor satisfaction demonstrated statistically significant deterioration in mean PVAS (from 2.07 to 4.67), questionnaire scores (ASES: from 74.56 to 59.80; SST: from 5.11 to 3.81), and acromiohumeral distance (from 7.19 to 5.06 mm) between the first and final follow-up (all P < .05). Patients with good satisfaction showed no significant difference or they improved (P > .05) from the first to the final follow-up. Among preoperative factors, fatty infiltration of the teres minor was identified as the only statistically significant factor affecting patient-rated satisfaction (P = .007). CONCLUSION: This study showed that arthroscopic partial repair may produce initial improvement in selected outcomes at 2-year follow-up. However, about half of the patients in the study were not satisfied with their outcomes, which had deteriorated over time. Preoperative fatty infiltration of the teres minor was the only factor that correlated with worse final outcomes and poor satisfaction after arthroscopic partial repair. PMID- 26015445 TI - Proliferation and Morphogenesis of the Endoplasmic Reticulum Driven by the Membrane Domain of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Plant Cells. AB - The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) has a key regulatory role in the mevalonate pathway for isoprenoid biosynthesis and is composed of an endoplasmic reticulum (ER)-anchoring membrane domain with low sequence similarity among eukaryotic kingdoms and a conserved cytosolic catalytic domain. Organized smooth endoplasmic reticulum (OSER) structures are common formations of hypertrophied tightly packed ER membranes devoted to specific biosynthetic and secretory functions, the biogenesis of which remains largely unexplored. We show that the membrane domain of plant HMGR suffices to trigger ER proliferation and OSER biogenesis. The proliferating membranes become highly enriched in HMGR protein, but they do not accumulate sterols, indicating a morphogenetic rather than a metabolic role for HMGR. The N-terminal MDVRRRPP motif present in most plant HMGR isoforms is not required for retention in the ER, which was previously proposed, but functions as an ER morphogenic signal. Plant OSER structures are morphologically similar to those of animal cells, emerge from tripartite ER junctions, and mainly build up beside the nuclear envelope, indicating conserved OSER biogenesis in high eukaryotes. Factors other than the OSER-inducing HMGR construct mediate the tight apposition of the proliferating membranes, implying separate ER proliferation and membrane association steps. Overexpression of the membrane domain of Arabidopsis (Arabidopsis thaliana) HMGR leads to ER hypertrophy in every tested cell type and plant species, whereas the knockout of the HMG1 gene from Arabidopsis, encoding its major HMGR isoform, causes ER aggregation at the nuclear envelope. Our results show that the membrane domain of HMGR contributes to ER morphogenesis in plant cells. PMID- 26015447 TI - Editorial for the Special Issue of Statistical Methods in Medical Research at the occasion of the 10th Anniversary of the Southampton Statistical Sciences Research Institute. PMID- 26015446 TI - Homeologs of the Nicotiana benthamiana Antiviral ARGONAUTE1 Show Different Susceptibilities to microRNA168-Mediated Control. AB - The plant ARGONAUTE1 protein (AGO1) is a central functional component of the posttranscriptional regulation of gene expression and the RNA silencing-based antiviral defense. By genomic and molecular approaches, we here reveal the presence of two homeologs of the AGO1-like gene in Nicotiana benthamiana, NbAGO1 1H and NbAGO1-1L. Both homeologs retain the capacity to transcribe messenger RNAs (mRNAs), which mainly differ in one 18-nucleotide insertion/deletion (indel). The indel does not modify the frame of the open reading frame, and it is located eight nucleotides upstream of the target site of a microRNA, miR168, which is an important modulator of AGO1 expression. We demonstrate that there is a differential accumulation of the two NbAGO1-1 homeolog mRNAs at conditions where miR168 is up-regulated, such as during a tombusvirus infection. The data reported suggest that the indel affects the miR168-guided regulation of NbAGO1 mRNA. The two AGO1 homeologs show full functionality in reconstituted, catalytically active RNA-induced silencing complexes following the incorporation of small interfering RNAs. Virus-induced gene silencing experiments suggest a specific involvement of the NbAGO1 homeologs in symptom development. The results provide an example of the diversity of microRNA target regions in NbAGO1 homeolog genes, which has important implications for improving resilience measures of the plant during viral infections. PMID- 26015448 TI - Wave Separation, Wave Intensity, the Reservoir-Wave Concept, and the Instantaneous Wave-Free Ratio: Presumptions and Principles. AB - Wave separation analysis and wave intensity analysis (WIA) use (aortic) pressure and flow to separate them in their forward and backward (reflected) waves. While wave separation analysis uses measured pressure and flow, WIA uses their derivatives. Because differentiation emphasizes rapid changes, WIA suppresses slow (diastolic) fluctuations of the waves and renders diastole a seemingly wave free period. However, integration of the WIA-obtained forward and backward waves is equal to the wave separation analysis-obtained waves. Both the methods thus give similar results including backward waves spanning systole and diastole. Nevertheless, this seemingly wave-free period in diastole formed the basis of both the reservoir-wave concept and the Instantaneous wave-Free Ratio of (iFR) pressure and flow. The reservoir-wave concept introduces a reservoir pressure, Pres, (Frank Windkessel) as a wave-less phenomenon. Because this Windkessel model falls short in systole an excess pressure, Pexc, is introduced, which is assumed to have wave properties. The reservoir-wave concept, however, is internally inconsistent. The presumed wave-less Pres equals twice the backward pressure wave and travels, arriving later in the distal aorta. Hence, in contrast, Pexc is minimally affected by wave reflections. Taken together, Pres seems to behave as a wave, rather than Pexc. The iFR is also not without flaws, as easily demonstrated when applied to the aorta. The ratio of diastolic aortic pressure and flow implies division by zero giving nonsensical results. In conclusion, presumptions based on WIA have led to misconceptions that violate physical principles, and reservoir-wave concept and iFR should be abandoned. PMID- 26015450 TI - Long-Term Reduction of High Blood Pressure by Angiotensin II DNA Vaccine in Spontaneously Hypertensive Rats. AB - Recent research on vaccination has extended its scope from infectious diseases to chronic diseases, including Alzheimer disease, dyslipidemia, and hypertension. The aim of this study was to design DNA vaccines for high blood pressure and eventually develop human vaccine therapy to treat hypertension. Plasmid vector encoding hepatitis B core-angiotensin II (Ang II) fusion protein was injected into spontaneously hypertensive rats using needleless injection system. Anti-Ang II antibody was successfully produced in hepatitis B core-Ang II group, and antibody response against Ang II was sustained for at least 6 months. Systolic blood pressure was consistently lower in hepatitis B core-Ang II group after immunization, whereas blood pressure reduction was continued for at least 6 months. Perivascular fibrosis in heart tissue was also significantly decreased in hepatitis B core-Ang II group. Survival rate was significantly improved in hepatitis B core-Ang II group. This study demonstrated that Ang II DNA vaccine to spontaneously hypertensive rats significantly lowered high blood pressure for at least 6 months. In addition, Ang II DNA vaccines induced an adequate humoral immune response while avoiding the activation of self-reactive T cells, assessed by ELISPOT assay. Future development of DNA vaccine to treat hypertension may provide a new therapeutic option to treat hypertension. PMID- 26015449 TI - Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet-Induced Arterial Stiffening in Female Mice. AB - Women are especially predisposed to development of arterial stiffening secondary to obesity because of consumption of excessive calories. Enhanced activation of vascular mineralocorticoid receptors impairs insulin signaling, induces oxidative stress, inflammation, and maladaptive immune responses. We tested whether a subpressor dose of mineralocorticoid receptor antagonist, spironolactone (1 mg/kg per day) prevents aortic and femoral artery stiffening in female C57BL/6J mice fed a high-fat/high-sugar western diet (WD) for 4 months (ie, from 4-20 weeks of age). Aortic and femoral artery stiffness were assessed using ultrasound, pressurized vessel preparations, and atomic force microscopy. WD induced weight gain and insulin resistance compared with control diet-fed mice and these abnormalities were unaffected by spironolactone. Blood pressures and heart rates were normal and unaffected by diet or spironolactone. Spironolactone prevented WD induced stiffening of aorta and femoral artery, as well as endothelial and vascular smooth muscle cells, within aortic explants. Spironolactone prevented WD induced impaired aortic protein kinase B/endothelial nitric oxide synthase signaling, as well as impaired endothelium-dependent and endothelium-independent vasodilation. Spironolactone ameliorated WD-induced aortic medial thickening and fibrosis and the associated activation of the progrowth extracellular receptor kinase 1/2 pathway. Finally, preservation of normal arterial stiffness with spironolactone in WD-fed mice was associated with attenuated systemic and vascular inflammation and an anti-inflammatory shift in vascular immune cell marker genes. Low-dose spironolactone may represent a novel prevention strategy to attenuate vascular inflammation, oxidative stress, and growth pathway signaling and remodeling to prevent development of arterial stiffening secondary to consumption of a WD. PMID- 26015451 TI - Chronic heart failure and aging - effects of exercise training on endothelial function and mechanisms of endothelial regeneration: Results from the Leipzig Exercise Intervention in Chronic heart failure and Aging (LEICA) study. AB - BACKGROUND: A reduction in number and function of endothelial progenitor cells (EPCs) occurs in both physiologic aging and chronic heart failure (CHF). We assessed whether disease and aging have additive effects on EPCs or whether beneficial effects of exercise training are diminished in old age. METHODS: We randomized 60 patients with stable CHF and 60 referent controls to a training or a control group. To detect possible aging effects we included subjects below 55 (young) and above 65 years (older). Subjects in the training group exercised four times daily at 60% to 70% of VO2max for four weeks under supervision. At baseline and after the intervention the number and function of EPCs were assessed. RESULTS: As compared with young referent controls, older referent controls showed at baseline a reduced EPC number (young: 190 +/- 37 CD34/KDR positive cells/ml blood; older: 131 +/- 26 CD34/KDR positive cells/ml blood; p < 0.05) and function (young: 230 +/- 41 migrated cells/1000 plated cells; older: 185 +/- 28 cells/1000 plated cells; p < 0.05). In young and older CHF patients EPC-number (young: 85 +/ 21 CD34/KDR positive cells/ml blood; older: 78 +/- 20 CD34/KDR positive cells/ml blood) and EPC-function (young: 113 +/- 26 cells/1000 plated cells; older: 120 +/ 27 cells/1000 plated cells) were impaired. As a result of exercise training, EPC function improved by 24% in older referent controls (p < 0.05), while it remained unchanged in young training referent controls and controls respectively. In young and older patients with CHF four weeks of exercise training resulted in a significant improvement in EPC numbers and EPC function (young: number +66% function +43%; p < 0.05; older: number +69% function +36%; p < 0.05). These results were accompanied by a significant increase in flow mediated dilatation in the training groups of young/older CHF patients and in older referent controls. CONCLUSIONS: Four weeks of exercise training are effective in improving EPC number and EPC function in CHF patients. These training effects were not impaired among older patients, emphasizing the potentials of rehabilitation interventions in a patient group where CHF has a high prevalence. PMID- 26015452 TI - Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations. AB - Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemia-reperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b(+) cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis. The CD11b(+)/Ly6C(high) population associated with the onset of renal injury and increase in proinflammatory cytokines, whereas the CD11b(+)/Ly6C(intermediate) population peaked during kidney repair. The CD11b(+)/Ly6C(low) population emerged with developing renal fibrosis. Principal component and hierarchical cluster analyses identified gene signatures unique to each population. The CD11b(+)/Ly6C(intermediate) population had a distinct phenotype of wound healing, confirmed by results of studies inhibiting the macrophage colony-stimulating factor 1 receptor,whereas the CD11b(+)/Ly6C(low) population had a profibrotic phenotype. All populations, including the CD11b(+)/Ly6C(high) population, carried differential inflammatory signatures. The expression of M2-specific markers was detected in both the CD11b(+)/Ly6C(intermediate) and CD11b(+)/Ly6C(low) populations, suggesting these in vivo populations do not fit into the traditional classifications defined by in vitro systems. Results of this study in a renal ischemia-reperfusion injury model allow phenotype and function to be assigned to CD11b(+)/Ly6C(+) monocyte/macrophage populations in the pathophysiology of disease after AKI. PMID- 26015454 TI - A Friend in Need: Activated Protein C Stabilizes YB-1 during Renal Ischemia Reperfusion Injury. PMID- 26015453 TI - Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure. AB - FSGS is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases. We previously identified Yes associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glomerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glomerular disease pathogenesis and its potential utility as a therapeutic target. PMID- 26015456 TI - Mechanomyographic mean power frequency during an isometric trapezoid muscle action at multiple contraction intensities. AB - This study examined the mechanomyographic mean power frequency (MMGMPF)-force relationships for five (age = 19.20 +/- 0.45 years) aerobically-trained (AT), five (age = 25 +/- 4.53 years) resistance-trained (RT), and five (age = 21.20 +/- 2.17 years) sedentary (SED) individuals. Participants performed isometric trapezoidal muscle actions at 50, 60, and 70% maximal voluntary contraction (MVC) of the leg extensors that included linearly increasing, steady force, and linearly decreasing segments. MMG was recorded from the vastus lateralis. Linear regressions were fit to the natural-log transformed MMGMPF versus natural log transformed force relationships (linearly increasing and decreasing segments) with the b (slope) and a (y-intercept) terms used for comparisons. MMGMPF was averaged for the entire steady force segment. The b and a terms were not different among training statuses (P > 0.05) or linearly increasing and decreasing segments (P > 0.05). There were muscle action-related differences in the b terms as a function of training status from the 70% MVC. The SED had greater b terms during the linearly increasing than decreasing muscle action (P = 0.010), and the converse was true for the AT (P = 0.013), whereas the RT displayed no muscle action-related differences (P > 0.05). The unique muscle action-related differences in the b terms as a function of training status may be the result of unique adaptations to motor unit activation and deactivation strategies. PMID- 26015457 TI - Roles of Testosterone Replacement in Cardiac Ischemia-Reperfusion Injury. AB - Testosterone is an anabolic steroid hormone, which is the major circulating androgen hormone in males. Testosterone levels decreasing below the normal physiological levels lead to a status known as androgen deficiency. Androgen deficiency has been shown to be a major risk factor in the development of several disorders, including obesity, metabolic syndrome, and ischemic heart disease. In the past decades, although several studies from animal models as well as clinical studies demonstrated that testosterone exerted cardioprotection, particularly during ischemia-reperfusion (I/R) injury, other preclinical and clinical studies have shown an inverse relationship between testosterone levels and cardioprotective effects. As a result, the effects of testosterone replacement on the heart remain controversial. In this review, reports regarding the roles of testosterone replacement in the heart following I/R injury are comprehensively summarized and discussed. At present, it may be concluded that chronic testosterone replacement at a physiological dose demonstrated cardioprotective effects, whereas acute testosterone replacement can cause adverse effects in the I/R heart. PMID- 26015455 TI - Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination. AB - Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undefined. Here, we investigated the role of TM-dependent aPC generation and therapeutic aPC application in a murine renal IRI model and in an in vitro hypoxia and reoxygenation (HR) model using proximal tubular cells. In renal IRI, endogenous aPC levels were reduced. Genetic or therapeutic reconstitution of aPC efficiently ameliorated renal IRI independently of its anticoagulant properties. In tubular cells, cytoprotective aPC signaling was mediated through protease activated receptor-1- and endothelial protein C receptor-dependent regulation of the cold shock protein Y-box binding protein-1 (YB-1). The mature 50 kD form of YB-1 was required for the nephro- and cytoprotective effects of aPC in vivo and in vitro, respectively. Reduction of mature YB-1 and K48-linked ubiquitination of YB-1 was prevented by aPC after renal IRI or tubular HR injury. aPC preserved the interaction of YB-1 with the deubiquitinating enzyme otubain-1 and maintained expression of otubain-1, which was required to reduce K48-linked YB-1 ubiquitination and to stabilize the 50 kD form of YB-1 after renal IRI and tubular HR injury. These data link the cyto- and nephroprotective effects of aPC with the ubiquitin-proteasome system and identify YB-1 as a novel intracellular target of aPC. These insights may provide new impetus for translational efforts aiming to restrict renal IRI. PMID- 26015458 TI - Open Visit Notes: A Patient's Perspective and Expanding National Experience. PMID- 26015459 TI - Patients and Physicians Can Discuss Costs of Cancer Treatment in the Clinic. AB - PURPOSE: As one solution to reducing costs and medical bankruptcies, experts have suggested that patients and physicians should discuss the cost of care up front. Whether these discussions are possible in an oncology setting and what their effects on the doctor-patient relationship are is not known. METHODS: We used the National Comprehensive Cancer Network (NCCN) Guidelines and the eviti Advisor platform to show patients with metastatic breast, lung, or colorectal cancer the costs associated with their chemotherapy and/or targeted therapy options during an oncology consultation. We measured provider attitudes and assessed patient satisfaction when consultations included discussion of costs. RESULTS: We approached 107 patients; 96 (90%) enrolled onto the study, three (3%) asked if they could be interviewed at a later date, and eight (7%) did not want to participate. Only five of 18 oncologists (28%) felt comfortable discussing costs, and only one of 18 (6%) regularly asked patients about financial difficulties. The majority of patients (80%) wanted cost information, and 84% reported that these conversations would be even more important if their co-pays were to increase. In total, 72% of patients responded that no health care professional has ever discussed costs with them. The majority of patients (80%) had no negative feelings about hearing cost information. CONCLUSION: In an era of rising co-pays, patients with cancer want cost-of-treatment discussions, and these conversations do not lead to negative feelings in the majority of patients. Additional training to prepare clinicians for how to discuss costs with their patients is needed. PMID- 26015460 TI - Does pulmonary rehabilitation reduce peripheral blood pressure in patients with chronic obstructive pulmonary disease? AB - Pulmonary rehabilitation (PR) can improve aerobic exercise capacity, health related quality of life and dyspnoea in patients with chronic obstructive pulmonary disease (COPD). Recent studies have suggested that exercise training may improve blood pressure and arterial stiffness, albeit in small highly selected cohorts. The aim of the study was to establish whether supervised outpatient or unsupervised home PR can reduce peripheral blood pressure. Resting blood pressure was measured in 418 patients with COPD before and after outpatient PR, supervised by a hospital-based team (HOSP). Seventy-four patients with COPD undergoing an unsupervised home-based programme acted as a comparator group (HOME). Despite significant improvements in mean (95% confidence interval) exercise capacity in the HOSP group (56 (50-60) m, p < 0.001) and HOME group (30 (17-42) m, p < 0.001) systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) did not change in either the HOSP (SBP: p = 0.47; DBP: p = 0.06; MAP: p = 0.38) or HOME group (SBP: p = 0.67; DBP: p = 0.38; MAP: p = 0.76). Planned subgroup analysis of HOSP patients with known hypertension and/or cardiovascular disease showed no impact of PR upon blood pressure. PR is unlikely to reduce blood pressure, and by implication, makes a mechanism of action in which arterial stiffness is reduced, less likely. PMID- 26015461 TI - Effects of different weight loss percentages on moderate to severe obstructive sleep apnoea syndrome. PMID- 26015462 TI - Is there a role for antimicrobial stewardship in bronchiectasis? PMID- 26015463 TI - Dual Inhibition of Interleukin-23 and Interleukin-17 Offers Superior Efficacy in Mouse Models of Autoimmunity. AB - Therapies targeting either interleukin (IL)-23 or IL-17 have shown promise in treating T helper 17 (Th17)-driven autoimmune diseases. Although IL-23 is a critical driver of IL-17, recognition of nonredundant and independent functions of IL-23 and IL-17 has prompted the notion that dual inhibition of both IL-23 and IL-17 could offer even greater efficacy for treating autoimmune diseases relative to targeting either cytokine alone. To test this hypothesis, we generated selective inhibitors of IL-23 and IL-17 and tested the effect of either treatment alone compared with their combination in vitro and in vivo. In vitro, using a novel culture system of murine Th17 cells and NIH/3T3 fibroblasts, we showed that inhibition of both IL-23 and IL-17 completely suppressed IL-23-dependent IL-22 production from Th17 cells and cooperatively blocked IL-17-dependent IL-6 secretion from the NIH/3T3 cells to levels below either inhibitor alone. In vivo, in the imiquimod induced skin inflammation model, and in the myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis model, we demonstrated that dual inhibition of IL-17 and IL-23 was more efficacious in reducing disease than targeting either cytokine alone. Together, these data support the hypothesis that neutralization of both IL-23 and IL-17 may provide enhanced benefit against Th17 mediated autoimmunity and provide a basis for a therapeutic strategy aimed at dual targeting IL-23 and IL-17. PMID- 26015464 TI - Now you see it, now you don't? PMID- 26015466 TI - Serial imaging changes during treatment of immunoglobulin G4-related disease with multiple pseudotumors. PMID- 26015467 TI - Aortic Dissection Manifesting as ST-Segment-Elevation Myocardial Infarction. PMID- 26015468 TI - Cardiology Patient Page. Chelation therapy: a new look at an old treatment for heart disease, particularly in diabetics. PMID- 26015469 TI - Letter by Nairooz et al Regarding Article, "Improved Quality of Life After 1 Year With an Invasive Versus a Noninvasive Treatment Strategy in Claudicants: One-Year Results of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial". PMID- 26015470 TI - Letter by Morris et al Regarding Article, "Improved Quality of Life After 1 Year With an Invasive Versus a Noninvasive Treatment Strategy in Claudicants: One-Year Results of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial". PMID- 26015472 TI - Correction. PMID- 26015471 TI - Response to Letter Regarding Article, "Improved Quality of Life After 1 Year With an Invasive Versus a Noninvasive Treatment Strategy in Claudicants: One-Year Results of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial". PMID- 26015473 TI - Developing relationships between care staff and people with dementia through Music Therapy and Dance Movement Therapy: A preliminary phenomenological study. AB - Background There is an increasing focus on providing effective psychosocial interventions to improve quality of life in dementia care. This study aims to explore the attitudes and perceptions of staff who participated regularly in Music Therapy (MT) and Dance Movement Therapy (DMT) groups for residents with dementia in a nursing home. Method In-depth interviews were conducted with seven members of care home staff. Data were analysed using interpretative phenomenological analysis. Results A representation modelling the impact of MT and DMT in a nursing care home. Three main themes were identified. 1) Discovering residents' skills and feelings; 2) Learning from the therapists to change approaches to care practice with subthemes: time, space and pace, choice, following the residents' lead; 3) Connection between staff and residents. Conclusion The model indicated that both interventions performed in parallel helped staff to discover residents' skills and feelings. Although it is a small sample size, this study strongly suggests that MT and DMT can have a positive influence in helping care staff to provide a meaningful care environment. PMID- 26015474 TI - Catch a Glimpse of Me: The development of staff videos to promote person-centered care. AB - Catch a Glimpse of Me is an ongoing project that uses video to help staff deliver more person-centered care for people with dementia living in long-term care. Focus groups consisting of residents, family and staff members were conducted to develop a template for the development of the videos. The five themes they identified as being important to include are: family; interests and hobbies; memories and moments; life space and getting personal. The article describes the process of developing the videos and discusses the ongoing potential of the Catch a Glimpse of Me project. PMID- 26015475 TI - IgG antibodies to endothelial protein C receptor-binding cysteine-rich interdomain region domains of Plasmodium falciparum erythrocyte membrane protein 1 are acquired early in life in individuals exposed to malaria. AB - Severe malaria syndromes are precipitated by Plasmodium falciparum parasites binding to endothelial receptors on the vascular lining. This binding is mediated by members of the highly variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We have previously identified a subset of PfEMP1 proteins associated with severe malaria and found that the receptor for these PfEMP1 variants is endothelial protein C receptor (EPCR). The binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDR) of the subtypes alpha1.1 and alpha1.4 to alpha1.8. In this study, we investigated the acquisition of anti-CIDR antibodies using plasma samples collected in four study villages with different malaria transmission intensities in northeastern Tanzania during a period with a decline in malaria transmission. We show that individuals exposed to high levels of malaria transmission acquire antibodies to EPCR-binding CIDR domains early in life and that these antibodies are acquired more rapidly than antibodies to other CIDR domains. The rate by which antibodies to EPCR binding CIDR domains are acquired in populations in areas where malaria is endemic is determined by the malaria transmission intensity, and on a population level, the antibodies are rapidly lost if transmission is interrupted. This indicates that sustained exposure is required to maintain the production of the antibodies. PMID- 26015476 TI - Neutrophils play an important role in protective immunity against Coxiella burnetii infection. AB - Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes the zoonotic disease Q fever. Although Q fever is mainly transmitted by aerosol infection, study of the immune responses in the lung following pulmonary C. burnetii infection is lacking. Neutrophils are considered the first immune cell to migrate into the lung and play an important role in host defense against aerosol infection with microbial pathogens. However, the role of neutrophils in the host defense against C. burnetii infection remains unclear. To determine the role of neutrophils in protective immunity against C. burnetii infection, the RB6 8C5 antibody was used to deplete neutrophils in mice before intranasal infection with C. burnetii. The results indicated that neutrophil-depleted mice developed more severe disease than their wild-type counterparts, suggesting that neutrophils play an important role in host defense against C. burnetii pulmonary infection. We also found that neither CXC chemokine receptor 2 (CXCR2) nor interleukin-17 (IL-17) receptor (IL-17R) deficiency changed the severity of disease following intranasal C. burnetii challenge, suggesting that keratinocyte derived chemokine and IL-17 may not play essential roles in the response to C. burnetii infection. However, significantly higher C. burnetii genome copy numbers were detected in the lungs of IL-1R(-/-) mice at 14 days postinfection. This indicates that IL-1 may be important for the clearance of C. burnetii from the lungs following intranasal infection. Our results also suggest that neutrophils are involved in protecting vaccinated mice from C. burnetii challenge-induced disease. This is the first study to demonstrate an important role for neutrophils in protective immunity against C. burnetii infection. PMID- 26015478 TI - Micropatterned macrophage analysis reveals global cytoskeleton constraints induced by Bacillus anthracis edema toxin. AB - Bacillus anthracis secretes the edema toxin (ET) that disrupts the cellular physiology of endothelial and immune cells, ultimately affecting the adherens junction integrity of blood vessels that in turn leads to edema. The effects of ET on the cytoskeleton, which is critical in cell physiology, have not been described thus far on macrophages. In this study, we have developed different adhesive micropatterned surfaces (L and crossbow) to control the shape of bone marrow-derived macrophages (BMDMs) and primary peritoneal macrophages. We found that macrophage F-actin cytoskeleton adopts a specific polar organization slightly different from classical human HeLa cells on the micropatterns. Moreover, ET induced a major quantitative reorganization of F-actin within 16 h with a collapse at the nonadhesive side of BMDMs along the nucleus. There was an increase in size and deformation into a kidney-like shape, followed by a decrease in size that correlates with a global cellular collapse. The collapse of F-actin was correlated with a release of focal adhesion on the patterns and decreased cell size. Finally, the cell nucleus was affected by actin reorganization. By using this technology, we could describe many previously unknown macrophage cellular dysfunctions induced by ET. This novel tool could be used to analyze more broadly the effects of toxins and other virulence factors that target the cytoskeleton. PMID- 26015477 TI - Host-like carbohydrates promote bloodstream survival of Vibrio vulnificus in vivo. AB - Sialic acids are found on all vertebrate cell surfaces and are part of a larger class of molecules known as nonulosonic acids. Many bacterial pathogens synthesize related nine-carbon backbone sugars; however, the role(s) of these non sialic acid molecules in host-pathogen interactions is poorly understood. Vibrio vulnificus is the leading cause of seafood-related death in the United States due to its ability to quickly access the host bloodstream, which it can accomplish through gastrointestinal or wound infection. However, little is known about how this organism persists systemically. Here we demonstrate that sialic acid-like molecules are present on the lipopolysaccharide of V. vulnificus, are required for full motility and biofilm formation, and also contribute to the organism's natural resistance to polymyxin B. Further experiments in a murine model of intravenous V. vulnificus infection demonstrated that expression of nonulosonic acids had a striking benefit for bacterial survival during bloodstream infection and dissemination to other tissues in vivo. In fact, levels of bacterial persistence in the blood corresponded to the overall levels of these molecules expressed by V. vulnificus isolates. Taken together, these results suggest that molecules similar to sialic acids evolved to facilitate the aquatic lifestyle of V. vulnificus but that their emergence also resulted in a gain of function with life-threatening potential in the human host. PMID- 26015479 TI - Intracellular Listeria monocytogenes comprises a minimal but vital fraction of the intestinal burden following foodborne infection. AB - Listeria monocytogenes is a highly adaptive bacterium that replicates as a free living saprophyte in the environment as well as a facultative intracellular pathogen that causes invasive foodborne infections. The intracellular life cycle of L. monocytogenes is considered to be its primary virulence determinant during mammalian infection; however, the proportion of L. monocytogenes that is intracellular in vivo has not been studied extensively. In this report, we demonstrate that the majority of wild-type (strain EGDe) and mouse-adapted (InlA(m)-expressing) L. monocytogenes recovered from the mesenteric lymph nodes (MLN) was extracellular within the first few days after foodborne infection. In addition, significantly lower burdens of L. monocytogenes were recovered from the colon, spleen, and liver of gentamicin-treated mice than of control mice. This led us to investigate whether intracellular replication of L. monocytogenes was essential during the intestinal phase of infection. We found that lipoate protein ligase-deficient L. monocytogenes (DeltalplA1) mutants, which display impaired intracellular growth, were able to colonize the colon but did not persist efficiently and had a significant defect in spreading to the MLN, spleen, and liver. Together, these data indicate that the majority of the L. monocytogenes burden in the gastrointestinal tract is extracellular, but the small proportion of intracellular L. monocytogenes is essential for dissemination to the MLN and systemic organs. PMID- 26015480 TI - Transcriptome reprogramming by plasmid-encoded transcriptional regulators is required for host niche adaption of a macrophage pathogen. AB - Rhodococcus equi is a facultative intracellular pathogen of macrophages, relying on the presence of a conjugative virulence plasmid harboring a 21-kb pathogenicity island (PAI) for growth in host macrophages. The PAI encodes a family of 6 virulence-associated proteins (Vaps) in addition to 20 other proteins. The contribution of these to virulence has remained unclear. We show that the presence of only 3 virulence plasmid genes (of 73 in total) is required and sufficient for intracellular growth. These include a single vap family member, vapA, and two PAI-located transcriptional regulators, virR and virS. Both transcriptional regulators are essential for wild-type-level expression of vapA, yet vapA expression alone is not sufficient to allow intracellular growth. A whole-genome microarray analysis revealed that VirR and VirS substantially integrate themselves into the chromosomal regulatory network, significantly altering the transcription of 18% of all chromosomal genes. This pathoadaptation involved significant enrichment of select gene ontologies, in particular, enrichment of genes involved in transport processes, energy production, and cellular metabolism, suggesting a major change in cell physiology allowing the bacterium to grow in the hostile environment of the host cell. The results suggest that following the acquisition of the virulence plasmid by an avirulent ancestor of R. equi, coevolution between the plasmid and the chromosome took place, allowing VirR and VirS to regulate the transcription of chromosomal genes in a process that ultimately promoted intracellular growth. Our findings suggest a mechanism for cooption of existing chromosomal traits during the evolution of a pathogenic bacterium from an avirulent saprophyte. PMID- 26015481 TI - Four-component Staphylococcus aureus vaccine 4C-staph enhances Fcgamma receptor expression in neutrophils and monocytes and mitigates S. aureus infection in neutropenic mice. AB - Staphylococcus aureus is a human bacterial pathogen causing a variety of diseases. The occurrence of multidrug-resistant strains of Staphylococcus aureus underlines the need for a vaccine. Defining immune correlates of protection may support the design of an effective vaccine. We used a murine Staphylococcus aureus infection model, in which bacteria were inoculated in an air pouch generated on the back of the animal. Analysis of the air-pouch content in mice immunized or not with an adjuvanted multiantigen vaccine formulation, four component S. aureus vaccine (4C-Staph), prior to infection allowed us to measure bacteria, cytokines, and 4C-Staph-specific antibodies and to analyze host immune cells recruited to the infection site. Immunization with 4C-Staph resulted in accumulation of antigen-specific antibodies in the pouch and mitigated the infection. Neutrophils were the most abundant cells in the pouch, and they showed the upregulation of Fcgamma receptor (FcgammaR) following immunization with 4C Staph. Reduction of the infection was also obtained in mice immunized with 4C Staph and depleted of neutrophils; these mice showed an increase in monocytes and macrophages. Upregulation of the FcgammaR and the presence of antigen-specific antibodies induced by immunization with 4C-Staph may contribute to increase bacterial opsonophagocytosis. Protection in neutropenic mice indicated that an effective vaccine could activate alternative protection mechanisms compensating for neutropenia, a condition often occurring in S. aureus-infected patients. PMID- 26015482 TI - A short-term Borrelia burgdorferi infection model identifies tissue tropisms and bloodstream survival conferred by adhesion proteins. AB - Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is able to persist in the joint, heart, skin, and central nervous system for the lifetime of its mammalian host. Borrelia species achieve dissemination to distal sites in part by entry into and travel within the bloodstream. Much work has been performed in vitro describing the roles of many B. burgdorferi outer surface proteins in adhesion to host cell surface proteins and extracellular matrix components, although the biological relevance of these interactions is only beginning to be explored in vivo. A need exists in the field for an in vivo model to define the biological roles of B. burgdorferi adhesins in tissue-specific vascular interactions. We have developed an in vivo model of vascular interaction of B. burgdorferi in which the bacteria are injected intravenously and allowed to circulate for 1 h. This model has shown that the fibronectin binding protein BB0347 has a tropism for joint tissue. We also have shown an importance of the integrin binding protein, P66, in binding to vasculature of the ear and heart. This model also revealed unexpected roles for Borrelia adhesins BBK32 and OspC in bacterial burdens in the bloodstream. The intravenous inoculation model of short term infection provides new insights into critical B. burgdorferi interactions with the host required for initial survival and tissue colonization. PMID- 26015485 TI - Sensory-Motor Systems of Copepods involved in their Escape from Suction Feeding. AB - Copepods escape well by detecting minute gradients in the flow field; they react quickly, and swim away strongly. As a key link in the aquatic food web, these small planktonic organisms often encounter suction-feeding fish. Studies have identified certain hydrodynamic features that are created by the approach of this visual predator and the generation of its suction flow for capturing food. Similarly, studies have identified certain hydrodynamic features that evoke the evasive response of copepods. This is a review of the copepod sensory motor system as pertains to understanding their response to suction-feeding fish. Analyses of the reaction time, threshold sensitivity, structure of sensors, and evasive behavior by this key prey of fish can be useful for evaluating the effectiveness of feeding tactics in response to suction flow. To illustrate, we present results comparing a copepod from a fishless lake (Hesperodiaptomus shoshone) to a copepod from a rich fishing ground (Calanus finmarchicus). We designed a flow mimic that produces a realistic mushroom-cap-shaped flow field and realistic accelerations of flow; the copepods treated the mimic as a threat and performed jumps directed up and away from the siphon. Calanus finmarchicus responded at an average threshold strain rate of 18.7/s, escaped at 0.46 m/s, and traveled 5.99 mm, most frequently as a single jump. Hesperodiaptomus shoshone responded at a strain rate of 15.1/s that is not significantly different, escaped more slowly at 0.22 m/s and traveled a shorter distance of 3.01 mm using a series of hops. The high variability noted in the initial angle of the body and the maximum change in body angle suggests that unpredictability in the escape maneuver is another aspect of the tactic of copepods. The speed of the escape by small copepods 2-3 mm long is overwhelmed by the speed of the attack by the much larger, faster fish; if the copepod reacts when it is within the fish's arena of capture (<1.5 mm from mouth), it will be eaten. The copepod, however, has an acutely sensitive array of mechanosensors that perceive the flow field of the fish at distances of 3-6 mm, or outside the fish's range of capture. The copepod also has a rapid and strong locomotory response, thereby increasing the odds that the copepod will survive-but speed is unlikely to be the best tactic for staying alive. Instead, the copepod accelerates from 61.3 to 96.5 m/s(2) or more than 20 times stronger than the lunge of a fish. This collection of capabilities of copepods enables them to remain one of the most abundant multicellular organisms on our planet. PMID- 26015486 TI - Identifying mental health symptoms in children and youth in residential and in patient care settings. AB - This study demonstrates the use of the interRAI assessment instruments to examine mental health symptoms in children and adults within residential and in-patient care settings. Regardless of service setting, children exhibited more harm to self and others than adults. Children in adult in-patient beds were more likely to exhibit suicide and self-harm and less likely to exhibit harm to others compared to children in child-specific service settings. Implications related to service system improvements are discussed. PMID- 26015483 TI - Chlamydia muridarum infection of macrophages elicits bactericidal nitric oxide production via reactive oxygen species and cathepsin B. AB - The ability of certain species of Chlamydia to inhibit the biogenesis of phagolysosomes permits their survival and replication within macrophages. The survival of macrophage-adapted chlamydiae correlates with the multiplicity of infection (MOI), and optimal chlamydial growth occurs in macrophages infected at an MOI of <=1. In this study, we examined the replicative capacity of Chlamydia muridarum in the RAW 264.7 murine macrophage cell line at different MOIs. C. muridarum productively infected these macrophages at low MOIs but yielded few viable elementary bodies (EBs) when macrophages were infected at a moderate (10) or high (100) MOI. While high MOIs caused cytotoxicity and irreversible host cell death, macrophages infected at a moderate MOI did not show signs of cytotoxicity until late in the infectious cycle. Inhibition of host protein synthesis rescued C. muridarum in macrophages infected at a moderate MOI, implying that chlamydial growth was blocked by activated defense mechanisms. Conditioned medium from these macrophages was antichlamydial and contained elevated levels of interleukin 1beta (IL-1beta), IL-6, IL-10, and beta interferon (IFN-beta). Macrophage activation depended on Toll-like receptor 2 (TLR2) signaling, and cytokine production required live, transcriptionally active chlamydiae. A hydroxyl radical scavenger and inhibitors of inducible nitric oxide synthase (iNOS) and cathepsin B also reversed chlamydial killing. High levels of reactive oxygen species (ROS) led to an increase in cathepsin B activity, and pharmacological inhibition of ROS and cathepsin B reduced iNOS expression. Our data demonstrate that MOI-dependent TLR2 activation of macrophages results in iNOS induction via a novel ROS- and cathepsin-dependent mechanism to facilitate C. muridarum clearance. PMID- 26015484 TI - Chlamydial variants differ in ability to ascend the genital tract in the guinea pig model of chlamydial genital infection. AB - An important question in the study of chlamydial genital tract disease is why some women develop severe upper tract disease while others have mild or even "silent" infections with or without pathology. Animal studies suggest that the pathological outcome of an infection is dependent upon both the composition of the infecting chlamydial population and the genotype of the host, along with host physiological effects, such as the cyclical production of reproductive hormones and even the size of the infecting inoculum or the number of repeated infections. In this study, we compared two variants of Chlamydia caviae, contrasting in virulence, with respect to their abilities to ascend the guinea pig genital tract. We then determined the effect of combining the two variants on the course of infection and on the bacterial loads of the two variants in the genital tract. Although the variants individually had similar infection kinetics in the cervix, SP6, the virulent variant, could be isolated from the oviducts more often and in greater numbers than the attenuated variant, AZ2. SP6 also elicited higher levels of interleukin 8 (IL-8) in the lower genital tract and increased leukocyte infiltration in the cervix and uterus compared to AZ2. When the two variants were combined in a mixed infection, SP6 outcompeted AZ2 in the lower genital tract; however, AZ2 was able to ascend the genital tract as readily as SP6. These data suggest that the ability of SP6 to elicit an inflammatory response in the lower genital tract facilitates the spread of both variants to the oviducts. PMID- 26015487 TI - Access to psychiatrists by French-speaking patients in Ontario hospitals: 2005 to 2013. AB - There has been a limited amount of research suggesting that cultural and linguistic variables may affect access to health services, but no study has examined the access of French-speaking Canadians to psychiatrists. The present study used data from the Ontario Mental Health Reporting System to examine patterns of daily contact with psychiatrists in the first 3 days of admission to mental health facilities in Ontario. The results showed that after controlling for a broad range of covariates, French-speaking Ontarians were about one-third as likely to have daily contact with psychiatrists in that time period compared to English-speaking patients. These results were not explained by regional differences. Instead, they point to the possibility that language poses an important barrier to specific and highly specialized mental health services in this province. PMID- 26015488 TI - A message from the Guest Editor. PMID- 26015489 TI - Use of control interventions in adult in-patient mental health services. AB - This study examined the prevalence of Control Intervention (CI) use in adult in patient psychiatric units/hospitals in Ontario and developed a profile of those patients who had CI use during their admission between April 2006 and March 2010. Control intervention types included mechanical/physical, chair prevents rising, acute control medications, and seclusion. The profiles of patients with control intervention use included an examination of sociodemographic, mental health service use, and mental health clinical characteristics. PMID- 26015490 TI - Using the RAI-MH to support shared decision-making in mental healthcare. AB - Persons with mental illness often struggle to meaningfully participate in decisions about their services. This study engaged persons with mental illness to understand how health information could empower them. Participants reported wanting information on diagnoses, medications, symptoms, and strengths as well as clinician notes and rationale. The Resident Assessment Instrument for Mental Health contains this information and is mandated in in-patient psychiatry. Its findings could be summarized and shared with individuals to promote and facilitate shared decision-making. PMID- 26015491 TI - Gender differences in the rate of restriction to room among Ontario forensic patients. AB - Gender can have separate and interacting effects on mental health. Gender-based analysis provides insight into these effects on mental health, and it can provide evidence to inform policy and practice to meet these gender-specific needs among persons in forensic mental health settings. Both individual and facility-level characteristics play a role in restriction to room as a form of control intervention in forensic mental health. Understanding the gender differences associated with the factors that increase a person's risk of restriction to room can allow for more targeted interventions and provide insight into policies that will help reduce these types of control interventions. PMID- 26015492 TI - Impact of aspartame and saccharin on the rat liver: Biochemical, molecular, and histological approach. AB - The current work was undertaken to settle the debate about the toxicity of artificial sweeteners (AS), particularly aspartame and saccharin. Twenty-five, 7 week-old male Wistar albino rats with an average body weight of 101 +/- 4.8 g were divided into a control group and four experimental groups (n = 5 rats). The first and second experimental groups received daily doses equivalent to the acceptable daily intake (ADI) of aspartame (250 mg/Kg BW) and four-fold ADI of aspartame (1000 mg/Kg BW). The third and fourth experimental groups received daily doses equivalent to ADI of saccharin (25 mg/Kg BW) and four-fold ADI of saccharin (100 mg/Kg BW). The experimental groups received the corresponding sweetener dissolved in water by oral route for 8 weeks. The activities of enzymes relevant to liver functions and antioxidants were measured in the blood plasma. Histological studies were used for the evaluation of the changes in the hepatic tissues. The gene expression levels of the key oncogene (h-Ras) and the tumor suppressor gene (P27) were also evaluated. In addition to a significant reduction in the body weight, the AS-treated groups displayed elevated enzymes activities, lowered antioxidants values, and histological changes reflecting the hepatotoxic effect of aspartame and saccharin. Moreover, the overexpression of the key oncogene (h-Ras) and the downregulation of the tumor suppressor gene (P27) in all treated rat groups may indicate a potential risk of liver carcinogenesis, particularly on long-term exposure. PMID- 26015493 TI - Complete Bypass of Restriction Systems for Major Staphylococcus aureus Lineages. AB - Staphylococcus aureus is a prominent global nosocomial and community-acquired bacterial pathogen. A strong restriction barrier presents a major hurdle for the introduction of recombinant DNA into clinical isolates of S. aureus. Here, we describe the construction and characterization of the IMXXB series of Escherichia coli strains that mimic the type I adenine methylation profiles of S. aureus clonal complexes 1, 8, 30, and ST93. The IMXXB strains enable direct, high efficiency transformation and streamlined genetic manipulation of major S. aureus lineages. IMPORTANCE: The genetic manipulation of clinical S. aureus isolates has been hampered due to the presence of restriction modification barriers that detect and subsequently degrade inappropriately methylated DNA. Current methods allow the introduction of plasmid DNA into a limited subset of S. aureus strains at high efficiency after passage of plasmid DNA through the restriction-negative, modification-proficient strain RN4220. Here, we have constructed and validated a suite of E. coli strains that mimic the adenine methylation profiles of different clonal complexes and show high-efficiency plasmid DNA transfer. The ability to bypass RN4220 will reduce the cost and time involved for plasmid transfer into S. aureus. The IMXXB series of E. coli strains should expedite the process of mutant construction in diverse genetic backgrounds and allow the application of new techniques to the genetic manipulation of S. aureus. PMID- 26015494 TI - Barrier-to-Autointegration Factor 1 (BAF/BANF1) Promotes Association of the SETD1A Histone Methyltransferase with Herpes Simplex Virus Immediate-Early Gene Promoters. AB - We have shown previously that A-type lamins and intranuclear localization of the herpes simplex virus (HSV) genome are critical for the formation of the VP16 activator complex on HSV immediate-early (IE) gene promoters in murine cells, which implies a critical role for lamin A and its associated proteins in HSV gene expression. Because barrier-to-autointegration factor 1 (BAF/BANF1) has been thought to bridge chromosomes to the nuclear lamina, we hypothesized that BAF might mediate viral genome targeting to the nuclear lamina. We found that overexpression of BAF enhances HSV-1 replication and knockdown of BAF decreases HSV gene expression, delays the kinetics of viral early replication compartment formation, and reduces viral yield compared to those in control small interfering RNA-transfected cells. However, BAF depletion did not affect genome complex targeting to the nuclear periphery. Instead, we found that the levels of a histone-modifying enzyme, SETD1A methyltransferase, and histone H3 lysine 4 trimethylation were reduced on IE and early (E) gene promoters in BAF-depleted cells during HSV lytic infection. Our results demonstrate a novel function of BAF as an epigenetic regulator of HSV lytic infection. We hypothesize that BAF facilitates IE and E gene expression by recruiting the SETD1A methyltransferase to viral IE and E gene promoters. IMPORTANCE: The nuclear lamina is composed of lamin proteins and numerous lamina-associated proteins. Previously, the chromatin structure of DNA localized proximally to the lamina was thought to be characterized by heterochromatin marks associated with silenced genes. However, recent studies indicate that both heterochromatin- and euchromatin-rich areas coexist on the lamina. This paradigm suggests that lamins and lamina-associated proteins dynamically regulate epigenetic modifications of specific genes in different locations. Our goal is to understand how the lamina and its associated proteins regulate the epigenetics of genes through the study of HSV infection of human cells. We have shown previously that A-type lamins are critical for HSV genome targeting to the nuclear lamina and epigenetic regulation in viral replication. In this study, we found that another lamina-associated protein, BAF, regulates HSV gene expression through an epigenetic mechanism, which provides basic insights into the nuclear lamina and its associated proteins' roles in epigenetic regulation. PMID- 26015495 TI - Staphylococcus aureus Fibronectin-Binding Protein A Mediates Cell-Cell Adhesion through Low-Affinity Homophilic Bonds. AB - Staphylococcus aureus is an important opportunistic pathogen which is a leading cause of biofilm-associated infections on indwelling medical devices. The cell surface-located fibronectin-binding protein A (FnBPA) plays an important role in the accumulation phase of biofilm formation by methicillin-resistant S. aureus (MRSA), but the underlying molecular interactions are not yet established. Here, we use single-cell and single-molecule atomic force microscopy to unravel the mechanism by which FnBPA mediates intercellular adhesion. We show that FnBPA is responsible for specific cell-cell interactions that involve the FnBPA A domain and cause microscale cell aggregation. We demonstrate that the strength of FnBPA mediated adhesion originates from multiple low-affinity homophilic interactions between FnBPA A domains on neighboring cells. Low-affinity binding by means of FnBPA may be important for biofilm dynamics. These results provide a molecular basis for the ability of FnBPA to promote cell accumulation during S. aureus biofilm formation. We speculate that homophilic interactions may represent a generic strategy among staphylococcal cell surface proteins for guiding intercellular adhesion. As biofilm formation by MRSA strains depends on proteins rather than polysaccharides, our approach offers exciting prospects for the design of drugs or vaccines to inhibit protein-dependent intercellular interactions in MRSA biofilms. IMPORTANCE: Staphylococcus aureus is a human pathogen that forms biofilms on indwelling medical devices, such as central venous catheters and prosthetic joints. This leads to biofilm infections that are difficult to treat with antibiotics because many cells within the biofilm matrix are dormant. The fibronectin-binding proteins (FnBPs) FnBPA and FnBPB promote biofilm formation by clinically relevant methicillin-resistant S. aureus (MRSA) strains, but the molecular mechanisms involved remain poorly understood. We used atomic force microscopy techniques to demonstrate that FnBPA mediates cell-cell adhesion via multiple, low-affinity homophilic bonds between FnBPA A domains on adjacent cells. Therefore, FnBP-mediated homophilic interactions represent an interesting target to prevent MRSA biofilms. We propose that such homophilic mechanisms may be widespread among staphylococcal cell surface proteins, providing a means to guide intercellular adhesion and biofilm accumulation. PMID- 26015496 TI - The Enterococcus faecalis EbpA Pilus Protein: Attenuation of Expression, Biofilm Formation, and Adherence to Fibrinogen Start with the Rare Initiation Codon ATT. AB - The endocarditis and biofilm-associated pili (Ebp) are important in Enterococcus faecalis pathogenesis, and the pilus tip, EbpA, has been shown to play a major role in pilus biogenesis, biofilm formation, and experimental infections. Based on in silico analyses, we previously predicted that ATT is the EbpA translational start codon, not the ATG codon, 120 bp downstream of ATT, which is annotated as the translational start. ATT is rarely used to initiate protein synthesis, leading to our hypothesis that this codon participates in translational regulation of Ebp production. To investigate this possibility, site-directed mutagenesis was used to introduce consecutive stop codons in place of two lysines at positions 5 and 6 from the ATT, to replace the ATT codon in situ with ATG, and then to revert this ATG to ATT; translational fusions of ebpA to lacZ were also constructed to investigate the effect of these start codons on translation. Our results showed that the annotated ATG does not start translation of EbpA, implicating ATT as the start codon; moreover, the presence of ATT, compared to the engineered ATG, resulted in significantly decreased EbpA surface display, attenuated biofilm, and reduced adherence to fibrinogen. Corroborating these findings, the translational fusion with the native ATT as the initiation codon showed significantly decreased expression of beta-galactosidase compared to the construct with ATG in place of ATT. Thus, these results demonstrate that the rare initiation codon of EbpA negatively regulates EbpA surface display and negatively affects Ebp-associated functions, including biofilm and adherence to fibrinogen. IMPORTANCE: Enterococcus faecalis is among the leading causes of serious infections in the hospital setting, and the endocarditis and biofilm-associated pili (Ebp) have been shown to play significant roles in E. faecalis pathogenesis. Understanding the regulation of virulence is important for the development of new approaches to counteract multidrug-resistant pathogens. We previously predicted that ATT, which has been reported to start protein synthesis only in rare instances, is the most likely translational start codon of EbpA in E. faecalis. Here, we demonstrate that ATT is the initiation codon of EbpA and, relative to a constructed ATG start codon, results in smaller amounts of EbpA on the surface of the cells, attenuating biofilm formation and fibrinogen adherence, phenotypes associated with the ability of E. faecalis to cause infections. This provides the first example of pilus regulation through the use of an ATT initiation codon. PMID- 26015497 TI - Cooperative roles for fimbria and filamentous hemagglutinin in Bordetella adherence and immune modulation. AB - Bordetella fimbriae (FIM) are generally considered to function as adhesins despite a lack of experimental evidence supporting this conclusion for Bordetella pertussis and evidence against a requirement for FIM in adherence of Bordetella bronchiseptica to mammalian cell lines. Using B. bronchiseptica and mice, we developed an in vivo adherence assay that revealed that FIM do function as critically important adhesins in the lower respiratory tract. In the first few days postinoculation, FIM-deficient B. bronchiseptica induced a more robust inflammatory response than wild-type bacteria did, suggesting that FIM, like filamentous hemagglutinin (FHA), allow B. bronchiseptica to suppress the innate immune response to infection. Localization analyses indicated that FIM are required for efficient attachment to airway epithelium, as bacteria lacking FIM localized to alveoli. FHA-deficient bacteria, in contrast, localized to airways. Bacteria unable to produce both FIM and FHA localized to alveoli and caused increased inflammation and histopathology identical to that caused by FIM deficient bacteria, demonstrating that lack of FIM is epistatic to lack of FHA. Coinoculation experiments provided evidence that wild-type B. bronchiseptica suppresses inflammation locally within the respiratory tract and that both FHA and FIM are required for defense against clearance by the innate immune system. Altogether, our data suggest that FIM-mediated adherence to airway epithelium is a critical first step in Bordetella infection that allows FHA-dependent interactions to mediate tight adherence, suppression of inflammation, and resistance to inflammatory cell-mediated clearance. Our results suggest that mucosal antibodies capable of blocking FIM-mediated interactions could prevent bacterial colonization of the lower respiratory tract. IMPORTANCE: Although fimbriae (FIM) have been shown to be important mediators of adherence for many bacterial pathogens, there is surprisingly little experimental evidence supporting this role for Bordetella fimbria. Our results provide the first demonstration that Bordetella FIM function as adhesins in vivo, specifically to airway epithelium. Furthermore, our results suggest that FIM mediate initial interactions with airway epithelial cells that are followed by tight filamentous hemagglutinin (FHA)-mediated binding and that together, FIM and FHA allow Bordetella to suppress inflammation, leading to prolonged colonization. Given the shortcoming of the current acellular component pertussis (aP) vaccine in preventing colonization, these findings suggest that generation of antibodies capable of blocking FIM-mediated adherence could potentially prevent Bordetella colonization. PMID- 26015498 TI - Niemann-pick C1 is essential for ebolavirus replication and pathogenesis in vivo. AB - Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus entry requirements of NPC1 in vitro, its roles in filovirus replication and pathogenesis in vivo remain unclear. Here, we evaluated the importance of NPC1, and its partner in cholesterol transport, NPC2, by using a mouse model of Ebolavirus (EBOV) disease. We found that, whereas wild-type mice had high viral loads and succumbed to EBOV infection, Npc1(-/-) mice were entirely free of viral replication and completely protected from EBOV disease. Interestingly, Npc1(+/-) mice transiently developed high levels of viremia, but were nevertheless substantially protected from EBOV challenge. We also found Npc2(-/-) mice to be fully susceptible to EBOV infection, while Npc1(-/-) mice treated to deplete stored lysosomal cholesterol remained completely resistant to EBOV infection. These results provide mechanistic evidence that NPC1 is directly required for EBOV infection in vivo, with little or no role for NPC1/NPC2-dependent cholesterol transport. Finally, we assessed the in vivo antiviral efficacies of three compounds known to inhibit NPC1 function or NPC1-glycoprotein binding in vitro. Two compounds reduced viral titers in vivo and provided a modest, albeit not statistically significant, degree of protection. Taken together, our results show that NPC1 is critical for replication and pathogenesis in animals and is a bona fide target for development of antifilovirus therapeutics. Additionally, our findings with Npc1(+/-) mice raise the possibility that individuals heterozygous for NPC1 may have a survival advantage in the face of EBOV infection. IMPORTANCE: Researchers have been searching for an essential filovirus receptor for decades, and numerous candidate receptors have been proposed. However, none of the proposed candidate receptors has proven essential in all in vitro scenarios, nor have they proven essential when evaluated using animal models. In this report, we provide the first example of a knockout mouse that is completely refractory to EBOV infection, replication, and disease. The findings detailed here provide the first critical in vivo data illustrating the absolute requirement of NPC1 for filovirus infection in mice. Our work establishes NPC1 as a legitimate target for the development of anti-EBOV therapeutics. However, the limited success of available NPC1 inhibitors to protect mice from EBOV challenge highlights the need for new molecules or approaches to target NPC1 in vivo. PMID- 26015499 TI - HAMP Domain Rotation and Tilting Movements Associated with Signal Transduction in the PhoQ Sensor Kinase. AB - HAMP domains are alpha-helical coiled coils that often transduce signals from extracytoplasmic sensing domains to cytoplasmic domains. Limited structural information has resulted in hypotheses that specific HAMP helix movement changes downstream enzymatic activity. These hypotheses were tested by mutagenesis and cysteine cross-linking analysis of the PhoQ histidine kinase, essential for resistance to antimicrobial peptides in a variety of enteric pathogens. These results support a mechanistic model in which periplasmic signals which induce an activation state generate a rotational movement accompanied by a tilt in alpha helix 1 which activates kinase activity. Biochemical data and a high-confidence model of the PhoQ cytoplasmic domain indicate a possible physical interaction of the HAMP domain with the catalytic domain as necessary for kinase repression. These results support a model of PhoQ activation in which changes in the periplasmic domain lead to conformational movements in the HAMP domain helices which disrupt interaction between the HAMP and the catalytic domains, thus promoting increased kinase activity. IMPORTANCE: Most studies on the HAMP domain signaling states have been performed with chemoreceptors or the HAMP domain of Af1503. Full-length structures of the HAMP-containing histidine kinases VicK and CpxA or a hybrid between the HAMP domain of Af1503 and the EnvZ histidine kinase agree with the parallel four-helix bundle structure identified in Af1503 and provide snapshots of structural conformations experienced by HAMP domains. We took advantage of the fact that we can easily regulate the activation state of PhoQ histidine kinase to study its HAMP domain in the context of the full-length protein in living cells and provide biochemical evidence for different conformational states experienced by Salmonella enterica serovar Typhimurium PhoQ HAMP domain upon signaling. PMID- 26015500 TI - Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection. AB - Toll-like receptors (TLRs) are sensors that recognize molecular patterns from viruses, bacteria, and fungi to initiate innate immune responses to invading pathogens. The emergence of highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) is a concern for global public health, as there is a lack of efficacious vaccine platforms and antiviral therapeutic strategies. Previously, it was shown that MyD88, an adaptor protein necessary for signaling by multiple TLRs, is a required component of the innate immune response to mouse adapted SARS-CoV infection in vivo. Here, we demonstrate that TLR3(-/-), TLR4(-/ ), and TRAM(-/-) mice are more susceptible to SARS-CoV than wild-type mice but experience only transient weight loss with no mortality in response to infection. In contrast, mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss, mortality, reduced lung function, increased lung pathology, and higher viral titers. Distinct alterations in inflammation were present in TRIF(-/-) mice infected with SARS-CoV, including excess infiltration of neutrophils and inflammatory cell types that correlate with increased pathology of other known causes of acute respiratory distress syndrome (ARDS), including influenza virus infections. Aberrant proinflammatory cytokine, chemokine, and interferon-stimulated gene (ISG) signaling programs were also noted following infection of TRIF(-/-) mice that were similar to those seen in human patients with poor disease outcome following SARS-CoV or MERS-CoV infection. These findings highlight the importance of TLR adaptor signaling in generating a balanced protective innate immune response to highly pathogenic coronavirus infections. IMPORTANCE: Toll-like receptors are a family of sensor proteins that enable the immune system to differentiate between "self" and "non self." Agonists and antagonists of TLRs have been proposed to have utility as vaccine adjuvants or antiviral compounds. In the last 15 years, the emergence of highly pathogenic coronaviruses SARS-CoV and MERS-CoV has caused significant disease accompanied by high mortality rates in human populations, but no approved therapeutic treatments or vaccines currently exist. Here, we demonstrate that TLR signaling through the TRIF adaptor protein protects mice from lethal SARS-CoV disease. Our findings indicate that a balanced immune response operating through both TRIF-driven and MyD88-driven pathways likely provides the most effective host cell intrinsic antiviral defense responses to severe SARS-CoV disease, while removal of either branch of TLR signaling causes lethal SARS-CoV disease in our mouse model. These data should inform the design and use of TLR agonists and antagonists in coronavirus-specific vaccine and antiviral strategies. PMID- 26015501 TI - Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. AB - Understanding cellular responses to environmental stimuli requires not only the knowledge of specific regulatory components but also the quantitative characterization of the magnitude and timing of regulatory events. The two component system is one of the major prokaryotic signaling schemes and is the focus of extensive interest in quantitative modeling and investigation of signaling dynamics. Here we report how the binding affinity of the PhoB two component response regulator (RR) to target promoters impacts the level and timing of expression of PhoB-regulated genes. Information content has often been used to assess the degree of conservation for transcription factor (TF)-binding sites. We show that increasing the information content of PhoB-binding sites in designed phoA promoters increased the binding affinity and that the binding affinity and concentration of phosphorylated PhoB (PhoB~P) together dictate the level and timing of expression of phoA promoter variants. For various PhoB regulated promoters with distinct promoter architectures, expression levels appear not to be correlated with TF-binding affinities, in contrast to the intuitive and oversimplified assumption that promoters with higher affinity for a TF tend to have higher expression levels. However, the expression timing of the core set of PhoB-regulated genes correlates well with the binding affinity of PhoB~P to individual promoters and the temporal hierarchy of gene expression appears to be related to the function of gene products during the phosphate starvation response. Modulation of the information content and binding affinity of TF-binding sites may be a common strategy for temporal programming of the expression profile of RR-regulated genes. IMPORTANCE: A single TF often orchestrates the expression of multiple genes in response to environmental stimuli. It is not clear how different TF-binding sites within the regulon dictate the expression profile. Our studies of Escherichia coli PhoB, a response regulator that controls expression of a core set of phosphate assimilation genes in response to phosphate starvation, showed that expression levels of PhoB regulated genes are under sophisticated control and do not follow a simple correlation with the binding affinity of PhoB~P to individual promoters. However, the expression timing correlates with the PhoB-binding affinity and gene functions. Genes involved in direct Pi uptake contain high-affinity sites and are transcribed earlier than genes involved in phosphorus scavenging. This illustrates an elaborate mechanism of temporally programmed gene expression, even for nondevelopmental pathways. PMID- 26015502 TI - A Multiprotein DNA Translocation Complex Directs Intramycelial Plasmid Spreading during Streptomyces Conjugation. AB - Conjugative DNA transfer in mycelial Streptomyces is a unique process involving the transfer of a double-stranded plasmid from the donor into the recipient and the subsequent spreading of the transferred plasmid within the recipient mycelium. This process is associated with growth retardation of the recipient and manifested by the formation of circular inhibition zones, named pocks. To characterize the unique Streptomyces DNA transfer machinery, we replaced each gene of the conjugative 12.1-kbp Streptomyces venezuelae plasmid pSVH1, with the exception of the rep gene required for plasmid replication, with a hexanucleotide sequence. Only deletion of traB, encoding the FtsK-like DNA translocase, affected efficiency of the transfer dramatically and abolished pock formation. Deletion of spdB3, spd79, or spdB2 had a minor effect on transfer but prevented pock formation and intramycelial plasmid spreading. Biochemical characterization of the encoded proteins revealed that the GntR-type regulator TraR recognizes a specific sequence upstream of spdB3, while Orf108, SpdB2, and TraR bind to peptidoglycan. SpdB2 promoted spheroplast formation by T7 lysozyme and formed pores in artificial membranes. Bacterial two-hybrid analyses and chemical cross linking revealed that most of the pSVH1-encoded proteins interacted with each other, suggesting a multiprotein DNA translocation complex of TraB and Spd proteins which directs intramycelial plasmid spreading. IMPORTANCE: Mycelial soil bacteria of the genus Streptomyces evolved specific resistance genes as part of the biosynthetic gene clusters to protect themselves from their own antibiotic, making streptomycetes a huge natural reservoir of antibiotic resistance genes for dissemination by horizontal gene transfer. Streptomyces conjugation is a unique process, visible on agar plates with the mere eye by the formation of circular inhibition zones, called pocks. To understand the Streptomyces conjugative DNA transfer machinery, which does not involve a type IV secretion system (T4SS), we made a thorough investigation of almost all genes/proteins of the model plasmid pSVH1. We identified all genes involved in transfer and intramycelial plasmid spreading and showed that the FtsK-like DNA translocase TraB interacts with multiple plasmid-encoded proteins. Our results suggest the existence of a macromolecular DNA translocation complex that directs intramycelial plasmid spreading. PMID- 26015503 TI - Escape of Actively Secreting Shigella flexneri from ATG8/LC3-Positive Vacuoles Formed during Cell-To-Cell Spread Is Facilitated by IcsB and VirA. AB - The enteropathogenic bacterium Shigella flexneri uses a type 3 secretion apparatus (T3SA) to transfer proteins dubbed translocators and effectors inside host cells, inducing bacterial uptake and subsequent lysis of the entry vacuole. Once in the cytoplasm, the outer membrane protein IcsA induces actin polymerization, enabling cytoplasmic movement and cell-to-cell spread of bacteria. During this infectious process, S. flexneri is targeted by ATG8/LC3. The effector IcsB was proposed to inhibit LC3 recruitment by masking a region of IcsA recognized by the autophagy pathway component ATG5. The effector VirA, a GTPase-activating protein (GAP) for Rab1, was also shown to prevent LC3 recruitment. However, the context of LC3 recruitment around S. flexneri is not fully understood. Here, we show that LC3 is recruited specifically around secreting bacteria that are still present in vacuoles formed during entry and cell-to-cell spread. While LC3 recruitment occurs around a small proportion of intracellular wild-type bacteria, the icsB, virA, and icsB virA mutants display incremental defaults in escape from LC3-positive vacuoles formed during cell-to cell spread. Our results indicate that IcsB and VirA act synergistically to allow bacteria to escape from LC3-positive vacuoles by acting at or in the immediate vicinity of the vacuole membrane(s). We also demonstrate that LC3 is recruited around bacteria still present in the single-membrane entry vacuole, in a manner akin to that seen with LC3-associated phagocytosis. Our results indicate that LC3 recruitment occurs around bacteria still, or already, in membrane compartments formed during entry and cell-to-cell spread, and not around bacteria free in the cytoplasm. IMPORTANCE: The targeting of S. flexneri by LC3 is a classic example of the targeting of foreign cytoplasmic particles by autophagy (so-called "xenoautophagy"). It is often assumed that LC3 is recruited around bacteria present in the cytoplasm through the formation of canonical double-membrane autophagosomes. Our results indicate that LC3 is recruited around the entry vacuole composed of a single membrane as in the case of LC3-associated phagocytosis. Effectors IcsB and VirA had been implicated in the blocking of LC3 recruitment, but it was not known if they acted on the same or distinct LC3 recruiting pathways. Our results indicate that LC3 is recruited exclusively around bacteria present in vacuoles formed during entry and cell-to-cell spread and that both IcsB and VirA intervene at the latter stage to facilitate bacterial escape. Our report reconciles several findings and may have broad implications for our understanding of the specific targeting of bacterial pathogens by LC3. PMID- 26015504 TI - Cytokines: The Good, the Bad, and the Deadly. AB - Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon beta reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor alpha in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions. PMID- 26015505 TI - The role of the induction of mild hypothermia in adult patient outcomes after cardiac arrest: Systematic review and meta-analysis of randomized controlled studies. AB - OBJECTIVE: To determine whether patients with return of spontaneous circulation (ROSC) following cardiac arrest who received mild hypothermia have improved mortality and neurological outcomes compared with those who do not receive mild hypothermia. METHODS: Online database searches were performed for English language randomized controlled trials published before March 2014, comparing mild hypothermia (32-34C) with normothermia or hypothermia other than mild hypothermia after cardiac arrest, in adults with ROSC. Data were independently extracted using a dedicated form. Mortality rates and neurological outcomes were recorded for the overall population and for in-hospital and prehospital mild hypothermia subgroups. RESULTS: Seven articles were identified for inclusion in the meta analysis. Mild hypothermia demonstrated no significant beneficial effects in terms of overall mortality or neurological outcomes. In addition, no significant outcome differences were observed between the pre- and in-hospital subgroups. CONCLUSIONS: On the basis of this limited data set, mild hypothermia does not improve mortality rates or neurological outcomes in patients with ROSC after cardiac arrest, regardless of the timing of the hypothermia. Larger trials need to be carried out to confirm these findings. PMID- 26015506 TI - Video-assisted thoracoscopic surgery in swine: an animal model for thoracoscopic lobectomy training. AB - OBJECTIVES: Minimally invasive thoracic procedures have been increasingly used; however, only a small number of lobectomies are performed by videothoracoscopy, showing the need for training on this technique. The objective of this study is to demonstrate the technique of lobectomy using videothoracoscopy in swine, highlighting the steps to be taken during its use in surgical experimentation. METHODS: During the advanced course on video-assisted and thoracoscopic procedures carried out at IRCAD Latin America, Barretos, Brazil, 40 swine were used for the hands-on course on video-assisted upper left lobectomy. Monopulmonary ventilation was performed by blocking the left main bronchus. Surgical procedures were performed using three ports and the anterior dissection technique (fissureless approach). The pulmonary hilar structures were dissected using conventional open surgery and video-assisted surgical tools. The first structure treated in the approach of the hilar structures was the upper lobe vein, followed by the bronchus and the branches of the pulmonary artery. RESULTS: The mean time required to anaesthetize the animals was 3 h. Intraoperative hypoventilation was observed in 26 animals (65%) and 4 (10%) of them had a poor outcome and died in the last third part of the surgery. Eight (20%) animals had bradycardia, and six responded to the use of atropine. In two (5%), it was not possible to revert the bradycardia and the animals died at the end of the procedures. The surgical procedures had a mean duration of 3 h and the total time of anaesthesia was about 6 h. DISCUSSION: Swine have been frequently used for hands-on training in surgery but there are no reports in the literature describing the anatomical, anaesthetic and technical peculiarities that must be observed during videothoracoscopic lobectomy training in swine. Video-assisted thoracoscopic surgery lobectomy using swine is an adequate method to train thoracic surgeons. For surgeons to make the best use of minimally invasive technique training, it is essential that issues related to the anatomy, anaesthesia, monopulmonary ventilation and surgical technique described in this study are taken into account. PMID- 26015507 TI - Investigation of the vasorelaxant effects of moxonidine and its relaxation mechanism on the human radial artery when used as a coronary bypass graft. AB - OBJECTIVES: In both low- and high-risk patients undergoing coronary artery bypass grafting, the internal mammary artery is the first choice of arterial graft, and the second choice is the radial artery (RA). Unfortunately, RA spasms are a significant problem for a surgical team to overcome in the perioperative and postoperative period. In current surgical practice, the use of vasodilator agents perioperatively in the pending graft preparation is generally accepted and these may be implemented topically, endoluminally or both ways. Moxonidine is the latest second-generation, centrally acting antihypertensive agent, and the intention in this paper is to investigate its direct vasorelaxant effects and relaxation mechanisms on the human radial artery in vitro. METHODS: RA rings were mounted in an organ bath and tested for changes in isometric tension in its relaxation response to moxonidine in the presence and absence of NG-nitro-L arginine methyl ester (L-NAME, non-specific inhibitor of nitric oxide synthase), idazoxan (non-selective I1 and alpha2-antagonist) and yohimbine (selective alpha2 antagonist). RESULTS: Moxonidine induced concentration-dependent relaxations on the RA rings precontracted with phenylephrine (P < 0.05). L-NAME and idazoxan significantly reduced the relaxation caused by moxonidine (P < 0.05), while yohimbine significantly increased the relaxation by moxonidine (P < 0.05). In the presence of L-NAME + idazoxan, the relaxation by moxonidine was eliminated completely (P < 0.05). CONCLUSIONS: We speculate that the relaxant effect of moxonidine may be attributed partly to the synthesis and/or release of nitric oxide, and partly to the stimulation of imidazoline I1 receptors. We suggest that moxonidine may help to prevent RA spasms during the preparation period in operation when used topically or/and endoluminally. PMID- 26015508 TI - Results of videothoracoscopic thymectomy in children: an analysis of 40 patients?. AB - OBJECTIVES: Experience in video-assisted thoracoscopic (VATS) thymectomy is limited in paediatric patients with non-thymomatous myasthenia gravis (MG). The aim of this study is to evaluate the medical status and surgical results of paediatric patients who underwent a VATS thymectomy. METHODS: Of the 367 VATS thymectomies performed for MG patients in our Department of Thoracic Surgery between June 2002 and April 2013, 40 patients were in the paediatric age group. The data were evaluated retrospectively. Age, sex, duration of disease, body mass index, prescribed medication, duration of the operation, complications, chest tube duration, length of postoperative hospital stay and pain score using a visual analogue scale were analysed. RESULTS: The average age was 14.8 +/- 2.2 years (range, 8-18 years), and 27 (68%) patients were female. The electromyography and acetylcholine receptor antibody tests were positive in 30 (75%) and 27 (67%) patients, respectively. The mean quantitative MG score was 11.5 +/- 5.3. The mean prescribed preoperative pyridostigmine bromide dosage was 209 +/- 112 mg. Eleven (27.5%) patients were on corticosteroid treatment and 22 (55%) received intravenous immunoglobulin treatment preoperatively. There were no open conversions or mortalities. The average duration of the operation was 48.9 +/- 31.3 min. All patients were extubated on the table and only one (2.5%) required mechanic ventilation for 18 h postoperatively. Three (7.5%) patients experienced complications. The average duration of chest drainage and postoperative stay were 20.5 +/- 12.1 h and 1.8 +/- 1.0 days, respectively. The average pain score using a visual analogue scale was 2.3 +/- 1.2. CONCLUSIONS: A right-sided VATS thymectomy is a safe procedure in paediatric patients with MG. PMID- 26015509 TI - What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (<50 mg/kg total dose) in cardiac surgery with cardiopulmonary bypass. Evidence from a large randomized controlled trial shows that patients receiving high-dose tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P < 0.001). There is also evidence that this risk of seizure is dose-dependent, with the greatest risk at higher doses of tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the strongest evidence for efficacy. PMID- 26015510 TI - Endovascular repair of a proximal ilio-iliac arterio-venous fistula and distal pseudoaneurysm of the hypogastric artery 23 years after penetrating trauma. AB - We report the treatment of a proximal ilio-iliac arterio-venous fistula and distal omolateral hypogastric artery pseudoaneurysm 23 years after incurring a gunshot wound in a 43-year old man presenting with lower back pain. No cardiac, pulmonary or omolateral lower limb alteration was observed. Endovascular exclusion of the arterio-venous fistula and pseudoaneurysm was performed, which included pseudoaneurysm embolization. Three procedure-related complications were registered. The follow-up at 12 months revealed stent grafts patency, pseudoaneurysm and fistula exclusion. PMID- 26015511 TI - FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers. AB - PURPOSE: FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. EXPERIMENTAL DESIGN: FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors. RESULTS: Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. CONCLUSIONS: FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC. PMID- 26015512 TI - Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy. AB - PURPOSE: Paclitaxel is used worldwide in the treatment of breast, lung, ovarian, and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented, or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCL) and Asian patients. METHODS: GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare with a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human-induced pluripotent stem cells were used for functional validation of candidate genes. RESULTS: SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10(-6)). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphologic changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05), including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphologic characteristics. CONCLUSIONS: We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy. PMID- 26015513 TI - Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions. AB - PURPOSE: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival. EXPERIMENTAL DESIGN: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody-drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification. RESULTS: We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification. CONCLUSIONS: These findings demonstrate the potential of PF-06647263 (anti-EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development. PMID- 26015514 TI - Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2 Positive Breast Tumors Treated with Anti-HER2 Therapy. AB - PURPOSE: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. EXPERIMENTAL DESIGN: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. RESULTS: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER(-)) converted to ER(+) upon anti-HER2 therapy. In ER(-)/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001). CONCLUSIONS: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER dependent survival mechanism potentially leading to anti-HER2 resistance. PMID- 26015516 TI - Head-to-Head Comparison and Evaluation of 92 Plasma Protein Biomarkers for Early Detection of Colorectal Cancer in a True Screening Setting. AB - PURPOSE: Novel noninvasive blood-based screening tests are strongly desirable for early detection of colorectal cancer. We aimed to conduct a head-to-head comparison of the diagnostic performance of 92 plasma-based tumor-associated protein biomarkers for early detection of colorectal cancer in a true screening setting. EXPERIMENTAL DESIGN: Among all available 35 carriers of colorectal cancer and a representative sample of 54 men and women free of colorectal neoplasms recruited in a cohort of screening colonoscopy participants in 2005 2012 (N = 5,516), the plasma levels of 92 protein biomarkers were measured. ROC analyses were conducted to evaluate the diagnostic performance. A multimarker algorithm was developed through the Lasso logistic regression model and validated in an independent validation set. The .632+ bootstrap method was used to adjust for the potential overestimation of diagnostic performance. RESULTS: Seventeen protein markers were identified to show statistically significant differences in plasma levels between colorectal cancer cases and controls. The adjusted area under the ROC curves (AUC) of these 17 individual markers ranged from 0.55 to 0.70. An eight-marker classifier was constructed that increased the adjusted AUC to 0.77 [95% confidence interval (CI), 0.59-0.91]. When validating this algorithm in an independent validation set, the AUC was 0.76 (95% CI, 0.65-0.85), and sensitivities at cutoff levels yielding 80% and 90% specificities were 65% (95% CI, 41-80%) and 44% (95% CI, 24-72%), respectively. CONCLUSIONS: The identified profile of protein biomarkers could contribute to the development of a powerful multimarker blood-based test for early detection of colorectal cancer. PMID- 26015515 TI - Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer. AB - PURPOSE: The aim of this study was to investigate the effect of VEGF-targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC). EXPERIMENTAL DESIGN: Multiple tumor samples (n = 187 samples) were taken from the primary renal tumors of patients with mccRCC who were sunitinib treated (n = 23, SuMR clinical trial) or untreated (n = 23, SCOTRRCC study). ITH of pathologic grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia, and stromal related genes). ITH was analyzed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene-expression clustering. RESULTS: Tumor grade heterogeneity was greater in treated compared with untreated tumors (P = 0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (P < 0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1, and CAIX, occurred in the treated samples. CONCLUSIONS: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy. PMID- 26015517 TI - Biomarkers, assays, and therapies for Alzheimer disease. PMID- 26015520 TI - Endovascular repair of posterior communicating artery aneurysms, associated with oculomotor nerve palsy: A review of nerve recovery. AB - PURPOSE: Oculomotor nerve palsy (ONP) is often the presenting symptom in patients with posterior communicating artery (PCOMM) aneurysms with variable recovery of oculomotor nerve function following treatment. In this study we report the ophthalmologic outcome of 20 patients treated by endovascular coiling for PCOMM aneurysm-induced ONP. METHODS: We performed 230 PCOMM aneurysm endovascular coilings between the years 2006 and 2011, of which 20 cases presented with ONP. We recorded the degree of nerve recovery - complete, partial or none - while also documenting other predictive factors, such as degree of pre-intervention nerve deficit, presence of subarachnoid haemorrhage (SAH), size and location of the PCOMM aneurysm and length of follow-up. RESULTS: Of the 20 patients, 9 (45%) presented with complete ONP and 11 (55%) with partial ONP. After an average follow-up period of 16 months, all patients achieved oculomotor nerve recovery; 9 (45%) patients had complete recovery and 11 (55%) patients had partial recovery. Of the 9 patients who presented with complete ONP, 5 (56%) patients made a complete recovery and 4 (44%) made a partial recovery. Of the 11 patients who initially presented with partial ONP, 4 (36%) made a complete recovery and 7 (64%) made a partial recovery. 7 (35%) patients also had a SAH, of whom 3 (43%) made a complete recovery with 4 (57%) making a partial recovery. CONCLUSIONS: ONP can occur with PCOMM aneurysm with or without SAH. Endovascular coiling is an effective treatment for ONP due to PCOMM aneurysms. PMID- 26015518 TI - Usefulness of interventional embolization of the middle meningeal artery for recurrent chronic subdural hematoma: Five cases and a review of the literature. AB - PURPOSE: Although several strategies against recurrent chronic subdural hematoma (CSDH) have been proposed, no consensus has been established. Recently, middle meningeal artery (MMA) embolization has been proposed as radical treatment for recurrent CSDH. We wanted to estimate the usefulness of MMA embolization for recurrent CSDH. METHODS: From February 2012 to June 2013, 110 patients with CSDH underwent single burr-hole surgery with irrigation and drainage. Among these patients, 13 showed recurrent hematoma formation and were retreated surgically. Furthermore, repeated recurrence of CSDH was observed in six patients. Five of these six patients underwent middle meningeal artery (MMA) embolization with polyvinyl alcohol particles. All five patients with interventional treatment were observed for four to 60 weeks. RESULTS: No more recurrence of CSDH was observed in any of the patients. During the follow-up period, no patients suffered from any side effects or complications from the interventional treatment. CONCLUSION: MMA embolization with careful attention paid to the procedure might be a treatment of choice for recurrent CSDH. PMID- 26015519 TI - Detection of acute femoral artery ischemia during neuroembolization by somatosensory and motor evoked potential monitoring. AB - Neuromonitoring can be used to map out particular neuroanatomical tracts, define physiologic deficits secondary to specific pathology or intervention, or predict postoperative outcome and proves essential in the detection of central and peripheral ischemic events during neurosurgical intervention. Herein, we describe an instance of elective balloon-assisted coiling of a recurrent basilar tip aneurysm in a 61-year-old woman, where intraoperative somatosensory evoked potentials (SSEPs) and transcranial motor evoked potentials (TcMEPs) were lost in the right lower extremity intraoperatively. We aim to highlight that targeted use of monitoring proves advantageous in both the open surgical and endovascular setting, even in the avoidance of potential iatrogenic peripheral nerve damage and limb ischemia as documented herein. Consideration of the increased risk for peripheral ischemia in the neurointerventional setting is especially imperative in particular populations where blood vessels might be of diminished size, such as in infants, young children, and severely deconditioned adults. PMID- 26015521 TI - Open direct carotid artery access for coiling of an intracranial aneurysm under conscious sedation. AB - We describe the case of a 61-year-old patient with significant medical co morbidities and tortuous vascular anatomy presenting with a large middle cerebral artery aneurysm. To avoid the risks of general anesthesia and circumvent a majority of the tortuous vessels, the aneurysm was accessed by direct open exposure of the common carotid artery under conscious sedation and local anesthesia. We were able to achieve complete endovascular occlusion of the aneurysm and the patient tolerated the procedure well with no intra- or post operative complications. Use of conscious sedation is possible and safe for direct open common carotid artery access in patients with significant vascular tortuosity that makes the standard trans-femoral approach difficult or impossible. PMID- 26015522 TI - Long-term occlusion results with SILK flow diversion in 28 aneurysms: Do recanalizations occur during follow-up? AB - BACKGROUND AND PURPOSE: The purpose of this article is to report on the long-term success rates of Silk flow-diverter (FD) treatment in a multicenter prospective study for the treatment of complex aneurysms. METHODS: Between May 2008 and January 2011, all consecutive patients featuring complex intracranial aneurysms eligible for FD treatment with the Silk in three neurovascular centers were included. Clinical and imaging data were assessed during hospitalization and follow-up. RESULTS: Five patients were initially asymptomatic, 20 patients showed various neurological symptoms. Twenty-eight FDs were implanted in 25 patients treating 28 aneurysms. The immediate procedure-related morbidity was 8% (two of 25), mortality 0%. One procedure-related death was observed during follow-up (in stent thrombosis). Compared to the immediate result nearly two of three aneurysms improved during follow-up; all angiographically confirmed inflow changes took place within six months after treatment. Final anatomic outcome in 24 aneurysms of 22 patients comprised 14 (59%) with complete occlusion, seven (29%) with a neck remnant, two (8%) with residual filling <50%, none with residual filling >50% and one (4%) unchanged in comparison to its pretreatment status. Postinterventional recanalizations were seen in three of 13 (23%) aneurysms treated with FD alone; none were observed in 15 aneurysms treated with adjunctive coiling. CONCLUSION: Anatomic presentation and location are key for successful FD treatment. The rate of successful occlusion increases during follow-up. Postinterventional monitoring for at least six months is paramount, as anatomic outcome is not reliably predictable and recanalizations may occur in initially completely occluded aneurysms. PMID- 26015523 TI - Onyx resorbtion with AVM recanalization after complete AVM obliteration. AB - Brain arteriovenous malformations (BAVM) are some of the most complex lesions treated by clinical neuroscientists. The recent publication of the ARUBA trial, showing higher complication rates with treatment compared with the natural history over a short period of follow-up, puts even more pressure on the physician to achieve complete BAVM eradication without complication. These lesions are often treated by multimodality therapy with some combination of endovascular embolization, radiosurgery, and microsurgical resection; however, multimodality therapy involves the additive risk of procedural complication with each procedure. While surgical resection has long been accepted as monotherapy with good cure rates, staged pre-operative endovascular embolization has facilitated microsurgical resection with lower blood loss. Endovascular embolization is more often utilized in conjunction with surgical resection, and often the portions of the AVM and feeders that are completely embolized with Onyx or glue may not be surgically resected since they have been "internally obliterated." We present a case where the AVM was preoperatively embolized with Onyx and subsequently partially surgically resected. Post-operative angiography showed complete obliteration or "cure" of the AVM with no filling of the nidus or early venous drainage. The patient presented 12 months later with seizures and imaging showed volume loss in the residual Onyx cast and recanalization of the AVM nidus. The patient subsequently underwent repeat resection with complete removal of the residual AVM and Onyx cast. To our knowledge this is the first published report of volume loss within the Onyx cast leading to recanalization of the AVM nidus. This suggests that extreme care should be taken with partial resection of the AVM nidus or with embolization for cure, as late recanalization may occur. PMID- 26015524 TI - Flow-diverter stenting in post-traumatic pseudoaneurysm of cavernous internal carotid artery with epistaxis. AB - This paper is a case report of a young patient after a major head trauma causing multiple skull base fractures. The trauma occasioned pseudoaneurysm (PSA) from intracavernous C4 segment of left internal carotid artery (ICA) protruding in the sphenoidal sinus. After two months, two episodes of massive epistaxis occurred. Consequently, the post-traumatic PSA was treated, after carotid occlusion test, with flow-diverter stent positioning. A computed tomography angiography study performed in the following days showed complete resolution of the post-traumatic PSA lesion and ICA patency. PMID- 26015525 TI - Aggressive change of a carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV. AB - The authors report a rare case of a carotid-cavernous fistula (CCF) secondary to Ehlers-Danlos syndrome (EDS) type IV which showed an aggressive angiographical change.A 59-year-old woman presented with headache, right pulsatile tinnitus, and diplopia on the right side. The diagnostic angiography demonstrated a right CCF. Accordingly transarterial embolization of the fistula was attempted 5 days later. The initial right internal carotid angiography showed an aneurysm on the petrous portion of the internal carotid artery (ICA) which was not recognized in the diagnostic angiography. Spontaneous reduction of the shunt flow and long dissection of the ICA were also revealed. The aneurysm was successfully occluded with coils, and only minor shunt flow was shown on the final angiogram. EDS type IV was diagnosed with a skin biopsy for a collagen abnormality. After the operation, the stenosis of the right ICA gradually progressed, although there was no recurrence of the CCF.Interventional treatment for patients with EDS can cause devastating vascular complication. We should be aware of the possibility of EDS type IV when a spontaneous CCF shows unusual angiographical change because early diagnosis of EDS type IV is crucial for determination of the optimum treatment option. PMID- 26015526 TI - Flow diversion in the treatment of carotid injury and carotid-cavernous fistula after transsphenoidal surgery. AB - We describe a case of iatrogenic carotid injury with secondary carotid-cavernous fistula (CCF) treated with a silk flow diverter stent placed within the injured internal carotid artery and coils placed within the cavernous sinus. Flow diverters may offer a simple and potentially safe vessel-sparing option in this rare complication of transsphenoidal surgery. The management options are discussed and the relevant literature is reviewed. PMID- 26015527 TI - Update of vertebral cementoplasty in porotic patients. AB - Vertebroplasty (VP) is a percutaneous mini-invasive technique developed in the late 1980s as antalgic and stabilizing treatment in patients affected by symptomatic vertebral fracture due to porotic disease, traumatic injury and primary or secondary vertebral spine tumors. The technique consists of a simple metameric injection of an inert cement (poly-methyl-methacrylate, PMMA), through a needle by trans-peduncular, parapeduncular or trans-somatic approach obtaining a vertebral augmentation and stabilization effect associated with pain relief. The technique is simple and fast, and should be performed under fluoroscopy or CT guidance in order to obtain a good result with low complication rate. The aim of this paper is to illustrate the utility of VP, the indications-contraindications criteria, how to technically perform the technique using imaging guidance, and the results and complications of this treatment in patients affected by symptomatic vertebral compression fracture. PMID- 26015528 TI - High-flow venous pouch aneurysm in the rabbit carotid artery: A model for large aneurysms. AB - BACKGROUND AND PURPOSE: Currently one of the most widely used models for the development of endovascular techniques and coiling devices for treatment of aneurysm is the elastase-induced aneurysm model in the rabbit carotid artery. Microsurgical techniques for creating an aneurysm with a venous pouch have also been established, although both techniques usually result in aneurysms less than 1 cm in diameter. We investigated whether an increase in blood flow toward the neck would produce larger aneurysms in a microsurgical venous pouch model. MATERIALS AND METHODS: Microsurgical operations were performed on 11 New Zealand white rabbits. Both carotid arteries and the right jugular vein were dissected, and the right carotid artery was temporarily clipped followed by an arteriotomy. The left carotid artery was also clipped proximally, ligated distally, and sutured onto the proximal half of the arteriotomy in the right carotid artery. The venous graft was sutured onto the distal half of the arteriotomy. Digital subtraction angiography was also performed. RESULTS: Angiography showed patent anastomosed vessels and aneurysms in the seven surviving rabbits. Mean aneurysm measurements among surviving rabbits with patent vessels were: 13.9 mm length, 9.3 mm width, and neck diameter 4.7 mm. The resulting mean aspect ratio was 3.35 and the mean bottleneck ratio was 3.05. CONCLUSION: A large venous graft and increased blood flow toward the base of the aneurysm seem to be key factors in the creation of large venous pouch aneurysms. These large aneurysms allow testing of endovascular devices designed for large and giant aneurysms. PMID- 26015529 TI - Direct percutaneous transorbital puncture under fluoroscopic guidance with a 3D skull reconstruction overlay for embolisation of intraorbital and cavernous sinus dural arteriovenous fistulas. AB - OBJECTIVE: To describe the direct percutaneous transorbital puncture technique for embolisation of the selected intraorbital and cavernous sinus dural arteriovenous fistula, which failed to be treated by conventional endovascular techniques. METHODS: One case of intraorbital and five cases of cavernous sinus dural arteriovenous fistula were embolised through direct percutaneous transorbital puncture in 2012, and the clinical data were reviewed. Under fluoroscopic guidance with a three-dimensional (3D) skull reconstruction overlay, the cavernous sinus or ophthalmic vein was punctured via the superior orbital fissure. Then a microcatheter was inserted via the needle, and Onyx was injected to embolise the fistula with or without a combination of coils. RESULTS: Complete obliteration of the fistula was achieved in all six patients. After operation all the patients experienced transient swelling of the punctured orbit persisting for three to five days. No other complications occurred. Follow-up of six patients at three to six months showed resolution of their initial neuro-ophthalmological symptoms in five and left visual loss in one did not recover. Six months follow up angiogram showed no recurrence of these fistulas. CONCLUSION: Direct percutaneous transorbital puncture provides an option for the intraorbital and cavernous sinus dural arteriovenous fistulas, particularly when the conventional transvenous routes are inaccessible. Overlay of the 3D skull reconstruction can facilitate the precise puncture of the superior orbital fissure. PMID- 26015530 TI - Initial experience with the AXERA 2 Femoral Access System in neurovascular procedures. AB - INTRODUCTION: Conventional cerebral angiography is a commonly performed procedure in medicine. Vascular closure devices have been developed as alternatives to manual compression at the arteriotomy site and prolonged bed rest. The risks of using these devices include arterial dissection, groin hematoma, and device failure. Herein, we describe our experience with the use of a novel device used for arterial access and closure, the AXERA 2 Access System. METHODS: A total of 13 patients underwent vascular access and closure with the AXERA 2 Access System. RESULTS: Arterial access using the AXERA 2 Access System was achieved in 11 of 13 patients. Amongst the patients with successful access, one patient experienced a groin hematoma requiring manual compression and two patients suffered occlusions of the common femoral artery due to dissections, with both patients requiring femoral artery thromboendarterectomies. CONCLUSIONS: This small series highlights a heretofore underreported serious complication rate of the AXERA 2 Access System. Additional studies are warranted to provide further insight into risk factors for device failure and complication development. PMID- 26015531 TI - Early middle cerebral artery stenosis following stent-assisted thrombectomy. AB - Stent-assisted thrombectomy (SAT) is an extensively used endovascular treatment method for stroke in which the thrombectomy stents come into direct contact with the vascular intimal surface and entrap the thrombus causing the arterial occlusion. Although there are a few studies that demonstrate that the vessel wall changes in the arteries where stroke intervention is performed, we observed progressive stenosis in early follow-up imaging studies in a case. We present a middle cerebral artery (MCA) stroke patient who had four repetitive stent passes during SAT and developed distal MCA stenosis 2 months after SAT at the control magnetic resonance angiography (MRA). Inclusion of early follow-up MRA studies would be helpful in defining the silent vascular changes in patients who have undergone repetitive SAT. PMID- 26015532 TI - Incidence of delayed angiographic femoral artery complications using the EXOSEAL vascular closure device. AB - BACKGROUND AND PURPOSE: Femoral artery injuries are known complications of percutaneous vascular closure devices (VCDs). We studied the incidence of delayed femoral artery angiographic irregularities after neurointerventional procedures in which the EXOSEAL extravascular closure device was used for femoral arterial puncture closure. METHODS: Adult patients who underwent femoral arterial puncture closures with an EXOSEAL VCD and had a follow-up femoral artery angiogram from June 2012 through August 2013 were reviewed. A blinded radiologist compared pre deployment and follow-up femoral arteriograms for the presence of femoral artery stenosis, dissection, pseudoaneurysm, or development of an arteriovenous fistula. Hospital records were reviewed for major or minor complications of the groin site or femoral artery. RESULTS: The EXOSEAL VCD achieved hemostasis, without evidence of a groin hematoma or requiring subsequent prolonged manual compression, in 400 of 441 closures following transfemoral arterial access, representing a device success rate of 90.7%. A total of 98 patients underwent 102 repeat angiograms following closure with the EXOSEAL VCD. The average time to the repeat angiogram was 73.5 days (range 0-488, median 28). Follow-up femoral arteriography demonstrated an irregularity in seven cases, all of which were vessel stenoses of <50%. There were no dissections, pseudoaneurysms, infections, or ischemic events in the study population. CONCLUSIONS: Angiographic irregularities were seen in 6.86% of cases after closure with the EXOSEAL VCD. There were no clinically significant vascular complications. Thus, femoral artery closure with EXOSEAL carries a low risk of clinically significant delayed angiographic findings. PMID- 26015533 TI - Is "cooling then freezing" a humane way to kill amphibians and reptiles? AB - What is the most humane way to kill amphibians and small reptiles that are used in research? Historically, such animals were often killed by cooling followed by freezing, but this method was outlawed by ethics committees because of concerns that ice-crystals may form in peripheral tissues while the animal is still conscious, putatively causing intense pain. This argument relies on assumptions about the capacity of such animals to feel pain, the thermal thresholds for tissue freezing, the temperature-dependence of nerve-impulse transmission and brain activity, and the magnitude of thermal differentials within the bodies of rapidly-cooling animals. A review of published studies casts doubt on those assumptions, and our laboratory experiments on cane toads (Rhinella marina) show that brain activity declines smoothly during freezing, with no indication of pain perception. Thus, cooling followed by freezing can offer a humane method of killing cane toads, and may be widely applicable to other ectotherms (especially, small species that are rarely active at low body temperatures). More generally, many animal-ethics regulations have little empirical basis, and research on this topic is urgently required in order to reduce animal suffering. PMID- 26015534 TI - The atlas of mouse development eHistology resource. AB - The Atlas of Mouse Development by Professor Mathew Kaufman is an essential text for understanding mouse developmental anatomy. This definitive and authoritative atlas is still in production and is essential for any biologist working with the mouse embryo, although the last revision dates back to 1994. Here, we announce the eHistology online resource that provides free access to high-resolution colour images digitized from the original histological sections (www.emouseatlas.org/emap/eHistology/index.php) used by Kaufman for the Atlas. The images are provided with the original annotations and plate numbering of the paper atlas and enable viewing the material to cellular resolution. PMID- 26015535 TI - At new heights - endodermal lineages in development and disease. AB - The endoderm gives rise to diverse tissues and organs that are essential for the homeostasis and metabolism of the organism: the thymus, thyroid, lungs, liver and pancreas, and the functionally diverse domains of the digestive tract. Classically, the endoderm, the 'innermost germ layer', was in the shadow of the ectoderm and mesoderm. However, at a recent Keystone meeting it took center stage, revealing astonishing progress in dissecting the mechanisms underlying the development and malfunction of the endodermal organs. In vitro cultures of stem and progenitor cells have become widespread, with remarkable success in differentiating three-dimensional organoids, which - in a new turn for the field can be used as disease models. PMID- 26015536 TI - How to make a midbrain dopaminergic neuron. AB - Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed. PMID- 26015537 TI - The origin of the mammalian kidney: implications for recreating the kidney in vitro. AB - The mammalian kidney, the metanephros, is a mesodermal organ classically regarded as arising from the intermediate mesoderm (IM). Indeed, both the ureteric bud (UB), which gives rise to the ureter and the collecting ducts, and the metanephric mesenchyme (MM), which forms the rest of the kidney, derive from the IM. Based on an understanding of the signalling molecules crucial for IM patterning and kidney morphogenesis, several studies have now generated UB or MM, or both, in vitro via the directed differentiation of human pluripotent stem cells. Although these results support the IM origin of the UB and the MM, they challenge the simplistic view of a common progenitor for these two populations, prompting a reanalysis of early patterning events within the IM. Here, we review our understanding of the origin of the UB and the MM in mouse, and discuss how this impacts on kidney regeneration strategies and furthers our understanding of human development. PMID- 26015538 TI - Generation of sensory hair cells by genetic programming with a combination of transcription factors. AB - Mechanosensory hair cells (HCs) are the primary receptors of our senses of hearing and balance. Elucidation of the transcriptional networks regulating HC fate determination and differentiation is crucial not only to understand inner ear development but also to improve cell replacement therapies for hearing disorders. Here, we show that combined expression of the transcription factors Gfi1, Pou4f3 and Atoh1 can induce direct programming towards HC fate, both during in vitro mouse embryonic stem cell differentiation and following ectopic expression in chick embryonic otic epithelium. Induced HCs (iHCs) express numerous HC-specific markers and exhibit polarized membrane protrusions reminiscent of stereociliary bundles. Transcriptome profiling confirms the progressive establishment of a HC-specific gene signature during in vitro iHC programming. Overall, this work provides a novel approach to achieve robust and highly efficient HC production in vitro, which could be used as a model to study HC development and to drive inner ear HC regeneration. PMID- 26015539 TI - Canonical Wnt signalling regulates epithelial patterning by modulating levels of laminins in zebrafish appendages. PMID- 26015540 TI - A small molecule screen identifies a novel compound that induces a homeotic transformation in Hydra. PMID- 26015541 TI - Matrix metalloproteinase 9 modulates collagen matrices and wound repair. AB - Acute and chronic injuries are characterized by leukocyte infiltration into tissues. Although matrix metalloproteinase 9 (Mmp9) has been implicated in both conditions, its role in wound repair remains unclear. We previously reported a zebrafish chronic inflammation mutant caused by an insertion in the hepatocyte growth factor activator inhibitor gene 1 (hai1; also known as spint1) that is characterized by epithelial extrusions and neutrophil infiltration into the fin. Here, we performed a microarray analysis and found increased inflammatory gene expression in the mutant larvae, including a marked increase in mmp9 expression. Depletion of mmp9 partially rescued the chronic inflammation and epithelial phenotypes, in addition to restoring collagen fiber organization, as detected by second-harmonic generation imaging. Additionally, we found that acute wounding induces epithelial cell mmp9 expression and is associated with a thickening of collagen fibers. Interestingly, depletion of mmp9 impaired this collagen fiber reorganization. Moreover, mmp9 depletion impaired tissue regeneration after tail transection, implicating Mmp9 in acute wound repair. Thus, Mmp9 regulates both acute and chronic tissue damage and plays an essential role in collagen reorganization during wound repair. PMID- 26015542 TI - A transcriptional network controlling glial development in the Drosophila visual system. AB - In the nervous system, glial cells need to be specified from a set of progenitor cells. In the developing Drosophila eye, perineurial glia proliferate and differentiate as wrapping glia in response to a neuronal signal conveyed by the FGF receptor pathway. To unravel the underlying transcriptional network we silenced all genes encoding predicted DNA-binding proteins in glial cells using RNAi. Dref and other factors of the TATA box-binding protein-related factor 2 (TRF2) complex were previously predicted to be involved in cellular metabolism and cell growth. Silencing of these genes impaired early glia proliferation and subsequent differentiation. Dref controls proliferation via activation of the Pdm3 transcription factor, whereas glial differentiation is regulated via Dref and the homeodomain protein Cut. Cut expression is controlled independently of Dref by FGF receptor activity. Loss- and gain-of-function studies show that Cut is required for glial differentiation and is sufficient to instruct the formation of membrane protrusions, a hallmark of wrapping glial morphology. Our work discloses a network of transcriptional regulators controlling the progression of a naive perineurial glia towards the fully differentiated wrapping glia. PMID- 26015545 TI - Innexin7a forms junctions that stabilize the basal membrane during cellularization of the blastoderm in Tribolium castaneum. AB - In insects, the fertilized egg undergoes a series of rapid nuclear divisions before the syncytial blastoderm starts to cellularize. Cellularization has been extensively studied in Drosophila melanogaster, but its thick columnar blastoderm is unusual among insects. We therefore set out to describe cellularization in the beetle Tribolium castaneum, the embryos of which exhibit a thin blastoderm of cuboidal cells, like most insects. Using immunohistochemistry, live imaging and transmission electron microscopy, we describe several striking differences to cellularization in Drosophila, including the formation of junctions between the forming basal membrane and the yolk plasmalemma. To identify the nature of this novel junction, we used the parental RNAi technique for a small-scale screen of junction proteins. We find that maternal knockdown of Tribolium innexin7a (Tc inx7a), an ortholog of the Drosophila gap junction gene Innexin 7, leads to failure of cellularization. In Inx7a-depleted eggs, the invaginated plasma membrane retracts when basal cell closure normally begins. Furthermore, transiently expressed tagged Inx7a localizes to the nascent basal membrane of the forming cells in wild-type eggs. We propose that Inx7a forms the newly identified junctions that stabilize the forming basal membrane and enable basal cell closure. We put forward Tribolium as a model for studying a more ancestral mode of cellularization in insects. PMID- 26015544 TI - Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells. AB - The transcription factor brachyury (T, BRA) is one of the first markers of gastrulation and lineage specification in vertebrates. Despite its wide use and importance in stem cell and developmental biology, its functional genomic targets in human cells are largely unknown. Here, we use differentiating human embryonic stem cells to study the role of BRA in activin A-induced endoderm and BMP4 induced mesoderm progenitors. We show that BRA has distinct genome-wide binding landscapes in these two cell populations, and that BRA interacts and collaborates with SMAD1 or SMAD2/3 signalling to regulate the expression of its target genes in a cell-specific manner. Importantly, by manipulating the levels of BRA in cells exposed to different signalling environments, we demonstrate that BRA is essential for mesoderm but not for endoderm formation. Together, our data illuminate the function of BRA in the context of human embryonic development and show that the regulatory role of BRA is context dependent. Our study reinforces the importance of analysing the functions of a transcription factor in different cellular and signalling environments. PMID- 26015543 TI - Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche. AB - Communication between stem and niche supporting cells maintains the homeostasis of adult tissues. Wnt signaling is a crucial regulator of the stem cell niche, but the mechanism that governs Wnt ligand delivery in this compartment has not been fully investigated. We identified that Wnt secretion is partly dependent on Rab8a-mediated anterograde transport of Gpr177 (wntless), a Wnt-specific transmembrane transporter. Gpr177 binds to Rab8a, depletion of which compromises Gpr177 traffic, thereby weakening the secretion of multiple Wnts. Analyses of generic Wnt/beta-catenin targets in Rab8a knockout mouse intestinal crypts indicate reduced signaling activities; maturation of Paneth cells - a Wnt dependent cell type - is severely affected. Rab8a knockout crypts show an expansion of Lgr5(+) and Hopx(+) cells in vivo. However, in vitro, the knockout enteroids exhibit significantly weakened growth that can be partly restored by exogenous Wnts or Gsk3beta inhibitors. Immunogold labeling and surface protein isolation identified decreased plasma membrane localization of Gpr177 in Rab8a knockout Paneth cells and fibroblasts. Upon stimulation by exogenous Wnts, Rab8a deficient cells show ligand-induced Lrp6 phosphorylation and transcriptional reporter activation. Rab8a thus controls Wnt delivery in producing cells and is crucial for Paneth cell maturation. Our data highlight the profound tissue plasticity that occurs in response to stress induced by depletion of a stem cell niche signal. PMID- 26015546 TI - In vitro myelin formation using embryonic stem cells. AB - Myelination in the central nervous system is the process by which oligodendrocytes form myelin sheaths around the axons of neurons. Myelination enables neurons to transmit information more quickly and more efficiently and allows for more complex brain functions; yet, remarkably, the underlying mechanism by which myelination occurs is still not fully understood. A reliable in vitro assay is essential to dissect oligodendrocyte and myelin biology. Hence, we developed a protocol to generate myelinating oligodendrocytes from mouse embryonic stem cells and established a myelin formation assay with embryonic stem cell-derived neurons in microfluidic devices. Myelin formation was quantified using a custom semi-automated method that is suitable for larger scale analysis. Finally, early myelination was followed in real time over several days and the results have led us to propose a new model for myelin formation. PMID- 26015547 TI - Estrogen Receptor alpha Regulates beta-Cell Formation During Pancreas Development and Following Injury. AB - Identifying pathways for beta-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17beta-estradiol (E2) and estrogen receptor (ER) signaling for stimulating beta-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERalpha transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERalpha in beta cells. PDL-induced proliferation of beta-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and beta-cell growth in PDL pancreas were impaired when ERalpha was turned off chemically or genetically (ERalpha(-/-)), whereas in situ delivery of E2 promoted beta-cell formation. In the embryonic pancreas, beta-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERalpha inactivation. The current study reveals that E2 and ERalpha signaling can drive beta-cell replication and formation in mouse pancreas. PMID- 26015548 TI - Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice. AB - Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients. PMID- 26015551 TI - Inner Workings: Inside the mind of a jumping spider. PMID- 26015549 TI - Increased Bile Acid Synthesis and Deconjugation After Biliopancreatic Diversion. AB - Biliopancreatic diversion (BPD) improves insulin sensitivity and decreases serum cholesterol out of proportion with weight loss. Mechanisms of these effects are unknown. One set of proposed contributors to metabolic improvements after bariatric surgeries is bile acids (BAs). We investigated the early and late effects of BPD on plasma BA levels, composition, and markers of BA synthesis in 15 patients with type 2 diabetes (T2D). We compared these to the early and late effects of Roux-en-Y gastric bypass (RYGB) in 22 patients with T2D and 16 with normal glucose tolerance. Seven weeks after BPD, insulin sensitivity had doubled and serum cholesterol had halved. At this time, BA synthesis markers and total plasma BAs, particularly unconjugated BAs, had markedly risen; this effect could not be entirely explained by low FGF19. In contrast, after RYGB, insulin sensitivity improved gradually with weight loss and cholesterol levels declined marginally; BA synthesis markers were decreased at an early time point (2 weeks) after surgery and returned to the normal range 1 year later. These findings indicate that BA synthesis contributes to the decreased serum cholesterol after BPD. Moreover, they suggest a potential role for altered enterohepatic circulation of BAs in improving insulin sensitivity and cholesterol metabolism after BPD. PMID- 26015550 TI - Obesity Appears to Be Associated With Altered Muscle Protein Synthetic and Breakdown Responses to Increased Nutrient Delivery in Older Men, but Not Reduced Muscle Mass or Contractile Function. AB - Obesity is increasing, yet despite the necessity of maintaining muscle mass and function with age, the effect of obesity on muscle protein turnover in older adults remains unknown. Eleven obese (BMI 31.9 +/- 1.1 kg . m(-2)) and 15 healthy weight (BMI 23.4 +/- 0.3 kg . m(-2)) older men (55-75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under postabsorptive (hypoinsulinemic-euglycemic clamp) and postprandial (hyperinsulinemic hyperaminoacidemic-euglycemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whereas leg lean mass, strength, and work done during maximal exercise were no different. Under postabsorptive conditions, MPS and LPB were equivalent between groups, whereas insulin and amino acid administration increased MPS in only healthy-weight subjects and was associated with lower leg glucose disposal (LGD) (63%) in obese men. Blunting of MPS in the obese men was offset by an apparent decline in LPB, which was absent in healthy-weight subjects. Lower postprandial LGD in obese subjects and blunting of MPS responses to amino acids suggest that obesity in older adults is associated with diminished muscle metabolic quality. This does not, however, appear to be associated with lower leg lean mass or strength. PMID- 26015552 TI - Laying a controversial smell theory to rest. PMID- 26015553 TI - Dynamic cross-links tune the solid-fluid behavior of living cells. PMID- 26015554 TI - Stop-loss order for forage fish fisheries. PMID- 26015556 TI - Low Serum Vitamin D Levels Are Associated With Increased Arterial Stiffness in Youth With Type 2 Diabetes. AB - OBJECTIVE: Adult studies demonstrate that low vitamin D (25[OH]D) is an independent risk factor for arterial stiffness. Similar studies have not been conducted in youth with type 2 diabetes mellitus (T2DM). The objective was to elicit the association between 25[OH]D and arterial stiffness in obese youth with and without T2DM. We hypothesized that 25[OH]D would be inversely correlated with arterial stiffness indices, including pulse wave velocity (PWV), augmentation index (AIx), and brachial distensibility (BrachD). RESEARCH DESIGN AND METHODS: Cross-sectional analysis was conducted in Cincinnati, OH, from 2004 to 2010. 25[OH]D, PWV, AIx, and BrachD were measured in 190 youth with T2DM, 190 obese control subjects without T2DM, and 190 lean control subjects without T2DM. Multivariate analyses were conducted to elicit the independent association between 25[OH]D and arterial stiffness indices by group. RESULTS: The mean age was 17.9 +/- 3.4 years, 55% were African American, and 34% were male. The mean 25[OH]D levels were 21.27, 14.29, and 14.13 ng/mL in lean individuals, obese individuals, and obese individuals with T2DM, respectively (P < 0.01). PWV, AIx, and BrachD worsened from lean to obese to T2DM (P < 0.01). General linear models found that 25[OH]D level was independently associated with PWV in lean individuals and with AIx in the group with T2DM such that a 3 ng/mL increase in 25[OH]D was associated with an AIx decrease of 1% (baseline AIx = 5.7 +/- 12.0%). CONCLUSIONS: 25[OH]D is inversely associated with some measures of arterial stiffness in lean adolescents and obese adolescents with T2DM but not in obese normoglycemic adolescents. Future studies are needed to determine if supplemental 25[OH]D is important for cardiovascular health. PMID- 26015557 TI - Impact of Physical Activity on Glycemic Control and Prevalence of Cardiovascular Risk Factors in Adults With Type 1 Diabetes: A Cross-sectional Multicenter Study of 18,028 Patients. AB - OBJECTIVE: Physical activity (PA) can improve cardiovascular risk in the general population and in patients with type 2 diabetes. Studies also indicate an HbA(1c) lowering effect in patients with type 2 diabetes. Since reports in patients with type 1 diabetes are scarce, this analysis aimed to investigate whether there is an association between PA and glycemic control or cardiovascular risk in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 18,028 adults (>=18 to <80 years of age) from Germany and Austria with type 1 diabetes from the Diabetes-Patienten-Verlaufsdokumentation (DPV) database were included. Patients were stratified according to their self-reported frequency of PA (PA0, inactive; PA1, one to two times per week; PA2, more than two times per week). Multivariable regression models were applied for glycemic control, diabetes-related comorbidities, and cardiovascular risk factors. Data were adjusted for sex, age, and diabetes duration. P values for trend were given. SAS 9.4 was used for statistical analysis. RESULTS: An inverse association between PA and HbA(1c), diabetic ketoacidosis, BMI, dyslipidemia (all P < 0.0001), and hypertension (P = 0.0150), as well as between PA and retinopathy or microalbuminuria (both P < 0.0001), was present. Severe hypoglycemia (assistance required) did not differ in PA groups (P = 0.8989), whereas severe hypoglycemia with coma was inversely associated with PA (P < 0.0001). CONCLUSIONS: PA seemed to be beneficial with respect to glycemic control, diabetes-related comorbidities, and cardiovascular risk factors without an increase of adverse events. Hence, our data underscore the recommendation for subjects with type 1 diabetes to perform regular PA. PMID- 26015558 TI - Depressive Symptoms in a Trial Behavioral Family Systems Therapy for Diabetes: A Post Hoc Analysis of Change. AB - OBJECTIVE: The objective was to test whether Behavioral Family Systems Therapy for Diabetes (BFST-D), an evidence-based family therapy, produces individual changes in depressive symptoms for adolescents with type 1 diabetes in suboptimal glycemic control (HbA(1c) >=9.0% [>=74.9 mmol/mol]). RESEARCH DESIGN AND METHODS: Data were from a randomized controlled trial (RCT) comparing two modes of BFST-D delivery: in clinic versus Internet videoconferencing. There were no significant differences between groups in the RCT, so groups were collapsed into a within group prepost design for secondary analyses. A multiple regression analysis was performed to test for mediation of treatment outcomes by changes in family processes. RESULTS: Significant improvements in glycemic control, depressive symptoms, and family functioning were found from pre- to posttreatment. A multiple regression analysis for within-subject mediation indicated that improvements in depressive symptoms were partially mediated by improvements in parent-youth conflict; however, family process changes did not mediate diabetes health outcomes. CONCLUSIONS: In addition to improving treatment adherence and glycemic control, BFST-D has collateral benefits on depressive symptoms. PMID- 26015559 TI - Contemporary Risk Estimates of Three HbA1c Variables for Myocardial Infarction in 101,799 Patients Following Diagnosis of Type 2 Diabetes. AB - OBJECTIVE: This study evaluated the risk of myocardial infarction (MI) by impaired glycemic control in a contemporary large cohort of patients with type 2 diabetes followed from diagnosis. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes diagnosed between 1995 and 2011 were retrieved from the Clinical Practice Research Datalink in the U.K., and followed from diagnosis until event of MI or end of study in 2013. Two subcohorts were defined: an early cohort with those diagnosed from 1997 to 2004 and a recent cohort with those diagnosed from 2004 to 2011. Association between each of three HbA1c metrics and MI was estimated using adjusted proportional hazards models. RESULTS: In the overall cohort (n = 101,799), the risk increase for MI per 1% (10 mmol/mol) increase in HbA(1c) was higher for updated latest and updated mean HbA(1c) of 1.11 (95% CI 1.09-1.13) and 1.15 (1.13-1.18) than for baseline HbA(1c) of 1.05 (1.03-1.06). In the early subcohort, the corresponding risk estimates were greater than those in the recent subcohort. When categorized, the updated latest variable showed an increased risk for HbA(1c) <6% (42 mmol/mol), relative category 6-7%, in the recent but not in the early subcohort, with hazard ratios of 1.23 (1.08-1.40) and 1.01 (0.84-1.22), respectively. CONCLUSIONS: The two time-updated HbA(1c) variables show a stronger relation with MI than baseline HbA(1c). The risk association between HbA(1c) and MI has decreased over time. In recently diagnosed patients with type 2 diabetes, an increased risk of MI exists at a current HbA(1c) of <6.0% (42 mmol/mol). PMID- 26015560 TI - Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites. AB - Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing (14)C-cabozantinib (100 uCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies <=1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 uM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 uM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 uM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL 1644 may represent potential for drug-drug interactions. PMID- 26015561 TI - Correction to: "PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation". PMID- 26015562 TI - Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium. AB - The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis. PMID- 26015563 TI - Defining and identifying Sleeping Beauties in science. AB - A Sleeping Beauty (SB) in science refers to a paper whose importance is not recognized for several years after publication. Its citation history exhibits a long hibernation period followed by a sudden spike of popularity. Previous studies suggest a relative scarcity of SBs. The reliability of this conclusion is, however, heavily dependent on identification methods based on arbitrary threshold parameters for sleeping time and number of citations, applied to small or monodisciplinary bibliographic datasets. Here we present a systematic, large scale, and multidisciplinary analysis of the SB phenomenon in science. We introduce a parameter-free measure that quantifies the extent to which a specific paper can be considered an SB. We apply our method to 22 million scientific papers published in all disciplines of natural and social sciences over a time span longer than a century. Our results reveal that the SB phenomenon is not exceptional. There is a continuous spectrum of delayed recognition where both the hibernation period and the awakening intensity are taken into account. Although many cases of SBs can be identified by looking at monodisciplinary bibliographic data, the SB phenomenon becomes much more apparent with the analysis of multidisciplinary datasets, where we can observe many examples of papers achieving delayed yet exceptional importance in disciplines different from those where they were originally published. Our analysis emphasizes a complex feature of citation dynamics that so far has received little attention, and also provides empirical evidence against the use of short-term citation metrics in the quantification of scientific impact. PMID- 26015565 TI - Elucidating microbial codes to distinguish individuals. PMID- 26015564 TI - Progressive maturation of silent synapses governs the duration of a critical period. AB - During critical periods, all cortical neural circuits are refined to optimize their functional properties. The prevailing notion is that the balance between excitation and inhibition determines the onset and closure of critical periods. In contrast, we show that maturation of silent glutamatergic synapses onto principal neurons was sufficient to govern the duration of the critical period for ocular dominance plasticity in the visual cortex of mice. Specifically, postsynaptic density protein-95 (PSD-95) was absolutely required for experience dependent maturation of silent synapses, and its absence before the onset of critical periods resulted in lifelong juvenile ocular dominance plasticity. Loss of PSD-95 in the visual cortex after the closure of the critical period reinstated silent synapses, resulting in reopening of juvenile-like ocular dominance plasticity. Additionally, silent synapse-based ocular dominance plasticity was largely independent of the inhibitory tone, whose developmental maturation was independent of PSD-95. Moreover, glutamatergic synaptic transmission onto parvalbumin-positive interneurons was unaltered in PSD-95 KO mice. These findings reveal not only that PSD-95-dependent silent synapse maturation in visual cortical principal neurons terminates the critical period for ocular dominance plasticity but also indicate that, in general, once silent synapses are consolidated in any neural circuit, initial experience-dependent functional optimization and critical periods end. PMID- 26015566 TI - Characterization of cooperative bicarbonate uptake into chloroplast stroma in the green alga Chlamydomonas reinhardtii. AB - The supply of inorganic carbon (Ci; CO2 and HCO3 (-)) is an environmental rate limiting factor in aquatic photosynthetic organisms. To overcome the difficulty in acquiring Ci in limiting-CO2 conditions, an active Ci uptake system called the CO2-concentrating mechanism (CCM) is induced to increase CO2 concentrations in the chloroplast stroma. An ATP-binding cassette transporter, HLA3, and a formate/nitrite transporter homolog, LCIA, are reported to be associated with HCO3 (-) uptake [Wang and Spalding (2014) Plant Physiol 166(4):2040-2050]. However, direct evidence of the route of HCO3 (-) uptake from the outside of cells to the chloroplast stroma remains elusive owing to a lack of information on HLA3 localization and comparative analyses of the contribution of HLA3 and LCIA to the CCM. In this study, we revealed that HLA3 and LCIA are localized to the plasma membrane and chloroplast envelope, respectively. Insertion mutants of HLA3 and/or LCIA showed decreased Ci affinities/accumulation, especially in alkaline conditions where HCO3 (-) is the predominant form of Ci. HLA3 and LCIA formed protein complexes independently, and the absence of LCIA decreased HLA3 mRNA accumulation, suggesting the presence of unidentified retrograde signals from the chloroplast to the nucleus to maintain HLA3 mRNA expression. Furthermore, although single overexpression of HLA3 or LCIA in high CO2 conditions did not affect Ci affinity, simultaneous overexpression of HLA3 with LCIA significantly increased Ci affinity/accumulation. These results highlight the HLA3/LCIA-driven cooperative uptake of HCO3 (-) and a key role of LCIA in the maintenance of HLA3 stability as well as Ci affinity/accumulation in the CCM. PMID- 26015567 TI - Outer-membrane translocation of bulky small molecules by passive diffusion. AB - The outer membrane (OM) of gram-negative bacteria forms a protective layer around the cell that serves as a permeability barrier to prevent unrestricted access of noxious substances. The permeability barrier of the OM results partly from the limited pore diameters of OM diffusion channels. As a consequence, there is an "OM size-exclusion limit," and the uptake of bulky molecules with molecular masses of more than ~ 600 Da is thought to be mediated by TonB-dependent, active transporters. Intriguingly, the OM protein CymA from Klebsiella oxytoca does not depend on TonB but nevertheless mediates efficient OM passage of cyclodextrins with diameters of up to ~ 15 A. Here we show, by using X-ray crystallography, molecular dynamics simulations, and single-channel electrophysiology, that CymA forms a monomeric 14-stranded beta-barrel with a large pore that is occluded on the periplasmic side by the N-terminal 15 residues of the protein. Representing a previously unidentified paradigm in OM transport, CymA mediates the passive diffusion of bulky molecules via an elegant transport mechanism in which a mobile element formed by the N terminus acts as a ligand-expelled gate to preserve the permeability barrier of the OM. PMID- 26015568 TI - BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. AB - B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a BCL-2 family protein with high homology to the multidomain proapoptotic proteins BAX and BAK, yet Bok(-/-) and even Bax(-/-)Bok(-/-) and Bak(-/-)Bok(-/-) mice were reported to have no overt phenotype or apoptotic defects in response to a host of classical stress stimuli. These surprising findings were interpreted to reflect functional compensation among the BAX, BAK, and BOK proteins. However, BOK cannot compensate for the severe apoptotic defects of Bax(-/-)Bak(-/-) mice despite its widespread expression. Here, we independently developed Bok(-/-) mice and found that Bok(-/ ) cells are selectively defective in their response to endoplasmic reticulum (ER) stress stimuli, consistent with the predominant subcellular localization of BOK at the ER. Whereas Bok(-/-) mouse embryonic fibroblasts exposed to thapsigargin, A23187, brefeldin A, DTT, geldanamycin, or bortezomib manifested reduced activation of the mitochondrial apoptotic pathway, the death response to other stimuli such as etoposide, staurosporine, or UV remained fully intact. Multiple organs in Bok(-/-) mice exhibited resistance to thapsigargin-induced apoptosis in vivo. Although the ER stress agents activated the unfolded protein response, both ATF4 and CHOP activation were diminished in Bok(-/-) cells and mice. Importantly, BAX and BAK were unable to compensate for the defective apoptotic response to ER stress observed in SV40-transformed and primary Bok(-/-) cells, and in vivo. These findings support a selective and distinguishing role for BOK in regulating the apoptotic response to ER stress, revealing--to our knowledge--the first bona fide apoptotic defect linked to Bok deletion. PMID- 26015569 TI - Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles. AB - Neurotransmission involves the calcium-regulated exocytic fusion of synaptic vesicles (SVs) and the subsequent retrieval of SV membranes followed by reformation of properly sized and shaped SVs. An unresolved question is whether each SV protein is sorted by its own dedicated adaptor or whether sorting is facilitated by association between different SV proteins. We demonstrate that endocytic sorting of the calcium sensor synaptotagmin 1 (Syt1) is mediated by the overlapping activities of the Syt1-associated SV glycoprotein SV2A/B and the endocytic Syt1-adaptor stonin 2 (Stn2). Deletion or knockdown of either SV2A/B or Stn2 results in partial Syt1 loss and missorting of Syt1 to the neuronal surface, whereas deletion of both SV2A/B and Stn2 dramatically exacerbates this phenotype. Selective missorting and degradation of Syt1 in the absence of SV2A/B and Stn2 impairs the efficacy of neurotransmission at hippocampal synapses. These results indicate that endocytic sorting of Syt1 to SVs is mediated by the overlapping activities of SV2A/B and Stn2 and favor a model according to which SV protein sorting is guarded by both cargo-specific mechanisms as well as association between SV proteins. PMID- 26015570 TI - Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy. AB - Tumor-specific molecules are needed across diverse areas of oncology for use in early detection, diagnosis, prognosis and therapy. Large and growing public databases of transcriptome sequencing data (RNA-seq) derived from tumors and normal tissues hold the potential of yielding tumor-specific molecules, but because the data are new they have not been fully explored for this purpose. We have developed custom bioinformatic algorithms and used them with 296 high-grade serous ovarian (HGS-OvCa) tumor and 1,839 normal RNA-seq datasets to identify mRNA isoforms with tumor-specific expression. We rank prioritized isoforms by likelihood of being expressed in HGS-OvCa tumors and not in normal tissues and analyzed 671 top-ranked isoforms by high-throughput RT-qPCR. Six of these isoforms were expressed in a majority of the 12 tumors examined but not in 18 normal tissues. An additional 11 were expressed in most tumors and only one normal tissue, which in most cases was fallopian or colon. Of the 671 isoforms, the topmost 5% (n = 33) ranked based on having tumor-specific or highly restricted normal tissue expression by RT-qPCR analysis are enriched for oncogenic, stem cell/cancer stem cell, and early development loci--including ETV4, FOXM1, LSR, CD9, RAB11FIP4, and FGFRL1. Many of the 33 isoforms are predicted to encode proteins with unique amino acid sequences, which would allow them to be specifically targeted for one or more therapeutic strategies- including monoclonal antibodies and T-cell-based vaccines. The systematic process described herein is readily and rapidly applicable to the more than 30 additional tumor types for which sufficient amounts of RNA-seq already exist. PMID- 26015571 TI - miRNA proxy approach reveals hidden functions of glycosylation. AB - Glycosylation, the most abundant posttranslational modification, holds an unprecedented capacity for altering biological function. Our ability to harness glycosylation as a means to control biological systems is hampered by our inability to pinpoint the specific glycans and corresponding biosynthetic enzymes underlying a biological process. Herein we identify glycosylation enzymes acting as regulatory elements within a pathway using microRNA (miRNA) as a proxy. Leveraging the target network of the miRNA-200 family (miR-200f), regulators of epithelial-to-mesenchymal transition (EMT), we pinpoint genes encoding multiple promesenchymal glycosylation enzymes (glycogenes). We focus on three enzymes, beta-1,3-glucosyltransferase (B3GLCT), beta-galactoside alpha-2,3 sialyltransferase 5 (ST3GAL5), and (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl 1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (ST6GALNAC5), encoding glycans that are difficult to analyze by traditional methods. Silencing these glycogenes phenocopied the effect of miR-200f, inducing mesenchymal-to-epithelial transition. In addition, all three are up-regulated in TGF-beta-induced EMT, suggesting tight integration within the EMT-signaling network. Our work indicates that miRNA can act as a relatively simple proxy to decrypt which glycogenes, including those encoding difficult-to-analyze structures (e.g., proteoglycans, glycolipids), are functionally important in a biological pathway, setting the stage for the rapid identification of glycosylation enzymes driving disease states. PMID- 26015572 TI - Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. AB - CD4(+) regulatory T (Treg) cells expressing CD25 and the transcription factor forkhead box P3 (FOXP3) are indispensable for immunological self-tolerance and homeostasis. FOXP3(+)CD25(+)CD4(+) T cells in humans, however, are heterogeneous in function and differentiation status, including suppressive or nonsuppressive cells as well as resting or activated Treg cells. We have searched for cell surface markers specific for suppression-competent Treg cells by using a panel of currently available monoclonal antibodies reactive with human T cells. We found that CD15s (sialyl Lewis x) was highly specific for activated, terminally differentiated, and most suppressive FOXP3(high) effector Treg (eTreg) cells and able to differentiate them in various clinical settings from nonsuppressive FOXP3(+) T cells secreting inflammatory cytokines. For example, CD15s(+)FOXP3(+) eTreg cells were increased in sarcoidosis, whereas it was nonsuppressive CD15s( )FOXP3(+) T cells that were expanded in lupus flares. FOXP3(+) cells induced from conventional CD4(+) T cells by T-cell receptor stimulation hardly expressed CD15s. CD15s(+)CD4(+) T-cell depletion was sufficient to evoke and enhance in vitro immune responses against tumor or viral antigens. Collectively, we have identified CD15s as a biomarker instrumental in both phenotypic and functional analysis of FOXP3(+)CD4(+) T-cell subpopulations in health and disease. It allows specific targeting of eTreg cells, rather than whole FOXP3(+)CD4(+) T cells, in controlling immune responses. PMID- 26015573 TI - Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes. AB - Invading human leukocyte antigen-G+ (HLA-G+) extravillous trophoblasts (EVT) are rare cells that are believed to play a key role in the prevention of a maternal immune attack on foreign fetal tissues. Here highly purified HLA-G+ EVT and HLA-G villous trophoblasts (VT) were isolated. Culture on fibronectin that EVT encounter on invading the uterus increased HLA-G, EGF-Receptor-2, and LIF Receptor expression on EVT, presumably representing a further differentiation state. Microarray and functional gene set enrichment analysis revealed a striking immune-activating potential for EVT that was absent in VT. Cocultures of HLA-G+ EVT with sample matched decidual natural killer cells (dNK), macrophages, and CD4+ and CD8+ T cells were established. Interaction of EVT with CD4+ T cells resulted in increased numbers of CD4+CD25(HI)FOXP3+CD45RA+ resting regulatory T cells (Treg) and increased the expression level of the Treg-specific transcription factor FOXP3 in these cells. However, EVT did not enhance cytokine secretion in dNK, whereas stimulation of dNK with mitogens or classical natural killer targets confirmed the distinct cytokine secretion profiles of dNK and peripheral blood NK cells (pNK). EVT are specialized cells involved in maternal fetal tolerance, the properties of which are not imitated by HLA-G-expressing surrogate cell lines. PMID- 26015574 TI - Production of extremely low volatile organic compounds from biogenic emissions: Measured yields and atmospheric implications. AB - Oxidation products of monoterpenes and isoprene have a major influence on the global secondary organic aerosol (SOA) burden and the production of atmospheric nanoparticles and cloud condensation nuclei (CCN). Here, we investigate the formation of extremely low volatility organic compounds (ELVOC) from O3 and OH radical oxidation of several monoterpenes and isoprene in a series of laboratory experiments. We show that ELVOC from all precursors are formed within the first minute after the initial attack of an oxidant. We demonstrate that under atmospherically relevant concentrations, species with an endocyclic double bond efficiently produce ELVOC from ozonolysis, whereas the yields from OH radical initiated reactions are smaller. If the double bond is exocyclic or the compound itself is acyclic, ozonolysis produces less ELVOC and the role of the OH radical initiated ELVOC formation is increased. Isoprene oxidation produces marginal quantities of ELVOC regardless of the oxidant. Implementing our laboratory findings into a global modeling framework shows that biogenic SOA formation in general, and ELVOC in particular, play crucial roles in atmospheric CCN production. Monoterpene oxidation products enhance atmospheric new particle formation and growth in most continental regions, thereby increasing CCN concentrations, especially at high values of cloud supersaturation. Isoprene derived SOA tends to suppress atmospheric new particle formation, yet it assists the growth of sub-CCN-size primary particles to CCN. Taking into account compound specific monoterpene emissions has a moderate effect on the modeled global CCN budget. PMID- 26015577 TI - A refined theory of magnetoelastic buckling matches experiments with ferromagnetic and superparamagnetic rods. AB - In its simplest form the magnetoelastic buckling instability refers to the sudden bending transition of an elastic rod experiencing a uniform induction field applied at a normal angle with respect to its long axis. This fundamental physics phenomenon was initially documented in 1968, and, surprisingly, despite many refinements, a gap has always remained between the observations and the theoretical expectations. Here, we first renew the theory with a simple model based on the assumption that the magnetization follows the rod axis as soon as it bends. We demonstrate that the magnetoelastic buckling corresponds to a classical Landau second-order transition. Our model yields a solution for the critical field as well as the shape of the deformed rods which we compare with experiments on flexible ferromagnetic nickel rods at the centimeter scale. We also report this instability at the micrometer scale with specially designed rods made of nanoparticles. We characterized our samples by determining all of the relevant parameters (radius, length, Young modulus, magnetic susceptibility) and, using these values, we found that the theory fits extremely well the experimental results for both systems without any adjustable parameter. The superparamagnetic feature of the microrods also highlights the fact that ferromagnetic systems break the symmetry before the buckling. We propose a magnetic "stick-slip" model to explain this peculiar feature, which was visible in past reports but never detailed. PMID- 26015576 TI - Oxytocin modulates fMRI responses to facial expression in macaques. AB - Increasing evidence has shown that oxytocin (OT), a mammalian hormone, modifies the way social stimuli are perceived and the way they affect behavior. Thus, OT may serve as a treatment for psychiatric disorders, many of which are characterized by dysfunctional social behavior. To explore the neural mechanisms mediating the effects of OT in macaque monkeys, we investigated whether OT would modulate functional magnetic resonance imaging (fMRI) responses in face responsive regions (faces vs. blank screen) evoked by the perception of various facial expressions (neutral, fearful, aggressive, and appeasing). In the placebo condition, we found significantly increased activation for emotional (mainly fearful and appeasing) faces compared with neutral faces across the face responsive regions. OT selectively, and differentially, altered fMRI responses to emotional expressions, significantly reducing responses to both fearful and aggressive faces in face-responsive regions while leaving responses to appeasing as well as neutral faces unchanged. We also found that OT administration selectively reduced functional coupling between the amygdala and areas in the occipital and inferior temporal cortex during the viewing of fearful and aggressive faces, but not during the viewing of neutral or appeasing faces. Taken together, our results indicate homologies between monkeys and humans in the neural circuits mediating the effects of OT. Thus, the monkey may be an ideal animal model to explore the development of OT-based pharmacological strategies for treating patients with dysfunctional social behavior. PMID- 26015578 TI - Correction for O'Donoghue et al., Destructin-1 is a collagen-degrading endopeptidase secreted by Pseudogymnoascus destructans, the causative agent of white-nose syndrome. PMID- 26015575 TI - Reduced endogenous Ca2+ buffering speeds active zone Ca2+ signaling. AB - Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (~ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission. PMID- 26015579 TI - The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. AB - P granules and other RNA/protein bodies are membrane-less organelles that may assemble by intracellular phase separation, similar to the condensation of water vapor into droplets. However, the molecular driving forces and the nature of the condensed phases remain poorly understood. Here, we show that the Caenorhabditis elegans protein LAF-1, a DDX3 RNA helicase found in P granules, phase separates into P granule-like droplets in vitro. We adapt a microrheology technique to precisely measure the viscoelasticity of micrometer-sized LAF-1 droplets, revealing purely viscous properties highly tunable by salt and RNA concentration. RNA decreases viscosity and increases molecular dynamics within the droplet. Single molecule FRET assays suggest that this RNA fluidization results from highly dynamic RNA-protein interactions that emerge close to the droplet phase boundary. We demonstrate than an N-terminal, arginine/glycine rich, intrinsically disordered protein (IDP) domain of LAF-1 is necessary and sufficient for both phase separation and RNA-protein interactions. In vivo, RNAi knockdown of LAF-1 results in the dissolution of P granules in the early embryo, with an apparent submicromolar phase boundary comparable to that measured in vitro. Together, these findings demonstrate that LAF-1 is important for promoting P granule assembly and provide insight into the mechanism by which IDP-driven molecular interactions give rise to liquid phase organelles with tunable properties. PMID- 26015580 TI - BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. AB - Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression. PMID- 26015581 TI - Group discussion improves lie detection. AB - Groups of individuals can sometimes make more accurate judgments than the average individual could make alone. We tested whether this group advantage extends to lie detection, an exceptionally challenging judgment with accuracy rates rarely exceeding chance. In four experiments, we find that groups are consistently more accurate than individuals in distinguishing truths from lies, an effect that comes primarily from an increased ability to correctly identify when a person is lying. These experiments demonstrate that the group advantage in lie detection comes through the process of group discussion, and is not a product of aggregating individual opinions (a "wisdom-of-crowds" effect) or of altering response biases (such as reducing the "truth bias"). Interventions to improve lie detection typically focus on improving individual judgment, a costly and generally ineffective endeavor. Our findings suggest a cheap and simple synergistic approach of enabling group discussion before rendering a judgment. PMID- 26015582 TI - Algorithmic lattice kirigami: A route to pluripotent materials. AB - We use a regular arrangement of kirigami elements to demonstrate an inverse design paradigm for folding a flat surface into complex target configurations. We first present a scheme using arrays of disclination defect pairs on the dual to the honeycomb lattice; by arranging these defect pairs properly with respect to each other and choosing an appropriate fold pattern a target stepped surface can be designed. We then present a more general method that specifies a fixed lattice of kirigami cuts to be performed on a flat sheet. This single pluripotent lattice of cuts permits a wide variety of target surfaces to be programmed into the sheet by varying the folding directions. PMID- 26015583 TI - Different types of multiethnic societies and different patterns of development and change in the prehistoric Near East. AB - After briefly examining the forms of cultural contact in pre- and protohistoric societies in relation to the problem of the varying perception of territories and their "borders" as well as of "membership" in those societies, and after a brief reconsideration of the concept of culture and ethnicity in such archaic contexts, this paper then examines three examples of multiethnic societies in the Near East, and specifically in Upper Mesopotamia and Southeast Anatolia, in the fifth, fourth, and at the beginning of the third millennia before the common era (BCE), respectively. These examples are dealt with as emblematic cases of different models of society, types of interaction with alien groups, levels of integration, and development dynamics. Each of these cases is examined with respect to its socioeconomic context, the archeological evidence of "multiethnicity," the types of interaction between different components, the degree of cultural integration achieved, and the effects on the dynamics of change and the development of the societies examined. By analyzing and comparing these examples, the paper aims to show how interethnic contact impacted differently on different societies according to their types, the reasons and purposes of the interaction, and the degree of integration achieved. PMID- 26015584 TI - Classification images reveal decision variables and strategies in forced choice tasks. AB - Despite decades of research, there is still uncertainty about how people make simple decisions about perceptual stimuli. Most theories assume that perceptual decisions are based on decision variables, which are internal variables that encode task-relevant information. However, decision variables are usually considered to be theoretical constructs that cannot be measured directly, and this often makes it difficult to test theories of perceptual decision making. Here we show how to measure decision variables on individual trials, and we use these measurements to test theories of perceptual decision making more directly than has previously been possible. We measure classification images, which are estimates of templates that observers use to extract information from stimuli. We then calculate the dot product of these classification images with the stimuli to estimate observers' decision variables. Finally, we reconstruct each observer's "decision space," a map that shows the probability of the observer's responses for all values of the decision variables. We use this method to examine decision strategies in two-alternative forced choice (2AFC) tasks, for which there are several competing models. In one experiment, the resulting decision spaces support the difference model, a classic theory of 2AFC decisions. In a second experiment, we find unexpected decision spaces that are not predicted by standard models of 2AFC decisions, and that suggest intrinsic uncertainty or soft thresholding. These experiments give new evidence regarding observers' strategies in 2AFC tasks, and they show how measuring decision variables can answer long standing questions about perceptual decision making. PMID- 26015585 TI - Measurement of true ileal phosphorus digestibility in meat and bone meal for broiler chickens. AB - An experiment was conducted to estimate true ileal phosphorus (P:) digestibility of 3 meat and bone meal samples (MBM-1, MBM-2: , and MBM-3:) for broiler chickens. Four semipurified diets were formulated from each sample to contain graded concentrations of P. The experiment was conducted as a completely randomized design with 6 replicates (6 birds per replicate) per dietary treatment. A total of 432 Ross 308 broilers were assigned at 21 d of age to the 12 test diets. The apparent ileal digestibility coefficient of P was determined by the indicator method, and the linear regression method was used to determine the true P digestibility coefficient. The apparent ileal digestibility coefficient of P in birds fed diets containing MBM-1 and MBM-2 was unaffected by increasing dietary concentrations of P (P > 0.05). The apparent ileal digestibility coefficient of P in birds fed the MBM-3 diets decreased with increasing P concentrations (linear, P < 0.001; quadratic, P < 0. 01). In birds fed the MBM-1 and MBM-2 diets, ileal endogenous P losses were estimated to be 0.049 and 0.142 g/kg DM intake (DMI:), respectively. In birds fed the MBM-3 diets, endogenous P loss was estimated to be negative (-0.370 g/kg DMI). True ileal P digestibility of MBM-1, MBM-2, and MBM-3 was determined to be 0.693, 0.608, and 0.420, respectively. True ileal P digestibility coefficients determined for MBM-1 and MBM-2 were similar (P < 0.05), but were higher (P < 0.05) than that for MBM-3. Total P and true digestible P contents of MBM-1, MBM 2, and MBM-3 were determined to be 37.5 and 26.0; 60.2 and 36.6; and 59.8 and 25.1 g/kg, respectively, on an as-fed basis. PMID- 26015586 TI - Changes in expression of an antimicrobial peptide, digestive enzymes, and nutrient transporters in the intestine of E. praecox-infected chickens. AB - Coccidiosis is a major intestinal disease of poultry, caused by several species of the protozoan Eimeria. The objective of this study was to examine changes in expression of digestive enzymes, nutrient transporters, and an antimicrobial peptide following an Eimeria praecox challenge of chickens at days 3 and 6 post infection. Gene expression was determined by real-time PCR and analyzed by one way ANOVA. In the duodenum, the primary site of E. praecox infection, a number of genes were downregulated at both d3 and d6 post-infection. These genes included liver expressed antimicrobial peptide 2 (LEAP2), the cationic (CAT1), anionic (EAAT3), and L-type (LAT1) amino acid transporters, the peptide transporter PepT1 and the zinc transporter ZnT1. Other transporters were downregulated either at d3 or d6. At both d3 and d6, there was downregulation of B(o)AT and CAT1 in the jejunum and downregulation of LEAP2 and LAT1 in the ileum. LEAP2, EAAT3, and ZnT1 have been found to be downregulated following challenge with other Eimeria species, suggesting a common cellular response to Eimeria. PMID- 26015587 TI - Effects of peroxidized corn oil on performance, AMEn, and abdominal fat pad weight in broiler chicks. AB - There is a trend to use more alternative lipids in poultry diets, either through animal-vegetable blends, distillers corn oil, or yellow grease. This has resulted in the use of lipids in poultry diets with a higher concentration of unsaturated fatty acids, which have a greater potential for peroxidation. The objective of this experiment was to determine the effects of peroxidized corn oil on broiler performance, dietary AMEn, and abdominal fat pad weight. The same refined corn oil sample was divided into 3 subsamples, 2 of which were exposed to different peroxidative processes. The 3 diets contained the unperoxidized corn oil (UO), a slowly peroxidized corn oil (SO; heated for 72 h at 95 degrees C with compressed air flow rate of 12 L/min), or a rapidly peroxidized corn oil (RO; heated for 12 h at 185 degrees C with compressed air flow rate of 12 L/min). Diets were fed from 0 to 14 d of age with each lipid fed at a 5% inclusion rate, continuing on from 15 to 27 d of age with each lipid fed at a 10% inclusion rate. There were 6 Ross 708 broiler chicks per cage with 10 replicates for each of the 3 dietary treatments. Abdominal fat pad and excreta collection was performed on d 27. Body weight gain, feed intake and feed efficiency were measured for the 0 to 14 and 0 to 27 d periods. The increased level of peroxidation reduced AMEn in broiler diets (UO = 3,490 kcal/kg; SO = 3,402 kcal/kg; RO = 3,344 kcal/kg on an as-is basis; SEM = 12.9, P <= 0.01). No significant treatment differences were observed among oil supplemented birds for BW gain, feed intake, feed efficiency, or abdominal fat pad weight. In conclusion, corn oil peroxidation status resulted in a decrease in dietary AMEn, but had minimal effects on broiler performance or fat pad weights. PMID- 26015588 TI - Effect of feeding an encapsulated source of butyric acid (ButiPEARL) on the performance of male Cobb broilers reared to 42 d of age. AB - The objective of this research was to determine the optimal level of an encapsulated butyric acid (ButiPEARL) based on the performance of male Cobb broilers reared to 42 d of age and to investigate its effects on intestinal morphology. Experiment 1 ( EXP 1: ) consisted of 4 treatments with 12 replicate pens that contained 45 broilers, and Experiment 2 ( EXP 2: ) consisted of 6 treatments with 8 replicate pens that contained 50 broilers. Birds were weighed by pen on d 0, 21, 35, and 42. In EXP 1, the treatments were as follows: 1) control ( C: ); 2) C + 100 g ButiPEARL/ton; 3) C + 200 g ButiPEARL/ton; and 4) C + 300 g ButiPEARL/ton. In EXP 2, the treatments were identical to EXP 1, with 2 additional treatments: 5) C + 400 g ButiPEARL/ton and 6) C + 500 g ButiPEARL/ton. In EXP 1, two 42-d-old broilers per pen were randomly selected for duodenal and jejunal tissue collection. Only the samples from the broilers fed the C or 300 g ButiPEARL treatments were analyzed for histology in EXP 1. For EXP 2, on d 21 and 35, two broilers per pen were randomly selected for duodenal, jejunal, and ileal tissue collection. For EXP 1 and 2, BW gain increased linearly with increasing butyric acid levels (P < 0.027 and P < 0.001, respectively). For EXP 1 and 2, feed conversion linearly improved with increasing butyric acid from 0 to 42 d (P < 0.001 and P < 0.001, respectively). In EXP 1, there were no differences in any intestinal morphology at 42 d between broilers fed the C or 300 g ButiPEARL treatments. In EXP 2, there were no differences in villus height at 21 or 35 d of age with any level of butyric acid. Based on the results of this research related to BW gain and feed conversion, the recommended optimum dosage level for ButiPEARL in broilers reared to 42 d of age is up to 500 g/ton. PMID- 26015589 TI - Using near infrared transmittance to generate sorted fractions of Fusarium infected wheat and the impact on broiler performance. AB - The objective of this study was to investigate the effects of naturally contaminated Fusarium wheat containing deoxynivalenol (DON) on growth and performance of broiler chickens from 0 to 35 d. The BoMill TriQ individual kernel sorting technology uses near infrared transmittance (NIT) spectra to separate Fusarium-damaged kernels (FDK) from healthy kernels based on individual kernel CP. Three Fusarium-contaminated wheat sources were individually sorted into 3 test fractions: outlier (10% of the source), high mycotoxin (20% of the source), and low mycotoxin (70% of the source). These fractions were reconstituted into 4 ratios-M0, M20, M40, and M60-relating to the proportion of the high mycotoxin fraction in the reconstituted diets. These 12 reconstituted wheat sources with varying levels of DON were incorporated at ~70% (starter) or ~75% (grower/finisher) into diets. The fractions of wheat used had FDK ranging from 0.1 to 25.8% and DON from 0.0 to 14.3 ppm. A total of 480 newly hatched Ross 308 male broilers were randomly divided into 96 cages. Each test diet was assigned to 8 replicates with 5 birds per replicate cage. At 21 d, 180 birds were transferred to 36 cages, allowing 3 replicates of 5 birds per diet until 35 d. A factorial arrangement analysis compared the 3 wheat sources and 4 ratios produced from each sorted wheat. Growth and performance were evaluated as BW (g), feed intake (FI; g/bird/day), feed conversion ratio (FCR; g:g), AME (kcal ME/kg diet), nitrogen retention (NR; %), and mortality (%) for 0 to 21 d and 21 to 35 d. Results indicate no significant difference in BW, FI, and FCR (P > 0.05). Significant differences were seen in AME and NR (P < 0.01). This study demonstrates the potential of this novel sorting technology to produce naturally contaminated diets with a large range of mycotoxin concentrations from a single wheat source to enable future investigations of mycotoxin exposure in any species. PMID- 26015590 TI - Sensory impact of chemical and natural antimicrobials on poultry products: a review. AB - Antimicrobial agents are added to poultry products after slaughter to prevent the growth of pathogenic and spoilage microorganisms and to extend the shelf-life of these products. Antimicrobials can be either natural or chemical, which may affect the sensory attributes at elevated concentrations, such as surface color, odor, flavor, taste, and texture of the poultry products. Thus, when selecting antimicrobials for use in poultry processing, it is vital to consider the antimicrobial-induced changes in sensory aspects from the consumers' perspectives. In spite of its importance, there has been no systematic review on the influences of antimicrobials on sensory aspects of poultry products. This paper reviews the major antimicrobial agents used in the poultry processing industry and their effects on sensory aspects of the poultry products. PMID- 26015591 TI - Prevalence and characteristics of Salmonella spp. isolated from commercial layer farms in Korea. AB - Salmonellosis is one of the most prevalent foodborne illnesses. The outbreak of this disease is often associated with eggs. In this study, the prevalence and characteristics of Salmonella was surveyed in layer farms in Korea. In addition, the risk factors affecting the prevalence of Salmonella in these farms were also assessed. Of the 32 farms and 67 flocks examined, 19 farms (59.3%) and 34 flocks (50.7%) were observed to be positive for Salmonella contamination. Salmonella was detected in the surrounding environment such as feces (41.8%), dust (40.3%), egg shells (17.2%), as well as the internal egg contents (5.2%). The incidence of Salmonella positives were tended to increase when the flock size is larger (P = 0.021). Differences in the provinces also affected Salmonella prevalence (P < 0.001). The most frequently observed Salmonella serovars in the flocks were Salmonella Bareilly (41.2%), Salmonella Mbandaka (32.4%), and Salmonella Rissen (17.6%). Twenty of the flocks revealed multi-serovar contamination, with the isolation of 2 to 4 serovars. Antimicrobial susceptibility testing revealed that 93 out of 101 isolates were susceptible to the 17 tested antimicrobial agents. The remaining isolates displayed resistance to ampicillin (4.0%), nalidixic acid (3.0%), tetracycline (1.0%), cephalothin (1.0%), and gentamicin (1.0%). As human salmonellosis has been repeatedly correlated to the consumption of poultry products worldwide, continuous studies are required to effectively minimize the Salmonella contamination in layer farms and egg products. PMID- 26015592 TI - Cytotoxic effects of oxytetracycline residues in the bones of broiler chickens following therapeutic oral administration of a water formulation. AB - Tetracyclines, which represent one of the most commonly used antibiotics for poultry, are known to be deposited in bones, where they can remain, despite the observation of appropriate withdrawal times. The aim of the study was to determine the concentration of oxytretracycline (OTC) residues in the bone and muscle of chickens, following the oral administration of a commercially available liquid formulation, and to test their cytotoxic effects on an in vitro cell culture model. Seventy-two 1-day-old broiler chickens were randomly allotted into 2 groups (control and treated animals). OTC (40 mg/kg BW) was administered via drinking water during the 1 to 5 and 20 to 25 days of life periods. At the end of the trial, the birds were slaughtered and the OTC residues in the target tissues were measured by means of liquid chromatography (LC) - tandem mass spectrometry (MS/MS). Cytotoxicity was assessed by evaluating the pro-apoptotic effect of the bone residues on the K562 erythroleukemic line and on the peripheral blood mononuclear cells (PBMC). In all the animals, the OTC residues in the muscle were far below the established MRL of 100 MUg/kg. The OTC levels in the bones of the treated animals were instead found in the parts per million (ppm) range. Cell cytotoxicity was assessed by evaluating the pro-apoptotic effect of OTC bone residues on the haematopoietic cell system. This in vitro system has revealed a significant pro-apoptotic effect on both the K562 cell line and PBMC cultures. This result suggests potential human and animal health risks due to the entry of tetracycline residues contained in the bones of treated livestock into the food chain. This could be of concern, particularly for canine and feline diets, as meat, bone meal, and poultry by-products represent some of the main ingredients of pet foods, especially in the case of dry pet food. Further studies are needed to define the underlying mechanisms of cytotoxicity and to evaluate the in vivo toxicological implications due to the observed in vitro effects. PMID- 26015593 TI - Use of combinations of re-esterified oils, differing in their degree of saturation, in broiler chicken diets. AB - Re-esterified oils contain higher proportions of mono- and diacylglycerols, and also higher proportions of saturated fatty acids (SFA) at the sn-2 position of acylglycerol molecules than does a native oil with the same degree of saturation, which enhances the apparent absorption of SFA. Moreover, as happens with native oils, their nutritive value could be further improved by blending re-esterified oils of extreme degrees of saturation. Therefore, the aim of the current study was to assess the effect of increasing the dietary unsaturated-to-saturated fatty acid ratio (UFA:SFA) by adding re-esterified soybean oil in replacement of re esterified palm oil, on fatty acid (FA) apparent absorption and its consequences on growth performance, carcass fat depots, and FA composition of abdominal adipose tissue. For this purpose, one hundred twenty 1-day-old female broiler chickens were randomly distributed in 30 cages. The 2 pure re-esterified oils, together with 3 re-esterified oil blends, were included in the basal diet at 6%. The increasing dietary UFA:SFA ratio resulted in an improved total FA apparent absorption (linear effect for the starter period, P = 0.001; quadratic effect for the grower-finisher period, P = 0.006) and, therefore, an improved feed conversion ratio (FCR) for the overall period (linear effect, P = 0.003). In the starter period, the improved fat absorption was due to the growing presence of linoleic acid and the enhanced absorption of SFA, mono- and polyunsaturated FA (associative effects among FA; P < 0.05). In the growing-finishing period, however, the absorption of mono- and polyunsaturated FA was not affected (P > 0.05). The UFA:SFA ratio of the abdominal adipose tissue varied in the same direction, but to a lesser extent than that of the diet. Whilst the deposited-to absorbed ratio of polyunsaturated FA remained relatively constant as the dietary UFA:SFA ratio increased, the deposited-to-absorbed ratio of SFA increased, and that of monounsaturated FA decreased. Taken together, the addition of re esterified soybean oil in replacement of re-esterified palm oil improved fat absorption, but no synergism was observed between re-esterified oils. PMID- 26015594 TI - Epithelial and stromal-specific immune pathway activation in the murine endometrium post-coitum. AB - The endometrium is a dynamic tissue, demonstrating cyclical growth/remodelling in preparation for implantation. In mice, seminal constituents trigger mechanisms to prepare the endometrium, a process dubbed 'seminal priming' that modifies immune system components and mediates endometrial remodelling in preparation for pregnancy. An array of cytokines has been reported to mediate this interaction, although much of the literature relates to in vitro studies on isolated endometrial epithelial cells. This study measured changes in immune-related gene expression in endometrial epithelial and stromal cells in vivo following natural mating. CD1 mice were naturally mated and sacrificed over the first 4 days post coitum (n=3 each day). Endometrial epithelial and stromal compartments were isolated by laser capture microdissection. Labelled cRNA was generated and hybridised to genome-wide expression microarrays. Pathway analysis identified several immune-related pathways active within epithelial and stromal compartments, in particular relating to cytokine networks, matrix metalloproteinases and prostaglandin synthesis. Cluster analysis demonstrated that the expression of factors involved in immunomodulation/endometrial remodelling differed between the epithelial and stromal compartments in a temporal fashion. This study is the first to examine the disparate responses of the endometrial epithelial and stromal compartments to seminal plasma in vivo in mice, and demonstrates the complexity of the interactions between these two compartments needed to create a permissive environment for implantation. PMID- 26015595 TI - Impact of Resistance Training in Subjects With COPD: A Systematic Review and Meta Analysis. AB - BACKGROUND: The goal of this study was to evaluate the effects of resistance training on subjects with COPD. METHODS: We performed a systematic search in MEDLINE, PubMed, Embase, CINAHL, Elsevier ScienceDirect, EBM Reviews, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov and also of leading respiratory journals for randomized controlled trials on COPD treatment for >= 4 weeks with resistance training compared with non-exercise control or with combined resistance and endurance training compared with endurance training alone. Data from these studies were pooled to calculate odds ratio and weighted mean differences (WMDs) with 95% CI. RESULTS: Eighteen trials with 750 subjects with advanced COPD met the inclusion criteria. There were 2 primary and 5 secondary outcomes. Compared with non-exercise control, resistance training led to significant improvements in the dyspnea domain of the Chronic Respiratory Disease Questionnaire (WMD of 0.59, 95% CI 0.26-0.93, I2 = 0%, P < .001), skeletal muscle strength, and percent-of-predicted FEV1 (WMD of 6.88%, 95% CI 0.41-13.35%, I2 = 0%, P = .04). The combination of resistance and endurance training significantly improved the St George Respiratory Questionnaire total score (WMD of -7.44, 95% CI -12.62 to -2.25, I2 = 0%, P = .005), each domain score, and skeletal muscle strength. There were no significant differences in 6 min walk distance, 6-min pegboard and ring test, maximum exercise work load, and maximum oxygen consumption between the 2 groups. There were no reports of adverse events related to resistance-training intervention. CONCLUSIONS: Resistance training can be successfully performed alone or in conjunction with endurance training without increased adverse events during pulmonary rehabilitation in COPD. PMID- 26015596 TI - EnD-Seq and AppEnD: sequencing 3' ends to identify nontemplated tails and degradation intermediates. AB - Existing methods for detecting RNA intermediates resulting from exonuclease degradation are low-throughput and laborious. In addition, mapping the 3' ends of RNA molecules to the genome after high-throughput sequencing is challenging, particularly if the 3' ends contain post-transcriptional modifications. To address these problems, we developed EnD-Seq, a high-throughput sequencing protocol that preserves the 3' end of RNA molecules, and AppEnD, a computational method for analyzing high-throughput sequencing data. Together these allow determination of the 3' ends of RNA molecules, including nontemplated additions. Applying EnD-Seq and AppEnD to histone mRNAs revealed that a significant fraction of cytoplasmic histone mRNAs end in one or two uridines, which have replaced the 1-2 nt at the 3' end of mature histone mRNA maintaining the length of the histone transcripts. Histone mRNAs in fly embryos and ovaries show the same pattern, but with different tail nucleotide compositions. We increase the sensitivity of EnD Seq by using cDNA priming to specifically enrich low-abundance tails of known sequence composition allowing identification of degradation intermediates. In addition, we show the broad applicability of our computational approach by using AppEnD to gain insight into 3' additions from diverse types of sequencing data, including data from small capped RNA sequencing and some alternative polyadenylation protocols. PMID- 26015598 TI - Graft choices for anterior cruciate ligament reconstruction. PMID- 26015597 TI - Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo. AB - RNA-regulatory factors bound to 3' UTRs control translation and stability. Repression often is associated with poly(A) removal. The deadenylase CAF1 is a core component of the CCR4-NOT complex. Our prior studies established that CAF1 represses translation independent of deadenylation. We sought the mechanism of its deadenylation-independent repression in Xenopus oocytes. Our data reveal a chain of interacting proteins that links CAF1 to CCR4-NOT and to Xp54 and 4E-T. Association of CAF1 with NOT1, the major subunit of CCR4-NOT, is required for repression by CAF1 tethered to a reporter mRNA. Affinity purification-mass spectrometry and coimmunoprecipitation revealed that at least five members of the CCR4-NOT complex were recruited by CAF1. The recruitment of these proteins required NOT1, as did the ability of tethered CAF1 to repress translation. In turn, NOT1 was needed to recruit Xp54 and 4E-T. We examined the role of 4E-T in repression using mutations that disrupted either eIF4E-dependent or -independent mechanisms. Expression of a 4E-T truncation that still bound eIF4E alleviated repression by tethered CAF1, NOT1, and Xp54. In contrast, a mutant 4E-T that failed to bind eIF4E did not. Repression of global translation was affected only by the eIF4E-dependent mechanism. Reporters bearing IRES elements revealed that repression via tethered CAF1 and Xp54 is cap- and eIF4E-independent, but requires one or more of eIF4A, eIF4B, and eIF4G. We propose that RNA-binding proteins, and perhaps miRNAs, repress translation through an analogous chain of interactions that begin with the 3' UTR-bound repressor and end with the noncanonical activity of 4E-T. PMID- 26015599 TI - Partial tears of anterior cruciate ligament: Results of single bundle augmentation. AB - BACKGROUND: Partial tears of the anterior cruciate ligament (ACL) are common and usually present with symptomatic instability. The remnant fibers are usually removed and a traditional ACL reconstruction is done. But with increased understanding of ACL double bundle anatomy, the remnant tissue preservation along with a single bundle augmentation of the torn bundle is also suggested. The purpose of this study was to evaluate the results of selective anatomic augmentation of symptomatic partial ACL tears. Our hypothesis is that this selective augmentation of partial ACL tears could restore knee stability and function. MATERIALS AND METHODS: Consecutive cases of 314 ACL reconstructions, 40 patients had intact ACL fibers in the location corresponding to the anteromedial (AM) or posterolateral (PL) bundle and were diagnosed as partial ACL tears perioperatively. All patients underwent selective augmentation of the torn bundle, while keeping the remaining fibers intact using autogenous hamstring graft. A total of 38 patients (28 males, 10 females) were available with a minimum of 3 years followup. 26 cases had AM bundle tears and 12 cases had PL bundle tears respectively. Patients were assessed with International Knee Documentation Committee (IKDC) 2000 Knee Evaluation Form, Lysholm score; instrumented knee testing was performed with the arthrometer (KT 2000). Statistical analysis was performed to compare the preoperative and postoperative objective evaluation. RESULTS: At 3 years followup, 31.6% patients were graded A, 65.8% were graded B and 2.6% was graded C at IKDC objective evaluation. Manual laxity tests, Lysholm's score, mean side to side instrumental laxity and Tegner activity score improved significantly. 76% patients returned to preinjury level of sports activity after augmentation. CONCLUSION: The results of anatomic single bundle augmentation in partial ACL tears are encouraging with excellent improvement in functional scores, side to side laxity and return to sports activity. PMID- 26015600 TI - Arthroscopic anatomical double bundle anterior cruciate ligament reconstruction: A prospective longitudinal study. AB - BACKGROUND: Single bundle anterior cruciate ligament (ACL) reconstruction has been the current standard of treatment for ACL deficiency. However, a significant subset of patients continue to report residual symptoms of instability with a poor pivot control. Cadaveric biomechanical studies have shown double bundle (DB) ACL reconstructions to restore the knee kinematics better. This study evaluates the outcome of DB ACL reconstruction. MATERIALS AND METHODS: 30 consecutive patients who underwent anatomic DB ACL reconstruction were included in this prospective longitudinal study. There were all males with a mean age of 25 +/- 7.45 years. All patients were prospectively evaluated using GeNouRoB (GNRB) arthrometer, functional knee scores (International Knee Documentation Committee [IKDC] and Lysholm) and postoperative magnetic resonance imaging (MRI) for comparing the graft orientation and footprint of the reconstructed ACL with that of the normal knee. RESULTS: The average followup was 36.2 months. At the time of final followup the mean Lysholm score was 93.13 +/- 3.31. As per the objective IKDC score, 26 patients (86.6%) were in Group A while 4 patients (13.3%) were in Group B. The mean differential anterior tibial translation by GNRB, arthrometer was 1.07 +/- 0.8 mm (range 0.1-2.3 mm). All cases had a negative pivot shift test. MRI scans of operated and the contralateral normal knee showed the mean sagittal ACL tibial angle coronal ACL tibial angle and tibial ACL footprint to be in accordance with the values of the contralateral, normal knee. CONCLUSION: The study demonstrates that DB ACL reconstruction restores the ACL anatomically in terms of size and angle of orientation. However, long term studies are needed to further substantiate its role in decreasing the incidence of early osteoarthritic changes compared to the conventional single bundle reconstructions. PMID- 26015601 TI - Ultrasonographic test for complete anterior cruciate ligament injury. AB - BACKGROUND: Although ultrasound (US) has a wide range of applications in orthopedic diagnostics, sonographic evaluation of traumatic anterior cruciate ligament (ACL) insufficiency is still inadequate. There is a growing need for diagnostic tests that allow for simple and reliable assessment of ACL instability. This investigation aims to evaluate feasibility of sonographic technique for diagnosing complete ACL insufficiency. MATERIALS AND METHODS: Eighty three consecutive patients suspected of ACL injury were examined with sonographic, dynamic test of anterior instability. The translation of the intercondylar eminence against the patellar tendon was measured in the injured and opposite (injured) knee. Subsequent magnetic resonance imaging was performed on all patients. Forty-seven of them underwent a further arthroscopy. Five patients have been examined for the 2(nd) time to evaluate interclass and intraclass agreement and bias. RESULTS: Complete ACL insufficiency has been confirmed in 37 patients. In those individuals, the total anterior knee translation and the difference between two joints (side-to-side difference) were significantly increased (8.67 mm standard deviation [SD] 2.65 mm in the affected knee versus 2.88 mm SD 1.26 mm in uninjured joint; P < 0.001). Based on a threshold of 2.0 mm for the side-to-side difference and 5.0 mm for the absolute translation, the sonographic test was found to have a sensitivity and specificity of 91.9% and 95.6%, respectively. CONCLUSIONS: The present technique supports the clinician with additional fast and noninvasive diagnostic procedure that can facilitate the evaluation of anterior knee instability. PMID- 26015602 TI - Outcome of transtibial AperFix system in anterior cruciate ligament injuries. AB - BACKGROUND: The anterior cruciate ligament (ACL) is one of the major stabilizing factor of the knee that resist anterior translation, valgus and varus forces. ACL is the most commonly ruptured ligament of the knee. The graft fixation to bone is considered to be the weakest link of the reconstruction. According to the parallel forces to the tibial drill hole and the quality of tibial metaphyseal bone is inferior to femoral bone stock, graft fixation to the tibia is more difficult to secure. AperFix system (Cayenne Medical, Inc., Scottsdale, Arizona, USA) which consists femoral and tibial component that includes bioinert polymer polyetheretherketone (PEEK) is one of the new choice for ACL reconstruction surgery. aim of this study was to assess the clinical outcomes and fixation durability of the AperFix (Cayenne Madical, Inc., Scottsdale, Arizona, USA) system and to determine the effect of patient's age in arthroscopic reconstruction of the anterior cruciate ligament. MATERIALS AND METHODS: Patients with symptomatic anterior cruciate ligament rupture underwent arthroscopic reconstruction. Patients were evaluated in terms of range of motion (ROM) values; Lysholm, Cincinati and Tegner activity scales; laxity testing and complications. Femoral tunnel widening was assessed by computer tomography scans. Early postoperative and last followup radiographs were compared. RESULTS: Fifty one patients were evaluated with mean followup of 29 months (range 25-34 months). Mean age at the surgery was 26.5 +/- 7.2 years. Lysholm, Cincinati and Tegner activity scales were significantly higher from preoperative scores (Lysholm scores: Preoperative: 51.4 +/- 17.2, postoperative: 88.6 +/- 7.7 [P < 0.001]; Tegner activity scores: Preoperative 3.3 +/- 1.38, postoperative: 5.3 +/- 1.6 [P < 0.001]; Cincinati scores: Preoperative: 44.3 +/- 17, postoperative: 81.3 +/- 13.9 [P < 0.001]). The mean femoral tunnel diameter increased significantly from 9.94 +/- 0.79 mm postoperatively to 10.79 +/- 0.95 mm (P < 0.05). The mean ROM deficit (involved vs. contra knee) was -7.2 +/- 16 (P < 0.001). There was no significant difference for knee score, ROM deficits (<30 years: -7.3 +/- 15 and >30 years -7.06 +/- 19) and femoral tunnel enlargement (<30 years: 0.83 +/- 0.52 and >30 years 0.87 +/- 0.43) of the patients with below and above 30 year. There was no significant difference for knee scores and femoral tunnel enlargement between patients with meniscal injuries and don't have meniscus lesions. CONCLUSION: The AperFix system gives satisfactory clinical and radiological results with low complication rate. However, long term clinical and radiological results are needed to decide the ideal anterior cruciate ligament reconstruction method. PMID- 26015603 TI - Outcome of combined autologous chondrocyte implantation and anterior cruciate ligament reconstruction. AB - BACKGROUND: Instability of the knee joint, after anterior cruciate ligament (ACL) injury, is contraindication to osteochondral defect repair. This prospective study is to investigate the role of combined autologous chondrocyte implantation (ACI) with ACL reconstruction. MATERIALS AND METHODS: Three independent groups of patients with previous ACL injuries undergoing ACI were identified and prospectively followed up. The first group had ACI in combination with ACL reconstruction (combined group); the 2(nd) group consisted of individuals who had an ACI procedure having had a previously successful ACL reconstruction (ACL first group); and the third group included patients who had an ACI procedure to a clinically stable knee with documented nonreconstructed ACL disruption (No ACL group). Their outcomes were assessed using the modified cincinnati rating system, the Bentley functional (BF) rating system (BF) and a visual analog scale (VAS). RESULTS: At a mean followup of 64.24 months for the ACL first group, 63 months for combined group and 78.33 months for the No ACL group; 60% of ACL first patients, 72.73% of combined group and 83.33% of the No ACL group felt their outcome was better following surgery. There was no significant difference demonstrated in BF and VAS between the combined and ACL first groups. Results revealed a significant affect of osteochondral defect size on outcome measures. CONCLUSION: The study confirms that ACI in combination with ACL reconstruction is a viable option with similar outcomes as those patients who have had the procedures staged. PMID- 26015604 TI - Magnetic resonance appearance of bioabsorbable anchor screws for double row arthroscopic rotator cuff repairs. AB - BACKGROUND: Little is known about the bioabsorbable, anchor related postoperative changes in rotator cuff surgery, which has become more popular recently. The purpose of the present study was to use magnetic resonance imaging (MRI) to analyze the degradation of bioabsorbable anchors and to determine the incidences and characteristics of early postoperative reactions around the anchors and their mechanical failures. MATERIALS AND METHODS: Postoperative MRIs of 200 patients who underwent arthroscopic rotator cuff repair were retrospectively analyzed. The tissue reactions around the bioanchors included fluid accumulations around the anchor, granulation tissue formation and changes in the condition of the surrounding osseous structure. The condition of the bioanchor itself was also examined, including whether the bioanchor failed mechanically. In the case of mechanical failure, the location of the failure was noted. Serial MRIs of 18 patients were available for analysis. RESULTS: The total number of medial row bioanchors was 124, while that of the lateral row was 338. A low signal intensity rim suggestive of sclerosis surrounded all lateral row bioanchors. Ninety three lateral row bioanchors (27%) showed a rim with signal intensity similar to or less than that of surrounding bone, which was granulation tissue or foreign body reaction (FBR). Similar signal intensity was seen around nine medial row bioanchors (7%). Fluid accumulation was seen around 4 lateral row bioanchors (1%) and around 14 medial row bioanchors (11%). Five lateral row bioanchors showed the breakage, while there was none in the medial row bioanchors. There were nine cases with a cuff re-tear (4.5%). There was no evidence of affection of glenohumeral articular surfaces or of osteolysis around any bioanchor. In serial MRI, there was no change in appearance of the bioanchors, but the granulation tissue or FBR around four bioanchors and the fluid around one bioanchor showed a decrease in successive MRI. CONCLUSION: This study highlights the normal and adverse reactions to Bioabsorbable anchors that surgeons can expect to see on MRI after rotator cuff repairs. PMID- 26015605 TI - Displaced avulsion fractures of the posterior cruciate ligament: Treated by stellate steel plate fixation. AB - BACKGROUND: The open reduction with internal fixation is an effective approach for treatment of avulsion fracture of posterior cruciate ligament. The previously used internal fixation materials including hollow screws, absorbable screw, tension bands and sutures have great defects such as insufficient fixation strength, susceptibility to re-fracture, etc. Stellate steel plate is novel material for internal fixation which has unique gear-like structure design. We used stellate steel plate for treatment of displaced avulsion fractures of posterior cruciate ligament in this study. MATERIALS AND METHODS: 14 patients (9 men, 5 women; aged, 19-35 years; mean age, 28 years) with displaced avulsion fractures of the tibial insertion of the posterior cruciate ligament were retrospectively analyzed between June 2009 and June 2011. The mean duration from injury to the operation was 8.3 days (range 6-15 days). All the patients were treated with open reduction and internal fixation of a stellate steel plate (DePuy, Raynham, MA 02767, USA). The Lysholm-Tegner knee function score criteria were used to analyze results. RESULTS: The mean followup was 24.6 months (range 18-32 months). After 6 months, all the fractures healed and knee joint activity was normal, with no knee stiffness or instability. The Lysholm-Tegner scores were 97.1 +/- 1.7 points at the final followup. CONCLUSION: Owing to its unique gear structure, the stellate steel plate design can effectively fix an avulsion fracture block and it is a simple operation with short postoperative rehabilitation time and firm fixation. PMID- 26015606 TI - Correlation between body mass index and chondral lesions in isolated medial meniscus tears. AB - BACKGROUND: Chondral lesions of the knee are commonly found during arthroscopic partial meniscectomy. The literature advises against arthroscopic medial meniscectomy in the presence of advanced chondral derangement because of unfavorable outcome. Recent studies have shown an association between obesity and chondropathy in patients with meniscal tears. The aim of this study was to assess whether body mass index (BMI) correlates with the severity of chondral lesions in patients with isolated medial meniscus tears (i.e. without ligamentous or lateral meniscal injury). MATERIALS AND METHODS: 837 knee arthroscopies were performed in a regional referral center of arthroscopic surgery between January 2011 and December 2012. Of these 168 (109 males, 59 females) patients with no axial knee deformity and no radiological signs of osteoarthritis who have had arthroscopic debridement for isolated torn medial meniscus were included in the study. The correlation between different demographic factors and the level of chondral damage reported at surgery was evaluated. The mean age of patient was 50 years (range 13-82 years) and an average BMI was 28.2 kg/m(2) (range17.5-42.5 kg/m(2)). RESULTS: Overall, regression analysis showed both age and BMI to be linearly correlated to chondral score (r = 0.53, P < 0.04); however, there were no advanced chondral lesions found in patients younger than 40 years of age and all severe lesions were at age 50 years or more. Therefore, further analysis was performed for age subgroups: patients were grouped as younger than 40, between the age of 40 and 50 (middle age) and older than 50 years. The BMI was linearly correlated to the severity of chondral score exclusively in the middle aged group (i.e. 40-50 years old). There was no correlation between activity level and chondral damage. Women had worse chondral lesions than men in all age groups. CONCLUSION: Higher BMI in middle aged patients with isolated medial meniscus tears and unremarkable radiographs may predict more advanced chondral lesions at arthroscopy. PMID- 26015607 TI - Fate of bone grafting for acetabular defects in total hip replacement. AB - BACKGROUND: The use of allografts and autografts in the management of acetabular defects have been reported with varying results. Trabecular metal is an expensive option in the management of these defects. This study aims to assess the fate and efficacy of bone grafting for acetabular bone defects in total hip arthroplasty. MATERIALS AND METHODS: A total of 30 hips in 28 patients with acetabular deficiencies were treated with bone grafting and total hip replacement (THR). Seventeen hips had American Academy of Orthopedic Surgeons (AAOS) type 2 (Paprosky type 2c) deficiency and 13 had AAOS type 3 (Paprosky type 3a) defects of the acetabulum. Allografts were used in 15 patients and autografts were used in the remaining 13. Cemented total hip arthroplasty was done in 18 hips and uncemented THR in 12. Seven patients underwent the procedure for, acetabular erosion and symptoms following hemiarthroplasty (4 out of 7), or, acetabular revision for failure (3 out of 7) following total hip arthroplasty. Acetabular deficiencies in other patients were due to posttraumatic causes, advanced primary hip arthritis and second stage treatment of postinfective arthritis. A mesh was used in 6 hips and screws were used in 13 hips for graft fixation. RESULTS: Patients were followed up clinicoradiologically for a period of 10 months to 4 years (mean 23.4 months). One patient required staged revision due to infection. Two patients had early asymptomatic cup migration. One patient had graft lysis and change in cup inclination with persistent pain. He was not keen on further intervention at last followup. Other patients were pain free at the time of followup with radiographs showing maintenance of graft and implant position. CONCLUSION: Bone grafting is a suitable option in the management of acetabular defects in total hip arthroplasty, especially in resource challenged countries. PMID- 26015608 TI - Bone impregnated hip screw in femoral neck fracture: Clinicoradiological results. AB - BACKGROUND: Femoral neck fractures are treated either by internal fixation or arthroplasty. Usually, cannulated cancellous screws are used for osteosynthesis of fracture neck of femur. The bone impregnated hip screw (BIHS) is an alternative implant, where osteosyntehsis is required in femoral neck fracture. MATERIALS AND METHODS: The BIHS is a hollow screw with thread diameter 8.3 mm, shank diameter 6.5 mm and wall thickness 2.2 mm and holes in the shaft of the screw with diameter 2 mm, placed in a staggered fashion. Biomechanical and animal experimental studies were done. Clinical study was done in two phases: Phase 1 in a group of volunteers, only with BIHS was used in a pilot study and phase 2 comparative study was done in a group with AO cannulated screws and the other group treated with BIHS. RESULTS: In the phase 1 study, out of 15 patients, only one patient had delayed union. In phase 2, there were 78 patients, 44 patients in BIHS showed early union, compared to the rest 34 cases of AO cannulated screws Out of 44 patients with BIHS, 41 patients had an excellent outcome, 2 had nonunions and one implant breakage was noted. CONCLUSIONS: Bone impregnated hip screw has shown to provide early solid union since it incorporates the biomechanical principles and also increases the osteogenic potential and hence, found superior to conventional cannulated cancellous screw. PMID- 26015609 TI - Comparative study of single lateral locked plating versus double plating in type C bicondylar tibial plateau fractures. AB - BACKGROUND: Bicondylar tibial plateau fractures are complex injuries and treatment is challenging. Ideal method is still controversial with risk of unsatisfactory results if not treated properly. Many different techniques of internal and external fixation are used. This study compares the clinical results in single locked plating versus dual plating (DP) using two incision approaches. Our hypothesis was that DP leads to less collapse and change in alignment at final followup compared with single plating. MATERIALS AND METHODS: 61 cases of Type C tibial plateau fractures operated between January 2007 and June 2011 were included in this prospective study. All cases were operated either by single lateral locked plate by anterolateral approach or double plating through double incision. All cases were followed for a minimum of 24 months radiologically and clinically. The statistical analysis was performed using software SPSS 10.0 to analyze the data. RESULTS: Twenty nine patients in a single lateral locked plate and 32 patients in a double plating group were followed for minimum 2 years. All fractures healed, however there was a significant incidence of malalignment in the single lateral plating group. Though there was a significant increase in soft tissue issues with the double plating group; however, there was only 3.12% incidence of deep infection. There was no significant difference in Hospital for special surgery score at 2 years followup. CONCLUSION: Double plating through two incisions resulted in a better limb alignment and joint reduction with an acceptable soft tissue complication rate. PMID- 26015610 TI - Management of distal femoral periprosthetic fractures by distal femoral locking plate: A retrospective study. AB - BACKGROUND: Management of periprosthetic supracondylar femoral fractures is difficult. Osteoporosis, comminution and bone loss, compromise stability with delayed mobility and poor functional outcomes. Open reduction and internal fixation (ORIF) with anatomic distal femoral (DF) locking plate permits early mobilization. However, this usually necessitates bone grafting (BG). Biological fixation using minimally invasive techniques minimizes periosteal stripping and morbidity. MATERIALS AND METHODS: 31 patients with comminuted periprosthetic DF fractures were reviewed retrospectively from October 2006 to September 2012. All patients underwent fixation using a DF locking compression plate (Synthes). 17 patients underwent ORIF with primary BG, whereas 14 were treated by closed reduction (CR) and internal fixation using biological minimally invasive techniques. Clinical and radiological followup were recorded for an average 36 months. RESULTS: Mean time to union for the entire group was 5.6 months (range 3 9 months). Patients of ORIF group took longer (Mean 6.4 months, range 4.5-9 months) than the CR group (mean 4.6 months, range 3-7 months). Three patients of ORIF and one in CR group had poor results. Mean knee society scores were higher for CR group at 6 months, but nearly identical at 12 months, with similar eventual range of motion. DISCUSSION: Locked plating of comminuted periprosthetic DF fractures permits stable rigid fixation and early mobilization. Fixation using minimally invasive biological techniques minimizes morbidity and may obviate the need for primary BG. PMID- 26015611 TI - Correction of coronal plane deformities around the knee using a tension band plate in children younger than 10 years. AB - BACKGROUND: Guided growth through temporary hemiepiphysiodesis has gained acceptance as the preferred primary treatment in treating pediatric lower limb deformities as it is minimally invasive with a lesser morbidity than the traditional osteotomy. The tension band plate is the most recent development in implants used for temporary hemiepiphysiodesis. Our aim was to determine its safety and efficacy in correcting coronal plane deformities around the knee in children younger than 10 years. MATERIALS AND METHODS: A total of 24 children under the age of 10 were operated for coronal plane deformities around the knee with a single extra periosteal tension band plate and two nonlocking screws. All the children had a pathological deformity for which a detailed preoperative work up was carried out to ascertain the cause of the deformity and rule out physiological ones. The average age at hemiepiphysiodesis was 5 years 3 months (range: 2 years to 9 years 1 month). RESULTS: The plates were inserted for an average of 15.625 months (range: 7 months to 29 months). All the patients showed improvement in the mechanical axis. Two patients showed partial correction. Two cases of screw loosening were observed. In the genu valgum group, the tibiofemoral angle improved from a preoperative mean of 19.89 degrees valgus (range: 10 degrees valgus to 40 degrees valgus) to 5.72 degrees valgus (range: 2 degrees varus to 10 degrees valgus). In patients with genu varum the tibiofemoral angle improved from a mean of 28.27 degrees varus (range: 13 degrees varus to 41 degrees varus) to 1.59 degrees valgus (range: 0-8 degrees valgus). CONCLUSION: Temporary hemiepiphysiodesis through the application of the tension band plate is an effective method to correct coronal plane deformities around the knee with minimal complications. Its ease and accuracy of insertion has extended the indication of temporary hemiepiphysiodesis to patients younger than 10 years and across a wide variety of diagnosis including pathological physis, which were traditionally out of the purview of guided growth. PMID- 26015612 TI - Supination external rotation ankle fractures: A simpler pattern with better outcomes. AB - BACKGROUND: Rotational injuries are the most common and usually classified as per the Lauge Hansen classification; with the most common subgroup being the supination external rotation (SER) mechanism. Isolated fractures of the distal fibula (SE2) without associated ligamentous injury are usually treated with a splint or brace and the patient may be allowed to weight bear as tolerated. This study reports the functional outcomes following a stable, low energy, rotational ankle fracture supination external rotation (SER2) when compared to unstable SER4 fractures treated operatively. MATERIALS AND METHODS: 64 patients who were diagnosed and treated nonoperatively for a stable SER2 ankle fracture were followed prospectively. In the comparison group, 93 operatively treated fibular fractures were extracted from a prospectively collected database and evaluated comparison. Baseline characteristics obtained by trained interviewers at the time of injury included: Patient demographics, short form-36, short musculoskeletal functional assessment (SMFA) and American Orthopedic Foot and Ankle Society (AOFAS) questionnaires. Patients were followed at 3, 6 and 12 months postsurgery. Additional information obtained at each followup point included any complications or evidence on fracture healing. Data were analyzed by the Student's t-test and theFisher's Exact Test to compare demographic and functional outcomes between the two cohorts. P < 0.05 was considered to be significant. RESULTS: The average of patients' age in the stable fracture cohort was 43 versus 45 in the SER4 group. Nearly 64% of the patient population was female when compared with 37% in the operative group. In the SER2 by 6 months all patients had returned to baseline functional status. There were 18 delayed unions (all healed by 6 months). Based on the functional outcome scores all patients had returned to preoperative level. In comparison, SE4 patients had less functional recovery at 3 and 6 months (P < 0.05) based on the SMFA scores and at 3, 6 and 12 months based on the AOFAS (P < 0.001) scores. There was no difference in pain levels between the two groups at all time points. There were three nonunions in the SE4 group and six delayed unions. CONCLUSIONS: An SER2 ankle fracture is a relatively benign injury with functional limitations resolving by 3 months while the need for surgical fixation in SER ankle fractures appears to affect lower extremity function to a greater degree for a longer time period. Patients should be counseled as to these expected outcomes. PMID- 26015613 TI - Measurement technique of calcaneal varus from axial view radiograph. AB - BACKGROUND: Medial displaced posterior calcaneal tubercle creates varus deformity of an intraarticular calcaneal fracture. The fracture involves posterior calcaneal facet and the calcaneal body so we developed a measurement technique representing the angle between posterior facet and long axis of calcaneus using lateral malleolus and longitudinal bone trabeculae of posterior calcaneal tubercle as references to obtain calcaneal varus angle. MATERIALS AND METHODS: 52 axial view calcaneal radiographs of 26 volunteers were studied. Angles between posterior facet and long axis of calcaneus were measured using the measurements 1 and 2. Angle of measurement 1, as gold standard, was obtained from long axis and posterior facet of calcaneus whereas measurement 2 was obtained from a line, perpendicular to apex curve of lateral cortex of the lateral malleolus and a line parallel to the longitudinal bone trabeculae of posterior calcaneal tubercle. No more than 3 degrees of difference in the angle of both measurements was accepted. Reliability of the measurement 2 was statistically tested. RESULTS: Angles of measurement 1 and 2 were 90.04 degrees +/- 4.00 degrees and 90.58 degrees +/- 3.78 degrees . Mean of different degrees of both measurements was 0.54 degrees +/- 2.31 degrees with 95% of confidence interval: 0.10 degrees 1.88 degrees . The statistical analysis of measurement 1 and 2 showed more than 0.75 of ICC and 0.826 of Pearson correlation coefficient. CONCLUSION: Technique of measurement 2 using lateral malleolus and longitudinal bone trabeculae of posterior calcaneal tubercle as references has strong reliability for representing the angle between long axis and posterior facet of calcaneus to achieve calcaneal varus angle. PMID- 26015614 TI - Locking plate versus retrograde intramedullary nail fixation for tibiotalocalcaneal arthrodesis: A retrospective analysis. AB - BACKGROUND: Tibiotalocalcaneal arthrodesis (TTCA) surgery is indicated for the end-stage disease of the tibiotalar and subtalar joints. Although different fixation technique of TTCA has been proposed to achieve high fusion rate and low complication rate, there is still no consensus upon this point. The purpose of this study is to compare the clinical efficacy of retrograde intramedullary nail fixation (RINF) and locking plate fixation (LPF) for TTCA. MATERIALS AND METHODS: Fifty four patients who underwent TTCA through the lateral approach with lateral fibular osteotomy using RINF (32 patients, 18 male/14 female, mean age: 48) or LPF (22 patients, 12 male/10 female, mean age: 51) between January 2007 and January 2010 were retrospectively analyzed. Demographic and clinical characteristics, surgery (operation time, blood loss) outcomes (postoperative fusion rates, visual analog scale and foot and ankle surgery score and complications) were compared. RESULTS: The LPF group had a shorter operation time (72.3 +/- 9.2 vs. 102.8 +/- 11.1 min, P < 0.001), less blood loss (75.9 +/- 20.2 vs. 140.0 +/- 23.8 ml, P < 0.001) and less intraoperative fluoroscopy sessions (3.6 +/- 0.9 vs. 8.4 +/- 1.3, P < 0.001) than the RINF group. Patients were followed up for 12-24 months (mean of 16.2 months). Both groups had similar postoperative fusion rates (90.6% and 95.4%) and the LPF group showed a nonsignificant lower complication rate (18.2% vs. 28.1% respectively). Patients at higher risk on nonunion due to rheumatoid diseases may have a lower nonunion rate with LPF than RINF (one out of eight vs. three out of nine, P < 0.001). CONCLUSIONS: The LPF for TTCA was simpler to perform compared with RINF, but with similar postoperative outcomes and complication rates. PMID- 26015615 TI - Medium term outcomes of primary and revision Coonrad-Morrey total elbow replacement. AB - BACKGROUND: Total elbow replacement (TER) is indicated in inflammatory arthritis, osteoarthritis and fractures that are not amenable to reconstruction. There is no series in literature, to the best of our knowledge, regarding the results of revision of the Souter-Strathclyde prosthesis (SSP) to the Coonrad-Morrey prosthesis (CMP). The aim of this study is to present the medium term results of primary CMP total elbow replacement and revision of the SSP to CMP. MATERIALS AND METHODS: 50 primary CMPs (Group I) and 11 revision CMPs (Group II) were included in the study. Demographic, operative, followup and radiological data were analysed. The indication for revision of the primary implant was peri-prosthetic fracture in six cases, aseptic loosening in four cases and instability in one case. RESULTS: The mean age in Group I was 67.28 +/- 12.45 years and in Group II was 57.09 +/- 11.25 years. The mean period of followup was 8.08 +/- 2.95 years and 7.46 +/- 2.39. There was a significant improvement in range of motion and pain in both groups. The complications seen were nerve palsy, infection, fractures and heterotopic ossification. The 5-year survival rate in Group I was 94%. The results were good in 36 elbows, fair in 8 elbows and poor in 5 elbows. In Group II, the results were good in 8 elbows, fair in 2 elbows and poor in 1 elbow. The complications seen were nerve palsy, fractures and heterotopic ossification. DISCUSSION: Primary CMP TER provides a functionally useful range of movement of 100 degrees which is enough to perform most activities of daily living. It also produces a pain free and stable joint. Similar results are achieved after revision of the SSP to CMP. The unique toggle-hinge mechanism of articulation provides inherent stability and good survivorship. CONCLUSION: Semiconstrained prostheses like CMP provide good functional results and survivorship and are the implant of choice in both primary and revision total elbow replacements. PMID- 26015616 TI - Fractalkine receptor chemokine (CX3CR1) influences on cervical and lumbar disc herniation. AB - BACKGROUND: Herniation of nuclear or disc material along with, inflammatory chemokines such as prostaglandin E2, interleukin-6, matrix metalloproteinase and nitric oxide has definite correlation, possibly they are over produced. CX3CL1 and its receptor (CX3CR1) are part of chemokine system involved in leukocyte recruitment and adhesion in chronic inflammatory disease, but its role in spinal herniated nucleus pulposus (HNP) is unknown. We evaluated the expression of CX3CL1 and CX3CR1 in patients with disc herniation to clarify the role of CX3CL1 and CX3CR1 in the disc degeneration and to compare between cervical and lumbar HNP. MATERIALS AND METHODS: The mRNA concentrations of CX3CL1/CX3CR1 chemokine were analyzed in the surgically obtained disc specimens from C-HNP (n = 13) and L HNP (n = 13) by real-time polymerase chain reaction (PCR). The localization of CX3CL1/CX3CR1 chemokine in the disc of C-HNP and L-HNP patients was determined using immunohistochemical study. Blood samples from patients with C-HNP and L-HNP patients were stained for CX3CR1 with flow cytometric analysis. RESULTS: The CX3CL1 positive cell ratio in the discs was observed in both groups by immunohistochemical study. CX3CR1 was strongly expressed on endothelial cells in C-spine disc, but sparely expressed in L-spine disc. There was greater CX3CR1 mRNA expression in C-HNP patients than in L-HNP patients as quantified by reversal transcription-PCR (P = 0.010). CX3CR1 positive cell frequencies and CX3CR1 expression levels were increased in CD4 (+) T-cells and natural killer (NK) cells from patients with C-HNP (P = 0.210 and P = 0.040). CONCLUSIONS: This study identified that increases in CX3CL1 and CX3CR1-expressing cells are significantly related to pathomechanism of HNP for the first time. Especially, CD4 (+) T-cells and NK cells expressing CX3CR1 may play an important role in developing C-HNP. PMID- 26015617 TI - Percutaneous vertebroplasty for single osteoporotic vertebral body compression fracture: Results of unilateral 3-D percutaneous puncture technique. AB - BACKGROUND: Percutaneous vertebroplasty (PVP) has been gradually used for osteoporotic vertebral compression fracture (OVCF) treatment, but severe osteoporotic vertebral body compression fractures (sOVCFs) due to the difficulty in performing a puncture and the characteristics of the fractured vertebrae, it has been considered as a contraindication to PVP. The aim of the following study was to evaluate the feasibility of a unilateral, three-dimensional (3D), accurate puncture in percutaneous vertebroplasty (PVP) for a single, severely osteoporotic vertebral body compression fracture (ssOVCFs). MATERIALS AND METHODS: 57 patients received PVP in the current study. Feasibility of a unilateral approach was judged before surgery using the 64-slice helical computed tomography (CT) multiplanar reconstruction technique, a 3D accurate puncture plan was then determined. The skin bone distance, puncture angle and needle insertion depth were recorded during surgery. 2D CT rechecking was performed for any complication at day 1 after operation. Preoperative and postoperative numerical data were compared. RESULTS: The procedure was completed smoothly in all patients. 2D CT scanning at day 1 after operation did not show any puncture related complications. Visual analog scoring (VAS) showed that the score at day 3 after surgery was reduced to 1.7 +/- 0.4 (0-2.9 scale) from the preoperative 7.9 +/- 2.1 (6.1-9.5 scale). No significant differences in measure numerical data were found before and after the surgery. At 12 months followup three patients presented with nonadjacent level fractures, VAS for other patients were 1.2 +/- 0.3 (0-2.1 scale). CONCLUSIONS: Application of CT scanning for a unilateral 3D puncture design helps realize an accurate puncture in PVP. It is a safe and effective method for ssOVCFs treatment. PMID- 26015618 TI - Arthroscopic one-piece reshaping for symptomatic discoid medial meniscus with anomalous amalgamating into anterior cruciate ligament. AB - Discoid shapes of lateral menisci are relatively common finding, whereas discoid medial menisci are less common. Discoid medial meniscus with associated anomalous variants has been reported. However, symptomatic complex tear of complete type discoid medial meniscus with anomalous blending with anterior cruciate ligament is an extremely rare pathology. A 35-year-old male was admitted to our hospital with left knee pain and loss of terminal extension for 2 years. On physical examination, the patient presented with clicking and restriction during the extension motion of the knee joint. Magnetic resonance imaging and arthroscopy indicated complex tear of complete discoid medial meniscus in association with anomalous connection between entire apical portion of discoid medial meniscus and tibial insertion portion of the anterior cruciate ligament. We obtained a successful outcome with arthroscopic resection and shaping in one-piece method using no. 11 scalpel blade. PMID- 26015619 TI - Anterior fracture dislocation of sacroiliac joint: A rare type of crescent fracture. AB - Crescent fractures of the pelvis are usually described as posterior sacro iliac fracture dislocations. Rarely anterior displacement of the fractured iliac fragment along with dislocation has been reported in crescent fractures. Four cases of anterior fracture dislocation of the sacro iliac joint managed in the last two years by a single surgeon are presented. The injury mechanism, radiological diagnosis, management protocol along with functional outcomes of all the four patients have been discussed. CT scan is essential in the diagnosis and preoperative planning of this injury pattern. Early fixation along with proper reduction leads to excellent functional outcome in this subset of lateral compression injuries of the pelvis. PMID- 26015620 TI - Intraarticular osteochondroma of the knee. PMID- 26015621 TI - Author's reply. PMID- 26015622 TI - Microendoscopic lumbar discectomy: Technique and results of 188 cases. PMID- 26015623 TI - Author's reply. PMID- 26015624 TI - Nonsurgical factors of digital replantation and survival rate: A metaanalysis. AB - The aim of this metaanalysis was to evaluate the association between nonsurgical factors and survival rate of digital replantation. A computer search of MEDLINE, OVID, EMBASE and CNKI databases was conducted to identify literatures for digital replantation, with the keywords of "digit," "finger" and "replantation" from their inception to June 10, 2014. Based on the inclusion and exclusion criteria, data were extracted independently by two authors using piloted forms. Review Manager 5.2 software was used for data analysis. The effect of some nonsurgical factors (gender, age, amputated finger, injury mechanisms, ischemia time and the way of preservation) on the survival rate of digital replantation was assessed. The metaanalysis result suggested that gender and ischemia time had no significant influence on the survival rate of amputation replantation. However, the survival rate of digital replantation of adults was significantly higher than that of children. The guillotine injury of a finger was easier to replant successfully than the crush and avulsion. The little finger was more difficult for replantation than thumb. Survival rate of fingers stored in low temperature was higher than that in common temperature. The present metaanalysis suggested that age, injury mechanism, amputated finger and the way of preservation were significantly associated with the survival rate of digital replantation. PMID- 26015625 TI - Morphometric analysis of the seventh cervical vertebra for pedicle screw insertion. AB - BACKGROUND: Anatomy of the pedicles of the seventh cervical vertebra (C7) at the cervicothoracic junction is different from other cervical vertebrae. Fixation of C7 is required during cervical vertebra and upper thoracic injuries in clinical practice. However, the typical pedicle screw insertion methods may have problems in clinical practice based on the anatomical features of C7. This study is to explore a new pedicle screw insertion technique for C7 and to provide anatomical and radiographic basis for clinical application. MATERIALS AND METHODS: C7 vertebral specimens from six human cadavers were observed for the relative position between the posterior bony landmark and the pedicle projection. Computed tomography (CT) was performed for 30 patients with cervical spondylosis (26-61 years old, mean age was 42.3 years old). The CT scan data were processed by Mimics 8.1 software for associated parameter measurement. Appropriate screw entry points (Eps) and insertion angles were selected. A total of 12 pedicle screws were inserted and then observed. The six specimens were observed after inserting the screw using this method. The junction site of the middle 1/3 and outer 1/3 segment of line G [The junction between point A (the intersection point of the superior margin of the lamina of C7 and the medial margin of the superior articular process) and point B (the intersection point of the lateral margin of the inferior articular process and the transverse process)] was taken as the Ep. The screw insertion direction parallel horizontally to the upper terminal lamina of C7 and the sagittal angle was between 35 degrees and 45 degrees . RESULTS: Gross and imaging observations revealed that pedicle projection was on the line (line G) between point A (the intersection point of the superior margin of the lamina of C7 and the medial margin of the superior articular process) and point B (the intersection point of the lateral margin of the inferior articular process and the transverse process) and located at the middle 1/3 and outer 1/3 segments of the line (point L[also it is the screw entry points (Eps)]. No significant difference in the measurements on the left and right sides were observed (P > 0.05). No penetration of the 12 screws through pedicle was observed. CONCLUSION: The junction site of the middle 1/3 and outer 1/3 segments of line G are the projection points of C7 pedicles on the lateral mass. The junction site anatomical position was simply and easy to be controlled during surgery, simultaneously avoided uncertainty of other methods. This study provides a new method for determining an Ep for C7 pedicle screw insertion. PMID- 26015626 TI - Mini posterior lumbar interbody fusion with presacral screw stabilization in early lumbosacral instability. AB - BACKGROUND: Surgical options for the management of early lumbosacral spondylolisthesis and degenerative disc disease with instability vary from open lumbar interbody fusion with transpedicular fixation to a variety of minimal access fusion and fixation procedures. We have used a combination of micro discectomy and axial lumbosacral interbody fusion with presacral screw fixation to treat symptomatic patients with lumbosacral spondylolisthesis or lumbosacral degenerative disc disease, which needed surgical stabilization. This study describes the above technique along with analysis of results. MATERIALS AND METHODS: Twelve patients with symptomatic lumbosacral (L5-S1) instability and degenerative lumbosacral disc disease were treated by micro discectomy and interbody fusion using presacral screw stabilization. Patients with history of bowel, bladder dysfunction and local anorectal diseases were excluded from this study. Postoperatively all patients were evaluated neurologically and radiologically for screw position, fusion and stability. Oswestry disability index was used to evaluate results. RESULTS: We had nine females and three males with a mean age of 47.33 years (range 26-68 years). Postoperative assessment revealed three patients to have screw placed in anterior 1/4(th) of the 1(st) sacral body, in rest nine the screws were placed in the posterior 3/4(th) of sacral body. At 2 years followup, eight patients (67%) showed evidence of bridging trabeculae at bone graft site and none of the patients showed evidence of instability or implant failure. CONCLUSION: Presacral screw fixation along with micro discectomy is an effective procedure to manage early symptomatic lumbosacral spondylolisthesis and degenerative disc disease with instability. PMID- 26015627 TI - Outcome of posterior lumbar interbody fusion for L4-L5 degenerative spondylolisthesis. AB - BACKGROUND: Posterior lumbar interbody fusion (PLIF) has become the standard in the treatment for degenerative spondylolisthesis since improvement of spinal instrumentation However, few published studies have reported long term outcomes of PLIF using a same surgical procedure. The purpose of this study is to evaluate a long term outcome of PLIF using a same surgical procedure for L4-L5 degenerative spondylolisthesis. MATERIALS AND METHODS: Out of 45 patients who underwent L4-L5 PLIF for degenerative spondylolisthesis between 1995 and 2003, 37 patients (16 males and 21 females) were evaluated in this study. Mean age was 61.8 years. The average followup period was 121 months. We evaluated % slip, lordosis at L4/L5, lumbar lordosis, Japanese Orthopedic Association's (JOA) score and adjacent segment degeneration. RESULTS: The % slip significantly improved from an average of 17.0% before surgery to 9.7% at the last followup. Lordosis at L4/L5 averaged 3.6 degrees before surgery, 8.2 degrees after surgery and 6.9 degrees at the last followup. Although patients experienced some loss of correction at last followup, their lordosis at L4/L5 at last followup still was significantly different from their lordosis at L4/L5 before surgery. Lumbar lordosis did not significantly change. Mean JOA score was 13.4 before surgery and 24.5 at the last followup; mean recovery ratio was 71.2%. Adjacent segment degeneration occurred in 40.5% of patients, almost all of which occurred in the cranial adjacent segment. Three patients (8.1%) required reoperation due to adjacent segment degeneration, at an average of 76 months after their initial surgery. CONCLUSIONS: With more than 10-year followup after L4-L5 PLIF for degenerative spondylolisthesis, the adjacent segment degeneration occurred in 40.5% and reoperation was required in 8.1%. PMID- 26015628 TI - Diffusion tensor imaging observation in Pott's spine with or without neurological deficit. AB - BACKGROUND: Diffusion tensor imaging (DTI) is based upon the phenomenon of water diffusion known as "Brownian motion." DTI can detect changes in compressed spinal cord earlier than magnetic resonance imaging and is more sensitive to subtle pathological changes of the spinal cord. DTI observation in compressed and noncompressed spinal cord in tuberculosis (TB) spine is not described. This study presents observations in Pott's spine patients with or without neural deficit. MATERIALS AND METHODS: Thirty consecutive cases of TB spine with mean age of 32.1 years of either sexes with paradiscal lesion, with/without paraplegia divided into two groups: Group A: (n = 15) without paraplegia and group B: (n = 15) with paraplegia were evaluated by DTI. The average fractional anisotropy (FA) and mean diffusivity (MD) values were calculated at 3 different sites, above the lesion (SOL)/normal, at the lesion and below SOL for both groups and mean was compared. Visual impression of tractography was done to document changes in spinal tracts. RESULTS: The mean canal encroachment in group A was 39.60% and group B 44.4% (insignificant). Group A mean FA values above SOL, at the lesion and below SOL were 0.608 +/- 0.09, 0.554 +/- 0.14, and 0.501 +/- 0.16 respectively. For group B mean FA values above SOL, at the lesion and below SOL were 0.628 +/- 0.09, 0.614 +/- 0.12 and 0.487 +/- 0.15 respectively. There was a significant difference in mean FA above the SOL as compared to the mean FA at and below SOL. P value above versus below the SOL was statistically significant for both groups (0.04), but P value for at versus below the SOL (0.01) was statistically significant only in group B. On tractography, disruption of fiber tract at SOL was found in 14/15 (93.3%) cases of group A and 14/15 cases (93.3%) of group B (6/6 grade 4, 3/3 grade 3 and 5/6 grade 2 paraplegic cases). CONCLUSION: The FA and MD above the lesion were same as reported for healthy volunteer hence can be taken as control. FA increases, and MD decreases at SOL in severe grade of paraplegia because of epidural collection while in milder grade, both decrease. In group A (without neurological deficit), mean FA and MD in patients with and without canal encroachment was similar. On tractography, both groups A and B (with or without neurological deficit) showed disruption of fiber tract at SOL and thickness of distally traced spinal cord was appreciably less than the upper cord. FA and MD could not differentiate between various grades of paraplegia. Although the number of patients in each group are small. PMID- 26015629 TI - Subacromial volume and rotator cuff tears: Does an association exist? AB - BACKGROUND: Rotator cuff pathology occurs commonly and its cause is likely multifocal in origin. The development and progression of rotator cuff injury, especially in relation to extrinsic shoulder compression, remain unclear. Traditionally, certain acromial morphologies have been thought to contribute to rotator cuff injury by physically decreasing the subacromial space. The relationship between subacromial space volume and rotator cuff tears (RCT) has, however, never been experimentally confirmed. In this study, we retrospectively compared a control patient population to patients with partial or complete RCTs in an attempt to quantify the relationship between subacromial volume and tear type. MATERIALS AND METHODS: We retrospectively identified a total of 46 eligible patients who each had shoulder magnetic resonance imaging (MRI) performed from January to December of 2008. These patients were stratified into control, partial RCT, and full-thickness RCT groups. Subacromial volume was estimated for each patient by averaging five sequential MRI measurements of subacromial cross sectional areas. These volumes were compared between control and experimental groups using the Student's t-test. RESULTS: With the numbers available, there was no statistically significant difference in subacromial volume measured between: the control group and patients diagnosed partial RCT (P > 0.339), the control group and patients with complete RCTs (P > 0.431). CONCLUSION: We conclude that subacromial volumes cannot be reliably used to predict RCT type. PMID- 26015630 TI - Results of reconstruction of massive irreparable rotator cuff tears using a fascia lata allograft. AB - BACKGROUND: Despite the advances in surgical treatment options, massive rotator cuff (r-c) tears still represent a challenge for orthopedic surgeons. This study assesses the effectiveness of fascia lata allograft in reconstruction of massive and irreparable r-c tear and to evaluate the healing and functional outcomes. MATERIALS AND METHODS: 68 patients (38 men, 30 women, mean age 64.9 years) with massive or irreparable r-c tears were treated with placement of fascia lata allograft to fill the defect between February 2006 and February 2010. At 43 months followup they were evaluated clinically using the constant score, preoperatively and postoperatively. Magnetic resonance imaging (MRI) and ultrasound were used postoperatively, to assess the integrity of the allograft at the repair site. Postoperatively, standard rehabilitation protocol was followed with gradual restoration. RESULTS: Postoperative constant score increased from 32.5 preoperatively to 88.7 postoperatively. The most important was the pain relief from 2.4 preoperatively to 14.1 postoperatively and range of motion. The results of the MRI were not reliable, but the ultrasound was satisfactory. Finally, there was no infection or rejection of the graft in any of the patients. CONCLUSIONS: Despite advances in surgical methods, there is still not a universally accepted treatment for massive and irreparable rotator cuff tears, because the standard methods have dubious results, with excessive retear rates and poor outcomes, necessitating the need for new repair strategies. We documented significant clinical improvement using fascia lata allograft in the repair of massive irreparable r-c tear, acting as scaffold to bridge the defect, enhancing the healing at the repair site. PMID- 26015631 TI - Open proximal phalangeal shaft fractures of the hand treated by theta fixation. AB - BACKGROUND: Many implants and techniques are used for the treatment of open phalangeal fractures with varying grades of stability. The ubiquitous and simple Kirschner (K) wiring does not provide adequate stability to allow early mobilization of fingers. Lister described a combination of coronal interosseous wire and oblique K-wire technique for phalangeal fracture fixation with a stable construct that allowed early mobilization. Due to the fancied resemblance of this construct to the Greek alphabet theta (theta), we have referred to this as the theta fixation. MATERIALS AND METHODS: Ten patients with open proximal phalangeal shaft (transverse) fractures were treated with theta fixation between January and June 2010. Outcome was analysed in terms of stability, early mobilization, fracture healing and function of hand. They were graded according to the Belsky score. RESULTS: 90% patients were graded excellent and 10% good, with none having fair or poor results. All fractures allowed the mobilization at a mean of 2.9 days and all healed at an average of 6.1 weeks. No loss of stability was seen on followup X-rays. All patients returned to their old profession. CONCLUSION: The theta fixation technique is a safe, simple and effective method for open transverse phalangeal fractures with results comparable to other techniques. This method gives superior fracture stability to allow early mobilization of joints and thus early return of function. It is also a cost effective way of management for the developing world. PMID- 26015632 TI - Early results of revision acetabular cup using antiprotrusio reconstruction rings and allografts. AB - BACKGROUND: Hip arthroplasty is one of the most frequently performed orthopedic procedures with high scores of success while its most common complication is aseptic loosening of the acetabular component, which may result from host bone loss or even from pelvis discontinuity. The purpose of the study was to evaluate results in patients after revision acetabular arthroplasty with reconstruction rings and allografts. MATERIALS AND METHODS: Retrospective data was collected from 69 revisions of acetabular components, performed in a group of 69 treated patients (the mean age 65.1 years). Before surgery, the patients had bone defects of type IIb (n = 5), IIc (n = 20), IIIa (n = 27) or IIIb (n = 17), according to Paprosky et al. RESULTS: The mean followup period of the patients was 7.2 years (range 3-19 years). A Kaplan-Meier analysis showed that a 3- and 10 year survival rate was 92.8% and 84.8% respectively, using further revision for any reason of the acetabular device as an end point. Eight patients revealed implant related complications. Four patients presented with ring loosening, one with a loose acetabular polyethylene cup, two hips demonstrated recurrent dislocations and one patient was with deep infection. Regarding the remaining 61 patients without re revision surgery, the mean Harris hip score improved from 30.5 to 73.8 points. CONCLUSION: A modified, antiprotrusion cage provides an acceptable survival rate and radiological results, but complications could still be expected. It seems that the observed massive bone loss with pelvic discontinuity and an insufficient fixation of the cage to the ischium may result in implant loosening. Stable fixation of the ischial ring flange with screws is an essential condition to expect a good outcome. PMID- 26015633 TI - WHOQOL-BREF Hindi questionnaire: Quality of life assessment in acetabular fracture patients. AB - BACKGROUND: The incidence of acetabular fractures in India has increased over the past years but so has the operating skills of pelvi-acetabular trauma surgeons. The outcomes of surgical management need to be assessed so as to be able to devise proper treatment plan and execute the same during and after surgery, which in turn requires assessment of quality of life indices as well as functional scores. While there are studies assessing Harris Hip scores (HHS) and world health organization quality of life BREF (WHOQOL BREF) in the western population there is no study which assesses the same in Indian population. We designed this study to evaluate and define reference values for use of WHOQOL BREF Hindi scores in QOL Assessment in patients with acetabular fractures and to assess the relationship between it and HHS. MATERIALS AND METHODS: 118 patients with acetabular fractures who were treated surgically were included in this retrospective study. Assessment of reduction quality (Matta's radiological criteria), clinical outcome (HHS) and functional outcome (WHOQOL-BREF score) were done. The affect of age, gender, fracture displacement, hip dislocation, delay in surgery and associated injury on the clinical and functional outcome was evaluated. RESULTS: The mean HHS was 90.65 (42-100) which showed an overall good to excellent outcome in 78.8% cases. WHOQOL-BREF Hindi score of domain-one was 63.06 +/- 20.31 (13-94), of domain-two was 58.22 +/- 19.57 (13-100), of domain three was 70.49 +/- 17.92 (13-100) and of domain-four was 64.48 +/- 18.46 (13 100), which showed significant functional deficit in domain-one (P = 0.0001) and domain-two (P = 0.0001) but not in domain-three (P = 0.458) and domain-four (P = 0.722) when compared to score of general healthy population. The domain scores of general population norms were achieved in 59.3%, 61.9%, 69.5% and 66.1% cases in domain one, two, three and four respectively. CONCLUSIONS: Based on these results one can conclude that WHOQOL-Hindi questionnaire is good enough for assessment of QOL in addition to clinical measures in acetabular fracture patients. PMID- 26015634 TI - Bipolar hip arthroplasty for avascular necrosis of femoral head in young adults. AB - BACKGROUND: Bipolar hip arthroplasty (BHA) is one of the options for treatment of avascular necrosis (AVN) of the femoral head. Acetabular erosion and groin pain are the most allowing for gross motion between the common complications. We propose that these complications are secondary to improper acetabular preparation allowing for motion between the BHA head and the acetabulum. MATERIALS AND METHODS: The current study retrospectively evaluated patients'records from case files and also called them for clinical and radiological followup. 96 hips with AVN of the femoral head treated with BHA were included in the study. All patients were males with a mean age of 42 years (range 30-59 years). In all cases, the acetabulum was gently reamed till it became uniformly concentric to achieve tight fitting trial cup. Clinical followup using Harris hip score (HHS) and radiological study for cup migration were done at followup. RESULTS: The mean followup was 7.52 years (range 4-16 years). The HHS significantly improved from a preoperative value of 39.3 (range, 54-30) to a postoperative value of 89.12 (range 74-96). According to HHS grades, the final outcome was excellent in 52 hips, good in 28 and fair in 16 hips. Hip and groin pain was reported in four hips (5%), but did not limit activity. Subsidence (less than 5 mm) of the femoral component was seen in 8 cases. Subgroup analysis showed patients with Ficat Stage 3 having better range of motion, but similar HHS as compared to Ficat Stage 4 patients. CONCLUSION: Bipolar hip arthroplasty (BHA) using tight fitting cup and acetabular reaming in AVN hip has a low incidence of groin pain, acetabular erosion and revision in midterm followup. Good outcome and mid term survival can be achieved irrespective of the Ficat Stage. PMID- 26015635 TI - Ceramic on ceramic hip arthroplasty in fused hips. AB - BACKGROUND: Most literature in the field of total hip arthroplasty (THA) for fused hips, until date has reported the results of using metal on polyethylene and ceramic on polyethylene bearings. Results of THA using ceramic on ceramic (CoC) bearings in fused hips have not been published in literature. This study reports the results of cementless THA using CoC articulation perfomed in fused hips. MATERIALS AND METHODS: Twenty-three patients (25 hips) with fused hips underwent conversion to THA using CoC bearings and were followed up for a mean 5.4 years. The conventional posterolateral approach was used in 15 hips, a modified two incision technique in 7 hips and a direct lateral approach with greater trochanteric osteotomy in 3 hips. Postoperatively, range of motion exercises were encouraged after 2-3 days of bed rest and subsequent gradual weight bearing using crutches was begun. RESULTS: Mean Harris hip score improved from 42.4 to 84.2 and mean leg lengthening of 36.6 mm was achieved. In the average 5.4 years (range 2.8-9.1 years) followup there were no cases with osteolysis around acetabular cup and femoral stem. In this study, there was no case of ceramic fracture. There was one case of squeaking. CONCLUSION: This study suggests that cementless THA performed for fused hips with CoC bearings can provide good early clinical results. PMID- 26015636 TI - Treatment of neglected femoral neck fractures using the modified dynamic hip screw with autogenous bone and bone morphogenetic protein-2 composite materials grafting. AB - BACKGROUND: The neglected femoral neck fracture is one where there has been a delay of more than 30 days to seek medical help from the time of the original injury. Salvage procedures, such as osteotomy and other treatment options such as vascularized and nonvascularized bone grafts have high failure rates and arthroplasty procedures are not ideal, given the patient's young age and higher levels of activity. We designed a hollow bone graft dynamic hip screw (Hb-DHS) (modified DHS, Hb-DHS) for use in neglected femoral neck fractures. This study evaluates the efficacy and safety of the modified dynamic hip screw (DHS) with autogenous bone and bone morphogenetic protein 2 (BMP-2) composite materials grafting for the treatment of the neglected femoral neck fractures. MATERIALS AND METHODS: A prospective study was carried out in twenty patients of neglected femoral neck fractures treated with the modified DHS with autogenous bone and BMP 2 composite materials grafting between July 2007 and February 2010. There were 14 men and 6 women with a mean age of 29.6 years (range 19-42 years). The mean time from injury to surgery was 9.7 weeks (range 6-16 weeks). The operation time, intraoperative blood loss, fracture healing time, Harris scoring for hip function and complications were recorded to evaluate treatment effects. RESULTS: The mean operation time was 75.8 min (range 55-100 min) with mean intraoperative blood loss volume of 105 mL (range 70-220 mL). The mean time to union was 17 weeks (range 12-24 weeks). One patient did not achieve union, and two patients had avascular necrosis of the femoral head. This patient with nonunion underwent intertrochanteric osteotomy. In patients with avascular necrosis one required total hip arthroplasty, the other did not require intervention at the last followup. A total of 14 patients (70%) had excellent results, 2 (10%) had good, 1 (5%) had moderate and 3 (15%) had poor results. CONCLUSION: The modified DHS with autogenous bone and BMP-2 composite materials grafting for the treatment of neglected femoral neck fractures waseffective and had less complications. PMID- 26015637 TI - A biomechanical comparison of proximal femoral nails and locking proximal anatomic femoral plates in femoral fracture fixation: A study on synthetic bones. AB - BACKGROUND: The incidence of fractures in the trochanteric area has risen with the increasing numbers of elderly people with osteoporosis. Although dynamic hip screw fixation is the gold standard for the treatment of stable intertrochanteric femur fractures, treatment of unstable intertrochanteric femur fractures still remains controversial. Intramedullary devices such as Gamma nail or proximal femoral nail and proximal anatomic femur plates are in use for the treatment of intertrochanteric femur fractures. There are still many investigations to find the optimal implant to treat these fractures with minimum complications. For this reason, we aimed to perform a biomechanical comparison of the proximal femoral nail and the locking proximal anatomic femoral plate in the treatment of unstable intertrochanteric fractures. MATERIALS AND METHODS: Twenty synthetic, third generation human femur models, obtained for this purpose, were divided into two groups of 10 bones each. Femurs were provided as a standard representation of AO/Orthopedic Trauma Associationtype 31-A2 unstable fractures. Two types of implantations were inserted: the proximal femoral intramedullary nail in the first group and the locking anatomic femoral plate in the second group. Axial load was applied to the fracture models through the femoral head using a material testing machine, and the biomechanical properties of the implant types were compared. RESULT: Nail and plate models were locked distally at the same level. Axial steady load with a 5 mm/m velocity was applied through the mechanical axis of femur bone models. Axial loading in the proximal femoral intramedullary nail group was 1.78-fold greater compared to the plate group. All bones that had the plate applied were fractured in the portion containing the distal locking screw. CONCLUSION: The proximal femoral intramedullary nail provides more stability and allows for earlier weight bearing than the locking plate when used for the treatment of unstable intertrochanteric fractures of the femur. Clinicians should be cautious for early weight bearing with locking plate for unstable intertrochanteric femur fractures. PMID- 26015638 TI - Trans-tibial guide wire placement for femoral tunnel in single bundle anterior cruciate ligament reconstruction. AB - BACKGROUND: Femoral tunnel location is of critical importance for successful outcome of ACL reconstruction. The aim was to study the femoral tunnel created by placing free hand guide wire through tibial tunnel, using the toggle of the guide wire in the tibial tunnel to improve femoral tunnel location. MATERIALS AND METHODS: 30 cases of a single bundle quadrupled hamstring graft anterior cruciate ligament reconstruction by trans-tibial free hand femoral tunnel creation is studied in this prospective study. The side to side play of the guide wire in the tibial tunnel was used to improve the tunnel location on femoral wall. The coronal angle of the femoral tunnel was measured on the anteroposterior radiograph. The femoral tunnel location on the lateral radiograph of the knee was recorded according to Amis method. Lysholm scoring was done preoperative and at each follow up. Assessment of laxity was done by Rolimeter (Aircast(TM)) and pivot shift test. RESULTS: The mean coronal angle of the femoral tunnel in postoperative radiograph was 47 degrees . In lateral radiograph, the femoral tunnel was found to be >60% posterior on Blumensaat line in 67% cases (n = 20) and in the 33% cases (n = 10) it was anterior. The mean Lysholm score improved from 74.6 preoperative to 93.17 postoperative with no objective evidence of laxity. CONCLUSION: The free hand trans-tibial creation of the femoral tunnel leads to satisfactory coronal obliquity, but it is difficult to recreate anatomic femoral tunnel by this method as the tunnel is consistently anterior in the sagittal plane. PMID- 26015639 TI - The effects of dabigatran etexilate on fracture healing in rats: An experimental study. AB - BACKGROUND: Deep vein thrombosis leading to pulmonary embolism is one of the major complication after fracture. After a fracture occurs, the coagulation cascade activates thrombin, a protease that finally generates clotting. Dabigatran etexilate reduce clot formation by inhibiting thrombin. Dabigatran etexilate is a widely used drug for thromboprophylaxis. There is no study of the effects of dabigatran etexilate on fracture healing in the literature, so we aimed to evaluate the effects of dabigatran etexilate on fracture healing. MATERIALS AND METHODS: Thirty-six female Sprague Dawley rats were divided into 6 groups, each consisting of 6 rats. In all rats, right tibias were used for the fracture model. An oral regimen of dabigatran etexilate suspension in 0.5% hydroxyethylcellulose was administered to the rats. Although the first and second groups received 10 mg/kg daily doses, the third and fourth groups received 50 mg/kg daily doses. The fifth and sixth groups were assigned as sham groups and only hydroxyethylcellulose solution was administered. The first, third and fifth groups were sacrificed on 14(th) days; whereas the second, fourth and sixth groups were sacrificed on 28(th) days. Results were evaluated radiologically and histologically. RESULTS: Radiologically and histologically no statistically significant differences were observed on the 14(th) day between the first, third and fifth groups; and on the 28(th) days between the second, fourth and sixth groups. CONCLUSION: Radiological and histological evaluations revealed that fracture healing was not affected by dabigatran etexilate. We think that dabigatran etexilate can be used for the prophylaxis of thromboembolism in patients with fractures, but further clinical studies are mandatory. PMID- 26015640 TI - Genetic disorders with heterotopic ossificans. AB - Fibrodysplasia ossificans progressiva (FOP) and progressive ossific heteroplasia (POH) are rare genetic disorders characterized by heterotopic bone formation leading to progressive loss of mobility and function. We report three cases of these rare disorders (two cases of FOP and one case of POH), which were clinically diagnosed and underwent genetic analysis. The aim of this report is to highlight the clinical features and the differences between these two conditions. We would also like to emphasize on the morbidity that can arise from unnecessary invasive investigations for diagnostic purposes. PMID- 26015641 TI - Ewing's sarcoma of proximal phalanx of the hand with skip metastases to metacarpals. AB - Ewing's sarcoma is the second most common malignant primary bone tumor of childhood and adolescence affecting mainly the diaphysis of long bones and flat bones. This tumor is extraordinarily rare in small bones of the hand and presents as a swelling with atypical radiological features of cystic and lytic lesion with scant periosteal reaction. The common differential diagnosis include osteomyelitis, tuberculosis, enchondroma and benign tumors. Moreover, skip metastasis to adjacent bones is even rarer. The prognosis of this condition is greatly influenced by the presence of metastasis at presentation, further emphasizing the importance of early diagnosis. Multimodality treatment using surgery, radiotherapy and chemotherapy is currently recommended though no consensus exists. We report a case of Ewing's sarcoma of the little finger proximal phalanx which was initially missed and developed skip metastasis to several metacarpals within 4 months. PMID- 26015642 TI - Irreducible, incarcerated vertical dislocation of the patella into a Hoffa fracture. PMID- 26015643 TI - Author's reply. PMID- 26015644 TI - Phytoneering: a new way of therapy for rhinosinusitis. AB - A growing amount of scientific evidence suggests that herbal medicine may be helpful as an adjuvant treatment in rhinosinusitis. Herein, we systematically review and determine the role, efficacy and safety of phytotherapy in the treatment of acute and chronic rhinosinusitis and establish the qualities of herbal drugs as demonstrated by in vitro and in vivo experiments. Eligible studies published in English or German from January 1990 until June 2014 were identified via electronic database searches. Keywords were: sinusitis, phytotherapy, phytomedicine and herbal drugs. Additional studies were obtained through the references of selected articles. Twenty-two articles met inclusion criteria. Overall, the publications indicated that herbal medicines can have mucolytic, antiviral, antimicrobial, anti-inflammatory and secretolytic effects in experimental animals. Phytotherapy has also been found to be efficacious in reducing the symptoms of acute and chronic rhinosinusitis in children and the adult population in vivo, demonstrating a high level of tolerability and safety. Herbal products developed using phytoneering techniques have shown improvements in performance compared with previous formulations. The current literature suggests that phytotherapy is an effective and safe form of ancillary treatment for rhinosinusitis. In particular, herbal drugs made with the technique of phytoneering have proven effective in acute rhinosinusitis. PMID- 26015645 TI - Tracheocutaneous fistula in patients undergoing supracricoid partial laryngectomy: the role of chronic aspiration. AB - The aim of the present retrospective controlled study was to analyse and compare risk factors for tracheocutaneous fistula in patients who received tracheostomy after supracricoid partial laryngectomy with those who received tracheostomy for other causes. We enrolled 39 patients with tracheocutaneous fistulas who were divided into two groups. The first received temporary tracheostomy for supracricoid partial laryngectomies (n = 21), while the control group consisted of patients who received temporary tracheostomy for other causes (n = 18). Risk factors believed to play a role in the pathogenesis of tracheocutaneous fistula were examined including advanced age, cardiopathy, local infections, radiotherapy, elevated body mass index, malnutrition, decannulation time and aspiration grade. The Leipzig and Pearson scale score was significantly higher in the supracricoid partial laryngectomy group (p = 0.006 and 0.031 for univariate and multivariate analyses, respectively). The penetration/aspiration scale score was significantly higher in the supracricoid partial laryngectomy group as determined by univariate analysis (p = 0.014). The decannulation time was significantly lower in the supracricoid partial laryngectomy group (p = 0.004 and 0.0004 for univariate and multivariate analyses, respectively). The number of surgical closures for tracheocutaneous fistula was significantly higher in the supracricoid partial laryngectomy group by univariate analysis (p = 0.027). These results suggest that chronic aspiration and related cough may be important pathogenic factors for tracheocutaneous fistula and could be responsible for the significantly higher rates of closure failure in patients after supracricoid partial laryngectomy. PMID- 26015646 TI - The immunohistochemical peptidergic expression of leptin is associated with recurrence of malignancy in laryngeal squamous cell carcinoma. AB - Leptin is a peptide that plays a key role in the control of satiety, energy expenditure, food intake and various reproductive processes. In the last years, the expression of leptin had been found in malignant cells of various origins. The aim of this study is to evaluate leptin expression in human laryngeal squamous cell carcinoma (SCC) and to investigate its possible role in predicting prognosis. Leptin expression was determined by immunohistochemistry in pathological and healthy tissue specimens from 24 patients with laryngeal SCC. Specimens were stained with an anti-leptin antibody. All measurements were performed using a computer-based image analysis system and scale of staining intensity was determined. All tumoural specimens showed significant immunoreactivity for leptin compared to healthy tissues (p <= 0.05), but showed different immunoreactivity that was related to clinicopathological features. High leptin expression was not significantly related with TNM, histological grading (HG) or advanced (III and IV) clinical stage (p > 0.05). Recurrence of malignancy was found to be significantly related with high expression of leptin by Spearman's rank correlation test (r = 0.59; p = 0.002), Fisher's test (p = 0.017) and Kaplan- Meier product-limit estimate (Log-rank test, p <= 0.05). In particular, multivariate logistic regression analysis showed that recurrences were significantly related with nodal involvement, HG and leptin expression (p <= 0.05). These preliminary results suggest that leptin may be a valuable parameter for predicting prognosis in laryngeal SCC. PMID- 26015647 TI - Doppler ultrasonography before thyroidectomy is not useful to prevent cerebrovascular accident. AB - Surgical manipulation of the cervical vascular bundle during neck surgery may promote a thromboembolic event. We evaluated if thyroid surgery is associated with any alterations in the carotid artery wall that would imply an augmented risk of cerebrovascular accident (CVA). A prospective evaluation of a consecutive series of patients who underwent total thyroidectomy was performed. High resolution Doppler ultrasonography (HR-DU) was performed the day before and three days after surgery in asymptomatic consenting patients scheduled for total thyroidectomy. Two hundred patients were recruited. Preoperatively, no hemodynamically significant stenosis (> 70%) was observed. Surgery was delayed in one patient because of asymptomatic subclavian steal syndrome. The remaining 199 patients underwent total thyroidectomy. No modification of preoperative findings was observed at the postoperative HR-DU evaluation. No CVA was observed. In the absence of any significant stenosis, thyroid surgery does not affect the presence and extent of arterial wall disease and the consequent risk of CVA. Thus, screening with HR-DU does not seem beneficial in a generally asymptomatic population without significant risk factors. PMID- 26015648 TI - First experience in Italy with a new transcutaneous bone conduction implant. AB - Since 2011, transcutaneous bone-anchored auditory implants have been an alternative to the classic percutaneous implant (Baha) for bilateral conductive/mixed hearing loss that cannot be corrected by surgery. Recently, a new transcutaneous device has been approved for clinical use. Its internal component is made of the classic titanium Baha fixture, coupled to a 27 mm diameter subcutaneous circular magnet. The external component includes a second circular magnet 29 mm in diameter and a digital sound processor. To date, there are no reports describing the results of the application of this device. The aim of the present study is to report on the anatomical and functional results of transcutaneous Baha implantation in three patients: two adults, one with syndromic aural atresia and one with bilateral conductive hearing loss due to bilateral tympanomastoidectomy, and an 8-year-old child with non-syndromic aural atresia. No major intraoperative or postoperative complications were observed. The three patients tolerated the external magnet, with no signs of skin irritation. Functional results were good: median unaided free-field PTA (0.5-3 kHz) was 50 dB HL (range = 41-66 dB HL); with the transcutaneous Baha median PTA (0.5-3 kHz) was 27 dB HL (range = 25-30 dB HL) and median gain was 25 dB HL (range = 11-39 dB HL). Preliminary results encourage use of the device as a valuable alternative to other implantable devices in these patients. To ensure the success of treatment, several precautions are suggested including gradually increasing use during the first post-operative months to favour skin adaptation to magnet pressure. In addition to skin reactions, in a paediatric age most concerns are related to the curvature of the skull, which may induce tenting of the skin over the internal magnet. PMID- 26015649 TI - Stretching stenoses of the external auditory canal: a report of four cases and brief review of the literature. AB - Acquired stenosis of the external auditory canal may be caused by a variety of insults, all sharing a common pathogenesis, namely a cascade of inflammatory changes leading to medial canal fibrosis. Previous surgery (canaloplasty or meatoplasty) and radiotherapy, especially if associated with a history of parotid surgery extended to the external auditory canal, have been implicated as possible causes. The literature offers advice on the management of stenosis consequent to otosurgery for congenital and acquired defects, but nothing on forms secondary to radiotherapy to the head and neck region. The proposed solutions are often cumbersome and difficult to fabricate, and therefore expensive. The aim of this paper, in which the cases of four patients are reported, is to present a new technique initially used for the most severe form - i.e. external auditory canal stenosis after surgery and radiotherapy - and then extended to forms due to different causes. This new technique involves the use of a series of surgical steel tubes of increasing dimension commonly used for tissue expansion in a body piercing practice called stretching and known as ear stretching tunnels or ear stretchers. This innovative approach proved effective in solving external auditory canal stenosis in our patients, with the least discomfort for the patient and the lowest cost. We consider this new solution to be feasible and practical and are convinced that it provides a new approach to an old problem. Further studies are needed to increase the number of clinical cases to verify how long the ear stretcher should be kept in place for the stenosis to stabilise, and to establish whether surgery is always necessary after ear stretcher application and, if so, the best timing for surgery. PMID- 26015650 TI - Efficacy and safety of ofloxacin and its combination with dexamethasone in chronic suppurative otitis media. A randomised, double blind, parallel group, comparative study. AB - The role of corticosteroid in patients of chronic suppurative otitis media (CSOM) is unknown. In the present study, the efficacy and safety of ofloxacin alone (OA) and the ofloxacin + dexamethasone combination (ODC) is compared by studying clinical cure rates and adverse drug reactions in patients with CSOM. After prior permission from the Institutional Review Board and written informed consent from patients, pre-treatment clinical assessment and bacteriology of the middle ear discharge were done. The middle ear was categorised into active, mucoid or inactive according to the type of discharge. Grades of otorrhoea and size of tympanic membrane perforation were noted. CSOM with organisms sensitive to ofloxacin were treated either with OA or ODC eardrops for a period of 15 days. Post-treatment clinical cure (when grade of otorrhoea become 0) was recorded on the 5(th), 10(th) and 15(th) days and bacteriological assessment was recorded at the last visit. All parameters were analysed using Fisher's exact test. A total 110 patients were randomised. The most common microorganism associated with CSOM was Pseudomonas aeruginosa (45.45 %). Clinical improvement was seen in 84.61% and 86.79% of cases, but bacteriological improvement in only 82.69% and 77.35% of cases treated with OA and ODC, respectively. Shift of middle ear discharge from active to inactive was noted in 71.15% and 64.15% patients by the 10th day in the OA and ODC groups, respectively. As there was no difference in clinical or bacteriological improvement, it may be unnecessary to combine steroids with topical antibiotic preparations for management of CSOM. PMID- 26015651 TI - Utility of Glidescope((r)) videolaryngoscopy in surgical procedures involving the larynx. AB - GlideScope((r)) is a recently developed videolaryngoscope that helps to achieve a good view of the laryngeal inlet and the vocal cords. Videolaryngoscopy has been proven effective in patients with unusual anatomical or pathological features, suggesting the possibility of a difficult endotracheal intubation. This device may also be useful for otorhinolaryngologists by facilitating access to the larynx and tongue base, especially in selected cases, where good visualisation of disease-altered structures is vital. According to the current literature, GlideScope((r)) has been used for surgical procedures involving the tongue base, such as biopsies, foreign body removal and radiofrequency treatment of obstructive sleep apnoea. We believe that the use of this kind of videolaryngoscopy might be also indicated for laryngeal surgery as a valid alternative to the placement of a direct laryngoscope. This technique, especially in those cases with anatomical issues or important comorbidities, may be preferred to ambulatorial flexible or rigid laryngoscopy, and in planning surgical procedures in "difficult" patients due to the operating room setting comprising constant anaesthesiological support. In our experience, we performed five procedures involving the larynx with the GlideScope((r)) in patients presenting unusual clinical characteristics that potentially compromised surgical outcome. No complications related to videolaryngoscopy were found. We recommend the use of GlideScope((r)) for small surgical procedures involving the larynx in selected patients. PMID- 26015652 TI - Intracapsular microenucleation technique in a case of intraparotid facial nerve schwannoma. Technical notes for a conservative approach. AB - We report a rare case of a large intraparotid facial nerve schwannoma (IFNS) in a 51-year-old female who presented with a painless, slow growing left parotid mass without peripheral facial nerve palsy, with non-specific findings at preoperative diagnostic work-up, that was treated with conservative surgery. Management of IFNS is very challenging because the diagnosis is often made intra-operatively, and in most cases resection may lead to severe facial nerve paralysis, with important aesthetic sequelae. Our experience suggests a new surgical option, namely intra-capsular enucleation using a microscope, currently used for schwannomas arising from a major peripheral nerve, which should be a safe and reliable treatment for IFNS. This surgical technique is the first experience of intracapsular microenucleation of facial nerve schwannoma described in the literature and allows preservation of the nerve without resection and reconstruction. PMID- 26015653 TI - Laryngotracheal reconstruction in glottic-subglottic stenosis associated with DiGeorge syndrome in a four and a half-month-old infant. AB - Neonatal subglottic stenosis still remains a substantial challenge for paediatric ENT surgeons. Herein, we present a case of a single stage laryngotracheal reconstruction for a glottic-subglottic stenosis in an 18-week-old, 7.2 kg infant with DiGeorge syndrome. Our surgical approach was compared with those reported in the literature. Paediatric airway surgery should be tailored to individual patients according to age, weight, comorbidities and family collaboration, with the ultimate objective to minimise the invasiveness of the procedure. PMID- 26015654 TI - Mucoepidermoid carcinoma of the base of tongue. AB - Mucoepidermoid carcinoma (MEC) is the most common malignant, locally-invasive tumour of the salivary glands, and accounts for approximately 35% of all malignancies of the major and minor salivary gland. Minor salivary glands are scattered in different areas of the oral cavity such as palate, retromolar area, floor of the mouth, buccal mucosa, lips and tongue. MECs of tongue base are not common. We present a rare case of MEC localised at the tongue base in a 42-year old Caucasian woman and discuss the histopathological types, management and review the literature. Adequate intra-oral excision was the treatment of choice in this case and in low-grade MEC. Prognosis of MEC is a function of the histological grade, adequacy of excision and clinical staging. PMID- 26015655 TI - Intra-operative sclerotherapy for treatment of a head and neck venous malformation. AB - Venous malformations of the head and neck are congenital lesions that grow steadily without spontaneous regression. We describe the management of a 47-year old woman with an extensive subcutaneous venous malformation of bilateral submandibular regions and the entire tongue, refractory to multiple surgical excisions and percutaneous sclerotherapy sessions. The tumour lacked prominent feeding arteries for embolisation, but maintained high blood outflow via a few substantial venous branches. Sclerotherapy to the lesion was prevented by major communicating branches from the mass to the internal jugular vein bilaterally. Our approach entailed direct surgical access to the malformation, ligation of these communicating veins and intraoperative sclerotherapy with ethanol injection into the vessel stumps. PMID- 26015656 TI - What's the big fuss about larger pictorial warnings on cigarette packs? PMID- 26015657 TI - Gliding along. PMID- 26015658 TI - Neutrophil extracellular traps: Their role in periodontal disease: Retraction. AB - [This retracts the article on p. 693 in vol. 18, PMID: 25624623.]. PMID- 26015659 TI - Salivary tumor necrosis factor-alpha and periodontal destruction. PMID- 26015660 TI - Author's reply: Salivary tumor necrosis factor-alpha: The way ahead. PMID- 26015661 TI - Interleukin polymorphisms in aggressive periodontitis: A literature review. AB - Aggressive periodontitis (AgP), occurs in a younger age group (<=35 years) and is associated with the rapid destruction of periodontal attachment and supporting bone. Genetic polymorphisms are allelic variants that occur in at least 1% of the population that could potentially alter the function of the proteins that they encode. Interleukins are a group of cytokines that have complex immunological functions including proliferation, migration, growth and differentiation of cells and play a key role in the immunopathogenesis of periodontal disease. The aim of this review was to summarize the findings of studies that reported associations or potential associations of polymorphisms in the interleukin family of cytokines, specifically with AgP. PMID- 26015662 TI - The epigenetic paradigm in periodontitis pathogenesis. AB - Epigenome refers to "epi" meaning outside the "genome." Epigenetics is the field of study of the epigenome. Epigenetic modifications include changes in the promoter CpG Islands, modifications of histone protein structure, posttranslational repression by micro-RNA which contributes to the alteration of gene expression. Epigenetics provides an understanding of the role of gene environment interactions on disease phenotype especially in complex multifactorial diseases. Periodontitis is a chronic inflammatory disorder that affects the supporting structures of the tooth. The role of the genome (in terms of genetic polymorphisms) in periodontitis pathogenesis has been examined in numerous studies, and chronic periodontitis has been established as a polygenic disorder. The potential role of epigenetic modifications in the various facets of pathogenesis of periodontitis is discussed in this paper based on the available literature. PMID- 26015663 TI - Is gamma-glutamyl transpeptidase a biomarker for oxidative stress in periodontitis? AB - CONTEXT: Periodontal disease and oxidative stress (OS) are part of a vicious cycle with each causing a deleterious effect on the other causing changes in the levels of antioxidants, and enzymes of antioxidant defense. Biomarkers and methods used for measuring OS are very expensive. AIMS: To see how gamma glutamyltransferase (GGT) fares, as a biomarker for OS in periodontits along with other routinely used biomarkers. DESIGN: A cross-sectional study involving 300 people of which 150 were cases and 150 were controls. SETTING: Candidates enrolled were patients visiting the OPD of MGV's Dental College and Hospital, Nasik, India between January 2011 and December 2012. MATERIALS AND METHODS: Serum samples of patients with periodontitis, and controls were analyzed for malondialdehyde, superoxide dismutase (SOD), glutathione peroxidase (GPx), uric acid, and GGT. STATISTICAL ANALYSIS USED: Analysis was performed using Student's t test. P <0.05 were considered to be significant. RESULTS: Malondialdehyde values were found to be significantly higher cases, while SOD, GPx and uric acid levels were found to be lower than controls. GGT levels were significantly higher in cases as compared to controls. CONCLUSIONS: GGT may be used as a cheap, quick, easy and precise marker for measuring OS. PMID- 26015664 TI - Impact of chronic periodontitis on quality-of-life and on the level of blood metabolic markers. AB - CONTEXT: Despite the recognition that systemic factors can alter the risk to the chronic periodontitis (CP), only recently has evidence begun to emerge, still under investigation, that infections of the oral cavity are related with low quality-of-life (QoL) and are able to influence the occurrence and severity of certain conditions and systemic diseases. AIMS: The aim of this study was to evaluate the impact of CP on the QoL and on the metabolic systemic condition of CP patients. SETTINGS AND DESIGNS: Cross-sectional, case-controlled, age- and gender-matched study. SUBJECTS AND METHODS: Quality-of-life assessment (Functional Assessment of Chronic Illness Therapy-Fatigue), periodontal examinations and blood tests were obtained from 20 CP patients and 20 age- and gender-matched healthy controls (HC). STATISTICAL ANALYSIS USED: parametric paired t-test for numerical data (metabolic parameters) and nonparametric paired Wilcoxon signed rank test to compare the QoL ordinal data of both groups. Statistical significance was determined at the 0.05 level. RESULTS: Healthy controls had fewer negative impacts in all QoL areas studied. CP patients showed higher levels of low-density lipoprotein cholesterol, glucose, and uric acid compared with the HC. CONCLUSIONS: Chronic periodontitis negatively affected the overall well-being and systemic condition of a group of Brazilian individuals. PMID- 26015665 TI - Interleukin-11 - its role in the vicious cycle of inflammation, periodontitis and diabetes: A clinicobiochemical cross-sectional study. AB - CONTEXT: Interleukin-11 (IL-11) is a multifunctional cytokine with a probable regulatory role in the inflamed periodontal tissue. It has also been shown to inhibit the production of potent proinflammatory cytokines like tumor necrosis factor-alpha, IL-6 and IL-1beta in vitro. Type 2 diabetes mellitus, which demonstrates an increase in proinflammatory cytokines, might hypothetically, display a decrease in the levels of IL-11, which down-regulates synthesis of the proinflammatory cytokines. AIMS: This clinicobiochemical cross-sectional study was undertaken to try to interpret the link between IL-11, diabetes and periodontitis and to explore the probable protective role of IL-11. MATERIALS AND METHODS: A total of 90 patients were included in the study and were divided into five groups based on community periodontal index scores and diabetes status. Probing pocket depth and clinical attachment level were measured in all the subjects. Gingival crevicular fluid (GCF) was collected from all the participants using micropipettes and blood samples were collected from subjects in Groups III, IV and V, for analysis of glycated hemoglobin. IL-11 levels were measured in GCF samples by enzyme-linked immunosorbent assay. STATISTICAL ANALYSIS: The data obtained were subjected to statistical analysis. RESULTS: The GCF IL-11 levels decreased from periodontal health to disease and in periodontitis patients with type 2 diabetes with decreasing glycemic control. CONCLUSIONS: Interleukin-11 may play an important role in the modulation of immune response via the reduction of proinflammatory cytokine production and periodontal tissue damage. It was seen in this study that IL-11 could be detected in GCF and the levels of IL-11 in GCF decreased progressively from healthy to periodontitis sites. IL-11 levels were significantly lower in chronic periodontitis group when compared to gingivitis group. The decrease in the levels of IL-11 probably indicates that both diabetes and periodontitis may play a synergistic role in the suppression of protective host responses. The potential of IL-11 as a probable biomarker of inflammation in both periodontal disease and diabetes mellitus is indicated by the changeability of IL-11 levels with the change in periodontal disease status and glycemic control. Further longitudinal studies are needed to validate IL-11 as a "biomarker of inflammation" in periodontal disease and diabetes progression and to prove its role in the connecting link between periodontal disease and type 2 diabetes mellitus. PMID- 26015666 TI - Comparison of the number of gingival blood vessels between type 2 diabetes mellitus and chronic periodontitis patients: An immunohistological study. AB - BACKGROUND: The relationship between diabetes and periodontitis has been studied for more than 50 years and is generally agreed that the periodontal disease is more prevalent in diabetic patients compared to nondiabetics. Vascular changes like increased thickness of basement membrane in small vessels has been reported in diabetic patients, but the quantity of blood vessels in gingiva of diabetic patients has not been discussed much. The aim of this study was to compare the number of blood vessels in gingiva between chronic periodontitis (CP) patients, CP with diabetes (type 2), and normal healthy gingiva. MATERIALS AND METHODS: The study included 75 patients, divided into three groups of 25 patients each-Group I with healthy periodontium (HP), Group II with CP, and Group III with CP with diabetes mellitus (CPDM). Gingival biopsies were obtained from the subjects undergoing crown lengthening procedure for Group I, and in patients with CP and in CPDM biopsies were collected from teeth undergoing extraction. Sections were prepared for immune histochemical staining with CD34. RESULTS: Difference was observed in the average number of blood vessels when compared between HP, CP, and CPDM groups. Statistical significant difference was observed when the HP and CP groups and HP and CPDM groups were compared. CONCLUSION: The results of the study indicated that the number of blood vessels in gingival connective tissue is significantly higher in CP and CPDM patients. PMID- 26015667 TI - Aggressive periodontitis: An appraisal of systemic effects on its etiology genetic aspect. AB - BACKGROUND: Myeloperoxidase (MPO) is a lysosomal enzyme found in the azurophilic granules of polymorphonuclear leukocytes and is able to mediate inflammatory tissue destruction in aggressive and chronic periodontitis (CP). Human telomerase is a multi subunit ribonucleoprotein enzyme concerned with telomeric lengthening and homeostasis in man and has been found to be elevated in inflammatory conditions such as rheumatoid arthritis and periodontitis. The aim of this study was to explore in aggressive periodontitis (AP) subjects: (i) The role of MPO 463G/A gene polymorphism and (ii) the level of telomerase expression. These parameters have been compared with the subjects of CP and that of the healthy controls. MATERIALS AND METHODS: A total of 45 subjects of the age group 20-50 years and free from any known systemic disease were included in the study. They were divided into three groups - Group I-periodontally healthy control (n = 15), Group II-CP (n = 15) and Group III-AP (n = 15). Peripheral blood samples and gingival tissue samples were collected for MPO gene polymorphism and telomerase expression, respectively, for detection by reverse transcriptase polymerase chain reaction. RESULTS: The frequencies of AG and AA genotypes in the MPO gene polymorphism were more common in the AP subjects when compared to the controls. The m-RNA expression of human telomerase reverse transcriptase (hTERT) was undetectable in the gingival tissue of the control group. Its expression in AP subjects was significantly higher than that of CP group (83.61 +/- 2.94 in CP and 104.27 +/- 6.06 in AP) (P < 0.0001). CONCLUSIONS: Our data suggest that MPO 463G/A may be associated with increased risk of AP. The level of tissue hTERT was elevated in AP subjects as compared to CP and healthy control groups. PMID- 26015668 TI - Antimicrobial efficacy of Acacia nilotica, Murraya koenigii L. Sprengel, Eucalyptus hybrid, and Psidium guajava on primary plaque colonizers: An in vitro comparison between hot and cold extraction process. AB - BACKGROUND: The potential drawbacks of the existing antiplaque agents call for innovative strategies that are safe, effective, and easily available. OBJECTIVE: The objective was to assess and compare antimicrobial efficacy of four plant extracts derived using hot and cold extraction methods against Streptococcus mutans, Streptococcus sanguis, and Streptococcus salivarius. MATERIALS AND METHODS: The leaves of Acacia nilotica, P. guajava, Eucalyptus hybrid, and Murraya konigii L. Sprengel were collected from the surrounding areas, identified and authenticated by a taxonomist. The leaves were washed, shade-dried, and hand crushed to obtain coarse powder. This was subsequently ground into a fine powder and extracted using ethanol by cold infusion and hot extraction process. The antimicrobial efficacy testing was done on American Type Culture Collection strains of S. mutans, S. sanguis, and S. salivarius using agar well diffusion method. 0.2% chlorhexidine and dimethyl sulfoxide were used as positive and negative controls. The mean inhibition zone using 10% concentration of these extracts was compared using independent sample t-test and one-way analysis of variance. RESULTS: All the four plant extracts inhibited the growth of S. mutans, S. sanguis, and S. salivarius irrespective of the method of extraction. The extracts of A. nilotica, P. guajava, and E. hybrid derived from both the methods of extraction exhibited a significantly higher inhibition zone against S. mutans in comparison with Murraya koenigii L. Sprengel and chlorhexidine. The cold extracts of A. nilotica and E. hybrid exhibited higher zone of inhibition against S. sanguis while the hot extracts of M. koenigii L. Sprengel exhibited a higher zone of inhibition against S. mutans. CONCLUSION: All the four plant extracts derived using either hot or cold extraction were effective against these bacteria and have the potential to be used as antiplaque agents. PMID- 26015669 TI - A randomised clinical study to measure the anti-erosion benefits of a stannous containing sodium fluoride dentifrice. AB - BACKGROUND: To compare the enamel protection efficacy of stannous-containing sodium fluoride and sodium monofluorophosphate (MFP)/triclosan dentifrices marketed in India in an in situ erosion model with acidic challenge. MATERIALS AND METHODS: This randomised and controlled, in situ, supervised, double-blind clinical trial employed a two-treatment, four-period crossover design, wherein subjects wore an appliance fitted with human enamel samples 6 h/day during each 10 day treatment period and swished twice daily with their assigned dentifrice slurry: Oral-B((r)) Pro-Health (maximum 1,000 ppm F as sodium fluoride with stannous chloride) or Colgate((r)) Strong Teeth with Cavity Protection (maximum 1,000 F as sodium MFP and triclosan). Subjects swished with 250 ml of orange juice over a 10 min period after each treatment and twice daily for the acidic erosive challenge. Enamel samples were measured for tooth surface loss using contact profilometry at baseline and day 10. RESULTS: A total of 34 subjects were randomised to treatment; 32 subjects completed the final visit. Baseline profilometry measurements of the specimen surfaces were near zero within +/- 0.3 MUm, and no statistically significant difference (P > 0.48) on average was observed between the two test dentifrices. At day 10, the stannous-containing dentifrice demonstrated 88% less erosion (P < 0.0001) relative to the MFP/triclosan dentifrice. Estimated medians (95% confidence intervals) were 0.21 MUm (0.17, 0.25) for the stannous-containing dentifrice versus 1.66 MUm (1.39, 1.99) for the MFP/triclosan dentifrice. Both dentifrices were well-tolerated. CONCLUSIONS: Compared with MFP/triclosan toothpaste, a stabilised stannous containing sodium fluoride dentifrice gave statistically significantly greater protection against tooth enamel surface loss in situ following repeated acid erosive challenge. PMID- 26015670 TI - Effect of scaling and root planing on serum interleukin-10 levels and glycemic control in chronic periodontitis and type 2 diabetes mellitus. AB - AIM: Chronic periodontal disease (CPD) and type 2 diabetes mellitus (T2DM) share common pathogenic pathways involving the cytokine network resulting in increased susceptibility to both diseases, leading to increased inflammatory destruction, insulin resistance, and poor glycemic control. Periodontal treatment may improve glycemic control. The aim of this study was to evaluate the effect of scaling and root planing (SRP) of T2DM patients with CPD on hyperglycemia and the levels of serum interleukin-10 (IL-10). MATERIALS AND METHODS: Forty-five subjects were divided into three groups comprising 15 subjects each as Group 1 (healthy controls), Group 2 (CPD patients), and Group 3 (T2DM patients with CPD). Plaque index, gingival index (GI), probing pocket depths (PPD), clinical attachment loss (AL), bleeding on probing (BoP), random blood sugar, glycosylated hemoglobin (HbA1C), and serum IL-10 were measured at baseline; SRP was performed on Groups 2 and 3 and the selected parameters recorded again at 6 months. RESULTS: Statistically significant (P < 0.05) differences were observed in the variables at baseline and 6 months after SRP between the three groups using one-way ANOVA. The paired samples t-test for PPD and AL in Group 3 was statistically significant. Group 3 revealed positive correlations between PPD and HbA1C, BoP and IL-10, respectively, at 6 months and a predictable association of HbA1C with PPD and GI, and IL-10 levels with BoP, respectively, at 6 months. CONCLUSION: Scaling and root planing is effective in reducing blood glucose levels in T2DM patient with pocket depths and effective in elevating systemic IL-10 levels in CPD patients and CPD patients with T2DM. PMID- 26015671 TI - Determination of clinical biologic width in chronic generalized periodontitis and healthy periodontium: A clinico-radiographical study. AB - BACKGROUND: The dimensions of dentogingival junction have been evaluated from autopsy jaw specimens. Previous studies demonstrated variability in histologic biologic width (BW) in periodontal health and mild periodontitis. Few studies have been done on the measurement of clinical BW in periodontitis. BW variation provides implications for selection of surgical or nonsurgical approaches. The purpose of this study was to determine clinical BW in periodontal health and chronic generalized periodontitis and to compare it with histologic dimensions of BW. MATERIALS AND METHODS: A total of 20 subjects with chronic generalized periodontitis and 20 subjects with healthy periodontium were included in the present study. Plaque index and community periodontal index of treatment needs were scored; moreover, probing depth (PD) and clinical attachment level were measured. Full mouth intraoral periapical radiographs were taken, and digitalized images were obtained to measure the crestal bone level using computerized software. RESULTS: Clinical BW was significantly greater in both healthy and periodontitis groups than previously reported histologic BW of 2.04 mm (P < 0.001). The mean clinical BW was 3.98 mm. CONCLUSION: Mean clinical BW in both groups was significantly greater than histologic BW and sites with shallow PDs demonstrated greatest BW, suggesting that these sites may be at increased risk for losing significant attachment during surgical procedures. PMID- 26015672 TI - Assessment of the width of attached gingiva using different methods in various age groups: A clinical study. AB - BACKGROUND: The width of attached gingiva varies from tooth to tooth and also among individuals with mixed opinions regarding an "adequate" or "sufficient" dimension of the gingiva. Although the need for a so-called adequate amount of keratinized tissue for maintenance of periodontal health is questionable, the mucogingival junction serves as an important clinical landmark in periodontal evaluation. There are various methods of locating the mucogingival junction namely the functional method and the visual method with and without histochemical staining, which aid in the measurement of the width of attached gingiva. MATERIALS AND METHODS: This study was carried out to assess the full mouth mid buccal width of attached gingiva in individuals of four different age groups. This study also evaluated the difference in visual and histochemical methods in identification of the mucogingival junction to calculate the width of attached gingiva. RESULTS: It was seen that the width of attached gingiva increases with age, and there was no significant difference in the width of attached gingiva by both the methods. CONCLUSION: Width of attached gingival varies in different areas of the mouth and also increases with age with no significant difference in the method of its assessment. PMID- 26015673 TI - Comparative evaluation of recession coverage with sub-epithelial connective tissue graft using macrosurgical and microsurgical approaches: A randomized split mouth study. AB - AIMS: The aim was to compare the recession coverage outcomes when done macrosurgically and microsurgically. BACKGROUND: Increasing interest in esthetics and the related problems such as hypersensitivity and root caries have favored the development of many root coverage procedures. Recession coverage up to a certain extent has solved these problems, but these procedures need good maintenance after the surgery for long-term benefits. With increasing advances in the field of recession coverage, microscope has added another dimension in undertaking the surgical procedure. MATERIALS AND METHODS: Thirty Miller's Class I and II recession were treated using the sub-epithelial connective tissue graft from the palate. In 15 sites, the graft was placed at the recipient site with unaided eye (Group A) and in other 15 sites the graft was placed using surgical microscope (Group B). Clinical evaluation was done at baseline, 12 weeks and 24 weeks postoperatively using plaque index, gingival index, vertical recession (VR), probing depth, clinical attachment level (CAL), width of attached gingiva, papilla height (PH) and width, malalignment index (MI) and esthetic appearance. STATISTICAL ANALYSIS USED: Paired and unpaired Student's t-test along with Wilcoxon Z-test were used to analyze the results and probability of P < 0.05 were accepted to reject the null hypothesis. Pearson correlation was used to correlate two parameters such as VR and CAL and MI and VR. RESULTS: Both the techniques demonstrated predictable mean root coverage (Group A 61.78% and Group B 67.58%) at 6 months postsurgery. CAL gain was slightly better in Group B patients when compared to Group A patients. A moderate positive correlation for Group A while a mild correlation in Group B was seen between the MI and VR. CONCLUSION: The use of the microscope enhances the results, but obtaining an expertise in using needs a lot of practice. The periodontal healing by both techniques should be evaluated histologically. PMID- 26015674 TI - Translation and validation of Hindi version of Oral Health Impact Profile-14. AB - TITLE OF THE STUDY: Validation of Hindi Version of Oral health Impact Profile (OHIP-14). AIM: To validate the Hindi version of OHIP-14. SETTINGS AND DESIGN: The study was carried out in K.M. Shah Dental College & Hospital, Vadodara. MATERIALS AND METHODS: OHIP-14 was translated into Hindi language.102 participants were given English as well as Hindi versions of OHIP-14. STATISTICAL ANALYSIS USED: Individual question were analyzed using Pearson Chi-Square test, Likelihood Ratio test and Linear-by-Linear Association test. The entire questionnaire in English and Hindi language were comparatively analyzed using Unpaired T test & Pearson correlation coefficient test. RESULTS: All the 14 questions showed no statistically significant difference between the English OHIP 14 and the translated Hindi version of OHIP-14. Results of Unpaired T test (P = 0.61) were statistically insignificant. Pearson Correlation coefficient test was 0.963 suggesting that the translated Hindi version was highly correlated to the original English version. CONCLUSION: The translated Hindi version of OHIP-14 is hence established as a valid tool for conduction of oral health related & quality of life surveys in Hindi language which is the most commonly used language in the Indian subcontinent. PMID- 26015675 TI - Assessment of the prevalence of periodontal diseases and treatment needs: A hospital-based study. AB - BACKGROUND: The periodontal diseases are the most prevalent oral diseases worldwide especially in developing countries like India. The objective of this cross-sectional survey was to determine the prevalence of periodontal diseases and treatment needs (TNs) in a hospital-based population. MATERIALS AND METHODS: Totally, 500 men and women (15-74 years) were recruited and periodontal status of each study subject and sextant was evaluated on the basis of community periodontal index of TNs, and thereafter TN for each subject and sextant was categorized on the basis of the highest code recorded during the examination. RESULTS: A total of 500 subjects (59% males and 41% females) was divided into seven age groups, that is, 15-19, 20-24, 25-34, 35-44, 45-54, 55-64, and 65-74 years and sextants were included from the 486 subjects. Healthy periodontium, bleeding on probing, calculus, shallow pockets, and deep pockets were found in 3.9%, 6.58%, 50.61%, 20.98%, and 17.90% subjects, respectively. Males were more affected with shallow and deep pockets as compared to females. Periodontal diseases in the early stages were more prevalent in the younger age groups, whereas advanced stages were more prevalent in older age groups. 17.90% subjects and 11.48% sextants need complex treatment. About 77.98% subjects and 73.15% sextants require either oral hygiene instructions or oral hygiene instructions and oral prophylaxis. Only 3.9% subjects and 15.36% sextants were healthy and needed no treatment. CONCLUSIONS: Periodontal diseases were found to be 96.30% in the study population and the results indicate that majority of the population need primary and secondary level of preventive program to reduce the chances of initiation or progression of periodontal diseases thereby improving their systemic health overall. PMID- 26015676 TI - An acellular dermal matrix allograft (Alloderm((r))) for increasing keratinized attached gingiva: A case series. AB - CONTEXT: Adequate amount of keratinized gingiva is necessary to keep gingiva healthy and free of inflammation. Autografts have been used for years with great success to increase the width of attached gingiva. Autografts, however, have the disadvantage of increasing postoperative morbidity and improper color match with the adjacent tissues. Alloderm((r)) allograft has been introduced as an alternative to autografts to overcome these disadvantages. AIM: In this study, the efficacy of alloderm((r)) in increasing the width of attached gingiva and the stability of gained attached gingiva was evaluated clinically. MATERIALS AND METHODS: Five patients with sites showing inadequate width of attached gingiva (<=1 mm) were enrolled for the study. The width of keratinized gingiva and other clinical parameters were recorded at baseline and 9th month postoperatively. RESULT: In all cases, there is the average increase of about 2.5 mm of attached gingiva and was maintained for 9-month. Percentage shrinkage of the graft is about 75% at the end of 3(rd) month in all cases. Excellent colors match with adjacent tissue has been obtained. CONCLUSION: The study signifies that Alloderm((r)) results in an adequate increase in the amount of attached gingiva and therefore can be used successfully in place of autografts. PMID- 26015677 TI - Plasma cell gingivitis. AB - The aim of the article is to present a report on the clinical presentation of plasma cell gingivitis with the use of herbal toothpowder. Plasma cell gingivitis [PCG] is a rare benign condition of the gingiva characterized by sharply demarcated erythematous and edematous gingivitis often extending to the mucogingival junction. As the name suggests it is diffuse and massive infiltration of plasma cells into the sub-epithelial gingival tissue. It is a hypersensitivity reaction to some antigen, often flavouring agents or spices found in chewing gums, toothpastes and lorenzes. A 27-yr old male with a chief complaint of painful, bleeding swollen mass in his lower front teeth region with prolong use of herbal toothpowder. The gingiva bled readily on probing. Patient was advised to refrain from the use of herbal toothpowder and along with periodontal treatment, no further reoccurrence was found. as more and more herbal products are gaining popularity, clinicians should be aware of effects of these products. Early diagnosis is essential as plasma cell gingivitis has similar pathologic changes seen clinically as in leukemia, HIV infection, discoid lupus erythematosis, atrophic lichen planus, desquamative gingivitis, or cicatrical pemphigoid which must be differentiated through hematologic and serologic testing. PMID- 26015678 TI - Application of 810-nm diode laser in the management of peripheral ossifying fibroma. AB - Peripheral ossifying fibroma (POF) is a reactive gingival growth, which accounts for 9.6% of gingival lesions. It exhibits a peak incidence between the second and third decades of life with a female predilection. Treatment includes surgical excision down to the periosteum and periodontal ligament with thorough root planning. Another option available in place of conventional surgical excision is the excision using lasers. Here is a case of POF affecting anterior maxillary gingiva in 19-year-old male patient successfully managed using an 810-nm diode laser. PMID- 26015679 TI - Long palatal connective tissue rolled pedicle graft with demineralized freeze dried bone allograft plus platelet-rich fibrin combination: A novel technique for ridge augmentation - Three case reports. AB - Replacement of missing maxillary anterior tooth with localized residual alveolar ridge defect is challenging, considering the high esthetic demand. Various soft and hard tissue procedures were proposed to correct alveolar ridge deformities. Novel techniques have evolved in treating these ridge defects to improve function and esthetics. In the present case reports, a novel technique using long palatal connective tissue rolled pedicle graft with demineralized freeze-dried bone allografts (DFDBAs) plus Platelet-rich fibrin (PRF) combination was proposed to correct the Class III localized anterior maxillary anterior alveolar ridge defect. The present technique resulted in predictable ridge augmentation, which can be attributed to the soft and hard tissue augmentation with a connective tissue pedicle and DFDBA plus PRF combination. This technique suggests a variation in roll technique with DFDBA plus PRF and appears to promise in gaining predictable volume in the residual ridge defect and can be considered for the treatment of moderate to severe maxillary anterior ridge defects. PMID- 26015680 TI - Treatment of multiple gingival recessions with vista technique: A case series. AB - Gingival recession is a common manifestation in most populations. Gingival recession is clinically manifested by an apical displacement of the gingival tissues, leading to root surface exposure. Gingival recession may be a concern for patients for a number of reasons such as root hypersensitivity, erosion, root caries, and esthetics (Wennstrom 1996). Recently, new techniques have been suggested for the surgical treatment of multiple adjacent recession type defects. These are mainly derived from the coronally advanced flap, a supraperiosteal envelope technique in combination with a subepithelial connective tissue graft, or its evolution as a tunnel technique. The current case reports introduce a novel, minimally invasive approach applicable for both isolated recession defects as well as multiple contiguous defects in the maxillary anterior region. Access to the surgical site is obtained by means of an approach referred to as vestibular incision subperiosteal tunnel access. PMID- 26015681 TI - Evidence of bone formation in the nasal floor around polished surface bi-cortical screw implants after indirect nasal lift in an atrophied maxilla: Cone beam computed tomography-based case report. AB - Maxillary jaw is restricted superiorly with maxillary sinus in the posterior region and nasal cavity in the anterior region. Augmentation of distal maxilla with recessed maxillary sinus has been documented since, last few decades. Sinus lifts the procedure either through crestal or lateral approach proves to be an effective way for augmenting bone for the placement of dental implants in atrophied posterior maxilla. However, when it comes to vertically deficient anterior maxilla, lifting of the nasal membrane is not considered. Perhaps, recent studies have shown greater success of dental implant placed after augmentation of the nasal floor. This report emphasizes on an observation of significant bone formation after indirect lifting of the nasal membrane with smooth polished surface bi-cortical implants. PMID- 26015683 TI - JPBS editorial dental supplement 2015 Indian Academy of Dental Specialists India. PMID- 26015684 TI - Surgery preceding orthodontics in bimaxillary cases. AB - Orthognathic surgery is performed to alter the shape of the jaws to increase the facial esthetic and improve the occlusions. Surgery prior orthodontics reduces the total length of the treatment of the patients, followed by orthodontics treatment. Advantages is positive outcome in short period of time. Surgical procedure includes Anterior Maxillary osteotomy and Anterior subapical mandibular osteotomy. Complication includes haemorrhage, paraesthesia, malunion of bone, etc. PMID- 26015682 TI - Multidrug resistance 1 gene polymorphism in amlodipine-induced gingival enlargement. AB - Gingival enlargement comprises any clinical condition in which an increase in the size of the gingiva is observed. It is a side effect associated with some distinct classes of drugs, such as anticonvulsants, immunosuppressant, and calcium channel blockers. Among calcium channel blockers, nifedipine causes gingival enlargement in about 10% of patients, whereas the incidence of amlodipine, a third-generation calcium channel blocker, induced gingival enlargement is very limited. Because the calcium antagonists, albeit to a variable degree, act as inhibitors of P-glycoprotein (P-gp), the gene product of multidrug resistance 1 (MDR1), and inflammation may modify P-gp expression. We hereby, report a case of amlodipine-induced gingival enlargement with MDR1 3435C/T polymorphism, associated with inflammatory changes due to plaque accumulation, in a 50-year-old hypertensive male patient. The genotype obtained for the polymorphism was a heteromutant genotype, thus supporting the contention that the MDR1 polymorphism may alter the inflammatory response to the drug. PMID- 26015685 TI - Palatal bone thickness measured by palatal index method using cone-beam computed tomography in nonorthodontic patients for placement of mini-implants. AB - INTRODUCTION: The purpose of this study was to compare the bone thickness of the palatal areas in different palatal index (PI) groups. MATERIALS AND METHODS: Cone beam computed tomography scans of 10 subjects were selected with ameanage group of 18 years. The measurements of palatal bone thickness were made at 36 sites using CareStream 3D Imaging software. The PIwas measured using Korkhaus ratio (palatal height/palatal width). One-way analysis of variance was used to analyze intergroup differences, as well as the PI difference. RESULTS: Bone thickness was higher in the anterior region than in the middle and posterior regions P <0.001. Furthermore, significant differences were found among the midline, medial, and lateralareas of the palate. CONCLUSIONS: These findings might be helpful for clinicians to enhance the successful useof temporary anchorage devices in the palate. PMID- 26015686 TI - Orthodontic instrument sterilization with microwave irradiation. AB - OBJECTIVE: This study was designed to evaluate the efficiency of microwave sterilization of orthodontic instruments and molar bands immersed in plain distilled water with and without oral rinse, and to ascertain the minimum time of exposure required to sterilize. MATERIALS AND METHODS: The orthodontic instruments (hinged and nonhinged), molar bands and mouth mirrorsused in the patient 's mouth were selected for the study. The instruments were divided into two groups - Group I with oral rinse-set A (0.01% chlorhexidine gluconate) and set B (0.025% betadine) and Group II (included sets C and D without oral rinse). The instruments of set A, B and C were microwaved at 2,450 MHz, 800 W for 5 min, whereas, set D was microwaved for 10 min at the same above mentioned specifications. The efficacy of sterilization was assessed by stab inoculation of the instruments onto trypticase soya agar plates. The plates were checked for bacterial growth following incubation at 37 degrees C for 24 h. For sterility control,Geobacillus stearothermophilus (MTCC 1518) was included. RESULTS: No growth was observed in the plates that were inoculated with the microwaved orthodontic instruments of sets A, B and D, whereas scanty bacterial growth was observed in the plates inoculatedwith the microwaved set C instruments. CONCLUSION: Effective sterilization was achieved when the orthodontic instruments and molar bands were immersed in distilled water without oral rinse and microwaved for 10 min as also for those that were immersed in distilled water with oral rinse and microwaved for 5 min. PMID- 26015687 TI - Comparison of frictional resistance of esthetic and semi-esthetic self-ligating brackets. AB - AIM: The frictional resistance encountered during sliding mechanics has been well established in the orthodontic literature, and it consists of complex interactions between the bracket, archwire, and method of ligation the claim of reduced friction with self-ligating brackets is often cited as a primary advantage over conventional brackets. This study was done to compare and evaluate the frictional forces generated between fully esthetic brackets and semi aesthetic self-ligating brackets, which are of passive form and SEM (scanning electron microscope) study of the Brackets after Frictional evaluation. MATERIALS AND METHODS: Two types of self-ligating esthetic brackets, Damon clear (Ormco) made of fully ceramic and Opal (Ultradent Products, USA) and, Two types of self ligating semi-esthetic brackets, Clarity SL (3M Unitek) and Damon 3 (Ormco) both of which are made of ceramic with metal slot. Arch wires with different dimensions and quality 17 * 25, 19 * 25 Titanium Molybdenum Alloy (TMA) and 17 * 25, 19 * 25 stainless steel that came from plain strands of wire were used for frictional comparison test. The brackets used in this study had 0.022 * 0.028 inch slot. RESULTS: The statistical tests showed significantly smaller amount of kinetic frictional forces is generated by Damon 3 (semi-esthetic self-ligating brackets). For each wire used, Damon 3 displayed significantly lower frictional forces (P <= 0.05) than any of the self-ligating system, followed by Opal (fully esthetic self-ligating brackets) which generated smaller amount of frictional forces but relatively on the higher side when compared with Damon 3. Damon clear (fully esthetic self-ligating brackets) generated the maximum amount of kinetic forces with all types of wire dimensions and properties when compared to the other three types of self-ligating system. Clarity SL (semi-esthetic self ligating brackets) generated smaller amount of frictional forces when compared with Damon clear and relatively higher amount of frictional forces when compared to Opal and Damon 3. PMID- 26015688 TI - Assessment of optimal condylar position with cone-beam computed tomography in south Indian female population. AB - AIM: The purpose of this study was to investigate, the condyle-fossa relationship, in clinically asymptomatic orthodontically untreated south Indian female volunteers, by cone-beam computed tomography (CBCT). MATERIALS AND METHODS: The study population consisted of 13 clinically symptom-free and orthodontically untreated angle's Class I female subjects with the mean age of 18 years (ranges from 17 years to 20 years). The normal disc position of the 13 subjects was confirmed by history, clinical examination and magnetic resonance imaging scan. Then, the images of the temporomandibular joint (TMJ)of the subjects were taken using CBCT to evaluate the optimal condylar position. Posterior joint space (PS), superior joint space (SS) and anterior joint space (AS) were measured, and the values were subjected to statistical analysis. Mean PS, SS and AS of right and left side TMJ ' and AS of right sid 's were calculated. Paired samples t-test were used for each measurement to evaluate the average differences between the right and left side for each element of the sample. RESULTS: The mean value of PS, SS and AS of right side TMJ 's were 2.1385, 2.2769 and 1.7615, respectively. The mean value of PS, SS and AS of left side TMJ 's were 2.1385, 2.5308 and 1.8538, respectively. Statistical analysis with the t-test indicated no significant differences in the AS, SS, or PS values between the right and left side. TMJ 's mean PS, SS, and AS measurements were2.1 mm (standard deviation [SD] +/-0.65 mm), 2.4 mm (SD +/- 0.58 mm), and 1.8 mm (SD +/- 0.52 mm), respectively. The ratios of SS and PS to AS, with AS set to 1.0, were 1.3 and 1.2, respectively. CONCLUSION: These data from optimal joints might serve as norms for the clinical assessment of condylar position obtained by CBCT. PMID- 26015689 TI - A new approach for evaluation of canine dento alveolar distraction using cone beam computed tomography. AB - OBJECTIVE: The aim was to evaluate and plan the canine dento alveolar distractions (DADs) with the use of cone-beam computed tomography (CBCT). MATERIALS AND METHODS: 5 patients are requiring 10 canine DADs were selected for the study. A custom-made DAD distractor was fabricated for the study. CBCT scans were taken prior to and post thedistraction. DAD parameters such as Canine retraction, canine and molar rotation, molar anchor loss and level of the osteotomy cut above the canine was evaluated. RESULTS: Average canine retraction was 7.5 mm in 17 days, molar anchor loss was 0.5 mm, canine and molar rotations were 8 degrees and 0.40 degrees and thedistance of the osteotomy cut to the canine was1.93 mm. CONCLUSION: The CBCT can be used to accurately evaluate the canine DADtechnique. PMID- 26015690 TI - Elongated styloid process: A study. AB - The styloid process (SP) on the temporal bone is a highly variable formation. The normal length of the SP ranges from 20 to 30 mm. In spite of its being normally distributed in the population, SPs could be divided into two groups - short SPs with >20 mm and long SPs with <20 mm in length. The SP is often denoted as elongated when it is longer than 30 mm or 33 mm. These dimensions, based on early reports, do not respect the natural variation of the SP. The aim of this study is to investigate the natural variation of the length of the SP. PMID- 26015691 TI - Assessment of bleeding during minor oral surgical procedures and extraction in patients on anticoagulant therapy. AB - INTRODUCTION: The risk of postoperative hemorrhage from oral surgical procedures has been a concern in the treatment of patients who are receiving long-term anticoagulation therapy. A study undertaken in our institution to address questions about the amount and severity of bleeding associated with minor outpatient oral surgery procedures by assessing bleeding in patients who did not alter their anticoagulant regimen. SUBJECTS AND METHODS: Eighty-three patients receiving long-term anticoagulant therapy visited Department of Oral and Maxillofacial Surgery from May 2010 to October 2011 for extractions and minor oral surgical procedures. Each patient was required to undergo preoperative assessment of prothrombin time (PT) and measurement of the international normalized ratio. Fifty-six patients with preoperative PT values within the therapeutic range 3-4 were included in the study. The patients' age ranged between 30 and 75 years. Application of surgispon was done following the procedure. Extraction of teeth performed with minimal trauma to the surrounding tissues, the socket margins sutured, and sutures removed after 5 days. RESULTS: There was no significant incidence of prolonged or excessive hemorrhage and wound infection and the healing process was normal. PMID- 26015692 TI - Role of DNA profiling in forensic odontology. AB - The recent advances in DNA profiling have made DNA evidence to be more widely accepted in courts. This has revolutionized the aspect of forensic odontology. DNA profiling/DNA fingerprinting has come a long way from the conventional fingerprints. DNA that is responsible for all the cell's activities, yields valuable information both in the healthy and diseased individuals. When other means of traditional identification become impossible following mass calamities or fire explosions, teeth provide a rich source of DNA as they have a high chemical as well as physical resistance. The recent evolution in the isolation of DNA and the ways of running a DNA fingerprint are highlighted in this literature review. PMID- 26015693 TI - Significance of corneal arcus. AB - The corneal arcus consists of cholesterol, phospholipids and triglycerides. As serum triglyceride is one of the accurate of lipid metabolic state, greater importance was given, and it was found to be elevated in 72% of patients and a positive correlation with increasing age. This suggests a strong correlation between impairment of lipid metabolism and incidence of corneal arcus. PMID- 26015694 TI - Ghost cell lesions. AB - Ghost cells have been a controversy for a long time. Ghost cell is a swollen/enlarged epithelial cell with eosnophilic cytoplasm, but without a nucleus. In routine H and E staining these cells give a shadowy appearance. Hence these cells are also called as shadow cells or translucent cells. The appearance of these cells varies from lesion to lesion involving odontogenic and nonodontogenic lesions. This article review about the origin, nature and significance of ghost cells in different neoplasms. PMID- 26015695 TI - Reticuloendothelial malignancy of head and neck: A comprehensive review. AB - The mononuclear phagocyte system consists of cells that have a common lineage whose primary function is phagocytosis. The specific immunity is achieved by the combined effects of macrophages and lymphocytes, and system has been called lymphoreticular system. Reticuloendothelial system means a special group of cells, scattered in different parts of the body, but all having some common characteristics. These cells are powerful phagocytes. PMID- 26015696 TI - Oral lichen planus: An overview. AB - Lichen planus is an immunologically mediated mucocutaneous disease that is triggered by varied etiological agents. The oral lichenoid reaction is considered a variant of the disease that needs to be clearly diagnosed as a separate entity from oral lichen planus and treated. They follow a strict cause-effector relationship, protocols that suggest the differentiation. Lichen planus has varied clinical forms in the oral mucosa and cutaneously that has different prognosis. This condition also arises in association with various other systemic conditions such as hypertension, diabetes mellitus. There have been cases reported in the esophagus, larynx, scalp, nail, cutaneous areas, especially arms and wrists, trunk. There is reported malignant transformation that essentiates careful examination, treatment protocol and regular follow-up sessions. This article throws light on the disease condition of oral lichen planus and oral lichenoid reaction that is essential for the differentiation and treatment. PMID- 26015697 TI - Antioxidant status in neonatal jaundice before and after phototherapy. AB - BACKGROUND: Neonatal jaundice refers to yellow coloration of the skin and the sclera (whites of the eyes) of newborn babies that result from the accumulation of bilirubin in the skin and mucous membranes. Because bilirubin is potentially toxic to the central nervous system. Genetic disorders of bilirubin conjugation, particularly the common Gilbert's syndrome, can also contribute to neonatal hyperbilirubinemia. OBJECTIVE: The aim of this study was to evaluate the lipid per-oxidation and antioxidant enzyme activities in patients with neonatal jaundice before and after phototherapy. MATERIALS AND METHODS: The study includes 50 neonatal jaundice patients with average age 2-15 days. All patients of neonatal jaundice receiving phototherapy except feeding, cleaning. Subjects selected were from the patients attending Pediatrics Department. Plasma malondialdehyde (MDA), erythrocyte glutathione peroxidase (GPX), superoxide dismutase and catalase (CAT) to monitor the bilirubin level. RESULTS: The results show increased levels of bilirubin compared with controls (P < 0.001) shows the level of plasma MDA in control, before and after phototherapy. Represents the level of GPX was significantly increased in after the phototherapy group when compared with before phototherapy and control SPSS soft ware: (P < 0.001). Shows the reduced glutathione (GSH) level in plasma was significantly decreased in the after phototherapy group when compared with before phototherapy and control (P < 0.001). And finally with ascorbic acid and CAT. CONCLUSION: It is evident from the study that increased oxidative stress in neonatal jaundice babies leads to decrease in the levels of antioxidants like GSH and ascorbic acid and disturb their metabolism, that weaken their ability to fight the growing stress. Intense oxidative stress and decreased antioxidants may contribute to neural cell death and alter the erythrocytomembrane structure processing in neonatal jaundice. PMID- 26015698 TI - Candida in potentially malignant oral disorders. AB - Oro-pharyngeal cancer is a significant component in the global burden of cancer. A considerable proportion of oral squamous carcinomas develop from preexsiting potentially malignant disorder of the oral cavity. The term potentially malignant oral disorders (PMD) were proposed for the precancerous lesions and conditions by World Health Organization in 2007. PMD are considered an in-between clinical state, which showed increased risk for cancer development. Etiology of PMD is multifactorial. Tobacco and alcohol are the major risk factors. In recent years, role of candidal infection is recognized as a significant factor in the development of PMD. There is an enduring discussion whether Candida infection can be a cause of PMD or a superimposed infection in a preexisting lesion. This article highlights the association between Candida and PMD. PMID- 26015699 TI - Leukoplakia: A short review on malignant potential. AB - Oral leukoplakia is one of the most common potentially malignant disorders. Right diagnosis of potentially malignant disorders may help to prevent these lesions from malignant transformation. Proper understanding, recognizing, identification and differentiating these lesions from normal mucosa are necessary for proper treatment. PMID- 26015700 TI - Ameloblastoma. AB - Ameloblastoma is a benign odontogenic tumor generally present in the jaw bone. The tumor originates from the residual epithelium of the tooth germ, epithelium of odontogenic cysts stratified squamous epithelium and epithelium of the enamel organ. It represents approximately 1% of oral tumors. About 80% of ameloblastomas occur in the mandible mainly the third molar region and the remaining 20% in the upper jaw. Ameloblastoma clinically appears as an aggressive odontogenic tumor, often asymptomatic and slow-growing, with no evidence of swelling. This article deals with a complete review on ameloblastoma. PMID- 26015701 TI - Fibrous dysplasia-recent concepts. AB - Fibrous dysplasia (FD) is a benign intramedullary fibro-osseous lesion. FD is a bone developmental anomaly characterized by replacement of normal bone and marrow bone by fibrous tissue. It involves any of the bones as single lesion (monostotic) or in multiple bone lesions (polyostotic) or all of the skeletal system (panostotic). Long bones are most commonly involved, which mostly identified incidentally and clinically appears asymptomatic. Clinical, radiographical and histopathological findings will help in confirming the lesion. There are many treatment option available, but still management of FD remains challenging. PMID- 26015702 TI - Circulating tumor cells in oral squamous cell carcinoma-an enigma or reality? AB - Oral squamous cell carcinoma (OSCC) is ranking 1(st) among males and 4(th) among females in India. In spite of major advances in diagnosis and treatment of OSCC, survival rates, have remained poor. Circulating tumor cells (CTCs) in the blood stream, play an important role in establishing metastases. It is important to identify patients suffering from nonlocalized tumor with "circulating" tumor cells to determine the tailor made, systemic therapy in addition to local resection and irradiation. Thus, detecting metastases at an early stage are needed for better prognosis and survival. CTCs as new prognostic marker to detect the metastatic potential will provide a novel insight into tumor burden and efficacy of therapy. The recent advances and its application in OSCC will be reviewed. PMID- 26015703 TI - Evolution of forensic odontology: An overview. AB - Forensic dentistry or forensic odontology admits dentists' participation or identification of the victim and assisting legal and criminal issues. It refers to the proper handling, examination, identification and evaluation of dental evidence. This article summarizes the evolution of forensic odontology that started right from Garden of Eden to the modern scenario in identification of the gang rape case which happened in the state capital. Forensic dentistry plays a significant role in identifying the victims of crime, deceased individuals through the examination of anatomical structures, dental appliances and dental restorations. PMID- 26015705 TI - Serum ferritin level and red blood cell parameters in healthy controls and chronic periodontitis patients. AB - Periodontitis, which is a chronic inflammatory disease causes reduction in the number of erythrocytes and hemoglobin. It is found to be caused by specific pathogenic subgingival plaque bacteria. Periodontitis is host mediated through release of pro inflammatory cytokines by local tissues and immune cells in response to bacterial flora and its products, especially lipopolysacharides. Periodontitis is found to have systemic effect and the cytokines produced inhibit proliferation and differentiation of erythrocytes leading to anaemia. This study evaluate level of hemoglobin erythrocytes, hematocrit and serum ferritin levels in healthy subjects and periodontitis patient. PMID- 26015704 TI - Naturally occurring products in cancer therapy. AB - Natural products have been used for the treatment of various diseases and are becoming an important research area for drug discovery. These products, especially phytochemicals have been extensively studies and have exhibited anti carcinogenic activities by interfering with the initiation, development and progression of cancer through the modulation of various mechanisms including cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. This concept is gaining attention because it is a cost-effective alternative to cancer treatment. In this article, we have discussed some of the naturally occurring products used in cancer treatment. PMID- 26015706 TI - Myoepithelial cells in pathology. AB - Myoepithelial cells are a normal constituent of the salivary acini and ducts and are found between the epithelial cells and the basement membrane. Microscopically myoepithelial cells are thin and spindle-shaped and ultrastructurally they possess a number of Cytoplasmic processes that extend between and over the acinar and ductal-lining cells, and they show features of both smooth muscle and epithelium. They play a vital role during expulsion of saliva and regulates the electrolytic exchange. They also perform as tumor suppressors and are considered to play a very important role in differentiation of various salivary gland tumors and help in the diagnosis of tumors. Neoplastic myoepithelial cells in both benign and malignant tumors can take numerous forms including epithelioid, plasmacytoid, spindle and clear cell variant, and this variability largely accounts for difficulties in histopathological diagnosis. PMID- 26015707 TI - Burning mouth syndrome. AB - Burning mouth syndrome (BMS) is a complex disorder that is characterized by warm or burning sensation in the oral mucosa without changes on physical examination. It occurs more commonly in middle-aged and elderly women and often affects the tip of the tongue, lateral borders, lips, hard and soft palate. This condition is probably of multi-factorial origin, often idiopathic, and its etiopathogensis is unknown. BMS can be classified into two clinical forms namely primary and secondary BMS. As a result, a multidisciplinary approach is required for better control of the symptoms. In addition, psychotherapy and behavioral feedback may also help eliminate the BMS symptoms. PMID- 26015708 TI - DNA adducts-chemical addons. AB - DNA adduct is a piece of DNA covalently bond to a chemical (safrole, benzopyrenediol epoxide, acetaldehyde). This process could be the start of a cancerous cell. When a chemical binds to DNA, it gets damaged resulting in abnormal replication. This could be the start of a mutation and without proper DNA repair, this can lead to cancer. It is this chemical that binds with the DNA is our prime area of concern. Instead of performing the whole body analysis for diagnosing cancer, this test could be carried out for early detection of cancer. When scanning tunneling microscope is used, the DNA results can be obtained earlier. DNA adducts in scientific experiments are used as biomarkers. PMID- 26015709 TI - A clinical study of retinoblastoma. AB - AIM: The aim was to analyze general incidence, age incidence, laterality, common mode of presentation, staging of the tumor, radiological evidence, histopathological confirmation, management and follow-up of cases, which were diagnosed as retinoblastoma. DESIGN: Interventional case series study from April 1997 to March 2000. MATERIALS AND METHODS: Detailed history regarding the symptoms such as white reflex, watering, pain, redness, protrusion of eyeball, squint, hyphema, and defective vision were obtained. Family history regarding consanguinity between parents, health of the siblings and other relatives were recorded. Ocular examination included vision, pupillary reaction, detailed fundus examination, ocular tension, and corneal diameter. Investigations included X-ray orbit and skull, computed tomography scan orbit and brain, B-scan orbit, serum and aqueous lactate dehydrogenase; enucleated eyes were subjected to holoprosencephaly (HPE). Enucleation, radiotherapy, cryotherapy and chemotherapy were modalities of treatment. The empty socket and the other apparently normal eye were examined carefully at each visit. RESULTS: The incidence of retinoblastoma is less when compared to other diseases of the eye. There was no sex predilection. Most of the cases diagnosed were sporadic and unilateral. Age of onset is earlier for bilateral cases than unilateral cases. Consanguinity bears close relationship with bilateral involvement. Predominant clinical sign is white reflex in the pupillary area. Majority of cases presented in the second stage of the disease. Enucleation plays a greater role in the management of retinoblastoma. HPE should include several sections of the optic nerve to find out skip lesions. PMID- 26015710 TI - Apoptosis in immune-mediated diseases. AB - Apoptosis plays a significant role in both the physiological and pathological process. A dysfunctional apoptotic system can lead to either excessive removal or prolonged survival of cells. Therefore, dysregulation is involved in the pathogenesis of a variety of immunological diseases. The present review aims to provide an overview regarding role of apoptosis in immune-mediated disease. PMID- 26015711 TI - Genodermatoses. AB - Genodermatoses are an inherited disorder, present with multisystem involvement. Help us to identify regular mutations and appalling skin diseases with recessive inheritance. Genetic heterogeneity is very common, and molecular diagnosis requires a broad effort. Recurrent mutations in unrelated families were seen in families with xeroderma, Griscelli. It seems likely that eventually oligonucleotide arrays will replace most other methods for routine mutation scanning of the more common diseases and planned sequencing will be increasingly used for rarer diseases. PMID- 26015712 TI - Imprint cytology. AB - A valuable information on morphological details of the cell can be obtained through imprint cytology. Though it has some pitfalls, it is still considered to be one of the best methods as it provides an excellent cytological clarity in fresh surgical specimens. This article shares knowledge about the procedure, uses, advantages and disadvantages of imprint cytology. PMID- 26015713 TI - Immunologically mediated oral diseases. AB - Immune mediated diseases of oral cavity are uncommon. The lesions may be self limiting and undergo remission spontaneously. Among the immune mediated oral lesions the most important are lichen planus, pemphigus, erythema multiformi, epidermolysis bullosa, systemic lupus erythematosis. Cellular and humoral mediated immunity play a major role directed against epithelial and connective tissue in chronic and recurrent patterns. Confirmatory diagnosis can be made by biopsy, direct and indirect immunoflouresence, immune precipitation and immunoblotting. Therapeutic agents should be selected after thorough evaluation of immune status through a variety of tests and after determining any aggravating or provoking factors. Early and appropriate diagnosis is important for proper treatment planning contributing to better prognosis and better quality of life of patient. PMID- 26015714 TI - A Paradigm shift in the concept for making dental impressions. AB - Digital dental impression is a revolutionary technological advancement that so surpasses the accuracy and efficiency of former techniques for obtaining replicas of prepared teeth for the purpose of fabricating restorations that its adoption by dentists is rapidly eclipsing the use of elastomeric impression materials. The ultimate goals of dentists dedicated to quality restorative dentistry are to make their treatment of patients as accurate, stressless, and efficient as possible. By elimination of the everyday problems described above, there is no question that the significant advantages of digital impressions will make intraoral digital scanning standard procedure in most dental offices within the next several years. Furthermore, digital impressions have proven to reduce remakes and returns, as well as increase overall efficiency. The patient also benefits by being provided a far more positive experience. Finally, through the use of digital impression making, it has been determined that laboratory products become more consistent and require less chair time at insertion. PMID- 26015715 TI - Rapid prototyping and stereolithography in dentistry. AB - The word rapid prototyping (RP) was first used in mechanical engineering field in the early 1980s to describe the act of producing a prototype, a unique product, the first product, or a reference model. In the past, prototypes were handmade by sculpting or casting, and their fabrication demanded a long time. Any and every prototype should undergo evaluation, correction of defects, and approval before the beginning of its mass or large scale production. Prototypes may also be used for specific or restricted purposes, in which case they are usually called a preseries model. With the development of information technology, three dimensional models can be devised and built based on virtual prototypes. Computers can now be used to create accurately detailed projects that can be assessed from different perspectives in a process known as computer aided design (CAD). To materialize virtual objects using CAD, a computer aided manufacture (CAM) process has been developed. To transform a virtual file into a real object, CAM operates using a machine connected to a computer, similar to a printer or peripheral device. In 1987, Brix and Lambrecht used, for the first time, a prototype in health care. It was a three-dimensional model manufactured using a computer numerical control device, a type of machine that was the predecessor of RP. In 1991, human anatomy models produced with a technology called stereolithography were first used in a maxillofacial surgery clinic in Viena. PMID- 26015716 TI - A comparative study on serum lipoprotein (a) and lipid profile between rheumatoid arthritis patients and normal subjects. AB - BACKGROUND: Rheumatoid arthritis is a chronic and systemic inflammatory disorder, in which Lipoprotein (a) [Lp (a)] increases plaque formation and thus promotes atherosclerosis. Coronary artery disease is one of the co-morbidity in rheumatoid arthritis patients. AIM: The aim of this study is to evaluate Lp (a) as a cardiovascular risk factor in patients with rheumatoid arthritis. This was a comparative study in which Lp (a) and lipid profile were compared in rheumatoid arthritis patients and controls. MATERIALS AND METHODS: The study included 30 sero-positive rheumatoid arthritis patients and 30 normal healthy subjects with an age and sex matched group of 25-80 years. Statistical analysis was performed using SPSS version 17. RESULTS: Serum Lp (a) concentration was significantly increased (P < 0.001) in rheumatoid arthritis patients compared with controls. Serum high-density lipoprotein-cholesterol was significantly lowered (P < 0.05) in patients as compared to controls. There was no significant difference in serum total cholesterol, triglycerides, and very low density lipoprotein-cholesterol between patients and controls. CONCLUSION: The findings indicate that the patients with rheumatoid arthritis are at high risk of developing cardiovascular disease in future due to the increased level of Lp (a). In addition to conventional lipid profile, estimation of Lp (a) can prove to be a valuable tool in risk assessment of population in general and management of disease in particular. PMID- 26015717 TI - Fiber reinforced composites in prosthodontics - A systematic review. AB - Fiber-reinforced composite (FRC), prostheses offer the potential advantages of optimized esthetics, low wear of the opposing dentition and the ability to bond the prosthesis to the abutment teeth, thereby compensating for less-than-optimal abutment tooth retention and resistance form. These prostheses are composed of two types of composite materials: Fiber-composites to build the substructure and hybrid or micro fill particulate composites to create the external veneer surface. This article reviews the various types of FRCs and its mechanical properties. PMID- 26015718 TI - Mandibular advancement device for obstructive sleep apnea: An overview. AB - This paper presents an overview of mandibular advancement device (MAD). The primary purpose of MAD is to move the mandible forwards relative to maxilla in ordered to widen the airway to prevent to closure. PMID- 26015719 TI - Osseointegration. AB - Direct rigid fixation of the implant into jawbones has become an accepted and proven treatment for edentulism. This paper reviews the concept of osseointegration. PMID- 26015720 TI - Bupivacaine versus lignocaine as the choice of locall anesthetic agent for impacted third molar surgery a review. AB - One of the most important goal in minor surgical procedures is to achieve proper and sufficient anesthesia and analgesia preoperatively, intraoperatively and in the immediate postoperative period. Several local anesthetic agents have been cited in the literature and studied. Bupivacaine is one of the most common long acting anesthetic agents being used for surgical removal of impacted third molars. Lignocaine is one of the commonest short-acting anesthetic agents being used for the same procedure. In this review article, the analgesic and anesthetic abilities of the bupivacaine versus lignocaine have been reviewed while surgical removal of impacted third molars. PMID- 26015721 TI - Immediate placement of endosseous implants into the extraction sockets. AB - Implant by definition "means any object or material, such as an alloplastic substance or other tissue, which is partial or completely inserted into the body for therapeutic, diagnostic, prosthetic, or experimental purpose." The placement of a dental implant in an extraction socket at the time of extraction or explantation is known as immediate implant placement whereas delayed placement of implant signifies the implant placement in edentulous areas where healing has completed with new bone formation after the loss of tooth/teeth. Recent idea goes by "why late when it can be done immediately." There are several advantages of immediate placement of implants, and lots of studies have been done. In this article, the advantages and disadvantages of immediate versus delayed placement of implants have been reviewed. PMID- 26015722 TI - One point fixation of zygomatic tripod fractures in the zygomatic buttress through Keen's intraoral approach: A review of 30 cases. AB - For decades, facial beauty and esthetics have been one of the most important quests of the human race. The lateral prominence and convexity of the zygomatic bone makes it the most important bone for providing the aesthetic facial look and sets up the facial width but at the same time this prominence and convexity makes this bone more vulnerable to injury. Zygomatic complex fractures or tripod fractures are the second most common fractures after nasal fractures among facial injuries. Several studies have been undertaken regarding the reduction and fixation of zygomatic fractures with mini plates and screws. In 2002 Fujioka et al in vivo studies successfully proved that one point fixation at the zygomaticomaxillary complex gives three point alignment and sufficient rigidity when the fractures are not comminuted. In this article, 30 cases have been reviewed with one point fixation of zygomatic complex tripod fractures at the zygomatic buttress through Keen's intraoral approach along with advantages and disadvantages. PMID- 26015723 TI - Management of tripod fractures (zygomaticomaxillary complex) 1 point and 2 point fixations: A 5-year review. AB - The zygomaticomaxillary complex (ZMC) plays a key role in the structure, function, and esthetic appearance of the facial skeleton. They can account for approximately 40% of mid-face fractures. They are the second most common facial bone fracture after nasal bone injuries. The fracture complex results from a direct blow to the malar eminence and results in three distinct fracture components that disrupt the anchoring of the zygoma. In addition, the fracture components may result in impingement of the temporalis muscle, trismus (difficulty with mastication) and may compromise the infraorbital foramen/nerve resulting in hypesthesia within its sensory distribution. A 4-year retrospective review of all patients treated with ZMC fractures at oral and maxillofacial surgery department, sree balaji dental college and hospital was performed. Computed tomography scans were reviewed. Demographics, treatment protocols, outcomes, complications, reoperations, and length of follow-up were identified. A total of 245 patients was identified by the Current Procedural Terminology codes for ZMC fractures. Closed or open reduction methods were performed with the goal of treatment being preservation of normal facial structure, sensory function, globe position, and mastication functionality. Unacceptably poor surgical outcomes are uncommon. Significant facial asymmetry requiring surgical revision occurs in 3-4% of patients. Postoperative infection rates are extremely low, and these infections nearly always resolve with oral antibiotics. In general, the long-term prognosis after repair of ZMC fractures is very good. PMID- 26015724 TI - Nitrousoxide as a conscious sedative in minor oral surgical procedure. AB - Nitrous oxide (N2O) is the most commonly used inhalation anesthetic in dentistry and is commonly used in emergency centers and ambulatory surgery centers as well. When used alone, it is incapable of producing general anesthesia reliably. However, as a single agent, it has an impressive safety and is excellent for providing minimal and moderate sedation for apprehensive minor oral surgical procedure. In this article, action of N2O in overcoming the anxiety and pain of the patient during the minor oral surgery and its advantages and disadvantages, have been reviewed. PMID- 26015725 TI - The incidence of cysts and tumors associated with impacted third molars. AB - Incidence of cysts and tumors associated with lower impacted third molars are very low prevalence, which might be because of the fact that most pathologies go unnoticed as many practitioners discard the erupted tissue after surgical removal of the impacted teeth rather than sending the tissue for histopathological examination. Our aim was to evaluate the patients who came for third molar surgical removal with due therapeutic prophylacis and an incidental finding. A proper study protocol both inclusion and exclusion criteria was strictly followed for all the cases, which were included in the study. The period of study was 6 years and the total number of cases assessed were 2778 patients out of which 70 cases reported pathology associated with the impacted third molars. Among 70 cases 61.4% were reported as cyst and tumors and 38.6% of the cases had chronic inflammatory reaction, including two cases with normal dental follicle. High incidence rate of pathology associated with third molar occurred between age group of 20 and 30 years older age groups showed very low incidence. Most common site of impaction was found to be left side of mandible and positions were vertical and distoangular impactions. Thus was male predominance in the younger groups. The examination is necessary whether the third molars impacted cases were symptomatic or asymptomatic. PMID- 26015726 TI - Benefits of Aloe vera in dentistry. AB - Aloe vera (Aloe barbadensis) is a plant that belongs to Liliaceae family. The name Aloe derives from the Arabic word "Alloeh" meaning shining bitter substance while "vera" in Latin means true. It contains various minerals and vitamins. It has got various properties such as immunomodulatory, antiviral and antiinflammatory in nature. A. vera can play a significant role in dentistry in treatment of lichen planus, oral submucous fibrosis, recurrent aphthous stomatitis, alveolar osteitis, periodontitis, etc. PMID- 26015727 TI - Macrolide resistance in Streptococcus species. AB - BACKGROUND: The Streptococci are Gram-positive spherical bacteria (cocci) that characteristically form pairs and chains during growth. Some macrolide-resistant bacteria lack the proper receptor on the ribosome (through methylation of the rRNA). This may be under plasmid or chromosomal control. AIM AND OBJECTIVES: The aim was to study the prevalence of macrolide resistance among the isolate and evaluate the degree of resistance by minimum inhibitory concentration (MIC) method. And also to detect the phenotypic pattern of macrolide resistance. MATERIALS AND METHODS: All age group attending general medicine OPD and pediatric OPD with symptoms of respiratory and pyogenic infections are included in the study. Various samples are collected with detailed case history and processed for macrolide resistance among beta hemolytic Streptococci MIC method and D-test. RESULTS: According to our studies resistance pattern in Group A Streptococci by D test, cMLS was 27.85%, iMLS was 13.92%, M-type was 55.69%, in GCS, cMLS was 17.6%, M-type was 82.35% In GGS, cMLS was 31.58%, iMLS was 10.53% and M-type was 57.89%. CONCLUSIONS: Therefore by this study, we would like to highlight the necessity to do antibiotic sensitivity testing for all isolates, and limit the usage of antibiotics, whenever necessary and select the appropriate antibiotics for resistant strains. PMID- 26015728 TI - Forensic radiology in dentistry. AB - Radiography can play an important part in forensic odontology, mainly to establish identification. This may take the precise form of comparison between antemortem and postmortem radiographs. Radiographs may also be taken to determine the age of a minor victim and even help in the assessment of the sex and ethnic group. Comparable radiographs are an essential factor to confirm identification in a mass disaster. PMID- 26015729 TI - Bruxism: Conceptual discussion and review. AB - Bruxism is commonly considered a detrimental motor activity, potentially causing overload of the stomatognathic structures. The etiology of bruxism is unclear, but the condition has been associated with stress, occlusal disorders, allergies and sleep positioning. Due to its nonspecific pathology, bruxism may be difficult to diagnose. Unfortunately, very little data exists on the subject of a cause-and effect relationship of bruxism to the point that expert opinions and cautionary approaches are still considered the best available sources for suggesting good practice indicators. The present paper reviewed current concepts on bruxism, etiology, diagnosis and management, underlining its effects on dental structures in an attempt to provide clinically useful suggestions based on scientifically sound data. PMID- 26015730 TI - Smile: A review. AB - "Beauty is in the mind of the beholder, each mind perceives a different beauty" famously said by writer Margeret Wolfe Hungerford. A beautiful smile is a gateway to the world. The aim of this article was to identify the criteria for designing the perfect smile. It was determined, smile design is a multifactorial process and various steps are involved in designing a radiant smile. PMID- 26015731 TI - Aggressive granular cell ameloblastoma: Report of a rare case. AB - Granular cell ameloblastoma is a slow growing odontogenic ectodermal tumor. The tumor shows typical ameloblastoma with the cells showing eosinophilic granularity. This variant of ameloblastoma is aggressive with high recurrence rates. We report a case of aggressive ameloblastoma of granular cell variant. PMID- 26015732 TI - Loop connectors in dentogenic diastema. AB - Patients with a missing tooth along with diastema have limited treatment options to restore the edentulous space. The use of a conventional fixed partial denture (FPD) to replace the missing tooth may result in too wide anterior teeth leading to poor esthetics. Loss of anterior teeth with existing diastema may result in excess space available for pontic. This condition presents great esthetic challenge for prosthodontist. If implant supported prosthesis is not possible because of inadequate bone support, FPD along with loop connector may be a treatment option to maintain the diastema and provide optimal esthetic restoration. Here, we report a clinical case where FPD along with loop connector was used to achieve esthetic rehabilitation in maxillary anterior region in which midline diastema has been maintained. PMID- 26015733 TI - Enhanced aesthetics with all ceramics restoration. AB - The demand for the dentist to achieve excellence in esthetics and function has driven modern advances in materials and restoration fabrication. The development of various casting alloys and precise casting systems has contributed to the successful use of metal-based restorations. However, patient requests for more aesthetic and biologically "safe" materials that have led to an increased demand for metal-free restorations. The following case presentation illustrates a successful aesthetic and functional application of this exciting computer-aided design/computer-aided manufacturing-digital zirconia-based system for a natural smile. PMID- 26015734 TI - Expanding digits of a maxillofacial prosthodontist. AB - Complete or partial loss of a finger is the most commonly encountered problem in prosthetic dentistry. The etiology of missing digit may either be congenital or acquired. Trauma is the most common cause for acquired defect of the digit. Loss of a digit results in functional and psychological impact on quality-of-life of the patient. This article portrays about the prosthetic management of a patient with an acquired defect of finger. PMID- 26015735 TI - Combination restoration in full mouth rehabilitation. AB - Successful restoration of the dentition requires plenty of contemporary and conventional treatment techniques and planning and attachment retained partial dentures are one such kind of treatment modality in prosthodontics. Satisfactory restoration in a patient with a partially edentulous situation can be challenging especially when unilateral or bilateral posterior segment of teeth is missing. One such treatment modality is attachment-retained cast partial dentures. The purpose of this article is to provide an overview of a case with maxillary complete denture and opposing cast partial denture with precision attachment. PMID- 26015736 TI - Treatment of calcifying epithelial odontogenic tumor/Pindborg tumor by a conservative surgical method. AB - Calcifying epithelial odontogenic tumor (CEOT) also known as Pindborg tumor is a rare odontogenic epithelial neoplasm. So far nearly 200 cases have been reported in literature. We are reporting a case of CEOT in a 42-year-old male patient with painless bony swelling in the mandible. Approximately, 50% of the cases are associated with an unerupted tooth or odontome, but was not so with our case. Considering the intrabony mandibular location of the lesion and its limited size, we opted for a more conservative surgery. The clinical, radiographic and histopathologic features and the surgical treatment done are discussed with relevant references. PMID- 26015737 TI - Role of dietary habits and diet in caries occurrence and severity among urban adolescent school children. AB - To identify the role of dietary habits (type of diet, skipping meals, snacking in between meals and frequency of visits to fast food restaurants) in caries occurrence and severity. To explore the correlation between frequency of intake of selected foods and dental caries. A cross-sectional study was carried out on adolescent children (n = 916) of age 13-19, following a two-stage random sampling technique. Data were collected using a pretested questionnaire. Questionnaire included demographic details, dietary habits of children and food frequency table that listed selected food items. The dependent variable-dental caries was measured using the decayed, missing, filled teeth (DMFT) index. The prevalence of dental caries in this study population was 36.7% (95% confidence interval: 33.58 39.82). The mean DMFT was 1.01 (+/-1.74). No statistically significant difference found between caries occurrence and type of diet (P = 0.07), skipping meals (P = 0.86), frequency of eating in fast food stalls (0.86) and snacking in between meals (0.08). Mean DMFT values were higher among nonvegetarians and among children who had the habit of snacking in between meals. Frequency of intake of selected food items showed that mean frequency intake of carbonated drinks and confectionery was higher among children who presented with caries when compared to caries-free children (P = 0.000). Significant correlation found between mean DMFT and mean frequency intake of carbonated drinks and confectionery. Odds ratios were calculated for the same for frequency >=4 times/day for confectionery and >=4/week for carbonated drinks and results discussed. Frequent intake of carbonated drinks and confectionery is harmful to oral health that eventually reflects on general health. Educating the adolescent children on healthy dietary habits should be put in the forefront. PMID- 26015738 TI - Transparent aligners: An invisible approach to correct mild skeletal class III malocclusion. AB - This case report highlights the treatment of a mild skeletal class III malocclusion with an invisible thermoplastic retainer. A 15-year-old female patient presented with a mild skeletal class III malocclusion with a retrognathic maxilla, orthognathic mandible, a low mandibular plane angle with Angle's class III malocclusion with maxillary lateral incisors in anterior cross-bite with crowding of maxillary anteriors, imbricated and rotated mandibular incisors and deep bite. Accurate upper and lower impressions and a bite registration were taken with polyvinyl siloxane rubber base impression material. This was then sent to the lab for the processing of a series of ClearPath aligners. The ClearPath virtual set-up sent from the lab provided the treatment plan and interproximal reduction estimation complete with posttreatment results. This enabled the clinician to actively participate in the treatment plan and provide the necessary suggestions. The ClearPath three-dimensional aligner was found to have effectively corrected the anterior cross-bite and crowding of the maxillary anteriors. PMID- 26015739 TI - Solitary median maxillary central incisor: A case report of a rare dental anomaly. AB - The solitary median maxillary central incisor (SMMCI) syndrome is a rare dental anomaly and has an incidence of 1:50,000 live births. In SMMCI, there is only one central incisor present, and it develops exactly at the midline. SMMCI occurrence has been described with growth hormone deficiency or other structural anomalies in the midline of the body. In this case, the 8-year-old female patient reported a single median maxillary central incisor with missing maxillary and mandibular frena, with apparently no other abnormalities. Early diagnosis and recognition of SMMCI are important for all practicing Orthodontists, as it may be a sign of other severe congenital or developmental abnormalities. PMID- 26015740 TI - A rare case of impacted supernumerary premolar causing resorption of mandibular first molar. AB - The management of patients with pain in today's general practice has become a major concern and sometimes this pain is related to some rare causes. A male patient aged 26 years reported with pain in the lower left molar region (36) and then an intra-oral periapical radiograph (IOPA), and orthopantomograph was taken. IOPA revealed the presence of supernumerary premolar causing pressure and root resorption of 36. Also, there was missing 21 and proximal decay in 11. Eleven was treated endodontically, and then bridge was done in relation to 11, 21 and 22. Lower anterior crowding was also present. The treatment plan was to extract 36 followed by orthodontic extrusion of the supernumerary premolar and also the correction of lower anterior crowding. Hidden approach (lingual orthodontics) was used as the patient was insisting upon the braces not being seen outside during the course of the treatment. Later all ceramic bridge was done in relation to 11, 21 and 22. Orthodontic tooth extrusion techniques offer excellent treatment options for Partially Impacted tooth. It is a well-documented clinical method for extruding sound tooth material from within the alveolar socket by light forces. The use of lingual technique for forced eruption enhance acceptance of orthodontic treatment by adults. The treatment of a young adult patient illustrates the importance of treatment planning from one discipline to another, communication among team members and the benefits of working together in an interdisciplinary approach. PMID- 26015741 TI - Gnathological splint therapy in temporomandibular joint disorder. AB - Temporomandibular joint (TMJ) forms an integral functional part of stomatognathic system. Position, shape, structure and function of teeth have an influence on the proper functioning and health of TMJ. But a problem associated with TMJ is often neglected, and treatment for it is mostly restricted to palliative therapy. A proper understanding of the underlying cause of temporomandibular joint disorder (TMD) is necessary to device a proper treatment plan. Etiology of TMDs varies from idiopathic reasons to systemic disorders. The option of Gnathological splint is a conservative, safe and an effective mode of therapy for TMDs caused by occlusal discrepancies (fulcrum/interferences). This article presents a case report of a patient with TMD caused by occlusal discrepancy. PMID- 26015742 TI - Serum fructosamine a better indicator than glycated hemoglobin for monitoring gestational diabetes mellitus. AB - Gestational Diabetes mellitus is the condition of glucose intolerance that begins during pregnancy which is associated with both fetal and maternal complications. The measurement of serum fructosamine and glycated hemoglobin in normal and diabetic pregnancy used to investigate the influence of maternal and gestational age on concentrations of glycated proteins in serum and used to evaluate the patient's treatment. This study was done to measure the level of serum fructosamine and Glycated hemoglobin (HbA1c) in Gestational Diabetes mellitus (GDM) patients and to compare with pregnant women without diabetes and healthy non-pregnant adults, to determine the pattern of change in serum fructosamine, influence of serum fructosamine and HbA1c values and to evaluate the efficacy of patient's treatment. In this study the level of fructosamine was positively correlated to HbA1c during 2(nd) trimesters of gestational period, implying that the level of fructosamine can be used to screen Gestational diabetes mellitus. Correlation of glycated hemoglobin values with serum fructosamine measurements in the accurate determination of glycaemic control provides confirmation of the utility of fructosamine measurement. PMID- 26015743 TI - Pulmonary function test in formalin exposed and nonexposed subjects: A comparative study. AB - BACKGROUND: The main function of the lung is gas exchange, which can be assessed in several ways. A spirometer measures the flow and the volumes of the inspired and expired air. The thoracic and abdominal muscle strength plays an important role in pulmonary function and diffusing lung capacity. AIMS AND OBJECTIVES: The aim of this study was to assess the effects of formalin exposure on the pulmonary function to compare with healthy individuals. To assess the chronic effects of formalin exposure on Pulmonary function tests (PFTs) in the faculties, lab technicians and attender of the Department of Anatomy and Pathology of SRM Medical Hospital and Research Centre, Kattankulathur. MATERIALS AND METHODS: This prospective study was carried out in 50 healthy formalin exposed subjects (at least 5 years exposure) from Department of Anatomy and Pathology of SRM Medical College Hospital and Research Centre, Kattankulathur and 50 healthy controls of same age group of this study were included after obtaining ethical clearance and consent 'Easy One Pro Spirometer (Ndd Medical Technologies, Cheshire SK 101LT, United Kingdom) was used to find out the PFT. RESULTS: Student's t-test was applied to compare the PFT parameters between formalin exposed and formalin nonexposed group. There was a significant difference in mean and standard deviation of pulmonary parameters with the P < 0.005 in formalin exposed, which shows that they have lesser ventilatory drive. CONCLUSION: The formalin exposed subjects in our study presented with a mixed disorder of both obstructive and restrictive type. We also found that there was a negative correlation of pulmonary function with that of the degree and duration of exposure to formalin. PMID- 26015744 TI - Serum uric acid in new and recent onset primary hypertension. AB - INTRODUCTION: Hyperuricemia is common among adults with prehypertension, especially when the microalbuminuria is present. Hyperuricemia precedes the development of hypertension. AIM: (1) To find the association of hyperuricemia in new-onset hypertensive patients. (2) To find the association of hyperuricemia in hypertensive patients with regard to gender and risk factors such as smoking and central obesity. MATERIAL AND METHODS: A total of 50 adults aged between 20 and 50 years who had mild early hypertension were selected for the study. Fifty controls without hypertension were enrolled and investigated. RESULTS: The association between uric acid (UA) and hypertension was analyzed using Student's t-test and statistical difference were assessed using Pearson coefficient. The study showed a significant difference in UA between the hypertensive subjects and the normotensive controls. There was not a significant difference between waist abnormality, smoking and UA in cases. Males have a higher degree of hyperuricemia than females in hypertensive patients. CONCLUSION: Serum UA is strongly associated with blood pressure (BP) in new and recent onset primary hypertension. The remarkable association of UA with BP in adults is consistent with recent animal model data and the hypothesis that the UA might have a pathogenic role in the development of hypertension. PMID- 26015745 TI - Antioxidant activity of ethanolic extract of Tinospora cordifolia on N nitrosodiethylamine (diethylnitrosamine) induced liver cancer in male Wister albino rats. AB - BACKGROUND: Cancer is a disease that evokes wide spread fear among people and is one of the leading causes of deaths in the world. Diethylnitrosamine (DEN) is a known carcinogen in rodent liver. DENs reported to undergo metabolic activation by cytochrome P450 enzymes to form reactive electrophiles that cause oxidative stress leading to cytotoxicity, mutagenicity and carcinogenicity. OBJECTIVE: The present study was carried out to evaluate the antioxidant activity of ethanolic extract of Tinospora cordifolia (EETC) in N-nitrosodiethylamine (DEN) induced liver cancer in male Wister albino rats. MATERIALS AND METHODS: The antioxidant activity was assessed by the levels of lipid peroxidation (LPO), enzymic and nonenzymic antioxidants. RESULT: A significant levels of LPO was increased as the enzymic and nonenzymic antioxidants values were decreased in liver cancer bearing animals. CONCLUSIONS: The administration of EETC to cancer bearing animals reverted the LPO levels, enzymic and nonenzymic antioxidants to near normal. PMID- 26015746 TI - Anatomy research under the knife of medical ethics. AB - There is increased awareness and anxiety in conducting research for publication and at the same time ignorance about getting Ethical Committee clearance at least in Anatomy Departments among Basic Medical Sciences. While people are actively presenting papers, collect data, Indian Council for Medical Research guidelines does not cover aspects pertaining to Anatomy oriented research activities. This review article is an eye opener for fraternity in the medical field, especially in anatomy. PMID- 26015747 TI - Things you don't learn in medical school: Caduceus. AB - It is a known fact that every symbol has a unique meaning. In that case what does this unique symbol, Caduceus, which is used, in various forms and modifications, by many medical organizations mean? Is it just a custom or does it have a deeper meaning? The story of this medical symbol started way back in 1400 BC, travelled through time, has undergone many changes, misconceptions and has finally reached the present state. Here we have tried to give you a glimpse of how it has evolved over time, what it actually means, what have we interpreted and what can we learn from it. PMID- 26015749 TI - Whats special in a child's larynx? AB - What's special in a child's larynx? Many of us know only a few specialties of the pediatric larynx, but there are much more features, which are unique and often not highlighted. To understand the pediatric larynx, we have reviewed the development, the functions in-utero and new born period and peculiarities. PMID- 26015748 TI - Intra cranial complications of tuberculous otitis media. AB - Tuberculosis is one of the most common infections in the world. It is seen that tuberculous otitis media (TOM) is almost secondary to pulmonary tuberculosis. In this review we have tried to deal with all the aspects of the intra cranial complications of TOM such as tuberculoma, otitic hydrocephalus, brain abscess and tuberculous meningitis. The aspects covered in this review are the pathology, clinical features, and investigations of the intra cranial manifestations. PMID- 26015750 TI - Rhinosporidiosis and the pond. AB - Rhinosporidiosis is a fungal disease caused by the organism Rhinosporidum seeberi. The life cycle and mode of infection are vague, and there are many hypothesis on it. Its prevalence in the world is unique as it is only limited to certain regions like India, Pakistan and Sri Lanka. We have tried to correlate the various factors, which will probably be associated with this pattern of prevalence of the disease. We have included factors like community practices, climatic conditions, rain fall pattern, water physiochemical properties, zoonotic and the aquatic organism composition in the specified regions. Thus, it serves as a wholesome idea of why the disease must only be prevalent in certain parts of the world. PMID- 26015751 TI - A case of mediastinitis secondary to retropharyngeal abscess. AB - A 50 year old male patient who consumed chicken bone soup, 4 days back, presented with dysphagia, high grade fever with chills, shortness of breath and swelling in face, neck and upper chest. Patient was toxic and in respiratory distress with room air oxygen saturation of 83%, which increased to 92% with 6 lit of oxygen through simple face mask. Indirect laryngoscopy revealed a retro pharyngeal abscess and CT chest revealed Sub-cutaneous and mediastinal emphysema. The abscess was immediately drained and followed with parenteral anti-microbials and high flow oxygen theapy. Patient improved and was discharged after 12 days. This case was reported as, foreign body causing Retro-pharyngeal abscess is a very rare entity in this anti-biotic era especially leading to a very rare complication of mediastinitis and Pneumomediastinum is unusual. PMID- 26015752 TI - A rare case of typhoid presenting with fever, ascites, hyponatremia, thrombocytopenia, mesenteric lymphadenitis, and multi-drug resistance. AB - A rare case of typhoid presenting with thrombocytopenia, hyponatremia, ascites mesenteric adenitis, and multi-drug resistance is being presented in this article. An 8-year-old girl was admitted with a history of fever, vomiting, abdominal pain and loose stools. Clinical examination revealed fever and hepatosplenomegaly. Investigations showed leucopenia, thrombocytopenia and hyponatremia. Blood Widal was positive, and blood culture grew Salmonella typhi. Ultrasound abdomen revealed ascites, hepatosplenomegaly, mesenteric lymphadenopathy and thickening of the gall bladder. She was treated with ciprofloxacin intravenously for 6 days and when the fever persisted injection ceftriaxone was added. Ciprofloxacin was given intravenously for a total of 15 days and injection ceftriaxone was given for 12 days. Even then, the fever persisted and hence oral azithromycin was added. Fever subsided completely in 3 days with azithromycin and she became asymptomatic without fever, loose stools, abdominal pain or anything on follow-up after 3 months. PMID- 26015753 TI - An unusual cause of fungal pneumonia. AB - A 65 year old female, known asthmatic on steroids intermittently, with no other co-morbidity presented with fever, breathlessness and cough with mucoid expectoration of ten days duration with bilateral crepts, went for Type II respiratory failure and was intubated followed by tracheostomy in view of prolonged ventilator support. In spite of high end antibiotics as per sputum culture sensitivity, weaning off the ventilator was not possible. Blood investigations revealed leucocytosis with neutrophilic predominance and IgE levels were within normal limits. CT chest showed multiple patchy consolidations of the right upper, middle and lower lobes with ground glass appearance and enlarged mediastinal lymph nodes. Work up for retrovirus, tuberculosis and Sputum for KOH mount was negative. No evidence of sputum and blood eosinophilia. BAL sample grew Curvularia species. Fluconazole 150mg OD was added. Serial imaging of the chest showed resolution of the consolidation and was weaned off the ventilator and was comfortable on room air. Pneumonia caused by Curvularia, in an immune competent patient is very rare. Even in broncho pulmonary involvement these fungi usually occur in allergic conditions as in ABPA than appearing as a solitary cause for lung infection. But if diagnosed and treated early, will respond well to triazoles. This case report highlights a unilateral fungal pneumonia with dramatic clinical improvement post treatment once the rare causative organism was identified. PMID- 26015754 TI - Bilateral angle closure glaucoma following general anaesthesia. AB - Angle closure glaucoma is one of the ophthalmic emergencies and treatment has to be given at the earliest. It is a rare complication of general anesthesia. A female patient underwent Hysterectomy under general anesthesia. Following this, patient developed bilateral angle closure glaucoma. This patient was treated with antiglaucoma medications followed by YAG laser iridotomy and patient regained vision. PMID- 26015755 TI - Nasal rhinosporidiosis with an atypical presentation. AB - Rhinosporidiosis is a unique disease, which is seen to be endemic in certain places in India such as Tamil Nadu and Sri Lanka. The disease is caused by Rhinosporidium seebri and it is transmitted by bathing in ponds contaminated by cattle feces containing spores of the organism. The disease usually presents as multiple granulomatous bleeding polyps. The case described here is a unique presentation where it occurs only in a single site and that too in an uncommon location where the suspicion of rhinosporidiosis is a last possibility. PMID- 26015756 TI - Erythema ab igne: Usual site, unusual cause. AB - Erythema ab igne is reticular erythematous pigmented dermatoses seen in patients exposed to prolonged or repeated sub-threshold Infrared radiation inadequate to cause burns. Here, we report a case of erythema ab igne in a 40-year-old male patient seen over the abdomen due to prolonged laptop use. PMID- 26015757 TI - Hypothyroidism with scholastic excellence. AB - A 9-year-old boy had presented with not gaining adequate height with complaints of constipation from 5 years, lethargy and loss of appetite from past 6 months. He was diagnosed to have hypothyroidism with high thyroid antibody levels. Though he was stunted his neurocognition and scholastic performance was excellent as evidenced by his school rank cards. His physical symptoms had improved after thyroxin supplement. PMID- 26015758 TI - Innovative management of nasal septal hematoma in an infant. AB - Nasal septal hematoma is a collection of blood between the cartilage or bone and mucoperichondrium or mucoperiosteum of the nose. This condition requires immediate surgical drainage to prevent complications. All patients need nasal packing postoperatively to prevent recurrence. This causes a lot of discomforts due to mouth breathing more in infants who are obligatory nose breathers. They can go for cyanosis in the postoperative period. Here, we discuss the case report of an infant who had tubular nasal pack with endotracheal tube postoperatively to maintain the patency of nose. PMID- 26015759 TI - An unusual case of pseudochylothorax. AB - A 25-year-old male patient presented with right-sided pleuritic chest pain and pain in the ankle. Radiological investigations revealed a right sided pleural effusion, lytic lesion in spine D10 with paravertebral abscess. Pleural fluid analysis showed elevated lactate dehydrogenase, adenosine deaminase, increased triglycerides, cholesterol, and no chylomicrons. Hence, a diagnosis of pseudochylothorax secondary to tuberculosis was made. Pleural fluid was drained by tube thoracostomy, decortication was done to improve the lung function and patient was started on anti-tuberculosis treatment (ATT). Patient improved with ATT. Pseudochylous effusion or chyliform effusions are uncommon. <200 cases has been reported in the international literature. The possibility of tuberculosis has to be considered in diagnosis and treatment of such cases. Here, we present a case of tuberculous pseudochylous effusion. PMID- 26015760 TI - Single umbilical artery. AB - The umbilical cord usually contains two arteries and one vein. The vein carries the oxygenated blood from the placenta to the fetus. The arteries carry the deoxygenated blood and the waste products from the fetus to the placenta. Occasionally, primary agenesis or secondary atrophy of one of the arteries occurs resulting in single umbilical artery. PMID- 26015761 TI - Correlation between arch form and facial form: A cross sectional study. AB - Arch form is a key determinant in teeth position. Teeth selection and placement must be based on the functional and esthetic needs of the patient. Keeping in mind, the biomechanics involved with the prosthesis. The aim of the study was to evaluate the correlation between arch form and facial form. About 40 individuals in the age group of 20-25 years were involved in the study. The arch form and facial form were analyzed statistically to check for any correlation. It was found that, 63.63% of leptoprosophic individuals had squarish arch form while, 54.6% of mesoprosophic faces had ovoid arch form. PMID- 26015762 TI - Comparative evaluation of the three different surface treatments - conventional, laser and Nano technology methods in enhancing the surface characteristics of commercially pure titanium discs and their effects on cell adhesion: An in vitro study. AB - The surface area of the titanium dental implant materials can be increased by surface treatments without altering their shape and form, thereby increasing the biologic properties of the biomaterial. A good biomaterial helps in early cell adhesion and cell signaling. In this study, the commercially pure titanium surfaces were prepared to enable machined surfaces to form a control material and to be compared with sandblasted and acid-etched surfaces, laser treated surfaces and titanium dioxide (20 nm) Nano-particle coated surfaces. The surface elements were characterized. The biocompatibility was evaluated by cell culture in vitro using L929 fibroblasts. The results suggested that the titanium dioxide Nano particle coated surfaces had good osteoconductivity and can be used as a potential method for coating the biomaterial. PMID- 26015763 TI - Health problems and stress in Information Technology and Business Process Outsourcing employees. AB - Stress is high in software profession because of their nature of work, target, achievements, night shift, over work load. 1. To study the demographic profile of the employees. 2. To access the level of job stress and quality of life of the respondents. 3. To study in detail the health problems of the employees. All employees working in IT and BPO industry for more than two years were included into the study. A detailed questionnaire of around 1000 IT and BPO employees including their personal details, stress score by Holmes and Rahe to assess the level of stress and master health checkup profile were taken and the results were analysed. Around 56% had musculoskeletal symptoms. 22% had newly diagnosed hypertension,10% had diabetes, 36% had dyslipidemia, 54% had depression, anxiety and insomnia, 40% had obesity. The stress score was higher in employees who developed diabetes, hypertension and depression. Early diagnosis of stress induced health problems can be made out by stress scores, intense lifestyle modification, diet advice along with psychological counselling would reduce the incidence of health problems in IT sector and improve the quality of work force. PMID- 26015764 TI - Evaluation depth of the curve of Spee in class I, class II, and class III malocclusion: A cross sectional study. AB - Occlusal plane is an essential consideration when multiple long-span posterior restorations are designed. When restorations are added to an existing tooth arrangement characterized by rotated, tipped, or extruded teeth, excursive interferences may be incorporated, resulting in detrimental squeal. The curve of Spee, which exists in the ideal natural dentition, allows harmony to exist between the anterior tooth and condylar guidance. This curve exists in the sagittal plane and is the best viewed from a lateral aspect. It permits total posterior disclusion on mandibular protrusion, given proper anterior tooth guidance. It is unclear that whether the curve of Spee is a description of the occlusal surface of each arch separately or in maximal intercuspation. The purpose of this study was to examine the differences in the depth of curve of Spee between the class I, class II, class III and to investigate the relationship of depth of curve of Spee with over jet, over-bite. PMID- 26015765 TI - Relationship between occlusal plane and ala-tragus line in dentate individuals: A Clinical pilot study. AB - Many methods have been used to establish the occlusal plane in complete denture prosthodontics. However, no single method seems to be fully accepted. Anteriorly, esthetic considerations help define the occlusal plane, and posteriorly the tongue, retromolar pad, and Stenson's duct are considered. Some dentists bisect the space between the residual ridges. The technique of using the ala-tragus line (Camper's line) to establish the occlusal plane is well documented. However, definitions of the ala-tragus line cause confusion, because the exact points of reference do not agree. For example, the glossary of prosthodontic terms states that the ala-tragus line runs from the inferior border of the ala of the nose to the superior border of the tragus of the ear while Spratley' describes it as running from the center of the ala to the center of the tragus. This article concerns us the exact relationship between the occlusal plane and ala-tragus line in dentate individuals. PMID- 26015766 TI - Self-perceived need for dental care. AB - AIMS: The aim of this study is to evaluate the self-perceived need for dental care among medical professionals and general public. SETTING AND DESIGN: (1) To determine the perceived oral health status. (2) To evaluate the results in understanding the perception of oral health. (3) To determine the patients attitude toward dentist. SUBJECTS AND METHODS: The study was carried out on 537 patients who came for their regular checkup and treatment. STATISTICAL ANALYSIS USED: The statistical analysis of this study was based on Chi-square test evaluation. The study was performed among in 537 participants. The participants included from age group of both <30 and >30. The study was made in the form of questionnaires enquiring how they would perceive their personal dental care and their attitude towards dentist. RESULTS: Self-perceived questionnaires in evaluating general public in age group of <30 and >30 shows, that people in age group more than 30 has good oral hygiene maintenance, whereas attitude toward dentist and attending dental problems were more among group less than 30 of age. CONCLUSIONS: I conclude that there must be more awareness created by public health dentist among people about various dental problems, their complications and the treatment needs. Hence, that people be aware of their dental problem at the small stage and get cured. By conducting varies Public Health Programs and camp they became very free to contact their dentist for their varies dental problems and people attitude about dentist and toward dentist completely changes. PMID- 26015767 TI - Identification of inflammatory mediators in patients with rhegmatogenous retinal detachment associated with choroidal detachment. AB - PURPOSE: To investigate the expression profile of intravitreous cytokines, chemokines, and growth factors in patients with rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) in comparison with patients with only rhegmatogenous retinal detachment (RRD). METHODS: Twenty RRDCD patients and 30 RRD patients were included in this case-control study. A multiplex bead-based immunoassay was performed to determine the expression of a wide range of 29 inflammatory mediators in undiluted vitreous from the patients. Data were analyzed using the Mann-Whitney U-test for nonparametric values and multivariate logistic regression analysis. RESULTS: Compared with the patients with RRD, intravitreous inflammatory mediators, including migration inhibitor factor (MIF), interleukin-6 (IL-6), CCL4, CCL11, CCL17, CCL19, CCL22, CXCL9, CXCL8, soluble inter-cellular adhesion molecule 1 (sICAM-1), transforming growth factor beta3 (TGF-beta3), and platelet-derived growth factor AA (PDGF-AA), were upregulated in patients with RRDCD. After calibrating the factors duration of detachment, preoperative proliferative vitreoretinopathy grade, and presence or absence of macular hole, the PDGF-AA concentrations were not significantly different according to the multivariate logistic regression analysis. MIF and sICAM-1 markers were significantly different between the two groups and represented a forward stepwise logistic regression trend. CONCLUSIONS: This is the first report to use multiplex bead analysis to investigate inflammatory mediators related to RRDCD. We proposed that the upregulated expression of these mediators may be involved in the inflammation process of RRDCD and that regulation of their expression may be potentially therapeutic by altering local inflammation. PMID- 26015768 TI - Expression-associated polymorphisms of CAV1-CAV2 affect intraocular pressure and high-tension glaucoma risk. AB - PURPOSE: The human CAV1-CAV2 locus has been associated with susceptibility to primary open-angle glaucoma in four studies of Caucasian, Chinese, and Pakistani populations, although not in several other studies of non-Korean populations. In this study with Korean participants, the CAV1-CAV2 locus was investigated for associations with susceptibility to primary open-angle glaucoma accompanied by elevated intraocular pressure (IOP), namely, high-tension glaucoma (HTG), as well as with IOP elevation, which is a strong risk factor for glaucoma. METHODS: Two single nucleotide polymorphisms (SNPs) were genotyped in 1,161 Korean participants including 229 patients with HTG and 932 healthy controls and statistically examined for association with HTG susceptibility and IOP. One SNP was rs4236601 G>A, which had been reported in the original study, and the other SNP was rs17588172 T>G, which was perfectly correlated (r2=1) with another reported SNP rs1052990. Expression quantitative trait loci (eQTL) analysis was performed using GENe Expression VARiation (Genevar) data. RESULTS: Both SNPs were associated with HTG susceptibility, but the rs4236601 association disappeared when adjusted for the rs17588172 genotype and not vice versa. The minor allele G of rs17588172 was associated significantly with 1.5-fold increased susceptibility to HTG (p=0.0069) and marginally with IOP elevation (p=0.043) versus the major allele T. This minor allele was also associated with decreased CAV1 and CAV2 mRNA in skin and adipose according to the Genevar eQTL analysis. CONCLUSIONS: The minor allele G of rs17588172 in the CAV1-CAV2 locus is associated with decreased expression of CAV1 and CAV2 in some tissues, marginally with IOP elevation, and consequently with increased susceptibility to HTG. PMID- 26015769 TI - RNA-seq identifies a role for the PPARbeta/delta inverse agonist GSK0660 in the regulation of TNFalpha-induced cytokine signaling in retinal endothelial cells. AB - PURPOSE: The peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a transcription factor with roles in metabolism, angiogenesis, and inflammation. It has yet undefined roles in retinal inflammation and diabetic retinopathy (DR). We used RNA-seq to better understand the role of the antagonist and inverse agonist of PPARbeta/delta, GSK0660, in TNFalpha-induced inflammation. Understanding the underlying mechanisms of vascular inflammation could lead to new treatments for DR. METHODS: RNA was isolated from human retinal microvascular endothelial cells treated with a vehicle, TNFalpha, or TNFalpha plus GSK0660. RNA-seq was performed with a 50 bp single read protocol. The differential expression was determined using edgeR and gene ontology, and a pathway analysis was performed using DAVID. RNA-seq validation was performed using qRT-PCR using the primers for ANGPTL4, CCL8, NOV, CXCL10, and PDPK1. RESULTS: TNFalpha differentially regulated 1,830 transcripts, many of which are involved in the cytokine-cytokine receptor interaction, chemokine signaling, and inflammatory response. Additionally, TNFalpha highly upregulated genes involved in leukocyte recruitment, including CCL5, CX3CL1, and CXCL10. GSK0660 differentially regulated 273 transcripts in TNFalpha-treated cells compared to TNFalpha alone. A pathway analysis revealed the enrichment of cytokine-cytokine receptor signaling. In particular, GSK0660 blocks the TNFalpha induced upregulation of CCL8, a chemokine involved in leukocyte recruitment. CONCLUSIONS: TNFalpha regulates several genes related to retinal leukostasis in retinal endothelial cells. GSK0660 blocks the effect of TNFalpha on the expressions of cytokines involved in leukocyte recruitment, including CCL8, CCL17, and CXCL10 and it may therefore block TNFalpha-induced retinal leukostasis. PMID- 26015770 TI - Keratoconus in vitro and the key players of the TGF-beta pathway. AB - PURPOSE: Keratoconus (KC) is a corneal thinning disease of unknown etiology whose pathophysiology is correlated with the presence of a thin corneal stroma and altered extracellular matrix (ECM). Transforming growth factor-beta (TGF-beta) signaling is a key regulator of ECM secretion and assembly in multiple tissues, including the anterior segment of the eye, and it has been linked to KC. We have previously shown that human keratoconus cells (HKCs) have a myofibroblast phenotype and altered ECM assembly compared to normal human corneal fibroblasts (HCFs). Moreover, TGF-beta3 treatment promotes assembly of a more normal stromal ECM and modulates the fibrotic phenotype in HKCs. Herein, we identify alterations in TGF-beta signaling that contribute to the observed fibrotic phenotype in HKCs. METHODS: HCFs and HKCs were stimulated with TGF-beta1, TGF-beta2, or TGF-beta3 isoforms (0.1 ng/mL) in the presence of a stable vitamin C derivative (0.5 mM) for 4 weeks. All samples were examined using RT-PCR and western blotting to quantify changes in the expressions of key TGF-beta signaling molecules between HCFs and HKCs. RESULTS: We found a significant downregulation in the SMAD6 and SMAD7 expressions by HKCs when compared to HCFs (p<=0.05). Moreover, stimulation of HKCs with any of the three TGF-beta isoforms did not significantly alter the expressions of SMAD6 or SMAD7. HCFs also showed an upregulation in TGF-betaRI, TGF-betaRII, and TGF-betaRIII following TGF-beta3 treatment, whereas HKCs showed a significant two-fold downregulation. CONCLUSIONS: Overall, our data shows the decreased expressions of the regulatory SMADs SMAD6 and SMAD7 by HKCs contribute to the pathological ECM structure observed in KC, and TGF-beta3 may attenuate this mechanism by downregulating the expression of the key profibrotic receptor, TGF-betaRII. Our study suggests a significant role of altered regulation of TGF beta signaling in KC progression and that it may enable novel therapeutic developments targeting TGF-beta receptor regulation. PMID- 26015771 TI - Interleukin-10 gene polymorphisms are associated with Behcet's disease but not with Vogt-Koyanagi-Harada syndrome in the Chinese Han population. AB - PURPOSE: This study aimed to investigate the association of interleukin (IL)-10 gene polymorphisms with Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in the Chinese Han population. METHODS: A two-stage association study was performed on 718 BD patients, 300 VKH patients, and 1,753 controls. Genotyping of the IL-10 gene was performed for six single nucleotide polymorphisms (SNPs), including rs1800871, rs1800872, rs1800896, rs3021094, rs3790622, and rs1554286 using PCR-restricted fragment length polymorphism or TaqMan SNP assays. Real-time PCR was performed to test the IL-10 mRNA expression of the associated polymorphisms. RESULTS: The first-stage result showed significantly increased frequencies of the rs1800871 T allele, rs1800872 A allele, and rs1554286 T allele in BD patients compared with controls (Pcorrected (Pcorr)=1.82*10(-5), OR=1.837; Pcorr=6.1*10(-5), OR=1.780; Pcorr=3.15*10(-5), OR=1.794, respectively). There was no association of the tested six SNPs with VKH syndrome. A second-stage study was therefore performed in BD patients to validate the result of the first stage, showing a significantly increased frequency of the rs1800871 T allele (Second stage, Pcorr=5.59*10(-5), OR=1.493; Combined data, Pcorr=3.65*10(-11), OR=1.632). Compared to the controls, an increased frequency of the rs1800871 T allele was observed in BD patients with extraocular findings, including genital ulcers, skin lesions, and a positive pathergy test. No difference was found among the mRNA expressions of IL-10 in the peripheral blood mononuclear cells (PBMCs) of controls with different genotypes of rs1800871 after stimulation of lipopolysaccharide (LPS) or anti-CD3/CD28 antibodies. CONCLUSIONS: The findings showed that IL-10 is a risk gene for BD but not for VKH syndrome. PMID- 26015772 TI - IGFBP-3 reduces eNOS and PKCzeta phosphorylation, leading to lowered VEGF levels. AB - PURPOSE: In models of diabetic retinopathy, insulin-like growth factor binding protein-3 (IGFBP-3) is protective to the retina, especially retinal microvascular endothelial cells (RECs), but the underlying mechanisms are unclear. For this study, we hypothesized that IGFBP-3 may reduce vascular endothelial growth factor (VEGF) levels through reduced endothelial nitric oxide synthase (eNOS) activity, which may be protective against macular edema. METHODS: To test this hypothesis, we grew primary human retinal endothelial cells in normal glucose (5 mM) or high glucose (25 mM) for three days, treated with IGFBP-3 NB plasmid (a plasmid of IGFBP-3 that cannot bind IGF-1), followed by western blotting for eNOS, protein kinase C zeta (PKCzeta), and VEGF. Additionally, we treated some cells with recombinant eNOS or PKCzeta, after IGFBP-3 NB plasmid transfection to validate that these pathways regulate VEGF levels. Immunoprecipitation experiments were done with the eNOS antibody, followed by western blotting for PKCzeta, to determine if eNOS and PKCzeta interact directly. RESULTS: Our results suggest that 1) IGFBP-3 inhibits the endothelial nitric oxide synthase (eNOS) and protein kinase C zeta (PKCzeta) pathway, which in turn inhibits VEGF production, and 2) that eNOS plays a role in activating PKCzeta to increase VEGF levels in diabetic retinopathy. CONCLUSIONS: In conclusion, IGFBP-3 may be a novel treatment for macular edema through the inhibition of eNOS and PKCzeta activation, leading to reduced VEGF levels. PMID- 26015773 TI - Interventions for body weight reduction in obese patients during short consultations: an open-label randomized controlled trial in the Japanese primary care setting. AB - BACKGROUND: Family physicians should maintain regular contact with obese patients to ensure they effectively reduce their body weight. However, family physicians in Japan have on average only 6 (min) per consultation, and conventional interventions for body weight reduction require a longer consultation or additional manpower. A brief intervention within the limited consultation time available is therefore needed. Here we investigated the effectiveness of a brief weight reduction intervention for obese patients and the related factors for reducing body weight during routine consultations in the primary care setting. METHOD: We conducted an open-label randomized controlled trial at a family medicine clinic in Fukushima, Japan from January 2010 to June 2011. Patients aged 30 to 69 years with body mass index >=25 who were diagnosed with hypertension, dyslipidemia, and/or type 2 diabetes mellitus were randomly assigned to the intervention or control group. At every consultation, body weight in the intervention group was measured by a family physician who provided weight reduction advice in addition to usual care. The primary outcome was body weight change at 1-year follow up. Analysis was done by intention to treat. RESULT: We randomly assigned 29 participants to the intervention group and 21 to the control group. Forty participants (80 %) remained in the trial until the 1-year follow up. At follow up, the median body weight change from baseline was not significantly different between the groups (p = 0.68), at -0.8 (interquartile range [IQR] -2.5 to 1.0) kg in the intervention group and 0.2 (IQR -2.4 to 0.8) kg in the control group. CONCLUSION: We devised an intervention method for physicians to measure body weight and advise on weight reduction during routine consultations. In our setting, this method did not extend the consultation time, but also had no significant additional effects on body weight reduction in moderately obese patients. TRIAL REGISTRATION: This trial is registered with the UMIN Clinical Trial Registry (UMIN000002967). PMID- 26015774 TI - Follow-up of patients with mycosis fungoides after interferon alpha2b treatment failure. AB - INTRODUCTION: Treatment of T cell cutaneous lymphoma( CTCL) is a controversial subject and the effectiveness of treatment is still low. AIM: Report of single center experience of management CTCL after progression after first line treatment. MATERIAL AND METHODS: We present 41 patients with CTCL, 29 received interferon alpha2b in first line, and 12 of them received second line therapy. RESULTS: Overall response rate for second line therapy was 60%. CONCLUSIONS: Results of the follow-up of patients with mycosis fungoides after interferon alpha2b treatment failure with the literature review and discussion. PMID- 26015775 TI - House-dust mite allergy: mapping of Dermatophagoides pteronyssinus allergens for dogs by two-dimensional immunoblotting. AB - INTRODUCTION: Specific immunotherapy has shown to be very useful for allergy control in dogs, with a common success rate ranging from 65% to 70%. However, this efficacy could probably be improved and the identification of individual allergomes, with the choice of more adequate molecular allergen pools for specific immunotherapy, being the strategy. AIM: To map Dermatophagoides pteronyssinus (Der p) allergens for mite-sensitized atopic dogs, for better understanding how individual allergograms may influence the response to house dust mite immunotherapy. MATERIAL AND METHODS: To identify the Der p mite allergome for dogs, 20 individuals allergic to dust-mites and sensitized to Der p, were selected. The extract from Der p was submitted to isoelectric focusing (IEF), one-dimensional (1-D) and two-dimensional (2-D) sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Separated proteins were blotted onto polyvinylidene difluoride (PVDF) membranes and immunoblottings were performed with patient sera. Allergen-bound specific IgE was detected. RESULTS: Eleven allergens were identified from isoelectric focusing (IEF), as well as from 1-D SDS PAGE. From 2-D SDS-PAGE, 24 spots were identified. CONCLUSIONS: Several similarities were found between dog and human allergograms and no absolute correlation between sensitization and allergy was observed either. As in humans, different individual allergograms do not seem to implicate different clinical patterns, but may influence the response to specific immunotherapy. The molecular epidemiology approach in veterinary allergy management, by the characterization of individual patients' allergoms and by choosing the best molecular allergen pool for each patient could also improve the efficacy of allergy immunotherapy. PMID- 26015776 TI - Prolidase activity in chronic plaque psoriasis patients. AB - INTRODUCTION: Psoriasis is a chronic, inflammatory, T-cell-mediated and hyperproliferative skin disease characterized by erythematous, squamous, sharply circumscribed and infiltrated plaques. The metabolisms of the collagen proteins undergo considerable changes due to the acceleration of their turnovers as a result of increased prolidase activity in psoriasis patients. AIM: To determine the level of prolidase activity in psoriasis patients and evaluate its relationship with the oxidative system. MATERIAL AND METHODS: The serum prolidase enzyme activity, total antioxidant levels and total oxidant levels of 40 psoriasis patients and a control group including 47 healthy individuals were analyzed by using their serum samples, and their oxidative stress indices were calculated. RESULTS: The prolidase levels (p < 0.01), total oxidant levels (p < 0.01) and oxidative stress index levels (p < 0.001) of the patient group were higher than the corresponding parameters in the control group. The total antioxidant level was low (p < 0.01). Although a positive correlation was found between the prolidase and total antioxidant levels and the total oxidant level, no correlation was found between prolidase and the oxidative stress index. CONCLUSIONS: It has been determined that the activity of the prolidase enzyme increases due to the increased collage turnover in psoriasis patients. Increased serum oxidant levels and oxidative stress indices values may play a role in the pathogenesis of psoriasis. PMID- 26015777 TI - Clinical practice trends in cryosurgery: a retrospective study of cutaneous lesions. AB - INTRODUCTION: Cryosurgery is an alternative treatment for many benign, premalignant, and malignant lesions of the skin. AIM: To review the indications of cryosurgery for cutaneous lesions. MATERIAL AND METHODS: The retrospective study was based on the assessment of medical records of 1031 dermatology patients who had cryosurgery. RESULTS: One thousand two hundred and forty-four sessions of cryosurgery were applied to the total of 1031 patients. Of the 1031 patients, the most frequent indication for cryosurgery was common warts which were present in 535 (61.59%) patients, followed by anogenital warts in 119 (11.54%) patients, callosity in 81 (7.85%) patients, actinic keratosis in 77 (7.46%) patients, molluscum contagiosum in 35 (3.39%) patients, and other benign or malignant skin lesions. CONCLUSIONS: Cryosurgery is still a valuable treatment of choice in various benign, premalignant, and malignant skin diseases but seems to be underused for indications other than viral warts. PMID- 26015778 TI - Assessment of the sensory threshold in patients with atopic dermatitis and psoriasis. AB - INTRODUCTION: Atopic dermatitis (AD) and psoriasis are chronic inflammatory skin diseases frequently accompanied by itching. The exact pathogenesis of dermatological pruritus remains unknown, but it is believed that altered skin innervation may play a role. AIM: The assessment of the sensory threshold in AD and psoriasis in relation to pruritus experienced by patients. MATERIAL AND METHODS: A total of 18 subjects with AD, 20 with psoriasis and 49 healthy controls were exposed to alternating current generated by the current source. A selected preset of current frequencies (ranging from 5 Hz to 2000 Hz) allowed a selective stimulation of different nerve endings (Abeta, Adelta and C-type). Pruritus severity was measured with visual analogue scale (VAS) and an itch questionnaire developed in house. All results were analyzed statistically. RESULTS: Sensory thresholds within the uninvolved skin of AD or psoriasis patients were significantly higher than in healthy volunteers (p < 0.001), and no significant differences were found between AD and psoriasis (p > 0.05). Similarly, sensory thresholds within the diseased skin of AD or psoriasis were significantly higher than in the normal skin (p < 0.01), and patients with psoriasis had also a significantly higher threshold than AD individuals (p < 0.05). The sensory threshold inversely correlated with pruritus severity in AD and psoriasis and the highest correlation was found for 5 Hz frequency predominantly stimulating C fibers (VAS: R = -0.32, p < 0.05; pruritus questionnaire: R = 0.54, p < 0.001). CONCLUSIONS: Evaluation of the sensory threshold may be a valuable tool for pruritus assessment, but further studies are still warranted. PMID- 26015779 TI - Effect of psoriasis activity on serum adiponectin and leptin levels. AB - INTRODUCTION: Psoriasis is an inflammatory and chronic skin disease associated with obesity, cardiovascular diseases, diabetes and metabolic syndrome. Adipokines, as bioactive substances secreted from adipose tissue, are involved in various metabolic diseases. AIM: To investigate the association between psoriasis severity and serum adiponectin and leptin levels in patients with psoriasis. MATERIAL AND METHODS: Serum fasting adiponectin and leptin levels were examined by an enzyme-linked immunosorbent assay in 49 patients with relapse of plaque type psoriasis and 16 healthy controls. The results were correlated with the Psoriasis Area and Severity Index (PASI), body mass index (BMI), several inflammatory markers, duration of the disease and present relapse. RESULTS: Serum adiponectin and leptin levels were significantly decreased in psoriatic patients in comparison to the control group. There were no correlations between the above measures and PASI scores, patients' age, duration of the disease, present relapse and hospitalization, neither between white blood cells or platelets counts. Serum adiponectin levels significantly correlated with C-reactive protein (CRP) levels. Adiponectin was negatively and leptin positively correlated to BMI at statistical significance. Multivariate analysis demonstrated a significant positive correlation between adiponectin and CRP or PASI concentrations as well as between BMI and leptin concentration. CONCLUSIONS: The data showed that serum adiponectin levels increase and serum leptin levels decrease with psoriasis severity. Leptin might be useful in assessing severity and the risk of complications of psoriasis. Moreover, these results confirmed the relationship between leptin, obesity and psoriasis. PMID- 26015780 TI - Exhaled nitric oxide correlates with IL-2, MCP-1, PDGF-BB and TIMP-2 in exhaled breath condensate of children with refractory asthma. AB - INTRODUCTION: There is evidence that parameters obtained from exhaled breath condensate (EBC) reflect changes in the level of the airway lining fluid. The telation between exhaled nitric oxide (NO) and EBC inflammatory markers has not been analyzed in the context of the inflammatory profile in the airways in asthmatic children. AIM: To show the cytokine profile in EBC of children with severe/refractory asthma as well as correlations between the fractional exhaled NO (FeNO) level and cytokine concentrations. MATERIAL AND METHODS: The study population consisted of eight children aged 8 to 17 years with IgE-dependent, severe/refractory asthma with a duration of at least 2 years. This was an observational study, the first consecutive eight patients with asthma symptoms on the day of the study visit, when EBC samples were obtained. RESULTS: The inter subject variability of study cytokines ranged from 8.6 to 54.6. Cytokines with coefficient of variation < 20% were: interferon-gamma, interleukins IL-2, IL-7, IL-15, IL-16, monokine induced by interferon gamma (MIG) and tumor necrosis factor alpha. We showed a significant positive correlation between the FeNO level and crucial mediators in asthma development and progression (IL-2, MCP-1), and potent markers of airway remodeling (PDGFBB, TIMP-2). All correlations between two different variables were controlled for the effects of age, forced expiratory volume in 1 s and number of asthma exacerbations during last 12 months. CONCLUSIONS: The profiling of cytokine expression in EBC can be reproducibly performed in children with severe/refractory asthma. When treating asthma in children, the FeNO level should be monitored as a prevention strategy of the progression of the remodeling leading to refractory/severe asthma. Exhaled breath condensate may be a useful tool to phenotype asthma via a non-invasive approach. PMID- 26015781 TI - Estimation of oral leukoplakia treatment records in the research of the Department of Maxillofacial and Oral Surgery, Medical University of Gdansk. AB - INTRODUCTION: Oral leukoplakia (OL) is the most common potentially malignant lesion of the oral cavity. AIM: The purpose of the study was clinical and epidemiological analysis of patients with OL diagnosed and treated in the Department of Maxillofacial and Oral Surgery, Medical University of Gdansk, comparison of effectiveness of treatment methods, defining whether van der Waal level of OL influences treatment effectiveness, correlation between localization of OL and treatment effectiveness, and defining the optimal OL therapeutic method. MATERIAL AND METHODS: Among 55 911 patients diagnosed and treated in the Department in the years 1999-2009, 204 people with OL were selected (104 women, 100 men, average age: 58.1 years). Treatment and observation period of 6 months was completed by 178 (87.25%) patients. Seventy-four patients were treated with cream containing 0.05% tretinoin. Sixty-three patients underwent cryosurgery, and 41 surgery. Control visits were made in week 2, 4, 6 and 8 and 6 months after completed treatment. RESULTS: Three hundred and twenty lesions of OL were diagnosed. According to van der Waal classification, the largest group of patients was classified into stage I and II. The percentage of totally cured patients was 90.07%. There were no statistic differences in effectiveness between surgical and cryosurgical treatment. CONCLUSIONS: Evaluation of OL treatment methods depends on localization of the lesions and its stage of progression. The effectiveness of treatment with locally applied tretinoin is smaller in comparison to surgery and cryosurgery. It allows to reduce the number and size of OL lesions, what makes it possible to reduce the number of ablative procedures. PMID- 26015782 TI - Genetic background of skin barrier dysfunction in the pathogenesis of psoriasis vulgaris. AB - Psoriasis is a common inflammatory skin disease. It is known to be a complex condition with multifactorial mode of inheritance, however the associations between particular pathogenic pathways remain unclear. A novel report on the pathogenesis of psoriasis has recently included the genetic determination of the skin barrier dysfunction. In this paper, we focus on specific genetic variants associated with formation of the epidermal barrier and their role in the complex pathogenesis of the disease. PMID- 26015783 TI - Acquired facial lipoatrophy: pathogenesis and therapeutic options. AB - Facial lipoatrophy refers to the loss of subcutaneous fat tissue presenting by flattening or indentation of convex contour of the face. Facial lipoatrophy is a feature of the normal ageing process. It may be also a manifestation of chronic diseases, most frequently it affects HIV-infected individuals treated with highly active antiretroviral therapy (HAART) and may constitute a complication of connective tissue diseases, like lupus erythematosus profundus or morphea. Early recognition and treatment of the active stage of connective tissue diseases is of essential significance in prevention of subsequent scarring and atrophy lesions. In HIV-positive patients undergoing HAART therapy, the attempt to modify thetreatment scheme so it has a less lipemic effect seems to be justified. Esthetic correction of facial lipoatrophy in chronic diseases is a great challenge. Improvement of appearance is very important for affected individuals, because it diminishes their stigmatization and psychosocial dysfunction. Facial volumetric correction includes surgical and dermatological procedures such as adipose transfer and injectable dermal fillers. PMID- 26015784 TI - Allergic reaction in the use of primacaine adrenaline. PMID- 26015785 TI - Pyoderma gangrenosum with monoclonal IgA gammopathy and pulmonary tuberculosis. Illustrative case and review. PMID- 26015787 TI - Antimicrobial shortages: Another hurdle for clinicians. PMID- 26015786 TI - The effect of a new communication template on anticipated willingness to initiate or resume allergen immunotherapy: an internet-based patient survey. AB - BACKGROUND: A patient's knowledge of his/her allergic condition and treatment is a key factor in adherence and effectiveness. METHODS: To assess patients' understanding of allergy and acceptance of allergen immunotherapy on the basis of (i) information given by their physician at the time of prescription and (ii) a new communication template viewed some months later, we performed an Internet based survey of patient panels in France, Germany, Spain, the USA and Russia. The survey participants were either recent "early abandoners" (having discontinued allergen immunotherapy before the end of the prescribed course) or "non-starters" (having decided not to initiate a course of allergen immunotherapy recommended by their physician). All participants completed an on-line questionnaire immediately before and immediately after viewing the new communication template. The study's main objectives were to validate the new communication template and to assess its impact on anticipated willingness to initiate or resume allergen immunotherapy. RESULTS: We surveyed a total of 261 patients (France: 57; Germany: 51; Spain: 52; USA: 51; Russia: 50), comprising 127 "early abandoners" and 134 "non-starters". The mean time since symptom onset and selection for the study was 14.5 years. Subcutaneous allergen immunotherapy had been prescribed in 60 % of cases. Twenty eight percent of the participants did not know for which allergy they were being treated. Early abandoners reported a perception of low effectiveness (39 %) and complained about expense (39 %) and practical constraints (32 %). Twenty-two percent of the non-starters feared side effects. The communication template was considered to be clear (by 92 % of the patients), convincing (by 75 %) and reassuring (by 89 %); 80 % of the participants felt better informed afterwards, and 67 % stated that viewing the communication template would have made them more likely to continue or initiate allergen immunotherapy (overall willingness score: 5.65 out of 10 before viewing and 7.1 out of 10 afterwards). CONCLUSIONS: After viewing a new communication template on allergy and allergen immunotherapy, patients participating in the survey felt better informed and more likely to initiate or complete this therapy. It now remains to investigate the communication template's effect on actual acceptance of and adherence to allergen immunotherapy. PMID- 26015788 TI - Childhood encephalitis in Canada in 2015. PMID- 26015789 TI - Public health response to a large-scale endoscopy infection control lapse in a nonhospital clinic. AB - OBJECTIVE: To determine whether transmission of blood-borne pathogens (BBPs) (hepatitis B virus [HBV], hepatitis C virus [HCV] and HIV) occurred as a result of endoscopy reprocessing failures identified during an inspection of a nonhospital endoscopy clinic in 2011. METHODS: The present analysis was a retrospective cohort study. Registered notification letters were mailed to 6992 patients who underwent endoscopy from 2002 to 2011 at one Canadian nonhospital endoscopy clinic, informing them of the infection control lapse and offering BBP testing. Multimedia communications and a telephone line supplemented notification. A retrospective study of patients with BBPs was performed with viral genetic testing and risk factor assessment for eligible patients. Risk for infection among patients whose procedure was within seven days of a known positive patient was compared with those whose procedure was performed more than seven days after a known postive patient. The seven-day period was selected as the period most likely to present a risk for transmission based on the documented cleaning procedures at the clinic and the available literature on virus survival. RESULTS: Ninety-five percent (6628 of 6992) of patients/estates were contacted and 5042 of 6728 (75%) living patients completed BBP testing. Three were newly diagnosed with HBV and 14 with HCV. Twenty-three and 48 tested positive for previously known HBV or HCV, respectively, 367 were immune to HBV due to natural infection and one was immune to HBV due to immunization. None tested positive for HIV. Sequencing did not reveal any relationships among the 46 unique case patients with viral genetic test results available. Ninety-three percent of patients reported alternative risk factors for BBP. An increased risk for infection among those who underwent a procedure within seven days of a known HBV or HCV case was not demonstrated. CONCLUSIONS: Endoscopy reprocessing failures were not associated with an increased risk for BBP among individuals tested. PMID- 26015790 TI - Prevalence of antimicrobial use in a network of Canadian hospitals in 2002 and 2009. AB - BACKGROUND: Increasing antimicrobial resistance has been identified as an important global health threat. Antimicrobial use is a major driver of resistance, especially in the hospital sector. Understanding the extent and type of antimicrobial use in Canadian hospitals will aid in developing national antimicrobial stewardship priorities. METHODS: In 2002 and 2009, as part of one day prevalence surveys to quantify hospital-acquired infections in Canadian Nosocomial Infection Surveillance Program hospitals, data were collected on the use of systemic antimicrobial agents in all patients in participating hospitals. Specific agents in use (other than antiviral and antiparasitic agents) on the survey day and patient demographic information were collected. RESULTS: In 2002, 2460 of 6747 patients (36.5%) in 28 hospitals were receiving antimicrobial therapy. In 2009, 3989 of 9953 (40.1%) patients in 44 hospitals were receiving antimicrobial therapy (P<0.001). Significantly increased use was observed in central Canada (37.4% to 40.8%) and western Canada (36.9% to 41.1%) but not in eastern Canada (32.9% to 34.1%). In 2009, antimicrobial use was most common on solid organ transplant units (71.0% of patients), intensive care units (68.3%) and hematology/oncology units (65.9%). Compared with 2002, there was a significant decrease in use of first-and second-generation cephalosporins, and significant increases in use of carbapenems, antifungal agents and vancomycin in 2009. Piperacillin-tazobactam, as a proportion of all penicillins, increased from 20% in 2002 to 42.8% in 2009 (P<0.001). There was a significant increase in simultaneous use of >1 agent, from 12.0% of patients in 2002 to 37.7% in 2009. CONCLUSION: From 2002 to 2009, the prevalence of antimicrobial agent use in Canadian Nosocomial Infection Surveillance Program hospitals significantly increased; additionally, increased use of broad-spectrum agents and a marked increase in simultaneous use of multiple agents were observed. PMID- 26015791 TI - Bacterial communities in neonatal feces are similar to mothers' placentae. AB - BACKGROUND: The gut microbiota plays an important role in human health. It is essential to understand how the composition of the gut microbiota in neonates is established. OBJECTIVES: To investigate the nature of the microbial community in the first feces of newborn infants compared with the mothers' placentae and vaginas. METHODS: One infant who was delivered via Cesarean section was compared with an infant who was delivered vaginally. Bar-coded pyro-sequencing of 16S ribosomal RNA genes was used to investigate the bacterial community composition and structure of each site. RESULTS: Neonatal feces of both infants had similar bacterial communities, and they were similar to the mother's placenta regardless of the method of delivery. The vaginal bacterial community differed between the two mothers, but not different sites within the vagina. The bacteria in the neonatal feces and the mothers' placentae demonstrated considerably higher diversity compared with the vaginas. The family Lactobacillaceae dominated in the vaginal samples, while the most abundant family in the fecal and placental samples was Micrococcineae. CONCLUSIONS: These results may provide new directions for the study of infant gut microbial formation. PMID- 26015792 TI - Progressive left-sided facial swelling and proptosis. PMID- 26015793 TI - A 52-year-old HIV-positive man with abdominal pain. PMID- 26015794 TI - A 19-year-old woman with pleuritic chest pain. PMID- 26015795 TI - A cluster of Bacillus cereus bacteremia cases among injection drug users. AB - Bacillus cereus is a ubiquitous spore-forming organism that is infrequently implicated in extraintestinal infections. The authors report three cases of B cereus bacteremia among injection drug users presenting within one month to an urban tertiary care hospital. Treatment with intravenous vancomycin was successful in all three cases. While temporal association suggested an outbreak, molecular studies of patient isolates using pulsed-field gel electrophoresis did not suggest a common source. A review of the association of B cereus infections with heroin use and treatment of this pathogen is provided. PMID- 26015796 TI - Empyema caused by Clostridium bifermentans: A case report. AB - A case of pneumonia with associated empyema caused by Clostridium bifermentans is described. C bifermentans is an anaerobic, spore-forming, Gram-positive bacillus. This organism is infrequently reported as a cause of infection in humans, and older publications tended to regard it as nonpathogenic. However, in more recent reports, C bifermentans has been documented as a cause of septic arthritis, osteomyelitis, soft tissue infection, abdominal infections, brain abscess, bacteremia and endocarditis. The present case is the third reported case of empyema caused by C bifermentans, and it serves to further define the spectrum of illness due to this uncommon organism. PMID- 26015797 TI - Sepsis due to Erysipelothrix rhusiopathiae in a patient with chronic lymphocytic leukemia associated with bronchopneumonia due to Pseudomonas aeruginosa and Escherichia coli: A case report. AB - INTRODUCTION: The present report describes a case of sepsis due to Erysipelothrix rhusiopathiae in a patient with B-cell chronic lymphocytic leukemia with no animal exposure, associated with concomitant bronchopneumonia due to Pseudomonas aeruginosa and Escherichia coli. CASE PRESENTATION: A 54-year-old Caucasian man presented to an emergency room with a three-day history of chest pain, fever, cough with purulent sputum, chills and dyspnea. The patient had associated erythematous papules on the chest and enlarged axillary, submandibular, pectoral and supraclavicular lymph nodes, which regressed under treatment with penicillin. The patient was found to have sepsis without endocarditis caused by E rhusiopathiae, associated with bronchopneumonia that was induced by a double Gram negative infection. CONCLUSIONS: The underlying-B cell chronic lymphocytic leukemia may have favoured the development of bacteremia due to E rhusiopathiae, which occurred subsequent to glossitis in an immunocompromised host being treated with methylprednisolone and cladribine. PMID- 26015798 TI - A 68-year-old woman with recurrent cystitis. PMID- 26015799 TI - 24(th) Annual Canadian Conference on HIV/AIDS Research/24(e) Congres Annuel Canadien de Recherche sur le VIH/sida CAHR Committees / Comites de l'ACRV. PMID- 26015800 TI - Association of Toll-like receptor 4 polymorphism with age-dependent systolic blood pressure increase in patients with coronary artery disease. AB - BACKGROUND: Systolic blood pressure (SBP) increases steadily with age and bears an independent continuous relationship with the incidence of cardiovascular events. Low-grade inflammation is a suspected pathomechanism causing vascular aging and promote coronary artery disease (CAD). Recent animal studies give evidence that Toll-like receptor 4 (TLR4) modulate inflammation and contribute to age-dependent SBP increase. However, there are no data about TLR4 and age dependent blood pressure increase in human. METHODS AND RESULTS: We therefor investigate a human cohort of 2679 patients with CAD aged between 50-80 years. Genotypes were determined for the TLR4 single nucleotide polymorphism rs4986790 (TLR4 896A/G). Patients were stratified according to tertiles of age and the upper tertile was compared to lower tertiles. In this cohort we show that older patients with the TLR4 896 G allele had significantly lower SBP (TLR4 G allele carriers: 148.2 +/- 30.4 mmHg versus A/A allele carrier: 154.9 +/- 27.2 mmHg; P < 0.05) and lower pulse pressure (TLR4 G allele carriers: 69.1 +/- 29.7 mmHg versus A/A allele carrier: 75.5 +/- 26.4 mmHg; P < 0.05) as compared to TLR4 896A/A allele carrier. CONCLUSION: We demonstrate an association between the TLR4 SNP rs4986790 genotype and age-dependant blood pressure increase in patients with coronary artery disease. PMID- 26015802 TI - E6/E7 mRNA testing for human papilloma virus-induced high-grade cervical intraepithelial disease (CIN2/CIN3): a promising perspective. AB - Since the introduction of biomolecular testing for the identification of high risk human papillomavirus DNA (hrHPV-DNA) in cervical cancer preventive strategies, many interesting aspects have emerged in this field; firstly, HPV-DNA testing has been demonstrated to have better sensitivity than conventional cytology in several settings: screening, triage of ASC-US and in follow-up after treatment. Despite this, some limitations of these new technologies have also been underlined: the major issue is the low specificity of the tests, which cannot discriminate between regressive and progressive infections. Thus, recent research has moved the attention towards novel markers of progression that could more precisely detect cases at real risk of cancer development. In view of the fact that progression to cancer is dependable of the E6/E7 proteins integration and transforming action, the overexpression of E6/E7 transcripts has been seen as a valuable marker of this risk. This review aims to summarise the literature data on this topic and to provide a clear view of the emerging perspectives. PMID- 26015803 TI - The SUMO conjugating enzyme UBC9 as a biomarker for cervical HPV infections. AB - Human papillomaviruses (HPVs) infect stratified epithelium and are the causative agents of cervical cancer, the second most common cause of cancer-related death in women. A critical aspect that still persists in the HPV field is the selection of very sensitive and specific HPV diagnostic assays. Here, we provide evidence that the crucial small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ubc9 is strongly upregulated in cervical lesions. Ubc9 detection could thus be used in diagnosing and/or monitoring the progression of an HPV oncogenic infection. PMID- 26015804 TI - Lymph node tuberculosis after allogeneic haematopoietic stem cell transplantation: an atypical presentation of an uncommon complication. AB - Mycobacterium tuberculosis infections are uncommon complications in the haematopoietic stem cell post-transplant period. Most cases are reactivations of latent infections affecting the lung. We present an atypical case of isolated lymph node tuberculosis after an allogeneic haematopoietic stem cell transplantation, which highlights the importance of having a high suspicion index, even in non-endemic countries. PMID- 26015801 TI - Aneuploidy and chromosomal instability in cancer: a jackpot to chaos. AB - Genomic instability (GIN) is a hallmark of cancer cells that facilitates the acquisition of mutations conferring aggressive or drug-resistant phenotypes during cancer evolution. Chromosomal instability (CIN) is a form of GIN that involves frequent cytogenetic changes leading to changes in chromosome copy number (aneuploidy). While both CIN and aneuploidy are common characteristics of cancer cells, their roles in tumor initiation and progression are unclear. On the one hand, CIN and aneuploidy are known to provide genetic variation to allow cells to adapt in changing environments such as nutrient fluctuations and hypoxia. Patients with constitutive aneuploidies are more susceptible to certain types of cancers, suggesting that changes in chromosome copy number could positively contribute to cancer evolution. On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis. Furthermore, mouse models for CIN have led to conflicting results. Taken together these findings suggest that the relationship between CIN, aneuploidy and cancer is more complex than what was previously anticipated. Here we review what is known about this complex menage a trois, discuss recent evidence suggesting that aneuploidy, CIN and GIN together promote a vicious cycle of genome chaos. Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis. PMID- 26015805 TI - The challenge of cancer in middle-income countries with an ageing population: Mexico as a case study. AB - Mexico is undergoing rapid population ageing as a result of its epidemiological transition. This study explores the interface between this rapid population ageing and the burden of cancer. The number of new cancer cases is expected to increase by nearly 75% by 2030 (107,000 additional cases per annum), with 60% of cases in the elderly (aged >= 65). A review of the literature was supplemented by a bibliometric analysis of Mexico's cancer research output. Cancer incidence projections for selected sites were estimated with Globocan software. Data were obtained from recent national census, surveys, and cancer death registrations. The elderly, especially women and those living in rural areas, face high levels of poverty, have low rates of educational attainment, and many are not covered by health insurance schemes. Out of pocket payments and private health care usage remain high, despite the implementation of Seguro Popular that was designed to achieve financial protection for the lowest income groups. A number of cancers that predominate in elderly persons are not covered by the scheme and individuals face catastrophic expenditure in seeking treatment. There is limited research output in those cancer sites that have a high burden in the elderly Mexican population, especially research that focuses on outcomes. The elderly population in Mexico is vulnerable to the effects of the rising cancer burden and faces challenges in accessing high quality cancer care. Based on our evidence, we recommend that geriatric oncology should be an urgent public policy priority for Mexico. PMID- 26015806 TI - Sarcoidosis with bone involvement mimicking metastatic disease at (18)F-FDG PET/CT: problem solving by diffusion whole-body MRI. AB - Bone involvement has been reported in 1-13% of patients with sarcoidosis. Both 18F-fluorodeoxyglucose ((18)F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) and conventional magnetic resonance imaging (MRI) are sensitive in detecting sarcoidosis bone lesions, but are not always reliable in differentiating sarcoidosis bone lesions from metastatic disease, thus often requiring bone biopsy. We describe the use of diffusion whole-body MRI for bone assessment in a patient with breast cancer and sarcoidosis, presenting with bone marrow lesions mimicking metastatic disease at (18)F-FDG PET/CT. In our case, diffusion whole-body MRI represented a useful tool for bone assessment and overcame the limitation of (18)F-FDG PET/CT in discriminating inflammatory bone marrow involvement from metastatic disease. PMID- 26015807 TI - Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell lines. AB - BACKGROUND: There has been considerable progress in the management of acute lymphoblastic leukemia (ALL) but further improvement is needed to increase long term survival. The thiopurine agent 6-mercaptopurine (6-MP) used for ALL maintenance therapy has a key influence on clinical outcomes and relapse prevention. Genetic inheritance in thiopurine metabolism plays a major role in interindividual clinical response variability to thiopurines; however, most cases of thiopurine resistance remain unexplained. METHODS: We used lymphoblastoid cell lines (LCLs) from healthy donors, selected for their extreme thiopurine susceptibility. Thiopurine metabolism was characterized by the determination of TPMT and HPRT activity. We performed genome-wide expression profiling in resistant and sensitive cell lines with the goal of elucidating the mechanisms of thiopurine resistance. RESULTS: We determined a higher TPMT activity (+44%; P = 0.024) in resistant compared to sensitive cell lines, although there was no difference in HPRT activity. We identified a 32-gene transcriptomic signature that predicts thiopurine resistance. This signature includes the GTPBP4 gene coding for a GTP-binding protein that interacts with p53. A comprehensive pathway analysis of the genes differentially expressed between resistant and sensitive cell lines indicated a role for cell cycle and DNA mismatch repair system in thiopurine resistance. It also revealed overexpression of the ATM/p53/p21 pathway, which is activated in response to DNA damage and induces cell cycle arrest in thiopurine resistant LCLs. Furthermore, overexpression of the p53 target gene TNFRSF10D or the negative cell cycle regulator CCNG2 induces cell cycle arrest and may also contribute to thiopurine resistance. ARHGDIA under expression in resistant cell lines may constitute a novel molecular mechanism contributing to thiopurine resistance based on Rac1 inhibition induced apoptosis and in relation with thiopurine pharmacodynamics. CONCLUSION: Our study provides new insights into the molecular mechanisms underlying thiopurine resistance and suggests a potential research focus for developing tailored medicine. PMID- 26015808 TI - Mutation signatures implicate aristolochic acid in bladder cancer development. AB - BACKGROUND: Aristolochic acid (AA) is a natural compound found in many plants of the Aristolochia genus, and these plants are widely used in traditional medicines for numerous conditions and for weight loss. Previous work has connected AA mutagenesis to upper-tract urothelial cell carcinomas and hepatocellular carcinomas. We hypothesize that AA may also contribute to bladder cancer. METHODS: Here, we investigated the involvement of AA-mutagenesis in bladder cancer by sequencing bladder tumor genomes from two patients with known exposure to AA. After detecting strong mutational signatures of AA exposure in these tumors, we exome-sequenced and analyzed an additional 11 bladder tumors and analyzed publicly available somatic mutation data from a further 336 bladder tumors. RESULTS: The somatic mutations in the bladder tumors from the two patients with known AA exposure showed overwhelming AA signatures. We also detected evidence of AA exposure in 1 out of 11 bladder tumors from Singapore and in 3 out of 99 bladder tumors from China. In addition, 1 out of 194 bladder tumors from North America showed a pattern of mutations that might have resulted from exposure to an unknown mutagen with a heretofore undescribed pattern of A > T mutations. Besides the signature of AA exposure, the bladder tumors also showed the CpG > TpG and activated-APOBEC signatures, which have been previously reported in bladder cancer. CONCLUSIONS: This study demonstrates the utility of inferring mutagenic exposures from somatic mutation spectra. Moreover, AA exposure in bladder cancer appears to be more pervasive in the East, where traditional herbal medicine is more widely used. More broadly, our results suggest that AA exposure is more extensive than previously thought both in terms of populations at risk and in terms of types of cancers involved. This appears to be an important public health issue that should be addressed by further investigation and by primary prevention through regulation and education. In addition to opportunities for primary prevention, knowledge of AA exposure would provide opportunities for secondary prevention in the form of intensified screening of patients with known or suspected AA exposure. PMID- 26015809 TI - The association between hyperandrogenemia and the metabolic syndrome in morbidly obese women. AB - BACKGROUND: Female abdominal obesity is associated with hyperandrogenemia (HA), but few studies have addressed the possible association between HA and metabolic syndrome (MetS) among obese women. Some studies indicate that insulin resistance may cause HA through different mechanisms. On the other hand, a bidirectional relationship between HA and insulin resistance has been suggested. Thus, we aimed to investigate if morbidly obese women with HA had higher odds of MetS and its components than those without HA (controls), independent of polycystic ovarian syndrome (PCOS) status. METHODS: This cross-sectional study comprised 1900 consecutive treatment seeking morbidly obese women <50 years. Free testosterone index (FTI) >0.6 defined HA. Women with previously diagnosed PCOS and those with oligo- / anovulation combined with clinical or biochemical hyperandrogenism were defined as having PCOS. Multiadjusted associations between HA and MetS were assessed by logistic regression analysis. RESULTS: Out of 1900 morbidly obese women, 1089 (57 %), 846 (45 %) and 312 (16 %) had MetS, HA and PCOS, respectively. Compared with controls (without HA), women with HA were younger (34 [1] years vs. 39 [2], p < 0.001) had a higher prevalence of MetS (62 % vs. 53 %, p < 0.001), type 2 diabetes (18 % vs. 15 %, p = 0.045), low HDL-cholesterol (65 % vs. 48 %, p < 0.001) and hypertriglyceridemia (48 % vs. 41 %, p = 0.004), but a lower prevalence of raised blood pressure (53 % vs. 59 %, p = 0.014). Multivariable analyses showed that HA was associated with increased odds of MetS (OR 1.61 [95 % CI 1.27, 2.02]), dysglycemia (1.65 [1.28, 2.11]), low HDL cholesterol (1.58 [1.27, 1.97]), and hypertriglyceridemia (1.43 [1.15, 1.79]). After stratification for the presence of PCOS, the results remained largely unchanged in women without PCOS; MetS (1.52 [1.18, 1.96), dysglycemia (1.71 [1.30, 2.25]), low HDL-cholesterol (1.55 [1.22, 1.98]) and hypertriglyceridemia (1.36 [1.06, 1.74]). CONCLUSION: Morbidly obese women with HA had an approximately 1.5-fold increased odds of having MetS even in the absence of PCOS. Randomized controlled clinical trials, including therapeutic strategies to lower free testosterone levels, are however necessary to explore any cause-and-effect relationship. PMID- 26015810 TI - MITOCHONDRIAL REDOX IMAGING FOR CANCER DIAGNOSTIC AND THERAPEUTIC STUDIES. AB - Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer. The redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D high-resolution (~ 50 * 50 * 10 MUm3) imaging of mitochondrial redox state in tissue on the basis of the fluorescence of NADH (reduced nicotinamide adenine dinucleotide) and Fp (oxidized flavoproteins including flavin adenine dinucleotide, i.e., FAD). In this review, we illustrate its basic principles, recent technical developments, and biomedical applications to cancer diagnostic and therapeutic studies in small animal models. Recently developed calibration procedures for the redox imaging using reference standards allow quantification of nominal NADH and Fp concentrations, and the concentration-based redox ratios, e.g., Fp/(Fp+NADH) and NADH/(Fp+NADH) in tissues. This calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings. A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10 MUm. Ex vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD imager. Applications of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors, predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts, differentiating precancerous and normal tissues, and monitoring the tumor treatment response to photodynamic therapy. Possible future directions for the development of redox imaging are also discussed. PMID- 26015811 TI - Tobacco smoking is associated with methylation of genes related to coronary artery disease. AB - BACKGROUND: Tobacco smoking, a risk factor for coronary artery disease (CAD), is known to modify DNA methylation. We hypothesized that tobacco smoking modifies methylation of the genes identified for CAD by genome-wide association study (GWAS). RESULTS: We selected genomic regions based on 150 single-nucleotide polymorphisms (SNPs) identified in the largest GWAS on CAD. We investigated the association between current smoking and the CpG sites within and near these CAD related genes. Methylation was measured with the Illumina Human Methylation 450K array in whole blood of 724 Caucasian subjects from the Rotterdam Study, a Dutch population based cohort study. A total of 3669 CpG sites within 169 CAD-related genes were studied for association with current compared to never smoking. Fifteen CpG sites were significantly associated after correction for multiple testing (Bonferroni-corrected p value <1.4 * 10(-5)). These sites were located in the genes TERT, SARS, GNGT2, SMG6, SKI, TOM1L2, SIPA1, MRAS, CDKN1A, LRRC2, FES and RPH3A. In 12 sites, current smoking was associated with a 1.2 to 2.4 % lower methylation compared to never smoking; and in three sites, it was associated with a 1.2 to 1.8 % higher methylation. The effect estimates were lower in 10 of the 15 CpG sites when comparing current to former smoking. One CpG site, cg05603985 (SKI), was found to be associated with expression of nearby CAD-related gene PRKCZ. CONCLUSIONS: Our study suggests an effect of tobacco smoking on DNA methylation of CAD-related genes and thus provides novel insights in the pathways that link tobacco smoking to risk of CAD. PMID- 26015814 TI - Plasma ProBNP Is Not a Specific Marker for Transient Myocardial Ischemia. AB - BACKGROUND: Plasma proBNP levels are increased in patients with acute myocardial infarction. Previous studies have shown conflicting data on the effect of transient myocardial ischemia on plasma BNP levels. We designed the current study to examine plasma proBNP levels in patients with transient myocardial ischemia during a percutaneous coronary intervention (PCI). This study was to study plasma proBNP as a marker of transient myocardial ischemia. METHODS: We enrolled 49 consecutive patients with a history of angina or abnormal stress test who presented for cardiac catheterization. We obtained plasma proBNP levels in all patients at 1) arterial access (proBNP-1), 2) the end of the procedure (proBNP-2) and 3) 4 hours after procedure (proBNP-3). Hotelling's T-squared test was used to evaluate the equality of means. Log transforms of proBNP were used to impart data normality. RESULTS: Twenty-two patients underwent diagnostic catheterization (DCA group) and 27 underwent PCI (PCI group). Both groups had normal left ventricular function and a baseline creatinine < 2 mg/dL. Baseline log (proBNP) was 4.7 + 0.99 (units) and rose significantly at 4 hours in both groups (P < 0.02), with no difference in rate of change. CONCLUSIONS: Plasma proBNP was increased in both DCA and PCI groups which limits its utility to identify transient myocardial ischemia. The etiology of increase in proBNP in both groups is speculative and may be related to injection of radiographic contrast media into the coronary artery which leads to microcirculatory impairment resulting in myocardial tissue hypoxia and transient increase in left ventricular pressure; however, further evaluation is required. PMID- 26015813 TI - Assessment of potential targets for deep brain stimulation in patients with Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting 36 million people worldwide and 5.2 million in the United States. The pathogenesis of AD is still elusive. Accumulations of abnormal proteins (beta amyloid and tau protein), inflammatory cascades, abnormal responses to oxidative stress and alteration in oxidative metabolism have been implicated in AD. There are few effective therapeutic options available for this disorder at present. Neuromodulation offers a novel treatment modality for patients with AD. The databases of Medline and PubMed were searched for various studies in English literature describing the deep brain stimulation (DBS) in patients with AD. Various animal and human clinical studies have shown promising initial results with bilateral DBS targeting various anatomical nodes. In this review, we attempt to highlight the pathophysiology, neural circuitry and potential neuromodulation options in patients with AD. In appropriately selected patients, DBS can potentially delay the cognitive decline, enhance memory functions and can improve the overall quality of life. However, further randomized controlled trials are required to validate the efficacy of neuromodulation and to determine the most optimal target for AD. PMID- 26015815 TI - Birth weight independently affects morbidity and mortality of extremely preterm neonates. AB - BACKGROUND: Neonates born between 24 + 0 and 27 + 6 gestational weeks, widely known as extremely preterm neonates, present a category characterized by increased neonatal mortality and morbidity. Main objective of the present study is to analyze the effect of various epidemiological and pregnancy-related parameters on unfavorable neonatal mortality and morbidity outcomes. METHODS: A retrospective study was performed enrolling cases delivered during 2003 - 2008 in our department. Cases of neonatal death as well as pathological Apgar score (<= 4 in the first and <= 7 in the fifth minute of life), need for emergency resuscitation, respiratory disease syndrome (RDS), neonatal asphyxia, intraventricular hemorrhage (IVH) and neonatal death were recorded for neonates of our analysis. A multivariate regression model was used to correlate these outcomes with gestational week at delivery, maternal age, parity, kind of gestation (singleton or multiple), intrauterine growth restriction (IUGR), birth weight (BW), preterm premature rupture of membranes (PPROM), mode of delivery (vaginal delivery or cesarean section) and antenatal use of corticosteroids. RESULTS: Out of 5,070 pregnancies delivered, 57 extremely preterm neonates were born (1.1%). Mean BW was 780.35 +/- 176.0, RDS was observed in 93.0% (n = 53), resuscitation was needed in 54.4% (n = 31) while overall mortality rate was 52.6% (n = 30). BW was independently associated with neonatal death (P = 0.004), pathological Apgar score in the first (P = 0.05) and fifth minute of life (P = 0.04) as well as neonatal sepsis (P = 0.05). CONCLUSION: BW at delivery is independently affecting neonatal mortality and morbidity parameters in extremely preterm neonates. PMID- 26015812 TI - Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes. AB - The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to provide new mechanistic insights into the genesis of diabetes and its severe vascular complications and identify a panel of epigenetic markers with diagnostic/prognostic and therapeutic relevance. PMID- 26015816 TI - Effect of distance and duration of illumination on retinal ganglion cells exposed to varying concentrations of brilliant blue green. AB - BACKGROUND: The objective of the study was to determine the safety parameters of using brilliant blue green (BBG) for chromovitrectomy by assessing the cytotoxicity of BBG on cultured retinal ganglion cells (RGCs) exposed to illumination. METHODS: RGCs were exposed to two concentrations of BBG (0.25 and 0.5 mg/mL) under metal halide illumination at varying distances (1 and 2.5 cm), intensities (990 and 2,000 Fc), and durations (1, 5 and 15 minutes). Cell viability was assessed using the WST-1 and CellTiter 96((r)) AQueous One solution cell proliferation assays. RESULTS: Using the WST-1 assay, with high-intensity illumination, viability of RGCs ranged from 97.5+/-16.4% of controls with minimum BBG and light exposure (0.25 mg/mL BBG and illuminated for 1 minute at 2.5 cm distance) to 53.1+/-11.3% of controls with maximum BBG and light exposure (0.50 mg/mL and illuminated for 15 minutes at 1 cm distance; P < 0.01). With medium intensity illumination, RGCs showed better viability, ranging from 95.1+/-7.2% of controls with minimum BBG and light exposure to 72.3+/-12.8% of controls with maximum BBG and light exposure. CellTiter 96((r)) AQueous One assay showed similar results. CONCLUSION: RGCs seem to safely tolerate up to 5 minutes of exposure to 0.5 mg/mL BBG under diffuse medium-intensity illumination (990 Fc). PMID- 26015817 TI - Depression in teenager pregnant women in a public hospital in a northern mexican city: prevalence and correlates. AB - BACKGROUND: Very little is known about prenatal depression in teenagers in Mexico. We determined the prevalence and correlates of prenatal depression in teenager women attending a public hospital in Durango City, Mexico. METHODS: We performed a cross-sectional study to assess depression in 181 teenager pregnant women who attended a public hospital for prenatal care. We used a validated Mexican version of the Edinburg postnatal depression scale (EPDS) to screen depression. Women with EPDS scores suggestive of depression were further examined to confirm depression by a psychiatric evaluation using the DSM-IV criteria. Bivariate and multivariate analyses were used to evaluate the prevalence association with socio-demographic, clinical and psychosocial characteristics of the pregnant women. RESULTS: Of the 181 teenager pregnant women studied, 61 (33.7%) had EPDS equal to or higher than 8 (range 8 - 23), and 37 of them were confirmed to have prenatal depression by the psychiatric evaluation. The general prevalence of prenatal depression in the teenager pregnant women studied was 20.4%. Of the 37 women with depression, 34 suffered from minor depression and three suffered from major depression. Thus, the prevalence of minor and major depression in the women studied was 18.8% and 1.7%, respectively. Multivariate analysis of the socio-demographic, clinical and psychosocial characteristics of the teenager pregnant women showed that prenatal depression was associated with a previous episode of depression during pregnancy (odds ratio (OR) = 6.12; 95% confidence interval (CI): 1.68 - 22.30; P = 0.006), and borderline associations with big fetal size (OR = 9.9; 95% CI: 0.94 - 104.24; P = 0.05) and family problems (OR = 3.83; 95% CI: 0.99 - 14.84; P = 0.05). CONCLUSIONS: Results demonstrate that prenatal depression is common in pregnant teenagers in Durango City, Mexico. The history of an episode of depression during pregnancy should alert physicians for further depression episodes during pregnancy in teenagers. Further research to elucidate the association of prenatal depression with size of the fetus and family problems in pregnant teenagers is needed. PMID- 26015818 TI - Early prediction and outcome of septic encephalopathy in acute stroke patients with nosocomial coma. AB - BACKGROUND: Septic encephalopathy (SE) is the most common acute encephalopathy in ICU; however, little attention has been focused on risk of SE in the course of acute stroke. Our aim is to investigate the early prediction and outcome of SE in stroke patients with nosocomial coma (NC). METHODS: A retrospective cohort study was conducted in an ICU of the tertiary teaching hospital in China from January 2006 to December 2009. Ninety-four acute stroke patients with NC were grouped according to with or without SE. Risk factors for patients with SE were compared with those without SE by univariate and multivariate analysis. RESULTS: Of 94 stroke patients with NC, 46 (49%) had NC with SE and 48 (51%) had NC without SE. The onset-to-NC time was significant later in stroke patients with SE than those without SE (P < 0.01). There was a significant difference in body temperature, heart rate, respiratory rate, white blood cell (WBC), systolic blood pressure (SBP), diastolic blood pressure (DBP), systemic inflammatory response syndrome (SIRS), acute respiratory failure, septic shock, hypernatremia, and sequential organ failure assessment (SOFA) score between the SE and non-SE group (P < 0.05). On a repeat head imaging, vasogenic edema (P = 0.023) and subcortical white matter lesions (P = 0.011) were significantly higher in patients with SE than those without SE, while hematoma growth (P = 0.000), infarction progress (P = 0.003), and recurrent subarachnoid hemorrhage (SAH) (P = 0.011) were significantly lower in patients with SE than those without SE. Patients with SE had higher adjusted rates of fever >= 39 degrees C (odds ratio (OR): 2.753; 95% confidence interval (CI): 1.116 - 6.794; P = 0.028) and SIRS >= 3 items (OR: 6.459; 95% CI: 2.050 - 20.351; P = 0.001). The 30-day mortality in stroke patients with SE was higher than those without SE (76.1% vs. 45.8%, P = 0.003). CONCLUSION: High fever and severe SIRS are two early predictors of stroke patients with SE, and survival rates were worse in stroke patients with SE than those without SE. PMID- 26015819 TI - Positive endocervical margins at conization: repeat conization or colposcopic follow-up? A retrospective study. AB - BACKGROUND: The presence of residual cervical lesions was evaluated in patients submitted to repeat conization due to a finding of positive endocervical margins in a previous loop electrosurgical excision procedure (LEEP) specimen. In addition, the correlation between the presence of a residual lesion and risk factors for cervical cancer, and the use of repeat conization as first-choice treatment were analyzed. METHODS: This retrospective study included 44 patients submitted to repeat cervical conization or total hysterectomy following a finding of affected endocervical margins in LEEP specimens. The risk factors analyzed in relation to the presence of residual lesions were age, smoking, cone depth, glandular involvement and the histopathology findings of cervical intraepithelial neoplasia (CIN) 1, CIN 2 or CIN 3/carcinoma in situ. The Chi-square test and the Mann-Whitney t-test were used, with significance defined at P < 0.05. RESULTS: Residual lesions were found in 23/44 patients (52.3%), with 3/23 cases (13.0%) being compatible with invasive squamous cell carcinoma. Of the 23 patients, six (26.1%) were submitted to total hysterectomy, with one case being compatible with a moderately differentiated invasive squamous cell carcinoma. Two patients with a histopathology finding of CIN 3/carcinoma in situ in the previous LEEP specimen were diagnosed with invasive squamous cell carcinoma in the repeat conization specimen. Residual lesions were not significantly associated with the risk factors evaluated. CONCLUSIONS: In view of the high frequency of residual disease found when positive endocervical margins were found in LEEP specimens, the indication for repeat cervical conization rather than colposcopic follow-up is viable and justified. Indeed, since the presence of a residual lesion and its progression in the cervical canal are more difficult to screen and control, patients unable to comply with regular colposcopic follow-up could benefit from repeat conization when trying to avoid a potentially negative outcome. PMID- 26015820 TI - Association Between Visit-to-Visit Variability in Blood Pressure and Cardiovascular Events in Hypertensive Patients After Successful Percutaneous Coronary Intervention. AB - BACKGROUND: Visit-to-visit variability (VVV) in blood pressure (BP) in addition to high BP has been shown to be a strong predictor of coronary events and stroke. Therefore, we investigated the associations between VVV in BP or BP levels and cardiovascular events after successful percutaneous coronary intervention (PCI). METHODS: We enrolled 176 hypertensive patients who had undergone successful PCI and who had four clinic visits to measure BP until follow-up coronary angiography (CAG) at 6 - 9 months after PCI. The patients were divided into those with acute coronary syndrome (ACS group; n = 50) and those with stable angina pectoris (SAP group; n = 126). We determined VVV in BP expressed as the standard deviation (SD) of average BP, average, and the maximum and minimum BP during the follow-up period. Major adverse cardiovascular events (MACEs) (myocardial infarction (MI), target lesion revascularization (TLR) and all-cause death) were also analyzed. RESULTS: There were no significant differences in VVV in BP, average BP or maximum or minimum BP between the patients with and without MACE in all patients, the ACS and SAP groups. Interestingly, in the ACS group, VVV in SBP and maximum SBP in patients with MI were significantly higher than those in patients without MI. The cut-off levels for VVV in BP and maximum SBP that gave the greatest sensitivity and specificity for MI in the ACS group were 15.1 and 138 mm Hg, respectively. CONCLUSION: Higher VVV in SBP and maximum SBP in patients with ACS after successful PCI were associated with the onset of MI. PMID- 26015821 TI - The association of air pollution with the patients' visits to the department of respiratory diseases. AB - BACKGROUND: The objective of this study was to evaluate the impact of air particulate matter 2.5 (PM2.5) on the daily number of patients' visits to the Department of Respiratory Diseases in a local general hospital. METHODS: The number of patients in outpatient department of respiratory diseases (ODRD) in a general hospital of Jinan, China, the air quality and meteorological data were collected for 1 year. By controlling the confounding factors such as "day of the week" effects and the meteorological factors, the generalized additive Poisson regression analysis was conducted to evaluate the impact of PM2.5 on the number of patients' visits to the ODRD. RESULTS: Within two consecutive days, if the cumulative PM2.5 was less than 200 ug/m(3), the daily number of patients in the ODRD did not increase significantly; however, it increased dramatically when the concentration of PM2.5 particles reached the range between 200 and 400 ug/m(3). CONCLUSION: There is a non-linear relationship between the concentration of atmospheric PM2.5 particles and the daily number of patients in the ODRD. PMID- 26015822 TI - Neonatal hyperbilirubinemia in a Turkish cohort: association of vitamin B12. AB - BACKGROUND: Deficiency of vitamin B12 (VitB12) causes failure of erytrocyte maturation leading to cell lysis. Red blood cell lysis causes excess heme production that ends with hyperbilirubinemia. In this study, we aimed to evaluate the role of VitB12 in neonatal hyperbilirubinemia (NNH) with prolonged jaundice and to compare patients with control group who did not develop hyperbilirubinemia. METHODS: A total of 20 patients (M/F = 13/7) with jaundice and 20 healthy controls (M/F = 11/9) were included in the study. RESULTS: The mean indirect bilirubin level of patient group was 9.91 +/- 1.90 mg/dL (6.71 - 15.2 mg/dL) and control group was 3.18 +/- 1.24 mg/dL (1.16 - 4.96 mg/dL). The mean VitB12 level of patient group was 119.9 +/- 43.9 ng/L (42.35 - 178 ng/L) and the control group was 286.17 +/- 97.43 ng/L (207.90 - 624.10 ng/L). There was a statistically significant difference in terms of VitB12 level (< 0.001) between the study groups. CONCLUSION: To our knowledge, this study is the first study showing that low VitB12 level has been observed as a risk factor in NNH for the first time in the literature. We suggest that prophylactic use of VitB12 by pregnant women so will greatly benefit to prevent VitB12 deficiency and its complications in the first years of life such as NNH. PMID- 26015823 TI - Retreatment of a maxillary lateral incisor with two separate root canals confirmed with cone beam computed tomography. AB - The purpose of this report is to present a rare case of a maxillary lateral incisor exhibiting two separate root canals confirmed by cone-beam computed tomography (CBCT). A 65-year-old female patient with an esthetic complaint regarding her maxillary left lateral incisor was referred to our clinic. During a radiographical examination, an endodontically treated root canal and an extra root canal with an apical lesion were observed. The retreatment was performed. CBCT findings confirmed the root canal mophology of the maxillary left lateral with two distinct canals. We conclude that the CBCT imaging is an adjunctive tool for better assessment of complex root canal systems. PMID- 26015824 TI - Trisomy 13 and massive fetomaternal hemorrhage. AB - This is the first case report of trisomy 13 complicated by massive fetomaternal hemorrhage (FMH). A pale male infant weighing 2,950 g was delivered with low Apgar scores by emergency cesarean section due to non-reassuring fetal status. The umbilical arterial pH and hemoglobin level were 6.815 and 6.9 g/dL (normal: 13 - 22 g/dL), respectively. The maternal hemoglobin-F and serum alpha fetoprotein levels were 6.0% (normal: < 1.0%) and 1,150 ng/mL (4.1 multiple of median), respectively. The neonate was diagnosed as having trisomy 13 by a subsequent chromosome examination. In the placenta, massive intervillous thrombosis was observed microscopically. This placental finding has been reported to be associated with both preeclampsia and massive FMH. In addition, the incidence of preeclampsia in pregnancies complicated by trisomy 13 has been reported to be significantly higher than normal karyotype populations. Therefore, the current finding may support the association between trisomy 13 and the incidence of massive FMH. PMID- 26015825 TI - Pleural epithelioid hemangioendothelioma: literature summary and novel case report. AB - Epithelioid hemangioendothelioma (EHE) is a rare malignant cancer of vascular origin that can affect multiple and varied tissue sites. A subtype of EHE, pulmonary epithelioid hemangioendothelioma (PHE), is more unusual with only 200 reported cases. Of these, only 27 have been classified as pleural in origin. Based on available literature, the average age of presentation of pleural PHE is 45.7 years with a male preponderance of 2.375. A summary of all published case reports reveals significant heterogeneity both in presentation and management. Here we add to this knowledge-base with a report of an unusual case of pleural PHE in a 36-year-old female who presented with a 6-week history of chest pain and breathlessness. Significant challenges in the diagnosis and management of patients with pleural PHE exist, including a wide initial differential diagnosis and difficulties in obtaining tissue specimens, coupled with relatively limited treatment options. Early referral to a cardiothoracic center for video-assisted thoracoscopic biopsy is crucial in facilitating a diagnosis and allowing adequate pleural drainage for symptomatic relief. PMID- 26015826 TI - Transformation of low-grade mucinous neoplasm of the appendix with pseudomyxoma peritonei to high-grade sarcomatoid carcinoma. AB - A 66-year-old man initially underwent appendectomy and cytoreductive surgery for a low-grade appendiceal mucinous neoplasm with pseudomyxoma peritonei. One and a half years later, multiple disseminated lesions developed in rectus abdominis muscle and peritoneal cavity. Biopsy showed histopathological transformation to sarcomatoid carcinoma. This case illustrates that evolution of low-grade pseudomyxoma peritonei to high-grade carcinoma truly develops in some patients. The development of this dedifferentiation appears associated with aggressive behavior and poor clinical outcome. PMID- 26015827 TI - An Overlapping Case of Lupus Nephritis and IgG4-Related Kidney Disease. AB - We report a case of a 71-year-old Filipino female who was admitted to the hospital for abdominal pain, vomiting and diarrhea of 8 days duration. The patient was found to have marked acute kidney injury (AKI), which required hemodialysis in the next 3 days. Extensive workup revealed hematuria, subnephrotic range proteinuria, elevated anti-nuclear antibody (ANA) and elevated total immunoglobulin G (IgG) levels, with normal IgG4 and anti-dsDNA levels. On kidney biopsy, mild membranous glomerulonephritis was found, along with autoimmune tubulointerstitial nephritis (TIN) with a "full-house" pattern of immune deposits. These findings were suggestive of lupus interstitial nephritis. However, IgG4+ plasma cells were detected in the interstitium by immunostaining, favoring a diagnosis of IgG4-related kidney disease (IgG4-RKD). Our case highlights the difficulty in differentiating lupus nephritis (LN) from IgG4-RKD in some patients, raising the suspicion that these two entities can co-exist. PMID- 26015828 TI - Current Status of the Screening of Chlamydia trachomatis Infection Among Japanese Pregnant Women. PMID- 26015829 TI - Preface to Special Topic: Select Papers from the 8th IEEE International Conference on Nano/Molecular Medicine and Engineering Held in Kaohsiung, Taiwan. PMID- 26015830 TI - Microwells support high-resolution time-lapse imaging and development of preimplanted mouse embryos. AB - A vital aspect affecting the success rate of in vitro fertilization is the culture environment of the embryo. However, what is not yet comprehensively understood is the affect the biochemical, physical, and genetic requirements have over the dynamic development of human or mouse preimplantation embryos. The conventional microdrop technique often cultures embryos in groups, which limits the investigation of the microenvironment of embryos. We report an open microwell platform, which enables micropipette manipulation and culture of embryos in defined sub-microliter volumes without valves. The fluidic environment of each microwell is secluded from others by layering oil on top, allowing for non invasive, high-resolution time-lapse microscopy, and data collection from each individual embryo without confounding factors. We have successfully cultured mouse embryos from the two-cell stage to completely hatched blastocysts inside microwells with an 89% success rate (n = 64), which is comparable to the success rate of the contemporary practice. Development timings of mouse embryos that developed into blastocysts are statistically different to those of embryos that failed to form blastocysts (p-value < 10(-10), two-tailed Student's t-test) and are robust indicators of the competence of the embryo to form a blastocyst in vitro with 94% sensitivity and 100% specificity. Embryos at the cleavage- or blastocyst-stage following the normal development timings were selected and transferred to the uteri of surrogate female mice. Fifteen of twenty-two (68%) blastocysts and four of ten (40%) embryos successfully developed into normal baby mice following embryo transfer. This microwell platform, which supports the development of preimplanted embryos and is low-cost, easy to fabricate and operate, we believe, opens opportunities for a wide range of applications in reproductive medicine and cell biology. PMID- 26015831 TI - Droplet confinement and leakage: Causes, underlying effects, and amelioration strategies. AB - The applicability of droplet-based microfluidic systems to many research fields stems from the fact that droplets are generally considered individual and self contained reaction vessels. This study demonstrates that, more often than not, the integrity of droplets is not complete, and depends on a range of factors including surfactant type and concentration, the micro-channel surface, droplet storage conditions, and the flow rates used to form and process droplets. Herein, a model microfluidic device is used for droplet generation and storage to allow the comparative study of forty-four different oil/surfactant conditions. Assessment of droplet stability under these conditions suggests a diversity of different droplet failure modes. These failure modes have been classified into families depending on the underlying effect, with both numerical and qualitative models being used to describe the causative effect and to provide practical solutions for droplet failure amelioration in microfluidic systems. PMID- 26015832 TI - Formation of lipid bilayer membrane in a poly(dimethylsiloxane) microchip integrated with a stacked polycarbonate membrane support and an on-site nanoinjector. AB - This paper describes a new and facile approach for the formation of pore-spanning bilayer lipid membranes (BLMs) within a poly(dimethylsiloxane) (PDMS) microfluidic device. Commercially, readily available polycarbonate (PC) membranes are employed for the support of BLMs. PC sheets with 5 MUm, 2 MUm, and 0.4 MUm pore diameters, respectively, are thermally bonded into a multilayer-stack, reducing the pore density of 0.4 MUm-pore PC by a factor of 200. The BLMs on this support are considerably stable (a mean lifetime: 17 h). This multilayer-stack PC (MSPC) membrane is integrated into the PDMS chip by an epoxy bonding method developed to secure durable bonding under the use of organic solvents. The microchip has a special channel for guiding a micropipette in the proximity of the MSPC support. With this on-site injection technique, tens to hundreds of nanoliters of solutions can be directly dispensed to the support. Incorporating gramicidin ion channels into BLMs on the MSPC support has confirmed the formation of single BLMs, which is based on the observation from current signals of 20 pS conductance that is typical to single channel opening. Based on the bilayer capacitance (1.4 pF), about 15% of through pores across the MSPC membrane are estimated to be covered with BLMs. PMID- 26015833 TI - Hydrodynamics of a self-actuated bacterial carpet using microscale particle image velocimetry. AB - Microorganisms can effectively generate propulsive force at the microscale where viscous forces overwhelmingly dominate inertia forces; bacteria achieve this task through flagellar motion. When swarming bacteria, cultured on agar plates, are blotted onto the surface of a microfabricated structure, a monolayer of bacteria forms what is termed a "bacterial carpet," which generates strong flows due to the combined motion of their freely rotating flagella. Furthermore, when the bacterial carpet coated microstructure is released into a low Reynolds number fluidic environment, the propulsive force of the bacterial carpet is able to give the microstructure motility. In our previous investigations, we demonstrated motion control of these bacteria powered microbiorobots (MBRs). Without any external stimuli, MBRs display natural rotational and translational movements on their own; this MBR self-actuation is due to the coordination of flagella. Here, we investigate the flow fields generated by bacterial carpets, and compare this flow to the flow fields observed in the bulk fluid at a series of locations above the bacterial carpet. Using microscale particle image velocimetry, we characterize the flow fields generated from the bacterial carpets of MBRs in an effort to understand their propulsive flow, as well as the resulting pattern of flagella driven self-actuated motion. Comparing the velocities between the bacterial carpets on fixed and untethered MBRs, it was found that flow velocities near the surface of the microstructure were strongest, and at distances far above, the surface flow velocities were much smaller. PMID- 26015834 TI - Disrupting the wall accumulation of human sperm cells by artificial corrugation. AB - Many self-propelled microorganisms are attracted to surfaces. This makes their dynamics in restricted geometries very different from that observed in the bulk. Swimming along walls is beneficial for directing and sorting cells, but may be detrimental if homogeneous populations are desired, such as in counting microchambers. In this work, we characterize the motion of human sperm cells ~60 MUm long, strongly confined to ~25 MUm shallow chambers. We investigate the nature of the cell trajectories between the confining surfaces and their accumulation near the borders. Observed cell trajectories are composed of a succession of quasi-circular and quasi-linear segments. This suggests that the cells follow a path of intermittent trappings near the top and bottom surfaces separated by stretches of quasi-free motion in between the two surfaces, as confirmed by depth resolved confocal microscopy studies. We show that the introduction of artificial petal-shaped corrugation in the lateral boundaries removes the tendency of cells to accumulate near the borders, an effect which we hypothesize may be valuable for microfluidic applications in biomedicine. PMID- 26015835 TI - Automated cell viability assessment using a microfluidics based portable imaging flow analyzer. AB - In this work, we report a system-level integration of portable microscopy and microfluidics for the realization of optofluidic imaging flow analyzer with a throughput of 450 cells/s. With the use of a cellphone augmented with off-the shelf optical components and custom designed microfluidics, we demonstrate a portable optofluidic imaging flow analyzer. A multiple microfluidic channel geometry was employed to demonstrate the enhancement of throughput in the context of low frame-rate imaging systems. Using the cell-phone based digital imaging flow analyzer, we have imaged yeast cells present in a suspension. By digitally processing the recorded videos of the flow stream on the cellphone, we demonstrated an automated cell viability assessment of the yeast cell population. In addition, we also demonstrate the suitability of the system for blood cell counting. PMID- 26015836 TI - Laser-based patterning for fluidic devices in nitrocellulose. AB - In this report, we demonstrate a simple and low cost method that can be reproducibly used for fabrication of microfluidic devices in nitrocellulose. The fluidic patterns are created via a laser-based direct-write technique that induces polymerisation of a photo-polymer previously impregnated in the nitrocellulose. The resulting structures form hydrophobic barriers that extend through the thickness of the nitrocellulose and define an interconnected hydrophilic fluidic-flow pattern. Our experimental results show that using this method it is possible to achieve microfluidic channels with lateral dimensions of ~100 MUm using hydrophobic barriers that form the channel walls with dimensions of ~60 MUm; both of these values are considerably smaller than those that can be achieved with other current techniques used in the fabrication of nitrocellulose based fluidic devices. A simple grid patterned nitrocellulose device was then used for the detection of C-reactive protein via a sandwich enzyme-linked immunosorbent assay, which served as a useful proof-of-principle experiment. PMID- 26015837 TI - Two-dimensional and three-dimensional dynamic imaging of live biofilms in a microchannel by time-of-flight secondary ion mass spectrometry. AB - A vacuum compatible microfluidic reactor, SALVI (System for Analysis at the Liquid Vacuum Interface), was employed for in situ chemical imaging of live biofilms using time-of-flight secondary ion mass spectrometry (ToF-SIMS). Depth profiling by sputtering materials in sequential layers resulted in live biofilm spatial chemical mapping. Two-dimensional (2D) images were reconstructed to report the first three-dimensional images of hydrated biofilm elucidating spatial and chemical heterogeneity. 2D image principal component analysis was conducted among biofilms at different locations in the microchannel. Our approach directly visualized spatial and chemical heterogeneity within the living biofilm by dynamic liquid ToF-SIMS. PMID- 26015838 TI - Parallelized ultra-high throughput microfluidic emulsifier for multiplex kinetic assays. AB - Droplet-based microfluidic technologies are powerful tools for applications requiring high-throughput, for example, in biochemistry or material sciences. Several systems have been proposed for the high-throughput production of monodisperse emulsions by parallelizing multiple droplet makers. However, these systems have two main limitations: (1) they allow the use of only a single disperse phase; (2) they are based on multiple layer microfabrication techniques. We present here a pipette-and-play solution offering the possibility of manipulating simultaneously 10 different disperse phases on a single layer device. This system allows high-throughput emulsion production using aqueous flow rates of up to 26 ml/h (>110 000 drops/s) leading to emulsions with user-defined complex chemical composition. We demonstrate the multiplex capabilities of our system by measuring the kinetics of beta-galactosidase in droplets using nine different concentrations of a fluorogenic substrate. PMID- 26015839 TI - Numerical simulation on the opto-electro-kinetic patterning for rapid concentration of particles in a microchannel. AB - This paper presents a mathematical model for laser-induced rapid electro-kinetic patterning (REP) to elucidate the mechanism for concentrating particles in a microchannel non-destructively and non-invasively. COMSOL((r))(v4.2a) multiphysics software was used to examine the effect of a variety of parameters on the focusing performance of the REP. A mathematical model of the REP was developed based on the AC electrothermal flow (ACET) equations, the dielectrophoresis (DEP) equation, the energy balance equation, the Navier-Stokes equation, and the concentration-distribution equation. The medium was assumed to be a diluted solute, and different electric potentials and laser illumination were applied to the desired place. Gold (Au) electrodes were used at the top and bottom of a microchannel. For model validation, the simulation results were compared with the experimental data. The results revealed the formation of a toroidal microvortex via the ACET effect, which was generated due to laser illumination and joule-heating in the area of interest. In addition, under some conditions, such as the frequency of AC, the DEP velocity, and the particle size, the ACET force enhances and compresses resulting in the concentration of particles. The conditions of the DEP velocity and the ACET velocity are presented in detail with a comparison of the experimental results. PMID- 26015840 TI - Biofunctionalized nanoslits for wash-free and spatially resolved real-time sensing with full target capture. AB - We propose biofunctionalized nanofluidic slits (nanoslits) as an effective platform for real-time fluorescence-based biosensing in a reaction-limited regime with optimized target capture efficiency. This is achieved by the drastic reduction of the diffusion length, thereby a boosted collision frequency between the target analytes and the sensor, and the size reduction of the sensing element down to the channel height comparable to the depletion layer caused by the reaction. Hybridization experiments conducted in DNA-functionalized nanoslits demonstrate the analyte depletion and the wash-free detection ~10 times faster compared to the best microfluidic sensing platforms. The signal to background fluorescence ratio is drastically increased at lower target concentrations, in favor of low-copy number analyte analysis. Experimental and simulation results further show that biofunctionalized nanoslits provide a simple means to study reaction kinetics at the single-pixel level using conventional fluorescence microscopy with reduced optical depth. PMID- 26015841 TI - Fatal intoxication caused by the application of the multiple transdermals patchs of fentanyl. AB - Fentanyl (N-phenyl-N-(1-2-phenylethyl-4-piperidyl)propanamide) is a potent synthetic narcotic analgesic. He has an analgesic effect 100 times greater than that of morphine. The use of transdermal fentanyl delivrery systems has increased over recent years especially in patients with chronic pain who are already treated with high doses of morphine or it is derivate. However, many cases of fentanyl intoxication through a variety of transderrmal systems have been reported. This paper reports a fatality due to excessive administered Fentanyl Sandoz(r) Matrix 50 ug/h transdermal therapeutic systems. PMID- 26015842 TI - Synchronous malignant renal mass in patient with a Lung cancer: case report and literature review. AB - The finding on imaging (computed tomography scan or magnetic resonance imaging) of synchronous malignant renal mass in patient with an active nonrenal malignancy without renal specific symptoms is not frequent and diagnostic evaluation can be challenging. We describe a 54-year-old Moroccan male former chronic smoker who presented to our hospital with dry cough and impairment of the performance status. The imaging found a tumor mass in the left upper lobe of the lung associated to mediastinal lymph node and a scanno-guided biopsy of this tumor showed a non small cell lung cancer. The radiological staging revealed a solitary renal mass in the right kidney. The patient received firstly two cycles of a lung cancer chemotherapy with a partial response in the lung and a stability of the renal mass. Consequently, he underwent a scanno-guided biopsy of this mass which confirmed a synchronous clear cell renal carcinoma. The patient got chemo radiotherapy for the lung cancer and then after that he got a partial nephrectomy. He is still under a good control with more than 2 years after the initial diagnosis. PMID- 26015843 TI - [Inaugural pseudo-meningitis revealing a chondrocalcinosis]. PMID- 26015844 TI - Spectrum of intracranial tumours in a tertiary health carefacility: our findings. AB - INTRODUCTION: Primary brain tumours are uncommon with an annual incidence of 5 10/100000. This study has attempted to analyse the histological pattern of intracranial tumours seen in our centre. METHODS: A retrospective study of cases of intracranial tumours seen was conducted over a period of 5 years ie from January 2008 to December 2012. All the slides were reviewed. The age, sex, diagnosis using the WHO grading and the histological subtypes were recorded. Data were analysed using the (SPSS) Software version 17. RESULTS: Altogether, 56 cases of intracranial tumours were seen out of a total of 12,610 biopsies representing 0.004%. The male to female ratio (M: F) was approximately 1:1.1 The mean age of the patients was 36+/-20.35 (range, 2 to 85). Astrocytomas accounted for 30% (17) while 29% (16) had Meningioma. Medulloblastoma accounted for 18%. (10). Of the cases of Gliomas, majority (52%) fell under WHO grade II. (38%)of the Meningioma were of the mixed type while 25% had transitional type. CONCLUSION: Astrocytomas was the commonest brain tumour. These patterns corroborated most studies that have been done. Metastasis to the brain was however, not seen in this study. PMID- 26015845 TI - [Pediatric onset systemic lupus erythematosus: about a case]. PMID- 26015846 TI - [Bilateral tuberculous dacryoadenitis: about a case]. PMID- 26015847 TI - Indoor household residual spraying program performance in Matabeleland South province, Zimbabwe: 2011 to 2012; a descriptive cross-sectional study. AB - INTRODUCTION: Matabeleland South launched the malaria pre-elimination campaign in 2012 but provincial spraying coverage has failed to attain 95% target, with some districts still encountering malaria outbreaks. A study was conducted to evaluate program performance against achieving malaria pre-elimination. METHODS: A descriptive cross sectional study was done in 5 districts carrying out IRS using the logical framework involving inputs, process, outputs and outcome evaluation. Health workers recruited into the study included direct program implementers, district and provincial program managers. An interviewer administered questionnaire, checklists, key informant interviewer guide and desk review of records were used to collect data. RESULTS: We enrolled 37 primary respondents and 5 key informants. Pre-elimination, Epidemic Preparedness and Response plans were absent in all districts. Shortages of inputs were reported by 97% of respondents, with districts receiving 80% of requested budget. Insecticides were procured centrally at national level. Spraying started late and districts failed to spray all targeted households by end of December. The province is using makeshift camps with inappropriate evaporation ponds where liquid DDT waste is not safely accounted for. The provincial IHRS coverage for 2011 was 84%. Challenges cited included; food shortages for spraymen, late delivery of inputs and poor state of IHRS equipment. CONCLUSION: The province has failed to achieve Malaria pre-elimination IRS coverage targets for 2011/12 season. Financial and logistical challenges led to delays in supply of program inputs, recruitment and training of sprayers. The Province should establish camping infrastructure with standard evaporation ponds to minimise contamination of the environment. PMID- 26015848 TI - [Epidemiology of severe domestic accidents of children admitted in pediatric intensive care unit of Children Hospital of Rabat-Morocco]. PMID- 26015849 TI - [The restless legs syndrome: incidence and risk factors in hemodialysis]. PMID- 26015850 TI - [Hahn Steinthal fracture treated by Herbert screw fixation: 3 cases]. PMID- 26015851 TI - Estimating the Sizes of Populations At Risk of HIV Infection From Multiple Data Sources Using a Bayesian Hierarchical Model. AB - In most countries in the world outside of sub-Saharan Africa, HIV is largely concentrated in sub-populations whose behavior puts them at higher risk of contracting and transmitting HIV, such as people who inject drugs, sex workers and men who have sex with men. Estimating the size of these sub-populations is important for assessing overall HIV prevalence and designing effective interventions. We present a Bayesian hierarchical model for estimating the sizes of local and national HIV key affected populations. The model incorporates multiple commonly used data sources including mapping data, surveys, interventions, capture-recapture data, estimates or guesstimates from organizations, and expert opinion. The proposed model is used to estimate the numbers of people who inject drugs in Bangladesh. PMID- 26015852 TI - Lymph node pick up by separate stations: Option or necessity. AB - AIM: To evaluate whether lymph node pick up by separate stations could be an indicator of patients submitted to appropriate surgical treatment. METHODS: One thousand two hundred and three consecutive gastric cancer patients submitted to radical resection in 7 general hospitals and for whom no information was available on the extension of lymphatic dissection were included in this retrospective study. RESULTS: Patients were divided into 2 groups: group A, where the stomach specimen was directly formalin-fixed and sent to the pathologist, and group B, where lymph nodes were picked up after surgery and fixed for separate stations. Sixty-two point three percent of group A patients showed < 16 retrieved lymph nodes compared to 19.4% of group B (P < 0.0001). Group B (separate stations) patients had significantly higher survival rates than those in group A [46.1 mo (95%CI: 36.5-56.0) vs 27.7 mo (95%CI: 21.3-31.9); P = 0.0001], independently of T or N stage. In multivariate analysis, group A also showed a higher risk of death than group B (HR = 1.24; 95%CI: 1.05-1.46). CONCLUSION: Separate lymphatic station dissection increases the number of retrieved nodes, leads to better tumor staging, and permits verification of the surgical dissection. The number of dissected stations could potentially be used as an index to evaluate the quality of treatment received. PMID- 26015853 TI - Pancreatectomy and splenectomy for a splenic aneurysm associated with segmental arterial mediolysis. AB - Segmental arterial mediolysis (SAM) is characterized by intra-abdominal, retroperitoneal bleeding or bowel ischemia, and the etiology is unknown. A 44 year-old man complaining of abdominal pain was admitted to our hospital. He had been admitted for a left renal infarction three days earlier and had a past medical history of cerebral aneurysm with spontaneous remission. The ruptured site of the splenic arterial aneurysm was clear via a celiac angiography, and we treated it using trans-arterial embolization. Unfortunately, the aneurysm reruptured after two weeks, and we successfully treated it with distal pancreatomy and splenectomy. We recommended a close follow-up and prompt radiological or surgical intervention because SAM can enlarge rapidly and rupture. PMID- 26015854 TI - Thoracoabdominal pseudocyst of pancreas: An rare location, managed by retrocolic retrogastric Roux-en-Y cystojejunostomy. AB - Pseudocyst formation is a common complication of acute and chronic pancreatitis. Most common site of pseudocyst is lesser sac; mediastinal extension of pseudocyst is rare. Other possibilities of posterior mediastinal cyst must be considered. This patient presented with computed tomography abdomen with thorax showing a large thoraco-abdominal pseudocyst with right sided pleural effusion. It was confirmed to be pancreatic pseudocyst by analyzing fluid for amylase and lipase during surgery. In our patient, the pseudocyst was accessible transabdominaly. Cystogastrostomy was not possible as it was causing twisting of cardio-esophageal junction; we did retrocolic and retrogastric Roux-en-Y cystojejunostomy. Only two such cases were reported in literature. PMID- 26015855 TI - Pulmonary hypertension in hereditary haemorrhagic telangiectasia. AB - Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain, liver and lungs. Pulmonary hypertension (PH) is increasingly recognised as a severe complication of HHT. PH may be categorised into two distinct types in patients with HHT. Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations. Less frequently, the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension. Differentiation between both forms of PH by right heart catheterisation is essential, since both entities are associated with severe morbidity and mortality with different treatment options. Therefore all HHT patients should be referred to an HHT centre. PMID- 26015856 TI - Insights into cardio-oncology: Polypharmacology of quinazoline-based alpha1 adrenoceptor antagonists. AB - New uses of cardiovascular drugs with proven experience are emerging, including for treating cancer. Quinazoline is a compound made up of two fused six member simple aromatic rings, benzene and pyrimidine rings, with several biological effects. Cardiologists first used quinazoline-based alpha1-adrenoceptor antagonists prazosin, doxazosin, and terazosin; currently available data support their use as safe, well tolerated, and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects. Recent findings highlight the anticancer effects of quinazoline-based alpha1-adrenoceptor antagonists, indicating that they may have a significant role in uncontrolled hypertensive cancer patients without signs of ischemia. PMID- 26015859 TI - Quantification of epicardial fat: Which method can predict significant coronary artery disease? AB - AIM: To compare the predictive value of three methods of epicardial fat (EF) assessment for presence of significant coronary artery disease (CAD) [i.e., epicardial fat volume (EFV), EFV indexed with body surface area (EFV/BSA) and EFV indexed with body mass index (EFV/BMI)]. METHODS: The study was performed on 170 patients (85 women and 85 men) with clinical suspicion of CAD. They aged 26-89 years with a median age of 54 years. The patients were classified into three groups: Group 1: 58 patients with normal coronary arteries; group 2: 48 patients with non-significant CAD and group 3: 64 patients with significant CAD. The three methods for assessment of epicardial fat were retrospectively studied to determine the best method to predict the presence of significant CAD. RESULTS: The three methods for epicardial fat quantification and measurements, i.e., EFV, EFV/BSA and EFV/BMI with post- hoc analysis showed a significant difference between patients with significant coronary artery disease compared to the normal group. Receiver operating characteristic curve analysis showed no significant difference between the three methods of epicardial fat measurements, the area under curve ranging between 0.6 and 0.62. The optimal cut-off was 80.3 cm(3) for EFV, 2.4 cm(3)/m(2) for EFV indexed with BMI and 41.7 cm(3)/(kg/m(2)) for EFV indexed with BSA. For this cut-off the sensitivity ranged between 0.92 and 0.94, while specificity varied from 0.31 to 0.35. CONCLUSION: Any one of the three methods for assessment of epicardial fat can be used to predict significant CAD since all have the same equivalent predictive value. PMID- 26015858 TI - Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses. AB - The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRalpha-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction. PMID- 26015860 TI - Myocarditis in athlete and myocardial bridge: An innocent bystander? AB - Myocarditis is a bacterial or viral inflammatory disease, often unnoticed or misdiagnosed. Athletes with myocarditis must stop practicing their activity since International medical Literature described some cases of sudden death. In the present report, we describe a case of an asymptomatic, apparently healthy, competitive athletes, who was diagnosed a myocarditis and as incidental finding a myocardial bridging. We focused the attention on the importance of anamnesis, electrocardiogram and athletes' entourage for the diagnosis of such insidious pathologies and we evaluated the follow up, focusing the attention on electrocardiogram changes as well as on restitution ad integrum and prognosis, especially for the athletes. PMID- 26015861 TI - Obesity Researches Over the Past 24 years: A Scientometrics Study in Middle East Countries. AB - BACKGROUND: Researchers, practitioners, and policy-makers call for updated valid evidences to monitor, prevent, and control of alarming trends of obesity. We quantify the trends of obesity/overweight researches outputs of Middle East countries. METHODS: We systematically searched Scopus database as the only sources for multidisciplinary citation reports, with the most coverage in health and biomedicine disciplines for all related obesity/overweight publications, from 1990 to 2013. These scientometrics analysis assessed the trends of scientific products, citations, and collaborative papers in Middle East countries. We also provided Information on top institutions, journals, and collaborative research centers in the field of obesity/overweight. RESULTS: Over 24-year period, the number of obesity/overweight publications and related citations in Middle East countries had increasing trend. Globally, during 1990-2013, 415,126 papers have been published, from them, 3.56% were affiliated to Middle East countries. Iran with 26.27%, compare with other countries in the regions, after Turkey (47.94%) and Israel (35.25%), had the third position. Israel, Turkey, and Iran were leading countries in citation analysis. The most collaborative country with Middle East countries was USA and within the region, the most collaborative country was Saudi Arabia. CONCLUSIONS: Despite the ascending trends in research outputs, more efforts required for promotion of collaborative partnerships. Results could be useful for better health policy and more planned studies in this field. These findings also could be used for future complementary analysis. PMID- 26015857 TI - Recent advances in the diagnosis and treatment of acute myocardial infarction. AB - The Third Universal Definition of Myocardial Infarction (MI) requires cardiac myocyte necrosis with an increase and/or a decrease in a patient's plasma of cardiac troponin (cTn) with at least one cTn measurement greater than the 99(th) percentile of the upper normal reference limit during: (1) symptoms of myocardial ischemia; (2) new significant electrocardiogram (ECG) ST-segment/T-wave changes or left bundle branch block; (3) the development of pathological ECG Q waves; (4) new loss of viable myocardium or regional wall motion abnormality identified by an imaging procedure; or (5) identification of intracoronary thrombus by angiography or autopsy. Myocardial infarction, when diagnosed, is now classified into five types. Detection of a rise and a fall of troponin are essential to the diagnosis of acute MI. However, high sensitivity troponin assays can increase the sensitivity but decrease the specificity of MI diagnosis. The ECG remains a cornerstone in the diagnosis of MI and should be frequently repeated, especially if the initial ECG is not diagnostic of MI. There have been significant advances in adjunctive pharmacotherapy, procedural techniques and stent technology in the treatment of patients with MIs. The routine use of antiplatelet agents such as clopidogrel, prasugrel or ticagrelor, in addition to aspirin, reduces patient morbidity and mortality. Percutaneous coronary intervention (PCI) in a timely manner is the primary treatment of patients with acute ST segment elevation MI. Drug eluting coronary stents are safe and beneficial with primary coronary intervention. Treatment with direct thrombin inhibitors during PCI is non inferior to unfractionated heparin and glycoprotein IIb/IIIa receptor antagonists and is associated with a significant reduction in bleeding. The intra-coronary use of a glycoprotein IIb/IIIa antagonist can reduce infarct size. Pre- and post conditioning techniques can provide additional cardioprotection. However, the incidence and mortality due to MI continues to be high despite all these recent advances. The initial ten year experience with autologous human bone marrow mononuclear cells (BMCs) in patients with MI showed modest but significant increases in left ventricular (LV) ejection fraction, decreases in LV end systolic volume and reductions in MI size. These studies established that the intramyocardial or intracoronary administration of stem cells is safe. However, many of these studies consisted of small numbers of patients who were not randomized to BMCs or placebo. The recent LateTime, Time, and Swiss Multicenter Trials in patients with MI did not demonstrate significant improvement in patient LV ejection fraction with BMCs in comparison with placebo. Possible explanations include the early use of PCI in these patients, heterogeneous BMC populations which died prematurely from patients with chronic ischemic disease, red blood cell contamination which decreases BMC renewal, and heparin which decreases BMC migration. In contrast, cardiac stem cells from the right atrial appendage and ventricular septum and apex in the SCIPIO and CADUCEUS Trials appear to reduce patient MI size and increase viable myocardium. Additional clinical studies with cardiac stem cells are in progress. PMID- 26015862 TI - Sociodemographic and Economic Determinants of Overweight and Obesity for Public school Children in Geneva State, Switzerland: A Cross-sectional Study. AB - BACKGROUND: Obesity among children and adolescents is a growing public health problem. The purpose of this study is to assess the prevalence, socioeconomic and demographic determinants of overweight and obesity in schoolchildren from Geneva. METHODS: A cross-sectional study was undertaken at the Public School of Geneva canton in Switzerland. A total of 8544 public school children were collected and analyzed: 2577 were in second grade, 2641 in fifth grade and 3326 in eighth grade. To identify overweight and obesity we used the definition issued by the International Obesity Task Force. Child characteristics included gender, age, socioeconomic status (SES) of father and mother, and school grade. The multivariate logistic regression model was used to examine potential predictors of overweight/obesity. RESULTS: The prevalence of overweight or obese children was 14.4% in second grade, 17.3% in fifth grade and 18.6% in eighth grade. Multivariate logistic regression analyses reveal that children that have a low economic status or certain citizenships are more likely to be overweight or obese. Children of Kosovar origin, have a higher risk of OBO in second grade (adjusted odds ratio [OR] = 2.19; 95% confidence interval [CI]: 1.20-4.00), fifth grade (adjusted OR = 2.36 95% CI: 1.27-4.39) and in eighth grade (adjusted OR = 2.15 95% CI: 1.27-4.39). Association between SES and overweight was high with regards to the father's SES in fifth grade (adjusted OR = 4.21 95% CI: 2.83 6.25). CONCLUSIONS: Overweight and obesity is associated to socioeconomic and sociodemographic factors. The analyzes reveals that children with a low economic status and/or from certain countries are more likely to be overweight or obese than Swiss children. There is an urgent need for action to prevent further increase in overweight or obesity among children. PMID- 26015863 TI - Awareness about "Ten Steps for Successful Breastfeeding" among Medical and Nursing Students. AB - BACKGROUND: Baby-friendly Hospital Initiative (BFHI) is a vital intervention supported by World Health Organization and UNICEF to reduce infant mortality and has been included as a part of the curriculum in nursing and medical courses. To know the extent of knowledge of students about BFHI along with its understanding and to find out the gap in their knowledge about BFHI steps. METHODS: A descriptive cross sectional study was carried out among the nursing (4(th) year) and medical students (3(rd) year MBBS) about ten steps of BFHI by a pretested and predesigned questionnaire. After ethical clearance, information was collected about their awareness and correct understanding concerning ten steps. RESULTS: A total of 102 (51.6%) medical and 96 (48.4%) nursing students comprising of 57 (28.8%) males and 141 (71.2%) females were interviewed, had similar mean score about the ten steps of BFHI. Female respondents 82.3% had best understood the step 2 (training), as compared to males 80.7%. About step 6 (no supplements) 94.3% females and 86% males had well understood the step. Step 7 (rooming in) was known to 85.8% females and 54.4% males respectively. Step 9 (no pacifiers) was known to 80.1% females while among males 56.1% were aware. There was statistically significant difference in their knowledge about the steps 2 and 4 (skin to skin), 5 (counseling), 7, and 9 as females were more aware about these steps than males. The least understood steps in medical and nursing students were step 1 (written policy) (15.7%, 15.6%), step 3 (prenatal education) (27.5%, 29.2%), step 8 (cues) (10.8%, 24%) and step ten (community support) (8.8%, 11.5%) respectively. CONCLUSIONS: BFHI is one of the successful international efforts undertaken to promote, protect and support breast feeding. Acquiring knowledge about the same by medical and nursing students is most crucial tool for better practices by them in the future. Continued medical education, workshops and seminars by lactation specialists in addition to the regular teaching about BFHI as part of the curriculum may be considered to ensure and update their knowledge about BFHI. PMID- 26015864 TI - Mutation of kisspeptin 1 gene in children with precocious puberty in isfahan city. AB - BACKGROUND: Considering the role of kisspeptin (KISS) in the process of puberty, this study aimed to determine the mutation of KISS1 gene among a group of patients with idiopathic central precocious puberty (ICPP). METHODS: In this case control study, a group of children with diagnosed ICPP and a group of healthy children were selected. Genomic DNA was extracted from peripheral blood of selected population. After proving the quality and quantity of extracted DNA samples by nano-drop instrument, PCR was performed using 3 set of primers to amplify all coding exons and flanking intron region of Kiss1 gene. RESULTS: In this study, 33 patients with idiopathic PP and 30 control age and sex matched children were studied. Genetic analysis indicated that there was not any polymorphism or mutation in studied participants of the control group. Among patients with ICPP, 4 single nucleotide polymorphisms within the promoter and coding regions of KISS1 gene were determined in 9 patients (5 boys and 4 girls). Among them, the c.-148 T > A was novel variant. CONCLUSIONS: The results of the current study identified one novel polymorphism and three reported polymorphism in KISS gene among patients with ICPP. It is recommended to design further studies for analysis other genes related to ICPP in accordance with more complementary biochemical evaluations is recommended also. PMID- 26015866 TI - Myosin heavy chain-9-related disorders (MYH9-RD): a case report. AB - Myosin heavy chain-9-related disorders (MYH9-RDs) are a group of autosomal dominant disorders caused by mutations in the MYH9 gene. The features include congenital macrothrombocytopaenia, inclusion bodies in neutrophils and a variable risk of developing sensorineural deafness, progressive renal impairment and presenile cataracts. A 44-year-old Caucasian man was initially thought to have Alport's syndrome and thrombocytopaenia secondary to idiopathic thrombocytopaenic purpura (ITP). A detailed family history and genetic analysis revealed a diagnosis of MYH9-RD. This case highlights the implications of a delayed diagnosis and the ongoing challenges encountered during management of individuals with this condition. PMID- 26015865 TI - Solenopsin A and analogs exhibit ceramide-like biological activity. AB - BACKGROUND: (-)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis. METHODS: Different analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated. RESULTS: In this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (-)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide. CONCLUSIONS: The requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (-)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt. PMID- 26015867 TI - Fluorescence Imaging of Interscapular Brown Adipose Tissue in Living Mice. AB - Brown adipose tissue (BAT) plays a key role in energy expenditure and heat generation and is a promising target for diagnosing and treating obesity, diabetes and related metabolism disorders. While several nuclear and magnetic resonance imaging methods are established for detecting human BAT, there are no convenient protocols for high throughput imaging of BAT in small animal models. Here we disclose a simple but effective method for non-invasive optical imaging of interscapular BAT in mice using a micellar formulation of the commercially available deep-red fluorescent probe, SRFluor680. Whole-body fluorescence imaging of living mice shows extensive accumulation of the fluorescent probe in the interscapular BAT and ex vivo analysis shows 3.5-fold selectivity for interscapular BAT over interscapular WAT. Additional imaging studies indicate that SRFluor680 uptake is independent of mouse species and BAT metabolic state. The results are consistent with an unusual pharmacokinetic process that involves irreversible translocation of the lipophilic SRFluor680 from the micelle nanocarrier into the adipocytes within the BAT. Multimodal PET/CT and planar fluorescence/X-ray imaging of the same living animal shows co-localization of BAT mass signal reported by the fluorescent probe and BAT metabolism signal reported by the PET agent, 18F-FDG. The results indicate a path towards a new, dual probe molecular imaging paradigm that allows separate and independent non-invasive visualization of BAT mass and BAT metabolism in a living subject. PMID- 26015868 TI - Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. AB - BACKGROUND: Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum based chemotherapy. Therefore, reliable biomarkers to identify DNA repair deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer. RESULTS: We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's rho 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy. CONCLUSIONS: Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens. PMID- 26015869 TI - Effect of enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with sepsis-induced acute respiratory distress syndrome. AB - BACKGROUND: In this study, the effects of an enteral diet enriched with eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and antioxidants were compared with a standard enteral diet in critically ill patients with sepsis induced acute respiratory distress syndrome (ARDS). METHODS: This study was a single-center, prospective, randomized, single-blind, controlled trial in our Advanced Critical Care Center. Patients were randomized to receive a continuous EPA, GLA, and antioxidant-enriched diet (study group), or an isocaloric standard diet (control group). RESULTS: Twenty-three of 46 patients were in the study group, and the other 23 were in the control group. Duration of mechanical ventilation, incidence of new nosocomial infections, changes over time in Sequential Organ Failure Assessment (SOFA) scores, and 60-day mortality were not significantly different between the two groups. The ratio of partial pressure of oxygen to fraction of inspired oxygen on day 7 was significantly higher in the study group (233.0 [185.5-282.8] vs. 274.0 [225.5-310.8], p = 0.021). Duration of ICU stay was significantly shorter in the study group than in the control group (24.0 [20.0-30.0] vs. 15.0 [11.0-24.0], p = 0.008). CONCLUSIONS: An enteral diet enriched with EPA, GLA, and antioxidants did not improve duration of mechanical ventilation, SOFA score, incidence of new nosocomial infections, or mortality but did favorably influence duration of ICU stay in critically ill patients with sepsis-induced ARDS. PMID- 26015870 TI - The expanding role of the endonasal endoscopic approach in pituitary and skull base surgery: A 2014 perspective. AB - BACKGROUND: The past two decades have been the setting for remarkable advancement in endonasal endoscopic neurosurgery. Refinements in camera definition, surgical instrumentation, navigation, and surgical technique, including the dual surgeon team, have facilitated purely endonasal endoscopic approaches to the majority of the midline skull base that were previously difficult to access through the transsphenoidal microscopic approach. METHODS: This review article looks at many of the articles from 2011 to 2014 citing endonasal endoscopic surgery with regard to approaches and reconstructive techniques, pathologies treated and outcomes, and new technologies under consideration. RESULTS: Refinements in approach and closure techniques have reduced the risk of cerebrospinal fluid leak and infection. This has allowed surgeons to more aggressively treat a variety of pathologies. Four main pathologies with outcomes after treatment were identified for discussion: pituitary adenomas, craniopharyngiomas, anterior skull base meningiomas, and chordomas. Within all four of these tumor types, articles have demonstrated the efficacy, and in certain cases, the advantages over more traditional microscope-based techniques, of the endonasal endoscopic technique. CONCLUSIONS: The endonasal endoscopic approach is a necessary tool in the modern skull base surgeon's armamentarium. Its efficacy for treatment of a wide variety of skull base pathologies has been repeatedly demonstrated. In the experienced surgeon's hands, this technique may offer the advantage of greater tumor removal with reduced overall complications over traditional craniotomies for select tumor pathologies centered near the midline skull base. PMID- 26015871 TI - Hemifacial spasm: 20-year surgical experience, lesson learned. AB - BACKGROUND: Hemifacial spasm is characterized by unilateral, paroxysmal, and involuntary contractions. It is more common in women on the left side. Its evolution is progressive, and it rarely improves without treatment. METHODS: Microvascular decompressions (N = 226) were performed in 194 Hispanic patients (May 1992-May 2011). Outcomes were evaluated on a 4-point scale: Excellent (complete remission); good (1-2 spasms/day); bad (>2 spasms/day); and recurrence (relapse after initial excellent/good response). RESULTS: Most patients were female (n = 123); 71 were male. Mean (+/-SD) age was 49.4 (+/-11.7) years; age at onset, 43.9 (+/-11.9) years; time to surgery, 5.7 (+/-4.7) years. The left side was affected in 114 patients. Typical syndrome occurred in 177 (91.2%); atypical in 17 (8.8%). Findings were primarily vascular compression (n = 185 patients): Anterior inferior cerebellar artery (n = 147), posterior inferior cerebellar artery (n = 12), basilar artery (n = 10), superior cerebellar artery (n = 8), and 2 vessels (n = 8); 9 had no compression. Postsurgical results were primarily excellent (79.9% [n = 155]; good, 4.6% [n = 9]; bad, 15.5% [n = 30]), with recurrence in 21 (10.8%) at mean 51-month (range, 1-133 months) follow-up. Complications included transient hearing loss and facial palsy. CONCLUSIONS: The anterior inferior cerebellar artery is involved in most cases of hemifacial spasm. Failure to improve postsurgically after 1 week warrants reoperation. Sex, side, and onset are unrelated to treatment response. Microvascular decompression is the preferred treatment. It is minimally invasive, nondestructive, and achieves the best long-term results, with minor morbidity. To our knowledge, this series is the largest to date on a Hispanic population. PMID- 26015872 TI - Hemichorea-hemiballismus caused by postoperative hyperperfusion after clipping of a giant unruptured middle cerebral artery aneurysm. AB - BACKGROUND: Movement disorders after the clipping for an unruptured giant aneurysm are rare. The information on the pathogenesis and treatment options for this condition is largely unknown. CASE DESCRIPTION: An 82-year-old female with no neurological deficits underwent a clipping for a giant middle cerebral artery (MCA) aneurysm. Immediately after surgery, she presented with hemichorea hemiballismus (HC-HB) on the left side. Postoperative angiograms and single photon emission computed tomography demonstrated the hyperperfusion in the right frontal cortex and the decreased perfusion in the basal ganglia, indicating that the abrupt hemodynamic changes due to the obliteration of the giant aneurysm caused the dysfunction of the frontal cortical and subcortical pathway and the basal ganglia. Administration of tiapride hydrochloride was dramatically effective in controlling the HC-HB until the hyperperfusion resolved. Single photon emission computed tomography obtained 8 weeks after surgery revealed that the cerebral blood flow had been normalized in the right frontal cortex. The relative hypoperfusion of the right basal ganglia was also resolved. Then tiapride hydrochloride was discontinued without a relapse of HC-HB. CONCLUSION: This case appears consistent with the theory that the connecting fibers responsible for the development of HC-HB are also located in the frontal lobe. The treatment of giant aneurysms involving the M1 portion can cause abrupt hemodynamic changes in both frontal cortex and the basal ganglia, which can potentially induce postoperative movement disorders. PMID- 26015874 TI - Erratum: Polytraumatization in an adult national sample and its association with psychological distress and self-esteem. PMID- 26015873 TI - Usefulness of repetitive intraoperative indocyanine green-based videoangiography to confirm complete obliteration of micro-arteriovenous malformations. AB - BACKGROUND: It is difficult to intraoperatively confirm the total disappearance of arteriovenous (AV) shunts during surgery for microarteriovenous malformations (micro-AVMs), especially when the nidus is extremely small or diffuse on preoperative angiography. Although intraoperative angiography is effective for evaluating residual shunts, procedure-related risks raise important concerns. The purpose of this study was to assess the usefulness of intraoperative indocyanine green-based videoangiography (ICG-VA) to determine complete disappearance of micro-AVMs during surgery. METHODS: We retrospectively analyzed eight patients with ruptured micro-AVMs who were treated using craniotomy with ICG-VA at our institution. RESULTS: Two patients underwent emergency partial evacuation of hematoma and external decompression before the diagnostic angiography. While three patients had a nidus smaller than 1 cm, five patients had only early draining veins without an appreciable nidus. The draining veins were superficial in six cases and deep in two cases. The average interval from onset to surgery was 33 days (range, 2-57). ICG-VA was repetitively conducted until disappearance of the AV shunt was confirmed. No residual AV shunt was observed on postoperative radiological examinations. In all cases, the diagnosis of AVM was confirmed from the results of postoperative pathological examination. CONCLUSIONS: ICG-VA could detect early draining veins more clearly in situ than diagnostic angiography. Although it is not as effective for visualizing lesions with deep draining veins, repetitive ICG-VA was safe and effective for confirming the disappearance of AV shunts with superficial drainage. PMID- 26015875 TI - Clinical asthma phenotyping: A trial for bridging gaps in asthma management. AB - Asthma is a common disease affecting millions of people worldwide and exerting an enormous strain on health resources in many countries. Evidence is increasing that asthma is unlikely to be a single disease but rather a series of complex, overlapping individual diseases or phenotypes, each defined by its unique interaction between genetic and environmental factors. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link pathophysiological mechanism to subtypes of asthma. Better characterization of those phenotypes is expected to be most useful for allocating asthma therapies. This article reviews different published researches in terms of unbiased approaches to phenotype asthma and emphasizes how the phenotyping exercise is an important step towards proper asthma treatment. It is structured into three sections; the heterogeneity of asthma, the impact of asthma heterogeneity on asthma management and different trials for phenotyping asthma. PMID- 26015876 TI - Appendicitis in children less than five years old: A challenge for the general practitioner. AB - Acute appendicitis is one of the most common indications for abdominal surgery in pediatrics with peak incidence in the second decade of life. Acute appendicitis in the first years of life is an uncommon event. The clinical presentation is often varied and the diagnosis may be overshadowed by other medical conditions. Gastroenteritis is the most common misdiagnosis, with a history of diarrhea present in 33% to 41% of patients. Pain is the most common presenting symptom in children less than 5 years old, followed by vomiting, fever, anorexia and diarrhea. The most common physical sign is focal tenderness (61% of the patients) followed by guarding (55%), diffuse tenderness (39%), rebound (32%), and mass (6%). Neonatal appendicitis is a very rare disease with high mortality; presenting symptoms are nonspecific with abdominal distension representing the main clinical presentation. The younger the patient, the earlier perforation occurs: 70% of patients less than 3 years develop a perforation within 48 h of onset of symptoms. A timely diagnosis reduces the risk of complications. We highlight the epidemiology, pathophysiology, clinical signs and laboratory clues of appendicitis in young children and suggest an algorithm for early diagnosis. PMID- 26015877 TI - Pyuria in patients with Kawasaki disease. AB - Kawasaki disease (KD) is an acute, febrile vasculitis that predominantly develops in children <= 5 years of age and can lead to multiple organ injuries including the kidneys. Of these injuries, pyuria is a common feature of patients with KD, occurring in 30%-80% of patients. Sterile pyuria is most common in KD patients <= 1 year of age. KD patients with sterile pyuria exhibit more severe inflammatory reactions and may have sub-clinical renal injuries. Sterile pyuria in KD is associated with mononuclear cells (not neutrophils) in the urine. Although sterile pyuria in KD was at one time thought to be due to urethritis caused by a non-specific vasculitis of the urethra, recent studies suggest that sterile pyuria in KD originates from the urethra, the kidney as a result of mild and sub clinical renal injuries, and/or the bladder due to cystitis. Pyuria is not always sterile in KD, but can result from a urinary tract infection (UTI). As causative pathogens, Escherichia coli and Klebsiella oxytoca have been reported. The clinical phenotypes do not differ between those with or without UTI. Because some KD patients with UTIs have urinary tract abnormalities such as vesicoureteral reflux, a complete UTI workup including renal ultrasound, voiding cystourethrogram and/or dimercaptosuccinic acid renal scan recommended in KD patients with UTIs. PMID- 26015878 TI - Endobronchial tumor in children: Unusual finding in recurrent pneumonia, report of three cases. AB - We are reporting 3 cases of pediatric endobronchial tumors presented with recurrent pneumonia. The median age of patients, at time of presentation, was 10.6 years. All patients presented with recurrent pneumonia with a mean time to occurrence, after onset of symptoms, of 14 mo. Bronchoscopy was early performed as part of diagnostic work-up and it revealed an endobronchial mass in every case. Complete surgical resection was performed in all cases, with lung preservation in two of them. Neither post-operative chemotherapy nor radiotherapy was required. The mean duration of follow-up was 7 years and all patients are still alive and disease-free. Recurrent pneumonia, in pediatrics, should raise the suspicion of an obstructing lesion, congenital malformation or systemic disease. A systematic approach is useful for organize the clinicians initial workup. Prompt diagnosis allows parenchymal-sparing surgery, which offers the best chance of cure and reduces clinical and functional complications in these patients. PMID- 26015879 TI - Plastic surgery training: a privilege and honor. PMID- 26015880 TI - Clinical application of three-dimensional printing technology in craniofacial plastic surgery. AB - Three-dimensional (3D) printing has been particularly widely adopted in medical fields. Application of the 3D printing technique has even been extended to bio cell printing for 3D tissue/organ development, the creation of scaffolds for tissue engineering, and actual clinical application for various medical parts. Of various medical fields, craniofacial plastic surgery is one of areas that pioneered the use of the 3D printing concept. Rapid prototype technology was introduced in the 1990s to medicine via computer-aided design, computer-aided manufacturing. To investigate the current status of 3D printing technology and its clinical application, a systematic review of the literature was conducted. In addition, the benefits and possibilities of the clinical application of 3D printing in craniofacial surgery are reviewed, based on personal experiences with more than 500 craniofacial cases conducted using 3D printing tactile prototype models. PMID- 26015881 TI - Does aging matter? The efficacy of carpal tunnel release in the elderly. AB - Open release remains the gold standard in the treatment of carpal tunnel syndrome in cases where conservative treatment fails. However, the efficacy of carpal tunnel release in the elderly has been debated in the literature throughout the years. This review aims to review the current evidence pertaining to the efficacy of carpal tunnel release in the elderly. Based on the current evidence, the outcome of carpal tunnel release is unpredictable in the elderly. Elderly patients are also less satisfied with the operation compared to younger patients. The authors recommend that these messages be conveyed to elderly patients before surgery. Moreover, open carpal tunnel release should be offered in the early stages of treatment whenever operative management is indicated. PMID- 26015882 TI - Rejuvenating Effects of Facial Hydrofilling using Restylane Vital. AB - BACKGROUND: Morphological changes that accompany aging, such as wrinkles and skin laxity, are particularly prominent on facial skin. Recently, facial rejuvenation using the hydrofilling effect of hyaluronic acid (HA) filler has been employed for improvement of skin texture. In this study, we studied rejuvenating effects of stabilized HA (Restylane Vital) through direct intradermal injections. METHODS: A total of 30 female patients underwent a series of procedures on face, including three sessions at intervals of four weeks. A total of 2 mL of Restylane Vital was injected along the whole face using an automatic injector. Improvement of skin surface roughness, elasticity, brightness, moisture, and fine wrinkles was evaluated. Patient satisfaction was evaluated, and pictures of patients were taken at each visit and 6 months after last treatment session. Scoring for each patient was performed by three doctors according in five subjects. Moisture, oil and elasticity were measured before the procedure and before the last treatment in 10 patients. RESULTS: The majority of patients (77%) were satisfied with the therapeutic outcomes. Approximately 66% of patients responded that the effects of this procedure persisted for longer than four months, and the majority of patients (77%) wanted to undergo this procedure again and would recommend this procedure to acquaintances. Regarding doctors' evaluation, scores for improvement of skin surface roughness, elasticity, and brightness were significantly higher than those for improvement of moisture and fine wrinkle. CONCLUSIONS: Intradermal injection of HA can have a rejuvenating effect on dry and tired facial skin, especially in improvement of skin surface roughness. PMID- 26015883 TI - Using local flaps in a chest wall reconstruction after mastectomy for locally advanced breast cancer. AB - BACKGROUND: Surgical ablation for locally advanced breast cancer results in large chest wall defects, which can then be managed with local flaps or skin grafts. The purpose of this article is to evaluate the outcomes of three types of local skin flaps. METHODS: Among 25 local flaps in 24 patients, 6 were bilateral advancement (BA) flaps, 9 were thoracoabdominal (TA) flaps, and 10 were thoracoepigastric (TE) flaps. Clinical outcomes were compared including complications, the need for a secondary surgical intervention, and the timing of adjuvant therapy. RESULTS: The mean defect size was 436.2 cm(2). Two patients with TA flaps and 6 patients with TE flaps developed distal flap necrosis, and skin grafts were needed to treat 2 patients with TE flaps. Radiation was administered to the BA, TA, and TE patients after average postoperative durations of 28, 30, or 41 days, respectively. The incidence of flap necrosis tended to be higher in TE patients, which lead to significant delays in adjuvant radiation therapy (P=0.02). CONCLUSIONS: Three types of local skin flaps can be used to treat large chest wall defects after the excision of locally advanced breast cancer. Each flap has its own merits and demerits, and selecting flaps should be based on strict indications based on the dimensions and locations of the defects. PMID- 26015884 TI - Glomus tumor of the hand. AB - BACKGROUND: Glomus tumors were first described by Wood in 1812 as painful subcutaneous tubercles. It is an uncommon benign neoplasm involving the glomus body, an apparatus that involves in thermoregulation of cutaneous microvasculature. Glomus tumor constitutes 1%-5% of all hand tumors. It usually occurs at the subungual region and more commonly in aged women. Its classical clinical triad consists of pain, tenderness and temperature intolerance, especially cold sensitivity. This study reviews 15 cases of glomus tumor which were analyzed according to its anatomic location, surgical approach and histologic findings. METHODS: Fifteen patients with subungual glomus tumors of the hand operated on between January 2006 and March 2013, were retrospectively reviewed. Patients were evaluated preoperatively with standard physical examination including ice cube test and Love's test. Diagnostic imaging consisted of ultrasonography, computed tomography, and magnetic resonance imaging. All procedures were performed with tourniquet control under local anesthesia. Eleven patients underwent excision using the transungual approach, 3 patients using the volar approach and 1 patient using the lateral subperiosteal approach. RESULTS: Total of 15 cases were reviewed. 11 tumors were located in the nail bed, 3 in the volar pulp and 1 in the radial aspect of the finger tip. After complete excision, patients remained asymptomatic in the immediate postoperative period. In the long term follow up, patients exhibited excellent cosmetic results with no recurrence. CONCLUSIONS: Accurate diagnosis should be made by physical, radiologic and pathologic examinations. Preoperative localization and complete extirpation is essential in preventing recurrence and subsequent nail deformity. PMID- 26015885 TI - Contralateral breast symmetrisation in immediate prosthetic breast reconstruction after unilateral nipple-sparing mastectomy: the tailored reduction/augmentation mammaplasty. AB - BACKGROUND: In the literature on nipple-sparing mastectomy (NSM) with one-stage immediate implant reconstruction, contralateral symmetrisation has drawn little attention, with many surgeons still performing standard cosmetic mammaplasty procedures. However, standard implant-based mammaplasty usually does not result in proper symmetry with the mastectomy side, especially regarding breast projection, overall shape, and volume distribution. METHODS: We retrospectively reviewed 19 consecutive patients undergoing unilateral NSM with immediate prosthetic reconstruction and contralateral simultaneous symmetrisation by using the tailored reduction/augmentation mammaplasty technique between June 2012 and August 2013. RESULTS: The average follow-up time was 13 months (range, 10-24 months). No major complications, such as infection, haematoma, and nipple-areola complex necrosis, were experienced. CONCLUSIONS: Our experience suggests that simultaneous contralateral symmetrisation with tailored reduction/augmentation mammaplasty after unilateral immediate implant reconstruction after NSM facilitates durable and pleasant symmetric outcomes. PMID- 26015886 TI - A prospective analysis of dynamic loss of breast projection in tissue expander implant reconstruction. AB - BACKGROUND: Breast projection is a critical element of breast reconstruction aesthetics, but little has been published regarding breast projection as the firm expander is changed to a softer implant. Quantitative data representing this loss in projection may enhance patient education and improve our management of patient expectations. METHODS: Female patients who were undergoing immediate tissue expander breast reconstruction with the senior author were enrolled in this prospective study. Three-dimensional camera software was used for all patient photographs and data analysis. Projection was calculated as the distance between the chest wall and the point of maximal projection of the breast form. Values were calculated for final tissue expander expansion and at varying intervals 3, 6, and 12 months after implant placement. RESULTS: Fourteen breasts from 12 patients were included in the final analysis. Twelve of the 14 breasts had a loss of projection at three months following the implant placement or beyond. The percentage of projection lost in these 12 breasts ranged from 6.30% to 43.4%, with an average loss of projection of 21.05%. CONCLUSIONS: This study is the first prospective quantitative analysis of temporal changes in breast projection after expander-implant reconstruction. By prospectively capturing projection data with three-dimensional photographic software, we reveal a loss of projection in this population by three months post-implant exchange. These findings will not only aid in managing patient expectations, but our methodology provides a foundation for future objective studies of the breast form. PMID- 26015887 TI - Evaluating the effectiveness of cryopreserved acellular dermal matrix in immediate expander-based breast reconstruction: a comparison study. AB - BACKGROUND: CGCryoDerm was first introduced in 2010 and offers a different matrix preservation processes for freezing without drying preparation. From a theoretical perspective, CGCryoDerm has a more preserved dermal structure and more abundant growth factors for angiogenesis and recellularization. In the current study, the authors performed a retrospective study to evaluate freezing- and freeze-drying-processed acellular dermal matrix (ADM) to determine whether any differences were present in an early complication profile. METHODS: Patients who underwent ADM-assisted tissue expander placement for two stage breast reconstruction between January of 2013 and March of 2014 were retrospectively reviewed and divided into two groups based on the types of ADM-assisted expander reconstruction (CGDerm vs. CGCryoDerm). Complications were divided into four main categories and recorded as follows: seroma, hematoma, infection, and mastectomy skin flap necrosis. RESULTS: In a total of 82 consecutive patients, the CGCryoDerm group had lower rates of seroma when compared to the CGDerm group without statistical significance (3.0% vs. 10.2%, P=0.221), respectively. Other complications were similar in both groups. Reconstructions with CGCryoDerm were found to have a significantly longer period of drainage when compared to reconstructions with CGDerm (11.91 days vs. 10.41 days, P=0.043). CONCLUSIONS: Preliminary findings indicate no significant differences in early complications between implant/expander-based reconstructions using CGCryoderm and those using CGDerm. PMID- 26015888 TI - Daily serum collection after acellular dermal matrix-assisted breast reconstruction. AB - BACKGROUND: The acellular dermal matrix (ADM)-assisted breast reconstruction technique is widely known, but discouraging results due to early postoperative complications have been reported. As the literature identifies seroma as the most common issue after breast surgery without identifying its pathogenesis, we aimed to report the trend of postoperative daily serum collection after ADM-assisted breast reconstruction and compare it with data in the literature in order to discover more about this little-known topic. METHODS: A retrospective study on 28 consecutive patients who received ADM-assisted breast reconstruction between February 2013 and February 2014 was performed. In order to reduce the number of variables that could affect serum production, only one brand of ADM was used and all tissues were handled gently and precisely. The daily drainage volume was recorded per patient during the first four days of hospitalization. Likewise, postoperative complications were noted during routine follow-up. RESULTS: In total, five (17.9%) bilateral and 23 (82.1%) unilateral ADM-assisted breast reconstructions (33 implants) were performed. The mean age, body mass index, and length of hospital stay were 53.6 years, 21.3 kg/m(2), and 4.5 days, respectively. One major complication led to implant loss (3.0%), and nine minor complications were successfully treated with ambulatory surgery (27.3%). Serum collection linearly decreased after 24 hours postoperatively. CONCLUSIONS: Daily drainage decreased following the theoretical decline of acute inflammation. In concordance with the literature, daily serum production may not be related to the use of ADM. PMID- 26015889 TI - Surgical Treatment of Carpal Tunnel Syndrome through a Minimal Incision on the Distal Wrist Crease: An Anatomical and Clinical Study. AB - BACKGROUND: An anatomical analysis of the transverse carpal ligament (TCL) and the surrounding structures might help in identifying effective measures to minimize complications. Here, we present a surgical technique based on an anatomical study that was successfully applied in clinical settings. METHODS: Using 13 hands from 8 formalin-fixed cadavers, we measured the TCL length and thickness, correlation between the distal wrist crease and the proximal end of the TCL, and distance between the distal end of the TCL and the palmar arch; the TCL cross sections and the thickest parts were also examined. Clinically, fasciotomy was performed on the relevant parts of 15 hands from 13 patients by making a minimally invasive incision on the distal wrist crease. Postoperatively, a two-point discrimination check was conducted in which the sensations of the first, second, and third fingertips and the palmar cutaneous branch injuries were monitored (average duration, 7 months). RESULTS: In the 13 cadaveric hands, the distal wrist crease and the proximal end of the TCL were placed in the same location. The average length of the TCL and the distance from the distal TCL to the superficial palmar arch were 35.30+/-2.59 mm and 9.50+/-2.13 mm, respectively. The thickest part of the TCL was a region 25 mm distal to the distal wrist crease (average thickness, 4.00+/-0.57 mm). The 13 surgeries performed in the clinical settings yielded satisfactory results. CONCLUSIONS: This peri-TCL anatomical study confirmed the safety of fasciotomy with a minimally invasive incision of the distal wrist crease. The clinical application of the technique indicated that the minimally invasive incision of the distal wrist crease was efficacious in the treatment of the carpal tunnel syndrome. PMID- 26015890 TI - Full-thickness skin grafting with de-epithelization of the wound margin for finger defects with bone or tendon exposure. AB - BACKGROUND: Full-thickness skin grafts (FTSGs) are generally considered unreliable for coverage of full-thickness finger defects with bone or tendon exposure, and there are few clinical reports of its use in this context. However, animal studies have shown that an FTSG can survive over an avascular area ranging up to 12 mm in diameter. In our experience, the width of the exposed bones or tendons in full-thickness finger defects is <7 mm. Therefore, we covered the bone or tendon-exposed defects of 16 fingers of 10 patients with FTSGs. METHODS: The surgical objectives were healthy granulation tissue formation in the wound bed, marginal de-epithelization of the normal skin surrounding the defect, preservation of the subdermal plexus of the central graft, and partial excision of the dermis along the graft margin. The donor site was the mastoid for small defects and the groin for large defects. RESULTS: Most of the grafts (15 of 16 fingers) survived without significant surgical complications and achieved satisfactory functional and aesthetic results. Minor complications included partial graft loss in one patient, a minimal extension deformity in two patients, a depression deformity in one patient, and mild hyperpigmentation in four patients. CONCLUSIONS: We observed excellent graft survival with this method with no additional surgical injury of the normal finger, satisfactory functional and aesthetic outcomes, and no need for secondary debulking procedures. Potential disadvantages include an insufficient volume of soft tissue and graft hyperpigmentation. Therefore, FTSGs may be an option for treatment of full thickness finger defects with bone or tendon exposure. PMID- 26015891 TI - Use of a barbed suture tie-over technique for skin graft dressings: a case series. AB - BACKGROUND: A tie-over dressing is the accepted method to secure skin grafts in order to prevent haematoma or seroma formation. We describe the novel application of a barbed suture tie-over for skin graft dressing. The barbs act as anchors in the skin so constant tensioning of the suture is not required. METHODS: From January 2014 to August 2014 we used the technique in 30 patients with skin defects requiring split-thickness or full-thickness grafts. Patient demographics, clinicopathological details and graft outcome were collected prospectively. RESULTS: The majority of cases were carried out for split-thickness skin grafts (n=19) used on the lower limb (n=20). The results of this novel technique were excellent with complete (100%) graft take in all patients. CONCLUSIONS: Our results demonstrate the clinical application of a barbed device for securing skin grafts with excellent results. We find the technique quick to perform and the barbed device easy to handle, which can be applied without the need for an assistant. PMID- 26015892 TI - Three cases of acquired simulated brown syndrome after blowout fracture operations. AB - Brown syndrome is known as limited elevation of the affected eye during adduction. It is caused by a disorder of the superior oblique tendon, which makes it difficult for the eyeball to look upward, especially during adduction. It is classified into congenital true sheath Brown syndrome and acquired simulated Brown syndrome. Acquired simulated Brown syndrome can be caused by trauma, infection, or inflammatory conditions. The surgical restoration of blowout fractures can also lead to limitations of ocular motility, including Brown syndrome. We report on three patients with acquired simulated Brown syndrome, who complained of diplopia and limitation of ocular motility after operations to treat blowout fractures. PMID- 26015893 TI - Four flaps technique for neoumbilicoplasty. AB - The absence or disfigurement of the umbilicus is both cosmetically and psychologically distressing to patients. The goal of aesthetically pleasing umbilical reconstruction is to create a neoumbilicus with sufficient depth and good morphology, with natural-looking superior hooding and minimal scarring. Although many reports have presented techniques for creating new and attractive umbilici, we developed a technique that we term the "four flaps technique" for creating a neoumbilicus in circumstances such as the congenital absence of the umbilicus or the lack of remaining umbilical tissue following the excision of a hypertrophic or scarred umbilicus. This method uses the neighboring tissue by simply elevating four flaps and can yield sufficient depth and an aesthetically pleasing shape with appropriate superior hooding. PMID- 26015894 TI - A portable mirror stand for clinical facial photo documentation. AB - In plastic surgery, patient photography is a vital component of clinical, educational, legal, and research documentation. Optimal acquisition of photographic data requires a dedicated photography studio or a three-dimensional anatomic scanner, both of which are financially impractical for most clinicians. Simplified photo standardization is proposed for use in random clinical settings by using a portable device called the Mirror Stand (MirS). This model device aims to mimic a studio environment by incorporating the basic elements of producing consistent photographs. The pilot MirS is designed for facial photography. Images of 40 random subjects were obtained using the MirS with three different cameras. Real anthropometric measurements of each subject were collected, compared with the photographic measurements, and analyzed. In this study, all three cameras produced equally reliable measurements. Actual facial measurements were comparable to the photogrammetric measurements obtained from photographs taken using the MirS. A constant formula was derived; it allowed the conversion of photographic values into real anthropometric values. The MirS produced consistent photographs with respect to the measurements. The photographs obtained could be translated reliably into their real anthropometric measurements. Therefore, the MirS can be applied in daily practice, providing an efficient alternative for obtaining a standard justifiable photograph. PMID- 26015895 TI - A simple, reliable, and inexpensive method for seroma drainage. PMID- 26015896 TI - Severe Facial Dermatitis Following Rhinoplasty due to an Unusual Etiopathogenesis: Rosacea. PMID- 26015897 TI - Extensive necrotizing fasciitis after fat grafting for bilateral breast augmentation: recommended approach and management. PMID- 26015898 TI - Beware of pyoderma gangrenosum complicating mastopexy: the importance of early detection and treatment. PMID- 26015899 TI - Warthin's Tumor of the Parotid Enlarged by a Facelift Suture. PMID- 26015901 TI - A rare case of transitional meningioma. PMID- 26015900 TI - A huge neurofibroma of the lower back invading the spinal cavity. PMID- 26015902 TI - Primary intraosseous meningioma. PMID- 26015903 TI - Benign Lymphoepithelial Lesion of Parotid Gland and Secondary Amyloidosis as Concurrent Manifestations in Sjogren's Syndrome. PMID- 26015904 TI - Soft tissue chondroma presenting as a dermal mass in the toe. PMID- 26015906 TI - Purified protein derivative test and its booster phenomenon in patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common disease in the community, with various complications. An appropriate solution is immunosuppressive drugs, which may lead to weakening of the cellular immune system and body unresponsiveness to tuberculosis (TB). As TB sensitivity is determined by the amount of induration created in the Purified Protein Derivative (PPD) test, this study aims to evaluate the immune response to the PPD test and its booster in RA patients. MATERIALS AND METHODS: This cross-sectional study was performed on rheumatoid arthritis patients referred to Alzahra Hospital, Isfahan, treated with <20 mg glucocorticoid daily or 7.5 mg Methotrexate (MTX) weekly. The sampling method was simple and accessible. The PPD test was performed in patients using the Mantoux method after 72 hours, and seven days later, the results were interpreted in 72 hours after the PPD booster injection. Induration >=5 mm was considered to be positive. The data was analyzed using the SPSS software. RESULTS: Nineteen patients had positive results in the initial and reminder tests and 81 patients had negative results in both tests. Six patients (6.9%) with negative results in the initial test changed to positive in the reminder test. There was no positive result in the initial test and negative result in the reminder one. The frequency distribution of the reminder test, based on the initial test was significant (P < 0.001). Also, the McNemar test showed that the changes in the reminder test based on the initial test had a significant difference (P = 0.031). CONCLUSION: It seems that in the endemic and developing areas, the PPD booster is applicable for diagnosing latent tuberculosis in patients with rheumatoid arthritis. PMID- 26015905 TI - Leptin and its cardiovascular effects: Focus on angiogenesis. AB - Leptin is an endocrine hormone synthesized by adipocytes. It plays a key role in the energy homeostasis in central and peripheral tissues and has additional roles are attributed to it, such as the regulation of reproduction, immune function, bone homeostasis, and angiogenesis. The plasma concentration of leptin significantly increases in obese individuals. In the present review, we give an introduction concerning leptin, its receptors, signaling pathways, and its effect on cardiovascular system, especially on angiogenesis. PMID- 26015907 TI - Ideal anesthetic agents for day-care gynecological procedures: A clinical trial comparing thiopentone with ketamine as adjuncts to propofol. AB - BACKGROUND: Day-care gynecological procedures require the use of anesthetic agents, which ensure rapid induction and recovery. Although propofol is the gold standard drug in day-care procedures, it has its own side effects like apnea, cardiovascular instability, pain on injection, as well as its cost. The ideal drug combination to achieve this end remains elusive. Therefore, a combination of propofol, thiopentone, and ketamine may be a better alternative. MATERIALS AND METHODS: This prospective, double-blind, randomized study was conducted on 60 women, aged 18-50 years, American Society of Anesthesiologists (ASA) physical status 1 and 2, undergoing day-care gynecological surgeries. The patients were allocated to two groups. Group T received an admixture containing 10 ml of 1% propofol and 10 ml of 1.25% thiopentone. Group K received an admixture containing 10 ml of 1% propofol and 10 ml of 0.5% ketamine. RESULTS: There was less variation in the mean systolic blood pressure of patients in Group K as compared to patients in Group T. The mean total dose of propofol required in Group K (0.85 mg/kg) was significantly less than that required in Group T (1.12 mg/kg) (P = 0.0004). The mean recovery time in Group T (3.67 minutes) was significantly less than in Group K (6.27 minutes; P = 0.0001). However, the mean discharge time in both the groups was similar. (P = 0.7392). The results were analyzed statistically using the Student's t-test and the Fisher's exact test. CONCLUSIONS: Both the propofol-thiopentone and propofol-ketamine admixtures provided adequate anesthesia. Propofol-ketamine proved superior to propofol thiopentone in terms of hemodynamic stability and requirement of a lesser total dose of propofol. However, the patients in the propofol-thiopentone group had faster recovery. PMID- 26015908 TI - Early and late posttraumatic seizures following traumatic brain injury: A five year follow-up survival study. AB - BACKGROUND: The main objective of this study was to determine the incidence, time to event, and risk factors for posttraumatic seizures (PTS) following traumatic brain injury (TBI) in a five-year follow-up survival design. MATERIALS AND METHODS: In a cohort study, between September 2008 and October 2013, 411 traumatic brain injury patients referring to the Emergency Units (EUs) of the Isfahan University Hospitals, who met the inclusion criteria, entered the study. Follow-up evaluations were conducted by telephone conversation or clinical examination, if needed. The patients were followed for up to five years after TBI or until a first seizure event if it occurred prior to the five-year anniversary. The survival rate data were collected and measured for all patients under follow up. Survival analysis on PTS and its related predictors was done using the Kaplan Meier curves and the Cox proportional hazards regression. All analyses were done using STATA and SPSS statistical software, and P-values smaller than 0.05 were considered to be statistically significant. RESULTS: The median duration of follow-up was 36 months (Interquartile range: 23-50). A significantly greater number of first seizures occurred in the first year after injury than all other years (57.7%). The overall incidence of posttraumatic seizures, in this study population, was 6.33% (95% CI: 3.96-8.69). Among the participants, the incidence rates for early and late posttraumatic seizures were 1.95 and 4.38%, respectively. The result of the Cox regression analysis showed that the Glasgow Coma Scale (GCS) score and trauma severity were associated with PTS. CONCLUSION: All in all, the present study highlighted the role of the trauma severity and GCS as effective factors in the incidence of seizure in patients with TBI. Particular care is advised for patients with these risk factors during the primary handling in the Emergency Units. PMID- 26015910 TI - The metabolic syndrome and associated lifestyle factors among the Iranian population. AB - BACKGROUND: This study aims to evaluate the impact of the Isfahan Healthy Heart Program (IHHP) interventions concerning healthy behavior, on the prevalence of the metabolic syndrome (MetS) and its components in the Iranian population. MATERIALS AND METHODS: The IHHP targeted the population at large in three districts in central Iran from 2000 to 2007. Numerous interventional activities were performed to improve lifestyle. The main intervention strategies were public education through mass media, intersectional cooperation, health professional education, marketing and organizational development, legislation and policy development, as well as research and evaluation. MetS was defined based on the Adult Treatment Panel (ATP) III definition. The logistic regression method was applied to explore the relationship between lifestyle factors with components of metabolic risk factors. RESULTS: The mean age of the participants was 44.68 +/- 14.43 years in 2001. The mean values of the MetS components differed from 2001 to 2007. The mean of systolic blood pressure (SBP) decreased from 126.7 +/- 22.31 to 124.21 +/- 20.0 and from 129.47 +/- 23.08 to 126.26 +/- 21.88 among females in both the intervention and reference areas. Similar changes were observed among males. The mean diastolic blood pressure (DBP) and triglycerides decreased significantly in the intervention area and increased significantly in the reference area in both sexes. High density protein cholesterol (HDL-C) was decreased in both sexes, from 2001 to 2007, in both areas. A strong relationship between tobacco control with high SBP and hypertriglyceridemia was found (P < 0.01). CONCLUSION: Lifestyle improvement programs could be useful to improve the MetS status among men and women. PMID- 26015909 TI - Role of endothelin-1 antagonist; bosentan, against cisplatin-induced nephrotoxicity in male and female rats. AB - BACKGROUND: Cisplatin (CP) is a chemotherapy drug, with the major side effect of nephrotoxicity. The level of endothelin-1 (ET-1) increases during nephrotoxicity, which is accompanied with vasoconstrictive properties. Bosentan (BOS) is a nonselective ET-1 receptor antagonist, having vasodilatory and anti-hypertension effects. The purpose of this study was to investigate the renoprotective effect of BOS against CP-induced nephrotoxicity in male and female rats. MATERIALS AND METHODS: Male and female rats were divided into six groups; groups 1-3 and 4-6 were male and female rats, respectively. Animals in groups 1 and 4 were considered as negative control and groups 2 and 5 considered as positive control groups received BOS (30 mg/kg/day) alone and CP (2.5 mg/kg/day) alone, respectively, for 1-week. The animals in groups 3 and 6 were treated with both CP and BOS. Finally, serum parameters were measured, and the kidney tissue was subjected to staining to evaluate tissue damage. RESULTS: The serum levels of blood urea nitrogen and creatinine, kidney tissue damage score and kidney weight elevated, and body weight significantly decreased in both CP alone and in CP plus BOS-treated groups when compared with the control groups (P < 0.05), while BOS did not ameliorate these parameters neither in males nor in females. No significant differences were observed in serum levels of nitrite and malondialdehyde between the groups, but kidney tissue level of nitrite decreased significantly in CP alone and CP plus BOS-treated groups (P < 0.05). CONCLUSION: Renoprotective effect of BOS, as ET-1 blocker, was not observed against CP induced nephrotoxicity neither in male nor in female rats. This is while BOS promoted the severity of injuries in females. PMID- 26015911 TI - Fecal calprotectin is a useful marker to diagnose ulcerative colitis from irritable bowel syndrome. AB - BACKGROUND: This study was aimed to evaluate the predictive value of fecal calprotectin in patients with ulcerative colitis from patients with irritable bowel syndrome (IBS). MATERIALS AND METHODS: Between May and October 2013, 88 adult patients, between the age 18 and 65 years with a history of chronic diarrhea of unknown origin were assessed. Standard colonoscopies were performed in all patients to assess ulcerative colitis. Before colonoscopies, they were asked to supply a stool specimen. Fecal calprotectin value was measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS: The mean of age, gender combination, and body mass index were not significantly different between patients with ulcerative colitis or IBS. The duration of disease in ulcerative colitis patients was significantly higher than IBS patients (P < 0.0001). The level of calprotectin in ulcerative colitis patients was significantly higher than IBS patients (265.9 vs 115.8, respectively, P = 0.001). Also, cutoff value >164 MUg/g with sensitivity and specify of 57 (CI: 41%-71.6%), and 75 (CI: 59.7% 56.8%), respectively, was the best for discrimination between patients with ulcerative colitis and those with IBS. CONCLUSION: Our results show that fecal calprotectin as a noninvasive method, which can be used to identify patients with ulcerative colitis from IBS patients has low sensitivity and specificity. PMID- 26015912 TI - The effect of sevoflurane versus propofol anesthesia on troponin I after congenital heart surgery, a randomized clinical trial. AB - BACKGROUND: The ischemic preconditioning phenomenon can save myocardium against move severe ischemic damages and reduce infarction size and furthermore a heart rhythm disturbance. In this study we examine relationship between troponin I (as a structural myocardial protein) level and anesthetic agents in the children. MATERIALS AND METHODS: In this study 84 children under 12 years age before cardiac surgery were divided randomly into two groups of 42 each. For anesthetic maintenance sevoflurane with dose of 0.5-1 MAC was used in Group 1 and 100-150 mg/kg/min of intravenous propofol in Group 2 for maintenance of anesthesia. Troponin I level was assessed 2 before and 1 hour after anesthetic induction. Outcome measures included the serum cardiac troponin I level in children before and after surgery in two study groups. RESULTS: There was no significant difference between two groups in indices and both groups were homogenous in this point of view. The troponin I level after surgery was significantly increased in two groups. In the sevoflurane group it was 0.04 +/- 0.12 to 0.05 +/- 0.09 ng/ml (P value = 0.003) and the propofol group was 0.12 +/- 0.26 to 0.19 +/- 0.38 ng/ml (P value = 0.001). CONCLUSIONS: In this study two Anesthetic regimens were compared to assess the mean troponin I level before and after pediatric closed heart surgery, and it was shown that mean troponin level before and after surgery in the sevoflurane group was less than the propofol group. But this result was not statistically significant. These results indicate that although more protective effects of sevoflurane on myocardial injuries during pediatric cardiac surgery is predominant but this effect has no significant difference in the propofol group. PMID- 26015913 TI - Isolation of toxigenic Clostridium difficile from ready-to-eat salads by multiplex polymerase chain reaction in Isfahan, Iran. AB - BACKGROUND: Since 2003, the incidence of community associated Clostridium difficile infection (CA-CDI) has increased; different types of food have been supposed to be the vectors of C. difficile strains. The purpose of this study is to investigate the occurrence of C. difficile strains in ready-to-eat salads distributed in food services. MATERIALS AND METHODS: A total of 106 ready-made salad specimens were sampled from different restaurants and food services located in Isfahan, in the center of Iran. Positive isolates of C. difficile were identified and confirmed for the existence of three genes including tpi, tcdA and tcdB by multiplex PCR. RESULTS: A total of six (5.66%) samples were positive for C. difficile strains. Of which, one strain (16.6%) was positive for A and B toxins. CONCLUSION: The existence of toxigenic C. difficile in ready-made salads could be a caution for public health. Further investigation is required to assess the relationship between the isolated strains in our study and those from diarrheic patients through molecular typing. PMID- 26015914 TI - Does nitrogen gas bubbled through a low density polymer gel dosimeter solution affect the polymerization process? AB - BACKGROUND: On account of the lower electron density in the lung tissue, the dose distribution in the lung cannot be verified with the existing polymer gel dosimeters. Thus, the aims of this study are to make a low density polymer gel dosimeter and investigate the effect of nitrogen gas bubbles on the R2 responses and its homogeneity. MATERIALS AND METHODS: Two different types of low density polymer gel dosimeters were prepared according to a composition proposed by De Deene, with some modifications. In the first type, no nitrogen gas was perfused through the gel solution and water. In the second type, to expel the dissolved oxygen, nitrogen gas was perfused through the water and gel solution. The post irradiation times in the gels were 24 and 5 hours, respectively, with and without perfusion of nitrogen gas through the water and gel solution. RESULTS: In the first type of gel, there was a linear correlation between the doses and R2 responses from 0 to 12 Gy. The fabricated gel had a higher dynamic range than the other low density polymer gel dosimeter; but its background R2 response was higher. In the second type, no difference in R2 response was seen in the dose ranges from 0 to 18 Gy. Both gels had a mass density between 0.35 and 0.45 g.cm( 3) and CT values of about -650 to -750 Hounsfield units. CONCLUSION: It appeared that reactions between gelatin-free radicals and monomers, due to an increase in the gel temperature during rotation in the household mixer, led to a higher R2 background response. In the second type of gel, it seemed that the collapse of the nitrogen bubbles was the main factor that affected the R2-responses. PMID- 26015915 TI - What is the important practical implication of detecting decreased G6PD levels in vitiligo? PMID- 26015916 TI - The relationship between carotid artery colour Doppler finding and cerebral oximetry. AB - BACKGROUND: In some cases, permanent reduction in cerebral functioning affects a high percentage of patients undergoing cardiovascular surgery. We studied the relationship between the results of preoperative bilateral carotid artery colour Doppler sonography and regional cerebral oxygen saturation (rSO2) during coronary artery bypass graft surgery (CABG). MATERIALS AND METHODS: This study was a cross sectional analytical study conducted with 96 candidates for off-pump CABG. This study determined the percentage of the correlation of rSO2 with demographic information, diabetes, hyperlipidemia, hypertension, myocardial infraction (MI), and smoking, and also provided information on the presence and type of plaque, intima-media thickness (IMT), and percentage of stenosis of carotid artery detected through colour Doppler sonography. Data were analyzed by the t-test, the Chi-square test, and simple linear regression. RESULTS: In this study, the mean value of rSO2 increased after intubation compared to the mean before intubation, the difference being statistically significant (P = 0.005). A comparison of the mean rSO2 of the right side of the brain and the percentage of right carotid obstruction (stenosis of less than 50% vs. stenosis with a range of 50-69%) revealed that the mean rSO2 at the time of the partial-clamp between carotid stenosis less than 50% and carotid stenosis with a range of 50-69% was statistically significant (P = 0.043). CONCLUSIONS: There is no statistically significant correlation between rSO2 and percentage of carotid artery stenosis less than 70%. It is advised that rSO2 and carotid stenosis of greater than 70% be studied in future. PMID- 26015917 TI - A girl with increased writing and painting activities associated with Turner's syndrome and autistic spectrum disorder. AB - This report describes the findings on the evaluation of a 9-year-old girl with disabling and pronounced increased writing and painting activities associated with Turner's syndrome and autistic spectrum disorder. She spent most of the time doing these activities which affected not only her academic performance, but also social relationships. A comprehensive treatment plan consists of both biological and psychological aspects, is the main point of this case. Low dose of risperidone (0.5 mg/day) was started to decrease the patient's stereotypic behaviors. Sertraline (12.5 mg/day) was prescribed for her phobia. She was also referred to an occupational therapist in order to improve her social skills. PMID- 26015918 TI - Pistachio supplementation attenuates motor and cognition impairments induced by cisplatin or vincristine in rats. AB - BACKGROUND: A large number of natural products and dietary components have been evaluated as potential chemoprotective agents. In the present investigation we report the effects of treatment with the dietary antioxidant, pistachio, on cisplatin- or vincristine-induced neurotoxicity in male Wistar rats. MATERIALS AND METHODS: Dietary pistachio (10%) was assessed for its neuroprotective effects through the alteration in performance of hippocampus- and cerebellum-related behaviors following chronic cisplatin (5 mg/kg) or vincristine (0.2 mg/kg) treatment in male rats. We also evaluated the effects of cisplatin, vincristine, and pistachio administration on nociception. Six behavioral tasks were used: open field, rotarod, grasping, Morris water maze (MWM), hot plate, and motor nerve conductive velocity (MNCV). RESULTS: We showed that the exposure of adolescent rats to cisplatin or vincristine resulted in a significant decrease in explorative behaviors and memory retention. Pistachio consumption somewhat improved memory and motor abilities in cisplatin- or vincristine-treated rats, while pistachio alone did not show any significant changes in these abilities compared to saline. Cisplatin and vincristine increased the latency of response to nociception, and pistachio did not reverse this effect. CONCLUSION: We conclude that pistachio in the diet following anticancer drugs such as cisplatin and vincristine might have a protective effect against anticancer drug-induced disruptions in motor and cognitive function. However, further studies are needed to elucidate the exact mechanisms of this protective effect of pistachio. PMID- 26015919 TI - The effect of time and temperature on viability and performance of Langerhans islets separated from Balb/c mouse after death. AB - BACKGROUND: Tissue transplantation plays a pivotal role in the treatment of diseases. Pancreatic beta cell transplantation is the best way to obtain normal blood glucose in patients with diabetes type 1. However, it is not clear how long endocrine pancreas cells can be used for transplantation after the donor's death. The present study was conducted to analyze the performance and viability of pancreatic islet cells after death. MATERIALS AND METHODS: Pancreas was separated from Balb/c mice at different times (0, 1, 4, 6, 12, and 24 h after death) at temperatures of 4 degrees C and 23 degrees C, and was cultured in Roswell_Park_Memorial_Institute (RPMI) 1640. Insulin shock, MTT assay, aldehyde fuchsin staining, dithizone staining, and florescence microscopy methods were applied to analyze the performance of beta cells, cell viability, islets' diagnosis, islet cells' diagnosis, and viable and necrotic cells diagnosis, respectively. RESULTS: Islets of Langerhans and beta cells were diagnosed. By increasing the temperature and time, the viability and performance of beta cells decreased significantly (P < 0.05). CONCLUSION: The best condition for keeping the islets of Langerhans in terms of viability and performance is 4 h after death at temperature of 4 degrees C. PMID- 26015920 TI - A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children. AB - BACKGROUND: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. MATERIALS AND METHODS: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. RESULTS: Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. CONCLUSION: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5 HT being evident. PMID- 26015921 TI - Use of restriction fragment length polymorphism to identify Candida species, related to onychomycosis. AB - BACKGROUND: Onychomycosis is one of the most common clinical forms of fungal infections due to both filamentous fungi and yeasts. The genus of Candida is one of the most prominent causes of onychomycosis in all around the world. Although Candida albicans is still the most frequent cause of nail infections, use of broad-spectrum antifungal agents has led to a shift in the etiology of C. albicans to non-albicans species. The aim of the present study is rapid and precise identification of candida species isolated from nail infection by using of PCR-RFLP technique. MATERIALS AND METHODS: A total of 360 clinical yeast strains were collected from nail infections in Iran. Genomic DNA was extracted using FTA(;) cards. ITS1-5.8SrDNA-ITS2 region was amplified using universal primers and subsequently products were digested with the restriction enzyme MspI. For identification of newly described species (C. parapsilosis complex), the SADH gene was amplified, followed by digestion with Nla III restriction enzyme. RESULTS: Candida albicans was the most commonly isolated species (41.1%), followed by C. parapsilosis (21.4%), C. tropicalis (12.8%), C. kefyr (9.4%), C. krusei (5.5%), C. orthopsilosis (4.1%), C. glabrata (2.8%), C. guilliermondii (1.4%), C. rugosa (0.8%), and C. lusitaniae (0.5%). Patients in the age groups of 51-60 and 81-90 years had the highest and lowest distribution of positive specimens, respectively. CONCLUSION: Rapid and precise identification of Candida species from clinical specimens lead to appropriate therapeutic plans. PMID- 26015922 TI - Evaluation of the effect of radiofrequency catheter ablation on autonomic function in patients with atrioventricular nodal reentrant tachycardia by head-up tilt table test. AB - BACKGROUND: One of the recommended treatments for atrioventricular nodal reentrant tachycardia (AVNRT), is radiofrequency catheter ablation (RFCA). However, RFCA may affect the autonomic system. This study aims to evaluate the effect of RFCA on autonomic system in patients with PSVT by head-up tilt table (HUTT) test. MATERIALS AND METHODS: In a before-after study, 22 patients with PSVT were enrolled. Data were collected with a data collection form that included two parts. Electrocardiogram (ECG), echocardiogram, 24-h Holter monitoring, HUTT test, heart rate variability (HRV) indexes, and symptoms of all patients were recorded 24 h before and 1 month after the ablation. Wilcoxon, McNemar, Mann Whitney U, and Chi-square tests were used to analyze the data. RESULTS: Of the total 22 patients, 31.8% were male and 68.2% were female. There were significant differences in heart palpitation (P < 0.0001) and non-specific symptoms (P = 0.031) and no significant difference in head-up tilt test results and HRV indices before and after RFCA. The results showed that there were no significant differences in specific and non-specific symptoms in patients with AVNRT with positive and negative HUTT before and after RFCA. CONCLUSIONS: The observed difference in heart palpitation and non-specific symptoms emphasized the role of AVNRT in causing these symptoms. Autonomic dysfunction is more probably an accompanying condition of AVNRT than causing symptoms. We could not find any significance in the results of HUTT after RFCA. HUTT cannot determine or predict the symptoms after RFCA. PMID- 26015923 TI - Is the ligation of hernial sac necessary in herniotomy for children? A randomized controlled trial of evaluating surgical complications and duration. AB - BACKGROUND: Herniotomy is a common operation done by pediatric surgeons. Recent studies have shown that high ligation in herniation in adult is not necessary, but this method was not fully evaluated in children. We compared non-ligation with high-ligation sac in herniotomy in terms of surgical complications and duration. MATERIALS AND METHODS: This randomized controlled trial study was done on 104 children with inguinal hernia at Al-Zahra Hospital, Isfahan, Iran, between 2011 and 2013. Patients were equally randomized to undergo herniotomy with ligation of sac at the internal ring level or to undergo herniotomy without sac ligation. Patients were followed up just after the operation, and in the 1(st), 6(th), and 12(th) weeks postoperation to discover early (scrotal hematoma, edema, wound infection, and postoperation fever) and late (adhesion and recurrence) complications. Also, duration of operation was recorded for each group. RESULTS: The incidence of early complications (nine cases in high-ligation and eight cases in non-ligation group) was the same in both groups (P = 0.402). No late complication was observed in any group. The mean duration of operation in high ligation group (18.84 +/- 5.47 min) was significantly shorter than non-ligation group (21.46 +/- 9.03 min) (P < 0.001). CONCLUSION: Complications are the same in herniotomy with or without ligation of the sac, but the duration of the non ligation procedure is shorter than that of high-ligation. We suggest that herniotomy without sac ligation in children be the procedure of choice to save time and also to prevent any other possible complications such as nerve damage, spermatic cord injury, or peritoneal tearing. PMID- 26015924 TI - Venous insufficiency after prolonged standing: Is joint hypermobility an important risk factor? AB - BACKGROUND: Varicose veins are extremely common disease which is due to elevated superficial venous pressures. We aimed to know that if joint hypermobility causes the venous insufficiency following the prolonged standing. MATERIALS AND METHODS: This prospective cohort study conducted on the soldiers of training periods in a military base of Iran Army in Isfahan in 2013. The active-duty soldiers were first examined by a physician and their Beighton scores (BSs) were obtained. At the onset of the training period, the presence of chronic venous insufficiency was clinically evaluated according to the C class of clinical, etiological, anatomical, and pathological classification. After 3 months, soldiers with and without joint hypermobility were reexamined for manifestations of venous insufficiency based on clinical examination. RESULTS: Of 718 soldiers, 211 subjects were diagnosed for joint hypermobility syndrome (29.3%). The mean BS was significantly higher in hypermobility soldiers (5.5 +/- 1.5) than the healthy ones (1.2 +/- 1.1). Before the training period, the prevalence of spider and varicose veins in soldiers with joint hypermobility was significantly higher than healthy subjects (P > 0.001). After the training period, the prevalence of venous insufficiency significantly increased in soldiers with joint hypermobility (P > 0.001) while there was no significant difference in healthy group before and after the period of training (P = 0.25). CONCLUSION: Hypermobility could be considered as a risk factor for the development of venous insufficiency, so it seems necessary to evaluate the population who need to be standing for a long time for evidence of joint hypermobility. PMID- 26015925 TI - Acute flaccid paralysis surveillance: A 6 years study, Isfahan, Iran. AB - BACKGROUND: Poliomyelitis is still an endemic disease in many areas of the world including Africa and South Asia. Iran is polio free since 2001. However, due to endemicity of polio in neighboring countries of Iran, the risk of polio importation and re-emergence of wild polio virus is high. Case definition through surveillance system is a well-defined method for maintenance of polio eradication in polio free countries. METHODS: In a cross-sectional survey from 2007 to 2013, we reviewed all the records of under 15 years old patients reported to Acute Flaccid Paralysis Committee (AFPC) in Isfahan province, Iran. All cases were visited by members of the AFPC. Three stool samples were collected from each reported case within 2 weeks of onset of paralysis and sent to National Polio Laboratory in Tehran, Iran, for poliovirus isolation. Data were analyzed by SSPS software (version 22). Student's t-test and Chi-square was used to compare variables. Statistical significance level was set at P < 0.05. RESULTS: In this 6 year period 85 cases were analyzed, 54 patients were male (63.5%) and 31 were female (36.5%). The mean age of patients was 5.7 +/- 3.9 years. The most common cause of paralysis among these patients was Guillian-Barre syndrome (83.5%). We did not found any poliomyelitis caused by wild polio virus. Only one case of vaccine associated poliomyelitis was reported. CONCLUSION: Since 1992, Iran has a routine and high percent coverage of polio vaccination program for infants (>94%), with six doses of oral polio vaccine (OPV). Accurate surveillance for poliomyelitis is essential for continuing eradication. PMID- 26015926 TI - Development of hen antihepatitis B antigen IgY-based conjugate for ELISA assay. AB - BACKGROUND: Chicken antibodies have many advantages to the mammalian antibodies and have several important differences against mammalian IgG with regard to their specificity and large-scale production. In this study, the production, purification, and HRP conjugation of polyclonal IgY against hepatitis virus surface antigen (HBsAg) were carried out. MATERIALS AND METHODS: Single Comb White Leghorn hens were immunized intramuscularly with hepatitis B vaccine in combination with Freund's adjuvants. Blood and eggs were collected before and during ten weeks after the first immunization. RESULTS: A highly purified of 180 KDa with specific activity of 200 mIU/ml was obtained by our purification protocol. One milligram of the purified IgY was labeled with horseradish peroxidase (HRP). Sandwich ELISA was used to determine the optimum titer of anti HbsAg IgY-conjugate which was found to be 1:20. CONCLUSIONS: This study showed that laying hens can be used as an alternative source for production of polyclonal antibodies against HBsAg and anti-HBs IgY could be labeled with HRP enzyme and could subsequently be used successfully as secondary antibody in ELISA for detection of HBsAg in the patients sera. PMID- 26015928 TI - The textbook on Lung Cancer: time for personalized medicine. PMID- 26015927 TI - The effect of hydroalcoholic extract from the leaves of Moringa peregrina (Forssk.) Fiori. on blood pressure and oxidative status in dexamethasone-induced hypertensive rats. AB - BACKGROUND: Moringa peregrina (Forssk.) Fiori. is a tropical tree growing in southeast of Iran. All parts of this plant have nutritional uses and pharmacological activities. The present study was designed to evaluate the effect of hydroalcoholic extract from the leaves of M. peregrina in dexamethasone (Dex) induced hypertension in rats. MATERIALS AND METHODS: Male Wistar rats received Dex (30 MUg/kg, subcutaneously; s.c.) or saline (as vehicle, 1 ml/kg, s.c.) for 14 days. In a prevention study, the rats received M. peregrina extract (100, 200 and 400 mg/kg, orally) for 4 days, followed by Dex for 14 days. In a reversal study, the animals received M. peregrina extract orally from day 8 to 14. The systolic blood pressure (SBP) was measured using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were assessed in plasma samples. RESULTS: Dex significantly increased the SBP and the plasma H2O2 and decreased the plasma FRAP value (P < 0.001). M. peregrina extract at a dose of 400 mg/kg prevented (P < 0.01) but did not reverse Dex-induced hypertension in rats. It also dose-dependently reduced the plasma H2O2 concentration and improved the FRAP value upon Dex administration. CONCLUSIONS: The findings of the present study indicated the antioxidant and partially antihypertensive effects of the hydroalcoholic extract from the leaves of M. peregrina in Dex-induced hypertension. Further experiments on other fractions of the leaves and also other parts of this plant are suggested for better evaluation of its antihypertensive effect and finding its mechanisms of action. PMID- 26015929 TI - Optimal management of sentinel lymph node positive biopsy patients in early breast cancer. PMID- 26015930 TI - Regional nodal management in the light of the AMAROS trial. PMID- 26015931 TI - Multidisciplinary teams in thoracic oncology-from tragic to strategic. PMID- 26015932 TI - A fishing trip to cure arrhythmogenic cardiomyopathy? AB - The paper entitled "Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy", as published in 2014 in Science Translational Medicine, examined the effects of the newly discovered drug SB216763 (SB21) on arrhythmogenic cardiomyopathy (ACM). In this paper, the authors focused on mechanisms underlying ACM and the accompanying molecular and cellular alterations. Most importantly they showed that SB21 was able to rescue and partly reverse the ACM phenotype in three different experimental models: (I) a zebrafish model of Naxos disease induced by the overexpression of the 2057del2 mutation in plakoglobin (PKG); (II) neonatal rat cardiomyocytes overexpressing the same mutation in PKG; (III) cardiomyocytes derived from induced pluripotent stem cells expressing two different forms of mutations in plakophilin-2. This editorial will focus on the potency and possible restrictions concerning SB21 treatment as a potential intervention for ACM and the usefulness of the applied zebrafish models in general. PMID- 26015933 TI - Role of intestinal Na(+)/H(+) exchanger inhibition in the prevention of cardiovascular and kidney disease. PMID- 26015934 TI - Preliminary results of single-port versus triple-port complete thoracoscopic lobectomy for non-small cell lung cancer. AB - OBJECTIVE: To compare the feasibility and safety of single-port vs. triple-port complete thoracoscopic lobectomy for non-small cell lung cancer (NSCLC). METHODS: A retrospective study was conducted on 82 patients with NSCLC who underwent complete thoracoscopic lobectomy from August 2014 to October 2014 in Department of Thoracic Surgery, Fujian Medical University Union Hospital. There were 33 cases in single-port complete thoracoscopic lobectomy group (single-port group) and the other 49 ones in triple-port complete thoracoscopic lobectomy group (triple-port group). Total lymph node harvest, mediastinal lymph node harvest, dissection of mediastinal lymph node groups, operation time, intraoperative blood loss, chest drainage duration, postoperative hospital stay, postoperative one-day pain visual analogue scale (POP-VAS), and the complications were thoroughly compared between the two groups. RESULTS: There were no significant differences in total lymph node harvest, mediastinal lymph node harvest, dissection of mediastinal lymph node groups, intraoperative blood loss, chest drainage duration, postoperative hospital stay, and complications between the two groups (P>0.05). However, the operation time of single-port group was significantly longer than that of triple-port group (181.3+/-27.5 vs. 149.5+/-30.9 min, P<0.05). POP-VAS in single-port group was significantly lower than that in triple port group (3.6+/-0.7 vs. 5.5+/-1.0, P<0.05). CONCLUSIONS: For NSCLC, the feasibility and safety of single-port complete thoracoscopic lobectomy is similar to triple-port complete thoracoscopic lobectomy. Compared with triple-port complete thoracoscopic lobectomy, the operation time of single-port complete thoracoscopic lobectomy is longer, but its postoperative pain is gentler. As the experience accumulating, single-port complete thoracoscopic lobectomy should be popularized with its merits of minimal invasiveness. PMID- 26015935 TI - CYP1A2 rs2069514 polymorphism and lung cancer susceptibility: a meta-analysis. AB - Many studies have examined the association between the CYP1A2 rs2069514 polymorphism gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. The PubMed was searched for case-control studies published up to Sep 01, 2014. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated. In this meta-analysis, we assessed six published studies involving comprising 1,168 cases and 1,598 controls of the association between CYP1A2 rs2069514 polymorphism and lung cancer risk. For the homozygote A/A and A allele carriers (G/A + A/A), the pooled ORs were 1.47 (95% CI, 1.15-1.99; P=0.007 for heterogeneity) and 1.43 (95% CI, 1.07 1.90; P=0.000 for heterogeneity), when compared with the homozygous wild-type genotype (G/G). In the stratified analysis by ethnicity, the significantly risks were found among non-Asians for both the A allele carriers and homozygote A/A. However, no significant associations were found in Asian population all genetic models. These results from the meta-analysis suggest that CYP1A2 rs2069514 polymorphism contributes to risk of lung cancer among non-Asian population. PMID- 26015936 TI - Timing of bariatric surgery in people with obesity and diabetes. AB - The use of bariatric surgery in the clinical management of type 2 diabetes in severely obese subjects has been included in the clinical practice recommendations released by the most influential diabetologic associations. However, the timing during the diabetic course in which this use may have the better benefit/risk ratio remains debated. Is it better to use surgery very early in the course of the disease in order to anticipate clinical deterioration, or we should favour a delayed approach in which we reserve the more risky surgery only to patients not adequately controlled with the maximal pharmacologic strategy? In this paper, past and recent evidences about the role of bariatric surgery in the different stages of the clinical course of type 2 diabetes have been revised, starting from pre-diabetes and ending to long-standing diabetic state with established or end-stage macro- and micro-vascular complications. Available evidences strongly advocate in favor of the application of bariatric surgery in the early phase of this course, possibly in the pre-diabetic or in very early diabetic stages. To reserve surgery to more advanced and complicated stages of the disease seems to confer less benefits for the clinical course of diabetes and exposes these more frail patients to the possible side effects of a rapid weight loss. PMID- 26015937 TI - Beyond the World Health Organization grading of infiltrating gliomas: advances in the molecular genetics of glioma classification. AB - BACKGROUND: Traditional classification of diffuse infiltrating gliomas (DIGs) as World Health Organization (WHO) grades II-IV is based on histological features of a heterogeneous population of tumors with varying prognoses and treatments. Over the last decade, research efforts have resulted in a better understanding of the molecular basis of glioma formation as well as the genetic alterations commonly identified in diffuse gliomas. METHODS: A systematic review of the current literature related to advances in molecular phenotypes, mutations, and genomic analysis of gliomas was carried out using a PubMed search for these key terms. Data was studied and synthesized to generate a comprehensive review of glioma subclassification. RESULTS: This new data helps supplement the existing WHO grading scale by subtyping gliomas into specific molecular groups. The emerging molecular profile of diffuse gliomas includes the studies of gene expression and DNA methylation in different glioma subtypes. The discovery of novel mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) provides new biomarkers as points of stratification of gliomas based on prognosis and treatment response. Gliomas that harbor CpG island hypermethylator phenotypes constitute a subtype of glioma with improved survival. The difficulty of classifying oligodendroglial lineage of tumors can be aided with identification of 1p/19q codeletion. Glioblastomas (GBMs) previously described as primary or secondary can now be divided based on gene expression into proneural, mesenchymal, and classical subtypes and the identification of mutations in the promoter region of the telomerase reverse transcriptase (TERTp) have been correlated with poor prognosis in GBMs. CONCLUSIONS: Incorporation of new molecular and genomic changes into the existing WHO grading of DIGs may provide better patient prognostication as well as advance the development of patient-specific treatments and clinical trials. PMID- 26015939 TI - Technical points of the operative procedure for robotic-assisted lung resection and lymph node dissection. PMID- 26015938 TI - The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC). AB - First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, produce reliable responses and survival benefits in selected patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who initially respond to first-line therapy with EGFR TKIs will experience disease progression in 1-2 years. To overcome the resistance of EGFR TKIs, the potent resistance mechanisms and novel therapeutic strategies have been developed. T790M mutation and activation of bypass signaling pathway are identified the predominant mechanisms of acquired resistance to TKIs. Several approaches have shown promise, such as next-generation EGFR TKIs, immunotherapy, and combinational therapies. And the limited clinical data suggest that all drugs are acceptable safe. Additionally, this review will also focus on the increasingly importance of re-biopsy at the time of disease progression, and the matching effective therapies is related to the identification of specific molecular types of tumors. PMID- 26015940 TI - Recurrent pneumothorax: the unexpected encounters. PMID- 26015942 TI - Bridging the gap: a second open-access sibling joins the MT family of journals. PMID- 26015941 TI - Complete restoration of multiple dystrophin isoforms in genetically corrected Duchenne muscular dystrophy patient-derived cardiomyocytes. AB - Duchenne muscular dystrophy (DMD)-associated cardiac diseases are emerging as a major cause of morbidity and mortality in DMD patients, and many therapies for treatment of skeletal muscle failed to improve cardiac function. The reprogramming of patients' somatic cells into pluripotent stem cells, combined with technologies for correcting the genetic defect, possesses great potential for the development of new treatments for genetic diseases. In this study, we obtained human cardiomyocytes from DMD patient-derived, induced pluripotent stem cells genetically corrected with a human artificial chromosome carrying the whole dystrophin genomic sequence. Stimulation by cytokines was combined with cell culturing on hydrogel with physiological stiffness, allowing an adhesion dependent maturation and a proper dystrophin expression. The obtained cardiomyocytes showed remarkable sarcomeric organization of cardiac troponin T and alpha-actinin, expressed cardiac-specific markers, and displayed electrically induced calcium transients lasting less than 1 second. We demonstrated that the human artificial chromosome carrying the whole dystrophin genomic sequence is stably maintained throughout the cardiac differentiation process and that multiple promoters of the dystrophin gene are properly activated, driving expression of different isoforms. These dystrophic cardiomyocytes can be a valuable source for in vitro modeling of DMD-associated cardiac disease. Furthermore, the derivation of genetically corrected, patient-specific cardiomyocytes represents a step toward the development of innovative cell and gene therapy approaches for DMD. PMID- 26015944 TI - Type 1 interferon gene transfer enhances host defense against pulmonary Streptococcus pneumoniae infection via activating innate leukocytes. AB - Pneumococcal infections are the leading cause of community-acquired pneumonia. Although the type 1 interferon-alpha (IFN-alpha) is a well-known antiviral cytokine, the role of IFN-alpha in antipneumococcal host defense and its therapeutic potential remain poorly understood. We have investigated these issues by using a murine transgene expression model. We found that in control animals, Streptococcus pneumoniae infection caused severe weight loss and excessive lung inflammation, associated with rapid bacterial outgrowth. In contrast, the animals that received a single dose of an adenoviral vector expressing IFN-alpha prior to pneumococcal infection demonstrated rapid and effective control of bacterial replication and lung inflammation and improved clinical outcome. Enhanced protection by IFN-alpha was due to increased activation of neutrophils and macrophages with increased release of reactive oxygen and nitrogen species and bacterial killing. Furthermore, we found that raised levels of IFN-alpha in the lung remained immune protective even when the gene transfer vector was given at a time postpneumococcal infection. Our study thus shows that the classically antiviral type 1 IFN can be exploited for enhancing immunity against pneumococcal infection via its activating effects on innate immune cells. Our findings hold implications for the therapeutic use of IFN-alpha gene transfer strategies to combat pneumococcal infections. PMID- 26015943 TI - Differential effects of two MRI contrast agents on the integrity and distribution of rAAV2 and rAAV5 in the rat striatum. AB - Intraoperative magnetic resonance imaging (MRI) has been proposed as a method to optimize intracerebral targeting and for tracking infusate distribution in gene therapy trials for nervous system disorders. We thus investigated possible effects of two MRI contrast agents, gadoteridol (Gd) and galbumin (Gab), on the distribution and levels of transgene expression in the rat striatum and their effect on integrity and stability of recombinant adeno-associated virus (rAAV) particles. MRI studies showed that contrast agent distribution did not predict rAAV distribution. However, green fluorescent protein (GFP) immunoreactivity revealed an increase in distribution of rAAV5-GFP, but not rAAV2-GFP, in the presence of Gd when compared with viral vector injected alone. In contrast, Gab increased the distribution of rAAV2-GFP not rAAV5-GFP. These observations pointed to a direct effect of infused contrast agent on the rAAV particles. Negative stain electron microscopy (EM), DNAase treatment, and differential scanning calorimetry (DSC) were used to monitor rAAV2 and rAAV5 particle integrity and stability following contrast agent incubation. EMs of rAAV2-GFP and rAAV5-GFP particles pretreated with Gd appear morphologically similar to the untreated sample; however, Gab treatment resulted in surface morphology changes and aggregation. A compromise of particle integrity was suggested by sensitivity of the packaged genome to DNAase treatment following Gab incubation but not Gd for both vectors. However, neither agent significantly affected particle stability when analyzed by DSC. An increase in T m was observed for AAV2 in lactated Ringer's buffer. These results thus highlight potential interactions between MRI contrast agents and AAV that might affect vector distribution and stability, as well as the stabilizing effect of lactated Ringer's solution on AAV2. PMID- 26015945 TI - Aurintricarboxylic acid increases yield of HSV-1 vectors. AB - Production of large quantities of viral vectors is crucial for the success of gene therapy in the clinic. There is a need for higher titers of herpes simplex virus-1 (HSV-1) vectors both for therapeutic use as well as in the manufacturing of clinical grade adeno-associated virus (AAV) vectors. HSV-1 yield increased when primary human fibroblasts were treated with anti-inflammatory drugs like dexamethasone or valproic acid. In our search for compounds that would increase HSV-1 yield, we investigated another anti-inflammatory compound, aurintricarboxylic acid (ATA). Although ATA has been previously shown to have antiviral effects, we find that low (micromolar) concentrations of ATA increased HSV-1 vector production yields. Our results showing the use of ATA to increase HSV-1 titers have important implications for the production of certain HSV-1 vectors as well as recombinant AAV vectors. PMID- 26015946 TI - Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy. AB - Different adeno-associated virus (AAV) serotypes efficiently transduce neurons from central and peripheral nervous systems through various administration routes. Direct administration of the vectors to the cerebrospinal fluid (CSF) could be an efficient and safe strategy. Here, we show that lumbar puncture of a nonhuman AAV leads to wide and stable distribution of the vector along the spinal cord in adult mice. AAVrh10 efficiently and specifically infects neurons, both in dorsal root ganglia (60% total sensory neurons) and in the spinal cord (up to one third of alpha-motor neurons). As a proof of concept, we demonstrate the efficacy of AAVrh10 in a mouse model of diabetic neuropathy, in which intrathecal delivery of the vector coding for insulin-like growth factor (IGF-I) favored the release of the therapeutic protein into the CSF through its expression by sensory and motor neurons. IGF-I-treated diabetic animals showed increased vascular endothelial growth factor expression, activation of Akt/PI3K pathway, and stimulated nerve regeneration and myelination in injured limbs. Moreover, we achieved restoration of nerve conduction velocities in both sensory and motor nerves by AAVrh10, whereas we reached only sensory nerve improvement with AAV1. Our results indicate that intrathecal injection of AAVrh10 is a promising tool to design gene therapy approaches for sensorimotor diseases. PMID- 26015947 TI - Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor. AB - Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4(+) T lymphocytes, and CD34(+) hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4 tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease. PMID- 26015948 TI - Enhancing gene delivery of adeno-associated viruses by cell-permeable peptides. AB - Adeno-associated virus type 2 (AAV2) is considered a promising gene delivery vector and has been extensively applied in several disease models; however, inefficient transduction in various cells and tissues has limited its widespread application in many areas of gene therapy. In this study, we have developed a general, but efficient, strategy to enhance viral transduction, both in vitro and in vivo, by incubating viral particles with cell-permeable peptides (CPPs). We show that CPPs increase internalization of viral particles into cells by facilitating both energy-independent and energy-dependent endocytosis. Moreover, CPPs can significantly enhance the endosomal escape process of viral particles, thus enhancing viral transduction to those cells that have exhibited very low permissiveness to AAV2 infection as a result of impaired intracellular viral processing. We also demonstrated that this approach could be applicable to other AAV serotypes. Thus, the membrane-penetrating ability of CPPs enables us to generate an efficient method for enhanced gene delivery of AAV vectors, potentially facilitating its applicability to human gene therapy. PMID- 26015949 TI - Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors. AB - Adoptive T-cell therapy of cancer is a treatment strategy where T cells are isolated, activated, in some cases engineered, and expanded ex vivo before being reinfused to the patient. The most commonly used T-cell expansion methods are either anti-CD3/CD28 antibody beads or the "rapid expansion protocol" (REP), which utilizes OKT-3, interleukin (IL)-2, and irradiated allogeneic feeder cells. However, REP-expanded or bead-expanded T cells are sensitive to the harsh tumor microenvironment and often short-lived after reinfusion. Here, we demonstrate that when irradiated and preactivated allosensitized allogeneic lymphocytes (ASALs) are used as helper cells to license OKT3-armed allogeneic mature dendritic cells (DCs), together they expand target T cells of high quality. The ASAL/DC combination yields an enriched Th1-polarizing cytokine environment (interferon (IFN)-gamma, IL-12, IL-2) and optimal costimulatory signals for T cell stimulation. When genetically engineered antitumor T cells were expanded by this coculture system, they showed better survival and cytotoxic efficacy under oxidative stress and immunosuppressive environment, as well as superior proliferative response during tumor cell killing compared to the REP protocol. Our result suggests a robust ex vivo method to expand T cells with improved quality for adoptive cancer immunotherapy. PMID- 26015950 TI - Human fetal liver cells for regulated ex vivo erythropoietin gene therapy. AB - Possible risks and lack of donor livers limit application of liver transplantation. Liver cell transplantation is, at this moment, not a feasible alternative because engraftment in the liver is poor. Furthermore, there is also shortage of cells suitable for transplantation. Fetal liver cells are able to proliferate in cell culture and could therefore present an alternative source of cells for transplantation. In this study, we investigated the utility of human fetal liver cells for therapeutic protein delivery. We transplanted human fetal liver cells in immunodeficient mice but were not able to detect engraftment of human hepatocytes. In contrast, transplantation of human adult hepatocytes led to detectable engraftment of hepatocytes in murine liver. Transplantation of fetal liver cells did lead to abundant reconstitution of murine liver with human endothelium, indicating that endothelial cells are the most promising cell type for ex vivo liver cell gene therapy. Human liver endothelial cells were subsequently transduced with a lentiviral autoregulatory erythropoietin expression vector. After transplantation in immunodeficient mice, these cells mediated long-term regulation of murine hematocrits. Our study shows the potential of human liver endothelial cells for long-term regulated gene therapy. PMID- 26015951 TI - EC4, a truncation of soluble N-cadherin, reduces vascular smooth muscle cell apoptosis and markers of atherosclerotic plaque instability. AB - Atherosclerotic plaque instability is precipitated by vascular smooth muscle cell apoptosis in the fibrous cap, weakening it and leading to plaque rupture. We previously showed that reducing smooth muscle cell apoptosis with soluble N cadherin (SNC) increased features of plaque stability. We have now identified the active site of SNC and examined whether a truncated form containing this site retains the antiapoptotic effect. SNC was mutated to prevent interaction with N cadherin or fibroblast growth factor receptor (FGFR). Interaction with FGFR in the extracellular (EC) 4 domain of SNC was essential for the antiapoptotic effect. Therefore, we made a truncated form consisting of the EC4 domain. EC4 significantly reduced smooth muscle cell, macrophage, and endothelial cell apoptosis in vitro by ~70%, similar to SNC. Elevation of plasma levels of EC4 in male apolipoprotein E-deficient mice with existing atherosclerosis significantly reduced apoptosis in brachiocephalic artery plaques by ~50%. EC4 reduced plaque size and the incidence of buried fibrous layers and the macrophage:smooth muscle cell ratio (surrogate markers of plaque instability). Interaction of EC4 with FGFR induced potent antiapoptotic signaling in vitro and in vivo. EC4 modulates atherosclerosis in mice demonstrating its therapeutic potential for retarding plaque size and instability. PMID- 26015952 TI - AAV shuffles to the liver: commentary on Lisowski et al. PMID- 26015953 TI - Codelivery of antigen and an immune cell adhesion inhibitor is necessary for efficacy of soluble antigen arrays in experimental autoimmune encephalomyelitis. AB - Autoimmune diseases such as multiple sclerosis (MS) are typified by the misrecognition of self-antigen and the clonal expansion of autoreactive T cells. Antigen-specific immunotherapies (antigen-SITs) have long been explored as a means to desensitize patients to offending self-antigen(s) with the potential to retolerize the immune response. Soluble antigen arrays (SAgAs) are composed of hyaluronic acid (HA) cografted with disease-specific autoantigen (proteolipid protein peptide) and an ICAM-1 inhibitor peptide (LABL). SAgAs were designed as an antigen-SIT that codeliver peptides to suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Codelivery of antigen and cell adhesion inhibitor (LABL) conjugated to HA was essential for SAgA treatment of EAE. Individual SAgA components or mixtures thereof reduced proinflammatory cytokines in cultured splenocytes from EAE mice; however, these treatments showed minimal to no in vivo therapeutic effect in EAE mice. Thus, carriers that codeliver antigen and a secondary "context" signal (e.g., LABL) in vivo may be an important design criteria to consider when designing antigen-SIT for autoimmune therapy. PMID- 26015954 TI - Specific tools for targeting and expression in Muller glial cells. AB - Despite their physiological roles, Muller glial cells are involved directly or indirectly in retinal disease pathogenesis and are an interesting target for therapeutic approaches for retinal diseases and regeneration such as CRB1 inherited retinal dystrophies. In this study, we characterized the efficiency of adeno-associated virus (AAV) capsid variants and different promoters to drive protein expression in Muller glial cells. ShH10Y and AAV9 were the most powerful capsids to infect mouse Muller glial cells. Retinaldehyde-binding protein 1 (RLBP1) promoter was the most powerful promoter to transduce Muller glial cells. ShH10Y capsids and RLBP1 promoter targeted human Muller glial cells in vitro. We also developed and tested smaller promoters to express the large CRB1 gene via AAV vectors. Minimal cytomegalovirus (CMV) promoter allowed expression of full length CRB1 protein in Muller glial cells. In summary, ShH10Y and AAV9 capsids, and RLBP1 or minimal CMV promoters are of interest as specific tools to target and express in mouse or human Muller glial cells. PMID- 26015955 TI - Lentiviral vectors containing mouse Csf1r control elements direct macrophage restricted expression in multiple species of birds and mammals. AB - The development of macrophages requires signaling through the lineage-restricted receptor Csf1r. Macrophage-restricted expression of transgenic reporters based upon Csf1r requires the highly conserved Fms-intronic regulatory element (FIRE). We have created a lentiviral construct containing mouse FIRE and promoter. The lentivirus is capable of directing macrophage-restricted reporter gene expression in mouse, rat, human, pig, cow, sheep, and even chicken. Rat bone marrow cells transduced with the lentivirus were capable of differentiating into macrophages expressing the reporter gene in vitro. Macrophage-restricted expression may be desirable for immunization or immune response modulation, and for gene therapy for lysosomal storage diseases and some immunodeficiencies. The small size of the Csf1r transcription control elements will allow the insertion of large "cargo" for applications in gene therapy and vaccine delivery. PMID- 26015956 TI - Proof of concept for AAV2/5-mediated gene therapy in iPSC-derived retinal pigment epithelium of a choroideremia patient. AB - Inherited retinal dystrophies (IRDs) comprise a large group of genetically and clinically heterogeneous diseases that lead to progressive vision loss, for which a paucity of disease-mimicking animal models renders preclinical studies difficult. We sought to develop pertinent human cellular IRD models, beginning with choroideremia, caused by mutations in the CHM gene encoding Rab escort protein 1 (REP1). We reprogrammed REP1-deficient fibroblasts from a CHM (-/y) patient into induced pluripotent stem cells (iPSCs), which we differentiated into retinal pigment epithelium (RPE). This iPSC-derived RPE is a polarized monolayer with a classic morphology, expresses characteristic markers, is functional for fluid transport and phagocytosis, and mimics the biochemical phenotype of patients. We assayed a panel of adeno-associated virus (AAV) vector serotypes and showed that AAV2/5 is the most efficient at transducing the iPSC-derived RPE and that CHM gene transfer normalizes the biochemical phenotype. The high, and unmatched, in vitro transduction efficiency is likely aided by phagocytosis and mimics the scenario that an AAV vector encounters in vivo in the subretinal space. We demonstrate the superiority of AAV2/5 in the human RPE and address the potential of patient iPSC-derived RPE to provide a proof-of-concept model for gene replacement in the absence of an appropriate animal model. PMID- 26015957 TI - Development and characterization of an enhanced nonviral expression vector for electroporation cancer treatment. AB - Nonviral plasmid DNA gene therapy represents a promising approach for the treatment of many diseases including cancer. Intracellular delivery of DNA can be achieved with the application of electroporation, which facilitates the initial transport of exogenous DNA across the cell membrane into the cytoplasm. However, it does not guarantee further transport of the DNA from the cytoplasm to the nucleus for subsequent mRNA expression, resulting in varying degrees of exogenous gene translation and a major limitation in comparison to viral approaches. To overcome these expression difficulties, we developed a proof-of-concept vector enhanced expression vector (EEV), which incorporates elements from viral systems including nuclear localization sequences and a viral replicase from the Semliki Forest virus. The replicase allows for cytoplasmic mRNA expression and bypasses the need for nuclear localization to generate high levels of gene expression. We have demonstrated that our EEV is capable of achieving high levels of expression in a variety of tissue types. Antitumor effects of pEEV were demonstrated by the delayed growth and increased survival of the nontherapeutic pEEV-treated CT26 tumor model. Using a novel endoscopic electroporation system, EndoVe, we demonstrate and compare, for the first time, both standard cytomegalovirus (CMV) promoter-driven plasmid and EEV gene expression in intraluminal porcine tissues. Our EEV plasmid displays reliable and superior expression capability, and due to its inherent induced oncolytic activity in transfected cells, it may enhance the efficacy and safety of several cancer immunogene therapy approaches. PMID- 26015958 TI - Kidney-specific expression of GFP by in-utero delivery of pseudotyped adeno associated virus 9. AB - Gene therapy targeting of kidneys has been largely unsuccessful. Recently, a recombinant adeno-associated virus (rAAV) vector was used to target adult mouse kidneys. Our hypothesis is that a pseudotyped rAAV 2/9 vector can produce fetal kidney-specific expression of the green fluorescent protein (GFP) gene following maternal tail vein injection of pregnant mice. Pregnant mice were treated with rAAV2/9 vectors with either the ubiquitous cytomegalovirus promoter or the minimal NPHS1 promoter to drive kidney-specific expression of GFP. Kidneys from dams and pups were analyzed for vector DNA, gene expression, and protein. Vector DNA was identified in kidney tissue out to 12 weeks at low but stable levels, with levels higher in dams than that in pups. Robust GFP expression was identified in the kidneys of both dams and pups treated with the cytomegalovirus (CMV)-enhanced green fluorescent protein (eGFP) vector. When treated with the NPHS1-eGFP vector, dams and pups showed expression of GFP only in kidneys, localized to the glomeruli. An 80-fold increase in GFP mRNA expression in dams and a nearly 12-fold increase in pups was found out to 12 weeks of life. Selective targeting of the fetal kidney with a gene therapy vector was achieved by utilizing the pseudotyped rAAV 2/9 vector containing the NPHS1 promoter. PMID- 26015959 TI - Optimizing the production of suspension cells using the G-Rex "M" series. AB - Broader implementation of cell-based therapies has been hindered by the logistics associated with the expansion of clinically relevant cell numbers ex vivo. To overcome this limitation, Wilson Wolf Manufacturing developed the G-Rex, a cell culture flask with a gas-permeable membrane at the base that supports large media volumes without compromising gas exchange. Although this culture platform has recently gained traction with the scientific community due to its superior performance when compared with traditional culture systems, the limits of this technology have yet to be explored. In this study, we investigated multiple variables including optimal seeding density and media volume, as well as maximum cell output per unit of surface area. Additionally, we have identified a novel means of estimating culture growth kinetics. All of these parameters were subsequently integrated into a novel G-Rex "M" series, which can accommodate these optimal conditions. A multicenter study confirmed that this fully optimized cell culture system can reliably produce a 100-fold cell expansion in only 10 days using 1L of medium. The G-Rex M series is linearly scalable and adaptable as a closed system, allowing an easy translation of preclinical protocols into the good manufacturing practice. PMID- 26015960 TI - Quantitative, noninvasive, in vivo longitudinal monitoring of gene expression in the brain by co-AAV transduction with a PET reporter gene. AB - In vivo imaging of vector transgene expression would be particularly valuable for repetitive monitoring of therapy in the brain, where invasive tissue sampling is contraindicated. We evaluated adeno-associated virus vector expression of a dopamine-2 receptor (D2R) mutant (D2R80A) by positron emission tomography in the brains of mice and cats. D2R80A is inactivated for intracellular signaling and binds subphysiologic amounts of the radioactive [(18)F]-fallypride analog of dopamine. The [(18)F]-fallypride signal bound to D2R80A in the injection site was normalized to the signal from endogenous D2R in the striatum and showed stable levels of expression within individual animals. A separate adeno-associated virus type 1 vector with identical gene expression control elements, expressing green fluorescent protein or a therapeutic gene, was coinjected with the D2R80A vector at equal doses into specific sites. Both transgenes had similar levels of gene expression by immunohistochemistry, in situ hybridization, and quantitative PCR assays, demonstrating that D2R80A is a faithful surrogate measure for expression of a gene of interest. This dual vector approach allows the D2R80A gene to be used with any therapeutic gene and to be injected into a single site for monitoring while the therapeutic gene can be distributed more widely as needed in each disease. PMID- 26015961 TI - Engineering new mycobacterial vaccine design for HIV-TB pediatric vaccine vectored by lysine auxotroph of BCG. AB - In this study, we have engineered a new mycobacterial vaccine design by using an antibiotic-free plasmid selection system. We assembled a novel Escherichia coli (E. coli)-mycobacterial shuttle plasmid p2auxo.HIVA, expressing the HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism for plasmid selection and maintenance based on glycine complementation in E. coli and lysine complementation in mycobacteria. This plasmid was first transformed into glycine auxotroph of E. coli strain and subsequently transformed into lysine auxotroph of Mycobacterium bovis BCG strain to generate vaccine BCG.HIVA(2auxo). We demonstrated that the episomal plasmid p2auxo.HIVA was stable in vivo over a 7-week period and genetically and phenotypically characterized the BCG.HIVA(2auxo) vaccine strain. The BCG.HIVA(2auxo) vaccine in combination with modified vaccinia virus Ankara (MVA). HIVA was safe and induced HIV-1 and Mycobacterium tuberculosis-specific interferon-gamma-producing T-cell responses in adult BALB/c mice. Polyfunctional HIV-1-specific CD8+ T cells, which produce interferon-gamma and tumor necrosis factor-alpha and express the degranulation marker CD107a, were induced. Thus, we engineered a novel, safer, good laboratory practice-compatible BCG-vectored vaccine using prototype immunogen HIVA. This antibiotic-free plasmid selection system based on "double" auxotrophic complementation might be a new mycobacterial vaccine platform to develop not only recombinant BCG-based vaccines expressing second generation of HIV-1 immunogens but also other major pediatric pathogens to prime protective response soon after birth. PMID- 26015962 TI - Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. AB - A preclinical safety study was conducted to evaluate the short- and long-term toxicity of a recombinant adeno-associated virus serotype 8 (AAV2/8) vector that has been developed as an immune-modulatory adjunctive therapy to recombinant human acid alpha-glucosidase (rhGAA, Myozyme) enzyme replacement treatment (ERT) for patients with Pompe disease (AAV2/8-LSPhGAApA). The AAV2/8-LSPhGAApA vector at 1.6 * 10(13) vector particles/kg, after intravenous injection, did not cause significant short- or long-term toxicity. Recruitment of CD4(+) (but not CD8(+)) lymphocytes to the liver was elevated in the vector-dosed male animals at study day (SD) 15, and in group 8 animals at SD 113, in comparison to their respective control animals. Administration of the vector, either prior to or after the one ERT injection, uniformly prevented the hypersensitivity induced by subsequent ERT in males, but not always in female animals. The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females. Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced. The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue. Given the lack of toxicity for AAV2/8LSPhGAApA, further consideration of clinical translation is warranted in Pompe disease. PMID- 26015963 TI - Biosafety studies of carrier cells infected with a replication-competent adenovirus introduced by IAI.3B promoter. AB - The use of carrier cells infected with oncolytic viruses in cancer gene therapy is an attractive method because it can overcome viral immunogenicity and induce tumor immunity and significant antitumor activity. To enable human clinical trials of this treatment, acute and chronic toxicity tests must first be performed to ensure safety. IAI.3B promoter, oncolytic adenovirus AdE3-IAI.3B introduced by IAI.3B promoter, and A549 carrier cells infected with AdE3-IAI.3B were highly active in cancer cells but not in normal cells. Freeze-thawing increased the antitumor effect of A549 carrier cells by promoting the translocation of oncolytic adenovirus particles from the nucleus to the cytoplasm following the rupture of the nuclear membranes. No deaths or abnormal blood test data resulted from acute toxicity tests conducted in nude mice after a single dose. In chronic toxicity tests in rabbits, there were no serious side effects after eight doses of 1.25 * 10(7) cells/kg or less for 4 weeks; a significant immune response is known to elicit increased numbers of antiadenovirus antibodies and enlarge the spleen. From these results, it could be concluded that cancer gene therapy of recurrent solid tumors using carrier cells can be safely trialed in humans. PMID- 26015964 TI - High-titer foamy virus vector transduction and integration sites of human CD34(+) cell-derived SCID-repopulating cells. AB - Foamy virus (FV) vectors are promising tools for gene therapy, but low titer is a major challenge for large-scale clinical trials. Here, we increased FV vector titer 50-fold by constructing novel vector plasmids and using polyethylenimine mediated transfection. FV and lentiviral (LV) vectors were used separately to transduce human CD34(+) cells at multiplicities of infection of 25, and those cells were transplanted into immunodeficient mice. FV vector transduction frequencies of repopulating human cells were 37.1 +/- 1.9% in unstimulated cells and 36.9 +/- 2.2% in prestimulated cells, and engraftment frequencies were 40.9 +/- 4.9% in unstimulated cells and 47.1 +/- 3.3% in prestimulated cells. Engraftment frequencies of FV vector-transduced cells were significantly higher than those of LV vector-transduced cells. Linear amplification-mediated PCR with Illumina paired-end runs showed that all human chromosomes contained FV provirus. FV had an integration preference near transcriptional start sites and CpG islands of RefSeq genes but not within genes. Repopulating lymphoid and myeloid cells contained common integration sites, suggesting that FV vector could transduce multilineage hematopoietic stem/progenitor populations. Our new FV vector backbone may be a suitable candidate for developing therapeutic FV vectors for use in clinical trials. PMID- 26015965 TI - Pre-TCRalpha supports CD3-dependent reactivation and expansion of TCRalpha deficient primary human T-cells. AB - Chimeric antigen receptor technology offers a highly effective means for increasing the anti-tumor effects of autologous adoptive T-cell immunotherapy, and could be made widely available if adapted to the use of allogeneic T-cells. Although gene-editing technology can be used to remove the alloreactive potential of third party T-cells through destruction of either the alpha or beta T-cell receptor (TCR) subunit genes, this approach results in the associated loss of surface expression of the CD3 complex. This is nonetheless problematic as it results in the lack of an important trophic signal normally mediated by the CD3 complex at the cell surface, potentially compromising T-cell survival in vivo, and eliminating the potential to expand TCR-knockout cells using stimulatory anti CD3 antibodies. Here, we show that pre-TCRalpha, a TCRalpha surrogate that pairs with TCRbeta chains to signal proper TCRbeta folding during T-cell development, can be expressed in TCRalpha knockout mature T-cells to support CD3 expression at the cell surface. Cells expressing pre-TCR/CD3 complexes can be activated and expanded using standard CD3/CD28 T-cell activation protocols. Thus, heterologous expression of pre-TCRalpha represents a promising technology for use in the manufacturing of TCR-deficient T-cells for adoptive immunotherapy applications. PMID- 26015966 TI - Prevention of adverse events of interferon gamma gene therapy by gene delivery of interferon gamma-heparin-binding domain fusion protein in mice. AB - Sustained gene delivery of interferon (IFN) gamma can be an effective treatment, but our previous study showed high levels of IFNgamma-induced adverse events, including the loss of body weight. These unwanted events could be reduced by target-specific delivery of IFNgamma after in vivo gene transfer. To achieve this, we selected the heparin-binding domain (HBD) of extracellular superoxide dismutase as a molecule to anchor IFNgamma to the cell surface. We designed three IFNgamma derivatives, IFNgamma-HBD1, IFNgamma-HBD2, and IFNgamma-HBD3, each of which had 1, 2, or 3 HBDs, respectively. Each plasmid-encoding fusion proteins was delivered to the liver, a model target in this study, by hydrodynamic tail vein injection. The serum concentration of IFNgamma-HBD2 and IFNgamma-HBD3 after gene delivery was lower than that of IFNgamma or IFNgamma-HBD1. Gene delivery of IFNgamma-HBD2, but not of IFNgamma-HBD3, effectively increased the mRNA expression of IFNgamma-inducible genes in the liver, suggesting liver-specific distribution of IFNgamma-HBD2. Gene delivery of IFNgamma-HBD2-suppressed tumor growth in the liver as efficiently as that of IFNgamma with much less symptoms of adverse effects. These results indicate that the adverse events of IFNgamma gene transfer can be prevented by gene delivery of IFNgamma-HBD2, a fusion protein with high cell surface affinity. PMID- 26015967 TI - Maintaining therapeutic activity in the operating room: compatibility of a gamma retroviral replicating vector with clinical materials and biofluids. AB - Toca 511 is a novel retroviral replicating vector, encoding a modified yeast cytosine deaminase, administered to recurrent high grade glioma patients in Phase 1 trials by stereotactic, transcranial injection into the tumor or into the walls of the resection cavity. A key issue, with little published data, is vector biocompatibility with agents likely to be encountered in a neurosurgical setting. We tested biocompatibility of Toca 511 with: delivery devices; MRI contrast agents, including ProHance supporting coinjection for real time MRI-guided intratumoral delivery; hemostatic agents; biofluids (blood and cerebrospinal fluid); potential adjuvants; and a needleless vial adapter that reduces risk of accidental needle sticks. Toca 511 is stable upon thawing at ambient temperature for at least 6 hours, allowing sufficient time for administration, and its viability is not reduced in the presence of: stainless steel and silica-based delivery devices; the potential MRI contrast agent, Feraheme; ProHance at several concentrations; the hemostatic agent SURGIFOAM; blood; cerebrospinal fluid; and the needleless vial adapter. Toca 511 is not compatible with the hemostatic agent SURGICEL or with extended exposures to titanium-based biopsy needles. PMID- 26015968 TI - In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies. AB - A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances. PMID- 26015969 TI - Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity. AB - We previously discovered one particular HLA-A*02:01 mutant that enhanced peptide specific cytotoxic T lymphocyte (CTL) recognition in vitro compared to wild-type HLA-A*02:01. This mutant contains a single amino acid substitution from histidine to leucine at position 74 (H74L) that is located in the peptide-binding groove. To investigate the effect of the H74L mutation on the in vivo CTL priming, we took advantage of the technology of the HLA class I single-chain trimer (SCT) in which three components involving a peptide, beta2 microglobulin and the HLA class I heavy chain are joined together via flexible linkers. We generated recombinant adenovirus expressing SCT comprised influenza A matrix protein (FMP)-derived peptide, beta2 microglobulin and the H74L heavy chain. HLA-A*02:01 transgenic mice were immunized with the adenovirus, and the induction of peptide-specific CTLs and antitumor immunity was investigated. It was clearly shown that the H74L mutation enabled the HLA-A*02:01 SCT molecule to dramatically enhance both in vivo priming of FMP-specific CTLs and protection against a lethal challenge of tumor cells expressing FMP. These data present the first evidence that a simple point mutation in the HLA class I heavy chain of SCT is beneficial for improving CTL-based immunotherapy and prophylaxis to control tumors. PMID- 26015970 TI - Generation and in vivo evaluation of IL10-treated dendritic cells in a nonhuman primate model of AAV-based gene transfer. AB - Preventing untoward immune responses against a specific antigen is a major challenge in different clinical settings such as gene therapy, transplantation, or autoimmunity. Following intramuscular delivery of recombinant adeno-associated virus (rAAV)-derived vectors, transgene rejection can be a roadblock to successful clinical translation. Specific immunomodulation strategies potentially leading to sustained transgene expression while minimizing pharmacological immunosuppression are desirable. Tolerogenic dendritic cells (TolDC) are potential candidates but have not yet been evaluated in the context of gene therapy, to our knowledge. Following intramuscular delivery of rAAV-derived vectors expressing an immunogenic protein in the nonhuman primate model, we assessed the immunomodulating potential of autologous bone marrow-derived TolDC generated in the presence of IL10 and pulsed with the transgene product. TolDC administered either intradermally or intravenously were safe and well tolerated. While the intravenous route showed a modest ability to modulate host immunity against the transgene product, intradermally delivery resulted in a robust vaccination of the macaques when associated to intramuscular rAAV-derived vectors based gene transfer. These findings demonstrate the critical role of TolDC mode of injection in modulating host immunity. This study also provides the first evidence of the potential of TolDC-based immunomodulation in gene therapy. PMID- 26015971 TI - Hemodynamics of a hydrodynamic injection. AB - The hemodynamics during a hydrodynamic injection were evaluated using cone beam computed tomography (CBCT) and fluoroscopic imaging. The impacts of hydrodynamic (5 seconds) and slow (60 seconds) injections into the tail veins of mice were compared using 9% body weight of a phase-contrast medium. Hydrodynamically injected solution traveled to the heart and drew back to the hepatic veins (HV), which led to liver expansion and a trace amount of spillover into the portal vein (PV). The liver volumes peaked at 165.6 +/- 13.3% and 165.5 +/- 11.9% of the original liver volumes in the hydrodynamic and slow injections, respectively. Judging by the intensity of the CBCT images at the PV, HV, right atrium, liver parenchyma (LP), and the inferior vena cava (IVC) distal to the HV conjunction, the slow injection resulted in the higher intensity at PV than at LP. In contrast, a significantly higher intensity was observed in LP after hydrodynamic injection in comparison with that of PV, suggesting that the liver took up the iodine from the blood flow. These results suggest that the enlargement speed of the liver, rather than the expanded volume, primarily determines the efficiency of hydrodynamic delivery to the liver. PMID- 26015972 TI - Different protein composition and functional properties of adeno-associated virus 6 vector manufactured from the culture medium and cell lysates. AB - Vectors based on recombinant adeno-associated viruses (rAAV) attract a growing interest for human gene therapy. Recently, it was shown that many rAAV serotypes produced by transient transfection of human embryonic kidney 293 cell line (HEK293) are efficiently released into culture medium and functionally equivalent to those purified from cell lysates. Here, we report that HEK293 cells produce and secrete Galectin 3-binding protein (huG3BP), a protein that efficiently binds rAAV6 in vivo. Importantly, intracellular G3BP and secreted G3BP have different properties: while the secreted protein had the same electrophoretic mobility as serum huG3BP and interacted with rAAV6, intracellular protein migrated faster and did not bind rAAV6. Consequently, rAAV6 purified from culture medium (secreted, rAAV6-S) was physically associated with huG3BP while rAAV6 harvested from cell lysates (cellular, rAAV6-C) was huG3BP-free. After systemic injections, rAAV6-S bound to huG3BP was 3 times less efficient compared to rAAV6-C and induced an immune response against huG3BP protein. Our findings show that protein content of rAAVs purified from culture medium or from cell lysates can be different and these differences may impact vector efficacy and/or immune response. PMID- 26015973 TI - Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model. AB - Using single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction profiles in the CNS. The DC injection route robustly and exclusively transduced the whole cerebellum, whereas the IT injection route primarily transduced the cerebellar lobules 9 and 10 close to the injection site and the spinal cord. An IV injection in neonatal mice weakly and homogenously transduced broad CNS areas. In the cerebellar cortex, the DC and IT injection routes transduced all neuron types, whereas the IV injection route primarily transduced Purkinje cells. To verify the usefulness of this method, we generated a mouse model of spinocerebellar ataxia type 1 (SCA1). Mice that received a DC injection of the ssAAV9 vector expressing mutant ATXN1, a protein responsible for SCA1, showed the intranuclear aggregation of mutant ATXN1 in Purkinje cells, significant atrophy of the Purkinje cell dendrites and progressive motor deficits, which are characteristics of SCA1. Thus, ssAAV9-mediated transduction areas, levels, and cell types change depending on the route of injection. Moreover, this approach can be used for the generation of different mouse models of CNS/neurodegenerative diseases. PMID- 26015974 TI - A simplified purification protocol for recombinant adeno-associated virus vectors. AB - We describe a new rapid, low cost, and scalable method for purification of various recombinant adeno-associated viruses (rAAVs) from the lysates of producer cells of either mammalian or insect origin. The method takes advantage of two general biochemical properties of all characterized AAV serotypes: (i) low isoelectric point of a capsid and (ii) relative biological stability of the viral particle in the acidic environment. A simple and rapid clarification of cell lysate toremove the bulk of proteins and DNA is accomplished by utilizing inexpensive off-the-shelf reagents such as sodium citrate and citric acid. After the low-speed centrifugation step, the supernatant is subjected to cation exchange chromatography via sulfopropyl (SP) column. The eluted virus may then be further concentrated by either centrifugal spin devices or tangential flow filtration yielding material of high titer and Good Manufacturing Practice (GMP) grade biochemical purity. The protocol is validated for rAAV serotypes 2, 8, and 9. The described method makes rAAV vector technology readily available for the low budget research laboratories and could be easily adapted for a large scale GMP production format. PMID- 26015975 TI - Suppression of leaky expression of adenovirus genes by insertion of microRNA targeted sequences in the replication-incompetent adenovirus vector genome. AB - Leaky expression of adenovirus (Ad) genes occurs following transduction with a conventional replication-incompetent Ad vector, leading to an induction of cellular immunity against Ad proteins and Ad protein-induced toxicity, especially in the late phase following administration. To suppress the leaky expression of Ad genes, we developed novel Ad vectors by incorporating four tandem copies of sequences with perfect complementarity to miR-122a or miR-142-3p into the 3' untranslated region (UTR) of the E2A, E4, or pIX gene, which were mainly expressed from the Ad vector genome after transduction. These Ad vectors easily grew to high titers comparable to those of a conventional Ad vector in conventional 293 cells. The leaky expression of these Ad genes in mouse organs was significantly suppressed by 2- to 100-fold, compared with a conventional Ad vector, by insertion of the miRNA-targeted sequences. Notably, the Ad vector carrying the miR-122a-targeted sequences into the 3'-UTR of the E4 gene expressed higher and longer-term transgene expression and more than 20-fold lower levels of all the Ad early and late genes examined in the liver than a conventional Ad vector. miR-122a-mediated suppression of the E4 gene expression in the liver significantly reduced the hepatotoxicity which an Ad vector causes via both adaptive and non-adaptive immune responses. PMID- 26015976 TI - Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. AB - Clinical data support the feasibility and safety of adeno-associated viral (AAV) vectors in gene therapy applications. Despite several clinical trials of AAV based gene transfer for hemophilia B, a unique set of obstacles impede the development of a similar approach for hemophilia A. These include (i) the size of the factor VIII (fVIII) transgene, (ii) humoral immune responses to fVIII, (iii) inefficient biosynthesis of human fVIII, and (iv) AAV vector immunity. Through bioengineering approaches, a novel fVIII molecule, designated ET3, was developed and shown to improve biosynthetic efficiency 10- to 100-fold. In this study, the utility of ET3 was assessed in the context of liver-directed, AAV-mediated gene transfer into hemophilia A mice. Due to the large size of the expression cassette, AAV-ET3 genomes packaged into viral particles as partial genome fragments. Despite this potential limitation, a single peripheral vein administration of AAV-ET3 into immune-competent hemophilia A mice resulted in correction of the fVIII deficiency at lower vector doses than previously reported for similarly oversized AAV-fVIII vectors. Therefore, ET3 appears to improve vector potency and mitigate at least one of the critical barriers to AAV-based clinical gene therapy for hemophilia A. PMID- 26015977 TI - Generation of X-CGD cells for vector evaluation from healthy donor CD34(+) HSCs by shRNA-mediated knock down of gp91(phox). AB - Innovative approaches for the treatment of rare inherited diseases are hampered by limited availability of patient derived samples for preclinical research. This also applies for the evaluation of novel vector systems for the gene therapy of monogenic hematological diseases like X-linked chronic granulomatous disease (X CGD), a severe primary immunodeficiency caused by mutations in the gp91(phox) subunit of the phagocytic NADPH oxidase. Since current gene therapy protocols involve ex vivo gene modification of autologous CD34(+) hematopoietic stem cells (HSC), the ideal preclinical model should simulate faithfully this procedure. However, the low availability of patient-derived CD34(+) cells limits the feasibility of this approach. Here, we describe a straightforward experimental strategy that circumvents this limitation. The knock down of gp91(phox) expression upon lentiviral delivery of shRNAs into CD34(+) cells from healthy donors generates sufficient amounts of X-CGD CD34(+) cells which subsequently can be used for the evaluation of novel gene therapeutic strategies using a codon optimized gp91(phox) transgene. We have used this strategy to test the potential of a novel gene therapy vector for X-CGD. PMID- 26015978 TI - AAV8-mediated Sirt1 gene transfer to the liver prevents high carbohydrate diet induced nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease worldwide, and evidence suggests that it promotes insulin resistance and type 2 diabetes. Caloric restriction (CR) is the only available strategy for NAFLD treatment. The protein deacetylase Sirtuin1 (SIRT1), which is activated by CR, increases catabolic metabolism and decreases lipogenesis and inflammation, both involved in the development of NAFLD. Here we show that adeno-associated viral vectors of serotype 8 (AAV8)-mediated liver-specific Sirt1 gene transfer prevents the development of NAFLD induced by a high carbohydrate (HC) diet. Long-term hepatic SIRT1 overexpression led to upregulation of key hepatic genes involved in beta-oxidation, prevented HC diet-induced lipid accumulation and reduced liver inflammation. AAV8-Sirt1-treated mice showed improved insulin sensitivity, increased oxidative capacity in skeletal muscle and reduced white adipose tissue inflammation. Moreover, HC feeding induced leptin resistance, which was also attenuated in AAV8-Sirt1-treated mice. Therefore, AAV-mediated gene transfer to overexpress SIRT1 specifically in the liver may represent a new gene therapy strategy to counteract NAFLD and related diseases such as type 2 diabetes. PMID- 26015979 TI - Developmental stage determines efficiency of gene transfer to muscle satellite cells by in utero delivery of adeno-associated virus vector serotype 2/9. AB - Efficient gene transfer to muscle stem cells (satellite cells) has not been achieved despite broad transduction of skeletal muscle by systemically administered adeno-associated virus serotype 2/9 (AAV-9) in mice. We hypothesized that cellular migration during fetal development would make satellite cells accessible for gene transfer following in utero intravascular injection. We injected AAV-9 encoding green fluorescent protein (GFP) marker gene into the vascular space of mice ranging in ages from post-coital day 12 (E12) to postnatal day 1 (P1). Satellite cell transduction was examined using: immunohistochemistry and confocal microscopy, satellite cell migration assay, myofiber isolation and FACS analysis. GFP positive myofibers were detected in all mature skeletal muscle groups and up to 100% of the myofibers were transduced. We saw gestational variation in cardiac and skeletal muscle expression. E16 injection resulted in 27.7 +/- 10.0% expression in satellite cells, which coincides with the timing of satellite cell migration, and poor satellite cell expression before and after satellite cell migration (E12 and P1). Our results demonstrate that efficient gene expression is achieved in differentiated myofibers and satellite cells after injection of AAV-9 in utero. These findings support the potential of prenatal gene transfer for muscle based treatment strategies. PMID- 26015980 TI - piggyBac-mediated phenotypic correction of factor VIII deficiency. AB - Hemophilia A, caused by a deficiency in factor VIII (FVIII), is the most severe inherited bleeding disorder. Hemophilia A is an attractive gene therapy candidate because even small increases in FVIII levels will positively alter the phenotype. While several vectors are under investigation, gene addition from an integrated transgene offers the possibility of long term expression. We engineered the DNA transposon-based vector, piggyBac (PB), to carry a codon-optimized B-domain deleted human FVIII cDNA. Evaluation of gene transfer efficiency in FVIII null mice demonstrated that PB containing the FVIII cDNA, delivered via hydrodynamic injection to immunocompetent hemophilia mice, conferred persistent gene expression, attaining mean FVIII activity of approximately 60% with 3/19 developing inhibitors. In addition to efficacious expression, a goal of gene transfer-based therapies is to develop vectors with low toxicity. To assess endoplasmic reticulum stress in hepatocytes stably expressing the transgene, we evaluated levels of ER stress markers via qPCR and found no evidence of cell stress. To evaluate phenotypic correction, a tail clip assay performed at the end of the study revealed reduced blood loss. These data demonstrate that PB can be used to achieve sustained FVIII expression and long-term therapeutic benefit in a mouse model. PMID- 26015981 TI - Gene electrotransfer enhanced by nanosecond pulsed electric fields. AB - The impact of nanosecond pulsed electric fields (nsPEFs) on gene electrotransfer has not been clearly demonstrated in previous studies. This study was conducted to evaluate the influence of nsPEFs on the delivery of plasmids encoding luciferase or green fluorescent protein and subsequent expression in HACAT keratinocyte cells. Delivery was performed using millisecond electric pulses (msEPs) with or without nsPEFs. In contrast to reports in the literature, we discovered that gene expression was significantly increased up to 40-fold by applying nsPEFs to cells first followed by one msEP but not in the opposite order. We demonstrated that the effect of nsPEFs on gene transfection was time restricted. The enhancement of gene expression occurred by applying one msEP immediately after nsPEFs and reached the maximum at posttreatment 5 minutes, slightly decreased at 15 minutes and had a residual effect at 1 hour. It appears that nsPEFs play a role as an amplifier without changing the trend of gene expression kinetics due to msEPs. The effect of nsPEFs on cell viability is also dependent on the specific pulse parameters. We also determined that both calcium independent and dependent mechanisms are involved in nsPEF effects on gene electrotransfer. PMID- 26015982 TI - An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models. AB - Friedreich ataxia (FRDA) is a genetic disease due to increased repeats of the GAA trinucleotide in intron 1 of the frataxin gene. This mutation leads to a reduced expression of frataxin. We have produced an adeno-associated virus (AAV)9 coding for human frataxin (AAV9-hFXN). This AAV was delivered by intraperitoneal (IP) injection to young conditionally knockout mice in which the frataxin gene had been knocked-out in some tissues during embryogenesis by breeding them with mice expressing the Cre recombinase gene under the muscle creatine kinase (MCK) or the neuron-specific enolase (NSE) promoter. In the first part of the study, different doses of virus were tested from 6 * 10(11) v.p. to 6 * 10(9) v.p. in NSE-cre mice and all leading to an increase in life spent of the mice. The higher and the lower dose were also tested in MCK-cre mice. A single administration of the AAV9 hFXN at 6 * 10(11) v.p. more than doubled the life of these mice. In fact the MCK cre mice treated with the AAV9-hFXN were sacrificed for further molecular investigations at the age of 29 weeks without apparent symptoms. Echography analysis of the heart function clearly indicated that the cardiac systolic function was better preserved in the mice that received 6 * 10(11) v.p. of AAV9 hFXN. The human frataxin protein was detected by ELISA in the heart, brain, muscles, kidney, and liver with the higher dose of virus in both mouse models. Thus, gene therapy with an AAV9-hFXN is a potential treatment of FRDA. PMID- 26015983 TI - Optimization of a gene electrotransfer procedure for efficient intradermal immunization with an hTERT-based DNA vaccine in mice. AB - DNA vaccination consists in administering an antigen-encoding plasmid in order to trigger a specific immune response. This specific vaccine strategy is of particular interest to fight against various infectious diseases and cancer. Gene electrotransfer is the most efficient and safest non-viral gene transfer procedure and specific electrical parameters have been developed for several target tissues. Here, a gene electrotransfer protocol into the skin has been optimized in mice for efficient intradermal immunization against the well-known telomerase tumor antigen. First, the luciferase reporter gene was used to evaluate gene electrotransfer efficiency into the skin as a function of the electrical parameters and electrodes, either non-invasive or invasive. In a second time, these parameters were tested for their potency to generate specific cellular CD8 immune responses against telomerase epitopes. These CD8 T-cells were fully functional as they secreted IFNgamma and were endowed with specific cytotoxic activity towards target cells. This simple and optimized procedure for efficient gene electrotransfer into the skin using the telomerase antigen is to be used in cancer patients for the phase 1 clinical evaluation of a therapeutic cancer DNA vaccine called INVAC-1. PMID- 26015984 TI - Recombinant rabies virus particles presenting botulinum neurotoxin antigens elicit a protective humoral response in vivo. AB - Botulinum neurotoxins are one of the most potent toxins found in nature, with broad medical applications from cosmetics to the treatment of various neuropathies. Additionally, these toxins are classified as Category A-Tier 1 agents, with human lethal doses calculated at as little as 90 ng depending upon the route of administration. Of the eight distinct botulinum neurotoxin serotypes, the most common causes of human illness are from serotypes /A, /B, and /E. Protection can be achieved by eliciting antibody responses against the receptor-binding domain of the neurotoxin. Our previous research has shown that recombinant rabies virus-based particles can effectively present heterologous antigens. Here, we describe a novel strategy using recombinant rabies virus particles that elicits a durable humoral immune response against the botulinum neurotoxin receptor binding domains from serotypes /A, /B, and /E. Following intramuscular administration of beta-propiolactone-inactivated rabies virus particles, mice elicited specific immune responses against the cognate antigen. Administration of a combination of these vectors also demonstrated antibody responses against all three serotypes based on enzyme-linked immunosorbent assay (ELISA) measurements, with minimal decay within the study timeline. Complete protection was achieved against toxin challenge from the serotypes /A and /B and partial protection for /E, indicating that a multivalent approach is feasible. PMID- 26015985 TI - Comparative analysis of lentiviral vectors and modular protein nanovectors for traumatic brain injury gene therapy. AB - Traumatic brain injury (TBI) remains as one of the leading causes of mortality and morbidity worldwide and there are no effective treatments currently available. Gene therapy applications have emerged as important alternatives for the treatment of diverse nervous system injuries. New strategies are evolving with the notion that each particular pathological condition may require a specific vector. Moreover, the lack of detailed comparative studies between different vectors under similar conditions hampers the selection of an ideal vector for a given pathological condition. The potential use of lentiviral vectors versus several modular protein-based nanovectors was compared using a controlled cortical impact model of TBI under the same gene therapy conditions. We show that variables such as protein/DNA ratio, incubation volume, and presence of serum or chloroquine in the transfection medium impact on both nanovector formation and transfection efficiency in vitro. While lentiviral vectors showed GFP protein 1 day after TBI and increased expression at 14 days, nanovectors showed stable and lower GFP transgene expression from 1 to 14 days. No toxicity after TBI by any of the vectors was observed as determined by resulting levels of IL-1beta or using neurological sticky tape test. In fact, both vector types induced functional improvement per se. PMID- 26015986 TI - Preclinical efficacy and safety of an anti-IL-1beta vaccine for the treatment of type 2 diabetes. AB - Neutralization of the inflammatory cytokine interleukin-1beta (IL-1beta) is a promising new strategy to prevent the beta-cell destruction, which leads to type 2 diabetes. Here, we describe the preclinical development of a therapeutic vaccine against IL-1beta consisting of a detoxified version of IL-1beta chemically cross-linked to virus-like particles of the bacteriophage Qbeta. The vaccine was well tolerated and induced robust antibody responses in mice, which neutralized the biological activity of IL-1beta, as shown both in cellular assays and in challenge experiments in vivo. Antibody titers were long lasting but reversible over time and not associated with the development of potentially harmful T cell responses against IL-1beta. Neutralization of IL-1beta by vaccine induced antibodies had no influence on the immune responses of mice to Listeria monocytogenes and Mycobacterium tuberculosis. In a diet-induced model of type 2 diabetes, immunized mice showed improved glucose tolerance, which was mediated by improved insulin secretion by pancreatic beta-cells. Hence, immunization with IL 1beta conjugated to virus-like particles has the potential to become a safe, efficacious, and cost-effective therapy for the prevention and long-term treatment of type 2 diabetes. PMID- 26015987 TI - Genetic rearrangements of variable di-residue (RVD)-containing repeat arrays in a baculoviral TALEN system. AB - Virus-derived gene transfer vectors have been successfully employed to express the transcription activator-like effector nucleases (TALENs) in mammalian cells. Since the DNA-binding domains of TALENs consist of the variable di-residue (RVD) containing tandem repeat modules and virus genome with repeated sequences is susceptible to genetic recombination, we investigated several factors that might affect TALEN cleavage efficiency of baculoviral vectors. Using a TALEN system designed to target the AAVS1 locus, we observed increased sequence instability of the TALE repeat arrays when a higher multiplicity of infection (MOI) of recombinant viruses was used to produce the baculoviral vectors. We also detected more deleterious mutations in the TALE DNA-binding domains when both left and right TALEN arms were placed into a single expression cassette as compared to the viruses containing one arm only. The DNA sequence changes in the domains included deletion, addition, substitution, and DNA strand exchange between the left and right TALEN arms. Based on these observations, we have developed a protocol using a low MOI to produce baculoviral vectors expressing TALEN left and right arms separately. Cotransduction of the viruses produced by this optimal protocol provided an improved TALEN cleavage efficiency and enabled effective site specific transgene integration in human cells. PMID- 26015989 TI - Erratum: Glial cells express nuclear Nrf2 after fumarate treatment for multiple sclerosis and psoriasis. AB - [This corrects the article on p. e99 in vol. 2, PMID: 25866832.]. PMID- 26015988 TI - Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates. AB - Respiratory Syncytial Virus (RSV) is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV) and Modified Vaccinia Ankara RSV (MVA-RSV) encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing. PMID- 26015990 TI - Acute lower motor neuron syndrome and spinal cord gray matter hyperintensities in HIV infection. AB - OBJECTIVE: To describe a novel manifestation of lower motor neuron disease in patients with well-controlled HIV infection. METHODS: A retrospective study was performed to identify HIV-positive individuals with acute, painful lower motor neuron diseases. RESULTS: Six patients were identified with HIV and lower motor neuron disease. Two patients met the inclusion criteria of well-controlled, chronic HIV infection and an acute, painful, unilateral lower motor neuron paralytic syndrome affecting the distal portion of the upper limb. These patients had segmental T2-hyperintense lesions in the central gray matter of the cervical spinal cord on MRI. One patient stabilized and the second patient improved with immunomodulatory therapy. CONCLUSIONS: This newly described syndrome expands the clinical spectrum of lower motor neuron diseases in HIV. PMID- 26015991 TI - Allergic encephalitis with gelastic status epilepticus induced by wasp sting. PMID- 26015992 TI - Relationship between Visual Impairment, Insomnia, Anxiety/Depressive Symptoms among Russian Immigrants. AB - BACKGROUND: Little is known about the association between visual impairment and insomnia symptoms in elderly populations. The purpose of this study was to ascertain associations between self-reported visual impairments and insomnia symptoms in a community-based sample of Russian immigrants. METHOD: Sample consisted of 307 community-residing Russians (ages: 25-95 years, mean=72.64 +/- 9.62; women=54% and men=46%). Semi-structured interviews assessed health-care needs and physical health characteristics. Collected demographic and health related data were analyzed using SPSS 19.0. RESULTS: Overall, 93% reported at least one of several major health problems: visual impairment (48.4%), hypertension (53%), diabetes (25.7%), arthritis (52.8%), cancer (10.5%), weight problems (34.1%), and anxiety/depressive symptoms (43%), 62% had an insomnia diagnosis. Unadjusted logistic regression analysis showed that individuals with visual impairment were nearly three times as likely as those without to report insomnia symptoms [OR = 2.73, p < 0.01; 95% CI = 1.68-4.48]. Adjusting for the presence of socio demographic variables reduced the odds to 2.68; further adjustment for social isolation and anxiety and depressed symptoms reduced the odds to 2.20.Anxiety/depression mediated the relationship between visual impairment and insomnia. CONCLUSION: Individuals with visual impairment have twice the odds of reporting insomnia independent of anxiety/depression and social isolation, two common problems affecting quality of life in that population. PMID- 26015993 TI - Global quantification of heterochromatin-associated histone methylations in cell lines with differential sensitivity to ionizing radiation. AB - Histone modifications are involved in the DNA damage response (DDR). Here, by utilizing an ELISA immunoassay we assessed the methylation at H3K9 (H3K9me2 and H3K9me3) in two cell lines with differential sensitivity to radiation-induced apoptosis, HeLa (sensitive) and MCF-7 (resistant). We found that DNA damage induction by gamma-irradiation leads to considerable accumulation (up to 5-fold) of H3K9me2 and H3K9me3, but not of H4K20me3 (control modification) in MCF-7 cells (p<0.05). Interestingly, a lower dose (2 Gy) was more effective than 5 Gy. In HeLa cells a smaller effect (approx. 1.5-1.8-fold) was evident only at 5 Gy. In conclusion, our findings reveal that DNA damage leads to specific accumulation of H3K9me2 and H3K9me3 in a cell-type specific manner. PMID- 26015994 TI - Characterization of ATPase activity of the AAA ARC from Bifidobacterium longum subsp. infantis. AB - Bifidobacteria are considered to be probiotics that exist in the large intestine and are helpful to maintain human health. Oral administration of bifidobacteria may be effective in improving the intestinal flora and environment, stimulating the immune response and possibly preventing cancer. However, for consistent and positive results, further well-controlled studies are urgently needed to describe the basic mechanisms of this microorganism. Analysis of the proteasome-lacking Bifidobacterium longum genome reveals that it possesses a gene, IPR003593 AAA ATPase core, which codes a 56 kDa protein containing one AAA ATPase domain. Phylogenetic classification made by CLANS, positioned this sequence into the ARC divergent branch of the AAA ATPase family of proteins. N-terminal analysis of the sequence indicates this protein is closely related to other ATPases such as the Rhodococcus erythropolis ARC, Archaeoglobus fulgidus PAN, Mycobacterium tuberculosis Mpa and the human proteasomal Rpt1 subunit. This gene was cloned, the full-length recombinant protein was overexpressed in Escherichia coli, purified as a high-molecular size complex and named Bl-ARC. Enzymatic characterization showed that Bl-ARC ATPase is active, Mg(+2)-dependent and sensitive to N-ethylmaleimide. Gene organization positions bl-arc in a region flanked by a cluster of genes that includes pup, dop and pafA genes. These findings point to a possible function as a chaperone in the degradation pathway via pupylation. PMID- 26015995 TI - Studies on the antioxidant properties of extracts from the roots and shoots of two Scutellaria species in human blood plasma. AB - We determined the in vitro antioxidant activity of methanolic extracts from the shoots and roots of Scutellaria species (S. altissima and S. alpina) against the action of strong oxidants: hydrogen peroxide (H2O2) and H2O2+Fe(2+) (donor of hydroxyl radicals) on plasma proteins and lipids. Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). Protein oxidation was measured by quantitation of thiol group. We observed that the extracts (5-50 ug ml(-1)) containing phenolic compounds from both Scutellaria species distinctly reduced oxidation of lipids and proteins in human plasma treated with H2O2. These results also indicated that the extracts have a protective effect against oxidative damage to the human plasma lipids and proteins by induced hydroxyl radical. The main components of the plant materials analysed were flavonoids, present as aglycones (luteolin) or glycosides (cynaroside, baicalin, wogonoside). In all of the extracts, the phenylethanoid verbascoside was also found. The properties of the tested plant extracts were also compared with the action of a well characterised commercial antioxidative polyphenolic extract from the berries of Aronia melanocarpa (Aronox((r))). The comparative studies indicated that the analysed plant extracts were comparable to or even more effective in reducing the oxidation processes than the A. melanocarpa extract. The present study suggests that natural extracts from S. altissima and S. alpina have antioxidant activities and, therefore, may be beneficial in the prevention of diseases related to oxidant stress, such as cancer, cardiovascular, and inflammatory diseases. PMID- 26015996 TI - Surfactant assisted formation of ruthenium nanochains under mild conditions and their catalytic CO oxidation activity. AB - Spontaneous formation of ruthenium nanochains is accomplished in aqueous medium under mild conditions using a seed mediated protocol with cetyl trimethylammonium bromide (CTAB) as the capping agent. They are formed due to the random self assembly of Ru seeds of ~3.5 nm size. These 1D nanostructures exhibit better catalytic activity towards the oxidation of CO relative to the ~3.5 nm seeds and 6 nm Ru nanospheres. The synthesis strategy adopted here is found to be simple, facile and environmentally friendly. PMID- 26015998 TI - Amphiphilic tertiary amine N-oxides: a mediated radical emulsion polymerization with non-formation of alkoxyamine dormant chains. AB - Octadecylamine ethoxylate (EO = 5) N-oxides (AO-1805) were presented which are one kind of interfacial tertiary amine N-oxides that differ from TEMPO derivatives. This method took the advantage of amphiphilic alkyldiethoxylated amine oxide to form micelles, and had novel "living" characteristics based on the non-formation of dormant chains. PMID- 26015997 TI - Stereoselective synthesis of epoxyisoprostanes: an organocatalytic and "pot economy" approach. AB - An efficient and direct synthetic route to epoxyisoprostane EC methyl ester has been accomplished in 8 steps (10% overall yield) from readily available starting materials using a series of asymmetric organocatalytic reactions and one-pot operations. PMID- 26015999 TI - Direct accessibility of mixed-metal (III/II) acid sites through the rational synthesis of porous metal carboxylates. AB - The scalable and environmentally-friendly synthesis of mixed Fe(III)/M(II) (M = Ni, Co, Mg) polycarboxylate porous MOFs based on the Secondary Building Unit approach is reported. A combination of in situ infrared spectroscopy, (57)Fe Mossbauer spectrometry and adsorption microcalorimetry confirms the direct accessibility of the iron(III) and metal(II) sites under low temperature activation conditions. PMID- 26016000 TI - "Atypical" macrophages. PMID- 26016001 TI - Response: Communication in education. A core competency for the cardiologist. PMID- 26016002 TI - Preface. Cardiomyocytes. PMID- 26016003 TI - T follicular helper cells. Preface. PMID- 26016004 TI - [Question: Please explain Sjogren disease]. PMID- 26016005 TI - [Endoscopic Surgery: Indications and results]. PMID- 26016006 TI - [Is sleep endoscopy effective in snoring?]. PMID- 26016007 TI - Paper of the Year 2013. AB - The Editorial Board is pleased to announce the 2013 Paper of the Year Award. The winning paper is chosen by a panel of members of our International Advisory Board who do not have a conflict of interest with any of the papers under consideration. The Award is given to a paper published in the 2013 calendar year which, in the opinion of the judges, has the best combination of scientific merit and application to the clinical practice of physiotherapy. The 2013 Award goes to 'Preventive exercises reduced injury-related costs among adult male amateur soccer players: a cluster-randomised trial' by Mark Krist and colleagues from the University Medical Centre Utrecht and the National Institute of Public Health and the Environment in The Netherlands. PMID- 26016008 TI - Retraction notice to: Impairment of central leptin-mediated PI3K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. PMID- 26016009 TI - Dangerous ingestions in children. PMID- 26016010 TI - A critical shortage of solution threatens unprecedented growth in peritoneal dialysis. PMID- 26016011 TI - Progress towards polio eradication worldwide, 2014-2015. PMID- 26016012 TI - How Liberia reached zero cases of Ebola virus disease. PMID- 26016013 TI - Achieving medication adherence through value-based insurance design. AB - Key findings. Five main features of value-based insurance design plans were found to be associated with higher rates of medication adherence: (1) Plans that provide more generous coverage (2) Plans that target high-risk patients (3) Plans that offer wellness programs (4) Plans that do not offer disease management programs (5) Plans that make the benefit available only for medication order by mail. PMID- 26016014 TI - How behavioral changes have affected U.S. population health since 1960. PMID- 26016015 TI - Why is infant mortality higher in the U.S. than in Europe? PMID- 26016016 TI - How health evolves after retirement: the role of education. PMID- 26016017 TI - Constituting children's bodily integrity. AB - Children have a constitutional right to bodily integrity. Courts do not hesitate to vindicate that right when children are abused by state actors. Moreover, in at least some cases, a child's right to bodily integrity applies within the family, giving the child the right to avoid unwanted physical intrusions regardless of the parents' wishes. Nonetheless, the scope of this right vis-a-vis the parents is unclear; the extent to which it applies beyond the narrow context of abortion and contraception has been almost entirely unexplored and untheorized. This Article is the first in the legal literature to analyze the constitutional right of minors to bodily integrity within the family by spanning traditionally disparate doctrinal categories such as abortion rights; corporal punishment; medical decisionmaking; and nontherapeutic physical interventions such as tattooing, piercing, and circumcision. However, the constitutional right of minors to bodily integrity raises complex philosophical questions concerning the proper relationship between family and state, as well as difficult doctrinal and theoretical issues concerning the ever-murky idea of state action. This Article canvasses those issues with the ultimate goal of delineating a constitutional right of bodily security and autonomy for children. PMID- 26016018 TI - [The dynamics of feed-forward loop depends on regulator type in indirect pathway]. AB - Gene networks contain a recurring motif, called the feed-forward loop, in which a transcription factor regulates target expression directly and indirectly via the second regulator. Here we present the results of mathematical modeling of feed forward loops with either the transcription factor or miRNA as a repressor in the indirect pathway. We showed that the substitution of the transcription factor with miRNA changes the dynamic behavior of the feed-forward loop and lends new properties critical for biological system functioning. PMID- 26016019 TI - [Modelling of Drosophila gap gene network under Bcd morphogen variation]. AB - Expression patterns of segmentation genes are formed under the influence of maternal transcription factor gradients, which initiate spatially localized expression in the cascade of segmentation genes. Bcd is one of these activators. We have studied one model of regulation in the gap gene network by varying the concentration of this protein. We have shown that the known gap gene network topology is not sufficient to explain experimental data on the shifts exhibited by the hb anterior expression domain by change in Bcd concentration in the embryo. As the result of modeling with these experimental data taken into account, a new topology is obtained that determines the correct shifts of the hb expression domain. These results suggest that interactions among the three hb, Kr and gt genes are key regulatory factors for the valid behaviour of the hb expression pattern with Bcd concentration changes. This study made it possible to specify the limits of validity for phenomenological models of gene networks. PMID- 26016020 TI - [Influence of silver and titanium dioxide nanoparticles on the expression of genes of biomarkers of inflammatory responses and apoptosis]. AB - In order to evaluate the toxic effect of silver (AgNP) and titanium dioxide (TiO2) nanoparticles their influence on the expression of genes of biomarkers of inflammatory responses and apoptosis in human lymphocytes was studied. An increase in the IL-6, IL-8, TNF-alpha and p53 genes expression in the concentration range of silver and titanium dioxide nanoparticles of 10-40 MUk g/ml was found. Increased expression of IL-6, IL-8, TNF-alpha and p53 genes under the nanoparticles action indicates the stimulation of the immune system and of apoptosis, respectively. PMID- 26016021 TI - [Circular dichroism of DNA liquid-crystalline dispersion particles]. AB - The optical activity of DNA liquid-crystalline dispersions is being investigated based on a theory for absorption of electromagnetic waves by large molecular aggregates. The impact on the dispersions-optical properties, exerted by the interaction between the complexes of nucleic acid molecules and nanoparticles, is being considered. PMID- 26016022 TI - [Decomposition of hemoglobin UV absorption spectrum into absorption spectra of prosthetic group and apoprotein by means of an additive model]. AB - The decomposition pathways of hemoglobin UV absorption spectrum into the absorption spectra of the protein and non-protein components are proposed and substantiated by means of an additive model. We have established that the heme component has an absorption band with a maximum at lambda(max) = 269.2 nm (epsilon = 97163) and the apoprotein component has an absorption band with a maximum at lambda(max) = 278.4 nm (epsilon = 48669) for the wavelength range from 240.0 to 320.0 nm. An integral relative proportion of absorption for the heme fraction (78.8%) and apoprotein (21.2%) in the investigating wavelength range is defined. PMID- 26016023 TI - [The accuracy of rapid equilibrium assumption in steady-state enzyme kinetics is the function of equilibrium segment structure and properties]. AB - Quantitative evaluation of the accuracy of the rapid equilibrium assumption in the steady-state enzyme kinetics was obtained for an arbitrary mechanism of an enzyme-catalyzed reaction. This evaluation depends only on the structure and properties of the equilibrium segment, but doesn't depend on the structure and properties of the rest (stationary part) of the kinetic scheme. The smaller the values of the edges leaving equilibrium segment in relation to values of the edges within the equilibrium segment, the higher the accuracy of determination of intermediate concentrations and reaction velocity in a case of the rapid equilibrium assumption. PMID- 26016024 TI - [Brownian dynamics simulations of protein-protein interactions in photosynthetic electron transport chain]. AB - The application of Brownian dynamics for simulation of transient protein-protein interactions is reviewed. The review focuses on theoretical basics of Brownian dynamics method, its particular implementations, advantages and drawbacks of the method. The outlook for future development of Brownian dynamics-based simulation techniques is discussed. Special attention is given to analysis of Brownian dynamics trajectories. The second part of the review is dedicated to the role of Brownian dynamics simulations in studying photosynthetic electron transport. Interactions of mobile electron carriers (plastocyanin, cytochrome c6, and ferredoxin) with their reaction partners (cytochrome b6f complex, photosystem I, ferredoxin:NADP-reductase, and hydrogenase) are considered. PMID- 26016025 TI - [Photo-induced processes and reaction dynamics in bacteriorhodopsin]. AB - In this review we have focused on the advances madein observing the photo-induced response in bacteriorhodopsin and understanding the mechanisms of retinal-protein interactions which are still obscure. We discuss our recent data obtained on the wild type of bacteriorhodopsin and model compounds. This paper presents our new spectroscopic data on amino acids obtained using FT-IR emission spectroscopy. Based on the characteristics of the structure and optical properties of glycine and L-lysine that simulate a photo-induced behaviour of an opsin under natural conditions we tried to find an answer to one of the most important questions concerning the role of protein in the primary processes in bacteriorhodopsin. PMID- 26016026 TI - [Effects of silver nitrate on the phase state of model multibilayer membranes]. AB - In order to study the effects caused by silver nitrate (AgNO3) on model lipid membranes, we studied multibilayer membranes based on L-alpha dipalmitoylphosphatidylcholine (DPPC) and AgNO3 aqueous soluitions in a wide concentration range (up to 30 wt%) by means of differential scanning calorimetry. It has been shown that the presence of AgNO3 leads both to an increase in the main phase transition temperature (T(m)) and appearance of an additional phase transition peak (T(m)), suggesting increasing of both density and heterogeneity of the lipid membrane. The effect of nitrate ions (NO ) was shown to be of the opposite nature (bilayer fluidizing), so the integral densifying effect of AgNO3 can be referred solely to the action of silver ions (Ag(+)). With increasing AgNO3 concentration, the tendency was observed to opposite changes in T(m) and T'(m) peaks intensity, thereby at about 26. wt% of AgNO3 the initial peak (T(m)) disappeared. In the range of Ag+ therapeutic concentrations (up to 2 wt%) no significant changes in the DPPC membrane were revealed. This can be one of the reasons of the absence of a damaging effect of silver drugs on a host organism with simultaneous pronounced bactericidal effect. PMID- 26016027 TI - [Analysis of the dynamics of bioluminescence intensity of luminous bacteria Photobacterium phosphoreum]. AB - This contribution presents the results of analysis of the dynamics of the bioluminescence of luminous bacteria Photobacterium phosphoreum IMV B-7071 under optimal conditions of their growth. A quasi-harmonic nature of the bacterial bioluminescence dynamics was detected. The observed periods of these changes have similar values compared with those in the earlier defined periods of changes in physicochemical properties of water. The relationship between biorhythms and a quasi-harmonic nature of changes in physicochemical properties of water is discussed. PMID- 26016028 TI - [Computer simulation of fibroblast effect on electrical activity in sinoatrial node cells]. AB - Computer simulation of the electrical activity in sinoatrial node cells interacting via gap junctions with fibroblasts revealed that interaction with fibroblasts results in greater oscillation frequency of sinoatrial node cells. We have found out that fibroblasts also decrease the oscillation amplitude of the intrinsic central cells or completely suppress their spontaneous activity, while weakly affect the oscillation amplitude of peripheral cells. PMID- 26016029 TI - [The use of the parameters of chlorophyll a fluorescence induction for assessment of plant state under anthropogenic load]. AB - The technique for recording of chlorophyll a fluorescence induction kinetics has been used for assessment of the physiological state of leaves of tillet (Tilia cordata), pendent white birch (Betula pendula), American arborvitae (Thuja occidentalis) in urban environments. Different sensitivity of plants to adverse growing conditions was observed. The most sensitive JIP test parameters such as PI(ABS), F(V)/F(0), F(V)/F(M), R(fd) are determined to be used as indicators of the physiological state of urban phytocenosis. Recommendations for the application of this technique in monitoring studies are given. PMID- 26016030 TI - [Propagation of autowaves in capillaries thick with moving viscous excitable medium]. AB - We consider the propagation of autowaves in the moving liquid excitable medium. The shapes of the autowave fronts in cases of the Poiseuille and Couette flows are determined in flat capillaries within a kinematic approach. We show the existence of a critical velocity for the flows above which the autowave fronts should break off. The possibility of a diode effect--the one-way capillary conductivity--is studied. The results of computer simulations are in good agreement with the theoretical predictions. PMID- 26016031 TI - [A mathematical model of hemodynamic processes for distal pulse wave formation]. AB - A mathematical model of the formation of distal arterial pulse wave signal in the blood vessels of the upper limbs was considered. The formation of distal arterial pulse wave is represented as a composition of forward and reverse pulse waves propagating along the human arterial system. The system of formal analogy between pulse waves propagation along the human arterial system and the propagation of electrical oscillations in electrical transmission lines with distributed parameters was proposed. Dependencies of pulse wave propagation along the human arterial system were obtained by solving the one-dimensional Navier-Stokes equations for a few special cases. PMID- 26016032 TI - [Comparative analysis of action of nitric oxide as a free radical and its storage form on the state of pro- and antioxidant blood systems]. AB - The dynamics of oxidative metabolism in healthy people's blood (n = 30) under the influence of gaseous nitric oxide and dinitrosyl iron complexes is explored. In all blood samples we studied lipid peroxidation intensity and malonic dialdehyde in plasma and erythrocytes, plasma antioxidant potential and activity of superoxide dismutase. During our investigations it was possible for the first time to identify the peculiarities in the responses of pro- and antioxidant blood systems in vitro to the treatment with nitrogen monoxide as the free. radical and its storage form (as a component of dinitrosyl iron complexes). So, a pronounced prooxidant effect for the gas flow from the "Plazon" apparatus moderately decreases when a tenfold dilution of a NO-containing mixture is made. Gas flow from the experimental NO-generator causes minimal prooxidant action, and injection of water solution of dinitrosyl iron complexes in blood specimens leads to an antioxidant action, as limitation of lipoperoxidation processes in plasma and stimulation of superoxide dismutase in erythrocytes. PMID- 26016034 TI - [Automatic detection of exudates in retinal images based on threshold moving average models]. AB - Since exudate diagnostic procedures require the attention of an expert ophthalmologist as well as regular monitoring of the disease, the workload of expert ophthalmologists will eventually exceed the current screening capabilities. Retinal imaging technology is a current practice screening capability providing a great potential solution. In this paper, a fast and robust automatic detection of exudates based on moving average histogram models of the fuzzy image was applied, and then the better histogram was derived. After segmentation of the exudate candidates, the true exudates were pruned based on Sobel edge detector and automatic Otsu's thresholding algorithm that resulted in the accurate location of the exudates in digital retinal images. To compare the performance of exudate detection methods we have constructed a large database of digital retinal images. The method was trained on a set of 200 retinal images, and tested on a completely independent set of 1220 retinal images. Results show that the exudate detection method performs overall best sensitivity, specificity, and accuracy of 90.42%, 94.60%, and 93.69%, respectively. PMID- 26016033 TI - [Transport of dinitrosyl iron complexes into animal lungs]. AB - Effective accumulation of binuclear dinitrosyl iron complexes with glutathione was shown after a subcutaneous para lymphatic injection of an aqueous solution of a dinitrosyl-iron complex into animal lung tissue at a single-dose of 2 micromoles per kilogram two times a day with a 2-h interval. Two hours later after the administration was repeated the concentration of these complexes was 16 micromoles per kilogram of tissue dropping down for the last two hours to 7 micromoles per kilogram of tissue. At one dose injection of binuclear dinitrosyl iron complexes with glutathione their concentration in 2 and 4 hours was two times lower than in the previous experiments. Presumably at the obtained concentration of dinitrosyl iron complexes a bactericidal effect in lungs can be observed against mycobacterium tuberculosis and rapidly proliferating lung tumors. PMID- 26016035 TI - [Polysuccinimide exhibited antitumor activity in the experiment]. AB - Antitumor activity of the novel for oncology compound, such as polysuccinimide, against some of experimental tumor models (Lewis lung carcinoma, Acatol adenocarcinoma, Ca-755 adenocarcinoma) has been established. This drug induced 60 80% tumor growth inhibition of these murine solid tumor strains. Polysuccinimide is also effective (60%) against development of metastatic process in lung (Lewis lung carcinoma). Polysuccinimide causes no changes in pH level in tumor tissue (P 388 leukemia, Acatol adenocarcinoma). This agent may be recommended for further profound preclinical study. PMID- 26016036 TI - [Influence of transcranial electromagnetic brain stimulation on development of conditioned reflex in rats]. AB - The influence of transcranial electromagnetic stimulation on the development of an active avoidance reflex with painful reinforcement in laboratory rats is investigated. It is shown, that an exposure of the rats' brain to electromagnetic radiation in the millimeter range ((lambda = 5,6 and 7,1 mm), modulated as a series of low-frequency pulses, leads to a suppression of the development of the conditioned avoidance reflex occurred in 50% of cases. In other 25% of cases irradiation leads to inhibition of reflex development. Transcranial electromagnetic stimulation after intraperitoneal injection of the blocking agent of serotonergic receptors (kitryl) has no influence on reflex development. Electromagnetic brain stimulation does not influence reflex retention in the case when it has been acquired. Based on the data obtained it is assumed that transcranial electromagnetic stimulation promotes the development of serotonin, exerting an inhibiting effect on the formation of temporal bindings of the studied conditioned reflex. PMID- 26016037 TI - [The dynamics of pulse rate and biochemical parameters in blood of healthy individuals in relation to Pc5-6 geomagnetic pulsations]. AB - Four experiments on long-term monitoring of pulse rate and blood biochemical parameters in four healthy volunteers (women) were conducted. The duration of each experiment was 90 minutes, electrocardiography was performed continuously, taking blood sampling every two minutes. In venous blood the current concentrations of triiodothyronine, cortisol, glucose, stable metabolites of nitrogen oxides (NO(x)) were determined. Synchronicity in oscillations of cortisol and free triiodothyronine levels in the blood of all four volunteers was detected, as well as the presence of the periods of 7-8 min and 15-17 min in the spectra of these biochemical parameters was observed. The periods in the spectra of NO(x) are equal to 7 min, 13 min and 25-30 min. It is shown that the, dynamics of variations in the heart rate is determined mostly by the rhythms of fluctuations in the level of NO(x) in the blood, and the periods in wavelet spectra of these physiological parameters in all four volunteers are close to the periods of their spectra synchronous variations of a. geomagnetic field vector in the frequency range of 0.5-3 mHz. The results obtained in this study indicate that. the presence of nitric oxide and its metabolites in the blood is a biochemical factor, with high probability of its participation in the developmental process of the fine "tuning" of the body to the variations of the geomagnetic field providing synchronization of variations in heart rate and geomagnetic fluctuations in the geomagnetic quiet conditions. PMID- 26016038 TI - [Local fractal analysis of noise-like time series by all permutations method for 1-115 min periods]. AB - Results of local fractal analysis of 329-per-day time series of 239Pu alpha-decay rate fluctuations by means of all permutations method (APM) are presented. The APM-analysis reveals in the time series some steady frequency set. The coincidence of the frequency set with the Earth natural oscillations was demonstrated. A short review of works by different authors who analyzed the time series of fluctuations in processes of different nature is given. We have shown that the periods observed in those works correspond to the periods revealed in our study. It points to a common mechanism of the phenomenon observed. PMID- 26016039 TI - [Transparent evolution of the energy/matter interactions on earth: from gas whirlwind to technogenic civilization]. AB - The paper presents the idea of transparent evolution through the long-term reaction of the planet Earth on the external flow of radiant energy from the Sun. Due to limitations of matter on Earth, as well as on any other planet, the continuous pumping flow of radiant energy was shown to lead to cyclization and transport of substance on emerging gradients. The evolution of energy-matter interaction follows the path of capturing and transferring more energy by the fewer matter, i.e., the path of growth of the amount of energy used by each unit mass. For this indicator, the least effective mass transfer is a simple mass transfer as vortices of gases, in the gradients of temperature and pressure, which occurred on the primary surface of the planet. A long-term natural selection related to the accumulation of water on the planet has played a special role in developing the interaction of energy and matter. Phase transformations (ice, water, vapor) and mechanical transfers are the most common energy-matter processes. Based on water cycles, cyclic transports and transformations, chemical transformation of substances became possible developing over time into a biological transformation. This kind of the interaction of energy and matter is most efficient. In particular, during photosynthesis the energy of our star "is captured and utilized" in the most active part of the spectrum of its radiation. In the process of biological evolution of heterotrophs, a rise (by a factor of hundreds) in the coefficient that characterizes the intensity of energy exchange from protozoa to mammals is most illustratory. The development and the current dominance of humans as the most energy-using active species in capturing the energy and meaningful organization of its new flows especially on the basis of organic debris of former biospheres is admirable, but quite natural from the energy positions. In the course of technological evolution of humankind, the measure of the intensity of energy for homoeothermic (warm-blooded) animals has increased 20 times, based on the process energy used by the "average" inhabitant of the world. Thus, the victory of our species in planetary evolution is easy to fit into the mainstream of evolution through energy-matter interactions: multiple growth of star energy was used to transform the matter on the surface of the irradiated planet. PMID- 26016040 TI - Asbestos related diseases among workers of asbestos processing plants in relation to type of production and asbestos use. AB - BACKGROUND: Asbestos dust is one of the most dangerous pneumoconiotic and carcinogenic agents. The aim of this study was to assess the occurrence of asbestosis and pleural mesothelioma, depending on asbestos consumption and the type of manufactured products, among former asbestos workers in Poland. MATERIAL AND METHODS: The study subjects included employees of 18 large state-owned asbestos processing enterprises operating in the Polish market in 1945-1998. The study is based on data obtained from asbestos company records and the Central Register of Occupational Diseases data on the cases of asbestosis and mesothelioma for the period from 1970 till 2012 as well as data from Amiantus Programme. The analysis was performed for 5 sectors comprising plants classified according to the products manufactured and applied production technology. RESULTS: In the study period, 2160 cases of asbestosis and 138 cases of mesothelioma were reported. The plants processed a total of about 2 million tons of asbestos, including about 7.5% of crocidolite. Total asbestosis consumption was a strong predictor of the rate of asbestosis incidence (R2 = 0.68, p = 0.055). The highest risk occurrence of asbestosis was observed in the production of textiles and sealing products. Mesothelioma occurred only in plants where crocidolite had been ever processed. CONCLUSIONS: Total asbestos consumption was a strong predictor of the rate of asbestosis incidence. The observation confirms the relationship between exposure to crocidolite and the occurrence of mesothelioma, regardless of the manufactured products, and suggests the absence of such a link for the total volume of asbestos consumption. PMID- 26016041 TI - Work-related symptoms among workers exposed to black tea dust. AB - BACKGROUND: Tea may be classified as unfermented green, semi-ferinented oolong and fermented black. All of these types are derived from Camellia sinensis, the Tea Plant, which contains the low molecular weight (LMW) agent Epigallocatechin gallate (EGCg), probably responsible for allergic reactions. The aim of our study was to asses the work-related allergic symptoms and IgE-mediated sensitivity among black tea packers. MATERIAL AND METHODS: Study groups comprised 26 black tea packers (group 1) and 20 office workers (group 2). A questionnaire, skin prick tests (SPTs) to common allergens and black tea, evaluation of specific IgE (asIgF) to Camellia sinensis and moulds, pre- and post-work-shift spirometry were performed. RESULTS: At least I symptom suggesting allergic disease was reported by 85% of the tea packers and 60% of the office workers. The most frequent positive results of SPTs were obtained with moulds (8%). A small decline in FE%1 (forced expiratory volume in I s) after the work shift was observed among tea packers sensitized to moulds. CONCLUSIONS: Although specific sensitization to black tea was not observed in our study groups, cough and skin symptoms were significantly more frequently among the tea packers than in office workers. The irritant impact on the airways and the skin of tea dust and/or sensitization to moulds contaminating tea leaves are being suspected. PMID- 26016042 TI - Determinants of self-rated health of a working population. AB - BACKGROUND: Self-rated health relates to the use of medical help and, as a consequence, determines sick leave in the population of employees. The aim of the study was to analyze the relationship between socioeconomic variables, selected forms of positive health behaviour and subjective evaluation of health in employees. MATERIAL AND METHODS: Five hundred and 99 subjects were included in the study - 331 females and 268 males, aged 18-67, working in the area of the Swietokrzyskie province. The authors' survey questionnaire on the selected elements of the state of health and positive health behavior in life style has been used in the study. Anthropometric measures were carried out. A Chi2 test for independence was used in'the statistical analysis. In order to evaluate the effect of the selected factors on the self-rated health of the studied subjects theresearchers have applied single- and multiple-factor logistic regression. RESULTS: In the multiple-factor logistic regression the features contributing to good or excellent self-rated health were the following: age up to 39 (odds ratio OR = 4.17; 95% confidence interval - Cl: 1.72-10.10; p < 0.002), higher education (OR = 3.01; 95% CI: 1.04-8.70; p < 0.05) and care for health (OR= 4.77; 95% CI: 2.81-8.09; p < 0.001). CONCLUSIONS: Working people with higher education are characterized by a better control over their own health and, consequently, by a better perception of it. Monitoring self-rated health in a working population is an invaluable indicator in the evaluation of health in employees and the need for medical care. PMID- 26016043 TI - [Carcinogenic and mutagenic agents in the workplace, Poland, 2011-2012]. AB - BACKGROUND: The objective of the study was the analysis of structure of carcinogenic or mutagenic chemical substances and dusts occurring in Polish enterprises, 2011-2012, including the number of exposed employees reported to the "Central register of data on exposure to carcinogenic or mutagenic chemical substances, mixtures, agents or technological processes", Nofer Institute of Occupational Medicine, Lodz. In the paper the aims, range and methodology of data collecting by the Central Register are presented. MATERIAL AND METHODS: Qualitative and quantitative analyses of the data on occupational expo- sure to carcinogenic substances and technological processes reported by employers were carried out. RESULTS: In 2011-2012 approximately 2600 plants reported more than 300 carcinogenic or mutageaic chemical substances annually. The most common occupational chemical carcinogens/mutagens were: benzene, one of the unspecified gasoline, chromium(VI) compounds, asbestos, chroniurn(VI) trioxide, ethylene oxide and benzo[a]pyrene. The highest number of employees was exposed to particular polycyclic aromatic hydrocarbons (PAHs). Hardwood dust was the major occupational carcinogen listed in the technological processes inventory with approximately 11 000 employees exposed in about 650 enterprises annually. CONCLUSIONS: The amended legislation concerning occupational exposure to carcinogens has not significantly influenced the exposure structure n Poland. Nevertheless it permited to determine the actual total number of the occupationally exposed to carcinoLens. PMID- 26016044 TI - [Occupational exposure to biological agents intentionally used in Polish enterprises]. AB - BACKGROUND: The paper presents the intentional use of biological agents for industrial, diagnostic and research purposes in Polish enterprises. MATERIAL AND METHODS: The National Register of Biological Agents (Krajowy Rejestr Czynnikow Biologicznych - KRCB) is an online database that collects the data on the intentional use of biological agents at work in Poland. RESULTS: As of December 2013 there were 533 notifications in KRCB, mainly for diagnostic (73%), research (20%) and industrial purposes (7%). Mostly there were hospital diagnostic laboratories (37%), and other laboratories (35%), as well as higher education and research institutions (11%). In total, 4015 workers (91.7% of women, 8.3% of men) were exposed tobiological agents. Agents classified in risk group 2 were used in 518 enterprises, and in risk group 3 in 107 enterprises. Of those agents the following bacteria were the most frequently used: Escherichia coli except for non pathogenic strains (455 enterprises and 3314 exposed workers); Staphylococcus aureus (445 and 3270); and Pseudomonas aeruginosa (406 and 2969, respectively). In 66 enterprises there were used biological agents recognized by the International Agency for Research on Cancer (IARC) as carcinogens. They are viruses: Epstein-Barr (7 enterprises, 181 exposed workers); hepatitis B (16 and 257); hepatitis C virus (15 and 243); human immunodefi- ciency virus (8 and 107); human papillomaviruses (2 and 4); parasites: Clonorchis viverrini (1 and 2 ); Clonorchos sinensis (1 and 2); Schistosoma haematobium (1 and 2) and bacteria Helicobacter pylori; (15 and 230, respectively). CONCLUSIONS: The National Register of Biological Agents at Work permits to evaluate the situation of occupational exposure to biological agents used intentionally in enterprises in Poland. PMID- 26016045 TI - [Microbiological air quality in some kindergartens and antibiotic resistance of bacteria of the Staphylococcus spp. genus]. AB - BACKGROUND: Microbiological contamination or tne air and the acquisition of the antibiotic resistance by pathogenic bacteria is a growing phenomenon that has a substantial impact on the quality of our health. This problem applies mainly to public areas where we spend a large part of our lives. This study was focused on the microbiological analysis of the air in some kindergartens and antibiotic resistance of bacteria of the Stephylococcus spp. genus. The identification of the isolated mould fungi has been also made. MATERIAL AND METHODS: Air samples were collected from classrooms in the seasonal cycle in the mornings and afternoons using 2 methods, sedimentation and impact. Air samples collected outside the kindergartens served as controls. Air quality assessments were based on the groups of indicator microorganisms, according to Polish standards. The susceptibility of isolated staphylococci was assessed with the disc-diffusion method, using 8 different classes of antibiotics, in line with the recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). RESULTS: The analyses show that, regardless of the method, the total number of heterothropic bacteria and staphylococci in the air of the analyzed kindergartens exceeded the allowable limits. There was no air-pollution with the fungal infection. Based on the antibiogram, it was found that Staphylococcus spp. strains showed the highest sensitivity to chloramphenicol and the lowest to penicillin and gentamicin. Among the fungi moulds of the genus Cladosporium predominated. CONCLUSIONS: The results of the analyses highlight the need for regular health checks and further research to help identify biological factors that may significantly affect the quality of health of people living in public spaces. PMID- 26016046 TI - [Employees with mental illness - possibilities and barriers in professional activity]. AB - In Poland patients with psychiatric problems form a large group; in 2010 there were almost 1.5 million people for whom outpatient psychiatric care was provided, whereas approximately 200 thousand ill individuals were treated in 24-h psychiatric wards. Only 17% of the mentally disabled are professionally active. The results of many researches show that despite the detrimental influence of mental disorders on the employment (e.g., lower productivity, absenteeism, presenteism, increased risk of accidents at the workplace), professional activity can play a key role in the7stabilization of the mental state, it can also help in disease recovery. People with mental disorders are a social group that is at the higher risk of exclusion from the job market. The opinion prevailing among employers is that mentally ill individuals have decreased ability to conduct professional activity, and social attitudes towards them tend to be based on marking and stigmatizing. This review tackles the advantages of working during the illness, barriers which people with mental disorders face on the job market when they want to either start or continue work, and professional functioning of people with diagnosed depression (e.g., affective disorders) and schizophrenia (representing psychotic disorders). The analysis of existing data show that to improve the situation of mentally ill people present on the job market close cooperation between the representatives of various medical specializations is necessary, as well as their active participation in the process of social and professional rehabilitation of people affected by mental disorders. PMID- 26016047 TI - [Workaholism - indications for diagnosis and review of interventions]. AB - Due to numerous psychological and health costs, the issue of workaholism requires taking appropriate actions by relevant specialists, including occupational medicine services. This paper presents the criteria and indicators used to diagnose this phenomenon, as well as the review of literature that discusses interventions aimed at preventing workaholism and reducing risk factors, workaholism detection and treatment. The review included 17 scientific publications from the science database Academic Search Complete, which met the basic criterion: the presentation of an intervention aimed directly at reducing workaholism/work addiction, not its side effects. The results of the review indicate a variety of potential actions, including individual, family and organization, which can be directly used in the practice of occupational medicine services (doctors and inspectors of working conditions). In addition, the review can be used as a reference material for other users, such as therapists, coaches, trainers, and human resources (HR) professionals. The article discusses the problem of the important role of occupational medicine services in both the diagnosis and the inhibition of workaholism development. It also presents guidelines how to conduct and analyse the effectiveness of interventions. PMID- 26016048 TI - [Application of recombinant latex allergens in diagnostics of occupational latex allergy]. AB - Over many years, allergy to natural rubber latex has been a major problem among health care workers (HCW). The diagnosis of occupational allergy requires methods of high diagnostic accuracy in view of certification implications (e.g., a sick worker quits a job). With the development of molecular methods, the frequency of application of recombinant allergens it the diagnostics of allergic diseases continues to increase. This paper reviews the applicability of laboratory tests which use recombinant allergens in the diagnostics of occupational allergy. The diagnosis of latex allergy is based on the presence of clinical symptoms linked with exposure to latex allergens, positive skin prick tests and detection of specific IgE antibodies to latex in serun. Moreover, in some cases specific challenge tests are conducted. The analysis of literature indicates that applying the panel of recombinant latex allergens in diagnostic tests, cross-reactivity can very likely be excluded and/or sensitization can be confirmed without the need for specific challenge tests, which in case of latex allergens carries a potential risk of aeneralized reactions. PMID- 26016049 TI - [Chemical hazards arising from shale gas extraction]. AB - The development of the shale industry is gaining momentum and hence the analysis of chemical hazards to the environment and health of the local population is extreiely timely and important. Chemical hazards are created during the exploitation of all minerals, but in the case of shale gas production, there is much more uncertainty as regards to the effects of new technologies application. American experience suggests the increasing risk of environmental contamination, mainly groundwater. The greatest, concern is the incomplete knowledge of the composition of fluids used for fracturing shale rock and unpredictability of long term effects of hydraulic fracturing for the environment and health of residents. High population density in the old continent causes the problem of chemical hazards which is much larger than in the USA. Despite the growing public discontent data on this subject are limited. First of all, there is no epidemiological studies to assess the relationship between risk factors, such as air and water pollution, and health effects in populations living in close proximity to gas wells. The aim of this article is to identify and discuss existing concepts on the sources of environmental contamination, an indication of the environment elements under pressure and potential health risks arising from shale gas extraction. PMID- 26016050 TI - Short telomeres in pulmonary fibrosis: from genetics to clinical significance. AB - Pulmonary fibrosis has been linked molecularly and pathophysiologically by abnormal telomere maintenance. Short telomere lengths are commonly found in both the familial and sporadic forms, telomerase mutations being the most common identifiable genetic cause of the disease. Telomeres are repeated nucleotide sequences that cap the ends of chromosomes and protect them from damage. Telomeres are eroded with cell division and shorten with age. Telomere integrity is mediated by the telomerase complex, a specialized polymerase that adds sequences to the ends of chromosomes. Mutations in the genes encoding telomerase (TERT and TERC) cause pulmonary fibrosis through low telomerase activity, accelerated telomere shortening and exhaustion of lung stem cells. Mutations in TERTor TERC account for only 19% of familial pulmonary fibrosis cases, and it is likely that additional environmental, genetic and epigenetic factors contribute to telomere erosion and to disease phenotype. Identification of short telomeres has potential clinical implications in pulmonary fibrosis: it may be a marker for an increased predisposition toward the development of the disease, it might affect risk stratification as it has been associated with lower survival rates and post-transplant complications that reflect the syndromic nature of this molecular defect. PMID- 26016051 TI - Neural respiratory drive measurement for COPD assessment and monitoring. AB - Currently there is an unmet need for more objective assessments that could determine COPD severity. Ideally such objective assessments could also anticipate COPD exacerbations in order to decrease the need for repeated hospital admissions. In this review we outline how patients' neural respiratory drive (NRD) may be determined using the electromyography of the diaphragm as an objective measurement of COPD severity. Respiratory muscle NRD is indeed less influenced by patients' voluntary effort limitation than for example when testing for exercise tolerance in which case the patients themselves decide when to stop. Exercise tolerance tests are better correlated with muscle weakness rather than COPD severity per se. NRD would also be less dependent upon patients' subjective perception of the severity of their breathlessness. A key further advantage is that recent studies showed that the diaphragm electromyography measurements using electrodes placed on the skin are correlated with those obtained using specific electrodes, therefore this method is non-invasive and more acceptable for routine clinical practice. Thus, NRD measurements could be used in COPD in a similar way as electrocardiography is used to evaluate and monitor ischemic heart disease. NRD measurements could therefore complement more established instruments such as lung function tests, FEV1, exercise tolerance tests, the BODE index etc. in COPD. This could lead to better COPD management and reduce the acute exacerbations which are amongst the most common causes of repeated hospital admissions and consume significant resources. PMID- 26016052 TI - Positive pressure therapy in patients with cardiac arrhythmias and obstructive sleep apnea. AB - BACKGROUND: Positive pressure therapy (CPAP) in patients with cardiac arrhythmias and obstructive sleep apnea (OSAS) may have favorable effects by correcting intermittent hypoxemia and sympathetic activation. OBJECTIVE: To assess the effect of CPAP added to pharmacological treatment in the rate control and prevention of arrhythmias recurrence in patients with OSA. MATERIALS AND METHODS: Prospective, interventional study study which included patients diagnosed with OSAS (cardiorespiratorypolygraphy, AHI>5/hour), and arrhythmias (ECG, Holter ECG), divided in two groups: group A (pharmacological therapy only) and group B (pharmacological therapy and CPAP). The patients were evaluated at enrollment (T0), at 3 and 6 months (T3 and T6) regarding the type, severity and recurrence of cardiac arrhythmias. RESULTS: 36 patients (31 men), mean age: 63.2 +/- 12 years were enroled. In group A: 7 patients with ventricular extrasystoles, 8 with permanent atrial fibrillation, 1 patient with atrial flutter and 2 patients with paroxystic supraventricular tachycardia. In group B: 8 patients with ventricular extrasystoles, 5 with permanent atrial fibrillation, 2 patients with recurrent episodes of atrial fibrillation and 3 with paroxystic supraventricular tachycardia. A positive correlation (r: 0.74, p < 0.001) between Oxygen Desaturation Index and AHI was found. At T6, 12 patients from group B, and 18 from group A were evaluated. In group B, the mean heart rate in patients with atrial fibrillation was 69/min., lower than in group A (82/min.), no cases with recurrent atrial fibrillation were found, and more patients with class II Lown ventricular extrasystoles passed in class I Lown, compared to group A. In group B, heart rate statistically correlated with AHI (r: 0.53, p < 0.005). CONCLUSION: In patients with OSAS, adding CPAP to pharmacological therapy has favorable effects on preventing recurrences, heart rate control in patients with atrial fibrillation and in reducing frequency and/or severity of ventricular extrasystoles. PMID- 26016053 TI - Nodular pulmonary amyloidosis--rare cause of calcified pulmonary nodules. AB - The article presents the case of a 60-year-old asymptomatic woman whose chest X ray screening showed bilateral pulmonary nodules of uncertain etiology. Initially, the main suspicion concerned multiple pulmonary metastases, but the anatomical pathology examination of two of the surgically removed lung nodules revealed a benign pattern--foreign body granulomatous reaction to cholesterol crystals. Patient follow-up with a repeat computed tomography one year later showed that some pulmonary nodules had slightly increased in number and size, so the diagnosis required re-evaluation. Congo red staining revealed a positive reaction in the amorphous material, pointing to a nodular form of pulmonary amyloidosis. This case attests to the wide range of investigations needed to examine multiple pulmonary nodules and to the great variety of possible diagnoses. Surgical biopsy, alongside histopathological examination and immunohistochemical tests of the lung are critical in establishing a positive diagnosis. Pulmonary amyloidosis requires additional investigations and long-term follow-up of the patient, as this condition is frequently associated with MALT (mucosa-associated lymphoid tissue) lymphoma or multiple myeloma. PMID- 26016054 TI - A curious case of yellow nail syndrome. AB - The Yellow Nail Syndrome is a rare clinical entity, first described in 1967 by P.D. Samman and W.F. White. The triad slow-growing dystrophic yellow nails, lymphedema and chronic respiratory disorders is the typical manifestation of the disease but some variations have been described as well as associations with chylothorax, chylous ascites, intestinal lymphangiectasia, thyroid abnormalities, malignancies and immunoglobulin A (IgA) deficiency. We present a case of a 55 years-old woman that had an insidious onset of respiratory disorders and chronic sinusitis, suspected to be infectious throughout the hospitalizations, associated with therapeutically neglected autoimmune thyroiditis. PMID- 26016055 TI - Mediastinal fibrosis and Hodgkin lymphoma mimicking bronchiolitis obliterans organizing pneumonia. AB - Bronchiolitis obliterans organizing pneumonia (BOOP) represents a kaleidoscope of concepts and morphologies, often being confused with a series of conditions, among which the most feared are Hodgkin's lymphoma and bronchioloalveolar carcinoma. We shall present the case of a 56-year-old patient, diagnosed in August 2013 with a pulmonary tumour of the right upper lobe, which was CTstaged - T4N0M0 (IIIA), who underwent a video-assisted thoracotomy for histopathological confirmation. A mediastino-pulmonary formation had been detected intraoperatively and multiple biopsies had been collected. The information brought by the histopathological examination suggested the presence of 2 synchronous pathologies, namely: the mediastinal biopsy showed an advanced degree of dense, compact fibrosis and the pulmonary biopsy highlighted the presence of granulation tissue and Masson bodies in the distal airspace with destruction of vascular and alveolar structures, an aspect which was compatible with organizing pneumonia (BOOP). Once a diagnosis was established, an oral corticosteroid therapy was initiated (Prednisone 30 mg/day) over a period of one month, but the symptomatology of the patient worsened. A new thoracic CT carried out in November 2013 highlighted the progression and extension of the paramediastinal tumoral formation, exhibiting central necrosis and invading the mediastinal vessels, causing their compression (superior vena cava syndrome) associated with multiple mediastinal and hilar adenopathies. The non-favorable evolution and the extensive array of conditions that may mimic the BOOP histopathological pattern have been the key elements, which were the basis of our persistence in getting a real diagnosis. Therefore, in this respect, the biopsy parts performed by thoracotomy were sent for immunohistochemical testing. The CD30 and CD15 positive markers distinctive for Reed-Sternberg cells allowed the diagnosis of Hodgkin's lymphoma. PMID- 26016056 TI - Interstitial pneumonitis after treatment for hepatitis C virus infection. AB - Pulmonary toxicity is a rare side effect of interferon treatment with a wide spectrum of lung tissue conditions, including interstitial pneumonitis, pulmonary sarcoidosis, bronchiolitis obliterans organizing pneumonia, pleural effusion, exacerbation of bronchial asthma, reversible pulmonary hypertension and acute respiratory distress syndrome. We report a case of interstitial pneumonitis in a patient treated with pegylated interferon alpha2-a and ribavirin for chronic hepatitis C virus infection, genotype 1. The case was marked by progression of the respiratory symptoms even after the withdrawn of the pegylated interferon. One-year treatment with systemic corticosteroid ensured a considerable resorption of CT lesions but only a moderate improvement of symptoms and diffusion capacity without a complete recovery. PMID- 26016057 TI - The pharmacological rationale for the use of inhaled tiotropium in asthma. AB - Tiotropium is an inhaled long-acting anticholinergic, with high M3 receptor subtype (M3R) binding affinity, exceedingly half-life at M3R, and functional selectivity. Molecular mechanisms explain binding to muscarinic receptors, long duration of action, kinetic selectivity, and its role as inverse agonist. Tiotropium inhibit airway smooth muscle M3Rs leading to bronchodilation. The intracellular signal transduction pathways for the muscarinic regulation of airway smooth muscle tone are complex. There are many molecular pharmacological reasons for combining this inhaled anticholinergic with beta-2-agonists, and potential non-bronchodilator actions of tiotropium were described. The Respimat SoftMist Inhaler (SMI) is a propellant-free, oral inhalation device, based on an uniblock nozzle system with colliding liquid jets, generating a very fine, slow moving, long-lasting liquid aerosol. This unique SMI is approved to administer tiotropium bromide in poorly controlled asthma patients. Many pharmacotechnological and pharmacoeducational advantages are discussed, and favourable cost-effectiveness aspects in patients with asthma are mentioned. PMID- 26016058 TI - A rat model of autologous oral mucosal epithelial transplantation for corneal limbal stem cell failure. AB - PURPOSE: To establish an animal model of autologous oral mucosa grafting for limbal stem cell deficiency. METHODS: The study was carried from August to October 2012. Fourteen SD rats were randomly and evenly allocated to study group A and control group B. Limbal stem cell deficiency was established by alkali burn in the right eye of each rat in both groups. Rats in group A received autologous oral mucosa strip transplantation following the chemical burn. Rats in group B did not receive surgery after the chemical burn. Topical antibiotics and dexamethasone were used in all rats. Corneal clarity, corneal fluorescein staining, oral mucosal graft survival, and complications at postoperative days 1, 3, 7, 14 were observed. RESULTS: The oral mucosa strip graft was detached in one rat in group A. Reepithelialization was observed starting from the graft position and was completed within 14 days in the remaining 6 eyes in group A. However, persistent corneal epithelium defect was observed in all eyes in group B, among which corneal melting and perforation was observed in 2 eyes and corneal opacification with neovascularization was observed in the remaining 5 eyes. CONCLUSION: Autologous oral mucosa strip grafting for limbal stem cell deficiency can be achieved by a rat model following chemical burn. The fate of the transplanted oral mucosal epithelial cells warrants further study. PMID- 26016059 TI - Magnetic resonance imaging and DWI features of orbital rhabdomyosarcoma. AB - PURPOSE: To describe the magnetic resonance imaging (MRI) features of orbital rhabdomyosarcoma (RMS). METHODS: Thirty-nine patients with histopathologically confirmed orbital RMS were retrospectively reviewed. All patients underwent orbital conventional MRI, including axial, sagittal, and coronal T1-weighted, T2 weighted, and postcontrast T1-weighted sequences. The location, shape, margin, and MRI signal of the 39 lesions were reviewed. DWI in 15 patients and susceptibility weighted imaging (SWI) in 2 patients were also analyzed. RESULTS: Orbital MRI was available in 39 patients and revealed a soft tissue mass in the orbital region in all cases. Of the 39 patients, the primary tumor sites were limited to the orbital proper in 31 cases, while 28 cases had extraocular muscle invasion and 8 cases had extraorbital invasion. All lesions were unilateral. Thirty-three cases were well-defined soft tissue masses and 6 cases appeared as less well-defined soft-issue masses. Thirty-four cases showed homogeneous isointense or slightly hypointense signals on T1-weighted imaging (T1WI) and hyperintense signal on T2-weighted imaging (T2WI) compared with extraocular muscles. Five cases had heterogeneous signals with focal areas of increased signal on T1WI or decreased signal on T2WI, including 1 case with hypointense signal on SWI. The mean apparent diffusion coefficient (ADC) value of the viable part of tumors was (0.925 +/- 0.09) x 10(-3) mm2/s. All cases showed moderate to marked enhancement after contrast administration. CONCLUSION: Several MRI features-including homogeneous isointense or slightly hypointense signal on T1WI and slightly hyperintense signal on T2WI, relative low ADC values, and moderate to marked enhancement, extraocular muscles invasion, and extraorbital extensionare helpful in the diagnosis of orbital RMS. PMID- 26016060 TI - Clinical analysis of the incidence and the treatment of pediatric cataract patients with optic-nerve maldevelopment. AB - PURPOSE: To interpret the incidence of optic-nerve maldevelopment in postoperative pediatric cataract patients, and evaluate the clinical efficacy of administration of murine nerve growth factor (mNGF) in such patients. METHODS: Pattern visual evoked potential (P-VEP) was used to measure the visual pathway function in 28 cases (56 eyes) with bilateral congenital cataract and 13 cases (13 eyes) with unilateral congenital cataract who underwent cataract extraction and intraocular lens implantation surgeries. The results were compared with 25 age-sex-matched healthy children (50 eyes). mNGF was administered in 13 cases (23 eyes) who had visual pathway disorder. The efficacy of mNGF injection was observed. P100 latencies, which were used as a main parameter in P-VEP measurement, were analyzed statistically. RESULTS: When compared with normal children, the P100 latency was significantly prolonged in the congenital cataract group (P < 0.05). A significant improvement was noted in the visual pathway of subjects treated with mNGF (P < 0.05). CONCLUSION: Compared with normal children, the congenital cataract patients are more vulnerable to optic-nerve maldevelopment. Murine NGF likely plays a protective and nutritive role in the development of optic nerve in cases of optic-nerve maldevelopment followed by congenital cataract surgery. PMID- 26016061 TI - Choroidal analysis of polypoidal choroidal vasculopathy by spectral domain optical coherence tomography. AB - PURPOSE: This study was designed to measure the changes in the subfoveal choroidal thickness (SFCT) and choroidal maximal vessel diameter (MVD) of the affected and unaffected fellow eyes in patients with polypoidal choroidal vasculopathy (PCV) and compare them to healthy controls. METHODS: In this cross sectional observational clinical study, SFCT and MVD were measured in both eyes of 53 patients with unilateral PCV. PCV eyes were subgrouped into group A and unaffected fellow eyes into group B. All patients were diagnosed with PCV by fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA). Sixty age- and gender-matched healthy subjects were enrolled in the control group (group C). RESULTS: No statistical difference was observed among groups in age and gender. Overall, SFCT was correlated with MVD in all subjects (P < 0.001; correlation coefficient: 0.759). P values were < 0.001 with a correlation coefficient of 0.686, 0.801, and 0.808 in groups A, B, and C, respectively. No statistical significance was noted in SFCT among groups A (266.45 +/- 99.51 MUm),B(269.57 +/- 105.10 MUm), and C (243.83 +/- 99.68 MUm) (P = 0.335). However, the. MVD in group, A was (202.55 +/-72.45 MUm), significantly larger than that in group C (166.45 +/- 56.18 MUm, P = 0.008), while the MVD in group B (194.75 +/- 85.27 MUm) was equally significantly greater than that in group C (166.45 +/- 56.18 MUm) (P = 0.038). CONCLUSION: For both PCV patients and healthy subjects, SFCT was positively correlated with MVD. No statistical significance was noted in SFCT between PCV eyes and unaffected fellow/normal eyes. However, MVD was significantly larger in the PCV affected eyes than in unaffected fellow or normal control eyes, suggesting that MVD could be considered as a sensitive indicator to evaluate choroidal perfusion in PCV patients. PMID- 26016062 TI - Application of high-frequency electrosurgical scalpel and methylene blue staining in endonasal dacryocystorhinostomy. AB - PURPOSE: To evaluate the application of a high-frequency electrosurgical scalpel and methylene blue staining in the endonasal dacryocystorhinostomy. METHODS: This retrospective study included 37 patients (43 eyes) undergoing endonasal dacryocystorhinostomy in our hospital between 2011 and 2013 using methylene blue staining of the lacrimal sac and a high-frequency electrosurgical scalpel for cutting nasal mucosa, intraoperative stanch, and fixation of lacrimal sac and nasal mucosal flaps. Surgical efficacy, intraoperative challenges, and corresponding handling methods were evaluated and summarized. RESULTS: Among 43 eyes, 42 were successfully cured (97.7%) and the symptoms in 1 eye were improved (2.3%). Total efficacy rate was 100%. All surgeries were successfully performed. No severe intraoperative complications were observed. CONCLUSION: A high frequency electrosurgical scalpel, combined with methylene blue staining of the lacrimal sac, is efficacious for nasal mucosal cutting, intraoperative stanch, and fixation of mucosal flap by cauterization, which significantly alleviates intraoperative complications and enhances surgical success rate. It deserves widespread application in clinical practice. PMID- 26016063 TI - Iontophoretic delivery of riboflavin into the rabbit cornea: a primary study. AB - PURPOSE: To determine the penetrability of riboflavin into the corneal stroma by iontophoresis and to compare the permeability effects of different solvents. METHODS: Twenty rabbits were randomly divided into four groups: a group that received 0.1% riboflavin-balanced salt solution (BSS) by iontophoresis, a group that received 0.1% riboflavin-saline solution by iontophoresis, a group that received 0.1% riboflavin-distilled water solution by iontophoresis, and a control group that received classical riboflavin instillation after corneal de epithelialization. The degree of yellowing of the de-epithelialized corneal stromal button from each rabbit was compared. RESULTS: The yellow color scores for the corneal stromal buttons in the three iontophoresis groups were compared with those of control group. Iontophoretic delivery of a 0.1% riboflavin distilled water solution yielded similar yellow changes in the corneal stromal button when compared with classical riboflavin instillation after de epithelialization. However, the other two solvents did not sufficiently enhance the permeability of riboflavin. CONCLUSION: Riboflavin can effectively penetrate into the corneal stroma to saturation levels by iontophoresis. Using distilled water as the solvent can promote penetrability. PMID- 26016064 TI - Tendency for evolution of high myopia in 308 Chinese school children from Xi'an city. AB - PURPOSE: To observe the refractive status, especially the tendency for evolution of high myopia, in eyes of Chinese school children from Xi'an city. METHODS: The study was conducted in 11514 eyes of the 5757 students aged between 7-18 years in Xi 'an city primary and high schools. The inclusion criterion was > -6D of the spherical equivalent refraction. The object ophthalmic examinations were done, included non-cycloplegic objective refraction, visual acuity, intraocular pressure, fundus evaluation by ophthalmologists and nurses with professional training. Specially designed questionnaires were filled in and the data were statistically analyzed with SPSS10.0. RESULTS: Of 11514 eyes, the detection rate was 81.4% (9376 eyes) for myopia and 5.3% (615 eyes) for high myopia. High myopia was found in 2.6% (300 eyes) of right eyes, 2.7% (315 eyes) in left eyes, and 2.4% (275 eyes) were in boys and 2.9% (340 eyes) in girls. Among 12 school grades, the detection rates of high myopia increased significantly with student age, with 0.9% in the 1st grade of primary school and 12.5% in the 3rd year of senior middle school. The average refractive error of spherical equivalent refraction was (-7.43 +/- 1.29) D with 95% confidence interval (-7.54, -7.33). No significant differences were found between the right and left eyes or both genders. The distribution of myopic severity was lowest(-6D) in primary school students younger than 12 years, was higher (-8D) in junior middle school students older than 13 years, and highest (-13D) in senior middle school students. CONCLUSION: A continuous growth was evident in the severity of high myopia throughout 12 years of primary and middle school except for the first year of primary school, with growth occurring in two transitional stages between the senior primary and junior middle school years, and between the junior and senior middle school years. The distribution of high myopia was lowest, at -6D, in primary school, increased to -8D in junior middle school, and progressed to -10D in senior middle school, indicating a high risk of development of pathologic myopia during the students' later lifespan. The adolescent period of 13 to 18 years of age in middle school is a critical period for the development of pathological myopia over -8D. PMID- 26016065 TI - Clinical experience of external -route retinal detachment surgery under a surgical microscope. AB - PURPOSE: To evaluate the efficacy of external-route retinal reattachment surgery under a surgical microscope. METHODS: A total of 86 patients (86 eyes) with rhegmatogenous retinal detachment underwent external-route retinal detachment surgery under a surgical microscope. Drainage of subretinal fluid, transscleral cryotherapy, scleral buckling, and intravitreal injection of gas were performed intraoperatively. RESULTS: Among 85 patients, 81 achieved postoperative retinal re-attachment after the first surgery and 5 after two surgeries. The visual acuity was elevated in 67 patients, unchanged in 15, and decreased in 4. CONCLUSION: External-route retinal reattachment surgery under a surgical microscope is a convenient procedure for physicians to master and worthy of widespread application in clinical settings. PMID- 26016067 TI - Ratio of primary episcleral buckling surgery versus primary vitrectomy for rhegmatogenous retinal detachment. AB - PURPOSE: To assess the ratio of the frequency of primary scleral buckling procedures versus the frequency of vitrectomies performed as treatment for rhegmatogenous retinal detachments in a primary retinal surgical department. METHODS: The study included all patients with rhegmatogenous retinal detachments who underwent retinal or vitreoretinal surgery in the study period from 2002 to 2006. The size of the retinal defect and the amount of proliferative vitreoretinopathy were not exclusion criteria. Patients with tractional retinal detachment due to proliferative ischemic retinopathies were excluded. RESULTS: In the study period, 875 primary retinal and vitreoretinal surgeries were performed on 875 eyes. Among the surgeries, episcleral sponges (42.9%) formed the largest part, followed by pars plana vitrectomies (35.0%) and encircling bands (22.2%). Combining episcleral sponges and encircling bands into an episcleral surgery group revealed that two thirds (65%) of the surgeries were episcleral interventions. In the episcleral sponge group, the retinal re-detachment rate after the first surgery was 13%. CONCLUSION: In a university department as a primary referral unit for retinal detachments, episcleral retinal surgery can still outnumber vitreoretinal interventions, with retinal re-detachment rates which do not differ markedly from the re-detachment rates reported in randomized trials comparing vitreoretinal surgery with episcleral surgery. PMID- 26016066 TI - IgG4-related Mikulicz's disease associated with thyroiditis: a case report and review of the literature. AB - PURPOSE: To report an unusual case of IgG4-related Mikulicz's disease associated with thyroiditis. CASE REPORT: We describe a 25-year-old Chinese man who presented with bilateral, painless swellings of the lachrymal glands, parotid glands, and thyroid nodules. The patient underwent left-sided dacryoadenectomy and the diagnosis of IgG4-related Mikulicz's disease was pathologically confirmed. The size of the right-sided lachrymal gland and parotid glands recovered fundamentally after one month of glucocorticoid therapy. CONCLUSION: IgG4-related Mikulicz's disease associated with thyroiditis should be considered in the differential diagnosis of bilateral swellings of lachrymal glands, salivary glands, and thyroid nodules. Surgical excision is recommended in order to treat the tumor and to ensure the pathological diagnosis. Glucocorticoid therapy should be considered in association with surgery after removal. PMID- 26016068 TI - Coordination skills during vitrectomy in treatment of proliferative diabetic retinopathy. AB - PURPOSE: To discuss effective nursing and coordination skills for vitrectomy in the treatment of diabetic retinopathy. METHODS: Fifty patients (51 eyes) with diabetic retinopathy required vitrectomy were enrolled in this study. Individual nursing service was delivered by strengthening preoperative preparation, providing psychological nursing, and intraoperative observation of the severity of diseases by circulating nurses; meticulous nursing was given postoperatively. RESULTS: All 50 patients underwent surgery successfully. Intraoperatively, patients had stable physical signs. Five patients had postoperative visual acuity < 0.05, 14 with 0.05 to 0.1, 20 with 0.1 to 0.3 and 16 with > 0.3. No complicated infection was seen. CONCLUSION: For patients diagnosed with proliferative diabetic retinopathy requiring vitrectomy, full preparations should be made and psychological nursing should be delivered preoperatively, the severity of diseases and clinical reactions should be closely observed intraoperatively, and proper processing and nursing measures should be taken postoperatively, which collectively enhance surgical success rate, decrease surgical complications, and attain favorable treatment efficacy. PMID- 26016069 TI - Short-term ocular toxicity and eye irritation tests following application of sufentanil in rabbits. AB - PURPOSE: To test the safe clinical application of sufentanil as topical ophthalmic drops by examining treated rabbit eyes for ophthalmic irritation signs or short-time toxic reactions. METHODS: Twenty-four rabbits were randomly divided into 8 groups (n = 3): The ocular toxicity at 14 d after eye drop ad- ministration was evaluated in groups 1 to 4, and at 30 d post- administration in groups 5 to 8. Groups 1 and 5 were treated with blank vehicle and served as normal controls. The left eyes of rabbits in groups 2 and 6 were exposed to low dose sufentanil.(5 MUg, 2 drops within 5 min), groups 3 and 7 received moderate dose sufentanil (7.5 MUg, 3 drops within 10 min), and groups 4 and 8 received high-dose sufentanil.(10 MUg, 4 drops within 15 min). As self-controls, the right eyes of each rabbit were administered an equivalent amount of sodium chloride (9 g/L) at the same drop intervals. At 14 and 30 d after exposure to sufentanil, ophthalmic irritation signs were evaluated and corneas were stained with fluorescein and observed by slit-lamp microscopy. Corneal endothelial counts were performed and toxic reactions were evaluated. RESULTS: Multiple parameters were compared in the control and experimental groups by visual inspection and slit lamp examination at 14 and 30 d after sufentanil administration. No evidence of irritation signs (including corneal opacity, conjunctival congestion, or edema), eye secretions, iris abnormalities, or temporal eye closure were noted. Corneal en- dothelial cell counts did not significantly differ between the control and experimental groups. Light microscopy revealed no pathological or morphological injury to the cornea, conjunctiva, iris, ciliary body, retina, or optic nerve in either group. The same observation outcomes were noted at 14 and 30 d after administration. CONCLUSION: Single ocular administration of sufentanil at a dose of 5-10 MUg in rabbits yields no ocular irritation or toxic responses at 14 or 30 d following eye drop delivery. PMID- 26016070 TI - Toric intraocular lens vs. peripheral corneal relaxing inci- sions to correct astigmatism in eyes undergoing cataract surgery. AB - PURPOSE: To compare toric intraocular lens implantation (Toric-IOL) with peripheral corneal relaxing incisions (PCRIs) for astigmatism correction in patients undergoing cataract surgery. METHODS: 54 patients (54 eyes) with more than 0.75 diopter (D) of preexisting corneal astigmatism were classified as group A (0.75-1.50D) or group B (1.75-2.50D). The patients were randomized to undergo Toric-IOL or PCRIs in the steep axis with spherical IOL implantation. LogMAR uncorrected visual acuity (LogMAR UCVA), LogMAR best corrected visual acuity (LogMAR BCVA), error of vector (|EV|), surgery induced refraction correction (|SIRC|), and correction rates (CR) were measured 1 month and 6 months postoperatively. RESULTS: At 6 months postoperatively, all 54 eyes had LogMAR BCVA <= 0.2. Patients who underwent PCRIs and Toric-IOL with LogMAR BCVA <= 0.1 showed no significant differences in group A (P = 1.00) or in group B (P = 0.59). Group A showed no significant differences in LogMAR UCVA (P = 0.70), |EV| (P = 0.13), |SIRC| (P = 0.71), and CR (P = 0.56) in patients underwent PCRIs and Toric IOL. However, group B showed significant differences in LogMAR UCVA (P < 0.01), |EV| (P < 0.01)), |SIRC| (P < 0.01), and CR (P < 0.01). The LogMAR UCVA and |EV| between 1 and 6 months showed no significant differences in patients in group A. However, in group B, they are significant differences. CONCLUSION: The efficacy and stability of Toric-IOL and PCRIs were equal in low astigmatic patients. Toric IOL achieved an enhanced effect over PCRIs in higher astigmatic patients. PCRIs had the more refractive regression than Toric-IOL in 6 months. PMID- 26016071 TI - Evaluation of tear malate dehydrogenase 2 in mild dry eye disease. AB - PURPOSE: To evaluate the effect of tear malate dehydrogenase 2 on monitoring ocular surface injury in mild dry eye (DE) disease. METHODS: A total of 15 DE patients (30 eyes) with mild subjective symptoms but no ocular surface fluorescein staining signs were enrolled in this study (DE group). The control group was 15 healthy age- and sex-matched volunteers (30 eyes). All subjects were asked to fill out a DE symptoms questionnaire and take different tests including tear MDH and MDH2 activities evaluation, tear breakup time (TBUT), Schirmer I, and slit-lamp examination of the ocular surface. We investigated different changes in tear MDH and MDH2 activities in the DE group and control group, discussed the association between tear MDH2 activity and DE symptoms, and the relationship between tear MDH2 activity and diagnostic tests (Schirmer I and TBUT). We also analyzed the changes in tear MDH2 activities after the treatment with artificial tears. RESULTS: Tear MDH activities in the DE group and control group were 288 +/- 102 U/L and 259 +/- 112 U/L, respectively, and this difference was not statistically significant (P > 0.05). The tear MDH2 activities in DE group were significantly increased compared with control group. Tear MDH2 was significantly and negatively correlated with the Schirmer's value (r = -0.733, P < 0.01) and the TBUT value (r = -0.841, P < 0.01). MDH2 also had a significant positive correlation with soreness symptoms (r = 0.687, P < 0.01). Treatment with artificial tears relieved or eliminated all discomfort symptoms, together with a considerable decrease in MDH2 activities (P < 0.01), but no significant changes in the Schirmer and the TBUT tests were observed. CONCLUSION: Tear MDH2 activity can indicate ocular surface injury in mild DE patients and may be used to monitor the response to therapy. PMID- 26016072 TI - Clinical efficacy of toric orthokeratology in myopic adolescent with moderate to high astigmatism. AB - PURPOSE: To observe the efficacy of toric design orthokera- tology (ortho-k) for correcting myopia and astigmatism in myopic adolescents with moderate to high astigmatism. METHODS: This was a self-controlled clinical study. Twenty-four subjects (42 eyes) aged 9 to 16 years with myopia of 2.50-6.00 D complicated with rule astigmatism of 1.50-3.50 D were fitted with Lucid Night Toric Ortho-k Lenses (LUCID,KO- REA). The changes in uncorrected visual acuity (UCVA), spherical degree, refraction, axial length (AL), and corneal status were assessed at baseline, 1 night, 1 week, 1 month, 3 months, 6 months, and 1 year after the commencement of ortho-k lens wear. RESULTS: The success rate of the first lens fit was 92.8%. The UCVA after ortho-k wearing was improved significantly compared to the baseline during each visit (all P < 0.01), and became stable 1 month after ortho-k. The manifest myopia was significantly reduced from (-3.41 +/- 1.27) D to (-0.41 +/- 0.37) D by toric ortho-k and the degree of astigmatism from (-1.81 +/- 0.53)D to (-0.41 +/- 0.39) D after 1 month of lens wear (P < 0.01). The mean AL was (24.47 +/- 0.91) mm at baseline, which did not significantly differ from (24.49 +/- 0.87) mm and (24.48 +/- 0.94) mm after 6 months and 1 year, respectively, of lens wear (both P > 0.05). Grade 1 corneal staining was observed at 1 week (23.8%), 1 month (21.4%), and 1 year (16.7%) following lens wear, and was improved by lens cleaning, discontinuing lens wear, and moistening the cornea with eye drops. No severe adverse events were reported. CONCLUSION: The toric ortho-k lens was effective and safe for correction of low to moderate myopia in children with moderate to high astigmatism. The lens also effectively controlled axial length elongation during 1 year of observation. However, the long-term efficacy remains to be elucidated. PMID- 26016073 TI - Effect of Avastin on the migration and invasion of pterygium fibroblasts. AB - PURPOSE: To evaluate the effect of Avastin on human pterygium fibroblast migration and invasiveness. METHODS: VEGF secretion was compared between human pterygium fibroblasts and conjunctival fibroblasts by measuring VEGF-A by ELISA. The influence of Avastin on HPF migration and invasiveness was observed by wound scratch and Transwell migration assays. The expression of p-ERK1/2 and p-FAK was analyzed by western blotting. RESULTS: (1)VEGF was secreted in higher amounts by human pterygium fibroblasts than by conjunctival fibroblasts. (2) Avastin treatment decreased HPF migration and invasion. (3) Avastin significantly decreased the expression of p-ERK1/2 and p-FAK in human pterygium fibroblasts. CONCLUSION: Avastin can inhibit migration and invasion of HPFs by decreasing the expression of p-ERK1/2 and p-FAK. PMID- 26016074 TI - Comparison of the mydriatic effects of mydrin-P and compound tropicamide in the screening of retinopathy of prematurity. AB - PURPOSE: To observe and compare the effects of pupil dilation between Mydrin-P and compound tropicamide in the screening of retinopathy of prematurity. METHODS: The right eyes of premature infants received My- drin-P eye drops as the treatment group, whereas the left eyes were administered with compound tropicamide as the control group. The eye drops were delivered every 5 min for three times. The pupil size was observed and recorded at 10, 15, and 20 min after administering mydriasis. RESULTS: The mean pupil diameter did not significantly differ between the treatment and control groups at 10 (6.24 +/- 0.72 mm vs. 6.24 +/- 0.68 mm, t = 0.00, P = 1.00), 15 (6.83 +/- 0.55 mm vs. 6.78 +/- 0.54 mm, t = 1.75, P = 0.083) or 20 min (7.22 +/- 0.40 mm vs. 7.15 +/- 0.50 mm, t = 1.62, P = 0.109), respectively. How- ever, the mean pupil size at any two time points significantly differed in both groups (all P < 0.001). CONCLUSION: Both Mydrin-P and compound tropicamide exert similar clinical efficacy in the screening of retinopathy of pre- maturity. The most appropriate time for screening was at 20 min after mydriasis. PMID- 26016075 TI - Image features of retinal astrocytic hamartoma in a patient with tuberous sclerosis complex. AB - PURPOSE: To describe the image features of retinal astrocytic hamartoma in a 35 year-old male patient with tuberous sclerosis complex (TSC). METHODS: Fundus photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), and spectral domain optical coherence tomography (SD-OCT) were performed for this retinal astrocytic hamartoma. RESULTS: Fundus photography showed that the retinal astrocytic hamartoma presented as a well-circumscribed, mulberry-like lesion consisting of glistening yellowish spherules of calcification. FAF demonstrated dense hyper-autofluorescence spots corresponding to retinal astrocytic hamartoma. FFA revealed leakage from dilated retinal capillaries over the hamartoma. SD-OCT indicated moth-eaten optically empty spaces and hyperreflective dots within the lesion. The lesion surface was fluctuate. CONCLUSION: FAF is a useful imaging modality for obtaining greater contrast between a retinal astrocytic hamartoma and the surrounding retina due to hyper-autofluorescence of calcification in the lesion. FFA is beneficial for monitoring the abnormal blood vessels in these lesions. SD-OCT is capable of visualization the structural details, such as the uneven surface and inner hyperreflective dots. PMID- 26016076 TI - Study of problems arising during perioperative care of postoperative endophthalmitis. AB - PURPOSE: To discuss the problems in perioperative nursing care for patients with postoperative infectious endophthalmitis. METHODS: The medical records of 34 patients (35 eyes) presenting with infectious endophthalmitis at Zhongshan Ophthalmic Center, Sun Yat-sen University between April 2002 and December 2013 were collected to analyze preoperative and postoperative nursing care for endophthalmitis after ocular surgery. RESULTS: Thirty-four patients (35 eyes) developed complications of infectious endophthalmitis after surgery. Thirty-three cases were successfully cured and only one patient (1 eye) was untreated due to Pseudomonas aeruginosa infection. CONCLUSION: Perioperative nursing care plays a pivotal role in preventing and controlling the incidence and development of postoperative infectious endophthalmitis. PMID- 26016077 TI - Surgical cooperation during implantation of a Boston type-I keratoprosthesis. AB - This study was designed to summarize the key points of surgical cooperation involving penetrating corneal transplantation combined with implantation of keratoprosthesis. Preoperative preparation and intraoperative procedures were fully implemented to ensure cooperation with the physicians, to observe the the severity of the disease, and to guarantee the success of the surgery. PMID- 26016078 TI - Pattern of refractive correction and timing of stage II IOL implantation after congenital cataract extraction. AB - Congenital cataract occurs during infancy when the axial length and corneal and visual function are in the sensitive stages of rapid development. Inappropriate surgical intervention not only fails to restore visual function, but also causes irreversible serious influences upon eyeball development in children diagnosed with congenital cataract. At present, the uncertainty of selection of intraocular lens (IOL) degrees during the eyeball development period is averted by using a main treatment of congenital cataract that includes two-stage surgery: stage I cataract extraction and stage II IOL implantation. However, the accurate selection of a refractive correction method and the timing of IOL implantation during stage II surgery for aphakic eyes remains controversial following stage I cataract extraction. This review retrospectively summarizes the current progress and existing problems indicated by related recent studies focusing on refractive correction pattern and IOL implantation timing. PMID- 26016079 TI - "Recognise crucial role nurses play in the NHS". PMID- 26016080 TI - Dip in number of ward nurses. PMID- 26016081 TI - Nurses "must support each other". PMID- 26016082 TI - Hospital Skypes Philippines in hunt for nurses. PMID- 26016083 TI - "Desperation" to fill posts pushes overseas registrations up by 45%. PMID- 26016084 TI - Staff pinch at London trust exposed. PMID- 26016085 TI - Labour admits "difficult choices" lie ahead over pay post-election. PMID- 26016086 TI - End-of-life care inadequate, say nine in 10 nurses. PMID- 26016087 TI - Second strike planned in dispute over wages. PMID- 26016088 TI - Practice nurses "need" mental health training. PMID- 26016089 TI - Most staff in care homes would welcome cameras, survey finds. PMID- 26016090 TI - Call to monitor staff pay levels in care homes. PMID- 26016091 TI - "Proper support is needed for all if we are to learn from errors". PMID- 26016092 TI - "Does it really need to be so tough to become a nurse?". PMID- 26016093 TI - Implementing the Friends and Family Test. AB - This article discusses the background to the Friends and Family Test, highlighting the commitment to improve the patient experience. It also demonstrates how patient feedback was used to improve services in Aintree University Hospital Foundation Trust. PMID- 26016094 TI - A new role to improve mentorship standards. AB - Practice education facilitators at a large health board in Wales have developed a lead mentor role for existing mentors who demonstrate positive role modelling. Lead mentors' responsibilities include supporting mentors and identifying their development needs. A study day for lead mentors was positively evaluated and pre registration students have provided positive post-practice evaluation. Leadership and constructive teamwork have a positive effect on patient outcomes, and developing existing mentors is one way of achieving this. PMID- 26016095 TI - PEG tubes: dealing with complications. AB - A percutaneous endoscopic gastronomy tube can be used to deliver nutrition, hydration and medicines directly into the patient's stomach. Patients will require a tube if they are unable to swallow safely, putting them at risk of aspiration of food, drink and medicines into their lungs. It is vital that nurses are aware of the complications that may arise when caring for a patient with a PEG tube. It is equally important that nurses know how to deal with these complications or from where tc seek advice. This article provides a quick troubleshooting guide to help nurses deal with complications that can arise with PEG feeding. PMID- 26016096 TI - Valuing patient and public involvement in research. AB - Patient and public involvement is now mandatory in funding applications for most health sciences research. This article offers a snapshot of views from patients and the public on their role in the research process. PMID- 26016098 TI - We are the champions. PMID- 26016097 TI - 60 seconds with Jo Collins. PMID- 26016099 TI - CQC report like "knife in heart". PMID- 26016100 TI - NICE sets out A&E nursing ratios. PMID- 26016101 TI - Nurses sacrifice days off to quell staff pressures. PMID- 26016102 TI - A&E shift worse than "war zone". PMID- 26016103 TI - Charity chiefs offer volunteers to A&E. PMID- 26016104 TI - Roll-out of electronic assessment allows closer student monitoring. PMID- 26016105 TI - Dehydration risk very high in care home residents. PMID- 26016106 TI - E-learning answer to global nurse shortage. PMID- 26016107 TI - Nurse develops hygiene-tracking technology. PMID- 26016108 TI - NMC proposes end to time limits for completion of nurse training. PMID- 26016109 TI - Trust tempts HCAs into nursing courses with paid work. PMID- 26016111 TI - "Health professionals can help create a more tolerant society". PMID- 26016110 TI - NMC hits six month referral to hearing target. PMID- 26016112 TI - "Nurses have a major role in making every contact count". PMID- 26016113 TI - The role of nurse leaders in improving health. AB - Premature deaths could be avoided and NHS resources saved if healthcare staff provided more effective support for people to improve health-related behaviour. All healthcare staff can deliver very brief interventions, which have been proved to have a positive effect. Nurse leaders play a vital role in helping frontline staff deliver behaviour change interventions, and in ensuring support is available for staff to stay healthy. This article--the first in a two-part series -outlines the action nurse leaders need to take. Part 2 (to be published next week) focuses on the role of frontline staff in integrating behaviour change interventions into their clinical work. PMID- 26016114 TI - Discussing CPR near the end of life. AB - Cardiopulmonary resuscitation can save a life, but is invasive and traumatic. Leaving people in the "default" position of receiving CPR if they go into cardiorespiratory arrest can result in treatment that is unwanted or offers no benefit. Updated guidance by the British Medical Association, the Resuscitation Council (UK) and the Royal College of Nursing states that good clinical practice includes making advanced individualised CPR decisions for people who are near the end of life or at risk of cardiorespiratory arrest. Staff should involve patients and/or their loved ones in the.decision-making process to reduce the risk of administering unwanted treatment. PMID- 26016115 TI - Starting end-of-life conversations in hospital. AB - The Conversation Project, part of The King's Fund/The Health Foundation Patient and Family-centred Care programme, aims to encourage health professionals to identify when patients are approaching the end of their lives and to ensure this is addressed in decision making and discussions. The project team explored the experience of staff based on a ward caring for older people. They found staff sometimes found it difficult to initiate end-of-life conversations and, therefore, to make patient-centred care plans. A development and support programme has improved staff confidence and resulted in more documented planning and discussion about the end of life. PMID- 26016116 TI - Protecting children from sexual exploitation. AB - Child sexual exploitation has been a largely hidden but significant issue for many years. Nurses need to be aware of its effects on health so they can identify children and young people affected and work with colleagues from other disciplines and agencies to provide treatment and care. PMID- 26016117 TI - 60 seconds with Mary Haight. PMID- 26016119 TI - New year, so let's look at the old you. PMID- 26016118 TI - Everyone is a change agent. PMID- 26016120 TI - Community care needs "big push". PMID- 26016121 TI - More student specialisms mooted. PMID- 26016122 TI - Compassion in Practice Awards winners announced. PMID- 26016123 TI - Managers told to prepare staff for revalidation. PMID- 26016124 TI - Tackling shortfall of 30,000 nurses requires drastic action. PMID- 26016125 TI - CNO calls for more BME nurse leaders. PMID- 26016126 TI - High death rate on shifts is not only "angel of death" indicator. PMID- 26016127 TI - Stroke nursing shortage is "worrying". PMID- 26016128 TI - "Time for talk is over" on need to react to Winterbourne View. PMID- 26016129 TI - Nurse-led project prepares children for adult services. PMID- 26016130 TI - "Recognise the health of children is crucial to our nation's future". PMID- 26016131 TI - "People who acquire disability may grieve their loss forever". PMID- 26016132 TI - Meeting deaf patients' communication needs. AB - Effective communication between nurses and patients is a vital part of safe and effective nursing care. However, few health professionals receive training in how to communicate with Deaf people; as a result, attempts to communicate with Deaf patients is often inappropriate and undertaken without knowledge or understanding of their communication needs. This article examines the literature on ways in which Deaf patients experience communicating with, and receive care from, nurses. PMID- 26016133 TI - Why do health workers decline flu vaccination? AB - Healthcare workers with influenza can easily pass on the flu virus to patients. Last year nurses (excluding those in GP practices) were the group least likely in the NHS to be vaccinated. This article explores the reasons for this and explains how NHS Employers' annual flu fighter campaign can improve uptake. PMID- 26016134 TI - Factors influencing glove use in student nurses. AB - BACKGROUND: Gloves can prevent infection but their use among student nurses is inconsistent. AIM: To explore pre-registration student nurses' views of non sterile glove use in clinical practice. METHOD: An online survey was conducted and focus groups carried out among third-year student nurses. RESULTS: The online survey showed that gloves were often worn inappropriately, while the focus groups revealed students conformed to their mentors' use of gloves. DISCUSSION: Student nurses' decisions on wearing gloves seem to be based on the culture of the clinical care environment rather than trust policy. Glove overuse deprives patients of therapeutic touch and may lead to contact dermatitis in nurses. CONCLUSION: All student nurses must be able to identify clinical situations when gloves are not indicated, using appropriate risk assessment. PMID- 26016137 TI - 60 seconds with Debra Moore. PMID- 26016135 TI - Embedding the 6Cs across health and social care. AB - The 6Cs were developed in 2012 against a backdrop of concerns about standards of nursing care in England. Over the last two years they have also been adopted by professionals and organisations outside of nursing. This article describes, and provides examples of, how the values of the 6Cs are becoming embedded across health and social care. PMID- 26016138 TI - [Radiotherapy for local recurrences of prostate cancer after radical prostatectomy]. AB - Basic and universally accepted method of treatment of local recurrence is local radiotherapy. The most researchers tend to favor of the early start of radiotherapy: PSA no more than 0.5-1.0 ng/ml, until manifestation of signs clinical recurrence of disease as well as in terms of PSA doubling for at least 6 months. Morphological verification of recurrence is not a necessary condition for the administration of radiotherapy. In cases of impossibility of verification or its negative result, it should focus primarily on the dynamics of PSA and data of instrumental examination. Standard methods remote radiotherapy (3D-conformal radiotherapy, intensity modulated radiation therapy--IMRT) can be successfully used in these patients at ODS 66-70 Gy, with the escalation of SOD 70 g more justified in a limited category of patients. Joining of hormone therapy in neoadjuvant and parallel with radiotherapy modes did not show significant improvement in disease-free survival rates however in certain categories of patients had advantages. PMID- 26016139 TI - [Radionuclide therapy for bone metastases: new opportunities]. AB - Treatment of patients with multiple bone metastases accompanied by pain syndrome is a complicated clinical task. Radionuclide therapy is one of its solutions, which is used to achieve long reduction of pain syndrome and significant improvement the quality of patients' life. However mechanism of action of bone seeking radiopharmaceuticals suggests not only pain control but antitumor effect as well. In early clinical studies of safety and efficacy of the most common bone seeking radiopharmaceuticals in single administration there were not any preferences in overall survival but individual clinical cases with extraordinary tumor regression after radionuclide therapy were reported. Repeated bone targeted therapy and combination with other treatment modalities can help to gain statistical significant increase in overall survival of patients. PMID- 26016140 TI - [Training of medical physicists in radiation therapy at the International Educational Center of the Association of Medical Physicists in Russia]. AB - The efficiency of radiotherapy treatment for cancer patients and use of the state of-the-art accelerator facilities, in the first place, depends on the qualification and number of medical physicists. The need for the training and continuing professional development (CPD) of medical radiation physicists in Russia and CIS countries has dramatically increased today. The article considers the system of refresher training which should provide the continuing professional development and advance training of medical radiation physicists. The authors analyze the experience of the International Educational Center of the Association of Medical Physicists in Russia involved in the CPD of medical physicists under the IAEA TC projects, RMAPO and N.N. Blokhin RCRC joint educational programs. PMID- 26016141 TI - [Analysis of predictors influencing the results of the combined treatment for anaplastic astrocytomas (grade III) of the brain]. AB - In our study the analysis of significant predictors affecting the results of treatment of anaplastic astrocytoma brain (grade III) is showed. According to our data to assess the effectiveness of special treatment of these patients is possible with such clearly defined predictors such as age, volume of surgery, initial tumor size and functional status (the Karnofsky index). The study demonstrates that in patients who underwent radiotherapy using single focal dose of 3 Gy overall survivals was comparable with the group of patients who underwent radiation therapy using small dose fractionation. The use of adjuvant chemoradiotherapy in patients with grade III glioma does not increase overall survival rate compared with patients who received only adjuvant radiotherapy. PMID- 26016142 TI - [The role of systemic radiotherapy in the combined treatment for hormone resistant prostate cancer]. AB - To relieve pain associated with multiple bone metastases radiopharmaceutical method of treatment is of great importance--the use of beta-emission isotope of strontium chloride-89 (metastron). Passing through the human skeletal system, strontium-89 accumulates in areas of high mineral density, which is it typical for osteoblastic metastases. In our institution in the frames of a randomized trial in 90 patients with metastatic hormone-resistant prostate cancer it was carried out systemic radiotherapy with strontium-89 chloride as a stage of complex treatment. Stabilization of pain syndrome during treatment was 72,7% and its progression was noted in 27,3% cases. Radiopharmaceutical therapy is well tolerated and can be used as a stage in complex treatment of patients with hormone-resistant prostate cancer. PMID- 26016143 TI - [The value of intraluminal brachytherapy in the treatment for esophageal cancer]. AB - To control dysphagia 202 patients with a verified esophageal cancer of stage cT1 4N0-2M0-1 underwent intraluminal brachytherapy with neoadjuvant chemoradiotherapy in the process of combined radiation/chemoradiation therapy and palliative treatment. Duration of event-free period in the group of patients, operated after neoadjuvant chemoradiotherapy was 10,1 +/- 2,7 months, after intraluminal brachytherapy at combined radiation/chemoradiation therapy was 6,2 +/- 2,6 months and at palliative brachytherapy--4,5 +/- 2,0 months. Frequency of complete clinical regressions was 16,7% after neoadjuvant chemoradiotherapy, 19,3% after brachytherapy in the frames of radiation/chemoradiation therapy for esophageal cancer, 15,7% as a result of palliative intraluminal brachytherapy. Complete morphological tumor regression after neoadjuvant chemoradiotherapy using intraluminal brachytherapy was registered in 23,1% patients. PMID- 26016144 TI - [The role of stereotactic radiotherapy in the treatment of patients with liver metastases]. AB - Application of modern linear electron accelerators, equipped with precise navigation systems, maximum conformal dose delivery as well as imaging of irradiated focus significantly increased possibilities of escalating of doses of ionizing radiation in a selected volume with the necessary protection of the surrounding critical structures. These technological solutions and modern ideas about possibilities of remote beam radiation therapy resulted in a significant increase of the role of radiation therapy and, in particular, stereotactic radiotherapy in the treatment of patients with liver metastases. This technique allows creating locally in metastatic tumor site a high dose of ionizing radiation causing by that the destruction of the tumor. This promising direction in treatment of liver metastases significantly expanded possibilities of complex treatment and enabled us to provide specific assistance to those patients who have been rejected from other methods of treatment. PMID- 26016145 TI - [Hodgkin's lymphoma and radiotherapy]. AB - After a median observation time of 4,5 years, 440 patients with Hodgkin's lymphoma stage I-IV to the Ann Arbor classification were treated with radiotherapy (2200 lymph areas) and ABVD (n=204) or BEACOPP (n=117) or CEA/ABVD (lomustine, etoposide, adriamycine, bleomycine, vinblastine and dacarbacine; n=119) regimens in 1995-2012. Correct allocation of groups with "CR or PR >=80%" and "PR: 0-79%", after first-line chemotherapy, is extremely important for following RT planning. Adaptation of patients with Hodgkin's lymphoma can take place only after successful treatment, the probability of relapse and fear of repeated courses strongly interfere with this process, especially in the first years after its closure. Duration of remission period, especially in young people, is no less important than the criteria for overall survival. It is impossible to build recommendations for treatment for Hodgkin's lymphoma, based only on long-term survival rates. Importance of radiotherapy in reducing the number of relapses is undeniable, so the idea that the development of the role of chemotherapy in the treatment of the ray method Hodgkin's lymphoma gradually becomes secondary is in serious doubt. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's lymphoma. PMID- 26016146 TI - [Immediate results of combined therapy for local recurrences of rectal cancer]. AB - The purpose of this paper was to increase the effectiveness of radiation therapy (RT) of local recurrence of rectal cancer (MRRPK) by setting the preferred modes and dynamic medium dose fractionation irradiation MRRPK, assessing immediate outcomes, identifying the frequency and severity of early radiation reactions during radiation therapy. The study included 60 patients with a diagnosis of "local recurrence of rectal cancer." The median age was 67 years. Terms of recurrence after surgical treatment averaged 20 months. The histological structure of the tumor was presented adenocarcinoma in 57 (95%) patients. Radiation therapy (RT) was carried out in medium or dynamic fractionation. Chemotherapy used pelleted 5-fluorouracil. In group 1 (20 patients) received palliative radiotherapy course with a fractional dose of 3 Gy to 42 Gy SOD (SDeq 51 Gy). In group 2 (20 patients) underwent a course of radiotherapy using dynamic dose fractionation: fractional dose--4, 3 and 2 Gy to 51 Gy SDeq. In the third group (20 patients) underwent combined treatment using dynamic dose fractionation: fractional dose--4, 3 and 2 Gy to 56 Gy SDeq and chemotherapy- Xeloda or ftorafur. In group 1 complete regression was achieved in 1 patient, partial regression--15, stabilization--at 3, progression--at 1, that is clinical effect was observed in 19 of 20 patients. In group 2, complete regression of the tumor was diagnosed in 3 patients, partial regression--17, therefore, 100% of patients had received clinical effect. According to follow-up, 5 patients in this group were subsequently. In the third group of complete regression of the tumor was diagnosed in 7 patients, partial regression--13, ie, 100% of patients had received clinical effect. According to follow-up, 7 patients in this group were subsequently operated. Among the radiation reaction in group 1 nausea 1 tbsp. was observed in 3 patients, radiation Recto 1-2 degree--15, radiation epithelitis 1-2 degree--4 patients; in group 2, nausea 1 degree--At 7, radiation Recto 1-2 degree -At 7, radiation epithelitis 1-2 degree--In 6 patients and 6 reactions were observed; in the third group of nausea 1st. was observed in 7 patients, radiation Recto 1-2 degree--At 9, radiation epithelitis 1-2 degree--At 8 and 3 patients reactions were observed. Thus, when irradiated in the dynamic fractionation showed less pronounced dose response as beam during treatment, and after. Increasing the total dose with the addition radiomodification increases the frequency of complete responses with acceptable toxicity. As a result of treatment in all patients achieved a significant reduction in pain, relief of bleeding. PMID- 26016147 TI - [An experience with dose-escalated conformal radiation therapy in hormone radiotherapy for prostate cancer]. AB - This study presents the short-term outcomes of conformal external beam radiation therapy given in conjunction with hormone therapy to 110 patients with prostate cancer. We performed a comparative analysis of the rate and degree of radiation reactions and complications following delivery of a total dose of 70 Gy and 72-76 Gy to the tumor. In prostate cancer, a continuous course of dose-escalated conformal radiation therapy resulted in satisfactory tolerance and acceptable levels of late complications. PMID- 26016148 TI - [Treatment of neoplastic lesions of the central bronchi and trachea using endotracheobronchial surgery, intraluminal brachytherapy, combined radiotherapy and chemoradiotherapy]. AB - There are summarized the foreign and domestic references of recent years devoted to methodology and the efficiency of the use of intraluminal high-dose radiation brachytherapy in patients with lesions of the central bronchi and trachea caused by primary and metastatic malignant tumors. It is presented own experience of applying this method in 207 patients. It is showed that in some patients to ensure the delivery of the radiation source to the area of interest it is advisable to perform firstly endotraheobronhial surgery with recanalization of the lumen of the respiratory pathways. The best is the use of intraluminal brachytherapy with high dose radiation. Palliative intraluminal irradiation of inoperable patients allowed achieving a good immediate results (65-95%), a significant reduction of the main symptoms--hemoptoe (87-95%), dyspnea (75-90%), obstructive pneumonia phenomena (50-85%), and significantly increasing survival median from 1-3 to 9-14 months. Following performance of chemoradiotherapy permitted increasing the survival median up to 15-20 months. The number of complications of intraluminal high-dose radiation brachytherapy was small, usually--pulmonary hemorrhage (2-7%) more likely developing when using large fractions--more than 10 g for 1 session. PMID- 26016149 TI - [Results of surgical and combined treatment for non-small cell lung cancer with postoperative hypofractionated radiotherapy: overall and disease-specific survival]. AB - Compared with surgical treatment the combined treatment of patients with non small cell lung cancer accompanied by post-operative radiotherapy in the mode of hypofractionation from 3 Gy to SOD-36-39 Gy (EQD2 = 43,2-46,8 Gy) allowed statistically significant increasing a 5- and 10-year overall and disease specific survival in patients with metastases to regional lymph nodes (pN1-2). The increase of overall and disease-specific survival was also observed in patients older than 60 years with the worst initial status (70-80 by the Karnofsky scale), II stage of disease, peripheral cancer and adenocarcinoma however for these groups survival differences did not reach a statistically significant level. The presented method of postoperative irradiation did not have severe toxicity and did not lead to a decrease in survival of elderly and functionally debilitated patients. PMID- 26016150 TI - [Radiosensitivity of bone metastases from tumors in different primary sites]. AB - The purpose of the current clinical trial was to evaluate efficiency of palliative external beam radiotherapy for symptomatic bone metastases from different primary tumors. The randomized study included 427 patients, treated for 616 sites of bone lesions. Breast was the primary site in 67,5% of cases, prostate and lung--in 7,5% each, renal--in 5,5%, other tumors--in 12%. The most frequent treatment site was the spine--47,8%, followed by pelvis--30,8%, long bones--14,4%, sacrum--2,9% and other sites--4%. The main indication for irradiation was pain not alleviated by systematic drug therapy. Radiotherapy protocol included 3 hypofractionation regimes with total dose of 26 Gy, 19,5 Gy and 13 Gy by 3, 4 and 2 fractions of 6,5 Gy correspondingly and standard treatment schedule with total dose of 26 Gy. The average follow-up period was 56 months. General pain relief (complete and partial) was observed in 96,1% of sites and was independent of primary tumor, metastases localization and irradiation schedules. Complete response rate (CRR) was higher for bone metastases form breast and prostate cancer 64,2% and 58,7% correspondingly in comparison with lung and renal cancer--43,5% and 26,5% respectively (p<0,05). At small number of observations metastases from melanoma and sarcomas proved high radiosensitivity with CRR 75% and 66,7% correspondingly. CRR for spine and pelvis localization of metastases was similar--63,4% and 59,3%, slightly lower for long bones--48,3% and significantly lower for sacrum isolated metastases--27,8% (p<0,05). CRR was higher for standard treatment schedule and significantly increased for 2, 3 and 4 fractions of 6,5 Gy correspondingly (p<0,03). In the multifactorial analysis tumor primary site and pain intensity before radiotherapy were the only independent prognostic factors of CRR. Therefore histogenesis of primary tumor is a predictor of radiosensitivity of bone metastases, it significantly affects the complete pain response rate. It is expedient to use hypofractionation regimes of 3 fractions of 6,5 Gy (total dose 19,5 Gy) for palliative radiotherapy of bone metastases in case of breast, prostate cancer, sarcomas and melanoma and 4 fractions of 6,5 Gy (total dose 26 Gy) in case of lung and renal cancer. PMID- 26016151 TI - [Results of combined and complex treatment for indolent and aggressive non Hodgkin lymphoma of the stomach]. AB - There were retrospectively assessed long-term outcomes of 125 patients with primary non-Hodgkin's lymphoma of the stomach (indolent--50, aggressive--75) using different programs of combined and complex treatment. The immediate results of the treatment in the group of indolent lymphomas were: complete remission 39 (78%), partial remission 7 (14%), the stabilization 3 (6%), progression 1 (2%) while in the group of aggressive lymphomas: complete remission 56 (74.7%), partial remission 8 (10.7%), without effect 3 (4%) and progression 8 (10.7%). It was revealed that primary indolent lymphomas of the stomach the efficiency of complex treatment is comparable to the efficiency of local methods of treatment (surgery, radiotherapy or its combination). The combination of chemotherapy and local methods of treatment gave better results compared with chemotherapy (a 5 year overall survival is 100% and 72% respectively). In the group of aggressive lymphomas the best rates in all types of survival were demonstrated by the subgroup of complex treatment as compared with the subgroup of local methods of treatment especially in terms of overall survival (100% and 65% respectively), and as compared with the subgroup where only chemotherapy was conducted, particularly in terms of disease-free survival (100% and 40% respectively). As an adjuvant therapy after surgical treatment it was preferable to use chemotherapy because such treatment program demonstrated the best rates of overall survival, which reached 92% on a 5-year and a 10-year milestone. PMID- 26016152 TI - [Prognostic value of clinical and morphological characteristics in radiation and combined treatment for tongue cancer]. AB - It is now possible to identify several key factors that determine biological characteristics of squamous cell cancer of the head and neck: genes p53, p16, cyclin D1, P13-K/Akt connected with metastasis proteins (proteases, proteins mesenchymal cells, cell adhesion molecules chemokines), angiogenesis factors (VEGF, PDGF, FGF, TGF-alpha and TGF-beta), IL-8; epidermal growth factor receptors. An important role of tumor cells plays microenvironment. Of course the above mentioned is only a small part of the factors that determine the livelihoods and the activity of cancer cells. All of these factors are potential predictors of the effectiveness of radiation and chemoradiation treatment and actively studied in recent decades. PMID- 26016153 TI - [The role of radiotherapy in chemoradiation treatment for nodal diffuse large B cell non-Hodgkin lymphoma]. AB - There is presented clinical observation of 125 patients with primary non-Hodgkin lymphomas stage I-IV (90 patients with diffuse large B-cell and 35 patients with primary mediastinal large B-cell lymphoma) treated with chemoradiotherapy. Radiotherapy was carried out in condition of conventional (60 patients) or multifractionation (65 patients). 75 (60.0%) patients underwent positron emission tomography with 18F-FDG of the whole body (130) in different periods of the clinical course of the disease. In addition patients with diffuse large B-cell lymphoma were monitored by main indicators of peripheral blood before and at different stages of treatment. It was found that after a period of drug treatment radiotherapy increased the frequency of complete remissions in patients with diffuse large B-cell and primary mediastinal large B-cell lymphoma by 24.4% and 44.2%, respectively, contributing to satisfactory long-term results. Fractionation regime did not significantly affect the results of treatment but radiation pneumonitis was observed only in the normal dose fractionation. Positron emission tomography with 18F-FDG in this category of patients was of great importance specifying the spread of the tumor. The frequency of complete metabolic response significantly increased after radiotherapy compared to drug treatment stage. Reduction of hematological parameters after radiotherapy in patients with diffuse large B-cell lymphoma was mostly of I-II degree and did not interfere with treatment. Leukopenia, neutropenia and thrombocytopenia were more significant when irradiation was performed two times a day compared to those in condition of conventional fractionation. PMID- 26016154 TI - [Middle fraction radiotherapy for non-small cell lung cancer. Effect of increasing the total focal dose]. AB - There were evaluated retrospectively the immediate and long-term results of radiotherapy in 259 patients with non-small cell lung cancer stages I-IV who had contraindications to surgery. Irradiation was carried out by middle fraction with single focal dose 3-4 Gr. We compared the results of treatment in two groups of patients differed in volume of total focal dose: I group (124 patients)--45 Gy, II group (125 patients)--60 Gy. An increase of total focal dose from 45 Gy to 60 Gy did not lead to an increase of the toxicity to vital organs including patients older than 60 years and patients with initially poorer somatic status. Disease free survival significantly increased in total in the group with total focal dose 60 Gy and predominantly in tumors over 5 cm, in patients with ECOG 2-3 and in III IV stage disease. An increase of total focal dose to 60 Gy in the group was significantly prolonged survival without local recurrences from 37% to 50% and by one-third reduced the frequency of locoregional recurrences. Identified benefits in overall and disease-specific survival the groups of non-small cell lung cancer patients with total focal dose 60 Gy compared with a group of non-small cell lung cancer patients who received radiotherapy in total focal dose 45 Gy at terms more than 5 years did not reach statistical significance. PMID- 26016155 TI - [The role of radiotherapy in the treatment for stage-IV Hodgkin lymphoma]. AB - The study included 140 patients with Hodgkin's lymphoma stage IV. 90 patients were exposed to chemoradiotherapy. Only chemotherapy was carried out in 50 cases. Overall survival of patients, undergone only chemotherapy, was 55% by a five-year term and 49% by a ten-year term, disease-free survival was equal to 38% as after five and ten years of observation and treatment failure-free survival--37%. Survival of patients, in the treatment program of whom after 4 or more cycles of chemotherapy combined with irradiation, including all extranodal lesions, was the best: a five-year and ten-year overall survival reached 80%, disease-free survival--70 and 61%, failure-free survival--59% and 51% respectively. Irradiation of foci of extranodal lesions after 4 or more cycles of chemotherapy resulted in a significant increase of rates of overall survival and disease-free survival regardless the presence or absence of adverse prognostic factors. Expansion of irradiation in patients with Hodgkin's lymphoma stage IV does not lead to an increase of rates of overall, disease-free and failure-free survival. PMID- 26016156 TI - [Radiation pneumonitis in the treatment of early-stage breast cancer]. AB - Despite of improvement of radiotherapy techniques and increasing usage of conformal radiation therapy which provides decrease of dose for normal tissues and organs, cases of radiation-induced injuries are still registrated. The aim of this study is to determine frequency and severity of lung toxicity in 513 breast cancer patients with Tis-2N0-2M0 disease after breast conserving surgery and chemotherapy depending from radiation therapy technique and irradiation volume. It is quite clear that in breast cancer patients frequency of lung toxicity after breast conserving surgery and RT increases from 20-24% when irradiating only breast to 37-41% when irradiating breast and regional lymph nodes. In our analysis the frequency of lung toxicity was quite similar for 2D conventional therapy (27,4%) and for 3D conformal therapy (28,7%). The risk of developing radiation pneumonitis increases dramatically with extension of V20 for ipsilateral lung more than 30%, mean lung dose more than 18 Gy, in patients with initial small volume of the lung (less than 110 cm3). PMID- 26016157 TI - [Possibilities of stereotactic radiotherapy in the palliative treatment of patients with pancreatic cancer]. AB - Morbidity and mortality from pancreatic cancer is steadily increasing. Resectable cases are not more than 20%. Conventional schemes of chemoradiation and radiation therapy are durable over the time, have toxicity and low treatment outcomes. Many foreign authors consider as promising the technique of stereotactic radiotherapy, which is often used in pancreatic cancer and permit achieving high local control. At our institution there has been developed and introduced into clinical practice a method of stereotactic radiotherapy for the palliative treatment of patients with pancreatic cancer, which improved not only the duration but also the quality of life of patients. PMID- 26016158 TI - [Prognostic value of hemoglobin concentration in the course of chemoradiotherapy of patients with oropharyngeal squamous cell carcinoma]. AB - There was performed a comparative analysis of the indicators of immediate and long-term results of chemoradiotherapy in 342 patients with squamous cell oropharyngeal carcinoma depending on hemoglobin level before and after treatment. In patients with normal level of hemoglobin a rate of response to treatment was almost two times higher than that of patients with anemia (75,3% vs. 23,5%) and complete regression of tumors was detected by more than three times often (65,4% vs. 17,6%). The overall five-year survival of patients with anemia was significantly worse than that of patients who had normal hemoglobin level (50,7% vs. 67,7%). Patients who had normal hemoglobin level at the time of discharge demonstrated a five-year overall survival of 75,7%, while those with a hemoglobin level below normal, but more than 80 g/l,--only 57,8%. Hemoglobin concentration was a significant prognostic factor for survival of patients with squamous cell carcinoma of the oral cavity and oropharynx. Low baseline of hemoglobin was also a negative prognostic factor for tumor response to treatment, especially to chemotherapy. PMID- 26016159 TI - [High-dose brachytherapy for prostate cancer in real time using 192-IR (specifics of dosimetric planning)]. AB - There were analyzed dosimetric plans obtained during the first session of HDR brachytherapy in 70 primary prostate cancer patients. Assessments were subjected to dosimetric parameters (V100, D90, D2cc, D10) obtained after implantation in the prostate needle-intrastats estimated before and after adjustment of contours of the prostate and surrounding organs at risk. It was showed that in most cases they were matched to the intended dosimetric parameters: V100 average--94,1% (V100 more than 90% in 97.2% of cases), D90 average--104,3% (D90 100% achieved in 95.7% of cases). In contrast, when using primary plan dosimetry without estimation of changing the geometry of the prostate and organs at risk in 38.6% patients V100 value was below 80%, in 41.4% patients--was in the range from 80% to 90%. In 24.3% patients index D90 did not exceed 80%, in 31.4% patients determined in the range from 80% to 90% and in 24.3% patients was close to 100%. In the absence of correction of contours of the urethra and the prostate in 18% patients the value of D10 for the urethra was higher border 115% and could increase to critical 189%. PMID- 26016160 TI - [10-year results of using segmental pelvic irradiation combined with local irradiation of the prostate in patients with prostate cancer with multiple bone metastases]. AB - The objective was to show the importance of external beam radiotherapy (EBRT) to increase the effectiveness of treatment and improve the quality of life of patients with generalized prostate cancer (PC). From 1992 to 2005 at our institution 205 patients with morphologically verified generalized (stages T1-4N0 1M1b) PC received EBRT. EBRT was conducted against the background of hormone therapy. Irradiation was begun with segmental pelvic irradiation with consistent reduction in the volume of exposure to locoregional and local irradiation of the prostate. The total tumor dose on the prostate was adjusted up to therapeutic level (66-72 Gy). In case of PC generalization with a primary lesion of the pelvis and lumbosacral spine, palliative EBRT according to the proposed method was justified. EBRT not only improved the quality of life of patients but also increased its duration. PMID- 26016161 TI - [The role of stereotactic radiotherapy in treatment of patients with metastatic lesion of lungs]. AB - Since February 2012, in order to increase the effectiveness of treatment and quality of life of patients with disseminated disease, there was developed and implemented a method of stereotactic radiotherapy for metastatic lesion of lungs by tumors of different histological types. 20 patients were treated by stereotactic radiotherapy ROD 7 Gy in five sessions during 5 days. There were evaluated results of treatment and prospects of this method. PMID- 26016162 TI - [Complications and effectiveness of treatment of patients with locally advanced prostate cancer after combined radiotherapy and radical prostatectomy with postoperative radiotherapy]. AB - Treatment for prostate cancer remains a significant social problem due to the continuing trend of growth of morbidity and mortality in Russia from this disease. In recent years a real alternative to surgical treatment is radiotherapy. In treatment of locally advanced stages of prostate cancer radiotherapy plays a dominant role. At our institution from 2005 till 2011, 105 patients with locally advanced prostate cancer underwent complex and combined treatment comprising in the first group the concomitant radiotherapy with Ir-192 and the control group--radical prostatectomy followed by adjuvant remote radiotherapy. In patients treated with concomitant radiotherapy compared to the control group there were occurred fewer number of genitourinary complications according to the RTOG scale (5,8% vs. 32,7%). In patients who had undergone radical prostatectomy followed by adjuvant radiotherapy urinary incontinence was met significantly often. PMID- 26016163 TI - [The use of fast neutrons in treatment of malignant tumors of the head and neck]. AB - The article presents issues of the application of neutron therapy in the combined and radiation therapy for head and neck tumors. There were developed methods of neutron and neutron-photon therapy in pre- and postoperative periods as well as in stand-alone option in unresectable tumors. The data obtained clearly demonstrate the superiority of new ways over standard methods of treatment. Neutron therapy is satisfactorily tolerated and allows improving the results of combined and radiation therapy patients with malignant tumors of the head and neck. PMID- 26016164 TI - The preoperative anesthesia evaluation--revisited. AB - This article discusses the importance of individualizing the preoperative anesthesia assessment. Establishing trust between the interviewer and patient results in a positive, calming effect from preoperative period through to PACU. An interviewing technique can eas- ily be developed to alleviate anxiety and still make patients aware of risks and potential outcomes. PMID- 26016165 TI - An old photograph promotes the certification of graduates by examination. PMID- 26016166 TI - NBCRNA response to Zambricki et al Guest Editorial. PMID- 26016167 TI - Evaluation of the anxiolytic and antidepressant effects of asiatic acid, a compound from Gotu kola or Centella asiatica, in the male Sprague Dawley rat. AB - Herbal medication use continues to rise and interactions with existing medications propose risks and may have significant effects and consequences on the administration of anesthesia. The purpose of this study was to investigate the anxiolytic and antidepressant effects of asiatic acid and its potential modulation of the gamma-aminobutyric acid (GABAA) receptor. Fifty-five male Sprague Dawley rats were divided into 5 groups: vehicle (DMSO), asiatic acid (AA), midazolam, or a combination of flumazenil + AA or midazolam + AA, and injected intraperitoneally 30 minutes prior to testing. The rats were tested on the Elevated Plus Maze (EPM) and the Forced Swim Test (FST). Data were analyzed using a two-tailed multivariate analysis of variance (MANOVA). Significance was found regarding the ratio of open arm time, maximum speed, and time spent mobile in the AA group and the midazolam + AA group (P < .05). Flumazenil decreased the anxiolytic effects, suggesting that AA modulates the benzodiazepine site on the GABAA receptor. Further studies are recommended to determine the efficacy of prolonged treatment for anxiety and depression. PMID- 26016168 TI - Core temperature--the intraoperative difference between esophageal versus nasopharyngeal temperatures and the impact of prewarming, age, and weight: a randomized clinical trial. AB - Unplanned perioperative hypothermia is a well-known complication to anesthesia. This study compares esophageal and nasopharyngeal temperature measured in the same patient for a period of 210 minutes of anesthesia. Forty-three patients undergoing colorectal surgery were randomly assigned in 2 groups, with or without a prewarming period (group A = prewarming [n = 21] or group B = no prewarming [n = 22]). Demographics were similar in both groups. Mean temperatures at 210 minutes were statistically different between the groups at both sites of measurement. Esophageal temperature in group A was 36.5 +/- 0.6 vs 35.8 +/- 0.7 in group B (P = .001), and nasopharyngeal temperature was 36.7 +/- 0.6 and 36.0 +/- 0.6 in group A and group B, respectively (P = .002). A negative correlation was found between esophageal temperature and age (r2 = -.381, P < .012). Esophageal temperature was different with respect to BMI below or above 25. The temperatures were 35.81 +/- 0.66 in the lower BMI group vs 36.46 +/- 0.59 (P < .001). These results demonstrate a difference between the 2 measurement techniques and that prewarming, age and BMI have an impact on measured temperatures. PMID- 26016169 TI - Worldwide experience with sugammadex sodium: implications for the United States. AB - Sugammadex sodium is a modified gamma-cyclodextrin with a very high affinity for rocuronium and, to a lesser extent, vecuronium molecules. In vivo administration results in immediate encapsulation of rocuronium and vecuronium, resulting in termination of neuro- muscular blockade, usually within 3 minutes. This new neuromuscular blocking agent is specific for the aminosteroidal neuromuscular blocking agents rocuronium and vecuronium. Experience gained through worldwide clinical use of sugammadex offers US anesthesia providers the opportunity to better understand this new drug and its clinical applications. The seminal and current literature concerning clinical use of sugammadex is reviewed, and considerations for its incorporation into practice are provided. PMID- 26016170 TI - Bivalirudin in off-pump coronary artery bypass graft in a patient with heparin induced thrombocytopenia: a case report of its use. AB - Heparin-induced thrombocytopenia (HIT) is an antibody-mediated reaction in which heparin administration causes a person to enter a pathological and highly prothrombotic state. When patients with known HIT undergo coronary artery bypass and grafting procedures, they must be appropriately anticoagulated. The dangers of heparin administration in this population necessitate the use of an alternative anticoagulant. The case describes the successful use of bivalirudin for procedural anticoagulation during an off-pump coronary artery bypass and grafting. PMID- 26016171 TI - Call-shift fatigue and use of countermeasures and avoidance strategies by certified registered nurse anesthetists: a national survey. AB - This study surveyed Certified Registered Nurse Anesthetist (CRNA) members of the American Association of Nurse Anesthetists (AANA) on their frequency of call shift fatigue, fatigue symptoms, medical errors associated with fatigue, and use of fatigue countermeasures and avoidance strategies. A secondary aim was to identify predictors of call-shift fatigue. An invitation to complete an anonymous electronic survey was sent to 2,500 randomly selected AANA members. Data were collected on CRNAs' fatigue experience, call-shift length and frequency, errors in patient care, and use of fatigue countermeasures and avoidance strategies. Analysis included descriptive and inferential statistics. Logistic regression was used to identify predictors of call-shift fatigue. Of 325 CRNAs who provided data, 82% reported experiencing call-shift fatigue, 87% used fatigue countermeasures, 77% used fatigue-avoidance strategies, and 28% reported committing a medical error because of fatigue. Predictors included hours to recovery from a call shift (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.04-1.12), working 5 to 6 calls per month (OR = 3.78, CI = 1.17-12.23), working 7 or more calls per month (OR = 4.87, CI = 1.93-12.33), use of fatigue countermeasures (OR = 5.44, CI = 2.15-13.77), and fatigue symptoms (OR = 2.19, CI = 1.03-4.67). Call-shift fatigue is a common problem among CRNAs and is associated with medical errors and negative health consequences. PMID- 26016172 TI - Self-efficacy, stress, and social support in retention of student registered nurse anesthetists. AB - Many studies document the presence of stress and the need for social support in anesthesia students. By addressing these, one can increase students' self efficacy, which is related to beliefs in one's ability to accomplish an objective. By measuring and instituting measures to increase self-efficacy, we could improve student selection in nurse anesthesia programs, and increase academic success and likelihood of retention. This article reviews the literature on this topic and makes recommendations for increasing student self-efficacy. PMID- 26016173 TI - Anesthesia and the developing brain. AB - Despite the profound evolution in the safety and efficacy of neonatal and pediatric anesthesia, questions remain concerning the long-term neurotoxic and neurocognitive effects of the drugs used in anesthetic care. A variety of prospective animal models and retrospective human studies exist that inconsistently demonstrate a detrimental effect of early life exposure to anesthetic drugs and subsequent learning performance. Limitations associated with both non-human and human observational studies are critiqued. Research currently underway is briefly described. A framework for discussing the relevant issues with concerned parents is presented. PMID- 26016174 TI - The $30 million question: How would you improve renal care? PMID- 26016175 TI - The case against 'incident to' for APs and PAs. PMID- 26016176 TI - Taking back control of my life. PMID- 26016177 TI - The year in review. PMID- 26016178 TI - [Transgress to progress]. PMID- 26016179 TI - [Cancer risk: a predominant role of chance?]. PMID- 26016180 TI - [Vertebral hydatidosis]. PMID- 26016181 TI - [Microscopic colitis]. AB - Microscopic colitis (MC), collagenous colitis (CC) and lymphocytic colitis (LC), represent a pathological entity causing chronic secretory diarrhea with endoscopically normal colon. Histological diagnosis is obtained by biopsies done throughout the colon. CC is defined by the thickening of the subepithelial collagen band of more than 10 pm and LC by more than 20% intraepithelial lymphocytes per epithelial cell. The incidence of MC has been steadily increasing and the prevalence of MC varies from 10-14% in patients with chronic diarrhea and endoscopically normal colon. The clinical presentation of MC is very close to that of functional diarrhea. The recent introduction of a new drug and autoimmune disease are the main factors associated with MC, and there is a special association with celiac disease is. Although rare complications can occur, MC are benign pathologies. Therapeutically, it is first necessary to eliminate a drug induced, drug discontinuation allowing the cure of colitis, and an associated celiac disease. In other cases, budesonide is the treatment of choice for the moderate to severe forms resistant to the usual symptomatic treatments; relapse is however frequent after the withdrawal of budesonide, and may necessitate its continuation at the lower possible dose. PMID- 26016182 TI - [Shulman syndrome]. PMID- 26016183 TI - [Statin against cirrhosis]. PMID- 26016185 TI - [Coronary artery diseases: a rapid and continuous decline in mortality]. PMID- 26016184 TI - [Liver donation (partial) does not effect the quality of life of donors ]. PMID- 26016186 TI - [Epidemiology of coronary artery disease]. AB - In developed countries, coronary artery diseases (CAD) represent a common and serious disease, and cardiovascular disease remains the leading cause of death. During the last decade, however, several epidemiological studies have suggested a significant reduction in the Incidence of myocardial infarction and cardiovascular mortality in many countries. In France, data from "FAST-MI programme" (observational studies including acute coronary syndrome) show a dramatic decline in mortality (approximatively 50%) regardless of the type of acute coronary syndrome. This evolution can be explained by several factors: overall improvement in organization of care, better implementation!of recommendations, substantial change in the patient risk profile, increasing use of invasive strategy, adjunctive therapies... However, decline mortality of stable CAD is more complex to evaluate.Therefore, the improved prognosis of patients with myocardial nfarction appears to be one of the factors that have contributed to the decline in cardiovascular mortality. For the future, the challenge will be to maintain these results, strengthen preventive measures and improve long-term prognosis in particular by developing the therapeutic education programs. PMID- 26016187 TI - [Natural history of coronary artery disease]. PMID- 26016188 TI - [Role of inflammation in coronary artery disease]. PMID- 26016189 TI - [Anti-PCSK9 in coronary artery disease: genetic progress, therapeutic approaches]. PMID- 26016190 TI - [How to diagnose an acute coronary syndrome in 2015?]. AB - Acute coronary syndromes (ACS) are characterized by sudden, reduced blood flow to the heart leading to myocardial ischemia, caused by atherosclerotic plaque rupture or erosion, with differing degrees of superimposed thrombosis. The most frequent clinical presentation is intermittent chest pain secondary to coronary artery subocclusion. The absence of electrocardiogram (ECG) abnormalities in a high proportion of patients after pain relief renders the diagnosis difficult. Clinical evaluation is of great importance to distinguish patients with ACS within the very large proportion with chest pain. Troponins play a central role in establishing the diagnosis, however false positive tests are frequent in patients with a low pretest probability and may lead to unnecessary invasive cardiac testing. Prolonged anginal pains of more than 10 minutes are generally secondary to epicardial coronary artery occlusion and associated with ECG abnormalities in a large majority of patients. Patients with persistent ST elevation should be immediately transported to the hospital for emergent early reperfusion therapy, which reduces myocardial injury and is associated with major improvement of prognosis. PMID- 26016191 TI - [New antiplatelet agents in the acute stage of coronary artery disease]. PMID- 26016192 TI - [Management of coronary artery disease at the acute phase]. AB - In patients with acute coronary syndrome (ACS), early management is of prime importance. However, the median time taken by the patient to call the emergency services is often very long, up to 2 hours. The presence of a physician as first responder ensures good quality resuscitation in case of cardiac arrest, and allows recording of a first ECG, which can be very informative, especially in ACS without ST segment elevation. Treatment at this stage is limited to sublingual nitroglycerin and aspirin. If the first ECG shows ST segment elevation, the patient should be immediately oriented for reperfusion, usually by percutaneous coronary intervention. in the absence of ST segment elevation, the diagnosis of ACS remains unconfirmed. This does not imply that the risk is lesser, but rather that the risk cannot be evaluated accurately in the pre-hospital setting. The use of risk scores can guide the choice of management towards an invasive strategy, including coronary angiography (immediately, or within 24-72 hours). Low-risk patients are candidates for an invasive strategy, provided non-invasive tests demonstrate the presence of ischemia. During the hospital phase, antiplatelet treatment should be initiated and must be adapted to the patient bleeding and thrombotic risk. Clopidogrel is recommended only in patients who are not amenable to prasugrel or ticagrelor. Statin therapy should be initiated from day one, regardless of the initial cholesterol level, preferably with 80 mg atorvastatin. Angiotensin-converting enzyme inhibitors and beta-blockers should also be prescribed to complete the medical prescription both in-hospital and in the long term. PMID- 26016193 TI - [Prescriptions in patients with coronary artery disease]. AB - The management of stable coronary artery disease has evolved in recent years and is now based on the latest recommendations of the European Society of Cardiology. Drug prescription takes into account two strategic approaches: on the one hand, pharmacological treatments that improve the prognosis and on the other hand treatments to improve symptoms and/or ischemia. Improving the prognosis involves reducing as well as stabilizing coronary plaque thanks to 3 therapeutic classes: aspirin, statins and renin-angiotensin system blockers (ACE inhibitors or ARBs). In parallel, a fast-acting nitrovasodilator associated with a beta-blocker or a heart-slowing calcium-channel blocker makes it possible to reduce the angina. In addition, pharmacological modifications and regular reassessments are fundamental aspects of CAD management. PMID- 26016194 TI - [Percutaneous coronary intervention vs coronary artery bypass grafting for patients with stable angina pectoris]. AB - Percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) must be considered among stable angina pectoris patients who remained symptomatic despite optimal medical treatment and to improve prognosis of patients with large myocardial lschemia when occurring at low workload. PCI is preferred for single coronary artery stenosis, while CABG is recommended for severe multivessel disease patients, particularly when diabetes is present. There is no simple decisional algorithm, and, for patients with multivessel disease, each situation must be debated within a multidisciplinary decision-making team (Heart Team), taking into consideration risks and benefits of PCI vs CABG, patients' comorbidities and local experience. PMID- 26016195 TI - [Lifestyle changes for patients with coronary artery disease]. AB - Shortening the hospitalization period during an acute coronary syndrome can lead to a trivialization of the event, and especially causes many questions among patients about their future lifestyle. A secondary medical care in rehabilitation centers allows to combine the numerous benefits of physical training and to answer to their questioning, through to both a collective and individual therapeutic education. PMID- 26016197 TI - [Coronary artery disease: a strong association with depression and job stress]. PMID- 26016196 TI - [Epidemiology of pancreatic adenocarcinomas]. AB - Pancreatic cancer, mostly represented by pancreatic ductal adenocarcinoma, is a major public health burden in developed countries. More than half a million people are expected to die from pancreatic cancer, worldwide, in 2030. Age and tobacco are the main identified risk factors in sporadic cases, when many genetic syndromes increase the risk significantly. History of pancreatic cancer is a significant risk factor for pancreatic cancer for any first-degree related individual, known as familial pancreatic cancer. The genetic signature of this syndrome is probably due to a still not identified autosomal dominantly inherited gene with reduced penetrance. The risk increases with the number of first-degree relatives involved. Precursor lesions are known to give rise to invasive pancreatic cancer. These particular lesions are either macroscopic (intraductal papillary mucinous neoplasia and mucinous cystic neoplasms), or microscopic (pancreatic intraepithelial neoplasia). It is possible to identify a orouo of hig h-risk individuals who could be candidate for screening. PMID- 26016198 TI - [Impact of molecular biology on the natural history of pancreatic cancer]. PMID- 26016199 TI - [Surgery for lesions at risk for pancreatic cancer]. AB - Preventive surgery of pancreatic adenocarcinoma is warranted by the substantial benefit in prognosis observed in some diseases at high-risk for malignant transformation. The main indication is intraductal papillary and mucinous neoplasms, in which surgical resection must be proposed in case of main duct involvement. Conversely, in branch-duct IPMN, surgical indications are selective and based mainly on imaging findings. Mucinous cystadenoma is almost exclusively observed in female, and often localized in the distal pancreas and amenable to a limited resection. Chronic alcoholic pancreatitis results in a moderately increased risk of pancreatic cancer but screening by imaging is difficult. Concerning familial chronic pancreatitis, risk of cancer is very important and warrants resection up to total pancreatectomy. Familial pancreatic cancer and some others genetic predispositions are less known. The first step of their management is an oncogenetician counsel. If screening is indicated, it should rely mainly on MRI and endoscopic ultrasound. However, indications of preventive pancreatectomy are difficult to established, both concerning time and extent of resection. PMID- 26016200 TI - [Conventional imaging of pancreatic cancer]. AB - Computed tomography has become the optimal imaging modality for both diagnosis and staging of pancreatic adenocarcinoma. It is especially highly accurate in assessing the relationship of the tumour to critical arterial and venous structures, since their involvement can preclude surgical resection. MRI provides additional staging information regarding presence of small liver metastases not seen at CT. Precise definition of tumour resectability is needed to facilitate optimal patient treatment. PMID- 26016201 TI - [Echo-endoscopic ultrasound and pancreatic cancer]. PMID- 26016202 TI - [Management of localized, locally advanced and metastatic pancreatic adenocarcinoma]. AB - Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy. The prognosis is extremely poor because PDAC is usually a systemic disease at diagnosis. All stages, the survival does not exceed 5% at 5 years. However 15% of PDAC can be resected and today a margin-negative resection followed by adjuvant chemotherapy remains the only potential for a prolonged survival. Postoperative mortality had significantly decreased and the benefit of postoperative adjuvant chemotherapy has been clearly shown. Substantial progress has been made in the field of palliative chemotherapy by introducing new chemotherapy regimens (FOLFIRINOX [folinic acid, 5 fluorouracil, irinotecan and oxaliplatin] and gemcitabine/nab-paclitaxel), when the patient's performance status allows the use of these drugs. The role of radiation therapy remains controversial. PMID- 26016203 TI - [Supportive care in pancreatic cancer]. AB - Pancreatic cancer is one of the most aggressive malignancy with an expected overall survival of less than one year in metastatic canes. Many refmactory symptoms may be present at diagnosis and must be adequaty managed to improve quality of life (and survival ?) of these patients This includes dedicated supportive care but also an early introduction of palliative care methods. The current manuscript details the mast common and problematic maaifestatiaas of pancreatic cancer including weight loss, anorexia, cachexia syndrome, pain management, venous thromboembolism, malignant biliary and gastric outlet obstruction. PMID- 26016204 TI - [Residents, health care system and social environment]. PMID- 26016205 TI - [Inflammatory syndrome: an important marker for the clinician]. PMID- 26016206 TI - [In the elderly, cognitive impairment or physiological aging?]. PMID- 26016207 TI - [Cancers of the cervix and uterine body: what risk factors?]. PMID- 26016208 TI - [The physician must act on lifestyles]. PMID- 26016209 TI - [Inflammation]. PMID- 26016210 TI - [Cognitive impairment in the elderly]. PMID- 26016211 TI - [Therapeutic lifestyle changes (diet and physical activity) in adults and children]. PMID- 26016212 TI - [Tumors of the cervix, endometrial tumors]. PMID- 26016213 TI - [News about the Galenic plague]. PMID- 26016214 TI - [Corruption and health care system]. AB - Corruption is a global problem that takes special place in health care system. A large number of participants in the health care system and numerous interactions among them provide an opportunity for various forms of corruption, be it bribery, theft, bureaucratic corruption or incorrect information. Even though it is difficult to measure the amount of corruption in medicine, there are tools that allow forming of the frames for possible interventions. PMID- 26016215 TI - [Influence of smoking on the nasal mucosa mucociliary transport]. AB - The aim of the study was to compare mucociliary transport between healthy smokers and nonsmokers and to evaluate the influence of the duration of smoking, number of cigarettes per day and age on mucociliary function. The study included 176 subjects divided into two groups. One group consisted of 96 smokers and the other group of 80 nonsmokers. The saccharin test that measures mucociliary transport was performed on all study subjects. Analysis of test results showed a statistically significant difference in mucociliary transport between smokers older than average and the younger ones (t=2.58; df=22; P=0.01 7). Damage to the mucociliary transport was more severe in older smokers. A statistically significant difference in mucociliary transport was also found in smokers with a longer than average duration of smoking habit (t=3.362; df=22; P=0.003). There was no statistically significantly slower mucociliary transport according to the number of cigarettes per day and age at starting smoking. In conclusion, mucociliary transport was statistically slower in smokers that were older and had a longer smoking history as compared with younger smokers having smoking for a shorter time. Smoking has an important effect on mucociliary transport of the nasal mucosa. PMID- 26016216 TI - [Asymptomatic hypertension in urban and rural population of the Posusje community, Bosnia & Herzegovina]. AB - The aim of the study was to determine the prevalence of newly detected asymptomatic hypertension in a random sample of urban and rural population of the Posusje community, and to assess the possible age and sex differences between these two population groups. The study included 2000 subjects that underwent blood pressure measurement. Elevated blood pressure was detected in 532 (26.60%) subjects that were divided into three groups according to the level of hypertension: mild, moderate and severe hypertension. Study results showed that there were no statistically significant age or sex differences according to the levels of asymptomatic hypertension, or between the urban and rural populations of the Posusje community. PMID- 26016217 TI - [Relationship of perception conflict and assertiveness in nurses]. AB - At their workplace, nurses are exposed to a number of conflict situations. On dealing with such situations, a significant role is played by assertiveness skills. Assertiveness is the necessity of efficient communication between nurses and patients. Thus, development of these skills can enhance patient confidence in the nursing profession. The aim of the study was to determine whether there are differences in assertiveness with respect to age and sex, and whether there is and what is the connection between assertiveness, potential sources of conflict at work, conflicts due to the behavior of associates, resolving conflicts and self-assessment in resolving conflicts. The survey included 87 hospital nurses. The questionnaire included assessment of assertiveness. On processing the results, we calculated the indicators of descriptive statistics, carried out the variance analysis and t-test, and calculated Pearson's correlation coefficients. It was found that the majority of subjects expressed a medium level of assertiveness, i.e. they could be considered as relatively assertive persons. There were significant differences in assertiveness according to age of the subjects and length of service, where the oldest age group was significantly less assertive. More assertive subjects frequently observed behaviors that may be a source of conflict and problems in the organization of work. At the same time, they often had conflicts because of such behavior, which indicated that more assertive subjects were bolder and more secure. More assertive subjects believed that they were more successful in resolving conflicts than non-assertive subjects. PMID- 26016218 TI - [Ovarian cancer - screening and diagnosis]. AB - Despite advances in gynecologic oncology, ovarian cancer is still mostly diagnosed very late or in advanced stages, which leads to adverse outcome of the disease. The pathogenesis of this disease as well as the risk factors for its development are not completely understood, while symptoms in the early stage of disease are sometimes nonspecific and delay earlier diagnosis. The aim is to present recent knowledge about the screening and diagnosis of ovarian cancer, with sp6cial reference to the role of ultrasound in recognizing the disease and referring patients for further consultation. PMID- 26016219 TI - [Oral allergy syndrome]. AB - Oral allergy syndrome (OAS) is an IgE antibody-mediated allergic reaction that occurs after consumption of fresh fruits and veg etables in patients with allergy to pollen. Symptoms arise due to cross-reactivity between pollen and plant derived food and another term used for this syndrome is pollen-food allergy syndrome. The patient is sensitized with pollen and exhibits an allergic reaction to food antigen with structural similarity to the pollen. OAS is rarely seen in young children, but the prevalence increases with age and OAS is the most common manifestation of food allergy in adolescents and adults. Symptoms are usually localized in the oral mucosa, but abdominal symptoms and anaphylaxis may occur as well. Patients generally tolerate thermally processed food, but in those with atopic dermatitis it may lead to worsening of eczema. In the case of generalized symptoms and anaphylaxis, strict avoidance and first aid measures including a self-injectable adrenaline are advised. PMID- 26016220 TI - [Early carotid endarterectomy in symptomatic patients - our experience]. AB - Carotid endarterectomy is the gold standard as a therapeutic regimen for patients with high grade symptomatic stenosis of the internal carotid artery (ACI). This study analyzed the effect of early carotid endarterectomy in patients undergoing an operative procedure 2-3 weeks after the development of ischemic neurologic symptoms, considering the frequency and type of complications in the postoperative period. Patients included in this study were those with significant symptomatic ACI stenosis (70%-99%), which caused ischemic stroke or transient ischemic attacks (TIA). Patients with ischemic stroke were operated within twenty days of the initial neurologic event, whilst in those with symptoms of TIA, surgery was performed immediately after diagnostic work-up. In all cases, carotid endarterectomy was performed under general anesthesia with the use of protective intraluminal shunt. In the vast majority of cases, tucking or Kunlin's sutures of the distal intima were applied. All procedures were performed between January 2008 and October 2012, and the total number of patients was 69. All patients underwent the same follow up program. Follow up carotid ultrasound was performed routinely on postoperative day 7 and at 1, 3, 6 and 12 months. In this study, 27 (39%) patients suffered minor ipsilateral stroke and 42 (61 %) patients had TIA symptoms with verified significant ACl stenosis. Postoperative complications were observed in four (5.26%) patients. Two (2.63%) patients developed ischemic stroke after the procedure and two (2.63%) patients developed ACI restenosis in the late postoperative period and were treated by endovascular stenting. In conclusion, we found that early carotid endarterectomy was of greater benefit than delayed endarterectomy, which is in keeping with the published studies. The leading observation was that in selected patients, early carotid endarterectomy was not associated with a higher risk of postoperative complications in comparison with delayed endarterectomy and could be performed safely. PMID- 26016221 TI - [Raynaud's phenomenon - first sign of malignancy: case report]. AB - Raynaud's phenomenon is a common phenomenon in the general population. It most commonly occurs in healthy individuals, in whom there is no associated illness or any other cause of Raynaud's phenomenon (primary or idiopathic Raynaud's phenomenon). Secondary Raynaud's phenomenon is common with rheumatic diseases (systemic sclerosis, systemic lupus erythematosus, primary Sjogren's syndrome, mixed connective tissue disease, etc.), occlusive vascular diseases, hematologic disorders, use of vibrating tools and use of some medications, and rarely with malignancy. We report on a patient who presented with a three-week history of painful Raynaud's attacks, which was the reason for seeking assistance of internists in emergency clinic. Upon admission to the hospital and diagnostic work-up, adenocarcinoma of the lung was found. Antinuclear antibodies (ANA), anti dsDNA antibodies, anticardiolipin IgM and IgG antibodies were present in a lower titer. It is known that rheumatoid factor or ANA characteristic of rheumatic disease are often present in patients with paraneoplastic rheumatic syndromes, which can lead to wrong conclusions about the possible systemic connective tissue diseases and ultimately delay the correct diagnosis. The first appearance of Raynaud's phenomenon as an isolated symptom in people older than 50, with painful signs of ischemia, as in our patient, or the occurrence of asymmetric grasping fingers, especially in men, regardless of the presence of RF, ANA, anti-dsDNA or other autoantibodies, requires broader diagnostic evaluation for malignancy. PMID- 26016222 TI - [Clinical features in DLBCL and translocation BCL2/c-MYC "double hit" lymphoma]. AB - Diffuse large B-cell lymphoma (DLBCL) is classified as lymphoma and various entities using the gene expression of proteins are classified into three groups. The aim of this study was to clarify the clinical, biological, immunophenotypic and cytogenetic features of DLBCL with translocation t (14; 18) and 8q24/c-MYC. Eleven DLBCL patients with dual translation were monitored during the 2000-2009 period. The characteristics of these patients included morphological, immunohistochemical and cytogenetic analysis. Study results showed that all patients had aggressive characteristics, presence of B symptoms (64%), general patient condition according to ECOG scale >= 2 (55%), elevated serum lactate dehydrogenase activity (73%), clinical stage III and IV (82%), extranodal involvement of the disease (73%), and IPI >= 2 (73%). Partial remission was achieved in 73% of all patients and all patients (73%) died within a short time. Patients were treated with CHOP and similar protocols (COP, CVP, CNOP), with the addition of MabThera. Immunophenotyping was performed and determined expression of the CD20, CD3, CD10, BCL6 and MUM1 markers. The cytogenetic analysis/fluorescence in situ hybridization revealed complex karyotype changes. Thus, we analyzed the presence of BCL2, BCL6 and c-MYC genes and found eight patients to have BCL2 and c-MYC translocation genes, while three had translocation of the BCL6 and c-MYC genes. Despite appropriate therapy, the patient prognosis is poor. The median survival in these patients was 1.85 years. DLBCL with BCL2 and c-MYC rearrangement of the subgroups of lymphoma is associated with very poor survival. The presence of these two translocations has an aggressive clinical course. PMID- 26016223 TI - [Rare disorders of extracranial carotid arteries]. AB - Abnormalities of the internal carotid arteries (ACI) are rare findings, usually not linked with neurologic symptoms and frequently are diagnosed during routine duplex scanning or angiographic examination. These abnormalities are predominantly elongation of the vessel that leads to kinking, coiling or tortuosity of the artery, and the origin is congenital or acquired related to atherosclerosis. We report on two symptomatic cases related to elongation of AC. The first case was a 56-year-old female that had bilateral coiling. The second patient was a 64-year-old female that suffered from symptomatic double coiling of the left ACI connected with high grade stenosis. In both cases, successful operation was done with resection of the elongated and stenosed ACI segment and reanastomosis of the ACI and common carotid artery. Postoperatively, symptoms were resolved. In symptomatic cases of isolated carotid elongations, surgical treatment is a better option than conservative medical treatment alone, whilst in asymptomatic ACI elongation, conservative medical treatment is advised. PMID- 26016224 TI - [Flexion and version of the uterus on pelvic ultrasound examination]. AB - In the longitudinal (sagittal) plane, the angle between the axis of the uterine body and the cervix defines the flexion, whereas the angle between the axis of the cervix and the axis of the vagina defines the version of the uterus. In that regard, there are four uterine positions in the pelvis: anteflexion, retroflexion, anteversion and retroversion. The anteflexion with anteversion of the uterus is considered the natural position of the uterus in the pelvis. The transabdominal ultrasound examination of the female pelvis is most frequently performed if, for any reason, it is not possible to make a more appropriate transvaginal ultrasound examination. Suprapubic region is scanned with a high frequency convex transducer in the longitudinal and transverse plane. The prerequisites for appropriate ultrasound examination are the filled urinary bladder, optimal quality of the ultrasound image, consistency in the sonographic technique and excellent knowledge of echomorphology of the pelvic organs. The commonest of the less common variants of the uterine position is retroflexion with retroversion. Although sometimes related with serious problems during childbirth as well as miscarriage, it usually does not cause any major problems. Yet, data on the uterine position may help the clinician in planning of various procedures. PMID- 26016225 TI - [Effects of tamoxifen on CD147 glycosylation and MMPs in the diabetic rat myocardium]. AB - OBJECTIVE: Over the last few decades, diabetic cardiomyopathy has been identified as a significant contributor in cardiac morbidity. However, the mechanisms of diabetic cardiomyopathy have not been clarified. METHODS: In the present study, a diabetic rat model was induced by the intraperitoneal injection of streptozotocin. The myocardial CD147 expression and extent of glycosylation, as well as thematrixmetalloproteinases(MMPs) expression and activity, were observed in the diabetic and synchronous rats. RESULTS: The results showed that CD147 located on sarcolemma of cardiomyocytes. The myocardial CD147 expression and glycosylation were significantly increased in the diabetic rats as compared with the control. Expression of MMP-2 protein, MMP-2 and MMP-9 activity were also increased in left ventricular myocardium in the diabetic rats. Tamoxifen only inhibited the enhanced expression of myocardial CD147 in the diabetic rats, but not in synchronous control rats. Tamoxifen inhibited glycosylation of myocardial CD147 in both diabetic and control rats. The inhibition of tamoxifen on CD147 glycosylation was stronger than on the expression in the myocardium. The extent of myocardial CD147glycosylation was positively related toMMP-2 and MMP-9 activity. Tamoxifen induced an inhibition of myocardial MMP-2 and MMP-9 activity in the control and diabetic rats. CONCLUSION: These results indicate that myocardial CD147 expression, especially the extent of glycosylation, regulates MMP-2 and MMP-9 activity, then accelerates cardiac pathological remodeling inducing diabetic cardiomyopathy. Tamoxifen inhibits myocardial CD147 glycosylation and further depress the activity of MMPs. Therefore, tamoxifen may protect the diabetic rats against diabetic myocardium. PMID- 26016226 TI - [Effects of acute cold exposure on pulmonary proinflammatory cytokine of rat]. AB - OBJECTIVE: To study the effects of acute cold exposure on the inflammation and pathologic injuries in pulmonary of rats, and explore the mechanism induced by cold stress. METHODS: Forty male Wistar rats were randomly divided into five groups(n = 8): control group (23 +/- 2) degrees C 2.5 h, -25 degrees C 0.5 h group, -25 degrees C 1 h group, -25 degrees C 2 h group and -25 degrees C 2.5 h group. Rats were exposed to cold at -25 degrees C and no wind by keeping them in a low temperature chamber except control group. Rectal temperatures of the rats were measured before and after cold exposure. The morphological changes of pulmonary were observed by the optics microscope. The levels of tumer necrosis factor-alpha(TNF- alpha), interleukin-6 (IL-6) and interleukin-beta (IL-1beta) in lung tissue homogenate were measured by ELISA. RESULTS: Compared to the control group, body core temperatures of the -25 degrees C 1 h group, -25 degrees C2 h group and -25 degrees C 2.5 h group were decreased significantly, and the D values of rectal temperature were increased before and after cold exposure (P < 0.05). The infiltration of inflammatory cells and alveolar edema fluid appeared in the lung tissue of the -25 degrees C 2.5 h group. The concentrations of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and inter- leukin-1beta (IL-1beta) in lung tissue homogenate were increased significantly in -25 degrees C l h group, -25 degrees C 2 h group and -25C degrees 2.5 h group (P < 0. 05). CONCLUSION: The infiltration of inflammatory cells and the increase in proinflammatory cytokine from pulmonary may lead to the lung tissue injury after acute cold exposure. PMID- 26016227 TI - [Effect of regular physical activity on type 2 diabetes for elderly]. PMID- 26016228 TI - [Effect of ambient PM2.5 on the anti-oxidative capacity and inflammatory response of myocardial tissue in rats under different cold stresses]. PMID- 26016230 TI - [Effects of oxygen supply unit for individual on HR and SaO2 at high altitude]. PMID- 26016229 TI - [Effects of Artesunate on hepatic fibrosis and its mechanism]. AB - OBJECTIVE: To investigate the effects of Artesunate(Art) on the LX-2 cell. METHODS: The cultured hepatic stellate cells were divided into control group and Art-treated groups with 250,350,450 umol/L. The rate of cellular proliferation was detected by MIT assay, the content of ceramide (Cer)was determined by HPLC method, the content of hydroxyproline (Hyp) was determined by enzyme digestion method, the expressions of PPAR-gamma, p53 and Caspase 3 were detected by Western blot. RESULTS: Compared with control group, IX-2 treated with Art were inhibited in a concentration-dependent manner(P < 0.01). Art could significantly increase the content of cerarnide in LX-2 ( P <0.01), and the content of Hyp was significantly decreased (P <0.05, P <0.01). The expressions of PPAR-gamma, p53 and Caspase 3 were increased compared with that of control group(P < 0.01). CONCLUSION: Artesunate could inhibit the proliferation and induce apoptosis of hepatic stellate cells through upregulating ceramide. PMID- 26016231 TI - [The changes of monocarboxylate transporter-2 in spinal cord horn in a rat model of chronic inflammatory pain]. AB - OBJECTIVE: To investigate the changes in the levels of monocarboxylate transporter-2 in spinal cord horn in a rat model of chronic inflammatory pain. METHODS: Male SD rats weighting 180 - 220 g were randomly divided into two groups(n = 48): normal saline group (NS group), complete Freund's adjuvant group (CFA group). Rats were given injections of CFA 100 ul in left hind paw in group CFA, and an equal volume of saline was given injection in group NS. Mechanical withdraw threshold(MWT) and thermal withdraw latency(TWL) were measured at before injection(T0 and 3 h, 1 d, 3 d, 7 d, 14 d, and 21 d after injection(T1-7). Four rats were chosen from each group at T0-7 and sacrificed, and L4-5 segments of the spinal cord horn were removed for measurement of the expression of monocarboxylate transporter-2 by Western blot analysis. RESULTS: In CFA group, mechanical hyperalgesia and allodynia appeared on the 3 h after CFA injection, then until the day 14. The expression of monocarboxylate transporter-2 in the spinal dorsal horn of rats in CFA group was significantly higher than that in normal control group at T1-6(P <0.05). The protein level of monocarboxylate transporter-2 was apparently correlated with MWT and TWL(P <0.01 and P <0.05) in CFA group. CONCLUSION: The level of monocarboxylate transporter-2 in spinal dorsal horn is significantly increased in a rat model of chronic inflammatory pain and the change may involve in the formation and maintenance of central sensitization in spinal cord of chronic inflammatory uain. PMID- 26016232 TI - [Establishment and evaluation of a rat model of type 2 diabetes associated with depression]. AB - OBJECTIVE: To establish and evaluate a rat model of type 2 diabetes mellitus (T2DM) associated with depression for further elaborating the disease. METHODS: Twenty-four Wistar rats were randomly divided into three groups: normal group (group N), T2DM group (group T) and T2DM with depression group (group T + D), with 8 rats in each group. The T2DM rat model was induced by high fat diet and low dose of Streptozotocin (STZ) injection, and in addition, the T2DM rats were made restraint stress for 21 days. After the model was established, the insulin tolerance test (ITT) and oral glucose tolerance test (OGTT) were performed. Then the rat depression level was analyzed by open field test, and the concentration of 5-hydroxytryptamine (5-HT) and dopamine (DA)was determined by ELISA to confirm the model identity. RESULTS: The blood glucose level in group T and group T + D didn't return to the normal level at 180 minutes in the ITT and OGTT test; Compared with the group N, the max movement distance, retaining time in the central zone and the retaining frequency within 5 minutes in the group T + D decreased; 5-HT and DA level in the serum of rats in. group T + D was reduced. CONCLUSION: A rat model of type 2 diabetes mellitus associated with depression has been successfully established by high fat diet and injection of low dose streptozotocin in combination with restraint stress for 21 days. This rat model is useful for further relevant studies. PMID- 26016233 TI - [Dynamic changes of IL-1beta in rat myocardium during hypoxia/ reoxygenation transition]. AB - OBJECTIVE: To investigate the expression profile of interleuki-1beta (IL-1beta) in rat myocardium at different time points during hypoxia/reoxygenation(H/R)transition. METHODS: The isolated Langendorff perfused rat heart model was established.Forty SD rats were randomly divided into sham group (A group) and hypoxia/reoxygenation group (H/R group). The H/R group rats were subdivided into H/R 0.5 h group(B group), H/R 1 h group(C group), H/R 2 h group(D group)according to reoxygenation time. The left ventricular development pressure(LVDP), maximal rates of increase/decrease of the left ventricular pressure(+/-dp/dtmax) were continuously recorded. The concentration of interleukin-1beta(IL-lbeta) and creatine kinase-MB (CK-MB) in myocardium was measured by ELISA. The mRNA expression of IL-lbeta in myocardium was determined by RT-PCR. Microstructure of myocardium was observed under light microscopy. RESULTS: The value of LVDP and +/-dp/dtmax in hypoxia/reoxygenation group rat were significantly lower than that in sham group(P < 0.05). The expression of IL lbeta and CK-MB at protein level and the expression of IL-1beta at mRNA level in hypoxia /reoxygenation group were higher than that in sham group(P < 0. 05). There were significant differences of the above parameters among H/R 0.5 h, 1 h, 2 h group(P <0.05). The concentration of IL-1beta and CK-MB, the mRNA expression of IL-1beta were higher in H/R 2 h group than that of other groups(P < 0.05). CONCLUSION: The high expression of IL-Ibeta in myocardium after myocardial hypoxia /reoxygenation in rats might lead to. ischemia/reperfusion injury. PMID- 26016234 TI - [Research of autophagy activity between rat bone marrow mesenchymal stem neural differentiation]. AB - OBJECTIVE: To study the autophagy activity between rat bone marrow stem cells (BMSCs) neural differentiation in order to explore the mechanism involve in this process. METHODS: BMSCs were passed by 3 generation, then was induced with the revulsant 2% (DMSO) + 200 umol/L (BHA), NSE expression was detected by immunocytochemical stain, the mRNA expression of autophagy associated genes L3B, Beclinl, Atg5, Atg7, Atg10 were detected by RT-PCR, the autophagy protein LC3B was examined by Western blot and flow cytometry analysis. RESULTS: BMSCs were passed by 3 generation, the purity of BMSCs could reach more than 90%, the morphology of cells were like fibroblasts, after the revulsant 2% DMSO + 200 umol/L BRA induced, cells were extended long neurites, like nerve cells, positive rate of NSE staining was (83+/-5) %, RT-PCR results showed that the expression of autophagy associated genes LC3B, Beclinl, Atg5, Atg7 Atg0 were rised after BMSCs neural differentiation, Western blot analysis showed that the LC3B-II protein expression was increased after neural differentiation and the MFI of L3B was highten by flow cytometry. CONCLUSION: Autophagy is increased after rat BMSC neural differentiation. PMID- 26016235 TI - [Decreased expression of calcium-sensing receptor involved in the progression of diabetic cardiomyopathy]. AB - OBJECTIVE: To observe the dynamic expression of calcium-sensing receptor(CaSR) in myocardium of diabetic rats. METHODS: Thirty male Wistar rats were randomly divided into 3 groups including control, diabetic-4 week and diabetic-8 week groups(n = 10). The type 2 diabetes mellitus models were established by intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat and high-sugar diet for one month. The cardiac morphology was observed by electron microscope. Western blot analyzed the expression of CaSR, phospholamban (PLN), a calcium handling regulator, and Ca+-ATPase(SERCA) in cardiac tissues. RESULTS: Compared with control group, the expressions of CaSR and SERCA were decreased, while the expression of PLN was significantly increased in a time-dependent manner in diabetic groups. Meanwhile diabetic rats displayed abnormal cardiac structure. CONCLUSION: These results indicate that the CaSR expression of myocardium is reduced in the progression of DCM, and its potential mechanism may be related to the imnaired intracellular calcium homeostasis. PMID- 26016236 TI - [Protective effect of curcumin derivative B06 on kidney of type 2 diabetic rats]. AB - OBJECTIVE: To observe the effect and mechanism of curcumin derivative B06 on kidney from rats with hyperlipidemia and type 2 diabetes. METHODS: Thirty five male SD rats were randomly divided into five groups(n = 7): the normal control group, high-fat group, high-fat + B06-treatd group, diabetic group, diabetic + B06-treated group. After fed with high-fat diet for 4 weeks, the later two groups were in- jected with streptozotocin intraperitoneally to induce type 2 diabetes mellitus. B06-treated groups were given B06 by gavage at a dosage of 0.2 mg/kg . d for 8 weeks. After the treatment, the serum creatinine, blood urea nitrogen and uric acid were detected biochemically, the morphology of kidney was observed with light and transmission electron microscopy, the expression of collagen fibers was observed with Masson staining, the protein expression of collogen IV and fibronectin in kidney were determined by Immunohistochemistry. RESULTS: It was showed that the levels of the serum creatinine and blood urea nitrogen elevated significantly in diabetic group. In high-fat and diabetic groups, increased glomerular mesangial matrix and collagen fiber and thicken glomerular basal membrane were observed under light microscopy, swelling and fusion of foot process were found under electron microscope; increased green matrix within glomeruli was observed under Masson staining. collogen IV and fibronectin protein expression were significantly enhanced in high-fat group and diabetic group. After B06's intervention, the levels of serum creatinine and blood urea nitrogen were decreased in diabetic groups, the morphological change of kidney was obviously relieved, Collogen IV and fibronectin protein expression reduced. CONCLUSION: Curcumin derivative B06 exerts a protective effect on kidney in type 2 diabetic rats, reduced expressions of collogen IV and fibronectin, inhibition of the accumulation of extracellular matrix and glomerular mesangial proliferation, and then prevention of renal fibrosis may be the mechanism. PMID- 26016237 TI - [Effects of yarn polysaccharide on antioxidant capacity of mice with Alzheimer disease]. PMID- 26016238 TI - [Effect of 5-HT1A receptors in the hippocampal DG on active avoidance learning in rats]. AB - OBJECTIVE: To investigate the effects of serotonin (5-HTIA) receptors in the hippocampal dentate gyrus (DG) on active avoidance learning in rats. METHODS: Totally 36 SD rats were randomly divided into control group, antagonist group and agonist group(n = 12). Active avoidance learning ability of rats was assessed by the shuttle box. The extracellular concentrations of 5-HT in the DG during active avoidance conditioned reflex were measured by microdialysis and high performance liquid chromatography (HPLC) techniques. Then the antagonist (WAY-100635) or agonist (8-OH-DPAT) of the 5-HT1A receptors were microinjected into the DG region, and the active avoidance learning was measured. RESULTS: (1) During the active avoidance learning, the concentration of 5-HT in the hippocampal DG was significantly increased in the extinction but not establishment in the conditioned reflex, which reached 164.90% +/- 26.07% (P <0.05) of basal level. (2) The microinjection of WAY-100635 (an antagonist of 5-HT1A receptor) into the DG did not significantly affect the active avoidance learning. (3) The microinjection of 8-OH-DPAT(an agonist of 5-HT1A receptor) into the DG significantly facilitated the establishment process and inhibited the extinction process during active avoidance conditioned reflex. CONCLUSION: The data suggest that activation of 5-HT1A receptors in hipocampal DG may facilitate active avoidance learning and memory in rats. PMID- 26016239 TI - [Wireless telemetry electrical activity of nucleus accumbens shell in morphine induced CPP rats]. AB - OBJECTIVE: To analyse the relationship between the electrical activity changes of nucleus accumbens (NAc) shell and the drug-seeking behavior by recording NAc shell electrical activity in conditioned place preference (CPP) rats induced by morphine. METHODS: Forty SD rats were randomly divided into operation-only control group and the morphine-induced CPP group after stereotaxic electrode was buried on rats NAc shell and the latter group was used to establish the morphine CPP model(n = 20). A CPP video system combining with the technique of electrical activity wireless telemetry was used in the study. The NAc electrical activity from each group of rats was recorded by wireless telemetry respectively, which included staying in black or white chamber of video box, shuttling between black white chambers and between white-black chambers. The electrical activity differences were analyzed by the percentage of each wave. RESULTS: When the morphine-induced rats staying in black chamber, compared with the operation-only control group, the NAc shell electrical activity showed that the percentage of 0 10 Hz was increased(P < 0.05), meanwhile, those of 10 - 20 Hz and 30 - 40 Hz were reduced(P < 0.05, P < 0.01); when the morphine-induced rats staying in white chamber, the NAc shell electrical activity showed that the percentage of 0 - 10 Hz and 30 - 40 Hz were increased(P < 0.05 , P < 0.01) , that of 10 - 20 Hz was reduced(P < 0.05 , P < 0. 01); when the morphine-induced rats in black- white shuttling status, the NAc shell electrical activity showed that the percentage of 0 - 10 Hz was increased(P <0.05, P <0.01), that of 10- 30 Hz was reduced( P <0.05); and in the white-black shuttling status, the electrical activity showed that the percentage of 0 - 10 Hz was reduced(P <0.05), that of 10 - 30 Hz was increased(P < 0.05) ; the electrical activity was further compared between staying status and shuttling status in the morphine-induced CPP group. There was no significant difference of electrical activity between the rats in white-black shuttling status and staying in white chamber. However, when rats in black-white shuttling status, compared with staying in black chamber, the electrical activity showed that the percentage of 0 - 10 Hz and 40 - 50 Hz were increased(P < 0.05), meanwhile, those of 10 - 20 Hz and 30 - 40 Hz were reduced(P <0.05). CONCLUSION: The electrical activity changes of NAc shell in morphine-induced CPP rats were different from those of the operation-only control group, and these changes might be associated to the rat's drug-seeking behavior. PMID- 26016240 TI - [Sodium ferulate protects against daunorubicin-induced cardiotoxicity in juvenile rats]. AB - OBJECTIVE: To investigate the protect effects of sodium ferulate (SF) on the daunormbicin(DNR-induced cardiotoxicity in juvenile rats. METHODS: Forty male juvenile SD rats were randomly divided into control group (Control), daunorubicin group (DNR), sodium ferudate treatment group (DNR + SF), sodium ferudate group (SF) (n = 10) . Juvenile rats were intraperitoneally treated with DNR (2.5 mg/kg every week for a cumulative dose of 10 mg/kg) preparation immature myocardial injury model in presence with SF (60 mg/kg) oral treat- ment for 25 days. The left ventricular pressure and its response to isoproterenol were measured using left ventricular catheter. Rat myocardium myocardial pathology specimens and ultrastructure changes were also observed. The expression of cardiac Troponin I (cTNI) was detected by Western blot and RT-PCR. Results: SF treatment could inhibit the decreasing of heart rates induced by DNR damage (P < 0.05); it could increase the left ventrivular end diastolic pressure(LVEDP), heart rate, the maximal left ventrivular systolic speed(LVP + dp/dtmax) and the maximal left ventrivular diastolic speed (LVP-dp/dtmax) responding to isoproterenol stimulation(P < 0.01); SF also could improve the myocardial ultrastructure injuries and inhibit the decreasing of cTNI expression caused by DNR damages (P < 0.05). CONCLUSION: SF treatment could alleviate the decreasing of cardiac reservation induced by DNR damages in juvenile rats, which might be related to its reversing the effects on the cardiac systolic and diastolic function injuries and its inhibiting effects on the decreasing of cTNI expression caused by DNR. The mechanism of SF preventing daunorubicin-induced cardiotoxicity in juvenile rats is relevant to inhabited cardiac Troponin I expression. PMID- 26016241 TI - [Effeces of total flavonoids of astragalus on single Ca2+ current of ventricular myocytes in BALB/c mouse with viral myocarditis]. PMID- 26016242 TI - [Effects of pumpkin polysaccharide on the blood glucose, blood lipid and oxidative stress in diabetes rat]. PMID- 26016243 TI - [Study on the biceps brachii microcirculation blood flow reserve capacity of the Chinese rowers]. AB - OBJECTIVE: To investigate the effect of chronic endurance exercise on microcirculatory reserve capacity of biceps brachii in Chinese rowers and provide a certain basis for the date standard foundation of monitoring of functional status and the foundation of database of reserve capacity of blood of Chinese rowers. METHODS: Empty stomach in the morning, 77 rowers from different groups and 24 common health people were noninvasive tested by using PeriFlux System 5000, the test indexes include the microcirculatory reserve capacity and other related indexes of biceps brachii. The test sites of all athletes were the same space in biceps brachii of the right side of body, there was no space differences of all athletes . All athletes were tested in the relatively stable functional status, common people were healthy. The test value included basic values and heating values, put the before and after heating of microcirculatory blood perfusion (MBP) as the microcirculatory reserve capacity. RESULTS: Heavyweight female (198. 97 +/- 98. 81) > heavyweight male (183. 45 +/- 64. 31) > lightweight male (151. 01 +/- 65. 96) > lightweight female(140.53 +/- 43.22) > common male people(127.21 +/- 56.38) > common female people(103.54 +/- 33.41), the microcirculatory reserve capacity of each group athletes were higher than common people, except the comparison between lightweight female and common male people, and there was no significant difference among the different group athletes. CONCLUSION: Chronic endurance exercise can improve the microcirculatory reserve capacity of rowers, especially the heavyweight rowers; the normal value of microcirculatory reserve capacity of heavy weight rowers should be more than 160, and lightweight rowers should be more than 120. There was no significant difference among different sex athletes, if the value of microcirculatory reserve capacity is significant lower than normal, it shows that athletes are in the state of fatigue. PMID- 26016244 TI - [Effects and mechanisms of low concentration dopamine on hydrogen peroxide induced apoptosis in cultured neonatal rat cardiomyocytes]. AB - OBJECTIVE: To study the effects of low concentration dopamine(DA) on hydrogen peroxide-induced apoptosis in cultured rat cardiomyocytes as well as the possible molecular mechanisms. METHODS: Cultured neonatal rat cardiomyocytes were randomly divided into the following groups: control group (control), hydrogen peroxide group (H2O2), pretreated with low concentration dopamine ( DA + H2O2), dopamine receptor l(DR1) antagonist group (DR1 + DA + H2O2), dopamine receptor 2(DR2) antagonist group (DR2 + DA + H2O2). The cell apoptosis was then assessed by MTT and flow cytometry. The cellular ultrastructure changes were observed by transmission electron micro- scope. The activity of lactate dehydrogenase(LDH )and superoxide dismutase (SOD) in cell medium was analyzed by colorimetry. The protein expressions of Cytochrone c, Caspase 3 and Caspase 9 were obtained by Western blot. RESULTS: Compared with hydrogen peroxide group, low concentration dopamine(10 umol/L) decreased the apoptosis rate and the expression of protein of apoptosis related protein, enhanced SOD activity, decreased LDH activity. DR1 antagonist SCH-23390 treatment inhibited dopamine induced cardiac protective effect. DR2 antagonist haloperido treatment had no changes compared with dopamine group. CONCLUSION: Above findings indicate that low concentration dopanine inhibits apoptosis induced by hydrogen peroxide in neonatal rat cardiomyocytes, which is partly associated with the activation of DR1. PMID- 26016245 TI - [The study of the expression and the prognostic value of Survivin and Ki67 in pancreatic endocrine tumors]. AB - OBJECTIVE: To explore the relationship between the expression of Survivin and Ki67 with prognosis of pancreatic endocrine tumors (PETs). METHODS: Immunohistochemistry for Survivin and Ki67 was performed in 25 cases of normal pancreatic tissues and 81 cases of PETs by tissue microarrays and to observe the expression and evaluate the relationship with prognosis. RESULTS: (1)The expression of Survivin and Ki67 in PETs was significantly higher than that in normal pancreatic tissues (P <0.01); (2)The expression of Survivin and Ki67 in PETs was correlated with tissue grading and the TNM-staging (P < 0.05), but not related with tumor size, location and functional status. In addition, the expression of nuclear Survivin was association with lymph node metastasis (P < 0.05). (3)The high expression of Ki67 was related with the expression of nuclear Survivin, but not related with the expression of cytoplasmic Survivin. CONCLUSION: Survivin and Ki67 were both expressed in PETs, which were closely related to the clinical pathological characteristics. They could be used as new indicators in the evaluation of prognosis of PETs. The expression of Survivin in nucleus had more diagnostic significance than that in cytoplasm, and that could be highly correlated with lymph node metastasis, which would be used as a new marker of poor prognosis. PMID- 26016246 TI - [The protective effect of Yuyin Ruangan Decoction on experimental hepatic injury]. AB - OBJECTIVE: To investigate the protective effects of Yuyin Ruangan Decoction(YRD, traditional Chinese medicine) on experimental hepatic injury in mice. METHODS: The mice were randomly divided into control group, model group and YRD low, middle and high dose group(n = 11). By ip injection of D-GalN, CCk or thioacetamide (TAA), three models of hepatic injury mice were established to investigate the effects of YRD through detecting the indexes of liver function in serum and, the content of antioxidant system in the hepatic tissue. RESULTS: YRD could decrease the content of alanine aminotransferase (ALT)and aspartate aminotransferase (AST) in serum and that of malonaldehyde (MDA) in the hepatic tissue, upregulate the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hepatic tissue. Furthermore, the above effects were dosedependent in a certain degree. CoNCLUSION: YRD has some protection effects on the model of experimental hepatic injury in mouse. PMID- 26016247 TI - [Effects of allicin on antioxidant ability and ATPase activity of rat's skeletal muscle]. PMID- 26016248 TI - [Effect of Dipsacus total saponins on the ability of learning and memory and acetylcholine metabolism of hippocampus in AD rats]. AB - OBJECTIVE: To study the effects of Dipsacus total saponins on the ability of learning and memory and its mechanism of action. METHODS: Forty rats were randomly divided into blank control group, model group, Dipsacus group and positive control group (n = 10), general situation of rats were observed, the ability of learning and memory of rats was tested by Square water maze, the activities of acetylcholinesterase (AChE)and choline acetyltransferase (ChAT) of hippocampus in rats were measured using double antibody sandwich method. RESULTS: During the period of treatment, general situation had no obvious change in model group, but general situation and the ability of activity were gradually improved in Dipsacus group and positive control group. Compared with blank control group, the swimming time was obviously prolonged and the number of mistakes was obviously increased at different time, the activity of AChE was significantly enhanced and the activity of ChAT was significantly decreased in model group. Compared with model group, the swimming time was obviously shortened and the number of mistakes was obviously reduced at different time, the activities of AChE were significantly decreased and the activities of ChAT were significantly enhanced in Dipsacus group and positive control group; Compared with positive control group, the swimming time and the number of mistakes at different time and the activities of AChE and ChAT had no significant difference in Dipsacus group. CONCLUSION: Dipsacus total saponins can improve the ability of learning and memory in Alzheimer' s disease(AD) rats, its mechanism of 'action may be related to regulating ACh metabolism of hippocampus. PMID- 26016249 TI - [Effect of epigallocatechin gallate against exercise-induced fatigue in mice]. AB - OBJECTIVE: To investigate the effects of epigallocatechin gallate (EGCG)against exercise-induced fatigue in mice. METHODS: Total 120 mice were randomly divided into three groups and tested separately. For each test, there were 30 mice subdivided into high dose (50 mg/kg . d EGCG) and low dose (10 mg/kg . d EGCG) groups as well as saline control group(1 ml/kg . d) with 10 in each. Burden swimming, running wheel endurance, stick climbing and hypoxia tolerance exercise were used to establish fatigue mice training model in three groups. And intraperitoneal injection with different doses of EGCG per day for consecutively 28 days and the mice in the control group were treated with normal saline. After the last each test, the blood lactic acid (BLA), blood urea nitrogen (BUN), blood lactate dehydrogenase (LDH), muscle glycogen (MG) and liver glycogen (LG) of each group of mice were determined. RESULTS: EGCG treatment groups(B and C)revealed a prolonged the mice survival time of burden swimming test, hypoxia tolerance, running wheel time and the ability of stick climbing(P < 0.05 or P <0.01), and increased LDH activity and MG and LG contents, reduced contents of BLA and BUN. High dose group had an obviously increase effect than lower dose group(P <0.05). CONCLUSION: EGCG has significant effects against exercise-induced fatigue in mice. PMID- 26016250 TI - [Effects of Lonicera Japonica flavone on immunomodulation in mice]. AB - OBJECTIVE: To study immunomodulating activity of Lonicera Japonica flavone by investigating immune enzymatic activity of serum and antoxidized activity of lymphoid organs in mice. METHODS: Fifty KM mice were randomly divided into control group, model group, low dose group, middle dose group and high dose group(n = 10), respectively. And low dose group, middle dose group and high dose group were given Lonicera Japonica flavone with 100 mg/kg, 200 mg/kg and 400 mg/kg every day, respectively, while control group and model group were administered with NS. After continuously giving drug 7 weeks, other groups were injected with Dexamethasome (Dex: 25 mg /kg) for 3 days by subcutaneous injection, but the control group were treated with NS. And after giving Lonicera Japonica flavone 1 week simultaneously, organ indexes , the activity of acid phosphatase (ACP), alkaline phosphatase (AKP) and lysozyme (LSZ) in serum , and the content of monoamine oxidase (MAO), total antioxidant capacity (T-AOC), total superoxide dismutase (SOD) and malondialdehyde (MDA) in lymphoid organs in mice were tested, respectively. RESULTS: Lonicera Japonica flavone could significantly improve the organ indexes, and significantly improve the activity of ACP, AKP and LSZ in serum, and significantly improve the contents of T-AOC and SOD, but reduce that of MAO and MDA in lymphoid organs in immunosuppressed mice. CONCLUSION: Ionicera Japonica flavone can significantly improve the activity of immune enzyme in serum and the antioxidized activity of lymphoid organs in mice. It suggests that Ionicera Japonica flavone has a good immunomodulatory effects. PMID- 26016251 TI - [Studies on association of HSL repeat polymorphism and aerobic endurance]. AB - OBJECTIVE: To investigate the relationship between hormone sensitive lipase (HSL) gene polymorphism and aerobic endurance. METHODS: The (CA)n repeats polymorphism genotypes in HSL intro 6 of 123 outstanding long distance runners and 127 controls of Han nationality in northern China were analyzed by PCR and Fluorescence labeled STR-genescan. Repeat polymorphisms were grouped according to segmentation point and alleles were divided into long or short chains. Chi-square test was used to analyze the frequency difference of allelic and genotypic between athlete and control groups. RESULTS: (CA) n repeats polymorphism in HSL gene was total of 9 different repeat number of alleles, which composed of 25 different genotypes. The chi-square test result showed that when compared short and long chain alleles split by 4, there was a significant difference (P <0.05) of genotype distribution in 5/10 km group compared with control. Compared the rest groups with control, there was no significant difference. CONCLUSION: Compared short and long chain alleles split by 4, the LL genotype of (CA)n of HSL was associated with aerobic endurance and it might be a molecular marker of elite 5/10 km long distance runners. PMID- 26016252 TI - It always begins with me. PMID- 26016253 TI - The road not taken. PMID- 26016254 TI - Guidance on the prevention and management of stress in the workplace. PMID- 26016255 TI - Health and social care leaders set out plans to transform people's health and improve services using technology. PMID- 26016256 TI - The Department of Health, Social Services and Public Safety (DHSSPS) publishes its 'Inpatient Patient Experience Survey 2014' report. PMID- 26016257 TI - Accountability versus blame. PMID- 26016258 TI - Perceptions of the assistant theatre practitioner role: a view from my ivory tower. AB - At a recent AfPP event, during a debating session amongst fellow perioperative practitioners, the role and remit of assistant theatre practitioner (ATP) was raised. The debating panel's views were sought from several quarters and the subject seemed to spark discussion and much 'harrumphing' in the audience. A recently qualified ATP, who, having spent an intensive two years studying for a foundation degree, expressed his frustration about on-going role ambiguity and the struggle to have his newly acquired knowledge and skills recognised in practice. As a heated discussion went around the room, polarised views were emergent, in particular themed around concerns about delegation, accountability and scope of practice. PMID- 26016259 TI - Assessing scrub practitioner non-technical skills: a literature review. AB - A review by Catchpole et al (2009) into the causes and types of harm experienced by the surgical patient emphasised the high risk nature of the perioperative period. Investigations into recent failures at NHS organisations have emphasised the relevance of non-technical skills education in improving clinical performance and patient outcomes. However, scrub practitioner non-technical skills are often developed on a tacit basis, making assessment of performance difficult. This literature review identifies strategies that facilitate assessment of non technical skills during surgery. Recommendations are made that will assist scrub practitioners in using a validated scrub practitioner non-technical skills assessment framework reliably. PMID- 26016260 TI - The anaesthetic practitioner and type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is a serious lifelong condition affecting many people in the UK. With the increasing prevalence of T1DM, it is inevitable that more patients will present for anaesthesia and surgery. This article will inform anaesthetic practitioners about the condition, the challenges involved with glycaemic control, complications such as hyperglycaemia and hypoglycaemia, and the importance of maintaining good glycaemic control. It will offer advice about what anaesthetic practitioners can do to help manage and care for their patients. PMID- 26016261 TI - The rapid sequence spinal for category 1 caesarean section: anaesthetic trainee knowledge and practice. AB - Rapid sequence induction of general anaesthesia (GA) is the fastest anaesthetic technique in a category-1 caesarean section (C1CS) for foetal distress. Recently rapid sequence spinal anaesthesia (RSS) has been explored as a technique to avoid the potential risks of GA in such cases. Out of hours, trainee anaesthetists are often required to provide anaesthesia for these emergencies. We surveyed their practices when performing a RSS. The aim of a RSS is to rapidly and safely achieve anaesthesia for C1CS, while optimising foetal oxygenation and preparing for possible GA. It requires anaesthetic skill, team work and communication. Many trainees understood the principles of the RSS, however, a significant number did not. Practice varied widely and no trainee had received any formal RSS training. Training for junior anaesthetists and those working in obstetric theatres, in the conduct of the RSS is crucial, to ensure safe practice, avoid delays in delivery and safely avoid the risks associated with GA in the C1CS. PMID- 26016263 TI - Has your hospital joined the 'Sign up to Safety: listen, learn, act' campaign? PMID- 26016262 TI - Amputation of the breast. AB - Today we take for granted the blessing of anaesthesia and it is almost impossible for us to imagine the agonies that surgical patients underwent in the past. This description of a mastectomy, performed in 1720 by Lorenz Heister, Professor of Surgery and Anatomy in Altdorf in the republic of Nurnberg, (now part of Germany), gives a vivid idea of major surgery in those days. In this much shortened abstract from his lengthy report, which appears in the 1775 English edition of his textbook entitled 'Medical, Chirurgical and Anatomical cases and Observations' he discusses the preoperative preparation, the mastectomy itself, performed as quickly as possible and the tedious postoperative dressings of the inevitably suppurating wound. PMID- 26016264 TI - A trip down memory lane. PMID- 26016265 TI - Largest ever study of awareness during general anaesthesia identifies risk factors and consequences for patients, including long-term psychological harm. PMID- 26016266 TI - Thousands of nurses and midwives sign up to improve patient care. PMID- 26016267 TI - Improved survival rates in joint ops. PMID- 26016268 TI - Coming to a theatre near you soon a witnessed CPR event'. AB - A current review of the last thirty years is indicative of improvement in outcome across surgical specialities with the implementation of safer working practices and initiatives in enhanced recovery, preparing patients to be 'fit' for surgery. The focus of training for nurses and operating department practitioners lies with assuring technical competence and the drive is to establish best practice based on evidence. Once qualified, training for professionals within the perioperative environment is developed to enable participation in areas of anaesthesia, surgery and recovery roles. Advanced, intermediate and basic life support as well as advanced scrub practitioner courses are available, further aspects for patient safety have been implemented and pathways developed. PMID- 26016269 TI - Surgical care practitioners: regulation and revalidation: a discussion. PMID- 26016270 TI - Improved patient education facilitates adherence to preoperative fasting guidelines. AB - Preoperative fasting is recognised as an important factor in perioperative patient care. Implementation of guidelines on preoperative fasting remains sub optimal. We audited perioperative fasting in a district general hospital, implemented changes to the preoperative information leaflet and improved fasting practices. The manner in which information is presented to patients impacts behavior and adherence to recommendations. Improving this domain of clinical practice requires thorough and conscious effort and repeated reassessment. PMID- 26016271 TI - Same day discharge following inter-scalene block administration for arthroscopic shoulder surgery: implementing a change in practice. AB - Patients who had arthroscopic shoulder surgery with the provision of an inter scalene nerve block (ISB) at Blackpool Teaching Hospitals, were previously required to remain in hospital overnight. We introduced a new protocol that allowed same day discharge following arthroscopic shoulder surgery under general anaesthesia and ISB. The aim of this study was to review the outcome of this change in practice. Our results indicated that providing a discharge protocol for patients having arthroscopic shoulder surgery with the inclusion of ISB can avoid unnecessary overnight stay and enable significant cost savings, without detriment to patient safety or satisfaction. PMID- 26016272 TI - The first resection of an aortic aneurysm. AB - In 1951 the report from Paris that an abdominal aortic aneurysm had been successfully resected greatly influenced surgeons throughout the world who, until then, had regarded such an operation as being outside the bounds of surgery. Indeed, as a young surgeon I could hardly believe such a procedure would be possible, having seen an unsuccessful attempt at producing thrombosis of the aneurysm by introducing coils of wire into the sac, (Colt's operation) and, in other cases, merely standing by helplessly as the patient exsanguinated from rupture of the aneurysm. PMID- 26016273 TI - Footprints and followers. AB - When I was seven years old Daisy Ayris was busy setting up NATN. We all know that very little is ever gained in isolation and our founder had the support of many willing nurses at this time. Amongst those committed nurses taking up the gauntlet was a lady also from Yorkshire called Isobel Curry. It is indeed thanks to Daisy, Isobel and many others that the Association has grown, developed and blossomed into the inclusive Association for Perioperative Practice (AfPP), now in its 51st year of existence. PMID- 26016274 TI - Haemophobia. AB - I recently finished an introductory session with a group of new start undergraduate nursing students about their responsibilities in clinical practice and was finishing up the session by checking if anyone had any questions. The usual questions were asked such as "why is it called off duty and not on duty?" Good question but once you have worked in clinical practice for a while the question of when you are off duty becomes very important more so than on duty! However, I was not expecting the following question which was, "I faint when I see blood do I need to tell the mentor when I am out in practice?" I am not often lost for words but this was one of those moments. PMID- 26016275 TI - Standard UK autologous transfusion label. PMID- 26016277 TI - "No medical evidence" to support gay blood donation ban. PMID- 26016276 TI - New web-based toolkit to tackle undermining and bullying behaviour in the workplace launched. PMID- 26016278 TI - Sharing learning from the Mary Seacole programme to improve patient care. PMID- 26016279 TI - The red zone. AB - This simple quality initiative won the best innovation in clinical practice at the recent CEO healthcare awards gala event in the North West of Ireland. It demonstrated how a simple collaborative idea led to improving the quality and safety of care in the operating room. As practitioners we have a huge contribution to make in providing quality and safe care to our patients. It is crucial that we share knowledge and have our input recognised. PMID- 26016280 TI - A retained catheter in the radial artery. AB - An 86 year old lady underwent trans-urethral resection of bladder tumour (TURBT) under general anaesthetic at a local hospital. She suffered from aortic stenosis and the anaesthetist inserted a radial artery line to monitor her blood pressure intraoperatively whilst using a phenylephrine infusion. Her surgery was uneventful and the arterial line dressing was cut off her wrist prior to removal of the line. The puncture site bled profusely and pressure was applied. The bleeding stopped and on examination, a rigid structure was palpable in her radial artery. This was believed to be the arterial line catheter which had been cut when the dressing was removed. There was no vascular compromise of her hand and she was referred to the local Vascular Centre. PMID- 26016281 TI - Improving preoperative medication instructions and patient adherence: a collaborative, hospital-based quality improvement project. AB - The goal of this project was to improve preoperative medication instructions. After baseline data were collected prospectively through standardised patient surveys, preoperative care providers were educated to convey clear, appropriate preoperative medication instructions. After the education period, patient surveys were again completed to assess improvement. Hospital-wide education effectively increased the percentage of medications with written, colour-coded, and medically appropriate instructions. Patients found the instructions clearer and easier to follow. PMID- 26016282 TI - Four steps to interpreting arterial blood gases. AB - This article examines acid-base balance and the interpretation of arterial blood gases (ABG). The article begins with a brief revision of related physiology, followed by a description of the primary disorders associated with acid-base imbalance. The normal ranges and the significance of abnormal ABG results are explored. The article concludes by providing an easy to follow four-step guide to ABG interpretation with practice examples presented in the CPD task section. PMID- 26016283 TI - Neurosurgical versus endovascular treatment of subarachnoid haemorrhage caused by ruptured cerebral aneurysm: comparison of patient outcomes. AB - The aim of this critical review is to determine whether endovascular treatment (EVT) of a subarachnoid haemorrhage (SAH) has better patient outcomes than neurosurgical treatment (NST). A review of six cohort studies (listed in Table 1) was carried out and the main findings were summarised in the conclusion. In addition the list of author's recommendations is included at the end of the paper. Theatre practitioners involved in neurosurgery might find this review useful in enhancing their understanding of how SAH is currently treated. It could also bring some insights about the reasons why a particular modality of the treatment was chosen for their patient. PMID- 26016285 TI - [The figures speak of our work]. PMID- 26016284 TI - The first identical twin renal transplant. AB - There is no doubt that it was the work of one man, Alexis Carrel, which laid the foundations of modern organ transplantation. Working first in his native city of Lyons, then in Chicago and finally at the Rockefeller Institute New York, he developed the techniques of successful anastomosis of blood vessels, using extremely fine silk sutures and tiny needles. As early as 1892, he successfully grafted a kidney into the neck of a dog. He was soon able to demonstrate that, although a dog's kidney transplanted into its own neck could survive, even when the opposite kidney was excised, transplant of a kidney to another animal would fail after a few days. Further experiments included transplantation of other organs, including ovary, thyroid, lower limb and heart. In 1914 he wrote to fellow Nobel Prize winning Swiss surgeon, Theodor Kocher about his experiments; "Concerning homoplastic transplantation (from one animal to another) of organs such as the kidney, I have never found positive results to continue after a few months, whereas ir autoplastic transplants the results were always positive. The biological side of the question has to be investigated very much more and we must find out by what means to prevent the reaction of the organism against a new organ" (my italics). This, in fact, was going to occupy the next half century of worldwide research! PMID- 26016286 TI - [Fasciocutaneous forearm flaps in the management of the catastrophic hand]. AB - This paper describes a series of cases with severe hand injury that required antebrachial flaps as part of treatment, and their functional results. The clinical records of patients with a diagnosis of traumatic hand injury and major skin cover losses, reconstructed with a reverse-flow forearm flap, were reviewed. The following variables were studied: type of flap, sex, age, mechanism of injury, receiver site, size, adjacent injuries and their treatment, vascular integrity test prior to flap placement, operative time, follow-up and complications. A total of 25 patients were included, with 25 reverse-flow fasciocutaneous forearm flaps; in 15 of them the blood supply was based on the radial artery and in 10 in the posterior interosseous artery. The Allen test was used in 13 cases of radial flaps (RF) to check the integrity of the superficial palmar arch; Doppler ultrasound was used in the remaining two cases. Sixteen cases (64%) underwent bone and tendon reconstruction, four cases (16%) isolated tenorrhaphy of one or several tendons, two cases (8%) isolated osteosynthesis, one case due to electrical burn underwent Littler opponensplasty with a radial flap in the anterior aspect of the wrist (4%), and in two cases (8%) an isolated flap was used. In one 67 year-old patient (4%) there was congestion and total loss of the posterior interosseous flap. The recommended indications for this type of flap are: coverage of the distal forearm, hand dorsum and fingers, first interdigital space, palmar region of the wrist and hand. Only two cases required coverage of the palmar region of the wrist and hand, and they were both treated with radial flaps, probably for reasons of anatomical convenience. PMID- 26016287 TI - [Hip fracture as risk factor for mortality in patients over 65 years of age. Case control study]. AB - INTRODUCTION: Hip fracture among older patients is a devastating injury in most cases. It profoundly affects the physical, mental, functional and social balance that patients used to have and, beyond the orthopedic injury, it reflects the aging process and its dire consequences. Some reports show that up to 50% of patients with hip fracture die within six months and many of those who survive do not recover their baseline independence and function. In recent decades the increase in life expectancy after 60 years of age has led to an exponential growth in hip fractures. This is why it is essential to determine the patient related and environmental factors leading to the increased mortality rates seen in patients with hip fracture, to improve the survival and quality of life of older adults. The objective was to determine the association between hip fracture and mortality in patients over 65 years of age. MATERIAL AND METHODS: An observational, longitudinal, retrospective, descriptive, comparative case-control study was conducted. The clinical records of all patients over 65 years of age admitted to the Orthopedics Service, Hospital Regional <>, ISSSTE, with a diagnosis of hip fracture during the previous 12 months were analyzed, regardless of the type of fracture and treatment they received. A group of patients without hip fracture was used as control group. Total sample size was 50 patients with hip fracture and 50 patients without hip fracture. The following data were collected in data collection forms: age, sex, time elapsed since the fracture, survival at one year and, in the case of deceased patients, the cause of death (pneumonia, sepsis, arrhythmia, hydroelectrolytic imbalance, heart failure and others). The results obtained are shown as tables and charts to facilitate their visual understanding. RESULTS: Patient demographics show that there were 40 (80%) female patients and 10 (20%) male patients with a diagnosis of hip fracture. The control group included 35 (70%) females and 15 (30) males. An association between hip fracture and increased mortality was found, with a significant p value of 0.001. The main cause of death among hip fracture patients in our study was sepsis in 7 (35%), while among the control group it was myocardial infarction in 3 (15%). Time wise, mortality was found to be higher within the first six months, with 10 deaths (50%), and within the first year, with six deaths (30%). DISCUSSION: Hip fracture is in fact a risk factor associated with mortality among patients over 65 years of age. Females are the group most prone to sustaining a hip fracture and, therefore, to increased mortality rates. The major cause of death among our patient population was sepsis, apparently caused by mismanagement of soft tissues, a poor aseptic technique during the surgical procedure, a long hospital stay or a poor family support network, and dementia, which is related to poor surgical wound care. The highest mortality rates were found in ages over 90 years, and they were associated with preexisting chronic-degenerative conditions. The age group at highest risk of hip fracture was 80-89 years. Patients with hip fracture should always be managed together with the internist and the geriatrician and they should be considered as orthopedic emergencies, as a long hospital stay and delayed surgical treatment are associated with major complications and increased mortality rates. PMID- 26016288 TI - [D-repeat polymorphism in the ASPN gene in knee osteoarthritis in females in Torreon, Coahuila. Case-control study]. AB - BACKGROUND: Knee osteoarthritis (OA) is one of the most common and disabling disorders of the musculoskeletal system. It may affect any ethnic group and causes variable degrees of disability. Various risk factors have been associated with the development and progression of this condition, such as: age, genetic and occupational factors, trauma, menopause, diabetes mellitus, obesity, and gender, among others. Distinguishing these factors, whether individually or altogether, is important to prevent or diagnose and treat the disease early on. METHODS: A case-control study was conducted in 260 females in Torre6n, Coahuila, to analyze the relationship between primary knee osteoarthritis and the D-repeat polymorphism in the ASPN gene (asporin). 130 females with knee osteoarthritis and 130 healthy female controls were included. RESULTS: In this study, menopause and the D16 allele variant were found to be significant risk factors for knee osteoarthritis (p = 0.002, OR 2.656, CI 95% 1.412-4.998; p = 0.026, OR 2.418, CI 95% 1.111-5.263, respectively). The D12 variant was found to be a significant protective allele. CONCLUSIONS: As far as we know, this is the first case-control study in Mexican women that suggests that menopause and the D-repeat polymorphism in the ASPN gene are associated with knee OA. PMID- 26016289 TI - [Elbow dislocation and lateral epicondyle fracture in a five year-old girl. Case report]. AB - Traumatic elbow dislocation in the pediatric population is a particularly unusual injury. It was first described by Stimson in 1900 and almost 100 years later revisited by Tachdjian in 1990. Three percent of cases are associated with lateral epicondyle fracture, so this is an infrequent injury that has been described in only a few papers as case reports. The mechanism of injury is not clearly known, nor is the best type of treatment or its complications. We report herein the case of a five year-old girl with fracture dislocation of the lateral epicondyle who was managed with closed reduction and percutaneous fixation with Kirschner nails, with good functional results. PMID- 26016290 TI - [Posterior tibial tenoscopy. Case report]. AB - Posterior tibial tendinitis occurs commonly in patients involved in sports activities. It may result from either excessive use or sudden overload of the tendon. This tendinitis may also occur in patients with systemic inflammatory conditions and is classified as posterior tibial tendon dysfunction stage I. Initial treatment, which has produced good results, is based on immobilization and rehabilitation. In cases without clinical improvement or in which tendinitis is associated with partial tendon rupture, open techniques may be used to perform tenosynovectomy and tendon revisions to improve painful symptoms. With the advent of minimally invasive techniques broad tendon revisions may be done that cause minimal damage or they may be combined with traditional techniques in cases of partial rupture. This paper describes the clinical case of a 35 year-old female patient with posterior tibial pathology and chronic pain. She underwent posterior tibial tenoscopy and was followed-up postoperatively for 24 months. Endoscopic and/or tenoscopic treatment is a simple and reproducible technique. We obtained excellent functional and cosmetic results in this patient. We need larger case series of patients subjected to this treatment. PMID- 26016291 TI - [Femoral head chondroblastoma and reconstruction with osteochondral allograft. Case report]. AB - Femoral head chondroblastoma is an infrequent tumor, accounting for approximately 1-2% of benign bone tumors. It occurs more frequently in young male patients. It's most frequent locations include the proximal humerus, proximal femur, distal femur and proximal tibia. The femoral head is the third most frequent site of this tumor. There is no specific treatment for this entity; reported treatments range from acetabular osteotomies and osteochondral grafts, to vascularized fibular grafts, all of them with good results. However, this tumor is clinically unpredictable if left untreated. We report a case managed with osteochondral graft and followed-up for three years after the surgical procedure. PMID- 26016292 TI - [Arthroscopic treatment of Hill-Sachs lesions in glenohumeral instability. "Remplissage" technique]. AB - Hill-Sachs lesion is a defect of the posterosuperior aspect of the humeral head that occurs during an episode of instability. Under abduction and external rotation, this lesion may engage the anterior glenoid border, thus favoring instability. It may be the cause of many failed surgical stabilization procedures. We herein describe the arthroscopic remplissage technique, which consists of filling the lesion through capsulotenodesis of the infraspinatus tendon. This maneuver should be always be performed together with anterior capsulolabral repair. The results obtained by the authors and published in the literature are good, with a loss of mobility similar to the one resulting from the isolated arthroscopic Bankart technique. We recommend performing remplissage together with Bankart repair in patients with glenohumeral instability with significant Hill-Sachs lesions without a glenoid defect or with defects less than 25%. PMID- 26016294 TI - Re: Medical students' views on selection tools for medical school--a mixed methods study. PMID- 26016295 TI - Medical education for the 21st century. PMID- 26016297 TI - Pitfalls of the urinary albumin creatinine ratio in detection of early diabetic kidney disease. PMID- 26016296 TI - Antibiotic prophylaxis in children with vesicoureteric reflux: has RIVUR answered all our questions? PMID- 26016298 TI - Does this child really have a penicillin allergy? AB - Penicillins, the most prescribed paediatric medications worldwide, are also the most commonly reported cause of medication allergy, although this is rarely confirmed. An oral penicillin challenge is considered the gold standard in assessing children with suspected allergy but is seldom performed due to lack of appropriately trained staff and insufficient facilities. We introduced a standardised nurse-led protocol to evaluate children with suspected penicillin allergy fulfilling low risk criteria. In total, 40 children participated, including 22 girls and 18 boys, of which 38 met study criteria. There were 36 (95%) negative challenges completed, allowing these children to be safely prescribed oral penicillin in the future. There were 2 (5%) positive challenges developing similar signs to their initial reaction. This standardised protocol appears to be safe for use and efficient in the evaluation of low risk children with suspected penicillin allergy. PMID- 26016299 TI - Neurodevelopmental outcome at seven years in term, acidotic newborns. AB - The objective was to follow up a cohort of acidotic full-term infants with or without hypoxic ischemic encephalopathy (HIE) and determine if at 7 years they displayed any neurodevelopmental delays. Children (n=44) were divided according to those with mild (n=25) or severe (n=19) acidosis and were then further subdivided into those with or without HIE. Participants were assessed using the Wechsler Intelligence Scale for Children (WISC-IVUK) and Achenbach Child Behaviour Checklist (CBCL). No differences in WISC-IVUK scores in children without HIE irrespective of the cord pH values were found. Children with HIE grade I scored significantly higher in perceptual reasoning than those with grade III (p<0.01). CBCL scores revealed no differences between groups. Findings suggest evidence of impairment at school-age that correlates with the degree of encephalopathy. Acidosis without the presence of clinical encephalopathy was associated with normal outcome. PMID- 26016300 TI - Does participation in CME SLG (small group learning) influence medical practice? The experience of general practitioners attending CME SLG after the introduction of the Medical Practitioners Act. AB - In Ireland, Continuing Medical Education (CME) for GPs is delivered by a national network of 37 tutors who coordinate learning sessions for between 2 and 5 small groups of physicians (SGL). Each group meets up to 8 times per year; 1100 to 1700 doctors attend CME-SGL nationally each month, with numbers increased since the Irish Medical Practitioners Act. This study investigated whether CME-SGL improves clinical knowledge of doctors. A questionnaire was administered by 35 CME tutors at their scheduled meetings in November/December 2012; 1366 (96%) attendees responded. In total 1312 (97%) doctors reported that they want to improve their clinical practice, and 1143 (86.3%) agreed that CME had helped them to do so. Of these, 1041 (91.1%) doctors gave specific examples. This survey provides evidence of how CME-SGL has impacted on the knowledge, skills, attitudes, prescribing, use of investigations, and application of guidelines and audit of these Irish GPs. PMID- 26016301 TI - Fitness to drive in cognitive impairment--a quantitative study of GPs' experience. AB - Assessing fitness to drive is part of the role of general practitioners. Cognitive impairment may affect an individual's ability to drive safely. The aims of our study were to question GPs about their experience of assessing patients with cognitive impairment for driving fitness and to explore their attitudes to this role. We carried out a quantitative cross-sectional anonymous postal survey of 200 GPs in counties Galway, Mayo and Roscommon. Ethical approval was obtained from the Irish College of General Practitioners. Data was analysed using Epi Info. The response rate was 62.5% (n=125). 86 (68.8%) GPs used guidelines when assessing fitness to drive in cognitive impairment. 83 (66.4%) respondents formally assess cognitive function. 52 (41.6%) GPs would certify someone as fit to drive with verbal restrictions. 102 (81.6%) respondents feel confident in assessing fitness to drive. 98 (78.4%) GPs have referred patients for further assessment. PMID- 26016302 TI - Predictors of outcome in decompensated liver disease: validation of the SOFA-L score. AB - A growing number of patients with liver disease are being referred for critical care support. We have recently shown that a combination of lactate and SOFA score (SOFA-L score) may provide an accurate, objective measurement of prognosis in a group of patients admitted to ICU with alcoholic liver disease. This score has not been validated in an independent patient cohort. A retrospective study was performed where patients admitted to our ICU with decompensated liver disease (any cause) were included. The SOFA-L score accurately predicted in-hospital mortality in this group of patients with an area under the ROC curve of 0.83. Sensitivity and specificity were 65% and 87% respectively SOFA-L performed superior to SOFA, MELD and MELD-Na scores. This study validates the use of the SOFA-L score in the initial 24 hours of ICU admission as an accurate predictor of mortality in this group of patients with a high mortality. PMID- 26016303 TI - Using softcast to treat torus fractures in a paediatric emergency department. AB - Wrist torus fractures in children are a frequent reason for Emergency Department (ED) visits. Torus fractures traditionally were treated with a backslab cast in the Children's ED and then referred to the Fracture Clinic. Guidelines were developed in order to standardise the care for children who attended the ED with a torus fracture. All patients who were seen & treated by the Advanced Nurse Practitioner (ANP) over a one year period with a diagnosis of a torus fracture were treated with immobilisation in a softcast. 119 patients met the criteria for inclusion. There were no adverse events recorded and no patient required subsequent visits to the Fracture Clinic. There was a cost savings of ?18,596 as compared with the normal referral pathway to the Fracture Clinic. PMID- 26016304 TI - Transition to adult care for adolescents with diabetes--a national survey. AB - Currently, there are no national guidelines on transition from paediatric to adult services for children with Type 1 Diabetes Mellitus (T1DM) in Republic of Ireland. There are 19 hospitals in Republic of Ireland looking after children with T1DM. Seventeen have a designated clinic for children with T1DM. Ten have a transition clinic for adolescents with T1DM. Most centres transition after patients finish secondary education. Six centres hold transition information sessions and 6 have access to a psychologist. Fifteen centres describe a gradual transition process. There is little national consistency in transition and there is a need for a collaborative national framework on T1DM transition. PMID- 26016305 TI - Bird fanciers lung in mushroom workers. AB - Hypersensitivity pneumonitis has been described in mushrooms workers caused by exposure to mushroom or fungal spores in the compost used to grow mushrooms. We describe two mushroom workers who developed hypersensitivity pneumonitis due to exposure to avian proteins found in poultry manure which was used in producing mushroom compost. Both workers were employed in the compost production area. Both presented with typical features of HP. Both workers had negative serological and precipitin studies to Apergillus fumigatus, Saccarhopolyspora rectivirgula and thermophilic actinomycetes but had positive responses to poultry antibodies. Neither was exposed to mushroom spores. Both workers required initial therapy with corticosteroids. Relocation with avoidance of further exposure resulted in complete cure in one worker and change in work practice with the use of personal protections equipment resulted in the second workerclinical stabilisation. These are the first reported cases of bird fanciers lung in mushroom workers. PMID- 26016306 TI - Hodgkin lymphoma in a patient with chronic lymphocytic leukaemia--a rare presentation of Richter's transformation. AB - Richter's transformation of chronic lymphocytic leukaemia (CLL) to high-grade B cell Non-Hodgkin lymphoma occurs in < 5% of CLL cases. Transformation of CLL to Hodgkin Lymphoma is a much rarer event and here we describe a patient who developed Richter's transformation into a Hodgkin Lymphoma presenting as rapidly progressive hepatosplenomegaly. PMID- 26016307 TI - Paediatric tonsillotomy--an Irish perspective on potential evolving indications. AB - Tonsillotomy is the preferred treatment of some otolaryngologists for younger patients (under 3 years) with low body weight (under 15 kgs) and a history of obstructive sleep apnoea. The use of the technique in the same patient cohort for recurrent tonsillitis remains controversial. The aim of this study was to evaluate the indications and outcomes of paediatric patients undergoing tonsillotomy (with or without adenoidectomy) at a paediatric ENT centre in Ireland. Patients were identified from a prospectively maintained database and chart review was completed. A total of 23 patients were identified who underwent tonsillotomy. The commonest indication was Obstructive Sleep Apnoea (OSA) in 15 patients (65%). Outcomes following tonsillotomy compared favourably with traditional tonsillectomy. No intra-operative or post-operative complications were recorded (0%). No patients required readmission or later tonsillectomy (0%). At follow-up 19/23 patients with OSA (82.6%) had complete symptom resolution. Tonsillotomy appears to represent a safe, effective treatment option in the paediatric population, however, its role in recurrent tonsillitis remains controversial. PMID- 26016308 TI - The initial management of epistaxis. AB - Epistaxis affects up to 60% of people. The basic first aid management of epistaxis is clearly stated in the literature and guidelines. Anecdotal evidence would suggest that these principles are not understood by patients and are not being conveyed to patients by their doctors. The aim was to assess current knowledge of epistaxis first aid management and identify the principle source of education in epistaxis control. This was a single centre cross-sectional study. The study population included those presenting to otolaryngology outpatients with epistaxis. 20 patients participated in this study over a 7 month period. Five (25%) patients did not use compression during an episode of epistaxis. Nine (60%) patients that used the compression technique failed to compress the lower one third of the nose. Only two (10%) of patients identified their GP as having taught them first aid for epistaxis. Knowledge of epistaxis management is poor. Education regarding the basic principles of first aid for epistaxis may reduce morbidity and unnecessary consultations from health professionals. PMID- 26016309 TI - Empathy and the wounded healer: a mixed-method study of patients and doctors views on empathy. AB - Empathy is increasingly being recognized as a crucial component for an effective doctor-patient relationship. Using a mixed method approach, we surveyed 125 patients and 361 medical practitioners (doctors and medical students) views of the doctor-patient relationship. We qualitatively assessed patients' views of what constituted a good doctor and qualitatively measured empathy using a validated scale in medical practitioners. Patients desire a doctor that is both clinically proficient 66 (55%) and caring 32 (27%). Doctors who have a personal experience of illness have a statistically higher empathy score. These doctors may be well placed to help develop and foster empathy in our profession. PMID- 26016310 TI - [Editorial]. PMID- 26016311 TI - [Comparison of results of two flexible ovarian hiperestimulation protocols with two different initial doses (150 vs >= 225)]. AB - BACKGROUND: With the use of new protocols Controlled ovarian hyperstimulation (COH) with lower doses of gonadotropins to the classics protocols and current trend of fewer embryos transferred, there is no agreement until today on the optimal dose start of a COH protocol. OBJECTIVE: Compare the results of two flexible protocols of HOC with different starting doses (150 vs 225 lU rFSH/hMG) plus a GnRH antagonist in cycles of IVF / ICSI. METHODS: Retrospective, descriptive study, we analyzed 231 cycles of IVF/ICSI being the primary variables: total FSH dose, dose increase, retrieved oocytes, embryos available for transfer and for cryopreservation. RESULTS: The total dose of FSH in group 11 was significantly higher versus group 1 (2096.0 vs 1447.9). The percentage of patients in whom the dose increased was higher in Group I vs Group 11 (26.4% vs 9.1%, p = 0.001). The number of retrieved oocytes was similar between the groups (10.5 vs 10.2, p = 0.76) as well as the number of embryos available the day of the transfer and the number of embryos that were vitrified 6.73 vs 6.08 (p = 0.97) and 1.5 and 1.3 (p=0.820) for Group I and I respectively. The clinical pregnancy rate was 39.3% (n = 91), and for groups I and 11 were 41.6 and 37.7% respectively. CONCLUSIONS: No significant differences between two loading dose was found (150 vs >= 225) in most of the primary endpoint. PMID- 26016312 TI - [Definitive contraception with Essure device: Single institutional experience on 517 procedures]. AB - OBJECTIVES: To analyse the outcomes of patients undergoing Essure sterilization in a single institution, interns of complications and technique failure. PATIENTS AND METHODS: Retrospective descriptive study of 517 patients underwent definitive contraception with Essure device in outpatient hysteroscopy office without anesthesia and controlled at 3 months with abdominal radiography, ultrasonography and hysterosalpingography in selected cases. RESULTS: The success rates of the insertion of Essure was 96.8%, similar to data reported in the literature with 3.7% of vagal reactions, as most prevalent complication. 7 (1.35%) unintended pregnancies were observed. CONCLUSIONS: Essure is a permanent birth control device, with high rate of successful insertion and a low rate of complications. Unintended pregnancies in our study are high and we must change the protocols of placement and monitoring, considering hysterosalpingography as a routine control test. PMID- 26016313 TI - [Induced abortion in Mexico: what do Mexican Ob/Gyn know, think and do]. AB - BACKGROUND: The causals for legal abortion in Mexico vary as established by the Constitution of each State; from 2007 it is legal in Mexico City. OBJECTIVE: To identify knowledge, attitudes and practice of abortion between gynecologists and obstetricians. MATERIAL AND METHODS: Survey study conducted between some of the gynaeco-obstetricians attended the 64th Mexican Congress of Gynecology and Obstetrics held in Mexico City, October 2013. RESULTS: From the 1,085 respondents, 77% correctly identified that abortion is legal accord to Constitutional Signs of each State; 17.5% said it is never legal and 5.7% thought that is always legal. The 67% comment that public institutions should have infrastructure and trained medical personnal to legal abortion practice. The 72% response they would attend or denounce the woman who underwent an abortion outlawed. The remaining 28% showed negative attitudes, from informing the couple or parents (18%), scold women (2%) or reporting it to the authorities (8%). In 39%, they felt that the medical profession who practice discriminates abortions; 28% admit stigmatize partener and 27% feel stigmatized if performing abortions. Percentage high hospitalized patients in case of early abortions, for surgical or medical treatment. CONCLUSIONS: It is necessary to increase and improve knowledge technical and legal about abortion, especially among gynaeco-obstetricians, they are who responsibility to comply about prescribed by law, in accordance with international recommendations and the exercise of reproductive rights of women. PMID- 26016314 TI - [Hypogastric arteries ligation: an experience in gynecological and obstetric patients at Hospital Universitario de Saltillo]. AB - BACKGROUND: Pelvic hemorrhage is a potential complication that occurs performing an obstetric or gynecological surgery, it is essential to know the distribution of pelvic vascular supplement, and implement preventive measures, can significantly reduce morbidity and mortality. OBJECTIVE: To describe the experience of hypogastric artery ligation, as a preventive and therapeutic measure of pelvic hemorrhage, this will give us new prospective lines for future investigation. METHODS: Retrospective observational study, in which all patient who were performed a surgical procedure and report hypogastric artery ligation at the Saltillo University Hospital, from January 2008 to July 2014 was studied. RESULTS: 41 patients were obtained with hypogastric artery ligation, 28 gynecological and 13 obstetric patients. Among gynecological indications, cancer surgery represents 67.85%, benign lesions 25% and pelvic abscess 7.12%. Obstetric indications were uterine hypotonia with 46%, placenta previa with 23.07% and uterine fibroids, broad ligament hematoma and abruptio placenta a total of 30.7%. There was one complication in relation with technique that was a laceration of internal iliac artery without any consequence linked to this. And uterine preserving of 62% was observed in obstetric patients. CONCLUSIONS: This technique is a feasible and safe for preventive and therapeutic management of pelvic surgery, with a low incidence of complications 3.5% in gynecological patients and 0% in obstetric, with a mortality of 0%. PMID- 26016315 TI - [Medical treatment of the uterine miomas in perimenopausal patients]. AB - BACKGROUND: Leiomyomas are the most common benign tumors of the uterus, frequently associated with abnormal uterine bleeding. Medroxyprogesterone (MP) acetate it is a therapeutic alternative. OBJECTIVE: To determine the efficacy of the medroxyprogesterone for abnormal uterine bleeding associated with leiomyomatosis in perimenopause women. METHODS: An observational, prospective, longitudinal study. We selected 31 patients with uterine myomas and abnormal uterine bleeding. Two years monthly doses of 150 mg of MP were given. If the bleeding did not stop at six months of treatment or increased a hysterectomy was performed. RESULTS: Two (6.4%) patients abandoned the treatment after a first doses; 21 (67.7%) completed the treatment without uterine bleeding (efficacy observed of 72.4%; CI 95% 54.4 to 90.4%, intention to treat efficacy 67.7%, CI 95% 49.6 to 86.8%). Eight (25.8%) patients persisted with uterine bleeding before 6 months of treatment and a hysterectomy was performed. There was no severity secondary effect informed. CONCLUSIONS: Management with medroxyprogesterone may be an effective treatment to control the uterine bleeding associated with myomatosis. Their use could reduce the necessity of some hysterectomies. PMID- 26016316 TI - [HELLP syndrome]. AB - Hypertensive disorders of pregnancy are one of the most common complications of pregnancy, but one of the most serious expressions of this pathology is HELLP syndrome. The HELLP syndrome is characterized by the presence of hypertension disorder more a triad: microangiopathic hemolysis, elevated liver enzymes and low platelet count. Patient with HELLP syndrome is associated with increased maternal risk complications such as: cerebral hemorrhage, retinal detachment, hematoma/ hepatic rupture, acute renal failure, disseminated intravascular coagulation, placental abruption and therefore a maternal death. For all these reasons it is recommended to search for findings of HELLP syndrome in patients with hypertensive disorder of pregnancy. The main clinical confusion of HELLP syndrome is acute fatty liver of pregnancy, however there are parameters that help correct identification. The presence of HELLP syndrome involves a rapid termination of pregnancy and the administration of corticosteroids does not improve maternal morbidity and mortality but may help raise the platelet count, thus decreasing the need for transfusion and shorten hospital stay. Much of the decline in maternal morbidity and mortality associated with hypertensive disorders of pregnancy is in proper diagnosis and effective management of HELLP syndrome. PMID- 26016318 TI - [About the no evidence of the "evidence". Twenty years after the start of its use]. PMID- 26016317 TI - [The EXIT procedure: Indications, limitations, risks and progress to the fetal endoscopical tracheal intubation]. AB - Congenital oral and neck masses are associated with a high perinatal mortality and morbidity secondary to airway obstruction due to a mass effect of the tumor with subsequent neonatal asphyxia and/or neonatal death. In 1997, the Ex Utero Intrapartum Treatment (EXIT) technique was designed to establish a secure neonatal airway. This procedure allows neonatal tracheal intubation while the uteroplacental circulation maintains fetal oxygenation in a partial fetal delivery during cesarean section. However, it must be emphasized that this technique requires a multidisciplinary team, maternal general anesthesia, high surgery times and potential maternal risks such as placental abruption and increased maternal blood loss due to uterine atony. In addition, the clinical algorithm to obtain a neonatal airway can be quite challenging and neonatal mortality has been reported due to the inability in obtaining an airway at birth. Recently, our Mexican group described a novel minimally invasive fetoscopical technique before cesarean delivery that allows prenatal airway control by means of a fetal endoscopic tracheal intubation (FETI) under maternal peridural anesthesia. This procedure attempted to avoid the need for an EXIT procedure and its potential risks. In this review we described the indications, risks and potential benefits of the EXIT technique and its possible replacement by the fetal endoscopic tracheal intubation technique. PMID- 26016319 TI - [Comparative analysis of imipramine intake reactions in catatonic and wistar rats]. AB - Chronic imipramine intake (7.5 mg/kg) leads to the stable decrease of excitable reactions to sound stimulant in Wistar rats and induced phase behavioral response in catatonic GC rats. Increased noradrenaline level in frontal cortex and striatum in Wistar animals was shown, whereas it didn't reveal noradrenaline level differences in any brain structures in GC rats. The higher blood corticosterone concentration was decreased under antidepressant reaction in GC rats. Differences between intact GC animals were found out: reduced triglyceride level, lesser body weight, and greater weight index of adrenals in comparison with Wistar rats. Various mechanisms of imipramine action in two rat strains were shown: influence on adrenergic brain system, taking part in the control of exiting behavior in Wistar rats and reaction in adrenals in GC rats. PMID- 26016320 TI - [Anxiolytic and antidepressant effects of 3-oxypiridine and succinic acid derivatives in alloxan diabetes]. AB - The effects of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) on affective disorders in rats with alloxan diabetes were studied. The efficiency of emoxipine, reamberin and mexidol was compared to alpha-lipoic acid, which is considered a "golden standard" in treatment of diabetic neuropathies. Emoxipine, reamberin and mexidol after seven administrations in single doses, that are equivalent to therapeutic range in humans, corrected the anxiety-depressive disorders in rats with alloxan diabetes. Unlike reamberin and alpha-lipoic acid, emoxipine and mexidol corrected the affective status concurrently with the decrease in hyperglycemia. At the same time, emoxipine outperformed mexidol in tranquilizing action (in maximal doses) but yielded mexidol in the antidepressant effect (in minimal doses). PMID- 26016321 TI - [Effects of activation of kappa-opioid receptors on the behavior at the postnatal development of the stress reactivity systems]. AB - It is known that stress changes state and reactivity of humoral systems of stress, particularly the hypothalamic-pituitary-adrenal system (HPA) and the dynorphin-K-opioid system (DKOS) in any age periods, including ones of early postnatal development. Supposedly these changes are underlying some disorders. Difference in state and reactivity of the HPA system is well established. But the role of DKOS is not clear. Further study of this requires summarizing of the literature data on physiology of DKOS activation and ethological features of the activation in different periods of postnatal development. It is possible to conclude that the mode of reaction to stimulation of the DKOS differs in the early development in contrast to adult animals. The mode of reaction can be changed in relation to the periods of development of the system of stress reactivity and can depend on prior activation of the stress system in a particular period. PMID- 26016322 TI - [Spatial memory and regulation of brain adenylyl cyclase by serotonin and dopamine in rat with streptozotocin diabetes]. AB - The most common complication of diabetes mellitus of the type 1 (DM1) is a cognitive deficiency, which develops as a result of neurodegenerative changes in the brain. The aim of this work was to study the learning and spatial memory in rats with streptozotocin DM1 with different duration (1.5 and 6 months), as well as the activity of adenylyl cyclase signaling system (ACSS) sensitive to agonists of the serotonin and the dopamine receptors in the brain of diabetic rats. Our experiments demonstrated that rats with 1.5-months DM1 has no changes in spatial memory which were evaluated in a Morris water maze whereas in rats with 6-months DM1 the spatial memory and learning ability were decreased. The alterations of the regulation of adenylyl cyclase by agonists of types 1 and 6 serotonin receptors and type 2 dopamine receptors were found in both the 1.5- and 6-months DM1 which indicates their importance in the development of cognitive deficiency. Abnormalities in the. brain ACSS can be considered as key factors in the etiology and pathogenesis of cognitive dysfunctions in DM1. Hypothesized that cognitive deficiency occurs only in the later stages of DM1 due to alterations in the serotonin and dopamine signaling systems of the brain. PMID- 26016323 TI - [Some aspects of heart rate variability estimation in rats]. AB - This study focuses on researching of heart rate variability (HRV) in rats with autoimmune myocarditis. Intact rats were investigated additionally. It was registered 2-, 5- and 20-min duration ECG from awake animals at rest-conditions and after cooling probe (CP), and then time domain and spectral parameters of HRV were calculated. We shown that 1) after CP decreasing of parasympathetic influence and augmentation of sympathetic influence on heart rate regulation in rats with autoimmune myocarditis was more manifested than in intact rats, 2) in CP with the 5-min ECG interval's duration was more informative for HRV estimation, 3) intracardiac inflammation leads to modification of correlation interconnection between some HRV-parameters, and that may talk about features of heart's chronotropic regulation in rats with autoimmune myocarditis. PMID- 26016324 TI - [Surfactant and water balance of lung in intracerebral hemorrhage at conditions of capsaicin blockade of vagus nerve]. AB - It is known that intracranial hemorrhage (ICH) is accompanied by the development of neurogenic pulmonary edema and insufficiency of surfactant function. The present study was undertaken for evaluation of the role of vagal afferents in the mechanisms of ICH effects on pulmonary surfactant and water balance of the lung. We explored the surface activity and biochemical composition of surfactant, as well as blood supply, total, intravascular and extravascular fluid content in lung after ICH, simulated by intraventricular administration of autologous blood against the background of bilateral blockade of capsaicin-sensitive vagal affere its. The blockade was caused by the capsaicin application (50 mcmol) on the cervical part of the nerves. Intracerebralhemorrhage was accompanied by the decrease of surfactant activity which appeared by the enhancement of minimal, maximal and static surface tension of bronchoalveolar lavage fluid (BAL), the reduction of total phospholipids including their main fraction phosphatidylcholine, the increase of lysophosphatidyicholine content and hyperhydration of the lung. The level of total proteins in BAL elevated, confirmed the enhanced permeability of the alveolar-blood barrier. The exhaustion of neuropeptides in capsaicin-sensitive vagal afferents led to the partial restoration of surface active properties of lung, normalization of phospholipids and protein contents and water balance parameters. The obtained results suggest that capsaicin-sensitive vagal afferents play a pivotal role in the disturbances of surfactant function and water balance of the lung after ICH. PMID- 26016325 TI - [Effects of chronic hypokinetic stress on microhemodynamics of tissue]. AB - By laser Doppler flowmetry investigated tissue microhemodynamics rats kept hypokinesia under 10 days. Investigation of the structure of rhythms blood flow oscillations in microvasculature revealed that chronic hypokinetic stress leads to a significant reduction of the oscillator and nonoscillation microhemodynamics indicators, reflected in the development of vasoconstriction, reducing the metabolic function of the endothelium and the allocation to them of nitric oxide, a violation of inflow and outflow of blood, the dominance of shunt blood flow, decreasing the number of functioning capillaries. PMID- 26016326 TI - [ATl- and calcium-dependent mechanisms of salicy- lates influence on electric potentials of neurons in mollusk Helix albescens]. AB - The article is devoted to investigation of mechanisms of salicylates influence on electric potentials in neurons of mollusk Helix albescens Rossm. It is shown that adenosinetriphosphate (5 x 10(-4) M) at the combined bath application with salicylates substantially modifies their neurotropic effects. It removes nonselective inhibition of impulse activity of neurons by acetylsalicylic acid and strengthens activating effects of cobalt and zinc acetylsalicylates. It is shown that at the blockade of Ca2+ entry by CdCl2 or BaCl2 (5 x 10(-5) and 5 x 10(-4) M) in a neuron from extracellular space or from intracellular depot do not change significantly neuronal responses to salicylates, what suggests that calcium mechanisms did not participate in these responses. PMID- 26016327 TI - [The function of the heart changes in implementation of the diving reactions in humans]. AB - The changes of chronotropic function of the heart and of the myocardium in the implementation of the diving response in humans were studied by the electrocardiographic method. The study involved 80 students aged 18-20 years. Diving simulation was performed by immersing the face in cold water during breath hold exhale. When the water temperature was 12.3 +/- 2.3 degrees C, average duration of apnea was 31 +/- 11 s. The oxygen content in the exhaled air after apnea was 98.8 +/- 8.7 mm Hg, carbon dioxide--49.1 +/- 3.5 mm Hg. It was observed slowing of the heart rate, mainly due to the increasing of diastole in 41 of the 80 surveyed during simulating diving. But it also can be observed symptoms of conduction deterioration: atrioventricular block type I (22% of reactive type and 29% of the highly reactive type subjects), and exceeds standards QTc-interval prolongation (at 7.5% of the subjects). These responses are adaptive in nature and disappear in the recovery process. But the fact abnormalities of conduction in the myocardium must be considered when using the diving reflex in medical practice, as may be due to a predisposition to a certain pathology of the cardiovascular system. PMID- 26016328 TI - [State temperature-pain sensitivity and morphological features of the skin back in patients with idiopathic scoliosis with stage III-IV]. AB - This study was aimed at revealing the features condition of thermal, pain sensitivity and morphological pattern of the skin of the human back at the apex of spinal deformity in the thoracic area in patients with idiopathic scoliosis with stage III-IV. The study included 41 adolescent with idiopathic scoliosis with stage III-IV. Temperature-pain sensitivity was studied in Th6-Th10 dermatomes on the right and the left. Biopsies (skin) for histological examination were taken intraoperatively in projection corresponding to the apex of the arc scoliosis of the spine. Significant disorders of the sensitivity to temperature and pain were found in the dermatomes to the apex of the thoracic spine deformity that were hyperesthesia, hypoesthesia, or absent thermal sensitivity. Histostrukturnye changes of the skin are significantly decreasing the thickness of the epidermis and dermis, reduction of capillaries and changing the structure of the small vessels, destruction of individual nerve fibers and free nerve endings. PMID- 26016329 TI - [Influence of the practice of meditation on the cardiovascular response in the perception and cognitive reassessment emotiogenic stimulus]. AB - This study examines the effects of meditation on cardiovascular activity during affective image processing. 22 meditators and 20 controls were shown affective images and were asked either to attend to the images or to down-regulate negative affect (for negative images) or to up-regulate positive affect (for positive images) while continuous cardiovascular activity were recorded. During natural viewing meditators manifested identical pre-stimulus total peripheral resistance (TPR) for all images, whereas controls exhibited greatest,pre-stimulus TPR for negative images and reduced it only in the emotion regulation condition. No between-group differences were revealed for natural viewing of positive images, whereas up-regulation was associated with greater cardiac activation in meditators. The results provide a contribution to the understanding of the mechanisms responsible for the beneficial influence of meditation on cardiovascular risk factors. PMID- 26016330 TI - [Role of opisthorchis felineus on induction of bile duct cancer]. AB - Opisthorchis felineus (Trematoda) is widespread in the Russian Federation, especially in Siberia, and other countries of Europe. Infestation of endemic area population with O. felineus reaches 80%. On animal models of the infection of closely related Opisthorchis viverrini combined with the nitrosamines' intake it has been shown that the parasite induces cholangiocarcinoma. However carcinogenic potential of O. felineus is still poorly studied. The present study is aimed to investigate the role of O. felineus in cholangiocarcinoma carcinogenesis in hamster treated additionally by dimethylnitrosamine (DMN). Golden hamsters were divided into 4 groups (15 specimens in the control group and 20 for other groups): (I) untreated control, (II) 12.5 ppm DMN solution intake, (III) infected with 50 metacercariae of O. felineus and (IV) infected with 50 metacercariae of O. felineus and 12.5 ppm DMN solution intake. According to the histological data, in the. O. felineus-infested group significant hyperplastic and dysplastic biliary changes were found considered as a precancerogenic state. Such pathological changes of bile ducts were more severe in group treated with both factors, with cholangiocarcinoma being found out at 18th week in all the animals of this group. These results demonstrate that O. felineus could play promoting role in two-step model in cholangiocarcinoma carcinogenesis and may be used to define the O.felineus group in the International Agency for Research on Cancer classification of agents, mixtures and exposures (IARC categories). PMID- 26016331 TI - [New data on trematodes of Antarctic fish]. AB - Deepwater fishes from the Amundsen Sea, d'Urville Sea, Ross Sea, Cooperation Sea, Weddell Sea, and open waters of the South-West part of the Pacific sector of the Antarctic were examined. Fourteen species of trematodes were found. Muraenolepitrema magnatestis Gaevskaya et Rodjuk, 1988 and Helicometrina sp. were found in the Antarctic for the first time. Muraenolepitrema magnatestis was redescribed and basing on this, diagnosis of the genus Muraenolepitrema was amended. Muraenolepitrema magnatestis possesses the uroproct and glandular cells that are loosely arranged around the external seminal vesicle (without a membranous sac). PMID- 26016332 TI - [Parasitological factors impeding the transmission of the agent of babesiosis (Babesia microti) to man from the tick Ixodes persulcatus]. AB - Based on the analysis of own and literature data, it is concluded that the following ma- in permanent system of ecologicalarasitological factors prevents the effective vector functions of the tick I. persulcatus in transmission of B. microti: lack of distinct nymphs' anthropophily; small spontaneous invasion of hungry adults; a duration of the parasitic phase in humans is insufficient to complete the sporogonic development, because victims interrupt the phase. Therefore, not excluding the possibility of sporadic babesiosis disea- ses, it can be stated that within the boundaries of a vast territory, where the taiga tick is the only potential source of infection for humans, the B. microti infection has not, and will not reach significant values in infectious pathology. PMID- 26016333 TI - [Cuticle ultrastructure of the fresh-water horsehair worm Gordionus alpestris (Villot, 1885) (Nematomorpha)]. AB - The cuticular structure of the horsehair worm Gordionus alpestris (Villot, 1885) was studied under scanning and transmission electron microscopes. Adult worms were collected in the Syuk River near Nickel' Village in the Republic of Adygea (Russia) in June 2013. In the sampling area, the G. alpestris juveniles parasitize diplopods Pachyiulus krivolutskyi Golovatch, 1977. Similarities with other Nematomorpha species with the known cuticle ultrastucture are discussed. PMID- 26016334 TI - [Role of the marsh frog tadpoles in the life cycle of Cosmocerca ornata (Nematoda: Cosmocercidae)]. AB - Experimental infestation of the marsh frog tadpoles with the Cosmocerca ornata (Du- jardin, 1845) larvae was conducted. In vitro development of the first, second and third larval stages of the helminth were studied. Tadpoles of different age were infested both i) by feeding larvae to them and ii) by placing them in containers simultaneously with the C. ornata larvae. In both cases dissection revealed the presence of living larvae of the nematode in the tadpoles' intestines. Despite their motility and activity, the I and II larval stages were not invasive; they never persisted inside the tadpoles' digestive tract. In 4-5 days after the second molt, a "temporary persistence" was observed. Living larvae were in suppressed condition, motility lowered, further development never occurred. In 3 days occurrence of the III stage nematode larvae lowered drastically. Gradual elimination of the most part of C. ornata larvae was observed. Elimination rate depended on the tadpole developmental stage. Later tadpole stages (those that had already developed arms and legs) were the first to get rid of the nematode larvae--on 7-th day after the infestation. On the 9-th day tadpoles of the early stage (those without limbs) got rid of the larvae. Larvae persisted for the longest time in the intestines of middle-staged tadpoles (with the hind legs)--up to 13 days. PMID- 26016335 TI - [Helminth fauna of the bank vole myodes glareolus (Schreber, 1780) in the Kizhi Archipelago]. AB - The present study was aimed to examine the specific features of the helminth fauna in insular populations of the bank vole (Myodes glareolus) in the north of the species range. The material was collected in and nearby the Kizhi Archipelago (Lake Onega, 62 degrees 1' N 35 degrees 12' E) during August 1997, 2005-2007, 2012 and 2013. Small mammals were trapped on 23 islands (varying from 2 to 15,000 ha) and on the mainland. Helminthological met- hods were applied to examine 301 specimens of M glareolus. Fourteen helminth species were found: trematodes- Skrjabinoplagiorchis vigisi; cestodes--Paranoplocephala omphalodes, P. gracilis, Catenotaenia henttoneni, Taenia mustelae, Cladotaenia globife- ra, Spirometra erinacei; nematodes--Trichocephalus muris, Aonchotheca murissylvatici, Hepaticola hepatica, Heligmosomum mixtum, Heligmosomoides glareoli, Longistriata minuta, Syphacia petrusewiczi. The parasites S. vigisi, S. erinaci, H. hepatica and T. muris were identified in the bank vole in Karelia for the first time. Significant differences were detected between the helminth faunas of local insular populations of the bank vole. A distinctive feature of all small islands was that samples from them lacked the widespread pa- rasitic nematode Heligmosomum mixtum. The studies have confirmed the general trends observed in the parasite fauna of most isolated populations of small mammals: a poorer species diversity and high infestation rates with certain species of parasites. The Kizhi Archipelago is characterized by the specific high abundance of regionally rare parasite species (H hepatica, A. murissylvatici), and by the absence of common parasites (H. mixtum, H. glareoli). PMID- 26016336 TI - [Dr. Zbigniew Kabata, 17.03.1924-04.07.2014]. PMID- 26016337 TI - [Protein profile strain specificity of Bifidobacterium genus members]. AB - AIM: Analysis of differences in protein spectra of various bifidobacteria strains of intestine microsymbiocenosis using identification results from MALDI-TOF mass spectrometer. MATERIALS AND METHODS: Results of mass-spectrometry ("Bruker Daltonics", Germany) for 57 intestine isolates' of Bifidobacterium spp. are provided. 500,laser impulses were used for obtaining every mass-spectrum; parameters of mass-spectrometer were optimized for the 1000-18000 m/z (mass to charge) range. RESULTS: Comparative analysis of mass-spectrometry biomarkers for Bifidobacterium genus members has detected variations in the quantity of peaks (4 to 56) among both various species and within bifidobacteria species, that reflects uniqueness of the protein profile of separate strains. Along with biomarkers, specific for most cultures, significant differences of the examined peaks were detected; including among microorganisms, that belong to the same species. As such, for B. bifidum species strains--only in 67 +/- 7.5% of cultures the presence of common peaks in'the 9282-9901 m/z was detected, whereas protein spectra in other ranges differed by both quantity and molecular mass. CONCLUSION: Differences in protein profile of Bifidobacterium genus microorganisms reflect uniqueness of protein spectra (proteome) of every separate strain; determining their functional activity, features of interaction, with associative microsymbionts and host organism in human associative symbiosis. PMID- 26016338 TI - [Deceleration of bacterial growth in Staphylococcus aureus and Pseudomonas Aeruginosa cultures in the presence of copper and zinc cations]. AB - AIM: Evaluate antibacterial effects of millimole concentrations of copper and zinc cations used as sulfates or chlorides in S. aureus and P. aeruginosa cultures. MATERIALS AND METHODS: Suspension of S. aureus or P. aeruginosa containing 108 CFU/ml were lawn-seeded onto Petri dishes with nutrient agar. 30 minutes later salt solution of copper or zinc with concentrations by metal cation from 10(-9) or 10(-6) M to 5 x 10(-1) M were applied to the surface of the lawn by 5 MU drops using a 36-channel stamp-replicator. Dishes with bacterial cultures were then incubated for 16-18 hours at 37 degrees C, and diameter of growth inhibition zone was measured afterwards. For evaluation of the presence (absence) ofviable bacteria in growth inhibition zones, seeding of the material from the center of the zone was carried out into tubes with nutrient broth that were thermostated up to 5 days at 37 degrees C, clarity of the nutrient broth was then evaluated. RESULTS: Inhibiting effects of zinc sulfate against S. aureus surpass effects of copper sulfate by 1.3-1.6 times (p < 0.001-0.05) within metal concentrations from 50 to 500 MM. The effects of zinc chloride in S. aureus culture surpass effects of copper chloride by 1.2-1.6 times (p < 0.02) for cation concentrations of 100 and 500 mM. In P. aeruginosa cultures, antibacterial effects of copper sulfate are comparable with effects of zinc sulfate. The effects of copper chloride on P. aeruginosa cells are 1.2 times more pronounced (p < 0.05) than effects of zinc chloride for metal concentration of 500 mM. Material seeding from zones of culture growth suppression detects turbidity of nutrient broth in samples with specimens from wells treated with zinc salts and broth clarity in samples from wells treated with copper salts. CONCLUSION: In millimole con- centrations, copper and zinc cations have pronounced antibacterial effects in cultures of S. aureus and P. aeruginosa. It is realized as bactericidal in the presence of copper cations and bacteriostatic - in the presence of zinc cations. S. aureus bacteria turn out to be more sensitive to the effects of zinc cations, evaluated by zones of growth inhibition, than P. aeruginosa. The latter show a higher, than S. aureus, tolerance to copper and zinc. Wherein, P. aeruginosa toler- ance to copper cations is surmountable. PMID- 26016339 TI - [Quantitative and qualitative composition of axilla microbiota in practically healthy individuals]. AB - AIM: Characteristics of quantitative and qualitative composition of cultured microorganisms isolated from axilla skin of practically healthy individuals. MATERIALS AND METHODS: 77 practically healthy individuals aged 18 to 40 years were examined. Species identification of microorganisms was carried out byculture morphologic, tinctorial and biochemical properties using time-of-flight mass spectrometer and rpoB gene amplification with subsequent direct sequencing. RESULTS: Quantitative evaluation of microbial composition of axilla skin microbiota in most of the practically healthy individuals varied in the 4-5 lg CFU/ml interval, whereas seeding of skin by this microbiota at the level of 8 lg CFU/ml was not detected. 158 strains of 24 microorganism species were identified in this biotope. Most of these strains (68.9%) belonged to Corynebacterium genus, 21.6% of strains--to Staphylococcus genus, 7.6% of strains--to Micrococcus genus and 1.9% of strains--Candida albicans. 16 species of corynebacteria were isolated with predomination of C. tuberculostearicum (40.3%), C. amycolatum (18.4%) and C. ureicelerivorans (14.8%) strains. The microbial landscape in most of the examined individuals (77.9%) was presented by microorganism association. CONCLUSION: Quantitative and qualitative species composition of cultured microorganisms isolated from axilla skin biotope of practically healthy individuals was characterized for the first time. PMID- 26016340 TI - [Epizootic and epidemic manifestation of natural foci of tularemia in Moscow region (1965-2013)]. AB - AIM: Detection of contemporary features of tularemia focimanifestations, determination of territories of high epidemic risk in various landscape zones and creation of a map of foci territories of Moscow Region for isolation of tularemia infectious agent cultures and registered human morbidity for justified planning of prophylaxis measures. MATERIALS AND METHODS: Report materials of epizootologic examinations of natural foci for 1965-2013, 156 maps of epidemiologic examination of cases of human infection with tularemia, results of studies of casting of predatory birds and dung of predatory mammals were used. Registered morbidity and isolation of tularemia infectious agent cultures from 1965 to date were applied to an electronic map of Moscow Region by sign method using modern. GIS technologies (MapInfo 10.5 program). Electronic maps Ingit at 1:200,000 scale, as well as Google Earth program were used to search for base points. RESULTS: Analysis of morbidity has revealed structure change in human tularemia morbidity- an increase of the fraction of urban population and a decrease of the fraction of patients among rural inhabitants, unimmunized against this infection are mostly ill. The presence of DNA of tularemia causative agent in biological objects in the complex with serologic and bacteriological studies was shown to allow to detect flaccid epizootics even at low numbers of rodents. CONCLUSION: Cartographic reflection of registered morbidity and isolation of tularemia infectious agent cultures allowed to show territories with various degrees of epizootic activity and epidemic manifestation. Positive results of serologic and molecular-genetic studies of environmental objects gives evident on epizootic activity and constant risk of aggravation of epidemic situation for this infection. PMID- 26016341 TI - [Role of laboratory methods in epidemic control of brucellosis outbreaks in Moscow zoo nursery]. AB - AIM: Evaluation of the role of contemporary methods in epidemic control of brucellosis outbreaks among employees of auxiliary facilities in Moscow zoo nursery. MATERIALS AND METHODS: During 2003-2013, biannually, sera from more than 200 employees of the nursery, that work during periods of epizootics of small and large cattle in nursery auxiliary facilities, were studied. A complex of laboratory methods for brucellosis was used: variations of traditional serologic agglutination method in tubes--Wright's reaction (WR), on glass--Huddleston's reaction, Coombs' anti-globulin reaction; enzyme immunoassay with immune-dominant S-LPS; realtime polymerase chain reaction with primers based on genus target of BCSP31 protein gene. RESULTS: After eradication of sheep brucellosis in 2003, the percentage of nursery facility employees, that react positively to brucellosis, has decreased from 42.7% to 15.9-17.2% in 2005-2006. RT-PCR detected human infection during epizootics 5.8 times more effectively compared with EIA. The repetition of the brucellosis epizootics in 2007 and 2009 among large cattle and a 2-year yak had initiated a rise in infection rate among employees, that had not previously (2003-2006) reacted to brucellosis. Acute clinical forms of brucellosis were not detected in 2012-2013 and antibody titers in EIA in previously infected employees have decreased in the absence ofbrucellosis epizootics in the nursery. 30 employees, infected with brucellosis causative agent, were detected for the entire period of examination, among those 10 individuals had developed clinical forms of brucellosis (6--acute, 4--chronic). CONCLUSION: Epidemic control for 11 years, based on a complex of laboratory methods, allowed to register infection and outbreaks of brucellosis in the nursery employees during epizootics of 2003, 2007 and 2009. RT-PCR--effective method of detection of infection in humans during brucellosis periods in the nursery. EIA--sensitive method during chronic forms of brucellosis in the periods between and after epizootics compared with RT-PCR. A variation of a traditional serologic method of diagnostics has shown a lower sensitivity, informativity with a larger duration of analysis compared with RT-PCR and EIA. PMID- 26016342 TI - [Prevalence of hepatitis E markers in children]. AB - AIM: Frequency of detection determination for past and current hepatitis E virus (HEV) infection markers in children with immune suppression, as well as children with normal immune status. MATERIALS AND METHODS: The presence of HEV markers (anti-HEV IgG and IgM, HEV RNA) was studied in 609 sera samples of children with neurologic pathologies, 87 samples--from children with immune deficiencies, as well as 3122 samples from conditionally healthy children of 6 regions of Russia. The children were divided into 5 age groups. Anti-HEV IgG and IgM determination was carried out in EIA, HEV RNA--by RT-PCR. RESULTS: The frequency of detection of anamnestic anti-HEV IgG turned out to be significantly higher among immune compromised. children compared with healthy children (5.7% against 1.4%, p < 0.05). Anti-HEV IgM, that testify to current or recent infection, were also detected significantly more frequently among children with immune-suppression (1.1-1.6%) compared with healthy children (0.25%, p < 0.05). HEV RNA was detected in 1 child with the absence of anti-HEV IgM and IgG. Nucleotide sequence analysis of HEV confirmed membership of this isolate in genotype 3, that is prevalent in non-endemic territories. CONCLUSION: The data obtained have demonstrated, that HEV-infection is prevalent among children in Russia and its course is, probably, asymptomatic in most cases. Immune suppression is a factor of increased risk of infection of children with HEV. PMID- 26016343 TI - [Selective-differential nutrient medium "Shewanella IRHLS agar" for isolation of Shewanella genus bacteria]. AB - AIM: Development of a selective-differential nutrient medium for isolation of Shewanella genus bacteria. MATERIALS AND METHODS: 73 strains of Shewanella bacteria (S. algae--3, S. baltica--26, S. putrefaciens--44) and 80 strains of 22 other bacteria genera were used. Shewanella species were identified by methods and criteria proposed by Nozue H. et al., 1992; Khashe S. et al., 1998. RESULTS: Nutrient media "Shewanella IRHLS Agar" for shewanella isolation was developed. Medium selective factors: irgazan DP-300 (I). 0.14-0.2 g/l and rifampicin (R) 0.0005-0.001 g/l. Shevanella colonies were detected by the production of hydrogen sulfide (H), lipase presence (L), lack of sorbitol fermentation (S). The medium suppressed the growth of hydrogen sulfide producers (Salmonella, Proteus) and blocked hydrogen sulfide production by Citrobacter. Growth of Escherichia, Enterobacter, Klebsiella, Shigella, Staphylococcus, Bacillus was also suppressed, Analytical sensitivity of the medium was 1-2 CFU/ml for Shewanella and Stenotrophomonas, Aerombnas, Serratia genera bacteria. 72 strains of Shewanella were isolated from water of Neva river in this medium, 91.7 +/- 3.2% of those produced H2S. 1 strain of S. algae was isolated from clinical material. CONCLUSION: The developed media allows to use it in a complex for Stenotrophomo- nas sp., Aeromonas sp., Serratia sp., Citrobactersp. and Shewanella bacteria isolation. PMID- 26016344 TI - [Biofilm formation by group A Streptococci of various types and study of antibiotics effect on this process]. AB - AIM: Evaluation of the ability to form biofilms by various M, T and MT-types of group A streptococci (GAS), as well as study of the effect of various antibiotics on biofilm formation. MATERIALS AND METHOD: 43 strains of various M and T type GAS were studied. The cultures were grown in Todd-Hewitt broth with the addition of 0.5% yeast extract. Comparative evaluation of the ability to form biofilm was carried out using photometry. Benzylpenicillin, oxacillin, cepha- losporin, cefuroxime and ceftriaxone antibiotics were used at various concentrations. RESULTS: GAS differ significantly by their ability to form biofilms. The highest ability was noted in 8 strains--2M, 9M, 12M, 13M, 19M, 30M, 36M-types and 6MT type. Simultaneous introduction of GAS cultures and antibiotics into the culture well, except for ceftriaxone, resulted in growth inhibition of both plankton cells and biofilms. CONCLUSION: The ability of GAS to form biofilm depends on streptococci serotype. During simultaneous introduction of GAS with antibiotics into the well, the biofilm does not form. PMID- 26016345 TI - [Features of biofilm morphology, formed by Corynebacterium diphtheriae gravis tox+ strains]. AB - AIM: Study the structure of homogenous microbial communities of Corynebacterium diphtheriae gravis tox+ strains during formation of biofilms in vitro. MATERIALS AND METHODS: Object of study--typical and biofilm cultures of C. diphtheriae gravis tox+ museum and circulating strains. Intensity of biofilm formation was evaluated by OD on microplate reader at 540 nm wave length studying 120 and 720 hour cultures. S-450 (Hitachi, Japan) scanning electron microscope was used. RESULTS: The peak of exopolysaccharide matrix (EPS) formation, that is formed in the process of biofilm formation, by museum strain takes place at earlier terms of cultivation (120 hours) than circulating (720 hours). An inverse correlation was established during analysis of bacterial cells of museum and circulating strains of C. diphtheriae during biofilm formation between them and intensity of EPS formation. At maximum EPS content, that took place at various terms of cultivation of the 2 studied strains of diphtheria causative agent, a reduction of corynebacteria cells was observed. CONCLUSION: Bacterial biofilms of museum and circulating strains of C. diphtheriae and patterns of dynamics of EPS reflect, probably, adaptive abilities of the causative agent, that determine its competitiveness in the fight for adhesion sites, resistance to factors of natural immunity and as a result--prolonged persistence in the organism of bacterial carriers. PMID- 26016346 TI - [Monitoring of influenza and other respiratory diseases causative agents in children, hospitalized with community-acquired pneumonia in 2012-2013 epidemic season]. AB - AIM: Study the circulation of respiratory viruses in children with community acquired pneumonia (CAP) during the period from October 2012 to May 2013. MATERIALS AND METHODS: 136 children with CAP aged from 3 months to 16 years with ARI symptoms at the disease debut were studied. RNA/DNA of influenza A, B, parainfluenza (PI); adeno-, rhino-, RS-viruses, corona-, metapneumo- (MPV) and bocaviruses were detected in nasopharynx smears by PCR with hybridization fluorescent detection in real time. Antibodies against influenza viruses A/H1N1/pdm09 California/07/09, epidemic reference strains of influenza viruses A/H1N1/Brisbane/59/07, A/ H3N2/Victoria/361/201 1, B/Wisconsin/1/10, against PI viruses type 1, 2, 3 were determined in paired sera by HAI. RESULTS: In February March 2013 the number of children protected by antibodies against influenza decreased, and circulation of influenza viruses A/H3N2 and A/H1N1/ pdm09 was detected. Rhinoviruses and PI viruses were determined throughout the epidemic season, bocavirus and adenoviruses--during the autumn-winter period, RS-virus and MPV--during winter-spring. Coronaviruses were not detected. The peak of virus detection was established in February when the threshold of influenza and ARI morbidity was exceeded. The main pathogens of children of the first 3 years of life are rhinoviruses, RS-virus, PI viruses and bocavirus. RS-virus infection at the debut of CAP in children younger than 3 years in 55.5% of cases is associated with the development of broncho-obstructive syndrome. Bocavirus infection in 50% of cases progresses with laryngo-tracheitis and bronchiolitis. CONCLUSION: The fraction of viruses in etiologic structure ofARI in children varies depending on immune layer, season and age of children. Etiology of viral infection at the debut of CAP could only be proven using specialized laboratory studies. PMID- 26016347 TI - [Detection of West Nile virus RNA and specific antibodies in blood donors of Volgograd region]. AB - AIM: Study infection level by West Nile virus (WNV) of donors living on the territory of West Nile fever (WNF) foci with long-term activity, and evaluate the possibility of non-transmissible transfer of the causative agent during use of donor blood. MATERIALS AND METHODS: Blood sera (432) collected in August and September 2012 in Volgograd and Volzhsky cities were studied by PCR and EIA. RESULTS: Antibodies to WNV were detected in 16.2% (70/432); 8.8% (38/432) donors had IgG; 0.93% (4/432)--IgM and 6.5% (28/432)--IgG and IgM antibodies simultaneously. WNV RNA was detected in one of the samples in the last group. Thus, 5 donors (1.1%, 5/432) were at the early stages after infection. CONCLUSION: The data obtained give evidence on the necessity to execute control of donor blood by PCR and EIA in WNF foci with long-term activity. PMID- 26016348 TI - [Evaluation of biological properties of Pseudomonas aeruginosa strains isolated from patients with sternum and rib osteomyelitis]. AB - AIM: Study of the role of P. aeruginosa in the development of osteomyelitis of sternum and ribs in cardio-surgery patients, and analysis of the main biological properties of the isolated bacterial strains. MATERIALS AND METHODS: 132 bacterial cultures were isolated from 83 hospital patients as a result of bacteriological examination during 2007-2013. Wound discharge was the study mate- rial. Sampling, seeding and identification of the isolated cultures was carried out by using the respective test-systems; antibiotic sensitivity was studied by disc-diffusion method. RESULTS: The proportion of P. aeruginosa was 10.6% (n = 14) that is comparable with data on wound infections of general surgery hospitals. A direct and strong correlation (R = 0.846, p = 0.000132) between hemolytic and phospholipase activity was established during evaluation of virulence properties of the isolated-strains. The degree of film-forming ability varied significantly from 0.122 to 1.412 OD; 64.3% ofthe studied cultures were highly film-forming variants. Statistically significant association between biofilm formation and other studied properties was not found. 4 strains produced VIM2-type metallo-betalactamase and had identical RAPD profiles. CONCLUSION: Considering that earlier the similar cultures were not detected and all of them were isolated at a short interval of time, we have made a conclusion, that their short-term circulation is probably associated with introduction, which was the reason for patient infection. P. aeruginosa could be the etio-pathogen of both early and later complications of cardio-surgical interventions. PMID- 26016349 TI - [Criteria of difference evaluation for-various types of hemorrhagic fever with renal syndrome foci. HFRS foci in various biotopes of northern barrens]. AB - AIM: Determine qualitative and quantitative criteria of evaluation of features for natural, natural-anthropourgic and anthropourgic foci of hantaviruses (using hemorrhagic fever with renal syndrome--HFRS foci as an example), that have formed in various areas of Saratov Region. MATERIALS AND METHODS: Epizootological and epidemiologic data from 1998 to 2012 were analyzed. During this period in all the types of foci of Atkarsk area (Northern barrens) 13,004 trap-nights were worked off, 2577 small mammals were procured. Genetic, population-ecological and ecological-epizootological methods and criteria were used for comparative analysis of 3 types of loci: PCR diagnostics and sequencing of pathogenic for humans hantaviruses, species cadaster and features of season dynamics of species composition of hantavirus carriers, domination indexes, parameters of quantity and infection of carriers by hantaviruses; distribution of the latter by biotopes, degree and character of population contacts with natural-foci complexes, epizootic potential of foci. RESULTS: Based on multi-year data analysis features of 3 types of HFRS foci were shown in various, mostly forest, biotopes of Northern and a part of typical barrens. A stable domination of Pumala genotype hantavirus was noted; a weakly expressed circulation in parasite systems with Apodemus genus carriers, first of all Dobrava genotype Apodemus agrarius, was established as well. CONCLUSION: A certain specter of most universal criteria;that are closely interconnected, are necessary during typing of HFRS foci and a number of other zoonozes. PMID- 26016350 TI - [Metagenomic studies and infectious diseases diagnostics]. AB - Principles of mass parallel sequencing, otherwise called next generation sequencing (NGS), appeared at the beginning of 2000s and were realized in dozens of NGS platforms. High performance and sequencing speed of NGS platforms opened wide horizons for scientists in the field of genomic studies, including metagenomic, first of all related to studies of structure of various microbiocenoses. Dozens of studies dedicated to studies of microbiome and virome of various biotopes of humans in normal state and pathology by using NGS platforms have appeared, forming novel conceptions on pathogenesis and epidemiology ofvarious infectious diseases. Significant cost reduction of the analysis facilitates expansion of sphere of application for NGS technologies not only in the field of fundamental, but also applied microbiologic studies, including etiologic diagnostics of infectious diseases. Due to the increase of the number of cases of infectious diseases, that do not have a typical clinical presentation, use of metagenomic approach is of particular importance, allowing to carry out detection of a wide spectrum of causative agents of bacterial, viral and parasitic infections. Technologic features of mass parallel sequencing platform, main methods of metagenomic studies and bioinformatics approaches, used for the analysis of data obtained, are presented in the review. Studies on healthy human microbiome and in pathology are described; possibilities and perspectives of metagenomic approach application in diagnos- tics and system of epidemiologic control of infectious diseases are examined. PMID- 26016351 TI - [Analysis of prophylactic and therapeutic effect of probiotic preparations from position of new scientific technologies]. AB - In this review new scientific technologies (genomics, proteomics, metabolomics, transcrip- tomics) were used to evaluate the prophylactic and therapeutic action of probiotics, which are a major component ofthe normal human microflora (microbiota). Modern terms, definitions, classification of probiotic preparations are provided in the paper, the list of the probiotics registered in the Russian Federation is also submitted. The review analyzes the majority of mechanisms of probiotics action on a human body. The problem of safe application of probiotics is considered along with the detailed characteristic of the most effective production probiotic strains. New scientific technology to assess the effects of probiotic bacteria on the various functions of the macroorganism are also examined. In the review the special attention is paid to discussion of effectiveness of the probiotics impact in chronic infectious and metabolic disease processes (atherosclerosis, lipid distress syndrome, type 2 diabetes, obesity, etc.), which are the most active during dysbacteriosis and the destruction of normal microflora. From data of this article clearly that new scientific technologies will allow us to establish the functions of proteins that regulate metabolic and signaling pathways and affect the expression of genes required for the adaptation of probiotic strains in contact with the human body. In this review it is shown that the successful solution of this problem is closely connected with application of new scientific technologies for studying the composition and functions of the human microbiota, methods of active influence on her, and also with development of more sophisticated and effective probiotic preparations. PMID- 26016352 TI - [Analysis of foreign experience of maintenance of biological safety of the Olympic Games]. AB - The analysis of the international experience in providing measures of health and disease safety at the Olympic Games was done. The stages of the formation of bio security system at public events were considered, including measures to prevent infection outbreaks, the use of computer and information technologies. PMID- 26016353 TI - [The epidemiological situation in the Republic of Abkhazia in 2013-2014 and Rospotrebnadzor participation in activities for its stabilization]. AB - Official statistics of Republican SES on infectious diseases are used. The characteristics of the current epidemiological situation in the Republic of Abkhazia is given. The analysis of infectious dis- eases from 2012 to 2014 is presented. It was found that the most widespread infectious diseases are acute respiratory viral and acute intestinal infection. During the analyzed period in the country outbreaks of dysentery, whooping cough and measles were reported. Epidemic threat is the presence of active natu- ral foci of infectious diseases and permanently disadvantaged anthrax points on the territory ofAbkhazia. Activities carried out by the Ministry of Health of the Republic of Abkhazia with the help and active participation of Rospotrebnadzor contributed stabilization the epidemiological situation. PMID- 26016355 TI - [Modern methods application of genotyping of infectious diseases pathogens in the context of operational work of specialized anti-epidemic team during the XXII Olympic Winter Games and XI Paralympic Winter Games]. AB - This paper considers the experience of genotyping and sequencing technologies in laboratories of specialized anti-epidemic team (SAET) during the XXII Olympic Winter Games and XI Paralympic Winter Games of 2014 in Sochi. The work carried out during the pre-Olympic period on performance of readiness by SAET for these studies is analyzed. The results of genotyping strains of pathogens during the Olympic Games are presented. A conclusion about the effectiveness of the use of molecular genetic techniques in terms of SAET is made. PMID- 26016354 TI - [Using modern information technology in the practice of the sanitary epidemiological surveiliance during the XXII Olympic Winter Games and XI Paralympic Winter Games in Sochi]. AB - To improve the sanitary and epidemiological surveillance at the Olympic Games has developed a system of GIS for monitoring objects and situations in the region of Sochi. The system is based on software package ArcGIS, version 10.2 server, with Web-java.lang. Object, Web-server Apach, and software developed in language java. During th execution of the tasks are solved: the stratification of the region of the Olympic Games for the private and aggregate epidemiological risk OCI various eti- ologies, ranking epidemiologically important facilities for the sanitary and hygienic conditions, monitoring of infectious diseases (in real time according to the preliminary diagnosis). GIS monitoring has shown its effectiveness: Information received from various sources, but focused on one portal. Information was available in real time all the specialists involved in ensuring epidemiological well-being and use at work during the Olympic Games in Sochi. PMID- 26016356 TI - Children's exercise capacity at high altitude in Tibet. AB - Maximal oxygen uptake (exercise capacity) is a vital parameter in the evaluation of adaptation to high altitude, providing an index of the integrated function of the oxygen transport system. Previous studies of maximal oxygen uptake in population at high altitude have mainly focused on adults and adolescents, though data on children are uncommon. Maximal oxygen uptake can be measured directly, using an oxygen analyser, or indirectly through the development of equations for estimation from the maximal power output (W(max)). Such estimations and studies of the physiological aspects of children's capacity to work and live at different altitudes in Tibet ancestry were not reported previously, although differences similar to those seen in adults may be expected to occur. The present paper summarized the findings of studies on exercise capacity among children living at high altitude in Tibet. PMID- 26016357 TI - Hypoxic preconditioning: effect, mechanism and clinical implication (Part 1). AB - Hypoxic preconditioning (HPC) refers to exposure of organisms, systems, organs, tissues or cells to moderate hypoxia/ischemia that is able to result in a resistance to subsequent severe hypoxia/ischemia in tissues and cells. The effects exerted by HPC are well documented. The original local in situ (LiHPC) is now broadened to remote ectopic organs-tissues (ReHPC) and extended crossly to cross pluripotential HPC(CpHPC) induced by a variety of stresses other than hypoxia/ischemia, including cancer, for example. We developed a unique animal model of repetitive autohypoxia in adult mice, and studied systematically on the effects and mechanisms of HPC on the model in our laboratory since the early 1960s. The tolerances to hypoxia and protection from injury increased significantly in this model. The adult mice behave like hypoxia-intolerant mammalian newborns and hypoxia-tolerant adult animals during their exposure to repetitive autohypoxia. The overall energy supply and demand decreased, the microorganization of the brain maintained and the spacial learning and memory ability improved but not impaired, the detrimental neurochemicals such as free radicals down-regulated and the beneficial neurochemicals such as adenosine(ADO) and antihypoxic gene(s)/factor(s) (AHGs/AHFs) up-regulated. Accordingly, we hypothesize that mechanisms for the tolerance/protective effects of HPC are fundamentally depending on energy saving and brain plasticity in particular. It is thought that these two major mechanisms are triggered by exposure to hypoxia/ischemia via oxygen sensing-transduction pathways and HIF-1 initiation cascades. We suggest that HPC is an intrinsic mechanism developed in biological evolution and is a novel potential strategy for fighting against hypoxia-ischemia and other stresses. Motivation of endogenous antihypoxic potential, activation of oxygen sensing--signal transduction systems and supplement of exogenous antihypoxic substances as well as development of HPC appliances and HPC medicines such as AHFs are encouraged based on our basic research on HPC. HPC may result in therapeutic augmentation of the endogenous cytoprotection in hypoxic-ischemic or suffering from other diseases' patients. Evolutionary consideration of HPC and clinical implications of HPC are both discussed to guide future research. The product of AHF is expected to be one of the most effective first aid medicines to rescue patients in critical condition. HPC is beginning to be used in surgery and is expected to be developed into a feasible adaptive medicine in the near future. PMID- 26016358 TI - [Pathophysiological changes in mitochondria of mammalian exposed to hypoxia at high altitude]. AB - As human beings ascend to high altitude, a number of reactions may occur against hypoxic injuries. These hypoxic responses are related to intake, transportation and utility of the oxygen. As a crucial subcellular organelle of oxygen utility, mitochondrion is a central link of high altitude acclimatization, adaptation and mountain sicknesses. In this review, we discussed the recent advances in researches on hypoxic mitochondrial responses at high altitude. PMID- 26016359 TI - [Role of HCN channels in the nervous system: membrane excitability and various modulations]. AB - Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, distributing in a variety of tissues, especially in excitable cells such as heart cells and many kinds of neurons, have an important role in the modulation of heart rate and neuronal excitability. Different from typical voltage-gated sodium channels and potassium channels, HCN channels were evoked inward currents when the cell was hyperpolarized. More and more recent studies have disclosed that HCN channels play important roles in the nervous system, which were linked with its special electrophysiological features as well as its regulatory effect on the cellular membrane excitability. HCN channels could be modulated by many factors including both extracellular molecules and intracellular signaling cascades, which made its functions complicated in the different condition. Based on its role, HCN channels are presumed to be a promising target for chronic pain and brain disorders. In this paper, we will focus on the advancement of roles of HCN channels in the neural system as well as its complex modulator factors. PMID- 26016360 TI - [How to deal with cerebral palsy in 21st century--a new epoch in clinic treatment]. AB - The aims of this paper were to define (1) criteria of cerebral palsy; (2) classification of cerebral palsy; (3) etiology, neuroimaging, and epidemiology of cerebral palsy; (4) different kinds of treatments of cerebral palsy. Data were drawn from an international survey of PUBMED (1994-2014) and CNKI (1994-2014). An expert panel used a consensus building technique. The10-point Jadad scale was used to assess the quality of the trials based on the following items, including allocation sequence generation, randomization concealment, methods of blinding, and descriptions of withdrawals and dropouts. Our clinical experience was also summarized. Below is a summary. (1) Further work is warranted to reach agreement for the classification of cerebral palsy. (2) A worldwide prevalence of 1.5-4.0 per 1 000 live births, with an average lifetime cost of 1 million dollars per person in the United States, while it is 1.8-6.0 per 1000 live births in China. (3) Comparison of clinical efficacy of different treatments. In this review, the current advances in different kind of treatments of brain injury are discussed with specific relevance to cerebral palsy. PMID- 26016362 TI - A rat model of high altitude polycythemia rapidly established by hypobaric hypoxia exposure. AB - OBJECTIVE: To investigate the effects of simple hypobaric hypoxia on parameters of hematology and blood rheology in order to establish a rat model of simulated high altitude polycythemia (HAPC) for the study of pathophysiologic mechanisms and medical prevention and treatment of HAPC. METHODS: Forty-eight male Wistar rats were randomly divided into three normal control groups and three hypoxia model groups. Normal control group rats were bred in normoxia conditions, and hypoxia group rats were subjected to hypoxic exposure for 8 hours per day at simulated 5 500 m high altitude in a hypobaric chamber. After hypoxic exposure for 2, 4, 12 weeks, one group of normal control and hypoxia model rats were killed and blood was collected, respectively. Then parameters of erythrocyte and blood rheology were examined. RESULTS: Mucous membrane of hypoxia model rats showed obviously cyanosis after 2 weeks hypoxic exposure. Hemoglobin concentration of hypoxia model rats were beyond 210 g/L after 2 weeks, 4 weeks and 12 weeks hypoxia exposure and significantly increased than that of normal control rats respectively. Besides, RBC counts, hematocrit, whole blood viscosity, erythrocyte aggregation index of hypoxia model rats were all notably higher than those of normal control rats respectively. CONCLUSION: A rat model of high altitude polycythemia can be rapidly established by hypobaric hypoxia exposure at simulated 5 500 m high altitude for 8 hours daily. PMID- 26016361 TI - Hematological parameters in high altitude residents: Tibetan natives versus Han migrants. AB - OBJECTIVE: Aim of our study was to compare hematological parameters in Tibetan natives with those in Han migrants living on the Tibet plateau in order to determine the potential effects of age, gender, and ethnicity on hematological response to hypoxia. METHODS: Blood hemoglobin (Hb, g/dl), hematocrit (Hct, %), red blood cells (RBC,10(6)/mm3) were measured in 3 588 healthy Tibetan natives and 3 371 Han migrants ranging in age from 5 to 72 years, living at a mean altitudes of 2 664 m, 3 813 m, 4 525m and 5 226 m. RESULTS: Hemoglobin (Hb) concentration analysis was made by multiple regression equations relating hemoglobin to altitude and age. For 2 093 Han males, Hb = 9.612+ 0.001440xaltitude+ 0.06148xage. For 1 948 Tibetan males, Hb =12.202+ 0.000462xaltitude+ 0.02893xage. For 1 278 Han females, Hb = 10.858+ 0.000939xaltitude+ 0.02632xage. For 1 640 Tibetan females, Hb = 11.402+ 0.000626xaltitude+ 0.00412xage. Each of the four equations was statistically significant (P < 0.001), and had variance (r2) of 0.86 or more, indicating that altitude and age accounted for at least 85% of the variation in hemoglobin levels. The coefficients for altitude and for age were higher (P < 0.05) in Han males than in Tibetan males and higher (P < 0.05) in Han females than in Tibetan females. The Tibetan postmenopausal females had higher Hb values than premenopausal females only presented at altitude above 4 000 m while this phenomenon was beginning at altitude of 2 664 m among Han females. CONCLUSION: We conclude that gender and increasing age in Tibetans are associated with lower hemoglobin values than those in Han at high altitude, and we speculate that genetic factors seems to be important. PMID- 26016363 TI - Plasma endothelin-1 and nitric oxide correlate with ligustrazine alleviation of pulmonary artery hypertension in patients of chronic cor pulmonale from high altitude plateau during acute exacerbation. AB - OBJECTIVE: To explore the mechanisms involved in the ligustrazine alleviation of the pulmonary artery hypertension (PAH) in patients of chronic obstructive pulmonary disease (COPD) associated with chronic cor pulmonale (CCP) during exacerbation. METHODS: Seventy patients of COPD and CCP with acute exacerbation were randomly and equally divided into control group and treatment group. The control group received standard treatment with antibiotics, antiasthmatic and expectorant medications, and oxygenation; and the ligustrazine treatment group received ligustrazine treatment (80 mg/d; i.v.; for 2 weeks) in addition to the standard treatment. Before and at the end of 2 week treatment, the clinic responses of the two regimens were evaluated, plasma levels of endothelin-1 (ET 1) and nitric oxide (NO) were determined; arterial oxygen partial pressure (PaO2, mean pulmonary arterial pressure (mPAP), outflow tract of right ventricle (RVOT), and internal diameter of right ventricle (RV) were measured. RESULTS: Good clinic benefits were achieved in both the standard and ligustrazine regimens, plasma level of ET-1, values of mPAP, RV and RVOT decreased significantly, plasma level of NO and PaO2 values decreased (all P < 0.01 vs pre-treatment to all parameters). Compared with the control group, ligustrazine greatly enhanced the clinic efficacy from 77.1% to 97.1% (P < 0.05), and also resulted in more significant changes of all these parameters (P < 0.01 vs control group for all parameters). For both groups, the levels of plasma ET-1 were positively correlated with values of mPAP, RVOT, and RV (r = 0.710, 0.853, and 0.766, respectively, all P = 0.000), and negatively correlated with plasma NO and PaO2 (r = - 0.823, and - 0.752, respectively, all P = 0.000). CONCLUSION: Ligustrazine is effective in treating pulmonary artery hypertension during acute exacerbation of COPD and CCP in patients from the plateau area. The observed changes in the plasma levels of NO and ET-1 in response to ligustrazine treatment suggest that ligustrazine may act through the selective effect on pulmonary blood vessels to enhance the synthesis and release of NO and suppress those of ET-1 from lung vascular endothelial cells, thus reducing pulmonary artery pressure and decreasing pulmonary arterial hypertension. PMID- 26016364 TI - Scene-trait coping style of military rescuers in Wenchuan earthquake. AB - OBJECTIVE: This study aimed to explore the scene-trait coping style of military rescuers in Wenchuan earthquake in an effort to provide scientific evidences for mental intervention program for Chinese military personnel. METHODS: By cluster sampling, a total of 151 military rescuers and 331 control servicemen were administered the military personnel scene-trait coping style scale (MPSTCSS). RESULTS: All active coping factor scores, and passive coping factor scores of affection, health and economy in the rescuer group were significantly higher than those in control group (P < 0.05). The 21-above age subgroup, the 3-year plus service subgroup, and the officer subgroup had significantly higher active coping factor scores on military tasks, military experience and personal development than those of the 21-below age subgroup, 3-year minus service subgroup and the soldier subgroup, respectively (P < 0.05 or P < 0.01). CONCLUSION: The earthquake relief servicemen can cope with stressful situations better than control group by taking active coping style. The officers, servicemen older than 21 years, and servicemen with more service duration than 3 years could usually take active coping style. PMID- 26016365 TI - Effect of acclimation training on physiological changes in a randomized controlled trial in hot-humid environment. AB - OBJECTIVE: This study was aimed to explore the physiological changes and the effect of heat acclimation training via a randomized control trial study. METHODS: Forty healthy male volunteers were chosen and divided into experimental group and control group randomly. Those in experimental group received heat acclimation training including but not limited to meditation, unarmed run, yoga, and stepping in hot lab environment. And then, subjective feeling, rectal temperature, average skin temperature, and sweat electrolytes concentration were detected in order to describe their physiological changes. Before and after the training, both groups received some tests and their 3 000 m run-race time, nervous reaction time and subjective perception scores were recorded to evaluate the effect of acclimation training. RESULTS: (1) There was no difference in 3 000 m between the 2 groups in the same environment. Subjects' 3 000 m race time in experimental group was obviously shortened than that in control group in room temperature environment (t = 2.326, P < 0.05). And subjects' 3 000 m race time in experimental group was obviously shortened than that in control group in hot humid environment (t = 4.518, P < 0.01). (2) Subjects' reaction time (RT) in experimental group was shortened than that in control group in room temperature environment (Z = 11.258, P < 0.05). And Subjects' RT in experimental group was sharply shortened than that in control group in hot-humid environment (Z = 6.519, P < 0.01). (3) No difference between the experimental and control groups was observed in subjective perception score (SPS) in room temperature environment. But subjects' SPS in experimental group was obviously lowered than that in control group and in hot-humid environment (t = 17.958, P < 0.01).(4) Anal temperature (AT) was lowered during training, while the change of mean skin temperature (MST) was not significant. Sweat sodium concentration (SSC) was lowered during training. SPS continued to decrease and entered plateau on the 13th day after training.(5) After acclimation training, the working capacity of the experimental group in hot-humid environment was over 85% of that in room temperature environment. While subjects' working capacity in control group in hot humid environment was about 80% of that in room temperature environment. CONCLUSION: Hot-humid environment acclimation training improved the working capacity. After training, subjects' working capacity in hot-humid environment remained over 85% of that in room temperature environment, which was higher than that of those subjects who did not take part in training. PMID- 26016366 TI - Stimulation of endothelial non-neuronal muscarinic receptor attenuates the progression of atherosclerosis via inhibiting endothelial cells activation. AB - OBJECTIVE: To investigate the effects of non-neuronal muscarinic receptors (NNMR) stimulation on atherosclerosis and endothelial cells activation. METHODS: Atherosclerosis model was established in ApoE-/- mice by a high fat diet for 7 weeks. During the experimental periods, animals were received a low (7 mg/kg/d) or a high (21 mg/kg/d) dose of arecoline by gavage. At the termination of the treatments, serum total cholesterol and NO levels were measured, and the aorta morphology was analyzed by hematoxylin and eosin staining. The gene expression of monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules in the thoracic aortas was determined by RT-PCR, and the MCP-1 protein expression and NF-kappaB activity were detected by Western blot analysis. NO production, MCP-1 secretion in cultured rat aortic endothelial cells (RAECs), and monocyte-endothelium adhesion assay were also performed after arecoline treatments. RESULTS: Arecoline efficiently decreased atherosclerotic plaque areas, increased serum nitric oxide (NO) content, suppressed the mRNA and protein expression of MCP-1, and modulated the IkappaB-alpha degradation and P65 phosphorylation in the aortae of ApoE-/- mice. Furthermore, arecoline promoted NO production and suppressed MCP-1 secretion in cultured RAECs after ox-LDL exposure, and either atropine or NG nitro-L-arginine methylester could abrogate these effects. Arecoline also significantly inhibited the adherence of U937 monocytes to the ox-LDL injured human umbilical vein endothelial cells, which could be abolished by atropine. CONCLUSION: Our results indicate that arecoline attenuates the progression of atherosclerosis and inhibits endothelial cells activation and adherence by stimulating endothelial NNMR. These effects, at least in part, are due to its modulation on NF-kappaB activity. PMID- 26016367 TI - Microvesicles derived from hypoxia/reoxygenation-treated human umbilical vein endothelial cells impair relaxation of rat thoracic aortic rings. AB - OBJECTIVE: To investigate the effects of microvesicles (MVs) derived from hypoxia/reoxygenation (H/R)-treated human umbilical vein endothelial cells (HUVECs) on endothelium-dependent relaxation of rat thoracic aortic rings. METHODS: H/R injury model was established to induce HUVECs to release H/R-EMVs. H/R-EMVs from HUVECs were isolated by ultracentrifugation from the conditioned culture medium. H/R-EMVs were characterized using 1 MUm latex beads and anti-PE CD144 by flow cytometry. Thoracic aortic rings of rats were incubated with 2.5, 5, 10, 20 MUg/ml H/R-EMVs derived from H/R-treated HUVECs for 4 hours, and their endothelium-dependent relaxation in response to acetylcholine (ACh) or endothelium-independent relaxation in response to sodium nitroprusside (SNP) was recorded in vitro. The nitric oxide (NO) production of ACh-treated thoracic aortic rings of rats was measured using Griess reagent. The expression of endothelial NO synthase (eNOS) and phosphorylated eNOS (p-eNOS, Ser-1177) in the thoracic aortic rings of rats was detected by Western blotting. Furthermore, the levels of SOD and MDA in H/R-EMVs-treated thoracic aortic rings of rats were measured using SOD and MDA kit. RESULTS: H/R-EMVs were induced by H/R-treated HUVECs and isolated by ultracentrifugation. The membrane vesicles (< 1 MUm) induced by H/R were CD144 positive. ACh-induced relaxation and NO production of rat thoracic aortic rings were impaired by H/R-EMVs treatment in a concentration dependent manner (P < 0.05, P < 0.01). The expression of total eNOS (t-eNOS) was not affected by H/R-EMVs. However, the expression of p-eNOS decreased after treated with H/R-EMVs. The activity of SOD decreased and the level of MDA increased in H/R-EMVs treated rat thoracic aortic rings (P < 0.01). CONCLUSION: ACh induced endothelium-dependent relaxation of thoracic aortic rings of rats was impaired by H/R-EMVs in a concentration-dependent manner. The mechanisms included a decrease in NO production, p-eNOS expression and an increase in oxidative stress. PMID- 26016368 TI - A dysfunction of CD4+ T lymphocytes in peripheral immune system of Parkinson's disease model mice. AB - OBJECTIVE: Parkinson's disease (PD), a neurodegenerative disorder, has been reported to be associated with brain neuroinflammation in its pathogenesis. Herein, changes in peripheral immune system were determined to better understand PD pathogenesis and provide possible target for treatment of PD through improvement of immune disorder. METHODS: 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) was intraperitoneally injected into mice to prepare PD model. Expression levels of pro-inflammatory and anti-inflammatory cytokines and transcription factors of CD4+ T lymphocyte subsets in spleen and mesenteric lymph nodes and concentrations of the cytokines in serum were examined on day 7 after MPTP injection. Percentages of CD4+ T lymphocyte subsets were measured by flow cytometry. RESULTS: MPTP induced PD-like changes such as motor and behavioral deficits and nigrostriatal impairment. Expression levels of the pro-inflammatory cytokines including interferon (IFN)-gamma, interleukin (IL)-2, IL-17 and IL-22, in spleen and mesenteric lymph nodes were upregulated and their concentrations in serum were elevated in PD progression. But, the concentrations of the anti inflammatory cytokines including IL-4, IL-10 and transforming growth factor (TGF) beta were not altered in the two lymphoid tissues or serum of PD mice. In addition, expression of T-box in T cells (T-bet), the specific transcription factor of helper T (Th) 1 cells, was downregulated, but expression of transcription factor forkhead box p3 (Foxp3), the transcription factor of regulatory T (Treg) cells, was upregulated. In support of the results, the numbers of IFN-gamma-producing CD4+ cells (Th1 cells) were reduced but CD4+CD25+ cells (Treg cells) were elevated in both the lymphoid tissues of PD mice. CONCLUSION: PD has a dysfunction of peripheral immune system. It manifests enhancement of proinflammatory response and CD4+ T cell differentiation bias towards Treg cells away from Th1 cells. PMID- 26016369 TI - [Preface for special issue on Anammox (2014)]. AB - Anaerobic ammonia oxidation (Anammox) is one of the important discoveries in the field of environmental microbiology, and it plays an indispensible role in the nitrogen removal from wastewaters and the biogeochemical nitrogen cycle. Through review research progress in anaerobic ammonia oxidation, an Anammox special issue is published so as to find problems, explore applications and outlook developments. The special issue consists of reviews and original papers, mainly involving in the following aspects: i) enrichment of Anaerobic ammonia oxidation bacteria (AnAOB); ii) community analysis of AnAOB; iii) preservation of granular AnAOB sludge; iv) effect of organic matter on Anammox; v) application of Anammox process, etc. PMID- 26016370 TI - [Application and obstacles of ANAMMOX process]. AB - Anaerobic ammonium oxidation (ANAMMOX), as its essential advantages of high efficiency and low cost, is a promising novel biological nitrogen elimination process with attractive application prospects. Over the past two decades, many processes based on the ANAMMOX reaction have been continuously studied and applied to practical engineering, with the perspective of reaching 100 full-scale installations in operation worldwide by 2014. Our review summarizes various forms of ANAMMOX processes, including partial nitritation-ANAMMOX, completely autotrophic nitrogen removal over nitrite, oxygen limited autotrophic nitrification and denitrification, denitrifying ammonium oxidation, aerobic deammonification, simultaneous partial nitrification, ANAMMOX and denitrification, single-stage nitrogen removal using ANAMMOX and partial nitritation. We also compare the operating conditions for one-stage and two-stage processes and summarize the obstacles and countermeasures in engineering application of ANAMMOX systems, such as moving bed biofilm reactor, sequencing batch reactor and granular sludge reactor. Finally, we discuss the future research and application direction, which should focus on the optimization of operating conditions and applicability of the process to the actual wastewater, especially on automated control and the impact of special wastewater composition on process performance. PMID- 26016371 TI - [Distribution and influence factors of Anammox bacteria in sewage treatment systems]. AB - Nitrogen removal techniques based on Anammox process are developing rapidly these years. The distribution and diversity of Anammox have become important research directions. A variety of Anammox have been detected till now, of which only Kuenenia and Brocadia are often detected in wastewater treatment systems. In addition, in a single niche there is only one type of Anammox bacteria. However, the distribution mechanism and transformation of Anammox bacteria in different niches are still ambiguous. Therefore, the distribution of Anammox in various conditions was summarized and analyzed in this article. And the key factors influencing the distribution of Anammox were concluded, including substrate concentration and the specific growth rate, sludge properties and microbial niche, the joint action and influence of multiple factors. The engineering significance research on the distribution and influencing factors of Anammox bacteria in the sewage system and proposed research prospects were expounded. PMID- 26016372 TI - [Effect of oxygen on partial nitrification in a membrane bioreactor]. AB - We studied the effects of the oxygen on partial nitrification in a membrane bioreactor (MBR), to find out critical dissolved oxygen (DO) concentrations for the optimal partial nitrification by monitoring the oxygen uptake rate (OUR) and oxygen supply rate (OSR). The nitrite accumulation occurred at a DO concentration of 1 mg/L, while the ratio of nitrite to ammonia in effluent was close to 1 at a DO concentration of 0.5 mg/L which was suitable to serve as the feed of an ANNAMOX system. When the mixed liquid suspended solids(MLSS) was 20 g/L in MBR, OUR and OSR were 19.86 mg O2/(L.s) and 0.369 mg O2/(L.s) respectively, indicating that the oxygen supply was the bottleneck of partial nitrification. "Low DO and high aeration rate" were suggested as a control strategy to further improve the efficiency of partial nitrification. PMID- 26016373 TI - [Simultaneous removal of carbon and nitrogen from organic-rich wastewater with Anammox]. AB - In order to simultaneously remove carbon and nitrogen from organic-rich wastewater, we used an up-flow anaerobic sludge bed/blanket (UASB) reactor that was started up with anammox with high concentration of carbon and nitrogen by gradually raising the organic loading of influent. We optimized the removal of nitrogen and carbon when the chemical oxygen demand (COD) concentration varied from 172 to 620 mg/L. During the entire experiment, the ammonium and total nitrogen removal efficiency was higher than 85%, while the average COD removal efficiency was 56.6%. The high concentration of organic matter did not restrain the activity of anammox bacteria. Based on polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and tapping sequencing analyses, the Planctomycete, Proteobacteria, Chloroflexi, Chlorobi bacteria are detected in the UASB reactor, which indicated complex removal pathway of carbon and nitrogen coexisted in the reactor. However, a part of Planctomycete which referred to anammox bacteria could tolerate a high content of organic carbon, and it provided help for high performance of nitrogen removal in UASB reactor. PMID- 26016374 TI - [Enrichment of anaerobic ammonium oxidation bacteria by expanded-granular sludge bed reactor]. AB - An expanded-granular sludge bed (EGSB) reactor was set-up with artificial water by seeding a 60 d stored ANAMMOX sludge. The nitrogen removal efficiency of ANAMMOX enrichment culture in the reactor was determined. In addition, the main microbial populations and the relative abundance of ANAMMOX bacteria were investigated by molecular approaches. Results show that the maximum nitrogen removal rate was 3.0 kg-N.m(-3).d(-1) after 185 d, and the ammonium and nitrite removal efficiencies were all over 85%. Analysis of 16S rRNA gene-cloning indicates that the main microbial population in the ANAMMOX enrichment culture was changed from Candidatus Brocadiafulgid and Candidatus Brocadia brasiliensis (0 day) to Candidatus Jettenia asiatica (185 day). Fluorescence in situ hybridization analysis shows that the relative abundance of ANAMMOX bacteria was increased from (57.69 +/- 4.79)% to (83.32 +/- 4.40)%. The results of qPCR further indicate that the gene copies of ANAMMOX bacteria in the granules were increased from 1.14 x 10(11) copies/g wet weight to 3.69 x 10(11) copies/g wet weight. PMID- 26016375 TI - [Physicochemical and ecological characteristics of the granular sludge during start-up of Anammox reactor]. AB - The anaerobic granular sludge from an Internal Circulation (IC) reactor of a paper mill wastewater treatment plant were seeded in an Anammox upflow anaerobic sludge blanket reactor. After 185 days operation, the reactor was finally started up by increasing the influent ammonium and nitrite concentrations to 224 mg/L and 255 mg/L, respectively, with volumetric nitrogen removal rate increasing to 3.76 kg/(m3.d). The physicochemical characteristics of the cultivated Anammox granules were observed by scanning electron microscope, transmission electron microscope and Fourier Transform infrared spectroscopy (FTIR). Results suggested that during the start-up course, the granular sludge initially disintegrated and then re aggregated. FTIR spectra results revealed that the Anammox granular sludge contained abundant functional groups, indicating that it may also possess good adsorption properties. The ecological structure of the granular sludge, analyzed by the metagenomic sequencing methods, suggested that the relative abundance of the dominant bacterial community in the seeding sludge, i.e., Proteobacteria, Firmicutes, Bacteroidetes, significantly reduced, while Planctomycetes which contains anaerobic ammonium oxidation bacteria remarkably increased from 1.59% to 23.24% in the Anammox granules. PMID- 26016376 TI - [Microbial community in the Anammox process of thermal denitration tail liquid]. AB - An anaerobic sequencing batch reactor (ASBR) was used to treat thermal denitration tail liquid and microbial community was studied. Activated sludge was taken from the reactor for scanning electron microscope analysis. The images showed that the dominant cells in the flora were oval cocci. Its diameter was about 0.7 MUm. Through a series of molecular biology methods such as extracting total DNA from the sludge, PCR amplification, positive clone authentication and sequencing, we obtained the 16S rDNA sequences of the flora. Phylogenetic tree and clone library were established. The universal bacteria primers of 27F-1492R PCR amplification system obtained 85 clones and could be divided into 21 OTUS. The proportions were as follows: Proteobacteria 61.18%; Acidobacteria 17.65%; Chlorobi 8.24%; Chlorofexi 5.88%; Gemmatimonadetes 3.53%; Nitrospirae 2.35% and Planctomycetes 1.18%. The specific anammox bacterial primers of pla46rc-630r and AMX368-AMX820 PCR amplification system obtained 45 clones. They were divided into 3 OTUS. Candidatus brocadia sp. occupied 95.6% and unknown strains occupied 4.4%. PMID- 26016377 TI - [Influence of preservation temperature on the characteristics of Anammox granular sludge]. AB - To study the effect of preservation temperature on the characteristics of anaerobic ammonium oxidation (Anammox) granules and optimize the preservation temperature of Anammox granules, the Anammox granules were cultivated in an upflow anaerobic sludge bed reactor through adjusting the hydraulic retention times, and the inorganic carbon with KHCO3/NaHCO3 was alternately supplied. Subsequently, the enriched Anammox granules were preserved at -40, 4 and 35 degrees C, and ambient temperature of (27 +/- 4) degrees C. NaHCO3 can be used as the inorganic carbon for the growth of anaerobic ammonium oxidizing bacterium (AnAOB). The best preservation temperature was 4 degrees C for maintaining Anammox biomass, Anammox activity, settleability, and the integrity of the Anammox granule and AnAOB cell structure. During the preservation period, the first-order exponential decay model can simulate the decay of Anammox biomass and activity, and the decay coefficients (bAN) of Anammox biomass and activity had positive correlation with the degree of AnAOB cell lysis. Meanwhile, the rate of Anammox biomass decay was larger than that of Anammox activity. The ratio of protein to polysaccharide in extracellular polymeric substances and heme c cannot effectively indicate the changes of Anammox granules settleability and activity, respectively, and the bioactivity has a negative association with the degree of AnAOB cell lysis. PMID- 26016378 TI - [Start-up of a full-scale system for short-cut nitrification and Anammox in treatment of pharmaceutical wastewater]. AB - In order to broaden the application area of the new nitrogen removal technology, a full-scale system for short-cut nitrification and anaerobic ammonium oxidation (Anammox) was investigated in the nitrogen removal from a strong-ammonium pharmaceutical wastewater. When the influent ammonium concentration was (430.40 +/- 55.43) mg/L, ammonia removal efficiency was (81.75 +/- 9.10)%. The short-cut nitrification and Anammox system could successfully remove nitrogen from the pharmaceutical wastewater. The start-up of short-cut nitrification system took about 74 d and the nitrite accumulation efficiency was (52.11 +/- 9.13)%, the two step mode using synthetic wastewater and actual wastewater was suitable for the start-up of short-cut nitrification system. The start-up of Anammox system took about 145 d and the maximum volumetric nitrogen removal rate was 6.35 kg N/(m3.d), dozens of times higher than those for the conventional nitrification denitrification process. The strategy achieving Anammox sludge by self-growth and biocatalyst addition was suitable for the start-up of Anammox system. PMID- 26016379 TI - [Screening of homoacetogen mixed culture converting H2/CO2 to acetate]. AB - Homoacetogens are a group of microorganisms with application potential to produce chemicals and biofuels by the bioconversion of synthesis gas. In this study, we collected waste activated sludge samples to screen homoacetogens by Hungate anaerobic technique, and studied the effect of pH on acetate and alcohol production from H2/CO2 gas. The mixed culture contained Clostridium ljungdahlii, Lysinibacillus fusiformis and Bacillus cereus. Acetate concentration achieved 31.69 mmol/L when the initial pH was 7. The mixed culture containing homoacetogen could converting H2/CO2 to acetate, which provides an efficient microbial resource for the bioconversion of synthesis gas. PMID- 26016380 TI - Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management. AB - OBJECTIVE: To review recent advances in the epidemiology, pathobiology, and management of weight gain and obesity in patients with schizophrenia and to evaluate the extent to which they should influence guidelines for clinical practice. METHOD: A Medline literature search was performed to identify clinical and experimental studies published in 2005-2014 decade. RESULTS: Weight gain and obesity increase the risk of adult-onset diabetes mellitus and cardiovascular disorders, non-adherence with pharmacological interventions, quality of life, and psychiatric readmissions. The etiology includes adverse effects of antipsychotics, pretreatment/premorbid genetic vulnerabilities, psychosocial and socioeconomic risk factors, and unhealthy lifestyle. Patients with schizophrenia have higher intake of calories in the form of high-density food and lower energy expenditure. The inverse relationship between baseline body mass index and antipsychotic-induced weight gain is probably due to previous antipsychotic exposure. In experimental models, the second-generation antipsychotic olanzapine increased the orexigenic stimulation of hypothalamic structures responsible for energy homeostasis. CONCLUSION: The management of weight gain and obesity in patients with schizophrenia centers on behavioural interventions using caloric intake reduction, dietary restructuring, and moderate-intensity physical activity. The decision to switch antipsychotics to lower-liability medications should be individualized, and metformin may be considered for adjunctive therapy, given its favorable risk-benefit profile. PMID- 26016381 TI - Medical educators: the rich symbiosis between clinical and teaching roles. AB - BACKGROUND: Although many medical educators now undertake formal courses in education, some to a high academic level, there has been little investigation into the ways in which their clinical and educational roles interact. In this qualitative study, we investigate these links and consider their importance. METHODS: We carried out semi-structured interviews with 18 medical educators from a variety of backgrounds and specialties to investigate the links between clinical and educational roles. Data were analysed for recurring themes. FINDINGS: We found an intuitive sharing of professional skills between the clinical and educational roles of doctors. Doctors came to see their practice as more complex and nuanced through their teaching, giving them a route to deepen their understanding of their own professional practice and enhance their self worth. When teaching, doctors drew upon clinical experience, particularly their communication and problem-solving skills, to develop their practice in a holistic way. We found an intuitive sharing of professional skills between the clinical and educational roles of doctors DISCUSSION: We have found that medical practitioners bring their experience and expertise in clinical medicine to their work as educators. In addition, developing as a medical educator affects and enhances clinical practice. These findings have important implications for those charged with the development of medical education and medical educators themselves, as well as the patients that they care for. PMID- 26016382 TI - Negative Cooperativity in the Binding of Imidazolium and Viologen Ions to a Pillar[5]arene-Crown Ether Fused Host. AB - A pillar[5]arene-crown ether fused bicyclic host 1 was found to be able to recognize an imidazolium ion G1 by its pillar[5]arene subunit and a viologen ion G2 by its crown ether receptor discriminatively. The simultaneous binding of G1 and G2 by 1 resulted in the formation of a three-component host-guest complex G1?1?G2. Negative heterotropic cooperative effects were displayed by G1 and G2 in their binding to 1 and were investigated by stepwise bindings of G1 and G2 to 1. PMID- 26016383 TI - Prevalence of human papillomavirus infection and RAS mutation in sporadic keratoacanthoma. AB - BACKGROUND: RAS gene activation and its association with human papillomavirus (HPV) infection have been extensively studied in various cancers. However, the correlation between RAS mutations and HPV in keratoacanthoma (KA) has not yet been investigated. METHODS: Detection of HPV DNA was performed by nested polymerase chain reaction in 28 KA specimens. Molecular analysis was also performed to identify oncogenic mutations (HRAS, KRAS, NRAS). Statistical analyses were performed using the Fisher's exact tests. RESULTS: HPV DNA was detected in eight (28.6%) of the 28 samples, and RAS mutations were detected in eight (28.6%). Six samples had an HRAS mutation, and two showed the NRAS mutation. The presence of an RAS mutation was significantly correlated with a history of chronic sun damage (P = 0.005). However, no significant correlation was observed between HPV infection and RAS mutation. CONCLUSIONS: Our findings suggest that mutational activation of the RAS gene is a common event in KA. However, RAS oncogene activation and HPV infection seem to represent two independent factors in the development of KA. PMID- 26016384 TI - Positive hepatitis B surface antibody is associated with reduced risk of diabetes mellitus in retired female Chinese workers. AB - BACKGROUND: To study the relationship between positivity for hepatitis B surface antibody (HBsAb) and the risk of diabetes mellitus in the retired Chinese population. METHODS: A cross-sectional analysis was conducted in 900 retired Chinese workers attending a health check-up program. HBsAb, hepatitis B surface antigen, oral glucose tolerance test (OGTT), fasting plasma glucose (FBG), 2-h plasma glucose 2hBG, and insulin levels were collected. RESULTS: Participants positive for HBsAb were younger, with lower blood pressure, lower FBG and 2hBG serum uric acid, and glutamic pyruvic transaminase than those who were HbsAb negative. There were 306 subjects with impaired glucose tolerance and 121 with type 2 diabetes (T2D) in the present cohort. Using Chi-squared analysis to assess the risk of diabetes, women positive for HBsAb had a lower prevalence of T2D than those negative for HBsAb (15.7% vs 26.5%, respectively; P < 0.01). Multivariate analysis revealed family history of diabetes, age, and waist circumference were independently associated with a higher prevalence of diabetes, and that HBsAb positivity was independently associated with a lower prevalence of diabetes (odds ratio 0.579; 95% confidence interval 0.388-0.918) when adjusted for sex, family history of hypertension and dyslipidemia, and body mass index. CONCLUSIONS: An HBsAb-positive status is associated with a low rate of diabetes and better metabolic status. A prospective study of patients with known vaccination records is needed to investigate whether hepatitis B virus vaccination could protect against the development of diabetes. PMID- 26016386 TI - Photoconductive Cathode Interlayer for Highly Efficient Inverted Polymer Solar Cells. AB - A highly photoconductive cathode interlayer was achieved by doping a 1 wt % light absorber, such as perylene bisimide, into a ZnO thin film, which absorbs a very small amount of light but shows highly increased conductivity of 4.50 * 10(-3) S/m under sunlight. Photovoltaic devices based on this kind of photoactive cathode interlayer exhibit significantly improved device performance, which is rather insensitive to the thickness of the cathode interlayer over a broad range. Moreover, a power conversion efficiency as high as 10.5% was obtained by incorporation of our photoconductive cathode interlayer with the PTB7-Th:PC71BM active layer, which is one of the best results for single-junction polymer solar cells. PMID- 26016385 TI - Combined ATRX/IDH1 immunohistochemistry predicts genotype of oligoastrocytomas. AB - AIMS: To assess whether in oligoastrocytomas ATRX deficiency, as a surrogate of the alternative lengthening of telomeres (ALT) pathway, has a role in predicting the presence or absence of loss of heterozygosity (LOH) of 1p and 19q, the genetic signature of oligodendroglial differentiation and a favourable prognostic marker. METHODS AND RESULTS: A series of 54 oligoastrocytomas were investigated by immunohistochemistry as well as microsatellite analysis for LOH 1p19q. Genetic findings were correlated with morphological assessment. CONCLUSIONS: ATRX deficiency was mutually exclusive with LOH. Conversely, ATRX-proficient tumours immunoreactive for R132H-mutant isocitrate dehydrogenase 1 (IDH1) showed a high rate (85%) of LOH. A more oligodendroglioma-like morphology was associated with a higher rate of LOH even in the morphologically ambiguous group of oligoastrocytomas. Our findings support the concept that oligoastrocytomas represent a morphological grey zone, rather than a group of truly 'mixed' or 'intermediate' tumours. More precise classification of diffuse gliomas may also improve grading of borderline cases. We propose an immunohistochemical algorithm for classification of morphologically ambiguous diffuse gliomas. PMID- 26016387 TI - Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols. AB - OBJECTIVE: After iontophoresis of vasoactive drugs into the skin, a decrease in perfusion is commonly observed. We delivered vaso-active drugs by iontophoresis using different delivery protocols to study how these affect this decrease in perfusion as measured using LDF. METHODS: We measured skin perfusion during iontophoresis of (ACh), MCh, and NA using a single pulse or separate pulses at different skin sites, and during repeated delivery of ACh at the same site. RESULTS: Perfusion half-life was 6.1 (5.6-6.6) minutes for ACh and 41 (29-69) minutes for MCh (p < 0.001). The maximum response with multiple pulses of ACh iontophoresis was lower than with a single pulse, 30 (22-37) PU vs. 43 (36-50) PU, p < 0.001. Vasoconstriction to NA was more rapid with a single pulse than with multiple pulses. The perfusion half-life of ACh decreased with repeated delivery of ACh at the same site-first 16 (14-18), second 5.9 (5.1-6-9) and third 3.2 (2.9-3.5) minutes, p < 0.001. CONCLUSIONS: The drug delivery protocol affects microvascular responses to iontophoresis, possibly as a result of differences in the dynamics of local drug concentrations. Perfusion half-life may be used as a measure to quantify the rate of perfusion recovery after iontophoresis of vasoactive drugs. PMID- 26016388 TI - Injectable and Self-Healing Carbohydrate-Based Hydrogel for Cell Encapsulation. AB - With the fast development of cell therapy, there has been a shift toward the development of injectable hydrogels as cell carriers that can overcome current limitations in cell therapy. However, the hydrogels are prone to damage during use, inducing cell apoptosis. Therefore, this study was carried out to develop an injectable and self-healing hydrogel based on chondroitin sulfate multiple aldehyde (CSMA) and N-succinyl-chitosan (SC). By varying the CSMA to SC ratio, the hydrogel stiffness, water content, and kinetics of gelation could be controlled. Gelation readily occurred at physiological conditions, predominantly due to a Schiff base reaction between the aldehyde groups on CSMA and amino groups on SC. Meanwhile, because of the dynamic equilibrium of Schiff base linkage, the hydrogel was found to be self-healing. Cells encapsulated in the hydrogel remained viable and metabolically active. In addition, the hydrogel produced minimal inflammatory response when injected subcutaneously in a rat model and showed biodegradability in vivo. This work establishes an injectable and self-healing hydrogel derived from carbohydrates with potential applications as a cell carrier and in tissue engineering. PMID- 26016390 TI - Enabling the detection of UV signal in multimodal nonlinear microscopy with catalogue lens components. AB - Using an optical system made from fused silica catalogue optical components, third-order nonlinear microscopy has been enabled on conventional Ti:sapphire laser-based multiphoton microscopy setups. The optical system is designed using two lens groups with straightforward adaptation to other microscope stands when one of the lens groups is exchanged. Within the theoretical design, the optical system collects and transmits light with wavelengths between the near ultraviolet and the near infrared from an object field of at least 1 mm in diameter within a resulting numerical aperture of up to 0.56. The numerical aperture can be controlled with a variable aperture stop between the two lens groups of the condenser. We demonstrate this new detection capability in third harmonic generation imaging experiments at the harmonic wavelength of ~300 nm and in multimodal nonlinear optical imaging experiments using third-order sum frequency generation and coherent anti-Stokes Raman scattering microscopy so that the wavelengths of the detected signals range from ~300 nm to ~660 nm. PMID- 26016391 TI - Establishment of baseline haematology and biochemistry parameters in wild adult African penguins (Spheniscus demersus). AB - There are few publications on the clinical haematology and biochemistry of African penguins (Spheniscus demersus) and these are based on captive populations. Baseline haematology and serum biochemistry parameters were analysed from 108 blood samples from wild, adult African penguins. Samples were collected from the breeding range of the African penguin in South Africa and the results were compared between breeding region and sex. The haematological parameters that were measured were: haematocrit, haemoglobin, red cell count and white cell count. The biochemical parameters that were measured were: sodium, potassium, chloride, calcium, inorganic phosphate, creatinine, cholesterol, serum glucose, uric acid, bile acid, total serum protein, albumin, aspartate transaminase and creatine kinase. All samples were serologically negative for selected avian diseases and no blood parasites were detected. No haemolysis was present in any of the analysed samples. Male African penguins were larger and heavier than females, with higher haematocrit, haemoglobin and red cell count values, but lower calcium and phosphate values. African penguins in the Eastern Cape were heavier than those in the Western Cape, with lower white cell count and globulin values and a higher albumin/globulin ratio, possibly indicating that birds are in a poorer condition in the Western Cape. Results were also compared between multiple penguin species and with African penguins in captivity. These values for healthy, wild, adult penguins can be used for future health and disease assessments. PMID- 26016389 TI - The Human Iron-Sulfur Assembly Complex Catalyzes the Synthesis of [2Fe-2S] Clusters on ISCU2 That Can Be Transferred to Acceptor Molecules. AB - Iron-sulfur (Fe-S) clusters are essential protein cofactors for most life forms. In human mitochondria, the core Fe-S biosynthetic enzymatic complex (called SDUF) consists of NFS1, ISD11, ISCU2, and frataxin (FXN) protein components. Few mechanistic details about how this complex synthesizes Fe-S clusters and how these clusters are delivered to targets are known. Here circular dichroism and Mossbauer spectroscopies were used to reveal details of the Fe-S cluster assembly reaction on the SDUF complex. SDUF reactions generated [2Fe-2S] cluster intermediates that readily converted to stable [2Fe-2S] clusters bound to uncomplexed ISCU2. Similar reactions that included the apo Fe-S acceptor protein human ferredoxin (FDX1) resulted in formation of [2Fe-2S]-ISCU2 rather than [2Fe 2S]-FDX1. Subsequent addition of dithiothreitol (DTT) induced transfer of the cluster from ISCU2 to FDX1, suggesting that [2Fe-2S]-ISCU2 is an intermediate. Reactions that initially included DTT rapidly generated [2Fe-2S]-FDX1 and bypassed formation of [2Fe-2S]-ISCU2. In the absence of apo-FDX1, incubation of [2Fe-2S]-ISCU2 with DTT generated [4Fe-4S]-ISCU2 species. Together, these results conflict with a recent report of stable [4Fe-4S] cluster formation on the SDUF complex. Rather, they support a model in which SDUF builds transient [2Fe-2S] cluster intermediates that generate clusters on sulfur-containing molecules, including uncomplexed ISCU2. Additional small molecule or protein factors are required for the transfer of these clusters to Fe-S acceptor proteins or the synthesis of [4Fe-4S] clusters. PMID- 26016392 TI - Mini-open removal of intradural spinal tumor. AB - Minimally invasive surgical (MIS) approaches have gained popularity in many surgical fields. Potential advantages to a minimally invasive, spinal intradural approach include decreased operative blood loss, shorter hospitalization, and less post-operative pain. Potential disadvantages include longer operative times, decreased exposure, and difficulty closing the dura. Prior case series from our group and others have demonstrated successful tumor resections using MIS techniques without increased complications. In this 3D video, we demonstrate the key steps in our mini-open, transpinous approach for the resection of an intradural, extramedullary lumbar schwannoma. This operation is performed through a midline incision confined to one or two levels. The spinous process is removed. The paraspinal muscles are spread using a series of sequentially larger tubular dilators, and the first dilator is placed in the space previously occupied by the target level spinous process. The expandable tube retractor is then placed over the largest dilator and docked into place over the target laminae. The expandable tubular retractor is 6 centimeters in depth and 2.5 centimeters in width before expansion and is adjustable to 9 centimeters in depth and 4-5 centimeters in diameter which allows removal of intradural lesions confined to one or two spinal segments. The video can be found here: http://youtu.be/l_C4VruKYng . PMID- 26016393 TI - Thoracoscopic transdiaphragmatic approach for ventral decompression and reconstruction of metastatic spine disease. AB - The management of metastatic spine disease is complex, but usually involves radiation therapy and/or surgical treatment. Surgery followed by radiation has a significant role in select patients presenting with metastatic spinal cord compression. Ventral decompression can be achieved through several surgical approaches including posterior, posterolateral, and anterior surgical approaches. Although open thoracotomy is the most common approach for ventral decompression, it is associated with significant spinal access morbidity. This video illustrates a thoracoscopic transdiaphragmatic approach for symptomatic L-1 metastatic spinal cord compression. This approach allows for a minimal incision in the diaphragm to expose the thoracolumbar junction and allows for corpectomy, spinal canal decompression, vertebral body replacement, and spinal stabilization via four small incisions along the chest wall. The step-by-step technique illustrates operative nuances and surgical pearls to safely perform this approach in a patient with thoracolumbar L-1 metastatic spinal cord compression. The video can be found here: http://youtu.be/w8fanV9bq-E . PMID- 26016394 TI - Surgical correction of a spinal arteriovenous fistula with an unusual presentation. AB - Spinal dural arteriovenous fistula (dAVF) is an acquired abnormal arterial-to venous connection within the spinal dura with a wide range of clinical presentations and natural history. Spinal dAVF occurs when a radicular artery makes a direct anomalous shunt with a radicular vein within the dura of the nerve root sleeve. Cervical dAVF is a rare entity as the majority of spinal dAVFs present within the thoracolumbar segment with myelopathy. Only a small number of cervical lesions have been described, and only one presented with brainstem dysfunction. Herein we present one patient with brainstem dysfunction secondary to a spinal dAVF. The fistula was located within the C-3 nerve root sleeve. The details of microsurgical techniques to disconnect the fistula will be discussed. Although the option of endovascular disconnection of the fistula is reasonable, the author elected to proceed with microsurgical disconnection after discussion regarding the risks of such an endovascular route for the cervical spinal cord. The video can be found here: http://youtu.be/t8rUnZ8qVfY . PMID- 26016395 TI - Intramedullary spinal cord tumor resection. AB - The authors present a case of a 27-year-old patient who presented with spastic gait and worsening difficulty walking over a 6 month period. Spinal MR imaging revealed a heterogeneously enhancing intramedullary spinal cord tumor (IMSCT) with associated syrinx in the cervical spine. The lesion was resected through posterior en bloc laminotomy, durotomy, and microscopic resection of the intramedullary component followed by laminoplasty reconstruction. Surgical resections with a goal of gross total resection can significantly improve overall survival and progression free survival in patients with low-grade IMSCT. The procedure is presented in an edited, high-definition format with accompanying narrative. The video can be found here: http://youtu.be/Ui9bn82PtP8 . PMID- 26016396 TI - Cervical ependymoma resection. AB - Intradural intramedullary cervical spinal cord tumors pose a significant challenge for the neurosurgeon to resect with minimal morbidity. We present the case of a 12-year-old male with a cervical ependymoma and demonstrate our resection technique. The video can be found here: http://youtu.be/5DHlnxdggU0 . PMID- 26016397 TI - Extreme lateral transcondylar approach for resection of ventrally based meningioma of the craniovertebral junction and upper cervical spine. AB - Ventrally based meningiomas at the craniovertebral junction can be challenging tumors to remove because of their deep location anterior to the lower brainstem and upper cervical spinal cord, and close association with complex neurovascular structures. The extreme lateral transcondylar approach provides excellent access and exposure to anterior and anterolateral intradural tumors involving the region of the craniovertebral junction, including the lower third of the clivus, the foramen magnum, and the upper cervical spine. This approach allows safe access for removal of these difficult tumors without any neural retraction. In this operative video manuscript, the author demonstrates an illustrative step-by-step technique for microsurgical resection of a ventrally based meningioma extending from the foramen magnum to C-2 using the extreme lateral transcondylar approach. The operative technique and surgical nuances, including the surgical approach, intradural tumor removal, and cranial base reconstruction, are illustrated in this video atlas. The video can be found here: http://youtu.be/4uvPpEtEShU . PMID- 26016398 TI - A far-lateral approach for removal of a C1-2 extradural neurofibroma. AB - A young man with type 1 neurofibromatosis presented with progressive myelopathy. Imaging revealed an anterolateral mass within the spinal canal at C1-2, with severe compression of the spinal cord. A far-lateral approach was used to remove the mass, which proved to be an extradural neurofibroma. This narrated stereoscopic video details the important steps of the operation. The video can be found here: http://youtu.be/td4MjLtiMbk . PMID- 26016399 TI - Minimally invasive lumbar intradural extramedullary tumor resection. AB - Intradural, extramedullary schwannomas have long been treated with open midline incision, laminectomy, and dural opening to expose and resect the lesion. While this technique is well established, today new surgical techniques can be utilized to perform the same procedure while minimizing pain, size of incision, and trauma to adjacent tissues. In cases of intradural surgery, minimally invasive surgery limits the degree of soft tissue disruption. As a result, there is significant decreased dead space within the surgical cavity that may decrease the rate of CSF leak complications. Minimally invasive techniques have continuously improved over the years and have reached a point where they can be used for intradural surgeries. In this case presentation, we demonstrate a minimally invasive approach to the lumbar spine with resection of an intradural schwannoma. Surgical techniques and the nuances of the minimally invasive approach to intradural tumors compared to the standard open procedure will be discussed. The video can be found here: http://youtu.be/XXrvAIq_H48 . PMID- 26016400 TI - Laser-assisted microsurgical resection of thoracic intramedullary spinal cord ependymoma. AB - The surgical management of intramedullary spinal cord ependymomas remains a formidable challenge amongst neurosurgeons because of the potential risk of surgical morbidity. From on an oncological perspective, complete resection-if technically feasible-should be the goal of surgery, since this can result in excellent local control and progression-free survival. Advances in microsurgical techniques, intraoperative neurophysiological monitoring, and the use of lasers have contributed to our ability to achieve gross-total resection. This is also largely dependent on the presence of an identifiable surgical plane of dissection between the tumor and spinal cord, which appears to have a positive prognosis with overall neurological improvement. In this operative video manuscript, the author demonstrates an illustrative step-by-step technique for microsurgical resection of a thoracic intramedullary spinal cord ependymoma (T-3 to T-5) associated with an extensive cervicothoracic syrinx. The application of a handheld non-contact CO2 laser for performing the midline myelotomy is also highlighted. The operative technique and surgical nuances, including the surgical approach, intradural tumor removal, and closure, are illustrated in this video atlas. The video can be found here: http://youtu.be/itE2tuBFmgw . PMID- 26016401 TI - Resection of an anterior spinal cord AVM through a far-lateral approach. AB - A small arteriovenous malformation near the craniocervical junction with contributions from the anterior spinal artery was discovered in a young developmentally-delayed woman after she presented with altered mental status and evidence of subarachnoid hemorrhage. The malformation could not be completely treated with endovascular therapy, so it was resected through a far-lateral approach. This stereoscopic video demonstrates how to gain the exposure needed to address a lesion in this area. The video can be found here: http://youtu.be/ByjPGm_eXLc . PMID- 26016402 TI - Early disruption of glial communication via connexin gap junction in multiple sclerosis, Balo's disease and neuromyelitis optica. AB - Multiple sclerosis (MS), neuromyelitis optica (NMO), and Balo's disease (BD) are inflammatory demyelinating diseases of the CNS. We previously reported anti aquaporin-4 (anti-AQP4) antibody-dependent AQP4 loss occurs in some NMO patients, while antibody-independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including MS, NMO and BD. To investigate the relationship between astrocytopathy and demyelination, we focused on connexins (Cxs), which form gap junctions (GJs) between astrocytes and oligodendrocytes and maintain homeostasis in the CNS. We evaluated expression of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 in autopsied materials from MS, NMO and BD patients. Astrocytic Cx43 and oligodendrocytic Cx32/Cx47 expressions were significantly diminished in both demyelinated and preserved myelin layers in all BD samples. In the leading edge of BD lesions, Cx43 and AQP4 loss preceded Cx32/Cx47 loss. Half of the NMO and MS samples showed preferential loss of astrocytic Cx43 expression in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte-oligodendrocyte GJs were lost. Cases with Cx43 loss were significantly associated with rapid disease progression, regardless of the disease phenotype. Pathologically, Cx43 loss was frequently accompanied by distal oligodendrogliopathy. Our findings suggest that Cx43 astrocytopathy can occur in MS, BD and NMO. Moreover, astrocytic Cx43 loss may be associated with disease aggressiveness and distal oligodendrogliopathy in demyelinating conditions. Early disruption of glial communications via GJs may cause loss of glia syncytium, thereby inducing oligodendroglial damage and myelin loss. Inhibition of Cx hemichannels and restoration of GJs may be a possible therapeutic target for demyelinating disorders. PMID- 26016403 TI - What COP and Kinematic Parameters Better Characterize Postural Control in Standing Balance Tasks? AB - The authors' aim was to determine which variables allow for the characterization of motor balance behavior. Traditional measures and nonlinear measures of center of pressure (COP; n = 30) and kinematics (n = 10) were tested in their absolute and relative consistency in a 30-s standing balance task protocol under stable and unstable conditions. Regarding COP variables, mean velocity (mVel), permutation entropy (PE) and detrended fluctuation analysis (DFA) exhibited high consistency between trials and ranked individuals more accurately compare with other metrics. In the kinematic signal mVel, PE and DFA had good intrasession reliability values in unstable conditions. Overall, the intrasession reliability values were better in the unstable condition than in the stable condition and the measures calculated using derived data had better intrasession reliability values. In conclusion, mVel, PE, and DFA allow for the good characterization of motor balance behavior in a simplified protocol where velocity time series are analyzed. PMID- 26016404 TI - Formation of porous SnS nanoplate networks from solution and their application in hybrid solar cells. AB - Herein, we present a facile solution-based route towards nanostructured, hybrid absorber layers based on tin mono-sulfide (SnS), an emerging, non-toxic absorber material for low-cost and large-scale PV applications. Charge photogeneration properties in the hybrid system are studied using transient absorption spectroscopy and fabricated solar cells show efficient photocurrent generation over a broad spectral range. PMID- 26016405 TI - Do elevated plasma S100A12 levels predict atherosclerosis in peritoneal dialysis patients? AB - AIM: Atherosclerotic cardiovascular disease is one of the major causes of mortality and morbidity in peritoneal dialysis (PD) patients. S100A12 is an endogenous receptor ligand of advanced glycation end-products. It was shown to contribute to the development of atherosclerosis in animal models. The aim of this study was to evaluate the relationship between S100A12 levels and carotid atherosclerosis in PD patients. METHODS: A cross-sectional study was performed in 56 PD patients and 20 control subjects. Plasma S100A12 levels were measured from all participants beside routine laboratory evaluation. All subjects underwent high-resolution B-mode ultrasonography to determine carotid intima media thickness (CIMT). S100A12 levels were compared between patient and control groups. Correlation analyses of S100A12 with other laboratory values and CIMT were also performed. RESULTS: Plasma S100A12 levels were higher in PD patients compared with control subjects (129.5 +/- 167.2 ng/mL vs. 48.5 +/- 30.3 ng/mL, respectively, p < 0.001). In the patient group, CIMT was found to be positively correlated with age (r = 0.354; p = 0.007), CRP level (r = 0.269; p = 0.045), and S100A12 (r = 0.293; p = 0.028) level while it was found to be negatively correlated with hemoglobin concentration (r = -0.264; p = 0.049). In the linear regression analysis, the model, including CRP, S100A12, age, and Hgb, was found to be significant (F: 4.177, p: 0.005). When the parameters are analyzed age and S100A12 were found to be independent determinants of CIMT (beta = 0.308, p = 0.018 and beta = 0.248, p = 0.049, respectively). CONCLUSIONS: This study suggests that an elevated plasma S100A12 level was closely associated with atherosclerosis. With aging elevated plasma S100A12 may show a powerful proatherogenic potential in patients undergoing PD. PMID- 26016407 TI - The effect of antidepressants and antipsychotics on weight gain in children and adolescents. AB - Psychiatric illness in the paediatric population is increasing and the weight effect of medications for these problems is often unclear. A comprehensive literature search was undertaken to identify studies reporting weight in relation to antipsychotic and antidepressant use in children and adolescents. From 636 articles, 42 were selected for review. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) do not cause weight gain and may lead to improvements in weight status over the short, but not, long term. Antipsychotics were generally associated with weight gain. In drug comparison studies, risperidone had a larger weight gain effect than lithium, divalproex sodium and pimozide. Studies assessing the weight-protective effects of augmentation therapy with metformin or topiramate show less weight gain with addition of these agents. In conclusion, prescribing of SSRIs and SNRIs may be associated with improvements in weight status in children and adolescents but trials assessing their use in obesity, outside of established psychiatric illness, are limited and still experimental. Youth prescribed antipsychotic medication should be monitored for exaggerated weight gain and in those where obesity is a pre-existing concern agents other than olanzapine, clozapine and risperidone may be advantageous. PMID- 26016406 TI - A workplace farmstand pilot programme in Omaha, Nebraska, USA. AB - OBJECTIVE: To explore the feasibility of a workplace farmstand programme through the utilization of an online ordering system to build awareness for local food systems, encourage community participation, and increase local fruit and vegetable availability. DESIGN: A 4-week pilot to explore feasibility of workplace farmstand programmes through a variety of outcome measures, including survey, mode of sale, weekly sales totals and intercept interviews. SETTING: A large private company in Sarpy County, Omaha, Nebraska, USA. SUBJECTS: Employees of the company hosting the farmstand programme. RESULTS: Pre-programme, a majority of employees indicated that quality (95.4 %), variety (94.6 %) and cost of fruits and vegetables (86.4 %) were driving factors in their fruit and vegetable selection when shopping. The availability of locally or regionally produced fruits and vegetables was highly important (78.1 %). Participants varied in their definition of local food, with nearly half (49.2 %) reporting within 80.5 km (50 miles), followed by 160.9 km (100 miles; 29.5 %) and 321.9 km (200 miles; 12.1 %). Weekly farmstand purchases (both walk-ups and online orders) ranged from twenty-eight to thirty-nine employees, with weekly sales ranging from $US 257.95 to 436.90 for the producer. The mode of purchase changed throughout the pilot, with higher use of online ordering in the beginning and higher use of walk-up purchasing at the end. CONCLUSIONS: The workplace farmstand pilot study revealed initial interest by both employees and a producer in this type of programme, helped to establish a sustained producer-employer relationship and led to additional opportunities for both the producer and employer. PMID- 26016408 TI - Evaluation of PARKIN gene variants in West Bengal Parkinson's disease patients. AB - Little information is available regarding the molecular pathogenesis of Parkinson's disease (PD) among the Bengalee population in West Bengal, India. This study was undertaken to determine the contribution of Parkin variants in well-defined ethnically identical Bengalee population of India and further to describe the clinical spectrum associated with these mutations. A total of 150 unrelated PD patients and 150 controls were recruited for the study. The entire cohort was screened for mutations in all the 12 exons of the gene along with flanking splice junctions by polymerase chain reaction and DNA sequencing. Eleven nucleotide variants including two novel changes were detected. Cerebrospinal fluid (CSF) parkin protein expression of the novel mutation, Val186Ile (found in heterozygous condition in one patient only) was almost 2.7 folds lower than the controls and other PD patients. Molecular characterization of polymorphisms Ser167Asn and Val380Leu depicted that homozygous Ser167 and Val380 are significantly associated with the disease. We did not find any linkage disequilibrium among the SNPs, the low r(2) for every pair of single-nucleotide polymorphisms (SNPs) indicated that these SNPs cannot be tagged by each other. Another novel intronic change, IVS8+48C>T was present in almost equally in PD patients and controls. Among the ethnically defined Bengalee population of West Bengal, occurrence of Parkin mutation is 4% (6/150) of the PD patient pool supported with decreased folds of expression of CSF PARKIN protein. Parkin polymorphisms, Ser167 and Val380 are risk factors for the progression of the disease, and their frequency is greatly influenced by ethnic origin. PMID- 26016409 TI - Association studies of SEPS1 gene polymorphisms with Hashimoto's thyroiditis in Han Chinese. AB - Although the connection between SEPS1 gene variants and Hashimoto's thyroiditis (HT) has been established in Europeans, the relationship between the SEPS1 gene and HT remains unclear in Han Chinese. Here we aimed to investigate the potential association between SEPS1 variants and HT in the Han population. In addition, the effects of SEPS1 haplotypes on the susceptibility of the development of immune mediated diseases with an inflammatory component will also be evaluated. Seven single-nucleotide polymorphisms (SNPs) with minor allele frequency ?0.05 were genotyped in 1013 HT patients and 2998 healthy controls from genetically independent Han Chinese individuals. We identified that the rs28665122 SNP was significantly associated with HT, both in the female group (allelic P=0.002644 and genotypic P=0.010326) and the combined data set (allelic P=0.000518 and genotypic P=0.002731). Further analyses based on haplotypes indicated that a two SNP haplotype (rs2009895-rs28665122) was significantly associated with HT (global P=0.0036), which was also observed in females (global P=0.0162) but not in males. Our findings provide further supporting evidence that confirms the results of previous studies, which suggested potential roles of the SEPS1 gene in the pathogenesis and etiology of HT. PMID- 26016410 TI - Compound heterozygous GFM2 mutations with Leigh syndrome complicated by arthrogryposis multiplex congenita. AB - Defects in the mitochondrial translation apparatus can impair energy production in affected tissues and organs. Most components of this apparatus are encoded by nuclear genes, including GFM2, which encodes a mitochondrial ribosome recycling factor. A few patients with mutations in some of these genes have been reported to date. Here, we present two female siblings with arthrogryposis multiplex congenita, optic atrophy and severe mental retardation. The younger sister had a progressive cerebellar atrophy and bilateral neuropathological findings in the brainstem. Although her cerebrospinal fluid (CSF) levels of lactate and pyruvate were not increased, brain magnetic resonance spectroscopy showed a lactate peak. Additionally, her CSF lactate/pyruvate and serum beta hydroxybutyrate/acetoacetate ratios were high, and levels of oxidative phosphorylation in skin fibroblasts were reduced. We therefore diagnosed Leigh syndrome. Genomic investigation confirmed the presence of compound heterozygous GFM2 mutations (c.206+4A>G and c.2029-1G>A) in both siblings, causing aberrant splicing with premature stop codons (p.Gly50Glufs*4 and p.Ala677Leufs*2, respectively). These findings suggest that GFM2 mutations could be causative of a phenotype of Leigh syndrome with arthrogryposis multiplex congenita. PMID- 26016411 TI - Two novel splicing mutations in the SLC45A2 gene cause Oculocutaneous Albinism Type IV by unmasking cryptic splice sites. AB - Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. OCA type IV (OCA4) is one of the four commonly recognized forms of albinism, and is determined by mutation in the SLC45A2 gene. Here, we investigated the genetic basis of OCA4 in an Italian child. The mutational screening of the SLC45A2 gene identified two novel potentially pathogenic splicing mutations: a synonymous transition (c.888G>A) involving the last nucleotide of exon 3 and a single-nucleotide insertion (c.1156+2dupT) within the consensus sequence of the donor splice site of intron 5. As computer-assisted analysis for mutant splice-site prediction was not conclusive, we investigated the effects on pre-mRNA splicing of these two variants by using an in vitro minigene approach. Production of mutant transcripts in HeLa cells demonstrated that both mutations cause the almost complete abolishment of the physiologic donor splice site, with the concomitant unmasking of cryptic donor splice sites. To our knowledge, this work represents the first in-depth molecular characterization of splicing defects in a OCA4 patient. PMID- 26016413 TI - Working With Families Affected by Disabilities. PMID- 26016412 TI - Aggregation of rare/low-frequency variants of the mitochondria respiratory chain related proteins in rheumatoid arthritis patients. AB - Exome sequencings were conducted using 59 patients having rheumatoid arthritis (RA) and 93 controls. After stepwise filtering, 107 genes showed less than 0.05 of P-values by gene-burden tests. Among 107 genes, NDUFA7 which is a subunit of the complex I in the mitochondrial respiratory chain was selected for further analysis based on previous reports. A case-control study was performed on the three single-nucleotide variants (SNVs) of NDUFA7 with 432 cases and 432 controls. An association was observed between NDUFA7 and RA with severe erosive arthritis. These results together with previous reports suggested the involvement of reactive oxygen species (ROS) in the pathogenesis of RA. In the next step, four SNVs from three genes related to the mitochondrial respiratory chain were selected, which is a major source of ROS, and conducted a case-control study. An association was observed based on a pathway-burden test comprising NDUFA7, SDHAF2, SCO1 and ATP5O: P=1.56E-04, odds ratio=2.16, 95% confidence interval=1.43 3.28. Previous reports suggested the involvement of ROS in the pathogenesis of RA. The aggregation of SNVs in the mitochondria respiratory chain suggests the pivotal role of those SNVs in the pathogenesis of RA with severe erosive arthritis. PMID- 26016416 TI - Interaction between tryptophan-Sm(III) complex and DNA with the use of a acridine orange dye fluorophor probe. AB - The interaction of the Trp-Sm(III) complex with herring sperm DNA (hs-DNA) was investigated with the use of acridine orange (AO) dye as a spectral probe for UV vis spectrophotometry and fluorescence spectroscopy. The results showed that the both the Trp-Sm(III) complex and the AO molecule could intercalate into the double helix of the DNA. The Sm(III)-(Trp)3 complex was stabilized by intercalation into the DNA with binding constants: K(?)25 degrees C = 7.14 * 10(5) L.mol(-1) and K(?) 37 degrees C = 5.28 * 10(4) L.mol(-1), and it could displace the AO dye from the AO-DNA complex in a competitive reaction. Computation of the thermodynamic functions demonstrates that Deltar Hm (?) is the primary driving power of the interaction between the Sm(III)(Trp)3 complex and the DNA. The results from Scatchard and viscometry methods suggested that the interaction mode between the Sm(III)(Trp)3 complex and the hs-DNA is groove binding and weak intercalation binding. PMID- 26016417 TI - Europium(ii)-activated oxonitridosilicate yellow phosphor with excellent quantum efficiency and thermal stability - a robust spectral conversion material for highly efficient and reliable white LEDs. AB - Knowing the physicochemical properties of a material is of great importance to design and utilize it in a suitable way. In this paper, we conduct a comprehensive survey of photoluminescence spectra, localized cathodoluminescence, temperature-dependent luminescence efficiency, and applications of Eu(2+)-doped Sr0.5Ba0.5Si2O2N2 in solid-state lighting. This phosphor exhibits a broad emission band with a maximum at 560-580 nm and a full-width at half maximum of 92 103 nm upon blue light excitation, whereas a dual-band emission (i.e., 470 nm and 550 nm) is observed under electron beam irradiation due to perhaps the intergrowth of BaSi2O2N2:Eu(2+) and Sr0.5+sigmaBa0.5-sigmaSi2O2N2:Eu(2+) in each phosphor particle. Under 450 nm blue light irradiation, this yellow phosphor exhibits excellent luminescence properties with absorption, internal and external efficiencies of 83.2, 87.7 and 72.6%, respectively. Furthermore, it also possesses high thermal stability, with the quantum efficiency being decreased by only 4.2% at 150 degrees C and a high quenching temperature of 450 degrees C. High-efficiency white LEDs using the title phosphor have a luminous efficacy, color temperature and color rendition of ~120 lm W(-1), 6000 K and 61, respectively, validating its suitability for use in solid-state white lighting. PMID- 26016418 TI - Angiogenesis Inhibitor, Endostar, Prevents Vasa Vasorum Neovascularization in a Swine Atherosclerosis Model. AB - AIM: Vasa vasorum neovascularization is a key feature of atherosclerosis (AS) and is strongly associated with inflammatory infiltration, lipid deposition, intraplaque hemorrhage, and hemosiderin deposit. Here we investigate the effects of Endostar, a strong anti-angiogenic drug, on vasa vasorum neovascularization in the experimental porcine model of early AS. METHODS: Eighteen adult male Ba-Ma mini pigs were randomized into three groups, with six animals in each group. The pigs in the normal (N) group were fed a normal diet for 18 weeks, without balloon injury surgery. The animals in the atherosclerotic (AS) control and AS+Endostar groups were fed a hypercholesterolemic diet for 12 weeks after balloon injury surgery; they received either saline or Endostar for an additional six weeks, while continuing the hypercholesterolemic diet. The atherosclerotic abdominal aorta and levels of serum lipids, TNF-alpha, IL-6, and hs-CRP were analyzed at 18 weeks. RESULTS: The AS group had a significantly higher body weight and serum lipid concentration levels than the N group (p < 0.05), confirming the success of the hypercholesterolemic diet. However, no statistical differences were noted between the AS and AS+Endostar groups. Histopathology results revealed that vasa vasorum density and intima-media thickness (IMT) had also increased in the AS group compared with those in the N group (p < 0.05). The Endostar treatment significantly alleviated AS with decreased vasa vasorum density and IMT (AS vs. AS+Endostar, p < 0.05). Western blot analysis indicated that the expression of VEGF, beta-catenin, and TNF-alpha in the atherosclerotic abdominal aorta was considerably reduced by the Endostar treatment. In addition, immunohistochemistry results showed that the angiogenesis markers VEGF and beta-catenin were predominately localized in endothelial cells of the adventitial vasa vasorum. The levels of the serum inflammatory markers TNF-alpha, hs-CRP, and IL-6 were markedly higher in the AS group than in the N group (p < 0.05) but showed no marked difference during the Endostar treatment, suggesting that the local inhibition of angiogenesis was not accompanied by a change in serum inflammatory markers and that the inhibitive effect of Endostar on local TNF-alpha expression could be because of the prevention of vasa vasorum neovascularization. CONCLUSIONS: Our results demonstrated that the Endostar treatment inhibited vasa vasorum neovascularization and AS progression in the experimental porcine model of early AS, supporting the role of vasa vasorum neovascularization in the development of AS and the therapeutic potential of anti-angiogenesis intervention in AS. PMID- 26016419 TI - Validating a Cantonese short version of the Zarit Burden Interview (CZBI-Short) for dementia caregivers. AB - OBJECTIVES: The present study aimed to develop and validate a Cantonese short version of the Zarit Burden Interview (CZBI-Short) for Hong Kong Chinese dementia caregivers. METHODS: The 12-item Zarit Burden Interview (ZBI) was translated into spoken Cantonese and back-translated by two bilingual research assistants and face validated by a panel of experts. Five hundred Chinese dementia caregivers showing signs of stress reported their burden using the translated ZBI and rated their depressive symptoms, overall health, and care recipients' physical functioning and behavioral problems. The factor structure of the translated scale was identified using principal component analysis and confirmatory factor analysis; internal consistency and item-total correlations were assessed; and concurrent validity was tested by correlating the ZBI with depressive symptoms, self-rated health, and care recipients' physical functioning and behavioral problems. RESULTS: The principal component analysis resulted in 11 items loading on a three-factor model comprised role strain, self-criticism, and negative emotion, which accounted for 59% of the variance. The confirmatory factor analysis supported the three-factor model (CZBI-Short) that explained 61% of the total variance. Cronbach's alpha (0.84) and item-total correlations (rho = 0.39 0.71) indicated CZBI-Short had good reliability. CZBI-Short showed correlations with depressive symptoms (r = 0.50), self-rated health (r = -0.26) and care recipients' physical functioning (r = 0.18-0.26) and disruptive behaviors (r = 0.36). CONCLUSIONS: The 12-item CZBI-Short is a concise, reliable, and valid instrument to assess burden in Chinese dementia caregivers in clinical and social care settings. PMID- 26016420 TI - Homogeneous large-scale crystalline nanoparticle-covered substrate with high SERS performance. AB - This article details the surface-enhanced Raman scattering (SERS) performance of plasmonic substrates fabricated by a physical metal evaporation technique that uses no precursor or intermediate coating. We outline a cost-effective nanofabrication protocol that uses common laboratory equipment to produce homogeneously covered crystalline nanoparticle substrates. Our fabrication yields a homogeneous SERS response over the whole surface. The platform is tested with methylene blue diluted at various concentrations to estimate the sensitivity, homogeneity, and reproducibility of the process. The capacity of the substrates is also confirmed with spectroscopic investigations of human microsomal cytochrome b5. PMID- 26016421 TI - Systematic Study of a Family of Butterfly-Like {M2Ln2} Molecular Magnets (M = Mg(II), Mn(III), Co(II), Ni(II), and Cu(II); Ln = Y(III), Gd(III), Tb(III), Dy(III), Ho(III), and Er(III)). AB - A family of 3d-4f [M(II)2Ln(III)2(MU3-OH)2(O2C(t)Bu)10](2-) "butterflies" (where M(II) = Mg, Co, Ni, and Cu; Ln(III) = Y, Gd, Tb, Dy, Ho, and Er) and [Mn(III)2Ln(III)2(MU3-O)2(O2C(t)Bu)10](2-) molecules (where Ln(III) = Y, Gd, Tb, Dy, Ho, and Er) has been synthesized and characterized through single-crystal X ray diffraction, SQUID magnetometry, and ab initio calculations. All dysprosium- and some erbium-containing tetramers showed frequency-dependent maxima in the out of-phase component of the susceptibility associated with slow relaxation of magnetization, and hence, they are single-molecule magnets (SMMs). AC susceptibility measurements have shown that the SMM behavior is entirely intrinsic to the Dy and Er sites and the magnitude of the energy barrier is influenced by the interactions between the 4f and the 3d metal. A trend is observed between the strength of the 3d-4f exchange interaction between and the maximum observed in the chi"M(T). PMID- 26016422 TI - Pediatric nasoseptal flap reconstruction for suprasellar approaches. AB - OBJECTIVES/HYPOTHESIS: To determine the pediatric age groups viable for nasoseptal flap (NSF) reconstruction of endoscopic endonasal approaches (EEA) to intracranial pathology of suprasella neoplasms. STUDY DESIGN: Retrospective cohort study. METHODS: Retrospective review of 16 pediatric patients who underwent EEA with NSF reconstruction for a suprasellar defect from 2012 to 2014. Radioanatomic analysis was utilized to assess feasibility of NSF reconstruction of suprasellar neoplasms approached via EEA. Computed tomography (CT) measurements for defect size and potential flap coverage were measured by preoperative maxillofacial CT. Radiographic measurements and surgical outcomes were compared to determine if flap size would be sufficient to cover said defects in two pediatric age groups: those>10 years of age (mean age 14 years) and those<10 years (mean age 6 years). RESULTS: Of all patients encountered in this cohort, one postoperative cerebrospinal fluid leak was identified in the >10 years of age population, and this was not due to insufficient flap coverage. Average potential flap length and width are sufficient to cover average suprasellar defect length and width in both age groups (P<.05 in all age groups). CONCLUSIONS: Patient selection is critical for successful pediatric EEA. Preoperative radiographic assessment of NSF feasibility is a critical to ensure adequate flap coverage for suprasellar defects. NSF appears to provide a sufficient and reliable coverage option in reconstruction of suprasellar defects in pediatric patients. LEVEL OF EVIDENCE: 4. PMID- 26016428 TI - Tackling medical student stress: beyond individual resilience. PMID- 26016429 TI - The evolution of cognitive load theory and its application to medical education. AB - Cognitive Load Theory (CLT) has started to find more applications in medical education research. Unfortunately, misconceptions such as lower cognitive load always being beneficial to learning and the continued use of dated concepts and methods can result in improper applications of CLT principles in medical education design and research. This review outlines how CLT has evolved and presents a synthesis of current-day CLT principles in a holistic model for medical education design. This model distinguishes three dimensions: task fidelity: from literature (lowest) through simulated patients to real patients (highest); task complexity: the number of information elements; and instructional support: from worked examples (highest) through completion tasks to autonomous task performance (lowest). These three dimensions together constitute three steps to proficient learning: (I) start with high support on low-fidelity low complexity tasks and gradually fade that support as learners become more proficient; (II) repeat I for low-fidelity but higher-complexity tasks; and (III) repeat I and II in that order at subsequent levels of fidelity. The numbers of fidelity levels and complexity levels within fidelity levels needed depend on the aims of the course, curriculum or individual learning trajectory. This paper concludes with suggestions for future research based on this model. PMID- 26016430 TI - Applying cognitive load theory to medical education: construct and measurement challenges. PMID- 26016431 TI - The Potential Role of Neglected and Underutilised Crop Species as Future Crops under Water Scarce Conditions in Sub-Saharan Africa. AB - Modern agricultural systems that promote cultivation of a very limited number of crop species have relegated indigenous crops to the status of neglected and underutilised crop species (NUCS). The complex interactions of water scarcity associated with climate change and variability in sub-Saharan Africa (SSA), and population pressure require innovative strategies to address food insecurity and undernourishment. Current research efforts have identified NUCS as having potential to reduce food and nutrition insecurity, particularly for resource poor households in SSA. This is because of their adaptability to low input agricultural systems and nutritional composition. However, what is required to promote NUCS is scientific research including agronomy, breeding, post-harvest handling and value addition, and linking farmers to markets. Among the essential knowledge base is reliable information about water utilisation by NUCS with potential for commercialisation. This commentary identifies and characterises NUCS with agronomic potential in SSA, especially in the semi-arid areas taking into consideration inter alia: (i) what can grow under water-scarce conditions, (ii) water requirements, and (iii) water productivity. Several representative leafy vegetables, tuber crops, cereal crops and grain legumes were identified as fitting the NUCS category. Agro-biodiversity remains essential for sustainable agriculture. PMID- 26016432 TI - Road-traffic noise: annoyance, risk perception, and noise sensitivity in the Finnish adult population. AB - Exposure to road-traffic noise commonly engenders annoyance, the extent of which is determined by factors not fully understood. Our aim was to estimate the prevalence and determinants of road-traffic noise annoyance and noise sensitivity in the Finnish adult population, while comparing the perceptions of road-traffic noise to exhausts as environmental health problems. Using a questionnaire that yielded responses from 1112 randomly selected adult Finnish respondents, we estimated road-traffic noise- and exhausts-related perceived exposures, health risk perceptions, and self-reported annoyance on five-point scales, while noise sensitivity estimates were based on four questions. Determinants of noise annoyance and sensitivity were investigated using multivariate binary logistic regression and linear regression models, respectively. High or extreme noise annoyance was reported by 17% of respondents. Noise sensitivity scores approximated a Gaussian distribution. Road-traffic noise and exhausts were, respectively, considered high or extreme population-health risks by 22% and 27% of respondents. Knowledge of health risks from traffic noise, OR: 2.04 (1.09 3.82) and noise sensitivity, OR: 1.07 (1.00-1.14) were positively associated with annoyance. Knowledge of health risks (p<0.045) and positive environmental attitudes (p<000) were associated with higher noise sensitivity. Age and sex were associated with annoyance and sensitivity only in bivariate models. A considerable proportion of Finnish adults are highly annoyed by road-traffic noise, and perceive it to be a significant health risk, almost comparable to traffic exhausts. There is no distinct noise-sensitive population subgroup. Knowledge of health risks of road-traffic noise, and attitudinal variables are associated with noise annoyance and sensitivity. PMID- 26016433 TI - Development of Primer Sets for Loop-Mediated Isothermal Amplification that Enables Rapid and Specific Detection of Streptococcus dysgalactiae, Streptococcus uberis and Streptococcus agalactiae. AB - Streptococcus dysgalactiae, Streptococcus uberis and Streptococcus agalactiae are the three main pathogens causing bovine mastitis, with great losses to the dairy industry. Rapid and specific loop-mediated isothermal amplification methods (LAMP) for identification and differentiation of these three pathogens are not available. With the 16S rRNA gene and 16S-23S rRNA intergenic spacers as targets, four sets of LAMP primers were designed for identification and differentiation of S. dysgalactiae, S. uberis and S. agalactiae. The detection limit of all four LAMP primer sets were 0.1 pg DNA template per reaction, the LAMP method with 16S rRNA gene and 16S-23S rRNA intergenic spacers as the targets can differentiate the three pathogens, which is potentially useful in epidemiological studies. PMID- 26016434 TI - Effects of Simulated Heat Waves with Strong Sudden Cooling Weather on ApoE Knockout Mice. AB - This study analyzes the mechanism of influence of heat waves with strong sudden cooling on cardiovascular diseases (CVD) in ApoE-/- mice. The process of heat waves with strong sudden cooling was simulated with a TEM1880 meteorological environment simulation chamber according to the data obtained at 5 a.m. of 19 June 2006 to 11 p.m. of 22 June 2006. Forty-eight ApoE-/- mice were divided into six blocks based on their weight. Two mice from each block were randomly assigned to control, heat wave, temperature drop, and rewarming temperature groups. The experimental groups were transferred into the climate simulator chamber for exposure to the simulated heat wave process with strong sudden temperature drop. After 55, 59, and 75 h of exposure, the experimental groups were successively removed from the chamber to monitor physiological indicators. Blood samples were collected by decollation, and the hearts were harvested in all groups. The levels of heat stress factors (HSP60, SOD, TNF, sICAM-1, HIF-1alpha), cold stress factors (NE, EPI), vasoconstrictor factors (ANGII, ET-1, NO), and four items of blood lipid (TC, TG, HDL-C, and LDL-C) were measured in each ApoE-/- mouse. Results showed that the heat waves increased the levels of heat stress factors except SOD decreased, and decreased the levels of vasoconstrictor factors and blood lipid factors except TC increased. The strong sudden temperature drop in the heat wave process increased the levels of cold stress factors, vasoconstrictor factors and four blood lipid items (except the level of HDL-C which decreased) and decreased the levels of heat stress factors (except the level of SOD which increased). The analysis showed that heat waves could enhance atherosclerosis of ApoE-/- mice. The strong sudden temperature drop during the heat wave process increased the plasma concentrations of NE and ANGII, which indicates SNS activation, and resulted in increased blood pressure. NE and ANGII are vasoconstrictors involved in systemic vasoconstriction especially in the superficial areas of the body and conducive to increased blood pressure. The increase in the blood lipid levels of TG, LDL-C, TC, and LDL-C/HDL-C further aggravated CVD. This paper explored the influence mechanism of the heat waves with sudden cooling on CVD in ApoE-/- mice. PMID- 26016435 TI - Are women in Turkey both risks and resources in disaster management? AB - From a global perspective, the universality of gender-related societal issues is particularly significant. Although gender inequality is considered a sociological problem, the large number of female victims in disasters warrants an assessment of disaster management sciences. In this article, related concepts are discussed based on their relevance sociologically and in disaster management to develop a common terminology and examine this complex topic, which is rooted in different social profiles and anthropological heterogeneity throughout the world. A brief history is discussed, and significant examples are provided from different disasters in Turkey to illustrate why a woman-oriented approach should be adopted when evaluating concepts of gender inequality. Observations of disasters have shown that it is important to apply international standards (humanitarian charter and minimum disaster response standards), especially during periods of response and rehabilitation. Relevant factors related to gender should be included in these standards, such as women's health and hygiene, which will be discussed in more detail. A woman-based approach is designed in relation to two aspects: risks and resources. Thus, gender-sensitive methods of mitigating and preventing disasters are provided. The main purpose of the article is to contribute to the development of a universal culture that prioritizes gender in disaster management. PMID- 26016436 TI - Polycyclic aromatic hydrocarbons in the dagang oilfield (china): distribution, sources, and risk assessment. AB - The levels of 16 polycyclic aromatic hydrocarbons (PAHs) were investigated in 27 upper layer (0-25 cm) soil samples collected from the Dagang Oilfield (China) in April 2013 to estimate their distribution, possible sources, and potential risks posed. The total concentrations of PAHs (?PAHs) varied between 103.6 ug.kg(-1) and 5872 ug.kg(-1), with a mean concentration of 919.8 ug.kg(-1); increased concentrations were noted along a gradient from arable desert soil (mean 343.5 ug.kg(-1)), to oil well areas (mean of 627.3 ug.kg(-1)), to urban and residential zones (mean of 1856 ug.kg(-1)). Diagnostic ratios showed diverse source of PAHs, including petroleum, liquid fossil fuels, and biomass combustion sources. Combustion sources were most significant for PAHs in arable desert soils and residential zones, while petroleum sources were a significant source of PAHs in oilfield areas. Based ontheir carcinogenity, PAHs were classified as carcinogenic (B) or not classified/non-carcinogenic (NB). The total concentrations of carcinogenic PAHs (?BPAHs) varied from 13.3 ug.kg(-1) to 4397 ug.kg(-1) across all samples, with a mean concentration of 594.4 ug.kg(-1). The results suggest that oilfield soil is subject to a certain level of ecological environment risk. PMID- 26016437 TI - Development of a quantitative methodology to assess the impacts of urban transport interventions and related noise on well-being. AB - Well-being impact assessments of urban interventions are a difficult challenge, as there is no agreed methodology and scarce evidence on the relationship between environmental conditions and well-being. The European Union (EU) project "Urban Reduction of Greenhouse Gas Emissions in China and Europe" (URGENCHE) explored a methodological approach to assess traffic noise-related well-being impacts of transport interventions in three European cities (Basel, Rotterdam and Thessaloniki) linking modeled traffic noise reduction effects with survey data indicating noise-well-being associations. Local noise models showed a reduction of high traffic noise levels in all cities as a result of different urban interventions. Survey data indicated that perception of high noise levels was associated with lower probability of well-being. Connecting the local noise exposure profiles with the noise-well-being associations suggests that the urban transport interventions may have a marginal but positive effect on population well-being. This paper also provides insight into the methodological challenges of well-being assessments and highlights the range of limitations arising from the current lack of reliable evidence on environmental conditions and well-being. Due to these limitations, the results should be interpreted with caution. PMID- 26016439 TI - A fully sealed plastic chip for multiplex PCR and its application in bacteria identification. AB - Multiplex PCR is an effective tool for simultaneous multiple target detection but is limited by the intrinsic interference and competition among primer pairs when it is performed in one reaction tube. Dividing a multiplex PCR into many single PCRs is a simple strategy to overcome this issue. Here, we constructed a plastic, easy-to-use, fully sealed multiplex PCR chip based on reversible centrifugation for the simultaneous detection of 63 target DNA sequences. The structure of the chip is quite simple, which contains sine-shaped infusing channels and a number of reaction chambers connecting to one side of these channels. Primer pairs for multiplex PCR were sequentially preloaded in the different reaction chambers, and the chip was enclosed with PCR-compatible adhesive tape. For usage, the PCR master mix containing a DNA template is pipetted into the infusing channels and centrifuged into the reaction chambers, leaving the infusing channels filled with air to avoid cross-contamination of the different chambers. Then, the chip is sealed and placed on a flat thermal cycler for PCR. Finally, amplification products can be detected in situ using a fluorescence scanner or recovered by reverse centrifugation for further analyses. Therefore, our chip possesses two functions: 1) it can be used for multi-target detection based on end-point in situ fluorescence detection; and 2) it can work as a sample preparation unit for analyses that need multiplex PCR such as hybridization and target sequencing. The performance of this chip was carefully examined and further illustrated in the identification of 8 pathogenic bacterial genomic DNA samples and 13 drug resistance genes. Due to simplicity of its structure and operation, accuracy and generality, high-throughput capacity, and versatile functions (i.e., for in situ detection and sample preparation), our multiplex PCR chip has great potential in clinical diagnostics and nucleic acid-based point-of-care testing. PMID- 26016438 TI - In search of an integrative measure of functioning. AB - International trends towards people-centred, integrative care and support require any measurement of functioning and disability to meet multiple aims. The information requirements of two major Australian programs for disability and rehabilitation are outlined, and the findings of two searches for suitable measures of functioning and disability are analysed. Over 30 current measures of functioning were evaluated in each search. Neither search found a generic measure of functioning suitable for these multibillion dollar programs, relevant to a wide range of people with a variety of health conditions and functioning experiences, and capable of indicating support needs, associated costs, progress and outcomes. This unsuccessful outcome has implications internationally for policy-relevant information for disability, rehabilitation and related programs. The paper outlines the features of an Integrative Measure of Functioning (IMF) based on the concepts of functioning and environmental factors in the International Classification of Functioning, Disability and Health (ICF). An IMF would be applicable across a variety of health conditions, settings and purposes, ranging from individual assessment to public health. An IMF could deliver person centred, policy-relevant information for a range of programs, promoting harmonised language and measurement and supporting international trends in human services and public health. PMID- 26016440 TI - In vivo monitoring of activated macrophages and neutrophils in response to ischemic osteonecrosis in a mouse model. AB - Ischemic osteonecrosis (IO) is caused by disruption of the blood supply to bone. It is a debilitating condition with pathological healing characterized by excessive bone resorption and delayed osteogenesis. Although the majority of research has focused on the role of osteoblasts and osteoclasts in the disease progression, we hypothesize that innate immune cells, macrophages and neutrophils, play a significant role. With the recent development of real-time imaging probes for neutrophils and macrophages, the purpose of this study was to investigate the kinetic immune cell response in a mouse model of IO. Our results show that induction of IO leads to a significant accumulation of activated neutrophils and macrophages at the affected tissue by 48 h after surgery. Additionally, the accumulation of these immune cells remained elevated in comparison to sham controls for up to 6 weeks, indicative of chronic inflammation. Immunohistochemistry confirmed the immune cell infiltration into the necrotic bone marrow and the increased presence of TNFalpha-positive cells, demonstrating, for the first time, a direct response of these cells to ischemia induced necrotic bone. These new findings support a hypothesis that IO is an osteoimmunologic condition where innate immune cells play a significant role in the chronic inflammation. PMID- 26016441 TI - Lutein suppresses inflammatory responses through Nrf2 activation and NF-kappaB inactivation in lipopolysaccharide-stimulated BV-2 microglia. AB - SCOPE: In this study, the effects of lutein on neuroinflammation in lipopolysaccharide (LPS)-activated BV-2 microglia were investigated. METHODS AND RESULTS: The production of proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide was measured in culture medium using enzyme immunoassay and Griess reagent, respectively. The expression of proteins was determined using Western blot. Pretreatment with lutein (50 MUM) prior to LPS (1 MUg/mL, 12 h) stimulation resulted in a significant inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression, as well as tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide production (p < 0.05). Further experiments demonstrated that lutein suppressed LPS-induced NF-kappaB activation by inhibiting the phosphorylation of p38 kinase, c-Jun N-terminal kinase (JNK), and Akt kinase (p < 0.05). Moreover, lutein markedly quenched reactive oxygen species and promoted antioxidant protein expression including heme oxygenase-1 and NAD(P)H: quinone oxidoreductase by enhancing the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) mediated NF-E2-related factor 2 (Nrf2) activation (p < 0.05). CONCLUSION: These results suggest that lutein attenuates neuroinflammation in LPS-activated BV-2 microglia partly through inhibiting p38-, JNK-, and Akt-stimulated NF-kappaB activation and promoting ERK induced Nrf2 activation, suggesting that lutein has great potential as a nutritional preventive strategy in inflammation-related neurodegenerative disorders. PMID- 26016442 TI - Differential sensitivity of porcine endogenous retrovirus to APOBEC3-mediated inhibition. AB - Pigs are considered to be suitable xenotransplantation organ donors. However, the risk of pathogen transmission from pigs to humans is a major concern in the transplantation of porcine tissues. The porcine endogenous retroviruses (PERVs) PERV-A, PERV-A/C, and PERV-B can infect human cells, but PERV-C is an ecotropic virus infecting only pig cells. Thus, several strategies have been proposed to reduce PERV transmission in xenograft recipients. Human APOBEC3G (huA3G) is a single-strand DNA cytosine deaminase, which inactivates the coding capacity of the virus by deamination of cDNA cytosines to uracils. This reaction occurs within the (-) DNA strand during reverse transcription, resulting in a G-to-A mutation in the (+) strand. While recent data have shown that PERV-B is severely inhibited by huA3G and porcine A3Z2-Z3 (poA3F) in a pseudotype assay, little is known about PERV-C. Here, we compare the antiretroviral activities of huA3G, huA3F and poA3Z2-Z3 against PERV-C. Our data show that APOBEC3 was packaged into PERV-C particles and inhibited PERV-C replication in a dose-dependent manner. PERV-C infectivity was strongly inhibited by poA3Z2-Z3, but it did not markedly reduce PERV-B infectivity. This suggests that PERV-C Gag interacts efficiently with poA3Z2-Z3. In addition, we constructed stably huA3G- and poA3Z2-Z3 expressing 293-PERV-PK-CIRCE cells (human 293 cells infected with PK15-derived PERVs) to examine whether PERV is resistant to poA3Z2-Z3 in a virus-spreading assay. The stably expressed huA3G and poA3Z2-Z3 were more packaging-competent than transiently expressed APOBEC3 proteins. These results suggest that poA3Z2-Z3 can inhibit PERV replication in a pseudotype assay as well as in a virus spreading assay. PMID- 26016443 TI - Interplay between influenza A virus and host factors: targets for antiviral intervention. AB - Influenza A viruses (IAVs) pose a major public health threat worldwide. Recent experience with the 2013 H7N9 outbreak in China and the 2009 "swine flu" pandemic have shown that antiviral vaccines and drugs fall short of controlling the spread of disease in a timely and effective manner. Major problems include rapid emergence of drug-resistant influenza virus strains and the slow process of vaccine production. With the threat of a highly pathogenic H5N1 bird-flu pandemic looming large, it is crucial to develop novel ways of combating influenza A viruses. Targeting the host factors critical for influenza A virus replication has shown promise as a strategy to develop novel antiviral molecules with broad spectrum protection. In this review, we summarize the role of currently identified host factors that play a critical role in the influenza A virus life cycle and discuss the most promising candidates for anti-influenza therapeutics. PMID- 26016444 TI - Protection against live rotavirus challenge in mice induced by parenteral and mucosal delivery of VP6 subunit rotavirus vaccine. AB - Live oral rotavirus (RV) vaccines are part of routine childhood immunization but are associated with adverse effects, particularly intussusception. We have developed a non-live combined RV - norovirus (NoV) vaccine candidate consisting of human RV inner-capsid rVP6 protein and NoV virus-like particles. To determine the effect of delivery route on induction of VP6-specific protective immunity, BALB/c mice were administered a vaccine containing RV rVP6 intramuscularly, intranasally or a combination of both, and challenged with murine RV. At least 65 % protection against RV shedding was observed regardless of delivery route. The levels of post-challenge serum VP6-specific IgA titers correlated with protection. PMID- 26016445 TI - Self-reported adverse tattoo reactions: a New York City Central Park study. AB - BACKGROUND: Although permanent tattoos are becoming increasingly commonplace, there is a paucity of epidemiological data on adverse tattoo reactions. Several European studies have indicated that tattoo reactions may be relatively common, although the extent of this phenomenon in the United States is largely unknown. OBJECTIVES: To provide insights into the prevalence and nature of adverse tattoo reactions. PATIENTS/MATERIALS/METHODS: We administered a survey about adverse tattoo reactions to 300 randomly selected tattooed people in Central Park, New York City. RESULTS: Of 300 participants, 31 (10.3%) reported experiencing an adverse tattoo reaction, 13 (4.3%) reported acute reactions, and 18 (6.0%) suffered from a chronic reaction involving a specific colour lasting for >4 months. Forty-four per cent of colour-specific reactions were to red ink, which was only slightly higher than the frequency of red ink in the sampled population (36%). Twenty-five per cent of chronic reactions were to black ink, which was less than expected based on the number of respondents with black tattoos (90.3%). Study participants with chronic, colour-specific reactions had more tattoo colours than those without reactions. CONCLUSIONS: This study shows that tattoo reactions are relatively common, and that further investigation into the underlying causes is merited. PMID- 26016446 TI - Comparative analysis of cytokeratin 15, TDAG51, cytokeratin 20 and androgen receptor in sclerosing adnexal neoplasms and variants of basal cell carcinoma. AB - BACKGROUND: Desmoplastic trichoepithelioma (DTE), morpheaform basal cell carcinoma (BCC) and microcystic adnexal carcinoma (MAC) are sclerosing adnexal neoplasms with overlapping histopathologic features. We compared cytokeratin 15, (CK15), T-cell death-associated gene 51 (TDAG51), cytokeratin 20 (CK20) and androgen receptor (AR) in differentiating these tumors and assessed their expression in BCC subtypes. METHODS: Fifteen DTE, 15 infundibulocystic BCC, 18 micronodular BCC, 18 morpheaform BCC and 6 MAC were assessed for CK15, TDAG51, CK20 and AR expression. RESULTS: Quantitative CK15 staining was higher in DTE compared with BCC (p < 0.0001) and MAC (p = 0.02). Quantitative TDAG51 staining was higher in DTE than BCC (p < 0.0001). The CK20+AR- immunophenotype was 100% sensitive and specific in diagnosing DTE. The CK20-AR+ immunophenotype was 95.24% specific and 83.33% sensitive for BCC. The CK20-AR- immunophenotype was 83.33% sensitive and 90.91% specific for MAC. CK15, CK20 and AR were positive in 87, 53 and 67% of infundibulocystic BCC cases, respectively. CONCLUSION: Combination of CK20 and AR best differentiated these sclerosing adnexal neoplasms. Greater positivity for CK15 and TDAG51 generally favors benign lesions. Infundibulocystic BCC has higher CK20 and lower AR immunopositivity than other BCC variants and a high degree of CK15 and TDAG51 positivity. PMID- 26016448 TI - Influence of multiple scattering and absorption on the full scattering profile and the isobaric point in tissue. AB - Light reflectance and transmission from soft tissue has been utilized in noninvasive clinical measurement devices such as the photoplethysmograph (PPG) and reflectance pulse oximeter. Incident light on the skin travels into the underlying layers and is in part reflected back to the surface, in part transferred and in part absorbed. Most methods of near infrared (NIR) spectroscopy focus on the volume reflectance from a semi-infinite sample, while very few measure transmission. We have previously shown that examining the full scattering profile (angular distribution of exiting photons) provides more comprehensive information when measuring from a cylindrical tissue. Furthermore, an isobaric point was found which is not dependent on changes in the reduced scattering coefficient. The angle corresponding to this isobaric point depends on the tissue diameter. We investigated the role of multiple scattering and absorption on the full scattering profile of a cylindrical tissue. First, we define the range in which multiple scattering occurs for different tissue diameters. Next, we examine the role of the absorption coefficient in the attenuation of the full scattering profile. We demonstrate that the absorption linearly influences the intensity at each angle of the full scattering profile and, more importantly, the absorption does not change the position of the isobaric point. The findings of this work demonstrate a realistic model for optical tissue measurements such as NIR spectroscopy, PPG, and pulse oximetery. PMID- 26016447 TI - Tumor inoculation site affects the development of cancer cachexia and muscle wasting. AB - The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor-bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF beta family, and found that levels of IL-6, TNF-alpha and activin A increased in both groups of tumor-bearing mice. Eotaxin and G-CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor-bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment. PMID- 26016449 TI - Errata: Lateral and axial measurement differences between spectral-domain optical coherence tomography systems. PMID- 26016450 TI - Design and Synthesis of Fluorinated Amphiphile as (19)F MRI/Fluorescence Dual Imaging Agent by Tuning the Self-Assembly. AB - Both (19)F MRI and optical imaging are powerful noninvasive molecular imaging modalities in biomedical applications. To integrate these two complementary imaging modalities, the design and synthesis of a novel (19)F MRI/fluorescence dual-modal imaging agent is reported herein. Through Sonogashira coupling reaction between the fluorinated phenylacetylene and 1,2,4,5-tetraiodobenzene, a fluorophore with 48 symmetrical fluorines at its periphery was constructed with high efficacy. High aqueous solubility was achieved by PEGylation of the fluorophore with monodisperse PEGs. However, an unexpected self-assembly of the PEGylated amphiphilic fluorophore in water "turned off" the (19)F NMR signal. However, hydrogenation of the triple bonds or introduction of branched monodisperse PEGs was able to efficiently tune the self-assembly, resulting in the "turning on" of the (19)F NMR signal. One of these amphiphiles combines the advantages of label-free fluorescence, high (19)F MRI sensitivity, biocompatibility, and excellent aqueous solubility. The results demonstrate the great potential of such amphiphiles for real-time (19)F MRI and fluorescence dual modality imaging. PMID- 26016452 TI - [Health evaluation of trichloroethylene in indoor air : communication from the German ad-hoc working group on indoor guidelines of the Indoor Air Hygiene Committee and of the states' supreme health authorities]. AB - In the European Hazardous Substances Regulation No 1272/2008 trichloroethylene has been classified as a probable human carcinogen and a suspected mutagen. According to several Committees (German Committee on Hazardous Substances, European Scientific Committee on Occupational Exposure Limits, European Chemicals Agency's Committee for Risk Assessment (ECHA-RAC)) concentrations of trichloroethylene cytotoxic to renal tubuli may increase the risk to develop renal cancer. At non-cytotoxic concentrations of trichloroethylene a much lower cancer risk may be assumed. Therefore, evaluating the cancer risk to the public following inhalation of trichloroethylene ECHA-RAC has assumed a sublinear exposure-response relationship for carcinogenicity of trichloroethylene. Specifically, ECHA-RAC assessed a cancer risk of 6.4 * 10(- 5) (mg/m(3))(- 1) following life time exposure to trichloroethylene below a NOAEC for renal cytotoxicity of 6 mg trichloroethylene/m(3). Further evaluation yields a life time risk of 10(- 6) corresponding to 0.02 mg trichloroethylene/m(3). This concentration is well above the reference (e.g. background) concentration of trichloroethylene in indoor air. Consequently the Ad-hoc Working Group on Indoor Guidelines recommends 0.02 mg trichloroethylene/m(3) as a risk-related guideline for indoor air. Measures to reduce exposure are considered inappropriate at concentrations below this guideline. PMID- 26016451 TI - Oxidative stress and paraoxonase 1 status in acute ischemic stroke patients. AB - OBJECTIVE: The connection of oxidative stress with dyslipidemia creates a newly emerging atherosclerosis risk factor involved in acute ischemic stroke development. This study analyzed the influence of oxidative stress on structural changes of high-density lipoprotein (HDL) particles connected with modification in protective paraoxonase 1 (PON1) activity. METHODS: This study used 185 patients with acute ischemic stroke and 185 apparently healthy controls. Oxidative stress status, PON1 status, lipids and high-sensitivity C-reactive protein (hsCRP) were determined. In isolated HDL lipoprotein fraction we determined selected markers of oxidative stress (malondialdehyde, MDA) and the content of total sulfhydryl (SH) groups. The capability of oxidative and PON1 status parameters to discriminate patients according to survival status was evaluated. RESULTS: Stroke patients had lower HDL-cholesterol than controls and a remarkable fall in PON1 activity (control group-227U/L, survivors-42U/L, lethal outcome group-61U/L, p < 0.001), along with more prominent inflammation. Pronounced oxidative stress and impaired antioxidative protection was present among patients. HDL fraction analysis revealed a significant decrease of SH groups content (control group vs. patients, p < 0.05) and increased in MDA content in patients (lethal outcome vs. control group, p < 0.05). According to logistic regression analysis, the best predictor of disease outcome was oxidative stress marker - prooxidative-antioxidative balance (PAB). CONCLUSIONS: Pronounced oxidative stress in this group of acute ischemic stroke patients probably led to HDL structural changes, which could further cause an alteration or decrease of PON1 activity. Evidence of increased prooxidant level associated with decreased protective, antioxidative factors suggests their mutual involvement in this complex pathology. PMID- 26016453 TI - [Health evaluation of indoor air carcinogens: first addendum to the basic scheme. Communication from the German Committee on Indoor Guidelines]. AB - According to the German Committee on Indoor Guidelines valid data on the usual occurrence of a carcinogenic substance in indoor air (e. g. the 95(th) percentile or reference value) and its exposure-risk relationship must be available for health evaluation. Depending on the mechanism of action of the substance the Committee decides which dose-response relationship is appropriate.Given a valid exposure-risk relationship the concentration of an indoor air carcinogen associated with a theoretical cancer risk of 10(-6) following lifetime exposure has to be estimated. The obtained concentration has to be compared to its reference value.If the concentration obtained from the exposure-risk relationship exceeds the reference value, it will be used as a risk-related guideline. If the concentration of the reference value is associated with a cancer risk above 10( 6), the reference value will be used as preliminary guideline. PMID- 26016454 TI - Xijiao Dihuang Decoction () and Rehmannia glutinosa Libosch. protect mice against lipopolysaccharide and tumor necrosis factor alpha-induced acute liver failure. AB - OBJECTIVE: To investigate the hepatoprotective effect of Xijiao Dihuang Decoction (, XJDHD) on lipopolysaccharide (LPS)- and tumor necrosis factor alpha (TNF alpha)-induced acute liver failure (ALF) as well as the underlying mechanism of action, and to clarify the key herbs and components of XJDHD. METHODS: LPS/D galactosamine (D-GalN) or TNF-alpha/D-GalN were intraperitoneally injected into C57BL/6J mice to induce ALF. Simultaneously, XJDHD or its individual herbs and components were orally administered. Survival rates, transaminase levels in serum, and hepatic histology were examined to evaluate the effects of XJDHD. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and real-time polymerase chain reaction were additionally performed to expound the mechanism underlying the anti-apoptotic activity of XJDHD. RESULTS: Oral administration of XJDHD protected mice from lethal liver failure induced by LPS and TNF-alpha, with notable amelioration of liver injury in histology and a significant decrease in transaminase levels in serum. XJDHD significantly inhibited apoptosis of hepatocytes and enhanced expression of the antiapoptosis genes, c-Flip, Iap1, Gadd45b and A20. In addition, Rehmannia glutinosa Libosch. was identified as the key herb of XJDHD and galactose as the effective component of Rehmannia glutinosa Libosch. that protects against ALF. CONCLUSIONS: XJDHD inhibits TNF-alpha-induced apoptosis of hepatocytes by promoting the expression of nuclear factor kappa B-regulated anti-apoptotic genes. Rehmannia glutinosa Libosch. is the effective herb of XJDHD and galactose is an active component in this protection. PMID- 26016455 TI - Oral oxymatrine preparation for chronic hepatitis B: A systematic review of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy and safety of oral oxymatrine preparation for the treatment of chronic hepatitis B (CHB). METHODS: Randomized controlled trials (RCTs) on oral oxymatrine preparation in treating patients with CHB were retrieved until October 2013 by searching PubMed, the Cochrane Library, Embase and four Chinese databases, irrespective of language and publication status. Data extraction and data analyses were conducted according to the Cochrane standards. The risk of bias for each included trials and the quality of evidence on pre specified outcomes were assessed. The RevMan software was used for statistical analyses. RESULTS: Totally 52 RCTs enrolling 5,227 participants were included, of which 51 RCTs were included in meta-analyses. Oral oxymatrine preparation including oxymatrine capsule and oxymatrine tablet were associated with statistically significant effect on the clearance of hepatitis B virus (HBV) DNA, HBV surface antigen and HBV e antigen, and were beneficial to the normalization of serum alanine aminotransferase and aspartate aminotransferase. Nevertheless, the overall methodological quality and the quality of evidence in the included trials were poor. In addition, safety of oral oxymatrine preparation was not confirmed. CONCLUSIONS: Oral oxymatrine preparation showed some potential benefits for patients with CHB. However, the overall quality of evidence was limited and the safety of oral oxymatrine preparation for CHB patients was still unproven. More high quality evidence from rigorously designed RCTs is warranted to support the clinical use of oral oxymatrine preparation for patients with CHB. PMID- 26016456 TI - [Current position on Vedolizumab for ulcerative colitis and Crohn's disease]. AB - Vedolizumab, the first drug in the class of anti-integrin molecules, is newly approved for ulcerative colitis and Crohn's disease and can be prescribed in Germany since mid-2014. By a specific receptor binding a relatively gut-selective mode of action was achieved without the known side effects of the systemic immunosuppression of the anti-TNF-alpha antibodies. According to the present data the safety profile of Vedolizumab appears to be more favorable than that of the anti-TNF- alpha therapy. Vedolizumab is suitable for induction therapy in patients with ulcerative colitis and Crohn's disease, however the kinetic of response compared with the anti-TNF-alpha antibodies seems to be slower. For maintenance therapy the Vedolizumab data show a deep and sustained remission in patients initially responding to induction therapy with a lower loss of efficacy in the long-term treatment known from the anti-TNF-alpha therapy. On the basis of currently available data the efficacy of Vedolizumab in ulcerative colitis appears to be slightly better than in Crohn's disease. PMID- 26016457 TI - Rg1 exhibits neuroprotective effects by inhibiting the endoplasmic reticulum stress-mediated c-Jun N-terminal protein kinase apoptotic pathway in a rat model of Alzheimer's disease. AB - The neuroprotective agents currently used to treat Alzheimer's disease (AD) often only target one aspect of the disease process. Therefore, identifying effective drug targets associated with the pathogenesis of AD is critical for the production of novel AD therapeutic strategies. The present study aimed to investigate the underlying mechanisms of the neuroprotective effects of Rg1 on a rat model of AD. A double transgenic beta-amyloid (Abeta) precursor protein/PS1 rat model was established, which co-expressed mutations associated with AD. Abeta plaques and neurofibrillary tangles (NFTs) were detected by immunohistochemistry. The detection of the protein expression levels of caspase-3 and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) staining were used to determine the level of apoptosis in the brain tissue. The expression levels of the endoplasmic reticulum (ER) stress biomarker, glucose-regulated protein 78 (Grp78), and the mitochondrial apoptosis biomarkers, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax), were analyzed by western blotting. Furthermore, the expression of the proteins associated with the ER stress unfolded protein response (UPR) was determined, in order to examine the levels of ER stress. The mRNA expression of downstream genes of UPR were also detected by reverse transcription-polymerase chain reaction. The protein expression levels of the apoptosis-associated phosphorylated-c-Jun N-terminal protein kinase (p-JNK), caspase-12 and cAMP response element-binding transcription factor homologous protein were determined by western blotting. The results of the present study indicated that the accumulation of NFTs and Abeta plaques was significantly decreased in the Rg1-treated AD rats, compared with untreated AD rats. The expression of caspase-3 and the number of TUNEL-positive cells were also significantly decreased in the Rg1-treated rats, as compared with the AD rats. Furthermore, treatment with Rg1 significantly reduced the expression of Grp78, and triggered inositol-requiring enzyme-1 (IRE-1) and phosphorylated protein kinase RNA-like ER kinase-associated ER stress. The IRE-1 UPR pathway downstream gene, tumor necrosis factor receptor-associated factor 2, was significantly decreased in rats treated with Rg1, compared with untreated AD rats. Furthermore, the activation of p-JNK was also inhibited when AD rats were treated with Rg1. In conclusion, Rg1 was shown to function as an important factor that inhibits the accumulation of NFTs and Abeta via inhibition of the ER stress-mediated pathway. Blocking of this pathway was triggered by the IRE-1 and TRAF2 pathway, as a result of inhibition of the expression of p-JNK. PMID- 26016458 TI - An Iodine-Catalyzed Hofmann-Loffler Reaction. AB - Iodine reagents have been identified as economically and ecologically benign alternatives to transition metals, although their application as molecular catalysts in challenging C-H oxidation reactions has remained elusive. An attractive iodine oxidation catalysis is now shown to promote the convenient conversion of carbon-hydrogen bonds into carbon-nitrogen bonds with unprecedented complete selectivity. The reaction proceeds by two interlocked catalytic cycles comprising a radical chain reaction, which is initiated by visible light as energy source. This unorthodox synthetic strategy for the direct oxidative amination of alkyl groups has no biosynthetic precedence and provides an efficient and straightforward access to a general class of saturated nitrogenated heterocycles. PMID- 26016459 TI - An exploration of diffusion tensor eigenvector variability within human calf muscles. AB - PURPOSE: To explore the effect of diffusion tensor imaging (DTI) acquisition parameters on principal and minor eigenvector stability within human lower leg skeletal muscles. MATERIALS AND METHODS: Lower leg muscles were evaluated in seven healthy subjects at 3T using an 8-channel transmit/receive coil. Diffusion encoding was performed with nine signal averages (NSA) using 6, 15, and 25 directions (NDD). Individual DTI volumes were combined into aggregate volumes of 3, 2, and 1 NSA according to number of directions. Tensor eigenvalues (lambda1 , lambda2 , lambda3 ), eigenvectors (epsilon1 , epsilon2 , epsilon3 ), and DTI metrics (fractional anisotropy [FA] and mean diffusivity [MD]) were calculated for each combination of NSA and NDD. Spatial maps of signal-to-noise ratio (SNR), lambda3 :lambda2 ratio, and zenith angle were also calculated for region of interest (ROI) analysis of vector orientation consistency. RESULTS: epsilon1 variability was only moderately related to epsilon2 variability (r = 0.4045). Variation of epsilon1 was affected by NDD, not NSA (P < 0.0002), while variation of epsilon2 was affected by NSA, not NDD (P < 0.0003). In terms of tensor shape, vector variability was weakly related to FA (epsilon1 :r = -0.1854, epsilon2 : ns), but had a stronger relation to the lambda3 :lambda2 ratio (epsilon1 :r = 0.5221, epsilon2 :r = -0.1771). Vector variability was also weakly related to SNR (epsilon1 :r = -0.2873, epsilon2 :r = -0.3483). Zenith angle was found to be strongly associated with variability of epsilon1 (r = 0.8048) but only weakly with that of epsilon2 (r = 0.2135). CONCLUSION: The second eigenvector (epsilon2 ) displayed higher directional variability relative to epsilon1 , and was only marginally affected by experimental conditions that impacted epsilon1 variability. PMID- 26016460 TI - Hepatic encephalopathy in acute-on-chronic liver failure. AB - The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed. PMID- 26016462 TI - Model for end-stage liver disease score and MELD exceptions: 15 years later. AB - The model for end-stage liver disease (MELD) score has been used as an objective scale of disease severity for management of patients with end-stage liver disease; it currently serves as the basis of an urgency-based organ-allocation policy in several countries. Implementation of the MELD score led to a reduction in waiting-list registration and waiting-list mortality and an increase in the number of deceased-donor transplants without adversely affecting long-term outcomes after liver transplantation (LT). The MELD score has been used for management of non-transplant patients with chronic liver disease. MELD exceptions serve as a mechanism to advance the needs of subsets of patients with liver disease not adequately addressed by MELD-based organ allocation. Several models have been proposed to refine and improve the MELD score as the environment within which it operates continues to evolve toward transplantation for sicker patients. The MELD score continues to serve and be used as a template to improve upon as an objective gauge of disease severity and as a metric enabling optimization of allocation of scarce donor organs for LT. PMID- 26016461 TI - Pattern and profile of chronic liver disease in acute on chronic liver failure. AB - The etiology of the chronic liver disease (CLD) in patients with acute on chronic liver failure (ACLF) may vary from region to region. The major cause of underlying CLD is viral (hepatitis B and C) in the East, while it is alcohol related in the West and in some parts of the Indian subcontinent. Autoimmune liver disease and Wilson's disease are the major underlying etiologies in the pediatric age group. The patients with CLD without cirrhosis should be included when defining ACLF. Non-alcoholic fatty liver disease related chronic liver insult in patients with known risk factors for progressive disease should be taken as a chronic liver disease in the setting of ACLF, whereas fatty liver with normal aminotransferases in low risk patients should not. The patients with CLD and previous decompensation should be excluded. Diagnosis of chronic liver disease in the setting of ACLF is made by history, physical examination and previously available or recent laboratory, endoscopic or radiological investigations. A liver biopsy through the transjugular route may help in cases where the presence of underlying CLD or its cause is not clear. The need of liver biopsy in ACLF should, however, be individualized. Standardization of liver biopsy assessment is essential for a uniform approach to the diagnosis and treatment of CLD and acute insult. Tools to measure liver stiffness may aid in identifying patients with advanced fibrosis. Studies are needed to validate the performance of these tests in the setting of ACLF. PMID- 26016463 TI - Twist in hepatocellular carcinoma: pathophysiology and therapeutics. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related disease worldwide. Although HCC is mainly associated with viral hepatitis and alcoholic cirrhosis, numerous physiological and biochemical events are associated with HCC progression. The transcription factor Twist, which plays a key role in epithelial to mesenchymal transition, is reported to be associated with HCC. Overexpression of Twist causes various biochemical changes, such as increase of cell proliferation, reduction of apoptosis, cell cycle deregulation, generation of hepatic cancer stem cells, and in some cases, drug resistance. These changes result in various physiological changes, such as angiogenesis, cellular migration and invasion, and vasculogenic mimicry, which ultimately causes hepatocellular metastasis. Interestingly, targeting Twist via different strategies, especially small RNA technology, has shown promising therapeutic potential for future HCC treatment. PMID- 26016464 TI - Sustained virologic response to standard interferon or pegylated interferon and ribavirin in patients with hepatitis C virus genotype 5: systematic review and meta-analysis of ten studies and 423 patients. AB - BACKGROUND: Interferon (IFN)-free therapy has vastly improved therapeutic options for those with hepatitis C virus infection (HCV). However, the lack of data and the expense limit its use for lesser known genotypes such as HCV-5, especially in countries with financial limitations. Previous reports estimate sustained virologic response (SVR) rates in HCV-5 to be ~40-70%. AIM: Our goal was to estimate pooled SVR rates for HCV-5 treatment-naive patients treated with IFN or peginterferon (PEG IFN) and ribavirin (RBV) combination therapy for 48 weeks. METHODS: We conducted a literature search to identify articles with HCV-5 patients treated with IFN/PEG IFN + RBV. Pooled SVR rates were reported by random effects modeling with 95% confidence intervals. Heterogeneity was defined by the Cochrane Q-statistic p <= 0.05 and I(2) statistic >=50%. RESULTS: A total of 423 patients from ten studies were included in the analysis. The pooled SVR rate for HCV-5 patients treated with IFN/PEG IFN + RBV for 48 weeks was 58.0% (CI 53.1% 62.7%). There was no evidence of heterogeneity (I(2) = 0, p = 0.61) or publication bias (Egger's test = 0.26). Pooled analysis of HCV-5 patients treated with PEG IFN + RBV was 55.0% (CI 49.4-61.5%). There was no evidence of heterogeneity (I(2) = 0.00, p = 0.75) or publication bias (Egger's test = 0.71). Combination therapy with IFN/PEG IFN + RBV had a pooled EVR of 90.2% (CI 76.8 96.2%). CONCLUSIONS: SVR for HCV-5 treated with combination therapy (IFN/PEG-IFN + RBV for 48 weeks) was approximately 60%. Current data are insufficient to evaluate variable duration of treatment (24 vs. 48 weeks), presence or absence of cirrhosis, effects of high versus low viral loads, or degree of fibrosis. The optimal treatment duration for HCV-5 patients with IFN-based combination remains to be established. Data and drug access are needed for treatment for HCV-5 in more resource-limited areas. PMID- 26016465 TI - Definition of ACLF and inclusion criteria for extra-hepatic organ failure. AB - A prominent characteristic of ACLF is rapid hepatic disease progression with subsequent extra-hepatic organ failure, manifesting as either hepatic coma or hepatorenal syndrome, which is associated with a high mortality rate in a short time. The APASL definition mainly emphasizes recognizing patients with hepatic failure. These patients may subsequently develop extra-hepatic multisystem organ failure leading to high mortality. It is therefore worthwhile to identify the short interim period between the development of liver failure and the onset of extra-hepatic organ failure, the potential therapeutic 'golden window.' Interventions during this period may prevent the development of complications and eventually change the course of the illness. Organ failure is suggested to be a central component of ACLF and may behave differently from chronic decompensated liver disease. Clear and practical criteria for the inclusion of organ failure are urgently needed so that patients with these life-threatening complications can be treated in a timely and appropriate manner. Recent studies suggested that the scoring systems evaluating organ failure [acute physiology, age and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA) scores] work better than those addressing the severity of liver disease [Child-Pugh and model of end-stage liver disease (MELD) scores] in ACLF. However, a key problem remains that the former scoring systems are reflective of organ failure and not predictive, thus limiting their value as an early indication for intervention. PMID- 26016466 TI - Synthesis of carbazoloquinone natural products 'on-water'. AB - The total synthesis of a number of carbazolo-1,4-quinone natural products using on-water chemistry is described. A recently developed domino 'in-water, on-water' process is employed to rapidly and efficiently generate koniginequinone A, which subsequently enables access to murrayaquinones B, C, D and E, and pyrayaquinones B and C, via a remarkably facile on-water catalysed Claisen rearrangement. PMID- 26016468 TI - Reply: To PMID 25303359. PMID- 26016467 TI - Antagonist and partial agonist at the dopamine D2 receptors in drug-naive and non drug-naive schizophrenia: a randomized, controlled trial. AB - Few data are available on the efficacy and safety of antipsychotics with different dopamine D2 receptor (D2-R)-binding properties in drug-naive and non drug-naive schizophrenia. Thus, we aimed to assess whether antipsychotic medication history influences efficacy and tolerability in schizophrenia, based on a randomized controlled study of antipsychotics with mechanisms involving either full antagonism or partial agonism of D2-R. Patients with schizophrenia were recruited and given perospirone or aripiprazole in a 12-week, flexible-dose, open-label, randomized controlled study. Data were analyzed after dividing the patients into antipsychotic-naive and antipsychotic-treated group according to antipsychotic medication histories. Efficacy and safety were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Drug-Induced Extrapyramidal Symptoms Scale, and the Barnes Akathisia Rating Scale. In patients receiving perospirone, the antipsychotic-naive group (n = 22) showed greater symptom improvement than that shown by the antipsychotic-treated group (n = 29), as assessed by efficacy evaluation scales such as the PANSS total, positive, and excited component score (p = .006, p < .001, p = .003, respectively). In patients receiving aripiprazole, however, there was no significant difference in efficacy between the antipsychotic-naive (n = 18) and antipsychotic-treated (n = 31) groups. No significant intra-group or inter-group difference was noted with respect to any of the tolerability-related parameters assessed. The present study data support the hypothesis that antipsychotic medication history may influence efficacy in patients who receive a D2-R full antagonist but not a D2-R partial agonist. PMID- 26016469 TI - Epithelial microRNA-9a regulates dendrite growth through Fmi-Gq signaling in Drosophila sensory neurons. AB - microRNA-9 (miR-9) is highly expressed in the nervous system across species and plays essential roles in neurogenesis and axon growth; however, little is known about the mechanisms that link miR-9 with dendrite growth. Using an in vivo model of Drosophila class I dendrite arborization (da) neurons, we show that miR-9a, a Drosophila homolog of mammalian miR-9, downregulates the cadherin protein Flamingo (Fmi) thereby attenuating dendrite development in a non-cell autonomous manner. In miR-9a knockout mutants, the dendrite length of a sensory neuron ddaE was significantly increased. Intriguingly, miR-9a is specifically expressed in epithelial cells but not in neurons, thus the expression of epithelial but not neuronal Fmi is greatly elevated in miR-9a mutants. In contrast, overexpression of Fmi in the neuron resulted in a reduction in dendrite growth, suggesting that neuronal Fmi plays a suppressive role in dendrite growth, and that increased epithelial Fmi might promote dendrite growth by competitively binding to neuronal Fmi. Fmi has been proposed as a G protein-coupled receptor (GPCR), we find that neuronal G protein Galphaq (Gq), but not Go, may function downstream of Fmi to negatively regulate dendrite growth. Taken together, our results reveal a novel function of miR-9a in dendrite morphogenesis. Moreover, we suggest that Gq might mediate the intercellular signal of Fmi in neurons to suppress dendrite growth. Our findings provide novel insights into the complex regulatory mechanisms of microRNAs in dendrite development, and further reveal the interplay between the different components of Fmi, functioning in cadherin adhesion and GPCR signalling. PMID- 26016470 TI - Prevalence and Correlates of HIV Infection Among Sex Workers in Papua New Guinea: First Results from the Papua New Guinea and Australia Sexual Health Improvement Project (PASHIP). AB - The primary objective of this study was to estimate the individual and combined impacts of socio-demographic and sexual behaviours on HIV diagnosis among 523 female sex workers who participated in the Papua New Guinea and Australia Sexual Health Improvement Project. Logistic regression models were used to identify the factors associated with HIV positivity. We estimated their population level impacts in order to quantify the proportion of HIV seropositivity is attributed to these factors. Less than 40 % of women consented to get tested for HIV. HIV prevalence was 7 % (95 % CI 4-11 %); lack of education and knowledge/awareness of HIV accounted for ~70 % of the HIV diagnoses. A major obstacle is lack of interest for testing. Our study underscored the major challenges in this culturally, linguistically heterogeneous country. The epidemic in Papua New Guinea requires targeted prevention interventions among those at highest risk of acquiring or transmitting infection. PMID- 26016471 TI - Peptide Folding in Translocon-Like Pores. AB - The cellular translocon, present in all three domains of life, is one of the most versatile and important biological nanopores. This complex molecular apparatus is directly responsible for the secretion of globular proteins across membranes as well as the insertion of integral membrane proteins into lipid bilayers. Recently determined structures of the archaean SecY translocon reveal an hour-glass-shaped pore, which accommodates the nascent peptide chain during translocation. While these structures provide important insights into ribosome binding to the translocon, threading of the nascent chain into the channel, and lateral gate opening for releasing the folded helical peptide into the membrane bilayer, the exact folding pathway of the peptide inside the protein-conducting channel during translocation and prior to the lateral release into the bilayer remains elusive. In the present study, we use molecular dynamics simulations to investigate atomic resolution peptide folding in hour-glass-shaped pore models that are based on the SecY translocon channel structure. The theoretical setup allows systematic variation of key determinants of folding, in particular the degree of confinement of the peptide and the hydration level of the pore. A 27-residue hydrophobic peptide was studied that is preferentially inserted into membranes by the translocon. Our results show that both pore diameter as well as channel hydration are important determinants for folding efficiency and helical stability of the peptide, therefore providing important insights into translocon gating and lateral peptide partitioning. PMID- 26016473 TI - The Effect of Processing Additives on Energetic Disorder in Highly Efficient Organic Photovoltaics: A Case Study on PBDTTT-C-T:PC71 BM. AB - Energetic disorder, an important parameter affecting the performance of organic photovoltaics, is significantly decreased upon the addition of processing additives in a highly efficient benzodithiophene-based copolymer blend (PBDTTT-C T:PC71 BM). Wide-angle and small-angle X-ray scattering measurements suggest that the origin of this reduced energetic disorder is due to increased aggregation and a larger average fullerene domain size together with purer phases. PMID- 26016474 TI - Does size matter? Separations on guard columns for fast sample analysis applied to bioenergy research. AB - BACKGROUND: Increasing sample throughput is needed when large numbers of samples have to be processed. In chromatography, one strategy is to reduce column length for decreased analysis time. Therefore, the feasibility of analyzing samples simply on a guard column was explored using refractive index and ultraviolet detection. Results from the guard columns were compared to the analyses using the standard 300 mm Aminex HPX-87H column which is widely applied to the analysis of samples from many biotechnology- and bioenergy-related experiments such as biomass conversions or fermentations. RESULTS: The 50 mm Rezex RFQ Fast Acid H(+) guard column was able to separate the most common fermentation products (ethanol, acetone, iso- and n-butanol) and promising precursors (furfural and 5 hydroxymethylfurfural) of biofuels and value-added chemicals. Compound profiles in fermentation samples were analyzed with similar accuracy compared to results using the 300 mm column. However, separation of glucose and xylose was not achieved. Nevertheless, it was possible to monitor the consumption of one of the two sugars during fermentation if the other one was absent or remained constant over the course of the experiment. If correct peak integration and interference subtraction was applied, concentration profiles from enzymatic digestibility experiments and even more complex samples (e.g. acetone-butanol-ethanol (ABE) fermentation) were reliably obtained. With the 50 mm guard column, samples were analyzed up to ten-times faster compared to the 300 mm column. A further decrease in analysis time was achieved by using the 30 mm Micro Guard Cation H guard column. This column is especially suitable for the rapid analysis of compounds with long elution times on the standard 300 mm column, such as biofuel-related alcohols (e.g., n-butanol, n-hexanol) and furan- and tetrahydrofuran-type molecules. CONCLUSION: Applied to a suitable set of samples, separations on a guard column can give rapid and sufficiently accurate information on compound changes over the course of an experiment. Therefore, it is an inexpensive and ideal tool for processing a large amount of samples, such as in screening or discovery experiments, where detecting relative changes is often sufficient to identify promising candidates for further analysis. PMID- 26016475 TI - Herpetofaunal community change in multiple habitats after fifteen years in a southwest Florida preserve, USA. AB - Herpetofaunal declines have been documented globally, and southern Florida, USA, is an especially vulnerable region because of high impacts from hydrological perturbations and nonindigenous species. To assess the extent of recent change in herpetofauna community composition, we established a baseline inventory during 1995-97 at a managed preserve in a habitat rich area of southwest Florida, and repeated our sampling methods fifteen years later (2010-11). Nine drift fence arrays were placed in four habitat types: mesic flatwood, mesic hammock, depression marsh, and wet prairie. Trapping occurred daily for one week during 7 8 sampling runs in each period (57 and 49 total sampling days, respectively). Species richness was maintained in mesic hammock habitats but varied in the others. Catch rates of several native species (Anaxyrus terrestris, Lithobates grylio, Anolis carolinensis, Nerodia fasciata) declined significantly. Other native species (Lithobates sphenocephalus, Siren lacertian, and Notophthalmus viridescens piaropicola) that were abundant in 1995-97 declined by greater than 50%. Catch rate of only two species (the nonindigenous Anolis sagrei and the native Diadophis punctatus) increased significantly. Hierarchical cluster analysis indicated similarity within habitat types but significant dissimilarity between sampling periods, confirming shifts in community composition. Analysis of individual species' contributions to overall similarity across habitats shows a shift from dominance of native species in the 1990s to increased importance of nonindigenous species in 2010-11. Although natural population fluctuations may have influenced differences between the two sampling periods, our results suggest considerable recent change in the structure and composition of this southwest Florida herpetofaunal community. The causes are unknown, but hydrological shifts and ecological impacts of nonindigenous species may have contributed. PMID- 26016477 TI - Which is the best repair of articular-sided rotator cuff tears: a meta-analysis. AB - BACKGROUND: Tear conversion followed by repair and trans-tendon techniques have been widely used for partial-thickness rotator cuff tears. Both of them showed favorable results with regard to the management of articular-sided partial thickness rotator cuff tears (PTRCTs) of more than 50% thickness. However, controversy continues with the best management. This study aims to compare the clinical outcomes between the two techniques. METHODS: The PubMed, Embase, and Cochrane library databases were searched for relevant studies published before October 1, 2014. Studies that clearly reported a comparison between the two procedures were selected. The American Shoulder and Elbow Surgeons scale (ASES) and the re-tear rate were evaluated. Statistical analysis was performed using the special meta-analysis software called "Comprehensive Meta Analysis". RESULTS: Final meta-analysis after the full-text review included four studies about tear conversion followed by repair and seven studies about trans-tendon technique. The trans-tendon technique showed no significant difference with the tear conversion followed by repair technique with regard to the ASES scale (P = 0.69). But the re tear rate (P < 0.05) was markedly lower in the trans-tendon technique group than the tear conversion and repair technique group. CONCLUSION: In conclusion, the meta-analysis suggests that the trans-tendon technique is better than the tear conversion followed by repair technique with regard to the management of articular-sided PTRCTs of more than 50% thickness in the re-tear rate aspect. PMID- 26016476 TI - Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization. AB - BACKGROUND: Overexpression or mutation of the epidermal growth factor receptor (EGFR) potently enhances the growth of many solid tumors. Tumor cells frequently display resistance to mechanistically-distinct EGFR-directed therapeutic agents, making it valuable to develop therapeutics that work by additional mechanisms. Current EGFR-targeting therapeutics include antibodies targeting the extracellular domains, and small molecules inhibiting the intracellular kinase domain. Recent studies have identified a novel prone extracellular tetrameric EGFR configuration, which we identify as a potential target for drug discovery. METHODS: Our focus is on the prone EGFR tetramer, which contains a novel protein protein interface involving extracellular domain III. This EGFR tetramer is computationally targeted for stabilization by small molecule ligand binding. This study performed virtual screening of a Life Chemicals, Inc. small molecule library of 345,232 drug-like compounds against a molecular dynamics simulation of protein-protein interfaces distinct to the novel tetramer. One hundred nine chemically diverse candidate molecules were selected and evaluated using a cell based high-content imaging screen that directly assessed induced internalization of the EGFR effector protein Grb2. Positive hits were further evaluated for influence on phosphorylation of EGFR and its effector ERK1/2. RESULTS: Fourteen hit compounds affected internalization of Grb2, an adaptor responsive to EGFR activation. Most hits had limited effect on cell viability, and minimally influenced EGFR and ERK1/2 phosphorylation. Docked hit compound poses generally include Arg270 or neighboring residues, which are also involved in binding the effective therapeutic cetuximab, guiding further chemical optimization. CONCLUSIONS: These data suggest that the EGFR tetrameric configuration offers a novel cancer drug target. PMID- 26016478 TI - Geometrical and mechanical properties control actin filament organization. AB - The different actin structures governing eukaryotic cell shape and movement are not only determined by the properties of the actin filaments and associated proteins, but also by geometrical constraints. We recently demonstrated that limiting nucleation to specific regions was sufficient to obtain actin networks with different organization. To further investigate how spatially constrained actin nucleation determines the emergent actin organization, we performed detailed simulations of the actin filament system using Cytosim. We first calibrated the steric interaction between filaments, by matching, in simulations and experiments, the bundled actin organization observed with a rectangular bar of nucleating factor. We then studied the overall organization of actin filaments generated by more complex pattern geometries used experimentally. We found that the fraction of parallel versus antiparallel bundles is determined by the mechanical properties of actin filament or bundles and the efficiency of nucleation. Thus nucleation geometry, actin filaments local interactions, bundle rigidity, and nucleation efficiency are the key parameters controlling the emergent actin architecture. We finally simulated more complex nucleation patterns and performed the corresponding experiments to confirm the predictive capabilities of the model. PMID- 26016479 TI - Detection of Cytosine methylation in ancient DNA from five native american populations using bisulfite sequencing. AB - While cytosine methylation has been widely studied in extant populations, relatively few studies have analyzed methylation in ancient DNA. Most existing studies of epigenetic marks in ancient DNA have inferred patterns of methylation in highly degraded samples using post-mortem damage to cytosines as a proxy for cytosine methylation levels. However, this approach limits the inference of methylation compared with direct bisulfite sequencing, the current gold standard for analyzing cytosine methylation at single nucleotide resolution. In this study, we used direct bisulfite sequencing to assess cytosine methylation in ancient DNA from the skeletal remains of 30 Native Americans ranging in age from approximately 230 to 4500 years before present. Unmethylated cytosines were converted to uracils by treatment with sodium bisulfite, bisulfite products of a CpG-rich retrotransposon were pyrosequenced, and C-to-T ratios were quantified for a single CpG position. We found that cytosine methylation is readily recoverable from most samples, given adequate preservation of endogenous nuclear DNA. In addition, our results indicate that the precision of cytosine methylation estimates is inversely correlated with aDNA preservation, such that samples of low DNA concentration show higher variability in measures of percent methylation than samples of high DNA concentration. In particular, samples in this study with a DNA concentration above 0.015 ng/MUL generated the most consistent measures of cytosine methylation. This study presents evidence of cytosine methylation in a large collection of ancient human remains, and indicates that it is possible to analyze epigenetic patterns in ancient populations using direct bisulfite sequencing approaches. PMID- 26016480 TI - Survivin expression and serum levels in pancreatic cancer. AB - BACKGROUND: Survivin, an inhibitor of apoptosis, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). Its expression is known to be associated with poor clinical outcome. However, to our knowledge, there has been no study to characterize its usefulness as a serum marker for human pancreatic cancer. Furthermore, the relation between survivin expression and the serum level of survivin has not been widely studied in PDAC. We performed this study to investigate the expression and serum level of survivin in PDAC and its clinical significance as a prognostic factor. METHODS: We performed immunohistochemical staining for survivin in formalin-fixed, paraffin-embedded blocks from 80 PDAC tissues. The serum level of survivin from the patients (n = 80) and age-matched healthy volunteers (n = 80) were analyzed by enzyme-linked immunosorbent assays (ELISAs) prior to surgical resection. Levels of expression were correlated with clinicopathological parameters. RESULTS: Serum survivin concentrations were significantly elevated in patients with PDAC when compared with healthy sera (P < 0.001). High serum survivin levels were significantly associated with perineural invasion, venous invasion, lymph node status (N stage), cell differentiation, and recurrence but not with the tumor size, age, gender of the patients, or tumor location. The median overall survival time of the group with normal serum survivin levels was longer than that of the group with elevated serum survivin. The independent factors associated with overall survival were advanced pancreatic cancer and elevated serum survivin level. Of the 80 cases of PDAC, 65 (81.25 %) were positive for survivin expression. There were significant associations between survivin expression and perineural invasion, venous invasion, and lymph node status. A significant difference in overall survival was associated with survivin expression. CONCLUSIONS: Patients with elevated serum survivin level and high survivin expression at diagnosis demonstrated a poor outcome. Detection of serum survivin or tissue survivin expression may predict the prognosis of patients with PDAC. PMID- 26016482 TI - Incidence of neuralgic amyotrophy (Parsonage Turner syndrome) in a primary care setting--a prospective cohort study. AB - OBJECTIVE: Neuralgic amyotrophy is considered a rare peripheral nervous system disorder but in practice seems grossly under recognized, which negatively affects care for these patients. In this study we prospectively counted the one-year incidence rate of classic neuralgic amyotrophy in a primary care setting. METHODS: In a prospective cohort study during the year 2012 we registered all new cases of neck, shoulder or arm complaints from two large primary care centers serving a population of 14,118. Prior to study, general practitioners received a short training on how to diagnose classic neuralgic amyotrophy. Neuralgic amyotrophy was defined according to published criteria irrespective of family history. Only patients with a classic phenotype were counted as definite cases. After inclusion, patients with suspected neuralgic amyotrophy who had not yet seen a neurologist were offered neurologic evaluation for diagnostic confirmation. RESULTS: Of the 492 patients identified with new onset neck, shoulder or arm complaints, 34 were suspected of having neuralgic amyotrophy. After neurologic evaluation the diagnosis was confirmed in 14 patients. This amounts to a one-year incidence rate for classic neuralgic amyotrophy of 1 per 1000. CONCLUSIONS: Our findings suggest that neuralgic amyotrophy is 30-50 times more common than previously thought. Unawareness of the disorder and its clinical presentation seems the most likely explanation for this difference. An incidence rate of 1 per 1000 and the long-term sequelae many patients suffer warrant more vigilance in diagnosing the disorder, to pave the way for timely treatment and prevent complications. PMID- 26016481 TI - Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides. AB - BACKGROUND: The laboratory mouse is the most commonly used model for studying variation in complex traits relevant to human disease. Here we present the whole genome sequences of two inbred strains, LG/J and SM/J, which are frequently used to study variation in complex traits as diverse as aging, bone-growth, adiposity, maternal behavior, and methamphetamine sensitivity. RESULTS: We identified small nucleotide variants (SNVs) and structural variants (SVs) in the LG/J and SM/J strains relative to the reference genome and discovered novel variants in these two strains by comparing their sequences to other mouse genomes. We find that 39% of the LG/J and SM/J genomes are identical-by-descent (IBD). We characterized amino-acid changing mutations using three algorithms: LRT, PolyPhen-2 and SIFT. We also identified polymorphisms between LG/J and SM/J that fall in regulatory regions and highly informative transcription factor binding sites (TFBS). We intersected these functional predictions with quantitative trait loci (QTL) mapped in advanced intercrosses of these two strains. We find that QTL are both over-represented in non-IBD regions and highly enriched for variants predicted to have a functional impact. Variants in QTL associated with metabolic (231 QTL identified in an F16 generation) and developmental (41 QTL identified in an F34 generation) traits were interrogated and we highlight candidate quantitative trait genes (QTG) and nucleotides (QTN) in a QTL on chr13 associated with variation in basal glucose levels and in a QTL on chr6 associated with variation in tibia length. CONCLUSIONS: We show how integrating genomic sequence with QTL reduces the QTL search space and helps researchers prioritize candidate genes and nucleotides for experimental follow-up. Additionally, given the LG/J and SM/J phylogenetic context among inbred strains, these data contribute important information to the genomic landscape of the laboratory mouse. PMID- 26016483 TI - Association between Benzodiazepine Use and Dementia: A Meta-Analysis. AB - BACKGROUND: The association between long-term benzodiazepine use and risk of dementia remains controversial. Therefore, current study aimed to quantify this association, and to explore a potential dose-response pattern. METHODS: We searched PubMed, Embase and the Cochrane Library through August 17, 2014. We included nested case-control or prospective cohort studies that provided risk estimates on the association of benzodiazepine use with risk of dementia, and a clear definition of status of benzodiazepine use. Overall effect size was calculated using a random-effects model. FINDINGS: Six studies were eligible for inclusion, involving 11,891 dementia cases and 45,391 participants. Compared with never users, pooled adjusted risk ratios (RRs) for dementia were 1.49 (95% confidence interval (CI) 1.30-1.72) for ever users, 1.55 (95% CI 1.31-1.83) for recent users, and 1.55 (95% CI 1.17-2.03) for past users. The risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR, 1.22, 95%CI 1.18-1.25). When we restricted our meta-analyses to unadjusted RRs, all initial significant associations persisted. CONCLUSIONS: Long-term benzodiazepine users have an increased risk of dementia compared with never users. However, findings from our study should be treated with caution due to limited studies and potential reverse causation. Large prospective cohort studies with long follow-up duration are warranted to confirm these findings. PMID- 26016484 TI - Trends in telemedicine use in addiction treatment. AB - INTRODUCTION: Telemedicine use in addiction treatment and recovery services is limited. Yet, because it removes barriers of time and distance, telemedicine offers great potential for enhancing treatment and recovery for people with substance use disorders (SUDs). Telemedicine also offers clinicians ways to increase contact with SUD patients during and after treatment. CASE DESCRIPTION: A project conducted from February 2013 to June 2014 investigated the adoption of telemedicine services among purchasers of addiction treatment in five states and one county. The project assessed purchasers' interest in and perceived facilitators and barriers to implementing one or more of the following telemedicine modalities: telephone-based care, web-based screening, web-based treatment, videoconferencing, smartphone mobile applications (apps), and virtual worlds. DISCUSSION AND EVALUATION: Purchasers expressed the most interest in implementing videoconferencing and smartphone mobile devices. The anticipated facilitators for implementing a telemedicine app included funding available to pay for the telemedicine service, local examples of success, influential champions at the payer and treatment agencies, and meeting a pressing need. The greatest barriers identified were: costs associated with implementation, lack of reimbursement for telemedicine services, providers' unfamiliarity with technology, lack of implementation models, and confidentiality regulations. This paper discusses why the project participants selected or rejected different telemedicine modalities and the policy implications that purchasers and regulators of addiction treatment services should consider for expanding their use of telemedicine. CONCLUSIONS: This analysis provides initial observations into how telemedicine is being implemented in addiction services in five states and one county. The project demonstrated that despite the considerable interest in telemedicine, implementation challenges exist. Future studies should broaden the sample analyzed and track technology implementation longitudinally to help the research and practitioner communities develop a greater understanding of technology implementation trends and practices. PMID- 26016485 TI - Primary Myofibroblasts Maintain Short-Term Viability following Submucosal Injection in Syngeneic, Immune-Competent Mice Utilizing Murine Colonoscopy. AB - The myofibroblast is an important stromal cell of the gastrointestinal tract. Current in vitro and in vivo models either do not accurately recreate stromal epithelial interactions or are not specific to myofibroblasts. We sought to create an animal model that would allow the study of myofibroblast-epithelial interactions. We isolated and cultured colonic myofibroblasts from FVB mice. Cells were alpha-SMA and vimentin positive but desmin negative on immunoblot analysis. We injected the myofibroblasts into the colonic submucosa of syngeneic adult mice (n = 8) via a miniendoscopic system. We then isolated green fluorescent protein (GFP) positive colonic myofibroblasts from C57BL/6-Tg(CAG EGFP)1Osb/J mice and injected them into the colonic lamina propria of C57BL/6J mice at 1x10(5) (n = 14), 1x10(6) (n = 9), or 5x10(6) cells/mL (n = 4). A subset of mice were injected with serum-free media and ink without cells (n = 3). Mice underwent repeat endoscopy and euthanasia one or 7 days after injection. Colons were isolated and either fixed in 10% formalin or the inked sites were individually excised and lysed for DNA. We assessed the injection sites via histology and immunohistochemical stains for alpha-SMA and GFP. We used qPCR to quantify GFP DNA transcripts at the lamina propria injection sites. Submucosal injection of myofibroblasts resulted in the formation of a subepithelial wheal on endoscopy, which persisted to day 7. Myofibroblasts injected either into the submucosa or lamina propria maintained viability on post-injection day 7 as evidenced by positive alpha-SMA staining. qPCR of lamina propria injections showed a dose-dependent increase in GFP DNA transcripts on post-injection day 1, whereas the number of transcripts on day 7 was equivalent for the concentrations injected. We demonstrate short-term survival of primary cultured colonic myofibroblasts in syngeneic mice. This may prove to be a valuable model for studying the role of myofibroblasts in states of health and disease. PMID- 26016487 TI - Diffuse cerebrovascular dilation: Case report of amezinium metilsulfate-induced reversible cerebral vasoconstriction syndrome. AB - BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries. CASE DESCRIPTION: A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months. DISCUSSION: Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS. PMID- 26016488 TI - Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study. AB - OBJECTIVE: To examine whether deviation from the standard intention to treat analysis has an influence on treatment effect estimates of randomised trials. DESIGN: Meta-epidemiological study. DATA SOURCES: Medline, via PubMed, searched between 2006 and 2010; 43 systematic reviews of interventions and 310 randomised trials were included. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: From each year searched, random selection of 5% of intervention reviews with a meta-analysis that included at least one trial that deviated from the standard intention to treat approach. Basic characteristics of the systematic reviews and randomised trials were extracted. Information on the reporting of intention to treat analysis, outcome data, risk of bias items, post-randomisation exclusions, and funding were extracted from each trial. Trials were classified as: ITT (reporting the standard intention to treat approach), mITT (reporting a deviation from the standard approach), and no ITT (reporting no approach). Within each meta analysis, treatment effects were compared between mITT and ITT trials, and between mITT and no ITT trials. The ratio of odds ratios was calculated (value <1 indicated larger treatment effects in mITT trials than in other trial categories). RESULTS: 50 meta-analyses and 322 comparisons of randomised trials (from 84 ITT trials, 118 mITT trials, and 108 no ITT trials; 12 trials contributed twice to the analysis) were examined. Compared with ITT trials, mITT trials showed a larger intervention effect (pooled ratio of odds ratios 0.83 (95% confidence interval 0.71 to 0.96), P=0.01; between meta-analyses variance tau(2)=0.13). Adjustments for sample size, type of centre, funding, items of risk of bias, post-randomisation exclusions, and variance of log odds ratio yielded consistent results (0.80 (0.69 to 0.94), P=0.005; tau(2)=0.08). After exclusion of five influential studies, results remained consistent (0.85 (0.75 to 0.98); tau(2)=0.08). The comparison between mITT trials and no ITT trials showed no statistical difference between the two groups (adjusted ratio of odds ratios 0.92 (0.70 to 1.23); tau(2)=0.57). CONCLUSIONS: Trials that deviated from the intention to treat analysis showed larger intervention effects than trials that reported the standard approach. Where an intention to treat analysis is impossible to perform, authors should clearly report who is included in the analysis and attempt to perform multiple imputations. PMID- 26016490 TI - Plant poisonings in livestock in Brazil and South Africa. AB - Information on intoxication of livestock by plants in Brazil, in terms of cause, clinical signs and pathology, is compared with information on livestock poisoning by plants in South Africa. Plant poisoning, including mycotoxicosis, is considered to be one of three major causes of death in livestock in Brazil, which is one of the top beef producing countries in the world, with a cattle population of more than 200 million. Cattle production in South Africa is on a more modest scale, but with some 600 species of plants and fungi known to cause toxicity in livestock, as opposed to some 130 species in Brazil, the risk to livestock in South Africa appears to be much greater. The comparisons discussed in this communication are largely restricted to ruminants. PMID- 26016489 TI - Effect of ghrelin on mortality and cardiovascular outcomes in experimental rat and mice models of heart failure: a systematic review and meta-analysis. AB - BACKGROUND: Heart failure (HF) continues to be a challenging condition in terms of prevention and management of the disease. Studies have demonstrated various cardio-protective effects of Ghrelin. The aim of the study is to determine the effect of Ghrelin on mortality and cardiac function in experimental rats/mice models of HF. METHODS: Data sources: PUBMED, Scopus. We searched the Digital Dissertations and conference proceedings on Web of Science. Search methods: We systematically searched for all controlled trials (upto November 2014) which assessed the effects of Ghrelin (irrespective of dose, form, frequency, duration and route of administration) on mortality and cardiac function in rats/ mice models of HF. Ghrelin administration irrespective of dose, form, frequency, duration and route of administration. Data collection and analysis: Two authors independently assessed each abstract for eligibility and extracted data on characteristics of the experimental model used, intervention and outcome measures. We assessed the methodological quality by SYRCLE's risk of bias tool for all studies and the quality of evidence by GRADEpro. We performed meta analysis using RevMan 5.3. RESULTS: A total of 325 animals (rats and mice) were analyzed across seven studies. The meta-analysis revealed that the mortality in Ghrelin group was 31.1% and in control group was 40% (RR 0.83, 95% CI 0.46 to 1.47) i.e Ghrelin group had 68 fewer deaths per 1000 (from 216 fewer to 188 more) as compared to the control group. The meta-analysis reveals that the heart rate in rats/mice on Ghrelin was higher (MD 13.11, 95% CI 1.14 to 25.08, P=0.66) while the mean arterial blood pressure (MD -1.38, 95% CI -5.16 to 2.41, P=0.48) and left ventricular end diastolic pressure (MD -2.45, 95% CI -4.46 to -0.43, P=0.02) were lower as compared to the those on placebo. There were insignificant changes in cardiac output (SMD 0.28, 95% CI -0.24 to 0.80, P=0.29) and left ventricular end systolic pressure (MD 1.48, 95% CI -3.86 to 6.82, P=0.59). CONCLUSIONS: The existing data provides evidence to suggest that Ghrelin may lower the risk of mortality and improve cardiovascular outcomes. However; the quality of evidence as assessed by GRADEpro is low to very low. Clinical judgments to administer Ghrelin to patients with HF must be made on better designed animal studies. PMID- 26016491 TI - Bizionia arctica sp. nov., isolated from Arctic fjord seawater, and emended description of the genus Bizionia. AB - A Gram-stain-negative, yellow-pigmented, aerobic, non-flagellated, non-gliding bacterial strain, designated SM1203(T), was isolated from surface seawater of Kongsfjorden, Svalbard. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain SM1203(T) was affiliated with the genus Bizionia in the family Flavobacteriaceae. The strain shared the highest 16S rRNA gene sequence similarity (>96%) with the type strains of Formosa spongicola (96.8%), Bizionia paragorgiae (96.3%), B. saleffrena (96.3%) and B. echini (96.1%) and 95.4-95.7% sequence similarity with the type strains of other known species of the genus Bizionia. The strain grew at 4-30 degrees C and in the presence of 1.0-5.0% (w/v) NaCl. The major fatty acids of strain SM1203(T) were iso-C15 : 0, iso-C15 : 1, anteiso-C15 : 0 and C15 : 0 and the main polar lipids were phosphatidylethanolamine and an unidentified lipid. The major respiratory quinone of strain SM1203(T) was menaquinone 6 (MK-6). The genomic DNA G+C content of strain SM1203(T) was 34.8 mol%. Based on the polyphasic characterization of strain SM1203(T) in this study, the strain represents a novel species in the genus Bizionia, for which the name Bizionia arctica sp. nov. is proposed. The type strain is SM1203(T) ( = CGMCC 1.12751(T) = JCM 30333(T)). An emended description of the genus Bizionia is also given. PMID- 26016492 TI - Rhizobium oryzicola sp. nov., potential plant-growth-promoting endophytic bacteria isolated from rice roots. AB - Bacterial strains ZYY136(T) and ZYY9 were isolated from surface-sterilized rice roots from a long-term experiment of rice-rice--Astragalus sinicus rotation. The 16S rRNA gene sequences of strains ZYY136(T) and ZYY9 showed the highest similarity, of 97.0%, to Rhizobium tarimense PL-41(T). Sequence analysis of the housekeeping genes recA, thrC and atpD clearly differentiated the isolates from currently described species of the genus Rhizobium. The DNA-DNA relatedness value between ZYY136(T) and ZYY9 was 82.3%, and ZYY136(T) showed 34.0% DNA-DNA relatedness with the most closely related type strain, R. tarimense PL-41(T). The DNA G+C content of strain ZYY136(T) was 58.1 mol%. The major cellular fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C16 : 0 and C16 : 0 3-OH. Strains ZYY136(T) and ZYY9 could be differentiated from the previously defined species of the genus Rhizobium by several phenotypic characteristics. Therefore, we conclude that strains ZYY136(T) and ZYY9 represent a novel species of the genus Rhizobium, for which the name Rhizobium oryzicola sp. nov. is proposed (type strain ZYY136(T) = ACCC 05753(T) = KCTC 32088(T)). PMID- 26016493 TI - Toward the Development of a More Integrated Aged Care Assessment Process for Rural Older Australians: Practitioners' Perspectives. AB - There is an identified need for more effective assessment processes in rural Australia, with prior research revealing little knowledge sharing and even duplication across existing services. This article aims to explore the challenges to more closely integrated assessment processes, drawing on interview data with practitioners from three agencies located in the same rural region. Findings highlight the challenges of rural assessment, both demand-driven (more older people with complex needs, geographic isolation) and supply issues (time and distance, funding formulae, workforce shortages). The need for closer collaboration is recognized but significant systemic issues require addressing if it is to be achieved. PMID- 26016495 TI - ANP and CNP activate CFTR expressed in Xenopus laevis oocytes by direct activation of PKA. AB - CONTEXT: Acting through different receptors, natriuretic peptides (atrial natriuretic peptide [ANP], brain type natriuretic peptide [BNP] and C-type natriuretic peptide [CNP]) increase intracellular cGMP, which then stimulates different pathways that activate fluid secretion. OBJECTIVE: We used two electrode voltage clamping to define the dominant pathway that is employed when natriuretic peptides activate cystic fibrosis transmembrane conductance regulator (CFTR) in the Xenopus oocyte expression system. Natriuretic peptides could activate CFTR by 1) cGMP cross-activation of protein kinase A (PKA), 2) cGMP activation of cGMP-dependent protein kinase II, 3) cGMP inhibition of phosphodiesterase type III (PDE3), or 4) direct activation of CFTR. MATERIALS AND METHODS: cRNA-microinjected Xenopus laevis oocytes were perfused with diverse compounds that examined these pathways of natriuretic peptide signaling. RESULTS AND DISCUSSION: ANP stimulated the shark CFTR (sCFTR)-mediated chloride conductance and this activation was inhibited by H-89, a specific inhibitor of PKA. After co-expression of the CNP receptor (NPR-B), sCFTR became stimulatable by CNP and was similarly inhibited by H-89, pointing to cross-activation of PKA. 8-pCPT-cGMP, a relatively cGKII-selective cGMP, failed to stimulate sCFTR. Another membrane-permeable and non-hydrolyzable analog of cGMP, 8-Br-cGMP, stimulated CFTR only at millimolar concentrations, consistent with cross activation of PKA. The PDE inhibitors EHNA, rolipram, cilostamide, and amrinone did not significantly increase chloride conductance, arguing against a significant role for PDE2, PDE3 and PDE4 signaling in the oocyte. Sildenafil, a PDE5 inhibitor, caused a partial activation of sCFTR channels and this effect was again inhibited by H-89. CONCLUSION: From these experiments we conclude that in the Xenopus oocyte system, natriuretic peptides, 8-Br-cGMP, and PDE5 inhibitors activate CFTR by cross-activation of PKA. PMID- 26016496 TI - Three novel electrochemical electrodes for the fabrication of conducting polymer/SWCNTs layered nanostructures and their thermoelectric performance. AB - Single-walled carbon nanotubes (SWCNTs), PEDOT: PSS/SWCNTs, and SWCNTs/ PEDOT: PSS nanofilms were used as working electrodes to electrodeposit polyaniline (PANI) in a mixed alcohol solution of isopropyl alcohol (IPA), boron trifluoride ethyl ether (BFEE), and polyethylene glycol (PEG). The thermoelectric (TE) performances of the resulting nanofilms were systematically investigated. SWCNTs/ PEDOT: PSS/PANI nanofilms showed a relatively high electrical conductivity value of 232.0 S cm(-1). The Seebeck coefficient was enhanced and exhibited the values of 33.8, 25.6, and 23.0 MUV K(-1) for the SWCNTs/PANI, PEDOT:PSS/SWCNTs/PANI, and SWCNTs/ PEDOT: PSS/PANI films, respectively. The maximum power factor achieved was 12.3 MUW m(-1) K(-2). This technique offers a facile and versatile approach to a class of layered nanostructures, and it may provide a general strategy for fabricating a new generation of conducting polymer/SWCNTs materials for further practical applications. PMID- 26016494 TI - The use of high-throughput sequencing methods for plant microRNA research. AB - MicroRNA (miRNA) acts as a critical regulator of gene expression at post transcriptional and occasionally transcriptional levels in plants. Identification of reliable miRNA genes, monitoring the procedures of transcription, processing and maturation of the miRNAs, quantification of the accumulation levels of the miRNAs in specific biological samples, and validation of miRNA-target interactions become the basis for thoroughly understanding of the miRNA-mediated regulatory networks and the underlying mechanisms. Great progresses have been achieved for sequencing technology. Based on the high degree of sequencing depth and coverage, the high-throughput sequencing (HTS, also called next-generation sequencing) technology provides unprecedentedly efficient way for genome-wide or transcriptome-wide studies. In this review, we will introduce several HTS platform-based methods useful for plant miRNA research, including RNA-seq (RNA sequencing), RNA-PET-seq (paired end tag sequencing of RNAs), sRNA-seq (small RNA sequencing), dsRNA-seq (double-stranded RNA sequencing), ssRNA-seq (single stranded RNA sequencing) and degradome-seq (degradome sequencing). In particular, we will provide some special cases to illustrate the novel use of HTS methods for investigation of the processing modes of the miRNA precursors, identification of the RNA editing sites on miRNA precursors, mature miRNAs and target transcripts, re-examination of the current miRNA registries, and discovery of novel miRNA species and novel miRNA-target interactions. Summarily, we opinioned that integrative use of the above mentioned HTS methods could make the studies on miRNAs more efficient. PMID- 26016497 TI - Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects. AB - Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings. PMID- 26016498 TI - Lack of Association between the TSPAN18 Gene and Schizophrenia Based on New Data from Han Chinese and a Meta-Analysis. AB - Tetraspanin-18 (TSPAN18) potentially plays a role in the calcium signaling that is associated with dopamine-induced cortical neuron apoptosis and is considered to be an important mechanism in the pathogenesis of schizophrenia (SCZ). Furthermore, a genome-wide association study (GWAS) identified TSPAN18 as a possible susceptibility gene for SCZ. To validate these findings and reveal the effects of different inheritance models, seven single nucleotide polymorphisms (SNPs) of the TSPAN18 gene were analyzed in 443 patients with SCZ and 628 controls of Han Chinese descent via the SNPscan method. Single SNP, genotype, and association analyses with different models (i.e., additive, dominant, and recessive models) were performed, and the published datasets (2062 cases and 2053 controls) were combined with our results to determine the inheritance effects of the SNPs on SCZ. We observed genotypes and allele distributions of TSPAN18 gene did not show any significant associations in the Han Chinese population based on our experimental and meta-analytical results. Our findings indicate that the TSPAN18 gene is unlikely to be a major susceptibility gene for schizophrenia in Han Chinese. PMID- 26016499 TI - Global proteomic analysis of brain tissues in transient ischemia brain damage in rats. AB - Ischemia-reperfusion injury resulting from arterial occlusion or hypotension in patients leads to tissue hypoxia with glucose deprivation, which causes endoplasmic reticulum (ER) stress and neuronal death. A proteomic approach was used to identify the differentially expressed proteins in the brain of rats following a global ischemic stroke. The mechanisms involved the action in apoptotic and ER stress pathways. Rats were treated with ischemia-reperfusion brain injuries by the bilateral occlusion of the common carotid artery. The cortical neuron proteins from the stroke animal model (SAM) and the control rats were separated using two-dimensional gel electrophoresis (2-DE) to purify and identify the protein profiles. Our results demonstrated that the SAM rats experienced brain cell death in the ischemic core. Fifteen proteins were expressed differentially between the SAM rats and control rats, which were assayed and validated in vivo and in vitro. Interestingly, the set of differentially expressed, down-regulated proteins included catechol O methyltransferase (COMT) and cathepsin D (CATD), which are implicated in oxidative stress, inflammatory response and apoptosis. After an ischemic stroke, one protein spot, namely the calretinin (CALB2) protein, showed increased expression. It mediated the effects of SAM administration on the apoptotic and ER stress pathways. Our results demonstrate that the ischemic injury of neuronal cells increased cell cytoxicity and apoptosis, which were accompanied by sustained activation of the IRE1-alpha/TRAF2, JNK1/2, and p38 MAPK pathways. Proteomic analysis suggested that the differential expression of CALB2 during a global ischemic stroke could be involved in the mechanisms of ER stress-induced neuronal cell apoptosis, which occurred via IRE1-alpha/TRAF2 complex formation, with activation of JNK1/2 and p38 MAPK. Based on these results, we also provide the molecular evidence supporting the ischemia-reperfusion-related neuronal injury. PMID- 26016500 TI - Chromate Reductase YieF from Escherichia coli Enhances Hexavalent Chromium Resistance of Human HepG2 Cells. AB - Hexavalent chromium (Cr(VI)) is a serious environmental pollutant and human toxicant. Mammalian cells are very sensitive to chromate as they lack efficient chromate detoxifying strategy, e.g., chromate-reducing genes that are widely present in prokaryotes. To test whether introduction of prokaryotic chromate reducing gene into mammalian cells could render higher chromate resistance, an Escherichia coli chromate-reducing gene yieF was transfected into human HepG2 cells. The expression of yieF was measured in stably transfected cells HepG2-YieF by quantitative RT-PCR and found up-regulated by 3.89-fold upon Cr(VI) induction. In chromate-reducing ability test, HepG2-YieF cells that harbored the reductase showed significantly higher reducing ability of Cr(VI) than HepG2 control cells. This result was further supported by the evidence of increased Cr(VI)-removing ability of crude cell extract of HepG2-YieF. Moreover, HepG2-YieF demonstrated 10% higher viability and decreased expression of GSH synthesizing enzymes under Cr(VI) stress. Subcellular localization of YieF was determined by tracing GFP YieF fusion protein that was detected in both nucleus and cytoplasm by laser confocal microscopy. Altogether, this study successfully demonstrated that the expression of a prokaryotic Cr(VI)-reducing gene yieF endowed mammalian cell HepG2 with enhanced chromate resistance, which brought new insight of Cr(VI) detoxification in mammalian cells. PMID- 26016503 TI - Regioselective alcoholysis of silychristin acetates catalyzed by lipases. AB - A panel of lipases was screened for the selective acetylation and alcoholysis of silychristin and silychristin peracetate, respectively. Acetylation at primary alcoholic group (C-22) of silychristin was accomplished by lipase PS (Pseudomonas cepacia) immobilized on diatomite using vinyl acetate as an acetyl donor, whereas selective deacetylation of 22-O-acetyl silychristin was accomplished by Novozym 435 in methyl tert-butyl ether/ n-butanol. Both of these reactions occurred without diastereomeric discrimination of silychristin A and B. Both of these enzymes were found to be capable to regioselective deacetylation of hexaacetyl silychristin to afford penta-, tetra- and tri-acetyl derivatives, which could be obtained as pure synthons for further selective modifications of the parent molecule. PMID- 26016486 TI - Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. AB - Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to beta-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions. PMID- 26016502 TI - Exposure of tumor-associated macrophages to apoptotic MCF-7 cells promotes breast cancer growth and metastasis. AB - Tumor-associated macrophages (TAMs) have been found to be associated with the progression and metastasis of breast cancer. To clarify the mechanisms underlying the crosstalk between TAMs and cancer stem cells (CSCs) in breast cancer recurrence and metastasis, we used a co-culture model of macrophages and apoptotic human breast cancer cell line MCF-7 cells to investigate the effects of TAMs on MCF-7 in vitro and in vivo. Macrophages co-cultured with apoptotic MCF-7 had increased tumor growth and metastatic ability in a nude mouse transplantation assay. The macrophages exposed to apoptotic cells also induce an increase in the proportion of CD44+/CD24- cancer stem-like cells, as well as their proliferative ability accompanied with an increase in mucin1 (MUC1) expression. During this process, macrophages secreted increased amounts of interleukin 6 (IL-6) leading to increased phosphorylation of signal transducers and activators of transcription 3 (STAT3), which likely explains the increased transcription of STAT3 target genes such as TGF-beta1 and HIF-1alpha. Our results indicate that when cancer cells endure chemotherapy induced apoptosis, macrophages in their microenvironment can then activate cancer stem cells to promote cancer growth and metastasis by secreting IL-6, which activates STAT3 phosphorylation to regulate the transcription of its downstream target genes. PMID- 26016504 TI - A Comprehensive Analysis of Codon Usage Patterns in Blunt Snout Bream (Megalobrama amblycephala) Based on RNA-Seq Data. AB - Blunt snout bream (Megalobrama amblycephala) is an important fish species for its delicacy and high economic value in China. Codon usage analysis could be helpful to understand its codon biology, mRNA translation and vertebrate evolution. Based on RNA-Seq data for M. amblycephala, high-frequency codons (CUG, AGA, GUG, CAG and GAG), as well as low-frequency ones (NUA and NCG codons) were identified. A total of 724 high-frequency codon pairs were observed. Meanwhile, 14 preferred and 199 avoided neighboring codon pairs were also identified, but bias was almost not shown with one or more intervening codons inserted between the same pairs. Codon usage bias in the regions close to start and stop codons indicated apparent heterogeneity, which even occurs in the flanking nucleotide sequence. Codon usage bias (RSCU and SCUO) was related to GC3 (GC content of 3rd nucleotide in codon) bias. Six GO (Gene ontology) categories and the number of methylation targets were influenced by GC3. Codon usage patterns comparison among 23 vertebrates showed species specificities by using GC contents, codon usage and codon context analysis. This work provided new insights into fish biology and new information for breeding projects. PMID- 26016507 TI - Electric Field-Assisted Matrix Coating Method Enhances the Detection of Small Molecule Metabolites for Mass Spectrometry Imaging. AB - Small molecule metabolites (SMMs, typically <500 Da) are important cellular constituents closely associated with tumor development and progression. However, in situ label-free detection of tissue SMMs has been limited due to interference from matrix and/or low sensitivity. Herein, we develop an electric field-assisted scanning-spraying (EFASS) matrix coating system to deposit matrix on tissue with crystal sizes of <10 MUm, followed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in negative ion mode. A comparison with other matrix deposition methods (i.e., airbrush and sublimation) using common matrixes (i.e., N-(1-naphthyl) ethylenediamine dihydrochloride (NEDC), 9 aminoacridine (9-AA), 2,5-dihydroxybenoic acid (DHB)) indicated that the EFASS system could effectively enhance detection sensitivity and the number of tissue SMMs detected. MSI of five gastric cancer tissues coated with NEDC by the EFASS system demonstrated that significantly increased levels of fatty acids (i.e., palmitic acid and oleic acid) and nucleosides monophosphate (i.e., uridine monophosphate, adenosine monophosphate, and guanosine monophosphate) and significantly decreased levels of nucleosides (i.e., inosine, guanosine, and uridine) and N-acetylneuraminic acid were observed in cancerous areas. PMID- 26016505 TI - The CYP51F1 Gene of Leptographium qinlingensis: Sequence Characteristic, Phylogeny and Transcript Levels. AB - Leptographium qinlingensis is a fungal associate of the Chinese white pine beetle (Dendroctonus armandi) and a pathogen of the Chinese white pine (Pinus armandi) that must overcome the terpenoid oleoresin defenses of host trees. L. qinlingensis responds to monoterpene flow with abundant mechanisms that include export and the use of these compounds as a carbon source. As one of the fungal cytochrome P450 proteins (CYPs), which play important roles in general metabolism, CYP51 (lanosterol 14-alpha demethylase) can catalyze the biosynthesis of ergosterol and is a target for antifungal drug. We have identified an L. qinlingensis CYP51F1 gene, and the phylogenetic analysis shows the highest homology with the 14-alpha-demethylase sequence from Grosmannia clavigera (a fungal associate of Dendroctonus ponderosae). The transcription level of CYP51F1 following treatment with terpenes and pine phloem extracts was upregulated, while using monoterpenes as the only carbon source led to the downregulation of CYP5F1 expression. The homology modeling structure of CYP51F1 is similar to the structure of the lanosterol 14-alpha demethylase protein of Saccharomyces cerevisiae YJM789, which has an N-terminal membrane helix 1 (MH1) and transmembrane helix 1 (TMH1). The minimal inhibitory concentrations (MIC) of terpenoid and azole fungicides (itraconazole (ITC)) and the docking of terpenoid molecules, lanosterol and ITC in the protein structure suggested that CYP51F1 may be inhibited by terpenoid molecules by competitive binding with azole fungicides. PMID- 26016508 TI - A new apotirucallane-type triterpenoid from Atalantia buxifolia. AB - A new triterpenoid (1) with apotirucallane skeleton was isolated from the ethanol extract of the roots of Atalantia buxifolia (Poir.) Oliv. The complete structural assignment of the new compound was elucidated by a combination of 1D, 2D NMR (HMQC, HMBC, COSY, and NOESY), and HR-ESI-MS analysis. Moreover, this new compound was evaluated in vitro for its cytotoxic, antimicrobial and enzymes inhibitory activities. PMID- 26016509 TI - Metals in Human Gall, Bladder, and Kidney Stones Based on an Electron Microprobe Investigation. AB - Several particles of copper accompanied by a few particles of nickel, lead, and a compound composed of selenium containing minor Ni, Si, Cu, and Co were found in human gall, kidney, and bladder stones. The investigated particles occur as tiny grains, <10 um in size, that are irregularly dispersed in the stones. Therefore, they were studied by scanning electron microscopy and qualitatively analyzed by energy dispersive system. One grain of copper contained a small amount of Ni and Zn, and some grains of nickel proved to contain Cr as trace element. Most of the discovered metals formed a single-phase grain. However, a few grains found in two gallstones were associated with inclusions of calcium and apatite. Based on the results presented in this contribution, we argue that most of the studied metals can be classified as endogenous particles, i.e., directly precipitated from the same fluids that formed their host human stones. This observation suggests that the precipitation and accumulation of metals in some human stones can be considered an efficient way to eliminate them from the human body. PMID- 26016510 TI - Spontaneous Blinking Kinetics on Paralytic Lagophthalmos After Lid Load with Gold Weight or Autogenous Temporalis Fascia Sling. AB - PURPOSE: To assess the upper eyelid kinematics during spontaneous blinking in unilateral paralytic lagophthalmos before and after upper eyelid load with gold weight (GW) or autogenous temporalis fascia (TF) sling. DESIGN: Comparative case series. SUBJECTS: Patients with long-standing unresolved unilateral facial palsy who underwent surgical treatment with GW (n = 8) or upper lid cerclage with TF (n = 10). The contralateral eyelid served as the control for each patient (control group). METHODS: Preoperative and postoperative measurements of spontaneous blink kinematics with magnetic search coil and clinical assessment of lid margin position, lagophthalmos and ocular surface exposure, and determine amplitude, maximum velocity and main sequence of spontaneous blinks; relative amplitude of blinks to the pupil center; ocular surface exposure scores; magnitude of lagophthalmos and mid-pupil lid distances. RESULTS: The mean (+/-SE) down-phase amplitude ratio between paralyzed and contralateral eyelids (blink gain) was 10.0% preoperatively for both groups and significantly increased to 29 +/- 6% for the GW group (p < 0.05) and 23 +/- 4% for the TF group (p < 0.05). At 6 months the gain was significant for the GW group only (32 +/- 7%, p < 0.05). There was no effect on the maximum velocity of the blinks or the main sequence of paretic and contralateral blinks with either surgery. Both procedures lowered the lid margin increasing the number of blinks that reached the pupil center. At 6 months this effect was prominent only for the GW group. Exposure keratopathy scores and lagophthalmos decreased postoperatively especially in the GW group. CONCLUSIONS: The beneficial effect of lid load surgeries result from a combination of a small increase on the spontaneous blink amplitude and a static effect due to the reduction of the distance between the lid margin and pupil center. PMID- 26016511 TI - Eicosapentaenoic Acid Prevents Saturated Fatty Acid-Induced Vascular Endothelial Dysfunction: Involvement of Long-Chain Acyl-CoA Synthetase. AB - AIM: Vascular endothelial dysfunction is considered an early predictor of atherosclerosis. It has been proven that elevated blood levels of free fatty acids pose a substantial risk for the development of cardiovascular disease. In this study, we examined the effects of palmitic acid (PA), a saturated fatty acid, on endothelial function by using the expression of adhesion molecule, cytokines, and inflammatory protein as indicators, as well as investigated the effects of eicosapentaenoic acid, an n-3 polyunsaturated fatty acid. METHODS: Human umbilical vein endothelial cells (HUVEC) were exposed to PA and EPA. RESULTS: When HUVEC were exposed to PA, there was an increase in the expression of adhesion molecule, cytokines, and inflammatory protein (ICAM-1, MCP-1, interleukin-6, PTX3). PA augmented the expression of long-chain acyl-CoA synthetase (ACSL) and the cyclin-dependent kinase inhibitor p21, and enhanced the phosphorylation of p65, a component of NF-kappaB. ACSL inhibition and siRNA mediated ACSL3 knockdown suppressed the PA-induced increase in the expression of adhesion molecule, cytokines, and inflammatory protein, and ACSL inhibition suppressed the enhancement of p65 phosphorylation. In addition, p21 knockdown suppressed the PA-induced increase in the expression of MCP-1 and ICAM-1. EPA suppressed the PA-induced increase in the expression of ACSL and p21, the enhancement of p65 phosphorylation, as well as the associated increase in the expression of ICAM-1, MCP-1, interleukin-6, and PTX3. CONCLUSIONS: These results suggest that the ACSL, p21, and NF-kappaB-dependent pathway may possibly be involved in PA-induced vascular endothelial dysfunction, and that EPA ameliorates this at least in part through the regulation of ACSL3 expression. PMID- 26016501 TI - What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment. AB - Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI with neuroimaging technologies, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and high definition fiber tracking (HDFT) show increasing sensitivity and specificity. Classical electrophysiological monitoring, together with newly established brain-on-chip, cerebral microdialysis techniques, both benefit TBI. First generation molecular biomarkers, based on genomic and proteomic changes following TBI, have proven effective and economical. It is conceivable that TBI-specific biomarkers will be developed with the combination of systems biology and bioinformation strategies. Advances in treatment of TBI include stem cell-based and nanotechnology-based therapy, physical and pharmaceutical interventions and also new use in TBI for approved drugs which all present favorable promise in preventing and reversing TBI. PMID- 26016512 TI - Association of Treatment for Hyperlipidemia with Decreased Total Mortality in Japanese Individuals: the Yamagata (Takahata) Study. AB - AIM: To evaluate the effects of treatment for hyperlipidemia on total mortality, we examined the association with adjustments for multiple factors, including those related to general health, such as blood hemoglobin and serum levels of albumin, adiponectin, brain natriuretic peptide, and lipids, using a prospective cohort study of a general Japanese population. METHODS: The population-based, longitudinal Takahata study enrolled 3,291 Japanese individuals (1515 male, 1776 female; age: 62.5 +/- 10.3 years) between 2004 and 2006. The incidence and causes of death were annually monitored until January 10, 2012 (median follow-up period: 2,655 days). RESULTS: During the follow-up period, there were 169 deaths. The Cox proportional hazard regression model analysis used to adjust for factors related to general health condition, cardiovascular disease risks, and serum lipid levels showed a significant association between treatment for hyperlipidemia and decreased total mortality compared with no treatment for hyperlipidemia [hazard ratio (HR): 0.24; 95% confidence interval (CI): 0.08-0.69) and subjects without hyperlipidemia (HR: 0.34;95%CI: 0.12-0.96). The Cox proportional hazard regression model analysis with adjustments for factors related to general health conditions showed a significantly lower total mortality in subjects without hyperlipidemia than that in subjects with untreated hyperlipidemia (HR: 0.70; 95%CI: 0.50-0.99). CONCLUSIONS: Not only antihyperlipidemic drugs used but also selection bias and non-evaluated factors, such as socio-economic status, educational level, health literacy, and daily nutrition, affected the results. Subjects taking treatment for hyperlipidemia were found to have reduced total mortality, which was independent of serum lipid levels. PMID- 26016513 TI - Tissue Factor and Atherothrombosis. AB - Atherosclerosis is a progressive disease characterized by the accumulation of lipids in medium to large sized arteries. Atherothrombosis is a term used to describe formation of a thrombus after rupture of an atherosclerotic plaque. Thrombosis can lead to myocardial infarction and stroke. Risk factors for atherosclerosis include hyperlipidemia, diabetes, smoking and hypertension all of which increase tissue factor (TF) expression. High levels of TF are present in atherosclerotic plaques due to expression by macrophages and vascular smooth muscle cells and the presence of cell-derived TF-positive microvesicles (MVs). In addition, hyperlipidemia leads to the formation of oxidized LDL, which induces TF expression in circulating monocytes and the release of TF-positive MVs. The major source of TF that drives thrombosis after plaque rupture is TF within the plaque. However, TF in the blood on monocytes and MVs may also contribute the thrombosis. Inhibition of the TF/factor VIIa complex is unlikely to be an effective strategy to reduce atherothrombosis due the essential role of the complex in hemostasis. However, selective blockade of pathologic TF without affecting protective TF may be effective in reducing atherothrombosis. For instance, statins have been shown to reduce TF expression in the plaque and in circulating monocytes, which would be expected to reduce thrombosis. Further studies are needed to determine safe strategies to reduce pathologic TF expression and atherothrombosis. PMID- 26016514 TI - Discordant human epidermal growth factor receptor 2 overexpression in primary and metastatic upper gastrointestinal adenocarcinoma signifies poor prognosis. AB - AIMS: Targeted therapy with trastuzumab has proved to be effective for patients with gastric cancer overexpressing the human epidermal growth factor receptor 2 (HER2). Further studies are needed to determine the best method for assessment of HER2 overexpression. Moreover, the prognostic value of HER2 overexpression, including the significance of tumour heterogeneity, remains unclear. METHODS AND RESULTS: HER2 overexpression and gene copy alterations were assessed by immunohistochemistry and silver in-situ hybridization, respectively, on tissue microarrays with primary tumours and a subset of paired lymph node metastases from 174 patients with oesophageal or gastric adenocarcinoma. Cox proportional hazards modelling was applied to assess the prognostic impact of HER2 overexpression, intratumoural heterogeneity and conversion from primary tumour to metastasis. The correlation between protein expression and gene amplification was in line with previous studies. Primary-metastatic conversion was observed in 12.9% of the cases. HER2 overexpression or intratumoural heterogeneity was not prognostic, but primary-metastatic conversion was an independent predictor of a shorter overall survival (hazard ratio = 4.93). CONCLUSIONS: As trastuzumab is emerging as an important targeted therapy for patients with upper gastointestinal cancer, these results underline the importance of further studies addressing the occurrence and clinical significance of discrepant HER2 expression in primary tumours and metastases. PMID- 26016515 TI - Coumarin-Based Turn-On Fluorescence Probe for Specific Detection of Glutathione over Cysteine and Homocysteine. AB - We have prepared a turn-on fluorescent probe for biothiols based on bromoketo coumarin (KC-Br). The emission intensity of the coumarin chromophore is modulated by both the heavy atom effect and internal charge transfer (ICT) process. The probe KC-Br is intrinsically nonfluorescent; however, after being reacted with thiols, the bromide moiety is substituted by the -SH group, which elicits a significant fluorescence increase. We surmised the free -NH2 group would further react with carbonyl in the Cys/Hcy-substituted intermediate product yielding to Schiff base compound KC-Cys/KC-Hcy, but not in compound KC-GSH. The ICT effect has a stronger influence in compound KC-GSH than that in compound KC-Cys/KC-Hcy, resulting in compound KC-GSH having a stronger fluorescence. Thus, the probe has a good selectivity for GSH over other various biologically relevant species and even two other similar biothiols (Cys/Hcy) and could image glutathione (GSH) in living cells. We expect the design concept presented in this work would be widely used for the design of fluorescent probes for distinguishing among biothiols. PMID- 26016516 TI - Accessibility, affordability and use of health services in an urban area in South Africa. AB - BACKGROUND: Inequalities in healthcare between population groups of South Africa existed during the apartheid era and continue to exist both between and within many population groups. Accessibility and affordability of healthcare is a human right. OBJECTIVES: The aim of the study was to explore and describe accessibility, affordability and the use of health services by the mixed race (coloured) population in the Western Cape, South Africa. METHOD: A cross sectional descriptive, non-experimental study with a quantitative approach was applied. A purposive convenient sample of 353 participants (0.6%) was drawn from a population of 63 004 economically-active people who lived in the residential areas as defined for the purpose of the study. All social classes were represented. The hypothesis set was that there is a positive relationship between accessibility, affordability and the use of health services. A pilot study was conducted which also supported the reliability and validity of the study. Ethics approval was obtained from the University of Stellenbosch and informed consent from respondents. A questionnaire was used to collect the data. RESULTS: The hypothesis was accepted. The statistical association between affordability (p = < 0.01), accessibility (p = < 0.01) and the use of health services was found to be significant using the Chi-square (chi2) test. CONCLUSION: The study has shown how affordability and accessibility may influence the use of healthcare services. Accessibility is not only the distance an individual must travel to reach the health service point but more so the utilisation of these services. Continuous Quality Management should be a priority in healthcare services, which should be user-friendly. PMID- 26016517 TI - Energy Transfer Between Squaraine Polymer Sections: From Helix to Zigzag and All the Way Back. AB - We provide a joint experimental and theoretical study of squaraine polymers in solution. The absorption spectra show evidence that two different conformations are present in the polymer: a helix and a zigzag structure. This unique situation allows investigating ultrafast energy-transfer processes between different structural segments within a single polymer chain in solution. The understanding of the underlying dynamics is of fundamental importance for the development of novel materials for light-harvesting and optoelectronic applications. Here, we combine femtosecond transient absorption spectroscopy with time-resolved 2D electronic spectroscopy in order to demonstrate that ultrafast energy transfer within the squaraine polymer chains proceeds from initially excited helix segments to zigzag segments or vice versa, depending on the solvent as well as on the excitation wavenumber. These observations contrast other conjugated polymers such as MEH-PPV where much slower intrachain energy transfer was reported. The reason for the very fast energy transfer in squaraine polymers is most likely a close matching of the density of states between donor and acceptor polymer segments because of the very small reorganization energy in these cyanine-like chromophores. PMID- 26016519 TI - Teaching and practising rectal examination in Pakistan. AB - BACKGROUND: Digital rectal examination (DRE) is an integral part of physical examination. The teaching and practising of DRE should start early in medical school for mastering the skills to perform DRE by the time of graduation. In recent years it has been observed that medical students are reluctant to learn and practise DRE because of a perception of the reduced importance of DRE as compared with other modalities of investigation. We evaluated the knowledge and attitude of medical students and interns towards the teaching and practising of DRE. METHODS: We conducted a cross-sectional survey of four medical institutions in Karachi, Pakistan. RESULTS: Of the 398 participants included in the study, almost half were medical students. Almost all (98%) of the participants appreciated the importance of DRE. Only half of the participants reported having been formally taught about DRE before reaching the final year of medical school. Only 16 per cent reported the use of manikins as an aide to demonstrate and practise DRE. The median number of times respondents had performed DRE was one. Patients' refusal to grant consent was the most common reason given for not performing DRE. Students are reluctant to learn and practise DRE because of a perception of its reduced importance CONCLUSION: Teaching sessions on DRE using manikins are suggested to begin early in medical school. It is also suggested that a minimum number of DREs should be performed under supervision before the completion of the internship. PMID- 26016518 TI - Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe-S Assembly Complex. AB - Iron-sulfur (Fe-S) clusters function as protein cofactors for a wide variety of critical cellular reactions. In human mitochondria, a core Fe-S assembly complex [called SDUF and composed of NFS1, ISD11, ISCU2, and frataxin (FXN) proteins] synthesizes Fe-S clusters from iron, cysteine sulfur, and reducing equivalents and then transfers these intact clusters to target proteins. In vitro assays have relied on reducing the complexity of this complicated Fe-S assembly process by using surrogate electron donor molecules and monitoring simplified reactions. Recent studies have concluded that FXN promotes the synthesis of [4Fe-4S] clusters on the mammalian Fe-S assembly complex. Here the kinetics of Fe-S synthesis reactions were determined using different electron donation systems and by monitoring the products with circular dichroism and absorbance spectroscopies. We discovered that common surrogate electron donor molecules intercepted Fe-S cluster intermediates and formed high-molecular weight species (HMWS). The HMWS are associated with iron, sulfide, and thiol-containing proteins and have properties of a heterogeneous solubilized mineral with spectroscopic properties remarkably reminiscent of those of [4Fe-4S] clusters. In contrast, reactions using physiological reagents revealed that FXN accelerates the formation of [2Fe 2S] clusters rather than [4Fe-4S] clusters as previously reported. In the preceding paper [Fox, N. G., et al. (2015) Biochemistry 54, DOI: 10.1021/bi5014485], [2Fe-2S] intermediates on the SDUF complex were shown to readily transfer to uncomplexed ISCU2 or apo acceptor proteins, depending on the reaction conditions. Our results indicate that FXN accelerates a rate-limiting sulfur transfer step in the synthesis of [2Fe-2S] clusters on the human Fe-S assembly complex. PMID- 26016520 TI - Child's verbal ability and gender are associated with age at diagnosis in a sample of young children with ASD in Europe. AB - BACKGROUND: Autism spectrum disorder can in some cases be reliably diagnosed by age 2 years, but in community settings, the mean age at diagnosis is often considerably higher. Later diagnosis has been found to be associated with lower symptom severity, lower parental socioeconomic status and fewer parental concerns. Gender differences in age at diagnosis have been examined, with mixed evidence. METHODS: We examined the association of child's verbal ability and gender, and parental education, with age at diagnosis in a large sample of young children with autism spectrum disorder in 18 European countries (n = 1410). RESULTS: There was considerable variation in age at diagnosis across countries. Children with better communication skills were diagnosed significantly later than non-verbal and minimally verbal children. There was also a significant interaction of gender with verbal ability on age at diagnosis, in that female children with complex phrase speech were diagnosed later than male children with the same level of verbal ability. CONCLUSIONS: Our findings highlight the need to implement public awareness initiatives and training for professionals to promote early detection and, consequently, early intervention for autism spectrum disorder in Europe. PMID- 26016521 TI - A genomewide association mapping study using ultrasound-scanned information identifies potential genomic regions and candidate genes affecting carcass traits in Nellore cattle. AB - The aim of this study was to identify candidate genes and genomic regions associated with ultrasound-derived measurements of the rib-eye area (REA), backfat thickness (BFT) and rumpfat thickness (RFT) in Nellore cattle. Data from 640 Nellore steers and young bulls with genotypes for 290 863 single nucleotide polymorphisms (SNPs) were used for genomewide association mapping. Significant SNP associations were explored to find possible candidate genes related to physiological processes. Several of the significant markers detected were mapped onto functional candidate genes including ARFGAP3, CLSTN2 and DPYD for REA; OSBPL3 and SUDS3 for BFT; and RARRES1 and VEPH1 for RFT. The physiological pathway related to lipid metabolism (CLSTN2, OSBPL3, RARRES1 and VEPH1) was identified. The significant markers within previously reported QTLs reinforce the importance of the genomic regions, and the other loci offer candidate genes that have not been related to carcass traits in previous investigations. PMID- 26016523 TI - [A Comparison of Dorsal Decompression and Dorsal Decompression Combined with the Dynamic Stabilisation Device LimiFlexTM]. AB - BACKGROUND: Lumbar spinal canal stenosis is commonly treated by dorsal decompression. However, resection of posterior elements increases the biomechanical instability and may lead to further complications. In order to prevent this, fusion of the involved segments is often performed. But further complications may be associated with this, for example, highly reduced flexibility. In order to overcome fusion-related problems, dynamic stabilisation devices, like the new LimiFlexTM Paraspinous Tension Band (PSB), have been developed. This prospective study compares dorsal decompression without stabilisation and dorsal decompression with stabilisation using the PSB in patients with lumbar canal stenosis. METHODS: Sixty-three patients with stenosis involving one or two lumbar vertebral levels were treated with dorsal decompression. Forty received the PSB following decompression surgery. Back, hip and leg pain as well as patient's degree of disability were assessed preoperatively and at 3, 6 and 12 months postoperatively for all patients. Evaluations were conducted using the visual analogue scale (VAS) and the Oswestry disability index (ODI). Adverse events during the study period were evaluated. RESULTS: Patients who received the PSB experienced a better pain relief and improvement in disability compared to patients who received treatment through decompression only. A significant difference of VAS and ODI development was found between both groups when treating two vertebral levels. Furthermore, the total number of adverse events was lower in the PSB group compared to the decompression group. CONCLUSION: Dynamic stabilisation using the PSB delivers better results in terms of VAS and ODI values when compared to only dorsal decompression. In addition, it is also associated with a lower number of complications. The PSB is most favourable when 2 levels are treated. PMID- 26016524 TI - [The Value of Ultrasonography Compared with Magnetic Resonance Imaging in the Diagnosis of Deltoid Ligament Injuries--Is there a Difference?]. AB - BACKGROUND: Ruptures of the deltoid ligament can lead to ankle instability which may cause arthrosis. Aim of this comparative clinical trial was to assess the value of ultrasonography (US) compared to magnetic resonance imaging (MRI) in the diagnosis of medial collateral (deltoid) ligament ruptures associated with Weber type B and C fractures. PATIENTS AND METHODS: All four components of the deltoid ligament of the ankles of 28 patients with Weber type B and 14 patients with Weber type C fractures were preoperatively evaluated by US and MRI for partial or complete ruptures. RESULTS: Deltoid ligament injuries were detected in 10 of 28 patients (35.7 %) with Weber type B and in 12 of 14 patients (85.7 %) with Weber type C fractures with MRI. US reliably identified all 17 patients with complete rupture of the deltoid ligament (sensitivity 100 %, specifity 92 %). However only half of the 6 patients who sustained a partial rupture were correctly identified (sensitivity 50 %, specifity 97.2 %). 26 of 30 ruptures (sensitivity 86.6 %, specifity 96.3 %) and 13 of 27 partial ruptures (sensitivity 48.1 %, specifity 97.8 %) of the four components of the deltoid ligament were correctly identified with US. CONCLUSION: US is a reliable procedure for detection of clinically relevant ruptures and uninjured components of the deltoid ligament after distal fibula fractures. However US is not suitable to reliably identify partial ruptures. The treatment decision for operation or conservative treatment of ankle fractures is based on the stability of the ankle. Patients with lateral malleolar fractures and intact medial malleolus but rupture of the deltoid ligament often show a spontaneous reduction of the talus in X-ray images and may therefore be falsely classified as stable (unrecognised medial instability). However, unstable malleolar fractures should be treated with open reduction and internal fixation in order to improve outcome. Hence US is able to influence therapeutic decisions by detecting medial ankle instability, which cannot be detected clinically or radiologically. PMID- 26016526 TI - Malaria genotyping for epidemiologic surveillance. PMID- 26016525 TI - Structure of a bacterial toxin-activating acyltransferase. AB - Secreted pore-forming toxins of pathogenic Gram-negative bacteria such as Escherichia coli hemolysin (HlyA) insert into host-cell membranes to subvert signal transduction and induce apoptosis and cell lysis. Unusually, these toxins are synthesized in an inactive form that requires posttranslational activation in the bacterial cytosol. We have previously shown that the activation mechanism is an acylation event directed by a specialized acyl-transferase that uses acyl carrier protein (ACP) to covalently link fatty acids, via an amide bond, to specific internal lysine residues of the protoxin. We now reveal the 2.15-A resolution X-ray structure of the 172-aa ApxC, a toxin-activating acyl transferase (TAAT) from pathogenic Actinobacillus pleuropneumoniae. This determination shows that bacterial TAATs are a structurally homologous family that, despite indiscernible sequence similarity, form a distinct branch of the Gcn5-like N-acetyl transferase (GNAT) superfamily of enzymes that typically use acyl-CoA to modify diverse bacterial, archaeal, and eukaryotic substrates. A combination of structural analysis, small angle X-ray scattering, mutagenesis, and cross-linking defined the solution state of TAATs, with intermonomer interactions mediated by an N-terminal alpha-helix. Superposition of ApxC with substrate-bound GNATs, and assay of toxin activation and binding of acyl-ACP and protoxin peptide substrates by mutated ApxC variants, indicates the enzyme active site to be a deep surface groove. PMID- 26016527 TI - Water-soluble chlorophyll protein is involved in herbivore resistance activation during greening of Arabidopsis thaliana. AB - Water-soluble chlorophyll proteins (WSCPs) constitute a small family of unusual chlorophyll (Chl)-binding proteins that possess a Kunitz-type protease inhibitor domain. In Arabidopsis thaliana, a WSCP has been identified, named AtWSCP, that forms complexes with Chl and the Chl precursor chlorophyllide (Chlide) in vitro. AtWSCP exhibits a quite unexpected expression pattern for a Chl binding protein and accumulated to high levels in the apical hook of etiolated plants. AtWSCP expression was negatively light-regulated. Transgenic expression of AtWSCP fused to green fluorescent protein (GFP) revealed that AtWSCP is localized to cell walls/apoplastic spaces. Biochemical assays identified AtWSCP as interacting with RD21 (responsive to desiccation 21), a granulin domain-containing cysteine protease implicated in stress responses and defense. Reconstitution experiments showed tight interactions between RD21 and WSCP that were relieved upon Chlide binding. Laboratory feeding experiments with two herbivorous isopod crustaceans, Porcellio scaber (woodlouse) and Armadillidium vulgare (pillbug), identified the apical hook as Achilles' heel of etiolated plants and that this was protected by RD21 during greening. Because Chlide is formed in the apical hook during seedling emergence from the soil, our data suggest an unprecedented mechanism of herbivore resistance activation that is triggered by light and involves AtWSCP. PMID- 26016528 TI - Evaluation of the Intrinsic Zn(II) Affinity of a Cys3His1 Site in the Absence of Protein Folding Effects. AB - Zinc finger transcription factors are the largest class of metalloproteins in the human genome. Binding of Zn(II) to their canonical Cys2His2, Cys3His1, or Cys4 sites results in metal-induced protein folding events required to achieve their biologically active structures. However, the coupled nature of metal binding and protein folding obscures the individual free energy contributions of each process toward overall zinc finger stabilization. Herein, we separate the energetic contributions of metal-ligand interactions from those of protein-protein interactions using a natural protein scaffold that retains essentially identical structures with and without Zn(II) bound, the 59 amino acid zinc binding domain of human transcription factor IIB (ZBD-TFIIB). The formation constant of Zn(II) ZBD-TFIIB, which contains a single Cys3His1 site, was determined to be 1.5 * 10(15) M(-1) via fluorimetry and isothermal titration calorimetry. Isothermal titration calorimetry showed that Zn(II) binding is entropically favored at pH 5.5, 7.0, and 8.0 and enthalpically favored at pH 8.0 but slightly enthalpically disfavored at pH 5.5 and 7.0. The conditional dissociation constants of Zn(II) ZBD-TFIIB and natural Cys3His1 zinc finger proteins were compared to determine the free energy cost of protein folding in the latter. Our analysis reveals that the energetic cost to fold zinc finger proteins is minimal relative to the contribution of Zn(II) binding and suggests that the true role of Zn(II) binding may be to modulate protein dynamics and/or kinetically template the protein folding process. PMID- 26016529 TI - Assembly, trafficking and function of alpha1beta2gamma2 GABAA receptors are regulated by N-terminal regions, in a subunit-specific manner. AB - GABAA receptors are pentameric ligand-gated ion channels that mediate inhibitory fast synaptic transmission in the central nervous system. Consistent with recent pentameric ligand-gated ion channels structures, sequence analysis predicts an alpha-helix near the N-terminus of each GABAA receptor subunit. Preceding each alpha-helix are 8-36 additional residues, which we term the N-terminal extension. In homomeric GABAC receptors and nicotinic acetylcholine receptors, the N terminal alpha-helix is functionally essential. Here, we determined the role of the N-terminal extension and putative alpha-helix in heteromeric alpha1beta2gamma2 GABAA receptors. This role was most prominent in the alpha1 subunit, with deletion of the N-terminal extension or further deletion of the putative alpha-helix both dramatically reduced the number of functional receptors at the cell surface. Conversely, deletion of the beta2 or gamma2 N-terminal extension had little effect on the number of functional cell surface receptors. Additional deletion of the putative alpha-helix in the beta2 or gamma2 subunits did, however, decrease both functional cell surface receptors and incorporation of the gamma2 subunit into mature receptors. In the beta2 subunit only, alpha helix deletions affected GABA sensitivity and desensitization. Our findings demonstrate that N-terminal extensions and alpha-helices make key subunit specific contributions to assembly, consistent with both regions being involved in inter-subunit interactions. N-terminal alpha-helices and preceding sequences of eukaryotic pentameric ligand-gated ion channels are absent in prokaryotic homologues, suggesting they may not be functionally essential. Here, we show that in heteropentameric alpha1beta2gamma2 GABAA receptors, the role of these segments is highly subunit dependent. The extension preceding the alpha-helix in the alpha subunit is crucial for assembly and trafficking, but is of little importance in beta and gamma subunits. Indeed, robust receptor levels remain when the extension and alpha-helix are removed in beta or gamma subunits. PMID- 26016530 TI - Aging in Place vs. Relocation for Older Adults with Neurocognitive Disorder: Applications of Wiseman's Behavioral Model. AB - Some older adults are more vulnerable to housing concerns due to physical and cognitive challenges, including those with a neurocognitive disorder who need extensive support. Environmental gerontology frameworks, including Wiseman's 1980 Behavioral Model of Elderly Migration, have informed scholarship on aging in place and relocation. Understanding Wiseman's model, including considerations for working with families confronting a neurocognitive disorder, can help practitioners ensure that older clients live in settings that best meet their wants and needs. PMID- 26016531 TI - Composition-selective fabrication of ordered intermetallic Au-Cu nanowires and their application to nano-size electrochemical glucose detection. AB - Bimetallic nanostructures can provide distinct and improved physicochemical properties by the coupling effect of the two metal components, making them promising materials for a variety of applications. Herein, we report composition selective fabrication of ordered intermetallic Au-Cu nanowires (NWs) by two-step chemical vapor transport method and their application to nano-electrocatalytic glucose detection. Ordered intermetallic Au3Cu and AuCu3 NWs are topotaxially fabricated by supplying Cu-containing chemicals to pre-synthesized single crystalline Au NW arrays. The composition of fabricated Au-Cu NWs can be selected by changing the concentration of Cu-containing species. Interestingly, Au3Cu NW electrodes show unique electrocatalytic activity for glucose oxidation, allowing us to detect glucose without interference from ascorbic acid. Such interference free detection of glucose is attributed to the synergistic effect, induced by incorporation of Cu in Au. We anticipate that Au3Cu NWs could show possibility as efficient nano-size electrochemical glucose sensors and the present fabrication method can be employed to fabricate valuable ordered intermetallic nanostructures. PMID- 26016532 TI - Efficacy of a Danish version of the Cool Kids program: a randomized wait-list controlled trial. AB - OBJECTIVE: The purpose of the study was to evaluate the efficacy of a Danish version of the Cool Kids program, a generic manualized group cognitive behavioural therapy (CBT) program for anxiety disorders among children and adolescents. METHOD: Children and adolescents (age 7-16) with a primary anxiety disorder diagnosis (n = 109) were randomly allocated to group CBT or a wait-list (WL) control condition at a Danish university clinic. RESULTS: Results showed that the Danish version of the Cool Kids program was efficacious with 48.2% free of all anxiety diagnoses at post-treatment, compared with 5.7% in the WL condition, and large effect sizes on self-report measures of child anxiety symptoms rated by child, mother, and father (etap2 range = 0.18-0.24). Children and adolescents improved further from post-treatment to 3-month follow-up, and this improvement was maintained at 12-month follow-up. Participants with a primary diagnosis of social phobia (SoP) showed less improvement compared with other anxiety diagnoses. CONCLUSION: The study contributes to the evidence base for the Cool Kids program, previously only evaluated by its developers in Australia. Generic group CBT programs may not be the most appropriate treatment for children and adolescents with primary SoP. PMID- 26016533 TI - The magnitude and pattern of diabetic retinopathy in Yaounde, Cameroon - a cross sectional hospital-based study. PMID- 26016534 TI - A field study of exposure to whole-body vibration due to agricultural machines in a full-time rice farmer over one year. AB - OBJECTIVES: The aims of this study were to clarify in detail the levels of whole body vibration (WBV) exposure from a variety of agricultural machines in a rice farmer over one year, and to evaluate the daily level of exposure compared with European and Japanese threshold limits. METHODS: The subject was a full-time, male rice farmer. We measured vibration accelerations on the seat pan and at the seat base of four tractors with various implements attached, one rice-planting machine, two combine harvesters, produced by the same manufacturer, and one truck used for transportation of agricultural machines. The position and velocity of the machines were recorded in parallel with WBV measurements. In addition, during the year starting in April 2010, the subject completed a questionnaire regarding his work (date, place, content, hours worked, machines used). We calculated the daily exposure to WBV, A(8), on all the days on which the subject used the agricultural machines. RESULTS: The WBV magnitude in farm fields was relatively high during tasks with high velocity and heavy mechanical load on the machine, and had no dominant axis. The subject worked for 159 days using the agricultural machines during the year, and the proportion of days on which A(8) values exceeded the thresholds was 90% for the Japan occupational exposure limit and 24% for the EU exposure action value. CONCLUSIONS: Our findings emphasize the need for rice farmers to have health management strategies suited to the farming seasons and measures to reduce WBV exposure during each farm task. PMID- 26016535 TI - Factors affecting radiation exposure dose in nursing staff during (18)F fluorodeoxyglucose positron emission tomography/computed tomography. AB - OBJECTIVES: We evaluated factors associated with increased radiation exposure dose in nursing staff who assisted patients with (18)F-fluorodeoxyglucose ((18)F FDG) positron emission tomography (PET)/computed tomography (CT) examinations. METHODS: The Barthel Index and Mini-Mental State Examination (MMSE) score were obtained before PET/CT examinations in 193 patients (mean age +/- SD, 77.7 +/- 8.0 yr). Three nurses self-measured their radiation exposure dose while assisting patients during each PET examination. Disturbance factors during PET examinations (use of a stretcher or wheelchair, use of lines or tubes connected to the patient, use of diapers or urethral catheterization, patient age), (18)F-FDG injection dose, and previous PET/CT experience in the patients and outpatient or inpatient status were evaluated as factors possibly associated with increased radiation exposure. Principle component analysis, univariate analysis, and multivariate regression analysis were used for assessing associations between radiation exposure dose and factors. RESULTS: The mean radiation exposure dose of the nursing staff was 6.07 +/- 5.71 uSv per examination. Statistically significant factors associated with increased radiation exposure (<8 or >=8 uSv/case) in the univariate analysis were the Barthel Index (<75 or >=75), MMSE score (<22 or >=22) of the patients, numbers of lines or tubes to the patient, use of a stretcher or wheelchair, and (18)F-FDG injection dose. Multivariate logistic regression modeling showed that the Barthel Index (<75 or >=75) and MMSE score (<22 or >=22) of the patients were significant factors in the final model. CONCLUSIONS: Lower Barthel Indexes (lower ADL) and lower MMSE scores (lower cognitive function) were independent factors associated with increased radiation exposure dose in nursing staff assisting during (18)F-FDG PET/CT. PMID- 26016536 TI - Cutaneous plasmacytosis: a clinicopathologic study of 12 cases in Taiwan revealing heterogeneous underlying causes. AB - BACKGROUND: Cutaneous plasmacytosis is clinically characterized by multiple pigmented papules and plaques that occur mainly on the trunk and many plasma cells in the lesional skin. Most of the cases reported have occurred in Japan. Whether cutaneous plasmacytosis is a unique reactive disease or a neoplastic condition has not been established. METHODS: We collected 12 cases fulfilling the criteria for a diagnosis of cutaneous plasmacytosis at our institution from 2001 to 2013. We analyzed clinicopathologic features and performed immunohistochemical and immunoglobulin gene rearrangement studies. RESULTS: All 12 patients presented with characteristic cutaneous lesions mainly on the trunk and proximal extremities. Many plasma cells were observed in the lesional skin, and the basal layer was hyperpigmented. Four patients had numerous plasma cells in lymph nodes, and one patient also had increased plasma cells in bone marrow. One patient fulfilled the criteria for immunoglobulin G4 (IgG4)-related lymphadenopathy. Elevated serum IgG and IgG4 concentrations were found in seven patients. Monoclonal immunoglobulin gene rearrangements were detected in four patients. The median duration of follow-up was four years. One patient was lost from follow-up. Partial remission of the cutaneous lesions was observed in five patients, and progressive disease was noted in five patients. One patient died of respiratory failure. CONCLUSIONS: Our study suggests that the so-called "cutaneous plasmacytosis" has heterogeneous underlying causes with or without systemic involvement and may be associated with clonal immunoglobulin gene rearrangements and IgG4-related lymphadenopathy. No effective treatment is available for this condition. PMID- 26016537 TI - Quoting out of context a good argument does not make: Response to Harvey Chochinov. PMID- 26016538 TI - Recent advances in microfluidic actuation and micro-object manipulation via surface acoustic waves. AB - The realization of microscale total analysis systems and lab-on-a-chip technologies requires efficient actuation (mixing, pumping, atomizing, nebulizing, driving, etc.) of fluids on the microscopic scale and dexterous manipulation (separation, sorting, trapping, concentration, merging, patterning, aligning, focusing, etc.) of micro-objects (cells, droplets, particles, nanotubes, etc.) in open (sessile droplets) as well as confined spaces (microchannels/chambers). These capabilities have been recently achieved using powerful acoustofluidic techniques based on high-frequency (10-1000 MHz) surface acoustic waves (SAWs). SAW-based miniaturized microfluidic devices are best known for their non-invasive properties, low costs, and ability to manipulate micro objects in a label-free manner. The energy-efficient SAWs are also compatible with conventional microfabrication technologies. The present work critically analyses recent reports describing the use of SAWs in microfluidic actuation and micro-object manipulation. Acoustofluidic techniques may be categorized according to the use of travelling SAWs (TSAWs) or standing SAWs (SSAWs). TSAWs are used to actuate fluids and manipulate micro-objects via acoustic streaming flow (ASF) as well as acoustic radiation force (ARF). SSAWs are mainly used for micro-object manipulation and are rarely employed for microfluidic actuation. We have reviewed reports of new technological developments that have not been covered in other recent reviews. In the end, we describe the future prospects of SAW-based acoustofluidic technologies. PMID- 26016539 TI - Tensor numerical methods in quantum chemistry: from Hartree-Fock to excitation energies. AB - We resume the recent successes of the grid-based tensor numerical methods and discuss their prospects in real-space electronic structure calculations. These methods, based on the low-rank representation of the multidimensional functions and integral operators, first appeared as an accurate tensor calculus for the 3D Hartree potential using 1D complexity operations, and have evolved to entirely grid-based tensor-structured 3D Hartree-Fock eigenvalue solver. It benefits from tensor calculation of the core Hamiltonian and two-electron integrals (TEI) in O(n log n) complexity using the rank-structured approximation of basis functions, electron densities and convolution integral operators all represented on 3D n * n * n Cartesian grids. The algorithm for calculating TEI tensor in a form of the Cholesky decomposition is based on multiple factorizations using algebraic 1D "density fitting" scheme, which yield an almost irreducible number of product basis functions involved in the 3D convolution integrals, depending on a threshold epsilon > 0. The basis functions are not restricted to separable Gaussians, since the analytical integration is substituted by high-precision tensor-structured numerical quadratures. The tensor approaches to post-Hartree Fock calculations for the MP2 energy correction and for the Bethe-Salpeter excitation energies, based on using low-rank factorizations and the reduced basis method, were recently introduced. Another direction is towards the tensor-based Hartree-Fock numerical scheme for finite lattices, where one of the numerical challenges is the summation of electrostatic potentials of a large number of nuclei. The 3D grid-based tensor method for calculation of a potential sum on a L * L * L lattice manifests the linear in L computational work, O(L), instead of the usual O(L(3) log L) scaling by the Ewald-type approaches. PMID- 26016543 TI - Combine Use of Selected Schizosaccharomyces pombe and Lachancea thermotolerans Yeast Strains as an Alternative to the Traditional Malolactic Fermentation in Red Wine Production. AB - Most red wines commercialized in the market use the malolactic fermentation process in order to ensure stability from a microbiological point of view. In this second fermentation, malic acid is converted into L-lactic acid under controlled setups. However this process is not free from possible collateral effects that on some occasions produce off-flavors, wine quality loss and human health problems. In warm viticulture regions such as the south of Spain, the risk of suffering a deviation during the malolactic fermentation process increases due to the high must pH. This contributes to produce wines with high volatile acidity and biogenic amine values. This manuscript develops a new red wine making methodology that consists of combining the use of two non-Saccharomyces yeast strains as an alternative to the traditional malolactic fermentation. In this method, malic acid is totally consumed by Schizosaccharomyces pombe, thus achieving the microbiological stabilization objective, while Lachancea thermotolerans produces lactic acid in order not to reduce and even increase the acidity of wines produced from low acidity musts. This technique reduces the risks inherent to the malolactic fermentation process when performed in warm regions.The result is more fruity wines that contain less acetic acid and biogenic amines than the traditional controls that have undergone the classical malolactic fermentation. PMID- 26016544 TI - Pretreatment with Relaxin Does Not Restore NO-Mediated Modulation of Calcium Signal in Coronary Endothelial Cells Isolated from Spontaneously Hypertensive Rats. AB - We demonstrated that in coronary endothelial cells (RCEs) from normotensive Wistar Kyoto rats (WKY), the hormone relaxin (RLX) increases NO production and reduces calcium transients by a NO-related mechanism. Since an impairment of the NO pathway has been described in spontaneously hypertensive rats (SHR), the present study was aimed at exploring RLX effects on RCEs from SHR, hypothesizing that RLX could restore calcium responsiveness to NO. RCEs were isolated from WKY and SHR. Calcium transients were evaluated by image analysis after the administration of angiotensin II or alpha-thrombin. Angiotensin II (1 uM) caused a prompt rise of [Ca2+]i in WKY and SHR RCEs and a rapid decrease, being the decay time higher in SHR than in WKY. NOS inhibition increased calcium transient in WKY, but not in SHR RCEs. Whereas RLX pretreatment (24 h, 60 ng/mL) was ineffective in SHR, it strongly reduced calcium transient in WKY in a NO dependent way. A similar behavior was measured using 30 U/mL alpha-thrombin. The current study offers evidence that RLX cannot restore NO responsiveness in SHR, suggesting an accurate selection of patients eligible for RLX treatment of cardiovascular diseases. PMID- 26016545 TI - The effect of phenol composition on the sensory profile of smoke affected wines. AB - Vineyards exposed to wildfire generated smoke can produce wines with elevated levels of lignin derived phenols that have acrid, metallic and smoky aromas and flavour attributes. While a large number of phenols are present in smoke affected wines, the effect of smoke vegetation source on the sensory descriptors has not been reported. Here we report on a descriptive sensory analysis of wines made from grapes exposed to different vegetation sources of smoke to examine: (1) the effect vegetation source has on wine sensory attribute ratings and; (2) associations between volatile and glycoconjugated phenol composition and sensory attributes. Sensory attribute ratings were determined by a trained sensory panel and phenol concentrations determined by gas chromatography-mass spectroscopy. Analysis of variance, principal component analysis and partial least squares regressions were used to evaluate the interrelationships between the phenol composition and sensory attributes. The results showed that vegetation source of smoke significantly affected sensory attribute intensity, especially the taste descriptors. Differences in aroma and taste from smoke exposure were not limited to an elevation in a range of detractive descriptors but also a masking of positive fruit descriptors. Sensory differences due to vegetation type were driven by phenol composition and concentration. In particular, the glycoconjugates of 4-hydroxy-3-methoxybenzaldehyde (vanillin), 1-(4-hydroxy-3 methoxyphenyl)ethanone (acetovanillone), 4-hydroxy-3,5-dimethoxybenzaldehyde (syringaldehyde) and 1-(4-hydroxy-3,5-dimethoxyphenyl)ethanone (acetosyringone) concentrations were influential in separating the vegetation sources of smoke. It is concluded that the detractive aroma attributes of smoke affected wine, especially of smoke and ash, were associated with volatile phenols while the detractive flavour descriptors were correlated with glycoconjugated phenols. PMID- 26016546 TI - Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist. AB - In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4 (benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4 dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 +/- 3% uncorrected radiochemical yield) and high specific activity (143 +/- 90 GBq.umol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 +/- 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg.kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned. PMID- 26016547 TI - Comparative Studies on Polyphenolic Composition, Antioxidant and Diuretic Effects of Nigella sativa L. (Black Cumin) and Nigella damascena L. (Lady-in-a-Mist) Seeds. AB - This study was performed to evaluate the phenolic profile, antioxidant and diuretic effects of black cumin and lady-in-a-mist seeds. In the phenolic profile, differences between the two species are significant. Qualitative and quantitative analyses of the phenolic compounds were performed using a HPLC-UV/MS method. Hyperoside was the only identified flavonoid glycoside (1.08 +/- 0.01 MUg?g-1 dw plant material), in the N. damascena extract. Regarding the flavonol profile, kaempferol was identified before the hydrolysis, only in the N. sativa extract (6.06 +/- 0.02 MUg?g-1 dw plant material) and quercetin only in N. damascena seeds (14.35 +/- 0.02 MUg?g-1 dw plant material). The antioxidant potential of the two species was tested through several electron transfer assays, which indicated, excepting for the FRAP assay, N. damascena as exhibiting a higher free radical scavenging activity. The diuretic activity of the two extracts was tested using a rat-experimental model on acute diuresis. Administration of the ethanolic extract of N. sativa (100 mg?kg-1) resulted in a significant increase in urine volume, although less than found with the reference drug; in addition N. damascena extract did not present a diuretic effect. In reference to the elimination of Na+, K+ and uric acid, the black cumin extract exhibited a higher natriuretic than kaluretic effect and a similar uricosuric effect with control and N. damascena. For N. damascena, the Na+/K+ ratio was sub unitary, but not due to an increasing of the kaluretic effect, but mostly to a decrease of Na+ excretion. PMID- 26016548 TI - Reactivity of Amine/E(C6F5)3 (E = B, Al) Lewis Pairs toward Linear and Cyclic Acrylic Monomers: Hydrogenation vs. Polymerization. AB - This work reveals the contrasting reactivity of amine/E(C6F5)3 (E = B, Al) Lewis pairs toward linear and cyclic acrylic monomers, methyl methacrylate (MMA) and biorenewable gamma-methyl-alpha-methylene-gamma-butyrolactone (gammaMMBL). While mixing of 2,2,6,6-tetramethylpiperidine (TMP) and B(C6F5)3 leads to a frustrated Lewis pair (FLP), Et3N reacts with B(C6F5)3 to form disproportionation products, ammonium hydridoborate ionic pair and iminium zwitterion. On the other hand, the stoichiometric reaction of either TMP or Et3N with Al(C6F5)3 leads to clean formation of a classic Lewis adduct (CLA). Neither TMP nor Et3N, when paired with E(C6F5)3, polymerizes MMA, but the Et3N/2B(C6F5)3 pair promotes transfer hydrogenation of MMA to form methyl isobutyrate. In contrast, the amine/E(C6F5)3 pairs promote rapid polymerization of gammaMMBL carrying the more reactive exocyclic methylene moiety, achieving full conversion in less than 3 min even at a low catalyst loading of 0.0625 mol %. TMP is more effective than Et3N for the polymerization when paired with either the borane or the alane, while the alane exhibits higher polymerization activity than the borane when paired with Et3N. Overall, the TMP/Al(C6F5)3 system exhibits the highest polymerization activity, achieving a maximum turn-over frequency of 96,000 h-1 at 0.125 mol % of catalyst loading, producing high molecular weight PgammaMMBL with Mn = 1.29 * 105 g?mol-1. PMID- 26016549 TI - Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography. AB - Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2-4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives. PMID- 26016550 TI - Xerogel-sequestered silanated organochalcogenide catalysts for bromination with hydrogen peroxide and sodium bromide. AB - While H2O2 is a powerful oxidant, decomposing into environmentally benign H2O and O2, a catalyst is often required for reactions with H2O2 to proceed at synthetically useful rates. Organotellurium and organoselenium compounds catalyze the oxidation of halide salts to hypohalous acids using H2O2. When sequestered into xerogel monoliths, the xerogel-chalcogenide combinations have demonstrated increased catalytic activity relative to the organochalcogen compound alone in solution for the oxidation of halide salts to hypohalous acids with H2O2. Diorganotellurides, diorganoselenides, and diorganodiselenides bearing triethoxysilane functionalities were sequestered into xerogel monoliths and their catalytic activity and longevity were investigated. The longevity of the catalyst xerogel combinations was examined by isolating and recycling the catalyst-xerogel combination. It was found tellurium-containing catalyst 3 and selenium-containing catalyst 8 maintained their catalytic activity through three recycling trials and adding electron-donating substituents to catalyst 3 also increased the catalytic rate. The presence of organotellurium and organoselenium groups in the +4 oxidation state was determined by X-ray photoelectron spectroscopy. PMID- 26016551 TI - Multidisciplinary Approach to Determine the Optimal Time and Period for Extracting the Essential Oil from Mentha suaveolens Ehrh. AB - A comprehensive study on essential oils (EOs) extracted from some Mentha suaveolens L. samples, collected in the countryside of Tarquinia, is reported. In this study, the procedure for essential oil preparation, in terms of harvesting and extraction time, was analyzed in detail for the first time. The GC/MS analysis, carried out on 18 samples, revealed that piperitenone oxide (PO), the main essential oils' chemical constituent, is primarily responsible for the related antifungal activity. Nevertheless, EOs with lower PO content indicate that other chemicals, such as para-cymenene, may participate in exerting the EOs' antifungal effect. Furthermore, the bacterial reverse mutation assay highlighted lack of mutagenic effect in all tested samples. Analysis of the results indicated that for higher activity, the essential oils should be produced with 3 h maximum hydrodistillation, regardless of the harvesting time. Differently, the maximum essential oil yield can be obtained in August and the highest piperitenone oxide percentage is obtainable in July. PMID- 26016552 TI - A Herbal Formula HT048, Citrus unshiu and Crataegus pinnatifida, Prevents Obesity by Inhibiting Adipogenesis and Lipogenesis in 3T3-L1 Preadipocytes and HFD Induced Obese Rats. AB - HT048 is a combination composed of Crataegus pinnatifida leaf and Citrus unshiu peel extracts. This study aimed to investigate potential anti-obesity effect of the combination. The 3T3-L1 adipocytes were treated with different doses of HT048 and triglyceride accumulation, glycerol release and adipogenesis-related genes were analyzed. For in vivo study, male Sprague Dawley rats were divided according to experimental diets: the chow diet group, the high-fat diet (HFD) group, the HFD supplemented with orlistat group, the HFD supplemented with HT048 group (0.2% or 0.4%) for 12 weeks. We measured the body weight, serum lipid levels and the expression of genes involved lipid metabolism. HT048 treatment dose-dependently suppressed adipocyte differentiation and stimulated glycerol release. The expressions of PPARgamma and C/EBPalpha mRNA were decreased by HT048 treatment in adipocytes. HT048 supplementation significantly reduced the body and fat weights in vivo. Serum lipid levels were significantly lower in the HT048 supplemented groups than those of the HFD group. Expression of the hepatic lipogenesis-related genes were decreased and expression of the beta-oxidation-related genes were increased in rats fed HT048 compared to that of animals fed HFD. These results suggest that HT048 has a potential benefit in preventing obesity through the inhibition of lipogenesis and adipogenesis. PMID- 26016553 TI - Purity Assessment of Aryltetralin Lactone Lignans by Quantitative 1H Nuclear Magnetic Resonance. AB - In the present work, a quantitative 1H Nuclear Magnetic Resonance (qHNMR) was established for purity assessment of six aryltetralin lactone lignans. The validation of the method was carried out, including specificity, selectivity, linearity, accuracy, precision, and robustness. Several experimental parameters were optimized, including relaxation delay (D1), scan numbers (NS), and pulse angle. 1,4-Dinitrobenzene was used as internal standard (IS), and deuterated dimethyl sulfoxide (DMSO-d6) as the NMR solvent. The purities were calculated by the area ratios of H-2,6 from target analytes vs. aromatic protons from IS. Six aryltetralin lactone lignans (deoxypodophyllotoxin, podophyllotoxin, 4 demethylpodophyllotoxin, podophyllotoxin-7'-O-beta-d-glucopyranoside, 4 demethylpodophyllotoxin-7'-O-beta-d-glucopyranoside, and 6''-acetyl podophyllotoxin-7'-O-beta -d-glucopyranoside) were analyzed. The analytic results of qHNMR were further validated by high performance liquid chromatography (HPLC). Therefore, the qHNMR method was a rapid, accurate, reliable tool for monitoring the purity of aryltetralin lactone lignans. PMID- 26016554 TI - Green extraction of antioxidants from different varieties of red grape pomace. AB - The extraction yield, phenolic content, anthocyanin content and antioxidant activity of extracts from different varieties of red grapes, Cabernet Sauvignon, Merlot, Petit Verdot, Syrah, Tempranillo and Tintilla, using pressurized green solvents have been analyzed. Two techniques were studied and compared: supercritical fluid extraction (SFE) with CO2 + 20% ethanol and pressurized liquid extraction (PLE) with either ethanol, water or an ethanol/water mixture as the extraction solvents. The Petit Verdot variety allowed the highest global and phenolic yield, and antioxidant activity. The best conditios for PLE obtained from the experimental design and kinetic study were 50% ethanol/water as the pressurized solvent at 90 bar, 120 degrees C, a flow rate of 5 g/min and, an extraction time of 90 min. A statistical analysis of variance has been performed and it was found that temperature is the only variable that has a statistical influence on the extraction yield. The antioxidant activity levels of the extracts are very promising and they are similar to those obtained with the antioxidant tocopherol. PMID- 26016555 TI - Multifunctional iron bound lactoferrin and nanomedicinal approaches to enhance its bioactive functions. AB - Lactoferrin (Lf), an iron-binding protein from the transferrin family has been reported to have numerous functions. Even though Lf was first isolated from milk, it is also found in most exocrine secretions and in the secondary granules of neutrophils. Antimicrobial and anti-inflammatory activity reports on lactoferrin identified its significance in host defense against infection and extreme inflammation. Anticarcinogenic reports on lactoferrin make this protein even more valuable. This review is focused on the structural configuration of iron containing and iron-free forms of lactoferrin obtained from different sources such as goat, camel and bovine. Apart for emphasizing on the specific beneficial properties of lactoferrin from each of these sources, the general antimicrobial, immunomodulatory and anticancer activities of lactoferrin are discussed here. Implementation of nanomedicinial strategies that enhance the bioactive function of lactoferrin are also discussed, along with information on lactoferrin in clinical trials. PMID- 26016556 TI - Isolation, in vitro culture and identification of a new type of mesenchymal stem cell derived from fetal bovine lung tissues. AB - Lung-derived mesenchymal stem cells (LMSCs) are considered to be important in lung tissue repair and regenerative processes. However, the biological characteristics and differentiation potential of LMSCs remain to be elucidated. In the present study, fetal lung-derived mesenchymal stem cells (FLMSCs) were isolated from fetal bovine lung tissues by collagenase digestion. The in vitro culture conditions were optimized and stabilized and the self-renewal ability and differentiation potential were evaluated. The results demonstrated that the FLMSCs were morphologically consistent with fibroblasts, were able to be cultured and passaged for at least 33 passages and the cell morphology and proliferative ability were stable during the first 10 passages. In addition, FLMSCs were found to express CD29, CD44, CD73 and CD166, however, they did not express hematopoietic cell specific markers, including CD34, CD45 and BOLA-DRalpha. The growth kinetics of FLMSCs consisted of a lag phase, a logarithmic phase and a plateau phase, and as the passages increased, the proliferative ability of cells gradually decreased. The majority of FLMSCs were in G0/G1 phase. Following osteogenic induction, FLMSCs were positive for the expression of osteopontin and collagen type I alpha2. Following neurogenic differentiation, the cells were morphologically consistent with neuronal cells and positive for microtubule associated protein 2 and nestin expression. It was concluded that the isolated FLMSCs exhibited typical characteristics of mesenchymal stem cells and that the culture conditions were suitable for their proliferation and the maintenance of stemness. The present study illustrated the potential application of lung tissue as an adult stem cell source for regenerative therapies. PMID- 26016557 TI - Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. AB - Maternal obesity is linked with adverse outcomes for mothers and babies. To get an overview of risks related to obesity in pregnant women, a systematic review of reviews was conducted. For inclusion, reviews had to compare pregnant women of healthy weight with women with obesity, and measure a health outcome for mother and/or baby. Authors conducted full-text screening, quality assurance using the AMSTAR tool and data extraction steps in pairs. Narrative analysis of the 22 reviews included show gestational diabetes, pre-eclampsia, gestational hypertension, depression, instrumental and caesarean birth, and surgical site infection to be more likely to occur in pregnant women with obesity compared with women with a healthy weight. Maternal obesity is also linked to greater risk of preterm birth, large-for-gestational-age babies, foetal defects, congenital anomalies and perinatal death. Furthermore, breastfeeding initiation rates are lower and there is greater risk of early breastfeeding cessation in women with obesity compared with healthy weight women. These adverse outcomes may result in longer duration of hospital stay, with concomitant resource implications. It is crucial to reduce the burden of adverse maternal and foetal/child outcomes caused by maternal obesity. Women with obesity need support to lose weight before they conceive, and to minimize their weight gain in pregnancy. PMID- 26016558 TI - Short-term effect of diode laser cyclophotocoagulation on intraocular pressure: a prospective study. AB - BACKGROUND: This aims to determine the immediate and short-term risk of intraocular pressure spikes following diode laser cyclophotocoagulation. DESIGN: This study is a prospective, consecutive cohort study in a UK teaching hospital. PARTICIPANTS: Fifty-three consecutive patients undergoing cyclophotocoagulation were invited to participate in this study. METHODS: Intraocular pressure (IOP) measurements were taken immediately prior to cyclodiode laser, hourly for the first 3 h after laser, on the first and seventh postoperative days, and at three months following laser. MAIN OUTCOME MEASURES: Eyes experiencing intraocular pressure elevation defined at two levels (>=3 mm Hg and >=10 mm Hg from the pretreatment level) were identified. RESULTS: Seventeen eyes (34%) had an elevation in intraocular pressure (>=3 mmHg) during the first 3 h postoperatively with a mean increase of 10.3 mmHg. No preoperative or perioperative associations were found for a postcyclodiode spike within the first 3 postoperative hours.No association was found between pressure spikes and visual acuity, reduction of glaucoma medication or final postoperative intraocular pressure at 3 months. Eyes that did not have an IOP spike during the first 3 h postoperatively had a greater reduction in IOP at 3 months (15.2 mmHg vs. 10.2 mmHg; P = 0.184). CONCLUSION: IOP spikes are common in the immediate period after cyclophotocoagulation. An elevation in IOP is noted after the first hour in the vast majority who experience a spike in the first 3 h post-procedure. PMID- 26016559 TI - Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use. AB - AIM: Deferasirox is a new oral iron chelating agent with several cases reporting renal adverse events in recent years. Our aim was to identify the incidence of deferasirox-related Fanconi syndrome (FS) and its risk factors. METHODS: All transfusion-dependent thalassaemic patients who received deferasirox at the outpatient department of the National Taiwan University Hospital (NTUH) from January 2006 to February 2014 were evaluated. RESULTS: This cohort study included 57 patients, and mean age of deferasirox initiation was 18.2 +/- 7.7 years. After 6.9 +/- 1.8 years of follow-up, 5 in 57 (8.8%) thalassaemic patients had FS. Age of starting deferasirox negatively correlated with incidence of FS (correlation coefficient -0.892, P = 0.008). Other factors were not significantly associated with FS. Serum creatinine level at the start of deferasirox compared to at the end of study or onset of FS did not show significant change (P = 0.277). All the deferasirox-related FS manifested with proximal renal tubular acidosis and hypophosphataemia, which needed specific treatment or withdrawal of deferasirox use. CONCLUSIONS: We recommend that children, especially of young age, who regularly use deferasirox should undergo routine urinalysis and blood testing for early detection of FS. PMID- 26016560 TI - Egg ovotransferrin-derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats. AB - SCOPE: Egg ovotransferrin-derived angiotensin converting enzyme (ACE) inhibitory peptide IRW was previously shown to reduce blood pressure in spontaneously hypertensive rats through reduced vascular inflammation and increased nitric oxide-mediated vasorelaxation. The main objective of the present study was to investigate the molecular mechanism of this peptide through transcriptome analysis by RNAseq technique. METHODS AND RESULTS: Total RNA was extracted from kidney and mesenteric arteries; the RNAseq libraries (from untreated and IRW treated groups) were constructed and subjected to sequence using HiSeq 2000 system (Illumina) system. A total of 12 764 and 13 352 genes were detected in kidney and mesenteric arteries, respectively. The differentially expressed (DE) genes between untreated and IRW-treated groups were identified and the functional analysis through ingenuity pathway analysis revealed a greater role of DE genes identified from mesenteric arteries than that of kidney in modulating various cardiovascular functions. Subsequent qPCR analysis further confirmed that IRW significantly increased the expression of ACE-2, ABCB-1, IRF-8, and CDH-1 while significantly decreased the expression ICAM-1 and VCAM-1 in mesenteric arteries. CONCLUSION: Our research showed for the first time that ACE inhibitory peptide IRW could contribute to its antihypertensive activity through increased ACE2 and decreased proinflammatory genes expression. PMID- 26016562 TI - Human resource crises in German hospitals--an explorative study. AB - BACKGROUND: The complexity of providing medical care in a high-tech environment with a highly specialized, limited labour force makes hospitals more crisis-prone than other industries. An effective defence against crises is only possible if the organizational resilience and the capacity to handle crises become part of the hospitals' organizational culture. To become more resilient to crises, a raised awareness--especially in the area of human resource (HR)--is necessary. The aim of this paper is to contribute to the process robustness against crises through the identification and evaluation of relevant HR crises and their causations in hospitals. METHODS: Qualitative and quantitative methods were combined to identify and evaluate crises in hospitals in the HR sector. A structured workshop with experts was conducted to identify HR crises and their descriptions, as well as causes and consequences for patients and hospitals. To evaluate the findings, an online survey was carried out to rate the occurrence (past, future) and dangerousness of each crisis. RESULTS: Six HR crises were identified in this study: staff shortages, acute loss of personnel following a pandemic, damage to reputation, insufficient communication during restructuring, bullying, and misuse of drugs. The highest occurrence probability in the future was seen in staff shortages, followed by acute loss of personnel following a pandemic. Staff shortages, damage to reputation, and acute loss of personnel following a pandemic were seen as the most dangerous crises. CONCLUSIONS: The study concludes that coping with HR crises in hospitals is existential for hospitals and requires increased awareness. The six HR crises identified occurred regularly in German hospitals in the past, and their occurrence probability for the future was rated as high. PMID- 26016561 TI - Swiss army knives: non-canonical functions of nuclear Drosha and Dicer. AB - The RNase III enzymes Drosha and Dicer are essential for the production of small non-coding RNAs (ncRNAs). In canonical RNAi, microRNAs (miRNAs) regulate gene expression by post-transcriptional gene silencing. In non-canonical RNAi, nuclear RNAi factors generate small ncRNAs that are essential for transcriptional gene silencing. Recent evidence points to the existence of additional non-canonical nuclear RNAi functions in various organisms, including in genome maintenance and editing, as well as in DNA repair. Drosha and Dicer directly regulate gene expression and RNA metabolism at different stages, such as transcriptional initiation and termination, and the processing of various RNA species, including pre-mRNAs. Furthermore, Dicer isoforms were recently discovered and attributed with roles in apoptosis, development and disease. PMID- 26016563 TI - LncRNA BCAR4 wires up signaling transduction in breast cancer. AB - Long noncoding RNAs (lncRNAs) are dysregulated in many cancer types and are believed to play crucial roles in regulating several hallmarks of cancer biology. Currently, most studies support the concept that lncRNAs are involved in either transcriptional or post-transcriptional processes via binding/targeting epigenetic modifiers or hRNP complexes. The discovery of new biological functions of lncRNA and novel RNA binding proteins suggests that lncRNAs may be implicated in a broad spectrum of biological processes such as signal transduction, allosteric regulation of cytoplasmic enzymatic activities, among other potential processes. In a recent report that we have made, based on open-ended lncRNA pulldown technology and a series of systematic analyses, we suggest that lncRNAs also play critical roles in the regulation of noncanonical Hedgehog/GLI 2 signal transduction pathways in cancer cells, which further broadens the scope of known lncRNA functions and aids in the discovery and design of more effective and evidence-based therapeutic targets for the treatment of human cancers and other diseases. PMID- 26016564 TI - Lumbosacral pedicle screw placement using a fluoroscopic pedicle axis view and a cannulated tapping device. AB - BACKGROUND: Pedicle screw insertions are commonly used for posterior fixation to treat various spine disorders. However, the misplacement of pedicle screws can lead to disastrous complications. Inaccurate pedicle screw placement is relatively common even when placement is performed under fluoroscopic control. In order to improve the accuracy of the screw placement, we applied a technique using guide wires and a cannulated tapping device with the assistance of a fluoroscopic pedicle axis view. METHODS: From 2006 to 2011, 854 pedicle screws were placed in 176 patients in lumbosacral spinal fusion surgeries. The accuracy of screw placement was evaluated using postoperative reconstructed computed tomography images. Screw misplacement was classified as minor (cortical perforation <3 mm), moderate (cortical perforation 3-6 mm), or severe (cortical perforation >6 mm). Using logistic regression analysis, we also investigated the potential risk factors associated with screw misplacement. RESULTS: Pedicle screw misplacement was observed in 37 screws (4.3%) in 34 patients. In the sub classification analysis, 28 screws (3.3%) were determined to be minor perforations, 7 screws (0.8%) were considered to be moderate perforations, and 2 screws (0.2%) was judged to be a severe perforation (cortical perforation >6 mm). None of the 28 screws that were considered to be minor perforations were associated with any significant symptoms in the patients. However, 2 of the 9 screws that were determined to be moderate or severe perforations caused neurological symptoms (1 of which required revision). No significant differences were observed in the incidence of screw misplacement among the vertebral levels. Significant risk factors for screw misplacement were obesity and degenerative scoliosis. The odds ratios of these significant risk factors were 3.593 (95% confidence interval (CI), 1.061-12.175) for obesity and 8.893 for degenerative scoliosis (95% CI, 1.200-76.220). CONCLUSIONS: A modified fluoroscopic technique using a pedicle axis view and a cannulated tapping instrument can achieve safe and accurate pedicle screw placement. In addition, obesity and degenerative scoliosis were identified as significant risk factors for screw misplacement. PMID- 26016567 TI - Structural and magnetic studies on three new mixed metal copper(II) selenites and tellurites. AB - Three new transition metal copper(II) selenites or tellurites, namely, CdCu(SeO3)2 (1), HgCu(SeO3)2 ()2, and Hg2Cu3(Te3O8)2 (3), have been obtained by conventional hydrothermal reactions of CdO (or Hg2Cl2), CuO and SeO2 (or TeO2). Compounds 1 and 2 are isostructural and crystallize in P2(1)/c. Their structures feature a 3D anionic framework of Cu(SeO3)2(2-) with 1D channels of eight membered rings (MRs) along the c-axis and a-axis, respectively, which are filled by Cd(2+) or Hg(2+) cations. Compound 3 crystallizes in a tetragonal system of space group P42(1)2. Its structure is characterized by a [Cu3(Te3O8)2](2-) honeycomb layer composed of [Te3O8](4-) anions interconnected by Cu(2+) ions with 1D channels of 8-MRs along the c-axis. TOPOS analysis indicates that the copper(ii) tellurite layer exhibits a new topological structure with a Schlafli symbol of {4(6).8(9)}(2){4(6)}(3). The above anionic copper(II) tellurite layers are further linked by dumbbell Hg2(2+) cations to form a novel 3D framework. Magnetic measurements based on magnetic susceptibility and heat capacity indicate that compounds 1 and 2 show a spin-singlet ground state with a spin gap based on the [Cu2O8](12-) dimeric model, whereas compound e3 xhibits a 2D spin-system with an antiferromagnetic ordering around 25 K correlated with its honeycomb [Cu3(Te3O8)2](2-) layer. Furthermore, crystalline structures, thermal stabilities, IR spectra and UV-Vis diffuse reflectance spectra have also been studied. PMID- 26016565 TI - A novel termini analysis theory using HTS data alone for the identification of Enterococcus phage EF4-like genome termini. AB - BACKGROUND: Enterococcus faecalis and Enterococcus faecium are typical enterococcal bacterial pathogens. Antibiotic resistance means that the identification of novel E. faecalis and E. faecium phages against antibiotic resistant Enterococcus have an important impact on public health. In this study, the E. faecalis phage IME-EF4, E. faecium phage IME-EFm1, and both their hosts were antibiotic resistant. To characterize the genome termini of these two phages, a termini analysis theory was developed to provide a wealth of terminal sequence information directly, using only high-throughput sequencing (HTS) read frequency statistics. RESULTS: The complete genome sequences of phages IME-EF4 and IME-EFm1 were determined, and our termini analysis theory was used to determine the genome termini of these two phages. Results showed 9 bp 3' protruding cohesive ends in both IME-EF4 and IME-EFm1 genomes by analyzing frequencies of HTS reads. For the positive strands of their genomes, the 9 nt 3' protruding cohesive ends are 5'-TCATCACCG-3' (IME-EF4) and 5'-GGGTCAGCG-3' (IME EFm1). Further experiments confirmed these results. These experiments included mega-primer polymerase chain reaction sequencing, terminal run-off sequencing, and adaptor ligation followed by run-off sequencing. CONCLUSION: Using this termini analysis theory, the termini of two newly isolated antibiotic-resistant Enterococcus phages, IME-EF4 and IME-EFm1, were identified as the byproduct of HTS. Molecular biology experiments confirmed the identification. Because it does not require time-consuming wet lab termini analysis experiments, the termini analysis theory is a fast and easy means of identifying phage DNA genome termini using HTS read frequency statistics alone. It may aid understanding of phage DNA packaging. PMID- 26016566 TI - Stable DNA Nanomachine Based on Duplex-Triplex Transition for Ratiometric Imaging Instantaneous pH Changes in Living Cells. AB - DNA nanomachines are becoming useful tools for molecular recognition, imaging, and diagnostics and have drawn gradual attention. Unfortunately, the present application of most DNA nanomachines is limited in vitro, so expanding their application in organism has become a primary focus. Hence, a novel DNA nanomachine named t-switch, based on the DNA duplex-triplex transition, is developed for monitoring the intracellular pH gradient. Our strategy is based on the DNA triplex structure containing C(+)-G-C triplets and pH-dependent Forster resonance energy transfer (FRET). Our results indicate that the t-switch is an efficient reporter of pH from pH 5.3 to 6.0 with a fast response of a few seconds. Also the uptake of the t-switch is speedy. In order to protect the t switch from enzymatic degradation, PEI is used for modification of our DNA nanomachine. At the same time, the dynamic range could be extended to pH 4.6-7.8. The successful application of this pH-depended DNA nanomachine and motoring spatiotemporal pH changes associated with endocytosis is strong evidence of the possibility of self-assembly DNA nanomachine for imaging, targeted therapies, and controllable drug delivery. PMID- 26016568 TI - Predictors of round window accessibility for adult cochlear implantation based on pre-operative CT scan: a prospective observational study. AB - BACKGROUND: Cochlear implantation has become a mainstream treatment option for patients with severe to profound sensorineural hearing loss. During cochlear implant, there are key surgical steps which are influenced by anatomical variations between each patient. The aim of this study is to determine if there are potential predictors of difficulties that may be encountered during the cortical mastoidectomy, facial recess approach and round window access in cochlear implant surgery based upon pre-operative temporal bone CT scan. METHODS: Fifty seven patients undergoing unilateral cochlear implantation were analyzed. Difficulty with 1) cortical mastoidectomy, 2) facial recess approach, and 3) round window access were scored intra-operatively by the surgeon in a blinded fashion (1 = "easy", 2 = "moderate", 3 = "difficult"). Pre-operative temporal bone CT scans were analyzed for 1) degree of mastoid aeration; 2) location of the sigmoid sinus; 3) height of the tegmen; 4) the presence of air cells in the facial recess, and 5) degree of round window bony overhang. RESULTS: Poor mastoid aeration and lower tegmen position, but not the location of sigmoid sinus, are associated with greater difficulty with the cortical mastoidectomy. Presence of an air cell around the facial nerve was predictive of easier facial recess access. However, the degree of round window bony overhang was not predictive of difficulty associated with round window access. CONCLUSION: Certain parameters on the pre-operative temporal bone CT scan may be useful in predicting potential difficulties encountered during the key steps involved in cochlear implant surgery. PMID- 26016569 TI - Influence of oxygen deficiency and the role of specific amino acids in cryopreservation of garlic shoot tips. AB - BACKGROUND: Garlic has lost its ability to form seeds in the course of its domestication. Therefore, the germplasm storage via cryopreservation is increasingly applied. The progression of the various steps within the cryopreservation procedure is accompanied by declining survival rates of the explants. Much of the recent work on cryo-stress has been focussed on osmotic and cold stress components. However, two decades after invention of garlic cryopreservation, the function of metabolites and oxygen in and around the cryopreserved tissues is still largely obscure. METHODS: In this study, hypoxia was characterized in cryopreservation of garlic with oxygen sensors and amino acid metabolism. Furthermore, malondialdehyde, soluble sugars and ammonium were quantified to demonstrate the influence of cryo-stress in declining survival rates. RESULTS: To better understand the possible reasons for a reduction in the survival rate at the subsequent steps of cryopreservation, the concentration of amino acids, ammonium, gamma-aminobutyric acid (GABA), soluble sugars, malondialdehyde (MDA), and oxygen were measured in garlic shoot tips undergoing cryopreservation. Using microsensors, a very low oxygen concentration (<0.1 MUM) was detected within the central meristem region of the shoot apex. When apices were immersed in cryoprotectant solution, the well-oxygenated peripheral regions (foliage leaf bases) became likewise hypoxic within a few minutes, probably resulting from strongly restricted gaseous diffusion. CONCLUSIONS: Tissue level oxygen measurements supported the occurrence of hypoxia while biochemical analysis indicated adaptive responses, in particular the modulation in alanine and glutamate metabolism. The possible role of serine and glycine metabolism during cryopreservation is also discussed. PMID- 26016573 TI - Analysis of Using I(125) Radiolabeling for Quantifying Protein on Contact Lenses. AB - PURPOSE: To investigate the accuracy of I(125) radiolabeling to quantitatively determine the deposition of protein onto various commercially available contact lens (CL) materials. METHODS: Commercially available silicone hydrogel and conventional hydrogel CL materials were examined for times ranging from 10 s to 1 week. Adsorption of free I(125) was measured directly for the CL. The use of dialyzing labeled proteins and/or using NaI to compete with free I(125) uptake was investigated as ways to minimize effects due to free I(125). RESULTS: At all time points and with all lens materials, there was 0.3 MUg/lens or greater of apparent mass attributable to free I(125) uptake. Dialyzing labeled proteins significantly reduced free I(125) uptake for all materials investigated. The benefit of using dialyzed protein was most prominent at shorter times, as free I(125) is continuously generated over time. Using NaI can reduce free I(125) uptake for some lens materials, but this is shown to directly affect protein deposition on some materials. CONCLUSIONS: Periodic replenishment of incubation solutions with freshly dialyzed labeled protein to limit free I(125) generation is recommended, but the incorporation of NaI onto the buffer solution is not. Irrespective of the exact procedure to limit free I(125) uptake, extra steps must be performed to quantify the amount of I(125) adsorbed onto contact lens materials, to determine thresholds of confidence with respect to the actual protein deposition that occurs. PMID- 26016572 TI - Exploring calcium oxalate crystallization: a constant composition approach. AB - Crystal growth rates have been extensively studied in calcium oxalate monohydrate (COM) crystallization, because COM crystals are the principal component in most kidney stones. Constant composition methods are useful for studying growth rates, but fail to differentiate concurrent nucleation and aggregation events. A constant composition method coupled with particle size determinations that addresses this deficiency was previously published for a calcium phosphate system, and this method was extended to COM crystallization in this report. A seeded constant composition experiment was combined with particle size determination and a separate near-equilibrium aggregation experiment to separate effects of growth rate, nucleation, and aggregation in COM crystal formation and to test the effects of various inhibitors relevant to stone formation. With no inhibitors present, apparent COM growth rates were heavily influenced by secondary nucleation at low seed crystal additions, but growth-related aggregation increased at higher seed crystal densities. Among small molecule inhibitors, citrate demonstrated growth rate inhibition but enhanced growth related aggregation, while magnesium did not affect COM crystallization. Polyanions (polyaspartate, polyglutamate, or osteopontin) showed strong growth rate inhibition, but large differences in nucleation and aggregation were observed. Polycations (polyarginine) did not affect COM crystal growth or aggregation. Mixtures of polyanions and polycations produced a complicated set of growth rate, nucleation, and aggregation behaviors. These experiments demonstrated the power of combining particle size determinations with constant composition experiments to fully characterize COM crystallization and to obtain detailed knowledge of inhibitor properties that will be critical to understanding kidney stone formation. PMID- 26016575 TI - Limited resections in high-risk patients. AB - PURPOSE OF REVIEW: The role of limited, sublobar resection in patients with early stage nonsmall cell lung cancer (NSCLC) remains controversial. Alternative treatments for surgical resection include stereotactic radiotherapy and radiofrequency ablation. In this review, the role of limited resection is discussed in patients presenting a s high-risk for s surgical intervention. RECENT FINDINGS: Clear definitions of high-risk patients are currently lacking, as well as, randomized prospective studies indicating which treatment to offer in this population. Awaiting results of two major ongoing trials, at this moment the decision-making process is heavily dependent on retrospective analyses. For selected patients sublobar resection may be a valid oncological option for clinical stage IA NSCLC. SUMMARY: Surgery remains the gold standard for NSCLC. In case of high-risk patients, a multidisciplinary consultation should advise the patient which treatment option to choose. In early-stage NSCLC, sublobar anatomical resection is preferred over nonsurgical procedures to determine nodal status and prognosis. In case of patients unfit for surgery, stereotactic radiotherapy is a good alternative. A randomized prospective study is necessary to determine survival in high-risk patients allocated to surgery (lobectomy or sublobar resection) or radiation-based treatment. PMID- 26016574 TI - Utility of forensic detection of rabies virus in decomposed exhumed dog carcasses. AB - This report describes four suspected rabies cases in domestic dogs that were involved inhuman exposures. In all these cases, the animals were buried for substantial times beforerabies testing was performed. Animal rabies is endemic in South Africa and domestic dogsare the main vector for transmission to humans. Diagnosis of rabies in humans is complicated,and diagnosis in the animal vector can provide circumstantial evidence to support clinicaldiagnosis of rabies in humans. The gold standard diagnostic method, fluorescent antibodytest (FAT), only delivers reliable results when performed on fresh brain material and thereforedecomposed samples are rarely submitted for diagnostic testing. Severely decomposed brainmaterial was tested for the presence of rabies virus genomic material using a quantitativereal-time reverse transcription polymerase chain reaction (q-real-time RT-PCR) assaywhen conventional molecular methods were unsuccessful. This may be a useful tool in theinvestigation of cases where the opportunity to sample the suspected animals post mortem wasforfeited and which would not be possible with conventional testing methodologies becauseof the decomposition of the material. PMID- 26016576 TI - What's new in thymic neoplasms. AB - PURPOSE OF REVIEW: The past 5 years have been marked with major developments in the field of thymic malignancies. RECENT FINDINGS: A lack of progress over decades has been transformed into dramatic advancements over the past 5 years through the creation of the International Thymic Malignancy Interest Group (ITMIG). ITMIG has brought together an engaged worldwide community interested in this field. An unprecedented global database has been developed and is being actively analyzed. Standard definitions have been established to allow collaboration; the histologic classification has been revised and the first formal stage classification system developed. Clinical trials and innovative research approaches are being implemented. The creation of the ITMIG infrastructure has yielded many successes and provides a solid foundation for future progress. SUMMARY: Clinicians and researchers should be aware of the knowledge, structure and tools that have been established. ITMIG provides an engaged community for collaboration and progress. PMID- 26016577 TI - Distinguishing complicated from uncomplicated parapneumonic effusions. AB - PURPOSE OF REVIEW: Treatment of parapneumonic effusions (PPEs) is challenged by the decision of whether or not to insert chest tubes. This review focuses on the factors that may aid in determining which patients require an immediate drainage of the pleural space, that is, have a complicated PPE. RECENT FINDINGS: Clinical guidelines advocate the evaluation of radiological (large effusion or loculation), bacteriological (Gram-positive stain or culture), biochemical (pH < 7.20 or glucose <60 mg/dl), and macroscopic (pus) characteristics of the pleural fluid to assist in the identification of complicated PPEs. In the past few years, a number of new pleural fluid biomarkers have been tested for the same purpose, but with the exception of C-reactive protein (CRP), they should be considered investigative. A pleural fluid CRP higher than 100 mg/l or a serum CRP higher than 200 mg/l, when combined with pleural fluid pH or glucose, may greatly increase our capability to predict the need for instituting tube thoracostomy. Although some ultrasonographic and computed tomography features favor the diagnosis of pleural infection, their role in uncomplicated-complicated PPE discrimination has not been systematically evaluated. SUMMARY: No pleural fluid tests, other than pH or glucose, have gained wide acceptance for the assessment of patients with PPE. However, if corroborated with further studies, the measurement of pleural fluid or serum CRP, in combination with the classical fluid parameters, may have the potential to be incorporated into medical decision making. PMID- 26016578 TI - Comparison of mesothelin and fibulin-3 in pleural fluid and serum as markers in malignant mesothelioma. AB - PURPOSE OF REVIEW: Malignant mesothelioma is an asbestos-induced, aggressive tumour, which frequently presents with pleural effusion. There are over 60 reported causes that can result in the development of a pleural effusion. Currently, there are no tumour biomarkers in widespread clinical use for the differential diagnosis of mesothelioma from other diseases. With the incidence of mesothelioma expected to continue to increase, it is timely to review the current status of effusion-based biomarkers for mesothelioma diagnosis. RECENT FINDINGS: The majority of recent studies have evaluated soluble mesothelin in effusions in a diagnostic setting for mesothelioma. However, at high specificity, the sensitivity of the assay is limited to approximately 60% at the time of diagnosis. There is considerable research effort directed toward the identification of new markers for mesothelioma through a variety of genomic, proteomic and immunomic based platforms. One of the few new biomarkers to be identified through a biomarker discovery pipeline and evaluated in pleural effusions is fibulin-3. Preliminary results on the diagnostic accuracy of fibulin 3 have been inconsistent. SUMMARY: To date, soluble mesothelin remains the best available biomarker for mesothelioma and a positive result is clinically useful in patients with pleural effusions in whom the diagnosis is uncertain. PMID- 26016579 TI - Outpatient thoracoscopy: safety and practical considerations. AB - PURPOSE OF REVIEW: Medical thoracoscopy, also known as pleuroscopy, has been utilized by chest physicians for more than a century. Despite this, it has only recently re-emerged as an important tool for interventional pulmonologists to diagnose and treat pleural diseases. The purpose of this review is to critically assess the recent literature related to medical thoracoscopy, specifically as it pertains to its safety and feasibility as an outpatient procedure. RECENT FINDINGS: Recent data have reaffirmed the clinical utility of medical thoracoscopy and suggest that it can be safely performed in an outpatient setting. A single-center study of 51 patients published in the past year described both the feasibility and safety of outpatient medical thoracoscopy. This study highlights the notion that the majority of patients do not require hospital admission after a routine diagnostic thoracoscopy in the absence of talc poudrage. Another study this year described the successful use of chest physician directed ultrasound-guided cutting needle biopsy when medical thoracoscopy was not technically possible. SUMMARY: The contribution of medical thoracoscopy in the diagnosis and management of pleural diseases is increasingly recognized. Evidence supports the routine practice of medical thoracoscopy on an outpatient basis in experienced centers. PMID- 26016580 TI - Treatment options for patients with recurrent, symptomatic pleural effusions secondary to heart failure. AB - PURPOSE OF REVIEW: Pleural effusions are a common finding in the nearly six million Americans diagnosed with heart failure. This review focuses on the historical, present and potential future trends in the management of such benign pleural effusions. RECENT FINDINGS: The management of symptomatic pleural effusions, in general, and in heart failure, specifically, has evolved in the last two decades. With more options, the treatment is often individualized for patients. Newer forms of therapy are also less invasive, resulting in less procedural morbidity, recuperation and cost. SUMMARY: The majority of patients with a pleural effusion resulting from heart failure will resolve their symptoms with medical therapy. Patients who experience symptoms from reaccumulation of their effusion have a selection of treatment options that can be individualized based on the patient's prognosis, functional status, need for future intervention and desires. PMID- 26016581 TI - The role of computed tomography in assessing pleural malignancy prior to thoracoscopy. AB - PURPOSE OF REVIEW: Computed tomography (CT) scanning is part of the routine diagnostic work up of patients with suspected pleural malignancy but has a wide variation in the reported sensitivity and specificity. This review was to appraise the recent literature on the utility of CT scanning. RECENT FINDINGS: When investigating patients for suspected pleural malignancy, the sensitivity of a malignant CT report may be higher than previously reported (68%), but the specificity seems significantly lower (78%). The predictive value of CT scanning (on all patients with pleural effusions) may be increased using a CT scoring system. Recent meta-analyses of the utility of PET give differing opinions on the value of this imaging modality. Further work needs to be done to define its place in the diagnostic pathway. SUMMARY: CT scoring systems may allow further risk stratification. However, a low negative predictive value of a 'negative' CT scan could lead to false reassurance and missed malignancy. PET/CT does not currently appear to add additional diagnostic value. Pulmonary emboli should be considered in all patients being investigated for clinically suspected malignant pleural disease. Respiratory physicians should be mindful of rare or unusual presentations. PMID- 26016582 TI - Can pharmacologic agents speed the rate of resorption of pleural fluid? AB - PURPOSE OF REVIEW: Pleural effusion is a common clinical problem resulting from a wide range of diseases. Treatment options include targeting the primary cause or, in persistent cases, invasive removal of the excess fluid from the pleural cavity. In this review, we summarize the experimental data concerning pharmacological agents that influence pleural fluid resorption and examine their potential as a novel noninvasive treatment strategy. RECENT FINDINGS: Recently published evidence indicates that adrenergic agents and corticosteroids can increase pleural fluid clearance from the cavity. On the contrary, paracetamol and certain nonsteroid anti-inflammatory drugs can impede fluid outflow. These concepts are based on data extracted by in-vivo studies using provoked hydrothoraces in rabbits and mice, as well as by ex-vivo electrophysiological experiments using sheep and human pleural tissue. SUMMARY: In conclusion, the available experimental data indicate that certain pharmacological agents may impact fluid resorption, thus affecting pleural fluid accumulation and the rate of pleural effusion resolution. PMID- 26016583 TI - Complications of chest tubes: a focused clinical synopsis. AB - PURPOSE OF REVIEW: Chest tube placement, or tube thoracostomy, is an invasive procedure designed to evacuate air and/or fluid from the thorax, whether emergent or elective. In the placement of these devices particular attention and effort must be made to understand safe and reliable anatomic techniques and device maintenance so as to avoid serious injury to the patient. This review focuses on complications of chest tube placement, with the emphasis on patient safety and error prevention. RECENT FINDINGS: There is a paucity of high-quality recent literature on tube thoracostomy complications. With the advent of value-driven healthcare, increasing emphasis is being placed on appropriate procedural indications, procedural safety, and patient satisfaction. Good clinical outcomes are critical to achieve and maintain in this context. SUMMARY: Given the high volume of tube thoracostomies globally, greater awareness of potential complications and preventive strategies is needed. The authors attempt to bridge this important gap. PMID- 26016584 TI - Repeated therapeutic thoracentesis to manage complicated parapneumonic effusions. AB - PURPOSE OF REVIEW: In complicated parapneumonic effusion (CPPE), antibiotics and evacuation of the infected pleural fluid are mandatory. The first-line evacuation treatment is still controversial. The aim of this article is to highlight the usefulness of repeated therapeutic thoracentesis (RTT) as a first-line treatment. RECENT FINDINGS: In the most recent study on RTT in CPPE, disposable pleural needles were used and the median number of thoracentesis was 3. The success rate was 81%, and only 4% of the patients were referred for thoracic surgery. The 1 year survival rate was 88%. On multivariate analysis, the observation of microorganisms in the pleural fluid after Gram staining and first thoracentesis volume at least 450 ml was associated with a higher risk of RTT failure. RTT is less invasive and can target different loculated pleural collections. Patients are less confined to beds between each procedure, and could even be ambulatory managed. The use of intrapleural fibrinolytics in association with DNase could most likely enhance the efficacy of RTT. SUMMARY: RTT is efficient and well tolerated in the management of CPPE, including pleural empyema, and could be proposed as a first-line therapy for CPPE. This technique could be used in association with intrapleural fibrinolytics and DNase. PMID- 26016585 TI - MRI of pleural diseases. AB - PURPOSE OF REVIEW: Imaging plays an important role in the diagnosis and optimal treatment of patients with pleural diseases. MRI is a noninvasive imaging modality, which is not commonly used as first-line investigation in this field, but is often called upon to solve specific dilemmas. In this review, the basic methodology of MRI and its usefulness in pleural diseases will be explored. RECENT FINDINGS: Recent advances in MRI technology have allowed the application of novel sequences, not only for anatomical but also for functional imaging. Improvement was mainly achieved by means of diffusion-weighted and dynamic contrast-enhanced MRI. These sequences can be used not only for detection, but also for characterization of pleural lesions. Even detection of pleural tumor recurrence and treatment response monitoring is possible. SUMMARY: The use of conventional and functional MR sequences has led to improvements in the detection and characterization of pleural diseases. This technique, whether or not in combination with SPECT and PET (so called multimodality approach), could be an added value in the near future. PMID- 26016587 TI - Celebrating Soft Matter's 10th anniversary: screening of the calcium-induced spontaneous curvature of lipid membranes. AB - Lipid membranes are key regulators of cellular function. An important step in membrane-related phenomena is the reshaping of the lipid bilayer, often induced by binding of macromolecules. Numerous experimental and simulation efforts have revealed that calcium, a ubiquitous cellular messenger, has a strong impact on the phase behavior, structural properties, and the stability of membranes. Yet, it is still unknown the way calcium and lipid interactions affect their macroscopic mechanical properties. In this work, we studied the interaction of calcium ions with membrane tethers pulled from giant unilamellar vesicles, to quantify the mechanical effect on the membrane. We found that calcium imposes a positive spontaneous curvature on negatively charged membranes, contrary to predictions we made based on the proposed atomic structure. Surprisingly, this effect vanishes in the presence of physiologically relevant concentrations of sodium chloride. Our work implies that calcium may be a trigger for membrane reshaping only at high concentrations, in a process that is robustly screened by sodium ions. PMID- 26016586 TI - An oral health education video game for high caries risk children: study protocol for a randomized controlled trial. AB - BACKGROUND: Tooth decay is the most common chronic disease of childhood in the world. Many children develop caries early in their lives, and go on to develop further caries and sepsis as they grow up, indicating failure in prevention. As a result, many end up requiring general anaesthesia to undergo treatment for a disease that is completely preventable. Previous studies have suggested that the families of these children need better oral health education as well as better support in implementing healthy practices at home, as they feel impeded by broader life challenges. Parents of these children have suggested utilizing modern technologies, such as the internet, DVDs and video games as methods of delivery of education that might fit in with their busy lifestyles. The aim of this investigation is to assess the acceptability and efficiency of an oral health education video game directed at these children and their families. METHODS/DESIGN: A two-armed phase-II randomized controlled trial will assess a children's oral health education video game in comparison with verbal oral health education in terms of: family satisfaction, effect on oral health knowledge, and effect on dietary and oral hygiene habits. Up to 110 four- to ten-year-old children, referred for tooth extraction under general anaesthesia due to caries, will be recruited. A sample of 45 participants in each group will be needed to provide 80% statistical power. The primary outcome measures for this study are: (1) parent and child satisfaction with the intervention, as indicated using a visual analogue scale; (2) improvement in the child's dietary knowledge measured by a pictorial dietary quiz; and (3) changes in the child's diet and oral hygiene habits, measured using a children's dietary questionnaire completed by the parent, and snacking and toothbrushing diaries completed by the child. Measures will be taken at baseline, directly after the intervention, and three months later. DISCUSSION: This study is a phase-II randomized controlled trial of an oral health education video game for high caries risk children and their families. Few protocols such as this are available in this much-needed research area. TRIAL REGISTRATION: ISRCTN94617251. PMID- 26016588 TI - Audio-Visual and Autogenic Relaxation Alter Amplitude of Alpha EEG Band, Causing Improvements in Mental Work Performance in Athletes. AB - The aim of the present study was to investigate the effect of regular audio visual relaxation combined with Schultz's autogenic training on: (1) the results of behavioral tests that evaluate work performance during burdensome cognitive tasks (Kraepelin test), (2) changes in classical EEG alpha frequency band, neocortex (frontal, temporal, occipital, parietal), hemisphere (left, right) versus condition (only relaxation 7-12 Hz). Both experimental (EG) and age-and skill-matched control group (CG) consisted of eighteen athletes (ten males and eight females). After 7-month training EG demonstrated changes in the amplitude of mean electrical activity of the EEG alpha bend at rest and an improvement was significantly changing and an improvement in almost all components of Kraepelin test. The same examined variables in CG were unchanged following the period without the intervention. Summing up, combining audio-visual relaxation with autogenic training significantly improves athlete's ability to perform a prolonged mental effort. These changes are accompanied by greater amplitude of waves in alpha band in the state of relax. The results suggest usefulness of relaxation techniques during performance of mentally difficult sports tasks (sports based on speed and stamina, sports games, combat sports) and during relax of athletes. PMID- 26016589 TI - First Molecular Detection of Rickettsia felis-Like Organism in Eulaelaps stabularis from the Changbai Mountain Area of China. AB - In 557 mites collected from rodents in the Changbai Mountain Area, 3 pools of Eulaelaps stabularis from Apodemus peninsulae and Apodemus agrarius showed a positive result by PCR amplifications of both the citrate synthase encoding gene (gltA) and outer membrane protein B encoding gene (ompB) of Rickettsia spp. Sequence analysis indicated that both gltA and ompB shared the high similarity (99%) to Rickettsia felis . The data presented in this paper extend the knowledge on the geographic distribution and host information of R. felis -like organism in China. PMID- 26016590 TI - BAG-S53P4 as an additive to bone allografts: A laboratory study using an uniaxial compression test. AB - We want to address the clinical issue of too sparse supply of allograft in total hip replacement and ambitions of controlling the grain size distribution. Bioglass BAG-S53P4 was evaluated as a bone graft additive to chemically treated allografts with controlled grain size distribution. Allografts were chemically cleaned (CG) and mixed with BAG-S53P4 additive (BG) for comparison. All samples were compacted with a dropped weight apparatus and then underwent a uniaxial compression test. The yield limit was determined by a uniaxial compression test and density was recorded while flowability was calculated. There was no difference between the yield stress limit of BG and CG after compaction (p=0.432). Adding BAG-S53P4 reduced flowability and could indicate better interlocking mechanism between particles. Adding BAG-S53P4 seems to have no impact on the yield stress limit. The extended allografts withstand the compaction equally good which makes it a valid bone substitute in total hip replacement. An in vivo loaded study is needed before clinical use can be recommended. PMID- 26016592 TI - The current status of theory evaluation in nursing. AB - AIMS: To identify the current status of theory evaluation in nursing and provide directions for theory evaluation for future development of theoretical bases of nursing discipline. BACKGROUND: Theory evaluation is an essential component in development of nursing knowledge, which is a critical element in development of nursing discipline. Despite earlier significant efforts for theory evaluation in nursing, a recent decline in the number of theory evaluation articles was noted and there have been few updates on theory evaluation in nursing. DESIGN: Discussion paper. DATA SOURCES: A total of 58 articles published from 2003-2014 were retrieved through searches using the PUBMED, PsyInfo and CINAHL. The articles were sorted by the area of evaluation and analysed to identify themes reflecting the theory evaluation process. IMPLICATIONS FOR NURSING: Diverse ways of theory evaluation need to be continuously used in future theory evaluation efforts. CONCLUSION: Six themes reflecting the theory evaluation process were identified: (a) rarely using existing theory evaluation criteria; (b) evaluating specifics; (c) using various statistical analysis methods; (d) developing instruments; (e) adopting in practice and education; and (f) evaluating mainly middle-range theories and situation-specific theories. PMID- 26016593 TI - Comparison of three DASH scoring paradigms and prevalent hypertension among older Hispanics. AB - Older Hispanics are less likely to be aware of their hypertension or adopt lifestyle modifications for hypertension control than non-Hispanic whites. Few reports exist Dietary Approaches to Stop Hypertension (DASH) accordance among Hispanics. This study was designed to: (1) assess accordance to a DASH pattern using three widely used DASH scoring paradigms; and (2) determine which DASH paradigm was most strongly associated with hypertension in 169 older Hispanics (mean age, 66 years and 73% female). Food frequency questionnaires were used to calculate DASH scores. Logistic regression modeling was performed for prevalent hypertension with the DASH scores, age, gender and acculturation. Using the Folsom et al. DASH scoring paradigm, 55% of adults were deemed DASH accordant compared with 17% using Fung et al. scores and 13% using the Toledo et al. Folsom et al. scores were predictive of prevalent hypertension (odds ratio=1.35, 95% confidence interval (1.04, 1.77) in this older Hispanic sample; the remaining two scoring systems were not associated with hypertension in this sample. PMID- 26016594 TI - Correlation between tea consumption and prevalence of hypertension among Singaporean Chinese residents aged ?40 years. AB - By a cross-sectional epidemiology study, we attempted to correlate the consumption of tea and/or health supplements, living habits and socio-demographic factors to the prevalence of hypertension among Singaporean Chinese residents. Singaporean Chinese residents aged ?40 years were randomly selected and interviewed face-to-face by clinical research assistants. Hypertension was defined as measured systolic blood pressure at least 140 mm Hg and/or diastolic blood pressure at least 90 mmHg or self-reported history/treatment for hypertension. The prevalence of hypertension among the whole investigated population (N=1184, 58.27% females) was 49.73% and the prevalence increased to 66.47% in the sub-population aged ?60 years. High risk of hypertension was associated with age ?60 years (odds ratio (OR): 4.15-4.19, P<0.01), obesity (body mass index >25 kg m(-2), OR: 2.10-2.11, P<0.01), family history of hypertension (OR: 2.69-2.76, P<0.01), diabetes history (OR: 2.29-2.33, P<0.01), hyperlipidemia history (OR: 1.79-1.80, P<0.01), male (OR: 1.56-1.59, P<0.01) and coffee intake (OR: 1.44-1.46, P<0.05). In contrast, drinking green tea at least 150 ml per week was associated with lower hypertension risk (OR: 0.63, 95% confidence interval (CI): 0.43-0.91, P<0.05). Drinking combination of green tea and British tea was associated with higher reduction in the risk of hypertension (OR: 0.58, 95% CI: 0.39-0.85, P<0.05). This cross-sectional study suggests that consumption of tea, especially green tea and British tea, was associated with lowering the risk of hypertension. On the other hand, consumption of coffee could be a risk factor of hypertension. These findings may provide useful information for health promotion to reduce risk of hypertension and warrant further study to confirm and elucidate such association. PMID- 26016595 TI - Population-based prevalence of high blood pressure among adults in an urban slum in Enugu, South East Nigeria. AB - In sub-Saharan Africa (SSA), rapid urbanization and changing lifestyle have modified the profile and pattern of various medical disorders. Apart from high prevalence rates, recent trends with regard to hypertension in Africa include: low levels of awareness, treatment and control. Although a large number of studies provide data about hypertension in SSA, few studies focused on special populations such as urban slum dwellers. The WHO STEP-wise approach to surveillance of noncommunicable diseases was used to access the prevalence of hypertension among adults in one of the urban slums in Enugu. Out of the 811 individuals aged 20 years and above surveyed, 774 (95.4%) cases were analyzed. About 4.7% and 2.7% reported a past history of diabetes and stroke, respectively, whereas 15% had a positive family history of hypertension. The mean (95% confidence interval (CI)) body mass index (BMI) was 23.7 (23.2-24.2) kg m(-2) among males and 26.6 (25.7-26.7) kg m(-2) among females (P<0.0001). The prevalence of hypertension was 52.5% (95% CI: 48.9-56.0) and 55.4% (95% CI: 49.5 61.3) in males and 50.8% (95% CI: 46.4-55.1) in females (P=0.23). It increased with age peaking at 45-54 years in females and ?55 years in males. About 40.1% were aware of their hypertension and 28.8% of those aware had normal blood pressure. In regression analysis, systolic (R(2)=0.192) and diastolic (R(2)=0.129) blood pressures increased with age and BMI. The prevalence of high blood pressure among adults in Enugu slums is very high and a cause for concern, and calls for urgent attention. PMID- 26016596 TI - Blood pressure percentiles by age and height for children and adolescents in Tehran, Iran. AB - To construct reference percentiles for blood pressure (BP) by sex, age and height for the first time in Iran, we used data on 16 972 healthy children, aged 1 month to 18 years, collected during 2000-2010 in Tehran. BP in this population rose steadily with age and height following a very similar trend in both genders up to the age of 14. Systolic BP (SBP) rise was more prominent in younger ages, and after puberty (15-18 years) was greater in boys compared with girls, while the rise in diastolic BP (DBP) was slightly higher in girls. Iranian norms, compared with 'Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents' (US-4th-Report) and the 'German BP Percentiles by Age and Height for Children and Adolescents' (KiGGS), showed a similar pattern of differences for both genders. For example, for Tehrani boys up to 6 years old whose heights were equal to 50th percentile of stature-for-age as well as length-for-age growth charts, the differences in 95th percentile for SBPs compared with the US-4th-report varied from 2-21 mm Hg while compared with KiGGS, maximum of differences was 9 mm Hg. For boys 7-15 years of age, ours were slightly higher than both. For ages of 16 and 17 years, we yielded figures lower than US-4th-report (2 mm Hg) but higher than KiGGS (3 mm Hg). Iranian 95th percentile for DBPs was lower than US-4th-report and KiGGS (1-11 mm Hg). Considering the differences with US-4th-report and KiGSS standards, the references presented in this study should rather be applied in Iranian population. PMID- 26016597 TI - Aboriginal vascular health and insights into atherosclerosis. PMID- 26016598 TI - Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. AB - Matrix Gla protein (MGP), a natural inhibitor of calcification, strongly correlates with the extent of coronary calcification. Vitamin K is the essential cofactor for the activation of MGP. The nonphosphorylated-uncarboxylated isoform of MGP (dp-ucMGP) reflects the status of this vitamin. We investigated whether there is an association between dp-ucMGP and stiffness of elastic and muscular type large arteries in a random sample from the general population. In a cross sectional design, we analyzed 1087 subjects from the Czech post-MONICA study. Aortic and femoro-popliteal pulse wave velocities (PWVs) were measured using a Sphygmocor device. Dp-ucMGP concentrations were assessed in freshly frozen samples by enzyme-linked immunosorbent assay methods using the InaKtif MGP iSYS pre-commercial kit developed by IDS and VitaK. Aortic PWV significantly (P<0.0001) increased across the dp-ucMGP quartiles. After adjustment for all potential confounders, aortic PWV independently correlated with dp-ucMGP (with beta coefficient (s.d.) 11.61 (5.38) and P-value=0.031). In a categorized manner, subjects in the top quartile of dp-ucMGP (? 671 pmol l(-1)) had a higher risk of elevated aortic PWV, with corresponding adjusted odds ratio (95% confidence interval) 1.73 (1.17-2.5). In contrast, no relation between dp-ucMGP and femoro popliteal PWV was found. In conclusion, increased dp-ucMGP, which is a circulating biomarker of vitamin K status and vascular calcification, is independently associated with aortic stiffness, but not with stiffness of distal muscular-type arteries. PMID- 26016599 TI - Individual 6-year systolic blood pressure change and impact on cardiovascular mortality in a French general population. AB - Impact of blood pressure (BP) visit-to-visit variability remains controversial for untreated hypertensives and for normotensive subjects. Association between 6 year systolic BP change and all-cause and cardiovascular (CVD) mortality was studied in general primary care population including untreated hypertensive and normotensive subjects. Normotensive individuals and untreated high BP patients (40,926 and 14,283, respectively) had two check-ups (interval: 5.8+/-2.2 years) at the IPC center (Paris). Follow-up was 6.1+/-3.2 years: 1131 people died, 114 from CVD causes. Systolic BP (SBP) change was assessed by tertiles of absolute differences between V1 and V2, and the relationship with mortality was analysed with multivariate Cox models (hazard ratio (HR), 95% confidence interval (CI)) including V1 or V2 parameters notably SBP. Adjusting for V1 variables, mortality was associated with SBP change, for the entire population (all-cause: HR=1.15 (95%: 1.01-1.30) and CVD: HR=1.95 (95%: 1.25-3.05)) and in hypertensive individuals: (HR=1.31 (95%: 1.08-1.59) and HR=2.51 (95%: 1.34-4.72), respectively). Adjustments for V2 variables gave similar results. For those who were normotensive at V1, the associations were not significant. In this primary care population, individual long-term visit-to-visit change of BP is an independent predictor of all-cause mortality in hypertensive individuals but not in those with normal BP. PMID- 26016600 TI - Regulation of Inflammation and Angiogenesis in Giant Cell Arteritis by Acute Phase Serum Amyloid A. AB - OBJECTIVE: Giant cell arteritis (GCA) is pathologically characterized by dysfunctional angiogenesis and inflammatory cell infiltration. Acute-phase serum amyloid A (A-SAA) is an acute-phase reactant, but is also produced at sites of inflammation and may contribute to vascular inflammation in atherosclerosis. This study was undertaken to examine the effect of A-SAA on proinflammatory pathways and angiogenesis in GCA, using a novel ex vivo temporal artery tissue explant model. METHODS: Serum A-SAA levels were measured by enzyme-linked immunosorbent assay (ELISA). Temporal artery explants and peripheral blood mononuclear cell (PBMC) cultures were established from patients with GCA. Temporal artery explant morphology, viability, and spontaneous release of proinflammatory mediators following 24-hour culture were assessed by hematoxylin and eosin, calcein viability staining, and ELISA. Temporal artery explants and PBMC cultures were stimulated with A-SAA (10 MUg/ml), and interleukin-6 (IL-6), IL-8, vascular endothelial growth factor, Ang2, and matrix metalloproteinase 2 (MMP-2)/MMP-9 were quantified by ELISA and gelatin zymography. The effect of conditioned medium from temporal artery explants on angiogenesis was assessed using endothelial cell Matrigel tube-formation assays. Temporal artery explants were also embedded in Matrigel, and myofibroblast outgrowth was assessed. RESULTS: Serum A-SAA levels were significantly higher in GCA patients versus healthy controls (P < 0.0001). Intact tissue morphology, cell viability, and spontaneous cytokine secretion were demonstrated in temporal artery explants. A-SAA treatment induced a significant increase in the levels of IL-6 and IL-8 from temporal artery explants (P < 0.05) and IL-8 from PBMCs (P < 0.05) compared to basal conditions. Conditioned medium from A-SAA-treated explants significantly induced angiogenic tube formation (P < 0.05 versus basal controls). Finally, A-SAA induced myofibroblast outgrowth and MMP-9 activation. CONCLUSION: Our findings demonstrate a functional role for A SAA in regulating temporal artery inflammation, angiogenesis, and invasion, all key processes in the pathogenesis of GCA. PMID- 26016601 TI - Low-Dimensional Structure Vacuum-Ultraviolet-Sensitive (lambda < 200 nm) Photodetector with Fast-Response Speed Based on High-Quality AlN Micro/Nanowire. AB - A low-dimensional-structure vacuum-ultraviolet-sensitive photodetector based on high-quality aluminum nitride (AlN) micro-/nanowires is reported. This work, for the first time, demonstrates that a semiconductor nanostructure can be applied in vacuum-ultraviolet (VUV) photon detection and opens a way for developing diminutive, power-saving, and low-cost VUV materials and sensors that can be potentially applied in geospace sciences and solar-terrestrial physics. PMID- 26016602 TI - Educational background of nurses and their perceptions of the quality and safety of patient care. AB - BACKGROUND: International health systems research confirms the critical role that nurses play in ensuring the delivery of high quality patient care and subsequent patient safety. It is therefore important that the education of nurses should prepare them for the provision of safe care of a high quality. The South African healthcare system is made up of public and private hospitals that employ various categories of nurses. The perceptions of the various categories of nurses with reference to quality of care and patient safety are unknown in South Africa (SA). OBJECTIVE: To determine the relationship between the educational background of nurses and their perceptions of quality of care and patient safety in private surgical units in SA. METHODS: A descriptive correlational design was used. A questionnaire was used for data collection, after which hierarchical linear modelling was utilised to determine the relationships amongst the variables. RESULTS: Both the registered- and enrolled nurses seemed satisfied with the quality of care and patient safety in the units were they work. Enrolled nurses (ENs) indicated that current efforts to prevent errors are adequate, whilst the registered nurses (RNs) obtained high scores in reporting incidents in surgical wards. CONCLUSION: From the results it was evident that perceptions of RNs and ENs related to the quality of care and patient safety differed. There seemed to be a statistically-significant difference between RNs and ENs perceptions of the prevention of errors in the unit, losing patient information between shifts and patient incidents related to medication errors, pressure ulcers and falls with injury. PMID- 26016603 TI - Primary stapedotomy in children with otosclerosis: A prospective study of 41 consecutive cases. AB - OBJECTIVES/HYPOTHESIS: To prospectively evaluate hearing outcomes in children with otosclerosis undergoing primary stapes surgery. STUDY DESIGN: A nonrandomized, nonblinded, prospective case series. METHODS: Thirty-four consecutive pediatric patients who underwent 41 primary stapedotomies for otosclerosis in a tertiary referral center were included. Patients were included when there was evidence of otosclerotic stapes fixation and they had available postoperative pure-tone audiometry. Patients underwent primary stapedotomy with vein graft interposition and reconstruction with a regular piston, bucket handle prosthesis, or total ossicular replacement prosthesis. Hearing results were evaluated using pre- and postoperative four-frequency (0.5, 1, 2, and 4 kHz) audiometry. Air-conduction thresholds, bone-conduction thresholds, and air-bone gaps were measured. Postoperative audiometry was performed at 3, 6, 9, 12, 18, and 24 months after surgery and at a yearly interval thereafter. RESULTS: Overall, a postoperative air-bone gap closure of 10 dB or less was achieved in 93% of cases and to within 20 dB in 98% of cases. Mean gain in air-conduction threshold was 23 dB for the entire case series, and mean air-bone gap closure was 23 dB. Postoperative sensorineural hearing loss, defined as changes in bone conduction thresholds exceeding 10 dB, occurred in one case at last follow-up. The bone-conduction threshold deteriorated 13 dB in this case. CONCLUSION: Primary stapedotomy is a safe and feasible treatment option in children with juvenile otosclerosis. LEVEL OF EVIDENCE: 4. PMID- 26016605 TI - Intraocular and systemic inflammation-related cytokines during one year of ranibizumab treatment for neovascular age-related macular degeneration. AB - PURPOSE: To determine inflammation-related intraocular and systemic cytokine concentrations in neovascular age-related macular degeneration (nAMD) compared with controls and to assess the influence of long-term intravitreal ranibizumab treatment over 1 year. METHODS: Aqueous humour and blood plasma of 21 controls and 17 treatment-naive nAMD patients were collected prior to cataract surgery or ranibizumab treatment. Follow-up specimens in nAMD patients were acquired immediately prior to subsequent ranibizumab injections as needed. Multiplex bead assays were conducted for ten inflammation-related cytokines and vascular endothelial growth factor (VEGF). p-values were Holm-Bonferroni-corrected for multiple comparisons. RESULTS: Prior to ranibizumab treatment, initiation aqueous humour levels of monocyte chemo-attractant protein (MCP)-1/CCL2 (p = 0.005) and vascular cell adhesin molecule (VCAM) (p = 0.002) were elevated in nAMD compared with controls. Other intraocular cytokines did not differ, including VEGF. In plasma, no differences between nAMD patients and controls were found at baseline. Pro re nata ranibizumab treatment over 12 months with 8 +/- 2 injections reduced aqueous VEGF (p < 0.0001) with a trend to reduced VEGF plasma concentrations (p = 0.046), with all specimens taken at least 28 days after the previous injection. All other local and systemic cytokines remained unchanged. CONCLUSION: Neovascular age-related macular degeneration is associated with local ocular MCP 1/CCL2 and VCAM elevations, suggesting a local inflammatory involvement in the pathophysiology of nAMD. We did not detect systemic differences. Ranibizumab treatment does not result in local or systemic changes of these cytokines, in contrast to VEGF suppression. MCP-1/CCL2 and VCAM may be potential additional treatment targets for nAMD. PMID- 26016604 TI - Targets for Combating the Evolution of Acquired Antibiotic Resistance. AB - Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal. PMID- 26016606 TI - Ultrasound-Triggered Phase-Transition Cationic Nanodroplets for Enhanced Gene Delivery. AB - Ultrasound as an external stimulus for enhanced gene transfection represents a safe, noninvasive, cost-effective delivery strategy for gene therapy. Herein, we have developed an ultrasound-triggered phase-transition cationic nanodroplet based on a novel perfluorinated amphiphilic poly(amino acid), which could simultaneously load perfluoropentane (PFP) and nucleic acids. The heptadecafluoroundecylamine (C11F17-NH2) was chosen to initiate beta-benzyl-L aspartate N-carboxyanhydride (BLA-NCA) ring-opening polymerization to prepare C11F17-poly(beta-benzyl-L-aspartate) (C11F17-PBLA). Subsequently, C11F17-poly{N [N'-(2-aminoethyl)]aspartamide} [C11F17-PAsp(DET)] was synthesized by aminolysis reaction of C11F17-PBLA with diethylenetriamine (DET). PFP/pDNA-loaded nanodroplets PFP-TNDs [PFP/C11F17-PAsp(DET)/LucDNA/gamma-PGA or poly(glutamic acid)-g-MeO-poly(ethylene glycol) (PGA-g-mPEG) ternary nanodroplets] were primarily formulated by an oil/water emulsification method, followed by surface modification with PGA-g-mPEG. The average diameter of PFP-TNDs ranged from 300 to 400 nm, and transmission electron microscopy images showed that the nanodroplets were nearly spherical in shape. The zeta potential of the nanodroplets dramatically decreased from +54.3 to +15.3 mV after modification with PGA-g-mPEG, resulting in a significant increase of the stability of the nanodroplets in the serum-containing condition. With ultrasound irradiation, the gene transfection efficiency was enhanced 14-fold on HepG2 cells, and ultrasound-triggered phase transition cationic nanodroplets also displayed a good ultrasound contrast effect. These results suggest that the PFP/DNA-loaded phase-transition cationic nanodroplets can be utilized as efficient theranostic agents for targeting gene delivery. PMID- 26016608 TI - Novel Targets of Drug Treatment for Pulmonary Hypertension. AB - Biomedical advances over the last decade have identified the central role of proliferative pulmonary arterial smooth muscle cells (PASMCs) in the development of pulmonary hypertension (PH). Furthermore, promoters of proliferation and apoptosis resistance in PASMCs and endothelial cells, such as aberrant signal pathways involving growth factors, G protein-coupled receptors, kinases, and microRNAs, have also been described. As a result of these discoveries, PH is currently divided into subgroups based on the underlying pathology, which allows focused and targeted treatment of the condition. The defining features of PH, which subsequently lead to vascular wall remodeling, are dysregulated proliferation of PASMCs, local inflammation, and apoptosis-resistant endothelial cells. Efforts to assess the relative contributions of these factors have generated several promising targets. This review discusses recent novel targets of therapies for PH that have been developed as a result of these advances, which are now in pre-clinical and clinical trials (e.g., imatinib [phase III]; nilotinib, AT-877ER, rituximab, tacrolimus, paroxetine, sertraline, fluoxetine, bardoxolone methyl [phase II]; and sorafenib, FK506, aviptadil, endothelial progenitor cells (EPCs) [phase I]). While substantial progress has been made in recent years in targeting key molecular pathways, PH still remains without a cure, and these novel therapies provide an important conceptual framework of categorizing patients on the basis of molecular phenotype(s) for effective treatment of the disease. PMID- 26016607 TI - Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants. AB - Psoriasis is a chronic autoimmune human skin disorder that is characterized by excessive proliferation of keratinocytes, scaly plaques, severe inflammation and erythema. The pathophysiology of psoriasis involves interplay between epidermal keratinocytes, T lymphocytes, leukocytes and vascular endothelium. Increased leukocyte recruitment and elevated levels of cytokines, growth factors and genetic factors like interleukin (IL)-1beta, IL-6, IL-17, IL-22, IL-23, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, toll-like receptor (TLR)-2, signal transducer and activator of transcription (STAT-3), 15-lipoxygenase (LOX)-2, coiled-coil alpha-helical rod protein 1 (CCHCR1), steroidogenic acute regulatory protein (StAR) and vitamin D receptor (VDR) are the most critical factors governing the exacerbation of psoriasis. In the present study, an attempt was made to elucidate the preventive role of herbal extracts of four dermo-protective Ayurvedic plants, Tinospora cordifolia (TC), Curcuma longa (CL), Celastrus paniculatus (CP) and Aloe vera (AV), against psoriasis-like dermatitis. Parkes (P) strain mice were initially induced with psoriasis-like dermatitis using topical application of imiquimod (IMQ, 5 %), followed by subsequent treatment with the herbal extracts to examine their curative effect on the psoriasis-like dermatitis-induced mice. The extracts were orally/topically administered to mice according to their ED/LD50 doses. Phenotypical observations, histological examinations, and semi-quantitative reverse transcription PCR (RT-PCR) analyses of the skin and blood samples of the control, IMQ-treated and herbal extract-treated psoriasis-like dermatitis-induced mice lead to the conclusion that the combination extract from all the plants was instrumental in downregulating the overexpressed cytokines, which was followed by the CL extract. Moreover, lesser yet positive response was evident from CP and TC extracts. The results suggest that these plants can prove to have tremendous preventive potential against the disease and can open the way to new therapeutic strategies for psoriasis treatment. PMID- 26016609 TI - Resurgence of anorexic symptoms during smoking cessation in patients with a history of anorexia nervosa: An unseen problem?--Report of two cases. AB - This report describes a resurgence of anorexic symptoms during a smoking cessation program in two patients with a history of anorexia nervosa. These two events were identified among patients lost to follow-up by using a strategy implemented to limit early drop out. In both cases, the resurgence of anorexic symptoms occurred rapidly after having reached abstinence from tobacco and was described as a response to the weight gain they had experienced just after the start of smoking cessation. The smoking cessation process itself was considered as the most plausible explanation for these two events. Given the potential serious consequences, further research is needed to determine whether such events are frequent during smoking cessation but being unseen because of being hidden in the loss to follow-up. This report also suggests that systematic screening for both binge eating and anorexic behaviors during smoking cessation is warranted. PMID- 26016610 TI - N-butylamine functionalized graphene oxide for detection of iron(III) by photoluminescence quenching. AB - An N-butylamine functionalized graphene oxide nanolayer was synthesized and characterized by ultraviolet (UV)-visible spectrometry, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and transmission electron microscopy. Detection of iron(III) based on photoluminescence spectroscopy was investigated. The N-butylamine functionalized graphene oxide was shown to specifically interact with iron (III), compared with other cationic trace elements including potassium (I), sodium (I), calcium (II), chromium (III), zinc (II), cobalt (II), copper (II), magnesium (II), manganese (II), and molybdenum (VI). The quenching effect of iron (III) on the luminescence emission of N-butylamine functionalized graphene oxide layer was used to detect iron (III). The limit of detection (2.8 * 10(-6) M) and limit of quantitation (2.9 * 10(-5) M) were obtained under optimal conditions. PMID- 26016611 TI - Aplasia cutis congenita: report of 22 cases. AB - BACKGROUND: Aplasia cutis congenita (ACC) is a rare malformation characterized by absent or scarred areas of skin at birth. Although most commonly found on the scalp, ACC can also involve other locations. Its etiology and pathogenesis remain unclear. OBJECTIVE: To describe the epidemiologic, clinical, therapeutic, and evolutionary aspects of ACC through a hospital series. METHODS: We conducted a retrospective study from 1995 to 2012 and reported all cases of ACC. RESULTS: We enrolled 22 cases (14 girls and eight boys) of ACC during 18 years. The mean age at diagnosis was 5.7 years. Sixteen ACC involved the scalp, five the trunk, and one the left buttock. ACC was oval-shaped in 20 cases, triangular in one case, and linear in one case. The mean size was 4 cm. ACC was associated with bone defects in two cases, various malformations in eight (37.1%), and with syndromic malformation in three (Adams-Olivier syndrome: two cases; Goltz syndrome: one case). Conservative treatment consisting of wound dressing with vaseline was indicated in six cases. Bone reconstruction was performed in two cases. Regular follow-up and no treatment was recommended in 14 cases. CONCLUSION: Our study emphasizes the frequent association of ACC with malformations (37.1%) and bone defects (9%). PMID- 26016612 TI - The effects of anaesthetics on postoperative physiological reactions: a meta analysis. AB - This study aimed to systematically investigate the effects of different anaesthetics on postoperative physiological reactions compared with placebo. The literature search was conducted using three databases: PubMed, EMBASE, and the Cochrane Library. Studies published from January 1990 to January 2015 were screened. The language was restricted to English. Heterogeneity was analyzed by the Q test and I(2) statistic. A fixed-effect model was used for homogenous data and a random-effects model for heterogeneous data. The odds ratio (OR) and 95% confidence interval (CI) were calculated to monitor the incidences of overall adverse events, arterial blood pressure, and cardiac abnormalities. Sensitivity analysis was performed to estimate the strength of the meta-analysis, and publication bias was analyzed using Egger's test. A total of 24 articles were included in this meta-analysis. There were 1,810 and 1,806 cases in the anaesthetic group and the placebo group, respectively. The incidence of overall adverse events was significantly lower in the anaesthetic group compared with the placebo group (OR = 0.57; 95% CI, 0.38-0.84). No publication bias was observed, and no inverse estimates were calculated using sensitivity analysis. There was no significant difference for the incidence of arterial blood pressure (OR = 4.62; 95% CI, 0.90-23.70) and cardiac abnormalities (OR = 1.18; 95% CI, 0.53-2.63) between the two groups. Although the incidence of overall adverse events was decreased in the anaesthetic group, it is impossible to determine whether the use of anaesthetics during surgical operation has a protective effect on postoperative physiological reactions. PMID- 26016616 TI - Culturally competent bioethics: analysis of a case study. AB - This paper discusses the Saudi Arabian case by Abdallah Adlan and Henk ten Have, published in a 2012 issue of the Journal of Bioethical Inquiry, regarding a congenitally disabled child enrolled in a research project examining the genetics of her condition. During the course of the study, her father was found not to be genetically related, and the case discussed the dilemma between disclosing to the family all findings as promised in consent documents or withholding paternity information because of the likely severe social repercussions. Using Adlan and ten Have's example, this paper proposes a framework to consider cases outside of the conventional bioethics frame of reference, splitting the bioethical task into three elements: understanding the problem from the patient's and the clinician's perspective and then engaging in dialogue to decide what to do next. The process of dialogue between affected parties is vital. Presuming that there is a common morality undermines the effectiveness of the dialogue needed to find a resolution. PMID- 26016617 TI - "Can a Company be Bitchy?" Corporate (and Political and Scientific) Social Responsibility. PMID- 26016618 TI - Macrocalyxin A inhibits proliferation and induces apoptosis of t (8;21) leukemia cells through mitochondrial signaling pathways and regulates AML-ETO mRNA expression. AB - Progress in the last decade has improved the treatment of acute myeloid leukemia (AML); however, the treatment of AML is also demanding and better treatments are required. The present study aimed to examine the antiproliferative and proapoptotic effects of macrocalyxin A (MA), a novel deterpenid compound, on AML cells. It was identified that MA significantly inhibits kasumi-1 cell proliferation in a time- and dose-dependent manner. Furthermore, low concentrations of MA were able to induce kasumi-1 cell differentiation; however, high concentrations of MA induced kasumi-1 cell apoptosis. MA was also able to increase the expression of mitochondrial membrane protein in a dose-dependent manner while the ?Psim was reduced. Additionally, Bad expression in kasumi-1 cells was increased when treated with MA, indicating that the intrinsic apoptotic pathway may be important in MA-induced kasumi-1 cell apoptosis, where the mitochondrial permeability transition pore is opened and the DeltaPsim is reduced. In addition, it was demonstrated that AML-ETO mRNA may also be important in MA-induced apoptosis. PMID- 26016619 TI - Detecting isocitrate dehydrogenase gene mutations in oligodendroglial tumors using diffusion tensor imaging metrics and their correlations with proliferation and microvascular density. AB - PURPOSE: Isocitrate dehydrogenase (IDH) mutations are frequently present in oligodendroglial tumors (OTs) and have prognostic value. We assessed whether diffusion tensor imaging (DTI) metrics could aid the noninvasive detection of IDH mutations and their correlations with tumor proliferation and microvascular density (MVD) in OTs. MATERIALS AND METHODS: Ninety patients with OTs who underwent conventional magnetic resonance imaging (MRI) and DTI were retrospectively reviewed (3T). IDH mutations were determined by immunohistochemical staining or direct sequencing. MVD and cell proliferation were evaluated by immunohistochemical staining with anti-CD31 and Ki-67, respectively. The Mann-Whitney U-test was applied to each of the imaging parameters. Spearman correlation analysis and receiver operating characteristic curve analysis were performed. RESULTS: The maximal fractional anisotropy (FA), ratio of maximal FA (rmFA), minimal ADC, and ratio of minimal (rmADC) values were demonstrated to be significantly different between the OTs with IDH1/2 mutations and those without mutations (P < 0.05). The areas under the curve (AUCs) for the maximal FA, rmFA, minimal ADC, and rmADC were 0.79, 0.82, 0.77, and 0.80, respectively. A combination rmFA and rmADC for the diagnosis of IDH1/2 mutations led to sensitivity, specificity, and AUC of 91.5%, 76.5%, and 0.86, respectively. The Ki-67 and MVD levels in the IDH-mutated samples were lower than those in the IDH wildtype cases (P < 0.05). CONCLUSION: DTI metrics may provide a noninvasive method for assessing the IDH statuses of OTs. Significantly higher minimal ADC and lower maximal FA in OTs with IDH mutations may suggest that IDH mutations lead to proliferation inhibition and an angiogenesis decrease. PMID- 26016620 TI - Synthesis, Crystal Structure, and Photoelectric Properties of a New Layered Bismuth Oxysulfide. AB - [Bi2O2]-containing tetragonal compounds have received enormous attention due to unique functions including ferroelectricity, photocatalysis, and superconductivity. Here, a new layered compound Bi9O7.5S6 was synthesized via a facile hydrothermal route. The compound, belonging to a new structure type crystallizes in a rhombohedral system with space group R3m (a = 4.0685(1) A, c = 31.029(5) A, V = 444.8(1) A(3), Z = 1). The overall crystal structure consists of alternatively packed unique [Bi2O2] and [BiS2] layers along [001] which are combined with each other by van der Waals interaction. The phase purity of the product is confirmed by powder X-ray diffraction. XPS analyses indicate +3 for Bi and -2 for S atoms. The temperature dependence of resistivity rho(T) indicates that the semiconducting sample follows the mechanisms of variable range hopping (VRH) and adiabatic small polaron hopping (SPH). The direct-transition band gap, Eg = 1.27 eV derived from optical absorption spectrum, falls in the optimal region of solar absorber materials. Accordingly, the photoelectric measurement demonstrates the potential for applications for photovoltaic devices. PMID- 26016621 TI - Primates' Socio-Cognitive Abilities: What Kind of Comparisons Makes Sense? AB - Referential gestures are of pivotal importance to the human species. We effortlessly make use of each others' referential gestures to attend to the same things, and our ability to use these gestures show themselves from very early in life. Almost 20 years ago, James Anderson and colleagues presented an experimental paradigm with which to examine the use of referential gestures in non-human primates: the object-choice task. Since then, numerous object-choice studies have been made, not only with primates but also with a range of other animal taxa. Surprisingly, several non-primate species appear to perform better in the object-choice task than primates do. Different hypotheses have been offered to explain the results. Some of these have employed generalizations about primates or subsets of primate taxa that do not take into account the unparalleled diversity that exists between species within the primate order on parameters relevant to the requirements of the object-choice task, such as social structure, feeding ecology, and general morphology. To examine whether these broad primate generalizations offer a fruitful organizing framework within which to interpret the results, a review was made of all published primate results on the use of gazing and glancing cues with species ordered along the primate phylogenetic tree. It was concluded that differences between species may be larger than differences between ancestry taxa, and it is suggested that we need to start rethinking why we are testing animals on experimental paradigms that do not take into account what are the challenges of their natural habitat. PMID- 26016622 TI - Altered long- and short-range functional connectivity in the patients with end stage renal disease: a resting-state functional MRI study. AB - To investigate alterations of functional connectivity density (FCD) in patients with end-stage renal disease (ESRD) by using resting-state functional magnetic resonance imaging (rs-fMRI). Medical research ethics committee approval from Jinling hospital and written informed consent from each subject were obtained. Forty six patients with ESRD, consisting of 21 patients minimal nephrotic encephalopathy (MNE) and 25 non-nephro-encephalopathy (non-NE), as well as 23 healthy controls underwent rs-fMRI. Neuropsychological tests were performed in all subjects, while laboratory tests were performed in ESRD patients. A voxel wise whole brain functional connectivity analysis was used to generate long- and short-range FCD maps. The maps among MNE, non-NE, and healthy controls groups were compared by using one-way analysis of variance tests. A multiple regression analysis was performed to evaluate the correlations between FCD and the variables of neuropsychological or laboratory tests. Compared with healthy controls, non-NE showed decreased long-range FCD mainly in parietal lobe. Moreover, MNE showed further decreased long-range FCD in bilateral middle prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and right superior frontal gyrus. Meanwhile, non NE showed decreased short-range FCD mainly in frontal cortex, and further reduction in bilateral ACC and right superior parietal gyrus in MNE. In addition, patients with ESRD mainly exhibited increased long-range FCD in left temporal lobe and caudate; and increased short-range FCD in bilateral orbitofrontal cortex and temporal gyri (P < 0.05, AlphaSim corrected). The number connection test type A score, serum creatinine, urea, and dialysis duration showed negative correlation with FCD in some brain regions, while the digital symbol test scores positively correlated with short-range FCD in left inferior parietal lobule (all P < 0.05, AlphaSim corrected). The prominent long- and short-range FCD reduction was found mainly in default mode network (DMN) and bilateral frontal and parietal lobes, while the progressively decreased long- and short-range FCD in ACC/MPFC and the long-range FCD in left superior frontal gyrus from non-NE to MNE was associated with cognition dysfunction in ESRD patients. PMID- 26016623 TI - Mental retardation in mucopolysaccharidoses correlates with high molecular weight urinary heparan sulphate derived glucosamine. AB - Mucopolysaccharidoses (MPS) are characterized by mental retardation constantly present in the severe forms of Hurler (MPS I), Hunter (MPS II) and Sanfilippo (MPS III) diseases. On the contrary, mental retardation is absent in Morquio (MPS IV) and Maroteaux-Lamy (MPS VI) diseases and absent or only minimal in the attenuated forms of MPS I, II and III. Considering that MPS patients affected by mental disease accumulate heparan sulfate (HS) due to specific enzymatic defects, we hypothesized a possible correlation between urinary HS-derived glucosamine (GlcN) accumulated in tissues and excreted in biological fluids and mental retardation. 83 healthy subjects were found to excrete HS in the form of fragments due to the activity of catabolic enzymes that are absent or impaired in MPS patients. On the contrary, urinary HS in 44 patients was observed to be composed of high molecular weight polymer and fragments of various lengths depending on MPS types. On this basis we correlated mental retardation with GlcN belonging to high and low molecular weight HS. We demonstrate a positive relationship between the accumulation of high molecular weight HS and mental retardation in MPS severe compared to attenuated forms. This is also supported by the consideration that accumulation of other GAGs different from HS, as in MPS IV and MPS VI, and low molecular weight HS fragments do not impact on central nervous system disease. PMID- 26016624 TI - Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests. AB - Minimal hepatic encephalopathy (MHE) is a frequent complication to liver cirrhosis that causes poor quality of life, a great burden to caregivers, and can be treated. For diagnosis and grading the international guidelines recommend the use of psychometric tests of different modalities (computer based vs. paper and pencil). To compare results of the Continuous Reaction time (CRT) and the Portosystemic Encephalopathy (PSE) tests in a large unselected cohort of cirrhosis patients without clinically detectable brain impairment and to clinically characterize the patients according to their test results. The CRT method is a 10-minute computerized test of a patient's motor reaction time stability (CRTindex) to 150 auditory stimuli. The PSE test is a 20-minute paper pencil test evaluating psychomotor speed. Both tests were performed at the same occasion in 129 patients. Both tests were normal in only 36% (n = 46) of the patients and this group had the best quality of life, a normal CRP, a low risk of subsequent overt HE, and a low short term mortality. Either the CRT or the PSE test was abnormal in a total of 64% of the patients (n = 83), the CRT in 53% (n = 69) and the PSE in 34% (n = 44). All these patients had a poorer quality of life, low-grade CRP elevation, moderate risk for subsequent overt HE, and a higher than 20% short term mortality. Both tests were abnormal in 23% (n = 30) of the patients and this group had more advanced cirrhosis and a 40 % short-term mortality. One of the tests was abnormal in the majority of the patients but concordant in only 60%. Most cirrhosis patients seem to have impairments of different cognitive domains and more domains with advancing disease. Two abnormal tests identified patients with an increased risk of overt HE and death. PMID- 26016625 TI - Predictors of Completion of Executive-Functioning Tasks in a Memory Clinic Dementia Sample. AB - It has been observed that persons subsequently diagnosed with dementia often have difficulty completing commonly administered tests of executive function (EF). Interpretation of incompletion is problematic given the composite nature of EF tasks and the multiple impairments often demonstrated by persons with dementia. The goal of the present study was to determine the rate of failure to complete the Color-Word Stroop and Part B of the Trail-Making Test (TMT-B) in a clinical sample of persons with dementia and to explore neuropsychological predictors of incompletion. This study analyzed neuropsychological test data from 213 persons diagnosed with dementia at an interdisciplinary memory clinic. Index scores from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were examined as potential predictors of Color-Word Stroop and TMT-B completion in hierarchical logistic regression models. Rates of incompletion were high for both tests (60.6% for the Color-Word Stroop and 67.6% for the TMT-B). RBANS Language Index scores on the Color-Word Stroop predicted completion, while scores on the RBANS Visuospatial, Attention, and Immediate Memory indexes predicted TMT B completion. The majority of the dementia sample was unable to complete the Color-Word Stroop and TMT-B executive tasks. Non-EF impairments may be implicated in completion of these tasks. PMID- 26016626 TI - Extensive in vitro gastrointestinal digestion markedly reduces the immune toxicity of Triticum monococcum wheat: implication for celiac disease. AB - SCOPE: The ancient diploid Triticum monococcum is of special interest as a candidate low-toxic wheat species for celiac disease patients. Here, we investigated how an in vitro gastro-intestinal digestion, affected the immune toxic properties of gliadin from diploid compared to hexaploid wheat. METHODS AND RESULTS: Gliadins from Triticum monococcum, and Triticum aestivum cultivars were digested using either a partial proteolysis with pepsin-chymotrypsin, or an extensive degradation that used gastrointestinal enzymes including the brush border membrane enzymes. The immune stimulatory properties of the digested samples were investigated on T-cell lines and jejunal biopsies from celiac disease patients. The T-cell response profile to the Triticum monococcum gliadin was comparable to that obtained with Triticum aestivum gliadin after the partial pepsin-chymotrypsin digestion. In contrast, the extensive gastrointestinal hydrolysis drastically reduced the immune stimulatory properties of Triticum monococcum gliadin. MS-based analysis showed that several Triticum monococcum peptides, including known T-cell epitopes, were degraded during the gastrointestinal treatment, whereas many of Triticum aestivum gliadin survived the gastrointestinal digestion. CONCLUSION: The pattern of Triticum monococcum gliadin proteins is sufficiently different from those of common hexaploid wheat to determine a lower toxicity in celiac disease patients following in vitro simulation of human digestion. PMID- 26016628 TI - Standard of Care for Small Renal Masses in the 21st Century. PMID- 26016627 TI - Inhibition of microglial activation contributes to propofol-induced protection against post-cardiac arrest brain injury in rats. AB - It has been suggested that propofol can modulate microglial activity and hence may have potential roles against neuroinflammation following brain ischemic insult. However, whether and how propofol can inhibit post-cardiac arrest brain injury via inhibition of microglia activation remains unclear. A rat model of asphyxia cardiac arrest (CA) was created followed by cardiopulmonary resuscitation. CA induced marked microglial activation in the hippocampal CA1 region, revealed by increased OX42 and P2 class of purinoceptor 7 (P2X7R) expression, as well as p38 MAPK phosphorylation. Morris water maze showed that learning and memory deficits following CA could be inhibited or alleviated by pre treatment with the microglial inhibitor minocycline or propofol. Microglial activation was significantly suppressed likely via the P2X7R/p-p38 pathway by propofol. Moreover, hippocampal neuronal injuries after CA were remarkably attenuated by propofol. In vitro experiment showed that propofol pre-treatment inhibited ATP-induced microglial activation and release of tumor necrosis factor alpha and interleukin-1beta. In addition, propofol protected neurons from injury when co-culturing with ATP-treated microglia. Our data suggest that propofol pre treatment inhibits CA-induced microglial activation and neuronal injury in the hippocampus and ultimately improves cognitive function. We proposed a possible mechanism of propofol-mediated brain protection after cardiac arrest (CA). CA induces P2X7R upregulation and p38 phosphorylation in microglia, which induces release of TNF-alpha and IL-1beta and consequent neuronal injury. Propofol could inhibit microglial activation and alleviate neuronal damage. Our results suggest propofol-induced anti-inflammatory treatment as a plausible strategy for therapeutic intervention in post-CA brain injury. PMID- 26016629 TI - Flying-fox roost disturbance and Hendra virus spillover risk. AB - Bats of the genus Pteropus (flying-foxes) are the natural host of Hendra virus (HeV) which periodically causes fatal disease in horses and humans in Australia. The increased urban presence of flying-foxes often provokes negative community sentiments because of reduced social amenity and concerns of HeV exposure risk, and has resulted in calls for the dispersal of urban flying-fox roosts. However, it has been hypothesised that disturbance of urban roosts may result in a stress mediated increase in HeV infection in flying-foxes, and an increased spillover risk. We sought to examine the impact of roost modification and dispersal on HeV infection dynamics and cortisol concentration dynamics in flying-foxes. The data were analysed in generalised linear mixed models using restricted maximum likelihood (REML). The difference in mean HeV prevalence in samples collected before (4.9%), during (4.7%) and after (3.4%) roost disturbance was small and non significant (P = 0.440). Similarly, the difference in mean urine specific gravity corrected urinary cortisol concentrations was small and non-significant (before = 22.71 ng/mL, during = 27.17, after = 18.39) (P= 0.550). We did find an underlying association between cortisol concentration and season, and cortisol concentration and region, suggesting that other (plausibly biological or environmental) variables play a role in cortisol concentration dynamics. The effect of roost disturbance on cortisol concentration approached statistical significance for region, suggesting that the relationship is not fixed, and plausibly reflecting the nature and timing of disturbance. We also found a small positive statistical association between HeV excretion status and urinary cortisol concentration. Finally, we found that the level of flying-fox distress associated with roost disturbance reflected the nature and timing of the activity, highlighting the need for a 'best practice' approach to dispersal or roost modification activities. The findings usefully inform public discussion and policy development in relation to Hendra virus and flying-fox management. PMID- 26016630 TI - The Effect of Pre-Condition Cerebella Fastigial Nucleus Electrical Stimulation within and beyond the Time Window of Thrombolytic on Ischemic Stroke in the Rats. AB - OBJECTIVE: To investigate the effect of neurogenic neuroprotection conferred by cerebellar fastigial nucleus stimulation (FNS) and the role of PPARgamma-mediated inflammation in a rat model of cerebral ischemia reperfusion. METHODS: After a continuous 1 hour fastigial nucleus electric stimulation, the male Sprague Dawley (SD) rats were given middle cerebral artery occlusion (MCAO) for 1, 3, 6, 9, 12 and 15 hours undergoing reperfusion with intravenous recombinant tissue plasminogen activator (rt-PA), while the control group received without FNS. After 72 h of reperfusion, the neurological deficits, infarct volume and brain edema were evaluated. The brain tissue in ischemic penumbra was determined the myeloperoxidase (MPO) activity by a spectrophotometer and expression of PPARgamma was measured by Rt-PCR and Western blotting. RESULTS: Our findings showed that FNS group had significantly reduced infarct volume and brain edema, and improved neurological deficits compared with the control group, especially in 6 h and 9 h reperfusion subgroups (p<0.05). The expression levels of PPARgamma increased gradually and the peak may be before and after 9 h reperfusion, the 3 h, 6 h, 9 h, 12 h and 15 h reperfusion subgroups were higher than each control group (p<0.05). The MPO activity of 6 h, 12 h and 15 h reperfusion subgroups were higher than each control group (p<0.05). CONCLUSIONS: The neuroprotective effects of FNS have been shown to prolong the therapeutic window in cerebral ischemia/reperfusion, which might be related to the PPARgamma mediated inflammation in penumbral region. PMID- 26016631 TI - Aflibercept for the treatment of neovascular glaucoma. AB - BACKGROUND: Neovascular glaucoma (NVG) is a potentially blinding disease associated with ocular ischaemia. Use of an anti-vascular endothelial growth factor agent has been reported as a treatment option for NVG. The purpose of this study was to investigate initial results regarding the treatment of NVG with intravitreal aflibercept. DESIGN: This study employed a prospective, interventional case series study design. PARTICIPANTS: Patients with newly diagnosed stage 1 or 2 neovascular glaucoma were eligible to participate in this study. METHODS: Four patients with newly diagnosed stage 1 or 2 NVG were treated with intravitreal aflibercept at the time of diagnosis, with planned repeat injection at 4 weeks, 8 weeks and then every 8 weeks thereafter up until 52 weeks after study initiation. MAIN OUTCOME MEASURES: Primary outcomes were regression of neovascularization of the iris and angle (NVI, NVA). Secondary outcome measurements included visual acuity and intraocular pressure (IOP). RESULTS: Intravitreal aflibercept resulted in rapid regression of NVI and NVA. IOP was stable or reduced in all patients at the 52-week study visit. CONCLUSIONS: These results suggest that intravitreal aflibercept may be an effective treatment for stage 1 and 2 NVG, resulting in rapid and sustained regression of NVI and NVA as well as control of IOP. Further research is needed to determine the full duration of effect and the optimal dose and timing of administration. PMID- 26016632 TI - Riding the waves: A functional-cognitive perspective on the relations among behaviour therapy, cognitive behaviour therapy and acceptance and commitment therapy. AB - Different types of therapy explain psychopathology and the effects of psychotherapy differently. Different explanations are, however, not necessarily mutually exclusive. Based on the idea that functional and cognitive explanations are situated at different levels, we argue that functional therapies such as traditional Behaviour Therapy (BT) and Acceptance and Commitment Therapy (ACT) are not necessarily incompatible with Cognitive Behaviour Therapy (CBT). Whether a functional and a cognitive therapy actually align depends on whether they highlight the same type of environmental causes. This functional-cognitive perspective reveals various differences and communalities among BT, CBT and ACT. PMID- 26016633 TI - Dressed to regress, but not for success. PMID- 26016634 TI - [Retinal regeneration with iPS cells - Clinical trials for retinal degenerative disorders]. AB - Potential for re-programming cells has become widely accepted as a tool for obtaining transplantation materials. There has been great interest in cell-based therapies, including retinal transplants, because there is a reduced risk of immune rejection. Stem cells have the capacity for self-renewal plus the capacity to generate several differentiated cells. They are derived from many sources including human adult-derived induced pluripotent stem (iPS) cells and have found early application in the context of ocular disease. In results, our established iPS-retinal pigment epithelial (RPE) cells are high-quality RPE cells. iPS cells derived RPE cells clearly showed polygonal morphology (mostly hexagonal) and contained melanin. Moreover, RPE cells derived from iPS cells had many characteristics of mature RPE cells in vivo, but no characteristics of pluripotent stem cells. Recently, we transplanted RPE cell sheets to treat a patient with wet age-related macular degeneration (September, 2014). In addition, we are now conducting experiments to determine whether allogeneic T cells can recognize iPS-RPE cells from HLA-A, B, DRB1 locus homozygote donors. iPS bank might be useful as allografts in retinal disorders, if the recipient T cells cannot respond to allogeneic RPE cells because of match to some of main HLA antigens. PMID- 26016635 TI - [Mesenchymal stem cells for the treatment and repair of inflammatory arthritis]. AB - Mesenchymal stem cells (MSCs) possess multipotent capacity and exhibit immunoregulatory properties. In particular, MSCs can be easily isolated from various organs, can differentiate into various types of cells and generate regulatory T cells. Using human MSC derived from bone marrow and adipose tissue, we have clarified the following novel findings in vitro. 1) MSCs differentiated into osteoblasts or osteocytes under osteoblast-conditioned medium including the inflammatory stimuli such as IL-1. 2) The combination of IL-6 and soluble IL-6 receptor induced differentiation of MSCs to chondrocyte, whereas IL-17 inhibited their differentiation. 3) MSCs highly produced osteoprotegerin and inhibited osteoclastogenesis. Furthermore, we developed a local delivery system of MSCs by using nano-fiber scaffold. MSCs seeded on nano-fiber scaffold suppressed arthritis and bone destruction due to inhibition of systemic inflammatory reaction and immune response by suppressing T cell proliferation and reducing anti-type II collagen antibody production in vivo. Thus, our data may serve as a new strategy for MSC-based therapy in inflammatory diseases and an alternative delivery method for the treatment of destruction of bone and joints. PMID- 26016636 TI - [Fully functional salivary gland regeneration as a next-generation regenerative therapy]. AB - Salivary gland hypofunction, or xerostomia (dry mouth syndrome), induces various clinical problems, such as dental decay, bacterial infection, and swallowing dysfunction. Xerostomia caused by autoimmune disease and aging affects an increasing number of patients. The development of novel functional treatments for xerostomia is needed, as currently available therapies are only palliative in nature. Tissue stem cell transplantation and gene therapy are currently being investigated as potential approaches to the restoration of salivary gland function. The final goal of regenerative therapy is fully functional regenerative organ replacement for dysfunctional organs. Previously, we developed a technology to reconstitute the organ germ (Organ Germ Method) using epithelial and mesenchymal stem cells. We have recently reported the regeneration of fully functional organs, such as teeth, hair and lacrimal glands, can be achieved by the transplantation of bioengineered organ germs. In this review, we describe the regeneration of the salivary gland as part of a feasibility study of a next generation regenerative therapy. PMID- 26016637 TI - [Pluripotent stem cells as a source for T cell research and clinical application]. AB - Recently, promising clinical outcomes of cancer immunotherapy including administration of an anti PD-1 antibody targeting for T cell reactivation has gained particular attention worldwide. Adoptive cell therapy with tumor infiltrating lymphocytes and TCR/CAR (Chimeric Antigen Receptor) transgenic T cells are also under development. Although it has become clearer that the efficacy of adoptive cell therapy correlate with the quality of infusing T cells, antigen specific T cells in patients with chronic infection and cancer have been exhausted. We have succeeded to generate rejuvenated antigen specific T cells by reprogramming to pluripotency and differentiation. In this article, we introduce fundamentals of this technology and describe its potential for adoptive cell therapy in the future. PMID- 26016638 TI - [Risk of serious infection in patients with rheumatoid arthritis]. AB - Studies in the pre-biologics era described elevated risk of infection in patients with rheumatoid arthritis (RA). Recently biologics have been popularized and glucocorticoids used still now in RA patients, which can lead to various infections. Incidence rates of infection in RA patients are reported to be higher than that in the general population. Several factors such as higher age, comorbidities including chronic lung disease and diabetes mellitus, and glucocorticoids are known to increase risk of serious infection. Significant correlation between methotrexate and infection is not established. Whether biologics, especially inhibitors of tumor necrosis factor alpha, increase the risk for infection is still controversial even with randomized control studies and the meta-analyses; however, time-dependent decrease of the risk was revealed. Our three-year analysis of RA patients for infections requiring hospitalization included 5441 patient-years (PY) in total and detected an incidence rate of 3.4/100 PY, of which the risk factors were higher age (70 years of age or older), male sex, progressed stage of arthritis, functional disorders, and use of glucocorticoids or biologics. Such risk factors should be kept in mind for therapeutic decisions in individual patients with RA. PMID- 26016639 TI - [13-year history of scleroderma complicated by renal crisis and thrombotic microangiopathy treated with plasma exchange: A case report]. AB - A 77-year-old man with a 13-year history of systemic sclerosis (SSc) was admitted to our hospital with fever, appetite loss, and disorientation. The patient was well 2 days prior to the admission and had been taking a low dose of a steroid and vasodilators over the previous 10 years. In regular clinic visits, his blood pressure was normotensive and serum creatinine (Cr) was within the normal range. On admission, hypertension (blood pressure 214/105 mmHg), proteinuria, and hypercreatinemia (3.6 mg/dL) led to the diagnosis of sclerotic renal crisis (SRC). Thrombocytopenia (5.4 * 10(4)/MUL), erythrocyte fragmentation, and elevated lactate dehydrogenase were suggestive of thrombotic microangiopathy (TMA). The immediate initiation of angiotensin-converting enzyme inhibitor therapy and plasma exchange (PE) rapidly improved the disorientation and thrombocytopenia. It is notable that SRC might occur in patients with a 13-year history of SSc. PE should be considered as a treatment option for SRC complicated by TMA. PMID- 26016640 TI - [A case of HELLP syndrome at 34w-pregnancy with systemic lupus erythematosus and antiphospholipid antibody syndrome;Importance of measurement of VW factor]. AB - SUMMARY: A 39-year-old woman was diagnosed with Systemic lupus erthymatosus (SLE) in 1993, and initially received 30 mg of prednisolone (PSL) daily as treatment. In 2012, the patient was diagnosed with pregnancy-induced hypertension (PIH) complecated with proteinurea, hypertension and pretibial edema at 24 weeks of gestation. At onset, protein urea was 1.6 g/day and she was given bed rest in the hospital with a protein-restricted and low salt diet, which led to a decrease in protein urea to approximately 1 g/day. At 34 weeks of gestation epigastric pain developed, and laboratory examinations showed liver dysfunction and low platelets. We made a diagnosis of hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome and performed an emergency cesarean procedure. Thereafter blood pressure was elevated, protein urea was 3.2 g/daily, anti-ds-DNA antibody level was elevated and serum C3/C4/CH50 was reduced, thus we gave. plasma exchange therapy, along with immunoadsorption and steroid pulse therapy (methyl prednisolone 500 mg/daily for 3 days), as well as PSL at 30 mg/day. Overtime clinical symptoms and laboratory data gradually improved. CONCLUSION: Some reports suggest that SLE during pregnancy is a risk factor for hypertension, nephritis, SLE relapse and HELLP syndrome. In the patient, ADAMTS13 activity did not decrease, while there was an increase in VW factor level. We assessed this case was as atypical thrombotic microangiopathy. And herein report HELLP syndrome during pregnancy associated with SLE in our patient. PMID- 26016641 TI - Pathway-focused PCR array profiling of enriched populations of laser capture microdissected hippocampal cells after traumatic brain injury. AB - Cognitive deficits in survivors of traumatic brain injury (TBI) are associated with irreversible neurodegeneration in brain regions such as the hippocampus. Comparative gene expression analysis of dying and surviving neurons could provide insight into potential therapeutic targets. We used two pathway-specific PCR arrays (RT2 Profiler Apoptosis and Neurotrophins & Receptors PCR arrays) to identify and validate TBI-induced gene expression in dying (Fluoro-Jade-positive) or surviving (Fluoro-Jade-negative) pyramidal neurons obtained by laser capture microdissection (LCM). In the Apoptosis PCR array, dying neurons showed significant increases in expression of genes associated with cell death, inflammation, and endoplasmic reticulum (ER) stress compared with adjacent, surviving neurons. Pro-survival genes with pleiotropic functions were also significantly increased in dying neurons compared to surviving neurons, suggesting that even irreversibly injured neurons are able to mount a protective response. In the Neurotrophins & Receptors PCR array, which consists of genes that are normally expected to be expressed in both groups of hippocampal neurons, only a few genes were expressed at significantly different levels between dying and surviving neurons. Immunohistochemical analysis of selected, differentially expressed proteins supported the gene expression data. This is the first demonstration of pathway-focused PCR array profiling of identified populations of dying and surviving neurons in the brain after TBI. Combining precise laser microdissection of identifiable cells with pathway-focused PCR array analysis is a practical, low-cost alternative to microarrays that provided insight into neuroprotective signals that could be therapeutically targeted to ameliorate TBI induced neurodegeneration. PMID- 26016643 TI - An electrochemical investigation of rutile TiO2 microspheres anchored by nanoneedle clusters for sodium storage. AB - Rutile TiO2 microspheres anchored by nanoneedle clusters, as a new class of anode materials, are successfully employed for sodium-ion batteries and manifested good energy storage behavior. The initial discharge capacity of 308.8 mA h g(-1) is obtained and a high reversible capacity of 121.8 mA h g(-1) is maintained after 200 cycles at a current density of 0.1 C, exhibiting a high capacity retention of 83.1%. All these merits are not only ascribed to the rutile TiO2 crystal structure, but also thanks to the porous morphology of hundreds of nanoneedle clusters in favor of sodium diffusion and accommodating the strain during the sodiation and desodiation processes. Therefore, it is highly expected that rutile TiO2, as a feasible electrochemical sodium storage material, can be a new promising candidate as an anode for sodium-ion batteries. PMID- 26016642 TI - Associations between FTO genotype and total energy and macronutrient intake in adults: a systematic review and meta-analysis. AB - Risk variants of fat mass and obesity-associated (FTO) gene have been associated with increased obesity. However, the evidence for associations between FTO genotype and macronutrient intake has not been reviewed systematically. Our aim was to evaluate the potential associations between FTO genotype and intakes of total energy, fat, carbohydrate and protein. We undertook a systematic literature search in OVID MEDLINE, Scopus, EMBASE and Cochrane of associations between macronutrient intake and FTO genotype in adults. Beta coefficients and confidence intervals (CIs) were used for per allele comparisons. Random-effect models assessed the pooled effect sizes. We identified 56 eligible studies reporting on 213,173 adults. For each copy of the FTO risk allele, individuals reported 6.46 kcal day(-1) (95% CI: 10.76, 2.16) lower total energy intake (P = 0.003). Total fat (P = 0.028) and protein (P = 0.006), but not carbohydrate intakes, were higher in those carrying the FTO risk allele. After adjustment for body weight, total energy intakes remained significantly lower in individuals with the FTO risk genotype (P = 0.028). The FTO risk allele is associated with a lower reported total energy intake and with altered patterns of macronutrient intake. Although significant, these differences are small and further research is needed to determine whether the associations are independent of dietary misreporting. PMID- 26016644 TI - Objective voice and speech analysis of persons with chronic hoarseness by prosodic analysis of speech samples. AB - Automatic voice assessment is often performed using sustained vowels. In contrast, speech analysis of read-out texts can be applied to voice and speech assessment. Automatic speech recognition and prosodic analysis were used to find regression formulae between automatic and perceptual assessment of four voice and four speech criteria. The regression was trained with 21 men and 62 women (average age 49.2 years) and tested with another set of 24 men and 49 women (48.3 years), all suffering from chronic hoarseness. They read the text 'Der Nordwind und die Sonne' ('The North Wind and the Sun'). Five voice and speech therapists evaluated the data on 5-point Likert scales. Ten prosodic and recognition accuracy measures (features) were identified which describe all the examined criteria. Inter-rater correlation within the expert group was between r = 0.63 for the criterion 'match of breath and sense units' and r = 0.87 for the overall voice quality. Human-machine correlation was between r = 0.40 for the match of breath and sense units and r = 0.82 for intelligibility. The perceptual ratings of different criteria were highly correlated with each other. Likewise, the feature sets modeling the criteria were very similar. The automatic method is suitable for assessing chronic hoarseness in general and for subgroups of functional and organic dysphonia. In its current version, it is almost as reliable as a randomly picked rater from a group of voice and speech therapists. PMID- 26016645 TI - Curative effect of sesame oil in a rat model of chronic kidney disease. AB - AIM: Chronic kidney disease causes a progressive and irreversible loss of renal function. We investigated the curative effect of sesame oil, a natural, nutrient rich, potent antioxidant, in a rat model of chronic kidney disease. METHODS: Chronic kidney disease was induced by subcutaneously injecting uni-nephrectomized rats with deoxycorticosterone acetate (DOCA) and 1% NaCl [DOCA/salt] in drinking water. Four weeks later, the rats were gavaged with sesame oil (0.5 or 1 mL/kg per day) for 7 days. Renal injury, histopathological changes, hydroxyl radical, peroxynitrite, lipid peroxidation, Nrf2, osteopontin expression, and collagen were assessed 24 h after the last dose of sesame oil. RESULTS: Blood urea nitrogen, creatinine, urine volume, and albuminuria were significantly higher in the DOCA/salt treated rats than in control rats. Sesame oil significantly decreased these four tested parameters in DOCA/salt treated rats. In addition, creatinine clearance rate and nuclear Nrf2 expression were significantly decreased in the DOCA/salt treated rats compared to control rats. Sesame oil significantly decreased hydroxyl radical, peroxynitrite level, lipid peroxidation, osteopontin, and renal collagen deposition, but increased creatinine clearance rate and nuclear Nrf2 expression in DOCA/salt treated rats. CONCLUSION: We conclude that supplementation of sesame oil mitigates DOCA/salt induced chronic kidney disease in rats by activating Nrf2 and attenuating osteopontin expression and inhibiting renal fibrosis in rats. PMID- 26016646 TI - Bacterial physiology. Linking cell differentiation and growth. PMID- 26016648 TI - Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines. AB - Monoamine systems are involved in the pathology and therapeutic mechanism of depression. The pineal gland contains large amounts of serotonin as a precursor for melatonin, and its activity is controlled by noradrenergic sympathetic nerves. Pineal diurnal activity and its release of melatonin are relevant to aberrant states observed in depression. We investigated the effects on pineal monoamines of serotonin-noradrenaline reuptake inhibitors, which are widely used antidepressants. Four days of milnacipran treatment led to an increase in noradrenaline and serotonin levels, whereas 4 days of venlafaxine treatment reduced 5-hydroxyindoleacetic acid levels; both agents induced an increase in dopamine levels. Our data suggest that milnacipran increases levels of the precursor for melatonin synthesis by facilitating the noradrenergic regulation of pineal activity and that venlafaxine inhibits serotonin reuptake into noradrenergic terminals on the pineal gland. PMID- 26016647 TI - Rating scales measuring the severity of psychotic depression. AB - OBJECTIVE: Unipolar psychotic depression (PD) is a severe and debilitating syndrome, which requires intensive monitoring. The objective of this study was to provide an overview of the rating scales used to assess illness severity in PD. METHOD: Selective review of publications reporting results on non-self-rated, symptom-based rating scales utilized to measure symptom severity in PD. The clinical and psychometric validity of the identified rating scales was reviewed. RESULTS: A total of 14 rating scales meeting the predefined criteria were included in the review. These scales grouped into the following categories: (i) rating scales predominantly covering depressive symptoms, (ii) rating scales predominantly covering psychotic symptoms, (iii) rating scales covering delusions, and (iv) rating scales covering PD. For the vast majority of the scales, the clinical and psychometric validity had not been tested empirically. The only exception from this general tendency was the 11-item Psychotic Depression Assessment Scale (PDAS), which was developed specifically to assess the severity of PD. CONCLUSION: In PD, the PDAS represents the only empirically derived rating scale for the measurement of overall severity of illness. The PDAS should be considered in future studies of PD and in clinical practice. PMID- 26016649 TI - The evolution of collagen fiber orientation in engineered cardiovascular tissues visualized by diffusion tensor imaging. AB - The collagen architecture is the major determinant of the function and mechanical behavior of cardiovascular tissues. In order to engineer a functional and load bearing cardiovascular tissue with a structure that mimics the native tissue to meet in vivo mechanical demands, a complete understanding of the collagen orientation mechanism is required. Several methods have been used to visualize collagen architecture in tissue-engineered (TE) constructs, but they either have a limited imaging depth or have a complicated set up. In this study, Diffusion Tensor Imaging (DTI) is explored as a fast and reliable method to visualize collagen arrangement, and Confocal Laser Scanning Microscopy (CLSM) was used as a validation technique. Uniaxially constrained TE strips were cultured for 2 days, 10 days, 3 and 6 weeks to investigate the evolution of the collagen orientation with time. Moreover, a comparison of the collagen orientation in high and low aspect ratio (length/width) TE constructs was made with both methods. Both methods showed similar fiber orientation in TE constructs. Collagen fibers in the high aspect ratio samples were mostly aligned in the constrained direction, while the collagen fibers in low aspect ratio strips were mainly oriented in the oblique direction. The orientation changed to the oblique direction by extending culture time and could also be visualized. DTI captured the collagen orientation differences between low and high aspect ratio samples and with time. Therefore, it can be used as a fast, non-destructive and reliable tool to study the evolution of the collagen orientation in TE constructs. PMID- 26016650 TI - Effects of an Individual Development Account Program on Retirement Saving: Follow up Evidence From a Randomized Experiment. AB - We examine the 10-year follow-up effects on retirement saving of an individual development account (IDA) program using data from a randomized experiment that ran from 1998 to 2003 in Tulsa, Oklahoma. The IDA program included financial education, encouragement to save, and matching funds for several qualified uses of the saving, including contributions to retirement accounts. The results indicate that as of 2009, 6 years after the program ended, the IDA program had no impact on the propensity to hold a retirement account, the account balance, or the sufficiency of retirement balances to meet retirement expenses. PMID- 26016651 TI - Principles of transverse flow fractionation of microparticles in superhydrophobic channels. AB - We propose a concept of fractionation of micron-sized particles in a microfluidic device with a bottom wall decorated by superhydrophobic stripes. The stripes are oriented at an angle alpha to the direction of a driving force, G, which generally includes an applied pressure gradient and gravity. Separation relies on the initial sedimentation of particles under gravity in the main forward flow, and their subsequent lateral deflection near a superhydrophobic wall due to generation of a secondary flow transverse to G. We provide some theoretical arguments allowing us to quantify the transverse displacement of particles in the microfluidic channel, and confirm the validity of theoretical predictions in test experiments with monodisperse fractions of microparticles. Our results can guide the design of superhydrophobic microfluidic devices for efficient sorting of microparticles with a relatively small difference in size and density. PMID- 26016653 TI - Atomic Zero Steric Potential and the Regioselectivity of Reactions. AB - A new function, called zero steric potential (ZSP(r) = |?rho(r)|(2) - 2rho(r)?(2)rho(r)), is proposed from the framework of density functional theory (DFT) to describe the regioselectivity of some selected reactions, including Diels-Alder reactions, addition of acids to alkenes, and Paterno-Buchi reactions. The ability of atomic zero steric potential (AZSP), which is obtained by integration of ZSP over an atomic basin, in predicting the major products of these reactions is checked. It is shown that for each reaction the least AZSP difference is observed for those atoms for which their binding leads to the main product. Therefore, it seems that the AZSP index could be used for predicting the reactive sites of reactants in a given chemical reaction. PMID- 26016652 TI - Native contact density and nonnative hydrophobic effects in the folding of bacterial immunity proteins. AB - The bacterial colicin-immunity proteins Im7 and Im9 fold by different mechanisms. Experimentally, at pH 7.0 and 10 degrees C, Im7 folds in a three-state manner via an intermediate but Im9 folding is two-state-like. Accordingly, Im7 exhibits a chevron rollover, whereas the chevron arm for Im9 folding is linear. Here we address the biophysical basis of their different behaviors by using native centric models with and without additional transferrable, sequence-dependent energies. The Im7 chevron rollover is not captured by either a pure native centric model or a model augmented by nonnative hydrophobic interactions with a uniform strength irrespective of residue type. By contrast, a more realistic nonnative interaction scheme that accounts for the difference in hydrophobicity among residues leads simultaneously to a chevron rollover for Im7 and an essentially linear folding chevron arm for Im9. Hydrophobic residues identified by published experiments to be involved in nonnative interactions during Im7 folding are found to participate in the strongest nonnative contacts in this model. Thus our observations support the experimental perspective that the Im7 folding intermediate is largely underpinned by nonnative interactions involving large hydrophobics. Our simulation suggests further that nonnative effects in Im7 are facilitated by a lower local native contact density relative to that of Im9. In a one-dimensional diffusion picture of Im7 folding with a coordinate- and stability-dependent diffusion coefficient, a significant chevron rollover is consistent with a diffusion coefficient that depends strongly on native stability at the conformational position of the folding intermediate. PMID- 26016657 TI - Music, illness, movement, and hope. PMID- 26016655 TI - Pyrosequencing analysis reveals changes in intestinal microbiota of healthy adults who received a daily dose of immunomodulatory probiotic strains. AB - The colon microbiota plays a crucial role in human gastrointestinal health. Current attempts to manipulate the colon microbiota composition are aimed at finding remedies for various diseases. We have recently described the immunomodulatory effects of three probiotic strains (Lactobacillus rhamnosus CNCM I-4036, Lactobacillus paracasei CNCM I-4034, and Bifidobacterium breve CNCM I 4035). The goal of the present study was to analyze the compositions of the fecal microbiota of healthy adults who received one of these strains using high throughput 16S ribosomal RNA gene sequencing. Bacteroides was the most abundant genus in the groups that received L. rhamnosus CNCM I-4036 or L. paracasei CNCM I 4034. The Shannon indices were significantly increased in these two groups. Our results also revealed a significant increase in the Lactobacillus genus after the intervention with L. rhamnosus CNCM I-4036. The initially different colon microbiota became homogeneous in the subjects who received L. rhamnosus CNCM I 4036. While some orders that were initially present disappeared after the administration of L. rhamnosus CNCM I-4036, other orders, such as Sphingobacteriales, Nitrospirales, Desulfobacterales, Thiotrichales, and Synergistetes, were detected after the intervention. In summary, our results show that the intake of these three bacterial strains induced changes in the colon microbiota. PMID- 26016656 TI - Sleeping under the Ocean: Despite Total Isolation, Nuclear Submariners Maintain Their Sleep and Wake Patterns throughout Their Under Sea Mission. AB - BACKGROUND: To assess the effects of isolation, inadequate exposure to light and specific shift work on the subjective and objective measurements of sleep and alertness of submariners. PURPOSE: A strictly controlled randomized crossover study with the polysomnography recorded twice during the mission. METHODS: Setting: Shift and night work with prolonged (70 days) social isolation from the real world (with no phone or Internet contact with families or friends during a routine mission aboard the "Temeraire" French Strategic Submarine with Ballistic Nuclear missiles (SSBN). Participants: 19 submariners working on a 24-hour shift for three days in a row schedule. Interventions: The participants attended two polysomnographic (PSG) recordings of night sleep on Day 21 (D21) and Day 51 (D51) of the 70-day patrol; urine cortisol levels were also taken after sleep, and subjective assessments of sleep, sleepiness, mood and anxiety on D21 and D51. The light and temperature on board were also recorded. RESULTS: PSG analyses showed that sleep did not significantly vary in length (total sleep time) or in quality between D21 and D51. The mariners reported the same subjective sleep, sleepiness, anxiety or mood (except for a slightly worse score for confusion on D51). Blood cortisol levels did not vary significantly. CONCLUSIONS: These results show that humans living in an isolated environment for more than two months with this specific shift schedule do not suffer from any significant effects on sleep, sleepiness and confusion between D21 and D51, when they follow an organized regular shift pattern with controlled light and temperature. PMID- 26016654 TI - Apples and cardiovascular health--is the gut microbiota a core consideration? AB - There is now considerable scientific evidence that a diet rich in fruits and vegetables can improve human health and protect against chronic diseases. However, it is not clear whether different fruits and vegetables have distinct beneficial effects. Apples are among the most frequently consumed fruits and a rich source of polyphenols and fiber. A major proportion of the bioactive components in apples, including the high molecular weight polyphenols, escape absorption in the upper gastrointestinal tract and reach the large intestine relatively intact. There, they can be converted by the colonic microbiota to bioavailable and biologically active compounds with systemic effects, in addition to modulating microbial composition. Epidemiological studies have identified associations between frequent apple consumption and reduced risk of chronic diseases such as cardiovascular disease. Human and animal intervention studies demonstrate beneficial effects on lipid metabolism, vascular function and inflammation but only a few studies have attempted to link these mechanistically with the gut microbiota. This review will focus on the reciprocal interaction between apple components and the gut microbiota, the potential link to cardiovascular health and the possible mechanisms of action. PMID- 26016658 TI - Afternoon nap and bright light exposure improve cognitive flexibility post lunch. AB - Beneficial effects of napping or bright light exposure on cognitive performance have been reported in participants exposed to sleep loss. Nonetheless, few studies investigated the effect of these potential countermeasures against the temporary drop in performance observed in mid-afternoon, and even less so on cognitive flexibility, a crucial component of executive functions. This study investigated the impact of either an afternoon nap or bright light exposure on post-prandial alterations in task switching performance in well-rested participants. Twenty-five healthy adults participated in two randomized experimental conditions, either wake versus nap (n=15), or bright light versus placebo (n=10). Participants were tested on a switching task three times (morning, post-lunch and late afternoon sessions). The interventions occurred prior to the post-lunch session. In the nap/wake condition, participants either stayed awake watching a 30-minute documentary or had the opportunity to take a nap for 30 minutes. In the bright light/placebo condition, participants watched a documentary under either bright blue light or dim orange light (placebo) for 30 minutes. The switch cost estimates cognitive flexibility and measures task switching efficiency. Increased switch cost scores indicate higher difficulties to switch between tasks. In both control conditions (wake or placebo), accuracy switch-cost score increased post lunch. Both interventions (nap or bright light) elicited a decrease in accuracy switch-cost score post lunch, which was associated with diminished fatigue and decreased variability in vigilance. Additionally, there was a trend for a post-lunch benefit of bright light with a decreased latency switch-cost score. In the nap group, improvements in accuracy switch-cost score were associated with more NREM sleep stage N1. Thus, exposure to bright light during the post-lunch dip, a countermeasure easily applicable in daily life, results in similar beneficial effects as a short nap on performance in the cognitive flexibility domain with possible additional benefits on latency switch-cost scores. PMID- 26016659 TI - Simultaneous Identification and Susceptibility Determination to Multiple Antibiotics of Staphylococcus aureus by Bacteriophage Amplification Detection Combined with Mass Spectrometry. AB - The continued advance of antibiotic resistance in clinically relevant bacterial strains necessitates the development and refinement of assays that can rapidly and cost-effectively identify bacteria and determine their susceptibility to a panel of antibiotics. A methodology is described herein that exploits the specificity and physiology of the Staphylococci bacteriophage K to identify Staphylococcus aureus (S. aureus) and determine its susceptibility to clindamycin and cefoxitin. The method uses liquid chromatography-mass spectrometry to monitor the replication of bacteriophage after it is used to infect samples thought to contain S. aureus. Amplification of bacteriophage K indicates the sample contains S. aureus, for it is only in the presence of a suitable host that bacteriophage K can amplify. If bacteriophage amplification is detected in samples containing the antibiotics clindamycin or cefoxitin, the sample is deemed to be resistant to these antibiotics, respectively, for bacteriophage can only amplify in a viable host. Thus, with a single work flow, S. aureus can be detected in an unknown sample and susceptibility to clindamycin and cefoxitin can be ascertained. This Article discusses implications for the use of bacteriophage amplification in the clinical laboratory. PMID- 26016660 TI - Regucalcin Expression as a Diagnostic Tool for the Illicit Use of Steroids in Veal Calves. AB - It has been previously demonstrated that sex steroid hormone treatment down regulates regucalcin gene expression in the accessory sex glands and testis of prepubertal and adult male bovines. The aim of this study was to investigate whether low doses of sex steroid hormones combined with other drugs significantly affect regucalcin gene expression in the accessory sex glands and testis of veal calves. The regucalcin expression was down-regulated in the bulbo-urethral glands of estrogen-treated calves, whereas it was up-regulated in the prostate of estrogen-treated calves. Only the testis of androgen-treated calves showed a down regulation of the regucalcin expression. Thus, the administration of sex steroid hormones, even in low doses and combined with other molecules, could affect regucalcin expression in target organs. Particularly, the specific response in the testis suggests regucalcin expression in this organ as a first molecular biomarker of illicit androgen administration in bovine husbandry. PMID- 26016665 TI - Porcine Model to Evaluate Real-Time Intraocular Pressure During Femtosecond Laser Cataract Surgery. AB - PURPOSE: To investigate the changes in intraocular pressure (IOP) in porcine eyes during femtosecond laser-assisted cataract surgery using a liquid-optic interface system. MATERIALS AND METHODS: Femtosecond laser cataract surgery with the CatalysTM was performed on freshly enucleated porcine eyes in Oftalvist Moncloa, Madrid, Spain. Capsulorhexis and lens fragmentation were completed in all the eyes without complications. IOP was measured with a reusable blood pressure transducer connected by direct cannulation to the anterior chamber, recording data before suction (basal), at the beginning of the suction phase, every five seconds during femtosecond procedure and after the removal of the suction ring from the eye. RESULTS: Nine porcine eyes were used in this study. Basal IOP before suction was 5.67 +/- 2.39 mmHg, rising to 20.33 +/- 4.18 mmHg at the beginning of the suction phase (p < 0.001). During femtosecond procedure, pressure reached a value of 19.74 +/- 4.31 mmHg, remaining stable during the entire process. The IOP recorded prior to removal of the suction ring was 21.00 +/- 6.93 mmHg, returning to basal values in all the eyes after the suction ring was removed, with no statistical differences between basal and post-suction IOPs. Total femtosecond procedure time was 125.9 +/- 15.9 s. CONCLUSIONS: Real-time IOP can be measured during surgery using a transducer connected to the anterior chamber. The results showed a significant increase in IOP during the procedure due to the pressure exerted by the suction ring but not by the effect of the femtosecond laser. PMID- 26016666 TI - Modulating bilayer mechanical properties to promote the coupled folding and insertion of an integral membrane protein. AB - Bilayer mechanical properties are not only of crucial importance to the mechanism of action of mechanosensation in lipid membranes but also affect preparative laboratory tasks such as membrane-protein refolding. We report this for coupled refolding and bilayer insertion of outer membrane phospholipase A (OmpLA), an integral membrane enzyme that catalyses the hydrolytic cleavage of glycerophospholipids. OmpLA can be refolded into a variety of detergent micelles and unilamellar vesicles composed of short-chain phospholipids but, in the absence of chemical or molecular chaperones, not into thicker membranes. Controlled modulation of bilayer mechanical properties by judicious use of subsolubilising concentrations of detergents induces monolayer curvature strain, acyl chain fluidisation, membrane thinning, and transient aqueous bilayer defects. This enables quantitative and functional refolding of OmpLA even into bilayer membranes composed of long-chain phospholipids to yield enzymatically active proteoliposomes without requiring membrane solubilisation. PMID- 26016667 TI - A GSDMB enhancer-driven HSV thymidine kinase-expressing vector for controlling occult peritoneal dissemination of gastric cancer cells. AB - BACKGROUND: Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, and Japan and Korea have the highest incidence in the world. Because most of the cases that are refractory to therapies die due to peritoneal dissemination (PD) of the cancer cells, controlling PD is important for patient survival. GSDMB is a member of the gasdermin gene family. Because GSDMB is expressed in many types of cancer, including GC, it is likely that the gene contains a regulatory region that is utilized for therapy of occult PD through cancer cell-specific expression of cytotoxic genes. METHODS: We performed reporter assays to identify the regulatory region for the cancer cell-specific expression. We also constructed a lentiviral therapeutic vector that expresses herpes simplex virus thymidine kinase (HSVtk) in a GC cell-specific manner, and tested it in a mouse model of PD. RESULTS: We identified the regulatory region at +496 to +989 from the GSDMB transcription start site and designated it as a GSDMB enhancer. The lentiviral therapeutic vector suppressed proliferation of a GC cell line, 60As6, in vitro in the presence of ganciclovir, and intraperitoneal administration of the vector prolonged the survival term of mice that were intraperitoneally inoculated with 60As6 one week prior to the administration. CONCLUSIONS: The GSDMB-driven HSVtk expression vector had a therapeutic effect on the occult PD model mice. This strategy can potentially be used to treat GC patients with PD. PMID- 26016669 TI - Seborrhoeic dermatitis of the scalp. AB - INTRODUCTION: Seborrhoeic dermatitis affects a variable proportion of the general population, ranging from 3% to 10%. Malassezia yeast species (previously referred to as Pityrosporum) are thought to be the responsible organisms, and cause inflammation by still poorly defined mechanisms. Seborrhoeic dermatitis tends to relapse after treatment. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of topical treatments for seborrhoeic dermatitis of the scalp in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: bifonazole, ciclopirox, ketoconazole, pyrithione zinc, selenium sulfide, tar shampoo, terbinafine, and topical corticosteroids (betamethasone valerate, clobetasol propionate, clobetasone butyrate, hydrocortisone, mometasone furoate). PMID- 26016668 TI - Use of the melanoma vaccine in 38 dogs: The South African experience. AB - The commercially available vaccine Oncept is indicated for the management of dogs with stage II or III oral melanoma after local control has been achieved. Survival times in dogs with both oral and digit melanoma have been shown to be significantly increased following vaccination. This retrospective study was designed to document the investigators' experiences with Oncept vaccine when used as an adjunct therapy for treatment of stage II-IV oral, digit and malignant melanoma of other sites after local control had been achieved in dogs presented to a South African specialist referral veterinary practice. Thirty-eight dogs diagnosed with melanoma (25 oral, 6 digit and 7 infiltrative at various other sites) underwent a combination of surgical excision and Oncept vaccination. At the end of the study period there were 16 live and 22 dead dogs; median survival time of the live dogs was 29 months (range 2-46 months) versus 8 months (range 2 16 months) for those that died from progressive disease. This study showed that by using a combination of surgical excision and vaccination with Oncept survival times in dogs with malignant melanoma of the oral cavity, digit and other sites can be increased significantly. PMID- 26016670 TI - Optimizing the interprofessional workforce for centralized intake of patients with osteoarthritis and rheumatoid disease: case study. AB - INTRODUCTION: This case study was part of a larger programme of research in Alberta that aims to develop an evidence-based model to optimize centralized intake province-wide to improve access to care. A centralized intake model places all referred patients on waiting lists based on severity and then directs them to the most appropriate provider or service. Our research focused on an in-depth assessment of two well-established models currently in place in Alberta to 1) enhance our understanding of the roles and responsibilities of staff in current intake processes, 2) identify workforce issues and opportunities within the current models, and 3) inform the potential use of alternative providers in the proposed centralized intake model. CASE DESCRIPTION: Our case study included two centralized intake models in Alberta associated with three clinics. One model involved one clinic that focuses on rheumatoid disease. The other model involved two clinics that focus on osteoarthritis. We completed a document review and interviews with managers and staff from both models. Finally, we reviewed the scope of practice regulations for a range of health-care providers to examine their suitability to contribute to the centralized intake process of osteoarthritis and rheumatoid disease. DISCUSSION AND EVALUATION: Interview findings from both models suggested a need for an electronic medical record and eReferral system to improve the efficiency of the current process and reduce staff workload. Staff interviewed also spoke of the need to have a permanent musculoskeletal screener available to streamline the intake process for osteoarthritis patients. Both models relied on registered nurses, medical office assistants, and physicians throughout their intake process. Our scope of practice review revealed that several providers have the competencies to screen, assess, and provide case management at different junctures in the centralized intake of patients with osteoarthritis and rheumatoid disease. CONCLUSIONS: Using a broader range of providers in the centralized intake of osteoarthritis and rheumatoid disease has the potential to improve access and care specifically related to the assessment and management of patients. This may enhance the patient care experience and address current access issues. PMID- 26016671 TI - Comparison of four different reduction methods for anterior dislocation of the shoulder. AB - BACKGROUND: Shoulder dislocations account for almost 50% of all major joint dislocations and are mainly anterior. OBJECTIVE: The aim is a comparative retrospective study of different reduction maneuvers without anesthesia to reduce the dislocated shoulder. METHODS: Patients were treated with different reduction maneuvers, including various forms of traction and external rotation, in the emergency departments of four training hospitals between 2009 and 2012. Each of the four hospitals had different treatment protocols for reduction and applying one of four maneuvers: Spaso, Chair, Kocher, and Matsen methods. Thirty-nine patients were treated by the Spaso method, 47 by the Chair reduction method, 40 by the Kocher method, and 27 patients by Matsen's traction-countertraction method. All patients' demographic data were recorded. Dislocation number, reduction time, time interval between dislocation and reduction, and associated complications, pre- and post-reduction period, were recorded prospectively. No anesthetic method was used for the reduction. RESULTS: All of the methods used included traction and some external rotation. The Chair method had the shortest reduction time. All surgeons involved in the study agreed that the Kocher and Matsen methods needed more force for the reduction. Patients could contract their muscles because of the pain in these two methods. The Spaso method includes flexion of the shoulder and blocks muscle contraction somewhat. The Chair method was found to be the easiest because the patients could not contract their muscles while sitting on a chair with the affected arm at their side. CONCLUSIONS: We suggest that the Chair method is an effective and fast reduction maneuver that may be an alternative for the treatment of anterior shoulder dislocations. Further prospective studies with larger sample size are needed to compare safety of different reduction techniques. PMID- 26016673 TI - Indian rotavirus vaccine concern over intussusception is unfounded, say researchers. PMID- 26016672 TI - Polyketide synthesis genes associated with toxin production in two species of Gambierdiscus (Dinophyceae). AB - BACKGROUND: Marine microbial protists, in particular, dinoflagellates, produce polyketide toxins with ecosystem-wide and human health impacts. Species of Gambierdiscus produce the polyether ladder compounds ciguatoxins and maitotoxins, which can lead to ciguatera fish poisoning, a serious human illness associated with reef fish consumption. Genes associated with the biosynthesis of polyether ladder compounds are yet to be elucidated, however, stable isotope feeding studies of such compounds consistently support their polyketide origin indicating that polyketide synthases are involved in their biosynthesis. RESULTS: Here, we report the toxicity, genome size, gene content and transcriptome of Gambierdiscus australes and G. belizeanus. G. australes produced maitotoxin-1 and maitotoxin-3, while G. belizeanus produced maitotoxin-3, for which cell extracts were toxic to mice by IP injection (LD50 = 3.8 mg kg(-1)). The gene catalogues comprised 83,353 and 84,870 unique contigs, with genome sizes of 32.5 +/- 3.7 Gbp and 35 +/- 0.88 Gbp, respectively, and are amongst the most comprehensive yet reported from a dinoflagellate. We found three hundred and six genes involved in polyketide biosynthesis, including one hundred and ninety-two ketoacyl synthase transcripts, which formed five unique phylogenetic clusters. CONCLUSIONS: Two clusters were unique to these maitotoxin-producing dinoflagellate species, suggesting that they may be associated with maitotoxin biosynthesis. This work represents a significant step forward in our understanding of the genetic basis of polyketide production in dinoflagellates, in particular, species responsible for ciguatera fish poisoning. PMID- 26016674 TI - Metabolic engineering of a tyrosine-overproducing yeast platform using targeted metabolomics. AB - BACKGROUND: L-tyrosine is a common precursor for a wide range of valuable secondary metabolites, including benzylisoquinoline alkaloids (BIAs) and many polyketides. An industrially tractable yeast strain optimized for production of L tyrosine could serve as a platform for the development of BIA and polyketide cell factories. This study applied a targeted metabolomics approach to evaluate metabolic engineering strategies to increase the availability of intracellular L tyrosine in the yeast Saccharomyces cerevisiae CEN.PK. Our engineering strategies combined localized pathway engineering with global engineering of central metabolism, facilitated by genome-scale steady-state modelling. RESULTS: Addition of a tyrosine feedback resistant version of 3-deoxy-D-arabino-heptulosonate-7 phosphate synthase Aro4 from S. cerevisiae was combined with overexpression of either a tyrosine feedback resistant yeast chorismate mutase Aro7, the native pentafunctional arom protein Aro1, native prephenate dehydrogenase Tyr1 or cyclohexadienyl dehydrogenase TyrC from Zymomonas mobilis. Loss of aromatic carbon was limited by eliminating phenylpyruvate decarboxylase Aro10. The TAL gene from Rhodobacter sphaeroides was used to produce coumarate as a simple test case of a heterologous by-product of tyrosine. Additionally, multiple strategies for engineering global metabolism to promote tyrosine production were evaluated using metabolic modelling. The T21E mutant of pyruvate kinase Cdc19 was hypothesized to slow the conversion of phosphoenolpyruvate to pyruvate and accumulate the former as precursor to the shikimate pathway. The ZWF1 gene coding for glucose-6-phosphate dehydrogenase was deleted to create an NADPH deficiency designed to force the cell to couple its growth to tyrosine production via overexpressed NADP(+)-dependent prephenate dehydrogenase Tyr1. Our engineered Zwf1(-) strain expressing TYRC ARO4(FBR) and grown in the presence of methionine achieved an intracellular L-tyrosine accumulation up to 520 MUmol/g DCW or 192 mM in the cytosol, but sustained flux through this pathway was found to depend on the complete elimination of feedback inhibition and degradation pathways. CONCLUSIONS: Our targeted metabolomics approach confirmed a likely regulatory site at DAHP synthase and identified another possible cofactor limitation at prephenate dehydrogenase. Additionally, the genome-scale metabolic model identified design strategies that have the potential to improve availability of erythrose 4-phosphate for DAHP synthase and cofactor availability for prephenate dehydrogenase. We evaluated these strategies and provide recommendations for further improvement of aromatic amino acid biosynthesis in S. cerevisiae. PMID- 26016677 TI - Time-dependent gel to gel transformation of a peptide based supramolecular gelator. AB - A dipeptide with a long fatty acid chain at its N-terminus gives hydrogels in phosphate buffer in the pH range 7.0-8.5. The hydrogel with a gelator concentration of 0.45% (w/v) at pH 7.46 (physiological pH) provides a very good platform to study dynamic changes within a supramolecular framework as it exhibits remarkable change in its appearance with time. Interestingly, the first formed transparent hydrogel gradually transforms into a turbid gel within 2 days. These two forms of the hydrogel have been thoroughly investigated by using small angle X-ray scattering (SAXS), powder X-ray diffraction (PXRD), field emission scanning electron microscopic (FE-SEM) and high-resolution transmission electron microscopic (HR-TEM) imaging, FT-IR and rheometric analyses. The SAXS and low angle PXRD studies substantiate different packing arrangements for the gelator molecules for these two different gel states (the freshly prepared and the aged hydrogel). Moreover, rheological studies of these two gels reveal that the aged gel is stiffer than the freshly prepared gel. PMID- 26016676 TI - Non-melanoma Skin Cancer in Canada Chapter 1: Introduction to the Guidelines. AB - BACKGROUND: Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy. OBJECTIVE: The aim of this document is to provide guidance to Canadian health care practitioners on NMSC management. METHODS: After conducting a literature review, the group developed recommendations for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas, and actinic keratoses. These tumour types are considered separately in the accompanying articles. The Grading of Recommendations Assessment, Development and Evaluation system was used to assign strength to each recommendation. RESULTS: This introduction describes the scope and structure of the guidelines and the methods used to develop them. The epidemiology of NMSC is reviewed, as are the pathophysiologic changes occurring with damage to the skin, which lead to the formation of actinic keratoses and invasive squamous or basal cell carcinomas. CONCLUSIONS: This introduction describes the need for primary prevention and offers an overview of treatment options that are discussed in later chapters of the guidelines. PMID- 26016678 TI - Age-related similarities and differences in first impressions of trustworthiness. AB - Trust is a particularly under-studied aspect of social relationships in older age. In the current study, young (n = 35) and older adults (n = 35) completed a series of one-shot social economic trust games in which they invested real money with trustees. There were potential gains with each investment and also a risk of losing everything if the trustee was untrustworthy. The reputation and facial appearance of each trustee were manipulated to make them appear more or less trustworthy. Results revealed that young and older adults invest more money with trustees whose facial appearance and reputation indicate that they are trustworthy rather than untrustworthy. However, older adults were more likely than young to invest with trustees who had a reputation for being untrustworthy. We discuss whether age-related differences in responding to negative information may account for an age-related increase in trust, particularly when trusting someone with a reputation for being uncooperative. PMID- 26016679 TI - Analysis of microbial volatile organic compounds produced by wood-decay fungi. AB - OBJECTIVES: Microbial volatile organic compounds (MVOCs) produced by the brown rot fungus Fomitopsis palustris and white-rot fungus Trametes versicolor grown on wood chip and potato dextrose agar were analyzed by GC-MS. RESULTS: In total, 110 organic compounds were identified as MVOCs. Among them, only 23 were MVOCs commonly observed in both types of fungi, indicating that the fungi have differential MVOC expression profiles. In addition, F. palustris and T. versicolor produced 38 and 22 MVOCs, respectively, which were detected only after cultivation on wood chip. This suggests that the fungi specifically released these MVOCs when degrading the cell-wall structure of the wood. Time course analysis of MVOC emission showed that both types of fungi produced the majority of MVOCs during the active phase of wood degradation. CONCLUSION: As both fungi produced specific MVOCs in the course of wood degradation indicates the possibility of the application of MVOCs as detection markers for wood-decay fungus existing in woody materials. PMID- 26016680 TI - Meeting the Reproductive Needs of Female Adolescents With Neurodevelopmental Disabilities. AB - The complexity of caring for female adolescents with neurodisabilities often overshadows normal biological changes. These young women may require additional or individualized support as they adapt to normal puberty and sexual maturation. Many choices are available to assist in managing menstrual problems, hygiene issues, and contraception. Special considerations regarding contraceptive methods, sexual education, and improving service accessibility are explored for clinicians. PMID- 26016681 TI - Effect of topical prostaglandin analogues on corneal hysteresis. PMID- 26016682 TI - Online investigation of respiratory quotients in Pinus sylvestris and Picea abies during drought and shading by means of cavity-enhanced Raman multi-gas spectrometry. AB - Photosynthesis and respiration are major components of the plant carbon balance. During stress, like drought, carbohydrate supply from photosynthesis is reduced and the Krebs cycle respiration must be fueled with other stored carbon compounds. However, the dynamics of storage use are still unknown. The respiratory quotient (RQ, CO2 released per O2 consumed during respiration) is an excellent indicator of the nature of the respiration substrate. In plant science, however, online RQ measurements have been challenging or even impossible so far due to very small gas exchange fluxes during respiration. Here we apply cavity enhanced multi-gas Raman spectrometry (CERS) for online in situ RQ measurements in drought-tolerant pine (Pinus sylvestris [L.]) and drought-intolerant spruce (Picea abies [L. H. Karst]). Two different treatments, drought and shading, were applied to reduce photosynthesis and force dependency on stored substrates. Changes in respiration rates and RQ values were continuously monitored over periods of several days with low levels of variance. The results show that both species switched from COH-dominated respiration (RQ = 1.0) to a mixture of substrates during shading (RQ = 0.77-0.81), while during drought only pine did so (RQ = 0.75). The gas phase measurements were complemented by concentration measurements of non-structural carbohydrates and lipids. These first results suggest a physiological explanation for greater drought tolerance in pine. CERS was proven as powerful technique for non-consumptive and precise real-time monitoring of respiration rates and respirational quotients for the investigation of plant metabolism under drought stress conditions that are predicted to increase with future climate change. PMID- 26016683 TI - Progression of subcortical atrophy and iron deposition in multiple system atrophy: a comparison between clinical subtypes. AB - Magnetic resonance imaging (MRI) can be useful not only for the diagnosis of multiple system atrophy (MSA) itself, but also to distinguish between different clinical subtypes. This study aimed to investigate whether there are differences in the progression of subcortical atrophy and iron deposition between two variants of MSA. Two serial MRIs at baseline and follow-up were analyzed in eight patients with the parkinsonian variant MSA (MSA-P), nine patients with cerebellar variant MSA (MSA-C), and fifteen patients with Parkinson's disease (PD). The R2* values and volumes were calculated for the selected subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) using an automated region-based analysis. In both volume and R2*, a higher rate of progression was identified in MSA-P patients. Volumetric analysis showed significantly more rapid progression of putamen and caudate nucleus in MSA-P than in MSA-C. With regard to R2* changes, a significant increase at follow-up and a higher rate of progression were identified in the putamen of MSA-P group compared to MSA-C and PD groups. This longitudinal study revealed different progression rates of MRI markers between MSA-P and MSA-C. Iron-related degeneration in the putamen may be more specific for MSA-P. PMID- 26016684 TI - Olfactory dysfunction in neuromyelitis optica spectrum disorders. AB - Few data were available for the understanding of olfactory function in neuromyelitis optica spectrum disorders (NMOSDs). The aims of our study were to investigate the incidence of olfactory dysfunction and characterize olfactory structures, using MRI, in patients with NMOSDs. Olfactory function was evaluated by olfactometer in 49 patients with NMOSDs and 26 matched healthy controls. MRI parameters such as olfactory bulb (OB) and the olfactory-related gray matter volume changes were assessed. The frequency of olfactory dysfunction was 53% in patients with NMOSDs. Olfactory detection thresholds were positively correlated with serum aquaporin-4 antibodies (fluorescent units) tested by fluorescent immunoprecipitation assay (FIPA) in NMOSDs (p = 0.009). Patients with olfactory dysfunction had smaller OB volume than did patients without olfactory dysfunction or controls (p < 0.01). Both detection and recognition thresholds for olfaction were negatively correlated with OB volume (p = 0.018, p < 0.01). The significant gray matter volume reduction in NMOSDs was found in the bilateral piriform cortex, orbitofrontal cortex, and parahippocampal gyri (FDR correction, p < 0.05, cluster size >200 voxels). Our data suggested that olfactory function deficits are prevalent in patients with NMOSDs. Reduced OB and olfactory-related cortex volume may be responsible for the olfactory dysfunction. PMID- 26016685 TI - Normalization of sensorimotor integration by repetitive transcranial magnetic stimulation in cervical dystonia. AB - Previous studies indicated that sensorimotor integration and plasticity of the sensorimotor system are impaired in dystonia patients. We investigated motor evoked potential amplitudes and short latency afferent inhibition to examine corticospinal excitability and cortical sensorimotor integration, before and after inhibitory 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex in patients with cervical dystonia (n = 12). Motor evoked potentials were recorded from the right first dorsal interosseous muscle after application of unconditioned transcranial magnetic test stimuli and after previous conditioning electrical stimulation of the right index finger at short interstimulus intervals of 25, 30 and 40 ms. Results were compared to a group of healthy age-matched controls. At baseline, motor evoked potential amplitudes did not differ between groups. Short latency afferent inhibition was reduced in cervical dystonia patients compared to healthy controls. Inhibitory 1 Hz sensory cortex repetitive transcranial magnetic stimulation but not motor cortex repetitive transcranial magnetic stimulation increased motor evoked potential amplitudes in cervical dystonia patients. Additionally, both 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex normalized short latency afferent inhibition in these patients. In healthy subjects, sensory repetitive transcranial magnetic stimulation had no influence on motor evoked potential amplitudes and short latency afferent inhibition. Plasticity of sensorimotor circuits is altered in cervical dystonia patients. PMID- 26016686 TI - Brain perfusion by arterial spin labeling MRI in multiple sclerosis. PMID- 26016687 TI - Facile Hydrothermal Synthesis of VS2/Graphene Nanocomposites with Superior High Rate Capability as Lithium-Ion Battery Cathodes. AB - In this study, a facile one-pot process for the synthesis of hierarchical VS2/graphene nanosheets (VS2/GNS) composites based on the coincident interaction of VS2 and reduced graphene oxide (rGO) sheets in the presence of cetyltrimethylammonium bromide is developed for the first time. The nanocomposites possess a hierarchical structure of 50 nm VS2 sheets in thickness homogeneously anchored on graphene. The VS2/GNS nanocomposites exhibit an impressive high-rate capability and good cyclic stability as a cathode material for Li-ion batteries, which retain 89.3% of the initial capacity 180.1 mAh g(-1) after 200 cycles at 0.2 C. Even at 20 C, the composites still deliver a high capacity of 114.2 mAh g(-1) corresponding to 62% of the low-rate capacity. Expanded studies show that VS2/GNS, as an anode material, also has a good reversible performance with 528 mAh g(-1) capacity after 100 cycles at 200 mA g( 1). The excellent electrochemical performance of the composites for reversible Li+ storage should be attributed to the exceptional interaction between VS2 and GNS that enabled fast electron transport between graphene and VS2, facile Li-ion diffusion within the electrode. Moreover, GNS provides a topological and structural template for the nucleation and growth of two-dimensional VS2 nanosheets and acted as buffer matrix to relieve the volume expansion/contraction of VS2 during the electrochemical charge/discharge, facilitating improved cycling stability. The VS2/GNS composites may be promising electrode materials for the next generation of rechargeable lithium ion batteries. PMID- 26016688 TI - Brief Report: Association Between Pregnancy Outcomes and Death From Cardiovascular Causes in Parous Women With Systemic Lupus Erythematosus: A Study Using Swedish Population Registries. AB - OBJECTIVE: To determine if maternal placental syndromes (MPS) are associated with an increased risk of death from cardiovascular causes in women with systemic lupus erythematosus (SLE). METHODS: Between 1973 and 2011, women with SLE and a history of pregnancy were identified using linked Swedish population registries. The outcome was death from primarily cardiovascular causes, defined as death from acute coronary syndrome or coronary artery disease, stroke, or peripheral vascular disease. The exposure was MPS, defined as any hypertensive disorders in pregnancy, stillbirth, placental abruption, or delivery of a small-for gestational-age infant. The association of preterm delivery (delivery at <34 weeks of gestation) with death from cardiovascular causes was also explored. Risk of death from cardiovascular causes was determined using logistic regression, adjusting for the year of first delivery, duration of SLE, number of inpatient admissions, and cardiovascular risk factors. RESULTS: A total of 3,977 women with SLE had 7,410 pregnancies during the study interval. Death from primarily cardiovascular causes occurred in 44 of the 325 women who died (13.5%). The median age at death from cardiovascular causes was 54 years (interquartile range 48-58 years), and these women were more likely to have had hypertension and renal disease. MPS was associated with an increased risk of death from primarily cardiovascular causes (adjusted odds ratio [OR] 2.19 [95% confidence interval (95% CI) 1.14-4.22]), specifically, a history of placental abruption (adjusted OR 5.78 [95% CI 1.61-20.72]). Delivery at <34 weeks of gestation, particularly when combined with MPS, was also associated with an increased risk of death from primarily cardiovascular causes (adjusted OR 2.49 [95% CI 1.06-5.85]). CONCLUSION: MPS in pregnancy is associated with a higher risk of death from primarily cardiovascular causes in women with SLE. PMID- 26016689 TI - Choosing the right chondrocyte cell line: Focus on nitric oxide. AB - Nitric oxide (NO) has been considered a catabolic factor that contributes to OA pathology by inducing chondrocytes apoptosis, matrix metalloproteinases synthesis, and pro-inflammatory cytokines expression. Thus, the research on NO regulation in chondrocytes represents a relevant field which needs to be explored in depth. However, to date, only the murine ATDC-5 cell line and primary chondrocytes are well-established cells to study NO production in cartilage tissues. The goal of this study is to determine whether two commonly used human chondrocytic cell lines: SW-1353 and T/C-28a2 cell lines are good models to examine lipopolysaccharide and/or pro-inflammatory cytokine-driven NO release and iNOS expression. To this aim, we carefully examined NO production and iNOS protein expression in human T/C-28a2 and SW-1353 chondrocytes stimulated with LPS and interleukin (IL)-1 alone or in combination. We also use ATDC-5 cells as a positive control for NO production. NO accumulation has been determined by colorimetric Griess reaction, whereas NOS type II expression was determined by Western Blot analysis. Our results clearly demonstrated that neither human T/C 28a2 nor SW-1353 chondrocytes showed a detectable increase in NO production or iNOS expression after bacterial endotoxin or cytokines challenge with IL-1. Our study demonstrated that T/C-28a2 and SW-1353 human cell lines are not suitable for studying NO release and iNOS expression confirming that ATDC5 and human primary cultured chondrocytes are the best in vitro cell system to study the actions derived from this mediator. PMID- 26016690 TI - Bacterial Renalase: Structure and Kinetics of an Enzyme with 2- and 6-Dihydro beta-NAD(P) Oxidase Activity from Pseudomonas phaseolicola. AB - Despite a lack of convincing in vitro evidence and a number of sound refutations, it is widely accepted that renalase is an enzyme unique to animals that catalyzes the oxidative degradation of catecholamines in blood in order to lower vascular tone. Very recently, we identified isomers of beta-NAD(P)H as substrates for renalase (Beaupre, B. A. et al. (2015) Biochemistry, 54, 795-806). These molecules carry the hydride equivalent on the 2 or 6 position of the nicotinamide base and presumably arise in nonspecific redox reactions of nicotinamide dinucleotides. Renalase serves to rapidly oxidize these isomers to form beta NAD(P)+ and then pass the electrons to dioxygen, forming H2O2. We have also shown that these substrate molecules are highly inhibitory to dehydrogenase enzymes and thus have proposed an intracellular metabolic role for this enzyme. Here, we identify a renalase from an organism without a circulatory system. This bacterial form of renalase has the same substrate specificity profile as that of human renalase but, in terms of binding constant (K(d)), shows a marked preference for substrates derived from beta-NAD+. 2-dihydroNAD(P) substrates reduce the enzyme with rate constants (k(red)) that greatly exceed those for 6-dihydroNAD(P) substrates. Taken together, k(red)/K(d) values indicate a minimum 20-fold preference for 2DHNAD. We also offer the first structures of a renalase in complex with catalytically relevant ligands beta-NAD+ and beta-NADH (the latter being an analogue of the substrate(s)). These structures show potential electrostatic repulsion interactions with the product and a unique binding orientation for the substrate nicotinamide base that is consistent with the identified activity. PMID- 26016691 TI - Complete destruction of deep-tissue buried tumors via combination of gene silencing and gold nanoechinus-mediated photodynamic therapy. AB - Cancer is one of the major diseases leading to human deaths. Complete destruction of deep tissue-buried tumors using non-invasive therapies is a grand challenge in clinical cancer treatments. Many therapeutic modalities were developed to tackle this problem, but only partial tumor suppression or delay growths were usually achieved. In this study, we report for the first time that complete destruction of deep tissue-buried tumors can be achieved by combination of gold nanoechinus (Au NEs)-mediated photodynamic therapy (PDT) and gene silencing under ultra-low doses of near infra-red (NIR) light irradiation (915 nm, 340 mW/cm(2); 1064 nm, 420 mW/cm(2)) in the first and second biological windows. The average lifespan of the mice treated by the above combined therapy is beyond 40 days, which are ~ 2.6 times longer than that (15 days) observed from the anticancer drug doxorubicin treated group. The current study points out a new direction for the therapeutic design to treat deeply seated tumors in future cancer treatments. PMID- 26016694 TI - Molecular mechanisms in dental follicle precursor cells during the osteogenic differentiation. AB - The discovery of dental stem cells received extensive attention because of its significance for the development of novel cellular therapies in dentistry. However, dental stem cells are also excellent for studies about cellular processes during dental tissue development or regeneration. Multipotent undifferentiated cells in the dental follicle (DFCs) are one example of dental stem cells. These cells have been used on studies about cellular processes during the differentiation into alveolar osteoblasts and cementoblasts. This review article summarizes current knowledge about the influence of signaling pathways, transcription factors and extracellular matrix proteins on the osteogenic differentiation of DFCs. PMID- 26016692 TI - Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells. AB - Adult and congenital cardiovascular diseases are significant health problems that are often managed using surgery. Bypass grafting is a principal therapy, but grafts fail at high rates due to hyperplasia, fibrosis, and atherosclerosis. Biocompatible, cellularized materials that attenuate these complications and encourage healthy microvascularization could reduce graft failure, but an improved understanding of biomaterial effects on human stem cells is needed to reach clinical utility. Our group investigates stem-cell-loaded biomaterials for placement along the adventitia of at-risk vessels and grafts. Here, the effects of substrate modulus on human CD34+ stem cells from umbilical cord blood were evaluated. Cells were isolated by immunomagnetic separation and encapsulated in 3, 4, and 6 weight% PEG hydrogels containing 0.032% gelatin and 0.0044% fibronectin. Gels reached moduli of 0.34, 4.5, and 9.1 kPa. Cell viability approached 100%. Cell morphologies appeared similar across gels, but proliferation was significantly lower in 6 wt% gels. Expression profiling using stem cell signaling arrays indicated enhanced self-renewal and differentiation into vascular endothelium among cells in the lower weight percent gels. Thus, modulus was associated with cell proliferation and function. Gels with moduli in the low kilopascal range may be useful in stimulating cell engraftment and microvascularization of graft adventitia. PMID- 26016693 TI - Psychotropic medicine prescriptions in Italian youths: a multiregional study. AB - The aim of the study was to evaluate the trend of paediatric psychotropic drug prescriptions in Italy. Data sources were regional, outpatient prescription databases. Seven Italian regions, covering 50 % of the Italian population, provided data from 2006 to 2011. Prevalence and incidence of prescriptions by age and gender were evaluated for psychotropic, antidepressant, antipsychotic, and attention-deficit/hyperactivity disorders (ADHD) medications. The hospital admission rate for psychiatric conditions was calculated, also at the local health unit (LHU) level. The presence of trends in prescription prevalence and incidence during the 6 year period was assessed. Finally, the correlation between prevalence, prescription, hospital admission rates, latitude, longitude, and average annual income at the LHU level was also investigated. In 2011, 8834 youths received at least one psychotropic drug prescription, with a prevalence of 1.76 0/00 (95 % CI 1.72-1.80). The incidence of new psychotropic drug users was 1.03 0/00 (1.00-1.06). The prevalence of antidepressants was 1.02 0/00 (0.99 1.04), while that of antipsychotics was 0.70 0/00 (0.68-0.72), and that of ADHD medications 0.19 0/00 (0.18-0.21). The psychotropic drug prevalence increased with increasing age. Males were more exposed to psychotropic drugs than females (AUC0-17 male/female = 1.23). Antipsychotics were the most prescribed psychotropic drugs in males, while antidepressants were in females. Between region prevalence ranged from 1.56 to 2.17 0/00. The overall prevalence of psychotropic drug from 2006 to 2011 was stable (chi(t)2 <= 0.001, p = 0.97). No correlation was found between prevalence and the variables investigated. Psychotropic drug prescription was very limited and stable. No geographical patterns were found. PMID- 26016695 TI - Complex Materials by Atomic Layer Deposition. AB - Complex materials are defined as nanostructured materials with combinations of structure and/or composition that lead to performance surpassing the sum of their individual components. There are many methods that can create complex materials; however, atomic layer deposition (ALD) is uniquely suited to control composition and structural parameters at the atomic level. The use of ALD for creating complex insulators, semiconductors, and conductors is discussed, along with its use in novel structural applications. PMID- 26016696 TI - Perceptions of professional nurses regarding introduction of the Batho Pele principles in State hospitals. AB - BACKGROUND: The South African health care delivery system has shifted focus to primary health care since 1994. For this purpose the Batho Pele principles were introduced. Nurses claim, however, that since the introduction of these principles patients and their families have been making unnecessary and sometimes impossible demands of nursing staff. This article presents the perceptions of the professional nurses regarding the introduction of the Batho Pele principles in their workplace. OBJECTIVES: To describe the perceptions of professional nurses regarding introduction of the Batho Pele principles and to recommend guidelines to facilitate measures to realise the objects of these principles. METHOD: A qualitative, exploratory, descriptive and contexual research design was used. Six audio-taped focus group discussions and field notes were used to collect data from purposively sampled participants who have worked in the outpatient departments of hospitals in the Port Elizabeth Hospital Complex. Guba's model of trustworthiness was used to confirm integrity of the study, whilst the participants were kept anonymous, protected from harm and participated voluntarily. Data analysis was done using Tesch's data analysis spiral and with the involvement of an independent-coder. RESULTS: Three themes emerged, revealing that the professional nurses perceived the objectives of the Batho Pele principles as difficult to uphold due to the inadequate planning prior to their implementation. Inadequacy of human and material resources aggravated this perception. CONCLUSION: Professional nurses are not happy with how things are in terms of introduction of the Batho Pele principles, but are optimistic of a positive change in the near future. PMID- 26016698 TI - A Computational Evaluation of Sentence Processing Deficits in Aphasia. AB - Individuals with agrammatic Broca's aphasia experience difficulty when processing reversible non-canonical sentences. Different accounts have been proposed to explain this phenomenon. The Trace Deletion account (Grodzinsky, 1995, 2000, 2006) attributes this deficit to an impairment in syntactic representations, whereas others (e.g., Caplan, Waters, Dede, Michaud, & Reddy, 2007; Haarmann, Just, & Carpenter, 1997) propose that the underlying structural representations are unimpaired, but sentence comprehension is affected by processing deficits, such as slow lexical activation, reduction in memory resources, slowed processing and/or intermittent deficiency, among others. We test the claims of two processing accounts, slowed processing and intermittent deficiency, and two versions of the Trace Deletion Hypothesis (TDH), in a computational framework for sentence processing (Lewis & Vasishth, 2005) implemented in ACT-R (Anderson, Byrne, Douglass, Lebiere, & Qin, 2004). The assumption of slowed processing is operationalized as slow procedural memory, so that each processing action is performed slower than normal, and intermittent deficiency as extra noise in the procedural memory, so that the parsing steps are more noisy than normal. We operationalize the TDH as an absence of trace information in the parse tree. To test the predictions of the models implementing these theories, we use the data from a German sentence-picture matching study reported in Hanne, Sekerina, Vasishth, Burchert, and De Bleser (2011). The data consist of offline (sentence picture matching accuracies and response times) and online (eye fixation proportions) measures. From among the models considered, the model assuming that both slowed processing and intermittent deficiency are present emerges as the best model of sentence processing difficulty in aphasia. The modeling of individual differences suggests that, if we assume that patients have both slowed processing and intermittent deficiency, they have them in differing degrees. PMID- 26016699 TI - Efficacy of Oral Itraconazole in the Treatment and Relapse Prevention of Moderate to Severe Seborrheic Dermatitis: A Randomized, Placebo-Controlled Trial. AB - BACKGROUND: Seborrheic dermatitis (SD) is a chronic and relapsing disease and topical therapy may be associated with failure, particularly in severe disease. Itraconazole has been suggested as an effective treatment for severe SD. Previous studies have been open clinical trials with variable results. OBJECTIVE: The aim of this study was to determine the efficacy of oral itraconazole in the treatment of patients with moderate to severe SD. METHODS: Sixty-eight patients with moderate to severe SD were randomly assigned to the itraconazole (n = 35) or placebo (n = 33) groups. The trial was undertaken in Razi Hospital, Tehran. An internet-generated table was used to allocate treatments. Patients and investigator were blinded to treatments. Itraconazole 200 mg/daily or placebo was prescribed for 1 week and then for the first 2 days of every month for the following 3 months. Patients were followed for 4 months and the Seborrheic Dermatitis Area Severity Index (SDASI) was measured on nine anatomical sites. Fifty-seven patients (29 in the itraconazole group and 28 in the placebo group) completed the study. RESULTS: Statistically significant improvement was observed in SDASI of both itraconazole and placebo groups (p = 0.000) but the itraconazole group showed significantly higher efficacy compared with placebo (p = 0.023). We observed clinical improvements of 93.8, 87.5, and 93.1% at the end of 2 weeks, 1 month, and 4 months, respectively, in the itraconazole group, and 82.1, 64.3, and 53.6% in the placebo group. Furthermore, recurrence rate in the itraconazole group was significantly lower than in the placebo group (p = 0.003). No blood test abnormality was seen in any patient. CONCLUSION: Itraconazole is not only an effective and safe therapy for controlling exacerbations of SD but may also be used as maintenance therapy to prevent disease recurrence. PMID- 26016697 TI - Effects of cognitive behavioural therapy for insomnia on the mental health of university students: study protocol for a randomized controlled trial. AB - BACKGROUND: Insomnia, defined as repeated difficulties getting or staying asleep, is common in the general population. Such sleep difficulties are a problem in their own right, but increasingly it is being recognised that they may also be a contributory factor in the development of a wide range of mental health problems. Our focus is upon the relationship between insomnia and psychotic experiences, such as paranoia and hallucinations. Psychotic experiences commonly occur in mild forms in the general population and have been linked to disrupted sleep. These psychotic-like experiences raise the risk of development of a clinical disorder. Our aim is to reduce insomnia in a large general population group, and examine the effect on paranoia and hallucinations at the age when mental health problems typically emerge. The primary hypotheses are that cognitive behaviour therapy (CBT) for insomnia will reduce insomnia and also levels of paranoia and hallucinations. The theoretical links will be substantiated by a planned mediation analysis. Improvements in a number of other mental health outcomes are also predicted. METHODS/DESIGN: We will carry out a parallel group, randomised controlled trial of 2,614 students with insomnia in universities across the UK. In the Oxford Access for Students Improving Sleep (OASIS) trial, participants will be randomised to digital CBT for insomnia (in addition to treatment as usual) or treatment as usual. Online assessments will take place at zero, three, 10 (post-treatment), and 22 (follow-up) weeks. Primary outcomes are insomnia and psychotic-like experiences (paranoia or hallucinatory experiences) at 10 weeks. Secondary outcomes are levels of mania, depression, anxiety, nightmares, psychological wellbeing, and the development of mental health disorders. All main analyses will be carried out at the end of the last follow-up assessment and will be based on the intention-to-treat principle. The trial is funded by the Wellcome Trust. DISCUSSION: This study will be the first large-scale causal test of the relationship between sleep disturbance and psychotic experiences. It will provide evidence concerning the clinical effects of treating insomnia in young adults. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN61272251 ) on 29 January 2015. PMID- 26016701 TI - Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents. AB - Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are two common functional gastrointestinal disorders that impair quality of life and pose a significant economic burden to the health care system. Current therapeutic options include lifestyle modifications, over-the counter (OTC) agents, antispasmodics, serotonin agonists, and lubiprostone and linaclotide, two prosecretory prescription drugs approved for the treatment of IBS-C and CIC. This review discusses the efficacy and safety of current treatments and emerging therapies for the treatment of IBS-C and CIC, with a focus on the prosecretory agents. A search of the PubMed database (1966-November 2014) was performed to identify relevant articles; clinical trials on emerging agents were also identified by searching the ClinicalTrials.gov registry. OTC laxatives may relieve constipation but do not treat abdominal pain and discomfort. Antispasmodics may provide short-term relief in patients with IBS-C, but their utility is limited by anticholinergic adverse effects. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors have shown benefit in providing global symptom relief and in improving abdominal discomfort, but further research is needed. Phase III clinical trials have demonstrated the efficacy of lubiprostone and linaclotide relative to placebo for the short-term treatment of IBS-C and CIC, with improvements reported in stool frequency, perceived constipation severity, and abdominal pain and discomfort. Relatively small response rates, higher costs, and adverse effects associated with lubiprostone and linaclotide will likely render these agents suitable as second-line therapies in the treatment of IBS-C and CIC. Emerging potential treatment options include prucalopride, plecanatide, elobixibat, and tenapanor. Several of these emerging therapies have novel mechanisms of action and may show promise in patients with IBS-C and CIC who have not responded to other therapies. PMID- 26016700 TI - Differentiation potential of individual olfactory c-Kit+ progenitors determined via multicolor lineage tracing. AB - Olfactory tissue undergoes lifelong renewal, due to the presence of basal neural stem cells. Multiple categories of globose basal stem cells have been identified, expressing markers such as Lgr5, Ascl1, GBC-2, and c-Kit. The differentiation potential of individual globose cells has remained unclear. Here, we utilized Cre/loxP lineage tracing with a multicolor reporter system to define c-Kit+ cell contributions at clonal resolution. We determined that reporter expression permitted identification of c-Kit derived progeny with fine cellular detail, and that clones were found to be comprised by neurons only, microvillar cells only, microvillar cells and neurons, or gland/duct cells. Quantification of reporter labeled cells indicated that c-Kit+ cells behave as transit amplifying or immediate precursors, although we also found evidence for longer-term c-Kit+ cell contributions. Our results from the application of multicolor fate mapping delineate the clonal contributions of c-Kit+ cells to olfactory epithelial renewal, and provide novel insight into tissue maintenance of an adult neuroepithelium. PMID- 26016702 TI - Preparation of Lentinula edodes polysaccharide-calcium complex and its immunoactivity. AB - Polysaccharide is a major bioactive component of mushrooms. In this study, for the first time, starting from a new Lentinula edodes polysaccharide L2, we prepared a novel L2-calcium complex and the process was optimized. Scanning electron microscopy and Fourier Transform infrared spectrometry were used for characterization. The immunostimulating activities of L2 and L2-calcium complex were measured by enhancing the production of two cytokines TNF-alpha and IL-6 in RAW264.7 cells. While L2-calcium complex significantly stimulates the secretions of TNF-alpha and IL-6 compared with the control, complex with calcium ion decreased the secretion of them. These facts indicate that calcium ion can modulate immune stimulating activity of Lentinula edodes polysaccharide L2. PMID- 26016703 TI - Clinicopathologic features and prognostic factors in patients with non-cutaneous malignant melanoma: a single-center retrospective study of 71 cases. AB - OBJECTIVES: This retrospective study was carried out to define the clinical features and prognostic differences in non-cutaneous malignant melanoma (non-CMM) originating from different anatomic sites. METHODS: Clinical and follow-up data for 71 patients with non-CMM were collected and reviewed. RESULTS: Of the 71 non CMM patients, 59 were diagnosed with mucosal malignant melanoma (MMM) and 12 with ocular malignant melanoma (OMM). In the 59 MMM patients, the nasal cavity was the most common anatomic site (n = 31, 43.7% of all non-CMM), followed by the oral cavity (n = 9, 12.7%), the genitourinary tract (n = 9, 12.7%), the anorectum (n = 8, 11.3%), and the gastrointestinal tract (n = 2, 2.8%). In the 12 patients with OMM, anatomic sites included the choroid (n = 8, 11.3% of all non-CMM) and the conjunctiva (n = 4, 5.6%). The survival outcome of patients with OMM was much better than that of patients with MMM (P < 0.001). In MMM patients, anorectal melanoma was associated with a worse survival outcome. Age of >= 70 years (P < 0.001) and tumor size of > 2 cm (P = 0.02) were significantly poor prognostic factors in MMM. Age (relative risk [RR] 1.068, 95% confidence interval [CI] 1.006 1.133; P = 0.03) and tumor size (RR 1.410, 95% CI 1.038-1.915; P = 0.028) were independent predictors for the postoperative survival of MMM patients. Patients with these two risk factors had a higher risk for recurrence or death (RR 3.107, 95% CI 1.627-5.595). CONCLUSIONS: Our findings demonstrate that prognoses differ in patients with different anatomic sites of primary non-CMM. Advanced age and larger tumor size are the main factors affecting prognosis. Patients with poor risk factors should be treated differently to improve their survival outcome. PMID- 26016704 TI - Field resistance to the Bacillus thuringiensis protein Cry1Ac expressed in Bollgard((r)) hybrid cotton in pink bollworm, Pectinophora gossypiella (Saunders), populations in India. AB - BACKGROUND: Bollgard((r)) cotton, expressing Cry1Ac insecticidal protein, was approved for commercial planting in India in 2002, and by 2009 constituted 87% of the Indian crop, reducing losses from lepidopteran pests, including pink bollworm (PBW), Pectinophora gossypiella. Inadequate control of PBW in fields of single gene Bollgard cotton was reported in 2009; surveys revealed heavy infestations of PBW in Bollgard, restricted to Gujarat state, but not elsewhere in India. RESULTS: Bioassays of PBW strains from Bollgard bolls showed that, while susceptible PBW could not complete development to third and later instar at 10.0 ug Cry1Ac mL(-1) , 66.1% of larvae from Gujarat Bollgard strains could. A field resistant strain, further selected in the laboratory, had susceptibility to Cry1Ac reduced by >2000-fold. Resistance to Cry1Ac did not confer cross resistance to the Cry2Ab2 protein. In 2010, Bollgard fields in Gujarat continued to be infested with PBW, and many Bollgard fields in the adjoining states of Maharashtra and Madhya Pradesh showed high-level infestation by PBW. CONCLUSION: Inadequate planting of refuges for PBW is the likely explanation for the field resistance to Bt cotton observed in Gujarat. These findings underscore the higher vulnerability of single-gene Bt products relative to dual-gene products expressing Cry1Ac and Cry2Ab2, and the increased risk of resistance evolution with low refuge compliance. PMID- 26016706 TI - Where angels fear to tread: donor bile duct division in living donor liver transplant. PMID- 26016707 TI - Effect of perioperative dexmedetomidine on the endocrine modulators of stress response: a meta-analysis. AB - This study examined the effects of perioperative dexmedetomidine treatment on physiological modulators of surgical stress response. The quality of the included studies was assessed prior to performing meta-analyses of the weighted mean differences in the changes from baseline of stress hormones and interpreted in the light of statistical heterogeneity between the studies. Nineteen studies (844 surgical subjects) data were used for this meta-analysis. Dexmedetomidine administration significantly decreased blood cortisol levels (MUg/dL) postoperatively (mean difference with 95% confidence interval (CI) from controls: -18.78 (-28.45, -9.10); P < 0.05). In the subgroup analysis, the mean difference between dexmedetomidine-treated and saline-treated subjects in the changes from baseline of the cortisol levels was -20.10 (-30.96, -9.25; P < 0.05) but, between dexmedetomidine- and comparator-treated subjects, it was not statistically significantly different (-15.13 (-49.78, 19.52); P < 0.05). Compared with controls, dexmedetomidine treatment also decreased adrenaline and noradrenaline levels significantly (mean difference in the percent changes from baseline: 90.41 (-145.79, -35.03)%; P < 0.05 and -62.82 (-85.47, -0.40.17)%; P < 0.05, respectively). Dexmedetomidine also decreased prolactin levels with a mean difference of -19.42 (-39.37, 0.52) MUg/L (P = 0.06). In conclusion, perioperative use of dexmedetomidine reduces serum catecholamine and cortisol levels but the decrease in cortisol levels was not statistically different from the comparator anaesthetics. More data will be required to assess the effects of dexmedetomidine on corticotropin, prolactin, and growth hormone. PMID- 26016709 TI - [In Process Citation]. PMID- 26016708 TI - [Minimally invasive chest surgery. Is palpation control still necessary with modern computed tomography?]. AB - BACKGROUND: A fundamental argument against minimally invasive oncological chest surgery is the risk of overlooking pulmonary nodules due to a lack of intraoperative palpation. In the literature this risk in the treatment of primary lung cancer is given as up to 8.4 % and as more than 15 % in the surgical treatment of pulmonary metastases. OBJECTIVE: The aim of this study was to evaluate if modern computed tomography (CT) is sensitive enough to replace intraoperative palpation and justify a minimally invasive approach. PATIENTS AND METHODS: The medical records from 92 patients who underwent 95 open lung resections due to pulmonary malignancies from April 2010 through September 2011 at the Medical School Hannover were retrospectively analysed. A comparison was carried out between the lesions detected preoperatively by CT and those removed during surgery and histologically confirmed as being malignant. Patients with more than five nodules suspected of being malignant in the preoperative CT scan were excluded. RESULTS: According to the final histopathological examination 125 malignant nodules were resected and 2 of these were not detected in the preoperative CT scan, which were performed in external hospitals with a slice thickness of 5 mm and 8 mm, respectively. This represents a sensitivity of 98 % for all CT scans in terms of detection of pulmonary nodules. With thin slice CT (slice thickness up to 1.5 mm) a sensitivity of 100 % was even achieved. CONCLUSION: The results demonstrate that a high sensitivity of thin slice CT for detection of lung nodules can be achieved. Based on these results the categorical reservation with respect to thoracoscopic resection of pulmonary metastases should be reconsidered in suitable patients where a minimally invasive resection is possible. The extent of lymph node dissection is not influenced by these data. Further studies with larger sample sizes are warranted to confirm these results. PMID- 26016710 TI - [Living liver donor: indications and technical aspects]. AB - Living donor liver transplantation (LDLT) nowadays represents an important and safe alternative to conventional deceased donor liver transplantation (DDLT). A major concern related to the LDLT procedure is still represented by donor safety because a serious operation not without risks must be carried out on a healthy individual. In the present review of the indications for LDLT the technical concepts of donor surgery, criteria for donor selection and evaluation and morbidity and mortality results related to the procedure are presented. In general, the indications for LDLT are almost the same as for DDLT. The donor hepatectomy (right, left or left lateral) is presented in five main phases. The reported morbidity rates vary between 10 % and 60 % and are strongly related to the experience of the transplant center. The currently reported postoperative mortality rates for left and right hepatectomy are 0.1 % and 0.5 %, respectively. The results of LDLT are similar if not even better than those for DDLT depending on the specific indications. PMID- 26016711 TI - [Liver and lung metastases of colorectal cancer. Long-term survival and prognostic factors]. AB - INTRODUCTION: The resection of liver and lung metastases from colorectal cancer has not yet been completely investigated. The aim of this study was to investigate the overall survival and prognostic factors for patients with liver and lung metastases from colorectal cancer. METHODS: A retrospective review of a prospective database of 52 patients with liver and lung metastases from colorectal cancer, undergoing metastasectomy with curative intent from 1999-2009 at a single institution was carried out. RESULTS: The mean overall survival (OS) was 64 months. For synchronous liver and lung metastases the mean overall survival was 63 months (5-year survival 54 %) and for metachronous liver and lung metastases 74 months (5-year survival 58 %, p = 0.451). A poor prognostic outcome was observed in cases of localization of the primary tumor in the rectum (OS 81 vs. 38 months, p = 0.004), with multiple lung metastases (>= 2 metastases, OS 74 vs. 59 months, p = 0.032) and with disease progression after premetastasectomy chemotherapy (OS 74 vs. 63 vs. 15 months, p < 0.001). No influence on overall survival was detected for bilateral lung metastases, thoracic lymph node metastases, disease recurrence and disease-free interval < 36 months. CONCLUSION: Metastasectomy for liver and lung metastases of colorectal cancer is associated with a good overall survival in selected cases. Patients with liver and lung metastases should not be routinely excluded from metastasectomy and patients with thoracic lymph node metastases should also not be routinely excluded. Negative prognostic factors for survival are localization of the tumor in the rectum, multiple metastases and disease progression after premetastasectomy chemotherapy. Patients with disease progression after premetastasectomy chemotherapy should be excluded from metastasectomy. PMID- 26016712 TI - [Not Available]. PMID- 26016713 TI - [Arterial and portal venous complications after HPB surgical procedures: Interdisciplinary management]. AB - The surgical treatment of hepatopancreatobiliary (HPB) diseases requires complex operative procedures. Within the last decades the morbidity (36-50 %) and mortality (<5 %) of these procedures could be reduced; nonetheless, postoperative complications still occur in 41.2 % of cases. Compared with hepatobiliary procedures, pancreatic surgery shows an increased rate of complications. Postoperative bleeding has a major effect on the outcome and the incidence is 6.7 % after pancreatic surgery and 3.2 % after hepatobiliary surgery. The major causes of early postoperative hemorrhage are related to technical difficulties in surgery whereas late onset postoperative hemorrhage is linked to anastomosis insufficiency, formation of fistulae or abscesses due to vascular arrosion or formation of pseudoaneurysms. In many cases, delayed hemorrhage is preceded by a self-limiting sentinel bleeding. The treatment is dependent on the point in time, location and severity of the hemorrhage. The majority of early postoperative hemorrhages require surgical treatment. Late onset hemorrhage in hemodynamically stable patients is preferably treated by radiological interventions. After interventional hemostatic therapy 8.2 % of patients require secondary procedures. In the case of hemodynamic instability or development of sepsis, a relaparotomy is necessary. The treatment concept includes surgical or interventional remediation of the underlying cause of the hemorrhage. Other causes of postoperative morbidity and mortality are arterial and portal venous stenosis and thrombosis. Following liver resection, thrombosis of the portal vein occurs in 8.5-9.1 % and in 11.6 % following pancreatic resection with vascular involvement. Interventional surgical procedures or conservative treatment are suitable therapeutic options depending on the time of diagnosis and clinical symptoms. The risk of morbidity and mortality after HPB surgery can be reduced only in close interdisciplinary cooperation, which is particularly true for vascular complications. PMID- 26016714 TI - [Biliary fistulas and biliary congestion after hepatopancreaticobiliary surgery]. AB - Biliary complications after hepatopancreaticobiliary surgery can have severe consequences for the long-term quality of life of patients. Adequate and timely diagnosis of the underlying problem by an experienced surgeon is essential. Ultrasonography, computed tomography, contrast-enhanced fluoroscopy of drains and endoscopic retrograde cholangiopancreatography (ERCP) are helpful examinations that can be employed in a step-wise approach. Early re-do surgery is indicated in the initial postoperative course. Interventional methods, such as ERCP and percutaneous transhepatic cholangiodrainage ( PTCD, plus stents and drains) offer a variety of additional therapeutic options that should be used by the experienced interventionalist in a patient-tailored interdisciplinary fashion. PMID- 26016716 TI - Influence of Electron-Withdrawing Substituents on the Electronic Structure of Oxidized Ni and Cu Salen Complexes. AB - Nickel (Ni(Sal(CF3))) and copper (Cu(Sal(CF3))) complexes of an electron-poor salen ligand were prepared, and their one-electron oxidized counterparts were studied using an array of spectroscopic and theoretical methods. The electrochemistry of both complexes exhibited quasi-reversible redox processes at higher potentials in comparison to the M(Sal(R)) (R = (t)Bu, OMe, NMe2) analogues, in line with the electron-withdrawing nature of the para-CF3 substituent. Chemical oxidation, monitored by ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy, afforded their corresponding one-electron oxidized products. Ligand-based oxidation was observed for [Ni(Sal(CF3))](+*), as evidenced by sharp NIR transitions in the UV-vis-NIR spectrum and a broad isotropic signal at g = 2.067 by solution electron paramagnetic resonance (EPR) spectroscopy. Such sharp NIR transitions observed for [Ni(Sal(CF3))](+*) are indicative of a delocalized electronic structure, which is in good agreement with electrochemical measurements and density functional theory (DFT) calculations. In addition, the increased Lewis acidity of [Ni(Sal(CF3))](+*), evident from the EPR g-value and DFT calculations, was further quantified by the binding affinity of axial ligands to [Ni(Sal(CF3))](+*). For [Cu(Sal(CF3))](+), an intense ligand-to metal charge transfer band at 18 700 cm(-1) in the UV-vis-NIR spectrum was observed, which is diagnostic for the formation of a Cu(III) species [J. Am. Chem. Soc., 2008, 130, 15448-15459]. The Cu(III) character for [Cu(Sal(CF3))](+) is further confirmed by (19)F NMR analysis. Taken together, these results show that the electron-deficient salen ligand H2Sal(CF3) increases the Lewis acidity of the coordinating metal center. PMID- 26016717 TI - Higher Baseline BMI is Associated with Greater Reduction of Apnea-Hypopnea Index After Bariatric Surgery. PMID- 26016715 TI - Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis. AB - Metformin is an antihyperglycemic drug that is widely prescribed for type 2 diabetes mellitus and is currently being investigated for the treatment of nonalcoholic steatohepatitis (NASH). NASH is known to alter hepatic membrane transporter expression and drug disposition similarly in humans and rodent models of NASH. Metformin is almost exclusively eliminated through the kidney primarily through active secretion mediated by Oct1, Oct2, and Mate1. The purpose of this study was to determine how NASH affects kidney transporter expression and metformin pharmacokinetics. A single oral dose of [(14)C]metformin was administered to C57BL/6J (wild type [WT]) and diabetic ob/ob mice fed either a control diet or a methionine- and choline-deficient (MCD) diet. Metformin plasma concentrations were slightly increased in the WT/MCD and ob/control groups, whereas plasma concentrations were 4.8-fold higher in ob/MCD mice compared with WT/control. The MCD diet significantly increased plasma half-life and mean residence time and correspondingly decreased oral clearance in both genotypes. These changes in disposition were caused by ob/ob- and MCD diet-specific decreases in the kidney mRNA expression of Oct2 and Mate1, whereas Oct1 mRNA expression was only decreased in ob/MCD mice. These results indicate that the diabetic ob/ob genotype and the MCD disease model alter kidney transporter expression and alter the pharmacokinetics of metformin, potentially increasing the risk of drug toxicity. PMID- 26016718 TI - The economics of counterfeit Avastin: a geospatial and statistical analysis of demographic correlates to FDA warning letters. AB - PURPOSE: In 2012, the Food and Drug Administration (FDA) sent warning notices to clinics and medical practitioners that may have purchased or administered counterfeited versions of the angiogenesis cancer drug Avastin Genentech, South San Francisco, California, USA. The purpose of this study was to explore potential differences in demographic, economic, and healthcare coverage characteristics between areas that received these counterfeit warning notices and those that did not receive notices. The aims of this study are to improve future counterfeit drug surveillance and better assess potential risk factors associated with counterfeit cancer drugs. METHODS: Addresses for warning notices sent to healthcare practitioners were obtained from the FDA and then geocoded using arcgis. Variables chosen for statistical and geospatial analyses were then identified and assessed based on their potential association with Avastin access and affordability. These variables included demographic and economic factors (percent below the poverty line, percent uninsured, and median household income) and healthcare coverage data (percent Medicare enrollees) available from the US Center for Medicare and Medicaid Services. All variables were analyzed at the US county level. RESULTS: Our analysis uncovered 401 distinct US counties where the FDA sent at least one counterfeit Avastin warning notice. A hot spot analysis of notices and variables was carried out using arcgis software to identify and visualize risk features with high and low values of clustering. In a multiple logistic regression model reassessing visually observed geospatial associations, the receipt of a notice was not significantly associated with percent uninsured (p = 0.3121), but was significantly associated with percent Medicare enrollees (OR = 0.874 per 10% increase; p = 0.0121), individuals below federal poverty line (OR = 2.990 per 10% increase; p < 0.0001), and median household income (OR = 2.698 per $10 000 increase; p < 0.0001). CONCLUSIONS: Our study found that county level economic and demographic factors are potentially associated with counterfeit Avastin warning receipt after controlling for the total number of people residing in each county. These geographic associations indicate that individuals in counties where patients have greater ability to afford more expensive treatment, and consequently where providers can seek higher reimbursement, may have been at higher risk to counterfeit Avastin exposure. These findings can help inform future efforts to improve drug safety surveillance and more proactively identify patients at the highest risk for counterfeit cancer drugs. PMID- 26016719 TI - Efficacy of coenzyme Q10 in mitigating spinal cord injury-induced osteoporosis. AB - Spinal cord injury (SCI)-induced osteoporosis may cause mild trauma to bone and increase the risk of bone fracture. The present study aimed to investigate the efficacy of coenzyme Q (CoQ10) on SCI-induced osteoporosis in rats. SCI was induced by surgical transection of the cord at the T10-12 level. Animals were treated with CoQ10 (10 mg/kg; intragastrically) daily from 12 h after the surgery and over 10 subsequent days. At the end of the experimental period, blood was collected from the animals and femurs and tibiae were removed for evaluation using biochemical assays. Treatment with CoQ10 prevented SCI-induced bone loss by rescuing the decreased levels of bone mineral density and bone mineral content observed in the SCI rats. Furthermore, CoQ10 administration reduced bone malondialdehyde levels with a concomitant increase in superoxide dismutase levels, thus alleviating SCI-induced oxidative injury. In addition, serum inflammatory cytokine levels were markedly increased in rats post-SCI, which was attenuated by treatment with CoQ10. Finally, the osteoclast-specific genes receptor activator of nuclear factor kappa-B ligand and cathepsin K were significantly upregulated and the osteoblast-specific gene core-binding factor alpha 1 in the femur was downregulated following SCI, which was effectively restored following treatment with CoQ10. The results suggested that CoQ10 treatment may be effective in attenuating SCI-induced osteoporosis. PMID- 26016720 TI - Decrease of B-type natriuretic peptide to less than 200 pg/mL predicts longer survival in cardiac immunoglobulin light chain amyloidosis. AB - Immunoglobulin light chain (AL) amyloidosis is a systemic disorder caused by depositions of insoluble amyloid fibrils that are composed of fragments of monoclonal light chains produced by abnormal plasma cells. The prognosis is reported to be poor; median survival time (MST) is 1-2 years overall, and is 6 months in patients with cardiac involvement. We here report the treatment outcomes of 24 patients with AL amyloidosis at our hospital between January 2008 and December 2012, including 11 patients with cardiac involvement. MST from the diagnosis was significantly shorter (9.8 months) in patients with cardiac involvement. Of these, patients who achieved a decrease of B-type natriuretic peptide (BNP) to <200 pg/mL after treatment survived longer than patients who did not (MST: not reached vs. 6.1 months; p = 0.003, log-rank test). The median time to decrease BNP to <200 pg/mL was 6.3 months. The decline of BNP to 200 pg/mL or less during treatment predicts longer survival in patients with cardiac AL amyloidosis. PMID- 26016721 TI - Groebke-Blackburn-Bienayme multicomponent reaction: emerging chemistry for drug discovery. AB - The Groebke-Blackburn-Bienayme reaction (GBBR) is used for the one-pot synthesis of therapeutically relevant fused imidazoles bridgehead nitrogen heterocyclic compounds from readily available aldehyde, isocyanide and amidine building blocks. The reaction is driven by a wide range of catalysts and can be performed either under solvent or solvent-free conditions, or under microwave irradiation as heat source. The GBBR products can be used for the synthesis of a variety of more complex scaffolds via postmodification reactions. These include cyclization and nucleophilic substitution as well as further MCRs. The GBBR reaction has seen diverse applications in combinatorial and medicinal chemistry and its products are of great use in drug discovery. In this review, we summarize the efforts of the chemistry community in the progress and applications of GBBR since 1998. This review also includes some biological profiles and synthetic scopes of GBBR products. The component variations, postmodifications and secondary transformations will also be discussed throughout this review. PMID- 26016722 TI - One-pot four-component synthesis of highly substituted [1,2,4]triazolo[1,5 a]pyrimidines. AB - A green one-pot four-component strategy has been developed for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives using an amine, 2,2,6 trimethyl-4H-1,3-dioxin-4-one, an aldehyde, and 3-amino-1,2,4-triazole in the presence of a catalytic amount of p-toluenesulfonic acid in water within 4-6 h. PMID- 26016723 TI - Iodine-catalyzed sp3 C-H bond activation by selenium dioxide: synthesis of diindolylmethanes and di(3-indolyl)selanides. AB - An efficient reaction protocol was developed for the synthesis of several diindolylmethane derivatives via the [Formula: see text] C-H bond activation of aryl methyl ketones by [Formula: see text] and indoles in the presence of catalytic amounts of [Formula: see text] at 80 [Formula: see text] using dioxane as solvent. Unexpectedly, an interesting class of di(3-indolyl)selenide compounds was isolated when the reaction was carried out at room temperature. PMID- 26016724 TI - A facile environment-friendly one-pot two-step regioselective synthetic strategy for 3,7-diarylpyrazolo[1,5-a]pyrimidines related to zaleplon and 3,6 diarylpyrazolo[1,5-a]pyrimidine-7-amines assisted by KHSO4 in aqueous media. AB - 3-Aminopyrazoles required for the synthesis of pyrazolo[1,5-a]pyrimidines were obtained by the reaction of enaminonitriles with hydrazine hydrate. The resulting aminopyrazoles are reacted with formylated acetophenones under reflux at [Formula: see text] assisted by KHSO[Formula: see text] in aqueous media to form regioselectively 3,7-diarylpyrazolo[1,5-a]pyrimidines and 3,6-diarylpyrazolo[1,5 a]pyrimidine-7-amines. X-ray crystallography of selected compounds 5b and 7i further confirmed the regioselective formation of these products. PMID- 26016725 TI - Vaginal douching and association with sexually transmitted infections among female sex workers in a prefecture of Yunnan Province, China. AB - Vaginal douching is a common practice and has been hypothesised to increase a woman's risk for human of contracting HIV and sexually transmitted infections (STIs). Our objective was to assess the prevalence of douching and its association with STIs, genital symptoms and HIV/STI knowledge among female sex workers (FSWs). We conducted a cross-sectional study of 837 FSWs with interviews and laboratory tests for HIV/STIs in a prefecture of Yunnan Province in southern China. Vaginal douching was reported by 84% of the women. We found a higher prevalence of vaginal douching practice among FSWs of Han ethnicity, and who were single or cohabitating. Douching was also significantly more common among more educated FSWs and those with greater knowledge of HIV/STIs, and as well as in FSWs who had experienced clinical symptoms in the previous 12 months. Douching was linked to higher risks of HIV (adjusted odds ratio = 2.29; 95% confidence interval 1.01-5.23) and herpes simplex virus type 2 infections (adjusted odds ratio = 2.18; 95% confidence interval 1.46-3.24) after adjusting for confounding factors. Medical professionals and public health workers should correct women's misconception about the effectiveness of douching and discourage women from douching through educational activities. More prospective studies among FSWs are urgently required to identify the relationship between vaginal douching and HIV/STIs. PMID- 26016726 TI - Characteristics and genotype profiles of antiretroviral-naive patients entering a Southern US HIV outpatient clinic 2009-2012. AB - The US city of New Orleans was ranked second in the nation for estimated HIV case rates in 2011. Opt-out testing was established at the Interim Louisiana Hospital in New Orleans in 2013. The majority of new diagnoses were referred to the HIV outpatient program. We conducted a retrospective chart review of newly referred antiretroviral-naive patients establishing HIV care between January 2009 and June 2013 to characterise demographic and genotype profiles to assist in clinical management and needed services. Of the eligible 226 patients, 68% were men, and 88% were African American. Nearly half of the study patients were younger than 35 years of age. Forty-six percent had an initial CD4 count <200 cells/mm(3), and 39% had a HIV viral load >100,000 copies/mL. The antiretroviral class with the most common major mutation was the non-nucleoside reverse transcriptase inhibitors (NNRTIs) where K103N was the most common major NNRTI mutation at presentation. We observed that male patients showed more advanced disease with later presentation to care, confirming the need for earlier HIV diagnosis. When considering initial antiretroviral therapy, baseline genotype information is encouraged, particularly if considering a NNRTI-based regimen. PMID- 26016727 TI - Future Directions in Emotion Dysregulation and Youth Psychopathology. AB - This article reviews central nervous system substrates and autonomic correlates of emotion dysregulation and offers several suggestions for future research. Studies conducted in the last two decades indicate that effective emotion regulation requires efficient top-down, cortically mediated regulation of bottom up, subcortically mediated individual differences in trait impulsivity and trait anxiety. Without making critical distinctions between highly heritable individual differences in trait impulsivity and trait anxiety, versus less heritable and more socialized deficiencies in emotion regulation, progress in understanding the development of psychopathology among children and adolescents will be hampered. Future research can also be improved by measuring emotion dysregulation across multiple level of analysis, specifying physiological mechanisms through which operant reinforcement shapes emotional lability, improving the internal and external validity of psychophysiological measures, integrating emotion dysregulation into factor analytic and behavioral genetic models of psychopathology, identifying molecular genetic risk for emotion dysregulation, and expanding neuroimaging research on emotion dysregulation among children and adolescents. PMID- 26016729 TI - Development of immunoaffinity chromatography to specifically knockout baicalin from Gegenqinlian Decoction. AB - Specific knockout technology provides a powerful tool to confirm the role of target compounds in a plant or its derived prescriptions, and this principle is the same as that with knockout genes. In this study, we generated an immunoaffinity column conjugated with an anti-baicalin monoclonal antibody and then loaded Gegenqinlian Decoction extracts, followed by washing with deionized water and an elution solvent. The results of the high-performance liquid chromatography fingerprints and high-performance liquid chromatography with mass spectrometry showed that the immunoaffinity column was able to specifically knockout baicalin, oroxylin A-7-O-glucuronide, wogonoside, wogonin, and baicalein from Gegenqinlian Decoction. A reliable one-step method to specifically knockout baicalin was established with an immunoaffinity column. Gegenqinlian Decoction and its knocked-out fraction induced the expression of superoxide dismutase and were compared in human umbilical vein endothelial cells cultured with a high glucose concentration; the results showed that the Gegenqinlian Decoction and its knocked-out fraction showed no significant difference, which indicated that the baicalin, oroxylin A-7-O-glucuronide, wogonoside, wogonin, and baicalein that were knocked out by the immunoaffinity column might not be key compounds for the induction of Gegenqinlian Decoction superoxide dismutase secretion. PMID- 26016728 TI - Phenolic compounds prevent the oligomerization of alpha-synuclein and reduce synaptic toxicity. AB - Lewy bodies, mainly composed of alpha-synuclein (alphaS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited alphaS fibrillation and destabilized preformed alphaS fibrils. Cumulative evidence suggests that low-order alphaS oligomers are neurotoxic and critical species in the pathogenesis of alpha-synucleinopathies. To develop disease modifying therapies for alpha-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on alphaS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited alphaS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of alphaS, whereas direct binding of RA to monomeric alphaS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated alphaS synaptic toxicity by inhibition of alphaS oligomerization. These results suggest that Myr and RA prevent the alphaS aggregation process, reducing the neurotoxicity of alphaS oligomers. To develop disease modifying therapies for alpha-synucleinopathies, we examined effects of phenolic compounds on alpha synuclein (alphaS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited alphaS oligomerization and secondary structure conversion. Myr and RA ameliorated alphaS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent alphaS aggregation process and reduce the neurotoxicity of alphaS oligomers. Phenolic compounds are good candidates of disease modifying drugs for alpha synucleinopathies. PMID- 26016730 TI - Lymphatic Mapping and Sentinel Node Biopsy in Melanoma. PMID- 26016731 TI - Advanced glycation end-products accelerate the cardiac aging process through the receptor for advanced glycation end-products/transforming growth factor-beta-Smad signaling pathway in cardiac fibroblasts. AB - AIMS: The current study was carried out to evaluate the effect of advanced glycation end-products (AGE) on cardiac aging and to explore its underlying mechanisms. METHODS: Neonatal rat cardiac fibroblasts were cultured and divided into four groups: control; AGE; AGE + receptor for AGE antibody and AGE + SB431542 (transforming growth factor-beta [TGF-beta]/Smad signaling pathway inhibitor, 10 MUmol/L) group. After being cultured for 48 h, the cells were harvested and the senescence-associated beta-galactosidase expression was analyzed. Then the level of p16, TGF-beta, Smad/p-smad and matrix metalloproteinases-2 was evaluated by western blot. RESULTS: Significantly increased senescence-associated beta-galactosidase activity as well as p16 level was observed in the AGE group. Furthermore, AGE also significantly increased the TGF-beta1, p-smad2/3 and metalloproteinases-2 expression in cardiac fibroblasts (all P < 0.01). Meanwhile, either pretreatment with receptor for AGE-Ab or SB431542 significantly inhibited the upregulated cardiac senescence (beta galactosidase activity and P16) and fibrosis-associated (TGF-beta1, p-smad2/3 and metalloproteinases-2) markers induced by AGE. CONCLUSIONS: Taken together, all these results suggested that AGE are an important factor for cardiac aging and fibrosis, whereas the receptor for AGE and TGF-beta/Smad signaling pathway might be involved in the AGE-induced cardiac aging process. PMID- 26016732 TI - Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus. AB - Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients. PMID- 26016733 TI - Teaching telehealth consultation skills. AB - BACKGROUND: Although teleconsultations have been used for many years in Australia, there has been a recent increase following new government incentives. There is a paucity of literature on enabling medical students to acquire the relevant skills. With a focus on equipping students for practice in rural and remote areas, our medical school has developed an innovative clinical skills lesson to prepare our students for their rural practice placements. METHODS: This lesson was delivered to all students in their third year of training in small groups to enable interactive learning. The objectives of the lesson were to familiarise students with: the various methods of conducting teleconsultations currently in use; the legal and ethical considerations; the technical and procedural issues; and the barriers and benefits for patients and doctors. Students rotated through four different stations over 2 hours and the lesson was evaluated using a student survey. RESULTS: Medical students self-reported statistically significant improvements in understanding the issues and procedures, and in confidence in conducting a telehealth consultation. DISCUSSION: Analysis of the results and student comments demonstrated that students recognise the value of telemedicine learning, and benefit from formal teaching on all aspects of telemedicine, including technology, ethics and protocols. Interestingly, the students found the opportunity to discuss areas such as the ethics of, and barriers to, the use of teleconsultations to be the most challenging and helpful of all of the stations. There is a paucity of literature on enabling medical students to acquire the relevant [teleconsultation] skills. PMID- 26016734 TI - Validation of Patient Selection for Endovascular Aneurysm Repair or Open Repair of Abdominal Aortic Aneurysm - Single-Center Study. AB - BACKGROUND: To validate the criteria for endovascular aneurysm repair (EVAR) or open repair of abdominal aortic aneurysm (AAA) at Nagoya University Hospital, the results of both treatments were retrospectively compared. METHODS AND RESULTS: Patient selection for EVAR was primarily based on suitable anatomy, minimum age 75 years, and significant comorbidity. From June 2007 to April 2014, 426 patients were treated via EVAR (EVAR group) and 346 patients were treated with open surgery (OS group). The mortality rates of the EVAR and OS groups were not significantly different (0.2% vs. 1.1%; P=0.33). Patient age, operation time, amount of bleeding, and duration of hospital stay were significantly lower in the EVAR group compared with the OS group. The incidence of comorbidity was higher in the EVAR group compared with the OS group. The incidence of early postoperative complications was significantly higher in the OS group, whereas the incidence of late complications for both groups was similar. The cumulative aneurysm-related survival rates were similar (98.9% vs. 98.5%; P=0.767). The cumulative survival rates and reintervention-free rates at 5 years were lower for the EVAR group (76% vs. 89%, P=0.019; 81% vs. 89%, P=0.046). CONCLUSIONS: Patient selection practices and criteria for EVAR and open repair at Nagoya University Hospital are generally acceptable. PMID- 26016735 TI - Maternal Death Due to Stroke Associated With Pregnancy-Induced Hypertension. AB - BACKGROUND: The aim of this study was to clarify the clinical features of maternal death due to stroke associated with pregnancy-induced hypertension (PIH) in Japan. METHODS AND RESULTS: Reported maternal deaths occurring between 2010 and 2012 throughout Japan were analyzed by the Maternal Death Exploratory Committee. Among a total of 154 reports of maternal death, those due to stroke with (n=12) or without (n=13) PIH were compared. Cerebral stroke occurred more frequently in the third trimester and during the second stage of labor in deaths with PIH, whereas it occurred at any time point in deaths not involving PIH. Although 83% of patients with PIH who died had experienced initial symptoms in a hospital, more than half of them required maternal transport due to lack of medical resources. Among the patients without PIH, some vascular abnormalities were identified, but no evidence was found among the patients with PIH. In addition, 58% of PIH cases resulting in stroke were complicated by hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. CONCLUSIONS: Appropriate management of PIH during pregnancy and labor, including anti hypertensive therapy and early maternal transport to tertiary hospital, may reduce the maternal death rate. PMID- 26016736 TI - Red blood cell sodium transport in patients with cirrhosis. AB - Patients with advanced cirrhosis have abnormal sodium homoeostasis. The study was undertaken to quantify the sodium transport across the plasma membrane of red blood cells (RBC) in patients with cirrhosis. RBC efflux and influx of sodium were studied in vitro with tracer (22) Na(+) according to linear kinetics in 24 patients with cirrhosis and 14 healthy controls. The sodium efflux was modified by ouabain (O), furosemide (F) and a combination of O and F (O + F). RBC sodium was significantly decreased (4.6 versus control 6.3 mmol l(-1) , P<0.001) and directly related to serum sodium (r = 0.57, P<0.05). The RBC fractional sodium efflux was higher in patients with cirrhosis (+46%, P<0.01) compared to controls. Inhibition in both high (145 mmol l(-1) )- and low (120 mmol l(-1) )-sodium buffers showed that the F-insensitive sodium efflux was twice as high in cirrhosis as in controls (P = 0.03-0.007), especially the O-sensitive, F insensitive efflux was increased (+ 225%, P = 0.01-0.006). Fractional F-sensitive transport was normal in cirrhosis. RBC sodium influx was largely normal in cirrhosis. In conclusion, RBC sodium content is reduced in patients with cirrhosis with a direct relation to serum sodium. Increased RBC sodium efflux is especially related to ouabain-sensitive, furosemide-insensitive transport and thus most likely due to upregulated activity of the sodium-potassium pump. The study gives no evidence to an altered intracellular/extracellular sodium ratio or to a reduced fractional furosemide-sensitive sodium transport in cirrhosis. PMID- 26016737 TI - Immuno-based detection of Shiga toxin-producing pathogenic Escherichia coli in food - A review on current approaches and potential strategies for optimization. AB - Certain pathogenic Escherichia coli known as Shiga toxin (Stx)-producing E. coli (STEC) are a public health threat to the consumer, and are problematic for the food industry. Food products containing STEC are deemed unfit for human consumption, and STEC illnesses can cause hemolytic uremic syndrome (HUS), a disease affecting the kidneys in susceptible individuals. Optimizing detection methods in foods have been focused on more prompt and accurate analysis. This review addresses the role and applications of immuno-based assays for STEC detection in food systems. Immunoassay antibody capture systems and flow cytometry platforms have been implemented into several food-based detection systems. By applying antibodies that will interact with target microorganisms, immunoassays can be used to directly detect and quantify pathogens. Immuno-based protocols could potentially be further implemented into the food industry, limit the duration of the detection process and increase accuracy. PMID- 26016738 TI - Congenital dacryocystoceles controlled by nCPAP via nasal mask in a neonate. AB - Congenital dacryocystocele is a relatively rare type of nasolacrimal duct obstruction that may induce respiratory distress during the early neonatal period. We encountered a case of bilateral congenital dacryocystoceles with intranasal cysts in a premature infant delivered at 34 weeks of gestation. The patient developed symptoms of respiratory failure immediately after birth, but no ophthalmologic symptoms. Treatment with nasal continuous positive airway pressure via a nasal mask, instead of a nasal prong, effectively relieved the symptoms. Early diagnosis and appropriate treatment are critical for infants with nasal obstruction. PMID- 26016739 TI - Exercise is More Effective at Altering Gut Microbial Composition and Producing Stable Changes in Lean Mass in Juvenile versus Adult Male F344 Rats. AB - The mammalian intestine harbors a complex microbial ecosystem that influences many aspects of host physiology. Exposure to specific microbes early in development affects host metabolism, immune function, and behavior across the lifespan. Just as the physiology of the developing organism undergoes a period of plasticity, the developing microbial ecosystem is characterized by instability and may also be more sensitive to change. Early life thus presents a window of opportunity for manipulations that produce adaptive changes in microbial composition. Recent insights have revealed that increasing physical activity can increase the abundance of beneficial microbial species. We therefore investigated whether six weeks of wheel running initiated in the juvenile period (postnatal day 24) would produce more robust and stable changes in microbial communities versus exercise initiated in adulthood (postnatal day 70) in male F344 rats. 16S rRNA gene sequencing was used to characterize the microbial composition of juvenile versus adult runners and their sedentary counterparts across multiple time points during exercise and following exercise cessation. Alpha diversity measures revealed that the microbial communities of young runners were less even and diverse, a community structure that reflects volatility and malleability. Juvenile onset exercise altered several phyla and, notably, increased Bacteroidetes and decreased Firmicutes, a configuration associated with leanness. At the genus level of taxonomy, exercise altered more genera in juveniles than in the adults and produced patterns associated with adaptive metabolic consequences. Given the potential of these changes to contribute to a lean phenotype, we examined body composition in juvenile versus adult runners. Interestingly, exercise produced persistent increases in lean body mass in juvenile but not adult runners. Taken together, these results indicate that the impact of exercise on gut microbiota composition as well as body composition may depend on the developmental stage during which exercise is initiated. PMID- 26016740 TI - Serological Evidence and Risk Factors for Swine Influenza Infections among Chinese Swine Workers in Guangdong Province. AB - During July to September 2014, we performed a controlled, cross-sectional, seroepidemiologic study among 203 swine workers and 115 control subjects in Guangdong Province. Sera were tested using a hemagglutination inhibition assay against locally-isolated swine H3N2 and H1N1 viruses and commercially-obtained human influenza viral antigens. We found swine workers had a greater prevalence and odds of seropositivity against the swine H3N2 virus (17.3% vs. 7.0%; adjusted OR, 3.4; 95% CI, 1.1 -10.7). Younger age, self-report of a respiratory illness during the last 12 months, and seropositivity against seasonal H3N2 virus were identified as significant risk factors for seropositivity against swine H3N2 virus. As swine workers in China may be exposed to novel influenza viruses, it seems prudent for China to conduct special surveillance for such viruses among them. It also seems wise to offer such workers seasonal influenza vaccines with a goal to reduce cross-species influenza virus transmission. PMID- 26016742 TI - Axon guidance: Setting up for seeing in slow motion. PMID- 26016741 TI - Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. AB - BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long term prophylaxis with twice-weekly intravenous injections of plasma-derived C1 inhibitor (pdC1-INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1-INH has not been studied in patients with HAE. METHODS: This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model-derived steady-state trough C1-INH functional activity. RESULTS: After SC CSL830 administration, a dose-dependent increase in trough functional C1-INH activity was observed. C1-INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1-INH SC injection with CSL830 showed a lower peak-to-trough ratio and more consistent exposures. All doses were well tolerated. Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event. CONCLUSIONS: Subcutaneous volume-reduced CSL830 was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1 INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation. PMID- 26016743 TI - Neural circuits: Pruning the projections. PMID- 26016745 TI - Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. AB - Ghrelin, a stomach-derived orexigenic peptide, transmits starvation signals to the hypothalamus via the vagus afferent nerve. Peripheral administration of ghrelin does not induce food intake in high fat diet (HFD)-induced obese mice. We investigated whether this ghrelin resistance was caused by dysfunction of the vagus afferent pathway. Administration (s.c.) of ghrelin did not induce food intake, suppression of oxygen consumption, electrical activity of the vagal afferent nerve, phosphorylation of ERK2 and AMP-activated protein kinase alpha in the nodose ganglion, or Fos expression in hypothalamic arcuate nucleus of mice fed a HFD for 12 weeks. Administration of anti-ghrelin IgG did not induce suppression of food intake in HFD-fed mice. Expression levels of ghrelin receptor mRNA in the nodose ganglion and hypothalamus of HFD-fed mice were reduced. Inflammatory responses, including upregulation of macrophage/microglia markers and inflammatory cytokines, occurred in the nodose ganglion and hypothalamus of HFD-fed mice. A HFD blunted ghrelin signaling in the nodose ganglion via a mechanism involving in situ activation of inflammation. These results indicate that ghrelin resistance in the obese state may be caused by dysregulation of ghrelin signaling via the vagal afferent. PMID- 26016746 TI - Dipeptidyl peptidase 4 inhibitor improves brain insulin sensitivity, but fails to prevent cognitive impairment in orchiectomy obese rats. AB - It is unclear whether the dipeptidyl peptidase 4 (DPP4) inhibitor can counteract brain insulin resistance, brain mitochondrial dysfunction, impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived obese rats. We hypothesized that DPP4 inhibitor vildagliptin improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. Thirty male Wistar rats received either a sham-operated (S, n=6) or bilateral orchiectomy (ORX, n=24). ORX rats were divided into two groups and fed with either a normal diet (ND (NDO)) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n=6/subgroup) to receive either a vehicle or vildagliptin (3 mg/kg per day, p.o.) for 4 weeks. After treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined in each rat. We found that HFO rats exhibited peripheral and brain insulin resistance, brain mitochondrial dysfunction, impaired hippocampal synaptic plasticity and cognitive decline. NDO rats did not develop peripheral and brain insulin resistance. However, impaired hippocampal synaptic plasticity and cognitive decline occurred. Vildagliptin significantly improved peripheral insulin sensitivity, restored brain insulin sensitivity and decreased brain mitochondrial reactive oxygen species production in HFO rats. However, vildagliptin did not restore hippocampal synaptic plasticity and cognitive function in both NDO and HFO rats. These findings suggest that vildagliptin could not counteract the impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived subjects, despite its effects on improved peripheral and brain insulin sensitivity as well as brain mitochondrial function. PMID- 26016747 TI - Effects of GnRH immunization on the reproductive axis and thymulin. AB - The bidirectional regulation of thymulin in the reproductive-endocrine function of the hypothalamic-pituitary-gonadal (HPG) axis of rats immunized against GnRH remains largely unclear. We explored the alterations in hormones in the HPG axis in immunized rats to dissect the repressive effect of immunization on thymulin, and to clarify the interrelation of reproductive hormones and thymulin in vivo. The results showed that, in the first 2 weeks of booster immunization, thymulin was repressed when reproductive hormones were severely reduced. The self-feedback regulation of thymulin was then stimulated in later immune stages: the rising circulating thymulin upregulated LH and FSH, including GnRH in the hypothalamus, although the levels of those hormones were still significantly lower than in the control groups. In astrocytes, thymulin produced a feedback effect in regulated GnRH neurons. However, in the arcuate nucleus (Arc) and the median eminence (ME), the mediator of astrocytes and other glial cells were also directly affected by reproductive hormones. Thus, in immunized rats, the expression of glial fibrillary acidic protein was distinctly stimulated in the Arc and ME. This study demonstrated that thymulin was downregulated by immunization against GnRH in early stage. Subsequently, the self-feedback regulation was provoked by low circulating thymulin. Thereafter, rising thymulin levels promoted pituitary gonadotropins levels, while acting directly on GnRH neurons, which was mediated by astrocytes in a region-dependent manner in the hypothalamus. PMID- 26016744 TI - Interoceptive predictions in the brain. AB - Intuition suggests that perception follows sensation and therefore bodily feelings originate in the body. However, recent evidence goes against this logic: interoceptive experience may largely reflect limbic predictions about the expected state of the body that are constrained by ascending visceral sensations. In this Opinion article, we introduce the Embodied Predictive Interoception Coding model, which integrates an anatomical model of corticocortical connections with Bayesian active inference principles, to propose that agranular visceromotor cortices contribute to interoception by issuing interoceptive predictions. We then discuss how disruptions in interoceptive predictions could function as a common vulnerability for mental and physical illness. PMID- 26016748 TI - When acute pain becomes chronic. PMID- 26016749 TI - Immunosuppressive treatment for giant cell arteritis: where do we stand? PMID- 26016750 TI - Cutaneous vasculitis associated with severe bacterial infections. A study of 27 patients from a series of 766 cutaneous vasculitis. AB - OBJECTIVES: To assess the clinical spectrum of severe bacterial infections presenting as cutaneous vasculitis (CV) in a defined population. METHODS: Unselected series of 766 patients with CV diagnosed at a single university referral center. RESULTS: An underlying severe bacterial infection was diagnosed in 27 (22 men/5 women; mean age +/- standard deviation [SD]: 53 +/- 18 years) of 766 cases presenting with CV (3.5%). These infections were: pneumonia (n=8), endocarditis (n=6), meningitis (n=4), intra-abdominal infections (n=3), septic arthritis (n=2), septicaemia (n=2), septic bursitis (n=1), and urinary tract infection (n=1). All the patients were admitted for suspected CV. The median delay from admission to the diagnosis of infection was 4 days. A typical palpable purpura without relevant visceral vasculitic involvement was the main clinical manifestation. Patients with severe bacterial infections were older, with male predominance, had more frequently fever, constitutional symptoms, focal infectious features, and leukocytosis with left shift and anaemia than the remaining patients with CV. Although antibiotics were prescribed in all the patients, seven also required the use of low-dose corticosteroids to achieve complete resolution of the cutaneous lesions. Most patients experienced full recovery but two of them underwent prosthetic cardiac valve replacement, and another two died due to infection-related complications. CONCLUSIONS: CV may be the presenting manifestation of a severe underlying bacterial infection. Physicians should keep in mind this fact to make an early diagnosis of infection and, consequently, prevent life-threatening complications. PMID- 26016751 TI - Predictors of renal survival in ANCA-associated vasculitis. Validation of a histopatological classification schema and review of the literature. AB - OBJECTIVES: In 2010 a histopathological classification of ANCA-associated glomerulonephritis was proposed to predict the outcomes at diagnosis. Our aim was to validate the proposed classification in our cohort of patients and to compare the studies already published. METHODS: The data of 93 patients who underwent kidney biopsy in a single Italian centre within 15 years were retrospectively collected. RESULTS: The 10-year renal and patients' survival were 60% and 81%, respectively. Biopsies were classified as 21% focal, 30% crescentic, 39% mixed and 10% sclerotic. Survival without ESRD at 5 years was 82% in focal, 37% in crescentic, 81% in mixed and 51% in sclerotic group. The Kaplan-Meier analysis highlights that renal survival was not different between sclerotic and crescentic groups (p=0.9) but both had a significantly worse prognosis than focal (p=0.04 and 0.015 respectively) and mixed groups (p=0.05 and 0.03 respectively). Focal and mixed groups had the same renal survival (p=0.7). At multivariate analysis the independent predictors of end-stage renal disease were less than 20% of normal glomeruli at kidney biopsy (p=0.022), high serum creatinine (p=0.009) and arterial hypertension at presentation (p= 0.006). CONCLUSIONS: In our cohort, the proposed histological classification was not predictive of renal prognosis. The focal and the mixed classes had the same prognosis and a significantly better renal outcome than both the crescentic and the sclerotic classes. At multivariate analysis among the histological features only less than 20% of normal glomeruli defines the renal prognosis together with renal function and arterial hypertension at baseline. PMID- 26016752 TI - Circulating microRNA expression pattern separates patients with anti-neutrophil cytoplasmic antibody associated vasculitis from healthy controls. AB - OBJECTIVES: Antineutrophil cytoplasmic antibody associated vasculitis (AAV) has an unpredictable course and better biomarkers are needed. Micro-RNAs in body fluids are protected from degradation and might be used as biomarkers for diagnosis and prognosis, here we explore the potential in AAV. METHODS: Plasma samples from two AAV cohorts (n=67 and 38) were compared with samples from healthy controls (n=27 and 45) and disease controls (n=20). A panel of 32 miRNAs was measured using a microfluidic quantitative real-time PCR system, and results were compared with clinical data. RESULTS: Seven individual miRNAs were differently expressed compared to controls in both cohorts; miR-29a, -34a, -142 3p and -383 were up-regulated and miR-20a, -92a and -221 were down-regulated. Cluster analysis as well as principal component analysis (PCA) indicated that patterns of miRNA expression differentiate AAV patients from healthy subjects as well as from renal transplant recipients. Loadings plots indicated similar contribution of the same miRNAs in both cohorts to the PCA. Renal engagement was important for miRNA expression but consistent correlations between estimated glomerular filtration rate and miRNA levels were not found. We found no significant correlation between treatment regimens and circulating miRNA levels. CONCLUSIONS: In this first study ever on circulating miRNA profiles in AAV, we find clear indication of their potential as biomarkers for diagnosis and classification, but more studies are needed to identify the best markers as well as the mechanisms responsible for variations. PMID- 26016753 TI - There is no benefit in routinely monitoring ANCA titres in patients with granulomatosis with polyangiitis. AB - OBJECTIVES: To analyse the link between antineutrophil cytoplasmic antibody (ANCA) levels and risk of relapse in patients with granulomatosis with polyangiitis (GPA), as the clinical benefit of monitoring ANCA levels is uncertain. METHODS: A retrospective analysis was made of all charts available from 43 patients diagnosed with GPA, fulfilling The American College of Rheumatology 1990 criteria, and followed between 1994 and 2012 at a general internal medicine department of a university hospital. Clinical and biochemical data (i.e. anti-proteinase 3 (PR3) levels) were collected and correlated. RESULTS: 43 relapses occurred in 25 patients (58.1% of 43 patients). When blood samples are routinely taken at a follow-up visit (i.e. low pre-test probability, +/- 5.5%) in the GPA-population, a 75%-increase in the PR3-level or its reappearance has only limited positive predictive value (PPV 15.0% and 22.5% respectively) for predicting relapse. Adversely, when clinical suspicion of relapse is high (i.e. high pre-test probability, for example 50%), an increase of 75% or reappearance of PR3 makes relapse even more likely (PPV 77.5%, 81.6% respectively). Conversely, a high negative predictive value (NPV) of 99.3% and a negative likelihood ratio (LR-) of 0.12 suggest that, in the absence of PR3, relapse is unlikely if patients had detectable ANCAs at diagnosis. CONCLUSIONS: Routine ANCA monitoring in patients diagnosed with GPA has limited value. However, targeted determination of ANCA levels may be useful if a relapse is clinically suspected (i.e. high pre-test probability). PMID- 26016755 TI - Is temporal artery biopsy essential in all cases of suspected giant cell arteritis? AB - OBJECTIVES: Temporal artery biopsy (TAB) is performed in cases of suspected giant cell arteritis (GCA), and is the gold-standard for diagnosis of the disease. Current American College of Rheumatology (ACR) classification criteria may aid in the diagnosis of GCA. We aimed to assess whether TAB is essential in all cases of suspected GCA, or whether ACR criteria can replace the need for this procedure in some cases. METHODS: Retrospective analysis of 216 patients who underwent TAB in a single hospital between 2000 and 2013. Pre-TAB and post-TAB ACR criteria were calculated. Sensitivity and specificity of ACR criteria for the diagnosis of GCA were assessed. RESULTS: Overall, 55 patients had histological evidence of GCA.Out of 161 patients with negative TAB findings, 34 were diagnosed with GCA, and 127 were not diagnosed with GCA. Sensitivity of TAB for the diagnosis of GCA was 61.7%. Sensitivity and specificity of ACR criteria for diagnosis of GCA before performing TAB were 68.5% and 58%, respectively. Sensitivity and specificity of ACR criteria after performing TAB biopsy were 89.8% and 64.5%, respectively. CONCLUSIONS: Temporal artery biopsy should be performed in the majority of patients with suspected GCA, and may be obviated only in patients with a pre-TAB ACR score of <= 1. In all other cases, when GCA is suspected, ACR criteria should not be a substitute to TAB, as they are not highly specific. PMID- 26016754 TI - Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts. AB - OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score >= 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 +/- 13.9 vs. 46.8 +/- 17.3 years), had higher Birmingham vasculitis activity score (19.5 +/- 9.1 vs. 16.9 +/- 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations. PMID- 26016756 TI - Effectiveness and safety of medium-dose prednisone in giant cell arteritis: a retrospective cohort study of 103 patients. AB - OBJECTIVES: To compare the effectiveness and safety of medium-dose (MD) and high dose (HD) prednisone regimens and to identify factors related to remission with a target maintenance dose of prednisone in patients with giant cell arteritis (GCA). METHODS: Retrospective cohort study conducted in an autoimmune diseases unit. Patients received <= 30 mg (MD group) or >30 mg (HD group) of daily prednisone as monotherapy or combined with methylprednisolone pulses and/or methotrexate, at the discretion of the physician. The primary endpoint was time to clinical and biological remission receiving a prednisone maintenance dose <= 7.5 mg/day. Factors related to the primary endpoint were identified by Cox regression analysis. RESULTS: Overall, 103 patients (MD=53, HD=50) were followed for a median (95%CI) of 2.85 (2.57-3.52) years. Both groups exhibited similar baseline features except for ocular ischaemic manifestations (MD=21%, HD=48%, p=0.004). Patients in the MD group had a shorter time to the primary endpoint (MD=186 [147-223], HD=236 [177-276] days, HR=1.70 [1.12-2.57], p=0.01) with no increase in relapses (MD=39%, HD=50%, p=0.29) or GCA complications (MD=11%, HD=16%, p=0.49). Cumulative prednisone doses at 6 months were 2.47 +/- 0.70 g for MD patients and 3.86 +/- 1.85 g for HD patients (p<0.001). Adverse effects were more frequent among HD recipients (MD=43%, HD=66%, p=0.02). The only independent factor associated with the primary endpoint was the use of methylprednisolone pulses (HR=2.21 [1.31-3.71], p=0.003). CONCLUSIONS: MD prednisone regimen may be an effective and safe alternative to HD prednisone regimen in GCA. Induction with methylprednisolone pulses predicts a better response, allowing for a less intensive prednisone regimen. PMID- 26016757 TI - Glucocorticoid usage in giant cell arteritis over six decades (1950 to 2009). AB - OBJECTIVES: To evaluate the trends in glucocorticoid (GC) therapy in patients with giant cell arteritis (GCA). METHODS: Using a population-based inception cohort, GC therapy details were collected for all patients with GCA diagnosed between 1950-2009. GC usage for patients diagnosed with GCA between 1980-2009 was compared to those diagnosed between 1950-1979. RESULTS: The mean starting dose was similar in both time-periods but the mean cumulative dosages at different time points were significantly higher for patients diagnosed between 1980-2009 than in 1950-1979 (at 1-year: 6.3 vs. 4.1g; and at 5 years 10.7 vs. 7.6g, respectively, p<0.001). The median time to permanent discontinuation of GC was 2.6 years for 1980-2009 vs. 1.5 years for 1950-1979 (p=0.004). The risk for GC associated adverse events was similar in both time periods (p=0.52). CONCLUSIONS: GCA patients diagnosed in the last three decades were treated with higher cumulative GC doses and were less likely to achieve GC discontinuation. However, their risks for GC-related complications were not significantly higher than their earlier counterparts. PMID- 26016758 TI - Fast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study. AB - OBJECTIVES: To investigate the effectiveness of a fast track pathway (FTP) on sight loss in patients with suspected giant cell arteritis (GCA). METHODS: A longitudinal observational cohort study was conducted in the secondary care rheumatology department. One hundred and thirty-five newly referred suspected GCA patients seen via the FTP (Jan. 2012-Dec. 2013) were compared to 81 patients seen through the conventional referral and review system (Jan. 2009-Dec. 2011). RESULTS: The FTP resulted in significant reduction in irreversible sight loss from 37.0% (as seen in the historical cohort 2009-2011) to 9.0 % (2012-2013, OR 0.17, p=0.001). Adjustment for clinical and demographic parameters including known risk factors for GCA associated blindness did not significantly change the primary result (OR 0.08, p=0.001). FTP resulted in a reduction of time from symptom onset to diagnosis, particularly by reduction of time from general practitioner's (GP) referral to the rheumatology review (79% of FTP patients were seen within one working day compared to 64.6 % in the conventional pathway, p=0.023). The FTP has seen a reduction in number of GP appointments. CONCLUSIONS: There was a significant reduction of permanent sight loss with a fast track GCA pathway. The effect may be due to multiple factors including better GP education and reduction in delayed diagnosis. These results need verification at other sites. PMID- 26016759 TI - Lack of association between endothelial nitric oxide synthase gene polymorphisms with vasculitis: a meta-analysis. AB - OBJECTIVES: We carried out this meta-analysis to evaluate the relationship between eNOS polymorphisms (G894T, T-786C, and intron-4ba) and vasculitis. METHODS: We systematically searched PubMed, EMBASE and the Cochrane Library for related genetic association studies. The associations between the G894T, T-786C and intron 4ba polymorphisms of eNOS and vasculitis were conducted using the recessive model and the dominant model. Odds ratio (OR) with 95% confidence interval (CI) of each study were calculated. Cochran's Q test was used to evaluate the between-study heterogeneity. RESULTS: A total of 17 studies were included in our study. Twelve studies with 1213 cases and 1499 controls were included in the G894T association study. The pooled OR of T allele compared to C allele in recessive model was 1.19 (95%CI: 0.76-1.87, p=0.44) in dominant model and was 1.25 (95%CI: 0.70-2.23, p=0.56) in recessive model, respectively. Nine studies with 910 cases and 1062 controls were included in the intron -4ba association study. The pooled OR of b allele compared with intron-4a allele was 1.02 (95%CI: 0.60-1.72, p=0.95) in dominant model and was 0.84 (95%CI: 0.58-1.21, p=0.35) in recessive model. No association was found between T-786C and vasculitis in both the dominant 0.81(95% CI: 0.59-1.11, p=0.19) and recessive model 0.87 (95%CI: 0.55-1.36, p=0.53). CONCLUSIONS: The eNOS G894T, T-786C and intron4ba polymorphisms are not associated with vasculitis. PMID- 26016760 TI - The ultrasound compression sign to diagnose temporal giant cell arteritis shows an excellent interobserver agreement. AB - OBJECTIVES: To compare the diagnostic performance between a vascular specialist and a rheumatologist not familiar with vascular ultrasound when applying the compression sign for the diagnosis of temporal arteritis. METHODS: Sixty consecutive patients with suspicion of giant cell arteritis were examined by both examiners. Compression of the temporal artery on both sides (stem and both branches) was performed to define whether signs of vasculitis, no vasculitis or an indefinite result were present. Each examiner was blinded to the result of the other. RESULTS: In 59/60 patients, the examiners found an identical result. The interobserver agreement (Krippendorf alpha) was 0.92. CONCLUSIONS: The new compression sign for the diagnosis of temporal arteritis is a simple and robust sonographic marker with an excellent interobserver agreement. PMID- 26016762 TI - Risk factors for pneumocystis pneumonia in giant cell arteritis: a single-centre cohort study. AB - OBJECTIVES: Pneumocystis jiroveci pneumonia (PCP) is a life-threatening opportunistic infection. Few PCP cases in giant cell arteritis (GCA) have been described, but it remains unknown, which patients need PCP prophylaxis. METHODS: Sixty-two patients with GCA from a prospective cohort were studied to identify treatment-related predictors of PCP infection. RESULTS: Four PCP infections occurred, all in patients treated with methotrexate in addition to prednisone. Moreover, PCP is associated with higher cumulative PDN doses and severe lymphocytopenia (<400/MUl). CONCLUSIONS: Our findings support PCP-prophylaxis in GCA patients who are treated with methotrexate and PDN, and need high prednisone doses to achieve remission, or develop severe lymphocytopenia. PMID- 26016763 TI - Life-threatening onset of systemic vasculitis requiring intensive care unit admission: a case series. AB - OBJECTIVES: Onset of ANCA-associated vasculitis (AAV) can be abrupt with life threatening manifestations requiring Intensive Care Unit (ICU) admission. A high level of suspicion leading to prompt diagnosis is essential. Our objective was to investigate the epidemiologic characteristics and the type of life-threatening manifestations. METHODS: Medical records of AAV patients were analysed, selecting those with an ICU onset to identify predictive signs or symptoms and past medical history warnings useful for diagnosis. RESULTS: Out of 90 patients with AAV, 10 (11.1%) showed an ICU onset. The most frequent AAV diagnosed in the ICU was eosinophilic granulomatosis with polyangiitis (EGPA) (60%), followed by granulomatosis with polyangiitis (GPA) (20%) and microscopic polyangiitis (MPA) (20%). Cardio-pulmonary involvement was the main cause for ICU admission (70%) and significantly distinguished the ICU onset group from other AAV. The most frequent anamnestic warnings were history of asthma (50%), nasal polyps (30%), eosinophilia (30%). Symptoms shortly preceding ICU admission were arthralgia, fever (30%) and purpuric lesions (20%). ANCA were positive in 60% of patients. Mean Birmingham Vasculitis Activity Score (BVAS) at diagnosis was 16+/-8.43 and 0.88+/-1.45 at the end of follow up. All patients survived with a 10% rate of chronic kidney disease and a mean Vasculitis Damage Index (VDI) of 2+/-1.15. CONCLUSIONS: Keeping a high level of suspicion for AAV is mandatory, particularly when treating life-threatening onset manifestations in the ICU. A history of asthma, nasal polyps, eosinophilia and arthralgia should always be investigated. ANCA are negative in about half of cases, therefore clinical expertise and strict collaboration with the rheumatologist are still pivotal. PMID- 26016764 TI - Gender differences in clinical and angiographic findings of patients with Takayasu arteritis. AB - OBJECTIVES: Because Takayasu arteritis (TA) predominantly affects females, few data regarding gender differences have been reported. The aim of the present study is to describe clinical features and angiographic findings of patients with TA according to gender. METHODS: According to the 1990 American College of Rheumatology criteria, 294 patients were diagnosed with TA between September 1994 and April 2014 at a single tertiary hospital. We reviewed clinical, laboratory, and radiologic data at the time of diagnosis. RESULTS: Among the 294 patients studied, 257 (87.4%) were female (male:female ratio=1:6.9). Female patients had a higher tendency to exhibit blood pressure differences between arms (p=0.595) and a weak pulse at the brachial artery (p=0.063). In male patients, we observed higher serum creatinine levels (p=0.038) and hypertension more frequently (p=0.061) than in females. Females exhibited more common lesions in the thoracic aorta and its branches, while males had more frequent lesions in the abdominal aorta and its branches. An analysis of angiographic classification according to the International TA Conference in Tokyo 1994 classification revealed that male patients had a higher incidence of type IV and females showed a higher incidence of types I, IIa, and IIb. CONCLUSIONS: Female patients with TA have more frequent involvement of the thoracic aorta and its branches, whereas involvement of the abdominal aorta and its branches is more common in males. Considering these gender-specific differences, adjustment of diagnostic criteria for TA according to gender may be necessary. PMID- 26016761 TI - Tobacco differentially affects the clinical-biological phenotypes of ANCA associated vasculitides. AB - OBJECTIVES: To describe the clinical-biological phenotype of ANCA-associated vasculitides (AAV) according to tobacco consumption. METHODS: We conducted a descriptive study to describe that phenotype at diagnosis according to tobacco use. AAV patients entered in the French Vasculitis Study Group database with data on smoking habits were analysed. The clinical-biological phenotypes at diagnosis were compared according to current tobacco use (current smokers) or not (including previous and never smokers). RESULTS: AAV diagnoses were: granulomatosis with polyangiitis (GPA) for 583 (50%), eosinophilic granulomatosis with polyangiitis (EGPA) for 326 (28%) and microscopic polyangiitis (MPA) for 256 (22%). Among them, 973 patients (84%) never smoked, 116 (10%) were previous smokers and only 76 (6%) were current smokers. Current smokers were younger age (p=0.01), male gender (p=0.004), less frequently EGPA (p=0.017) and MPA (p=0.036), and had less frequent kidney involvement (p=0.10). Among GPA patients, current smokers, compared to non-current smokers, were younger age (p=0.02), male gender (p=0.08), more frequent skin involvement (p=0.03) and less frequent ENT involvement (p=0.06). Among EGPA patients, current smokers, compared to non current smokers, were also younger (p=0.028) and had less frequent constitutional symptoms (p=0.02), arthralgias (p=0.04), renal involvement (p=0.025) and MPO-ANCA (p=0.02). Finally, analysis of MPA patients was impossible because only 6 (2%) were current smokers. CONCLUSIONS: These results suggest that tobacco use could differentially affect GPA and EGPA clinical-biological phenotypes, and support the role of environmental exposures in AAV development and its phenotype. PMID- 26016765 TI - Small-vessel vasculitis with prominent IgG4 positive plasma cell infiltrates as potential part of the spectrum of IgG4-related disease: a case report. AB - IgG4-related disease (IgG4-RD) is a systemic entity characterised by multiorgan inflammatory lesions with abundant IgG4+ plasma cells, obliterative phlebitis, and storiform fibrosis. Involvement of several organs such as the pancreas, gastrointestinal tract, salivary glands, periorbital tissue and lymph nodes has been described. Up to now, vascular involvement by IgG4-RD has been thought to be essentially confined to large vessels. We present a patient with small-vessel systemic vasculitis involving muscle, peripheral nerve and kidney (glomerulonephritis) in the context of IgG4-RD diagnosed on the basis of elevated serum IgG4+ concentrations and histologically consistent signs in all biopsied tissues. Thoracic and abdominal aortic aneurysms in addition to aortitis, suggestive of large-vessel involvement, were also present. This observation expands the spectrum of vascular involvement in the context of IgG4-RD and supports the inclusion of IgG4-RD in the category of vasculitis associated with systemic disorder. PMID- 26016766 TI - Successful treatment of gynaecological involvement of granulomatosis with polyangiitis (Wegener's granulomatosis) by rituximab. AB - Granulomatosis with polyangiitis, formerly called Wegener's granulomatosis, is a disease for which the treatment options are increasing, with the recent publication of several studies concerning the use of rituximab. The disease typically involves the upper airways, lungs and kidneys, but other far less frequent localisations are possible. Here, we describe a case of isolated relapse of granulomatosis with polyangiitis affecting the uterine cervix and upper vagina which dramatically responded to rituximab therapy, after failure of methotrexate treatment. This is the first documented response to rituximab of gynaecological involvement in granulomatosis with polyangiitis. PMID- 26016767 TI - Systemic vasculitides: a critical digest of the most recent literature. AB - Herewith we provide our annual digest of the recent literature on systemic vasculitides. In this manuscript, we reviewed all the articles published during the last 12 months on large-, medium- and small-vessel vasculitis and selected the most relevant studies regarding the epidemiology, pathogenesis and management of systemic vasculitis. In particular, we focused the attention on giant cell arteritis, ANCA-associated vasculitis and cryoglobulinaemia. PMID- 26016768 TI - Respiratory and otolaryngologic manifestations of giant cell arteritis. AB - OBJECTIVES: The classical presentation of giant cell arteritis (GCA) includes the new onset of headache, scalp tenderness, facial pain or jaw claudication in an older patient. Many patients with GCA have features consistent with the diagnosis of polymyalgia rheumatic (PMR) and nearly all have elevated markers of inflammation such as the erythrocyte sedimentation rate (ESR) or the serum C reactive protein (CRP). Respiratory and ear-nose-throat (ENT) signs and symptoms such as cough, tongue infarction, trismus, hearing loss and facial swelling are less commonly described, yet they may be the initial presentation of GCA. Our aim was to review the published literature on the topic of respiratory and otologic manifestations of GCA. METHODS: A literature search was performed on PUBMED and MEDLINE using the following keywords: GCA, temporal arteritis, pulmonary, respiratory, ENT, cough, tongue necrosis. RESULTS: The upper and lower airways manifestations of GCA include a wide variety of conditions that could be caused by ischaemia due to the vasculitis. CONCLUSIONS: It is important to recognize these atypical presentations because they may be the sole initial manifestation of the disease. Early suspicion and confirmation of the diagnosis of GCA can help to prevent more catastrophic consequences of unrecognized disease, including stroke and blindness. PMID- 26016769 TI - Pulmonary arterial hypertension and orbital involvement in a patient with eosinophilic granulomatosis with polyangiitis. PMID- 26016770 TI - Increased co-expression of the natural killer cell receptor NKG2D and further natural killer cell receptors on CD4+ T cells in granulomatosis with polyangiitis. PMID- 26016771 TI - The relationship between peer support, medication adherence, and quality of life among patients with vasculitis. PMID- 26016772 TI - Age specific survival rates of Steller sea lions at rookeries with divergent population trends in the Russian Far East. AB - After a dramatic population decline, Steller sea lions have begun to recover throughout most of their range. However, Steller sea lions in the Western Aleutians and Commander Islands are continuing to decline. Comparing survival rates between regions with different population trends may provide insights into the factors driving the dynamics, but published data on vital rates have been extremely scarce, especially in regions where the populations are still declining. Fortunately, an unprecedented dataset of marked Steller sea lions at rookeries in the Russian Far East is available, allowing us to determine age and sex specific survival in sea lions up to 22 years old. We focused on survival rates in three areas in the Russian range with differing population trends: the Commander Islands (Medny Island rookery), Eastern Kamchatka (Kozlov Cape rookery) and the Kuril Islands (four rookeries). Survival rates differed between these three regions, though not necessarily as predicted by population trends. Pup survival was higher where the populations were declining (Medny Island) or not recovering (Kozlov Cape) than in all Kuril Island rookeries. The lowest adult (> 3 years old) female survival was found on Medny Island and this may be responsible for the continued population decline there. However, the highest adult survival was found at Kozlov Cape, not in the Kuril Islands where the population is increasing, so we suggest that differences in birth rates might be an important driver of these divergent population trends. High pup survival on the Commander Islands and Kamchatka Coast may be a consequence of less frequent (e.g. biennial) reproduction there, which may permit females that skip birth years to invest more in their offspring, leading to higher pup survival, but this hypothesis awaits measurement of birth rates in these areas. PMID- 26016773 TI - Bubble pump: scalable strategy for in-plane liquid routing. AB - We present an on-chip liquid routing technique intended for application in well based microfluidic systems that require long-term active pumping at low to medium flowrates. Our technique requires only one fluidic feature layer, one pneumatic control line and does not rely on flexible membranes and mechanical or moving parts. The presented bubble pump is therefore compatible with both elastomeric and rigid substrate materials and the associated scalable manufacturing processes. Directed liquid flow was achieved in a microchannel by an in-series configuration of two previously described "bubble gates", i.e., by gas-bubble enabled miniature gate valves. Only one time-dependent pressure signal is required and initiates at the upstream (active) bubble gate a reciprocating bubble motion. Applied at the downstream (passive) gate a time-constant gas pressure level is applied. In its rest state, the passive gate remains closed and only temporarily opens while the liquid pressure rises due to the active gate's reciprocating bubble motion. We have designed, fabricated and consistently operated our bubble pump with a variety of working liquids for >72 hours. Flow rates of 0-5.5 MUl min(-1), were obtained and depended on the selected geometric dimensions, working fluids and actuation frequencies. The maximum operational pressure was 2.9 kPa-9.1 kPa and depended on the interfacial tension of the working fluids. Attainable flow rates compared favorably with those of available micropumps. We achieved flow rate enhancements of 30-100% by operating two bubble pumps in tandem and demonstrated scalability of the concept in a multi-well format with 12 individually and uniformly perfused microchannels (variation in flow rate <7%). We envision the demonstrated concept to allow for the consistent on-chip delivery of a wide range of different liquids that may even include highly reactive or moisture sensitive solutions. The presented bubble pump may provide active flow control for analytical and point-of-care diagnostic devices, as well as for microfluidic cells culture and organ-on-chip platforms. PMID- 26016774 TI - The Soluble Heparin-Binding EGF-Like Growth Factor Stimulates EGF Receptor Trafficking to the Nucleus. AB - Most ligands of epidermal growth factor receptor (EGFR) have the ability to induce EGFR translocation into the nucleus, where EGFR acts as an important transcriptional regulator. Soluble form of heparin-binding EGF-like growth factor (sHB-EGF) is one of the ligands for EGFR in many cell types; however, there is no evidence for the ability of sHB-EGF to induce EGFR nuclear importation. Here, we demonstrated that treatment of A431 cells with sHB-EGF resulted in nuclear localization of EGFR and such translocation occurs via retrograde pathway. It was shown by confocal microscopy and co-immunoprecipitation assay that the translocation complex consisted of both ligand and receptor. The chromatin immunoprecipitation assay showed the association of sHB-EGF-EGFR complex with promoter region of cyclin D1 in the cell nucleus and this association was prevented by application of EGFR kinase inhibitor AG-1478. The obtained data suggest that sHB-EGF acts similarly to other EGFR ligands and is capable to induce EGFR nuclear translocation as a part of ligand-receptor complex in a tyrosine phosphorylation-dependent manner. PMID- 26016775 TI - Development of a nucleic Acid extraction procedure for simultaneous recovery of DNA and RNA from diverse microbes in water. AB - Drinking and environmental water samples contain a diverse array of constituents that can interfere with molecular testing techniques, especially when large volumes of water are concentrated to the small volumes needed for effective molecular analysis. In this study, a suite of enteric viruses, bacteria, and protozoan parasites were seeded into concentrated source water and finished drinking water samples, in order to investigate the relative performance of nucleic acid extraction techniques for molecular testing. Real-time PCR and reverse transcription-PCR crossing threshold (CT) values were used as the metrics for evaluating relative performance. Experimental results were used to develop a guanidinium isothiocyanate-based lysis buffer (UNEX buffer) that enabled effective simultaneous extraction and recovery of DNA and RNA from the suite of study microbes. Procedures for bead beating, nucleic acid purification, and PCR facilitation were also developed and integrated in the protocol. The final lysis buffer and sample preparation procedure was found to be effective for a panel of drinking water and source water concentrates when compared to commercial nucleic acid extraction kits. The UNEX buffer-based extraction protocol enabled PCR detection of six study microbes, in 100 L finished water samples from four drinking water treatment facilities, within three CT values (i.e., within 90% difference) of the reagent-grade water control. The results from this study indicate that this newly formulated lysis buffer and sample preparation procedure can be useful for standardized molecular testing of drinking and environmental waters. PMID- 26016776 TI - Photoinduced Ultrafast Intramolecular Excited-State Energy Transfer in the Silylene-Bridged Biphenyl and Stilbene (SBS) System: A Nonadiabatic Dynamics Point of View. AB - The photoinduced intramolecular excited-state energy-transfer (EET) process in conjugated polymers has received a great deal of research interest because of its important role in the light harvesting and energy transport of organic photovoltaic materials in photoelectric devices. In this work, the silylene bridged biphenyl and stilbene (SBS) system was chosen as a simplified model system to obtain physical insight into the photoinduced intramolecular energy transfer between the different building units of the SBS copolymer. In the SBS system, the vinylbiphenyl and vinylstilbene moieties serve as the donor (D) unit and the acceptor (A) unit, respectively. The ultrafast excited-state dynamics of the SBS system was investigated from the point of view of nonadiabatic dynamics with the surface-hopping method at the TDDFT level. The first two excited states (S1 and S2) are characterized by local excitations at the acceptor (vinylstilbene) and donor (vinylbiphenyl) units, respectively. Ultrafast S2-S1 decay is responsible for the intramolecular D-A excitonic energy transfer. The geometric distortion of the D moiety play an essential role in this EET process, whereas the A moiety remains unchanged during the nonadiabatic dynamics simulation. The present work provides a direct dynamical approach to understand the ultrafast intramolecular energy-transfer dynamics in SBS copolymers and other similar organic photovoltaic copolymers. PMID- 26016777 TI - SeqGL Identifies Context-Dependent Binding Signals in Genome-Wide Regulatory Element Maps. AB - Genome-wide maps of transcription factor (TF) occupancy and regions of open chromatin implicitly contain DNA sequence signals for multiple factors. We present SeqGL, a novel de novo motif discovery algorithm to identify multiple TF sequence signals from ChIP-, DNase-, and ATAC-seq profiles. SeqGL trains a discriminative model using a k-mer feature representation together with group lasso regularization to extract a collection of sequence signals that distinguish peak sequences from flanking regions. Benchmarked on over 100 ChIP-seq experiments, SeqGL outperformed traditional motif discovery tools in discriminative accuracy. Furthermore, SeqGL can be naturally used with multitask learning to identify genomic and cell-type context determinants of TF binding. SeqGL successfully scales to the large multiplicity of sequence signals in DNase- or ATAC-seq maps. In particular, SeqGL was able to identify a number of ChIP-seq validated sequence signals that were not found by traditional motif discovery algorithms. Thus compared to widely used motif discovery algorithms, SeqGL demonstrates both greater discriminative accuracy and higher sensitivity for detecting the DNA sequence signals underlying regulatory element maps. SeqGL is available at http://cbio.mskcc.org/public/Leslie/SeqGL/. PMID- 26016778 TI - Perception of naturopathy for female patients with metastatic gynecological cancer: A qualitative study. AB - OBJECTIVE: Women with gynecological cancer have been reported as very high users of complementary medicine. The goal of our study was to explore the perceptions of patients with an advanced gynecological cancer who use naturopathy as complementary medicine. We were looking more specifically at patients' opinions on the effect of naturopathy on their quality of life and its relation to conventional oncological treatments. METHOD: This pilot qualitative study used semistructured interviews, and data were analyzed using grounded theory and qualitative methods. The main criterion for inclusion in the study was the use of naturopathy as a treatment complementary to conventional cancer treatment for gynecological metastatic cancer on the oncology day care unit. RESULTS: Six patients were included until data saturation. They express the physical and psychological impact of treatments and disease. Usually, chemotherapy is perceived as something that may be curative or may at least lead to remission. Unlike conventional treatments, naturopathy is not perceived as drugs, and it is seen as a way to relieve symptoms, improve well-being, and as a way of enabling them to take an active decision-making role in their care journey. Patients want to have more information about naturopathy. SIGNIFICANCE OF RESULTS: This study suggests that patients are aware of the benefits of a specific cancer treatment as chemotherapy, but they resort to naturopathy for symptom control, and also to take a more active role during treatment. PMID- 26016779 TI - Can butterflies evade fire? Pupa location and heat tolerance in fire prone habitats of Florida. AB - Butterflies such as the atala hairstreak, Eumaeus atala Poey, and the frosted elfin, Callophrys irus Godart, are restricted to frequently disturbed habitats where their larval host plants occur. Pupae of these butterflies are noted to reside at the base of host plants or in the leaf litter and soil, which may allow them to escape direct mortality by fire, a prominent disturbance in many areas they inhabit. The capacity of these species to cope with fire is a critical consideration for land management and conservation strategies in the locations where they are found. Survival of E. atala pupae in relation to temperature and duration of heat pulse was tested using controlled water bath experiments and a series of prescribed fire field experiments. Survival of E. atala pupae was correlated to peak temperature and heat exposure in both laboratory and field trials. In addition, E. atala survival following field trials was correlated to depth of burial; complete mortality was observed for pupae at the soil surface. Fifty percent of E. atala survived the heat generated by prescribed fire when experimentally placed at depths >= 1.75 cm, suggesting that pupation of butterflies in the soil at depth can protect from fatal temperatures caused by fire. For a species such as E. atala that pupates above ground, a population reduction from a burn event is a significant loss, and so decreasing the impact of prescribed fire on populations is critical. PMID- 26016780 TI - Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation, design and in vivo evaluation. AB - The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56 +/- 8.57 nm, 0.27 +/- 0.028 and 83.66 +/- 5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA(r) tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p < 0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA(r) tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC. PMID- 26016781 TI - Behavior of Malondialdehyde in Oil-in-Water Emulsions. AB - The impact of temperature, emulsifier, and protein type on the reactivity of malondialdehyde in oil-in-water emulsions was elucidated. Malondialdehyde recoveries in aqueous buffer, protein solutions, saturated oil, and fully hydrogenated coconut oil-in-water emulsions stabilized by whey proteins or Tween 20 at 4 or 40 degrees C were compared. At both temperatures, the reactivity of malondialdehyde in aqueous buffer was the same. In protein solutions, malondialdehyde concentrations were reduced further and its decrease was protein dependent. Similar trends were found for emulsions. Surprisingly, malondialdehyde was very reactive in saturated oil because only 15% was recovered at 40 degrees C. However, the degradation in oil proved to be strongly temperature-dependent; at 4 degrees C, losses amounted to only 8%. This study revealed that malondialdehyde is a very reactive molecule, both in the presence and absence of proteins. Its use as a general oxidation marker should therefore be considered with care. PMID- 26016782 TI - Clinical Differences between Subtypes of Atrial Fibrillation and Flutter: Cross Sectional Registry of 407 Patients. AB - INTRODUCTION: Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce. OBJECTIVE: To investigate the arrhythmia subtype of atrial fibrillation and flutter patients in the emergency setting and compare the clinical profile, thromboembolic risk and anticoagulants use. METHODS: Cross-sectional retrospective study, with data collection from medical records of every patient treated for atrial fibrillation and flutter in the emergency department of Instituto de Cardiologia do Rio Grande do Sul during the first trimester of 2012. RESULTS: We included 407 patients (356 had atrial fibrillation and 51 had flutter). Patients with paroxysmal atrial fibrillation were in average 5 years younger than those with persistent atrial fibrillation. Compared to paroxysmal atrial fibrillation patients, those with persistent atrial fibrillation and flutter had larger atrial diameter (48.6 +/- 7.2 vs. 47.2 +/- 6.2 vs. 42.3 +/- 6.4; p < 0.01) and lower left ventricular ejection fraction (66.8 +/- 11 vs. 53.9 +/- 17 vs. 57.4 +/- 16; p < 0.01). The prevalence of stroke and heart failure was higher in persistent atrial fibrillation and flutter patients. Those with paroxysmal atrial fibrillation and flutter had higher prevalence of CHADS2 score of zero when compared to those with persistent atrial fibrillation (27.8% vs. 18% vs. 4.9%; p < 0.01). The prevalence of anticoagulation in patients with CHA2DS2-Vasc <= 2 was 40%. CONCLUSIONS: The population in our registry was similar in its comorbidities and demographic profile to those of North American and European registries. Despite the high thromboembolic risk, the use of anticoagulants was low, revealing difficulties for incorporating guideline recommendations. Public health strategies should be adopted in order to improve these rates. PMID- 26016783 TI - Impact of physical activity interventions on blood pressure in Brazilian populations. AB - BACKGROUND: High blood pressure is associated with cardiovascular disease, which is the leading cause of mortality in the Brazilian population. Lifestyle changes, including physical activity, are important for lowering blood pressure levels and decreasing the costs associated with outcomes. OBJECTIVE: Assess the impact of physical activity interventions on blood pressure in Brazilian individuals. METHODS: Meta-analysis and systematic review of studies published until May 2014, retrieved from several health sciences databases. Seven studies with 493 participants were included. The analysis included parallel studies of physical activity interventions in adult populations in Brazil with a description of blood pressure (mmHg) before and after the intervention in the control and intervention groups. RESULTS: Of 390 retrieved studies, eight matched the proposed inclusion criteria for the systematic review and seven randomized clinical trials were included in the meta-analysis. Physical activity interventions included aerobic and resistance exercises. There was a reduction of -10.09 (95% CI: -18.76 to 1.43 mmHg) in the systolic and -7.47 (95% CI: -11.30 to -3.63 mmHg) in the diastolic blood pressure. CONCLUSIONS: Available evidence on the effects of physical activity on blood pressure in the Brazilian population shows a homogeneous and significant effect at both systolic and diastolic blood pressures. However, the strength of the included studies was low and the methodological quality was also low and/or regular. Larger studies with more rigorous methodology are necessary to build robust evidence. PMID- 26016785 TI - Comparison of inhibitory activity of bioactive molecules on the dextransucrase from Streptococcus mutans. AB - The effect of chitosan with different molecular weights and other natural substances on dextransucrase (DSase) activity from a representative oral pathogen Streptococcus mutans was elucidated. Among other bioactive substances, amino monosaccharides such as glucosamine, mannosamine, and galactosamine exerted the enzyme inhibitory activity over 95% of DSase. The specified hydrolysates derived from the hydrolysis of high molecular weight chitosan (HMWC) designated to CTSN, CTSN-P, CTSN-B, and CTSN-S with different molecular weights ranging from 3 to 8 kDa showed the similar inhibitory activity toward DSase. Also, the hyaluronic acid (MW 8.9 kDa), sulfated chitin, and amino-monosaccharides demonstrated the significant activity, CTSN, CTSN-P, CTSN-B, and CTSN-S are of potent bioactive substances that can be prepared in the cheapest way compared with other molecules tested available for antibacterial agent useful for human oral health. PMID- 26016784 TI - Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression. AB - BACKGROUND: Previous reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers. OBJECTIVE: To assess the association between changes in lipid markers and regression of CPV using published data. METHODS: We collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV. RESULTS: Twenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non-HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume. CONCLUSION: A significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression. PMID- 26016786 TI - Aggregated clumps of lithistid sponges: a singular, reef-like bathyal habitat with relevant paleontological connections. AB - The advent of deep-sea exploration using video cameras has uncovered extensive sponge aggregations in virtually all oceans. Yet, a distinct type is herein reported from the Mediterranean: a monospecific reef-like formation built by the lithistid demosponge Leiodermatium pfeifferae. Erect, plate-like individuals (up to 80 cm) form bulky clumps, making up to 1.8 m high mounds (1.14 m on average) on the bottom, at a 760 m-deep seamount named SSS. The siliceous skeletal frameworks of the lithistids persist after sponge death, serving as a complex 3D substratum where new lithistids recruit, along with a varied fauna of other sessile and vagile organisms. The intricate aggregation of lithistid mounds functions as a "reef" formation, architecturally different from the archetypal "demosponge gardens" with disaggregating siliceous skeletons. Leiodermatium pfeifferae also occurred at two additional, close seamounts (EBJ and EBS), but, unlike at SSS, the isolated individuals never formed accretive clumps. The general oceanographic variables (temperature, salinity, dissolved nutrients, chlorophyll, and oxygen) revealed only minimal between-seamount differences, which cannot explain why sponge abundance at SSS is about two orders of magnitude higher than at EBJ or EBS. Large areas of the dense SSS aggregation were damaged, with detached and broken sponges and a few tangled fishing lines. Satellite vessel monitoring revealed low fishing activity around these seamounts. In contrast, international plans for gas and oil extraction at those locations raise serious concerns over the need for protecting urgently this unique, vulnerable habitat to avoid further alteration. Modern lithistids are a relict fauna from Jurassic and Cretaceous reefs and the roots of the very genus Leiodermatium can be traced back to those fossil formations. Therefore, understanding the causes behind the discovered lithistid aggregation is critical not only to its preservation, but also to elucidate how the extraordinary Mesozoic lithistid formations developed and functioned. PMID- 26016787 TI - Avian poxvirus in a free-range juvenile speckled (rock) pigeon (Columba guinea). AB - A flightless wild juvenile rock pigeon (Columba guinea) with pox-like lesions was picked up on the premises of the Faculty of Veterinary Science, University of Pretoria, Onderstepoort. The pigeon was housed overnight for possible treatment the following day but died before any other intervention could be instituted. At necropsy, coalescing masses of yellowish nodular cutaneous tumour-like lesions principally on the featherless areas were noticed on the dead pigeon's head as well as the beak. Histological examination of the sampled skin lesions revealed multifocal areas of hypertrophic and hyperplastic epidermal epithelial cells with eosinophilic intracytoplasmic inclusion bodies (Bollinger bodies). Extract from the lesion was processed and inoculated on the chorioallantoic membranes (CAM) of 11-day-old embryonated chicken eggs and this produced pocks on one of the CAM at day 7 post-inoculation. Electron microscopy confirmed the presence of poxvirus in the CAM with the pock lesions. PMID- 26016789 TI - Cancer screening: continuing instability. PMID- 26016788 TI - Efficient Mapping of Sulfated Glycotopes by Negative Ion Mode nanoLC-MS/MS-Based Sulfoglycomic Analysis of Permethylated Glycans. AB - We have previously developed the enabling techniques for sulfoglycomics based on mass spectrometry (MS) analysis of permethylated glycans, which preserves the attractive features of more reliable MS/MS sequencing compared with that performed on native glycans, while providing an easy way to separate and hence enrich the sulfated glycans. Unlike LC-MS/MS analysis of native glycans in negative ion mode that has been more widely in use, the characteristics and potential benefits of similar applications based on permethylated sulfated glycans have not been fully investigated. We report here the important features of reverse phase-based nanoLC-MS/MS analysis of permethylated sulfated glycans in negative ion mode and demonstrate that complementary sets of diagnostic fragment ions afforded can allow rapid identification of various fucosylated, sialylated, sulfated glycotopes and definitive determination of the location of sulfate in a way difficult to achieve by other means. A parallel acquisition of both higher collision energy and trap-based MS(2) coupled with a product dependent MS(3) is conceivably the most productive sulfoglycomic workflow currently possible and the manually curated fragmentation characteristics presented here will allow future developments in automating data analysis. PMID- 26016790 TI - Cancer screening in France: third edition of the EDIFICE survey. AB - The EDIFICE programme began in 2005 and set out to provide a clearer insight over time into the participation of the French population in cancer screening. EDIFICE 3 was conducted in 2011 by phone interviews among a representative sample of 1603 individuals aged between 40 and 75 years using the quota method. The analysis focused on the target populations (50-74 years) of the national screening programmes for breast and colorectal cancer. The same populations were also assessed with respect to prostate cancer screening. In 2005, 93% of the sample population had undergone at least one mammogram in their lifetime; this figure reached 94% in 2008 and 95% in 2011. Compliance with recommended intervals improved between 2005 and 2011, and significantly so for women aged 65-74 years. In 2005, 25% of respondents reported having undergone at least one colorectal cancer screening test; this figure reached 38% in 2008 and 59% in 2011. Recommended intervals were respected by 30 and 51% in 2008 and 2011, respectively. In 2005, 2008 and 2011, a total of 36, 49 and 50% of men reported having undergone at least one prostate cancer screening test. This rate decreased significantly in men aged 50-59 years between 2008 and 2011 (44 vs. 37%, P<=0.05). Attendance rates in national screening programmes are high and stable for breast cancer, and although currently improving for colorectal cancer, the European guideline target has not yet been reached. Despite the absence of recommendations for prostate cancer screening, participation remains constant. PMID- 26016791 TI - Breast cancer screening controversy: too much or not enough? AB - The Cochrane analysis exploring the risk/benefit ratio of breast cancer screening resulted in a controversy worldwide spread by the mass media. Our survey sought to assess the impact of this controversy in terms of breast cancer screening awareness and attendance. A nationwide observational study, recorded in the EDIFICE iterative surveys, with a representative sample of 451 women aged 40-75 years, living in France, was carried out in the 3 months after the start of the controversy in January 2013. Of the 405 women with no personal history of cancer, 69 (17%) declared having heard of the controversy (aware group). Women remembering the controversy were more likely to belong to higher socioprofessional categories and to have a higher level of education. The most frequently remembered issues were overdiagnosis (38%), unreliability (16%) and radiation risk (9%). Compared with women who were unaware of the controversy, the aware group knew more about the limits of breast cancer screening (undiagnosed cancers, 20 vs. 7%, P<0.05 and risk of false positives, 20 vs. 2%, P<0.05) and were more likely to change their opinion for the worse over the mass media debate (8.7 vs. 1.2%, P<0.05). Nevertheless, only 1% of the aware-group declared their intention to subsequently undergo screening less frequently. The low impact of the controversy on the behaviour of women with respect to screening suggests that it should not be seen as a threat to screening attendance rates, but more as an opportunity to improve awareness. PMID- 26016792 TI - Social stratification, risk factor prevalence and cancer screening attendance. AB - This analysis aimed to assess the extent to which exposure to cancer risk factors and attendance of screening programmes are influenced by social characteristics. The validated Evaluation of deprivation and health inequalities in public health centres (EPICES) index was used to measure social deprivation. A sample of the general population (N=1603) was assessed to search for potential correlations between screening attendance, risk factors and any components of the EPICES score. In 2011, 33% of the population studied was classified as 'vulnerable'. Sex had no significant impact on this rating (32% men, 35% women), whereas occupational status did. Vulnerable individuals were more likely already to have cancer (10 vs. 7%; nonsignificant difference; odds ratio 1.43 [0.98-2.10]). The mean BMI was 26.0 kg/m (SD 4.9) for the vulnerable population versus 24.8 kg/m (SD 3.9) in the nonvulnerable population (P<0.01). The prevalence of current smoking was higher in the vulnerable group (38 vs. 23%, odds ratio 2.03 [1.61 2.56]). In contrast, no statistically significant difference was observed between attendance rates for nationwide organized cancer screening programmes (breast and colorectal; target age group 50-74 years) by the vulnerable and nonvulnerable groups. Social indicators of vulnerable populations are associated with increased rates of risk factors for cancer, but not with screening attendance. Our data support the previously reported marked impact of organized programmes that reduce or even remove inequalities in access to cancer screening. However, although the organized programmes have indeed enabled population-wide, nonselective access to screening, primary prevention as it stands today remains inadequate in the underserved population and further improvements are warranted. PMID- 26016793 TI - Lung cancer risks, beliefs and healthcare access among the underprivileged. AB - One of the current goals of the French national cancer plan is to reduce healthcare inequalities. This study investigated the potential links between vulnerable social status, exposure to lung cancer risk factors and access to healthcare to highlight ways to improve lung cancer control in this population. The nationwide observational study EDIFICE 3 was carried out through phone interviews of a representative sample of 1603 individuals (age 40-75 years). The EPICES validated questionnaire was used to assess and classify vulnerable respondents. The vulnerable population identified represented 33% of the sample. Compared with nonvulnerable individuals, they had more risk factors for cancer: a higher BMI (26.0 vs. 24.8, P<=0.01), 38% were active smokers (vs. 23%, P<=0.01) with a heavier and longer-lasting tobacco consumption (16.0 cigarettes/day vs. 10.1, P<=0.01 and 29.4 vs. 26.3 years of smoking, P<=0.01) and they were less likely to undertake any physical activities (42 vs. 77%, P<=0.01). They also presented more comorbidities (on average 2.2 vs. 1.8, P<=0.01). Access to healthcare, however, was not discriminatory: vulnerable individuals declared consulting a general practitioner or an oncologist more often than the nonvulnerable subgroup (5.4 vs. 3.7 and 6.7 vs. 2.5 consultations in the previous 12 months, respectively, P<=0.01). Because access to healthcare and screening attendance show no signs of discrimination against vulnerable populations, efforts to reduce inequities in lung cancer control should focus on prevention. PMID- 26016794 TI - Future perspectives for cancer screening. AB - The past 20 years have seen major advances in screening for different cancer types. Screening is however destined to evolve, in terms of target populations, procedures used and the overall positioning of screening in the fight against the different forms of cancer. At the same time, screening is expected progressively to become more closely tailored to the level of risk; the type of tests and the frequency with which they are used will be adjusted in a more personalized approach. A critical issue is also to provide the population at large with more extensive information on the advantages and disadvantages, particularly of screening programmes known for the potentially high rate of overdiagnosis. These issues and their evolution are considered herein, in the context of screening for different forms of cancer (breast, prostate, colorectal, lung, cervical and melanoma). PMID- 26016795 TI - MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism. AB - BACKGROUND: Recent studies have indicated the possible function of miR-217 in tumorigenesis. However, the roles of miR-217 in colorectal cancer (CRC) are still largely unknown. METHODS: We examined the expression of miR-217 and AEG-1 in 50 CRC tissues and the corresponding noncancerous tissues by qRT-PCR. The clinical significance of miR-217 was analyzed. CRC cell lines with miR-217 upregulation and AEG-1 silencing were established and the effects on tumor growth in vitro and in vivo were assessed. Dual-luciferase reporter gene assays were also performed to investigate the interaction between miR-217 and AEG-1. RESULTS: Our data demonstrated that miR-217 was significantly downregulated in 50 pairs of colorectal cancer tissues. MiR-217 expression levels were closely correlated with tumor differentiation. Moreover, decreased miR-217 expression was also associated with shorter overall survival of CRC patients. MiR-217 overexpression significantly inhibited proliferation, colony formation and invasiveness of CRC cells by promoting apoptosis and G0/G1 phase arrest. Interestingly, ectopic miR 217 expression decreased AEG-1 expression and repressed luciferase reporter activity associated with the AEG-1 3'-untranslated region (UTR). AEG-1 silencing resulted in similar biological behavior changes to those associated with miR-217 overexpression. Finally, in a nude mouse xenografted tumor model, miR-217 overexpression significantly suppressed CRC cell growth. CONCLUSIONS: Our findings suggest that miR-217 has considerable value as a prognostic marker and potential therapeutic target in CRC. PMID- 26016796 TI - Erratum: Mesenchymal stem cell pretreatment of non-heart-beating-donors in experimental lung transplantation. PMID- 26016797 TI - Utilization of research findings for health policy making and practice: evidence from three case studies in Bangladesh. AB - BACKGROUND: In striving to contribute towards improved health outcomes, health research institutions generate and accumulate huge volumes of relevant but often underutilized data. This study explores activities undertaken by researchers from the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), an international research institution that promotes the utilization of their findings in the policymaking processes in Bangladesh. METHODS: The study used an exploratory case study design and employed qualitative methods to explore activities implemented to promote research utilization and the extent to which researchers felt that their findings contributed to the policymaking process. Data were collected between September and December 2011 through key informant interviews, focus group discussions with study investigators, and database and document reviews. We reviewed findings from 19 reproductive health studies conducted and completed by icddr,b researchers between 2001 and 2011. We interviewed 21 key informants, including 13 researchers, two policy makers, and six programme implementers. Data were entered into Microsoft Word and analyzed manually following a thematic framework approach. Following the World Health Organization/Turning Research into Practice (WHO/TRIP) framework, three case studies of how research findings were utilized in the policymaking processes in Bangladesh were documented. RESULTS: Activities implemented to promote research utilization included conducting dissemination workshops, publishing scientific papers, developing policy briefs, providing technical assistance to policymakers and programme implementers, holding one-on-one meetings, and joining advocacy networks. The majority of the researchers (12 of 13) reported that their study findings were utilized to influence policymaking processes at different levels. However, some researchers reported being unaware of whether and how their findings were utilized. As regards actual utilization of research findings, the evidence from the three case studies indicate that research findings can be utilized instrumentally, conceptually and symbolically, and at different stages within the policymaking process, including agenda setting and policy formulation and implementation. CONCLUSIONS: The results show that research findings from icddr,b were promoted and utilized in health policymaking processes in Bangladesh using a variety of utilization approaches. These results suggest a need for using multiple approaches to promote utilization of research findings in health policymaking processes. PMID- 26016798 TI - Together we cry: Social motives and preferences for group-based sadness. AB - Group-based emotions play an important role in helping people feel that they belong to their group. People are motivated to belong, but does this mean that they actively try to experience group-based emotions to increase their sense of belonging? In this investigation, we propose that people may be motivated to experience even group-based emotions that are typically considered unpleasant to satisfy their need to belong. To test this hypothesis, we examined people's preferences for group-based sadness in the context of the Israeli National Memorial Day. In two correlational (Studies 1a and 1b) and two experimental (Studies 2 and 3) studies, we demonstrate that people with a stronger need to belong have a stronger preference to experience group-based sadness. This effect was mediated by the expectation that experiencing sadness would be socially beneficial (Studies 1 and 2). We discuss the implications of our findings for understanding motivated emotion regulation and intergroup relations. PMID- 26016799 TI - 1,3:2,4-Dibenzylidene-D-sorbitol (DBS) and its derivatives--efficient, versatile and industrially-relevant low-molecular-weight gelators with over 100 years of history and a bright future. AB - Dibenzylidene-D-sorbitol (DBS) has been a well-known low-molecular-weight gelator of organic solvents for over 100 years. As such, it constitutes a very early example of a supramolecular gel--a research field which has recently developed into one of intense interest. The ability of DBS to self-assemble into sample spanning networks in numerous solvents is predicated upon its 'butterfly-like' structure, whereby the benzylidene groups constitute the 'wings' and the sorbitol backbone the 'body'--the two parts representing the molecular recognition motifs underpinning its gelation mechanism, with the nature of solvent playing a key role in controlling the precise assembly mode. This gelator has found widespread applications in areas as diverse as personal care products and polymer nucleation/clarification, and has considerable potential in applications such as dental composites, energy technology and liquid crystalline materials. Some derivatives of DBS have also been reported which offer the potential to expand the scope and range of applications of this family of gelators and endow the nansocale network with additional functionality. This review aims to explain current trends in DBS research, and provide insight into how by combining a long history of application, with modern methods of derivatisation and analysis, the future for this family of gelators is bright, with an increasing number of high tech applications, from environmental remediation to tissue engineering, being within reach. PMID- 26016800 TI - De novo transcriptome characterization and gene expression profiling of the desiccation tolerant moss Bryum argenteum following rehydration. AB - BACKGROUND: The desiccation-tolerant moss Bryum argenteum is an important component of the Biological Soil Crusts (BSCs) found in the Gurbantunggut desert. Desiccation tolerance is defined as the ability to revive from the air dried state. To elucidate the molecular mechanisms related to desiccation tolerance, we employed RNA-Seq and digital gene expression (DGE) technologies to study the genome-wide expression profiles of the dehydration and rehydration processes in this important desert plant. RESULTS: We applied a two-step approach to investigate the gene expression profile upon rehydration in the moss Bryum argenteum using Illumina HiSeq2000 sequencing platform. First, a total of 57,247 transcript assembly contigs (TACs) were obtained from 54.79 million reads by de novo assembly, with an average length of 863 bp and N50 of 1,372 bp. Among the reconstructed TACs, 36,916 (64.5%) revealed similarity with existing protein sequences in the public databases. 23,509 and 21,607 TACs were assigned GO and KEGG annotation information, respectively. Second, samples were taken from 3 hydration stages: desiccated (Dry), rehydrated 2 h (R2) and rehydrated 24 h (R24), and DEG libraries were constructed for Differentially Expressed Genes (DEGs) discovery. 4,081 and 6,709 DEGs were identified in R2 and R24, compared with Dry, respectively. Compared to the desiccated sample, up-regulated genes after two hours of hydration are primarily related to stress responses. GO function enrichment network, EKGG metabolic pathway and MapMan analysis supports the idea of the rapid recovery of photosynthesis after 24 h of rehydration. We identified 770 transcription factors (TFs) which were classified into 50 TF families. 142 TF transcripts were up-regulated upon rehydration including 23 members of the ERF family. CONCLUSIONS: In this study, we constructed a pioneering, high-quality reference transcriptome in B. argenteum and generated three DGE libraries to elucidate the changes of gene expression upon rehydration. Expression profiles consistent with the rapid recovery of photosynthesis (at R2) and the re-establishment of a positive carbon balance following rehydration (at R24) were observed. Our study will extend our knowledge of bryophyte transcriptomes and provide further insight into the molecular mechanisms related to rehydration and desiccation-tolerance. PMID- 26016802 TI - Cognitive profile and activities of daily living: 35 patients with alpha mannosidosis. AB - BACKGROUND: Alpha-mannosidosis (OMIM 248500) (AM) is a rare lysosomal storage disease caused by a deficiency of the alpha-mannosidase enzyme. The typical signs consist of hearing impairment, intellectual disabilities, coarse facial features and motor function disturbances. We report on the cognitive function and activities of daily living in patients with AM. METHODS: Thirty five AM patients, age 6-35 years, were included in the study. As a cognitive function test, we used the Leiter international performance scale-revised (Leiter-R), which consists of two batteries: the visual function and reasoning battery and the memory and attention battery, the latter including a memory screening. Additional two questionnaires, The Childhood Health Assessment Questionnaire (CHAQ) and EQ-5D-5 L, were filled out. RESULTS: We found IQ in the range of 30-81 in our cohort. The total equivalent age (mental age) was significantly reduced, between 3-9 years old for the visual function and reasoning battery, between 2.3-10.2 years for the memory screening. Data suggested a specific developmental profile for AM with a positive intellectual development until the chronological age 10-12 years, followed by a static or slightly increasing intellectual level. All patients were to varying degrees socially and practically dependent and unable to take care of themselves in daily life. CONCLUSIONS: Intellectual disability is a consistent finding in patients with alpha-mannosidosis but with extensive variation. We assess that this group of patients has, despite their intellectual disabilities, a potential for continuous cognitive development, especially during childhood and early teenage years. This should be included and supported in the individual educational planning. PMID- 26016803 TI - Potential role of age, sex, body mass index and pain to identify patients with knee osteoarthritis. AB - AIM: To evaluate the potential role of age, sex, body mass index (BMI), radiographic features and pain in knee osteoarthritis (OA) case ascertainment. METHODS: A cross-sectional study was performed using information from the EPIPorto cohort; social, demographic, behavioral and clinical data was obtained. Pain was assessed using a pain frequency score (regarding ever having knee pain, pain in the last year, in the last 6 months and in the last month). Knee radiographs were classified using the Kellgren-Lawrence scale (0-4). Path analysis was used to assess the plausibility of the causal assumptions and a classification tree to identify characteristics that could improve the identification of patients with radiographic OA. RESULTS: Higher age and higher BMI were associated with higher radiographic score, but sex had no statistical association. Females, higher age, higher BMI and higher radiographic score were statistically associated with higher pain scores. For both genders, the classification tree estimated age as the first variable to identify individuals with knee radiographic features. In females older than 56 years, pain frequency score is the second discriminator characteristic, followed by age (> 65 years) and (BMI > 30 kg/m2 ). Higher pain frequency and BMI > 29 kg/m2 were relevant for identifying OA in men with ages between 43.5 and 55.5 years. CONCLUSIONS: Age, BMI and pain frequency are independently associated with radiographic OA and the use of information on these characteristics can improve the identification of patients with knee OA. Beyond age, pain complaints are particularly relevant but the level of pain is different by sex. PMID- 26016804 TI - Comparison of intraoral radiography and cone-beam computed tomography for the detection of periodontal defects: an in vitro study. AB - BACKGROUND: This study aimed to compare the diagnostic accuracy of cone-beam computed tomography (CBCT) unit with digital intraoral radiography technique for detecting periodontal defects. METHODS: The study material comprised 12 dry skulls with maxilla and mandible. Artificial defects (dehiscence, tunnel, and fenestration) were created on anterior, premolar and molar teeth separately using burs. In total 14 dehiscences, 13 fenestrations, eight tunnel and 16 without periodontal defect were used in the study. These were randomly created on dry skulls. Each teeth with and without defects were images at various vertical angles using each of the following modalities: a Planmeca Promax Cone Beam CT and a Digora photostimulable phosphor plates. Specificity and sensitivity for assessing periodontal defects by each radiographic technique were calculated. Chi square statistics were used to evaluate differences between modalities. Kappa statistics assessed the agreement between observers. Results were considered significant at P < 0.05. RESULTS: The kappa values for inter-observer agreement between observers ranged between 0.78 and 0.96 for the CBCT, and 0.43 and 0.72 of intraoral images. The Kappa values for detecting defects on anterior teeth was the least, following premolar and molar teeth both CBCT and intraoral imaging. CONCLUSIONS: CBCT has the highest sensitivity and diagnostic accuracy for detecting various periodontal defects among the radiographic modalities examined. PMID- 26016801 TI - Mitochondrial transcript maturation and its disorders. AB - Mitochondrial respiratory chain deficiencies exhibit a wide spectrum of clinical presentations owing to defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mitochondrial DNA (mtDNA) or mutations in nuclear genes coding for mitochondrially-targeted proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial biology including expression of mtDNA encoded genes. Expression of the mitochondrial genes is extensively regulated at the post-transcriptional stage and entails nucleolytic cleavage of precursor RNAs, RNA nucleotide modifications, RNA polyadenylation, RNA quality and stability control. These processes ensure proper mitochondrial RNA (mtRNA) function, and are regulated by dedicated, nuclear-encoded enzymes. Recent growing evidence suggests that mutations in these nuclear genes, leading to incorrect maturation of RNAs, are a cause of human mitochondrial disease. Additionally, mutations in mtDNA-encoded genes may also affect RNA maturation and are frequently associated with human disease. We review the current knowledge on a subset of nuclear-encoded genes coding for proteins involved in mitochondrial RNA maturation, for which genetic variants impacting upon mitochondrial pathophysiology have been reported. Also, primary pathological mtDNA mutations with recognised effects upon RNA processing are described. PMID- 26016805 TI - 4D Flow MRI-based pressure loss estimation in stenotic flows: Evaluation using numerical simulations. AB - PURPOSE: To assess how 4D flow MRI-based pressure and energy loss estimates correspond to net transstenotic pressure gradients (TPGnet) and their dependence on spatial resolution. METHODS: Numerical velocity data of stenotic flow were obtained from computational fluid dynamics (CFD) simulations in geometries with varying stenosis degrees, poststenotic diameters and flow rates. MRI measurements were simulated at different spatial resolutions. The simplified and extended Bernoulli equations, Pressure-Poisson equation (PPE), and integration of turbulent kinetic energy (TKE) and viscous dissipation were compared against the true TPGnet . RESULTS: The simplified Bernoulli equation overestimated the true TPGnet (8.74 +/- 0.67 versus 6.76 +/- 0.54 mmHg). The extended Bernoulli equation performed better (6.57 +/- 0.53 mmHg), although errors remained at low TPGnet . TPGnet estimations using the PPE were always close to zero. Total TKE and viscous dissipation correlated strongly with TPGnet for each geometry (r(2) > 0.93) and moderately considering all geometries (r(2) = 0.756 and r(2) = 0.776, respectively). TKE estimates were accurate and minorly impacted by resolution. Viscous dissipation was overall underestimated and resolution dependent. CONCLUSION: Several parameters overestimate or are not linearly related to TPGnet and/or depend on spatial resolution. Considering idealized axisymmetric geometries and in absence of noise, TPGnet was best estimated using the extended Bernoulli equation. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance. PMID- 26016806 TI - Al2O3 on Black Phosphorus by Atomic Layer Deposition: An in Situ Interface Study. AB - In situ "half cycle" atomic layer deposition (ALD) of Al2O3 was carried out on black phosphorus ("black-P") surfaces with modified phosphorus oxide concentrations. X-ray photoelectron spectroscopy is employed to investigate the interfacial chemistry and the nucleation of the Al2O3 on black-P surfaces. This work suggests that exposing a sample that is initially free of phosphorus oxide to the ALD precursors does not result in detectable oxidation. However, when the phosphorus oxide is formed on the surface prior to deposition, the black-P can react with both the surface adventitious oxygen contamination and the H2O precursor at a deposition temperature of 200 degrees C. As a result, the concentration of the phosphorus oxide increases after both annealing and the atomic layer deposition process. The nucleation rate of Al2O3 on black-P is correlated with the amount of oxygen on samples prior to the deposition. The growth of Al2O3 follows a "substrate inhibited growth" behavior where an incubation period is required. Ex situ atomic force microscopy is also used to investigate the deposited Al2O3 morphologies on black-P where the Al2O3 tends to form islands on the exfoliated black-P samples. Therefore, surface functionalization may be needed to get a conformal coverage of Al2O3 on the phosphorus oxide free samples. PMID- 26016807 TI - Investigating the Structural Variability and Binding Modes of the Glioma Targeting NFL-TBS.40-63 Peptide on Tubulin. AB - NFL-TBS.40-63 is a 24 amino acid peptide corresponding to the tubulin-binding site located on the light neurofilament subunit, which selectively enters glioblastoma cells, where it disrupts their microtubule network and inhibits their proliferation. We investigated its structural variability and binding modes on a tubulin heterodimer using a combination of NMR experiments, docking, and molecular dynamics (MD) simulations. Our results show that, while lacking a stable structure, the peptide preferentially binds on a specific single site located near the beta-tubulin C-terminal end, thus giving us precious hints regarding the mechanism of action of the NFL-TBS.40-63 peptide's antimitotic activity at the molecular level. PMID- 26016808 TI - Women's Experiences With Early Breastfeeding After Gestational Diabetes. AB - OBJECTIVE: To explore the lived experience of early breastfeeding for postpartum women who had gestational diabetes mellitus (GDM) in pregnancy. DESIGN: A qualitative phenomenological research design. SETTING: Participants were recruited from community hospitals, postpartum clinics, and lactation clinics in rural and urban facilities in the Midwest and Atlantic Regions of the United States. PARTICIPANTS: A purposive sample of 27 women who had been diagnosed with GDM and who had initiated breastfeeding following delivery. METHODS: Questions were used as prompts to initiate conversation and to provide structure for focus group discussions and interviews. Data were analyzed independently and then collaboratively with the researchers and experts to compare findings, including interpretations and concerns before revisions were made in preparation of the final, composite description. RESULTS: Three themes emerged from the data reflecting the participants' interpreted experience: Breastfeeding Challenges and Breastfeeding Support, Milk Supply Challenges, and Concern for Infant Health. Delayed lactogenesis II was reported by 30% of the women, and 44% perceived decreased milk supply. CONCLUSIONS: Participants identified breastfeeding facilitators and barriers, many of which could have been modified. The women expressed a need for consistent lactation advice, education, assistance, and strategies to address breastfeeding challenges and milk supply issues. PMID- 26016809 TI - The Role of MicroRNAs and Human Epidermal Growth Factor Receptor 2 in Proliferative Lupus Nephritis. AB - OBJECTIVE: To understand the roles of microRNAs (miRNAs) in proliferative lupus nephritis (LN). METHODS: A high-throughput analysis of the miRNA pattern of the kidneys of LN patients and controls was performed by molecular digital detection. Urinary miRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target gene expression in human mesangial cells was evaluated by arrays and qRT-PCR. Human epidermal growth factor receptor 2 (HER-2) was analyzed by immunohistochemistry in kidney samples from LN patients and in a murine model of lupus. Urinary levels of HER-2, monocyte chemotactic protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured by enzyme linked immunosorbent assay. RESULTS: Levels of the miRNAs miR-26a and miR-30b were decreased in the kidneys and urine of LN patients. In vitro these miRNAs controlled mesangial cell proliferation, and their expression was regulated by HER-2. HER-2 was overexpressed in lupus-prone NZM2410 mice and in the kidneys of patients with LN, but not in other mesangioproliferative glomerulonephritides. HER-2 was found to be up-regulated by interferon-alpha and interferon regulatory factor 1. Urinary HER-2 was increased in LN and reflected disease activity, and its levels correlated with those of 2 other recognized LN biomarkers, MCP-1 and VCAM-1. CONCLUSION: The kidney miRNA pattern is broadly altered in LN, which contributes to uncontrolled cell proliferation. Levels of the miRNAs miR-26a and miR-30b are decreased in the kidneys and urine of LN patients, and they directly regulate the cell cycle in mesangial cells. The levels of these miRNAs are controlled by HER-2, which is overexpressed in NZM2410 mice and in the kidneys and urine of LN patients. HER-2, miR-26a, and miR-30b are thus potential LN biomarkers, and blocking HER-2 may be a promising new strategy to decrease cell proliferation and damage in this disease. PMID- 26016810 TI - Changes in macular layers in the early course of non-arteritic ischaemic optic neuropathy. AB - PURPOSE: To characterise the changes of the retinal layers in patients with acute anterior ischaemic optic neuropathy (AION), aiming to identify imaging markers for predicting the residual visual function. METHODS: This was a retrospective review of consecutive patients with unilateral AION from January 2010 to December 2013. We analysed affected eyes at baseline and 1 month later, compared to fellow healthy eyes. Utilising novel image analysis software, we conducted algorithmic segmentation in layers and division in early treatment of diabetic retinopathy study (ETDRS) quadrants of optical coherence tomography images of the macula. Pearson product moment regression analysis of retinal layer thickness and best corrected visual acuity (BCVA) in logMAR units and mean deviation of the SITA 24 2 visual field (VF) were carried out at the 1-month time point. RESULTS: Twenty eyes from 20 patients were included and compared to 20 healthy fellow eyes. At baseline, we found a significantly increased mean thickness of the retinal nerve fibre layer (RNFL) of 42.2 MUm (+/-6.7SD) in AION eyes compared to 37.9 MUm (+/ 4.2 SD) in healthy eyes (p = 0.002). The outer nuclear layer (ONL) was also significantly thickened at 96.6 MUm (+/-7.2 SD) compared to 90.8 MUm (+/-5.7 SD) in the fellow eye (p < 0.001). After 1 month, the RNFL and the ganglion cell layer (GCL) were thinned 17.7 % [to 31.2 MUm (+/-6.4 SD), p < 0.001] and 19.3 % [to 66.5 MUm (+/-7.0 SD), p < 0.001] compared to the contralateral eye. Additionally, the ONL remained thickened at 96.7 MUm (+/-7.0 SD, p < 0.001). At baseline, we found a significant correlation between the ONL thickness and the VF (r = -0.482, p = 0.005) and the BCVA at discharge (r = 0.552, p < 0.001), indicating that a thicker ONL correlates with poorer visual function. The GCL thickness also correlates with the BCVA at discharge (r = 0.411, p = 0.02), where a thinner GCL predicts worse BCVA. At the 1-month time point, the GCL thinning was correlated with both the VF (r = 0.471, p = 0.005) and the BCVA (r = -0.456, p = 0.007), indicating worse visual function. CONCLUSIONS: Changes in the thickness of different layers of the retina occur early in the course of AION and evolve over time, resulting in the atrophy of the GCL and RNFL. ONL thickening at baseline is associated with visual dysfunction. Thinning of the GCL after 1 month correlates with poorer VF and BCVA at 1 month after acute AION. PMID- 26016812 TI - Moving with and beyond CANTOS: How to put out the fire of inflammation in atherosclerosis? PMID- 26016811 TI - Correlation between visual acuity changes and optical coherence tomography morphological findings in idiopathic epiretinal membranes. AB - PURPOSE: To analyze the influence of spectral-domain optical coherence tomography (SD-OCT) features on visual acuity changes in patients with idiopathic epiretinal membranes (ERMs). METHODS: Seventy-nine eyes of 71 patients were included in this study. SD-OCT was performed for all patients; data were collected upon ERM diagnosis and at the final visit. The patients were divided into subgroups based on their SD-OCT features. The initial best corrected visual acuity (BCVA) and changes in BCVA for each subgroup were compared. A multivariate analysis was performed to assess the factors associated with changes in BCVA. RESULTS: During a mean follow-up period of 20.78 months, the mean change in logMAR visual acuity was 0.052 +/- 0.089. Eyes with inner segment/outer segment (IS/OS) junction disruption and cystoid macular edema (CME) had a significantly lower mean initial BCVA than those without disruption and CME (P = 0.036 and P = 0.012, respectively). However, only eyes with CME had significant changes in BCVA (P = .034). Multivariate analysis revealed the presence of CME as the only factor that had a significant correlation with VA changes. CONCLUSIONS: In patients with idiopathic ERMs, the presence of CME and IS/OS disruption detected by OCT correlated with a poorer initial BCVA. Most patients' visual acuity remained stable during follow-up. The presence of CME with OCT represented a predictor of the progression of visual acuity. These results may provide valuable clinical information regarding the management of patients with idiopathic ERMs. We demonstrated that the presence of CME and IS/OS disruption detected with OCT correlated with a poorer BCVA in idiopathic ERMs. The visual acuity of most patients was stable during the follow-up period. The presence of CME in OCT represented a predictor of vision deterioration for patients with idiopathic ERMs. PMID- 26016813 TI - Molecular engineering of a dual emission near-infrared ratiometric fluorophore for the detection of pH at the organism level. AB - A near-infrared ratiometric fluorophore (NIR-HBT) was rationally designed and constructed by expanding both the excitation and emission wavelength of the classical ratiometric fluorophore 2-(benzothiazol-2-yl)phenol (HBT) into the near infrared region. The NIR-HBT was easily synthesized by incorporating the HBT module into the hemicyanine skeleton and showed evident NIR ratiometric fluorophore characteristics. Further application of the new fluorophore for pH detection demonstrated that NIR-HBT possesses superior overall analytical performance and NIR-HBT was successfully applied for detection of acidosis caused by inflammation in living animal tissue, which indicated the potential application value of NIR-HBT in biological imaging and sensing. PMID- 26016814 TI - Characterization of a novel thermostable patatin-like protein from a Guaymas basin metagenomic library. AB - Deep-sea hydrothermal vents are a natural habitat for thermophiles, in which contain plenty of enzymes that can function at high temperatures. In this work, we constructed a fosmid library in Escherichia coli using metagenomic DNA isolated from a chimney sample collected in the hydrothermal vents in Guaymas Basin. The library was screened for lipolytic activity and positive clones were subjected to subcloning. A novel patatin-like protein (PLP) that exhibited less than 45 % identity in amino acid sequence to known enzymes was obtained. Common features of the patatin-like proteins, such as four conserved blocks, were detected. Interestingly, there was an Ala at site 42 in PLP instead of the first Gly-residue in the consensus sequence Gly-X-Ser-X-Gly found in other PLP homologs. The active sites of PLP were Ser44 and Asp160. Spectrophotometric assays with different p-nitrophenyl esters demonstrated a preference for p nitrophenyl butyrate (C4) and p-nitrophenyl decanoate (C10). Moreover, PLP demonstrated optimal activity at 70 degrees C and at pH 9.0 (Tris-HCl). The activation energy from the linear Arrhenius plot was found to be 38.3 +/- 0.9 kJ/mol. The K m and V max of PLP for C4 were 304 +/- 38 MUM and 14 +/- 0.38 MUmol min(-1) mg(-1), respectively. Gene-mining of the metagenome dataset that was generated by pyrosequencing the same chimney sample resulted in identification of 20 PLP homolog gene fragments, which could represent promising examples of this category of thermostable proteins. PMID- 26016815 TI - An Electrochromic Bipolar Membrane Diode. AB - Conducting polymers with bipolar membranes (a complementary stack of selective membranes) may be used to rectify current. Integrating a bipolar membrane into a polymer electrochromic display obviates the need for an addressing backplane while increasing the device's bistability. Such devices can be made from solution processable materials. PMID- 26016816 TI - The learning experiences of mentees and mentors in a nursing school's mentoring programme. AB - BACKGROUND: A School of Nursing supports third-year undergraduate students (mentees) by means of a mentoring programme in which critical-care nursing students (mentors) are involved. However, the programme designers needed to find out what gaps were evident in the programme. OBJECTIVES: The objectives of the study were to explore and describe the learning experiences of the mentees and mentors and to obtain recommendations for improving the programme. METHOD: An action-research method was used to develop and to refine the student-mentoring programme and to identify student needs. However, for the purposes of this article a descriptive design was selected and data were gathered by means of a nominal-group technique. Fourteen mentees and five mentors participated in the research. RESULTS: The findings indicated that attention should be paid to the allocation and orientation of both mentors and mentees. Amongst the positive experiences was the fact that the mentees were reassured by the mentor's presence and that a relationship of trust developed between them. In consequence, the mentees developed critical thinking skills, were able to apply their knowledge and improved their ability to integrate theory and practice. Not only did the mentees gain respect for the mentors' knowledge and competence, but they also lauded the mentoring programme as a memorable and vital experience. CONCLUSION: The findings indicated that several changes would be needed to improve the structure of the mentoring programme before a new group of mentees could be placed in critical-care units. PMID- 26016817 TI - Peristomal pyoderma gangrenosum: A report of three cases. PMID- 26016818 TI - The Impact of Reading Intervention on Brain Responses Underlying Language in Children With Autism. AB - Deficits in language comprehension have been widely reported in children with autism spectrum disorders (ASD), with behavioral and neuroimaging studies finding increased reliance on visuospatial processing to aid in language comprehension. However, no study to date, has taken advantage of this strength in visuospatial processing to improve language comprehension difficulties in ASD. This study used a translational neuroimaging approach to test the role of a visual imagery-based reading intervention in improving the brain circuitry underlying language processing in children with ASD. Functional magnetic resonance imaging (MRI), in a longitudinal study design, was used to investigate intervention-related change in sentence comprehension, brain activation, and functional connectivity in three groups of participants (age 8-13 years): an experimental group of ASD children (ASD-EXP), a wait-list control group of ASD children (ASD-WLC), and a group of typically developing control children. After intervention, the ASD-EXP group showed significant increase in activity in visual and language areas and right hemisphere language area homologues, putamen, and thalamus, suggestive of compensatory routes to increase proficiency in reading comprehension. Additionally, ASD children who had the most improvement in reading comprehension after intervention showed greater functional connectivity between left-hemisphere language areas, the middle temporal gyrus and inferior frontal gyrus while reading high imagery sentences. Thus, the findings of this study, which support the principles of dual coding theory [Paivio 2007], suggest the potential of a strength-based reading intervention in changing brain responses and facilitating better reading comprehension in ASD children. PMID- 26016819 TI - Efficacy comparison of ustekinumab between anti-tumor necrosis factor-alpha drug naive and anti-tumor necrosis factor-alpha drug-resistant Japanese psoriasis cases. AB - Ustekinumab is highly efficacious for psoriasis; however, it has not been fully clarified whether previous failure in anti-tumor necrosis factor-alpha (TNF alpha) therapy affects the treatment response with ustekinumab. Therefore, we evaluated the efficacy of ustekinumab in anti-TNF-alpha-naive and anti-TNF-alpha resistant cases and compared the clinical efficacies of adalimumab and ustekinumab in biologic naive cases. Thirty-five patients with plaque psoriasis who showed resistance to conventional therapies were enrolled; 26 patients, who had never been treated with biologics, were allocated to ustekinumab or adalimumab; nine patients who failed to achieve psoriasis area and severity index (PASI) 50 at week 16 with one or two TNF-alpha antagonists were switched to ustekinumab. The end of the study was defined as 52 weeks after starting the first biologic for anti-TNF-alpha-naive patients and after switching to ustekinumab for anti-TNF-alpha-resistant patients. The primary outcome measurement was the percentage of patients achieving PASI75 at week 16. In patients treated with ustekinumab, 87.5% of anti-TNF-alpha-naive and 77.8% of anti-TNF-alpha-resistant cases achieved a PASI75 response at week 16, and no statistically significant difference was found between the treatment response rates (P = 0.60). When comparing the treatment efficacy of ustekinumab and adalimumab among anti-TNF-alpha-naive patients, there was also no statistically significant difference in PASI75 achievement rates (87.5 vs. 83.3%, P = 0.79). Our study suggests that ustekinumab can be considered as a first-line biologic for psoriasis and a rescue therapy for anti-TNF-alpha-resistant cases. PMID- 26016820 TI - A novel once-daily fixed-dose combination of memantine extended release and donepezil for the treatment of moderate to severe Alzheimer's disease: two phase I studies in healthy volunteers. AB - BACKGROUND: Combining two standard-of-care medications for Alzheimer's disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake. METHODS: Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated. RESULTS: The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments. CONCLUSIONS: An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce. PMID- 26016822 TI - Ligand-Free Copper-Catalyzed Negishi Coupling of Alkyl-, Aryl-, and Alkynylzinc Reagents with Heteroaryl Iodides. AB - Reported herein is an unprecedented ligand-free copper-catalyzed cross-coupling of alkyl-, aryl-, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 degrees C) is required for aryl-heteroaryl and alkynyl heteroaryl couplings. PMID- 26016821 TI - Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. AB - The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18-92). There were 59 IDH1-R132, 83 IDH2-R140, and 23 IDH2-R172 mutations. Clinicopathologic characteristics associated with IDH-mutations included older age, less frequent therapy-related status, and increased incidence of intermediate-risk cytogenetics, FLT3-ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage-1 (S1), 42%; and Salvage-2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies. PMID- 26016823 TI - Lung Volume Reduction Surgery and Improvement of Endothelial Function and Blood Pressure in Patients with Chronic Obstructive Pulmonary Disease. A Randomized Controlled Trial. AB - RATIONALE: Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Preliminary studies have shown that both airflow obstruction and systemic inflammation may contribute to endothelial dysfunction in COPD. Lung volume reduction surgery (LVRS) is a treatment option in selected patients with COPD with emphysema that improves breathing mechanics and lung function. OBJECTIVES: To determine the effect of LVRS on endothelial function and systemic inflammation. METHODS: We conducted a randomized controlled trial in 30 patients scheduled for LVRS. In the intervention group, immediate LVRS was performed after baseline evaluation followed by reassessment 3 months later. In the control group, reassessment followed 3 months after baseline evaluation, and thereafter LVRS was performed. MEASUREMENTS AND MAIN RESULTS: The primary outcome measures were the treatment effect on endothelial function and systemic inflammation. In the LVRS group 14 patients completed the trial and 13 in the control group. LVRS led to a relative reduction in mean (SD) residual volume/total lung capacity of -12% (12%) and an increase in FEV1 of 29% (27%). Flow-mediated dilatation of the brachial artery increased in the intervention group as compared with the control group (+2.9%; 95% confidence interval, +2.1 to +3.6%; P < 0.001), whereas there was no significant change in systemic inflammation. A significant treatment effect on mean blood pressure was observed (-9.0 mm Hg; 95% confidence interval, -17.5 to 0.5; P = 0.039). CONCLUSIONS: Endothelial function and blood pressure are improved 3 months after LVRS in patients with severe COPD and emphysema. LVRS may therefore have beneficial effects on cardiovascular outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 01020344). PMID- 26016824 TI - Synthesis and insecticidal activity of beta-dihydroagarofuran ether analogues. AB - BACKGROUND: 1beta, 2beta, 4alpha, 6alpha, 8beta, 9alpha, 12-hepthydroxyl-beta dihydroagarofuran is the main skeleton of beta-dihydroagarofuran sesquiterpenoids, which exhibit excellent insecticidal activity. To study further the structure-activity relationship of beta-dihydroagarofuran sesquiterpenoids towards finding novel botanical pesticides, two series of new structurally modified ether analogues were designed and synthesised, and their insecticidal activities were evaluated. RESULTS: Twenty-two ether derivatives were synthesised using 1beta, 2beta, 4alpha, 6alpha, 8beta, 9alpha, 12-hepthydroxyl-beta dihydroagarofuran as starting material. Bioassay results indicated that most of the derivatives, particularly compounds 5.1.2, 5.1.3, 5.1.7, 5.2.3, 5.2.6 and 5.2.7, exhibited significant insecticidal activity against the third-instar larvae of the oriental armyworm Mythimna separata. Most importantly, compound 5.2.7 showed the lowest LD50 value of 29.2 ug g(-1) among these synthesised compounds, which provides some important hints for further design, synthesis and structural modification of beta-dihydroagarofuran sesquiterpenoids towards developing novel botanical insecticides. CONCLUSION: The structure-activity relationship illustrated that the moiety at the 1-position affected the insecticidal activity significantly, and that specifically the derivatives with two or three carbon atoms at the 1-position showed promising insecticidal activity, with mortality over 60%, while those with o-F-Bn and p-F-Bn at the 6 position showed similar activity. PMID- 26016825 TI - Improvements in Dutch heart transplant patient outcomes: lessons for the future. PMID- 26016826 TI - Efficacy of perioperative dexmedetomidine in postoperative neurocognitive function: a meta-analysis. AB - Neuroprotective effects of dexmedetomidine are reported in preclinical and clinical studies but evidence regarding the postoperative neurocognitive function is not as clear. This study performed a meta-analysis on outcomes of studies which examined neurocognitive performance by using valid assessment tools before and after perioperative dexmedetomidine treatment. Literature was searched in several electronic databases and studies were selected by following precised inclusion criteria. Meta-analyses of mean differences in percent changes from baseline in neurocognitive assessment scores were carried out and subgroup analyses were performed. Eighteen studies were included. Initial dose of dexmedetomidine (mean +/- SD) was 1.28 +/- 0.97 MUg/kg and maintenance dose was 0.41 +/- 0.11 MUg/kg per hour. In healthy volunteers, there was no significant difference in the neurocognitive performance between dexmedetomidine and controls/comparators (mean difference (95% confidence interval (CI)): -12.72 ( 50.25, 24.80) %; P = 0.51). Perioperative dexmedetomidine treatment was associated with significantly better neurocognitive performance in comparison with saline (mean difference (95% CI): 9.10 (3.03, 15.16) %; P = 0.003) as well as with comparator anaesthetics (mean difference: 5.50 (0.15, 10.86) %; P = 0.04) treated patients. In the submeta-analyses of studies which utilized neurocognitive assessment tools other than Mini-Mental State Examination (mean difference: 6.66 (-3.42, 16.74); P = 0.20) or studies with patients under 60 years of age (mean difference: 7.48 (-3.00, 17.96); P = 0.16), the differences were not significant between dexmedetomidine- and saline-/comparator-treated patients. Perioperative dexmedetomidine treatment is associated with significantly better neurocognitive function postoperatively in comparison with both saline controls and comparator anaesthetics (predominantly midazolam). PMID- 26016827 TI - From Stiba- and Bismaheteroboroxines to N,C,N-Chelated Diorganoantimony(III) and Bismuth(III) Cations-An Unexpected Case of Aryl Group Migration. AB - An unprecedented transfer of an aryl group from boron to Sb and Bi is observed in the reaction of heteroboroxines of general formula ArM[(OBR)2O] [where M = Sb, Bi; Ar = C6H3-2,6-(CH2NMe2)2; R = Ph, 4-CF3C6H4, 4-BrC6H4] with corresponding boronic acid RB(OH)2. Using this procedure, ion pairs [ArMR](+)[R4B5O6](-) were obtained [where M = Sb and R = Ph (4), 4-CF3C6H4 (5), 4-BrC6H4 (6); where M = Bi and R = Ph (7), 4-CF3C6H4 (8), 4-BrC6H4 (9)]. All compounds were characterized using elemental analysis, electrospray ionization mass spectrometry, and multinuclear NMR spectroscopy, and molecular structures of 4 and 7 were determined by single-crystal X-ray diffraction analysis. The central metal atoms in 4-9 were arylated by respective boronic acids, which represents, to the best of our knowledge, unprecedented reaction path in the chemistry of heavier group 15 elements. Investigation of the mechanism of this transformation indicated that Lewis pairs consisting of monomeric oxides ArMO and boroxine rings are probably key intermediates. In this regard, molecular structures of ArSbO[(4 CF3C6H4)3B3O3].(4-CF3C6H4)B(OH)2 (10) and {ArSbO[(3,5-(CF3)2C6H3)3B3O3]} (13) were established by single-crystal X-ray diffraction analysis, and compound 13 was also fully characterized in solution by multinuclear NMR spectroscopy. The bonding in 13 was analyzed in detail by using density functional theory and natural bond order calculations and compared with known adduct ArSbOB(C6F5)3 (14) and hypothetical ArSbO monomer. PMID- 26016828 TI - [Soft-tissue infection with Mycobacterium abscessus subsp. abscessus after liposuction and panniculectomy in the Caribbean]. AB - We report the case of a 36-year-old woman who presented with a surgical site infection with atypical mycobacteria several months after liposuction in the Caribbean. Postoperative wound infections with Mycobacterium abscessus present as subcutaneous nodular abscesses with partly putrid secretion. Due to the necessity of specific diagnostic measures, diagnosis is often delayed. Treatment is difficult because Mycobacterium abscessus is resistant to conventional tuberculostatics and many other antibiotics. Clarithromycin combined with amikacin is the commonly used empirical treatment. Treatment duration is several months. PMID- 26016829 TI - [Molecular diagnosis of methicillin-resistent Staphylococcus aureus: Methods and efficacy]. AB - Methicillin-resistant Staphylococcus aureus (MRSA) isolates are a serious public health problem whose ever-increasing rate is commensurate with the pressure it is exerting on the healthcare system. At present, more than 20% of clinical S. aureus isolates in German hospitals are methicillin-resistant, in Austria less than 10%. Strategies from low-prevalence countries show that this development is not necessarily inevitable. In the Scandinavian countries and the Netherlands, thanks to a rigorous prevention programme, MRSA prevalence has been kept at an acceptably low level (< 1-3%). Central to these search-and-destroy control strategies is an admission screening using several MRSA swabs taken from mucocutaneous colonisation sites of high-risk patients (MRSA surveillance). It has also been reported that the speed with which MRSA carriage is detected has an important role, as it is a key component of any effective strategy to prevent the pathogen from spreading. Since MRSA culturing involves a 2-3 day delay before the final results are available, rapid detection techniques (commonly referred to as MRSA rapid tests) using polymerase chain reaction (PCR) methods and, most recently, rapid culturing methods have been developed. The implementation of rapid tests reduces the time of detection of MRSA carriers from 48-72 to 2-5 h. Clinical evaluation data have shown that MRSA can thus be detected with very high sensitivity. Specificity, however, is sometimes impaired due to false-positive PCR signals occurring in mixed flora specimens. In order to rule out false positive PCR results, a culture screen must always be carried out simultaneously. The data provide preliminary evidence that a PCR assay can reduce nosocomial MRSA transmission in high-risk patients or high-risk areas, whereas an approach that screens all patients admitted to the hospital is probably not effective. Information concerning the cost effectiveness of rapid MRSA tests is still sparse and thus the issue remains debated. PMID- 26016832 TI - Health literacy among pharmacy visitors in the Netherlands. AB - PURPOSE: Health literacy is defined as the ability to obtain, understand and apply information to make appropriate health decisions. Most health literacy research has been performed in the USA. Our objective was to study the prevalence of limited health literacy among adult pharmacy visitors in the Netherlands and to assess the association between health literacy and understanding of drug label information. METHODS: A cross-sectional study was performed in community pharmacies belonging to the Utrecht Pharmacy Practice network for Education and Research. Adult pharmacy visitors (aged >=18 years) were approached in the pharmacy waiting area and invited for a brief interview including the newest vital sign, a validated health literacy assessment measure and questions about understanding of standard drug label instructions. RESULTS: A total of 984 pharmacy visitors were included in the study: 63% were women, mean age was 56 years and the majority was of native origin (84%). Based on newest vital sign scores, 52% had limited health literacy skills. Pharmacy visitors with limited health literacy skills had significantly lower understanding of drug label instructions (p < 0.001). CONCLUSION: Approximately half of the pharmacy visitors in this study had limited health literacy skills. These individuals experienced more difficulties understanding drug label instructions. These findings emphasize the need to identify patients with limited health literacy skills, as these patients might be at increased risk for drug-related problems caused by misunderstanding of information. PMID- 26016830 TI - Evaluation of traps and lures for mosquito vectors and xenomonitoring of Wuchereria bancrofti infection in a high prevalence Samoan Village. AB - BACKGROUND: Elimination of lymphatic filariasis (LF) in Samoa continues to be challenging despite multiple annual mass drug campaigns aimed at stopping transmission by reducing the prevalence and density of microfilaraemia. The persistence of transmission may be partly related to the highly efficient Aedes vectors. The assessment of pathogen transmission by mosquito vectors and of vector control relies on the ability to capture mosquitoes efficiently. The aims of this study are to compare trapping methods to capture LF-infected mosquitoes and determine the role in transmission of the species of Aedes mosquitoes in the area. METHODS: Fasitoo-Tai village was the chosen site because of persistent transmission despite annual mass drug administration. Sampling methods included BioGents Sentinel (BGS) trap, human-baited collections (HBC) and the Centers for Disease Control (CDC) trap. BGS and CDC traps were baited with BG-lure, CO2, and/or octenol. Individual trap locations were geo-located and efficiency of sampling methods was evaluated using a randomized Latin-square design in two locations. Number of mosquitoes collected (male and female), as well as species for each trapping method were determined. Additionally, Ae. polynesiensis and Ae. (Finlaya) spp. females were pooled by trap method and analysed for filarial DNA. Infection prevalence was estimated using the PoolScreen software. RESULTS: The BGS trap with any type of bait collected more mosquitoes compared to both the CDC trap and the HBC. The BGS trap baited with BG-lure collected more mosquitoes than with CO2 and octenol. There were no significant differences between trapping methods in terms of proportions of infected females collected. The prevalence of filarial infection in Ae. polynesiensis and Ae. (Finlaya) spp. was estimated at 4.7% and 0.67% respectively. CONCLUSIONS: This study supports the use of the BGS trap for research on and surveillance of the mosquito vectors of LF in Samoa. The BGS trap is a suitable and safer alternative to HBC for sampling Ae. polynesiensis and Ae. (Finlaya) spp., which continue to be the predominant vectors of LF. Of concern was the high prevalence of LF in mosquitoes despite a recent mass drug administration programme. This highlights the urgency for updated policies concerning filariasis elimination in Samoa. PMID- 26016833 TI - A rare cause of shortness of breath: relaxatio diaphragmatica. PMID- 26016835 TI - The deep sulcus sign indicates free air in the abdomen. PMID- 26016837 TI - Why Do Pediatricians Retire? PMID- 26016836 TI - Lymphadenopathy With Ipsilateral Eye Involvement. PMID- 26016834 TI - Exercise training improves cardiopulmonary and endothelial function in women with breast cancer: findings from the Diana-5 dietary intervention study. AB - To investigate whether exercise training (ET) improves cardiopulmonary and endothelial function in women with breast cancer (BC). Fifty-one female patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (diet and androgens)-5 Trial were subdivided into 2 groups: an ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60-70 % VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and at 1-year follow-up, all patients underwent cardiopulmonary exercise stress test (CPET) and measurements of vascular endothelial function by peripheral artery tonometry (Reactive Hyperemia Index, RHI). There were no significant differences between the groups in baseline anthropometrical, BC characteristics, and metabolic profile. No differences in baseline CPET and RHI parameters were found. Peak oxygen consumption (VO2peak) significantly increased in ET group (from 12.4 +/- 2.9 to 14.3 +/- 3.3 mL/kg/min, p < 0.001) compared to the control group (from 12.8 +/- 2.5 to 12.6 +/- 2.8 mL/kg/min, p = 0.55; p < 0.001 between groups). Compared to the control group (from 2.0 +/- 0.4 to 1.9 +/- 0.4, p = 0.62), the ET group showed a significant improvement of RHI after 1 year (from 2.1 +/- 0.7 to 2.5 +/- 0.8, p < 0.001). Changes in VO2peak were correlated with changes in RHI (DeltaVO2peak vs. DeltaRHI: r = 0.47, p = 0.017). In BC survivors, ET program improves cardiopulmonary functional capacity and vascular endothelial function after 12 months. Whether these changes may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution should be investigated. PMID- 26016838 TI - Expanding Horizons: A Pilot Mentoring Program Linking College/Graduate Students and Teens With ASD. AB - A small pilot program of 9 youth 13 to 18 years old with high-functioning autism spectrum disorder (ASD) or Asperger's syndrome assessed the feasibility, acceptability, and potential efficacy of an individualized mentoring program. Youth met weekly for 6 months with trained young adult mentors at a local boys and girls club. Participants reported improvements in self-esteem, social anxiety, and quality of life. Participants, parents, mentors, and staff reported that the program improved participants' social connectedness. Although the pilot study was small, it provides preliminary data that mentoring for youth with ASD has promise for increasing self-esteem, social skills, and quality of life. PMID- 26016839 TI - Neuroprotective effects of quercetin in a mouse model of brain ischemic/reperfusion injury via anti-apoptotic mechanisms based on the Akt pathway. AB - The present study provided experimental evidence for the neuroprotective effects of quercetin using a rat model of global brain ischemic/reperfusion (I/R) injury. Pre-treatment with quercetin (5 or 10 mg/kg orally (p.o.); once daily) induced a dose-dependent reduction in I/R-induced hippocampal neuron cell loss, with 10 mg/kg/day being the lowest dose that achieved maximal neuroprotection. Administration of 10 mg/kg quercetin over at least 3 days prior to I/R was required to improve the survival rate of I/R rats. Fluorescence-assisted cell sorting, hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling indicated neuronal cell loss in the CA1 hippocampus. Rats that had undergone transient global cerebral ischemia for 15 min followed by 1 h of reperfusion exhibited a significant increase in reactive oxygen species (ROS) production in the hippocampus. The I/R-induced ROS overproduction in the hippocampus at 1, 12 and 24 h following I/R was significantly decreased by quercetin pre-treatment. Western blot analysis revealed that the neuroprotective effects of quercetin (5 and 10 mg/kg/day, p.o.) were associated with an upregulation of the I/R-induced suppression of B-cell lymphoma-2 (Bcl-2), Bcl extra large and survivin expression as well as phosphorylation of Bcl-2 associated death promoter. Furthermore, the neuroprotective effects of quercetin (5, 10 mg/kg/day) in the brain were associated with an upregulation of Akt signaling. These findings suggested that the inhibition of I/R-induced brain injury by quercetin likely involves a transcriptional mechanism to enhance anti apoptotic signaling. PMID- 26016840 TI - World Health Assembly hears warnings over WHO's relationship with industry. PMID- 26016841 TI - Clinical approaches to treat patients with non-small cell lung cancer and epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance. AB - The discovery of epidermal growth factor receptor activating mutations (EGFR Mut+) has determined a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). In several phase III studies, patients with NSCLC EGFR Mut+ achieved a significantly better progression-free survival when treated with a first- (gefitinib, erlotinib) or second-generation (afatinib) EGFR tyrosine kinase inhibitor (TKI) compared with standard chemotherapy. However, despite these impressive results, most patients with NSCLC EGFR Mut+ develop acquired resistance to TKIs. This review will discuss both the mechanisms of resistance to TKIs and the therapeutic strategies to overcome resistance, including emerging data on third-generation TKIs. PMID- 26016842 TI - Both Low and High 24-Hour Diastolic Blood Pressure Are Associated With Worse Cognitive Performance in Type 2 Diabetes: The Maastricht Study. AB - OBJECTIVE: Hypertension and diabetes are both risk factors for cognitive decline, and individuals with both might have an especially high risk. We therefore examined linear and nonlinear (quadratic) associations of 24-h blood pressure (BP) with cognitive performance in participants with and without type 2 diabetes. We also tested the association of nocturnal dipping status with cognitive performance. RESEARCH DESIGN AND METHODS: This study was performed as part of the Maastricht Study, an ongoing population-based cohort study. Cross-sectional associations of 24-h BP (n = 713, of whom 201 had type 2 diabetes) and nocturnal dipping status (n = 686, of whom 196 had type 2 diabetes) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition were tested using linear regression analysis and adjusted for demographics, vascular risk factors, cardiovascular disease, depression, and lipid-modifying and antihypertensive medication use. RESULTS: After full adjustment, we found quadratic (inverted U-shaped) associations of 24-h diastolic blood pressure (DBP) with information processing speed (b for quadratic term = -0.0267, P < 0.01) and memory (immediate word recall: b = -0.0180, P < 0.05; delayed word recall: b = 0.0076, P < 0.01) in participants with diabetes, but not in those without. No clear pattern was found for dipping status. CONCLUSIONS: This study shows that both low and high 24-h DBP are associated with poorer performance on tests of information processing speed and memory in individuals with type 2 diabetes. PMID- 26016843 TI - Laser-stimulated fluorescence in paleontology. AB - Fluorescence using ultraviolet (UV) light has seen increased use as a tool in paleontology over the last decade. Laser-stimulated fluorescence (LSF) is a next generation technique that is emerging as a way to fluoresce paleontological specimens that remain dark under typical UV. A laser's ability to concentrate very high flux rates both at the macroscopic and microscopic levels results in specimens fluorescing in ways a standard UV bulb cannot induce. Presented here are five paleontological case histories that illustrate the technique across a broad range of specimens and scales. Novel uses such as back-lighting opaque specimens to reveal detail and detection of specimens completely obscured by matrix are highlighted in these examples. The recent cost reductions in medium power short wavelength lasers and use of standard photographic filters has now made this technique widely accessible to researchers. This technology has the potential to automate multiple aspects of paleontology, including preparation and sorting of microfossils. This represents a highly cost-effective way to address paleontology's preparatory bottleneck. PMID- 26016844 TI - Environmental Enrichment Reduces Anxiety by Differentially Activating Serotonergic and Neuropeptide Y (NPY)-Ergic System in Indian Field Mouse (Mus booduga): An Animal Model of Post-Traumatic Stress Disorder. AB - Exposure to a predator elicits an innate fear response and mimics several behavioral disorders related to post-traumatic stress disorder (PTSD). The protective role of an enriched condition (EC) against psychogenic stressors in various animal models has been well documented. However, this condition has not been tested in field mice in the context of PTSD. In this study, we show that field mice (Mus booduga) housed under EC exhibit predominantly proactive and less reactive behavior compared with mice housed under standard conditions (SC) during exposure to their natural predator (field rat Rattus rattus). Furthermore, we observed that EC mice displayed less anxiety-like behavior in an elevated plus maze (EPM) and light/dark-box after exposure to the predator (7 hrs/7 days). In EC mice, predator exposure elevated the level of serotonin (5-Hydroxytrypamine, [5-HT]) in the amygdala as part of the coping response. Subsequently, the serotonin transporter (SERT) and 5-HT1A receptor were up-regulated significantly, but the same did not occur in the 5-HT2C receptor, which is associated with the activation of calmodulin-dependent protein kinase-II (CaMKII) and a transcription factor cAMP response element binding protein (CREB). Our results show that predator exposure induced the activation of CaMKII/CREB, which is accompanied with increased levels of histone acetylation (H3, H4) and decreased histone deacetylases (HDAC1, 2). Subsequently, in the amygdala, the transcription of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY) and its Y1 receptor were up-regulated, whereas the Y2 receptor was down-regulated. Therefore, EC facilitated a coping response against a fear associated cue in a PTSD animal model and reduced anxiety by differentially activating serotonergic and NPY-ergic systems. PMID- 26016845 TI - Disseminated Aspergillosis in the Immunocompetent Host: A Case Report and Literature Review. AB - Disseminated aspergillosis is very rare in immunocompetent hosts and is typically associated with a poor prognosis. We describe the case of a 66-year-old, immunocompetent man who developed pneumonia, endophthalmitis and probable spondylitis caused by Aspergillus species. The patient was successfully treated with antifungal drugs. We reviewed the English-language literature between 1980 and 2012 for disseminated aspergillosis cases in immunocompetent hosts, using the keywords "dissemin*" and "aspergillo*." Disseminated aspergillosis in immunocompetent hosts is very rare in the literature. However, awareness of possible dissemination of Aspergillus spp. is necessary in patients who have a probable lung lesion and in cases with unusual presentation of a disseminated infection, even if the patient has no risk factors. PMID- 26016846 TI - Usefulness of MALDI-TOF Mass Spectrometry for Routine Identification of Candida Species in a Resource-Poor Setting. AB - BACKGROUND: Identification of fungal clinical isolates is essential for therapeutic management. In resource-limited settings, identification mostly relies on biochemical tests whose sensitivity and specificity are known to be insufficient for identification of closely related or newly described species. MALDI-TOF has been shown in favored countries to be a reliable and powerful tool for microorganism identification, including yeasts. The aim of this study was to compare MALDI-TOF with routine identification procedures in a resource-poor context. METHODS: A total of 734 clinical specimens (502 vaginal swabs, 147 oral swabs, 61 bronchoalveolar lavage fluids and 24 stool samples) have been tested in the mycology unit of Fann Hospital, Dakar, Senegal. Strains isolated from culture were identified by both conventional phenotypic methods (germ tube formation and biochemical panels) and MALDI-TOF Saramis/VITEK MS, bioMerieux, France. In addition to comparing the final identification, we determined the time of obtaining the results and the cost for both approaches. RESULTS: Overall, 218 (29.7 %) samples were positive for Candida. MALDI-TOF MS enabled the identification of 214 of the 218 strains isolated (98.1 %) at species level. Phenotypic approach yielded identification for 208 strains (95.4 %). Congruence between the tests was observed for 203 isolates. A discrepancy was observed for one isolate identified as Candida krusei with the phenotypic approach and Candida tropicalis with the MALDI-TOF. In addition, ten isolates identified at genus level by phenotypic methods were identified as C. glabrata (n = 8), C. tropicalis (n = 1) and C. parapsilosis (n = 1) by MALDI-TOF. The turnaround time for identification was <1 h using the MALDI-TOF compared to our routine procedures (48 h). The overall cost (reagents + expendables) per isolate was at 1.35 for the MALDI-TOF MS. CONCLUSION: MALDI-TOF clearly outperformed the diagnosis capacities of phenotypic methods by reducing the delay of results and giving accurate identification at species level. Moreover, this approach appears to be cost-effective and should be implemented especially in resource-poor context. PMID- 26016848 TI - Haematuria increases progression of advanced proteinuric kidney disease. AB - BACKGROUND: Haematuria has been traditionally considered as a benign hallmark of some glomerular diseases; however new studies show that haematuria may decrease renal function. OBJECTIVE: To determine the influence of haematuria on the rate of chronic kidney disease (CKD) progression in 71 proteinuric patients with advanced CKD (baseline eGFR <30 mL/min) during 12 months of follow-up. RESULTS: The mean rate of decline in eGFR was higher in patients with both haematuria and proteinuria (haemoproteinuria, HP, n=31) than in patients with proteinuria alone (P patients, n=40) (-3.8+/-8.9 vs 0.9+/-9.5 mL/min/1.73 m2/year, p<0.05, respectively). The deleterious effect of haematuria on rate of decline in eGFR was observed in patients <65 years (-6.8+/-9.9 (HP) vs. 0.1+/-11.7 (P) mL/min/1.73 m2/year, p<0.05), but not in patients >65 years (-1.2+/-6.8 (HP) vs. 1.5+/-7.7 (P) mL/min/1.73 m2/year). Furthermore, the harmful effect of haematuria on eGFR slope was found patients with proteinuria >0.5 g/24 h (-5.8+/-6.4 (HP) vs. -1.37+/- 7.9 (P) mL/min/1.73 m2/year, p<0.05), whereas no significant differences were found in patients with proteinuria < 0.5 g/24 h (-0.62+/-7.4 (HP) vs. 3.4+/-11.1 (P) mL/min/1.73 m2/year). Multivariate analysis reported that presence of haematuria was significantly and independently associated with eGFR deterioration after adjusting for traditional risk factors, including age, serum phosphate, mean proteinuria and mean serum PTH (beta=-4.316, p=0.025). CONCLUSIONS: The presence of haematuria is closely associated with a faster decrease in renal function in advanced proteinuric CKD patients, especially in younger CKD patients with high proteinuria levels; therefore this high risk subgroup of patients would benefit of intensive medical surveillance and treatment. PMID- 26016849 TI - Assessment of the genetic polymorphism and physiological characterization of indigenous Oenococcus oeni strains isolated from Aglianico del Vulture red wine. AB - The aim of this study was a reliable intra-species discrimination and strain biodiversity in Oenococcus oeni populations of two different Aglianico wineries by molecular, biochemical, and physiological characterization. Pulsed field gel electrophoresis (PFGE) analysis revealed a high polymorphism related to the origin (winery) of strains, while differential display PCR (DD-PCR) allowed a further discrimination of strains from the same winery. Moreover, the heterogeneity of these natural populations was investigated by capillary electrophoresis and enzymatic assays. A variability related to a different surface charge distribution was observed among strains, linked to their origin. Malolactic activity study evidenced strain-specific differences in malic acid degradation, and then, only the presence of L(-)-malic acid in the medium induced the mle gene. This study provided evidences on the importance of intra-species biodiversity of malolactic bacterial populations in wine ecosystems, as each wine possess peculiar winemaking conditions and physical-chemical properties which make specific the bacterial survival and growth. This study highlighted a great biodiversity among O. oeni strains that can be also winery specific. Such biodiversity within a certain winery and winemaking area is important for selecting malolactic starters, and strain-specific trait identification is especially important to match individual strains to specific industrial process. PMID- 26016850 TI - Multiplying therapies and reducing toxicity in metastatic melanoma. AB - Prior to 2011, only 2 systemic treatments were approved for the treatment of melanoma and these had limited efficacy. In the past 4 years, 6 novel agents have received FDA approval. Herein, we will focus on 4 recently published NEJM papers reporting the results of clinical trials, comprising 4 agents targeting the MAPK pathway: the BRAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitors trametinib and cobimetenib. These have been developed in parallel with a class of immunologic mediators often referred to as "immune checkpoint inhibitors." These recent studies represent a marked acceleration of progress in the treatment of metastatic melanoma. While it was hoped that combining BRAF and MEK inhibitors would significantly mitigate drug resistance, such combinations have yielded only modestly better results than monotherapy. However, these combinations were successful in reducing the development of cutaneous squamous cell carcinomas and keratocanthomas. Therefore, combination therapies are clearly warranted. Thus far there are only limited data addressing the value of combinations of immunotherapeutic agents: a phase 1 trial of concurrent nivolumab plus ipilimumab suggested enhanced activity that may not depend on BRAF mutation status. Despite the attention and publicity given to the progress achieved in the therapy of melanoma, the majority of patients with metastatic disease still have a poor prognosis. Even novel combination regiments of BRAF and MEK inhibitors achieve complete response in only 13% of patients and a median PFS of 11.4 months in all patients. Better therapies remain desperately needed, especially for the 30-40% of patients with wild-type BRAF, for whom BRAF/MAPK inhibition offers no benefit. In the latter benefit is expected from emerging immunotherapies either singly or in combinations. The extent to which immunotherapies will add to regimens targeting BRAF remains to be determined. PMID- 26016847 TI - Adiposity as a cause of cardiovascular disease: a Mendelian randomization study. AB - BACKGROUND: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. METHODS: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. RESULTS: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (beta = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12 3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. CONCLUSIONS: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke. PMID- 26016851 TI - C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. AB - OBJECTIVE: An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed. METHODS: Gene expression profiling utilised total RNA extracted from motor neurons and lymphoblastoid cell lines derived from human ALS patients, including those with an expansion of C9ORF72, and controls. In lymphoblastoid cell lines, expansion length and the frequency of sense and antisense RNA foci was also examined. RESULTS: Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding 'RNA splicing' proteins. There was a significant overlap of these genes with an independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length. SIGNIFICANCE: Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity. PMID- 26016852 TI - Phototoxic Risk Assessments on Benzophenone Derivatives: Photobiochemical Assessments and Dermal Cassette-Dosing Pharmacokinetic Study. AB - This study aimed to qualify photosafety screening on the basis of photochemical and pharmacokinetic (PK) data on dermally applied chemicals. Six benzophenone derivatives (BZPs) were selected as model compounds, and in vitro photochemical/phototoxic characterization and dermal cassette-dosing PK study were carried out. For comparison, an in vivo phototoxicity test was also conducted. All of the BZPs exhibited strong UVA/UVB absorption with molar extinction coefficients of over 2000 M(-1) * cm(-1), and benzophenone and ketoprofen exhibited significant reactive oxygen species (ROS) generation upon exposure to simulated sunlight (about 2.0 mW/cm(2)); however, ROS generation from sulisobenzone and dioxybenzone was negligible. To verify in vitro phototoxicity, a 3T3 neutral red uptake phototoxicity test was carried out, and benzophenone and ketoprofen were categorized to be phototoxic chemicals. The dermal PK parameters of ketoprofen were indicative of the highest dermal distribution of all BZPs tested. On the basis of its in vitro photochemical/phototoxic and PK data, ketoprofen was deduced to be highly phototoxic. The rank of predicted phototoxic risk of BZPs on the basis of the proposed screening strategy was almost in agreement with the results from the in vivo phototoxicity test. The combined use of photochemical and cassette-dosing PK data would provide reliable predictions of phototoxic risk for candidates with high productivity. PMID- 26016854 TI - Efficient dye regeneration at low driving force achieved in triphenylamine dye LEG4 and TEMPO redox mediator based dye-sensitized solar cells. AB - Minimizing the driving force required for the regeneration of oxidized dyes using redox mediators in an electrolyte is essential to further improve the open circuit voltage and efficiency of dye-sensitized solar cells (DSSCs). Appropriate combinations of redox mediators and dye molecules should be explored to achieve this goal. Herein, we present a triphenylamine dye, LEG4, in combination with a TEMPO-based electrolyte in acetonitrile (E(0) = 0.89 V vs. NHE), reaching an efficiency of up to 5.4% under one sun illumination and 40% performance improvement compared to the previously and widely used indoline dye D149. The origin of this improvement was found to be the increased dye regeneration efficiency of LEG4 using the TEMPO redox mediator, which regenerated more than 80% of the oxidized dye with a driving force of only ~0.2 eV. Detailed mechanistic studies further revealed that in addition to electron recombination to oxidized dyes, recombination of electrons from the conducting substrate and the mesoporous TiO2 film to the TEMPO(+) redox species in the electrolyte accounts for the reduced short circuit current, compared to the state-of-the-art cobalt tris(bipyridine) electrolyte system. The diffusion length of the TEMPO electrolyte based DSSCs was determined to be ~0.5 MUm, which is smaller than the ~2.8 MUm found for cobalt-electrolyte based DSSCs. These results show the advantages of using LEG4 as a sensitizer, compared to previously record indoline dyes, in combination with a TEMPO-based electrolyte. The low driving force for efficient dye regeneration presented by these results shows the potential to further improve the power conversion efficiency (PCE) of DSSCs by utilizing redox couples and dyes with a minimal need of driving force for high regeneration yields. PMID- 26016853 TI - The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans. AB - GATA transcription factors play critical roles in cellular differentiation and development. However, their roles in mature tissues are less understood. In C. elegans larvae, the transcription factor ELT-2 regulates terminal differentiation of the intestine. It is also expressed in the adult intestine, where it was suggested to maintain intestinal structure and function, and where it was additionally shown to contribute to infection resistance. To study the function of elt-2 in adults we characterized elt-2-dependent gene expression following its knock-down specifically in adults. Microarray analysis identified two ELT-2 regulated gene subsets: one, enriched for hydrolytic enzymes, pointed at regulation of constitutive digestive functions as a dominant role of adult elt-2; the second was enriched for immune genes that are induced in response to Pseudomonas aeruginosa infection. Focusing on the latter, we used genetic analyses coupled to survival assays and quantitative RT-PCR to interrogate the mechanism(s) through which elt-2 contributes to immunity. We show that elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1. This demonstrates a mechanism through which the constitutively nuclear elt-2 can impact induced responses, and play a dominant role in C. elegans immunity. PMID- 26016855 TI - Effects of statin use on volumetric mammographic density: results from the KARMA study. AB - BACKGROUND: Epidemiological data on statins and breast cancer risk have been inconclusive. The aim of this study was to clarify the role of statins in breast cancer risk by studying their effect on mammographic density. METHODS: The KARolinska MAmmography project for risk prediction of breast cancer (KARMA) includes 70,877 women who underwent either a screening or clinical mammography from January 2011 to December 2013. In total, 41,102 women responded to a web based questionnaire, and had raw digital mammograms stored. Volumetric mammographic density was measured using VolparaTM and information on statin use was obtained through linkage with the Swedish National Prescription Register. Analysis of covariance was used to study the effect of statin use on mammographic density, adjusting for a large set of potential confounders. We also studied the effects of statin class and treatment duration and tested for potential effect modification by hormone replacement therapy (HRT). RESULTS: Statin use was recorded in 3,337 women (8.1 %) of the study population and lipophilic statins was the most commonly prescribed type (93.4 % of all statin users). After multivariable adjustment, percent dense volume was lower in statin users than in non-users (P < 0.001). This association was explained by a larger absolute non dense volume in statin users (P < 0.001). Overall, no difference in absolute dense volume was detected, but interaction analyses revealed a larger dense volume among statin users who reported ever HRT use (P = 0.03). No differential effects were observed according to statin lipophilicity and treatment duration. CONCLUSIONS: We observed no overall effect of statin use on mammographic density in terms of absolute dense volume, although a larger absolute dense volume was observed in statin users who reported ever HRT use, which requires further investigation. PMID- 26016856 TI - What's in a Name? Sound Symbolism and Gender in First Names. AB - Although the arbitrariness of language has been considered one of its defining features, studies have demonstrated that certain phonemes tend to be associated with certain kinds of meaning. A well-known example is the Bouba/Kiki effect, in which nonwords like bouba are associated with round shapes while nonwords like kiki are associated with sharp shapes. These sound symbolic associations have thus far been limited to nonwords. Here we tested whether or not the Bouba/Kiki effect extends to existing lexical stimuli; in particular, real first names. We found that the roundness/sharpness of the phonemes in first names impacted whether the names were associated with round or sharp shapes in the form of character silhouettes (Experiments 1a and 1b). We also observed an association between femaleness and round shapes, and maleness and sharp shapes. We next investigated whether this association would extend to the features of language and found the proportion of round-sounding phonemes was related to name gender (Analysis of Category Norms). Finally, we investigated whether sound symbolic associations for first names would be observed for other abstract properties; in particular, personality traits (Experiment 2). We found that adjectives previously judged to be either descriptive of a figuratively 'round' or a 'sharp' personality were associated with names containing either round- or sharp-sounding phonemes, respectively. These results demonstrate that sound symbolic associations extend to existing lexical stimuli, providing a new example of non arbitrary mappings between form and meaning. PMID- 26016857 TI - Electroacupuncture remediates glial dysfunction and ameliorates neurodegeneration in the astrocytic alpha-synuclein mutant mouse model. AB - BACKGROUND: The acupuncture or electroacupuncture (EA) shows the therapeutic effect on various neurodegenerative diseases. This effect was thought to be partially achieved by its ability to alleviate existing neuroinflammation and glial dysfunction. In this study, we systematically investigated the effect of EA on abnormal neurochemical changes and motor symptoms in a mouse neurodegenerative disease model. METHODS: The transgenic mouse which expresses a mutant alpha synuclein (alpha-syn) protein, A53T alpha-syn, in brain astrocytic cells was used. These mice exhibit extensive neuroinflammatory and motor phenotypes of neurodegenerative disorders. In this study, the effects of EA on these phenotypic changes were examined in these mice. RESULTS: EA improved the movement detected in multiple motor tests in A53T mutant mice. At the cellular level, EA significantly reduced the activation of microglia and prevented the loss of dopaminergic neurons in the midbrain and motor neurons in the spinal cord. At the molecular level, EA suppressed the abnormal elevation of proinflammatory factors (tumor necrosis factor-alpha and interleukin-1beta) in the striatum and midbrain of A53T mice. In contrast, EA increased striatal and midbrain expression of a transcription factor, nuclear factor E2-related factor 2, and its downstream antioxidants (heme oxygenase-1 and glutamate-cysteine ligase modifier subunits). CONCLUSIONS: These results suggest that EA possesses the ability to ameliorate mutant alpha-syn-induced motor abnormalities. This ability may be due to that EA enhances both anti-inflammatory and antioxidant activities and suppresses aberrant glial activation in the diseased sites of brains. PMID- 26016858 TI - Dietary intake of minerals and risk of esophageal squamous cell carcinoma: results from the Golestan Cohort Study. AB - BACKGROUND: Dietary factors have been hypothesized to affect the risk of esophageal cancer via different mechanisms, but the intake of minerals is understudied and the evidence is conflicting. OBJECTIVE: The objective was to evaluate the associations of dietary intake of minerals with risk of esophageal squamous cell carcinoma (ESCC). DESIGN: We used data from the Golestan Cohort Study, which was launched in a high-risk region for esophageal cancer in Iran. Participants were enrolled in 2004-2008 and were followed to 2014. Intakes of minerals were assessed with a validated food-frequency questionnaire. A Cox proportional hazards model was used to estimate HRs and 95% CIs of ESCC for dietary intakes of selected minerals. RESULTS: We identified 201 ESCC cases among 47,405 subjects. Calcium intake was significantly inversely associated with the risk of ESCC (HR per 100-mg/d increase: 0.88; 95% CI: 0.81, 0.96; P = 0.005; quartile 4 vs. quartile 1 HR: 0.49; 95% CI: 0.29, 0.82; P-trend = 0.013). Zinc intake was also inversely associated with ESCC, but the quartile association did not reach significance (HR per 1-mg/d increase: 0.87; 95% CI: 0.77, 0.98; P = 0.027; quartile 4 vs. quartile 1 HR: 0.56; 95% CI: 0.28, 1.12; P-trend = 0.097). The relations between dietary intakes of selenium, magnesium, and copper and risk of ESCC were nonlinear (P-nonlinear trend = 0.001, 0.016, and 0.029, respectively). There was no relation between dietary intake of manganese and the risk of ESCC. CONCLUSION: The results suggest that higher intakes of calcium and zinc are associated with a lower risk of ESCC in a high-risk region of Iran. PMID- 26016859 TI - Magnesium supplementation affects metabolic status and pregnancy outcomes in gestational diabetes: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: To our knowledge, prior research has not examined the effects of magnesium supplementation on metabolic status and pregnancy outcomes in maternal child dyads affected by gestational diabetes (GDM). OBJECTIVE: This study was designed to assess the effects of magnesium supplementation on metabolic status and pregnancy outcomes in magnesium-deficient pregnant women with GDM. DESIGN: A randomized, double-blind, placebo-controlled clinical trial was performed in 70 women with GDM. Patients were randomly assigned to receive either 250 mg magnesium oxide (n = 35) or a placebo (n = 35) for 6 wk. Fasting blood samples were taken at baseline and after a 6-wk intervention. RESULTS: The change in serum magnesium concentration was greater in women consuming magnesium than in the placebo group (+0.06 +/- 0.3 vs. -0.1 +/- 0.3 mg/dL, P = 0.02). However, after controlling for baseline magnesium concentrations, the changes in serum magnesium concentrations were not significantly different between the groups. Changes in fasting plasma glucose (-9.7 +/- 10.1 vs. +1.8 +/- 8.1 mg/dL, P < 0.001), serum insulin concentration (-2.1 +/- 6.5 vs. +5.7 +/- 10.7 MUIU/mL, P = 0.001), homeostasis model of assessment-estimated insulin resistance (-0.5 +/- 1.3 vs. +1.4 +/- 2.3, P < 0.001), homeostasis model of assessment-estimated beta cell function (-4.0 +/- 28.7 vs. +22.0 +/- 43.8, P = 0.006), and the quantitative insulin sensitivity check index (+0.004 +/- 0.021 vs. -0.012 +/- 0.015, P = 0.005) in supplemented women were significantly different from those in women in the placebo group. Changes in serum triglycerides (+2.1 +/- 63.0 vs. +38.9 +/- 37.5 mg/dL, P = 0.005), high sensitivity C-reactive protein (-432.8 +/- 2521.0 vs. +783.2 +/- 2470.1 ng/mL, P = 0.03), and plasma malondialdehyde concentrations (-0.5 +/- 1.6 vs. +0.3 +/- 1.2 MUmol/L, P = 0.01) were significantly different between the supplemented women and placebo group. Magnesium supplementation resulted in a lower incidence of newborn hyperbilirubinemia (8.8% vs. 29.4%, P = 0.03) and newborn hospitalization (5.9% vs. 26.5%, P = 0.02). CONCLUSION: Magnesium supplementation among women with GDM had beneficial effects on metabolic status and pregnancy outcomes. This trial was registered at www.irct.ir as IRCT201503055623N39. PMID- 26016860 TI - What is the best reference site for a single MRI slice to assess whole-body skeletal muscle and adipose tissue volumes in healthy adults? AB - BACKGROUND: Whole-body magnetic resonance imaging (MRI) is the gold standard for the assessment of skeletal muscle (SM) and adipose tissue volumes. It is unclear whether single-slice estimates can replace whole-body data. OBJECTIVE: We evaluated the accuracy of the best single lumbar and midthigh MRI slice to assess whole-body SM, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). DESIGN: Whole-body MRI was performed in 142 healthy adults aged 19-65 y [mean +/- SD age: 37.0 +/- 11.8 y; BMI (in kg/m(2)): 25.3 +/- 5.9]. Single slices were taken at lumbar vertebrae L1-L5 plus intervertebral discs and the thigh (midthigh, 10 cm distally from the midthigh, and 10 cm proximally from the midthigh). The value of single-slice areas was also tested in a longitudinal study on 48 healthy volunteers during weight loss (8.2 +/- 5.2 kg). RESULTS: Cross-sectionally, all SM and adipose tissue single-slice areas correlated with total tissue volumes (P < 0.01). Because of the close associations between L3 areas and corresponding tissue volumes (r = 0.832-0.986, P < 0.01), this location was identified as the reference to estimate SM and adipose tissue in both sexes. SM, SAT, and VAT areas at L3 explained most of the variance of total tissue volumes (69-97%, with SEs of estimation of 1.96 and 2.03 L for SM, 0.23 and 0.61 L for VAT, and 4.44 and 2.47 L for SAT for men and women, respectively. There was no major effect on the explained variance compared with that for optimal slices. For SM, the optimal slice area was shown at midthigh. With weight-loss changes in total SM, VAT, and SAT, volumes were significantly different from those at baseline (SM changes: -2.8 +/- 2.9 L; VAT changes: -0.7 +/- 1.0 L; SAT changes: 5.1 +/- 6.0 L). The area at L3 reflected changes in total VAT and SAT. To assess changes in total SM volumes, areas at midthigh showed the best evidence. CONCLUSION: In both sexes, a single MRI scan at the level of L3 is the best compromise site to assess total tissue volumes of SM, VAT, and SAT. By contrast, L3 does not predict changes in tissue components. This trial was registered at clinicaltrials.gov as NCT01737034. PMID- 26016861 TI - Effects of egg consumption on carotenoid absorption from co-consumed, raw vegetables. AB - BACKGROUND: Dietary lipids are one of the most effective stimulators of carotenoid absorption, but very limited data exist on the impact of endogenous food sources of lipids to enhance carotenoid absorption. The co-consumption of whole egg with carotenoid-rich foods may increase overall carotenoid absorption via lipid-rich egg yolk. OBJECTIVE: We designed this study to assess the effects of egg consumption on carotenoid absorption from a carotenoid-rich, raw mixed vegetable salad. DESIGN: Healthy young men (n = 16) consumed the same salad (all served with 3 g canola oil) with no egg (control), 75 g scrambled whole eggs (1.5 eggs) [low egg (LE)], and 150 g scrambled whole eggs (3 eggs) [high egg (HE)] (a randomized crossover design). Control, LE, and HE meals contained 23 mg, 23.4 mg (0.4 mg from eggs), and 23.8 mg (0.8 mg from eggs) total carotenoids and 3 g, 10.5 g (7.5 g from eggs), and 18 g (15 g from eggs) total lipids, respectively. Blood was collected hourly for 10 h, and the triacylglycerol-rich lipoprotein (TRL) fraction was isolated. Total and individual carotenoid contents, including lutein, zeaxanthin , alpha-carotene, beta-carotene, and lycopene in TRL were analyzed, and composite areas under the curve (AUCs) were calculated. RESULTS: The total mean (+/-SE) carotenoid AUC0-10h in TRL was higher for the HE meal than for LE and control meals [125.7 +/- 19.4(a) compared with 44.8 +/- 9.2(b) compared with 14.9 +/- 5.2(b) nmol/L . 10 h, respectively (values without a common superscript letter differ); P < 0.0001]. The TRL AUC(0-10h) of lutein and zeaxanthin increased 4-5-fold (P < 0.001), and the TRL AUC(0-10h) of carotenoid not present in eggs, including alpha-carotene, beta-carotene, and lycopene, increased 3-8-fold (P < 0.01) for the HE meal compared with the control meal. CONCLUSION: These findings support the claim that co-consuming cooked whole eggs is an effective way to enhance carotenoid absorption from other carotenoid-rich foods such as a raw mixed-vegetable salad. This trial was registered at clinicaltrials.gov as NCT01951313. PMID- 26016862 TI - Vitamin A: potential misclassification of vitamin A status among patients with type 2 diabetes and hypertension in urban Ghana. AB - BACKGROUND: Sub-Saharan Africa is facing a double burden of malnutrition: vitamin A deficiency (VAD) prevails, whereas the nutrition-related chronic conditions type 2 diabetes (T2D) and hypertension are emerging. Serum retinol-a VAD marker increases in kidney disease and decreases in inflammation, which can partly be attributed to alterations in the vitamin A-transport proteins retinol-binding protein 4 (RBP4) and prealbumin. Kidney dysfunction and inflammation commonly accompany T2D and hypertension. OBJECTIVE: Among urban Ghanaians, we investigated the associations of T2D and hypertension with serum retinol as well as the importance of kidney function and inflammation in this regard. DESIGN: A hospital based, case-control study in individuals for risk factors of T2D, hypertension, or both was conducted in Kumasi, Ghana (328 controls, 197 with T2D, 354 with hypertension, and 340 with T2D plus hypertension). In 1219 blood samples, serum retinol, RBP4, and prealbumin were measured. Urinary albumin and estimated glomerular filtration rate (eGFR) defined kidney function. C-reactive protein (CRP) >5 mg/L indicated inflammation. We identified associations of T2D and hypertension with retinol by linear regression and calculated the contribution of RBP4, prealbumin, urinary albumin, eGFR, and CRP to these associations as the percentages of the explained variance of retinol. RESULTS: VAD (retinol <1.05 MUmol/L) was present in 10% of this predominantly female, middle-aged, overweight, and deprived population. Hypertension, but not T2D, was positively associated with retinol (beta: 0.12; 95% CI: 0.08, 0.17), adjusted for age, sex, socioeconomic factors, anthropometric measurements, and lifestyle. In addition to RBP4 (72%) and prealbumin (22%), the effect of increased retinol on individuals with hypertension was mainly attributed to impaired kidney function (eGFR: 30%; urinary albumin: 5%) but not to inflammation. CONCLUSIONS: In patients with hypertension, VAD might be underestimated because of increased serum retinol in the context of kidney dysfunction. Thus, the interpretation of serum retinol in sub-Saharan Africa should account for hypertension status. PMID- 26016863 TI - Higher dietary anthocyanin and flavonol intakes are associated with anti inflammatory effects in a population of US adults. AB - BACKGROUND: Although growing evidence from trials and population-based studies has supported a protective role for flavonoids in relation to risk of certain chronic diseases, the underlying mechanisms remain unclear. Several previous studies focused on individual inflammatory biomarkers, but because of the limited specificity of any individual marker, an assessment of a combination of biomarkers may be more informative. OBJECTIVE: We used an inflammation score (IS) that integrated 12 individual inflammatory biomarkers for the examination of associations with intakes of different flavonoid classes. DESIGN: The study was a cross-sectional analysis of 2375 Framingham Heart Study Offspring Cohort participants. Intakes of total flavonoids and their classes (anthocyanins, flavonols, flavanones, flavan-3-ols, polymers, and flavones) were calculated from validated food-frequency questionnaires. Individual inflammatory biomarkers were ranked, standardized, and summed to derive an overall IS and subgroup scores of functionally related biomarkers. RESULTS: In multivariate analyses, an inverse association between higher anthocyanin and flavonol intakes and IS was observed with a mean +/- SE difference between quintile categories 5 and 1 of -1.48 +/- 0.32 (P-trend <= 0.001) and -0.72 +/- 0.33 (P-trend = 0.01), respectively. Results remained significant after additional adjustment for physical activity and vitamin C and fruit and vegetable intakes. Higher anthocyanin intake was inversely associated with all biomarker subgroups, whereas higher flavonol intake was associated only with lower cytokine and oxidative stress biomarker concentrations. In food-based analyses, higher intakes of apples and pears, red wine, and strawberries were associated with a lower IS with differences between quintiles 5 and 1 of -1.02 +/- 0.43 (P = 0.006), -1.73 +/- 0.39 (P < 0.001), and 0.44 +/- 0.88 (P = 0.02), respectively. Although intakes of other classes were not associated with a reduction in overall IS, higher intakes of flavan-3-ols and their polymers were associated with a significant reduction in oxidative stress biomarkers. CONCLUSION: These findings provide evidence to suggest that an anti inflammatory effect may be a key component underlying the reduction in risk of certain chronic diseases associated with higher intakes of anthocyanins and flavonols. The Framingham Offspring Study was registered at clinicaltrials.gov as NCT00005121 (Framingham Heart Study). PMID- 26016864 TI - Best (but oft-forgotten) practices: designing, analyzing, and reporting cluster randomized controlled trials. AB - Cluster randomized controlled trials (cRCTs; also known as group randomized trials and community-randomized trials) are multilevel experiments in which units that are randomly assigned to experimental conditions are sets of grouped individuals, whereas outcomes are recorded at the individual level. In human cRCTs, clusters that are randomly assigned are typically families, classrooms, schools, worksites, or counties. With growing interest in community-based, public health, and policy interventions to reduce obesity or improve nutrition, the use of cRCTs has increased. Errors in the design, analysis, and interpretation of cRCTs are unfortunately all too common. This situation seems to stem in part from investigator confusion about how the unit of randomization affects causal inferences and the statistical procedures required for the valid estimation and testing of effects. In this article, we provide a brief introduction and overview of the importance of cRCTs and highlight and explain important considerations for the design, analysis, and reporting of cRCTs by using published examples. PMID- 26016865 TI - Fecal menaquinone profiles of overweight adults are associated with gut microbiota composition during a gut microbiota-targeted dietary intervention. AB - BACKGROUND: Emerging evidence supports novel roles for vitamin K in cardiometabolic health, some of which may be unique to the bacterially synthesized vitamin K forms known as menaquinones. However, factors influencing menaquinone biosynthesis by the gut microbiota and associations with cardiometabolic health have not been examined. OBJECTIVE: The objective of this study was to identify associations between fecal menaquinone profiles, gut microbiota composition, and biomarkers of cardiometabolic health. DESIGN: The menaquinone profile and gut microbiota structure were periodically measured in fecal samples collected from 77 overweight Chinese adults who consumed a prescribed diet previously shown to alter gut microbiota composition and to improve cardiometabolic biomarkers. RESULTS: Covariance among menaquinones within individual fecal samples partitioned individuals into 2 distinct groups, herein introduced as menaquinotypes of the human gut. Menaquinotypes were characterized by differences in menaquinone (MK) 5 and MK9-MK13 and differences in the relative abundance of several operational taxonomic units (OTUs) delineated at the species level, predominantly within the genera Prevotella spp. and Bacteroides spp. Fecal MK4, MK6, and MK8 decreased during the intervention (P < 0.05); and longitudinal changes in the relative abundance of >100 OTUs were associated with altered fecal content of >=1 individual menaquinone. The strongest and most consistent relations were between Prevotella spp. and MK5 and MK11-MK13, between Bacteroides spp. and MK9 and MK10, and between Escherichia/Shigella spp. and MK8. Neither individual menaquinones nor menaquinotypes were longitudinally associated with markers of glycemia, insulin resistance, or inflammation. CONCLUSIONS: These findings suggest that variability in fecal menaquinone content is predominantly determined by relatively few genera within the gut microbiota and that diet mediated alterations in gut microbiota composition may provide a feasible approach for altering gut menaquinone content. This trial was registered at the Chinese Clinical Trials Registry as ChiCTR-TRC-09000353. PMID- 26016866 TI - Flavanones protect from arterial stiffness in postmenopausal women consuming grapefruit juice for 6 mo: a randomized, controlled, crossover trial. AB - BACKGROUND: The consumption of citrus fruits is associated with health benefits. However, clinical data regarding the effects of grapefruit flavanone consumption on vascular function are lacking. OBJECTIVE: The objective of the present study was to address the role of flavanones in the long-term effects induced by grapefruit juice (GFJ) consumption on vascular function in healthy postmenopausal women. DESIGN: Forty-eight healthy postmenopausal women aged 50-65 y within 3-10 y since menopause, a body mass index (in kg/m(2)) of 19-30, and a waist size >88 cm completed this double-blind, randomized, controlled, crossover trial. These volunteers were randomly assigned to consume 340 mL GFJ/d, providing 210 mg naringenin glycosides, or a matched control drink without flavanones for 6 mo each, with a 2-mo washout between beverages. The primary endpoint was the assessment of endothelial function in the brachial artery by using flow-mediated dilation. Blood pressure, arterial stiffness, and endothelial function in the peripheral arterial bed were also evaluated as indicators of vascular function. These measurements and blood collection for clinical biochemical markers were performed in overnight-fasted subjects before and after the 6-mo treatment periods. RESULTS: The mean +/- SD carotid-femoral pulse wave velocity, which reflects central aortic stiffness, was statistically significantly lower after consumption of GFJ (7.36 +/- 1.15 m/s) than after consumption of the matched control drink without flavanones (7.70 +/- 1.36 m/s), with a P value of 0.019 for the treatment effect. Endothelial function in macro- and microcirculation, blood pressure, anthropometric measures, glucose metabolism, and biomarkers of inflammation and oxidative stress were not affected by the intervention. CONCLUSIONS: Regular GFJ consumption by middle-aged, healthy postmenopausal women is beneficial for arterial stiffness. This effect may be related to flavanones present in grapefruit. This trial was registered at clinicaltrials.gov as NCT01272167. PMID- 26016867 TI - Supplementation with a blend of krill and salmon oil is associated with increased metabolic risk in overweight men. AB - BACKGROUND: Krill is an increasingly popular source of marine n-3 (omega-3) PUFA that is seen as a premium product. However, to our knowledge, the effect of krill oil supplementation on insulin sensitivity in humans has not been reported. OBJECTIVE: We assessed whether supplementation with a blend of krill and salmon (KS) oil [which is rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] affects insulin sensitivity in overweight men. DESIGN: The design was a randomized, double-blind, controlled crossover trial. A total of 47 men with a mean +/- SD age of 46.5 +/- 5.1 y, who were overweight [body mass index (in kg/m(2)) from 25 to 30] but otherwise healthy, received 5 1-g capsules of KS oil or a control (canola oil) for 8 wk and crossed over to another treatment after an 8-wk washout period. The primary outcome was insulin sensitivity assessed by using the Matsuda method from an oral-glucose-tolerance test. Secondary outcomes included lipid profiles, inflammatory markers, 24-h ambulatory blood pressure, and carotid artery intimamedia thickness. RESULTS: Unexpectedly, insulin sensitivity (per the Matsuda index) was 14% lower with the KS oil than with the control oil (P = 0.049). A mediation analysis showed that, after controlling for the likely positive effects of blood EPA and DHA (i.e., the omega-3 index), the reduction in insulin sensitivity after KS-oil supplementation was more marked [27% lower than with the control oil (P = 0.009)]. CONCLUSIONS: Supplementation with a blend of KS oil is associated with decreased insulin sensitivity. Thus, krill-oil supplementation in overweight adults could exacerbate risk of diabetes and cardiovascular disease. This trial was prospectively registered at the Australian New Zealand Clinical Trials Registry as ACTRN12611000602921. PMID- 26016868 TI - Higher nutritional quality at no additional cost among low-income households: insights from food purchases of "positive deviants". AB - BACKGROUND: It is unknown whether diet quality is correlated with actual food expenditure. According to the positive deviance theory, the study of actual food expenditure by people with limited economic resources could help identify beneficial food-purchasing behavior. OBJECTIVES: The aims were to investigate the relation between actual expenditure on food and nutritional quality and to identify "positive deviants" among low-income households. DESIGN: Individuals in deprived social situations (n = 91) were recruited as part of the "Opticourses" nutrition intervention conducted in 2012-2014 in poor districts of Marseille, France. Opticourses participants collected food-purchase receipts for their household over a 1-mo period. "Actual diet costs" and "estimated diet costs" were calculated per 2000 kcal of food purchases by using actual expenditures and a standard food price database of food consumed by a representative sample of French adults, respectively. Mean adequacy ratio (MAR), mean excess ratio (MER), and energy density (ED) were used as nutritional quality indicators. "Positive deviants" were defined as having a higher MAR and a lower MER than the respective median values. RESULTS: Opticourses participants selected less-expensive food options than the average French population, both within a food group and for a given food item. Higher diet costs were associated with higher nutritional quality (higher MAR, lower ED), regardless of whether costs were calculated from actual expenditure or on the basis of standard food prices. Twenty-one positive deviants were identified. They made significantly healthier purchases than did other participants (MAR: +13%; MER: -90%. ED: -22%) at higher estimated diet costs. Yet, they did not spend more on food (having the same actual diet costs), which showed that they purchased food with a higher nutritional quality for their price. CONCLUSION: In this low-income population, actual diet cost was positively correlated with nutritional quality, yet the results showed that higher diet quality is not necessarily more costly when foods with higher nutritional quality for their price are selected. The Opticourses intervention was registered at clinicaltrials.gov as NCT02383875. PMID- 26016869 TI - Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. AB - BACKGROUND: Public health strategies to lower cardiovascular disease (CVD) risk involve reducing dietary saturated fatty acid (SFA) intake to <=10% of total energy (%TE). However, the optimal type of replacement fat is unclear. OBJECTIVE: We investigated the substitution of 9.5-9.6%TE dietary SFAs with either monounsaturated fatty acids (MUFAs) or n-6 (omega-6) polyunsaturated fatty acids (PUFAs) on vascular function and other CVD risk factors. DESIGN: In a randomized, controlled, single-blind, parallel-group dietary intervention, 195 men and women aged 21-60 y from the United Kingdom with moderate CVD risk (>=50% above the population mean) followed one of three 16-wk isoenergetic diets (%TE target compositions, total fat:SFA:MUFA:n-6 PUFA) that were rich in SFAs (36:17:11:4, n = 65), MUFAs (36:9:19:4, n = 64), or n-6 PUFAs (36:9:13:10, n = 66). The primary outcome measure was flow-mediated dilatation; secondary outcome measures included fasting serum lipids, microvascular reactivity, arterial stiffness, ambulatory blood pressure, and markers of insulin resistance, inflammation, and endothelial activation. RESULTS: Replacing SFAs with MUFAs or n-6 PUFAs did not affect the percentage of flow-mediated dilatation (primary endpoint) or other measures of vascular reactivity. Of the secondary outcome measures, substitution of SFAs with MUFAs attenuated the increase in night systolic blood pressure (-4.9 mm Hg, P = 0.019) and reduced E-selectin (-7.8%, P = 0.012). Replacement with MUFAs or n-6 PUFAs lowered fasting serum total cholesterol (-8.4% and -9.2%, respectively), low-density lipoprotein cholesterol (-11.3% and -13.6%), and total cholesterol to high-density lipoprotein cholesterol ratio (-5.6% and -8.5%) (P <= 0.001). These changes in low-density lipoprotein cholesterol equate to an estimated 17-20% reduction in CVD mortality. CONCLUSIONS: Substitution of 9.5-9.6%TE dietary SFAs with either MUFAs or n-6 PUFAs did not significantly affect the percentage of flow-mediated dilatation or other measures of vascular function. However, the beneficial effects on serum lipid biomarkers, blood pressure, and E-selectin offer a potential public health strategy for CVD risk reduction. This trial was registered at www.clinicaltrials.gov as NCT01478958. PMID- 26016870 TI - Potential role of milk fat globule membrane in modulating plasma lipoproteins, gene expression, and cholesterol metabolism in humans: a randomized study. AB - BACKGROUND: Butter is rich in saturated fat [saturated fatty acids (SFAs)] and can increase plasma low density lipoprotein (LDL) cholesterol, which is a major risk factor for cardiovascular disease. However, compared with other dairy foods, butter is low in milk fat globule membrane (MFGM) content, which encloses the fat. We hypothesized that different dairy foods may have distinct effects on plasma lipids because of a varying content of MFGM. OBJECTIVE: We aimed to investigate whether the effects of milk fat on plasma lipids and cardiometabolic risk markers are modulated by the MFGM content. DESIGN: The study was an 8-wk, single-blind, randomized, controlled isocaloric trial with 2 parallel groups including overweight men and women (n = 57 randomly assigned). For the intervention, subjects consumed 40 g milk fat/d as either whipping cream (MFGM diet) or butter oil (control diet). Intervention foods were matched for total fat, protein, carbohydrates, and calcium. Subjects were discouraged from consuming any other dairy products during the study. Plasma markers of cholesterol absorption and hepatic cholesterol metabolism were assessed together with global gene-expression analyses in peripheral blood mononuclear cells. RESULTS: As expected, the control diet increased plasma lipids, whereas the MFGM diet did not [total cholesterol (+/-SD): +0.30 +/- 0.49 compared with -0.04 +/- 0.49 mmol/L, respectively (P = 0.024); LDL cholesterol: +0.36 +/- 0.50 compared with +0.04 +/- 0.36 mmol/L, respectively (P = 0.024); apolipoprotein B:apolipoprotein A-I ratio: +0.03 +/- 0.09 compared with -0.05 +/- 0.10 mmol/L, respectively (P = 0.007); and non-HDL cholesterol: +0.24 +/- 0.49 compared with 0.14 +/- 0.51 mmol/L, respectively (P = 0.013)]. HDL-cholesterol, triglyceride, sitosterol, lathosterol, campesterol, and proprotein convertase subtilisin/kexin type 9 plasma concentrations and fatty acid compositions did not differ between groups. Nineteen genes were differentially regulated between groups, and these genes were mostly correlated with lipid changes. CONCLUSIONS: In contrast to milk fat without MFGM, milk fat enclosed by MFGM does not impair the lipoprotein profile. The mechanism is not clear although suppressed gene expression by MFGM correlated inversely with plasma lipids. The food matrix should be considered when evaluating cardiovascular aspects of different dairy foods. This trial was registered at clinicaltrials.gov as NCT01767077. PMID- 26016872 TI - Next-generation sequencing yields the complete mitochondrial genome of the longfang moray, Enchelynassa canina (Anguilliformes: Muraenidae). AB - In this study, the complete mitogenome sequence of the longfang moray, Enchelynassa canina (Anguilliformes: Muraenidae) has been sequenced by the next generation sequencing method. The length of the assembled mitogenome is 16,592 bp, which includes 13 protein coding genes, 22 transfer RNAs, and 2 ribosomal RNAs genes. The overall base composition of longfang moray is 28.4% for A, 28.0% for C, 18.4% for G, 25.1% for T, and show 82% identities to Kidako moray, Gymnothorax kidako. The complete mitogenome of the longfang moray provides an essential and important DNA molecular data for further phylogeography and evolutionary analysis for moray eel phylogeny. PMID- 26016871 TI - Cost-effectiveness of malaria diagnosis using rapid diagnostic tests compared to microscopy or clinical symptoms alone in Afghanistan. AB - BACKGROUND: Improving access to parasitological diagnosis of malaria is a central strategy for control and elimination of the disease. Malaria rapid diagnostic tests (RDTs) are relatively easy to perform and could be used in primary level clinics to increase coverage of diagnostics and improve treatment of malaria. METHODS: A cost-effectiveness analysis was undertaken of RDT-based diagnosis in public health sector facilities in Afghanistan comparing the societal and health sector costs of RDTs versus microscopy and RDTs versus clinical diagnosis in low and moderate transmission areas. The effect measure was 'appropriate treatment for malaria' defined using a reference diagnosis. Effects were obtained from a recent trial of RDTs in 22 public health centres with cost data collected directly from health centres and from patients enrolled in the trial. Decision models were used to compare the cost of RDT diagnosis versus the current diagnostic method in use at the clinic per appropriately treated case (incremental cost-effectiveness ratio, ICER). RESULTS: RDT diagnosis of Plasmodium vivax and Plasmodium falciparum malaria in patients with uncomplicated febrile illness had higher effectiveness and lower cost compared to microscopy and was cost-effective across the moderate and low transmission settings. RDTs remained cost-effective when microscopy was used for other clinical purposes. In the low transmission setting, RDTs were much more effective than clinical diagnosis (65.2% (212/325) vs 12.5% (40/321)) but at an additional cost (ICER) of US$4.5 per appropriately treated patient including a health sector cost (ICER) of US$2.5 and household cost of US$2.0. Sensitivity analysis, which varied drug costs, indicated that RDTs would remain cost-effective if artemisinin combination therapy was used for treating both P. vivax and P. falciparum. Cost-effectiveness of microscopy relative to RDT is further reduced if the former is used exclusively for malaria diagnosis. In the health service setting of Afghanistan, RDTs are a cost-effective intervention compared to microscopy. CONCLUSIONS: RDTs remain cost-effective across a range of drug costs and if microscopy is used for a range of diagnostic services. RDTs have significant advantages over clinical diagnosis with minor increases in the cost of service provision. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under identifier NCT00935688. PMID- 26016873 TI - DNA barcoding reveals species level divergence between populations of the microhylid frog genus Arcovomer (Anura: Microhylidae) in the Atlantic Rainforest of southeastern Brazil. AB - The microhylid frogs belonging to the genus Arcovomer have been reported from lowland Atlantic Rainforest in the Brazilian states of Espirito Santo, Rio de Janeiro, and Sao Paulo. Here, we use DNA barcoding to assess levels of genetic divergence between apparently isolated populations in Espirito Santo and Rio de Janeiro. Our mtDNA data consisting of cytochrome oxidase subunit I (COI) nucleotide sequences reveals 13.2% uncorrected and 30.4% TIM2 + I + Gamma corrected genetic divergences between these two populations. This level of divergence exceeds the suggested 10% uncorrected divergence threshold for elevating amphibian populations to candidate species using this marker, which implies that the Espirito Santo population is a species distinct from Arcovomer passarellii. Calibration of our model-corrected sequence divergence estimates suggests that the time of population divergence falls between 12 and 29 million years ago. PMID- 26016874 TI - The complete mitogenome of Fusarium culmorum. AB - The structure of the Fusarium culmorum mitogenome is similar to that of closely related Fusarium spp.: it has a total length of 103,844 bp, the base composition of the genome is the following: A (35.4%), T (32.9%), C (14.6%), and G (17.1%). The mitogenome contains 13 protein-coding genes, 2 ribosomal RNA (rRNA), and 28 transfer RNA (tRNA) genes, all coded on the same strand of DNA. The gene order is identical to that of the other Fusarium and Hypocreales mitogenomes. Maximum likelihood and Bayesian analysis based on the concatenated amino acid dataset of mitochondrial protein-coding genes confirmed close genetic relationship of F. culmorum to the other type B trichothecene producers F. graminearum and F. gerlachii. PMID- 26016875 TI - The complete mitochondrial genome of Lithobates sylvaticus (Anura: Ranidae). AB - The complete mitochondrial genome of Lithobates sylvaticus (Anura: Ranidae) was sequenced. The genome is a circular molecule of 17,343 bp in length and contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a large non-coding region. The gene order and mitochondrial genome information of L. sylvaticus is similar to most other frogs. The overall AT content of L. sylvaticus mitochondrial DNA is 59.3%. In BI and MLtrees, we found L. sylvaticus is a sister clade to L. catesbeianus. The monophyly of Lithobates, Rana, Odorrana, Glandirana, Pelophylax, and Amolops is well supported, but the paraphyly of Babina is supported. PMID- 26016876 TI - Mitogenomic sequence and phylogenetic placement of the Hortle's whipray Himantura hortlei (Elasmobranchii: Dasyatidae). AB - Chondrichthyans are a class of fishes threatened with habitat destruction and fishing pressures. The current study presents the complete mitochondrial genome sequence (17,688 bp) of the vulnerable Hortle's whipray, Himantura hortlei. The mitochondrial genome arrangement is consistent with that seen in most vertebrates, containing 13 protein-coding, 22 tRNA, 2 rRNA genes, and 1 control region. Phylogenetic analyses were performed based on mitogenome and ND2 sequences. Under our taxon sampling scheme, Himantura hortlei was found to be most closely related to H. fai. PMID- 26016877 TI - A novel mitochondrial DNA deletion in a patient with Pearson syndrome and neonatal diabetes mellitus provides insight into disease etiology, severity and progression. AB - Pearson syndrome (PS) is a rare, mitochondrial DNA (mtDNA) deletion disorder mainly affecting hematopoietic system and exocrine pancreas in early infancy, which is characterized by multi-organ involvement, variable manifestations and poor prognosis. Since the clinical complexity and uncertain outcome of PS, the ability to early diagnose and anticipate disease progression is of great clinical importance. We described a patient with severe anemia and hyperglycinemia at birth was diagnosed with neonatal diabetes mellitus, and later with PS. Genetic testing revealed that a novel mtDNA deletion existed in various non-invasive tissues from the patient. The disease course was monitored by mtDNA deletion heteroplasmy and mtDNA/nucleus DNA genome ratio in different tissues and at different time points, showing a potential genotype-phenotype correlation. Our findings suggest that for patient suspected for PS, it may be therapeutically important to first perform detailed mtDNA analysis on non-invasive tissues at the initial diagnosis and during disease progression. PMID- 26016878 TI - Structural characteristics of the Relict Gull (Larus relictus) mitochondrial DNA control region and its comparison to other Laridae. AB - The structure of the mitochondrial DNA control region in the Relict Gull (Larus relictus) was predicted and compared with data from the National Center for Biotechnology Information (NCBI) on five other gulls. The results showed that the control regions of the six gulls comprise three domains. Sequences of CSB-1-like (domain I) and CSB-1 (domain III) in L. relictus have the highest similarity with those in the other five gulls. The insertion fragments are located in downstream domain I of L. ridibundus, L. brunnicephalus, and L. saundersi. Seven conserved sequence boxes (additional box, F-box, E-box, D-box, C-box, bird-similarity-box, and B-box) are located in domain II in all six gulls. It is suggested that the CSB-2/3 sequence, the origin of H-strand replication, and bidirectional light- and heavy-strand transcription promoters in domain III of L. relictus have some distinguishing features to those of other gulls. Some repeat units are contained in the 3' end of the control region in the five gulls; however, no repeat units are found in the sequence CAAACAACAAA in L. relictus. The distribution of nucleotide diversity analysis will provide the useful information on the selected DNA fragment within the control region for genetic analyses among gulls. PMID- 26016879 TI - Complete mitochondrial DNA sequence and phylogenic analysis of Oxyeleotris lineolatus (Perciformes, Eleotridae). AB - In this study, the mitochondrial genome of Oxyeleotris lineolatus was first determined. The length of entire mtDNA sequence was 16,522 bp with (A + T) content of 53.81%, and it contained 13 protein-coding genes, two rRNAs, 22 tRNAs, and a control region. The gene order and the orientation are similar to some typical fish species. The data will provide useful molecular information for phylogenetic studies concerning O. lineolatus and its related species. PMID- 26016880 TI - The complete mitochondrial genome of the desert darkling beetle Asbolus verrucosus (Coleoptera, Tenebrionidae). AB - The complete mitochondrial genome of the desert darkling beetle Asbolus verrucosus (LeConte, 1851) was sequenced using paired-end technology to an average depth of 42,111* and assembled using De Bruijn graph-based methods. The genome is 15,828 bp in length and conforms to the basal arthropod mitochondrial gene composition with the same gene orders and orientations as other darkling beetle mitochondria. This arrangement includes a control region, 22 tRNA genes, 2 rRNA genes and 13 protein-coding genes. The main coding strand is probably replicated as the lagging strand (GC skew of -0.36 and AT skew of +0.19). Phylogenomics analyses are consistent with taxonomic classifications and indicate that Tenebrio molitor is the closest relative that has a completely sequenced mitochondrial genome available for analysis. This is the first fully assembled mitogenome sequence for a darkling beetle in the subfamily Pimeliinae and will be useful for population studies on members of this ecologically important group of beetles. PMID- 26016881 TI - The complete mitochondrial genome of the Black-spot tuskfish (Choerodon schoenleinii). AB - Choerodon schoenleinii, a critically endangered ocean fish, is also a highly prized commercial fish. In this study, we present the complete mitochondrial genome of C. schoenleinii based on NGS. The length of C. schoenleinii mitochondrial genome is 16,504 bp which consists of 13 protein-coding genes, two rRNA genes, 22 tRNA genes, and a D-loop. The gene order and the composition of mitochondrial genome in C. schoenleinii were similar to other vertebrates. The nucleotide compositions of the light strand are 28.23% of A, 30.51% of C,24.04% of T, and 17.22% of G. Except for ND6 and eight tRNA genes, the rest of mitochondrial genes are encoded on the heavy strand. The construction of phylogenetic trees based on the entire mitochondrial genome sequence of 11 Perciformes species constructed by the NJ method has suggested that the Choerodon schoenleinii has closer relationship to the Chlorurus sordidus, Scarus ruborviolaceus, Scarus forsteri, and Scarus schlegeli, and that they constitute a sister group. PMID- 26016882 TI - The complete mitochondrial genome of the cryptic "lineage A" big-fin reef squid, Sepioteuthis lessoniana (Cephalopoda: Loliginidae) in Indo-West Pacific. AB - In this study, the complete mitogenome sequence of the cryptic "lineage A" big fin reef squid, Sepioteuthis lessoniana (Cephalopoda: Loliginidae) has been sequenced by the next-generation sequencing method. The assembled mitogenome consists of 16,605 bp, which includes 13 protein-coding genes, 22 transfer RNAs, and 2 ribosomal RNAs genes. The overall base composition of "lineage A" S. lessoniana is 37.5% for A, 17.4% for C, 9.1% for G, and 35.9% for T and shows 87% identities to "lineage C" S. lessoniana. It is also noticed by its high T + A content (73.4%), two non-coding regions with TA tandem repeats. The complete mitogenome of the cryptic "lineage A" S. lessoniana provides essential and important DNA molecular data for further phylogeography and evolutionary analysis for big-fin reef squid species complex. PMID- 26016883 TI - Complete mitochondrial genome sequence of Heteropneustes fossilis obtained by paired end next generation sequencing. AB - In the present study, the complete mitochondrial genome sequence of Heteropneustes fossilis is reported using massive parallel sequence technology. The complete mitogenome of H. fossilis is obtained by de novo assembly of paired end Illumina sequences using CLC Genomics Workbench version 7.0.4, which is 16,489 bp in length. It comprised of 13 protein- coding genes, 22 tRNAs, 2 rRNA genes and a putative control region along with the gene order and organization, being similar to most of vertebrates. The mitogenome in the present study has 99% similarity to the complete mitogneome sequence of H. Fossilis, as reported earlier. Phylogenetic analysis of Siluriformes depicted that Heteropneustids were closer to Clariids. The mitogenome sequence of H. fossilis contributes better understanding of population genetics, phylogenetics and evolution of Indian catfish species. PMID- 26016884 TI - The Mediating Role of Perceived Burdensomeness in Relations Between Domains of Cognitive Functioning and Indicators of Suicide Risk. AB - OBJECTIVES: Psychiatric inpatients are at elevated risk for suicide, but there are mixed findings regarding cognitive functioning (i.e., executive functioning and problem-solving abilities) and suicide risk in this population. We hypothesized that a mediating variable (i.e., perceived burdensomeness) may explain these mixed findings. METHOD: This hypothesis was tested in a sample of psychiatric inpatients admitted for suicide-related concerns (N = 110; 58.18% female, M(age) = 36.45) using a nonparametric bootstrapping procedure. RESULTS: Perceived burdensomeness did not act as a mediator between any domain of cognitive functioning and current suicide ideation nor presence of recent suicide attempts. However, perceived burdensomeness was the strongest predictor of suicide ideation and mediated the relation between objective problem-solving skill and suicide risk (a weighted variable comprising current ideation and previous attempts). CONCLUSIONS: Perceived burdensomeness may be associated with elevated suicide ideation, suggesting that perceived burdensomeness should be assessed to inform suicide risk decisions. PMID- 26016885 TI - Ethical deliberations about involuntary treatment: interviews with Swedish psychiatrists. AB - BACKGROUND: Involuntary treatment is a key issue in healthcare ethics. In this study, ethical issues relating to involuntary psychiatric treatment are investigated through interviews with Swedish psychiatrists. METHODS: In-depth interviews were conducted with eight Swedish psychiatrists, focusing on their experiences of and views on compulsory treatment. In relation to this, issues about patient autonomy were also discussed. The interviews were analysed using a descriptive qualitative approach. RESULTS: The answers focus on two main aspects of compulsory treatment. Firstly, deliberations about when and why it was justifiable to make a decision on involuntary treatment in a specific case. Here the cons and pros of ordering compulsory treatment were discussed, with particular emphasis on the consequences of providing treatment vs. refraining from ordering treatment. Secondly, a number of issues relating to background factors affecting decisions for or against involuntary treatment were also discussed. These included issues about the Swedish Mental Care Act, healthcare organisation and the care environment. CONCLUSIONS: Involuntary treatment was generally seen as an unwanted exception to standard care. The respondents' judgments about involuntary treatment were typically in line with Swedish law on the subject. However, it was also argued that the law leaves room for individual judgments when making decisions about involuntary treatment. Much of the reasoning focused on the consequences of ordering involuntary treatment, where risk of harm to the therapeutic alliance was weighed against the assumed good consequences of ensuring that patients received needed treatment. Cases concerning suicidal patients and psychotic patients who did not realise their need for care were typically held as paradigmatic examples of justified involuntary care. However, there was an ambivalence regarding the issue of suicide as it was also argued that risk of suicide in itself might not be sufficient for justified involuntary care. It was moreover argued that organisational factors sometimes led to decisions about compulsory treatment that could have been avoided, given a more patient-oriented healthcare organisation. PMID- 26016886 TI - Novel keratin preparation supports growth and differentiation of odontoblast-like cells. AB - AIM: To fabricate a keratin hydrogel, characterize its functionality as a biomaterial and investigate the effects of keratin on growth and differentiation of odontoblast-like cells. METHODOLOGY: Keratins were extracted from sheep wool using a well-established technique. The extracted proteins were purified by dialysis, quantified by gel electrophoresis, mass spectrometry, amino acid analysis and inductively coupled mass spectrometry. The microstructure of the fabricated keratin hydrogels was studied by scanning electron microscopy, flow characteristics by rheometer, hydrolytic stability and cytocompatibility by Live/Dead((r)) cell assay. Furthermore, the influence of keratin on odontoblast like cells (MDPC-23) was assessed to confirm their bioactivity at different dilutions. Cell proliferation was studied using alamarBlue((r)) assay and differentiation by alkaline phosphatase enzyme activity, alizarin red staining and calcium quantification, reverse transcription polymerase chain reaction (rt PCR) and immunocytochemical staining for dentine matrix protein- 1 (DMP-1) expression. anova with Tukey's tests was performed for statistical comparison. RESULTS: The characterized hydrogel was injectable with a highly porous architecture that underwent slow degradation, and its cytocompatibility was statistically equivalent to collagen hydrogel (P > 0.05). Cell proliferation and differentiation were enhanced at the optimal keratin concentration of 0.1 mg mL( 1) . At this concentration, the influence of keratin on cell differentiation was demonstrated by marked elevation in alkaline phosphatase activity (P < 0.05), calcium deposition (P < 0.01), gene expression (P < 0.01) and positive immunostaining for DMP-1. CONCLUSION: The presence of keratin enhanced odontoblast cell behaviour. Keratin hydrogels may be a potential scaffold for pulp-dentine regen-eration. PMID- 26016887 TI - I just ran a thousand analyses: benefits of multiple testing in understanding equivocal evidence on gene-environment interactions. AB - BACKGROUND: In psychiatric genetics research, the volume of ambivalent findings on gene-environment interactions (G x E) is growing at an accelerating pace. In response to the surging suspicions of systematic distortion, we challenge the notion of chance capitalization as a possible contributor. Beyond qualifying multiple testing as a mere methodological issue that, if uncorrected, leads to chance capitalization, we advance towards illustrating the potential benefits of multiple tests in understanding equivocal evidence in genetics literature. METHOD: We focused on the interaction between the serotonin-transporter-linked promotor region (5-HTTLPR) and childhood adversities with regard to depression. After testing 2160 interactions with all relevant measures available within the Dutch population study of adolescents TRAILS, we calculated percentages of significant (p < .05) effects for several subsets of regressions. Using chance capitalization (i.e. overall significance rate of 5% alpha and randomly distributed findings) as a competing hypothesis, we expected more significant effects in the subsets of regressions involving: 1) interview-based instead of questionnaire-based measures; 2) abuse instead of milder childhood adversities; and 3) early instead of later adversities. Furthermore, we expected equal significance percentages across 4) male and female subsamples, and 5) various genotypic models of 5-HTTLPR. RESULTS: We found differences in the percentages of significant interactions among the subsets of analyses, including those regarding sex-specific subsamples and genetic modeling, but often in unexpected directions. Overall, the percentage of significant interactions was 7.9% which is only slightly above the 5% that might be expected based on chance. CONCLUSION: Taken together, multiple testing provides a novel approach to better understand equivocal evidence on G x E, showing that methodological differences across studies are a likely reason for heterogeneity in findings - but chance capitalization is at least equally plausible. PMID- 26016888 TI - Identification of a putative quantitative trait nucleotide in guanylate binding protein 5 for host response to PRRS virus infection. AB - BACKGROUND: Previously, we identified a major quantitative trait locus (QTL) for host response to Porcine Respiratory and Reproductive Syndrome virus (PRRSV) infection in high linkage disequilibrium (LD) with SNP rs80800372 on Sus scrofa chromosome 4 (SSC4). RESULTS: Within this QTL, guanylate binding protein 5 (GBP5) was differentially expressed (DE) (p < 0.05) in blood from AA versus AB rs80800372 genotyped pigs at 7,11, and 14 days post PRRSV infection. All variants within the GBP5 transcript in LD with rs80800372 exhibited allele specific expression (ASE) in AB individuals (p < 0.0001). A transcript re-assembly revealed three alternatively spliced transcripts for GBP5. An intronic SNP in GBP5, rs340943904, introduces a splice acceptor site that inserts five nucleotides into the transcript. Individuals homozygous for the unfavorable AA genotype predominantly produced this transcript, with a shifted reading frame and early stop codon that truncates the 88 C-terminal amino acids of the protein. RNA seq analysis confirmed this SNP was associated with differential splicing by QTL genotype (p < 0.0001) and this was validated by quantitative capillary electrophoresis (p < 0.0001). The wild-type transcript was expressed at a higher level in AB versus AA individuals, whereas the five-nucleotide insertion transcript was the dominant form in AA individuals. Splicing and ASE results are consistent with the observed dominant nature of the favorable QTL allele. The rs340943904 SNP was also 100 % concordant with rs80800372 in a validation population that possessed an alternate form of the favorable B QTL haplotype. CONCLUSIONS: GBP5 is known to play a role in inflammasome assembly during immune response. However, the role of GBP5 host genetic variation in viral immunity is novel. These findings demonstrate that rs340943904 is a strong candidate causal mutation for the SSC4 QTL that controls variation in host response to PRRSV. PMID- 26016890 TI - The PsychSimCentre: teaching out-of-hours psychiatry to non-psychiatrists. AB - BACKGROUND: Junior doctors have limited experience in psychiatry before starting their training placements. The out-of-hours setting offers specific challenges, and trainees are expected to cope despite being underprepared. We hyphothesised that simulation-based training would increase trainees' competence and confidence in approaching high-risk out-of-hours scenarios. METHODS: A pilot study focused upon the first cohort of psychiatry trainees joining the North East London NHS Foundation Trust in 2012. During their induction (and prior to any clinical duties) each trainee took part in five high-risk clinical scenarios, assessed by a senior psychiatrist and service-user representative. The trainees were required to complete a survey exploring their confidence across nine core psychiatric clinical domains, both before and after the simulation training. RESULTS: The simulation training increased trainee confidence in all nine clinical domains. Before the simulation training, over half of the nine trainees self-rated themselves as having 'no confidence' in six of the nine clinical competencies. After the training, confidence levels had significantly increased, with only two of the competencies scoring any 'no confidence' ratings. There were mixed feelings by trainees on the use of service-user representatives in the training of doctors. Junior doctors have limited experience in psychiatry before starting their training placements DISCUSSION: We found that high-fidelity simulation training is a useful tool to prepare junior trainees in psychiatry to familiarise themselves with some of the high-risk scenarios that they are likely to encounter during out-of-hour on-call duties. We showed that this intervention increased trainees' confidence across a range of core psychiatric skills. This has significant implications in the provision of safe and effective patient care. PMID- 26016889 TI - The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. AB - We examined the role of the mechanistic target of rapamycin (mTOR) pathway in delayed diazoxide (DZ)-induced preconditioning of cultured rat primary cortical neurons. Neurons were treated for 3 days with 500 MUM DZ or feeding medium and then exposed to 3 h of continuous normoxia in Dulbecco's modified eagle medium with glucose or with 3 h of oxygen-glucose deprivation (OGD) followed by normoxia and feeding medium. The OGD decreased viability by 50%, depolarized mitochondria, and reduced mitochondrial respiration, whereas DZ treatment improved viability and mitochondrial respiration, and suppressed reactive oxygen species production, but did not restore mitochondrial membrane potential after OGD. Neuroprotection by DZ was associated with increased phosphorylation of protein kinase B (Akt), mTOR, and the major mTOR downstream substrate, S6 Kinase (S6K). The mTOR inhibitors rapamycin and Torin-1, as well as S6K-targeted siRNA abolished the protective effects of DZ. The effects of DZ on mitochondrial membrane potential and reactive oxygen species production were not affected by rapamycin. Preconditioning with DZ also changed mitochondrial and non-mitochondrial oxygen consumption rates. We conclude that in addition to reducing reactive oxygen species (ROS) production and mitochondrial membrane depolarization, DZ protects against OGD by activation of the Akt-mTOR-S6K pathway and by changes in mitochondrial respiration. Ischemic strokes have limited therapeutic options. Diazoxide (DZ) preconditioning can reduce neuronal damage. Using oxygen-glucose deprivation (OGD), we studied Akt/mTOR/S6K signaling and mitochondrial respiration in neuronal preconditioning. We found DZ protects neurons against OGD via the Akt/mTOR/S6K pathway and alters the mitochondrial and non-mitochondrial oxygen consumption rate. This suggests that the Akt/mTOR/S6k pathway and mitochondria are novel stroke targets. PMID- 26016891 TI - Simultaneous quantification of the major bile acids in artificial Calculus bovis by high-performance liquid chromatography with precolumn derivatization and its application in quality control. AB - An accurate and sensitive high-performance liquid chromatography method coupled with ultralviolet detection and precolumn derivatization was developed for the simultaneous quantification of the major bile acids in Artificial Calculus bovis, including cholic acid, hyodeoxycholic acid, chenodeoxycholic acid, and deoxycholic acid. The extraction, derivatization, chromatographic separation, and detection parameters were fully optimized. The samples were extracted with methanol by ultrasonic extraction. Then, 2-bromine-4'-nitroacetophenone and 18 crown ether-6 were used for derivatization. The chromatographic separation was performed on an Agilent SB-C18 column (250 * 4.6 mm id, 5 MUm) at a column temperature of 30 degrees C and liquid flow rate of 1.0 mL/min using water and methanol as the mobile phase with a gradient elution. The detection wavelength was 263 nm. The method was extensively validated by evaluating the linearity (r(2) >= 0.9980), recovery (94.24-98.91%), limits of detection (0.25-0.31 ng) and limits of quantification (0.83-1.02 ng). Seventeen samples were analyzed using the developed and validated method. Then, the amounts of bile acids were analyzed by hierarchical agglomerative clustering analysis and principal component analysis. The results of the chemometric analysis showed that the contents of these compounds reflect the intrinsic quality of artificial Calculus bovis, and two compounds (hyodeoxycholic acid and chenodeoxycholic acid) were the most important markers for quality evaluating. PMID- 26016892 TI - The effects of exercise training under mild hypoxic conditions on body composition and circulating adiponectin in postmenopausal women. AB - PURPOSE: This study aimed to examine the effects of exercise training under mild hypoxic conditions on body composition and circulating adiponectin levels in postmenopausal women. METHODS: Fourteen postmenopausal women (56 +/- 1 years) were assigned to a normoxic (N group) or hypoxic (H group) exercise group. Aquatic exercise training was performed at an intensity of 50% peak oxygen uptake level for 30 min per training session, 4 days per week, for 8 weeks. The H group performed the exercise under hypobaric hypoxic conditions, which corresponds to 2000 m above sea level, and each participant was exposed to these conditions for 2 h per session. RESULTS: After the training, no significant changes were observed in any of the measured values for the N group. Conversely, body mass (57.3 +/- 2.5 to 54.5 +/- 2.3 kg), body mass index (24.6 +/- 0.8 to 23.4 +/- 0.7 kg m-2 ), body fat (30.7 +/- 1.9 to 28.1 +/- 1.6%) and preperitoneal fat thickness as an index of visceral fat accumulation (10.3 +/- 1.7 to 6.4 +/- 1.0 mm) significantly reduced only in the H group. Circulating adiponectin levels significantly increased (9.5 +/- 1.8 to 11.4 +/- 2.0 MUg ml-1 ), and the changes in adiponectin were significantly correlated with those in body mass (r = -0.81) and body mass index (r = -0.85). CONCLUSIONS: These results suggest that exercise training under mild hypoxic conditions could more effectively reduce body fat and increase adiponectin levels in postmenopausal women in a shorter period, than exercise training in normoxia. PMID- 26016893 TI - Prognostic value of handgrip strength in people aged 60 years and older: A systematic review and meta-analysis. AB - AIM: The aim of the present study was to systematically review the literature on the predictive value of handgrip strength as a marker for vulnerability. Furthermore, we aimed to update a recent systematic review on the association between handgrip strength and mortality. METHODS: Literature searches using Cochrane, PubMed and Embase databases, and searching reference lists of included studies. Eligible studies were observational longitudinal studies presenting handgrip strength at baseline as an independent variable and its association with cognition, depression, mobility, functional status, hospitalization or mortality at follow up in a general population aged 60 years and older. With respect to mortality, we updated a recent systematic review. RESULTS: We included 34 articles. Most of them involved the association between handgrip strength and cognition (n = 9), functional status (n = 12), mobility (n = 6) or mortality (n = 22), and mainly found a positive relationship, meaning that higher handgrip strength at baseline is protective for declines in these outcome measures. Statistical pooling was carried out for functional status and mortality, with a pooled ratio for functional status of 1.78 (95% CI 1.28-2.48) for categorical variables (high vs low handgrip strength) and 0.95 (95% CI 0.92-0.99) for handgrip strength as a continuous variable. The pooled hazard ratio for mortality was 1.79 (95% CI 1.26-2.55) for categorical variables and 0.96 (95% CI 0.93-0.98) for continuous variables. CONCLUSIONS: Handgrip strength has a predictive validity for decline in cognition, mobility, functional status and mortality in older community-dwelling populations. PMID- 26016894 TI - Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma. AB - About one-third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS-driven malignancies barely affect overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Polo-like kinase 1 (Plk1) expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo, and first mechanistic data that an MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS-driven melanoma. As mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins. PMID- 26016895 TI - The CASC15 Long Intergenic Noncoding RNA Locus Is Involved in Melanoma Progression and Phenotype Switching. AB - In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma. PMID- 26016896 TI - HPV Type 16 Infection Switches Keratinocytes from Apoptotic to Proliferative Fate under TWEAK/Fn14 Interaction. AB - Previously, tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) had been known to be an inducer of apoptosis of keratinocytes by engaging the Fn14 receptor. However, the high-risk human papillomavirus (HPV) infection confers a proliferation advantage on keratinocytes that may consequently harbor tumorigenicity. This study was designed to investigate the cross-talk in keratinocytes between TWEAK/Fn14 signaling and HPV type 16 infection, which may cooperate in regulating cell-cycle progression. TWEAK and Fn14 expression was determined in anogenital warts and normal skin. Both primary keratinocytes and HaCaT cells were transfected with HPV16 E6/E7 genes. The results showed that Fn14 is highly expressed upon HPV16 transfection and accompanied by an increase in Ras GTPase activity and TNF-receptor-associated factor 2 (TRAF2) expression. Moreover, the E6/E7-transfected keratinocytes exhibit a shift of TNF receptor profile from type 1 to type 2 and weakened apoptotic response to TNF-alpha stimuli, when compared with the normal control. Surprisingly, significant increase in proliferation but not apoptosis was seen in E6/E7-positive keratinocytes, as TWEAK was additionally supplemented. In conclusion, the HPV16 infection in keratinocytes causes a switch of apoptotic to proliferative fate under TWEAK/Fn14 interaction, possibly by favoring Ras and TRAF2 activation and modulating TNF receptor expression. PMID- 26016897 TI - The Possible Interaction between Receptor Activator of Nuclear Factor Kappa-B Ligand Expressed by Extramammary Paget Cells and its Ligand on Dermal Macrophages. PMID- 26016898 TI - Molecular Diagnosis of alpha0-Thalassemia Through Urine DNA: A Novel DNA Source to Facilitate Prevention Programs in Remote Geographical Areas. AB - We assessed whether urinary DNA sediment was a feasible sample type for the molecular diagnosis of alpha-thalassemia (alpha-thal) mutations. Urine samples (5 10 mL) were collected from 218 male and female volunteers. The cells were centrifuged, and DNA was isolated according to the protocol of a commercial DNA isolation kit. Detection of the alpha(0)-thal [Southeast Asian (- -(SEA)) and - (THAI)] deletions was performed using quantitative real-time polymerase chain reaction (q-PCR), in addition to conventional gap-PCR. The results revealed that DNA extracted from urinary sediment presented an average DNA content of 11.2 +/- 5.5 ng/uL, and the 260/280 ratio indicative of DNA purity, was 1.2 +/- 0.2. The overall q-PCR threshold cycle was 31.2 +/- 2.3. The melting temperature for the - -(SEA) deletion was 87.3 +/- 0.1 degrees C, while that of the wild type sequence was 92.5 +/- 0.2 degrees C. There were 16 (7.3%) alpha(0)-thal SEA genotypes detected. These results were in agreement with those of the conventional gap-PCR and blood DNA analyses. Thus, DNA from urinary sediment can be efficiently used for the molecular diagnosis of alpha(0)-thal mutations. This approach allows for rapid diagnosis, is non invasive, and could be useful for preventing Hb Bart's (gamma4) hydrops fetalis syndrome. PMID- 26016900 TI - Identification of Hb Constant Spring (HBA2: c.427T > C) by an Automated High Performance Liquid Chromatography Method. AB - Laboratory investigation of hemoglobinopathies includes complete blood count (CBC), hemoglobin (Hb) typing by high performance liquid chromatography (HPLC) and DNA analysis. DNA analysis is the most reliable method but requires a manually laborious procedure and is time consuming. A more practical method of detecting abnormal Hbs is the HPLC technique, because it is more rapid and easier to interpret. Hb Constant Spring (Hb CS; HBA2: c.427T > C) is an abnormal variant that is labile and difficult to detect using conventional methods. To evaluate the efficiency of Hb CS determination by HPLC, blood samples from 578 subjects were analyzed using an automated cell analyzer for hematological parameters, automated HPLC for Hb identification, and polymerase chain reaction (PCR) for alpha-thalassemia (alpha-thal) and Hb CS confirmation. These included 169 normal, 119 heterozygous alpha-thal-2, 30 homozygous alpha-thal-2, 177 heterozygous alpha thal-1, 59 heterozygous Hb CS, seven homozygous Hb CS and 17 compound heterozygous alpha-thal-2 and Hb CS subjects. The results showed that sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of Hb CS by HPLC were 93.78, 99.80, 98.73 and 99.00%, respectively. The mean of misdiagnosis value of the three groups of Hb CS subjects (total 83) was 6.02% (n = 5), with percentages for heterozygous Hb CS, homozygous Hb CS, and compound heterozygous alpha-thal-2 and Hb CS being 6.8, 0.0 and 5.9%, respectively. The HPLC method yielded good results, although it may also lead to misdiagnosis of Hb CS due to the relatively small amount and lability. PMID- 26016899 TI - Efficacy of Rapamycin as Inducer of Hb F in Primary Erythroid Cultures from Sickle Cell Disease and beta-Thalassemia Patients. AB - Phenotypic improvement of hemoglobinopathies such as sickle cell disease and beta thalassemia (beta-thal) has been shown in patients with high levels of Hb F. Among the drugs proposed to increase Hb F production, hydroxyurea (HU) is currently the only one proven to improve the clinical course of these diseases. However, Hb F increase and patient's response are highly variable, indicating that new pharmacological agents could be useful for patients not responding to HU or showing a reduction of response during long-term therapy. In this study we evaluated the efficacy of rapamycin, a lypophilic macrolide used for the prevention of acute rejection in renal transplant recipients, as an inducer of Hb F production. The analyses were performed in cultured erythroid progenitors from 25 sickle cell disease and 25 beta-thal intermedia (beta-TI) patients. The use of a quantitative Real-Time-polymerase chain reaction ReTi-PCR technique and high performance liquid chromatography (HPLC) allowed us to determine the increase in gamma-globin mRNA expression and Hb F production in human erythroid cells treated with rapamycin. The results of our study demonstrated an increase in vitro of gamma-globin mRNA expression in 15 sickle cell disease and 14 beta-TI patients and a corresponding Hb F increase. The induction by rapamycin, even if lower or similar in most of samples analyzed, in some cases was higher than HU. These data suggest that rapamycin could be a good candidate to be used in vivo for the treatment of hemoglobinopathies. PMID- 26016901 TI - Compound Heterozygosity for HKalphaalpha and an in Cis Deletion of Double alpha Genes Presents as alpha-Thalassemia Trait. AB - The HKalphaalpha (Hong Kongalphaalpha) allele is an unusual rearrangement of the alpha-globin gene cluster containing both the -alpha(3.7) (rightward) and alphaalphaalpha(anti 4.2) crossover deletion/insertion. During our thalassemia screening program, we identified 10 adult individuals and two newborns who were confirmed to be compound heterozygotes for HKalphaalpha and the Southeast Asian deletion (- -(SEA)). Their hematological data showed a typical alpha-thalassemia (alpha-thal) trait. The routine gap-polymerase chain reaction (gap-PCR) based assay revealed the presence of -alpha(3.7), - -(SEA) and normal alpha2 alleles in the alpha-globin gene clusters. These confusing findings indicated the existence of more complex derivative alleles produced possibly by repeated unequal crossover of recombinant alleles between alpha-globin gene clusters. A two-round nested PCR strategy confirmed the diagnosis of HKalphaalpha. Considering the large-scale population screening in the thalassemia-prevalent regions in China, the current diagnostic strategy might need to be modified accordingly. The detection of HKalphaalpha would improve accuracy in genetic counseling, especially in couples where one partner was a - -(SEA) carrier and the other carries a -alpha(3.7) deletion identified by routine gap-PCR methods. PMID- 26016902 TI - Multiplex Minisequencing of the HBB Gene: A Rapid Strategy to Confirm the Most Frequent beta-Thalassemia Mutations in the Tunisian Population. AB - The beta hemoglobinopathies [beta-thalassemia (beta-thal) and structural hemoglobin (Hb) variants such as Hb S (HBB: c.20A > T) and Hb E (HBB: c.79G > A)] are among the most common inherited diseases worldwide. In Tunisia, due to the high prevalence of consanguineous marriages, the recurrent risk of this disease is high. The average prevalence of hemoglobinopathies is 4.48%, reaching 12.50% in some focus regions. The molecular investigations on thalassemia contributed to establishing the spectrum of mutations in the Tunisian population. The total number of HBB gene mutations identified was 24. The two most frequent mutations, codon 39 (C > T) (HBB: c.118C > T) and IVS-I-110 (G > A) (HBB: c.93-21G > A) accounted for 70.0% of the total encountered beta-thal cases. These two mutations together with IVS-I-2 (T > G) (HBB: c.92 + 2T > G) and the Hb S variant account for more than 90.0% of all HBB genetic variants in Tunisia. Thus, developing rapid, inexpensive and reliable mutation-specific molecular diagnostic assays targeting our Tunisian populations is our aim to facilitate routine detection of hemoglobinopathies. In this report, we describe the successful application of the multiplex minisequencing assay as an alternative strategy for genetic diagnosis of HBB gene disorders in Tunisia. PMID- 26016903 TI - Not Performing a Sentinel Node Biopsy for Older Patients With Early-Stage Invasive Breast Cancer. PMID- 26016904 TI - Gene expression during testis development in Duroc boars. AB - Androstenone is a steroid pheromone occurring in the pubertal Leydig cells. Breeding against androstenone can decrease pheromone odour in swine meat but appears to cause unwanted side effects such as delayed onset of puberty. To study causality, global gene expression in developing boar testes at 12, 16, 20 and 27 weeks was investigated using a porcine cDNA microarray. The morphological status and androgenic levels of the same individuals have been described in a previous publication. In the present paper, expression of genes and pathways has been analysed with reference to these findings. Nine clusters of genes with significant differential expression over time and 49 functional charts were found in the analysed testis samples. Prominent pathways in the prepubertal testis were associated with tissue renewal, cell respiration and increased endocytocis. E cadherines may be associated with the onset of pubertal development. With elevated steroidogenesis (weeks 16 to 27), there was an increase in the expression of genes in the MAPK pathway, STAR and its analogue STARD6. A pubertal shift in genes coding for cellular cholesterol transport was observed. Increased expression of meiotic pathways coincided with the morphological onset of puberty. Puberty-related change in Ca(2+) pathway transcripts, neurosteroids, neuronal changes and signalling in redox pathways suggested a developmental-specific period of neuromorphogenesis. Several growth factors were found to increase differentially over time as the testis matured. There may be interactions between MAPK, STAR and growth factors during specific periods. In conclusion, pathways for neurogenesis, morphological pathways and several transcripts for growth factors, which have known modulating effects on steroidogenesis and gonadotropins in humans and rodents, act at specific ages and developmental stages in the boar testis. The age dependency and complexity shown for development-specific testis transcripts must be considered when selecting phenotypic parameters for genetic selection for low androstenone. The results of selection based on measurement of phenotypic maturation and androstenone (or other steroid) levels at one specific age may differ depending on the age used. More research is necessary to find the optimal phenotype to use in order to reduce the unwanted side effects. PMID- 26016905 TI - Two novel Brugada syndrome-associated mutations increase KV4.3 membrane expression and function. AB - The human cardiac fast transient outward K+ channel is composed of the KV4.3 alpha subunit encoded by KCND3 and the K+ channel-interacting protein 2 (KChIP2) beta subunit, and determines the early repolarization of the action potential (AP). Two human mutations (G600R and L450F) in KV4.3 are associated with Brugada syndrome and they increase the KV4.3/KChIP2-encoded fast transient outward K+ current (Ito,f) and cause the stable loss of the AP dome. However, the detailed mechanisms underlying the gain of Ito,f function by these two mutations are largely unknown. The experiments in the present study were undertaken to investigate the effect of these mutations and the underlying mechanism. Whole cell patch-clamp recording was performed in HEK-293 cells expressing KV4.3-wild type (WT) and KV4.3 mutants with KChIP2. The two individual mutant-encoded currents were significantly increased but the kinetics of the channels affected by the two mutations were different. The two mutations slowed KV4.3/KChIP2 encoded channel inactivation; they did not increase the recovery from the KV4.3/KChIP2-encoded channel inactivation. Western blotting showed that total KV4.3 protein was significantly augmented in HEK-293 cells expressing the two individual mutants with KChIP2. Furthermore, immunofluorescence confocal microscopy demonstrated that the KV4.3 channel protein was expressed more in the cell membrane compared to the cytoplasm in cells that expressed individual mutants with KChIP2. Also, KChIP2 increased the amount of channel protein in the cell membrane of KV4.3 mutants significantly more than KV4.3-WT. Reverse transcription-polymerase chain reaction showed that KV4.3 mRNA was not significantly changed by individual mutations in the presence of KChIP2. Taken together, the present study revealed that the mutations cause a gain-of-function of KV4.3/KChIP2-encoded channels by increasing membrane protein expression and slowing channel inactivation. PMID- 26016907 TI - Assessing and correcting topographic effects on forest canopy height retrieval using airborne LiDAR data. AB - Topography affects forest canopy height retrieval based on airborne Light Detection and Ranging (LiDAR) data a lot. This paper proposes a method for correcting deviations caused by topography based on individual tree crown segmentation. The point cloud of an individual tree was extracted according to crown boundaries of isolated individual trees from digital orthophoto maps (DOMs). Normalized canopy height was calculated by subtracting the elevation of centres of gravity from the elevation of point cloud. First, individual tree crown boundaries are obtained by carrying out segmentation on the DOM. Second, point clouds of the individual trees are extracted based on the boundaries. Third, precise DEM is derived from the point cloud which is classified by a multi scale curvature classification algorithm. Finally, a height weighted correction method is applied to correct the topological effects. The method is applied to LiDAR data acquired in South China, and its effectiveness is tested using 41 field survey plots. The results show that the terrain impacts the canopy height of individual trees in that the downslope side of the tree trunk is elevated and the upslope side is depressed. This further affects the extraction of the location and crown of individual trees. A strong correlation was detected between the slope gradient and the proportions of returns with height differences more than 0.3, 0.5 and 0.8 m in the total returns, with coefficient of determination R2 of 0.83, 0.76, and 0.60 (n = 41), respectively. PMID- 26016906 TI - Evaluation of two novel 64Cu-labeled RGD peptide radiotracers for enhanced PET imaging of tumor integrin alphavbeta3. AB - PURPOSE: Our goal was to demonstrate that suitably derivatized monomeric RGD peptide-based PET tracers, targeting integrin alphavbeta3, may offer advantages in image contrast, time for imaging, and low uptake in nontarget tissues. METHODS: Two cyclic RGDfK derivatives, (PEG)2-c(RGDfK) and PEG4-SAA4-c(RGDfK), were constructed and conjugated to NOTA for (64)Cu labeling. Their integrin alphavbeta3-binding properties were determined via a competitive cell binding assay. Mice bearing U87MG tumors were intravenously injected with each of the (64)Cu-labeled peptides, and PET scans were acquired during the first 30 min, and 2 and 4 h after injection. Blocking and ex vivo biodistribution studies were carried out to validate the PET data and confirm the specificity of the tracers. RESULTS: The IC50 values of NOTA-(PEG)2-c(RGDfK) and NOTA-PEG4-SAA4-c(RGDfK) were 444 +/- 41 nM and 288 +/- 66 nM, respectively. Dynamic PET data of (64)Cu-NOTA (PEG)2-c(RGDfK) and (64)Cu-NOTA-PEG4-SAA4-c(RGDfK) showed similar circulation t 1/2 and peak tumor uptake of about 4 %ID/g for both tracers. Due to its marked hydrophilicity, (64)Cu-NOTA-PEG4-SAA4-c(RGDfK) provided faster clearance from tumor and normal tissues yet maintained excellent tumor-to-background ratios. Static PET scans at later time-points corroborated the enhanced excretion of the tracer, especially from abdominal organs. Ex vivo biodistribution and receptor blocking studies confirmed the accuracy of the PET data and the integrin alphavbeta3-specificity of the peptides. CONCLUSION: Our two novel RGD-based radiotracers with optimized pharmacokinetic properties allowed fast, high contrast PET imaging of tumor-associated integrin alphavbeta3. These tracers may facilitate the imaging of abdominal malignancies, normally precluded by high background uptake. PMID- 26016908 TI - Self-organizing distributed architecture supporting dynamic space expanding and reducing in indoor LBS environment. AB - Indoor location-based services (iLBS) are extremely dynamic and changeable, and include numerous resources and mobile devices. In particular, the network infrastructure requires support for high scalability in the indoor environment, and various resource lookups are requested concurrently and frequently from several locations based on the dynamic network environment. A traditional map based centralized approach for iLBSs has several disadvantages: it requires global knowledge to maintain a complete geographic indoor map; the central server is a single point of failure; it can also cause low scalability and traffic congestion; and it is hard to adapt to a change of service area in real time. This paper proposes a self-organizing and fully distributed platform for iLBSs. The proposed self-organizing distributed platform provides a dynamic reconfiguration of locality accuracy and service coverage by expanding and contracting dynamically. In order to verify the suggested platform, scalability performance according to the number of inserted or deleted nodes composing the dynamic infrastructure was evaluated through a simulation similar to the real environment. PMID- 26016909 TI - GNSS space-time interference mitigation and attitude determination in the presence of interference signals. AB - The use of Space-Time Processing (STP) in Global Navigation Satellite System (GNSS) applications is gaining significant attention due to its effectiveness for both narrowband and wideband interference suppression. However, the resulting distortion and bias on the cross correlation functions due to space-time filtering is a major limitation of this technique. Employing the steering vector of the GNSS signals in the filter structure can significantly reduce the distortion on cross correlation functions and lead to more accurate pseudorange measurements. This paper proposes a two-stage interference mitigation approach in which the first stage estimates an interference-free subspace before the acquisition and tracking phases and projects all received signals into this subspace. The next stage estimates array attitude parameters based on detecting and employing GNSS signals that are less distorted due to the projection process. Attitude parameters enable the receiver to estimate the steering vector of each satellite signal and use it in the novel distortionless STP filter to significantly reduce distortion and maximize Signal-to-Noise Ratio (SNR). GPS signals were collected using a six-element antenna array under open sky conditions to first calibrate the antenna array. Simulated interfering signals were then added to the digitized samples in software to verify the applicability of the proposed receiver structure and assess its performance for several interference scenarios. PMID- 26016910 TI - Optimization and application of reflective LSPR optical fiber biosensors based on silver nanoparticles. AB - In this study, we developed a reflective localized surface plasmon resonance (LSPR) optical fiber sensor, based on silver nanoparticles (Ag NPs). To enhance the sensitivity of the LSPR optical sensor, two key parameters were optimized, the length of the sensing area and the coating time of the Ag NPs. A sensing length of 1.5 cm and a 1-h coating time proved to be suitable conditions to produce highly sensitive sensors for biosensing. The optimized sensor has a high refractive index sensitivity of 387 nm/RIU, which is much higher than that of other reported individual silver nanoparticles in solutions. Moreover, the sensor was further modified with antigen to act as a biosensor. Distinctive wavelength shifts were found after each surface modification step. In addition, the reflective LSPR optical fiber sensor has high reproducibility and stability. PMID- 26016911 TI - Microfabrication and integration of a sol-gel PZT folded spring energy harvester. AB - This paper presents the methodology and challenges experienced in the microfabrication, packaging, and integration of a fixed-fixed folded spring piezoelectric energy harvester. A variety of challenges were overcome in the fabrication of the energy harvesters, such as the diagnosis and rectification of sol-gel PZT film quality and adhesion issues. A packaging and integration methodology was developed to allow for the characterizing the harvesters under a base vibration. The conditioning circuitry developed allowed for a complete energy harvesting system, consisting a harvester, a voltage doubler, a voltage regulator and a NiMH battery. A feasibility study was undertaken with the designed conditioning circuitry to determine the effect of the input parameters on the overall performance of the circuit. It was found that the maximum efficiency does not correlate to the maximum charging current supplied to the battery. The efficiency and charging current must be balanced to achieve a high output and a reasonable output current. The development of the complete energy harvesting system allows for the direct integration of the energy harvesting technology into existing power management schemes for wireless sensing. PMID- 26016912 TI - A low-cost sensing system for cooperative air quality monitoring in urban areas. AB - Air quality in urban areas is a very important topic as it closely affects the health of citizens. Recent studies highlight that the exposure to polluted air can increase the incidence of diseases and deteriorate the quality of life. Hence, it is necessary to develop tools for real-time air quality monitoring, so as to allow appropriate and timely decisions. In this paper, we present uSense, a low-cost cooperative monitoring tool that allows knowing, in real-time, the concentrations of polluting gases in various areas of the city. Specifically, users monitor the areas of their interest by deploying low-cost and low-power sensor nodes. In addition, they can share the collected data following a social networking approach. uSense has been tested through an in-field experimentation performed in different areas of a city. The obtained results are in line with those provided by the local environmental control authority and show that uSense can be profitably used for air quality monitoring. PMID- 26016913 TI - Amorphous silicon p-i-n structure acting as light and temperature sensor. AB - In this work, we propose a multi-parametric sensor able to measure both temperature and radiation intensity, suitable to increase the level of integration and miniaturization in Lab-on-Chip applications. The device is based on amorphous silicon p-doped/intrinsic/n-doped thin film junction. The device is first characterized as radiation and temperature sensor independently. We found a maximum value of responsivity equal to 350 mA/W at 510 nm and temperature sensitivity equal to 3.2 mV/K. We then investigated the effects of the temperature variation on light intensity measurement and of the light intensity variation on the accuracy of the temperature measurement. We found that the temperature variation induces an error lower than 0.55 pW/K in the light intensity measurement at 550 nm when the diode is biased in short circuit condition, while an error below 1 K/uW results in the temperature measurement when a forward bias current higher than 25 uA/cm2 is applied. PMID- 26016914 TI - Random and directed walk-based top-(k) queries in wireless sensor networks. AB - In wireless sensor networks, filter-based top- query approaches are the state-of the-art solutions and have been extensively researched in the literature, however, they are very sensitive to the network parameters, including the size of the network, dynamics of the sensors' readings and declines in the overall range of all the readings. In this work, a random walk-based top- query approach called RWTQ and a directed walk-based top- query approach called DWTQ are proposed. At the beginning of a top- query, one or several tokens are sent to the specific node(s) in the network by the base station. Then, each token walks in the network independently to record and process the readings in a random or directed way. A strategy of choosing the "right" way in DWTQ is carefully designed for the token(s) to arrive at the high-value regions as soon as possible. When designing the walking strategy for DWTQ, the spatial correlations of the readings are also considered. Theoretical analysis and simulation results indicate that RWTQ and DWTQ both are very robust against these parameters discussed previously. In addition, DWTQ outperforms TAG, FILA and EXTOK in transmission cost, energy consumption and network lifetime. PMID- 26016915 TI - A novel software architecture for the provision of context-aware semantic transport information. AB - The effectiveness of Intelligent Transportation Systems depends largely on the ability to integrate information from diverse sources and the suitability of this information for the specific user. This paper describes a new approach for the management and exchange of this information, related to multimodal transportation. A novel software architecture is presented, with particular emphasis on the design of the data model and the enablement of services for information retrieval, thereby obtaining a semantic model for the representation of transport information. The publication of transport data as semantic information is established through the development of a Multimodal Transport Ontology (MTO) and the design of a distributed architecture allowing dynamic integration of transport data. The advantages afforded by the proposed system due to the use of Linked Open Data and a distributed architecture are stated, comparing it with other existing solutions. The adequacy of the information generated in regard to the specific user's context is also addressed. Finally, a working solution of a semantic trip planner using actual transport data and running on the proposed architecture is presented, as a demonstration and validation of the system. PMID- 26016916 TI - Modeling battery behavior on sensory operations for context-aware smartphone sensing. AB - Energy consumption is a major concern in context-aware smartphone sensing. This paper first studies mobile device-based battery modeling, which adopts the kinetic battery model (KiBaM), under the scope of battery non-linearities with respect to variant loads. Second, this paper models the energy consumption behavior of accelerometers analytically and then provides extensive simulation results and a smartphone application to examine the proposed sensor model. Third, a Markov reward process is integrated to create energy consumption profiles, linking with sensory operations and their effects on battery non-linearity. Energy consumption profiles consist of different pairs of duty cycles and sampling frequencies during sensory operations. Furthermore, the total energy cost by each profile is represented by an accumulated reward in this process. Finally, three different methods are proposed on the evolution of the reward process, to present the linkage between different usage patterns on the accelerometer sensor through a smartphone application and the battery behavior. By doing this, this paper aims at achieving a fine efficiency in power consumption caused by sensory operations, while maintaining the accuracy of smartphone applications based on sensor usages. More importantly, this study intends that modeling the battery non-linearities together with investigating the effects of different usage patterns in sensory operations in terms of the power consumption and the battery discharge may lead to discovering optimal energy reduction strategies to extend the battery lifetime and help a continual improvement in context-aware mobile services. PMID- 26016917 TI - A new, effective and low-cost three-dimensional approach for the estimation of upper-limb volume. AB - The aim of this research was to validate a new procedure (SkanLab) for the three dimensional estimation of total arm volume. SkanLab is based on a single structured-light Kinect sensor (Microsoft, Redmond, WA, USA) and on Skanect (Occipital, San Francisco, CA, USA) and MeshLab (Visual Computing Lab, Pisa, Italy) software. The volume of twelve plastic cylinders was measured using geometry, as the reference, water displacement and SkanLab techniques (two raters and repetitions). The right total arm volume of thirty adults was measured by water displacement (reference) and SkanLab (two raters and repetitions). The bias and limits of agreement (LOA) between techniques were determined using the Bland Altman method. Intra- and inter-rater reliability was assessed using the intraclass correlation coefficient (ICC) and the standard error of measurement. The bias of SkanLab in measuring the cylinders volume was -21.9 mL (-5.7%) (LOA: 62.0 to 18.2 mL; -18.1% to 6.7%) and in measuring the volume of arms' was -9.9 mL (-0.6%) (LOA: -49.6 to 29.8 mL; -2.6% to 1.4%). SkanLab's intra- and inter-rater reliabilities were very high (ICC >0.99). In conclusion, SkanLab is a fast, safe and low-cost method for assessing total arm volume, with high levels of accuracy and reliability. SkanLab represents a promising tool in clinical applications. PMID- 26016918 TI - An energy-efficient underground localization system based on heterogeneous wireless networks. AB - A precision positioning system with energy efficiency is of great necessity for guaranteeing personnel safety in underground mines. The location information of the miners' should be transmitted to the control center timely and reliably; therefore, a heterogeneous network with the backbone based on high speed Industrial Ethernet is deployed. Since the mobile wireless nodes are working in an irregular tunnel, a specific wireless propagation model cannot fit all situations. In this paper, an underground localization system is designed to enable the adaptation to kinds of harsh tunnel environments, but also to reduce the energy consumption and thus prolong the lifetime of the network. Three key techniques are developed and implemented to improve the system performance, including a step counting algorithm with accelerometers, a power control algorithm and an adaptive packets scheduling scheme. The simulation study and experimental results show the effectiveness of the proposed algorithms and the implementation. PMID- 26016919 TI - Investigation of two novel approaches for detection of sulfate ion and methane dissolved in sediment pore water using Raman spectroscopy. AB - The levels of dissolved sulfate and methane are crucial indicators in the geochemical analysis of pore water. Compositional analysis of pore water samples obtained from sea trials was conducted using Raman spectroscopy. It was found that the concentration of SO42- in pore water samples decreases as the depth increases, while the expected Raman signal of methane has not been observed. A possible reason for this is that the methane escaped after sampling and the remaining concentration of methane is too low to be detected. To find more effective ways to analyze the composition of pore water, two novel approaches are proposed. One is based on Liquid Core Optical Fiber (LCOF) for detection of SO42 . The other one is an enrichment process for the detection of CH4. With the aid of LCOF, the Raman signal of SO42- is found to be enhanced over 10 times compared to that obtained by a conventional Raman setup. The enrichment process is also found to be effective in the investigation to the prepared sample of methane dissolved in water. By CCl4 extraction, methane at a concentration below 1.14 mmol/L has been detected by conventional Raman spectroscopy. All the obtained results suggest that the approach proposed in this paper has great potential to be developed as a sensor for SO42- and CH4 detection in pore water. PMID- 26016920 TI - Reducing systematic centroid errors induced by fiber optic faceplates in intensified high-accuracy star trackers. AB - Compared with traditional star trackers, intensified high-accuracy star trackers equipped with an image intensifier exhibit overwhelmingly superior dynamic performance. However, the multiple-fiber-optic faceplate structure in the image intensifier complicates the optoelectronic detecting system of star trackers and may cause considerable systematic centroid errors and poor attitude accuracy. All the sources of systematic centroid errors related to fiber optic faceplates (FOFPs) throughout the detection process of the optoelectronic system were analyzed. Based on the general expression of the systematic centroid error deduced in the frequency domain and the FOFP modulation transfer function, an accurate expression that described the systematic centroid error of FOFPs was obtained. Furthermore, reduction of the systematic error between the optical lens and the input FOFP of the intensifier, the one among multiple FOFPs and the one between the output FOFP of the intensifier and the imaging chip of the detecting system were discussed. Two important parametric constraints were acquired from the analysis. The correctness of the analysis on the optoelectronic detecting system was demonstrated through simulation and experiment. PMID- 26016921 TI - Real-time human pose estimation and gesture recognition from depth images using superpixels and SVM classifier. AB - In this paper, we present human pose estimation and gesture recognition algorithms that use only depth information. The proposed methods are designed to be operated with only a CPU (central processing unit), so that the algorithm can be operated on a low-cost platform, such as an embedded board. The human pose estimation method is based on an SVM (support vector machine) and superpixels without prior knowledge of a human body model. In the gesture recognition method, gestures are recognized from the pose information of a human body. To recognize gestures regardless of motion speed, the proposed method utilizes the keyframe extraction method. Gesture recognition is performed by comparing input keyframes with keyframes in registered gestures. The gesture yielding the smallest comparison error is chosen as a recognized gesture. To prevent recognition of gestures when a person performs a gesture that is not registered, we derive the maximum allowable comparison errors by comparing each registered gesture with the other gestures. We evaluated our method using a dataset that we generated. The experiment results show that our method performs fairly well and is applicable in real environments. PMID- 26016922 TI - IL23R gene polymorphism with juvenile idiopathic arthritis and its association with serum IL-17A. AB - AIM: Interleukin 23 (IL-23) and its receptor (IL-23R) seem to play a major role in differentiation of CD4+ T cells into Th17 cells, induction of IL-17 production, and activation of inflammatory pathways. Recent studies have suggested the association of IL-23R polymorphisms with bone and articular inflammation in diseases such as ankylosing spondylitis and rheumatoid arthritis. The aim of this study was to determine the association between IL-23R polymorphisms and juvenile idiopathic arthritis (JIA). METHOD: A case-control study on 55 patients with JIA and 78 healthy controls was performed. All samples were genotyped for eight single nucleotide polymorphisms (SNPs) of IL23R (rs1004819, rs2201841, rs10889677, rs1495965, rs7517847, rs10489629, rs11209026 and rs1343151), using real-time polymerase chain reaction Taqman genotyping technique. Forty-two patients and 42 healthy controls were chosen randomly to measure the level of serum IL-17A using enzyme-linked immunosorbent assay. RESULTS: Although the heterozygous genotype of rs1004819 (GA) showed a weak, but statistically significant protective effect on polyarticular subtype (P = 0.03), none of the selected SNPs were associated with JIA overall. Indeed the analysis of haplotypes did not show any significant association with JIA. Serum IL-17A level was not significantly different among patients and healthy controls and between JIA subtypes, as well. Moreover, there was no significant correlation between SNPs and serum IL-17A concentration. CONCLUSION: This is the first study of the IL-23R gene in Iranian patients with JIA. Our results did not show any strong association between IL-23R polymorphisms and JIA disease or serum IL-17A levels. The only association was seen between rs1004819 and polyarticular JIA. Further larger studies may help clarify the role, if any, of the IL-23/IL-17 pathway in the pathogenesis of JIA. PMID- 26016923 TI - Subendocardial Systolic Dysfunction in Asymptomatic Normotensive Diabetic Patients. AB - BACKGROUND: It remains uncertain whether diabetes itself causes specific echocardiographic features of myocardial morphology and function in the absence of hypertension or ischemic heart disease. The purpose of the present study was to determine the characteristics of pure diabetic cardiomyopathy-related echocardiographic morphology and function using layer-by-layer evaluation with myocardial strain echocardiography. METHODS AND RESULTS: We enrolled 104 patients with poorly controlled type 2 diabetes mellitus (mean HbA1c level, 10%) with (n=74) or without (n=40) hypertension and 24 age- and sex-matched healthy volunteers. Patients with coronary artery stenosis or structural heart disease were excluded. Myocardial layer-specific strain was analyzed by speckle tracking echocardiography. Compared with the healthy control group, the normotensive diabetes group showed no significant difference in ejection fraction, left ventricular mass index, diastolic properties, left atrial volume index, or B-type natriuretic protein (BNP) level, but global longitudinal strain and subendocardial radial strain were significantly deteriorated. The deterioration of longitudinal strain correlated with body mass index (R=0.49, P<0.01) and blood pressure (R=0.36, P<0.01) in the normotensive diabetes group. CONCLUSIONS: Deterioration of left ventricular longitudinal shortening accompanied by decreased subendocardial wall thickening are the characteristic functional abnormalities of diabetic cardiomyopathy in patients without hypertrophy, diastolic dysfunction, or elevated BNP. Obesity and blood pressure may also play important roles in this strain abnormality in asymptomatic patients with type 2 diabetes. PMID- 26016924 TI - Incidence, Clinical Course, and Risk Factors of Amiodarone-Induced Thyroid Dysfunction in Japanese Adults With Congenital Heart Disease. AB - BACKGROUND: Although amiodarone (AMD)-induced thyroid dysfunction (AITD) is an important complication of AMD therapy, little is known about AITD in adult Japanese patients with congenital heart disease (CHD). METHODS AND RESULTS: We retrospectively studied 131 adult patients with CHD who were on low-dose AMD (median, 150 mg/day). The median patient age was 28 years, and the median follow up was 44 months. The incidence, clinical course, and risk factors of AITD, including AMD-induced thyrotoxicosis (AIT) and AMD-induced hypothyroidism (AIH), were evaluated. The total incidence of AITD was 30% (AIT: 18%, n=24; AIH: 12%, n=16). Approximately 67% of patients with AIT displayed deterioration of tachyarrhythmia, and 38% patients underwent steroid therapy. Although thyroid function and symptoms associated with AIT improved within 6 months after diagnosis in most patients with AIT (92%), 1 patient died suddenly during an acute phase of AIT. No patient with AIH exhibited deterioration of tachyarrhythmia, and 9 patients underwent thyroid hormone replacement therapy. Cox multivariate analysis identified no independent risk factor for AIT, whereas liver dysfunction (hazard ratio 2.573; 95% confidence interval 1.102-5.795) was an independent risk factor for AIH. CONCLUSIONS: AITD commonly occurred in adult Japanese patients with CHD even though they were on a low-dose AMD regimen. Risk factors for AITD may vary according to ethnicity and diet. PMID- 26016925 TI - Clinical and Pathological Impact of Tissue Fibrosis on Lethal Arrhythmic Events in Hypertrophic Cardiomyopathy Patients With Impaired Systolic Function. AB - BACKGROUND: The natural history of hypertrophic cardiomyopathy (HCM) varies from an asymptomatic benign course to a poor prognosis. Myocardial fibrosis may play a critical role in ventricular tachyarrhythmias (VT/VF); however, the clinical significance of tissue fibrosis by right ventricular (RV) biopsy in the long-term prognosis of HCM patients remains unclear. METHODS AND RESULTS: We enrolled 185 HCM patients (mean age, 57+/-14 years). The amount of fibrosis (%area) was quantified using a digital microscope. Hemodynamic, echocardiographic, and electrophysiologic parameters were also evaluated. Patients with severe fibrosis had longer QRS duration and positive late potential (LP) on signal-averaged ECG, resulting in a higher incidence of VT/VF. At the 5+/-4 year follow-up, VT/VF occurred in 31 (17%) patients. Multivariate Cox regression analysis revealed that tissue fibrosis (hazard ratio (HR): 1.65; P=0.003 per 10% increase), lower left ventricular ejection fraction (HR: 0.64; P=0.001 per 10% increase), and positive SAECG (HR: 3.14; P=0.04) led to a greater risk of VT/VF. The combination of tissue fibrosis severity and lower left ventricular ejection fraction could be used to stratify the risk of lethal arrhythmic events in HCM patients. CONCLUSIONS: Myocardial fibrosis in RV biopsy samples may contribute to abnormal conduction delay and spontaneous VT/VF, leading to a poor prognosis in HCM patients. PMID- 26016926 TI - Circulating Fibroblast Growth Factor 23 Has a U-Shaped Association With Atrial Fibrillation Prevalence. AB - BACKGROUND: Atrial fibrillation (AF) occurs more frequently among patients with renal dysfunction. We investigated the possible association between prevalence of AF and serum fibroblast growth factor 23 (FGF23), which has been shown to be increased in subjects with renal dysfunction. METHODS AND RESULTS: Among the total enrollment of 851 cardiac patients, 188 patients had AF (paroxysmal AF, 95; non-paroxysmal AF, 93). Prevalence of AF for FGF23 octile had a U-shaped relationship with the lowest prevalence at the fifth octile. On logistic regression analysis, when the third FGF23 quartile was used as the reference, the first and fourth FGF23 quartiles were associated with prevalence of AF with an odds ratio (OR) of 3.34 (95% confidence interval [CI]: 1.89-5.88) and 2.58 (95% CI: 1.45-4.58), respectively, after adjusting for confounding factors including estimated glomerular filtration rate (eGFR). Among the subgroup of 416 patients for whom serum parathyroid hormone and 25-hydroxy vitamin D data were available, OR of the first and the fourth FGF23 quartile were calculated to be 3.52 and 2.97, respectively, when further adjusted for these two variables in the statistical model. CONCLUSIONS: Serum FGF23 had a U-shaped relationship with prevalence of AF among Japanese cardiac patients, which was independent of other calcium/phosphate metabolism-related parameters and eGFR. Pathophysiology underlying the observed link, if at all, awaits further investigation. PMID- 26016927 TI - Monitoring of the Enzymatically Catalyzed Degradation of Biodegradable Polymers by Means of Capacitive Field-Effect Sensors. AB - Designing novel or optimizing existing biodegradable polymers for biomedical applications requires numerous tests on the effect of substances on the degradation process. In the present work, polymer-modified electrolyte-insulator semiconductor (PMEIS) sensors have been applied for monitoring an enzymatically catalyzed degradation of polymers for the first time. The thin films of biodegradable polymer poly(D,L-lactic acid) and enzyme lipase were used as a model system. During degradation, the sensors were read-out by means of impedance spectroscopy. In order to interpret the data obtained from impedance measurements, an electrical equivalent circuit model was developed. In addition, morphological investigations of the polymer surface have been performed by means of in situ atomic force microscopy. The sensor signal change, which reflects the progress of degradation, indicates an accelerated degradation in the presence of the enzyme compared to hydrolysis in neutral pH buffer media. The degradation rate increases with increasing enzyme concentration. The obtained results demonstrate the potential of PMEIS sensors as a very promising tool for in situ and real-time monitoring of degradation of polymers. PMID- 26016928 TI - Gecko gaskets for self-sealing and high-strength reversible bonding of microfluidics. AB - We report in this work a novel reversible bonding technique for elastomeric microfluidic devices by integrating gecko-inspired dry adhesives with microfluidic channels which greatly enhances the bonding strength of reversibly sealed channels. The concept is applicable to nearly any elastomer and can be used to bond against any smooth surface which allows for van der Waals interactions. It does not require any solvents or glues or sources for plasma activation or thermal-compressive loading to aid the bonding process and is achievable at zero extra cost. We also demonstrate a quick fabrication technique involving soft master thermo-compressive molding of these microfluidic devices with thermoplastic elastomers. The resultant devices can be used for both pressure driven and non-pressure driven flows. We report the maximum contained pressure of these devices manufactured from two grades of styrene ethylene butylene styrene (SEBS) by conducting a burst pressure test with various substrates. PMID- 26016929 TI - Effect of total splenectomy in the lipid profile in mice. AB - PURPOSE: To analyze total splenectomy effect on the lipid profile - total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), very-low-density lipoprotein cholesterol (VLDL) and triglycerides levels, in Balb/c mice. METHODS: Thirty Balb/c male mice, one (1) month old and average weight 26.2g +/- 4.0 were used in the experiment. They were distributed into three groups of 10 animals each: a control group (non-operated), a simulation group (spleen manipulation) and the splenectomy group. The animals were subjected to blood sampling to measure plasma lipid levels, at three different times: before surgery, days 30 and 75 of the experiment. RESULTS: Increased total cholesterol and LDL were observed in the control group from the start to end of the experiment. The simulation group showed increased rates of VLDL and triglycerides at the 30th and 75th days. Splenectomized animals showed no significant change. CONCLUSION: Total splenectomy did not induce increased plasma lipids levels of in Balb/c mice. PMID- 26016930 TI - Study of renal and hepatic toxicity in rats supplemented with creatine. AB - PURPOSE: To evaluate the renal and hepatic function, through biochemical analysis after 14 days of creatine supplementation in physically inactive rats. METHODS: Twenty four male, adult, Wistar rats were used which were kept in individual metabolic cages and were distributed into four groups, and received the following treatments by gavage:1) CONTROL: distilled water; 2)Creatine 0.5g/Kg/day; 3) Creatine 1g/Kg/day; 4) Creatine 2g/Kg/day. Their urinary outputs as well as food and water intake were daily measured. At the end of the experiment, the animals were euthanized and serum samples were stored for biochemical analysis. RESULTS: Creatine supplementation at the doses given produced no significant changes in plasma levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, glucose, creatinine, urea, and creatinine clearance, compared to control group (p> 0.05) Similarly, water and food intake, as well as urinary output, did not show significant changes among the four groups studied. CONCLUSION: At the doses used, oral creatine supplementation did not result in renal and/or hepatic toxicity. PMID- 26016931 TI - The effect of simvastatin on relapse of tooth movement and bone mineral density in rats measured by a new method using microtomography. AB - PURPOSE: To evaluate the effect of simvastatin on relapse of tooth movement in rats using microtomography (micro CT), as well as the correlation of bone density with the orthodontic relapse. METHODS: Twenty-five adult male Wistar rats, divided into two groups, had stainless steel springs installed on left maxillary first molar. The molars were moved for 18 days, and after removing the springs, were applied by oral gavage, 5mg/kg of simvastatin in the experimental group for 20 days. Tooth relapse was assessed with a micro CT scanner, and the images chosen through the Data Viewer software 1.5.0.0 had their measurement guides made and checked by the software Image ProR plus 5.1, and compared by Mann-Whitney test. After rats were sacrificed, bone mineral density was evaluated by micro CT through the software CT Analyzer 1.13 and compared by independent T-test, as well as by Spearman correlation test. RESULTS: Relapse and bone mineral density (BMD) was lower in the experimental group than in the control group, however without a statistically significant difference. CONCLUSION: Simvastatin did not inhibit the relapse of tooth movement in rats, and there was no correlation between bone density and orthodontic relapse. PMID- 26016932 TI - Tissue content of sulfomucins and sialomucins in the colonic mucosa, without fecal stream, undergoing daily intervention with sucralfate. AB - PURPOSE: To measure the content of acidic mucin, sialomucin, and sulfomucins in the colonic mucosa without fecal stream submit to intervention with sucralfate (SCF). METHODS: Thirty-six rats were submitted to a right colostomy and a distal mucous fistula and divided into two groups according to sacrifice to be performed two or four weeks. Each group was divided into three subgroups according daily application of enemas containing saline, SCF at 1.0 g/kg/day or 2.0 g/kg/day. Colitis was diagnosed by histological analysis. Acid mucins were determined with the Alcian-Blue and sulfomucin and sialomucin by high iron diamine-alcian blue (HID-AB) techniques. The mucins were quantified by computer-assisted image analysis. Mann-Whitney and ANOVA tests were used to analyze the results establishing the level of significance of 5% for both (p<0.05). RESULTS: SCF enemas decreased the inflammation score and was related to the concentration used and time of the intervention. SCF at both concentrations increased the content of acid mucin, which was related to the concentration used and to the improvement in the inflammatory score. There was an increase in the content of sulfomucins and sialomucins in SCF groups. SCF increased sulfomucins from 2 weeks of intervention, which was not related to the dose or time of application. The increase in sialomucin content was related to the time and dose used in the intervention. CONCLUSION: Sucralfate increased the content of acidic mucins, primarily at the expense of sialomucin, which was affected by the dose and time of intervention. PMID- 26016933 TI - Effects of vardenafil on the kidney of Wistar rats submitted to acute ischemia and reperfusion. AB - PURPOSE: To investigate the effect of vardenafil in kidney of rats submitted to acute ischemia and reperfusion. METHODS: Twenty-eight rats were randomly distributed into two groups. Right nephrectomy was performed and the vardenafil group received vardenafil solution (at a concentration of 1 mg/ml in 10 mg/kg) while the control group received 0.9% saline solution (SS) one hour prior to the ligature of the left renal pedicle. After one hour of ischemia, animals were submitted to twenty-four hours of reperfusion, followed by left nephrectomy. The kidney's histological parameters evaluated on the study included vacuolar degeneration and tubular necrosis. Apoptosis was assessed by immunohistochemistry for cleaved caspase-3 using the point-counting and digital methods (Cytophotometry). Also, a biochemical analysis for creatinine was conducted. RESULTS: There were statistically significant differences between groups only with regards to the vacuolar degeneration parameter and to the cleaved caspase-3 digital method. CONCLUSION: Vardenafil showed a protective effect on the kidney of rats subjected to acute ischemia and reperfusion in this model. PMID- 26016934 TI - Effects of L-arginine and L-NAME on ischemia-reperfusion in rat liver. AB - PURPOSE: To evaluated the effects of L-arginine (a NO donor) and L-NAME (Nw-nitro L-arginine methyl ester - a NOS inhibitor) on ischemia-reperfusion in rat livers. METHODS: One hundred fifty two male Wistar rats were divided into four groups: control (simulated surgery); hepatic IR; pretreatment with L-arginine plus hepatic IR; and L-NAME plus hepatic IR. The hepatocellular damage was evaluated at the first, third and seventh days after the procedures through the alanine aminotransferase (ALT) and aspartate-aminotransaminase (AST) levels, as well as histopathological features: vascular congestion (VC); steatosis (STE); necrosis (NEC); and inflammatory infiltration (INF). The mortality rate was also evaluated. RESULTS: The pretreatment with L-NAME significantly worsened the AST levels after hepatic IR (p<0.05) at first day and L-arginine demonstrated an attenuating effect on ALT levels at seventh day (p<0.05). Furthermore, the administration of L-arginine was able to reduce the VC and STE in the seventh day after hepatic IR (p<0.05). The analysis of the mortality rates did not demonstrate any difference between the groups. Nevertheless, there was not effect of L-arginine and L-NAME on the mortality of the animals. CONCLUSION: L arginine/NO pathway has a role in the hepatic IR because the pretreatment with L arginine partially had attenuated the hepatocellular damage induced by hepatic IR in rats. PMID- 26016935 TI - Fibrogenesis and epithelial coating of skin wounds in rats treated with angico extract (Anadenanthera colubrina var. cebil). AB - PURPOSE: To evaluate the effects of angico bark extract (Anadenanthera colubrina var. cebil) in the healing process of the skin of rats. METHODS: Twenty adult male rats were divided into four groups of five animals each, according to the respective postoperative days, as follow: G4, G7, G14 and G21. Each group received two incisions on skin and subcutaneous tissue in the right and left antimere of the thoracic region, separated by a distance of 2 cm. The right lesion was treated daily with saline and the left with the angico alcoholic extract (5%). At the end of each experimental period, the animals were euthanized and fragments of the wound area with the edges were removed, fixed in 10% formaldehyde solution and processed for paraffin embedding. Histological sections (5 MUm of thickness) were stained with hematoxylin and eosin (HE), Gomori trichromic and picrosisirus red for morphological and morphometric analyses. Statistical analysis was done by ANOVA and Tukey-Kramer test (p<0.05). RESULTS: Morphological analysis showed larger fibroblasts and a higher concentration of collagen fibers in skyn wounds treated with the angico extract. Morphometric analysis demonstrated a significant increase in the number of fibroblasts at 7th and collagen in 7th and 14th days (p<0.01) in wounds treated with the angico extract. CONCLUSION: The angico alcoholic extract (Anadenanthera colubrina var. cebil) induces the acceleration of wound healing in skin wounds of rats. PMID- 26016936 TI - Alternative solution for ex vivo lung perfusion, experimental study on donated human lungs non-accepted for transplantation. AB - PURPOSE: To evaluate a new perfusate solution to be used for ex vivo lung perfusion. METHODS: Randomized experimental study using lungs from rejected brain dead donors harvested and submitted to 1 hour of ex vivo lung perfusion (EVLP) using mainstream solution or the alternative. RESULTS: From 16 lungs blocs tested, we found no difference on weight after EVLP: Steen group (SG) = 1,097+/ 526g; Alternative Perfusion Solution (APS) = 743+/-248g, p=0.163. Edema formation, assessed by Wet/dry weigh ratio, was statistically higher on the Alternative Perfusion Solution group (APS = 3.63 +/- 1.26; SG = 2.06 +/- 0.28; p = 0.009). No difference on PaO2 after EVLP (SG = 498+/-37.53mmHg; APS = 521+/ 55.43mmHg, p=0.348, nor on histological analyses: pulmonary injury score: SG = 4.38+/-1.51; APS = 4.50+/-1.77, p=0.881; apoptotic cells count after perfusion: SG = 2.4 +/- 2.0 cells/mm2; APS = 4.8 +/- 6.9 cells/mm2; p = 0.361). CONCLUSION: The ex vivo lung perfusion using the alternative perfusion solution showed no functional or histological differences, except for a higher edema formation, from the EVLP using Steen Solution(r) on lungs from rejected brain-dead donors. PMID- 26016937 TI - Fructo-oligosaccharide effects on serum cholesterol levels. An overview. AB - PURPOSE: To address the effects of fructooligosaccharides (FOS) intake on serum cholesterol levels. METHODS: We performed a search for scientific articles in MEDLINE database from 1987 to 2014, using the following English keywords: fructooligosaccharides; fructooligosaccharides and cholesterol. A total of 493 articles were found. After careful selection and exclusion of duplicate articles 34 references were selected. Revised texts were divided into two topics: "FOS Metabolism" and "FOS effects on plasma cholesterol." RESULTS: The use of a FOS diet prevented some lipid disorders and lowered fatty acid synthase activity in the liver in insulin-resistant rats. There was also reduction in weight and total cholesterol in beagle dogs on a calorie-restricted diet enriched with short-chain FOS. Another study found that 2g FOS daily consumption increased significantly serum HDL cholesterol levels but did not ensure a significant reduction in levels of total cholesterol and triglycerides.. Patients with mild hypercholesterolemia receiving short-chain FOS 10.6g daily presented no statistically significant reduction in serum cholesterol levels. However, when FOS was offered to patients that changed their lifestyle, the reduction of LDL cholesterol and steatosis was higher. CONCLUSIONS: Fructooligosaccharides intake may have a beneficial effect on lipid metabolism and regulation of serum cholesterol levels in individuals that change their lifestyle. FOS supplementation use in diets may therefore be a strategy for lowering cholesterol. PMID- 26016938 TI - Experience report on teaching surgical technique without animal use. AB - PURPOSE: To report the experience of the school in implementing the 3 Rs replace, reduce and refine; showing time and assembling cost of the experimental models used in the teaching of Surgical Technique and Experimental Surgery. METHODS: Assembly time and costs of models: grafts and flaps performed in pork belly, model of intestinal anastomosis and jejunostomy done in Bahiana box and black box model for training videosurgery. RESULTS: Average time and cost estimate: ten minutes-pork belly, cost $ 6.00 per kilogram; two minutes-Bahiana box, cost $ 27.2; Black box-3.6 hours for manufacturing, cost $ 100.00. The repetition of each practice the cost is $ 3.20 for Bahiana box and at no cost to the black box. CONCLUSION: The experimental models presented are easily reproducible and of low cost. PMID- 26016939 TI - A review of knee pain in adolescent females. AB - Primary care practitioners are in a position to educate patients and parents about the risk factors that may increase the incidence of knee pain in adolescent females. This article highlights patellofemoral pain syndrome, Sinding-Larsen Johansson syndrome, Osgood-Schlatter disease, and meniscal tears. PMID- 26016940 TI - A Cyclic Mimic of HIV Tat Differentiates Similar TAR RNAs on the Basis of Distinct Dynamic Behaviors. AB - Efforts toward the development of RNA-based drug leads have been challenging because of the complexity and dynamic nature of RNA structures as therapeutic targets. The transactivation response (TAR) RNA and cognate Tat protein of HIV have long been recognized as promising antiviral targets, and recent works have identified potentially potent inhibitors of the viral RNA-protein interaction. A new class of such inhibitors, conformationally constrained cyclic peptide mimetics of Tat, has been demonstrated to inhibit the HIV life cycle. We have previously probed the complexity and dynamics of TAR RNAs in their free states, as well as conformational shifting by various peptide and small molecule ligands. In this work, we have used an ultrafast dynamics approach to probe the interactions between TAR RNAs and one of the representatives of cyclic peptide inhibitors, L22. Our studies demonstrated that cyclic L22 specifically recognizes TAR RNAs with a unique single binding site compared to two binding sites for linear Tat protein. Although both Tat and L22 bind to the TAR RNAs as a beta hairpin structure, cyclization in L22 allows it to be a more efficient ligand from a population shifting perspective. This study provided unique insights into drug design with desired properties to differentiate similar structures based on distinct dynamic behaviors. PMID- 26016941 TI - Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. AB - Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold. PMID- 26016942 TI - Understanding the comparative molecular field analysis (CoMFA) in terms of molecular quantum similarity and DFT-based reactivity descriptors. AB - The three-dimensional quantitative structure-activity relationship (3D QSAR) models have many applications, although the inherent complexity to understand the results coming from 3D-QSAR arises the necessity of new insights in the interpretation of them. Hence, the quantum similarity field as well as reactivity descriptors based on the density functional theory were used in this work as a consistent approach to better understand the 3D-QSAR studies in drug design. For this purpose, the quantification of steric and electrostatic effects on a series of bicycle [4.1.0] heptane derivatives as melanin-concentrating hormone receptor 1 antagonists were performed on the basis of molecular quantum similarity measures. The maximum similarity superposition and the topo-geometrical superposition algorithms were used as molecular alignment methods to deal with the problem of relative molecular orientation in quantum similarity. In addition, a chemical reactivity analysis using global and local descriptors such as chemical hardness, softness, electrophilicity, and Fukui functions, was developed. Overall, our results suggest that the application of this methodology in drug design can be useful when the receptor is known or even unknown. PMID- 26016943 TI - Dual functions of Lewis acid and base of Se in F2C=Se and their interplay in F 2CSe***NH 3***HX. AB - High-level quantum chemical calculations of the ternary systems F2CSe???NH3???HX (X=BeH, BH2, OH, CN, OCH3, Cl, and F) and the corresponding binary systems have been carried out in view of geometries, vibrational frequencies, interaction energies, orbital interactions, and electron densities. The molecular electrostatic potentials of F2CSe demonstrate that the Se atom could play a dual role of Lewis acid and base to form a chalcogen bond with NH3 and a hydrogen bond or a covalent interaction with HX, respectively. The chalcogen bond can compete with the hydrogen bond for the complexes involving F2CSe, but the covalent interaction is far stronger than the chalcogen bond. In the ternary complexes, both types of interactions are strengthened by each other, characterized by a shorter binding distance, a larger electron density, and a stronger orbital interaction. The covalent interaction has a greater enhancing effect on the chalcogen bond than the hydrogen bond does, resulting in a prominent shortening of ~0.23 A distance for the Se???N distance in F2CSe???NH3???BH3. The enhancement of both interactions in the ternary complexes has been understood with the electrostatic potentials and orbital interactions. Graphical Abstract The dual functions of Lewis acid and base of Se in F2CSe are enhanced each other in the ternary complexes. PMID- 26016944 TI - Effects of plyometric exercise session on markers of bone turnover in boys and young men. AB - INTRODUCTION: The acute exercise effects on bone markers in adults are unclear, while in children, there are no such data. PURPOSE: To investigate the acute response of biochemical markers of bone turnover to a high-impact exercise session consisting of high-mechanical loading in boys and young men. METHODS: Twelve boys (10.2 +/- 0.4 years) and 14 men (22.0 +/- 0.8 years) underwent a protocol of plyometric jumping exercises (total 144 jumps). Venous blood samples were collected pre-, 5 min, 1 and 24 h post-exercise, and analyzed for markers of bone formation and resorption: bone-specific alkaline phosphatase (bone ALP), osteoprotegerin (OPG), amino-terminal cross-linking telopeptide (NTx), and receptor activator of nuclear factor kappa beta ligand (RANKL). RESULTS: Boys had higher resting bone ALP (111.9 +/- 29.2 vs. 30.6 +/- 11.2 ug/L, p < 0.05) and NTx levels (49.8 +/- 13.2 vs. 21.7 +/- 5.9 nM BCE, p < 0.05) than men but no group differences were observed in resting OPG or RANKL. Following exercise (24 h), bone ALP and NTx increased in both boys and men (bone ALP: 24.1 vs. 9.9%, respectively; NTx: 23.5 vs. -5%, respectively), although the group-by-time interaction was not statistically significant. OPG increased significantly (p < 0.05) in both groups (5.7 and 16.1 %, respectively). CONCLUSION: Even one session of plyometric exercises appear to stimulate bone formation in boys and men, as reflected by the increase in bone ALP and OPG. The boys' response appears more pronounced than the men's, suggesting that during growth, cellular bone activities respond with greater magnitude to mechanical stimuli. PMID- 26016946 TI - Doctors should expect to repay state investment with NHS service. PMID- 26016945 TI - Heart rate recovery and parasympathetic modulation in boys and girls following maximal and submaximal exercise. AB - PURPOSE: This study examined heart rate recovery (HRR) and heart rate variability (HRV) following submaximal and maximal exercise in boys (n = 13; 10.1 +/- 0.8 years) and girls (n = 12; 10.1 +/- 0.7 years). METHODS: Participants completed 10 min of supine rest followed by a graded exercise test to maximal effort. On a separate day, participants performed submaximal exercise at ventilatory threshold. Immediately following both exercise bouts, 1-min HRR was assessed in the supine position. HRV variables were analyzed under controlled breathing in the time and frequency domains over the final 5 min of rest and recovery. RESULTS: There were no significant differences in HRR following maximal and submaximal exercise between boys (58 +/- 8 and 59 +/- 8 beats min(-1), respectively) and girls (54 +/- 6 and 52 +/- 19 beats min(-1), respectively). There also were no significant interactions between groups from rest to recovery from maximal exercise for any HRV variables. However, there was a difference in the response between sexes from rest to recovery from submaximal exercise for log transformed standard deviation of NN intervals (lnSDNN) and log transformed total power (lnTP). No differences were observed for lnSDNN at rest (boys = 4.61 +/- 0.28 vs. girls = 4.28 +/- 0.52 ms) or during recovery (lnSDNN: boys 3.78 +/- 0.46 vs. girls 3.87 +/- 0.64 ms and lnTP: boys 7.33 +/- 1.09 vs. girls; 7.44 +/- 1.24 ms(2)). Post hoc pairwise comparisons showed a significant difference between boys and girls for lnTP at rest (boys = 9.14 +/- 0.42 vs. girls = 8.30 +/- 1.05 ms(2)). CONCLUSION: Parasympathetic modulation was similar between boys and girls at rest and during recovery from exercise, which could explain similarities observed in HRR. PMID- 26016948 TI - Knowledge, Attitudes and Provider Advice by Pre-Pregnancy Weight Status: A Qualitative Study of Pregnant Latinas With Excessive Gestational Weight Gain. AB - Latina women are at high risk of excessive gestational weight gain (GWG) during pregnancy; yet little is known about whether factors related to GWG differ by pre pregnancy body mass index (BMI) within this population. We conducted in-depth interviews with 62 pregnant Latina women with pre-pregnancy BMIs in the healthy, overweight, and obese ranges, gestational age >=22 weeks, and GWG for gestational age above Institute of Medicine (IOM) guidelines. Compared to healthy weight and obese women, overweight women least often reported viewing weight as important, making efforts to control their GWG, being aware of the role of diet on GWG, and receiving GWG advice from health-care providers. Among those who received GWG advice, overweight women more often recalled a target GWG above IOM guidelines. Obese women more often reported low acceptance of their GWG, concern about GWG, having received GWG advice from providers, difficulty following providers' dietary advice, and emotional eating as a challenge for controlling GWG. Participants welcomed practical advice to manage GWG. Future interventions to prevent excessive GWG among Latina women should consider differences among women of varying pre-pregnancy BMIs and include multi-level strategies to address psychosocial as well as provider factors. PMID- 26016947 TI - Hospitalization Type and Subsequent Severe Sepsis. AB - RATIONALE: Hospitalization is associated with microbiome perturbation (dysbiosis), and this perturbation is more severe in patients treated with antimicrobials. OBJECTIVES: To evaluate whether hospitalizations known to be associated with periods of microbiome perturbation are associated with increased risk of severe sepsis after hospital discharge. METHODS: We studied participants in the U.S. Health and Retirement Study with linked Medicare claims (1998-2010). We measured whether three hospitalization types associated with increasing severity of probable dysbiosis (non-infection-related hospitalization, infection related hospitalization, and hospitalization with Clostridium difficile infection [CDI]) were associated with increasing risk for severe sepsis in the 90 days after hospital discharge. We used two study designs: the first was a longitudinal design with between-person comparisons and the second was a self-controlled case series design using within-person comparison. MEASUREMENTS AND MAIN RESULTS: We identified 43,095 hospitalizations among 10,996 Health and Retirement Study Medicare participants. In the 90 days following non-infection-related hospitalization, infection-related hospitalization, and hospitalization with CDI, adjusted probabilities of subsequent admission for severe sepsis were 4.1% (95% confidence interval [CI], 3.8-4.4%), 7.1% (95% CI, 6.6-7.6%), and 10.7% (95% CI, 7.7-13.8%), respectively. The incidence rate ratio (IRR) of severe sepsis was 3.3 fold greater during the 90 days after hospitalizations than during other observation periods. The IRR was 30% greater after an infection-related hospitalization versus a non-infection-related hospitalization. The IRR was 70% greater after a hospitalization with CDI than an infection-related hospitalization without CDI. CONCLUSIONS: There is a strong dose-response relationship between events known to result in dysbiosis and subsequent severe sepsis hospitalization that is not present for rehospitalization for nonsepsis diagnoses. PMID- 26016949 TI - Wild growing mushrooms for the Edible City? Cadmium and lead content in edible mushrooms harvested within the urban agglomeration of Berlin, Germany. AB - Health effects by consuming urban garden products are discussed controversially due to high urban pollution loads. We sampled wild edible mushrooms of different habitats and commercial mushroom cultivars exposed to high traffic areas within Berlin, Germany. We determined the content of cadmium and lead in the fruiting bodies and analysed how the local setting shaped the concentration patterns. EU standards for cultivated mushrooms were exceeded by 86% of the wild mushroom samples for lead and by 54% for cadmium but not by mushroom cultures. We revealed significant differences in trace metal content depending on species, trophic status, habitat and local traffic burden. Higher overall traffic burden increased trace metal content in the biomass of wild mushrooms, whereas cultivated mushrooms exposed to inner city high traffic areas had significantly lower trace metal contents. Based on these we discuss the consequences for the consumption of mushrooms originating from urban areas. PMID- 26016952 TI - Total parenteral nutrition treatment efficacy in adolescent eating disorders. AB - BACKGROUND: Management of adolescent patients with severe eating disorders who refuse treatment for weight loss is complicated. Nutritional rehabilitation is most important during the growth period; thus, strong support in the form of total parenteral nutrition (TPN) as soon as possible is necessary in severe cases. No studies involving detailed, long-term follow up have evaluated biochemical markers and gonadotropin in patients undergoing TPN treatment. METHODS: Twenty-five adolescent female patients admitted to hospital received TPN immediately, and biochemical marker and gonadotropin levels were measured and analyzed. If subsequent weight gain was observed, TPN treatment was gradually reduced and stopped. RESULTS: No patients dropped out of the study. A significant increase in weight was observed during hospitalization (average, 8.0 kg). Under this treatment, serum total bilirubin was significantly decreased at 3 months, total cholesterol was significantly decreased at 2 months, and alkaline phosphatase (ALP) was significantly increased at 3 and 6 months. Follicle stimulating hormone response significantly preceded both luteinizing hormone response and appetite recovery. After this treatment, nine of the 25 patients were readmitted for recurrence of appetite loss. Two patients required additional TPN treatment, but seven immediately recovered their appetite after hospitalization without TPN treatment. Bodyweight gain per day was significantly lower and ALP on admission was significantly higher in patients with than without recurrence. CONCLUSIONS: Most patients had a remarkable recovery of appetite without refusal behaviors and without evidence of malnutrition after admission. Nutrition maintenance with TPN support is particularly important during the growth period. PMID- 26016950 TI - MEG-EEG Information Fusion and Electromagnetic Source Imaging: From Theory to Clinical Application in Epilepsy. AB - The purpose of this study is to develop and quantitatively assess whether fusion of EEG and MEG (MEEG) data within the maximum entropy on the mean (MEM) framework increases the spatial accuracy of source localization, by yielding better recovery of the spatial extent and propagation pathway of the underlying generators of inter-ictal epileptic discharges (IEDs). The key element in this study is the integration of the complementary information from EEG and MEG data within the MEM framework. MEEG was compared with EEG and MEG when localizing single transient IEDs. The fusion approach was evaluated using realistic simulation models involving one or two spatially extended sources mimicking propagation patterns of IEDs. We also assessed the impact of the number of EEG electrodes required for an efficient EEG-MEG fusion. MEM was compared with minimum norm estimate, dynamic statistical parametric mapping, and standardized low-resolution electromagnetic tomography. The fusion approach was finally assessed on real epileptic data recorded from two patients showing IEDs simultaneously in EEG and MEG. Overall the localization of MEEG data using MEM provided better recovery of the source spatial extent, more sensitivity to the source depth and more accurate detection of the onset and propagation of IEDs than EEG or MEG alone. MEM was more accurate than the other methods. MEEG proved more robust than EEG and MEG for single IED localization in low signal-to-noise ratio conditions. We also showed that only few EEG electrodes are required to bring additional relevant information to MEG during MEM fusion. PMID- 26016951 TI - Somatosensory Event-Related Potentials and Association with Tactile Behavioral Responsiveness Patterns in Children with ASD. AB - The goal of this study was to explore neural response to touch in children with and without autism spectrum disorder (ASD). Patterns of reduced (hypo responsiveness) and enhanced (hyper-responsiveness) behavioral reaction to sensory input are prevalent in ASD, but their neural mechanisms are poorly understood. We measured event-related potentials (ERP) to a puff of air on the fingertip and collected parent report of tactile hypo- and hyper-responsiveness in children with ASD (n = 21, mean (SD) age 11.25 (3.09), 2 female), and an age matched typically developing comparison group (n = 28, mean (SD) age 10.1 (3.08, 2 female). A global measure of ERP response strength approximately 220-270 ms post-stimulus was associated with tactile hypo-responsiveness in ASD, while tactile hyper-responsiveness was associated with earlier neural response (approximately 120-220 ms post-stimulus) in both groups. These neural responses also related to autism severity. These results suggest that, in ASD, tactile hypo and hyper-responsiveness may reflect different waypoints in the neural processing stream of sensory input. The timing of the relationship for hyper responsiveness is consistent with somatosensory association cortical response, while that for hypo-responsiveness is more consistent with later processes that may involve allocation of attention or emotional valence to the stimulus. PMID- 26016953 TI - Adverse Events in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. AB - OBJECTIVE: Patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) have a poorer prognosis compared to those with idiopathic PAH, but little is known about the differences in treatment-related adverse events (AEs) and serious adverse events (SAEs) between these groups. This study was undertaken to characterize these differences. METHODS: Individual patient-level data from 10 randomized controlled trials of therapies for PAH were obtained from the US Food and Drug Administration. Patients diagnosed as having either CTD-associated PAH or idiopathic PAH were included. A treatment-by diagnosis interaction term was used to examine whether the effect of treatment on occurrence of AEs differed between patients with CTD-associated PAH and those with idiopathic PAH. Studies were pooled using fixed-effect models. RESULTS: The study sample included 2,370 participants: 716 with CTD-associated PAH and 1,654 with idiopathic PAH. In the active treatment group compared to the placebo group, the risk of AEs was higher among patients with CTD-associated PAH than among those with idiopathic PAH (odds ratio [OR] 1.57, 95% confidence interval [95% CI] 1.00-2.47 versus OR 0.94, 95% CI 0.69-1.26; P for interaction = 0.061), but there was no difference in the risk of SAEs in analyses adjusted for age, race, sex, hemodynamic findings, and laboratory values. Despite the higher occurrence of AEs in patients with CTD-associated PAH assigned to active therapy compared to those receiving placebo, the risk of drug discontinuation due to an AE was similar to that in patients with idiopathic PAH assigned to active therapy (P for interaction = 0.27). CONCLUSION: Patients with CTD-associated PAH experienced more treatment-related AEs compared to those with idiopathic PAH in therapeutic clinical trials. These findings suggest that the overall benefit of advanced therapies for PAH may be attenuated by the greater frequency of AEs. PMID- 26016955 TI - A Randomized Trial of a Bereavement Intervention for Pregnancy Loss. AB - OBJECTIVE: To examine the effects of a secondary bereavement intervention on grieving in women who experienced a miscarriage (pregnancy loss) at 12-20 weeks gestation. DESIGN: Experimental, posttest only, control group design. SETTING: Obstetric emergency center of a county hospital in a large city. PARTICIPANTS: Forty women who experienced complete spontaneous miscarriages in the first or second trimester (8-20 weeks gestation). METHODS: Participants were randomly assigned to the grief intervention treatment group or usual standard care control group. The Medical Professional Guidelines for Health Care Professionals were used to construct the perinatal grief intervention. The Perinatal Grief Scale (PGS) was completed during a routine follow-up visit 2 weeks postloss. RESULTS: A one-way multiple ANOVA (MANOVA) was used to examine the difference in grieving between the control and experimental groups. Three dependent variables were used: despair, difficulty coping, and active grieving. Analysis revealed a significant difference on the combined dependent variables, F(3, 36) = 22.40, p < .000. When considering the three dependent variables separately, the treatment group displayed significantly lower levels of despair, F(1, 38) = 42.27, p < .001. Active grieving was high in both groups with the treatment group mean higher than the control group. Group means were similar for coping difficulty. CONCLUSION: A bereavement intervention administered immediately after the miscarriage promotes women's ability to cope with early pregnancy loss. PMID- 26016956 TI - Dispersed Fluorescence Spectroscopy of Jet-Cooled 2-, 3-, and 4-Methylcyclohexoxy Radicals. AB - Vibrational structures of the nearly degenerate X and A states of the 2-, 3-, and 4-methylcyclohexoxy (MCHO) radicals were studied by jet-cooled dispersed fluorescence (DF) spectroscopy. The observed transitions were assigned on the basis of vibrational frequencies and Franck-Condon factors predicted by quantum chemical calculations. Intensities of vibronic transitions in the DF spectra are dependent on the laser-induced fluorescence (LIF) bands pumped in the experiment, which can be explained by the difference in geometry and symmetry between the lower X/A states and the highly excited B state. All three studied isomers of MCHO have close-lying X and A states although their energy separations are affected by the position of the methyl group. It is suggested by quantum chemical calculations that the lowest-energy conformers of all three isomers have the half filled orbital oriented perpendicular to the OCH plane, which is consistent with the observed relative intensities of the B -> X and B -> A origin bands. When the origin and the CO-stretch bands of the B <- X LIF excitation spectra were pumped, the DF spectra were dominated by CO-stretch progressions. When non-CO-stretch vibrational levels of the B state were pumped, progressions of CO-stretch modes combined with the pumped vibrational mode were observed. Excited-state vibrational population relaxation from the CO stretch level to the vibrational ground level and from combination levels of the CO stretch mode and other vibrational modes to the non-CO stretch modes was observed. Analysis of the DF spectra confirms the previous conclusion that all strong LIF bands observed under jet-cooled conditions belong to a single conformer of each positional isomer (Lin et al. RSC Adv. 2012, 2, 583-589). PMID- 26016957 TI - Acute overnight painful swelling of a finger. AB - Gouty tophus represents а specific clinical substrate of а specific metabolic disease which requires specific treatment in order to reduce the levels of serum urate. Although curable, the painful tophi enlarge slowly and the time depending response to the standard anti-gout therapy is longer, which significantly worsens the quality of life of those patients. We present the case of a patient with painful gouty tophus, which was eradicated by a micro invasive surgical technique, leading to an immediate positive effect on the pain symptoms. The performance of surgical techniques for excision of gouty tophus should be considered in all patients with strongly pronounced painful symptoms as well as those who show functional disorders caused by the painful swellings. Although not specific for this disease, the application of this therapeutic option produces substantial and immediate improvement of the painful symptoms and the quality of life of these patients. PMID- 26016954 TI - Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis. AB - A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL 10+ B cells in Graves' disease (GD), Hashimoto's thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure induced IL-10+ B-cell differentiation in GD. A similar tendency was observed in healthy donors, but not in cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4+ T cells. To assess the maximal frequency of inducible IL-10+ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10+ B-cell frequency was similar in the three groups and correlated with free T3 levels in GD patients. IL 10+ B cells from both patient groups displayed CD25 or TIM-1 more frequently than did those from healthy donors. B-cell expression of two surface marker combinations previously associated with regulatory B-cell functions, CD24hiCD38hi and CD27+CD43+, did not differ between patients and healthy donors. In conclusion, our findings indicate that autoimmune thyroiditis is not associated with reduced frequency of IL-10+ B cells. These results do not rule out regulatory B-cell dysfunction, however. The observed phenotypic differences between IL-10+ B cells from patients and healthy donors are discussed. PMID- 26016958 TI - Sarcoidosis exclusion criteria: the ?simple truth? for a ?complicated diagnosis?. AB - The differentiation between sarcoidosis and sarcoid-type reactions remains a clinical and histopathologic diagnostic dilemma. A definitive distinction is yet to be determined according to the current literature data. Sarcoid-like tissue reactions with identifiable infectious or other immunogenic antigens, should be classified as non-specific clinical manifestations of a specific disease. The current assignment of this type of reaction under the generic umbrella of ?sarcoidosis? is incorrect and may result in the subsequent misinterpretation of the definition of the disease in general. On the other hand, this may lead to clinical studies with incorrectly selected inclusion criteria and, therefore, contradictory statements regarding the epidemiology and pathogenesis of the disease. Thus we propose the introduction of new criteria for exclusion of sarcoidosis as an autonomous disease. Recent trials on patients with probable sarcoidosis have focused on ideal criteria, or have provided information about the genetic and immunological profile of patients with specific infections or other diseases, which manifest themself as sarcoidal granulomas. This could explain the heterogeneous clinical and/or genetic profiles of the reported patients, who in fact were not affected by the autonomous disease ?sarcoidosis?. The simplification of the current available data regarding this issue will be of fundamental importance for the correct direction of future studies, whose aim is to unravel the pathogenesis of the immunological cascade in patients with sarcoidosis and sarcoid-like type of reaction. It is expected that the introduction of exclusion criteria will inevitably lead to a change in the approach to diagnosis as well as the fundamental understanding of this mysterious disease, known as sarcoidosis. PMID- 26016959 TI - Failure of vismodegib in advanced Basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common malignant tumor of mankind. For locally advanced and metastatic BCC treatment options are limited. Recently, the first hedgehog signal pathway inhibitor, vismodegib, has been approved for such tumors. Although high response rates have been reported for spontaneous BCC and Gorlin-Goltz syndrome, some tumors do not respond primarily or secondarily. We report about a 38-year-old female patient with a large multicentric BCC of temple with primary chemoresistance of the tumor. We discuss possible mechanism and other limitations of vismodegib in BCC. PMID- 26016960 TI - Generalized eruptive histiocytoma in adult patient. AB - Generalized eruptive histiocytoma is a rare benign skin disorder with less than 50 cases reported world-wide. It belongs to type IIb of histiocytoses. The histiocytic cells are CD68 positive but lack other markers like CD1a or S100. We report on a 60-year-old male patient with generalized eruptive histiocytoma treated successfully by PUVA combined with topical corticosteroids. PMID- 26016961 TI - Schnitzler syndrome responding to interleukin-1 antagonist anakinra. AB - Since 2005, an 82-year-old female patient suffered from relapsing, generalized urticarial rash with relapsing fever episodes, arthralgias and burning tibial pain sensations. She unintentionally lost about 10 kg of body weight within 9 months. Systemic treatment with desloratadine, ranitidine, prednisolone and later, ciclosporin A was started. All these efforts could not control the symptoms but caused adverse effects including glaucoma and hypertension. Several years later a therapy with interleukin-1 inhibitor anakinra 100 mg s.c. once daily was started. The patient became symptom-free within 24 h after the first injection. With a follow up of three years the patient remained completely symptom-free with no fever or burning sensations. Later on, the dosage was reduced to 100 mg s.c. every other day. Anakinra reduces pro-inflammatory cytokine release due to lipopolysaccharide stimulation. In a long-term use the drug does not lose effectiveness. PMID- 26016962 TI - Nodular epitheloid sarcoma of the upper limb. A case report and review of the literature. AB - Epitheloid sarcoma is a rare malignant soft tissue sarcoma. We present a 36-year old male patient with a primary tumour on his wrist and subcutaneous spread in a sporotrichoid pattern along the upper extremity. Early surgical treatment with micrographic control of all margins provides best long term outcome as long as a solitary lesion is present. In case of cutaneous and internal spread of the disease treatment options are only palliative. Early diagnosis, therefore, is most crucial. PMID- 26016963 TI - Foot ulcers in klippel-trenaunay syndrome: two case reports and one metatypical Basal cell carcinoma. AB - Klippel-Trenaunay syndrome (KTS) is a congenital malformation with vascular anomalies of capillaries, veins and lymphatics and hypertrophy of bones and soft tissues, associated with microdeletion of 2q37.3 and upregulation of angiogenic factor AGGF1. Although KTS predisposes to venous thromboembolic diseases and may be associate with potentially life-threatening vascular complications including bleeding, pulmonary embolism, and deep vein thrombosis, the development of leg or foot ulcers is uncommon. We present two adult patients with KTS and foot ulcers and advise doctors to keep in mind that chronic foot ulcers in KTS may have an underlying neoplasia. PMID- 26016964 TI - Life-threatening onychomycosis imitator. AB - Although onychomycosis is one of the most common dermatological conditions, the exact diagnosis should be carefully confirmed, especially in therapy-resistant cases. Considering the potential for development of various nail disorders that could resemble the clinical picture of typical onychomycosis, the performing of a diagnostic biopsy is sometimes of paramount importance, in order to exclude the possibility of a life threatening onychomycosis imitators. Here, we present a case of subungual malignant melanoma, diagnosed by histological examination in a patient who had received long term, ineffective treatment for onychomycosis. PMID- 26016965 TI - Sarcoid sine sarcoidosis? A classificative, semantic and therapeutic dilemma. AB - Differentiation between sarcoidosis and sarcoid type reactions at the present time remains problematic, if not impossible. Criteria for clinical behavior and/or a systematic diagnostic approach in cases of proven epithelioid cell granulomas in lesional tissue do not currently exist. This is probably the main reason for chronicity of the sarcoid-type reactions within a specific disease or for their progression with the application of incorrect therapy. The refinement of the diagnostic criteria and the classification of both conditions remain objects of further consideration. We present a model for recommendations for an optimal diagnostic approach in patients with epitheloid cell granulomas, aiming to facilitate the differentiation between sarcoidosis and sarcoid type reactions, hopefully leading to optimization of subsequent therapy. PMID- 26016966 TI - Sarcoid type reaction: medical hypotheses. AB - Sarcoid-type reactions could not always be clearly distinct from the independent disease sarcoidosis. Particular attention should be paid to paraneoplastic type of sarcoid reaction which until recent literature was characterized as 1) sarcoidosis associated with tumor disease or 2) sarcoidosis classified and presented as paraneoplastic disease. The analogy between sarcoidosis and paraneoplastic type of sarcoid reaction are the pure epithelioid cell granulomas. The role of molecular mimicry in paraneoplastic type of reaction is probably significant but not yet fully proven and understood. Future studies on this issue should be directed to identify the genetic defects (regarding the inflammasome and those recently established at EOS and Blau Syndrome) as well as screening programs for early detection of cancers, with a view to optimization of the subsequent therapy. PMID- 26016967 TI - Psycho-neuro-endocrine-immunology and low dose cytokines therapy: principles and evidences for an innovative medical approach in acute and chronic inflammatory diseases. AB - The development of the Psycho-Neuro-Endocrine-Immunology (P.N.E.I.), induced a fundamental paradigm shift in the interpretation of the biological functions of the body; from a separatist point of view to an unifying one, centered on the recognized importance of the cross-talk between cells, organs and systems. This interplay is regulated by a great number of messenger molecules and their circulating levels are key parameters for the definition of both physiological and pathological conditions; indeed, the pathological phenomenon can be described as an imbalance in intercellular signaling. The restoration of the impaired signalling molecules balance is the goal of Low Dose Medicine (LDM), a new medical approach based on the administration of low physiological doses of messenger molecules (which act as homeostatic modulating agents). The validity of the Low Dose Medicine conceptual approach in terms of efficacy and safety is assessed by five years of scientific research in this field. In particular the role of low dose Sequential Kinetic Activation (SKA) signalling molecules oral administration in inflammatory status management is demonstrated. PMID- 26016968 TI - Treating skin diseases according to the low dose medicine principles. Data and hypotheses. AB - Cytokines, hormones and growth factors, also defined with the collective name of ?signaling molecules? are key regulating agents of physiological (and also pathological) functions according to the principles of Psycho-Neuro-Endocrine Immunology (P.N.E.I.). From the latest evidences in the fields of Molecular Biology, P.N.E.I. and nano-concentration, a new medical approach surfaces: the Low Dose Medicine (LDM), a new tool for the study and the design of therapeutic strategies based on immune rebalance interventions. LDM suggest the use of low doses of activated signaling molecules in order to restore P.N.E.I. homeostatic conditions and an increasing number of scientific evidences of LDM approach efficacy and safety support LDM-based therapeutic approach for the treatment of many dermatological diseases such as Psoriasis Vulgaris, Vitiligo and Atopic Dermatitis. PMID- 26016969 TI - Desmoplastic malignant melanoma associated with pigmented ocular tumor: second documented problematic case from the board of ?adcrstr-association for dermatohistopathologic control, re-evaluation and subsequent therapeutic recommendations?. AB - Malignant melanoma is the most malignant skin tumor, whose incidence is rising gradually. It usually occurs in pre-existing lesions in photo-exposed areas of the skin, and, despite its occurrence across a broad age range, its appearance prevails among the elderly. It has a tendency to metastasize rapidly. Secondary lesions are often located on mucous membranes including the conjunctiva, which in turn leads to higher mortality. Despite significant achievements in tumor diagnostics, explicit verification of a possible malignant melanoma is achieved by surgical removal of the lesion and its subsequent detailed histopathology. The prognosis for patients is determined by the stage of the primary tumor, tumor thickness and the presence or absence of additional risk factors, respectively. We present the case of a 39-year old female patient who was diagnosed with malignant melanoma of the left shoulder with a tumor thickness of 1 mm. No further microscopic prognostic criteria were described in the histological report. The lack of additional histopathological criteria in the pathologist?s report, such as mitotic activity and angio-lymphatic invasion from a lesion with this sort of tumor thickness, is followed almost always by risky or inadequate diagnostic and therapeutic decisions that may have fatal consequences for patients. The newly created Association for Dermatohistopathologic Control, Reevaluation and Subsequent Therapeutic Reccomendation in Sofia, Bulgaria aims to focus attention on these errors, in order to promote a unified histopathologic assessment of skin tumors in accordance with generally accepted European and World standards. This should ultimately help the clinician by increasing the efficiency of subsequent diagnostic and therapeutic decisions. PMID- 26016970 TI - Are microscopic satellites in melanoma indicative of lymphovascular invasion? A preliminary case study. AB - Microscopic satellites (microsatellites) in primary melanoma are defined as one or more discontinuous nests of neoplastic melanocytes measuring more than 0.05 mm in diameter that are clearly separated by normal dermis (i.e., no fibrosis or inflammation) from the main invasive component of the melanoma by a distance of at least 0.3 mm. Long considered an adverse prognostic variable, there has been debate about whether these satellites in fact represent lymphovascular invasion. In this preliminary study, 6 cases of primary cutaneous melanoma containing microsatellites were stained immunohistochemically for endothelial cells, using the markers CD31 and D2-40 (podoplanin, a marker of lymphatic endothelium). In none of the cases was positive staining found to surround the tumor deposits. In one case that also showed independent lymphovascular and perineural invasion, a small CD31 positive vessel within the microsatellite was found to contain tumor cells. The possible significance of these findings is discussed. PMID- 26016971 TI - Melanoma of the heel ? a case series of a rare melanoma subtype. AB - Melanoma of the heel is a rare subtype of the disease, which shows some variations of its incidence in different geographic areas as well as atypical clinical manifestations, resembling numerous other dermatologic conditions, which often leads to misdiagnosis at the early stages of the disease. We present a case series of four patients with malignant melanoma of the heel, with delay of diagnosis due to their atypical presentation, which is illustrated by tumor thickness, Clark level (VI and V), and tumor stage. All of the reported cases are from our own files and demonstrate the challenges with melanoma of the heel, with the aim to emphasize the necessity to biopsy all lesions with unknown significance to avoid the delay in diagnosis and prevent wrong subsequential treatments. PMID- 26016972 TI - ?Melanoma imitators?- how to prevent the aggressive approach? AB - Melanoma imitators could be lesions of different genres; vascular, infectious (granulomatous) and non-melanocytic tumors in addition to various skin artifacts. Their early recognition is essential for the subsequent and sometimes invasive diagnostic and therapeutic approach by the clinician. This paper focuses on several unique cases involving patients with clinical signs of advanced stage melanoma that actually had either benign lesions or circumstances where surgical excision could be avoided. We also analyze the means through which an early aggressive approach to these lesions could be avoided. The performance of confocal microscopy in dermatologic oncology units is one of the most modern trends in dermatology. Thanks to this method, the differentiation between melanocytic and non melanocytic lesions as well as between vascular lesions and lesions with granulomatous genesis, is substantially facilitated. The use of this methodology in the field of dermatologic oncology can be essential in improving the efficiency of medical services and reducing the number of unjustified surgical excisions. PMID- 26016973 TI - Basal cell carcinoma or not Basal cell carcinoma? That is the question! AB - Basal cell carcinoma is the most frequent malignant tumor in mankind. Although diagnosis often is based on clinical signs confirmed by histopathology, there are simulators of this tumor and there are basal cell carcinomas with misleading clinical appearance. Here we present 4 samples that illustrate the challenge in diagnostics. We also discuss differential diagnosis and treatment. PMID- 26016974 TI - Dysplastic nevi, melanoma and pregnancy- where is the relationship? AB - Dysplastic nevus is a precursor and a risk factor for the development of malignant melanoma, which explains the scientific interest in this field. Its etiology includes various of endogenous and exogenous factors, as we are considering the influence of hormonal status on the possible malignancy of congenital nevi in particular. The occurrence of some typical melanocytic lesions such as chloasma during pregnancy, where the hormone effect is demonstrated, as well as the more frequent changes of the dysplastic nevi namely within the pregnancy, leads to the idea for the endocrine dependence of the malignant transformation of some melanocytic lesions. We present a case of 37-year-old female patient whom consulted with the dermatologist due to occurrence of pigmented lesions on her left breast. The lesion changed significantly during both her pregnancies with a pause in growth between them and without any signs of regression after the births. During pregnancy, all pigmented skin lesions should be observed with caution because of the increased risk of malignant transformation. Lesions with any suspected changes are required to be immediately removed surgically with appropriate anaesthesia, without waiting to give birth. PMID- 26016975 TI - Vascular neoplasm or pseudovascular nevus? Potential pitfalls in diagnosis. AB - Melanocytic nevi, on histopathologic evaluation, occasionally contain slit-like clefts or spaces that may resemble vascular or lymphatic spaces. The spaces may contain blood or, perhaps more concerning, nests of melanocytes that could suggest lymphatic invasion of melanoma. When lined by melanocytes rather than true endothelium, these pseudovascular spaces within melanocytic nevi are generally attributable to tissue processing artifact. When the space in question is pronounced, a proper diagnostic work-up is prudent in order to exclude a true vascular neoplasm or melanoma. In this case series we present several melanocytic lesions with prominent vascular-appearing spaces that warranted further investigation. PMID- 26016976 TI - A case of perforating folliculitis in association with antisynthetase syndrome. AB - Perforating folliculitis (PF) describes the process by which altered dermal material is eliminated from the epidermis through a follicular unit resulting in keratotic, follicular papules that favor hair-bearing regions of the forearms, arms, buttocks, and thighs. Diabetes mellitus (DM) and chronic renal failure (CRF) are commonly associated with PF. The more general term, acquired perforating dermatosis, has been applied to PF as well as Kyrle?s disease and the non-inherited form of perforating collagenosis. In this report, we describe an instance of PF that arose in the setting of preexisting antisynthetase syndrome. PMID- 26016977 TI - Polyamide hair implant (biofibre(r)): evaluation of efficacy and safety in a group of 133 patients. AB - One of the greatest challenges in medicine is treatment of both feminine and masculine baldness. Among several surgical treatments available, artificial hair implantation has to be listed. We report the efficacy and safety of hair fibre implants, (Biofibre(r)), through the follow-up of 133 patients in three years. One-hundred-and-thirty-three patients, 98 male and 38 female, with alopecia or baldness, were treated with the hair implant (Biofibre(r)) which is made from a mixture of polyamides. The patients included had good state of health, healthy scalp and they were diligent in scalp cleaning. Patients with atopic dermatitis, lupus, seborrhoeic dermatitis and other skin diseases were excluded. Patients' scalps had to be normalized in case of local diseases. A clinical evaluation was carried out after 1 month, 4 months, and every other 4 months after the implant. Efficacy and safety of the product were evaluated in each patient. The most represented group consisted of men aged between 30 and 60, belonging to a scale of Hamilton III to IV. They underwent implants of up to 6000 fibres (average of 5 6 implants in three months). The fibre loss was of no more than 10% per year in 91.4% of the cases, 15% in 7.8% of the cases and 20% in 0.8% of the cases. 96.2% of patients declared to be satisfied from the result of the implant while 3.8% declared to not be satisfied. As for post-implantation tolerability and complications, 90.3% of patients recorded no pathology after surgery/ies. The 5.9% presented mild infection pathologies and the 3.8% presented inflammation pathologies (mainly from the use of wrong chemical substances). The resolution of the septic and chemical pathologies occurred in 97.9% of the cases within an average of 15 days with the use of systemic antibiotic and/or steroid local therapy. In 2.1% of the cases it was necessary to remove the fibres which took place without leaving any lasting scar. The implant of polyamide hairs (Biofibre(r)) can be considered an efficient surgical technique that allows immediate aesthetic results. In our study, hair implant technique demonstrated to be safe and well tolerated by patients. PMID- 26016978 TI - Heel melanoma: the final result of wrong diagnostic and therapeutic approach in another bulgarian patient. First documented case from the board of the ?adcrstr association for dermatohistopathologic control, reevaluation and subsequent therapeutic recomme. AB - Difficulties with frequent misdiagnoses and incorrectly defined tumor thicknesses applied to the same histopathological preparation occurring among Bulgarian patients, has led to the creation of national and/or international associations or boards for control in problematic circumstances, particularly for patients with melanocytic and non melanocytic cutaneous tumors. Once again we report a problematic case of a patient with acral lentiginous melanomа, localized in the heel area of the right foot, in an otherwise healthy 69-year old woman. A pigmented lesion gradually developed in her heel area, where the patient had been previously treated several times with invasive therapeutic methods (cryosurgery, shave curettage) due to misdiagnosis as a verrucous lesion or as a viral wart in the absence of any prior histopathology report. Years later, the lesion progressed and changed in color, leading to surgical removal, followed by several histopathological evaluations that produced very different results on three separate occasions. The first result described the lesion as melanocytic nevus, and removed with tumor-free margins. The second report from the Department of Dermatology and Venereology, Military Academy in Sofia , Bulgaria, stated ?no data for Verrucous carcinoma?. Only on the third assessment the correct diagnosis of ?malignant melanoma? was given. A relapse of the melanoma occurred as only at the time of the last histopathologic evaluation, (following surgical resection of the lesion with adequate margins, performed in the ?Onkoderma?- Policlinic for Dermatology, Venereology and Dermatologic Surgery, Sofia, Bulgaria) were criteria followed for appropriate pathological evaluation consistent with the recommendations of the AJCC for reporting of melanomas. Tumor thickness at that time was 1.31 mm. Removal of the draining lymph node, followed by inguinal lymphadenectomy was performed in the National Oncological Hospital in accordance with the recommendations of the AJCC. Unfortunately disease progression was observed with loco-regional lymph node involvement. Systemic therapy with interferon was planned. The incorrect therapeutic approach in this patient, as well as the several subsequent misdiagnoses that were made in the leading pathology departments of the capital, undoubtedly helped lead to the creation of a national board with international participation in order to minimize errors in the diagnostic and therapeutic approach in dermatology, surgery and histopathology. The already-created Association for Dermatohistopathologic Control, Reevaluation and Subsequent Therapeutic Recommendations-ADCRSTR, aims to take control of histopathological preparations with wrong diagnoses and subsequent therapy in patients with cutaneous tumors, as well as their documentation. Another task of the Institution is to focus on the preservation and protection of the rights and interests of affected patients. PMID- 26016979 TI - Intralymphatic histiocytosis overlying hip implantation treated with pentoxifilline. AB - Intralymphatic histiocytosis (IH) is a rare condition that presents with livedoid, erythematous to violaceous patches and plaques near affected joints most commonly in patients with rheumatoid arthritis and in at least 8 reports overlying metal implants. We report the case of a 58 year-old Caucasian woman who developed an indurated violaceous reticulated plaque overlying her right hip after placement of a metal hip implant 6 years prior for treatment of osteoarthritis. Histopathology revealed a proliferation of D2-40-positive dilated lymphatic spaces in the dermis and intralymphatic proliferation of CD68-positive histiocytes. Lab results included negative serology for rheumatoid factor and negative leukocyte function testing for metal allergies. The patient was treated with pentoxifylline, which resulted in decreased induration and erythema of the lesion with almost complete resolution of the plaque. This case highlights the diagnostic and therapeutic challenges of cutaneous reactive angiomatoses, which are rare skin conditions that can present with similar clinical and histologic findings and can be differentiated on the basis of immunostains that highlight vascular and lymphatic endothelium and histiocytes. Pentoxifylline may be considered as a therapeutic option because of its anti-inflammatory and antiplatelet activity. PMID- 26016980 TI - Giant congenital melanocytic nevus localized in the axillary area: serial excisions as optimal treatment option. AB - Congenital melanocytic nevi are relatively rare lesions (1-6%). Their size and location can cause cosmetic and functional disorders of varying degrees of severity, but in addition they can also undergo transformation to malignant melanoma. Different types of treatments have been described as being effective for these lesions, the choice of the most appropriate method depending on the size and the location of the nevi as well as the patient?s age. While locally destructive methods for superficial treatment could successfully reduce the pigmentation, recurrences are not rare and incomplete elimination of the melanocytic nevus would not exclude the possible development of subsequent malignancy. Surgical excision is the only reliable method allowing for complete removal of the lesion and the provision of material for subsequent histological examination. Complete surgical excision is a good option for prevention of future malignant transformation, but it is not always possible to carry out, especially in the case of large melanocytic nevi. In such cases, serial or staged surgical excisions represent an optimal therapeutic approach with the greatest assurance of total removal of the lesion, even large. We present the case of a female patient with a congenital melanocytic nevus located in the axillary area that had increased significantly in size during her pregnancy. The lesion was successfully treated through a series of surgical excisions with excellent aesthetic results in Onkoderma-Policlinic for Dermatology and Dermatologic Surgery, Sofia, Bulgaria. PMID- 26016981 TI - Nonsyndromic aplasia cutis congenita: a case report. AB - Aplasia cutis congenita (ACC) is a rare disorder, which is defined by the localized, or less commonly widespread absence of skin involving the epidermis, dermis and subcutaneous tissue with an incidence of 1/10.000 newborns. The underlying bone and dura mater can be also affected, and muscle and bone involvement occur in approximately 20 to 30% of the cases. Aplasia cutis congenita most often occurs in isolated form, but it has also been reported as part of a heterogeneous group of syndromes. Conservative treatment, surgery, or a combination of these has been described as possible treatment options. In the neonatal period, conservative treatment is more appropriate as a management strategy. We present a rare case of a 2-month old female patient with isolated aplasia cutis congenita, localized on the vertex of the scalp, treated conservatively since birth with good results. PMID- 26016982 TI - Ulcerated cutaneous myeloid sarcoma associated with myelodysplastic syndrome. AB - Cutaneous myeloid sarcoma is a rare extramedullary neoplasia of myeloid differentiation. It can be a herald of myelodysplastic syndrome, myeloproliferative disorder and leukemia. We present two cases of ulcerated cutaneous myeloid sarcoma of the aleukemic type, both associated with myelodysplastic syndrome: a male patient of 67 years with multifocal lesions and an 83-year old woman with a chronic foot ulcer. Differential diagnoses and treatment are discussed. Survival rates are lower in cutaneous myeloid sarcoma associated with acute myeloid leukemia than in aleukemic patients. Early recognition of the disease helps to improve the prognosis. PMID- 26016983 TI - Non-healing facial lesions: cutaneous old world leishmaniasis in dresden. AB - Cutaneous leishmaniasis is a common vector-borne disease world-wide but not in Central Europe. The typical clinical manifestation is an enlarging papule on the site of infection. Vectors are sandflies and reservoirs may be wild animals like rodents, dogs or even humans. Patients with any kind of immunodeficiency are at risk. We report on two otherwise healthy patients, 16 and 18 years-of-age, who presented non-healing facial lesions. The diagnosis of cutaneous leishmaniasis was confirmed through intracellular amastigotes in Giemsa stains of skin biopsies. One infection was of Syrian origin and the other was contracted in Tuscany. Since both lesions were classified as complex cutaneous lesions, drug therapy was initiated with itraconazole orally or intralesional meglumine antimonite. A complete response was obtained in both patients. No other adverse effects rather than injection pain with meglumine antimonite were observed. We should be aware of cutaneous leishmaniasis in travelers returning from endemic regions or from migrants and refugees from endemic regions. PMID- 26016984 TI - Vitiligo: successful combination treatment based on oral low dose cytokines and different topical treatments. AB - The current treatments for Vitiligo are not completely satisfactory in terms of clinical, aesthetic and compliance results for patients. Recently, combination therapies had been introduced with positive results. In this paper the combination between systemic oral treatment with Low Dose Cytokines in association with other topical treatments was evaluated. Positive results were obtained both with Low Dose Cytokines alone or in association with microphototherapy with positive percentage of skin repigmentation varying between 74% and 90%. Collected data allow the authors to affirm that the treatment with oral low dose SKA drugs is efficacious per se and highly efficacious in association with targeted phototherapy. PMID- 26016985 TI - Pattern of antimicrobial usage in livestock animals in south-western Nigeria: The need for alternative plans. AB - Resistance to antibiotics has continued to increase, placing future animal and human disease management in real danger. The developing countries characterised by widespread indiscriminate antibiotic use and in which 'third-generation' antibiotics are not readily available or affordable are the worst affected. A 3 year (2010-2012) retrospective survey of antibiotic usage in livestock production in three selected states of south-western Nigeria was conducted. Data obtained from eight purposively selected licensed veterinary pharmaceutical sales establishments in the area, based on keeping detailed sales records for the study period, were analysed using Stata Version 12. Results showed that tetracyclines (33.6%), fluoroquinolones (26.5%) and beta-lactams/aminoglycosides (20.4%) constituted the majority of the antibiotics used over the 3 years. The differences in the quantities of antibiotic types used within each antimicrobial class were statistically significant for tetracyclines (F = 59.87; p < 0.0001) and fluoroquinolones (F = 43.97; p < 0.0001) but not for beta lactams/aminoglycosides (F = 3.21; p = 0.148). Furthermore, antibiotic consumption increased by 40.4% between 2010 and 2012. Although statistically insignificant (F = 0.277; p = 0.762), the increasing trend across the years was at rates of 23.5% between 2010 and 2011 and 13.8% between 2011 and 2012. In addition, the findings show a significantly higher consumption rate (t = 15.21; df = 5; p < 0.0001) during the rainy (52.5%) than the dry (47.5%) seasons. The current increasing trend in antibiotic usage holds a serious danger for the future and therefore calls for alternative plans to safeguard future livestock production, food security and human health. This becomes more imperative considering emerging resistance against tetracyclines and fluoroquinolones, the foremost remedies for livestock diseases in most developing countries. PMID- 26016987 TI - Organocatalytic Activation of the Leaving Group in the Intramolecular Asymmetric SN 2' Reaction. AB - A Bronsted-acid-catalyzed intramolecular enantioselective SN 2' reaction was developed utilizing trichloroacetimidate as a leaving group. The findings indicated that dual activation of the substrates is operative. This metal-free allylic alkylation allows highly enantioselective access to 2-vinylpyrrolidines bearing various substituents. PMID- 26016986 TI - Nerve cross-bridging to enhance nerve regeneration in a rat model of delayed nerve repair. AB - There are currently no available options to promote nerve regeneration through chronically denervated distal nerve stumps. Here we used a rat model of delayed nerve repair asking of prior insertion of side-to-side cross-bridges between a donor tibial (TIB) nerve and a recipient denervated common peroneal (CP) nerve stump ameliorates poor nerve regeneration. First, numbers of retrogradely labelled TIB neurons that grew axons into the nerve stump within three months, increased with the size of the perineurial windows opened in the TIB and CP nerves. Equal numbers of donor TIB axons regenerated into CP stumps either side of the cross-bridges, not being affected by target neurotrophic effects, or by removing the perineurium to insert 5-9 cross-bridges. Second, CP nerve stumps were coapted three months after inserting 0-9 cross-bridges and the number of 1) CP neurons that regenerated their axons within three months or 2) CP motor nerves that reinnervated the extensor digitorum longus (EDL) muscle within five months was determined by counting and motor unit number estimation (MUNE), respectively. We found that three but not more cross-bridges promoted the regeneration of axons and reinnervation of EDL muscle by all the CP motoneurons as compared to only 33% regenerating their axons when no cross-bridges were inserted. The same 3-fold increase in sensory nerve regeneration was found. In conclusion, side-to-side cross-bridges ameliorate poor regeneration after delayed nerve repair possibly by sustaining the growth-permissive state of denervated nerve stumps. Such autografts may be used in human repair surgery to improve outcomes after unavoidable delays. PMID- 26016988 TI - The Faces in Infant-Perspective Scenes Change over the First Year of Life. AB - Mature face perception has its origins in the face experiences of infants. However, little is known about the basic statistics of faces in early visual environments. We used head cameras to capture and analyze over 72,000 infant perspective scenes from 22 infants aged 1-11 months as they engaged in daily activities. The frequency of faces in these scenes declined markedly with age: for the youngest infants, faces were present 15 minutes in every waking hour but only 5 minutes for the oldest infants. In general, the available faces were well characterized by three properties: (1) they belonged to relatively few individuals; (2) they were close and visually large; and (3) they presented views showing both eyes. These three properties most strongly characterized the face corpora of our youngest infants and constitute environmental constraints on the early development of the visual system. PMID- 26016989 TI - Micro actions in colorectal cancer screening participation: a population-based survey study. AB - BACKGROUND: Low uptake of colorectal cancer (CRC) screening is a cause for concern. This study explored people's anticipated response to receiving the test kit to shed light on past screening uptake and help inform future interventions to increase participation. METHODS: Face-to-face interviews were conducted with respondents living in England who were eligible for CRC screening as part of a population-based 'omnibus' survey. Respondents were asked what they would do ('micro actions') if they received a CRC screening test kit through the mail (apart from completing it or not), and their unprompted responses were coded (multiple codes allowed). Past 'ever' uptake and screening intention were also recorded. The final analysis included 1237 respondents aged 60-70. RESULTS: Respondents who said that they would decide after some thought' (p < .001), 'put [it] aside to deal with later' (p < .001), 'put it on the "to do list/ pile"' (p < .05) or 'discuss it with a health care professional' (p < .01) had decreased odds of having participated. Those who said they would 'read the instruction leaflet' (p < .001), 'put the kit near the toilet' (p < .001) or 'decide when to do the test' (p < .05) were more likely to have taken part in CRC screening. With the exception of 'decide when to do the test' and 'discuss it with a health care professional', all associations with past uptake remained significant after adjusting for other micro actions and screening intention. 'Make a note somewhere (to remind myself)' was mentioned by less than 1 % of respondents. CONCLUSIONS: Delay-causing and preparatory micro actions were associated with past CRC screening uptake. Self-regulatory micro actions (e.g. making a note to remind oneself) were rarely mentioned as responses to receiving a screening invitation. Interventions aimed at reducing delay and facilitating preparatory and self regulatory behaviours might help increase uptake. The behaviour-focused survey method is a promising avenue for future health behaviour research. PMID- 26016990 TI - Case of alopecia areata accompanied by polymyalgia rheumatica. PMID- 26016991 TI - Ultrafast surface-enhanced Raman spectroscopy. AB - Ultrafast surface-enhanced Raman spectroscopy (SERS) with pico- and femtosecond time resolution has the ability to elucidate the mechanisms by which plasmons mediate chemical reactions. Here we review three important technological advances in these new methodologies, and discuss their prospects for applications in areas including plasmon-induced chemistry and sensing at very low limits of detection. Surface enhancement, arising from plasmonic materials, has been successfully incorporated with stimulated Raman techniques such as femtosecond stimulated Raman spectroscopy (FSRS) and coherent anti-Stokes Raman spectroscopy (CARS). These techniques are capable of time-resolved measurement on the femtosecond and picosecond time scale and can be used to follow the dynamics of molecules reacting near plasmonic surfaces. We discuss the potential application of ultrafast SERS techniques to probe plasmon-mediated processes, such as H2 dissociation and solar steam production. Additionally, we discuss the possibilities for high sensitivity SERS sensing using these stimulated Raman spectroscopies. PMID- 26016992 TI - Chromatic response of polydiacetylene vesicle induced by the permeation of methotrexate. AB - The noble vesicular system of polydiacetylene showed a red shift using two types of detecting systems. One of the systems involves the absorption of target materials from the outer side of the vesicle, and the other system involves the permeation through the vesicular layers from within the vesicle. The chromatic mixed vesicles of N-(2-aminoethyl)pentacosa-10,12-diynamide (AEPCDA) and dimethyldioctadecylammonium chloride (DODAC) were fabricated by sonication, followed by polymerization by UV irradiation. The stability of monomeric vesicles was observed to increase with the polymerization of the vesicles. Methotrexate was used as a target material. The polymerized mixed vesicles having a blue color were exposed to a concentration gradient of methotrexate, and a red shift was observed indicating the adsorption of methotrexate on the polydiacetylene bilayer. In order to check the chromatic change by the permeation of methotrexate, we separated the vesicle portion, which contained methotrexate inside the vesicle, and checked chromatic change during the permeation of methotrexate through the vesicle. The red shift apparently indicates the disturbance in the bilayer induced by the permeation of methotrexate. The maximum contrast of color appeared at the equal molar ratio of AEPCDA and DODAC, indicating that the formation of flexible and deformable vesicular layers is important for red shift. Therefore, it is hypothesized that the system can be applicable for the chromatic detection of the permeation of methotrexate through the polydiacetylene layer. PMID- 26016993 TI - The Cortical Hyperexcitability Index (CHi): a new measure for quantifying correlates of visually driven cortical hyperexcitability. AB - INTRODUCTION: Aberrations of visual experience, including visual hallucinations and visual distortions, are known to be associated with increased cortical hyperexcitability. As a consequence, the presence, intensity and frequency of certain experiences may well be indicative of an underlying increase in cortical hyperexcitability. METHODS: The current study presents a new proxy measure of cortical hyperexcitability, the Cortical Hyperexcitability Index (CHi). Two hundred and fifty healthy participants completed the CHi with the results subjected to exploratory factor analysis (EFA). RESULTS: The EFA revealed a three factor model as the most parsimonious solution. The three factors were defined as: (1) heightened visual sensitivity and discomfort; (2) negative aura-type visual aberrations; and (3) positive aura-type visual aberrations. The identification of three factors suggests that multiple mechanisms underlie the notion of cortical hyperexcitability, providing researchers with new and greater precision in delineating these underlying features. CONCLUSIONS: The factorial structure of the CHi and the increased precision could aid the interpretation of findings from neuroscientific (i.e., brain imaging/stimulation) examinations of cortical processes underlying aberrant perceptions across a host of clinical, neurological and pathological conditions. As a consequence, the CHi is a useful and comprehensive proxy measure of cortical hyperexcitability with considerable scientific and clinical utility. PMID- 26016994 TI - [Endovascular treatment for acute ischemic stroke : Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN)]. PMID- 26016995 TI - Relationship between Modelling Accuracy and Inflection Point Attributes of Several Equations while Modelling Stand Diameter Distributions. AB - In this study, seven popular equations, including 3-parameter Weibull, 2 parameter Weibull, Gompertz, Logistic, Mitscherlich, Korf and R distribution, were used to model stand diameter distributions for exploring the relationship between the equations' inflection point attributes and model accuracy. A database comprised of 146 diameter frequency distributions of Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.) plantations was used to demonstrate model fitting and comparison. Results showed that the inflection points of the stand diameter cumulative percentage distribution ranged from 0.4 to 0.6, showing a 1/2 close rule. The equation's inflection point attribute was strongly related to its model accuracy. Equation with an inflection point showed much higher accuracy than that without an inflection point. The larger the effective inflection point interval of the fitting curve of the equation was, and the closer the inflection point was to 0.5 for the equations with fixed inflection points, the higher the equation's accuracy was. It could be found that the equation's inflection point had close relationship with skewness of diameter distribution and stand age, stand density, which provided a scientific basis for model selection of a stand diameter distribution for Chinese fir plantations and other tree species. PMID- 26016996 TI - Obesity-associated microRNA-26b regulates the proliferation of human preadipocytes via arrest of the G1/S transition. AB - MicroRNAs (miRNAs) are short, 20-24 nucleotide non-coding RNAs, which are involved in multiple biological processes, including obesity. Our previous investigation revealed that miRNA (miR)-26b is differentially expressed in preadipocytes and mature adipocytes in humans. However, its role in the proliferation of human preadipocytes remains to be fully elucidated. In the present study, intracellular lipid accumulation was assessed using oil red O staining and the trigycerlide (TG) content was quantified using a TG assay kit, adipogenesis associated genes and cyclin D2 were analyzed using western blotting, and the effects of miR-26b on the proliferation of preadipocytes was investigated using Cell Counting Kit-8 assays and cell cycle analysis. Human preadipocytes overexpressing miR-26b exhibited increased TG content in the adipocytes. During differentiation, the protein expression levels of adipogenesis-associated marker genes, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, fatty acid-binding protein and hormone-sensitive lipase were upregulated in cells overexpressing miR-26b, compared with the negative control cells. In addition, growth of human preadipocytes overexpressing miR-26b occurred a slower rate and more remained in the G1 phase, compared with the negative control cells. In addition, miR-26b downregulated the protein expression of cyclin D2. These results demonstrated that miR-26b promoted differentiation and, at least party by targeting cyclin D2, attenuated cell proliferation via arresting the G1/S transition. PMID- 26016999 TI - Accessibility and Responsiveness Review Tool: community agency capacity to respond to survivors with disabilities. AB - For persons with disabilities who have experienced trauma in the forms of abuse and violence, options for accessible and trauma-informed services are often limited. Using a self-assessment and planning process, disability service providers and victim/survivor service providers are able to strategize ways of addressing the needs of survivors with disabilities. The Accessibility and Responsiveness Review Tool (Review Tool) incorporates the principles of universal design and trauma-informed practices into an agency-wide discussion tool leading to increases in knowledge, reduction in barriers, and overall improved programs for survivors with disabilities. Results of agencies that participated in the Review Tool process are presented. PMID- 26016997 TI - Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2. AB - Leukemic stem cells (LSCs) reside within bone marrow niches that maintain their relatively quiescent state and convey resistance to conventional treatment. Many of the microenvironmental signals converge on RAC GTPases. Although it has become clear that RAC proteins fulfill important roles in the hematopoietic compartment, little has been revealed about the downstream effectors and molecular mechanisms. We observed that in BCR-ABL-transduced human hematopoietic stem/progenitor cells (HSPCs) depletion of RAC2 but not RAC1 induced a marked and immediate decrease in proliferation, progenitor frequency, cobblestone formation and replating capacity, indicative for reduced self-renewal. Cell cycle analyses showed reduced cell cycle activity in RAC2-depleted BCR-ABL leukemic cobblestones coinciding with an increased apoptosis. Moreover, a decrease in mitochondrial membrane potential was observed upon RAC2 downregulation, paralleled by severe mitochondrial ultrastructural malformations as determined by automated electron microscopy. Proteome analysis revealed that RAC2 specifically interacted with a set of mitochondrial proteins including mitochondrial transport proteins SAM50 and Metaxin 1, and interactions were confirmed in independent co immunoprecipitation studies. Downregulation of SAM50 also impaired the proliferation and replating capacity of BCR-ABL-expressing cells, again associated with a decreased mitochondrial membrane potential. Taken together, these data suggest an important role for RAC2 in maintaining mitochondrial integrity. PMID- 26017000 TI - Trauma informed care in medicine: current knowledge and future research directions. AB - Traumatic events (including sexual abuse, domestic violence, elder abuse, and combat trauma) are associated with long-term physical and psychological effects. These events may influence patients' health care experiences and engagement in preventative care. Although the term trauma-informed care (TIC) is widely used, it is not well understood how to apply this concept in daily health care practice. On the basis of a synthesis of a review of the literature, the TIC pyramid is a conceptual and operational framework that can help physicians translate TIC principles into interactions with patients. Implications for clinical practice and future research are discussed in this article. PMID- 26017001 TI - Screening and intervening: evaluating a training program on intimate partner violence and reproductive coercion for family planning and home visiting providers. AB - Project Connect training aims to reduce barriers to screening for and intervening with women with histories of intimate partner violence and reproductive coercion. This study sought to assess the effectiveness of trainings, provider facility with Project Connect tools, and areas for improvement in a pilot state. Results indicated that providers found training useful, and those in supervisory roles particularly appreciated the universal tools and skill set given to participants. Providing these tools supports the provision of trauma-informed care. Areas for improvement included increased emphasis on initiating screening, enhancing training for different types of providers, and developing follow-up training. PMID- 26017002 TI - Theories and assumptions that inform trauma-specific interventions for incarcerated women. AB - The field of interventional outcomes research in programs designed to treat trauma in correctionally involved women involves contributions from researchers in a variety of disciplines. In this review, we asked how recent interventional studies addressed 3 theoretical touchstones-relational cultural theory, trauma theory, and addiction theory. We found that few outcomes studies engaged theory directly on any of these points and concluded that the opportunity for field defining debate may risk getting lost in a quest for numbers or outcomes. We recommended that researchers more explicitly position their work, especially with respect to key theories and points of debate. PMID- 26017003 TI - Assessing the feasibility of providing a parenting intervention for war-affected families in northern Uganda. AB - This article reports the results of a feasibility study of an intervention, Enhancing Family Connection (EFC), conducted in Northern Uganda in 2012. Enhancing Family Connection's sessions were an adaption of the Parent Management Training, Oregon model. Three interrelated areas of feasibility were assessed: (a) acceptability, (b) usability, and (c) limited efficacy. This study utilized questionnaires and semi-structured interviews completed by mothers and a focal child pre- and post-intervention. Results indicated that mothers found the intervention acceptable to their families and culture and showed promise for Enhancing Family Connection's efficacy in changing parenting behaviors. This study supports continued development of this intervention. PMID- 26017004 TI - Group attachment-based intervention: trauma-informed care for families with adverse childhood experiences. AB - This article outlines the main premises of an innovative trauma-informed intervention, group attachment-based intervention, specifically developed to target vulnerable families with infants and toddlers, living in one of the poorest urban counties in the nation. It also reports on the trauma-relevant characteristics of 60 families entering a clinical trial to study the effectiveness of Group Attachment-Based Intervention. Initial survey results revealed high levels of neglect, abuse, and household dysfunction in mothers' histories (77% reported >=4 adverse childhood experiences, with more than 90% reporting 2 or more current toxic stressors, including poverty, obesity, domestic and community violence, and homelessness). PMID- 26017005 TI - AIE-induced fluorescent vesicles containing amphiphilic binding pockets and the FRET triggered by host-guest chemistry. AB - A series of tetraphenylethylene (TPE)-bile acid conjugates was described. It was found that the synergetic combination of the distinct properties of TPE and bile acid units could directly afford uniform fluorescent vesicles with amphiphilic binding pockets in the membrane. This structural features of such vesicles provides a unique opportunity for facile construction of functional chemical systems through host-guest chemistry. PMID- 26017007 TI - Ultra-bright and stimuli-responsive fluorescent nanoparticles for bioimaging. AB - Fluorescent nanoparticles (NPs) are unique contrast agents for bioimaging. Examples of molecular-based fluorescent NPs with brightness similar or superior to semiconductor quantum dots have been reported. These ultra-bright NPs consist of a silica or polymeric matrix that incorporate the emitting dyes as individual moieties or aggregates and promise to be more biocompatible than semiconductor quantum dots. Ultra-bright materials result from heavy doping of the structural matrix, a condition that entails a close mutual proximity of the doping dyes. Ground state and excited state interactions between the molecular emitters yield aggregation-caused quenching (ACQ) and proximity-caused quenching (PCQ). In combination with Foster resonance energy transfer (FRET) ACQ and PCQ originate collective phenomena that produce amplified quenching of the nanoprobes. In this focus article, we discuss strategies to achieve ultra-bright nanoprobes avoiding ACQ and PCQ also exploiting aggregation-induced emission (AIE). Amplified quenching, on the other hand, is also proposed as a strategy to design stimuli responsive fluorogenic probes through disaggregation-induced emission (DIE) in alternative to AIE. As an advantage, DIE consents to design stimuli-responsive materials starting from a large variety of precursors. On the contrary, AIE is characteristic of a limited number of species. Examples of stimuli-responsive fluorogenic probes based on DIE are discussed. PMID- 26017006 TI - From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria. AB - BACKGROUND: The survival of malaria parasites, under substantial haem-induced oxidative stress in the red blood cells (RBCs) is dependent on the pentose phosphate pathway (PPP). The PPP is the only source of NADPH in the RBC, essential for the production of reduced glutathione (GSH) and for protection from oxidative stress. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, therefore, increases the vulnerability of erythrocytes to oxidative stress. In Plasmodium, G6PD is combined with the second enzyme of the PPP to create a unique bifunctional enzyme, named glucose-6-phosphate dehydrogenase-6 phosphogluconolactonase (G6PD-6PGL). RRx-001 is a novel, systemically non-toxic, epigenetic anticancer agent currently in Phase 2 clinical development for multiple tumour types, with activity mediated through increased nitric oxide (NO) production and PPP inhibition. The inhibition of G6PD and NO overproduction induced by RRx-001 suggested its application in cerebral malaria (CM). METHODS: Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice is an experimental model of cerebral malaria (ECM) with several similar pathological features to human CM. This study uses intravital microscopy methods with a closed cranial window model to quantify cerebral haemodynamic changes and leukocyte adhesion to endothelial cells in ECM. RESULTS: RRx-001 had both single agent anti-parasitic activity and significantly increased the efficacy of artemether. In addition, RRx-001 preserved cerebral perfusion and reduced inflammation alone or combined with artemether. RRx-001's effects were associated with inhibition of PPP (G6PD and G6PD-6PGL) and by improvements in microcirculatory flow, which may be related to the NO donating properties of RRx-001. CONCLUSION: The results indicate that RRx 001 could be used to potentiate the anti-malarial action of artemisinin, particularly on resistant strains, and to prevent infection. PMID- 26017008 TI - Death of Neurons following Injury Requires Conductive Neuronal Gap Junction Channels but Not a Specific Connexin. AB - Pharmacological blockade or genetic knockout of neuronal connexin 36 (Cx36) containing gap junctions reduces neuronal death caused by ischemia, traumatic brain injury and NMDA receptor (NMDAR)-mediated excitotoxicity. However, whether Cx36 gap junctions contribute to neuronal death via channel-dependent or channel independent mechanism remains an open question. To address this, we manipulated connexin protein expression via lentiviral transduction of mouse neuronal cortical cultures and analyzed neuronal death twenty-four hours following administration of NMDA (a model of NMDAR excitotoxicity) or oxygen-glucose deprivation (a model of ischemic injury). In cultures prepared from wild-type mice, over-expression and knockdown of Cx36-containing gap junctions augmented and prevented, respectively, neuronal death from NMDAR-mediated excitotoxicity and ischemia. In cultures obtained form from Cx36 knockout mice, re-expression of functional gap junction channels, containing either neuronal Cx36 or non-neuronal Cx43 or Cx31, resulted in increased neuronal death following insult. In contrast, the expression of communication-deficient gap junctions (containing mutated connexins) did not have this effect. Finally, the absence of ethidium bromide uptake in non-transduced wild-type neurons two hours following NMDAR excitotoxicity or ischemia suggested the absence of active endogenous hemichannels in those neurons. Taken together, these results suggest a role for neuronal gap junctions in cell death via a connexin type-independent mechanism that likely relies on channel activities of gap junctional complexes among neurons. A possible contribution of gap junction channel-permeable death signals in neuronal death is discussed. PMID- 26017009 TI - Detecting pulmonary capillary blood pulsations using hyperpolarized xenon-129 chemical shift saturation recovery (CSSR) MR spectroscopy. AB - PURPOSE: To investigate whether chemical shift saturation recovery (CSSR) MR spectroscopy with hyperpolarized xenon-129 is sensitive to the pulsatile nature of pulmonary blood flow during the cardiac cycle. METHODS: A CSSR pulse sequence typically uses radiofrequency (RF) pulses to saturate the magnetization of xenon 129 dissolved in lung tissue followed, after a variable delay time, by an RF excitation and subsequent acquisition of a free-induction decay. Thereby it is possible to monitor the uptake of xenon-129 by lung tissue and extract physiological parameters of pulmonary gas exchange. In the current studies, the delay time was instead held at a constant value, which permitted observation of xenon-129 gas uptake as a function of breath-hold time. CSSR studies were performed in 13 subjects (10 healthy, 2 chronic obstructive pulmonary disease [COPD], 1 second-hand smoke exposure), holding their breath at total lung capacity. RESULTS: The areas of the tissue/plasma and the red-blood-cell peaks in healthy subjects varied by an average of 1.7+/-0.7% and 15.1+/-3.8%, respectively, during the cardiac cycle. In 2 subjects with COPD these peak pulsations were not detectable during at least part of the measurement period. CONCLUSION: CSSR spectroscopy is sufficiently sensitive to detect oscillations in the xenon-129 gas-uptake rate associated with the cardiac cycle. PMID- 26017012 TI - The systematic approach to describing conformational rearrangements in G quadruplexes. AB - Conformational changes in DNA G-quadruplex (GQ)-forming regions affect genome function and, thus, compose an interesting research topic. Computer modelling may yield insight into quadruplex folding and rearrangement, particularly molecular dynamics simulations. Here, we show that specific parameters, which are distinct from those commonly used in DNA conformational analyses, must be introduced for adequate interpretation and, most importantly, convenient visual representation of the quadruplex modelling results. We report a set of parameters that comprehensively and systematically describe GQ geometry in dynamics. The parameters include those related to quartet planarity, quadruplex twist, and quartet stacking; they are used to quantitatively characterise various types of quadruplexes and rearrangements, such as quartet distortion/disruption or deviation/bulging of a single nucleotide from the quartet plane. Our approach to describing conformational changes in quadruplexes using the new parameters is exemplified by telomeric quadruplex rearrangement, and the benefits of applying this approach to analyse other structures are discussed. PMID- 26017011 TI - Unravelling the genome of Holy basil: an "incomparable" "elixir of life" of traditional Indian medicine. AB - BACKGROUND: Ocimum sanctum L. (O. tenuiflorum) family-Lamiaceae is an important component of Indian tradition of medicine as well as culture around the world, and hence is known as "Holy basil" in India. This plant is mentioned in the ancient texts of Ayurveda as an "elixir of life" (life saving) herb and worshipped for over 3000 years due to its healing properties. Although used in various ailments, validation of molecules for differential activities is yet to be fully analyzed, as about 80 % of the patents on this plant are on extracts or the plant parts, and mainly focussed on essential oil components. With a view to understand the full metabolic potential of this plant whole nuclear and chloroplast genomes were sequenced for the first time combining the sequence data from 4 libraries and three NGS platforms. RESULTS: The saturated draft assembly of the genome was about 386 Mb, along with the plastid genome of 142,245 bp, turning out to be the smallest in Lamiaceae. In addition to SSR markers, 136 proteins were identified as homologous to five important plant genomes. Pathway analysis indicated an abundance of phenylpropanoids in O. sanctum. Phylogenetic analysis for chloroplast proteome placed Salvia miltiorrhiza as the nearest neighbor. Comparison of the chemical compounds and genes availability in O. sanctum and S. miltiorrhiza indicated the potential for the discovery of new active molecules. CONCLUSION: The genome sequence and annotation of O. sanctum provides new insights into the function of genes and the medicinal nature of the metabolites synthesized in this plant. This information is highly beneficial for mining biosynthetic pathways for important metabolites in related species. PMID- 26017013 TI - Combining odours isolated from phylogenetically diverse sources yields a better lure for yellow jackets. AB - BACKGROUND: Invasive wasps have major impacts on bird populations and other biodiversity in New Zealand beech forests, and new solutions are needed for their management. Baits were combined from four phylogenetically diverse sources (protein and carbohydrate) to improve attraction to a level that could be used as the basis for more powerful attract-and-kill systems. Many compounds from honey, scale insect honeydew, fermenting brown sugar and green-lipped mussels were highly attractive and, when combined, outcompeted known attractants. RESULTS: The equivolumetric lure (equal parts of 3-methylbut-1-yl acetate, 2-ethyl-1-butanol, 1-octen-3-ol, 3-octanone, methyl phenylacetate and heptyl butanoate), gave a 5-10 fold improvement over the known attractant, octyl butanoate, and other previously patented lures. An economically optimised lure of the same compounds, but in a ratio of 2:1.6:1:1:2:2.4, was equally attractive as the equal-ratio lure. Pilot mass trapping attempts with this latter lure revealed that >400 wasps trap(-1) day(-1) could be caught at the peak of the season. CONCLUSION: The new lures are comprised of compounds from animals, plants and fungi, thus targeting the omnivorous behaviour of these wasps. PMID- 26017014 TI - Sesamol Enhances Cell Growth and the Biosynthesis and Accumulation of Docosahexaenoic Acid in the Microalga Crypthecodinium cohnii. AB - Sesamol is a strong antioxidant phenolic compound found in sesame seed. It possesses the ability to scavenge intracellular reactive oxygen species (ROS) and to inhibit malic enzyme activity and NADPH supply, resulting possibly in cell proliferation and alteration in the fatty acid composition. In the present study, the effect of sesamol on the growth and accumulation of docosahexaenoic acid (DHA) was investigated in the marine microalga Crypthecodinium cohnii, a prolific producer of DHA. C. cohnii showed a great decrease in the intracellular ROS level with the addition of sesamol. In contrast, the biomass concentration, DHA content (% of total fatty acids), and DHA productivity were significantly increased by 44.20, 11.25, and 20.00%, respectively (P < 0.01). Taken together, this work represents the first report of employing sesamol for enhanced production of DHA by C. cohnii, providing valuable insights into this alga for future biotechnological applications. PMID- 26017010 TI - Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. AB - BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat. METHODS: The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received >=1 year of continuous miglustat therapy (for >=90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if >=3/4 domain scores were lower/unchanged, and as 'progressed' if <3 scores were lower/unchanged between enrolment and last follow-up visit. RESULTS: In total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (>=15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data. CONCLUSIONS: Disability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years. PMID- 26017015 TI - Research partnerships between high and low-income countries: are international partnerships always a good thing? AB - BACKGROUND: International partnerships in research are receiving ever greater attention, given that technology has diminished the restriction of geographical barriers with the effects of globalisation becoming more evident, and populations increasingly more mobile. DISCUSSION: In this article, we examine the merits and risks of such collaboration even when strict universal ethical guidelines are maintained. There has been widespread examples of outcomes beneficial and detrimental for both high and low -income countries which are often initially unintended. SUMMARY: The authors feel that extreme care and forethought should be exercised by all involved parties, despite the fact that many implications from such international work can be extremely hard to predict. However ultimately the benefits gained by enhancing medical research and philanthropy are too extensive to be ignored. PMID- 26017016 TI - A systematic review of the safety and efficacy of distal coronary artery anastomotic devices. AB - Interest in minimally invasive and off-pump cardiac surgical techniques has promoted the development of automated distal anastomotic devices (DADs) to facilitate construction of coronary artery anastomosis. Several DADs have been proposed for potential use in coronary surgery. However, a number of technical failures and uncertainty around both short-term morbidity and long-term patency have limited the generalized uptake of these devices. A systematic literature search identified 28 studies, incorporating 970 patients who underwent coronary artery bypass grafting using a DAD. Eight different devices were identified including Heartflo, St Jude, U-clip, vessel closure system, C-port, magnetic vascular positioner and coronary anastomosis coupler. Thirty-day mortality, cardiac-specific mortality and myocardial infarction were equal between DADs and hand-sewn cases (1.3, 0.3 and 0.8%, respectively). The overall proportion of postoperative haemorrhage was higher in the anastomotic device group (2.3%) than in the group with hand-sewn anastomoses (1.5%) although not statistically significant. Overall graft patency was 97.2% at <1 month, 94.6% at 1-3 months and 92.3% at >3 months. Of the currently available systems, the U-clip device was found to provide the best overall postoperative outcomes, which included a patency of 96.1% at >3months. The current literature is limited by its predominantly observational study design and lack of directly comparative studies. Furthermore, inter-study variation in patient selection, anticoagulation strategies and follow-up periods prevents quantitative comparison. Future research necessitates multicentre randomized, controlled studies to provide a direct comparison of current and future anastomotic device systems with established hand-sewn techniques in both the short and long term. PMID- 26017017 TI - Mini-open vacuum-assisted closure therapy with instillation for debilitated and septic patients with pleural empyema. AB - OBJECTIVES: This prospective study is an evaluation of the mini-open vacuum assisted closure with instillation (Mini-VAC-Instill) therapy for the treatment of complicated pleural empyema. METHODS: We investigated septic patients in poor general physical condition (Karnofsky index <=50%) with multimorbidity and/or immunosuppression who were treated by minimally invasive intrathoracic VAC Instill therapy without the insertion of an open-window thoracostomy (OWT) between December 2012 and November 2014. All patients underwent mini-thoracotomy with position of a tissue retractor, surgical debridement and local decortication. Surgery was followed by intrathoracic vacuum therapy including periodic instillation using antiseptics. The VAC dressings were changed under general anaesthesia and the chest wall was closed during the same hospital stay. All patients received systemic antibiotic therapy. RESULTS: Fifteen patients (13 males, median age: 71 years) underwent intrathoracic Mini-VAC-Instill dressings for the management of pleural empyema without bronchopleural fistula. The median length of vacuum therapy was 9 days (5-25 days) and the median number of VAC changes per patient was 1 (1-5). In-hospital mortality was 6.7% (n = 1) and was not related to Mini-VAC-Instill therapy or intrathoracic infection. Control of intrathoracic infection and closure of the chest cavity was achieved in 85.7% of surviving patients (12 of 14). After the follow-up at an average of 13.2 months (range, 3-25 months), we observed recurrence once, 21 days after discharge. Two patients died in the late postoperative period (Day 43 and Day 100 after discharge) of fulminant urosepsis and carcinoma-related multiorgan failure, respectively. Analysis of the follow-up interviews in the outpatient clinic showed a good quality of life and a subjectively good long-term aesthetic result. CONCLUSIONS: Mini-VAC-Instill therapy is an upgrade of Mini-VAC, which guarantees the advantage of an open treatment, including flushing but without OWT. This procedure is minimally invasive, highly compatible especially with patients in poor general condition and may be an alternative to the OWT in selected patients. Consequently, a very short course of therapy results in good patient acceptance. PMID- 26017018 TI - Cracking the nut of service-learning in nursing at a higher educational institution. AB - BACKGROUND: The readiness of academics to engage in the service-learning (SL) institutionalisation process is not accentuated in research on SL institutionalisation in South Africa. The argument has been advanced that SL scholarship and willingness of key stakeholders are crucial for SL institutionalisation at the academic programme level. AIM: The research focus of the study being reported here was on readiness of respondents to embed SL in the curricula of the nursing programme. METHOD: This study used a quantitative, exploratory and descriptive design. A self-administered structured questionnaire was used to collect data from a stratified sample comprising 34 respondents. The data were analysed for descriptive statistics using SPSS 19. RESULTS: The demographic profile of the respondents indicated that 31 (66%) were between 31 and 50 years old; 36 (75.16%) had a minimum of 10 years' nursing experience; 19 (39.6%) had a master's degree, two (4.2%) had a doctorate; and 29 (60.4%) had been employed by the school for a maximum of five years. The results indicated that the nurse educators were in need of SL capacity-building because 9 (18.8%) had limited or no knowledge of SL and 24 (50%) confused SL with other forms of community engagement activities. However, only 15 (33%) of the clinical supervisors and 13 (27%) of the lecturers indicated a willingness to participate in such a programme. CONCLUSION: The school was not ready to embed SL in the academic programme because of a lack of SL scholarship and willingness to remediate the identified theory-practice gaps. PMID- 26017019 TI - Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation. AB - BACKGROUND: Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy. OBJECTIVES: We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT. SEARCH METHODS: We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results. AUTHORS' CONCLUSIONS: There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed. PMID- 26017020 TI - A one-step, modular route to optically-active diphos ligands. AB - A chlorosilane elimination reaction has been developed that allows the efficient synthesis of optically pure C1-symmetric, C1-backboned diphosphines with a wide variety of stereoelectronic characteristics. PMID- 26017021 TI - Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta analysis of observational studies. AB - PURPOSE: Pneumonia is one of the major leading causes of morbidity and mortality among persons aged 65 years or older. Recently, several studies suggested an association between antipsychotic (AP) use and risk of pneumonia in elderly patients. The aim of the present systematic review and meta-analysis of observational studies was to investigate if first-generation and second generation AP drugs increase the risk of pneumonia in the elderly and also in the younger population, and to ascertain the risk associated with exposure to individual drugs. METHODS: All observational cohort or case-control studies that reported data on pneumonia outcomes in individuals exposed to AP drugs as compared with individuals unexposed or with past exposure to AP drugs were included in the systematic review and meta-analysis. Study participants were of either sex and of any age with no restrictions in terms of diagnostic categories. RESULTS: The risk of pneumonia was significantly increased by exposure to first generation AP drugs (odds ratio (OR) 1.68, 95% confidence interval (95%CI) 1.39 2.04, I(2) = 47%) and exposure to second-generation AP drugs (OR 1.98, 95%CI 1.67-2.35, I(2) = 36.7%). The risk was similar among different diagnostic categories and age groups, in elderly and young-adult populations; the finding on age was corroborated by a meta-regression analysis, which did not detect any relationship between age and risk of pneumonia. Only few studies provided data on individual drugs. CONCLUSION: Systematic review of current observational evidence suggests that exposure to first-generation and second-generation AP drugs is associated with an increased risk of pneumonia. The present systematic review expands previous knowledge by showing that the increased risk not only applies to elderly individuals but also to younger patients. The information about the risk of pneumonia for individual compounds is still very limited. PMID- 26017022 TI - A novel role for the condensin II complex in cellular senescence. AB - Although cellular senescence is accompanied by global alterations in genome architecture, how the genome is restructured during the senescent processes is not well understood. Here, we show that the hCAP-H2 subunit of the condensin II complex exists as either a full-length protein or an N-terminus truncated variant (DeltaN). While the full-length hCAP-H2 associates with mitotic chromosomes, the DeltaN variant exists as an insoluble nuclear structure. When overexpressed, both hCAP-H2 isoforms assemble this nuclear architecture and induce senescence associated heterochromatic foci (SAHF). The hCAP-H2DeltaN protein accumulates as cells approach senescence, and hCAP-H2 knockdown inhibits oncogene-induced senescence. This study identifies a novel mechanism whereby condensin drives senescence via nuclear/genomic reorganization. PMID- 26017024 TI - Synthesis and Temperature-Induced Structural Phase and Spin Transitions in Hexadecylboron-Capped Cobalt(II) Hexachloroclathrochelate and Its Diamagnetic Iron(II)-Encapsulating Analogue. AB - Template condensation of dichloroglyoxime with n-hexadecylboronic acid on the corresponding metal ion as a matrix under vigorous reaction conditions afforded n hexadecylboron-capped iron and cobalt(II) hexachloroclathrochelates. The complexes obtained were characterized using elemental analysis, MALDI-TOF mass spectrometry, IR, UV-vis, (1)H and (13)C{(1)H} NMR, (57)Fe Mossbauer spectroscopies, SQUID magnetometry, electron paramagnetic resonance, and cyclic voltammetry (CV) and by X-ray crystallography. The multitemperature single crystal X-ray diffraction, SQUID magnetometry, and differential scanning calorimetry experiments were performed to study the temperature-induced spin crossover [for the paramagnetic cobalt(II) complex] and the crystal-to-crystal phase transitions (for both of these clathrochelates) in the solid state. Analysis of their crystal packing using the molecular Voronoi polyhedra and the Hirshfeld surfaces reveals the structural rearrangements of the apical long-chain alkyl substituents resulting from such phase transitions being more pronounced for a macrobicyclic cobalt(II) complex. Its fine-crystalline sample undergoes the gradual and fully reversible spin transition centered at approximately 225 K. The density functional theory calculated parameters for an isolated molecule of this cobalt(II) hexachloroclathrochelate in its low- and high-spin states were found to be in excellent agreement with the experimental data and allowed to localize the spin density within a macrobicyclic framework. CV of the cobalt(II) complex in the cathodic range contains one reversible wave assigned to the Co(2+/+) redox couple with the reduced anionic cobalt(I)-containing species stabilized by the electronic effect of six strong electron-withdrawing chlorine substituents. The quasireversible character of the Fe(2+/+) wave suggests that the anionic iron(I) containing macrobicyclic species undergo substantial structural changes and side chemical reactions after such metal-centered reduction. PMID- 26017023 TI - Genetic interrelationships of North American populations of giant liver fluke Fascioloides magna. AB - BACKGROUND: Population structure and genetic interrelationships of giant liver fluke Fascioloides magna from all enzootic North American regions were revealed in close relation with geographical distribution of its obligate definitive cervid hosts for the first time. METHODS: Variable fragments of the mitochondrial cytochrome c oxidase subunit I (cox1; 384 bp) and nicotinamide dehydrogenase subunit I (nad1; 405 bp) were applied as a tool. The concatenated data set of both cox1 and nad1 sequences (789 bp) contained 222 sequences that resulted in 50 haplotypes. Genetic data were analysed using Bayesian Inference (BI), Maximum Likelihood (ML) and Analysis of Molecular Variance (AMOVA). RESULTS: Phylogenetic analysis revealed two major clades of F. magna, which separated the parasite into western and eastern populations. Western populations included samples from Rocky Mountain trench (Alberta) and northern Pacific coast (British Columbia and Oregon), whereas, the eastern populations were represented by individuals from the Great Lakes region (Minnesota), Gulf coast, lower Mississippi, and southern Atlantic seaboard region (Mississippi, Louisiana, South Carolina, Georgia, Florida) and northern Quebec and Labrador. Haplotype network and results of AMOVA analysis confirmed explicit genetic separation of western and eastern populations of the parasite that suggests long term historical isolation of F. magna populations. CONCLUSION: The genetic makeup of the parasite's populations correlates with data on historical distribution of its hosts. Based on the mitochondrial data there are no signs of host specificity of F. magna adults towards any definitive host species; the detected haplotypes of giant liver fluke are shared amongst several host species in adjacent populations. PMID- 26017025 TI - Tunable Friction Behavior of Photochromic Fibrillar Surfaces. AB - Grasslike compliant micro/nano crystals made of diarylethene (DAE) photochromic molecules are spontaneously formed on elastomer films after dipping them in a solution containing the photochromic molecules. The frictional forces of such micro- and nanofibrillar surfaces are reversibly tuned upon ultraviolet (UV) irradiation and dark storage cycles. This behavior is attributed to the Young's modulus variation of the single fibrils due to the photoisomerization process of the DAE molecules, as measured by advanced atomic force microscopy (AFM) techniques. In fact, a significant yet reversible decrease of the stiffness of the outer part of the fibrils in response to the UV light irradiation is demonstrated. The modification of the molecular structure of the fibrils influences their mechanical properties and affects the frictional behavior of the overall fibrillar surfaces. These findings provide the possibility to develop a system that controllably and accurately generates both low and high friction forces. PMID- 26017026 TI - Mechanically Robust and Self-Healable Superlattice Nanocomposites by Self Assembly of Single-Component "Sticky" Polymer-Grafted Nanoparticles. AB - A simple, scalable synthesis of mechanically robust and self-healable superlattice nanocomposites is achieved through self-assembly of single-component "sticky" polymer-grafted nanoparticles. The multi-valent hydrogen-bonding interactions between the nanoparticles provide strong cohesive energy, binding the nanoparticles into strong and tough materials. Furthermore, the dynamic hydrogen-bonding interactions afford the formation of highly dynamic, self healing, and mechanochromic nanocomposite materials in the bulk. PMID- 26017027 TI - Investigation of interleukin-12, interleukin-17 and interleukin-23 receptor gene polymorphisms in alopecia areata. AB - OBJECTIVE: To investigate the distribution of interleukin (IL)-12 (IL12; 1188A/C), IL17 (A7488G) and IL-23 receptor (IL23R; +2199A/C) gene polymorphisms in patients with alopecia areata. METHODS: Patients with alopecia areata and healthy controls were enrolled in this case-control study. Genotyping of the IL12 (1188A/C), IL17 (A7488G) and IL23R (+2199A/C) polymorphisms was undertaken. Genotype frequencies were compared between the two groups. RESULTS: The study enrolled 100 patients with alopecia areata and 71 control subjects. No significant differences were found in the frequencies for the IL12 and IL23R gene polymorphisms between the patient and control groups. The IL17 GG genotype was significantly more common and the IL17 GA genotype was significantly less common in patients with alopecia areata compared with controls, but only 10% of patients had the GG genotype. CONCLUSION: The IL17 GG genotype was associated with susceptibility for alopecia areata, but this genotype was only present in a small number of patients. The IL12 and IL23R gene polymorphisms were not found to have a significant association with alopecia areata. PMID- 26017028 TI - Differential Expression of Cell Cycle Regulators During Hyperplastic and Hypertrophic Growth of Broiler Subcutaneous Adipose Tissue. AB - Hyperplastic growth and hypertrophic growth within adipose tissue is tightly associated with cell cycle activity. In this study, CCNG2 and CDKN2C were found to be correlated with cell cycle inhibition during fat cell differentiation, whereas CCND3, CCNA1, and ANAPC5 were positively associated with cell cycle activity during fat cell proliferation after selection based on GEO datasets available on the NCBI website. The findings were validated through comparison of expressions of these genes among different tissues/fractions in broiler chickens and time points during primary cell culture using quantitative real-time PCR. Development of broiler subcutaneous adipose tissue was investigated on embryonic days 15 and 17 and on post-hatch days 0, 5, 11, and 33 using H&E staining and PCNA immunostaining with DAPI counter stain. In addition, mRNA expressions of five cell cycle regulators as well as precursor cell and adipocyte markers were measured at those time points. The results suggest that cellular proliferation activity decreased as the fat pad grows, but a population of precursor cells seemed to be maintained until post-hatch day 5 despite increasing differentiation activity. Hypertrophic growth gradually intensified despite a slight cessation on post-hatch day 0 due to increased energy expenditure during hatching and delayed food access. From post-hatch day 5 to day 11, most of the precursor cells may become differentiated. After post-hatch day 11, hyperplastic growth seemed to slow, while hypertrophic growth may become dominant. This study provides further understanding about broiler fat tissue development which is imperative for effective control of fat deposition. PMID- 26017029 TI - Structural Characterization of Neutral Glycosphingolipids from 3T3-L1 Adipocytes. AB - In recent years, obesity has been considered a pathological stage of early lifestyle-related diseases, and adipose tissue and adipocyte research has been active. Glycosphingolipids are involved in the pathogenesis of type 2 diabetes induced by insulin resistance, but the details of the glycosphingolipid molecular species composition of adipocytes have yet to be elucidated. We used 3T3-L1 adipocytes and the 1,2-dichloroethane-wash method to remove triacylglycerols, which are abundant in adipocytes, and analyzed the structures of glycosphingolipids, particularly neutral glycosphingolipids, using liquid chromatography-mass spectrometry. PMID- 26017030 TI - Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis. AB - Acquired alpha-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients. PMID- 26017031 TI - Genetic variant near TERC influencing the risk of gliomas with older age at diagnosis in a Chinese population. AB - A recent genome-wide association study has identified an association between rs1920116 near TERC and high-grade glioma in populations of European ancestry. In order to evaluate the effect of the SNP rs1920116 near TERC in the Chinese population, we examined associations of this candidate SNP with glioma in a sample of 1970 Chinese Han individuals. SNP genotype data were available for 980 Chinese glioma patients and 990 healthy controls. Logistic regression analyses were performed to evaluate the association between rs1920116 and glioma risk adjusted for age, gender and stratified by tumor grade where appropriate. The allele G at TERC rs1920116 are risk factors for gliomas, and its association with glioma risk was consistent across tumor subgroups in the Chinese Han population (OR = 1.18-1.21). In order to assess variation in SNP effect size at different patient ages, glioma cases and controls were divided into 3 age strata, in years: <50, 50-59, and 60+. The results of multiple logistic regression analyses indicate that the SNP has age-specific effects on the risk of developing glioma. Our report confirmed the effects of rs1920116 near TERC on glioma occurring in older peoples in the Chinese Han population for the first time. As TERC is a candidate for inter-individual variation in telomere length, our study supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life. PMID- 26017035 TI - The horseshoe kidney. PMID- 26017033 TI - Protracted dormancy of pre-leukemic stem cells. AB - Cancer stem cells can escape therapeutic killing by adopting a quiescent or dormant state. The reversibility of this condition provides the potential for later recurrence or relapse, potentially many years later. We describe the genomics of a rare case of childhood BCR-ABL1-positive, B-cell precursor acute lymphoblastic leukemia that relapsed, with an acute myeloblastic leukemia immunophenotype, 22 years after the initial diagnosis, sustained remission and presumed cure. The primary and relapsed leukemias shared the identical BCR-ABL1 fusion genomic sequence and two identical immunoglobulin gene rearrangements, indicating that the relapse was a derivative of the founding clone. All other mutational changes (single-nucleotide variant and copy number alterations) were distinct in diagnostic or relapse samples. These data provide unambiguous evidence that leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent but potentially reactivatable for more than two decades. PMID- 26017034 TI - P-Glycoprotein-Mediated Drug Interactions in Pregnancy and Changes in the Risk of Congenital Anomalies: A Case-Reference Study. AB - INTRODUCTION: Drug use in pregnancy is very common but may cause harm to the fetus. The teratogenic effect of a drug is partly dependent on the drug level in the fetal circulation, which is associated with the transport across the placenta. Many drugs are substrates of P-glycoprotein (P-gp), an efflux transporter that acts as a protective barrier for the fetus. We aim to identify whether drug interactions associated with P-gp promote any changes in fetal drug exposure, as measured by the risk of having children with congenital anomalies. METHODS: In this study, cases (N = 4634) were mothers of children with congenital anomalies registered in the EUROCAT Northern Netherlands registry, and the reference population were mothers of children (N = 25,126) from a drug prescription database (IADB.nl). RESULTS: Drugs that are associated with P-gp transport were commonly used in pregnancy in cases (10 %) and population (12 %). Several drug classes, which are substrates for P-gp, were shown to have a higher user rate in mothers of cases with specific anomalies. The use of this subset of drugs in combination with other P-gp substrates increased the risk for specific anomalies (odds ratio [OR] 4.17, 95 % CI 1.75-9.91), and the addition of inhibitors further increased the risk (OR 13.03, 95 % CI 3.37-50.42). The same pattern of risk increment was observed when the drugs were analyzed separately according to substrate specificity. CONCLUSIONS: The use of drugs associated with P-gp transport was common during pregnancy. For several drug classes associated with specific anomalies, P-gp-mediated drug interactions are associated with an increased risk for those specific anomalies. PMID- 26017032 TI - Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98 HOXA9-induced myeloid disease. AB - Acute myeloid leukemia (AML) occurs when multiple genetic aberrations alter white blood cell development, leading to hyperproliferation and arrest of cell differentiation. Pertinent animal models link in vitro studies with the use of new agents in clinical trials. We generated a transgenic zebrafish expressing human NUP98-HOXA9 (NHA9), a fusion oncogene found in high-risk AML. Embryos developed a preleukemic state with anemia and myeloid cell expansion, and adult fish developed a myeloproliferative neoplasm (MPN). We leveraged this model to show that NHA9 increases the number of hematopoietic stem cells, and that oncogenic function of NHA9 depends on downstream activation of meis1, the PTGS/COX pathway and genome hypermethylation through the DNA methyltransferase, dnmt1. We restored normal hematopoiesis in NHA9 embryos with knockdown of meis1 or dnmt1, as well as pharmacologic treatment with DNA (cytosine-5) methyltransferase (DNMT) inhibitors or cyclo-oxygenase (COX) inhibitors. DNMT inhibitors reduced genome methylation to near normal levels. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of a histone deacetylase inhibitor plus either a DNMT inhibitor or COX inhibitor to block the effects of NHA9 on zebrafish blood development. Our work proposes novel drug targets in NHA9-induced myeloid disease, and suggests rational therapies by combining minimal doses of known bioactive compounds. PMID- 26017036 TI - Imaging of tailgut cysts. AB - Tailgut cysts are congenital lesions that arise from the primitive hindgut in the true embryonic tail but fail to regress during gestation. These lesions are rare and more frequently encountered later in life and more commonly in women, and are the most common primary retrorectal tumor. Tailgut cysts may be asymptomatic or cause rectal bleeding, pain, or symptoms related to mass effect on the rectum or bladder. Pathologically, tailgut cysts are typically multilocular, lined with a variety of epithelial cell types, and are most frequently benign. Imaging is the linchpin of diagnosis due risks associated with biopsy. The purpose of this pictorial review is to present the spectrum of imaging findings associated with tailgut cysts on CT and MRI with focus on the use of advanced MRI and diffusion weighted imaging. We present case examples of tailgut cysts, their CT and MR imaging findings, and diagnostic and management considerations. PMID- 26017037 TI - Unravelling of a mechanism of resistance to colistin in Klebsiella pneumoniae using atomic force microscopy. AB - OBJECTIVES: In this study we focused on the mechanism of colistin resistance in Klebsiella pneumoniae. METHODS: We used two strains of K. pneumoniae: a colistin susceptible strain (K. pneumoniae ATCC 700603, KpATCC) and its colistin-resistant derivative (KpATCCm, MIC of colistin 16 mg/L). We performed a genotypic analysis based on the expression of genes involved in LPS synthesis and L-Ara4N moiety addition. We also explored the status of the mgrB gene. Then, a phenotypic analysis was performed using atomic force microscopy (AFM). The Young modulus was extracted from force curves fitted using the Hertz model, and stiffness values were extracted from force curves fitted using the Hooke model. RESULTS: We failed to observe any variation in the expression of genes implicated in LPS synthesis or L-Ara4N moiety addition in KpATCCm, in the absence of colistin or under colistin pressure (versus KpATCC). This led us to identify an insertional inactivation/mutation in the mgrB gene of KpATCCm. In addition, morphology results obtained by AFM showed that colistin removed the capsule from the susceptible strain, but not from the resistant strain. Nanomechanical data on the resistant strain showed that colistin increased the Young modulus of the capsule. Extend force curves recorded on top of the cells allowed us to make the following hypothesis about the nanoarchitecture of the capsule of the two strains: KpATCC has a soft capsule consisting of one layer, whereas the KpATCCm capsule is harder and organized in several layers. CONCLUSIONS: We hypothesize that capsular polysaccharides might be implicated in the mechanism of colistin resistance in K. pneumoniae, depending on its genotype. PMID- 26017038 TI - Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations. AB - OBJECTIVES: The objective of this study was to characterize the underlying molecular mechanisms in consecutive clinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance. METHODS: Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7, P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes were analysed by sequencing (including FKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR (CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulence was determined in the insect model Galleria mellonella and evaluated by log-rank Mantel-Cox tests. RESULTS: P-1 + P-2 were susceptible, P-3 + P-4 fluconazole resistant, P-5 pan-azole resistant, P-6 + P-7 pan-azole and echinocandin resistant and P-8 + P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4 harboured four changes in Erg11 (E266D, G307S, G450E and V488I), increased expression of ERG11 and CDR2 and a change in Tac1 (R688Q). P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression of CDR1, CDR2 and ERG11 (except for P-7) and a different amino acid change in Tac1 (R673L). Echinocandin-resistant isolates harboured the Fks1 S645P alteration. Polyene-resistant P-8 + P-9 lacked ergosterol and harboured a frameshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates, but higher than in the azole- and echinocandin-resistant unrelated control strain. CONCLUSIONS: C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novel resistance-inducing mutations in TAC1, ERG11 and ERG2 require independent validation. PMID- 26017039 TI - Next-generation sequencing offers new insights into the resistance of Candida spp. to echinocandins and azoles. AB - OBJECTIVES: MDR Candida strains are emerging. Next-generation sequencing (NGS), which enables extensive and deep genome analysis, was used to investigate echinocandin and azole resistance in clinical Candida isolates. METHODS: Six genes commonly involved in antifungal resistance (ERG11, ERG3, TAC1, CgPDR1, FKS1 and FKS2) were analysed using NGS in 40 Candida isolates (18 Candida albicans, 15 Candida glabrata and 7 Candida parapsilosis). The strategy was validated using strains with known sequences. Then, 8 clinical strains displaying antifungal resistance and 23 sequential isolates collected from 10 patients receiving antifungal therapy were analysed. RESULTS: A total of 391 SNPs were detected, among which 6 coding SNPs were reported for the first time. Novel genetic alterations were detected in both azole and echinocandin resistance genes. A C. glabrata strain, which was resistant to echinocandins but highly susceptible to azoles, harboured an FKS2 S663P mutation plus a novel presumed loss-of-function CgPDR1 mutation. This isolate was from a patient with deep-seated and urinary candidiasis. Another C. glabrata isolate, with an MDR phenotype, carried a new FKS2 S663A mutation and a new putative gain-of-function CgPDR1 mutation (T370I); this isolate showed mutated (80%) and WT (20%) populations and was collected after 75 days of exposure to caspofungin from a patient who underwent complicated abdominal surgery. CONCLUSIONS: This study shows that NGS can be used for extensive assessment of genetic mutations involved in antifungal resistance. This type of wide genome approach will become very valuable for detecting mechanisms of resistance in clinical strains subjected to multidrug pressure. PMID- 26017040 TI - The complete mitochondrial genome sequence of Pterophyllum scalare (Cichliformes: Cichlidae). AB - Pterophyllum scalare belongs in the family Cichlidae of Cichliformes. This species and its congeners are characterized by a compressed and disc-shaped body with dorsal and anal spiny rays increasing in length from anterior to posterior part of the fin. In this study, we determine and describe the complete mitogenome sequence of Pterophyllum scalare for the first time, which is 16,494 bp in length, and contains 37 genes, including 13 protein-coding genes, 2 rRNAs, 22 tRNAs, 1 origin of replication on the light-strand (OL) and a putative control region. The overall base composition is 27.5% A, 26.8% T, 30.1% C and 15.6% G, with a slight AT bias (54.3%). All protein-coding genes share the start codon ATG, except for COI that begins with GTG. These results are expected to provide useful molecular data for phylogenetic studies of Cichlidae and Cichliformes. Maximum Likelihood (ML) tree and Bayesian analyses based on partitioned nucleotide sequences of 12 mitochondrial protein-coding genes were constructed and both yielded trees with identical topologies. PMID- 26017041 TI - The complete mitochondrial genome of the Amur rat-snake Elaphe schrenckii (Squamata: Colubridae). AB - In this study, the whole mitochondrial genome of Elaphe schrenckii (Squamata: Colubridae) is first sequenced. It is a circular molecule of 17,165 bp in size and consists of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and 2 control regions (CRI and CRII). Except for eight tRNAs and ND6 gene, all other mitochondrial genes were encoded on the heavy strand (H strand). The gene order and orientation of E. schrenckii mitogenome are basically identical to that of other alethinophidian snakes. Mitochondrial genome analyses based on MP, ML and NJ yielded identical phylogenetic trees, indicating a close phylogenetic affinity of 12 species of Colubridae snakes. This study will facilitate the further research of the population genetics of this species and systematic analyses of the genus Elaphe. PMID- 26017042 TI - Mitochondrial intergenic COII/tRNA(Lys) 9-bp deletion, a biomarker for hepatocellular carcinoma? AB - The COII/tRNA(Lys) intergenic 9-bp deletion is one of the most commonly studied human mitochondrial DNA (mtDNA) polymorphisms. It consists of the loss of one of two tandemly repeated copies of the sequence CCCCCTCTA from a non-coding region located between cytochrome oxidase II (COII) and tRNA(Lys) gene. Most recently, case-control studies have shown a positive association between this deletion with hepatocellular cancer. In this study, we first performed a detailed analysis between this deletion and clinical diseases; moreover, we took the phylogenetic approach to examine the pathogenicity status of 9-bp deletion. PMID- 26017043 TI - The complete mitochondrial genome of the orb-weaver spider Cyclosa argenteoalba Boes. et Str. (Araneae: Araneidae). AB - The complete mitochondrial genome of an orb-weaver spider Cyclosa argenteoalba is determined in this article. The genome encodes the same 37 genes with a length of 14,575 bp as all other metazoan mitogenomes. The A + T content of the majority strand is 73.1%. Among the protein-coding genes, one gene (COI) begins with TTA, three (COII, COIII and ND6) start with ATT, three (ATP6, ND3 and ND4) begin with ATA and other six genes use ATT as initiation codon. All the protein-coding genes end with the canonical termination codons (TAA or TAG), except for ND3 and ND4L, which use an incomplete stop codon (T). Thirteen transfer RNAs genes lack the potential to form the cloverleaf-shaped secondary structure. The A + T-rich region is 1052 bp in length with an A + T content of 68.9%. In the phylogenetic analyses, C. argenteoalba was nested within Araneidae and the species from the superfamily Araneoidea form a momophyletic group. PMID- 26017044 TI - Complete mitochondrial genome organization of Tor tor (Hamilton, 1822). AB - The complete mitochondrial genome of Tor tor, a threatened "Mahseer" was sequenced for the first time. The mitochondrial genome size determined to be 16,554 bp in length and consisted of 13 protein-coding genes (PCGs), 22 tRNAs, 2 rRNA genes and a control region or displacement loop (D-Loop) region, resembling the typical organizational pattern of most of the teleost. The overall base composition found was A: 31.8%, T: 25%, G: 15.7% and C: 27.4%; A + T: 56.9% and G + C: 43.1%. The phylogenetic tree constructed using 11 other cyprinids' total mtDNA datasets confirmed the location of present species among mahseers. The total sequence data could support further study in molecular systematics, species identification, evolutionary and conservation genetics. PMID- 26017045 TI - The mitochondrial genome of Gnathopogon imberbis (Cypriniformes, Cyprinidae). AB - In the present study, the complete mitogenome sequence of Gnathopogon imberbis is determined using PCR amplification and DNA sequencing, which contains 13 protein coding genes, 22 tRNA genes, 2 rRNA genes and a non-coding control region with the total length of 16,598 bp. Except for eight tRNA and ND6 genes, all other mitochondrial genes are encoded on the H-strand. The codon usage followed the typical vertebrate mitochondrial pattern (ATG or GTG for start codon and TAA or TAG for stop codon). The overall nucleotide composition was 30.0% A, 27.0% T, 25.8% C and 17.2% G, with an A + T bias of 57.0%. The complete mitochondrial genome sequence will be useful for phylogenetic analysis and studies of population genetics of G. imberbis. PMID- 26017046 TI - DNA barcoding Satyrine butterflies (Lepidoptera: Nymphalidae) in China. AB - We investigated the effectiveness of the standard 648 bp mitochondrial COI barcode region in discriminating among Satyrine species from China. A total of 214 COI sequences were obtained from 90 species, including 34 species that have never been barcoded. Analyses of genetic divergence show that the mean interspecific genetic divergence is about 16-fold higher than within species, and little overlap occurs between them. Neighbour-joining (NJ) analyses showed that 48 of the 50 species with two or more individuals, including two cases with deep intraspecific divergence (>3%), are monophyletic. Furthermore, when our sequences are combined with the conspecific sequences sampled from distantly geographic regions, the "barcoding gap" still exists, and all related species are recovered to be monophyletic in NJ analysis. Our study demonstrates that COI barcoding is effective in discriminating among the satyrine species of China, and provides a reference library for their future molecular identification. PMID- 26017047 TI - The complete mitochondrial genome of Meriones libycus (Rodentia: Cricetidae) and its phylogenetic analysis. AB - Meriones libycus belongs to the genus Meriones in Gerbillinae, its complete mitochondrial genome is 16,341 bp in length. The heavy strand contains 32.8% A, 13.1% G, 25.3% C, 28.8% T, protein-coding genes approximately accounting for 69.54%. Results of phylogenetic analysis showed that M. libycus and Meriones unguiculatus were clustered together, and it was consistent with that of primary morphological taxonomy. This study verifies the evolutionary status of M. libycus in Meriones at the molecular level. The mitochondrial genome would be a significant supplement for the gene pool of Rodentia and the conclusion of phylogenetic analysis could be an important molecular evidence for the classification of Gerbillinae. PMID- 26017048 TI - The chloroplast genome sequence of an important medicinal plant Dioscorea nipponica. AB - Dioscorea nipponica is an important medicinal plant belonging to Dioscoreaceae, a family which is vital for the evolution of monocotyledon. In the present study, the nucleotide sequence of the D. nipponica chloroplast genome was determined. It was an AT-rich (63.3%) chloroplast genome with 152,946 bp in length, containing a pair of 23,113 bp inverted repeats, which were separated by a large and a small single copy region of 83,557 bp and 23,064 bp in length, respectively. It encodes 120 unique genes, including 89 protein-coding genes, 27 tRNA genes and 4 rRNA genes. The predicted gene-coding regions covered 58.7% of the genome sequences. Ten genes contained one intron, while two genes had two introns. Phylogenetic analyses showed the present chloroplast genome can be used as a potential supper barcode to distinguish D. nipponica from its closely related species. Furthermore, the chloroplast genome provides a molecular base for the next investigation on this important medicinal species. PMID- 26017049 TI - Complete mitochondrial genome of the Trichogaster microlepis (Anabantoidei: Osphronemidae). AB - The complete mitochondrial genome of Trichogaster microlepis was determined in this study. It is 16,435 bp in size and consists of 2 rRNA genes, 13 protein coding genes, 22 tRNA genes and a non-coding control region (D-loop). The overall base composition of the heavy strand of the T. microlepis mitochondrial genome is A: 29.50%, T: 28.38%, C: 26.62%, and G: 15.49%. The total length of the 13 protein-coding genes was 11,427 bp. This study provides an important data set for the phylogenetic and taxonomic analyses of the Trichogaster species. PMID- 26017050 TI - Complete mitochondrial genome sequences of Atlantic sturgeon, Acipenser oxyrinchus oxyrinchus, Gulf sturgeon, A. o. desotoi and European sturgeon A. sturio (Acipenseriformes: Acipenseridae) obtained through next generation sequencing. AB - Complete mitochondrial genome sequences of European sturgeon and two subspecies of the North American, Atlantic and Gulf sturgeons were determined using MiSeq Illumina technology. All three genomes show typical vertebrate organization. They possess 22 tRNA genes, 13 protein-coding genes, 2 rRNA (ribosomal RNA) genes and a non-coding control region. Excluding ND6, all protein-coding genes are on the heavy strand. The whole mitogenome sequences have been deposited in GenBank under accession numbers KP997216-KP997218. PMID- 26017051 TI - Group cognitive analytic therapy for female survivors of childhood sexual abuse. AB - OBJECTIVES: The effectiveness of cognitive analytic therapy delivered in groups has been under-researched considering the popularity of the approach. This study sought to investigate the effectiveness of 24 sessions of group cognitive analytic therapy (GCAT) delivered in routine practice for female survivors of childhood sexual abuse (CSA). METHODS: In a longitudinal cohort design, N = 157 patients were treated with 24 sessions of GCAT. Validated outcome measures were administered at assessment, pre-GCAT, and post-GCAT. This enabled rates of reliable and clinically significant change to be compared between wait time and active group treatment. The uncontrolled treatment effect size was then benchmarked against outcomes from matched studies. RESULTS: On the primary outcome measure, GCAT facilitated a moderate effect size of 0.34 with 11% of patients completing treatment meeting 'recovery' criteria. The dropout rate was 19%. Significant improvements in interpersonal functioning, anxiety, and well being occurred during GCAT in comparison with wait time on secondary outcome measures. CONCLUSIONS: Group cognitive analytic therapy appears a promising intervention for adult female CSA survivors, with further controlled evaluation indicated. PRACTITIONER POINTS: Group cognitive analytic therapy appears a promising and acceptable intervention for female CSA survivors experiencing high levels of psychological distress. Long-term follow-up studies are required with CSA survivors to index the clinical durability of GCAT. A GCAT treatment fidelity measure needs to be developed and evaluated. PMID- 26017052 TI - Dynamic cerebral autoregulation to induced blood pressure changes in human experimental and clinical sepsis. AB - Previous studies have demonstrated that dynamic cerebral autoregulation to spontaneous fluctuations in blood pressure is enhanced following lipopolysaccharide (LPS) infusion, a human experimental model of early sepsis, whereas by contrast it is impaired in patients with severe sepsis or septic shock. In this study, we hypothesized that this pattern of response would be identical during induced changes in blood pressure. Dynamic cerebral autoregulation was assessed in nine healthy volunteers and six septic patients. The healthy volunteers underwent a 4-h intravenous infusion of LPS (total dose: 2 ng kg-1 ). Mean arterial blood pressure (MAP, arterial transducer) and middle cerebral artery blood flow velocity (MCAv, transcranial Doppler ultrasound) were recorded continuously during thigh-cuff deflation-induced changes in MAP for the determination of a modified rate of regulation (RoR). This was performed before and after LPS infusion in healthy volunteers, and within 72 h following clinical diagnosis of sepsis in patients. In healthy volunteers, thigh-cuff deflation caused a MAP reduction of 16 (13-20) % at baseline and 18 (16-20) % after LPS, while the MAP reduction was 12 (11-13) % in patients (P<0.05 versus volunteers at baseline; P<0.01 versus volunteers after LPS). The corresponding RoR values increased from 0.46 (0.31-0.49) s-1 at baseline to 0.58 (0.36-0.74) s-1 after LPS (P<0.05) in healthy volunteers, whereas they were similar to values observed in patients [0.43 (0.36-0.52) s-1 ; P = 0.91 versus baseline; P = 0.14 versus LPS]. While our findings support the concept that dynamic cerebral autoregulation is enhanced during the very early stages of sepsis, they remain inconclusive with regard to more advanced stages of disease, because thigh-cuff deflation failed to induce sufficient MAP reductions in patients. PMID- 26017054 TI - Photocatalytic decomposition of graphene over a ZnO surface under UV irradiation. AB - Highly reactive radicals or chemicals are generated on the surfaces of oxide semiconductors via reactions between photo-induced charges and ambient gas molecules. These radicals or chemicals have been utilized in heterogeneous photosynthesis and photocatalysis. In this study, we demonstrated that the photocatalytic reactions on the surface of ZnO promoted the oxidation and decomposition of graphene. Raman spectra were used to analyze the evolution of the G and 2D peaks. The oxidation of graphene on a ZnO substrate by UV radiation was faster than that in the absence of ZnO. During oxidation, the resistivity and the transmittance of graphene also increased. The XPS results showed that functional groups related to the oxidation of graphene were formed during the photocatalytic reactions. This simple and clean approach will be also effective for selective surface modification by enhancing the surface chemical reactions that pattern graphene via oxidation. PMID- 26017055 TI - An 'all pigment' model of excitation quenching in LHCII. AB - The rapid, photoprotective down-regulation of plant light-harvesting in bright light proceeds via the non-photochemical quenching of chlorophyll excitation energy in the major photosystem II light-harvesting complex LHCII. However, there is currently no consensus regarding the precise mechanism by which excess energy is quenched. Current X-ray structures of this complex correspond to a dissipative conformation and therefore correct microscopic theoretical modelling should capture this property. Despite their accuracy in explaining the steady state spectroscopy of this complex, chlorophyll-only models (those that neglect the energetic role of carotenoids) do not explain the observed fluorescence quenching. To address this gap, we have used a combination of the semi-empirical MNDO-CAS-CI and the Transition Density Cube method to model all chlorophyll carotenoid energy transfer pathways in the highly quenched LHCII X-ray structure. Our simulations reveal that the inclusion of carotenoids in this microscopic model results in profound excitation quenching, reducing the predicted excitation lifetime of the complex from 4 ns (chlorophyll-only) to 67 ps. The model indicates that energy dissipation proceeds via slow excitation transfer (>20 ps) from chlorophyll to the forbidden S1 excited state of the centrally bound lutein molecules followed by the rapid (~10 ps) radiationless decay to the ground state, with the latter being assumed from experimental measurements of carotenoid excited state lifetimes. Violaxanthin and neoxanthin do not contribute to this quenching. This work presents the first all-pigment microscopic model of LHCII and the first attempt to capture the dissipative character of the known structure. PMID- 26017053 TI - A Taxonomic Revision of the Wallemia sebi Species Complex. AB - Wallemia sebi is a xerophilic food- and air-borne fungus. The name has been used for strains that prevail in cold, temperate and tropical climates. In this study, multi-locus phylogenetic analyses, using the internal transcribed spacer (ITS) regions, DNA replication licensing factor (MCM7), pre-rRNA processing protein (TSR1), RNA polymerase II largest subunit (RPB1), RNA polymerase II second largest subunit (RPB2) and a new marker 3'-phosphoadenosine-5'-phosphatase (HAL2), confirmed the previous hypothesis that W. sebi presents a complex of at least four species. Here, we confirm and apply the phylogenetic analyses based species hypotheses from a companion study to guide phenotypic assessment of W. sebi like strains from a wide range of substrates, climates and continents allowed the recognition of W. sebi sensu stricto and three new species described as W. mellicola, W. Canadensis, and W. tropicalis. The species differ in their conidial size, xerotolerance, halotolerance, chaotolerance, growth temperature regimes, extracellular enzyme activity profiles, and secondary metabolite patterns. A key to all currently accepted Wallemia species is provided that allow their identification on the basis of physiological, micromorphological and culture characters. PMID- 26017056 TI - Influence of socio-economic status on access to different components of SCI management across Indian population. AB - OBJECTIVES: To assess the influence of financial constraints on access to different components of spinal cord injury (SCI) management in various socio economic strata of the Indian population. SETTING: Indian Spinal Injuries Centre (ISIC). METHODS: One hundred fifty SCI individuals who came for follow-up at ISIC between March 2009 and March 2013 with at least 1 year of community exposure after discharge were included in the study. Socio-economic classification was carried out according to the Kuppuswamy scale, a standard scale for the Indian population. A self-designed questionnaire was administered. RESULTS: No sample was available from the lower group. There was a statistically significant difference (P<0.05) for the levels of difficulty perceived by different socio economic groups in accessing different components of SCI management. Aided upper lower group was dependent on welfare schemes for in-hospital treatment but could not access other components of management once discharged. Unaided upper lower group either faced severe difficulty or could not access management. Majority of lower middle group faced severe difficulty. Upper middle group was equally divided into facing severe, moderate or no difficulty. Most patients in the upper group faced no difficulty, whereas some faced moderate and a small number of severe difficulty. CONCLUSION: Financial constraints affected all components of SCI management in all except the upper group. The results of the survey suggest that a very large percentage of the Indian population would find it difficult to access comprehensive SCI management and advocate extension of essential medical coverage to unaided upper lower, lower middle and upper middle groups. PMID- 26017057 TI - Intraoperative Fluorescence Imaging for Sentinel Lymph Node Detection: Prospective Clinical Trial to Compare the Usefulness of Indocyanine Green vs Technetium Tc 99m for Identification of Sentinel Lymph Nodes. AB - IMPORTANCE: The metastatic status of regional lymph nodes is the most relevant prognostic factor in breast cancer, melanoma, and other solid organ tumors with a lymphatic spread. The current gold standard for detection and targeted excision of the sentinel lymph node is preoperative lymphoscintigraphy with technetium Tc 99m. Because of the worldwide shortage of technetium Tc 99m, physicians are looking for nonradioactive dyes for sentinel lymph node labeling. Based on several retrospective studies, the fluorescent dye indocyanine green is considered a possible alternative to technetium Tc 99m. OBJECTIVE: To analyze the feasibility and clinical benefit of intraoperative near infrared fluorescence sentinel lymph node excision (SLNE) compared with standard technetium Tc 99m guided SLNE using malignant melanoma in which SLNE is firmly established. DESIGN, SETTING, AND PARTICIPANTS: Analysis of a prospective clinical trial at the Skin Cancer Center, University Hospital Essen. Eighty patients with malignant melanoma on the trunk or extremities (upper and lower) who were scheduled to undergo SLNE were included in this study from January 1, 2013, to June 27, 2014. MAIN OUTCOMES AND MEASURES: Concordance of preoperative and intraoperative sentinel lymph node detection rates. RESULTS: During the study period, 80 patients were operated on with an additional intraoperative application of a near infrared fluorescent dye. In these 80 surgical procedures, 147 SLNs were excised. Detection of a technetium Tc 99m-marked SLN before surgery was possible in all cases. Intraoperative visualization of the SLN by indocyanine green before skin incision was successful in only 17 of 80 patients (21%). The number of SLNs identified using the near infrared fluorescence technique in the operative site after skin incision and initial tissue preparation was 141 of 147 (96%). CONCLUSIONS AND RELEVANCE: Among patients in whom the lymph node basin cannot be predicted correctly (eg, in cutaneous melanoma on the trunk), the use of indocyanine green for SLN detection is severely limited compared with SLNE using standard technique guided by technetium Tc 99m. Therefore, SLNE with the use of radiocolloid, followed if possible by single-photon emission computed tomography, remains the gold standard. TRIAL REGISTRATION: German Clinical Trials Register identifier DRKS00004619. PMID- 26017058 TI - The Benefits of Following Your Pride: Authentic Pride Promotes Achievement. AB - Although the emotion authentic pride has been posited to promote achievement, it remains unclear precisely how this works. Here, we tested whether authentic pride promotes adaptive downstream achievement outcomes by motivating individuals to engage in appropriate behavioral responses to success and failure. In two longitudinal studies (N = 1,132), we measured pride emotional responses to a prior performance and subsequent changes in achievement-oriented behavior and performance outcomes among (a) adults training for long-distance running races and (b) undergraduates completing class exams. Authentic pride shifted in direct response to achievement outcomes, such that those who performed well felt greater pride. Furthermore, individuals who felt low authentic pride responded to these feelings by changing their achievement behavior in a functional manner. In Studies 2a, 2b, and 2c, we found that pride-driven behavioral changes led to improved future performance among low performers. In these studies we also demonstrated that the effect of authentic pride on achievement is independent of that of self-efficacy, which in fact works in an opposite manner. Taken together, these results suggest that authentic pride functions as a barometer of achievement, promoting behavioral responses that lead to improved performance. PMID- 26017059 TI - Malignant Peripheral Nerve Sheath Tumor of the Lower Eyelid: Case Presentation and Literature Review. AB - Solitary benign neurogenic tumors are common in the orbit, but only rarely arise from peripheral nerves in the eyelids. In contrast, malignant tumors of neural or nerve sheath elements are exceedingly rare in the orbit and, to date, have never been reported in the lower eyelid. The authors report a 55-year-old man with multiple recurrent lower eyelid masses initially treated as chalazia then misdiagnosed as neurotropic malignant melanoma on pathology. Diagnosis of malignant peripheral nerve sheath tumor was ultimately confirmed histopathologically after surgical resection. The patient has since undergone multiple resections and adjuvant radiotherapy. Twenty-two months since the last procedure, the patient remains disease-free. PMID- 26017060 TI - "Low Fat" Spindle Cell Lipoma of the Eyelid: A Diagnostic Challenge. AB - The authors describe a spindle cell lipoma that occurred in the anterior lamellae of the eyelid in a 47-year-old man. This benign tumor was reported previously only once within that location and poses histologic challenges when a "low fat" or "fat free" variant is present. PMID- 26017061 TI - Mammalian target of rapamycin overexpression antagonizes chronic hypoxia triggered pulmonary arterial hypertension via the autophagic pathway. AB - Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disorder with high morbidity and mortality, and is characterized by excessive growth of endothelial cells. Recently, the mammalian target of rapamycin (mTOR) has attracted increasing attention due to its potential as a therapeutic target against certain diseases associated with proliferative and metabolic abnormalities. However, the effect on mTOR on PAH has not yet been elucidated. In the present study, a marked downregulation of mTOR was observed in PAH patients. Following construction of a mouse model of PAH by chronic exposure to hypoxia, adenovirus-mediated upregulation of mTOR significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy and wall thickness of pulmonary arterioles, indicating a protective effect of mTOR on PAH. Further analysis confirmed that mTOR overexpression inhibited autophagy triggered by hypoxia through blocking light chain 3 II expression and increasing p62 levels. In vitro, hypoxia enhanced the proliferation of human pulmonary artery endothelial cells (PAECs), which was markedly abrogated by mTOR overexpression. Of note, upregulation of mTOR inhibited the hypoxia-induced autophagy pathway, which contributed to cell proliferation, while silencing of autophagy by RNA interference with ATG5 significantly inhibited cell proliferation. In conclusion, the results of the present study suggested a potential protective effect of mTOR on the progression of PAH by suppressing PAEC proliferation through blocking the autophagic pathway. Therefore, the present study suggested that mTOR is a promising therapeutic agent against PAH. PMID- 26017062 TI - Most people with insurance from US exchanges are satisfied with coverage, survey finds. PMID- 26017063 TI - Cats and Toxoplasma gondii: A systematic review and meta-analysis in Iran. AB - Toxoplasma gondii is a cosmopolitan zoonotic intracellular coccidian of the phylum Apicomplexa infecting warm-blooded animals and human beings. This protozoan causes a significant public health problem in humans and imposes considerable economic losses and damages to husbandry industries. The final host, cats, accounts for all of these significant burdens. Hence the present study was designed to analyse and review the overall prevalence rate of T. gondii infection in cats in Iran for the first time. In the present study data collection (published and unpublished papers, abstracts of proceedings of national parasitology congresses and dissertations) was systematically undertaken on electronic databases including PubMed, Google Scholar, Ebsco, Science Direct, Scopus, Magiran, Irandoc, IranMedex and Scientific Information Database. A total of 21 studies from 1975 to 2013 reporting prevalence of Toxoplasma infection in cats from different areas in Iran met the eligibility criteria. The pooled proportion of toxoplasmosis using the random-effect model amongst cats was estimated at 33.6% (95% confidence interval [CI] 22.05-46.41). The prevalence rate of cat toxoplasmosis in various regions of Iran ranged from 1.2% to 89.2%. Firstly, this study establishes a crude prevalence rate of T. gondii infection in cats. Secondly, it discusses the role of significant risk factors including sex, age and being either household or stray cats, in the epidemiology of the disease. Furthermore, the current study determines gaps and drawbacks in the prior studies that are useful to keep in mind to assist in designing more accurate investigations in future. PMID- 26017064 TI - Long-Term Clinical Outcomes of Medical Therapy for Coronary Chronic Total Occlusions in Elderly Patients (>=75 Years). AB - BACKGROUND: Limited data are available on the clinical outcomes of medical therapy (MT) compared with revascularization in elderly patients with coronary chronic total occlusion (CTO). METHODS AND RESULTS: Between March 2003 and February 2012, we retrospectively analyzed 311 patients aged >=75 years in the Samsung Medical Center CTO registry. Among these, 153 patients were treated with MT and 158 patients with revascularization by intervention or surgery. Inverse probability of treatment weighting (IPTW) and propensity score-matching were performed. The primary outcome was cardiac death during follow-up. Median follow up duration was 34 (interquartile range: 15-58) months. Overall, patients in the MT group were high-risk subjects. Cardiac death of 30 patients (19.6%) occurred in the MT group vs. 17 patients (10.8%) in revascularization group (P=0.027). In the multivariate analysis, there was no significant difference between groups in the rate of cardiac death (hazard ratio [HR], 1.67; 95% confidence interval [CI], 0.86-3.24, P=0.13). After adjustment with IPTW, MT showed comparable risk of cardiac death with revascularization therapy (HR, 1.26; 95% CI, 0.71-2.21, P=0.43). In the propensity score-matched population, there was no significant difference in the rate of cardiac death between the MT and revascularization groups (HR, 1.52; 95% CI, 0.76-3.07, P=0.24). CONCLUSIONS: In the treatment of CTO in elderly patients, MT alone did not increase the risk of long-term cardiac death when compared with aggressive revascularization treatment. PMID- 26017065 TI - Perioperative Hypoalbuminemia Affects Improvement in Exercise Tolerance After Left Ventricular Assist Device Implantation. AB - BACKGROUND: Although survival rates have improved for patients receiving implantable continuous flow left ventricular assist devices (I-CF LVAD), postoperative exercise tolerance levels are not necessarily satisfactory. METHODS AND RESULTS: We enrolled 51 patients who had received an I-CF LVAD and underwent follow-up between 2006 and 2014; all patients underwent cardiopulmonary exercise testing 3 months following surgery: 26 (51%) patients achieved peak oxygen consumption (PVO2) >=14 ml.kg(-1).min(-1)and had significantly lower readmission rates for cardiovascular events than those with PVO2<14 ml.kg(-1).min(-1)during 2 years of LVAD treatment (17 vs. 43%, P=0.033). Uni- and multivariate logistic regression analyses showed that the preoperative serum albumin (S-ALB) level was an independent predictor for PVO2>=14 ml.kg(-1).min(-1)at 3 months (P=0.023, odds ratio 6.132). Patients with persistently normal S-ALB levels during the perioperative period had the lowest preoperative serum C-reactive protein level (S-CRP, 0.7+/-0.9 mg/dl), and the majority (77%) showed improved exercise tolerance. Conversely, patients with persistently low S-ALB levels during this period had the highest preoperative S-CRP level (2.8+/-1.2 mg/dl) and did not achieve the test endpoint. CONCLUSIONS: Both pre- and postoperative low S-ALB impedes recovery of exercise tolerance after I-CF LVAD surgery, and this may be attributable to inflammatory responses caused by heart failure. PMID- 26017066 TI - Are the rates of hypertension and diabetes higher in people from lower socioeconomic status in Bangladesh? Results from a nationally representative survey. AB - OBJECTIVE: A well-established belief regarding inequalities in health around the world is that hypertension and diabetes are higher in groups of lower socioeconomic status. We examined whether rates of hypertension, diabetes, and the coexistence of hypertension and diabetes are higher in people from a lower socioeconomic status than in those from a higher socioeconomic status in Bangladesh. METHODS: We investigated a nationally representative dataset from the 2011 Bangladesh Demographic and Health Survey with objective measures for hypertension and diabetes. A wealth index was constructed from data on household assets using principal components analysis. Chi-square tests and logistic regressions were performed to test the associations between wealth level, hypertension and diabetes. FINDINGS: People from the highest wealth quintile were significantly more likely to have hypertension (Adjusted odds ratios [AOR] = 1.65, 95% confidence interval [CI] = 1.22-2.25), diabetes (AOR = 1.81, 95% CI = 1.21-2.71), and the coexistence of hypertension and diabetes (AOR = 2.17, 95% CI = 1.05-4.49) than people from the lowest wealth quintile. The odds of having hypertension, diabetes, and their coexistence were higher for older people, women, people who engaged in less physical labor, and people who were overweight and obese. CONCLUSION: Wealthier people, particularly people from the fourth and highest wealth quintiles, should be careful to avoid unhealthy lifestyles to prevent hypertension and diabetes. Health policy makers and planners are urged to target wealthier strata in terms of hypertension and diabetes initiatives while paying special attention to older people, women, people who engage in less physical labor, and individuals who are overweight. PMID- 26017067 TI - Ozone, Fine Particulate Matter, and Chronic Lower Respiratory Disease Mortality in the United States. AB - RATIONALE: Short-term effects of air pollution exposure on respiratory disease mortality are well established. However, few studies have examined the effects of long-term exposure, and among those that have, results are inconsistent. OBJECTIVES: To evaluate long-term association between ambient ozone, fine particulate matter (PM2.5, particles with an aerodynamic diameter of 2.5 MUm or less), and chronic lower respiratory disease (CLRD) mortality in the contiguous United States. METHODS: We fit Bayesian hierarchical spatial Poisson models, adjusting for five county-level covariates (percentage of adults aged >=65 years, poverty, lifetime smoking, obesity, and temperature), with random effects at state and county levels to account for spatial heterogeneity and spatial dependence. MEASUREMENTS AND MAIN RESULTS: We derived county-level average daily concentration levels for ambient ozone and PM2.5 for 2001-2008 from the U.S. Environmental Protection Agency's down-scaled estimates and obtained 2007-2008 CLRD deaths from the National Center for Health Statistics. Exposure to ambient ozone was associated with an increased rate of CLRD deaths, with a rate ratio of 1.05 (95% credible interval, 1.01-1.09) per 5-ppb increase in ozone; the association between ambient PM2.5 and CLRD mortality was positive but statistically insignificant (rate ratio, 1.07; 95% credible interval, 0.99-1.14). CONCLUSIONS: This study links air pollution exposure data with CLRD mortality for all 3,109 contiguous U.S. counties. Ambient ozone may be associated with an increased rate of death from CLRD in the contiguous United States. Although we adjusted for selected county-level covariates and unobserved influences through Bayesian hierarchical spatial modeling, the possibility of ecologic bias remains. PMID- 26017068 TI - The developmental environment, epigenetic biomarkers and long-term health. AB - Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life. PMID- 26017069 TI - Label-Free in Situ Discrimination of Live and Dead Bacteria by Surface-Enhanced Raman Scattering. AB - Techniques to distinguish between live and dead bacteria in a quantitative manner are in high demand in numerous fields including medical care, food safety, and public security as well as basic science research. This work demonstrates new nanostructures (silver nanoparticles coating bacteria structure, Bacteria@AgNPs) and their utility for rapid counting of live and dead bacteria by surface enhanced Raman scattering (SERS). We found that suspensions containing Gram negative organisms as well as AgNPs give strong SERS signals of live bacteria when generated selectively on the particle surface. However, almost no SERS signals can be detected from Bacteria@AgNPs suspensions containing dead bacteria. We demonstrate successful quantification of different percentages of dead bacteria both in bulk liquid and on glass surfaces by using SERS mapping on a single cell basis. Furthermore, different chemicals have been used to elucidate the mechanism involved in this observation. Finally, we used the Bacteria@AgNPs method to detect antibiotic resistance of E. coli strains against several antibiotics used in human medicine. PMID- 26017070 TI - Overall survival differences between patients with inflammatory and noninflammatory breast cancer presenting with distant metastasis at diagnosis. AB - Inflammatory breast cancer (IBC) is a rare and aggressive disease. Previous studies have shown that among patients with stage III breast cancer, IBC is associated with a worse prognosis than noninflammatory breast cancer (non-IBC). Whether this difference holds true among patients with stage IV breast cancer has not been studied. We tested the hypothesis that overall survival (OS) is worse in patients with IBC than in those with non-IBC among patients with distant metastasis at diagnosis (stage IV disease). We reviewed the records of 1504 consecutive patients with stage IV breast cancer (IBC: 206; non-IBC: 1298) treated at our institution from 1987 through 2012. Survival curves for IBC and non-IBC subcohorts were compared. The Cox proportional hazards model was used to determine predictors of OS. The median follow-up period was 4.7 years. IBC was associated with shorter median OS time than non-IBC (2.27 vs. 3.40 years; P = 0.0128, log-rank test). In a multicovariate Cox model that included 1389 patients, the diagnosis of IBC was a significant independent predictor of worse OS (hazard ratio = 1.431, P = 0.0011). Other significant predictors of worse OS included Black (vs. White) ethnicity, younger age at diagnosis, negative HER2 status, and visceral (vs. nonvisceral) site of metastasis. IBC is associated with shorter OS than non-IBC in patients with distant metastasis at diagnosis. The prognostic impact of IBC should be taken into consideration among patients with stage IV breast cancer. PMID- 26017071 TI - Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. AB - Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess ACT occurrence and clinical and genetic risk factors in early breast cancer patients. In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy-seven patients treated between 2000 and 2010 with 3-6 cycles of (neo) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) > 10 % and cardiac failure grade 3-5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, left-sided radiotherapy, occurrence of febrile neutropenia, and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni- and multivariable logistic regression analysis. Additionally, exploratory analyses including 11 additional SNPs related to the metabolism of anthracyclines were performed. After a median follow-up of 3.62 years (range 0.40-9.60), a LVEF decline of > 10 % occurred in 153 patients (17.5 %) and cardiac failure in 16 patients (1.8 %). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of > 10 % (OR 1.3, 95 % CI 1.1-1.4, p < 0.001 and OR 1.6, 95 % CI 1.1-2.3, p = 0.02). Radiotherapy for left-sided breast cancer was associated with cardiac failure (OR 3.7, 95 % CI 1.2-11.5, p 0.026). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to anthracycline metabolism were retained in the multivariate model for prediction of LVEF decline. ACT in breast cancer patients is related to number of received cycles of epirubicin and left-sided radiotherapy. Additional studies should be performed to independently confirm the potential association between rs246221 in ABCC1 and LVEF. PMID- 26017072 TI - Infectious complications in the era of MELD. AB - BACKGROUND: Infections are a major cause for morbidity and mortality in liver transplant recipients. So far there has been no study systematically investigating the correlation between the MELD (Model for End-Stage Liver Disease) scoring system and complications caused by infections. The aim of the present retrospective study was to evaluate the impact of the pretransplant MELD score on incidence and mortality of pneumonia and septicemia in liver transplant recipients. MATERIAL AND METHODS: The clinical courses of 201 liver transplant recipients between 12/2006 and 3/2009 were recorded and analyzed on the basis of chart review. Patients were stratified into three groups (pretransplant MELD score: group I 6-20, group II >= 21-30, group III >= 31-40) and compared in terms of incidence of infection and survival. RESULTS: The mean pretransplant MELD score was 22 +/- 12. There were 81 patients in group I, 65 patients in group II, and 55 patients in group III. There was no difference in incidence of infections between the MELD groups. However, septicemia-associated mortality was significantly higher in group III. CONCLUSIONS: A high MELD score is not associated with higher incidence of infections but it is associated with a significantly higher mortality in the case of septicemia. Prevention of infections is of utmost importance, especially in liver transplant recipients with high MELD scores. PMID- 26017073 TI - 25 years of Hepatitis C. PMID- 26017074 TI - Association of caffeine intake and liver fibrosis in patients with chronic hepatitis C. AB - BACKGROUND: Caffeine consumption has been associated to decreased levels of liver enzymes and lower risk of fibrosis in patients with hepatitis C virus. Objectives This study aimed to evaluate the association between caffeine consumption and inflammatory activity or degree of liver fibrosis in patients with hepatitis C virus infection. METHODS: A cross-sectional study of patients with chronic hepatitis C virus infection treated in an outpatient Gastroenterology Unit of Santa Casa Hospital (Porto Alegre - Brasil). Patients were interviewed regarding the consumption of caffeine and anthropometric assessment was performed. Liver biopsy was performed in a maximum period of 36 months before inclusion in the study. RESULTS: There were 113 patients, 67 (59.3%) females, 48 (42.5%) were aged between 52 and 62 years, and 101 (89.4%) were white. The average caffeine consumption was 251.41 +/- 232.32 mg/day, and 70 (62%) patients consumed up to 250 mg/day of caffeine. There was no association between caffeine consumption and inflammatory activity on liver biopsy. On the other hand, when evaluating the caffeine consumption liver fibrosis an inverse association was observed. CONCLUSIONS: The greater consumption of caffeine was associated with lower liver fibrosis. There was no association between caffeine consumption and inflammatory activity. PMID- 26017075 TI - Prevalence of the hepatitis C virus among University employees in Sao Paulo, Southeastern Brazil: predictive factors and geoprocessing spatial analysis. AB - BACKGROUND: There are limited studies on the prevalence and risk factors associated with hepatitis C virus (HCV) infection. Objective Identify the prevalence and risk factors for HCV infection in university employees of the state of Sao Paulo, Brazil. METHODS: Digital serological tests for anti-HCV have been performed in 3153 volunteers. For the application of digital testing was necessary to withdraw a drop of blood through a needlestick. The positive cases were performed for genotyping and RNA. Chi-square and Fisher's exact test were used, with P-value <0.05 indicating statistical significance. Univariate and multivariate logistic regression were also used. RESULTS: Prevalence of anti-HCV was 0.7%. The risk factors associated with HCV infection were: age >40 years, blood transfusion, injectable drugs, inhalable drugs (InDU), injectable Gluconergam(r), glass syringes, tattoos, hemodialysis and sexual promiscuity. Age (P=0.01, OR 5.6, CI 1.4 to 22.8), InDU (P<0.0001, OR=96.8, CI 24.1 to 388.2), Gluconergam(r) (P=0.0009, OR=44.4, CI 4.7 to 412.7) and hemodialysis (P=0.0004, OR=90.1, CI 7.5 - 407.1) were independent predictors. Spatial analysis of the prevalence with socioeconomic indices, Gross Domestic Product and Human Development Index by the geoprocessing technique showed no positive correlation. CONCLUSIONS: The prevalence of HCV infection was 0.7%. The independent risk factors for HCV infection were age, InDU, Gluconergan(r) and hemodialysis. There was no spatial correlation of HCV prevalence with local economic factors. PMID- 26017076 TI - Triple therapy in chronic hepatitis C: initial series in a public health program in the South of Brazil. AB - BACKGROUND: Chronic hepatitis C has great impact on world's health. Current therapy for genotype 1 hepatitis C virus includes protease inhibitors boceprevir and telaprevir, associated to standard therapy - peginterferon alfa + ribavirin. There are no published data in Brazil on the results of this new therapy, and it is interesting an evaluation of what was accomplished up to this moment. Objectives To evaluate virologic response to triple therapy, as well as the safety profile and tolerability. METHOD: This study is a clinical series of patients receiving triple therapy for C hepatitis in a single center of a Public Health System of South Brasil. Out of the 121 patients that initiated the triple therapy, the first patients that finished the treatment and evaluated the sustained virological response (24 weeks after the end of treatment) were included. RESULTS: Twenty four genotype 1 chronic hepatitis C monoinfected patients were included. Nineteen (79.2%) patients had been previously treated. Thirteen (54.2%) patients were cirrhotic. Nineteen (79.2%) patients completed the planned therapy. By the end of the treatment, 14 (58.3%) out of 24 patients had undetectable viral load. Sustained virologic response occurred in 12 (50.0%) out of 24 patients, 07 (58.3%) in telaprevir group and 05 (41.7%) in boceprevir group. Out of 24 patients under triple therapy, 58% (n=14) presented anemia. CONCLUSIONS: In conclusion, despite the small number of patients treated with triple therapy evaluated in the current study, it possibly reflects the population under this therapy in real-life. PMID- 26017077 TI - Hepatitis B in Rondonia (Western amazon region, Brazil): descriptive analysis and spatial distribution. AB - BACKGROUND: The Amazon is one of the regions who have the highest rates of infection by the hepatitis B virus in the world. Objectives This study aimed to evaluate the epidemiological data and spatial distribution of hepatitis B cases reported between 2002 and 2012 in the Brazilian State of Rondonia. METHODS: Social and clinical data of these individuals were studied through the Information System for Notifiable Diseases (SINAN), including the following variables: gender, age group, vaccination, contact with a known patient with HBV, exposure to risk factors, source of infection, and clinical status. RESULTS: There were 7,132 cases reported in Rondonia, with an average incidence rate of 42/100,000 inhabitants per year. The municipalities with the highest incidence rates were Monte Negro (187.6/100,000 inhabitants) and Ariquemes (157.2/100,000 inhabitants). The 20-39 year-old age group had the highest number of cases (n = 3,834), and 69.9% of patients were likely infected via sexual contact. Regarding the clinical disease status, most of the patients (80.7%) were in the chronic phase. CONCLUSIONS: There was a recent 402% increase in the diagnosis of hepatitis B, which is likely owing to the improvements in the public diagnostic system. This highlights the need for public policies to prevent and control the disease. PMID- 26017078 TI - Usefulness of a new prognostic index for alcoholic hepatitis. AB - BACKGROUND: Alcoholic liver disease is a major cause of end-stage liver disease worldwide and severe forms of alcoholic hepatitis are associated with a high short-term mortality. Objectives To analyze the importance of age-bilirubin-INR creatinine (ABIC) score as an index of mortality and predictor for complications in patients with alcoholic hepatitis. To evaluate its correlation with those complications, with risk of death, as well as the scores model for end stage liver disease (MELD) and Maddrey's discriminat function. METHODS: A total of 46 medical records of patients who had been hospitalized with alcoholic hepatitis were assessed retrospectively with lab tests on admission and after seven days. Score calculations were carried out and analyzed as well. RESULTS: The scores showed positive reciprocal correlation and were associated with both hepatic encephalopathy and ascites. ABIC index, which was classified as high risk, presented as a risk factor for these complications and for death. In univariate logistic regression analysis of mortality, the ABIC index at hospital admission odds ratio was 19.27, whereas after 7 days, it was 41.29. The average survival of patients with ABIC of low and intermediate risk was 61.1 days, and for those with high risk, 26.2 days. CONCLUSIONS: ABIC index is a predictor factor for complications such as ascites and hepatic encephalopathy, as well as for risk of death. Thus, it is a useful tool for clinical practice. PMID- 26017079 TI - Effect of swallowed bolus viscosity and body position on esophageal transit, contraction and perception of transit. AB - BACKGROUND: The esophagus has a different response in relation to the characteristics of a swallowed bolus. Bolus viscosity and body position may affect esophageal contraction and transit. Objectives To investigate the effect of bolus viscosity and body position on esophageal contraction, transit and perception. METHODS: Esophageal contraction, transit and perception of transit were evaluated in 26 asymptomatic volunteers, 13 men and 13 women aged 18-60 years, mean: 33.6 (12.2) years. Esophageal contraction (manometry) and transit (impedance) were measured with a solid state catheter with sensors located 5, 10, 15, and 20 cm from the lower esophageal sphincter. Each volunteer swallowed in duplicate and in random sequence a 5 mL low viscous (LV) liquid bolus of an isotonic drink with pH 3.3, and a 5 mL high viscous (HV) paste bolus, which was prepared with 7.5 g of instant food thickener diluted in 50 mL of water (pH: 6.4). RESULTS: Total bolus transit time, in the sitting position, was longer with the HV bolus than with the LV bolus. Esophageal transit was longer in the supine position than in the sitting position. Bolus head advance time was longer with the HV bolus than with the LV bolus in both positions. Contraction esophageal amplitude was higher in the supine position than in the sitting position. The perception of bolus transit was more frequent with the HV bolus than with the LV bolus, without differences related to position. CONCLUSIONS: The viscosity of the swallowed bolus and body position during swallows has an influence on esophageal contractions, transit and perception of transit. PMID- 26017080 TI - Influence of age on swallows of a highly viscous liquid bolus. AB - BACKGROUND: Swallow function has a decline with aging, mainly in those over 80 years old. In the population over 69 years, about 11% of subjects reported symptoms indicative of significant dysphagia. OBJECTIVES: Our objective was to evaluate the hypothesis that older asymptomatic subjects before 80 years old have compensations to sustain a safe and efficient swallow, at least with swallows of liquid bolus. METHODS: We performed videofluoroscopic evaluation of swallows in 55 normal volunteers, a younger group with 33 subjects (16 men and 17 women) aged 19 to 55 years, mean 35.5+/-9.8 years, and an older group with 22 subjects (15 men and 7 women) aged 56 to 77 years, mean 64.8+/-6.8 years. The subjects swallowed in duplicate 5 mL and 10 mL of liquid barium with a pH of 7.9, density of 1.82 g/cm3, and viscosity of 895 cp. Results The mean duration of pharyngeal transit, pharyngeal clearance, upper esophageal sphincter opening, hyoid movement and oral-pharyngeal transit were longer in the younger group compared with the older group. The relation between pharyngeal clearance duration and hyoid movement duration was similar in younger and older subjects, for 5 mL and 10 mL bolus volumes. CONCLUSIONS: On average, a highly viscous liquid bolus crosses the pharynx faster in older subjects (56-77 years old) than in younger subjects (19 55 years old), which suggested an adaptation to the aging process to maintain a safe swallow. PMID- 26017081 TI - Excessive weight--muscle depletion paradox and cardiovascular risk factors in outpatients with inflammatory bowel disease. AB - BACKGROUND: Evidence suggests a nutritional transition process in patients with inflammatory bowel disease. Obesity, which was once an uncommon occurrence in such patients, has grown in this population at the same prevalence rate as that found in the general population, bringing with it an increased risk of cardiovascular disease. Objective The aim of the present study was to determine the nutritional status and occurrence of cardiovascular risk factors in patients with inflammatory bowel disease. METHODS: A case-series cross-sectional study was conducted involving male and female adult outpatients with inflammatory bowel disease. Data were collected on demographic, socioeconomic, clinical and anthropometric variables as well as the following cardiovascular risk factors: sedentary lifestyle, excess weight, abdominal obesity, medications in use, comorbidities, alcohol intake and smoking habits. The significance level for all statistical tests was set to 5% (P< 0.05). RESULTS: The sample comprised 80 patients with inflammatory bowel disease, 56 of whom (70.0%) had ulcerative colitis and 24 of whom (30.0%) had Crohn's disease. Mean age was 40.3+/-11 years and the female genre accounted for 66.2% of the sample. High frequencies of excess weight (48.8%) and abdominal obesity (52.5%) were identified based on the body mass index and waist circumference, respectively, in both groups, especially among those with ulcerative colitis. Muscle depletion was found in 52.5% of the sample based on arm muscle circumference, with greater depletion among patients with Crohn's disease (P=0.008). The most frequent risk factors for cardiovascular disease were a sedentary lifestyle (83.8%), abdominal obesity (52.5%) and excess weight (48.8%). CONCLUSION: The results of the complete anthropometric evaluation draw one's attention to a nutritional paradox, with high frequencies of both - muscle depletion, as well as excess weight and abdominal obesity. PMID- 26017082 TI - Peptic ulcer frequency differences related to h. Pylori or aines. AB - BACKGROUND: Peptic ulcer etiology has been changing because of H. pylori decline. OBJECTIVES: To estimate peptic ulcer prevalence in 10 years-interval and compare the association with H. pylori and use of non-steroidal anti-inflammatory drugs. Methods Records assessment in two periods: A (1997-2000) and B (2007-2010), searching for peptic ulcer, H. pylori infection and non-steroidal anti inflammatory drugs use. RESULTS: Peptic ulcer occurred in 30.35% in A and in 20.19% in B. H. pylori infection occurred in 73.3% cases in A and in 46.4% in B. Non-steroidal anti-inflammatory drugs use was 3.5% in A and 13.3% in B. Neither condition occurred in 10.4% and 20.5% in A and B respectively. Comparing both periods, we observed reduction of peptic ulcer associated to H. pylori (P=0.000), increase of peptic ulcer related to non-steroidal anti-inflammatory drugs (P=0.000) and idiopathic peptic ulcer (P=0.002). The concurrent association of H. pylori and non-steroidal anti-inflammatory drugs was also higher in B (P=0.002). Rates of gastric ulcer were higher and duodenal ulcer lower in the second period. CONCLUSIONS: After 10 years, the prevalence of peptic ulcer decreased, as well as ulcers related to H. pylori whereas ulcers associated to non-steroidal anti inflammatory drugs increased. There was an inversion in the pattern of gastric and duodenal ulcer and a rise of idiopathic peptic ulcer. PMID- 26017083 TI - FECAL CALPROTECTIN: levels for the ethiological diagnosis in Brazilian patients with gastrointestinal symptoms. AB - BACKGROUND: Determination of fecal calprotectin can provide an important guidance for the physician, also in primary care, in the differential diagnosis of gastrointestinal disorders, meanly between inflammatory bowel diseases and irritable bowel syndrome. Objectives The aims of the present study were to prospectively investigate, in Brazilian adults with gastrointestinal complaints, the value of fecal calprotectin as a biomarker for the differential diagnosis between functional and organic disorders and to correlate the concentrations with the activity of inflammatory bowel diseases. METHODS: The study included consecutive patients who had gastrointestinal complaints in which the measurement levels of fecal calprotectin were recommended. Fecal calprotectin was measured using a Buhlmann (Basel, Switzerland) ELISA kit. RESULTS: A total of 279 patients were included in the study, with median age of 39 years (range, 18 to 78 years). After clinical and laboratorial evaluation and considering the final diagnosis, patients were allocated into the following groups: a) Irritable Bowel Syndrome: 154 patients (102 female and 52 male subjects). b) Inflammatory Bowel Diseases group: 112 patients; 73 with Crohn's disease; 38 female and 35 male patients; 52.1% (38/73) presented active disease, and 47.9% (35/73) had disease in remission and 39 patients with ulcerative colitis;19 female and 20 male patients; 48.7% (19/39) classified with active disease and 49.3% (20/39) with disease in remission. A significant difference (P<0.001) was observed between the median value of fecal calprotectin in Irritable Bowel Syndrome group that was 50.5 ug/g (IQR=16 - 294 ug/g); 405 ug/g (IQR=29 - 1980 ug/g) in Crohn's disease patients and 457 ug/g (IQR=25 - 1430 ug/g) in ulcerative colitis patients. No difference was observed between the values found in the patients with Crohn's disease and ulcerative colitis. Levels of fecal calprotectin were significantly lower in patients with inflammatory bowel diseases in remission when compared with active disease (P<0.001). CONCLUSIONS: The present study showed that the determination of fecal calprotectin assists to differentiate between active and inactive inflammatory bowel diseases and between inflammatory bowel diseases and irritable bowel syndrome. PMID- 26017084 TI - The prevalence of celiac disease among patients with familial mediterranean Fever. AB - BACKGROUND: Familial Mediterranean Fever and celiac disease are both related to auto-inflammation and/or auto-immunity and they share some common clinical features such as abdominal pain, diarrhea, bloating and flatulence. Objectives We aimed to determine the association of these two diseases, if present. METHODS: Totally 112 patients diagnosed with Familial Mediterranean Fever and 32 cases as healthy control were included in the study. All participants were examined for the evidence of celiac disease, with serum tissue transglutaminase IgA levels (tTG IgA). RESULTS: Totally 144 cases, 112 with Familial Mediterranean Fever and 32 healthy control cases were included in the study. tTG IgA positivity was determined in three cases with Familial Mediterranean Fever and in one case in control group. In that aspect there was no significant difference regarding the tTG IgA positivity between groups (P=0.81). Duodenum biopsy was performed to the tTG IgA positive cases and revealed Marsh Type 3b in two Familial Mediterranean Fever cases and Marsh Type 3c in the other one while the biopsy results were of the only tTG IgA positive case in control group was Marsh Type 3b. In HLA evaluation of the celiac cases; HLA DQ2 was present in two celiac cases of the Familial Mediterranean Fever group and in the only celiac case of the control group while HLA DQ8 was present in one celiac case of the Familial Mediterranean Fever group. CONCLUSIONS: We did not determine an association of Familial Mediterranean Fever with celiac disease. Larger studies with subgroup analysis are warranted to determine the relationship of these two diseases. PMID- 26017085 TI - Endoscopic and histopathologic gastric changes in chronic users of proton-pump inhibitors. AB - BACKGROUND: Proton-pump inhibitors have been used for at least two decades. They are among the most commonly sold drugs in the world. However, some controversy remains about the indications for their use and the consequences of their prolonged use. OBJECTIVES: To evaluate and compare the endoscopic and histopathologic gastric changes in chronic users of proton-pump inhibitors to changes in non-users. METHODS: A prospective study performed at a tertiary Public Hospital involving 105 patients undergoing upper-gastrointestinal endoscopy. Subjects included 81 proton-pump inhibitor users and 24 non-users (control group). Biopsies of the antral-type mucosa, the antral-fundic transition, and the fundus were evaluated by the Sydney System. The presence of erosion or ulceration, lymphatic follicles, reactive gastropathy, and polypoid or epithelial hyperplasia was also determined. Serum levels of gastrin were measured. RESULTS: We found two polyps, one in each group, both of which were negative for Helicobacter pylori. There were two cases of parietal cell hyperplasia in users of proton-pump inhibitors. Gastrin was elevated in 28 users of proton-pump inhibitors and in four members of the control group. We did not find statistically significant differences in the endoscopic or histopathologic findings between the two groups. CONCLUSIONS: Chronic use of proton-pump inhibitors for the duration examined was not associated with significant gastric changes. An interesting finding was that the 4 chronic users of proton-pump inhibitors who had serum gastrin levels above 500 pg/mL also had positive serology for Chagas disease. PMID- 26017086 TI - Cirrhosis induces apoptosis in renal tissue through intracellular oxidative stress. AB - BACKGROUND: Renal failure is a frequent and serious complication in patients with decompensated cirrhosis. OBJECTIVES: We aimed to evaluate the renal oxidative stress, cell damage and impaired cell function in animal model of cirrhosis. METHODS: Secondary biliary cirrhosis was induced in rats by ligation of the common bile duct. We measured TBARS, ROS and mitochondrial membrane potential in kidney as markers of oxidative stress, and activities of the antioxidant enzymes. Relative cell viability was determined by trypan blue dye-exclusion assay. Annexin V-PE was used with a vital dye, 7-AAD, to distinguish apoptotic from necrotic cells and comet assay was used for determined DNA integrity in single cells. RESULTS: In bile duct ligation animals there was significant increase in the kidney lipoperoxidation and an increase of the level of intracellular ROS. There was too an increase in the activity of all antioxidant enzymes evaluated in the kidney. The percentage viability was above 90% in the control group and in bile duct ligation was 64.66% and the dominant cell death type was apoptosis. DNA damage was observed in the bile duct ligation. There was a decreased in the mitochondrial membrane potential from 71.40% +/- 6.35% to 34.48% +/- 11.40% in bile duct ligation. CONCLUSIONS: These results indicate that intracellular increase of ROS cause damage in the DNA and apoptosis getting worse the renal function in cirrhosis. PMID- 26017087 TI - Percutaneous endoscopic gastrostomy with jejunal extension plus percutaneous endoscopic gastrostomy (PEG-j plus PEG) in patients with gastric/duodenal cancer outlet obstruction. AB - BACKGROUND: Stent palliation is the gold standard for gastric/duodenal cancer outlet obstruction. When stenting is impossible, feeding may be achieved through a gastrojejunostomy (PEG-J), but displacement of jejunal tube is frequent due to manipulation for feeding and drainage. Gastric outlet obstruction results on increased gastroesophageal reflux or extra-tube leakage. In order to reduce the jejunostomy tube manipulation and the gastric residuum, we created a second gastrostomy (PEG) dedicated to gastric drainage, reducing the PEG-J handling. OBJECTIVE: Our aim was evaluating of the usefulness of an added second gastrostomy in a PEG-J patient, for: 1. controlling symptomatic reflux and extra tube leakage; 2. preventing jejunal tube dislocation. Methods We retrospectively evaluated patients were stent palliation of gastric/duodenal cancer outlet obstruction was not achieved, who were referred and underwent PEG-J. We selected four of these patients who needed a second PEG dedicated to gastric drainage, which was performed a few centimetres apart from the gastrojejunostomy. In order to achieve an efficient gastric drainage and provide the maximum comfort to the patient, the drainage PEG tube could be linked to an ileostomy bag. RESULTS: The four PEG-J cancer patients with longer survival developed symptoms associated with an important gastric residuum. After the drainage gastrostomy, symptoms subsided or vanished and there were no jejunal tube dislocations. CONCLUSIONS: When stenting is not possible in patients with gastric/duodenal outlet obstruction due to cancer growing, feeding PEG-J plus drainage PEG may be an alternative, allowing duodenal/jejunal feeding and gastric drainage with minimal manipulation of the jejunal tube. PMID- 26017088 TI - Biosimilars in inflammatory bowel diseases: an important moment for Brazilian gastroenterologists. AB - Biosimilars are not generic drugs. These are more complex medications than small molecules, with identical chemical structures of monoclonal antibodies that lost their patency over time. Besides identical to the original product at the end, the process of achieving its final forms differs from the one used in the reference products. These differences in the formulation process can alter final outcomes such as safety and efficacy of the drugs. Recently, a biosimilar of Infliximab was approved in some countries, even to the management of inflammatory bowel diseases. However, this decision was based on studies performed in rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis. Extrapolation of the indications from rheumatologic conditions was done for Crohn's disease and ulcerative colitis based on these studies. In this article, the authors explain possible different mechanisms in the pathogenesis between rheumatologic conditions and inflammatory bowel diseases, that can lead to different actions of the medications in different diseases. The authors also alert the gastroenterological community for the problem of extrapolation of indications, and explain in full details the reasons for being care with the use of biosimilars in inflammatory bowel diseases without specific data from trials performed in this scenario. PMID- 26017090 TI - Supporting Families of Children With Disabilities. AB - Advanced technology combined with improvements in neonatal care have increased the survival rates of low-birth-weight infants and infants born with severe birth defects. These infants are at greater risk for long-term health and developmental problems. The effect of having a child with a disability on the family is described, and emerging interventions and resources available for these families are provided. PMID- 26017093 TI - Metals in infectious diseases and nutritional immunity. PMID- 26017091 TI - Associations between serotonin transporter gene (SLC6A4) methylation and clinical characteristics and cortical thickness in children with ADHD. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Additionally, environmental factors such as perinatal stress and early adversities contribute to the occurrence and severity of ADHD. Recently, DNA methylation has emerged as a mechanism that potentially mediates gene-environmental interaction effects in the aetiology and phenomenology of psychiatric disorders. Here, we investigated whether serotonin transporter gene (SLC6A4) methylation patterns were associated with clinical characteristics and regional cortical thickness in children with ADHD. METHOD: In 102 children with ADHD (age 6-15 years), the methylation status of the SLC6A4 promoter was measured. Brain magnetic resonance imaging was obtained and ADHD symptoms were evaluated. RESULTS: A higher methylation status of the SLC6A4 promoter was significantly associated with worse clinical presentations (more hyperactive-impulsive symptoms and more commission errors). Additionally, a negative correlation was observed between SLC6A4 methylation levels and cortical thickness values in the right occipito-temporal regions. CONCLUSIONS: Our results suggest that the SLC6A4 methylation status may be associated with certain symptoms of ADHD, such as behavioural disinhibition, and related brain changes. Future studies that use a larger sample size and a control group are required to corroborate these results. PMID- 26017092 TI - Is the Homeostatic Model Assessment of Insulin Resistance a Poor Predictor of Cardiovascular Disease in Rheumatoid Arthritis? Comment on the Article by Giles et al. PMID- 26017094 TI - Advanced Technologies in Sialic Acid and Sialoglycoconjugate Analysis. AB - Although the structural diversity of sialic acid (Sia) is rapidly expanding, understanding of its biological significance has lagged behind. Advanced technologies to detect and probe diverse structures of Sia are absolutely necessary not only to understand further biological significance but also to pursue medicinal and industrial applications. Here we describe analytical methods for detection of Sia that have recently been developed or improved, with a special focus on 9-O-acetylated N-acetylneuraminic acid (Neu5,9Ac), N glycolylneuraminic acid (Neu5Gc), deaminoneuraminic acid (Kdn), O-sulfated Sia (SiaS), and di-, oligo-, and polysialic acid (diSia/oligoSia/polySia) in glycoproteins and glycolipids. Much more attention has been paid to these Sia and sialoglycoconjugates during the last decade, in terms of regulation of the immune system, neural development and function, tumorigenesis, and aging. PMID- 26017095 TI - Assembly of poly(dopamine)/poly(acrylamide) mixed coatings by a single-step surface modification strategy and its application to the separation of proteins using capillary electrophoresis. AB - In this work, a facile approach was developed to modify a fused-silica capillary inner surface based on poly(dopamine) and poly(acrylamide) mixed coatings for protein separation by capillary electrophoresis. The surface morphology, thickness, and chemical components of poly(dopamine)/poly(acrylamide) mixed coatings on glass slides and silicon wafers were studied by atom force microscopy, ellipsometry, and X-ray photoelectron spectroscopy, respectively. The hydrophilicity and stability of the mixed coatings on glass slides were investigated by static water contact angle measurements. A comparative study of electroosmotic flow showed that the poly(dopamine)/poly(acrylamide) mixed coatings could provide effective suppression of electroosmotic flow. Meanwhile, the fast and efficient separations of the mixture of four alkaline proteins, the mixture of acidic, basic, and neutral proteins and egg white proteins were obtained by capillary electrophoresis. Furthermore, the consecutive protein separation runs and low RSDs of migration time demonstrated that these poly(dopamine)/poly(acrylamide) mixed coatings were capable of minimizing protein adsorption during the protein separation by using capillary electrophoresis. PMID- 26017096 TI - Heterogeneous Kinetics of cis-Pinonic Acid with Hydroxyl Radical under Different Environmental Conditions. AB - To understand the atmospheric fate of secondary organic aerosol (SOA), heterogeneous degradation behaviors of a specific tracer derived from alpha pinene-cis-pinonic acid (CPA), initiated by hydroxyl radicals (OH), were investigated under different environmental conditions using a flow reactor. The second-order rate constant (k2) of the CPA-OH reaction was determined to be (6.17 +/- 1.07) * 10(-12) cm(3).molecule(-1).s(-1) at 25 degrees C and 40% relative humidity (RH). Higher temperature promoted this reaction, while relative humidity had a little inhibiting effect on it. The atmospheric lifetime of CPA varied from 2.1 to 3.3 days under different environmental conditions. Infrared spectrometry (IR), density functional theory (DFT) calculation and gas chromatography coupled mass spectrometry (GC-MS) results indicated that the oxidation products should be ascribed to poly(carboxylic acid)s. This study shows that the heterogeneous degradation of CPA initiated by OH radical is appreciable, and the concentrations of CPA measured in field measurements may underestimate the corresponding precursors of SOA. PMID- 26017097 TI - Muscle strength: A better index of low physical performance than muscle mass in older adults. AB - AIM: The most appropriate muscle index for the definition of sarcopenia has not been agreed on. We aimed to investigate the associations of muscle mass and strength with 5-year mortality and low physical performance. METHODS: We included 560 participants aged 65 years or older in the analysis. Muscle and fat mass were assessed by dual-energy X-ray absorptiometry. Leg muscle and grip strength were measured using dynamometers. The clinical outcomes were 5-year mortality and low physical performance (Short Physical Performance Battery score < 9) in 5 years. Associations between muscle indices and clinical outcomes were analyzed. A Cox proportional hazard model for mortality and a logistic regression model for physical performance were used. RESULTS: Decreases in leg muscle and grip strength were significantly associated with 5-year mortality and low physical performance in both sexes. Total muscle mass in men and appendicular skeletal mass in both sexes were associated with mortality, but not with low physical performance. Lower leg muscle strength (OR 0.107; P = 0.020) was an independent predictor of low physical performance in women after adjusting for age, fat, cognition, and depression. Lower leg muscle (OR 0.123; P = 0.031) and lower grip strength (OR 0.950; P = 0.012) were independent predictors of low physical performance in men. CONCLUSIONS: Muscle strength is a better indicator of 5-year adverse clinical outcomes of mortality and low physical performance than muscle mass. Muscle strength was an independent predictor of low physical performance in 5 years. Geriatr Gerontol Int 2016; 16: 577-585. PMID- 26017098 TI - Cutaneous S100-negative, CD1a-positive histiocytosis successfully treated with combination therapy of oral methotrexate and corticosteroid. AB - S100-negative, CD1a-positive histiocytosis is a rare histiocytic disorder characterized by proliferation of histiocytic cells possessing a phenotype of epidermal Langerhans cells except for the lack of S100 expression and Birbeck granules. We report the case of a Japanese man suffering from S100-negative, CD1a positive histiocytosis. The patient showed numerous smooth erythematous 5-10-mm papules/nodules on most of his body. The key histopathological feature was the presence of dermal infiltrates of non-epidermotropic S100-negative CD1a-positive mononuclear cells. No systemic involvement was detected. Initially bath-psoralen plus ultraviolet A therapy was effective, but the lesions became recalcitrant to this treatment. Methylprednisolone pulse therapy followed by low-dose methotrexate (up to 30 mg/week) in combination with prednisolone (15 mg/day) effectively controlled the skin lesions. PMID- 26017099 TI - Nanostructured lipid carriers based temozolomide and gene co-encapsulated nanomedicine for gliomatosis cerebri combination therapy. AB - BACKGROUND: Co-delivery of gene and anticancer drug into the same cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment. In this study, nanostructured lipid carriers (NLCs) were constructed as multifunctional nanomedicine for co-delivery of enhanced green fluorescence protein plasmid (DNA) and temozolomide (TMZ). METHODS: TMZ- and DNA-loaded NLCs (TMZ/DNA-NLCs) were prepared. Their particle size, zeta potential, gene-loading capacity (GL) and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study TMZ/DNA-NLCs was tested in U87 malignant glioma cells (U87 MG cells). In vivo gene transfection and anti-tumor efficacy of the carriers were evaluated on mice bearing malignant glioma model. RESULTS: The optimum TMZ/DNA NLCs formulations with the particle size of 179 nm and with a +23 mV surface charge; got 91% of GL and 83% of EE. The growth of U87 MG cells in vitro was obviously inhibited. TMZ/DNA-NLCs also displayed the highest gene transfection efficiency and the best antitumor activity than other formulations in vivo. CONCLUSION: The results demonstrated that TMZ/DNA-NLCs were efficient in selective delivery to malignant glioma cells. Also TMZ/DNA-NLCs transfer both drug and gene to the gliomatosis cerebri, enhance the antitumor capacity and gene transfection efficacy. Thus, TMZ/DNA-NLCs could prove to be a superior co delivery nanomedicine to achieve therapeutic efficacy and this report could be a new promising strategy for treatment in malignant gliomatosis cerebri. PMID- 26017100 TI - Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats. AB - OBJECTIVE: Insulin is a hormone used in the treatment of diabetes mellitus. Multiple injections of insulin every day may causes pain, allergic reactions at injection site, which lead to low patient compliance. The aim of this work was to develop and evaluate an efficient solid lipid nanoparticle (SLN) carrier for oral delivery of insulin. METHODS: SLNs were prepared by double emulsion solvent evaporation (w/o/w) technique, employing glyceryltrimyristate (Dynasan 114) as lipid phase and soy lecithin and polyvinyl alcohol as primary and secondary emulsifier, respectively, and evaluated in vitro for particle size, polydispersity index (PDI) and drug entrapment. RESULTS: Among the eight different developed formulae (F1-F8), F7 showed an average particle size (99 nm), PDI (0.021), high entrapment of drug (56.5%). The optimized formulation (F7) was further evaluated by FT-IR, DSC, XRD, in vitro release, permeation, stability, bioavailability and pharmacological studies. Insulin-loaded SLNs showed better protection from gastrointestinal environment as evident from the relative bioavailability, which was enhanced five times as compared to the insulin solution. A significant enhancement of relative bioavailability of insulin was observed, i.e. approximately five times of pure insulin solution when loaded in SLN (8.26% versus 1.7% only). PMID- 26017101 TI - Diagnosis approach of chronic lymphocytic leukemia on unstained blood smears using Raman microspectroscopy and supervised classification. AB - We have investigated the potential of Raman microspectroscopy combined with supervised classification algorithms to diagnose a blood lymphoproliferative disease, namely chronic lymphocytic leukemia (CLL). This study was conducted directly on human blood smears (27 volunteers and 49 CLL patients) spread on standard glass slides according to a cytological protocol before the staining step. Visible excitation at 532 nm was chosen, instead of near infrared, in order to minimize the glass contribution in the Raman spectra. After Raman measurements, blood smears were stained using the May-Grunwald Giemsa procedure to correlate spectroscopic data classifications with cytological analysis. A first prediction model was built using support vector machines to discriminate between the two main leukocyte subpopulations (lymphocytes and polymorphonuclears) with sensitivity and specificity over 98.5%. The spectral differences between these two classes were associated to higher nucleic acid content in lymphocytes compared to polymorphonuclears. Then, we developed a classification model to discriminate between neoplastic and healthy lymphocyte spectra, with a mean sensitivity and specificity of 88% and 91% respectively. The main molecular differences between healthy and CLL cells were associated with DNA and protein changes. These spectroscopic markers could lead, in the future, to the development of a helpful medical tool for CLL diagnosis. PMID- 26017102 TI - Difficult thyroidectomies. AB - The "difficult thyroidectomies" (DT) are motivated by several factors that, alone or in association with each other, make surgery more laborious and increase the related risks. Topographical, technical and anatomical criteria have been used by us to classify DT with a view to illustrating specific problems and suggesting appropriate strategies. According to topographical criteria we considered mediastinal goiter and resurgery; according to technical criteria we considered the presence of auto-immune thyroiditis and locally advanced malignancies; on the basis of anatomical criteria, we considered the presence of "non recurrent" laryngeal nerve and of a pre-operatory vocal cord palsy. PMID- 26017103 TI - The influence of the risk factor on the abdominal complications in colon injury management. AB - INTRODUCTION: The management of colon injuries has distinctly evolved over the last three decades. However, trauma surgeons often find themselves in a dilemma, whether to perform a diversion or to perform a primary repair. The purpose of this study is to evaluate risk factors in colon injury management and their influence on abdominal complications. PATIENTS AND METHODS: This is a prospective study conducted at a national level I trauma center in Tirana, Albania from January 2009 to December 2012. The data with respect to demographics, physiological risk factors, intraoperative findings, and surgical procedures were collected. Colonic injury-related morbidity and mortality were analyzed. Multivariate logistic regression analysis was performed by assessing the influence of risk factors on abdominal complications. RESULTS: Of the 157 patients treated with colon injury, was performed a primary repair in 107 (68.15%) of the patients and a diversion in the remaining 50 (31.85%). The mean PATI was 18.6, while 37 (23.6%) of patients had PATI greater than 25. The complications and their frequencies according to the surgical technique used (primay repair vs diversion respectively) includes: wound infections (9.3% vs 50%), anastomotic leak (1.8% vs 8.7%), and intra-abdominal abscess (1.8% vs 6.5%). The multivariate analysis identified two independent risk factors for abdominal complications: transfusions of 4 units of blood within the first 24 hours (OR = 1.2 95% CI (1.03 - 1.57) p =0.02), and diversion (OR = 9.6, 95% CI 4.4 - 21.3, p<0.001). CONCLUSION: Blood transfusions of more than 4 units within the first 24 hours and diversion during the management of destructive colon injuries are both independent risk factors for abdominal complications. The socioeconomic impact and the need for a subsequent operation in colostomy patients are strong reasons to consider primary repair in the management of colon injuries. PMID- 26017104 TI - Papillary glioneuronal tumor: case report and review of literature. AB - Papillary glioneuronal tumor (PGNT) is a recently described central nervous system neoplasm that mostly occurs in the supratentorial system, adjacent to the lateral ventricles. In 2007, WHO classified PGNT as grade I neuronal-glial tumor because of the characteristic papillary architecture and bipartite (astrocytic and neuronal/neurocytic) cell population. As a newly established entity of mixed glioneuronal tumor family, PGNT attracted extensive attention recently. In our report we discuss the clinical, neuroradiological and surgical features. The final result is compared with literature data. PMID- 26017105 TI - Esophageal perforation during laparoscopic adjustable gastric band: conversion to open sleeve gastrectomy and endoscopic stent placement. AB - Laparoscopic adjustable gastric band (LAGB) is one of the most popular bariatric surgical procedures both in Europe and United States, because it is considered to be a safe and effective way of treating morbid obesity. This minimally invasive frequently employed bariatric procedure has many reported complications, but only a few cases of esophageal perforation have been reported. We present a case of iatrogenic esophageal perforation in an 18-year-old patient occurring during attempt to place an adjustable gastric band laparoscopically, which was diagnosed intraoperatively. Conversion to open sleeve gastrectomy with primary suturing of the perforation and drainage were performed. On the early postoperative period leak from the intra-abdominal part of the esophagus was diagnosed and treated with endoscopic placement of a self-expandable metal stent. After 2-years of follow-up the patient continues to have no sequelae from the perforation or symptoms of dysphagia, while Excess Weight Loss is 74. PMID- 26017106 TI - Unusual liver abscess secondary to ingested foreign body: laparoscopic management. AB - Liver abscess is a cause of febrile abdominal pain and usually the origin of a liver abscess is ascending cholangitis, hemathological diffusion, via the portal vein or the hepatic artery, or superinfection of necrotic tissue. Solitary pyogenic abscess with no obvious systemic cause may be secondary to a local event such as the migration of an ingested foreign body. We report the case of a solitary liver abscess caused by an ingested foreign body, a fish bone, migrated through the gastric wall into the left lobe. PMID- 26017107 TI - Renal tuberculosis: a case report. AB - Tuberculosis or TB (tubercle bacillus) remains a major public health problem in developing countries. Over the last decades extrapulmonary locations of the disease have become more frequent due to the increased prevalence of acquired immune deficiency syndrome and the increase number of organ transplants. The urogenital localization represents about 27% of all extra-pulmonary localizations of TB and may be due either to a disseminated infection or to a primitive genitourinary localization. The majority of patients, has pyuria, sometimes with hematuria. The diagnosis of urinary tuberculosis is based on the finding of pyuria in the absence of infection by common bacteria. The initial medical treatment includes isoniazide, rifampicin, pyrazinamide, ethambutol and streptomycin. This disease should be suspected in patients with unexplained urinary tract infections, especially if immunocompromised and/or coming from endemic areas. PMID- 26017108 TI - A rare localization of cerebral venous sinus thrombosis. Case report. AB - In this work the Authors report their experience on the treatment of a case of cavernous venous sinus thrombosis. The diagnosis is clinical and neuroradiological, CT, MRN, cerebral angiography and orbital venography have aided in establishing the diagnosis during life. Very interesting is the therapeutic approach. PMID- 26017111 TI - Experience of fetoscopic laser photocoagulation and cord transection for twin reversed arterial perfusion sequence. AB - AIM: The purpose of this study was to evaluate the usefulness of fetoscopic laser photocoagulation of placental communicating vessels or umbilical cord for twin reversed arterial perfusion (TRAP) sequence. MATERIAL AND METHODS: We report a retrospective case series of all cases of TRAP sequence identified from 2006 to 2014 at out institutions. Fetoscopic laser photocoagulation of placental arterioarterial and venovenous anastomoses was performed in diamniotic twins, and in cases of monoamniotic twins we performed laser photocoagulation and transection of the umbilical cord of the acardiac twin to prevent cord entanglement. Pregnancy and perinatal outcomes were estimated. RESULTS: Ten cases were included in the study. The median gestational age at procedure was 21.3 weeks (range, 16.7-27.3 weeks). All cases completed the procedure. Two cases were treated with laser photocoagulation and transection of the umbilical cord of the acardiac twin. No major immediate complications were noted. Preterm rupture of membranes occurred in four cases (40%). One case resulted in miscarriage. The other fetuses were delivered alive. Median gestational age at delivery was 35.4 weeks (range, 25.6-42.0 weeks). Median interval of treatment to delivery was 85 days (range, 43-153 days). Five out four infants were delivered preterm. The overall neonatal survival was 9/10. CONCLUSION: This case series demonstrated favorable outcome, and fetoscopic laser photocoagulation seems to be a useful treatment for TRAP sequence. In particular, transection of the umbilical cord is effective to prevent cord entanglement of monoamniotic twins. PMID- 26017112 TI - A multibiomarker approach to explore interactive effects of propranolol and fluoxetine in marine mussels. AB - A multi-biomarker approach, including several lysosomal parameters, activity and mRNA expression of antioxidant enzymes, and DNA damage, was employed to investigate the nominal effects of 0.3 ng/L fluoxetine (FX) and 0.3 ng/L propranolol (PROP) alone or in combination (0.3 ng/L FX + 0.3 ng/L PROP) on Mediterranean mussels after a 7 day treatment. FX co-exposure appears to facilitate PROP bioaccumulation because PROP only accumulated in digestive gland of FX + PROP treated mussels. Lysosomal parameters were significantly impaired by FX + PROP treatment, while no clear antioxidant responses at the catalytic and transcriptional levels were observed. Biomarker responses led to a "medium stress level" diagnosis in FX + PROP treated mussels, according to the Expert System, whereas 0.3 ng/L PROP or FX alone did not induce consistent stress conditions. These findings suggest vulnerability of coastal marine mussels to FX and PROP contamination at environmentally relevant levels. PMID- 26017113 TI - Risk of human exposure to polycyclic aromatic hydrocarbons: A case study in Beijing, China. AB - Polycyclic aromatic hydrocarbons (PAHs) can cause adverse effects on human health. The relative contributions of their two major intake routes (diet and inhalation) to population PAH exposure are still unclear. We modeled the contributions of diet and inhalation to the overall PAH exposure of the population of Beijing in China, and assessed their human incremental lifetime cancer risks (ILCR) using a Mont Carlo simulation approach. The results showed that diet accounted for about 85% of low-molecular-weight PAH (L-PAH) exposure, while inhalation accounted for approximately 57% of high-molecular-weight PAH (H PAH) exposure of the Beijing population. Meat and cereals were the main contributors to dietary PAH exposure. Both gaseous- and particulate-phase PAHs contributed to L-PAH exposure through inhalation, whereas exposure to H-PAHs was mostly from the particulate-phase. To reduce the cancer incidence of the Beijing population, more attention should be given to inhaled particulate-phase PAHs with considerable carcinogenic potential. PMID- 26017115 TI - Peptide profiling of Internet-obtained Cerebrolysin using high performance liquid chromatography - electrospray ionization ion trap and ultra high performance liquid chromatography - ion mobility - quadrupole time of flight mass spectrometry. AB - Cerebrolysin, a parenteral peptide preparation produced by controlled digestion of porcine brain proteins, is an approved nootropic medicine in some countries. However, it is also easily and globally available on the Internet. Nevertheless, until now, its exact chemical composition was unknown. Using high performance liquid chromatography (HPLC) coupled to ion trap and ultra high performance liquid chromatography (UHPLC) coupled to quadrupole-ion mobility-time-of-flight mass spectrometry (Q-IM-TOF MS), combined with UniProt pig protein database search and PEAKS de novo sequencing, we identified 638 unique peptides in an Internet-obtained Cerebrolysin sample. The main components in this sample originate from tubulin alpha- and beta-chain, actin, and myelin basic protein. No fragments of known neurotrophic factors like glial cell-derived neurotrophic factor (GDNF), neurotrophin nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) were found, suggesting that the activities reported in the literature are likely the result of new, hitherto unknown cryptic peptides with nootropic properties. PMID- 26017116 TI - Implicit and explicit self-related processing in relation to insight in patients with schizophrenia. AB - INTRODUCTION: Self-related processing (SRP) has been associated with clinical and cognitive insight. We investigated the relationship between implicit SRP (ISRP) and explicit SRP (ESRP) and insight. We first hypothesised that impaired insight is associated with the extent to which implicit feedback is incorporated in the self-image and subsequently influences behaviour. Second, we hypothesised that impaired insight is related to the way patients handle explicit feedback and use it to guide subsequent behaviour, therefore we expected to find a positive relationship between level of insight and the explicit self-related processing task. METHODS: Thirty-four schizophrenia patients and 23 healthy controls participated in the study. Patients were assessed with the Schedule for the Assessment of Insight-Expanded and the Beck Cognitive Insight Scale. ISRP was measured using a working memory two-back priming task. ESRP was measured with an adapted version of the Wisconsin Card Sorting Task where patients received explicit feedback on their performance. RESULTS: Cognitive insight, but not clinical insight, was positively associated with ISRP after implicit positive cues. Both clinical and cognitive insight were positively associated with the ability to adjust performance upon receiving explicit feedback, though cognitive insight was more strongly associated with overall task performance. CONCLUSIONS: Priming with positive cues improved performance on a working memory task in patients with good cognitive insight, but worsened performance in patients with impaired cognitive insight. Furthermore, our findings suggest that the ability to adequately use feedback may be a specific capacity that is related to insight. PMID- 26017118 TI - 2015 HPS Meeting Grid. PMID- 26017117 TI - Podocalyxin promotes cisplatin chemoresistance in osteosarcoma cells through phosphatidylinositide 3-kinase signaling. AB - Osteosarcoma (OS) is the most common type of primary bone malignancy. The use of multiagent, intensive chemotherapy has markedly improved the long-term survival rate of patients with OS. However, chemoresistance continues to be the principal reason for poor survival and disease recurrence in patients with OS. Innate or acquired resistance to cisplatin, which is one of the most effective drugs against OS, is common. Understanding the molecular basis underlying cisplatin chemoresistance in OS cells may serve as a basis for the identification of novel therapeutic targets and biomarkers. High expression levels of podocalyxin (PCX) have been shown to be correlated with poor outcome in various types of cancer. A recent study suggested that PCX may contribute to cancer chemoresistance. The present study aimed to explore the role of PCX in OS by determining its effects on cisplatin chemoresistance in OS cells. Stable overexpression and knockdown of PCX were performed in MG-63 and U2OS human OS cell lines. Overexpression of PCX in the two cell lines significantly increased the half maximal inhibitory concentration (IC50) of cisplatin, cell colony formation, phosphatidylinositide 3 kinase (PI3K) activity and Akt phosphorylation at serine 473, and decreased cisplatin-induced cell apoptosis. Furthermore, the effects of PCX were largely attenuated by treatment with the selective PI3K inhibitor BKM120. Conversely, knockdown of PCX expression markedly decreased the IC50 of cisplatin, cell colony formation, PI3K activity and Akt phosphorylation at serine 473, and increased cisplatin-induced cell apoptosis. In conclusion, the present study was the first, to the best of our knowledge, to provide evidence that PCX promotes cisplatin chemoresistance in OS cells through a PI3K-dependent mechanism. The results of the present study provided novel insight not only into the functional role of PCX in cancer, but also into the molecular mechanisms underlying OS chemoresistance. PMID- 26017120 TI - Gluttony in the ICU: is it really a deadly sin? PMID- 26017119 TI - Brimonidine reduces TGF-beta-induced extracellular matrix synthesis in human Tenon's fibroblasts. AB - BACKGROUND: Brimonidine is a highly selective alpha2 adrenergic agonist that has been widely used in anti-glaucoma eyedrops. The aim of this study was to investigate its putative anti-fibrotic role in the fibrosis caused by activated Tenon's fibroblasts. METHODS: Primary cultured human Tenon's fibroblasts were exposed to 2.0 ng/mL of transforming growth factor-beta1 (TGF-beta1) for up to 48 h. In the presence of various concentrations of brimonidine (from 0.0 to 10.0 MUM), the expression levels of fibronectin, collagen types I and III, and beta actin were determined by Western immunoblots. The expression of phosphorylated SMAD2/3 (p-SMAD2/3) was then evaluated using immunofluorescence. RESULTS: TGF beta1 significantly increased the synthesis of fibronectin and collagens in human Tenon's fibroblasts; however brimonidine treatment distinctly attenuated the TGF beta1-induced production of extracellular matrix (ECM) proteins. TGF-beta1 also changed the cellular morphology to be plump, while brimonidine treatment returned the cells to a spindle shape, similar to control fibroblasts. Regarding p SMAD2/3, brimonidine treatment did not show any apparent changes in its expression. CONCLUSIONS: Our data revealed that brimonidine reduces TGF-beta induced ECM synthesis in human Tenon's fibroblasts in vitro. This finding implies that topical administration of brimonidine may be helpful in reducing the fibrosis caused by the long-term use of topical anti-glaucoma medications. PMID- 26017121 TI - Infection control in times of Ebola: how well are we training the next generation of intensivists in Australia and New Zealand? PMID- 26017122 TI - Outcomes of decompressive craniectomy in patients after traumatic brain injury. AB - OBJECTIVE: Traumatic brain injury (TBI) can result in cerebral oedema and vascular changes resulting in an increase in intracranial pressure (ICP), which can lead to further secondary damage. Decompressive craniectomy (DC) is a surgical option in the management of ICP. We aimed to investigate outcomes of DC after TBI. DESIGN: We performed a retrospective audit of 57 adult patients (aged > 15 years) who underwent DC after TBI, at the Royal Melbourne Hospital from 1 January 2005 to 30 June 2011. Our functional outcome measure was the Extended Glasgow Outcome Scale (GOSE). RESULTS: Patients had a median age of 30 years (range, 17- 73 years). The hospital mortality rate was 47% (27 patients). A higher postoperative median ICP was the most significant predictor of hospital mortality (OR, 1.1; 95% CI, 1-1.3). There was a mean decrease of 7.7mmHg in ICP between the mean preoperative and postoperative ICP values (95% CI, - 10.5 to - 5.0mmHg). There was a mean decrease of 3.5mmHg in the mean cerebral perfusion pressure (CPP) from preoperative to postoperative CPP values (95% CI, - 6.2 to - 0.8mmHg). At the 6-month follow-up, a poor outcome (GOSE score, 1-4) was seen in 39 patients (68%), while a good outcome (GOSE score, 5- 8) was noted in 15 patients (26%). A high APACHE II score on admission was the most significant predictor of a worse GOSE score at 6 months (OR, 1.3; 95% CI, 1.1-1.5). Analysis of the APACHE II and IMPACT scores as models for predicting mortality at 6 months showed an area under the curve (AUC) of 0.792 and 0.805, respectively, and for predicting poor outcome at 6 months, showed an AUC of 0.862 and 0.883, respectively. CONCLUSION: DC decreased ICP postoperatively. The IMPACT and APACHE II scores are good models for prediction of death and poor outcome at 6 months. PMID- 26017123 TI - The intensive care workforce summit. AB - In the past 5 years, there has been a significant rise in the number of trained and fully qualified specialists in intensive care medicine. Recent concerns about saturation of specialist employment opportunities and the prospect of new Fellows unable to find appropriate employment after completion of training has brought intensive care workforce issues to the forefront. The board members of the College of Intensive Care Medicine (CICM) and Australia and New Zealand Intensive Care Society (ANZICS) held the Intensive Care Workforce Summit with presidents of other medical colleges, government officials and legal experts. Current data were presented on College trainee numbers and graduates and compared with similar data from other colleges. Results of workforce surveys of intensive care units and recent CICM graduates were also presented. Projections of future workforce requirements are notoriously uncertain but there was clear agreement among the group that currently, the employment opportunities for new Fellows at consultant level are limited. Recent changes to the selection process for new trainees have had a dramatic impact on the number of new trainees in 2014 but the enduring effect of this is yet to be determined. The group discussed potential growth areas for employment of intensive care consultants, including changes in employment patterns and also the impact of reduced numbers of trainees on unit staffing. CICM and ANZICS have agreed to continue to monitor and discuss the situation on a regular basis. PMID- 26017124 TI - Hospital outcomes associated with introduction of a two-tiered response to the deteriorating patient. AB - BACKGROUND: Liverpool Hospital introduced the medical emergency team system in 1990 and it has recently been adopted at a national and international level. New South Wales, Australia, has introduced a standardised rapid response system in over 250 acutecare hospitals: the two-tiered (clinical review call [CRC] and rapid response call [RRC]) "between the flags" (BTF) program. OBJECTIVES: To describe the effect of the introduction of a twotiered response to the deteriorating patient on the number of RRCs, cardiac arrests and hospital deaths. METHODS: Our study was undertaken at an 850-bed teaching hospital in the south west of Sydney, Australia, with about 80 000 hospital admissions each year. Rates of RRCs, cardiac arrests and all hospital deaths (with and without not-for resuscitation orders) were compared before the introduction of the BTF program (2009) and after implementation, until June 2013. The rates of CRCs after implementation were measured. Changes in the reasons for RRCs were also compared for the 12-month period before and the 36 months after the introduction of the BTF program. RESULTS: The monthly rate of RRCs before introduction of the program was 18.8 per 1000 hospital admissions (95% CI, 17.8- 19.8 per 1000 admissions) and was estimated to increase by 4% after program implementation (95% CI, 3.2% 4.7%; P < 0.001). The rate of CRCs increased by 13.2% (95% CI, 10.9%-15.6%) during the study period. The cardiac arrest rate before implementation of clinical review was 1.1 per 1000 admissions (95% CI, 0.9-1.3 per 1000 admissions) and after implementation was estimated to have changed by 1% (95% CI, - 1.9 to 3.9; P = 0.48). The hospital death rate before implementation of the BTF program was 10.8 per 1000 admissions (95% CI, 10.1-11.5 per 1000 admissions), and after implementation was estimated to increase by 2% (95% CI, 1.2%-3%, P < 0.001). The reasons for RRCs before and after the introduction of the BTF program did not change (all P values > 0.2), apart from the "worried" criterion, that decreased from 30% to 17% of all calls after implementation (P < 0.001). CONCLUSION: After introduction of the BTF program, there was a progressive increase in documented CRCs and an increase in RRCs. There was no decrease in cardiac arrests or hospital deaths. RRCs based on objective physiological criteria increased. More research is needed to evaluate two-tiered response systems. PMID- 26017125 TI - Continuous renal replacement therapy: current practice in Australian and New Zealand intensive care units. AB - BACKGROUND: Large multicentre studies of continuous renal replacement therapy (CRRT) in critically ill patients may influence its bedside prescription and practical application. Despite this, many aspects of CRRT may not be informed by evidence but remain a product of clinician preference. Little was known about current CRRT practice in Australia and New Zealand and it is not known if the evidence from recent studies has been integrated into practice. DESIGN AND SETTING: A prospective online survey of CRRT practice was sent to intensive care unit medical and nursing clinicians via three national databases in Australian and New Zealand ICUs in December 2013 to March 2014. RESULTS: There were 194 respondents from 106 ICUs; 49 ICUs (47%) were in tertiary metropolitan hospitals. One hundred and two respondents (54%) reported continuous venovenous haemodiafiltration as the most common CRRT technique, with a combination of predilution and postdilution of CRRT solutions. The prescription for CRRT was variable, with respondents indicating preferences for therapy based on L/hour (53%) or a weight-adjusted treatment in mL/kg/hour (47%). For all modes of CRRT, the common blood flow rates applied were 151-200mL/ minute and 201-250mL/minute. Few respondents reported preferring flow rates < 150 mL/minute or > 300mL/minute. Unfractionated heparin was the most commonly used anticoagulant (83%), followed by regional citrate. Femoral vein vascular access was preferred and, typically, a 20 cm length catheter was used. Bard Niagara and Arrow catheters were most frequently used. The Gambro Prismaflex was the dominant machine used (71%). CONCLUSIONS: Our results provide insight into existing clinical management of CRRT. There is considerable variation in the prescription of CRRT in Australian and New Zealand ICUs. PMID- 26017126 TI - Protocol for a multicentre randomised controlled trial of early and sustained prophylactic hypothermia in the management of traumatic brain injury. AB - INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Prophylactic hypothermia is effective in laboratory models, but clinical studies to date have been inconclusive, partly because of methodological limitations. Our Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomised controlled trial is currently underway comparing early, sustained hypothermia versus standard care in patients with severe TBI. We describe our study protocol and the challenges in conducting prophylactic hypothermia research in TBI. DESIGN: We aim to randomise 500 patients to either prophylactic 33 degrees C hypothermia initiated within 3 hours of injury and continued for at least 72 hours, or standard normothermic management. Patients will be enrolled by paramedic services in the prehospital setting, or by emergency department staff at participating sites in Australia, New Zealand and Europe. The primary outcome will be the eight-level extended Glasgow outcome scale (GOSE), dichotomised to favourable and unfavourable outcomes at 6 months after injury. Secondary outcomes will include mortality at hospital discharge and at 6 months, ordinal analyses of 6-month GOSE outcomes, quality of life with health economic evaluations and the differential proportion of adverse events. We will predefine subgroup and interaction analyses. DISCUSSION: After a run-in phase, recruitment for our main study began in December 2010. When the study is completed, we aim to provide evidence on the efficacy of prophylactic hypothermia in TBI to guide clinicians in their management of this devastating condition. PMID- 26017127 TI - Agreement between radial and femoral arterial blood pressure measurements during orthotopic liver transplantation. AB - OBJECTIVE: To study agreement between radial and femoral arterial pressure measurements in orthotopic liver transplantation (OLTx) surgery to determine whether arterial cannulation sites are interchangeable. DESIGN, SETTING AND PARTICIPANTS: Prospective observational study of 25 patients undergoing OLTx surgery. METHODS: Radial and femoral arteries were cannulated with standardised arterial line kits. Radial and femoral mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and pulse pressure (PP) were measured at four time points (30 minutes after induction of anaesthesia, 30 minutes after the start of the anhepatic phase, 30 minutes after liver graft reperfusion and 30 minutes after the start of bile duct anastomosis). MAIN OUTCOME MEASURES: The bias, precision and limits of agreement between radial and femoral arterial pressures were calculated in accordance with Bland-Altman statistics. RESULTS: Radial-femoral differences in MAP (mean difference, 4.8 mmHg [SD, 4.5 mmHg]), limits of agreement (- 13.6 and 8.8, P < 0.001) and DAP showed clinically acceptable agreement between measurement sites across all time points. However, clinically significant differences between radial and femoral SAPs (mean difference, - 14.9 mmHg [SD, 24.8 mmHg]) and limits of agreement (- 63.5 and 33.7, P < 0.001) occurred overall. This difference started after portal vein clamping and remained significant throughout the remainder of the operation. CONCLUSION: Radial artery SAP underestimates femoral artery measurements significantly but unpredictably. As femoral measurement is more likely to reflect central arterial pressure, radial SAP measurement is not reliable in adults undergoing OLTx. PMID- 26017128 TI - Do we practise low tidal-volume ventilation in the intensive care unit? a 14-year audit. AB - BACKGROUND: Low tidal volume ventilation (LTVV) has been shown to reduce mortality of patients with acute lung injury (ALI) but uptake by clinicians has been low. Recent studies have shown that LTVV results in survival benefit at 24 months after discharge and, importantly, benefits patients without ALI. OBJECTIVE: To determine adherence to LTVV in patients on mechanical ventilation (MV). DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of ventilator settings recorded within the clinical information system of a 15-bed general ICU in a tertiary referral hospital, between 1 January 2000 and 31 May 2013. METHODS: Analysis of mandatory MV with volume or pressure control. MAIN OUTCOME MEASURES: Adherence to LTVV (_6.5 mL/ kg predicted body weight [PBW]). RESULTS: We studied 4923 patients with a median age of 66 years (interquartile range [IQR], 57-74 years), and a median Acute Physiology and Chronic Health Evaluation II score of 16 (IQR, 13-19). Included were 3486 men (70.8%), and 3386 (66.8%) had undergone cardiac surgery. There were 249 450 ventilator measurements, with a median per patient of 75 measurements (IQR, 17-255 measurements). The median tidal volume was 8.15 mL/kg PBW (IQR, 7.15- 9.34 mL/kg PBW) for an adherence of 13.4%. Independent factors associated with adherence were sex, high inspiratory pressures, high positive end expiratory pressure and low PaO2/FiO2 ratio. CONCLUSION: Adherence to LTVV in a general cohort of ICU patients was low, but it was better in patients with more severe lung disease. Overestimation of PBW may have contributed to our findings. Regular auditing of LTVV adherence might be considered a clinical indicator of good MV practice. PMID- 26017129 TI - A cluster-randomised trial of a multifaceted quality improvement intervention in Brazilian intensive care units (Checklist-ICU trial): statistical analysis plan. AB - BACKGROUND: The Checklist During Multidisciplinary Visits for Reduction of Mortality in Intensive Care Units (Checklist- ICU) trial is a pragmatic, two-arm, cluster-randomised trial involving 118 intensive care units in Brazil, with the primary objective of determining if a multifaceted qualityimprovement intervention with a daily checklist, definition of daily care goals during multidisciplinary daily rounds and clinician prompts can reduce inhospital mortality. OBJECTIVE: To describe our trial statistical analysis plan (SAP). METHODS: This is an ongoing trial conducted in two phases. In the preparatory observational phase, we collect three sets of baseline data: ICU characteristics; patient characteristics, processes of care and outcomes; and completed safety attitudes questionnaires (SAQs). In the randomised phase, ICUs are assigned to the experimental or control arms and we collect patient data and repeat the SAQ. RESULTS: Our SAP includes the prespecified model for the primary and secondary outcome analyses, which account for the cluster-randomised design and availability of baseline data. We also detail the multiple mediation models that we will use to assess our secondary hypothesis (that the effect of the intervention on inhospital mortality is mediated not only through care processes targeted by the checklist, but also through changes in safety culture). We describe our approach to sensitivity and subgroup analyses and missing data. CONCLUSION: We report our SAP before closing our study database and starting analysis. We anticipate that this should prevent analysis bias and enhance the utility of results. PMID- 26017130 TI - Haemodynamic and biochemical responses to fluid bolus therapy with human albumin solution, 4% versus 20%, in critically ill adults. AB - BACKGROUND: Fluid bolus therapy (FBT) is common in critically ill patients. With the exception of use in patients with traumatic brain injury, FBT with human albumin solution (HAS) appears safe and perhaps superior in severe sepsis. OBJECTIVE: To determine the physiological effects of FBT with 4% v 20% HAS. DESIGN, SETTING AND PARTICIPANTS: A retrospective observational study of 202 critically ill patients receiving FBT with HAS in a tertiary intensive care unit between April 2012 and March 2013. METHODS: FBT was instituted with 4% or 20% HAS, according to clinician preference. MAIN OUTCOME MEASURES: We compared biochemical and haemodynamic data between groups at baseline and at 1, 2 and 4 hours after FBT. RESULTS: Patients who had received 20% HAS had more liver disease, a greater need for renal replacement therapy and higher Acute Physiology and Chronic Health Evaluation III scores on admission. Patients who had received 4% HAS received a median volume of 500 mL (interquartile range [IQR], 350-500 mL), compared with 100mL (IQR, 100- 200 mL) in the 20% HAS group (P < 0.0001); a median of 70 mmol v 10 mmol of sodium (P < 0.0001); and a median of 64 mmol v 2 mmol of chloride (P < 0.0001). There was a trend toward higher mean arterial pressures in the 20% group after FBT (78.2 mmHg v 76.4 mmHg, P = 0.03). There were no significant differences in the absolute or percentage change for any haemodynamic parameters. Serum biochemical test results were comparable with a non-significant signal of higher serum chloride and more negative base excess in patients receiving 4% HAS. CONCLUSIONS: Haemodynamically, FBT with 100mL of 20% HAS performs in an equivalent way to 500 mL of 4% HAS but delivers much less fluid, sodium and chloride. PMID- 26017131 TI - A multicentre audit of temperature patterns after traumatic brain injury. AB - BACKGROUND: Elevation of body temperature is common after traumatic brain injury (TBI). Suppressing fever may be beneficial. HYPOTHESIS: In clinical practice, temperature is maintained _37 degrees C. PARTICIPANTS, SETTING AND METHODS: A retrospective, multicentre, cohort study of patients with an intensive care unit admission diagnosis of TBI over a 6-month period. MAIN OUTCOME MEASURES: The mean proportion of time per day that temperature _37 degrees C or _38 degrees C (to correct for unequal measurements between patients, imputation was used between consecutive temperature measurements and a linear relationship was assumed); and the proportion of patients on each day with a peak temperature _37 degrees C. RESULTS: 217 patients with TBI were admitted to eight ICUs. The mean Acute Physiology and Chronic Health Evaluation II score of the cohort was 15.7 (SD, 7.7) and intracranial pressure monitoring was done in 29% of patients. The mean proportion of time on each day that temperature was _37 degrees C varied between 56% (SE, 2.6%) on Day 1 and 89% (SE, 3.7%) on Day 14. The mean proportion of time per day that temperature was > 38 degrees C was between a minimum of 11% (SE, 1.5%) on Day 1 and a maximum of 25% (SE, 4.4%) Day 11. The proportion of patients for whom daily peak temperature was > 37 degrees C ranged between a minimum of 73.2% (153/209) on Day 1 and a maximum of 97.4% (26/33) on Day 13. CONCLUSION: In patients with TBI, a substantial proportion of time is spent with a temperature _37 degrees C. Prospective validation of these data are required. PMID- 26017132 TI - Auditing an intensive care unit recycling program. AB - BACKGROUND: The provision of health care has significant direct environmental effects such as energy and water use and waste production, and indirect effects, including manufacturing and transport of drugs and equipment. Recycling of hospital waste is one strategy to reduce waste disposed of as landfill, preserve resources, reduce greenhouse gas emissions, and potentially remain fiscally responsible. We began an intensive care unit recycling program, because a significant proportion of ICU waste was known to be recyclable. OBJECTIVES: To determine the weight and proportion of ICU waste recycled, the proportion of incorrect waste disposal (including infectious waste contamination), the opportunity for further recycling and the financial effects of the recycling program. METHODS: We weighed all waste and recyclables from an 11-bed ICU in an Australian metropolitan hospital for 7 non-consecutive days. As part of routine care, ICU waste was separated into general, infectious and recycling streams. Recycling streams were paper and cardboard, three plastics streams (polypropylene, mixed plastics and polyvinylchloride [PVC]) and commingled waste (steel, aluminium and some plastics). ICU waste from the waste and recycling bins was sorted into those five recycling streams, general waste and infectious waste. After sorting, the waste was weighed and examined. Recycling was classified as achieved (actual), potential and total. Potential recycling was defined as being acceptable to hospital protocol and local recycling programs. Direct and indirect financial costs, excluding labour, were examined. RESULTS: During the 7-day period, the total ICU waste was 505 kg: general waste, 222 kg (44%); infectious waste, 138 kg (27%); potentially recyclable waste, 145 kg (28%). Of the potentially recyclable waste, 70 kg (49%) was actually recycled (14% of the total ICU waste). In the infectious waste bins, 82% was truly infectious. There was no infectious contamination of the recycling streams. The PVC waste was 37% contaminated (primarily by other plastics), but there was less than 1% contamination of other recycling streams. The estimated cost of the recycling program was about an additional $1000/year. CONCLUSION: In our 11-bed ICU, we recycled 14% of the total waste produced over 7-days, which was nearly half of the potentially recyclable waste. There was no infectious contamination of recyclables and minimal contamination with other waste streams, except for the PVC plastic. The estimated annual cost of the recycling program was $1000, reflecting the greater cost of disposal of some recyclables (paper and cardboard v most plastic types). PMID- 26017133 TI - The intensive care medicine workforce in Australia and New Zealand: oversupplied or underdemanded? PMID- 26017134 TI - The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia. PMID- 26017135 TI - Ventilator auto-triggering in brain death: still a trap for the unwary? PMID- 26017137 TI - A Comparison of ToxCast Test Results with In Vivo and Other In Vitro Endpoints for Neuro, Endocrine, and Developmental Toxicities: A Case Study Using Endosulfan and Methidathion. AB - INTRODUCTION: The U.S. Environmental Protection Agency's (EPA's) Toxicity Forecaster (ToxCast) is a potential tool for chemical prioritization, hazard identification, and risk assessment. We conducted a case study to compare ToxCast data with endpoints from other in vitro and in vivo studies for two data-rich pesticides: endosulfan and methidathion. METHODS: ToxCast assays for endocrine disruption, development (zebrafish), and neurotoxicity were qualitatively compared to traditional neurotoxicity, developmental and reproductive toxicity findings. We also used in vitro-in vivo extrapolation to convert half-maximal activity concentrations in active ToxCast assays to rat oral equivalent doses, and quantitatively compared these to the lowest observable effect level (LOEL) from in vivo studies. RESULTS: Endosulfan was inactive for GABAA R, unlike in vivo; but active with dopamine transporter assays and was neurotoxic in zebrafish as expected. Methidathion was not active for these endpoints in vivo or in vitro. Acetylcholinesterase inhibition was ToxCast-inactive, although both pesticides are inhibitors in vivo. ToxCast results were generally inactive for endosulfan estrogen receptor agonism and androgen receptor antagonism unlike in vivo. Calculated oral equivalent doses for estrogen receptor and androgen receptor pathways and for zebrafish assays for both compounds were generally consistent with in vivo LOELs. Endosulfan showed neurotoxicity and both pesticides showed developmental effects in the zebrafish assays, although methidathion is not developmentally toxic in vivo. CONCLUSIONS: ToxCast's predictions showed concordance on some endpoints and nonconcordance, consisting mainly of false inactives, in several critical endpoints, likely due to a lack of metabolic activation and limitations in assay design. Zebrafish assays were good predictors of developmental toxicity and neurotoxicity for endosulfan. PMID- 26017136 TI - The biphasic effects of oxidized-low density lipoprotein on the vasculogenic function of endothelial progenitor cells. AB - Late-outgrowth endothelial progenitor cells (EPCs) are stress-resistant and responsible for reparative functions in the cardiovascular system. Oxidized-LDL (oxLDL) plays a critical role in cardiovascular disease pathogenesis. However, it is largely unknown what the impacts of oxLDL are on late-outgrowth EPCs. This study aimed to investigate the concentration-related effects of oxLDL on EPC functions and related angiogenesis, in vitro and in vivo. In this study, early and late-outgrowth EPCs were generated from circulating human mononuclear cells. oxLDL may regulate EPC vasculogenic function via the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1). Lower concentrations (5 MUg/mL) of oxLDL can potentiate EPC tube formation in vitro and in vivo by activating eNOS mechanisms, which are mediated by p38 MAPK- and SAPK/JNK-related pathways. Higher concentrations of oxLDL (10-50 MUg/mL) impaired EPC function via the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways and consequent inhibition of eNOS activity, which could be reversed by anti-oxidants (diphenylene iodonium and apocynin) and gp91phox siRNA. In conclusion, oxLDL has concentration-dependent biphasic effects on human late-outgrowth EPC tube formation in vitro and in vivo. PMID- 26017138 TI - Insights into the structure and inhibition of Giardia intestinalis arginine deiminase: homology modeling, docking, and molecular dynamics studies. AB - Giardia intestinalis arginine deiminase (GiADI) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes GiADI an attractive target for drug design against G. intestinalis. One approach in the design of inhibitors of GiADI could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three dimensional structure of GiADI obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of GiADI identified through molecular dynamics simulation studies. An in silico analysis of druggability using the structure of GiADI was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential GiADI inhibitors were identified by docking of a set of 3196 commercial and 19 in-house benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand-enzyme complexes. PMID- 26017140 TI - Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Abeta40 Peptide Oligomerization. AB - Nonfibrillar neurotoxic amyloid beta (Abeta) oligomer structures are typically rich in beta-sheets, which could be promoted by metal ions like Zn(2+). Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Abeta40 peptide conformations and Zn(2+) binding modes to probe the effects of secondary structure on Abeta dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. Zn(2+) couples with preformed secondary structures (alpha-helix and beta-hairpin) to speed dimerization and stabilize the resulting dimer. Partial alpha-helices increase the dimerization speed, and dimers with alpha-helix rich conformations have the lowest energy. When Zn(2+) coordinates with residues D1, H6, H13, and H14, Abeta40 beta-hairpin monomers have the fastest dimerization speed. Dimers with experimentally observed zinc coordination (E11, H6, H13, and H14) form with slower rate but have lower energy. Zn(2+) cannot stabilize fibril-like beta-arch dimers. However, Zn(2+)-bound beta arch tetramers have the lowest energy. Collectively, zinc-stabilized beta-hairpin oligomers could be important in the nucleation-polymerization of cross-beta structures. Our results are consistent with experimental findings that alpha helix to beta-structural transition should accompany Abeta aggregation in the presence of zinc ions and that Zn(2+) stabilizes nonfibrillar Abeta oligomers and, thus, inhibits formation of less toxic Abeta fibrils. PMID- 26017139 TI - Altered LINE-1 Methylation in Mothers of Children with Down Syndrome. AB - Down syndrome (DS, also known as trisomy 21) most often results from chromosomal nondisjunction during oogenesis. Numerous studies sustain a causal link between global DNA hypomethylation and genetic instability. It has been suggested that DNA hypomethylation might affect the structure and dynamics of chromatin regions that are critical for chromosome stability and segregation, thus favouring chromosomal nondisjunction during meiosis. Maternal global DNA hypomethylation has not yet been analyzed as a potential risk factor for chromosome 21 nondisjunction. This study aimed to asses the risk for DS in association with maternal global DNA methylation and the impact of endogenous and exogenous factors that reportedly influence DNA methylation status. Global DNA methylation was analyzed in peripheral blood lymphocytes by quantifying LINE-1 methylation using the MethyLight method. Levels of global DNA methylation were significantly lower among mothers of children with maternally derived trisomy 21 than among control mothers (P = 0.000). The combination of MTHFR C677T genotype and diet significantly influenced global DNA methylation (R2 = 4.5%, P = 0.046). The lowest values of global DNA methylation were observed in mothers with MTHFR 677 CT+TT genotype and low dietary folate. Although our findings revealed an association between maternal global DNA hypomethylation and trisomy 21 of maternal origin, further progress and final conclusions regarding the role of global DNA methylation and the occurrence of trisomy 21 are facing major challenges. PMID- 26017141 TI - Aortic intima-media thickness and aortic diameter in small for gestational age and growth restricted fetuses. AB - OBJECTIVE: The objective of this study is to measure aortic intima-media thickness (aIMT) and aortic diameter (AD) in appropriate for gestational age (AGA) fetuses, small for gestational age (SGA) fetuses, and intrauterine growth restricted (IUGR) fetuses. METHODS: Case-control study performed between June 2011 and June 2012. Forty-nine AGA fetuses, 40 SGA fetuses, and 35 IUGR fetuses underwent concomitant measurement of aIMT and AD at a mean gestational age of 34.4 weeks. RESULTS: Median aIMT was higher in fetuses with IUGR (0.504 mm [95%CI: 0.477-0.530 mm]), than in SGA fetuses (0.466 mm [95% CI: 0.447-0.485 mm]), and AGA fetuses (0.471 mm [95% CI: 0.454-0.488 mm]) (p = 0.023). Mean AD was significantly lower in fetuses with IUGR (4.451 mm [95% CI: 4.258-4.655 mm]), than in AGA fetuses (4.74 mm [95% CI: 4.63-4.843 mm]) (p = 0.028). CONCLUSIONS: Growth restricted fetuses have a thicker aortic wall than AGA and SGA fetuses, which possibly represents preclinical atherosclerosis and a predisposition to later cardiovascular disease. PMID- 26017142 TI - Inhibition of NADPH oxidase activation reduces EAE-induced white matter damage in mice. AB - BACKGROUND: To evaluate the role of NADPH oxidase-mediated reactive oxygen species (ROS) production in multiple sclerosis pathogenesis, we examined the effects of apocynin, an NADPH oxidase assembly inhibitor, on experimental autoimmune encephalomyelitis (EAE). METHODS: EAE was induced by immunization with myelin oligodendrocyte glycoprotein (MOG (35-55)) in C57BL/6 female mice. Three weeks after initial immunization, the mice were analyzed for demyelination, immune cell infiltration, and ROS production. Apocynin (30 mg/kg) was given orally once daily for the entire experimental course or after the typical onset of clinical symptom (15 days after first MOG injection). RESULTS: Clinical signs of EAE first appeared on day 11 and reached a peak level on day 19 after the initial immunization. The daily clinical symptoms of EAE mice were profoundly reduced by apocynin. The apocynin-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination, reduced infiltration by encephalitogenic immune cells including CD4, CD8, CD20, and F4/80-positive cells. Apocynin reduced MOG-induced pro-inflammatory cytokines in cultured microglia. Apocynin also remarkably inhibited EAE-associated ROS production and blood-brain barrier (BBB) disruption. Furthermore, the present study found that post treatment with apocynin also reduced the clinical course of EAE and spinal cord demyelination. CONCLUSIONS: These results demonstrate that apocynin inhibits the clinical features and neuropathological changes associated with EAE. Therefore, the present study suggests that inhibition of NADPH oxidase activation by apocynin may have a high therapeutic potential for treatment of multiple sclerosis pathogenesis. PMID- 26017143 TI - HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis. AB - During prolonged hypoxia, hypoxia-inducible factors (HIFs) mediate an increase in erythropoiesis, leading to an increased red blood cell (RBC) mass and polycythemia. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by the preferential destruction of hypoxia-formed young RBCs, a phenomenon termed neocytolysis. The molecular and biochemical mechanisms involved in neocytolysis are unknown. We developed a murine model of neocytolysis by exposing mice to 12 % oxygen for 10 days followed by return to normoxia. Upon return to normoxia, there was excessive accumulation of reactive oxygen species (ROS) in RBCs from an increased reticulocyte mitochondrial mass correlating with decreased Bnip3L transcripts (Bnip3L mediates reticulocyte mitophagy) and reduced catalase activity. During hypoxia, upregulated miR-21 resulted in low catalase activity in young RBCs. Furthermore, neocytolysis was attenuated by antioxidants and plasma catalase and blunted in mice that had constitutively high expression of HIFs. Among human neonates studied, we report data supporting the existence of neocytolysis during the first week of life. Together, these experiments indicate that the major mechanisms causing neocytolysis involve (1) production of young RBCs with low catalase during hypoxia and (2) lysis of the young RBCs after return to normoxia, mediated by ROS from an increased mitochondrial mass. KEY MESSAGES: We report a mouse model of neocytolysis. Neocytolysis is caused by excessive ROS formation mediated by HIF. ROS is generated from increased mitochondria in reticulocytes. Hypoxia-generated RBCs have low catalase and are preferentially destroyed. Reduced catalase is regulated by increased microRNA-21. PMID- 26017144 TI - The Peripheral Olfactory Repertoire of the Lightbrown Apple Moth, Epiphyas postvittana. AB - The lightbrown apple moth, Epiphyas postvittana is an increasingly global pest of horticultural crops. Like other moths, E. postvittana relies on olfactory cues to locate mates and oviposition sites. To detect these cues, moths have evolved families of genes encoding elements of the peripheral olfactory reception system, including odor carriers, receptors and degrading enzymes. Here we undertake a transcriptomic approach to identify members of these families expressed in the adult antennae of E. postvittana, describing open reading frames encoding 34 odorant binding proteins, 13 chemosensory proteins, 70 odorant receptors, 19 ionotropic receptors, nine gustatory receptors, two sensory neuron membrane proteins, 27 carboxylesterases, 20 glutathione-S-transferases, 49 cytochrome p450s and 18 takeout proteins. For the odorant receptors, quantitative RT-PCR corroborated RNAseq count data on steady state transcript levels. Of the eight odorant receptors that group phylogenetically with pheromone receptors from other moths, two displayed significant male-biased expression patterns, one displayed significant female-biased expression pattern and five were expressed equally in the antennae of both sexes. In addition, we found two male-biased odorant receptors that did not group with previously described pheromone receptors. This suite of olfaction-related genes provides a substantial resource for the functional characterization of this signal transduction system and the development of odor-mediated control strategies for horticultural pests. PMID- 26017145 TI - Patent foramen ovale (PFO): is there life before death in the presence of PFO? AB - Patent foramen ovale (PFO) is an embryologic remnant with incomplete postnatal adhesion of the cardiac atrial septum primum and secundum. After birth, the prevalence of PFO decreases from about 35% at young to approximately 20% at old age. PFO has been associated with numerous conditions such as decompression illness in divers, migraine, high-altitude pulmonary oedema, cerebrovascular and coronary ischaemia, and obstructive sleep apnoea syndrome. PFO is the cause of intermittent atrial right-to-left shunt, and it can be the source of cardiac paradoxical embolism. So far, randomized controlled trials have not documented a reduced rate of cerebrovascular recurrent events in patients receiving PFO device closure as compared to those on medical treatment. The purpose of this article was to critically evaluate evidence on the pathophysiologic, clinical as well as prognostic relevance of PFO. PMID- 26017147 TI - Aquaporins-2 and -4 regulate glycogen metabolism and survival during hyposmotic anoxic stress in Caenorhabditis elegans. AB - Periods of oxygen deprivation can lead to ion and water imbalances in affected tissues that manifest as swelling (edema). Although oxygen deprivation-induced edema is a major contributor to injury in clinical ischemic diseases such as heart attack and stroke, the pathophysiology of this process is incompletely understood. In the present study we investigate the impact of aquaporin-mediated water transport on survival in a Caenorhabditis elegans model of edema formation during complete oxygen deprivation (anoxia). We find that nematodes lacking aquaporin water channels in tissues that interface with the surrounding environment display decreased edema formation and improved survival rates in anoxia. We also find that these animals have significantly reduced demand for glycogen as an energetic substrate during anoxia. Together, our data suggest that reductions in membrane water permeability may be sufficient to induce a hypometabolic state during oxygen deprivation that reduces injury and extends survival limits. PMID- 26017146 TI - STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis. AB - Calcium (Ca(2+)) regulates a plethora of cellular functions including hallmarks of cancer development such as cell cycle progression and cellular migration. Receptor-regulated calcium rise in nonexcitable cells occurs through store dependent as well as store-independent Ca(2+) entry pathways. Stromal interaction molecules (STIM) and Orai proteins have been identified as critical constituents of both these Ca(2+) influx pathways. STIMs and Orais have emerged as targets for cancer therapeutics as their altered expression and function have been shown to contribute to tumorigenesis. Recent data demonstrate that they play a vital role in development and metastasis of a variety of tumor types including breast, prostate, cervical, colorectal, brain, and skin tumors. In this review, we will retrospect the data supporting a key role for STIM1, STIM2, Orai1, and Orai3 proteins in tumorigenesis and discuss the potential of targeting these proteins for cancer therapy. PMID- 26017148 TI - miR-29c induction contributes to downregulation of vascular extracellular matrix proteins by glucocorticoids. AB - Maternal undernutrition increases maternal glucocorticoids (GCs) and alters microRNA expression in offspring. Given that the mechanisms of GC action on vascular development are not clear, this study examined the influence of GCs on microRNA 29c (miR-29c) and its predicted targets in primary rat aorta smooth muscle cells (RAOSMCs). Dexamethasone (Dex) and corticosterone (Cor) time dependently increased miR-29c expression and reduced collagen type III (Col3A1), collagen type IV (Col4A5), elastin (ELN), and matrix metalloproteinase-2 (MMP2) protein in RAOSMCs. These effects were blocked by mifepristone. These genes were also targeted by miR-29c, as confirmed by a significant decrease in luciferase reporter activity of Col3A1 (34%), Col4A5 (45%), ELN (17%), and MMP2 (28%). In cells transfected with reporter plasmids, including the 3'-untranslated region of genes targeted by miR-29c, treatment with Dex or Cor also resulted in decreases in luciferase activity. Gain or loss of function of miR-29c significantly altered mRNA expression of Col3A1 (26% and 26%, respectively), Col4A5 (28% and 32%, respectively), and MMP2 (24% and 14%, respectively) but did not affect ELN. Gain or loss of function of miR-29c also significantly altered protein levels of Col3A1 (51% and 16%, respectively), Col4A5 (56% and 22%, respectively), ELN (53% and 71%, respectively), and MMP2 (28% and 53%, respectively). Coincubation of anti-miR-29c with Dex or Cor partially attenuated the effects of these steroids on protein expression of Col3A1 (25% and 24%, respectively), Col4A5 (26% and 44%, respectively), ELN (31% and 55%, respectively), and MMP2 (46% and 26%, respectively) in RAOSMCs compared with anti-miR negative controls. Our results demonstrate that GCs regulate the expression of Col3A1, Col4A5, ELN, and MMP2, at least in part, through induction of miR-29c. PMID- 26017149 TI - Cerebral beta-Amyloidosis in Mice Investigated by Ultramicroscopy. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder. AD neuropathology is characterized by intracellular neurofibrillary tangles and extracellular beta-amyloid deposits in the brain. To elucidate the complexity of AD pathogenesis a variety of transgenic mouse models have been generated. An ideal imaging system for monitoring beta-amyloid plaque deposition in the brain of these animals should allow 3D-reconstructions of beta-amyloid plaques via a single scan of an uncropped brain. Ultramicroscopy makes this possible by replacing mechanical slicing in standard histology by optical sectioning. It allows a time efficient analysis of the amyloid plaque distribution in the entire mouse brain with 3D cellular resolution. We herein labeled beta-amyloid deposits in a transgenic mouse model of cerebral beta-amyloidosis (APPPS1 transgenic mice) with two intraperitoneal injections of the amyloid-binding fluorescent dye methoxy-X04. Upon postmortem analysis the total number of beta-amyloid plaques, the beta-amyloid load (volume percent) and the amyloid plaque size distributions were measured in the frontal cortex of two age groups (2.5 versus 7-8.5 month old mice). Applying ultramicroscopy we found in a proof-of-principle study that the number of beta-amyloid plaques increases with age. In our experiments we further observed an increase of large plaques in the older age group of mice. We demonstrate that ultramicroscopy is a fast, and accurate analysis technique for studying beta-amyloid lesions in transgenic mice allowing the 3D staging of beta amyloid plaque development. This in turn is the basis to study neural network degeneration upon cerebral beta-amyloidosis and to assess Abeta-targeting therapeutics. PMID- 26017150 TI - Impact of rapid influenza PCR testing on hospitalization and antiviral use: A retrospective cohort study. AB - Rapid PCR-based influenza tests are increasingly used as point-of-care diagnostics in hospitals and clinics. To our knowledge, no prior studies have described clinical outcomes with implementation of rapid PCR-based influenza tests in hospitalized adult inpatients. Electronic medical records were used to assess differences in laboratory testing time and antiviral use among a subset of 175 consecutive adult inpatients tested for influenza in two respiratory seasons before and after implementation of rapid PCR-based influenza testing at an academic medical center. Of the 350 hospitalized inpatients included in this analysis, 96 (27%) were over 65 years of age and 308 (88%) had a comorbid condition. The overall time to result decreased significantly from 25.2 to 1.7 hr (P < 0.001) after implementation of rapid PCR-based influenza testing. Among influenza-negative patients, the frequency of oseltamivir initiation remained unchanged (before: 43% vs. after: 45%; P = 0.60), though the median duration of oseltamivir was significantly decreased from 1.1 to 0.0 days (P < 0.001). By providing an earlier result to clinicians, rapid PCR-based influenza tests may decrease unnecessary antiviral use among adult inpatients who test negative for influenza. PMID- 26017151 TI - GABAergic inhibition is weakened or converted into excitation in the oxytocin and vasopressin neurons of the lactating rat. AB - BACKGROUND: Increased secretion of oxytocin and arginine vasopressin (AVP) from hypothalamic magnocellular neurosecretory cells (MNCs) is a key physiological response to lactation. In the current study, we sought to test the hypothesis that the GABAA receptor-mediated inhibition of MNCs is altered in lactating rats. RESULTS: Gramicidin-perforated recordings in the rat supraoptic nucleus (SON) slices revealed that the reversal potential of GABAA receptor-mediated response (EGABA) of MNCs was significantly depolarized in the lactating rats as compared to virgin animals. The depolarizing EGABA shift was much larger in rats in third, than first, lactation such that GABA exerted an excitatory, instead of inhibitory, effect in most of the MNCs of these multiparous rats. Immunohistochemical analyses confirmed that GABAergic excitation was found in both AVP and oxytocin neurons within the MNC population. Pharmacological experiments indicated that the up-regulation of the Cl(-) importer Na(+)-K(+) 2Cl(-) cotransporter isotype 1 and the down-regulation of the Cl(-) extruder K(+) Cl(-) cotransporter isotype 2 were responsible for the depolarizing shift of EGABA and the resultant emergence of GABAergic excitation in the MNCs of the multiparous rats. CONCLUSION: We conclude that, in primiparous rats, the GABAergic inhibition of MNCs is weakened during the period of lactation while, in multiparous females, GABA becomes excitatory in a majority of the cells. This reproductive experience-dependent alteration of GABAergic transmission may help to increase the secretion of oxytocin and AVP during the period of lactation. PMID- 26017152 TI - Knowledge, attitudes and practices toward breast cancer screening in a rural South African community. AB - OBJECTIVES: The study assessed the knowledge, attitudes and breast cancer screening practices amongst women aged 30-65 years residing in a rural South African community. METHOD: A quantitative, descriptive cross-sectional design was used and a systematic sampling technique was employed to select 150 participants. The questionnaire was pretested for validity and consistency. Ethical considerations were adhered to in protecting the rights of participants. Thereafter, data were collected and analysed descriptively using the Predictive Analytics Software program. RESULTS: Findings revealed that the level of knowledge about breast cancer of women in Makwarani Community was relatively low. The attitude toward breast cancer was negative whereas the majority of women had never performed breast cancer diagnostic methods. CONCLUSION: Health education on breast cancer screening practices is lacking and the knowledge deficit can contribute negatively to early detection of breast cancer and compound late detection. Based on the findings, community-based intervention was recommended in order to bridge the knowledge gap. PMID- 26017154 TI - Standardisation of the FAERS database: a systematic approach to manually recoding drug name variants. AB - PURPOSE: The US Food and Drug Administration Adverse Event Reporting System (FAERS), one of the world's largest spontaneous reporting systems, is difficult to use because of report duplication and a lack of standardisation in the recording of drug names. Unresolved data quality issues may distort statistical analyses, rendering the results difficult to interpret when detecting and monitoring adverse effects of pharmaceutical products. The aim of this study was to develop and implement a data cleaning protocol to identify and resolve drug nomenclature issues. The key 'data treatment' plan involved standardising drug names held in the FAERS database. METHODS: Four million five hundred and six thousand five hundred and seventy-seven. Individual Safety Reports submitted to the FAERS between 1 January 2003 and 31 August 2012 were included for this study. OpenRefine was used to standardise drug name variants in the database such that they were consistent with international non-proprietary nomenclature defined by the World Health Organisation Anatomical Therapeutic Chemical classification. Drug variants where generic constituents could not be confidently determined, undecipherable drug names and non-medicinal products were retained verbatim. RESULTS: After the standardisation process, more than 16 611 916 drug entries were cleaned to their relevant international non-proprietary name. The cleaned drug table comprised 71 858 drug name variants and includes both standardised and original terms. Ninety-nine per cent of drug names was standardised using this method. CONCLUSIONS: The millions of reports enclosed in the FAERS contain valuable information that is of interest to pharmacovigilance, toxicology and post-marketing surveillance researchers. With the standardisation of the drug nomenclature, the database can be better utilised by research groups around the world. PMID- 26017153 TI - Early life microbial colonization of the gut and intestinal development differ between genetically divergent broiler lines. AB - BACKGROUND: Host genetic makeup plays a role in early gut microbial colonization and immune programming. Interactions between gut microbiota and host cells of the mucosal layer are of paramount importance for a proper development of host defence mechanisms. For different livestock species, it has already been shown that particular genotypes have increased susceptibilities towards disease causing pathogens. The objective of this study was to investigate the impact of genotypic variation on both early microbial colonization of the gut and functional development of intestinal tissue. From two genetically diverse chicken lines intestinal content samples were taken for microbiota analyses and intestinal tissue samples were extracted for gene expression analyses, both at three subsequent time-points (days 0, 4, and 16). RESULTS: The microbiota composition was significantly different between lines on each time point. In contrast, no significant differences were observed regarding changes in the microbiota diversity between the two lines throughout this study. We also observed trends in the microbiota data at genus level when comparing lines X and Y. We observed that approximately 2000 genes showed different temporal gene expression patterns when comparing line X to line Y. Immunological related differences seem to be only present at day 0, because at day 4 and 16 similar gene expression is observed for these two lines. However, for genes involved in cell cycle related processes the data show higher expression over the whole course of time in line Y in comparison to line X. CONCLUSIONS: These data suggest the genetic background influences colonization of gut microbiota after hatch in combination with the functional development of intestinal mucosal tissue, including the programming of the immune system. The results indicate that genetically different chicken lines have different coping mechanisms in early life to cope with the outside world. PMID- 26017155 TI - mTORC1 signaling activates NRF1 to increase cellular proteasome levels. AB - Defects in the maintenance of protein homeostasis, or proteostasis, has emerged as an underlying feature of a variety of human pathologies, including aging related diseases. Proteostasis is achieved through the coordinated action of cellular systems overseeing amino acid availability, mRNA translation, protein folding, secretion, and degradation. The regulation of these distinct systems must be integrated at various points to attain a proper balance. In a recent study, we found that the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway, well known to enhance the protein synthesis capacity of cells while concordantly inhibiting autophagy, promotes the production of more proteasomes. Activation of mTORC1 genetically, through loss of the tuberous sclerosis complex (TSC) tumor suppressors, or physiologically, through growth factors or feeding, stimulates a transcriptional program involving the sterol regulatory element binding protein 1 (SREBP1) and nuclear factor erythroid derived 2-related factor 1 (NRF1; also known as NFE2L1) transcription factors leading to an increase in cellular proteasome content. As discussed here, our findings suggest that this increase in proteasome levels facilitates both the maintenance of proteostasis and the recovery of amino acids in the face of an increased protein load consequent to mTORC1 activation. We also consider the physiological and pathological implications of this unexpected new downstream branch of mTORC1 signaling. PMID- 26017157 TI - Reduction of ((t)BuN?)NbCl3(py)2 in a Salt-Free Manner for Generating Nb(IV) Dinuclear Complexes and Their Reactivity toward Benzo[c]cinnoline. AB - The organosilicon reducing reagent 2,3,5,6-tetramethyl-1,4-bis(trimethylsilyl) 1,4-diaza-2,5-cyclohexadiene (1a) was used for the one-electron, salt-free reduction of ((t)BuN?)NbCl3(py)2 (2), resulting in the formation of a neutral, triply chloride-bridged dinuclear niobium(IV) complex, [((t)BuN?)ClNb(py)](MU Cl)3[((t)BuN?)Nb(py)2] (3) in moderately high yield. Heating 3 in toluene at 80 degrees C caused a unique intramolecular rearrangement of 3 to another neutral dinuclear complex, [Cl2Nb(py)](MU-Cl)(MU-N(t)Bu)2[ClNb(py)2] (4), in which two niobium(IV) atoms were bridged by one chloride atom and two imido ligands. Reaction of complex 3 with benzo[c]cinnoline produced a benzo[c]cinnoline-bridged dinuclear niobium(V) complex 7 by an overall two-electron reduction of benzo[c]cinnoline through a disproportionation of 3 into a mixture of a niobium(V) complex 2 and a niobium(III) complex, the latter of which efficiently reduced benzo[c]cinnoline. PMID- 26017156 TI - Hypothalamic Agouti-Related Peptide mRNA is Elevated During Natural and Stress Induced Anorexia. AB - As part of their natural lives, animals can undergo periods of voluntarily reduced food intake and body weight (i.e. animal anorexias) that are beneficial for survival or breeding, such as during territorial behaviour, hibernation, migration and incubation of eggs. For incubation, a change in the defended level of body weight or 'sliding set point' appears to be involved, although the neural mechanisms reponsible for this are unknown. We investigated how neuropeptide gene expression in the arcuate nucleus of the domestic chicken responded to a 60-70% voluntary reduction in food intake measured both after incubation and after an environmental stressor involving transfer to unfamiliar housing. We hypothesised that gene expression would not change in these circumstances because the reduced food intake and body weight represented a defended level in birds with free access to food. Unexpectedly, we observed increased gene expression of the orexigenic peptide agouti-related peptide (AgRP) in both incubating and transferred animals compared to controls. Also pro-opiomelanocortin (POMC) mRNA was higher in incubating hens and significantly increased 6 days after exposure to the stressor. Conversely expression of neuropeptide Y and cocaine- and amphetamine-regulated transcript gene was unchanged in both experimental situations. We conclude that AgRP expression remains sensitive to the level of energy stores during natural anorexias, which is of adaptive advantage, although its normal orexigenic effects are over-ridden by inhibitory signals. In the case of stress-induced anorexia, increased POMC may contribute to this inhibitory role, whereas, for incubation, reduced feeding may also be associated with increased expression in the hypothalamus of the anorexigenic peptide vasoactive intestinal peptide. PMID- 26017162 TI - A Method to Evaluate Fetal Erythropoiesis from Postnatal Survival of Fetal RBCs. AB - Fetal RBCs are produced during a period of very rapid growth and stimulated erythropoiesis under hypoxic intrauterine conditions. Fetal RBC life span varies with gestational age (GA) and is shorter than that in healthy adults. Due to the special kinetic properties of life span-based survival of human RBCs, a mathematical model-based kinetic analysis of the survival of fetal RBCs shortly after birth provides a unique opportunity to "look backward in time" to evaluate fetal erythropoiesis. This work introduces a novel method that utilizes postnatal in vivo RBC survival data collected within 2 days after birth to study both nonsteady-state (non-SS) in utero RBC production and changing fetal RBC life span over time. The effect of changes in erythropoiesis rate and RBC life span and the effect of multiple postnatal phlebotomies on the RBC survival curves were investigated using model-based simulations. This mathematical model, which considers both changes in the rate of erythropoiesis and RBC life span and which accurately accounts for the confounding effect of multiple phlebotomies, was applied to survival curves for biotin-labeled RBCs from ten anemic very low birth weight preterm infants. The estimated mean fetal RBC production rate scaled by body weight was 1.07 * 10(7) RBCs/day g, and the mean RBC life span at birth was 52.1 days; these values are consistent with reported values. The in utero RBC life span increased at a rate of 0.51 days per day of gestation. We conclude that the proposed mathematical model and its implementation provide a flexible framework to study in utero non-SS fetal erythropoiesis in newborn infants. PMID- 26017163 TI - Drug Carriers: Not an Innocent Delivery Man. AB - Biomaterials used as drug carriers are often considered inactive and assumed to have no other roles than modifying pharmacokinetics and biodistribution of a drug. On the other hand, there are several examples in which the carrier materials show bioactivities in the body, which may have been underestimated or inadvertently ignored. This review highlights several examples where biomaterials used as drug carriers bring biological effects, known or newly discovered, and discusses their implications in development of new drug delivery systems. PMID- 26017165 TI - Fibular head transfixion wire and its relationship to common peroneal nerve: cadaveric analysis. AB - Proximal tibio-fibular joint is routinely stabilised during leg lengthening, peri articular fractures and deformity corrections of tibia. Potential injury to the common peroneal nerve at the level of the fibula head/neck junction during wire insertion is a recognised complication. Previous studies have mapped the course of the common peroneal nerve and its branches at the level of the fibular head, and guidelines are published regarding placement of proximal tibial wires. This study aims to relate the course of the common peroneal nerve to the placement of a lateral insertion fibula head transfixion wire. Standard 1.8-mm Ilizarov 'olive' wires were inserted in the fibula head of 10 un-embalmed cadaveric knees. Wires were inserted percutaneously to the fibula head using surface anatomy landmarks and palpation technique. The course of the common peroneal nerve was then dissected. Distances from wire entry point to the course of the common peroneal nerve were measured post-wire insertion. The mean distance of the common peroneal nerve from the anterior aspect of the broadest point of the fibular head was 24.5 mm (range 14.2-37.7 mm). Common peroneal nerve was seen to cross the neck of fibula at a mean distance of 34.8 mm from the tip of fibula (range 21.5 44.3 mm). Wire placement was found to be on average, 52 % of the maximal AP diameter of the fibula head and 64 % of the distance from tip of fibula to the point of nerve crossing fibula neck. When inserting a fibula head transfixion wire, care must be taken not to place wire entry point too distal or posterior on the fibula head. Observing a safe zone in the anterior half of the proximal 20 mm of the fibula head would avoid injury to the nerve. In cases where palpation of fibula is difficult due to patient habitus, we recommend consideration of the use of fluoroscopic guidance during wire transfixion of the proximal tibio-fibular articulation to avoid wire insertion too distally and subsequent potential nerve injury. PMID- 26017164 TI - Long-term follow-up of dogs with leishmaniosis treated with meglumine antimoniate plus allopurinol versus miltefosine plus allopurinol. AB - BACKGROUND: Visceral leishmaniosis is a potentially life-threatening illness caused by a protozoan parasite of the genus Leishmania. It is found mainly in areas where both the parasite and its vector are endemic and is one of the most challenging infectious diseases in the world to control. HIV infected patients are vulnerable to Leishmania infections, and the main reservoir hosts of Leishmania infantum parasites are domestic dogs. Here, we evaluated the long-term efficacy of treatment with meglumine antimoniate plus allopurinol (G1) compared to miltefosine plus allopurinol (G2) in dogs naturally infected L. infantum. METHODS: Eighteen dogs with leishmaniosis were divided into the following two groups: G1 (n = 9) was treated subcutaneously with meglumine antimoniate (100 mg/kg/day/30 days) plus allopurinol (10 mg/kg/per day/30 days), while G2 (n = 9) was treated orally with miltefosine (2 mg/Kg/day/30 days) plus allopurinol (10 mg/kg/day/30 days). Thereafter, the same dose of allopurinol was administered to both groups for 6 years. Leishmania DNA in lymph node aspirates from the G1 and G2 dogs was quantified by real-time quantitative PCR at baseline and every 3 months for 24 months, and then at 28, 36, 48, 60 and 72 months. At each assessment, the dogs were examined for signs of disease, and their clinical scores were recorded. RESULTS: Both combination therapies produced significant clinical improvements in the dogs, with a significant reduction in the parasitic load in the lymph nodes of the dogs from both groups after 3 months of treatment. Clinical relapses were observed in four dogs from G2 (miltefosine/allopurinol), and just one dog from G1 (meglumine antimoniate/allopurinol). All dogs that relapsed had increased clinical scores, and increased anti-Leishmania antibody titers and parasitic loads in their lymph nodes. CONCLUSIONS: Long-term, the clinical and laboratory findings of the G1 dogs were more stable than those of the G2 dogs, thus indicating that meglumine antimoniate had better clinical efficacy than miltefosine. The results suggest that treatment with allopurinol as a maintenance therapy is crucial for stabilizing the care of canine leishmaniosis. PMID- 26017166 TI - Bone marrow necrosis in acute leukemia: Clinical characteristic and outcome. AB - Bone marrow necrosis (BMN) is characterized by infarction of the medullary stroma, leading to marrow necrosis with preserved cortical bone. In reported small series, BMN in hematological malignancies is associated with poor prognosis. We sought to find the impact of BMN on clinical outcome in a relatively larger cohort of patients with acute leukemias. Overall we evaluated 1,691 patients; 1,051 with acute myeloid leukemia (AML) and 640 with acute lymphocytic leukemia referred to our institution between 2002 and 2013. Patients with AML and acute lymphoblastic leukemia (ALL) were evaluated separately to determine the incidence of BMN, associated clinical features and its prognostic significance. At initial diagnosis, BMN was observed in 25 (2.4%) patients with AML and 20 (3.2%) patients with ALL. In AML, BMN was significantly associated with French-American-British AML M5 morphology (32% vs. 10%, P = 0.002). The complete remission (CR) rate in AML with and without BMN was 32% and 59% respectively (P = 0.008). Likewise, CR rate in ALL with BMN was also inferior, 70% vs. 92% (P = 0.005). The median overall survival (OS) in AML with BMN was significantly poorer, 3.7 months compared to 14 months without BMN (P = 0.003). Similarly, the median OS in ALL with and without BMN was 61.7 and 72 months respectively (P = 0.33). BMN is not a rare entity in AML and ALL, but is infrequent. BMN in AML and in ALL is suggestive of inferior response and poor prognosis. PMID- 26017167 TI - Lutein, Trolox, ascorbic acid and combination of Trolox with ascorbic acid can improve boar semen quality during cryopreservation. AB - BACKGROUND: Due to pour quality of cryopreserved boar semen, artificial innsemination with frozen-thawed semen is quite limited. Developing protocols of boar semen cryopreservation represents a priority but also a challange. OBJECTIVE: The goal of the present study was to evaluate the antioxidant potential of lutein, Trolox, ascorbic acid, and certain combinations of Trolox with ascorbic acid on boar semen cryopreservation procedure. MATERIALS AND TMETHODS: Antioxidants were added to lactose-egg yolk extender, containing a final concentration of 3% glycerol and 0.5% Equex-STM. Semen of six boars was cryopreserved using straw-freezing procedure. After cryopreservation semen was thawed and evaluated for motility, normal apical ridge (NAR), hypo-osmotic swelling test (HOST) and DNA fragmentation index (DFI). Data were analyzed by one way ANOVA. RESULTS: The results showed better motility after thawing at the concentration of 10 MUM lutein, 200 MUM Trolox, 200 MUM ascorbic acid and 400-200 MUM Trolox and ascorbic acid. The supplementation on boar freezing extender with 10 MUM lutein increased post-thawed motility, NAR and HOST values (P < 0.01), and decrease DFI (P < 0.05) in comparison with control group. Similar results were obtained using 400-200 MUM Trolox and ascorbic acid, with better results in the case of DFI (P < 0.01). In comparison with the control group, a concentration of 200 MUM Trolox and 200 MUM ascorbic acid provided significant differences (P < 0.01) of motility and NAR. CONCLUSION: The analysis of sperm characteristics showed that lutein and the mix between Trolox and ascorbic acid used in boar semen cryopreservation can improve the quality of spermatozoa. PMID- 26017168 TI - A feasibility study towards cryopreservation of silkworm eggs: response of non diapause silkworm eggs to low temperature. AB - Insect embryos are very sensitive to chilling temperatures and vary with species and their developmental stages. Insect eggs are small and can supercool to temperatures ranging from -5 degrees C to -40 degrees C. In general, insects rely on a variety of ecological and physiological adaptations to survive low temperatures, making cryopreservation technique significantly complex. Mulberry silkworm (Bombyx mori L., Lepidoptera: Bombycidae) eggs are cleidoic with chorion (approximately 20-25 MUm thick). Preservation of non-diapause eggs to a limited period is practiced usually to delay hatching. The advantage of early embryonic periods having resistance to low temperature is utilized for chilling of eggs and preservation for long periods. However, technique for cryopreservation of silkworm eggs is not yet developed and the identification of precise embryonic stage and chill sensitivity is necessary for effective silkworm cryopreservation. The paper reports the chill-sensitivity and tolerance of non-diapause silkworm embryos of mulberry silkworm at various embryonic stages. Silkworm embryo of 48h age are relatively chill-sensitive as compared to other embryonic ages. This is vital information for the development of cryopreservation protocol for silkworm eggs. PMID- 26017169 TI - Cryopreservation effect on proliferation and differentiation potential of cultured chorion cells. AB - BACKGROUND: Fetoplacental tissues including the early chorion contain stem cells with various morphological and functional characteristics. Cultured chorionic cells may be used in perspective therapies of different pathologies. OBJECTIVE: To investigate the effect of cryopreservation on proliferation and differentiation potential of chorion cell culture (ChCC). MATERIALS AND METHODS: Five freezing programs for ChCC were compared: Program 1, cooling from 25 degrees C down to -30 degrees C at 0.5 degrees C/min; Program 2, cooling from 25 degrees C down to -30 degrees C at 1 degrees C/min; Program 3, cooling from 25 degrees C down to -10 degrees C at 1 degrees C/min with further cooling down to - 80 degrees C at 10 degrees C/min; Program 4, cooling from 25 degrees C down to -5 degrees C at 1 degrees C/min with further cooling down to -80 degrees C at 10 degrees C/min; Program 5, cooling from 25 degrees C down to -6 degrees C at 1 degrees C/min with further crystal seeding by adding the surplus nitrogen into the chamber, and cooling down to -80 degrees C at 10 degrees C/min. Viability, adhesion, proliferation and directed differentiation were examined. RESULTS: Freezing program 5 achieved the best result, with the highest viability, adhesion, proliferation and directed differentiation. CONCLUSION: The data may help establishing better cryopreservation protocols for perspective chorionic cell lines and their further application in biotechnology. PMID- 26017170 TI - Effects of mechanical delipation in porcine oocytes on mitochondrial distribution, ROS activity and viability after vitrification. AB - BACKGROUND: Porcine oocytes were sensitive to cooling because of the presence of excessive lipids. OBJECTIVE: To evaluate the effect of lipid removal on the mitochondrial distribution, the formation of reactive oxygen species (ROS) and the viability of porcine oocytes after vitrification. MATERIALS AND METHODS: Porcine oocytes were cultured in vitro, and lipid droplets were removed at the MII stage by mechanical delipation via micromanipulation. Mitochondrial distribution, ROS activity and oocyte viability were assessed after delipation and vitrification. RESULTS: Vitrification disrupted mitochondrial distribution in oocytes. The vitrified groups had a significantly lower rate of oocytes with normal mitrochondrial distribution than the fresh control group (39.6% and 58.5% versus 88.9%). The percentage of oocytes with normal mitochondrial distribution was significantly lower in the delipated group than that in the undelipated group after vitrification (39.6% vs 58.5%, p < 0.05). Vitrification also increased the ROS activity (p < 0.05); but there was no significant difference between the delipated and the undelipated groups (p > 0.05). Delipated oocytes developed into blastocysts via parthenogenetic activation without vitrification. Delipation significantly decreased the rate of blastocyst formation. Vitrification also decreased the rates of cleavage and blastocyst formation (p < 0.05). The delipated group had a significantly higher cleavage rate than the undelipated group after vitrification (21.4% versus 10.4%). CONCLUSION: Lipid removal at the MII stage via micromanipulation impaired their subsequent development of porcine oocytes. Although vitrification causes an abnormal distribution of mitochondria and an increase in ROS production in porcine oocytes, the removal of lipid droplets improves subsequent development after vitrification. PMID- 26017171 TI - Can additives ameliorate oxidative stress and improve development of Greenshell mussel (Perna canaliculus) oocytes during cryopreservation? AB - BACKGROUND: Cryopreservation of P. canaliculus oocytes has not yet been achieved. OBJECTIVE: The present study is to investigate whether the incorporation of: DMSO (0.09%), alpha-tocopherol (0.1 mM) plus taurine (1 mM) and ethylenediaminetetraacetic acid (EDTA; 0.1 mM), is beneficial during cryopreservation. METHODS: These three additives were incorporated to both the cryoprotectant (CPA) and recovery media, and evaluated in terms of development and oxidative stress at three key stages of cryopreservation: 1) cryoprotectant addition [10% v/v ethylene glycol plus 0.2M trehalose; final concentration], 2) cooling to -6 degrees C, and 3) cooling to -35 degrees C and liquid nitrogen immersion. RESULTS: Over all treatments (including controls) progressive cryopreservation steps resulted in a decrease in fertilization and development to D-larvae, an increase in macromolecular oxidative damage markers (protein carbonyls, lipid hydroperoxides and oxidized DNA), and a decrease in enzymatic (superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase) and non-enzymatic antioxidants. CONCLUSION: Whilst results varied, the major effects of the additives were the improved percentage fertilization and a decrease in macromolecular damage. PMID- 26017172 TI - Hydroxyapatite nanoparticles improved survival rate of vitrified porcine oocytes and its mechanism. AB - BACKGROUND: Cryopreservation of oocyte has become most essential for the long term conservation and widespread dispersion of animal genetic resources, but the efficiency of oocyte cryopreservation remains low. OBJECTIVE: The present study is to study the effect of hydroxyapatite (HA) nanoparticles on the survival rate of vitrified oocytes and the possible mechanism of cryopreserving oocytes with nanoparticles. MATERIALS AND METHODS: Porcine oocytes were vitrified in cryoprotectant (CPA) with biocompatible HA nanoparticles by Cryotop. The recrystallization of nano-CPA was observed with cryomicroscope. RESULTS: When 0.01%, 0.02%, 0.05% and 0.1% HA nanoparticles were added into vitrification solution, the survival rate of oocytes after in vitro maturation ranged from 25.9% to 35.4%, which is significantly higher than group without HA nanoparticles (14.7%). The microphotographs of oocytes in different solutions during freezing, thawing and melting showed that HA nanoparticles at a certain concentration can hinder the recrystallization of vitrification solution during rewarming. CONCLUSION: We speculate that preventing the recrystallization is the reason that nano-CPA can promote the survival rate of vitrified oocytes. PMID- 26017173 TI - Cryopreservation of sugarcane using the V cryo-plate technique. AB - BACKGROUND: Sugarcane is a tropical crop of major importance primarily for its high sucrose content. It is difficult to conserve it in the field or in vitro because of biotic and abiotic stresses. Cryopreservation of sugarcane germplasm is an appropriate approach for conserving its genetic diversity. OBJECTIVE: This study was carried out to develop an efficient and practical cryopreservation protocol for sugarcane with high post-cryopreservation recovery. MATERIALS AND METHODS: Factors affecting regrowth after cryopreservation using the V cryo-plate method including preculture medium, size of shoot tips, sucrose concentration in loading solution, exposure time to PVS2, light conditions after liquid nitrogen exposure, presence and absence of alginate gel and recovery medium composition were studied. RESULTS: Shoot tips with a length of 1.5 to 2.0 mm, precultured on semi-solid 1/2 MS medium for 1 day and semi-solid MS medium with 0.5 M sucrose for 1 day, treated with LS containing 2.0 M glycerol + 1.6 M sucrose for 30 min and exposed to PVS2 for 30 min showed maximum (100%) recovery after cryopreservation. It was also observed that removing the alginate gel and keeping the cultures in the dark for 7 days after cryopreservation significantly improved recovery. After optimizing the cryopreservation conditions using sugarcane variety Ni-1, 10 additional varieties were cryopreserved using the optimized protocol, with regrowth ranging from 56.7% to 100%. CONCLUSION: This study showed that V cryo-plate is an efficient and practical method for cryopreservation of sugarcane shoot tips in genebanks. PMID- 26017174 TI - Vapor pressures above the vitrified sucrose solution at low temperatures. AB - BACKGROUND: Vitrified solutions are encountered in food and biomaterial preservation. Data of the equilibrium water vapor pressure above the vitrified solution are scarce at temperatures below 0 degrees C. OBJECTIVE: The study measures the water vapor pressures above vitrified sucrose solutions. MATERIALS AND METHODS: Sucrose solutions with concentration ranging from 75% to 79% (wt) were vitrified by cooling in liquid nitrogen, and placed in a thermostat bath. Vapor pressure was measured with a high precision pressure gauge using static method. The vitrification of sucrose solution was verified with DSC. RESULTS: Experimental data were compared with two models. The empirical Zobrist model fits the experimental data well. The free volume model was improved by fitting the interaction parameter to experimental data. The average discrepancy could be reduced from 5.57% to 2.86%. CONCLUSION: The data have significant implications in the driving force of water removal in secondary drying process. PMID- 26017175 TI - Successful production of piglets derived from mature oocytes vitrified using OPS method. AB - OBJECTIVE: Examination of effect of vitrification solution with or without foetal calf serum (FCS) on the in vitro and in vivo survival of matured pig oocytes. MATERIALS AND METHODS: Exp. 1: oocytes were exposed to vitrification solutions: VSa (15% DMSO, 15% EG, 0.5 M sucrose dissolved in TCM-199 with FCS) or VSb (VSa without FCS). Exp. 2: oocytes were vitrified in VSa or VSb using OPS. A fraction of vitrified oocytes were transferred to 6 synchronised and inseminated recipients.. RESULTS: Survival rate after exposure and vitrification was the same for VSa and VSb. Transfer of 48 oocytes vitrified in VSb resulted with two pregnancies and 12 live piglets. Molecular analysis results: eight piglets originated from the surrogate mother's oocytes, four piglets from vitrified oocytes.. CONCLUSION: The use of DMSO and EG as cryoprotectants without serum supplementation was advantageous for the in vivo development of vitrified mature porcine oocytes. PMID- 26017176 TI - Manganese and the Evolution of Photosynthesis. AB - Oxygenic photosynthesis is the most important bioenergetic event in the history of our planet-it evolved once within the Cyanobacteria, and remained largely unchanged as it was transferred to algae and plants via endosymbiosis. Manganese plays a fundamental role in this history because it lends the critical redox behavior of the water-oxidizing complex of photosystem II. Constraints from the photoassembly of the Mn-bearing water-oxidizing complex fuel the hypothesis that Mn(II) once played a key role as an electron donor for anoxygenic photosynthesis prior to the evolution of oxygenic photosynthesis. Here we review the growing body of geological and geochemical evidence from the Archean and Paleoproterozoic sedimentary records that supports this idea and demonstrates that the oxidative branch of the Mn cycle switched on prior to the rise of oxygen. This Mn-oxidizing phototrophy hypothesis also receives support from the biological record of extant phototrophs, and can be made more explicit by leveraging constraints from structural biology and biochemistry of photosystem II in Cyanobacteria. These observations highlight that water-splitting in photosystem II evolved independently from a homodimeric ancestral type II reaction center capable of high potential photosynthesis and Mn(II) oxidation, which is required by the presence of homologous redox-active tyrosines in the modern heterodimer. The ancestral homodimer reaction center also evolved a C-terminal extension that sterically precluded standard phototrophic electron donors like cytochrome c, cupredoxins, or high-potential iron-sulfur proteins, and could only complete direct oxidation of small molecules like Mn(2+), and ultimately water. PMID- 26017178 TI - Microparticulated systems based on chitosan and poly(vinyl alcohol) with potential ophthalmic applications. AB - Spherical microparticles for encapsulation of drugs for the treatment of diseases, with a diameter ranging between 2 and 4 um, were obtained by double crosslinking (ionic and covalent) of chitosan and poly(vinyl alcohol) blend in a water-in-oil emulsion. Microparticles characterisation was carried out in terms of structural, morphological and swelling properties in aqueous media. The presence of chitosan in particles composition confers them a pH-sensitive character. Toxicity and hemocompatibility tests prove the biocompatible character of microparticles. The pilocarpine loading capacity is high as well as the release efficiency which increases up to 72 and 82% after 6 h. The obtained results recommend the microparticles as sustained release drug carriers for the treatment of eye diseases. PMID- 26017177 TI - Long-term Outcome of Extranodal NK/T Cell Lymphoma Patients Treated With Postremission Therapy Using EBV LMP1 and LMP2a-specific CTLs. AB - Extranodal NK/T-cell lymphoma (ENKTCL) is associated with latent Epstein-Barr virus (EBV) infection and frequent relapse even after complete response (CR) to intensive chemotherapy and radiotherapy. The expression of EBV proteins in the tumor provides targets for adoptive immunotherapy with antigen-specific cytotoxic T cells (CTL). To evaluate the efficacy and safety of EBV latent membrane protein (LMP)-1 and LMP-2a-specific CTLs (LMP1/2a CTLs) stimulated with LMP1/2a RNA transferred dendritic cells, we treated 10 ENKTCL patients who showed complete response to induction therapy. Patients who completed and responded to chemotherapy, radiotherapy, and/or high-dose therapy followed by stem cell transplantation (HDT/SCT) were eligible to receive eight doses of 2 * 10(7) LMP1/2a CTLs/m(2). Following infusion, there were no immediate or delayed toxicities. The 4-year overall survival (OS) and progression-free survival (PFS) were 100%, and 90% (95% CI: 71.4 to 100%) respectively with a median follow-up of 55.5 months. Circulating IFN-gamma secreting LMP1 and LMP2a-specific T cells within the peripheral blood corresponded with decline in plasma EBV DNA levels in patients. Adoptive transfer of LMP1/2a CTLs in ENKTCL patients is a safe and effective postremission therapeutic approach. Further randomized studies will be needed to define the role of EBV-CTLs in preventing relapse of ENKTCL. PMID- 26017179 TI - Aesthetic Breast Augmentation Mastopexy Followed by Post-surgical Pyoderma Gangrenosum (PSPG): Clinic, Treatment, and Review of the Literature. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a rare autoinflammatory neutrophilic ulcerative skin disease, often developing after a trauma or surgical wounds. In the literature there are several reports of post-surgical PG (PSPG) of the breast. The authors of this article experienced an impressive case of PSPG after an aesthetic breast augmentation mastopexy. PSPG is a rare but severe complication in this elective aesthetic surgical procedure. METHOD: A systematic review of the literature was performed, focusing on PSPG after aesthetic breast surgery (augmentation mammoplasty/mastopexy). The online databases Pubmed, Medline, and Cochrane were used and additionally a Google(c) search was conducted. We compared the data obtained from a systematic literature review to an index case of PSPG after esthetic augmentation mammoplasty. RESULTS: The literature search identified seven articles describing eight cases of PSPG after aesthetic breast surgery. In four of these cases augmentation mammoplasty had been carried out, in two cases mastopexy and in two cases augmentation mammoplasty and mastopexy (augmentation mastopexy). The patient we treated and describe in this paper underwent an augmentation mastopexy outside our clinic. Eight patients suffered from local disease, at the site of surgical wounds, one patient had disseminated disease. Leukocytosis was present in five cases (out of nine). Eight patients had received corticosteroid treatment, one patient refused such treatment. The duration of corticosteroid treatment was on average for 41 days (range 21-60 days). In all cases, the areola had been spared. Complete healing of PSPG was observed on average after 5 months (range 1.5 months-1 year). DISCUSSION: PSPG of the breast after aesthetic breast surgery is rare, but every plastic surgeon should consider this possibility, especially if skin disease develops post-surgery, mimicking wound infection that does not respond to broad spectrum antibiotic treatment. CONCLUSION: Although the literature does not recommend this step, implant removal is recommended by the authors because bacterial wound infection normally cannot be ruled out definitely in the early stages of disease. Additional surgical intervention should be limited to the absolute necessary and performed only under adequate systemic immunosuppressive therapy. PMID- 26017180 TI - Inverted Supernumerary Nostril Together with Tessier 3 Incomplete Cleft: A Rare Congenital Deformity Case Report. AB - Supernumerary nostril and oblique facial cleft are both rare congenital anomalies. Here, we present a 2-year-old patient with a supernumerary nostril and a Tessier 3 incomplete facial cleft, which have not been reported previously. It should also be mentioned that the nostril and ala of this supernumerary nostril were inverted, which differs from the previous cases. Surgery was undertaken to excise the supernumerary nostril and correct the facial cleft anomaly, and the outcomes were both functionally and aesthetically satisfactory. PMID- 26017181 TI - Vaginal Rejuvenation with Gore-Mycromesh. AB - Recently, we introduced functional vaginal rejuvenation with elastic silicone threads. However, some patients with specific indications need other biocompatible materials for rejuvenation of the vagina. Gore-Mycromesh is one of the most commonly used materials in plastic and reconstructive surgical fields and it is composed of expanded poly-tetrafluroethylene. In this study, we introduced our clinical experience with static vaginal rejuvenation using Gore Mycromesh to specifically assess the overall patient satisfaction (Female Sexual Function Index, FSFI). This study included 50 patients who underwent vaginal rejuvenation with a Gore-Mycromesh between 2010 and 2012. After marking two incisions at the inner side of the vaginal inlet and posterior wall, respectively, we performed submucosal dissection at the posterior vaginal wall and then grafted and secured a Gore-Mycromesh to the dissected area (muscle/fascia). Overall the FSFI improved as time progressed up to a year postoperatively. This is especially prominent in the FSFI satisfaction subscore. All but eight patients (42/50, 84 %) were "very satisfied (5)" or "satisfied (4)" with the outcomes after the vaginal rejuvenation. The overall complication rate was 8 %. Based on our clinical experience with the 50 cases, we think that vaginal rejuvenation with Gore-Mycromesh significantly improved postoperative outcomes, resulting in improved sexual function with a focus on improving the FSFI satisfaction subscore in mid-term follow-up. Elderly patients experience better outcomes using gore mycromesh rather than silicone thread because we can plicate the vaginal posterior wall with senile changes simultaneously using an open technique. However, further studies would be warranted for better positioning and adherence of grafted implants to surrounding tissue and for increasing the tightening effect of the implant and its sufficient longevity. PMID- 26017182 TI - Unilateral static and dynamic hamstrings stretching increases contralateral hip flexion range of motion. AB - Static (SS) and dynamic stretching (DS) can lead to subsequent performance impairments or enhancement with the stretched limb. Crossover or non-local muscle fatigue (NLMF) refers to unilateral fatigue-induced impairments in a contralateral or non-exercised muscle. Whereas there are conflicting findings in the NLMF literature, there are few studies examining the effect of an acute bout of SS or DS on contralateral flexibility, torque or power. Fourteen highly trained subjects (means +/- standard deviations: 18 +/- 2 years; 179.4 +/- 4.6 cm; 70.5 +/- 6.3 kg; %body fat: 10.7 +/- 2.5%) were tested before and following separate sessions of eight repetitions of 30 s of unilateral hip flexion SS or DS. Pre- and postintervention testing at 1 and 10 min included hip flexor range of motion (ROM), isokinetic leg flexion torque and power at 60 degrees .s-1 and 300 degrees .s-1 of the stretched and contralateral limbs. The stretched limb had a 6.3% (P = 0.01; ES: 0.91) ROM increase with DS at 10 min. The contralateral non stretched hip flexors experienced ROM increases with SS of 5.7% (P = 0.02; ES: 0.68) from pretest to 1 min post-test, whereas DS showed 7.1% (P<0.0001; ES: 1.09) and 8.4% (P = 0.005; ES: 0.89) increases, respectively. There were no relative differences in ROM changes between conditions or limbs nor any stretch induced changes in isokinetic torque or power. In conclusion, unilateral SS and DS augment contralateral limb ROM likely through an increased stretch tolerance. PMID- 26017183 TI - Family functioning in paediatric obsessive compulsive and related disorders. AB - OBJECTIVE: Research among youths with obsessive compulsive disorder (OCD) has shown a significant relationship between illness severity, treatment outcome, and the family environment yet little work has been undertaken among the broader class of obsessive compulsive and related disorders (OCRDs) - Trichotillomania, body dysmorphic disorder (BDD), skin picking disorder (SPD), and hoarding. The aim of this study was to (1) review the family functioning literature among paediatric OCRDs, (2) address limitations to previous studies, and (3) highlight areas in need of further research. METHODS: A review of the literature was conducted using several databases (i.e., Google Scholar, PubMed, ScienceDirect) and employing key search terms (e.g., 'family functioning', 'paediatric OCD'). The resultant articles examined several domains subsumed under the broader heading of family environment including parental mental health, parenting practices, family dynamics, family involvement with symptoms, and family emotional climate. RESULTS: The literature reviewed demonstrated a strong relationship between paediatric OCD and adverse family functioning (e.g., parental symptoms of anxiety and depression, family accommodation, family strain and stress, parental guilt and fear) in all identified domains. While family functioning research in paediatric HPD was relatively scant, research suggested similar familial dysfunction (e.g., limited independence, low family cohesion, family violence). Collectively, only 1 article, examining BDD, assessed family functioning within other OCRDs. CONCLUSIONS: This review supports the need for further research in the OCRDs. Limitations to the available literature and targeted suggestions for future research are discussed. PRACTITIONER POINTS: The domains of family environment in this study indicate specific family functioning deficits that may serve as aetiological and/or maintenance factors in paediatric OCRDs, possibly contributing to the understanding of these complex disorders. The recognition of family deficits in paediatric OCRDs may prove beneficial in developing or bolstering preventative and/or therapeutic interventions. Insufficient number of articles pertaining to family functioning in some paediatric OCRDs (i.e., hoarding, skin picking) inhibits formal conclusions. Magnitudes of family functioning effects were not calculated; therefore, future research should consider meta-analytic analyses. PMID- 26017185 TI - Cigarette smokers develop structurally modified hemoglobin: a possible way of increasing oxidative stress. AB - CONTEXT: Increased levels of free radicals and various reactive species along with reduced antioxidant defence system are the major threat to erythrocyte in tobacco smokers. Thus, the hemoglobin (Hb) within the erythrocyte is very prone to oxidative damage. Earlier reports suggest that cigarette smoking is related with the glutathionylation and formation of adducts of Hb. OBJECTIVE: We have highlighted the possible changes in secondary and tertiary structures of Hb in cigarette smokers and its physiological consequences. MATERIAL AND METHOD: Twenty smokers and 18 non-smokers, aged 25-35 years were volunteered in this study. We used flow cytometry for measuring intracellular reactive oxygen species (IcROS). The purified Hb was subjected to different spectrophotometric, fluoremetric and circular dichroic (CD) analysis. The hydrophobicity, thermal stability, heme release and oxidation of purified Hb were also studied. RESULT: We observed that the IcROS was also higher in cigarette smokers than non-smokers. The data of intrinsic fluorescence, synchronous fluorescence and tryptophan quenching studies showed that the microenvironments of beta37 tryptophan and tyrosine residues of Hb were moved toward more hydrophobic region in cigarette smokers. Increased hydrophobicity and thermal stability furthermore indicated more compactness of smokers' hemoglobin. From CD spectra, we confirmed an overall modification of the secondary and tertiary structures of hemoglobin in smokers. Both auto- and co oxidation rates of purified Hb were found to be higher in cigarette smokers. DISCUSSION AND CONCLUSION: We conclude that the modified Hb in cigarette smokers may further enhance the oxidative insult within the cell. PMID- 26017186 TI - PM2.5-rich dust collected from the air in Fukuoka, Kyushu, Japan, can exacerbate murine lung eosinophilia. AB - PM2.5 can exacerbate asthma. Organic substances adsorbed on PM2.5-rich dust (PM2.5rd) were inactivated by heating at 360 degrees C. To characterize the role of organic substances, the effects of PM2.5rd and heated PM2.5-rich dust (H-PM2.5 rd) on allergic lung inflammation were investigated. BALB/c mice were intratracheally administered PM2.5rd or H-PM2.5rd with or without ovalbumin (OVA) four times at 2-week intervals. PM2.5rd, but not H-PM2.5rd, caused neutrophilic alveolitis and bronchitis. In the presence of OVA, PM2.5rd caused severe eosinophil infiltration and goblet cells proliferation in airways, along with a marked induction of the Th2 cytokines interleukin (IL)-4 and IL-13, and the eosinophil-related cytokine IL-5 in bronchoalveolar lavage fluid (BALF). OVA + H PM2.5rd caused a weaker response. PM2.5rd showed adjuvant effects on OVA-specific immunoglobulin E (IgE) and IgG1 production, but H-PM2.5rd showed minimal effects. These findings suggested that PM2.5rd-bound substances might aggravate lung eosinophilia. To clarify the roles of TLR2, TLR4, and MyD88 on cytokine production in PM2.5rd, murine bone marrow-derived macrophages (BMDMs) from wild type (WT), TLR2(-/-), TLR4(-/-), and MyD88(-/-) BALB/c mice were stimulated with dust. Cytokine production was low or undetectable in TLR4(-/-) cells, but occurred from TLR2(-/-) cells, and production by MyD88(-/-) cells was higher than by TLR4(-/-) cells. These results suggest that TLR4 and TLR2 ligands (LPS and beta-glucan, respectively) mainly contributed to cytokines production induced by PM2.5rd. In addition to chemical substances, PM2.5-bound microbial substances might act in inflammatory and allergic lung diseases. PMID- 26017187 TI - The structure of chloromethyl thiocyanate, CH2ClSCN, in gas and crystalline phases. AB - The structural and conformational properties of chloromethyl thiocyanate, CH2ClSCN, were studied in the solid phase and in the gas phase using in situ low temperature single-crystal X-ray diffraction experiments (XRD) and gas electron diffraction (GED), respectively. Depending on the mutual orientation of the Cl-C bond and the -SCN group, two conformations, gauche and anti, were found to coexist in the gas phase. The gauche conformer, with a dihedral angle phi(ClC-SC) = 71.8(4) degrees , is the most stable form, with an abundance of 89(3)% at ambient temperature. High level quantum-chemical calculations at the CCSD(T)/cc pVTZ level of approximation reproduce these experimental results. In the solid state only gauche conformers were found to be present. The crystal structure shows specific intermolecular interactions including chalcogen-type interactions. The experimental electron density distribution was determined by high-angle X-ray diffraction. The atoms in molecules (AIM) theory was applied to analyze the charge density topology for a better characterization of intermolecular interactions present in the crystal. PMID- 26017184 TI - Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARgamma Levels. AB - Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARgamma in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARgamma mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARgamma expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARgamma levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID- 26017188 TI - beta-Blockade and Operative Mortality in Noncardiac Surgery: Harmful or Helpful? AB - IMPORTANCE: The use of perioperative pharmacologic beta-blockade in patients at low risk of myocardial ischemic events undergoing noncardiac surgery (NCS) is controversial because of the risk of stroke and hypotension. Published studies have not found a consistent benefit in this cohort. OBJECTIVE: To determine the effect of perioperative beta-blockade on patients undergoing NCS, particularly those with no risk factors. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective observational analysis of patients undergoing surgery in Veterans Affairs hospitals from October 1, 2008, through September 31, 2013. METHODS: beta Blocker use was determined if a dose was ordered at any time between 8 hours before surgery and 24 hours postoperatively. Data from the Veterans Affairs electronic database included demographics, diagnosis and procedural codes, medications, perioperative laboratory values, and date of death. A 4-point cardiac risk score was calculated by assigning 1 point each for renal failure, coronary artery disease, diabetes mellitus, and surgery in a major body cavity. Previously validated linear regression models for all hospitalized acute care medical or surgical patients were used to calculate predicted mortality and then to calculate odds ratios (ORs). MAIN OUTCOMES AND MEASURES: The end point was 30 day surgical mortality. RESULTS: There were 326,489 patients in this cohort: 314,114 underwent NCS and 12,375 underwent cardiac surgery. beta-Blockade lowered the OR for mortality significantly in patients with 3 to 4 cardiac risk factors undergoing NCS (OR, 0.63; 95% CI, 0.43-0.93). It had no effect on patients with 1 to 2 risk factors. However, beta-blockade resulted in a significantly higher chance of death in patients (OR, 1.19; 95% CI, 1.06-1.35) with no risk factors undergoing NCS. CONCLUSIONS AND RELEVANCE: In this large series, beta-blockade appears to be beneficial perioperatively in patients with high cardiac risk undergoing NCS. However, the use of beta-blockers in patients with no cardiac risk factors undergoing NCS increased risk of death in this patient cohort. PMID- 26017190 TI - Photoprotection and Extended Drug Delivery by UV Blocking Contact Lenses. AB - PURPOSE: Extended release of photo-unstable drugs from ophthalmic inserts is not useful unless the loaded drug is protected from degradation. Because of the recent interest in extended drug delivery from contact lenses, it is critical to assess whether photo-unstable drugs can be stabilized by loading in lenses. Here, we focus on dexamethasone, which is prone to degradation and has been explored as a candidate for extended release from contact lenses for periods ranging from 10 hours to several days. METHODS: Degradation rates of dexamethasone were measured in phosphate-buffered saline and after loading in contact lenses. The degradation rates were measured in a humidified, constant-temperature (32 degrees C) chamber with controlled UV exposure. Contact lenses with various degrees of UV blocking were used to explore the relationship between degradation rates and UV exposure. It is known that vitamin E absorbs UV radiation; thus, it was loaded into the lenses to explore the feasibility of reducing the degradation rates. RESULTS: About 85% of dexamethasone degraded in 20 hours in non-UV blocking lenses, whereas less than 1% degraded in class 1 UV blocking lenses. Incorporation of vitamin E into the non-UV blocking lenses reduced the fractional degradation to 30%. Degradation rates in phosphate-buffered saline were significantly higher than even in non-UV blocking contact lenses. CONCLUSIONS: The degradation of dexamethasone can be minimized by using a UV blocking contact lens or incorporating vitamin E into a non-UV blocking lens. Vitamin E incorporation has the dual benefits of improving drug stability and release profiles. PMID- 26017189 TI - Massive haemorrhage associated with inadvertent incision of a suspected carotid artery pseudoaneurysm in a cat. AB - A 12-year-old, castrated male, domestic long-haired cat experienced massive haemorrhage associated with an incision of a swelling on the neck 2 weeks after right-sided ventral bulla osteotomy. Emergent control of haemorrhage was gained through unilateral carotid artery ligation. Cardiopulmonary resuscitation was provided in conjunction with massive blood transfusion. The cat made an unremarkable recovery. Carotid artery pseudoaneurysm due to surgical disruption of the carotid artery during ventral bulla osteotomy, specifically through the use of self-retaining retractors, was suspected. This case highlights the development of pseudoaneurysm as a potential complication of head and neck surgery, and additionally describes a case of massive transfusion in a cat. PMID- 26017191 TI - Klebsiella Endophthalmitis as Retinal Vasculitis with Prostatic Abscess. AB - PURPOSE: To describe an unusual case of endogenous Klebsiella endophthalmitis associated with prostatic abscess in an immunocompetent patient. CASE REPORT: A 59-year-old previously healthy man presented with rapidly progressive retinal vasculitis in the left eye. He received an empirical antibiotic and antiviral agent intravenously followed by oral prednisolone until the etiology was identified; however, intraocular inflammation in the left eye continued to worsen, followed by the development of subretinal abscess in the contralateral eye. Finally, a diagnosis of endogenous Klebsiella endophthalmitis associated with prostatic abscess was made through a culture of the vitreous acquired by diagnostic vitrectomy. However, we could not save the vision of the left eye despite the intensive treatment with intravenous and intravitreal injections of antibiotics. CONCLUSIONS: Rapidly progressive retinal vasculitis could be an initial sign of endogenous Klebsiella endophthalmitis even in an immunocompetent patient. PMID- 26017192 TI - Effect of lentivirus-mediated survivin transfection on the morphology and apoptosis of nucleus pulposus cells derived from degenerative human disc in vitro. AB - Lower back pain is a common concern, and 40% of all cases involve the degeneration of the intervertebral disc (IVD). However, the excessive apoptosis of disc cells plays an important role in IVD degeneration, particularly in the nucleus pulposus (NP). Thus, anti-apoptotic gene therapy to attenuate or reverse the degenerative process within the NP is being developed. Survivin is a unique inhibitor of apoptosis (IAP) and has been extensively investigated in cancer cells. However, little is known of the effects of survivin transfection on NP cells derived from degenerative human disc. In this study, we aimed to investigate the effects of lentivirus (LV)-mediated survivin transfection on the morphology and apoptosis of NP cells derived from degenerative human disc in vitro. NP cells were transfected with LV-mediated survivin. Subsequently, cell morphology was observed and the survivin mRNA expression levels were measured by RT-qPCR. Apoptosis was analyzed by flow cytometry and by measuring caspase-3 activity. The results revealed that the morphology of the NP cells derived from degenerative human disc transfected with LV-mediated survivin was significantly altered as evidenced by cytomorphosis, the reduction of the cytoplasm and cell shrinkage. Following transfection, survivin gene expression significantly increased in the transfected cells and subsequent generation cells; however, no significant differences in the cell apoptotic rate and caspase-3 activity were observed. We found that transfection of the survivin gene into NP cells led to the stable expression of survivin and induced marked changes in cell morphology. Furthermore, no significant anti-apoptotic effects were observed following LV mediated survivin transfection. Overall, our findings demonstrate that LV carrying surviving may be used to successfully enforce the expression of survivin in NP cells. However, cell morphology was evidently altered, whereas the apoptotic rate did not decrease. Comprehensive studies on the feasibility of using survivin in gene therapy in an aim to attenuate disc degeneration are warranted. Further research on the mechanisms responsible for the changes in cell morphology and cell function are also required. PMID- 26017193 TI - T-SPOT.TB Interferon-gamma Release Assay Performance in Healthcare Worker Screening at Nineteen U.S. Hospitals. AB - RATIONALE: Interferon-gamma release assays have significant advantages over tuberculin skin testing in many clinical situations. However, recent studies have called into question their reliability in serial testing of healthcare workers because of reportedly high rates of positivity and high conversion/reversion rates on retesting. OBJECTIVES: To define the performance characteristics of the T-SPOT.TB test, an interferon-gamma release assay, during serial screening programs of healthcare workers at 19 U.S. hospitals. METHODS: A total of 42,155 T SPOT.TB test results from healthcare workers at 19 geographically diverse hospitals obtained for routine tuberculosis screening programs were analyzed to determine the rates of positivity, reversion, and conversion in serial testing data. MEASUREMENTS AND MAIN RESULTS: In 19,630 evaluable serial pairs from 16,076 healthcare workers, the mean test positivity rate was 2.3% (range, 0.0-27.4%). The mean conversion rate was 0.8% (range, 0.0-2.5%), and the mean reversion rate was 17.6%. Positivity and conversion rates correlated with known tuberculosis risk factors including age and sex. The observed specificity of the T-SPOT.TB test was at least 98.6%. CONCLUSIONS: The high concordance and test completion rates in this study suggest that the T-SPOT.TB test is a reliable tool for healthcare worker serial screening. As expected, the observed positivity rates were lower compared with the tuberculin skin test, likely reflecting the higher specificity of this test. Furthermore, the observed rates of conversion were low and significantly correlated with the geographic incidence of tuberculosis. Our findings suggest that the T-SPOT.TB test is an accurate and reliable way to screen healthcare workers. PMID- 26017194 TI - Parasites of pigs in two farms with poor husbandry practices in Bishoftu, Ethiopia. AB - A cross-sectional study was conducted from November 2011 to April 2012 on a total of 384 pigs from two privately owned intensive farms in Bishoftu, Ethiopia. The objectives of the study were to identify and determine the prevalence of common parasites of pigs. For the determination of gastrointestinal (GIT) parasites, faecal samples were collected from the study animals and subjected to standard parasitological examination techniques. Physical examination was conducted for the presence of skin parasitic lesions and skin scrapings were collected to determine prevalence of ectoparasites. The overall prevalence of GIT parasites in the pigs was 25% (96/384). Examination of faecal samples revealed the ova or oocysts of four different gastrointestinal parasites, namely Coccidia (12%), Strongyles (5.2%), Ascaris suum (4.9%) and Trichuris suis (2.9%). Mixed infection by at least two parasite species was observed in 3.65% (14/384) of the pigs. The only ectoparasite species identified was Sarcoptes scabiei var. suis, with a prevalence of 2.6%. This study indicates that pig parasites are a major problem in the study area, hence implementation of strategic control measures and appropriate hygienic management systems are recommended to reduce the prevalence of parasites. PMID- 26017195 TI - Ambivalent covariance models. AB - BACKGROUND: Evolutionary variations let us define a set of similar nucleic acid sequences as a family if these different molecules execute a common function. Capturing their sequence variation by using e. g. position specific scoring matrices significantly improves sensitivity of detection tools. Members of a functional (non-coding) RNA family are affected by these variations not only on the sequence, but also on the structural level. For example, some transfer-RNAs exhibit a fifth helix in addition to the typical cloverleaf structure. Current covariance models - the unrivaled homology search approach for structured RNA - do not benefit from structural variation within a family, but rather penalize it. This leads to artificial subdivision of families and loss of information in the RFAM database. RESULTS: We propose an extension to the fundamental architecture of covariance models to allow for several, compatible consensus structures. The resulting models are called ambivalent covariance models. Evaluation on several RFAM families shows that coalescence of structural variation within a family by using ambivalent consensus models is superior to subdividing the family into multiple classical covariance models. CONCLUSION: A prototype and source code is available at http://bibiserv.cebitec.uni-bielefeld.de/acms. PMID- 26017196 TI - Incentives and models of governance. AB - This short commentary on Oliver's review of incentives relates that review to four models of governance: Trust and Altruism (T&A), Choice and Competition (C&C), Naming and Shaming (N&S) and Targets and Terror (T&T). PMID- 26017197 TI - Non-invasive assessment of vasospasm following aneurysmal SAH using C-arm FDCT parenchymal blood volume measurement in the neuro-interventional suite: Technical feasibility. AB - INTRODUCTION: Cerebral vasospasm is the leading cause of morbidity and mortality in patients with aneurysmal subarachnoid haemorrhage (SAH) surviving the initial ictus. Commonly used techniques for vasospasm assessment are digital subtraction angiography and transcranial Doppler sonography. These techniques can reliably identify only the major vessel spasm and fail to estimate its haemodynamic significance. To overcome these issues and to enable comprehensive non-invasive assessment of vasospasm inside the interventional suite, a novel protocol involving measurement of parenchymal blood volume (PBV) using C-arm flat detector computed tomography (FDCT) was implemented. MATERIALS AND METHODS: Patients from the neuro-intensive treatment unit (ITU) with suspected vasospasm following aneurysmal SAH were scanned with a biplane C-arm angiography system using an intravenous contrast injection protocol. The PBV maps were generated using prototype software. Contemporaneous clinically indicated MR scan including the diffusion- and perfusion-weighted sequences was performed. C-arm PBV maps were compared against the MR perfusion maps. RESULTS: Distribution of haemodynamic impairment on C-arm PBV maps closely matched the pattern of abnormality on MR perfusion maps. On visual comparison between the two techniques, the extent of abnormality indicated PBV to be both cerebral blood flow and cerebral blood volume weighted. CONCLUSION: C-arm FDCT PBV measurements allow an objective assessment of the severity and localisation of cerebral hypoperfusion resulting from vasospasm. The technique has proved feasible and useful in very sick patients after aneurysmal SAH. The promise shown in this early study indicates that it deserves further evaluation both for post-SAH vasospasm and in other relevant clinical settings. PMID- 26017198 TI - Room Temperature Cation Exchange Reaction in Nanocrystals for Ultrasensitive Speciation Analysis of Silver Ions and Silver Nanoparticles. AB - To evaluate the toxicity of silver nanoparticles (AgNPs) and Ag(+) and gain deep insight into the transformation of AgNPs in the environment or organisms, ultrasensitive analytical methods are needed for their speciation analysis. About 40-fold of Cd(2+) in CdTe ionic nanocrystals can be "bombarded-and-exploded" (exchanged) in less than 1 min simply by mixing the nanocrystals with Ag(+) solution at room temperature, while this cation exchange reaction did not occur when only silver nanoparticles were present. On the basis of this striking difference, an ultrasensitive method was developed for speciation analysis of Ag(+) and AgNPs in complex matrices. The released Cd(2+) was reduced to its volatile species by sodium tetrahydroborate, which was separated and swept to an inductively coupled plasma mass spectrometer (ICPMS) or an atomic fluorescence spectrometer (AFS) for the indirect but ultrasensitive detection of Ag(+). Owing to the remarkable signal amplification via the cation exchange reaction and the advantages of chemical vapor generation for sampling, the limit of detection was 0.0003 MUg L(-1) for Ag(+) by ICPMS, which was improved by 100-fold compared to the conventional method. Relative standard deviations are better than 2.5% at a concentration of 0.5 MUg L(-1) Ag(+) or AgNPs regardless of the detector. The proposed method retains several unique advantages, including ultrahigh sensitivity, speciation analysis, simplicity and being organic reagent-free, and has been successfully utilized for speciation analysis of Ag(+) and AgNPs in environmental water samples and paramecium cells. PMID- 26017199 TI - Trazodone and omeprazole interaction causing frequent second-degree Mobitz type 1 atrioventricular (AV) block (Wenckebach phenomenon) and syncope: a case report and literature review. AB - BACKGROUND: This case report highlights serious cardiovascular adverse effects with a conventional dose of trazodone as a result of its potential interaction with omeprazole. CASE REPORT: A 54-year-old man who was a former smoker, with dyslipidemia, coronary artery disease, and anxiety disorder developed lightheadedness and syncope the morning of admission. He was taking trazodone 50 mg daily, omeprazole 20 mg daily, and simvastatin 20 mg at bedtime. He doubled the dose of trazodone 50 mg on the night prior to presentation to calm his anxiety. An electrocardiogram revealed sinus rhythm at 60 beats per minute and second-degree Mobitz type 1 atrioventricular (AV) block with 5:4 AV conduction. Results of basic metabolic panel, thyroid-stimulating hormone, and chest radiograph were normal. A transthoracic echocardiogram revealed aortic valve sclerosis. We tested for Lyme disease given his history of hunting in the woods 8 months prior to presentation, but the titer was negative. Trazodone and omeprazole were discontinued. By the 3rd day of medication discontinuation, all symptoms had resolved and the frequency of second-degree AV Mobitz type 1 AV block had decreased to once per hour. CONCLUSIONS: Due diligence and meticulous attention to detail needs to be exercised to uncover drug interactions as potential causes of lethal and nonlethal patient symptomatology, as in this case of syncope caused by concomitant use of trazodone and a widely prescribed medication, omeprazole. PMID- 26017200 TI - Neurotrophic factors and tension-type headache: another brick in the wall? PMID- 26017201 TI - Behind the faces: Alzheimer's disease and emotional blindness. PMID- 26017202 TI - Facial expression recognition in Alzheimer's disease: a longitudinal study. AB - Facial recognition is one of the most important aspects of social cognition. In this study, we investigate the patterns of change and the factors involved in the ability to recognize emotion in mild Alzheimer's disease (AD). Through a longitudinal design, we assessed 30 people with AD. We used an experimental task that includes matching expressions with picture stimuli, labelling emotions and emotionally recognizing a stimulus situation. We observed a significant difference in the situational recognition task (p <= 0.05) between baseline and the second evaluation. The linear regression showed that cognition is a predictor of emotion recognition impairment (p <= 0.05). The ability to perceive emotions from facial expressions was impaired, particularly when the emotions presented were relatively subtle. Cognition is recruited to comprehend emotional situations in cases of mild dementia. PMID- 26017203 TI - Clinical predictors of cognitive impairment and psychiatric complications in Parkinson's disease. AB - OBJECTIVE: To estimate the clinical and demographics aspects that may contribute to cognitive impairment and psychiatric symptoms in Parkinson's disease (PD). METHOD: All patients answered a structured standardized clinical questionnaire. Two movement disorders specialists performed the following scale: Unified Parkinson's disease rating score (UPDRS), the modified Hoehn and Yahr staging, Schwab and England Scale, SCOPA cognition (SCOPA-COG), SCOPA-Psychiatric complications (SCOPA-PC) and Non-Motor Symptoms Scale (NMSS). We built a generalized linear model to assess predictors for the SCOPA-COG and SCOPA-PC scores. RESULTS: Almost 37% of our patients were demented as per SCOPA-COG scores. Level of education and the UPDRS-Subscale III were predictors of cognitive impairment. Higher scores in domain 3 of NMSS and male gender were associated with psychiatric complications as assessed per the SCOPA-PC. CONCLUSION: Level of education and disease severity are predictors of dementia in PD. Psychiatric complications are more commonly observed in men. PMID- 26017204 TI - Coherence of brain electrical activity: a quality of life indicator in Alzheimer's disease? AB - OBJECTIVE: To investigate the relationships between quality of life (QOL) and clinical and electroencephalogram (EEG) aspects in patients with Alzheimer's disease (AD). METHOD: Twenty-eight patients with mild or moderate AD, 31 with Parkinson's disease (PD), and 27 normal controls (NC) were submitted to: CERAD neuropsychological battery, Hamilton Depression and Anxiety Rating Scales, Functional Activities Questionnaire, QOL scale for patients with AD, and quantitative EEG measures. RESULTS: AD and PD patients had similar QOL (31.0 +/- 5.8; 31.7 +/- 4.8, respectively), worse than that of NC (37.5 +/- 6.3). AD patients had lower global interhemispheric theta coherence (0.49 +/- 0.04; 0.52 +/- 0.05; 0.52 +/- 0.05; respectively) than PD and NC. Multiple linear regression for QOL of AD patients revealed that global interhemispheric theta coherence, and Hamilton depression scores were significant factors (coefficients; 58.2 and 0.27, respectively; R2, 0.377). CONCLUSION: Interhemispheric coherence correlates with QOL regardless of cognitive and functional variables and seems to be a neurophysiological indicator of QOL in AD patients. PMID- 26017205 TI - The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study. AB - OBJECTIVE: To compare visual fixation at social stimuli in Rett syndrome (RT) and autism spectrum disorders (ASD) patients. METHOD: Visual fixation at social stimuli was analyzed in 14 RS female patients (age range 4-30 years), 11 ASD male patients (age range 4-20 years), and 17 children with typical development (TD). Patients were exposed to three different pictures (two of human faces and one with social and non-social stimuli) presented for 8 seconds each on the screen of a computer attached to an eye-tracker equipment. RESULTS: Percentage of visual fixation at social stimuli was significantly higher in the RS group compared to ASD and even to TD groups. CONCLUSION: Visual fixation at social stimuli seems to be one more endophenotype making RS to be very different from ASD. PMID- 26017206 TI - Multidetector computed tomography angiography in clinically suspected hyperacute ischemic stroke in the anterior circulation: an etiological workup in a cohort of Brazilian patients. AB - OBJECTIVE: The potential of computed tomography angiography (CTA) was assessed for early determination of stroke subtypes in a Brazilian cohort of patients with stroke. METHOD: From July 2011 to July 2013, we selected patients with suspected hyperacute stroke (< 6 hours). Intracranial and cervical arteries were scrutinized on CTA and their imaging features were correlated with concurrent subtype of stroke. RESULTS: Stroke was documented in 50/106 selected patients (47.2%) based on both clinical grounds and imaging follow-up (stroke group), with statistically significant arterial stenosis and vulnerable plaques on CTA. Intracranial large artery disease was demonstrated in 34% of patients in the stroke group. Partial territorial infarct prevailed (86%) while artery-to-artery embolization was the most common stroke mechanism (52%). CONCLUSION: Multidetector CTA was useful for the etiologic work-up of hyperacute ischemic stroke and facilitated the knowledge about the topographic pattern of brain infarct in accordance with its causative mechanism. PMID- 26017207 TI - Predictors of pneumonia in acute stroke in patients in an emergency unit. AB - OBJECTIVE: To evaluate the risk factors and comorbid conditions associated with the development of pneumonia in patients with acute stroke. To determine the independent predictors of pneumonia. METHOD: Retrospective study from July to December 2011. We reviewed all medical charts with diagnosis of stroke. RESULTS: 159 patients (18-90 years) were admitted. Prevalence of pneumonia was 32%. Pneumonia was more frequent in patients with hemorrhagic stroke (OR: 4.36; 95%CI: 1.9-10.01, p < 0.001), higher National Institute of Health Stroke Scale (NIHSS) (p = 0.047) and, lower Glasgow Coma Score (GCS) (p < 0.0001). Patients with pneumonia had longer hospitalization (p < 0.0001). Multivariable logistic regression analysis identified NIHSS as an independent predictor of pneumonia (95%CI: 1.049-1.246, p = 0.002). CONCLUSION: Pneumonia was associated with severity and type of stroke and length of hospital stay. The severity of the deficit as evaluated by the NIHSS was shown to be the only independent risk factor for pneumonia in acute stroke patients. PMID- 26017208 TI - Neurotrophic factors in tension-type headache. AB - Neurotrophic factors (NF) are involved in pain regulation and a few studies have suggested that they may play a pathophysiological role in primary headaches. The aim of this study was to investigate NF levels in patients with tension type headache (TTH). We carried out a cross sectional study including 48 TTH patients and 48 age and gender matched controls. Beck Depression and Anxiety Inventories, and Headache Impact Test were recorded. Serum levels of NF were determined by ELISA. There were not significant differences between NF levels between TTH patients and controls. Patients with chronic and episodic TTH had not significant differences in NF levels. The presence of headache at the time of evaluation did not significantly alter the levels of NF. Depression and anxiety scores as well as headache impact did not correlate with NF levels. Our study suggest that the serum levels of NF are not altered in TTH. PMID- 26017209 TI - Surgical exposure of the internal auditory canal through the retrosigmoid approach with semicircular canals anatomical preservation. AB - OBJECTIVE: Evaluate the feasibility of an adequate exposure with anatomical preservation of labyrinth structures through retrosigmoid transmeatal approach (RSA) in surgeries for resection of acoustic neuromas/vestibular schwannomas (VS). METHOD: Thirty patients underwent surgical resection and were preoperatively evaluated with fine slice high definition CT scans and 3D-MRI volumetric reconstructions. Extension of internal auditory canal (IAC) opening during surgery was measured using 3 mm right-angle calibrated hook and neuronavigation parameters. Postoperatively, the extension of IAC opening and integrity of the labyrinth were confirmed through preoperatively images procedures. RESULTS: The preoperative length of IACs varied between 7.8 and 12.0 mm (mean 9.3 mm, SD 0.98, 95%CI 8.9 to 9.6, and median 9.0 mm). Postoperative images demonstrated adequate opening of the IAC and semicircular channels integrity. CONCLUSION: A complete drilling of the posterior wall of IAC through the RSA is feasible and allows direct visualization of the IAC-fundus without damaging the semicircular canals. PMID- 26017210 TI - Orbitofrontal sulcal and gyrus pattern in human: an anatomical study. AB - The anatomical characterization of the orbitofrontal cortex in human is limited in literature instead of many functional and clinical studies involving it. OBJECTIVE: Anatomically define the orbitofrontal region aiming to possible neurosurgical treatments and unify the scientific nomenclature as well. METHOD: We analyze eighty four human hemispheres using a surgical microscope. Then we chose four hemispheres and dissect them according to Klinger' technique. RESULTS: We found five main sulcus: olfatory sulcus, orbital medial sulcus, orbital lateral sulcus, orbital transverse sulcus and orbital intermediate sulcus. These sulcus, excluding the intermediate sulcus, delimit five gyrus: rectus gurys, orbital medial gyrus, orbital anterior gyrus, orbital lateral gyrus and orbital posterior gyrus. The main sulcal configuration can be divided on four more frequently patterns. CONCLUSION: Orbitofrontal cortex is associated with many psychiatric disorders. Better anatomical and functional characterization of the orbitofrontal cortex and its connections will improve our knowledge about these diseases. PMID- 26017211 TI - Psychometric properties of the Brazilian version of the Pain Catastrophizing Scale for acute low back pain. AB - Measurement instruments of pain catastrophizing for middle-aged and elderly individuals are needed to understand its impact on low back pain. The goals were to cross-culturally adapt the Pain Catastrophizing Scale, assess the construct validity through Rasch analysis, and verify reliability and convergent validity of pain catastrophizing with psychosocial factors. 131 individuals aged 55 years and older with acute low back pain were interviewed . The intra-rater reliability was Kp = 0.80 and interrater Kp = 0.75. The Rasch analysis found adequate reliability coefficients (0.95 for items and 0.90 for individuals ). The separation index for the elderly was 2.95 and 4.59 items. Of the 13 items, one did not fit the model, which was justified in the sample evaluated. The pain catastrophizing correlated with most psychosocial factors. The instrument proved to be clinically useful. Subsequent studies should carry out the same analysis in different populations. PMID- 26017212 TI - Evaluation of the SLICS use in the treatment of subaxial cervical spine injuries. AB - The SLICS (Sub-axial Cervical Spine Injury Classification System) was proposed to help in the decision-making of sub-axial cervical spine trauma (SCST), even though the literature assessing its safety and efficacy is scarce. METHOD: We compared a cohort series of patients surgically treated based on surgeon's preference with patients treated based on the SLICS. RESULTS: From 2009-10, 12 patients were included. The SLICS score ranged from 2 to 9 points (mean of 5.5). Two patients had the SLICS < 4 points. From 2011-13, 28 patients were included. The SLICS score ranged from 4 to 9 points (mean of 6). There was no neurological deterioration in any group. CONCLUSION: After using the SLICS there was a decrease in the number of patients with less severe injuries that were treated surgically. This suggests that the SLICS can be helpful in differentiating mild from severe injuries, potentially improving the results of treatment. PMID- 26017213 TI - Aspects correlates with Scandinavian Stroke Scale for predicting early neurological impairment. AB - OBJECTIVE: To investigate the correlation between the Alberta Program Early CT Score (ASPECTS) and the Scandinavian Stroke Scale (SSS) for the evaluation of neurological impairment in patients with acute stroke. METHOD: 59 patients with a first acute ischemic stroke were evaluated. The ASPECTS were evaluated by 2 neurologists at admission and by another neurologist after 48 hours. The NIHSS and SSS was applied to determinate stroke severity. Correlations and agreements were analysed statistically by Spearman and Kappa tests. RESULTS: ASPECTS was correlated with National Institute of Health Stroke Scale (NIHSS) at admission (r = -0.52; p < 0.001) and SSS (r = 0.50; p < 0.001). The ASPECTS and SSS items were most correlated with arm (r = 0.52; p < 0.001) and hand (r = 0.49; p < 0.001) motor power, and speech (r = 0.51; p < 0.001). The SSS of 25.5 shows sensitivity (68%) and specificity (72%) when associated with ASPECTS <= 7. CONCLUSION: The SSS can predict worst neurological impairment when associated with lower values of ASPECTS. PMID- 26017214 TI - Non-motor signs in Parkinson's disease: a review. AB - During the past decade the view of Parkinson's disease (PD) as a motor disorder has changed significantly and currently it is recognized as a multisystem process with diverse non-motor signs (NMS). In addition to been extremely common, these NMS play a major role in undermining functionality and quality of life. On the other hand, NMS are under recognized by physicians and neglected by patients. Here, we review the most common NMS in PD, including cognitive, psychiatric, sleep, metabolic, and sensory disturbances, discuss the current knowledge from biological, epidemiological, clinical, and prognostic standpoints, highlighting the need for early recognition and management. PMID- 26017215 TI - French school and World War First: neurological consequences of a frightening time. AB - Some aspects of a dark period in the history of the modern neurology, that of the World War I (WWI), are here remembered, mainly by the neurological French School participation . Some personalities and their works related to the WWI are presented such as Joseph Babinski, Jules Froment, Clovis Vincent, Jules Joseph Dejerine, Augusta Dejerine-Klumpke, Jules Tinel, Pierre Marie, Achille Alexandre Souques, Charles Foix, and Georges Guillain. PMID- 26017216 TI - Association of optic atrophy and type 1 diabetes: clinical hallmarks for the diagnosis of Wolfram syndrome. PMID- 26017217 TI - Cerebrospinal fluid cell cannibalism in metastatic breast adenocarcinoma. PMID- 26017218 TI - Spag17 deficiency results in skeletal malformations and bone abnormalities. AB - Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area and the ratio of bone area to total area, leading to reductions in the ratio of marrow area/total area in the femur. Micro CTs and von Kossa staining demonstrated increased mineral in the femur. Moreover, osteocalcin and osterix were more highly expressed in mutant mice than in wild type mice femurs. These data suggest that femur bone shortening may be due to premature ossification. On the other hand, tibias appear to be shorter due to a delay in cartilage and bone development. Morphometric studies showed reduction in growth plate and bone formation. These defects did not affect bone mineralization, although the volume of primary bone and levels of osteocalcin and osterix were higher. Other skeletal malformations were observed including fused sternebrae, reduced mineralization in the skull, medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from knockout mice were shorter and fewer cells had primary cilia in comparison to cells from wild-type mice. In addition, Spag17 knockdown in wild type MEFs by Spag17 siRNA duplex reproduced the shorter primary cilia phenotype. Our findings disclosed unexpected functions for Spag17 in the regulation of skeletal growth and mineralization, perhaps because of its role in primary cilia of chondrocytes and osteoblasts. PMID- 26017219 TI - Effectiveness of an Obstetrics-Based Advanced Cardiac Life Support Education Program. AB - OBJECTIVE: To study the effectiveness of an obstetrics-based advanced cardiac life support education (ACLS OB) program with pre- and postcourse maternal mock code drills and surveys evaluating satisfaction and self-confidence in abilities of labor and delivery (L&D) nurses to perform ACLS algorithms. DESIGN: Quasi experimental pretest/posttest study. SETTING: Obstetric units in a community hospital system. PARTICIPANTS: Labor and delivery nurses (N = 96). METHODS: Nurses rotated through an ACLS OB course when their ACLS recertification was due. Two studies were done. Prior to the class, nurses participated in a maternal mock code drill during annual skills review, and performances were scored. One year later, nurses participated in maternal mock code drills. Results were compared with the previous year's scores. In the second study, pre- and postclass surveys were completed reflecting nurses' satisfaction and self-confidence with successfully completing elements of American Heart Association (AHA) algorithms following attendance at traditional ACLS classes versus ACLS OB. RESULTS: The scores of nurses who completed the ACLS OB course were significantly greater overall when performing ACLS MegaCode algorithms (z = -6.08, p < .001) for 18 of 21 individual elements of the algorithm. Nurses reported statistically significant increases (p < .001) in all 13 elements of satisfaction and self confidence following completion of ACLS OB over traditional ACLS courses. CONCLUSIONS: Emphasizing changes in ACLS for obstetric patients during the precourse and using patient scenarios encountered in obstetric settings improved nurses' performance in maternal MegaCode scenarios. The course also increased self-satisfaction and self-confidence of obstetric nurses in their ability to perform ACLS algorithms. PMID- 26017220 TI - The prosodic licensing of coda consonants in early speech: interactions with vowel length. AB - English has a word-minimality requirement that all open-class lexical items must contain at least two moras of structure, forming a bimoraic foot (Hayes, 1995).Thus, a word with either a long vowel, or a short vowel and a coda consonant, satisfies this requirement. This raises the question of when and how young children might learn this language-specific constraint, and if they would use coda consonants earlier and more reliably after short vowels compared to long vowels. To evaluate this possibility we conducted an elicited imitation experiment with 15 two-year-old Australian English-speaking children, using both perceptual and acoustic analysis. As predicted, the children produced codas more often when preceded by short vowels. The findings suggest that English-speaking two-year-olds are sensitive to language-specific lexical constraints, and are more likely to use coda consonants when prosodically required. PMID- 26017221 TI - Inhibition of Inflammation and Bone Erosion by RNA Interference-Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis. AB - OBJECTIVE: The nuclear protein heterogeneous nuclear RNP A2/B1 (hnRNP A2/B1) is involved in posttranscriptional regulation of gene expression. It is constitutively expressed in lymphoid organs and highly up-regulated in the synovial tissue of patients with rheumatoid arthritis (RA), who may also generate autoantibodies to this protein. This study was undertaken to investigate the potential involvement of hnRNP A2/B1 in the pathogenesis of autoimmune arthritis, by silencing hnRNP A2/B1 expression in 2 animal models of RA. METHODS: Collagen induced arthritis (CIA) and the K/BxN serum-transfer model were used as animal models of RA. Efficient silencing of hnRNP A2/B1 was achieved using a liposome based carrier system for delivery of small interfering RNAs. Expression of hnRNP A2/B1 was analyzed by flow cytometry, reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The number of osteoclasts was determined by tartrate-resistant acid phosphatase staining. Cytokine levels and anticollagen antibody levels were measured by enzyme-linked immunosorbent assay. RESULTS: Efficient silencing of hnRNP A2/B1 was achieved in all lymphoid organs. In both experimental models, the incidence and severity of arthritis were largely reduced and bone erosion was not detectable as compared to the control groups. Down-modulation of hnRNP A2/B1 significantly interfered with the production of proinflammatory cytokines from monocyte/macrophages, but not from T cells. Consistent with these findings, production of T cell cytokines was not impaired when cells were restimulated in vitro with type II collagen. Furthermore, levels of anticollagen antibodies were not affected by hnRNP A2/B1 silencing. CONCLUSION: Our findings suggest that hnRNP A2/B1 has an important role in regulation of the innate immune system, especially at the level of monocyte/macrophage activation. Therefore, down-modulation of hnRNP A2/B1 seems to affect primarily the effector phase of autoimmune arthritis. PMID- 26017222 TI - Storage temperature controls the timing of garlic bulb formation via shoot apical meristem termination. AB - MAIN CONCLUSION: Timing of bulb formation and floral stem induction in garlic is controlled by preplanting storage temperature and shoot apical meristem termination, probably via FLOWERING LOCUS T (FT) genes. Garlic is planted in the winter, undergoes a vegetative stage, then forms bulbs in response to increasing temperature and lengthening photoperiod. Herein, the storage conditions for propagation bulbs are shown to potentially affect future vegetative-stage length and timing of bulb formation. Storage temperatures of 2 or 33 degrees C inhibited internal bud growth. Levels of endogenous abscisic acid (ABA) and its inactive isomer trans-ABA were significantly higher in the internal bud of cloves stored at 33 vs. 2 degrees C, and exogenous ABA treatment before planting confirmed its inhibitory effect on foliage leaf development. Bulb formation started 30 and 60 days after planting of cloves stored at 2 and 33 degrees C, respectively. Warm storage temperature induced the formation of multiple leaves and cloves after planting. Plants from cloves stored at warm temperature developed a floral stem, whereas those from cold storage did not. Allium sativum FLOWERING LOCUS T1 (AsFT1) was upregulated 2.5- and 4.5-fold in the internal bud and storage leaf, respectively, after 90 and 150 days of cold vs. warm storage. Expression of AsFT4, expected to be antagonist to AsFT1, was 2- to 3-fold lower in the internal bud from cold storage. Expression of AsFT2, associated with floral termination, was 2- to 3- and 10- to 12-fold higher for cold vs. warm storage temperatures, in the internal bud and storage leaf, respectively. Early bulb formation, induced by cold storage, is suggested to inhibit normal foliage leaf development and transition of the shoot apical meristem to reproductive meristem, through regulation of FT genes. PMID- 26017223 TI - Validation of Normalizations, Scaling, and Photofading Corrections for FRAP Data Analysis. AB - Fluorescence Recovery After Photobleaching (FRAP) has been a versatile tool to study transport and reaction kinetics in live cells. Since the fluorescence data generated by fluorescence microscopy are in a relative scale, a wide variety of scalings and normalizations are used in quantitative FRAP analysis. Scaling and normalization are often required to account for inherent properties of diffusing biomolecules of interest or photochemical properties of the fluorescent tag such as mobile fraction or photofading during image acquisition. In some cases, scaling and normalization are also used for computational simplicity. However, to our best knowledge, the validity of those various forms of scaling and normalization has not been studied in a rigorous manner. In this study, we investigate the validity of various scalings and normalizations that have appeared in the literature to calculate mobile fractions and correct for photofading and assess their consistency with FRAP equations. As a test case, we consider linear or affine scaling of normal or anomalous diffusion FRAP equations in combination with scaling for immobile fractions. We also consider exponential scaling of either FRAP equations or FRAP data to correct for photofading. Using a combination of theoretical and experimental approaches, we show that compatible scaling schemes should be applied in the correct sequential order; otherwise, erroneous results may be obtained. We propose a hierarchical workflow to carry out FRAP data analysis and discuss the broader implications of our findings for FRAP data analysis using a variety of kinetic models. PMID- 26017224 TI - Development of a Rapid and Accurate Identification Method for Citrobacter Species Isolated from Pork Products Using a Matrix-Assisted Laser-Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). AB - Previous detection methods for Citrobacter are considered time consuming and laborious. In this study, we have developed a rapid and accurate detection method for Citrobacter species in pork products, using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). A total of 35 Citrobacter strains were isolated from 30 pork products and identified by both MALDI-TOF MS and 16S rRNA gene sequencing approaches. All isolates were identified to the species level by the MALDI-TOF MS, while 16S rRNA gene sequencing results could not discriminate them clearly. These results confirmed that MALDI-TOF MS is a more accurate and rapid detection method for the identification of Citrobacter species. PMID- 26017225 TI - Properties of a Bacteriocin Produced by Bacillus subtilis EMD4 Isolated from Ganjang (Soy Sauce). AB - A Bacillus species, EMD4, with strong antibacterial activity was isolated from ganjang (soy sauce) and identified as B. subtilis. B. subtilis EMD4 strongly inhibited the growth of B. cereus ATCC14579 and B. thuringiensis ATCC33679. The antibacterial activity was stable at pH 3-9 but inactive at pH 10 and above. The activity was fully retained after 15 min at 80 degrees C but reduced by 50% after 15 min at 90 degrees C. The activity was completely destroyed by proteinase K and protease treatment, indicating its proteinaceous nature. The bacteriocin (BacEMD4) was partially purified from culture supernatant by ammonium sulfate precipitation, and QSepharose and Sephadex G-50 column chromatographies. The specific activity was increased from 769.2 AU/mg protein to 8,347.8 AU/mg protein and the final yield was 12.6%. The size of BacEMD4 was determined to be 3.5 kDa by Tricine SDS-PAGE. The N-terminal amino acid sequence was similar with that of Subtilosin A. Nucleotide sequencing of the cloned gene confirmed that BacEMD4 was Subtilosin A. BacEMD4 showed bactericidal activity against B. cereus ATCC14579. PMID- 26017226 TI - Purification and Biochemical Characterization of a Novel Fibrinolytic Enzyme from Streptomyces sp. P3. AB - A novel proteolytic enzyme with fibrinolytic activity, FSP3, was purified from the recently isolated Streptomyces sp. P3, which is a novel bacterial strain isolated from soil. FSP3 was purified to electrophoretic homogeneity by ammonium sulfate precipitation, anion exchange, and gel filtration. FSP3 is considered to be a single peptide chain with a molecular mass of 44 kDa. The maximum activity of the enzyme was observed at 50 degrees C and pH 6.5, and the enzyme was stable between pH 6 and 8 and below 40 degrees C. In a fibrin plate assay, FSP3 showed more potent fibrinolytic activity than urokinase, which is a clinical thrombolytic agent acting as a plasminogen activitor. The activity was strongly inhibited by the serine protease inhibitor PMSF, indicating that it is a serine protease. Additionally, metal ions showed different effects on the activity. It was significantly suppressed by Mg(2+) and Ca(2+) and completely inhibited by Cu(2+), but slightly enhanced by Fe(2+). According to LC-MS/MS results, its partial amino acid sequences are significantly dissimilar from those of previously reported fibrinolytic enzymes. The sequence of a DNA fragment encoding FSP3 contained an open reading frame of 1287 base pairs encoding 428 amino acids. FSP3 is a bifunctional enzyme in nature. It hydrolyzes the fibrin directly and activates plasminogen, which may reduce the occurrence of side effects. These results suggest that FSP3 is a novel serine protease with potential applications in thrombolytic therapy. PMID- 26017227 TI - Dealcoholized Korean Rice Wine (Makgeolli) Exerts Potent Anti-Tumor Effect in AGS Human Gastric Adenocarcinoma Cells and Tumor Xenograft Mice. AB - Makgeolli is a traditional wine in Korea and has been traditionally believed to exhibit health benefits. However, the inhibitory effect of dealcoholized makgeolli (MK) on cancer has never been investigated scientifically. In this study, MK exhibited an anti-angiogenic effect by inhibiting tube formation in human umbilical vein endothelial cells, without cytotoxicity. Treatment with MK reduced the proliferation of AGS human gastric adenocarcinoma cells in a dose dependent manner and increased the sub-G1 population. Next, we evaluated whether MK could induce apoptosis in AGS cells by using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay or Annexin V method. Treatment with MK at 500 and 1,000 MUg/ml increased the number of TUNEL-positive AGS cells. Under the same conditions, MK-treated (500 and 1,000 MUg/ml) cells showed significant induction of early or late apoptosis, compared with untreated cells (no induction). In addition, MK also induced phosphatase and tensin homolog (PTEN) expression in AGS cells. However, p53 expression in AGS cells was not changed by MK treatment. Furthermore, MK at 500 mg/kg.d reduced the tumor size and volume in AGS tumor xenografts. Taken together, MK may be useful for the prevention of cancer cell growth. PMID- 26017228 TI - An Efficient PEG/CaCl2-Mediated Transformation Approach for the Medicinal Fungus Wolfiporia cocos. AB - Sclerotia of Wolfiporia cocos are of medicinal and culinary value. The genes and molecular mechanisms involved in W. cocos sclerotial formation are poorly investigated because of the lack of a suitable and reproducible transformation system for W. cocos. In this study, a PEG/ CaCl2-mediated genetic transformation system for W. cocos was developed. The promoter Pgpd from Ganoderma lucidum effectively drove expression of the hygromycin B phosphotransferase gene in W. cocos, and approximately 30 transformants were obtained per 10 MUg DNA when the protoplast suspension density was 10(6) protoplasts/ml. However, no transformants were obtained under the regulation of the PtrpC promoter from Aspergillus nidulans. PMID- 26017229 TI - Heat Shock RNA 1, Known as a Eukaryotic Temperature-Sensing Noncoding RNA, Is of Bacterial Origin. AB - Heat shock RNA 1 (HSR1) is described as a "eukaryotic heat-sensing noncoding RNA" that regulates heat shock response in human and other eukaryotic cells. Highly conserved HSR1 sequences have been identified from humans, hamsters, Drosophila, Caenorhabditis elegans, and Arabidopsis. In a previous study, however, it was suggested that HSR1 had originated from a bacterial genome. HSR1 showed no detectible nucleotide sequence similarity to any eukaryotic sequences but harbored a protein coding region that showed amino-acid sequence similarity to bacterial voltage-gated chloride channel proteins. The bacterial origin of HSR1 was not convincible because the nucleotide sequence similarity was marginal. In this study, we have found that a genomic contig sequence of Comamonas testosteroni strain JL14 contained a sequence virtually identical to that of HSR1, decisively confirming the bacterial origin of HSR1. Thus, HSR1 is an exogenous RNA, which can ectopically trigger heat shock response in eukaryotes. Therefore, it is no longer appropriate to cite HSR1 as a "eukaryotic functional noncoding RNA." PMID- 26017230 TI - Assessing information system readiness for mitigating malpractice risk through simulation: results of a multi-site study. AB - OBJECTIVE: To develop and test an instrument for assessing a healthcare organization's ability to mitigate malpractice risk through clinical decision support (CDS). MATERIALS AND METHODS: Based on a previously collected malpractice data set, we identified common types of CDS and the number and cost of malpractice cases that might have been prevented through this CDS. We then designed clinical vignettes and questions that test an organization's CDS capabilities through simulation. Seven healthcare organizations completed the simulation. RESULTS: All seven organizations successfully completed the self assessment. The proportion of potentially preventable indemnity loss for which CDS was available ranged from 16.5% to 73.2%. DISCUSSION: There is a wide range in organizational ability to mitigate malpractice risk through CDS, with many organizations' electronic health records only being able to prevent a small portion of malpractice events seen in a real-world dataset. CONCLUSION: The simulation approach to assessing malpractice risk mitigation through CDS was effective. Organizations should consider using malpractice claims experience to facilitate prioritizing CDS development. PMID- 26017231 TI - Rhupus; unusual presentations. AB - BACKGROUND: The coexistence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) named Rhupus is an unusual clinical condition. Previous reports mentioned that Rhupus patients have prominent RA-associated clinical manifestations and only mild organic damage related to SLE. Progressive or life threatening manifestations are rare in Rhupus patients. METHODS: Three patients with Rhupus are described in this article. Two of them presented antiphospholipid syndrome (APS) in addition to Rhupus. Also, we searched for similar cases in published literature. RESULTS: We present three patients with Rhupus syndrome. One of the patients has only Rhupus, the second patient has Rhupus and APS, and the third patient has Rhupus accompanied by severe Raynaud's syndrome with digital ulcers, APS, pulmonary hypertension and two malignancies. Several studies have shown that Rhupus patients have an increased prevalence of positive antiphospholipid antibodies that resembles SLE. However, the presence of these antibodies is not associated with APS. There is only one case of Rhupus with secondary APS in which the patient presented headache and papilloedema due to cerebral venous thrombosis. Secondary Raynaud's syndrome is rare in Rhupus patients, and to the best of our knowledge, only three cases of this are mentioned in literature. Secondary pulmonary hypertension and malignancies were never reported before in Rhupus patients. CONCLUSIONS: Rheumatologists should be aware of the possibility that Rhupus may be accompanied by progressive or life threatening conditions such as APS, severe Raynaud's syndrome with digital ulcers, pulmonary hypertension, or malignancies. PMID- 26017232 TI - Chikungunya infection in the general population and in patients with rheumatoid arthritis on biological therapy. AB - Chikungunya infection is a febrile illness, which currently is afflicting the Caribbean islands including the Dominican Republic. We would like to report our experience with Chikungunya-related musculoskeletal manifestations in our arthritis clinics in the Dominican Republic. A total of 514 patients presented for the first time to our arthritis clinic exhibiting musculoskeletal manifestations, 473/514 (92%) exhibiting symmetric polyarthralgias, 344/514 (67%) arthritis, and 385 (75%) skin rash. The great majority 457.46 (89%) exhibited very good clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs), 370 (72%) require low-dose steroids, and only 5 patients (0.97%) required methotrexate therapy. In addition, of a total of 328 patients with rheumatoid arthritis on biological treatment, 53 exhibited Chikungunya-related musculoskeletal manifestations; 51/53 (96.2%) exhibited symmetric polyarthralgias, 25/53 (47.1%) arthritis, and 13/53 (24.5%) tendinopathy. Of most patients, 51/53 responded to NSAIDs, of which, 23 patients only responded partially, and in total 25 (47.1%) required low-dose steroids. Disease-modifying antirheumatic drug (DMARD) therapy including biologics remained unchanged in this population. PMID- 26017233 TI - On-plate enzyme and inhibition assay of glucose-6-phosphate dehydrogenase using thin-layer chromatography. AB - We performed on-plate enzyme and inhibition assays of glucose 6-phosphate dehydrogenase using thin-layer chromatography. The assays were accomplished based on different retardation factors of the substrates, enzyme, and products. All the necessary steps were integrated on-plate in one developing process, including substrate/enzyme mixing, reaction starting, and quenching as well as product separation. In order to quantitatively measure the enzyme reaction, the developed plate was then densitometrically evaluated to determine the peak area of the product. Rapid and high-throughput assays were achieved by loading different substrate spots and/or enzyme (and inhibition) spots in different tracks on the plate. The on-plate enzyme assay could be finished in a developing time of only 4 min, with good track-to-track and plate-to-plate repeatability. Moreover, we determined the Km values of the enzyme reaction and Ki values of the inhibition (Pb(2+) Cd(2+) and Cu(2+) as inhibitors), as well as the corresponding kinetics using the on-plate assay. Taken together, our method expanded the application of thin-layer chromatography in enzyme assays, and it could be potentially used in research fields for rapid and quantitative measurement of enzyme activity and inhibition. PMID- 26017234 TI - Margaret McCartney: Medical journals and their parasitical profit. PMID- 26017235 TI - Impact of hospitalization on modification of drug regimens: Results of the criteria to assess appropriate medication use among elderly complex patients study. AB - AIM: To assess the impact of hospitalization on modification of drug burden among elderly patients. METHODS: The present prospective cohort study was carried out in acute care hospitals in Italy. The difference in the number of drugs used before hospital admission and those prescribed at discharge was calculated. The prevalence of (i) any increase (1 or more drugs); and (ii) an increase >50% in the number of drugs from admission to discharge was calculated, and the factors associated with these conditions were identified. RESULTS: The mean age of 1082 participants was 81.2 +/- 7.3 years and 606 were women (56.0%), an increase in the number of drugs (1 or more drugs) between admission and discharge was observed in 672 participants (62.1% of study sample) and an "increase >50%" was observed in 372 participants (34.3%). "Any increase" was inversely associated with age and the number of drugs used before hospitalization, and it was positively associated with length of stay and diagnoses, including chronic obstructive pulmonary disease, ischemic heart disease and diabetes. "Increase >50%" was inversely associated with female sex, the number of drugs before hospitalization, involuntary loss of weight and intact cognitive status, and was positively associated with length of stay, chronic obstructive pulmonary disease, heart failure and diabetes. CONCLUSIONS: Not only disease, but also demographic factors (age and gender) and geriatric syndromes (weight loss and cognitive status) might influence pharmacological burden. These data might be useful in order to target interventions aimed at improving drug use and reducing iatrogenic illness. Geriatr Gerontol Int 2016; 16: 593-599. PMID- 26017236 TI - Tribute to Jacopo Tomasi. PMID- 26017237 TI - Autobiography of Jacopo Tomasi. PMID- 26017241 TI - Mycobacterium haemophilum infection with prominent facial manifestation mimicking leprosy. AB - Mycobacterium haemophilum is a slow-growing non-tuberculous mycobacterium that is rarely known to cause human skin infection, particularly in immunocompromised patients. We recently experienced a 69-year-old Japanese woman with this infection who had been under immunosuppressive treatment for recalcitrant rheumatoid arthritis. The patient showed disseminated erythematous plaques and subcutaneous nodules on the face and extremities, and interestingly, the face manifested with a striking "facies leontina" appearance. Biopsy revealed abscess and granulomatous dermatitis with the involvement of peripheral nerve bundles and the presence of innumerable acid-fast bacilli, thus necessitating differentiation from lepromatous leprosy. M. haemophilum was identified by molecular characterization as well as by successful culture with iron supplements. Although drug susceptibility testing indicated responsiveness to multiple antibiotics administrated simultaneously for the treatment, it took over 6 months to achieve significant improvement, and we also employed concurrent oral potassium iodide administration and repeated surgical excision. This case highlights the importance of continuous combination therapy for successful outcome in this rare infection. Furthermore, application of potassium iodide for mycobacterial infection warrants further evaluation by accumulating more cases. PMID- 26017242 TI - Neuro-protective potential of a vesicular system of a standardized extract of a new chemotype of Withania somnifera Dunal (NMITLI118RT+) against cerebral stroke in rats. AB - Withania somnifera Dunal is an Indian medicinal plant with significant pharmacological properties, such as adaptogenic, anti-inflammatory, anti-oxidant, anti-platelet, anti-hypertensive, hypoglycemic and hypolipidemic effects. Several chemotypes of W. somnifera include NMITLI-101, NMITLI-118 and NMITLI-128. The present work elaborates the optimization and development of a liposomal delivery system for efficient delivery of NMITLI118RT+ [a standardized ethanolic extract of a new chemotype of W. somnifera Dunal (NMITLI-118) roots] against cerebral stroke in rats. Liposomal systems were prepared using thin-film hydration method and characterized on the basis of size, zeta potential, physical stability, FT IR, DSC-TGA analysis and surface morphological studies by TEM. NMITLI118RT+ and its formulations (NMITLI118RT+LF) were evaluated for biological activity utilizing middle cerebral artery occlusion model in rats. The Z average of the developed liposomal formulation was about 142.6 +/- 0.09 nm with a zeta potential of -31.20 +/- 1.0 mV. Results of TEM revealed spherical particles in the range of 200 nm. The entrapment efficiency was found to be 94.603 +/- 2%. The formulation was found to be physically stable over a 3-week period. Results were suggestive of the fact that both NMITLI118RT+ and its delivery system possess significant neuroprotective activity in cerebral ischemia. The liposomal system largely exhibits better performance over NMITLI118RT+ precisely in the post-treatment group. The present studies could elucidate the successful development of a delivery system for NMITLI118RT+ and demonstrate their beneficial neuro protective potential in overcoming and reversing the consequences of I/R injury following stroke. PMID- 26017243 TI - Study on enhanced lymphatic exposure of polyamidoamin-alkali blue dendrimer for paclitaxel delivery and influence of the osmotic pressure on the lymphatic targeting. AB - In this study, paclitaxel (PTX)-loaded polyamidoamin-alkali blue (PTX-P-AB) was prepared in order to investigate the intralymphatic targeting ability and anti cancer effect after subcutaneous (s.c.) administration. The physicochemical properties and in vitro drug release were evaluated. The lymphatic drainage and lymph nodes (LNs) uptake were examined by pharmacokinetics and distribution recovery of PTX in plasma, LNs, injection site (IS) and tissues after s.c. injection in healthy mice and in tumor-bearing mice. The osmotic pressure of PTX P-AB affecting the lymphatic targeting was studied. The anti-tumor activity of PTX-P-AB was investigated in mice bearing S180 metastatic tumors. Results showed that PTX-P-AB with suitable and stable physicochemical properties could be used for in vivo lymphatic studies, and displayed the more rapid lymphatic absorption, the higher AUC value in LNs, the longer LNs residence time and the higher metastasis-inhibiting rate compared with Taxol(r). Enhanced lymphatic drainage from the IS and uptake into lymph by increasing the osmotic pressure of PTX-P-AB indicated that PTX-P-AB possesses the double function of lymphatic tracing and lymphatic targeting, and suggested the potential for the development of lymphatic targeting vectors and the lymphatic tracer for treatment and diagnosis. PMID- 26017244 TI - Evaluation of an in-house real-time polymerase chain reaction method to identify group B streptococcus colonization in pregnancy. AB - AIM: The aim of this study was to evaluate the performance of in-house real-time polymerase chain reaction (qPCR) in detecting group B streptococcus (GBS) colonization compared with the standard culture method in a cohort of pregnant women. MATERIAL AND METHODS: A total of 134 rectovaginal swabs were collected from 125 pregnant women, of whom 108 were known carriers or presented with preterm prelabor rupture of membranes. The swabs were placed in Standard Methods Broth (Todd-Hewitt broth supplemented with 6 MUg/mL gentamicin and 15 MUg/mL nalidixic acid) for culture identification of GBS. An in-house qPCR was also performed from the broth and after overnight incubation of the broth. RESULTS: The detection rate of GBS in this cohort was 30.6% and 50.7% using standard culture method and qPCR, respectively. GBS-specific qPCR assay gave sensitivities of 97.6% and 100%, specificities of 73.1% and 71.0%, and negative predictive values of 98.6% and 100% from direct specimen and from broth after overnight incubation, respectively. CONCLUSIONS: The in-house qPCR test has high sensitivity in detecting GBS colonization. The high negative predictive value helps to avoid unnecessary use of antibiotics in uncolonized women. PMID- 26017245 TI - Red meat consumption and ischemic heart disease. A systematic literature review. AB - Several lines of evidence attest that diet may strongly influence the cardiovascular risk. We performed an electronic search in Medline (with PubMed interface), Scopus and ISI Web of Science, to identify epidemiological studies on the association between red meat intake and the overall risk of ischemic heart disease (IHD). Eleven studies (8 prospective and 3 case-control) were finally selected for this systematic literature review. Although a larger intake of red meat was found to be a significant risk factor for IHD in four studies (2 prospective and 2 case-control), no significant association was found in five other trials (4 prospective and 1 case-control). We suggest that future diet recommendations for prevention of cardiovascular disease should take into account that the current literature data does not support the existence of a clear relationship between large intake of red meat and increased risk of myocardial ischemia. PMID- 26017246 TI - Patterns of drug abuse among drug users with regular and irregular attendance for treatment as detected by comprehensive UHPLC-HR-TOF-MS. AB - The most severe consequences of drug abuse include infectious diseases, overdoses, and drug-related deaths. As the range of toxicologically relevant compounds is continually changing due to the emergence of new psychoactive substances (NPS), laboratories are encountering analytical challenges. Current immunoassays are insufficient for determining the whole range of the drugs abused, and a broad-spectrum screening method is therefore needed. Here, the patterns of drug abuse in two groups of drug users were studied from urine samples using a comprehensive screening method based on high-resolution time-of flight mass spectrometry. The two groups comprised drug abusers undergoing opioid maintenance treatment (OMT) or drug withdrawal therapy and routinely visiting a rehabilitation clinic, and drug abusers with irregular attendance at a harm reduction unit (HRU) and suspected of potential NPS abuse. Polydrug abuse was observed in both groups, but was more pronounced among the HRU subjects with a mean number of concurrent drugs per sample of 3.9, whereas among the regularly treated subjects the corresponding number was 2.1. NPS and pregabalin were more frequent among HRU subjects, and their abuse was always related to drug co-use. The most common drug combination for an HRU subject included amphetamine, cannabis, buprenorphine, benzodiazepine, and alpha-pyrrolidinovalerophenone. A typical set of drugs for treated subjects was buprenorphine, benzodiazepine, and occasionally amphetamine. Abuse of several concurrent drugs poses a higher risk of drug intoxication and a threat of premature termination of OMT. Since the subjects attending treatment used fewer concurrent drugs, this treatment could be valuable in reducing polydrug abuse. PMID- 26017247 TI - Paxilitaxel induces apoptosis accompanied by protective autophagy in osteosarcoma cells through hypoxia-inducible factor-1alpha pathway. AB - Paxilitaxel, a drug used in cancer chemoprevention and treatment, has shown promising anti-cancer effects against a broad spectrum of tumors. However, the effect of paxilitaxel on osteoblasts has remained to be elucidated. The aim of the present study was to investigate the anti-tumor effect of paxilitaxel on human osteosarcoma cancer cells, the underlying molecular mechanism as well as drug resistance involved. The results showed that paxilitaxel not only induced apoptosis via the mitochondrial pathway but also induced autophagy, which partially inhibited cell apoptosis. The present study also demonstrated that paxilitaxel induced autophagy through the hypoxia-inducible factor (HIF)-1alpha pathway. Moreover, paxilitaxel-induced apoptosis decreased following incubation with with the autophagy inducer rapamycin. By contrast, co-treatment with the HIF 1alpha inhibitor YC-1 or autophagy inhibitor 3-methyladenine significantly blocked autophagy and augmented the anti-tumor effects of paxilitaxel. Therefore, the results of the present study suggested that the combination of paxilitaxel with an autophagy inhibitor or a HIF-1alpha inhibitor may be an effective and potent strategy for improved chemotherapy of osteosarcoma in the future. PMID- 26017248 TI - Dehydrocostus Lactone Inhibits Proliferation, Antiapoptosis, and Invasion of Cervical Cancer Cells Through PI3K/Akt Signaling Pathway. AB - OBJECTIVES: Recent studies found that dehydrocostus lactone (DHC), a traditional Chinese medicine in curing chronic ulcer and inflammation, can inhibit several type of tumor cells. The purpose of this study was to define the role of DHC on cervical cancer cells and to explore its mechanism of action. METHODS: We used DHC alone or in combination with PI3K/Akt-specific inhibitor LY294002 (LY) to treat Hela cells [human papillomavirus (HPV)-18 positive] and C33a cells (HPV negative). The proliferation, apoptosis, and Akt activation were assessed. Cell invasive ability was assayed in transwell chambers. RESULTS: We found that DHC significantly inhibited proliferation, antiapoptosis, and invasion of both cells, and reduced the level of p-Akt phosphorylation in these cells, in a dose- or time dependent manner. In addition, these inhibitions of DHC were significantly strengthened by LY. CONCLUSIONS: The result suggested that DHC plays a potent role in anticervical cancer in multiple biological aspects through PI3K/Akt signaling pathway, independently of HPV infection. This finding surely adds new knowledge to understand the role of DHC in fighting cancers. PMID- 26017249 TI - Robotic Hysterectomy for Endometrial Cancer in Obese Patients With Comorbidities: Evaluating Postoperative Complications. AB - OBJECTIVES: The objective of this study is to determine (1) if there is a relationship between increasing body mass index (BMI) and postoperative complications in patients undergoing robotic hysterectomy for endometrial cancer and (2) if there are additional patient characteristics, specifically preoperative comorbidities, which increase the risk of postoperative complication METHODS: A retrospective chart review was conducted on women who underwent a robotic staging surgery for endometrial cancer from 2006 to 2012. Basic demographics and preoperative and postoperative complications were extracted from the medical records. Obesity was divided into 4 categories, and complication rates were compared across these subgroups. Patients were also divided by the number of comorbidities and compared. RESULTS: The cohort included 543 patients. The BMI ranged from 17.3 to 69.5 kg/m. Three hundred eighty patients (70%) were obese (BMI >30 kg.m). One hundred ninety patients (35%) had no comorbidities other than obesity, and 180 patients (33%) had only 1 comorbidity other than obesity (Table 1).Postoperative complications occurred in 102 (18.7%) of the patients. Severe postoperative complications, including intensive care unit admission, reintubation, reoperation, and perioperative death, occurred in 14 patients (2.6%). Of the nonobese patients, 27 (16.5%) had postoperative complications; of the obese patients, 75 (19.7%) had a complication (P = 0.38). In patients with no comorbidities, 16.3% had a complication; 18% of patients with 1 to 2 comorbidities had a complication, and 28% of patients with 3 or more comorbidities had a complication (P = 0.08). CONCLUSIONS: The postoperative complication rate based on BMI or number of comorbidities was not statistically significant, but patients with greater number of comorbidities had an increased rate of postoperative complications. Patients with certain comorbidities, cardiac and renal specifically, had the highest rates of postoperative complications. PMID- 26017250 TI - Talking About The Smokes: a large-scale, community-based participatory research project. AB - OBJECTIVE: To describe the Talking About The Smokes (TATS) project according to the World Health Organization guiding principles for conducting community-based participatory research (PR) involving indigenous peoples, to assist others planning large-scale PR projects. DESIGN, SETTING AND PARTICIPANTS: The TATS project was initiated in Australia in 2010 as part of the International Tobacco Control Policy Evaluation Project, and surveyed a representative sample of 2522 Aboriginal and Torres Strait Islander adults to assess the impact of tobacco control policies. The PR process of the TATS project, which aimed to build partnerships to create equitable conditions for knowledge production, was mapped and summarised onto a framework adapted from the WHO principles. MAIN OUTCOME MEASURES: Processes describing consultation and approval, partnerships and research agreements, communication, funding, ethics and consent, data and benefits of the research. RESULTS: The TATS project involved baseline and follow up surveys conducted in 34 Aboriginal community-controlled health services and one Torres Strait community. Consistent with the WHO PR principles, the TATS project built on community priorities and strengths through strategic partnerships from project inception, and demonstrated the value of research agreements and trusting relationships to foster shared decision making, capacity building and a commitment to Indigenous data ownership. CONCLUSIONS: Community based PR methodology, by definition, needs adaptation to local settings and priorities. The TATS project demonstrates that large-scale research can be participatory, with strong Indigenous community engagement and benefits. PMID- 26017251 TI - Past quit attempts in a national sample of Aboriginal and Torres Strait Islander smokers. AB - OBJECTIVES: To describe past attempts to quit smoking in a national sample of Aboriginal and Torres Strait Islander people, and to compare their quitting activity with that in the general Australian population. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes (TATS) project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community controlled health services and one community in the Torres Strait. We surveyed 1643 smokers and 78 recent quitters between April 2012 and October 2013. Baseline results for daily smokers (n = 1392) are compared with results for daily smokers (n = 1655) from Waves 5 to 8.5 (2006-2012) of the Australian International Tobacco Control Policy Evaluation Project (ITC Project). MAIN OUTCOME MEASURES: Ever having tried to quit, tried to quit in the past year, sustained a quit attempt for 1 month or more. RESULTS: Compared with the general population, a smaller proportion of Aboriginal and Torres Strait Islander daily smokers had ever tried to quit (TATS, 69% v ITC, 81.4%), but attempts to quit within the past year were similar (TATS, 48% v ITC, 45.7%). More Aboriginal and Torres Strait Islander daily smokers than those in the general population reported sustaining past quit attempts for short periods only. Aboriginal and Torres Strait Islander smokers whose local health services had tobacco control resources were more likely to have tried to quit, whereas men and people who perceived they had experienced racism in the past year were less likely. Younger smokers, those who had gone without essentials due to money spent on smoking, and those who were often unable to afford cigarettes were more likely to have tried to quit in the past year, but less likely to have ever sustained an attempt for 1 month or more. Smokers who were unemployed, those who had not completed Year 12 and those from remote areas were also less likely to sustain a quit attempt. CONCLUSIONS: Existing comprehensive tobacco control programs appear to be motivating Aboriginal and Torres Strait Islander smokers to quit but do not appear to overcome challenges in sustaining quit attempts, especially for more disadvantaged smokers and those from remote areas. PMID- 26017252 TI - Predictors of wanting to quit in a national sample of Aboriginal and Torres Strait Islander smokers. AB - OBJECTIVE: To describe factors that predict wanting to quit smoking in a national sample of Aboriginal and Torres Strait Islander people. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes (TATS) project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community controlled health services and one community in the Torres Strait. Baseline survey data were collected from 1643 current smokers between April 2012 and October 2013. MAIN OUTCOME MEASURE: Wanting to quit smoking. RESULTS: More than two-thirds of smokers (70%) said they want to quit. Many factors were associated with wanting to quit, including past quitting activity. Interest in quitting was lower among men and smokers from economically disadvantaged areas, but there was no difference by age, remoteness or other measures of economic disadvantage. Attitudes and beliefs negatively associated with wanting to quit included enjoying smoking and believing quitting to be very difficult, and those positively associated included regretting ever starting to smoke, perceiving that local Aboriginal and Torres Strait Islander community leaders disapprove of smoking, believing non-smokers set a good example to children, worrying about future smoking-related health effects and believing quitting to be beneficial. Reporting support from family and friends was predictive of wanting to quit, but factors related to smoking in the social network were not. Associations with health and wellbeing were mixed. While most tobacco control policy exposure variables were positively associated with wanting to quit, two - receiving advice to quit from a health professional, and recall of targeted anti-tobacco advertising - appeared to have an effect that extended beyond influencing relevant attitudes and beliefs. CONCLUSION: Interest in quitting among Aboriginal and Torres Strait Islander smokers appears to be influenced by a broad range of factors, highlighting the importance of taking a comprehensive approach to tobacco control. Advice from health professionals and targeted advertising appear to be important intervention strategies. PMID- 26017253 TI - Talking About The Smokes: summary and key findings. PMID- 26017254 TI - Smoke-free homes and workplaces of a national sample of Aboriginal and Torres Strait Islander people. AB - OBJECTIVE: To examine Aboriginal and Torres Strait Islander people's protection from second-hand smoke at home and work. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project surveyed 2522 Aboriginal and Torres Strait Islander people from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait, using quota sampling, from April 2012 to October 2013. We made comparisons with data from Australian smokers in the International Tobacco Control Policy Evaluation Project (ITC Project), collected from either July 2010 to May 2011 or September 2011 to February 2012. MAIN OUTCOME MEASURES: Whether smoking was not allowed anywhere in the home, or not allowed in any indoor area at work. RESULTS: More than half (56%) of Aboriginal and Torres Strait Islander smokers and 80% of non-smokers reported that smoking was never allowed anywhere in their home. Similar percentages of daily smokers in our sample and the Australian ITC Project data reported bans. Most employed Aboriginal and Torres Strait Islander daily smokers (88%) reported that smoking was not allowed in any indoor area at work, similar to the Australian ITC Project estimate. Smokers working in smoke-free workplaces were more likely to have smoke-free homes than those in workplaces where smoking was allowed indoors (odds ratio, 2.85; 95% CI, 1.67-4.87). Smokers who lived in smoke-free homes were more likely to have made a quit attempt in the past year, to want to quit, and to have made quit attempts of 1 month or longer. CONCLUSION: Most Aboriginal and Torres Strait Islander people are protected from second-hand smoke at work, and similar proportions of Aboriginal and Torres Strait Islander smokers and other Australian smokers do not allow smoking inside their homes. PMID- 26017255 TI - Dependence in a national sample of Aboriginal and Torres Strait Islander daily smokers. AB - OBJECTIVES: To examine indicators of nicotine dependence in a national sample of Aboriginal and Torres Strait Islander daily smokers and their association with sustaining a quit attempt for at least 1 month, and to make comparisons with a national sample of Australian daily smokers. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used a quota sampling design to recruit 1392 daily smokers from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait from April 2012 to October 2013. These were compared with 1010 daily smokers from the general Australian population surveyed by the International Tobacco Control Policy Evaluation Project from September 2011 to February 2012. MAIN OUTCOME MEASURES: Cigarettes per day (CPD), time to first cigarette, Heaviness of Smoking Index (HSI), other indicators of dependence, and whether smokers had ever sustained a quit attempt for at least 1 month. RESULTS: There was little difference in the mean HSI scores for Aboriginal and Torres Strait Islander and other Australian daily smokers. A higher proportion of Aboriginal and Torres Strait Islander daily smokers smoked <= 10 CPD (40% v 33.4%), but more also smoked their first cigarette within 30 minutes of waking (75% v 64.6%). Lower proportions of Aboriginal and Torres Strait Islander smokers reported having strong urges to smoke at least several times a day (51% v 60.7%) or that it would be very hard to quit (39% v 47.9%). Most Aboriginal and Torres Strait Islander smokers reported experiencing difficulties during their most recent quit attempt. All indicators of dependence, except CPD and strong urges, were positively associated with not having made a sustained quit attempt. Reported difficulties during the most recent quit attempt were more strongly associated with being unable to sustain quit attempts than were traditional measures of dependence. CONCLUSION: Aboriginal and Torres Strait Islander smokers' experiences of past attempts to quit may be more useful than conventional indicators of nicotine dependence in understanding their dependence. PMID- 26017256 TI - Smoking-related knowledge and health risk beliefs in a national sample of Aboriginal and Torres Strait Islander people. AB - OBJECTIVES: To describe general knowledge and perceived risk of the health consequences of smoking among Aboriginal and Torres Strait Islander people; and to assess whether knowledge varies among smokers and whether higher knowledge and perceived risk are associated with quitting. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used quota sampling to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. Baseline survey data were collected from 2522 Aboriginal and Torres Strait Islander adults from April 2012 to October 2013. MAIN OUTCOME MEASURES: Knowledge of direct effects of smoking and harms of second hand smoke (SHS), risk minimisation, health worry, and wanting and attempting to quit. RESULTS: Most Aboriginal and Torres Strait Islander participants who were daily smokers demonstrated knowledge that smoking causes lung cancer (94%), heart disease (89%) and low birthweight (82%), but fewer were aware that it makes diabetes worse (68%). Similarly, almost all daily smokers knew of the harms of SHS: that it is dangerous to non-smokers (90%) and children (95%) and that it causes asthma in children (91%). Levels of knowledge among daily smokers were lower than among non-daily smokers, ex-smokers and never-smokers. Among smokers, greater knowledge of SHS harms was associated with health worry, wanting to quit and having attempted to quit in the past year, but knowledge of direct harms of smoking was not. CONCLUSION: Lack of basic knowledge about the health consequences of smoking is not an important barrier to trying to quit for Aboriginal and Torres Strait Islander smokers. Framing new messages about the negative health effects of smoking in ways that encompass the health of others is likely to contribute to goal setting and prioritising quitting among Aboriginal and Torres Strait Islander people. PMID- 26017257 TI - Research methods of Talking About The Smokes: an International Tobacco Control Policy Evaluation Project study with Aboriginal and Torres Strait Islander Australians. AB - OBJECTIVE: To describe the research methods and baseline sample of the Talking About The Smokes (TATS) project. DESIGN: The TATS project is a collaboration between research institutions and Aboriginal community-controlled health services (ACCHSs) and their state and national representative bodies. It is one of the studies within the International Tobacco Control Policy Evaluation Project, enabling national and international comparisons. It includes a prospective longitudinal study of Aboriginal and Torres Strait Islander smokers and recent ex smokers; a survey of non-smokers; repeated cross-sectional surveys of ACCHS staff; and descriptions of the tobacco policies and practices at the ACCHSs. Community members completed face-to-face surveys; staff completed surveys on paper or online. We compared potential biases and the distribution of variables common to the main community baseline sample and unweighted and weighted results of the 2008 National Aboriginal and Torres Strait Islander Social Survey (NATSISS). The baseline survey (Wave 1) was conducted between April 2012 and October 2013. SETTING AND PARTICIPANTS: 2522 Aboriginal and Torres Strait Islander people in 35 locations (the communities served by 34 ACCHSs and one community in the Torres Strait), and 645 staff in the ACCHSs. MAIN OUTCOME MEASURES: Sociodemographic and general health indicators, smoking status, number of cigarettes smoked per day and quit attempts. RESULTS: The main community baseline sample closely matched the distribution of the Aboriginal and Torres Strait Islander population in the weighted NATSISS by age, sex, jurisdiction and remoteness. There were inconsistent differences in some sociodemographic factors between our sample and the NATSISS: our sample had higher proportions of unemployed people, but also higher proportions who had completed Year 12 and who lived in more advantaged areas. In both surveys, similar percentages of smokers reported having attempted to quit in the past year, and daily smokers reported similar numbers of cigarettes smoked per day. CONCLUSION: The TATS project provides a detailed and nationally representative description of Aboriginal and Torres Strait Islander smoking behaviour, attitudes, knowledge and exposure to tobacco control activities and policies, and their association with quitting. PMID- 26017258 TI - Personal attitudes towards smoking in a national sample of Aboriginal and Torres Strait Islander smokers and recent quitters. AB - OBJECTIVES: To describe attitudes towards smoking in a national sample of Aboriginal and Torres Strait Islander smokers and recent quitters and assess how they are associated with quitting, and to compare these attitudes with those of smokers in the general Australian population. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1392 daily smokers, 251 non-daily smokers and 78 recent quitters from April 2012 to October 2013. MAIN OUTCOME MEASURES: Personal attitudes towards smoking and quitting, wanting to quit, and attempting to quit in the past year. RESULTS: Aboriginal and Torres Strait Islander daily smokers were less likely than daily smokers in the general Australian population to report enjoying smoking (65% v 81%) and more likely to disagree that smoking is an important part of their life (49% v 38%); other attitudes were similar between the two groups. In the Aboriginal and Torres Strait Islander sample, non-daily smokers generally held less positive attitudes towards smoking compared with daily smokers, and ex-smokers who had quit within the past year reported positive views about quitting. Among the daily smokers, 78% reported regretting starting to smoke and 81% reported spending too much money on cigarettes, both of which were positively associated with wanting and attempting to quit; 32% perceived smoking to be an important part of their life, which was negatively associated with both quit outcomes; and 83% agreed that smoking calms them down when stressed, which was not associated with the quitting outcomes. CONCLUSIONS: Aboriginal and Torres Strait Islander smokers were less likely than those in the general population to report positive reasons to smoke and held similar views about the negative aspects, suggesting that factors other than personal attitudes may be responsible for the high continuing smoking rate in this population. PMID- 26017259 TI - Social acceptability and desirability of smoking in a national sample of Aboriginal and Torres Strait Islander people. AB - OBJECTIVES: To describe social normative beliefs about smoking in a national sample of Aboriginal and Torres Strait Islander people, and to assess the relationship of these beliefs with quitting. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1392 daily smokers, 251 non-daily smokers, 311 ex-smokers and 568 never-smokers from April 2012 to October 2013. MAIN OUTCOME MEASURES: Eight normative beliefs about smoking; wanting and attempting to quit. RESULTS: Compared with daily smokers in the general Australian population, Aboriginal and Torres Strait Islander daily smokers were less likely to report that mainstream society disapproves of smoking (78.5% v 62%). Among Aboriginal and Torres Strait Islander daily smokers, 40% agreed that Aboriginal and Torres Strait Islander community leaders where they live disapprove of smoking, 70% said there are increasingly fewer places they feel comfortable smoking, and most (90%) believed non-smokers set a good example to children. Support for the government to do more to tackle the harm caused by smoking was much higher than in the general Australian population (80% v 47.2%). These five normative beliefs were all associated with wanting to quit. Non smokers reported low levels of pressure to take up smoking. CONCLUSION: Tobacco control strategies that involve the leadership and participation of local Aboriginal and Torres Strait Islander community leaders, particularly strategies that emphasise protection of others, may be an important means of reinforcing beliefs that smoking is socially unacceptable, thus boosting motivation to quit. PMID- 26017260 TI - Tobacco control policies and activities in Aboriginal community-controlled health services. AB - OBJECTIVES: To describe tobacco control policies and activities at a nationally representative sample of Aboriginal community-controlled health services (ACCHSs). DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes (TATS) project used a quota sampling design to recruit 34 ACCHSs around Australia. Between April 2012 and October 2013, a representative at each ACCHS completed a survey about the service's tobacco control policies and activities. Questions about support for smoke-free policies were also included in the TATS project survey of 2435 Aboriginal and Torres Strait Islander members of the communities served by the ACCHSs. MAIN OUTCOME MEASURES: ACCHS tobacco control policies and activities. RESULTS: Thirty-two surveys were completed, covering 34 sites. Most ACCHSs (24/32) prioritised tobacco control "a great deal" or "a fair amount", and all services had smoke-free workplace policies. Most had staff working on tobacco control and had provided tobacco control training within the past year. A range of quit-smoking information and activities had been provided for clients and the community, as well as extra smoking cessation support for staff. There was strong support for smoke-free ACCHSs from within the Aboriginal communities, with 87% of non-smokers, 85% of ex-smokers and 77% of daily smokers supporting a complete ban on smoking inside and around ACCHS buildings. CONCLUSIONS: The high level of commitment and experience within ACCHSs provides a strong base to sustain further tobacco control measures to reduce the very high smoking prevalence in Aboriginal and Torres Strait Islander populations. PMID- 26017261 TI - Recall of anti-tobacco advertising and information, warning labels and news stories in a national sample of Aboriginal and Torres Strait Islander smokers. AB - OBJECTIVES: To describe recall of anti-tobacco advertising (mainstream and targeted), pack warning labels, and news stories among a national sample of Aboriginal and Torres Strait Islander smokers, and to assess the association of these messages with attitudes that support quitting, including wanting to quit. DESIGN, SETTING AND PARTICIPANTS: A quota sampling design was used to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1643 Aboriginal and Torres Strait Islander smokers from April 2012 to October 2013. MAIN OUTCOME MEASURES: Frequency of recall of advertising and information, warning labels and news stories; recall of targeted and local advertising; attitudes about smoking and wanting to quit. RESULTS: More smokers recalled often noticing warning labels in the past month (65%) than recalled advertising and information (45%) or news stories (24%) in the past 6 months. When prompted, most (82%) recalled seeing a television advertisement. Just under half (48%) recalled advertising that featured an Aboriginal or Torres Strait Islander person or artwork (targeted advertising), and 16% recalled targeted advertising from their community (local advertising). Frequent recall of warning labels, news stories and advertising was associated with worry about health and wanting to quit, but only frequent advertising recall was associated with believing that society disapproves of smoking. The magnitude of association with relevant attitudes and wanting to quit increased for targeted and local advertising. CONCLUSIONS: Strategies to tackle Aboriginal and Torres Strait Islander smoking should sustain high levels of exposure to anti-tobacco advertising, news stories and warning labels. More targeted and local information may be particularly effective to influence relevant beliefs and subsequently increase quitting. PMID- 26017262 TI - Smoking cessation advice and non-pharmacological support in a national sample of Aboriginal and Torres Strait Islander smokers and ex-smokers. AB - OBJECTIVES: To describe recall among a national sample of Aboriginal and Torres Strait Islander smokers and recent ex-smokers of having received advice to quit smoking and referral to non-pharmacological cessation support from health professionals, and their association with quit attempts. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used a quota sampling design to recruit 1721 smokers and ex-smokers who had quit <= 12 months previously from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. Baseline surveys were conducted from April 2012 to October 2013. Results for daily smokers were compared with 1412 Australian daily smokers surveyed by the International Tobacco Control Policy Evaluation Project between 2006 and 2011. MAIN OUTCOME MEASURES: Participants' recall of having been: seen by a health professional in the past year, asked if they smoke, advised to quit, and referred to other cessation support services; and having made a quit attempt in the past year. RESULTS: Compared with other Australian daily smokers, higher proportions of Aboriginal and Torres Strait Islander daily smokers saw a health professional in the past year (76% v 68.1%) and were advised to quit smoking (75% v 56.2% of those seen). Most Aboriginal and Torres Strait daily smokers who saw a health professional recalled being asked if they smoke (93%). Aboriginal and Torres Strait Islander daily smokers who had been advised to quit were more likely to have made a quit attempt in the past year than those who had not (odds ratio, 2.00; 95% CI, 1.58-2.52). Among all Aboriginal and Torres Strait Islander smokers and recent ex-smokers who had been advised to quit, 49% were given a pamphlet or brochure on how to quit, but fewer were referred to the telephone Quitline (28%), a quit-smoking website (27%) or a local quit course, group or clinic (16%). CONCLUSION: Most Aboriginal and Torres Strait Islander daily smokers recalled being recently advised by a health professional to quit, which was associated with making a quit attempt. PMID- 26017263 TI - Use of nicotine replacement therapy and stop-smoking medicines in a national sample of Aboriginal and Torres Strait Islander smokers and ex-smokers. AB - OBJECTIVE: To examine the use of nicotine replacement therapy (NRT) and the stop smoking medicines (SSMs) varenicline and bupropion in a national sample of Aboriginal and Torres Strait Islander smokers and recent ex-smokers. DESIGN, SETTINGS AND PARTICIPANTS: The Talking About The Smokes (TATS) project used a quota sampling design to recruit a nationally representative sample of 1721 smokers and ex-smokers who had quit <= 12 months before from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. Baseline surveys were conducted from April 2012 to October 2013. These were compared with 1017 daily smokers from the general Australian population surveyed by the International Tobacco Control Policy Evaluation Project (ITC Project) from July 2010 to May 2011. MAIN OUTCOME MEASURES: Past and intended use of NRT and SSMs, duration of use, and whether participants thought NRT and SSMs help smokers to quit. RESULTS: Compared with other daily Australian smokers, lower proportions of Aboriginal and Torres Strait Islander daily smokers had ever used any NRT or SSMs (TATS, 37% v ITC, 58.5%) or used them in the past year (TATS, 23% v ITC, 42.1%). Nicotine patches were most commonly used by Aboriginal and Torres Strait Islander smokers and recent ex-smokers (24%), followed by varenicline (11%) and nicotine gum (10%); most (74%) had got their last NRT at no cost. Among dependent Aboriginal and Torres Strait Islander daily smokers, those who were more socioeconomically advantaged were more likely than the disadvantaged to have used NRT or SSMs. Similar proportions of Aboriginal and Torres Strait Islander daily smokers and other Australian daily smokers said that NRT or SSMs help smokers to quit (TATS, 70% v ITC, 74.2%). Dependent Aboriginal and Torres Strait Islander smokers who had previously used NRT or SSMs were more likely to believe they help in quitting and to intend to use them in the future. CONCLUSION: Aboriginal and Torres Strait Islander daily smokers, particularly those who are most disadvantaged, are less likely to have used NRT or SSMs than other Australian daily smokers. Some of the barriers to use, including cost, are being overcome, but further improvements are possible. PMID- 26017264 TI - Smoking among a national sample of Aboriginal and Torres Strait Islander health service staff. AB - OBJECTIVE: To examine smoking among Aboriginal and Torres Strait Islander staff of Aboriginal community-controlled health services (ACCHSs). DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes (TATS) project surveyed 374 Aboriginal and Torres Strait Islander staff at a national sample of 31 ACCHSs, from April 2012 to October 2013. We made comparisons with adult participants in the 2008 National Aboriginal and Torres Strait Islander Social Survey (NATSISS) and with 1643 smokers in a community sample of 2522 Aboriginal and Torres Strait Islander people also surveyed in the TATS project. MAIN OUTCOME MEASURES: Smoking status, smoking behaviour at work, quitting behaviour, attitudes and beliefs about smoking and quitting. RESULTS: Aboriginal and Torres Strait Islander ACCHS staff had a lower smoking prevalence than among all Aboriginal and Torres Strait Islander adults surveyed in the NATSISS (38% v 49.8%), but this difference was smaller when compared with only employed adults (38% v 44.8%). Staff smokers had higher odds than smokers in their communities of ever trying to quit (odds ratio [OR], 2.1; 95% CI, 1.1-3.7), of having often noticed anti-smoking advertising (OR, 2.8; 95% CI, 1.4-5.6), and of having used stop-smoking medications (OR, 3.0; 95% CI, 1.6-5.7), often with the support of their ACCHS. There was a significant association (P < 0.001) between the smoking status of Aboriginal and Torres Strait Islander staff and their confidence in talking to others about smoking and quitting; ex-smokers were most likely to report being confident. Most Aboriginal and Torres Strait Islander staff who smoked (74%) agreed that being a non-smoker sets a good example to patients at their health service, and most did not smoke with patients or at work where patients could see them. CONCLUSION: Smoking prevalence among Aboriginal and Torres Strait Islander ACCHS staff is only modestly lower than among other employed Aboriginal and Torres Strait Islander people. Given that ex-smokers feel more confident to help others quit than any other group, smoking cessation in ACCHS staff is a useful contributor to reducing community smoking rates. PMID- 26017265 TI - Conformational analysis, part 43. A theoretical and LIS/NMR investigation of the conformations of substituted benzamides. AB - A refined Lanthanide-Induced-Shift Analysis (LISA) is used with molecular mechanics and ab initio calculations to investigate the conformations of benzamide (1), N-methylbenzamide (2), N,N-dimethylbenzamide (3) and the conformational equilibria of 2-fluoro (4), 2-chloro (5) and N-methyl-2-methoxy benzamide (6). The amino group in 1 is planar in the crystal but is calculated to be pyramidal with the CO/phenyl torsional angle (omega) of 20-25 degrees . The LISA analysis gave acceptable agreement factors (Rcryst <= 1%) for the ab initio geometries when omega was decreased to 0 degrees , the other geometries were not as good. In 2, the N-methyl is coplanar with the carbonyl group in all the geometries. Good agreement was obtained for the RHF geometries, with omega 25 degrees , the other geometries were only acceptable with increased values of omega. In 3, good agreement for the RHF and PCModel geometries was found when omega was changed from the calculated values of 40 degrees (RHF) and 90 degrees (PCModel) to ca. 60 degrees , the X-ray and B3LYP geometries were not as good. The two substituted compounds 4, 5 and 6 are interconverting between the cis (O,X) and trans (O,X) conformers. The more stable trans conformer is planar in 4 and 6 but the cis form non-planar. Both the cis and trans conformers of 5 are non planar. There is an additional degree of freedom in 6 due to the 2-methoxy group, which can be either planar or orthogonal to the phenyl ring in both conformers. The conformer ratios were obtained from the LISA analysis to give Ecis-Etrans in 4 > 2.3 kcal/mol (CDCl3 ) and 1.7 kcal/mol (CD3 CN), in 5 0.0 kcal/mol (CD3 CN) and in 6 > 2.5 kcal/mol (CDCl3 ) and 2.0 kcal/mol (CD3 CN). These values were used with the observed versus calculated (1) H shifts to determine the conformer ratios and energies in DMSO solvent to give Ecis-Etrans 1.1, -0.1 and 1.8 kcal/mol for (4), (5) and (6). Comparison of the observed versus calculated conformer energies show that both the MM and ab initio calculations overestimate the NH..F hydrogen bond in (4) by ca. 2 kcal/mol. PMID- 26017266 TI - Inhibition of Janus kinases by tyrosine phosphorylation inhibitor, Tyrphostin AG 490. AB - Janus kinases (JAKs) belong to a crucial family of tyrosine kinases, implicated in the patho-physiology of multiple cancer types, and serve as striking therapeutic targets. To date, many potent, either ATP-competitive (PTK domain) or non-ATP-competitive JAK inhibitors have been identified. Among them, Tyrphostin AG-490 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-2-propenamide) is a well known ATP-competitive inhibitor. However, its mode of action, details of interacting residues, and induced conformational changes in JAK-specific binding sites remain elusive. Here, through comparative structure analysis, molecular docking, and molecular dynamics simulation assays, we explored comparative binding patterns of AG-490 against JAK1, JAK2, and JAK3. Our results entail noteworthy observations about the binding affinity of AG-490 by illustrating distinctive amino acid residues lying at the conserved ATP-binding domains of JAK family members. By subsequent assessment of their structural homology and conserved structural folds, we highlight intriguing prospects to design more specific and potent inhibitors for selective targeting of JAK family members. Our comparative study provides a platform for the rational design of precise and potent inhibitor for selective targeting of JAK family members. PMID- 26017267 TI - Heterocyclic Regioisomer Enumeration (HREMS): A Cheminformatics Design Tool. AB - We report the development and implementation of a cheminformatics tool which aids in the design of compounds during exploratory chemistry and lead optimization. The Heterocyclic Regioisomer Enumeration and MDDR Search (HREMS) tool allows medicinal chemists to build greater structural diversity into their synthetic planning by enabling a systematic, automated enumeration of heterocyclic regioisomers of target structures. To help chemists overcome biases arising from past experience or synthetic accessibility, the HREMS tool further provides statistics on clinical testing for each enumerated regioisomer substructure using an automated search of a commercial database. Ready access to this type of information can help chemists make informed choices on the targets they will pursue being mindful of past experience with these structures in drug development. This tool and its components can be incorporated into other cheminformatics workflows to leverage their capabilities in triaging and in silico compound enumeration. PMID- 26017268 TI - Psychotic and schizotypal symptoms in non-psychotic patients with obsessive compulsive disorder. AB - BACKGROUND: Research is scarce with regard to the role of psychotic and schizotypal symptoms in treatment of obsessive-compulsive disorder (OCD). The aim of the current study was to investigate the occurrence and specificity of psychotic and schizotypal symptoms among non-psychotic OCD patients, and to examine whether such symptoms was associated with response to exposure and response prevention (ERP), and whether ERP for OCD had an impact on psychotic and schizotypal symptoms. METHODS: Non-psychotic OCD patients (n = 133) and a general non-psychotic psychiatric outpatient sample (n = 110) were assessed using self report inventories before and after psychological treatment. RESULTS: Non psychotic OCD patients did not report greater degree of psychotic or schizotypal symptoms than the control group. Psychotic and schizotypal symptoms were not associated with OCD symptoms before or after ERP. Psychotic and schizotypal symptom were significantly reduced following ERP. CONCLUSIONS: Psychotic and schizotypal symptoms seem to be equally prevalent among non-psychotic OCD patients and non-psychotic psychiatric controls. These symptoms were more linked to depressive symptoms than OCD symptoms. In non-psychotic OCD patients, ERP seems sufficient in reducing OCD symptoms despite the presence of psychotic- and schizotypal symptoms, and reductions in psychotic- and schizotypal symptoms were observed following ERP. PMID- 26017269 TI - Ossification Pattern of Estuarine Dolphin (Sotalia guianensis) Forelimbs, from the Coast of the State of Espirito Santo, Brazil. AB - The estuarine dolphin, Sotalia guianensis, is one of the most abundant cetacean species in Brazil. Determination of age and of aspects associated with the development of this species is significant new studies. Counts of growth layer groups in dentin are used to estimate age of these animals, though other ways to evaluate development are also adopted, like the measurement of total length (TL). This study presents a procedure to evaluate the development of the estuarine dolphin based on the ossification pattern of forelimbs. Thirty-seven estuarine dolphins found in the state of Espirito Santo, Brazil, were examined. Age was estimated, TL was measured and ossification of epiphyses was examined by radiography. We analyzed results using the Spearman correlation. Inspection of radiographs allowed evaluation of the significance of the correlation between age and development of the proximal (r = 0.9109) and distal (r = 0.9092) radial epiphyses, and of the distal ulnar epiphyses (r = 0.9055). Radiographic analysis of forelimbs proved to be an appropriate method to evaluate physical maturity, and may be a helpful tool to estimate age of these animals in ecological and population studies. PMID- 26017271 TI - Accurate, fully-automated NMR spectral profiling for metabolomics. AB - Many diseases cause significant changes to the concentrations of small molecules (a.k.a. metabolites) that appear in a person's biofluids, which means such diseases can often be readily detected from a person's "metabolic profile"-i.e., the list of concentrations of those metabolites. This information can be extracted from a biofluids Nuclear Magnetic Resonance (NMR) spectrum. However, due to its complexity, NMR spectral profiling has remained manual, resulting in slow, expensive and error-prone procedures that have hindered clinical and industrial adoption of metabolomics via NMR. This paper presents a system, BAYESIL, which can quickly, accurately, and autonomously produce a person's metabolic profile. Given a 1D 1H NMR spectrum of a complex biofluid (specifically serum or cerebrospinal fluid), BAYESIL can automatically determine the metabolic profile. This requires first performing several spectral processing steps, then matching the resulting spectrum against a reference compound library, which contains the "signatures" of each relevant metabolite. BAYESIL views spectral matching as an inference problem within a probabilistic graphical model that rapidly approximates the most probable metabolic profile. Our extensive studies on a diverse set of complex mixtures including real biological samples (serum and CSF), defined mixtures and realistic computer generated spectra; involving > 50 compounds, show that BAYESIL can autonomously find the concentration of NMR detectable metabolites accurately (~ 90% correct identification and ~ 10% quantification error), in less than 5 minutes on a single CPU. These results demonstrate that BAYESIL is the first fully-automatic publicly-accessible system that provides quantitative NMR spectral profiling effectively-with an accuracy on these biofluids that meets or exceeds the performance of trained experts. We anticipate this tool will usher in high-throughput metabolomics and enable a wealth of new applications of NMR in clinical settings. BAYESIL is accessible at http://www.bayesil.ca. PMID- 26017270 TI - Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages. AB - Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX 2, IL-1beta, IL-6, INF-beta, and TNF-alpha. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll like receptor 4 (TLR4)- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation. PMID- 26017272 TI - Tubular Unimolecular Transmembrane Channels: Construction Strategy and Transport Activities. AB - Lipid bilayer membranes separate living cells from their environment. Membrane proteins are responsible for the processing of ion and molecular inputs and exports, sensing stimuli and signals across the bilayers, which may operate in a channel or carrier mechanism. Inspired by these wide-ranging functions of membrane proteins, chemists have made great efforts in constructing synthetic mimics in order to understand the transport mechanisms, create materials for separation, and develop therapeutic agents. Since the report of an alkylated cyclodextrin for transporting Cu(2+) and Co(2+) by Tabushi and co-workers in 1982, chemists have constructed a variety of artificial transmembrane channels by making use of either the multimolecular self-assembly or unimolecular strategy. In the context of the design of unimolecular channels, important advances have been made, including, among others, the tethering of natural gramicidin A or alamethicin and the modification of various macrocycles such as crown ethers, cyclodextrins, calixarenes, and cucurbiturils. Many of these unimolecular channels exhibit high transport ability for metal ions, particularly K(+) and Na(+). Concerning the development of artificial channels based on macrocyclic frameworks, one straightforward and efficient approach is to introduce discrete chains to reinforce their capability to insert into bilayers. Currently, this approach has found the widest applications in the systems of crown ethers and calixarenes. We envisioned that for macrocycle-based unimolecular channels, control of the arrangement of the appended chains in the upward and/or downward direction would favor the insertion of the molecular systems into bilayers, while the introduction of additional interactions among the chains would further stabilize a tubular conformation. Both factors should be helpful for the formation of new efficient channels. In this Account, we discuss our efforts in designing new unimolecular artificial channels from tubular pillar[n]arenes by extending their lengths with various ester, hydrazide, and short peptide chains. We have utilized well-defined pillar[5]arene and pillar[6]arene as rigid frameworks that allow the appended chains to afford extended tubular structures. We demonstrate that the hydrazide and peptide chains form intramolecular N H...O?C hydrogen bonds that enhance the tubular conformation of the whole molecule. The new pillar[n]arene derivatives have been successfully applied as unimolecular channels for the selective transport of protons, water, and amino acids and the voltage-gated transport of K(+). We also show that aromatic hydrazide helices and macrocycles appended with peptide chains are able to mediate the selective transport of NH4(+). PMID- 26017274 TI - Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients. AB - PURPOSE: Concerns were raised about the safety of antiplatelet thienopyridine derivatives after a randomized control trial reported increased risks of cancer and cancer deaths in prasugrel users. We investigate whether clopidogrel, a widely used thienopyridine derivative, was associated with increased risk of cancer-specific or all-cause mortality in cancer patients. METHODS: Colorectal, breast and prostate cancer patients, newly diagnosed from 1998 to 2009, were identified from the National Cancer Data Repository. Cohorts were linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2012). Unadjusted and adjusted hazard ratios (HRs) for cancer-specific and all-cause mortality in post diagnostic clopidogrel users were calculated using time-dependent Cox regression models. RESULTS: The analysis included 10 359 colorectal, 17 889 breast and 13 155 prostate cancer patients. There was no evidence of an increase in cancer specific mortality in clopidogrel users with colorectal (HR = 0.98 95% confidence interval (CI) 0.77, 1.24) or prostate cancer (HR = 1.03 95%CI 0.82, 1.28). There was limited evidence of an increase in breast cancer patients (HR = 1.22 95%CI 0.90, 1.65); however, this was attenuated when removing prescriptions in the year prior to death. CONCLUSIONS: This novel study of large population-based cohorts of colorectal, breast and prostate cancer patients found no evidence of an increased risk of cancer-specific mortality among colorectal, breast and prostate cancer patients using clopidogrel. PMID- 26017273 TI - Delay and probability discounting of sexual and monetary outcomes in individuals with cocaine use disorders and matched controls. AB - Individuals with cocaine use disorders are disproportionately affected by HIV/AIDS, partly due to higher rates of unprotected sex. Recent research suggests delay discounting of condom use is a factor in sexual HIV risk. Delay discounting is a behavioral economic concept describing how delaying an event reduces that event's value or impact on behavior. Probability discounting is a related concept describing how the uncertainty of an event decreases its impact on behavior. Individuals with cocaine use disorders (n = 23) and matched non-cocaine-using controls (n = 24) were compared in decision-making tasks involving hypothetical outcomes: delay discounting of condom-protected sex (Sexual Delay Discounting Task), delay discounting of money, the effect of sexually transmitted infection (STI) risk on likelihood of condom use (Sexual Probability Discounting Task), and probability discounting of money. The Cocaine group discounted delayed condom protected sex (i.e., were more likely to have unprotected sex vs. wait for a condom) significantly more than controls in two of four Sexual Delay Discounting Task partner conditions. The Cocaine group also discounted delayed money (i.e., preferred smaller immediate amounts over larger delayed amounts) significantly more than controls. In the Sexual Probability Discounting Task, both groups showed sensitivity to STI risk, however the groups did not differ. The Cocaine group did not consistently discount probabilistic money more or less than controls. Steeper discounting of delayed, but not probabilistic, sexual outcomes may contribute to greater rates of sexual HIV risk among individuals with cocaine use disorders. Probability discounting of sexual outcomes may contribute to risk of unprotected sex in both groups. Correlations showed sexual and monetary results were unrelated, for both delay and probability discounting. The results highlight the importance of studying specific behavioral processes (e.g., delay and probability discounting) with respect to specific outcomes (e.g., monetary and sexual) to understand decision making in problematic behavior. PMID- 26017275 TI - Enhanced surveillance and data feedback loop associated with improved malaria data in Lusaka, Zambia. AB - BACKGROUND: Accurate and timely malaria data are crucial to monitor the progress towards and attainment of elimination. Lusaka, the capital city of Zambia, has reported very low malaria prevalence in Malaria Indicator Surveys. Issues of low malaria testing rates, high numbers of unconfirmed malaria cases and over consumption of anti-malarials were common at clinics within Lusaka, however. The Government of Zambia (GRZ) and its partners sought to address these issues through an enhanced surveillance and feedback programme at clinic level. METHODS: The enhanced malaria surveillance programme began in 2011 to verify trends in reported malaria, as well as to implement a data feedback loop to improve data uptake, use, and quality. A process of monthly data collection and provision of feedback was implemented within all GRZ health clinics in Lusaka District. During clinic visits, clinic registers were accessed to record the number of reported malaria cases, malaria test positivity rate, malaria testing rate, and proportion of total suspected malaria that was confirmed with a diagnostic test. RESULTS AND DISCUSSION: Following the enhanced surveillance programme, the odds of receiving a diagnostic test for a suspected malaria case increased (OR = 1.54, 95 % CI = 0.96-2.49) followed by an upward monthly trend (OR = 1.05, 95 % CI = 1.01-1.09). The odds of a reported malaria case being diagnostically confirmed also increased monthly (1.09, 95 % CI 1.04-1.15). After an initial 140 % increase (95 % CI = 91 183 %), costs fell by 11 % each month (95 % CI = 5.7-10.9 %). Although the mean testing rate increased from 18.9 to 64.4 % over the time period, the proportion of reported malaria unconfirmed by diagnostic remained high at 76 %. CONCLUSIONS: Enhanced surveillance and implementation of a data feedback loop have substantially increased malaria testing rates and decreased the number of unconfirmed malaria cases and courses of ACT consumed in Lusaka District within just two years. Continued support of enhanced surveillance in Lusaka as well as national scale-up of the system is recommended to reinforce good case management and to ensure timely, reliable data are available to guide targeting of limited malaria prevention and control resources in Zambia. PMID- 26017276 TI - Disclosure of HIV status to sexual partners by people living with HIV. AB - BACKGROUND: Disclosure of one's HIV status to a sexual partner can have significant health implications. From a health promotion point of view, disclosure is seen as a cornerstone for the prevention of HIV transmission between partners. Despite its importance as a strategy for controlling the spread of HIV, there are challenges that inhibit voluntary disclosure. OBJECTIVES: In exploring factors associated with disclosure of HIV status, the study had two complementary objectives related to: (1) investigation of participants' views about HIV-positive status disclosure to sexual partners; and (2) a broader identification of factors that influence disclosure of HIV-positive status. METHOD: The study explored factors associated with disclosure of the HIV status of people living with HIV to their sexual partners. Purposive sampling was used to select 13 participants living with HIV who attended a wellness clinic. Primary data were collected via an in-depth interview with each of the participants. RESULTS: The exploration showed that male participants were notably more reluctant to disclose to their sexual partners for fear of rejection; and secrecy was commonly reported around sexual matters. Female participants (who were in the majority) were relatively more willing to disclose their HIV status to their sexual partners. Despite the complexity of disclosure, all participants understood the importance of disclosure to their sexual partners. CONCLUSION: There is a need for HIV prevention strategies to focus on men in particular, so as to strengthen disclosure counselling services provided to people living with HIV and to advocate strongly for partner testing. PMID- 26017277 TI - Lower Cambrian polychaete from China sheds light on early annelid evolution. AB - We herein report a fossilized polychaete annelid, Guanshanchaeta felicia gen. et sp. nov., from the Lower Cambrian Guanshan Biota (Cambrian Series 2, stage 4). The new taxon has a generalized polychaete morphology, with biramous parapodia (most of which preserve the evidence of chaetae), an inferred prostomium bearing a pair of appendages, and a bifid pygidium. G. felicia is the first unequivocal annelid reported from the Lower Cambrian of China. It represents one of the oldest annelids among those from other early Paleozoic Lagerstatten including Sirius Passet from Greenland (Vinther et al., Nature 451: 185-188, 2011) and Emu Bay from Kangaroo island (Parry et al., Palaeontology 57: 1091-1103, 2014), and adds to our increasing roll of present-day animal phyla recognized in the early Cambrian Guanshan Biota. This finding expands the panorama of the Cambrian 'explosion' exemplified by the Guanshan Biota, suggesting the presence of many more fossil annelids in the Chengjiang Lagerstatte and the Kaili Biota. In addition, this new taxon increases our knowledge of early polychaete morphology, which suggests that polychaete annelids considerably diversified in the Cambrian. PMID- 26017278 TI - Abnormal corticosteroid signalling in airway smooth muscle: mechanisms and perspectives for the treatment of severe asthma. AB - Growing in vivo evidence supports the concept that airway smooth muscle produces various immunomodulatory factors that could contribute to asthma pathogenesis via the regulation of airway inflammation, airway narrowing and remodelling. Targeting ASM using bronchial thermoplasty has provided undeniable clinical benefits for patients with uncontrolled severe asthma who are refractory to glucocorticoid therapy. The present review will explain why the failure of glucocorticoids to adequately manage patients with severe asthma could derive from their inability to affect the immunomodulatory potential of ASM. We will support the view that ASM sensitivity to glucocorticoid therapy can be blunted in severe asthma and will describe some of the factors and mechanisms that could be responsible for glucocorticoid insensitivity. PMID- 26017279 TI - Tapentadol for chronic musculoskeletal pain in adults. AB - BACKGROUND: Chronic musculoskeletal pain is a prevalent condition and a major cause of disability and absence from the workplace worldwide. Opioids are frequently used to treat chronic pain, although adverse effects often restrict their long-term benefits. Tapentadol is an opioid and norepinephrine re-uptake inhibitor, which may cause a lower incidence (and severity) of adverse effects compared to other strong opioids. OBJECTIVES: To determine the efficacy, safety and tolerability of tapentadol extended release for moderate-to-severe pain for at least three months for any musculoskeletal cause. SEARCH METHODS: We searched electronic databases (CENTRAL, MEDLINE, EMBASE, Web of Science) to March 2014, unrestricted by language, as well as trials registers and reference lists from retrieved studies. We contacted drug manufacturers for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of tapentadol in people with chronic musculoskeletal pain, compared to placebo or active control. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias of included studies and extracted data. We performed two meta-analyses for the comparisons tapentadol extended release vs. placebo, and tapentadol extended release vs. active-control (oxycodone). We used random-effects and fixed-effect models according to the presence or not of heterogeneity, respectively. Also, we performed subgroup analyses. The primary efficacy outcome was pain control assessed by change in pain intensity scores and responder's rate (at least 50% pain relief). Primary safety outcome was withdrawal rate due to adverse effects. MAIN RESULTS: Four parallel-design RCTs of moderate quality including 4094 patients with osteoarthritis or back pain, or both, met the inclusion criteria. Three trials were phase III studies with 12 weeks follow-up and the fourth trial was an open-label safety study of 52-weeks follow-up. All trials were oxycodone-controlled and three were also placebo controlled. Two trials included patients with knee osteoarthritis, one evaluated patients with low back pain and one enrolled both. All studies reported last observation-carried-forward (LOCF) as imputation method. We requested baseline observation-carried-forward (BOCF) imputed analyses and any unpublished data from the manufacturer but the manufacturers denied the request. Two out of the four oxycodone-controlled studies and one out of the three placebo-controlled studies did not provided data on responder's rate. Two studies were considered to be of high risk of bias.In comparison to placebo, tapentadol was associated with a mean reduction of 0.56 points (95% confidence interval (CI) 0.92 to 0.20) in the 11 point numerical rating scale (NRS) at 12 weeks and with a 1.36 increase (95% CI 1.13 to 1.64) in the risk of responding to treatment (number needed to treat for an additional beneficial outcome (NNTB) 16; 95% CI 9 to 57, for 12-weeks). Moderate-to-high heterogeneity was found for the efficacy outcome estimates. Tapentadol was associated with a 2.7 fold increase (95% CI 2.05 to 3.52) in the risk of discontinuing treatment due to adverse effects number needed to treat for an additional harmful outcome (NNTH) 10; 95%CI 7 to 12, for 12 weeks).In comparison to oxycodone, pooled data showed a 0.24 points (95%CI 0.43 to 0.05) reduction in pain intensity from baseline in the 11-point NRS. The two studies that evaluated responder's rate showed a non-significant 1.46 increase (95% CI 0.92 to 2.32) in the risk of responding to treatment among tapentadol treated patients. Tapentadol was associated with a 50% risk reduction (95% CI 42% to 60%) of discontinuing treatment due to adverse effects (NNTB 6; 95% CI 5 to 7, for 12 weeks). Tapentadol was also associated with a 9% reduction (95% CI 4 to 15) in the overall risk of adverse effects (NNTH 18; 95% CI 12 to 35, for 12 weeks) and with a non-significant 43% reduction (95% CI 33 to 76) in the risk of serious adverse effects. Moderate to high heterogeneity was found for most efficacy (except for the primary outcome) and safety outcome estimates. Subgroup analysis showed a higher improvement with tapentadol among patients with knee osteoarthritis and among pooled results from studies of higher quality and shorter follow-up period, although there were no statistical significant differences in the effect size between these subgroups. AUTHORS' CONCLUSIONS: Tapentadol extended release is associated with a reduction in pain intensity in comparison to placebo and oxycodone. However, the clinical significance of the results is uncertain due to the following reasons: modest difference between interventions in efficacy outcomes, high heterogeneity in some comparisons and outcomes, high withdrawals rates, lack of data for the primary outcome in some studies and impossibility to use BOCF as imputation method. Tapentadol is associated with a more favourable safety profile and tolerability than oxycodone. PMID- 26017280 TI - USP7 saves RIDDLE for the end. PMID- 26017282 TI - beta-Hydrogen Elimination Reactions of Nickel and Palladium Methoxides Stabilised by PCP Pincer Ligands. AB - Nickel and palladium methoxides [((iPr)PCP)M-OMe], which contain the (iPr)PCP pincer ligand, decompose upon heating to give products of different kinds. The palladium derivative cleanly gives the dimeric Pd(0) complex [Pd(MU-(iPr)PCHP)]2 ((iPr)PCHP = 2,6-bis(diisopropylphosphinomethyl)phenyl) and formaldehyde. In contrast, decomposition of [((iPr)PCP)Ni-OMe] affords polynuclear carbonyl phosphine complexes. Both decomposition processes are initiated by beta-hydrogen elimination (BHE), but the resulting [((iPr)PCP)M-H] hydrides undergo divergent reaction sequences that ultimately lead to the irreversible breakdown of the pincer units. Whereas the Pd hydride spontaneously experiences reductive C-H coupling, the decay of its Ni analogue is brought about by its reaction with formaldehyde released in the BHE step. Kinetic measurements showed that the BHE reaction is reversible and less favourable for Ni than for Pd for both kinetic and thermodynamic reasons. DFT calculations confirmed the main conclusions of the kinetic studies and provided further insight into the mechanisms of the decomposition reactions. PMID- 26017281 TI - ARE/SUZ12 dual specifically-regulated adenoviral TK/GCV system for CML blast crisis cells. AB - BACKGROUND: Treatment of blast phase chronic myeloid leukemia (BP-CML) remains a challenge, and the median survival is less than 6 months. Because effective treatments are lacking, we studied tight targeting of blast crisis CML cells using adenoviral (Ad) vectors expressing a HSV-TK system under dual control of a specific SUZ12 promoter and an antioxidant response element (ARE). METHODS: A potential SUZ12 promoter fragment was designed with bioinformatics databases and identified with a luciferase assay. Next, we cloned the ARE element of the NQO1 gene and developed Ad vectors expressing TK kinase or luciferase under the dual control of a specific SUZ12 promoter and an ARE element. An in vitro transfection assay with Ad-ARE/SUZ12-Luc was used to determine promoter activity of ARE/SUZ12 regulatory element in blast crisis CML cells. After incubating human BP-CML derived cells with Ad-ARE/SUZ12-TK and ganciclovir, Western blot, CCK8, Immunofluorescent assays and Annexin V assays were conducted to assess the efficacy of an ARE/SUZ12 dual-specific TK/GCV system for BP-CML cell lines. RESULTS: Here, luciferase data confirmed significantly higher and specificer promoter activity of the ARE/SUZ12 composite component in CML blast crisis derived cell lines (K562, KCL22, and K562/G01) compared to HepG2 cells, and Ad-AS TK/GCV system could exhibit enhanced apoptotic effects and decreased cell viability for BP-CML cell lines. Additionally, Ad-AS-TK/GCV system altered expression of cycle-related and apoptosis-related proteins in BP-CML cell lines. CONCLUSIONS: Thus, ARE/SUZ12 dual targeting TK/GCV system was effective in killing BP-CML cells. Moreover, efficacy and specificity of CML cell eradication were enhanced by synergistic effects of ARE/SUZ12 dual-specific regulation. We conclude that suicide gene-targeted therapy might hold promise for BP-CML treatment. PMID- 26017285 TI - A Novel Approach to Flurbiprofen Pulsatile Colonic Release: Formulation and Pharmacokinetics of Double-Compression-Coated Mini-Tablets. AB - A significant plan is executed in the present study to study the effect of double compression coating on flurbiprofen core mini-tablets to achieve the pulsatile colonic delivery to deliver the drug at a specific time as per the patho physiological need of the disease that results in improved therapeutic efficacy. In this study, pulsatile double-compression-coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH sensitive Eudragit S100 outer compression coat. Then, the tablets were evaluated for both physical evaluation and drug-release studies, and to prove these results, in vivo pharmacokinetic studies in human volunteers were conducted. From the in vitro drug-release studies, F6 tablets were considered as the best formulation, which retarded the drug release in the stomach and small intestine (3.42 +/- 0.12% in 5 h) and progressively released to the colon (99.78 +/- 0.74% in 24 h). The release process followed zero-order release kinetics, and from the stability studies, similarity factor between dissolution data before and after storage was found to be 88.86. From the pharmacokinetic evaluation, core mini tablets producing peak plasma concentration (C max) was 14,677.51 +/- 12.16 ng/ml at 3 h T max and pulsatile colonic tablets showed C max = 12,374.67 +/- 16.72 ng/ml at 12 h T max. The area under the curve for the mini and pulsatile tablets was 41,238.52 and 72,369.24 ng-h/ml, and the mean resident time was 3.43 and 10.61 h, respectively. In conclusion, development of double-compression-coated tablets is a promising way to achieve the pulsatile colonic release of flurbiprofen. PMID- 26017284 TI - In Vivo Evaluation of 5-ASA Colon-Specific Tablets Using Experimental-Induced Colitis Rat Animal Model. AB - Colonic drug delivery is intended not only for local treatment in inflammatory bowel disease (IBD) but also for systemic delivery of therapeutics. Intestinal myeloperoxidase (MPO) determination could be used to estimate the average level of inflammation in colon as well as to determine the efficacy of drugs to be used in the treatment of inflammatory bowel diseases or study the specificity of dosage forms to be used for colonic targeting of anti-inflammatory drugs. Colonic prodrug sulfasalazine (SASP) gets metabolized to give 5-aminosalicylic acid (5 ASA), which is the active portion of SASP. However, when given orally, 5-ASA is absorbed in upper part of gastrointestinal tract (GIT) and not made available in colon. In the present study, colon-targeted delivery of 5-ASA was achieved by formulating tablets with two natural polymers namely guar gum and pectin using compression coating method. Colonic specificity of 5-ASA tablets (prepared using guar gum and pectin as polymers) was evaluated in vitro using simulated fluids mimicking in vivo environment as well as in vivo method using chemically (2,4,6 trinitrobenzenesulfonic acid and acetic acid)-induced colitis rat model. Both colon-specific formulations of 5-ASA (guar gum and pectin) were observed to be more effective in reducing inflammation in chemically induced colitis rat models when compared to colon-specific prodrug sulfasalazine as well as conventional 5 ASA administered orally. PMID- 26017283 TI - 90Y-Labeled Anti-ROBO1 Monoclonal Antibody Exhibits Antitumor Activity against Small Cell Lung Cancer Xenografts. AB - INTRODUCTION: ROBO1 is a membrane protein that contributes to tumor metastasis and angiogenesis. We previously reported that 90Y-labeled anti-ROBO1 monoclonal antibody (90Y-anti-ROBO1 IgG) showed an antitumor effect against ROBO1-positive tumors. In this study, we performed a biodistribution study and radioimmunotherapy (RIT) against ROBO1-positive small cell lung cancer (SCLC) models. METHODS: For the biodistribution study, 111In-labeled anti-ROBO1 monoclonal antibody (111In-anti-ROBO1 IgG) was injected into ROBO1-positive SCLC xenograft mice via the tail vein. To evaluate antitumor effects, an RIT study was performed, and SCLC xenograft mice were treated with 90Y-anti-ROBO1 IgG. Tumor volume and body weight were periodically measured throughout the experiments. The tumors and organs of mice were then collected, and a pathological analysis was carried out. RESULTS: As a result of the biodistribution study, we observed tumor uptake of 111In-anti-ROBO1 IgG. The liver, kidney, spleen, and lung showed comparably high accumulation of 111In-labeled anti-ROBO1. In the RIT study, 90Y anti-ROBO1 IgG significantly reduced tumor volume compared with baseline. Pathological analyses of tumors revealed coagulation necrosis and fatal degeneration of tumor cells, significant reduction in the number of Ki-67 positive cells, and an increase in the number of apoptotic cells. A transient reduction of hematopoietic cells was observed in the spleen, sternum, and femur. CONCLUSIONS: These results suggest that RIT with 90Y-anti-ROBO1 IgG is a promising treatment for ROBO1-positive SCLC. PMID- 26017286 TI - Wetting effects versus ion pairs diffusivity: interactions of anionic surfactants with highly soluble cationic drugs and its impact on tablet dissolution. AB - A study was conducted to develop a mechanistic understanding of dissolution of a highly soluble cationic drug, metformin hydrochloride, under the influence of anionic surfactants, sodium alkyl sulfates. The surfactants did not influence the saturated solubility of the drug, but reduced the surface tension of the dissolution media as the alkyl chain length increased. Their influence on tablet wetting based on the contact angles did not show any trend. The dissolution of 850 mg metformin hydrochloride tablets in 0.1 N HCl and pH 4.5 acetate buffer with 0.01% (w/v) sodium n-octyl sulfate (C8), sodium n-decyl sulfate (C10), or sodium n-tetradecyl sulfate (C14) was similar to the control, but was enhanced by sodium lauryl sulfate (C12). At 0.1% (w/v) concentration, the dissolution was not enhanced by C12 because the reduction in surface tension was counterbalanced by an increase in hydrophobic ion pairs that showed slower diffusivity by nuclear magnetic resonance. At 0.1% (w/v), metformin also formed an insoluble salt (1:2 molar ratios) with C10 (pH 1.2), C12, and C14 (pH 1.2 and 4.5) but not with C8. Three competing factors influenced the drug dissolution by surfactants: reduction in surface tension of the dissolution media, ion pairs with low diffusivity, and formation of an insoluble salt. PMID- 26017287 TI - Dry-Spun Single-Filament Fibers Comprising Solely Cellulose Nanofibers from Bioresidue. AB - We demonstrated that low-cost and environmentally friendly filaments of native cellulose can be prepared by dry spinning an aqueous suspension of cellulose nanofibers (CNF). The CNF were extracted from banana rachis, a bioresidue from banana cultivation. The relationship between spinning rate, CNF concentration, and the mechanical properties of the filaments were investigated and the results showed that the modulus of the filaments was increased from 7.8 to 12.6 GPa and the strength increased from 131 to 222 MPa when the lowest concentration and highest speed was used. This improvement is believed to be due to an increased orientation of the CNF in the filament. A minimum concentration of 6.5 wt % was required for continuous filament spinning using the current setup. However, this relatively high concentration is thought to limit the orientation of the CNF in the filament. The process used in this study has a good potential for upscaling providing a continuous filament production with well-controlled speed, but further work is required to increase the orientation and subsequently the mechanical properties. PMID- 26017289 TI - Evaluation of the new vacuum infiltration vitrification (viv) cryopreservation technique for native Australian plant shoot tips. AB - BACKGROUND: The application of a vacuum during the incubation in cryoprotective agents such as PVS2 allows for increased penetration, reducing total incubation times required before vitrification and post-cryopreservation regeneration is achieved. OBJECTIVE: This study compared a conventional droplet-vitrification protocol to the new vacuum infiltration vitrification protocol in four Australian plant species. MATERIALS AND METHODS: The new vacuum infiltration vitrification applied an 80 kPa vacuum during incubations in loading solution and PVS2. Infiltration of the cryoprotective agents into shoot tips was determined by differential scanning calorimetry measuring ice formation in the thermographs comparing a range of loading solution and PVS2 incubation times. RESULTS AND CONCLUSION: The application of the vacuum infiltration vitrification technique resulted in a significantly reduced PVS2 incubation time for cryogenic survival and regeneration for all four species, reducing the time needed to adequately protect shoot tips by half to a quarter when compared to a conventional droplet vitrification technique. PMID- 26017288 TI - KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance. AB - Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP+ cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 MUg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V+ SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP+ cases but was only 26 and 41 months for KIT D816V+ SM and JAK2 V617F+ MPN-eo, respectively. Eosinophilia of >=2 * 10(9) /l was identified as discriminator for inferior survival in KIT D816V+ and/or JAK2 V617F+ patients (median survival 20 months vs. not reached, P = 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia. PMID- 26017290 TI - Strain preservation of rats: vitrification of two-cell stage embryos for multiple inbred strains. AB - OBJECTIVE: We examined whether the vitrification method using P10 and PEPeS is suitable for the cryopreservation of two-cell stage embryos collected from multiple rat strains with the objective of strain preservation of inbred rat strains. RESULTS: The average numbers of two-cell stage embryos collected per female for F344/Jcl, ACI/N, BUF/N, and WKY/N strains were 7.0 to 12.0, and survival rates of the embryos after vitrification were 94.2 to 96.3 % The in vitro development rates of vitrified embryos transferred were 47.1 to 60.8 %. CONCLUSION: At least two offspring produced from the embryos collected from one female are required for strain preservation of inbred strain. Taken together, the results of the experiment indicated expected numbers of surviving fetuses for embryos collected from one female were 3.2 to 6.7, and all were usable for strain preservation. The results suggest that this vitrification method is suitable for strain preservation of multiple inbred rat strains. PMID- 26017291 TI - Similar cold stress induces sex-specific neuroendocrine and working memory responses. AB - BACKGROUND: Men have higher cold-induced neuroendocrine response than women; nevertheless, it is not known whether a different stress hormone rise elicits different effects on cognition during whole body cooling. OBJECTIVE: The objective was to compare the effect of cold-induced neuroendocrine responses on the performance of working memory sensitive tasks between men and women. MATERIALS AND METHODS: The cold stress continued until rectal temperature reached 35.5 degree C or for a maximum of 170 min. Working memory performance and stress hormone concentrations were monitored. RESULTS: During cold stress, body temperature variables dropped in all subjects (P < 0.001) and did not differ between sexes. Cold stress raised plasma epinephrine and serum cortisol levels only in men (P < 0.05). Cold stress adversely affected memory performance in men but not in women (P < 0.05). CONCLUSION: The present study indicated that similar moderate cold stress in men and women induces sex-specific neuroendocrine and working memory responses. PMID- 26017292 TI - First steps of in vitro gastrulation in rabbit vitrified embryos. AB - BACKGROUND: The in vitro rabbit embryo production and their cryopreservation methodologies such as vitrification generate less viable embryos, and occasionally, with significant differences from those that are not subjected to any treatment. Besides, in vitrified rabbit embryos little information is available about exactly when and where begin to emerge the first differences that finally result in foetal losses comparing with non-vitrified embryos. OBJECTIVE: The aim of this study was to evaluate the vitrification effects on the early in vitro gastrulation events. MATERIALS AND METHODS: After oviductal transfers of vitrified and non-vitrified embryos (control) in rabbit recipients, blastocysts from 144h (6-day-old) were recovered and cultured into TCM199 supplemented with rabbit homologous serum media for 48 hours. Gastrula stage and measures of perimeter and area of blastocyst and gastrula were noted. Moreover, eight independent pools consisting of six embryos each one were generated for each experimental group (control and vitrified) and total RNA was isolated to study the OCT4 gene expression. RESULTS: Of 151 control and 164 vitrified morulae transferred, 69.5 % and 70.1 % developed in vivo to 6-day-old blastocyst respectively. After 24 hour of in vitro culture, 41.8 % of vitrified blastocyst had begun the neurulation (stage 5-) versus 22.8 % of control group. Nevertheless, the vitrified group showed the highest percentage of collapsed blastocyst at 48 hours (26.8 %). Non morphometric differences differences were observed in perimeter and area of blastocyst and gastrula between control and vitrified group at 0 and 24 hours. By contrast, perimeter and gastrula areas were slightly higher for the vitrified group than those for the control group at 48 hours of in vitro culture. CONCLUSION: The study reveal the existence of the first morphological differences in vitrified blastocysts of 7 and 8-day-old, marked by a further development of gastrulation in the vitrified group. PMID- 26017293 TI - Cryopreservation of rainbow trout spermatozoa (Onchorhynchus mykiss) using different cryodiluents. AB - An experiment was conducted to evaluate the potential of extenders on sperm motility and to delineate the effect of cyodiluent compostion on post thaw motility, fertilization and hatching percentage in rainbow trout (Onchorhynchus mykiss) sperm. The mature males of rainbow trout with an average weight of (340 15) g and average size (28.8 0.6) cm were used. In the trials for testing the suitability of cryoprotectants, DMSO yielded higher motility percentage with extenders Zhang and Liu and 0.6 M Sucrose. Significantly (P <0.05) higher value of % post thaw motility and fertilization was recorded in cryodiluent composition of 8 % DMSO and Zhang and Liu. Additionally, composition of 8 % DMSO with Zhang and Liu led to significant (P <0.05) increase in percentage hatching. Overall, results indicated that the combination of (8 % DMSO + Zhang and Liu) produced best results in terms of percentage post thaw motility, fertilization and hatching. PMID- 26017294 TI - Evaluation of different methods of cryopreservation of Ehrlich tumor cells. AB - BACKGROUND: The Ehrlich Ascitic Carcinoma (EAC) is an experimental transplantable neoplasm that develops in several species of mice. The maintenance of the tumor occurs in vivo. Thus, freezing the cells would reduce the number of passages between animals, ensuring genetic stability and storage for longs period of experimentation. OBJECTIVE: Search by EAC cryoprotectants. MATERIALS AND METHODS: The combinations of nutrient medium (Tris, hen egg yolk, and DEMEN) and cryoprotective agent (Glicerol, Trehalose and DMSO) on freezing EAC cells and the transplantability after defrosting were evaluated. The cooling was conducted at 2 C/min. until -180 degree C and the thawing by immersion in water at 37 degree C. The transplantability was evaluated from cell inoculation in mice for 14 days. RESULTS: The best results were the associations IA (Cryoprotective agent Glycerol 6 % and medium containing 3.0 % Tris w / v, 1.8 % Citric acid w / v, 1.3 % D fructose w / v and 20 % hen egg yolk v / v) and IIB (Cryoprotective agent Trehalose 100mM and medium containing 50 % coconut water v / v, 25 % sodium citrate 5 % v / v and 20 % hen egg yolk v / v) with 85.2 % and 55.1 % viable cells, respectively. CONCLUSION: These transplantable cells were efficient for tumor development, therefore demonstrating that this method of cryopreservation is simple and affordable. PMID- 26017295 TI - Differential proteomic expression of himalayan psychrotrophic diazotroph Pseudomonas palleroniana N26 under low temperature diazotrophic conditions. AB - BACKGROUND: In low temperature nitrogen-deficient ecosystems, native microorganisms must possess adaptive mechanisms to cope with environmental stress as well as nitrogen (N) starvation-like conditions. However, moderate information is available about the cold adapted diazotrophs and diazotrophy. OBJECTIVE: The aim of this study was to examine the proteomic response(s) of Himalayan psychrotrophic diazotroph under low temperature nitrogen fixing conditions. MATERIALS AND METHODS: Proteomic analysis of Pseudomonas palleroniana N26 was carried out using two dimensional electrophoresis technique. RESULTS: Altogether, fifty three protein spots were found to be differentially expressed revealing several mechanisms thought to be involved in low temperature adaptation and nitrogen fixation, including general stress adaptation, protein synthesis and modifications, and energy metabolism. Expression profiling of the spots revealed the up-regulation of low molecular weight acidic proteins; a majority of which were stress proteins. The largest group of down-regulated proteins were related to biosynthetic processes; thereby, providing the evidence for stress-associated metabolic adaptations. CONCLUSION: The present study, which provides an overview of the cold diazotrophy of a Himalayan psychrotrophic bacterium and its adaptive responses, can facilitate further studies of low temperature nitrogen fixing mechanisms, psychrophilic diazotrophic markers, and transgenic microorganism(s)/crop(s) development. PMID- 26017296 TI - Sage (Salvia officinalis) and fennel (Foeniculum vulgare) improve cryopreserved boar epididymal semen quality study. AB - The aim of this study was to evaluate the effect of fennel and sage extracts and the influence of the egg yolk source (fresh or pasteurized) on the success of freezing boar epididymal spermatozoa. In experiment 1, epididymal sperm was recovered by flushing and cryopreserved in a lactose-egg yolk solution supplemented with various concentrations (10, 5 and 2.5 g/L) of sage or fennel. Sperm quality was evaluated (motility, viability, HOST and acrosome integrity) at 0 h and 2 h after thawing. Fennel 10 g/L and sage 5 g/L and control (no extracts) were selected for experiment 2 which also compared fresh or pasteurized egg yolk in the freezing extender and measured DNA integrity of the frozen sperm. Results showed that the interaction between fennel and sage antioxidants with fresh egg yolk significantly improved post thaw sperm quality and protected boar epididymal spermatozoa from cryopreservation damage as a result of oxidative stress. PMID- 26017297 TI - Cryopreservation of gemmae of Marchantia polymorpha L. (Marchantiophyta, Marchantiaceae) without prior pretreatment. AB - BACKGROUND: Successful cryopreservation of gametophytic material of bryophytes requires pretreatment with sucrose or abscisic acid. Compared to gametophyte materials, spore and gemmae cryopreservation may be more efficient, simple and stable systems for storing large amounts of genetic diversity of bryophytes within a small space. However, there has still been no attempt at cryopreserving bryophyte gemmae. OBJECTIVE: The aim of this study is to determine whether bryophyte gemmae with differing levels of desiccation tolerance could survive and germinate after cryopreservation without prior encapsulation and pretreatment. MATERIALS AND METHODS: Gemmae of Marchantia polymorpha L. were dried with silica gel for different times and then rapidly cooled in liquid nitrogen. RESULTS: The germination level of fresh gemmae was 95 % After 3 h predrying and 1 d in LN, germination was 68 % and was still up to 59 % after storage for 75 days. CONCLUSION: We conclude that the natural desiccation tolerance of bryophyte gemmae permits cryopreservation without prior pretreatment other than drying. PMID- 26017298 TI - Effect of the pH pre-adjustment in the freezing extender on post-thaw boar sperm quality. AB - BACKGROUND: During freezing the selective precipitation of substances in the medium may provoke a pH shift and lead to sperm damage. OBJECTIVE: To study the effect of the pH pre-adjustment in the freezing extender on post-thaw boar sperm quality. METHODS: A total of 15 ejaculates from different boars were obtained and divided into six aliquots prior to a standard straw cryopreservation in freezing extender (lactose-egg yolk-glycerol-Orvus ES Paste) with different pH. After thawing, sperm quality (plasma membrane integrity, motility and acrosome status) were assessed at 30 and 90 minutes of post-thaw incubation at 37 degree C. RESULTS: When the boar sperm were frozen in a freezing media with pH basic, and particularly at pH 8, it had higher post-thaw sperm quality. CONCLUSION: The pre adjustment at pH 8 of the freezing extender (lactose-egg yolk-glycerol-Orvus ES Paste) is able to improve the post-thaw boar sperm quality. PMID- 26017299 TI - Efficient biological conversion of carbon monoxide (CO) to carbon dioxide (CO2) and for utilization in bioplastic production by Ralstonia eutropha through the display of an enzyme complex on the cell surface. AB - An enzyme complex for biological conversion of CO to CO2 was anchored on the cell surface of the CO2-utilizing Ralstonia eutropha and successfully resulted in a 3.3-fold increase in conversion efficiency. These results suggest that this complexed system may be a promising strategy for CO2 utilization as a biological tool for the production of bioplastics. PMID- 26017300 TI - Immunopotentiator-Loaded Polymeric Microparticles as Robust Adjuvant to Improve Vaccine Efficacy. AB - PURPOSE: Adjuvants are required to ensure the efficacy of subunit vaccines. Incorporating molecular immunopotentiators within particles could overcome drawbacks of molecular adjuvants (such as solubility and toxicity), and improve adjuvanticity of particles, achieving stronger adjuvant activity. Aim of this study is to evaluate the adjuvanticity of immunopotentiator-loaded polymeric particles for subunit vaccine. METHODS: PLGA microparticles (PMPs) and imiquimod (TLR-7 ligand)-loaded PLGA microparticles (IPMPs) were prepared by SPG premix membrane emulsification. In vitro and in vivo studies were performed to their adjuvant activity, using ovalbumin and H5N1 influenza split vaccine as antigens. RESULTS: Incorporating imiquimod into microparticles significantly improved the efficacy of PLGA microparticles in activating BMDCs and pMPhis, and antigen uptake by pMPhis was also promoted. IPMPs showed stronger adjuvanticity to augment OVA-specific immune responses than PMPs. IgG subclass profiles and cytokine secretion levels by splenocytes indicated that IPMPs elicited more Th1 polarized immune response, compared to PMPs. In vivo study using H5N1 influenza split vaccine as antigen also confirmed the effects of IPMPs on antigen-specific cellular immunity. CONCLUSIONS: Considering adjuvanticity and safety profiles (PLGA and IMQ, both approved by FDA), we conclude that IMQ-loaded PLGA microparticles are promising robust adjuvant for subunit vaccines. PMID- 26017301 TI - Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs. AB - PURPOSE: Many enabling formulations give rise to supersaturated solutions wherein the solute possesses higher thermodynamic activity gradients than the solute in a saturated solution. Since flux across a membrane is driven by solute activity rather than concentration, understanding how solute thermodynamic activity varies with solution composition, particularly in the presence of solubilizing additives, is important in the context of passive absorption. METHODS: In this study, a side-by-side diffusion cell was used to evaluate solute flux for solutions of nifedipine and felodipine in the absence and presence of different solubilizing additives at various solute concentrations. RESULTS: At a given solute concentration above the equilibrium solubility, it was observed that the solubilizing additives could reduce the membrane flux, indicating that the extent of supersaturation can be reduced. However, the flux could be increased back to the same maximum value (which was determined by the concentration where liquid liquid phase separation (LLPS) occurred) by increasing the total solute concentration. Qualitatively, the shape of the curves of solute flux through membrane as a function of total solute concentration is the same in the absence and presence of solubilizing additives. Quantitatively, however, LLPS occurs at higher solute concentrations in the presence of solubilizing additives. Moreover, the ratios of the LLPS onset concentration and equilibrium solubility vary significantly in the absence and presence of additives. CONCLUSIONS: These findings clearly point out the flaws in using solute concentration in estimating solute activity or supersaturation, and reaffirm the use of flux measurements to understand supersaturated systems. Clear differentiation between solubilization and supersaturation, as well as thorough understanding of their respective impacts on membrane transport kinetics is important for the rational design of enabling formulations for poorly soluble compounds. PMID- 26017302 TI - N-glycan PK Profiling Using a High Sensitivity nanoLCMS Work-Flow with Heavy Stable Isotope Labeled Internal Standard and Application to a Preclinical Study of an IgG1 Biopharmaceutical. AB - PURPOSE: In this study an innovative, highly sensitive work-flow is presented that allows the analysis of a possible influence of individual glyco-variants on pharmacokinetics already during pre-clinical development. Possible effects on the pharmacokinetics caused by glyco-variants have been subject of several studies with in part contradictory results which can be related to differences in the set up. METHODS: Using 96-well plate based affinity purification an IgG1 antibody was isolated from preclinical samples and glycans were analyzed individually by nanoLCMS. Prerequisite was a reference standard based on stable heavy isotope labeled glycans. The high sensitivity and low sample consumption enabled the integration into the preclinical development program. RESULTS: The data of an IgG1 biopharmaceutical from a preclinical rabbit study showed that some N glycoforms have a different PK profile compared with the average of all molecule variants as determined by ELISA. IgG1 high mannose glycoforms M5 and M6 were removed from circulation at a higher rate. CONCLUSION: The results of the preclinical study demonstrated the applicability of the developed innovative workflow. The PK profile of glyco-variants could be determined individually. It was concluded that M6 was converted by mannosidases in circulation to M5 which in turn was selectively cleared by mannose receptor binding which is in-line with previously published results. Therefore the developed technology delivers reliable results and can be applied for PK profiling of other mAbs and other types of biopharmaceuticals. PMID- 26017303 TI - Extended-Cycle Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol (Seasonique((r))): A Review of Its Use as an Oral Contraceptive. AB - A 91-day extended-cycle oral contraceptive (OC) consisting of levonorgestrel/ethinylestradiol 150/30 ug for 84 days and ethinylestradiol 10 ug for 7 days (Seasonique((r))) has recently been approved for the prevention of pregnancy in adult women in the EU. This regimen allows for a reduction in the number of withdrawal bleeding episodes to four per year, compared with 13 episodes per year with conventional 28-day regimens. Seasonique((r)) was effective in preventing pregnancy in a large (n = 1006), noncomparative trial of healthy, sexually active women. In this trial, the overall Pearl index (pregnancies per 100 woman-years of use) in women aged 18-35 years (n = 621) was 0.76 and the Pearl index for method-failure (compliant use) was 0.26. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with a mean of 2 days of bleeding and 1 day of spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting was highest during the first few cycles of use and decreased thereafter. Seasonique((r)) was generally well tolerated, with a tolerability profile in line with that expected for OCs. Seasonique((r)) extends the contraceptive options currently available to women, particularly in those who desire fewer withdrawal bleeding episodes. PMID- 26017304 TI - Pasireotide in Acromegaly: A Review. AB - Pasireotide (Signifor((r)), Signifor((r)) LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide and lanreotide, which bind preferentially to somatostatin receptor (SSTR)-2, pasireotide binds to multiple SSTRs. This article reviews the clinical use and summarizes the pharmacological properties of intramuscular pasireotide in the treatment of acromegaly. The efficacy of pasireotide 40 mg every 28 days was superior to that of intramuscular octreotide 20 mg every 28 days with regard to biochemical control in a 12-month, phase III trial in medically naive patients. Similarly, in a 6-month, phase III trial in patients with acromegaly inadequately controlled with somatostatin analogues for at least 6 months, the efficacy of pasireotide 40 or 60 mg was superior to that of continued octreotide 30 mg or lanreotide autogel 120 mg (each drug was administered once every 28 days) with regard to biochemical control. The tolerability profile of intramuscular pasireotide is generally similar to that of first-generation agents, except for a higher incidence of hyperglycaemia-related adverse events with pasireotide. In clinical trials, the risk of developing pasireotide-associated hyperglycaemia was numerically greater in patients categorized as diabetic or prediabetic at baseline than in those with normal glucose tolerance. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed. PMID- 26017305 TI - Patient-reported outcomes in a large community-based pain medicine practice: evaluation for use in phenotype modeling. AB - BACKGROUND: An academic, community medicine partnership was established to build a phenotype-to-outcome model targeting chronic pain. This model will be used to drive clinical decision support for pain medicine in the community setting. The first step in this effort is an examination of the electronic health records (EHR) from clinics that treat chronic pain. The biopsychosocial components provided by both patients and care providers must be of sufficient scope to populate the spectrum of patient types, treatment modalities, and possible outcomes. METHODS: The patient health records from a large Midwest pain medicine practice (Michigan Pain Consultants, PC) contains physician notes, administrative codes, and patient-reported outcomes (PRO) on over 30,000 patients during the study period spanning 2010 to mid-2014. The PRO consists of a regularly administered Pain Health Assessment (PHA), a biopsychosocial, demographic, and symptomology questionnaire containing 163 items, which is completed approximately every six months with a compliance rate of over 95%. The biopsychosocial items (74 items with Likert scales of 0-10) were examined by exploratory factor analysis and descriptive statistics to determine the number of independent constructs available for phenotypes and outcomes. Pain outcomes were examined both in the aggregate and the mean of longitudinal changes in each patient. RESULTS: Exploratory factor analysis of the intake PHA revealed 15 orthogonal factors representing pain levels; physical, social, and emotional functions; the effects of pain on these functions; vitality and health; and measures of outcomes and satisfaction. Seven items were independent of the factors, offering unique information. As an exemplar of outcomes from the follow-up PHAs, patients reported approximately 60% relief in their pain. When examined in the aggregate, patients showed both a decrease in pain levels and an increase in coping skills with an increased number of visits. When examined individually, 80-85% of patients presenting with the highest pain levels reported improvement by approximately two points on an 11-point pain scale. CONCLUSIONS: We conclude that the data available in a community practice can be a rich source of biopsychosocial information relevant to the phenotypes of chronic pain. It is anticipated that phenotype linkages to best treatments and outcomes can be constructed from this set of records. PMID- 26017306 TI - Cancer: Precise control of localized signals. PMID- 26017308 TI - Cell biology: the micronucleus gets its big break. PMID- 26017307 TI - Interaction and signalling between a cosmopolitan phytoplankton and associated bacteria. AB - Interactions between primary producers and bacteria impact the physiology of both partners, alter the chemistry of their environment, and shape ecosystem diversity. In marine ecosystems, these interactions are difficult to study partly because the major photosynthetic organisms are microscopic, unicellular phytoplankton. Coastal phytoplankton communities are dominated by diatoms, which generate approximately 40% of marine primary production and form the base of many marine food webs. Diatoms co-occur with specific bacterial taxa, but the mechanisms of potential interactions are mostly unknown. Here we tease apart a bacterial consortium associated with a globally distributed diatom and find that a Sulfitobacter species promotes diatom cell division via secretion of the hormone indole-3-acetic acid, synthesized by the bacterium using both diatom secreted and endogenous tryptophan. Indole-3-acetic acid and tryptophan serve as signalling molecules that are part of a complex exchange of nutrients, including diatom-excreted organosulfur molecules and bacterial-excreted ammonia. The potential prevalence of this mode of signalling in the oceans is corroborated by metabolite and metatranscriptome analyses that show widespread indole-3-acetic acid production by Sulfitobacter-related bacteria, particularly in coastal environments. Our study expands on the emerging recognition that marine microbial communities are part of tightly connected networks by providing evidence that these interactions are mediated through production and exchange of infochemicals. PMID- 26017309 TI - Microbiology: Exclusive networks in the sea. PMID- 26017310 TI - Chromothripsis from DNA damage in micronuclei. AB - Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome. PMID- 26017311 TI - Cancer: Opening LOX to metastasis. PMID- 26017312 TI - A prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation. AB - Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal-thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, the nucleus reuniens of the thalamus, and the CA1 region of the hippocampus in rats. Lesioning or optogenetic silencing of the nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data suggest that projections from medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behaviour and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation. PMID- 26017313 TI - The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. AB - Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications. PMID- 26017314 TI - Estimation of Surgery Capacity in Haiti: Nationwide Survey of Hospitals. AB - BACKGROUND: Haiti's surgical capacity was significantly strained by the 2010 earthquake. As the government and its partners rebuild the health system, emergency and essential surgical care must be a priority. METHODS: A validated, facility-based assessment tool developed by WHO was completed by 45 hospitals nationwide. The hospitals were assessed for (1) infrastructure, (2) human resources, (3) surgical interventions and emergency care, and (4) material resources for resuscitation. Fisher's exact test was used to compare hospitals by sectors: public compared to private and mixed (public-private partnerships). RESULTS: The 45 hospitals included first-referral level to the national referral hospital: 20 were public sector and 25 were private or mixed sector. Blood banks (33% availability) and oxygen concentrators (58%) were notable infrastructural deficits. For human resources, 69% and 33% of hospitals employed at least one full-time surgeon and anaesthesiologist, respectively. Ninety-eight percent of hospitals reported capacity to perform resuscitation. General and obstetrical surgical interventions were relatively more available, for example 93% provided hernia repairs and 98% provided cesarean sections. More specialized interventions were at a deficit: cataract surgery (27%), cleft repairs (31%), clubfoot (42%), and open treatment of fractures (51%). CONCLUSION: Deficiencies in infrastructure and material resources were widespread and should be urgently addressed. Physician providers were mal-distributed relative to non-physician providers. Formal task-sharing to midlevel and general physician providers should be considered. The parity between public and private or mixed sector hospitals in availability of Ob/Gyn surgical interventions is evidence of concerted efforts to reduce maternal mortality. This ought to provide a roadmap for strengthening of surgical care capacity. PMID- 26017315 TI - Promoter-Autonomous Functioning in a Controlled Environment using Single Molecule FISH. AB - Transcription is a highly regulated biological process, initiated through the assembly of complexes at the promoter that contain both the general transcriptional machinery and promoter-specific factors. Despite the abundance of studies focusing on transcription, certain questions have remained unanswered. It is not clear how the transcriptional profile of a promoter is affected by genomic context. Also, there is no single cell method to directly compare transcriptional profiles independent of gene length and sequence. In this work, we employ a single genetic site for isolating the transcriptional kinetics of yeast promoters. Utilizing single molecule FISH, we directly compare the transcriptional activity of different promoters, considering both synthesis and cell-to-cell variability. With this approach, we provide evidence suggesting promoters autonomously encode their associated transcriptional profiles, independent of genomic locus, gene length and gene sequence. PMID- 26017316 TI - Management of Small Kidney Cancers in the New Millennium: Contemporary Trends and Outcomes in a Population-Based Cohort. AB - IMPORTANCE: With the significant downward size and stage migration of localized kidney cancers, the management options for small kidney cancers have expanded and evolved. OBJECTIVE: To describe trends and outcomes in the management of small kidney cancers in the first decade of the new millennium. DESIGN, SETTING, AND PARTICIPANTS: Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked to Medicare claims were used to identify patients 66 years or older with a pathologically confirmed small kidney cancer (<4 cm) diagnosed between January 1, 2001, and December 31, 2009; analysis was performed between February 1, 2014, and December 31, 2014. Multivariable logistic regression was used to assess the likelihood of nonsurgical management vs surgical intervention. Cox proportional hazards regression was used to assess the relationships between treatment approach and overall and cancer-specific survival. The effect of treatment approach on cancer-specific survival was analyzed in a competing risks framework. MAIN OUTCOMES AND MEASURES: The likelihood of receiving no surgery vs surgical intervention as a function of demographic and disease characteristics, as well as the relationships between treatment approach and overall and cancer specific survival. RESULTS: Of 6664 patients, 5994 individuals (90.0%) had surgical treatment; the care of 670 patients (10.0%) was managed nonsurgically. Use of radical nephrectomy decreased over time (from 69.0% to 42.5%), and the use of nephron-sparing surgery (partial nephrectomy and ablation) increased (from 21.5% to 49.0%); the proportion of patients who did not undergo surgery remained stable (9.5% and 8.5%). During a median follow-up of 63 months (interquartile range, 43-89 months) (follow-up for vital status through December 31, 2011), 2119 patients (31.8%) patients died, including 293 individuals (4.4%) of kidney cancer. Although overall survival was better in patients who received surgical treatment, only nephron-sparing surgery was associated with a benefit in cancer specific survival (adjusted hazard ratio, 0.47; 95% CI, 0.31-0.69; P < .001). CONCLUSIONS AND RELEVANCE: Surgery continues to be the most common treatment for patients with small kidney cancers. The use of nephron-sparing surgery exceeds radical nephrectomy in patients who receive surgery. Although our findings suggest that nonsurgical management is acceptable for certain patients, use of this approach remains low. PMID- 26017317 TI - Long-term life expectancy for children with ependymoma and medulloblastoma. AB - OBJECTIVES: There is a paucity of long-term follow-up data for children with intracranial ependymoma (IE) and medulloblastoma (MB). What happens to these children 20, 30, or 40 years after diagnosis? Do they have potential for a normal lifespan? The purpose of this study was to ascertain the long-term survival potential in children with MB or IE who have survived 5 years from diagnosis. METHODS: A retrospective analysis was conducted using the SEER Program. Children (ages 0-19 years) from 1973 to 2011 with a diagnosis of MB or IE were identified. A cohort was created of potentially cured patients who survived 5 years from diagnosis. Cox proportional hazards models and Kaplan-Meier estimates were utilized to analyze long-term survival. RESULTS: We identified 876 patients with MB and 474 patients with IE who were alive 5 years from diagnosis. Patients with MB had a 30-year overall survival (OS) and cancer-specific survival (CSS) of 70.2% and 80.1%, respectively. Patients with IE had a 30-year OS and CSS of 57.3% and 68.8%, respectively. When comparing MB with IE, MB had improved CSS (P = 0.04) and trended toward increased OS (P = 0.10). CONCLUSIONS: A significant number of deaths due to disease occur for several decades after treatment for both IE and MB. Despite this, the potential for long-term survival exists in 5 year survivors of both histologies. If alive at 5 years from diagnosis, patients with MB tend to have a lower risk of death from disease compared to those with IE. PMID- 26017318 TI - Successful treatment of intra-abdominal eumycotic mycetoma caused by Penicillium duponti in a dog. AB - A 2-year-old female neutered golden retriever was presented for investigation of an intra-abdominal mass. Computed tomography revealed a mass associated with the caudal pole of the right kidney. Incisional biopsy findings were consistent with eumycotic mycetoma. The mass was subsequently removed in conjunction with right ureteronephrectomy. Two years later, the dog re-presented with a splenic mass and fungal plaques located throughout the peritoneum. Splenectomy was performed and the mass was diagnosed as eumycotic mycetoma caused by Penicillium duponti. Indefinite systemic treatment with 10 mg/kg itraconazole orally once a day was initiated. Thirty-two months after the last surgery, there were no clinical signs apart from mild polydipsia. Haematology and biochemistry results were unremarkable. To the authors' knowledge, this is the first report of successful treatment of intra-abdominal eumycotic mycetoma with a combination of surgery and systemic antifungal therapy in the dog. Penicillium duponti has not apparently been reported to cause disease in animals or humans. PMID- 26017319 TI - 2-Pyridinyl-4(3H)-quinazolinone: a scaffold for anti-influenza A virus compounds. AB - A series of 2-pyridinyl-3-substituted-4(3H)-quinazolinones were synthesized, and their anti-influenza A virus activities were determined using the cytopathic effect inhibition assay. Most of the compounds were potent with IC50 values ranging from 51.6 to 93.0 MUm, which are better than that of the currently marketed drug ribavirin. The molecular mechanisms of the new compounds were investigated using neuraminidase inhibition assay, cellular NF-kappaB signaling pathway inhibition assay, and computational docking. Compound 4e, which is a N3 imidazol-1-ylpropyl-substituted derivative of 2-pyridinyl-4(3H)-quinazolinone, had the most potent anti-influenza A virus activity in vitro, and inhibited both virus neuraminidase and cellular NF-kappaB signaling pathway. In conclusion, 2 pyridinyl-4(3H)-quinazolinone is a new scaffold for the design of potent anti influenza A virus compounds, offering an alternative approach to tackle influenza drug resistance. PMID- 26017320 TI - Visceral adiposity and subclinical atherosclerosis in healthy young men. AB - BACKGROUND: Atherosclerosis begins in childhood and develops silently for decades before clinical events such as myocardial infarction or stroke occur. Only few studies have evaluated the relationship between CVD risk factors and carotid artery Intimal Media Thickness (IMT) in young asymptomatic people. AIM: The aim of this study is to investigate risk factors for cardiovascular disease associated with higher Carotid Intimal Media Thickness (IMT) in healthy young subjects. METHODS: A cohort of 106 healthy young men, mean age 21 +/- 2 years (mean +/- SD), BMI 24.4 +/- 2.8 (kg/m(2)), on military duty, participated in this cross-sectional study. Waist circumference, carotid intima-media thickness (IMT), blood pressure, and plasma concentrations of relevant metabolic parameters were measured at fasting. Smoking and habitual dietary patterns were evaluated by a semiquantitative questionnaire. RESULTS: The population was divided into two groups on the basis of IMT values: the lowest three quartiles versus the highest quartile (cut-off value = 0.7 mm). BMI, waist circumference, systolic (SBP), and diastolic (DBP) blood pressure were significantly higher in the group with higher IMT (p = 0.02). All other variables, including dietary parameters and smoking, were similar in the two groups. Data analysis showed that IMT values correlated positively with SBP (r = 0.22; p = 0.025), DBP (r = 0.27; p = 0.005), waist circumference (r = 0.29; p = 0.002), and fat mass (r = 0.24; p = 0.01), and negatively with kcal/kg of body weight (r = -0.220.22; p = 0.022) - an indirect marker of physical activity. Based on multiple regression analysis, waist circumference and DBP were the only variables independently associated with IMT (p = 0.029). CONCLUSIONS: In a non-selected sample of healthy young adult males, a larger waist circumference and a higher diastolic blood pressure - albeit within normal values - are the only parameters independently associated with higher IMT. PMID- 26017322 TI - Development of an in vitro digestive model for studying the peptide profile of breast milk. AB - Human milk is a highly valuable food for newborns and infants. Its protein fraction plays an important role for the development of the newborn. In the present study, an in vitro digestive model, developed for resembling closely the digestive system of an infant, was applied to human milk in order to identify and characterize the peptide profile. The peptide profile obtained after digestion was analyzed by MULC-LTQ-Orbitrap-MS. A total of 149 peptides from beta-casein, 30 peptides from alpha-lactalbumin, 26 peptides from alphas1-casein, 24 peptides from kappa-casein, 28 peptides from osteopontin, and 29 from lactoferrin was recovered. The identified peptide profile of partially hydrolyzed proteins, such as caseins, alpha-lactalbumin, and osteopontin, was different from that previously reported demonstrating a different performance of the developed neonatal digestive system with respect to other previously applied. These results would be useful as a starting point to investigate the physiological function of breast milk peptides. PMID- 26017321 TI - Study design and methods for a randomized crossover trial substituting brown rice for white rice on diabetes risk factors in India. AB - India has the second largest number of people with diabetes in the world following China. Evidence indicates that consumption of whole grains can reduce the risk of type 2 diabetes. This article describes the study design and methods of a trial in progress evaluating the effects of substituting whole grain brown rice for polished (refined) white rice on biomarkers of diabetes risk (glucose metabolism, dyslipidemia, inflammation). This is a randomized controlled clinical trial with a crossover design conducted in Chennai, India among overweight but otherwise healthy volunteers aged 25-65 y with a body mass index >=23 kg/m(2) and habitual rice consumption >=200 g/day. The feasibility and cultural appropriateness of this type of intervention in the local environment will also be examined. If the intervention is efficacious, the findings can be incorporated into national-level policies which could include the provision of brown rice as an option or replacement for white rice in government institutions and food programs. This relatively simple dietary intervention has the potential to substantially diminish the burden of diabetes in Asia and elsewhere. PMID- 26017323 TI - Effects of eicosapentaenoic acid on hepatic dyslipidemia and oxidative stress in high fat diet-induced steatosis. AB - We investigated the ability of eicosapentaenoic acid (EPA) to prevent high-fat diet (HFD)-induced obesity and non-alcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed standard chow (5.3% fat content), an HFD (32.0% fat content) or an HFD + EPA (1 g/kg/day EPA for the last 6 weeks) for 12 weeks. Serum total cholesterol, hepatic triglyceride and total cholesterol levels were significantly increased in the HFD group, in comparison with those of normal mice (p < 0.01). In contrast, hepatic triglyceride and total cholesterol levels were significantly decreased in the HFD + EPA group, in comparison with those of the HFD group (p < 0.05). In addition, EPA decreased the body weight of obese mice and improved hepatic function. Hepatic superoxide dismutase activity and glutathione levels were significantly decreased in obese mice, but increased with EPA administration. Our data suggest that EPA supplementation has a beneficial effect on NAFLD progression. PMID- 26017324 TI - Influence of steeping conditions (time, temperature, and particle size) on antioxidant properties and sensory attributes of some white and green teas. AB - The influence of commonly used steeping times and temperatures, as well as leaf size on the antioxidant activity and sensory attributes of tea were studied. Five unblended white and green tea samples from China and Malawi, infused in hot (70 degrees C and 90 degrees C; 7 min) or cold water (room temperature: 15, 30, 60, or 120 min) either as whole leaves or as milled, were analyzed. Total phenolic and flavonoid contents as well as antioxidant power (ABTS assay) were measured. The results show that the maximum extraction efficiency occurs with cold water for 120 min and with hot water at 90 degrees C and that only in the case of teas from whole, large leaves, the extraction was greater in cold than in hot infusions. Moreover, tea infusions prepared from milled leaves have the greatest antioxidant activity. In the sensory evaluation of some of the tea infusions, white teas were perceived more fragrant than green ones and were judged as the most favorite by the majority of the judges, especially for the brew prepared in cold water from whole leaves; all infusions obtained from the milled leaves in fact have a more bitter and astringent taste. PMID- 26017325 TI - Virulence gene profiles of avian pathogenic Escherichia coli isolated from chickens with colibacillosis in Bulawayo, Zimbabwe. AB - Colibacillosis, a disease caused by avian pathogenic Escherichia coli (APEC), is one of the main causes of economic losses in the poultry industry worldwide. This study was carried out in order to determine the APEC-associated virulence genes contained by E. coli isolates causing colibacillosis in chickens. A total of 45 E. coli isolates were obtained from the diagnostics and research branch of the Central Veterinary Laboratories, Bulawayo, Zimbabwe. These isolates were obtained from chickens with confirmed cases of colibacillosis after postmortem examination. The presence of the iutA, hlyF, ompT, frz, sitD, fimH, kpsM, sitA, sopB, uvrY, pstB and vat genes were investigated by multiplex polymerase chain reaction (PCR) assay. Of the 45 isolates, 93% were positive for the presence of at least one virulence gene. The three most prevalent virulence genes were iutA (80%), fimH (33.3%) and hlyF (24.4%). The kpsM, pstB and ompT genes had the lowest prevalence, having been detected in only 2.2% of the isolates. All 12 virulence genes studied were detected in the 45 APEC isolates. Virulence gene profiles were constructed for each APEC isolate from the multiplex data. The APEC isolates were profiled as 62.2% fitting profile A, 31.1% profile B and 6.7% profile C. None of the isolates had more than seven virulence genes. Virulence profiles of Zimbabwean APEC isolates are different from those previously reported. Zimbabwean APEC isolates appear to be less pathogenic and may rely on environmental factors and stress in hosts to establish infection. PMID- 26017326 TI - Acute Gastric Volvulus in a 16-Year-Old Male Adolescent: A Case Report. AB - OBJECTIVE: We described a case of acute mesenteroaxial gastric volvulus in a male adolescent who presented to the pediatric emergency department (ED). CASE: A previously healthy male adolescent presented to the pediatric ED with gradual onset of epigastric pain, emesis, and a soft and nondistended abdomen. After evaluation, management, and resolution of the pain, the patient was discharged home with a primary care follow-up plan. Approximately 5 hours after discharge, the patient returned to the pediatric ED with worsening abdominal pain, the inability to tolerate oral intake, and a firm and distended abdomen. Subsequent evaluation identified an acute mesenteroaxial gastric volvulus. Pediatric surgeons performed an exploratory laparotomy, reduction of the gastric volvulus, and gastropexy, and the patient was discharged after a brief hospitalization. CONCLUSIONS: Acute gastric volvulus can present with symptoms similar to benign abdominal etiologies. Timely diagnosis and intervention are key to improved outcomes for patients. PMID- 26017327 TI - Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. AB - BACKGROUND: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, clinically heterogeneous disease due to heritable mutations that lead to misfolding of a precursor protein and multisystem disease. This study sought to define the clinical characteristics, distribution of mutations and phenotypic presentation of patients presenting to our center with hereditary ATTR amyloidosis. METHODS: With institutional review board approval, the study retrospectively identified patients who had hereditary ATTR amyloidosis and presented to Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. RESULTS: Of the 266 patients with the diagnosis of hereditary ATTR amyloidosis, a pathogenic mutation was identified in 206; the most common mutation was Thr60Ala (68 patients [25%]). Median age at diagnosis was 63.3 years; median survival after diagnosis was 56.8 months (10th-90th percentile, 16.0-297.9). On multivariate analysis, age at diagnosis (risk ratio, 15.65; p < 0.0001), Thr60Ala mutation (risk ratio, 1.52; p = 0.04), Val122Ile mutation (risk ratio, 2.83; p = 0.003), peripheral neuropathy (risk ratio, 1.69; p = 0.013) and weight loss (risk ratio, 1.81; p = 0.002) were risk factors for death. CONCLUSION: Our data characterize the features of hereditary ATTR amyloidosis in a large cohort, demonstrate the heterogeneity among mutations and support the need to better characterize the clinical progression of individual mutations. PMID- 26017328 TI - Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis. AB - BACKGROUND: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis. METHODS: Diflunisal was administered orally at 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean +/- SD: 38.0 +/- 31.2 months). RESULTS: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (p = 0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment. CONCLUSIONS: Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment. PMID- 26017329 TI - The first pure form of Ostertag-type amyloidosis in Japan: a sporadic case of hereditary fibrinogen Aalpha-chain amyloidosis associated with a novel frameshift variant. PMID- 26017330 TI - Lycium ruthenicum extract alleviates high-fat diet-induced nonalcoholic fatty liver disease via enhancing the AMPK signaling pathway. AB - Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that currently has no standard treatment. The present study aimed to evaluate the effects of Lycium ruthenicum extract (LRE) on high-fat diet (HFD)-induced NAFLD, and elucidate the underlying molecular mechanisms. To determine the hepatoprotective effect of LRE, C57BL/6 mice were fed a normal control diet, high-fat diet (HFD), HFD supplemented with 2 g/kg LRE, or HFD supplemented with 5 g/kg LRE. Treatment with LRE markedly decreased the levels of triglycerides, total cholesterol, aspartate aminotransferase and alanine aminotransferase in the serum of mice fed a HFD, and improved glucose metabolism and insulin sensitivity in NAFLD mice. In addition, treatment with LRE significantly decreased the expression levels of sterol regulatory element-binding protein 1c and fatty acid synthase, and markedly increased the expression of peroxisome proliferator-activated receptor alpha and peroxisome proliferator-activated receptor gamma co-activator 1alpha. Furthermore, LRE treatment significantly increased the activation of adenosine monophosphate-activated protein kinase (AMPK) in the liver. These results suggested that LRE is able to suppress lipid accumulation in HFD-fed C57BL/6 mice via enhancement of the AMPK pathway. PMID- 26017331 TI - Levels of sparganum infections and phylogenetic analysis of the tapeworm Spirometra erinaceieuropaei sparganum in wild frogs from Henan Province in central China. AB - Sparganosis is a serious food-borne parasitic zoonosis caused by infection with Spirometra spargana. The prevalence of sparganum infection in wild frogs (Rana nigromaculata, R. limmochari, R. temporaria and Bufo gargarizans) was investigated in Henan Province of central China during 2008-2012. Of 3482 caught wild frogs, 565 (16.23%) were found to be infected with plerocercoids (spargana) of the genus Spirometra. Spargana were found in 14.85% (320/2155) of R. nigromaculata, 20.82% (233/1119) of R. limmochari and 10.91% (12/110) of R. temporaria frogs. However, no sparganum was found in B. gargarizans. To investigate the phylogenetic position of collected spargana, three mitochondrial DNA (mtDNA) regions, namely cytochrome c oxidase subunits 1 and 3 (cox1 and cox3), and NADH dehydrogenase subunit 4 (nad4), were amplified, sequenced and analysed. Sequences of cox1, cox3 and pnad4 were 417, 390 and 578 bp in length, respectively. The base composition of cox1, cox3 and pnad4 were generally AT rich with a mean of 63.5%, 68.3% and 67% AT, respectively. Phylogenetic analysis showed that all the sparganum isolates in Henan Province represented Spirometra erinaceieuropaei and were a well-supported clade. These findings demonstrated clearly the usefulness of the three mtDNA sequences for molecular identification and population genetics studies of S. erinaceieuropaei spargana of human and animal health significance. PMID- 26017332 TI - Motility of Fasciola hepatica miracidia assessed with a computer-assisted sperm analyser. AB - The motility parameters of Fasciola hepatica miracidia were assessed at different temperatures and times post-hatching using computer-assisted sperm analysis. Eggs were incubated at 22 degrees C or 25 degrees C for 14 days. Five motion parameters were evaluated at different incubation temperatures up to 10 h post hatching. No differences were observed in the percentage that hatched after incubation at the two different temperatures. However, the straight-line velocity of miracidia following incubation at 22 degrees C was significantly different from that observed at 25 degrees C (P< 0.01). All miracidium motion parameters at different post-hatching temperatures showed an overall decrease at the end of the experiment. Those miracidia hatching from eggs incubated at 25 degrees C had a higher velocity of 1673.3 MUm/s compared with 1553.3 MUm/s at 22 degrees C. Velocity parameters increased as the post-hatching temperature increased from 22 degrees C to 37 degrees C. PMID- 26017333 TI - Acute-phase responses in cattle infected with hydatid cysts and microbial agents. AB - The aim of this study was to investigate the effect of hydatid cysts and microbial agents on the acute-phase response in cattle. Twenty-seven cattle with hydatid cysts and eight apparently healthy cattle comprised the study and control groups, respectively. Parasitological, microbiological, histopathological and immunohistochemical examinations of the liver and lungs were undertaken, and 49 of these organs were infected with cysts. In 14 of 31 (45.1%) livers and 10 of 18 (55.5%) lungs microbial growth was observed. The most frequent species occurring in the liver were Staphylococcus aureus, Escherichia coli, Corynebacterium spp. and Campylobacter spp., whereas in the lungs the most common species was Candida spp., followed by Streptococcus spp., Mannheimia haemolytica, Corynebacterium spp., Micrococcus spp. and S. aureus. The concentration of serum interleukin (IL 6) in infected cattle, 455.35 +/- 39.68 pg/ml, was significantly higher than that of 83.02 +/- 17.87 pg/ml in the control group (P0.05). The highest concentrations of IL-6 were detected in serum of the cattle where microbial growth had been detected, followed by cattle infected with bacteria + Trichostrongylus sp. (P< 0.001). Consequently, SAA showed an important increase in the group infected with hydatid cysts, whereas haptoglobin level decreased. It was noticed that IL-6, like SAA, had a significant role in hydatid cyst infection. Therefore IL-6 and SAA appear to be major markers in the detection of infection of cattle with hydatid cysts. PMID- 26017334 TI - Characterization of ascaris from ecuador and zanzibar. AB - To shed light on the epidemiology of ascariasis in Ecuador and Zanzibar, 177 adult worms retrieved by chemo-expulsion from either people or pigs were collected, measured and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the ribosomal internal transcribed spacer (ITS) region. Upon double digestion with RsaI and HaeIII, PCR RFLP analysis revealed the presence of A. lumbricoides in people and A. suum in pigs in Ecuador. In contrast, while there are no pigs on Zanzibar, of the 56 worms obtained from people, one was genotyped as A. suum. No additional genetic variation was detected upon further PCR-RFLP analysis with several other restriction enzymes. Upon measurement, worm mass and length differed by location and by species, A. suum being lighter and longer. While there is no evidence to suggest zoonotic transmission in Ecuador, an enduring historical signature of previous zoonotic transmission remains on Zanzibar. PMID- 26017335 TI - Vasotonic Angina as a Cause of Myocardial Ischemia in Women. AB - The frequency, presentation, prognosis, and treatment of myocardial ischemia differ in men and women. A large proportion of women who have "normal" coronary arteries on angiography without any significant evidence of flow-limiting disease also have biochemical or imaging evidence of myocardial ischemia. In these women it is believed to be a dysfunction of coronary microcirculation and/or macrocirculation, or vasotonic angina (VA), that leads to abnormal vasoconstriction, and potentially to myocardial infarction, ventricular arrhythmias, and sudden death. Despite having a "normal" or near normal coronary angiography, these women should therefore undergo additional testing with acetylcholine to assess endothelial function. Long-term survival is believed to be relatively good. Predictors of poorer prognosis include documentation of severe endothelial dysfunction and presence of concurrent angiographycally visible coronary atherosclerosis. Because atherosclerosis is common in patients with VA, medical and lifestyle interventions for preventing or treating atherosclerosis should be implemented when appropriate. Angiotensin converting enzyme inhibitors are the mainstays of medical therapy for VA. Other agents have been tried with variable success, including beta-blockers. There are no available data on any specific treatment of VA in women (versus men). PMID- 26017337 TI - Metaethnographic Synthesis of Fathers' Experiences of the Neonatal Intensive Care Unit Environment During Hospitalization of Their Premature Infants. AB - OBJECTIVE: To synthesize existing qualitative findings about fathers' experiences of the neonatal intensive care unit (NICU) environment. DATA SOURCES: Relevant key terms including preterm, father, and NICU were used to search the databases of CINAHL Plus, Academic Search Premier, MEDLINE, and PsychInfo. STUDY SELECTION: Only primary qualitative studies were included. Studies were excluded that did not focus on the NICU environment. DATA EXTRACTION: Twenty-four studies were included. All authors critically appraised and extracted data relating to fathers' experiences in the NICU using an agreed data extraction form. DATA SYNTHESIS: Findings were synthesized by translating the initial concepts and findings from an identified key paper into the data from the remaining 23 studies. Initially this was done separately by each author followed by further group discussion and synthesis. Emergent themes included Proximity, Parental Autonomy, Vulnerability, Communication and Exclusion, and Isolation. CONCLUSIONS: The needs of fathers to interact and be involved with their infants' care was a prominent factor that enhanced their experiences in the NICU. Staff in the NICU can play a key role in facilitating this interaction through encouragement and reassurance. PMID- 26017338 TI - Finite Dilution Inverse Gas Chromatography as a Versatile Tool To Determine the Surface Properties of Biofillers for Plastic Composite Applications. AB - An improved understanding of a filler's surface properties is important for determining the most effective polymer reinforcement fillers. In this work, the surface characteristics of two biofillers, namely, clam shell modified by hydrochloric acid (AMF) and furfural (FMF), were investigated using inverse gas chromatography (IGC). The IGC results showed that the dispersive surface energy (gamma(S)(D)) contributed the major part to the total surface energy for the biofillers. The values changed as a function of surface coverages, meaning that both samples were energetically fairly heterogeneous. The gamma(S)(D) calculated with the Dorris-Gray method was larger than that calculated with the Schultz method, with a gamma(S,Dorris-Gray)(D)/gamma(S,Schultz)(D) ratio of 1.10. Compared to AMF, FMF possessed higher gamma(S)(D) value; however, this difference was compensated by specific (acid-base) surface energy (gamma(S)(AB)). Both samples predominantly interacted with ethanol and acetonitrile, implying an amphoteric nature of the material surfaces. Gutmann acid and base number profiles indicated that the surfaces of both samples were more basic in nature. The FMF showed a lower total work of cohesion (W(Coh)(total)) value compared to the AMF, which could lead to an increase in composite performance. PMID- 26017336 TI - Mechanisms underlying neurocognitive dysfunctions in recurrent major depression. AB - Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression - mild cognitive impairment - dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions. PMID- 26017340 TI - Fat gain with physical detraining is correlated with increased glucose transport and oxidation in periepididymal white adipose tissue in rats. AB - As it is a common observation that obesity tends to occur after discontinuation of exercise, we investigated how white adipocytes isolated from the periepididymal fat of animals with interrupted physical training transport and oxidize glucose, and whether these adaptations support the weight regain seen after 4 weeks of physical detraining. Male Wistar rats (45 days old, weighing 200 g) were divided into two groups (n=10): group D (detrained), trained for 8 weeks and detrained for 4 weeks; and group S (sedentary). The physical exercise was carried out on a treadmill for 60 min/day, 5 days/week for 8 weeks, at 50-60% of the maximum running capacity. After the training protocol, adipocytes isolated from the periepididymal adipose tissue were submitted to glucose uptake and oxidation tests. Adipocytes from detrained animals increased their glucose uptake capacity by 18.5% compared with those from sedentary animals (P<0.05). The same cells also showed a greater glucose oxidation capacity in response to insulin stimulation (34.55%) compared with those from the S group (P<0.05). We hypothesize that, owing to the more intense glucose entrance into adipose cells from detrained rats, more substrate became available for triacylglycerol synthesis. Furthermore, this increased glucose oxidation rate allowed an increase in energy supply for triacylglycerol synthesis. Thus, physical detraining might play a role as a possible obesogenic factor for increasing glucose uptake and oxidation by adipocytes. PMID- 26017341 TI - Evaluation of a father and son with atypical chronic myeloid leukemia with SETBP1 mutations and a review of the literature. AB - We report the case of a father and son diagnosed with atypical chronic myeloid leukemia (aCML). Both patients harbored SETBP1 mutations, which are present in 24.3% of aCML patients. Moreover, both shared the variant encoding p.Pro737His, but the aCML severity was greater in the son because of the presence of two other missense mutations causing p.Asp868Asn and p.Ser885Arg alterations. SETBP1 mutations may be associated with an adverse prognosis, so their detection would help in the diagnosis of aCML and the determination of a patient's prognosis. PMID- 26017342 TI - CTLA4 enhances the osteogenic differentiation of allogeneic human mesenchymal stem cells in a model of immune activation. AB - Allogeneic mesenchymal stem cells (allo-MSCs) have recently garnered increasing interest for their broad clinical therapy applications. Despite this, many studies have shown that allo-MSCs are associated with a high rate of graft rejection unless immunosuppressive therapy is administered to control allo-immune responses. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a co-inhibitory molecule expressed on T cells that mediates the inhibition of T-cell function. Here, we investigated the osteogenic differentiation potency of allo-MSCs in an activated immune system that mimics the in vivo allo-MSC grafting microenvironment and explored the immunomodulatory role of the helper T cell receptor CTLA4 in this process. We found that MSC osteogenic differentiation was inhibited in the presence of the activated immune response and that overexpression of CTLA4 in allo-MSCs suppressed the immune response and promoted osteogenic differentiation. Our results support the application of CTLA4 overexpressing allo-MSCs in bone tissue engineering. PMID- 26017344 TI - Accuracy of dose planning for prostate radiotherapy in the presence of metallic implants evaluated by electron spin resonance dosimetry. AB - Radiotherapy is one of the main approaches to cure prostate cancer, and its success depends on the accuracy of dose planning. A complicating factor is the presence of a metallic prosthesis in the femur and pelvis, which is becoming more common in elderly populations. The goal of this work was to perform dose measurements to check the accuracy of radiotherapy treatment planning under these complicated conditions. To accomplish this, a scale phantom of an adult pelvic region was used with alanine dosimeters inserted in the prostate region. This phantom was irradiated according to the planned treatment under the following three conditions: with two metallic prostheses in the region of the femur head, with only one prosthesis, and without any prostheses. The combined relative standard uncertainty of dose measurement by electron spin resonance (ESR)/alanine was 5.05%, whereas the combined relative standard uncertainty of the applied dose was 3.35%, resulting in a combined relative standard uncertainty of the whole process of 6.06%. The ESR dosimetry indicated that there was no difference (P>0.05, ANOVA) in dosage between the planned dose and treatments. The results are in the range of the planned dose, within the combined relative uncertainty, demonstrating that the treatment-planning system compensates for the effects caused by the presence of femur and hip metal prostheses. PMID- 26017345 TI - Molecular detection of field isolates of Turkey Eimeria by polymerase chain reaction amplification of the cytochrome c oxidase I gene. AB - Oocysts of Eimeria spp. were isolated from litter samples obtained from 30 commercial turkey farms. Genomic DNA was extracted from clean oocysts, and polymerase chain amplification of the species-specific cytochrome c oxidase subunit I (COI) gene was performed for five species of turkey Eimeria. The species tested were Eimeria adenoeides, Eimeria meleagrimitis, Eimeria meleagridis, Eimeria dispersa, and Eimeria gallopavonis. All DNA samples were positive for E. meleagrimitis, nine were positive for E. adenoeides, two were positive for E. dispersa, and none for E. meleagridis and E. gallopavonis. E. meleagrimitis occurred as a single species in 21 (70 %) of the farms while 9 (30 %) farms had a mixed species with E. meleagrimitis and E. adenoeides and 2 (7 %) were triple positive with E. meleagrimitis, E. adenoeides, and E. dispersa. This is the first account of the field prevalence of turkey Eimeria species using molecular methods. PMID- 26017346 TI - The role of domestic tap water on Acanthamoeba keratitis in non-contact lens wearers and validation of laboratory methods. AB - Acanthamoeba is increasingly recognized as an important cause of keratitis in non contact lens wearers while contact lens wear is the leading risk factor for Acanthamoeba keratitis (AK). It is unlikely that the Acanthamoeba colonization is a feature which is effective only in patient's homes with infectious keratitis since the organism has been isolated from domestic tap water. Two hundred and thirty-one (231) corneal scrapings were taken from infectious keratitis cases, and four contact lens solutions and domestic tap waters were taken from 22 out of 44 AK-diagnosed patient's homes. Microscopic examination, culture, PCR, real-time PCR and DNA sequencing analyses were used for AK-diagnosed samples. The real-time PCR was the most sensitive (100 %) one among the methods used in diagnosis of AK. The 44 (19.0 %) out of 231 corneal scrapings, 4/4 (100 %) contact lens solution and 11/22 (50 %) of domestic tap water samples were found to be positive by real time PCR for Acanthamoeba. A. griffini (T3), A. castellanii (T4) and A. jacobsi (T15) genotypes were obtained from corneal scrapings, contact lens solutions and domestic tap water samples taken from the patient's homes diagnosed with AK. The isolation of Acanthamoeba containing 6/22 (27.3 %) A. griffini (T3), 14/22 (63.6 %) A. castellanii (T4) and 2/22 (9.1 %) A. jacobsi (T15) from the domestic tap water outlets of 22 of 44 (50 %) of patient's homes revealed that is a significant source of these organisms. A. griffini (T3) and A. jacobsi (T15) genotypes have not been determined from AK cases in Turkey previously. Thus, we conclude that Acanthamoeba keratitis is associated with exposition of patients who has ocular trauma or ocular surface disease to domestic tap water in endemic or potentially endemic countries. PMID- 26017347 TI - Isolation precautions for visitors. PMID- 26017349 TI - Anti-GAD-associated inflammatory myopathy presenting with dropped head syndrome. PMID- 26017348 TI - Clinical Phenotype Classifications Based on Static Varus Alignment and Varus Thrust in Japanese Patients With Medial Knee Osteoarthritis. AB - OBJECTIVE: To investigate the association between knee pain during gait and 4 clinical phenotypes based on static varus alignment and varus thrust in patients with medial knee osteoarthritis (OA). METHODS: Patients in an orthopedic clinic (n = 266) diagnosed as having knee OA (Kellgren/Lawrence [K/L] grade >=1) were divided into 4 phenotype groups according to the presence or absence of static varus alignment and varus thrust (dynamic varus): no varus (n = 173), dynamic varus (n = 17), static varus (n = 50), and static varus + dynamic varus (n = 26). The knee range of motion, spatiotemporal gait parameters, visual analog scale scores for knee pain, and scores on the Japanese Knee Osteoarthritis Measure were used to assess clinical outcomes. Multiple logistic regression analyses identified the relationship between knee pain during gait and the 4 phenotypes, adjusted for possible risk factors, including age, sex, body mass index, K/L grade, and gait velocity. RESULTS: Multiple logistic regression analysis showed that varus thrust without varus alignment was associated with knee pain during gait (odds ratio [OR] 3.30, 95% confidence interval [95% CI] 1.08-12.4), and that varus thrust combined with varus alignment was strongly associated with knee pain during gait (OR 17.1, 95% CI 3.19-320.0). Sensitivity analyses applying alternative cutoff values for defining static varus alignment showed comparable results. CONCLUSION: Varus thrust with or without static varus alignment was associated with the occurrence of knee pain during gait. Tailored interventions based on individual malalignment phenotypes may improve clinical outcomes in patients with knee OA. PMID- 26017350 TI - Genetic findings of Cypriot spinal muscular atrophy patients. AB - Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families. PMID- 26017352 TI - Family Medicine Department Chairs' Opinions Regarding Scope of Practice. AB - PURPOSE: Family physicians are trained broadly to provide the majority of health care across multiple settings; however, their scope of practice has narrowed. Department chairs' role modeling of a broad scope of practice may set the tone for faculty and trainees. METHOD: In 2013, the authors surveyed family medicine department chairs about their scope of practice, personal and department characteristics, and attitudes and beliefs about scope of practice and role modeling. They used descriptive statistics and bivariate analyses to test for associations between scope of practice, personal and department characteristics, and attitudes and beliefs. They created a Scope of Practice Index by summing the number of services each respondent provided to compare scope of practice across chairs. RESULTS: Of 146 chairs, 88 responded (60.3% response rate); 85 were included in the final analysis. Sixty-five (77.4%) respondents were male; 73 (86.9%) were 51 years or older. Respondents spent a mean of 19.7% of their time in direct patient care and had a mean Scope of Practice Index of 11.9. Fifty three (62.4%) disagreed that the scope of practice of family medicine was too broad for practicing physicians to keep up in all areas, and 56 (65.9%) believed that faculty should role model the full scope of practice to learners. Responses generally did not vary by respondents' personal scope of practice. CONCLUSIONS: Family medicine department chairs believe that role modeling a broad scope of practice increases students' interest in family medicine and encourages residency graduates to provide a wide range of services. PMID- 26017351 TI - Workers with disability: the case of multiple sclerosis. AB - The impact of the multiple sclerosis (MS) on the individual's ability to work is important especially because the onset of the disease occurs mainly between 20 and 30 years of age. This study evaluated different factors associated with job maintenance using a questionnaire that defined what factors are considered obstacle or help in work management. A cross-sectional study of people with MS was carried out in Italy. A total of 1016 individuals with MS were enrolled in the study. Our results showed that negative item related to job maintenance as 'attitudes of other in the workplace' was associated with a lower likelihood of being employed (OR 0.65, 95% CI 0.57-0.76), while 'your attitudes toward work' (OR 1.37, 95% CI 1.19-1.59), 'attitudes of other in the workplace' (OR 1.41, 95% CI 1.17-1.69) and 'personal considerations' (OR 1.54, 95% CI 1.23-1.93), positive items related to job maintenance, were associated with a higher likelihood of being employed. In addition, a poor quality of life and severity disease as well same demographic characteristics (i.e. to be resident in South Italy or in the Islands, living in own original family, have lower educational level) inhibited significantly the job maintenance together with a heavy job and a fixed-term contract. In conclusion, a complex set of variables contribute to the barriers faced by PwMS who are employed suggesting that different stakeholders may play an important role in difficult management of the work for people with MS. PMID- 26017353 TI - What motivates occasional faculty developers to lead faculty development workshops? A qualitative study. AB - PURPOSE: The demand for faculty development is ongoing, and many medical schools will need to expand their pool of faculty developers to include physicians and scientists whose primary expertise is not education. Insight into what motivates occasional faculty developers can guide recruitment and retention strategies. This study was designed to understand the motivations of faculty developers who occasionally (one to three times each year) lead faculty development workshops. METHOD: Qualitative data were collected in March and April 2012 from interviews with faculty developers who occasionally taught workshops from 2007 to 2012 in the University of California, San Francisco, School of Medicine's faculty development program. The interviews were audiotaped and transcribed. The authors thematically analyzed the transcripts using a general inductive approach and developed codes sensitized by motivation theories. RESULTS: The authors interviewed 29/30 (97%) occasional faculty developers and identified five themes: mastery (desire to learn and develop professionally), relatedness (enjoyment of working with and learning from others), duty (sense of obligation to give back and be a good academic citizen), purpose (commitment to improving local teaching and ultimately patient care), and satisfaction (fun and enjoyment). CONCLUSIONS: Four of the themes the authors found are well addressed in motivation theory literature: mastery, relatedness, duty, and purpose. Whereas these four are motivators for occasional faculty developers, it is the fifth theme-satisfaction that the authors feel is foundational and links the others together. Armed with this understanding, individuals leading faculty development programs can develop strategies to recruit and retain occasional faculty developers. PMID- 26017354 TI - Putting communities in the driver's seat: the realities of community-engaged medical education. AB - "Community" has featured in the discourse about medical education for over half a century. This discourse has explored relationships between medical education programs and communities in community-oriented medical education and community based medical education and, in recent years, has extended to community-engaged medical education (CEME). This Perspective explores the developing focus on "community" in medical education, describes CEME as a concept, and presents examples of CEME in action at Flinders University School of Medicine (Australia), the Northern Ontario School of Medicine (Canada), and Ateneo de Zamboanga University School of Medicine (Philippines).The authors describe the ways in which CEME, which features active community participation, can improve medical education while meeting community needs and advancing national and international health equity agendas. They suggest that CEME can redefine student learning as taking place at the center of the partnership between communities and medical schools. They also consider the challenges of CEME and caution that criteria for community engagement must be sensitive to cultural variations and to the nature of the social contract in different sociocultural settings.The authors argue that CEME is effective in producing physicians who choose to practice in rural and underserved areas. Further research is required to demonstrate that CEME contributes to improved health, and ultimately health equity, for the populations served by the medical school. PMID- 26017355 TI - How Medical School Applicant Race, Ethnicity, and Socioeconomic Status Relate to Multiple Mini-Interview-Based Admissions Outcomes: Findings From One Medical School. AB - PURPOSE: To examine associations of medical school applicant underrepresented minority (URM) status and socioeconomic status (SES) with Multiple Mini-Interview (MMI) invitation and performance and acceptance recommendation. METHOD: The authors conducted a correlational study of applicants submitting secondary applications to the University of California, Davis, School of Medicine, 2011 2013. URM applicants were black, Southeast Asian, Native American, Pacific Islander, and/or Hispanic. SES from eight application variables was modeled (0-1 score, higher score = lower SES). Regression analyses examined associations of URM status and SES with MMI invitation (yes/no), MMI score (mean of 10 station ratings, range 0-3), and admission committee recommendation (accept versus not), adjusting for age, sex, and academic performance. RESULTS: Of 7,964 secondary application applicants, 19.7% were URM and 15.1% self-designated disadvantaged; 1,420 (17.8%) participated in the MMI and were evaluated for acceptance. URM status was not associated with MMI invitation (OR 1.14; 95% CI 0.98 to 1.33), MMI score (0.00-point difference, CI -0.08 to 0.08), or acceptance recommendation (OR 1.08; CI 0.69 to 1.68). Lower SES applicants were more likely to be invited to an MMI (OR 5.95; CI 4.76 to 7.44) and recommended for acceptance (OR 3.28; CI 1.79 to 6.00), but had lower MMI scores (-0.12 points, CI -0.23 to -0.01). CONCLUSIONS: MMI-based admissions did not disfavor URM applicants. Lower SES applicants had lower MMI scores but were more likely to be invited to an MMI and recommended for acceptance. Multischool collaborations should examine how MMI based admissions affect URM and lower SES applicants. PMID- 26017356 TI - Fast quantitative analysis of four tyrosine kinase inhibitors in different human plasma samples using three-way calibration-assisted liquid chromatography with diode array detection. AB - A simple method has been developed by combining high-performance liquid chromatography with diode array detection with the alternating trilinear decomposition method for simultaneous determination of four tyrosine kinase inhibitors in different human plasma samples. Chromatographic separation of the analytes was performed on a reversed-phase column with methanol (65%, v/v, A) and 0.1% aqueous solution of formic acid (35%, v/v, B). Analysis time was 5.0 min per run and analytes could be completely eluted within 2.8--3.8 min. The calibration concentration ranges of vandetanib, pazopanib, afatinib and dasatinib were designed as 0.50-6.10, 0.50-6.10, 0.70-7.00 and 0.70-7.00 MUg.mL(-1), respectively. The intra- and inter-day RSDs ranged between 0.1 and 8.9%. Quantitative information could be extracted from the unsegregated interferences of different human plasma samples with the aid of the "second-order advantage" of three-way (second-order) calibration methods. All results demonstrated that the proposed method for direct quantitative analysis of four tyrosine kinase inhibitors in different complex systems possessed good characteristics of rapidity, sensitivity and efficiency, and it is expected to be an attractive choice in the fast analysis of clinical samples. PMID- 26017357 TI - Depression in left-behind elderly in rural China: Prevalence and associated factors. AB - AIM: Several studies have reported the prevalence of depressive symptoms in the urban population of China, but no study reports the prevalence of depression in rural left-behind elderly. The present study investigated the prevalence of depression and the associated factors that influence depression in the left behind elderly population in a rural area of China. METHODS: A cross-sectional study was carried out. A total of 509 participants were surveyed, and all participants completed the Geriatric Depression Scale (long form). Information on sex, age, education level, living situation, number of chronic diseases, amount of economic support received, frequency of children's visits and physical activity was collected. RESULTS: The prevalence of depressive symptoms in rural left-behind elderly was 36.94%. The prevalence of depressive symptoms was higher in women (45.10%) than in men (33.43%). The prevalence of severe depression was 1.96%. The prevalence of depressive symptoms in the 71-80 years age group (45.19%) was higher than the 65-70 years (37.44%) and >80 years age groups (5.97%). However, the prevalence of moderate and severe depression was higher in the 65-70 years age group (3.95%) than in other age groups. The frequency of children's visits, living situation, physical activity, number of chronic diseases and education level were the main risk factors of depression. CONCLUSIONS: The prevalence of depressive symptoms is higher in left-behind elderly in rural areas than in the general elderly population. Psychological intervention is necessary for improving the mental health of elderly people living in rural areas of China. Geriatr Gerontol Int 2016; 16: 638-643. PMID- 26017358 TI - MANTIS: an R package that simulates multilocus models of pathogen evolution. AB - BACKGROUND: In host-pathogen systems the development of immunity by the host places pressure on pathogens, by setting up competition between genetic variants due to the establishment of cross-protective responses. These pressures can lead to pathogen-specific, ubiquitous dynamic behaviours. Understanding the evolutionary forces that shape these patterns is one of the key goals of computationally simulated epidemiological models. Despite the contribution of such research methods in recent years to our current understanding of pathogen evolution, the availability of free software tools for the general public remains scarce. RESULTS: We developed the Multilocus ANTIgenic Simulator (MANTIS) software package for the R statistical environment. MANTIS can simulate and analyse epidemiological time-series generated under the biological assumptions of the strain theory of host-pathogen systems by Gupta et al. CONCLUSIONS: MANTIS wraps a C/C++ ordinary-differential equations system and Runge-Kutta solver into a set of user-friendly R functions. These include routines to numerically simulate the system and others to analyse, visualize and export results. For this, the package offers its own set of time-series plotting and exportation functions. MANTIS's main goal is to serve as a free, ready-to-use academic software tool. Its open source nature further provides an opportunity for users with advanced programming skills to expand its capabilities. Here, we describe the background theory, implementation, basic functionality and usage of this package. MANTIS is freely available from http://www.eeid.ox.ac.uk/mantis under the GPL license. PMID- 26017359 TI - Close correlation of herpes zoster-induced voiding dysfunction with severity of zoster-related pain: A single faculty retrospective study. AB - Herpes zoster (HZ), a common vesiculo-erythematous skin disease associated with reactivation of varicella zoster virus in the cranial nerve, dorsal root, and autonomic ganglia, is accompanied by several related symptoms represented by postherpetic neuralgia. Among them, involvement of vesicorectal dysfunction is relatively rare. The vesicorectal symptom can usually be recovered in transient course, but is quite important in terms of impaired quality of life. Male individuals affected with HZ and skin lesions on sacral dermatome have been reported as independent risk factors of zoster-related voiding dysfunction. In this study, urinary symptoms were focused upon and six patients with zoster related voiding dysfunction at a single faculty of dermatology in Japan from 2009 to 2014 were retrospectively analyzed. All patients showed HZ lesions on the sacral area and the urinary symptom recovered in approximately 2 months (14 days to 7 months). The term of treatment for zoster-associated urinary dysfunction was positively correlated with that for zoster-related pain without significance (r = 0.661, P = 0.153). Average treatment term for pain relief of sacral HZ accompanied by voiding dysfunction (91.3 +/- 76.44 days) was significantly longer than that of sacral HZ without urinary symptom (18.9 +/- 20.42 days) (P = 0.032). These results suggested that zoster-related voiding dysfunction would mainly be involved in sacral HZ and closely associated with severity of zoster-related pain. Dermatologists should be aware that severe zoster-related pain accompanied by sacral HZ, which is related to prolonged treatment of pain relief, can be a predictive factor of voiding dysfunction. PMID- 26017360 TI - Hydrated Electron Transfer to Nucleobases in Aqueous Solutions Revealed by Ab Initio Molecular Dynamics Simulations. AB - We present an ab initio molecular dynamics (AIMD) simulation study into the transfer dynamics of an excess electron from its cavity-shaped hydrated electron state to a hydrated nucleobase (NB)-bound state. In contrast to the traditional view that electron localization at NBs (G/A/C/T), which is the first step for electron-induced DNA damage, is related only to dry or prehydrated electrons, and a fully hydrated electron no longer transfers to NBs, our AIMD simulations indicate that a fully hydrated electron can still transfer to NBs. We monitored the transfer dynamics of fully hydrated electrons towards hydrated NBs in aqueous solutions by using AIMD simulations and found that due to solution-structure fluctuation and attraction of NBs, a fully hydrated electron can transfer to a NB gradually over time. Concurrently, the hydrated electron cavity gradually reorganizes, distorts, and even breaks. The transfer could be completed in about 120-200 fs in four aqueous NB solutions, depending on the electron-binding ability of hydrated NBs and the structural fluctuation of the solution. The transferring electron resides in the pi*-type lowest unoccupied molecular orbital of the NB, which leads to a hydrated NB anion. Clearly, the observed transfer of hydrated electrons can be attributed to the strong electron-binding ability of hydrated NBs over the hydrated electron cavity, which is the driving force, and the transfer dynamics is structure-fluctuation controlled. This work provides new insights into the evolution dynamics of hydrated electrons and provides some helpful information for understanding the DNA-damage mechanism in solution. PMID- 26017361 TI - A synthesis of qualitative research exploring the barriers to staying in work with chronic musculoskeletal pain. AB - PURPOSE: Qualitative research can help to advance our understanding, management and prevention of work disability. Our aim was to integrate qualitative research findings in order to increase our understanding of barriers to stay in work with chronic pain. METHODS: We searched five electronic bibliographic databases until September 2012, supplemented by citation tracking and hand-searching. We used meta-ethnography to synthesis our findings. Central to meta-ethnography is identifying "concepts" and developing a conceptual model. Concepts were compared and organised into categories. RESULTS: The following categories can have an impact on the decision to remain in work: struggling to affirm myself as a good worker; balancing life and work in the face of unpredictable symptoms; my work colleagues don't believe me; the system does not facilitate return to work; the battle for legitimacy. CONCLUSIONS: Our innovation is to present an internationally relevant model based on a conceptual synthesis. This model highlights the adversarial work experience of people with chronic. The papers span 15 years of qualitative research. A significant finding is that these themes continue to pervade the current work environment for those in pain, and this has clear implications for education, social care and policy. IMPLICATIONS FOR REHABILITATION: People with chronic pain face an adversarial struggle to maintain their credibility at work. Strategies to maintain personal credibility can have an adverse effect on working lives. Changes at a systems level are needed to facilitate continuance and return to work. Cultural changes in the way that we view people with pain would help to keep people in work. PMID- 26017362 TI - Women's experiences of living with neurogenic bladder and bowel after spinal cord injury: life controlled by bladder and bowel. AB - PURPOSE: Neurogenic bladder and bowel (NBB) is a chronic condition hindering the functioning and quality of life (QOL) of people with spinal cord injury (SCI). NBB research has focused on men with SCI leaving unanswered questions about women's experiences of living with NBB. The purpose of this study was to identify and describe women's experiences of living with SCI and NBB. METHOD: Secondary analysis of semi-structured interviews from a larger qualitative study of women with SCI (N = 50) was carried out. Transcripts were coded for bowel and bladder content. Pile-sorting techniques were used to identify emergent themes related to NBB. Meta-themes were categorized under the International Classification of Functioning, Disability and Health. RESULTS: Bladder and bowel topics were spontaneously discussed by 46 out of 50 study participants suggesting the salience of this issue for women with SCI. We identified 6 meta-themes: life controlled by bladder and bowel, bladder and bowel accidents, women's specific challenges, life course disruption, bladder and bowel medical management, and finding independence. CONCLUSIONS: Findings describe concerns, strategies, and the detrimental impact of NBB in the lives of women with SCI. Findings inform policy makers, health care and rehabilitation professionals to improve accessibility and quality of life for women with NBB. IMPLICATIONS FOR REHABILITATION: Women with spinal cord injury (SCI) reported gender specific challenges to living with neurogenic bladder and bowel (NBB). Interventions designed for women with SCI can address these problems and provide recommendations for prevention and treatment. Women described the detrimental impact of NBB on life course expectations, emotional, social, physical health, and quality of life domains. Psychosocial and educational programs can be developed to address these challenges and improve overall quality of life. Recommendations for special treatment and policy considerations are needed to maximize women's independence and health while living with NBB after SCI. PMID- 26017363 TI - Differential predation by age and sex classes in blue wildebeest in Serengeti: study of a modern carnivore den in Olduvai Gorge (Tanzania). AB - Age and sex selection of prey is an aspect of predator ecology which has been extensively studied in both temperate and African ecosystems. This dimension, along with fecundity, survival rates of prey and mortality factors other than predation are important in laying down the population dynamics of prey and have important implications in the management of species. A carnivore den located in the short-grassland ecological unit of the Serengeti was studied. Sex- and age- class (using five age categories) of the wildebeest remains recovered were analyzed through horn morphology, biometrics of the bones and tooth wear patterns. We compared our results with previous studies from lion and hyaena kills through multivariate analyses. Seasonality of the accumulation was analyzed through tooth histology. PCA and CVA results show that age class selection by predators depends on season, habitat-type, and growth rate of the wildebeest population. Female-biased predation was found to contradict classical hypotheses based on territorial male behaviour. The lion and spotted hyaena showed strong selection on age classes, contrary to previous studies. Migratory wildebeest sex ratio is regulated through differential predation by seasons and female deaths in the wet season are a trade-off for population stability. These data are crucial for an effective management of the species and the new method created may be useful for different carnivore species and their prey. PMID- 26017364 TI - Bioreactance Is Not Interchangeable with Thermodilution for Measuring Cardiac Output during Adult Liver Transplantation. AB - BACKGROUND: Thermodilution technique using a pulmonary artery catheter is widely used for the assessment of cardiac output (CO) in patients undergoing liver transplantation. However, the unclearness of the risk-benefit ratio of this method has led to an interest in less invasive modalities. Thus, we evaluated whether noninvasive bioreactance CO monitoring is interchangeable with thermodilution technique. METHODS: Nineteen recipients undergoing adult-to-adult living donor liver transplantation were enrolled in this prospective observational study. COs were recorded automatically by the two devices and compared simultaneously at 3-minute intervals. The Bland-Altman plot was used to evaluate the agreement between bioreactance and thermodilution. Clinically acceptable agreement was defined as a percentage error of limits of agreement <30%. The four quadrant plot was used to evaluate concordance between bioreactance and thermodilution. Clinically acceptable concordance was defined as a concordance rate >92%. RESULTS: A total of 2640 datasets were collected. The mean CO difference between the two techniques was 0.9 l/min, and the 95% limits of agreement were -3.5 l/min and 5.4 l/min with a percentage error of 53.9%. The percentage errors in the dissection, anhepatic, and reperfusion phase were 50.6%, 56.1%, and 53.5%, respectively. The concordance rate between the two techniques was 54.8%. CONCLUSION: Bioreactance and thermodilution failed to show acceptable interchangeability in terms of both estimating CO and tracking CO changes in patients undergoing liver transplantation. Thus, the use of bioreactance as an alternative CO monitoring to thermodilution, in spite of its noninvasiveness, would be hard to recommend in these surgical patients. PMID- 26017365 TI - Unruptured second-trimester ovarian pregnancy. AB - Ovarian ectopic pregnancies are rare, with the majority diagnosed in the first trimester and often treated due to symptoms related to ovarian rupture. We report our experience with the diagnosis, management, and histologic evaluation of an unruptured second-trimester ovarian ectopic pregnancy. A 37-year-old woman presented with vague abdominal discomfort and irregular menses. Ultrasound detected a 16-week 4-day gestation with cardiac motion in the right adnexa and no evidence of an intrauterine pregnancy. Laparotomy with right salpingo oophorectomy was performed, with removal of an unruptured pregnancy from the ovary. Although intraoperative examination and postoperative histopathologic evaluation demonstrated the classic Speigelberg criteria, it did not assist in the preoperative diagnosis, nor impact the treatment of the ovarian ectopic pregnancy in this case. PMID- 26017366 TI - A Self-Assembling Peptide Scaffold for the Multivalent Presentation of Antigens. AB - Self-assembling peptides can be used to create tunable higher-order structures for the multivalent presentation of a variety of ligands. We describe a novel, fiber-forming coiled-coil-based peptide that assembles to display, simultaneously, carbohydrate and peptide ligands recognized by biomacromolecules. Preassembly decoration of the scaffold with a diphtheria toxin peptide epitope or a mannose motif did not interfere with self-assembly of the nanostructure. The resulting multivalent display led to tighter binding by antidiphtheria toxin antibodies and mannose-specific carbohydrate binding proteins, respectively. The potential of this self-assembling peptide to display ligands in bioanalytical assays is illustrated by its decoration with a disaccharide glycotope from the Leishmania parasite. Carbohydrate-specific antibodies produced in response to a Leishmania infection are detected more sensitively in human and canine sera due to the multivalent presentation on the self-assembled scaffold. Thus, nanofibers based on coiled-coil peptides are a powerful tool for the development of bioassays and diagnostics. PMID- 26017367 TI - Establishing the common ground in European psychotraumatology. PMID- 26017368 TI - Prehospital Trauma Triage Decision-making: A Model of What Happens between the 9 1-1 Call and the Hospital. AB - We describe the decision-making process used by emergency medical services (EMS) providers in order to understand how 1) injured patients are evaluated in the prehospital setting; 2) field triage criteria are applied in-practice; and 3) selection of a destination hospital is determined. We conducted separate focus groups with advanced and basic life support providers from rural and urban/suburban regions. Four exploratory focus groups were conducted to identify overarching themes and five additional confirmatory focus groups were conducted to verify initial focus group findings and provide additional detail regarding trauma triage decision-making and application of field triage criteria. All focus groups were conducted by a public health researcher with formal training in qualitative research. A standardized question guide was used to facilitate discussion at all focus groups. All focus groups were audio-recorded and transcribed. Responses were coded and categorized into larger domains to describe how EMS providers approach trauma triage and apply the Field Triage Decision Scheme. We conducted 9 focus groups with 50 EMS providers. Participants highlighted that trauma triage is complex and there is often limited time to make destination decisions. Four overarching domains were identified within the context of trauma triage decision-making: 1) initial assessment; 2) importance of speed versus accuracy; 3) usability of current field triage criteria; and 4) consideration of patient and emergency care system-level factors. Field triage is a complex decision-making process which involves consideration of many patient and system-level factors. The decision model presented in this study suggests that EMS providers place significant emphasis on speed of decisions, relying on initial impressions and immediately observable information, rather than precise measurement of vital signs or systematic application of field triage criteria. PMID- 26017369 TI - Identification of proteins interacting with protein kinase C-delta in hyperthermia-induced apoptosis and thermotolerance of Tca8113 cells. AB - The purpose of the present study was to investigate the differential proteins that interact with protein kinase C-delta (PKC-delta) in hyperthermia-induced apoptosis as well as thermotolerance in Tca8113 cells, and furthermore, to investigate the mechanisms of these processes in tumor cells. Activation of PKC delta was previously indicated to be involved in the heat sensitivity and thermal resistance of tongue squamous carcinoma cells. Tca8113 cell apoptosis was induced by incubation at 43C for 80 min and the thermotolerant Tca8113 cells (TT-Tca8113) were generated through a gradient temperature-elevating method. The apoptotic rate of the cells was determined by flow cytometry, while cleavage and activation of PKC-delta were analyzed by western blot analysis. The proteins that interacted with PKC-delta in the Tca8113 and TT-Tca8113 cells were identified by co immunoprecipitation coupled with mass spectrometry. Co-immunoprecipitation analysis followed by electrospray ionization mass spectrometric analysis were utilized to identify the pro- and anti-apoptotic proteins that interacted with PKC-delta. Significant cell apoptosis was observed in Tca8113 cells following hyperthermia, and the apoptotic rate was significantly higher than that in the control group (P<0.05). Marked PKC-delta cleavage fragmentation was also identified. By contrast, the apoptotic rate of the TT-Tca8113 cells was not significantly increased following hyperthermia and no PKC-delta cleavage fragmentation was observed. Among the proteins interacting with PKC-delta, 39 were found to be involved in the promotion of apoptosis and 16 in the inhibition of apoptosis of Tca8113 cells; these proteins were known to be involved in the regulation of cell proliferation, apoptosis, transcription and intracellular protein transport. The results of the present study provided evidence that PKC delta is a crucial factor in the heat sensitivity and thermal resistance of tongue squamous carcinoma cells and elucidated the underlying molecular basis, which may aid in the improvement of hyperthermic cancer treatments. PMID- 26017371 TI - Message From the President of ECTSS. PMID- 26017373 TI - Schedule of events. PMID- 26017374 TI - MRC review of 2014. PMID- 26017375 TI - Does Formal Employment Reduce Informal Caregiving? AB - Using the Survey of Income and Program Participation, we examine the impact of formal employment on informal caregiving. We instrument for individual work hours with state unemployment rates. We find that, among women of prime caregiving ages (40-64 years), working 10% more hours per week reduces the probability of providing informal care by about 2 percentage points. The effects are stronger for more time-intensive caregiving and if care recipients are household members. Our results imply that work-promoting policies have the unintended consequence of reducing informal caregiving in an aging society. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26017370 TI - Explaining variation in cancer survival between 11 jurisdictions in the International Cancer Benchmarking Partnership: a primary care vignette survey. AB - OBJECTIVES: The International Cancer Benchmarking Partnership (ICBP) is a collaboration between 6 countries and 12 jurisdictions with similar primary care led health services. This study investigates primary care physician (PCP) behaviour and systems that may contribute to the timeliness of investigating for cancer and subsequently, international survival differences. DESIGN: A validated survey administered to PCPs via the internet set out in two parts: direct questions on primary care structure and practice relating to cancer diagnosis, and clinical vignettes, assessing management of scenarios relating to the diagnosis of lung, colorectal or ovarian cancer. PARTICIPANTS: 2795 PCPs in 11 jurisdictions: New South Wales and Victoria (Australia), British Columbia, Manitoba, Ontario (Canada), England, Northern Ireland, Wales (UK), Denmark, Norway and Sweden. PRIMARY AND SECONDARY OUTCOME MEASURES: Analysis compared the cumulative proportion of PCPs in each jurisdiction opting to investigate or refer at each phase for each vignette with 1-year survival, and conditional 5-year survival rates for the relevant cancer and jurisdiction. Logistic regression was used to explore whether PCP characteristics or system differences in each jurisdiction affected the readiness to investigate. RESULTS: 4 of 5 vignettes showed a statistically significant correlation (p<0.05 or better) between readiness to investigate or refer to secondary care at the first phase of each vignette and cancer survival rates for that jurisdiction. No consistent associations were found between readiness to investigate and selected PCP demographics, practice or health system variables. CONCLUSIONS: We demonstrate a correlation between the readiness of PCPs to investigate symptoms indicative of cancer and cancer survival rates, one of the first possible explanations for the variation in cancer survival between ICBP countries. No specific health system features consistently explained these findings. Some jurisdictions may consider lowering thresholds for PCPs to investigate for cancer-either directly, or by specialist referral, to improve outcomes. PMID- 26017376 TI - Water-soluble oxoglaucine-Y(III), Dy(III) complexes: in vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis. AB - Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3].CH3OH (1) and [Dy(OG)2(NO3)3].H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin. PMID- 26017377 TI - Home-based carers' perceptions of health promotion on sexual health communication in Vhembe District. AB - BACKGROUND: The introduction of home-based care in rural communities in the 1980s contributed immensely toward the upliftment of the personal and environmental health of communities. Women's groups provided health promotion skills and health education to communities and made a difference in health-related behaviour change. OBJECTIVE: The purpose of the study was to explore and describe the home based carers' perception regarding health promotion concerning sexual health communication in Vhembe district, in the context of HIV, amongst communities still rooted in their culture. METHOD: A qualitative, explorative and descriptive design was used in order to understand home-based carers' perceptions regarding health promotion on sexual health communication amongst rural communities which may adversely impact on health promotion practices. The population were home based organisations in Vhembe. The sample was purposive and randomly selected and data were gathered through semi-structured face-to-face interviews and focus groups which determined data saturation. Open coding was used for analysis of data. RESULTS: The results indicated that sexual communication was absent in most relationships and was not seen as necessary amongst married couples. Socioeconomic conditions, power inequity and emotional dependence had a negative impact on decision making and sexual communication. CONCLUSION: This study, therefore, recommends that educational and outreach efforts should focus on motivating change by improving the knowledge base of home-based carers. Since they are health promoters, they should be able to change the perceptions of the communities toward sexually-transmitted infections and HIV by promoting sexual health communication. PMID- 26017378 TI - O-Methyltransferases involved in biphenyl and dibenzofuran biosynthesis. AB - Biphenyls and dibenzofurans are the phytoalexins of the Malinae involving apple and pear. Biosynthesis of the defence compounds includes two O-methylation reactions. cDNAs encoding the O-methyltransferase (OMT) enzymes were isolated from rowan (Sorbus aucuparia) cell cultures after treatment with an elicitor preparation from the scab-causing fungus, Venturia inaequalis. The preferred substrate for SaOMT1 was 3,5-dihydroxybiphenyl, supplied by the first pathway specific enzyme, biphenyl synthase (BIS). 3,5-Dihydroxybiphenyl underwent a single methylation reaction in the presence of S-adenosyl-l-methionine (SAM). The second enzyme, SaOMT2, exhibited its highest affinity for noraucuparin, however the turnover rate was greater with 5-hydroxyferulic acid. Both substrates were only methylated at the meta-positioned hydroxyl group. The substrate specificities of the OMTs and the regiospecificities of their reactions were rationalized by homology modeling and substrate docking. Interaction of the substrates with SAM also took place at a position other than the sulfur group. Expression of SaOMT1, SaOMT2 and SaBIS3 was transiently induced in rowan cell cultures by the addition of the fungal elicitor. While the immediate SaOMT1 products were not detectable in elicitor-treated cell cultures, noraucuparin and noreriobofuran accumulated transiently, followed by increasing levels of the SaOMT2 products aucuparin and eriobofuran. SaOMT1, SaOMT2 and SaBIS3 were N- and C-terminally fused with the super cyan fluorescent protein and a modified yellow fluorescent protein, respectively. All the fluorescent reporter fusions were localized to the cytoplasm of Nicotiana benthamiana leaf epidermis cells. A revised biosynthetic pathway of biphenyls and dibenzofurans in the Malinae is presented. PMID- 26017379 TI - [Towards more precision in the therapy of brain tumors. Possibilities and limits of MRI]. AB - Due to the introduction of advanced functional and spectroscopic magnetic resonance (MR) sequences, MR imaging has gained significant importance in neuro oncology. In contrast to recent years when neuro-oncological imaging was mostly limited to contrast-enhanced T1-weighted images, advanced MR methods provide direct visualization and assessment of tumor pathophysiology. This article summarizes the most relevant MR methods for neuro-oncological imaging and highlights the pathophysiological background as well as potential clinical applications. Ultimately, this article gives a glimpse into the future and introduces potential applications of ultra-high field MRI. PMID- 26017380 TI - Comparison of Immediate and Delayed Blood Alcohol Concentration Testing. AB - The effects of storage time and temperature on blood alcohol concentration were evaluated in this two-part study involving 34 ethanol-negative and 21 ethanol positive volunteers. Multiple 10-mL Vacutainer((r)) blood tubes containing 100 mg of sodium fluoride and 20 mg of potassium oxalate were collected from living persons and subjected to various storage conditions. The time from collection to analysis ranged from 0 to 60 days and storage temperatures ranged from 3 to 20 degrees C. Regardless of the storage conditions, all ethanol-negative samples remained negative (<0.0025 g/100 mL) throughout the study. There was no increase in the concentration of ethanol-positive samples beyond the expected variability of the method, regardless of storage time or temperature. Many ethanol-positive samples demonstrated decreases in concentration during storage compared with the original immediate analysis. The findings from this study support previous research, which demonstrates that microbial formation of ethanol in properly collected antemortem blood is unlikely. PMID- 26017381 TI - Quantitative Assay Validation for Oxandrolone in Human Plasma Using LC-MS-MS. AB - A high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the determination of oxandrolone concentration in human plasma (0.5 mL) was developed and validated according to the 2001 FDA Bioanalytical Guidelines. Oxandrolone is an anabolic steroid used to promote weight gain for cachectic patients with severe burn injuries, HIV/AIDS, hepatitis C and other wasting syndromes. The assay procedure involved a liquid-liquid extraction of oxandrolone and methyltestosterone (the internal standard, IS) from plasma with n butyl chloride. The organic layer was clarified by centrifugation and evaporated to dryness under a stream of air. The residue was reconstituted in a solution containing 25% methanol and 75% Milli-Q water, and injected onto a Luna C18 reversed-phase HPLC column (30 mm * 2.0 mm, 2 MUm). Separation of oxandrolone and methyltestosterone was achieved with a mobile phase starting composition of 55% methanol and 45% ammonium formate buffer at a flow rate of 0.1 mL/min. The total run time was 21 min per sample. Selected reaction monitoring mode was used for quantifying oxandrolone (m/z 307 -> 271) and the IS, methyltestosterone (m/z 301 > 149). To the authors' knowledge, this is the first LC-MS-MS method validated for oxandrolone quantification in human plasma. This method can be used in future pharmacokinetic studies involving oxandrolone. PMID- 26017382 TI - Degradation of polyomavirus JC T-antigen by stress involves the LIP isoform of C/EBP. AB - Endoplasmic reticulum (ER) stress is caused by the accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum. CCAAT/enhancer binding proteins are one of the cellular proteins whose expression is upregulated during ER stress. Previously, we have identified C/EBPbeta isoforms, especially LIP, as a negative regulator of polyomavirus JC (JCV), the causative agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). Here, we show that the induction of ER stress by thapsigargin increase the expression of endogenous LIP and the degradation of JCV T-antigen in a JCV-transgenic mouse tumor cell line. Our results also revealed that overexpression of LIP significantly reduced the level of T-Ag and this effect is reversed upon siRNA mediated silencing of LIP. Immunoprecipitation/Western blot experiments indicated that LIP interacts with T-antigen directly. Treatment of cells that overexpress LIP with MG115, a proteasome inhibitor, partially rescued LIP-mediated degradation of T-antigen. Our observations point to a role of LIP in ER stress regulation of T-antigen stability and may open a new avenue to study host-virus interaction during ER stress. PMID- 26017383 TI - Psychological interventions for women with non-metastatic breast cancer. AB - BACKGROUND: Breast cancer is the most common cancer affecting women worldwide. It is a distressing diagnosis and, as a result, considerable research has examined the psychological sequelae of being diagnosed and treated for breast cancer. Breast cancer is associated with increased rates of depression and anxiety and reduced quality of life. As a consequence, multiple studies have explored the impact of psychological interventions on the psychological distress experienced after a diagnosis of breast cancer. OBJECTIVES: To assess the effects of psychological interventions on psychological morbidities, quality of life and survival among women with non-metastatic breast cancer. SEARCH METHODS: We searched the following databases up to 16 May 2013: the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO; and reference lists of articles. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov for ongoing trials in addition to handsearching. SELECTION CRITERIA: Randomised controlled trials that assessed the effectiveness of psychological interventions for non-metastatic breast cancer in women. DATA COLLECTION AND ANALYSIS: Two review authors independently appraised and extracted data from eligible trials. Any disagreement was resolved by discussion. Extracted data included information about participants, methods, the intervention and outcome. MAIN RESULTS: Twenty-eight randomised controlled trials comprising 3940 participants were included. The most frequent reasons for exclusion were non randomised trials and the inclusion of women with metastatic disease. A wide range of interventions were evaluated, with 24 trials investigating a cognitive behavioural therapy and four trials investigating psychotherapy compared to control. Pooled standardised mean differences (SMD) from baseline indicated less depression (SMD -1.01, 95% confidence interval (CI) -1.83 to -0.18; P = 0.02; 7 studies, 637 participants, I(2) = 95%, low quality evidence), anxiety (SMD -0.48, 95% CI -0.76 to -0.21; P = 0.0006; 8 studies, 776 participants, I(2) = 64%, low quality evidence) and mood disturbance (SMD -0.28, 95% CI -0.43 to -0.13; P = 0.0003; 8 studies, 1536 participants, I(2) = 47%, moderate quality evidence) for the cognitive behavioural therapy group than the control group. For quality of life, only an individually-delivered cognitive behavioural intervention showed significantly better quality of life than the control with an SMD of 0.65 (95% CI 0.07 to 1.23; P = 0.03; 3 studies, 141 participants, I(2) = 41%, very low quality evidence). Pooled data from two group-delivered studies showed a non-significant overall survival benefit favouring cognitive behavioural therapy compared to control (pooled hazard ratio (HR) 0.76, 95% CI 0.25 to 2.32; P = 0.63; 530 participants, I(2) = 84%, low quality evidence). Four studies compared psychotherapy to control with one to two studies reporting on each outcome. The four studies were assessed as high risk of bias and provided limited evidence of the efficacy of psychotherapy. Adverse events were not reported in any of the included studies. AUTHORS' CONCLUSIONS: A psychological intervention, namely cognitive behavioural therapy, produced favourable effects on some psychological outcomes, in particular anxiety, depression and mood disturbance. However, the evidence for survival improvement is still lacking. These findings are open to criticism because of the notable heterogeneity across the included studies and the shortcomings of the included studies. PMID- 26017384 TI - Language differences in the brain network for reading in naturalistic story reading and lexical decision. AB - Differences in how writing systems represent language raise important questions about whether there could be a universal functional architecture for reading across languages. In order to study potential language differences in the neural networks that support reading skill, we collected fMRI data from readers of alphabetic (English) and morpho-syllabic (Chinese) writing systems during two reading tasks. In one, participants read short stories under conditions that approximate natural reading, and in the other, participants decided whether individual stimuli were real words or not. Prior work comparing these two writing systems has overwhelmingly used meta-linguistic tasks, generally supporting the conclusion that the reading system is organized differently for skilled readers of Chinese and English. We observed that language differences in the reading network were greatly dependent on task. In lexical decision, a pattern consistent with prior research was observed in which the Middle Frontal Gyrus (MFG) and right Fusiform Gyrus (rFFG) were more active for Chinese than for English, whereas the posterior temporal sulcus was more active for English than for Chinese. We found a very different pattern of language effects in a naturalistic reading paradigm, during which significant differences were only observed in visual regions not typically considered specific to the reading network, and the middle temporal gyrus, which is thought to be important for direct mapping of orthography to semantics. Indeed, in areas that are often discussed as supporting distinct cognitive or linguistic functions between the two languages, we observed interaction. Specifically, language differences were most pronounced in MFG and rFFG during the lexical decision task, whereas no language differences were observed in these areas during silent reading of text for comprehension. PMID- 26017385 TI - A Comprehensive Review on Recent advances in Synthesis & Pharmacotherapeutic potential of Benzothiazoles. AB - Heterocyclic analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. Benzothiazole is a class of heterocyclic compounds having 2 hetero atoms namely, sulphur and nitrogen. The analogues of benzothiazoles and its derivatives have a significant role in research area especially in synthetic, medicinal and pharmaceutical chemistry because of their biological and pharmacological activity. These compounds have special significance in the field of Medicinal chemistry due to their remarkable pharmacological potentialities. Benzothiazole is an organosulfur heterocyclic compound, weakly basic in nature. They are widely found in bioorganic and medicinal chemistry with wide application in drug discovery. Benzothiazoles are fused membered rings, which contain the heterocycles bearing thiazole as central moiety. A large number of therapeutic agents are synthesized with the help of benzothiazoles nucleus. In addition, benzothiazoles act as core nucleus in various drugs due to their various activities e.g. pramipexole, probenazole, lubeluzole, zopolrestat, ethoxazolamide and bentaluron etc. and their derivatives have attracted a great deal of interest due to their wide range of biological activities such as anticancer, antimicrobial, antitubercular, anti-HIV, cardiovascular, local anaesthetic, anti inflammatory, anticonvulsant and anti-diabetic. The therapeutic properties of the heterocycles have encouraged the medicinal chemist to synthesize a large number of novel chemotherapeutic agents. This review is mainly an attempt to present the research work reported in the recent scientific literature focusing on different biological activities of benzothiazoles compounds. PMID- 26017386 TI - Going cheap: determinants of bird price in the Taiwanese pet market. AB - BACKGROUND: International wildlife trade is the largest emerging source of vertebrate invasive alien species. In order to prevent invasions, it is essential to understand the mechanics of trade and, in particular, which traded species are most likely to be released or escape into the wild. A species' economic value is a key factor, because we expect cheaper species to be less assiduously secured against escaping, and more likely to be deliberately released. Here, we investigate determinants of the price of species in the Taiwanese bird trade. Taiwan is an international hub for bird trade, and several native species are threatened by alien bird species. METHODOLOGY: We investigated the relationship between the traded species sale price in Taiwan and the species availability for trade (the number of birds for sale, geographic range size and their origin, conservation and CITES status) and traits (body size, coloration, song attractiveness). We used phylogenetic generalized least squares models, with multi-model inference, to assess the variables that are best related to the price of birds in the Taiwanese pet trade. PRINCIPAL FINDINGS/CONCLUSIONS: We found that species available for sale in larger numbers, native to Taiwan, not globally endangered, and small-bodied are all relatively cheaper, as too are species lacking yellow coloration and without attractive songs. Our models of price revealed high levels of phylogenetic correlation, and hence that closely related species tended to be sold for similar prices. We suggest that, on the basis of price, native species are more likely to be deliberately or accidentally released than alien species. Nevertheless, our survey of bird shops recorded 160 species alien to Taiwan (7,631 individuals), several of which are for sale cheaply and in large numbers. Alien bird species in trade therefore present an ongoing, non trivial invasion risk on the island. PMID- 26017388 TI - Correction: The Association of Statin Use after Cancer Diagnosis with Survival in Pancreatic Cancer Patients: A SEER-Medicare Analysis. PMID- 26017387 TI - The Prognostic Value of the Work Ability Index for Sickness Absence among Office Workers. AB - BACKGROUND: The work ability index (WAI) is a frequently used tool in occupational health to identify workers at risk for a reduced work performance and for work-related disability. However, information about the prognostic value of the WAI to identify workers at risk for sickness absence is scarce. OBJECTIVES: To investigate the prognostic value of the WAI for sickness absence, and whether the discriminative ability differs across demographic subgroups. METHODS: At baseline, the WAI (score 7-49) was assessed among 1,331 office workers from a Dutch financial service company. Sickness absence was registered during 12-months follow-up and categorised as 0 days, 0=15 days in one year. Associations between WAI and sickness absence were estimated by multinomial regression analyses. Discriminative ability of the WAI was assessed by the Area Under the Curve (AUC) and Ordinal c-index (ORC). Test characteristics were determined for dichotomised outcomes. Additional analyses were performed for separate WAI dimensions, and subgroup analyses for demographic groups. RESULTS: A lower WAI was associated with sickness absence (>=15 days vs. 0 days: per point lower WAI score OR=1.27; 95%CI 1.21-1.33). The WAI showed reasonable ability to discriminate between categories of sickness absence (ORC=0.65; 95%CI 0.63-0.68). Highest discrimination was found for comparing workers with >=15 sick days with 0 sick days (AUC=0.77) or with 1-5 sick days (AUC=0.69). At the cut-off for poor work ability (WAI<=27) the sensitivity to identify workers at risk for >=15 sick days was 7.5%, the specificity 99.6%, and the positive predictive value 82%. The performance was similar across demographic subgroups. CONCLUSIONS: The WAI could be used to identify workers at high risk for prolonged sickness absence. However, due to low sensitivity many workers will be missed. Hence, additional factors are required to better identify workers at highest risk. PMID- 26017389 TI - Magnetically Active Carbon Nanotubes at Work. AB - Endohedral and exohedral assembly of magnetic nanoparticles (MNPs) and carbon nanotubes (CNTs) recently gave birth to a large body of new hybrid nanomaterials (MNPs-CNTs) featuring properties that are otherwise not in reach with only the graphitic or metallic cores themselves. These materials feature enhanced magnetically guided motions (rotation and translation), magnetic saturation and coercivity, large surface area, and thermal stability. By guiding the reader through the most significant examples in this Concept paper, we describe how researchers in the field engineered and exploited the synergistic combination of these two types of nanoparticles in a large variety of current and potential applications, such as magnetic fluid hyperthermia therapeutics and in magnetic resonance imaging to name a few. PMID- 26017390 TI - The Impact of Sonication on the Surface Quality of Single-Walled Carbon Nanotubes. AB - Sonication process is regularly adopted for dispersing single-walled carbon nanotubes (SWCNTs) in an aqueous medium. This can be achieved by either covalent functionalization of SWCNTs with strong acid or by noncovalent functionalization using dispersants that adsorb onto the surface of SWCNTs during dispersion. Because the dispersion process is usually performed using sonication, unintentional free radical formation during sonication process may induce covalent modification of SWCNT surface. Herein, we have systematically investigated the status of SWCNT surface modification under various sonication conditions using Raman spectroscopy. Comparing ID /IG (Raman intensities between D and G bands) ratio of SWCNTs under various sonication conditions suggests that typical sonication conditions (1-6 h bath sonication with sonication power between 3 and 80 W) in aqueous media do not induce covalent modification of SWCNT surface. In addition, we confirm that SWCNT dispersion with single-stranded DNA (ssDNA) involves noncovalent adsorption of ssDNA onto the surface of SWCNTs, but not covalent linkage between ssDNA and SWCNT surface. PMID- 26017391 TI - Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet. AB - Health is influenced by interplay of molecular, physiological and environmental factors. To effectively maintain health and prevent disease, health-relevant relations need to be understood at multiple levels of biological complexity. Network-based methods provide a powerful platform for integration and mining of data and knowledge characterizing different aspects of health. Previously, we have reported physiological and gene expression changes associated with adaptation of murine epididymal white adipose tissue (eWAT) to 5 days and 12 weeks of high-fat diet (HFD) and low-fat diet feeding (Voigt et al. in Mol Nutr Food Res 57:1423-1434, 2013. doi: 10.1002/mnfr.201200671 ). In the current study, we apply network analysis on this dataset to comprehensively characterize mechanisms driving the short- and long-term adaptation of eWAT to HFD across multiple levels of complexity. We built a three-layered interaction network comprising enriched biological processes, their transcriptional regulators and associated changes in physiological parameters. The multi-layered network model reveals that early eWAT adaptation to HFD feeding involves major changes at a molecular level, including activation of TGF-beta signalling pathway, immune and stress response and downregulation of mitochondrial functioning. Upon prolonged HFD intake, initial transcriptional response tails off, mitochondrial functioning is even further diminished, and in turn the relation between eWAT gene expression and physiological changes becomes more prominent. In particular, eWAT weight and total energy intake negatively correlate with cellular respiration process, revealing mitochondrial dysfunction as a hallmark of late eWAT adaptation to HFD. Apart from global understanding of the time-resolved adaptation to HFD, the multi layered network model allows several novel mechanistic hypotheses to emerge: (1) early activation of TGF-beta signalling as a trigger for structural and morphological changes in mitochondrial organization in eWAT, (2) modulation of cellular respiration as an intervention strategy to effectively deal with excess dietary fat and (3) discovery of putative intervention targets, such those in pathways related to appetite control. In conclusion, the generated network model comprehensively characterizes eWAT adaptation to high-fat diet, spanning from global aspects to mechanistic details. Being open to further exploration by the research community, it provides a resource of health-relevant interactions ready to be used in a broad range of research applications. PMID- 26017392 TI - Prostanoids and NSAIDs in cardiovascular biology and disease. AB - Prostanoids and related arachidonic acid derivatives are important physiologic modulators in arteries, as well as mediators of inflammation, hemostasis, and cell proliferation. Their participation in atherosclerosis and in acute thrombotic events is complex, as demonstrated by untoward cardiovascular (CV) effects associated with clinical use of inhibitors of prostaglandin synthesis for treatment of chronic pain, inflammatory states, or cancer prophylaxis. Newer understanding of the pathophysiology of atherosclerosis and the pharmacology of prostanoids promises potential resolution of current problems resulting from the hazards of available prostanoid-altering drugs. PMID- 26017394 TI - Straightforward Micropatterning of Oligonucleotides in Microfluidics by Novel Spin-On ZrO2 Surfaces. AB - DNA biochip assays often require immobilization of bioactive molecules on solid surfaces. A simple biofunctionalization protocol and precise spatial binding represent the two major challenges in order to obtain localized region specific biopatterns into lab-on-a-chip (LOC) systems. In this work, a simple strategy to anchor oligonucleotides on microstructured areas and integrate the biomolecules patterns within microfluidic channels is reported. A photosensitive ZrO2 system is proposed as an advanced platform and versatile interface for specific positioning and oriented immobilization of phosphorylated DNA. ZrO2 sol-gel structures were easily produced on fused silica by direct UV lithography, allowing a simple and fast patterning process with different geometries. A thermal treatment at 800 degrees C was performed to crystallize the structures and maximize the affinity of DNA to ZrO2. Fluorescent DNA strands were selectively immobilized on the crystalline patterns inside polydimethylsiloxane (PDMS) microchannels, allowing high specificity and rapid hybridization kinetics. Hybridization tests confirmed the correct probe anchoring and the bioactivity retention, while denaturation experiments demonstrated the possibility of regenerating the surface. PMID- 26017393 TI - Malignant MCA Stroke: an Update on Surgical Decompression and Future Directions. AB - Despite a decline over the past decade in overall stroke mortality, hemispheric strokes retain a strikingly high mortality due to their potential for malignant edema and herniation. The pathogenesis of ischemic cerebral edema is steered by disruption of ionic homeostasis in the neurogliovascular unit. Significant effort has been made to identify potential medical therapies targeting edema formation with promising results. To date, decompressive craniectomy remains the therapy with the most robust impact on mortality. Historically, patient selection for surgical treatment of malignant supratentorial strokes has focused on a strict age cutoff and hemispheric dominance. Recent evidence supports a significant mortality benefit in elderly population, although the impact in morbidity is modest. Careful patient selection for surgical treatment in conjunction with comprehensive neurocritical care and inclusion of family in the educated decision making process remain the mainstay of care for such shattering disease. PMID- 26017396 TI - Radiolabelling rituximab with (99m)Tc in three steps procedure. AB - Lymphomas are the most frequent haematological malignancy. In non-Hodgkin's lymphomas (NHL), more than 90% of tumor cells express the cluster of differentiation (CD) 20 antigen. At the end of frontline therapy, the evaluation of remission is based on computed tomography (CT) and positron emission tomography coupled with computer tomography (PET/CT) with [(18)F] fluorodeoxyglucose ([(18)F]FDG). Unfortunately, these techniques are not specific and cannot distinguish residual active tumor from inflammation. The aim of this study was to develop a specific radiotracer of NHL CD 20+ cells for clinical applications. The radiolabelling technique presented, based on the use of tricarbonyl compound, does not include an antibody reduction because this step could damage the protein. Actually, rituximab, an anti-CD 20 chimeric antibody used for the treatment of these NHL, was radiolabelled with Isolink(r) (99m)Tc tricarbonyl compound in a three-step procedure without using a specific antibody reducer. Radiolabelling yield was greater than 97%. In vitro experiments showed a conservation of antibody integrity. In vivo experiments using Single-photon emission computed tomography/CT showed significant tumor targeting 24 h after injection of the radiotracer. It was consequently possible to develop an immunoradiolabelling method to specifically detect the residual disease. As this procedure is fast, reproducible and gentle, it will be possible to comply with Good Manufacturing Practices. PMID- 26017395 TI - Ultrasonographic assessment of splenic volume at presentation and after anti malarial therapy in children with malarial anaemia. AB - BACKGROUND: Splenic enlargement is a component of the host response to malaria and may also influence the genesis and progression of malarial anaemia. Few cross sectional and no longitudinal studies have assessed the relationship between splenic volume measured ultrasonographically and haemoglobin concentrations in children with malaria. METHODS: Fifteen Papua New Guinean children with severe malarial anaemia (SMA; haemoglobin<50 g/L) and ten with moderate malarial anaemia (MMA; 51-99 g/L) were recruited. The SMA patients were given intramuscular artemether followed by oral artemisinin combination therapy (ACT), and were transfused one unit of packed cells 0.3-4.0 days post-admission. The MMA patients were treated with ACT. Splenic enlargement (Hackett's grade, subcostal distance and ultrasonographically determined volume) and haemoglobin concentrations were measured on days 0, 1, 2, 3, 7, 14, 28, and 42. RESULTS: Associations between Hackett's grade, subcostal distance and splenic volume were modest (rs<=0.62, P<0.001). Baseline splenic volume was not associated with age or haemoglobin (P>=0.90). Mean splenic volume had fallen by approximately 50% at day 14 in children with MMA (P<=0.011 vs days 0, 1 and 2), but there was no change in the SMA group (P>=0.30). There was no change in haemoglobin in the MMA group during follow-up but a rise in the SMA group to day 7 (P<=0.05 vs days 0, 1, 2, and 3) which paralleled the packed cell volume transfused. CONCLUSIONS: Clinical assessment of splenomegaly is imprecise compared with ultrasonography. Serial splenic volumes and haemoglobin concentrations suggest that the spleen does not influence post-treatment haemoglobin, including after transfusion. PMID- 26017397 TI - Thromboembolic resolution assessed by CT pulmonary angiography after treatment for acute pulmonary embolism. AB - The systematic assessment of residual thromboembolic obstruction after treatment for acute pulmonary embolism (PE) has been understudied. This assessment is of potential clinical importance, should clinically suspected recurrent PE occur, or as tool for risk stratification of cardiopulmonary complications or recurrent venous thromboembolism (VTE). This study aimed to assess the rate of PE resolution and its implications for clinical outcome. In this prospective, multi center cohort study, 157 patients with acute PE diagnosed by CT pulmonary angiography (CTPA) underwent follow-up CTPA-imaging after six months of anticoagulant treatment. Two expert thoracic radiologists independently assessed the presence of residual thromboembolic obstruction. The degree of obstruction at baseline and follow-up was calculated using the Qanadli obstruction index. All patients were followed-up for 2.5 years. At baseline, the median obstruction index was 27.5 %. After six months of treatment, complete PE resolution had occurred in 84.1 % of the patients (95 % confidence interval (CI): 77.4-89.4 %). The median obstruction index of the 25 patients with residual thrombotic obstruction was 5.0 %. During follow-up, 16 (10.2 %) patients experienced recurrent VTE. The presence of residual thromboembolic obstruction was not associated with recurrent VTE (adjusted hazard ratio: 0.92; 95 % CI: 0.2 4.1).This study indicates that the incidence of residual thrombotic obstruction following treatment for PE is considerably lower than currently anticipated. These findings, combined with the absence of a correlation between residual thrombotic obstruction and recurrent VTE, do not support the routine use of follow-up CTPA-imaging in patients treated for acute PE. PMID- 26017398 TI - Development of a consensus-base list of criteria for prescribing medication in a pediatric population. AB - BACKGROUND: Although many people are involved in the optimal use of a medication within this process, the use of medications carries risks of adverse events, which are greater in the pediatric population because of many factors. OBJECTIVE: In this context, our aim was to develop a consensus-based list of criteria for the safety of the pediatric medication-use process or circuit (referred to from now on as the CIRCUS tool: CIRcuit-of-Child-drug-USe). SETTING: Multicenter with a trio of experts from eight university hospitals. METHODS: A literature search (1998-2013) was conducted in order to identify the different safety practice domains for the pediatric medication use process. Twenty-six safety practice domains were identified and 48 compliance criteria were formulated. In order to reach a consensus on the most relevant compliance criteria for safety practices, an international 24 French-speaking multidisciplinary panelists (8 doctors, 8 pharmacists and 8 nurses) selected to represent a broad range of experience levels and specialties took part in a two round Delphi survey which was conducted between March and July 2013. Each panelist was asked to rate each proposed criterion on a 1-9 Likert scale in order to show their level of agreement (i.e. 1 reflects strong disagreement and 9 reflects strong agreement). MAIN OUTCOME MEASURE: Development of a consensus-base list for safety practices in pediatrics. RESULTS: Twenty-two of the 24 professionals invited to take part in this survey (92% participation rate) completed the two Delphi rounds. At the end of the two Delphi rounds, a total of 38/48 (79%) safety practice compliance criteria achieved consensus by the panelists. The criteria were grouped into 23 domains. CONCLUSION: This study presents the development of a self-assessment tool for safety practices in the pediatric drug-use process using a Delphi method. This tool may be used in order to record and compare the prevalence of best safety practices in the pediatric drug-use process. PMID- 26017399 TI - The organizational framework of community pharmacies in Europe. AB - BACKGROUND: The role of the pharmacist has undergone profound changes over the recent years. In most European countries, the tendency seems to be that pharmacists are moving from being product-oriented to service-oriented. An interesting series of papers describing care related services of pharmacy in various countries has been published in 2006, but much has changed since then. This paper aims to provide an updated view on the overall health care sector in Europe, with a special focus on services in community pharmacy. OBJECTIVE: To list and compare health care and community pharmacy structure in Europe; and to discuss the facilitators and barriers that can be found in health care systems and may promote or hinder the implementation of new community pharmacy services. SETTING: European community pharmacy practice. METHODS: A cross-sectional study was undertaken where data were collected using an online survey sent to a purposive sample of representatives from 27 European countries. Main outcome measure variation in professional community pharmacy services across Europe. RESULTS: Data were obtained from 22 respondents in 19 countries (70.4%). Health care is mainly provided by a form of public National Health Services in 17 of the 19 countries. Demographic criteria for founding new pharmacies were present in 17 countries. Medicines are exclusively available in pharmacies in approximately one third of the countries. Smoking cessation (93.8%), drug waste management (81.3%) and pharmaceutical care programmes for specific diseases (77.8%) were reported as the most widely disseminated services in European pharmacies. CONCLUSIONS: There are still major differences between community pharmacy practice in Europe. Differences are mostly due to the legal framework and remuneration issues, which impact on the range of services available from pharmacies to the community of each country. PMID- 26017400 TI - Suboptimal antimicrobial drug exposure in patients with renal impairment. AB - BACKGROUND: Recommendations on drug dose adjustment in patients with renal impairment may vary between the references. It is often unknown which approach the dosing schemes were based on and what drug exposure is likely to be achieved. OBJECTIVE: To develop a simple method to evaluate recommended dosing schemes for patients with renal impairment, to apply this method to selected antibacterial drugs in order to evaluate expected drug concentrations using dosing schemes recommended for patients with severe infections, and to evaluate the expected consequences. SETTING: This was a theoretical study, which was based on data from published clinical trials. METHODS: Clinically established dosing schemes for 46 antibacterial drugs, as recommended for patients with renal impairment in the Summary of Product Characteristics, were analysed using a newly developed graphical method. Consistency of the dosing schemes with two general dose adjustment rules, the proportional rule and the eliminated fraction rule, was determined and drug exposure was predicted. MAIN OUTCOME MEASURE: Predicted drug exposure. Consistency of recommended dosing schemes with the general dose adjustment rules. RESULTS: Only 30% of the recommended dosing schemes were associated with similar average concentrations as expected in patients with normal renal function (44 % were associated with higher and 26% with lower concentrations). The highest median exposure was found in beta-lactams (170%, range 58-443%, for creatinine clearance of <15 ml/min, and 155%, range 54-232%, for creatinine clearance of 15 to <30 ml/min), where the medians were significantly different from 100% (P < 0.02). Consistency with a dosing rule was found in 59% of the dosing schemes (proportional rule 46%, eliminated fraction rule 50%, both rules 4%). CONCLUSIONS: Relative low exposure was found for several drugs, including ceftazidime, cefotaxime, imipenem, erythromycin, ciprofloxacin, levofloxacin, and teicoplanin, where dosing schemes should be reconsidered or used only in clinical situations where a lower than maximum exposure appears adequate. General application of the proportional rule for calculating drug dose adjustments would lead to lower than clinically established dose practice for 44% of drugs. PMID- 26017401 TI - Sipuleucel-T for the Treatment of Metastatic Hormone-Relapsed Prostate Cancer: A NICE Single Technology Appraisal; An Evidence Review Group Perspective. AB - The National Institute for Health and Care Excellence (NICE) invited Dendreon, the company manufacturing sipuleucel-T, to submit evidence for the clinical and cost effectiveness of sipuleucel-T for asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer patients in whom chemotherapy is not yet clinically indicated, as part of NICE's single technology appraisal process. The comparator was abiraterone acetate (AA) or best supportive care (BSC). The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper describes the company submission (CS), ERG review, and subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost-effectiveness evidence of sipuleucel-T based upon the CS. Clinical effectiveness data relevant to the decision problem were taken from three randomised controlled trials (RCTs) of sipuleucel-T and a placebo (PBO) comparator of antigen-presenting cells (APC) being re-infused (APC-PBO) (D9901, D9902A and D9902B), and one RCT (COU-AA-302) of AA plus prednisone vs. PBO plus prednisone. Two trials reported a significant advantage for sipuleucel-T in median overall survival compared with APC-PBO: for trial D9901, an adjusted hazard ratio (HR) 0.47; (95 % confidence interval [CI] 0.29, 0.76) p < 0.002; for D9902B, adjusted HR 0.78 (95 % CI 0.61, 0.98) p = 0.03. There was no significant difference between groups in D9902A, unadjusted HR 0.79 (95 % CI 0.48, 1.28) p = 0.331. Sipuleucel-T and APC-PBO groups did not differ significantly in time to disease progression, in any of the three RCTs. Most adverse events developed within 1 day of the infusion, and resolved within 2 days. The CS included an indirect comparison of sipuleucel-T (D9902B) and AA plus prednisone (COU-AA-302). As trials differed in prior use of chemotherapy, an analysis of only chemotherapy naive patients was included, in which the overall survival for sipuleucel-T and AA was not significantly different, HR 0.94 (95 % CI 0.69, 1.28) p = 0.699. The ERG had several concerns regarding the data and assumptions incorporated within the company's cost-effectiveness analyses and conducted exploratory analyses to quantify the impact of making alternative assumptions or using alternative data inputs. The deterministic incremental cost-effectiveness ratio (ICER) for sipuleucel-T vs. BSC when using the ERG's preferred data and assumptions was L 108,585 per quality-adjusted life-year (QALY) in the whole licensed population and L 61,204/QALY in the subgroup with low prostate-specific antigen at baseline. The ERG also conducted an incremental analysis comparing sipuleucel-T with both AA and BSC in the chemotherapy-naive subgroup. Sipuleucel-T had a deterministic ICER of L 111,682/QALY in this subgroup, when using the ERG's preferred assumptions, and AA was extendedly dominated. The ERG also concluded that estimates of costs and benefits for AA should be interpreted with caution given the limitations of the indirect comparison. The AC noted that the ICER for sipuleucel-T was well above the range usually considered cost effective, and did not recommend sipuleucel-T for the treatment of asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer. PMID- 26017402 TI - High-Resolution Three-Dimensional Computed Tomography Analysis of the Clinical Efficacy of Cultured Autogenous Periosteal Cells in Sinus Lift Bone Grafting. AB - BACKGROUND AND PURPOSE: Sinus lift (SL) using cultured autogenous periosteal cells (CAPCs) combined with autogenous bone and platelet-rich plasma (PRP) was performed to evaluate the effect of cell administration on bone regeneration, by using high-resolution three-dimensional computed tomography (CT). MATERIALS AND METHODS: SL with autogenous bone and PRP plus CAPC [CAPC(+)SL] was performed in 23 patients. A piece of periosteum taken from the mandible was cultured in M199 medium with 10% fetal bovine serum (FBS) for 6 weeks. As control, 16 patients received SL with autogenous bone and PRP [CAPC(-)SL]. Three-dimensional CT imaging was performed before and 4 months and 1 year after SL, and stratification was performed based on CT numbers (HUs) corresponding to soft tissue and cancellous or cortical bone. RESULTS: The augmented bone in CAPC(+)SL revealed an increase in HUs corresponding to cancellous bone as well as a decrease in HUs corresponding to grafted cortical bone. In addition, HUs corresponding to cancellous bone in the graft bed were increased in CAPC(+)SL but were decreased in CAPC(-)SL. Insertion torque during implant placement was significantly higher in CAPC(+)SL. CONCLUSION: By promoting bone anabolic activity both in augmented bone and graft bed, CAPCs are expected to aid primary fixation and osseointegration of implants in clinical applications. PMID- 26017403 TI - The UDP-glucose: glycoprotein glucosyltransferase (UGGT), a key enzyme in ER quality control, plays a significant role in plant growth as well as biotic and abiotic stress in Arabidopsis thaliana. AB - BACKGROUND: UDP-glucose: glycoprotein glucosyltransferase (UGGT) is a key player in the quality control mechanism (ER-QC) that newly synthesized glycoproteins undergo in the ER. It has been shown that the UGGT Arabidopsis orthologue is involved in ER-QC; however, its role in plant physiology remains unclear. RESULTS: Here, we show that two mutant alleles in the At1g71220 locus have none or reduced UGGT activity. In wild type plants, the AtUGGT transcript levels increased upon activation of the unfolded protein response (UPR). Interestingly, mutants in AtUGGT exhibited an endogenous up-regulation of genes that are UPR targets. In addition, mutants in AtUGGT showed a 30% reduction in the incorporation of UDP-Glucose into the ER suggesting that this enzyme drives the uptake of this substrate for the CNX/CRT cycle. Plants deficient in UGGT exhibited a delayed growth rate of the primary root and rosette as well as an alteration in the number of leaves. These mutants are more sensitive to pathogen attack as well as heat, salt, and UPR-inducing stressors. Additionally, the plants showed impairment in the establishment of systemic acquired resistance (SAR). CONCLUSIONS: These results show that a lack of UGGT activity alters plant vegetative development and impairs the response to several abiotic and biotic stresses. Moreover, our results uncover an unexpected role of UGGT in the incorporation of UDP-Glucose into the ER lumen in Arabidopsis thaliana. PMID- 26017404 TI - Factors Affecting Haul-Out Behavior of Harbor Seals (Phoca vitulina) in Tidewater Glacier Inlets in Alaska: Can Tourism Vessels and Seals Coexist? AB - Large numbers of harbor seals (Phoca vitulina) use habitat in tidewater glaciers in Alaska for pupping, breeding, and molting. Glacial fjords are also popular tourist destinations; however, visitation by numerous vessels can result in disturbance of seals during critical life-history phases. We explored factors affecting haul-out behavior of harbor seals at a glacial site frequented by tourism vessels. In 2008-10, we deployed VHF transmitters on 107 seals in Endicott Arm, Alaska. We remotely monitored presence and haul-out behavior of tagged seals and documented vessel presence with time-lapse cameras. We evaluated the influence of environmental and physical factors on the probability of being hauled out, duration of haul-out bouts, and as factors associated with the start and end of a haulout. Location, season, hour, and interactions of location by year, season, hour, and sex significantly influenced haul-out probability, as did ice, weather, and vessels. Seals were more likely to be hauled out with greater ice availability during the middle of the day, and less likely to be hauled out if vessels were present. Cruise ships had the strongest negative effect; however, most vessel types negatively affected haul-out probability. Haul-out duration was longest in association with starting on incoming tides, clear skies, no precipitation, occurring in the middle of the day, and ending in the late afternoon or evening. End of haulouts was associated with increasing cloud cover, low ice availability, and vessel presence; large-sized tourism vessels or all vessel-types combined were significant predictors of ending a haul-out bout. Probability of being hauled out was highest in June, during pupping season. Potential disturbances of harbor seals could be reduced, enabling longer resting times for seals and fewer interruptions for nursing pups, if vessels focused the majority of visits to glacial habitat to before or after the hours of 08:00-17:00 or, less optimally, 09:00-16:00. PMID- 26017405 TI - Trading places. PMID- 26017406 TI - Wakey wakey. PMID- 26017407 TI - Silicon smarts. PMID- 26017408 TI - Eat insects for fun, not to help the environment. PMID- 26017420 TI - Trade treaties centre on science. PMID- 26017421 TI - Bacterial arms race revs up. PMID- 26017422 TI - Ebola R&D woes spur action. PMID- 26017423 TI - Scientists step in to assess carbon-emissions pledges. PMID- 26017424 TI - Surgeon commits misconduct. PMID- 26017425 TI - Correction. PMID- 26017426 TI - Military technology: Laser weapons get real. PMID- 26017427 TI - Clever fish. PMID- 26017428 TI - Robotics: Ethics of artificial intelligence. PMID- 26017432 TI - Environment: Deforestation soars in the Amazon. PMID- 26017433 TI - Correction. PMID- 26017434 TI - Instrumentation: The mystery of the microscope in mud. PMID- 26017435 TI - Plant breeding: UK bioscientists push for crop policy. PMID- 26017436 TI - Conservation: Marine protection is a UK priority. PMID- 26017437 TI - Artificial intelligence: Robots with instincts. PMID- 26017438 TI - Ocean science: The origins of a climate oscillation. PMID- 26017439 TI - Cancer metabolism: A waste of insulin interference. PMID- 26017440 TI - Palaeoanthropology: The middle Pliocene gets crowded. PMID- 26017441 TI - Machine intelligence. PMID- 26017442 TI - Deep learning. AB - Deep learning allows computational models that are composed of multiple processing layers to learn representations of data with multiple levels of abstraction. These methods have dramatically improved the state-of-the-art in speech recognition, visual object recognition, object detection and many other domains such as drug discovery and genomics. Deep learning discovers intricate structure in large data sets by using the backpropagation algorithm to indicate how a machine should change its internal parameters that are used to compute the representation in each layer from the representation in the previous layer. Deep convolutional nets have brought about breakthroughs in processing images, video, speech and audio, whereas recurrent nets have shone light on sequential data such as text and speech. PMID- 26017443 TI - Reinforcement learning improves behaviour from evaluative feedback. AB - Reinforcement learning is a branch of machine learning concerned with using experience gained through interacting with the world and evaluative feedback to improve a system's ability to make behavioural decisions. It has been called the artificial intelligence problem in a microcosm because learning algorithms must act autonomously to perform well and achieve their goals. Partly driven by the increasing availability of rich data, recent years have seen exciting advances in the theory and practice of reinforcement learning, including developments in fundamental technical areas such as generalization, planning, exploration and empirical methodology, leading to increasing applicability to real-life problems. PMID- 26017444 TI - Probabilistic machine learning and artificial intelligence. AB - How can a machine learn from experience? Probabilistic modelling provides a framework for understanding what learning is, and has therefore emerged as one of the principal theoretical and practical approaches for designing machines that learn from data acquired through experience. The probabilistic framework, which describes how to represent and manipulate uncertainty about models and predictions, has a central role in scientific data analysis, machine learning, robotics, cognitive science and artificial intelligence. This Review provides an introduction to this framework, and discusses some of the state-of-the-art advances in the field, namely, probabilistic programming, Bayesian optimization, data compression and automatic model discovery. PMID- 26017445 TI - Science, technology and the future of small autonomous drones. AB - We are witnessing the advent of a new era of robots - drones - that can autonomously fly in natural and man-made environments. These robots, often associated with defence applications, could have a major impact on civilian tasks, including transportation, communication, agriculture, disaster mitigation and environment preservation. Autonomous flight in confined spaces presents great scientific and technical challenges owing to the energetic cost of staying airborne and to the perceptual intelligence required to negotiate complex environments. We identify scientific and technological advances that are expected to translate, within appropriate regulatory frameworks, into pervasive use of autonomous drones for civilian applications. PMID- 26017446 TI - Design, fabrication and control of soft robots. AB - Conventionally, engineers have employed rigid materials to fabricate precise, predictable robotic systems, which are easily modelled as rigid members connected at discrete joints. Natural systems, however, often match or exceed the performance of robotic systems with deformable bodies. Cephalopods, for example, achieve amazing feats of manipulation and locomotion without a skeleton; even vertebrates such as humans achieve dynamic gaits by storing elastic energy in their compliant bones and soft tissues. Inspired by nature, engineers have begun to explore the design and control of soft-bodied robots composed of compliant materials. This Review discusses recent developments in the emerging field of soft robotics. PMID- 26017447 TI - From evolutionary computation to the evolution of things. AB - Evolution has provided a source of inspiration for algorithm designers since the birth of computers. The resulting field, evolutionary computation, has been successful in solving engineering tasks ranging in outlook from the molecular to the astronomical. Today, the field is entering a new phase as evolutionary algorithms that take place in hardware are developed, opening up new avenues towards autonomous machines that can adapt to their environment. We discuss how evolutionary computation compares with natural evolution and what its benefits are relative to other computing approaches, and we introduce the emerging area of artificial evolution in physical systems. PMID- 26017448 TI - New species from Ethiopia further expands Middle Pliocene hominin diversity. AB - Middle Pliocene hominin species diversity has been a subject of debate over the past two decades, particularly after the naming of Australopithecus bahrelghazali and Kenyanthropus platyops in addition to the well-known species Australopithecus afarensis. Further analyses continue to support the proposal that several hominin species co-existed during this time period. Here we recognize a new hominin species (Australopithecus deyiremeda sp. nov.) from 3.3-3.5-million-year-old deposits in the Woranso-Mille study area, central Afar, Ethiopia. The new species from Woranso-Mille shows that there were at least two contemporaneous hominin species living in the Afar region of Ethiopia between 3.3 and 3.5 million years ago, and further confirms early hominin taxonomic diversity in eastern Africa during the Middle Pliocene epoch. The morphology of Au. deyiremeda also reinforces concerns related to dentognathic (that is, jaws and teeth) homoplasy in Plio-Pleistocene hominins, and shows that some dentognathic features traditionally associated with Paranthropus and Homo appeared in the fossil record earlier than previously thought. PMID- 26017450 TI - A kiloparsec-scale internal shock collision in the jet of a nearby radio galaxy. AB - Jets of highly energized plasma with relativistic velocities are associated with black holes ranging in mass from a few times that of the Sun to the billion-solar mass black holes at the centres of galaxies. A popular but unconfirmed hypothesis to explain how the plasma is energized is the 'internal shock model', in which the relativistic flow is unsteady. Faster components in the jet catch up to and collide with slower ones, leading to internal shocks that accelerate particles and generate magnetic fields. This mechanism can explain the variable, high energy emission from a diverse set of objects, with the best indirect evidence being the unseen fast relativistic flow inferred to energize slower components in X-ray binary jets. Mapping of the kinematic profiles in resolved jets has revealed precessing and helical patterns in X-ray binaries, apparent superluminal motions, and the ejection of knots (bright components) from standing shocks in the jets of active galaxies. Observations revealing the structure and evolution of an internal shock in action have, however, remained elusive, hindering measurement of the physical parameters and ultimate efficiency of the mechanism. Here we report observations of a collision between two knots in the jet of nearby radio galaxy 3C 264. A bright knot with an apparent speed of (7.0 +/- 0.8)c, where c is the speed of light in a vacuum, is in the incipient stages of a collision with a slower-moving knot of speed (1.8 +/- 0.5)c just downstream, resulting in brightening of both knots--as seen in the most recent epoch of imaging. PMID- 26017451 TI - Extreme ultraviolet high-harmonic spectroscopy of solids. AB - Extreme ultraviolet (EUV) high-harmonic radiation emerging from laser-driven atoms, molecules or plasmas underlies powerful attosecond spectroscopy techniques and provides insight into fundamental structural and dynamic properties of matter. The advancement of these spectroscopy techniques to study strong-field electron dynamics in condensed matter calls for the generation and manipulation of EUV radiation in bulk solids, but this capability has remained beyond the reach of optical sciences. Recent experiments and theoretical predictions paved the way to strong-field physics in solids by demonstrating the generation and optical control of deep ultraviolet radiation in bulk semiconductors, driven by femtosecond mid-infrared fields or the coherent up-conversion of terahertz fields to multi-octave spectra in the mid-infrared and optical frequencies. Here we demonstrate that thin films of SiO2 exposed to intense, few-cycle to sub-cycle pulses give rise to wideband coherent EUV radiation extending in energy to about 40 electronvolts. Our study indicates the association of the emitted EUV radiation with intraband currents of multi-petahertz frequency, induced in the lowest conduction band of SiO2. To demonstrate the applicability of high-harmonic spectroscopy to solids, we exploit the EUV spectra to gain access to fine details of the energy dispersion profile of the conduction band that are as yet inaccessible by photoemission spectroscopy in wide-bandgap dielectrics. In addition, we use the EUV spectra to trace the attosecond control of the intraband electron motion induced by synthesized optical transients. Our work advances lightwave electronics in condensed matter into the realm of multi-petahertz frequencies and their attosecond control, and marks the advent of solid-state EUV photonics. PMID- 26017452 TI - Robots that can adapt like animals. AB - Robots have transformed many industries, most notably manufacturing, and have the power to deliver tremendous benefits to society, such as in search and rescue, disaster response, health care and transportation. They are also invaluable tools for scientific exploration in environments inaccessible to humans, from distant planets to deep oceans. A major obstacle to their widespread adoption in more complex environments outside factories is their fragility. Whereas animals can quickly adapt to injuries, current robots cannot 'think outside the box' to find a compensatory behaviour when they are damaged: they are limited to their pre specified self-sensing abilities, can diagnose only anticipated failure modes, and require a pre-programmed contingency plan for every type of potential damage, an impracticality for complex robots. A promising approach to reducing robot fragility involves having robots learn appropriate behaviours in response to damage, but current techniques are slow even with small, constrained search spaces. Here we introduce an intelligent trial-and-error algorithm that allows robots to adapt to damage in less than two minutes in large search spaces without requiring self-diagnosis or pre-specified contingency plans. Before the robot is deployed, it uses a novel technique to create a detailed map of the space of high performing behaviours. This map represents the robot's prior knowledge about what behaviours it can perform and their value. When the robot is damaged, it uses this prior knowledge to guide a trial-and-error learning algorithm that conducts intelligent experiments to rapidly discover a behaviour that compensates for the damage. Experiments reveal successful adaptations for a legged robot injured in five different ways, including damaged, broken, and missing legs, and for a robotic arm with joints broken in 14 different ways. This new algorithm will enable more robust, effective, autonomous robots, and may shed light on the principles that animals use to adapt to injury. PMID- 26017453 TI - Ocean impact on decadal Atlantic climate variability revealed by sea-level observations. AB - Decadal variability is a notable feature of the Atlantic Ocean and the climate of the regions it influences. Prominently, this is manifested in the Atlantic Multidecadal Oscillation (AMO) in sea surface temperatures. Positive (negative) phases of the AMO coincide with warmer (colder) North Atlantic sea surface temperatures. The AMO is linked with decadal climate fluctuations, such as Indian and Sahel rainfall, European summer precipitation, Atlantic hurricanes and variations in global temperatures. It is widely believed that ocean circulation drives the phase changes of the AMO by controlling ocean heat content. However, there are no direct observations of ocean circulation of sufficient length to support this, leading to questions about whether the AMO is controlled from another source. Here we provide observational evidence of the widely hypothesized link between ocean circulation and the AMO. We take a new approach, using sea level along the east coast of the United States to estimate ocean circulation on decadal timescales. We show that ocean circulation responds to the first mode of Atlantic atmospheric forcing, the North Atlantic Oscillation, through circulation changes between the subtropical and subpolar gyres--the intergyre region. These circulation changes affect the decadal evolution of North Atlantic heat content and, consequently, the phases of the AMO. The Atlantic overturning circulation is declining and the AMO is moving to a negative phase. This may offer a brief respite from the persistent rise of global temperatures, but in the coupled system we describe, there are compensating effects. In this case, the negative AMO is associated with a continued acceleration of sea-level rise along the northeast coast of the United States. PMID- 26017455 TI - Making health insurance pro-poor: evidence from a household panel in rural China. AB - BACKGROUND: In 2002, China launched the largest public health insurance scheme in the world, the New Cooperative Medical Scheme (NCMS). It is intended to enable rural populations to access health care services, and to curb medical impoverishment. Whether the scheme can reach its equity goals depends on how it is used, and by whom. Our goal is to shed light on whether and how income levels affect the ability of members to reap insurance benefits. METHODS: We exploit primary panel data consisting of a complete census (over 3500 individuals) in three villages in Puding County, Guizhou province, collected in 2004, 2006, 2009 and 2011. Data was collected during in-person interviews with household member(s). The data include yearly gross and net medical expenses for all individuals, and socio-economic information. We apply probit, ordinary least squares, and tobit multivariate regression analyses to the three waves in which NCMS was active (2006, 2009 and 2011). Explained variables include obtainment, levels and rates of NCMS reimbursement. Household income is the main explanatory variable, with household- and individual-level controls. We restrict samples to rule out self-selection, and exploit the 2009 NCMS reform to highlight equity enhancing features of insurance. RESULTS: Prior to 2009 reforms, higher income in our sample was statistically significantly related to higher probability of obtaining reimbursement, as well as higher levels and rates of reimbursement. These relations all disappear after the reform, suggesting lower-income households were better able to reap insurance benefits after the scheme was reformed. Regression results suggest this is partly explained by reimbursement for chronic diseases. CONCLUSIONS: The post-reform NCMS distributed benefits more equitably in our study area. Making health insurance pro-poor may require a focus on outpatient costs, credit constraints and chronic diseases, rather than catastrophic illnesses. PMID- 26017456 TI - Two Unusual but Treatable Causes of Refractory Ascites After Liver Transplantation. AB - Refractory ascites (RA) is thought to complicate the postoperative course of 5-7% (Nishida et al. in Am J Transplant. 6: 140-149, 2006; Gotthardt et al. in Ann Transplant. 18: 378-383, 2013) of liver transplant recipients. RA after liver transplantation is often a frustrating diagnostic dilemma with few good management options unless an obvious mechanical factor is identified. Supportive therapies often fail until a treatable precipitating cause is identified and removed. We describe two patients who developed RA following liver transplantation for primary sclerosing cholangitis, and hepatitis C and alcoholic liver disease, respectively. The cause for RA was hyperkinetic portal hypertension secondary to splenomegaly in the first case and a pancreatic AVM in the 2nd case. After failure of other interventions, surgical splenectomy resulted in immediate and durable resolution of the previously intractable ascites. PMID- 26017449 TI - Whole-genome characterization of chemoresistant ovarian cancer. AB - Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1. PMID- 26017457 TI - The genetics of East African populations: a Nilo-Saharan component in the African genetic landscape. AB - East Africa is a strategic region to study human genetic diversity due to the presence of ethnically, linguistically, and geographically diverse populations. Here, we provide new insight into the genetic history of populations living in the Sudanese region of East Africa by analysing nine ethnic groups belonging to three African linguistic families: Niger-Kordofanian, Nilo-Saharan and Afro Asiatic. A total of 500 individuals were genotyped for 200,000 single-nucleotide polymorphisms. Principal component analysis, clustering analysis using ADMIXTURE, FST statistics, and the three-population test were used to investigate the underlying genetic structure and ancestry of the different ethno-linguistic groups. Our analyses revealed a genetic component for Sudanese Nilo-Saharan speaking groups (Darfurians and part of Nuba populations) related to Nilotes of South Sudan, but not to other Sudanese populations or other sub-Saharan populations. Populations inhabiting the North of the region showed close genetic affinities with North Africa, with a component that could be remnant of North Africans before the migrations of Arabs from Arabia. In addition, we found very low genetic distances between populations in genes important for anti-malarial and anti-bacterial host defence, suggesting similar selective pressures on these genes and stressing the importance of considering functional pathways to understand the evolutionary history of populations. PMID- 26017458 TI - Nephrogenic Systemic Fibrosis Manifesting a Decade After Exposure to Gadolinium. AB - IMPORTANCE: Nephrogenic systemic fibrosis (NSF) is a fibrosing skin disorder that develops in patients with kidney failure and has been linked to exposure to gadolinium-containing contrast agents. The time between exposure to gadolinium and the initial presentation of NSF is typically weeks to months but has been documented to be as long as 31/2 years. We report a case of NSF developing 10 years after exposure to gadolinium. OBSERVATIONS: A long-term hemodialysis patient was exposed to gadolinium several times between 1998 and 2004 during magnetic resonance angiography of his abdominal vessels and arteriovenous fistula. In 2014, he was seen at our clinic with new dermal papules and plaques. Biopsy of affected skin showed thickening of collagen, CD34+ spindle cells, and increased mucin in the dermis, supporting the diagnosis of NSF. CONCLUSIONS AND RELEVANCE: The clinical history and histopathological features of this case support the diagnosis of NSF 10 years after exposure to gadolinium. Although the use of gadolinium contrast agents in patients with kidney failure has markedly decreased, patients with exposure to gadolinium years to decades previously may manifest the disease. PMID- 26017459 TI - Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation. AB - BACKGROUND: It is unclear whether there is a causative relationship between the development of metabolic syndrome (MS) and increased risk of early cardiovascular morbidity in patients receiving hematopoietic stem cell transplantation (HSCT) during childhood. Early identification of risk factors associated with insulin resistance, MS, and abnormal glucose tolerance during childhood or adolescence in these patients could represent a useful tool for preventing cardiovascular disorders. PROCEDURE: In a single-center, prospective, descriptive, cross sectional study, we studied 45 survivors of hematological malignancies (age: 13.9 +/- 4.8 years) treated with HSCT before the age of 18 years and 90 matched healthy controls. We collected clinical, imaging, and laboratory data including oral glucose tolerance test (OGTT). RESULTS: 7/45 patients (15.6%) showed abnormal glucose tolerance at OGTT, 1/45 (2.2%) was obese, and none fulfilled the criteria for MS. A waist/height ratio >0.5 was associated with patients with abnormal glucose tolerance (85.7% of cases), compared to patients with normal glucose tolerance (42.1%) and controls (23.3%). In patients with abnormal glucose tolerance, use of total body irradiation (TBI) as conditioning regimen was more common, and time elapsed from HSCT was longer. CONCLUSIONS: Patients treated with HSCT may develop insulin resistance early after transplantation. They do not show overt obesity, but have redistribution of fat tissue with central fat accumulation. The main factors associated with increased metabolic risk are TBI and time from HSCT. Evaluation of MS and glucose tolerance should be part of hormonal follow-up, which should be routinely proposed to these patients. PMID- 26017460 TI - Enrichment assessment of multiple virtual screening strategies for Toll-like receptor 8 agonists based on a maximal unbiased benchmarking data set. AB - Toll-like receptor 8 agonists, which activate adaptive immune responses by inducing robust production of T-helper 1-polarizing cytokines, are promising candidates for vaccine adjuvants. As the binding site of toll-like receptor 8 is large and highly flexible, virtual screening by individual method has inevitable limitations; thus, a comprehensive comparison of different methods may provide insights into seeking effective strategy for the discovery of novel toll-like receptor 8 agonists. In this study, the performance of knowledge-based pharmacophore, shape-based 3D screening, and combined strategies was assessed against a maximum unbiased benchmarking data set containing 13 actives and 1302 decoys specialized for toll-like receptor 8 agonists. Prior structure-activity relationship knowledge was involved in knowledge-based pharmacophore generation, and a set of antagonists was innovatively used to verify the selectivity of the selected knowledge-based pharmacophore. The benchmarking data set was generated from our recently developed 'mubd-decoymaker' protocol. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore (Phar1) screening, shape-based 3D similarity search (Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists. PMID- 26017461 TI - Tailoring of optical properties of fluorescein using green synthesized gold nanoparticles. AB - Dye-nanoparticle mixtures hold great promise in biological as well as photonics applications due to their capability to tailor the emission behavior of dye by tuning the nanoparticles parameters. However, as compared to the well-defined dye nanoparticle distance, studies lack the understanding of homogenous mixtures of dye and nanoparticles. In this work, we investigate the influence of shape and concentration of gold nanoparticles prepared via green synthesis on the optical properties of fluorescein dye in a dye-nanoparticle mixture. We have investigated the radiative path of deexcitation using steady state fluorescence and the non radiative path is probed using a laser based dual-beam thermal lens technique. The energy transfer efficiency as well as dye-nanoparticle distance is studied using both techniques. Furthermore, we have explored the influence of nanoparticles parameters on the fluorescence quantum yield of fluorescein using the thermal lens technique. The studies indicate that spherical nanoparticles are efficient quenchers while star shaped nanoparticles can probe larger dye-NP distances. The tailoring of dye properties by tuning nanoparticle parameters can be utilized in diverse areas including bioimaging, solar cells, and sensors. PMID- 26017462 TI - ADPRtool: A novel predicting model for identification of ASP-ADP-Ribosylation sites of human proteins. AB - Post-translational modifications (PTMs) occur in the vast majority of proteins, and they are essential for many protein functions. Computational prediction of the residue location of PTMs enhances the functional characterization of proteins. ADP-Ribosylation is an important type of PTM, because it is implicated in apoptosis, DNA repair, regulation of cell proliferation, and protein synthesis. However, mass spectrometric approaches have difficulties in identifying a vast number of protein ADP-Ribosylation sites. Therefore, a computational method for predicting ADP-Ribosylation sites of human proteins seems useful and necessary. Four types of sequence features and an incremental feature selection technique are utilized to predict protein ADP-Ribosylation sites. The final feature set for ADPR prediction modeling is optimized, based on a minimum redundancy maximum relevance criterion, so as to make more accurate predictions on aspartic acid ADPR modified residues. Our prediction model, ADPRtool, is capable to predict Asp-ADP-Ribosylation sites with a total accuracy of 85.45%, which is as good as most computational PTM site predictors. By using a sequence-based computational method, a new ADP-Ribosylation site prediction model - ADPRtool, is developed, and it has shown great accuracies with total accuracy, Matthew's correlation coefficient and area under receiver operating characteristic curve. PMID- 26017463 TI - A new approach to human microRNA target prediction using ensemble pruning and rotation forest. AB - MicroRNAs (miRNAs) are small non-coding RNAs that have important functions in gene regulation. Since finding miRNA target experimentally is costly and needs spending much time, the use of machine learning methods is a growing research area for miRNA target prediction. In this paper, a new approach is proposed by using two popular ensemble strategies, i.e. Ensemble Pruning and Rotation Forest (EP-RTF), to predict human miRNA target. For EP, the approach utilizes Genetic Algorithm (GA). In other words, a subset of classifiers from the heterogeneous ensemble is first selected by GA. Next, the selected classifiers are trained based on the RTF method and then are combined using weighted majority voting. In addition to seeking a better subset of classifiers, the parameter of RTF is also optimized by GA. Findings of the present study confirm that the newly developed EP-RTF outperforms (in terms of classification accuracy, sensitivity, and specificity) the previously applied methods over four datasets in the field of human miRNA target. Diversity-error diagrams reveal that the proposed ensemble approach constructs individual classifiers which are more accurate and usually diverse than the other ensemble approaches. Given these experimental results, we highly recommend EP-RTF for improving the performance of miRNA target prediction. PMID- 26017464 TI - The omics era of Fusarium graminearum: opportunities and challenges. PMID- 26017465 TI - A survey of the causes of cattle organs and/or carcass condemnation, financial losses and magnitude of foetal wastage at an abattoir in Dodoma, Tanzania. AB - Slaughterhouses provide a safeguard that prevents the public from consuming meat of poor quality or meat which may be infected with zoonotic diseases. This work reviews a 3-year database of cattle that were slaughtered and inspected between 2010 and 2012 at Dodoma abattoir, Tanzania. In addition, meat inspection was undertaken for 1 month (December 2013). The aim of this study was to establish causes of organ and carcass condemnations and their financial implications as well as the magnitude of slaughter of pregnant cows at Dodoma abattoir. During retrospective study, it was found that a total of 9015 (10.5%) lungs, 6276 (7.3%) intestines, 5402 (6.3%) livers, 3291 (3.8%) kidneys and 41 (0.05%) carcasses were condemned. Pulmonary emphysema (3.4%), fasciolosis (4.5%), pimply gut (5.7%), kidney congenital cysts (1.9%) and hydatidosis (3.1%) were major causes of organ condemnations. This large number of condemned edible organs and/or carcasses implies that public health considerations result in deprivation of valuable protein. Occurrence of hydatidosis, cysticercosis, fasciolosis and tuberculosis illustrates the possible public health problem and presence of environmental infections. Of the 794 cows slaughtered in December 2013, 46% were pregnant. Financial loss as a result of organ and/or carcass condemnations was estimated at $9892. Condemnation of organs and/or carcasses and indiscriminate slaughter of pregnant cows represent a significant loss of meat and revenue and a reduction in growth of future herds, which has a negative effect on the livestock industry. This justifies appropriate surveillance and disease control programmes coupled with strict enforcement of legislation governing animal welfare to curb the slaughter of pregnant animals. PMID- 26017466 TI - Is one month treatment with dabigatran before cardioversion of atrial fibrillation sufficient to prevent thromboembolism? AB - AIMS: The use of direct oral anticoagulants (DOACs) in patients undergoing elective direct current (DC) cardioversion of non-acute atrial fibrillation (AF) can potentially shorten the time from initiation of anticoagulation treatment to cardioversion, compared with warfarin. The safety of this strategy needs to be investigated. Data from subgroup analysis from clinical trials with DOAC do not clarify whether 4-week treatment with DOAC is sufficient to prevent thromboembolism (TE) after cardioversion. The aim of this retrospective study was to assess the incidence of TE in anticoagulant naive patients converted after one month's pre-treatment with dabigatran. METHODS AND RESULTS: We scrutinized the medical records of 631 patients where dabigatran had been used prior to elective DC cardioversion. Transoesophageal echocardiography was rarely performed. Thromboembolism within 30 days of cardioversion was the primary endpoint. A total of 570 patients were naive to OAC when dabigatran was initiated. The mean age in this group was 64.2 +/- 11 years and 31.7% were women. The mean CHA2DS2-VASc score was 2.0 +/- 1.5. The dose of dabigatran was 150 mg b.i.d. in 94% of the patients. The median time from initiation of dabigatran to cardioversion was 32.0 +/- 15 days. In 91% cardioversion resulted in sinus rhythm. During the 30-day follow-up, three TE occurred for an incidence of 0.53% (0.18-1.54). CONCLUSION: In this retrospective study from clinical material, we found a low incidence of TE when dabigatran was used as TE prophylaxis in association with elective cardioversion. These results indicate that dabigatran is a safe alternative strategy to warfarin during cardioversion in patients with AF. PMID- 26017467 TI - Can we rely on machines? Device-detected atrial high rates correspond well with atrial arrhythmias in cardiac resynchronization recipients. AB - AIMS: The aim of the study was to verify in what proportion of patients, device detected atrial high rate (AHR) episodes are indeed atrial arrhythmias (AAs). We investigated also the reasons for inappropriate arrhythmia classification and assessed if patients with misdiagnosed arrhythmias have distinct characteristics that would help to identify them. METHODS AND RESULTS: The study population consisted of 304 consecutive patients implanted with cardiac resynchronization therapy defibrillators (CRT-Ds) and subsequently monitored via remote monitoring for a median follow-up (FU) of 30.5 months. Intracardiac electrograms of every recorded AHR episode were assessed and classified (AA vs. no AA) by two experienced cardiologists. During FU, 14 386 episodes of AHR were recorded and classified in 176 (57.9%) patients. In 89.2% of them, these episodes were true AA (94% atrial fibrillation, 62% de novo). The reasons for AHR misdiagnosis were atrial far-field signals (89.5%) and noise (10.5%). The mean per cent of day spent in AHR (54.9 vs. 5.86%; P < 0.001) and the occurrence of periods with low CRT pacing (82.8 vs. 55%; P = 0.003) were significantly higher in AA subjects than in those with misdiagnosed AHR. Episode duration of properly detected AHRs was longer than that of misdiagnosed AHRs. Higher per cent of time spent in AHR was an independent marker of appropriate arrhythmia detection [adjusted hazard ratio (HR) 1.04; P = 0.023]. CONCLUSION: Nearly two-thirds of CRT-D patients had AHR episodes within 2.5 years after implantation. Almost 90% of AHRs were indeed AA. Misdetections were caused by far-field sensing or noise. A two-step diagnostic algorithm (>9% of time spent in AHRs and episode duration >36 s) allowed for proper detection of AA with a high hit-rate and specificity. PMID- 26017468 TI - Prevalence of auricular thrombosis before atrial flutter cardioversion: a 17-year transoesophageal echocardiographic study. AB - AIMS: Prevalence of left appendage thrombosis ranges from 6 to 18% in persistent atrial fibrillation (AF). Few and low sample size studies have assessed left and right atrial thrombosis in persistent atrial flutter (AFL) and a wide variety of frequencies, from 1 to 21%, has been reported. The aim of this study was to evaluate the prevalence of atrial appendage thrombosis in a large population of patients undergoing transoesophageal echocardiography (TEE)-guided cardioversion (CV) for recent AFL onset and compare it with AF. METHODS AND RESULTS: From 1999 to September 2014, we collected data of 1081 patients to CV: 877 affected by AF (81.1%) and 204 by AFL (18.9%). The presence of auricular thrombosis was evaluated by TEE in AF or AFL persisting for more than 48 h. The presence of appendage thrombosis, Doppler emptying velocities, and severe spontaneous echo contrast (SEC) was studied. The overall prevalence of atrial thrombosis was 9.62% (104/1081). Frequency of atrial thrombosis in AFL patients was 6.4% (13/204) vs. 10.5% among AF (92/877), P = 0.074. Comparing the two appendages, frequency of left atrial appendage thrombosis was in AFL 5.9% (12/204) vs. 9.9% (87/877) in the AF group, P = 0.07. Right atrial appendage thrombosis was present in 0.5% (1/204) in the AFL group vs. 0.8% (7/877) in the AF group, P = 0.64. Moderate to severe SEC (3+/4+) was present in 28% of AFL patients (57/204) vs. 35% of AF patients (307/877), P = 0.05. CONCLUSION: Auricular thrombosis is not an infrequent finding in AFL before CV. Our study suggests the use of TEE screening in AFL, as well as in AF, when patients arrive to clinical attention after more than 48 h from arrhythmia onset. PMID- 26017469 TI - Mid-term clinical and echocardiographic evaluation of super responders with and without pacing: the preliminary results of a prospective, randomized, single centre study. AB - AIMS: Super response to cardiac resynchronization therapy (CRT) is related to excellent long-term prognosis. However, it is not known whether super responders (SRs) are in remission or have made a complete recovery. In other words, is CRT a destination therapy or a bridge to recovery? The objective was to assess the evolution of the clinical and echocardiographic data of SRs without pacemaker activity at the mid-term follow-up. METHODS AND RESULTS: A total of 19 SRs were randomly assigned to a deactivated pacemaker function (Off-Pace group) or a continued pacemaker activity (On-Pace group). Clinical and echocardiographic parameters were evaluated before implantation, at randomization, and after 6 and 12 months of this randomization. Patients assigned to the Off-Pace group deteriorated in terms of the New York Heart Association class (from 1.3 +/- 0.5 to 2.4 +/- 0.7), 6-min walk distance (from 569 +/- 68 to 343 +/- 162 m), and echocardiographic data, including left ventricular ejection fraction (from 55 +/- 3 to 36 +/- 12%), left ventricular end-systolic volume (from 61 +/- 10 to 117 +/- 36 mL), left ventricular end-diastolic diameter (from 53 +/- 3 to 61 +/- 6 mm), and left ventricular end-systolic diameter (from 40 +/- 3 to 53 +/- 8 mm) at 12 months, whereas no change was observed in the On-Pace group. Turning off the pacemaker function was also related to hospitalization for heart failure and appropriate cardioverter-defibrillator device intervention. CONCLUSION: Super responders without pacing had poor clinical and echocardiographic outcomes at the mid-term follow-up. PMID- 26017470 TI - Interpretation of discrete potential in idiopathic outflow tract ventricular arrhythmia: more consideration. PMID- 26017471 TI - Relationship of the Dental Aesthetic Index to the oral health-related quality of life. AB - OBJECTIVE: To assess the impact of malocclusion on the quality of life. MATERIALS AND METHODS: This cross-sectional study involved 150 subjects attending the Primary Care Unit with no history of orthodontic treatment. The Dental Aesthetic Index (DAI) with 10 occlusal characteristics were measured on study models. Oral health-related quality of life (OHRQoL) was assessed with the Malaysian version of the Oral Health Impact Profile questionnaire (OHIP-14). The Spearman rank order correlation coefficient was used to evaluate the relationship between the malocclusion and quality of life. RESULTS: Significantly weak correlations (r = .176) were found between the DAI and the OHRQoL. Females and the younger age group (12-19 years) tended to score higher on the OHIP-14 than their counterparts. For males, domain 3 (psychological discomfort; r = .462), domain 4 (physical disability; r = .312), domain 7 (handicap; r = .309), and overall score (r = .289) were weak correlates but significant to the DAI compared with females. The older age group showed a significant weak correlation in domain 3 (psychological discomfort; r = .268) and domain 7 (handicap; r = .238), whereas the younger age group showed no correlation with any domain. CONCLUSIONS: The DAI score does not predict the effect of malocclusion on the OHRQoL. PMID- 26017472 TI - Phenotypic differentiation in love song traits among sibling species of the Lutzomyia longipalpis complex in Brazil. AB - BACKGROUND: Brazilian populations of Lutzomyia longipalpis may constitute a complex of cryptic species, and this report investigates the distribution and number of potential sibling species. One of the main differences observed among Brazilian populations is the type of acoustic signal produced by males during copulation. These copulation song differences seem to be evolving faster than neutral molecular markers and have been suggested to contribute to insemination failure observed in crosses between these sibling species. In previous studies, two main types of copulation songs were found, burst-type and pulse-type. The latter type can, in turn, be further subdivided into five different patterns. METHODS: We recorded male song from 13 new populations of the L. longipalpis complex from Brazil and compared the songs with 12 already available. RESULTS: Out of these 25 populations, 16 produce burst-type and 9 produce pulse-type songs. We performed a principal component analysis in these two main groups separately and an additional discriminant analysis in the pulse-type group. The pulse-type populations showed a clear separation between the five known patterns with a high correspondence of individuals to their correct group, confirming the differentiation between them. The distinctiveness of the burst-type subgroups was much lower than that observed among the pulse-type groups and no clear population structure was observed. This suggests that the burst-type populations represent a single species. CONCLUSION: Overall, our results are consistent with the existence in Brazil of at least six species of the L. longipalpis complex, one with a wide distribution comprising all the populations with burst-type songs, and five more closely related allopatric siblings with different pulse-type song patterns and more restricted distribution ranges. PMID- 26017473 TI - Sanguinarine inhibits angiotensin II-induced apoptosis in H9c2 cardiac cells via restoring reactive oxygen species-mediated decreases in the mitochondrial membrane potential. AB - Cell apoptosis induced by Angiotensin II (Ang II) has a critical role in the development of cardiovascular diseases. The aim of the present study was to investigate whether sanguinarine (SAN), a drug which was proved to have anti oxidant, anti-proliferative and immune enhancing effects, can abolish cell apoptosis induced by Ang II. In the present study, H9c2 cardiac cells were stimulated with 10 uM Ang II with or without SAN. The level of intracellular reactive oxygen species (ROS) generation was assessed using dichlorodihydrofluorescein diacetate, and changes of the mitochondrial membrane potential (MMP) were assessed using JC-1 staining. Furthermore, mRNA expression of NOX2 was determined by reverse transcription quantitative polymerase chain reaction, and apoptosis was detected by Annexin V/propidium iodide staining and flow cytometry. The expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) as well as cleaved (c)-caspase 3 and -9 were detected by western blot analysis, and the activity of caspase 3 and -9 was detected using an ELISA. The results of the present study showed that NOX2 expression and ROS generation induced by Ang II were inhibited by SAN, and the Ang 2-induced MMP loss was also ameliorated. Furthermore, Ang II-induced H9c2 cardiac cell apoptosis as well as c caspase 3 and -9 levels were significantly reduced by SAN. Investigation of the possible pathway involved in the anti-apoptotic effect of SAN showed that the expression of Bcl-2 was decreased, while that of Bax was increased following stimulation with Ang II, which was reversed following treatment with SAN. In addition, Ang II enhanced the activity of caspase 9 and cleaved downstream caspases such as caspase-3, initiating the caspase cascade, while pre-treatment of H9c2 cardiac cells with SAN blocked these effects. In conclusion, the findings of the present study indicated that SAN inhibits the apoptosis of H9c2 cardiac cells induced by Ang II, most likely via restoring ROS-mediated decreases of the MMP. PMID- 26017475 TI - Windows of opportunity for setting the critical path for healthy growth. PMID- 26017474 TI - Interactive Effect of Child Maltreatment and Substance Use on Depressed Mood Among Adolescents Presenting to Community-Based Substance Use Treatment. AB - Adolescents referred to community behavioral health centers (CBHC) for substance use (SU) problems report high rates of child maltreatment. Although SU and maltreatment are independent risk factors for adolescent depression, few studies have examined their interactive effects. This study examined the interactive effects of SU (alcohol and marijuana) and exposure to different types of trauma on depressed mood among 74 adolescents referred to a CBHC for SU. Hierarchical regressions controlling for sex and common adolescent comorbidities showed that sexual abuse had a stronger relationship with depressed mood than other types of maltreatment. Although SU was not independently related to depressed mood, consistent with the self-medication hypothesis, increased SU was associated with lower levels of depressed mood among adolescents with greater exposure to sexual abuse. Results suggest that teens presenting to CBHCs for SU should be assessed for multiple forms of maltreatment and for depressed mood. PMID- 26017476 TI - Stunting at birth: recognition of early-life linear growth failure in the western highlands of Guatemala. AB - OBJECTIVE: Measurements of length at birth, or in the neonatal period, are challenging to obtain and often discounted for lack of validity. Hence, classical 'under-5' stunting rates have been derived from surveys on children from 6 to 59 months of age. Guatemala has a high prevalence of stunting (49.8%), but the age of onset of growth failure is not clearly defined. The objective of the study was to assess length-for-age within the first 1.5 months of life among Guatemalan infants. DESIGN: As part of a cross-sectional observational study, supine length was measured in young infants. Mothers' height was measured. Length-for-age Z scores (HAZ) were generated and stunting was defined as HAZ <-2 using WHO growth standards. SETTING: Eight rural, indigenous Mam-Mayan villages (n 200, 100% of Mayan indigenous origin) and an urban clinic of Quetzaltenango (n 106, 27% of Mayan indigenous origin), Guatemala. SUBJECTS: Three hundred and six newborns with a median age of 19 d. RESULTS: The median rural HAZ was -1.56 and prevalence of stunting was 38%; the respective urban values were -1.41 and 25%. Linear regression revealed no relationship between infant age and HAZ (r = 0.101, r(2) = 0.010, P = 0.077). Maternal height explained 3% of the variability in HAZ (r = 0.171, r(2) = 0.029, P = 0.003). CONCLUSIONS: Stunting must be carried over from in utero growth retardation in short-stature Guatemalan mothers. As linear growth failure in this setting begins in utero, its prevention must be linked to maternal care strategies during gestation, or even before. A focus on maternal nutrition and health in an intergenerational dimension is needed to reduce its prevalence. PMID- 26017477 TI - Barriers to access for severe acute malnutrition treatment services in Pakistan and Ethiopia: a comparative qualitative analysis. AB - OBJECTIVE: To understand and compare the primary barriers households face when accessing treatment for cases of childhood severe acute malnutrition (SAM) in different cultural settings with different types of implementing agencies. DESIGN: The study presents a comparative qualitative analysis of two SAM treatment services, selected to include: (i) one programme implemented by a non governmental organization and one by a Ministry of Health; and (ii) programmes considered to be successful, defined as either coverage level achieved or extent of integration within government infrastructure. Results from individual interviews and group discussions were recorded and analysed for themes in barriers to access. SETTING: Sindh Province, Pakistan; Tigray Region, Ethiopia. SUBJECTS: Beneficiary communities and staff of SAM treatment services in two countries. RESULTS: Common barriers were related to distance, high opportunity costs, knowledge of services, knowledge of malnutrition and child's refusal of ready-to-use foods. While community sensitization mechanisms were generally strong in these well-performing programmes, in remote areas with less programme exposure, beneficiaries experienced barriers to remaining in the programme until their children recovered. CONCLUSIONS: Households experienced a number of barriers when accessing SAM treatment services. Integration of SAM treatment with other community-based interventions, as the UN recommends, can improve access to life-saving services. Efforts to integrate SAM treatment into national health systems should not neglect the community component of health systems and dedicated funding for the community component is needed to ensure access. Further research and policy efforts should investigate feasible mechanisms to effectively reduce barriers to access and ensure equitable service delivery. PMID- 26017478 TI - MicroRNA-19a and CD22 Comprise a Feedback Loop for B Cell Response in Sepsis. AB - BACKGROUND: MicroRNA-19a (miR-19a), an oncogenic microRNA, has been recently reported to target CD22 in B cell lymphoma cell lines, but its role in inflammatory response is unclear. CD22 is a negative regulator for BCR signaling, and we hypothesize that miR-19a regulates B cell response by targeting CD22 in sepsis. MATERIAL AND METHODS: In order to determine whether miR-19a-CD22 pathway was involved in sepsis, and what role it played in the regulatory mechanisms, we detected the levels of miR-19a in B cells obtained from patients with sepsis, and measured the levels of miR-19a and CD22 expression in B cells activated by LPS in vitro. Additionally, we investigated the correlation between miR-19a and CD22, as well as the influence of this pathway on BCR signaling, in transfected B cells. RESULTS: We found that septic patients displayed up-regulated miR-19a in B cells. In vitro, miR-19a was increased in activated B cells, with CD22 expression initially enhanced but subsequently decreased. Moreover, overexpression of miR 19a resulted in an amplified BCR signaling, while overexpression of CD22 attenuated the effect of miR-19a and increased its expression. CONCLUSIONS: Our study demonstrated that miR-19a and CD22 comprised a feedback loop for B cell response in sepsis, providing a potential therapeutic target to recover the immune homeostasis. PMID- 26017479 TI - Medications and Breastfeeding for Mothers With Chronic Illness. AB - Mothers with chronic illnesses are often discouraged from breastfeeding by health care professionals, most often because of use of medication and fear of adverse effects in the infant. Most medications taken by mothers are not contraindicated for breastfeeding. Understanding factors that affect transfer of medications into human milk can help providers give appropriate guidance to mothers with chronic illnesses who want to breastfeed. PMID- 26017480 TI - Enzymatic Menthol Production: One-Pot Approach Using Engineered Escherichia coli. AB - Menthol isomers are high-value monoterpenoid commodity chemicals, produced naturally by mint plants, Mentha spp. Alternative clean biosynthetic routes to these compounds are commercially attractive. Optimization strategies for biocatalytic terpenoid production are mainly focused on metabolic engineering of the biosynthesis pathway within an expression host. We circumvent this bottleneck by combining pathway assembly techniques with classical biocatalysis methods to engineer and optimize cell-free one-pot biotransformation systems and apply this strategy to the mint biosynthesis pathway. Our approach allows optimization of each pathway enzyme and avoidance of monoterpenoid toxicity issues to the host cell. We have developed a one-pot (bio)synthesis of (1R,2S,5R)-(-)-menthol and (1S,2S,5R)-(+)-neomenthol from pulegone, using recombinant Escherichia coli extracts containing the biosynthetic genes for an "ene"-reductase (NtDBR from Nicotiana tabacum) and two menthone dehydrogenases (MMR and MNMR from Mentha piperita). Our modular engineering strategy allowed each step to be optimized to improve the final production level. Moderate to highly pure menthol (79.1%) and neomenthol (89.9%) were obtained when E. coli strains coexpressed NtDBR with only MMR or MNMR, respectively. This one-pot biocatalytic method allows easier optimization of each enzymatic step and easier modular combination of reactions to ultimately generate libraries of pure compounds for use in high-throughput screening. It will be, therefore, a valuable addition to the arsenal of biocatalysis strategies, especially when applied for (semi)-toxic chemical compounds. PMID- 26017481 TI - A Model to Predict the Feasibility of Concurrent Chemoradiotherapy With Temozolomide in Glioblastoma Multiforme Patients Over Age 65. AB - OBJECTIVES: It is controversial whether concurrent chemoradiotherapy (CRT) with temozolomide is feasible and beneficial in elderly patients with glioblastoma. MATERIALS AND METHODS: Retrospective analysis of 74 elderly glioblastoma patients (65 y and above) treated with concurrent CRT with temozolomide. Factors influencing prognosis and feasibility of CRT were investigated. RESULTS: The median overall survival was 11.3 months. Univariate analysis showed a significant difference in median overall survival for cumulative dose of concurrent temozolomide (optimal cutoff, 2655 mg/m; 13.9 mo for >2655 mg/m vs. 4.9 mo for <=2655 mg/m; P=0.0216, adjusted for multiple testing). Furthermore, cumulative dose of concurrent temozolomide >2655 mg/m was a significant independent prognostic parameter in multivariate analysis (hazard ratio, 0.33; P=0.002). Hematotoxicity was the most common cause of treatment interruption or discontinuation in patients with an insufficient cumulative temozolomide dose. Prognostic factors for successful performance of CRT with a cumulative dose of concurrent temozolomide >2655 mg/m were female sex (odds ratio [OR], 0.174; P=0.006), age (OR, 0.826 per year; P=0.017), and pretreatment platelet count (OR, 1.013 per 1000 platelets/uL; P=0.001). For easy clinical application of the model an online calculator was developed, which is available at http://www.OldTMZ.com. CONCLUSIONS: The probability of successful performance of concurrent CRT with temozolomide can be estimated based on the patient's age, sex, and pretreatment platelet count using the model developed in this study. Thus, a subgroup of elderly glioblastoma patients suitable for chemoradiation with temozolomide can be identified. PMID- 26017482 TI - Locoregional and Overall Recurrence After Neaodjuvant Endocrine Therapy Versus Chemotherapy in Postmenopausal Women With Estrogen Receptor+ HER2- Breast Cancer. AB - PURPOSE: We report clinical outcomes in patients treated with neoadjuvant endocrine therapy (NET) versus neoadjuvant cytotoxic chemotherapy (NCT) in a cohort of postmenopausal women with ER+, HER2- breast cancer. MATERIALS AND METHODS: We retrospectively reviewed 140 patients treated between May 1998 and September 2010 and collected patient, disease, and treatment characteristics, response to neoadjuvant therapy, and clinical outcome. RESULTS: The median age was 59.5 years. Stage group: stage I 2.2%, stage II 26.8%, stage III 71%, the median tumor size 6 cm (range, 1.5 to 19 cm). Fifty-seven (40.7%) received NET and 83 (59.3%) NCT. One patient (1.8%) in the NET group and 7 (8.4%) in the NCT group had a pathologic complete response (P=0.142). The median follow-up was 48.1 months. Five-year cumulative incidence of locoregional recurrence (LRR) among the entire cohort was 4.1% (95% confidence interval [CI]: 1.5, 8.9), and any recurrence 25.3% (95% CI: 17.6, 33.6). There was no difference in cumulative incidence of LRR or overall recurrence between NET and NCT. On multivariate analysis adjusting for receipt of chemotherapy, presenting stage, and positive lymph nodes, the use of adjuvant radiation therapy was associated with decreased risk of LRR (hazard ratio [HR]=0.24, P=0.035), and ypN2 status with higher risk of LRR (HR=4.91, P=0.032). When the same multivariate model was fitted for any recurrence outcome, only ypN2 status was a significant predictor of overall recurrence (HR=3.02, P=0.005). CONCLUSIONS: We have demonstrated equivalent locoregional and overall outcomes in patients receiving NET versus NCT in a cohort of postmenopausal women with locally advanced ER+HER2-tumors. PMID- 26017483 TI - Dose-Volume Predictors of Esophagitis After Thoracic Stereotactic Body Radiation Therapy. AB - OBJECTIVES: Esophageal toxicity has become a major concern as stereotactic hypofractionated radiation therapy is increasingly utilized for central pulmonary tumors. Our purpose was to define esophageal dosimetric parameters that predict potentially dose-limiting toxicities. MATERIALS AND METHODS: In total, 157 patients with a planning target volume <=5 cm from the esophagus were selected from an institutional database. Toxicity was scored with the CTCAE v4.0. Esophageal Dmax and Dv (dose D in Gy covering volume v in mL) in 0.5 mL increments were collected. Corresponding biologically effective dose (BED) was calculated for alpha/beta=10,3 (BED10, BED3). Normal tissue complication probability was computed with conventionally fractionated radiotherapy parameters and equivalent dose in 2 Gy per fraction (EQD2). Dosimetric predictors were identified with multivariate logistic regression with a manual forward stepwise selection technique. RESULTS: The grade>=2 esophagitis rate was 5.7%. BED10 to 1.5 mL was the best predictor of esophagitis. BED10 to 0.5, 1.0, 2.0, 3.0, and 3.5 mL were also predictive but less strong. Results were similar when BED3 and physical dose were examined. Tumor-esophageal distance correlated with esophagitis (10.5% risk of>=grade 2 events with distance<=3.9 cm vs. 1.3% when>3.9 cm, P=0.016). BED10 to 1.5 mL correlated well with EQD2 normal tissue complication probability estimates. CONCLUSIONS: BED to 1.5 mL was the strongest predictor of grade>=2 esophagitis (independent of alpha/beta ratio) with a 10.6% toxicity risk when BED10>21.1 Gy (14.3 Gy in 3 fractions, 16.0 Gy in 5). The overall rate of severe toxicity is low, suggesting that higher doses may be tolerable. PMID- 26017484 TI - Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. AB - BACKGROUND: We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM). MATERIALS AND METHODS: We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of overall survival (OS), and secondary endpoints of local control, distant intracranial failure, and radiation necrosis were compared using Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazards method. RESULTS: Fifty-four consecutive MBM patients were identified, with 20 (37.0%) receiving ipilimumab within 4 months of SRS. Ipilimumab-treated and non ipilimumab-treated patients had similar baseline characteristics. No difference in symptomatic radiation necrosis or hemorrhage was identified between cohorts. Compared with patients in the nonipilimumab group, 1 year local control (71.4% vs. 92.3%, P=0.40) and intracranial control (12.7% vs. 29.1%, P=0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs. 38.5%, P=0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these difference were not statistically significant. Univariate analysis and multivariate analysis both confirmed single brain metastasis, controlled primary, and active systemic disease as predictors for OS. CONCLUSIONS: Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, our retrospective institutional experience with this treatment regimen was not associated with improved outcomes. PMID- 26017486 TI - Substandard Sanitation in Hospital Canteens Poses Problems in Developing Countries. PMID- 26017487 TI - Knowledge of dental caries and salivary factors related to the disease: influence of the teaching-learning process. AB - Knowledge of factors related to caries and the possible consequences in controlling the disease may show the use of education as a relevant tool for achieving success in terms of dental health maintenance. Therefore, the aim of the present study was to investigate the relationship between acquired knowledge and salivary factors related to dental caries for freshmen students (n = 44) and trainees (n = 32) of the Piracicaba Dental School. Knowledge about dental caries was evaluated by a discursive questionnaire analyzed by the content analysis technique. Salivary flow and pH, buffer capacity, salivary sucrase activity, microbiological counts (total microorganisms, mutans, and lactobacilli) and inorganic concentration of calcium, phosphorus, and fluoride in saliva were evaluated and compared between groups using the Mann-Whitney test, with a significance of 5%. Trainees demonstrated knowledge of the disease, whereas freshmen showed unspecific and confusing concepts. Among the factors analyzed, statistically significant differences were observed for pH, buffer capacity, sucrase activity, total microorganisms, and calcium and fluoride concentrations in saliva. Knowledge about the disease increases and improves over time during the undergraduate program (highest among trainees); although the students from the final year of the program consume more sugar than those from the previous one, they try to balance this activity with greater exposure to fluorides. PMID- 26017488 TI - Analysis of the reproducibility of the gray values and noise of a direct digital radiography system. AB - The aim of this study was to evaluate the reproducibility of the gray values and noise of a direct digital radiography system (Visualix eHD) for various exposure times and analyzed regions. To obtain radiographic images in a standardized manner, the digital sensor of the system and a stepwedge were positioned in a phantom at a focus-film distance of 30 cm in a dental device at 70 kV, 7 mA and 2.2 mm filtration. Ten consecutive repetitions of X-ray imaging were performed at each exposure time (0.05, 0.07, 0.09 and 0.13 s). Gray values were analyzed using ImageJ software in five regions of interest (ROIs): alveolar bone (AB), soft tissue (ST) and three steps of the stepwedge (S1, S2 and S3). The results showed that both the variability of the gray values and the noise were statistically greater (p < 0.05) in the most radiolucent region (ST). Only the noise was affected by the exposure time. In conclusion, the reproducibility of the gray values and the noise of the Visualix eHD system can vary in specific areas with different radiolucency. PMID- 26017489 TI - Association between temporomandibular disorders and abnormal head postures. AB - This study examines the possible correlation between the prevalence of temporomandibular disorders (TMD) and different head postures in the frontal and sagittal planes using photographs of undergraduate students in the School of Dentistry at the Universidade de Brasilia - UnB, Brazil. In this nonrandomized, cross-sectional study, the diagnoses of TMD were made with the Research Diagnostic Criteria (RDC)/TMD axis I. The craniovertebral angle was used to evaluate forward head posture in the sagittal plane, and the interpupillary line was used to measure head tilt in the frontal plane. The measurements to evaluate head posture were made using the Software for the Assessment of Posture (SAPO). Students were divided into two study groups, based on the presence or absence of TMD. The study group comprised 46 students and the control group comprised 80 students. Data about head posture and TMD were analyzed with the Statistical Package for the Social Sciences, version 13. Most cases of TMD were classified as degenerative processes (group III), followed by disk displacement (group II) and muscle disorders (group I). There was no sex predominance for the type of disorder. No association was found between prevalence rates for head postures in the frontal plane and the occurrence of TMD. The same result was found for the association of TMD diagnosis with craniovertebral angle among men and women, and the group that contained both men and women. Abnormal head postures were common among individuals both with and without TMD. No association was found between head posture evaluated in the frontal and sagittal planes and TMD diagnosis with the use of RDC/TMD. PMID- 26017485 TI - First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. AB - Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA. PMID- 26017490 TI - Changes in irradiance and energy density in relation to different curing distances. AB - The present study aimed to assess the influence of curing distance on the loss of irradiance and power density of four curing light devices. The behavior in terms of power density of four different dental curing devices was analyzed (Valo, Elipar 2, Radii-Cal, and Optilux-401) using three different distances of photopolymerization (0 mm, 4 mm, and 8 mm). All devices had their power density measured using a MARC simulator. Ten measurements were made per device at each distance. The total amount of energy delivered and the required curing time to achieve 16 J/cm(2) of energy was also calculated. Data were statistically analyzed with one-way analysis of variance and Tukey's tests (p < 0.05). The curing distance significantly interfered with the loss of power density for all curing light devices, with the farthest distance generating the lowest power density and consequently the longer time to achieve an energy density of 16 J/cm(2) (p < 0.01). Comparison of devices showed that Valo, in extra power mode, showed the best results at all distances, followed by Valo in high power mode, Valo in standard mode, Elipar 2, Radii-Cal, and Optilux-401 halogen lamp (p < 0.01). These findings indicate that all curing lights induced a significant loss of irradiance and total energy when the light was emitted farther from the probe. The Valo device in extra power mode showed the highest power density and the shortest time to achieve an energy density of 16 J/cm(2) at all curing distances. PMID- 26017491 TI - Effects of fludrocortisone on water and sodium intake of C57BL/6 mice. AB - Little is known about steroidal control of thirst- and salt-appetite behaviors of mice. The current study investigates effects of fludrocortisone acetate (FCA), a steroid with potent glucocorticoid and mineralocorticoid effects, on thirst- and salt-appetite responses of C57BL/6 mice. Treatment with FCA produced dose dependent (5, 10, and 25 mg/kg) increases in both magnitude and duration of water and sodium intake. Chronic elevation of water and saline intake was achieved with daily injections of FCA. Daily injection of FCA, when only 0.9% saline was available, produced a remarkably rapid increase in saline intake. A single injection of FCA stimulated brisk diuresis and natriuresis in fluid-restricted animals. This work is the first to demonstrate copious water drinking by mice in response to FCA. The results are discussed in terms of the possibility that the renal effects of FCA promote increases in water and sodium turnover and thereby, increases in water and sodium ingestion. PMID- 26017492 TI - Contrary seasonal changes of rates of nutrient uptake, organ mass, and voluntary food intake in red deer (Cervus elaphus). AB - Northern ungulates acclimatize to winter conditions with restricted food supply and unfavorable weather conditions by reducing energy expenditure and voluntary food intake. We investigated in a study on red deer whether rates of peptide and glucose transport in the small intestines are also reduced during winter as part of the thrifty phenotype of winter-acclimatized animals, or whether transport rates are increased during winter in order to exploit poor forage more efficiently. Our results support the latter hypothesis. We found in a feeding experiment that total energy intake was considerably lower during winter despite ad libitum feeding. Together with reduced food intake, mass of visceral organs was significantly lower and body fat reserves were used as metabolic fuel in addition to food. However, efficacy of nutrient absorption seemed to be increased simultaneously. Extraction of crude protein from forage was higher in winter animals, at any level of crude protein intake, as indicated by the lower concentration of crude protein in feces. In line with these in vivo results, Ussing chamber experiments revealed greater electrogenic responses to both peptides and glucose in the small intestines of winter-acclimatized animals, and peptide uptake into jejunal brush-border membrane vesicles was increased. We conclude that reduced appetite of red deer during winter avoids energy expenditure for unproductive search of scarcely available food and further renders the energetically costly maintenance of a large gut and visceral organs unnecessary. Nevertheless, extraction of nutrients from forage is more efficient in the winter to attenuate an inevitably negative energy balance. PMID- 26017493 TI - The differential role of renoguanylin in osmoregulation and apical Cl-/HCO3- exchange activity in the posterior intestine of the Gulf toadfish (Opsanus beta). AB - The guanylin family of peptides are effective regulators of intestinal physiology in marine teleosts. In the distal intestinal segments, they inhibit or reverse fluid absorption by inhibiting the absorptive short-circuit current (Isc). The present findings demonstrate that mRNA from guanylin and uroguanylin, as well as at least one isoform of the guanylin peptide receptor, apical guanylyl cyclase-C (GC-C), was highly expressed in the intestine and rectum of the Gulf toadfish (Opsanus beta). In the posterior intestine, GC-C, as well as the cystic fibrosis transmembrane conductance regulator and basolateral Na(+)/K(+)/2Cl(-) cotransporter, which comprise a Cl(-)-secretory pathway, were transcriptionally upregulated in 60 parts per thousand (ppt). The present study also shows that, in intestinal tissues from Gulf toadfish held in 35 ppt, renoguanylin (RGN) expectedly causes net Cl(-) secretion, inhibits both the absorptive Isc and fluid absorption, and decreases HCO3(-) secretion. Likewise, in intestinal tissues from Gulf toadfish acclimated to 60 ppt, RGN also inhibits the absorptive Isc and fluid absorption but to an even greater extent, corresponding with the mRNA expression data. In contrast, RGN does not alter Cl(-) flux and, instead, elevates HCO3(-) secretion in the 60-ppt group, suggesting increased apical Cl( )/HCO3(-) exchange activity by SLC26a6. Overall, these findings reinforce the hypotheses that the guanylin peptide system is important for salinity acclimatization and that the secretory response could facilitate the removal of solids, such as CaCO3 precipitates, from the intestine. PMID- 26017494 TI - Anatomical organization of the rat organum vasculosum laminae terminalis. AB - The organum vasculosum of the laminae terminalis (OVLT) is a circumventricular organ located along the ventral part of the anterior wall of the third ventricle. Because it lacks a complete blood-brain barrier (BBB), blood-borne signals detected in the OVLT provide the brain with information from the periphery and contribute to the generation of centrally mediated responses to humoral feedback and physiological stressors. Experimental studies on the rat OVLT are hindered by a poor understanding of its precise anatomical dimensions and cellular organization. In this study, we use histological techniques to characterize the spatial outline of the rat OVLT and to examine the location of neurons, astrocytes, tanycytes, and ependymocytes within its confines. Our data reveal that OVLT neurons are embedded in a dense network of tanycyte processes. Immunostaining against the neuronal marker NeuN revealed that neurons are distributed throughout the OVLT, except for a thick midline septum, which comprises densely packed cells of unknown function or lineage. Moreover, the most ventral aspect of the OVLT is devoid of neurons and is occupied by a dense network of glial cell processes that form a thick layer between the neurons and the pial surface on the ventral aspect of the nucleus. Lastly, combined detection of NeuN and c-Fos protein following systemic injection of hypertonic NaCl revealed that neurons responsive to this stimulus are located along the entire midline core of the OVLT, extending from its most anterior ventral aspect to the more caudally located "dorsal cap" region. PMID- 26017495 TI - Complementary expression and phosphorylation of Cx46 and Cx50 during development and following gene deletion in mouse and in normal and orchitic mink testes. AB - Gap junction-mediated communication helps synchronize interconnected Sertoli cell activities. Besides, coordination of germ cell and Sertoli cell activities depends on gap junction-mediated Sertoli cell-germ cell communication. This report assesses mechanisms underlying the regulation of connexin 46 (Cx46) and Cx50 in mouse testis and those accompanying a "natural" seasonal and a pathological arrest of spermatogenesis, resulting from autoimmune orchitis (AIO) in mink. Furthermore, the impact of deleting Cx46 or Cx50 on the expression, phosphorylation of junction proteins, and spermatogenesis is evaluated. Cx46 mRNA and protein expression increased, whereas Cx50 decreased with adulthood in normal mice and mink. Cx46 mRNA and protein expression increased, whereas Cx50 decreased with adulthood in normal mice and mink. During the mink active spermatogenic phase, Cx50 became phosphorylated and localized to the site of the blood-testis barrier. By contrast, Cx46 was dephosphorylated and associated with annular junctions, suggesting phosphorylation/dephosphorylation of Cx46 and Cx50 involvement in the barrier dynamics. Cx46-positive annular junctions in contact with lipid droplets were found. Cx46 and Cx50 expression and localization were altered in mink with AIO. The deletion of Cx46 or Cx50 impacted on other connexin expression and phosphorylation and differently affected tight and adhering junction protein expression. The level of apoptosis, determined by ELISA, and a number of Apostain-labeled spermatocytes and spermatids/tubules were higher in mice lacking Cx46 (Cx46-/-) than wild-type and Cx50-/- mice, arguing for life sustaining Cx46 gap junction-mediated exchanges in late-stage germ cells secluded from the blood by the barrier. The data show that expression and phosphorylation of Cx46 and Cx50 are complementary in seminiferous tubules. PMID- 26017497 TI - Brief Report: Clinical Course Over Two Years in Patients With Early Nonradiographic Axial Spondyloarthritis and Patients With Ankylosing Spondylitis Not Treated With Tumor Necrosis Factor Blockers: Results From the German Spondyloarthritis Inception Cohort. AB - OBJECTIVE: To investigate the clinical course of disease over 2 years in patients with nonradiographic axial spondylarthritis (SpA) and patients with ankylosing spondylitis (AS). METHODS: The study group comprised 303 patients with axial SpA (158 patients with AS and a symptom duration of <=10 years and 145 patients with nonradiographic axial SpA and a symptom duration of <=5 years) who did not receive tumor necrosis factor (TNF) blockers during 2 years of followup. RESULTS: The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) did not differ between patients with nonradiographic axial SpA and those with AS at any time point during followup. The Bath Ankylosing Spondylitis Functional Index was significantly higher in patients with AS at baseline only, but spinal mobility was generally better in patients with nonradiographic SpA compared with those with AS. At all time points, C-reactive protein (CRP) levels were significantly higher in patients with AS compared with patients with nonradiographic axial SpA. Accordingly, the Ankylosing Spondylitis Disease Activity Score (ASDAS) was significantly higher in the patients with AS at 2 of 4 time points. When patients with a BASDAI score of >=4 plus an elevated CRP level at baseline were analyzed over time, there were no significant differences in the proportions of patients with nonradiographic axial SpA and those with AS who reached low disease activity status at >=2 time points during 2 years of followup when a clinical definition of low disease activity was used (38% and 35%, respectively, achieved a BASDAI score of <4, and 13% and 15%, respectively, achieved a score of <=2). When definitions that included the CRP level were used, however, a greater percentage of patients with nonradiographic axial SpA achieved low disease activity (25% of patients with nonradiographic axial SpA and 10% of patients with AS achieved a BASDAI score of <4 and a normal CRP level, and 13% of patients with nonradiographic axial SpA and 3% of those with AS achieved ASDAS-defined low disease activity). CONCLUSION: Patients with nonradiographic axial SpA and those with AS who were not treated with TNF blockers demonstrated a similar clinical disease course over 2 years. Patients with nonradiographic axial SpA achieved a status of low disease activity more frequently than those with AS if outcome parameters that included the CRP level were used. PMID- 26017498 TI - Association between employee benefits and frailty in community-dwelling older adults. AB - AIM: The phenotype of frailty has been associated with an increased vulnerability for the development of adverse health-related outcomes. The origin of frailty is multifactorial and financial issues could be implicated, as they have been associated with health status, well-being and mortality. However, the association between economic benefits and frailty has been poorly explored. Therefore, the objective was to determine the association between employee benefits and frailty. METHODS: A cross-sectional study of 927 community-dwelling older adults aged 70 years and older participating in the Mexican Study of Nutritional and Psychosocial Markers of Frailty was carried out. Employee benefits were established according to eight characteristics: bonus, profit sharing, pension, health insurance, food stamps, housing credit, life insurance, and Christmas bonus. Frailty was defined according to a slightly modified version of the phenotype proposed by Fried et al. Multinomial logistic regression models were run to determine the association between employee benefits and frailty adjusting by sociodemographic and health covariates. RESULTS: The prevalence of frailty was 14.1%, and 4.4% of participants rated their health status as "poor." Multinomial logistic regression analyses showed that employee benefits were statistically and independently associated with the frail subgroup (OR 0.85; 95% CI 0.74-0.98; P = 0.027) even after adjusting for potential confounders. CONCLUSIONS: Fewer employee benefits are associated with frailty. Supporting spreading employee benefits for older people could have a positive impact on the development of frailty and its consequences. Geriatr Gerontol Int 2016; 16: 606-611. PMID- 26017499 TI - Epstein-Barr virus-related post-transplant lymphoproliferative disorder in the skin. PMID- 26017500 TI - tcR: an R package for T cell receptor repertoire advanced data analysis. AB - BACKGROUND: The Immunoglobulins (IG) and the T cell receptors (TR) play the key role in antigen recognition during the adaptive immune response. Recent progress in next-generation sequencing technologies has provided an opportunity for the deep T cell receptor repertoire profiling. However, a specialised software is required for the rational analysis of massive data generated by next-generation sequencing. RESULTS: Here we introduce tcR, a new R package, representing a platform for the advanced analysis of T cell receptor repertoires, which includes diversity measures, shared T cell receptor sequences identification, gene usage statistics computation and other widely used methods. The tool has proven its utility in recent research studies. CONCLUSIONS: tcR is an R package for the advanced analysis of T cell receptor repertoires after primary TR sequences extraction from raw sequencing reads. The stable version can be directly installed from The Comprehensive R Archive Network ( http://cran.r project.org/mirrors.html ). The source code and development version are available at tcR GitHub ( http://imminfo.github.io/tcr/ ) along with the full documentation and typical usage examples. PMID- 26017501 TI - Burden of migraine: what should we say more? AB - Several international campaigns to increase awareness on the high burden of migraine stimulated population-based studies in the last few years that provided broader data on prevalence, correlates, and impact of migraine. The last version of the Global Burden of Disease 2010 posed migraine with a twofold increase with respect to the previous version as one of the first disabling diseases. Migraine, and in general headache disorders are among the top ten causes of disability because they are common and disabling: that is now clear. It is also clear that the descriptive epidemiology of migraine has reached its maturity. The prevalence rates and sociodemographic correlates have been stable across 50 years. Last but not least, despite international efforts an illness that can be relieved does not, and the heavy burden that it poses at individual and societal levels, persists when it could be mitigated. Describing and accounting the burden of migraine worldwide is not enough anymore, we need to change our paradigm again and move towards new pathways. The opportunity is provided by the biopsychosocial approach that enables to act on the environment once the most adequate medical therapy has been provided. To reduce the burden, international efforts should focus certainly on development of new drugs but mainly on improving health care systems' response to millions of migraine and headache sufferers. PMID- 26017496 TI - Myocardial performance and adaptive energy pathways in a torpid mammalian hibernator. AB - The hearts of mammalian hibernators maintain contractile function in the face of severe environmental stresses during winter heterothermy. To enable survival in torpor, hibernators regulate the expression of numerous genes involved in excitation-contraction coupling, metabolism, and stress response pathways. Understanding the basis of this transition may provide new insights into treatment of human cardiac disease. Few studies have investigated hibernator heart performance during both summer active and winter torpid states, and seasonal comparisons of whole heart function are generally lacking. We investigated the force-frequency relationship and the response to ex vivo ischemia-reperfusion in intact isolated hearts from 13-lined ground squirrels (Ictidomys tridecemlineatus) in the summer (active, July) and winter (torpid, January). In standard euthermic conditions, we found that winter hearts relaxed more rapidly than summer hearts at low to moderate pacing frequencies, even though systolic function was similar in both seasons. Proteome data support the hypothesis that enhanced Ca(2+) handling in winter torpid hearts underlies the increased relaxation rate. Additionally, winter hearts developed significantly less rigor contracture during ischemia than summer hearts, while recovery during reperfusion was similar in hearts between seasons. Winter torpid hearts have an increased glycogen content, which likely reduces development of rigor contracture during the ischemic event due to anaerobic ATP production. These cardioprotective mechanisms are important for the hibernation phenotype and highlight the resistance to hypoxic stress in the hibernator. PMID- 26017502 TI - Approaches to treatments of chronic migraine associated with medication overuse: a comparison between different intensity regimens. AB - Treatment of chronic migraine with medication overuse requires withdrawal from acute medications. However, guidelines and clear indications for different intensity regimens, i.e., day hospital (DH) vs. inpatient treatment, are not available. Patients completed disability, quality of life (QoL) and depression questionnaires; headaches frequency and overused medications category were collected. Mann-Whitney U test and Chi square were used to assess differences between inpatients and DH patients; Bonferroni correction was applied. 194 patients aged 43.9 +/- 12 (160 females) were enrolled (100 from DH, 94 inpatients). Inpatients were older, less educated and with lower employment rates. Inpatients had higher MIDAS scores (P = 0.003) and headache frequency (P = 0.002). They had lower QoL for restrictive (P = 0.002) and preventive components; no difference was found for disability, mood state and QoL emotional component. Patients treated during hospitalization had higher disease severity and lower quality of life, but similar disability and mood state than those treated in DH. PMID- 26017503 TI - Difficulties in work activities and the pervasive effect over disability in patients with episodic and chronic migraine. AB - Migraine is associated with reduced productivity in work-related activities. The degree to which problems with work are, in turn, associated to the level of migraine-related disability as well as to headache frequency has been poorly explored. The aim of the study was to assess if migraine patients with different degrees of work difficulties showed a different level of migraine-related disability. A consecutive sample of patients with episodic migraine (EM) or with chronic migraine (CM) with medication overuse (MO) attending the Headache Centre of the Neurological Institute C. Besta of Milan was studied. All patients completed the MIDAS and the WHODAS 2.0 questionnaires. The total scores of both questionnaires, frequency of headaches, average pain intensity, and the scores of each subscale of the WHODAS 2.0 were calculated separately for EM and CM patients. The score of WHODAS 2.0 "Work difficulties" subscale was used to divide the studied patients into two groups, i.e. those above and those below the median "Work difficulties" subscale score. Independent sample t test was used to compare these two groups as far as all the other studied variables. A total of 296 patients (102 with EM and 194 with CM-MO) were enrolled. Patients with higher work difficulties score also displayed higher scores in the other WHODAS 2.0 subscales; for those with CM-MO, the differences were significant. The results of this study indicate that having more and more severe workplace problems is associated to a higher disability level in migraineurs. Further studies are needed to better understand workplace disability in different migraine forms, particularly in a qualitative way. PMID- 26017504 TI - Physiopathology of cephalic pain: where are we? AB - Cephalic pain and psychiatric disease physiopathology is one of the most elusive issues in medical research, and the cause might be common. Going through the possible reasons of the failure in understanding the physiopathology of these diseases might be helpful to project new studies that might overcome the difficulties encountered and thus open a window on cephalic pain and psychiatric disease. New approaches to psychiatric disease might be applied to cephalic pain. PMID- 26017505 TI - Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism. AB - The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold. PMID- 26017506 TI - The role of intracranial hypertension in the chronification of migraine. AB - Besides a similar clinical presentation, idiopathic intracranial hypertension (IIH) and chronic migraine (CM) also share relevant risk factors, show a higher prevalence of allodynic symptoms and both respond to topiramate. Moreover, sinus stenosis, a radiological marker of IIH, in CM patients is much more prevalent than expected. As a consequence of these striking similarities, IIH without papilledema (IIHWOP) may be easily misdiagnosed as CM. Actually, IIHWOP has been found in up to 14 % of CM clinical series. Considering that, on one hand, an asymptomatic sinus stenosis-associated raised intracranial pressure (ICP) may be highly prevalent in the general population, and on the other, that IIH clinical presentation with chronic headache may require a migraine predisposition, we have proposed that an overlooked IIHWOP could represent a risk factor for migraine progression. This hypothesis prompted us to investigate the prevalence of IIHWOP and its possible role in the process of migraine chronification in a consecutive series of CM patients selected for unresponsiveness to medical treatment and evidence of significant sinus stenosis. The main finding of our study is that the large majority of such patients actually suffer from a chronic headache secondary to IIHWOP. This implies that an IIHWOP mimicking CM is much more prevalent than believed, is commonly misdiagnosed as CM on the basis of ICHD criteria and is strictly predicted by refractoriness to preventive treatments. However, our data fully comply with the alternative hypothesis that an overlooked IIHWOP, although highly prevalent amongst healthy individuals, in migraine-prone subjects is a powerful (and modifiable) risk factor for the progression and the refractoriness of pain. The normalization of ICP by even a single LP with CSF withdrawal may be effective in a significant proportion of patients with a long history of refractory chronic headache, who represent about one-fifth of the patients screened in our study. We suggest that IIHWOP should be considered in all patients with almost daily migraine pain, with evidence of sinus stenosis and unresponsive to medical treatment, referred to specialized headache clinics. PMID- 26017507 TI - Rationale for use of onabotulinum toxin A (BOTOX) in chronic migraine. AB - Chronic migraine is a severely disabling headache evolving from episodic migraine as a result of different transforming factors and characterized by atypical pain modulation and peripheral and central sensitization. Discovered by serendipity, onabotulinum toxin A (BoNT-A) represents the only drug specifically approved for CM prophylaxis. According to the dominant opinion, BoNT-A acts peripherally, impairing the exocytosis of neuropeptide and neurotransmitter and the delivery of receptors and ion channels on the cell surface of peripheral trigeminal endings, thereby indirectly reducing central sensitization. However, it is not excluded that BoNT-A has also a central antinociceptive action, probably associated with an enhanced opioidergic and GABA-ergic transmission. This review discusses the rationale for use of BoNT-A in CM including its mechanisms of action and molecular targets and provides suggestions for a more tailored BoNT-A prophylaxis in patients with CM. PMID- 26017508 TI - Onabotulinum toxin A (Botox) for chronic migraine treatment: an Italian experience. AB - Chronic migraine is a common and debilitating headache syndrome. Botulinum neurotoxin, a potent toxin produced by the anaerobic bacterium clostridium botulinum, used largely for treatment of disorders associated with increased muscle tone and hyperhidrosis, is used for patients suffering from chronic migraine. In this study, a group of patients suffering from chronic migraine with medication overuse was treated with onabotulinum toxin A (Botox) to verify its efficacy for chronic migraine. The results confirmed the efficacy of onabotulinum toxin A (Botox) when used at the dosage of 155 UI according to the PREEMPT protocol. Although these results are preliminary, they led to intense efforts to evaluate the analgesic properties of onabotulinum toxin A (Botox) and to assess its use in clinical practice, in particular in migraine field. PMID- 26017509 TI - Vestibular migraine pathophysiology: insights from structural and functional neuroimaging. AB - Vestibular migraine (VM) has been increasingly recognized as a frequent cause of episodic vertigo, affecting up to 1 % of the general population, with female preponderance. Recently, both the Barany Society and the Migraine Classification Subcommittee of the International Headache Society have proposed original diagnostic criteria for VM, which have been included in the recent edition of the ICHD-3 beta version. VM diagnosis implies that vestibular symptoms are present during a migraine attack, with or without headache, in the absence of objectively demonstrated interictal vestibulopathy. Nevertheless, despite a growing body of literature, there is still an ongoing debate regarding whether VM origin is principally central or peripheral. However, during the past few years, the extensive application of advanced MRI techniques has contributed to significantly improve the understanding VM pathophysiology. Functional and structural abnormalities have been detected in brain areas involved in multisensory vestibular control and central vestibular processing in patients with VM. In this brief review, we will focus on these recent neuroimaging findings. PMID- 26017510 TI - Resting-state fMRI functional connectivity: a new perspective to evaluate pain modulation in migraine? AB - Resting-state (RS) functional magnetic resonance imaging (fMRI) is a relatively novel tool which explores connectivity between functionally linked, but anatomically separated, brain regions. The use of this technique has allowed the identification, at rest, of the main brain functional networks without requiring subjects to perform specific active tasks. Methodologically, several approaches can be applied for the analysis of RS fMRI, including seed-based, independent component analysis-based and/or cluster-based methods. The most consistently described RS network is the so-called "default mode network". Using RS fMRI, several studies have identified functional connectivity abnormalities in migraine patients, mainly located at the level of the pain-processing network. RS functional connectivity is generally increased in pain-processing network, whereas is decreased in pain modulatory circuits. Significant abnormalities of RS functional connectivity occur also in affective networks, the default mode network and the executive control network. These results provide a strong characterization of migraine as a brain dysfunction affecting intrinsic connectivity of brain networks, possibly reflecting the impact of long lasting pain on brain function. PMID- 26017511 TI - Resting state fMRI in cluster headache: which role? AB - The pathophysiology of cluster headache (CH) is not well-known. For several years, the most widely accepted theory was that CH was triggered by hypothalamus with secondary activation of the trigeminal-autonomic reflex. However, it was recently suggested that the posterior hypothalamus might be an actor of the pain modulating network more involved in terminating rather than triggering attacks. To investigate this hypothesis, resting state fMRI could provide valuable information on functional connectivity between brainstem and hypothalamus, as well as other brain structures that could be involved in CH pathophysiology. In this framework, here we review recent studies investigating functional connectivity by means of resting state fMRI. Despite the important findings of these studies, we suggest that important steps in the comprehension of CH pathophysiology will be done when the scientific community will use the new methodological approaches recently suggested to study functional connectivity in the brainstem. PMID- 26017512 TI - Chronic headaches: a clinician's experience of ICHD-3 beta. AB - The International Classification of Headache Disorders, 3rd edition (beta version) has significantly improved the categorization of chronic headaches. From a clinical standpoint, however, it still has a few limitations, both general and specific. Among the former is the fact that international headache classifications are aimed less at defining the disease than at characterizing the features of attacks, meaning that their structure is ill suited to dealing with chronic headaches where the patient must be the focus of the discussion. Among the latter is the fact that the diagnostic criteria for chronic migraine do not distinguish between cases differing widely in severity and that the issue of whether medication overuse headache can be considered an autonomous entity is still unsolved. We propose that changes be made in the systematizations of chronic migraine and medication overuse headache to make them more consistent with clinical practice. PMID- 26017513 TI - Migraine with aura: which patients are most at risk of stroke? AB - The complex association between migraine (M) and ischemic stroke (IS) is discussed. Epidemiological studies and meta-analyses show that M with aura (MA) and not M without aura, doubles the risk of IS. The risk is higher for female gender, young age and higher headache attacks frequency. Smoking habit and oral contraceptives, especially if associated, increase stroke risk. The underlying pathogenetic mechanisms are not completely understood, but it is hypothesized that a particular brain susceptibility to cortical spread depression could explain the association between MA and IS. The absolute risk of IS in migraineurs is relatively low and an antithrombotic primary prevention is not indicated, but it is mandatory to investigate and treat associated risk factors for IS and, in young MA women, consider only progestinic oral contraceptives, if needed, and smoking cessation. PMID- 26017514 TI - Migraine with aura and patent foramen ovale: myth or reality? AB - Several observational studies report that subjects with migraine with aura have a higher prevalence of right-to left shunt, commonly due to patent foramen ovale, and that patent foramen ovale is more prevalent in subjects with migraine with aura. Although migraine without aura has been less extensively studied, it does not seem to be associated with an increased prevalence of right-to left shunt. The mechanism that underlies the possible relationship between patent foramen ovale and migraine with aura remains speculative. The proposed mechanisms are migraine-triggering vasoactive chemicals bypassing the pulmonary filter and reaching the cerebral circulation and paradoxical microembolization. However, it is unclear, at this time, if there is a causal or comorbid association between the two conditions. In some families atrial shunts show a dominant inheritance that seems to be linked to inheritance of migraine with aura. Migraine with aura is an independent risk factor for ischemic stroke, and patent foramen ovale is present more frequently in patients with cryptogenic stroke than in controls. At this moment, there is no convincing evidence that excess stroke risk of migraine is simply mediated by patent foramen ovale through paradoxical embolism. Several non-controlled studies suggest that closure of the foramen ovale significantly reduces attack frequency in migraine patient, but the only prospective placebo controlled trial does not support these results. Patent foramen ovale closure, at present, is not indicated as a treatment for migraine in clinical practice. PMID- 26017515 TI - Headache in subarachnoid hemorrhage and headache attributed to intracranial endovascular procedures. AB - Headache is a critical problem in the emergency setting. In this paper we briefly review the epidemiological data regarding headache in Subarachnoid Hemorrhage (SAH), considering the role of headache as a warning symptom and the other clinical manifestation of SAH. We have also introduced a recent clinical entity, represented by headache associated to intracranial endovascular procedures (IEPs). PMID- 26017516 TI - Confusional state as first symptom of HaNDL syndrome. AB - HaNDL (transient headache and neurological deficits with cerebrospinal fluid lymphocytosis) syndrome is an infrequent condition included at group 7 "headache attributed to non-vascular intracranial disorder" in the recent International Classification of Headache Disorders (ICHD-3), code 7.3.5. The description states "migraine-like headache episodes (typically 1-12) accompanied by neurological deficits including hemiparaesthesia, hemiparesis and/or dysphasia, but positive visual symptoms only uncommonly, lasting several hours. There is lymphocytic pleocytosis. The disorder resolves spontaneously within 3 months". In this description confusional state is not considered as a main symptom, even if in the literature this aspect is frequently reported. Here, we report the cases of two young boys presenting with confusional state as the main complaint. The possible pathogenesis of the different clinical presentation is discussed. PMID- 26017517 TI - Headache in multiple sclerosis and autoimmune disorders. AB - The headache may be considered among the neuropathic pain syndromes of multiple sclerosis (MS). Several studies have showed that it is more frequent in MS patients than in controls or general population. Headache may occur at the pre symptomatic phase, at clinical onset and during the course of the disease. Tension-type headache and migraine without aura are the most common primary headaches reported in MS patients. The disease-modifying therapies, such as interferons, may cause or exacerbate headache, although the new available treatments do not seem to increase the risk of pain. Pharmacological and not pharmacological approach may be considered in selected patients to prevent the risk of headache, ameliorate quality of life and increase the adherence to treatment. PMID- 26017518 TI - Migraine in perimenopausal women. AB - Hormonal changes during the reproductive cycle are thought to account for the variation in migraine occurrence and intensity. Although the majority of women and the specialists treating them do not consider migraine as a component of the climacteric syndrome, many women, in fact, do experience migraine during perimenopause. If a woman already suffers from migraine, the attacks often worsen during menopausal transition. Initial onset of the condition during this period is relatively rare. Women with the premenstrual syndrome (PMS) prior to entering menopause are more likely to experience, during late menopausal transition, an increased prevalence of migraine attacks. Hormone replacement therapy (HRT) can be initiated during the late premenopausal phase and the first years of postmenopause to relieve climacteric symptoms. The effect of HRT on migraine, either as a secondary effect of the therapy or as a preventive measure against perimenopausal migraine, has been variously investigated. HRT preparations should be administered continuously, without intervals, to prevent sudden estrogen deprivation and the migraine attacks that will ensue. Wide varieties of formulations, both systemic and topical, are available. Treatment with transdermal patches and estradiol-based gels is preferable to oral formulations as they maintain constant blood hormone levels. Natural menopause is associated with a lower incidence of migraine as compared with surgical menopause; data on the role of hysterectomy alone or associated with ovariectomy in changing the occurrence of migraine are till now unclear. PMID- 26017519 TI - Headaches attributed to visual disturbances. AB - Ocular pain due to ophthalmological diseases is most commonly associated with redness and inflammation of the ocular surface and surrounding tissues. Pain in a quiet eye can be referred as headache and can be the first sign of a number of ocular or orbital conditions. Painful symptoms may be considered non-specific if signs of targeted diseases are not identified. Collection of appropriate history of pain around the eye and associated symptoms or signs should be considered to recognize when ophthalmological examination is needed. Some painful diseases such as intermittent angle closure glaucoma, uveitis or optic neuritis, can lead to severe and permanent visual loss and require a prompt diagnosis and treatment. PMID- 26017520 TI - Adolescent migraine: diagnostic and therapeutic approaches. AB - Migraine prevalence increases from infancy to adolescence thus suggesting the important role of adolescent somatic and emotional maturation in supporting the disease. New family and society relationship and scholastic experiences represent more or less stress moments, producing risk factors for adolescent migraine. There are few studies adequately assessing migraine treatment efficacy in adolescent attack and prevention. Adolescent migraine's treatment with pharmacological and nonpharmacological therapies needs an individualized approach considering adolescent development degree, risk factors and trigger circumstances, psychological correlates and even psychiatric or other comorbidities. PMID- 26017521 TI - Migraine attacks in the pharmacy: a gender subanalysis on treatment preferences. AB - In 2014 our group published the results of a survey conducted in Piedmont, Italy, on the patterns of use and dispensing of drugs in patients requesting assistance from pharmacists for relief of a migraine attack. Epidemiological studies on migraine have consistently shown that migraine is far more common among women than men. This gender difference is also reflected in the higher percentage of women visiting a pharmacy to obtain treatment or advice for headache attacks. In this study, we further explored gender differences in healthcare-seeking behavior and use of migraine medications. The aim of the study was to determine whether women made better selective use of migraine medications and whether visiting a headache center for consultation and treatment reflected awareness of how best to manage their condition. Among the drugs usually taken for relieving head pain, there was no statistically significant difference between men and women in the routine use of NSAIDs (55.6 vs. 51.6 %) or ergot derivatives (8.7 vs. 9.3 %). Statistically significant differences emerged between men and women (27.9 vs. 35.4 %) in the use of triptans (p = 0.003; OR 1.41, 95 % CI 1.12-1.78) and in the use of combined medications (8.5 vs. 12.2 %) (p = 0.029; OR 1.49, 95 % CI 1.04 2.14) but not in the use of simple OTC non-NSAIDs. Less men than women sought professional medical care for managing migraine (65.7 vs. 72.4 %) (p = 0.003; OR 0.71, 95 % CI 0.57-0.89); more women than men sought treatment at a headache center (21.7 vs. 17.4 %) (p = 0.044; OR 1.31, 95 % CI 1.07-1.72). PMID- 26017522 TI - Migraine and lifestyle in childhood. AB - Migraine is one of the most frequently reported somatic complaints in childhood, with a negative impact on health-related quality of life. The incidence of migraine in childhood has substantially increased over the past 30 years, probably due to both increased awareness of the disease and lifestyle changes in this age group. Indeed, several conditions have been identified as risk factors for migraine in childhood. Amongst these, dysfunctional family situation, the regular consumption of alcohol, caffeine ingestion, low level of physical activity, physical or emotional abuse, bullying by peers, unfair treatment in school and insufficient leisure time seem to play a critical role. Nevertheless, there are only few studies about the association between migraine and lifestyle in childhood, due to previous observations specifically focused on "headache" in children. In this brief review, we will concentrate upon recent studies aimed to explore migraine and lifestyle risk factors in childhood. PMID- 26017523 TI - The lesson of chronic migraine. AB - The hypothesis that central sensitization/allodynia is the common final mechanism responsible for the progression of migraine pain is supported by the possibility of tracing back to allodynic mechanisms the action of the main risk factors for chronic migraine validated by the recent literature. The comorbidity between migraine and idiopathic intracranial hypertension without papilledema is emerging as a new, commonly overlooked risk factor for migraine progression whose putative mechanism might also converge on the sensitization of central pain pathways. If headache progression always occurs at the end of a pathogenetic sequence typical of an individual susceptibility to allodynia, then the primary character of chronic migraine might be debated. Allodynia is not specific to migraine but is implied in the progressive amplification of pain after repeated stimuli, a universal adaptive phenomenon. Being largely conditioned by the individual comorbidity profile, allodynia may only in part be defined as primary in itself. Many migraine comorbid conditions, including a hidden idiopathic intracranial hypertension without papilledema, may emphasize susceptibility to allodynia and promote chronic migraine. These factors and comorbid conditions require to be individually assessed and adequately treated to optimize the therapeutic response. PMID- 26017524 TI - Emerging treatments for the primary headache disorders. AB - Migraine and cluster headache are common, episodic, often chronic and disabling disorders of the brain. Although there are many standard treatment techniques, none are ideal. This article reviews various novel pharmacologic and device related treatments for migraine and cluster headache. Emphasis is given to recent advances in the development of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) and its receptor, including promising results from phase 2 trials studying the safety and efficacy of LY2951742, ALD403 and TEV 48125, three anti-CGRP mAbs. Other new pharmacologic treatments discussed include the 5-HT1F receptor agonist lasmiditan and glial cell modulator ibudilast. Also reviewed is neuromodulation for migraine and cluster headache, including promising recent results of randomized controlled trials studying sphenopalatine ganglion stimulation, trigeminal nerve stimulation, transcutaneous vagus nerve stimulation, and transcranial magnetic stimulation. Finally, we discuss patch, inhaled, and intranasal methods of triptan and dihydroergotamine delivery. PMID- 26017525 TI - Electromyography data in chronic migraine patients by using neurostimulation with the Cefaly(r) device. AB - The objective of this observational study is to report clinical and instrumental results obtained in 23 chronic migraine sufferers treated with transcutaneous neurostimulation with the Cefaly((r)) device. The electrom yography (EMG) parameters of the patients monitored before and during neurostimulation with the Cefaly((r)) device showed a significant increase in the EMG amplitude and frequency values in the frontalis, anterior temporalis, auricularis posterior and middle trapezius muscles. The Cefaly((r)) device could act on the inhibitory circuit in the spinal cord thus causing a neuromuscular facilitation and may help reduce contraction of frontalis muscles. PMID- 26017526 TI - Role of neurostimulation in migraine. AB - Chronic forms of headache characterized by daily or almost daily headache, affect almost 3 % of general population. They represent the most disabling forms of headache inducing high degree of disability, poor quality of life for patients. During the last decades, several neuromodulatory surgical techniques have been developed for the management of headaches that are unresponsive to medical treatment. Invasive and non invasive central and/or peripheral neurostimulation techniques have been developed by different research groups with encouraging results for different type of headaches. In this report, the acute effect of non invasive vagus nerve stimulation (nVNS) (gammacore) was evaluated to treat migraine attacks in a population of patients affected by high-frequency episodic migraine or chronic migraine. The aim of this study was to verify the efficacy of nVNS to treat migraine attacks in this specific category of patients. PMID- 26017527 TI - Advanced technologies and novel neurostimulation targets in trigeminal autonomic cephalalgias. AB - The trigeminal autonomic cephalalgias (TACs) are a group of rare but disabling primary headache disorders. Their management is challenging, since only few effective treatments are available and high doses may be required to control the headache, compromising patients' adherence to treatments. A significant minority of patients, who fail to respond to or tolerate established treatments, are left with enormous level of disability and disruption to their quality of life. A growing body of evidence demonstrates the efficacy of central and peripheral neuromodulation approaches for management of patients with refractory TACs. In view of the potential risks related to deep brain stimulation of the posterior hypothalamic region, occipital nerve stimulation is currently considered the first treatment option for refractory chronic TACs. However, in view of the presence of paraesthesia induced by the stimulator, no robust controlled trials have been possible so far. Additionally, the equipment used for occipital nerve stimulation is not designed specifically for peripheral nerve stimulation, thus a significant proportion of patients experience device-related complications that often require surgical revisions. To overcome these issues, new neurostimulation technologies using less invasive or non-invasive approaches and modulating different neuroanatomical targets have been recently studied. PMID- 26017528 TI - Surgery for treatment of refractory chronic cluster headache: toward standard procedures. AB - The degree of disability due to chronic cluster headache refractory to conservative treatments justifies surgical procedures as second-line treatments. Many studies and reports nowadays confirm the efficacy of the two mostly used surgical techniques in such cases. Both deep brain stimulation and occipital nerve stimulation are in fact currently utilized for this purpose but the surgical technique has not yet been standardized. We describe the surgical steps of both procedures. PMID- 26017529 TI - Headache attributed to intracranial pressure alterations: applicability of the International Classification of Headache Disorders ICHD-3 beta version versus ICHD-2. AB - The association between headache and changes in intracranial pressure is strong in clinical practice. Syndromes associated with abnormalities of cerebrospinal fluid (CSF) pressure include spontaneous intracranial hypotension (SIH) and idiopathic intracranial hypertension (IIH). In 2013, the Headache Classification Committee of the International Headache Society (IHS) published the third International Classification of Headache Disorders (ICHD-3 beta version). The aim of this study was to investigate applicability of the new ICHD-3 versus ICHD-2 criteria in a clinical sample of patients with intracranial pressure (ICP) alterations. Patients admitted at our Headache Center for headache evaluation in whom a diagnosis of ICP alterations was performed were reviewed. 71 consecutive patients were studied. 40 patients (Group A) were diagnosed as IIH, 22 (Group B) as SIH, 7 (Group C) and 2 (Group D), respectively, as symptomatic intracranial hypertension and symptomatic intracranial hypotension. Main headache features were: in Group A, daily or nearly-daily headache (100 %) with diffuse/non pulsating pain (73 %), aggravated by coughing/straining (54 %) and migrainous associated symptoms (43 %). In Group B, an orthostatic headache (100 %) with nausea (29 %), vomiting (24 %), hearing disturbance (33 %), neck pain (48 %), hypacusia (24 %), photophobia (22 %) was reported. In Group C, a diffuse non pulsating headache was present in 95 % with vomiting (25 %), sixth nerve palsy (14 %) and tinnitus (29 %). In Group D, an orthostatic headache with neck stiffness was reported by 100 %. Regarding applicability of ICHD-2 criteria in Group A, 73 % of the patients fitted criterion A; 100 %, criterion B; 100 %, criterion C; and 75 %, criterion D; while applying ICHD-3 beta version criteria, 100 % fitted criterion A; 97.5 %, criterion B; 100 %, criterion C; and 100 %, criterion D. In Group B, application of ICHD-2 showed 91 % patients fitting criterion A; 100 %, criterion B; 100 %, criterion C; and 68 %, criterion D; while applying ICHD-3 beta version all patients, 100 % fitted criterion A, B, C, D. 73 % patients of Group A fitted all ICHD-2 criteria and 97.5 % all ICHD-3 beta version criteria for headache attributed to IIH. 68 % patients of Group B fitted all ICHD-2 criteria and 100 % all ICHD-3 beta version criteria for headache attributed to SIH. In Group C and Group D, although patients fitted some clinical criteria, the underlying disorder caused exclusion of both ICHD-2 and ICHD-3 beta version applicability for headache attributed to IIH and SIH; they were coded in criteria for the secondary headaches. In summary, ICHD-3 beta version seems to have better applicability but worse reliability in defining headache features in CSF alterations. PMID- 26017530 TI - Familial cluster headache in an Italian case series. AB - To investigate the familial occurrence of cluster headache (CH) in a series of Italian patients, we focused on possible differences in the mean age of onset between familial and non-familial CH cases. We considered all consecutive patients referred to the Parma Headache Centre between 1975 and 2013 affected by CH; we subsequently reviewed these cases applying the ICHD3-beta criteria (785 probands, 569 men and 216 women). We identified those cases who reported at least a first-degree relative with a diagnosis of CH, which was confirmed by the clinical documentation they provided. Each one of the "familial cases" was matched by sex and age (+/-2 years) at the first visit to three consecutive CH patients who did not report any first-degree relative affected by CH. A positive family history of CH was found in 40 probands (5.1 %), 28 men (4.9 %), and 12 women (5.6 %). The male:female ratio was 2.3:1 among the 40 CH familial cases, while it was 2.7:1 among all the CH non-familial cases (745 patients). The mean age of onset was significantly (p < 0.01) lower in women with familial CH (28.5 years, SD 17.7 years, range 10-63 years) than in women with non-familial CH (46.7 years, SD 13.7 years, range 11-74 years); we did not find a significant age difference among men (the mean age of onset for the familial cases was 29.6 years, SD 13.6 years, range 6-63 years; while for the non-familial cases, it was 29.3 years, SD 13.2 years, range 13-59 years). Our study suggests that genetic factors may play a role in the female gender causing an earlier age of onset and a lower male-to-female sex ratio in familial cases. PMID- 26017531 TI - Osmophobia in allodynic migraineurs: cause or consequence of central sensitization? AB - Migraine is a primary headache characterized by recurrent attacks of head pain associated with nausea or vomit, photophobia, phonophobia and osmophobia. The presence of osmophobia during migraine attacks seems to be a very specific complaint. Cutaneous allodynia (CA) is very common in migraineurs, and it is the most evident clinical manifestation of central sensitization, a mechanism involved in migraine chronification. This study was aimed at identifying the possible correlation between osmophobia and CA in migraineurs. 673 migraineurs were studied (492 episodic, 181 chronic). The prevalence of both CA and osmophobia was higher in chronic than in episodic migraineurs. The association between these two symptoms was significant in chronic migraineurs at Chi square test. The highlighted relationship between CA and osmophobia may be interpreted in different ways: central sensitization induced by recurrent pain stimulation may in parallel induce a distortion of both cutaneous sensitivity (CA) and olfaction (osmophobia); alternatively, the recurrent olfactory stimulation in subjects with a hypersensitivity to olfactory stimuli may co-work with repetitive pain stimulation to induce the central sensitization process. PMID- 26017532 TI - Headache in cerebral venous thrombosis associated with extracranial tumors: a clinical series. AB - Cerebral venous thrombosis (CVT) may represent the clinical onset of malignancies or complicate their course, also in phase of quiescence. In literature, there are several case reports on the association between CVT and tumors, but there are few articles on its clinical characteristics in cancer patients (Pts). Our aim was to analyze the clinical characteristics of CVT associated with extracranial tumors. We identified nine cases of CVT in adults affected by extracranial tumors in 6 years from six hospitals. The median age was 40 years; eight Pts were female. Associated tumors were: lymphoma (4/9); breast (2/9), rhinopharynges (1/9) and gastric (1/9) carcinomas. One patient presented a kidney tumor and a melanoma at the same time. Multiple sinuses were affected in seven Pts. MRI showed parenchymal lesions in most cases (7/9). Clinical manifestations were: focal deficits (7/9), headache (6/9), early seizures (4/9) and consciousness disorders (3/9). Headache was the onset symptom in six Pts. In four of these Pts, headache preceded the onset of the focal deficit and/or seizures than 2-15 days. The characteristics of the headache were variable in intensity, location and type but all the Pts agreed in saying that it was an unusual headache, unresponsive to common pain medications. Five of the six Pts complaining of headache in the course of CVT presented focal deficits and parenchymal lesions at admission to the emergency room. All nine Pts were anticoagulated without further haemorrhagic complications. At discharge, the Pts presented a complete recovery in four cases, mild sequelae in four and moderate sequelae in one. In conclusion, we would like to underline the importance of particular care to cancer Pts complaining of headache, since the early diagnosis and the appropriate anticoagulant treatment could prevent the appearance of parenchymal lesions and the consequent neurological deficits. Also in the cases of normal brain CT, a brain MRI/MR venography should be performed in emergency setting if CVT is suspected. PMID- 26017533 TI - Persistent orthostatic headache without intracranial hypotension: which treatment? AB - Orthostatic headache can be the leading symptom of intracranial hypotension, however, not all orthostatic headaches are due to cerebrospinal fluid leaks and these forms can be a clinical problem, especially for treatment. Aim of this study was to review patients with persistent orthostatic headache in whom a detailed head and spinal MRI follow-up did not reveal any sign of intracranial hypotension and to evaluate which treatment can be considered the first choice. Patients admitted to our headache center for evaluation of persistent orthostatic headache and followed after first admission with clinical and neuroradiological controls were systematically reviewed. 11 patients (7 M, 4 F) followed in a period lasted from 10 months up to 2 years were studied. Six patients (54, 5 %) reported a MRI performed previously elsewhere with a suspect diagnosis of intracranial hypotension which was not confirmed at MRI at our hospital such as during the radiological follow-up. Three patients (27.2 %) had developed orthostatic headache short after a neck or head trauma with no evidence of neuroradiological pathological signs and two patients (18 %) had a previous history of psychiatric disorder. We administrated antidepressants in five patients, atypical neuroleptic in three patients, association of antidepressant and antipsychotic in one patient and muscle relaxants in two cases. All patients showed a certain improvement of headache in the weeks after introduction of the pharmacological treatment; six (54, 5 %) had pain relief during the follow-up and five (45, 5 %) were pain free at the last clinical control. We found out that patients with the best outcome were the ones treated with antidepressants. Persistent orthostatic headache without any neuroradiological sign of intracranial hypotension is a challenging problem for clinicians. Although the International Classification of Headache Disorders (ICHD-3 beta version) criteria suggests the possibility of epidural blood patch in orthostatic headache without causes, we believe that a pharmacological treatment tailored on each patient should be always considered and antidepressants can be the first choice. PMID- 26017534 TI - Triptan use among hospital workers affected by migraine. AB - Triptans represent the most specific and effective treatment for migraine attacks. Nevertheless, in clinical practice, they are often underused. Hospital workers, in particular physicians, are expected to be more aware of the correct use of specific drugs, especially for a very common disease such as migraine. Aim of this study was to evaluate whether different hospital workers affected by migraine are able to correctly manage the most suitable therapy for their migraine attacks. During a 1-year period, we submitted hospital employees to a structured interview with a questionnaire to investigate the presence of headache and its characteristics. In particular, in the subpopulation of subjects affected by migraine, we took information regarding their usual treatment for the control of attacks. The type of drug and the category of the working activity were synthesized as two different ordinal variables. Difference in the distribution of the different drug categories was evaluated with Chi squared test. Statistics was performed with SPSS 13.0 for Windows systems. We enrolled 1250 consecutive subjects: 20.3 % of the population (254 patients) was affected by migraine. Triptans use was significantly lower than that of non-steroidal anti-inflammatory drugs. The distribution of the use of the drugs was significantly different (p < 0.0001) at Chi squared test. Among migraineur physicians, only 10.7 % used triptans. Even in this subgroup, we observed a significant difference (p < 0.0001) in the distribution of the use of the drugs at Chi squared test. Our findings show a reduced use of triptans among hospital workers. These data reflect the unsatisfactory dissemination of knowledge regarding the correct management of migraine attacks and the advantages of treatment with triptans. An incorrect therapeutic approach to migraine contributes to the risk of the most important complications, such as drugs abuse or illness chronicization. These findings suggest that an insufficient awareness of migraine-related therapeutic options also involves hospital workers, including physicians. PMID- 26017535 TI - Early (<= 1-h) vs. late (>1-h) administration of frovatriptan plus dexketoprofen combination vs. frovatriptan monotherapy in the acute treatment of migraine attacks with or without aura: a post hoc analysis of a double-blind, randomized, parallel group study. AB - The early use of triptan in combination with a nonsteroidal anti-inflammatory drug after headache onset may improve the efficacy of acute migraine treatment. In this retrospective analysis of a randomized, double-blind, parallel group study, we assessed the efficacy of early or late intake of frovatriptan 2.5 mg + dexketoprofen 25 or 37.5 mg (FroDex 25 and FroDex 37.5) vs. frovatriptan 2.5 mg alone (Frova) in the acute treatment of migraine attacks. In this double-blind, randomized parallel group study 314 subjects with acute migraine with or without aura were randomly assigned to Frova, FroDex 25, or FroDex 37.5. Pain free (PF) at 2-h (primary endpoint), PF at 4-h and pain relief (PR) at 2 and 4-h, speed of onset at 60, 90, 120 and 240-min, and sustained pain free (SPF) at 24-h were compared across study groups according to early (<=1-h; n = 220) or late (>1-h; n = 59) intake. PF rates at 2 and 4-h were significantly larger with FroDex 37.5 vs. Frova (early intake, n = 71 FroDex 37.5 and n = 75 Frova: 49 vs. 32 % and 68 vs. 52 %, p < 0.05; late intake, n = 20 Frodex 37.5, and n = 18 Frova: 55 vs. 17 %, p < 0.05 and 85 vs. 28 %, p < 0.01). Also with FroDex 25, in the early intake group (n = 74) PF episodes were significantly higher than Frova. PR at 2 and 4-h was significantly better under FroDex 37.5 than Frova (95 % vs. 50 %, p < 0.001, 100 % vs. 72 %, p < 0.05) in the late intake group (n = 21). SPF episodes at 24-h after early dosing were 25 % (Frova), 45 % (FroDex 25) and 41 % (FroDex 37.5, p < 0.05 combinations vs. monotherapy), whereas they were not significantly different with late intake. All treatments were equally well tolerated. FroDex was similarly effective regardless of intake timing from headache onset. PMID- 26017536 TI - Proposal of a model for multidisciplinary treatment program of chronic migraine with medication overuse: preliminary study. AB - The treatment of patients with chronic migraine associated with medication overuse is challenging in clinical practice; different strategies of treatment have been recently developed, multidisciplinary treatment approaches have been developed in academic headache centers. Education and support of patients are necessary to improve patients' adherence to pharmacological treatments as well as to non-pharmacological therapies. This study reports a clinical experience conducted at our Headache center with a group of female patients, suffering from chronic migraine complicated by medication overuse, treated by a multidisciplinary approach and followed for a period of 1 year after withdrawal. Results confirm the efficacy of a multifaceted treatment to manage this problematic category of patients. PMID- 26017538 TI - An Outbreak of Cryptosporidium parvum across England & Scotland Associated with Consumption of Fresh Pre-Cut Salad Leaves, May 2012. AB - BACKGROUND: We report a widespread foodborne outbreak of Cryptosporidium parvum in England and Scotland in May 2012. Cases were more common in female adults, and had no history of foreign travel. Over 300 excess cases were identified during the period of the outbreak. Speciation and microbiological typing revealed the outbreak strain to be C. parvum gp60 subtype IIaA15G2R1. METHODS: Hypothesis generation questionnaires were administered and an unmatched case control study was undertaken to test the hypotheses raised. Cases and controls were interviewed by telephone. Controls were selected using sequential digit dialling. Information was gathered on demographics, foods consumed and retailers where foods were purchased. RESULTS: Seventy-four laboratory confirmed cases and 74 controls were included in analyses. Infection was found to be strongly associated with the consumption of pre-cut mixed salad leaves sold by a single retailer. This is the largest documented outbreak of cryptosporidiosis attributed to a food vehicle. PMID- 26017540 TI - Polydopamine-coated open tubular column for the separation of proteins by capillary electrochromatography. AB - The separation and determination of proteins in food is an important aspect in food industry. Inspired by the self-polymerization of dopamine under alkaline conditions and the natural adhesive properties of polydopamine, in this paper, a simple and economical method was developed for the preparation of polydopamine coated open tubular column, in which ammonium persulfate was used as the source of oxygen to induce and facilitate the polymerization of dopamine to form polydopamine. In comparison with a naked fused-silica capillary, the direction and magnitude of the electro-osmotic flow of the as-prepared polydopamine-coated open tubular column could be manipulated by varying the pH values of background solutions due to the existence of amine and phenolic hydroxyl groups on polydopamine coating. The surface morphology of the polydopamine-coated open tubular column was studied by scanning electron microscopy, and the thickness of polydopamine coating was 106 nm. The performance of the polydopamine-coated open tubular column was validated by analysis of proteins. The relative standard deviations of migration times of proteins representing run-to-run, day-to-day, and column-to-column were less than 3.5%. In addition, the feasibility of the polydopamine-coated open tubular column for real samples was verified by the separation of proteins in chicken egg white and pure milk. PMID- 26017539 TI - Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. AB - BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. METHODS: Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. RESULTS: The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. CONCLUSION: Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. PMID- 26017541 TI - Peer support need fulfillment among adults with spinal cord injury: relationships with participation, life satisfaction and individual characteristics. AB - PURPOSE: To test the hypothesis among people with spinal cord injury (SCI) that greater fulfillment of peer support needs to be associated with greater participation and life satisfaction. A secondary objective was to identify characteristics of people in great need of SCI peer support. METHOD: The participants consisted of a population-based sample of 1549 adults with SCI. The participants completed a survey with questions on peer support, participation, life satisfaction and provided demographic and SCI-related information. A secondary analysis of cross-sectional survey data was conducted. A set of regression analyses tested the primary purpose and a partition analysis was conducted to examine the secondary objective. RESULTS: In regression analyses, peer support need fulfillment was positively associated with autonomous-outdoors participation (p < 0.05), health participation (p < 0.05), and work/education participation (p < 0.05), as well as life satisfaction (p < 0.001) after controlling demographic and SCI-related variables. However, peer support need fulfillment was not related with overall participation or other subdomains of participation: autonomy indoors, social relationships and family role. The number of unmet SCI-related needs, injury characteristics and education were associated with fulfillment of SCI peer support needs. CONCLUSIONS: The results provide some evidence that SCI peer support plays an important role in promoting participation and life satisfaction. Individuals with many SCI-related unmet needs are most likely to report a need for peer support. IMPLICATIONS FOR REHABILITATION: The receipt of peer support after a spinal cord injury (SCI) is positively related to aspects of social participation and life satisfaction. Provision of peer support can play an important role in the SCI rehabilitation process. Education, injury related characteristics, and the number of other unmet needs are factors that rehabilitation professionals can use to identify those in particular need of peer support. Rehabilitation professionals should encourage patients who have sustained an SCI, to participate in peer support programs. PMID- 26017542 TI - Disability, caregiver's dependency and patterns of access to rehabilitation care: results from a national representative study in Peru. AB - PURPOSE: To determine the prevalence of disability in Peru, explore dependency on caregiver's assistance and assess access to rehabilitation care. METHOD: Data from Disability National Survey (ENEDIS), including urban and rural areas, were analyzed. Disability was defined as a permanent limitation on movement, vision, communication, hearing, learning/remembering or social relationships. Dependency was defined as the self-reported need for a caregiver to help with daily activities; and access to rehabilitation care was defined as the self-report of any therapy for disabilities. Estimates and projections were calculated using sample strata, primary sampling units and population weights, and prevalence ratios (PRs) and 95%CI were reported. RESULTS: From 798,308 people screened, 37,524 (5.1%; 95%CI 4.9--5.2%) had at least one disability. A total of 37,117 were included in further analysis, mean age 57.8 (SD +/- 24.1) years, 52.1% women. Dependency was self-reported by 14,980 (40.5%; 95%CI: 39.2-41.9%) individuals with disabilities. A family member, usually female, was identified as a caregiver in 94.3% (95%CI: 93.3-95.3%) of dependent participants. Only 2881 (10.7%; 95%CI: 9.7-11.9%) of people with disabilities reported access to rehabilitation care. Major inequality patterns of disability burden versus access to rehabilitation care were observed by age and education level. Older age groups had higher disability burden yet lower chances of access to rehabilitation care. Conversely, the higher the education level, the lesser the overall disability burden but also the higher chances of reporting receiving care. Private healthcare insurance doubled the probability of having access to rehabilitation compared with those without insurance. CONCLUSIONS: Approximately 1.6 million Peruvians have at least one disability, and 40% of them require assistance with daily activities. Informal caregiving, likely female and relative-provided, is highly common. Rehabilitation care access is low and inequitable. Our results signal a major need to implement strategies to guarantee the highest standard of health care for people with disabilities. IMPLICATIONS FOR REHABILITATION: Major inequality patterns in terms of burden of disability versus access to rehabilitation care were observed: those groups who concentrate more disability reported receiving less rehabilitation care. Caregiving is mostly informal and provided by a direct relative, mainly a woman, who resigned to their usual activities in order to help care for the person with disability. As a result, there is a need to develop appropriate support and training for caregivers. Access to care services in Peru is low and inequitable, but especially for people with disabilities: they experience greater barriers when accessing healthcare services even in the case of having health insurance. PMID- 26017543 TI - Renal and obstetric outcomes in pregnancy after kidney transplantation: Twelve year experience in a Singapore transplant center. AB - AIM: Renal and obstetric outcomes in pregnancy after kidney transplantation in Singapore were last studied in 2002. A review of these outcomes in Singapore is now timely following advances in transplant and obstetric medicine. The aim was to evaluate the renal and obstetric outcomes in pregnancy after kidney transplantation in a Singapore tertiary center. METHODS: Kidney transplant recipients who underwent pregnancy after transplantation at Singapore General Hospital between January 2001 and December 2012 were identified. Data on demographics, comorbidities and clinical outcomes were collected. RESULTS: There were 10 pregnancies identified in nine recipients. The median age of recipient at childbearing was 34.6 years (IQR, 32.8-36.8) and the median interval from transplantation to conception was 69 months (IQR, 38-97). There was no difference between the median pre-pregnancy estimated glomerular filtration rate (eGFR) (47.9 mL/min/1.73 m(2); IQR, 38.4-56.8) and median eGFR at time of last post partum follow up (43.9 mL/min/1.73 m(2); IQR, 34.5-48.7, P = 0.549). Borderline allograft rejection occurred in one recipient (10.0%) 36 days after birth due to non-adherence to immunosuppressive medication, with subsequent allograft loss 37 months after birth. No mortalities were recorded during the study period. All the 10 pregnancies (100%) ended in singleton live births. Pre-eclampsia occurred in five pregnancies (50.0%), and there were seven (70.0%) preterm deliveries. The median gestational age was 35.4 weeks (IQR, 32.6-38.2) and the median birthweight was 2353 g (IQR, 1811-2648). CONCLUSION: Post-transplantation pregnancies ended successfully with no significant worsening of allograft function, but they were associated with risks to both recipients and newborns. PMID- 26017544 TI - Advances in complementary-metal-oxide-semiconductor-based integrated biosensor arrays. PMID- 26017545 TI - Personalization of models with many model parameters: an efficient sensitivity analysis approach. AB - Uncertainty quantification and global sensitivity analysis are indispensable for patient-specific applications of models that enhance diagnosis or aid decision making. Variance-based sensitivity analysis methods, which apportion each fraction of the output uncertainty (variance) to the effects of individual input parameters or their interactions, are considered the gold standard. The variance portions are called the Sobol sensitivity indices and can be estimated by a Monte Carlo (MC) approach (e.g., Saltelli's method [1]) or by employing a metamodel (e.g., the (generalized) polynomial chaos expansion (gPCE) [2, 3]). All these methods require a large number of model evaluations when estimating the Sobol sensitivity indices for models with many parameters [4]. To reduce the computational cost, we introduce a two-step approach. In the first step, a subset of important parameters is identified for each output of interest using the screening method of Morris [5]. In the second step, a quantitative variance-based sensitivity analysis is performed using gPCE. Efficient sampling strategies are introduced to minimize the number of model runs required to obtain the sensitivity indices for models considering multiple outputs. The approach is tested using a model that was developed for predicting post-operative flows after creation of a vascular access for renal failure patients. We compare the sensitivity indices obtained with the novel two-step approach with those obtained from a reference analysis that applies Saltelli's MC method. The two-step approach was found to yield accurate estimates of the sensitivity indices at two orders of magnitude lower computational cost. PMID- 26017547 TI - A potential application of sludge-based catalysts for the anaerobic bio decolorization of tartrazine dye. AB - Two highly efficient (K2CO3/sludge carbon and ZnCl2/sludge carbon) solids were prepared by chemical addition following carbonization at 800 degrees C and were tested for anaerobic reduction of tartrazine dye in a continuous upflow packed bed biological reactor, and their performance was compared to that of commercial activated carbon (CAC). The chemical and structural information of the solids was subjected to various characterizations in order to understand the mechanism for anaerobic decolorization, and efficiency for SBCZN800 and SBCPC800 materials was 87% and 74%, respectively, at a short space time (tau) of 2.0 min. A first-order kinetic model fitted the experimental points and kinetic constants of 0.40, 0.92 and 1.46 min(-1) were obtained for SBCZN800, SBCPC800 and CAC, respectively. The experimental results revealed that performance of solids in the anaerobic reduction of tartrazine dye can depend on several factors including chemical agents, carbonization, microbial population, chemical groups and surface chemistry. The Langmuir and Freundlich models are successfully described in the batch adsorption data. Based on these observations, a cost-effective sludge-based catalyst can be produced from harmful sewage sludge for the treatment of industrial effluents. PMID- 26017546 TI - Differences in ADHD medication usage patterns in children and adolescents from different cultural backgrounds in the Netherlands. AB - PURPOSE: Differences in incidence and prevalence of ADHD medication use between ethnic groups have been reported. Goal of this study was to determine whether there are also differences in usage patterns of ADHD medication among native Dutch children and adolescents and those with a Moroccan, Turkish and Surinam cultural background in the Netherlands between 1999 and 2010. METHODS: In a cohort of ADHD patients <19 years (N = 817) incident use and discontinuation of ADHD medication were measured for ethnicity and adjusted for age, gender and socio-economic status. RESULTS: A significant higher proportion of ADHD-diagnosed patients from Moroccan (32 %) and Turkish (42 %) cultural background never used ADHD medication compared to Dutch natives (21 %). One-fifth of native Dutch and Turkish patients already used ADHD medication before the ADHD diagnosis date. Discontinuation of ADHD medication within 5 years was significantly higher in Moroccan [HR 2.4 (95 % CI 1.8-3.1)] and Turkish [HR 1.7 (95 % CI 1.1-2.6)] patients. A sensitivity analysis with a zip code-matched comparison between Dutch natives and non-natives showed similar results, suggesting this effect is probably not explained by socio-economic status (SES). CONCLUSION: Differences are found in prescribing and use of ADHD medication between patients with a different cultural background. Native Dutch and Turkish patients start more frequently with ADHD medication before the ADHD diagnose date, which can be an indication of differences in either referral patterns and/or access to care. A higher percentage of patients with a Moroccan and Turkish cultural background never start using ADHD medication at all and discontinuation rate is higher compared to Dutch natives and Surinamese. PMID- 26017548 TI - An engineered polypeptide around nano-sized manganese-calcium oxide: copying plants for water oxidation. AB - Synthesis of new efficient catalysts inspired by Nature is a key goal in the production of clean fuel. Different compounds based on manganese oxide have been investigated in order to find their water-oxidation activity. Herein, we introduce a novel engineered polypeptide containing tyrosine around nano-sized manganese-calcium oxide, which was shown to be a highly active catalyst toward water oxidation at low overpotential (240 mV), with high turnover frequency of 1.5 * 10(-2) s(-1) at pH = 6.3 in the Mn(III)/Mn(IV) oxidation range. The compound is a novel structural and efficient functional model for the water oxidizing complex in Photosystem II. A new proposed clever strategy used by Nature in water oxidation is also discussed. The new model of the water-oxidizing complex opens a new perspective for synthesis of efficient water-oxidation catalysts. PMID- 26017549 TI - The state of social media policies in higher education. AB - This paper presents an analysis of the current state of development of social media policies at institution of higher education. Content analysis of social media policies for all institutions listed in the Carnegie Classification Data File revealed that less than one-quarter of institutions had an accessible social media policy. Analysis was done by institution and campus unit, finding that social media policies were most likely to appear at doctorate-granting institutions and health, athletics, and library units. Policies required that those affiliated with the institution post appropriate content, represent the unit appropriately, and moderate conversations with coworkers and external agencies. This analysis may inform the development and revision of social media policies across the field of higher education, taking into consideration the rapidly changing landscape of social media, issues of academic freedom, and notions of interoperability with policies at the unit and campus levels. PMID- 26017550 TI - Correction: AGAPE (Automated Genome Analysis PipelinE) for Pan-Genome Analysis of Saccharomyces cerevisiae. PMID- 26017551 TI - Scaling Analysis of Ocean Surface Turbulent Heterogeneities from Satellite Remote Sensing: Use of 2D Structure Functions. AB - Satellite remote sensing observations allow the ocean surface to be sampled synoptically over large spatio-temporal scales. The images provided from visible and thermal infrared satellite observations are widely used in physical, biological, and ecological oceanography. The present work proposes a method to understand the multi-scaling properties of satellite products such as the Chlorophyll-a (Chl-a), and the Sea Surface Temperature (SST), rarely studied. The specific objectives of this study are to show how the small scale heterogeneities of satellite images can be characterised using tools borrowed from the fields of turbulence. For that purpose, we show how the structure function, which is classically used in the frame of scaling time series analysis, can be used also in 2D. The main advantage of this method is that it can be applied to process images which have missing data. Based on both simulated and real images, we demonstrate that coarse-graining (CG) of a gradient modulus transform of the original image does not provide correct scaling exponents. We show, using a fractional Brownian simulation in 2D, that the structure function (SF) can be used with randomly sampled couple of points, and verify that 1 million of couple of points provides enough statistics. PMID- 26017552 TI - Centerband-only analysis of rotor-unsynchronized spin echo for measurement of lipid (31) P chemical shift anisotropy. AB - Structural diversity and molecular flexibility of phospholipids are essential for biological membranes to play key roles in numerous cellular processes. Uncovering the behavior of individual lipids in membrane dynamics is crucial for understanding the molecular mechanisms underlying biological functions of cell membranes. In this paper, we introduce a simple method to investigate dynamics of lipid molecules in multi-component systems by measuring the (31) P chemical shift anisotropy (CSA) under magic angle spinning (MAS) conditions. For achieving both signal separation and CSA determination, we utilized a centerband-only analysis of rotor-unsynchronized spin echo (COARSE). This analysis is based on the curve fitting of periodic modulation of centerband intensity along the interpulse delay time in rotor-unsynchronized spin-echo experiments. The utility of COARSE was examined by using phospholipid vesicles, a three-component lipid raft model system, and archaeal purple membranes. We found that the apparent advantages of this method are high resolution and high sensitivity given by the moderate MAS speed and the one-dimensional acquisition with short spin-echo delays. COARSE provides an alternative method for CSA measurement that is effective in the investigation of lipid polymorphologies. PMID- 26017553 TI - Intervals to Plasmodium falciparum recurrence after anti-malarial treatment in pregnancy: a longitudinal prospective cohort. AB - BACKGROUND: Plasmodium falciparum infections adversely affect pregnancy. Anti malarial treatment failure is common. The objective of this study was to examine the duration of persistent parasite carriage following anti-malarial treatment in pregnancy. METHODS: The data presented here are a collation from previous studies carried out since 1994 in the Shoklo Malaria Research Unit (SMRU) on the Thailand Myanmar border and performed using the same unique methodology detailed in the Materials and Methods section. Screening for malaria by microscopy is a routine part of weekly antenatal care (ANC) visits and therapeutic responses to anti malarials were assessed in P. falciparum malaria cases. Women with microscopy confirmed P. falciparum malaria had a PCR blood spot from a finger-prick sample collected. Parasite DNA was extracted from the blood-spot samples using saponin lysis/Chelex extraction method and genotyped using polymorphic segments of MSP1, MSP2 and GLURP. Recurrent infections were classified by genotyping as novel, recrudescent or indeterminate. Factors associated with time to microscopy detected recrudescence were analysed using multivariable regression techniques. RESULTS: From December 1994 to November 2009, 700 women were treated for P. falciparum and there were 909 recurrent episodes (481 novel and 428 recrudescent) confirmed by PCR genotyping. Most of the recurrences, 85% (770/909), occurred after treatment with quinine monotherapy, artesunate monotherapy or artesunate clindamycin. The geometric mean number of days to recurrence was significantly shorter in women with recrudescent infection, 24.5 (95%: 23.4-25.8), compared to re-infection, 49.7 (95%: 46.9-52.7), P<0.001. The proportion of recrudescent P. falciparum infections that occurred after days 28, 42 and 63 from the start of treatment was 29.1% (124/428), 13.3% (57/428) and 5.6% (24/428). Recrudescent infections>=100 days after treatment occurred with quinine and mefloquine monotherapy, and quinine+clindamycin and artesunate+atovaquone-proguanil combination therapy. Treatments containing an artemisinin derivative or an intercalated Plasmodium vivax infection increased the geometric mean interval to recrudescence by 1.28-fold (95% CI: 1.09-1.51) and 2.19-fold (1.77-2.72), respectively. Intervals to recrudescence were decreased 0.83-fold (0.73-0.95) if treatment was not fully supervised (suggesting incomplete adherence) and 0.98 fold (0.96-0.99) for each doubling in baseline parasitaemia. CONCLUSIONS: Prolonged time to recrudescence may occur in pregnancy, regardless of anti malarial treatment. Long intervals to recrudescence are more likely with the use of artemisinin-containing treatments and also observed with intercalated P. vivax infections treated with chloroquine. Accurate determination of drug efficacy in pregnancy requires longer duration of follow-up, preferably until delivery or day 63, whichever occurs last. PMID- 26017555 TI - Influence of the Synthetic Conditions on the Structural and Electrochemical Properties of Carbon Nano-Onions. AB - Thermal annealing of nanodiamonds with diameters of a few nanometers (in an inert atmosphere and at temperatures in the range: 1500-1800 degrees C) leads to the formation of carbon nano-onions (CNOs) with diameters between 5 and 6 nm, which correspond to nanostructures with six to eight graphitic layers. The resulting spherical CNO structures were thermally modified under different atmospheres and characterized by SEM, TEM, thermogravimetric analysis and spectroscopic (Raman and diffuse reflectance infrared Fourier transform/FTIR) spectroscopy. The electrochemical properties of the CNOs prepared under different conditions were determined and compared. The results reveal that the CNOs show different structures with predominant spherical "small" carbon nano-onions. The aim of this article is to investigate the impact of the CNO's synthesis conditions on the resulting structures and study the effect of further thermal modifications on the sizes, shapes and homogeneity of these carbon nanostructures. PMID- 26017554 TI - Having a lot of a good thing: multiple important group memberships as a source of self-esteem. AB - Membership in important social groups can promote a positive identity. We propose and test an identity resource model in which personal self-esteem is boosted by membership in additional important social groups. Belonging to multiple important group memberships predicts personal self-esteem in children (Study 1a), older adults (Study 1b), and former residents of a homeless shelter (Study 1c). Study 2 shows that the effects of multiple important group memberships on personal self esteem are not reducible to number of interpersonal ties. Studies 3a and 3b provide longitudinal evidence that multiple important group memberships predict personal self-esteem over time. Studies 4 and 5 show that collective self-esteem mediates this effect, suggesting that membership in multiple important groups boosts personal self-esteem because people take pride in, and derive meaning from, important group memberships. Discussion focuses on when and why important group memberships act as a social resource that fuels personal self-esteem. PMID- 26017557 TI - Editorial: Small molecule therapeutics for Alzheimer's disease. PMID- 26017556 TI - DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion. AB - The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair and is also frequently overexpressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. We found that DNA PKcs participates in melanoma primary tumor and metastasis development by stimulating angiogenesis, migration and invasion. Comparison of conditioned medium content from DNA-PKcs-proficient and deficient cells reveals that DNA-PKcs controls secretion of at least 103 proteins (including 44 metastasis-associated with FBLN1, SERPINA3, MMP-8, HSPG2 and the inhibitors of matrix metalloproteinases, such as alpha-2M and TIMP-2). High throughput analysis of secretomes, proteomes and transcriptomes, indicate that DNA-PKcs regulates the secretion of 85 proteins without affecting their gene expression. Our data demonstrate that DNA-PKcs has a pro-metastatic activity via the modification of the tumor microenvironment. This study shows for the first time a direct link between DNA damage repair and cancer metastasis and highlights the importance of DNA-PKcs as a potential target for anti-metastatic treatment. PMID- 26017558 TI - Alzheimer's disease, astrocytes and kynurenines. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease and the most common cause of dementia. The etiology of AD is not entirely clear and despite the increasing knowledge regarding the pathomechanism, no effective disease modifying therapy is yet available. Astrocytes earlier presumed to serve merely supportive roles for the neuronal network, have recently been shown to play an active role in the synaptic dysfunction, impairment of homeostasis, inflammation as well as excitotoxicity in relation to AD pathology. This review focuses on the pathomechanism of AD with special attention to the role of the astrocytes, excitotoxicity and the alterations in the kynurenine metabolism in the development of the disease. The correction of the neuroprotective/neurotoxic imbalance in the kynurenine pathway may represent a novel target for pharmaceutical interventions in dementia related to neurodegenerative disorders. PMID- 26017559 TI - 1950 MHz Electromagnetic Fields Ameliorate Abeta Pathology in Alzheimer's Disease Mice. AB - The involvement of radiofrequency electromagnetic fields (RF-EMF) in the neurodegenerative disease, especially Alzheimer's disease (AD), has received wide consideration, however, outcomes from several researches have not shown consistency. In this study, we determined whether RF-EMF influenced AD pathology in vivo using Tg-5xFAD mice as a model of AD-like amyloid beta (Abeta) pathology. The transgenic (Tg)-5xFAD and wild type (WT) mice were chronically exposed to RF EMF for 8 months (1950 MHz, SAR 5W/kg, 2 hrs/day, 5 days/week). Notably, chronic RFEMF exposure significantly reduced not only Abeta plaques, APP, and APP carboxyl-terminal fragments (CTFs) in whole brain including hippocampus and entorhinal cortex but also the ratio of Abeta42 and Abeta40 peptide in the hippocampus of Tg-5xFAD mice. We also found that parenchymal expression of beta amyloid precursor protein cleaving enzyme 1(BACE1) and neuroinflammation were inhibited by RF-EMF exposure in Tg-5xFAD. In addition, RF-EMF was shown to rescue memory impairment in Tg-5xFAD. Moreover, gene profiling from microarray data using hippocampus of WT and Tg- 5xFAD following RF-EMF exposure revealed that 5 genes (Tshz2, Gm12695, St3gal1, Isx and Tll1), which are involved in Abeta, are significantly altered inTg-5xFAD mice, exhibiting different responses to RF-EMF in WT or Tg-5xFAD mice; RF-EMF exposure in WT mice showed similar patterns to control Tg-5xFAD mice, however, RF-EMF exposure in Tg- 5xFAD mice showed opposite expression patterns. These findings indicate that chronic RF-EMF exposure directly affects Abeta pathology in AD but not in normal brain. Therefore, RF-EMF has preventive effects against AD-like pathology in advanced AD mice with a high expression of Abeta, which suggests that RF-EMF can have a beneficial influence on AD. PMID- 26017560 TI - Functional Activities Questionnaire Items that Best Discriminate and Predict Progression from Clinically Normal to Mild Cognitive Impairment. AB - BACKGROUND: Impairment in instrumental activities of daily living (IADL) emerges in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. Some IADL scales are sensitive to early deficits in MCI, but none have been validated for detecting subtle functional changes in clinically normal (CN) elderly at risk for AD. METHODS: Data from 624 subjects participating in the Alzheimer's Disease Neuroimaging Initiative and 524 subjects participating in the Massachusetts Alzheimer's Disease Research Center, which are two large cohorts including CN elderly and MCI subjects, were used to determine which Functional Activities Questionnaire items best discriminate between and predict progression from CN to MCI. RESULTS: We found that "Remembering appointments" and "assembling tax records" best discriminated between CN and MCI subjects, while worse performance on "paying attention and understanding a TV program", "paying bills/balancing checkbook", and "heating water and turning off the stove" predicted greater hazard of progressing from a diagnosis of CN to MCI. CONCLUSIONS: These results demonstrate that certain questions are especially sensitive in detecting the earliest functional changes in CN elderly at risk for AD. As the field moves toward earlier intervention in preclinical AD, it is important to determine which IADL changes can be detected at that stage and track decline over time. PMID- 26017561 TI - Novel Layer-by-Layer Deposition Technique for the Preparation of Double-Chambered Nanoparticle Formulations. AB - In this work, we report a novel method of layer-by-layer (LbL) deposition using concentration tubes that enables faster process and less damage to fragile nanocores than previously described methods. Such methods are generally based on continuous cycles of centrifugation/resuspension for long times and at high speeds, which may eventually lead to the aggregation of the deflocculated suspension of nanoparticles into a compact, non-resuspendable cake. The new method was applied to the preparation of a double-chambered nanocarrier system, which was successfully loaded with a fluorescently labeled model protein (lysozyme) and a model small molecule (fluorescein) in two defined and separate compartments, namely the poly lactide-co-glycolide (PLGA) core (~110 nm) and an outer shell obtained by LbL surface coating. The new method yielded stable suspensions of drug-loaded, LbL-coated PLGA nanoparticles, while centrifugation at high speeds and long time intervals leads to a compact cake of non resuspendable aggregates. These nanocarriers were taken up by MDCK cells in vitro, where a colocalization of both model compounds was shown by confocal imaging. PMID- 26017562 TI - LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. AB - Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that act upon the adaptation of cancer cells to hypoxia. LW6, an HIF-1 inhibitor, was hypothesized to improve resistance to cancer therapy in hypoxic tumors by inhibiting the accumulation of HIF-1alpha. A clear anti-tumor effect under low oxygen conditions would indicate that LW6 may be an improved treatment strategy for cancer in hypoxia. In the present study, the HIF-1 inhibition potential of LW6 on the growth and apoptosis of A549 lung cancer cells in association with oxygen availability was evaluated. LW6 was observed to inhibit the expression of HIF-1alpha induced by hypoxia in A549 cells at 20 mM, independently of the von Hippel-Lindau protein. In addition, at this concentration, LW6 induced hypoxia selective apoptosis together with a reduction in the mitochondrial membrane potential. The intracellular reactive oxygen species levels increased in LW6 treated hypoxic A549 cells and LW6 induced a hypoxia-selective increase of mitochondrial O2*-. In conclusion, LW6 inhibited the growth of hypoxic A549 cells by affecting the mitochondria. The inhibition of the mitochondrial respiratory chain is suggested as a potentially effective strategy to target apoptosis in cancer cells. PMID- 26017563 TI - The influence of the type of lime on the hygric behaviour and bio-receptivity of hemp lime composites used for rendering applications in sustainable new construction and repair works. AB - The benefits of using sustainable building materials are linked not only to the adoption of manufacturing processes that entail reduced pollution, CO2 emissions and energy consumption, but also to the onset of improved performance in the building. In particular, hemp-lime composite shows low shrinkage and high thermal and acoustic insulating properties. However, this material also shows a great ability to absorb water, an aspect that can turn out to be negative for the long term durability of the building. For this reason, the hygric properties of hemp based composites need to be studied to ensure the correct use of this material in construction and repair works. The water absorption, drying and transpirability of hemp composites made with aerial (in the form of dry powder and putty) and hydraulic limes were investigated here and related to the microbial growth induced by the water movements within the material. Results show that hemp natural hydraulic lime mixes exhibit the highest transpirability and drying rate, the lowest water absorption by immersion and capillary uptake and the least intense microbial attack and chromatic change. A microscopical study of the hemp shives also related their great ability to absorb water to the near-irreversible swelling of their structure under dry-wet conditions. PMID- 26017565 TI - Do Cyclodextrins Aggregate in Water? Insights from NMR Experiments. AB - One decade ago Bonini et al. [Langmuir 2006, 22, 1478-1484] reported the occurrence of aggregates of beta-cyclodextrin in aqueous solutions with sizes in the range from 90 nm to a few micrometers. The experimental technique used was cryo-TEM. This work followed a number of previous studies involving other physical parameters, such as viscosities and activity coefficients, the results of which were interpreted in terms of self-aggregation of cyclodextrins. Since then, the ability of cyclodextrins to self-assemble were often used to explain and rationalize the supramolecular mechanisms involving cyclodextrins. Here, the question of aggregation of native cyclodextrins (alpha-, beta-, and gamma-) in aqueous solutions is addressed by using (1)H NMR techniques, including NMR diffusometry, relaxometry, and proton peak intensities. Within the detection limit of the NMR experiments, no aggregates of cyclodextrin were observed. If aggregates are present, the fraction of cyclodextrin in aggregates is quite small less than 1%. However, we cannot exclude the presence of transient clusters involving several cyclodextrin molecules where the lifetime of the cluster is short. PMID- 26017564 TI - Coaching patients in the use of decision and communication aids: RE-AIM evaluation of a patient support program. AB - BACKGROUND: Decision aids educate patients about treatment options and outcomes. Communication aids include question lists, consultation summaries, and audio recordings. In efficacy studies, decision aids increased patient knowledge, while communication aids increased patient question-asking and information recall. Starting in 2004, we trained successive cohorts of post-baccalaureate, pre medical interns to coach patients in the use of decision and communication aids at our university-based breast cancer clinic. METHODS: From July 2005 through June 2012, we used the RE-AIM framework to measure Reach, Effectiveness, Adoption, Implementation and Maintenance of our interventions. RESULTS: 1. Reach: Over the study period, our program sent a total of 5,153 decision aids and directly administered 2,004 communication aids. In the most recent program year (2012), out of 1,524 eligible patient appointments, we successfully contacted 1,212 (80%); coached 1,110 (73%) in the self-administered use of decision and communication aids; sent 958 (63%) decision aids; and directly administered communication aids for 419 (27%) patients. In a 2010 survey, coached patients reported self-administering one or more communication aids in 81% of visits 2. Effectiveness: In our pre-post comparisons, decision aids were associated with increased patient knowledge and decreased decisional conflict. Communication aids were associated with increased self-efficacy and number of questions; and with high ratings of patient preparedness and satisfaction 3. Adoption: Among visitors sent decision aids, 82% of survey respondents reviewed some or all; among those administered communication aids, 86% reviewed one or more after the visit 4. IMPLEMENTATION: Through continuous quality adaptations, we increased the proportion of available staff time used for patient support (i.e. exploitation of workforce capacity) from 29% in 2005 to 84% in 2012 5. Maintenance: The main barrier to sustainability was the cost of paid intern labor. We addressed this by testing a service learning model in which student interns work as program coaches in exchange for academic credit rather than salary. The feasibility test succeeded, and we are now expanding the use of unpaid interns. CONCLUSION: We have sustained a clinic-wide implementation of decision and communication aids through a novel staffing model that uses paid and unpaid student interns as coaches. PMID- 26017566 TI - Structure-activity relationship studies of 4-methylcoumarin derivatives as anticancer agents. AB - CONTEXT: Cancer is a leading cause of death worldwide and novel chemotherapeutic agents with better efficacy and safety profiles are much needed. Coumarins are natural polyphenolic compounds with important pharmacological activities, which are present in many dietary plants and herbal remedies. OBJECTIVES: The objective of this study is to investigate natural and synthetic coumarin derivatives with considerable anticancer capacity against three human cancer cell lines. MATERIALS AND METHODS: We synthesized 27 coumarin derivatives (mostly having 4-methyl moiety) and examined their cytotoxic effect on three human cancer cell lines, K562 (chronic myelogenous leukemia), LS180 (colon adenocarcinoma), and MCF-7 (breast adenocarcinoma) by MTT reduction assay. Screened compounds included 7 hydroxy-4-methylcoumarins (7-HMCs), 7-acetoxy-4-methylcoumarins (7-AMCs), and different dihydroxy-4-methylcoumarin (DHMC) and diacetoxy-4-methylcoumarin (DAMC) derivatives. Some compounds with methoxy, amine, and bromine substitutions were also examined. RESULTS: 7,8-DHMCs bearing alkyl groups at C3 position were the most effective subgroup, and of which, the most potent is compound 11, with an n decyl chain at C3, which had IC50 values of 42.4, 25.2, and 25.1 uM against K562, LS180, and MCF-7 cells, respectively. The second most active subgroup was 7,8 DAMCs containing ethoxycarbonylmethyl and ethoxycarbonylethyl moieties at C3 position. Compound 27 (6-bromo-4-bromomethyl-7-hydroxycoumarin), the only derivative containing bromine also showed reasonable cytotoxic activities (IC50 range: 32.7-45.8 uM). DISCUSSION AND CONCLUSION: This structure-activity relationship (SAR) study of 4-methylcoumarins shows that further investigation of these derivatives may lead to the discovery of novel anticancer agents. PMID- 26017567 TI - Bisbibenzyls, novel proteasome inhibitors, suppress androgen receptor transcriptional activity and expression accompanied by activation of autophagy in prostate cancer LNCaP cells. AB - CONTEXT: Bisbibenzyl compounds have gained our interests for their potential antitumor activity in malignant cell-types. OBJECTIVE: The objective of this study is to investigate the effect of bisbibenzyl compounds riccardin C (RC), marchantin M (MM), and riccardin D (RD) on androgen receptor (AR) in prostate cancer (PCa) cells. MATERIALS AND METHODS: After exposure to 10 MUM of the compounds for 24 h, cell cycle and cell survival analyses were performed using FACS and MTT assay to confirm the effect of these bisbibenzyls on PCa LNCaP cells. Changes in the AR expression and function, as the result of exposure to the compounds, were investigated using real-time PCR, ELISA, transient transfection, western blotting (WB), immunoprecipitation, and immunofluorescence staining (IF). Chemical-induced autophagy was examined by WB, IF, and RNAi. RESULTS: RC, MM, and RD reduced the viability of LNCaP cells accompanied with arrested cell cycle in the G0/G1 phase and induction of apoptosis. Further investigation revealed that these compounds significantly inhibited AR expression at mRNA and protein levels, leading to the suppression of AR transcriptional activity. Moreover, inhibition of proteasome activity by bisbibenzyls, which in turn caused the induction of autophagy, as noted by induction of LC3B expression, conversion, and accumulation of punctate dots in treated cells. Co-localization of AR/LC3B and AR/Ub suggested that autophagy contributed to the degradation of polyubiquitinated-AR when proteasome activity was suppressed by the bisbibenzyls. DISCUSSION AND CONCLUSION: Suppression of proteasome activity and induction of autophagy were involved in bisbibenzyl-mediated modulation of AR activities and apoptosis, suggesting their potential in treating PCa. PMID- 26017569 TI - Rapid Synthesis of Thiophene-Based, Organic Dyes for Dye-Sensitized Solar Cells (DSSCs) by a One-Pot, Four-Component Coupling Approach. AB - This one-pot, four-component coupling approach (Suzuki-Miyaura coupling/C-H direct arylation/Knoevenagel condensation) was developed for the rapid synthesis of thiophene-based organic dyes for dye-sensitized solar cells (DSSCs). Seven thiophene-based, organic dyes of various donor structures with/without the use of a 3,4-ethylenedioxythiophene (EDOT) moiety were successfully synthesized in good yields based on a readily available thiophene boronic acid pinacol ester scaffold (one-pot, 3-step, 35-61%). Evaluation of the photovoltaic properties of the solar cells that were prepared using the synthesized dyes revealed that the introduction of an EDOT structure beside a cyanoacrylic acid moiety improved the short-circuit current (Jsc) while decreasing the fill factor (FF). The donor structure significantly influenced the open-circuit voltage (Voc), the FF, and the power conversion efficiency (PCE). The use of a n-hexyloxyphenyl amine donor, and our originally developed, rigid, and nonplanar donor, both promoted good cell performance (eta=5.2-5.6%). PMID- 26017568 TI - The maize cytochrome P450 CYP79A61 produces phenylacetaldoxime and indole-3 acetaldoxime in heterologous systems and might contribute to plant defense and auxin formation. AB - BACKGROUND: Plants produce a group of aldoxime metabolites that are well known as volatiles and as intermediates in cyanogenic glycoside and glucosinolate biosynthesis in particular plant families. Recently it has been demonstrated that aldoximes can also accumulate as part of direct plant defense in poplar. Cytochrome P450 enzymes of the CYP79 family were shown to be responsible for the formation of aldoximes from their amino acid precursors. RESULTS: Here we describe the identification and characterization of maize CYP79A61 which was heterologously expressed in yeast and Nicotiana benthamiana and shown to catalyze the formation of (E/Z)-phenylacetaldoxime and (E/Z)-indole-3-acetaldoxime from L phenylalanine and L-tryptophan, respectively. Simulated herbivory on maize leaves resulted in an increased CYP79A61 transcript accumulation and in elevated levels of L-phenylalanine and (E/Z)-phenylacetaldoxime. Although L-tryptophan levels were also increased after the treatment, (E/Z)-indole-3-acetaldoxime could not be detected in the damaged leaves. However, simulated herbivory caused a significant increase in auxin concentration. CONCLUSIONS: Our data suggest that CYP79A61 might contribute to the formation of (E/Z)-phenylacetaldoxime in maize. Since aldoximes have been described as toxic compounds for insect herbivores and pathogens, the increased accumulation of (E/Z)-phenylacetaldoxime after simulated herbivory indicates that this compound plays a role in plant defense. In addition, it is conceivable that (E/Z)-indole-3-acetaldoxime produced by recombinant CYP79A61 could be further converted into the plant hormone indole-3 acetic acid after herbivore feeding in maize. PMID- 26017570 TI - Requirements for reflection in the critical care environment. AB - BACKGROUND: Reflection is recognised as an important method for practice development. The importance of reflection is well documented in the literature, but the requirements for reflection remain unclear. OBJECTIVES: To explore and describe the requirements for reflection in the critical care environment as viewed by educators of qualified critical care nurses. METHOD: A focus group interview was conducted to explore and describe the views of educators of qualified critical care nurses regarding requirements for reflection in the critical care environment. RESULTS: The themes that emerged from the focus group were buy-in from stakeholders -management, facilitators and critical care nurses, and the need to create an environment where reflection can occur. CONCLUSION: Critical care nurses should be allowed time to reflect on their practice and be supported by peers as well as a facilitator in a non-intimidating way to promote emancipatory practice development. PMID- 26017571 TI - A meta-analysis of the prevalence of Toxoplasma gondii in animals and humans in Ethiopia. AB - BACKGROUND: Toxoplasmosis is a worldwide zoonosis. The objectives of this study were to estimate the prevalence and assess the potential risk factors of Toxoplasma gondii infections in animals and humans in Ethiopia by using meta analytical methods. METHODS: Published studies on T. gondii in animals and humans in Ethiopia were searched in Medline, Google Scholar and the lists of references of articles. Eligible studies were selected by using inclusion and exclusion criteria. The risks of within and across study biases, and the variations in prevalence estimates attributable to heterogeneities were assessed. Pooled prevalence was estimated by the DerSimonian and Laird random effects model. RESULTS: Thirty two studies were eligible and data from 5689 animals and 5718 humans were used for quantitative syntheses. The pooled IgG seroprevalence in cats, small ruminants and humans were estimated at 87.72% (95% CI = 78.63, 93.28), 34.59% (95% CI = 21.08, 51.12) and 74.73% (95% CI = 61.85, 84.36), respectively. The odds of infections were higher in pregnant than in non pregnant women (OR = 3.96), in individuals that had contact with cats than those with no contact (OR = 2.53), and in urban than in rural inhabitants (OR = 2.06). CONCLUSIONS: Toxoplasmosis is highly prevalent and could be a cause of considerable reproductive wastage in small ruminants and multiple diseases in humans in Ethiopia. Public education on preventive measures could help reduce the transmission of the parasite to humans. PMID- 26017573 TI - The 'dark side' of social capital: trust and self-rated health in European countries. AB - BACKGROUND: Generalized interpersonal trust (as an indicator of social capital) has been linked to health status at both the individual and ecological level. We sought to examine how changes in contextual and individual trust are associated with changes in self-rated health in the European Social Surveys 2002-12. METHODS: A multilevel analysis using a variance components model was performed on 203 452 individuals nested within 145 country cohorts covering 35 countries. Conditional on sociodemographic covariates, we sought to examine the association between self-rated health and individual trust, country average trust and a cross level interaction between the two. RESULTS: Although individual trust perceptions were significantly correlated with self-rated health [OR = 0.95, 95% confidence interval (0.94-0.96)], country-level trust was not associated [OR = 1.12, 95% confidence interval (0.95-1.32)]. There was, however, a strong crosslevel interaction between contextual and individual trust (P < 0.001), such that individuals with high interpersonal trust reported better health in contexts in which other individuals expressed high average interpersonal trust. Conversely, low trust individuals reported worse health in high trust contexts. CONCLUSION: Our findings suggest that contexts with increasing average trust can be harmful for low trust individuals, which might reflect the negative impact that social capital can have in certain groups. These findings suggest that contextual trust has a complex role in explaining health inequalities and individual self-rated health. PMID- 26017572 TI - Engineering the Controlled Assembly of Filamentous Injectisomes in E. coli K-12 for Protein Translocation into Mammalian Cells. AB - Bacterial pathogens containing type III protein secretion systems (T3SS) assemble large needle-like protein complexes in the bacterial envelope, called injectisomes, for translocation of protein effectors into host cells. The application of these "molecular syringes" for the injection of proteins into mammalian cells is hindered by their structural and genomic complexity, requiring multiple polypeptides encoded along with effectors in various transcriptional units (TUs) with intricate regulation. In this work, we have rationally designed the controlled expression of the filamentous injectisomes found in enteropathogenic Escherichia coli (EPEC) in the nonpathogenic strain E. coli K 12. All structural components of EPEC injectisomes, encoded in a genomic island called the locus of enterocyte effacement (LEE), were engineered in five TUs (eLEEs) excluding effectors, promoters and transcriptional regulators. These eLEEs were placed under the control of the IPTG-inducible promoter Ptac and integrated into specific chromosomal sites of E. coli K-12 using a marker-less strategy. The resulting strain, named synthetic injector E. coli (SIEC), assembles filamentous injectisomes similar to those in EPEC. SIEC injectisomes form pores in the host plasma membrane and are able to translocate T3-substrate proteins (e.g., translocated intimin receptor, Tir) into the cytoplasm of HeLa cells reproducing the phenotypes of intimate attachment and polymerization of actin-pedestals elicited by EPEC bacteria. Hence, SIEC strain allows the controlled expression of functional filamentous injectisomes for efficient translocation of proteins with T3S-signals into mammalian cells. PMID- 26017574 TI - Improved white spruce (Picea glauca) genome assemblies and annotation of large gene families of conifer terpenoid and phenolic defense metabolism. AB - White spruce (Picea glauca), a gymnosperm tree, has been established as one of the models for conifer genomics. We describe the draft genome assemblies of two white spruce genotypes, PG29 and WS77111, innovative tools for the assembly of very large genomes, and the conifer genomics resources developed in this process. The two white spruce genotypes originate from distant geographic regions of western (PG29) and eastern (WS77111) North America, and represent elite trees in two Canadian tree-breeding programs. We present an update (V3 and V4) for a previously reported PG29 V2 draft genome assembly and introduce a second white spruce genome assembly for genotype WS77111. Assemblies of the PG29 and WS77111 genomes confirm the reconstructed white spruce genome size in the 20 Gbp range, and show broad synteny. Using the PG29 V3 assembly and additional white spruce genomics and transcriptomics resources, we performed MAKER-P annotation and meticulous expert annotation of very large gene families of conifer defense metabolism, the terpene synthases and cytochrome P450s. We also comprehensively annotated the white spruce mevalonate, methylerythritol phosphate and phenylpropanoid pathways. These analyses highlighted the large extent of gene and pseudogene duplications in a conifer genome, in particular for genes of secondary (i.e. specialized) metabolism, and the potential for gain and loss of function for defense and adaptation. PMID- 26017576 TI - Anti-inflammatory treatment for carditis in acute rheumatic fever. AB - BACKGROUND: Rheumatic heart disease remains an important cause of acquired heart disease in developing countries. Although prevention of rheumatic fever and management of recurrences have been well established, optimal management of active rheumatic carditis remains unclear. This is an update of a review published in 2003, and previously updated in 2009 and 2012. OBJECTIVES: To assess the effects, both harmful and beneficial, of anti-inflammatory agents such as aspirin, corticosteroids and other drugs in preventing or reducing further valvular damage in patients with acute rheumatic fever. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (2013, Issue 9 of 12), MEDLINE (Ovid, 1948 to 2013 October Week 1), EMBASE (Ovid, 1980 to 2013 Week 41) and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 17 October 2013). We last searched Index Medicus (1950 to April 2001) in 2001. We checked reference lists of identified studies and applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials comparing anti inflammatory agents (e.g. aspirin, steroids, immunoglobulins, pentoxifylline) versus placebo or controls, or comparing any of the anti-inflammatory agents versus one another, in adults and children with acute rheumatic fever diagnosed according to Jones, or modified Jones, criteria. The presence of cardiac disease one year after treatment was the major outcome criterion selected. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias using the methodology outlined in the Cochrane Handbook of Systematic Reviews of Interventions. Standard methodological procedures as expected by The Cochrane Collaboration were used. MAIN RESULTS: No new studies were included in this update. Eight randomised controlled trials involving 996 people were selected for inclusion in the review. Researchers compared several steroidal agents such as corticotrophin, cortisone, hydrocortisone, dexamethasone, prednisone and intravenous immunoglobulin versus aspirin, placebo or no treatment. Six trials were conducted between 1950 and 1965; one was done in 1990 and the final study was published in 2001. Overall there were no observed significant differences in risk of cardiac disease at one year between corticosteroid-treated and aspirin-treated groups (six studies, 907 participants, risk ratio 0.87, 95% confidence interval 0.66 to 1.15). Similarly, use of prednisone (two studies, 212 participants, risk ratio 1.13, 95% confidence interval 0.52 to 2.45) compared with aspirin did not reduce the risk of heart disease after one year. Investigators in five studies did not report adverse events. The three studies reporting on adverse events reported substantial adverse events. However, all results should be interpreted with caution because of the age of the studies and the substantial risk of bias. AUTHORS' CONCLUSIONS: Little evidence of benefit was found when corticosteroids or intravenous immunoglobulins were used to reduce the risk of heart valve lesions in patients with acute rheumatic fever. The antiquity of most of the trials restricted adequate statistical analysis of the data and acceptable assessment of clinical outcomes by current standards. In addition, risk of bias was substantial, so results should be viewed with caution. New randomised controlled trials in patients with acute rheumatic fever are warranted to assess the effects of corticosteroids such as oral prednisone and intravenous methylprednisolone and the effects of other new anti-inflammatory agents. Advances in echocardiography will allow more objective and precise assessments of cardiac outcomes. PMID- 26017575 TI - Predictive modelling-based design and experiments for synthesis and spinning of bioinspired silk fibres. AB - Scalable computational modelling tools are required to guide the rational design of complex hierarchical materials with predictable functions. Here, we utilize mesoscopic modelling, integrated with genetic block copolymer synthesis and bioinspired spinning process, to demonstrate de novo materials design that incorporates chemistry, processing and material characterization. We find that intermediate hydrophobic/hydrophilic block ratios observed in natural spider silks and longer chain lengths lead to outstanding silk fibre formation. This design by nature is based on the optimal combination of protein solubility, self assembled aggregate size and polymer network topology. The original homogeneous network structure becomes heterogeneous after spinning, enhancing the anisotropic network connectivity along the shear flow direction. Extending beyond the classical polymer theory, with insights from the percolation network model, we illustrate the direct proportionality between network conductance and fibre Young's modulus. This integrated approach provides a general path towards de novo functional network materials with enhanced mechanical properties and beyond (optical, electrical or thermal) as we have experimentally verified. PMID- 26017577 TI - Can Households Cope with Health Shocks in Vietnam? AB - This paper investigates the economic impact of health shocks on working-age adults in Vietnam during 2004-2008, using a fixed effects specification. Health shocks cover disability and morbidity and are measured by 'days unable to carry out regular activity', 'days in bed due to illness/injury', and 'hospitalization'. Overall, Vietnamese households are able to smooth total non health expenditures in the short run in the face of a significant rise in out-of pocket health expenditures. However, this is accomplished through vulnerability enhancing mechanisms, especially in rural areas, including increased loans and asset sales and decreased education expenditures. Female-headed and rural households are found to be the least able to protect consumption. Results highlight the need to extend and deepen social protection and universal health coverage. (c) 2015 The Authors. Health Economics published by John Wiley & Sons Ltd. PMID- 26017578 TI - Pott's Puffy Tumor Caused by Chronic Sinusitis Resulting in Sinocutaneous Fistula. PMID- 26017579 TI - Phosphorylated alpha-synuclein in skin nerve fibres differentiates Parkinson's disease from multiple system atrophy. AB - Deposition of phosphorylated SNCA (also known as alpha-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinson's disease. Thus far, no pre-mortem studies investigating the presence of phosphorylated SNCA in skin sympathetic nerve fibres of multiple system atrophy, another synucleinopathy, have been conducted. In this in vivo study, skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinson's disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. Phosphorylated SNCA deposits in skin sympathetic nerve fibres and dermal nerve fibre density were assessed. All patients with Parkinson's disease expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with multiple system atrophy and essential tremor control subjects. These findings support that phosphorylated SNCA deposition is causative for nerve fibre degeneration in Parkinson's disease. Moreover, pre mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinson's disease from multiple system atrophy. PMID- 26017580 TI - Dissecting the phenotypes of Dravet syndrome by gene deletion. AB - Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Nav1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Nav1.1 in parvalbumin- or somatostatin expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Nav1.1 in parvalbumin- or somatostatin expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Nav1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Nav1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Nav1.1 in parvalbumin-expressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types. PMID- 26017581 TI - A Nicotiana attenuata cell wall invertase inhibitor (NaCWII) reduces growth and increases secondary metabolite biosynthesis in herbivore-attacked plants. AB - Plant invertases are sucrolytic enzymes that are essential for the regulation of carbohydrate metabolism and source-sink relationships. While their activity has been well documented during abiotic and biotic stresses, the role of proteinaceous invertase inhibitors in regulating these changes is unknown. Here, we identify a putative Nicotiana attenuata cell wall invertase inhibitor (NaCWII) which is strongly up-regulated in a jasmonate (JA)-dependent manner following simulated attack by the specialist herbivore Manduca sexta. To understand the role of NaCWII in planta, we silenced its expression by RNA interference and measured changes in primary and secondary metabolism and plant growth following simulated herbivory. NaCWII-silenced plants displayed a stronger depletion of carbohydrates and a reduced capacity to increase secondary metabolite pools relative to their empty vector control counterparts. This coincided with the attenuation of herbivore-induced CWI inhibition and growth suppression characteristic of wild-type plants. Together our findings suggest that NaCWII may act as a regulatory switch located downstream of JA accumulation which fine-tunes the plant's balance between growth and defense metabolism under herbivore attack. Although carbohydrates are not typically viewed as key factors in plant growth and defense, our study shows that interfering with their catabolism strongly influences plant responses to herbivory. PMID- 26017582 TI - A variant of multicystic biliary hamartoma presenting as an intrahepatic cystic neoplasm. AB - A rare case of an intrahepatic multicystic tumor is described. A 26-year-old man visited our hospital because of abdominal discomfort. Contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography revealed a 10 * 7 cm multicystic tumor of the bile duct in the right side of the liver. The gross appearance of the tumor resembled an intraductal papillary neoplasm of the bile duct, and right hepatectomy with regional lymphadenectomy was performed. Histologically, these cystic lesions were composed of variably and irregularly dilated duct structures lined by columnar epithelium resembling bile duct lining. There were no atypical cells and no papillary growth of the epithelial cells. Interestingly, the dilated ducts contained inspissated bile, and the inter-cystic parenchyma contained variable but irregularly distributed and hamartomatous hepatic parenchyma with an abnormal lobular pattern. Though it had atypical features of a hamartoma in some aspects (age, smooth muscle), this case could finally be regarded as a variant of multicystic biliary hamartoma. PMID- 26017584 TI - The Role of B-Vitamins in Bone Health and Disease in Older Adults. AB - The risk of osteoporosis and bone fractures increases with age. Several other factors are also related to bone disease including gender, race/ethnicity, physical activity, alcohol, smoking, estrogen, and calcium and vitamin D. B vitamins (folate, B12, and B6) are also emerging dietary factors related to bone health, both individually and through their action on influencing total plasma homocysteine concentrations (tHcy). The primary objective of this review is to summarize the available data on B-vitamins and bone health, highlighting clinical trials and observational data. In populations without folic acid fortification, the totality of evidence suggests that elevated tHcy has a small but significant association with bone fracture risk and bone quality but not on bone mineral density (BMD) or bone turnover biomarkers. Very little supportive evidence exists for a direct role of folate for either BMD or fracture risk; however, the data available are quite limited. Meta-analyses and some cross-sectional and cohort studies suggest a small but significant role of vitamin B12 status on risk of fracture but not on BMD. The mechanism by which tHcy and B12 may influence bone health is not well characterized but may be through modulation of collagen cross linking or through altering osteoclasts or osteoblasts. Much more data are needed particularly the role that each vitamin directly has on bone, or whether the vitamins only exert their effect though tHcy concentrations. Nevertheless, consistent findings across different populations with different study designs suggest a role for tHcy and B12 in reducing fracture risk. PMID- 26017585 TI - A New Specimen of Carroll's Mystery Hupehsuchian from the Lower Triassic of China. AB - A new specimen of an enigmatic hupehsuchian genus is reported. The genus was first recognized by Robert L. Carroll and Zhi-ming Dong in 1991, who refrained from naming it because of the poor quality of the only specimen known at the time. After more than two decades, we finally report a second specimen of this genus, which remained unprepared until recently. The new specimen preserves most of the skeleton except the skull, allowing us to erect a new genus and species, Eretmorhipis carrolldongi. The new species shares many characters with Parahupehsuchus longus, including the strange axial skeleton that forms a bony body tube. However, the body tube is short in the new species, being limited to the pectoral region. The vertebral count and limb morphology considerably differ between the new species and P. longus. The forelimb of E. carrolldongi is markedly larger than its hind limb as in Hupehsuchus nanchangensis but unlike in P. longus. The new species is unique among hupehsuchians in a list of features. It has manual and pedal digits that spread radially, forming manus and pes that are almost as wide as long. The third-layer elements of the dermal armor are unusually large, spanning four vertebral segments, yet there are substantial gaps among them. With the addition of the unique paddle, it is now clear that Hupehsuchia had diverse forelimb morphologies spanning from paddles to flippers, unlike ichthyopterygians that were taxonomically more diverse yet only had flippers. PMID- 26017583 TI - The Vestibular System: A Newly Identified Regulator of Bone Homeostasis Acting Through the Sympathetic Nervous System. AB - The vestibular system is a small bilateral structure located in the inner ear, known as the organ of balance and spatial orientation. It senses head orientation and motion, as well as body motion in the three dimensions of our environment. It is also involved in non-motor functions such as postural control of blood pressure. These regulations are mediated via anatomical projections from vestibular nuclei to brainstem autonomic centers and are involved in the maintenance of cardiovascular function via sympathetic nerves. Age-associated dysfunction of the vestibular organ contributes to an increased incidence of falls, whereas muscle atrophy, reduced physical activity, cellular aging, and gonadal deficiency contribute to bone loss. Recent studies in rodents suggest that vestibular dysfunction might also alter bone remodeling and mass more directly, by affecting the outflow of sympathetic nervous signals to the skeleton and other tissues. This review will summarize the findings supporting the influence of vestibular signals on bone homeostasis, and the potential clinical relevance of these findings. PMID- 26017586 TI - Unusual bleeding of a giant cell fibroblastoma: a soft tissue sarcoma of the skin mimicking metastatic melanoma. AB - A 56 year-old man presented to the emergency department after a spontaneous bleeding of a giant mass located on the right axilla. Clinical diagnosis was recurrent hemorrhagic nodular melanoma. Ten months previously a malignant melanoma had been removed from the dorsum by radical excision and surgical margins had been disease-free (MM: Breslow IV, Clark IV, lung and lynphnode metastases). The patient required immediate emergency surgical intervention to prevent death by hemorrhagic shock. The tumor was bleeding and the patient required a transfusion. Subjective symptoms included pain in palpation and spontaneous hemorrhage, poor general appearance, pale skin, BP 80/40 mmHg, HR 100/min with overall symptoms of hypovolemic shock. At the time of surgery, radical tumor excision was performed with an approximately 3 cm circumferential gross tumor free margin. The resultant defect was reconstructed by pectoral rotation fascio-cutaneous flap. The histological diagnosis demonstrated an undifferentiated high-grade pleomorphic sarcoma with microscopic tumor free margins. PMID- 26017587 TI - Enhanced dye-sensitized solar cell photocurrent and efficiency using a Y-shaped, pyrazine-containing heteroaromatic sensitizer linkage. AB - A new sensitizer motif for dye sensitized solar cells (DSSC) has been developed. A heteroaromatic moiety containing a pyrazine ring links two porphyrin chromophores to the metal oxide surface via two carboxylic acid attachment groups. A test DSSC sensitized with the new molecule was 3.5 times more efficient than a similar cell sensitized by a single porphyrin model compound. The open circuit photovoltage was increased by a modest factor of 1.3, but the photocurrent increased by a factor of 2.7. Most of the increase is attributed to a reduced rate of charge recombination of the charge separated state formed by photoinduced electron transfer from the excited sensitizer to the TiO2, although some of the difference is due to increased light absorption resulting from more dye on the photoanode. Increased light absorption due to the pyrazine-containing group may also play a role. The design illustrated here could also be used to link complementary sensitizers or antenna moieties in order to increase spectral coverage. PMID- 26017588 TI - Bilateral Mastectomy versus Breast-Conserving Surgery for Early-Stage Breast Cancer: The Role of Breast Reconstruction. AB - BACKGROUND: Although breast-conserving surgery is oncologically safe for women with early-stage breast cancer, mastectomy rates are increasing. The objective of this study was to examine the role of breast reconstruction in the surgical management of unilateral early-stage breast cancer. METHODS: A retrospective cohort study of women diagnosed with unilateral early-stage breast cancer (1998 to 2011) identified in the National Cancer Data Base was conducted. Rates of breast-conserving surgery, unilateral and bilateral mastectomy with contralateral prophylactic procedures (per 1000 early-stage breast cancer cases) were measured in relation to breast reconstruction. The association between breast reconstruction and surgical treatment was evaluated using a multinomial logistic regression, controlling for patient and disease characteristics. RESULTS: A total of 1,856,702 patients were included. Mastectomy rates decreased from 459 to 360 per 1000 from 1998 to 2005 (p < 0.01), increasing to 403 per 1000 in 2011 (p < 0.01). The mastectomy rates rise after 2005 reflects a 14 percent annual increase in contralateral prophylactic mastectomies (p < 0.01), as unilateral mastectomy rates did not change significantly. Each percentage point of increase in reconstruction rates was associated with a 7 percent increase in the probability of contralateral prophylactic mastectomies, with the greatest variation explained by young age(32 percent), breast reconstruction (29 percent), and stage 0 (5 percent). CONCLUSIONS: Since 2005, an increasing proportion of early-stage breast cancer patients have chosen mastectomy instead of breast-conserving surgery. This trend reflects a shift toward bilateral mastectomy with contralateral prophylactic procedures that may be facilitated by breast reconstruction availability. PMID- 26017589 TI - Effects of nitroglycerin ointment on mastectomy flap necrosis in immediate breast reconstruction: a randomized controlled trial. AB - BACKGROUND: Mastectomy flap necrosis is a common complication of immediate breast reconstruction that impacts recovery time and reconstructive success. Nitroglycerin ointment is a topical vasodilator that has been shown to improve skin flap survival in an animal model. The objective of this study was to evaluate whether the application of nitroglycerin ointment to the breast skin after mastectomy and immediate reconstruction causes a decrease in the rate of mastectomy flap necrosis compared with placebo. METHODS: This study was conducted as a randomized controlled trial and included patients aged 21 to 69 years undergoing mastectomy and immediate breast reconstruction at the University of British Columbia-affiliated hospitals (Vancouver, British Columbia, Canada). Patients with a medical history that precluded the administration of nitroglycerin were excluded from the study. The target sample size was 400 patients. Nitroglycerin ointment (45 mg) or a placebo was applied to the mastectomy skin at the time of surgical dressing. RESULTS: The trial was stopped at the first interim analysis after 165 patients had been randomized (85 to the treatment group and 80 to the placebo group). Mastectomy flap necrosis developed in 27 patients (33.8 percent) receiving placebo and in 13 patients (15.3 percent) receiving nitroglycerin ointment; the between-group difference was 18.5 percent (p = 0.006; 95 percent CI, 5.3 to 31.0 percent). Postoperative complications were similar in both groups [nitroglycerin, 22.4 percent (19 of 85); placebo, 28.8 percent (23 of 80)]. CONCLUSIONS: In patients undergoing mastectomy and immediate reconstruction, there was a marked reduction in mastectomy flap necrosis in patients who received nitroglycerin ointment. Nitroglycerin ointment application is a simple, safe, and effective way to help prevent mastectomy flap necrosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 26017590 TI - Treatment of breast animation deformity in implant-based reconstruction with pocket change to the subcutaneous position. AB - Breast animation may be an unfortunate result of subpectoral implant-based reconstruction following mastectomy. This article reviews a novel approach to the treatment of animation deformity in cases of reconstruction, whereby the pectoralis major muscle is sutured down to the chest wall and the implant is transferred to the subcutaneous plane. A retrospective review was performed on 19 breasts undergoing pocket change. In selected cases, fat grafting was added to augment the soft-tissue framework around the implant. Demographics, operative details, outcomes, and complications were recorded. All 19 breasts had complete resolution of their animation deformity. Complications were seen in five breasts (26.3 percent). Four breasts (21.1 percent) developed Baker grade III or IV capsular contracture requiring capsulectomy that was curative. One seroma (5.3 percent) required in-office drainage. There were no visible implant deformities, infections, or implant removals. In appropriately selected patients, pocket change to a subcutaneous plane is a safe and effective technique for correction of severe animation deformity following implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017591 TI - Can functional septorhinoplasty independently treat obstructive sleep apnea? AB - BACKGROUND: The purpose of this study was to determine whether functional rhinoplasty alone results in a significant improvement in obstructive sleep apnea parameters in patients with nasal obstruction. METHODS: Records of consecutive adult patients with nasal obstruction who underwent surgery to repair their nasal inlet and completed preoperative and postoperative polysomnography were reviewed. Patients underwent polysomnography before and after functional septorhinoplasty. Long-term follow-up using Nasal Obstruction Symptom Evaluation scores was conducted. Statistical analysis was performed using the Wilcoxon signed rank sum test. A Holm-Bonferroni sequential correction was also used because of multiple statistical comparisons being made. RESULTS: Twenty-six patients were included in this study. Mean apnea-hypopnea index scores preoperatively was 24.7, which dropped to a mean postoperative apnea-hypopnea index of 16, a reduction of 35 percent (p = 0.013). Excluding patients with a body mass index greater than 30 resulted in improved apnea-hypopnea index scores, from 22.5 to 9.6, a mean 57 percent reduction (p < 0.01). CONCLUSIONS: Functional rhinoplasty may have the potential to significantly improve the severity of obstructive sleep apnea for select patients with nasal obstruction. The nasal airflow improvement may modify pharyngeal aerodynamics. This is a fast and minimally invasive approach to consider in patients with obstructive sleep apnea and nasal obstruction, especially in patients with a body mass index less than 30. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017592 TI - The Role of the Superwet Technique in Face Lift: An Analysis of 1089 Patients over 23 Years. AB - BACKGROUND: The use of superwet technique of infiltration and autologous tissue sealants during rhytidectomy has benefits of decreasing bleeding and edema, improving visualization, and easing dissection. The purpose of this study was to analyze whether these intraoperative strategies resulted in more consistent and reproducible outcomes and significantly decreased hematoma rates. METHODS: A retrospective review was performed on 1089 consecutive face lifts performed by a single surgeon. Fisher's exact test was used to determine significant differences in hematomas between those patients who received platelet-rich plasma and superwet technique and those who did not. Multivariate logistic regression was used to evaluate demographic variables and intraoperative interventions for risk of complication. RESULTS: Five hundred eighty-seven of 1089 face lifts received platelet-rich plasma and 926 of 1089 underwent a superwet technique. Ten hematomas were recorded, six in the group that did not receive platelet-rich plasma compared to four who did (p = 0.527). One hematoma was observed before implementation of the superwet technique and nine were in the group after (p = 1.00). Multivariate analysis showed male sex to be a significant factor for hematoma (p < 0.001). CONCLUSIONS: This analysis showed excellent outcomes with a hematoma rate of 0.9 percent. Although no significant differences were noted, the authors attribute their consistent and reproducible results to the use of the superwet technique and platelet-rich plasma. The superwet technique allows for improved safety and visualization with improved hemostasis. Platelet-rich plasma potentially decreases ecchymosis and edema. Prospective studies are needed to determine significant differences between these intraoperative interventions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017593 TI - Readability assessment of online patient resources for breast augmentation surgery. AB - BACKGROUND: Patients increasingly rely on Internet resources for medical information. Well-informed patients are more likely to be active participants in their health care, contributing to higher satisfaction and better overall outcomes. Access to online patient material, however, can be limited by inadequate functional health literacy. The National Institutes of Health and the American Medical Association recommend that educational content be written at a sixth-grade reading level. This study aims to assess the readability of online patient resources for breast augmentation surgery. METHODS: A Web search for "breast implant surgery" was performed using the largest public search engine. After sponsored results were excluded, the 12 most accessed sites were identified. Patient-directed information from all relevant articles immediately linked from the main site was downloaded and formatted into plain text. The readability of 110 articles was evaluated using 10 established analyses, both overall and by Web site. RESULTS: The overall average readability of the 12 most popular Internet resources for breast augmentation was at a thirteenth-grade reading level (Coleman-Liau, 13.4; Flesch-Kincaid, 12.7; FORCAST, 11.3; Fry, 13; New Dale-Chall, 12.9; New Gunning Fog, 13.8; Raygor Estimate, 15; and Simple Mesaure of Gobbledygook Formula, 14.3). The Flesch Reading Ease index was 41, which falls into a "difficult" reading category. No individual article or Web site was at the recommended sixth-grade level. CONCLUSIONS: Online resources for breast augmentation are above recommended reading levels. This may potentially serve as a barrier to patients seeking this type of surgery. Plastic surgeons should be aware of potential gaps in understanding and direct patients toward more appropriate resources. PMID- 26017594 TI - Cryolipolysis for fat reduction and body contouring: safety and efficacy of current treatment paradigms. AB - BACKGROUND: Cryolipolysis is a nonsurgical technique for localized fat reduction. With the increased risk of complications from more invasive methods such as liposuction, cryolipolysis presents a promising method for nonsurgical body contouring. This study presents a systematic review of the available clinical data, with an emphasis on the efficacy, methods, safety, and complications of cryolipolysis. METHODS: To identify clinical studies that assessed outcomes of cryolipolysis, a systematic review of the MEDLINE and Cochrane databases was performed with the search algorithm cryolipolysis OR cool sculpting OR fat freezing OR lipocryolysis. RESULTS: The primary literature search returned 319 articles. After inclusion criteria were applied and additional articles were idenfied via manual review of article references, 19 studies were selected for review. Average reduction in caliper measurement ranged from 14.67 percent to 28.5 percent. Average reduction by ultrasound ranged from 10.3 percent to 25.5 percent. No significant impact on lipid levels or liver function tests after cryolipolysis treatments was noted in any study. Only mild, short-term side effects, such as erythema, swelling, and pain, were noted. Paradoxical adipose hyperplasia was described in one patient. CONCLUSIONS: Cryolipolysis is a promising procedure for nonsurgical fat reduction and body contouring and presents a compelling alternative to liposuction and other, more invasive methods. This procedure appears to be safe in the short term, with a limited side effect profile, and results in significant fat reduction when used for localized adiposities. It remains unclear whether posttreatment manual massage and multiple treatments in the same anatomic area enhance the efficacy of cryolipolysis. PMID- 26017595 TI - Taking it on the chin: recognizing and accounting for lower face asymmetry in chin augmentation and genioplasty. AB - During the course of thousands of preoperative facial analyses, it has become apparent that the chin, in most individuals, appears weaker on the left than on the right. This previously unreported disparity spans age, sex, and ethnicity. To document this finding, frontal and lateral photographs of 20 random patients from the senior author's practice were subjected to a battery of soft-tissue measurements. Analysis of four celebrities further demonstrated the ubiquity of relative left chin weakness. Precedent for asymmetry in human anatomy is abundant (e.g., handedness). Asymmetry, moreover, often is conserved throughout the population (e.g., sidedness of visceral orientation). Left-sided chin weakness appears to be another example of well-preserved anatomical asymmetry. The presence of this asymmetry should be considered in planning chin augmentation and genioplasty. PMID- 26017596 TI - Negative predictors for satisfaction in patients seeking facial cosmetic surgery: a systematic review. AB - BACKGROUND: Facial cosmetic surgery is becoming more popular. Patients generally indicate they are satisfied with the results. Certain patient characteristics, however, have been described as negative predictors for satisfaction. Psychopathology such as body dysmorphic disorder and personality disorders are notorious. Psychosocial and cultural factors are more difficult to distinguish. This systematic review defines the predictors, other than body dysmorphic disorder, of an unsatisfactory outcome after facial cosmetic surgery. The authors are also interested in whether valid preoperative assessment instruments are available to determine these factors. METHODS: An extensive systematic PubMed/MEDLINE and Cochrane Library search was performed. In addition, relevant studies from the reference lists of the selected articles were added. There were no publication-year restrictions, and the last search was conducted on July 20, 2014. All factors described as negative predictors for patient satisfaction after facial cosmetic surgery were identified. RESULTS: Twenty-seven articles were analyzed, including 11 prospective studies, two retrospective studies, one case study, eight reviews, and five expert opinions. The following factors were identified: male sex, young age, unrealistic expectations, minimal deformities, demanding patients, "surgiholics," relational or familial disturbances, an obsessive personality, and a narcissistic personality. CONCLUSIONS: This review indicates the possible demographic and psychosocial predictors for an unsatisfactory outcome of facial cosmetic surgery. A brief personality assessment tool that could be used to address predictors preoperatively was not found. The authors suggest use of the Glasgow Benefit Inventory to assess patient satisfaction postoperatively. Further research is being undertaken to develop such an instrument. PMID- 26017597 TI - Effects of intersyringe processing on adipose tissue and its cellular components: implications in autologous fat grafting. AB - BACKGROUND: Autologous fat grafting is a popular technique in plastic surgery. A mechanical processing method is used to facilitate fat injection. No study has investigated whether this process affects cell quality and preservation of biological functionality. This study analyzed the influence of quick mechanical processing through two interconnected small-diameter syringes ("shuffling") on both structure and viability of fat tissue, and on viability, clonogenicity, and differentiation of the freshly isolated stromal vascular fraction. METHODS: Lipoaspiration was performed in six healthy donors, followed by shuffling the fat either zero, five, or 30 times between two 10-cc syringes. Thereafter, fat was applied through a 1.5-mm cannula as in a clinical setting for autologous fat grafting. Analysis of different treatment conditions was conducted. Immunofluorescent staining allowed assessment of morphology, viability, composition, and damage of the tissue. The stromal vascular fraction was examined for isolation yield, viability, clonogenicity, and differentiation capacity. RESULTS: The process of shuffling changed the macroscopic but not the microscopic structure of the lipoaspirated fat. No difference in cell number, viability, number of lipid droplets, vascular architecture, or ratio of cell composition was found. Analysis of the stromal vascular fraction, apart from large interdonor variability, did not show a significant change in isolation yield, viability, clonogenicity, or adipogenic differentiation capacity of the expanded cells. CONCLUSIONS: The mechanical procedure of shuffling lipoaspirated fat does not alter its tissue viability or its microscopic structure. The absence of impact on the stromal vascular fraction in the assessed parameters suggests that shuffling can be executed according to surgical needs. PMID- 26017599 TI - Providing a sense of touch to prosthetic hands. AB - Each year, approximately 185,000 Americans suffer the devastating loss of a limb. The effects of upper limb amputations are profound because a person's hands are tools for everyday functioning, expressive communication, and other uniquely human attributes. Despite the advancements in prosthetic technology, current upper limb prostheses are still limited in terms of complex motor control and sensory feedback. Sensory feedback is critical to restoring full functionality to amputated patients because it would relieve the cognitive burden of relying solely on visual input to monitor motor commands and provide tremendous psychological benefits. This article reviews the latest innovations in sensory feedback and argues in favor of peripheral nerve interfaces. First, the authors examine the structure of the peripheral nerve and its importance in the development of a sensory interface. Second, the authors discuss advancements in targeted muscle reinnervation and direct neural stimulation by means of intraneural electrodes. The authors then explore the future of prosthetic sensory feedback using innovative technologies for neural signaling, specifically, the sensory regenerative peripheral nerve interface and optogenetics. These breakthroughs pave the way for the development of a prosthetic limb with the ability to feel. PMID- 26017600 TI - Using the Patient Reported Outcomes Measurement Information System to Evaluate Psychosocial Functioning among Children with Craniofacial Anomalies. AB - BACKGROUND: Children with craniofacial anomalies are at risk for social exclusion, bullying, and psychological symptoms, all of which are associated with poor developmental and health outcomes. The National Institutes of Health developed Patient Reported Outcomes Measurement Information System instruments may be useful tools for monitoring psychosocial functioning in clinical settings and for integrating patient and parent perspectives. METHODS: The current study included 74 children (50 percent male) with craniofacial anomalies recruited through a multidisciplinary clinic. The authors obtained child self-report and parent-proxy ratings of depression, anxiety, and peer relationship quality using National Institutes of Health Patient Reported Outcomes Measurement Information System instruments. The authors compared sample means to Patient Reported Outcomes Measurement Information System instruments norms and analyzed the reliability of parents' and children's reporting of psychosocial variables. RESULTS: All reliability statistics were satisfactory (alpha values ranging from 0.74 to 0.96) and sample standard deviations were similar to those obtained in a general population, suggesting that Patient Reported Outcomes Measurement Information System instruments are reliable among children with craniofacial anomalies. In general, children and parents did not report unusual levels of psychological distress; however, they did report poorer peer relationship quality relative to normed data, a trend that was particularly pronounced among boys. CONCLUSIONS: National Institutes of Health Patient Reported Outcomes Measurement Information System instruments are efficient and accurate tools for monitoring psychosocial adjustment among children with craniofacial anomalies. It may be especially important to monitor social functioning, particularly among boys. PMID- 26017598 TI - Role of gender in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation. AB - BACKGROUND: Heterotopic ossification most commonly occurs after burn injury, joint arthroplasty, and trauma. Male gender has been identified as a risk factor for the development of heterotopic ossification. It remains unclear why adult male patients are more predisposed to this pathologic condition than adult female patients. In this study, the authors use their validated tenotomy/burn model to explore differences in heterotopic ossification between male and female mice. METHODS: The authors used their Achilles tenotomy and burn model to evaluate the osteogenic potential of mesenchymal stem cells of male and female injured and noninjured mice. Groups consisted of injured male (n = 3), injured female (n = 3), noninjured male (n = 3), and noninjured female (n = 3) mice. The osteogenic potential of cells harvested from each group was assessed through RNA and protein levels and quantified using micro-computed tomographic scan. Histomorphometry was used to verify micro-computed tomographic findings, and immunohistochemistry was used to assess osteogenic signaling at the site of heterotopic ossification. RESULTS: Mesenchymal stem cells of male mice demonstrated greater osteogenic gene and protein expression than those of female mice (p < 0.05). Male mice in the burn group formed 35 percent more bone than female mice in the burn group. This bone formation correlated with increased pSmad and insulin-like growth factor 1 signaling at the heterotopic ossification site in male mice. CONCLUSIONS: The authors demonstrate that male mice form quantitatively more bone compared with female mice using their burn/tenotomy model. These findings can be explained at least in part by differences in bone morphogenetic protein and insulin-like growth factor 1 signaling. PMID- 26017601 TI - Reconstruction of congenital tragal malformations accompanied by dystopic cartilage growth (accessory tragus). AB - BACKGROUND: Patients with solitary-type congenital tragal malformations accompanied by dystopic cartilage growth (accessory tragus) show not only a disfigured or absent tragus but also unnecessary tragal or pretragal lumps. Furthermore, an absent tragus causes a wholly exposed external auditory canal. MATERIALS: Sixty-five ears (54 patients) showing congenital tragal malformations accompanied by dystopic cartilage growth were reconstructed from March of 1991 to February of 2014. Reconstructions were reviewed using medical records and photographs, surgical methods were analyzed, and postoperative outcomes were evaluated. RESULTS: Six kinds of tragal framework fabrication methods were used in the reconstructions: free cartilage grafting (n = 7); cartilage transposition and anchoring (n = 7); cartilage folding and anchoring (n = 46); vascularized chondrocutaneous island flap (n = 4); and costal cartilage grafting (n = 1). Immediate postoperatively, four cases showed congestion of the covered skin. Forty-three patients (78 percent) were followed up for an average period of 15 months. The following were observed: larger tragus (n = 3); flat tragus without peak (n = 2); posterior protrusion of the tragal wall (n = 2); and hypertrophic scar (n = 1). All cases with a wholly exposed external auditory canal were corrected. The average score of the aesthetic outcomes, rated on a four-point Likert scale (1 = poor, 2 = fair, 3 = good, 4 = excellent), was 3.8 points. CONCLUSIONS: Cartilage and covered skin from the dystopic cartilage growth provided the best-available tissues for new tragal reconstructions. Different surgical techniques were used in accordance with the severity of the tragal malformation encountered. Most techniques provided aesthetically pleasing outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017602 TI - A retrospective review of the outcomes of migraine surgery in the adolescent population. AB - BACKGROUND: Migraine surgery has been studied extensively in adult patients with refractory headaches. The purpose of this study was to review a single surgeon's outcomes following migraine surgery in an adolescent population. METHODS: A retrospective review of all patients operated on by the senior author (B.G.) from 2000 to 2014 was performed. All patients aged 18 years or younger with at least 1 year of follow-up after surgery were included. Preoperative and postoperative migraine frequency, duration, severity, and migraine headache days and migraine index were analyzed for statistical significance. RESULTS: A total of 14 patients and 15 operations were analyzed. After an average follow-up of 38.2 months, the frequency of migraine headaches per 30-day period was reduced from 25 to 5 (p < 0.0001), the migraine headache index decreased from 148.1 to 12.4 (p < 0.0001), the duration of headaches (number of hours per 24 hours) declined from 0.71 to 0.25 (p = 0.002), severity of headaches diminished from 8.2 to 4.3 (p = 0.0004), and migraine days per month declined from 25 to 5 (p < 0.0001). Five patients remained free of any symptoms following surgery. One patient had no improvement in frequency of headaches, but did have improvement in severity and duration of headaches. No postoperative complications were noted in this group of patients. CONCLUSION: In the adolescent population with migraine headaches refractory to traditional medical management, migraine surgery may offer symptomatic improvement of migraine headache frequency, duration, and severity in patients with identifiable anatomical trigger sites. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017603 TI - Regenerative biomaterials: a review. AB - The authors present a review of biomaterials, substances traditionally derived from human or animal tissue or, more recently, biodegradable synthetics modeled after naturally occurring resources. These constructs differ from purely synthetic materials in that they are degraded or incorporated into a host's tissue. These biomaterials include a diverse array of medical products, such as acellular dermal matrix, bone substitutes, and injectables. In this review, the authors examine various clinical applications, including burn reconstruction and wound healing, breast surgery, complex abdominal wall reconstruction, craniofacial repair, and cosmetic surgery. Biomaterials such as acellular dermal matrix have proven beneficial in difficult-to-treat applications; however, more prospective data are needed to determine their true efficacy and cost effectiveness. PMID- 26017604 TI - So ... are you failing the marshmallow test? Connecting and disconnecting in our information-rich world. PMID- 26017606 TI - Salvage palmar fasciectomy after initial treatment with collagenase clostridium histolyticum. AB - BACKGROUND: Collagenase clostridium histolyticum was approved for clinical use in 2010 and has become an accepted treatment modality for Dupuytren's contracture. Because longitudinal experience with injectable collagenase remains limited, the effect of treatment on future surgery is not well defined. METHODS: A retrospective review of the senior author's practice from February of 2010 through March of 2014 was performed. Eleven patients were identified who had digital or palmar fasciectomy after at least one previous injection of collagenase clostridium histolyticum. Cases were reviewed for functional outcomes and operative difficulty. RESULTS: Seven metacarpophalangeal joints and 12 proximal interphalangeal joints in 11 patients were treated. Nine of the 11 patients were referred to the senior author after collagenase clostridium histolyticum injections by other hand surgeons; two patients had previous injections by the senior author. The average interval between most recent injection and salvage fasciectomy was 12 months. Intraoperative findings demonstrated disruption of normal architecture and areolar tissue, with extensive scar in the dissection planes after previous injection. Mean preoperative/postinjection joint contracture for metacarpophalangeal and proximal interphalangeal joints was 42 and 60 degrees, respectively; after surgery, joint contractures were 0 and 21 degrees, respectively. Significant improvement in postoperative range of motion was seen for both metacarpophalangeal and proximal interphalangeal joints after palmar fasciectomy. CONCLUSIONS: Collagenase clostridium histolyticum injections may produce a deeply scarred bed and increase the technical difficulty of salvage fasciectomy. However, results of palmar fasciectomy are comparable to those of primary fasciectomy even in the setting of recurrent or progressive disease. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017607 TI - Presurgical nasoalveolar molding for cleft lip and palate: the application of digitally designed molds. AB - BACKGROUND: The authors present a novel nasoalveolar molding protocol by prefabricating sets of nasoalveolar molding appliances using three-dimensional technology. METHODS: Prospectively, 17 infants with unilateral complete cleft lip and palate underwent the authors' protocol before primary cheiloplasty. An initial nasoalveolar molding appliance was created based on the patient's first and only in-person maxillary cast, produced from a traditional intraoral dental impression. Thereafter, each patient's molding course was simulated using computer software that aimed to narrow the alveolar gap by 1 mm each week by rotating the greater alveolar segment. A maxillary cast of each predicted molding stage was created using three-dimensional printing. Subsequent appliances were constructed in advance, based on the series of computer-generated casts. Each patient had a total three clinic visits spaced 1 month apart. Anthropometric measurements and bony segment volumes were recorded before and after treatment. RESULTS: Alveolar cleft widths narrowed significantly (p < 0.01), soft-tissue volume of each segment expanded (p < 0.01), and the arc of the alveolus became more contiguous across the cleft (p < 0.01). One patient required a new appliance at the second visit because of bleeding and discomfort. Eleven patients had mucosal irritation and two experienced minor mucosal ulceration. CONCLUSIONS: Three-dimensional technology can precisely represent anatomic structures in pediatric clefts. Results from the authors' algorithm are equivalent to those of traditional nasoalveolar molding therapies; however, the number of required clinic visits and appliance adjustments decreased. As three-dimensional technology costs decrease, multidisciplinary teams may design customized nasoalveolar molding treatment with improved efficiency and less burden to medical staff, patients, and families. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017608 TI - Fibrous dysplasia: management of the optic canal. AB - BACKGROUND: Fibrous dysplasia is an abnormal growth of bone that can lead to severe facial disfigurement. A dreaded outcome is compression of the optic nerve, leading to blindness. Controversy has surrounded the role of optic nerve unroofing for circumferential involvement of the optic canal. At present, many neurosurgeons unroof the nerve therapeutically in the setting of optic nerve dysfunction. Prophylactic unroofing (i.e., unroofing the nerve prior to the development of visual symptoms) has been previously proposed, although reported outcomes have been mixed. The authors present their long-term results of patients who have undergone optic nerve unroofing. METHODS: From 1975 to 2012, patients with fibrous dysplasia were investigated. Their age, demographics, operative procedure, optic nerve involvement (radiologically and clinically), and long-term outcomes and complications were recorded. RESULTS: Over 37 years, the senior author (S.A.W.) operated on 32 patients with fibrous dysplasia. Average follow-up was 5 years. Nine patients underwent optic nerve unroofing. Two patients had bilateral unroofing. Three patients who underwent therapeutic optic nerve unroofing ultimately went on to complete vision loss. The remaining seven patients who underwent prophylactic unroofing had no immediate postoperative visual compromise. CONCLUSIONS: Therapeutic optic nerve unroofing is advocated in fibrous dysplasia patients with continuous deterioration of vision. However, the authors believe prophylactic unroofing is safe, and it should be performed not necessarily as a primary surgical procedure, but as a procedure along with excision of fibrous dysplasia in the anterior skull base during the same operation performed for orbitocranial deformity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26017609 TI - Contemporary solutions for the treatment of facial nerve paralysis. AB - LEARNING OBJECTIVES: After reviewing this article, the participant should be able to: 1. Understand the most modern indications and technique for neurotization, including masseter-to-facial nerve transfer (fifth-to-seventh cranial nerve transfer). 2. Contrast the advantages and limitations associated with contiguous muscle transfers and free-muscle transfers for facial reanimation. 3. Understand the indications for a two-stage and one-stage free gracilis muscle transfer for facial reanimation. 4. Apply nonsurgical adjuvant treatments for acute facial nerve paralysis. SUMMARY: Facial expression is a complex neuromotor and psychomotor process that is disrupted in patients with facial paralysis breaking the link between emotion and physical expression. Contemporary reconstructive options are being implemented in patients with facial paralysis. While static procedures provide facial symmetry at rest, true 'facial reanimation' requires restoration of facial movement. Contemporary treatment options include neurotization procedures (a new motor nerve is used to restore innervation to a viable muscle), contiguous regional muscle transfer (most commonly temporalis muscle transfer), microsurgical free muscle transfer, and nonsurgical adjuvants used to balance facial symmetry. Each approach has advantages and disadvantages along with ongoing controversies and should be individualized for each patient. Treatments for patients with facial paralysis continue to evolve in order to restore the complex psychomotor process of facial expression. PMID- 26017610 TI - Evolution of Bilateral Free Flap Breast Reconstruction over 10 Years: Optimizing Outcomes and Comparison to Unilateral Reconstruction. AB - BACKGROUND: There is an increasing trend for contralateral prophylactic mastectomy, but studies focusing on bilateral free flap breast reconstruction are lacking. METHODS: A retrospective review was performed of all bilateral free flap breast reconstructions performed from 2000 to 2010. RESULTS: Overall, 488 patients underwent bilateral breast reconstruction (bilateral immediate, n = 283; bilateral delayed, n = 93; and bilateral immediate/delayed, n = 112), which more than doubled from the years 2000-2005 to 2006-2010 [147 versus 341 (232.0 percent)]. Comparison of contralateral prophylactic mastectomy demonstrated a similar increase over the decade [139 versus 282 (203.9 percent)]. There was an increasing trend toward perforator flaps [70 versus 203 (290 percent)] compared to traditional transverse rectus abdominis myocutaneous flaps [99 versus 17 (17 percent)] between the first and second halves of the decade. Patients undergoing a bilateral immediate/delayed reconstruction were significantly more likely to undergo a revision (p = 0.05), particularly on the immediate reconstructed breast (OR, 1.59; p = 0.05). Delayed reconstruction and obesity were significantly associated with postoperative complications. Obesity, smoking, and radiation therapy significantly increased fat necrosis rates, 2.77 (p = 0.01), 2.31 (p = 0.03), and 2.38 times (p = 0.03), respectively. In comparison to unilateral reconstruction, bilateral reconstruction had significantly higher flap loss rates (p = 0.004), comparable donor-site complications, and equivalent rates of revisions. CONCLUSIONS: There has been an increase in bilateral free flap breast reconstruction. Bilateral immediate/delayed reconstruction had higher revision rates of the prophylactic breast to achieve symmetry. Obesity, smoking, and radiation therapy were associated with increased complications, including fat necrosis, but successful reconstruction can be achieved with acceptable risks. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26017611 TI - Nipple-sparing mastectomy in patients with previous breast surgery: comparative analysis of 775 immediate breast reconstructions. AB - BACKGROUND: An increasing number of women are candidates for nipple preservation with mastectomy. It is unclear how previous breast surgery impacts nipple-sparing mastectomy and immediate breast reconstruction. METHODS: A single-institution retrospective review was performed between June of 2007 and June of 2013. RESULTS: Four hundred forty-four patients underwent 775 immediate breast reconstructions after nipple-sparing mastectomy. Of these, 160 patients and 187 reconstructions had previous breast surgery, including 154 lumpectomies, 27 breast augmentations, and six reduction mammaplasties. Two hundred eighty-four patients with 588 reconstructions without previous breast surgery served as the control group. The previous breast surgery patients were older (49.6 years versus 45.8 years; p < 0.001) but otherwise had similar demographics. Previous breast surgery reconstructions were more often unilateral, therapeutic, and associated with preoperative radiotherapy (p < 0.001 for each). Extension of breast scars was common with previous breast surgery, whereas the inframammary incision was most frequent if no scars were present (p < 0.001). Multivariate regression analysis showed that previous breast surgery was not a significant risk factor for ischemic complications or nipple loss. Subgroup analysis showed extension of prior irradiated incisions was predictive of skin flap necrosis (OR, 9.518; p = 0.05). A higher number of lumpectomy patients had preoperative radiotherapy (41 versus 11; p < 0.001), and patients with breast augmentation had more single stage reconstructions (85.2 percent versus 62.9 percent; p = 0.02). CONCLUSION: Nipple-sparing mastectomy and immediate reconstruction can be performed in patients with prior breast surgery with no significant increase in nipple loss or ischemic complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26017612 TI - The use of reduction mammaplasty with breast conservation therapy: an analysis of timing and outcomes. AB - BACKGROUND: Oncoplastic reduction mammaplasty is often used to prevent or correct breast conservation therapy deformities. The purpose of this review was to evaluate surgical outcomes, patient satisfaction, and aesthetic outcomes of this procedure when performed before or after radiation therapy. METHODS: Breast cancer patients treated with breast conservation therapy and reduction mammaplasty between 2005 and 2012 were divided into immediate reconstruction, delayed immediate reconstruction, and delayed reconstruction. Greater than 6 month follow-up was required for inclusion. Patient demographics and clinical outcomes, including complications, patient satisfaction, and aesthetic result, were queried. Patient satisfaction was determined using the BREAST-Q survey. Postoperative photographs were used to rate aesthetic outcomes blinded to the timing of the procedure. RESULTS: Patients in the immediate reconstruction group had fewer complications (immediate reconstruction, 20.5 percent; delayed immediate reconstruction, 33.3 percent; delayed reconstruction, 60.0 percent; p < 0.001) and asymmetry (immediate reconstruction, 8.5 percent; delayed immediate reconstruction, 44.4 percent; delayed reconstruction, 24.0 percent; p < 0.001), and required fewer procedures to complete the reconstruction (immediate reconstruction, 1.2; delayed immediate reconstruction, 2.4; delayed reconstruction, 2.2; p < 0.001). Delayed reconstruction resulted in higher complication and fat necrosis rates (immediate reconstruction, 0.9 percent; delayed immediate reconstruction, 0.0 percent; delayed reconstruction, 8.0 percent; p = 0.047). Although patient satisfaction and aesthetic outcomes were better in the immediate reconstruction group, this difference was not statistically significant. CONCLUSIONS: Oncoplastic reduction techniques performed before radiation therapy result in fewer complications. Good patient satisfaction and aesthetic outcomes can be achieved when reduction is performed before or after radiation therapy, but patient selection and education are important. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26017613 TI - Venous thromboembolism in body contouring: an analysis of 17,774 patients from the National Surgical Quality Improvement databases. AB - BACKGROUND: The purpose of this study was to examine the incidence and predictors of venous thromboembolism following body contouring. METHODS: The authors reviewed the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2012 for all body contouring cases. A multivariate logistic regression was performed to determine predictors of venous thromboembolism, and used to define risk scores for each significant predictor. RESULTS: Seventeen thousand seven hundred seventy-four patients underwent body contouring during the study period. Venous thromboembolism occurred in 99 individuals (0.56 percent). Multivariate logistic regression revealed that age older than 45 years [45 to 60 years (OR, 1.54; p = 0.1); older than 60 years (OR 3.1, p < 0.001)], undergoing contouring of the trunk (OR, 2.75; p < 0.001), obesity [body mass index of 30 to 34.9 (OR, 3.35; p < 0.001); body mass index of 35 to 39.9 (OR, 4.41; p < 0.001); body mass index >= 40 (OR, 3.14; p = 0.001)], and admission on an inpatient basis (OR, 3.01; p < 0.001) were associated with increased odds of venous thromboembolism. Patients' total scores were categorized as low (0 to 4), medium (5 to 7), or high risk (8 to 9). The low-risk cohort exhibited a venous thromboembolism incidence of 0.14 percent, the medium-risk cohort experienced an incidence of 0.97 percent, and the high-risk group experienced a venous thromboembolism incidence of 2.95 percent. CONCLUSIONS: This study identifies predictors of venous thromboembolism and creates a simple risk scoring model using a large, prospective data set. The authors' analysis demonstrates that in the presence of certain risk factors, the incidence of venous thromboembolism increases dramatically; in these cases, venous thromboembolism prophylaxis may be warranted. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 26017614 TI - Tendon regeneration with a novel tendon hydrogel: in vitro effects of platelet rich plasma on rat adipose-derived stem cells. AB - BACKGROUND: Tendon hydrogel is a promising new injectable substance that has been shown to improve repair strength after tendon injury. This study assesses the capacity of platelet-rich plasma to stimulate proliferation and migration of rat adipose-derived stem cells in tendon hydrogel in vitro. METHODS: To assess proliferation, adipose-derived stem cells were exposed to plasma, plasma supplemented with growth factors, or platelet-rich plasma in culture medium and tendon hydrogel. To assess migration, adipose-derived stem cells were plated onto tendon hydrogel -coated wells and covered with medium containing plasma, plasma supplemented with growth factors, platelet-rich plasma, or bovine serum albumin. Migration from cell-seeded to cell-free zones was assessed at 12-hour intervals. RESULTS: Platelet-rich plasma augmented proliferation to a greater extent compared with plasma and plasma supplemented with growth factors (10%: optical density, 1.18 versus 0.75 versus 0.98, respectively). Platelet-rich plasma was superior to plasma in tendon hydrogel (10%: optical density, 1.19 versus 0.85) but did not augment proliferation to the extent that plasma supplemented with growth factors did (10%: optical density, 1.19 versus 1.56). Platelet-rich plasma enhanced the migration of adipose-derived stem cells compared with serum-free medium (bovine serum albumin) (36 hours: platelet-rich plasma, 1.88; plasma, 1.51; plasma plus growth factor, 1.80; bovine serum albumin, 1.43). CONCLUSIONS: Tendon healing is mediated by migration of cells to the injured area and cellular proliferation at that site. Tendon hydrogel supplemented with platelet-rich plasma stimulates these processes. Future studies will evaluate this combination's ability to stimulate healing in chronic tendon injuries in vivo. PMID- 26017615 TI - Osteoprotegerin deficiency results in disruption of posterofrontal suture closure in mice: implications in nonsyndromic craniosynostosis. AB - BACKGROUND: Little is known about the role of osteoclasts in cranial suture fusion. Osteoclasts are predominantly regulated by receptor activator of nuclear factor kappa B and receptor activator of nuclear factor kappa B ligand, both of which lead to osteoclast differentiation, activation, and survival; and osteoprotegerin, a soluble inhibitor of receptor activator of nuclear factor kappa B. The authors' work examines the role of osteoprotegerin in this process using knockout technology. METHODS: Wild-type, osteoprotegerin-heterozygous, and osteoprotegerin-knockout mice were imaged by serial micro-computed tomography at 3, 5, 7, 9, and 16 weeks. Suture density measurements and craniometric analysis were performed at these same time points. Posterofrontal sutures were harvested from mice after the week-16 time point and analyzed by means of histochemistry. RESULTS: Micro-computed tomographic analysis of the posterofrontal suture revealed reduced suture fusion in osteoprotegerin-knockout mice compared with wild-type and heterozygous littermates. Osteoprotegerin deficiency resulted in a statistically significant decrease in suture bone density in knockout mice. There was no reduction in the density of non-suture-containing calvarial bone between wild-type and osteoprotegerin-knockout mice. Histochemistry of suture sections supported these micro-computed tomographic findings. Finally, osteoprotegerin knockout mice had reduced anteroposterior skull distance at all time points and an increased interorbital distance at the week-16 time point. CONCLUSION: The authors' data suggest that perturbations in the expression of osteoprotegerin and subsequent changes in osteoclastogenesis lead to alterations in murine cranial and posterofrontal suture morphology. PMID- 26017616 TI - Inhibition of liver fibrosis using vitamin A-coupled liposomes to deliver matrix metalloproteinase-2 siRNA in vitro. AB - Hepatic fibrosis is a common form of wound healing in response to chronic liver injuries and can lead to more serious complications, including mortality. It is well-established that hepatic stellate cells (HSCs) are central mediators of hepatic fibrosis, and matrix metalloproteinase-2 (MMP-2) is important in the formation of liver fibrosis. In addition, HSCs are the primary cells secreting MMP-2 and extracellular matrix, therefore, there has been increasing interest in developing agents with high selectivity towards HSCs. However, no clinical drugs based on MMP-2, directed against HSCs, have been used to prevent fibrosis. Following consideration of the abundant vitamin A (VitA) receptors expressed on the cellular membrane of HSCs, the present study constructed VitA-coupled liposomes (VitA-lips) using dicyclohexylcarbodiimide-1, 3-diaminopentane condensation, rotatory film processing and ultrasonic oscillation. The results revealed that the liposomes exhibited low cytotoxicity and a suitable binding ability to MMP-2 small interference (si)RNA. Furthermore, the liposomes effectively delivered MMP-2 siRNA to the HSC-T6 cells. When HSCs were treated with the liposomes carrying MMP-2 siRNA (VitA-lip-MMP-2 siRNA), the mRNA expression and activity of MMP-2, and the protein expression levels of alpha smooth muscle actin and type I collagen were significantly reduced. These results suggested that inhibition of the expression of MMP-2 in HSC-T6 cells may contribute to preventing hepatic fibrosis, and provided experimental support to the development of specific drugs against MMP-2 to prevent fibrogenesis in chronic liver disease. PMID- 26017617 TI - Synthesis of [(2)H6]ceftazidime as a stable isotopically labeled internal standard. AB - Ceftazidime is a third generation cephalosporin antibiotic that has activity against a wide range of Gram-negative and Gram-positive bacterial pathogens, including Escherichia coli and Pseudomonas aeruginosa. Stable isotope-labeled ceftazidime was required for use as an internal standard in LC-MS/MS assays, and a route was developed to make [(2)H6]ceftazidime in eight steps from the commercially available labeled starting material [(2)H7]isobutyric acid. PMID- 26017618 TI - Training in Buprenorphine and Office-Based Opioid Treatment: A Survey of Psychiatry Residency Training Programs. AB - OBJECTIVE: Psychiatrists are well suited to provide office-based opioid treatment (OBOT), but the extent to which psychiatry residents are exposed to buprenorphine training and OBOT during residency remains unknown. METHODS: Psychiatry residency programs in the USA were recruited to complete a survey. RESULTS: Forty-one programs were included in the analysis for a response rate of 23.7 %. In total, 75.6 % of the programs currently offered buprenorphine waiver training and 78.1 % provided opportunities to treat opioid dependence with buprenorphine under supervision. Programs generally not only reported favorable beliefs about OBOT and buprenorphine waiver training but also reported numerous barriers. CONCLUSIONS: The majority of psychiatry residency training programs responding to this survey offer buprenorphine waiver training and opportunities to treat opioid dependent patients, but numerous barriers continue to be cited. More research is needed to understand the role residency training plays in impacting future practice of psychiatrists. PMID- 26017619 TI - The Impact of Financial Disclosure on Attendee Assessment of Objectivity in Continuing Medical Education Programs in Psychiatry: A Randomized, Controlled Trial. AB - OBJECTIVE: The purpose of financial conflict of interest disclosures by speakers at continuing medical education (CME) programs is to assist attendees in their assessment of the objectivity of the information presented. This empirical study was undertaken to determine what level of disclosure is optimal to achieve this goal. METHODS: Attendees at five CME programs were randomly assigned to receive either a standard financial disclosure, an intermediate level that included whether speakers received more or less than 5% of their income from each company they disclosed, or a high level of disclosure that included the percent of their income derived from each company. A total of 169 attendees (85.4% response rate) completed a questionnaire regarding the objectivity of the CME presentation they attended. RESULTS: Attendees receiving the highest level of disclosure came significantly closer to the ratings of speaker bias made by peer reviewers than did attendees receiving medium or low levels of disclosure (p = 0.03; effect size 0.31). Among the minority of attendees who received the highest level of disclosure but whose assessment of bias differed from that of peer reviewers, however, there was a tendency to underestimate bias (5.9 vs 31.4%; p < 0.0001). CONCLUSIONS: The major limitation of this study was an overall low level of bias in the presentations, making it difficult to generalize these findings to less objective programs. The study did not address whether the process of disclosure had an impact on speakers' behavior. This study provides mixed support for higher levels of financial disclosure than are currently required for CME programs. PMID- 26017620 TI - Neuromodulation of Electrically Induced Hyperalgesia in the Trigeminocervical System. AB - OBJECTIVE: Trigeminal and cervical afferents converge on neurons of the trigeminocervical complex and may significantly alter the function of these neurons. This interaction may have implications for the pathophysiology and treatment of primary headache disorders. Therefore, the aim of this work was to study pain modulatory mechanisms within the trigeminocervical complex. SUBJECTS: We used an electrical pain model challenging pro- and antinociceptive systems in 19 healthy volunteers. METHODS: Transcutaneous supraorbital noxious electrical low-frequency stimulation (0.5 Hz), known to induce both hyperalgesia due to central sensitization (as a marker of pain facilitation) and habituation (as a marker of pain inhibition), was combined with different noxious stimulation paradigms applied to the innervation territory of upper cervical afferents. We investigated the effects of concurrent stimulation in the cervical/extratrigeminal system on habituation profiles, hyperalgesic area, pain, and detection thresholds in the trigeminal system. RESULTS: It was previously shown that conditioning 20-Hz noxious electrical stimuli may provoke centrally mediated sensory decline that possesses heterotopic antihyperalgesic properties. Occipital and forearm costimulation at a frequency of 20 Hz had no significant modulating effect on supraorbital pain adaptation, hyperalgesic area, or pain perception. Effects for trigeminal stimulation were independent of occipital stimulus intensity. Furthermore, for single occipital stimulation at 0.5 and 20 Hz, no somatosensory changes could be demonstrated within the trigeminal system. CONCLUSION: Trigeminal nociception stayed unchanged despite of occipital costimulation. PMID- 26017621 TI - Inhibition of prostate cancer cell growth by 3',4',5'-trimethoxyflavonol (TMFol). AB - PURPOSE: TMFol (3',4',5'-trimethoxyflavonol) is a synthetic analogue of the naturally occurring flavonol fisetin and quercetin, which have been considered of potential usefulness in the management of prostate cancer. We investigated whether TMFol may have preclinical features superior to those of its two flavonol congeners. METHODS: The ability of the three flavonols to compromise prostate cancer cell survival was tested in four prostate cancer cell types 22Rv1, TRAMP C2, PC-3 and LNCaP. The effect of TMFol on prostate cancer development in vivo was investigated in nude mice bearing the 22Rv1 or TRAMP C2 tumours. RESULTS: TMFol inhibited cell growth in vitro in all four prostate cancer cell types more potently than fisetin and quercetin. It also interfered with TRAMP C2 tumour development in vivo, while fisetin and quercetin at equivalent doses were without activity in this model. Likewise, TMFol slowed the growth of the 22Rv1 tumour in vivo. Efficacy in either model was accompanied by induction of apoptosis, although in vitro only TRAMP C2 cells, but not 22Rv1, underwent apoptosis when exposed to TMFol. CONCLUSIONS: The results support the notion that among the three congeneric flavonols, quercetin, fisetin and TMFol, the latter may be the most suitable candidate agent for potential development in prostate cancer management. PMID- 26017622 TI - Magnetism-Driven Ferroelectricity in Double Perovskite Y2NiMnO6. AB - We report the discovery of multiferroic behavior in double perovskite Y2NiMnO6. X ray diffraction shows that the material has a centrosymmetric crystal structure of space group P2(1)/n with Ni(2+)/Mn(4+) ordering. This result is further confirmed by aberration-corrected scanning transmission electron microscopy combined with atomic resolution electron energy loss spectroscopy. The appearance of ferroelectric polarization coincides with the magnetic phase transition (~67 K), which indicates that the ferroelectricity is driven by magnetism, and this is further confirmed by its strong magnetoelectric (ME) effect. We proposed the origin of the ferroelectricity is associated with the combination of Ni(2+)/Mn(4+) charge ordering and the ???? spin ordering. When compared with other known magnetic multiferroics, Y2NiMnO6 displays several attractive multiferroic properties, including high polarization (~145 MUC/m(2)), a high multiferroic transition temperature (~67 K), and strong ME coupling (~21%). PMID- 26017623 TI - Residual Distribution and Risk Assessment of Polychlorinated Biphenyls in Surface Sediments of the Pearl River Delta, South China. AB - We analyzed residual PCBs in surface sediments at 19 sites in the Pearl River Delta in the wet and dry seasons. Seven indicative PCB congeners (PCB28, PCB52, PCB101, PCB118, PCB153, PCB138 and PCB180) were detected in the surface sediments, among which the detection rate and mass concentrations of PCB52 were the highest. Total concentrations of the seven PCBs ranged from 19.8 to 111 MUg/kg, with an average of 48.2 MUg/kg. For the spatial distribution, the sum of the seven PCB (?PCB) concentrations for the stations that were located in the city region of the Pearl River Delta were significantly higher than the ?PCB concentrations for the eight outlets of the Pearl River Delta (p < 0.05). According to the US National Oceanic and Atmospheric Administration ERL and ERM guideline concentrations, the PCB concentrations may occasionally lead to adverse effects, especially in the dry season. PMID- 26017624 TI - Learning-guided automatic three dimensional synapse quantification for drosophila neurons. AB - BACKGROUND: The subcellular distribution of synapses is fundamentally important for the assembly, function, and plasticity of the nervous system. Automated and effective quantification tools are a prerequisite to large-scale studies of the molecular mechanisms of subcellular synapse distribution. Common practices for synapse quantification in neuroscience labs remain largely manual or semi-manual. This is mainly due to computational challenges in automatic quantification of synapses, including large volume, high dimensions and staining artifacts. In the case of confocal imaging, optical limit and xy-z resolution disparity also require special considerations to achieve the necessary robustness. RESULTS: A novel algorithm is presented in the paper for learning-guided automatic recognition and quantification of synaptic markers in 3D confocal images. The method developed a discriminative model based on 3D feature descriptors that detected the centers of synaptic markers. It made use of adaptive thresholding and multi-channel co-localization to improve the robustness. The detected markers then guided the splitting of synapse clumps, which further improved the precision and recall of the detected synapses. Algorithms were tested on lobula plate tangential cells (LPTCs) in the brain of Drosophila melanogaster, for GABAergic synaptic markers on axon terminals as well as dendrites. CONCLUSIONS: The presented method was able to overcome the staining artifacts and the fuzzy boundaries of synapse clumps in 3D confocal image, and automatically quantify synaptic markers in a complex neuron such as LPTC. Comparison with some existing tools used in automatic 3D synapse quantification also proved the effectiveness of the proposed method. PMID- 26017626 TI - The academic advantage: gender disparities in patenting. AB - We analyzed gender disparities in patenting by country, technological area, and type of assignee using the 4.6 million utility patents issued between 1976 and 2013 by the United States Patent and Trade Office (USPTO). Our analyses of fractionalized inventorships demonstrate that women's rate of patenting has increased from 2.7% of total patenting activity to 10.8% over the nearly 40-year period. Our results show that, in every technological area, female patenting is proportionally more likely to occur in academic institutions than in corporate or government environments. However, women's patents have a lower technological impact than that of men, and that gap is wider in the case of academic patents. We also provide evidence that patents to which women--and in particular academic women--contributed are associated with a higher number of International Patent Classification (IPC) codes and co-inventors than men. The policy implications of these disparities and academic setting advantages are discussed. PMID- 26017625 TI - Emerging mHealth and eHealth interventions for serious mental illness: a review of the literature. AB - BACKGROUND: Serious mental illness (SMI) is one of the leading causes of disability worldwide. Emerging mobile health (mHealth) and eHealth interventions may afford opportunities for reaching this at-risk group. AIM: To review the evidence on using emerging mHealth and eHealth technologies among people with SMI. METHODS: We searched MEDLINE, PsychINFO, CINAHL, Scopus, Cochrane Central, and Web of Science through July 2014. Only studies which reported outcomes for mHealth or eHealth interventions, defined as remotely delivered using mobile, online, or other devices, targeting people with schizophrenia, schizoaffective disorder, or bipolar disorder, were included. RESULTS: Forty-six studies spanning 12 countries were included. Interventions were grouped into four categories: (1) illness self-management and relapse prevention; (2) promoting adherence to medications and/or treatment; (3) psychoeducation, supporting recovery, and promoting health and wellness; and (4) symptom monitoring. The interventions were consistently found to be highly feasible and acceptable, though clinical outcomes were variable but offered insight regarding potential effectiveness. CONCLUSIONS: Our findings confirm the feasibility and acceptability of emerging mHealth and eHealth interventions among people with SMI; however, it is not possible to draw conclusions regarding effectiveness. Further rigorous investigation is warranted to establish effectiveness and cost benefit in this population. PMID- 26017627 TI - Evaluation of safety and effectiveness of factor VIII treatment in haemophilia A patients with low titre inhibitors or a personal history of inhibitor. Patient Data Meta-analysis of rAFH-PFM Post-Authorization Safety Studies. AB - There is no prospective evidence on inhibitor recurrence among haemophilia A patients with low titre inhibitors or history of inhibitors, and whether or how therapeutic choices affect the risk of recurrence. The aims of this study were to synthesise safety data in patients with moderate-severe haemophilia A and with low titre inhibitors or inhibitor history enrolled in the rAHF PFM (ADVATE) - Post-Authorization Safety Studies (ADVATE-PASS) international programme. The study was conducted in clinics participating to the ADVATE PASS programme. The patient population consisted of patients entering the studies with low titre (<= 5 BU) inhibitors or a positive personal history of inhibitors. Patients on Immune Tolerance Induction at study entry were excluded. Primary outcome was new or recurrent inhibitor titre > 5 BU. Secondary outcomes were any increase of inhibitor titre not reaching 5 BU; any unexplained change in treatment regimen. Primary analysis was done by two-stage random effects meta-analysis. Secondary analysis was done by a hierarchical Bayesian random effects logistic model. A total of 219 patients from seven studies were included. Of these 214 (97.7 %) patients had been previously treated for more than 50 exposure days. Two hundred ten patients had positive history for inhibitors, nine a baseline measurable titre. No patient presented a primary outcome event (95 % confidence interval [CI] 0-1.6 %). Six patients with previous history developed a low titre recurrence (overall rate 2.2, 95 %CI 0-4.8 %). When any increase of inhibitor titre or any treatment change was accounted for, overall 3.7 % (95 % CI 0 %-8.0 %) of patients experienced the outcome. In conclusion, the observed rate of events does not support the definition of this population as at high risk for inhibitor development. PMID- 26017628 TI - Immunological and hematological toxicities challenging clinical translation of nucleic acid-based therapeutics. AB - INTRODUCTION: Nucleic acid-based therapeutics (NATs) are proven agents in correcting disorders caused by gene mutations, as treatments against cancer, microbes and viruses, and as vaccine adjuvants. Although many traditional small molecule NATs have been approved for clinical use, commercialization of macromolecular NATs has been considerably slower, and only a few have successfully reached the market. Preclinical and clinical evaluation of macromolecular NATs has revealed many assorted challenges in immunotoxicity, hematotoxicity, pharmacokinetics (PKs), toxicology and formulation. Extensive review has been given to the PK and toxicological concerns of NATs including approaches designed to overcome these issues. Immunological and hematological issues are a commonly reported side effect of NAT treatment; however, literature exploring the mechanistic background of these effects is sparse. AREAS COVERED: This review focuses on the immunomodulatory properties of various types of therapeutic nucleic acid concepts. The most commonly observed immunological and hematological toxicities are described for various NAT classes, with citations of how to circumvent these toxicities. EXPERT OPINION: Although some success with overcoming immunological and hematological toxicities of NATs has been achieved in recent years, immunostimulation remains the main dose-limiting factor challenging clinical translation of these promising therapies. Novel delivery vehicles should be considered to overcome this challenge. PMID- 26017629 TI - Homocysteine levels in schizophrenia patients newly admitted to an acute psychiatric ward. AB - OBJECTIVE: After the discovery of 'homocystinuria syndrome', many studies have suggested that high blood levels of homocysteine may be associated with schizophrenia. The aim of this study was to analyse the association between hyperhomocysteinaemia and schizophrenia. METHODS: In a population of inpatients suffering from exacerbated schizophrenic disorders (N=100), we evaluated homocysteine levels the day after their admission to an acute psychiatric ward and compared it with that of a non-patient control group (N=110), matched for age and gender. We statistically analysed the correlation between homocysteine levels and selected variables: gender, age, years of illness and number of previous psychiatric admissions as well as Brief Psychiatric Rating Scale, Positive Negative Syndrome Scale and Global Assessment Functioning (GAF) Scores. RESULTS: We observed elevated homocysteine levels (an increase of 7.84 uM on average per patient) in 32% of the patients, but we did not find any statistically significant difference between the homocysteine levels of our patients and controls. Hyperhomocysteinaemia presented a positive statistically significant correlation with years of illness (p<0.005) and a negative statistically significant correlation with GAF score (p<0.001), but not with other clinical variables. CONCLUSIONS: Hyperhomocysteinaemia, which occurred in our schizophrenia patients with poor social and relational functioning after many years of illness, could represent an effect of altered lifestyle due to psychosis, but not a specific marker for schizophrenia. PMID- 26017631 TI - Current Resources for Evidence-Based Practice, July/August 2015. PMID- 26017630 TI - Bronchiectasis is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis. AB - OBJECTIVE: To examine the potential of chronic severe bacterial infection to generate rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), by studying patients with bronchiectasis (BR) alone and BR patients with rheumatoid arthritis (BR/RA). METHODS: We studied 122 patients with BR alone, 50 patients with BR/RA, and 50 RA patients without lung disease, as well as 87 patients with asthma and 79 healthy subjects as controls. RF levels were measured using an automated analyzer, and cyclic citrullinated peptide 2 (CCP-2) was used to detect ACPAs. The fine specificities of citrullinated alpha-enolase peptide 1 (CEP-1), Cit-vimentin, and Cit-fibrinogen to their arginine-containing control peptides (arginine-containing alpha-enolase peptide 1 [REP-1], vimentin, and fibrinogen) were measured by enzyme-linked immunosorbent assay. RESULTS: Among the BR patients and control subjects, 39% and 42%, respectively, were ever smokers. The frequency of RF positivity in serum was increased in BR patients compared with controls (25% versus 10%), as were the frequencies of antibodies to CCP-2 (5% versus 0%), CEP-1 (7% versus 4%), Cit-vimentin (7% versus 4%), and Cit fibrinogen (12% versus 4%), although only the differences for RF and Cit fibrinogen were significant (P < 0.05). We observed a corresponding increase in the frequency of antibodies to the arginine-containing control peptides in BR patients compared with controls (for REP-1, 19% versus 4% [P < 0.01]; for vimentin, 16% versus 4% [P < 0.05]), demonstrating that the ACPA response in patients with BR is not citrulline specific. The lack of citrulline specificity was further confirmed by absorption studies. In BR/RA patients, all ACPA responses were highly citrulline specific. CONCLUSION: Bronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that the ACPA response is not citrulline specific during the early stages of tolerance breakdown but becomes more specific in patients with BR in whom BR/RA develops. PMID- 26017632 TI - Building Local Infrastructure for Community Adoption of Science-Based Prevention: The Role of Coalition Functioning. AB - The widespread adoption of science-based prevention requires local infrastructures for prevention service delivery. Communities That Care (CTC) is a tested prevention service delivery system that enables a local coalition of community stakeholders to use a science-based approach to prevention and improve the behavioral health of young people. This paper uses data from the Community Youth Development Study (CYDS), a community-randomized trial of CTC, to examine the extent to which better internal team functioning of CTC coalitions increases the community-wide adoption of science-based prevention within 12 communities, relative to 12 matched comparison communities. Specifically, this paper examines the potential of both a direct relationship between coalition functioning and the community-wide adoption of science-based prevention and a direct relationship between functioning and the coalition capacities that ultimately enable the adoption of science-based prevention. Findings indicate no evidence of a direct relationship between four dimensions of coalition functioning and the community wide adoption of a science-based approach to prevention, but suggest a relationship between coalition functioning and coalition capacities (building new member skills and establishing external linkages with existing community organizations) that enable science-based prevention. PMID- 26017633 TI - Research Designs for Intervention Research with Small Samples II: Stepped Wedge and Interrupted Time-Series Designs. AB - The stepped wedge design (SWD) and the interrupted time-series design (ITSD) are two alternative research designs that maximize efficiency and statistical power with small samples when contrasted to the operating characteristics of conventional randomized controlled trials (RCT). This paper provides an overview and introduction to previous work with these designs and compares and contrasts them with the dynamic wait-list design (DWLD) and the regression point displacement design (RPDD), which were presented in a previous article (Wyman, Henry, Knoblauch, and Brown, Prevention Science. 2015) in this special section. The SWD and the DWLD are similar in that both are intervention implementation roll-out designs. We discuss similarities and differences between the SWD and DWLD in their historical origin and application, along with differences in the statistical modeling of each design. Next, we describe the main design characteristics of the ITSD, along with some of its strengths and limitations. We provide a critical comparative review of strengths and weaknesses in application of the ITSD, SWD, DWLD, and RPDD as small sample alternatives to application of the RCT, concluding with a discussion of the types of contextual factors that influence selection of an optimal research design by prevention researchers working with small samples. PMID- 26017634 TI - Expression of insulin-like factor 3 hormone-receptor system in the reproductive organs of male goats. AB - Relaxin-like factor (RLF), generally known as insulin-like factor 3 (INSL3), is essential for testis descent during fetal development. However, its role in adult males is not fully understood. We investigate the function of INSL3 in male Saanen goats by identifying cell types expressing its receptor, relaxin/insulin like family peptide receptor (RXFP)2 and by characterizing the developmental expression pattern of INSL3 and RXFP2 and the binding of INSL3 to target cells in the male reproductive system. A highly specific RXFP2 antibody that co-localizes with an anti-FLAG antibody in HEK-293 cells recognizes RXFP2-transcript expressing cells in the testis. INSL3 and RXFP2 mRNA expression is upregulated in the testis, starting from puberty. INSL3 mRNA and protein expression has been detected in Leydig cells, whereas RXFP2 mRNA and protein localize to Leydig cells, to meiotic and post-meiotic germ cells and to the epithelium and smooth muscle of the cauda epididymis and vas deferens. INSL3 binds to all of these tissues and cell types, with the exception of Leydig cells, in a hormone-specific and saturable manner. These results provide evidence for a functional intra- and extra-testicular INSL3 ligand-receptor system in adult male goats. PMID- 26017635 TI - Increased cardiac remodeling in cardiac-specific Flt-1 receptor knockout mice with pressure overload. AB - Vascular endothelial growth factor (VEGF) inhibition has previously been shown to have damaging effects on the heart. Because the role of Flt-1 (a phosphotyrosine kinase receptor for VEGF) in cardiac function and hypertrophy is unclear, we generated mice lacking Flt-1 only in their cardiomyocytes (Flt-1 KO). The hearts from 8- to 10-week-old mice were measured by using echocardiography and histology. No significant differences were seen in fraction shortening, cross sectional area of cardiomyocytes, and interstitial collagen fraction between littermate controls and KO mice at baseline. To test the hypothesis that Flt-1 is involved in cardiac remodeling, we performed transverse aorta constriction (TAC) by ligating the transverse ascending aorta. Four weeks after TAC, echocardiography of the mice was performed, and the hearts were excised for pathological analysis and Western blotting. No difference in mortality was found between Flt-1 KO mice and controls; however, KO mice showed a greater cardiomyocyte cross-sectional area and interstitial collagen fraction than controls. Western blotting indicated that AKT was activated less in Flt-1 KO hearts after TAC compared with that in control hearts. Thus, Flt-1 deletion in cardiomyocytes increased hypertrophy, fibrosis, and regression of AKT phosphorylation. Our study suggests that Flt-1 plays a critical role in cardiac hypertrophy induced by pressure overload via the activation of AKT, which seems to be cardioprotective. PMID- 26017637 TI - A review on the effect of macrocyclic lactones on dung-dwelling insects: Toxicity of macrocyclic lactones to dung beetles. AB - Avermectins and milbemycins are commonly used in agro-ecosystems for the control of parasites in domestic livestock. As integral members of agro-ecosystems with importance in maintaining pasture health through dung burial behaviour, dung beetles are an excellent nontarget bio-indicator taxon for examining potential detrimental effects of pesticide application. The current review focuses on the relative toxicity of four different anthelmintics (ivermectin, eprinomectin, doramectin and moxidectin) in dung residues using dung beetles as a bioindicator species. One of the implications of this review is that there could be an effect that extends to the entire natural assemblage of insects inhabiting and feeding on the dung of cattle treated with avermectin or milbemycin products. Over time, reduced reproductive rate would result in decreased dung beetle populations and ultimately, a decrease in the rate of dung degradation and dung burial. PMID- 26017638 TI - Effect of Intraarticular Corticosteroid Foot Injections on Walking Function in Children With Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To evaluate gait dynamics and self-reported foot-related disability before and after treatment with intraarticular corticosteroid injections (IACI) in children with juvenile idiopathic arthritis (JIA) and foot involvement, and determined whether children with polyarticular and oligoarticular disease responded similarly to IACI treatment. METHODS: Forty-three children (35 girls and 8 boys) with JIA were consecutively recruited (mean +/- SD age 11.1 +/- 4.2 years, mean disease duration 4.5 +/- 3.6 years). Sixty-five percent were diagnosed with polyarthritis. All children received IACI treatment for ankle and/or foot joint synovitis. Fifty-eight percent received additional injections in the knee and/or hip joint. Forty healthy children, matched by age and sex, comprised the control group. Gait dynamics and foot-related disability were assessed before IACI treatment and at 3 weeks and 3 months following the injections. RESULTS: Foot-related disability and inflammatory joint symptoms improved following treatment. Gait dynamics were compromised before treatment and did not improve following treatment (mean +/- SD nondimensional walking speed 0.49 +/- 0.05 in the control group; 0.44 +/- 0.07 in the JIA group pretreatment; 0.43 +/- 0.10 in the JIA group 3 weeks following treatment; and 0.43 +/- 0.07 in the JIA group 3 months following treatment) (P = 0.001 in controls versus pretreatment JIA group, P = 0.45 JIA over time). Mean +/- SD ankle power was 3.81 +/- 0.67 in the control group; 3.01 +/- 1.19 in the JIA group pretreatment; 3.19 +/- 1.30 in the JIA group 3 weeks after treatment; and 3.22 +/- 1.03 in the JIA group 3 months after treatment (P < 0.001 in controls versus pretreatment JIA group, P = 0.51 JIA over time). The ankle power to hip power ratio was reduced (P = 0.01 in controls versus pretreatment JIA group), indicating a power shift from the ankles to the hips, which was more prominent in children with polyarthritis. CONCLUSION: As a result of IACI treatment, improvements were found in self reported foot-related disability and inflammatory joint symptoms, but gait dynamics were unchanged. Children with polyarticular disease and those with greater self-reported walking difficulties prior to IACI treatment demonstrated worse outcomes, and children in these groups should be monitored carefully after treatment. PMID- 26017636 TI - Molecular architecture and function of the hemidesmosome. AB - Hemidesmosomes are multiprotein complexes that facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane. The mechanical stability of hemidesmosomes relies on multiple interactions of a few protein components that form a membrane-embedded tightly-ordered complex. The core of this complex is provided by integrin alpha6beta4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes. Integrin alpha6beta4 binds to the extracellular matrix protein laminin-332, whereas P1a forms a bridge to the cytoplasmic keratin intermediate filament network. Other important components are BPAG1e, the epithelial isoform of bullous pemphigoid antigen 1, BPAG2, a collagen-type transmembrane protein and CD151. Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering. Modulation of hemidesmosome function is of crucial importance for a variety of biological processes, such as terminal differentiation of basal keratinocytes and keratinocyte migration during wound healing and carcinoma invasion. Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post translational mechanisms. PMID- 26017639 TI - The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis. AB - A key step in the de novo formation of the embryonic vasculature is the migration of endothelial precursors, the angioblasts, to the position of the future vessels. To form the first axial vessels, angioblasts migrate towards the midline and coalesce underneath the notochord. Vascular endothelial growth factor has been proposed to serve as a chemoattractant for the angioblasts and to regulate this medial migration. Here we challenge this model and instead demonstrate that angioblasts rely on their intrinsic expression of Apelin receptors (Aplr, APJ) for their migration to the midline. We further show that during this angioblast migration Apelin receptor signaling is mainly triggered by the recently discovered ligand Elabela (Ela). As neither of the ligands Ela or Apelin (Apln) nor their receptors have previously been implicated in regulating angioblast migration, we hereby provide a novel mechanism for regulating vasculogenesis, with direct relevance to physiological and pathological angiogenesis. PMID- 26017640 TI - Antioxidant stilbenoid and flavanonol from stem of Erythrophleum suaveolens (Guill. & Perr.). PMID- 26017641 TI - Single-versus double-row arthroscopic rotator cuff repair in massive tears. AB - BACKGROUND: It is a challenge for orthopaedic surgeons to treat massive rotator cuff tears. The optimal management of massive rotator cuff tears remains controversial. Therefore, the goal of this study was to compare arthroscopic single- versus double-row rotator cuff repair with a larger sample size. MATERIAL AND METHODS: Of the subjects with massive rotator cuff tears, 146 were treated using single-row repair, and 102 were treated using double-row repair. Pre- and postoperative functional outcomes and radiographic images were collected. The clinical outcomes were evaluated for a minimum of 2 years. RESULTS: No significant differences were shown between the groups in terms of functional outcomes. Regarding the integrity of the tendon, a lower rate of post-treatment retear was observed in patients who underwent double-row repair compared with single-row repair. CONCLUSIONS: The results suggest that double-row repair is relatively superior in shoulder ROM and the strength of tendon compared with single-row repair. Future studies involving more patients in better-designed randomized controlled trials will be required. PMID- 26017642 TI - Effect of bariatric surgery on cardiometabolic risk in elderly patients: A population-based study. AB - AIM: Obesity is a major cardiovascular (CV) risk factor. Bariatric surgery (BSx) is an approved therapeutic alternative for class II-III obesity, but little evidence focuses on older adults. We assessed the effect of BSx on cardiometabolic variables and long-term CV risk in older adults. METHODS: We carried out a population-based, observational study from 1990-2009, of 40 consecutive elderly (age >=60 years) residents of Olmsted County, MN, USA, with class II-III obesity treated with BSx at a University-based, academic health center. Data were obtained from the Rochester Epidemiology Project. Metabolic syndrome (MetS) was defined using American Heart Association/National Heart, Lung, Blood Institute (AHA/NHLBI) criteria (increased triglycerides, low high density lipoprotein, increased blood pressure, increased glucose and body mass index as a modified measure of obesity instead of waist circumference). Change in CV risk factors, MetS prevalence, and impact on predicted CV risk using the Framingham risk score was ascertained at 1 year postoperatively and assessed statistically. RESULTS: Mean age and body mass index were 64.4 +/- 3.7 and 45.0 +/- 6.3 kg/m(2) , respectively, and 28 out of 40 (70%) were women. One participant died during the 11-month study period after BSx from respiratory complications related to BSx, and one participant died at 2 years. Percentage of excess weight loss decreased by 57.5% at 1 year. Prevalence 1 year after BSx decreased for diabetes (57.5% to 22.5%; P < 0.03), hypertension 87.5% to 73.7% (P = 0.003), dyslipidemia (80% to 42.5%; P < 0.001) and sleep apnea (62.5% to 23.7%; P < 0.001).MetS prevalence decreased from 80% to 45% (P < 0.002). Baseline risk was 14.1%, which changed at follow up at 8.2%. CONCLUSIONS: In older adults, BSx induces considerable weight loss, improves CV risk factors, decreases MetS prevalence and is an effective treatment in this population. Geriatr Gerontol Int 2016; 16: 618-624. PMID- 26017643 TI - Liver transplant associated with paracetamol overdose: results from the seven country SALT study. AB - AIMS: Acute drug overdose, especially with paracetamol, may cause acute liver failure leading to registration for transplantation (ALFT). Population statistics and between-country differences for ALFT related to overdose have been poorly described. The aim of the present study was to evaluate overdose ALFT in the multi-country Study of Acute Liver Transplantation (SALT). METHODS: All adult overdose-related ALFT, with or without suicidal intent, in France, Greece, Ireland, Italy, the Netherlands, Portugal and the UK between 2005 and 2007 were identified from liver transplant registries and hospital records. These were compared with whole-country and per capita use of paracetamol. RESULTS: Six hundred cases of ALFT were identified in 52 of 57 eligible transplant centres, of which 114 involved overdose (72 intentional, 10 non-intentional, 32 uncertain). Overdose represented 20% of all-cause ALFT: Ireland 52%, UK 28%, France 18%, the Netherlands 8%, and Italy 1%. Overdose ALFT were mostly females (61%), mean age 33.6 +/- 10.9 years. A total of 111 (97%) of the overdoses involved paracetamol. Event rates ranged from one ALFT for 20.7 tons of paracetamol in Ireland, to one for 1074 tons in Italy and one case in 60 million inhabitants over 3 years in Italy to one case in 286 000 inhabitants per year in Ireland. Per-country event rates for non-overdose ALFT exposed to paracetamol were between 2.5 and 4.0 per million treatment-years sold. CONCLUSIONS: Paracetamol overdose was found to represent one-sixth of all-cause ALFT. There was a 50-fold difference in Europe in the rates of paracetamol overdose ALFT, and a 200-fold difference per million inhabitants. PMID- 26017644 TI - Analysis of static and dynamic balance in healthy elderly practitioners of Tai Chi Chuan versus ballroom dancing. AB - OBJECTIVE: To determine whether Tai Chi Chuan or ballroom dancing promotes better performance with respect to postural balance, gait, and postural transfer among elderly people. METHODS: We evaluated 76 elderly individuals who were divided into two groups: the Tai Chi Chuan Group and the Dance Group. The subjects were tested using the NeuroCom Balance Master- force platform system with the following protocols: static balance tests (the Modified Clinical Tests of Sensory Interaction on Balance and Unilateral Stance) and dynamic balance tests (the Walk Across Test and Sit-to-stand Transfer Test). RESULTS: In the Modified Clinical Test of Sensory Interaction on Balance, the Tai Chi Chuan Group presented a lower sway velocity on a firm surface with open and closed eyes, as well as on a foam surface with closed eyes. In the Modified Clinical Test of Sensory Interaction on Unilateral Stance, the Tai Chi Chuan Group presented a lower sway velocity with open eyes, whereas the Dance Group presented a lower sway velocity with closed eyes. In the Walk Across Test, the Tai Chi Chuan Group presented faster walking speeds than those of the Dance Group. In the Sit-to-stand Transfer Test, the Tai Chi Chuan Group presented shorter transfer times from the sitting to the standing position, with less sway in the final standing position. CONCLUSION: The elderly individuals who practiced Tai Chi Chuan had better bilateral balance with eyes open on both types of surfaces compared with the Dance Group. The Dance Group had better unilateral postural balance with eyes closed. The Tai Chi Chuan Group had faster walking speeds, shorter transfer times, and better postural balance in the final standing position during the Sit-to-stand Test. PMID- 26017645 TI - Differentiation between tuberculosis and leukemia in abdominal and pelvic lymph nodes: evaluation with contrast-enhanced multidetector computed tomography. AB - PURPOSE: To compare the characteristics of tubercular vs. leukemic involvement of abdominopelvic lymph nodes using multidetector computed tomography (CT). MATERIALS AND METHODS: We retrospectively reviewed multidetector computed tomography features including lymph node size, shape, enhancement patterns, and anatomical distribution, in 106 consecutive patients with newly diagnosed, untreated tuberculosis (55 patients; 52%) or leukemia (51 patients; 48%). In patients with leukemia, 32 (62.7%) had chronic lymphocytic leukemia, and 19 (37.3%) had acute leukemias; of these, 10 (19.6%) had acute myeloid leukemia, and 9 (17.6%) had acute lymphocytic leukemia. RESULTS: The lower para-aortic (30.9% for tuberculosis, 63.2% for acute leukemias and 87.5% for chronic lymphocytic leukemia) and inguinal (9.1% for tuberculosis, 57.9% for acute leukemias and 53.1% for chronic lymphocytic leukemia) lymph nodes were involved more frequently in the three types of leukemia than in tuberculosis (both with p <0.017). Tuberculosis showed peripheral enhancement, frequently with a multilocular appearance, in 43 (78.2%) patients, whereas patients with leukemia (78.9% for acute myeloid leukemia and acute lymphocytic leukemia, 87.5% for chronic lymphocytic leukemia) demonstrated predominantly homogeneous enhancement (both with p <0.017). For the diagnosis of tuberculosis, the analysis showed that a peripheral enhancement pattern had a sensitivity of 78.2%, a specificity of 100%, and an accuracy of 88.7%. For the diagnosis of leukemia, the analysis showed that a homogeneous enhancement pattern was associated with a sensitivity of 84.3%, a specificity of 94.5%, and an accuracy of 89.6%. CONCLUSION: Our findings indicate that the anatomical distribution and enhancement patterns of lymphadenopathy seen on multidetector computed tomography are useful for differentiating between untreated tuberculosis and leukemia of the abdominopelvic lymph nodes. PMID- 26017646 TI - Increased circulating macrophage migration inhibitory factor levels are associated with coronary artery disease. AB - BACKGROUND: To evaluate the macrophage migration inhibitory factor and E-selectin levels in patients with acute coronary syndrome. MATERIALS/METHODS: We examined the plasma migration inhibitory factor and E-selectin levels in 87 patients who presented with chest pain at our hospital. The patients were classified into two groups according to their cardiac status. Sixty-five patients had acute myocardial infarction, and 22 patients had non-cardiac chest pain (non-coronary disease). We designated the latter group of patients as the control group. The patients who presented with acute myocardial infarction were further divided into two subgroups: ST-elevated myocardial infarction (n = 30) and non-ST elevated myocardial infarction (n = 35). RESULTS: We found higher plasma migration inhibitory factor levels in both acute myocardial infarction subgroups than in the control group. However, the E-selectin levels were similar between the acute myocardial infarction and control patients. In addition, we did not find a significant difference in the plasma migration inhibitory factor levels between the ST elevated myocardial infarction and NST-elevated myocardial infarction subgroups. DISCUSSION: The circulating concentrations of migration inhibitory factor were significantly increased in acute myocardial infarction patients, whereas the soluble E-selectin levels were similar between acute myocardial infarction patients and control subjects. Our results suggest that migration inhibitory factor may play a role in the atherosclerotic process. PMID- 26017647 TI - Quality of life of adolescents with type 1 diabetes. AB - INTRODUCTION: Diabetes mellitus is a highly prevalent chronic disease. Type 1 diabetes mellitus usually develops during infancy and adolescence and may affect the quality of life of adolescents. OBJECTIVE: To evaluate the quality of life of adolescents with type 1 diabetes mellitus in a metropolitan region of western central Brazil. METHODS: Adolescents aged 10-19 years who had been diagnosed with type 1 diabetes mellitus at least 1 year previously were included. Patients with verbal communication difficulties, severe disease, and symptomatic hypo- or hyperglycemic crisis as well as those without an adult companion and who were <18 years of age were excluded. The self-administered Diabetes Quality of Life for Youths instrument was applied. RESULTS: Among 96 adolescents (57% females; 47% white, and 53% nonwhite), 81% had an HbA1c level of >7%. In general, the adolescents consistently reported having a good quality of life. The median scores for the domains of the instrument were as follows: "satisfaction": 35; "impact": 51; and "worries": 26. The total score for all domains was 112. Bivariate analysis showed significant associations among a lower family income, public health assistance, and insulin type in the "satisfaction" domain; and a lower family income, public health assistance, public school attendance, and a low parental education level in the "worries" domain and for the total score. A longer time since diagnosis was associated with a worse total score. Multivariable analysis confirmed the association of a worse quality of life with public health assistance, time since diagnosis, and sedentary lifestyle in the "satisfaction" domain; female gender in the "worries" domain; and public health assistance for the total score. CONCLUSIONS: Overall, the adolescents evaluated in this study viewed their quality of life as good. Specific factors that led to the deterioration of quality of life, including public assistance, time since diagnosis, sedentary lifestyle, and female gender, were identified. No potential conflict of interest was reported. PMID- 26017648 TI - Outcomes of carotid artery stenting at a high-volume Brazilian interventional neuroradiology center. AB - OBJECTIVES: Carotid artery stenting is an emerging revascularization alternative to carotid endarterectomy. However, guidelines have recommended carotid artery stenting only if the rate of periprocedural stroke or death is < 6% among symptomatic patients and < 3% among asymptomatic patients. The aim of this study is to evaluate and compare clinical outcomes of symptomatic and asymptomatic patients who had undergone carotid artery stenting as a first-intention treatment. METHOD: A retrospective analysis of patients who underwent carotid artery stenting by our interventional neuroradiology team was conducted. Patients were divided into two groups: symptomatic and asymptomatic patients. The primary endpoints were ipsilateral ischemic stroke, ipsilateral parenchymal hemorrhage and major adverse cardiac and cerebrovascular events at 30 days. The secondary endpoints included ipsilateral ischemic stroke, ipsilateral parenchymal hemorrhage, ipsilateral transient ischemic attack and major adverse cardiac and cerebrovascular events between the 1- and 12-month follow-ups. RESULTS: A total of 200 consecutive patients were evaluated. The primary endpoints obtained in the symptomatic vs. asymptomatic groups were ipsilateral stroke (2.4% vs. 2.7%, p = 1.00), ipsilateral parenchymal hemorrhage (0.8% vs. 0.0%, p = 1.00) and major adverse cardiac and cerebrovascular events (4.7% vs. 2.7%, p = 0.71). The secondary endpoints obtained in the symptomatic vs. asymptomatic groups were ipsilateral ischemic stroke (0.0% vs. 0.0%), ipsilateral parenchymal hemorrhage (0.0% vs. 0.0%), ipsilateral TIA (0.0% vs. 0.0%, p = 1.00) and major adverse cardiac and cerebrovascular events (11.2% vs. 4.1%, p = 0.11). CONCLUSIONS: In this retrospective study, carotid artery stenting was similarly safe and effective when performed as a first-intention treatment in both symptomatic and asymptomatic patients. The study results comply with the safety requirements from current recommendations to perform carotid artery stenting as an alternative treatment to carotid endarterectomy. PMID- 26017649 TI - Local anesthesia with epinephrine is safe and effective for oral surgery in patients with type 2 diabetes mellitus and coronary disease: a prospective randomized study. AB - OBJECTIVE: To investigate the variations in blood glucose levels, hemodynamic effects and patient anxiety scores during tooth extraction in patients with type 2 diabetes mellitus T2DM and coronary disease under local anesthesia with 2% lidocaine with or without epinephrine. STUDY DESIGN: This is a prospective randomized study of 70 patients with T2DM with coronary disease who underwent oral surgery. The study was double blind with respect to the glycemia measurements. Blood glucose levels were continuously monitored for 24 hours using the MiniMed Continuous Glucose Monitoring System. Patients were randomized into two groups: 35 patients received 5.4 mL of 2% lidocaine, and 35 patients received 5.4 mL of 2% lidocaine with 1:100,000 epinephrine. Hemodynamic parameters (blood pressure and heart rate) and anxiety levels were also evaluated. RESULTS: There was no difference in blood glucose levels between the groups at each time point evaluated. Surprisingly, both groups demonstrated a significant decrease in blood glucose levels over time. The groups showed no significant differences in hemodynamic and anxiety status parameters. CONCLUSION: The administration of 5.4 mL of 2% lidocaine with epinephrine neither caused hyperglycemia nor had any significant impact on hemodynamic or anxiety parameters. However, lower blood glucose levels were observed. This is the first report using continuous blood glucose monitoring to show the benefits and lack of side effects of local anesthesia with epinephrine in patients with type 2 diabetes mellitus and coronary disease. PMID- 26017650 TI - Quality of continuous chest compressions performed for one or two minutes. AB - OBJECTIVES: This study was designed to assess cardiopulmonary resuscitation quality and rescuer fatigue when rescuers perform one or two minutes of continuous chest compressions. METHODS: This prospective crossover study included 148 lay rescuers who were continuously trained in a cardiopulmonary resuscitation course. The subjects underwent a 120-min training program comprising continuous chest compressions. After the course, half of the volunteers performed one minute of continuous chest compressions, and the others performed two minutes, both on a manikin model. After 30 minutes, the volunteers who had previously performed one minute now performed two minutes on the same manikin and vice versa. RESULTS: A comparison of continuous chest compressions performed for one and two minutes, respectively, showed that there were significant differences in the average rate of compressions per minute (121 vs. 124), the percentage of compressions of appropriate depth (76% vs. 54%), the average depth (53 vs. 47 mm), and the number of compressions with no errors (62 vs. 47%). No parameters were significantly different when comparing participants who performed regular physical activity with those who did not and participants who had a normal body mass index with overweight/obese participants. CONCLUSION: The quality of continuous chest compressions by lay rescuers is superior when it is performed for one minute rather than for two minutes, independent of the body mass index or regular physical activity, even if they are continuously trained in cardiopulmonary resuscitation. It is beneficial to rotate rescuers every minute when performing continuous chest compressions to provide higher quality and to achieve greater success in assisting a victim of cardiac arrest. PMID- 26017651 TI - Arterial blood and end-tidal concentrations of sevoflurane during the emergence from anesthesia in gynecologic patients. AB - OBJECTIVE: The end-tidal concentration of inhalation anesthetics is a clinical indicator for predicting the emergence from anesthesia. This study was conducted to assess the relationship between arterial blood and end-tidal sevoflurane concentrations during emergence. METHODS: Thirty-two female American Society of Anesthesiologists physical status I-II patients receiving general anesthesia for elective gynecologic surgery were included. A fixed dose of 3.5% inspiratory sevoflurane in 6 L min-1 oxygen was maintained until the end of surgery. At 20 and 10 minutes before and 0, 5, 10, 15, and 20 minutes after discontinuing sevoflurane, as well as at the time of eye opening by verbal command, defined as awakening, 1 ml arterial blood was obtained to measure its sevoflurane concentration by gas chromatography. Simultaneous inspiratory and end-tidal concentrations of sevoflurane were detected by an infrared analyzer and tested by Bland-Altman agreement analysis. RESULTS: The arterial blood concentrations of sevoflurane were similar to the simultaneous end-tidal concentrations during emergence: 0.36% (0.10) and 0.36% (0.08) sevoflurane at awakening, respectively. The mean time from discontinuing sevoflurane to eye opening was 15.8 minutes (SD 2.9, range 10-26) and was significantly correlated with the duration of anesthesia (52-192 minutes) (P = 0.006) but not with the body mass index or total fentanyl dose. CONCLUSION: The mean awakening arterial blood concentration of sevoflurane was 0.36%. The time to awakening was prolonged in accordance with the anesthetic duration within 3 hours. With well-assisted ventilation during emergence, the sevoflurane end-tidal concentration was nearly equal to its arterial blood concentration, which could be a feasible predictor for awakening. PMID- 26017652 TI - Comparison of therapeutic effects between drainage blood reinfusion and temporary clamping drainage after total knee arthroplasty in patients with rheumatoid arthritis. AB - OBJECTIVE: To compare the therapeutic effects between drainage blood reinfusion and temporary clamping drainage after total knee arthroplasty in patients with rheumatoid arthritis to provide a basis for clinical practice. METHODS: Data from 83 patients with rheumatoid arthritis undergoing total knee arthroplasty were retrospectively analyzed. The 83 patients were divided into a drainage blood reinfusion group (DR group, n = 45) and a temporary clamping drainage group (CD group, n = 38). In the DR group, postoperative drainage blood was used for autotransfusion. In the CD group, closed drainage was adopted, and the drainage tube was clamped for 2 h postoperatively followed by patency. The postoperative drainage amount, hemoglobin level, rate and average volume of allogeneic blood transfusion, swelling and ecchymosis of the affected knee joint, time to straight leg raising and range of active knee flexion were compared between the two groups. RESULTS: The total drainage volume was higher in the DR group than in the CD group (P = 0.000). The average volume of postoperative allogeneic blood transfusion (P = 0.000) and the decrease in the hemoglobin level 24 h after total knee arthroplasty (P = 0.012) were lower in the DR group than in the CD group. Swelling and ecchymosis of the affected knee joint, time to straight-leg raising and the range of active knee flexion were improved in the DR group compared with the CD group (all P<0.05). CONCLUSION: Compared with temporary clamping drainage, drainage blood reinfusion after total knee arthroplasty can reduce the allogeneic blood transfusion volume and is conducive to early rehabilitation in patients with rheumatoid arthritis. PMID- 26017653 TI - Clinical and pathological evaluation of fibrolamellar hepatocellular carcinoma: a single center study of 21 cases. AB - OBJECTIVES: Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver tumor that differs from conventional hepatocellular carcinoma in several aspects. The aim of this study was to describe the clinical, surgical and histopathological features of fibrolamellar hepatocellular carcinoma and to analyze the factors associated with survival. METHODS: We identified 21 patients with histopathologically diagnosed fibrolamellar hepatocellular carcinoma over a 22-year period. Clinical information was collected from medical records and biopsies, and surgical specimens were reviewed. RESULTS: The median age at diagnosis was 20 years. Most patients were female (67%) and did not have associated chronic liver disease. Most patients had a single nodule, and the median tumor size was 120 mm. Vascular invasion was present in 31% of patients, and extra-hepatic metastases were present in 53%. Fourteen patients underwent surgery as the first-line therapy, three received chemotherapy, and four received palliative care. Eighteen patients had "pure fibrolamellar hepatocellular carcinoma," whereas three had a distinct area of conventional hepatocellular carcinoma and were classified as having "mixed fibrolamellar hepatocellular carcinoma." The median overall survival was 36 months. The presence of "mixed fibrolamellar hepatocellular carcinoma" and macrovascular invasion were predictors of poor survival. Vascular invasion was associated with an increased risk of recurrence in patients who underwent surgery. CONCLUSION: Fibrolamellar hepatocellular carcinoma was more common in young female patients without chronic liver disease. Surgery was the first therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was a risk factor for tumor recurrence. The presence of macrovascular invasion and areas of conventional hepatocellular carcinoma were directly related to poor survival. PMID- 26017654 TI - Compensatory sweating after restricting or lowering the level of sympathectomy: a systematic review and meta-analysis. AB - OBJECTIVE: To compare compensatory sweating after lowering or restricting the level of sympathectomy. METHOD: A systematic review and meta-analysis were conducted of all randomized controlled trials published in English that compared compensatory sweating after lowering or restricting the level of sympathectomy. The Cochrane collaboration tool was used to assess the risk of bias, and the Mantel-Haenszel odds ratio method was used for the meta-analysis. RESULTS: A total of 11 randomized controlled trials were included, including a total of 1079 patients. Five of the randomized controlled trials studied restricting the level of sympathectomy, and the remaining six studied lowering the level of sympathectomy. CONCLUSIONS: The compiled randomized controlled trial results published so far in the literature do not support the claims that lowering or restricting the level of sympathetic ablation results in less compensatory sweating. PMID- 26017656 TI - Errata. PMID- 26017655 TI - Molecular characterization of the complement C1q, C2 and C4 genes in Brazilian patients with juvenile systemic lupus erythematosus. AB - OBJECTIVE: To perform a molecular characterization of the C1q, C2 and C4 genes in patients with juvenile systemic lupus erythematosus. METHODS: Patient 1 (P1) had undetectable C1q, patient 2 (P2) and patient 3 (P3) had decreased C2 and patient 4 (P4) had decreased C4 levels. All exons and non-coding regions of the C1q and C2 genes were sequenced. Mononuclear cells were cultured and stimulated with interferon gamma to evaluate C1q, C2 and C4 mRNA expression by quantitative real time polymerase chain reaction. RESULTS: C1q sequencing revealed heterozygous silent mutations in the A (c.276 A>G Gly) and C (c.126 C>T Pro) chains, as well as a homozygous single-base change in the 3' non-coding region of the B chain (c*78 A>G). C1qA mRNA expression without interferon was decreased compared with that of healthy controls (p<0.05) and was decreased after stimulation compared with that of non-treated cells. C1qB mRNA expression was decreased compared with that of controls and did not change with stimulation. C1qC mRNA expression was increased compared with that of controls and was even higher after stimulation. P2 and P3 had Type I C2 deficiency (heterozygous 28 bp deletion at exon 6). The C2 mRNA expression in P3 was 23 times lower compared with that of controls and did not change after stimulation. The C4B mRNA expression of P4 was decreased compared with that of controls and increased after stimulation. CONCLUSIONS: Silent mutations and single-base changes in the 3' non-coding regions may modify mRNA transcription and C1q production. Type I C2 deficiency should be evaluated in JSLE patients with decreased C2 serum levels. Further studies are needed to clarify the role of decreased C4B mRNA expression in JSLE pathogenesis. PMID- 26017657 TI - Evolutionary optimization of compact dielectric lens for farfield sub-wavelength imaging. AB - The resolution of conventional optical lenses is limited by diffraction. For decades researchers have made various attempts to beat the diffraction limit and realize subwavelength imaging. Here we present the approach to design modified solid immersion lenses that deliver the subwavelength information of objects into the far field, yielding magnified images. The lens is composed of an isotropic dielectric core and anisotropic or isotropic dielectric matching layers. It is designed by combining a transformation optics forward design with an inverse design scheme, where an evolutionary optimization procedure is applied to find the material parameters for the matching layers. Notably, the total radius of the lens is only 2.5 wavelengths and the resolution can reach lambda/6. Compared to previous approaches based on the simple discretized approximation of a coordinate transformation design, our method allows for much more precise recovery of the information of objects, especially for those with asymmetric shapes. It allows for the far-field subwavelength imaging at optical frequencies with compact dielectric devices. PMID- 26017658 TI - Estimating the Cost of Early Infant Male Circumcision in Zimbabwe: Results From a Randomized Noninferiority Trial of AccuCirc Device Versus Mogen Clamp. AB - BACKGROUND: Safe and cost-effective programs for implementing early infant male circumcision (EIMC) in Africa need to be piloted. We present results on a relative cost analysis within a randomized noninferiority trial of EIMC comparing the AccuCirc device with Mogen clamp in Zimbabwe. METHODS: Between January and June 2013, male infants who met inclusion criteria were randomized to EIMC through either AccuCirc or Mogen clamp conducted by a doctor, using a 2:1 allocation ratio. We evaluated the overall unit cost plus the key cost drivers of EIMC using both AccuCirc and Mogen clamp. Direct costs included consumable and nonconsumable supplies, device, personnel, associated staff training, and environmental costs. Indirect costs comprised capital and support personnel costs. In 1-way sensitivity analyses, we assessed potential changes in unit costs due to variations in main parameters, one at a time, holding all other values constant. RESULTS: The unit costs of EIMC using AccuCirc and Mogen clamp were $49.53 and $55.93, respectively. Key cost drivers were consumable supplies, capacity utilization, personnel costs, and device price. Unit prices are likely to be lowest at full capacity utilization and increase as capacity utilization decreases. Unit prices also fall with lower personnel salaries and increase with higher device prices. CONCLUSIONS: EIMC has a lower unit cost when using AccuCirc compared with Mogen clamp. To minimize unit costs, countries planning to scale-up EIMC using AccuCirc need to control costs of consumables and personnel. There is also need to negotiate a reasonable device price and maximize capacity utilization. PMID- 26017659 TI - Lower Self-Reported Quality of Life in HIV-Infected Patients on cART and With Low Comorbidity Compared With Healthy Controls. AB - BACKGROUND: Self-reported quality of life (QoL) has previously been found to be impaired in patients living with HIV and associated with viral replication, degree of immunodeficiency, and comorbidity. We aimed at investigating QoL in a group of HIV-infected patients with suppressed viral replication and with low comorbidity, compared with healthy controls. We furthermore aimed to identify factors associated with QoL. DESIGN AND METHODS: Cross-sectional study of 52 HIV infected patients and 23 healthy controls matched on age, gender, education, and comorbidity. HIV-infected patients and healthy controls had previously been examined regarding cognitive, physical, metabolic, and immunological parameters. QoL was investigated using the Medical Outcomes Study HIV Health Survey (MOS HIV). Linear multiple regression models were created to find factors associated with mental health summary score (MHS) and physical health summary score (PHS). RESULTS: HIV-infected patients reported lower QoL compared with controls. In HIV infected patients, female gender and depression score were associated with lower MHS. In controls, years of education, depression score, and cognitive test performance were associated with lower MHS. In HIV-infected patients, years of education, depression score, and body mass index were associated with lower PHS, whereas in controls, years of education and fitness level were associated with PHS. CONCLUSIONS: Even well-treated HIV-infected patients with low level of comorbidity reported lower QoL compared with healthy controls. Especially, depression score and body mass index were associated with QoL in HIV-infected patients. PMID- 26017660 TI - Cancer Among Children With Perinatal Exposure to HIV and Antiretroviral Medications--New Jersey, 1995-2010. AB - BACKGROUND: Concerns remain regarding the cancer risk associated with perinatal antiretroviral (ARV) exposure among infants. No excessive cancer risk has been found in short-term studies. METHODS: Children born to HIV-infected women (HIV exposed) in New Jersey from 1995 to 2008 were identified through the Enhanced HIV/AIDS Reporting System and cross-referenced with data from the New Jersey State Cancer Registry to identify new cases of cancer among children who were perinatally exposed to ARV. Matching of individuals in the Enhanced HIV/AIDS Reporting System to the New Jersey State Cancer Registry was conducted based on name, birth date, Social Security number, residential address, and sex using AutoMatch. Age- and sex-standardized incidence ratio (SIR) and exact 95% confidence intervals (CIs) were calculated using New Jersey (1979-2005) and US (1999-2009) cancer rates. RESULTS: Among 3087 children (29,099 person-years; median follow-up: 9.8 years), 4 were diagnosed with cancer. Cancer incidence among HIV-exposed children who were not exposed to ARV prophylaxis (22.5 per 100,000 person-years) did not differ significantly from the incidence among children who were exposed to any perinatal ARV prophylaxis (14.3 per 100,000 person-years). Furthermore, the number of cases observed among individuals exposed to ARV did not differ significantly from cases expected based on state (SIR = 1.21; 95% CI: 0.25 to 3.54) and national (SIR = 1.27; 95% CI: 0.26 to 3.70) reference rates. CONCLUSIONS: Our findings are reassuring that current use of ARV for perinatal HIV prophylaxis does not increase cancer risk. We found no evidence to alter the current federal guidelines of 2014 that recommend ARV prophylaxis of HIV-exposed infants. PMID- 26017662 TI - HIV-1 Group O Resistance Against Integrase Inhibitors. AB - BACKGROUND: HIV-1 group O (HIV-O) is a rare variant that is characterized by a high number of natural polymorphisms in the integrase coding region that may impact on susceptibility to integrase strand transfer inhibitors (INSTIs) and on the emergence of resistance substitutions. We previously reported that HIV-O is more susceptible to RAL than HIV-1 group M (HIV-M). METHODS: The aim of this study was to assess pathways of resistance to INSTIs in group 0 variants. Accordingly, we selected for resistance to each of raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) in cord blood mononuclear cells using HIV group O subtypes A and B, an HIV-O divergent isolate, and HIV-1 group M (subtype B, which served as a reference). Site-directed mutagenesis was performed on the pCOM2.5 HIV group 0 infectious clone to ascertain the impact of INSTI resistance substitutions at positions Q148R, N155H, and R263K within integrase on susceptibility to INSTIs and infectiousness. RESULTS: Cell culture selections of group O variants yielded similar patterns of resistance to RAL, EVG, and DTG as observed for subtype B. In the DTG selections, subtype B yielded S153Y, whereas a natural S153A polymorphism sometimes led to A153V in group O. The pCMO2.5/Q148R and pCMO2.5/N155H variants displayed far higher levels of resistance to DTG (>1000 FC) than was seen for group M viruses. CONCLUSIONS: HIV-O harboring Q148R and N155H shows higher resistance to DTG compared with HIV-M subtype B. PMID- 26017661 TI - Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study. AB - BACKGROUND: Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. METHODS: A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox proportional hazards models. RESULTS: Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). CONCLUSIONS: Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART. PMID- 26017663 TI - Are incidence and epidemiology of anaerobic bacteremia really changing? AB - Incidence, prognosis and need of performing blood cultures for anaerobic bacteria are under debate, mainly due to the belief that the presence of anaerobes in blood can be easily suspected on clinical basis. We aimed to assess these three points in a retrospective analysis of a 10-year experience in our tertiary hospital. All episodes of significant anaerobic bacteremia diagnosed from 2003 to 2012 were included. Risk factors for mortality and clinical predictability of anaerobic bacteremia were evaluated in 113 randomly selected episodes. Overall incidence of anaerobic bacteremia was 1.2 episodes/1000 admissions, with no significant changes during the 10-year study period. B. fragilis group (38.1 %) and Clostridium spp. (13.7 %) were the most frequent isolated microorganisms. As for the clinical study, 43.4 % of the patients had a comorbidity classified as ultimately fatal or rapidly fatal according to the McCabe and Jackson scale. Clinical manifestations suggestive of anaerobic involvement were present in only 55 % of the patients. Twenty-eight patients (24.8 %) died during the hospitalization. Independent predictive factors of mortality were a high Charlson's comorbidity index and presentation with septic shock, whereas, an adequate source control of the infection was associated with a better outcome. In our centre, incidence of anaerobic bacteremia remained stable during the last decade. The routine use of anaerobic BCs seems to be adequate, since in about half of the cases anaerobes could not be suspected on clinical bases. Moreover, prompt source control of infection is essential in order to reduce mortality of patients with anaerobic bacteremia. PMID- 26017664 TI - Point prevalence of appropriate antimicrobial therapy in a Dutch university hospital. AB - Antimicrobial stewardship teams have been shown to increase appropriate empirical antibiotic therapy and reduce medical errors and costs in targeted populations, but the effect in non-targeted populations is still unclear. The aim of this study was to determine the prevalence of inappropriate antibiotic use in a large university hospital and identify areas in which antimicrobial stewardship will be the most effective. In a point prevalence survey we assessed the appropriateness of antibiotic therapy using an electronic surveillance system in combination with a standardized method for duration of therapy, dosage, dosage interval, route of administration, and choice of antibiotic drug. Patients using at least one antibiotic drug were included. Among 996 patients admitted in the surveyed wards, 337 patients (33.8 %) used one or more antibiotic drugs. Two hundred and twenty one patients (22.2 %) used antibiotic medication therapeutically, with a total of 307 antibiotic prescriptions. Antibiotic therapy was deemed inappropriate in 90 (29.3 %) of these prescribed antibiotics, with an unjustified prescription as the most common reason for an inappropriate prescription. Use of fluoroquinolones and amoxicillin/clavulanic acid and a presumed diagnosis of fever of unknown origin, urinary tract infection, and respiratory tract infection were associated with inappropriate antibiotic therapy. Our study provides insight into the (in)appropriateness of antibiotic prescriptions in a tertiary care center in the Netherlands and identifies areas for improvement. The use of an electronic surveillance system for this point prevalence study is easy and may serve as a baseline measurement for the future effect of antibiotic stewardship. PMID- 26017665 TI - Differences between endocarditis caused by Streptococcus bovis and Enterococcus spp. and their association with colorectal cancer. AB - Streptococcus bovis group and Enterococcus spp. share phenotypic characteristics and intestinal habitat. Both have been associated with endocarditis and colorectal neoplasm (CRN). We studied all cases of endocarditis diagnosed between 1988 and 2014 in our centre and caused by S. bovis (109, 48.8 % of the bacteremia) and by Enterococcus spp. (36, 3.4 % of the bacteremia). Patients were seen until death or during a long-term follow-up, in order to rule out a concomitant CRN. The 109 cases of S. bovis endocarditis (SbIE) compared with the 36 caused by enterococci showed: a higher proportion of males (91 % vs. 72 %, p=0.005), more multivalvular involvement (28 % vs. 6 %, p=0.004), embolic complications (44 vs. 22 %, p=0.02) and colorectal neoplasm (64 % vs. 25 %, p=0.001). SbIE showed fewer co-morbidities (32 vs. 58 %, p=0.005), and less frequently urinary infection source (0 vs. 25 %, p=0.001) and healthcare-related infection (2 vs. 44 %, p=0.001). A total of 123 patients were followed up for an extended period (mean: 65.9 +/- 57.5 months). During the follow-up, 6 of 28 (21 %) cases with enterococcal endocarditis and 43 of 95 (45.2 %, p=0.01) cases with SbIE developed a new CRN. These neoplasiae appeared a mean of 60.4 months later (range 12-181 months). Among the 43 cases with SbIE and CRN, 12 had had a previously normal colonoscopy and 31 had had a previous CRN and developed a second neoplasm. Cases of SbIE present important differences with those caused by Enterococcus spp. Colonoscopy must be mandatory both in the initial evaluation of SbIE, as during the follow-up period. PMID- 26017666 TI - Lipophorin Drives Lipid Incorporation and Metabolism in Insect Trypanosomatids. AB - Insect trypanosomatids are inhabitants of the insect digestive tract. These parasites can be either monoxenous or dixenous. Plant trypanosomatids are known as insect trypanosomatids once they and are transmitted by phytophagous insects. Such parasites can be found in latex, phloem, fruits and seeds of many plant families. Infections caused by these pathogens are a major cause of serious economic losses. Studies by independent groups have demonstrated the metabolic flow of lipids from the vertebrate host to trypanosomatids. This mechanism is usually present when parasites possess an incomplete de novo lipid biosynthesis pathway. Here, we show that both insect trypanosomatids Phytomonas francai and Leptomonas wallacei incorporate (3)H-palmitic acid and inorganic phosphate. These molecules are used for lipid biosynthesis. Moreover, we have isolated the main hemolymphatic lipoprotein, Lipophorin (Lp) from Oncopeltus fasciatus, the natural insect vector of such parasites. Both parasites were able to incorporate Lp to be utilized both as a lipid and protein source for their metabolism. Also, we have observed the presence of Lp binding sites in the membrane of a parasite. In conclusion, we believe that the elucidation of trypanosomatid metabolic pathways will lead to a better understanding of parasite-host interactions and the identification of novel potential chemotherapy targets. PMID- 26017667 TI - Novel pathophysiological cause for post-partum hemorrhage: Case report of post partum hemorrhage with occult abnormal artery diagnosed on pelvic angiography. AB - To the best of our knowledge, this is the first report of post-partum hemorrhage (PPH) caused by an occult abnormal artery detected shortly after delivery on pelvic angiography (PAG). Initially, a diagnosis of uterine atony was made because the apparent cause of hemorrhage was not detected via the usual obstetrical examination. An abnormal artery, however, was suspected on PAG and confirmed on pathology. This case suggests a novel cause of persistent PPH resistant to obstetric management. Obstetricians should be aware that an abnormal artery may cause PPH, and that radiology may be required for diagnosis. PMID- 26017668 TI - Facile synthesis of Fe3O4@polyethyleneimine modified with 4-formylphenylboronic acid for the highly selective extraction of major catecholamines from human urine. AB - The levels of catecholamines, especially dopamine, epinephrine and norepinephrine in urine and plasma have been used to assist the diagnosis and treatment of psychosis. Due to their low endogenous concentrations, the determination of the three major catecholamines is very difficult. Boronate adsorbents are often employed to extract these cis-diol compounds from complex matrices. In this work, a novel type of magnetic nanoparticles modified with 4-formylphenylboronic named Fe3O4@PEI-FPBA was synthesized by a facile two-step approach. The abundant amino groups of polyethyleneimine provided the rich binding sites for boronate ligands. Herein, the adsorption capacity of Fe3O4@PEI-FPBA is greatly improved with a value of 3.45 mg/g towards epinephrine, which is much larger than that of analogous material without polyethyleneimine. The magnetic nanoparticles also exhibited high magnetization (72.25 emu/g) and specific selectivity towards the catecholamines. Finally, a liquid chromatography tandem mass spectrometry method based on Fe3O4@PEI-FPBA nanoparticles was successfully used to determine the three catecholamines from human urine samples. The linearity, limit of quantitation, recovery and precision of the method were satisfactory. Based on the method, it is found that the levels of dopamine, epinephrine and norepinephrine in depressive patients are higher than those in healthy controls. PMID- 26017669 TI - Modelling of the batch biosorption system: study on exchange of protons with cell wall-bound mineral ions. AB - The interchange of the protons with the cell wall-bound calcium and magnesium ions at the interface of solution/bacterial cell surface in the biosorption system at various concentrations of protons has been studied in the present work. A mathematical model for establishing the correlation between concentration of protons and active sites was developed and optimized. The sporadic limited residence time reactor was used to titrate the calcium and magnesium ions at the individual data point. The accuracy of the proposed mathematical model was estimated using error functions such as nonlinear regression, adjusted nonlinear regression coefficient, the chi-square test, P-test and F-test. The values of the chi-square test (0.042-0.017), P-test (<0.001-0.04), sum of square errors (0.061 0.016), root mean square error (0.01-0.04) and F-test (2.22-19.92) reported in the present research indicated the suitability of the model over a wide range of proton concentrations. The zeta potential of the bacterium surface at various concentrations of protons was observed to validate the denaturation of active sites. PMID- 26017670 TI - Identifying Residents' Health Issues Six Weeks after the Great East Japan Earthquake. AB - OBJECTIVE: The aim of this study was to identify the characteristics and health issues of residents in need of assistance in a town affected by the Great East Japan Earthquake, six weeks after the disaster, through an outreach initiative. DESIGN AND SAMPLE: A cross-sectional qualitative design was used. Public health nurses conducted comprehensive semi-structured interviews during home visits with residents. A total of 5,082 residents from the affected town. MEASURES: These included demographic information, public records of the extent of the damages, and qualitative interview data to determine the urgency of the necessary interventions. RESULTS: A total of 281 residents needed some kind of assistance and were identified as "requiring early intervention (within two weeks)" or "requiring assistance (within 12 weeks)." The most common health issue requiring early intervention was "interruption of treatment" (25.0%), followed by "need for mental care." The most frequent health issue requiring assistance within 12 weeks was the "need for mental health care" (39.7%), followed by "interruption of treatment," and "need for nursing care." CONCLUSIONS: During a disaster, it is imperative to identify cases requiring early intervention. Home-visit interviews were necessary to identify existing health concerns to prevent the development of more serious health problems. PMID- 26017671 TI - Spy1 induces de-ubiquitinating of RIP1 arrest and confers glioblastoma's resistance to tumor necrosis factor (TNF-alpha)-induced apoptosis through suppressing the association of CLIPR-59 and CYLD. AB - Glioblastoma multiforme (GBM), a grade-IV glioma, is resistant to TNF-alpha induced apoptosis. CLIPR-59 modulates ubiquitination of RIP1, thus promoting Caspase-8 activation to induce apoptosis by TNF-alpha. Here we reported that CLIPR-59 was down-regulated in GBM cells and high-grade glioma tumor samples, which was associated with decreased cancer-free survival. In GBM cells, CLIPR-59 interacts with Spy1, resulting in its decreased association with CYLD, a de ubiquitinating enzyme. Moreover, experimental reduction of Spy1 levels decreased GBM cells viability, while increased the lysine-63-dependent de-ubiquitinating activity of RIP1 via enhancing the binding ability of CLIPR-59 and CYLD in GBM, thus promoting Caspase-8 and Caspase-3 activation to induce apoptosis by TNF alpha. These findings have identified a novel Spy1-CLIPR-59 interplay in GBM cell's resistance to TNF-alpha-induced apoptosis revealing a potential target in the intervention of malignant brain tumors. PMID- 26017672 TI - TonB Energy Transduction Systems of Riemerella anatipestifer Are Required for Iron and Hemin Utilization. AB - Riemerella anatipestifer (R. anatipestifer) is one of the most important pathogens in ducks. The bacteria causes acute or chronic septicemia characterized by fibrinous pericarditis and meningitis. The R. anatipestifer genome encodes multiple iron/hemin-uptake systems that facilitate adaptation to iron-limited host environments. These systems include several TonB-dependent transporters and three TonB proteins responsible for energy transduction. These three tonB genes are present in all the R. anatipestifer genomes sequenced so far. Two of these genes are contained within the exbB-exbD-tonB1 and exbB-exbD-exbD-tonB2 operons. The third, tonB3, forms a monocistronic transcription unit. The inability to recover derivatives deleted for this gene suggests its product is essential for R. anatipestifer growth. Here, we show that deletion of tonB1 had no effect on hemin uptake of R. anatipestifer, though disruption of tonB2 strongly decreases hemin uptake, and disruption of both tonB1 and tonB2 abolishes the transport of exogenously added hemin. The ability of R. anatipestifer to grow on iron-depleted medium is decreased by tonB2 but not tonB1 disruption. When expressed in an E. coli model strain, the TonB1 complex, TonB2 complex, and TonB3 protein from R. anatipestifer cannot energize heterologous hemin transporters. Further, only the TonB1 complex can energize a R. anatipestifer hemin transporter when co-expressed in an E. coli model strain. PMID- 26017673 TI - Characterization and PCR Detection Of Binary, Pir-Like Toxins from Vibrio parahaemolyticus Isolates that Cause Acute Hepatopancreatic Necrosis Disease (AHPND) in Shrimp. AB - Unique isolates of Vibrio parahaemolyticus (VPAHPND) have previously been identified as the causative agent of acute hepatopancreatic necrosis disease (AHPND) in shrimp. AHPND is characterized by massive sloughing of tubule epithelial cells of the hepatopancreas (HP), proposed to be induced by soluble toxins released from VPAHPND that colonize the shrimp stomach. Since these toxins (produced in broth culture) have been reported to cause AHPND pathology in reverse gavage bioassays with shrimp, we used ammonium sulfate precipitation to prepare protein fractions from broth cultures of VPAHPND isolates for screening by reverse gavage assays. The dialyzed 60% ammonium sulfate fraction caused high mortality within 24-48 hours post-administration, and histological analysis of the moribund shrimp showed typical massive sloughing of hepatopancreatic tubule epithelial cells characteristic of AHPND. Analysis of the active fraction by SDS PAGE revealed two major bands at marker levels of approximately 16 kDa (ToxA) and 50 kDa (ToxB). Mass spectrometry analysis followed by MASCOT analysis revealed that both proteins had similarity to hypothetical proteins of V. parahaemolyticus M0605 (contig034 GenBank accession no. JALL01000066.1) and similarity to known binary insecticidal toxins called 'Photorhabdus insect related' proteins A and B (Pir-A and Pir-B), respectively, produced by the symbiotic, nematode bacterium Photorhabdus luminescens. In in vivo tests, it was shown that recombinant ToxA and ToxB were both required in a dose dependent manner to cause AHPND pathology, indicating further similarity to Pir-A and -B. A single-step PCR method was designed for detection of the ToxA gene and was validated using 104 bacterial isolates consisting of 51 VPAHPND isolates, 34 non-AHPND VP isolates and 19 other isolates of bacteria commonly found in shrimp ponds (including other species of Vibrio and Photobacterium). The results showed 100% specificity and sensitivity for detection of VPAHPND isolates in the test set. PMID- 26017674 TI - Has-miR-125a and 125b are induced by treatment with cisplatin in nasopharyngeal carcinoma and inhibit apoptosis in a p53-dependent manner by targeting p53 mRNA. AB - MicroRNA (miRNA) is a class of non-coding RNA, which targets mRNAs of interest and suppresses its expression by degradation or translational inhibition. miRNA (miR)-125a and miR-125b were previously demonstrated to translationally and transcriptionally inhibit the expression of p53. The observed downregulation of the protein level of p53 in cisplatin-treated patients with nasopharyngeal carcinoma (NPC) indicates the association between cisplatin resistance, miR-125a and miR-125b. In the present study, through the detection of the expression levels of miR-125a and miR-125b, a significant upregulation of these miRs was demonstrated in cisplatin-treated patients with NPC. As a consequence, the protein expression level of p53 decreased notably. To confirm the induction of miR-125a and miR-125b by treatment with cisplatin, a cisplatin-resistant TW03 cell model (TW03/DDP) was constructed. As expected, in the TW03/DDP cells, the expression levels of miR-125a and miR-125b were upregulated, and this caused downregulation of p53. Ectopic expression of these miRNAs in the TW03 cell model sensitized TW03 to cisplatin by decreasing the protein expression levels of p53, whereas ectopic expression in the antisense oligos of these microRNAs demonstrated the opposite effect. In addition, the present demonstrated that the cisplatin-induced expression of miR-125a and miR-125b inhibited cisplatin-induced apoptosis in the TW03 cells by decreasing the protein expression levels of p53. Taken together, the present study revealed for the first time, to the best of our knowledge, that induction of the expression of miR-125a and miR-125b by treatment with cisplatin resulted in resistance to the cisplatin drug in the NPC cells. PMID- 26017675 TI - Green Approach to the Fabrication of Superhydrophobic Mesh Surface for Oil/Water Separation. AB - We report a simple and environment friendly method to fabricate superhydrophobic metallic mesh surfaces for oil/water separation. The obtained mesh surface exhibits superhydrophobicity and superoleophilicity after it was dried in an oven at 200 degrees C for 10 min. A rough silver layer is formed on the mesh surface after immersion, and the spontaneous adsorption of airborne carbon contaminants on the silver surface lower the surface free energy of the mesh. No low-surface energy reagents and/or volatile organic solvents are used. In addition, we demonstrate that by using the mesh box, oils can be separated and collected from the surface of water repeatedly, and that high separation efficiencies of larger than 92 % are retained for various oils. Moreover, the superhydrophobic mesh also possesses excellent corrosion resistance and thermal stability. Hence, these superhydrophobic meshes might be good candidates for the practical separation of oil from the surface of water. PMID- 26017677 TI - Chiral Bronsted Acid as a True Catalyst: Asymmetric Mukaiyama Aldol and Hosomi Sakurai Allylation Reactions. AB - Highly diastereo- and enantioselective Mukaiyama aldol reaction catalyzed by a new chiral Bronsted acid, N-(perfluorooctanesulfonyl)thiophosphoramide, is described. The perfluorooctyl substituent on the sulfonyl group of the catalyst plays an essential role in the stereoselection. The catalyst also allows the asymmetric Hosomi-Sakurai allylation, which has been considerably challenging due to the low reactivity of allylsilanes. (29)Si and (31)P NMR monitoring reveals the characteristic feature of the thiophosphoramide catalyst, acting as a strong Bronsted acid even in the presence of excess silyl nucleophiles, which cannot be found in other related phosphoric acid analogues. PMID- 26017676 TI - Effects of cash transfers on Children's health and social protection in Sub Saharan Africa: differences in outcomes based on orphan status and household assets. AB - BACKGROUND: Unconditional and conditional cash transfer programmes (UCT and CCT) show potential to improve the well-being of orphans and other children made vulnerable by HIV/AIDS (OVC). We address the gap in current understanding about the extent to which household-based cash transfers differentially impact individual children's outcomes, according to risk or protective factors such as orphan status and household assets. METHODS: Data were obtained from a cluster randomised controlled trial in eastern Zimbabwe, with random assignment to three study arms - UCT, CCT or control. The sample included 5,331 children ages 6-17 from 1,697 households. Generalized linear mixed models were specified to predict OVC health vulnerability (child chronic illness and disability) and social protection (birth registration and 90% school attendance). Models included child level risk factors (age, orphan status); household risk factors (adults with chronic illnesses and disabilities, greater household size); and household protective factors (including asset-holding). Interactions were systematically tested. RESULTS: Orphan status was associated with decreased likelihood for birth registration, and paternal orphans and children for whom both parents' survival status was unknown were less likely to attend school. In the UCT arm, paternal orphans fared better in likelihood of birth registration compared with non paternal orphans. Effects of study arms on outcomes were not moderated by any other risk or protective factors. High household asset-holding was associated with decreased likelihood of child's chronic illness and increased birth registration and school attendance, but household assets did not moderate the effects of cash transfers on risk or protective factors. CONCLUSION: Orphaned children are at higher risk for poor social protection outcomes even when cared for in family-based settings. UCT and CCT each produced direct effects on children's social protection which are not moderated by other child- and household-level risk factors, but orphans are less likely to attend school or obtain birth registration. The effects of UCT and CCT are not moderated by asset holding, but greater household assets predict greater social protection outcomes. Intervention efforts need to focus on ameliorating the additional risk burden carried by orphaned children. These efforts might include caregiver education, and additional incentives based on efforts made specifically for orphaned children. PMID- 26017678 TI - New cerebral lesions at magnetic resonance imaging after carotid artery stenting versus endarterectomy: an updated meta-analysis. AB - BACKGROUND: Carotid endarterectomy (CEA) or stenting (CAS) are associated with a relatively low rate of clinical events, but diffusion-weighted imaging (DWI) is increasingly being used to compare the incidence of new ischemic lesions. Therefore, we conducted an updated meta-analysis on the occurrence of post procedural new DWI lesions after CAS versus CEA. METHODS AND RESULTS: MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases were searched and 20 studies (2 randomized and 18 non-randomized) with a total of 2104 procedures (CAS = 989; CEA = 1115) were included. The incidence of new DWI cerebral lesions was significantly greater after CAS than CEA (40.3% vs 12.2%; 20 studies; 2104 patients; odds ratio [OR] 5.17; 95% confidence interval [CI], 3.31-8.06; p<0.00001). Also peri-procedural stroke (17 studies; 1833 patients; OR 2.01; 95% CI, 1.14-3.55; p=0.02) and stroke or TIA (17 studies; 1833 patients; OR 2.40; 95% CI, 1.42-4.08; p=0.001) were significantly increased after CAS. This latter clinical advantage in the CEA group over CAS was tempered when CEA procedures were performed with shunting in all instead of selective shunting or when CAS was performed with only closed cell stents instead of both closed and open cell stents, however, no significant differences between subgroups emerged. CONCLUSIONS: CAS is associated with an increased incidence of post-procedural brain DWI lesions. This greater amount of ischemic burden may also reflect a higher rate of cerebral events after CAS. However, whether recent technical advances mainly for CAS could potentially reduce these ischemic events still remains to be evaluated. PMID- 26017679 TI - Prevalence of Nonalcoholic Fatty Liver Disease and Economy. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a growing health issue around the world. AIM: This study is to investigate whether adult prevalence of NAFLD correlates with national economic status. METHODS: Literature search on PubMed database was conducted to identify eligible records fully published before September 2014. Gross national income (GNI) per capita was chosen to evaluate national economic status. Pearson coefficient, linear regression, and unpaired t test were performed in the statistical analyses. RESULTS: Twenty-one population based surveys (seven in East Asia, five in South Asia, three in Middle East, and six in Europe) were included. The pooled prevalence of NAFLD was 24.24%, and the global prevalence was positively correlated with GNI per capita (r = 0.4782, P = 0.0283). Europe witnessed a higher prevalence (28.04%) than Middle East (12.95%, P = 0.0092) and East Asia (19.24%, P = 0.0083). Male presented a higher prevalence than female (P = 0.019), especially in Europe (P = 0.0132) and in Caucasians (P = 0.0383). Furthermore, male prevalence and rural prevalence individually were correlated with economic status (r = 0.5725, P = 0.0257 and r = 0.7389, P = 0.0060). Lastly, the urban (23.93%) witnessed a higher prevalence than the rural or the urban + rural (12.65%, P = 0.0141) in the countries of GNI per capita <$10,000. CONCLUSIONS: This study suggested that countries with higher economic status tend to present a higher prevalence of NAFLD. It is believed to provide a distinctive epidemiologic perspective to global situation of NAFLD. PMID- 26017680 TI - Association of pyrethroid pesticide exposure with attention-deficit/hyperactivity disorder in a nationally representative sample of U.S. children. AB - BACKGROUND: Pyrethroid pesticides cause abnormalities in the dopamine system and produce an ADHD phenotype in animal models, with effects accentuated in males versus females. However, data regarding behavioral effects of pyrethroid exposure in children is limited. We examined the association between pyrethroid pesticide exposure and ADHD in a nationally representative sample of US children, and tested whether this association differs by sex. METHODS: Data are from 8-15 year old participants (N = 687) in the 2001-2002 National Health and Nutrition Examination Survey. Exposure was assessed using concurrent urinary levels of the pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA). ADHD was defined by either meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria on the Diagnostic Interview Schedule for Children (DISC) or caregiver report of a prior diagnosis. ADHD symptom counts were determined via the DISC. Multivariable logistic regression examined the link between pyrethroid exposure and ADHD, and poisson regression investigated the link between exposure and ADHD symptom counts. RESULTS: Children with urinary 3-PBA above the limit of detection (LOD) were twice as likely to have ADHD compared with those below the LOD (adjusted odds ratio [aOR] 2.42; 95 % confidence interval [CI] 1.06, 5.57). Hyperactive-impulsive symptoms increased by 50 % for every 10-fold increase in 3 PBA levels (adjusted count ratio 1.50; 95 % CI 1.03, 2.19); effects on inattention were not significant. We observed possible sex-specific effects: pyrethroid biomarkers were associated with increased odds of an ADHD diagnosis and number of ADHD symptoms for boys but not girls. CONCLUSIONS: We found an association between increasing pyrethroid pesticide exposure and ADHD which may be stronger for hyperactive-impulsive symptoms compared to inattention and in boys compared to girls. Given the growing use of pyrethroid pesticides, these results may be of considerable public health import. PMID- 26017681 TI - Bursting reverberation as a multiscale neuronal network process driven by synaptic depression-facilitation. AB - Neuronal networks can generate complex patterns of activity that depend on membrane properties of individual neurons as well as on functional synapses. To decipher the impact of synaptic properties and connectivity on neuronal network behavior, we investigate the responses of neuronal ensembles from small (5-30 cells in a restricted sphere) and large (acute hippocampal slice) networks to single electrical stimulation: in both cases, a single stimulus generated a synchronous long-lasting bursting activity. While an initial spike triggered a reverberating network activity that lasted 2-5 seconds for small networks, we found here that it lasted only up to 300 milliseconds in slices. To explain this phenomena present at different scales, we generalize the depression-facilitation model and extracted the network time constants. The model predicts that the reverberation time has a bell shaped relation with the synaptic density, revealing that the bursting time cannot exceed a maximum value. Furthermore, before reaching its maximum, the reverberation time increases sub-linearly with the synaptic density of the network. We conclude that synaptic dynamics and connectivity shape the mean burst duration, a property present at various scales of the networks. Thus bursting reverberation is a property of sufficiently connected neural networks, and can be generated by collective depression and facilitation of underlying functional synapses. PMID- 26017682 TI - 1beta-Hydroxyalantolactone, a sesquiterpene lactone from Inula japonica, attenuates atopic dermatitis-like skin lesions induced by 2,4 dinitrochlorobenzene in the mouse. AB - CONTEXT: 1beta-Hydroxyalantolactone (IJ-5) is a sesquiterpene lactone compound isolated from Inula japonica Thunb (Asteraceae). Sesquiterpene lactones have been shown to modulate many processes that influence inflammatory reactions. OBJECTIVE: The present study examines the protective effect of IJ-5 on atopic dermatitis (AD) in a mouse model induced by 2,4-dinitrochlorobenzene (DNCB). MATERIALS AND METHODS: AD-like skin lesions were induced in Balb/c mice by sensitizing once with painting 100 MUL of 5% DNCB on their shaved back skin and then challenging with 20 MUL of 0.2% DNCB five times on their right ears at 3 d interval starting on day 5 post-sensitization. IJ-5 was administrated intraperitoneally at 10 mg/kg 1 h before each DNCB challenge. RESULTS: IJ-5 treatment attenuated DNCB-induced dermatitis severity and right ear swelling. The serum levels of IgE, IL-4, and IL-6 in IJ-5-treated mice were reduced by 54.7, 56.5, and 53.0%, respectively, while the mRNA levels of TNFalpha, IL-1, IL-4, and IL-6 in back skin lesions of IJ-5-treated mice were reduced by 47.7, 61.5, 57.5, and 58.5%, respectively, compared with untreated controls. Histopathological examination showed that IJ-5 treatment decreased DNCB-induced hypertrophy, hyperkeratosis, and infiltration of inflammatory cells in both ear and back skins. Moreover, IJ-5 suppressed the expression of TNFalpha, IL-1, and IL-6 with IC50 values of 6.58, 9.48, and 7.01 MUM, respectively, and inhibited the activation of NF-kappaB pathway in TNFalpha-stimulated HaCat cells. DISCUSSION AND CONCLUSION: The present study demonstrates the protective effects of IJ-5 against AD-like skin inflammation and highlights IJ-5 as a potential therapeutic agent for AD. PMID- 26017683 TI - Water-Insoluble Surface Coatings of Polyion-Surfactant Ion Complex Salts Respond to Additives in a Surrounding Aqueous Solution. AB - Hydrated, but water-insoluble, "complex salts" (CS) composed of alkyltrimethylammonium surfactant ions with polyacrylate counterions are known to exhibit a rich phase behavior in bulk mixtures with water and have recently been shown to act as water-responsive surface coatings. Here it is shown, by SAXS measurements, that surface coatings of CS also respond to various added solutes in a surrounding aqueous solution, by altering their liquid crystalline structure. The obtained results provide new information on the phase behavior of CS in contact with water and aqueous solutions. Solutes such as acids, salts, excess ionic surfactant, or water-soluble polymers act on the CS by altering the polyion charge density, screening the electrostatic interaction, changing the curvature of the surfactant aggregate, or increasing the osmotic pressuring in the surrounding solution, all of which may result in a phase transition in the film. In water, all studied CS surface coatings had a micellar cubic structure, which could change to 2D hexagonal, HCP, or disordered micellar structure, depending on the identity of the CS and the identity and concentration of the added solute. For some systems, even dissolved CO2 from the ambient air was sufficient to induce a structural change in the film. Especially the films containing the long polyions remained intact even for large concentrations of solutes in the contacting solutions, and extensive washing in water resulted, in most cases, in films with the "original" structure found in water. PMID- 26017685 TI - Parents' experience of childhood atopic eczema in the public health sector of Gauteng. AB - BACKGROUND: The World Allergy Organization found that 20% - 30%of the world's population suffers from an allergic disease. Most allergic patients are seen by non-allergy-trained healthcare workers. The public primary healthcare (PHC) management of childhood atopic eczema (CAE) in the central Gauteng district was the focus of the overall study. The focus of this article is the parents' experience of CAE and the management thereof. The research question was: What is the experience of parents living with a child with atopic eczema (AE)? OBJECTIVES: The overall purpose was to develop validated PHC management guidelines for CAE. One of the objectives was to explore and describe the experiences of parents regarding the AE of their children and the management thereof. METHOD: An embedded single case study design using a qualitative, explorative, descriptive and contextual strategy was employed. Data was collected through semi-structured individual interviews from a purposively selected sample and field notes. Ten parents were interviewed, after which data saturation occurred. Data were analysed according to Tesch's steps of descriptive data analysis. Lincoln and Guba's model was used to ensure trustworthiness. RESULTS: Three main themes were identified. This article focuses on theme one: The physical, emotional and social impact of CAE. Theme two identified the management challenges and theme three indicated recommendations regarding the management of CAE. CONCLUSION: The facilitation of management of CAE focuses on developing PHC guidelines and addressing management challenges in order to achieve better controlled CAE. PMID- 26017684 TI - Characterization of Nanoparticle Tracking Analysis for Quantification and Sizing of Submicron Particles of Therapeutic Proteins. AB - Submicron particles may play important roles in therapeutic protein product quality, stability, and adverse effects in patients. However, quantitation of these particles has been challenging. Nanoparticle tracking analysis (NTA) is capable of both sizing and counting submicron particles. We investigated the effects of product and instrument parameters on NTA results for nanoparticle standards and therapeutic protein samples. To obtain proper particle size distributions, complete tracking numbers of at least 200 and 400 were required for latex nanobeads and protein nanoparticles, respectively. In addition, when set at suboptimal values, the minimum expected particle size parameter led to inaccurate sizing and counting for all particles types investigated. A syringe pump allowed for higher sampling volumes, and results were reproducible for nanoparticle sizing and counts at flow rates <=7 MUL/min. Finally, because therapeutic protein products are being formulated at relatively high protein concentrations, we investigated the effects of protein concentration on nanoparticle characterization. With high protein concentrations, nanoparticle sizing was not affected, whereas particle concentrations were significantly reduced. Linear relationships between particle count and dilution factor were obtained when a high protein concentration formulation was diluted into particle free solutions at the same protein concentrations, but not when dilutions were made into buffer. PMID- 26017686 TI - RNA Nanoparticles Derived from Three-Way Junction of Phi29 Motor pRNA Are Resistant to I-125 and Cs-131 Radiation. AB - Radiation reagents that specifically target tumors are in high demand for the treatment of cancer. The emerging field of RNA nanotechnology might provide new opportunities for targeted radiation therapy. This study investigates whether chemically modified RNA nanoparticles derived from the packaging RNA (pRNA) three way junction (3WJ) of phi29 DNA-packaging motor are resistant to potent I-125 and Cs-131 radiation, which is a prerequisite for utilizing these RNA nanoparticles as carriers for targeted radiation therapy. pRNA 3WJ nanoparticles were constructed and characterized, and the stability of these nanoparticles under I 125 and Cs-131 irradiation with clinically relevant doses was examined. RNA nanoparticles derived from the pRNA 3WJ targeted tumors specifically and they were stable under irradiation of I-125 and Cs-131 with clinically relevant doses ranging from 1 to 90 Gy over a significantly long time up to 20 days, while control plasmid DNA was damaged at 20 Gy or higher. PMID- 26017688 TI - Directional Dynamic Covalent Motion of a Carbonyl Walker on a Polyamine Track. AB - Controlled directional displacement of a molecular group has been achieved based on dynamic covalent motions implementing the reactional features of the imine bond. ortho-Carboxybenzaldehyde derivatives are able to form stable adducts with both primary and secondary amines as imines or as amino lactones, respectively, depending on the acidity of the medium. They may thus perform pH-driven intramolecular "walking" along a non-symmetric polyamine chain, in which an imine serves as the terminus under basic conditions on one end of the chain and a lactone formed on a secondary hydroxylamine nitrogen on the other end serves as the terminal site upon addition of acid. The displacement between the termini occurs stochastically through reversible change in valency at the carbon site of the carbonyl group between imine, aminal, iminium and amino lactone form. On the other hand, the directionality results from the stabilisation of the terminal products under given pH conditions. By its ability to undergo interconversion between C=N and O-C-N moieties, the ortho-carboxybenzaldehyde group extends the realm of dynamic covalent chemistry of imines to secondary amines and opens new perspectives in this field. PMID- 26017687 TI - A Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease. AB - In observational studies, type-2 diabetes (T2D) is associated with an increased risk of coronary heart disease (CHD), yet interventional trials have shown no clear effect of glucose-lowering on CHD. Confounding may have therefore influenced these observational estimates. Here we use Mendelian randomization to obtain unconfounded estimates of the influence of T2D and fasting glucose (FG) on CHD risk. Using multiple genetic variants associated with T2D and FG, we find that risk of T2D increases CHD risk (odds ratio (OR)=1.11 (1.05-1.17), per unit increase in odds of T2D, P=8.8 * 10(-5); using data from 34,840/114,981 T2D cases/controls and 63,746/130,681 CHD cases/controls). FG in non-diabetic individuals tends to increase CHD risk (OR=1.15 (1.00-1.32), per mmol.per l, P=0.05; 133,010 non-diabetic individuals and 63,746/130,681 CHD cases/controls). These findings provide evidence supporting a causal relationship between T2D and CHD and suggest that long-term trials may be required to discern the effects of T2D therapies on CHD risk. PMID- 26017689 TI - Resolving the contributions of two cooperative mechanisms to the DNA binding of AGT. AB - The O(6)-alkylguanine DNA alkyltransferase (AGT) is a DNA repair enzyme that binds DNA with moderate cooperativity. This cooperativity is important for its search for alkylated bases. A structural model of the cooperative complex of AGT with DNA predicts short-range interactions between nearest protein neighbors and long-range interactions between proteins separated in the array. DNA substrates ranging from 11bp to 30bp allowed us to use differences in binding stoichiometry to resolve short- and long-range protein contributions to the stability of AGT complexes. We found that the short-range component of DeltaG degrees (coop) was nearly independent of DNA length and protein packing density. In contrast the long-range component oscillated with DNA length, with a period equal to the occluded binding site size (4bp). The amplitude of the long-range component decayed from ~-4 kcal/mole of interaction to ~-1.2 kcal/mol of interaction as the size of cooperative unit increased from 4 to 7 proteins, suggesting a mechanism to limit the size of cooperative clusters. These features allow us to make testable predictions about AGT distributions and interactions with chromatin structures in vivo. PMID- 26017690 TI - Characterization of an activation-tagged mutant uncovers a role of GLABRA2 in anthocyanin biosynthesis in Arabidopsis. AB - In Arabidopsis, anthocyanin biosynthesis is controlled by a MYB-bHLH-WD40 (MBW) transcriptional activator complex. The MBW complex activates the transcription of late biosynthesis genes in the flavonoid pathway, leading to the production of anthocyanins. A similar MBW complex regulates epidermal cell fate by activating the transcription of GLABRA2 (GL2), a homeodomain transcription factor required for trichome formation in shoots and non-hair cell formation in roots. Here we provide experimental evidence to show that GL2 also plays a role in regulating anthocyanin biosynthesis in Arabidopsis. From an activation-tagged mutagenized population of Arabidopsis plants, we isolated a dominant, gain-of-function mutant with reduced anthocyanins. Molecular cloning revealed that this phenotype is caused by an elevated expression of GL2, thus the mutant was named gl2-1D. Consistent with the view that GL2 acts as a negative regulator of anthocyanin biosynthesis, gl2-1D seedlings accumulated less whereas gl2-3 seedlings accumulated more anthocyanins in response to sucrose. Gene expression analysis indicated that expression of late, but not early, biosynthesis genes in the flavonoid pathway was dramatically reduced in gl2-1D but elevated in gl2-3 mutants. Further analysis showed that expression of some MBW component genes involved in the regulation of late biosynthesis genes was reduced in gl2-1D but elevated in gl2-3 mutants, and chromatin immunoprecipitation results indicated that some MBW component genes are targets of GL2. We also showed that GL2 functions as a transcriptional repressor. Taken together, these results indicate that GL2 negatively regulates anthocyanin biosynthesis in Arabidopsis by directly repressing the expression of some MBW component genes. PMID- 26017692 TI - Death of a Neonate With a Negative Autopsy and Ketoacidosis: A Case Report of Propionic Acidemia. AB - Facing a sudden neonatal death in the forensic setting brings to mind enormous differential diagnostic possibilities. This case report demonstrates that at times, when no anatomical cause of death is apparent after a postmortem examination, ancillary testing can lead to diagnosis. In this case, ancillary testing showed ketosis and further workup showed presence of propionic acidemia in a 3-day-old neonate. PMID- 26017691 TI - Ethnobotany of wild plants used for starting fermented beverages in Shui communities of southwest China. AB - BACKGROUND: Shui communities of southwest China have an extensive history of using wild plants as starters (Xiaoqu) to prepare fermented beverages that serve important roles in interpersonal relationships and cultural events. While the practice of using wild plants as starters for the preparation of fermented beverages was once prevalent throughout China, this tradition has seen a decline nationally since the 1930s. The traditional technique of preparing fermented beverages from wild plant starters remains well preserved in the Shui communities in southwest China and provides insight on local human-environment interactions and conservation of plant biodiversity for cultural purposes. The present study sought to examine the ethnobotany of wild plants used as starters for the preparation of fermented beverages including an inventory of plants used as a starter in liquor fermentation and associated knowledge and practices. METHODS: Field surveys were carried out that consisted of semi-structured surveys and plant species inventories. One hundred forty-nine informants in twenty Shui villages were interviewed between July 2012 and October 2014 to document knowledge associated with wild plants used as a liquor fermentation starter. The inventories involved plant voucher specimens and taxonomic identification of plant collections. RESULTS: A total of 103 species in 57 botanical families of wild plants were inventoried and documented that are traditionally used as starters for preparing fermented beverages by Shui communities. The majority of the species (93.2%) have multiple uses in addition to being used as a starter with medicinal purposes being the most prevalent. Shui women are the major harvesters and users of wild plants used as starters for preparing fermented beverages and transfer knowledge orally from mother to daughter. CONCLUSIONS: Findings from this study can serve as a basis for future investigation on fermented beverages and foods and associated knowledge and cultural practices. However, with rapid development, utilization of wild plants and the cultural systems that support them are at risk of erosion. Cultural preservation practices are necessary in Shui communities for the continued use and transmission of this ethnobiological knowledge as well as associated biodiversity. PMID- 26017693 TI - Splenic Artery Aneurysm Invaded by Desmoid-Type Fibromatosis. AB - Despite the benign histologic appearance and negligible metastatic potential, desmoid tumors can be locally aggressive, invading into adjacent structures and organs. We report an unusual case of desmoid-type fibromatosis causing the death of an otherwise healthy individual by rupturing the splenic artery. PMID- 26017694 TI - Detection of Mercury in Human Organs and Hair in a Case of a Homicidal Poisoning of a Woman Autopsied 6 Years After Death. AB - In the described case of the death of a 53-year-old woman, no toxicological examination was performed directly after death (only an anatomopathological autopsy), although symptoms of serious gastrointestinal disturbances had been present (the woman had been hospitalized twice in the course of several months). It was assumed that the cause of death was myocardial infarction. Five years later, some new circumstances came to light which suggested that somebody could have administered some poison (metals, cyanides) to the woman. Toxicological analysis of postmortem samples from the corpse, exhumed 6 years after death by order of the public prosecutor's office, revealed high tissue mercury contents in biological material (cold vapor atomic absorption spectrometry): small intestine, 1516 ng/g; large intestine, 487 ng/g; liver, 1201 ng/g; heart muscle, 1023 ng/g; and scalp hair, 227 ng/g. In samples of soil from places near the coffin, negligible traces of mercury were found (0.5-1.5 ng/g); contamination by mercury from the environment was ruled out. The presented case is a rare example of recognition of mercury poisoning on the basis of the results of analysis of biological material from an exhumed cadaver. PMID- 26017695 TI - Tightrope Walking: Using Predictors of 25(OH)D Concentration Based on Multivariable Linear Regression to Infer Associations with Health Risks. AB - The debate on the causal association between vitamin D status, measured as serum concentration of 25-hydroxyvitamin D (25[OH]D), and various health outcomes warrants investigation in large-scale health surveys. Measuring the 25(OH)D concentration for each participant is not always feasible, because of the logistics of blood collection and the costs of vitamin D testing. To address this problem, past research has used predicted 25(OH)D concentration, based on multivariable linear regression, as a proxy for unmeasured vitamin D status. We restate this approach in a mathematical framework, to deduce its possible pitfalls. Monte Carlo simulation and real data from the National Health and Nutrition Examination Survey 2005-06 are used to confirm the deductions. The results indicate that variables that are used in the prediction model (for 25[OH]D concentration) but not in the model for the health outcome (called instrumental variables), play an essential role in the identification of an effect. Such variables should be unrelated to the health outcome other than through vitamin D; otherwise the estimate of interest will be biased. The approach of predicted 25(OH)D concentration derived from multivariable linear regression may be valid. However, careful verification that the instrumental variables are unrelated to the health outcome is required. PMID- 26017696 TI - Ex Vivo Fluorescence Confocal Microscopy of Eccrine Syringomatous Carcinoma: A Report of 2 Cases. PMID- 26017698 TI - Rational Design of Antimalarial Drugs Using Molecular Modeling and Statistical Analysis. AB - Artemisinin is an antimalarial compound isolated from Artemisia annua L. that is effective against Plasmodium falciparum. This paper proposes the development of new antimalarial derivatives of artemisinin from a SAR study and statistical analysis by multiple linear regression (MLR). The HF/6-31G** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. MEP maps and molecular docking were used to study the interface between ligand and receptor (heme). The Pearson correlation was used to choose the most important properties interrelated to the antimalarial activity: Hydration Energy (HE), Energy of the Complex (Ecplex), bond length (FeO1), and maximum index of R/Electronegativity of Sanderson (RTe+). After the Pearson correlation, 72 MLR models were built between antimalarial activity and molecular properties; the statistical quality of the models was evaluated by means of correlation coefficient (r), squared correlation coefficient (r(2)), explained variance (adjusted R(2)), standard error of estimate (SEE), and variance ratio (F), and only four models showed predictive ability. The selected models were used to predict the antimalarial activity of ten new artemisinin derivatives (test set) with unknown activity, and only eight of these compounds were predicted to be more potent than artemisinin, and were therefore subjected to theoretical studies of pharmacokinetic and toxicological properties. The test set showed satisfactory results for six new artemisinin compounds which is a promising factor for future synthesis and biological assays. PMID- 26017700 TI - Erratum. PMID- 26017697 TI - Successful collaboration in dementia care from the perspectives of healthcare professionals and informal carers in Germany: results from a focus group study. AB - BACKGROUND: Informal carers of persons with dementia are in contact with numerous healthcare professionals (HCP) in a complex healthcare system. Successful collaboration between the parties involved appears to be essential for good dementia care. Thus, we investigated the perceptions of both HCP and informal carers regarding successful collaboration and sought to describe obstacles and facilitators. METHODS: As part of the 7(th) framework EU project RightTimePlaceCare, five focus groups were conducted with HCP and informal carers of persons with dementia in Germany (n = 30 participants/ time: Oct/Nov 2011). A supplementary secondary data analysis was performed, applying qualitative content analysis with open coding. RESULTS: The derived categories were sorted into three overarching themes: collaboration between HCP and informal carers, collaboration among HCP and the impact of resources and healthcare system. HCP and informal carers largely agree on what facilitates or impedes successful collaboration between them. Making the initial contact appears to be a major challenge. While HCP expect to be contacted, informal carers hesitate to seek assistance, primarily due to inner barriers. Permanent contact person/institution, well trained, empathetic HCP who can establish a trustful relationship are regarded as facilitating collaboration. The relational perspective is more clearly emphasised by HCP than by informal carers. This may be attributed to the absence of a permanent contact person in Germany. Sufficient information relay, clear responsibilities, motivation and defined aims, and a personal relationship between professionals are mentioned as facilitators. External factors, such as rapid staff turnover, insufficient time resources and conditions specified by the health and long-term care system causing financial competition between providers, are described as general barriers to successful collaboration. CONCLUSIONS: HCP and informal carers had comparable perceptions of successful collaboration among them. The initial contact seems to be particularly challenging. Better strategies are urgently needed to facilitate the access to professional support. A permanent contact person (e.g., a case manager) might improve collaboration among all the parties involved, but this is not available regularly. Constraints created by the healthcare system may considerably hinder successful collaboration. PMID- 26017701 TI - Functional diversity of photobiological traits within the genus Symbiodinium appears to be governed by the interaction of cell size with cladal designation. AB - Dinoflagellates of the genus Symbiodinium express broad diversity in both genetic identity (phylogeny) and photosynthetic function to presumably optimize ecological success across extreme light environments; however, whether differences in the primary photobiological characteristics that govern photosynthetic optimization are ultimately a function of phylogeny is entirely unresolved. We applied a novel fast repetition rate fluorometry approach to screen genetically distinct Symbiodinium types (n = 18) spanning five clades (A D, F) for potential phylogenetic trends in factors modulating light absorption (effective cross-section, reaction center content) and utilization (photochemical vs dynamic nonphotochemical quenching; [1 - C] vs [1 - Q]) by photosystem II (PSII). The variability of PSII light absorption was independent of phylogenetic designation, but closely correlated with cell size across types, whereas PSII light utilization intriguingly followed one of three characteristic patterns: (1) similar reliance on [1 - C] and [1 - Q] or (2) preferential reliance on [1 - C] (mostly A, B types) vs (3) preferential reliance on [1 - Q] (mostly C, D, F types), and thus generally consistent with cladal designation. Our functional trait-based approach shows, for the first time, how Symbiodinium photosynthetic function is governed by the interplay between phylogenetically dependent and independent traits, and is potentially a means to reconcile complex biogeographic patterns of Symbiodinium phylogenetic diversity in nature. PMID- 26017704 TI - Genetic pathways explored for role in cystic fibrosis. PMID- 26017705 TI - 23andme obtains permission to market Bloom syndrome test. PMID- 26017707 TI - Recent neuroimaging advances in the study of primary headaches. AB - Neuroimaging techniques can be used to investigate both functional and structural features of the brain in patients who have primary headache disorders such as migraine or cluster headache. Improved treatments are needed for both, and this goal will likely be facilitated by a better understanding of the underlying biology. Functional imaging studies have identified regions active during attacks, as well as abnormalities that are present during the interictal period. Volumetric, surface-based morphometric, and tractography studies have revealed structural changes, although whether these represent a cause or effect of the condition remains to be determined. The development of new techniques and modalities promises to yield additional insights in the future. This article aims to review the major findings and most recent advances in neuroimaging of migraine and cluster headache. PMID- 26017708 TI - Neuroimaging of headaches associated with vascular disorders. AB - Headaches from vascular causes need to be differentiated from primary headaches because a misdiagnosis may lead to dire consequences for the patient. Neuroimaging is critical in identifying patients with vascular headaches and identifying the nature of the pathologic disorder causing these headaches. In addition, the imaging findings guide the physician regarding the optimal treatment modality for these lesions. This review summarizes the nuances of differentiating patients with secondary headaches related to vascular disease and discusses pertinent neuroimaging studies. PMID- 26017709 TI - Appropriate use of neuroimaging in headache. AB - Headache may be caused by primary disorders, such as migraines, or secondary disorders, such as intracranial neoplasm or hemorrhage. Imaging plays an important role in differentiating between primary and secondary headache disorders. This article reviews the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of a patient with a headache. It also discusses the utility and cost-effectiveness of performing imaging studies in patients with a headache and a normal neurological exam. Emerging imaging techniques such as functional MRI, positron emission tomography (PET) scans, and voxel-based morphometry (VBM) are also discussed. PMID- 26017710 TI - Neuroimaging and the clinical manifestations of Chiari Malformation Type I (CMI). AB - Chiari malformation type I (CMI) involves the caudal displacement of the cerebellar tonsils through the foramen magnum with resultant brainstem compression in some individuals. Due to pathophysiologic changes, secondary conditions may arise, such as syringohydromyelia (SH) and scoliosis. This disorder is unique, as the diagnosis is confirmed through radiologic findings. At times CMI is discovered incidentally on neuroimaging, but more frequently a patient will present with specific symptoms, the most common being a prototypic occipital headache. Although the true etiology of this complex condition remains speculative, the advent of neuroimaging has allowed for clarification of the enigmatic relationship between cerebrospinal fluid (CSF) dynamics, neuroanatomical compression, and clinical symptoms. Recent advancements in magnetic resonance imaging (MRI) such as diffusion tensor imaging (DTI) and CSF flow studies show promise in clarifying the underlying fluid dynamics in CMI patients and can aid in the prognosis and diagnosis of this complex disorder. PMID- 26017711 TI - Trigeminal neuralgia and facial pain imaging. AB - The trigeminal nerve or fifth cranial nerve has an extensive distribution in the head and face. It is the source for pain conduction and thereby is often implicated in a variety of disorders including inflammatory and neoplastic diseases. To determine the disease source, understanding the trigeminal nerve anatomy is essential, and further being able to image the trigeminal nerve provides insight into the location and type of pathology. The best approach to imaging is to consider the nerve in segments. The nerve segments may be divided into the brainstem, cisternal, Meckel's cave, cavernous sinus, and peripheral divisions. This review utilizes these segments to explore imaging options to help understand trigeminal neuralgia and pain in the trigeminal nerve distribution. PMID- 26017712 TI - Cut-off values of myocardial perfusion gated-SPECT phase analysis parameters of normal subjects, and conduction and mechanical cardiac diseases. AB - BACKGROUND: The aim of this study was to determine the cut-off values of gated myocardial perfusion rest SPECT phase analysis parameters of normal subjects, and conduction (CCD) and mechanical cardiac diseases (MCD). METHODS: We prospectively analyzed 455 patients by means of phase analysis using SyncToolTM (Emory Cardiac ToolboxTM). Of these, 150 corresponded to the control group (group 1, normal subjects) and 305 corresponded to patients with cardiac diseases (group 2, 63 with only CCD, 121 with only MCD, and 121 with CCD plus MCD). The optimal cut-off (CO) values of the peak phase (P), standard deviation (SD), bandwidth (B), skewness (S), and kurtosis (K) for discriminating between normal and dyssynchrony were obtained. RESULTS: In order to differentiate group 1 from group 2, CO of SD > 18.4 and CO of B > 51 were the most sensitive parameters (75.7%, 95% CI 70.5% 80.4%, and 78.7%, 95% CI 73.7%-83.1%, respectively), and CO of S <= 3.2 and CO of K <= 9.3 were the most specific (92%, 95% CI 86.4%-95.8%, and 94.7%, 95% CI 89.8% 97.7%, respectively). In order to differentiate patients with CCD and MCD, CO values were SD > 26.1, B > 70, S <= 2.89, and K <= 10.2. In order to differentiate between patients with (n: 26) and without (n: 216) criteria of cardiac resynchronization therapy, CO values were SD > 40.2, B > 132, S <= 2.3, and K <= 4.6. CONCLUSIONS: In this pilot study, different CO values of phase histogram parameters were observed between normal subjects and patients with conduction and MCD, and between patients with and without criteria of cardiac resynchronization therapy. PMID- 26017714 TI - Why LV dilatation with vasodilator stress in hypertrophic cardiomyopathy? PMID- 26017713 TI - Effect of changes in perfusion defect size during serial regadenoson myocardial perfusion imaging on cardiovascular outcomes in high-risk patients. AB - BACKGROUND: The prognostic value of single-photon emission computed tomography myocardial perfusion imaging (MPI) is well established. There is a paucity of data on the prognostic value of changes in perfusion defect size (PDS) on serial MPIs. METHODS: From the MPI database at the University of Alabama at Birmingham, consecutive patients who underwent two regadenoson stress MPIs between July 2008 and March 2013 were identified. The MPIs were analyzed side-by-side using an automated software program for presence and change in PDS. Improvement in PDS was defined as a reduction >=5% of left ventricle. A drop in left ventricular ejection fraction (LVEF) was defined as a decrease >=5%. The primary outcome was a composite of death, myocardial infarction (MI), and coronary revascularization (CR). RESULTS: There were 698 patients (61 +/- 11 years, 53% male, 48% diabetes, 25% prior MI, 49% prior CR) who underwent two regadenoson MPIs within 16 +/- 9 months for clinical indications. The primary outcome occurred in 167 (24%) patients (8% death, 9% MI, 15% CR) during 24 +/- 16 months of follow-up after the second MPI. The MPIs were normal in both studies in 399 (57%, Group 1), showed improvement in 94 (14%, Group 2, PDS 15% +/- 16% vs 28% +/- 18%, P < .001) and no change or worsening in 205 patients (29%, Group 3, 28% +/- 17% vs 20% +/- 17%, P < .001). The best outcomes were seen in Group 1 and the worst in Group 3 (log rank P < .001). Similar trends were seen for the components of the primary outcome (P = .04 for death, P < .001 for MI, P < .001 for CR). In a Cox regression model that adjusted for baseline factors including PDS and LVEF on initial MPI, the hazard ratios for primary outcome were 2.0 (P = .02) and 3.9 (P < .001) for Groups 2 and 3 compared to Group 1, respectively. In addition, an LVEF drop >=5% was independently associated with the primary outcome (HR 1.5, P = .01). CONCLUSION: Changes in PDS and LVEF on serial MPIs provide incremental prognostic information to initial and follow-up MPI findings. Lack of improvement or an increase in PDS and a drop in LVEF identify high-risk patients. PMID- 26017716 TI - Human aortic endothelial cell morphology influenced by topography of porous silicon substrates. AB - Porous silicon has received much attention because of its optical properties and for its usefulness in cell-based biosensing, drug delivery, and tissue engineering applications. Surface properties of the biomaterial are associated with cell adhesion and with proliferation, migration, and differentiation. The present article analyzes the behavior of human aortic endothelial cells in macro- and nanoporous collagen-modified porous silicon samples. On both substrates, cells are well adhered and numerous. Confocal microscopy and scanning electron microscopy were employed to study the effects of porosity on the morphology of the cells. On macroporous silicon, filopodia is not observed but the cell spreads on the surface, increasing the lamellipodia surface which penetrates the macropore. On nanoporous silicon, multiple filopodia were found to branch out from the cell body. These results demonstrate that the pore size plays a key role in controlling the morphology and growth rate of human aortic endothelial cells, and that these forms of silicon can be used to control cell development in tissue engineering as well as in basic cell biology research. PMID- 26017715 TI - The effectiveness of low-dose desmopressin in improving hypothermia-induced impairment of primary haemostasis under influence of aspirin - a randomized controlled trial. AB - BACKGROUND: Mild hypothermia (34-35 degrees C) increases perioperative blood loss. Our previous studies showed that desmopressin could have in vitro beneficial effects on hypothermia-induced primary haemostasis impairment. In this study, we investigate the in vitro effects of desmopressin on hypothermia-induced primary haemostasis impairment under the influence of aspirin in healthy volunteers. METHODS: Sixty healthy volunteers were randomly allocated to taking aspirin 100 mg or placebo for three days. On the sixth day blood samples were taken before and after the injection of desmopressin (1.5 microgram or 5 microgram) or normal saline subcutaneously. Measurements including Platelet Function Analyzer (PFA-100(r)) closure times, plasma von Willebrand Factor antigen, haemoglobin and platelet levels were made at 32 degrees C and 37 degrees C respectively. RESULTS: Collagen/epinephrine closure time (EPICT) was significantly prolonged by 21.13 % (95 %CI 2.34-39.74 %, p = 0.021) in aspirin group at 37 degrees C. While hypothermia alone prolonged both collagen/adenosine diphosphate (ADPCT) and EPICT by 17.63 % (95 %CI 13.5-20.85 %, p < 0.001) and 8.0 % (95 %CI 6.38-10.04 %, p = 0.024) respectively, addition of aspirin only further prolonged EPICT by 19.9 % (95 %CI 3.32-36.49 %, p = 0.013). In aspirin group, desmopressin 1.5 microgram and 5 microgram significantly reduced ADPCT to below baseline levels at 37 degrees C (p = 0.025 and <0.001 respectively), whereas reduction in EPICT was seen with desmopressin 5 microgram (p =0.008). The effect was less pronounced at 32 degrees C, with a significant reduction in EPICT obtained with a dosage of 5 microgram only (p = 0.011). CONCLUSION: It was shown that aspirin could further potentiate the hypothermia-induced closure time prolongations. Low dose desmopressin (1.5 microgram) reduced PFA-100(r) closure times towards baseline. A higher dosage (5 microgram) further reduced the closure times below baseline. Therefore low dose desmopressin (1.5 microgram) might have the potential to correct hypothermia-induced primary haemostasis impairment under the influence of aspirin during the perioperative period. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01382134. PMID- 26017717 TI - Methacrylated gelatin and mature adipocytes are promising components for adipose tissue engineering. AB - In vitro engineering of autologous fatty tissue constructs is still a major challenge for the treatment of congenital deformities, tumor resections or high graded burns. In this study, we evaluated the suitability of photo-crosslinkable methacrylated gelatin (GM) and mature adipocytes as components for the composition of three-dimensional fatty tissue constructs. Cytocompatibility evaluations of the GM and the photoinitiator Lithium phenyl-2,4,6 trimethylbenzoylphosphinate (LAP) showed no cytotoxicity in the relevant range of concentrations. Matrix stiffness of cell-laden hydrogels was adjusted to native fatty tissue by tuning the degree of crosslinking and was shown to be comparable to that of native fatty tissue. Mature adipocytes were then cultured for 14 days within the GM resulting in a fatty tissue construct loaded with viable cells expressing cell markers perilipin A and laminin. This work demonstrates that mature adipocytes are a highly valuable cell source for the composition of fatty tissue equivalents in vitro. Photo-crosslinkable methacrylated gelatin is an excellent tissue scaffold and a promising bioink for new printing techniques due to its biocompatibility and tunable properties. PMID- 26017719 TI - Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disease. It is the most common cause of chronic congestive heart failure and the most frequent reason for heart transplantation in young adults. There is increasing evidence demonstrating that genetic defects are involved in the pathogenesis of idiopathic DCM. Recent studies have shown that genetically defective LRRC10 predisposes animals to DCM. However, the association of LRRC10 with DCM in humans has not been reported. In the current study, the whole coding region and flanking splice junction sites of the LRRC10 gene were sequenced in 220 unrelated patients with idiopathic DCM. The available relatives of the index patients harboring identified mutations and 200 unrelated ethnically matched healthy individuals used as controls were also genotyped for LRRC10. The functional effect of the LRRC10 mutations was analyzed in silico. As a result, two novel heterozygous LRRC10 mutations, p.L41V and p.L163I, were identified in two families with DCM, respectively, with a mutational prevalence of ~0.91%. Genetic analyses of the pedigrees showed that in each family, the mutation co segregated with DCM was transmitted as an autosomal dominant trait with complete penetrance. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across various species. Functional analysis in silico indicated that the LRRC10 mutations were causative. This study firstly reports the association of LRRC10 mutations with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, and contributes to the development of novel prophylactic and therapeutic strategies for DCM. PMID- 26017720 TI - Development and Validation of an Assessment of Regional Anesthesia Ultrasound Interpretation Skills. AB - BACKGROUND: Interpretation of ultrasound images and knowledge of anatomy are essential skills for ultrasound-guided peripheral nerve blocks. Competency-based educational models promoted by the Accreditation Council for Graduate Medical Education require the development of assessment tools for the achievement of different competency milestones to demonstrate the longitudinal development of skills that occur during training. METHODS: A rigorous study guided by psychometric principles was undertaken to identify and validate the domains and items in an assessment of ultrasound interpretation skills for regional anesthesia. A survey of residents, academic faculty, and community anesthesiologists, as well as video recordings of experts teaching ultrasound guided peripheral nerve blocks, was used to develop short video clips with accompanying multiple choice-style questions. Four rounds of pilot testing produced a 50-question assessment that was subsequently administered online to residents, fellows, and faculty from multiple institutions. RESULTS: Test results from 90 participants were analyzed with Item Response Theory model fitting indicating that a 47-item subset of the test fits the model well (P = 0.11). There was a significant linear relation between expected and predicted item difficulty (P < 0.001). Overall test scores increased linearly with higher levels of formal anesthesia training, regional anesthesia training, number of ultrasound guided blocks performed per year, and a self-rating of regional anesthesia skill (all P < 0.001). CONCLUSIONS: This study provides evidence for the reliability, content validity, and construct validity of a 47-item multiple choice-style online test of ultrasound interpretation skills for regional anesthesia, which can be used as an assessment of competency milestone achievement in anesthesiology training. PMID- 26017718 TI - Diagnosis of toxoplasmosis and typing of Toxoplasma gondii. AB - Toxoplasmosis, caused by the obligate intracellular protozoan Toxoplasma gondii, is an important zoonosis with medical and veterinary importance worldwide. The disease is mainly contracted by ingesting undercooked or raw meat containing viable tissue cysts, or by ingesting food or water contaminated with oocysts. The diagnosis and genetic characterization of T. gondii infection is crucial for the surveillance, prevention and control of toxoplasmosis. Traditional approaches for the diagnosis of toxoplasmosis include etiological, immunological and imaging techniques. Diagnosis of toxoplasmosis has been improved by the emergence of molecular technologies to amplify parasite nucleic acids. Among these, polymerase chain reaction (PCR)-based molecular techniques have been useful for the genetic characterization of T. gondii. Serotyping methods based on polymorphic polypeptides have the potential to become the choice for typing T. gondii in humans and animals. In this review, we summarize conventional non-DNA-based diagnostic methods, and the DNA-based molecular techniques for the diagnosis and genetic characterization of T. gondii. These techniques have provided foundations for further development of more effective and accurate detection of T. gondii infection. These advances will contribute to an improved understanding of the epidemiology, prevention and control of toxoplasmosis. PMID- 26017721 TI - Innate Immunity to Campylobacter jejuni in Guillain-Barre Syndrome. AB - OBJECTIVE: Guillain-Barre syndrome (GBS) is a postinfectious neuropathy most frequently caused by Campylobacter jejuni. Lipo-oligosaccharides (LOS), expressed by C. jejuni induce antibodies that cross-react with self-glycolipids in peripheral nerves, causing neuropathy. Less than 1 in 1,000 persons infected with C. jejuni develop GBS, and the factors that determine GBS susceptibility are poorly understood. We hypothesized that these persons have a high intrinsic dendritic cell (DC) response to C. jejuni LOS through Toll-like receptor 4 (TLR4) activation. METHODS: Intrinsic DC responsiveness to C. jejuni LOS was investigated first in 20 healthy controls at three time points with a 3-month interval, and second in patients, who previously developed GBS after a C. jejuni infection (n = 27) and controls (n = 26). RESULTS: The DC response to C. jejuni LOS was highly variable between, but not within, healthy individuals, suggesting that intrinsic factors determine the magnitude of TLR4-mediated innate response. High responsiveness to C. jejuni LOS by former GBS patients was evidenced by increased expression of CD38 and CD40. Frequency of CD38, CD40 and type I interferon high responders was significantly increased in the GBS group. INTERPRETATION: These results suggest that a strong response to TLR4 stimulation is a critical host condition for the development of GBS after an infection with C. jejuni. PMID- 26017722 TI - Intermittent Hypoxia Impairs Endothelial Function in Early Preatherosclerosis. AB - Intermittent hypoxia seems to be a major pathomechanism of obstructive sleep apnea-associated progression of atherosclerosis. The goal of the present study was to assess the influence of hypoxia on endothelial function depending on the initial stage of vasculopathy. We used 16 ApoE-/- mice were exposed to a 6-week intermittent hypoxia either immediately (early preatherosclerosis) or after 5 weeks of high-cholesterol diet (advanced preatherosclerosis). Another 16 ApoE-/- mice under normoxia served as corresponding controls. Endothelial function was measured by an organ bath technique. Blood plasma CD31+/annexin V+ endothelial microparticles as well as sca1/flk1+ endothelial progenitor cells in blood and bone marrow were analyzed by flow cytometry. The findings were that intermittent hypoxia impaired endothelial function (56.6+/-6.2% of maximal phenylephrine induced vasoconstriction vs. 35.2+/-4.1% in control) and integrity (increased percentage of endothelial microparticles: 0.28+/-0.05% vs. 0.15+/-0.02% in control) in early preatherosclerosis. Peripheral repair capacity expressed as the number of endothelial progenitor cells in blood was attenuated under hypoxia (2.0+/-0.5% vs. 5.3+/-1.9% in control), despite the elevated number of these cells in the bone marrow (2.0+/-0.4% vs. 1.1+/-0.2% in control). In contrast, endothelial function, as well as microparticle and endothelial progenitor cell levels were similar under hypoxia vs. control in advanced preatherosclerosis. We conclude that hypoxia aggravates endothelial dysfunction and destruction in early preatherosclerosis. PMID- 26017723 TI - Vertigo with a Vestibular Dysfunction in Children During Respiratory Tract Infections. AB - Sudden balance disorders with violent vegetative symptoms (nausea and vomiting) pose a diagnostic and therapeutic problem. In children vertigo/dizziness with symptoms of vestibular dysfunction is rare, but as vascular etiology is unlikely in children such symptoms arouse concern. This article presents two cases of this type of vertigo. The patients were two boys (6 and 9 years old). They came down with similar symptoms: sudden dizziness, disabled walking, nausea and vomiting, spontaneous nystagmus, and a positive Romberg test. The onset of the balance disorder was preceded by respiratory infection: common cold with symptoms of inflammation of the mucous membrane in the nose and throat. Laboratory tests revealed increased levels of C-reactive protein only in the older boy. Neuroinfection and a displacement process were ruled out. Videonystagmography revealed vestibular dysfunction and vestibular neuronitis on the left side. PMID- 26017724 TI - The Influence of Online Health Information on the Attitude and Behavior of People Aged 50. AB - E-patients 'empowered' by Web information are much more likely to participate in health care decision processes and take responsibility for their own health. The purpose of the study was to determine the influence of Internet use and online health information on the attitude, behavior, and emotions of Polish citizens aged 50+, with special regard to their attitude towards health professionals and the health care system. A total of 323 citizens, aged 50 years and above, who used the Internet for health purposes, were selected from the Polish population by random sampling. The sample collection was carried out by Polish opinion poll agencies in 2005, 2007, and 2012. The Internet was used by 27.8 % of Polish citizens aged 50+ for health purposes in the years 2005-2012. 69.7 % of respondents were looking for health information that might help them to deal with a consultation, 53.9 % turned to the Internet to prepare for a medical appointment, and 63.5 % to assess the outcome of a medical consultation and obtain a 'second opinion'. The most likely effects of health related use of the Internet were: willingness to change diet or other life-style habits (48.0 % of respondents) and making suggestions or queries on diagnosis or treatment by the doctor (46.1 %). Feelings of reassurance or relief after obtaining information on health or illness were reported by a similar number of respondents as feelings of anxiety and fear (31.0 % and 31.3 % respectively). Online health information can affect the attitudes, emotions, and health behaviors of Polish citizens aged 50+ in different ways. PMID- 26017725 TI - Pulmonary Rehabilitation in Advanced Lung Cancer Patients During Chemotherapy. AB - The aim of this study was to investigate the utility of pulmonary rehabilitation for improving of exercises efficiency, dyspnea, and quality of life of patients with lung cancer during chemotherapy. After the enrollment selection, the study included 20 patients with newly diagnosed advanced lung cancer and performance status 0-2. There were 12 patients randomly allocated to the pulmonary rehabilitation group and another 8 constituted the control group that did not undergo physical rehabilitation. Both groups of patients had continual cycles of chemotherapy. Data were analyzed before and after 8 weeks of physical rehabilitation, and before and after 8 weeks of observation without rehabilitation in controls. The inpatient rehabilitation program was based on exercise training with ski poles and respiratory muscle training. We found a tendency for enhanced mobility (6 Minute Walk Test: 527.3 +/- 107.4 vs. 563.9 +/ 64.6 m; p > 0.05) and a significant increase in forced expired volume in 1 s (66.9 +/- 13.2 vs. 78.4 +/- 17.7 %predicted; p = 0.016), less dyspnea (p = 0.05), and a tendency for improvement in the general quality of life questionnaire after completion of pulmonary rehabilitation as compared with the control group. This report suggests that pulmonary rehabilitation in advanced lung cancer patients during chemotherapy is a beneficial intervention to reduce dyspnea and enhance the quality of life and mobility. PMID- 26017726 TI - Unmet Needs of Patients with Chronic Respiratory Diseases Within Primary Healthcare. AB - There is no data on the level of unmet needs in the heterogenic group of chronically ill patients. The purpose of this study was to define the degree of unmet needs in patients with chronic respiratory diseases and to identify the factors that determine them. The study group consisted of 214 adult patients with the median age of 65 (min-max: 18-90 years). Variables affecting the level of satisfied needs were the following: gender, age, marital status, place of residence, number of chronic diseases, somatic symptoms, level of disease acceptance, level of quality of life (QoL), and health behaviors. The prevention program to increase the level of satisfied needs in patients with chronic respiratory diseases, apart from obviously being addressed to those with low levels of health satisfaction and quality of life indices, should be addressed to men, the elderly, those having no partner, living in the countryside, and having multiple somatic symptoms. Patients with a high level of disease acceptance, those maintaining physical quality of life and advantageous health behaviors should be considered as well. PMID- 26017727 TI - Socioeconomic Indicators Shaping Quality of Life and Illness Acceptance in Patients with Chronic Obstructive Pulmonary Disease. AB - Quality of life (QoL) combined with the acceptance of illness reflects the efficiency of therapy and the level of patients' satisfaction with medical care. Education, marital status, and place of residence were used as the socio-economic status indicators. The purpose of this study was to determine the relationship between the levels of QoL and acceptance of illness (AI) and the socio demographic data in patients with chronic obstructive pulmonary disease (COPD). The study involved 264 adult COPD patients. The average duration of COPD was 9 years (Q1-Q3: 3.0-12.0). The duration of the disease was significantly shorter in patients from rural areas. QoL correlated positively with AI (r = 0.69, p < 0.0001). The general QoL and AI were most strongly influenced by education, gender, and age. Education is a strong predictor of QoL and AI, and the latter correlate with the socioeconomic status of COPD patients. It is recommended that COPD patients with a low level of education have regular medical check-ups and are included in the preventive programs by general practitioners to improve their somatic status and QoL level. PMID- 26017728 TI - Pulmonary Function Abnormalities in Regard to Age at the Time of Diagnosis of Hypersensitivity Pneumonitis. AB - Hypersensitivity pneumonitis (HP) is a complex syndrome caused by exaggerated immune response to inhalation of a variety of organic particles in susceptible individuals. In this study we assessed the relationship between age at the time of diagnosis and the degree of functional and radiological changes in HP. The diagnosis of HP was made on the basis of a combination of clinical symptoms, medical history, serological tests, radiologic evidence of diffuse lung disease, and absence of other identifiable causes of lung disease. We reviewed the records of 111 patients (68 women) diagnosed with HP over a period of 18 years (1995 2013). The patients were stratified into 3 age-groups: <30, 30-49, and >=50 years old. The commonest cause of HP was avian antigens (56.8 %). Dyspnea was present in 97.3 % of patients, weight loss in 54.7 % of patients, and respiratory insufficiency in 24.3 % of patients. Lung fibrosis in chest computed tomography was found in 35.1 % of patients. Lung function was impaired more seriously in the youngest age-group, with lung diffusing capacity for carbon monoxide (DLCO) <40 % in 69.2 % of these patients. Restrictive pattern was present in 92.3 % of patients in this group, as compared with the 41.0 % in the whole cohort. In this group, desaturation in the six minute walk test also was most notable, amounting to a median of 11 %. In conclusion, diagnosis of HP at young age is predictive of a more severe clinical course of disease, with lung fibrosis and higher disturbances in pulmonary function. PMID- 26017729 TI - Effects on Lung Function of Small-Volume Conventional Ventilation and High Frequency Oscillatory Ventilation in a Model of Meconium Aspiration Syndrome. AB - For treatment of severe neonatal meconium aspiration syndrome (MAS), lung protective mechanical ventilation is essential. This study compared short-term effects of small-volume conventional mechanical ventilation and high-frequency oscillatory ventilation on lung function in experimentally-induced MAS. In conventionally-ventilated rabbits, MAS was induced by intratracheal instillation of meconium suspension (4 ml/kg, 25 mg/ml). Then, animals were ventilated conventionally with small-volume (f-50/min; VT-6 ml/kg) or with high frequency ventilation (f-10/s) for 4 h, with the evaluation of blood gases, ventilatory pressures, and pulmonary shunts. After sacrifice, left lung was saline-lavaged and cells in bronchoalveolar lavage fluid (BALF) were determined. Right lung was used for the estimation of lung edema formation (wet/dry weight ratio). Thiobarbituric acid-reactive substances (TBARS), oxidative damage markers, were detected in lung tissue and plasma. Meconium instillation worsened gas exchange, and induced inflammation and lung edema. Within 4 h of ventilation, high frequency ventilation improved arterial pH and CO2 elimination compared with conventional ventilation. However, no other significant differences in oxygenation, ventilatory pressures, shunts, BALF cell counts, TBARS concentrations, or edema formation were observed between the two kinds of ventilation. We conclude that high frequency ventilation has only a slight advantage over small-volume conventional ventilation in the model of meconium aspiration syndrome in that it improves CO2 elimination. PMID- 26017730 TI - Peroxynitrite in Sarcoidosis: Relation to Mycobacterium Stationary Phase. AB - There is evidence that the same mycobacterial heat shock proteins (Mtb-HSPs), especially HSP16, the main marker of mycobacteria dormant stage, occur in sarcoid tissues and in circulated immune complexes and prompt the immune responses against the different genetic background, leading to the development of acute sarcoidosis (SA)/Lofgren syndrome, chronic SA, latent tuberculosis (TB), or active TB. In SA there is increased monocytes phagocytic activity, decreased clearance of antigens/immune complexes by monocytes, which are resistant to apoptosis, and decreased serum microbicidal/degradable nitrate/nitrite (NOx) concentration. Reduction in NOx may result from the reaction of NOx with superoxide with subsequent production of peroxynitrite (ONOO-). In this study, therefore, we evaluated NOx and ONOO- levels in supernatants of peripheral blood mononuclear cells cultures treated with Mtb-HSPs from 20 SA patients, 19 TB patients, and 21 healthy volunteers using Griess and rhodamine fluorescence methods. We found significantly greater NOx and ONOO- concentrations with/without Mtb-HSPs stimulation in SA and TB patients than in controls. However, there were significantly lower NOx and higher ONOO- levels after Mtb-HSPs induction in SA than TB patients. In summary, in contrast to active TB, increased ONOO- concentration may explain the low level of NOx with induction of M. tuberculosis genetic dormancy program via higher Mtb-HSP16 expression in SA. PMID- 26017731 TI - How Do Skeletal Muscles Die? An Overview. AB - Clarifying the confusion regarding the term "muscle death" is of great importance, especially for clinicians. In response to various stimuli, skeletal muscle may undergo pathological changes, leading to muscle atrophy and consequently resulting in the loss of muscle strength and function. Depending on the stimulus, skeletal muscles can be induced to die through different mechanisms mainly via apoptosis, autophagy and necrosis. Muscle death may occur secondary to various physiological and pathological conditions such as aging, starvation, immobilization, denervation, inflammation, muscle diseases and cancer. This overview aims to elucidate the medical terminology and pathways used to describe muscle death, which are commonly confused. In addition, some of the common pathological conditions that lead to muscle death such as cachexia and sarcopenia of aging are dwelled on. PMID- 26017732 TI - Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review: reply. PMID- 26017733 TI - Understanding the Origin of Enhanced Performances in Core-Shell and Concentration Gradient Layered Oxide Cathode Materials. AB - Core-shell and concentration-gradient layered oxide cathode materials deliver superior electrochemical properties such as long cycle life and outstanding thermal stability. However, the origin of enhanced performance is not clear and seldom investigated until now. Here, a specific structured layered oxide (LiNi0.5Co0.2Mn0.3O2) consisting of concentration-gradient core, transition layer, and stable outer shell, is designed and achieved from double-shelled precursors to overcome the great challenge by comparison with the normal layered LiNi0.5Co0.2Mn0.3O2. As expected, the specific structured layered oxide displays excellent cycle life and thermal stability. After numerous cycles, the valence state of Ni and Co at normal layered oxide surface tends to a higher oxidation state than that of the specific structured oxide, and the spinel phase is observed on particle surface of normal layered oxide. Also, the deficient spinel/layered mixed phases lead to high surface film and charge-transfer resistance for normal layered oxide, whereas the specific structured one still remains a layered structure. Those results first illustrate the origin of improved electrochemical performance of layered core-shell and concentration gradient cathode materials for lithium-ion batteries. PMID- 26017734 TI - PET/MRI and PET/CT in advanced gynaecological tumours: initial experience and comparison. AB - PURPOSE: To compare the diagnostic accuracy of PET/MRI and PET/CT for staging and re-staging advanced gynaecological cancer patients as well as identify the potential benefits of each method in such a population. MATERIAL AND METHODS: Twenty-six patients with suspicious or proven advanced gynaecological cancer (12 ovarian, seven cervical, one vulvar and four endometrial tumours, one uterine metastasis, and one primary peritoneal cancer) underwent whole-body imaging with a sequential trimodality PET/CT/MR system. Images were analysed regarding primary tumour detection and delineation, loco-regional lymph node staging, and abdominal/extra-abdominal distant metastasis detection (last only by PET/CT). RESULTS: Eighteen (69.2 %) patients underwent PET/MRI for primary staging and eight patients (30.8 %) for re-staging their gynaecological malignancies. For primary tumour delineation, PET/MRI accuracy was statistically superior to PET/CT (p < 0.001). Among the different types of cancer, PET/MRI presented better tumour delineation mainly for cervical (6/7) and endometrial (2/3) cancers. PET/MRI for local evaluation as well as PET/CT for extra-abdominal metastases had therapeutic consequences in three and one patients, respectively. PET/CT detected 12 extra abdominal distant metastases in 26 patients. CONCLUSION: PET/MRI is superior to PET/CT for primary tumour delineation. No differences were found in detection of regional lymph node involvement and abdominal metastases detection. KEY POINTS: * PET/MRI is superior to PET/CT for primary tumour delineation * PET/CT represents a reliable tool to detect extra-abdominal distant metastasis * PET/MRI might be the preferred imaging modality for staging cervical and endometrial tumours * Whole-body staging for detection and evaluation of extra-abdominal metastases is mandatory. PMID- 26017735 TI - Imaging features of rosette-forming glioneuronal tumours (RGNTs): A Series of seven cases. AB - OBJECTIVE: Rosette-forming glioneuronal tumours (RGNTs) are a recently described, rare, distinct nosological entity of the glioneuronal family. We describe imaging findings (CT and MRI) in seven patients with RGNTs. MATERIALS AND METHODS: This retrospective study includes seven RGNT patients (4 male, 3 female; age range: 7 42 years; mean age: 25 years) diagnosed and treated at our institute. MR studies were performed on 3 T and 1.5-T clinical MR systems. All patients were reviewed by two experienced neuroradiologists and imaging findings were tabulated. RESULTS: Five tumours were located in the posterior fossa, and two were in the pineal region. One of the tumours demonstrated multiple satellite lesions, which involved the midbrain, pons, medulla as well as the cervical cord. Tumours located in the pineal region compressed the 3rd ventricle/aqueduct and extended below the tentorium cerebelli. All the tumours demonstrated enhancement, and susceptibility was evident in six of the seven patients. CSF dissemination was present in two patients. CONCLUSION: RGNTs are usually solid-cystic tumours and frequently demonstrate peripheral/heterogeneous enhancement upon post-contrast study. Haemorrhage is a common feature which may not be evident on CT. Cerebrospinal fluid (CSF) dissemination is a feature and appropriate imaging should be performed whenever an RGNT is suspected. KEY POINTS: CT and MRI findings of seven RGNT cases were retrospectively reviewed. RGNTs are predominantly posterior fossa tumours. RGNTs are typically T1 hypointense and T2 hyperintense. Haemorrhage and peripheral/heterogeneous enhancement are common features of RGNTs. CSF dissemination is a feature of RGNTs and requires appropriate imaging. PMID- 26017736 TI - Non-contrast-enhanced MRA of renal artery stenosis: validation against DSA in a porcine model. AB - OBJECTIVES: To compare 3D-inversion-recovery balanced steady-state free precession (IR-bSSFP) non-contrast-enhanced magnetic resonance angiography (MRA) with 3D-contrast-enhanced MRA (CE-MRA) for assessment of renal artery stenosis (RAS) using digital subtraction angiography (DSA) as the reference standard. METHODS: Bilateral RAS were surgically created in 12 swine. IR-bSSFP and CE-MRA were acquired at 1.5 T and compared to rotational DSA. Three experienced cardiovascular radiologists evaluated the IR-bSSFP and CE-MRA studies independently. Linear regression models were used to calibrate and assess the accuracy of IR-bSSFP and CE-MRA, separately, against DSA. The coefficient of determination and Cohen's kappa coefficient were also generated. RESULTS: Calibration of the three readers' RAS grading revealed R(2) values of 0.52, 0.37 and 0.59 for NCE-MRA and 0.48, 0.53 and 0.71 for CE-MRA. Inter-rater agreement demonstrated Cohen's kappa values ranging from 0.25 to 0.65. Distal renal artery branch vessels were visible to a significantly higher degree with NCE-MRA compared to CE-MRA (p < 0.001). Image quality was rated excellent for both sequences, although image noise was higher with CE-MRA (p < 0.05). In no cases did noise interfere with image interpretation. CONCLUSIONS: In a well-controlled animal model of surgically induced RAS, IR-bSSFP based NCE-MRA and CE-MRA accurately graded RAS with a tendency for stenosis overestimation, compared to DSA. KEY POINTS: * IR-bSSFP and CE-MRA are accurate methods for diagnosis of renal artery stenosis * IR-bSSFP and CE-MRA demonstrate excellent agreement with DSA * Both IR-bSSFP and CE-MRA have a tendency to overestimate renal artery stenosis. PMID- 26017737 TI - Feasibility of mesorectal vascular invasion in predicting early distant metastasis in patients with stage T3 rectal cancer based on rectal MRI. AB - OBJECTIVES: To evaluate the feasibility of mesorectal vascular invasion (MVI) in predicting early distant metastasis developed within 1 year of diagnosis of T3 rectal cancer using magnetic resonance imaging (MRI) METHODS: Sixty-five patients with T3 rectal cancer (early metastasis, n = 28; non-metastasis, n = 37) were enrolled in this study. Early distant metastases developed in 28 patients (liver, n = 15; lung, n = 9; both, n = 4). Logistic regression was used to determine the independent predictors for early distant metastasis. RESULTS: In univariate analysis, tumour location, carcinoembryonic antigen (CEA), lymphovascular invasion (LVI), MRI-detected MVI, and mesorectal fat infiltration (MFI) (odds ratio [OR], 4.533, 9.583, 5.539, 27.046, and 5.539, respectively) were associated with early distant metastasis. Multivariate analysis demonstrated that MVI (OR, 29.949; P < 0.002) and LVI (OR, 6.684; P = 0.033) were independent factors for early distant metastasis. Specificity and positive predictive value (PPV) of MVI (94.59%, and 89.47%, respectively) were significantly higher than those of LVI (64.86%, and 61.76%), but sensitivity and negative predictive value were not significantly different between MVI (60.71%, and 76.09%) and LVI (75.00%, and 77.42%). CONCLUSIONS: While sensitivity of MRI-detected MVI was equal to that of CEA in predicting early distant metastasis from T3 rectal cancer, specificity and PPV may be improved by assessing MVI. KEY POINTS: * Mesorectal vascular invasion (MVI) may be a radiologic prognostic factor for rectal cancer. * Specificity of MVI was higher than lymphovascular invasion in predicting early metastasis. * Mesorectal vascular invasion may be a better predictor for early distant metastasis. PMID- 26017738 TI - Assessment of renal allograft function early after transplantation with isotropic resolution diffusion tensor imaging. AB - OBJECTIVES: To investigate the value of diffusion tensor imaging (DTI) and tractography in renal allografts at the early stage after kidney transplantation. METHODS: This study was approved by the institutional ethical review committee, and written informed consent was obtained. A total of 54 renal allograft recipients 2-3 weeks after transplantation and 26 age-matched healthy volunteers underwent renal DTI with a 3.0-T magnetic resonance imaging (MRI) system. Recipients were divided into three groups according to the estimated glomerular filtration rate (eGFR). Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of the cortex and medulla were measured and compared among the groups. Whole-kidney tractography was performed. Correlation of eGFR with diffusion parameters was evaluated. RESULTS: In allografts with stable function, the medullary ADC was higher and the cortical FA was lower (p < 0.001) than in healthy kidneys. The cortical ADC, medullary ADC and FA decreased as the allograft function declined, and with a positive correlation with eGFR (p < 0.001); cortical FA did not. Tractography demonstrated a decrease of tract density in impaired functional allografts. CONCLUSIONS: Renal DTI produces reliable results to assess renal allograft function at the early stage after transplantation. KEY POINTS: * DTI and tractography can evaluate renal allograft function at an early stage * Medullary FA, cortical and medullary ADC can effectively evaluate allograft function * Medullary FA, cortical and medullary ADC are correlated with eGFR in renal allografts * Medullary ADC increased and cortical FA decreased in stable allografts compared to control subjects * Medullary FA, cortical and medullary ADC decreased and allograft function declined. PMID- 26017740 TI - Distribution of liver metastases based on the site of primary pancreatic carcinoma. AB - OBJECTIVES: To investigate whether the different location of pancreatic adenocarcinoma affects the lobar distribution of metastases to the liver. METHODS: From all patients who underwent multidetector computed tomography (MDCT) examinations for staging of pancreatic adenocarcinoma in the last 4 years we selected 80 patients (42 men, 38 women; mean age, 60.56 years) with liver metastases and a pancreatic adenocarcinoma of the head (group A, 40 patients; diameter, 32.41 +/- 2.28 mm) or body-tail (group B, 40 patients; diameter, 52.21 +/- 2.8 mm). We analysed tumour site, diameter, vascular invasion and number of metastases in each lobe of the liver. The total number of metastases was compared between the two groups with an unpaired t-test, while Fisher's test was used to compare the number of metastases within the two lobes. RESULTS: As expected, the number of liver metastases was higher in group B than in group A. The ratio of metastases in the right-to-left hemi-liver was 7.4:1 for group A compared with 3.3:1 for group B (p < 0.0001). CONCLUSIONS: Although the number of liver metastases is higher in the right lobe than in the left lobe in both groups, there is a significant difference in the ratio of metastases between the right and the left hemi-liver. This supports the existence of a streamline phenomenon and a selective lobar distribution of metastases within the liver. KEY POINTS: * Pancreatic adenocarcinoma presents with liver metastases in 40% of cases * The presence of liver metastases disqualifies the patient from curative surgery * The distribution of metastases within the liver depends on the site of pancreatic adenocarcinoma * The distribution of liver metastases is due to the streamline phenomenon. PMID- 26017739 TI - Estimating GFR prior to contrast medium examinations--what the radiologist needs to know! AB - Creatinine-based equations to estimate glomerular filtration rate (GFR) are increasingly used in radiological practice and in studies on contrast medium induced acute kidney injury (CIAKI). Their use is recommended in guidelines and contrast medium textbooks to identify patients at risk of CIAKI or nephrogenic systemic fibrosis. There is also an increased interest in cystatin C-based equations. Adopting GFR equations requires local creatinine and cystatin C assay calibrations to equal those used in developing the equations to avoid overestimation or underestimation of renal function. Methods should preferably be traceable to international standards, and assay traceability should be defined in CIAKI studies. Absolute GFR (mL/min) should be used when dosing contrast media and relating the dose to CIAKI instead of commonly used relative GFR (mL/min/1.73 m(2)) estimates. Accuracy of creatinine and cystatin C equations (percentage of GFR estimates within 30% of measured GFR) ranges between 75% and 85%. Equations combining creatinine and cystatin C may reach 90%, an accuracy similar to clearance methods (used as a reference test when developing and validating equations) when compared to the gold standard, renal clearance of inulin. The local laboratory or nephrology experts should be consulted in matters of method calibration and choice of GFR equation. KEY POINTS: * Traceability of creatinine/cystatin C assays used in GFR equations must be defined. * Absolute, not relative, GFR should be used when dosing contrast media. * Consult the local laboratory or nephrologist to choose the proper GFR equation. PMID- 26017741 TI - Conclusions for mammography screening after 25-year follow-up of the Canadian National Breast Cancer Screening Study (CNBSS). AB - Twenty-five-year follow-up data of the Canadian National Breast Cancer Screening Study (CNBSS) indicated no mortality reduction. What conclusions should be drawn? After conducting a systematic literature search and narrative analysis, we wish to recapitulate important details of this study, which may have been neglected: Sixty-eight percent of all included cancers were palpable, a situation that does not allow testing the value of early detection. Randomisation was performed at the sites after palpation, while blinding was not guaranteed. In the first round, this "randomisation" assigned 19/24 late stage cancers to the mammography group and only five to the control group, supporting the suspicion of severe errors in the randomisation process. The responsible physicist rated mammography quality as "far below state of the art of that time". Radiological advisors resigned during the study due to unacceptable image quality, training, and medical quality assurance. Each described problem may strongly influence the results between study and control groups. Twenty-five years of follow-up cannot heal these fundamental problems. This study is inappropriate for evidence-based conclusions. The technology and quality assurance of the diagnostic chain is shown to be contrary to today's screening programmes, and the results of the CNBSS are not applicable to them. KEY POINTS: * The evidence base of the Canadian study (CNBSS) has to be questioned.* Severe flaws in the randomization process and test methods occurred. * Problems were criticized during and after conclusion of the trial by experts.* The results are not applicable to quality-assured screening programs. * The evidence base of this study must be re-analyzed. PMID- 26017744 TI - Treatment of septic arthritis of the knee: a comparison between arthroscopy and arthrotomy. AB - PURPOSE: The aim of this study was to compare the efficacy of arthroscopy and arthrotomy in patients with septic monarthritis of the knee. METHODS: Seventy consecutive patients who underwent surgery because of a bacterial monarthritis were evaluated. Patients were either treated with arthroscopy or with arthrotomy. Our primary outcome was the early recurrence of infection (>3 months after surgery), which made a second surgical procedure necessary. Furthermore, the influence of potential confounders on treatment outcome was analysed. RESULTS: Of the 70 patients, 41 were treated arthroscopically and 29 with arthrotomy. Eight patients (11.4 %) had to undergo a second surgical procedure because of early re infection. The rate was significantly higher in patients treated with arthrotomy (n = 6; 20.7 %) compared with those treated by arthroscopy (n = 2) (p = 0.041). Range of motion was significantly better in patients who underwent arthroscopy (p < 0.001). Male sex had negative influence on the treatment success (p = 0.03). CONCLUSIONS: Patients with bacterial monarthritis of the knee who were treated with arthroscopy had a significantly lower re-infection rate and a better functional outcome than those treated with arthrotomy. As arthroscopy is the less invasive method, it should be considered the routine treatment, according to our data. LEVEL OF EVIDENCE: Therapeutic study, Level III. PMID- 26017743 TI - Is overcorrection preferable for repair of degenerated articular cartilage after open-wedge high tibial osteotomy? AB - PURPOSE: This study was performed to determine whether the overcorrected knee could obtain a higher ratio of articular cartilage repair in the medial compartment of the femorotibial joint after open-wedge high tibial osteotomy (HTO). The hypothesis of the study was that overcorrected knees had a higher ratio of articular cartilage repair than moderately corrected knees. METHODS: A total of 71 knees that underwent arthroscopy to evaluate the articular cartilage during open-wedge HTO and second-look arthroscopy were reviewed. The articular cartilage was classified as no repair or repair according to Koshino et al. Overcorrection was defined as knees with femorotibial angle <=166 degrees . RESULTS: Second-look arthroscopy was performed 410 +/- 64 days after HTO. Based on arthroscopic observations, 45 knees (63.4 %) showed no repair and 26 knees (36.6 %) showed repair. In terms of the ratio of cartilage repair, there was no difference between overcorrected knees with mean femorotibial angle of 165 degrees +/- 1 degrees and moderately corrected knees with mean femorotibial angle of 170 degrees +/- 2 degrees (n.s.). CONCLUSIONS: No significant differences were found in the ratio of cartilage repair between overcorrected and moderately corrected knees. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 26017742 TI - The effect of subacromial injections of autologous conditioned plasma versus cortisone for the treatment of symptomatic partial rotator cuff tears. AB - PURPOSE: Rotator cuff tears are one of the most common causes of shoulder malfunction and pain, which lead to a significant reduction in the quality of life. This present study investigated the effects of subacromial platelet-rich plasma injections [i.e. autologous conditioned plasma (ACP) injections] as compared to standard subacromial cortisone injection therapy in 50 patients with partial rotator cuff tears. METHODS: Before injection, and 6 weeks, 12 weeks and 6 months thereafter, the patients were assessed by the Constant-Murley score (CMS), the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), the simple shoulder test (SST) and a pain visual analogue scale (VAS). An MRI was also performed before and 6 months after injection. RESULTS: Both patient groups had statistically significant better shoulder score outcomes over time. ASES, SST and CMS outcomes after 12 versus 6 weeks were better in the ACP group as compared to the cortisone group. VAS, ASES and CMS outcomes after 12 weeks versus baseline in the ACP group were better as compared to the cortisone group. There was a statistically significant difference between ACP group and cortisone group 12 weeks after injection regarding VAS, ASES, SST and CMS in favour of the ACP group. The MRI showed an improvement in grade of tendinopathy in both groups, however, without statistically significant differences between the two groups. CONCLUSION: Compared with cortisone injections, ACP injections show earlier benefit as compared to cortisone injections although a statistically significant difference after 6 months could not be found. Therefore, subacromial ACP injections are a good alternative to subacromial cortisone injections, especially in patients with contraindication to cortisone. LEVEL OF EVIDENCE: Therapeutic study, Level III. PMID- 26017745 TI - The improvement of postural control in patients with mechanical ankle instability after lateral ankle ligaments reconstruction. AB - PURPOSE: Lateral ankle sprain is the most common injury. A previous study demonstrated that patients with mechanical ankle instability suffered deficits in postural control, indicating that structural damage of the lateral ankle ligaments may produce a balance deficit. The purpose of this study was to confirm that lateral ligaments reconstruction could improve postural control in patients with mechanical ankle instability. METHODS: A total of 15 patients were included in the study. Each patient had a history of an ankle sprain with persistent symptoms of ankle instability and a positive anterior drawer test and had been treated nonoperatively for at least 3 months. All patients were diagnosed with lateral ankle ligaments tear by ultrasonography and magnetic resonance imaging. They underwent arthroscopic debridement and open lateral ankle ligaments reconstruction with a modified Brostrom procedure. One day before and 6 months after the operation, all of the participants underwent single-limb postural sway tests. The anterior drawer test and the American Orthopedic Foot and Ankle Society scale score were used to evaluate the clinical results in these patients. RESULTS: At 6 months after the operation, with the patients' eyes closed, there was significantly decreased postural sway in the anteroposterior direction, the circumferential area, and the total path length on the operated ankles compared with those measurements before the operation. With eyes open, however, no difference was found in postural sway before and after the operation. CONCLUSIONS: Postural control was improved by reconstructing the lateral ligaments. LEVEL OF EVIDENCE: IV. PMID- 26017746 TI - Different role of spinal 5-HT (hydroxytryptamine) 7 receptors and descending serotonergic modulation in inflammatory pain induced in formalin and carrageenan rat models British Journal of Anaesthesia, 2014; 113(1): 138-47, DOI 10.1093/bja/aet336. PMID- 26017747 TI - The contribution of occult precipitation to nutrient deposition on the west coast of South Africa. AB - The Strandveld mediterranean-ecosystem of the west coast of South Africa supports floristically diverse vegetation growing on mostly nutrient-poor aeolian sands and extending from the Atlantic Ocean tens of kilometers inland. The cold Benguela current upwelling interacts with warm onshore southerly winds in summer causing coastal fogs in this region. We hypothesized that fog and other forms of occult precipitation contribute moisture and nutrients to the vegetation. We measured occult precipitation over one year along a transect running inland in the direction of the prevailing wind and compared the nutrient concentrations with those in rainwater. Occult deposition rates of P, N, K, Mg, Ca, Na, Al and Fe all decreased with distance from the ocean. Furthermore, ratios of cations to Na were similar to those of seawater, suggesting a marine origin for these. In contrast, N and P ratios in occult precipitation were higher than in seawater. We speculate that this is due to marine foam contributing to occult precipitation. Nutrient loss in leaf litter from dominant shrub species was measured to indicate nutrient demand. We estimated that occult precipitation could meet the demand of the dominant shrubby species for annual N, P, K and Ca. Of these species, those with small leaves intercepted more moisture and nutrients than those with larger leaves and could take up foliar deposits of glycine, NO3(-), NH4(+) and Li (as tracer for K) through leaf surfaces. We conclude that occult deposition together with rainfall deposition are potentially important nutrient and moisture sources for the Strandveld vegetation that contribute to this vegetation being floristically distinct from neighbouring nutrient-poor Fynbos vegetation. PMID- 26017748 TI - Measuring steps with the Fitbit activity tracker: an inter-device reliability study. AB - Activity trackers like Fitbit are used for self-tracking of physical activity by an increasing number of individuals. Comparing physical activity scores with peers can contribute to the desired behavioural change. However, for meaningful social comparison a high inter-device reliability is paramount. This study aimed to determine the inter-device reliability of Fitbit activity trackers in measuring steps. Ten activity trackers (Fitbit Ultra) were worn by a single person (male, 46 years) during eight consecutive days. Inter-device reliability was assessed on three different levels of aggregation (minutes, hours, days) with various methods, including intra-class correlation coefficient (ICC), Bland Altman plots, limits of agreement (LOA) and Mixed Model Analysis. Results showed that the inter-device reliability of the Fitbit in measuring steps is good at all levels of aggregation (minutes, hours, days), but especially when steps were measured per day. This implies that individuals can reliably compare their daily physical activity scores with peers. PMID- 26017749 TI - Association between statin use and plasma D-dimer levels. A systematic review and meta-analysis of randomised controlled trials. AB - D-dimers, specific breakdown fragments of cross-linked fibrin, are generally used as circulating markers of activated coagulation. Statins influence haemostatic factors, but their effect on plasma D-dimer levels is controversial. Therefore, the aim of this meta-analysis was to evaluate the association between statin therapy and plasma D-dimer levels. We searched PubMed, Web of Science, Cochrane Library, Scopus and EMBASE (up to September 25, 2014) to identify randomised controlled trials (RCTs) investigating the impact of statin therapy on plasma D dimer levels. Two independent reviewers extracted data on study characteristics, methods and outcomes. Meta-analysis of data from nine RCTs with 1,165 participants showed a significant effect of statin therapy in reducing plasma D dimer levels (standardised mean difference [SMD]: -0.988 ug/ml, 95 % confidence interval [CI]: -1.590 - -0.385, p=0.001). The effect size was robust in sensitivity analysis and omission of no single study significantly changed the overall estimated effect size. In the subgroup analysis, the effect of statins on plasma D-dimer levels was significant only in the subsets of studies with treatment duration >= 12 weeks (SMD: -0.761 ug/ml, 95 %CI: -1.163- -0.360; p< 0.001), and for lipophilic statins (atorvastatin and simvastatin) (SMD: -1.364 ug/ml, 95 % CI: -2.202- -0.526; p=0.001). Hydrophilic statins (pravastatin and rosuvastatin) did not significantly reduce plasma D-dimer levels (SMD: -0.237 ug/ml, 95 %CI: -1.140-0.665, p=0.606). This meta-analysis of RCTs suggests a decrease of plasma D-dimer levels after three months of statin therapy, and especially after treatment with lipophilic statins. Well-designed trials are required to validate these results. PMID- 26017750 TI - Correlation between amygdala volume and impulsivity in adults with attention deficit hyperactivity disorder. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a chronic neurobiological disorder with childhood onset and persistence through adolescence and adulthood. ADHD patients frequently show exaggerated emotional responses. The amygdala plays an important role in emotion processing and in the activation of the frontal lobe. We hypothesised that smaller amygdala volumes in ADHD patients would be associated with less control of impulsivity and emotional instability. METHODS: We studied nine adult patients with ADHD and nine group-matched healthy volunteers using a 1.5 T magnetic resonance imaging scanner. We manually obtained morphometric measurements, which were later processed and compared. RESULTS: Significant negative correlation between the right amygdala volume and Barratt's impulsivity scores was observed (r=-0.756, p=0.018). No correlation was found between impulsivity scores and the volume of the left amygdala. Age was not found to be a contributor of the results. CONCLUSIONS: Smaller amygdala volumes have been observed in patients with ADHD. Our results suggest that greater emotional processing and less control of impulsivity are associated with smaller amygdala volumes in ADHD patients. Furthermore, the right amygdala would play a bigger role in impulsivity and behaviour control than the left amygdala. Further studies involving larger samples of adult patients with ADHD and using multimodal designs are needed. PMID- 26017751 TI - Reply: To PMID 25504899. PMID- 26017752 TI - Seroprevalence of Bluetongue virus in domestic yaks (Bos grunniens) in Tibetan regions of China based on circulating antibodies. AB - The bluetongue (BT) is an infectious, non-contagious disease of ruminants with a substantial impact on income and welfare of animals. To date, scarce information about this disease in domestic yaks is available in Tibetan area of China. Seroprevalence of circulating antibodies to Bluetongue virus (BTV) in yaks from three regions of Tibet and Hongyuan area of Sichuan Province in China was investigated by a commercial competitive enzyme-linked immunosorbent assay kits. A total of 736 blood samples were collected during the year 2012 and 2013, and nearly 2% serum samples were found positive for BTV antibodies in Hongyuan area during the year 2012, and 4.89 and 3.88% of samples showed positive results for BTV in Tibetan and Hongyuan area, respectively, in 2013. The results indicated the occurrence of BT infection in Chinese yaks for the first time in Tibet and Hongyuan area of Sichuan Province with the presence of BTV antibodies in these ruminants. PMID- 26017753 TI - First serological and molecular evidence of PPRV occurrence in Ghardaia district, center of Algeria. AB - In February 2012, an outbreak of peste des petits ruminants (PPR) was suspected in Ghardaia district at the center of Algeria. Clinical, serological, and molecular investigations were performed to confirm the occurrence of PPRV. The overall morbidity, mortality, and case fatality rates of the ten flocks investigated were 12.2, 2.5, and 20.3 %, respectively. At the flock level, positivity to PPR was 100, 90, and 100 % by competitive ELISA (c-ELISA), RT-PCR of blood samples, and oculo-nasal swabs, respectively. At the individual levels, the present study showed that out of 186 samples collected from the same animals 17/62 (27.41 %), 14/62 (22.85 %), and 36/62 (58.06 %) were positive by c-ELISA, RT-PCR of blood samples, and RT PCR of oculo-nasal swabs, respectively. The positivity of PPR was significantly higher using RT-PCR of oculo-nasal swabs than c-ELISA and RT-PCR of blood samples. The N gene partial sequence of five PPRV positive amplicons revealed 100 % homology among them and phylogenetically belonged to lineage IV. The sequences also showed similarity range of 97-99 % with the strains implicated in the Moroccan and Tunisian outbreaks, however, suggesting that a similar strain is circulating across this area of the Maghreb and highlighting the need for a regional control approach. PMID- 26017754 TI - Effects of partial silencing of genes coding for enzymes involved in glycolysis and tricarboxylic acid cycle on the enterance of human fibroblasts to the S phase. AB - BACKGROUND: Previously published reports indicated that some enzymes of the central carbon metabolism (CCM), particularly those involved in glycolysis and the tricarboxylic acid cycle, may contribute to regulation of DNA replication. However, vast majority of such works was performed with the use of cancer cells, in the light of carcinogenesis. On the other hand, recent experiments conducted on bacterial models provided evidence for the direct genetic link between CCM and DNA replication. Therefore, we asked if silencing of genes coding for glycolytic and/or Krebs cycle enzymes may affect the control of DNA replication in normal human fibroblasts. RESULTS: Particular genes coding for these enzymes were partially silenced with specific siRNAs. Such cells remained viable. We found that silencing of certain genes resulted in either less efficient or delayed enterance to the S phase. This concerned following genes: HK2, PFKM, TPI, GAPDH, ENO1, LDHA, CS1, ACO2, SUCLG2, SDHA, FH and MDH2. Decreased levels of expression of HK2, GADPH, CS1, ACO2, FH and MDH2 caused also a substantial impairment in DNA synthesis efficiency. CONCLUSIONS: The presented results illustrate the complexity of the influence of genes coding for enzymes of glycolysis and the tricarboxylic acid cycle on the control of DNA replication in human fibroblasts, and indicate which of them are especially important in this process. PMID- 26017755 TI - A comprehensive study on the behavior of a novel bacterial strain Acinetobacter guillouiae for bioremediation of divalent copper. AB - Biological methods have been successfully used to mitigate heavy metal pollution problem in wastewater. The present study was aimed towards isolation of a novel indigenous bacterial strain, Acinetobacter guillouiae from activated sludge and its subsequent application in remediation of copper (Cu(2+)) from aqueous solution. Kinetic study of bioremediation was performed for initial Cu(2+) concentrations ranging from 40 to 150 mg L(-1). Optimum values of nutrient dosage, pH, macronutrients [Nitrogen (N)-Phosphorus (P)-Potassium (K)] dosage, aerobic and facultative anaerobic conditions, temperature, and inoculum volume were determined by conducting separate batch bioremediation studies at 80 mg L( 1) initial concentration of Cu(2+). Kinetic study showed that A. guillouiae removed 98.7 % Cu(2+) for 80 mg L(-1) initial concentration of Cu(2+) after 16 h at an optimum solution pH of 7.0. Results also revealed that A. guillouiae showed maximum growth at double the standard composition of N, P and standard composition of K in nutrient dosage. Experimental data obtained in present study were utilized to validate different growth kinetic models such as Monod, Powell, Haldane, Luong, and Edwards. Growth kinetics of A. guillouiae was better understood by Luong model (R (2) = 0.97). Higher values of coefficient of determination (R (2) = 0.97-0.99) confirmed the suitability of the three-half order kinetic model for representing the Cu(2+) bioremediation. A. guillouiae showed a robust removal mechanism for the bioremediation of Cu(2+). PMID- 26017756 TI - Biosynthesis of silver nanoparticles and its antibacterial and antifungal activities towards Gram-positive, Gram-negative bacterial strains and different species of Candida fungus. AB - Biomimetic and economic method for the synthesis of silver nanoparticles (AgNPs) with controlled size has been reported in presence of shape-directing cetlytrimethylammonium bromide (CTAB). Biochemical reduction of Ag(+) ions in micellar solution with an aqueous lemon extract produced spherical and polyhedral AgNPs with size ranging from 15 to 30 nm. The influence of [CTAB] and [lemon extract] on the size of particles, fraction of metallic silver and their antimicrobial properties is discussed. The AgNPs were evaluated for their antimicrobial activities (antibacterial and antifungal) against different pathogenic organisms. For this purpose, AgNPs were tested against two model bacteria (Staphylococcus aureus (MTCC3160) and Escherichia coli (MTCC405)) and three species of Candida fungus (Candida albicans (ATCC90028), Candida glabrata (ATCC90030) and Candida tropicalis (ATCC750). AgNPs were found to be highly toxic towards both bacteria. The inhibition action was due to the structural changes in the protein cell wall. PMID- 26017757 TI - Relationship between haemoglobin concentration and packed cell volume in cattle blood samples. AB - A convention that has been adopted in medicine is to estimate haemoglobin (HB) concentration as a third of packed cell volume (PCV) or vice versa. The present research set out to determine whether a proportional relationship exists between PCV and Hb concentration in cattle blood samples, and to assess the validity of the convention of estimating Hb concentration as a third of PCV. A total of 440 cattle in Ghana from four breeds (Ndama, 110; West African Short Horn, 110; Zebu, 110 and Sanga, 110) were bled for haematological analysis, specifically packed cell volume, using the microhaematocrit technique and haemoglobin concentration using the cyanmethaemoglobin method. Means, standard deviations, standard errors of mean and 95% confidence intervals were calculated. Trendline analyses generated linear regression equations from scatterplots. For all the cattle, a significant and consistent relationship (r = 0.74) was found between Hb concentration and PCV (%). This was expressed as Hb concentration (g/dL) = 0.28 PCV + 3.11. When the Hb concentration was estimated by calculating it as a third of PCV, the relationship was expressed in linear regression as Hb concentration (g/dL) = 0.83 calculated Hb + 3.11. The difference in the means of determined (12.2 g/dL) and calculated (10.9 g/dL) Hb concentrations for all cattle was significant (p < 0.001), whereas the difference in the means of determined Hb and corrected calculated Hb was not significant. In conclusion, a simplified relationship of Hb (g/dL) = (0.3 PCV) + 3 may provide a better estimate of Hb concentration from the PCV of cattle. PMID- 26017758 TI - Further Evidence Supporting a Parent-of-Origin Effect in Psoriatic Disease. AB - OBJECTIVE: To further explore the "parent-of-origin" effect in a large cohort of well-phenotyped patients with cutaneous psoriasis without arthritis (PsC) and psoriatic arthritis (PsA). METHODS: Self-reported family history was obtained from PsA patients from Toronto and Newfoundland satisfying the Classification of Psoriatic Arthritis criteria, and PsC patients from Toronto, who were examined by a rheumatologist to exclude PsA. Proportions of probands with paternally and maternally transmitted psoriatic disease were compared by McNemar's and chi square tests. Baseline clinical and genetic characteristics of probands with paternally and maternally transmitted disease were compared using logistic regression. RESULTS: A total of 849 probands reported a first-degree relative affected with psoriatic disease (PsC or PsA), of which 532 (63%) reported an affected parent. A significantly larger proportion of probands reported an affected father compared to an affected mother with psoriatic disease (289 [57%] versus 220 [43%], respectively; P = 0.003). This paternal transmission bias was evident in PsA (P = 0.006) and PsC probands, although it did not reach statistical significance in PsC probands (P = 0.20). Furthermore, the proportion of paternal PsC-proband PsA pairs (161 of 214 paternal transmissions [75%]) was significantly larger than maternal PsC-proband PsA pairs (103 of 161 maternal transmissions [64%]) (P = 0.02). Newfoundland probands with paternally transmitted disease had higher HLA-B*08 carriage (P = 0.04) and lower MICA-129Met carriage (P = 0.03). Males had higher HLA-B*38 carriage (P = 0.05) and a higher prevalence of nail lesions (P = 0.01). CONCLUSION: We have provided further epidemiologic evidence of a paternal transmission bias in psoriatic disease. PMID- 26017759 TI - DOSY NMR and MALDI-TOF evidence of covalent binding the DNA duplex by trimethylammonium salts of topotecan upon near UV irradiation. AB - Using DOSY NMR and MALDI-TOF MS techniques, we present evidence that quaternary trimethylammonium salts of topotecan, [TPT-NMe3 ](+) X(-) (X = CF3SO3, HCOO), bind covalently the natural DNA oligomer upon near UV irradiation in water under physiological conditions. It is shown that formate salt is very reactive at pH 7 and requires short irradiation time. This weak irradiation at 365 nm paves the way for a new application of TPT derivatives in clinical use, which can dramatically increase the therapeutic effects of a medicine. PMID- 26017760 TI - Do we have to anticoagulate patients with cerebral venous thrombosis? AB - Cerebral venous thrombosis (CVT) is a rare form of venous thromboembolism (VTE). Although anticoagulation is recommended for the initial and long term treatment with regards to thrombotic risks for patients with CVT, the role of anticogalution has not been fully elucidated. The aim of our literature based review was collect articles showing the benefit of anticoagulation in CVT and gathering the data of follow-up studies focusing on the recurrence of CVT and other thrombotic events. We have identified 15 follow-up studies studies with 2422 patients. The mean duration of follow-up was 37.9 months. Death occured in 6.5% and 76.4% of the patients had favorable outcome; 85.5% received initial anticoagulation with ultrafractionated or low molecular weight heparin and 82.1% received long-term anticoagulation. Recurent CVT occured in 3.7% and other thrombotic event occured in 5.4%. The mentioned studies have led to incoclusive results with regards to the clinical outcome and the presence or absence of anticoagulation. The role of long term anticoagulation should be clarified in randomized multicentre studies as the recurrence rate seems to be low and the outcome of a second event as good as that of the first one irrespective of underlying risk factors. PMID- 26017761 TI - Retroperitoneal access for abdominal aortic aneurysms: a single center experience. AB - BACKGROUND: Abdominal aortic aneurysms (AAA) may be treated through different surgical techniques. In this endovascular era, surgery remains a mainstay in the management of this disease, especially in patients unsuitable for EVAR. The purpose of this study was to compare retrospectively the postoperative outcomes and survival rates of the transperitoneal and the retroperitoneal approach for the abdominal aortic aneurysm repair in our Unit. METHODS: A retrospective analysis of 840 consecutive patients affected by AAA who were electively admitted in our unit from 1996 to 2011 was performed. Five hundred and sixty patients underwent surgical treatment, 193 through a transperitoneal approach (TP group) and 367 by a retroperitoneal approach (RP group). Short and long-term postoperative outcomes were compared in the two groups. RESULTS: The RP group was characterized by significantly fewer ICU admissions and fewer respiratory and cardiac postoperative complications. Canalization and oral feeding occurred earlier and the mean length of hospital stay for the RP group was shorter compared with that for the TP group. Twelve months survival rate in the RP group was significantly higher comparing with the TP group. Similarly higher survival rates were also observed at 180 months follow-up. CONCLUSIONS: In our study the repair of AAA through a retroperitoneal approach was associated with positive outcomes particularly in high-risk patients. It represents a valid therapeutic option especially in subjects not suitable for endovascular procedures. Surgical training and competence should be maintained to ensure the selection of the appropriate therapy for each patient. PMID- 26017762 TI - Useful predictors for critical limb ischemia in severely ischemic limbs. AB - BACKGROUND: The aim of this paper was to determine useful predictors for critical limb ischemia (CLI) occurrence in severely ischemic limbs. The contralateral limbs of patients with unilateral CLI were evaluated, with special respect to pulse volume recording (PVR). METHODS: Retrospective analysis of 102 consecutive patients (110 limbs) with unilateral CLI. We excluded patients with bilateral CLI, or without PVR data. PVR data were automatically quantitatively expressed as upstroke time (UT) and percentage mean artery pressure (%MAP). The role of PVR parameters was examined in relation to arterial occlusive disease in the lower limbs. Baseline characteristics and non-invasive laboratory data (including Ankle Brachial Index [ABI] and PVR data) were analyzed as predictors for CLI. RESULTS: After exclusion, 73 contralateral limbs of unilateral CLI patients (mean age, 70+/-12 years; 51 male, 70%) were investigated. Fifty patients (68%) had diabetes, and 41 patients (56%) were receiving hemodialysis. UT was longer in patients with crural arterial occlusive disease (214+/-55 versus 183+/-57 ms, P=0.02), although ABI was not different (P=0.31). In the follow-up of 19+/-12 months, 25 limbs progressed to CLI, and the cumulative incidence was 28% and 51% at 1 and 3 years, respectively. Multivariate analysis confirmed that abnormal %MAP (hazard ratio 5.9; 95% confidence interval, 1.8-27.0; P<0.01), coronary artery disease (CAD), and hypoalbuminemia were significant risk factors. CONCLUSIONS: %MAP, CAD, and hypoalbuminemia predicted CLI occurrence in the contralateral limbs of unilateral CLI patients. PMID- 26017763 TI - Comparison of different methods investigating functional and morphological markers of early atherogenesis in obese women with polycystic ovary syndrome. AB - BACKGROUND: The prognostic importance of preclinical markers of atherosclerosis and their interrelationship are inconclusive. In this study interrelationship between different methods investigating endothelial function and intima media thickness (IMT) was investigated in patients with polycystic ovary syndrome (PCOS). METHODS: Endothelial function was assessed by endothelium-dependent flow mediated dilation (FMD), nitrate-mediated dilation (NMD), low-flow-mediated constriction (L-FMC) and peripheral arterial tonometry (PAT). Arterial stiffness was determined by pulse wave velocity (PWV) and the Augmentation Index (AI). The IMT of carotid arteries was measured. RESULTS: Twenty-eight obese women were recruited with the diagnosis of PCOS, mean age 27+/-7.2 years and Body Mass Index 38.8+/-6.3 kg/m2. A relationship between FMD and NMD (r=0.44, P=0.02) was shown. FMD as well as NMD of the brachial artery were not correlated with L-FMC or PAT. The AI and PWV, indicators of arterial stiffness were not interrelated with FMD, and there was no significant interrelationship between IMT and FMD or NMD. The AI was related only to IMT (r=0.45, P=0.30). CONCLUSIONS: The relationship between available methods for evaluation of endothelial function/dysfunction is weak in PCOS. This indicates that different methods investigate different mechanisms and various sections of the circulatory system. PMID- 26017764 TI - Cerumen impaction shown by brain magnetic resonance imaging in patients with cognitive impairment. AB - AIM: Hearing loss is a risk factor for the progression of dementia. Cognitive improvement is occasionally found after removal of cerumen impaction. Because patients with dementia do not usually complain about cerumen impaction, detection methods are important. The present study aimed to investigate whether cerumen impaction is observable using brain magnetic resonance imaging. METHODS: Participants were six patients whose hearing level improved 15 dB or more unilaterally or bilaterally after the removal of cerumen impaction. A radiologist who was blind to the impaction side and whether magnetic resonance imaging scans were taken before or after impaction removal classified cerumen impaction as positive, negative or unclear. RESULTS: Three ears classified as impaction positive and five ears classified as impaction negative corresponded accurately to the presence or absence of cerumen impaction. Among four ears classified as unclear, two did and two did not have cerumen impaction. CONCLUSION: Careful examination of the external ear canal on brain magnetic resonance imaging can be used to detect cerumen impaction. PMID- 26017765 TI - Evaluating the merit of research in clinical cardiology: from citation to declaration. PMID- 26017766 TI - From Embryo to Adult: Hematopoiesis along the Drosophila Life Cycle. AB - Studies on Drosophila hematopoiesis have thus far focused on the embryonic and larval origin of hemocytes, the fly blood cells. In this issue of Developmental Cell, Ghosh et al. (2015) identify adult hematopoietic hubs containing progenitors that can differentiate into different blood cell types. PMID- 26017767 TI - Muscles get dendrites into shape. AB - Sensory neurons interact with muscles in many contexts, but muscle-derived signals that pattern sensory dendrites have not been extensively characterized. In this issue of Developmental Cell, Liang et al. (2015) report a signaling system in which positional cues from muscle are transduced to hypodermal cells to direct sensory dendrite outgrowth. PMID- 26017768 TI - A Notch above Sonic Hedgehog. AB - Cell fate specification requires tightly orchestrated cellular responses to extracellular factors. In this issue of Developmental Cell, Kong et al. (2015) reveal that Notch signaling activity facilitates the interpretation of Sonic hedgehog (Shh) signals by regulating signaling in the cilia, influencing fate specification of neural stem and progenitor cells. PMID- 26017769 TI - Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish. AB - Interruption of the coronary blood supply severely impairs heart function with often fatal consequences for patients. However, the formation and maturation of these coronary vessels is not fully understood. Here we provide a detailed analysis of coronary vessel development in zebrafish. We observe that coronary vessels form in zebrafish by angiogenic sprouting of arterial cells derived from the endocardium at the atrioventricular canal. Endothelial cells express the CXC motif chemokine receptor Cxcr4a and migrate to vascularize the ventricle under the guidance of the myocardium-expressed ligand Cxcl12b. cxcr4a mutant zebrafish fail to form a vascular network, whereas ectopic expression of Cxcl12b ligand induces coronary vessel formation. Importantly, cxcr4a mutant zebrafish fail to undergo heart regeneration following injury. Our results suggest that chemokine signaling has an essential role in coronary vessel formation by directing migration of endocardium-derived endothelial cells. Poorly developed vasculature in cxcr4a mutants likely underlies decreased regenerative potential in adults. PMID- 26017770 TI - The CXCL12/CXCR4 Axis Plays a Critical Role in Coronary Artery Development. AB - The chemokine CXCL12 and its receptor CXCR4 have many functions during embryonic and post-natal life. We used murine models to investigate the role of CXCL12/CXCR4 signaling in cardiac development and found that embryonic Cxcl12 null hearts lacked intra-ventricular coronary arteries (CAs) and exhibited absent or misplaced CA stems. We traced the origin of this phenotype to defects in the early stages of CA stem formation. CA stems derive from the peritruncal plexus, an encircling capillary network that invades the wall of the developing aorta. We showed that CXCL12 is present at high levels in the outflow tract, while peritruncal endothelial cells (ECs) express CXCR4. In the absence of CXCL12, ECs were abnormally localized and impaired in their ability to anastomose with the aortic lumen. We propose that CXCL12 is required for connection of peritruncal plexus ECs to the aortic endothelium and thus plays a vital role in CA formation. PMID- 26017771 TI - CXCL12 Signaling Is Essential for Maturation of the Ventricular Coronary Endothelial Plexus and Establishment of Functional Coronary Circulation. AB - Maturation of a vascular plexus is a critical and yet incompletely understood process in organ development, and known maturation factors act universally in all vascular beds. In this study, we show that CXCL12 is an organ-specific maturation factor of particular relevance in coronary arterial vasculature. In vitro, CXCL12 does not influence nascent vessel formation, but promotes higher-order complexity of preinitiated vessels. In the heart, CXCL12 is expressed principally by the epicardium, and its receptor CXCR4 is expressed by coronary endothelial cells. CXCL12 is not a chemotactic signal for endothelial cell migration, but rather acts in a paracrine manner to influence the maturation of the coronary vascular plexus. Mutants in CXCL12 signaling show an excess of immature capillary chains and a selective failure in arterial maturation, and become leaky with the onset of coronary perfusion. Failed maturation of the coronary system explains the late gestation lethality of these mutants. PMID- 26017772 TI - Improving executive function using transcranial infrared laser stimulation. AB - Transcranial infrared laser stimulation is a new non-invasive form of low-level light therapy that may have a wide range of neuropsychological applications. It entails using low-power and high-energy-density infrared light from lasers to increase metabolic energy. Preclinical work showed that this intervention can increase cortical metabolic energy, thereby improving frontal cortex-based memory function in rats. Barrett and Gonzalez-Lima (2013, Neuroscience, 230, 13) discovered that transcranial laser stimulation can enhance sustained attention and short-term memory in humans. We extend this line of work to executive function. Specifically, we ask whether transcranial laser stimulation enhances performance in the Wisconsin Card Sorting Task that is considered the gold standard of executive function and is compromised in normal ageing and a number of neuropsychological disorders. We used a laser of a specific wavelength (1,064 nm) that photostimulates cytochrome oxidase - the enzyme catalysing oxygen consumption for metabolic energy production. Increased cytochrome oxidase activity is considered the primary mechanism of action of this intervention. Participants who received laser treatment made fewer errors and showed improved set-shifting ability relative to placebo controls. These results suggest that transcranial laser stimulation improves executive function and may have exciting potential for treating or preventing deficits resulting from neuropsychological disorders or normal ageing. PMID- 26017773 TI - Updating algal evolutionary relationships through plastid genome sequencing: did alveolate plastids emerge through endosymbiosis of an ochrophyte? AB - Algae with secondary plastids of a red algal origin, such as ochrophytes (photosynthetic stramenopiles), are diverse and ecologically important, yet their evolutionary history remains controversial. We sequenced plastid genomes of two ochrophytes, Ochromonas sp. CCMP1393 (Chrysophyceae) and Trachydiscus minutus (Eustigmatophyceae). A shared split of the clpC gene as well as phylogenomic analyses of concatenated protein sequences demonstrated that chrysophytes and eustigmatophytes form a clade, the Limnista, exhibiting an unexpectedly elevated rate of plastid gene evolution. Our analyses also indicate that the root of the ochrophyte phylogeny falls between the recently redefined Khakista and Phaeista assemblages. Taking advantage of the expanded sampling of plastid genome sequences, we revisited the phylogenetic position of the plastid of Vitrella brassicaformis, a member of Alveolata with the least derived plastid genome known for the whole group. The results varied depending on the dataset and phylogenetic method employed, but suggested that the Vitrella plastids emerged from a deep ochrophyte lineage rather than being derived vertically from a hypothetical plastid-bearing common ancestor of alveolates and stramenopiles. Thus, we hypothesize that the plastid in Vitrella, and potentially in other alveolates, may have been acquired by an endosymbiosis of an early ochrophyte. PMID- 26017774 TI - Minimally invasive surgical approaches for temporal lobe epilepsy. AB - Surgery can be a highly effective treatment for medically refractory temporal lobe epilepsy (TLE). The emergence of minimally invasive resective and nonresective treatment options has led to interest in epilepsy surgery among patients and providers. Nevertheless, not all procedures are appropriate for all patients, and it is critical to consider seizure outcomes with each of these approaches, as seizure freedom is the greatest predictor of patient quality of life. Standard anterior temporal lobectomy (ATL) remains the gold standard in the treatment of TLE, with seizure freedom resulting in 60-80% of patients. It is currently the only resective epilepsy surgery supported by randomized controlled trials and offers the best protection against lateral temporal seizure onset. Selective amygdalohippocampectomy techniques preserve the lateral cortex and temporal stem to varying degrees and can result in favorable rates of seizure freedom but the risk of recurrent seizures appears slightly greater than with ATL, and it is not clear whether neuropsychological outcomes are improved with selective approaches. Stereotactic radiosurgery presents an opportunity to avoid surgery altogether, with seizure outcomes now under investigation. Stereotactic laser thermo-ablation allows destruction of the mesial temporal structures with low complication rates and minimal recovery time, and outcomes are also under study. Finally, while neuromodulatory devices such as responsive neurostimulation, vagus nerve stimulation, and deep brain stimulation have a role in the treatment of certain patients, these remain palliative procedures for those who are not candidates for resection or ablation, as complete seizure freedom rates are low. Further development and investigation of both established and novel strategies for the surgical treatment of TLE will be critical moving forward, given the significant burden of this disease. PMID- 26017775 TI - Integration of Transcriptomic and Proteomic Approaches Provides a Core Set of Genes for Understanding of Scallop Attachment. AB - Attachment is an essential physiological process in life histories of many marine organisms. Using a combination of transcriptomic and proteomic approach, scallop byssal proteins (Sbps) and their associated regulatory network genes were investigated for the first time. We built the first scallop foot transcriptome library, and 75 foot-specific genes were identified. Through integration of transcriptomic-proteomic approach, seven unique Sbps were identified. Of them, three showed significant amino acid sequence homology to known proteins. In contrast, the rest did not show significant protein matches, indicating they are possibly novel proteins. Our transcriptomic and proteomic analyses also suggest that post-translational modification may be one of the significant features for Sbps as well. Taken together, our study provides the first multidimensional collection of a core set of genes that may be potentially involved in scallop byssal attachment. PMID- 26017776 TI - Impact of Thermal Stress on Kidney-Specific Gene Expression in Farmed Regional and Imported Rainbow Trout. AB - Seasonal water temperatures can be stressful for fish in aquaculture and can therefore negatively influence their welfare. Although the kidney is the crucial organ associated with the primary stress response, knowledge about the stress modulated kidney transcriptome in salmonids is limited. In the present study, we used a comparative microarray approach to characterize the general gene expression profiles of rainbow trout trunk kidney after a 2-week acclimation to mild heat (23 degrees C) and cold stress (8 degrees C). Hypothesizing that local adaptation influences stress performance, we aimed to identify differences in the temperature-induced gene expression in the regional trout strain BORN, in addition to a common imported strain. Moderate temperature challenge provoked typical stress response clusters, including heat-shock proteins or cold-inducible factors, in addition to altered energy metabolism in trout kidney. Mild cold, in particular, enhanced renal protein degradation processes, as well as mRNA and protein synthesis, while it also triggered fatty acid biosynthesis. Mild heat led to cytoskeleton-stabilizing processes and might have facilitated cell damage and infection. Furthermore, both breeding lines used different strategies for energy provision, cellular defense, and cell death/survival pathways. As a main finding, the genes involved in energy provision showed generally higher transcript levels at both temperatures in BORN trout compared to imported trout, indicating adjusted metabolic rates under local environmental conditions. Altogether, this study provides a general overview of stress-induced transcriptional patterns in rainbow trout trunk kidney, in addition to identifying genes and networks that contribute to the robustness of the BORN strain. Our analyses suggest SERPINH1 and CIRBP as general marker genes for heat stress and cold stress in trout, respectively. PMID- 26017777 TI - Transnational corporations as 'keystone actors' in marine ecosystems. AB - Keystone species have a disproportionate influence on the structure and function of ecosystems. Here we analyze whether a keystone-like pattern can be observed in the relationship between transnational corporations and marine ecosystems globally. We show how thirteen corporations control 11-16% of the global marine catch (9-13 million tons) and 19-40% of the largest and most valuable stocks, including species that play important roles in their respective ecosystem. They dominate all segments of seafood production, operate through an extensive global network of subsidiaries and are profoundly involved in fisheries and aquaculture decision-making. Based on our findings, we define these companies as keystone actors of the Anthropocene. The phenomenon of keystone actors represents an increasingly important feature of the human-dominated world. Sustainable leadership by keystone actors could result in cascading effects throughout the entire seafood industry and enable a critical transition towards improved management of marine living resources and ecosystems. PMID- 26017778 TI - Mad1 at the Golgi apparatus: a story beyond kinetochores. PMID- 26017780 TI - Proteome-wide analysis of the amino terminal status of Escherichia coli proteins at the steady-state and upon deformylation inhibition. AB - A proteome wide analysis was performed in Escherichia coli to identify the impact on protein N-termini of actinonin, an antibiotic specifically inhibiting peptide deformylase (PDF). A strategy and tool suite (SILProNaQ) was employed to provide large-scale quantitation of N-terminal modifications. In control conditions, more than 1000 unique N-termini were identified with 56% showing initiator methionine removal. Additional modifications corresponded to partial or complete Nalpha acetylation (10%) and N-formyl retention (5%). Among the proteins undergoing these N-terminal modifications, 140 unique N-termini from translocated membrane proteins were highlighted. The very early time-course impact of actinonin was followed after addition of bacteriostatic concentrations of the drug. Under these conditions, 26% of all proteins did not undergo deformylation any longer after 10 min, a value reaching more than 60% of all characterized proteins after 40 min of treatment. The N-formylation ratio measured on individual proteins increased with the same trend. Upon early PDF inhibition, two major categories of proteins retained their N-formyl group: a large number of inner membrane proteins and many proteins involved in protein synthesis including factors assisting the nascent chains in early cotranslational events. All MS data have been deposited in the ProteomeXchange with identifiers PXD001979, PXD002012 and PXD001983 (http://proteomecentral.proteomexchange.org/dataset/PXD001979, http://proteomecentral.proteomexchange.org/dataset/PXD002012 and http://proteomecentral.proteomexchange.org/dataset/PXD001983). PMID- 26017779 TI - Thicker temporal cortex associates with a developmental trajectory for psychopathic traits in adolescents. AB - Psychopathy is a clinical condition characterized by a failure in normal social interaction and morality. Recent studies have begun to reveal brain structural abnormalities associated with psychopathic tendencies in children. However, little is known about whether variations in brain morphology are linked to the developmental trajectory of psychopathic traits over time. In this study, structural magnetic resonance imaging (sMRI) data from 108 14-year-old adolescents with no history of substance abuse (54 males and 54 females) were examined to detect cortical thickness variations associated with psychopathic traits and individual rates of change in psychopathic traits from ages 9 to 18. We found cortical thickness abnormalities to correlate with psychopathic traits both cross-sectionally and longitudinally. Specifically, at age 14, higher psychopathic scores were correlated with thinner cortex in the middle frontal gyrus, particularly in females, and thicker cortex in the superior temporal gyrus, middle temporal gyrus, and parahippocampal gyrus, particularly in males. Longitudinally, individual rates of change in psychopathic tendency over time were correlated with thicker cortex in the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, parahippocampal gyrus, and posterior cingulate gyrus, particularly in males. Findings suggest that abnormal cortical thickness may reflect a delay in brain maturation, resulting in disturbances in frontal and temporal functioning such as impulsivity, sensation-seeking, and emotional dysregulation in adolescents. Thus, findings provide initial evidence supporting that abnormal cortical thickness may serve as a biomarker for the development of psychopathic propensity in adolescents. PMID- 26017781 TI - Atonal homolog 1 protein stabilized by tumor necrosis factor alpha induces high malignant potential in colon cancer cell line. AB - Patients with inflammatory bowel disease (IBD) have an increased risk of developing colitis-associated colorectal cancer (CAC). CAC cells often develop chemoresistance, resulting in a poorer prognosis than that of sporadic colorectal cancer (CRC). The mechanism by which CAC enhances malignant potential remains unknown. We have previously reported that the proteasomal degradation of the transcription factor Atonal homolog 1 (Atoh1) protein results in the non-mucinous form of CRC. It also remains unknown whether Atoh1 protein is expressed in CAC. Therefore, in the present study, we investigated whether Atoh1 protein stabilizes in CAC. Consequently, the treatment with TNF-alpha stabilized Atoh1 protein through the inactivation of GSK-3beta via Akt, resulting in the mucinous form of CRC cell lines. Atoh1 protein also enriched cancer stem cells with upregulated Lgr5 expression and cells in G0/G1 cell cycle phase, resulting in both the chemoresistance to 5-fluorouracil and oxaliplatin and the promotion of cell migration. Immunofluorescence of the human mucinous CAC specimens showed the accumulation of NF-kappaB p65 at nuclei with the expression of Atoh1 in mucinous cancer. In conclusion, the inflammation associated with carcinogenesis may preserve the differentiation system of intestinal epithelial cell (IEC), resulting in the acquisition of both the mucinous phenotype and high malignant potential associated with the enrichment of cancer stem cell. PMID- 26017783 TI - Simultaneous removal of phosphorus and EfOM using MIEX, coagulation, and low pressure membrane filtration. AB - The feasibility of using magnetic ion exchange (MIEX) treatment, in-line alum coagulation, and low-pressure membrane filtration was investigated for the simultaneous removal of total phosphorus (TP) and effluent organic matter (EfOM) from biologically treated wastewater. The focus was also placed on minimizing fouling of polyvinylidene fluoride and polyethersulfone membranes, which are the most commonly used low-pressure membranes in new and retrofit wastewater treatment plants. MIEX alone was effective for the removal of EfOM, and MIEX plus a small alum dose was very effective in removing both EfOM and TP. MIEX removed phosphorus, but organic acids in EfOM were preferentially removed, and the effects of competing anions on the removal of EfOM were insignificant. All the pretreatment strategies decreased the resistance to filtration. The greatest decrease in fouling was achieved by using MIEX (15 mL L-1) plus a very low dose of alum (~0.5 mg Al L-1). Sweep floc coagulation using alum and without MIEX also significantly decreased fouling but did not effectively remove EfOM and produced high floc volume that could be problematic for inside-out hollow-fibre modules. The addition of these reagents into rapid mix followed by membrane filtration would provide operational simplicity and could be easily retrofitted at existing membrane filtration facilities. PMID- 26017782 TI - Geldanamycin Enhances Retrograde Transport of Shiga Toxin in HEp-2 Cells. AB - The heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) has been shown to alter endosomal sorting, diverting cargo destined for the recycling pathway into the lysosomal pathway. Here we investigated whether GA also affects the sorting of cargo into the retrograde pathway from endosomes to the Golgi apparatus. As a model cargo we used the bacterial toxin Shiga toxin, which exploits the retrograde pathway as an entry route to the cytosol. Indeed, GA treatment of HEp 2 cells strongly increased the Shiga toxin transport to the Golgi apparatus. The enhanced Golgi transport was not due to increased endocytic uptake of the toxin or perturbed recycling, suggesting that GA selectively enhances endosomal sorting into the retrograde pathway. Moreover, GA activated p38 and both inhibitors of p38 or its substrate MK2 partially counteracted the GA-induced increase in Shiga toxin transport. Thus, our data suggest that GA-induced p38 and MK2 activation participate in the increased Shiga toxin transport to the Golgi apparatus. PMID- 26017784 TI - Enhanced Activity of CuCeO Catalysts for CO Oxidation: Influence of Cu2O and the Dispersion of Cu2O, CuO, and CeO2. AB - CuCeO catalysts prepared by a hydrothermal method with subsequent calcination are tested for the catalytic oxidation of CO. This synthesis method leads to a homogeneous dispersion of Cu2 O, CuO, and CeO2 in the catalysts. The composition of the catalysts is determined by the molar ratio of the metals, the hydrothermal process, and calcination temperature and influences the catalytic performance. The catalyst containing Cu2 O exhibits high catalytic activity with almost 100 % CO conversion at 105 degrees C and shows excellent stability with the conversion ratio not decreasing after four months of storage. PMID- 26017785 TI - Mapping the Drivers of Climate Change Vulnerability for Australia's Threatened Species. AB - Effective conservation management for climate adaptation rests on understanding the factors driving species' vulnerability in a spatially explicit manner so as to direct on-ground action. However, there have been only few attempts to map the spatial distribution of the factors driving vulnerability to climate change. Here we conduct a species-level assessment of climate change vulnerability for a sample of Australia's threatened species and map the distribution of species affected by each factor driving climate change vulnerability across the continent. Almost half of the threatened species assessed were considered vulnerable to the impacts of climate change: amphibians being the most vulnerable group, followed by plants, reptiles, mammals and birds. Species with more restricted distributions were more likely to show high climate change vulnerability than widespread species. The main factors driving climate change vulnerability were low genetic variation, dependence on a particular disturbance regime and reliance on a particular moisture regime or habitat. The geographic distribution of the species impacted by each driver varies markedly across the continent, for example species impacted by low genetic variation are prevalent across the human-dominated south-east of the country, while reliance on particular moisture regimes is prevalent across northern Australia. Our results show that actions to address climate adaptation will need to be spatially appropriate, and that in some regions a complex suite of factors driving climate change vulnerability will need to be addressed. Taxonomic and geographic variation in the factors driving climate change vulnerability highlights an urgent need for a spatial prioritisation of climate adaptation actions for threatened species. PMID- 26017786 TI - Medical education at the University of Sao Paulo Medical School. PMID- 26017787 TI - Developing strategies to be added to the protocol for antenatal care: an exercise and birth preparation program. AB - OBJECTIVES: To describe the implementation process of a birth preparation program, the activities in the protocol for physical and birth preparation exercises, and the educational activities that have been evaluated regarding effectiveness and women's satisfaction. The birth preparation program described was developed with the following objectives: to prevent lumbopelvic pain, urinary incontinence and anxiety; to encourage the practice of physical activity during pregnancy and of positions and exercises for non-pharmacological pain relief during labor; and to discuss information that would help women to have autonomy during labor. METHODS: The program comprised the following activities: supervised physical exercise, relaxation exercises, and educational activities (explanations of lumbopelvic pain prevention, pelvic floor function, labor and delivery, and which non-pharmacological pain relief to use during labor) provided regularly after prenatal consultations. These activities were held monthly, starting when the women joined the program at 18-24 weeks of pregnancy and continuing until 30 weeks of pregnancy, fortnightly thereafter from 31 to 36 weeks of pregnancy, and then weekly from the 37th week until delivery. Information and printed materials regarding the physical exercises to be performed at home were provided. Clinicaltrials.gov: NCT01155804. RESULTS: The program was an innovative type of intervention that systematized birth preparation activities that were organized to encompass aspects related both to pregnancy and to labor and that included physical, educational and home-based activities. CONCLUSIONS: The detailed description of the protocol used may serve as a basis for further studies and also for the implementation of birth preparation programs within the healthcare system in different settings. PMID- 26017788 TI - Expenditures in the health care system in Brazil: the participation of states and the Federal District in financing the health care system from 2002 to 2013. AB - OBJECTIVE: To analyze the public expenditures of states on health care and the participation of states and the Federal District in financing the Unified Health System, better known by the acronym SUS. To develop the research, two targets were used: "to rescue expenses per government source (federal, state and municipal) during the period from 2002 to 2013" and "to rescue resource transfers from the federal SUS to the states and also to municipalities". METHODS: This research is bibliographic, documentary and descriptive and used a quantitative approach. Data were extracted from the Information System Public Health Budget, and additional data were collected from the public managers of states, municipalities and the Federal District during the period from 2002 to 2013. Federal data from the Undersecretary of Planning and Budget (originally extracted from the Integrated System of Financial Administration of the Federal Government and available on the Budget Public Health System webpage) were also collected. RESULTS: The data revealed that during the same researched period, the Federal District has maintained the health care system budget, whereas states and municipalities have increased their budgets for the same spending. CONCLUSIONS: By analyzing the results, there is clearly a disparity regarding the investment expended by the entities of the Federation. Although municipalities and states have gradually increased their application of resources to health care, the federal state has maintained the same budget. These results reveal a bit of concern about public health funding. PMID- 26017789 TI - Computed tomography imaging of early coronary artery lesions in stable individuals with multiple cardiovascular risk factors. AB - OBJECTIVES: To investigate the prevalence, extent, severity, and features of coronary artery lesions in stable patients with multiple cardiovascular risk factors. METHODS: Seventy-seven patients with more than 3 cardiovascular risk factors were suspected of having coronary artery disease. Patients with high-risk factors and 39 controls with no risk factors were enrolled in the study. The related risk factors included hypertension, impaired glucose tolerance, dyslipidemia, smoking history, and overweight. The characteristics of coronary lesions were identified and evaluated by 64-slice coronary computed tomography angiography. RESULTS: The incidence of coronary atherosclerosis was higher in the high-risk group than in the no-risk group. The involved branches of the coronary artery, the diffusivity of the lesion, the degree of stenosis, and the nature of the plaques were significantly more severe in the high-risk group compared with the no-risk group (all p < 0.05). CONCLUSION: Among stable individuals with high risk factors, early coronary artery lesions are common and severe. Computed tomography has promising value for the early screening of coronary lesions. PMID- 26017790 TI - Is local resection sufficient for parathyroid carcinoma? AB - OBJECTIVES: Parathyroid carcinoma is a rare malignant disease of the parathyroid glands that appears in less than 1% of patients with primary hyperparathyroidism. In the literature, the generally recommended treatment is en bloc tumor excision with ipsilateral thyroid lobectomy. Based on our 12 years of experience, we discuss the necessity of performing thyroid lobectomy on parathyroid carcinoma patients. RESULTS: Eleven parathyroid carcinoma cases were included in the study. All operations were performed at the Department of Endocrine Surgery at Ankara University Medical School. Seven of the patients were male (63.6%), and the mean patient age was 48.9 +/- 14.0 years. Hyperparathyroidism was the most common indication for surgery (n ? 10, 90.9%). Local disease was detected in 5 patients (45.5%), invasive disease was detected in 5 patients (45.5%) and metastatic disease was detected in 1 patient (9.1%). The mean follow-up period was 99.6 +/- 42.1 months, and the patients' average disease-free survival was 96.0 +/- 49.0 months. During the follow-up period, only 1 patient died of metastatic parathyroid carcinoma. CONCLUSION: Parathyroid carcinoma has a slow-growing natural progression, and regional lymph node metastases are uncommon. Although our study comprised few patients, it nevertheless showed that in selected cases, parathyroid carcinoma could be solely treated with parathyroidectomy. PMID- 26017791 TI - Tanshinone IIA attenuates interleukin-17A-induced systemic sclerosis patient derived dermal vascular smooth muscle cell activation via inhibition of the extracellular signal-regulated kinase signaling pathway. AB - OBJECTIVE: Salvia miltiorrhiza has long been used to treat systemic sclerosis. Tanshinone IIA, one of the phytochemicals derived from the roots of Salvia miltiorrhiza, exhibits multiple biological activities. The present study aimed to investigate whether tanshinone IIA has an effect on the interleukin-17A-induced functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells. METHODS: Systemic sclerosis patient-derived dermal vascular smooth muscle cells were incubated with various dosages of tanshinone IIA in the presence of interleukin-17A or the serum of systemic sclerosis patients. Cell proliferation was assessed using Cell Counting Kit-8. The expression of collagen 1 and 3 in cells was evaluated by immunofluorescence. Cell migration was measured using a transwell assay. The expression of phospho-extracellular signal-regulated kinase was detected by Western blotting. RESULTS: Our data demonstrate that tanshinone IIA exerts an inhibitory effect on interleukin-17A-induced systemic sclerosis patient-derived dermal vascular smooth muscle cell proliferation, collagen synthesis and migration. CONCLUSION: These findings suggest that tanshinone IIA might serve as a promising therapeutic agent for the treatment of systemic sclerosis. PMID- 26017792 TI - The diagnostic value of circulating microRNAs for middle-aged (40-60-year-old) coronary artery disease patients. AB - OBJECTIVE: Circulating microRNAs have been recognized as promising biomarkers for various diseases. The present study aimed to explore the potential roles of circulating miR-149, miR-424 and miR-765 as non-invasive biomarkers for the diagnosis of coronary artery disease in middle-aged (40-60-year-old) patients. METHODS: Sixty-five stable coronary artery disease patients (49-57 years old), 30 unstable coronary artery disease patients (49-58 years old), and 32 non-coronary artery disease patients (49--57 years old) who were matched for age, sex, smoking habits, hypertension and diabetes were enrolled in this study. Total RNA was isolated from plasma with TRIzol reagent. Circulating miRNA levels were measured by quantitative real-time polymerase chain reaction. RESULTS: Circulating miR-149 levels were decreased 4.49-fold in stable coronary artery disease patients (1.18 +/- 0.84) and 5.09-fold in unstable coronary artery disease patients (1.04 +/- 0.65) compared with non-coronary artery disease patients (5.30 +/- 2.57) (p<0.001). Circulating miR-424 levels were reduced 3.6-fold in stable coronary artery disease patients (1.18 +/- 0.60) and 5-fold in unstable coronary artery disease patients (0.86 +/- 0.54) compared with non-coronary artery disease patients (4.35 +/- 2.20) (p<0.001). In contrast, circulating miR-765 levels were elevated 3.98-fold in stable coronary artery disease patients (6.09 +/- 2.27) and 5.33-fold in unstable coronary artery disease patients (8.17 +/- 2.77) compared with non-coronary artery disease patients (1.53 +/- 0.99) (p<0.001). Receiver operating characteristic curve analysis revealed that the respective areas under the curve for circulating miR-149, miR-424 and miR-765 were 0.938, 0.919 and 0.968 in stable CAD patients and 0.951, 0.960 and 0.977 in unstable coronary artery disease patients compared with non-coronary artery disease patients. CONCLUSION: Our results suggest that circulating miR-149, miR-424 and miR-765 might be novel, non-invasive biomarkers for the diagnosis of coronary artery disease in middle-aged patients. However, future prospective trials in large patient cohorts are necessary before reaching a solid conclusion. PMID- 26017793 TI - Serum alkaline phosphatase predicts survival outcomes in patients with skeletal metastatic nasopharyngeal carcinoma. AB - OBJECTIVE: Bone metastasis is frequently associated with nasopharyngeal carcinoma. The diagnosis and follow-up of bone metastatic patients usually relies on skeletal X-ray and bone scintigraphy, which are time-consuming and costly. This study aimed to evaluate whether serum alkaline phosphatase offers clinical value in predicting the clinical response and survival outcome for skeletal metastatic nasopharyngeal carcinoma. METHODS: Serum alkaline phosphatase was measured at baseline and then before each cycle of treatment in 416 nasopharyngeal carcinoma patients with bone metastasis. The correlations between the pre-treatment and post-treatment alkaline phosphatase levels and the treatment efficacy were analyzed using the chi-square test. Survival was analyzed using the Kaplan-Meier method and then compared using the log-rank test. RESULTS: Patients with elevated pre-treatment alkaline phosphatase (>110 IU/L) had significantly worse progression-free survival (P<0.001) and overall survival (P<0.001) than those with a normal level of this marker (<=110 IU/L). Patients with elevated post-treatment alkaline phosphatase had worse progression-free survival (P<0.001) and overall survival (P<0.001) compared with those with a normal level. Patients with normal pre-treatment and post-treatment alkaline phosphatase showed the most favorable prognosis. The Cox multivariate analysis revealed that only the pre-treatment and post-treatment alkaline phosphatase levels were independent prognostic factors for progression-free survival (HR ? 1.656, P<0.001; HR ? 2.226, P<0.001) and for overall survival (HR ? 1.794, P<0.001; HR ? 2.657, P<0.001). CONCLUSIONS: Serum alkaline phosphatase appears to be a significant independent prognostic index in patients with skeletal metastatic nasopharyngeal carcinoma, which could reflect the short-term treatment response of palliative chemotherapy and the long-term survival outcomes. PMID- 26017794 TI - Post-treatment neutrophil-lymphocyte ratio independently predicts amputation in critical limb ischemia without operation. AB - OBJECTIVES: Limited information is available concerning the post-treatment neutrophil-lymphocyte ratio in critical limb ischemia patients who receive conservative therapy. Accordingly, this study was designed to evaluate the predictive value of the post-treatment neutrophil-lymphocyte ratio in critical limb ischemia patients without surgery. METHOD: From January 2009 to January 2011, critical limb ischemia patients were admitted to a vascular center. The demographic data, patient histories, comorbidities and risk factors were documented, and the differential cell count was determined at admission and seven days later after conservative therapy. The cutoff value of the post-treatment neutrophil-lymphocyte ratio was determined by an ROC curve. Patients were divided into groups A and B according to the cutoff value. Amputation-free survival was compared between groups. Univariate and multivariate analyses were used to identify independent risk factors. RESULT: A total of 172 patients were identified with a mean age 71.98+/-10.09 years; among them, 122 were male. A value of 3.8 was identified as the cutoff value of the post-treatment neutrophil lymphocyte ratio. Groups A (post-treatment neutrophil-lymphocyte ratio >=3.8) and B (post-treatment neutrophil-lymphocyte ratio <3.8) showed a significant difference in amputation-free survival (P<0.001). The 1-year, 2-year and 3-year amputation-free survival rates were 79.6%, 55.6% and 46.3%, respectively, in group A; however, in group B, these values were 89.7%, 79.3% and 75.9%, respectively. The post-treatment neutrophil-lymphocyte ratio was identified as an independent predictive factor for amputation in critical limb ischemia patients (P<0.001). CONCLUSION: The post-treatment neutrophil-lymphocyte ratio is an independent predictive factor for amputation in critical limb ischemia patients. Patients with a post-treatment neutrophil-lymphocyte ratio >=3.8 are likely to suffer from amputation; amputation-free survival usually occurs in patients with a post-treatment neutrophil-lymphocyte ratio <3.8. PMID- 26017795 TI - Validity and reliability of the Brazilian Portuguese version of the BACS (Brief Assessment of Cognition in Schizophrenia). AB - OBJECTIVE: To assess the validity and reliability of the Brazilian Portuguese version of the Brief Assessment of Cognition in Schizophrenia by examining its temporal stability, internal consistency, and discriminant and convergent validity. METHODS: The Brief Assessment of Cognition in Schizophrenia was administered to 116 stable patients with schizophrenia and 58 matched control subjects. To assess concurrent validity, a subset of patients underwent a traditional neuropsychological assessment. RESULTS: The patients with schizophrenia performed significantly worse than the controls (p<0.001) on all subtests of the Brief Assessment of Cognition in Schizophrenia and on the total score, which attests to the discriminant validity of the test. The global score of the Brief Assessment of Cognition in Schizophrenia was significantly correlated with all of the subtests and with the global score for the standard battery. The Brief Assessment of Cognition in Schizophrenia also had good test retest reliability (rho>0.8). The internal consistency of the Brief Assessment of Cognition in Schizophrenia was high (Cronbach's alpha ? 0.874). CONCLUSION: The Brazilian Portuguese version of the Brief Assessment of Cognition in Schizophrenia exhibits good reliability and discriminant and concurrent validity and is a promising tool for easily assessing cognitive impairment in schizophrenia and for comparing the performance of Brazilian patients with that of patients from other countries. PMID- 26017796 TI - Teleaudiometry as a screening method in school children. AB - OBJECTIVE: To compare the efficacy and feasibility of teleaudiometry with that of sweep audiometry in elementary school children, using pure-tone audiometry as the gold standard. METHODS: A total of 243 students with a mean age of 8.3 years participated in the study. Of these, 118 were boys, and 125 were girls. The following procedures were performed: teleaudiometry screening with software that evaluates hearing at frequencies of 1,000, 2000 and 4000 Hz at 25 dBHL; sweep audiometry screening in an acoustic booth (20 dBHL at the same frequencies); pure tone audiometry thresholds in an acoustic booth (frequencies of 500, 1000, 2000 and 4000 Hz); and acoustic immittance measurements. RESULTS: The diagnostic capacities of the teleaudiometry/sweep audiometry screening methods were as follows: sensitivity ? 58%/65%; specificity ? 86%/99%; positive predictive value ? 51%/91%; negative predictive value ? 89%/92%; and accuracy ? 81%/92%. Teleaudiometry and sweep audiometry showed moderate agreement. Furthermore, the use of these methods in series with immittance testing improved the specificity, whereas parallel testing improved the sensitivity. CONCLUSION: Teleaudiometry was found to be reliable and feasible for screening hearing in school children. Moreover, teleaudiometry is the preferred method for remote areas where specialized personnel and specific equipment are not available, and its use may reduce the costs of hearing screening programs. PMID- 26017797 TI - Annual national direct and indirect cost estimates of the prevention and treatment of cervical cancer in Brazil. AB - OBJECTIVE: To estimate the annual direct and indirect costs of the prevention and treatment of cervical cancer in Brazil. METHODS: This cost description study used a "gross-costing" methodology and adopted the health system and societal perspectives. The estimates were grouped into sets of procedures performed in phases of cervical cancer care: the screening, diagnosis and treatment of precancerous lesions and the treatment of cervical cancer. The costs were estimated for the public and private health systems, using data from national health information systems, population surveys, and literature reviews. The cost estimates are presented in 2006 USD. RESULTS: From the societal perspective, the estimated total costs of the prevention and treatment of cervical cancer amounted to USD $1,321,683,034, which was categorized as follows: procedures (USD $213,199,490), visits (USD $325,509,842), transportation (USD $106,521,537) and productivity losses (USD $676,452,166). Indirect costs represented 51% of the total costs, followed by direct medical costs (visits and procedures) at 41% and direct non-medical costs (transportation) at 8%. The public system represented 46% of the total costs, and the private system represented 54%. CONCLUSION: Our national cost estimates of cervical cancer prevention and treatment, indicating the economic importance of cervical cancer screening and care, will be useful in monitoring the effect of the HPV vaccine introduction and are of interest in research and health care management. PMID- 26017798 TI - Heart rate turbulence analysis in female patients with fibromyalgia. AB - OBJECTIVE: Fibromyalgia is characterized by diffuse musculoskeletal pain and discomfort. There are several reports regarding autonomic nervous system dysfunction in patients with fibromyalgia. Heart rate turbulence is expressed as ventriculophasic sinus arrhythmia and has been considered to reflect cardiac autonomic activity. Heart rate turbulence has been shown to be an independent and powerful predictor of sudden cardiac death in various cardiac abnormalities. The aim of this study is to determine whether heart rate turbulence is changed in female patients with fibromyalgia compared with healthy controls. METHODS: Thirty seven female patients (mean age, 40+/-11 years) with fibromyalgia, and 35 age- and sex-matched healthy female control subjects (mean age, 42+/-9 years) were included. Twenty-four hours of ambulatory electrocardiography recordings were collected for all subjects, and turbulence onset and turbulence slope values were automatically calculated. RESULTS: The baseline clinical characteristics of the two groups were similar. There were no significant differences in turbulence onset and turbulence slope measures between patients and control subjects (turbulence onset: -1.648+/-1.568% vs. -1.582+/-1.436%, p ? 0.853; turbulence slope: 12.933+/-5.693 ms/RR vs. 13.639+/-2.505 ms/RR, p ? 0.508). Although body mass index was negatively correlated with turbulence slope (r ? -0.258, p ? 0.046), no significant correlation was found between body mass index and turbulence onset (r ? 0.228, p ? 0.054). CONCLUSION: To the best of our knowledge, this is the first study to evaluate heart rate turbulence in patients with fibromyalgia. It appears that heart rate turbulence parameters reflecting cardiac autonomic activity are not changed in female patients with fibromyalgia. PMID- 26017800 TI - Stereoselective gold(I) domino catalysis of allylic isomerization and olefin cyclopropanation: mechanistic studies. AB - Gold(I) catalysis of olefin activation is still a rare feature in the repertoire of that metal. Mechanistic studies on the gold(I)-catalyzed cyclopropanation of allyl-substituted sulfonium ylides, including kinetic analysis as well as detailed computational studies, reveal that the reaction proceeds through activation of the alkene moiety. Furthermore, a novel competitive allylic isomerization pathway that interconverts "linear" and "branched" allylic isomers is uncovered. The subtle interplay of cyclopropanation and olefin isomerization results in an intriguing domino process where two independent catalytic transformations combine with near-perfect regio- and stereoselectivities. PMID- 26017799 TI - Cardiac troponin and C-reactive protein for predicting all-cause and cardiovascular mortality in patients with chronic kidney disease: a meta analysis. AB - Elevated serum levels of cardiac troponin and C-reactive protein are associated with all-cause and cardiovascular mortality in patients with end-stage renal disease. However, the relationship between these two biomarker levels and mortality in patients with chronic kidney disease remains unclear. We conducted a meta-analysis to quantify the association of cardiac troponin and C-reactive protein levels with all-cause and cardiovascular mortality in patients with chronic kidney disease. Relevant studies were identified by searching the MEDLINE database through November 2013. Studies were included in the meta-analysis if they reported the long-term all-cause or cardiovascular mortality of chronic kidney disease patients with abnormally elevated serum levels of cardiac troponin or C-reactive protein. Summary estimates of association were obtained using a random-effects model. Thirty-two studies met our inclusion criteria. From the pooled analysis, cardiac troponin and C-reactive protein were significantly associated with all-cause (HR 2.93, 95% CI 1.97-4.33 and HR 1.21, 95% CI 1.14 1.29, respectively) and cardiovascular (HR 3.27, 95% CI 1.67-6.41 and HR 1.19, 95% CI 1.10-1.28, respectively) mortality. In the subgroup analysis of cardiac troponin and C-reactive protein, significant heterogeneities were found among the subgroups of population for renal replacement therapy and for the proportion of smokers and the C-reactive protein analysis method. Elevated serum levels of cardiac troponin and C-reactive protein are significant associated with higher risks of all-cause and cardiovascular mortality in patients with chronic kidney disease. Further studies are warranted to explore the risk stratification in chronic kidney disease patients. PMID- 26017801 TI - Students' perspectives on promoting healthful food choices from campus vending machines: a qualitative interview study. AB - BACKGROUND: Increasing the healthfulness of campus food environments is an important step in promoting healthful food choices among college students. This study explored university students' suggestions on promoting healthful food choices from campus vending machines. It also examined factors influencing students' food choices from vending machines. METHODS: Peer-led semi-structured individual interviews were conducted with 43 undergraduate students (33 females and 10 males) recruited from students enrolled in an introductory nutrition course in a large national university in the United Arab Emirates. Interviews were audiotaped, transcribed, and coded to generate themes using N-Vivo software. RESULTS: Accessibility, peer influence, and busy schedules were the main factors influencing students' food choices from campus vending machines. Participants expressed the need to improve the nutritional quality of the food items sold in the campus vending machines. Recommendations for students' nutrition educational activities included placing nutrition tips on or beside the vending machines and using active learning methods, such as competitions on nutrition knowledge. CONCLUSIONS: The results of this study have useful applications in improving the campus food environment and nutrition education opportunities at the university to assist students in making healthful food choices. PMID- 26017802 TI - Twice as smart behavior of tert-butylthiacalix[4]arene derivative in glassy and crystalline form. AB - A studied tert-butylthiacalix[4]arene derivative with four N-(2 acetoxyethyl)carbamoylmethoxy substituents on its lower rim in partial-cone configuration (calixarene 1) can remember its previous treatment in three essentially different ways by the formation either of a molecular glass or two metastable polymorphs after heating or the removal of an included guest molecule. Guest-induced memory is very selective with a polymorph created only after the release of a few included guests among a large series of those studied and is detected via an exothermic transition. Along with ordinary properties, like glass transition, curing and cold crystallization, the molecular glass from 1 is selective due to its ability to crystallize in solvent vapors and vapor mixtures over a well-defined concentration range. Being cooperative, this property may be used for the visual detection of ethanol content in water solution when it reaches a threshold value. PMID- 26017804 TI - Single-phased white-light-emitting Ca4(PO4)2O:Ce3+,Eu2+ phosphors based on energy transfer. AB - A novel single-composition Ca4(PO4)2O:Ce(3+),Eu(2+) phosphor emitting white light was synthesized by conventional solid-state reaction for light-emitting diode applications. X-ray diffraction, photoluminescence spectra, and luminescence decay spectra were used to characterize the samples. Energy transfer from Ce(3+) to Eu(2+) ions was observed in the co-doped samples, and the transfer mechanism in the Ca4(PO4)2O:Ce(3+),Eu(2+) phosphors was dipole-dipole interaction. The emission hue of Ca4(PO4)2O:Ce(3+),Eu(2+) was found to vary from blue (0.165, 0.188) to white (0.332, 0.300) and eventually to orange (0.519, 0.366) by precisely controlling the ratio of Ce(3+) to Eu(2+). The combination of a 380 nm near-ultraviolet chip with a Ca4(PO4)2O:0.02Ce(3+),0.012Eu(2+) phosphor produced a diode emitting white light with ultra-wideband emission and a correlated color temperature of 4124 K. Overall, results indicated that the prepared samples may be potentially applied in white-light-emitting diodes. PMID- 26017805 TI - Transthoracic and Three-Dimensional Transesophageal Echocardiographic Presentation of Anomalous Circumflex Origin from Right Coronary Artery in Patient with Severe Mitral Stenosis. PMID- 26017803 TI - Impacts of autophagy-inducing ingredient of areca nut on tumor cells. AB - Areca nut (AN) is a popular carcinogen used by about 0.6-1.2 billion people worldwide. Although AN contains apoptosis-inducing ingredients, we previously demonstrated that both AN extract (ANE) and its 30-100 kDa fraction (ANE 30-100K) predominantly induce autophagic cell death in both normal and malignant cells. In this study, we further explored the action mechanism of ANE 30-100K-induced autophagy (AIA) in Jurkat T lymphocytes and carcinoma cell lines including OECM-1 (mouth), CE81T/VGH (esophagus), SCC25 (tongue), and SCC-15 (tongue). The results showed that chemical- and small hairpin RNA (shRNA)-mediated inhibition of AMP activated protein kinase (AMPK) resulted in the attenuation of AIA in Jurkat T but not in OECM-1 cells. Knockdown of Atg5 and Beclin 1 expressions ameliorated AIA in OECM-1/CE81T/VGH/Jurkat T and OECM-1/SCC25/SCC-15, respectively. Furthermore, ANE 30-100K could activate caspase-3 after inhibition of Beclin 1 expression in OECM-1/SCC25/SCC15 cells. Meanwhile, AMPK was demonstrated to be the upstream activator of the extracellular-regulated kinase (ERK) in Jurkat T cells, and inhibition of MEK attenuated AIA in Jurkat T/OECM-1/CE81T/VGH cells. Finally, we also found that multiple myeloma RPMI8226, lymphoma U937, and SCC15 cells survived from long-term non-cytotoxic ANE 30-100K treatment exhibited stronger resistance against serum deprivation through upregulated autophagy. Collectively, our studies indicate that Beclin-1 and Atg5 but not AMPK are commonly required for AIA, and MEK/ERK pathway is involved in AIA. Meanwhile, it is also suggested that long-term AN usage might increase the resistance of survived tumor cells against serum-limited conditions. PMID- 26017806 TI - Recent developments in the chemistry and biological applications of benzoxaboroles. PMID- 26017807 TI - Systematic evaluation of dissolved lead sorption losses to particulate syringe filter materials. AB - Distinguishing between soluble and particulate lead in drinking water is useful in understanding the mechanism of lead release and identifying remedial action. Typically, particulate lead is defined as the amount of lead removed by a 0.45 MUm filter. Unfortunately, there is little guidance regarding selection of filter membrane material and little consideration to the possibility of the sorption of dissolved lead to the filter. The objective of this work was to examine the tendency of 0.45-MUm syringe filter materials to adsorb lead. Tests were performed with water containing 40 and 24 MUg/L soluble lead at pH 7 buffered with 50 mg C/L dissolved inorganic concentration (DIC). The amounts of lead sorbed greatly varied by filter, and only two filter types, polypropylene and mixed cellulose esters, performed well and are recommended. Great care must be taken in choosing a filter when filtering soluble lead and interpreting filter results. PMID- 26017808 TI - Assessment of water quality based on Landsat 8 operational land imager associated with human activities in Korea. AB - Water pollution such as green algae blooms and eutrophication in freshwater fatally influences both water quality and human society. Water quality issues in the 4 major rivers in Korea, including the Nakdong, have recently become a major concern. For this reason, it is essential to monitor water quality parameters (WQPs) that have a widespread characteristic to ensure maintenance of an effective water management system. The possibility of utilizing remote sensing technology for monitoring water quality on a regional scale has been recently investigated. The main objective of this study is to evaluate potential applications of the Landsat 8 Operational Land Imager (OLI) for estimating water quality in the Nakdong River, Korea. Correlations between Landsat 8 bands and in situ measurements are determined, and water quality models are established for estimating suspended solids (SS), total nitrogen (TN), chlorophyll-a (Chl-a), and total phosphorus (TP). The results demonstrate that WQPs correlated well with band reflectance values from Landsat 8. Band 5 was reasonably correlated with all WQPs, particularly with SS (R = -0.74) and Chl-a (R = -0.71). This study constructed multiple regression equations for WQPs based on correlation analysis through band combination and band ratio. The spatial distribution of WQPs in the Nakdong River on October 27, 2013 and May 16, 2014 indicate that the river was nearly eutrophic from human activities. Based on the results, the Landsat 8 OLI may be an appropriate data for estimating and monitoring water quality parameters on a regional scale. However, further validation is required to support the findings of this study. PMID- 26017809 TI - Evaluation of three satellite-based latent heat flux algorithms over forest ecosystems using eddy covariance data. AB - We have evaluated the performance of three satellite-based latent heat flux (LE) algorithms over forest ecosystems using observed data from 40 flux towers distributed across the world on all continents. These are the revised remote sensing-based Penman-Monteith LE (RRS-PM) algorithm, the modified satellite-based Priestley-Taylor LE (MS-PT) algorithm, and the semi-empirical Penman LE (UMD SEMI) algorithm. Sensitivity analysis illustrates that both energy and vegetation terms has the highest sensitivity compared with other input variables. The validation results show that three algorithms demonstrate substantial differences in algorithm performance for estimating daily LE variations among five forest ecosystem biomes. Based on the average Nash-Sutcliffe efficiency and root-mean squared error (RMSE), the MS-PT algorithm has high performance over both deciduous broadleaf forest (DBF) (0.81, 25.4 W/m(2)) and mixed forest (MF) (0.62, 25.3 W/m(2)) sites, the RRS-PM algorithm has high performance over evergreen broadleaf forest (EBF) (0.4, 28.1 W/m(2)) sites, and the UMD-SEMI algorithm has high performance over both deciduous needleleaf forest (DNF) (0.78, 17.1 W/m(2)) and evergreen needleleaf forest (ENF) (0.51, 28.1 W/m(2)) sites. Perhaps the lower uncertainties in the required forcing data for the MS-PT algorithm, the complicated algorithm structure for the RRS-PM algorithm, and the calibrated coefficients of the UMD-SEMI algorithm based on ground-measured data may explain these differences. PMID- 26017810 TI - Kinetic and isotherms studies of phosphorus adsorption onto natural riparian wetland sediments: linear and non-linear methods. AB - Riparian wetlands provide critical functions for the improvement of surface water quality and storage of nutrients. Correspondingly, investigation of the adsorption characteristic and capacity of nutrients onto its sediments is benefit for utilizing and protecting the ecosystem services provided by riparian areas. The Langmuir and Freundlich isotherms and pseudo-second-order kinetic model were applied by using both linear least-squares and trial-and-error non-linear regression methods based on the batch experiments data. The results indicated that the transformations of non-linear isotherms to linear forms would affect the determination process significantly, but the non-linear regression method could prevent such errors. Non-linear Langmuir and Freundlich isotherms both fitted well with the phosphorus adsorption process (r (2) > 0.94). Moreover, the influences of temperature and ionic strength on the adsorption of phosphorus onto natural riparian wetland sediments were also studied. Higher temperatures were suitable for phosphorus uptake from aqueous solution using the present riparian wetland sediments. The adsorption capacity increased with the enhancement of ionic strength in agreement with the formation of inner-sphere complexes. The quick adsorption of phosphorus by the sediments mainly occurred within 10 min. The adsorption kinetic was well-fitted by pseudo-second-order kinetic model (r (2) > 0.99). The scanning electron microscopy (SEM) and Fourier transformation infrared (FT-IR) spectra analyses before and after phosphorus adsorption revealed the main adsorption mechanisms in the present system. PMID- 26017811 TI - Primary Retroperitoneal Hydatid Cyst. PMID- 26017812 TI - Oxidized-low density lipoprotein accumulates cholesterol esters via the PKCalpha adipophilin-ACAT1 pathway in RAW264.7 cells. AB - Oxidized low-density lipoprotein (ox-LDL) can increase the expression of adipophilin and the accumulation of intracellular lipid droplets. However, the detailed mechanisms remain to be fully elucidated. The present study aimed to investigate the mechanism underlying the effect of ox-LDL on the expression of adipophilin and the accumulation of intracellular cholesterol esters. The results revealed that ox-LDL increased the activation of protein kinase C alpha (PKCalpha), expression of adipophilin and acyl-coenzymeA: cholesterol acyltransferse 1 (ACAT1) and increased accumulation of intracellular cholesterol esters. In addition, PKCalpha siRNA abrogated ox-LDL-induced adipophilin, expression of ATAC1 and accumulation of cholesterol esters. Furthermore, ox-LDL increased the accumulation of intracellular cholesterol esters and expression of ACAT1, and this effect were reversed by transfection with adipophilin siRNA. Taken together, these results demonstrated that ox-LDL induces the accumulation of cholesterol esters, which is mediated by the PKCalpha-adipophilin-ACAT1 pathway. PMID- 26017813 TI - Evo-devo of Child Growth: The Role of Weaning in the Transition from Infancy to Childhood. AB - Homo sapiens are unique in having a life history phase of childhood, which follows infancy, as defined by breastfeeding. This review uses evolutionary life history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies for transition from infancy to childhood. We have previously shown that a delayed infancy-childhood transition has a lifelong impact on stature. Feeding practices during infancy are fundamental elements of nutrition as they program for future growth and body composition. A relationship between the duration of breastfeeding and the nature of weaning has been suggested as a possible cause for later obesity and growth patterns. This review highlights the role that breast milk feeding and variations in the weaning age have on transition to childhood, growth, and body composition. PMID- 26017815 TI - Computational Fluid Dynamics Simulation of Hydrodynamics and Stresses in the PhEur/USP Disintegration Tester Under Fed and Fasted Fluid Characteristics. AB - Disintegration of oral solid dosage forms is a prerequisite for drug dissolution and absorption and is to a large extent dependent on the pressures and hydrodynamic conditions in the solution that the dosage form is exposed to. In this work, the hydrodynamics in the PhEur/USP disintegration tester were investigated using computational fluid dynamics (CFD). Particle image velocimetry was used to validate the CFD predictions. The CFD simulations were performed with different Newtonian and non-Newtonian fluids, representing fasted and fed states. The results indicate that the current design and operating conditions of the disintegration test device, given by the pharmacopoeias, are not reproducing the in vivo situation. This holds true for the hydrodynamics in the disintegration tester that generates Reynolds numbers dissimilar to the reported in vivo situation. Also, when using homogenized US FDA meal, representing the fed state, too high viscosities and relative pressures are generated. The forces acting on the dosage form are too small for all fluids compared to the in vivo situation. The lack of peristaltic contractions, which generate hydrodynamics and shear stress in vivo, might be the major drawback of the compendial device resulting in the observed differences between predicted and in vivo measured hydrodynamics. PMID- 26017814 TI - Optimized Near-IR Fluorescent Agents for in Vivo Imaging of Btk Expression. AB - Bruton's tyrosine kinase (Btk) is intricately involved in anti-apoptotic signaling pathways in cancer and in regulating innate immune response. A number of Btk inhibitors are in development for use in treating B-cell malignancies and certain immunologic diseases. To develop robust companion imaging diagnostics for in vivo use, we set out to explore the effects of red wavelength fluorochrome modifications of two highly potent irreversible Btk inhibitors, Ibrutinib and AVL 292. Surprisingly, we found that subtle chemical differences in the fluorochrome had considerable effects on target localization. Based on iterative designs, we developed a single optimized version with superb in vivo imaging characteristics enabling single cell Btk imaging in vivo. This agent (Ibrutinib-SiR-COOH) is expected to be a valuable chemical tool in deciphering Btk biology in cancer and host cells in vivo. PMID- 26017816 TI - Effect of Automated Online Counseling on Clinical Outcomes and Quality of Life Among Adolescents With Acne Vulgaris: A Randomized Clinical Trial. AB - IMPORTANCE: Effective patient education is necessary for treating patients with acne vulgaris. Automated online counseling simulates face-to-face encounters and may be a useful tool to deliver education. OBJECTIVE: To compare the effectiveness of a standard educational website with that of an automated counseling website in improving clinical outcomes and quality of life among adolescents with acne. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted between March 27, 2014, and June 27, 2014, including a 12-week follow-up in a local inner-city high school. Ninety-eight students aged at least 13 years with mild to moderate acne were eligible for participation. A per protocol analysis of the evaluable population was conducted on clinical outcome data. INTERVENTIONS: Participants viewed either a standard educational website or an automated-counseling website. MAIN OUTCOMES AND MEASURES: The primary outcome was the total acne lesion count. Secondary measures included the Children's Dermatology Life Quality Index (CDLQI) scores and general skin care behavior. RESULTS: Forty-nine participants were randomized to each group. At baseline, the mean (SD) total acne lesion count was not significantly different between the standard-website group and the automated-counseling-website group (21.33 [10.81] vs 25.33 [12.45]; P = .10). Improvement in the mean (SD) acne lesion count was not significantly different between the standard-website group and the automated counseling-website group (0.20 [9.26] vs 3.90 [12.19]; P = .10). The mean (SD) improvement in CDLQI score for the standard-website group was not significantly different from that of the automated-counseling-website group (0.17 [2.64] vs 0.39 [2.94]; P = .71). After 12 weeks, a greater proportion of participants in the automated-counseling-website group maintained or adopted a recommended anti acne skin care routine compared with the standard-website group (43% vs 22%; P = .03). CONCLUSIONS AND RELEVANCE: Internet-based acne education using automated counseling was not superior to standard-website education in improving acne severity and quality of life. However, a greater proportion of participants who viewed the automated-counseling website reported having maintained or adopted a recommended anti-acne skin care regimen. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02031718. PMID- 26017817 TI - Folding stability modulation of the villin headpiece helical subdomain by 4 fluorophenylalanine and 4-methylphenylalanine. AB - HP36, the helical subdomain of villin headpiece, contains a hydrophobic core composed of three phenylalanine residues (Phe47, Phe51, and Phe58). Hydrophobic effects and electrostatic interactions were shown to be the critical factors in stabilizing this core and the global structure. To assess the interactions among Phe47, Phe51, and Phe58 residues and investigate how they affect the folding stability, we implanted 4-fluorophenylalanine (Z) and 4-methylphenylalanine (X) into the hydrophobic core of HP36. We chemically synthesized HP36 and its seven variants including four single mutants whose Phe51 or Phe58 was replaced with Z or X, and three double mutants whose Phe51 and Phe58 were both substituted. Circular dichroism and nuclear magnetic resonance measurements show that the variants exhibit a native HP36 like fold, of which F51Z and three double mutants are more stable than the wild type. Molecular modeling provided detailed interaction energy within the phenylalanine residues, revealing that electrostatic interactions dominate the stability modulation upon the introduction of 4-fluorophenylalanine and 4-methylphenylalanine. Our results show that these two non-natural amino acids can successfully tune the interactions in a relatively compact hydrophobic core and the folding stability without inducing dramatic steric effects. Such an approach may be applied to other folded motifs or proteins. PMID- 26017818 TI - Independent effect of polymeric nanoparticle zeta potential/surface charge, on their cytotoxicity and affinity to cells. AB - OBJECTIVES: Up to now, little research has been focussed on discovering how zeta potential independently affects polymeric nanoparticle (NP) cytotoxicity. METHODS: Polymeric nanoparticles of gradient zeta potential ranging from -30 mv to +40 mv were fabricated using the same poly-3-hydroxybutyrate-co-3 hydroxyhexanoate (PHBHHx) biopolymer. Interaction forces between nanoparticles and cells were measured by atomic force microscopy (AFM). Cytotoxicity of the nanoparticles to cells was investigated by using MTT (3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. RESULTS: Four kinds of nanoparticle with similar sizes and gradient zeta potentials, were fabricated. Those with positive surface charges were found to be more toxic than those with negative surface charges. Positively charged nanoparticles or nanoparticles with higher 'like' charges, offered higher interaction force with cells. CONCLUSION: This work proposes a novel approach for investigating interaction between NPs and cells, and discloses the importance of controlling zeta potential in developing NPs-based formulations in the future. PMID- 26017819 TI - Soluble carbohydrates and relative growth rates in chloro-, cyano- and cephalolichens: effects of temperature and nocturnal hydration. AB - This growth chamber experiment evaluates how temperature and humidity regimes shape soluble carbohydrate pools and growth rates in lichens with different photobionts. We assessed soluble carbohydrates, relative growth rates (RGRs) and relative thallus area growth rates (RTA GRs) in Parmelia sulcata (chlorolichen), Peltigera canina (cyanolichen) and Peltigera aphthosa (cephalolichen) cultivated for 14 d (150 MUmol m(-2) s(-1) ; 12-h photoperiod) at four day : night temperatures (28 : 23 degrees C, 20 : 15 degrees C, 13 : 8 degrees C, 6 : 1 degrees C) and two hydration regimes (hydration during the day, dry at night; hydration day : night). The major carbohydrates were mannitol (cephalolichen), glucose (cyanolichen) and arabitol (chlorolichen). Mannitol occurred in all species. During cultivation, total carbohydrate pools decreased in cephalo /cyanolichens, but increased in the chlorolichen. Carbohydrates varied less than growth with temperature and humidity. All lichens grew rapidly, particularly at 13 : 8 degrees C. RGRs and RTA GRs were significantly higher in lichens hydrated for 24 h than for 12 h. Strong photoinhibition occurred in cephalo- and cyanolichens kept in cool dry nights, resulting in positive relationships between RGR and dark-adapted photosystem II (PSII) efficiency (Fv /Fm ). RGR increased significantly with the photobiont-specific carbohydrate pools within all species. Average RGR peaked in the chlorolichen lowest in total and photobiont carbohydrates. Nocturnal hydration improved recovery from photoinhibition and/or enhanced conversion rates of photosynthates into growth. PMID- 26017820 TI - The good merger. PMID- 26017821 TI - Unanimity on death with dignity--legalizing physician-assisted dying in Canada. PMID- 26017822 TI - Screening for lung cancer with low-dose CT--translating science into Medicare coverage policy. PMID- 26017823 TI - Latent Mycobacterium tuberculosis infection. PMID- 26017824 TI - Images in clinical medicine. Disseminated Lyme disease. PMID- 26017825 TI - Case records of the Massachusetts General Hospital. Case 17-2015. A 44-year-old woman with intractable pain due to metastatic lung cancer. PMID- 26017826 TI - Medicaid at 50--from welfare program to nation's largest health insurer. PMID- 26017827 TI - Braking bad hypertrophy. PMID- 26017828 TI - Peanut consumption in infants at risk for peanut allergy. PMID- 26017829 TI - Peanut consumption in infants at risk for peanut allergy. PMID- 26017830 TI - Peanut consumption in infants at risk for peanut allergy. PMID- 26017831 TI - Peanut consumption in infants at risk for peanut allergy. PMID- 26017832 TI - Peanut consumption in infants at risk for peanut allergy. PMID- 26017833 TI - Community-acquired pneumonia among U.S. children. PMID- 26017834 TI - Community-acquired pneumonia among U.S. children. PMID- 26017835 TI - Community-acquired pneumonia among U.S. children. PMID- 26017836 TI - Smoking and mortality--beyond established causes. PMID- 26017837 TI - Smoking and mortality--beyond established causes. PMID- 26017838 TI - Smoking and mortality--beyond established causes. PMID- 26017839 TI - Smoking and mortality--beyond established causes. PMID- 26017840 TI - Enduring and emerging challenges of informed consent. PMID- 26017841 TI - Enduring and emerging challenges of informed consent. PMID- 26017842 TI - Enduring and emerging challenges of informed consent. PMID- 26017843 TI - Reduction in ephedra poisonings after FDA ban. PMID- 26017844 TI - Videos in clinical medicine. Treatment of hematoma of the nasal septum. PMID- 26017845 TI - Images in clinical medicine. Orofacial fistulae associated with Crohn's disease. PMID- 26017847 TI - From Homogeneous to Segregated Structure of Poly(dimethylsiloxane)/Cellulose Derivative Mixed Langmuir Films Depending on Composition: An in Situ Neutron Reflectivity Study. AB - The mixing behavior of deuterated polydimethylsiloxane (PDMSd) and cellulose acetate butyrate (CAB) spread as Langmuir films at the air-water interface was studied by means of surface pressure-area isotherms, Brewster angle microscopy (BAM) observations, and in situ neutron reflectivity. The contrast variation method was used with different D2O/H2O mixtures as subphase, allowing contrast matching to either CAB, PDMSd, or PDMSd/CAB mixed film if homogeneous. At PDMSd volume fractions Phi lower than 0.6, the mixed film is a homogeneous monolayer throughout the film compression, in agreement with the monophasic film observed by BAM and the attractive interactions between PDMSd and CAB evidenced from the isotherm measurements. In contrast, at PDMSd volume fractions Phi higher than 0.6, a vertically segregated structure of the mixed film is highlighted. Indeed, whatever the surface pressure, a bilayer structure is observed with a PDMSd layer in contact with the air over a thin CAB layer in contact with the subphase. These results show that the structure of the film is mainly driven by the PDMSd volume fraction which allows obtaining either a homogeneous membrane which composition can be tuned or a vertically segregated system. In contrast, only the thickness of the layers varies with the surface pressure while the structure of the film is not affected. PMID- 26017846 TI - Modulation of voltage-gated Ca2+ channels by G protein-coupled receptors in celiac-mesenteric ganglion neurons of septic rats. AB - Septic shock, the most severe complication associated with sepsis, is manifested by tissue hypoperfusion due, in part, to cardiovascular and autonomic dysfunction. In many cases, the splanchnic circulation becomes vasoplegic. The celiac-superior mesenteric ganglion (CSMG) sympathetic neurons provide the main autonomic input to these vessels. We used the cecal ligation puncture (CLP) model, which closely mimics the hemodynamic and metabolic disturbances observed in septic patients, to examine the properties and modulation of Ca2+ channels by G protein-coupled receptors in acutely dissociated rat CSMG neurons. Voltage clamp studies 48 hr post-sepsis revealed that the Ca2+ current density in CMSG neurons from septic rats was significantly lower than those isolated from sham control rats. This reduction coincided with a significant increase in membrane surface area and a negligible increase in Ca2+ current amplitude. Possible explanations for these findings include either cell swelling or neurite outgrowth enhancement of CSMG neurons from septic rats. Additionally, a significant rightward shift of the concentration-response relationship for the norepinephrine (NE)-mediated Ca2+ current inhibition was observed in CSMG neurons from septic rats. Testing for the presence of opioid receptor subtypes in CSMG neurons, showed that mu opioid receptors were present in ~70% of CSMG, while NOP opioid receptors were found in all CSMG neurons tested. The pharmacological profile for both opioid receptor subtypes was not significantly affected by sepsis. Further, the Ca2+ current modulation by propionate, an agonist for the free fatty acid receptors GPR41 and GPR43, was not altered by sepsis. Overall, our findings suggest that CSMG function is affected by sepsis via changes in cell size and alpha2-adrenergic receptor-mediated Ca2+ channel modulation. PMID- 26017848 TI - Cultural and health beliefs of pregnant women in Zambia regarding pregnancy and child birth. AB - BACKGROUND: Health beliefs related to pregnancy and childbirth exist in various cultures globally. Healthcare practitioners need to be aware of these beliefs so as to contextualise their practice in their communities. OBJECTIVES: To explore the health beliefs regarding pregnancy and childbirth of women attending the antenatal clinic at Chawama Health Center in Lusaka Zambia. METHOD: This was a descriptive, cross-sectional survey of women attending antenatal care(n = 294) who were selected by systematic sampling. A researcher-administered questionnaire was used for data collection. RESULTS: Results indicated that women attending antenatal care at Chawama Clinic held certain beliefs relating to diet, behaviour and the use of medicinal herbs during pregnancy and post-delivery. The main beliefs on diet related to a balanced diet, eating of eggs, okra, bones, offal, sugar cane, alcohol consumption and salt intake. The main beliefs on behaviour related to commencement of antenatal care, daily activities, quarrels, bad rituals, infidelity and the use of condoms during pregnancy. The main beliefs on the use of medicinal herbs were on their use to expedite the delivery process, to assist in difficult deliveries and for body cleansing following a miscarriage. CONCLUSION: Women attending antenatal care at the Chawama Clinic hold a number of beliefs regarding pregnancy and childbirth. Those beliefs that are of benefit to the patients should be encouraged with scientific explanations, whilst those posing a health risk should be discouraged respectfully. PMID- 26017849 TI - Comorbidity in Emetophobia (Specific Phobia of Vomiting). AB - BACKGROUND: Emetophobia (fear of vomiting) is an anxiety disorder in which individuals report clinical levels of fear that they may vomit or be exposed to the vomit of others. The prevalence of comorbidity of emetophobia with other conditions has previously only been investigated using self-report instruments. METHOD: Sixty-four adults with emetophobia participated in an online structured clinical diagnostic interview assessing the presence of emetophobia and other conditions. RESULTS: Higher comorbidity for depression, generalized anxiety disorder, panic disorder, social anxiety disorder and obsessive-compulsive disorder were found in participants compared with general population norms. CONCLUSIONS: Emetophobia is commonly comorbid with other anxiety and depressive disorders. Comorbidity rates, when assessed using a structured clinical interview, were lower than previously reported using self-report alone. Copyright (c) 2015 John Wiley & Sons, Ltd. Key Practitioner Message Emetophobia (specific phobia of vomiting) is a clinical fear of vomiting. Individuals with emetophobia show high comorbidity with other anxiety and mood disorders. The most common comorbid conditions were generalized anxiety disorder, panic disorder, hypochondriasis and obsessive-compulsive disorder. Clinicians should ensure that they assess for the presence of comorbid conditions when treating emetophobia. PMID- 26017851 TI - Improving tablet coating robustness by selecting critical process parameters from retrospective data. AB - CONTEXT: Although tablet coating processes are widely used in the pharmaceutical industry, they often lack adequate robustness. Up-scaling can be challenging as minor changes in parameters can lead to varying quality results. OBJECTIVE: To select critical process parameters (CPP) using retrospective data of a commercial product and to establish a design of experiments (DoE) that would improve the robustness of the coating process. MATERIALS AND METHODS: A retrospective analysis of data from 36 commercial batches. Batches were selected based on the quality results generated during batch release, some of which revealed quality deviations concerning the appearance of the coated tablets. The product is already marketed and belongs to the portfolio of a multinational pharmaceutical company. RESULTS: The Statgraphics 5.1 software was used for data processing to determine critical process parameters in order to propose new working ranges. DISCUSSION AND CONCLUSIONS: This study confirms that it is possible to determine the critical process parameters and create design spaces based on retrospective data of commercial batches. This type of analysis is thus converted into a tool to optimize the robustness of existing processes. Our results show that a design space can be established with minimum investment in experiments, since current commercial batch data are processed statistically. PMID- 26017850 TI - The role of MRI in active surveillance for prostate cancer. AB - Approximately one in seven American men will be diagnosed with prostate cancer during his lifetime, and at least 50% of newly diagnosed patients will present with low-risk disease. In the last decade, the decision-making paradigm for management has shifted due to high rates of disease detection and overtreatment, attributed to prostate-specific antigen screening, with more men deferring definitive treatment for active surveillance. The advent of multiparametric magnetic resonance imaging (MP-MRI) and MRI/ transrectal ultrasound-guided fusion guided prostate biopsy has refined the process of diagnosis, identifying patients with clinically-significant cancer and larger disease burden who would most likely benefit from intervention. In parallel, the utilization of MP-MRI in the surveillance of low-grade, low-volume disease is on the rise, reflecting support in a growing body of literature. The aim of this review is to appraise and summarize the data evaluating the role of magnetic resonance imaging in active surveillance for prostate cancer. PMID- 26017852 TI - Construction of a Chiral Silicon Center by Rhodium-Catalyzed Enantioselective Intramolecular Hydrosilylation. AB - Rhodium-catalyzed enantioselective desymmetrizing intramolecular hydrosilylation of symmetrically disubstituted hydrosilanes is described. The original axially chiral phenanthroline ligand (S)-BinThro (Binol-derived phenanthroline) was found to work as an effective chiral catalyst for this transformation. A chiral silicon stereogenic center is one of the chiral motifs gaining much attention in asymmetric syntheses and the present protocol provides cyclic five-membered organosilanes incorporating chiral silicon centers with high enantioselectivities (up to 91 % ee). The putative active Rh(I) catalyst takes the form of an N,N,O tridentate coordination complex, as determined by several complementary experiments. PMID- 26017853 TI - Electronic Raman scattering as an ultra-sensitive probe of strain effects in semiconductors. AB - Semiconductor strain engineering has become a critical feature of high performance electronics because of the significant device performance enhancements that it enables. These improvements, which emerge from strain induced modifications to the electronic band structure, necessitate new ultra sensitive tools to probe the strain in semiconductors. Here, we demonstrate that minute amounts of strain in thin semiconductor epilayers can be measured using electronic Raman scattering. We applied this strain measurement technique to two different semiconductor alloy systems using coherently strained epitaxial thin films specifically designed to produce lattice-mismatch strains as small as 10( 4). Comparing our strain sensitivity and signal strength in Al(x)Ga(1-x)As with those obtained using the industry-standard technique of phonon Raman scattering, we found that there was a sensitivity improvement of 200-fold and a signal enhancement of 4 * 10(3), thus obviating key constraints in semiconductor strain metrology. PMID- 26017854 TI - The rate constant of the reaction NCN + H2 and its role in NCN and NO modeling in low pressure CH4/O2/N2-flames. AB - Bimolecular reactions of the NCN radical play a key role in modeling prompt-NO formation in hydrocarbon flames. The rate constant of the so-far neglected reaction NCN + H2 has been experimentally determined behind shock waves under pseudo-first order conditions with H2 as the excess component. NCN3 thermal decomposition has been used as a quantitative high temperature source of NCN radicals, which have been sensitively detected by difference UV laser absorption spectroscopy at [small nu, Greek, tilde] = 30383.11 cm(-1). The experiments were performed at two different total densities of rho~ 4.1 * 10(-6) mol cm(-3) and rho~ 7.4 * 10(-6) mol cm(-3) (corresponding to pressures between p = 324 mbar and p = 1665 mbar) and revealed a pressure independent reaction. In the temperature range 1057 K < T < 2475 K, the overall rate constant can be represented by the Arrhenius expression k/(cm(3) mol(-1) s(-1)) = 4.1 * 10(13) exp(-101 kJ mol( 1)/RT) (Deltalog k = +/-0.11). The pressure independent reaction as well as the measured activation energy is consistent with a dominating H abstracting reaction channel yielding the products HNCN + H. The reaction NCN + H2 has been implemented together with a set of reactions for subsequent HNCN and HNC chemistry into the detailed GDFkin3.0_NCN mechanism for NOx flame modeling. Two fuel-rich low-pressure CH4/O2/N2-flames served as examples to quantify the impact of the additional chemical pathways. Although the overall NCN consumption by H2 remains small, significant differences have been observed for NO yields with the updated mechanism. A detailed flux analysis revealed that HNC, mainly arising from HCN/HNC isomerization, plays a decisive role and enhances NO formation through a new HNC -> HNCO -> NH2-> NH -> NO pathway. PMID- 26017855 TI - Paroxysmal supraventricular tachycardia in pregnant women and birth outcomes of their children: a population-based study. AB - The aim of the study was to estimate the possible association of pregnant women with paroxysmal supraventricular tachycardia (PSVT) with the possible risk for adverse birth outcomes, particularly different congenital abnormalities (CAs) in their children. Prospectively and medically recorded PSVT was evaluated in 103 pregnant women who later had offspring with CA (case group) and 149 pregnant women who later delivered newborn infants without CA (control group) and matched to cases in the population-based data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980-1996. Of 252 pregnant women with PSVT, 115 (45.6%) had the onset of this condition before the study pregnancy, that is, their PSVT was a chronic condition, while the rest (N = 137) of PSVT was considered as new onset in the study pregnancy. The comparison of occurrence of PSVT in pregnant women who had offspring with different CA groups and in control mothers showed a higher risk for cardiovascular CAs (adjusted OR with 95% CI: 2.1, 1.1-3.8) explained mainly by secundum atrial septal defect. This association was confirmed in pregnant women with PSVT in the second and/or third gestational month, that is, critical period of cardiovascular CAs. In conclusion PSVT in pregnant women associates with a higher risk of secundum atrial septal defect in their children. PMID- 26017856 TI - FHL1 inhibits the growth of tongue squamous cell carcinoma cells via G1/S cell cycle arrest. AB - Four and a half LIM protein 1 (FHL1) has been characterized as a tumor suppressor in various types of tumor. However, the biological function and underlying mechanism of FHL1 in tongue squamous cell carcinoma (TSCC) remain to be elucidated. The present study demonstrated that FHL1 inhibits anchorage-dependent and -independent growth of TSCC cells in vitro and tumor growth in nude mice, as determined by cell proliferation and soft agar assays. Knockdown of FHL1 with FHL1 small interfering RNA (siRNA) promoted tumor growth in nude mice. Mechanistically, flow cytometric analysis showed that knockdown of FHL1 promoted G1/S cell cycle progression. Furthermore, expression of cell cycle-associated regulators, cyclin D and cyclin E, were detected by western blotting and reverse transcription-quantitative polymerase chain reaction. Cyclin D and cyclin E were markedly elevated at both the protein and mRNA level in the FHL1 siRNA transfected cells. These results suggested that FHL1 has a tumor suppressive role in TSCC and that FHL1 may be a useful target for TSCC gene therapy. PMID- 26017857 TI - [Frontiers in Live Bone Imaging Researches. Intravital imaging of osteoclast dynamics]. AB - Osteoclasts are bone-resorbing giant polykaryons that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursors. Upon the stimulation of essential factors such as M-CSF and RANKL, osteoclast precursor monocytes attach to the bone surface ( "migration" ), fuse with each other to form giant cells ( "differentiation" ) and mediate bone resorption ( "function" ). To reveal the regulatory mechanism of these three dynamic steps of osteoclastic activity, we have originally established an advanced imaging system for visualizing living bone tissues with intravital multiphoton microscopy. By means of the system, we have recently succeeded in visualization of osteoclast migration, differentiation, and function in living bone tissues in vivo. In this review we summarize the latest data of intravital imaging of osteoclast dynamics, and discuss novel lines of osteoclast-targeted therapies that will impact future treatment of bone destructive diseases. PMID- 26017858 TI - [Frontiers in Live Bone Imaging Researches. In vivo imaging of osteoblasts]. AB - Osteoblasts are bone-forming cells and lately osteoblastic niche is getting a lot more attention as a candidate of hematopoietic niche. Although there have been many previous studies about osteoblasts, there are few studies about the dynamics of osteoblasts. Recent rapid advance of fluorescent imaging techniques enables us to observe cellular dynamics and there are some reports that osteoblasts were visualized in live bone by using intravital two-photon microscopy. Here we show past reports about live cell imaging of osteoblasts and our latest data of live cell imaging of osteoblasts in vivo and in vitro. PMID- 26017859 TI - [Frontiers in Live Bone Imaging Researches. In vivo imaging of bone marrow microenvironment]. AB - The function of hematopoietic stem cells and leukemia stem cells depends on their interaction with complex microenvironment within the bone marrow. Conventional methods could not observe the dynamic cell movement in living bone marrow. Recently rapid development of live imaging techniques enables us to understand the cellular interaction. Intravital two-photon imaging is the ideal method to understand the nature of bone marrow because of visualizing the cellular dynamics in vivo and observing the bone marrow long time. Here we show the latest reports about bone marrow microenvironment by intravital imaging, and also discuss its further application. PMID- 26017860 TI - [Frontiers in Live Bone Imaging Researches. In vivo imaging of cutaneous immune responses]. AB - Skin is an outermost organ that serves as an interface between the host and the environment. The skin provides not only mechanical barrier functions, but also an active immunological barrier that provides the first line of defense against infections. For the effective clearance of pathogens or antigens in the skin, immune cells must quickly exert their effector functions while avoiding the host damage by their excess activation. Therefore, the quality, magnitude, and the duration of the immune cell activity must be carefully regulated. Here, we will review our recent findings on the regulatory mechanisms for effector T cells activation in the skin, which was revealed by the live imaging techniques using two-photon microscopy. PMID- 26017861 TI - [Frontiers in Live Bone Imaging Researches. In vivo vascular imaging of thrombosis and thrombopoiesis]. AB - In vivo imaging technique can elucidate dynamic molecular and cellular mechanisms in various fields. We applied two photon microscopy technique to living animals, and combined with light based cell manipulation system. We applied two photon microscopy technique to living animals, and combined with light based cell manipulation system. We elucidated the detailed cellular processes of thrombosis and thrombopoiesis in vivo. In this review, we introduce our recent findings of in vivo platelet activation, hemostasis and thrombopoiesis from bone marrow megakaryocytes. PMID- 26017862 TI - [Frontiers in Live Bone Imaging Researches. In vivo imaging of immune tissues]. AB - In vivo imaging analysis of the immune tissues, especially secondary lymphoid tissues such as lymph nodes, has greatly increased our understanding of how immune responses are promoted and regulated by immune cell trafficking. Recently, in vivo tracking of follicular helper T (Tfh) cells, a vital T cell subset for B cell responses to produce antibodies, by imaging analysis and light-induced cell labeling not only revealed their migration dynamics, but also provided new insights into how Tfh cells may be involved in the generation of immunological memory. PMID- 26017863 TI - [Frontiers in Live Bone Imaging Researches. In vivo imaging of neuron and glia]. AB - Glial cells originate the Greek word'glue'had traditionally been only thought as supporting cells for neurons. Because glial cells are electrically non-excitable, neuroscience researchers have focused on elucidation of excitable cell properties, neuron. Recent advanced optical methods lead us to observe glial structure, motility and their function in normal physiological conditions. These approaches let us to know that they are not just the supporting cells for neuron but could receive signal from neurons through receptors for neurotransmitters and to regulate neuronal functions, thus modulating behavior phenotype. Such studies also suggest that glial cells are highly dynamic and actively maintain brain homeostasis. Here, we review physiological function of glial cells through a new perspective clarified by innovations of imaging technology including two-photon microscope. PMID- 26017864 TI - [Frontiers in Live Bone Imaging Researches. Two-Photon Excitation Microscopy, principles and technologies]. AB - The "two photon absorption" phenomenon had been predicted by the American Physicist, Maria Ghoppert-Mayer in 1931. Denk and Webb group had proved it in 1990 and the first product had been launched in the market in 1996. But ever since the product became available, the number of users are not increased. Moreover, the system had been too difficult to use and the system sometimes stay not working in labs. But recently, the new easier-to-use products are released and the ultra short pulse IR laser became stable. And its applications are extending from neuro-science to oncology or immunology fields. Due to these reasons, the shipment of multi-photon microscope in Japan in 2013 is approximately 40 units which is 3 times bigger than in 2010. In this paper, I would like to discuss the principles of two-photon microscopy and some of the new technologies for the higher signal capture efficiency. PMID- 26017865 TI - [Frontiers in Live Bone Imaging Researches. Development of fluorescent pH probe for imaging osteoclast activation]. AB - For the clinical diagnosis of osteoporosis, X-ray CT and biochemical bone metabolism markers, however, there is no method to monitor osteoclast activity in the living system. We have developed the fluorescent probe to monitor osteoclast activity, by the combination of pH sensitive fluorescent dye with bisphosphonate which is delivered to the bone surface by its high affinity to hydroxyl apatite, which is named BAp-E. In vivo mouse imaging of activated osteoclast was successfully demonstrated using two photon excitation laser microscope. PMID- 26017866 TI - [Frontiers in Live Bone Imaging Researches. Novel fluorescent proteins for in vivo imaging]. AB - Bone tissue is maintained by dynamic equilibrium of various types of cells. Thus, real time intravital imaging of movement and phenotypic changes of cells in the steady state and in pathophysiological state help us to understand molecular mechanism of bone tissue maintenance. Therefore, this review introduces Fucci-Tg mice for cell cycle imaging, caspase-3 indicator SCAT3.1 mice for cell death, and photoconvertible protein Kaede-Tg mice and cell-type specific KikGR mice for visualization of cell movement within intra-organ and between inter-organs. PMID- 26017867 TI - [Frontiers in Live Bone Imaging Researches. Functional cross talk between bone and nervous system]. AB - Bone homeostasis is maintained by bone formation and bone resorption. The traditional view of bone metabolism as a primarily endocrine regulation has been expanded in recent years following the identification of nervous system controlling bone metabolism. Especially, sympathetic and parasympathetic nervous system regulates bone formation and bone resorption. In addition, sensory nervous system also has been shown to be involved in the regulation of bone homeostasis. These studies demonstrated that nervous system is closely related to bone remodeling. PMID- 26017868 TI - [Frontiers in Live Bone Imaging Researches. Amazing function of osteocyte]. AB - Osteocytes, the most numerous and least well studied bone cells, are stellate shaped cells enclosed within the bone lacuno-canalicular network of bone. Based on the osteocyte location within the bone matrix and the cellular morphology, it is proposed that osteocytes potentially contribute to the regulation of bone remodeling in response to mechanical and endocrine stimuli. Although the potential importance of osteocytes has been recognized, there has been limited evidence for functional roles of osteocytes in bone remodeling. However, studies of mice gene targeting and human gene mutations have contributed to recent progress of osteocyte biology. Furthermore, bone has been traditionally regarded as a part of the skeletal and locomotor system, but recent studies suggest that osteocytes regulate systemic biological functions based on the inseparable link between bone and other systems. PMID- 26017869 TI - [Frontiers in Live Bone Imaging Researches. Novel drug discovery by means of intravital bone imaging technology]. AB - Recent advances in intravital bone imaging technology has enabled us to grasp the real cellular behaviors and functions in vivo , revolutionizing the field of drug discovery for novel therapeutics against intractable bone diseases. In this chapter, I introduce various updated information on pharmacological actions of several antibone resorptive agents, which could only be derived from advanced imaging techniques, and also discuss the future perspectives of this new trend in drug discovery. PMID- 26017870 TI - Clinics and churches: lifeworlds and health-seeking practices of older women with noncommunicable disease in rural South Africa. AB - BACKGROUND: In this article we describe a phenomenological lifeworld study based on the theory of communicative action of 13 women with noncommunicable disease (NCDs) in a rural area in South Africa. The purpose of the study was to generate key concepts of health care access and the management of NCDs in a rural South African context. METHODS: The study employed a qualitative methodology with serial semistructured interviews. We used a content analytical approach to analyse key themes and patterns in participants' narratives of NCDs and health care access. RESULTS: The findings are reported by theme and include analyses of narrative sequences related to 1) family environment, 2) experiences of NCDs, 3) understandings of the causes of NCDs, 4) accessibility of formal health care services, 5) experiences of formal health care services, 6) treating NCDs, and 7) experiences of informal health care services. The findings suggest that participation in the routines prescribed by formal health care services and reinforced by families and faith-based communities normalises the experience of NCDs to the extent that narratives of NCDs form the background, rather than the focus of broader illness narratives. Such narratives rather tend to focus on significant life events and relationships. The key features of the narratives include connections between social or autobiographical and biological understandings of NCDs, the appropriation of modern concepts of disease in illness narratives, and reflexive commentary on the modern features of NCDs. In the context of such narrative expertise formal health care services have a high level of acceptability in this rural area. CONCLUSION: Lifeworld analysis of health care access based on the theory of communicative action places consensual understandings of NCDs and their treatment as central to the health care experience. Our findings suggest that such analyses can facilitate potential feedback processes between health care users and professionals which generate consensus as well as institutional reform within formal health care services. PMID- 26017872 TI - Solution-Processed Ag Nanowires + PEDOT:PSS Hybrid Electrode for Cu(In,Ga)Se2 Thin-Film Solar Cells. AB - To reduce the cost of the Cu(In,Ga)Se2 (CIGS) solar cells while maximizing the efficiency, we report the use of an Ag nanowires (NWs) + poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) hybrid transparent electrode, which was deposited using all-solution-processed, low-cost, scalable methods. This is the first demonstration of an Ag NWs + PEDOT: PSS transparent electrode applied to CIGS solar cells. The spin-coated 10-nm-thick PEDOT: PSS conducting polymer layer in our hybrid electrode functioned as a filler of empty space of an electrostatically sprayed Ag NW network. Coating of PEDOT: PSS on the Ag NW network resulted in an increase in the short-circuit current from 15.4 to 26.5 mA/cm(2), but the open-circuit voltage and shunt resistance still needed to be improved. The limited open-circuit voltage was found to be due to interfacial recombination that is due to the ineffective hole-blocking ability of the CdS film. To suppress the interfacial recombination between Ag NWs and the CdS film, a Zn(S,O,OH) film was introduced as a hole-blocking layer between the CdS film and Ag NW network. The open-circuit voltage of the cell sharply improved from 0.35 to 0.6 V, which resulted in the best cell efficiency of 11.6%. PMID- 26017871 TI - SPIRONOLACTONE FOR NONRESOLVING CENTRAL SEROUS CHORIORETINOPATHY: A RANDOMIZED CONTROLLED CROSSOVER STUDY. AB - PURPOSE: To evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, for nonresolving central serous chorioretinopathy. METHODS: This is a prospective, randomized, double-blinded, placebo-controlled crossover study. Sixteen eyes of 16 patients with central serous chorioretinopathy and persistent subretinal fluid (SRF) for at least 3 months were enrolled. Patients were randomized to receive either spironolactone 50 mg or placebo once a day for 30 days, followed by a washout period of 1 week and then crossed over to either placebo or spironolactone for another 30 days. The primary outcome measure was the changes from baseline in SRF thickness at the apex of the serous retinal detachment. Secondary outcomes included subfoveal choroidal thickness and the ETDRS best-corrected visual acuity. RESULTS: The mean duration of central serous chorioretinopathy before enrollment in study eyes was 10 +/- 16.9 months. Crossover data analysis showed a statistically significant reduction in SRF in spironolactone treated eyes as compared with the same eyes under placebo (P = 0.04). Secondary analysis on the first period (Day 0-Day 30) showed a significant reduction in subfoveal choroidal thickness in treated eyes as compared with placebo (P = 0.02). No significant changes were observed in the best-corrected visual acuity. There were no complications related to treatment observed. CONCLUSION: In eyes with persistent SRF due to central serous chorioretinopathy, spironolactone significantly reduced both the SRF and the subfoveal choroidal thickness as compared with placebo. PMID- 26017873 TI - Mixing studies in lupus anticoagulant testing are required at least in some type of samples. AB - BACKGROUND: According to the ISTH guidelines for lupus anticoagulant (LAC) testing, the second step in the three-step procedure (screening, mixing, and confirmation) is the mixing test, which improves the discrimination between the presence of an inhibitor and coagulation factor deficiencies such as those occurring in patients receiving vitamin K antagonists (VKAs). OBJECTIVES: From a retrospective analysis of dilute Russell viper venom (dRVVT) results, we evaluated the impact of the mixing test result on the interpretation of LAC positivity. METHODS: We interpreted the dRVVT clotting times with and without taking into account the results of the mixing test in a patient population with prolonged screening test (n = 267) with special attention to the patients receiving VKAs. RESULTS AND CONCLUSIONS: The number of samples classified as 'LAC positive' differed substantially depending on the method of interpretation; 170 and 235 of 267 samples were classified as LAC positive with the three- and two step procedure, respectively. Discrepancy between the two-step (without mixing step) and the three-step procedure was due to not including a mixing test and was more pronounced in the VKA patient population. Screen/confirm ratios carried out on a 1:1 mix of patient and normal pooled plasma (NPP) gave a lower incidence of 59 of 267. We advise continuing to perform mixing test to avoid false-positives. In patients with discrepant results between the two- and three-step dRVVT interpretation, mainly observed in VKA-treated patients, we advise retesting of the patients preferable beyond the period of anticoagulant therapy and additional testing for anti-beta2GPI and/or anti-cardiolipin antibodies. PMID- 26017874 TI - Review of renal cell carcinoma with rhabdoid features with focus on clinical and pathobiological aspects. AB - Rhabdoid morphology in renal cell carcinoma (RCC) may, like sarcomatoid change, be perceived as a type of dedifferentiation, and is a poor prognostic factor. Histologically, rhabdoid neoplastic cells are round to polygonal cells with globular eosinophilic cytoplasmic inclusions and eccentric vesicular nuclei and enlarged nucleoli. All types of RCC, including clear cell, papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, acquired cystic disease-associated RCC, ALK-positive renal cancer and unclassified RCC, may display a variably prominent rhabdoid phenotype. Immunohistochemically, the cytoplasm of rhabdoid cells shows positivity for vimentin and/or cytokeratin. Ultrastructurally, cytoplasmic whorls/aggregates of intermediate filaments correspond to light microscopically observed inclusions. Genetically, a previous report suggests that combined loss of BAP1 and PBRM1 may be associated with rhabdoid morphology. As with sarcomatoid change, pathologists should describe, estimate and state the proportion of tumor cells with a rhabdoid phenotype in the routine pathology report of RCC. PMID- 26017875 TI - Alterations of Wnt/beta-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus. AB - The Wnt/Fzd/beta-catenin signaling pathway plays a significant role in physiology and pathology of the liver. The role of beta-catenin is linked mainly to the canonical pathway of the system. Phosphorylation of beta-catenin and abnormalities in function of the E-cadherin-catenin unit lead to loss of intercellular junctions, progression in liver fibrosis, and development of cirrhosis and hepatocellular carcinoma (HCC). Progression of liver diseases is noted to be accompanied by disturbances in beta-catenin expression (mainly with its overexpression), with its cytoplasmic or nuclear translocation and with lowered expression of E-cadherin. Increase in transcriptional activity of beta catenin is associated mainly with mutations of CTNNB1. Detailed mechanisms of HCC development are not known. More beta-catenin mutations are manifested in hepatitis C virus (HCV)-associated than in HBV-related HCC. In recent years the role of nonstructural proteins and of the core protein of HCV has been accentuated in induction of the Wnt pathway. HCV proteins affect in a double manner expression of E-cadherin, including modulation of the Wnt pathway and reduction of E-cadherin expression at the transcriptional level. This review presents current data on mechanisms of hepatocarcinogenesis involving participation of the Wnt canonical pathway and, in particular, interaction of Wnt pathway components with HCV genome products in the process. PMID- 26017876 TI - Application of immunohistochemistry for detection of metastases in sentinel lymph nodes of non-advanced breast cancer patients. AB - Any diagnostic method for detection of occult metastases in sentinel lymph node (SLN) could change postoperative therapeutic management. In this study, we attempted to evaluate the usefulness of immunohistochemical (IHC) studies for histopathological SLN examination and their impact on the diagnosis of metastatic lesions. Analyzed data concerned 1358 breast cancer patients referred for sentinel lymph node biopsy (SLNB) between 2004 and 2012 with particular emphasis on broadening the scope of postoperative SLN histopathological assessment to include IHC. Sentinel lymph node involvement was diagnosed in 22.2% of patients. Use of the IHC method facilitated detection of 21.4% of all diagnosed SLN lesions (9.9% of macrometastases, 60.0% of micrometastases, 100% of isolated tumor cells). 61.6% sensitivity and 100% specificity were obtained in the group of patients who underwent intraoperative SLN histopathological examination. Use of immunohistochemistry for diagnostics of sentinel lymph node metastases in patients with breast cancer enables detection of a greater proportion of metastases, thus modifying both surgical (SLN macrometastases) and adjuvant treatment. As compared to pN0 patients and those with a metastasis found in HE staining, in patients with a metastasis in the sentinel lymph node diagnosed in IHC studies, no statistically significant differences were found concerning the long-term results of the implemented treatment. PMID- 26017877 TI - Invasive ductal carcinoma of no special type and its corresponding lymph node metastasis: do they have the same immunophenotypic profile? AB - In the present study we compared the immunophenotypic subtypes of breast ductal invasive carcinomas with their ipsilateral, axillary lymph node metastasis. The ER (estrogen receptor), PR (progesterone receptor), Her2 (human epidermal growth factor receptor 2), and CK5 (cytokeratin 5) status and the proliferation marker Ki-67 were determined by immunohistochemistry on specimens from 43 women. All selected cases were diagnosed as invasive breast carcinomas, of no special type (NST), G2 grade of differentiation. The most frequently encountered subtype at both sites was luminal B. We determined that tumor profile evaluated by surrogate markers is not stable during the metastatic process. The total rate of shifted cases was 23.26% (10 cases), and the highest rate of shifting (6.98%) was encountered from luminal B/Ki-67 to luminal A subtype. In five cases, the subtype shifted to a poorer one according to prognosis. These data support the hypothesis that breast cancer is a heterogeneous disease, with substantial variability of cellular components within each category, a statement applicable to invasive breast carcinomas of NST type too. The receptor profile of this carcinoma, indicated by surrogate markers, is not stable throughout the metastatic process. PMID- 26017878 TI - Severe dysplasia can be distinguished from moderate and mild dysplasia of bronchial mucosa by changes in Ki-67 index. AB - Preneoplastic lesions on small bronchial biopsy specimens may cause a diagnostic dilemma. The aim of this study was to estimate karyometric variables and the Ki 67 index of preneoplastic bronchial lesions and squamous cell carcinoma of the lung. The study was performed on endoscopic samples of squamous cell carcinoma (n = 22), normal appearing mucosa surrounding carcinoma (n = 10), bronchial dysplasia of mild (n = 7), moderate (n = 6), and severe grade (n = 6), carcinoma in situ (n = 17), and normal mucosa from patients with chronic bronchitis (n = 26). Karyometric analysis was done using the image analyzer ImageJ 1.47q. Ki-67 activity was also quantified by ImageJ 1.47q with the plugin Cell Counter. The highest values of nuclear area were found in squamous cell carcinoma, and differences were statistically significant compared to normal mucosa, all grades of dysplasia and normal appearing mucosa surrounding carcinoma (p < 0.01). The Ki 67 index was significantly higher in squamous cell lung carcinoma compared to normal mucosa, mild and moderate dysplasia and normal appearing mucosa surrounding carcinoma (p < 0.01). The Ki-67 index was significantly higher in severe dysplasia than in mild and moderate dysplasia (p < 0.01). In conclusion, the Ki-67 index is a useful parameter for more objective grading and can be of prognostic value to determine the biological potential of preneoplastic bronchial lesions. PMID- 26017880 TI - Effects of folic acid on dyslipidemia and serum homocysteine in a rat model of cholestasis and hepatic fibrosis. AB - The liver is the major site for storage and metabolism of folate. Folate deficiency is common in many liver diseases and causes severe effects on cellular metabolism and increases oxidative stress and the homocysteine (Hcy) level. The objective of this research was to investigate the effects of folic acid on dyslipidemia and serum Hcy concentrations in an experimental rat model of cholestasis. Eighty-one male Wistar rats were divided into nine groups: control, sham-operated, folic acid control, bile duct-ligated (BDL), and BDL+ folic acid groups. In folic acid treated groups, folic acid (1, 5, and 10 mg/kg body weight) was given orally for 28 days. After taking blood and liver samples, plasma lipid profiles and Hcy and hepatic reduced and oxidized glutathione concentrations were measured. Histopathological features of cholestasis were assessed by Masson's trichrome staining. Treatment of folic acid in BDL rats significantly prevented the progression of hepatic fibrosis and improved the serum and liver biochemical changes. These results suggest that folic acid protects the liver against cholestasis by reducing serum Hcy and by its antioxidant properties. Folic acid can be an important therapeutic intervention in dyslipidemia caused by cholestasis. PMID- 26017879 TI - Augmented immunoexpression of survivin correlates with parameters of aggressiveness in prostate cancer. AB - The clinical significance of the immunoexpression of survivin in prostate cancer and its correlation with the biological aggressiveness of prostate cancer remains unclear. Therefore, the present study was undertaken to compare the immunoexpression of survivin in prostate cancer (PCa) and benign prostatic hyperplasia (BPH) as well as to determine whether this immunoexpression could correlate with Gleason score, proliferation activity and prostate specific antigen (PSA) levels. The prostate needle biopsies from 28 patients with elevated serum PSA levels were studied. As a control, 12 needle biopsies of prostate diagnosed as BPH were used. The immunoexpression of survivin was evaluated semiquantitatively, whereas the Ki-67 index was assessed quantitatively. The immunoexpression of survivin and Ki-67 in epithelial cells in the prostate cancer group was significantly increased as compared to BPH cases. In the prostate cancer group there were positive significant correlations between the immunoexpression of survivin and Gleason score as well as Ki-67 antigen. The correlation between the immunoexpression of survivin and PSA levels was also positive, but it did not reach statistical significance. In conclusion, we can confirm that in prostate cancer the immunoexpression of survivin is augmented as compared to BPH and positively correlated with parameters of tumor aggressiveness. PMID- 26017881 TI - Evaluation of different p16 immunostaining methods and the prognostic role of p16/Ki-67 combined expression in non-muscle invasive bladder cancers. AB - There are many scoring methods evaluating the expression of p16 in the bladder immunohistochemically. In this study our aim was to determine an optimal p16 scoring method by discussing different staining methods related with p16 expression in bladder cancers and to establish the association of p16 and Ki-67 expressions, alone or in combination, with recurrence and progression. Ninety patients undergoing their first transurethral resection for bladder cancer and newly diagnosed papillary urothelial carcinoma (pTa and pT1) were included in the study. Four different scoring methods were used for p16 (p16a, p16b, p16c, p16d). The patients were divided into two groups based on recurrence and progression. There was a statistically significant difference between recurrence and abnormal p16d staining (p = 0.005). In other staining patterns of p16, there was no statistically significant difference in terms of recurrence or progression.In the multivariate logistic regression analysis, combined Ki-67 >= 10 and abnormal p16d staining was found to be the only independent predictive factor for recurrence (OR = 2.26, 95% CI: 0.13-46.41, p = 0.035) and no independent predictive factor for progression was found. Determining an adequate expression scoring by taking normal transitional epithelial staining pattern as a reference would be an objective approach in p16 evaluation. Moreover, it was found that evaluating p16d and Ki-67 in combination would be significant in predicting recurrence in pTa and pT1 urothelial carcinomas. PMID- 26017882 TI - Association between -41657C/T single nucleotide polymorphism of DNA repair gene XRCC2 and endometrial cancer risk in Polish women. AB - AIM OF THE STUDY: The XRCC2 gene plays a crucial role in double-strand DNA break repair by homologous recombination. Current literature provides clear evidence that XRCC2 polymorphisms may be associated with the development of certain types of cancer; however, still little is known about their association with endometrial cancer (EC). MATERIAL AND METHODS: The single nucleotide polymorphism (SNP) -41657C/T (rs718282) of the XRCC2 gene was investigated by PCR-RFLP in 304 patients with EC and in 200 age- and sex-matched non-cancer controls. RESULTS: The analysis revealed a relationship between XRCC2 -41657C/T polymorphism and the incidence of EC. Endometrial cancer patients showed overrepresentation of the T allele of the SNP. The T/T homozygous variant increased the cancer risk. There were no significant differences between the distribution of XRCC2 -41657C/T genotypes in the subgroups according to histological grade. CONCLUSIONS: This is the first study that links the SNP -41657C/T (rs718282) of the XRCC2 gene with EC in Polish women. The results support the hypothesis that this polymorphism may be positively correlated with the incidence of EC. PMID- 26017883 TI - Malignant metastasizing solitary fibrous tumors of the liver: a report of three cases. AB - Solitary fibrous tumors are rare neoplasms of mesenchymal origin that have been reported in various other extrathoracic sites, including the liver. We present a case series of three malignant solitary fibrous tumors of the liver, occurring in two women 74 and 80 years old and one 65-year-old man. No clinical features were predictive of malignancy except the large sizes and synchronous presence of lung metastases in two of the three cases. Histological examinations revealed the presence of high pleomorphic cellularity with nuclear atypia, necrosis and high mitotic ratios. All patients died of disease progression. PMID- 26017884 TI - Neuro-folliculo-sebaceous cystic hamartoma is a unique entity. AB - Folliculosebaceous cystic hamartoma (FSCH) is a distinct type of cutaneous hamartoma of pilosebaceous origin that usually occurs on the face. For FSCH, other parts have been reported such as the genital area, and the trunk. A 50-year old woman presented with an asymptomatic dome-shaped scalp nodule. The clinical diagnosis was pilar cyst or tumor. Histopathological assessment showed FSCH with absolute neural component as the only mesenchymal stroma, leading to the diagnosis of folliculosebaceous cystic neural hamartoma. To the best of our knowledge, absolute neural stroma in FSCH has not been reported previously in the literature. PMID- 26017885 TI - Uncontrolled human papilloma virus infection in a 28-year-old man leading to death - case report and review of literature. AB - Recurrent respiratory papillomatosis is an increasingly common disease which leads to organic and functional limitations. Clinical symptoms depend on the location and extent of the papillomatosis. They include hoarseness, cough, and, in some cases, significant narrowing of the respiratory and digestive tracts. The present report describes a fatal case of a young man (28 years old) who developed a very dynamic papilloma infection of the larynx, which spread to the trachea, the oesophagus, the soft tissues of the neck, and the mediastinum. Multimodal treatment did not stop the progression of the disease. The papillomatous lesion was removed with a CO2 laser used in a Kleinsasser microlaryngoscopy and under a microscope using a electrocoagulation loop with argon plasma during the gastroscopy. Antiviral treatment with cidofovir was introduced, as well as in further follow-up radiotherapy. Congenital or acquired immunodeficiency was also excluded. Despite multimodal treatment, successful eradication of the infection was not possible. In our case, aggressive progression of the disease was observed. We were unable to confirm malignant transformation. Papillomatosis was the only disease, and its aggressive development led to the patient's death. In the case of aggressive, uncontrolled progression - when the infiltration spreads beyond the larynx and the hypopharynx - there are no alternative treatment methods that would lead to an effective cure. PMID- 26017886 TI - Gastric gastrointestinal stromal tumor with incomplete duplication cyst - a case with possibility of neoplasia in fetal-period malformed tissues. AB - The coincidence of GIST and other gastric malignancies are documented well but arising GIST from congenital anomalies is still rarity in literature. To date, only a few papers have been concerned on the possibility of arising neoplasms from duplication cyst of gastrointestinal tract. There, are dominating usual cancers, neuroendocrine cancers or lymphomas but GIST has been noted only once. Here, we report a case of 73 years old female-patient with typical gastric stromal tumor comprised centrally locked an incomplete duplication cyst. PMID- 26017887 TI - Letter to the Editor: Re: Co-existence of intramuscular spindle cell lipoma with an intramuscular ordinary lipoma: Report of a case. Response to Laliotis et al. PMID- 26017888 TI - Minilaparoscopy in urology: initial results after 32 cases. AB - PURPOSE: The use of minilaparoscopic instruments has gained interest in recent years, permitting a less invasive treatment for many surgical procedures. Its application in urological surgeries has not been established yet. METHODS: Between November 2012 and December 2014, 32 patients underwent minilaparoscopic surgeries, using 3.5-mm instruments. The procedures performed included pyeloplasties (16 cases), radical nephrectomies (2), simple nephrectomies (4), renal cyst decortication (5), ureterolithotomy (2) ureteral reimplantation (2) and partial ureterectomy (1). RESULTS: All the procedures were performed minilaparoscopically, except for one simple nephrectomy and one renal cyst decortication that were converted to a standard laparoscopic approach, due to intensive perioperative bleeding. One pyeloplasty had to be reoperated for a urinary fistula repair. All the patients had good-to-excellent cosmetic outcomes, except for one patient who developed keloids at her scars. Functional results were comparable to the ones described in the literature. CONCLUSION: Minilaparoscopy is a feasible option for patients and physicians searching for a even less invasive procedure compared with the laparoscopic approach, with better cosmetic and the same functional and oncologic outcomes. PMID- 26017889 TI - Retrograde access of the left atrium for pulmonary vein isolation using magnetic navigation after closure of an atrial septum defect. AB - Transseptal puncture is the most commonly used technique to perform electrophysiological procedures in the left atrium. This case report describes a pulmonary vein isolation in a patient with a paroxysmal atrial fibrillation, complicated by the presence of an oversized Amplatzer device (AGA Medical Corp., Golden Valley, MN). A retrograde approach using the magnetic navigation system (Niobe, Stereotaxis Inc., St Louis, USA) was performed, and showed to provide a feasible, safe and successful alternative for catheter ablation of cardiac arrhythmias in patients in whom the classic transseptal approach is impossible. PMID- 26017890 TI - A patient with progressive dyspnoea. AB - Our case report describes the strong ability of noninvasive diagnostic techniques to detect cardiac involvement in advanced systemic amyloid light chain amyloidosis, which was confirmed at autopsy. PMID- 26017891 TI - ECG screening in athletes: optional or mandatory? PMID- 26017892 TI - CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas. AB - OBJECTIVE: CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood. METHODS: We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expression of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1(R132H) cells transfected with lentivirus encoding mutant and WT CIC. RESULTS: We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p = 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation of normally CIC repressed genes ETV1, ETV4, ETV5, and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1(R132H) and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1. INTERPRETATION: CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma. PMID- 26017893 TI - Female pelvic medicine and reconstructive surgery practice patterns: IUGA member survey. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study is to describe the current practice patterns of the International Urogynecological Association (IUGA) members regarding the diagnosis, evaluation, and surgical management of stress urinary incontinence (SUI) and pelvic organ prolapse (POP). METHODS: A 30-item internet-based survey was sent to IUGA members. Response to the survey was voluntary, and subjects answered questions regarding demographics, the evaluation of POP and SUI, including urodynamics (UDS) testing, preferred management of POP and SUI, and the application of mesh in reconstructive surgery. RESULTS: Three hundred and thirty-four IUGA members responded to the survey; most of the responses were from Europe (40 %) and North America (23 %). After the FDA safety communication regarding serious complications of using transvaginal mesh, 45 % of responders reported decreased use of mesh, while 31 % reported that it had no effect or that they did not use mesh for transvaginal prolapse (23.6 %). Regarding the evaluation and treatment of SUI, 51 % of responders would perform urodynamics (UDS) before surgical correction of uncomplicated SUI and 78.5 % of responders would perform UDS if no urine leakage was demonstrated on examination. The preferred method of treatment for SUI is midurethral sling (MUS), regardless of prior treatments (65.1 %), concomitant surgeries (74.5 %), or examination findings (50.8-92.6 %). Regarding POP repair, the preferred approach for apical (61 %) and posterior (99.4 %) prolapse repair is vaginal. CONCLUSIONS: Most respondents use a vaginal approach for POP surgery. The FDA safety communication regarding serious complications related to the use of transvaginal mesh for prolapse surgery led to a global decrease in the employment of mesh for POP. Synthetic midurethral slings are predominant in the current treatment of SUI. Despite new recommendations, many responders still perform UDS for uncomplicated SUI. PMID- 26017894 TI - Does preoperative anal physiology testing or ultrasonography predict clinical outcome with sacral neuromodulation for fecal incontinence? AB - INTRODUCTION AND HYPOTHESIS: To determine the value of preoperative anal physiology testing and transanal ultrasonography in predicting clinical response to sacral neuromodulation for fecal incontinence. METHODS: We report a retrospective study of all patients treated with sacral neuromodulation for fecal incontinence in a single practice between 2011 and 2014 was performed. Patient demographics included age, gender, comorbidities, presence of an ultrasound defined external sphincter defect, and history of prior anal sphincter repair. Cleveland Clinic Florida (CCF) scores were used to assess the severity of fecal incontinence at baseline, and at 3, 6 and 12 months. Pearson's correlation coefficient was used to evaluate the relationship between preoperative physiology testing and ultrasonography and patient outcome. RESULTS: Sacral neuromodulation was trialed in 60 patients, of whom 31 had anorectal physiology testing and 29 did not. Patients who were tested were younger (60.9 vs. 71.4 years, p = 0.013) and more likely to have had a prior overlapping sphincteroplasty (40.5% vs. 15%, p = 0.043). Among patients who progressed to complete system implantation, CCF scores at 3 and 12 months were similar whether they had physiology testing or not. Likewise, patient outcome did not correlate with the finding of an ultrasound-defined external sphincter defect. Pearson's correlation coefficient was used to evaluate the relationship between the test results and the 3-month CCF scores. CCF scores 3 months after full system implantation did not correlate with the presence or size of an external sphincter defect, resting or squeeze pressure, pudendal nerve terminal motor latency, rectoanal inhibitory reflex, or minimum detectable volume. CONCLUSIONS: Anal physiology testing and ultrasonography were not predictive of clinical outcomes among patients treated with sacral neuromodulation for fecal incontinence. PMID- 26017896 TI - Editorial: hormonal crosstalk in plants: the ultimate determiner of plant fate. PMID- 26017895 TI - Sex chromosome-to-autosome transposition events counter Y-chromosome gene loss in mammals. AB - BACKGROUND: Although the mammalian X and Y chromosomes evolved from a single pair of autosomes, they are highly differentiated: the Y chromosome is dramatically smaller than the X and has lost most of its genes. The surviving genes are a specialized set with extraordinary evolutionary longevity. Most mammalian lineages have experienced delayed, or relatively recent, loss of at least one conserved Y-linked gene. An extreme example of this phenomenon is in the Japanese spiny rat, where the Y chromosome has disappeared altogether. In this species, many Y-linked genes were rescued by transposition to new genomic locations, but until our work presented here, this has been considered an isolated case. RESULTS: We describe eight cases of genes that have relocated to autosomes in mammalian lineages where the corresponding Y-linked gene has been lost. These gene transpositions originated from either the X or Y chromosomes, and are observed in diverse mammalian lineages: occurring at least once in marsupials, apes, and cattle, and at least twice in rodents and marmoset. For two genes- EIF1AX/Y and RPS4X/Y--transposition to autosomes occurred independently in three distinct lineages. CONCLUSIONS: Rescue of Y-linked gene loss through transposition to autosomes has previously been reported for a single isolated rodent species. However, our findings indicate that this compensatory mechanism is widespread among mammalian species. Thus, Y-linked gene loss emerges as an additional driver of gene transposition from the sex chromosomes, a phenomenon thought to be driven primarily by meiotic sex chromosome inactivation. PMID- 26017897 TI - Detection and characterization of OXA-48-producing Klebsiella pneumoniae originated in Bulgaria. AB - We report the identification of OXA-48-producing Klebsiella pneumoniae, causing peritonitis in a cancer patient admitted to the Oncology Hospital in Sofia. The isolate had reduced susceptibility to carbapenems but remained susceptible to extended-spectrum cephalosporins. PCR and sequencing confirmed the presence of blaOXA-48 gene flanked by two intact copies of IS1999 on truncated DeltaTn1999.1. This transposon was located on unusual non-typeable 29-kb plasmid that could be transferred only by transformation. Multilocus sequence typing (MLST) indicated the presence of the sequence type ST530.This is the first documented infection due to OXA-48-producing Enterobacteriaceae strain in Bulgaria. PMID- 26017898 TI - Impact of bridging with perioperative low-molecular-weight heparin on cardiac and bleeding outcomes of stented patients undergoing non-cardiac surgery. AB - When patients with coronary stents undergo non-cardiac surgery, bridging therapy with low-molecular-weight heparin (LMWH) is not infrequent in clinical practice. However, the efficacy and safety of this approach is poorly understood. This was a retrospective analysis of patients with coronary stent(s) on any antiplatelet therapy undergoing non-cardiac surgery between March 2003 and February 2012. The primary efficacy endpoint was the 30-day incidence of major adverse cardiac or cerebrovascular events (MACCE), defined as the composite of cardiac death, myocardial infarction, acute coronary syndrome leading to hospitalisation, or stroke. The primary safety endpoint was the 30-day composite of Bleeding Academic Research Consortium (BARC) bleedings >= 2. Among 515 patients qualifying for the analysis, LMWH bridging was used in 251 (49 %). At 30 days, MACCE occurred more frequently in patients who received LMWH (7.2 % vs 1.1 %, p=0.001), driven by a higher rate of myocardial infarction (4.8 % vs 0 %, p< 0.001). This finding was consistent across several instances of statistical adjustment and after the propensity matching of 179 pairs. Patients bridged with LMWH also experienced a significantly higher risk of BARC bleedings >= 2 (21.9 % vs 11.7 %, p=0.002) compared to those who were not, which remained significant across different methods of statistical adjustment and propensity matching. In conclusion, LMWH bridging in patients with coronary stents undergoing surgery is a common and possibly harmful practice, resulting in worse ischaemic outcomes at 30 days, and a significant risk of bleeding. PMID- 26017899 TI - Peripheral interleukin-6 promotes resilience versus susceptibility to inescapable electric stress. AB - OBJECTIVE: Accumulating evidences suggest that pro-inflammatory cytokines such as interleukin-6 (IL-6) play a role in the pathophysiology of depression. In the learned helplessness (LH) paradigm, ~35% rats are resilient to inescapable stress. METHODS: Levels of IL-6 in the serum and medial prefrontal cortex (mPFC) of LH rats (susceptible) and non-LH rats (resilience) were measured using enzyme linked immunosorbent assay and western blot analysis, respectively. RESULTS: Serum levels of IL-6 in the LH rats were significantly higher than those of control and non-LH rats. In contrast, tissue levels of IL-6 in the mPFC were not different among three groups. CONCLUSION: The results suggest that peripheral IL 6 may contribute to resilience versus susceptibility to inescapable stress. PMID- 26017900 TI - Impact of vegetable crop agriculture on anopheline agressivity and malaria transmission in urban and less urbanized settings of the South region of Cameroon. AB - BACKGROUND: The use of inland valley swamps for vegetable crop agriculture contributes to food security in urban and less urbanized settings in Africa. The impact of this agriculture on aggressive mosquitoes' diversity and malaria transmission in central Africa is poorly documented. This study is aimed at assessing the impact of vegetable crop agriculture on these entomological parameters in urban and less urbanized settings of the forest area, south of Cameroon. METHODS: The human bait technique was used for the capture of aggressive mosquitoes from January to December 2012. For three consecutive days each month, captures were performed on volunteers in hydro-agricultural and river bank sites of Akonolinga and Yaounde. Physico-chemical characteristics of mosquito breeding sites were recorded. Molecular alongside morpho-taxonomic techniques were used for the identification of mosquito species; ELISA test was used to reveal Plasmodium falciparum infected mosquitoes through the detection of CSP. Mosquito diversity, aggressivity and malaria transmission in sites and settings were determined and compared. RESULTS: Biting rates were higher in hydro agricultural sites of less urbanized and urban settings (31.8 b/p/n and 28.6 b/p/n respectively) than in river banks sites (6.83 b/p/n and 3.64 b/p/n respectively; p < 0.0001). Physico-chemical parameters of breeding sites were not fundamentally different. Five anopheline species were identified; An. gambiae, An. funestus s.s., An. moucheti s.s., An. hancocki and An. nili s.s. In hydro agricultural sites 2 species were captured in the urban setting versus 4 in the less urbanized setting, meanwhile in river bank sites, 3 species were captured in the urban setting versus 4 species in the less urbanized setting. An. nili s.s. was found in river banks only. An. hancocki was not found to insure Plasmodium falciparum Welch transmission. EIR in hydro-agricultural sites varied from 1.86 ib/p/n (urban area) to 2.13 ib/p/n (less urbanized area) with higher rates in April/May and August. Overall, EIR was higher in less urbanized areas (p < 0.0001) but the difference was nullified with the practice of vegetable crop agriculture (p = 0.2). CONCLUSION: These results highlight the need for specific preventive measures that take into account the ecological peculiarities related to vegetable crop agriculture on hydro-agricultural lands, in order to protect inhabitants from malaria. PMID- 26017902 TI - Less known pathophysiological mechanisms of anemia in patients with diabetic nephropathy. AB - Diabetes mellitus (DM) is currently considered a modern global epidemic, and diabetic nephropathy (DN) is the most common cause of chronic kidney disease (CKD). Anemia is one of the most significant complications of CKD, and it is mainly attributed to insufficient erythropoietin (EPO) production. However, anemia develops earlier in the course of CKD among patients with DM, and the severity of anemia tends to be more marked in these patients compared to nondiabetic subjects, regardless of the stage of CKD. In this review, we focus on the "less known" complex interacting mechanisms which are involved in the pathophysiology of anemia associated with DN. Although the major cause of anemia in DN is considered to be an inappropriate response of the plasma EPO concentration to anemia, several other possible mechanisms have been suggested. Glomerular hyperfiltration, proteinuria, renal tubular dysfunction and interstitial fibrosis are among the main culprits. On the other hand, systemic effects such as chronic inflammation, autonomic neuropathy and the renin angiotensin system are also involved. Finally, several medications are considered to aggravate anemia associated with DN. Since anemia is an important predictor of quality of life and is implicated in the increased burden of cardiovascular morbidity and mortality, further research is required to elucidate its pathogenesis in diabetic patients. PMID- 26017903 TI - Functional anatomy of the lacrimal gland in African black ostrich Struthio camelus domesticus in the embryonic and postnatal period. AB - The aim of the present study was morphological and histochemical analysis of the lacrimalgland (LG) in African black ostrich Struthio camelus domesticus in the embryonic and postnatalperiod. Studies were conducted on 50 ostriches aged between the 28th day of incubation until7 months old. Tissue sections were stained with haematoxylin and eosin, Azan trichrome,periodic acid-Schiff, Alcian blue pH 2.5, aldehyde fuchsin and Hale's dialysed iron. The LGin ostrich was classified as a tubulo-acinar type. The primordia of the lobes were determinedin the LG structure on the 28th day of incubation, whilst the weakly visible lobes with aciniand tubules were observed on the 40th day of incubation. Morphometric studies of the LGshowed steady growth, characterised by an increase in both length and width. Histometricmeasurements of lobe size showed little difference between the first, second and third agegroups, whilst in the fourth age group a marked increase in size of lobes was observed.The study showed that, apart from morphological changes, during the growth of the LGthe character of acid mucopolysaccharides changed. Sulphated acid mucopolysaccharideswere indicated, particularly with aldehyde fuchsin (AF) staining in the fourth age group.The Hale's dialysed iron (HDI) staining showed a low concentration of carboxylated acidmucopolysaccharides in the first and second age groups and a higher concentration in thethird and fourth age groups. Periodic acid-Schiff staining (PAS)-positive cells were observedin each age group, but only a small number of cells with a weakly PAS-positive reaction weredemonstrated in the first age group. PMID- 26017904 TI - Understanding the Association of Fatigue With Other Symptoms of Fibromyalgia: Development of a Cluster Model. AB - OBJECTIVE: To develop a symptoms cluster model that can describe factors of fibromyalgia syndrome (FMS) associated with fatigue severity as reported by the sample and to explore FMS clinical symptom subclusters based on varying symptom intensities. METHODS: FMS individuals (n = 120, 82% ages 31-60 years, 90% women, 59% white) diagnosed with the 1990 or 2010 American College of Rheumatology diagnostic criteria were enrolled. Participants completed multiple validated self report questionnaires to measure fatigue, pain, depression, anxiety, pain catastrophizing, daytime sleepiness, cognitive function, and FMS-related polysymptomatic distress. Cluster analysis using SPSS 19.0 and structural equation modeling using AMOS 17.0 were used. RESULTS: Final structural equation modeling the symptoms cluster model showed good fit and revealed that FMS fatigue was associated with widespread pain, symptoms severity, pain intensity, pain interference, cognitive dysfunction, catastrophizing, anxiety, and depression (chi(2) = 121.72 (98df), P > 0.05, chi(2) /df = 1.242, comparative fit index = 0.982, root mean square error of approximation = 0.045). Two distinct clinical symptom subclusters emerged: subcluster 1 (78% of total subjects), defined by widespread pain, unrefreshed waking, and somatic symptoms, and subcluster 2 (22% of total subjects), defined by fatigue and cognitive dysfunction with pain being a less severe and less widespread occurrence. CONCLUSION: Overall, subcluster 1 had more intense symptoms than subcluster 2. FMS symptoms may be categorized into 2 clinical subclusters. These findings have implications for an illness whose diagnosis and management are symptom dependent. A longitudinal study capturing the variability in the symptom experience of FMS subjects is warranted. PMID- 26017905 TI - Evaluation of the effect of a laparoscopic robotized needle holder on ergonomics and skills. AB - BACKGROUND: Laparoscopy generates technical and ergonomics difficulties due to limited degrees of freedom (DOF) of forceps. To reduce this limitation, a new 5 mm robotized needle holder with two intracorporeal DOF, Jaimy((r)), has been developed. The aim of this study was to evaluate its effects on ergonomics and skills. METHODS: Fourteen surgeons including eight senior and six residents were crossover randomized and stratified based on experience. Three suturing tasks were performed with both Jaimy((r)) and a classic needle holder (NH): task 1: Peg Board; task 2: hexagonal suture; task 3: frontal suture. Postural ergonomics of the dominant arm were evaluated with an ergonomics score (RULA score) thanks to motion capture, and muscular ergonomics with electromyography of six muscular groups (flexor and extensor carpis, biceps, triceps, deltoid, trapeze). Performance outcomes are a quantitative and qualitative score, and skills outcomes are the measurement of the number of movements and the path length travelled by the instrument. RESULTS: The RULA score showed a statistically improved posture with Jaimy((r)) (p < 0.001). The cumulative muscular workload (CMW) of four muscles was not different. However, the CMW was in favor of the NH for the flexor carpi ulnaris (p < 0.001) and the triceps (p = 0.027). The number of movements was not different (p = 0.39) although the path length was shorter with Jaimy((r)) (p = 0.012). The score for task 1 was in favor of the NH (p = 0.006) with a higher quantity score. Task 2 score was not different (p = 0.086): The quality part of the score was in favor of Jaimy((r)) (p = 0.009) and the quantity part was higher with the NH (p = 0.04). The score for task 3 was higher with Jaimy((r)) (p = 0.001). CONCLUSION: This study suggests that the use of a robotized needle holder improves both posture and the quality of laparoscopic sutures. PMID- 26017906 TI - In vitro assessment of the performance of a new multiband mucosectomy device for endoscopic resection of early upper gastrointestinal neoplasia. AB - BACKGROUND AND STUDY AIMS: Multiband mucosectomy (MBM) is widely used for the endoscopic resection of early neoplasia in the upper gastrointestinal tract. A new MBM-device may have advantages over the current MBM-device with improved visualization, easier passage of accessories, and higher suction power due to different trip wire and cap. METHODS: Rubber bands were released one by one for both MBM-devices while endoscopic images were collected. First, free endoscopic view was assessed by computer-assisted measurements (quantitative) and by ranking the images by a panel of 11 endoscopists (qualitative). Second, using a visual analog scale, three 'blinded' endoscopists assessed introduction and advancement of three types of endoscopic devices through the working channel of a diagnostic endoscope with the MBM-devices assembled. Third, suction power was evaluated by a manometer attached to the cap of the assembled MBM-devices in four endoscopes. Negative pressures were measured after 5 and 10 s of suction and repeated five times. The passage and suction experiments were performed with dry trip wires and repeated after soaking with bloody, mucous fluids. RESULTS: With all bands present, endoscopic views were 90 and 40% in the new and current MBM-device, respectively. With the release of more bands, differences slowly disappeared. The panel scored a better endoscopic view in the new MBM-device (p = 0.03). Passage of all accessories was considered significantly easier in the new MBM-device. With the associated snare in the working channel, suction power was significantly better with the new MBM-device. CONCLUSION: Compared to the currently available MBM-device, the new MBM-device provides improved endoscopic visibility, smoother passage of accessories, and higher suction power. PMID- 26017907 TI - Design of wormlike automated robotic endoscope: dynamic interaction between endoscopic balloon and surrounding tissues. AB - BACKGROUND: The current design of capsule endoscope is limited by the inability to control the motion within gastrointestinal tract. The rising incidence of gastrointestinal cancers urged improvement in the method of screening endoscopy. OBJECTIVES: This preclinical study aimed to design and develop a novel locomotive module for capsule endoscope. We investigated the feasibility and physical properties of this newly designed caterpillar-like capsule endoscope with a view to enhancing screening endoscopy. DESIGN: This study consisted of preclinical design and experimental testing on the feasibility of automated locomotion for a prototype caterpillar endoscope. The movement was examined first in the PVC tube and then in porcine intestine. The image captured was transmitted to handheld device to confirm the control of movement. The balloon pressure and volume as well as the contact force between the balloon and surroundings were measured when the balloon was inflated inside (1) a hard PVC tube, (2) a soft PVC tube, (3) muscular sites of porcine colons and (4) less muscular sites of porcine colons. RESULTS: The prototype caterpillar endoscope was able to move inward and backward within the PVC tubing and porcine intestine. Images were able to be captured from the capsule endoscope attached and being observed with a handheld device. Using the onset of a contact force as indication of the buildup of the gripping force between the balloon and the lumen walls, it is concluded from the results of this study that the rate of change in balloon pressure and volume is two good estimators to optimize the inflation of the balloon. CONCLUSION: The results of this study will facilitate further refinement in the design of caterpillar robotic endoscope to move inside the GI tract. PMID- 26017908 TI - Prediction of excess weight loss after laparoscopic Roux-en-Y gastric bypass: data from an artificial neural network. AB - INTRODUCTION: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has become the gold standard for surgical weight loss. The success of LRYGB may be measured by excess body mass index loss (%EBMIL) over 25 kg/m(2), which is partially determined by multiple patient factors. In this study, artificial neural network (ANN) modeling was used to derive a reasonable estimate of expected postoperative weight loss using only known preoperative patient variables. Additionally, ANN modeling allowed for the discriminant prediction of achievement of benchmark 50% EBMIL at 1 year postoperatively. METHODS: Six hundred and forty-seven LRYGB included patients were retrospectively reviewed for preoperative factors independently associated with EBMIL at 180 and 365 days postoperatively (EBMIL180 and EBMIL365, respectively). Previously validated factors were selectively analyzed, including age; race; gender; preoperative BMI (BMI0); hemoglobin; and diagnoses of hypertension (HTN), diabetes mellitus (DM), and depression or anxiety disorder. Variables significant upon multivariate analysis (P < .05) were modeled by "traditional" multiple linear regression and an ANN, to predict %EBMIL180 and %EBMIL365. RESULTS: The mean EBMIL180 and EBMIL365 were 56.4 +/- 16.5 % and 73.5 +/- 21.5%, corresponding to total body weight losses of 25.7 +/- 5.9% and 33.6 +/ 8.0%, respectively. Upon multivariate analysis, independent factors associated with EBMIL180 included black race (B = -6.3%, P < .001), BMI0 (B = -1.1%/unit BMI, P < .001), and DM (B = -3.2%, P < .004). For EBMIL365, independently associated factors were female gender (B = 6.4%, P < .001), black race (B = 6.7%, P < .001), BMI0 (B = -1.2%/unit BMI, P < .001), HTN (B = -3.7%, P = .03), and DM (B = -6.0%, P < .001). Pearson r(2) values for the multiple linear regression and ANN models were 0.38 (EBMIL180) and 0.35 (EBMIL365), and 0.42 (EBMIL180) and 0.38 (EBMIL365), respectively. ANN prediction of benchmark 50% EBMIL at 365 days generated an area under the curve of 0.78 +/- 0.03 in the training set (n = 518) and 0.83 +/- 0.04 (n = 129) in the validation set. CONCLUSIONS: Available at https://redcap.vanderbilt.edu/surveys/?s=3HCR43AKXR, this or other ANN models may be used to provide an optimized estimate of postoperative EBMIL following LRYGB. PMID- 26017909 TI - Transtracheal thoracic natural orifice transluminal endoscopic surgery (NOTES) in a swine model. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) has the potential to be the final frontier in minimally invasive procedures in thoracic surgery. In order for thoracic pleural NOTES to 1 day be ready for clinical trials, each step of the procedure must be independently evaluated for both safety and efficacy. The aim of this study was to evaluate the trachea as a portal of entry for thoracic NOTES. METHODS: Eight 40-kg swine underwent right thoracic pleuroscopy in a survival model. In order to avoid inadvertent injury to the superior vena cava, endobronchial ultrasound was employed to select the location of airway incision. A 7-mm linear incision was then performed at the chosen location using an endoscopic electrocautery needle knife through a therapeutic flexible videobronchoscope. The mediastinal fat and parietal pleura were then dissected with electrocautery, and complete right pleuroscopy was performed. The tracheal and mediastinal portal of entry were then sealed with 1-2 cc of fibrin sealant. The pigs were kept alive for 21 days postoperatively. Postmortem diagnostic bronchoscopy was performed to assess tracheal healing. All tracheal specimens underwent histologic examination for healing and signs of mediastinal infection. RESULTS: Thoracic NOTES procedures on all eight pigs were successful. There were no intraoperative complications except for one minor bleeding episode within the mediastinal dissection site which stopped spontaneously. Two pigs died from severe laryngospasm in the early postoperative period. Six pigs survived for 21 days post-procedure and experienced uneventful postoperative courses. Postmortem examination demonstrated complete tracheal healing with appropriate scarring in all pigs. CONCLUSIONS: The trachea appears to be a safe port of entry for thoracic NOTES procedures in a swine model. Smaller tracheal incisions followed by balloon dilatation are associated with less postoperative morbidity and mortality. Tracheal incisions sealed with fibrin sealant healed rapidly and without signs of mediastinal infection. This procedure represents a work in progress and is not yet ready for human trials. PMID- 26017910 TI - General surgery training and robotics: Are residents improving their skills? AB - BACKGROUND: While robotic-assisted operations have become more prevalent, many general surgery residencies do not have a formal robotic training curriculum. We sought to ascertain how well current general surgery training permits acquisition of robotic skills by comparing robotic simulation performance across various training levels. STUDY DESIGN: Thirty-six participants were categorized by level of surgical training: eight medical students (MS), ten junior residents (JR), ten mid-level residents (MLR), and eight senior residents (SR). Participants performed three simulation tasks on the da Vinci ((r)) Skills Simulator (MatchBoard, EnergyDissection, SutureSponge). Each task's scores (0-100) and cumulative scores (0-300) were compared between groups. RESULTS: There were no differences in sex, hand dominance, video gaming history, or prior robotic experience between groups; however, SR was the oldest (p < 0.001). The median overall scores did not differ: 188 (84-201) for MS, 183 (91-234) for JR, 197 (153 218) for MLR, and 205 (169-229) for SR (p = 0.14). The median SutureSponge score was highest for SR (61, range 39-81) compared to MS (43, range 26-61), JR (43, range 11-72), and MLR (55, range 36-68) (p = 0.039). However, there were no significant differences in MatchBoard (p = 0.27) or EnergyDissection (p = 0.99) scores between groups. There was a positive correlation between SutureSponge score and number of laparoscopic cases logged (p = 0.005, r(2) = 0.21), but this correlation did not exist for the MatchBoard or EnergyDissection tasks. Lastly, there was no correlation between total lifetime hours of video gaming and overall score (p = 0.89, R(2) = 0.0006). CONCLUSIONS: Robotic skillsets acquired during general surgery residency show minimal improvement during the course of training, although laparoscopic experience is correlated with advanced robotic task performance. Changes in residency curricula or pursuit of fellowship training may be warranted for surgeons seeking proficiency. PMID- 26017911 TI - New models for advanced laparoscopic suturing: taking it to the next level. AB - BACKGROUND: Current simulations for laparoscopic suturing do not reflect the complexity of the skills required in the operating room. The purpose of this study was to develop three novel advanced suturing tasks with assessment metrics and to collect validity evidence for their measures of suturing skill. METHODS: We developed three tasks based on training gaps identified through a previous needs assessment: needle handling (NH), suturing under tension (UT), and continuous suturing (CS). Minimally invasive surgeons (MIS) and senior surgical residents (SR) completed these tasks and a questionnaire regarding their educational value. Performance was assessed by two raters based on time and accuracy. Validity was assessed by comparing performance according to the level of training and self-reported experience. The inter-rater reliability and internal consistency of the tasks were calculated. RESULTS: Thirty-one subjects (13 MIS, 18 SR) were enrolled in the study (median age 32; 77% male). Compared to the SR group, the MIS group had significantly greater scores on all tasks. While all MIS surgeons completed the three tasks within the allotted time, six (33%) residents could not complete at least one out of the three tasks. Laparoscopic suturing experience correlated positively with the scores of all tasks (NH 0.51, UT 0.70, CS 0.65. p < 0.01). Inter-rater reliability for all tasks was 0.99, and internal consistency was 0.80. The majority of participants agreed that the tasks were relevant to practice, helped improve technical competence, and adequately measured suturing ability. CONCLUSIONS: This study provides validity evidence for three novel advanced laparoscopic suturing tasks. Performance on all tasks correlated significantly with training level and self-reported experience. Integrating these tasks into educational curricula may help improve residents' suturing skills and better prepare residents for the operating room. PMID- 26017912 TI - Surgeons have knowledge gaps in the safe use of energy devices: a multicenter cross-sectional study. AB - BACKGROUND: Despite the widespread use of surgical energy devices and the potential for rare but serious complications, pilot data from North America suggest that surgeons and surgical trainees have knowledge gaps in their safe use. The purpose of this study was to determine baseline knowledge of general surgeons and surgical trainees regarding the safe use of electrosurgery (ES) across varying levels of experience in Japan. METHODS: Participants completed a 35-item multiple-choice question examination, testing critical knowledge of ES. The examination was developed according to the objectives and blueprints of SAGES' Fundamental Use of Surgical EnergyTM curriculum. Sections of the examination included: "principles of ES," "ES-related adverse events," "monopolar and bipolar devices," and "pediatric considerations and interference with implantable devices." Scores were compared between PGY > 5 and PGY 1-5 participants. RESULTS: A total of 145 general surgeons and surgical trainees of all years after medical school (PGY 1-5: 57, PGY > 5: 88) from ten academic and five community hospitals completed the assessment (mean age 35; 91% male). The mean score in the entire cohort was 58 +/- 12% (range 23-83%), with significantly higher scores in the PGY > 5 group compared to the PGY 1-5 group (60 +/- 11 vs. 53 +/- 12%, p < 0.01). Among all participants, 92% were not familiar with best practices when using ES on patients with a pacemaker; 44% believe that ES uses thermal energy from cautery; 19% did not know how to manage an operating room fire; 16% thought that a dispersive electrode should be cut to fit a child; and 27% believe that insulation failure in minimally invasive surgical instruments is mostly visible under careful inspection. CONCLUSIONS: General surgeons and trainees at all levels have knowledge gaps in the safe and effective use of energy devices, regardless of years of experience. There is a need for educational curricula to help address these gaps and contribute to safer surgery. PMID- 26017913 TI - Endoscopic placement of self-expandable metallic stents for rectovaginal fistula after colorectal resection: a comparison with proximal diverting ileostomy alone. AB - BACKGROUND: Self-expandable metal stents can be used to treat patients with rectovaginal fistula after colorectal resection for cancer. METHODS: Fifteen patients with rectovaginal fistula, after colorectal resection for cancer, were treated with endoscopic placement of a self-expandable metal stent. In four patients, a diverting proximal stoma had been performed elsewhere. Mean age was 58 years. All patients had preoperative radiotherapy. In ten patients, the stent was placed as initial form of treatment. Four patients were referred after multiple failed operations. The control group consisted of ten patients who had rectovaginal fistula and underwent proximal diverting ileostomy and percutaneous drainage of the surrounding abscess RESULTS: One patient was not able to tolerate the stent, which was removed. At a mean follow-up of 22 months, the rectovaginal fistula healed in 12 patients. In the remaining two patients, the fistula has reduced significantly in size to allow a successful flap transposition. The fistula healed only in five out of the ten patients who had only a proximal ileostomy. CONCLUSIONS: Endoscopic placement of self-expandable metal stents represents a valid adjunctive to treat patients with rectovaginal fistula, after colorectal resection for cancer. PMID- 26017915 TI - Conformational analysis: 3JHCOC and 3JHCCC Karplus relationships for methylene 1H nuclei. AB - NAMFIS (NMR Analysis of Molecular Flexibility In Solution) was applied to 1-[2 (benzyloxy)phenyl]ethanone using quantitative (1)H-(1)H NOE distances and (3)J proton-carbon coupling constant (CC) restraints for averaged methylene proton (3)J(HCOC) and (3)J(HCCC) pathways H2-(3)J-X imposed by density functional theory generated Karplus relationships. Comparison of the NOE-only versus the NOE + CC conformational selections illustrates that the experimentally measured average (3)J coupling constants of methylene protons can be used for solution conformational analysis, potentially valuable in the study of small-molecule drugs and natural products which lack the typically studied H1-(3)J-X Karplus relationships. PMID- 26017914 TI - Risk factors for prolonged ileus following colon surgery. AB - BACKGROUND: Prolonged ileus is one of the most common postoperative complications after colorectal surgery. We sought to investigate the predictors of prolonged ileus following elective colon resections procedures. METHODS: The national participant user files of NSQIP databases were utilized to examine the clinical outcomes of patients undergoing elective colon resection during 2012-2013. Multivariate regression analysis was performed to investigate predictors of prolonged ileus. Prolonged ileus was defined as no return of bowel function in 7 days. RESULTS: We sampled a total of 27,560 patients who underwent colon resections; of these, 3497 (12.7%) patients had prolonged ileus. Patients with ileocolonic anastomosis (ICA) had a significantly higher rate of prolonged ileus compared to patients with colorectal anastomosis (CRA) (15 vs. 11.5%, AOR 1.25, P < 0.01). Prolonged ileus was significantly associated with intra-abdominal infections (13 vs. 2.8%, AOR 2.56, P < 0.01) and anastomotic leakage (12 vs. 2.4%, AOR 2.50, P < 0.01). Factors such as preoperative sepsis (AOR 1.63, P < 0.01), disseminated cancer (AOR 1.24, P = 0.01), and chronic obstructive pulmonary disease (AOR 1.27, P = 0.02) were associated with an increased risk of prolonged ileus, whereas oral antibiotic bowel preparation (AOR 0.77, P < 0.01) and laparoscopic surgery (AOR 0.51, P < 0.01) are associated with decreased prolonged ileus risk. CONCLUSIONS: Prolonged ileus is a common condition following colon resection, with an incidence of 12.7%. Among colon surgeries, colectomy with ICA resulted in the highest rate of postoperative prolonged ileus. Prolonged ileus is positively associated with anastomotic leak and intra abdominal infections; thus, a high index of suspicion must be had in all patients with prolonged postoperative ileus. PMID- 26017917 TI - Treatment of very large cranial defects with individually shaped polypropylene polyester knitwear prostheses - series of 11 cases. AB - Very large cranial defects are not very common in neurosurgical practice and there is not any widely acknowledged standard of their treatment. One of the useful methods in such cases is individual forming of polypropylene - polyester knitwear. Such material was used in the past but before 2008 it was available only as standardized plates. Currently, it can be also produced as individually shaped implants. The authors give their definition of very large cranial defects and present their experience with this cranioplastic method in such defects. The authors collected data on 11 cases of patients with very large cranial defects, from a total of 156 cases, operated on in 5 Polish neurosurgical departments. The necessary implants were prepared for individual patients according to the data provided by a computed tomography examination and with the use of computer aided machining. All defects were larger than 120 sqcm (129 to 178 sqcm) and exceeded 1/4 of the calvaria area. Patients were operated between 2008 to 2012. In all patients, a very good aesthetic result and correct skull reconstruction was achieved. The follow up time in all cases exceeded 1 year and reached 4 years in 1 case. No complications were noted. The advantages and limitations of this method of cranioplasty are discussed below. Individually pre-shaped polypropylene - polyester knitwear prostheses are a good alternative to existing cranioplasty methods, particularly in very large cranial defects. PMID- 26017916 TI - One-Step Reverse-Transcription FRET-PCR for Differential Detection of Five Ebolavirus Species. AB - Ebola is an emerging infectious disease caused by a deadly virus belonging to the family Filoviridae, genus Ebolavirus. Based on their geographical distribution, Ebolavirus has been classified into total five species so far, mainly Zaire, Sudan, Tai Forest, Bundibugyo and Reston. It is important to be able to differentiate the Ebolavirus species as they significantly differ in pathogenicity and more than one species can be present in an area. We have developed a one-step step-down RT-PCR detecting all five Ebolavirus species with high sensitivity (1 copy of Ebolavirus DNA, 10 copies of RNA and 320 copies of RNA spiked in 1 ml whole blood). The primers and FRET-probes we designed enabled us to differentiate five Ebolavirus species by distinct Tm (Zaire: flat peaks between 53.0 degrees C and 56.9 degrees C; Sudan: 51.6 degrees C; Reston: flat peaks between 47.5 degrees C and 54.9 degrees C; Tai Forest: 52.8 degrees C; Bundibugyo: dual peaks at 48.9 degrees C and 53.5 degrees C), and by different amplicon sizes (Zaire 255 bp, Sudan 211 bp, Reston 192 bp, Tai Forest 166 bp, Bundibugyo 146 bp). This one-size-fit-all assay enables the rapid detection and discrimination of the five Ebolavirus species in a single reaction. PMID- 26017918 TI - Comparison of the Victorian Audit of Surgical Mortality with coronial cause of death. AB - BACKGROUND: The Victorian Audit of Surgical Mortality (VASM) is designed to improve the level of patient care by educating surgeons of areas for improvement in patient management during a surgical admission. Coronial data obtained via the National Coronial Information System were used as an independent method to validate the cause of death as determined by the treating surgeon. METHOD: The audit prospectively collected 4905 cases that underwent peer assessment and 842 (17%) received an in-depth second-line assessment of which 200 (24%) also underwent a coronial review. Using the coronial assessment as the reference standard, retrospective comparison of coronial diagnoses compared with the audit case outcomes was conducted to determine the overall accuracy of the stated cause of death. The degree of agreement was also analysed based on whether the patient received a full autopsy (internal examination) or an external examination only. The time taken to obtain the coronial and audit case closure was also analysed. RESULTS: Overall, 195 of the 200 cases had a cause of death identified by the coroner. In 82%, the cause of death reported to VASM by the treating surgeon matched the cause of death determined by the coroner. Concordance was not affected by the extent of post-mortem performed. Time taken to finalize cases was slightly shorter for the coronial process, but unclosed coronial findings resulted in the exclusion of 103 cases. CONCLUSION: The causes of death data in VASM are accurate when compared with the coronial data independent of whether the coronial investigation included a complete autopsy. PMID- 26017919 TI - Magnetic Resonance Imaging and Pathologic Findings of 26 Cases With Uterine Adenomatoid Tumors. AB - OBJECTIVE: To analyze the magnetic resonance imaging (MRI) features and pathologic findings of uterine adenomatoid tumors (ATs) for improved diagnostic accuracy and facilitating differential diagnosis of the tumors. METHODS: We investigated retrospectively 26 patients with uterine ATs confirmed by pathology. Before operation, all patients accepted multiple MRI scans, including T1-weighted image (T1WI), T2-weighted image (T2WI), T2WI/spectrally adiabatic inversion recovery, and T1-weighted enhanced imaging. Two radiologists reviewed all the MRI sequences on PACS workstations for all patients to evaluate the location, shape, size, margin, intensity, and enhancement of ATs. RESULTS: All uterine ATs exhibited either single round solid (n = 24) or predominantly cystic (n = 2) masses with either well-defined (n = 23) or ill-defined margin (n = 3). The diameter range of the tumors was 1.0 to 7.0 cm (mean, 3.8 cm). Solid masses were isointensive on T1WI and hypointensive on T2WI with moderate enhancement. The degree of enhancement in solid tumors was either lower than (18/24 [75%]) or equal to (6/24 [25%]) that of the myometrium. Predominantly cystic masses presented as cystic lesions with a little irregular solid nodule inside. The cystic parts were hypointensive on T1WI and hyperintensive on T2WI without enhancement, whereas the solid nodules were isointensive on both T1WI and T2WI with moderate enhancement. A large part of the uterine ATs (69.2% [18/26]) coexisted with other uterine diseases. On pathology, uterine ATs were characterized as gland-like structures with irregular expansion of tubular cavities, which might be correlated with low enhancement of tumors. The tumors were lined with flat or cuboidal mesothelial cells and residue of smooth muscle component, which might contribute to their hypointensive appearance on T2WI. CONCLUSIONS: Small solid uterine masses with homogeneous hypointensity on T2WI and lower enhancement or cystic lesions with inner irregular solid nodule may indicate the diagnosis of uterine ATs, and final diagnosis can be determined with pathology. PMID- 26017920 TI - Apparent Diffusion Coefficient Value Is Not Dependent on Magnetic Resonance Systems and Field Strength Under Fixed Imaging Parameters in Brain. AB - OBJECTIVE: The aim of the study was to investigate the causes of apparent diffusion coefficient (ADC) measurement errors and to determine the optimal scanning parameters that are independent of the field strength and vendors of the magnetic resonance (MR) system. MATERIALS AND METHODS: Brain MR images of 10 healthy volunteers were scanned using 6 MR scanners of different field strengths and vendors in 2 different institutions. Ethical review board approvals were obtained for this study, and all volunteers gave their informed consents. Coefficient of variation (CV) of ADC values were compared for their differences in various MR scanners and in the scanned subjects. RESULTS: The CV of ADC values for 6 different scanners of 6 brains was 3.32%. The CV for repeated measurements in 1 day (10 scans per day) and in 10 days (scan per day for 10 days) for 1 subject was 1.72% and 2.96%, respectively (n = 5, P < 0.001). The CV of measurements for 10 healthy subjects was 5.22%. The measurement errors of the ADC values for 6 different MR units in 1 subject were higher than the intrascanner variance for the same subject but were lower than the intersubject variance for the same scanner. CONCLUSIONS: The variance in the ADC values for different MR scanners is reasonably small if appropriate scanning parameters (repetition time, >3000 ms; echo time, minimum; and high enough signal-to-noise ratio of high-b diffusion-weighted image) are used. PMID- 26017921 TI - Plasmacytoma of Liver Mimicking Hepatocellular Carcinoma at Multiphasic Computed Tomography Evaluation. AB - Plasmacytoma of liver is a rare hepatic tumor more often seen at autopsy than described in the literature; it is also more likely diagnosed in the setting of multiple myeloma than as isolated extramedullary plasmacytoma. However, when found in the setting of multiple myeloma, it is associated with worse clinical outcome. The authors describe a case of an elderly man presenting with nonspecific chronic abdominal pain and a new 4-cm hepatic mass. At multiphasic computed tomography, the mass demonstrated an enhancement pattern identical to that expected of hepatocellular carcinoma; however, thorough history failed to uncover necessary risk factors for hepatic cirrhosis. Ultrasound-guided core biopsy of the mass, as well as additional clinical and radiologic assessment, subsequently confirmed a diagnosis of multiple myeloma. PMID- 26017922 TI - Mantle margin morphogenesis in Nodipecten nodosus (Mollusca: Bivalvia): new insights into the development and the roles of bivalve pallial folds. AB - BACKGROUND: Despite extensive knowledge on bivalve anatomy and development, the formation and differentiation of the mantle margin and its associated organs remain largely unclear. Bivalves from the family Pectinidae (scallops) are particularly promising to cast some light on these issues, because they exhibit a complex mantle margin and their developmental stages are easily obtained from scallop farms. We investigated the mantle margin of the scallop Nodipecten nodosus (L. 1758) during larval and postmetamorphic development. METHODS: A thorough analysis of the mantle margin development in Nodipecten nodosus, from veliger larvae to mature adults, was conducted by means of integrative microscopy techniques, i.e., light, electron, and confocal microscopy. RESULTS: Initially unfolded, the pallial margin is divided into distal and proximal regions by the periostracum-forming zone. The emergence of the pallial musculature and its neural innervation are crucial steps during bivalve larval development. By the late pediveliger stage, the margin becomes folded, resulting in a bilobed condition (i.e., outer and inner folds), a periostracal groove, and the development of different types of cilia. After metamorphosis, a second outgrowth process is responsible for emergence of the middle mantle fold from the outer surface of the inner fold. Once the three-folded condition is established, the general adult features are rapidly formed. CONCLUSIONS: Our data show that the middle mantle fold forms from the outer surface of the inner fold after metamorphosis and that the initial unfolded mantle margin may represent a common condition among bivalves. The first outgrowth process, which gives rise to the outer and inner folds, and the emergence of the pallial musculature and innervation occur during larval stages, highlighting the importance of the larval period for mantle margin morphogenesis in Bivalvia. PMID- 26017923 TI - Sino-Nasal Outcome Test-22: translation, cultural adaptation and validation in Portugal. AB - OBJECTIVES: Sino-Nasal Outcome Test-22 is a questionnaire that evaluates the specific quality of life in chronic rhinosinusitis and was widely used in scientific literature. The aim of our study was to translate and culturally adapt Sino-Nasal Outcome Test-22 for the Portuguese reality and validate the version obtained for use in Portugal. DESIGN: We translate Sino-Nasal Outcome Test-22 into European Portuguese according to the methodology recommended by the scientific literature. After translation, we proceeded with the evaluation of the questionnaire regarding its feasibility, reliability (internal consistency and test-retest reproducibility) and discriminant validity. Statistical analysis was performed using spss 22.0. SETTING: Patients treated at a single institute. PARTICIPANTS: We applied Sino-Nasal Outcome Test-22 questionnaire to 15 volunteers with no nasal or sinus disease and to 50 patients with chronic rhinosinusitis. MAIN OUTCOME MEASURES: Feasibility, reliability (internal consistency and test-retest reproducibility) and discriminant validity. RESULTS: We observed good internal consistency, with general Cronbach's alpha coefficient of 0.935, good test-retest reproducibility (32.5 versus 32, P < 0.001), with Pearson coefficient of 0.99 (P < 0.001) and Cohen Kappa coefficient of 0.898. The discriminant validity of the Portuguese version of Sino-Nasal Outcome Test-22 was confirmed by applying the Mann-Whitney U-test (P < 0.001). CONCLUSIONS: Until now, there were no validated questionnaires to evaluate quality of life in patients with chronic rhinosinusitis in Portugal. Translation and validation of Sino-Nasal Outcome Test-22 in Portugal will allow a more consistent assessment of the specific quality of life of these patients and the comparison with international data. Thus, we recommend this version for use with the Portuguese population with chronic rhinosinusitis. PMID- 26017924 TI - Direct identification of on-bead peptides using surface-enhanced Raman spectroscopic barcoding system for high-throughput bioanalysis. AB - Recently, preparation and screening of compound libraries remain one of the most challenging tasks in drug discovery, biomarker detection, and biomolecular profiling processes. So far, several distinct encoding/decoding methods such as chemical encoding, graphical encoding, and optical encoding have been reported to identify those libraries. In this paper, a simple and efficient surface-enhanced Raman spectroscopic (SERS) barcoding method using highly sensitive SERS nanoparticles (SERS ID) is presented. The 44 kinds of SERS IDs were able to generate simple codes and could possibly generate more than one million kinds of codes by incorporating combinations of different SERS IDs. The barcoding method exhibited high stability and reliability under bioassay conditions. The SERS ID encoding based screening platform can identify the peptide ligand on the bead and also quantify its binding affinity for specific protein. We believe that our SERS barcoding technology is a promising method in the screening of one-bead-one compound (OBOC) libraries for drug discovery. PMID- 26017925 TI - Smoking-Associated DNA Methylation Biomarkers and Their Predictive Value for All Cause and Cardiovascular Mortality. AB - BACKGROUND: With epigenome-wide mapping of DNA methylation, a number of novel smoking-associated loci have been identified. OBJECTIVES: We aimed to assess dose response relationships of methylation at the top hits from the epigenome-wide methylation studies with smoking exposure as well as with total and cause specific mortality. METHODS: In a population-based prospective cohort study in Germany, methylation was quantified in baseline blood DNA of 1,000 older adults by the Illumina 450K assay. Deaths were recorded during a median follow-up of 10.3 years. Dose-response relationships of smoking exposure with methylation at nine CpGs were modeled by restricted cubic spline regression. Associations of individual and aggregate methylation patterns with all-cause, cardiovascular, and cancer mortality were assessed by multiple Cox regression. RESULTS: Clear dose response relationships with respect to current and lifetime smoking intensity were consistently observed for methylation at six of the nine CpGs. Seven of the nine CpGs were also associated with mortality outcomes to various extents. A methylation score based on the top two CpGs (cg05575921 and cg06126421) showed the strongest associations with all-cause, cardiovascular, and cancer mortality, with adjusted hazard ratios (95% CI) of 3.59 (2.10, 6.16), 7.41 (2.81, 19.54), and 2.48 (1.01, 6.08), respectively, for participants with methylation levels in the lowest quartile at both CpGs. Adding methylation at those two CpGs into a model that included the variables of the Systematic Coronary Risk Evaluation chart for fatal cardiovascular risk prediction improved the predictive discrimination. CONCLUSION: The novel methylation biomarkers are highly informative for both smoking exposure and smoking-related mortality outcomes. In particular, these biomarkers may substantially improve cardiovascular risk prediction. Nevertheless, the findings of the present study need to be further validated in additional large longitudinal studies. CITATION: Zhang Y, Schottker B, Florath I, Stock C, Butterbach K, Holleczek B, Mons U, Brenner H. 2016. Smoking-associated DNA methylation biomarkers and their predictive value for all cause and cardiovascular mortality. Environ Health Perspect 124:67-74; http://dx.doi.org/10.1289/ehp.1409020. PMID- 26017926 TI - Efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin and S-1 for resectable locally advanced gastric cancer. AB - BACKGROUND: The prognosis for locally advanced gastric cancer (AGC) remains unsatisfactory, even with S-1 adjuvant chemotherapy. We investigated the efficacy of neoadjuvant chemotherapy consisting of docetaxel, cisplatin and S-1 (DCS). METHODS: We retrospectively reviewed 59 patients who underwent neoadjuvant DCS therapy for clinical stage III tumors or serosa-positive tumors between January 2009 and December 2013 at Niigata Cancer Center Hospital. The patients received S 1 (40 mg/m(2) bid) on days 1-14, and docetaxel (35 mg/m(2)) and cisplatin (35 mg/m(2)) on days 1 and 15 every 4 weeks. RESULTS: Forty-three patients (72.9 %) received two courses of DCS therapy, while 16 patients (27.1 %) received one course of treatment. The clinical response rate of the primary tumor was 74.6 %, and the disease control rate was 100 %. A pathological response, defined as one third or more of the affected tumor, was observed in 71.2 % of patients. The common grade 3/4 adverse events from chemotherapy were leucopenia (16.9 %), neutropenia (44.1 %), febrile neutropenia (8.5 %), anemia (10.2 %), anorexia (8.5 %) and nausea (6.8 %). Postoperative complications occurred in 11 patients (18.6 %). There was no treatment-related mortality or reoperation. The 3- and 5-year overall survival rates were 88 and 68.6 %, respectively. Clinical responders had a significantly higher survival rate than non-responders. Multivariate analysis identified clinical response as the only independent prognostic factor. CONCLUSIONS: Neoadjuvant DCS therapy demonstrated a very high clinical and pathological response rate with acceptable toxicities. Therefore, this therapy may improve the prognosis of locally AGC. PMID- 26017927 TI - Melatonin Suppression by Light in Humans Is More Sensitive Than Previously Reported. AB - The retina drives various non-image-forming photoresponses, including circadian photoentrainment and pupil constriction. Previous investigators showed that in humans, photic suppression of the clock-controlled hormone melatonin is most sensitive to 460-nm blue light, with a threshold of ~12 log photons cm(-2) s(-1). This threshold is surprising because non-image-forming vision is mediated by intrinsically photosensitive retinal ganglion cells, which receive rod-driven synaptic input and can respond to light levels as low as ~7 log photons cm(-2) s( 1). Using a protocol that enhances data precision, we have found the threshold for human melatonin suppression to be ~10 log photons cm(-2) s(-1) at 460 nm. This finding has far-reaching implications since there is mounting evidence that nocturnal activation of the circadian system can be harmful. PMID- 26017928 TI - Shift Work in Rats Results in Increased Inflammatory Response after Lipopolysaccharide Administration: A Role for Food Consumption. AB - The suprachiasmatic nucleus (SCN) drives circadian rhythms in behavioral and physiological variables, including the inflammatory response. Shift work is known to disturb circadian rhythms and is associated with increased susceptibility to develop disease. In rodents, circadian disruption due to shifted light schedules (jet lag) induced increased innate immune responses. To gain more insight into the influence of circadian disruption on the immune response, we characterized the inflammatory response in a model of rodent shift work and demonstrated that circadian disruption affected the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. Since food consumption is a main disturbing element in the shift work schedule, we also evaluated the inflammatory response to LPS in a group of rats that had no access to food during their working hours. Our results demonstrated that the shift work schedule decreased basal TNF-alpha levels in the liver but not in the circulation. Despite this, we observed that shift work induced increased cytokine response after LPS stimulation in comparison to control rats. Also, Kupffer cells (liver macrophages) isolated from shift work rats produced more TNF-alpha in response to in vitro LPS stimulation, suggesting important effects of circadian desynchronization on the functionality of this cell type. Importantly, the effects of shift work on the inflammatory response to LPS were prevented when food was not available during the working schedule. Together, these results show that dissociating behavior and food intake from the synchronizing drive of the SCN severely disturbs the immune response. PMID- 26017929 TI - Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation. AB - Accumulating evidence suggests that obesity and enhanced inflammatory reactions are predisposing conditions for developing colon cancer. Obesity is associated with high levels of circulating leptin. Leptin is an adipocytokine that is secreted by adipose tissue and modulates immune response and inflammation. Lipid droplets (LD) are organelles involved in lipid metabolism and production of inflammatory mediators, and increased numbers of LD were observed in human colon cancer. Leptin induces the formation of LD in macrophages in a PI3K/mTOR pathway dependent manner. Moreover, the mTOR is a serine/threonine kinase that plays a key role in cellular growth and is frequently altered in tumors. We therefore investigated the role of leptin in the modulation of mTOR pathway and regulation of lipid metabolism and inflammatory phenotype in intestinal epithelial cells (IEC-6 cells). We show that leptin promotes a dose- and time-dependent enhancement of LD formation. The biogenesis of LD was accompanied by enhanced CXCL1/CINC-1, CCL2/MCP-1 and TGF-beta production and increased COX-2 expression in these cells. We demonstrated that leptin-induced increased phosphorylation of STAT3 and AKT and a dose and time-dependent mTORC activation with enhanced phosphorilation of the downstream protein P70S6K protein. Pre-treatment with rapamycin significantly inhibited leptin effects in LD formation, COX-2 and TGF beta production in IEC-6 cells. Moreover, leptin was able to stimulate the proliferation of epithelial cells on a mTOR-dependent manner. We conclude that leptin regulates lipid metabolism, cytokine production and proliferation of intestinal cells through a mechanism largely dependent on activation of the mTOR pathway, thus suggesting that leptin-induced mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma. PMID- 26017931 TI - The Relationship Between Water Structure and Blood Compatibility in Poly(2 methoxyethyl Acrylate) (PMEA) Analogues. AB - Six types of poly(2-methoxyethyl acrylate) (PMEA) analogues were synthesized and the water structure in the hydrated polymers was characterized using differential scanning calorimetry (DSC). The hydrated PMEA analogues exhibited the different amounts of intermediate water. Non-thrombogenicity evaluation was performed on PMEA analogues for platelet adhesion and protein adsorption. Platelet adhesion was suppressed on PMEA analogues. In addition, the protein adsorption and deformation were suppressed by increasing the amount of intermediate water. This study demonstrates that the amount of intermediate water might play a key role in expressing the blood compatibility of polymeric materials. PMID- 26017930 TI - Agreement between prospective diary data and retrospective questionnaire report of abdominal pain and stooling symptoms in children with irritable bowel syndrome. AB - BACKGROUND: In functional gastrointestinal disorders, patient recall of symptoms drives diagnostic decisions and evaluation of treatment response, and research conclusions about potential treatments. In pediatrics, parent report also impacts assessment and care. Hence, identifying methods for accurately capturing patient and parent report of irritable bowel syndrome (IBS) symptoms is important. This study evaluated correspondence between retrospective questionnaire (parent and child report) and prospective diary data for children and adolescents with IBS. METHODS: Participants included 50 children/adolescents with IBS per Rome III criteria. Children completed a 2-week pain and stool diary. Children and parents subsequently completed a 2-week recall questionnaire, reporting number of pain days, maximum pain, days without bowel movement, and days with diarrhea during the diary interval. Intraclass correlation coefficients and Bland-Altman plots assessed agreement. KEY RESULTS: For pain and days without bowel movement, overall agreement between child recall questionnaire and child diary was strong, although under conditions likely to facilitate agreement and with individual variation observed. Parent recall and child diary were less concordant, and agreement about diarrhea was poor for parent and child. Age did not significantly correlate with agreement. CONCLUSIONS & INFERENCES: Child questionnaire with short recall interval may be a reasonable approximation for diary data, although this varies by individual and replication/investigation of lengthier recall are needed. Relying on parent questionnaire does not appear a suitable proxy, and recall of stool form by both parent and child appears more problematic. These results combined with existing literature support use of diary data whenever possible. PMID- 26017932 TI - Nitrifying biomass characterization and monitoring during bioaugmentation in a membrane bioreactor. AB - A membrane bioreactor (MBR), fed with domestic wastewater, was bioaugmented with nitrifying biomass selected in a side-stream MBR fed with a synthetic high nitrogen-loaded influent. Microbial communities evolution was monitored and comparatively analysed through an extensive bio-molecular investigation (16S rRNA gene library construction and terminal-restriction fragment length polymorphism techniques) followed by statistical analyses. As expected, a highly specialized nitrifying biomass was selected in the side-stream reactor fed with high-strength ammonia synthetic wastewater. The bioaugmentation process caused an increase of nitrifying bacteria of the genera Nitrosomonas (up to more than 30%) and Nitrobacter in the inoculated MBR reactor. The overall structure of the microbial community changed in the mainstream MBR as a result of bioaugmentation. The effect of bioaugmentation in the shift of the microbial community was also verified through statistical analysis. PMID- 26017933 TI - Unraveling the Degradation Mechanism of Purine Nucleotides Photosensitized by Pterins: The Role of Charge-Transfer Steps. AB - Photosensitized reactions contribute to the development of skin cancer and are used in many applications. Photosensitizers can act through different mechanisms. It is currently accepted that if the photosensitizer generates singlet molecular oxygen ((1) O2 ) upon irradiation, the target molecule can undergo oxidation by this reactive oxygen species and the reaction needs dissolved O2 to proceed, therefore the reaction is classified as (1) O2 -mediated oxidation (type II mechanism). However, this assumption is not always correct, and as an example, a study on the degradation of 2'-deoxyguanosine 5'-monophosphate photosensitized by pterin is presented. A general mechanism is proposed to explain how the degradation of biological targets, such as nucleotides, photosensitized by pterins, naturally occurring (1) O2 photosensitizers, takes place through an electron-transfer-initiated process (type I mechanism), whereas the contribution of the (1) O2 -mediated oxidation is almost negligible. PMID- 26017934 TI - Community and the family as units of analysis for health-related activities. PMID- 26017935 TI - Association between social support and quality of life of relative caregivers of elderly dependents. AB - OBJECTIVE: to ascertain the association between the social support and the quality of life of relative caregivers of elderly dependents at home. METHOD: a cross-sectional study conducted with 58 relative caregivers of elderly dependents, registered in the Family Health Strategy. Data were collected from the Katz instrument, sociodemographic, Zarit Burden Interview, WHOQOL-bref, and analyzed using descriptive statistics and multiple linear regression. RESULTS: the majority of caregivers were women, who took care full-time and presented moderate to severe burden. Most caregivers are satisfied with their social relationships and the social support received. It is found that the burden and the time of care correlated with the social relationships domain, which is associated with social support, and consequently, reduced quality of life. CONCLUSION: social support for caregivers is important to prevent health implications, burden, biopsychosocial stress, and provide favorable conditions for quality of life, by allowing greater freedom to develop their daily activities. PMID- 26017936 TI - [Community-based organizations and the aids epidemic in Amazonas state, Brazil]. AB - The scope of this paper was to analyze the perception of community-based organizations and their contributions to the history of tackling Aids in Amazonas State. It involved qualitative research with the use of oral and documental sources. Data were collected between June and September 2013 by means of semi structured interviews with the leaders of eight organizations that work or worked with more vulnerable communities. Based on Discourse Analysis the conclusion drawn is that that the organizations perceive two distinct phases since the decentralization of funds from the Sexually-Transmitted Diseases Aids and Viral Hepatitis Department to the local leaders. The first phase was marked by the strengthening of organizations, collective empowerment and active political participation. The current phase has seen the distancing between organizations, a loss of political momentum and weakening of common response and organization. PMID- 26017937 TI - Translation, adaptation and validation of "Community Integration Questionnaire". AB - OBJECTIVE: To translate, adapt, and validate the "Community Integration Questionnaire (CIQ)," a tool that evaluates community integration after traumatic brain injury (TBI). METHODS: A study of 61 TBI survivors was carried out. The appraisal of the measurement equivalence was based on a reliability assessment by estimating inter-rater agreement, item-scale correlation and internal consistency of CIQ scales, concurrent validity, and construct validity. RESULTS: Inter-rater agreement ranged from substantial to almost perfect. The item-scale correlations were generally higher between the items and their respective domains, whereas the intra-class correlation coefficients were high for both the overall scale and the CIQ domains. The correlation between the CIQ and Disability Rating Scale (DRS), the Extended Glasgow Outcome Scale (GOSE), and the Rancho Los Amigos Level of Cognitive Functioning Scale (RLA) reached values considered satisfactory. However, the factor analysis generated four factors (dimensions) that did not correspond with the dimensional structure of the original tool. CONCLUSION: The resulting tool herein may be useful in globally assessing community integration after TBI in the Brazilian context, at least until new CIQ psychometric assessment studies are developed with larger samples. PMID- 26017938 TI - Community Theater as social support for youth: agents in the promotion of health. AB - There has been much discussion on promotion of the health of young people in vulnerable situations; but little work has been done analyzing its actual operation - and this is especially true in relation to programs and projects that are outside the health services. This article aims to analyze the relationship of an experience in Community Theater with the promotion of health. It is a qualitative, ethnographic study made at the Pombas Urbanas Institute, in the Cidade Tiradentes district of the municipality of Sao Paulo, and is coordinated by a theater group with a history that is relevant to the objective of the study. Participatory observation was carried out for one year, with semi-structured interviews with young people, and with actors of the Pombas Urbanas group, and analysis of documents. The theoretical framework that was used is made up of concepts from the fields of collective health, Community Theater, and liberation pedagogy. The results are presented in two interlinked sub-categories which have arisen from the empiric material and from the references adopted: (i) 'True friends', and (ii) 'Dialog'. The analysis clearly shows the importance of this type of theatrical joint experience for the promotion of health by transforming the quality of relationships between people. Concepts of health, culture and education were used in analysis of the results. PMID- 26017939 TI - Divorce in families of children with Down Syndrome or Rett Syndrome. AB - This study evaluates the impact in the stability and management of the marriage of parents of a child with Down or Rett Syndrome. Morbidity of the syndromes and the marital status of the couples before and after the birth of the affected children were considered variables. The divorce rate in families with Down syndrome was 10%, similar to the Brazilian rate population. In Rett Syndrome, the divorce rate was significantly higher, 23.5%. The higher morbidity of Rett Syndrome, and the moment of diagnosis could be relevant factors for the increased divorce rate related to this syndrome. PMID- 26017940 TI - [Limitations of social behavior among users of the psychosocial care network in the south of Brazil]. AB - This cross-sectional study aims to assess through analysis of data suggested by the Social Behavior Schedule (SBS) quantitatively and qualitatively distinguishing between the limitations of social interaction presented by users of substitute services. Analyses were performed of 385 instruments applied to users of Therapeutic Residential Services (SRT) and the Centers for Psychosocial Care (CAPS). Twenty-one items from the Social Behaviour Schedule (SBS, BR). The data indicate that the individuals studied had from zero to 15 social behavior problems, with an average of 2.5 problems per service user with a standard deviation of 2.84. The majority of the sample appeared to have 1-2 problems among those identified by the scale, and the nonspecific behaviors are present in greater proportion in both services, followed by panic attacks among CAPS users and problems with personal appearance and hygiene in SRT users. In this way, the use of tools that make it possible to assess the data on the social aspects of the psychological distress deserves to be encouraged as a way to further research in this area, and rethink ways of effecting social reintegration of these individuals. PMID- 26017941 TI - Public health agendas addressing violence against rural women - an analysis of local level health services in the State of Rio Grande do Sul, Brazil. AB - This study analyses health managers' perceptions of local public health agendas addressing violence against rural women in municipalities in the southern part of the State Rio Grande do Sul in Brazil. It consists of an exploratory descriptive study utilizing a qualitative approach. Municipal health managers responsible for planning actions directed at women's health and primary health care were interviewed. The analysis sought to explore elements of programmatic vulnerability related to violence in the interviewees' narratives based on the following dimensions of programmatic vulnerability: expression of commitment, transformation of commitment into action, and planning and coordination. It was found that local health agendas directed at violence against rural women do not exist. Health managers are therefore faced with the challenge of defining lines of action in accordance with the guidelines and principles of the SUS. The repercussions of this situation are expressed in fragile comprehensive services for these women and programmatic vulnerability. PMID- 26017942 TI - [Characterization of parent-adolescent communication: a study of socio demographic variables]. AB - Parent-adolescent communication seems to depend largely of some socio-demographic characteristics. The main goal of this research is the analysis of parent adolescent perception about their communication considering some socio demographic variables: sex, residence, socioeconomic status, education and family composition. A quantitative cross-sectional design was used to analyze the perception of 336 parents and 268 children about the quality of communication using the Perception Scale of Parenting Communication.: It was revealed that: boys tend to share their problems mostly with fathers; mothers have better perception of communication; there weren't statistical differences on communicational conflict in the sex variable; members of high socioeconomic classes and urban contexts have better perception about communication; and adolescents of post-divorce families tend to share their problems mostly with mothers than adolescents of intact nuclear families. Considering the influence of some socio-demographic variables on parent-adolescent communication, it is possible design concrete clinical interventions. It suggests the need to pay attention to particular contexts (rural places and low socioeconomic classes). These results demystify the belief that post-divorce families have more difficulties than nuclear intact families. PMID- 26017943 TI - [Measures of intergenerational transmission of obesity in Brazil]. AB - A growing proportion of overweight individuals in Brazilian population highlights the importance of research in this area. Thus, this paper investigates the obesity problem from the point of view of intergenerational approach using Body Mass Index (BMI) of parents and their children. The information concerning BMI and socioeconomic control variables are obtained from the Household Budget Survey (POF) 2008-2009. The methodology of analysis considers the Markov transition matrix, quantile regressions and logistic regressions taking into account gender and family structure. The results suggest the existence of a strong association of BMI between parents and children, with the fraction of obese children increasing in families with single parents and households where both parents are obese. The analysis of quantile intergenerational elasticity indicates the higher children's age and their more intense BMI index is the intergenerational effect of parental health. Finally, the effect of maternal obesity is greater than the effect of paternal obesity in terms of intergenerational transmission of obesity for the children, regardless of gender. PMID- 26017944 TI - Tobacco use and friendship networks: a cross-sectional study among Brazilian adolescents. AB - AIM: To determine the prevalence of tobacco use and its association with types of friendship networks, socioeconomic status and gender among Brazilian adolescents. METHODS: A cross-sectional study was carried out with a representative sample of 905 students aged 15 to 19 years. Information on social networks and tobacco use was collected by the self-administered questionnaire 'Alcohol, Smoking and Substance Involvement Screening Test" and the question "What is your most important group of close friends?'. Socioeconomic status was assessed using an area-based social vulnerability index and type of school. Multinomial logistic regression analysis was employed to test associations between tobacco use and the independent variables. RESULTS: The overall prevalence of tobacco use was 18.9%. Female adolescents had 3.80-fold greater odds of reporting weekly to daily tobacco use compared to male adolescents. Participants who reported that their most important groups of close friends were from church had a lower risk of reporting weekly to daily tobacco use in comparison to those who reported that their best friends were from school. CONCLUSIONS: The prevalence of tobacco use was high and was associated with school-based (as compared to church-based) friendship networks, female gender and higher area-level socioeconomic status. PMID- 26017945 TI - [Spending on private health insurance plans of Brazilian families: a descriptive study with data from the Family Budget Surveys 2002-2003 and 2008-2009]. AB - Spending on health insurance represents an important share of private expenditure on health in Brazil. The study aimed to describe the evolution of spending on private health insurance plans of Brazilian families, according to their income. Data from the Family Budget Surveys (POF) 2002-2003 and 2008-2009 were used. To compare the spending figures among the surveys, the Consumer Price Index (IPCA) was applied. The proportion of families with private health insurance expenses remained stable in both surveys (2002-2003 and 2008-2009), around 24%. However, the household spending on health insurance plans increased. Among those families who spent money oh health insurance plans, the average spending increased from R$154.35 to R$183.97. The average spending on health insurance plans was greater with increasing household income, as well as portions of the family income and total expenditure committed to these expenses. Spending on health insurance is concentrated among higher-income families, for which it was the main component of total health expenditure. PMID- 26017946 TI - Family relations in eating disorders: the Genogram as instrument of assessment. AB - The present study aimed to evaluate the transactional patterns in families of women with EDs, through the use of the Genogram. The study included 12 girls and women linked to a multidisciplinary service. For the preparation of Genograms, a semistructured interview script was built that included specific topics regarding family relationships. Genograms' analysis followed the recommendations professed by the specialized literature. It was evident that families presented few skills in managing stressful events and resolving conflicts, resulting in emotional distance between members and vulnerability of bonds. The Genogram was proved useful as a resource for research and evaluation in the area of EDs, and the generated data was convergent with the literature. Results provide important subsidies for health professionals, since they indicate the need for care and development of therapeutic alliance with the family in the treatment for EDs. PMID- 26017947 TI - Moderate hyperopia prevalence and associated factors among elementary school students. AB - Hyperopia is the most common refractive condition in childhood. There are few studies on moderate hyperopia and associated factors. This study aims to investigate the prevalence of moderate hyperopia and associated factors among school children. A cross-sectional study comprising 1,032 students attending 1st to 8th grades at two public schools was conducted in a Southern Brazilian urban area in 2012. Cycloplegia was used to examine both eyes and refractive error was measured through auto-refraction. A socioeconomic and cultural questionnaire was administered. Multivariable analysis was performed through Poisson regression. Moderate hyperopia prevalence was 13.4% (95% CI, 11.2-15.4) and 85% of these did not wear glasses. Age was inversely associated with moderate hyperopia, while female gender RP = 1.39 (95%CI, 1.02 - 1.90) and white skin RP = 1.66 (95%CI, 1.04 - 2.66) were risk factors for this outcome. This study makes progress in estimating mild and moderate hyperopia prevalence both by age range and specific age. It emphasizes how the lack of this condition being corrected in southern Brazil is a serious problem. It highlights the importance of detailing and characterizing the amount of time spent on close-range, long-range and outdoor activities. PMID- 26017948 TI - Low birthweight and postnatal weight in full-term infants under six months old, Rio de Janeiro, RJ, Brazil. AB - This study investigated the association between low birthweight and postnatal weight in full-term infants, taking social, economic, maternal and babies characteristics into account. A cross-sectional study was conducted with infants under six months old at 27 primary healthcare units in the Rio de Janeiro municipality, Brazil, in 2007. Only singleton full-term babies were included. The association between full-term low birthweight and postnatal weight was tested using the multiple regression model adjusted for the gender and age of the baby, as well as potential confounding factors. A total of 875 babies were evaluated, of whom 4.5% were small for gestational age. Small-for-gestational-age babies weighted, on average, 977.4 grams less than those born with adequate weight for gestational age, after adjustment by gender and age, as well as marital status and parity. Girls were 426.74 grams lighter than boys; children from mothers with live-in partners were 146.2 grams heavier than those of single mothers, and the babies of primiparae weighed 204.67 grams less than the children of multiparae. Low birthweight is an unfavorable factor for postnatal weight of full-term infants. These children, particularly daughters of primipara single mothers, must be followed more frequently in relation to their postnatal growth. PMID- 26017949 TI - The social in health: trajectory and contributions of Maria Cecilia Ferro Donnangelo. AB - This text covers the professional and scientific career of Maria Cecilia Ferro Donnangelo, professor, researcher and influential intellectual in the area of Collective Health. Born in 1940, and killed in a car accident in 1983, she actively participated in the emergence of Collective Health in Brazil and greatly influenced the creation of the sub-areas of Social Science and the Humanities in the health field. Her brief biography, contextualized professional choices and scientific production is hereby presented. Graduated in pedagogy at the time of national developmentalism with a post graduation in Sociology, Donnangelo fell into the triangulated area of Education, Sociology and Health, focusing medicine as a social practice and as a profession in society. Always with an eye to human rights and an ongoing dialogue with the modern Brazilian state and public policy, she examined questions of the social aspects in health and education, as well as questions of health education as a social tool. An educator of great prestige, her published work was limited. However, due to her foundational presence, her writings are classic references with assured presence and contributions for today and also vital to the future development of the Brazilian Collective Health. PMID- 26017950 TI - Resilience in aging: literature review. AB - Psychological resilience is comprised of an adaptive functioning standard before the current and accumulated risks of life. Furthermore, it has a comprehensive range of psychological resources which are essential to overcome adversities, such as personal competences, self-beliefs and interpersonal control which interact with the social networks support. The objectives are to show the concepts of psychological resilience in elderly, relative to dominant theoretical models and the main data about psychological resilience in aging, found in an international and Brazilian review from 2007 to 2013. The descriptors "resilience, psychological resilience and aging", "resiliencia e envelhecimento, velhice e velho", were used in PubMed, PsychInfo, SciELO and Pepsic databases. Fifty three international and eleven national articles were selected. The international articles were classified in four categories: psychological and social coping resources, emotional regulation before stressing experiences, successful resilience and aging and correlates, and resilience measures. The Brazilian articles were grouped in three: psychological and social resources, resilience in carers and theory review. Articles on psychological resources and on emotional regulation prevailed as key factors associated with psychological resilience in aging. PMID- 26017951 TI - [Pay-for-performance in health care services: a review of the best evidence available]. AB - Pay-for-performance (P4P) has been widely used around the world seeking to improve health outcomes, and in Brazil it is the basis of the National Program for Improving Access and Quality (PMAQ). The literature published between 1998 and January 2013 that evaluated the effectiveness of P4P to produce results or patterns of access and quality in health was scrutinized. A total of 138 studies, with the inclusion of a further 41 studies (14 systematic reviews, 07 clinical trials and 20 observational studies) were retrieved and analyzed Among the more rigorous studies, favorable conclusions for P4P were less frequent, whereas observational studies were more favorable to positive effects of P4P on the quality of, and access to, health services. Methodological limitations of observational studies may have contributed to these results, but the range of results is more linked to the conceptual and contextual aspects of the use of the P4P schemes reviewed, the heterogeneity of P4P models and results. P4P can be helpful in promoting the achievement of objectives in health care systems, especially in the short term and for specific actions requiring less effort of health care providers, but should be used with caution and with a rigorous planning model, also considering undesirable or adverse effects. PMID- 26017952 TI - Social mobility and smoking: a systematic review. AB - The purpose of this study is to review the literature on longitudinal studies that have evaluated the effect of social mobility on the occurrence of smoking in various populations. Articles were selected from the web databases PubMed and Web of Science using the words: follow up, cohort longitudinal prospective, social mobility, social change life, course socioeconomic, smoking, and tobacco. Of the six studies identified in this review, four used occupational classification to measure social mobility. All six were carried out on the continent of Europe. The results indicate higher proportions of tobacco users among those with lower socioeconomic level during the whole period of observation (for all variables analyzed); and that people who suffered downward mobility, that is to say people who were classified as having a higher socioeconomic level at the beginning of life, tended to mimic habits of the new group when they migrated to a lower social group. PMID- 26017953 TI - Post-diagnosis abortion in women living with HIV/Aids in the south of Brazil. AB - OBJECTIVE: To understand how the HIV diagnosis combines with other factors that influence the decision to abort. METHODOLOGY: Data were collected during a crossover study of women aged between 18 and 49 years old and seen in public health services in Porto Alegre, Brazil. The life stories of 18 interviewees who had post-diagnosis abortion were reconstructed on a timeline, using information collected quantitatively. RESULTS: The time between the diagnosis and abortion was 2 years or less for more than half of the women. For some, post-diagnosis abortion did not mean the end of reproductive life. The most frequent reason for terminating pregnancy was to be living with HIV; however, only some of the women who stated having this motivation did not have post-diagnosis children. Changing partners between pregnancies was a recurring finding; however, in most pregnancies that ended in abortion, the women lived with their partners. DISCUSSION: The analysis of the reproductive trajectory of the women studied showed that there is no specific profile of the woman who aborts after receiving the HIV diagnosis. Although this diagnosis may be involved in the decision to terminate a pregnancy, it does not necessarily result in the end of a woman's reproductive trajectory. Thus, abortion should be understood within a diversity of decision-making processes and the specific moment of a woman's life story. PMID- 26017954 TI - Social, economic, and behavioral variables associated with oral health-related quality of life among Brazilian adults. AB - The aim of this study was to investigate the association between sociodemographic, socioeconomic, psychosocial, and behavioral variables and oral health as assessed using the 14-question short version of the Oral Health Impact Profile (OHIP-14). A cross-sectional study was performed with 1095 adult residents from 38 census tracts in the municipality of Sao Leopoldo, State of Rio Grande do Sul, Brazil. Responses to the OHIP-14 were dichotomized, and bivariate (Chi-square) and multivariate analysis (logistic regression and Wald's test) were performed. In the bivariate analysis, the worse effects were reported by female individuals, the elderly, those with low family income, less schooling, those reporting a lower quality of life and social support, and smokers. In the multivariate analysis the following variables maintained their statistical significance: gender (female), age (50-59 years), family income (low), quality of life (low), social support (low, moderate), and smoking (smokers). Individuals' self-perception of their oral health was related to sociodemographic, socioeconomic, psychosocial, and behavioral variables, thus confirming that emphasis should be placed on social factors when addressing oral health problems. PMID- 26017955 TI - Indidence of tuberculosis in children in the state of Sao Paulo, Brazil, under spatial approach. AB - The aim of this study was to identify spatial patterns in the incidence of childhood tuberculosis in cities in the state of Sao Paulo. An ecological and exploratory study was carried with data on new cases of tuberculosis in children 0 to 14 years old for the period 2001 to 2005 and from 2006 to 2010, obtained from DATASUS. Data of the population of this age group were collected and raised rates per 100 000 inhabitants. Moran's index (I) was calculated for both periods. Thematic maps with the rates and its difference besides Moran maps, maps with Kernel densities, educational level and income were constructed using using TerraView software. The average rates were 3.23 / 100 000 inhabitants in the first period (2881 cases reported) and 2.13 / 100 000 inhabitants in the second period (2513 cases reported); the Moran index in the first period was I = 0.03 (p = 0.16) and I = 0.06 (p = 0.01) in the second period; the thematic map identified 462 municipalities with higher interest rates in the second period; the kernel map identified higher density rates in the metropolitan region of Sao Paulo, west coastal cities and in the first period and the second period, the metropolitan region of Sao Paulo and coastal cities. The data presented in this study provide informations to local and regional managers to implement policies for tuberculosis control. PMID- 26017956 TI - Motives for requesting an electrocardiogram in primary health care. AB - The management of requests for diagnostic exams presents its own inherent characteristics in primary health care and reflects the specific nature of the physician-patient relationship. The scope of the study was to identify the reasons for requesting an electrocardiogram (ECG) in primary health care. A cross sectional study was conducted in an urban region in Portugal, establishing the motives to ask for an ECG consecutively over two years, starting on 01/03/2007 using data retrieved from structured forms filled out by the physician at the moment of requesting the exam. A total of 870 ECGs of 817 patients were included. Symptoms manifested during the patient visit justified 48.5% of the ECGs, and follow-up of cardiovascular risk factors motivated 25.2%. A global health examination accounted for 22.8% of the requests. Multivariate analysis showed that the presence of symptoms (p < 0.001), presence of any cardiovascular risk factor (p = 0.002), hypertension (p < 0.001), diabetes (p = 0.002), and urgency (p < 0.001) were the main factors associated with the requests. The requests for electrocardiograms are predominantly for clinical reasons as a result of patients symptoms. The integration of expectations and beliefs of the patients is present in the decision-making process. PMID- 26017957 TI - Health with equality: a proposal for the incorporation of the gender perspective in health care systems. AB - This paper presents an analysis of the incorporation of the gender perspective in health care-related policies. Based on the recommendations of international organizations, the importance of the incorporation of the gender concept in the health field is analyzed, in order to design health policies that seeking to redress existing inequalities by virtue of sex/gender. This paper presents an analysis of the published guidelines in order to facilitate the incorporation of the gender perspective in health care systems. The article concludes with a proposal of gender-sensitive health indicators that can ensure the gender perspective in health care policies. PMID- 26017958 TI - [Dietary patterns in menopausal women receiving outpatient care in Southern Brazil]. AB - The scope of this paper is to identify dietary patterns and the relationship with menopausal status. It involved a cross-sectional study with 646 women in outpatient care in southern Brazil. Dietary intake was assessed by a frequency questionnaire and five dietary patterns were identified by main component analysis. The menopausal status was classified as premenopausal, perimenopausal and postmenopausal women. Five dietary patterns were identified: fruit and vegetables; Brazilian fare (rice, beans and milk); snacks (cake, burgers, pizza and sweetbread); health diet (fish, fruit juice, bread and vegetable soup), and regional (typical food in the Serra Gaucha, like red meat, pasta and yams). After adjusting for sociodemographic characteristics, there was no significant association between menopausal status and dietary patterns. Only age, education and income were associated with dietary patterns. Five dietary patterns that described the food consumption of the population studied were identified, which are similar to those indicated as ideal for the Brazilian population. The findings reveal that the dietary pattern of women in menopause are significantly influenced by age, education and income but are not influenced by the menopausal status per se. PMID- 26017959 TI - Prevalence of low back pain and associated factors in adults from a middle-size Brazilian city. AB - OBJECTIVE: To determine the prevalence of low back pain and some related variables among adults of both genders. METHODS: Was conduct a cross-sectional study of population-based in the urban area of Presidente Prudente, Sao Paulo. The sample consisted of 743 adult residents for over two years in this city. Low back pain, quality of sleep and physical activity were collected through face to face interview at the residence of respondents. Was used the chi-square test to analyze the association between variables, later was created tree multivariate models with hierarchical inclusion of confounding factors. RESULTS: The prevalence of low back pain reported last year was 50.2% (95% CI: 46.6, 53.8), and the last week 32.3% (95% CI: 28.9, 35.6). Was association among low back pain and females (p-value = 0.031), older age, lower education, altered sleep and overweight, the adjusted model found that people over the age of 45 years (45 to 59.9 years, OR = 13.1 [1.72-98.5] and >= 60 years, OR = 9.10 [1.15-71.7]), with some alteration of sleep (OR = 3.21 [1.84-5.61]) and obese (OR = 2.33 [1:26 to 4:33]) seems to be a risk group for low back pain. CONCLUSION: The prevalence of low back pain is high and obese people aged over 45 years, with any sleep disturbance are a group at higher risk for low back pain. PMID- 26017960 TI - Social scientists in public health: a fuzzy approach. AB - This study aims to describe and analyze the presence of social scientists, anthropologists, sociologists and political scientists in the field of public health. A survey by the Lattes Curriculum and sites of Medical Colleges, Institutes of Health Research Collective, seeking professionals who work in healthcare and have done some stage of their training in the areas of social sciences. In confluence with Norbert Elias' concepts of social networks and configuration of interdependence it was used fuzzy logic, and the tool free statistical software R version 2.12.0 which enabled a graphic representation of social scientists interdependence in the field of social sciences-health-social sciences. A total of 238 professionals were ready in 6 distinct clusters according to the distance or closer of each professional in relation to public health and social sciences. The work was shown with great analytical and graphical representation possibilities for social sciences of health, in using this innovative quantitative methodology. PMID- 26017961 TI - [Macronutrient food sources in a probabilistic sample of Brazilian adults]. AB - Once it is available, the information on food intake (FI) may enable the development of strategies to intervene, monitor and explore dietary patterns with more sophisticated statistical methods. Thus, the purpose of this study was to document the quantitative dietary characteristics in a probabilistic sample of adults in Niteroi in the State of Rio de Janeiro. A 24-hour dietary recall of a typical day was conducted. The food eaten by most adults (> 50%) was white rice, coffee, black beans, refined sugar and French bread. Whole milk was ingested by more adults than skimmed or semi-skimmed milk. Beef was ingested by more adults than chicken, fish or pork. More adults ingested sodas than fruit juices and fruits were eaten by a relatively high percentage of adults (63.3%). The combination of white rice, black beans, beef and French bread was responsible for at least 25% of energy, protein and carbohydrate and 17% of lipids. A total of 65 food items accounted for approximately 90% of energy and macronutrients. The list generated is somewhat similar to the one used in a similar survey conducted in Sao Paulo. The list can serve as the basis for a single food frequency questionnaire to be used for the southeastern Brazilian urban population. PMID- 26017962 TI - Access to treatment for phenylketonuria by judicial means in Rio Grande do Sul, Brazil. AB - Treatment of phenylketonuria (PKU) includes the use of a metabolic formula which should be provided free of charge by the Unified Health System (SUS). This retrospective, observational study sought to characterize judicial channels to obtain PKU treatment in Rio Grande do Sul (RS), Brazil. Lawsuits filed between 2001- 2010 and having as beneficiaries PKU patients requesting treatment for the disease were included. Of 20 lawsuits filed, corresponding to 16.8% of RS patients with PKU, 19 were retrieved for analysis. Of these, only two sought to obtain therapies other than metabolic formula. In all the other 17 cases, prior treatment requests had been granted by the State Department of Health. Defendants included the State (n = 19), the Union (n = 1), and municipalities (n = 4). In 18/19 cases, the courts ruled in favor of the plaintiffs. Violation of the right to health and discontinuation of State-provided treatment were the main reasons for judicial recourse. Unlike other genetic diseases, patients with PKU seek legal remedy to obtain a product already covered by the national pharmaceutical assistance policy, suggesting that management failures are a driving factor for judicialization in Brazil. PMID- 26017963 TI - Exploring Mexican adolescents' perceptions of environmental health risks: a photographic approach to risk analysis. AB - The objective of this study was to explore Mexican adolescents' perceptions of environmental health risks in contaminated urban areas, and to test the environmental photography technique as a research tool for engaging adolescents in community-based health research. The study was conducted with 74 adolescents from two communities in the city of San Luis Potosi, Mexico. Participants were provided with disposable cameras and asked to take photographs of elements and situations which they believed affected their personal health both at home and outside their homes. They were also asked to describe each photograph in writing. Photographs and written explanations were analyzed by using quantitative and qualitative content analysis. Risk perception plays a crucial role in the development of Risk Communication Programs (RCPs) aimed at the improvement of community health. The photography technique opens up a promising field for environmental health research since it affords a realistic and concise impression of the perceived risks. Adolescents in both communities perceived different environmental health risks as detrimental to their well-being, e.g. waste, air pollution, and lack of hygiene. Yet, some knowledge gaps remain which need to be addressed. PMID- 26017964 TI - [The role of cultural identities and public health services in the municipalization process taken place in recent decades on small towns of Rio Grande do Sul, Brazil]. AB - The paper presents a preliminary results of an ethnographic study in which we observe how is socially experienced the municipality process in six counties of the Forqueta Watershed in Rio Grande do Sul, where the municipal fragmentation has been used as an administrative strategy since the 1990s. Deal about cultural elements and social actions that support construction and/or reconstruction identities to define territories-county's borders. Sociological and anthropological theories have been used to think the identities and the assumption that the integration of social spaces into a territory creates the social necessity to produce a territorial identity, closely linked to a socio political context and cultural setting. We realize that the decentralization process in small municipalities helps stem the rural exodus, being health services determinant in curbing the migratory flow that characterized these locations reality in recent decades as a result of the agribusiness growth. Today, in these same places, health services represent the main support of collective identity with the territory-county and, instead of emigration, stimulate the immigration. PMID- 26017967 TI - [Errata]. PMID- 26017969 TI - Enhanced photocatalytic activity of Cl-residual rutile TiO2 nanorods after targeted co-modification with phosphoric and boric acids. AB - The promotion of O2 adsorption on semiconductor surfaces for effectively capturing photogenerated electrons in the photocatalytic degradation of pollutants is highly desired. In this study, the targeted co-modification of residual chlorine rutile TiO2 nanorods with phosphoric and boric acids has been accomplished for the first time by simple wet chemical processes. The key to targeted co-modification is to connect -P-OH and -B-OH to the Cl-residual TiO2 surfaces by -Ti-OH and -Ti-Cl, respectively, consequently forming -Ti-O-P-OH and Ti-Cl:B-OH ends. By means of the atmosphere-controlled surface photovoltage spectroscopy, the degrees for capturing photogenerated electrons by the adsorbed O2 as receptors on the resulting TiO2 nanorods are quantitatively analyzed. It is confirmed that the targeted co-modification could greatly promote the capture of the photogenerated electrons compared to the phosphate and borate modification alone. This is attributed to increased amounts of adsorbed O2 based on electrochemical O2 reduction and O2 temperature-programmed desorption measurements, further leading to the enhanced separation of photogenerated charges, characterized by an increase in the amount of produced hydroxyl radicals. This is responsible for the obviously enhanced photocatalytic activity of TiO2 nanorods towards the degradation of colorless gas-phase acetaldehyde and liquid-phase phenol. This work would provide us a feasible route for the co modification with inorganic acids to synthesize efficient nanosized TiO2-based photocatalysts. PMID- 26017968 TI - Direct Detection by the Xpert MTB/RIF Assay and Characterization of Multi and Poly Drug-Resistant Tuberculosis in Guinea-Bissau, West Africa. AB - BACKGROUND: This study aimed to evaluate the usefulness of the Xpert MTB/RIF assay for the rapid direct detection of M. tuberculosis complex (MTBC) strains and rifampicin resistance associated mutations in a resource-limited setting such as Guinea-Bissau and its implications in the management of tuberculosis (TB) and drug resistant tuberculosis, complementing the scarce information on resistance and genotypic diversity of MTBC strains in this West African country. METHODS AND RESULTS: This cross-sectional prospective study included 100 consecutive TB patients with positive acid-fast smears at two months of anti-tuberculosis treatment or in a re-treatment situation, between May and December 2012. Resistance to rifampicin was detected using the GeneXpert system and the Xpert MTB/RIF assay. MTBC isolates obtained with the BACTEC MGIT 960 system were tested for susceptibility to first- and second-line anti-tuberculosis drugs. Overall, the prevalence of multidrug-resistant tuberculosis (MDR-TB) was found to be 9 cases. Of these, 67% (6 patients) of confirmed MDR-TB cases had no past history of TB treatment and 33% (3 patients) were previously treated cases. Extensively drug-resistant TB was not found. Molecular typing of the MDR-TB strains revealed recent transmission patterns of imported MDR strains. CONCLUSIONS: The Xpert MTB/RIF assay was reliable for the detection of rifampicin resistant MTBC strains directly from sputum samples of patients undergoing first-line treatment for two months, being more trustworthy than the simple presence of acid-fast bacilli in the smear. Its implementation is technically simple, does not require specialized laboratory infrastructures and is suitable for resource-limited settings when a regular source of electricity and maintenance is available as well as financial and operation sustainability is guaranteed by the health authorities. A high prevalence of MDR-TB among patients at risk of MDR-TB after two months of first line treatment was found, in support of the WHO recommendations for its use in the management of this risk group. PMID- 26017970 TI - Tryptophan hydroxylase Is Required for Eye Melanogenesis in the Planarian Schmidtea mediterranea. AB - Melanins are ubiquitous and biologically important pigments, yet the molecular mechanisms that regulate their synthesis and biochemical composition are not fully understood. Here we present a study that supports a role for serotonin in melanin synthesis in the planarian Schmidtea mediterranea. We characterize the tryptophan hydroxylase (tph) gene, which encodes the rate-limiting enzyme in serotonin synthesis, and demonstrate by RNA interference that tph is essential for melanin production in the pigment cups of the planarian photoreceptors. We exploit this phenotype to investigate the biological function of pigment cups using a quantitative light-avoidance behavioral assay. Planarians lacking eye pigment remain phototactic, indicating that eye pigmentation is not essential for light avoidance in S. mediterranea, though it improves the efficiency of the photophobic response. Finally, we show that the eye pigmentation defect observed in tph knockdown animals can be rescued by injection of either the product of TPH, 5-hydroxytryptophan (5-HTP), or serotonin. Together, these results highlight a role for serotonin in melanogenesis, perhaps as a regulatory signal or as a pigment substrate. To our knowledge, this is the first example of this relationship to be reported outside of mammalian systems. PMID- 26017971 TI - Antialbuminuric actions of calcilytics in the remnant kidney. AB - Hyperphosphatemia accelerates the progression of chronic kidney diseases. In the present study, the effects of ronacaleret, a calcilytic agent, on renal injury were assessed in the following four groups of rats: 5/6-nephrectomized Wistar rats as a control (C group), rats treated with ronacaleret (3 mg.kg(-1).day(-1); R group), rats treated with calcitriol (30 ng.kg(-1).day(-1); V group), and rats treated with both ronacaleret and calcitriol (R + V group). Three months later, rats were euthanized under anesthesia, and the remnant kidneys were harvested for analysis. Albuminuria was lower in the R and V groups than in the C group (P < 0.05). Creatinine clearance was elevated in the R and V groups compared with the C group (P < 0.05). Serum Ca(2+) and renal ANG II were higher in the R + V group than in the C group (P < 0.05 for each), and serum phosphate was reduced in the R group compared with the C group (P < 0.05). Fibroblast growth factor-23 was lower in the R group and higher in the V and R + V groups than in the C group. However, parathyroid hormone did not differ significantly among the four groups. Renal klotho expression was elevated in the R and V groups compared with the C group (P < 0.05). The present data indicate that ronacaleret preserves klotho expression and renal function with reductions in serum phosphate and albuminuria in 5/6 nephrectomized rats. Our findings demonstrate that vitamin D prevents declines in klotho expression and renal function, suppressing albuminuria. PMID- 26017972 TI - ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. II. Bafilomycin-sensitive H+ secretion. AB - Epithelial Na(+) channel (ENaC) blockade stimulates stilbene-sensitive conductive Cl(-) secretion in the mouse cortical collecting duct (CCD). This study's purpose was to determine the co-ion that accompanies benzamil- and DIDS-sensitive Cl(-) flux. Thus transepithelial voltage, VT, as well as total CO2 (tCO2) and Cl(-) flux were measured in CCDs from aldosterone-treated mice consuming a NaCl-replete diet. We reasoned that if stilbene inhibitors (DIDS) reduce conductive anion secretion they should reduce the lumen-negative VT. However, during ENaC blockade (benzamil, 3 MUM), DIDS (100 MUM) application to the perfusate reduced net H(+) secretion, which increased the lumen-negative VT. Conversely, ENaC blockade alone stimulated H(+) secretion, which reduced the lumen-negative VT. Application of an ENaC inhibitor to the perfusate reduced the lumen-negative VT, increased intercalated cell intracellular pH, and reduced net tCO2 secretion. However, benzamil did not change tCO2 flux during apical H(+)-ATPase blockade (bafilomycin, 5 nM). The increment in H(+) secretion observed with benzamil application contributes to the fall in VT observed with application of this diuretic. As such, ENaC blockade reduces the lumen-negative VT by inhibiting conductive Na(+) absorption and by stimulating H(+) secretion by type A intercalated cells. In conclusion, 1) in CCDs from aldosterone-treated mice, benzamil application stimulates HCl secretion mediated by the apical H(+)-ATPase and a yet to be identified conductive Cl(-) transport pathway; 2) benzamil induced HCl secretion is reversed with the application of stilbene inhibitors or H(+)-ATPase inhibitors to the perfusate; and 3) benzamil reduces VT not only by inhibiting conductive Na(+) absorption, but also by stimulating H(+) secretion. PMID- 26017973 TI - Role of the brain stem in tibial inhibition of the micturition reflex in cats. AB - This study examined the role of the brain stem in inhibition of bladder reflexes induced by tibial nerve stimulation (TNS) in alpha-chloralose-anesthetized decerebrate cats. Repeated cystometrograms (CMGs) were performed by infusing saline or 0.25% acetic acid (AA) to elicit normal or overactive bladder reflexes, respectively. TNS (5 or 30 Hz) at three times the threshold (3T) intensity for inducing toe movement was applied for 30 min between CMGs to induce post-TNS inhibition or applied during the CMGs to induce acute TNS inhibition. Inhibition was evident as an increase in bladder capacity without a change in amplitude of bladder contractions. TNS applied for 30 min between saline CMGs elicited prolonged (>2 h) poststimulation inhibition that significantly (P < 0.05) increased bladder capacity to 30-60% above control; however, TNS did not produce this effect during AA irritation. TNS applied during CMGs at 5 Hz but not 30 Hz significantly (P < 0.01) increased bladder capacity to 127.3 +/- 6.1% of saline control or 187.6 +/- 5.0% of AA control. During AA irritation, naloxone (an opioid receptor antagonist) administered intravenously (1 mg/kg) or directly to the surface of the rostral brain stem (300-900 MUg) eliminated acute TNS inhibition and significantly (P < 0.05) reduced bladder capacity to 62.8 +/- 22.6% (intravenously) or 47.6 +/- 25.5% (brain stem application). Results of this and previous studies indicate 1) forebrain circuitry rostral to the pons is not essential for TNS inhibition; and 2) opioid receptors in the brain stem have a critical role in TNS inhibition of overactive bladder reflexes but are not involved in inhibition of normal bladder reflexes. PMID- 26017975 TI - Pleiotropic signaling evoked by tumor necrosis factor in podocytes. AB - TNF has been implicated in glomerular diseases, but its actions on podocytes are not well understood. Endogenous TNF expression is markedly increased in mouse podocytes exposed to sera from patients with recurrent focal segmental glomerulosclerosis, and TNF is able to increase its own expression in these cells. Exposure of podocytes to TNF increased phosphorylation of NF-kappaB p65 RelA followed by increased tyrosine phosphorylation of STAT3. STAT3 activation was blocked by the NF-kappaB inhibitor JSH-23 and by the STAT3 inhibitor stattic, whereas TNF-evoked NF-kappaB activation was not affected by stattic. TNF treatment increased nuclear accumulation of nuclear factor of activated T cells (NFAT)c1 in podocytes, a process that occurred downstream of STAT3 activation. TNF also increased expression of cyclin D1 but had no effect on cyclin-dependent kinase 4, p27(kip), or podocin. Despite its effects on cyclin D1, TNF treatment for up to 72 h did not cause podocytes to reenter the cell cycle. TNF increased total expression of transient receptor potential (TRP)C6 channels through a pathway dependent on NFATc1 and increased the steady-state expression of TRPC6 subunits on the podocyte cell surface. TNF effects on TRPC6 trafficking required ROS. Consistent with this, La(3+)-sensitive cationic currents activated by a diacylglycerol analog were increased in TNF-treated cells. The effects of TNF on NFATc1 and TRPC6 expression were blocked by cyclosporine A but were not blocked by the pan-TRP inhibitor SKF-96365. TNF therefore influences multiple pathways previously implicated in podocyte pathophysiology and is likely to sensitize these cells to other insults. PMID- 26017976 TI - Molecular nephropathology: ready for prime time? AB - In the current era of precision medicine, the existing nephropathology paradigm of light microscopy, immunofluorescence, and electron microscopy will become increasingly insufficient. There will be an expectation to supplement these traditional diagnostic tools with patient-specific information related to a growing understanding of molecular pathophysiology. Next generation sequencing technologies are expected to play a key role in the future of nephropathology, but transcriptomics is poised to represent the first major foray into routine molecular testing. The introduction of molecular techniques into clinical nephropathology has been hindered in part by the reliance of existing platforms on fresh tissue samples. The NanoString gene expression system works with formalin-fixed paraffin-embedded tissue and thus represents a promising solution to this technical barrier that may finally allow for the translation of recent transcriptomics discoveries into the enhancement of patient care. Widespread adoption of this new diagnostic dimension will require ongoing multidisciplinary cooperation between pathologists and clinicians, including molecular testing consensus generation and rigorous multicenter validation. PMID- 26017974 TI - Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age. AB - Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27 mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers alpha-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E cadherin and beta-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-beta, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age. PMID- 26017977 TI - Inhibition of COX-1 attenuates the formation of thromboxane A2 and ameliorates the acute decrease in glomerular filtration rate in endotoxemic mice. AB - Thromboxane (Tx) A2 has been suggested to be involved in the development of sepsis-induced acute kidney injury (AKI). Therefore, we investigated the impact of cyclooxygenase (COX)-1 and COX-2 activity on lipopolysaccharide (LPS)-induced renal TxA2 formation, and on endotoxemia-induced AKI in mice. Injection of LPS (3 mg/kg ip) decreased glomerular filtration rate (GFR) and the amount of thrombocytes to ~50% of basal values after 4 h. Plasma and renocortical tissue levels of TxB2 were increased ~10- and 1.7-fold in response to LPS, respectively. The COX-1 inhibitor SC-560 attenuated the LPS-induced fall in GFR and in platelet count to ~75% of basal levels. Furthermore, SC-560 abolished the increase in plasma and renocortical tissue levels of TxB2 in response to LPS. The COX-2 inhibitor SC-236 further enhanced the LPS-induced decrease in GFR to ~40% of basal values. SC-236 did not alter thrombocyte levels nor the LPS-induced increase in plasma and renocortical tissue levels of TxB2. Pretreatment with clopidogrel inhibited the LPS-induced drop in thrombocyte count, but did not attenuate the LPS-induced decrease in GFR and the increase in plasma TxB2 levels. This study demonstrates that endotoxemia-induced TxA2 formation depends on the activity of COX-1. Our study further indicates that the COX-1 inhibitor SC-560 has a protective effect on the decrease in renal function in response to endotoxin. Therefore, our data support a role for TxA2 in the development of AKI in response to LPS. PMID- 26017979 TI - Care for the caregivers. PMID- 26017978 TI - Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity. AB - Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09 142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease. PMID- 26017980 TI - A call for universal alcohol, drug screening. PMID- 26017981 TI - Staying with the patient. PMID- 26017982 TI - Degree compensation. PMID- 26017983 TI - Nursing history. PMID- 26017984 TI - Rapid response teams. PMID- 26017985 TI - New health care vision. PMID- 26017986 TI - In nursing it still pays more to be a man. PMID- 26017987 TI - Rural youths commit suicide almost twice as often as urban counterparts. PMID- 26017988 TI - First U.S. nurse to contract Ebola sues Texas Health Resources. PMID- 26017989 TI - Health care reform at five years. PMID- 26017992 TI - Nurse Advice New Mexico presents its model at CDC Preparedness Summit. PMID- 26017994 TI - The excessive waste of prescription drugs. PMID- 26017995 TI - The effects on growth of inhaled corticosteroids in children with persistent asthma. PMID- 26018005 TI - Cultivating mindfulness to enhance nursing practice. PMID- 26018010 TI - Culturally competent care: using the ESFT model in nursing. PMID- 26018011 TI - Preventing central line air embolism. AB - The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, birthing centers, and abortion facilities must file information on incidents and serious events.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID- 26018012 TI - Ms. Lisa and Ms. MRSA. AB - Nurses aren't just healers-they're teachers, too. PMID- 26018013 TI - Genetic variability and phenotypic plasticity of metric thoracic traits in an invasive drosophilid in America. AB - Thermal phenotypic plasticity of 5 metric thoracic traits (3 related to size and 2 to pigmentation) was investigated in Zaprionus indianus with an isofemale line design. Three of these traits are investigated for the first time in a drosophilid, i.e. thorax width and width of pigmented longitudinal white and black stripes. The reaction norms of white and black stripes were completely different: white stripes were insensitive to growth temperature while the black stripes exhibited a strong linear decrease with increasing temperatures. Thorax width exhibited a concave reaction norm, analogous but not identical to those of wing length and thorax length: the temperatures of maximum value were different, the highest being for thorax width. All traits exhibited a significant heritable variability and a low evolvability. Sexual dimorphism was very variable among traits, being nil for white stripes and thorax width, and around 1.13 for black stripes. The ratio thorax length to thorax width (an elongation index) was always >1, showing that males have a more rounded thorax at all temperatures. Black stripes revealed a significant increase of sexual dimorphism with increasing temperature. Shape indices, i.e. ratios between size traits all exhibited a linear decrease with temperature, the least sensitive being the elongation index. All these results illustrate the complexity of developmental processes but also the analytical strength of biometrical plasticity studies in an eco-devo perspective. PMID- 26018015 TI - Dear prime minister.... PMID- 26018014 TI - Early medical skull surgery for treatment of post-traumatic osteomyelitis 5,000 years ago. AB - Here we describe the findings of a unique example of the early techniques adopted in neurosurgery around 5000 years ago, consisting in a double well healed skull trephination associated with a post-cranial traumatic event occurring intra vitam to a young male from the Early Chalcolithic cemetery of Pontecagnano (South Italy, ca. 4,900 - 4,500 cal BP). Morphological, X-ray and 3D-CT scan skull-cap evaluation revealed that the main orifice was produced by scraping, obtained by clockwise rotary motion of a right-handed surgeon facing the patient, while the partial trephination was carried out by using a stone point as a drilling tool. In both cases, bone regrowth is indicative of the individual's prolonged postoperative survival and his near-complete recovery. The right femur shows a poorly healed mid-shaft fracture presumably induced by a high energy injury, and a resulting chronic osteomyelitis, affecting both femurs by hematogenous spread of the infection. Our observations on the visual and radiological features of skull and femur lesions, along with evidence on the timing of experimental bone regrowth vs. healing of lower limb fractures associated to long-term bone infections now suggest that this young man underwent a double skull trephination in order to alleviate his extremely painful condition induced by chronic osteomyelitis, which is thought to have been the cause of death. PMID- 26018016 TI - Pilot: Care Makers in a CCG. PMID- 26018017 TI - Appropriate care for children with eating disorders and obesity. AB - Eating disorders are essentially psychological diseases that are characterised by abnormal eating habits. Anorexia nervosa and bulimia are the most common forms of eating disorders. There is an increased recognition of eating disorders among both men and women, and growing numbers of children and teenagers seeking help for eating disorders. Fear of body-weight gain is central to both anorexia nervosa and bulimia. Before the diagnosis of an eating disorder is made, it is essential to exclude organic diseases that may present with similar symptoms to eating disorders. Management initially should focus on correcting the nutritional deficiencies and dehydration at a paediatric or paediatric gastroenterology department, followed by a multidisciplinary approach. At the other extreme, the prevalence of obesity in children is increasing at an alarming rate, and presents a serious public health challenge. PMID- 26018018 TI - Personal and professional challenges of nurse prescribing in Ireland. AB - This article presents the challenges regarding the development of a collaborative practice agreement in order to undertake nurse prescribing in an emergency department in a large teaching hospital. Nurse prescribing has been introduced quite recently in Ireland. Although there is a plethora of knowledge regarding the topic, there are many personal and professional challenges in relation to this emerging role. The nurse prescribing initiative in Ireland is continually developing and many nurses now have the authority to prescribe from almost the same range of medicines as doctors. Prescribing has the potential to improve job satisfaction, autonomy and ultimately improves patient outcomes. However, nurses need to be cognisant of the impact it can have on the dynamics of the healthcare team. An analysis of some complexities of nurse prescribing is given, in conjunction with reflective thoughts on a clinical incident in the area of morphine prescribing. PMID- 26018019 TI - Leaving work at work: a balanced, compassionate, separate home life. AB - We all know it's important to keep our work and home lives separate, but in an age of new media, of being constantly 'on', how can we do this in practice? These issues are even more acute for nurses, argues Aysha Mendes, since the emotional nature of their work makes 'switching off' all the harder. PMID- 26018020 TI - The mentor as a role model and the importance of belongingness. AB - Nursing staff are frontline workers and service users are constantly observing their behaviour and what, how and when they do things. Being professional at all times is essential for nurses and other health professionals. Student nurses in the learning environment will emulate staff nurses and mentors as role models for their future practice. This article will focus on the importance of role modelling and 'belongingness' in practice, and how mentors may influence the pre registration student nurse while in the learning environment. This is the final article in a series of five articles on mentoring. PMID- 26018021 TI - Noise at night in hospital general wards: a mapping of the literature. AB - English NHS inpatient surveys consistently identify that noise at night in hospitals and its impact on patients' sleep is a persisting problem that needs addressing. To identify how noise at night in hospital affects patients on general wards and the range of interventions aimed at reducing the problem, a systematic mapping of the literature was undertaken. All primary studies and relevant literature published January 2003-July 2013 were included. Key issues identified in the literature included noise levels and causes, impact on patient experience, and lack of staff awareness. Interventions to reduce noise were targeted at staff education, behaviour modification, care organisation and environmental solutions. The scoping suggested that when compared with specialist units, there is little evidence on effective interventions reducing disturbance from night-time noise on general wards. The available evidence suggests a whole systems approach should be adopted to aid quality sleep and promote recovery. PMID- 26018022 TI - Clean intermittent self-catheterisation: to teach or not to teach? PMID- 26018023 TI - Parliamentary and Health Service Ombudsman: addressing the failings. AB - John Tingle discusses the Patients Association follow-up report which details major failings in the way the Parliamentary and Health Service Ombudsman deals with NHS complaints. PMID- 26018024 TI - Protecting students who raise concerns about care delivery. AB - Alan Gasper, emeritus professor at the University of Southampton, discusses revised legislation launched in April 2015, which has been formulated to protect student nurses and midwives from retaliation or victimisation when they raise concerns about things they have witnessed in practice. PMID- 26018025 TI - Relationships: from staff nurse to nurse consultant. Part 6: with senior managers. PMID- 26018026 TI - Education for workforce planning. PMID- 26018027 TI - Is 'boarding' appropriate to help reduce overcrowding in A&E? PMID- 26018028 TI - Hypoxia enhances cholangiocarcinoma invasion through activation of hepatocyte growth factor receptor and the extracellular signal-regulated kinase signaling pathway. AB - Hypoxia is associated with tumor progression and poor prognosis in several cancer types. The present study aimed to examine the contribution of hypoxia (1% O2) to cancer progression in a cholangiocarcinoma cell line, RMCCA-1. The molecular basis of the hypoxic response pathway was investigated. The results showed that hypoxia significantly accelerated cancer cell proliferation and enhanced cell invasion (P<0.05). By using receptor tyrosine kinase and intracellular signaling antibody array kits, an increased phosphorylation/activation of a number of signaling molecules, particularly hepatocyte growth factor receptor (Met) and extracellular signal-regulated kinase (ERK) 1/2, was identified. Inhibition of Met and ERK by small hairpin RNA and U0126, respectively, significantly inhibited hypoxia-induced the invasive potential of RMCCA-1 cells (P<0.05). However, according to immunohistochemical analysis, hypoxia-inducible factor-1alpha expression was not correlated with cancer staging or tumor differentiation in 44 samples of cholangicarcinoma cases. The findings of the present study emphasized the importance of Met/ERK pathway activation as a key molecular event that may be responsible for a more invasive phenotype in hypoxic tumors and suggest Met as a potential target for the treatment of cholangiocarcinoma. PMID- 26018029 TI - Aquifer Vulnerability Assessment Based on Sequence Stratigraphic and 39Ar Transport Modeling. AB - A large-scale groundwater flow and transport model is developed for a deep-seated (100 to 300 m below ground surface) sedimentary aquifer system. The model is based on a three-dimensional (3D) hydrostratigraphic model, building on a sequence stratigraphic approach. The flow model is calibrated against observations of hydraulic head and stream discharge while the credibility of the transport model is evaluated against measurements of (39)Ar from deep wells using alternative parameterizations of dispersivity and effective porosity. The directly simulated 3D mean age distributions and vertical fluxes are used to visualize the two-dimensional (2D)/3D age and flux distribution along transects and at the top plane of individual aquifers. The simulation results are used to assess the vulnerability of the aquifer system that generally has been assumed to be protected by thick overlaying clayey units and therefore proposed as future reservoirs for drinking water supply. The results indicate that on a regional scale these deep-seated aquifers are not as protected from modern surface water contamination as expected because significant leakage to the deeper aquifers occurs. The complex distribution of local and intermediate groundwater flow systems controlled by the distribution of the river network as well as the topographical variation (Toth 1963) provides the possibility for modern water to be found in even the deepest aquifers. PMID- 26018030 TI - Ebola virus disease and the veterinary perspective. AB - Ebola virus disease (EVD) is a potentially fatal haemorrhagic disease of humans. The last and most serious outbreak of Ebola virus (EBOV) started in December 2013 in West Africa and also affected other continents. Animals such as fruit bats and non-human primates are potential sources of EBOV. This review highlights the clinical features of EVD in humans and animals and addresses the public health implications of EVD outbreaks from the veterinary perspective. PMID- 26018032 TI - Optimizing Informed Decision Making for Basal Cell Carcinoma in Patients 85 Years or Older. PMID- 26018033 TI - Reply to BRCA2-associated pancreatic cancer and current screening guidelines. PMID- 26018031 TI - Nicotine and the adolescent brain. AB - Adolescence encompasses a sensitive developmental period of enhanced clinical vulnerability to nicotine, tobacco, and e-cigarettes. While there are sociocultural influences, data at preclinical and clinical levels indicate that this adolescent sensitivity has strong neurobiological underpinnings. Although definitions of adolescence vary, the hallmark of this period is a profound reorganization of brain regions necessary for mature cognitive and executive function, working memory, reward processing, emotional regulation, and motivated behavior. Regulating critical facets of brain maturation are nicotinic acetylcholine receptors (nAChRs). However, perturbations of cholinergic systems during this time with nicotine, via tobacco or e-cigarettes, have unique consequences on adolescent development. In this review, we highlight recent clinical and preclinical data examining the adolescent brain's distinct neurobiology and unique sensitivity to nicotine. First, we discuss what defines adolescence before reviewing normative structural and neurochemical alterations that persist until early adulthood, with an emphasis on dopaminergic systems. We review how acute exposure to nicotine impacts brain development and how drug responses differ from those seen in adults. Finally, we discuss the persistent alterations in neuronal signaling and cognitive function that result from chronic nicotine exposure, while highlighting a low dose, semi-chronic exposure paradigm that may better model adolescent tobacco use. We argue that nicotine exposure, increasingly occurring as a result of e-cigarette use, may induce epigenetic changes that sensitize the brain to other drugs and prime it for future substance abuse. PMID- 26018034 TI - Work related etiology of de Quervain's tenosynovitis: a case-control study with prospectively collected data. AB - BACKGROUND: The etiology of de Quervain's tenosynovitis (dQ) has been based on conflicting small case series and cohort studies lacking methodological rigor. A prospective case-control study was conducted to analyze the most common risk factors for dQ. METHODS: Between January 2003 and May 2011, 189 patients surgically treated for dQ vs. 198 patients with wrist ganglia (WG) (controls) were identified in our clinic's electronic database. Sample characteristics, exertional, anatomical, and medical risk factors were compared between groups. RESULTS: dQ vs. WG differed by average age (52 vs. 43 years) and gender ratio (15/62 vs. 26/39). No significant difference between dQ vs. WG was found after subgrouping professional activities (manual labor: 18 % vs. 26 %, respectively, p = 0.23). No asymmetric distribution of comorbidities, wrist trauma, forceful or repetitive manual work, or medication was observed. CONCLUSIONS: Neither heavy manual labor nor trauma could be shown to be predisposing risk factors for dQ. PMID- 26018035 TI - Expression profiles of astakine-like transcripts in the tarnished plant bug, Lygus lineolaris, exposed to fungal spores of Beauveria bassiana. AB - Astakines are hematopoietic cytokines originally isolated from crustaceans. We identified three astakine-like transcripts in the tarnished plant bug (Lygus lineolaris), LlAst-1, LlAst-2 and LlAst-3, containing prokineticin domains. Quantitative real-time PCR showed variation in expression patterns of astakines in different tissues and between sexes. Relative expression levels of LlAst-1 were highest in the fat bodies of females, while LlAst-2 expression was highest in the fat bodies of both males and females. LlAst-3 expression was higher in male legs compared with the female legs, but lower in all other tissues. Infection with the entomopathogenic fungus Beauveria bassiana slightly elevated LlAst-1 expression 48 h after infection in both males and females. In contrast, the expression levels of LlAst-2 and LlAst-3 were not significantly changed in males and females. Compared with 12:00 h, LlAst-1 level was higher in both sexes at 18:00 h and 00:00 h (midnight). By 6:00 h, the LlAst-1 level in females was significantly reduced while that in males remained high. LlAst-2 and -3 had highest relative expression levels in females at midnight but were significantly lower than in males at midnight and in both sexes at 18:00 h and 6:00 h. This is the first report of expression of astakine-like cytokines from insects. PMID- 26018037 TI - ALK-positive anaplastic large cell lymphoma with prominent bone involvement. PMID- 26018036 TI - Randomized, Double-Blind, Placebo-Controlled Study on Decolonization Procedures for Methicillin-Resistant Staphylococcus aureus (MRSA) among HIV-Infected Adults. AB - BACKGROUND: HIV-infected persons have increased risk of MRSA colonization and skin and soft-tissue infections (SSTI). However, no large clinical trial has examined the utility of decolonization procedures in reducing MRSA colonization or infection among community-dwelling HIV-infected persons. METHODS: 550 HIV infected adults at four geographically diverse US military HIV clinics were prospectively screened for MRSA colonization at five body locations every 6 months during a 2-year period. Those colonized were randomized in a double-blind fashion to nasal mupirocin (Bactroban) twice daily and hexachlorophene (pHisoHex) soaps daily for 7 days compared to placeboes similar in appearance but without specific antibacterial activity. The primary endpoint was MRSA colonization at 6 months post-randomization; secondary endpoints were time to MRSA clearance, subsequent MRSA infections/SSTI, and predictors for MRSA clearance at the 6-month time point. RESULTS: Forty-nine (9%) HIV-infected persons were MRSA colonized and randomized. Among those with 6-month colonization data (80% of those randomized), 67% were negative for MRSA colonization in both groups (p = 1.0). Analyses accounting for missing 6-month data showed no significant differences could have been achieved. In the multivariate adjusted models, randomization group was not associated with 6-month MRSA clearance. The median time to MRSA clearance was similar in the treatment vs. placebo groups (1.4 vs. 1.8 months, p = 0.35). There was no difference on subsequent development of MRSA infections/SSTI (p = 0.89). In a multivariable model, treatment group, demographics, and HIV-specific factors were not predictive of MRSA clearance at the 6-month time point. CONCLUSION: A one-week decolonization procedure had no effect on MRSA colonization at the 6 month time point or subsequent infection rates among community-dwelling HIV infected persons. More aggressive or novel interventions may be needed to reduce the burden of MRSA in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00631566. PMID- 26018038 TI - Redox-Controlled Ion-Pairing Association of Anionic Surfactant to Ferrocene Terminated Self-Assembled Monolayers. AB - The redox-induced pairing from aqueous solution of a homologous series of sodium n-alkyl sulfate (NaCnSO4) surfactants of 6, 8, 10, and 12 carbons with gold tethered self-assembled monolayers (SAMs) of ferrocenyldodecanethiolate (FcC12SAu) is investigated by cyclic voltammetry combined with surface plasmon resonance (SPR) spectroscopy. The adsorbed layer thicknesses and surface coverages are consistent with the formation of a monolayer of CnSO4(-) at the oxidized FcC12SAu SAM/aqueous solution interface. A comparison of the anodic charge density with the SPR data indicates that approximately 60% of the adsorbed surfactant anions are paired with SAM-bound ferroceniums, suggesting an interdigitated layer structure. The ion-pairing capabilities of the longer-chain NaC12SO4, NaC10SO4, and NaC8SO4 relative to the short-chain NaC6SO4 are compared using the relative ion-pair formation constants calculated from the apparent SAM redox potentials and IC50 values obtained from competitive association experiments. A longer alkyl chain increases the overall hydrophobicity of the CnSO4(-) anion, thereby increasing its ability to pair with and stabilize the ferrocenium in the nonpolar environment of the SAM. Binary mixtures of NaC12SO4 and NaC6SO4 of different compositions are used to demonstrate that the differences in ion-pairing abilities can be exploited to selectively pair and adsorb C12SO4(-). PMID- 26018039 TI - Patterns of a culture of aggression amongst Grade 10 learners in a secondary school in the Sedibeng District, South Africa. AB - BACKGROUND: A number of reports to the Department of Education indicated high levels of aggression in a Grade 10 A class in a secondary school in Sedibeng District, Gauteng. Teachers, the school management team, school governing body, school-based support team, parents, community leaders and learners seemed unable to manage this constructively. Neither the culture of aggression nor the influence of this phenomenon on those entrapped in it were understood. No published research reports could be found on cultures of aggression in South African secondary schools. There was therefore a dire need to explore and describe the culture of aggression in this specific Grade 10 A class. OBJECTIVES: This article reports on patterns of a culture of aggression observed amongst learners in a Grade 10 class in a secondary school in the Sedibeng District of the Gauteng Department of Education. METHOD: A qualitative, exploratory, descriptive and contextual research design was followed with an ethnographic approach. Purposive sampling was used to select participants. Data consisted of observations of 'rich points', interviews and field notes, and thematic data analysis and an independent coder were used. RESULTS: Findings reflected four patterns of a culture of aggression amongst learners, namely patterns of anger, bullying, fighting, and challenges to moral values. At the root of these were neglect of and non-adherence to human rights and a sound base of morals. CONCLUSION: The challenge is to assist the involved learners to respect each other's human dignity, so that relationships can be developed in which those involved act with sensitivity towards each other's needs. Such relationships often also result in the development of self-respect and a nuanced future orientation as part and parcel of mental health. PMID- 26018040 TI - Bone marrow mesenchymal stem cells could acquire the phenotypes of epithelial cells and accelerate vaginal reconstruction combined with small intestinal submucosa. AB - Grafting material for vaginal reconstruction commonly includes the bowel, peritoneum, skin, and amniotic membrane. Bone marrow mesenchymal stem cells (MSCs) have the potential of multilineage differentiation into a variety of cells and have been widely explored in tissue engineering. In the current study, we examined whether MSCs could be differentiated to vaginal epithelial cells (VECs) upon co-culturing with VECs. We also examined whether Wnt/beta-catenin signaling pathway is implicated in such differentiation. Co-culture of MSCs with VECs using a transwell insert system (with no direct contact) induced the expression of VECs marker AE1/AE3 in MSCs. MSCs combined with small intestinal submucosa (SIS) scaffold were implanted in place of the native vagina in rats to observe the implications for vaginal reconstruction in vivo. Anatomic repair of neovagina was assessed by histological staining for H/E and Masson's Trichrome. GSK-3beta and beta-catenin, main members of Wnt/beta-catenin signaling pathway, in MSCs were increased upon co-culturing with VECs. Exposure of co-cultured MSCs to a Wnt/beta catenin signaling activator, lithium chloride (LiCl, 20 uM) increased phosphorylated GSK-3beta and beta-catenin and enhanced expression of AE1/AE3. In vivo-grafted cells displayed significant matrix infiltration and expressed epithelial markers in neovagina. These findings suggest that MSCs could acquire the phenotype of VECs when co-cultured with VECs, possibly via activation of Wnt/beta-catenin signaling. MSCs provide an alternative cell source for potential use in vaginal tissue engineering. PMID- 26018041 TI - Reasoning training in veteran and civilian traumatic brain injury with persistent mild impairment. AB - Traumatic brain injury (TBI) is a chronic health condition. The prevalence of TBI, combined with limited advances in protocols to mitigate persistent TBI related impairments in higher order cognition, present a significant challenge. In this randomised study (n = 60), we compared the benefits of Strategic Memory Advanced Reasoning Training (SMART, n = 31), a strategy-based programme shown to improve cognitive control, versus an active learning programme called Brain Health Workshop (BHW, n = 29) in individuals with TBI with persistent mild functional deficits. Outcomes were measured on cognitive, psychological health, functional, and imaging measures. Repeated measures analyses of immediate post training and 3-month post-training demonstrated gains on the cognitive control domain of gist reasoning (ability to abstract big ideas/goals from complex information/tasks) in the SMART group as compared to BHW. Gains following the SMART programme were also evident on improved executive function, memory, and daily function as well as reduced symptoms associated with depression and stress. The SMART group showed an increase in bilateral precuneus cerebral blood flow (CBF). Improvements in gist reasoning in the SMART group were also associated with an increase in CBF in the left inferior frontal region, the left insula and the bilateral anterior cingulate cortex. These results add to prior findings that the SMART programme provides an efficient set of strategies that have the potential to improve cognitive control performance and associated executive functions and daily function, to enhance psychological health, and facilitate positive neural plasticity in adults with persistent mild impairment after TBI. PMID- 26018042 TI - Stretching the Traditional Notion of Experiment in Computing: Explorative Experiments. AB - Experimentation represents today a 'hot' topic in computing. If experiments made with the support of computers, such as computer simulations, have received increasing attention from philosophers of science and technology, questions such as "what does it mean to do experiments in computer science and engineering and what are their benefits?" emerged only recently as central in the debate over the disciplinary status of the discipline. In this work we aim at showing, also by means of paradigmatic examples, how the traditional notion of controlled experiment should be revised to take into account a part of the experimental practice in computing along the lines of experimentation as exploration. Taking inspiration from the discussion on exploratory experimentation in the philosophy of science-experimentation that is not theory-driven-we advance the idea of explorative experiments that, although not new, can contribute to enlarge the debate about the nature and role of experimental methods in computing. In order to further refine this concept we recast explorative experiments as socio technical experiments, that test new technologies in their socio-technical contexts. We suggest that, when experiments are explorative, control should be intended in a posteriori form, in opposition to the a priori form that usually takes place in traditional experimental contexts. PMID- 26018044 TI - Free electrons and ionic liquids: study of excited states by means of electron energy loss spectroscopy and the density functional theory multireference configuration interaction method. AB - The technique of low energy (0-30 eV) electron impact spectroscopy, originally developed for gas phase molecules, is applied to room temperature ionic liquids (IL). Electron energy loss (EEL) spectra recorded near threshold, by collecting 0 2 eV electrons, are largely continuous, assigned to excitation of a quasi continuum of high overtones and combination vibrations of low-frequency modes. EEL spectra recorded by collecting 10 eV electrons show predominantly discrete vibrational and electronic bands. The vibrational energy-loss spectra correspond well to IR spectra except for a broadening (~0.04 eV) caused by the liquid surroundings, and enhanced overtone activity indicating a contribution from resonant excitation mechanism. The spectra of four representative ILs were recorded in the energy range of electronic excitations and compared to density functional theory multireference configuration interaction (DFT/MRCI) calculations, with good agreement. The spectra up to about 8 eV are dominated by pi-pi* transitions of the aromatic cations. The lowest bands were identified as triplet states. The spectral region 2-8 eV was empty in the case of a cation without pi orbitals. The EEL spectrum of a saturated solution of methylene green in an IL band showed the methylene green EEL band at 2 eV, indicating that ILs may be used as a host to study nonvolatile compounds by this technique in the future. PMID- 26018043 TI - Temporal regulation of kin recognition maintains recognition-cue diversity and suppresses cheating. AB - Kin recognition, the ability to distinguish kin from non-kin, can facilitate cooperation between relatives. Evolutionary theory predicts that polymorphism in recognition cues, which is essential for effective recognition, would be unstable. Individuals carrying rare recognition cues would benefit less from social interactions than individuals with common cues, leading to loss of the genetic-cue diversity. We test this evolutionary hypothesis in Dictyostelium discoideum, which forms multicellular fruiting bodies by aggregation and utilizes two polymorphic membrane proteins to facilitate preferential cooperation. Surprisingly, we find that rare recognition variants are tolerated and maintain their frequencies among incompatible majority during development. Although the rare variants are initially excluded from the aggregates, they subsequently rejoin the aggregate and produce spores. Social cheating is also refrained in late development, thus limiting the cost of chimerism. Our results suggest a potential mechanism to sustain the evolutionary stability of kin-recognition genes and to suppress cheating. PMID- 26018045 TI - Exon 3 deletion of ryanodine receptor causes left ventricular noncompaction, worsening catecholaminergic polymorphic ventricular tachycardia, and sudden cardiac arrest. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant genetic channelopathy associated with exertional syncope and reproducible polymorphic ventricular tachycardia with exercise. Approximately 65% of patients with CPVT are found to have a disease causing mutation in the RYR2 gene. RYR2 encodes a calcium ion transporter in the sarcomeric reticulum, and is responsible for the calcium induced calcium release that results in ventricular contraction. Recently, exon 3 deletion of RYR2 has been reported to be associated with left ventricular noncompaction. Herein we describe a patient with a novel, de novo deletion of exon 3 in the RYR2 gene that resulted in a severe CPVT phenotype and sudden cardiac arrest (SCA), and the development of left ventricular non-compaction (LVNC) coinciding with worsening arrhythmias. This case is unique in that the patient initially presented with exertional syncope and developed LVNC that coincided with increasingly severe ventricular arrhythmias and multiple episodes of SCA. This case supports the idea that RYR2 deletions cause a severe subtype of CPVT associated with LVNC and suggests LVNC may play a role in exacerbating the arrhythmias of CPVT. Deletion duplication testing should be considered in the context of CPVT and LVNC or SCA. PMID- 26018046 TI - MicroRNA-199a induces differentiation of induced pluripotent stem cells into endothelial cells by targeting sirtuin 1. AB - The ability to reprogram induced pluripotent stem (iPS) cells from somatic cells may facilitate significant advances in regenerative medicine. MicroRNAs (miRNAs) are involved in a number of core biological processes, including cardiogenesis, hematopoietic lineage differentiation and oncogenesis. An improved understanding of the complex molecular signals that are required for the differentiation of iPS cells into endothelial cells (ECs) may allow specific targeting of their activity in order to enhance cell differentiation and promote tissue regeneration. The present study reports that miR-199a is involved in EC differentiation from iPS cells. Augmented expression of miR-199a was detected during EC differentiation, and reached higher levels during the later stages of this process. Furthermore, miR-199a inhibited the differentiation of iPS cells into smooth muscle cells. Notably, sirtuin 1 was identified as a target of miR-199a . Finally, the ability of miR-199a to induce angiogenesis was evaluated in vitro, using Matrigel plugs assays. This may indicate a novel function for miR-199a as a regulator of the phenotypic switch during vascular cell differentiation. The present study provides support to the notion that with an understanding of the molecular mechanisms underlying vascular cell differentiation, stem cell regenerative therapy may ultimately be developed as an effective treatment for cardiovascular disease. PMID- 26018047 TI - [Factors associated with depressive symptoms in blue-collar and white-collar male workers]. AB - OBJECTIVES: Mental disorders are increasing and their influence on productivity is a concern in the workplace. However, few studies have investigated depression among blue-collar and white-collar workers in the manufacturing industry. The purpose of this study was to clarify the factors associated with depressive symptoms, focusing on lifestyles and insomnia. METHODS: A self-administered questionnaire survey was conducted of 1,963 workers at an annual health checkup in a manufacturing company. Of the 1,712 respondents (response rate: 87%), 1,258 male worker subjects (blue-collar 674; white-collar 584) were analyzed after excluding those with mental diseases. The questionnaire included items on basic attributes and lifestyle. The Athens Insomnia Scale (AIS) and The Center for Epidemiologic Studies for Depression Scale (CES-D) were used to evaluate insomnia and depressive symptoms. RESULTS: The incidence of depressive symptoms with CES-D scores of >=16 was 15.1% in both the blue-collar and the white-collar workers. Insomnia with AIS scores of >=6 were encountered in 18.8% of the blue-collar workers and 18.3% of the white-collar workers. Multiple logistic regression analyses showed that for the blue-collar workers, depressive symptoms were associated with "AIS scores >=6" (Odds ratio (OR): 10.93; 95% confidence interval (CI): 6.12-19.15), "not get rid of fatigue with sleep" (OR: 3.36; 95%CI: 1.85 6.09), "skip breakfast over 3 times a week" (OR: 3.10; 95%CI:1.42-6.76), "no family living together" (OR: 2.08; 95%CI: 1.05-4.12), and "commuting time" (OR: 1.01; 95%CI: 1.00-1.02). For the white-collar workers, depressive symptoms were related to "AIS scores >=6" (OR: 14.91; 95%CI: 7.54-29.49), and "no family living together" (OR: 2.54; 95%CI: 1.27-5.09). Sleep time was not associated with depression in both blue- and white-collar workers. Depressive symptoms were found in 51.6% of the blue-collar workers with insomnia with AIS scores >=6 and 53.8% of white-collar workers. CONCLUSIONS: Depressive symptoms were found at the same prevalence rate in both blue-collar and white-collar workers, which suggests that health measures for depression are necessary for both types of worker. Depressive symptoms were significantly associated with insomnia. Health advice focusing on insomnia as well as lifestyle may be important for workers. PMID- 26018049 TI - Endoscopic pilonidal sinus treatment in the Asian population. AB - INTRODUCTION: This study aims to evaluate the early results of endoscopic pilonidal sinus treatment (EPSiT) in the Asian population and illustrate the surgical technique and its modifications by a video presentation (Supplemental Digital Content 1, http://links.lww.com/SLE/A115). MATERIALS AND METHODS: Retrospective review of 9 patients with pilonidal sinus disease treated with EPSiT is performed in a single institution. Surgical outcomes of sinus healing, pain, and discharge were reviewed in the outpatient clinic and patient satisfaction levels were assessed through a standardized phone interview. RESULTS: The median age was 24 years (range, 16 to 41 y). The median duration of follow-up was 2.5 months (range, 1 to 5 mo). Median duration of sinus healing is 6 weeks (range, 2 to 7 wk). One patient had pain despite sinus healing. Satisfaction rate was 78% (7/9). CONCLUSIONS: EPSiT is a minimally invasive and cosmetically favorable procedure. A larger sample size and a longer follow-up is required to determine if it improves healing time and long-term recurrence rate. PMID- 26018048 TI - A cluster randomized Hybrid Type III trial testing an implementation support strategy to facilitate the use of an evidence-based practice in VA homeless programs. AB - BACKGROUND: The Housing and Urban Development-Veterans Affairs Supportive Housing (HUD-VASH) program is one of the largest initiatives to end Veteran homelessness. However, mental health and substance use disorders continue to reduce client stability and impede program success. HUD-VASH programs do not consistently employ evidence-based practices that address co-occurring mental health and substance use disorders. This paper presents a study protocol to evaluate the implementation of an evidence-based, co-occurring disorder treatment called Maintaining Independence and Sobriety Through Systems Integration, Outreach, and Networking-Veterans Edition (MISSION-Vet) in HUD-VASH using an implementation strategy called Getting To Outcomes (GTO). METHODS/DESIGN: In three large VA Medical Centers, this Hybrid Type III trial will randomize case managers and their clients by HUD-VASH sub-teams to receive either MISSION-Vet Implementation as Usual (IU-standard training and access to the MISSION-Vet treatment manuals) or MISSION-Vet implementation augmented by GTO. In addition to testing GTO, effectiveness of the treatment (MISSION-Vet) will be assessed using existing Veteran-level data from the HUD-VASH data monitoring system. This project will compare GTO and IU case managers and their clients on the following variables: (1) fidelity to the MISSION-Vet intervention; (2) proportion of time the Veteran is housed; (3) mental health, substance use, and functional outcomes among Veterans; and (4) factors key to the successful deployment of a new treatment as specified by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model. DISCUSSION: This project is an important step for developing an implementation strategy to increase adoption of evidence-based practice use in VA homeless programs, and to further examine efficacy of MISSION-Vet in HUD-VASH. This project has important implications for program managers, policy makers, and researchers within the homelessness field. VA Central IRB approval for this study was granted in October 2011. The three sites were trained on MISSION-Vet and GTO in the first half of 2013. The first GTO planning meetings began after training occurred, between January 2013 and November 2013, across the three sites. The data collection-via a fidelity measure embedded into the VA Computerized Patient Record System-began as each site initiated MISSION-Vet, between April 2013 and January 2014. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01430741. PMID- 26018050 TI - The Use of Mesh in Laparoscopic Large Hiatal Hernia Repair: A Survey of European Surgeons. AB - PURPOSE: The aim of this study was to evaluate the current opinion of the individual European surgeons on the use of mesh in large hiatal hernia repair. METHODS: A Web-based questionnaire was e-mailed to European upper gastrointestinal surgeons identified by the European Association for Endoscopic Surgery. RESULTS: The questionnaire was completed by 165 surgeons. Mesh is routinely applied by 24 respondents (14.5%), selectively by 128 (77.6%), never used by 11 (6.7%), and 2 failed to respond. A polypropylene mesh is used by 81 (52.6%), polyester by 24 (15.6%), PTFE by 12 (7.8%), ePTFE by 49 (31.8%), and biomesh by 43 respondents (27.9%). A vast variation in mesh configuration and positioning is used. Esophageal erosions were encountered by 33 (20.0%) and esophageal stenosis due to dense fibrosis by 34 (20.6%). CONCLUSIONS: The results of this survey are very instructive for the individual surgeons throughout the world as these illustrate how colleagues in Europe handle the controversial issues in large hiatal hernia repair. PMID- 26018051 TI - Robotic Thyroidectomy: Is it a Futile Surgical Approach? PMID- 26018052 TI - Safety and efficacy of palliative colorectal stent placement using a nasal endoscope technique. AB - The purpose of this study was to evaluate the safety and efficacy of palliative self-expanding metallic stent (SEMS) placement using a nasal endoscope technique in the context of colorectal malignant obstruction. Eighteen patients with malignant colorectal obstruction who underwent palliative SEMS insertion using a nasal endoscope technique at the Toyonaka Municipal Hospital from August 2005 to August 2011 were enrolled and retrospectively analyzed. In all cases, a guidewire could be inserted on the oral side of the tumor. The placement success rate was 94.4% (17/18), and the complication rate was 23.5% (4 cases). The stent migrated in 3 cases, and perforation occurred in 1 case following bevacizumab chemotherapy. These outcomes indicate that stenting is useful for terminal patients and that nasal endoscopy is useful in cases of difficult guidewire placement. PMID- 26018053 TI - Open Versus Laparoscopic Inguinal Herniotomy in Children: A Systematic Review and Meta-Analysis Focusing on Postoperative Complications. AB - PURPOSE: There is an ongoing debate about whether laparoscopic or open herniorrhaphy (LH or OH) is the best choice for inguinal hernia in children. The aim of this study was to compare both of the surgical strategies as regards operative time, recurrence rate, postoperative complications by means of a systematic review, and meta-analysis of the available literatures. METHODS: A systematic search for randomized clinical trials comparing OH and LH was conducted. Studies were reviewed for quality, inclusion and exclusion criteria, operative time for bilateral and unilateral hernias, recurrence, and complications. RESULTS: Five randomized clinical trials with a total of 553 children (OH 278, LH 275) fulfilled the inclusion criteria and were analyzed in this review. Compared with OH, shorter operative time for unilateral hernias was noted in extraperitoneal approaches' group [95% confidence interval (CI), -6.71 to -3.71; I2=0%] as well as for bilateral hernias (95% CI, -12.18 to -3.79; I2=82%). Besides, less total postoperative complications was found in LH group, especially for major postoperative complications in male children (95% CI, 0.01 0.78; I2=0%). However, no significant difference was observed between LH and OH in patients' recurrence. CONCLUSIONS: This meta-analysis favors LH in the repair of bilateral hernias and for unilateral hernias in extraperitoneal approaches' group. Total postoperative complications were significantly reduced in LH, especially for major postoperative complications in male children. PMID- 26018054 TI - Effectiveness of Local Anesthetics in Laparoscopic Cholecystectomy: A Randomized Clinical Trial. AB - BACKGROUND: Laparoscopic cholecystectomy is the gold standard for gallstone disease. Postoperative pain still is considerable and may prevent early discharge. METHODS: A randomized controlled blind clinical trial was designed for all patients undergoing laparoscopic cholecystectomy. The groups were control (group A), preincisional trocar wound infiltration with bupivacaine (group B), and preincisional trocar wound infiltration and intraperitoneal instillation of bupivacaine over the gallbladder and liver surface before starting the dissection (group C). The operative technique and postoperative analgesia were standardized. The pain in 6 hours was assessed with the visual analog scale as the primary outcome. RESULTS: The visual analog pain scores in the intraperitoneal bupivacaine were similar to the trocar wound infiltration alone and both were lower than the control group (P=0.05616). CONCLUSIONS: Intraperitoneal application of local anesthetics and trocar wound infiltration did not lower the pain scores in comparison with trocar wound infiltration in our study. PMID- 26018055 TI - Laparoscopic Pyloroduodenal Wrap Utilizing the Lesser Omentum: A Novel Emergency Surgery Technique. AB - BACKGROUND: It has been a long time since Roscoe Graham in 1938 started his technique using the greater omentum patching perforated peptic ulcers. The traditional technique was suitable for the open surgical access but not for the laparoscopic one. The lesser omentum offers a more readily potent tissue flap that is both anatomically and surgically optimistic to the laparoscopic technique. MATERIALS AND METHODS: This is a preliminary case series pilot study describing a new surgical technique for repair of perforated peptic ulcer. Between February 2013 and April 2014, 27 adult patients were recruited for the study. RESULTS: All patients were operated by laparoscopy with no case conversion to open. Patient's data and results are scheduled in tables. Neither postoperative complication nor reperforation was recorded. CONCLUSIONS: Gastroduodenal wrap utilizing the lesser omentum is a novel technique based on solid concepts that suits laparoscopic specialty as a separate identity from open surgery. PMID- 26018056 TI - Re: Comparison of Stapling Techniques and Management of the Mesoappendix in Laparoscopic Appendectomy. PMID- 26018058 TI - Wear Independent Similarity. AB - This study presents a new factor that can be used to design materials where desired surface properties must be retained under in-system wear and abrasion. To demonstrate this factor, a synthetic nonwetting coating is presented that retains chemical and geometric performance as material is removed under multiple wear conditions: a coarse vitrified abradant (similar to sanding), a smooth abradant (similar to rubbing), and a mild abradant (a blend of sanding and rubbing). With this approach, such a nonwetting material displays unprecedented mechanical durability while maintaining desired performance under a range of demanding conditions. This performance, herein termed wear independent similarity performance (WISP), is critical because multiple mechanisms and/or modes of wear can be expected to occur in many typical applications, e.g., combinations of abrasion, rubbing, contact fatigue, weathering, particle impact, etc. Furthermore, these multiple wear mechanisms tend to quickly degrade a novel surface's unique performance, and thus many promising surfaces and materials never scale out of research laboratories. Dynamic goniometry and scanning electron microscopy results presented herein provide insight into these underlying mechanisms, which may also be applied to other coatings and materials. PMID- 26018057 TI - Gap Effect Abnormalities during a Visually Guided Pro-Saccade Task in Children with Attention Deficit Hyperactivity Disorder. AB - Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that starts in early childhood and has a comprehensive impact on psychosocial activity and education as well as general health across the lifespan. Despite its prevalence, the current diagnostic criteria for ADHD are debated. Saccadic eye movements are easy to quantify and may be a quantitative biomarker for a wide variety of neurological and psychiatric disorders, including ADHD. The goal of this study was to examine whether children with ADHD exhibit abnormalities during a visually guided pro-saccadic eye-movement and to clarify the neurophysiological mechanisms associated with their behavioral impairments. Thirty-seven children with ADHD (aged 5-11 years) and 88 typically developing (TD) children (aged 5-11 years) were asked to perform a simple saccadic eye-movement task in which step and gap conditions were randomly interleaved. We evaluated the gap effect, which is the difference in the reaction time between the two conditions. Children with ADHD had a significantly longer reaction time than TD children (p < 0.01) and the gap effect was markedly attenuated (p < 0.01). These results suggest that the measurement of saccadic eye movements may provide a novel method for evaluating the behavioral symptoms and clinical features of ADHD, and that the gap effect is a potential biomarker for the diagnosis of ADHD in early childhood. PMID- 26018059 TI - Landscape of Deceased Donors Labeled Increased Risk for Disease Transmission Under New Guidelines. AB - Deceased donors are labeled increased risk for disease transmission (IRD) if they meet certain criteria. New PHS guidelines were recently implemented; the impact of these changes remains unknown. We aimed to quantify the impact of the new guidelines on the proportion of deceased donors labeled IRD, as well as demographic and clinical characteristics. We used Poisson regression with an interaction term for era (new vs. old guidelines) to quantify changes. Under the new guidelines, 19.5% donors were labeled IRD, compared to 10.4%, 12.2%, and 12.3% in the 3 most recent years under the old guidelines (IRR = 1.45, p < 0.001). Increases were consistent across OPOs: 44/59 had an increase in the percent of donors labeled IRD, and 14 OPOs labeled 25% of their donors IRD under the new guidelines (vs. 5 OPOs under the old). African-Americans were 52% more likely to be labeled IRD under the new guidelines (RR = 1.52, p = 0.01). There has been a substantial increase in donors labeled IRD under the new PHS guidelines; it is important to understand the mechanism and consequences to ensure an optimal balance of patient safety and organ utilization is achieved. PMID- 26018060 TI - [Family, job and career -- is that possible?]. PMID- 26018061 TI - [News from the international literature]. PMID- 26018062 TI - [Anesthesia in interventional pulmonology -- endoscopic interventions: part 2]. AB - Endobronchial ultrasound-guided transbronchial needle aspiration can be used efficiently for pathological diagnosis of bronchial walls and surrounding structures. Patients with hemoptysis, fistulas or foreign-body-aspiration can be treated bronchoscopically, but remain a challenge for the hospital team involved. PMID- 26018063 TI - [Can anaesthetic management improve the outcome?]. AB - Despite anaesthesia-specific pharmacological and technological innovations in the last decades we are definitely aware that anaesthesia per se has the potential to induce changes in the balance of human physiology that in turn may have relevant consequences, i.e. an increase in postoperative morbidity and mortality. Today anaesthesia appears to be extremely safe, with the number of deaths solely attributed to anaesthesia having reached its lowest point in history (0.055 per 10 000 anaesthetics). However, the available data regarding anaesthesia-related mortality, solely or contributory, are not consistent and the interpretation and legibility is limited. Fortunately, the issue of "patient safety in anaesthesiology" has gained increasing interest in the last few years, yielding some very promising projects. Since most of the ideas are focused on intraoperative safety improvement strategies, it seems to be reasonable in the near future to expand to the complete perioperative period, especially the postoperative care on the ward in high-risk patients. This knowledge, combined with an ongoing promotion of patient safety in anaesthesiology and provision of adequate resources definitely will increase patient safety. Hopefully, in the end, our efforts will contribute to integrate the "patient safety in anaesthesiology concept" in daily clinical routine. PMID- 26018064 TI - [Adjuvants in modern anesthesia - lidocaine]. AB - Local anesthetics (LA) are well known for their antinociceptive and antiarrhythmic properties, but exert alternative effects, i.e. anti-inflammatory activity, as well. These immunomodulatory properties might contribute to the beneficial effects observed in the clinical setting, when intravenous lidocaine is given perioperatively. Systemic LA were shown to attenuate postoperative pain, accelerate the return of bowel function and shorten length of hospital stay in patients undergoing abdominal surgery. PMID- 26018065 TI - [Perioperative heart failure - a special challenge for anaesthesiology]. PMID- 26018066 TI - [Perioperative heart failure - acute intraoperative heart failure]. AB - With respect to the fact that - with the notable exception of patients undergoing cardiac surgery - only sparse data and limited guideline recommendations on optimal treatment strategies in patients with intraoperative acute heart failure are available. Consecutively it is rather difficult to make clear suggestions for the optimal treatment of this complication. However, data based on treatment of medical patients with acute heart failure suggest that it may be reasonable first to echocardiographically determine the specific cardiac pathology, especially with respect to systolic and diastolic function and/or presence of acute myocardial ischemia and subsequently treat the specific problem in a goal directed approach. Importantly, one has to to take into account that the use of beta-mimetic drugs for the treatment of acute heart failure is increasingly recognized as an isolated mortality factor. This suggests to use inotropes as restrictive as possible, and if inotropic treatment becomes inevitable, to use levosimendan as the only inotrope that has been shown to improve mortality in several meta-analyses. PMID- 26018067 TI - [Perioperative heart failure - anesthetic management and monitoring]. AB - Due to the demographic and medical development, the number of patients with heart failure needing anaesthesiological care will continue to grow in the upcoming years. For the optimal care of these patients close coordination between the surgically treating, the cardiology and the anesthesiological department is important. Cardiac function and structural characters, such as cardiac valve defects should be known preoperatively. Thus, the anaesthetic management, intraoperative monitoring, as well as necessary pharmacological interventions can be tailored. Especially in high-risk patients goal directed hemodynamic therapy is useful. For this, in addition to the established monitoring procedures, less invasive monitoring devices areincreasingly used. During an acutehaemodynamic instability, thetransoesophageal echocardiography is gaining importance due to its wide diagnostic evaluation. PMID- 26018068 TI - [Part-time concepts in anaesthesia -example of a department of anaesthesiology at a university hospital in Germany]. AB - Part-time work concepts are requested for different reasons from an increasing number of employees. Despite this fact there are no systematic part-time work concepts published in the German literature, especially for physicians working in hospitals. This article describes background and circumstances of a part-time work concept which was established two years ago in a department of anaesthesiology at a university hospital in Germany. This concept considers needs of young families as well as older employees. We are convinced that a transparent part-time work concept is a good argument for job-seeking physicians when deciding for an employer. The benefit for the already employed colleagues has at least the same value. PMID- 26018069 TI - [Internet Law, Personnel & Co]. PMID- 26018071 TI - [Industrial forum]. PMID- 26018072 TI - Medullary lateral line units of rudd, Scardinius erythrophthalmus, are sensitive to Karman vortex streets. AB - We investigated the responses of medullary lateral line units of the rudd, Scardinius erythrophthalmus, to bulk water flow (7 cm s(-1)) and to water flow that contained vortices shed by an upstream half cylinder (diameter 1, 2, and 3 cm). Thirty-five percent of the medullary units either increased or decreased their discharge rate with the increasing cylinder diameter. In some units, the spike patterns revealed the vortex shedding frequency, i.e., in these units the amplitude of spike train frequency spectra was similar or identical to the vortex shedding frequency. PMID- 26018073 TI - Prion-Protein-interacting Amyloid-beta Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models. AB - Alzheimer disease (AD) is characterized by amyloid-beta accumulation, with soluble oligomers (Abetao) being the most synaptotoxic. However, the multivalent and unstable nature of Abetao limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Abetao forms throughout the life span of various AD mice and in post-mortem human brain. Abetao exists in several populations, where prion protein (PrP(C))-interacting Abetao is a high molecular weight Abeta assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Abetao match closely with mouse memory and are equal or superior to other Abeta measures in predicting behavioral impairment. However, Abetao metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Abetao (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Abetao (APP/PSEN1). These findings highlight the relative contributions and interplay of Abetao forms in AD. PMID- 26018074 TI - TPX2 Inhibits Eg5 by Interactions with Both Motor and Microtubule. AB - The microtubule-associated protein, TPX2, regulates the activity of the mitotic kinesin, Eg5, but the mechanism of regulation is not established. Using total internal reflection fluorescence microscopy, we observed that Eg5, in extracts of mammalian cells expressing Eg5-EGFP, moved processively toward the microtubule plus-end at an average velocity of 14 nm/s. TPX2 bound to microtubules with an apparent dissociation constant of ~ 200 nm, and microtubule binding was not dependent on the C-terminal tails of tubulin. Using single molecule assays, we found that full-length TPX2 dramatically reduced Eg5 velocity, whereas truncated TPX2, which lacks the domain that is required for the interaction with Eg5, was a less effective inhibitor at the same concentration. To determine the region(s) of Eg5 that is required for interaction with TPX2, we performed microtubule gliding assays. Dimeric, but not monomeric, Eg5 was differentially inhibited by full length and truncated TPX2, demonstrating that dimerization or residues in the neck region are important for the interaction of TPX2 with Eg5. These results show that both microtubule binding and interaction with Eg5 contribute to motor inhibition by TPX2 and demonstrate the utility of mammalian cell extracts for biophysical assays. PMID- 26018075 TI - Structure-Function Analysis of the Drosophila melanogaster Caudal Transcription Factor Provides Insights into Core Promoter-preferential Activation. AB - Regulation of RNA polymerase II transcription is critical for the proper development, differentiation, and growth of an organism. The RNA polymerase II core promoter is the ultimate target of a multitude of transcription factors that control transcription initiation. Core promoters encompass the RNA start site and consist of functional elements such as the TATA box, initiator, and downstream core promoter element (DPE), which confer specific properties to the core promoter. We have previously discovered that Drosophila Caudal, which is a master regulator of genes involved in development and differentiation, is a DPE-specific transcriptional activator. Here, we show that the mouse Caudal-related homeobox (Cdx) proteins (mCdx1, mCdx2, and mCdx4) are also preferential core promoter transcriptional activators. To elucidate the mechanism that enables Caudal to preferentially activate DPE transcription, we performed structure-function analysis. Using a systematic series of deletion mutants (all containing the intact DNA-binding homeodomain) we discovered that the C-terminal region of Caudal contributes to the preferential activation of the fushi tarazu (ftz) Caudal target gene. Furthermore, the region containing both the homeodomain and the C terminus of Caudal was sufficient to confer core promoter-preferential activation to the heterologous GAL4 DNA-binding domain. Importantly, we discovered that Drosophila CREB-binding protein (dCBP) is a co-activator for Caudal-regulated activation of ftz. Strikingly, dCBP conferred the ability to preferentially activate the DPE-dependent ftz reporter to mini-Caudal proteins that were unable to preferentially activate ftz transcription themselves. Taken together, it is the unique combination of dCBP and Caudal that enables the co activation of ftz in a core promoter-preferential manner. PMID- 26018076 TI - Human SLC4A11 Is a Novel NH3/H+ Co-transporter. AB - SLC4A11 has been proposed to be an electrogenic membrane transporter, permeable to Na(+), H(+) (OH(-)), bicarbonate, borate, and NH4 (+). Recent studies indicate, however, that neither bicarbonate or borate is a substrate. Here, we examined potential NH4 (+), Na(+), and H(+) contributions to electrogenic ion transport through SLC4A11 stably expressed in Na(+)/H(+) exchanger-deficient PS120 fibroblasts. Inward currents observed during exposure to NH4Cl were determined by the [NH3]o, not [NH4 (+)]o, and current amplitudes varied with the [H(+)] gradient. These currents were relatively unaffected by removal of Na(+), K(+), or Cl(-) from the bath but could be reduced by inclusion of NH4Cl in the pipette solution. Bath pH changes alone did not generate significant currents through SLC4A11, except immediately following exposure to NH4Cl. Reversal potential shifts in response to changing [NH3]o and pHo suggested an NH3/H(+) coupled transport mode for SLC4A11. Proton flux through SLC4A11 in the absence of ammonia was relatively small, suggesting that ammonia transport is of more physiological relevance. Methylammonia produced currents similar to NH3 but with reduced amplitude. Estimated stoichiometry of SLC4A11 transport was 1:2 (NH3/H(+)). NH3-dependent currents were insensitive to 10 MUM ethyl-isopropyl amiloride or 100 MUM 4,4'- diisothiocyanatostilbene-2,2'-disulfonic acid. We propose that SLC4A11 is an NH3/2H(+) co-transporter exhibiting unique characteristics. PMID- 26018077 TI - Adaptive Engineering of Phytochelatin-based Heavy Metal Tolerance. AB - Metabolic engineering approaches are increasingly employed for environmental applications. Because phytochelatins (PC) protect plants from heavy metal toxicity, strategies directed at manipulating the biosynthesis of these peptides hold promise for the remediation of soils and groundwaters contaminated with heavy metals. Directed evolution of Arabidopsis thaliana phytochelatin synthase (AtPCS1) yields mutants that confer levels of cadmium tolerance and accumulation greater than expression of the wild-type enzyme in Saccharomyces cerevisiae, Arabidopsis, or Brassica juncea. Surprisingly, the AtPCS1 mutants that enhance cadmium tolerance and accumulation are catalytically less efficient than wild type enzyme. Metabolite analyses indicate that transformation with AtPCS1, but not with the mutant variants, decreases the levels of the PC precursors, glutathione and gamma-glutamylcysteine, upon exposure to cadmium. Selection of AtPCS1 variants with diminished catalytic activity alleviates depletion of these metabolites, which maintains redox homeostasis while supporting PC synthesis during cadmium exposure. These results emphasize the importance of metabolic context for pathway engineering and broaden the range of tools available for environmental remediation. PMID- 26018078 TI - All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells: ROLE OF NOTCH1 AND TRANSFORMING GROWTH FACTOR (TGFbeta). AB - All-trans-retinoic acid (ATRA) is a natural compound proposed for the treatment/chemoprevention of breast cancer. Increasing evidence indicates that aberrant regulation of epithelial-to-mesenchymal transition (EMT) is a determinant of the cancer cell invasive and metastatic behavior. The effects of ATRA on EMT are largely unknown. In HER2-positive SKBR3 and UACC812 cells, showing co-amplification of the ERBB2 and RARA genes, ATRA activates a RARalpha dependent epithelial differentiation program. In SKBR3 cells, this causes the formation/reorganization of adherens and tight junctions. Epithelial differentiation and augmented cell-cell contacts underlie the anti-migratory action exerted by the retinoid in cells exposed to the EMT-inducing factors EGF and heregulin-beta1. Down-regulation of NOTCH1, an emerging EMT modulator, is involved in the inhibition of motility by ATRA. Indeed, the retinoid blocks NOTCH1 up-regulation by EGF and/or heregulin-beta1. Pharmacological inhibition of gamma-secretase and NOTCH1 processing also abrogates SKBR3 cell migration. Stimulation of TGFbeta contributes to the anti-migratory effect of ATRA. The retinoid switches TGFbeta from an EMT-inducing and pro-migratory determinant to an anti-migratory mediator. Inhibition of the NOTCH1 pathway not only plays a role in the anti-migratory action of ATRA; it is relevant also for the anti proliferative activity of the retinoid in HCC1599 breast cancer cells, which are addicted to NOTCH1 for growth/viability. This effect is enhanced by the combination of ATRA and the gamma-secretase inhibitor N-(N-(3,5 difluorophenacetyl)-l-alanyl)-S-phenylglycine t-butyl ester, supporting the concept that the two compounds act at the transcriptional and post-translational levels along the NOTCH1 pathway. PMID- 26018079 TI - Interaction of Phospholipase A/Acyltransferase-3 with Pex19p: A POSSIBLE INVOLVEMENT IN THE DOWN-REGULATION OF PEROXISOMES. AB - Phospholipase A/acyltransferase (PLA/AT)-3 (also known as H-rev107 or AdPLA) was originally isolated as a tumor suppressor and was later shown to have phospholipase A1/A2 activity. We have also found that the overexpression of PLA/AT-3 in mammalian cells results in specific disappearance of peroxisomes. However, its molecular mechanism remained unclear. In the present study, we first established a HEK293 cell line, which stably expresses a fluorescent peroxisome marker protein (DsRed2-Peroxi) and expresses PLA/AT-3 in a tetracycline-dependent manner. The treatment with tetracycline, as expected, caused disappearance of peroxisomes within 24 h, as revealed by diffuse signals of DsRed2-Peroxi and a remarkable decrease in a peroxisomal membrane protein, PMP70. A time-dependent decrease in ether-type lipid levels was also seen. Because the activation of LC3, a marker of autophagy, was not observed, the involvement of autophagy was unlikely. Among various peroxins responsible for peroxisome biogenesis, Pex19p functions as a chaperone protein for the transportation of peroxisomal membrane proteins. Immunoprecipitation analysis showed that PLA/AT-3 binds to Pex19p through its N-terminal proline-rich and C-terminal hydrophobic domains. The protein level and enzyme activity of PLA/AT-3 were increased by its coexpression with Pex19p. Moreover, PLA/AT-3 inhibited the binding of Pex19 to peroxisomal membrane proteins, such as Pex3p and Pex11betap. A catalytically inactive point mutant of PLA/AT-3 could bind to Pex19p but did not inhibit the chaperone activity of Pex19p. Altogether, these results suggest a novel regulatory mechanism for peroxisome biogenesis through the interaction between Pex19p and PLA/AT-3. PMID- 26018080 TI - Interplay between TAp73 Protein and Selected Activator Protein-1 (AP-1) Family Members Promotes AP-1 Target Gene Activation and Cellular Growth. AB - Unlike p53, which is mutated at a high rate in human cancers, its homologue p73 is not mutated but is often overexpressed, suggesting a possible context dependent role in growth promotion. Previously, we have shown that co-expression of TAp73 with the proto-oncogene c-Jun can augment cellular growth and potentiate transactivation of activator protein (AP)-1 target genes such as cyclin D1. Here, we provide further mechanistic insights into the cooperative activity between these two transcription factors. Our data show that TAp73-mediated AP-1 target gene transactivation relies on c-Jun dimerization and requires the canonical AP-1 sites on target gene promoters. Interestingly, only selected members of the Fos family of proteins such as c-Fos and Fra1 were found to cooperate with TAp73 in a c-Jun-dependent manner to transactivate AP-1 target promoters. Inducible expression of TAp73 led to the recruitment of these Fos family members to the AP 1 target promoters on which TAp73 was found to be bound near the AP-1 site. Consistent with the binding of TAp73 and AP-1 members on the target promoters in a c-Jun-dependent manner, TAp73 was observed to physically interact with c-Jun specifically at the chromatin via its carboxyl-terminal region. Furthermore, co expression of c-Fos or Fra1 was able to cooperate with TAp73 in potentiating cellular growth, similarly to c-Jun. These data together suggest that TAp73 plays a vital role in activation of AP-1 target genes via direct binding to c-Jun at the target promoters, leading to enhanced loading of other AP-1 family members, thereby leading to cellular growth. PMID- 26018081 TI - Histidine 114 Is Critical for ATP Hydrolysis by the Universally Conserved ATPase YchF. AB - GTPases perform a wide range of functions, ranging from protein synthesis to cell signaling. Of all known GTPases, only eight are conserved across all three domains of life. YchF is one of these eight universally conserved GTPases; however, its cellular function and enzymatic properties are poorly understood. YchF differs from the classical GTPases in that it has a higher affinity for ATP than for GTP and is a functional ATPase. As a hydrophobic amino acid-substituted ATPase, YchF does not possess the canonical catalytic Gln required for nucleotide hydrolysis. To elucidate the catalytic mechanism of ATP hydrolysis by YchF, we have taken a two-pronged approach combining classical biochemical and in silico techniques. The use of molecular dynamics simulations allowed us to complement our biochemical findings with information about the structural dynamics of YchF. We have thereby identified the highly conserved His-114 as critical for the ATPase activity of YchF from Escherichia coli. His-114 is located in a flexible loop of the G-domain, which undergoes nucleotide-dependent conformational changes. The use of a catalytic His is also observed in the hydrophobic amino acid-substituted GTPase RbgA and is an identifier of the translational GTPase family. PMID- 26018082 TI - Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. AB - Leber congenital amaurosis 9 (LCA9) is an autosomal recessive retinal degeneration condition caused by mutations in the NAD(+) biosynthetic enzyme NMNAT1. This condition leads to early blindness but no other consistent deficits have been reported in patients with NMNAT1 mutations despite its central role in metabolism and ubiquitous expression. To study how these mutations affect NMNAT1 function and ultimately lead to the retinal degeneration phenotype, we performed detailed analysis of LCA-associated NMNAT1 mutants, including the expression, nuclear localization, enzymatic activity, secondary structure, oligomerization, and promotion of axonal and cellular integrity in response to injury. In many assays, most mutants produced results similar to wild type NMNAT1. Indeed, NAD(+) synthetic activity is unlikely to be a primary mechanism underlying retinal degeneration as most LCA-associated NMNAT1 mutants had normal enzymatic activity. In contrast, the secondary structure of many NMNAT1 mutants was relatively less stable as they lost enzymatic activity after heat shock, whereas wild type NMNAT1 retains significant activity after this stress. These results suggest that LCA associated NMNAT1 mutants are more vulnerable to stressful conditions that lead to protein unfolding, a potential contributor to the retinal degeneration observed in this syndrome. PMID- 26018084 TI - Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb. AB - OBJECTIVE: Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. METHODS: We collected a total of 24 blood brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. RESULTS: We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. INTERPRETATION: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb. PMID- 26018083 TI - Lipid and Carbohydrate Modifications of alpha-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation. AB - The ability of different glycosphingolipids (GSLs) to activate type I natural killer T cells (NKT cells) has been known for 2 decades. The possible therapeutic use of these GSLs has been studied in many ways; however, studies are needed in which the efficacy of promising GSLs is compared under identical conditions. Here, we compare five unique GSLs structurally derived from alpha galactosylceramide. We employed biophysical and biological assays, as well as x ray crystallography to study the impact of the chemical modifications of the antigen on type I NKT cell activation. Although all glycolipids are bound by the T cell receptor of type I NKT cells in real time binding assays with high affinity, only a few activate type I NKT cells in in vivo or in vitro experiments. The differences in biological responses are likely a result of different pharmacokinetic properties of each lipid, which carry modifications at different parts of the molecule. Our results indicate a need to perform a variety of assays to ascertain the therapeutic potential of type I NKT cell GSL activators. PMID- 26018085 TI - Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis. AB - Dysregulation of androgen signaling and pericellular proteolysis is necessary for prostate cancer progression, but the links between them are still obscure. In this study, we show how the membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth, and metastasis. We found that matriptase serves as a substrate for TMPRSS2 in mediating this proinvasive action of androgens in prostate cancer. Further, we determined that higher levels of TMPRSS2 expression correlate with higher levels of matriptase activation in prostate cancer tissues. Lastly, we found that the ability of TMPRSS2 to promote prostate cancer tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin beta1 in tumor xenografts. In summary, our results establish that TMPRSS2 promotes the growth, invasion, and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer. PMID- 26018087 TI - Vacuolar-ATPase Inhibition Blocks Iron Metabolism to Mediate Therapeutic Effects in Breast Cancer. AB - Generalized strategies to improve breast cancer treatment remain of interest to develop. In this study, we offer preclinical evidence of an important metabolic mechanism underlying the antitumor activity of inhibitors of the vacuolar-type ATPase (V-ATPase), a heteromultimeric proton pump. Specifically, our investigations in the 4T1 model of metastatic breast cancer of the V-ATPase inhibitor archazolid suggested that its ability to trigger metabolic stress and apoptosis associated with tumor growth inhibition related to an interference with hypoxia-inducible factor-1alpha signaling pathways and iron metabolism. As a consequence of disturbed iron metabolism, archazolid caused S-phase arrest, double-stranded DNA breaks, and p53 stabilization, leading to apoptosis. Our findings link V-ATPase to cell-cycle progression and DNA synthesis in cancer cells, and highlight the basis for the clinical exploration of V-ATPase as a potentially generalizable therapy for breast cancer. PMID- 26018086 TI - Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors. AB - The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and ~70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK(+) NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ~10 months. Kinase domain mutations are detectable in 25% to 37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications. PMID- 26018088 TI - Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth. AB - Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFalpha and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFalpha, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFalpha, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer. PMID- 26018089 TI - Burden of high fracture probability worldwide: secular increases 2010-2040. AB - The number of individuals aged 50 years or more at high risk of osteoporotic fracture worldwide in 2010 was estimated at 158 million and is set to double by 2040. INTRODUCTION: The aim of this study was to quantify the number of individuals worldwide aged 50 years or more at high risk of osteoporotic fracture in 2010 and 2040. METHODS: A threshold of high fracture probability was set at the age-specific 10-year probability of a major fracture (clinical vertebral, forearm, humeral or hip fracture) which was equivalent to that of a woman with a BMI of 24 kg/m(2) and a prior fragility fracture but no other clinical risk factors. The prevalence of high risk was determined worldwide and by continent using all available country-specific FRAX models and applied the population demography for each country. RESULTS: Twenty-one million men and 137 million women had a fracture probability at or above the threshold in the world for the year 2010. The greatest number of men and women at high risk were from Asia (55 %). Worldwide, the number of high-risk individuals is expected to double over the next 40 years. CONCLUSION: We conclude that individuals with high probability of osteoporotic fractures comprise a very significant disease burden to society, particularly in Asia, and that this burden is set to increase markedly in the future. These analyses provide a platform for the evaluation of risk assessment and intervention strategies. PMID- 26018090 TI - Persistence, adherence, and medication-taking behavior in women with postmenopausal osteoporosis receiving denosumab in routine practice in Germany, Austria, Greece, and Belgium: 12-month results from a European non-interventional study. AB - Persistence with and adherence to osteoporosis therapy are critical for fracture reduction. This non-interventional study is evaluating medication-taking behavior of women with postmenopausal osteoporosis (PMO) receiving denosumab in Germany, Austria, Greece, and Belgium. Patients were representative of the PMO population and highly persistent with and adherent to denosumab at 12 months. INTRODUCTION: Persistence with and adherence to osteoporosis therapy are important for optimal treatment efficacy, namely fracture reduction. This ongoing, non-interventional study will evaluate medication-taking behavior of women with postmenopausal osteoporosis (PMO) receiving denosumab in routine practice in four European countries. METHODS: The study enrolled women who had been prescribed subcutaneous denosumab (60 mg every 6 months) in accordance with prescribing information and local guidelines. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection. Adherence was defined as receiving two consecutive injections within 6 months +/- 4 weeks of each other. Medication coverage ratio (MCR) was calculated using the time a patient was covered with denosumab, as assessed from prescription records. Treatment was assigned prior to and independently of enrollment; outcomes are recorded during routine practice. RESULTS: These planned 12-month interim analyses included data from 1500 patients from 141 sites. Mean age was 66.4-72.4 years, mean baseline total hip T-scores ranged from -2.0 to -2.1 and femoral neck T-scores from -2.2 to -2.6, and 30.7-62.1% of patients had prior osteoporotic fracture. Persistence was 87.0-95.3%, adherence 82.7-89.3%, and MCR 91.3-95.4%. In a univariate analysis, increased age, decreased mobility, and increased distance to the clinic were associated with significantly decreased persistence; parental history of hip fracture was associated with significantly increased persistence. CONCLUSIONS: These data extend the real-world evidence regarding persistence with and adherence to denosumab, both of which are critical for favorable clinical outcomes, including fracture risk reduction. PMID- 26018091 TI - Is the Swedish FRAX model appropriate for Swedish immigrants? AB - The incidence of hip fracture in Sweden is substantially lower in immigrants than in the population born in Sweden. Thus, the use of a FRAX(r) model in immigrants overestimates the risk of fracture, and the use of country of origin-specific models may be more appropriate. INTRODUCTION: Age-specific fracture and mortality rates vary between countries so that FRAX tools are country-specific. In the case of immigrants, it is not known whether the model for the original or the new country is most appropriate. The aim of this study was to compare the incidence of hip fractures in foreign-born and Swedish-born individuals residing in Sweden. METHODS: We studied the incidence of hip fracture in all men and women aged 50 years or more in Sweden between 1987 and 2002. The population comprised 2.8 million Swedish-born and 270,000 foreign-born individuals. RESULTS: Incident hip fractures occurred in 239,842 Swedish-born and 12,563 foreign-born individuals. The hip fracture incidence rose with age for both groups and was higher for women than men amongst both Swedish-born and foreign-born individuals. The hip fracture incidence for the Swedish-born cohort was approximately twice that of immigrants. For example, at the age of 70 years, the annual hip fracture incidence (per 100,000) was 450 (95 % CI 446-454) for a Swedish-born woman and 239 (95 % CI 223 257) for a foreign-born woman at the time of immigration. The hip fracture incidence rose slowly with time from immigration (0.6 % per annum, 95 % CI 0.5 0.8 %) but remained significantly lower than for Swedish-born individuals even after 40 years of residence. CONCLUSIONS: The incidence of hip fracture in Sweden is substantially lower in immigrants than in the population native to Sweden. Although there was a small rise in age- and sex-specific incidence after immigration, the incidence remained markedly lower than that observed in Swedish born individuals. Thus, the use of a FRAX model for Sweden will overestimate the risk of fracture for foreign-born individuals living in Sweden. PMID- 26018092 TI - Inconsistent data in text and tables. PMID- 26018093 TI - Caregiver Expectations of Family-based Pediatric Obesity Treatment. AB - OBJECTIVE: To explore caregivers' expectations of pediatric weight management prior to starting treatment. METHODS: Interviews conducted with 25 purposefully selected caregivers of children, ages 8-12 years, waiting to begin 4 different weight management programs. Interviews were conducted and recorded via telephone and coded using a multistage inductive approach. RESULTS: Caregivers listed specific motivators for seeking treatment that did not often align with clinical measures of success: caregivers perceived child's socio-emotional health improvement to be an important success measure. Caregivers understood the program's approach, but were unsure of the commitment required. Caregivers were confident they would complete treatment but not in being successful. CONCLUSIONS: Caregivers' expectations of treatment success and their role in treatment may be a hindrance to adherence. PMID- 26018095 TI - Sleep duration and sleep disorder with red blood cell distribution width. AB - OBJECTIVE: To examine the association of sleep duration and sleep disorder with red blood cell distribution width (RDW). METHODS: Data from the 2005-2012 National Health and Nutrition Examination Survey were used, including 17,621 adults. A questionnaire was used to assess sleep duration and sleep disorder, with a blood sample used to assess RDW. RESULTS: Compared to persons getting 7-8 hours/night of sleep, those getting 5, 9, and >= 10 hours/night respectively had a 23%, 29%, and 67% increased odds of having an elevated RDW (p < .05 for all odds ratios). Participants with a physician-diagnosed sleep disorder had a higher RDW (beta = 0.08; p = .04). CONCLUSIONS: Sleep duration and sleep disorder are associated with elevated RDW. PMID- 26018094 TI - College Women's Weight-related Behavior Profiles Differ by Sexual Identity. AB - OBJECTIVES: To identify and describe homogenous profiles of female college students based on weight-related behaviors and examine differences across 5 sexual orientation groups. METHODS: Data from the 2009-2013 College Student Health Survey (Minnesota-based survey of 2- and 4-year college students) were used to fit latent class models. RESULTS: Four profiles were identified across all sexual orientation groups: "healthier eating habits," "moderate eating habits," "unhealthy weight control," and "healthier eating habits, more physically active." Differences in patterns and prevalence of profiles across sexual orientation suggest need for interventions addressing insufficient physical activity and unhealthy weight control behaviors. CONCLUSIONS: Future interventions should consider the diversity of behavioral patterns across sexual orientation to more effectively address weight-related behavioral disparities. PMID- 26018096 TI - Institutional characteristics and the connection to college student health. AB - OBJECTIVE: To examine whether 6 institutional characteristics were associated with health behavior and outcomes among college students. METHODS: Chisquare statistics and ANOVAs were used to determine relationships between institutional characteristics and health issues among undergraduate participants (N = 81,242) for the spring 2011 American College Health Association-National College Health Assessment II. RESULTS: Most institutional characteristics were significantly associated with all health issues. However, Cramer's V and eta 2 were frequently weak. Relationships between institutional characteristics and health outcomes were complex with few clear patterns. CONCLUSIONS: This exploratory study provides insight into environmental influences specific to college health. Future research should consider individual student differences and campus offerings to improve understanding of how the environment affects college student health. PMID- 26018098 TI - Prevalence of dog walking and sociodemographic characteristics of dog walkers in the U. S.: an update from 2001. AB - OBJECTIVES: To describe and estimate the prevalence of dog walking using a nationwide sample. METHODS: 2009 National Household Travel Survey data (N = 5100) were analyzed for: duration of dog walks, number of dog walks/day, total dog walking minutes/day. RESULTS: In a one-day period, 67% of dog walkers took at least one walk >= 10 minutes, 20% walked a dog for at least 30 minutes, and 28% took more than one dog walk. Older participants and participants with children were more likely to accumulate >= 30 minutes of dog walking in a one-day period. CONCLUSIONS: A majority of dog walks occurred in bouts >= 10 minutes, suggesting dog walking is a legitimate form of health-enhancing physical activity which contributes to meeting physical activity guidelines. PMID- 26018097 TI - Intervention markers of physical activity maintenance in older adults. AB - OBJECTIVES: To identify intervention components that may promote longterm changes of physical activity among older adults in a behavioral theory-based physical activity trial. METHODS: Participants (N = 24; aged 65 +/- 8.79 years) shared perceptions of intervention components at the end of the intervention and physical activity was assessed at 18 months. Mixed-methods analyses using a pragmatic content analysis of interview data were conducted. RESULTS: Active study participants (25%) cited more specific goals/actions to achieve goals and more social support from family/friends, and had significantly higher self determined motivation mean scores at 18 months than insufficiently active study participants (75%). CONCLUSIONS: Specific goal-setting behaviors and social support from family/friends may be key elements of physical activity maintenance in older adults. PMID- 26018099 TI - A resilience intervention in African-American adults with type 2 diabetes. AB - OBJECTIVES: To explore the feasibility and outcomes of a resilience-based diabetes self-management education (RB-DSME) program to improve psychological and physiological health in African-American adults with type 2 diabetes. METHODS: An experimental group (N = 32) received RB-DSME and a comparison group (N = 33) received standard DSME. Psychological and physiological measures were taken at baseline and 6 months. ANCOVAs assessed whether the experimental group improved its overall outcome relative to the comparison group, while controlling for baseline scores. RESULTS: The experimental group's outcomes were significantly improved vis-a-vis the comparison group for diabetes knowledge, positive meaning, HDL cholesterol, and fasting blood glucose. CONCLUSIONS: The RB-DSME shows feasibility and promise for enhancing health; a full-scale randomized trial is warranted. PMID- 26018100 TI - Little Cigar and Cigarillo Beliefs and Behaviors among African-American Young Adults. AB - OBJECTIVES: To inform the development of future research and culturally-targeted interventions to address little cigar and cigarillo (LCC) use among an at-risk population: African-American (AA) young adults. Additionally, this project assesses LCC use and perception differences between college- and non-college attending AA young adults who use LCCs. METHODS: Separate focus groups with college and non-college attending AA young adult LCC users assessed participants' attitudes, norms, and perceived behavioral controls regarding LCC use, which was guided by the Theory of Planned Behavior. A thematic analysis following standard qualitative methods procedures revealed 5 themes. RESULTS: Participants shared overwhelmingly positive attitudes toward LCC use, ubiquitous use in their communities, and limited barriers to use. Additionally, participants had difficulty separating LCC and marijuana use practices because LCCs often served as carriers for marijuana. There were no substantive differences between the college and non-college samples with respect to overall themes. CONCLUSIONS: Future research should assess LCC intended versus altered use and create culturally relevant intervention measures. PMID- 26018101 TI - Perspectives of Stakeholders on Implementing a Farm-to-University Program at an HBCU. AB - OBJECTIVE: To explore the perspectives of various stakeholders on whether an HBCU has the resources to establish a farm-to-university program that can improve fruits and vegetables intake among African American students. Additionally, this study assessed students' satisfaction with fruits and vegetables served in University dining halls, and their desire for changes in policies to increase local fruits and vegetables access on campus. METHODS: This study employed a mixed method data collection strategy. Semi-structured interviews were used to explore the stakeholders' perspectives and self-administered questionnaires were used to assess students' satisfaction with fruits and vegetables and desire for policy changes. RESULTS: Barriers reported by both food service administrators and farmers were cost and variation in supply and demand. Students expressed lack of satisfaction with fresh produce served in campus dining halls and a desire for change in policies to increase local fruits and vegetables access on campus. CONCLUSION: While there is student desire for improved access to fresh produce on campus, there are perceived barriers to overcome. University partnerships are needed to address the desired nutritional improvements. PMID- 26018102 TI - The impact of nutrition labeling on menus: a naturalistic cohort study. AB - OBJECTIVES: To examine the impact of a calorie label intervention on cafeteria menus. METHODS: Exit surveys were conducted in a university cafeteria. Participants were surveyed at baseline and one week after calorie labels were displayed. We assessed changes in noticing and use of nutrition information, the calorie content of food purchased, and estimated calorie consumption. RESULTS: The intervention was associated with significant increases in noticing nutrition information (92.5% vs 39.6%; p < .001), and the use of nutrition information to guide food purchases (28.9% vs 8.8%; p < .001). The calorie content of foods purchased decreased after calorie labels were posted (B = -88.69, p = .013), as did the estimated amount of calories consumed (B = -95.20, p = .006). CONCLUSIONS: Findings suggest that displaying calorie amounts on menus can help reduce excess energy intake. PMID- 26018103 TI - Mental illness and substance use problems in relation to homelessness onset. AB - OBJECTIVES: The relationships among youth (<= 24 years) versus adult (>24 years) homelessness onset, lifetime serious mental illness, and substance use problems is not well understood. We sought to explore these associations among 394 homeless adults, 124 of whom reported youth-onset homelessness. METHODS: Covariate-adjusted logistic regression analyses evaluated the associations among homelessness onset, serious mental illness, and self-reported substance use problems. RESULTS: Youth-onset homelessness was associated with greater likelihood of serious mental illness and sedative problems, and a lower likelihood of cocaine problems, in adjusted analyses (p values <= .04). CONCLUSIONS: Serious mental illness and sedative problems may characterize homeless youth who are vulnerable to adulthood homelessness, although longitudinal cohort studies are needed to explicate temporal relations between variables. PMID- 26018104 TI - Energy Expenditure and Intensity in Healthy Young Adults during Exergaming. AB - OBJECTIVES: To examine and compare the energy expenditure (EE) and intensity of Xbox 360 Kinect exergames in healthy young adults. METHODS: Seventeen young adults (22.0 +/- 2.9 years; 7 men) were enrolled and asked to complete 6 exergames using Xbox 360 Kinect. Oxygen consumption (VO2) and heart rate (HR) were measured throughout each exergame, and metabolic equivalents (METs) and EE were calculated from VO2. RESULTS: Boxing (6.8 +/- 1.9 METs) and soccer (6.2 +/- 1.7 METs) provided vigorous intensity of physical activity, which was significantly greater than track and field, ping-pong, and bowling (5.0 +/- 1.5, 4.0 +/- 1.6, and 2.6 +/- 0.8 METs, respectively; all p < .01). Beach volleyball (5.7 +/- 1.8 METs) was greater than ping-pong and bowling (both p < .01). EE exhibited a similar pattern. These results remained after adjusting for participants' previous exergaming experience and resting HR. CONCLUSIONS: Kinect Sports from Xbox 360 Kinect is capable of providing a moderate-to-vigorous level of physical activity in young healthy adults. These exergames may be used as an alternative mode of exercise to promote physical activity participation in this population. Future research that evaluates the feasibility of using exergames as an alternative mode of exercise in other populations is warranted. PMID- 26018105 TI - Correlates of Physical Activity among Blacks and Whites with Arthritis. AB - OBJECTIVE: To evaluate the correlates of physical activity (PA) participation among white and black individuals with diagnosed arthritis. METHODS: This study used a cross-sectional design, grounded in the Social Ecological Model. Participants (N = 205) completed a survey regarding PA participation and potential correlates of PA. Bivariate and multivariate analyses were used to examine the correlates of PA. RESULTS: Nearly 30% of the population met the current guidelines for aerobic PA. A greater proportion of Whites (35.3%) than Blacks (20.9%) met current guidelines (chi(2) = 4.98, p = .03). In bivariate analyses, ethnicity, income, body mass index, self-efficacy for exercise, exercise outcome expectations, physical function, physician advice to exercise, and perceived safety from neighborhood crime and traffic were associated with meeting PA guidelines (p < .05). In regression analyses adjusted for socio demographic characteristics, exercise self-efficacy and physician's advice to exercise were the only significant predictors of PA (p < .05). This finding was confirmed with stepwise forward regression. CONCLUSIONS: PA interventions for people with arthritis should focus on enhancing self-efficacy for exercise and include strategies to optimize communication about PA by healthcare providers. PMID- 26018106 TI - Intention to receive influenza vaccine after an acute respiratory illness. AB - OBJECTIVE: To determine the effects of symptoms and presence of confirmed influenza on intention to receive an influenza vaccine, specifically in patients recovering from a medically-attended acute (<= 7 days' duration) respiratory illness (ARI). METHODS: During the 2013-14 influenza season individuals seeking outpatient care for an ARI that included cough were tested for influenza using reverse transcription polymerase chain reaction assays (PCR) and completed surveys. Children (6 months-18 years) and adults (>= 18 years) were grouped by their combined current season's influenza vaccination status (vaccinated/not vaccinated) and their vaccination intentions for next season (intend/do not intend). RESULTS: Overall, 41% (323/786) were unvaccinated at enrollment; of those, nearly half (151/323) intended to be vaccinated next season. When adjusting for demographic, health, and other factors, unvaccinated individuals who intended to be vaccinated next season were approximately 1.5 times more likely to have PCR-confirmed influenza compared with vaccinated individuals who intended to be vaccinated next season. CONCLUSION: The combined experience of not being vaccinated against influenza and seeking medical attention for an ARI seemed to influence approximately one-half of unvaccinated participants to consider influenza vaccination for next season. PMID- 26018107 TI - Spatial and Census Data to Evaluate Obese Persons and their Environment (SCOPE). AB - OBJECTIVE: To evaluate the built environment and its relationship to BMI for individuals in eastern Idaho. METHODS: Geospatial analyses were coupled to demographic data of adult individuals. ArcGIS Community Analyst was used to compare demographics relative to median BMI. RESULTS: For every kilometer increase in distance to prepared food sites, BMI went down by 1.3% and every kilometer increase in distance to green space, BMI went down by 0.8% (p < .001). For every kilometer increase in distance to trails, BMI went up by 1.5%. No other built environment variables had a statistically significant association with BMI. CONCLUSION: The distance to prepared foods and trails was associated with expected changes in BMI. Conversely, increased distance to green space was associated with a lower BMI. PMID- 26018108 TI - The efficacy and safety of hepatic arterial infusion of oxaliplatin plus intravenous irinotecan, leucovorin and fluorouracil in colorectal cancer with inoperable hepatic metastasis. AB - Hepatic arterial infusion (HAI) was evaluated for different drugs to treat hepatic metastasis from colorectal cancer (CRC). Combination treatment with 5 fluorouracil (5-FU), leucovorin, oxaliplatin and irinotecan (FOLFOXIRI) is effective for CRC. A phase II study was conducted to evaluate concomitant HAI administration of oxaliplatin and intravenous leucovorin, 5-FU and irinotecan (FOLFIRI) for patients with inoperable liver metastasis, which had chemotherapy with oxaliplatin (OX) 85 mg/m(2) HAI plus systemic intravenous chemotherapy [leucovorin 200 mg/m(2), 5-FU 2400 mg/m(2) and irinotecan (IRI) 160 mg/m(2) in 48 hours]. We treated 24 patients. Neutropaenia was the most frequent toxicity. The main HAI-related toxicity was pain. Two patients (8%) obtained complete response and 17 patients (70%) partial response, giving an objective response rate of 78%. Median follow-up was 22.8 months, and median overall and disease-free survival times were 29 and 20 months, respectively. Therefore, OX HAI and intravenous FOLFIRI is feasible and effective in patients with metastatic CRC. PMID- 26018109 TI - A clonal outbreak of tuberculosis in a homeless population in the interior of British Columbia, Canada, 2008-2015. AB - A tuberculosis (TB) case was reported May 2008 in Kelowna, British Columbia, leading to a multi-year outbreak in homeless persons. The epidemiological characteristics and social networks of cases are described. Outbreak-related cases were identified from epidemiological information in medical records and from genotyping of TB isolates. Social network information from case interviews were used to identify potential locations of TB transmission, where symptom screening and tuberculin skin testing was conducted. Fifty-two cases that were predominantly male (47/52), Canadian-born (44/50), and were homeless or associated with homeless individuals (42/52) were reported from May 2008 to May 2014. Many isolates (40/49) had partial resistance to isoniazid. Transmission primarily occurred at two homeless shelters, with potential further transmission at sites visited by the general population. TB outbreaks in homeless populations can occur in small, low-incidence cities. Social network information helped prioritize sites for TB screening, thereby improving detection of persons with TB disease or latent infection for treatment. PMID- 26018110 TI - Determination of the optimal time of vaccination against infectious bursal disease virus (Gumboro) in Algeria. AB - This study was conducted to determine the effect of maternally derived antibody (MDA) on live vaccine against infectious bursal disease. A total of 140 chicks selected from vaccinated parent stock were used in this investigation. In a preset vaccination schedule, blood samples were collected to check for the actual effect. It was noticed that on day 1 the chicks contained a high level (6400.54 +/- 2993.67) of maternally derived antibody that gradually decreased below a positive level within 21 days (365.86 +/- 634.46). It was found that a high level of MDA interferes with the vaccine virus, resulting in no immune response. For better immune response, it is suggested that the chickens should be vaccinated at day 21, as the uniformity of MDA is poor (coefficient of the variation [CV] > 30%), and boosted at day 28. Indeed, two vaccinations are necessary to achieve good protection against infectious bursal disease virus of the entire flock. PMID- 26018111 TI - Atypical haemolytic uraemic syndrome in a Japanese patient with DGKE genetic mutations. PMID- 26018112 TI - Role of vitamin C as an adjuvant therapy to different iron chelators in young beta-thalassemia major patients: efficacy and safety in relation to tissue iron overload. AB - BACKGROUND: Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). AIM: To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with beta-thalassemia major (beta-TM) in relation to tissue iron overload. METHODS: This randomized prospective trial that included 180 beta-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. RESULTS: Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. CONCLUSIONS: Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron overloaded vitamin C-deficient patients with beta-TM, with no adverse events. PMID- 26018113 TI - Monitoring the menstrual cycle: Comparison of urinary and serum reproductive hormones referenced to true ovulation. AB - OBJECTIVE: The aim of the study was to examine relationships and interindividual variations in urinary and serum reproductive hormone levels relative to ultrasound-observed ovulation in menstrual cycles of apparently normally menstruating women. METHODS: This was a prospective study of normally menstruating women (no known subfertility), aged 18-40 years (n = 40), who collected daily urine samples and attended the study centre for blood samples and transvaginal ultrasound during one complete menstrual cycle. Serum luteinising hormone (LH), progesterone, estradiol, urinary LH, pregnanediol-3- glucuronide (P3G) and estrone-3-glucuronide were measured. Ultrasound was conducted by two physicians and interpreted by central expert review. RESULTS: Menstrual cycle length varied from 22 to 37 days (median 27 days). Ovulation by ultrasound ranged from day 8 to day 26 (median day 15). Serum and urinary hormone profiles showed excellent agreement. Estrogen and LH hormone peaks in urine and serum showed a range of signal characteristics across the study group before and after ovulation. The rise in estrogen and LH always occurred before ovulation; the progesterone rise from baseline always occurred after ovulation. CONCLUSIONS: Urinary and serum reproductive hormones showed excellent agreement and may be used interchangeably. The beginning of the surge in serum and urinary LH was an excellent predictor of ovulation. The rise in progesterone and P3G above baseline was a consistent marker of luteinisation confirming ovulation. Both LH and progesterone surges delivered clear, sharp signals in all volunteers, allowing reliable detection and confirmation of ovulation. PMID- 26018114 TI - Selective isolation of bacteria for metagenomic analysis: Impact of membrane characteristics on bacterial filterability. AB - For indirect DNA extraction for metagenomics studies, bacterial cells can be effectively separated from sample debris by using a simple size exclusion technique, such as filtration, and thereafter lysed. The requirement for the optimal recovery of cells in filtrates is critical to achieve sufficient DNA yield and a representative population. Particles smaller than the filter pore size are expected to be found in the filtrate, whereas particles larger than the filter pore sizes are excluded. However, this is not always the case. It is established that the membrane pore size influences filtration efficiency to some degree. In addition the physicochemical characteristics of the filter suspension and characteristics of the microbial cells being filtered influence the exclusion property of a membrane. This review provides an overview of membrane filtration techniques and the factors that affect filterability of bacteria cells through a filter membrane. PMID- 26018115 TI - Herpes Zoster Reactivation in Patients With Rheumatoid Arthritis: Analysis of Disease Characteristics and Disease-Modifying Antirheumatic Drugs. AB - OBJECTIVE: To identify the rheumatoid arthritis (RA) characteristics associated with increased herpes zoster (HZ) risk in the Corrona registry RA patients, and to evaluate the risk in initiators of tumor necrosis factor inhibitors (TNFi) or non-TNFi biologic agents or (among those who were currently on or had been previously treated with methotrexate [MTX]) conventional synthetic disease modifying antirheumatic drugs (csDMARDs) other than MTX. METHODS: Cox regression modeling estimated the association between first HZ incidence and selected RA characteristics, including disease activity. Medication-related risk for HZ in RA patients taking current or past MTX (to exclude milder RA disease) were categorized by treatment initiation (TNFi versus non-TNFi versus csDMARD). Hazard ratios (HRs) estimated HZ risk of each treatment initiation category after stratification on trimmed propensity score (PS) quintiles to control for potential confounders. RESULTS: A total of 28,852 patients contributed 95,287 person-years. Seven hundred twenty-nine observed HZ cases yielded a 7.7 (95% confidence interval [95% CI] 7.1-8.2) per 1,000 patient-years crude incidence rate, lower than found in prior RA cohorts. However, consistent with prior studies, increasing age (HR 1.14, 95% CI 1.09-1.19 per 5 years) and prednisone therapy >=7.5 mg/day (HR 1.81, 95% CI 1.23-2.67) were associated with a higher HZ risk. Referent to TNFi exposure, PS-stratified analysis showed an HR for csDMARDs of 1.36 (95% CI 0.82-2.25) and for non-TNFi of 0.83 (95% CI 0.51-1.38). CONCLUSION: In the Corrona registry, the HZ risk in RA patients taking prior or current MTX increased with older age and higher prednisone dose. The HZ risk among these patients with RA was comparable after initiation of TNFi versus non TNFi versus csDMARDs. PMID- 26018116 TI - The accuracy and cost-effectiveness of hepatitis C core antigen assay in the monitoring of anti-viral therapy in patients with chronic hepatitis C genotype 4. AB - BACKGROUND: Quantitative hepatitis C (HCV) polymerase chain reaction (qtHCV-PCR), the gold standard for monitoring HCV therapy, is an expensive, time-consuming procedure that requires equipped laboratories and trained personnel. AIMS: To assess the accuracy and cost-effectiveness of the automated Abbott ARCHITECT HCV Ag assay (Wiesbaden, Germany) in monitoring response to pagylated interferon (PEG IFN) and ribavirin therapy for chronic HCV genotype 4 (G4). METHODS: This longitudinal, non-inferiority study compared the efficacy and cost benefit of an All-HCV core antigen assay protocol and a hybrid qtHCV RNA PCR and HCV core Ag assay protocol to the standard All-qtHCV-PCR protocol in chronic HCV G4 patients treated with pegylated interferon (PEG IFN) and ribavirin. RESULTS: Four hundred and ten patients with chronic hepatitis C genotype 4 met inclusion criteria and were enrolled in the study. The sustained virological response rate (SVR) was 66.34%. The All-HCV core antigen and hybrid monitoring assays resulted in the significant cost savings without compromising performance. A good correlation existed between HCV viral load and HCV core antigen levels (r = 0.944; P < 0.0001). Baseline HCV RNA values <600 IU/mL, baseline HCV core Ag levels <2000 fmol/L, rapid virological response, rapid decline in HCV core antigen were strong predictors of SVR. CONCLUSION: Hepatitis C core Ag assay is a point-of-care, reproducible, reliable, cost-effective monitoring tool with rapid turnaround time that, which can effectively replace or adjunct to qRT-PCR in monitoring interferon based or interferon-free anti-viral therapy in chronic hepatitis genotype 4 patients in resource-limited countries with a high burden of hepatitis C. PMID- 26018117 TI - Simultaneous detection of Entamoeba histolytica/dispar, Giardia duodenalis and cryptosporidia by immunochromatographic assay in stool samples from patients living in the Greater Cairo Region, Egypt. AB - Gastrointestinal infection due to intestinal parasites is an enormous health problem in developing countries and its reliable diagnosis is demanding. Therefore, this study aimed at evaluating a commercially available immunochromatographic assay (ICA) for the detection of cryptosporidia, Giardia duodenalis, and Entamoeba histolytica/dispar for its usefulness in the Greater Cairo Region, Egypt. Stool samples of 104 patients who presented between October 2012 and March 2013 with gastrointestinal symptoms or for the exclusion of parasites at Kasr-Al-Ainy University Medical School were examined by light microscopy of wet mounts and the triple ICA. Microscopy revealed in 20% of the patients [95% confidence interval (CI), 13.5-29.0%] parasites with Hymenolepis nana, E. histolytica/dispar and Blastocystis hominis being the most frequent ones, but was not able to detect G. duodenalis and cryptosporidia, whereas ICA was positive in 21% (95% CI, 14.3-30.0%) and detected E. histolytica/dispar in 12.5% (95% CI, 7.3-20.4%), cryptosporidia in 6.7% (95% CI, 3.1-13.5%) and G. duodenalis in 15.4% (95% CI, 9.6-23.6%) of the patients. Detection of one or more pathogens was associated with access to water retrieved from a well or pump (p = 0.01). Patients between 20 and 29 years of age (p = 0.08) and patients with symptoms of 5 days or longer (p = 0.07) tended to have a higher risk to be infected than patients of other age groups or with shorter-lasting symptoms. In conclusion, the ICA was easy to perform and timesaving. Importantly, it enabled the detection of cryptosporidia, which cannot be found microscopically in unstained smears, demonstrated a higher sensitivity for the detection of G. duodenalis than microscopy, and was more specific for distinguishing E. histolytica/dispar from apathogenic amoeba. PMID- 26018118 TI - (1) H and (13) C NMR assignments for a series of Diels-Alder adducts of anthracene and 9-substituted anthracenes. PMID- 26018119 TI - A neonate with recurrent tetany: questions and answers. PMID- 26018122 TI - Hypertension and proteinuria-the needle in the haystack?: Questions. PMID- 26018121 TI - Paediatric obesity and renal transplantation: current challenges and solutions. AB - The increased incidence of obesity in the paediatric population poses significant challenges to renal transplantation. Whilst the body mass index appears to be widely used as a measure of obesity in adults, there are no standardised definitions in the paediatric population, making comparative analyses difficult. In the paediatric transplant population, obesity is associated with an increased incidence of surgical complications, diabetes, hyperlipidaemia and cardiovascular morbidity, leading to diminished graft function and impacting patient and graft survival. Management of obesity in renal transplantation requires multiple interventions starting with life-style and behavioural modification combined with medical and possibly surgical therapies, representing a unique challenge in the childhood setting. In this review we discuss the current challenges of obesity and potential solutions in the setting of paediatric transplantation. PMID- 26018123 TI - Hypertension and proteinuria-the needle in the haystack?: Answers. PMID- 26018124 TI - A large multicenter study analysis of adverse events associated with single operator cholangiopancreatoscopy. AB - AIM: Cholangiopancreatoscopy (CP) is an endoscopic technique that allows for direct visualization of the biliary and pancreatic ducts using a narrow caliber endoscope that passes through the working channel of a duodenoscope directly into the bile and/or pancreatic ducts. Little data is available on the safety of CP. We performed a multicenter retrospective study to evaluate the frequency and severity of adverse events with single operator CP. METHODS: A multicenter retrospective study was conducted. RESULTS: A total of 282 single operator peroral CP procedures were performed in 224 patients (128 M, 96 F). Most procedures involved the performance of therapeutic maneuvers, with most cases including multiple therapeutic maneuvers. Cholangioscopic or pancreatoscopic assisted tissue sampling was performed in 222 procedures. Thirty-seven patients underwent electrohydraulic lithotripsy (EHL) for the treatment of common bile duct stones. Adverse events in patients undergoing single cholangioscopy and pancreatoscopy included post-ERCP pancreatitis (N.=11, 3.9%, all mild), post-ERCP cholangitis (N.=4, 1.4%), bleeding (N.=3, 1%), and perforation (N.=2, 0.7%). CONCLUSION: Overall, our data shows that ERCP performed with single operator cholangioscopy or pancreatoscopy is safe with adverse events similar to that seen in large studies of ERCP performed without these additional techniques. Of note, vigorous irrigation of the bile ducts was not associated with increased rates of post-procedure cholangitis in our study. PMID- 26018125 TI - Stop the shooting: it is time for partnerships between police and mental health nurses. PMID- 26018126 TI - Service users on interview panels in mental health. PMID- 26018128 TI - Diagnostic and Prognostic Value of 18F-FDG PET/CT in Male Breast Cancer: Results From a Bicentric Population. AB - PURPOSE: We aim to assess the diagnostic and prognostic values of 18Ffluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in a small population with male breast cancer (MBC). MATERIALS AND METHODS: From May 2005 to Jul 2013, we retrospectively reinterpreted 31 FDG PET/CT scans of 25 men (mean age: 67 years; range: 51-81 years) with a proven breast cancer diagnosis, from two Italian centers. In the majority of patients, an invasive ductal cancer was present (68%). PET/CT scan was performed for initial staging in 5 (16%), restaging in 18 (58%), restaging for the increase of tumor markers in 4 (13%), response to therapy in 2 (6%) and during follow-up in 2 cases (6%). The prognostic impact of PET/CT in this male breast cancer population was assessed by using Kaplan-Meier analysis. RESULTS: Nuclear medicine imaging was negative in 10 subjects while it resulted positive in the residual 15 patients (60%). At initial staging, in four out of five cases, PET/CT showed a significant uptake in the primary cancer and of those three had also a loco regional lymphatic and distant metastatic involvement. In restaging setting, PET/CT was more accurate than conventional imaging for detection of distant metastases, resolving two false-positive findings. Finally, a positive PET/CT scan was demonstrated to be prognostically unfavorable as compared to a negative exam. CONCLUSIONS: MBC is a rare tumor with similar biological and metabolic characteristics of female breast cancer. FDG PET/CT seems to be useful, particularly in the restaging setting, to delineate the correct therapeutic approach and to predict the prognosis. PMID- 26018127 TI - "Keeping Moving": factors associated with sedentary behaviour among older people recruited to an exercise promotion trial in general practice. AB - BACKGROUND: Sedentary behaviour is detrimental to health, even in those who achieve recommended levels of physical activity. Efforts to increase physical activity in older people so that they reach beneficial levels have been disappointing. Reducing sedentary behaviour may improve health and be less demanding of older people, but it is not clear how to achieve this. We explored the characteristics of sedentary older people enrolled into an exercise promotion trial to gain insights about those who were sedentary but wanted to increase activity. METHOD: Participants in the ProAct65+ trial (2009-2013) were categorised as sedentary or not using a self-report questionnaire. Demographic data, health status, self-rated function and physical test performance were examined for each group. 1104 participants aged 65 & over were included in the secondary analysis of trial data from older people recruited via general practice. Results were analysed using logistic regression with stepwise backward elimination. RESULTS: Three hundred eighty seven (35 %) of the study sample were characterised as sedentary. The likelihood of being categorised as sedentary increased with an abnormal BMI (<18.5 or >25 g/m(2)) (Odds Ratio 1.740, CI 1.248 2.425), ever smoking (OR 1.420, CI 1.042-1.934) and with every additional medication prescribed (OR 1.069, CI 1.016-1.124). Participants reporting better self-rated physical health (SF-12) were less likely to be sedentary; (OR 0.961, 0.936-0.987). Participants' sedentary behaviour was not associated with gender, age, income, education, falls, functional fitness, quality of life or number of co-morbidities. CONCLUSION: Some sedentary older adults will respond positively to an invitation to join an exercise study. Those who did so in this study had poor self-rated health, abnormal BMI, a history of smoking, and multiple medication use, and are therefore likely to benefit from an exercise intervention. TRIAL REGISTRATION: ISRCTN reference: ISRCTN43453770. PMID- 26018130 TI - A versatile reporter system for CRISPR-mediated chromosomal rearrangements. AB - Although chromosomal deletions and inversions are important in cancer, conventional methods for detecting DNA rearrangements require laborious indirect assays. Here we develop fluorescent reporters to rapidly quantify CRISPR/Cas9 mediated deletions and inversions. We find that inversion depends on the non homologous end-joining enzyme LIG4. We also engineer deletions and inversions for a 50 kb Pten genomic region in mouse liver. We discover diverse yet sequence specific indels at the rearrangement fusion sites. Moreover, we detect Cas9 cleavage at the fourth nucleotide on the non-complementary strand, leading to staggered instead of blunt DNA breaks. These reporters allow mechanisms of chromosomal rearrangements to be investigated. PMID- 26018131 TI - Effectiveness of influenza vaccination of schoolchildren in the city of Sao Paulo, Brazil, 2009. AB - BACKGROUND: Children play an important role in maintaining the transmission of influenza. Evidence suggests that vaccination of school-age children can reduce transmission to unvaccinated household contacts. We evaluated the direct and indirect effectiveness of the 2009 inactivated seasonal influenza vaccine in vaccinated schoolchildren and their unvaccinated household contacts. METHODS: This was a double-blind cluster randomized trial involving 10 schools and 1742 schoolchildren as well as 5406 household contacts. The schools were randomly assigned to receive the influenza vaccine or the control vaccine. After vaccination, the schoolchildren and household contacts were followed for 6 months to identify cases of acute respiratory infection (ARI). Reverse-transcriptase polymerase chain reaction was performed for the diagnosis of influenza. RESULTS: A total of 632 ARI cases were detected. Of those, 103 tested positive for influenza virus (influenza virus A[H1N1]pdm09 virus in 55 and seasonal influenza viruses in 48). The effectiveness of the vaccine in protecting against seasonal influenza virus infection was 65.0% for the household contacts (95% CI, 19.6 84.3) and 65.0% for the schoolchildren (95% CI, 20.9-84.5). CONCLUSION: Vaccination of schoolchildren significantly protected them and their household contacts against seasonal influenza. PMID- 26018132 TI - Hepatocellular Carcinoma Surveillance: Are We Utilizing It? AB - BACKGROUND AND GOALS: International guidelines recommend 6-monthly ultrasound scan surveillance in cirrhotic patients for hepatocellular carcinoma (HCC) screening. The aim of this study was to evaluate HCC surveillance and to provide the outcomes for the largest reported cirrhosis cohort in the United Kingdom. STUDY: We retrospectively reviewed all cirrhotic patients during the 6 months before April 1, 2014 at 3 teaching hospitals within the Imperial College Healthcare NHS Trust. All patients with cirrhosis eligible for HCC screening in the cohort were reviewed for evidence of screening and were characterized as either "routine" or "overdue." Reasons for failure to meet guidelines were identified in overdue patients. Univariate analyses were conducted to determine clinical and sociodemographic predictors of surveillance with a view to performing multivariate analysis. RESULTS: Of the 898 patients eligible for inclusion, 65% patients had HCC surveillance performed in the past 6 months. During the observation period, 61 (6.8%) cases of HCC were detected. Thirty-eight were picked up on surveillance, 9 incidentally and in 14 cases it could not be determined from the notes. Within this cohort HCCs diagnosed on surveillance did not demonstrate significantly superior outcomes compared with those picked up incidentally. CONCLUSIONS: Surveillance of patients with cirrhosis within this cohort is suboptimal. Although disappointing at a local level, this is likely to be reflective of practice elsewhere. PMID- 26018133 TI - Treatment Outcomes With First-line Therapies With Entecavir and Tenofovir in Treatment-Naive Chronic Hepatitis B Patients in a Routine Clinical Practice. AB - BACKGROUND: Given their high efficacy, entecavir (ETV) and tenofovir (TDF), are the recommended first-line therapies for chronic hepatitis B, but it is not clear whether the efficacy reported from pivotal trials is similar to the outcomes seen in routine practice. GOALS: Our goal was to examine the treatment outcomes of antiviral therapy in such setting. PATIENTS AND METHODS: We conducted a retrospective study of 557 consecutive treatment-naive patients who started either ETV (n=443) or TDF (n=114) at 3 US liver clinics between January 2005 and 2012. Primary study endpoint was complete viral suppression (CVS) rate (hepatitis B virus DNA<40 IU/mL). RESULTS: The majority of patients in both ETV and TDF groups were Asians, hepatitis B e antigen (HBeAg) negative, male, and with similar pretreatment alanine aminotransferase and hepatitis B virus DNA levels. Similar proportions of patients in the ETV and TDF groups achieved CVS at 24 months: 87.7% versus 87.0%, respectively. Cumulative rates of virological breakthrough in the ETV and TDF groups were 1.0% versus 4.8% (P=0.26) and 3.7% versus 9.8% (P=0.04) at month 12 and 24, respectively; and all were associated with medication nonadherence. Cumulative rate of medication nonadherence was lower in the ETV than TDF group: 4.6% versus 7.8% at month 12 and 8.9% versus 16.9% at month 24, respectively. CONCLUSIONS: Patients treated with either ETV or TDF achieve a similar rate of CVS at 24 months. The primary contributor to suboptimal response was medication nonadherence. Attention to medication adherence is needed in a routine clinical setting. PMID- 26018134 TI - Distribution and diversity of the vectors of Rift Valley fever along the livestock movement routes in the northeastern and coastal regions of Kenya. AB - BACKGROUND: Knowledge of vector ecology is important in understanding the transmission dynamics of vector borne disease. In this study, we determined the distribution and diversity of mosquitoes along the major nomadic livestock movement routes (LMR) in the traditional pastoral ecozone of northeastern Kenya. We focused on the vectors of Rift Valley fever virus (RVFv) with the aim of understanding their ecology and how they can potentially influence the circulation of RVFv. METHODS: Mosquito surveys were conducted during the short and long rainy seasons from November 2012 to August 2014 using CO2-baited CDC light traps at seven sites selected for their proximity to stopover points that provide pasture, water and night bomas (where animals spend nights). We compared mosquito abundance and diversity across the sites, which were located in three ecological zones (IV, V and VI), based on the classification system of agro ecological zones in Kenya. RESULTS: Over 31,000 mosquitoes were trapped comprising 21 species belonging to 6 genera. Overall mosquito abundance varied significantly by ecological zones and sites. Mansonia species (Ma. uniformis and Ma. africana) were predominant (n = 12,181, 38.3%). This was followed by the primary RVF vectors, Ae. ochraceus and Ae. mcintoshi comprising 17.9 and 14.98%, respectively, of the total captures and represented across all sites and ecological zones. The Shannon diversity index ranged from 0.8 to 2.4 with significant zone, site and seasonal variations. There was also significant species richness of RVF vector across ecological zones. CONCLUSION: Our findings highlight differential occurrence of RVFv vectors across ecological zones and sampling sites, which may be important in determining areas at risk of emergence and circulation of RVFv. Moreover, the vector distribution map along LMR generated in this study will guide potential interventions for control of the disease, including strategic vaccination for livestock. PMID- 26018135 TI - Few-layer bismuth selenides exfoliated by hemin inhibit amyloid-beta1-42 fibril formation. AB - Inhibiting amyloid-beta (Abeta) fibril formation is the primary therapeutic strategy for Alzheimer's disease. Several small molecules and nanomaterials have been used to inhibit Abeta fibril formation. However, insufficient inhibition efficiency or poor metabolization limits their further applications. Here, we used hemin to exfoliate few-layer Bi(2)Se(3) in aqueous solution. Then we separated few-layer Bi(2)Se(3) with different sizes and thicknesses by fractional centrifugation, and used them to attempt to inhibit Abeta(1-42) aggregation. The results show that smaller and thinner few-layer Bi(2)Se(3) had the highest inhibition efficiency. We further investigated the interaction between few-layer Bi(2)Se(3) and Abeta(1-42) monomers. The results indicate that the inhibition effect may be due to the high adsorption capacity of few-layer Bi(2)Se(3) for Abeta(1-42) monomers. Few-layer Bi(2)Se(3) also decreased Abeta-mediated peroxidase-like activity and cytotoxicity according to in vitro neurotoxicity studies under physiological conditions. Therefore, our work shows the potential for applications of few-layer Bi(2)Se(3) in the biomedical field. PMID- 26018136 TI - In Vitro Effects of Bisphenol A beta-D-Glucuronide (BPA-G) on Adipogenesis in Human and Murine Preadipocytes. AB - BACKGROUND: Exposure to common environmental substances, such as bisphenol A (BPA), has been associated with a number of negative health outcomes. In vivo, BPA is rapidly converted to its predominant metabolite, BPA-glucuronide (BPA-G), which has long been believed to be biologically inactive because it lacks estrogenic activity. However, the effects of BPA-G on cellular metabolism have not been characterized. In the present study we examined the effect of BPA-G on adipogenesis. METHODS: The effect of BPA-G on the differentiation of human and 3T3L1 murine preadipocytes was evaluated in vitro by quantifying lipid accumulation and the expression of adipogenic markers. RESULTS: Treatment of 3T3L1 preadipocytes with 10 MUM BPA-G induced a significant increase in lipid accumulation, mRNA expression of the adipogenic markers sterol regulatory element binding factor 1 (SREBF1) and lipoprotein lipase (LPL), and protein levels of LPL, aP2, and adipsin. Treatment of primary human preadipocytes with BPA-G also induced adipogenesis as determined by aP2 levels. Co-treatment of cells with the estrogen receptor (ER) antagonist fulvestrant (ICI) significantly inhibited the BPA-G-induced increase in LPL and aP2 levels, whereas treatment with ICI alone had no effect. Moreover, BPA-G did not display any significant estrogenic activity. CONCLUSIONS: To our knowledge, this study is the first to report that BPA-G induces adipocyte differentiation and is not simply an inactive metabolite. The fact that BPA-G induced adipogenesis and was inhibited by an ER antagonist yet showed no estrogenic activity suggests that it has no classical ER transcriptional activation function and acts through a pathway that remains to be determined. PMID- 26018137 TI - High glucose promotes TGF-beta1 production by inducing FOS expression in human peritoneal mesothelial cells. AB - BACKGROUND: High glucose (HG) induces production of transforming growth factor beta1 (TGF-beta1), but the mechanism remains elusive. The aim of this study was to determine the gene(s) involved in HG-induced TGF-beta1 production in human peritoneal mesothelial cells (HPMCs). METHODS: Microarray analysis was performed following a 3-h preincubation of HPMCs in 4 or 0.1% glucose medium. Transcriptional genes were selected using Gene Ontology analysis for biological processes, including regulation of transcription and DNA-dependent. The effects of small interfering RNA (siRNA) treatments on the up-regulation of TGF-beta1 mRNA were assessed by quantitative real-time polymerase chain reaction (qPCR). Finally, enzyme-linked immunosorbent assay (ELISA) was performed to determine which gene(s) contribute to the production of TGF-beta1 protein in the medium. RESULTS: Microarray analysis revealed that the expression of 51 genes increased by more than 3-fold. Gene ontology analysis identified 13 genes for further study. qPCR confirmed mRNA amplification for 9 of the 13 genes. Furthermore, HG induced up-regulation of TGF-beta1 mRNA was attenuated by the siRNA of 4 genes: MDS1 and EVI1 complex locus (MECOM), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), FBJ murine osteosarcoma viral oncogene homolog (FOS) and activating transcription factor 3 (ATF3). ELISA showed that siRNA treatment of FOS, but not MECOM, FOSB or ATF3, suppressed the increase of TGF-beta1 protein in the medium. CONCLUSIONS: FOS is a downstream effector of HG stimulation in HPMCs that contributes to TGF-beta1 production, suggesting that blocking FOS expression may be a therapeutic target for peritoneal fibrosis. PMID- 26018138 TI - Transgenic maize event TC1507: Global status of food, feed, and environmental safety. AB - Maize (Zea mays) is a widely cultivated cereal that has been safely consumed by humans and animals for centuries. Transgenic or genetically engineered insect resistant and herbicide-tolerant maize, are commercially grown on a broad scale. Event TC1507 (OECD unique identifier: DAS-O15O7-1) or the Herculex(r)(#) I trait, an insect-resistant and herbicide-tolerant maize expressing Cry1F and PAT proteins, has been registered for commercial cultivation in the US since 2001. A science-based safety assessment was conducted on TC1507 prior to commercialization. The safety assessment addressed allergenicity; acute oral toxicity; subchronic toxicity; substantial equivalence with conventional comparators, as well as environmental impact. Results from biochemical, physicochemical, and in silico investigations supported the conclusion that Cry1F and PAT proteins are unlikely to be either allergenic or toxic to humans. Also, findings from toxicological and animal feeding studies supported that maize with TC1507 is as safe and nutritious as conventional maize. Maize with TC1507 is not expected to behave differently than conventional maize in terms of its potential for invasiveness, gene flow to wild and weedy relatives, or impact on non-target organisms. These safety conclusions regarding TC1507 were acknowledged by over 20 regulatory agencies including United States Environment Protection Agency (US EPA), US Department of Agriculture (USDA), Canadian Food Inspection Agency (CFIA), and European Food Safety Authority (EFSA) before authorizing cultivation and/or food and feed uses. A comprehensive review of the safety studies on TC1507, as well as some benefits, are presented here to serve as a reference for regulatory agencies and decision makers in other countries where authorization of TC1507 is or will be pursued. PMID- 26018140 TI - Platinum-ruthenium bimetallic clusters on graphite: a comparison of vapor deposition and electroless deposition methods. AB - Bimetallic Pt-Ru clusters have been grown on highly ordered pyrolytic graphite (HOPG) surfaces by vapor deposition and by electroless deposition. These studies help to bridge the material gap between well-characterized vapor deposited clusters and electrolessly deposited clusters, which are better suited for industrial catalyst preparation. In the vapor deposition experiments, bimetallic clusters were formed by the sequential deposition of Pt on Ru or Ru on Pt. Seed clusters of the first metal were grown on HOPG surfaces that were sputtered with Ar(+) to introduce defects, which act as nucleation sites for Pt or Ru. On the unmodified HOPG surface, both Pt and Ru clusters preferentially nucleated at the step edges, whereas on the sputtered surface, clusters with relatively uniform sizes and spatial distributions were formed. Low energy ion scattering experiments showed that the surface compositions of the bimetallic clusters are Pt-rich, regardless of the order of deposition, indicating that the interdiffusion of metals within the clusters is facile at room temperature. Bimetallic clusters on sputtered HOPG were prepared by the electroless deposition of Pt on Ru seed clusters from a Pt(+2) solution using dimethylamine borane as the reducing agent at pH 11 and 40 degrees C. After exposure to the electroless deposition bath, Pt was selectively deposited on Ru, as demonstrated by the detection of Pt on the surface by XPS, and the increase in the average cluster height without an increase in the number of clusters, indicating that Pt atoms are incorporated into the Ru seed clusters. Electroless deposition of Ru on Pt seed clusters was also achieved, but it should be noted that this deposition method is extremely sensitive to the presence of other metal ions in solution that have a higher reduction potential than the metal ion targeted for deposition. PMID- 26018139 TI - Nosema ceranae Can Infect Honey Bee Larvae and Reduces Subsequent Adult Longevity. AB - Nosema ceranae causes a widespread disease that reduces honey bee health but is only thought to infect adult honey bees, not larvae, a critical life stage. We reared honey bee (Apis mellifera) larvae in vitro and provide the first demonstration that N. ceranae can infect larvae and decrease subsequent adult longevity. We exposed three-day-old larvae to a single dose of 40,000 (40K), 10,000 (10K), zero (control), or 40K autoclaved (control) N. ceranae spores in larval food. Spores developed intracellularly in midgut cells at the pre-pupal stage (8 days after egg hatching) of 41% of bees exposed as larvae. We counted the number of N. ceranae spores in dissected bee midguts of pre-pupae and, in a separate group, upon adult death. Pre-pupae exposed to the 10K or 40K spore treatments as larvae had significantly elevated spore counts as compared to controls. Adults exposed as larvae had significantly elevated spore counts as compared to controls. Larval spore exposure decreased longevity: a 40K treatment decreased the age by which 75% of adult bees died by 28%. Unexpectedly, the low dose (10K) led to significantly greater infection (1.3 fold more spores and 1.5 fold more infected bees) than the high dose (40K) upon adult death. Differential immune activation may be involved if the higher dose triggered a stronger larval immune response that resulted in fewer adult spores but imposed a cost, reducing lifespan. The impact of N. ceranae on honey bee larval development and the larvae of naturally infected colonies therefore deserve further study. PMID- 26018141 TI - Dendritic Glycopolymer as Drug Delivery System for Proteasome Inhibitor Bortezomib in a Calcium Phosphate Bone Cement: First Steps Toward a Local Therapy of Osteolytic Bone Lesions. AB - Establishment of drug delivery system (DDS) in bone substitute materials for local treatment of bone defects still requires ambitious solutions for a retarded drug release. We present two novel DDS, a weakly cationic dendritic glycopolymer and a cationic polyelectrolyte complex, composed of dendritic glycopolymer and cellulose sulfate, for the proteasome inhibitor bortezomib. Both DDS are able to induce short-term retarded release of bortezomib from calcium phosphate bone cement in comparison to a burst-release of the drug from bone cement alone. Different release parameters have been evaluated to get a first insight into the release mechanism from bone cements. In addition, biocompatibility of the calcium phosphate cement, modified with the new DDS was investigated using human mesenchymal stromal cells. PMID- 26018142 TI - An assessment of the realism of digital human manikins used for simulation in ergonomics. AB - In this study, the accuracy of the joint centres of the manikins generated by RAMSIS and Human Builder (HB), two digital human modelling (DHM) systems widely used in industry for virtual ergonomics simulation, was investigated. Eighteen variously sized females and males were generated from external anthropometric dimensions and six joint centres (knee, hip and four spine joints) were compared with their anatomic locations obtained from the three-dimensional reconstructed bones from a low-dose X-ray system. Both RAMSIS and HB could correctly reproduce external anthropometric dimensions, while the estimation of internal joint centres location presented an average error of 27.6 mm for HB and 38.3 mm for RAMSIS. Differences between both manikins showed that a more realistic kinematic linkage led to better accuracy in joint location. This study opens the way to further research on the relationship between the external body geometry and internal skeleton in order to improve the realism of the internal skeleton of DHMs, especially for a biomechanical analysis requiring information of joint load and muscle force estimation. PRACTITIONER SUMMARY: This study assessed two digital human modelling (DHM) systems widely used in industry for virtual ergonomics. Results support the need of a more realistic human modelling, especially for a biomechanical analysis and a standardisation of DHMs. PMID- 26018143 TI - Photophysical Properties of Intramolecular Charge Transfer in a Tribranched Donor pi-Acceptor Chromophore. AB - The photophysical properties of intramolecular charge transfer (ICT) in a novel tribranched donor-pi-acceptor chromophore, triphenoxazine-2,4,6-triphenyl-1,3,5 triazine (tri-PXZ-TRZ), with thermally activated delayed fluorescence character was investigated in different aprotic solvents by steady-state spectroscopy and femtosecond and nanosecond transient absorption spectroscopy measurements. Increasing the solvent polarity led to a significant increase in the Stokes shift. The large Stokes shift in highly polar solvents was attributed to ICT properties upon excitation; this resulted in a strong interaction between the tri PXZ-TRZ molecule and the surrounding solvent, which led to a strong solvation process. Quantum-chemical calculations and changes in the dipole moment showed that this compound has a large degree of ICT. Furthermore, an apolar environment helped to preserve the symmetry of tri-PXZ-TRZ and to enhance its emission efficiency. The femtosecond and nanosecond transient absorption spectroscopy results indicated that the excited-state dynamics of this push-pull molecule were strongly influenced by solvent polarity through the formation of a solvent stabilized ICT state. The excited-state relaxation mechanism of tri-PXZ-TRZ was proposed by performing target model analysis on the femtosecond transient absorption spectra. In addition, the delayed fluorescence of tri-PXZ-TRZ was significantly modulated by a potential competition between solvation and intersystem crossing processes. PMID- 26018144 TI - Lipids containing medium-chain fatty acids are specific to post-whole genome duplication Saccharomycotina yeasts. AB - BACKGROUND: Yeasts belonging to the subphylum Saccharomycotina have been used for centuries in food processing and, more recently, biotechnology. Over the past few decades, these yeasts have also been studied in the interest of their potential to produce oil to replace fossil resources. Developing yeasts for massive oil production requires increasing yield and modifying the profiles of the fatty acids contained in the oil to satisfy specific technical requirements. For example, derivatives of medium-chain fatty acids (MCFAs, containing 6-14 carbons) are used for the production of biodiesels, cleaning products, lubricants and cosmetics. Few studies are available in the literature on the production of MCFAs in yeasts. RESULTS: We analyzed the MCFA content in Saccharomyces cerevisiae grown in various conditions. The results revealed that MCFAs preferentially accumulated when cells were grown on synthetic media with a high C/N ratio at low temperature (23 degrees C). Upon screening deletion mutant strains for genes encoding lipid droplet-associated proteins, we found two genes, LOA1 and TGL3, involved in MCFA homeostasis. A phylogenetic analysis on 16 Saccharomycotina species showed that fatty acid profiles differed drastically among yeasts. Interestingly, MCFAs are only present in post-whole genome duplication yeast species. CONCLUSIONS: In this study, we produced original data on fatty acid diversity in yeasts. We demonstrated that yeasts are amenable to genetic and metabolic engineering to increase their MCFA production. Furthermore, we revealed that yeast lipid biodiversity has not been fully explored, but that yeasts likely harbor as-yet-undiscovered strains or enzymes that can contribute to the production of high-value fatty acids for green chemistry. PMID- 26018145 TI - Relation between uric acid and metabolic syndrome in subjects with cardiometabolic risk. AB - Objective To identify possible relations between serum uric acid levels and metabolic syndrome and its components in a population with cardiometabolic risk. Methods This cross-sectional study included 80 subjects (46 women), with mean age of 48+/-16 years, seen at the Cardiovascular Health Program. Results The prevalence of hyperuricemia and metabolic syndrome was 6.3% and 47.1%, respectively. Uric acid level was significantly higher in individuals with metabolic syndrome (5.1+/-1.6mg/dL), as compared to those with no syndrome or with pre-syndrome (3.9+/-1.2 and 4.1+/-1.3mg/dL, respectively; p<0.05). The uric acid levels were significantly higher in men presenting abdominal obesity, and among women with abdominal obesity, lower HDL-c levels and higher blood pressure (p<0.05). Conclusion Uric acid concentrations were positively related to the occurrence of metabolic syndrome and its components, and there were differences between genders. Our results indicate serum uric acid as a potential biomarker for patients with cardiometabolic risk. PMID- 26018146 TI - Breast necrosis induced by the use of coumadin: case report and review of literature. AB - The coumadin-induced skin necrosis is rare and occurs more frequently in the breasts, thighs and buttocks. We describe the first case of coumadin necrosis of the breast in Brazil in a 62-year-old patient. PMID- 26018147 TI - Neonatal spontaneous pneumomediastinum and the Spinnaker-Sail sign. PMID- 26018148 TI - Tuberculosis axillary lymph node coexistent breast cancer in adjuvant treatment: case report. AB - Coexistence of breast cancer and tuberculosis is rare. In most cases, involvement by tuberculosis occurs in axillary lymph nodes. We report a case of a 43-years old patient who had undergone adenomastectomy and left sentinel lymph node biopsy due to a triple negative ductal carcinoma. At the end of adjuvant treatment, the patient had an atypical lymph node in the left axilla. Lymph node was excised, and after laboratory analysis, the diagnosis was ganglion tuberculosis. The patient underwent treatment for primary tuberculosis. The development of these two pathologies can lead to problems in diagnosis and treatment. An accurate diagnosis is important to avoid unnecessary surgical procedures. PMID- 26018149 TI - Corneal complication caused by gonococcal conjunctivitis. PMID- 26018150 TI - Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists. AB - The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5'-triphosphate (5'ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5'ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5'pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5'pppRNA structures, RIG-I aptamers, or poly(I.C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5'pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses. IMPORTANCE: The development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100 fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5'pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists. PMID- 26018151 TI - Promotion of Endoplasmic Reticulum-Associated Degradation of Procathepsin D by Human Herpesvirus 8-Encoded Viral Interleukin-6. AB - The interleukin-6 homologue (viral interleukin-6 [vIL-6]) of human herpesvirus 8 is implicated in viral pathogenesis due to its proproliferative, inflammatory, and angiogenic properties, effected through gp130 receptor signaling. In primary effusion lymphoma (PEL) cells, vIL-6 is expressed latently and is essential for normal cell growth and viability. This is mediated partly via suppression of proapoptotic cathepsin D (CatD) via cocomplexing of the endoplasmic reticulum (ER)-localized CatD precursor, pro-CatD (pCatD), and vIL-6 with the previously uncharacterized ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). vIL-6 suppression of CatD occurs also during reactivated productive replication in PEL cells and is likely to contribute to proreplication functions of vIL-6. Here, we report that vIL-6 suppresses CatD through vIL-6, VKORC1v2, and pCatD association with components of the ER-associated degradation (ERAD) machinery. In transfected cells, expression of vIL-6 along with CatD led to proteasome-dependent (inhibitor-sensitive) decreases in CatD levels and the promotion of pCatD polyubiquitination. Depletion of particular ERAD-associated isomerases, lectins, and translocon components, including ERAD E3 ubiquitin ligase HRD1, diminished suppression of CatD by vIL-6. Coprecipitation assays identified direct or indirect interactions of VKORC1v2, vIL-6, and pCatD with translocon proteins (SEL1L and/or HRD1) and ERAD-associated lectins OS9 and XTP3 B. Endogenous CatD expression in PEL cells was increased by depletion of ERAD components, and suppression of CatD by vIL-6 overexpression in PEL cells was dependent on HRD1. Our data reveal a new mechanism of ER-localized vIL-6 activity and further characterize VKORC1v2 function. IMPORTANCE: Human herpesvirus 8 (HHV 8) viral interleukin-6 (vIL-6), unlike cellular IL-6 proteins, is secreted inefficiently and sequestered mainly in the endoplasmic reticulum (ER), from where it can signal through the gp130 receptor. We have recently reported that vIL-6 also associates with a novel membrane protein termed vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2) and mediates suppression of VKORC1v2-cointeracting cathepsin D, a stress-released proapoptotic protein negatively impacting HHV-8 latently infected primary effusion lymphoma (PEL) cell viability and reactivated virus productive replication. Here, we have examined the mechanistic basis of the VKORC1v2-vIL-6 interaction-dependent suppression of cathepsin D and have found that this novel activity of vIL-6 is mediated through coassociation of VKORC1v2, procathepsin D, and vIL-6 with components of the ER associated degradation (ERAD) machinery. Our findings provide information of significance for potential antiviral and therapeutic targeting of VKORC1v2 mediated vIL-6 activities and also indicate the nature of VKORC1v2 function in normal cell biology. PMID- 26018152 TI - Immunization with Immune Complexes Modulates the Fine Specificity of Antibody Responses to a Flavivirus Antigen. AB - The antibody response to proteins may be modulated by the presence of preexisting antigen-specific antibodies and the formation of immune complexes (ICs). Effects such as a general increase or decrease of the response as well as epitope specific phenomena have been described. In this study, we investigated influences of IC immunization on the fine specificity of antibody responses in a structurally well-defined system, using the envelope (E) protein of tick-borne encephalitis (TBE) virus as an immunogen. TBE virus occurs in Europe and Asia and together with the yellow fever, dengue, West Nile, and Japanese encephalitis viruses-represents one of the major human-pathogenic flaviviruses. Mice were immunized with a dimeric soluble form of E (sE) alone or in complex with monoclonal antibodies specific for each of the three domains of E, and the antibody response induced by these ICs was compared to that seen after immunization with sE alone. Immunoassays using recombinant domains and domain combinations of TBE virus sE as well as the distantly related West Nile virus sE allowed the dissection and quantification of antibody subsets present in postimmunization sera, thus generating fine-specificity patterns of the polyclonal responses. There were substantially different responses with two of the ICs, and the differences could be mechanistically related to (i) epitope shielding and (ii) antibody-mediated structural changes leading to dissociation of the sE dimer. The phenomena described may also be relevant for polyclonal responses upon secondary infections and/or booster immunizations and may affect antibody responses in an individual-specific way. IMPORTANCE: Infections with flaviviruses such as yellow fever, dengue, Japanese encephalitis, West Nile, and tick-borne encephalitis (TBE) viruses pose substantial public health problems in different parts of the world. Antibodies to viral envelope protein E induced by natural infection or vaccination were shown to confer protection from disease. Such antibodies can target different epitopes in E protein, and the fine specificities of polyclonal responses can differ between individuals. We conducted a mouse immunization study with TBE E protein alone or complexed to monoclonal antibodies specific for each of the three protein domains. We demonstrated that phenomena such as epitope shielding and antibody-induced structural changes can profoundly influence the fine specificity of antibody responses to the same immunogen. The study thus provided important new information on the potential immunomodulatory role of preexisting antibodies in a flavivirus system that can be relevant for understanding individual-specific factors influencing antibody responses in sequential flavivirus infections and/or immunizations. PMID- 26018153 TI - Local Virus Extinctions following a Host Population Bottleneck. AB - A small number of African green monkeys (AGMs) were introduced into the Caribbean from West Africa in the 1600s. To determine the impact of this population bottleneck on the AGM virome, we used metagenomics to compare the viral nucleic acids in the plasma of 43 wild AGMs from West Africa (Gambia) to those in 44 AGMs from the Caribbean (St. Kitts and Nevis). Three viruses were detected in the blood of Gambian primates: simian immunodeficiency virus (SIVagm; in 42% of animals), a novel simian pegivirus (SPgVagm; in 7% of animals), and numerous novel simian anelloviruses (in 100% of animals). Only anelloviruses were detected in the Caribbean AGMs with a prevalence and levels of viral genetic diversity similar to those in the Gambian animals. A host population bottleneck therefore resulted in the exclusion of adult-acquired SIV and pegivirus from the Caribbean AGMs. The successful importation of AGM anelloviruses into the Caribbean may be the result of their early transmission to infants, very high prevalence in African AGMs, and frequent coinfections with as many as 11 distinct variants. IMPORTANCE: The extent to which viruses can persist in small isolated populations depends on multiple host, viral, and environmental factors. The absence of prior infections may put an immunologically naive population at risk for disease outbreaks. Isolated populations originating from a small number of founder individuals are therefore considered at increased risk following contact with populations with a greater variety of viruses. Here, we compared the plasma virome of West African green monkeys to that in their descendants after importation of a small number of animals to the Caribbean. A lentivirus and a pegivirus were found in the West African population but not in the Caribbean population. Highly diverse anelloviruses were found in both populations. A small founder population, limited to infants and young juvenile monkeys, may have eliminated the sexually transmitted viruses from the Caribbean AGMs, while anelloviruses, acquired at an earlier age, persisted through the host population bottleneck. PMID- 26018154 TI - A Multiantigenic DNA Vaccine That Induces Broad Hepatitis C Virus-Specific T-Cell Responses in Mice. AB - There are 3 to 4 million new hepatitis C virus (HCV) infections annually around the world, but no vaccine is available. Robust T-cell mediated responses are necessary for effective clearance of the virus, and DNA vaccines result in a cell mediated bias. Adjuvants are often required for effective vaccination, but during natural lytic viral infections damage-associated molecular patterns (DAMPs) are released, which act as natural adjuvants. Hence, a vaccine that induces cell necrosis and releases DAMPs will result in cell-mediated immunity (CMI), similar to that resulting from natural lytic viral infection. We have generated a DNA vaccine with the ability to elicit strong CMI against the HCV nonstructural (NS) proteins (3, 4A, 4B, and 5B) by encoding a cytolytic protein, perforin (PRF), and the antigens on a single plasmid. We examined the efficacy of the vaccines in C57BL/6 mice, as determined by gamma interferon enzyme-linked immunosorbent spot assay, cell proliferation studies, and intracellular cytokine production. Initially, we showed that encoding the NS4A protein in a vaccine which encoded only NS3 reduced the immunogenicity of NS3, whereas including PRF increased NS3 immunogenicity. In contrast, the inclusion of NS4A increased the immunogenicity of the NS3, NS4B, andNS5B proteins, when encoded in a DNA vaccine that also encoded PRF. Finally, vaccines that also encoded PRF elicited similar levels of CMI against each protein after vaccination with DNA encoding NS3, NS4A, NS4B, and NS5B compared to mice vaccinated with DNA encoding only NS3 or NS4B/5B. Thus, we have developed a promising "multiantigen" vaccine that elicits robust CMI. IMPORTANCE: Since their development, vaccines have reduced the global burden of disease. One strategy for vaccine development is to use commercially viable DNA technology, which has the potential to generate robust immune responses. Hepatitis C virus causes chronic liver infection and is a leading cause of liver cancer. To date, no vaccine is currently available, and treatment is costly and often results in side effects, limiting the number of patients who are treated. Despite recent advances in treatment, prevention remains the key to efficient control and elimination of this virus. Here, we describe a novel DNA vaccine against hepatitis C virus that is capable of inducing robust cell-mediated immune responses in mice and is a promising vaccine candidate for humans. PMID- 26018155 TI - Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62. AB - Autophagic flux involves formation of autophagosomes and their degradation by lysosomes. Autophagy can either promote or restrict viral replication. In the case of Dengue virus (DENV), several studies report that autophagy supports the viral replication cycle, and describe an increase of autophagic vesicles (AVs) following infection. However, it is unknown how autophagic flux is altered to result in increased AVs. To address this question and gain insight into the role of autophagy during DENV infection, we established an unbiased, image-based flow cytometry approach to quantify autophagic flux under normal growth conditions and in response to activation by nutrient deprivation or them TOR inhibitor Torin1.We found that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Early after infection, basal and activated autophagic flux was enhanced. However, during established replication, basal and Torin1-activated autophagic flux was blocked, while autophagic flux activated by nutrient deprivation was reduced, indicating a block to AV formation and reduced AV degradation capacity. During late infection AV levels increased as a result of inefficient fusion of autophagosomes with lysosomes. In addition, endolysosomal trafficking was suppressed, while lysosomal activities were increased.We further determined that DENV infection progressively reduced levels of the autophagy receptor SQSTM1/p62 via proteasomal degradation. Importantly, stable overexpression of p62 significantly suppressed DENV replication, suggesting a novel role for p62 as a viral restriction factor. Overall, our findings indicate that in the course of DENV infection, autophagy shifts from a supporting to an antiviral role, which is countered by DENV. IMPORTANCE: Autophagic flux is a dynamic process starting with the formation of autophagosomes and ending with their degradation after fusion with lysosomes. Autophagy impacts the replication cycle of many viruses. However, thus far the dynamics of autophagy in case of Dengue virus (DENV) infections has not been systematically quantified. Therefore, we used high-content, imaging-based flow cytometry to quantify autophagic flux and endolysosomal trafficking in response to DENV infection. We report that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Further, lysosomal activity was increased, but endolysosomal trafficking was suppressed confirming the block of autophagic flux. Importantly, we provide evidence that p62, an autophagy receptor, restrict DENV replication and was specifically depleted in DENV-infected cells via increased proteasomal degradation. These results suggest that during DENV infection autophagy shifts from a proviral to an antiviral cellular process, which is counteracted by the virus. PMID- 26018156 TI - Identification of Influenza A Virus PB2 Residues Involved in Enhanced Polymerase Activity and Virus Growth in Mammalian Cells at Low Temperatures. AB - Mutations in the polymerase genes are known to play a major role in avian influenza virus adaptation to mammalian hosts. Despite having avian origin PA and PB2, the 2009 pandemic H1N1 virus (pH1N1) can replicate well in mammalian respiratory tracts, suggesting that these proteins have acquired mutations for efficient growth in humans. We have previously shown that PA from the pH1N1 virus A/California/04/09 (Cal) strongly enhances activity of an otherwise avian polymerase complex derived from A/chicken/Nanchang/3-120/01 (Nan) in mammalian cells. However, this enhancement was observed at 37 degrees C but not at the lower temperature of 34 degrees C. An additional introduction of Cal PB2 enhanced activity at 34 degrees C, suggesting the presence of unidentified residues in Cal PB2 that are required for efficient growth at low temperature. Here, we sought to determine the key PB2 residues which confer enhanced polymerase activity and virus growth in human cells at low temperature. Using a reporter gene assay, we identified novel mutations, PB2 V661A and V683T/A684S, which are involved in enhanced Cal polymerase activity at low temperature. The PB2 T271A mutation, which we previously reported, also contributed to enhanced activity. The growth of recombinant Cal containing PB2 with Nan residues 271T/661V/683V/684A was strongly reduced in human cells compared to wild-type virus at low temperature. Among the four residues, 271A and 684S are conserved in human and pH1N1 viruses but not in avian viruses, suggesting an important role in mammalian adaptation of pH1N1 virus. IMPORTANCE: The PB2 protein plays a key role in the host adaptation, cold sensitivity, and pathogenesis of influenza A virus. Despite containing an avian origin PB2 lacking the mammalian adaptive mutations 627K or 701N, pH1N1 influenza virus strains can replicate efficiently in the low temperature upper respiratory tract of mammals, suggesting the presence of unknown mutations in the pH1N1 PB2 protein responsible for its low temperature adaptation. Here, in addition to PB2 271A, which has been shown to increase polymerase activity, we identified novel PB2 residues 661A and 683T/684S in pH1N1 which confer enhanced polymerase activity and virus growth in mammalian cells especially at low temperature. Our findings suggest that the presence of these PB2 residues contributes to efficient replication of the pH1N1 virus in the upper respiratory tract, which resulted in efficient human-to-human transmission of this virus. PMID- 26018157 TI - Human Blood-Circulating Basophils Capture HIV-1 and Mediate Viral trans-Infection of CD4+ T Cells. AB - Cell-associated HIV-1 infection has been proposed to play a pivotal role in the spread of HIV-1 infection. Granulocytes are a category of white blood cells, comprising mainly basophils, neutrophils, and eosinophils, and participate in various inflammatory reactions and defense against pathogens. Here, we investigated the role of human blood granulocytes in the dissemination of HIV-1. These cells were found to express a variety of HIV-1 attachment factors (HAFs). Basophils expressed HAFs dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM3)-grabbing nonintegrin (DC-SIGN), DC immunoreceptor (DCIR), heparan sulfate proteoglycan (HSPG), and alpha4beta7 integrin and mediated the most efficient capture of HIV-1 on the cell surface. Neutrophils were found to express DCIR and demonstrated limited efficiency of viral capture. Eosinophils expressed alpha4beta7 integrin but exhibited little or no virus-binding capacity. Intriguingly, following direct contact with CD4+ T cells, viruses harbored on the surface of basophils were transferred to T cells. The contact between basophils and CD4+ T cells and formation of infectious synapses appeared necessary for efficient HIV-1 spread. In HIV-1-infected individuals, the frequency of basophils remained fairly stable over the course of disease, regardless of CD4+ T depletion or the emergence of AIDS-associated opportunistic infections. Collectively, our results provide novel insights into the roles of granulocytes, particularly basophils, in HIV-1 dissemination. Thus, strategies designed to prevent basophil mediated viral capture and transfer may be developed into a new form of therapy. IMPORTANCE: Cell-associated HIV-1 infection has been proposed to play a pivotal role in the spread of HIV-1 infection. Here, we demonstrated that human blood circulating granulocytes, particularly basophils, can capture HIV-1 and mediate viral trans-infection of CD4+ T cells. The expression of a variety of HIV-1 attachment factors, such as the C-type lectins, etc., facilitates viral capture and transfer. Intriguingly, the frequency of basophils in patients with different levels of CD4+ T counts remains fairly stable during the course of disease. Our results provide novel insights into the roles of granulocytes, particularly basophils, in HIV-1 dissemination. We suggest that strategies designed to prevent basophil-mediated viral capture and transfer may be a new direction for the development of anti-HIV therapy. PMID- 26018158 TI - The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel. AB - The region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2ZM109-1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. The epitope of monoclonal antibody 830A is discontinuous and composed of three segments: (i) Thr175, Tyr177, Leu179, and Asp180 at the kink overlapping the integrin-binding site; (ii) Arg153 and Val154 in V1; and (iii) Ile194 at the C terminus of V2. This report thus provides the atomic details of the immunogenic "V2i epitope." IMPORTANCE: Data from the RV144 phase III clinical trial suggested that the presence of antibodies to the first and second variable regions (V1V2) of gp120 was associated with the modest protection afforded by the vaccine. V1V2 is a highly variable and immunogenic region of HIV-1 surface glycoprotein gp120, and structural information about this region and its antigenic landscape will be crucial in the design of an effective HIV-1 vaccine. We have determined a crystal structure of V1V2 in complex with human MAb 830A and have shown that MAb 830A recognizes a region overlapping the alpha4beta7 integrin-binding site. We also showed that V1V2 forms a 5-stranded beta barrel, an elegant structure allowing sequence variations in the strand-connecting loops while preserving a conserved core. PMID- 26018159 TI - Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates. AB - To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen. PMID- 26018160 TI - Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease. AB - Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here, we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate virus-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterize the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, and fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory cytokine interleukin 10 and reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus-induced arthritis, acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall, the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis. IMPORTANCE: The hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas, with approximately 1 million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently, there is no licensed specific treatment for alphavirus disease, and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects, and is currently licensed under the name Elmiron for the treatment of cystitis in the United States. Our findings show that RRV infection damages the articular cartilage, including a loss of proteoglycans within the joint. Furthermore, treatment with PPS reduced the severity of both RRV- and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting that PPS is a promising candidate for drug repurposing for the treatment of alphavirus-induced arthritis. PMID- 26018161 TI - Global Diversity within and between Human Herpesvirus 1 and 2 Glycoproteins. AB - Human herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are large-genome DNA viruses that establish a persistent infection in sensory neurons and commonly manifest with recurring oral or genital erosions that transmit virus. HSV encodes 12 predicted glycoproteins that serve various functions, including cellular attachment, entry, and egress. Glycoprotein G is currently the target of an antibody test to differentiate HSV-1 from HSV-2; however, this test has shown reduced capacity to differentiate HSV strains in East Africa. Until the recent availability of 26 full-length HSV-1 and 36 full-length HSV-2 sequences, minimal comparative information was available for these viruses. In this study, we use a variety of sequence analysis methods to compare all available sequence data for HSV-1 and HSV-2 glycoproteins, using viruses isolated in Europe, Asia, North America, the Republic of South Africa, and East Africa. We found numerous differences in diversity, nonsynonymous/synonymous substitution rates, and recombination rates between HSV-1 glycoproteins and their HSV-2 counterparts. Phylogenetic analysis revealed that while most global HSV-2 glycoprotein G sequences did not form clusters within or between continents, one clade (supported at 60.5%) contained 37% of the African sequences analyzed. Accordingly, sequences from this African subset contained unique amino acid signatures, not only in glycoprotein G, but also in glycoproteins I and E, which may account for the failure of sensitive antibody tests to distinguish HSV-1 from HSV-2 in some African individuals. Consensus sequences generated in the study can be used to improve diagnostic assays that differentiate HSV-1 from HSV-2 in global populations. IMPORTANCE: Human herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are large DNA viruses associated with recurring oral or genital erosions that transmit virus. Up to 12 HSV-1 and HSV-2 glycoproteins are involved in HSV cell entry or are required for viral spread in animals, albeit some are dispensable for replication in vitro. The recent availability of comparable numbers of full-length HSV-1 and HSV-2 sequences enabled comparative analysis of gene diversity of glycoproteins within and between HSV types. Overall, we found less glycoprotein sequence diversity within HSV-2 than within the HSV-1 strains studied, while at the same time, several HSV-2 glycoproteins were evolving under less selective pressure. Because HSV glycoproteins are the focus of antibody tests to detect and differentiate between infections with the two strains and are constituents of vaccines in clinical-stage development, these findings will aid in refining the targets for diagnostic tests and vaccines. PMID- 26018162 TI - Population Bottlenecks and Pathogen Extinction: "Make This Everyone's Mission to Mars, Including Yours". AB - Kapusinszky et al. (J Virol 89:8152-8161, 2015, http://dx.doi.org/10.1128/JVI.00671-15) report that host population bottlenecks may result in pathogen extinction, which provides a compelling argument for an alternative approach to vaccination for the control of virus spread. By comparing the prevalence levels of three viral pathogens in two populations of African green monkeys (AGMs) (Chlorocebus sabaeus) from Africa and two Caribbean Islands, they convincingly show that a major host bottleneck resulted in the eradication of select pathogens from a given host. PMID- 26018163 TI - The Baculovirus Antiapoptotic p35 Protein Functions as an Inhibitor of the Host RNA Interference Antiviral Response. AB - RNA interference (RNAi) is considered an ancient antiviral defense in diverse organisms, including insects. Virus infections generate double-strand RNAs (dsRNAs) that trigger the RNAi machinery to process dsRNAs into virus-derived short interfering RNAs (vsiRNAs), which target virus genomes, mRNAs, or replication intermediates. Viruses, in turn, have evolved viral suppressors of RNAi (VSRs) to counter host antiviral RNAi. Following recent discoveries that insects mount an RNAi response against DNA viruses, in this study, we found that Autographa californica multiple nucleopolyhedrovirus (AcMNPV) infection similarly induces an RNAi response in Spodoptera frugiperda cells by generating a large number of vsiRNAs postinfection. Interestingly, we found that AcMNPV expresses a potent VSR to counter RNAi. The viral p35 gene, which is well known as an inhibitor of apoptosis, was found to be responsible for the suppression of RNAi in diverse insect and mammalian cells. The VSR activity of p35 was further confirmed by a p35-null AcMNPV that did not suppress the response. In addition, our results showed that the VSR activity is not due to inhibition of dsRNA cleavage by Dicer-2 but acts downstream in the RNAi pathway. Furthermore, we found that the VSR activity is not linked to the antiapoptotic activity of the protein. Overall, our results provide evidence for the existence of VSR activity in a double-stranded DNA virus and identify the responsible gene, which is involved in the inhibition of RNAi as well as apoptosis. IMPORTANCE: Our findings demonstrate the occurrence of an insect RNAi response against a baculovirus (AcMNPV) that is highly utilized in microbial control, biological and biomedical research, and protein expression. Moreover, our investigations led to the identification of a viral suppressor of RNAi activity and the gene responsible for the activity. Notably, this gene is also a potent inhibitor of apoptosis. The outcomes signify the dual role of a virus-encoded protein in nullifying two key antiviral responses, apoptosis and RNAi. PMID- 26018164 TI - Nonglycosylated G-Protein Vaccine Protects against Homologous and Heterologous Respiratory Syncytial Virus (RSV) Challenge, while Glycosylated G Enhances RSV Lung Pathology and Cytokine Levels. AB - New efforts are under way to develop a vaccine against respiratory syncytial virus (RSV) that will provide protective immunity without the potential for vaccine-associated disease enhancement such as that observed in infants following vaccination with formalin-inactivated RSV vaccine. In addition to the F fusion protein, the G attachment surface protein is a target for neutralizing antibodies and thus represents an important vaccine candidate. However, glycosylated G protein expressed in mammalian cells has been shown to induce pulmonary eosinophilia upon RSV infection in a mouse model. In the current study, we evaluated in parallel the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain (amino acids 67 to 298) expressed in Escherichia coli (REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model. Vaccination with REG generated neutralizing antibodies against RSV A2 in 7/11 BALB/c mice, while RMG did not elicit neutralizing antibodies. Total serum binding antibodies against the recombinant proteins (both REG and RMG) were measured by surface plasmon resonance (SPR) and were found to be >10-fold higher for REG- than for RMG-vaccinated animals. Reduction of lung viral loads to undetectable levels after homologous (RSV-A2) and heterologous (RSV-B1) viral challenge was observed in 7/8 animals vaccinated with REG but not in RMG-vaccinated animals. Furthermore, enhanced lung pathology and elevated Th2 cytokines/chemokines were observed exclusively in animals vaccinated with RMG (but not in those vaccinated with REG or phosphate-buffered saline [PBS]) after homologous or heterologous RSV challenge. This study suggests that bacterially produced unglycosylated G protein could be developed alone or as a component of a protective vaccine against RSV disease. IMPORTANCE: New efforts are under way to develop vaccines against RSV that will provide protective immunity without the potential for disease enhancement. The G attachment protein represents an important candidate for inclusion in an effective RSV vaccine. In the current study, we evaluated the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain produced in E. coli (REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model (strains A2 and B1). The unglycosylated G generated high protective immunity and no lung pathology, even in animals that lacked anti-RSV neutralizing antibodies prior to RSV challenge. Control of viral loads correlated with antibody binding to the G protein. In contrast, the glycosylated G protein provided poor protection and enhanced lung pathology after RSV challenge. Therefore, bacterially produced unglycosylated G protein holds promise as an economical approach to a protective vaccine against RSV. PMID- 26018165 TI - Discovery of Dengue Virus NS4B Inhibitors. AB - The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50,>20 M). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial "hit" (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3 infected patients. PMID- 26018166 TI - Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2. AB - Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because only two genomes have been determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage-number clinical isolate strain, each from a different geographical area. In this study, we report the nearly complete genome sequences of 34 HSV-2 low-passage-number and laboratory strains, 14 of which were collected in Uganda, 1 in South Africa, 11 in the United States, and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with the maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity, as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. These results are interpreted in light of HSV-2 evolution, epidemiology, and pathogenesis. Finally, the newly generated sequences more closely resemble the low-passage-number SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. IMPORTANCE: Herpes simplex virus 2 (HSV-2) is a causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability is central to preventing and treating genital herpes. However, only two full length HSV-2 genomes have been reported. In this study, we sequenced 34 additional HSV-2 low-passage-number and laboratory viral genomes and initiated analysis of the genetic diversity of HSV-2 strains from around the world. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV 2. This information will also contribute to our understanding of HSV evolution. PMID- 26018168 TI - Innovations in Undergraduate Science Education: Going Viral. AB - Bacteriophage discovery and genomics provides a powerful and effective platform for integrating missions in research and education. Implementation of the Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA PHAGES) program facilitates a broad impact by including a diverse array of schools, faculty, and students. The program generates new insights into the diversity and evolution of the bacteriophage population and presents a model for introducing first-year undergraduate students to discovery-based research experiences. PMID- 26018169 TI - Dark Matter of the Biosphere: the Amazing World of Bacteriophage Diversity. AB - Bacteriophages are the most abundant biological entities in the biosphere, and this dynamic and old population is, not surprisingly, highly diverse genetically. Relative to bacterial genomics, phage genomics has advanced slowly, and a higher resolution picture of the phagosphere is only just emerging. This view reveals substantial diversity even among phages known to infect a common host strain, but the relationships are complex, with mosaic genomic architectures generated by illegitimate recombination over a long period of evolutionary history. PMID- 26018167 TI - Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope. AB - Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector- and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen. IMPORTANCE: Many in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodies with greater neutralization breadth. PMID- 26018171 TI - Functional Analysis of the 60-Nucleotide Duplication in the Respiratory Syncytial Virus Buenos Aires Strain Attachment Glycoprotein. AB - There are two subgroups of respiratory syncytial virus (RSV), A and B, and within each subgroup, isolates are further divided into clades. Several years ago, multiple subgroup B isolates which contained a duplication of 60 nucleotides in the glycoprotein (G) gene were described. These isolates were given a new clade designation of BA based on the site of isolation, Buenos Aires, Argentina. BA RSV strains have since become the predominant circulating clade of RSV B viruses. We hypothesized that the duplicated region in G serves to enhance the function of G in the virus life cycle. We generated recombinant viruses that express a consensus BA G gene or a consensus BA G gene lacking the duplication (GDeltadup). We determined that the duplicated region functions during virus attachment to cells. Additionally, we showed that in vitro, the virus containing the duplication has a fitness advantage compared to the virus without the duplication. Our data demonstrate that the duplicated region in the BA strain G protein augments virus attachment and fitness. IMPORTANCE: Respiratory syncytial virus (RSV) is an important pathogen for infants for which there is no vaccine. Different strains of RSV circulate from year to year, and the predominating strains change over time. Subgroup B RSV strains with a duplication in the attachment glycoprotein (G) emerged and then became the dominant B genotype. We found that a recombinant virus harboring the duplication bound more efficiently to cells and was more fit than a recombinant strain lacking the duplication. Our work advances a mechanism for an important natural RSV mutation. PMID- 26018170 TI - Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells. AB - During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA) mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2 Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. IMPORTANCE: During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly and particle formation. Activated small Rho GTPases and effectors are regulators of actin dynamics and membrane remodeling. We thus studied the effects of the Rac1, Cdc42, and RhoA GTPases and their specific effectors on HIV-1 Gag membrane localization and viral particle release in T cells. Our results show that activated Rac1 and the IRSp53-Wave2-Arp2/3 signaling pathway are involved in Gag plasma membrane localization and viral particle production. This work uncovers a role for cortical actin through the activation of Rac1 and the IRSp53/Wave2 signaling pathway in HIV-1 particle formation in CD4 T lymphocytes. PMID- 26018172 TI - Protective Efficacy of Recombinant Modified Vaccinia Virus Ankara Delivering Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory disease in humans. We tested a recombinant modified vaccinia virus Ankara (MVA) vaccine expressing full-length MERS-CoV spike (S) glycoprotein by immunizing BALB/c mice with either intramuscular or subcutaneous regimens. In all cases, MVA MERS-S induced MERS-CoV-specific CD8(+) T cells and virus-neutralizing antibodies. Vaccinated mice were protected against MERS-CoV challenge infection after transduction with the human dipeptidyl peptidase 4 receptor. This MERS-CoV infection model demonstrates the safety and efficacy of the candidate vaccine. PMID- 26018174 TI - Dynamics of single polyelectrolyte chains in salt-free dilute solutions investigated by analytical ultracentrifugation. AB - The dynamics of polyelectrolytes in salt-free solution is an unsolved problem. We have investigated the sedimentation and diffusion of xanthan and poly(N-methyl 4 vinyl pyridine iodide) (P4VPI) in salt-free dilute solutions by analytical ultracentrifugation (AUC) using sedimentation velocity (SV) as a function of polyelectrolyte concentration (Cp). Our study reveals two concentration regimes distinguished in either polyanion (xanthan) or polycation (P4VPI) dilute aqueous solution. When Cp is below the Debye concentration (Cd) at which the chain separation (d) is close to the debye length (lD), the interchain electrostatic repulsion is negligible, and the reciprocal apparent sedimentation coefficient (1/s), apparent diffusion coefficient (D) or reciprocal apparent molecular weight (1/Mw) is linearly related to Cp. In the range Cp > Cd with d < lD, the interchain electrostatic repulsion is present, and the dynamics of polyelectrolytes becomes complex. The real sedimentation coefficient (s0), the diffusion coefficient (D0) and the molecular weight (Mw,0) of the single polyelectrolyte chain in salt-free dilute solution can be obtained by extrapolating the concentration to zero. The present study reveals that the complex dynamics of polyelectrolytes in salt-free dilute solutions arises due to the interchain electrostatic repulsion. PMID- 26018173 TI - Comparative Analysis of the Glycosylation Profiles of Membrane-Anchored HIV-1 Envelope Glycoprotein Trimers and Soluble gp140. AB - The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, which consists of the gp120 and gp41 subunits, is the focus of multiple strategies for vaccine development. Extensive Env glycosylation provides HIV-1 with protection from the immune system, yet the glycans are also essential components of binding epitopes for numerous broadly neutralizing antibodies. Recent studies have shown that when Env is isolated from virions, its glycosylation profile differs significantly from that of soluble forms of Env (gp120 or gp140) predominantly used in vaccine discovery research. Here we show that exogenous membrane-anchored Envs, which can be produced in large quantities in mammalian cells, also display a virion-like glycan profile, where the glycoprotein is extensively decorated with high-mannose glycans. Additionally, because we characterized the glycosylation with a high-fidelity profiling method, glycopeptide analysis, an unprecedented level of molecular detail regarding membrane Env glycosylation and its heterogeneity is presented. Each glycosylation site was characterized individually, with about 500 glycoforms characterized per Env protein. While many of the sites contain exclusively high-mannose glycans, others retain complex glycans, resulting in a glycan profile that cannot currently be mimicked on soluble gp120 or gp140 preparations. These site-level studies are important for understanding antibody-glycan interactions on native Env trimers. Additionally, we report a newly observed O-linked glycosylation site, T606, and we show that the full O-linked glycosylation profile of membrane associated Env is similar to that of soluble gp140. These findings provide new insight into Env glycosylation and clarify key molecular-level differences between membrane-anchored Env and soluble gp140. IMPORTANCE: A vaccine that protects against human immunodeficiency virus type 1 (HIV-1) infection should elicit antibodies that bind to the surface envelope glycoproteins on the membrane of the virus. The envelope glycoproteins have an extensive coat of carbohydrates (glycans), some of which are recognized by virus-neutralizing antibodies and some of which protect the virus from neutralizing antibodies. We found that the HIV-1 membrane envelope glycoproteins have a unique pattern of carbohydrates, with many high-mannose glycans and also, in some places, complex glycans. This pattern was very different from the carbohydrate profile seen for a more easily produced soluble version of the envelope glycoprotein. Our results provide a detailed characterization of the glycans on the natural membrane envelope glycoproteins of HIV-1, a carbohydrate profile that would be desirable to mimic with a vaccine. PMID- 26018175 TI - Investigating a Relationship between the Mutagenicity of Arylboronic Acids and (11)B NMR Chemical Shifts. AB - The mutagenicity of arylboronic acids has recently become an important area of research because of their potential to be genotoxic impurities in active pharmaceutical ingredients. There is no known mechanism, so currently all structure-activity relationships have been derived using Ames test data. We present preliminary data supporting a hypothesis that the mutagenicity of arylboronic acids is related to the (11)B NMR chemical shift. This could indicate that the mutagenic activity of the arylboronic acids is related to the reactivity of the boron center. PMID- 26018176 TI - The effect of information technology on hospital performance. AB - While healthcare entities have integrated various forms of health information technology (HIT) into their systems due to claims of increased quality and decreased costs, as well as various incentives, there is little available information about which applications of HIT are actually the most beneficial and efficient. In this study, we aim to assist administrators in understanding the characteristics of top performing hospitals. We utilized data from the Health Information and Management Systems Society and the Center for Medicare and Medicaid to assess 1039 hospitals. Inputs considered were full time equivalents, hospital size, and technology inputs. Technology inputs included personal health records (PHR), electronic medical records (EMRs), computerized physician order entry systems (CPOEs), and electronic access to diagnostic results. Output variables were measures of quality, hospital readmission and mortality rate. The analysis was conducted in a two-stage methodology: Data Envelopment Analysis (DEA) and Automatic Interaction Detector Analysis (AID), decision tree regression (DTreg). Overall, we found that electronic access to diagnostic results systems was the most influential technological characteristics; however organizational characteristics were more important than technological inputs. Hospitals that had the highest levels of quality indicated no excess in the use of technology input, averaging one use of a technology component. This study indicates that prudent consideration of organizational characteristics and technology is needed before investing in innovative programs. PMID- 26018177 TI - The lived experience of people with progressive advanced cancer. AB - Cancer is a long-term, life-limiting condition, and its end-of-life stage is complex. This study aimed to understand the lived experience of patients with progressive advanced oncological disease. Seven women in an acute hospital in Portugal were interviewed and the results analysed using a phenomenological approach to understand their lived experience. The analysis indicated that lived experience of these patients has six essential constituents: information about one's own health; perception of the disease; emotional reactions; aid strategies by nurses; imitations imposed by the disease; and changes in life perspective. The experience of advanced progressive cancer is very powerful and complex. The authors believe that this study has contributed to the understanding of this situation, particularly in terms of helping to improve palliative care practices. PMID- 26018178 TI - Prevention and early detection of cervical cancer in the UK. AB - This literature review explores the prevention and early detection of cervical cancer in the UK. Current findings indicate that there is a risk for women under the age of 25 years, who may develop cervical cancer. There appears to be a gap in UK policy that may overlook these women, who are beneath the age for initial screening but exceed the age for vaccination. Despite the inextricable link between sexual activity and cervical cancer, cervical screening and sexual health promotion still appear to be disjointed, and the role of a sexually transmitted infection leading to the development of cervical cancer has not been emphasised enough in public health messages. Further training should be provided and its impact monitored, designed to address this anomaly in health promotion. There are many barriers to health promotion including, those of a societal, cultural and religious nature. Additional research is required to ascertain the types of educational and awareness interventions that would be most effective in promoting and encouraging positive sexual behaviours among young people, and to explore how these might be successfully implemented. PMID- 26018179 TI - Cancer nursing: working in partnership. PMID- 26018180 TI - Non-sting barrier cream in radiotherapy-induced skin reactions. AB - A pilot evaluation was undertaken in 13 patients with head and neck cancer exploring the use of a non-sting barrier film (Sorbaderm((r),) Aspen Medical Europe Ltd). The Society of Radiographers issued guidance in 2013 warning their members that the use of Aqueous cream for moisturising the skin during radiotherapy was potentially harmful. Patients were monitored over a period of 6 weeks and the aim was to explore whether applying non-sting barrier cream provided a protective barrier that did not impair treatment, slowed or prevented skin damage, was easy and simple to apply for patients and carers, improved quality of life for patients during radiotherapy or aided healing. There appeared to be a delay in skin breakdown in this evaluation from week 3 to week 4 and then only mild pain was recorded and with a maximum Radiation Therapy Oncology Group scale of 2.5 in the patient that had combined chemotherapy and radiotherapy. The patients' overall assessment demonstrated that the use of non-sting barrier cream provided symptom relief in both dry, tightening and itching of the skin associated with radiotherapy. All except one patient found the cream easy to apply. The head and neck nursing team rated the product as 'good' to 'very good'. PMID- 26018181 TI - Lung cancer clinical nurse specialist. PMID- 26018182 TI - Infusion pumps: constantly evolving. PMID- 26018183 TI - Body image concerns after colorectal cancer surgery. AB - Body image is understood to be a person's perception of his or her own physical appearance although, as this article highlights, it embraces a greater range of bodily attributes than is often appreciated. It can be significantly affected by a diagnosis of colorectal cancer and subsequent treatment, which may modify the way the body looks, feels and functions. One of the major aesthetic and functional consequences of colorectal cancer surgery is the possibility of stoma formation, which is of particular concern to many. However, the range of other bodily effects following surgery should not be overlooked, not least because of they may result in distress. While concerns about changes in body image generally decrease over time, people recovering from cancer treatment often feel their relationship with their body has been permanently altered. Specialist support is often required when adjusting to any changes in bodily appearance and function. Care outcomes can be improved by having a sound understanding of the body image concerns likely to arise following treatment, as well as the skills to identify and support patients at risk of altered body image. This article provides guidance to nurses caring for individuals who may be experiencing distress over how their body is now perceived by themselves and others following colorectal cancer surgery. PMID- 26018184 TI - Apelin/APJ signaling promotes hypoxia-induced proliferation of endothelial progenitor cells via phosphoinositide-3 kinase/Akt signaling. AB - Endothelial progenitor cells (EPCs) can adhere to the endothelium at sites of hypoxia/ischemia and participate in the formation of novel vessels through differentiating into endothelial cells (ECs). Apelin is an endogenous ligand for the G protein-coupled receptor APJ, and apelin/APJ signaling has a role in cardiovascular function. The present study aimed to investigate the role of apelin/APJ signaling in the regulation of EPC proliferation under hypoxia. The results showed that hypoxia was able to induce EPC proliferation, accompanied with an upregulation of hypoxia-inducible factor (HIF)-1alpha as well as apelin/APJ signaling. Further investigation indicated that siRNA-mediated knockdown of apelin or APJ expression attenuated the hypoxia-induced proliferation of EPCs, suggesting that apelin/APJ signaling has an important role in hypoxia-induced EPC proliferation. Moreover, the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway was found to be involved in the apelin/APJ-mediated EPC proliferation under hypoxia. Based on these findings, the present study suggested that hypoxia-induced upregulation of HIF-1alpha promotes the expression of apelin and APJ, which further activate the downstream PI3K/Akt signaling pathway, a key promoter of EPC proliferation. In conclusion, the present study highlighted the role of apelin/APJ in the regulation of EPC proliferation, and apelin/APJ may therefore serve as a potential target for the prevention of hypoxic ischemic injury. PMID- 26018186 TI - Modeled Changes in Potential Grassland Productivity and in Grass-Fed Ruminant Livestock Density in Europe over 1961-2010. AB - About 25% of European livestock intake is based on permanent and sown grasslands. To fulfill rising demand for animal products, an intensification of livestock production may lead to an increased consumption of crop and compound feeds. In order to preserve an economically and environmentally sustainable agriculture, a more forage based livestock alimentation may be an advantage. However, besides management, grassland productivity is highly vulnerable to climate (i.e., temperature, precipitation, CO2 concentration), and spatial information about European grassland productivity in response to climate change is scarce. The process-based vegetation model ORCHIDEE-GM, containing an explicit representation of grassland management (i.e., herbage mowing and grazing), is used here to estimate changes in potential productivity and potential grass-fed ruminant livestock density across European grasslands over the period 1961-2010. Here "potential grass-fed ruminant livestock density" denotes the maximum density of livestock that can be supported by grassland productivity in each 25 km * 25 km grid cell. In reality, livestock density could be higher than potential (e.g., if additional feed is supplied to animals) or lower (e.g., in response to economic factors, pedo-climatic and biotic conditions ignored by the model, or policy decisions that can for instance reduce livestock numbers). When compared to agricultural statistics (Eurostat and FAOstat), ORCHIDEE-GM gave a good reproduction of the regional gradients of annual grassland productivity and ruminant livestock density. The model however tends to systematically overestimate the absolute values of productivity in most regions, suggesting that most grid cells remain below their potential grassland productivity due to possible nutrient and biotic limitations on plant growth. When ORCHIDEE-GM was run for the period 1961-2010 with variable climate and rising CO2, an increase of potential annual production (over 3%) per decade was found: 97% of this increase was attributed to the rise in CO2, -3% to climate trends and 15% to trends in nitrogen fertilization and deposition. When compared with statistical data, ORCHIDEE-GM captures well the observed phase of climate-driven interannual variability in grassland production well, whereas the magnitude of the interannual variability in modeled productivity is larger than the statistical data. Regional grass-fed livestock numbers can be reproduced by ORCHIDEE-GM based on its simple assumptions and parameterization about productivity being the only limiting factor to define the sustainable number of animals per unit area. Causes for regional model-data misfits are discussed, including uncertainties in farming practices (e.g., nitrogen fertilizer application, and mowing and grazing intensity) and in ruminant diet composition, as well as uncertainties in the statistical data and in model parameter values. PMID- 26018188 TI - Estrogen, Stress, and Depression: A Neurocognitive Model. PMID- 26018187 TI - Active dendrites mediate stratified gamma-range coincidence detection in hippocampal model neurons. AB - KEY POINTS: Quantitative metrics for the temporal window of integration/coincidence detection, based on the spike-triggered average, were employed to assess the emergence and dependence of gamma-range coincidence detection in hippocampal pyramidal neurons on various ion channel combinations. The presence of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels decreased the coincidence detection window (CDW) of the neuronal compartment to the gamma frequency range. Interaction of HCN channels with T-type calcium channels and persistent sodium channels further reduced the CDW, whereas interaction with A-type potassium channels broadened the CDW. When multiple channel gradients were co-expressed, the high density of resonating conductances in the distal dendrites led to a slow gamma CDW in the proximal dendrites and a fast-gamma CDW in the distal dendrites. The presence of resonating and spike generating conductances serve as a mechanism underlying the emergence of stratified gamma-range coincidence detection in the dendrites of CA1 pyramidal neurons, enabling them to perform behaviour- and state-dependent gamma frequency multiplexing. ABSTRACT: Hippocampal pyramidal neurons exhibit gamma-phase preference in their spikes, selectively route inputs through gamma frequency multiplexing and are considered part of gamma-bound cell assemblies. How do these neurons exhibit gamma-frequency coincidence detection capabilities, a feature that is essential for the expression of these physiological observations, despite their slow membrane time constant? In this conductance-based modelling study, we developed quantitative metrics for the temporal window of integration/coincidence detection based on the spike-triggered average (STA) of the neuronal compartment. We employed these metrics in conjunction with quantitative measures for spike initiation dynamics to assess the emergence and dependence of coincidence detection and STA spectral selectivity on various ion channel combinations. We found that the presence of resonating conductances (hyperpolarization-activated cyclic nucleotide-gated or T-type calcium), either independently or synergistically when expressed together, led to the emergence of spectral selectivity in the spike initiation dynamics and a significant reduction in the coincidence detection window (CDW). The presence of A-type potassium channels, along with resonating conductances, reduced the STA characteristic frequency and broadened the CDW, but persistent sodium channels sharpened the CDW by strengthening the spectral selectivity in the STA. Finally, in a morphologically precise model endowed with experimentally constrained channel gradients, we found that somatodendritic compartments expressed functional maps of strong theta frequency selectivity in spike initiation dynamics and gamma-range CDW. Our results reveal the heavy expression of resonating and spike-generating conductances as the mechanism underlying the robust emergence of stratified gamma range coincidence detection in the dendrites of hippocampal and cortical pyramidal neurons. PMID- 26018189 TI - BRCA2-associated pancreatic cancer and current screening guidelines. PMID- 26018190 TI - Impaired M. tuberculosis Antigen-Specific IFN-gamma Response without IL-17 Enhancement in Patients with Severe Cavitary Pulmonary Tuberculosis. AB - BACKGROUND: Th1 cells play an essential role in immune protection against tuberculosis. Th17 cells might be involved with immune pathology in active human tuberculosis (TB). The balance between Th1 and Th17 cells in patients with cavitary tuberculosis needs to be clarified which might help understanding the immunological basis of pathologic pathogenesis in TB. METHOD: Initially treated pulmonary TB (PTB) patients with or without cavities were recruited before chemotherapy. We isolated peripheral blood mononuclear cells, stimulated with phytohemagglutinin (PHA), PPD, or ESAT-6 antigens, and assayed supernatant IFN gamma and IL-17 by ELISA after 24 or 72 hours incubation, respectively. Cells were also stained with antibodies to CD3, CD4, CD8, IFN-gamma or IL-17 and the proportion of stained cells was measured by flow cytometry. RESULTS: We found wide variation of IFN-gamma response in active PTB patients, but less subject-to subject variation of IL-17 was observed as we previously reported. There were no significant differences in IFN-gamma and IL-17 between cavitary and non-cavitary PTB; however, we found decreased IFN-gamma secretion in severe cavitary PTB compared to mild lesion non-cavitary PTB (p < 0.05). We also found a decrease in the proportion of CD3+CD4+ T cells in the blood of severe cavitary PTB patients (p < 0.05). CONCLUSIONS: IL-17 seemed to have no association with the formation of cavities in active PTB from the study of PBMC. Impaired IFN-gamma without IL 17 enhancement occurs in peripheral blood during severe cavitary PTB. Our results demonstrate that M. tuberculosis antigen-specific Th1 response is decreased when PTB lesions develop to severe cavities. PMID- 26018191 TI - Microbiome structure of the fungid coral Ctenactis echinata aligns with environmental differences. AB - The significance of bacteria for eukaryotic functioning is increasingly recognized. Coral reef ecosystems critically rely on the relationship between coral hosts and their intracellular photosynthetic dinoflagellates, but the role of the associated bacteria remains largely theoretical. Here, we set out to relate coral-associated bacterial communities of the fungid host species Ctenactis echinata to environmental settings (geographic location, substrate cover, summer/winter, nutrient and suspended matter concentrations) and coral host abundance. We show that bacterial diversity of C. echinata aligns with ecological differences between sites and that coral colonies sampled at the species' preferred habitats are primarily structured by one bacterial taxon (genus Endozoicomonas) representing more than 60% of all bacteria. In contrast, host microbiomes from lower populated coral habitats are less structured and more diverse. Our study demonstrates that the content and structure of the coral microbiome aligns with environmental differences and denotes habitat adequacy. Availability of a range of coral host habitats might be important for the conservation of distinct microbiome structures and diversity. PMID- 26018193 TI - Mechanisms and clinical applications of chromosomal instability in lymphoid malignancy. AB - Lymphocytes are unique among cells in that they undergo programmed DNA breaks and translocations, but that special property predisposes them to chromosomal instability (CIN), a cardinal feature of neoplastic lymphoid cells that manifests as whole chromosome- or translocation-based aneuploidy. In several lymphoid malignancies translocations may be the defining or diagnostic markers of the diseases. CIN is a cornerstone of the mutational architecture supporting lymphoid neoplasia, though it is perhaps one of the least understood components of malignant transformation in terms of its molecular mechanisms. CIN is associated with prognosis and response to treatment, making it a key area for impacting treatment outcomes and predicting prognoses. Here we will review the types and mechanisms of CIN found in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma and the lymphoid leukaemias, with emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair; telomere function; and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the means by which chromosome-level genetic aberrations may give rise to multiple pathogenic mutations required for carcinogenesis and conclude with a discussion of the clinical applications of CIN and aneuploidy to diagnosis, prognosis and therapy. PMID- 26018192 TI - Genome-Wide Identification of the Target Genes of AP2-O, a Plasmodium AP2-Family Transcription Factor. AB - Stage-specific transcription is a fundamental biological process in the life cycle of the Plasmodium parasite. Proteins containing the AP2 DNA-binding domain are responsible for stage-specific transcriptional regulation and belong to the only known family of transcription factors in Plasmodium parasites. Comprehensive identification of their target genes will advance our understanding of the molecular basis of stage-specific transcriptional regulation and stage-specific parasite development. AP2-O is an AP2 family transcription factor that is expressed in the mosquito midgut-invading stage, called the ookinete, and is essential for normal morphogenesis of this stage. In this study, we identified the genome-wide target genes of AP2-O by chromatin immunoprecipitation-sequencing and elucidate how this AP2 family transcription factor contributes to the formation of this motile stage. The analysis revealed that AP2-O binds specifically to the upstream genomic regions of more than 500 genes, suggesting that approximately 10% of the parasite genome is directly regulated by AP2-O. These genes are involved in distinct biological processes such as morphogenesis, locomotion, midgut penetration, protection against mosquito immunity and preparation for subsequent oocyst development. This direct and global regulation by AP2-O provides a model for gene regulation in Plasmodium parasites and may explain how these parasites manage to control their complex life cycle using a small number of sequence-specific AP2 transcription factors. PMID- 26018194 TI - Half a world apart? Overlap in nonbreeding distributions of Atlantic and Indian Ocean thin-billed prions. AB - Distant populations of animals may share their non-breeding grounds or migrate to distinct areas, and this may have important consequences for population differentiation and dynamics. Small burrow-nesting seabirds provide a suitable case study, as they are often restricted to safe breeding sites on islands, resulting in a patchy breeding distribution. For example, Thin-billed prions Pachyptila belcheri have two major breeding colonies more than 8,000 km apart, on the Falkland Islands in the south-western Atlantic and in the Kerguelen Archipelago in the Indian Ocean. We used geolocators and stable isotopes to compare at-sea movements and trophic levels of these two populations during their non-breeding season, and applied ecological niche models to compare environmental conditions in the habitat. Over three winters, birds breeding in the Atlantic showed a high consistency in their migration routes. Most individuals migrated more than 3000 km eastwards, while very few remained over the Patagonian Shelf. In contrast, all Indian Ocean birds migrated westwards, resulting in an overlapping nonbreeding area in the eastern Atlantic sector of the Southern Ocean. Geolocators and isotopic signature of feathers indicated that prions from the Falklands moulted at slightly higher latitudes than those from Kerguelen Islands. All birds fed on low trophic level prey, most probably crustaceans. The phenology differed notably between the two populations. Falkland birds returned to the Patagonian Shelf after 2-3 months, while Kerguelen birds remained in the nonbreeding area for seven months, before returning to nesting grounds highly synchronously and at high speed. Habitat models identified sea surface temperature and chlorophyll a concentration as important environmental parameters. In summary, we show that even though the two very distant populations migrate to roughly the same area to moult, they have distinct wintering strategies: They had significantly different realized niches and timing which may contribute to spatial niche partitioning. PMID- 26018195 TI - The strengths of families in supporting mentally-ill family members. AB - BACKGROUND: Although families caring for a mentally-ill family member may experience challenges, some of these families may display strengths that help them to overcome difficulties and grow even stronger in caring for their family member. In cases where these families are unable to cope, the mentally-ill family member tends to relapse. This indicated the need to explore the strengths of families that cope with caring for mentally-ill family members. OBJECTIVE: The purpose of this study was to explore and describe the strengths of families in supporting mentally-ill family members in Potchefstroom in the North-West Province. METHOD: A qualitative, explorative, descriptive and contextual design was employed, with purposive sampling and unstructured individual interviews with nine participants. Tesch's eight steps of thematic content analysis were used. RESULTS: Twelve themes emerged from the data. This involved strengths such as obtaining treatment, utilising external resources, faith, social support, supervision, calming techniques, keeping the mentally-ill family member busy, protecting the mentally-ill family member from negative outside influences, creative communication, praise and acceptance. CONCLUSION: Families utilise external strengths as well as internal strengths in supporting their mentally-ill family member. Recommendations for nursing practice, nursing education and for further research could be formulated. Psychiatric nurses should acknowledge families' strengths and, together with families, build on these strengths, as well as empower families further through psycho-education and support. PMID- 26018196 TI - In Situ Conductance Analysis of Zinc Oxide Nucleation and Coalescence during Atomic Layer Deposition on Metal Oxides and Polymers. AB - Real time in situ conductance is collected continuously during atomic layer deposition (ALD) of zinc oxide films, and trends are used to study ALD nucleation on polypropylene, nylon-6, SiO2, TiO2, and Al2O3 substrates. The detailed conductance change during the ALD cycle is ascribed to changes in surface band bending upon precursor/reactant exposure. Conductive pathways form earlier on the inorganic surfaces than on the polymers, with Al2O3 substrates showing more rapid nucleation than SiO2 or TiO2, consistent with the expected density of nucleation sites (e.g., hydroxyl groups) on these different materials. The measured conductance is ohmic, and both two- and four-electrode configurations show the same data trends. Detailed analysis of conductivity at deposition temperatures between 100 and 175 degrees C shows faster conductivity decay at higher temperature during the water purge step, ascribed to thermally activated water desorption kinetics. Analysis of real-time conductivity during ALD of other material systems could provide further insight into key aspects of film nucleation and nuclei coalescence. PMID- 26018197 TI - Successful remote delivery of a treatment for phonological alexia via telerehab. AB - A growing body of literature supports the effectiveness of the remote delivery of rehabilitation services, i.e., telerehab. Aphasia treatment is particularly well suited for telerehab because of the verbal and visual nature of speech-language therapy, but scientific research investigating aphasia telerehab is in its infancy. No studies to date have evaluated whether treatment of acquired reading disorders by a live clinician can be feasibly, effectively, or efficiently conducted via telerehab. Here we address this gap in the literature by reporting our success remotely remediating the reading deficits of two participants with phonological alexia. We adapted for the telerehab setting a previously validated treatment for phonological alexia (Friedman, Sample, & Lott, 2002 ), which uses a paired-associate design to train reading of problematic words. Both telerehab participants significantly improved their reading of trained words in similar time frames as previous participants (Friedman et al., 2002 ; Kurland et al., 2008 ; Lott, Sample, Oliver, Lacey, & Friedman, 2008 ); furthermore, both participants reported high satisfaction with the telerehab setting. Although telerehab with alexic patients poses unique challenges, we conclude that treatment for alexia via telerehab is nevertheless feasible, may be equally effective as in-person treatment, and saves substantial resources for participants as well as clinicians. PMID- 26018198 TI - Adrenal Insufficiency in Mitochondrial Disease: A Rare Case of GFER-Related Mitochondrial Encephalomyopathy and Review of the Literature. AB - GFER-related mitochondrial encephalomyopathy has been previously described only in 3 siblings of a consanguineous Moroccan family. Their phenotype included congenital cataracts, hypotonia, developmental delay, and sensorineural hearing loss. Multiple mitochondrial respiratory chain complex deficiencies were identified on muscle biopsy. We describe a now-19-year-old woman with adrenal insufficiency, lactic acidosis, congenital cataracts, and respiratory insufficiency secondary to mitochondrial disorder, who was reported by North et al (1996) as a toddler. Compound heterozygous GFER mutations c.373C>T (Q125X) and c.581G>A (R194 H) were recently discovered in this patient. The purpose of this report is (1) to expand the phenotype this ultra-rare disorder and (2) to provide a review of the literature describing the unique finding of adrenal insufficiency in patients with molecularly confirmed disorders of mitochondrial metabolism. PMID- 26018199 TI - Visual Evoked Potentials as a Readout of Cortical Function in Infants With Tuberous Sclerosis Complex. AB - Tuberous sclerosis complex is an autosomal dominant genetic disorder that confers a high risk for neurodevelopmental disorders, such as autism spectrum disorder and intellectual disability. Studies have demonstrated specific delays in visual reception skills that may predict the development of autism spectrum disorder and intellectual disability. Based on evidence for alterations in the retinogeniculate pathway in animal models of tuberous sclerosis complex, we asked whether children with tuberous sclerosis complex demonstrate alterations in early visual processing that may undermine the development of higher-level visual behaviors. Pattern-reversal visual evoked potentials were recorded in infants with tuberous sclerosis complex (n = 16) and typically developing infants (n = 18) at 12 months of age. Infants with tuberous sclerosis complex demonstrated remarkably intact visual evoked potentials even within the context of intellectual disability and epilepsy. Infants with tuberous sclerosis complex show intact visual cortical processing, suggesting that delays in visually mediated behaviors in tuberous sclerosis complex may not be rooted in early visual processing deficits. PMID- 26018200 TI - Do Mesenchymal Stromal Cells Influence Microscopic Residual or Metastatic Osteosarcoma in a Murine Model? AB - BACKGROUND: Mesenchymal stromal cells (MSCs) have been shown in rodent models to promote primary and pulmonary metastatic sarcoma growth when injected in the presence of gross tumor. In theory, this would limit their use in a clinical setting after limb salvage treatment for osteosarcoma. Although concerning, these models do not translate to the clinical setting wherein MSCs could be used after primary tumor resection to aid in bone healing and incorporation of tumor endoprostheses. If we can determine whether the use of MSCs in this setting is safe, it might improve our ability to augment bone healing in patients undergoing limb salvage. QUESTIONS/PURPOSES: The purpose of this study was to determine (1) whether MSCs promote pulmonary metastatic disease progression in a murine osteosarcoma model; and/or (2) whether they affect local disease recurrence in the presence of microscopic residual osteosarcoma. METHODS: An orthotopic model of luciferase-expressing osteosarcoma was developed. At 10 days, resection of the primary tumor was performed. One hundred fourteen female C3H mice were inoculated with DLM8-luc osteosarcoma in the proximal tibia. Ninety-four mice developed orthotopic osteosarcoma with luciferase expression. Mice with bioluminescent evidence of a primary tumor received either a microscopically "clean" amputation at a time when residual microscopic metastatic disease was present in the lungs (pulmonary metastasis group; n = 65) or a "dirty" amputation (local recurrence group; n = 29). Mice were randomized to receive intravenous MSCs, MSCs at the surgical site, or no MSCs. Mice were monitored for development and progression of pulmonary metastasis and local recurrence by bioluminescence imaging and daily measurements at the surgical site. The number of pulmonary nodules, time to first evidence of metastasis, and size of recurrent tumor were compared using Kruskal Wallis, analysis of variance, Welch's, t-tests, or Mann-Whitney tests as appropriate for the specific data sets with p < 0.05 considered significant. RESULTS: Mice receiving intravenous MSCs had a faster time to first detection of pulmonary metastasis (2.93 +/- 1.90 days) compared with mice with local injection of MSCs (6.94 +/- 6.78 days) or no MSCs (5.93 +/- 4.55 days) (p = 0.022). MSC treatment did not influence whether mice developed local recurrence (p = 0.749) or size of recurrent tumors (p = 0.221). CONCLUSIONS: MSCs delivered to the surgical site did not promote local recurrence or size of recurrent tumors, but intravenous injection of MSCs did hasten onset of detection of pulmonary metastatic disease. Although local administration of MSCs into a surgical site does not appear to promote either pulmonary metastatic disease or local recurrence, large variation within groups and small numbers diminished statistical power such that a Type II error cannot be ruled out. CLINICAL RELEVANCE: If MSCs are to be used to augment bone healing in the postlimb salvage setting in patients with osteosarcoma, it will be important to understand their influence, if any, on pulmonary micrometastsis or residual microscopic local disease. Although murine models do not completely recapitulate the clinical scenario, these results suggest that intravenous delivery of MSCs may promote micrometastatic pulmonary disease. Local administration into a surgical wound, even in the presence of residual microscopic disease, may be safe, at least in this murine model, but further investigation is warranted before considering the use of MSCs for clinical use in patients with osteosarcoma. PMID- 26018201 TI - Superdense teleportation using hyperentangled photons. AB - Transmitting quantum information between two remote parties is a requirement for many quantum applications; however, direct transmission of states is often impossible because of noise and loss in the communication channel. Entanglement enhanced state communication can be used to avoid this issue, but current techniques require extensive experimental resources to transmit large quantum states deterministically. To reduce these resource requirements, we use photon pairs hyperentangled in polarization and orbital angular momentum to implement superdense teleportation, which can communicate a specific class of single-photon ququarts. We achieve an average fidelity of 87.0(1)%, almost twice the classical limit of 44% with reduced experimental resources than traditional techniques. We conclude by discussing the information content of this constrained set of states and demonstrate that this set has an exponentially larger state space volume than the lower-dimensional general states with the same number of state parameters. PMID- 26018202 TI - Expression and purification of the mGITR-Fc fusion protein and its effect on CD4+ T cells and dendritic cells in vitro. AB - Glucocorticoid-induced tumor necrosis factor receptor related protein (GITR) is a member of the tumor necrosis factor receptor superfamily. The present study attempted to obtain the mouse GITR-Fc fusion protein and investigate its function on the proliferation of CD4+ T cells and on the expression of mGITR ligand (mGITRL) on dendritic cells. The sequences of the mouse (m)GITR gene and mouse immunoglobulin G Fc (mIgGFc) were amplified from mouse spleen cells and introduced into a pET-32a(+) vector. Following the induction, purification and validation of the mGITR-Fc fusion protein, the mGITR-Fc fusion protein was used to analyze its function on the proliferation of CD4+ T cells and on the expression of mGITR on dendritic cells. A recombinant plasmid containing the mGITR gene fragment and mIgGFc was constructed, and the recombinant mGITR-Fc fusion protein was successfully expressed. The exogenous mGITR-Fc fusion protein inhibited the proliferation of CD4+ T cells, dependent on the presence of mGITRL. The exogenous mGITR-Fc fusion protein also inhibited the expression of mGITRL on the dendritic cells. In conclusion, the mGITR-Fc fusion protein was confirmed to exhibit biological functions of a co-stimulatory signal and reverse signal. These experiments provide the basis for further investigation of the function of the mGITR-Fc fusion protein on certain autoimmune diseases. PMID- 26018203 TI - Recurrent episodes of micturition with expulsion of symphyseal plate screws following pelvic ring fixation: case report. AB - BACKGROUND: Based on a computer-assisted literature search, this case is the first description of repeated loosening of metallic internal fixation implants after pelvic ring stabilization, associated with intravesical metal migration and micturition with expulsion of two bone screws. CASE PRESENTATION: A 62-year old woman was seen after the urinary expulsion of a 6.5 mm diameter cancellous screw. About seven years earlier, she had been hit by a motorcyclist while crossing the street. On admission at the time of the initial injury, thoraco-abdominal computerized tomography with intravenous contrast material revealed a bladder injury and pelvic ring fractures. An anterior-posterior type injury to the pelvic ring was diagnosed with symphyseal pubis disruption, and widening of the left sacroiliac joint with an associated sacral fracture. Explorative laparotomy revealed two bladder lacerations of both the posterior and the anterior bladder wall, which were repaired primarily. Orthopedic surgeons reduced the pelvis and stabilized it with two plates and screws. Seven years after the original injury, the patient presented with recurrent abdominal pain after expelling a screw into the toilet while urinating. Planar radiographs showed only five of the original screws remaining in the two symphyseal plates, and all screws appeared to have loosened when compared to the original fixation radiograph. CONCLUSION: This clinical report emphasizes the importance of symphyseal plate positioning and the sequelae of imprecise positioning, especially postero-superiorly adjacent to the Retzius space. The presence of protruding metal prominences, even smooth ones like a plate corner or screw head, might endanger the bladder. When using superior plates, imprecise contouring may lead to plate edge protrusion which could damage the bladder even long after application. PMID- 26018204 TI - Ovulation of the preovulatory follicle originating from the first-wave dominant follicle leads to formation of an active corpus luteum. AB - The objective of our study was to compare the characteristics of the corpus luteum (CL) formed after ovulation of the dominant follicle (DF) of the first follicular wave (W1) and those of the CL formed after ovulation of the DF of the second (induced) follicular wave (W2). Non-lactating Holstein cows were used for this study. In Experiment 1, cows were treated with PGF2alpha and GnRH on days 6 and 8 (day 0 = day of follicular wave emergence) for W1 (n = 6) and W2 (n = 6), respectively. Dominant follicles were aspirated on day 9 to quantify the amounts of mRNA (VEGF120, VEGF164, FGF-2, StAR, P450-scc and 3beta-HSD) in granulosa cells (GC). In Experiment 2, the size and blood flow area of the CL formed after ovulation of the DF in W1 (W1CL; n = 6) and W2 (W2CL; n = 6) (the day of DF ovulation in W1 and W2 was day 10) were evaluated on days 12, 15, 18 and 21. The plasma P4 concentration was measured on days 10 to 21. The amounts of VEGF164, P450-scc and 3beta-HSD mRNA were higher (P < 0.05) in the DF in W1, and those of VEGF120,FGF-2 and StAR mRNA tended to be higher (P < 0.1) in the DF in W1. The size of the CL was greater in the W1CL on days 15, 18 and 21. The blood flow area of the CL was greater in the W1CL on days 12 and 15. The plasma P4 concentrations were higher in the W1CL. These results indicate that the CL formed after ovulation of the DF in W1 was greater in terms of size, blood flow and plasma P4 concentration. PMID- 26018206 TI - Gravure-Printed Sol-Gels on Flexible Glass: A Scalable Route to Additively Patterned Transparent Conductors. AB - Gravure printing is an attractive technique for patterning high-resolution features (<5 MUm) at high speeds (>1 m/s), but its electronic applications have largely been limited to depositing nanoparticle inks and polymer solutions on plastic. Here, we extend the scope of gravure to a new class of materials and on to new substrates by developing viscous sol-gel precursors for printing fine lines and films of leading transparent conducting oxides (TCOs) on flexible glass. We explore two strategies for controlling sol-gel rheology: tuning the precursor concentration and tuning the content of viscous stabilizing agents. The sol-gel chemistries studied yield printable inks with viscosities of 20-160 cP. The morphology of printed lines of antimony-doped tin oxide (ATO) and tin-doped indium oxide (ITO) is studied as a function of ink formulation for lines as narrow as 35 MUm, showing that concentrated inks form thicker lines with smoother edge morphologies. The electrical and optical properties of printed TCOs are characterized as a function of ink formulation and printed film thickness. XRD studies were also performed to understand the dependence of electrical performance on ink composition. Printed ITO lines and films achieve sheet resistance (Rs) as low as 200 and 100 Omega/?, respectively (rho~2*10(-3) Omega cm) for single layers. Similarly, ATO lines and films have Rs as low as 700 and 400 Omega/? with rho~7*10(-3) Omega-cm. High visible range transparency is observed for ITO (86-88%) and ATO (86-89%). Finally, the influence of moderate bending stress on ATO films is investigated, showing the potential for this work to scale to roll-to-roll (R2R) systems. PMID- 26018205 TI - Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure. AB - Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h+/-2h and death occurred 13h+/-3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002). Conclusions: MicroRNAs were released passively into the circulation in response to acetaminophen-induced cellular damage. A significant increase in global microRNA was detectable prior to significant increases in miR122, miR192 and miR124-1, which were associated with clinical evidence of liver, kidney and brain injury respectively. PMID- 26018207 TI - Primary prevention of skin dysplasia in renal transplant recipients with photodynamic therapy: a randomized controlled trial. AB - Organ transplant recipients (OTRs) are at high risk of developing cutaneous squamous cell carcinoma (SCC); prevention includes early treatment of premalignant actinic keratosis (AK). Photodynamic therapy (PDT) is a noninvasive field therapy that reduces new AKs in patients with existing AK and delays SCC development in mice. We investigated the effect of repeated PDT over 5 years for primary prophylaxis of skin dysplasia. These data represent an interim analysis of an on-going randomized controlled trial. During 2008-2011, 25 renal transplant recipients with clinically normal skin were randomized to split-side PDT of the face, forearm and hand, the contralateral side serving as untreated control. Patients received PDT on inclusion and at 6-monthly intervals for 5 years. Blinded evaluation was performed at each visit. We found that prophylactic PDT significantly delayed onset of AK compared with untreated skin, p = 0.020. At 3 year follow-up, we observed AK in 63% of patients in untreated skin areas compared with 28% of patients in PDT-treated skin, with a total number of cumulated AKs in untreated skin (n = 43) compared with PDT-treated skin (n = 8), p = 0.005. These preliminary data indicate a novel approach to early prevention of skin dysplasia that may reduce morbidity from multiple AKs and SCCs in OTR. PMID- 26018209 TI - Feminist Framework Plus: Knitting Feminist Theories of Rape Etiology Into a Comprehensive Model. AB - The radical-liberal feminist perspective on rape posits that the assault is motivated by power and control rather than sexual gratification and is a violent rather than a sexual act. However, rape is a complex act. Relying on only one early strand of feminist thought to explain the etiology of rape limits feminists' understanding of rape and the practice based upon the theory. The history of the adoption of the "power, not sex" theory is presented and the model critiqued. A more integrated model is developed and presented, the Feminist Framework Plus, which knits together five feminist theories into a comprehensive model that better explains the depth and breadth of the etiology of rape. Empirical evidence that supports each theory is detailed as well as the implications of the model on service provision, education, and advocacy. PMID- 26018208 TI - Depression, Anxiety, and Pharmacotherapy Around the Time of Pregnancy in Hawaii. AB - BACKGROUND: Depression and anxiety are common conditions among pregnant and postpartum women, but population-based information is lacking on treatments and help-seeking behaviors. PURPOSE: This study described the prevalence of depression, anxiety, pharmaceutical treatment, and help-seeking behaviors among a multiethnic population of women with recent live births in Hawaii. METHOD: Hawaii Pregnancy Risk Assessment Monitoring System data from 4735 respondents were weighted to be representative of all pregnancies resulting in live births in Hawaii in 2009-2011 and were used to estimate the prevalence of several indicators related to anxiety and depression before, during, and after pregnancy among women with recent live births. RESULTS: Of Hawaii women with live births in 2009-2011, 7.3 % reported visiting a healthcare worker to be checked or treated for depression or anxiety in the year before their most recent pregnancy, 4.9 % reported having depression in the 3 months before pregnancy, 5.9 % reported having anxiety in the same period, 9.1 % screened positive for postpartum depression, and 6.9 % reported asking a doctor, nurse, or other healthcare worker for help for anxiety postpartum. The prevalence of antianxiety and antidepressant prescription drug use was 2.3 % in the month before pregnancy and 1.4 % during pregnancy. Hawaii had lower prevalence of pre-pregnancy depression, anxiety, and depression/anxiety health visits than other US states. Pre-pregnancy depression and anxiety and postpartum anxiety help-seeking behaviors differed significantly by race/ethnicity. CONCLUSION: Depression and anxiety are common among pregnant and postpartum women in Hawaii. More research could better inform heath care professionals and patients of the treatment options available and their potential risks and benefits. PMID- 26018210 TI - Intimate Partner Violence in Self-Identified Lesbians: A Systematic Review of Its Prevalence and Correlates. AB - This article presents the first systematic review on intimate partner violence (IPV) in self-identified lesbians in same-sex couples. Studies published from January 1990 to December 2013 were analyzed. Of the 687 studies reviewed, 59 were preselected, of which 14 studies were selected that met the inclusion and methodological quality criteria. A summary is presented of the characteristics of the studies, the participants, the prevalence of IPV victimization and perpetration, and its correlates. All the studies were carried out in the United States and used a nonprobabilistic sampling method. The majority of participants were White with a high educational level. The results indicate that all the forms of violence occur, but the most prevalent is emotional/psychological violence. The correlates positively associated with IPV are certain personality characteristics, fusion, previous IPV experience, a family history of violence, and alcohol consumption. This review finds significant limitations in the analyzed literature. Methodological recommendations are made for future studies. PMID- 26018211 TI - Posthemorrhagic hydrocephalus in extremely low birth weight infants: Ommaya reservoir vs. ventriculoperitoneal shunt. AB - PURPOSE: The aim of this study was to analyze morbidity and initial surgery in infants with posthemorrhagic hydrocephalus (PHH) by comparing infants who were treated with a subcutaneous cerebrospinal fluid reservoir (Ommaya reservoir = CSF_R) with infants who primarily received a ventriculoperitoneal shunt (VPS). METHOD: Inclusion criteria were infants born between January 2006 and June 2014 who had a diagnosis of intraventricular hemorrhage (IVH) and underwent surgical intervention for hydrocephalus. RESULTS: Twenty-five infants, with a median gestational age (GA) of 26.5 (28 +/- 4) weeks and a median birth weight (BW) of 980 g (1205 +/- 837), were included. The median umbilical artery pH (UApH) was 7.30 (7.20 +/- 0.25). The median Apgar score at 10 min was 8 (7.4 +/- 2). Twenty five peri- and postnatal adverse events were encountered preoperatively. The IVH grades were grade II (n = 1), grade III (n = 17), grade IV (n = 6), and unknown grade (n = 1). Primary treatment consisted of CSF_R (n = 18) or VPS (n = 7) placement. There was a statistically significant difference between the postnatal ages of infants with CSF_R (32.5 days; 42 +/- 28) and infants with VPS (163 days; 161 +/- 18). Furthermore, we found a difference regarding GA but not BW between both groups. Arrest of PHH with shunt independence occurred in two infants from the CSF_R group (11%). CONCLUSIONS: In the present study, early insertion of CSF_R allowed stabilization of the infants and thus postponement of permanent VPS insertion. However, in a subgroup of patients, PHH develops over a more prolonged course, and VPS insertion can be performed initially without the need for CSF_R. PMID- 26018212 TI - Overall Quality of Life in Adult Biliary Atresia Survivors with or without Liver Transplantation: Results from a National Cohort. AB - Background Biliary atresia (BA) is a rare cholestatic disease of infancy. Kasai portoenterostomy and liver transplantation (LT) are the two sequential treatment options. An increasing number of patients survive into adulthood. Little is known about their health-related quality of life (HRQOL). This study aims to compare HRQOL of transplanted and nontransplanted patients in a cohort of young adult BA survivors. Patients and Methods RAND-36 and Liver Disease Index Score (LDSI) questionnaires were sent to eligible adult patients with BA. Clinical characteristics were obtained from the NeSBAR (Netherlands Study group on Biliary Atresia Registry) and the national pediatric LT database. RAND-36 domain and summary scores were compared with those of an age-matched Dutch reference group. The correlations between several clinical variables and HRQOL were analyzed. Results Mean RAND-36 domain and summary scores of transplanted (n = 15) and nontransplanted (n = 25) patients with BA (response 74%) were similar to the reference scores, with the exception of a decreased general health perception in nontransplanted patients (63 +/- 21 vs. 75 +/- 17; [p < 0.001], particularly in females. RAND-36 domain and summary scores were not significantly correlated to age at LT, time since LT, serum bilirubin, aspartate amino transferase or albumin levels, but were moderately to strongly correlated to LDSI total scores (r values 0.35-0.77). Conclusions Overall, young adult patients with BA have a HRQOL similar to an age-matched reference group. However, general health perception of nontransplanted patients, particularly of females, was decreased. HRQOL is correlated to liver disease symptoms but not to liver biochemistry parameters. Nontransplanted females and patients suffering from liver disease-associated symptoms may be a target for tailored supportive interventions. PMID- 26018213 TI - Epidural versus Patient-Controlled Analgesia after Pediatric Thoracotomy for Malignancy: A Preliminary Review. AB - Introduction The use of thoracic epidural is standard in adult thoracotomy patients facilitating earlier mobilization, deep breathing, and minimizing narcotic effects. However, a recent randomized trial in pediatric patients who undergo repair of pectus excavatum suggests patient-controlled analgesia (PCA) produces a less costly, minimally invasive postoperative course compared with epidural. Given that thoracotomy is typically less painful than pectus bar placement, we compared the outcomes of epidural to PCA for pain management after pediatric thoracotomy. Methods A retrospective review of 17 oncologic thoracotomies was performed at a children's hospital from 2004 to 2013. Data points included operative details, epidural or PCA use, urinary catheterization, days to regular diet, days to oral pain regimen, postoperative pain scores, length of stay, and anesthesia charges. Patients were excluded if they did not have epidural or PCA following thoracotomy. Results Six thoracotomies were managed with an epidural and 11 with a PCA. Three epidural patients were opiate naive compared with two with a PCA. The most common indication for thoracotomy was metastatic osteosarcoma (n = 13). When comparing epidural to PCA, there was no significant difference in days to removal of Foley catheter, regular diet, oral pain control, length of stay, or total operating room time. Postoperative pain scores were also comparable. The mean anesthesia charges were significantly higher in patients with an epidural than with a PCA. Conclusion Epidural catheter and PCA provided comparable pain relief and objective recovery course in children who underwent thoracotomy for oncologic disease; however, epidural catheter placement was associated with increased anesthesia charges, suggesting that PCA is a noninvasive, cost-effective alternative. PMID- 26018214 TI - Quality of Life in Female Epispadias. AB - Introduction and Aim Female epispadias is a rare congenital anomaly associated with significant urinary incontinence. This study aims to evaluate the results of its treatment in terms of continence, sexuality, and impact of incontinence on quality of life. Materials and Methods We retrospectively reviewed nine patients (5-39 years) treated of female epispadias in our hospital during the period 1976 2013. Urinary continence (ICIQ-SF), sexuality, impact of incontinence on quality of life (Potenziani-14-CI-IO-2000-QOL), and overall quality of life (SF-36) were evaluated. Results All nine women were treated by bladder neck reconstruction (Young-Dees-Leadbetter) and genitoplasty; four received 2.5 (R = 1-5) endoscopic bladder neck injections; one required enterocystoplasty, urinary diversion, and bladder neck closure because of persistent incontinence; five performed pelvic floor rehabilitation; and two took anticholinergics. Three achieved continence; five had mild urinary incontinence; and 1 had moderate urinary incontinence and was awaiting an endoscopic injection. Of the seven who were older than 18 years, five answered the questionnaires of quality of life and sexuality. All had a general quality of life (SF-36) that does not differ from the normal population and had a slight impact (7 [0-15] points) of incontinence on quality of life (Potenziani-14-CI-IO-QOL-2000). Four had a normal sex life, and the fifth had lack of self-confidence due to her incontinence. Conclusion Patients with female epispadias have good long-term results regarding quality of life and sexuality, despite having some degree of urinary incontinence. PMID- 26018215 TI - The Use of CT Scan in Hemodynamically Stable Children with Blunt Abdominal Trauma: Look before You Leap. AB - We set out to determine the diagnostic value of computed tomographic (CT) scans in relation to the radiation dose, tumor incidence, and tumor mortality by radiation for hemodynamically stable pediatric patients with blunt abdominal injury. We focused on the changes in management because of new information obtained by CT. CT scans for suspected pediatric abdominal injury performed in our accident and emergency department were retrieved from the radiology registry and analyzed for: injury and hemodynamic parameters, changes in therapy, and radiological interventions. The dose length product (DLP) was used to calculate the effective dose (ED) and with the BEIR VII report we calculated the estimated induced lifetime tumor and mortality risk. Seventy-two patients underwent abdominal CT scanning for suspicion of abdominal injury and eight patients were excluded for hemodynamic instability, leaving 64 hemodynamically stable patients. Four patients died (6%). On the remaining 60 patients, only one laparotomy was performed for suspicion of duodenal perforation. Only in three out of the 64 hemodynamically stable cases (5%), a CT scan brought forward an indication for intervention or change in management. One patient was suspected of a duodenal perforation and underwent a laparotomy. A grade II hepatic laceration, but no duodenal, injury was found. Two patients underwent embolization of the splenic artery. One for an arterial blush caused by splenic laceration as was observed on the contrast enhanced-CT. Patient remained stable and during the angiogram the blush had disappeared. The second patient underwent (prophylactic) selective arterial embolization for having sustained a grade V splenic injury. The median radiation dosage was 11.43 mSv (range 1.19-23.76 mSv) in our patients. The use of the BEIR VII methodology results in an estimated increase in the lifetime tumor incidence of 0.17% (range, 0.05-0.67%) and an estimated increase in lifetime tumor incidence of 0.08% (0.02-0.28%). The results of our data suggest that the use of CT scans can largely be avoided in hemodynamically stable children with blunt abdominal injury. PMID- 26018216 TI - Disrupted vasculature and blood-brain barrier in Huntington disease. PMID- 26018217 TI - In vitro activity of a recombinant ABC transporter protein in the processing of plantaricin E pre-peptide. AB - Most bacteriocins of lactic acid bacteria (LAB) are initially synthesized as pre peptides with an N-terminal extension (leader peptides). Generally, the precursor peptides containing a double-glycine-type leader are processed by a dedicated ATP binding cassette (ABC) transporter. The ABC transporter and an accessory protein lead to the cleavage of inactive pre-peptide with the concomitant export of the mature peptide across the cytoplasmic membrane. Plantaricins E, F, J, and K belong to class IIb 2-peptide bacteriocins and are synthesized as pre-peptides containing N-terminal G-G leader peptide. In this study, the heterologous expression, purification, and characterization of PlnE pre-peptide, ABC transporter (PlnG), and accessory protein (PlnH) from Lactobacillus plantarum LR/14 in Escherichia coli BL21 (DE3) strain were reported. An in vitro assay was conducted with the inactive PlnE pre-peptide, which after cleavage by the addition of ABC transporter protein exhibited antimicrobial activity against some LAB species. The activity of cleaved pre-peptide was comparable to the activity of mature peptide. Accessory protein was also heterologously expressed and purified; however, no effect on processing activity was detected by the addition of the accessory protein, which suggests that accessory protein is not involved in cleavage, but it might help in the transport of mature plantaricins across the membrane. PMID- 26018218 TI - The Association of Alcohol Severity and Sleep Quality in Problem Drinkers. AB - AIMS: The association between alcohol use and sleep problems is well established and clinically meaningful, particularly as predictors of relapse. This study aims to elucidate the relationship between sleep disturbances and alcohol problems in a non-treatment-seeking community sample using an alcoholism problem severity factor. METHODS: Participants were problem drinkers (N = 295) from the Los Angeles community who had a breath alcohol content (BrAC) of 0.00 g/dl when they completed an in-person assessment battery comprised of measures of sleep quality, anxiety and depression, cigarette smoking, as well as multiple assessments of alcohol use and alcohol use problems. RESULTS: A series of hierarchical regressions showed that alcohol problem severity explained a significant amount of variance in sleep disturbance beyond demographic, mood and smoking variables. Alcohol problem severity was predictive of the PSQI global score (B = 1.11, P < 0.001), perceived sleep quality factor (B = 0.18, P < 0.001) and daily disturbance factor (B = 0.28, P < 0.001). However, contrary to study hypothesis, alcohol problem severity was predictive of improved sleep efficiency (B = -0.14, P < 0.05). CONCLUSIONS: In sum, alcohol problem severity may be predictive of sleep disturbances. Given the complex nature of these relationships, further work is needed to develop adequate treatment for sleep disturbance during alcohol recovery. Nonetheless, this study suggests that as alcohol problem severity increases so do sleep problems. Thus, attending to sleep problems at early stages of alcohol problems may be warranted. PMID- 26018219 TI - Evaluation of a Multilevel and Integrated Program to Raise Awareness of the Harmful Effects of Prenatal Alcohol Exposure in a Local Community. AB - AIMS: To evaluate a multilevel program to raise awareness of the risks of prenatal exposure to alcohol in the area of Treviso (Italy). The program started in 2008 and consists of an action-research experience involving health professionals of maternal-child services, and in the campaign 'Mamma Beve Bimbo Beve', targeted to the childbearing-aged population. METHODS: A comparative study was carried out in 2013. Surveys using semi-structured self-report questionnaires were carried out among professionals and pregnant women in Treviso, and among control groups belonging to another local area of Italy (Verona). The questionnaires investigated awareness and opinions about alcohol and pregnancy, as well as sources and kind of information provided and received. RESULTS: Health professionals in Treviso, who had been exposed both to the action-research experience and to the campaign, showed a more rational approach to alcohol than colleagues in the control group, and were more aware and sensitized about the risks of alcohol consumption during pregnancy. Physicians and midwives had a higher probability of having advised pregnant women to abstain from alcohol in Treviso. Pregnant women in Treviso, who had received information through the campaign and from professionals, had a higher probability of having received only correct advice about the issue of alcohol and pregnancy, but did not hold perceptions different to women in Verona. CONCLUSIONS: The multilevel program carried out in the Treviso area was effective in increasing awareness and improving attitudes towards the risks of alcohol use during pregnancy among local healthcare professionals, compared with the control group. PMID- 26018220 TI - What strategies are used to build practitioners' capacity to implement community based interventions and are they effective?: a systematic review. AB - BACKGROUND: Numerous agencies are providing training, technical assistance, and other support to build community-based practitioners' capacity to adopt and implement evidence-based prevention interventions. Yet, little is known about how best to design capacity-building interventions to optimize their effectiveness. Wandersman et al. (Am J Community Psychol.50:445-59, 2102) proposed the Evidence Based System of Innovation Support (EBSIS) as a framework to guide research and thereby strengthen the evidence base for building practitioners' capacity. The purpose of this review was to contribute to further development of the EBSIS by systematically reviewing empirical studies of capacity-building interventions to identify (1) the range of strategies used, (2) variations in the way they were structured, and (3) evidence for their effectiveness at increasing practitioners' capacity to use evidence-based prevention interventions. METHODS: PubMed, EMBASE, and CINAHL were searched for English-language articles reporting findings of empirical studies of capacity-building interventions that were published between January 2000 and January 2014 and were intended to increase use of evidence-based prevention interventions in non-clinical settings. To maximize review data, studies were not excluded a priori based on design or methodological quality. Using the EBSIS as a guide, two researchers independently extracted data from included studies. Vote counting and meta-summary methods were used to summarize findings. RESULTS: The review included 42 publications reporting findings from 29 studies. In addition to confirming the strategies and structures described in the EBSIS, the review identified two new strategies and two variations in structure. Capacity-building interventions were found to be effective at increasing practitioners' adoption (n = 10 of 12 studies) and implementation (n = 9 of 10 studies) of evidence-based interventions. Findings were mixed for interventions' effects on practitioners' capacity or intervention planning behaviors. Both the type and structure of capacity-building strategies may have influenced effectiveness. The review also identified contextual factors that may require variations in the ways capacity-building interventions are designed. CONCLUSIONS: Based on review findings, refinements are suggested to the EBSIS. The refined framework moves the field towards a more comprehensive and standardized approach to conceptualizing the types and structures of capacity-building strategies. This standardization will assist with synthesizing findings across studies and guide capacity-building practice and research. PMID- 26018222 TI - Relationships among acylation-stimulating protein, insulin resistance, lipometabolism, and fetal growth in gestational diabetes mellitus women. AB - The aim of this study was to investigate the potential relationship between acylation-stimulating protein (ASP), insulin resistance, lipometabolism, the intrauterine metabolic environment and fetal growth in well-controlled gestational diabetes mellitus (GDM) women. A total of 55 well-controlled GDM women, 66 pregnant women with normal glucose tolerance (NGT) and their newborns, were included in this study. Fasting maternal and cord blood ASP, serum lipid profiles, glucose level, insulin level, HOMA-IR, in addition to neonatal anthropometry data, were measured. Maternal blood ASP in GDM is higher than that in NGT. In the GDM group, maternal blood ASP has a positive correlation with TG, FFA and HOMA-IR. Maternal and cord blood ASP levels of LGA fetuses correlate with elevated birth weight and SF4. Similarly, cord blood ASP levels of LGA fetuses also correlate with birth weight and SF4 in the NGT group. The maternal blood ASP level of GDM mothers is associated with lipometabolism, insulin resistance and LGA fetal growth. Nevertheless, the cord blood ASP level correlates with FFA of GDM mothers, LGA fetal growth of GDM and NGT mothers. ASP may be a biomarker for evaluating insulin resistance of GDM and LGA fetal growth. PMID- 26018221 TI - Quality of artemisinin-based combination formulations for malaria treatment: prevalence and risk factors for poor quality medicines in public facilities and private sector drug outlets in Enugu, Nigeria. AB - BACKGROUND: Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. METHODS: ACAs were purchased using three sampling approaches--convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. RESULTS: Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. CONCLUSION: Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained. PMID- 26018223 TI - Correlation between frictional force and surface roughness of orthodontic archwires. AB - Lateral force microscopy measures the lateral bending of the cantilever depending on the frictional force acting between the tip and surface. The aim of this study was to investigate and compare the relationship between the surface roughness and frictional resistance of four archwire and bracket combinations consisting of the 0.016-inch NiTi and 0.019 * 0.025-inch stainless steel archwires interacting clinically with two representative self-ligating brackets, active-type Clippy C((r)) ceramic self-ligating brackets, and passive-type Damon((r)) stainless steel self-ligating brackets, using the lateral force microscopy technique. A 0.016-inch NiTi archwire interacting with passive-type Damon((r)) stainless steel self-ligating brackets showed the smoothest surface roughness and the lowest frictional resistance compared to other combinations. The archwires interacting with passive-type Damon((r)) stainless steel self-ligating brackets showed significantly lower surface roughness and frictional resistance than those interacting with active-type Clippy-C((r)) ceramic self-ligating brackets. The frictional force in the in vivo archwire and bracket system increased with increasing surface roughness of the archwire. This positive correlation suggests that surface roughness can be used as an evaluating marker for estimating the efficiency of orthodontic treatment, rather than the direct measurement of frictional force. PMID- 26018224 TI - A simulation study on the statistical monitoring of condemnation rates from slaughterhouses for syndromic surveillance: an evaluation based on Swiss data. AB - Syndromic surveillance (SyS) systems currently exploit various sources of health related data, most of which are collected for purposes other than surveillance (e.g. economic). Several European SyS systems use data collected during meat inspection for syndromic surveillance of animal health, as some diseases may be more easily detected post-mortem than at their point of origin or during the ante mortem inspection upon arrival at the slaughterhouse. In this paper we use simulation to evaluate the performance of a quasi-Poisson regression (also known as an improved Farrington) algorithm for the detection of disease outbreaks during post-mortem inspection of slaughtered animals. When parameterizing the algorithm based on the retrospective analyses of 6 years of historic data, the probability of detection was satisfactory for large (range 83-445 cases) outbreaks but poor for small (range 20-177 cases) outbreaks. Varying the amount of historical data used to fit the algorithm can help increasing the probability of detection for small outbreaks. However, while the use of a 0.975 quantile generated a low false-positive rate, in most cases, more than 50% of outbreak cases had already occurred at the time of detection. High variance observed in the whole carcass condemnations time-series, and lack of flexibility in terms of the temporal distribution of simulated outbreaks resulting from low reporting frequency (monthly), constitute major challenges for early detection of outbreaks in the livestock population based on meat inspection data. Reporting frequency should be increased in the future to improve timeliness of the SyS system while increased sensitivity may be achieved by integrating meat inspection data into a multivariate system simultaneously evaluating multiple sources of data on livestock health. PMID- 26018226 TI - Epigenetic Regulation of Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) are multipotent progenitors that have the abilities of self-renewal and multiple direction differentiation. The osteogenic potential of MSCs holds great promise for bone defect repair and bone disease treatment. For a long time studies about osteogenic differentiation of MSCs have emphasized on the effect of extrinsic regulators and the corresponding transcription factors controlling cell fate. In fact, cell fate is determined by lineage specific gene expression that is regulated more specifically by epigenetic mechanism. Over the last decade, some progress has been made in epigenetic researches of MSCs osteogenic differentiation. DNA methylation, histone modifications and microRNA (miRNA) are all verified important mechanisms regulating MSCs differentiation. Epigenetic regulation might provide novel treatment targets for promoting bone formation. In this review, we will summarize the recent advance about the epigenetic mechanism that control MSCs commitment to osteoblasts and the potential clinical application of MSCs epigenetics in future. PMID- 26018225 TI - The effect of cognitive-motor dual-task training on cognitive function and plasma amyloid beta peptide 42/40 ratio in healthy elderly persons: a randomized controlled trial. AB - BACKGROUND: Physical activity reduces the incidence and progression of cognitive impairment. Cognitive-motor dual-task training, which requires dividing attention between cognitive tasks and exercise, may improve various cognitive domains; therefore, we examined the effect of dual-task training on the executive functions and on plasma amyloid beta peptide (Abeta) 42/40 ratio, a potent biomarker of Alzheimer's disease, in healthy elderly people. METHODS: Twenty seven sedentary elderly people participated in a 12-week randomized, controlled trial. The subjects assigned to the dual-task training (DT) group underwent a specific cognitive-motor dual-task training, and then the clinical outcomes, including cognitive functions by the Modified Mini-Mental State (3MS) examination and the Trail-Making Test (TMT), and the plasma Abeta 42/40 ratio following the intervention were compared with those of the control single-task training (ST) group by unpaired t-test. RESULTS: Among 27 participants, 25 completed the study. The total scores in the 3MS examination as well as the muscular strength of quadriceps were equally improved in both groups after the training. The specific cognitive domains, "registration & recall", "attention", "verbal fluency & understanding", and "visuospatial skills" were significantly improved only in the DT group. Higher scores in "attention", "verbal fluency & understanding", and "similarities" were found in the DT group than in the ST group at post intervention. The absolute changes in the total (8.5 +/- 1.6 vs 2.4 +/- 0.9, p = 0.004, 95 % confidence interval (CI) 0.75-3.39) and in the scores of "attention" (1.9 +/- 0.5 vs -0.2 +/- 0.4, p = 0.004, 95 % CI 2.25-9.98) were greater in the DT group than in the ST group. We found no changes in the TMT results in either group. Plasma Abeta 42/40 ratio decreased in both groups following the training (ST group: 0.63 +/- 0.13 to 0.16 +/- 0.03, p = 0.001; DT group: 0.60 +/- 0.12 to 0.25 +/- 0.06, p = 0.044), although the pre- and post-intervention values were not different between the groups for either measure. CONCLUSIONS: Cognitive-motor dual-task training was more beneficial than single-task training alone in improving broader domains of cognitive functions of elderly persons, and the improvement was not directly due to modulating Abeta metabolism. PMID- 26018227 TI - Mesenchymal Stem Cells for Enhancing Biologic Healing after Anterior Cruciate Ligament Injuries. AB - Arthroscopic anterior cruciate ligament (ACL) reconstruction using tendon grafts is the current gold standard for the treatment of ACL tears in active patients. However, many patients still experience residual knee instability, knee pain and progressive cartilage degeneration following ACL reconstruction. Recent developments in mesenchymal stem cell (MSC)-based approaches for treating musculoskeletal injuries have led to the application of MSCs for enhancing healing after ACL injuries. The purpose of this article is to review recent pre clinical and clinical studies using MSCs for the enhancement of biologic healing of ACL injuries. Because of the success of pre-clinical studies, MSC-based approaches are now thought to be promising treatment options for enhancing biologic healing of ACL grafts and restoring the functional properties to the levels of the native ACL, and ultimately improving clinical outcomes. PMID- 26018228 TI - Vybrant DyeCycle Violet Stain Discriminates Two Different Subsets of CD34+ Cells. AB - INTRODUCTION: Studies are needed to understand the role of CD34 expressing cells with regard to efficient engraftment, especially in the adjuvant treatment of cancer. MATERIALS AND METHODS: In this study we have used a modified method in our laboratory for routinely counting CD34+ cells. Unlysed whole blood samples were stained with the DNA-selective and cell membrane-permeant Vibrant DyeCycle Violet stain. RESULTS: CD34+ cells exhibit a consistent and differential Vybrant Dye Cycle Violet staining pattern. Based on their different DCV intensity, we classified these subpopulations as CD34+/DCV(high) and CD34+/DCV(low) cells. In general, DCV(high) cells are about 12-times brighter than DCV(low) cells. CONCLUSION: DCV staining may be used to discriminate subsets of CD34+ cells similarly to other methods which have previously defined different functional properties that can be related to the characterization, resolution, and purification of primitive hematopoietic stem cells in combination with specific useful markers for multicolor flow cytometric measurements. PMID- 26018229 TI - Peroxisome Proliferator-Activated Receptor-gamma: Master Regulator of Adipogenesis and Obesity. AB - Obesity, which is a key risk for the development of hyperglycemia, hypertension, hyperlipidemia and insulin resistance and is totally referred to as the metabolic disorders, has aroused people's great attention because of its alarming increase rate around the world. It is widely known that the occurrence of obesity can be attributed to both environmental and genetic factors. Peroxisome proliferators activated receptor (PPAR), a member of ligand-dependent receptor, is one of the important genetic factors. PPAR includes three isoforms: PPAR-alpha, PPAR- beta and PPAR- gamma, all of which are exerting critical influences on the maintenance of the metabolism of saccharides, lipids and proteins. PPAR-gamma is of great importance in the regulation of adipogenesis; in addition, it is essential in the prevention of adiposis and the treatment of 2-diabetes mellitus. In this review, we focus on giving a brief introduction about PPAR family, the indispensible function of PPAR-gamma in adipogenesis and the inseparable relationship between PPAR-gamma and obesity, deriving from the understanding of how these receptors activated will provide windows of opportunities for the treatment of obesity and associated metabolism syndromes. PMID- 26018230 TI - MicroRNAs and Peroxisome Proliferator-Activated Receptors Governing the Differentiation of Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) have the self-renewal ability and the ability to produce multiple differentiation. Elucidating the genetic circuits that govern MSC self-renewal and differentiation is necessary to improve our comprehension of MSCs and their role in regenerative medicine. microRNAs (miRNAs) play important roles in the regulation of transcription, and are strongly linked with MSCs regarding the maintenance of pluripotency properties. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormonereceptor family. Interestingly, PPARs not only regulate glucose metabolism and lipidhomeostasis, but also contribute to cell proliferation, cell differentiation, and cell apoptosis. The aim of the present review was to provide an insight into the roles of miRNAs and PPARs in the differentiation of MSCs. Understanding the miRNA signature interactions in conjunction with the role of PPARs is critical for the development of improved strategies to regulate the differentiation of MSCs. PMID- 26018231 TI - Modelling and treating amyotrophic lateral sclerosis through induced-pluripotent stem cells technology. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease affecting primarily the population of motor neurons, even though a non-cell autonomous component, involving neighbouring non-neuronal cells, is more and more described. Despite 140 years of disease experience, still no efficient treatment exists against ALS. The inability to readily obtain the faulty cell types relevant to ALS has impeded progress in drug discovery for decades. However, the pioneer work of Shinya Yamanaka in 2007 in the stem cell field was a real breakthrough. Recent advances in cell reprogramming now grant access to significant quantities of CNS disease-affected cells. Induced pluripotent stem cells (iPSc) have been recently derived from patients carrying mutations linked to familial forms of ALS as well as from sporadic patients. Precise and mature protocols allow now their differentiation into ALS-relevant cell subtypes; sustainable and renewable sources of human motor neurons or glia are being available for ALS disease modelling, drug screening or for the development of cell therapies. In few years, the proof-of-concept was made that ALS disease related phenotypes can be reproduced with iPSc and despite some remaining challenges, we are now not so far to provide platforms for the investigation of ALS therapeutics. This paper also reviews the pioneering studies regarding the applicability of iPSc technology in ALS animal models. From modest slowing down of ALS progression to no severe adverse effects, iPSc-based cell therapy resulted in promising premises in ALS preclinical paradigms, although long-term surveys are highly recommended. PMID- 26018232 TI - Morin: A Promising Natural Drug. AB - Morin is a natural polyphenol, originally isolated from members of the Moraceae family that can be extracted from leaves, fruits, stems and branches of numerous plants. Several evidence have demonstrated that Morin could have a beneficial effect on several human diseases. In fact, Morin exerts antioxidant, antidiabetic, anti-inflammatory, antitumoral, antihypertensive, antibacterial, hypouricemic, and neuroprotective effects, by modulating the activity of many enzymes. In some cases, Morin shows a systemic protective action, reducing negative side effects of several drugs, without interfering with their functions. In addition, in vitro and in vivo studies demonstrated that Morin exhibits very low toxicity levels and its chronic administration is well tolerated. All these findings suggest that Morin could be used, either alone or in combination with other drugs, to prevent many human pathologies. PMID- 26018233 TI - Isolation and characterization of Meniscus derived stem cells from rabbit as a possible treatment for damages meniscus. AB - Background The successful surgical restoration of damaged meniscus has been a challenge, largely owing to a lack of characterization of meniscus cells and their precursors. Numerous strategies to repair or replace meniscus have achieved only limited success. Several recent studies have shown beneficial effect of mesenchymal stem cells in meniscus repair. The objective of our study was to characterize meniscus derived mesenchymal stem cells in terms of , colony formation, proliferation ,multi potency and self-renewal capacity. Methods Mesenchymal stem cells were isolated from menisci, patella tendon and bone marrow of rabbits. The multi differentiating potential colony morphology and proliferation were studied in vitro. The expression of differential markers was studied by immunocytochemistry, qPCR and western blotting. Results Three groups of cells appeared similar in colony formation and morphology. All of them were found to express high levels of stem cell markers including SSEA-4, Nanog and nucleostemin. High level of collagen II expression was detected in meniscus derived stem cells. Moreover, these cells appeared to have a pronounced tendency to chondrogenic differentiation under specialized culture conditions. Conclusions MMSCs possessed all the necessary criteria of stem cells, including clonogenicity, self-renewal and multipotent differentiation capacity and possessed a tendency to differentiate into chondrocytes. Our results offer new insights into the biology of meniscus cells, and may assist in future strategies to treat damaged meniscus. PMID- 26018234 TI - Mesenchymal stem cell therapy for inflammatory bowel diseases: promise and challenge. AB - Inflammatory Bowel Disease (IBD) is a complicated disease that arises as a consequence of the interaction among environment, genetic factors and autoimmunity. Available therapeutic interventions with pharmacological or biological drugs have a very selective action. Mesenchymal stem cells (MSCs) have been emerging as a promising cellular therapy for the treatment of IBD due to their multifaceted functions. This article summarizes recent progress in both preclinical studies and clinical trials employing MSCs in IBD treatment. We justify the use of MSC-based cell therapy as a novel strategy for IBD, discuss the biological roles that MSCs play underlying their therapeutic effects focusing on their immune-suppressive effects, illustrate methods to improve MSCs for better repair, and pinpoint the obstacles hindering their success and the challenges to overcome before their ultimate application. PMID- 26018235 TI - Telocytes Contribute as Cell Progenitors and Differentiation Inductors in Tissue Regeneration. AB - According to recent literature data, a peculiar connective tissue cell, called telocyte (TC), is present in almost all organs. Furthermore, TC subtypes, often coexisting in the same organ, but having different immunohistochemical and ultrastructural characteristics, have been demonstrated. Characteristically, TC, by connecting to each other and/or with other cell types, build three-dimensional networks. In the latter case they form a mixed network. TC, therefore, may be part of an integrated system to maintain tissue/organ function. Several roles have been proposed for the TC some of which support the importance of these cells in the differentiation and regenerative processes. Indeed, TC might behave as inductors/regulators of differentiation during morphogenesis due to their ability to release molecular signals and to construct the scaffold necessary for the parenchymal organization. In the adulthood, TC may be considered mesenchymal stromal cells able to differentiate in different cell types, such as the interstitial cells of Cajal, the resident myofibroblasts and the fibroblasts. Furthermore, the TC might be essential for the survival, proliferation, differentiation, maturation and guidance of the parenchymal stem cells located in the niches of several organs and, eventually, stimulate and sustain the regenerative processes. PMID- 26018236 TI - Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following gastrointestinal bleeding. A meta-analysis. AB - Gastrointestinal (GI) bleeding commonly complicates anticoagulant therapy. We aimed to systematically review the published literature to determine the risk of thromboembolism, recurrent GI bleeding and mortality for patients on long-term anticoagulation who experience GI bleeding based on whether anticoagulation therapy was resumed. We performed a systematic review of phase III randomised controlled trials and cohort studies in patients with atrial fibrillation or venous thromboembolism who received oral anticoagulant. We searched MEDLINE, EMBASE and CENTRAL (from 1996-July 2014), conferences abstracts (from January 2006-July 2014) and www.clinicaltrials.gov (up to the last week of July 2014) with no language restriction. Two reviewers independently performed study selection, data extraction and study quality assessment. A total of three studies were included in the meta-analysis. The resumption of warfarin was associated with a significant reduction in thromboembolic events (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.52 to 0.88, p<0.004, I(2)=82%). There was an increase in recurrent GI bleeding but not statistically significant for patients who restarted warfarin compared to those who did not (HR 1.20, 95% CI 0.97 to 1.48, p = 0.10, I(2) = 0%). Resumption of warfarin was associated with significant reduction in mortality (HR 0.76, 95% CI 0.66 to 0.88, p<0.001, I(2) = 87%). This meta-analysis demonstrates that resumption of warfarin following interruption due to GI bleeding is associated with a reduction in thromboembolic events and mortality without a statistically significant increase in recurrent GI bleeding. PMID- 26018238 TI - Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia. AB - OBJECTIVE: Azacitidine is the standard of care for higher-risk myelodysplastic syndromes (MDS). We evaluated factors affecting the outcome of azacitidine treatment in 196 'real-world' patients, retrospectively collected by two Italian cooperative groups. METHODS: The study included 184 MDS and 12 low blast count acute myeloid leukemia (AML). Azacitidine was administered at the standard dose of 75 mg/m(2)/d for 7 d (SD) in 163 patients and 100 mg/d for 5-7 d in 33 patients. RESULTS: After a median of 4.5 azacitidine cycles (range 7-15 cycles), 182 patients were evaluable for response. Nineteen percent achieved complete remission (CR), 17% partial remission (PR), and 21% hematological improvement (HI). The disease was stable or progressive in 29% and 14% of patients, respectively. The probability of response was significantly higher in patients who received the 75 mg/m(2)/7 d compared with 100 mg through 5-7 d dose (CR/PR/HI: 63 vs. 29%, P = 0.0005). Median overall survival was 17.1 months. Low MDS-CI and achievement of CR/PR/HI were significant predictors of survival in the multivariable analysis. CONCLUSIONS: Our data show that maximal azacitidine efficacy is associated with the standard dose and with prolonged treatment, beyond 4-6 cycles, with the goal of also improving the 'quality' of response. Lower MDS-CI and IPSS-R scores, hematologic response and disease stability, are associated with longer survival. The risk of febrile events is highest during the first treatment cycles and is associated with active disease. PMID- 26018239 TI - Design principles for cancer therapy guided by changes in complexity of protein protein interaction networks. AB - BACKGROUND: The ever-increasing expanse of online bioinformatics data is enabling new ways to, not only explore the visualization of these data, but also to apply novel mathematical methods to extract meaningful information for clinically relevant analysis of pathways and treatment decisions. One of the methods used for computing topological characteristics of a space at different spatial resolutions is persistent homology. This concept can also be applied to network theory, and more specifically to protein-protein interaction networks, where the number of rings in an individual cancer network represents a measure of complexity. RESULTS: We observed a linear correlation of R = -0.55 between persistent homology and 5-year survival of patients with a variety of cancers. This relationship was used to predict the proteins within a protein-protein interaction network with the most impact on cancer progression. By re-computing the persistent homology after computationally removing an individual node (protein) from the protein-protein interaction network, we were able to evaluate whether such an inhibition would lead to improvement in patient survival. The power of this approach lied in its ability to identify the effects of inhibition of multiple proteins and in the ability to expose whether the effect of a single inhibition may be amplified by inhibition of other proteins. More importantly, we illustrate specific examples of persistent homology calculations, which correctly predict the survival benefit observed effects in clinical trials using inhibitors of the identified molecular target. CONCLUSIONS: We propose that computational approaches such as persistent homology may be used in the future for selection of molecular therapies in clinic. The technique uses a mathematical algorithm to evaluate the node (protein) whose inhibition has the highest potential to reduce network complexity. The greater the drop in persistent homology, the greater reduction in network complexity, and thus a larger potential for survival benefit. We hope that the use of advanced mathematics in medicine will provide timely information about the best drug combination for patients, and avoid the expense associated with an unsuccessful clinical trial, where drug(s) did not show a survival benefit. PMID- 26018240 TI - Palp ratio as a field identification tool for two members of the Anopheles gambiae complex in Ghana (A. melas and A. gambiae). AB - BACKGROUND: The Anopheles gambiae Giles complex is the most widely studied and the most important insect vector group. We explored the use of the palp ratio method as a field tool to identify A. melas and A. gambiae in Ghana. METHODS: Human landing catches were conducted to collect mosquitoes in the coastal area of Western Region of Ghana. Palps were removed and segments 3 and 4 + 5 measured using a compound microscope. DNA extraction and downstream PCR for species identification was carried out using the legs and wings. Known A. gambiae collected from the Ashanti Region of Ghana were used for comparison. RESULTS: A total of 2120 A. gambiae were collected. Lengths of segments 3 and 4 + 5 were significantly correlated in samples from both regions. Using a palp ratio of 0.81 as the cut-off value, 14.9% outliers (>=0.81) from our study area were confirmed by PCR as A. melas. PCR also confirmed outliers from the Ashanti Region with palp ratio < 0.81 (10.2%) as A. gambiae. CONCLUSION: The palp ratio method proved to be a useful tool to identify populations of salt and freshwater A. melas and A. gambiae. PMID- 26018241 TI - Use of plastinated specimens in rural medical and nursing education: a novel solution. PMID- 26018242 TI - Quality of life after total laparoscopic hysterectomy: a one-year follow-up study. AB - BACKGROUND: A small prospective observational cohort study with the aim to evaluate postoperative health-related quality of life (HRQOL) at one-year follow up after total laparoscopic hysterectomy for benign gynecological conditions and to assess postoperative functions in terms of return to work, sexual activity and driving was conducted. METHODS: Sixty out of 65 women with a mean age of 45.7+/ 5.4 responded to the questionnaire. Change in HRQOL was assessed by comparing the preoperative and postoperative QOL on scale of 1-5 grades. RESULTS: HRQOL improved significantly at 12 months postoperatively. Multiple logistic regression analysis showed that the presence of irregular periods (P=0.048) and dyspareunia (P=0.017) were significant predictors of overall postoperative improvement in QOL by 3 or more grades. Women with ovarian preservation were more likely to report overall improvement in HRQOL by 3 or more grades compared to those who had bilateral salpingo-oophrectomy (P=0.04). There was statistically significant improvement in QOL postoperatively as compared to preoperatively (P<0.0001). CONCLUSIONS: In our study we found that women presenting with dyspareunia were more likely to report higher improvement in postoperative QOL. This highlights that dyspareunia is a symptom which is a marker for chronic pelvic pain conditions like endometriosis, adenomyosis, fibroids and adhesions. PMID- 26018245 TI - Infrastructure systems, risk analysis, and resilience--research gaps and opportunities. PMID- 26018243 TI - Impact of Bariatric Surgery on Patients With Rheumatoid Arthritis. AB - OBJECTIVE: To investigate the effect of weight loss after bariatric surgery among patients with rheumatoid arthritis (RA). METHODS: We conducted a retrospective cohort study of RA patients who underwent bariatric surgery (Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, or sleeve gastrectomy) at 2 medical centers. We obtained information on anthropometrics, laboratory values, RA disease activity, and medication use at baseline (prior to surgery), at 6 and 12 months following surgery, and at the most recent followup visits. RA disease activity was determined by clinical or validated measures. At each postsurgical visit, characteristics were compared to baseline. RESULTS: We identified 53 RA patients who underwent bariatric surgery. At baseline prior to surgery, mean +/- SD body mass index was 47.8 +/- 7.7 kg/m(2), mean +/- SD weight was 128.2 +/- 24.1 kg, and 57% had moderate to high RA disease activity. Twelve months following surgery, subjects lost a mean +/- SD weight of 41.0 +/- 17.3 kg, mean +/- SD 70% +/- 24% excess weight (P < 0.001). RA disease activity significantly improved at postsurgical visits (P < 0.001). At 12 months following surgery, 6% had moderate to high disease activity, compared to 57% at baseline (P < 0.001). At the most recent followup (mean +/- SD 5.8 +/- 3.2 years after surgery), 74% were in remission, compared to 26% at baseline (P < 0.001). Subjects had significantly lower erythrocyte sedimentation rate, C-reactive protein level, and RA-related medication use at followup visits compared to baseline (P < 0.05). CONCLUSION: After substantial weight loss from bariatric surgery, RA patients had lower disease activity, decreased serum inflammatory markers, and less RA-related medication use. Weight loss may be an important nonpharmacologic strategy to reduce RA disease activity. However, other factors, such as improved efficacy of medications, improved physical activity, and metabolic changes, may also have contributed to these postsurgical improvements. PMID- 26018246 TI - Topological performance measures as surrogates for physical flow models for risk and vulnerability analysis for electric power systems. AB - Critical infrastructure systems must be both robust and resilient in order to ensure the functioning of society. To improve the performance of such systems, we often use risk and vulnerability analysis to find and address system weaknesses. A critical component of such analyses is the ability to accurately determine the negative consequences of various types of failures in the system. Numerous mathematical and simulation models exist that can be used to this end. However, there are relatively few studies comparing the implications of using different modeling approaches in the context of comprehensive risk analysis of critical infrastructures. In this article, we suggest a classification of these models, which span from simple topologically-oriented models to advanced physical-flow based models. Here, we focus on electric power systems and present a study aimed at understanding the tradeoffs between simplicity and fidelity in models used in the context of risk analysis. Specifically, the purpose of this article is to compare performance estimates achieved with a spectrum of approaches typically used for risk and vulnerability analysis of electric power systems and evaluate if more simplified topological measures can be combined using statistical methods to be used as a surrogate for physical flow models. The results of our work provide guidance as to appropriate models or combinations of models to use when analyzing large-scale critical infrastructure systems, where simulation times quickly become insurmountable when using more advanced models, severely limiting the extent of analyses that can be performed. PMID- 26018247 TI - Trends in Media Reports, Oral Bisphosphonate Prescriptions, and Hip Fractures 1996-2012: An Ecological Analysis. AB - Bisphosphonates are effective for the treatment of osteoporosis despite recent reports of safety concerns such as atypical femur fracture. We conducted an ecological analysis of relevant media reports, oral bisphosphonate use, and fracture outcomes in the United States. Trends in media reports and public interest of bisphosphonates were quantified using data from Google Trends. Data from the Medical Expenditure Panel Survey (MEPS) and the National Inpatient Sample (NIS) were used to estimate the trends in oral bisphosphonate use among patients aged 55 years and older and hospitalizations for intertrochanteric and subtrochanteric fractures, respectively. These trends in the prevalence of oral bisphosphonate use and the age-adjusted incidence rate of intertrochanteric and subtrochanteric fractures were examined from 1996 to 2012. A series of spikes in Internet search activity for alendronate (Fosamax) occurred between 2006 and 2010 immediately following media reports of safety concerns. Oral bisphosphonate use declined by greater than 50% between 2008 and 2012 (p < 0.001) after increasing use for more than a decade. The decline was more common in patients with lower education levels. Intertrochanteric hip fractures declined from 1996 through 2006 (p < 0.001) and continued to decline from 2008 to 2012 (p < 0.05). Subtrochanteric and diaphyseal fractures showed a steady and significant increase from 2002 to 2011 (p < 0.05). However, the incidence decreased from a peak of 30.5 per 100,000 in 2011 to 26.7 per 100,000 in 2012. The plateauing and subsequent decline in oral bisphosphonate use since 2006 coincided with reports of safety concerns of bisphosphonates, despite the fact that U.S. Food and Drug Administration (FDA) and American Society of Bone and Mineral Research (ASBMR) reports did not recommend any safety restrictions on their use. This decline in oral bisphosphonate use was followed by the decline in the incidence of subtrochanteric and diaphyseal fractures. PMID- 26018248 TI - C-Terminal Clostridium perfringens Enterotoxin-Mediated Antigen Delivery for Nasal Pneumococcal Vaccine. AB - Efficient vaccine delivery to mucosal tissues including mucosa-associated lymphoid tissues is essential for the development of mucosal vaccine. We previously reported that claudin-4 was highly expressed on the epithelium of nasopharynx-associated lymphoid tissue (NALT) and thus claudin-4-targeting using C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) effectively delivered fused antigen to NALT and consequently induced antigen-specific immune responses. In this study, we applied the C-CPE-based vaccine delivery system to develop a nasal pneumococcal vaccine. We fused C-CPE with pneumococcal surface protein A (PspA), an important antigen for the induction of protective immunity against Streptococcus pneumoniae infection, (PspA-C-CPE). PspA-C-CPE binds to claudin-4 and thus efficiently attaches to NALT epithelium, including antigen sampling M cells. Nasal immunization with PspA-C-CPE induced PspA-specific IgG in the serum and bronchoalveolar lavage fluid (BALF) as well as IgA in the nasal wash and BALF. These immune responses were sufficient to protect against pneumococcal infection. These results suggest that C-CPE is an efficient vaccine delivery system for the development of nasal vaccines against pneumococcal infection. PMID- 26018249 TI - Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development. AB - The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor. Transgenic overexpression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined: 1) GPA2 and GPB5 expression in osteoblasts and osteoclasts, 2) the skeletal consequences of thyrostimulin deficiency in GPB5 knockout (KO) mice, and 3) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the noncanonical Akt, ERK, or mitogen-activated protein kinase (P38) signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development. PMID- 26018252 TI - [Ganoderic acid A suppresses proliferation and invasion and induces apoptosis in human osteosarcoma cells]. AB - OBJECTIVE: To investigate the effect of ganoderic acid A (GA-A) on the biological behaviors of human osteosarcoma cells in vitro. METHODS: MG63 and HOS cells were treated with 0.1, 0.25, and 0.5 mmol/L GA-A, and the changes in cell proliferation, apoptosis and migration were evaluated using MTT assay, flow cytometry, and Transwell assay, respectively. The expressions of STAT3, p38, and NF-kappaB1 in the cells were analyzed by Western blotting. RESULTS: GA-A effectively inhibited the proliferation of human osteosarcoma HOS and MG-63 cells in a dose-dependent manner, and induced obvious cell apoptosis in both cells. Treatment with 0.5 mmol/L GA-A also resulted in significant inhibition of the invasion of both cells. The results of Western blotting showed that GA-A down regulated the expression level of phosphorylated STAT3 and increased the phosphorylation level of p38 and NF-kappaB1 expression in both cells. CONCLUSION: GA-A can induce proliferation inhibition, apoptosis and suppression of invasion in human osteosarcoma HOS and MG-63 cells. PMID- 26018250 TI - Testing the Critical Window Hypothesis of Timing and Duration of Estradiol Treatment on Hypothalamic Gene Networks in Reproductively Mature and Aging Female Rats. AB - At menopause, the dramatic loss of ovarian estradiol (E2) necessitates the adaptation of estrogen-sensitive neurons in the hypothalamus to an estrogen depleted environment. We developed a rat model to test the "critical window" hypothesis of the effects of timing and duration of E2 treatment after deprivation on the hypothalamic neuronal gene network in the arcuate nucleus and the medial preoptic area. Rats at 2 ages (reproductively mature or aging) were ovariectomized and given E2 or vehicle replacement regimes of differing timing and duration. Using a 48-gene quantitative low-density PCR array and weighted gene coexpression network analysis, we identified gene modules differentially regulated by age, timing, and duration of E2 treatment. Of particular interest, E2 status differentially affected suites of genes in the hypothalamus involved in energy balance, circadian rhythms, and reproduction. In fact, E2 status was the dominant factor in determining gene modules and hormone levels; age, timing, and duration had more subtle effects. Our results highlight the plasticity of hypothalamic neuroendocrine systems during reproductive aging and its surprising ability to adapt to diverse E2 replacement regimes. PMID- 26018253 TI - [Omics of vector mosquitoes: a big data platform for vector biology and vector borne diseases]. AB - Recently the studies on mosquito genomics, transcriptomics and small RNAomics developed rapidly with the novel biotechnologies of the next generation sequencing techniques. The genome sequences of several important vector mosquitoes including Anopheles gambiae, Culex quinquefasciatus, and Aedes aegypti have been published. The genome sizes vary among the different species of mosquitoes and are consistent with the number of the repeat regions. The released genome sequences facilitate gene cloning and identification as for OBP, OR and dsx genes. Transcriptomics provides a useful tool for functional analyses of the mosquito genes, and using this technique, the molecular basis of mosquito blooding, gland proteins and diapauses have been explored. Studies on small RNAomics suggest important roles of miRNAs and piRNAs in ovary development, blood digestion, and immunity against virus infection. The studies on mosquito omics have generated a big data platform for investigation of vector biology and vector transmitted disease prevention. PMID- 26018254 TI - [Effect of serum from patients with chronic renal insufficiency and indoxyl sulfate on lipid accumulation in macrophages in vitro]. AB - OBJECTIVE: To investigate the pathologies of aortic root atherosclerotic lesion in uremic apoE-/- mice and explore the effect of serum from patients with chronic renal insufficiency (CRI) and the uremic toxin, indoxyl sulfate (IS), on the expression of cholesterol transporting receptors and lipid accumulation in macrophages in vitro. METHODS: The uremic apoE-/- mouse model was established by surgical operation. Frozen sections of the aortic root were collected from uremic apoE-/- mice, sham-operated apoE-/- mice and C57BL/6J mice and stained with oil red O to calculate the relative area of atherosclerotic plaque. Murine macrophage RAW264.7 cell line was treated for 12 h with different concentrations of IS or serum samples from CRI patients and healthy individuals, and the mRNA expressions of cholesterol transporting receptors (SR-A1, CD36, ABCA1, ABCG1 and SR-B1) were detected. After treatment for 24 h, the cells were induced into foam cells to determine lipid contents using oil red O staining. RESULTS: The relative area of the atherosclerotic plaques in the aortic root increased significantly in uremic apoE-/- mice compared with that in sham-operated apoE-/- mice. CRI serum (5%) and IS (250 umol/L) obviously increased the mRNA expression of CD36 and lipid accumulation in the macrophages, but did not affect the mRNA expression of other cholesterol transporting receptors. CONCLUSION: CRI can accelerate the progression of atherosclerosis through the mechanism that IS in CRI serum promotes lipid accumulation in macrophages by enhancing the mRNA expression of CD36, which contributes to the formation of foam cells. PMID- 26018251 TI - An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes. AB - Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of beta-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D. PMID- 26018255 TI - [Application of 3D visualization, 3D printing and 3D laparoscopy in the diagnosis and surgical treatment of hepatic tumors]. AB - OBJECTIVE: To study the value of three-dimensional (3D) visualization, 3D printing and 3D laparoscopy (3-3D techniques) in the diagnosis and surgical treatment of hepatic tumors. METHODS: From November 2013 to January 2015, 22 patients with hepatic tumors admitted in our department underwent abdominal thin slice CT scanning. The CT images were imported into Medical Image three Dimensional Visualization System (MI-3DVS) for 3D reconstruction. Standard Template Library (STL) files were exported for 3D printing. The hepatic vascular classification and predicted liver resection were performed with the aid of MI 3DVS system. The 3D models were then printed and virtual liver resections were executed accordingly. Based on these preoperative surgical planning data, we performed anatomical hepatectomy using 3D laparoscopy, and the intraoperative blood loss, volume of virtual and actual liver resection and postoperative hospital stay were recorded. RESULTS: According to Michels's classifications, 19 patients had type I, 2 had type II, and 1 had type VIII hepatic arteries; based on Cheng classifications, the portal vein was classified into type I in 17 cases, type II in 2 cases, and type III in 2 cases, and type IV in 1 case; according to Nakamura classifications, the right hemiliver hepatic vein was classified into type I in 10 cases, type II in 7 cases, and type III in 5 cases. In the virtual operations, the mean volume of liver resected was 490 +/- 228 ml and the mean remnant liver volume was 885 +/- 139 ml, with a remnant to functional liver volume ratio of (71 +/- 11)%. The 3D printed models stereoscopically displayed the location of the liver tumors and adjacent liver vascular structure clearly. Laparoscopic hepatectomy was performed successfully in 20 patients guided by the 3-3D techniques, and the other 2 patients required convertion to open hepatectomy. The mean operation time was 186 +/- 92 min, the intraoperative blood loss was 284 +/- 286 ml, the mean actual liver resection volume was 491 +/- 192 ml, and the mean postoperative hospital stay of the patients was 8.6 +/- 3.7 days. CONCLUSIONS: The 3-3D technique can facilitate the evaluation of preoperative risk and critical anatomical structures and navigate the surgical procedure in real time in anatomical hepatectomy for hepatic tumors. PMID- 26018256 TI - [Effects of angiotensin-(1-7) on hippocampal expressions of GFAP and GDNF and cognitive function in rats with diabetes mellitus]. AB - OBJECTIVE: To explore the effects of angiotensin-(1-7) on the learning and memory abilities and the expressions of glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor (GDNF) in the hippocampus of diabetic rats. METHODS: Forty male SD rats were randomly assigned into 4 groups, namely the control group, diabetic group, Ang(1-7)-treated diabetic group (DM1 group), and Ang-(1-7)- and Mas receptor antagonist A779-treated diabetic group (DM2 group). Diabetic rat models were established by a single intraperitoneal injection of streptozotocin (60 mg/kg). The cognitive function of the rats was assessed with Morris water maze (MWM) test. The expressions of GDNF in the hippocampus were examined by RT-PCR and Western blot. Nissl staining was performed to evaluate the morphological changes in rat hippocampus. The expressions of glial fibrillary acidic protein (GFAP, a key indicator of astrocytic reactivity) and caspase-3 were measured by immunohistochemistry. RESULTS: Compared with the control group, the diabetic rats exhibited significantly impaired learning and memory abilities (P<0.05) with lowered expression of GDNF and increased caspase-3 expression in the hippocampus (P<0.05) and significant hippocampal neuronal and astrocyte injuries (P<0.05). Treatment with Ang(1-7) obviously improved the learning and memory abilities of the diabetic rats (P<0.05), increased GDNF and GFAP expressions (P<0.05), lowered caspase-3 expression (P<0.05), and increased the number of surviving neurons in the hippocampus (P<0.05). Such effects of Ang(1-7) effect was blocked by treatment with A779 of the diabetic rats. CONCLUSION: Ang(1 7) can alleviate cognitive dysfunction in diabetic rats possibly by up-regulating the expressions of GFAP and GDNF and promoting neuron survival in the hippocampus. PMID- 26018257 TI - [Lentivirus-mediated angiotensin-converting enzyme 2 overexpression inhibits angiotensin II-induced albumin down-regulation and enhancement of migration in rat hepatocytes]. AB - OBJECTIVE: To investigate the inhibitory effect of angiotensin-converting enzyme 2 (ACE2) on angiotensin II (Ang II)-induced down-regulation of albumin expression and enhancement of cell migration in rat hepatocytes. METHODS: Cultured rat hepatocyte were treated with Ang II (10-7 mol/L) for different time lengths, and the protein expressions of vimentin and albumin and cell migration were detected. The cells transfected with lentiGFP or lentiACE2 were treated with A779 for 1 h and then with Ang II, and Western blotting and immunofluorescent cytochemistry were used to detect the protein levels; the cell migration was evaluated by Transwell assay. RESULT: Ang II induced significantly increased vimentin expression and reduced albumin expression in rat hepatocytes in a time-dependent manner. Overexpression of ACE2 obviously inhibited the up-regulation of vimentin expression, reduction of albumin expression, and enhancement of cell migration induced by Ang II. CONCLUSION: ACE2 overexpression can inhibit Ang II-induced up regulation of vimentin, reduction of albumin expression, and enhancement of cell migration in rat hepatocytes. PMID- 26018258 TI - [Characterization of a Clonorchis sinensis antigen, calmodulin, and its relationship with liver fibrosis]. AB - OBJECTIVE: To characterize the biological function of calmodulin (CaM) from Clonorchis sinensis (C. sinensis, Cs) and investigate its role in clonorchiasis associated hepatic fibrosis. METHODS: The full-length sequence of CsCaM gene was isolated from Cs cDNA library and its homologues were searched using BLASTx for comparison. Bioinformatics analysis was performed to compare the homologues and predict the physiochemical characteristics and functional domains. The gene was cloned in a prokaryotic plasmid and expressed in E. coli, and the recombinant protein was purified by affinity chromatography for immunizing rats to produce polyclonal antibodies, whose titer was determined using ELISA analysis. Immunoblotting analysis was carried out to determine of the purity and antibody recognition of CsCaM. Immunofluorescence assay was employed to analyze the tissue location of the protein. A rat model of liver fibrosis was established by introperitoneal injection of the recombinant protein. RESULTS: The recombinant CsCaM protein obtained contained 150 amino acids with a theoretical molecular mass of 23.4 kD. CsCaM homologue had EF hand motifs. The recombinant pET-30a CsCaM plasmid expressed in BL21 E. coli was about 23.4 kD. The total IgG antibody titer in the immunized mice reached the peak level (over 1: 51200) 2 to 4 weeks after the first injection. Immunohistochemistry showed that CsCaM located in the testis of adult C. sinensis. The rats receiving intraperitoneal injection of CsCaM showed severe liver inflammation with mild to moderate liver fibrosis. CONCLUSION: The pro-inflammation and pro-fibrosis effects of CsCaM in rat liver suggest its involvement in clonorchiasis- associated hepatic fibrosis. PMID- 26018259 TI - [Effect of emodin on proliferation and cell cycle of human oral squamous carcinoma Tca8113 cells in vitro]. AB - OBJECTIVE: To investigate the effect of emodin on proliferation and cell cycle distribution of human oral squamous carcinoma cells in vitro. METHODS: Cultured human oral squamous carcinoma Tca8113 cells were treated with 2.5, 5, 10, 20, 40, 60 and 80 umol/L emodin for 24, 48 or 72 h, with the cells treated with 0.1% DMSO as control. MTT assay and flow cytometry were used to evaluate the changes in cell proliferation and cell cycle distribution, respectively. Western blotting was employed to analyze the changes in the expression levels of the cell cycle related proteins CDK2, cyclin E and P21 after emodin treatment. RESULTS: Emodin significantly inhibited the growth and proliferation of Tca8113 cells within 72 h in a time- and dose-dependent manner, and caused cell cycle arrest in G0-G1 phase. Western blotting revealed that emodin treatment significantly lowered the expression levels of CDK2, cyclin E and P21 proteins in Tca8113 cells (P<0.05). CONCLUSION: Emodin can inhibit the proliferation of Tca8113 cells and affect their cell cycle distribution possibly by inhibiting the signaling pathways of cell cycle regulation. PMID- 26018260 TI - [Effect of small interfering RNA-mediated angiotensin II type 1 receptor knockdown on first-phase insulin secretion in isolated diabetic rat islets]. AB - OBJECTIVE: To investigate the effects of angiotensin II type 1 receptor (AT1R) knockdown on the first-phase insulin secretion in isolated islets of db/db mice and explore the possible mechanisms. METHODS: Islets were isolated from db/db and db/m mice and the expression level of AT1R in the islets was assayed. A recombinant adenovirus containing siRNA targeting AT1R (Ad-siAT1R) and a recombinant adenovirus with nonspecific siRNA (Ad-siControl) were constructed to infect the isolated islets for 72 h. AT1R, GLUT-2, and GCK expressions in the islets were investigated and islet perifusion was performed to evaluate the kinetics of insulin release. RESULTS: The expression level of AT1R in the isolated islets from db/db mice was twice that of islets from db/m mice. The islets treated with Ad-siAT1R showed significantly decreased AT1R mRNA and protein levels and significantly increased expression of GLUT-2 (by 190%) and GCK (by 121%) compared to those treated with Ad-siControl (P<0.05). In response to stimulation with 16.7 mmol/L glucose, the first-phase insulin secretion was impaired in both Ad-siControl group and mock infected group with the peak insulin levels only 1.8 times of the basal level; the first-phase insulin secretion was markedly improved in islets treated with Ad-siAT1R, with a peak insulin level reaching 2.8 times of the basal level. CONCLUSIONS: In isolated islets of db/db mice, selective AT1R inhibition can restore the first phase insulin secretion by up-regulating GLUT-2 and GCK, which may be one of the potential mechanisms by which AT1R blockers improve insulin secretion function. PMID- 26018261 TI - [beta-arrestin1 promotes chronic myeloid leukemia cell proliferation by activating JNK signaling pathway]. AB - OBJECTIVE: To investigate the signaling pathways involved in beta-arrestin1 induced proliferation of K562 cells. METHODS: We established stable cell lines K562-sibeta1 and K562-beta1 by lentivirus-mediated beta-arrestin1 knock-down or overexpression in K562 cells, with cells transfected with non-specific siRNA as the control (K562-Ctrl). The proliferation of these cells were evaluated by cell counting and CCK-8 assays. Western blotting was used to detect the expression of JNK and p-JNK in the cells, and co-immunoprecipitation (Co-IP) assay was employed to investigate the interaction between beta-arrestin1 and Src. RESULTS: K562 beta1 cells showed significantly greater but K562-sibeta1 cells had significantly lower proliferation ability and cell survival rate than K562-Ctrl cells. Western blotting showed that beta-arrestin1 specifically enhanced the expression of p JNK, and the JNK inhibitor SP600125 obviously suppressed p-JNK and cell proliferation of K562 cells. Co-IP assay revealed the binding of beta-arrestin1 to Src. CONCLUSIONS: In K562 cells, beta-arrestin1 activates JNK signaling pathway by binding to Src to promote the cell proliferation. PMID- 26018262 TI - [Changes in HBsAg titer and HBV DNA load and their correlation in patients with chronic hepatitis B and HBV-related liver cirrhosis]. AB - OBJECTIVE: To explore the changes in HBsAg titer and HBV DNA load and their correlation in patients with chronic hepatitis B (CHB) and HBV-related liver cirrhosis (HBV-LC). METHODS: Forty-six patients with mild to moderate CHB (CHB LM), 24 patients with severe CHB (CHB-S), and 28 patients with HBV-LC at admission, and 51 patients with HBV-LC at 4.08 +/- 3.06 months during antiviral treatment were tested for serum HBsAg titer and HBV DNA load using Abbott chemiluminescence and fluorescence quantitative PCR, respectively. RESULTS: The serum HBsAg titer and HBV DNA load gradually decreased with increased disease severity (from CHB-LM, CHB-S to HBV-LC; chi(2)=12.537 and 8.381, respectively, P<0.05). HBsAg titer and HBV DNA load were significantly higher in CHB-LM and CHB S groups than in HBV-LC group (P<0.05), but comparable between CHB-LM and CHB-S groups (Z=-0.649 and 0.032, respectively, P>0.05). Among HBeAg-positive patients, HBsAg titer and HBV DNA load tended to decrease with increased disease severity (from CHB-LM, CHB-S to HBV-LC; chi(2)=6.146, P=0.046 and chi(2)=1.017, P>0.05; respectively), and CHB-LM group had significantly higher HBsAg titer than HBV-LC group (Z=-2.247, P=0.025). Among the HBeAg-negative patients, serum HBsAg and HBV DNA load gradually declined with the disease severity (chi(2)=8.660 and 13.581, respectively, P<0.05), and were obviously higher in CHB-LM and CHB-S groups than in HBV-LC group (P<0.05). Positive correlations were found between serum HBsAg and HBV DNA levels in CHB-LM (r=0.389, P=0.009) and HBV-LC groups (r=0.431, P=0.022), but not in CHB-S group (r=0.348, P=0.104). After antiviral therapy, the serum HBsAg titer was slightly decreased (Z=-1.050, P=0.294) while HBV DNA load markedly reduced (Z=-5.415, P<0.001), showing no correlation between them (r=0.241, P=0.111) or between the measurements before and after treatment (r=0.257, P=0.085). CONCLUSION: Serum HBsAg titer and HBV DNA load decreases progressively from CHB-LM to CHB-S and HBV-LC in both HBeAg- positive and negative patients. The serum HBsAg titer is positively correlated with HBV DNA load, but their levels are not consistently parallel. PMID- 26018263 TI - [Effects of chloroquine in reversing multidrug resistance in HNE1/DDP cell line]. AB - OBJECTIVE: To investigate the effect of chloroquine in reversing multidrug resistance (MDR) of HNE1/DDP cell line and explore the mechanism. METHODS: MTT assay was used to detect the cell viability of HNE1 and HNE1/DDP after exposure to different concentrations of DDP (2, 4, 8, 16 and 32 umol/L) and different concentrations of chloroquine (5, 10, 20, 40, and 80 umol/L). q-PCR was used to assess the expression of MDR1 mRNA and Western blotting was employed to detect P glycoprotein (P-gp) expression in HNE1 and HNE1/DDP cells exposed to 5 and 10 umol/L chloroquine. The cell apoptosis rate of HNE1 and HNE1/DDP cells exposed to 10 and 20 umol0.05), but rSO2, SjvO2, and JBP increased significantly in both groups (P<0.01). Compared with those in the middle-aged group, rSO2, SjvO2, and JBP increased significantly and Da-jO2decreased at 2, 3 in the elderly group (P<0.01), but jugular vein blood glucose or lactic acid content showed no significant difference between the two groups (P>0.05). CONCLUSION: Pneumoperitoneum and Trendelenburg position cause more obvious cerebral blood backflow in elderly patients than in middle-aged patients but do not affect cerebral metabolism of oxygen. PMID- 26018269 TI - [High central pulse pressure level is associated with cardiovascular disease in patients receiving maintenance peritoneal dialysis]. AB - OBJECTIVE: To evaluate the association between central pulse pressure level and cardiovascular diseases (CVD) in patients receiving maintenance peritoneal dialysis. METHODS: This cross-sectional study was conducted in 234 patients on maintenance peritoneal dialysis. Central pulse pressure levels were measured using a SphygmoCor analyzer, and cardiovascular diseases were defined as diagnosed ischemic heart disease, heart failure, stroke or peripheral vascular disease. RESULTS: The central pulse pressure levels of patients with CVD were significantly higher than those without CVD (51.7 +/- 22.5 vs 43.7 +/- 17.8 mmHg, P=0.004), while the brachial pulse pressure levels were comparable between the two patient groups. After adjusting for brachial pulse pressure and other relevant risk factors, central pulse pressure level was found to independently associate with CVD (adjusted OR=1.33, 95% CI 1.01-1.73, P=0.04 ). CONCLUSION: High central pulse pressure level may serve as a risk factor for CVD in patients on maintenance peritoneal dialysis. PMID- 26018270 TI - [Detection of serum antibodies against Japanese encephalitis virus in bats in Hainan and Guangdong Provinces of China]. AB - OBJECTIVE: To investigate the prevalence of serum antibodies against Japanese encephalitis virus (JEV) in bats. METHODS: Blood samples from the heart were obtained from bats captured in Guangdong and Hainan Provinces in 2013. The anti JEV antibodies in bat sera were tested using indirect ELISA and virus neutralization test. RESULTS: A total of 201 bat serum samples were tested, in which the total positivity rate of anti-JEV antibodies was 46.27% (93/201). The positive rate of anti-JEV antibodies in bats from Hainan and Guangdong Provinces was 88.89% (48/54) and 30.61% (45/147), respectively. All the samples from Rousettus leschenaultia, Miniopterus schreibersii, Pipistrellus abramus, and Rhinolophus macrotis were positive for anti-JEV antibodies, and up to 95.56% (43/45) of the samples from Miniopterus schreibersii (from Hainan Province) yielded positive results. Of the 28 samples with positive results by indirect ELISA, 15 showed positive results in virus neutralization test (53.57%) with neutralization antibody titers ranging from 1:10 to 1:28.22. CONCLUSION: Bats from different regions and of different species can be naturally infected with JEV and have a high prevalence of anti-JEV antibodies in their sera. The role of bats in the natural cycle of JEV awaits further study. PMID- 26018271 TI - [Effect of capsaicin on intestinal permeation of P-glycoprotein substrate rhodamine 123 and fluorescein sodium in rats]. AB - OBJECTIVE: To investigate the role of capsaicin in regulating permeation of P-gp substrate rhodamine 123 (R123) across the jejunum, ileum and colon membranes of rats. METHODS: The permeability of R123 or fluorescein sodium (CF) across the jejunum, ileum and colon membranes of male SD rats was evaluated using a Ussing chamber. The concentration of R123 or CF in the receptor was determined using fluorospectrophotometry to calculate the apparent permeability coefficient (Papp). RESULTS: Compared with the blank control group, capsaicin increased the permeability of R123 across jejunal membranes in the mucosal-to-serosal (M-S) direction and decreased its permeability in the serosal-to-mucosal (S-M) direction, but produced no obvious effect on R123 transport across the ileum or colon membranes. Capsaicin caused a regional increase in the permeability of CF across the jejunal membranes compared with the control group, but CF transport across the ileum and colon membranes was not affected. CONCLUSION: Capsaicin can affect the transport of R123 and CF across rat jejunal membranes, and this effect is shows an obvious intestine segment-related difference probably because of the different distribution of P-gp or tight junction in the intestines. This finding suggests that capsaicin is a weak P-gp inhibitor and an improver of mucous membrane channels. PMID- 26018272 TI - [Expressions of CDX2 and beta-catenin and their correlation in acute myeloid leukemia]. AB - OBJECTIVE: To investigate the expressions of CDX2 and beta-catenin and their correlation in acute myeloid leukemia (AML). METHODS: Real-time PCR was used to examine the expressions of CDX2 and beta-catenin mRNA in 92 de novo AML and 30 non-malignant patients (control), and Western blot was employed to detect CDX2 and beta-catenin protein expressions in 26 de novo AML and 8 non-malignant patients. RESULTS: The positivity rates of CDX2 mRNA and protein expressions in AML group were 84.78% and 76.92%, respectively, but no CDX2 mRNA or protein expression were detected in control group (P<0.01). The expressions of beta catenin mRNA and protein were detected in all the patients in both groups but its expressions in AML group were significantly higher (P<0.01). The expressions of CDX2 and beta-catenin mRNA were significantly correlated with WBC counts and LDH levels (P<0.01). The expression of CDX2 mRNA was not detected and the expression of beta-catenin mRNA was decreased to normal level in AML patients with complete remission, while the expressions of CDX2 and beta-catenin mRNA were increased again in those with disease relapse. There were significantly positive correlations between CDX2 and beta-catenin expressions at both mRNA and protein levels (P<0.01). CONCLUSION: Up-regulation of CDX2 gene and activation of Wnt/beta-catenin pathway co-exist in AML patients and the expressions of CDX2 and beta-catenin are positively correlated. PMID- 26018273 TI - [Changes of telemetry electrical activity in the infralimbic cortex of morphine dependent rats with extinguished drug-seeking behavior]. AB - OBJECTIVE: To investigate the changes of telemetry electrical activity in the infralimbic cortex (IL) of morphine-dependent rats with extinguished drug-seeking behavior. METHODS: SD rats were randomly divided into model group and control group and received operations of brain stereotaxic electrode embedding in the IL. The rats in the model group were induced to acquire morphine dependence and then received subsequent extinction training, and the changes of electrical activity in the IL were recorded with a physical wireless telemetry system. RESULTS: In rats with morphine dependence, the time staying in the white box was significantly longer on days 1 and 2 after withdrawal than that before morphine injection and that of the control rats, but was obviously reduced on days 1 and 2 after extinction training to the control level. Compared with the control group, the morphine-dependent rats on day 2 following withdrawal showed significantly increased beta wave and decreased delta wave when they stayed in the white box but significantly increased delta wave and decreased alpha wave and beta wave when they shuttled from the black to the white box. On day 2 of extinction, the model rats, when staying in the white box, showed significantly decreased theta wave compared with that of the control rats group but decreased beta wave and theta wave and increased delta wave compared with those in the withdrawal period. When they shuttled from black to white box, the model rats showed decreased delta wave and increased alpha wave and beta wave compared with those in the withdrawal period. CONCLUSION: Morphine-dependent rats have abnormal changes of electrical activity in the IL in drug-seeking extinction to affect their drug-seeking motive and inhibit the expression and maintenance of drug-seeking behaviors. PMID- 26018274 TI - [Differential gene expression profiling for identification of potential pathogenic genes and pathways in carotid unstable plaques]. AB - OBJECTIVE: To explore the molecular mechanism in the formation of unstable plaques. METHODS: The cDNA microarray E-MTAB-2055 was downloaded from ArrayExpress database to screen the differentially expressed genes in 24 ruptured plaques against 24 stable plaques. Functional enrichment analysis was conducted to define the biological processes and pathways involved in disease progression. The protein-protein interaction network was constructed to identify the risk modules with close interactions. Five pairs of carotid specimens were used to validate 3 differentially expressed genes of the risk modules by real-time PCR. RESULTS: A total of 439 genes showed differential expression in our analysis, including 232 up-regulated and 207 down-regulated genes according to the data filter criteria. Immune-related biological processes and pathways were greatly enriched. The protein-protein interaction network and module analysis suggested that TYROBP, VCL and CXCR4 might play critical roles in the development of unstable plaques, and differential expressions of CXCR4 and TYROBP in carotid plaques were confirmed by real-time PCR. CONCLUSION: Our study shows the differential gene expression profile, potential biological processes and signaling pathways involved in the process of plaque rupture. TYROBP may be a new candidate disease gene in the pathogenesis of unstable plaques. PMID- 26018275 TI - [Clinical significance of plasma miR-24 dysregulation in nasopharyngeal carcinoma]. AB - OBJECTIVE: To examine the expression level of miR-24 in the plasma of nasopharyngeal carcinoma (NPC) patients and investigate the clinical significance of miR-24 in NPC development. METHODS: Blood samples were from 217 NPC patients admitted in our Department between December, 2007 and June, 2011, with those from 73 patients with chronic purulent otitis media or chronic sinusitis as control. The follow-up data of all the patients were reviewed and the expression of miR-24 in the plasma was examined by qRT-PCR. The correlation of miR-24 expression with clinical staging of NPC was analyzed, and miR-24 levels before and after the treatment were compared. RESULTS: Compared with the control group, the NPC patients showed significantly up-regulated level of miR-24 in the plasma (P<0.001). Plasma miR-24 level differed significantly among patients with different T stages (P=0.007) and was negatively correlated with the N stages (P=0.028) and plasma EBV-DNA (P=0.048). The expression levels of miR-24 were significantly reduced after treatment in the NPC patients and were significantly lowered in patients without relapse or metastasis (P=0.001). CONCLUSION: Plasma miR-24 may serve as a novel molecular biomarker for early diagnosis and prognosis of NPC. PMID- 26018276 TI - [Compound K suppresses myeloid-derived suppressor cells in a mouse model bearing CT26 colorectal cancer xenograft]. AB - OBJECTIVE: To investigate the effect of ginseng-derived compound K (C-K) on apoptosis, immunosuppressive activity, and pro-inflammatory cytokine production of myeloid-derived suppressor cells (MDSCs) from mice bearing colorectal cancer xenograft. METHODS: Flow-sorted bone marrow MDSCs from Balb/c mice bearing CT26 tumor xenograft were treated with either C-K or PBS for 96 h and examined for apoptosis with Annexin V/7-AAD, Cox-2 and Arg-1 expressions using qRT-PCR, and supernatant IL-1beta, IL-6, and IL-17 levels with ELISA. C-K- or PBS-treated MDSCs were subcutaneously implanted along with CT26 tumor cells in WT Balb/c mice, and the tumor size and morphology were evaluated 21 days later. RESULTS: C K treatment significantly increased the percentages of early and late apoptotic MDSCs in vitro (P<0.01 and P<0.05, respectively), decreased the expressions of immunosuppression-related genes Cox-2 (P<0.05) and Arg-1 (P<0.01), and suppressed the production of IL-1beta (P<0.05), IL-6 (P<0.01), and IL-17 (P<0.05) by the MDSCs . Compared with PBS-pre-treated cells, C-K-pretreated MDSCs showed significantly attenuated activity in promoting CT26 tumor growth in mice (P<0.01). CONCLUSION: C-K can suppress the immunosuppresive effect of MDSCs to inhibit tumor cell proliferation in mice, which suggests a new strategy of tumor therapy by targeting MDSCs. PMID- 26018277 TI - [Therapeutic effects of crizotinib in EML4-ALK-positive patients with non-small cell lung cancer]. AB - OBJEVTIVE: To evaluate the therapeutic effects of different therapeutic regimens for non-small-cell lung cancer (NSCLC) with or without EML4-ALK rearrangement. METHODS: Twenty-one ALK-positive and 50 ALK-negative NSCLC patients who received voluntarily EML4-ALK testing and 75 NSCLC patients without AL testing were enrolled in this study. The 3 groups of patients received different treatments, and the therapeutic effects, progression-free survival (PFS), and treatment related adverse events were analyzed. RESULTS: Crizotinib treatment obviously prolonged the PFS in EML4-ALK-positive patients with an objective response rate (OOR) of 61.9% and a median response duration of 16 months, which were significantly better than those in with ALK-negative patients and patients without ALK testing who received different second-line therapies. CONCLUSION: Crizotinib is superior to platinum-based chemotherapy in NSCLC patients with ALK rearrangement. ALK rearrangement id not a modifier of the effect of chemotherapy regimens in NSCLC patients. PMID- 26018278 TI - [Effects of different concentrations of putrescine on proliferation, migration and apoptosis of human skin fibroblasts]. AB - OBJECTIVE: To explore the effects of different concentrations of putrescine on the proliferation, migration and apoptosis of human skin fibroblasts (HSF). METHODS: HSF cultured in the presence of 0.5, 1.0, 5.0, 10, 50, 100, 500, and 1000 ug/ putrescine for 24 h were examined for the changes in the cell proliferation, migration, and apoptosis using MTS assay, Transwell migration assay, and flow cytometry, respectively. RESULTS: Compared with the control cells, HSF cultured with 0.5, 1.0, 5.0, and 10 ug/ putrescine showed significantly increased cell proliferation (P<0.01), and the effect was the most obvious with 1 ug/ putrescine, whereas 500 and 1000 ug/ putrescine significantly reduced the cell proliferation (P<0.01); 50 and 100 ug/ did not obviously affect the cell proliferation (P>0.05). Putrescine at 1 ug/ most significantly enhanced the cell migration (P<0.01), while at higher doses (50, 100, 500, and 1000 ug/) putrescine significantly suppressed the cell migration (P<0.05); 0.5, 5.0, and 10 ug/ putrescine produced no obvious effects on the cell migration (P>0.05). HSF treated with 0.5, 1.0, 5.0, and 10 ug/ putrescine obvious lowered the cell apoptosis rate compared with the control group (P<0.01), and the cell apoptosis rate was the lowest in cells treated with 1 ug/ putrescine; but at the concentrations of 100, 500, and 1000 ug/, putrescine significantly increased the cell apoptosis rate (P<0.01), while 50 ug/ml putrescine produced no obvious effect on cell apoptosis (P>0.05). CONCLUSION: Low concentrations of putrescine can obviously enhance the proliferation ability and maintain normal migration ability of HSF in vitro, but at high concentrations, putrescine can obviously inhibit the cell migration and proliferation and induce cells apoptosis, suggesting the different roles of different concentrations of putrescine in wound healing. PMID- 26018279 TI - [Urinary metabolomics study of renal cell carcinoma based on gas chromatography mass spectrometry]. AB - OBJECTIVE: To identify the biomarkers of renal cell cancer (RCC) through urine metabolic analysis. METHODS: Urine samples of 27 RCC patients, 26 patients with other urinary cancers and 26 healthy volunteers were examined with gas chromatography-mass spectrometry (GC-MS). SIMCA-P+12.0.1.0 software was used for principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) to screen for the differential metabolites. RESULTS: PCA (R2X=0.846, Q2=0.575) and OPLS-DA (R2X=0.736, R2Y=0.974, Q2Y=0.897) model were established for the RCC patients and control subjects. Fourteen metabolites were selected as the characteristic metabolites, including pentanoic acid, malonic acid, glutaric acid, adipic acid, amino quinoline, quinoline, indole acetic acid, and tryptophan, whose levels in the urine were significantly higher in the RCC patients than in the normal subjects (P<0.01); the RCC patients showed significantly higher urine contents of pentanoic acid, phenylalanine, and 6-methoxy-nitro quinoline than those with other urinary tumors (P<0.01). CONCLUSION: The urine metabolites identified based on GC-MS analysis can distinguish RCC patients from patients with other urinary cancers and healthy subjects, suggesting their potential as diagnostic markers for RCC. PMID- 26018280 TI - [Role of CTHRC1 in proliferation, migration and invasion of human colorectal cancer cells]. AB - OBJECTIVE: To explore the expression of collagen triple helix repeat containing 1 (CTHRC1) in colorectal cancer and study its role in regulating the biological behaviors of colorectal cancer LoVo cells in vitro. METHODS: Real-time PCR and Western blotting were used to detect the expressions of CTHRC1 in colorectal cancer tissue and paired adjacent nontumorous tissue and in 5 colorectal cancer cells. pGPU6-CTHRC1-shRNA was transfected into LoVo cells and the changes in cell proliferation was assessed using cell counting kit-8 (CCK8) assay; the changes in cell migration and invasion were investigated using Transwell assay; plate colony forming test was used to evaluate the adhesion and colony forming activity of the cells. Western blotting was used to analyze the changes in the expressions of the related pathway markers. RESULTS: The relative expression of CTHRC1 mRNA in the cancer tissue specimens was 0.0411?0.054, significantly higher than that in the adjacent tissues (P=0.016); this result was consistent with that of the protein assay. SW620 and LoVo cells showed obviously higher expressions of CTHRC1 than HT29 and SW480 cells at both mRNA and protein levels. LoVo cells transfected with CTHRC1 shRNA exhibited significantly suppressed proliferation, migration, invasion and colony-forming ability (P<0.05) and lowered expression of phosphorylated ERK1/2 (P-ERK1/2), but the expression of total ERK1/2 showed no obvious changes. CTHRC1 inhibition caused reverse epithelial-mesenchymal transition LoVo cells shown by increased E-cadherin expression and decreased expressions of N-cadherin, vimentin, and beta-catenin. CONCLUSION: CTHRC1 is up regulated in colorectal cancer tissues and SW620 and LoVo cells to promote the cell proliferation, migration, invasion and colony formation. CTHRC1 can enhance epithelial-mesenchymal transition of colorectal cancer cells by activating ERK1/2 to promote tumor cell metastasis and invasion. PMID- 26018281 TI - [Association of dietary habits with gestational diabetes mellitus among Cantonese women]. AB - OBJECTIVE: To evaluate the relationship between dietary habits and the risk of gestational diabetes mellitus (GDM) in Cantonese women. METHDS: This a cross sectional study included 571 pregnant women who underwent a 75-g oral glucose challenge test at the 24th to 28th gestational week. Food frequency questionnaire (FFQ) was used by three dieticians to evaluate all the subjects' dietary habits. RESULTS: 13% of the investigated subjects were identified to have GDM (GDM+). No significant differences were found between the GDM+ and GDM- groups in the intake of energy, macronutrients, fibers, or cholesterol. The amount of low- and middle GI fruits consumed daily in the two groups was not statistically different, but the GDM+ subjects reported a significantly greater amount of high-GI fruit intake as well as energy-dense foods than the GDM- subjects (P<0.05). Multiple logistic regression analysis revealed that increased consumption of energy-dense snack foods and high glycemic-index fruits were strongly associated with the risk of GDM. CONCLUSION: Local dietary composition (high-GI fruit and energy-dense foods) is closely related to the risk of GDM in Cantonese women, for whom intensive health education of dietary behavior is needed to control GDM. PMID- 26018282 TI - Nutrient loads of small-scale swine manure composting to groundwater and its prevention by covering: a case study. AB - Small-scale composting is applied to recycle manure and biomass around the globe. Piles frequently site outside near field where bio-waste comes or compost goes within developing rural regions. However, little equipment or policy besides cover of common materials addressed concerns about its exposure to rainfall and subsequent leachate towards groundwater. In addition, little is known about its nutrient load to groundwater and covers' effect on nutrient unloading. Differently covered swine manure piles were composted outdoors with exposure to rain, then columns consisted of resultant compost of varying maturing age and soil were leached by simulated rainfall. Leachate TN, NH4 (+)-N, NO3 (-)-N, TP, and DP were modeled by regression analysis, and further, integral of quadratic curve or nutrient load index (NLI) was designated as proxy for nutrient load. Log response ratio was employed to qualify covers' effect on nutrient unloading. This case raised higher concern about leachate NH4 (+)-N than NO3 (-)-N for former's lower category in groundwater quality standard. The integrated NLIs or general nutrient load for six intervals, averagely divided from composting day of 60-120, decreased by 31, 37, 45, 56, and 73 % consecutively. Covers could unload nutrient to underground and function better to prevent P than N from leaching. Capabilities of piles covered by rice straw (CR) and soil (CS) to unload respectively are 77 and 72 % of by film (CF). PMID- 26018283 TI - Effects of permissible maximum-contamination levels of VOC mixture in water on total DNA, antioxidant gene expression, and sequences of ribosomal DNA of Drosophila melanogaster. AB - In this study, we aimed to investigate the mutagenic and carcinogenic potential of a volatile organic compound (VOC) mixture with references to the response of D.melanogaster using selected antioxidant gene expressions, RAPD assay and base pair change of ribosomal 18S, and the internal transcribed spacer, ITS2 rDNA gene sequences. For this purpose, Drosophila melanogaster Oregon R, reared under controlled conditions on artificial diets, were treated with the mixture of thirteen VOCs, which are commonly found in water in concentrations of 10, 20, 50, and 75 ppb for 1 and 5 days. In the random amplified polymorphic DNA (RAPD) assay, band changes were clearly detected, especially at the 50 and 75 ppb exposure levels, for both treatment periods, and the band profiles exhibited clear differences between the treated and untreated flies with changes in band intensity and the loss/appearance of bands. Quantitative real-time PCR (qRT-PCR) analysis of Mn-superoxide dismutase (Mn-SOD), catalase (CAT) and glutathione synthetase (GS) expressions demonstrated that these markers responded significantly to VOC-induced oxidative stress. Whilst CAT gene expressions increased linearly with increasing concentrations of VOCs and treatment times, the 50- and 75-ppb treatments caused decreases in GS expressions compared to the control at 5 days. Treatment with VOCs at both exposure times, especially in high doses, caused gene mutation of the 18S and the ITS2 ribosomal DNA. According to this research, we thought that the permissible maximum-contamination level of VOCs can cause genotoxic effect especially when mixed. PMID- 26018284 TI - Using live algae at the anode of a microbial fuel cell to generate electricity. AB - Live green microalgae Chlorella pyrenoidosa was introduced in the anode of a microbial fuel cell (MFC) to act as an electron donor. By controlling the oxygen content, light intensity, and algal cell density at the anode, microalgae would generate electricity without requiring externally added substrates. Two models of algal microbial fuel cells (MFCs) were constructed with graphite/carbon electrodes and no mediator. Model 1 algal MFC has live microalgae grown at the anode and potassium ferricyanide at the cathode, while model 2 algal MFC had live microalgae in both the anode and cathode in different growth conditions. Results indicated that a higher current produced in model 1 algal MFC was obtained at low light intensity of 2500 lx and algal cell density of 5 * 10(6) cells/ml, in which high algal density would limit the electricity generation, probably by increasing oxygen level and mass transfer problem. The maximum power density per unit anode volume obtained in model 1 algal MFC was relatively high at 6030 mW/m(2), while the maximum power density at 30.15 mW/m(2) was comparable with that of previous reported bacteria-driven MFC with graphite/carbon electrodes. A much smaller power density at 2.5 mW/m(2) was observed in model 2 algal MFC. Increasing the algal cell permeability by 4-nitroaniline would increase the open circuit voltage, while the mitochondrial acting and proton leak promoting agents resveratrol and 2,4-dinitrophenol would increase the electric current production in algal MFC. PMID- 26018285 TI - Urinary heavy metals, phthalates, phenols, thiocyanate, parabens, pesticides, polyaromatic hydrocarbons but not arsenic or polyfluorinated compounds are associated with adult oral health: USA NHANES, 2011-2012. AB - Links between environmental chemicals and human health have emerged over the last few decades, but the effects on oral health have been less studied. Therefore, it was aimed to study the relationships of different sets of urinary chemical concentrations and adult oral health conditions in a national and population based setting. Data was retrieved from the United States National Health and Nutrition Examination Surveys, 2011-2012 including demographics, self-reported oral health conditions and urinary environmental chemical concentrations (one third representative sample of the study population). Chi-square test, t test, and survey-weighted logistic and multi-nominal regression modeling were performed. Of 4566 American adults aged 30-80, 541 adults (11.9 %) reported poor teeth health while 1020 adults (22.4 %) reported fair teeth. Eight hundred fifty five people (19.1 %) claimed to have gum disease, presented with higher levels of urinary cadmium, cobalt and polyaromatic hydrocarbons. Six hundred three adults (13.3 %) had bone loss around the mouth, presented with higher levels of cadmium, nitrate, thiocyanate, propyl paraben and polyaromatic hydrocarbons. Eight hundred forty-five adults (18.5 %) had tooth loose not due to injury, presented with higher level of cadmium, thiocyanate and polyaromatic hydrocarbons. Eight hundred forty-five adults (18.5 %) with higher levels of lead, uranium, polyaromatic hydrocarbons but lower level of triclosan noticed their teeth did not look right. Three hundred fifty-one adults (7.7 %) often had aching in the mouth and 650 (14.3 %) had it occasionally, presented with higher levels of phthalates, pesticides and polyaromatic hydrocarbons. Benzophenone-3 and triclosan elicited protective effects. Regulation of environmental chemicals in prevention of adult oral health might need to be considered in future health and environmental policies. PMID- 26018286 TI - Linking groundwater pollution to the decay of 15th-century sculptures in Burgos Cathedral (northern Spain). AB - Precipitation of salts-mainly hydrated Mg-Na sulfates-in building materials is rated as one of the most severe threats to the preservation of our architectural and cultural heritage. Nevertheless, the origin of this pathology is still unknown in many cases. Proper identification of the cause of damage is crucial for correct planning of future restoration actions. The goal of this study is to identify the source of the degradation compounds that are affecting the 15th century limestone sculptures that decorate the retro-choir of Burgos Cathedral (northern Spain). To this end, detailed characterization of minerals by in situ (Raman spectroscopy) and laboratory techniques (XRD, Raman and FTIR) was followed by major elements (ICP and IC) and isotopic analysis (delta(34)S and delta(15)N) of both the mineral phases precipitated on the retro-choir and the dissolved salts in groundwater in the vicinity of the cathedral. The results reveal unequivocal connection between the damage observed and capillary rise of salts bearing water from the subsoil. The multianalytical methodology used is widely applicable to identify the origin of common affections suffered by historical buildings and masterpieces. PMID- 26018287 TI - Improving of understanding of beta-hexachlorocyclohexane (HCH) adsorption on activated carbons by temperature-programmed desorption studies. AB - In order to understand the interactions between beta-hexachlorocyclohexane (HCH) and chemical groups at activated carbon (AC) surface, the solid samples were hydrogenated aiming to decrease the amounts of oxygenated groups. Two AC samples designated by BagH2O and BagP1.5 were prepared by water vapor activation and phosphoric acid activation, respectively, of sugarcane bagasse used as an AC precursor. A more simple molecule 1,2,3-trichloropropane (TCP) is used as a model of chlorinated compound. The AC were characterized by infrared, X-ray photoelectron spectroscopy (XPS), Raman resonance spectroscopies, as well as temperature-programmed desorption coupled with mass spectrometry (TPD-MS). BagP1.5 and BagH2O AC surface contained oxygenated groups. Upon hydrogenation, a decrease of most of these group amxounts was observed for both samples, while hydroxyl groups increased. On the basis of temperature-programmed desorption data obtained for AC samples contaminated with TCP or HCH, it was possible to determine the type of hydrogen bond formed between each AC and HCH. PMID- 26018288 TI - Possibility of biological control of primocane fruiting raspberry disease caused by Fusarium sambucinum. AB - Biological control agents are a promising alternative to chemical pesticides for plant disease suppression. The main advantage of the natural biocontrol agents, such as antagonistic bacteria compared with chemicals, includes environmental pollution prevention and a decrease of chemical residues in fruits. This study is aimed to evaluate the impact of three Bacillus strains on disease of primocane fruiting raspberry canes caused by Fusarium sambucinum under controlled infection load and uncontrolled environmental factors. Bacillus subtilis, Bacillus licheniformis, and Bacillus amyloliquefaciens were used for biocontrol of plant disease in 2013 and 2014 which differed by environmental conditions. The test suspensions were 10(5) CFU/ml for each bacterial strain. To estimate the effect of biological agents on Fusarium disease, canes were cut at the end of vegetation, and the area of outer and internal lesions was measured. In addition to antagonistic effect, the strains revealed the ability to induce plant resistance comparable with chitosan-based formulation. Under variable ways of cane treatment by bacterial strains, the more effective were B. subtilis and B. licheniformis demonstrating dual biocontrol effect. However, environmental factors were shown to impact the strain biocontrol ability; changes in air temperature and humidity led to the enhanced activity of B. amyloliquefaciens. For the first time, the possibility of replacing chemicals with environmentally benign biological agents for ecologically safe control of the raspberry primocane fruiting disease was shown. PMID- 26018289 TI - Causal relationship between CO2 emissions, real GDP, energy consumption, financial development, trade openness, and urbanization in Tunisia. AB - The aim of this paper is to examine the causal relationship between CO2 emissions, real GDP, energy consumption, financial development, trade openness, and urbanization in Tunisia over the period of 1971-2012. The long-run relationship is investigated by the auto-regressive distributed lag (ARDL) bounds testing approach to cointegration and error correction method (ECM). The results of the analysis reveal a positive sign for the coefficient of financial development, suggesting that the financial development in Tunisia has taken place at the expense of environmental pollution. The Tunisian case also shows a positive monotonic relationship between real GDP and CO2 emissions. This means that the results do not support the validity of environmental Kuznets curve (EKC) hypothesis. In addition, the paper explores causal relationship between the variables by using Granger causality models and it concludes that financial development plays a vital role in the Tunisian economy. PMID- 26018290 TI - Investigating the degradation process of kraft lignin by beta-proteobacterium, Pandoraea sp. ISTKB. AB - The present study investigates the kraft lignin (KL) degrading potential of novel alkalotolerant Pandoraea sp. ISTKB utilizing KL as sole carbon source. The results displayed 50.2 % reduction in chemical oxygen demand (COD) and 41.1 % decolorization after bacterial treatment. The maximum lignin peroxidase (LiP) and manganese peroxidase (MnP) activity detected was 2.73 and 4.33 U ml(-1), respectively, on day 3. The maximum extracellular and intracellular laccase activities observed were 1.32 U ml(-1) on day 5 and 4.53 U ml(-1) on day 4, respectively. The decolorization and degradation was maximum on day 2. Further, it registered an increase with the production of extracellular laccase. This unusual trend of decolorization and degradation was studied using various aromatic compounds and dyes. SEM and FTIR results indicated significant change in surface morphology and functional group composition during the course of degradation. Gas chromatography and mass spectroscopy (GC-MS) analysis confirmed KL degradation by emergence of new peaks and the identification of low molecular weight aromatic intermediates in treated sample. The degradation of KL progressed through the generation of phenolic intermediates. The identified intermediates implied the degradation of hydroxyphenyl, ferulic acid, guaiacyl, syringyl, phenylcoumarane, and pinoresinol components commonly found in lignin. The degradation, decolorization, and GC-MS analysis indicated potential application of the isolate Pandoraea sp. ISTKB in treatment of lignin-containing pollutants and KL valorization. PMID- 26018291 TI - Mitochondrial respiratory dysfunctions of blood mononuclear cells link with cardiac disturbance in patients with early-stage heart failure. AB - Patients with cardiometabolic risk factors and asymptomatic cardiac hypertrophy are hallmarks of early-stage heart failure (HF). We hypothesized that mitochondrial respiratory dysfunctions of peripheral blood mononuclear cells (PBMCs) may be associated with inflammation and oxidative stress in early-stage HF patients complicated with cardiometabolic risk factors. Totally 49 subjects were enrolled with 25 early-stage HF patients (stages A and B) having cardiac hypertrophy and dysfunction and 24 healthy controls. It showed that excessive inflammation and reduced antioxidant capacity were closely associated with cardiac abnormalities in early-stage HF patients. Furthermore, the values of mitochondrial respiratory functional parameters R, CIOXPHOS, CIIOXPHOS, CI+IIOXPHOS, CI+IIETS and CIIETS were significantly lowered in early-stage HF patients. Interestingly, these respiratory parameters were correlated with inflammation and antioxidant capacity in participants. Finally, cardiometabolic risk factors such as salt intake and blood pressure were related to the mitochondrial respiratory dysfunctions, which were further validated by in vitro experiments. Our study indicated that cardiometabolic risk factor-mediated mitochondrial respiratory dysfunctions of PBMCs link with the cellular inflammation / oxidative stress and cardiac disturbance in early-stage HF. PMID- 26018292 TI - Cost of Chronic and Episodic Migraine. A pilot study from a tertiary headache centre in northern Italy. AB - BACKGROUND: Chronic migraine (CM) has a high impact on functional performance and quality of life (QoL). CM also has a relevant burden on the National Health Service (NHS), however precise figures are lacking. In this pilot study we compared the impact in terms of costs of CM and episodic migraine (EM) on the individual and on the National Health System (NHS). Furthermore, we comparatively evaluated the impact of CM and EM on functional capability and on QoL of sufferers. METHODS: We enrolled 92 consecutive patients attending the Pavia headache centre: 51 subjects with CM and 41 with episodic migraine (EM). Patients were tested with disability scales (MIDAS, HIT-6, SF-36) and with an ad hoc semi structured questionnaire. RESULTS: The direct mean annual cost (in euro) per patient suffering from CM was ?2250.0 +/- 1796.1, against ?523.6 +/- 825.8 per patient with EM. The cost loaded on NHS was ?2110.4 +/- 1756.9 for CM, ?468.3 +/- 801.8 for EM. The total economic load and the different sub-items were significantly different between groups (CM vs. EM p = 0.001 for each value). CM subjects had higher scores than EM for MIDAS (98.4 +/- 72,3 vs 15.5 +/- 17.7, p = 0.001) and for HIT-6 (66.1 +/- 8.4 vs 58.7 +/- 10.1, p = 0.001). The SF-36 score was 39.9 +/- 14,74 for CM and 66.2 +/- 18.2 for EM (p = 0.001). CONCLUSIONS: CM is a disabling condition with a huge impact on the QoL of sufferers and a significant economic impact on the NHS. The adequate management of CM, reverting it back to EM, will provide a dual benefit: on the individual and on the society. PMID- 26018293 TI - Patients with migraine are right about their perception of temperature as a trigger: time series analysis of headache diary data. AB - BACKGROUND: Researches to date on the association between headache and weather have yielded inconsistent results. Only a limited number of studies have examined the clinical significance of self-reported weather sensitivity. This study aimed to identify the difference in the association of headache with temperature between migraine patients with and without temperature sensitivity. METHODS: 66 migraine patients (75.8 % female; mean age 43.3 +/- 12.9 years) provided their 1 year headache diaries from 2007 to a headache clinic in Taipei, Taiwan. 34 patients (51.5 %) reported sensitivity to temperature change but 32 (48.5 %) did not. Time series of daily headache incidence was modeled and stratified by temperature sensitivity. Empirical mode decomposition was used to identify temporal weather patterns that were correlated to headache incidence, and regression analysis was used to examine the amount of variance in headache incidence that could be explained by temperature in different seasons. RESULTS: Among all migraine patients, temperature change accounted for 16.5 % of variance in headache incidence in winter and 9.6 % in summer. In winter, the explained variance increased to 29.2 % among patients with temperature sensitivity, but was not significant among those without temperature sensitivity. Overall, temperature change explained 27.0 % of the variance of the mild headache incidence but only 4.8 % of the incidence of moderate to severe headache during winter. CONCLUSIONS: This diary-based study provides evidence to link the perception of temperature sensitivity and headache incidence in migraine patients. Those who reported temperature sensitivity are more likely to have headache increase during the winter, particular for mild headaches. PMID- 26018294 TI - Simultaneous localization and calibration for electromagnetic tracking systems. AB - BACKGROUND: In clinical environments, field distortion can cause significant electromagnetic tracking errors. Therefore, dynamic calibration of electromagnetic tracking systems is essential to compensate for measurement errors. METHODS: It is proposed to integrate the motion model of the tracked instrument with redundant EM sensor observations and to apply a simultaneous localization and mapping algorithm in order to accurately estimate the pose of the instrument and create a map of the field distortion in real-time. Experiments were conducted in the presence of ferromagnetic and electrically-conductive field distorting objects and results compared with those of a conventional sensor fusion approach. RESULTS: The proposed method reduced the tracking error from 3.94+/-1.61 mm to 1.82+/-0.62 mm in the presence of steel, and from 0.31+/-0.22 mm to 0.11+/-0.14 mm in the presence of aluminum. CONCLUSIONS: With reduced tracking error and independence from external tracking devices or pre-operative calibrations, the approach is promising for reliable EM navigation in various clinical procedures. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26018296 TI - Male-specific coliphages for source tracking fecal contamination in surface waters and prevalence of Shiga-toxigenic Escherichia coli in a major produce production region of the Central Coast of California. AB - To provide data for traditional trace-back studies from fork to farm, it is necessary to determine the environmental sources for Shiga-toxigenic Escherichia coli. We developed SYBR green based reverse-transcriptase PCR methods to determine the prevalence of F+ RNA coliphages (FRNA) as indicators of fecal contamination. Male-specific coliphages, determined using a single-agar overlay method, were prevalent in all surface waters sampled for 8 months. F+ DNA coliphages (FDNA) were predominant compared to FRNA in water samples from majority of sampling locations. Most (90%) of the FRNA were sourced to humans and originated from human-impacted sites. Members of genogroup III represented 77% of FRNA originated from human sources. Furthermore, 93% of FRNA sourced to animals were also detected in water samples from human-impacted sites. Eighty percent of all FRNA were isolated during the winter months indicating seasonality in prevalence. In contrast, FDNA were more prevalent during summer months. E. coli O157:H7 and Shiga-toxigenic E. coli were detected in water samples from locations predominantly influenced by agriculture. Owing to their scarcity, their numbers could not be correlated with the prevalence of FRNA or FDNA in water samples. Both coliform bacteria and generic E. coli from agricultural or human-impacted sites were similar in numbers and thus could not be used to determine the sources of fecal contamination. Data on the prevalence of male-specific coliphages may be invaluable for predicting the sources of fecal contamination and aid in developing methods to prevent enteric pathogen contamination from likely sources during produce production. PMID- 26018295 TI - The genetic prehistory of domesticated cattle from their origin to the spread across Europe. AB - BACKGROUND: Cattle domestication started in the 9(th) millennium BC in Southwest Asia. Domesticated cattle were then introduced into Europe during the Neolithic transition. However, the scarcity of palaeogenetic data from the first European domesticated cattle still inhibits the accurate reconstruction of their early demography. In this study, mitochondrial DNA from 193 ancient and 597 modern domesticated cattle (Bos taurus) from sites across Europe, Western Anatolia and Iran were analysed to provide insight into the Neolithic dispersal process and the role of the local European aurochs population during cattle domestication. RESULTS: Using descriptive summary statistics and serial coalescent simulations paired with approximate Bayesian computation we find: (i) decreasing genetic diversity in a southeast to northwest direction, (ii) strong correlation of genetic and geographical distances, iii) an estimated effective size of the Near Eastern female founder population of 81, iv) that the expansion of cattle from the Near East and Anatolia into Europe does not appear to constitute a significant bottleneck, and that v) there is evidence for gene-flow between the Near Eastern/Anatolian and European cattle populations in the early phases of the European Neolithic, but that it is restricted after 5,000 BCE. CONCLUSIONS: The most plausible scenario to explain these results is a single and regionally restricted domestication process of cattle in the Near East with subsequent migration into Europe during the Neolithic transition without significant maternal interbreeding with the endogenous wild stock. Evidence for gene-flow between cattle populations from Southwestern Asia and Europe during the earlier phases of the European Neolithic points towards intercontinental trade connections between Neolithic farmers. PMID- 26018297 TI - An important impact of the molecule-electrode coupling asymmetry on the efficiency of bias-driven redox processes in molecular junctions. AB - Two recent experimental and theoretical studies (Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 1282-1287; Phys. Chem. Chem. Phys., 2014, 16, 25942-25949) have addressed the problem of tuning the molecular charge and vibrational properties of single molecules embedded in nanojunctions. These are molecular characteristics escaping so far from an efficient experimental control in broad ranges. Here, we present a general argument demonstrating why, out of various experimental platforms possible, those wherein active molecules are asymmetrically coupled to electrodes are to be preferred to those symmetrically coupled for achieving a(n almost) complete redox process, and why an electrochemical environment has advantages over "dry" setups. This study aims at helping to nanofabricate molecular junctions using the most appropriate platforms allowing the broadest possible bias-driven control over the redox state and vibrational modes of single molecules linked to electrodes. PMID- 26018298 TI - Fractionation of yeast extract by nanofiltration process to assess key compounds involved in CHO cell culture improvement. AB - Yeast extract (YE) is known to greatly enhance mammalian cell culture performances, but its undefined composition decreases process reliability. Accordingly, in the present study, the nature of YE compounds involved in the improvement of recombinant CHO cell growth and IgG production was investigated. First, the benefits of YE were verified, revealing that it increased maximal concentrations of viable cells and IgG up to 73 and 60%, respectively compared to a reference culture. Then, the analyses of YE composition highlighted the presence of molecules such as amino acids, vitamins, salts, nucleobase, and glucose that were contained in reference medium, while others including peptides, trehalose, polysaccharides, and nucleic acids were not. Consequently, YE was fractionated by a nanofiltration process to deeper evaluate its effects on CHO cell cultures. The YE molecules already contained in reference medium were mainly isolated in the permeate fraction together with trehalose and short peptides, while other molecules were concentrated in the retentate. Permeate, which was free of macromolecules, exhibited a similar positive effect than raw YE on maximal concentrations. Additional studies on cell energetic metabolism underlined that dipeptides and tripeptides in permeate were used as an efficient source of nitrogenous substrates. PMID- 26018299 TI - Direct synthesis of graphene 3D-coated Cu nanosilks network for antioxidant transparent conducting electrode. AB - Transparent conducting film occupies an important position in various optoelectronic devices. To replace the costly tin-doped indium oxide (ITO), promising materials, such as metal nanowires and graphene, have been widely studied. Moreover, a long-pursued goal is to consolidate these two materials together and express their outstanding properties simultaneously. We successfully achieved a direct 3D coating of a graphene layer on an interlacing Cu nanosilks network by the low pressure chemical vapor deposition method. High aspect ratio Cu nanosilks (13 nm diameter with 40 MUm length) were synthesized through the nickel ion catalytic process. Large-size, transparent conducting film was successfully fabricated with Cu nanosilks ink by the imprint method. A magnetic manipulator equipped with a copper capsule was used to produce high Cu vapor pressure on Cu nanosilks and realize the graphene 3D-coating. The coated Cu@graphene nanosilks network achieved high transparency, low sheet resistance (41 Ohm sq(-1) at 95% transmittance) and robust antioxidant ability. With this technique, the transfer process of graphene is no longer needed, and a flexible, uniform and high-performance transparent conducting film could be fabricated in unlimited size. PMID- 26018300 TI - Optical extinction efficiency measurements on fine and accumulation mode aerosol using single particle cavity ring-down spectroscopy. AB - A new experiment is presented for the measurement of single aerosol particle extinction efficiencies, Qext, combining cavity ring-down spectroscopy (CRDS, lambda = 405 nm) with a Bessel beam trap (lambda = 532 nm) in tandem with phase function (PF) measurements. This approach allows direct measurements of the changing optical cross sections of individual aerosol particles over indefinite time-frames facilitating some of the most comprehensive measurements of the optical properties of aerosol particles so far made. Using volatile 1,2,6 hexanetriol droplets, Qext is measured over a continuous radius range with the measured Qext envelope well described by fitted cavity standing wave (CSW) Mie simulations. These fits allow the refractive index at 405 nm to be determined. Measurements are also presented of Qext variation with RH for two hygroscopic aqueous inorganic systems ((NH4)2SO4 and NaNO3). For the PF and the CSW Mie simulations, the refractive index, nlambda, is parameterised in terms of the particle radius. The radius and refractive index at 532 nm are determined from PFs, while the refractive index at 405 nm is determined by comparison of the measured Qext to CSW Mie simulations. The refractive indices determined at the shorter wavelength are larger than at the longer wavelength consistent with the expected dispersion behaviour. The measured values at 405 nm are compared to estimates from volume mixing and molar refraction mixing rules, with the latter giving superior agreement. In addition, the first single-particle Qext measurements for accumulation mode aerosol are presented for droplets with radii as small as ~300 nm. PMID- 26018301 TI - How free of germs is germ-free? Detection of bacterial contamination in a germ free mouse unit. AB - Management of germ free animals has changed little since the beginning of the 20th century. The current upswing in their use, however, has led to interest in improved methods of screening and housing. Traditionally, germ free colonies are screened for bacterial colonization by culture and examination of Gram stained fecal samples, but some investigators have reported using PCR-based methods of microbial detection, presumably because of perceived increased sensitivity. The accuracy and detection limit for traditional compared to PCR-based screening assays are not known. The purpose of this study was to determine the limit of detection of bacterial contamination of mouse feces by aerobic and anaerobic culture, Gram stain, and qPCR, and to compare the accuracy of these tests in the context of a working germ free mouse colony. We found that the limit of detection for qPCR (approximately 10(5) cfu/g of feces) was lower than for Gram stain (approximately 10(9) cfu/g), but that all 3 assays were of similar accuracy. Bacterial culture was the most sensitive, but the least specific, and qPCR was the least sensitive and most specific. Gram stain but not qPCR detected heat killed bacteria, indicating that bacteria in autoclaved diet are unlikely to represent a potential confounding factor for PCR screening. We conclude that as a practical matter, bacterial culture and Gram stain are adequate for screening germ free mouse colonies for bacterial contaminants, but that should low numbers of unculturable bacteria be present, they would not be detected with any of the currently available means. PMID- 26018302 TI - Environment and bone regeneration: how biomaterials, host mediators and even bacterial products can boost bone cells towards better clinical outcomes. PMID- 26018303 TI - Reliability and reproducibility of three-dimensional cephalometric landmarks using CBCT: a systematic review. AB - OBJECTIVE: The aim of this study was to review the reliability and reproducibility of 3D-CBCT (cone beam computed tomography) cephalometric landmark identification. METHODS: Electronic databases (Pubmed, Scopus, Web of Science) were searched for papers published from 1998 to October 2014. Specific strategies were developed for each database, with the guidance of a librarian. Two reviewers independently analyzed the titles and abstracts for inclusion. The articles that met the inclusion and exclusion criteria were selected for full-text reading, and the selected articles went through methodological quality evaluation. After the exclusion of repeated articles, the titles of the remaining ones were read and 1,328 of them were excluded. The abstracts of 173 articles were read, of which 43 were selected, read in full and submitted to the inclusion and exclusion criteria. Fourteen articles or studies with reliable methodology and reproducibility remained. The data were collected, organized into figures and analyzed for determination of the reliability and reproducibility of the three dimensional cephalometric landmarks. RESULTS: Overall, the landmarks on the median sagittal line and dental landmarks had the highest reliability, while the landmarks on the condyle, porion and the orbitale presented lower levels of reliability. Point S must be marked in the multiplanar views associated with visualization in 3D reconstruction. Further studies are necessary for evaluating soft tissue landmarks. PMID- 26018304 TI - Evaluation of protein undernourishment on the condylar process of the Wistar rat mandible correlation with insulin receptor expression. AB - The mandible condylar process cartilage (CP) of Wistar rats is a secondary cartilage and acts as a mandibular growth site. This phenomenon depends on adequate proteins intake and hormone actions, including insulin. OBJECTIVES: The present study evaluated the morphological aspects and the expression of the insulin receptor (IR) in the cartilage of the condylar process (CP) of rats subjected to protein undernourishment. MATERIAL AND METHODS: The nourished group received a 20% casein diet, while the undernourished group (U) received a 5% casein diet. The re-nourished groups, R and RR, were used to assess the effects of re-nutrition during puberty and adulthood, respectively. CPs were processed and stained with picro-sirius red, safranin-O and azocarmine. Scanning electron microscopy and immunohistochemistry were also performed. RESULTS: The area of the CP cartilage and the number of cells in the chondroblastic layer decreased in the U group, as did the thickness of the CP layer in the joint and hypertrophic layer. Renourishment during the pubertal stage, but not during the adult phase, restored these parameters. The cell number was restored when re-nutrition occurred in the pubertal stage, but not in the adult phase. The extracellular matrix also decreased in the U group, but was restored by re-nutrition during the pubertal stage and further increased in the adult phase. IR expression was observed in all CPs, being higher in the chondroblastic and hypertrophic cartilage layers. The lowest expression was found in the U and RR groups. CONCLUSIONS: Protein malnutrition altered the cellularity, the area, and the fibrous cartilage complex, as well as the expression of the IRs. PMID- 26018305 TI - Exposure of periodontal ligament progenitor cells to lipopolysaccharide from Escherichia coli changes osteoblast differentiation pattern. AB - Periodontal ligament mesenchymal stem cells (PDLMSCs) are an important alternative source of adult stem cells and may be applied for periodontal tissue regeneration, neuroregenerative medicine, and heart valve tissue engineering. However, little is known about the impact of bacterial toxins on the biological properties of PDLSMSCs, including self-renewal, differentiation, and synthesis of extracellular matrix. OBJECTIVE: This study investigated whether proliferation, expression of pro-inflammatory cytokines, and osteogenic differentiation of CD105 enriched PDL progenitor cell populations (PDL-CD105(+) cells) would be affected by exposure to bacterial lipopolysaccharide from Escherichia coli (EcLPS). MATERIAL AND METHODS: Toll-like receptor 4 (TLR4) expression was assessed in PDL CD105(+) cells by the immunostaining technique and confirmed using Western blotting assay. Afterwards, these cells were exposed to EcLPS, and the following assays were carried out: (i) cell viability using MTS; (ii) expression of the interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-alpha) genes; (iii) osteoblast differentiation assessed by mineralization in vitro, and by mRNA levels of run-related transcription factor-2 (RUNX2), alkaline phosphatase (ALP) and osteocalcin (OCN) determined by quantitative PCR. RESULTS: PDL-CD105+ cells were identified as positive for TLR4. EcLPS did not affect cell viability, but induced a significant increase of transcripts for IL-6 and IL-8. Under osteogenic condition, PDL-CD105+ cells exposed to EcLPS presented an increase of mineralized matrix deposition and higher RUNX2 and ALP mRNA levels when compared to the control group. CONCLUSIONS: These results provide evidence that CD105-enriched PDL progenitor cells are able to adapt to continuous Escherichia coli endotoxin challenge, leading to an upregulation of osteogenic activities. PMID- 26018306 TI - The effects of frenotomy on breastfeeding. AB - Although the interference of tongue-tie with breastfeeding is a controversial subject, The use of lingual frenotomy has been widely indicated by health professionals. OBJECTIVE: To observe changes in breastfeeding patterns after lingual frenotomy concerning the number of sucks, pause length between groups of sucking and mother's complaints. MATERIAL AND METHODS: Oral yes/no questions about breastfeeding symptoms and sucking/swallowing/breathing coordination were answered by the mothers of 109, 30 day old infants. On the same day the infants had their lingual frenulum assessed by administering a lingual frenulum protocol. After the assessment, all tongue-tied infants were referred for frenotomy; nevertheless, only 14 underwent the surgery. Of the 109 infants, 14 infants who did not have frenulum alterations were included as controls. Birth order and gender were the criteria for recruiting the control group. The tongue-tied infants underwent lingual frenotomy at 45 days of age. At the conclusion of the frenotomy, the infants were breastfed. At 75 days old, both groups--control and post-frenotomy--were reassessed. Before the reassessment the same oral yes/no questions were answered by the mothers of the 14 infants who underwent frenotomy. The mothers of the control group answered the questionnaire only at the time of the first assessment. Data were subjected to statistical analysis. RESULTS: After frenotomy, the number of sucks increased and the pause length between sucking decreased during breastfeeding. The controls maintained the same patterns observed in the first assessment. From the questionnaire answered by the mothers of the 14 tongue-tied infants, at 30 days and 75 days, we observed that the symptoms concerning breastfeeding and sucking/swallowing/breathing coordination were improved after lingual frenotomy. CONCLUSIONS: After lingual frenotomy, changes were observed in the breastfeeding patterns of the the tongue-tied infants while the control group maintained the same patterns. Moreover, all symptoms reported by the mothers of the tongue-tied infants had improved after frenotomy. PMID- 26018307 TI - Antimicrobial and cytotoxic effects of phosphoric acid solution compared to other root canal irrigants. AB - Phosphoric acid has been suggested as an irrigant due to its effectiveness in removing the smear layer. OBJECTIVES: The purpose of this study was to compare the antimicrobial and cytotoxic effects of a 37% phosphoric acid solution to other irrigants commonly used in endodontics. MATERIAL AND METHODS: The substances 37% phosphoric acid, 17% EDTA, 10% citric acid, 2% chlorhexidine (solution and gel), and 5.25% NaOCl were evaluated. The antimicrobial activity was tested against Candida albicans, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Actinomyces meyeri, Parvimonas micra, Porphyromonas gingivalis, and Prevotella nigrescens according to the agar diffusion method. The cytotoxicity of the irrigants was determined by using the MTT assay. RESULTS: Phosphoric acid presented higher antimicrobial activity compared to the other tested irrigants. With regard to the cell viability, this solution showed results similar to those with 5.25% NaOCl and 2% chlorhexidine (gel and solution), whereas 17% EDTA and 10% citric acid showed higher cell viability compared to other irrigants. CONCLUSION: Phosphoric acid demonstrated higher antimicrobial activity and cytotoxicity similar to that of 5.25% NaOCl and 2% chlorhexidine (gel and solution). PMID- 26018309 TI - Expression of epithelial-mesenchymal transition markers at the invasive front of oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is one of the most common malignances. In epithelial-mesenchymal transition (EMT), epithelial cells switch to mesenchymal like cells exhibiting high mobility. This migratory phenotype is significant during tumor invasion and metastasis. OBJECTIVE: The aim of this study is to evaluate the expression of the EMT markers E-cadherin, N-cadherin and vimentin in OSCC. MATERIAL AND METHODS: Immunohistochemical detection of E-cadherin, N cadherin and vimentin was performed on 20 OSCC samples. Differences in the expression of each protein at the invasive front (IF) and in the central/superficial areas (CSA) of the tumor were assessed. Differences in the expression of each protein at the IF of both histologically high- and low invasive OSCCs were evaluated. Associations among expression of proteins at the IF were assessed. Correlations between the expression levels of each protein at the IF and the tumor stage and clinical nodal status were also evaluated. RESULTS: Reduced expression of E-cadherin was detected in 15 samples (75%). E cadherin expression was reduced at the IF when compared to the CSA and in high invasive tumors when compared to low-invasive tumors. All samples were negative for N-cadherin, even though one sample showed an inconspicuous expression. Positive expression of vimentin was observed in 6 samples (30%). Nevertheless, there was no difference in vimentin expression between the IF and the CSA regions or between the low- and high-invasive tumors. Furthermore, no association was observed among protein expression levels at the IF. Finally, no correlations were observed between each protein's expression levels and tumor stage or clinical nodal status. CONCLUSIONS: Reduced E-cadherin expression at the IF and its association with histological invasiveness suggest that this protein is a noteworthy EMT marker in OSCC. Although vimentin was also detected as an EMT marker, its expression was neither limited to the IF nor was it related to histological invasiveness. PMID- 26018308 TI - Comparison of the effects of TripleGates and Gates-Glidden burs on cervical dentin thickness and root canal area by using cone beam computed tomography. AB - The search for new instruments to promote an appropriate cervical preparation has led to the development of new rotary instruments such as TripleGates. However, to the best of the authors' knowledge, there is no study evaluating TripleGates effect on the "risk zone" of mandibular molars. OBJECTIVES: The aim of this study was to evaluate the effects of a crown-down sequence of Gates-Glidden and TripleGates burs on the remaining cervical dentin thickness and the total amount of dentin removed from the root canals during the instrumentation by using cone beam computed tomography. The number of separated instruments was also evaluated. MATERIAL AND METHODS: Mesial roots of 40 mandibular first molars were divided into 2 equal groups: crown-down sequence of Gates-Glidden (#3, #2, #1) and TripleGates burs. Cervical dentin thickness and canal area were measured before and after instrumentation by using cone beam computed tomography and image analysis software. Student's t-test was used to determine significant differences at p < 0.05. RESULTS: No significant differences (p > 0.05) were observed between the instruments, regarding the root canal area and dentin wall thickness. CONCLUSION: Both tested instruments used for cervical preparation were safe to be used in the mesial root canal of mandibular molars. PMID- 26018310 TI - Influence of the magnetic field on microorganisms in the oral cavity. AB - Since the beginning of their lives, all living organisms are exposed to the influence of geomagnetic fields. OBJECTIVES: With respect to the positive effects that magnetic fields have on human tissues, especially the bactericidal effect, this investigation aimed to assess their influence on the reduction of oral microorganisms. MATERIAL AND METHODS: In order to obtain adequate specimens of dental plaque deposit, microbes such as Streptococcus parasanguinis, Staphylococcus epidermidis, Rhodococcus equi and Candida albicans were isolated from the human mouth. To establish the intensity of microbial growth on the basis of the modified optical density (OD) of agar turbidimetry assay, microbial count and spectrophotometry were applied. The study was carried out with two microbial concentrations (1 and 10 CFU/ml) after periods of incubation of 24 and 48 h and using micromagnets. RESULTS: A positive effect of the magnetic field, resulting in the reduction of dental plaque microbes in vitro, was found. In the first 24 hours of exposure to the magnetic field, the number of all isolated microbes was significantly reduced. The most potent influence of magnets and the most intensified reduction after 24 hours were evident in Candida albicans colonies. The decrease in the influence of magnets on microbes in vitro was also detected. CONCLUSIONS: Magnets reduce the number of microbes and might be recommended as a supplement in therapy for reduced periodontal tissues. This is important because periodontal tissues that are in good conditions provide prolonged support to the oral tissues under partial and supradental denture. PMID- 26018311 TI - Differential expression of immunologic proteins in gingiva after socket preservation in mini pigs. AB - During healing following tooth extraction, inflammation and the immune response within the extraction socket are related to bone resorption. OBJECTIVE: We sought to identify how the alloplastic material used for socket preservation affects the immune responses and osteoclastic activity within extraction sockets. MATERIAL AND METHODS: Using a porcine model, we extracted teeth and grafted biphasic calcium phosphate into the extraction sockets. We then performed a peptide analysis with samples of gingival tissue from adjacent to the sockets and compared the extraction only (EO) and extraction with socket preservation (SP) groups. We also used real-time polymerase chain reaction (PCR) to evaluate the expression level of immunoglobulins, chemokines and other factors related to osteoclastogenesis. Differences between the groups were analyzed for statistical significance using paired t tests. RESULTS: Levels of IgM, IgG and IGL expression were higher in the EO group than in the SP group 1 week post-extraction, as were the levels of CCL3, CCL5, CXCL2, IFN-gamma and TNF-alpha expression (p < 0.05). In addition, receptor activator of nuclear factor kappa-B ligand (RANKL) was also significantly upregulated in the EO group (p < 0.05), as were IL-1beta, IL-6 and IL-8 (p < 0.05). CONCLUSIONS: These results suggest that the beneficial effect of socket preservation can be explained by suppression of immune responses and inflammation. PMID- 26018312 TI - Effect of prosthodontic planning on lateral occlusion scheme: a comparison between conventional and digital planning. AB - Recently, digital wax-up is proposed as a tool to aid prosthodontic planning. However, there are no data about the effect of prosthodontic planning on lateral occlusion scheme. OBJECTIVE: This study aims to evaluate the impact of conventional and digital prosthodontic planning on lateral occlusion scheme. MATERIAL AND METHODS: Dental models of 10 patients were collected. All models had Angle Class I occlusion and were undergoing prosthodontic treatment that would influence the lateral occlusion scheme. Each set of models had received both conventional wax-up and digital wax-up. In relation to the lateral occlusion scheme, the following variables were evaluated: the prevalence of the different lateral occlusion scheme, number of contacting teeth and percentage of each contacting tooth. Four excursive positions on the working side were included: 0.5, 1.0, 2.0 and 3.0 mm from the maximal intercuspation position. RESULTS: The lateral occlusion scheme of the two wax-up models was subjected to alterations following excursion. There was a tendency for the prevalence of canine-guided occlusion to increase and for the prevalence of group function occlusion to decrease with increasing excursion. The number of contacting teeth was decreasing with the increasing magnitude of excursion. For the 0.5 mm and 1.0 mm positions, the two wax-ups had significantly greater contacts than the pre-treatment models, while at the 2.0 mm and 3.0 mm positions, all the models were similar. For all models, canines were the most commonly contacting teeth, followed by the teeth adjacent to them. No difference was observed between the two wax-ups in relation to the number of contacting teeth. CONCLUSION: Although the prosthodontic planning had influenced the pattern of the lateral occlusion scheme and contacts, there was no difference between the conventional and digital prosthodontic planning. PMID- 26018313 TI - Expression of osteoblastic phenotype in periodontal ligament fibroblasts cultured in three-dimensional collagen gel. AB - OBJECTIVE: To investigate the influence of a three-dimensional cell culture model on the expression of osteoblastic phenotype in human periodontal ligament fibroblast (hPDLF) cultures. MATERIAL AND METHODS: hPDLF were seeded on bi dimensional (2D) and three-dimensional (3D) collagen type I (experimental groups) and and on a plastic coverslip (control) for up to 14 days. Cell viability and alkaline phosphatase (ALP) activity were performed. Also, cell morphology and immunolabeling for alkaline phosphatase (ALP) and osteopontin (OPN) were assessed by epifluorescence and confocal microscopy. The expression of osteogenic markers, including alkaline phosphatase, osteopontin, osteocalcin (OC), collagen I (COL I) and runt-related transcription factor 2 (RUNX2), were analyzed using real-time polymerase chain reaction (RT-PCR). Mineralized bone-like nodule formation was visualized by microscopy and calcium content was assessed quantitatively by alizarin red assay. RESULTS: Experimental cultures produced an increase in cell proliferation. Immunolabeling for OPN and ALP in hPDLF were increased and ALP activity was inhibited by three-dimensional conditions. OPN and RUNX2 gene expression was significantly higher on 3D culture when compared with control surface. Moreover, ALP and COL I gene expression were significantly higher in three-dimensional collagen than in 2D cultures at 7 days. However, at 14 days, 3D cultures exhibited ALP and COL I gene expression significantly lower than the control, and the COL I gene expression was also significantly lower in 3D than in 2D cultures. Significant calcium mineralization was detected and quantified by alizarin red assay, and calcified nodule formation was not affected by tridimensionality. CONCLUSION: This study suggests that the 3D cultures are able to support hPDLF proliferation and favor the differentiation and mineralized matrix formation, which may be a potential periodontal regenerative therapy. PMID- 26018314 TI - Minimally traumatic alveolar ridge augmentation with a tunnel injectable thermo sensitive alginate scaffold. AB - Injectable bone substitutes and techniques have been developed for use in minimally invasive procedures for bone augmentation. OBJECTIVE: To develop a novel injectable thermo-sensitive alginate hydrogel (TSAH) as a scaffold to induce bone regeneration, using a minimally invasive tunnelling technique. MATERIAL AND METHODS: An injectable TSAH was prepared from a copolymer solution of 8.0 wt% Poly(N-isopropylacrylamide) (PNIPAAm) and 8.0 wt% AAlg-g-PNIPAAm. In vitro properties of the material, such as its microstructure and the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2), were investigated. Then, with the subperiosteal tunnelling technique, this material, carrying rhBMP-2, was injected under the labial periosteum of the maxillary anterior alveolar ridge in a rabbit model. New bone formation was evaluated by means of X-ray, micro-computed tomography (micro-CT), fluorescence labelling, histological study, and immunohistochemistry study. RESULTS: The material exhibited good injectability and thermo-irreversible properties. SEM showed an interconnected porous microstructure of the TSAH. The result of ALP activity indicated sustained delivery of BMP-2 from the TSAH from days 3 to 15. In a rabbit model, both TSAH and TSAH/rhBMP-2 induced alveolar ridge augmentation. The percentage of mineralised tissue in the TSAH/rhBMP-2 group (41.6 +/- 3.79%) was significantly higher than in the TSAH group (31.3 +/- 7.21%; p < 0.05). The density of the regenerating tissue was higher in the TSAH/rhBMP-2 group than in the other groups (TSAH group, positive control, blank control; p < 0.05). CONCLUSIONS: The TSAH provided convenient handling properties for clinical application. To some extent, TSAH could induce ridge augmentation and mineral deposition, which can be enhanced when combined with rhBMP-2 for a minimally invasive tunnelling injection. PMID- 26018315 TI - Interrelationship between implant and orthognathic surgery for the rehabilitation of edentulous cleft palate patients: a case report. AB - A 43-year-old woman with a unilateral cleft lip and palate, presenting a totally edentulous maxilla and mandible with marked maxillomandibular discrepancy, attended the Prosthodontics section of the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo for treatment. She could not close her mouth and was dissatisfied with her complete dentures. Treatment planning comprised placement of six implants in the maxilla, four in the mandible followed by prostheses installation and orthognathic surgery. The mandibular full arch prosthesis guided the occlusion for orthognathic positioning of the maxilla. The maxillary complete prosthesis was designed to assist the orthognathic surgery with a provisional prosthesis (no metal framework), allowing reverse treatment planning. Maxillary and mandibular realignment was performed. Three months later, a relapse in the position of the maxilla was observed, which was offset with a new maxillary prosthesis. This isa complex interdisciplinary treatment and two year follow-up is presented and discussed. It should be considered that this type of treatment could also be applied in non-cleft patients. PMID- 26018316 TI - New insight into the anatomy of the hyolingual apparatus of Alligator mississippiensis and implications for reconstructing feeding in extinct archosaurs. AB - Anatomical studies of the cranium of crocodilians motivated by an interest in its function in feeding largely focused on bite force, the jaw apparatus and associated muscles innervated by the trigeminal nerve. However, the ossified and cartilaginous elements of the hyoid and the associated hyolingual muscles, innervated by the facial, hypoglossal and glossopharyngeal nerves, received much less attention. Crocodilians are known to retain what are ancestrally the 'Rhythmic Hyobranchial Behaviors' such as buccal oscillation, but show diminished freedom and movement for the hyobranchial apparatus and the tongue in food transport and manipulation. Feeding among crocodilians, generally on larger prey items than other reptilian outgroups, involves passive transport of the food within the mouth. The tongue in extant crocodilians is firmly attached to the buccal floor and shows little movement during feeding. Here, we present a detailed anatomical description of the myology of the hyolingual apparatus of Alligator mississippiensis, utilizing contrast-enhanced micro-computed tomography and dissection. We construct the first three-dimensional (3D) description of hyolingual myology in Alligator mississippiensis and discuss the detailed implications of these data for our understanding of hyolingual muscle homology across Reptilia. These anatomical data and an evaluation of the fossil record of hyoid structures also shed light on the evolution of feeding in Reptilia. Simplification of the hyoid occurs early in the evolution of archosaurs. A hyoid with only one pair of ceratobranchials and a weakly ossified or cartilaginous midline basihyal is ancestral to Archosauriformes. The comparison with non archosaurian reptilian outgroup demonstrates that loss of the second set of ceratobranchials as well as reduced ossification in basihyal occurred prior to the origin of crown-clade archosaurs, crocodilians and birds. Early modification in feeding ecology appears to characterize the early evolution of the clade. Hyoid simplification has been linked to ingestion of large prey items, and this shift in hyoid-related feeding ecology may occur in early archosauriform evolution. A second transformation in hyoid morphology occurs within the crocodilian stem lineage after the split from birds. In Crocodyliformes, deflections in the ceratobrachials become more pronounced. The morphology of the hyoid in Archosauriformes indicates that aspects of the hyolingual apparatus in extant crocodilians are derived, including a strong deflection near the midpoint of the ceratobranchials, and their condition should not be treated as ancestral for Archosauria. PMID- 26018317 TI - Metabolic Instability of Cyanothiazolidine-Based Prolyl Oligopeptidase Inhibitors: a Structural Assignment Challenge and Potential Medicinal Chemistry Implications. AB - As part of the development of cyanothiazolidine-based prolyl oligopeptidase inhibitors, initial metabolism studies suggested multiple sites of oxidation by P450 enzymes. Surprisingly, in-depth investigations revealed that epimerization at multiple stereogenic centers was responsible for the conversion of the single primary metabolite into a panel of secondary metabolites. The rapid isomerization of all seven detected molecules precluded the use of NMR spectroscopy or X-ray crystallography for complete structural determination, presenting an interesting structure elucidation challenge. Through a combination of LC-MS analysis, synthetic work, deuterium exchange studies, and computational predictions, we were able to characterize all metabolites and to elucidate their dynamic behavior in solution. In the context of drug development, this study reveals that cyanothiazolidine moieties are problematic due to their rapid P450-mediated oxidation and the unpredictable stability of the corresponding metabolites. PMID- 26018318 TI - Twist promotes invasion and cisplatin resistance in pancreatic cancer cells through growth differentiation factor 15. AB - Pancreatic cancer (PC) is an aggressive and devastating disease with a poor prognosis. Cisplatin, a commonly used chemotherapeutic agent for solid tumors, is effective as a single agent or in combination with other drugs for the treatment of PC. Previous studies have suggested that Twist and growth differentiation factor 15 (GDF15) are involved in the progression of PC. However, the role of Twist and GDF15 in PC remains to be elucidated. In the present study, the individual effect of and interaction between Twist and GDF15 in PC cell invasion and chemoresistance to cisplatin was examined. Twist and/or GDF15 were stably overexpressed or knocked down in ASPC-1 and BXPC-3 human PC cells. Overexpression of Twist in the two cell lines markedly increased GDF15 expression, cell invasion, matrix metalloproteinase-2 expression/activity and the half maximal inhibitory concentration (IC50) values of cisplatin, which was eradicated by GDF15 knockdown or the selective p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (10 uM). By contrast, Twist knockdown significantly decreased GDF15 expression, cell invasion, matrix metalloproteinase-2 expression/activity and the IC50 values of cisplatin, which was completely reversed by overexpression of GDF15. In addition, while overexpression and knockdown of Twist increased and decreased p38 MAPK activity, respectively, GDF15 demonstrated no significant effect on p38 MAPK activity in PC cells. In conclusion, the present study, for the first time, to the best of our knowledge, demonstrated that Twist promotes PC cell invasion and cisplatin chemoresistance through inducing GDF15 expression via a p38 MAPK-dependent mechanism. The present study provides new insights into the molecular mechanisms underlying PC progression and chemoresistance. PMID- 26018320 TI - REESTABLISHING "THE SOCIAL" IN RESEARCH ON DEMOCRATIC PROCESSES: MID-CENTURY VOTER STUDIES AND PAUL F. LAZARSFELD'S ALTERNATIVE VISION. AB - Voter studies conducted in the United States during the first decades after World War II transformed social scientific research on democracy. Especially important were the rapid innovations in survey research methods developed by two prominent research centers at Columbia University and the University of Michigan. This article argues that the Columbia and Michigan voter studies presented two visions for research on democracy. Where the Michigan research produced quantitative measures expressing the 'political behavior' of the electorate, the Columbia studies, and especially Paul F. Lazarsfeld, presented an alternative vision for qualitative research on political choice. Largely ignored by later voter studies, this vision prefigured much contemporary research on democracy that embraces a qualitative or interpretive approach. This article reconstructs Lazarsfeld's alternative vision, describes the institutional context in which scholars disregarded it in favor of formal quantitative models, and argues for its recognition as a forerunner to qualitative research on democratic processes. PMID- 26018319 TI - Frozen blastocyst embryo transfer using a supplemented natural cycle protocol has a similar live birth rate compared to a programmed cycle protocol. AB - PURPOSE: The purpose of this study is to compare outcomes for a supplemented natural cycle with a programmed cycle protocol for frozen blastocyst transfer. METHODS: A retrospective analysis was performed of frozen autologous blastocyst transfers, at a single academic fertility center (519 supplemented natural cycles and 106 programmed cycles). Implantation, clinical pregnancy, miscarriage, and live birth and birth weight were compared using Pearson's Chi-squared test, T test, or Fisher's exact test. RESULTS: There was no significant difference between natural and programmed frozen embryo transfers with respect to implantation (21.9 vs. 18.1 %), clinical pregnancy (35.5 vs. 29.2 %), and live birth rates (27.7 vs. 23.6 %). Mean birth weights were also similar between natural and programmed cycles for singletons (3354 vs. 3340 g) and twins (2422 vs. 2294 g) CONCLUSION: Frozen blastocyst embryo transfers using supplemented natural or programmed protocols experience similar success rates. Patient preference should be considered in choosing a protocol. PMID- 26018321 TI - Red blood cell antigen genotype analysis for 9087 Asian, Asian American, and Native American blood donors. AB - BACKGROUND: There has yet to be a comprehensive analysis of blood group antigen prevalence in Asian Americans and Native Americans. There may be ethnic differences in blood group frequencies that would result in clinically important mismatches through transfusion. STUDY DESIGN AND METHODS: Blood donors who self identified as Asian or Native American were tested using a single-nucleotide polymorphism (SNP) DNA array (HEA BeadChip kit, Bioarray Solutions Ltd) that predicts expression of 38 human erythrocyte antigens (HEAs) and by serology for ABO, D, C, M, N, Jk(a) , and Jk(b) . The prevalence of blood group antigens was compared to published European prevalence. Discrepancies between SNP-predicted and serology-detected antigens were tallied. RESULTS: A total of 9087 blood donors were tested from nine Asian and Native American heritages. The predicted prevalence of selected antigens in the RHCE, JK, FY, MNS, LU, CO, and DO blood group systems were variable between Asian populations, but overall not significantly different than Europeans. Compared to European frequencies, Kell blood group allele frequencies were significantly different in the Chinese, Native American, Hawaiian/Pacific Islander, South Asian, and Southeast Asian heritage blood donors; Diego antigens Di(a) and Di(b) were different in donors of Native American and South Asian ancestries (p < 0.05). Of the donors tested, 4.5% showed a SNP-serology discrepancy that segregated within specific ethnic groups. CONCLUSION: This study provides HEA allele frequency and antigen prevalence data in a cohort of Asian and Native Americans donors. Several ethnic groups exhibited differences in HEA frequencies compared to Europeans. Genotype-serotype discrepancies were detected in all systems studied. PMID- 26018326 TI - Use of 99mTc-Doxorubicin scintigraphy in women with breast cancer: a pilot study. AB - OBJECTIVES: Doxorubicin is an antitumor agent widely used in the treatment of breast cancer, and can be used for tumor tracking when labeled with a radionuclide. Here, we present the results obtained with 99mTc-Doxorubicin, using the direct method, to evaluate its uptake in breast cancer. METHODS: Four women with confirmed breast carcinoma diagnosis and Breast Image Reporting and Data System (BI-RADS(r)) category 5 on mammography underwent whole-body and thorax SPECT/CT imaging 1 and 3 h after 99mTc-Doxorubicin administration. RESULTS: We observed increased uptake in breast carcinoma lesions and elimination via renal and hepatic pathways. CONCLUSIONS: These preliminary results suggest that 99mTc Doxorubicin may be a promising radiopharmaceutical for the evaluation of patients with breast cancer. Further studies are ongoing. Advances in Knowledge: To our knowledge, this is the first study to evaluate the use of a directly-labeled Doxorubicin tracer in humans. 99mTc-Doxorubicin could provide information on the response of tumors to doxorubicin. PMID- 26018327 TI - A modified version of the three-compartment model to predict fatigue during submaximal tasks with complex force-time histories. AB - The three-compartment model (3CM) was validated previously for prediction of endurance times by modifying its fatigue and recovery rates. However, endurance times do not typically represent work demands, and it is unknown if the current version of the 3CM is applicable for ergonomics analysis of all occupational tasks. The purpose of this study was to add biological fidelity to the 3CM, and validate the model against a series of submaximal force plateaus. The fatigue and recovery rates were modified to represent graded physiological motor unit characteristics (termed 3CM(GMU)). In nine experiments of submaximal efforts, the 3CM(GMU) produced a root-mean squared difference (RMSD) of 4.1 +/- 0.5% MVC over experiments with an average strength loss (i.e., fatigue) of 31.0 +/- 1.1% MVC. The 3CM(GMU) model performed poorly for endurance tasks. The 3CM(GMU) model is an improvement for evaluating submaximal force patterns consisting of intermittent muscle contractions of the hand and forearm. PRACTITIONER SUMMARY: We modified an existing fatigue model using known physiological properties in order to predict fatigue during nine different submaximal force profiles; consistent with efforts seen in industrial work. We expect this model to be included in digital human modelling software, for the assessment of repetitive work and muscle fatigue in repetitive tasks. SOCIAL MEDIA Summary: The proposed model has applications for estimating task fatigue in proactive ergonomic analyses of complex force patterns using digital human models. PMID- 26018328 TI - Cancer registry data: Engaging the clinician to improve quality. PMID- 26018329 TI - Short-term clinical outcomes after hybrid coronary revascularization versus off pump coronary artery bypass for the treatment of multivessel or left main coronary artery disease: a meta-analysis. AB - BACKGROUND: Hybrid coronary revascularization (HCR) and off-pump coronary artery bypass grafting (OPCABG) are both feasible, less invasive techniques for coronary revascularization. Although both techniques utilize the left internal mammary artery to left anterior descending artery graft, HCR uses drug-eluting stents instead of saphenous vein bypass. It remains unclear whether HCR is equal to, better or worse than OPCABG. METHODS AND RESULTS: A meta-analysis was carried out using a random-effects model. Seven observational studies were included. There was no significant difference either in in-hospital mortality [relative risk (RR) 0.57, 95% confidence interval (CI) 0.13-2.59, P=0.47] or in the MACCE rate (RR 0.63, 95% CI 0.24-1.64, P=0.34) between the HCR group and the OPCABG group. A significant difference was observed between the two groups in the length of hospitalization (RR 0.55, 95% CI 0.13-0.97, P=0.01), length of ICU stay (RR 0.45, 95% CI 0.10-0.80, P<0.05), intubation time (RR 0.48, 95% CI 0.13-0.84, P<0.01), need for red blood transfusion (RR 0.67, 95% CI 0.56-0.82, P<0.001), and total in hospital costs (RR 0.90, 95% CI 0.39-1.42, P<0.01). CONCLUSION: Compared with OPCABG, HCR did not improve early survival but decreased the length of hospitalization, length of ICU stay, intubation time, and need for red blood transfusion, and increased total in-hospitalcosts. PMID- 26018330 TI - Age-related effects of smoking on culprit lesion plaque vulnerability as assessed by grayscale and virtual histology-intravascular ultrasound. AB - BACKGROUND: Although smoking is a risk factor for coronary atherosclerosis, the age-related impact on lesion characteristics and plaque instability remains unclear. PATIENTS AND METHODS: In ADAPT-DES, 780 patients with 916 culprit lesions were evaluated by preprocedural grayscale and virtual histology intravascular ultrasound. RESULTS: Current smokers (smoking within 1 month) more often presented with acute coronary syndrome (67 vs. 51 vs. 51%, P<0.05) compared with former smokers (no smoking for >1 month) or nonsmokers. In patients 65 or more years of age, current smokers (vs. nonsmokers) showed larger normalized volumes of plaque and media [8.6 (7.8-9.4) vs. 7.2 (6.8-7.7) mm/mm, P=0.016] and external elastic membrane [14.4 (13.2-15.5) vs. 12.8 (12.2-13.4) mm/mm, P=0.05]. At the minimal lumen area site, despite a greater plaque burden, the larger external elastic membrane area [14.4 (13.1-15.7) vs. 12.0 (11.3-12.7) mm, P=0.003] contributed toward preserving the minimal lumen area [2.6 (2.4-2.7) vs. 2.6 (2.5-2.7) mm, P=0.91] in current smokers (vs. nonsmokers) 65 or more years of age. Moreover, current smokers (vs. nonsmokers) 65 or more years of age showed a greater normalized necrotic core volume [1.19 (0.96-1.46) vs. 0.75 (0.66-0.85) mm/mm, P=0.0007], more thin-cap fibroatheromas (61 vs. 48%, P=0.04), and plaque ruptures (38 vs. 26%, P=0.051). Conversely, in patients younger than 65 years of age, there was no significant difference in culprit lesion morphology among current, former, and nonsmokers. CONCLUSION: In patients 65 or more years (not in patients<65 years), smoking increased culprit lesion plaque instability (greater plaque with more necrotic core, thin-cap fibroatheromas, positive remodeling, and plaque ruptures). PMID- 26018331 TI - Inter-rater reliability of the Hayes Ability Screening Index in a sample of Australian prisoners. AB - BACKGROUND: Reliable ascertainment of intellectual disability (ID) is important to identify those with special needs, in order for those needs to be met in the criminal justice system. Although the Hayes Ability Screening Index (HASI) is valid and widely used for the identification of possible ID, the risk of inter rater bias between researchers when scoring the HASI has not yet been established. The current paper estimates the inter-rater reliability of the HASI in a sample of Indigenous and non-Indigenous prisoners in Western Australia. METHODS: We estimated intra-class correlation coefficients (ICC) for the consistency of agreement among three blinded raters using a two-way random effects model assessing the inter-rater agreement of the HASI. Kappa was also estimated for the dichotomous HASI screening threshold outcome between the raters. RESULTS: The HASI exhibited very good within-subject consistency of agreement for Section B (ICC = 0.95; 95%CI:0.94-0.96), Section C (ICC = 0.97; 95%CI: 0.96-0.98) and Section D (ICC = 0.90; 95%CI: 0.87-0.92) subscales and for the total scaled score (ICC = 0.97; 95%CI: 0.96-0.98). The inter-rater reliability of the dichotomous adult ID screening threshold (<85) was also very good (Kappa = 0.95). CONCLUSIONS: The current study provides new evidence that the HASI has a low risk of bias from between-rater scoring and can be reliably scored by both non-clinicians and clinicians with little training, when administered in prison settings. Pre-scoring training should focus on the more subjective 'clock-drawing' section, in order to maximise inter-rater reliability. PMID- 26018332 TI - Facilitative and obstructive factors in the clinical learning environment: Experiences of pupil enrolled nurses. AB - BACKGROUND: The clinical learning environment is a complex social entity that influences student learning outcomes in the clinical setting. Students can experience the clinical learning environment as being both facilitative and obstructive to their learning. The clinical environment may be a source of stress, creating feelings of fear and anxiety which in turn affect the students' responses to learning. Equally, the environment can enhance learning if experienced positively. OBJECTIVES: This study described pupil enrolled nurses' experiences of facilitative and obstructive factors in military and public health clinical learning settings. METHOD: Using a qualitative, contextual, exploratory descriptive design, three focus group interviews were conducted until data saturation was reached amongst pupil enrolled nurses in a military School of Nursing. RESULTS: Data analysed provided evidence that acceptance by clinical staff and affordance of self-directed learning facilitated learning. Students felt safe to practise when they were supported by the clinical staff. They felt a sense of belonging when the staff showed an interest in and welcomed them. Learning was obstructed when students were met with condescending comments. Wearing of a military uniform in the public hospital and horizontal violence obstructed learning in the clinical learning environment. CONCLUSION: Students cannot have effective clinical preparation if the environment is not conducive to and supportive of clinical learning, The study shows that military nursing students experience unique challenges as they are trained in two professions that are hierarchical in nature. The students experienced both facilitating and obstructing factors to their learning during their clinical practice. Clinical staff should be made aware of factors which can impact on students' learning. Policies need to be developed for supporting students in the clinical learning environment. PMID- 26018333 TI - Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial. AB - IMPORTANCE: Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that "withdrawal" from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD). OBJECTIVE: To examine the role of estradiol withdrawal in PMD. DESIGN, SETTING, AND PARTICIPANTS: Initial open label treatment with estradiol followed by randomized, double-blind, placebo controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance. INTERVENTIONS: After 3 weeks of open-label administration of transdermal estradiol (100 ug/d), participants were randomized to a parallel design to receive either estradiol (100 ug/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions. MAIN OUTCOMES AND MEASURES: Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits. RESULTS: None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo. CONCLUSIONS AND RELEVANCE: In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00060736. PMID- 26018334 TI - Retractions of DOI: 10.1089/neu.2008.0707 and 10.1089/neu.2011.1842. PMID- 26018335 TI - The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013. AB - Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (?IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether ?IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N = 218) or multiplex ligation-dependent probe amplification (N = 116) analyses. ?IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P < 0.001) and overall survival (pOS; 73% vs. 89%; P = 0.001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, ?IKZF1 was the strongest independent factor for relapse and death. ?IKZF1 was present in 27% of cases with non-informative cytogenetics ('BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P < 0.001). Importantly, neither MRD nor WBC count predicted events in the ?IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and ?IKZF1 increased the risk of relapse (75% vs. 30% for cases with only ?IKZF1; P = 0.045), indicating that BCP other ALL with both P2RY8-CRLF2 and ?IKZF1 constitutes a particularly high-risk group. PMID- 26018336 TI - Safety Indices during Fetal Echocardiography at the Time of First-Trimester Scan Are Machine Dependent. AB - The aim of our study was to evaluate the thermal index (TI) and mechanical index (MI), during the assessment of the fetal heart at the time of first-trimester scan, with different ultrasound machines. This was part of an observational study conducted in patients undergoing routine first-trimester screening. Cases were examined with Voluson E8 or 730Pro scanners using 2-8 MHz transabdominal probes. TI and MI were retrieved from the saved displays while in gray mode, color flow mapping and pulsed-wave (PW) Doppler examinations of the fetal heart and also from the ductus venosus (DV) assessment. We evaluated 552 fetal cardiac examinations, 303 (55%) performed with Voluson E8 and 249 (45%) with Voluson 730Pro ultrasound machines. The gray-scale exam of the heart and the PW Doppler DV assessment had TI values significantly lower for the Voluson E8 group (median, 0.04 vs. 0.2 and 0.1 vs. 0.2, respectively). The MI values from gray-scale and color flow mapping of the heart were significantly lower (median, 0.6 vs, 1.2 and 0.7 vs. 1) and for PW Doppler exam of the tricuspid flow were significantly higher (median 0.4 vs. 0.2) in the Voluson E8 group. The TI values from Doppler examinations of the heart, either color flow or PW imaging and MI values from DV assessment were not significantly different between the two groups. A different (newer) generation of ultrasound equipment provides lower or at least the same safety indices for most of the first-trimester heart examinations. PMID- 26018337 TI - Characterization of Silver Nanoparticles in Cell Culture Medium Containing Fetal Bovine Serum. AB - Nanoparticles are being increasingly used in consumer products worldwide, and their toxicological effects are currently being intensely debated. In vitro tests play a significant role in nanoparticle risk assessment, but reliable particle characterization in the cell culture medium with added fetal bovine serum (CCM) used in these tests is not available. As a step toward filling this gap, we report on silver ion release by silver nanoparticles and on changes in the particle radii and in their protein corona when incubated in CCM. Particles of a certified reference material, p1, and particles of a commercial silver nanoparticle material, p2, were investigated. The colloidal stability of p1 is provided by the surfactants polyethylene glycol-25 glyceryl trioleate and polyethylene glycol-20 sorbitan monolaurate, whereas p2 is stabilized by polyvinylpyrrolidone. Dialyses of p1 and p2 reveal that their silver ion release rates in CCM are much larger than in water. Particle characterization was performed with asymmetrical flow field-flow fractionation, small-angle X-ray scattering, dynamic light scattering, and electron microscopy. p1 and p2 have similar hydrodynamic radii of 15 and 16 nm, respectively. The silver core radii are 9.2 and 10.2 nm. Gel electrophoresis and subsequent peptide identification reveal that albumin is the main corona component of p1 and p2 after incubation in CCM that consists of Dulbecco's modified Eagle medium with 10% fetal bovine serum added. PMID- 26018338 TI - An evaluation of the implementation of maternal obesity pathways of care: a mixed methods study with data integration. AB - OBJECTIVES: Maternal obesity has multiple associated risks and requires substantial intervention. This research evaluated the implementation of maternal obesity care pathways from multiple stakeholder perspectives. STUDY DESIGN: A simultaneous mixed methods model with data integration was used. Three component studies were given equal priority. 1: Semi-structured qualitative interviews explored obese pregnant women's experiences of being on the pathways. 2: A quantitative and qualitative postal survey explored healthcare professionals' experiences of delivering the pathways. 3: A case note audit quantitatively assessed pathway compliance. Data were integrated using following a thread and convergence coding matrix methods to search for agreement and disagreement between studies. RESULTS: Study 1: Four themes were identified: women's overall (positive and negative) views of the pathways; knowledge and understanding of the pathways; views on clinical and weight management advice and support; and views on the information leaflet. Key results included positive views of receiving additional clinical care, negative experiences of risk communication, and weight management support was considered a priority. Study 2: Healthcare professionals felt the pathways were worthwhile, facilitated good practice, and increased confidence. Training was consistently identified as being required. Healthcare professionals predominantly focussed on women's response to sensitive obesity communication. Study 3: There was good compliance with antenatal clinical interventions. However, there was poor compliance with public health and postnatal interventions. There were some strong areas of agreement between component studies which can inform future development of the pathways. However, disagreement between studies included a lack of shared priorities between healthcare professionals and women, different perspectives on communication issues, and different perspectives on women's prioritisation of weight management. CONCLUSION: The differences between healthcare professionals' and women's priorities and perspectives are important factors to consider when developing care pathways. Shared perspectives could help facilitate more effective implementation of the pathway interventions that have poor compliance. PMID- 26018339 TI - Multiparametric AFM reveals turgor-responsive net-like peptidoglycan architecture in live streptococci. AB - Cell-wall peptidoglycan (PG) of Gram-positive bacteria is a strong and elastic multi-layer designed to resist turgor pressure and determine the cell shape and growth. Despite its crucial role, its architecture remains largely unknown. Here using high-resolution multiparametric atomic force microscopy (AFM), we studied how the structure and elasticity of PG change when subjected to increasing turgor pressure in live Group B Streptococcus. We show a new net-like arrangement of PG, which stretches and stiffens following osmotic challenge. The same structure also exists in isogenic mutants lacking surface appendages. Cell aging does not alter the elasticity of the cell wall, yet destroys the net architecture and exposes single segmented strands with the same circumferential orientation as predicted for intact glycans. Together, we show a new functional PG architecture in live Gram-positive bacteria. PMID- 26018340 TI - The characteristics of patients frequently admitted to academic medical centers in the United States. AB - BACKGROUND: The recent intense attention to hospital readmissions and their implications for quality, safety, and reimbursement necessitates understanding specific subsets of readmitted patients. Frequently admitted patients, defined as patients who are admitted 5 or more times within 1 year, may have some distinguishing characteristics that require novel solutions. METHODS: A comprehensive administrative database (University HealthSystem Consortium's Clinical Data Base/Resource Manager) was analyzed to identify demographic, social, and clinical characteristics of frequently admitted patients in 101 US academic medical centers. RESULTS: We studied 28,291 frequently admitted patients with 180,185 admissions over a 1-year period (2011-2012). These patients comprise 1.6% of all patients, but account for 8% of all admissions and 7% of direct costs. Their admissions are driven by multiple chronic conditions; compared to other hospitalized patients, they have significantly more comorbidities (an average of 7.1 vs 2.5), and 84% of their admissions are to medical services. A minority, but significantly more than other patients, have comorbidities of psychosis or substance abuse. Moreover, although they are slightly more likely than other patients to be on Medicaid or to be uninsured (27.6% vs 21.6%), nearly three-quarters have private or Medicare coverage. CONCLUSIONS: Patients who are frequently admitted to US academic medical centers are likely to have multiple complex chronic conditions and may have behavioral comorbidities that mediate their health behaviors, resulting in acute episodes requiring hospitalization. This information can be used to identify solutions for preventing repeat hospitalization for this small group of patients who consume a highly disproportionate share of healthcare resources. PMID- 26018341 TI - The relationship between prospective memory and episodic future thinking in younger and older adulthood. AB - Episodic future thinking (EFT), the ability to project into the future to "preexperience" an event, and prospective memory (PM), remembering to perform an intended action, are both examples of future-oriented cognition. Recently it has been suggested that EFT might contribute to PM performance but to date few studies have examined the relationship between these two capacities. The aim of the present study was to investigate the nature and specificity of this relationship, as well as whether it varies with age. Participants were 125 younger and 125 older adults who completed measures of EFT and PM. Significant, positive correlations between EFT and PM were identified in both age groups. Furthermore, EFT ability accounted for significant unique variance in the young adults, suggesting that it may make a specific contribution to PM function. Within the older adult group, EFT did not uniquely contribute to PM, possibly indicating a reduced capacity to utilize EFT, or the use of compensatory strategies. This study is the first to provide systematic evidence for an association between variation in EFT and PM abilities in both younger and older adulthood and shows that the nature of this association varies as a function of age. PMID- 26018342 TI - Production of Xylitol from D-Xylose by Overexpression of Xylose Reductase in Osmotolerant Yeast Candida glycerinogenes WL2002-5. AB - Efficient bioconversion of D-xylose into various biochemicals is critical for the developing lignocelluloses application. In this study, we compared D-xylose utilization in Candida glycerinogenes WL2002-5 transformants expressing xylose reductase (XYL1) in D-xylose metabolism. C. glycerinogenes WL2002-5 expressing XYL1 from Schefferomyces stipitis can produce xylitol. Xylitol production by the recombinant strains was evaluated using a xylitol fermentation medium with glucose as a co-substrate. As glucose was found to be an insufficient co substrate, various carbon sources were screened for efficient cofactor regeneration, and glycerol was found to be the best co-substrate. The effects of glycerol on the xylitol production rate by a xylose reductase gene (XYL1) overexpressed mutant of C. glycerinogenes WL2002-5 were investigated. The XYL1 overexpressed mutant produced xylitol from D-xylose using glycerol as a co substrate for cell growth and NAD (P) H regeneration: 100 g/L D-xylose was completely converted into xylitol when at least 20 g/L glycerol was used as a co substrate. XYL1 overexpressed mutant grown on glycerol as co-substrate accumulated 2.1-fold increased xylitol concentration over those cells grown on glucose as co-substrate. XYL1 overexpressed mutant produced xylitol with a volumetric productivity of 0.83 g/L/h, and a xylitol yield of 98 % xylose. Recombinant yeast strains obtained in this study are promising candidates for xylitol production. This is the first report of XYL1 gene overexpression of C. glycerinogenes WL2002-5 for enhancing the efficiency of xylitol production. PMID- 26018343 TI - Conversion of Isoflavone Glucosides to Aglycones by Partially Purified beta Glucosidases from Microbial and Vegetable Sources. AB - Isoflavone aglycones have been shown to be more rapidly and efficiently absorbed into intestines than isoflavone glucosides. Helpfully, beta-glucosidases can be used to convert isoflavone glucosides to aglycones. In this study, beta glucosidases from microbial (Aspergillus niger) and vegetable lima bean (Phaseolus lunatus) sources were characterized, purified, and then employed to convert isoflavone glycosides to aglycones. The microbial crude extract showed maximum activity at 60 degrees C and pH 5.0. It was highly stable between 40 and 60 degrees C and between pH 4.0 and 9.0. Optimum activity for the vegetable crude extract was achieved also at 60 degrees C and pH 5.5. Similarly, it presented great stability at high temperatures and a wide pH range. The microbial enzyme was purified by a factor of 14-fold to a yield of 2.2 % and a specific activity of 17 IU/mg. The vegetable enzyme was purified by a factor of fourfold to a yield of 77 % and a specific activity of 0.18 IU/mg protein. Both beta glucosidases produced satisfactory conversion rates of daidzin and genistin into daidzein and genistein; however, the microbial enzyme performed better than the vegetable enzyme. Our results suggest a potential use of these enzymes to enhance the bioavailability of isoflavones in food products. PMID- 26018344 TI - Biodegradation of Benzene, Toluene, Ethylbenzene, and o-, m-, and p-Xylenes by the Newly Isolated Bacterium Comamonas sp. JB. AB - A bacterium designated strain JB, able to degrade six benzene, toluene, ethylbenzene, and o-, m-, and p-xylene (BTEX) compounds, was isolated from petroleum-contaminated soil. Taxonomic analyses showed that the isolate belonged to Comamonas, and until now, the genus Comamonas has not included any known BTEX degraders. The BTEX biodegradation rate was slightly low on the mineral salt medium (MSM), but adding a small amount of yeast extract greatly enhanced the biodegradation. The relationship between specific degradation rate and individual BTEX was described well by Michaelis-Menten kinetics. The treatment of petrochemical wastewater containing BTEX mixture and phenol was shown to be highly efficient by BTEX-grown JB. In addition, toxicity assessment indicated the treatment of the petrochemical wastewater by BTEX-grown JB led to less toxicity than untreated wastewater. PMID- 26018345 TI - Single Amino Acid Substitution in the Pullulanase of Klebsiella variicola for Enhancing Thermostability and Catalytic Efficiency. AB - Based on conserved sites and homology modeling analysis, the residue Phe581 in the Klebsiella variicola SHN-1 pullulanase was selected as the potential thermostability-related site and its role on thermostability and activity was investigated by site-saturated mutagenesis. Compared with the wild-type pullulanase, the optimum temperature of the mutants including F581L, F581Q, F581R, F581T, F581V, and F581Y was increased from 53 to 56 degrees C, and correspondingly the half lives of these mutants at 55 degrees C were increased by 4.20, 3.70, 1.90, 7.16, 3.01, and 1.75 min, respectively. By modeling the structure of the pullulanase, formation of more hydrogen bonds by single-site substitution was supposed to be responsible for the improvement of thermostability. Of these mutants, furthermore, F581L and F581V exhibited higher values of V max and k cat/K m, compared with the wild-type enzyme. Therefore, the residue Phe581 was identified as an important site relevant to the activity and thermostability of the pullulanase of K. variicola, and by mutation at this single site, the mutated enzymes with enhanced thermostability and catalytic efficiency were achieved consequently. PMID- 26018346 TI - Intrahepatic transplantation of adipose-derived stem cells attenuates the progression of non-alcoholic fatty liver disease in rats. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury affecting the general health of various populations. In the present study, adipose tissue-derived stem cells (ADSCs), which were isolated from the adipose tissues of Sprague-Dawley rats, were transplanted into the liver of high fat-diet-induced NAFLD rats via the portal vein to attenuate the disease progression of NAFLD. The results demonstrated that ADSC transplantation reduced the serum levels of alanine aminotransferase, total bilirubin, total cholesterol, triglycerides and fatty acids, and reduced the content of malondialdehyde in the liver homogenates. By contrast, ADSC transplantation caused a significant increase in superoxide dismutase activity. These data suggested that the ADSC transplantation improved the liver function, and reduced lipid metabolism and oxidative stress. In addition, the hepatic pathological changes were decelerated, lipid accumulation was reduced, and serum levels of the pro-inflammatory factors, tumor necrosis factor-alpha and interleukin-6, were downregulated by the ADSC transplantation. Taken together, transplantation with ADSCs attenuates the disease progression of high-fat-diet induced NAFLD, therefore, may offer a potential therapeutic approach for the treatment of NAFLD. PMID- 26018347 TI - Early Application of Auxiliary Partial Orthotopic Liver Transplantation in Murine Model of Wilson Disease. AB - BACKGROUND: Liver transplantation (LT) is the only option of treatment for Wilson disease (WD) when chelation therapy fails, but it is limited due to the shortage of donor. Auxiliary partial orthotopic LT (APOLT) has been performed successfully in end-stage WD patients, which expands the donor pool. METHODS: Atp7bmice were used as experimental model of WD. Eight- and 20-week-old mice were used as different timepoints to perform APOLT. Serum copper, tissue copper, serum ceruloplasmin (CP), and liver histological examination were observed after operation. RESULTS: Hepatic and serum copper levels in Atp7b mice decreased after APOLT, and copper metabolism disorder of WD mice was relieved at both early and late stages. The progression of pathology in the native liver was delayed only when transplantation was performed at an early stage. CONCLUSIONS: Auxiliary partial orthotopic LT can significantly improve copper metabolism disorder in the Atp7b mice, and early transplantation may prevent the disease progression. PMID- 26018348 TI - Calcineurin Inhibitor Free De Novo Immunosuppression in Liver Transplant Recipients With Pretransplant Renal Impairment: Results of a Pilot Study (PATRON07). AB - BACKGROUND: Renal impairment and high model of end-stage liver disease scores before liver transplantation (LT) are increasingly common. PATIENTS AND METHODS: This was a single-arm, 2-step prospective trial of bottom-up calcineurin inhibitor (CNI)-free de novo immunosuppressive treatment (mycofenolate mofetil, steroids, basiliximab) with delayed introduction of sirolimus in patients with renal impairment. Primary endpoint was immunologic safety assessed by the incidence of steroid-resistant rejection within the first 30 days after liver transplantation. RESULTS: Twenty-seven patients were included with a median age of 56 years and labMELD of 28. Baseline glomerular filtration rate was 38 (Cockroft-Gault) and 24 mL/min (modification of diet in renal disease). No steroid-resistant rejections occurred within 30 days. Incidence of biopsy proven acute rejection was 18.5%. Sirolimus was started on day 10 (range, day 1 to day 48). The rate switched to CNI treatment by 1 year was 44%; 1-year overall survival was 93%. Renal function improved significantly, reflected by a Deltaglomerular filtration rate of 31 mL/min from baseline to 1 year (P = 0.006). Per protocol analysis revealed freedom from CNI, but not presence of sirolimus within the first 30 days, as critical for renal recovery. CONCLUSIONS: Initial de novo CNI-free immunosuppressive bottom-up treatment is safe in selected patient groups. The critical period for relevant recovery of renal function seems to be the early period (first 30 days), independent from presence of sirolimus. PMID- 26018349 TI - Renal Extracellular Matrix Scaffolds From Discarded Kidneys Maintain Glomerular Morphometry and Vascular Resilience and Retains Critical Growth Factors. AB - BACKGROUND: Extracellular matrix (ECM) scaffolds, obtained through detergent based decellularization of native kidneys, represent the most promising platform for investigations aiming at manufacturing kidneys for transplant purposes. We previously showed that decellularization of the human kidney yields renal ECM scaffolds (hrECMs) that maintain their basic molecular components, are cytocompatible, stimulate angiogenesis, and show an intact innate vasculature. However, evidence that the decellularization preserves glomerular morphometric characteristics, physiological parameters (pressures and resistances of the vasculature bed), and biological properties of the renal ECM, including retention of important growth factors (GFs), is still missing. METHODS: To address these issues, we studied the morphometry and resilience of hrECMs' native vasculature with resin casting at electronic microscopy and pulse-wave measurements, respectively. Moreover, we determined the fate of 40 critical GFs post decellularization with a glass chip-based multiplex enzyme-linked immunosorbent assay array and in vitro immunofluorescence. RESULTS: Our method preserves the 3 dimensional conformation of the native glomerulus. Resin casting and pulse-wave measurements, showed that hrECMs preserves the microvascular morphology and morphometry, and physiological function. Moreover, GFs including vascular endothelial growth factor and its receptors are retained within the matrices. CONCLUSIONS: Our results indicate that discarded human kidneys are a suitable source of renal scaffolds because they maintain a well-preserved structure and function of the vasculature, as well as GFs that are fundamental to achieve a satisfying recellularization of the scaffold in vivo due to their angiogenic properties. PMID- 26018350 TI - A Phase I/II Trial of the Interleukin-6 Receptor-Specific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients. AB - BACKGROUND: Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti-IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy. METHODS: From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months. RESULTS: No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 +/- 10.5 months but after TCZ was 8.1 +/- 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 +/- 25 mL/min. CONCLUSIONS: Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy PMID- 26018351 TI - Discrepancy in Psychological Attitudes Toward Living Donor Liver Transplantation Between Recipients and Donors. AB - BACKGROUND: Mutual understanding between recipients and donors is indispensable when living donor liver transplantation (LDLT) is performed, which, however, has gained little attention and remains unaddressed in the literature. METHODS: Fifty seven pairs, a recipient (mean +/- SD age at the operation, 48.3 +/- 10.6 years; mean +/- SD years after the operation, 6.2 +/- 4.7 years) and his or her donor, who underwent LDLT completed a 13-item questionnaire on a 7-point Likert scale (1: strongly agree to 7: strongly disagree) that was designed to assess for their psychological attitudes toward transplantation. They were also asked to estimate their donor's or recipient's response to the questionnaire, respectively. Values of interest were compared between groups, using paired t tests. Following Bonferroni correction, a P value less than 0.0038 (0.05/13) was considered statistically significant. RESULTS: Significant differences were observed between actually answered and estimated responses in 7 of the 13 items in the questionnaire for donors. For example, donors did not feel pressure to become a donor to the same degree as their recipients estimated (4.6 +/- 1.9 vs 3.4 +/- 1.8). In contrast, only 1 item showed a significant difference between actually answered and estimated responses in the questionnaire for recipients; recipients did not worry about the transplanted liver compared to their donors' estimation (3.1 +/- 1.9 vs 2.1 +/- 0.8). CONCLUSIONS: Recipients did not fully understand the donors' feelings toward LDLT, whereas donors almost correctly understood their recipients' attitudes. Our findings clearly revealed the gap in their mutual understanding and emphasize the need of psychological education to bridge the gap. PMID- 26018352 TI - The Role of Natural Killer Cells in Humoral Rejection. AB - Antibody-mediated rejection (AMR) has been identified among the most important factors limiting long-term outcome in cardiac and renal transplantation. Therapeutic management remains challenging and the development of effective treatment modalities is hampered by insufficient understanding of the underlying pathophysiology. However, recent findings indicate that in addition to AMR triggered activation of the classical complement pathway, antibody-dependent cellular cytotoxicity by innate immune cell subsets also promotes vascular graft injury. This review summarizes the accumulating evidence for the contribution of natural killer cells, the key mediators of antibody-dependent cellular cytotoxicity, to human AMR in allotransplantation and xenotransplantation and illustrates the current mechanistic conceptions drawn from animal models. PMID- 26018353 TI - Generation of Alloreactive-Anergized Tr1 Cells From Patients on Dialysis for the Induction of Renal Transplant Tolerance: Are We There Yet? PMID- 26018354 TI - Evaluating the Emergency Department as a Site of Transplant Care. PMID- 26018355 TI - Prognostic Significance of Creeping Proteinuria in the First Year After Transplantation. AB - BACKGROUND: Proteinuria changes have a prognostic significance in proteinuric nephropathies. Proteinuria has been related to kidney transplant outcomes, but there are no information about the impact of increasing proteinuria during the first year on long-term graft and patient survival. METHODS: Retrospective cohort study of 591 kidney transplants to analyze the effect on long-term prognosis of: proteinuria at 3 (n = 591) and 12 (n = 583) months (no proteinuria: 150-299 mg/24 hours, 300-999 mg/24 hours, and >=1 g/24 hours), and changes in proteinuria during the first year in such patients with proteinuria at 3 months (reduction >=50% of proteinuria from 3 to 12 months, variation <50%, and increase >=50% or "creeping proteinuria") (n = 283). RESULTS: Higher levels of proteinuria, at both 3 and 12 months, were progressively related to lower graft survival (P < 0.0001). Proteinuria at 12 months was related to mortality (P = 0.026). Creeping proteinuria, which was present in 35 patients (12.4%), was related to graft failure (P < 0.0001) and mortality (P = 0.030), even at lower levels of proteinuria at 3 months. De novo HLA antibody development was the only factor related to creeping proteinuria (hazard ratio, 2.946; 95% confidence interval, 1.158-7.491; P = 0.023). CONCLUSIONS: Creeping proteinuria during the first year was associated with long-term graft failure and mortality and could be considered as a surrogate of kidney disease progression in the renal transplant population, as it is in proteinuric nephropathies. It could also be viewed as an expression of immunological damage. PMID- 26018356 TI - Reemergence of Ibaraki disease in southern Japan in 2013. AB - In Japan in 2013, two cattle in the northwestern part of Kagoshima Prefecture developed fever and swallowing difficulty and were suspected of having Ibaraki disease. The epizootic hemorrhagic virus (EHDV) genome was detected from diseased and asymptomatic cattle by reverse transcription-polymerase chain reaction (RT PCR). High neutralization antibody titers to Ibaraki virus (IBAV) ranging from 1:128 to 1:1,024 were observed in the RT-PCR-positive cattle, and the virus was isolated in one of the IBAV-positive farms. A pairwise alignment and phylogenetic analysis based on the major outer coat protein VP2 encoded in segment 2 revealed a close relationship between the isolated viruses and previous IBAV isolates. The phylogeny of VP2 also suggested that an IBAV variant isolated in 1997 was distinct from IBAV and sorted into a heterogeneous serotype, EHDV serotype 7. The findings revealed the reemergence of Ibaraki disease in Japan after a 26-year absence. Interestingly, the co-circulation of EHDV serotype 1 with IBAV was observed in the affected region, suggesting the potential reassortment between two heterogeneous serotypes in the field. Sentinel surveillance in Kagoshima Prefecture indicated that the incursion of IBAV occurred in October 2013 and that its spread was limited within the small area. Inadequate environmental temperatures for vector transmission in late autumn might have limited the virus spread to a wider region. The reemergence of Ibaraki disease showed us the importance of continuous vaccination to prevent economic losses. PMID- 26018357 TI - Effects of papaverine on carbachol- and high K+ -induced contraction in the bovine abomasum. AB - The effects of papaverine on carbachol (CCh) -and high K(+)- induced contraction in the bovine abomasum were investigated. Papaverine inhibited CCh (1 uM) -and KCl (65 mM) -induced contractions in a concentration-dependent manner. Forskolin or sodium nitroprusside inhibited CCh-induced contractions in a concentration dependent manner in association with increases in the cAMP or cGMP contents, whereas papaverine increased cGMP contents only at 30 uM. Changes in the extracellular Ca(2+) from 1.5 mM to 7.5 mM reduced verapamil-induced relaxation in high K(+)-depolarized muscles, but papaverine-induced relaxation did not change. Furthermore, papaverine (30 uM) and NaCN (300 uM) decreased the creatine phosphate contents. These results suggest that the relaxing effects of papaverine on the bovine abomasum are mainly due to the inhibition of aerobic energy metabolism. PMID- 26018358 TI - Oral pharmacokinetics of acetaminophen to evaluate gastric emptying profiles of Shiba goats. AB - The pharmacokinetics of acetaminophen was investigated following oral dosing to Shiba goats in order to evaluate the properties of gastric emptying. Acetaminophen was intravenously and orally administered at 30 mg/kg body weight to goats using a crossover design with a 3-week washout period. The stability of acetaminophen in rumen juice was also assessed. Acetaminophen concentrations were measured by HPLC. Since acetaminophen was stable in rumen juice for 24 hr, the extremely low bioavailability (16%) was attributed to its hepatic extensive first pass effect. The mean absorption time and absorption half-life were unexpectedly short (4.93 and 3.35 hr, respectively), indicating its marked absorption from the forestomach, which may have been due to its smaller molecular weight. Therefore, acetaminophen was considered to be unsuitable for evaluating gastric emptying in Shiba goats. PMID- 26018359 TI - Chirality-based Au@Ag Nanorod Dimers Sensor for Ultrasensitive PSA Detection. AB - A novel biosensor for ultrasensitive detection of prostate-specific antigen (PSA) was established based on gold nanorod (Au NR) dimers assembly. The circular dichroism signal was significantly amplified by a silver shell depositing on the surface of the Au NR dimers. A low limit of detection of 0.076 aM and high specificity were observed within the range of 0.1 to 50 aM target PSA. The developed biosensor has the potential to serve as a general platform for the detection of cancer biomarkers. PMID- 26018360 TI - [Dermatohistopathology in pediatric skin diseases]. PMID- 26018361 TI - Frequent bacterial skin and soft tissue infections: diagnostic signs and treatment. AB - Skin and soft tissue infections rank among the most frequent infections worldwide. Classic erysipelas is defined as a non-purulent infection by beta hemolytic streptococci. The typical signs are tender, warm, bright erythema with tongue-like extensions and early systemic symptoms such as fever or at least chills. Erysipelas always and best responds to penicillin. Limited soft tissue infection or limited cellulitis are the terms we have introduced for infections frequently caused by S. aureus and often originating from chronic wounds or acute trauma. Clinically, they are marked by tender, erythematous swelling which, unlike erysipelas, exhibit a darker red hue and is not always accompanied by fever or chills at onset. Severe cellulitis is a purulent, partially necrotic infection extending to the fascia, with general symptoms of infection, requiring surgical management in addition to antibiotics. It often fulfils criteria of so called complicated soft tissue infections according to the definition of the FDA, due to their frequent association with e.g. severe diabetes mellitus, peripheral arterial occlusive disease or severe immunosuppression. In contrast, the rare necrotizing skin and soft tissue infections represent a distinct entity, characterized by rapid progression to ischemic necroses and shock due to special bacterial toxins. Limited cellulitis should be treated with cephalosporins group 1 or 2, or, when S.aureus is the isolated or highly likely causative agent, isoxazolyl-penicillins (exploiting their minimal selection pressure on other bacteria). For severe cellulitis, initial antibiotic treatment (mostly iv) includes - depending on the location - agents also active against gram-negative and/or anaerobic bacteria. (e.g. clindamycine, aminopeniclilline with inhibitors of betalaktamase, fluochinolons, cephalosporines group 4). For cutaneous abscesses, drainage presents the therapy of choice. Only under certain conditions additional antibiotic therapy is required. Adherence to the diagnostic criteria and to evidence-based or consensus-derived treatment recommendations as presented herein should allow for an antibiotic therapy with a good balance of efficacy, tolerability by patients and low selection pressure for highly resistant bacteria. PMID- 26018364 TI - Pharmacokinetic characteristics of therapeutic antibodies. AB - Because of their high molecular weight and their highly hydrophilic character, therapeutic antibodies behave differently in terms of absorption, distribution and elimination compared to conventional drugs. Also, their pharmacokinetic profile varies significantly among individuals. After subcutaneous administration, antibodies are absorbed via the lymphatic system and become systemically bioavailable with some delay. The physicochemical properties of the molecules hinder their distribution from the bloodstream into the tissue. Elimination occurs by proteolysis in various organs (skin, muscle, liver), but mainly within the reticuloendothelial system. Also relevant is the elimination through target antigens (especially in the case of cell-bound target antigens) as well as a recycling process through binding to the neonatal Fc receptor that provides protection from lysosomal degradation. Depending on the immunogenicity of the therapeutic antibody and the individual immune response, neutralizing antibodies can develop. Pharmacokinetic conditions can be optimized by coadministration of, for example, methotrexate. Moreover, risk factors for the loss of immunological tolerance, such as on-demand therapy or elective switching of therapeutic antibodies, should be avoided. PMID- 26018366 TI - Pediatric dermatohistopathology--histopathology of skin diseases in newborns and infants. AB - While neonatal skin physiology has been thoroughly examined using non-invasive techniques in recent years, only few systematic studies and review articles addressing the histopathology of neonatal skin have been published thus far. In most cases, histopathological findings of dermatoses in neonatal skin do not significantly differ from those seen in adult skin. Nevertheless, a comprehensive knowledge of embryonic and fetal skin development as well as the microanatomical structure of neonatal skin can contribute to a better understanding of various dermatoses of infancy. In the first part of this review article, we present the histopathological features of such skin diseases, which, though generally rare, almost exclusively appear during the first weeks of life due to distinctive structural and functional features of neonatal skin. The second part is dedicated to classic dermatoses of infancy and their histopathological features. PMID- 26018367 TI - Q-switched Nd:YAG laser treatment for labial lentigines associated with Peutz Jeghers syndrome. AB - BACKGROUND AND OBJECTIVE: Labial lentigines associated with Peutz-Jeghers syndrome are cosmetically disfiguring and distressful. Although multiple treatment modalities including Q-switched ruby laser and Q-switched alexandrite laser have been proposed, experience with Q-switched Nd:YAG laser has been lacking. This study aimed to retrospectively evaluate the efficacy and safety of Q-switched Nd:YAG laser (532 nm) for labial lentigines in Peutz-Jeghers syndrome. PATIENTS AND METHODS: Demographic and clinical data of 11 patients diagnosed with Peutz-Jeghers syndrome were analyzed. A quartile grading system was used. All patients were treated with a Q-switched Nd:YAG laser system with the following parameters: wavelength 532 nm; spot size 3 mm; pulse duration 5-20 ns; fluence 1.8-2.2 J/cm(2) . RESULTS: After two to six (mean 3.6) treatment sessions, an average grade of 3.73 was achieved. Eight patients (72.7 %) showed an excellent response with more than 75 % lesion clearance. Three patients (27.3 %) showed a good response. Repeated treatments led to improved clearance of labial lentigines. Age, gender, and Fitzpatrick skin type were not statistically associated with efficacy grades after the first treatment session. Neither recurrence in treated areas nor significant complications were observed. CONCLUSIONS: Q-switched Nd:YAG laser provides an effective and safe treatment option for labial lentigines associated with Peutz-Jeghers syndrome. PMID- 26018369 TI - Efficacy of adapalene/benzoyl peroxide combination in moderate inflammatory acne and its impact on patient adherence. AB - BACKGROUND AND OBJECTIVES: Adapalene 0.1 %/benzoyl peroxide (BPO) 2.5 % (Epiduo(r)) is the first, fixed-dose topical combination gel developed for the once-daily treatment of acne. The objective of this observational study was to assess efficacy and patient adherence under daily clinical practice conditions in a large population of young adults and adolescents (12 to 20 years) with moderate inflammatory acne. PATIENTS AND METHODS: A total of 2 780 patients receiving adapalene-BPO were evaluated in this multicenter, open-label, prospective non interventional observational study. Observation time per patient was approximately 12 weeks. Assessment parameters included changes in acne severity, treatment success, safety, and therapeutic adherence. RESULTS: After 12 weeks, the majority of patients (91.5 %) showed improvement of acne under adapalene-BPO treatment, with an initial therapeutic response noted after a median time of 14 days. Overall, 21.8 % of participants displayed complete resolution of visible acne lesions. Treatment adherence was assessed as good in 63.2 % of patients. The majority of individuals (69.5 %) experienced no or only mild local skin irritations. No serious adverse drug reactions (ADR) were reported during the course of the study. CONCLUSIONS: Adapalene-BPO is effective and safe in the treatment of moderate inflammatory acne. The fixed-dose combination and easy application simplifies the therapeutic regimen, leading to good treatment adherence in the majority of patients. PMID- 26018372 TI - Metastatic Crohn's disease: a diagnostic and therapeutic challenge. PMID- 26018375 TI - Sigmoid diverticulosis--a risk factor for perforation of the sigmoid colon due to ipilimumab-associated enterocolitis? PMID- 26018377 TI - Fixed eruption induced by sunlight. PMID- 26018379 TI - Vegetating plaques in a patient with a seizure disorder. PMID- 26018381 TI - Successful wound closure using artificial dermis and split-skin grafting in deep bilateral scalp necrosis caused by giant cell arteritis. PMID- 26018385 TI - [Laudation: Prof. Dr. med. Klaus-Michael Taube on his 65th birthday]. PMID- 26018386 TI - [Regional Dermatology Training Center Moshi, Tanzania - the heart of Dermatology in East Africa]. PMID- 26018388 TI - [Evaluation of the new ImmunoCard STAT!(r) CGE test for the diagnosis of Amebiasis]. AB - For many years, microscopic examination of stool samples has been considered to be the "gold standard" for diagnosis of intestinal parasites although the Polymerase Chain Reaction (PCR) analysis is increasingly utilized due to its high accuracy. Recently, PCR has been approved by the World Health Organization as the current method of choice for the diagnosis of Entamoeba histolytica infection. In this study we evaluated a novel immunochromatographic antigen detection rapid test, ImmunoCardSTAT CGE (Meridian Bioscence, Milan, Italy), which has been proposed for the diagnosis of infections caused by Cryptosporidium parvum-Giardia intestinalis-Entamoeba histolytica. There is another rapid test with a similar name, the ImmunoCard STAT! Crypto/Giardia, but it is just for Cryptosporidium and Giardia. We aimed to compare E. histolytica results obtained from the rapid test with those of a rt-PCR for the detection of E. histolytica / E. dispar DNA. The new ImmunoCard rapid antigen detection test exhibited 88% sensitivity and 92% specificity (if assessed on rt-PCR negative samples) but showed a high proportion of cross-reaction between the pathogenic E. histolytica and the non pathogenic E. dispar. PMID- 26018389 TI - Management of rectourinary fistula after urological interventions using biodesigned mesh: first experiences of an innovative technique. AB - PURPOSE: Rectourinary fistula (RUF) is an uncommon but devastating condition that usually occurs as a complication of surgical treatment or radiotherapy of prostate cancer. Although operative fistula repair remains the most successful treatment, there still is no consensus concerning the management of RUF. We present first experiences and transanal surgical technique using biological mesh for fistula repair after urological intervention. MATERIAL AND METHODS: From January 2009 to December 2013, four cases of RUF were reported at our university hospital. Fistula occurred after extraperitoneal laparoscopic radical prostatectomy, open radical prostatectomy, and high-intensity focused ultrasound, respectively. All patients were initially treated with transanal Cook BiodesignTM mesh, whereas two patients received reoperation with rectal mucosa advancement flap and gracilis muscle flap interposition, respectively. Mean follow-up was 36 months (range 9-62). RESULTS: Fistula diameters ranged from 0.6 to 3.0 cm and were located 5 to 6 cm of anocutaneous line. The time from diagnosis to fistula repair was 3 to 7 weeks. The median operative time for Cook BiodesingTM mesh procedure was 79 min (IQR 60, 98). The initial success rate for biological mesh was 50 % (2/4 patients). Larger fistulae were minimalized successfully and finally closed with reoperation mentioned above. No deterioration of continence was documented. CONCLUSIONS: Management of rectourinary fistula is still challenging. Using biomaterials for fistula closure seems to be a promising and minimally invasive transanal technique in future. Further analysis including more patients is needed to clarify its exact role in comparison to traditional surgical techniques. PMID- 26018392 TI - [The rehabilitation of patients who are (still) unfit for rehabilitation]. PMID- 26018390 TI - Selective recruitment of nuclear factors to productively replicating herpes simplex virus genomes. AB - Much of the HSV-1 life cycle is carried out in the cell nucleus, including the expression, replication, repair, and packaging of viral genomes. Viral proteins, as well as cellular factors, play essential roles in these processes. Isolation of proteins on nascent DNA (iPOND) was developed to label and purify cellular replication forks. We adapted aspects of this method to label viral genomes to both image, and purify replicating HSV-1 genomes for the identification of associated proteins. Many viral and cellular factors were enriched on viral genomes, including factors that mediate DNA replication, repair, chromatin remodeling, transcription, and RNA processing. As infection proceeded, packaging and structural components were enriched to a greater extent. Among the more abundant proteins that copurified with genomes were the viral transcription factor ICP4 and the replication protein ICP8. Furthermore, all seven viral replication proteins were enriched on viral genomes, along with cellular PCNA and topoisomerases, while other cellular replication proteins were not detected. The chromatin-remodeling complexes present on viral genomes included the INO80, SWI/SNF, NURD, and FACT complexes, which may prevent chromatinization of the genome. Consistent with this conclusion, histones were not readily recovered with purified viral genomes, and imaging studies revealed an underrepresentation of histones on viral genomes. RNA polymerase II, the mediator complex, TFIID, TFIIH, and several other transcriptional activators and repressors were also affinity purified with viral DNA. The presence of INO80, NURD, SWI/SNF, mediator, TFIID, and TFIIH components is consistent with previous studies in which these complexes copurified with ICP4. Therefore, ICP4 is likely involved in the recruitment of these key cellular chromatin remodeling and transcription factors to viral genomes. Taken together, iPOND is a valuable method for the study of viral genome dynamics during infection and provides a comprehensive view of how HSV-1 selectively utilizes cellular resources. PMID- 26018391 TI - Individual biases, cultural evolution, and the statistical nature of language universals: the case of colour naming systems. AB - Language universals have long been attributed to an innate Universal Grammar. An alternative explanation states that linguistic universals emerged independently in every language in response to shared cognitive or perceptual biases. A computational model has recently shown how this could be the case, focusing on the paradigmatic example of the universal properties of colour naming patterns, and producing results in quantitative agreement with the experimental data. Here we investigate the role of an individual perceptual bias in the framework of the model. We study how, and to what extent, the structure of the bias influences the corresponding linguistic universal patterns. We show that the cultural history of a group of speakers introduces population-specific constraints that act against the pressure for uniformity arising from the individual bias, and we clarify the interplay between these two forces. PMID- 26018393 TI - [Neuropsychological treatment of cognitive deficits in substance abuse disorders, affective disorders, anxiety disorders and obsessive-compulsive disorders - current status and perspectives]. AB - Neuropsychological treatment represents a promising therapeutic approach in the amelioration of cognitive deficits in many neuropsychiatric disorders. Cognitive impairment constitutes a core feature that often persists beyond psychopathological symptoms having a significant impact on psychosocial functioning. However, research interest and evidence of efficacy vary considerably between disease groups. Although neuropsychological treatment is frequently used in clinical practice, there are, with the exception of schizophrenia, relatively few studies on its effectiveness. PMID- 26018394 TI - [Eye contact in adult patients with Asperger syndrome]. AB - INTRODUCTION: It is unclear if individuals with autism spectrum disorders rarely hold direct eye contact because eyes are unimportant for them, or if it is actively avoided. The aim of the current investigation was to gain a better understanding for their views on direct eye contact by exploring adult patients with Asperger syndrome. METHOD: 63 adult patients with Asperger syndrome (28 females, 35 males, 21 - 62 years old) were explored about using and sensing direct eye contact by means of a standardised questionnaire. RESULT: 87 % of investigated patients depict direct eye contact as being disagreeable. They describe it as arduous and distracting. Therefore they mostly actively avoid direct eye contact. DISCUSSION: The here gained knowledge about aversion towards direct eye contact in individuals with autism should lead to a stronger understanding and acceptance of this problem in the non-autistic population. PMID- 26018395 TI - [German translation and validation of the Stress Appraisal Measure (SAM)]. AB - OBJECTIVE: In the present study, the German-language version of the Stress Appraisal Measure (SAM) by Peacock and Wong was validated in a student population. SAM is a relatively short questionnaire (28 items) that evaluates a current, stress-triggering event. The theoretical background is provided by the stress model of Lazarus and Folkman. METHOD: 85 students (age: 23; 59 female, 26 male) were exposed to two stress scenarios in order to test whether they were suited to provoke stress. A factor analysis was performed and the internal consistency of the seven SAM scales was determined. In addition, the convergent validity of SAM with State and Trait Anxiety Inventory (STAI), Coping Inventory for Stressful Situations (CISS) and specific emotion scales was investigated via Pearson's product-moment correlation. RESULTS: The two stress scenarios were suited to evoke stress. The factor structure and the internal consistency of the individual scales, as well as the convergent validity of SAM were replicated with minor limitations in the present German version. Some items (especially from the fifth factor) were only replicated partially. CONCLUSION: SAM can also be employed in the German language version. PMID- 26018396 TI - [Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation]. AB - Malignant gliomas like glioblastoma multiforme (GBM) release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. We report the case of a patient with GBM treated with the AMPA receptor blocker Perampanel (PER) in combination therapy for partial seizures. Histological work-up of a biopsy showed the tissue of a GBM without mutation of the isocitrate dehydrogenase 1 (IDH1) and without promotor methylation of the O6 methylguanine-DNA methyltransferase (MGMT). In a group of patients with IDH 1 wild type and non-methylated MGMT a median survival of 199 days after surgery (i. e. 6.5 months) was described. Our patient lived about one year longer. PER rendered our patient seizure-free for at least the last seven months of his life. It was well tolerated and did not increase the toxicity of temozolomide. When choosing an antiepileptic drug (AED) for the treatment of seizures in patients with malignant brain tumors, the efficacy, the tolerability and perhaps possible effects on tumor progression of the AED should be taken into account. PMID- 26018397 TI - [Relational frame theory - a theoretical framework for contextual behavioral science]. AB - Therapists have to deal with verbal systems and often work with verbal exchange. Therefore, a psychological theory is required, which teaches the therapist how to accomplish this task. The BRT is a theory of human language and cognition that explains how people use their verbal behavior as stimuli in their interrelations and how they act and react, based on the resulting relationships. This behavior is learned very early in the course of language acquisition and functions as a generalized operant. A prerequisite for this is the ability of people to undergo mental simulation. This enables them to construct diverse relational frameworks between individual stimuli. Without relational frameworks, people cannot function. The ability to establish a relational framework is a prerequisite for the formation of rule-governed behavior. Rule-governed behavior economizes complex decision processes, creates interpersonal security and enables dealing with events before they take place. On the other hand, the same properties that enable people to solve problems effectively can also contribute to rigid adherence to rules and experience avoidance. Relational frameworks, once established, outweigh other sources of behavioral regulation. Thus, it can become the basis of psychopathology. Poor contextual control makes it difficult for people to devote flexible, focused and voluntary attention to the present and align their actions with the immediate present. Contextual psychotherapy methods that are based on the BRT start precisely at this point: Targeted establishment of new contingencies in the therapeutic interaction through systematic strengthening of metacognitive mode and through the establishment of new rules that make possible a change in the rule-governed behavior enable undermining of dysfunctional rule-governed behavior and build up desirable behavior. This allows any therapeutic process to be more effective - regardless of the patient's expressed symptoms. PMID- 26018398 TI - Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models. AB - Add-on therapy is a common strategy to improve efficacy and tolerability of antiepileptic drugs (AEDs). Anticonvulsant potential and appropriate safety of docosahexaenoic acid (DHA) makes it a promising candidate for combination therapy. We evaluated influence of DHA on anticonvulsant activity of AEDs phenytoin, valproate, and lamotrigine in maximal electroshock (MES), pentylenetetrazole (PTZ), and kindling models of epilepsy. The dose-response to DHA was obtained 15 min after intracerebroventricular (i.c.v.) injection in PTZ model of clonic seizures in mice, MES model of tonic seizures in mice, and kindling model of complex partial seizures in rats. The dose-response curve of valproate (30 min after i.p. injection to mice) in PTZ, phenytoin (60 min after i.p. injection to mice) in MES, and lamotrigine (60 min after i.p. injection to rats) in kindling models were obtained. Dose-response curves of the AEDs were then achieved in the presence of ED25 of DHA. DHA had no anticonvulsant effect in the MES model. However, it showed a dose-dependent protective effect against PTZ (ED50 = 0.13 MUM) and kindled seizures (ED50 = 1.08 mM). DHA at ED25 caused a 3.6 fold increase in potency of valproate as its ED50 value from 117.5 (98.3-135.3) decreased to 32.5 (21.6-44.1) mg/kg. Moreover, a 4.9-fold increase in potency of lamotrigine occurred, as its ED50 value from 13.10 (11.50-14.9) decreased to 2.65 (0.8-5.6) mg/kg. CompuSyn analysis indicated synergistic anticonvulsant interaction between DHA and both valproate and lamotrigine. Co-administration strategy of the safe and inexpensive anticonvulsant compound DHA with AEDs should be favorably regarded in clinical studies of epilepsy treatment. PMID- 26018399 TI - Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. AB - OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant expression of the transcription factor DUX4. However, it is still difficult to correlate these genotypes with the phenotypes observed in patients. Because we have recently shown that mice with disrupted Fat1 functions exhibit FSHD-like phenotypes, we have investigated the expression of the human FAT1 gene in FSHD. METHODS: We first analyzed FAT1 expression in FSHD adult muscles and determined whether FAT1 expression was driven by DUX4. We next determined FAT1 expression levels in 64 muscles isolated from 16 control fetuses. These data were further complemented with analysis of Fat1 expression in developing mouse embryos. RESULTS: We demonstrated that FAT1 expression is independent of DUX4. Moreover, we observed that (1) in control fetal human biopsies or in developing mouse embryos, FAT1 is expressed at lower levels in muscles that are affected at early stages of FSHD progression than in muscles that are affected later or are nonaffected; and (2) in adult muscle biopsies, FAT1 expression is lower in FSHD muscles compared to control muscles. INTERPRETATION: We propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset, whereas DUX4 may worsen the muscle phenotype. PMID- 26018400 TI - Effectiveness of Viabahn in the Treatment of Superficial Femoral Artery Occlusive Disease: A Systematic Review and Meta-analysis. AB - PURPOSE: To evaluate the effectiveness of the Viabahn stent-graft in the treatment of superficial femoral artery (SFA) occlusive disease. METHODS: A systematic review and meta-analysis of published studies was performed to evaluate the efficacy of the Viabahn for SFA lesions. Studies were stratified according to controlled vs uncontrolled design and analyzed using random-effects models. Outcomes are reported as the risk ratio (RR) and 95% confidence interval (CI). Four prospective randomized controlled trials, one retrospective controlled study, and 9 uncontrolled studies were identified. RESULTS: In controlled studies, primary patency with the Viabahn was superior to other interventions at 1 year (RR 0.63, 95% CI 0.49 to 0.82, p<0.001) and ankle-brachial index (ABI) improvement was greater at 6 months (mean difference 0.05, 95% CI 0.01 to 0.09, p=0.01) compared with other interventions. Subgroup analysis demonstrated a lower incidence of stent fracture in lesions with >15-cm stented lengths. In uncontrolled studies, ABI improvement was consistently superior at all measurement points during follow-up. CONCLUSIONS: Current evidence suggests that the Viabahn stent-graft is a safe and effective option for symptomatic SFA lesions. Prospective multicenter randomized controlled trials with long-term follow-up are needed to confirm the sustained efficacy of the Viabahn device. PMID- 26018401 TI - Pulmonary tuberculosis space-time clustering and spatial variation in temporal trends in Portugal, 2000-2010: an updated analysis. AB - Portugal, a medium- to low-level endemic country (21.6 cases/100 000 population in 2012), has one of the highest European Union tuberculosis (TB) incidences. Although incidence is declining progressively, the country's heterogeneity in both regional endemics and their evolution suggests the importance of a better understanding of subnational epidemiology to customize TB control efforts. We aimed to update knowledge on municipality-years pulmonary TB incidence clustering, identify areas with different time trends, and show the potential of combining complementary clustering methods in control of infectious diseases. We used national surveillance municipality-level data (mainland Portugal, 2000 2010). Space-time clustering and spatial variation in temporal trends methods were applied. Space-time critical clusters identified (P < 0.001) were still the Lisbon and Oporto regions. The global incidence declined at a 5.81% mean annual percentage change, with high space-time heterogeneity and distinct time trend clusters (P < 0.001). Municipalities with incidences declining more rapidly belonged to critical areas. In particular, the Oporto trend cluster had a consistent -8.98% mean annual percentage change. Large space-time heterogeneities were identified, with critical incidences in the greater Lisbon and Oporto regions, but declining more rapidly in these regions. Oporto showed a consistent, steeper decrease and could represent a good example of local control strategy. Combining results from these approaches gives promise for prospects for infectious disease control and the design of more effective, focused interventions. PMID- 26018402 TI - An analytical bond-order potential for carbon. AB - Carbon is the most widely studied material today because it exhibits special properties not seen in any other materials when in nano dimensions such as nanotube and graphene. Reduction of material defects created during synthesis has become critical to realize the full potential of carbon structures. Molecular dynamics (MD) simulations, in principle, allow defect formation mechanisms to be studied with high fidelity, and can, therefore, help guide experiments for defect reduction. Such MD simulations must satisfy a set of stringent requirements. First, they must employ an interatomic potential formalism that is transferable to a variety of carbon structures. Second, the potential needs to be appropriately parameterized to capture the property trends of important carbon structures, in particular, diamond, graphite, graphene, and nanotubes. Most importantly, the potential must predict the crystalline growth of the correct phases during direct MD simulations of synthesis to achieve a predictive simulation of defect formation. Because an unlimited number of structures not included in the potential parameterization are encountered, the literature carbon potentials are often not sufficient for growth simulations. We have developed an analytical bond order potential for carbon, and have made it available through the public MD simulation package LAMMPS. We demonstrate that our potential reasonably captures the property trends of important carbon phases. Stringent MD simulations convincingly show that our potential accounts not only for the crystalline growth of graphene, graphite, and carbon nanotubes but also for the transformation of graphite to diamond at high pressure. PMID- 26018403 TI - Screening for IgG4-type anti-nuclear antibodies in IgG4-related disease. AB - BACKGROUND: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and infiltration of IgG4(+) plasma cells into multiple organs. It is not known whether serum IgG4 is autoreactive in IgG4-RD. METHODS: We measured anti-nuclear antibody (ANA) in 19 IgG4-RD cases, determined IgG subclasses of the ANA, and compared them with those of other systemic autoimmune diseases (systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, and polymyositis), using subclass-based ANA test (indirect immunofluorescence). RESULTS: 58 % of IgG4-RD cases were ANA-positive (cut-off: 1:40). Whereas their subclass of ANA was predominantly IgG2, we observed no IgG4-type ANA. In systemic autoimmune diseases, subclasses of ANA were mostly IgG1, 2, or 3, but IgG4-type ANA was very rarely detected. We also found several patients in whose serum ANA patterns differed among IgG subclasses, probably due to the difference of corresponding autoantigens. CONCLUSIONS: Although IgG4 is highly elevated in sera of IgG4-RD patients, their ANA do not include IgG4 subclass. These results offer new insight into the role of IgG4 and the pathogenesis of IgG4-RD, implying that each IgG subclass tends to cover its own spectrum of antigens, and IgG4 is not preferentially used to make ANA. PMID- 26018404 TI - The histological components of the phoniatrical body-cover model in minipigs of different ages. AB - Pigs are models in human phoniatry. However, features of maturation and ageing have not been considered with regard to the so-called body-cover model in this species. Therefore, the glottis of "young" (2-3 months; n = 6) and "old" (4-7 years; n = 6) minipigs was investigated. Their cranial (CraF) and caudal (CauF) vocal folds were histomorphometrically and stratigraphically analysed with emphasis on their amounts of collagen structures and elastic fibres. A dense subepithelial layer (SEL) was a distinct feature of CraF and CauF of both age groups; it was spread upon the underlying loose, flexible "cover" like a fibro elastic membrane. The "cover" was characterised by the so-called superficial layer (SL), which was distinctly loose in the "young" minipigs, but had a much denser texture in the "old" minipigs. Here, the SL was dominated by elastic fibres in the CraF, but was of mixed qualities (collagenous and elastic) in the CauF. The structural requirements for the SL's function as a loose "cover" were thus met only in the "young" animals. A clearly demarcated intermediate layer (IL)--characterised by high amounts of elastic fibres (as in humans)--was only found in the CraF of the "young" animals. In the "old" animals, it had lost its demarcation. In the depth of the CraF of the "old" animals, many thick collagen fibre bundles were detected in a location equivalent to that of the vocal muscle in the CauF. The development of their large diameters was interpreted as part of the maturation process, thereby supporting the hypothesis of their functional importance as a component of the "body." In the CauF, the amounts of collagen structures increased throughout the entire lamina propria, resulting in a loss of demarcated stratigraphical subdivisions in the "old" minipigs. This situation resembled that described in the vocal fold of geriatric humans. PMID- 26018405 TI - Classic thrombophilic gene variants. AB - Thrombophilia is defined as a condition predisposing to the development of venous thromboembolism (VTE) on the basis of a hypercoagulable state. Over the past decades, great advances in the pathogenesis of VTE have been made and nowadays it is well established that a thrombophilic state may be associated with acquired and/or inherited factors. The rare loss-of-function mutations of the genes encoding natural anticoagulant proteins (i. e. protein C, protein S and antithrombin) and the more common gain-of-function polymorphisms factor V Leiden and prothrombin G20210A are the main genetic determinants of thrombophilia. In addition, non-O blood group has been consistently demonstrated to be the most frequent inherited marker of an increased risk of VTE. The mechanism role of these inherited thrombophilia markers will be discussed in this narrative review. PMID- 26018407 TI - Black tattoos protect against UVR-induced skin cancer in mice. AB - BACKGROUND: Black tattoos may involve risk of cancer owing to polycyclic aromatic hydrocarbons including benzo(a)pyrene (BaP) in inks. Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and black tattoo may therefore potentially be very problematic, but has not been previously studied. METHODS: Immunocompetent C3.Cg/TifBomTac mice (n = 99) were tattooed on the back with Starbrite Tribal Black(TM) . This ink has a high content of the carcinogen BaP. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. Controls were 'tattooed' without ink. RESULTS: All irradiated mice developed SCCs while no malignant tumours were found in the nonirradiated group. In the tattooed and irradiated group, the development of the first, second and third SCC was significantly delayed in comparison with the irradiated controls without black tattoos (212, 232, 247 days vs. 163, 183, 191 days, P < 0.001). CONCLUSION: In UVR-irradiated black tattoos, remarkably, the development of UVR-induced skin cancer was delayed by the tattoos. Skin reflectance measurement indicated that the protective effect of black pigment in the dermis might be attributed to UVR absorption by black pigment below the epidermis and thereby reduction of backscattered radiation. PMID- 26018408 TI - Medically inoperable peripheral lung cancer treated with stereotactic body radiation therapy. AB - BACKGROUND: Lung cancer is the most frequent cause of cancer-related death in North America. There is wide variation between patients who are medically inoperable and those managed surgically. The use of stereotactic body radiotherapy (SBRT) has narrowed the gap in survival rates between operative and non-operative management for those with early stage disease. This retrospective study reports outcomes for the treatment of peripheral non-small cell lung carcinoma (NSCLC) with SBRT from a single community practice. METHODS: Sixty seven consecutive patients (pts) with inoperable, untreated peripheral lung tumors were treated from 2010 through 2012 and included in this study. Stereotactic targeting was facilitated by either spine or lung-based image guidance, either with or without fiducial marker tracking with a frameless robotic radiosurgery system. Peripheral tumors received a median biological effective dose (BED) of 105.6 Gy10 or in terms of a median physical dose, 48 Gy delivered over 4 daily fractions. Survival was measured using the Kaplan-Meier method to determine rates of local control, progression of disease and overall survival. The Cox proportional hazards regression model was used to study the effects of tumor size, stage, histology, patient age, tumor location (lobe), tracking method, and BED on the survival distributions. RESULTS: The median follow-up for this cohort was 24.5 months (range: 2.4-50.3) with an overall (OS) 3-year survival of 62.4 % (95 % CI: 74.3-47.3). The median progression-free survival was 28.5 months (95 % CI: 15.8 months to not reached). Local control (LC), defined as a lack of FDG uptake on PET/CT or the absence of tumor growth was achieved in 60 patients (90.9 %) at the time of first follow-up (median 3 months, range: 1-6). Local control at one year for the entire cohort was 81.8 % (95 % CI, 67.3-90.3). The one-year OS probability among those who achieved local control at first follow-up was 86.2 % (95 % CI, 74.3-92.9) but no patients who did not achieve LC at first follow-up survived one year. Of the 60 pts that achieved initial LC, 16 have died. The rates of local control, progression-free survival and overall survival were not statistically different for patients treated using a fiducial target tracking system versus non-invasive guidance. (p = 0.44, p = 0.97 and p = 0.66, respectively). No National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE-4) grade 3 or greater toxicity was observed. CONCLUSION: SBRT is an effective treatment for medically inoperable NSCLC patients with peripherally located tumors. This therapy appears to be well tolerated with low toxicity, and patient outcomes when using non invasive tumor tracking systems are not inferior to traditional fiducial-based techniques. PMID- 26018409 TI - Pharmacokinetic study of isatin in dog plasma by liquid chromatography tandem mass spectrometry. AB - AIM: A sensitive and selective method was developed and validated to study the pharmacokinetics of isatin. METHODS: The blood samples were pretreated by protein precipitation method using methanol. Quetiapine was used as an internal standard. After pretreatment, the samples were assayed by LC/MS/MS method and the pharmacokinetic parameters were calculated by WinNonlin 5.2 using non-compartment model. The separation was performed on a Venusil XBP PH column (5 um, 2.0*100 mm) with an isocratic mobile phase consisted of methanol-water (containing 50 mM ammonium formate) (65:35, v/v) at a flow rate of 0.3 mL/min. The Agilent G6410B triple quadrupole LC/MS system was operated under the multiple reactions monitoring mode (MRM) using the electrospray ionization technique in positive mode. RESULTS: The lower limits of quantification (LLOQ) of the analyte of the method was 10 ng/mL. The method was linear with correlation coefficient >0.995. The intraday and interday accuracy and precision of the assay were acceptable. CONCLUSION: This method has been applied successfully to a pharmacokinetic study involving the oral and intravenous administration of isatin to beagle dogs. PMID- 26018410 TI - Association of Anemic Hypoxia and Increased Pulmonary Artery Systolic Pressure in Patients With Systemic Lupus Erythematosus. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare but serious complication of systemic lupus erythematosus (SLE). Chronic hypoxia is known to cause PAH resulting from pulmonary vascular remodeling. We investigated the association between anemic hypoxia and PAH in SLE patients. METHODS: Systolic pulmonary artery pressure (PAP) was measured in 132 SLE patients by echocardiography. Increased PAP was defined as resting PAP > 40 mm Hg. Oxygen delivery (DO2) was estimated as the product of cardiac output and arterial oxygen content. RESULTS: Of 132 patients, 17 (12.9%) had increased PAP, and these patients had significantly lower DO2 values than patients with normal PAP (P = 0.002). The DO2 values inversely correlated with PAP values (gamma = -0.308, P < 0.001) and plasma N-terminal pro-brain natriuretic peptide levels (gamma = 0.323, P = 0.001), but positively correlated with hemoglobin levels (gamma = 0.402, P < 0.001). Compared to those with normal PAP, patients with increased PAP had significantly longer durations of anemia over the preceding 6-24 months. Patients with anemia of longer durations (>=3 months) in the preceding 6 months had a higher risk of increased PAP compared to those with shorter durations (P < 0.001). When SLE patients were divided into 3 groups according to hemoglobin and PAP, serum interleukin-6 (IL-6) levels increased across groups with higher PAP (P = 0.001 for trend), but decreased across tertiles of hemoglobin levels (P = 0.008 for trend). CONCLUSION: Our data indicate an association between chronic anemic hypoxia and increased PAP in SLE patients and suggest that increased IL-6 might participate in this process. PMID- 26018412 TI - Influence of plant community composition on biomass production in planted grasslands. AB - United States energy policy mandates increased use of renewable fuels. Restoring grasslands could contribute to a portion of this requirement through biomass harvest for bioenergy use. We investigated which plant community characteristics are associated with differences in biomass yield from a range of realistic native prairie plantings (n = 11; i.e., conservation planting, restoration, and wildlife cover). Our primary goal was to understand whether patterns in plant community composition and the Floristic Quality Index (FQI) were related to productivity as evidenced by dormant season biomass yield. FQI is an objective measure of how closely a plant community represents that of a pre-European settlement community. Our research was conducted in planted fields of native tallgrass prairie species, and provided a gradient in floristic quality index, species richness, species diversity, and species evenness in south-central Wisconsin during 2008 and 2009. We used a network of 15 randomly located 1 m2 plots within each field to characterize the plant community and estimate biomass yield by clipping the plots at the end of each growing season. While plant community composition and diversity varied significantly by planting type, biomass yield did not vary significantly among planting types (ANOVA; P >0.05). Biomass yield was positively correlated with plant community evenness, richness, C4 grass cover, and floristic quality index, but negatively correlated with plant species diversity in our multi-season multiple linear mixed effects models. Concordantly, plots with biomass yield in the lowest quartile (biomass yield < 3500 kh/ha) had 8% lower plant community evenness and 9% lower FQI scores than those in the upper quartile (biomass yield > 5800 kh/ha). Our results suggest that promoting the establishment of fields with high species evenness and floristic quality may increase biomass yield, while simultaneously supporting biodiversity. PMID- 26018413 TI - Dynamic Proteome Response of Pseudomonas aeruginosa to Tobramycin Antibiotic Treatment. AB - Genetically susceptible bacteria become antibiotic tolerant during chronic infections, and the mechanisms responsible are poorly understood. One factor that may contribute to differential sensitivity in vitro and in vivo is differences in the time-dependent tobramycin concentration profile experienced by the bacteria. Here, we examine the proteome response induced by subinhibitory concentrations of tobramycin in Pseudomonas aeruginosa cells grown under planktonic conditions. These efforts revealed increased levels of heat shock proteins and proteases were present at higher dosage treatments (0.5 and 1 MUg/ml), while less dramatic at 0.1 MUg/ml dosage. In contrast, many metabolic enzymes were significantly induced by lower dosages (0.1 and 0.5 MUg/ml) but not at 1 MUg/ml dosage. Time course proteome analysis further revealed that the increase of heat shock proteins and proteases was most rapid from 15 min to 60 min, and the increased levels sustained till 6 h (last time point tested). Heat shock protein IbpA exhibited the greatest induction by tobramycin, up to 90-fold. Nevertheless, deletion of ibpA did not enhance sensitivity to tobramycin. It seemed possible that the absence of sensitization could be due to redundant functioning of IbpA with other proteins that protect cells from tobramycin. Indeed, inactivation of two heat shock chaperones/proteases in addition to ibpA in double mutants (ibpA/clpB, ibpA/PA0779 and ibpA/hslV) did increase tobramycin sensitivity. Collectively, these results demonstrate the time- and concentration-dependent nature of the P. aeruginosa proteome response to tobramycin and that proteome modulation and protein redundancy are protective mechanisms to help bacteria resist antibiotic treatments. PMID- 26018415 TI - Interruptions to supply of high-dose hydrocortisone tablets and the incidence of adrenal crises. PMID- 26018414 TI - The Human Pathogen Streptococcus pyogenes Releases Lipoproteins as Lipoprotein rich Membrane Vesicles. AB - Bacterial lipoproteins are attractive vaccine candidates because they represent a major class of cell surface-exposed proteins in many bacteria and are considered as potential pathogen-associated molecular patterns sensed by Toll-like receptors with built-in adjuvanticity. Although Gram-negative lipoproteins have been extensively characterized, little is known about Gram-positive lipoproteins. We isolated from Streptococcus pyogenes a large amount of lipoproteins organized in vesicles. These vesicles were obtained by weakening the bacterial cell wall with a sublethal concentration of penicillin. Lipid and proteomic analysis of the vesicles revealed that they were enriched in phosphatidylglycerol and almost exclusively composed of lipoproteins. In association with lipoproteins, a few hypothetical proteins, penicillin-binding proteins, and several members of the ExPortal, a membrane microdomain responsible for the maturation of secreted proteins, were identified. The typical lipidic moiety was apparently not necessary for lipoprotein insertion in the vesicle bilayer because they were also recovered from the isogenic diacylglyceryl transferase deletion mutant. The vesicles were not able to activate specific Toll-like receptor 2, indicating that lipoproteins organized in these vesicular structures do not act as pathogen associated molecular patterns. In light of these findings, we propose to name these new structures Lipoprotein-rich Membrane Vesicles. PMID- 26018416 TI - Interaction between hyperdirect and indirect basal ganglia pathways. PMID- 26018418 TI - Spirobisnaphthalenes effectively inhibit carbonic anhydrase. AB - This study explores the correlation between human carbonic anhydrase (CA, EC 4.2.1.1) isoforms I and II (hCA I, II) and the inhibitory features of some spirobisnaphthalene derivatives. A group of spirobisnaphthalenes was synthesized and their hCA I and II inhibitory effects was investigated. The Ki values were similar for both CA isoenzymes, the compounds showing good inhibitory activity. Ki values ranged between 1.60 and 460.42 uM for hCA I and between 0.39 and 419.42 uM for hCA II, respectively. The spirobisnaphthalenes derivatives might be useful for designing CA inhibitors belonging to novel chemotypes compared to the highly investigated sulfonamides, sulfamates or coumarins. PMID- 26018417 TI - Streptococcus uberis and Staphylococcus aureus forefoot and blood stream co infection in a haemodialysis patient: a case report. AB - BACKGROUND: Streptococcus uberis, the most frequent cause of mastitis in lactating cows, is considered non-pathogenic for humans. Only a few case reports have described human infections with this microorganism, which is notoriously difficult to identify. CASE PRESENTATION: We report the case of a 75-year-old male haemodialysis patient, who developed a severe foot infection with osteomyelitis and bacteraemia. Both Streptococcus uberis and Staphylococcus aureus were identified in wound secretion and blood samples using mass spectrometry. The presence of Streptococcus uberis was confirmed by superoxide dismutase A sequencing. The patient recovered after amputation of the forefoot and antibiotic treatment with ampicillin/sulbactam. He had probably acquired the infection while walking barefoot on cattle pasture land. CONCLUSION: This is the first case report of a human infection with Streptococcus uberis with identification of the microorganism using modern molecular technology. We propose that Staphylococcus aureus co-infection was a prerequisite for deep wound and bloodstream infection with Streptococcus uberis. PMID- 26018419 TI - Purification of glutathione S-transferase from Van Lake fish (Chalcalburnus tarichii Pallas) muscle and investigation of some metal ions effect on enzyme activity. AB - Glutathione S-transferases (GSTs) are an important enzyme family which play a critical role in detoxification system. In our study, GST was purified from muscle tissue of Chalcalburnus tarichii Pallas with 301.5-fold purification and 19.07% recovery by glutathione agarose affinity chromatography. The purity of enzyme was checked by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, showing a two band, because of having heterodimer structure. KM values were 1.59 and 0.53 mM for 1-chloro-2,4-dinitrobenzene (CDNB) and glutathione (GSH), respectively. Vmax values for CDNB and GSH were also determined as 5.58 and 1.88 EU/mL, respectively. In addition, inhibition effects of Ag(+), Cu(2+), Cd(2+), Fe(3+), Pb(2+), Cr(2+), Co(2+) and Zn(2+) metal ions were investigated on the enzyme activity and IC50, Ki values were calculated for these metal ions. PMID- 26018420 TI - Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect. AB - CONTEXT: Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. OBJECTIVE: To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. MATERIALS AND METHODS: In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. RESULTS: Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. DISCUSSION: These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. CONCLUSION: The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation. PMID- 26018421 TI - QSAR and docking studies of anthraquinone derivatives by similarity cluster prediction. AB - Forty anthraquinone derivatives have been downloaded from PubChem database and investigated in a quantitative structure-activity relationships (QSAR) study. The models describing log P and LD50 of this set were built up on the hypermolecule scheme that mimics the investigated receptor space; the models were validated by the leave-one-out procedure, in the external test set and in a new version of prediction by using similarity clusters. Molecular docking approach using Lamarckian Genetic Algorithm was made on this class of anthraquinones with respect to 3Q3B receptor. The best scored molecules in the docking assay were used as leaders in the similarity clustering procedure. It is demonstrated that the LD50 data of this set of anthraquinones are related to the binding energies of anthraquinone ligands to the 3Q3B receptor. PMID- 26018422 TI - Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells. AB - Cucurbitacin B (Cuc B), a natural compound extracted from cucurbitaceous plants, demonstrated potent anticancer activities, while the underlying mechanisms remain unclear. We investigated the anticancer effect of Cuc B on MCF-7 breast cancer cells. Cuc B drastically decreased cell viability in a concentration-dependent manner. Cuc B treatment caused DNA damage, as shown by long tails in the comet assay and increased gammaH2AX protein expression. Immunofluorescence staining showed that Cuc B treatment induced nuclear gammaH2AX foci. Cuc B activated DNA damage pathways by phosphorylation of ATM/ATR [two large phosphatidylinositol-3 kinase-like kinase family (PIKKs) members]. Furthermore, it also induced autophagy, as evidenced by monodansylcadaverine (MDC) staining and autophagic protein expression. In addition, Cuc B treatment led to increased reactive oxygen species (ROS) formation, which was inhibited by N-acetyl-L-cysteine (NAC) pretreatment. NAC pretreatment inhibited Cuc-B-induced DNA damage and autophagy. Taken together, these results suggest that ROS-mediated Cuc-B-induced DNA damage and autophagy in MCF-7 cells, which provides new insights into the anticancer molecular mechanism of Cuc B. PMID- 26018423 TI - The relationship between balance measured with a modified bathroom scale and falls and disability in older adults: a 6-month follow-up study. AB - BACKGROUND: There are indications that older adults who suffer from poor balance have an increased risk for adverse health outcomes, such as falls and disability. Monitoring the development of balance over time enables early detection of balance decline, which can identify older adults who could benefit from interventions aimed at prevention of these adverse outcomes. An innovative and easy-to-use device that can be used by older adults for home-based monitoring of balance is a modified bathroom scale. OBJECTIVE: The objective of this paper is to study the relationship between balance scores obtained with a modified bathroom scale and falls and disability in a sample of older adults. METHODS: For this 6-month follow-up study, participants were recruited via physiotherapists working in a nursing home, geriatricians, exercise classes, and at an event about health for older adults. Inclusion criteria were being aged 65 years or older, being able to stand on a bathroom scale independently, and able to provide informed consent. A total of 41 nursing home patients and 139 community-dwelling older adults stepped onto the modified bathroom scale three consecutive times at baseline to measure their balance. Their mean balance scores on a scale from 0 to 16 were calculated-higher scores indicated better balance. Questionnaires were used to study falls and disability at baseline and after 6 months of follow-up. The cross-sectional relationship between balance and falls and disability at baseline was studied using t tests and Spearman rank correlations. Univariate and multivariate logistic regression analyses were conducted to study the relationship between balance measured at baseline and falls and disability development after 6 months of follow-up. RESULTS: A total of 128 participants with complete datasets--25.8% (33/128) male-and a mean age of 75.33 years (SD 6.26) were included in the analyses of this study. Balance scores of participants who reported at baseline that they had fallen at least once in the past 6 months were lower compared to nonfallers--8.9 and 11.2, respectively (P<.001). The correlation between mean balance score and disability sum-score at baseline was .51 (P<.001). No significant associations were found between balance at baseline and falls after 6 months of follow-up. Baseline balance scores were significantly associated with the development of disability after 6 months of follow-up in the univariate analysis--odds ratio (OR) 0.86 (95% CI 0.76-0.98)-but not in the multivariate analysis when correcting for age, gender, baseline disability, and falls at follow-up-OR 0.94 (95% CI 0.79-1.11). CONCLUSIONS: There is a cross sectional relationship between balance measured by a modified bathroom scale and falls and disability in older adults. Despite this cross-sectional relationship, longitudinal data showed that balance scores have no predictive value for falls and might only have limited predictive value for disability development after 6 months of follow-up. PMID- 26018424 TI - Gout and the risk of dementia: a nationwide population-based cohort study. AB - INTRODUCTION: Uric acid was proposed to have anti-oxidant property and possible neuroprotective effects. We examined the association between gout and dementia with population database. METHODS: The study utilized the claims data from the nationwide representative sample of Taiwan National Health Insurance Research Database (NHIRD). We ascertained patients with gout and dementia covering vascular and non-vascular (including Alzheimer's) subtypes using International Classification of Diseases Ninth Revision, Clinical Modification (ICD9-CM) codes. A control group matched on sex, age, and index date of gout patients was randomly sampled with a ratio of 1:4 from the same database for comparison. RESULTS: From 2002 to 2008, 28,769 gout patients who were older than 50 years old were identified, and 114,742 control patients was matched into the study. During follow-up, 7,119 patients developed dementia (1,214 with gout, and 5,905 without gout). After adjusting for age, sex, and relevant comorbidities, a Cox regression analysis showed that gout patients had a lower risk of developing non-vascular dementia (hazard ratio (HR): 0.77; 95% confidence interval (CI): 0.72-0.83; p < 0.001) and vascular dementia (HR: 0.76; 95% CI: 0.65-0.88; p < 0.001). CONCLUSIONS: Patients with gout have a lower risk of developing dementia. This phenomenon exists for both non-vascular and vascular types of dementia. PMID- 26018425 TI - VoICE: A semi-automated pipeline for standardizing vocal analysis across models. AB - The study of vocal communication in animal models provides key insight to the neurogenetic basis for speech and communication disorders. Current methods for vocal analysis suffer from a lack of standardization, creating ambiguity in cross laboratory and cross-species comparisons. Here, we present VoICE (Vocal Inventory Clustering Engine), an approach to grouping vocal elements by creating a high dimensionality dataset through scoring spectral similarity between all vocalizations within a recording session. This dataset is then subjected to hierarchical clustering, generating a dendrogram that is pruned into meaningful vocalization "types" by an automated algorithm. When applied to birdsong, a key model for vocal learning, VoICE captures the known deterioration in acoustic properties that follows deafening, including altered sequencing. In a mammalian neurodevelopmental model, we uncover a reduced vocal repertoire of mice lacking the autism susceptibility gene, Cntnap2. VoICE will be useful to the scientific community as it can standardize vocalization analyses across species and laboratories. PMID- 26018426 TI - Study of the chlorpyrifos neurotoxicity using neural differentiation of adipose tissue-derived stem cells. AB - Chlorpyrifos (CPF) is the most commonly used organophosphorus insecticide which causes neurodevelopmental toxicity. So far, animals have been used as ideal models for neurotoxicity studies, but working with animals is very expensive, laborious, and ethically challenging. This has encouraged researchers to seek alternatives. During recent years, several studies have reported successful differentiation of embryonic and adult stem cells to neurons. This has provided an excellent model for neurotoxicologic studies. In this study, neural differentiation of mouse adipose tissue-derived stem cells (ADSCs) was used as an in vitro model for investigation of CPF neurotoxicity. For this purpose, mouse ADSCs were cultured in a medium containing knockout serum replacement and were treated with different concentrations of CPF at several stages of differentiation. Cytotoxic effect of CPF and the expression of neuron-specific genes and proteins were studied in the differentiating ADSCs. Furthermore, the activity of acetylcholinesterase was assessed by Ellman assay at different stages of differentiation. This study showed that up to 500 MUM CPF did not alter viability of the undifferentiated ADSCs, whereas viability of the differentiating cells decreased with 500 MUM CPF. CPF upregulated the expression of some neuron specific genes and seemed to decrease the number of beta-tubulin III and MAP2 proteins-expressing cells. There was no detectable acetylcholine esterase activity in differentiated ADSCs. In summary, it was shown that CPF treatment can decrease the viability of ADSC-derived neurons and dysregulate the expression of some neuronal markers through acetylcholinesterase-independent mechanisms. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1510-1519, 2016. PMID- 26018427 TI - The human transmembrane proteome. AB - BACKGROUND: Transmembrane proteins have important roles in cells, as they are involved in energy production, signal transduction, cell-cell interaction, cell cell communication and more. In human cells, they are frequently targets for pharmaceuticals; therefore, knowledge about their properties and structure is crucial. Topology of transmembrane proteins provide a low resolution structural information, which can be a starting point for either laboratory experiments or modelling their 3D structures. RESULTS: Here, we present a database of the human alpha-helical transmembrane proteome, including the predicted and/or experimentally established topology of each transmembrane protein, together with the reliability of the prediction. In order to distinguish transmembrane proteins in the proteome as well as for topology prediction, we used a newly developed consensus method (CCTOP) that incorporates recent state of the art methods, with tested accuracies on a novel human benchmark protein set. CCTOP utilizes all available structure and topology data as well as bioinformatical evidences for topology prediction in a probabilistic framework provided by the hidden Markov model. This method shows the highest accuracy (98.5 % for discrinimating between transmembrane and non-transmembrane proteins and 84 % for per protein topology prediction) among the dozen tested topology prediction methods. Analysis of the human proteome with the CCTOP indicates that it contains 4998 (26 %) transmembrane proteins. Besides predicting topology, reliability of the predictions is estimated as well, and it is demonstrated that the per protein prediction accuracies of more than 60 % of the predictions are over 98 % on the benchmark sets and most probably on the predicted human transmembrane proteome too. CONCLUSIONS: Here, we present the most accurate prediction of the human transmembrane proteome together with the experimental topology data. These data, as well as various statistics about the human transmembrane proteins and their topologies can be downloaded from and can be visualized at the website of the human transmembrane proteome ( http://htp.enzim.hu ). PMID- 26018428 TI - Investigation of bone quality of the first and second sacral segments amongst trauma patients: concerns about iliosacral screw fixation. AB - BACKGROUND: Iliosacral screw fixation has become a common method for surgical stabilization of acute disruptions of the pelvic ring. Placement of iliosacral screws into the first sacral (S1) body is the preferred method of fixation, but size limitations and sacral dysmorphism may preclude S1 fixation. In these clinical situations, fixation into the second sacral (S2) body has been recommended. The objective of this study was to evaluate the bone quality of the S1 compared to S2 in the described "safe zone" of iliosacral screw fixation in trauma patients. MATERIALS AND METHODS: The pelvic computed tomography scans of 25 consecutive trauma patients, ages 18-49, at a level 1 trauma center were prospectively analyzed. Hounsfield units, a standardized computed tomography attenuation coefficient, was utilized to measure regional cancellous bone mineral density of the S1 and S2. No change in the clinical protocol or treatment occurred as a consequence of inclusion in this study. RESULTS: A statically significant difference in bone quality was found when comparing the first and second sacral segment (p = 0.0001). Age, gender, or smoking status did not independently affect bone quality. CONCLUSION: In relatively young, otherwise healthy trauma patients there is a statistically significant difference in the bone density of the first sacral segment compared to the second sacral segment. This study highlights the need for future biomechanical studies to investigate whether this difference is clinically relevant. Due to the relative osteopenia in the second sacral segment, which may impact the quality of fixation, we feel this technique should be used with caution. PMID- 26018430 TI - Size-dependent electronic structure controls activity for ethanol electro oxidation at Ptn/indium tin oxide (n = 1 to 14). AB - Understanding the factors that control electrochemical catalysis is essential to improving performance. We report a study of electrocatalytic ethanol oxidation - a process important for direct ethanol fuel cells - over size-selected Pt centers ranging from single atoms to Pt14. Model electrodes were prepared by soft-landing of mass-selected Ptn(+) on indium tin oxide (ITO) supports in ultrahigh vacuum, and transferred to an in situ electrochemical cell without exposure to air. Each electrode had identical Pt coverage, and differed only in the size of Pt clusters deposited. The small Ptn have activities that vary strongly, and non monotonically with deposited size. Activity per gram Pt ranges up to ten times higher than that of 5 to 10 nm Pt particles dispersed on ITO. Activity is anti correlated with the Pt 4d core orbital binding energy, indicating that electron rich clusters are essential for high activity. PMID- 26018429 TI - Detection of Labile Low-Molecular-Mass Transition Metal Complexes in Mitochondria. AB - Liquid chromatography was used with an online inductively coupled plasma mass spectrometer to detect low-molecular-mass (LMM) transition metal complexes in mitochondria isolated from fermenting yeast cells, human Jurkat cells, and mouse brain and liver. These complexes constituted 20-40% of total mitochondrial Mn, Fe, Zn, and Cu ions. The major LMM Mn complex in yeast mitochondria, called Mn1100, had a mass of ~1100 Da and a concentration of ~2 MUM. Mammalian mitochondria contained a second Mn species with a mass of ~2000 Da at a comparable concentration. The major Fe complex in mitochondria isolated from exponentially growing yeast cells had a mass of ~580 Da; the concentration of Fe580 in mitochondria was ~100 MUM. When mitochondria were isolated from fermenting cells in postexponential phase, the mass of the dominant LMM Fe complex was ~1100 Da. Upon incubation, the intensity of Fe1100 declined and that of Fe580 increased, suggesting that the two are interrelated. Mammalian mitochondria contained Fe580 and two other Fe species (Fe2000 and Fe1100) at concentrations of ~50 MUM each. The dominant LMM Zn species in mitochondria had a mass of ~1200 Da and a concentration of ~110 MUM. Mammalian mitochondria contained a second major LMM Zn species at 1500 Da. The dominant LMM Cu species in yeast mitochondria had a mass of ~5000 Da and a concentration in yeast mitochondria of ~16 MUM; Cu5000 was not observed in mammalian mitochondria. The dominant Co species in mitochondria, Co1200, had a concentration of 20 nM and was probably a cobalamin. Mammalian but not yeast mitochondria contained a LMM Mo species, Mo730, at a concentration of ~1 MUM. Increasing Mn, Fe, Cu, and Zn concentrations 10-fold in the medium increased the concentration of the same element in the corresponding isolated mitochondria. Treatment with metal chelators confirmed that these LMM species were labile. The dominant S species at 1100 Da was not free glutathione or glutathione disulfide. PMID- 26018432 TI - Maintenance Electroconvulsive Therapy: Cost-effectiveness and Patient/Family Satisfaction. PMID- 26018431 TI - High-resolution and specific detection of bacteria on complex surfaces using nanoparticle probes and electron microscopy. AB - The study of the interaction of bacteria with surfaces requires the detection of specific bacterial groups with high spatial resolution. Here, we describe a method to rapidly and efficiently add nanogold particles to oligonucleotide probes, which target bacterial ribosomal RNA. These nanogold-labeled probes are then used in an in situ hybridization procedure that ensures both cellular integrity and high specificity. Electron microscopy subsequently enables the visualization of specific cells with high local precision on complex surface structures. This method will contribute to an increased understanding of how bacteria interact with surface structures on a sub-micron scale. PMID- 26018433 TI - Morphology and crystallinity control of ultrathin TiO2 layers deposited on carbon nanotubes by temperature-step atomic layer deposition. AB - Carbon nanotubes (CNTs) coated with titanium oxide (TiO2) have generated considerable interest over the last decade and become a promising nanomaterial for a wide range of energy applications. The efficient use of the outstanding electrical properties of this nanostructure relies heavily on the quality of the interface and the thickness and morphology of the TiO2 layer. However, complete surface coverage of the chemically inert CNTs and appropriate control of the morphology of the TiO2 layer have not been achieved so far. Here, we report a new strategy to obtain ultrathin TiO2 coatings deposited by "Temperature-step" Atomic Layer Deposition (TS-ALD) with complete surface coverage of non-functionalized multiwall carbon nanotubes (MWCNTs) and controlled morphology and crystallinity of the TiO2 film. This strategy consists of adjusting the temperature during the ALD deposition to obtain the desired morphology. Complete coverage of long non functionalized MWCNTs with conformal anatase layers was obtained by using a low temperature of 60 degrees C during the nucleation stage followed by an increase to 220 degrees C during the growth stage. This resulted in a continuous and amorphous TiO2 layer, covered with a conformal anatase coating. Starting with the deposition at 220 degrees C and reducing to 60 degrees C resulted in sporadic crystal grains at the CNT/TiO2 interface covered with an amorphous TiO2 layer. The results were accomplished through an extensive study of nucleation and growth of titanium oxide films on MWCNTs, of which a detailed characterization is presented in this work. PMID- 26018434 TI - Cloud Point and Liquid-Liquid Equilibrium Behavior of Thermosensitive Polymer L61 and Salt Aqueous Two-Phase System. AB - The cloud point of thermosensitive triblock polymer L61, poly(ethylene oxide) poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO), was determined in the presence of various electrolytes (K2HPO4, (NH4)3C6H5O7, and K3C6H5O7). The cloud point of L61 was lowered by the addition of electrolytes, and the cloud point of L61 decreased linearly with increasing electrolyte concentration. The efficacy of electrolytes on reducing cloud point followed the order: K3C6H5O7 > (NH4)3C6H5O7 > K2HPO4. With the increase in salt concentration, aqueous two-phase systems exhibited a phase inversion. In addition, increasing the temperature reduced the concentration of salt needed that could promote phase inversion. The phase diagrams and liquid-liquid equilibrium data of the L61 K2HPO4/(NH4)3C6H5O7/K3C6H5O7 aqueous two-phase systems (before the phase inversion but also after phase inversion) were determined at T = (25, 30, and 35) degrees C. Phase diagrams of aqueous two-phase systems were fitted to a four parameter empirical nonlinear expression. Moreover, the slopes of the tie-lines and the area of two-phase region in the diagram have a tendency to rise with increasing temperature. The capacity of different salts to induce aqueous two phase system formation was the same order as the ability of salts to reduce the cloud point. PMID- 26018435 TI - Generalized Degenerative Joint Disease in Osteoprotegerin (Opg) Null Mutant Mice. AB - Bone structure is modulated by the interaction between receptor activator of nuclear factor-kappaB (RANK) and RANK ligand (RANKL). Osteoprotegerin (OPG), a decoy receptor for RANKL, modifies osteoclast-mediated bone resorption directly and spares articular cartilage indirectly in rodents with immune-mediated arthritis by preventing subchondral bone destruction. The OPG/RANKL balance also seems to be critical in maintaining joint integrity in osteoarthritis, a condition featuring articular bone and cartilage damage in the absence of profound inflammation. The current study explored the role of OPG in sparing articular cartilage by evaluating joint lesions in adult C57BL/6J mice lacking osteoprotegerin (Opg (-) (/-)). At 3, 5, 7, 9, and 12 months of age, both sexes of Opg (-) (/-) mice developed severe degenerative joint disease (DJD) characterized by progressive loss of cartilage matrix and eventually articular cartilage. Lesions developed earlier and more severely in Opg (-) (/-) mice relative to age-matched, wild-type (Opg (+) (/+)), or heterozygous (Opg (+) (/-)) littermates (P <= .05). The femorotibial joint was affected bilaterally at 3 months, while other key weight-bearing diarthrodial joints (eg, coxofemoral, scapulohumeral, humeroradioulnar) were affected later and unilaterally. Cortical bone in subchondral plates and long bone diaphyses of Opg (-) (/-) mice but not Opg (+/+) or Opg (+) (/-) animals was osteoporotic by 3 months of age (P <= .05); the extent of porosity was less than the degree of DJD. Closure of the physes in long bones (P <= .05) and cartilage retention in the femoral primary spongiosa (P <= .05) affected chiefly Opg (-) (/-) mice. These data suggest that OPG plays an essential direct role in maintaining cartilage integrity in the articular surfaces and physes. PMID- 26018436 TI - Fibroblast Growth Factor 23: A New Dimension to Diseases of Calcium-Phosphorus Metabolism. AB - Traditionally, control of phosphorus in the body has been considered secondary to the tighter control of calcium by parathyroid hormone and vitamin D. However, over the past decade, substantial advances have been made in understanding the control of phosphorus by the so-called phosphatonin system, the lynchpin of which is fibroblast growth factor 23 (FGF23). FGF23 binds to the klotho/FGFR1c receptor complex in renal tubular epithelial cells, leading to upregulation of Na/Pi cotransporters and subsequent excretion of phosphorus from the body. In addition, FGF23 inhibits parathyroid hormone and the renal 1alpha-hydroxylase enzyme, while it stimulates 24-hydroxylase, leading to decreased 1,25-dihydroxyvitamin D3. FGF23 is intimately involved in the pathogenesis of a number of diseases, particularly the hereditary hypophosphatemic rickets group and chronic kidney disease, and is a target for the development of new treatments in human medicine. Little work has been done on FGF23 or the other phosphatonins in veterinary medicine, but increases in FGF23 are seen with chronic kidney disease in cats, and increased FGF23 expression has been found in soft tissue sarcomas in dogs. PMID- 26018437 TI - Synthesis and photovoltaic properties of two new alkoxylphenyl substituted thieno[2,3-f]benzofuran based polymers. AB - Two new alkoxylphenyl substituted thieno[2,3-f]benzofuran (TBFP)-based polymers (PTBFP-BT and PTBFP-BO) were designed and synthesized. Their structures were verified by nuclear magnetic resonance (NMR) spectroscopy, the molecular weights were determined by gel permeation chromatography (GPC) and the thermal properties were investigated by thermogravimetric analysis (TGA). The two polymers showed similar UV-Vis absorption spectra with a broad and strong absorption band from 300-750 nm in solid state. The resulting copolymers exhibited relatively deep highest occupied molecular orbital (HOMO) energy levels (-5.47 and -5.61 eV) for PTBFP-BT and PTBFP-BO, respectively. The device fabricated with PTBFP-BT : PC71BM (1 : 2) showed better balanced hole and electron mobility of 2.49 * 10(-4) cm(2) V(-1) s(-1) and 9.12 * 10(-4) cm(2) V(-1) s(-1), respectively, than those of PTBFP-BO based devices. The polymer solar cells (PSCs), based on the single layer device structure of ITO/PEDOT:PSS/PTBFP-BT : PC71BM (1 : 2, w/w)/ZrAcac/Al with 3 vol% 1,8-diiodooctane (DIO) as additive, showed a relatively high power conversion efficiency (PCE) of 6% under the illumination of AM 1.5G, 100 mW cm( 2), with a high fill factor (FF) of 0.69. PMID- 26018438 TI - The evolving paradigm of cancer risk related to cyclophosphamide therapy in granulomatosis with polyangiitis. PMID- 26018439 TI - Stubbing it out: tackling smoking in rheumatology clinics. PMID- 26018440 TI - Special focus: Asia endemic diseases. PMID- 26018441 TI - Letter from the editor. PMID- 26018442 TI - Comparable quality attributes of hepatitis E vaccine antigen with and without adjuvant adsorption-dissolution treatment. AB - Most vaccines require adjuvants for antigen stabilization and immune potentiation. Aluminum-based adjuvants are the most widely used adjuvants for human vaccines. Previous reports demonstrated the preservation of antigen conformation and other antigen characteristics after recovery from adjuvanted Hepatitis B and human papillomavirus vaccines. In this study, we used a combination of various physiochemical and immunochemical methods to analyze hepatitis E vaccine antigen quality attributes after recovery from adjuvants. All biochemical and biophysical methods showed similar characteristics of the p239 protein after recovery from adjuvanted vaccine formulation compared to the antigen in solution which never experienced adsorption/desorption process. Most importantly, we demonstrated full preservation of key antigen epitopes post recovery from adjuvanted vaccine using a panel of murine monoclonal antibodies as exquisite probes. Antigenicity of p239 was probed with a panel of 9 mAbs using competition/blocking ELISA, surface plasmon resonance and sandwich ELISA methods. These multifaceted analyses demonstrated the preservation of antigen key epitopes and comparable protein thermal stability when adsorbed on adjuvants or of the recovered antigen post-dissolution treatment. A better understanding of the antigen conformation in adjuvanted vaccine will enhanced our knowledge of antigen adjuvant interactions and facilitate an improved process control and development of stable vaccine formulation. PMID- 26018443 TI - Long term follow-up study to evaluate immunogenicity and safety of a single dose of live attenuated hepatitis a vaccine in children. AB - Worldwide, viral hepatitis continues to be a cause of considerable morbidity and mortality. Mass immunization with a single dose of live attenuated HAV has been shown to significantly reduce disease burden in the community. This was a phase IV, 5-year follow up study carried out at 4 centers (Kolkata, Delhi, Mumbai and Chennai) across India. The subjects with antibody titer <20 mIU/mL at baseline were evaluated for long term immunogenicity. Of the 503 subjects enrolled, 349 subjects were baseline seronegative with an anti-HAV antibody titer <20 mIU/mL. Overall, 343 subjects could be followed up at some point of time during this 5 y post vaccination period. In the last year (60 months) of follow-up, 108 subjects (97.3%) of 111 subjects (who came for follow-up at the end of 5 y) had a protective antibody titer (anti-HAV antibody titer >20 mIU/mL). The seroconversion rates considering seroprotection levels of anti-HAV antibody titer >20 mIU/mL, following vaccination starting from 6 weeks, 6 months, 12 months, 24 months, 36 months, 48 months and 60 months were 95.1%, 97.9%, 98.3%, 96.2%, 97.8%, 92.6% and 97.3%, respectively. The geometric mean concentration (GMC) over the years increased from 64.9 mIU/mL at 6 weeks to 38.1 mIU/mL and 135.2 mIU/mL at 6 months and 12 months, respectively and was maintained at 127.1 mIU/mL at 60 months. In conclusion, the result of this 5-year follow up study showed that the single dose of live attenuated vaccine is well tolerated and provides long-term immunogenicity in healthy Indian children. PMID- 26018445 TI - Erratum. PMID- 26018444 TI - New tools for NTD vaccines: A case study of quality control assays for product development of the human hookworm vaccine Na-APR-1M74. AB - Na-APR-1(M74) is an aspartic protease that is rendered enzymatically inactive by site-directed mutagenesis and is a candidate antigen component in the Human Hookworm Vaccine. The mutant protease exerts vaccine efficacy by inducing antibodies that neutralize the enzymatic activity of wild type enzyme (Na-APR 1wt) in the gut of the hookworm, thereby depriving the worm of its ability to digest its blood meal. Previously, canines immunized with Na-APR-1(M74) and challenged with Ancylostoma caninum were partially protected against hookworm challenge infection, especially from the loss in hemoglobin observed in control canines and canine immunoglobulin (Ig) G raised against Na-APR-1 was shown to inhibit the enzymatic activity of Na-APR-1 wt in vitro, thereby providing proof of concept of Na-APR-1(M74) as a vaccine antigen. The mutated version, Na-APR 1(M74), was then expressed at the cGMP level using a Nicotiana benthamiana expression system (Fraunhofer, CMB, Delaware, MD), formulated with Alhydrogel(r), and used to immunize mice in a dose-ranging study to explore the enzyme neutralizing capacity of the resulting anti- Na-APR-1(M74) IgG. As little as 0.99 MUg of recombinant Na-APR-1(M74) could induce anti Na-APR-1(M74) IgG in mice that were capable of inhibiting Na-APR-1w t-mediated digestion of a peptide substrate by 89%. In the absence of enzymatic activity of Na-APR-1(M74) as a surrogate marker of protein functionality, we developed an assay based on the binding of a quenched fluorescence-labeled inhibitor of aspartic proteases, BODIPY-FL pepstatin A (BDP). Binding of BDP in the active site of Na-APR-1 wt was demonstrated by inhibition of enzymatic activity, and competitive binding with unlabelled pepstatin A. BDP also bound to Na-APR-1(M74) which was assessed by fluorescence polarization, but with an ~ 50-fold reduction in the dissociation constant. Taken together, these assays comprise a "toolbox" that could be useful for the analyses of Na-APR-1(M74) as it proceeds through the clinical development as part of the Human Hookworm Vaccine pipeline. PMID- 26018446 TI - Corrigendum. PMID- 26018447 TI - Corrigendum. PMID- 26018448 TI - Exploring the relationship between lifestyles, diets and genetic adaptations in humans. AB - BACKGROUND: One of the most important dietary shifts underwent by human populations began to occur in the Neolithic, during which new modes of subsistence emerged and new nutrients were introduced in diets. This change might have worked as a selective pressure over the metabolic pathways involved in the breakdown of substances extracted from food. Here we applied a candidate gene approach to investigate whether in populations with different modes of subsistence, diet-related genetic adaptations could be identified in the genes AGXT, PLRP2, MTRR, NAT2 and CYP3A5. RESULTS: At CYP3A5, strong signatures of positive selection were detected, though not connected to any dietary variable, but instead to an environmental factor associated with the Tropic of Cancer. Suggestive signals of adaptions that could indeed be connected with differences in dietary habits of populations were only found for PLRP2 and NAT2. Contrarily, the demographic history of human populations seemed enough to explain patterns of diversity at AGXT and MTRR, once both conformed the evolutionary expectations under selective neutrality. CONCLUSIONS: Accumulated evidence indicates that CYP3A5 has been under adaptive evolution during the history of human populations. PLRP2 and NAT2 also appear to have been modelled by some selective constrains, although clear support for that did not resist to a genome wide perspective. It is still necessary to clarify which were the biological mechanisms and the environmental factors involved as well as their interactions, to understand the nature and strength of the selective pressures that contributed to shape current patterns of genetic diversity at those loci. PMID- 26018449 TI - Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei. AB - A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP) expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3) inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds. PMID- 26018450 TI - Geographic distribution of phlebotomine sandfly species (Diptera: Psychodidae) in Central-West Brazil. AB - This study updates the geographic distributions of phlebotomine species in Central-West Brazil and analyses the climatic factors associated with their occurrence. The data were obtained from the entomology services of the state departments of health in Central-West Brazil, scientific collections and a literature review of articles from 1962-2014. Ecological niche models were produced for sandfly species with more than 20 occurrences using the Maxent algorithm and eight climate variables. In all, 2,803 phlebotomine records for 127 species were analysed. Nyssomyia whitmani, Evandromyia lenti and Lutzomyia longipalpis were the species with the greatest number of records and were present in all the biomes in Central-West Brazil. The models, which were produced for 34 species, indicated that the Cerrado areas in the central and western regions of Central-West Brazil were climatically more suitable to sandflies. The variables with the greatest influence on the models were the temperature in the coldest months and the temperature seasonality. The results show that phlebotomine species in Central-West Brazil have different geographical distribution patterns and that climate conditions in essentially the entire region favour the occurrence of at least one Leishmania vector species, highlighting the need to maintain or intensify vector control and surveillance strategies. PMID- 26018451 TI - Recombinant hepatitis C virus-envelope protein 2 interactions with low-density lipoprotein/CD81 receptors. AB - Hepatitis C virus (HCV) envelope protein 2 (E2) is involved in viral binding to host cells. The aim of this work was to produce recombinant E2B and E2Y HCV proteins in Escherichia coli and Pichia pastoris, respectively, and to study their interactions with low-density lipoprotein receptor (LDLr) and CD81 in human umbilical vein endothelial cells (HUVEC) and the ECV304 bladder carcinoma cell line. To investigate the effects of human LDL and differences in protein structure (glycosylated or not) on binding efficiency, the recombinant proteins were either associated or not associated with lipoproteins before being assayed. The immunoreactivity of the recombinant proteins was analysed using pooled serum samples that were either positive or negative for hepatitis C. The cells were immunophenotyped by LDLr and CD81 using flow cytometry. Binding and binding inhibition assays were performed in the presence of LDL, foetal bovine serum (FCS) and specific antibodies. The results revealed that binding was reduced in the absence of FCS, but that the addition of human LDL rescued and increased binding capacity. In HUVEC cells, the use of antibodies to block LDLr led to a significant reduction in the binding of E2B and E2Y. CD81 antibodies did not affect E2B and E2Y binding. In ECV304 cells, blocking LDLr and CD81 produced similar effects, but they were not as marked as those that were observed in HUVEC cells. In conclusion, recombinant HCV E2 is dependent on LDL for its ability to bind to LDLr in HUVEC and ECV304 cells. These findings are relevant because E2 acts to anchor HCV to host cells; therefore, high blood levels of LDL could enhance viral infectivity in chronic hepatitis C patients. PMID- 26018452 TI - Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group. AB - Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and cytotoxic properties have been attributed to the presence of the nitro group. However, we synthesised nitroimidazoles with activity against the trypomastigotes of Trypanosoma cruzi, but that were not genotoxic. Herein, nitroimidazoles (11 19) bearing different substituent groups were investigated for their potential induction of genotoxicity (comet assay) and mutagenicity (Salmonella/Microsome assay) and the correlations of these effects with their trypanocidal effect and with megazol were investigated. The compounds were designed to analyse the role played by the position of the nitro group in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable groups at N-1 as an anion receptor group and the role of a methyl group at C-2. Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to those bearing NO 2 at C-5. However, when there was a CH3 at C-2, the position of the NO2 group had no influence on the genotoxic activity. Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3 at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4 NO2; N-CH2OHCH2Cl) and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on genotoxicity. This study contributes to the future search for new and safer prototypes and provide. PMID- 26018454 TI - Stream dynamics and chemical transformations control the environmental fate of silver and zinc oxide nanoparticles in a watershed-scale model. AB - Mathematical models are needed to estimate environmental concentrations of engineered nanoparticles (NPs), which enter the environment upon the use and disposal of consumer goods and other products. We present a spatially resolved environmental fate model for the James River Basin, Virginia, that explores the influence of daily variation in streamflow, sediment transport, and stream loads from point and nonpoint sources on water column and sediment concentrations of zinc oxide (ZnO) and silver (Ag) NPs and their reaction byproducts over 20 simulation years. Spatial and temporal variability in sediment transport rates led to high NP transport such that less than 6% of NP-derived metals were retained in the river and sediments. Chemical transformations entirely eliminated ZnO NPs and doubled Zn mobility in the stream relative to Ag. Agricultural runoff accounted for 23% of total metal stream loads from NPs. Average NP-derived metal concentrations in the sediment varied spatially up to 9 orders of magnitude, highlighting the need for high-resolution models. Overall, our results suggest that "first generation" NP risk models have probably misrepresented NP fate in freshwater rivers due to low model resolutions and the simplification of NP chemistry and sediment transport. PMID- 26018453 TI - The innervation of the zebrafish pharyngeal jaws and teeth. AB - Zebrafish (Danio rerio) teeth are increasingly used as a model to study odontogenesis in non-mammalians. Using serial semi-thin section histology and immunohistochemistry, the nerves innervating the pharyngeal jaws and teeth have been identified. The last pair of branchial arches, which are non-gill bearing but which carry the teeth, are innervated by an internal branch of a post trematic ramus of the vagal nerve. Another, external, branch is probably responsible for the motor innervation of the branchiomeric musculature. Nerve fibres appear in the pulp cavity of the teeth only late during cytodifferentiation, and are therefore likely not involved in early steps of tooth formation. The precise role of the nervous system during continuous tooth replacement remains to be determined. Nonetheless, this study provides the necessary morphological background information to address this question. PMID- 26018455 TI - Biocatalysis at Work: Applications in the Development of Sagopilone. AB - For the antitumour agent sagopilone, an epothilone analogue, a large-scale synthesis was developed to synthesise the active pharmaceutical ingredient for clinical trials, exploring enzymatic and microbial methods to produce chiral building blocks on a multi-kilogram scale. The three building blocks were identified as key intermediates in the synthesis and needed to be produced with high optical purity in yields higher than those previously published. The improved syntheses of two of these building blocks are detailed herein. For building block A, the chemical research synthesis was abandoned, and a novel chemical route was developed leading to building block A via an enzymatic hydrolysis process. For building blocks C, replacement of a chemical catalytic procedure by a microbial process meant that the development of a new starting material could be avoided, thereby accelerating the development process. For the clinical development process, a human metabolite of sagopilone was required as a reference. To accelerate the synthesis of the metabolite, no chemical synthesis was investigated; rather, we relied solely on oxidoreductases. The human metabolite of sagopilone was synthesised on a multi-gram scale in a single-step process using genetically engineered E. coli expressing human cytochrome P450 enzyme 2C19. The integration of enzymatic and microbial processes provided tools that enable the synthesis of highly functionalised intermediates and metabolites. PMID- 26018456 TI - Differences in anatomical relationship between vertebral artery and internal jugular vein in children and adults measured by ultrasonography. AB - Cannulation of the internal jugular vein (IJV) under ultrasound guidance can reduce complications, such as common carotid artery (CCA) puncture, accidental vertebral artery (VA) puncture. However, these complications still occur, especially in pediatric patients probably due to anatomical predisposition of VA. This study compared differences in anatomical location of VA and IJV between pediatric and adult patients. Children with body weight <20 kg (n = 16) and adults who required central venous or pulmonary arterial pressure monitoring (n = 21) were enrolled. After induction of general anesthesia and tracheal intubation, patients were positioned for IJV cannulation. Images of the right CCA, IJV and VA were recorded by ultrasonography. The size of each vessel, anatomical relationship of other vessels, distance between vessels and between each vessel and skin were measured. The size of VA relative to IJV was significantly larger in children than in adults (14 vs 7 %, P < 0.001). The absolute and relative distance between IJV and VA were significantly shorter in children than those in adults (P < 0.01). The anatomical relationships between IJV and CCA and that between IJV and VA were not different between children and adults. In children, VA was relatively larger and located closer to IJV than adults. The results call for careful attention to the position of VA during ultrasound-guided IJV cannulation especially in children. PMID- 26018457 TI - Bioelectrical impedance spectroscopy to estimate fluid balance in critically ill patients. AB - Fluid management is a crucial issue in intensive-care medicine. This study evaluated the feasibility and reproducibility of bioimpedance spectroscopy to measure body-water composition in critically ill patients, and compared fluid balance and daily changes in total body water (TBW) measured by bioimpedance. This observational study included 25 patients under mechanical ventilation. Fluid balance and bioimpedance measurements were recorded on 3 consecutive days. Whole body bioimpedance spectroscopy was performed with exact or ideal body weights entered into the device, and with or without ICU monitoring. Reproducibility of bioimpedance spectroscopy was very good in all conditions despite ICU monitoring and mechanical ventilation. Bioimpedance measurements using an ideal body weight varied significantly, making the weighing procedure necessary. Comparison of fluid balance and daily changes in body weight provided the best correlation (rho = 0.74; P < 0.0001). Daily changes in TBW were correlated with fluid balance (Spearman coefficient rho = 0.31; P = 0.003) and this correlation was improved after exclusion of patients with a SOFA score >10 (rho = 0.36; P = 0.05) and with extracorporeal circulation (rho = 0.50; P = 0.005). Regardless of the technique used to estimate volume status, important limits of agreement were observed. Non invasive determination of body-water composition using bioimpedance spectroscopy is feasible in critically ill patients but requires knowledge of the patient's weight. The best method to assess volume status after fluid resuscitation and the value gained from information about body composition provided by bioimpedance techniques needs further evaluation. PMID- 26018459 TI - Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling. AB - Determining the molecular phenotype is a key to understanding and predicting the metastatic potential and the prognosis for patients with lung cancer. Our previous study demonstrated that increased expression of cyclin-dependent kinase 5 (CDK5) in patients with non-small cell lung cancer (NSCLC) is associated with a poorer prognosis. The present study aimed to further investigate the underlying mechanism of CDK5 in vitro and in vivo using the A549 human NSCLC cell line. A 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to quantify the proliferation of the A549 cells; migration assay and invasiveness assays were performed using Transwell chambers and wound healing assays were used to assess cell motility, which was assessed by measuring the movement of cells. Inhibition of CDK5 by roscovitine and small interfering (si)RNA was used to investigate the mechanism of CDK5 in the process of A549 lung cancer cell proliferation, migration and invasion. The results demonstrated that functional inhibition of CDK5 using roscovitine and siRNA markedly suppressed the proliferation of A549 cells and resulted in a reduced tumor mass in vivo. In addition, the hinhibition of CDK5 reduced the migration and invasiveness of the A549 cells in vitro and in vivo. Notably, CDK5 inhibition also impaired tumor cell cytoskeletal remodeling and led to loss of cell polarity, which may partially explain the reduction of A549 cell mobility and invasiveness. The results of the present study revealed that CDK5 may be important in the regulation of migration and invasiveness in NSCLC through its effects on cytoskeletal remodeling. PMID- 26018460 TI - Analysis of volatiles from stored wheat and Rhyzopertha dominica (F.) with solid phase microextraction-gas chromatography mass spectrometry. AB - BACKGROUND: Volatile organic compounds (VOCs) contribute significantly to food flavour and can be used as indicators of quality, age of storage, and hygiene condition of stored products. The VOCs in the headspace of three different samples - healthy wheat, Rhyzopertha dominica, and wheat with R. dominica - were analysed at 25 degrees C by solid phase micro-extraction (SPME) coupled with gas chromatography-flame ionisation detection (GC-FID) and gas chromatography-mass spectrometry (GC-MS). All the experimental conditions were kept consistent except a polar column and a non-polar column were used to assess the differences in volatile fingerprints. RESULTS: A total of 114 volatiles were identified by both the polar and non-polar columns, of which 48 were specific to one of the three samples tested. The volatiles were mainly carbonyl chemical compounds such as aldehydes, ketones and alcohols. GC-MS results showed slightly more VOCs were identified from the polar column. The total number for the three samples was 43 from the polar column compared to 39 from the non-polar column. Conversely, 30 VOCs unique to a given sample were identified from the non-polar column compared to 18 from the polar column. CONCLUSION: The use of both polar and non-polar columns is essential to capture the full range of VOCs produced by the three specific sample types investigated. The data can form the basis of enquiry into the relationship between storage and grain quality, and insect infestation and grain quality by observing the impact that these circumstances have on the production of volatile organic compounds. PMID- 26018458 TI - Near-infrared spectroscopy determined cerebral oxygenation with eliminated skin blood flow in young males. AB - We estimated cerebral oxygenation during handgrip exercise and a cognitive task using an algorithm that eliminates the influence of skin blood flow (SkBF) on the near-infrared spectroscopy (NIRS) signal. The algorithm involves a subtraction method to develop a correction factor for each subject. For twelve male volunteers (age 21 +/- 1 yrs) +80 mmHg pressure was applied over the left temporal artery for 30 s by a custom-made headband cuff to calculate an individual correction factor. From the NIRS-determined ipsilateral cerebral oxyhemoglobin concentration (O2Hb) at two source-detector distances (15 and 30 mm) with the algorithm using the individual correction factor, we expressed cerebral oxygenation without influence from scalp and scull blood flow. Validity of the estimated cerebral oxygenation was verified during cerebral neural activation (handgrip exercise and cognitive task). With the use of both source detector distances, handgrip exercise and a cognitive task increased O2Hb (P < 0.01) but O2Hb was reduced when SkBF became eliminated by pressure on the temporal artery for 5 s. However, when the estimation of cerebral oxygenation was based on the algorithm developed when pressure was applied to the temporal artery, estimated O2Hb was not affected by elimination of SkBF during handgrip exercise (P = 0.666) or the cognitive task (P = 0.105). These findings suggest that the algorithm with the individual correction factor allows for evaluation of changes in an accurate cerebral oxygenation without influence of extracranial blood flow by NIRS applied to the forehead. PMID- 26018461 TI - Blood graft cellular composition and posttransplant recovery in non-Hodgkin's lymphoma patients mobilized with or without plerixafor: a prospective comparison. AB - BACKGROUND: Autologous stem cell transplantation is commonly used to treat non Hodgkin's lymphomas (NHLs). Cellular composition of the blood grafts apparently has a role in the posttransplant hematologic and immune recovery. Plerixafor increases the mobilization of CD34+ cells and higher amounts of various lymphocyte subsets have been reported in the grafts. Limited prospective data are available in regard to graft cellular composition, hematologic and immune recovery, and patient outcomes in NHL patients who receive plerixafor added to chemomobilization. STUDY DESIGN AND METHODS: Forty-one patients with NHL participated in this prospective study. All patients received chemomobilization and 15 poor mobilizers also received plerixafor. CD34+ cell subsets and lymphocyte subsets of cell grafts, posttransplant hematologic and immune recovery, and outcome were evaluated. RESULTS: Blood grafts in the plerixafor group contained a significantly higher proportion of CD34+133+CD38- cells and more lymphocytes of all major subsets except B lymphocytes. Neutrophil engraftment was comparable and platelet recovery slightly slower in the plerixafor group. Natural killer cell recovery was significantly faster in patients mobilized with plerixafor. Otherwise hematologic and immune recovery as well as short-time outcome were comparable even though there was a trend for progression-free survival and overall survival benefit in the plerixafor group. CONCLUSIONS: In poorly mobilizing NHL patients, plerixafor added to chemomobilization is safe and effective. It also modifies the blood graft composition in many ways, some of which have been linked to better outcomes in previous studies. Larger sets of patients and longer follow-up are needed to see whether plerixafor-mobilized grafts are associated with superior outcome of the patients. PMID- 26018462 TI - Differential effect of metabolic syndrome on various parameters of arterial stiffness. AB - Metabolic syndrome (MetSy) is associated with a high risk of cardiovascular complications. Arterial stiffness is an independent predictor of cardiovascular morbidity and mortality. This study investigated the effect of individual MetSy risk factors on central and peripheral parameters of aortic stiffness. In the Czech post-MONICA study, we measured aortic pulse-wave velocity (aPWV), lower extremity pulse-wave velocity (lePWV), augmentation index (AIx) and central augmentation pressure (cAP) in 936 subjects. Based on the definition of MetSy, we divided subjects according to number of risk factors. We used univariate and multivariate linear regression analysis to assess the association between number of risk factors and aPWV, lePWV, AIx and cAP. In analyses adjusted for age, gender, heart rate and mean arterial pressure, aPWV was higher in subjects with MetSy (MetSy+ group) than in those without (MetSy + group) (8.3 vs. 7.7 m/s; p < 0.0001), but lePWV was not significantly different between the groups (11.0 vs. 11.2 m/s; p = 0.2037). After adjustment for covariates, AIx in MetSy+ was lower than in MetSy- respondents (143.2 vs. 146.8; p = 0.014). In adjusted analysis, aPWV rose with increasing number of MetSy risk factors (7.3 +/- 0.1 vs. 9.0 +/- 0.1 m/s; p for trend < 0.0001). The number of MetSy risk factors did not affect lePWV (p = 0.11). AIx decreased with higher number of MetSy risk factors (148.3 vs. 141.5; p = 0.020). This finding confirms the fact that PWV and AIx may have different associations with risk factors and AIx should not be used as an isolated parameter of arterial stiffness. The individual MetSy risk factors have only a small effect on lower extremity arterial stiffness. PMID- 26018463 TI - Multifunctional phosphate-based inorganic-organic hybrid nanoparticles. AB - Phosphate-based inorganic-organic hybrid nanoparticles (IOH-NPs) with the general composition [M](2+)[Rfunction(O)PO3](2-) (M = ZrO, Mg2O; R = functional organic group) show multipurpose and multifunctional properties. If [Rfunction(O)PO3](2-) is a fluorescent dye anion ([RdyeOPO3](2-)), the IOH-NPs show blue, green, red, and near-infrared fluorescence. This is shown for [ZrO](2+)[PUP](2-), [ZrO](2+)[MFP](2-), [ZrO](2+)[RRP](2-), and [ZrO](2+)[DUT](2-) (PUP = phenylumbelliferon phosphate, MFP = methylfluorescein phosphate, RRP = resorufin phosphate, DUT = Dyomics-647 uridine triphosphate). With pharmaceutical agents as functional anions ([RdrugOPO3](2-)), drug transport and release of anti inflammatory ([ZrO](2+)[BMP](2-)) and antitumor agents ([ZrO](2+)[FdUMP](2-)) with an up to 80% load of active drug is possible (BMP = betamethason phosphate, FdUMP = 5'-fluoro-2'-deoxyuridine 5'-monophosphate). A combination of fluorescent dye and drug anions is possible as well and shown for [ZrO](2+)[BMP](2 )0.996[DUT](2-)0.004. Merging of functional anions, in general, results in [ZrO](2+)([RdrugOPO3]1-x[RdyeOPO3]x)(2-) nanoparticles and is highly relevant for theranostics. Amine-based functional anions in [MgO](2+)[RaminePO3](2-) IOH-NPs, finally, show CO2 sorption (up to 180 mg g(-1)) and can be used for CO2/N2 separation (selectivity up to alpha = 23). This includes aminomethyl phosphonate [AMP](2-), 1-aminoethyl phosphonate [1AEP](2-), 2-aminoethyl phosphonate [2AEP](2 ), aminopropyl phosphonate [APP](2-), and aminobutyl phosphonate [ABP](2-). All [M](2+)[Rfunction(O)PO3](2-) IOH-NPs are prepared via noncomplex synthesis in water, which facilitates practical handling and which is optimal for biomedical application. In sum, all IOH-NPs have very similar chemical compositions but can address a variety of different functions, including fluorescence, drug delivery, and CO2 sorption. PMID- 26018464 TI - The lived experiences of children living on the streets of Hillbrow. AB - BACKGROUND: The effects of daily abuse and hardship on the streets lead to poor mental health in children living on the streets, resulting in them choosing ineffective and self-destructive coping strategies that impact their physical health and overall sense of wellbeing. The facilitation of the mental health of children living on the streets who are subjected to daily threats to their survival is thus crucial. OBJECTIVES: The aim of this research was to explore and describe the lived experiences of children living on the streets of Hillbrow, Johannesburg. METHOD: The research design was qualitative, exploratory, descriptive and contextual. A purposive sample was selected through a temporary shelter in Johannesburg, Gauteng, South Africa and consisted of 14 male children living on the streets. Data were collected using drawings, in-depth phenomenological interviews and field notes. The central interview opening statement was: 'Tell me about your life on the street'. RESULTS: The results obtained indicated that children living on the streets are threatened, exploited and exposed to physical, sexual and emotional abuse on a daily basis by the community, the authorities and other street dwellers. This leads to feelings of sadness, fear, anxiety, misery, despair, hopelessness, helplessness and suicide ideation, which in turn lead to drug abuse and criminal activities. In contrast, positive feelings of sympathy for other children living on the streets emerged and these children also displayed perseverance, resilience and a striving for autonomy. CONCLUSION: Street life exposes children to a variety of experiences, both positive and negative. A striving after autonomy is clearly depicted by these children, who are able to tap into a range of responses, both on- and off street. PMID- 26018467 TI - Time to be taken seriously. PMID- 26018465 TI - The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated. AB - Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag-p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag-specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165 DRFYKSLRA173 epitope. Our data demonstrate that the 165 DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral-load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV-2 encoding the "PPP-gag" sequence and both strong gag-specific CTL responses as well as lower viral load. PMID- 26018466 TI - Psychotic Experiences in the General Population: A Cross-National Analysis Based on 31,261 Respondents From 18 Countries. AB - IMPORTANCE: Community-based surveys find that many otherwise healthy individuals report histories of hallucinations and delusions. To date, most studies have focused on the overall lifetime prevalence of any of these psychotic experiences (PEs), which might mask important features related to the types and frequencies of PEs. OBJECTIVE: To explore detailed epidemiologic information about PEs in a large multinational sample. DESIGN, SETTING, AND PARTICIPANTS: We obtained data from the World Health Organization World Mental Health Surveys, a coordinated set of community epidemiologic surveys of the prevalence and correlates of mental disorders in representative household samples from 18 countries throughout the world, from 2001 through 2009. Respondents included 31,261 adults (18 years and older) who were asked about lifetime and 12-month prevalence and frequency of 6 types of PEs (2 hallucinatory experiences and 4 delusional experiences). We analyzed the data from March 2014 through January 2015. MAIN OUTCOMES AND MEASURES: Prevalence, frequency, and correlates of PEs. RESULTS: Mean lifetime prevalence (SE) of ever having a PE was 5.8% (0.2%), with hallucinatory experiences (5.2% [0.2%]) much more common than delusional experiences (1.3% [0.1%]). More than two-thirds (72.0%) of respondents with lifetime PEs reported experiencing only 1 type. Psychotic experiences were typically infrequent, with 32.2% of respondents with lifetime PEs reporting only 1 occurrence and 31.8% reporting only 2 to 5 occurrences. We found a significant relationship between having more than 1 type of PE and having more frequent PE episodes (Cochran Armitage z = -10.0; P < .001). Lifetime prevalence estimates (SEs) were significantly higher among respondents in middle- and high-income countries than among those in low-income countries (7.2% [0.4%], 6.8% [0.3%], and 3.2% [0.3%], respectively; chi22 range, 7.1-58.2; P < .001 for each) and among women than among men (6.6% [0.2%] vs 5.0% [0.3%]; chi21 = 16.0; P < .001). We found significant associations with lifetime prevalence of PEs in the multivariate model among nonmarried compared with married respondents (chi22 = 23.2; P < .001) and among respondents who were not employed (chi24= 10.6; P < .001) and who had low family incomes (chi23 = 16.9; P < .001). CONCLUSIONS AND RELEVANCE: The epidemiologic features of PEs are more nuanced than previously thought. Research is needed that focuses on similarities and differences in the predictors of the onset, course, and consequences of distinct PEs. PMID- 26018469 TI - People with negative views of old age more likely to end up lonely. PMID- 26018470 TI - Trust rating system on safe staffing to be launched this summer. PMID- 26018471 TI - Technology helps patients get in touch with the past. PMID- 26018472 TI - Care home career pathway needs creative revamp. PMID- 26018473 TI - RCN endorses revised guidance on post-death care. PMID- 26018474 TI - Newly qualified nurse wins award for infection control. PMID- 26018475 TI - One in five dying people do not receive the palliative care they need. PMID- 26018479 TI - Difficult decisions. PMID- 26018486 TI - Practice question. Pain assessment and management. PMID- 26018487 TI - Does ageism still exist in nurse education? AB - Worldwide demographic changes mean that older people represent a significant group of patients for nurses everywhere. Ageism is increasingly recognised as an issue among healthcare professionals and evidence suggests that problems with quality of care remain. Nursing curricula have to address the needs of an ageing population in a variety of settings, reflect the importance of therapeutic care and explore nursing students' attitudes, in order to provide them with the appropriate skills to meet the needs of older people. This article debates the main factors influencing gerontological content in nursing curricula and suggests that ageism is still evident in nurse education. A variety of strategies are identified to assist in developing appropriate curriculum content. PMID- 26018488 TI - Inclusion of carers when confused relatives are admitted to hospital. AB - It is well recognised that many older people have dementia but have never been investigated or received a formal diagnosis. If they are admitted to acute hospitals from their own homes or long-term care settings with confusion and little background information about their usual condition, it can be challenging for staff to determine if they have dementia, delirium, delirium superimposed on pre-existing dementia or confusion with a reversible cause such as vitamin deficiency. A careful history and information seeking from carers or family members about their loved one's pre-admission baseline can inform nursing and medical assessments and help nurses to provide high quality care. PMID- 26018490 TI - Making connections. PMID- 26018489 TI - An overview of appetite decline in older people. AB - Poor appetite is a common problem in older people living at home and in care homes, as well as hospital inpatients. It can contribute to weight loss and nutritional deficiencies, and associated poor healthcare outcomes, including increased mortality. Understanding the causes of reduced appetite and knowing how to measure it will enable nurses and other clinical staff working in a range of community and hospital settings to identify patients with impaired appetite. A range of strategies can be used to promote better appetite and increase food intake. PMID- 26018491 TI - Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. AB - Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti-multiple myeloma (MM) activity. This phase I dose-escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m(2) ; 30-min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1-21), vorinostat (300 or 400 mg; days 1-7, 15-21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28-d cycles. No dose-limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m(2) , lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade >=3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow-up of 10 months, median progression-free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM. PMID- 26018493 TI - Inflected words in production: Evidence for a morphologically rich lexicon. AB - Current evidence suggests that there is a difference between the representations of multimorphemic words in production and perception. In perception, it is widely believed that both whole-word and root representations exist, while in production there is little evidence for whole-word representations. The present investigation demonstrates that whole-word and root frequency independently predict the duration of words suffixed with -ing, -ed, and -s, which reveals that both root and word representations play a role in the production of inflected English words. In a second line of analysis, we find that the number of inflected phonological neighbours independently predicts the duration of monomorphemic words, which extends these results and suggests that whole-word representations exist at the lexical level. Together these results suggest that both root and word representations of inflected words are stored in the lexicon and are relevant for the production of both monomorphemic and multimorphemic words. PMID- 26018494 TI - More than a mnemonic. PMID- 26018492 TI - eIF1A augments Ago2-mediated Dicer-independent miRNA biogenesis and RNA interference. AB - MicroRNA (miRNA) biogenesis and miRNA-guided RNA interference (RNAi) are essential for gene expression in eukaryotes. Here we report that translation initiation factor eIF1A directly interacts with Ago2 and promotes Ago2 activities in RNAi and miR-451 biogenesis. Biochemical and NMR analyses demonstrate that eIF1A binds to the MID domain of Ago2 and this interaction does not impair translation initiation. Alanine mutation of the Ago2-facing Lys56 in eIF1A impairs RNAi activities in human cells and zebrafish. The eIF1A-Ago2 assembly facilitates Dicer-independent biogenesis of miR-451, which mediates erythrocyte maturation. Human eIF1A (heIF1A), but not heIF1A(K56A), rescues the erythrocyte maturation delay in eif1axb knockdown zebrafish. Consistently, miR-451 partly compensates erythrocyte maturation defects in zebrafish with eif1axb knockdown and eIF1A(K56A) expression, supporting a role of eIF1A in miRNA-451 biogenesis in this model. Our results suggest that eIF1A is a novel component of the Ago2 centred RNA-induced silencing complexes (RISCs) and augments Ago2-dependent RNAi and miRNA biogenesis. PMID- 26018495 TI - Organic Selenium Alleviated the Formation of Ethylene Glycol-Induced Calcium Oxalate Renal Calculi by Improving Osteopontin Expression and Antioxidant Capability in Dogs. AB - Twenty one-year-old local male dogs were randomly assigned into four groups (five dogs per group). The control and the ethylene glycol (EG) groups were fed basal diets without and with EG, and the EG+sodium selenite (EG+SS) and EG+selenium yeast (EG+SY) groups were fed basal diets with EG containing SS and SY, respectively. Blood, urine, and renal samples were taken after 18 weeks of feeding. The results showed that compared with the control group, the serum calcium levels and antioxidase activities significantly decreased in the EG group. Serum creatinine, urea nitrogen, and malondialdehyde (MDA) levels and urine calcium and oxalate levels significantly increased. Calcium oxalate crystal deposition and osteopontin (OPN) messenger RNA and protein expression in the renal tissues significantly increased. These changes above in the EG group were reversed within limits by adding selenium in the diets (both EG+SS and EG+SY groups). Further, compared with the EG+SS group, the EG+SY group showed better effects in decreasing the formation of EG-induced calcium oxalate renal calculi and OPN expression and improving antioxidant capability in dogs. It indicates that organic selenium has the potential value to alleviate the formation of EG induced calcium oxalate renal calculi. PMID- 26018496 TI - Streptozotocin Aggravated Osteopathology and Insulin Induced Osteogenesis Through Co-treatment with Fluoride. AB - The role of insulin in the mechanism underlying the excessive fluoride that causes skeletal lesion was studied. The in vitro bone marrow stem cells (BMSC) collected from Kunming mice were exposed to varying concentrations of fluoride with or without insulin. The cell viability and early differentiation of BMSC co treated with fluoride and insulin were measured by using cell counting kit-8 and Gomori modified calcium-cobalt method, respectively. We further investigated the in vivo effects of varying dose of fluoride on rats co-treated with streptozotocin (STZ). Wistar rats were divided into six groups which included normal control, 10 mg fluoride/kg day group, 20 mg fluoride/kg day group, STZ control, STZ+10 mg fluoride/kg day group, and STZ+20 mg fluoride/kg day group. The rats were administered with sodium fluoride (NaF) by gavage with water at doses 10 and 20 mg fluoride/kg day for 2 months. In a period of one month, half of rats in every group were treated with streptozotocin (STZ) once through intraperitoneal injection at 52 mg/kg body weight. The serum glucose, HbA1c, and insulin were determined. Bone mineral content and insulin release were assessed. The results showed insulin combined with fluoride stimulated BMSC cell viability in vitro. The bone mineral content reduced in rats treated with higher dose of fluoride and decreased immensely in rat co-treated with fluoride and STZ. Similarly, a combination treatment of a high dose of fluoride and STZ decreased insulin sensitivity and activity. To sum up, these data indicated fluoride influenced insulin release, activity, and sensitivity. Furthermore, the insulin state in vivo interfered in the osteogenesis in turn and implied there was a close relation between insulin and bone pathogenesis in the mechanism of fluoride toxicity. PMID- 26018497 TI - Hesperidin and Silibinin Ameliorate Aluminum-Induced Neurotoxicity: Modulation of Antioxidants and Inflammatory Cytokines Level in Mice Hippocampus. AB - Mounting evidence suggests that long-term aluminum exposure results in severe toxic effects, including neurobehavioral and neurochemical anomalies. The present study was performed to examine the neuroprotective potential of hesperidin and silibinin against aluminum chloride (AlCl3)-induced neurotoxicity in mice. AlCl3 (100 mg/kg/day) was injected daily through oral gavage for 42 days. Concomitantly, hesperidin (50 and 100 mg/kg/day, p.o.) and silibinin (100 and 200 mg/kg/day, p.o.) was administered for 42 days in different groups. The extent of cognitive impairment was assessed by Morris water maze and novel object recognition test on the 43rd day. Neurotoxicity was assessed by measuring oxido nitrosative stress and proinflammatory cytokines in the hippocampus of mice. Six weeks treatment with AlCl3 caused cognitive impairment as indicated by an increase in the retention latency time and reduction in the percentage of recognition index. AlCl3-treated group showed oxido-nitrosative stress as indicated by increase in the level of lipid peroxidation, nitrite and depleted reduced glutathione, catalase activity in the hippocampus. Moreover, the chronic AlCl3 administration raised the proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha) level and increased acetylcholinesterase activity and reduced the BDNF content in the hippocampus of AlCl3-treated animals. However, chronic treatment with hesperidin and silibinin at higher doses significantly ameliorated the AlCl3-induced cognitive impairment and hippocampal biochemical anomalies. The present study clearly indicated that hesperidin and silibinin exert neuroprotective effects against AlCl3-induced cognitive impairment and neurochemical changes. Amelioration of cognitive impairment may be attributed to the impediment of oxido-nitrosative stress and inflammation in the hippocampus. PMID- 26018498 TI - Effects of small interfering RNA-mediated downregulation of the Kruppel-like factor 4 gene on collagen metabolism in human hepatic stellate cells. AB - The nuclear transcription factor Kruppel-like factor 4 (KLF4) has an important role in cellular biological processes. However, the influence of KLF4 on collagen metabolism remains to be elucidated. In the present study, the effects and underlying mechanism of action of KLF4 on collagen metabolism was investigated in human hepatic stellate cells (HSC), by downregulating KLF4 expression using small interfering RNA (siRNA). The effects of KLF4 silencing by three predesigned siRNAs (siRNA1-3) were evaluated using both reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting in the human LX2 HSC line. The mRNA expression levels of KLF4 were decreased by ~34, 40, and 69% in the siRNA1, siRNA2, and siRNA3 groups, respectively, as compared with the control group. These results were concordant with the protein expression levels of KLF4, as determined by western blot analysis. In the siRNA3 group, the quantity of type I and type III collagen, and the expression levels of collagen metabolism proteins including matrix metalloproteinase-1 (MMP-1) and tissue inhibitors of metalloproteinases-1 (TIMP-1), were determined using both RT-qPCR and western blotting. Both the mRNA and protein expression levels of type I and type III collagen were significantly decreased in the siRNA3 group, as compared with the control group. The mRNA and protein expression levels of TIMP-1 were also significantly reduced in the siRNA3-treated cells, whereas the mRNA and protein expression levels of MMP-1 were significantly upregulated. Furthermore, KLF4 gene silencing significantly decreased the expression levels of numerous cytokines, including transforming grow factor-beta1, tumor necrosis factor-alpha, and interleukin-1beta. The results of the present study provide evidence of siRNA mediated silencing of KLF4 expression, which may promote extracellular matrix (ECM) degradation, and inhibition of ECM synthesis. Therefore, KLF4 may be a promising target for the development of novel antifibrotic therapies. PMID- 26018499 TI - Optimization of cellulase production by Penicillium oxalicum using banana agrowaste as a substrate. AB - The purpose of this study was to produce a higher amount of cellulase by using an alternative carbon source, such as banana agrowaste, and to optimize the fermentation parameters for a high yield. In the present study, cellulase producing Penicillium was isolated from a decaying wood sample. Different nutritional and environmental factors were investigated to assess their effect on cellulase production. The highest crude enzyme production was observed at a pH 6.0 and a temperature of 28 degrees C in a medium that was supplemented with banana agrowaste as the carbon source. Pretreatment with 2N NaOH, at 7% substrate (banana agrowaste) concentration yielded the highest cellulase activity. Further to this, the effect of other parameters such as inoculum age, inoculum size, static and agitated conditions were also studied. It is concluded that Penicillium oxalicum is a powerful cellulase-producer strain under our tested experimental conditions using banana agrowaste as the carbon source. PMID- 26018500 TI - Characterization of giant spheroplasts generated from the aerobic anoxygenic photosynthetic marine bacterium Roseobacter litoralis. AB - We generated and characterized giant spheroplasts from the aerobic anoxygenic photosynthetic marine bacterium Roseobacter litoralis. The giant spheroplasts contained vacuole-like structures within the cells, mainly consisting of a single membrane. The in vivo absorption spectrum of the giant spheroplasts did not have peaks typically observed for bacteriochlorophyll a. The culture media pH decreased during the growth of the giant spheroplasts. The change in the pH profile for cells grown under light was no different from that for cells grown in the dark. These results showed that the R. litoralis giant spheroplasts formed lost their photosynthetic apparatus in culture. Most of the giant spheroplasts returned to their original size, likely via filamentous cells. The culture media pH increased during the growth of the filamentous cells. Some filamentous cells had septum-like structures. In such filamentous cells, DNA was separated. Initially, the color of the separated cells was white. Two weeks later, the cells changed to red in the dark, and the in vivo absorption spectrum of the cells had peaks typically observed for bacteriochlorophyll a. Our findings strongly suggest that the giant spheroplasts of R. litoralis can control the genetic information, return to their original cell size, and regain their original functions. PMID- 26018501 TI - Study on Streptococcus thermophilus isolated from Qula and associated characteristic of acetaldehyde and diacetyl in their fermented milk. AB - In this study, the lactic acid bacterial population of Qula cheese from the Gansu and Sichuan provinces of China were isolated and identified. Eight strains of Streptococcus thermophilus were isolated, of which five strains were selected for further characterization based on their fermentation properties. The changes in a number of parameters, including titration acidity, pH, viable counts, PrtS protease activity and the production of acetaldehyde, diacetyl and organic acid, were monitored during fermentation and the storage of fermented milks produced by the respective strain. All of the strains displaying acidifying capacity and all five fermented milks maintained high viable counts of S. thermophilus from fermentation to storage. Our study found that the changes in the monitored parameters were strain-specific and varied considerably among the five tested strains. Fermented milks produced by strain IMAU80809 had the highest concentration of acetaldehyde and were most favorable in the sensory evaluation. This study confirms that Qula cheese is a good source for isolating novel lactic acid bacterial strains with different fermentation properties, which will be very useful for further development and industrialization of traditionally fermented dairy products. PMID- 26018502 TI - Ukulactone C, a new NADH-fumarate reductase inhibitor produced by Talaromyces sp. FKI-6713. AB - Screening for NADH-fumarate reductase inhibitors led to the isolation of a new ukulactone analog, ukulactone C, as a major polyene compound produced by Talaromyces sp. FKI-6713. The structure of the compound was elucidated as a reduced analog of ukulactone A by 1D- and 2D-NMR experiments. Ukulactone C possessed a potent inhibitory activity (IC(50) = 62 nM) against NADH-fumarate reductase of the roundworm Ascaris suum in vitro. PMID- 26018503 TI - A single-nucleotide substitution in phasin gene leads to enhanced accumulation of polyhydroxyalkanoate (PHA) in Escherichia coli harboring Aeromonas caviae PHA biosynthetic operon. PMID- 26018504 TI - Semi-Blind Error Resilient SLM for PAPR Reduction in OFDM Using Spread Spectrum Codes. AB - High peak to average power ratio (PAPR) is one of the major problems of OFDM systems. Selected mapping (SLM) is a promising choice that can elegantly tackle this problem. Nevertheless, side information (SI) index is required to be transmitted which reduces the overall throughput. This paper proposes a semi blind error resilient SLM system that utilizes spread spectrum codes for embedding the SI index in the transmitted symbols. The codes are embedded in an innovative manner which does not increase the average energy per symbol. The use of such codes allows the correction of probable errors in the SI index detection. A new receiver, which does not require perfect channel state information (CSI) for the detection of the SI index and has relatively low computational complexity, is proposed. Simulations results show that the proposed system performs well both in terms SI index detection error and bit error rate. PMID- 26018505 TI - Improving the Anticancer Efficacy of Laminin Receptor-Specific Therapeutic Ruthenium Nanoparticles (RuBB-Loaded EGCG-RuNPs) via ROS-Dependent Apoptosis in SMMC-7721 Cells. AB - Functionalization can promote the uptake of nanoparticles into cancer cells via receptor-mediated endocytosis, enabling them to exert their therapeutic effects. In this paper, epigallocatechin gallate (EGCG), which has a high binding affinity to 67 kDa laminin receptor (67LR) overexpressed in HCC cells, was employed in the present study to functionalized ruthenium nanoparticles (RuNPs) loaded with luminescent ruthenium complexes to achieve antiliver cancer efficacy. [Ru(bpy)2(4 B)] (ClO4)2.2H2O (RuBB)-loaded EGCG-RuNPs (bpy = 2,2'-bipyridine) showed small particle size with narrow distribution, better stability, and high selectivity between liver cancer and normal cells. The internalization of RuBB-loaded EGCG RuNPs was inhibited by 67LR-blocking antibody or laminin, suggesting that 67LR mediated endocytosis played an important role in the uptake into HCC cells. Moreover, transmission electron microscopy and confocal microscopic images showed that RuBB-loaded EGCG-RuNPs accumulated in the cytoplasm of SMMC-7721 cells. Furthermore, our results indicated that the EGCG-functionalized nanoparticles displayed enhanced anticancer effects in a target-specific manner. Concentrations of RuBB-loaded EGCG-RuNPs, nontoxic in normal L-02 cells, showed direct reactive oxygen species-dependent cytotoxic, pro-apoptotic, and anti-invasive effects in SMMC-7721 cells. Furthermore, in vivo animal study demonstrated that RuBB-loaded EGCG-RuNPs possessed high antitumor efficacy on tumor-bearing nude mice. It is encouraging to conclude that the multifunctional RuNPs may form the basis of new strategies on the treatment of liver cancer and other malignancies. PMID- 26018506 TI - Effect of multiple freezing/thawing cycles on the structural and functional properties of waxy rice starch. AB - The structural and functional properties of non-gelatinized waxy rice starch were investigated after 1, 3, 7, and 10 freezing/thawing cycles. Freezing caused an increasing damaged starch from 1.36% in native waxy rice starch to 5.77% in 10 freezing/thawing-treated starch (FTS), as evidenced by the cracking surface on starch granules. More dry matter concentration was leached, which was characterized by high amylopectin concentration (4.34 mg/mL). The leaching was accompanied by a decrease in relative crystallinity from 35.19% in native starch to 31.34% in 10 FTS. Freezing treatment also led to significant deviations in the functional characteristics, for instance decreased gelatinization temperature range, enthalpy, and pasting viscosities. The resistant starch content of 10FTS significantly decreased from 58.9% to 19%, whereas the slowly digested starch content greatly increased from 23.8% in native starch to 50.3%. The increase in susceptibility to enzyme hydrolysis may be attributed to porous granular surface, amylopectin leaching, and the decrease in the relative crystallinity caused by freezing water. PMID- 26018507 TI - The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways. AB - Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a de-ubiquitinating enzyme, which enzymatic activity relies on the C90 site. The function of UCHL1 is controversial in different types of cancer, and its role in gastric cancer progression remains unclear. In this study, immunohistochemistry staining was applied to detect the expression of UCHL1 in primary gastric cancer and liver metastases from gastric cancer. MKN45 and BGC823 cell lines with stable expression of de-ubiquitinase active UCHL1 or inactive UCHL1-variant C90S were established by lentiviral infection. The effect of UCHL1 on cell proliferation was evaluated by MTT and colony formation assays. The abilities of cell migration and invasion were determined by transwell assay. Protein expression levels were determined by Western blot. The results indicated that UCHL1 had a significantly higher positive expression rate in liver metastases from gastric cancer compared with primary gastric cancer. Overexpression of UCHL1 in MKN45 and BGC823 cells promoted cell proliferation, migration, and invasion depending on its de ubiquitinase activity. UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion. These findings demonstrated that UCHL1 promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity by activating Akt and Erk1/2, which may account for its higher positive expression rate in liver metastases from gastric cancer. UCHL1 could be a candidate biomarker and a therapeutic target for gastric cancer metastasis. PMID- 26018508 TI - Overexpression of miR-100 inhibits growth of osteosarcoma through FGFR3. AB - Osteosarcoma (OS) is a prevalent, fast growing cancer. Identification of molecular regulation of OS growth may result in development of a novel therapy. Previous studies have highlighted a role of microRNAs (miRNAs) in the regulation of the carcinogenesis of OS, whereas the underlying mechanisms are not completely understood. Moreover, a role of miR-100 in the growth control of OS is not clear. Here we reported significantly higher levels of fibroblast growth factor receptor 3 (FGFR3) and significantly lower levels of miR-100 in the OS specimen, compared to those in the paired normal bone tissues. Bioinformatics analysis and luciferase reporter assay suggest that miR-100 binds to the 3'UTR of FGFR3 mRNA to prevent its translation. To prove it, we modified miR-100 levels in OS cells. We found that overexpression of miR-100 in OS cells decreased FGFR3 protein levels, whereas inhibition of miR-100 increased FGFR3 protein levels, without affecting FGFR3 transcripts. Moreover, overexpression of miR-100 suppressed the OS growth in vitro and in vivo, while inhibition of miR-100 significantly increased OS growth. Taken together, our data demonstrate that miR-100 may inhibit the growth of OS through FGFR3. PMID- 26018509 TI - miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2. AB - MicroRNAs play critical roles in the development and progression of human cancers. Although it has been reported that miR-106a* is downregulated in follicular lymphoma, its role in renal cell carcinoma (RCC) remains unknown. This study investigated the expression and role of miR-106a* in human RCC. Our results showed that the miR-106a* expression decreased dramatically in clinical RCC tissues and cell lines. In vitro, overexpression of miR-106a* suppressed RCC cell proliferation and S/G2 transition, whereas inhibition of miR-106a* promoted cell proliferation and S/G2 transition. It was also found that miR-106a* expression was inversely correlated with the expression of insulin receptor substrate 2 (IRS 2). IRS-2 was determined to be a direct target of miR-106a* by a luciferase reporter assay. Importantly, silencing IRS-2 resulted in the same biologic effects as those of miR-106a* overexpression in RCC cells, including inhibition of RCC cell proliferation and triggering of S/G2 cell cycle arrest with inhibition of the PI3K/Akt signaling pathway. These results indicate that miR 106a* affects RCC progression by targeting IRS-2 with suppression of the PI3K/Akt signaling pathway in RCC cells. The findings suggest miR-106a* as a novel strategy for RCC treatment. PMID- 26018510 TI - Serum DLK1 is a potential prognostic biomarker in patients with hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death in developing countries, especially in East Asia and South Africa, and the identification of new biomarkers for early diagnosis and prognosis is needed. Delta-like 1 homologue (Drosophila) (DLK1) is expressed in malignancies and promotes cancer cell stemness and tumourigenicity, which makes this molecule a potential target for therapies directed against cancer stem/progenitor cells. Here, we aimed to assess the predictive value of DLK1 as a diagnostic and prognostic biomarker in HCC. With this purpose, serum DLK1 levels were detected using an enzyme-linked immunosorbent assay (ELISA) in serum specimens from 397 HCC patients, 114 healthy individuals, 43 patients with chronic hepatitis B virus (HBV) infection and 24 cirrhotic liver patients with HBV infection, and the correlation between DLK1 levels and clinical features was evaluated. Our data showed that the serum DLK1 level was significantly higher in HCC patients than in healthy individuals or patients with chronic HBV infection (HBV carriers) (P < 0.05). Moreover, the serum DLK1 levels were positively correlated with tumour size and alpha-fetoprotein (AFP) levels, but not with gender, age, histological grade, HBV infection, intrahepatic metastasis or cirrhosis in HCC patients. Kaplan-Meier analysis indicated that higher DLK1 levels were associated with shorter survival in HCC patients. These results suggest that the serum levels of DLK1 may serve as a prognostic biomarker for HCC patients. PMID- 26018512 TI - Advances in the Endoscopic Assessment of Inflammatory Bowel Diseases: Cooperation between Endoscopic and Pathologic Evaluations. AB - Endoscopic assessment has a crucial role in the management of inflammatory bowel disease (IBD). It is particularly useful for the assessment of IBD disease extension, severity, and neoplasia surveillance. Recent advances in endoscopic imaging techniques have been revolutionized over the past decades, progressing from conventional white light endoscopy to novel endoscopic techniques using molecular probes or electronic filter technologies. These new technologies allow for visualization of the mucosa in detail and monitor for inflammation/dysplasia at the cellular or sub-cellular level. These techniques may enable us to alter the IBD surveillance paradigm from four quadrant random biopsy to targeted biopsy and diagnosis. High definition endoscopy and dye-based chromoendoscopy can improve the detection rate of dysplasia and evaluate inflammatory changes with better visualization. Dye-less chromoendoscopy, including narrow band imaging, iScan, and autofluorescence imaging can also enhance surveillance in comparison to white light endoscopy with optical or electronic filter technologies. Moreover, confocal laser endomicroscopy or endocytoscopy have can achieve real time histology evaluation in vivo and have greater accuracy in comparison with histology. These new technologies could be combined with standard endoscopy or further histologic confirmation in patients with IBD. This review offers an evidence-based overview of new endoscopic techniques in patients with IBD. PMID- 26018513 TI - Pathology-MRI Correlation of Hepatocarcinogenesis: Recent Update. AB - Understanding the important alterations during hepatocarcinogenesis as well as the characteristic magnetic resonance imaging (MRI) and histopathological features will be helpful for managing patients with chronic liver disease and hepatocellular carcinoma. Recent advances in MRI techniques, such as fat/iron quantification, diffusion-weighted images, and gadoxetic acid-enhanced MRI, have greatly enhanced our understanding of hepatocarcinogenesis. PMID- 26018514 TI - Effectiveness and limitations of core needle biopsy in the diagnosis of thyroid nodules: review of current literature. AB - Fine needle aspiration (FNA) is currently accepted as an easy, safe, and reliable tool for the diagnosis of thyroid nodules. Nonetheless, a proportion of FNA samples are categorized into non-diagnostic or indeterminate cytology, which frustrates both the clinician and patient. To overcome this limitation of FNA, core needle biopsy (CNB) of the thyroid has been proposed as an additional diagnostic method for more accurate and decisive diagnosis for thyroid nodules of concern. In this review, we focus on the effectiveness and limitations of CNB, and what factors should be considered when CNB is utilized in the diagnosis of thyroid nodules. PMID- 26018515 TI - Proposal of an appropriate decalcification method of bone marrow biopsy specimens in the era of expanding genetic molecular study. AB - BACKGROUND: The conventional method for decalcification of bone specimens uses hydrochloric acid (HCl) and is notorious for damaging cellular RNA, DNA, and proteins, thus complicating molecular and immunohistochemical analyses. A method that can effectively decalcify while preserving genetic material is necessary. METHODS: Pairs of bilateral bone marrow biopsies sampled from 53 patients were decalcified according to protocols of two comparison groups: EDTA versus HCl and RDO GOLD (RDO) versus HCl. Pairs of right and left bone marrow biopsy samples harvested from 28 cases were allocated into the EDTA versus HCl comparison group, and 25 cases to the RDO versus HCl comparison group. The decalcification protocols were compared with regards to histomorphology, immunohistochemistry, and molecular analysis. For molecular analysis, we randomly selected 5 cases from the EDTA versus HCl and RDO versus HCl groups. RESULTS: The decalcification time for appropriate histomorphologic analysis was the longest in the EDTA method and the shortest in the RDO method. EDTA was superior to RDO or HCl in DNA yield and integrity, assessed via DNA extraction, polymerase chain reaction, and silver in situ hybridization using DNA probes. The EDTA method maintained intact nuclear protein staining on immunohistochemistry, while the HCl method produced poor quality images. Staining after the RDO method had equivocal results. RNA in situ hybridization using kappa and lambda RNA probes measured RNA integrity; the EDTA and RDO method had the best quality, followed by HCl. CONCLUSIONS: The EDTA protocol would be the best in preserving genetic material. RDO may be an acceptable alternative when rapid decalcification is necessary. PMID- 26018516 TI - Smad1 expression in follicular lymphoma. AB - BACKGROUND: Follicular lymphomas present with various immunohistologic patterns. The immunohistochemical markers used in the diagnosis of follicular lymphoma show variable degrees of sensitivity and specificity, and thus, additional germinal center markers are required. Smad1 has been reported to be overexpressed in follicular lymphoma, but little is known regarding the expression patterns of Smad proteins in human lymphoid tissue. METHODS: In the present study, we performed immunohistochemistry for traditional germinal center markers and for Smad1 in human reactive lymphoid and follicular lymphoma tissues to investigate Smad1's usefulness in the diagnosis of follicular lymphoma. RESULTS: In the reactive germinal centers, most cells were positive for Smad1. Among the 27 follicular lymphoma cases, 17 of 21 (80%) were Smad1 positive, 17 of 27 (63%) were positive for CD10, and 23 of 27 (85%) were positive for Bcl6. Notably, three cases expressed CD10 only, and one only expressed Bcl6. All these cases were grade 3 tumors and showed follicular and diffuse growth patterns. CONCLUSIONS: These results indicate that Smad1 is a candidate as a germinal center marker. Furthermore, they suggest that the Smad signaling pathway might be involved in follicular lymphoma. PMID- 26018511 TI - Galectins: Double-edged Swords in the Cross-roads of Pregnancy Complications and Female Reproductive Tract Inflammation and Neoplasia. AB - Galectins are an evolutionarily ancient and widely expressed family of lectins that have unique glycan-binding characteristics. They are pleiotropic regulators of key biological processes, such as cell growth, proliferation, differentiation, apoptosis, signal transduction, and pre-mRNA splicing, as well as homo- and heterotypic cell-cell and cell-extracellular matrix interactions. Galectins are also pivotal in immune responses since they regulate host-pathogen interactions, innate and adaptive immune responses, acute and chronic inflammation, and immune tolerance. Some galectins are also central to the regulation of angiogenesis, cell migration and invasion. Expression and functional data provide convincing evidence that, due to these functions, galectins play key roles in shared and unique pathways of normal embryonic and placental development as well as oncodevelopmental processes in tumorigenesis. Therefore, galectins may sometimes act as double-edged swords since they have beneficial but also harmful effects for the organism. Recent advances facilitate the use of galectins as biomarkers in obstetrical syndromes and in various malignancies, and their therapeutic applications are also under investigation. This review provides a general overview of galectins and a focused review of this lectin subfamily in the context of inflammation, infection and tumors of the female reproductive tract as well as in normal pregnancies and those complicated by the great obstetrical syndromes. PMID- 26018517 TI - MUC2 Expression Is Correlated with Tumor Differentiation and Inhibits Tumor Invasion in Gastric Carcinomas: A Systematic Review and Meta-analysis. AB - BACKGROUND: While MUC2 is expressed in intestinal metaplasia and malignant lesions, the clinicopathological significance of MUC2 expression is not fully elucidated in gastric carcinoma (GC). METHODS: The present study investigated the correlation between MUC2 expression and clinicopathological parameters in 167 human GCs. In addition, to confirm the clinicopathological significance of MUC2 expression, we performed a systematic review and meta-analysis in 1,832 GCs. RESULTS: MUC2 expression was found in 58 of 167 GCs (34.7%). MUC2-expressing GC showed lower primary tumor (T), regional lymph node (N), and tumor node metastasis (TNM) stages compared with GCs without MUC2 expression (p=.001, p=.001, and p=.011, respectively). However, MUC2 expression was not correlated with Lauren's classification and tumor differentiation. In meta-analysis, MUC2 expression was significantly correlated with differentiation and lower tumor stage (odds ratio [OR], 1.303; 95% confidence interval [CI], 1.020 to 1.664; p = .034 and OR, 1.352; 95% CI, 1.055 to 1.734; p = .017, respectively) but not with Lauren's classification, pN stage, or pTNM stage. CONCLUSIONS: MUC2 expression was correlated with a lower tumor depth and lower lymph node metastasis in our study; the meta-analysis showed a correlation of MUC2 expression with tumor differentiation and lower tumor depth. PMID- 26018518 TI - IDH Mutation Analysis in Ewing Sarcoma Family Tumors. AB - BACKGROUND: Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to yield alpha-ketoglutarate (alpha-KG) with production of reduced nicotinamide adenine dinucleotide (NADH). Dysfunctional IDH leads to reduced production of alpha-KG and NADH and increased production of 2 hydroxyglutarate, an oncometabolite. This results in increased oxidative damage and stabilization of hypoxia-inducible factor alpha, causing cells to be prone to tumorigenesis. METHODS: This study investigated IDH mutations in 61 Ewing sarcoma family tumors (ESFTs), using a pentose nucleic acid clamping method and direct sequencing. RESULTS: We identified four cases of ESFTs harboring IDH mutations. The number of IDH1 and IDH2 mutations was equal and the subtype of IDH mutations was variable. Clinicopathologic analysis according to IDH mutation status did not reveal significant results. CONCLUSIONS: This study is the first to report IDH mutations in ESFTs. The results indicate that ESFTs can harbor IDH mutations in previously known hot-spot regions, although their incidence is rare. Further validation with a larger case-based study would establish more reliable and significant data on prevalence rate and the biological significance of IDH mutations in ESFTs. PMID- 26018519 TI - Follicular proliferative lesion arising in struma ovarii. AB - Malignant struma ovarii is extremely rare and difficult to diagnose histologically, particularly in cases of follicular carcinoma. This case study is intended to describe three cases of follicular proliferative lesion arising in struma ovarii that we experienced. The first case was clearly malignant given the clinical picture of multiple recurrences, but there was little histological evidence of malignancy. Our second case featured architectural and cellular atypia and necrosis and was diagnosed as malignant despite the absence of vascular and stromal invasion. Our third case exhibited solid microfollicular proliferation without any definite evidence of malignancy (even the molecular data was negative); however, we could not completely exclude malignant potential after conducting a literature review. In cases such as our third case, it has been previously suggested that a diagnostic term recognizing the low-grade malignant potential, such as "proliferative stromal ovarii" or "follicular proliferative lesion arising in the stromal ovarii" would be appropriate. PMID- 26018520 TI - Traumatic bowel perforation and inguinal hernia masking a mesenteric calcifying fibrous tumor. PMID- 26018521 TI - Cytomegalovirus-associated intussusception with florid vascular proliferation in an infant. PMID- 26018522 TI - A case of primary subpleural pulmonary microcystic myxoma coincidentally occurred with pulmonary adenocarcinoma. PMID- 26018523 TI - Effects of rosuvastatin combined with fasudil therapy on rabbits with dyslipidemia. AB - BACKGROUND: Present study was conducted to investigate the effects of rosuvastatin combined with fasudil on rabbits with dyslipidemia. METHODS: Dyslipidemia model of rabbits were produced by prescribing atherogenic diet for 2 weeks. Thereafter, 40 rabbits with dyslipidemia were randomly and evenly divided into four groups as follow: untreated group (orally prescribed 3 ml of normal saline), rosuvastatin group (orally prescribed 3 mg/kg body weight daily, dissolved in 3 ml of normal saline), fasudil group (intravenously prescribed 0.5 mg/kg body weight daily, dissolved in 3 ml of normal saline), and combined group (the same doses of rosuvastatin and fasudil as aforementioned). At baseline, 2 weeks of dyslipidemia establishment and 2 weeks of medical therapy, fasting venous blood was drawn for laboratory examination. RESULTS: After 2 weeks' atherogenic diet treatment, lipid disorders and impaired fasting glucose were observed. Systemic inflammation and oxidation were also promoted as revealed by increased serum levels of high sensitive C-reactive protein (Hs-CRP) and malondialdehyde (MDA). Notably, endothelial function has been impaired significantly as reflected by decreased nitric oxide (NO) production and increased serum asymmetric dimethylarginine (ADMA) level. RhoA associated kinase (ROCK) activity was also profoundly enhanced (P < 0.05). Inter-group comparisons showed that when compared to untreated group, modest improvements of endothelial function, inflammation and oxidation were observed in rosuvastatin and fasudil groups (P > 0.05). These benefits were improved more prominently in combined group (P < 0.05). Intra-group comparisons also showed that when compared to 2 weeks of dyslipidemia, slight improvement of endothelial function, inflammation and oxidation in rosuvastatin and fasudil groups were observed (P > 0.05). The improvements were more prominent in the combined groups (P < 0.05). CONCLUSION: Rosuvastatin combined with fasudil conferred synergistic effects on endothelium protection and inflammation- and oxidation-amelioration in the setting of early stage of dyslipidemia. PMID- 26018525 TI - Psychiatric Disorders in HTLV-1-Infected Individuals with Bladder Symptoms. AB - BACKGROUND: Previous studies have reported high rates of depression and anxiety in HTLV-1 infected individuals with the neurological disease and in the asymptomatic phase. No study has investigated the rates in individuals that already show bladder symptoms without severe neurological changes; that is, during the oligosymptomatic phase. The present study investigated patients in this intermediate form on the spectrum of the infection. METHODOLOGY/PRINCIPAL FINDINGS: Participants answered a sociodemographic questionnaire, the Mini International Neuropsychiatric Interview Brazilian Version 5.0.0 (MINI PLUS) and the Hospital Anxiety and Depression Scale (HADS). Data analysis was performed in STATA statistical software (version 12.0). Depressive disorder was the most frequent comorbidity. Current depressive disorder was higher in the group of overactive bladder subjects (11.9%), and lifelong depression was more frequent in the HAM/TSP group (35%). The three groups had similar frequencies of anxiety disorders. Increased frequency and severity of anxiety and depression symptoms were observed in the overactive bladder group. CONCLUSION/SIGNIFICANCE: The results suggest that individuals with overactive bladders need a more thorough assessment from the mental health perspective. These patients remain an understudied group regarding psychiatric comorbidities. PMID- 26018524 TI - Selective Targeting of CTNBB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs. AB - The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for beta-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK 1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes. PMID- 26018526 TI - Does a minimal invasive approach reduce anterior chest wall numbness and postoperative pain in plate fixation of clavicle fractures? AB - BACKGROUND: Fractures of the clavicle present very common injuries with a peak of incidence in young active patients. Recently published randomized clinical trials demonstrated an improved functional outcome and a lower rate of nonunions in comparison to non-operative treatment. Anterior chest wall numbness due to injury of the supraclavicular nerve and postoperative pain constitute common surgery related complications in plate fixation of displaced clavicle fractures. We recently developed a technique for mini open plating (MOP) of the clavicle to reduce postoperative numbness and pain. The purpose of this study was to analyze the size of anterior chest wall numbness and the intensity of postoperative pain in MOP in comparison to conventional open plating (COP) of clavicle fractures. METHODS: 24 patients (mean age 38.2 +/- 14.2 yrs.) with a displaced fracture of the clavicle (Orthopaedic Trauma Association B1.2-C1.2) surgically treated using a locking compression plate (LCP) were enrolled. 12 patients underwent MOP and another 12 patients COP. Anterior chest wall numbness was measured with a transparency grid on the second postoperative day and at the six months follow up. Postoperative pain was evaluated using the Visual Analog Scale (VAS). RESULTS: Mean ratio of skin incision length to plate length was 0.61 +/- 0.04 in the MOP group and 0.85 +/- 0.06 in the COP group (p < 0.05). Mean ratio of the area of anterior chest wall numbness to plate length was postoperative 7.6 +/- 5.9 (six months follow-up 4.7 +/- 3.9) in the MOP group and 22.1 +/- 19.1 (16.9 +/- 14.1) in the COP group (p < 0.05). Mean VAS was 2.6 +/- 1.4 points in the MOP group and 3.4 +/- 1.6 points in the COP group (p = 0.20). CONCLUSIONS: In our study, MOP significantly reduced anterior chest wall numbness in comparison to a conventional open approach postoperative as well as at the six months follow-up. Postoperative pain tended to be lower in the MOP group, however this difference was not statistically significant. TRIAL REGISTRATION: ClinicalTrials.gov NCT02247778 . Registered 21 September 2014. PMID- 26018527 TI - Normal tissue complication models for clinically relevant acute esophagitis (>= grade 2) in patients treated with dose differentiated accelerated radiotherapy (DART-bid). AB - BACKGROUND: One of the primary dose-limiting toxicities during thoracic irradiation is acute esophagitis (AE). The aim of this study is to investigate dosimetric and clinical predictors for AE grade >= 2 in patients treated with accelerated radiotherapy for locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 66 NSCLC patients were included in the present analysis: 4 stage II, 44 stage IIIA and 18 stage IIIB. All patients received induction chemotherapy followed by dose differentiated accelerated radiotherapy (DART-bid). Depending on size (mean of three perpendicular diameters) tumors were binned in four dose groups: <2.5 cm 73.8 Gy, 2.5-4.5 cm 79.2 Gy, 4.5-6 cm 84.6 Gy, >6 cm 90 Gy. Patients were treated in 3D target splitting technique. In order to estimate the normal tissue complication probability (NTCP), two Lyman models and the cutoff-logistic regression model were fitted to the data with AE >= grade 2 as statistical endpoint. Inter-model comparison was performed with the corrected Akaike information criterion (AICc), which calculates the model's quality of fit (likelihood value) in relation to its complexity (i.e. number of variables in the model) corrected by the number of patients in the dataset. Toxicity was documented prospectively according to RTOG. RESULTS: The median follow up was 686 days (range 84-2921 days), 23/66 patients (35 %) experienced AE >= grade 2. The actuarial local control rates were 72.6 % and 59.4 % at 2 and 3 years, regional control was 91 % at both time points. The Lyman-MED model (D50 = 32.8 Gy, m = 0.48) and the cutoff dose model (Dc = 38 Gy) provide the most efficient fit to the current dataset. On multivariate analysis V38 (volume of the esophagus that receives 38 Gy or above, 95 %-CI 28.2-57.3) was the most significant predictor of AE >= grade 2 (HR = 1.05, CI 1.01-1.09, p = 0.007). CONCLUSION: Following high dose accelerated radiotherapy the rate of AE >= grade 2 is slightly lower than reported for concomitant radio-chemotherapy with the additional benefit of markedly increased loco-regional tumor control. In the current patient cohort the most significant predictor of AE was found to be V38. A second clinically useful parameter in treatment planning may be MED (mean esophageal dose). PMID- 26018528 TI - Ancient DNA analysis of the oldest canid species from the Siberian Arctic and genetic contribution to the domestic dog. AB - Modern Arctic Siberia provides a wealth of resources for archaeological, geological, and paleontological research to investigate the population dynamics of faunal communities from the Pleistocene, particularly as the faunal material coming from permafrost has proven suitable for genetic studies. In order to examine the history of the Canid species in the Siberian Arctic, we carried out genetic analysis of fourteen canid remains from various sites, including the well documented Upper Paleolithic Yana RHS and Early Holocene Zhokhov Island sites. Estimated age of samples range from as recent as 1,700 years before present (YBP) to at least 360,000 YBP for the remains of the extinct wolf, Canis cf. variabilis. In order to examine the genetic affinities of ancient Siberian canids species to the domestic dog and modern wolves, we obtained mitochondrial DNA control region sequences and compared them to published ancient and modern canid sequences. The older canid specimens illustrate affinities with pre-domestic dog/wolf lineages while others appear in the major phylogenetic clades of domestic dogs. Our results suggest a European origin of domestic dog may not be conclusive and illustrates an emerging complexity of genetic contribution of regional wolf breeds to the modern Canis gene pool. PMID- 26018529 TI - Calibration and cross-validation of MCCB and CogState in schizophrenia. AB - RATIONALE: Cognitive impairment associated with schizophrenia is a key predictor of functional outcomes. The FDA-accepted MATRICS Consensus Cognitive Battery (MCCB) is held to be the gold standard measure but there are concerns about its ease of administration, reliance on language causing problems with translation and possible practice effects. The CogState Schizophrenia Battery (SB) is suggested as a non-language-based alternative but there is no substantial, independent comparison. OBJECTIVES: The objective of this study was to assess the reliability and validity of these two assessment batteries. METHODS: One hundred forty-three participants with DSM-IV schizophrenia and schizoaffective disorder were recruited into three similar studies. Each study administered MCCB and SB tests on consecutive days (baseline 1 and 2) and follow-up 3-4 weeks later. RESULTS: Batteries' test-retest reliability was similar: SB composites correlated r = 0.66-0.78 between baselines, MCCB domains r = 0.69-0.90. Baseline 2 and follow-up SB composites correlated r = 0.65-0.80 and MCCB domains r = 0.62-0.87. MCCB tasks' practice effects (Glass' ? = 0.02-0.46) exceeded SB's (Glass' ? = 0.02-0.34). While the batteries' total scores correlated strongly (r = 0.79 0.82), apparently equivalent cognitive domains on each battery (e.g. psychomotor attention) correlated r = 0.22-0.60, indicating substantial differences between some supposed counterparts. CONCLUSIONS: Clinical trials using either battery would benefit from initial practice sessions to ameliorate practice effects but the SB may be more suitable to measure change in the absence of repeated baselines. The MCCB domains' better correlations with social skills performance suggest that it may have an advantage for measuring cognition in relation to functional outcome. PMID- 26018530 TI - Developmental emergence of an obsessive-compulsive phenotype and binge behavior in rats. AB - RATIONALE: Obsessive-compulsive disorder (OCD) gradually emerges and reaches clinical significance during early adulthood. Whether a predisposition for OCD manifests as binge eating disorder earlier during adolescence is proposed. OBJECTIVES: To further characterize how OCD-like behaviors increase across maturation and to determine whether an OCD-like predisposition increases the likelihood of binge eating during adolescence. METHODS: Male and female Sprague Dawley rats were injected with the tricyclic antidepressant clomipramine (CMI, 15 mg/kg) or saline vehicle twice daily between postnatal days 9-15. Both groups were tested for perseverative (spontaneous alternation) and anxiety-like (elevated plus maze; marble burying) behaviors during juvenility (day 28), adolescence (day 60), and adulthood (day 90). Both motivations to eat sucrose pellets and binge eating on fat were investigated. RESULTS: Sex- and age dependent increases in anxiety-like and perseverative behavior were observed in CMI subjects. Differences in consummatory behaviors emerged during late adolescence, while no significant differences in alternation or anxiety-like behaviors were detected between CMI and vehicle animals until adulthood. Adolescent CMI females consumed more sucrose pellets in 30 min relative to vehicle females, whereas adolescent CMI males consumed approximately half as much as vehicle males. Sucrose consumption did not differ between groups in adulthood. Adolescent CMI rats demonstrated more fat bingeing than vehicles, independent of sex. CONCLUSIONS: OCD-like behaviors are emerging during adolescence, but sucrose consumption and fat bingeing in CMI-treated animals significantly precedes the appearance of anxiety and perseveration. This OCD-like phenotype emerges fully during adulthood, suggesting that eating may likely serve as a coping strategy in these animals. PMID- 26018531 TI - Detection of plaque structure and composition using OCT combined with two-photon luminescence (TPL) imaging. AB - BACKGROUND AND OBJECTIVES: Atherosclerosis and plaque rupture leads to myocardial infarction and stroke. A novel hybrid optical coherence tomography (OCT) and two photon luminescence (TPL) fiber-based imaging system was developed to characterize tissue constituents in the context of plaque morphology. STUDY DESIGN/MATERIALS AND METHODS: Ex vivo coronary arteries (34 regions of interest) from three human hearts with atherosclerotic plaques were examined by OCT-TPL imaging. Histological sections (4 MUm in thickness) were stained with Oil Red O for lipid, Von Kossa for calcium, and Verhoeff-Masson Tri-Elastic for collagen/elastin fibers and compared with imaging results. RESULTS: Biochemical components in plaques including lipid, oxidized-LDL, and calcium, as well as a non-tissue component (metal) are distinguished by multi-channel TPL images with statistical significance (P < 0.001). TPL imaging provides complementary optical contrast to OCT (two-photon absorption/emission vs scattering). Merged OCT-TPL images demonstrate the distribution of lipid deposits in registration with detailed plaque surface profile. CONCLUSIONS: Results suggest that multi-channel TPL imaging can effectively identify lipid sub-types and different plaque components. Furthermore, fiber-based hybrid OCT-TPL imaging simultaneously detects plaque structure and composition, improving the efficacy of vulnerable plaque detection and characterization. PMID- 26018533 TI - Gamma Interferon Assays Used in the Diagnosis of Tuberculosis. AB - Tuberculosis (TB) is an ancient disease that has infected humans for thousands of years. However, despite diagnostic tests that detect the disease and effective therapy, there are still millions of people worldwide who are infected with TB. The first TB test used to detect infected patients was a skin test that identifies individuals actively infected with TB. This test used a mix of proteins from culture filtrates of the bacteria Mycobacterium tuberculosis. Recently, two new diagnostic tests have been introduced; these two new tests can detect TB infection in patients by challenging peripheral blood cells with specific TB proteins. These assays measure the cellular immune response to these proteins. This minireview evaluates the new assays and compares them to the use of the TB skin test. The use of these new assays may have some advantages in detecting individuals with active tuberculosis. However, there is still a role for the use of the skin test, especially in young patients. PMID- 26018532 TI - Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study. AB - BACKGROUND: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. METHODS: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. RESULTS: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). CONCLUSIONS: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease. PMID- 26018534 TI - Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1. AB - Caveolin-1 (Cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. Several viruses exploit caveolae to facilitate viral infections. However, the roles of Cav-1 in herpes simplex virus 1 (HSV-1) infection have not fully been elucidated. Here, we report that Cav-1 downregulates the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in dendritic cells (DCs) during HSV-1 infection. As a result, Cav-1 deficiency led to an accelerated elimination of virus and less lung pathological change following HSV-1 infection. This protection was dependent on iNOS and NO production in DCs. Adoptive transfer of DCs with Cav-1 knockdown was sufficient to confer the protection to wild-type (WT) mice. In addition, Cav-1 knockout (KO) (Cav-1(-/-)) mice treated with an iNOS inhibitor exhibited significantly reduced survival compared to that of the nontreated controls. We found that Cav-1 colocalized with iNOS and HSV-1 in caveolae in HSV-1-infected DCs, suggesting their interaction. Taken together, our results identified Cav-1 as a novel regulator utilized by HSV-1 to evade the host antiviral response mediated by NO production. Therefore, Cav-1 might be a valuable target for therapeutic approaches against herpesvirus infections. PMID- 26018535 TI - Impaired Antigen-Specific Immune Response to Vaccines in Children with Antibody Production Defects. AB - The impaired synthesis of antigen-specific antibodies, which is indispensable for an adaptive immune response to infections, is a fundamental pathomechanism that leads to clinical manifestations in children with antibody production defects. The aim of this study was to evaluate the synthesis of antigen-specific antibodies following immunization in relation to peripheral blood B cell subsets in young children with hypogammaglobulinemia. Twenty-two children, aged from 8 to 61 months, with a deficiency in one or more major immunoglobulin classes participated in the study. Postvaccination antibodies against tetanus and diphtheria toxoids, the surface antigen of the hepatitis B virus, and the capsular Haemophilus influenzae type b polysaccharide antigen were assessed along with an immunophenotypic evaluation of peripheral blood B lymph cell maturation. A deficiency of antibodies against the tetanus toxoid was assessed in 73% of cases and that against the diphtheria toxoid was assessed in 68% of cases, whereas a deficiency of antibodies against the surface antigen of the hepatitis B virus was revealed in 59% of the children included in the study. A defective response to immunization with a conjugate vaccine with the Haemophilus influenzae type b polysaccharide antigen was demonstrated in 55% of hypogammaglobulinemic patients. Increased proportions of transitional B lymph cells and an accumulation of plasmablasts accompanied antibody deficiencies. The defective response to vaccine protein and polysaccharide antigens is a predominating disorder of humoral immunity in children with hypogammaglobulinemia and may result from a dysfunctional state of the cellular elements of the immune system. PMID- 26018536 TI - Therapeutic Transcutaneous Immunization with a Band-Aid Vaccine Resolves Experimental Otitis Media. AB - Transcutaneous immunization (TCI) is a noninvasive strategy to induce protective immune responses. We describe TCI with a band-aid vaccine placed on the postauricular skin to exploit the unique organization of the stratum corneum and to promote the development of immune responses to resolve active experimental otitis media due to nontypeable Haemophilus influenzae (NTHI). This therapeutic immunization strategy induced significantly earlier resolution of middle ear fluid and rapid eradication of both planktonic and mucosal biofilm-resident NTHI within 7 days after receipt of the first immunizing band-aid vaccine. Efficacy was ascribed to the homing of immunogen-bearing cutaneous dendritic cells to the nasal-associated lymphoid tissue, induction of polyfunctional CD4(+) T cells, and the presence of immunogen-specific IgM and IgG within the middle ear. TCI using band-aid vaccines could expand the use of traditional parenteral preventative vaccines to include treatment of active otitis media, in addition to other diseases of the respiratory tract due to NTHI. PMID- 26018537 TI - Rapid Point-of-Contact Tool for Mapping and Integrated Surveillance of Wuchereria bancrofti and Onchocerca volvulus Infection. AB - Elimination programs for Wuchereria bancrofti and Onchocerca volvulus are in critical need of sensitive, specific, and point-of-contact (POC) tools that can be used for surveillance years beyond cessation of mass drug administration when infection intensities are low. Previously, Wb123 and Ov16 were identified individually as potential filarial antigens for an antibody-based POC test. The present study compares single-antigen Wb123- and Ov16-based POC tests with an integrated configuration to detect antibodies to Wb123 and Ov16 simultaneously. Wb123 and Ov16 isolates were striped onto lateral flow strips containing anti IgG4. Sera from W. bancrofti-, O. volvulus-, and other helminth-infected or uninfected individuals were added to the strips with buffer. Strips were read for the appearance of a positive or negative test line for both antigens at 20 min and following drying. Sensitivity, specificity, and predictive values were calculated for the single-antigen and biplex strips. Single and biplex lateral flow strips showed nearly identical results, with >90% sensitivity for Ov16 and >92% sensitivity for Wb123. Overall specificities for the single and biplex tests were 98% and 96% for Ov16 and Wb123, respectively. Biplex tests performed as well as the single-antigen tests regardless of the intensity of patient IgG4 response. The high sensitivity and specificity make these new biplex tests extremely useful for POC long-term surveillance following mass drug administration in Africa that should reduce time and cost in areas where bancroftian filariasis and onchocerciasis are coendemic. PMID- 26018540 TI - [In Process Citation]. PMID- 26018541 TI - [Memorandum on sustainable reinforcement of prevention and health promotion: challenges at the federal, state and local level]. AB - Research-based evidence and practice-based experience are core requirements for the effective implementation of preventive interventions. The knowledge gained in the Prevention Research Funding Initiative of the German Federal Ministry of Education and Research (2004-2013) was therefore amalgamated, reflected and consolidated in the Cooperation for Sustainable Prevention Research (KNP) meta project. In annual strategy meetings, researchers and practitioners from the field and other experts developed 3 memoranda providing recommendations for the further development of research and practice in the field of prevention and health promotion. Memorandum III is primarily aimed at decision-makers in politics and administration at the federal, state and local level, in civil society and in the workplace. Its recommendations show that structuring efforts are urgently needed to achieve sustainable policy, particularly in the fields of health, education, employment and social affairs. Memorandum III brings together the knowledge extracted and problems identified in research projects. More so than its 2 predecessors, Memorandum III abstracts knowledge from the individual projects and attempts to derive guidance for action and decision-making, as shown by the 7 recommendations that appear to useful for consensus-building in practice and research. Value judgments are inevitable. Prevention and health promotion are an investment in the future: of social health, social capital and social peace. Improvement of the framework conditions is needed to achieve the harmonized awareness and the sustained effectiveness of these structure-building efforts in different policy areas, spheres of life, fields of action, and groups of actors. This includes the implementation of an overall national strategy as well as the expansion of sources of funding, extension of the legal framework, overarching coordination, and the establishment of a National Center of Excellence to develop and safeguard prevention and health promotion. The memorandum is intended to stimulate a discourse resulting in structure-building and stabilizing measures designed to ensure the sustainability of prevention and health promotion. PMID- 26018542 TI - Electronic Cigarette Use among Irish Youth: A Cross Sectional Study of Prevalence and Associated Factors. AB - PURPOSE: To examine prevalence of, and factors associated with, e-cigarette use among young people aged 16-17 in Ireland. METHODS: In 2014, a representative sample of 821 young people aged 16-17 recruited from secondary schools completed a pen and paper survey on e-cigarette use, tobacco use, and socio-demographic items. FINDINGS: A total of 23.8% of respondents had used e-cigarettes at least once. Dual trial of tobacco and e-cigarettes was common with 69.5% of regular smokers and 30.4% of 'ever' smokers having tried e-cigarettes and 10.6% of current smokers using e-cigarettes regularly. 4.2% of never smokers have tried e cigarettes. Overall, current e-cigarette use (once a month or more) was low (3.2%). Binary logistic regression conducted through generalized estimating equations (GEE) determined that controlling for other variables, current tobacco use and 'ever' tobacco use predicted ever e-cigarette use. Gender and school level socioeconomic status were also independent predictors of ever e-cigarette use. Gender stood as the only predictor of on-going e-cigarette use, with males being more likely to regularly use e-cigarettes at least once a month. CONCLUSIONS: E-cigarette use among 16-17 year olds in Ireland is of note, with nearly a quarter of students having tried them. Concurrent or experimental use of e-cigarettes and tobacco is more common than sole use, while a small number have tried e-cigarettes without having tried tobacco. PMID- 26018543 TI - Reverse logistics in the construction industry. AB - Reverse logistics in construction refers to the movement of products and materials from salvaged buildings to a new construction site. While there is a plethora of studies looking at various aspects of the reverse logistics chain, there is no systematic review of literature on this important subject as applied to the construction industry. Therefore, the objective of this study is to integrate the fragmented body of knowledge on reverse logistics in construction, with the aim of promoting the concept among industry stakeholders and the wider construction community. Through a qualitative meta-analysis, the study synthesises the findings of previous studies and presents some actions needed by industry stakeholders to promote this concept within the real-life context. First, the trend of research and terminology related with reverse logistics is introduced. Second, it unearths the main advantages and barriers of reverse logistics in construction while providing some suggestions to harness the advantages and mitigate these barriers. Finally, it provides a future research direction based on the review. PMID- 26018544 TI - Exploring views on what is important for patient-centred care in end-stage renal disease using Q methodology. AB - BACKGROUND: This study aimed to explore views on what is considered important for Patient-Centred Care (PCC) among patients and the healthcare professionals treating them in a haemodialysis department. METHODS: Interviews were conducted among 14 patients with end-stage renal disease receiving dialysis and 12 healthcare professionals (i.e. 2 doctors, 4 staff members, and 6 nurses) working at a haemodialysis department. Participants were asked to rank-order 35 statements representing eight dimensions of PCC previously discussed in the literature. Views on PCC, and communalities and differences between them, were explored using by-person factor analysis. RESULTS: Four views on what is important for PCC in end-stage renal disease were identified. In viewpoint 1, listening to patients and taking account of their preferences in treatment decisions is considered central to PCC. In viewpoint 2, providing comprehensible information and education to patients so that they can take charge of their own care is considered important. In viewpoint 3, several aspects related to the atmosphere at the department were put forward as important for PCC. In viewpoint 4, having a professional or acquaintance that acts as care coordinator, making treatment decisions with or for them, was considered particularly beneficial. All views agreed about the relative importance of certain PCC dimensions; the patient preferences and information and education dimensions were generally considered most important, while the family and friends and the access to care dimensions were considered least important. CONCLUSIONS: The four views on PCC among patients in a haemodialysis department and the professionals treating them suggest that there is no one size fits all strategy for providing PCC to patients with end-stage renal disease. Some patients may benefit from educational interventions to improve their self-management skills and place them in charge of their own care, whereas other patients may benefit more from the availability of a care coordinator to make decisions for them, or with them. Furthermore, our results suggest that not all eight dimensions of PCC need to be given equal consideration in the care for patients with end-stage renal disease in order to improve patient outcomes. PMID- 26018545 TI - Formation of a single polar flagellum by two distinct flagellar gene sets in Sphingomonas sp. strain A1. AB - Gram-negative Sphingomonas sp. strain A1, originally identified as a non-motile and aflagellate bacterium, possesses two sets of genes required for flagellar formation. In this study, we characterized the flagellar genes and flagellum formation in strain A1. Flagellar gene cluster set I contained 35 flagellar genes, including one flagellin gene (p6), where the gene assembly structure resembled that required for the formation of lateral flagella in gammaproteobacteria. The set II flagellar genes were arranged in eight shorter clusters with 46 flagellar genes, including two flagellin genes (p5 and p5') and flhF, which is required for polar flagella. Our molecular phylogenetic analysis of the bacterial flagellins also demonstrated that, in contrast to p5 and p5', p6 was categorized as a lateral flagellin group. The motile phenotype appeared in strain A1 cells when they were subcultured on semisolid media. The motile strain A1 cells produced a single flagellum at the cell pole. DNA microarray analyses using non-motile and motile strain A1 cells indicated that flagellar formation was accompanied by increased transcription of both flagellar gene sets. The two flagellins p5 and p6 were major components of the flagellar filaments isolated from motile strain A1 cells, indicating that the polar flagellum is formed by lateral and non-lateral flagellins. PMID- 26018547 TI - Preventable hospital admissions: are they? PMID- 26018546 TI - Physiological, biomass elemental composition and proteomic analyses of Escherichia coli ammonium-limited chemostat growth, and comparison with iron- and glucose-limited chemostat growth. AB - Escherichia coli physiological, biomass elemental composition and proteome acclimations to ammonium-limited chemostat growth were measured at four levels of nutrient scarcity controlled via chemostat dilution rate. These data were compared with published iron- and glucose-limited growth data collected from the same strain and at the same dilution rates to quantify general and nutrient specific responses. Severe nutrient scarcity resulted in an overflow metabolism with differing organic byproduct profiles based on limiting nutrient and dilution rate. Ammonium-limited cultures secreted up to 35% of the metabolized glucose carbon as organic byproducts with acetate representing the largest fraction; in comparison, iron-limited cultures secreted up to 70 % of the metabolized glucose carbon as lactate, and glucose-limited cultures secreted up to 4% of the metabolized glucose carbon as formate. Biomass elemental composition differed with nutrient limitation; biomass from ammonium-limited cultures had a lower nitrogen content than biomass from either iron- or glucose-limited cultures. Proteomic analysis of central metabolism enzymes revealed that ammonium- and iron limited cultures had a lower abundance of key tricarboxylic acid (TCA) cycle enzymes and higher abundance of key glycolysis enzymes compared with glucose limited cultures. The overall results are largely consistent with cellular economics concepts, including metabolic tradeoff theory where the limiting nutrient is invested into essential pathways such as glycolysis instead of higher ATP-yielding, but non-essential, pathways such as the TCA cycle. The data provide a detailed insight into ecologically competitive metabolic strategies selected by evolution, templates for controlling metabolism for bioprocesses and a comprehensive dataset for validating in silico representations of metabolism. PMID- 26018548 TI - The triumph of medicine: how overdiagnosis is turning healthy people into patients. PMID- 26018550 TI - Risk factors for idiopathic cystitis in Norwegian cats: a matched case-control study. AB - OBJECTIVES: The aim of the study was to compare a group of cats with feline idiopathic cystitis (FIC) with a group of control cats without present or previous signs of lower urinary tract disease in order to identify factors in characteristics, personality, behaviour, environment and daily life that would make them more susceptible to the disease. METHODS: The study was a matched case control study comparing results from telephone interviews based on a standardised questionnaire. The questions were organised into six subject groups: the characteristics of the cat; the cat's environment; the presence of other pets in the household; the cat's feeding and drinking regime; management of the cat's litter box; and the cat's opportunity to perform natural behaviour. RESULTS: The results from the present study showed that a cat diagnosed with FIC was more likely to be overweight and to be of a nervous disposition than the control cats. In addition, several differences between cases and controls were detected at a univariable level of analysis, related to outdoor access and the cats' perceived safety and comfort in their home environments. While not significant after multivariable analysis, these variables may still be of importance owing to potential interrelations. CONCLUSIONS AND RELEVANCE: Several significant differences between cats with FIC and control cats were revealed, and the results support the hypothesis of environmental stress as being a potential factor in the development of FIC. PMID- 26018549 TI - Shifts in temperature within the physiologic range modify strand-specific expression of select human microRNAs. AB - Previous studies have revealed that clinically relevant changes in temperature modify clinically relevant gene expression profiles through transcriptional regulation. Temperature dependence of post-transcriptional regulation, specifically, through expression of miRNAs has been less studied. We comprehensively analyzed the effect of 24 h exposure to 32 degrees C or 39.5 degrees C on miRNA expression profile in primary cultured human small airway epithelial cells (hSAECs) and its impact on expression of a targeted protein, protein kinase C alpha (PKCalpha). Using microarray, and solution hybridization based nCounter assays, with confirmation by quantitative RT-PCR, we found significant temperature-dependent changes in expression level of only five mature human miRNAs, representing only 1% of detected miRNAs. Four of these five miRNAs are the less abundant passenger (star) strands. They exhibited a similar pattern of increased expression at 32 degrees C and reduced expression at 39.5 degrees C relative to 37 degrees C. As PKCalpha mRNA has multiple potential binding sites for three of these miRNAs, we analyzed PKCalpha protein expression in HEK 293T cells and hSAECs. PKCalpha protein levels were lowest at 32 degrees C and highest at 39.5 degrees C and specific miRNA inhibitors reduced these effects. Finally, we analyzed cell-cycle progression in hSAECs and found 32 degrees C cells exhibited the greatest G1 to S transition, a process known to be inhibited by PKCalpha, and the effect was mitigated by specific miRNA inhibitors. These results demonstrate that exposure to clinically relevant hypothermia or hyperthermia modifies expression of a narrow subset of miRNAs and impacts expression of at least one signaling protein involved in multiple important cellular processes. PMID- 26018551 TI - Evaluation of biochemical and haematological parameters and prevalence of selected pathogens in feral cats from urban and rural habitats in South Korea. AB - OBJECTIVES: In this study, we evaluated the potential association between the habitat types of feral cats and the prevalence of selected infectious pathogens and health status based on a set of blood parameters. METHODS: We live-trapped 72 feral cats from two different habitat types: an urban area (n = 48) and a rural agricultural area (n = 24). We compared blood values and the prevalence of feline immunodeficiency virus (FIV), feline leukaemia virus (FeLV) and haemotropic Mycoplasma infection in feral cats from the two contrasting habitats. RESULTS: Significant differences were observed in several blood values (haematocrit, red blood cells, blood urea nitrogen, creatinine) depending on the habitat type and/or sex of the cat. Two individuals from the urban area were seropositive for FIV (3.0%), and eight (12.1%) were positive for FeLV infection (five from an urban habitat and three from a rural habitat). Haemoplasma infection was more common. Based on molecular analysis, 38 cats (54.3%) were positive for haemoplasma, with a significantly higher infection rate in cats from rural habitats (70.8%) compared with urban cats (47.8%). CONCLUSIONS AND RELEVANCE: Our study recorded haematological and serum biochemical values, and prevalence of selected pathogens in feral cat populations from two different habitat types. A subset of important laboratory parameters from rural cats showed values under or above the corresponding reference intervals for healthy domestic cats, suggesting potential differences in the health status of feral cats depending on the habitat type. Our findings provide information about the association between 1) blood values (haematological and serum biochemistry parameters) and 2) prevalence of selected pathogen infections and different habitat types; this may be important for veterinarians who work with feral and/or stray cats and for overall cat welfare management. PMID- 26018552 TI - A cross-sectional survey study to evaluate phototherapy training in dermatology residency. PMID- 26018554 TI - How attractive is the combination of a sodium glucose co-transporter 2 inhibitor with a dipeptidyl peptidase 4 inhibitor in the treatment of type 2 diabetes? PMID- 26018553 TI - Nuclear Localization Signal and p53 Binding Site in MAP/ERK Kinase Kinase 1 (MEKK1). AB - Previously, we showed that Mekk1 translocates to the nucleus, interacts with tumor suppressor protein p53, and co-represses PKD1 transcription via an atypical p53 binding site on the minimal PKD1 promoter (JBC 285:38,818-38,831, 2010). In this study, we report the mechanisms of Mekk1 nuclear transport and p53 binding. Using GFP-linked constitutively active-Mekk1 (CA-Mekk1) and a deletion strategy, we identified a nuclear localization signal (HRDVK) located at amino acid (aa) residues 1,349-1,353 in the C-terminal Mekk1 catalytic domain. Deletion of this sequence in CA-Mekk1 and full-length Mekk1 significantly reduced their nuclear translocation in both HEK293T and COS-1 cells. Using co-immunoprecipitation, we identified an adjacent sequence (GANLID, aa 1,354-1,360) in Mekk1 responsible for p53 binding. Deletion of this sequence markedly reduced the interaction of Mekk1 with p53. Mekk1 does not appear to affect phosphorylation of Ser15, located in the Mdm2 interaction site, or other Ser residues in p53. However, Mekk1 mediates p53 protein stability in the presence of Mdm2 and reduces p53 ubiquitination, suggesting an interference with Mdm2-mediated degradation of p53 by the ubiquitin proteasome pathway. PMID- 26018555 TI - HLA Typing for the Next Generation. AB - Allele-level resolution data at primary HLA typing is the ideal for most histocompatibility testing laboratories. Many high-throughput molecular HLA typing approaches are unable to determine the phase of observed DNA sequence polymorphisms, leading to ambiguous results. The use of higher resolution methods is often restricted due to cost and time limitations. Here we report on the feasibility of using Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing technology for high-resolution and high-throughput HLA typing. Seven DNA samples were typed for HLA-A, -B and -C. The results showed that SMRT DNA sequencing technology was able to generate sequences that spanned entire HLA Class I genes that allowed for accurate allele calling. Eight novel genomic HLA class I sequences were identified, four were novel alleles, three were confirmed as genomic sequence extensions and one corrected an existing genomic reference sequence. This method has the potential to revolutionize the field of HLA typing. The clinical impact of achieving this level of resolution HLA typing data is likely to considerable, particularly in applications such as organ and blood stem cell transplantation where matching donors and recipients for their HLA is of utmost importance. PMID- 26018556 TI - Elicitation of health state utilities associated with varying severities of flares in Systemic Lupus Erythematosus. AB - BACKGROUND: Systemic Lupus Erythematosus (SLE) is characterised by fluctuating periods of minimal disease activity and 'flare'. Flare is an important outcome variable impacting the disease burden associated with SLE. The objective of this study was to obtain population-based utility values for varying severities of flare to measure the impact on health-related quality of life (HRQoL) in Australia, Canada, France, Japan, Spain and the UK. METHODS: Six health states (HS) for varying severities of flare were developed based on literature, patient blogs, and interviews with patients (n = 12), rheumatologists (n = 7) and nurses (n = 2). HS were validated by independent clinical experts (n = 6) and pilot interviews (n = 10, UK). HS were evaluated using the time-trade-off (TTO) method during face-to-face interviews with a minimum representative sample (n = 100) of the general population, per-country. Visual Analog Scale (VAS) scores were obtained to validate TTO scores. TTO scores were converted into utility values. RESULTS: The highest mean TTO utility scores were observed for the anchor HS (minimal disease activity) across all countries; means ranged from 0.66 in Japan to 0.82 in UK. All flare HS were associated with a disutility compared with the anchor HS (p < 0.001), means ranged across countries: mild flare HS: 0.55-0.71, moderate flare HS: 0.38-0.53, severe renal flare HS: 0.33-0.45, severe central nervous system (CNS) flare HS: 0.30-0.45 and severe generalised flare HS: 0.19 0.33. Mean VAS scores followed the same trend. CONCLUSIONS: These results show increasing severity of flare has a detrimental impact on HRQoL. The severe generalised flare HS received the lowest mean utility score suggesting that the perceived day-to-day impact of a severe generalised flare was greater than a severe CNS or severe renal flare. This is, to the best of our knowledge, the first utility study to assess varying severities of flare in SLE across six different countries. PMID- 26018557 TI - In Vivo Expression of the PTB-deleted Odin Mutant Results in Hydrocephalus. AB - Odin has been implicated in the downstream signaling pathway of receptor tyrosine kinases, such as the epidermal growth factor and Eph receptors. However, the physiologically relevant function of Odin needs to be further determined. In this study, we used Odin heterozygous mice to analyze the Odin expression pattern; the targeted allele contained a beta-geo gene trap vector inserted into the 14th intron of the Odin gene. Interestingly, we found that Odin was exclusively expressed in ependymal cells along the brain ventricles. In particular, Odin was highly expressed in the subcommissural organ, a small ependymal glandular tissue. However, we did not observe any morphological abnormalities in the brain ventricles or ependymal cells of Odin null-mutant mice. We also generated BAC transgenic mice that expressed the PTB-deleted Odin (dPTB) after a floxed GFP STOP cassette was excised by tissue-specific Cre expression. Strikingly, Odin dPTB expression played a causative role in the development of the hydrocephalic phenotype, primarily in the midbrain. In addition, Odin-dPTB expression disrupted proper development of the subcommissural organ and interfered with ependymal cell maturation in the cerebral aqueduct. Taken together, our findings strongly suggest that Odin plays a role in the differentiation of ependymal cells during early postnatal brain development. PMID- 26018558 TI - Whole-Genome Resequencing Analysis of Hanwoo and Yanbian Cattle to Identify Genome-Wide SNPs and Signatures of Selection. AB - Over the last 30 years, Hanwoo has been selectively bred to improve economically important traits. Hanwoo is currently the representative Korean native beef cattle breed, and it is believed that it shared an ancestor with a Chinese breed, Yanbian cattle, until the last century. However, these two breeds have experienced different selection pressures during recent decades. Here, we whole genome sequenced 10 animals each of Hanwoo and Yanbian cattle (20 total) using the Illumina HiSeq 2000 sequencer. A total of approximately 3.12 and 3.07 billion sequence reads were mapped to the bovine reference sequence assembly (UMD 3.1) at an average of approximately 10.71- and 10.53-fold coverage for Hanwoo and Yanbian cattle, respectively. A total of 17,936,399 single nucleotide polymorphisms (SNPs) were yielded, of which 22.3% were found to be novel. By annotating the SNPs, we further retrieved numerous nonsynonymous SNPs that may be associated with traits of interest in cattle. Furthermore, we performed whole-genome screening to detect signatures of selection throughout the genome. We located several promising selective sweeps that are potentially responsible for economically important traits in cattle; the PPP1R12A gene is an example of a gene that potentially affects intramuscular fat content. These discoveries provide valuable genomic information regarding potential genomic markers that could predict traits of interest for breeding programs of these cattle breeds. PMID- 26018560 TI - Four-year incidence and predictors of coronal caries in south Brazilian elderly. AB - OBJECTIVES: To determine the incidence and predictors of coronal caries among community-dwelling elderly in a southern Brazilian city. METHODS: A cohort study was conducted using a simple random sample of persons aged 60 years or older in Carlos Barbosa city, southern Brazil. Interviews and oral examinations were conducted among 388 dentate individuals at baseline and among 273 at 4-year follow-up. The incidence of coronal caries was modeled by means of negative binomial regression. RESULTS: Some 184 (76.7%) participants presented with new coronal caries lesions or restorations, whose mean number was 2.2 +/- 2.1, whereas the 4-year mean coronal caries incidence rate was 0.28 +/- 0.29. In the multivariate model that controlled for baseline predictors, older age, male gender, living in a rural area, current smoking, and negative self-perception of oral health were associated with coronal caries incidence. Among clinical variables, the use of partial dentures was a predictor, whereas higher saliva flow rate was a protective factor for the outcome. CONCLUSIONS: Demographic factors, primary determinants of health, behavioral, and clinical variables were predictors of the incidence of coronal caries. As people enter old age, even stronger emphasis should be put on preventive strategies. PMID- 26018559 TI - Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species. AB - Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been--and still are--considered an exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC) or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl) tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA) and their genetically matched wild-type vhl (RCC4 VHL) counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066) with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with apoptosis induction in VHL deficient cell line as demonstrated with PARP activation and Annexin V staining. Our study demonstrated the feasibility of selectively targeting the loss of the vhl tumor suppressor gene for potential clinical benefit. Our results may have great impact on the development of new targeted therapies from natural products for the treatment of cancer and other genetic diseases. PMID- 26018561 TI - Taxonomic composition and trophic structure of the continental bony fish assemblage from the early late cretaceous of Southeastern Morocco. AB - The mid-Cretaceous vertebrate assemblage from south-eastern Morocco is one of the most diversified continental vertebrate assemblages of this time worldwide. The bony fish component (coelacanths, lungfishes and ray-finned fishes) is represented by relatively complete specimens and, mostly, by fragmentary elements scattered along 250 kilometres of outcrops. Here we revisit the bony fish assemblage by studying both isolated remains collected during several fieldtrips and more complete material kept in public collections. The assemblage comprises several lungfish taxa, with the first mention of the occurrence of Arganodus tiguidiensis, and possibly two mawsoniid coelacanths. A large bichir cf. Bawitius, is recorded and corresponds to cranial elements initially referred to 'Stromerichthys' from coeval deposits in Egypt. The ginglymodians were diversified with a large 'Lepidotes' plus two obaichthyids and a gar. We confirm here that this gar belongs to a genus distinctive from Recent gars, contrary to what was suggested recently. Teleosteans comprise a poorly known ichthyodectiform, a notopterid, a probable osteoglossomorph and a large tselfatiiform, whose cranial anatomy is detailed. The body size and trophic level for each taxon are estimated on the basis of comparison with extant closely related taxa. We plotted the average body size versus average trophic level for the Kem Kem assemblage, together with extant marine and freshwater assemblages. The Kem Kem assemblage is characterized by taxa of proportionally large body size, and by a higher average trophic level than the trophic level of the extant compared freshwater ecosystems, but lower than for the extant marine ecosystems. These results should be regarded with caution because they rest on a reconstructed assemblage known mostly by fragmentary remains. They reinforce, however, the ecological oddities already noticed for this mid-Cretaceous vertebrate ecosystem in North Africa. PMID- 26018562 TI - Laminin-rich blood vessels display activated growth factor signaling and act as the proliferation centers in Dupuytren's contracture. AB - INTRODUCTION: Dupuytren's contracture (DC) is a chronic fibroproliferative disease of the hand, which is characterized by uncontrolled proliferation of atypical myofibroblasts at the cellular level. We hypothesized that specific areas of the DC tissue are sustaining the cell proliferation and studied the potential molecular determinants that might contribute to the formation of such niches. METHODS: We studied the expression pattern of cell proliferation marker Ki67, phosphorylated AKT (Ak mouse strain thymoma) kinase, DC-associated growth factors (connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), insulin-like growth factor 2 (IGF-2)) and extracellular matrix components (laminins, fibronectin, collagen IV) in DC tissue and normal palmar fascia using immunofluorescence microscopy and quantitative real-time polymerase chain reaction (qPCR). RESULTS: We found that proliferative cells in the DC nodules were concentrated in the immediate vicinity of small blood vessels and localized predominantly in the myofibroblast layer. Correspondingly, the DC-associated blood vessels contained increased levels of phosphorylated AKT, a hallmark of activated growth factor signaling. When studying the expression of potential activators of AKT signaling we found that the expression of bFGF was confined to the endothelium of the small blood vessels, IGF-2 was present uniformly in the DC tissue and CTGF was expressed in the DC-associated sweat gland acini. In addition, the blood vessels in DC nodules contained increased amounts of laminins 511 and 521, which have been previously shown to promote the proliferation and stem cell properties of different cell types. CONCLUSIONS: Based on our findings, we propose that in the DC-associated small blood vessels the presence of growth factors in combination with favorable extracellular matrix composition provide a supportive environment for sustained proliferation of myofibroblasts and thus the blood vessels play an important role in DC pathogenesis. PMID- 26018565 TI - Understanding Nonurgent Pediatric Emergency Department Visits: Using Hospital and Family-Centric Data to Inform System Redesign. AB - We conducted a mixed-method study to analyze the population and financial impact of emergency department use for pediatric nonurgent problems. Findings from this initial study led to our phase 2 case study, in which we interviewed 23 adults accompanying children younger than 4 years with nonemergent fever. The resulting qualitative analysis revealed that participants were unable to distinguish urgent from nonurgent conditions, perceived access limitations to care, and although they preferred the child's primary care physician, went to the emergency department for care. PMID- 26018564 TI - CHARMM Drude Polarizable Force Field for Aldopentofuranoses and Methyl aldopentofuranosides. AB - An empirical all-atom CHARMM polarizable force filed for aldopentofuranoses and methyl-aldopentofuranosides based on the classical Drude oscillator is presented. A single electrostatic model is developed for eight different diastereoisomers of aldopentofuranoses by optimizing the existing electrostatic and bonded parameters as transferred from ethers, alcohols, and hexopyranoses to reproduce quantum mechanical (QM) dipole moments, furanose-water interaction energies and conformational energies. Optimization of selected electrostatic and dihedral parameters was performed to generate a model for methyl-aldopentofuranosides. Accuracy of the model was tested by reproducing experimental data for crystal intramolecular geometries and lattice unit cell parameters, aqueous phase densities, and ring pucker and exocyclic rotamer populations as obtained from NMR experiments. In most cases the model is found to reproduce both QM data and experimental observables in an excellent manner, whereas for the remainder the level of agreement is in the satisfactory regimen. In aqueous phase simulations the monosaccharides have significantly enhanced dipoles as compared to the gas phase. The final model from this study is transferrable for future studies on carbohydrates and can be used with the existing CHARMM Drude polarizable force field for biomolecules. PMID- 26018566 TI - Interrupted Time Series Versus Statistical Process Control in Quality Improvement Projects. AB - To measure the effect of quality improvement interventions, it is appropriate to use analysis methods that measure data over time. Examples of such methods include statistical process control analysis and interrupted time series with segmented regression analysis. This article compares the use of statistical process control analysis and interrupted time series with segmented regression analysis for evaluating the longitudinal effects of quality improvement interventions, using an example study on an evaluation of a computerized decision support system. PMID- 26018567 TI - An Integrative Review on Development of "QUality Of care Through the patients' Eyes" (QUOTE) Instruments. AB - "QUality Of care Through the patients' Eyes" (QUOTE) instruments for measuring care quality were classified in terms of procedures, structures, and content. The content and structures of each instrument were found to include (a) participation of the client in the tool development process, (b) evaluation of the importance and performance of care based on the client's needs, and PMID- 26018563 TI - Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. AB - Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3 kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiation and progression of autophagy. The class II enzyme emerged only recently as an alternative source of PtdIns3P and autophagic initiator. However, the orthodox paradigm is challenged by findings that the PIK3CB catalytic subunit of class I PI3K acts as a positive regulator of autophagy, and PIK3C3 was thought to be an amino acid sensor for MTOR, which curbs autophagy. At present, a number of PtdIns3K and PI3K inhibitors, including specific PIK3C3 inhibitors, have been developed for suppression of autophagy and for clinical applications in autophagy-related human diseases. PMID- 26018568 TI - Beyond the EDGE with EDAM: Prioritising British Plant Species According to Evolutionary Distinctiveness, and Accuracy and Magnitude of Decline. AB - Conservation biologists have only finite resources, and so must prioritise some species over others. The EDGE-listing approach ranks species according to their combined evolutionary distinctiveness and degree of threat, but ignores the uncertainty surrounding both threat and evolutionary distinctiveness. We develop a new family of measures for species, which we name EDAM, that incorporates evolutionary distinctiveness, the magnitude of decline, and the accuracy with which decline can be predicted. Further, we show how the method can be extended to explore phyogenetic uncertainty. Using the vascular plants of Britain as a case study, we find that the various EDAM measures emphasise different species and parts of Britain, and that phylogenetic uncertainty can strongly affect the prioritisation scores of some species. PMID- 26018569 TI - Acceptability of neonatal circumcision by pregnant women in KwaZulu-Natal, South Africa. AB - BACKGROUND: Studies on voluntary medical male circumcision (VMMC) have provided convincing evidence on its efficacy to provide partial protection against female to-male HIV transmission in circumcised men. The World Health Organization and UNAIDS subsequently formulated recommendations for VMMC implementation that included implementation of neonatal medical male circumcision (NMMC) to all infants up to two months old. Knowledge regarding the acceptability of NMMC by pregnant women who are candidates for granting of consents for NMMC procedures or its ideal placement within health programmes is low. OBJECTIVES: We sought to establish NMMC acceptability by pregnant women and the feasibility of its integration within Maternal, Child and Women's Health (MCWH) programmes to inform implementation guidelines. METHOD: Nurses and counsellors at two public health facilities were trained to provide NMMC counselling and offer NMMC to 1778 pregnant women presenting for antenatal care services. Univariate and bivariate analyses were performed on data collected on NMMC acceptance and refusals. Thematic analysis was also performed on qualitative reasons for refusals. RESULTS: Acceptability of NMMC by women was high (82.9%). Refusals resulted from the need for consultations with partners and/or family members prior to consenting (41.3%), fear of the procedure (23.8%), cultural reasons (15.9%) and no reasons given (15.3%). CONCLUSION: The acceptability of NMMC by pregnant women and its integration with MCWH services was feasible. However socio-cultural factors, including the need for further consultation prior to consenting for NMMC procedures and preference of traditional circumcision by some women, need to be addressed in order to increase uptakes. PMID- 26018570 TI - Toward Synthesizing Our Knowledge of Morphology: Using Ontologies and Machine Reasoning to Extract Presence/Absence Evolutionary Phenotypes across Studies. AB - The reality of larger and larger molecular databases and the need to integrate data scalably have presented a major challenge for the use of phenotypic data. Morphology is currently primarily described in discrete publications, entrenched in noncomputer readable text, and requires enormous investments of time and resources to integrate across large numbers of taxa and studies. Here we present a new methodology, using ontology-based reasoning systems working with the Phenoscape Knowledgebase (KB; kb.phenoscape.org), to automatically integrate large amounts of evolutionary character state descriptions into a synthetic character matrix of neomorphic (presence/absence) data. Using the KB, which includes more than 55 studies of sarcopterygian taxa, we generated a synthetic supermatrix of 639 variable characters scored for 1051 taxa, resulting in over 145,000 populated cells. Of these characters, over 76% were made variable through the addition of inferred presence/absence states derived by machine reasoning over the formal semantics of the source ontologies. Inferred data reduced the missing data in the variable character-subset from 98.5% to 78.2%. Machine reasoning also enables the isolation of conflicts in the data, that is, cells where both presence and absence are indicated; reports regarding conflicting data provenance can be generated automatically. Further, reasoning enables quantification and new visualizations of the data, here for example, allowing identification of character space that has been undersampled across the fin-to limb transition. The approach and methods demonstrated here to compute synthetic presence/absence supermatrices are applicable to any taxonomic and phenotypic slice across the tree of life, providing the data are semantically annotated. Because such data can also be linked to model organism genetics through computational scoring of phenotypic similarity, they open a rich set of future research questions into phenotype-to-genome relationships. PMID- 26018571 TI - Extensive Horizontal Transfer and Homologous Recombination Generate Highly Chimeric Mitochondrial Genomes in Yeast. AB - The frequency of horizontal gene transfer (HGT) in mitochondrial DNA varies substantially. In plants, HGT is relatively common, whereas in animals it appears to be quite rare. It is of considerable importance to understand mitochondrial HGT across the major groups of eukaryotes at a genome-wide level, but so far this has been well studied only in plants. In this study, we generated ten new mitochondrial genome sequences and analyzed 40 mitochondrial genomes from the Saccharomycetaceae to assess the magnitude and nature of mitochondrial HGT in yeasts. We provide evidence for extensive, homologous-recombination-mediated, mitochondrial-to-mitochondrial HGT occurring throughout yeast mitochondrial genomes, leading to genomes that are highly chimeric evolutionarily. This HGT has led to substantial intraspecific polymorphism in both sequence content and sequence divergence, which to our knowledge has not been previously documented in any mitochondrial genome. The unexpectedly high frequency of mitochondrial HGT in yeast may be driven by frequent mitochondrial fusion, relatively low mitochondrial substitution rates and pseudohyphal fusion to produce heterokaryons. These findings suggest that mitochondrial HGT may play an important role in genome evolution of a much broader spectrum of eukaryotes than previously appreciated and that there is a critical need to systematically study the frequency, extent, and importance of mitochondrial HGT across eukaryotes. PMID- 26018572 TI - Do mirror glasses have the same effect on brain activity as a mirror box? Evidence from a functional magnetic resonance imaging study with healthy subjects. AB - Since its original proposal, mirror therapy has been established as a successful neurorehabilitative intervention in several neurological disorders to recover motor function or to relieve pain. Mirror therapy seems to operate by reactivating the contralesional representation of the non-mirrored limb in primary motor- and somatosensory cortex. However, mirror boxes have some limitations which prompted the use of additional mirror visual feedback devices. The present study evaluated the utility of mirror glasses compared to a mirror box. We also tested the hypothesis that increased interhemispheric communication between the motor hand areas is the mechanism by which mirror visual feedback recruits the representation of the non-mirrored limb. Therefore, mirror illusion capacity and brain activations were measured in a within-subject design during both mirror visual feedback conditions in counterbalanced order with 20 healthy subjects inside a magnetic resonance imaging scanner. Furthermore, we analyzed task-dependent functional connectivity between motor hand representations using psychophysiological interaction analysis during both mirror tasks. Neither the subjective quality of mirror illusions nor the patterns of functional brain activation differed between the mirror tasks. The sensorimotor representation of the non-mirrored hand was recruited in both mirror tasks. However, a significant increase in interhemispheric connectivity between the hand areas was only observed in the mirror glasses condition, suggesting different mechanisms for the recruitment of the representation of the non-mirrored hand in the two mirror tasks. We conclude that the mirror glasses might be a promising alternative to the mirror box, as they induce similar patterns of brain activation. Moreover, the mirror glasses can be easy applied in therapy and research. We want to emphasize that the neuronal mechanisms for the recruitment of the affected limb representation might differ depending on conceptual differences between MVF devices. However, our findings need to be validated within specific patient groups. PMID- 26018573 TI - Deceptive Intentions: Can Cues to Deception Be Measured before a Lie Is Even Stated? AB - Can deceitful intentions be discriminated from truthful ones? Previous work consistently demonstrated that deceiving others is accompanied by nervousness/stress and cognitive load. Both are related to increased sympathetic nervous system (SNS) activity. We hypothesized that SNS activity already rises during intentions to lie and, consequently, cues to deception can be detected before stating an actual lie. In two experiments, controlling for prospective memory, we monitored SNS activity during lying, truth telling, and truth telling with the aim of lying at a later instance. Electrodermal activity (EDA) was used as an indicator of SNS. EDA was highest during lying, and compared to the truth condition, EDA was also raised during the intention to deceive. Moreover, the switch from truth telling toward lying in the intention condition evoked higher EDA than switching toward non-deception related tasks in the lie or truth condition. These results provide first empirical evidence that increased SNS activity related to deception can be monitored before a lie is stated. This implies that cues to deception are already present during the mere intention to lie. PMID- 26018574 TI - Osteochondral regeneration with a novel aragonite-hyaluronate biphasic scaffold: up to 12-month follow-up study in a goat model. AB - BACKGROUND: The regeneration of articular hyaline cartilage remains an elusive goal despite years of research. Recently, an aragonite-hyaluronate (Ar-HA) biphasic scaffold has been described capable of cartilage regeneration over a 6 month follow-up period. This study was conducted in order to assess the fate of the regenerated osteochondral tissue in a 12-month-long validated caprine model. HYPOTHESIS/PURPOSE: The hypothesis was that the implantation of the Ar-HA implant leads to tissue regeneration and maturation. STUDY DESIGN: A two-arm caprine model of a critical osteochondral defect compares the fate of acute osteochondral defects (group A) to Ar-HA implanted defects (group B). METHODS: Critical 6 mm in diameter and 10-mm in depth osteochondral defects were created in the load bearing medial femoral condyle of 20 mature goats and randomized into two groups. In group A (n = 6), a blood clot spontaneously filled the defect; in group B (n = 14), a single Ar-HA implant reconstructed the defect. The animals were sacrificed after either 6 or 12 months. Parameters assessed included clinical evaluation, x rays, micro-CT, ultrasound and histology at both time points, and specimen high field magnetic resonance imaging with T2 mapping at the 12-month time point. RESULTS: In most group A animals, the defects were not reconstructed (1/3 at 6 months, and 0/3 at 12 months). Defects in group B were mostly reconstructed (5/7 at 6 months and 6/7 at 12 months). Group A defects were either empty or contained fibrous repair tissue; while group B filling was compatible with hyaline cartilage and normal bone. CONCLUSION: Ar-HA scaffolds implanted in critical osteochondral defects result in hyaline cartilage formation and subchondral bone regeneration. The results improved at the 12-month time point compared to the 6 month time point, indicating a continuous maturation process without deterioration of the repair tissue. CLINICAL RELEVANCE: Osteochondral defects are common in humans; the results of the current study suggest that an acellular Ar HA scaffold might induce cartilage and subchondral bone regeneration. PMID- 26018575 TI - The importance of the human footprint in shaping the global distribution of terrestrial, freshwater and marine invaders. AB - Human activities such as transport, trade and tourism are likely to influence the spatial distribution of non-native species and yet, Species Distribution Models (SDMs) that aim to predict the future broad scale distribution of invaders often rely on environmental (e.g. climatic) information only. This study investigates if and to what extent do human activities that directly or indirectly influence nature (hereafter the human footprint) affect the global distribution of invasive species in terrestrial, freshwater and marine ecosystems. We selected 72 species including terrestrial plants, terrestrial animals, freshwater and marine invasive species of concern in a focus area located in NW Europe (encompassing Great Britain, France, The Netherlands and Belgium). Species Distribution Models were calibrated with the global occurrence of species and a set of high-resolution (9*9 km) environmental (e.g. topography, climate, geology) layers and human footprint proxies (e.g. the human influence index, population density, road proximity). Our analyses suggest that the global occurrence of a wide range of invaders is primarily limited by climate. Temperature tolerance was the most important factor and explained on average 42% of species distribution. Nevertheless, factors related to the human footprint explained a substantial amount (23% on average) of species distributions. When global models were projected into the focus area, spatial predictions integrating the human footprint featured the highest cumulative risk scores close to transport networks (proxy for invasion pathways) and in habitats with a high human influence index (proxy for propagule pressure). We conclude that human related information currently available in the form of easily accessible maps and databases-should be routinely implemented into predictive frameworks to inform upon policies to prevent and manage invasions. Otherwise we might be seriously underestimating the species and areas under highest risk of future invasions. PMID- 26018576 TI - A Novel Approach to Surgical Instructions for Scrub Nurses by Using See-Through Type Head-Mounted Display. AB - In order to facilitate assists in surgical procedure, it is important for scrub nurses to understand the operation procedure and to share the operation status with attending surgeons. The potential utility of head-mounted display as a new imaging monitor has been proposed in the medical field. This study prospectively evaluated the usefulness of see-through-type head-mounted display as a novel intraoperative instructional tool for scrub nurses. From January to March 2014, scrub nurses who attended gasless laparoendoscopic single-port radical nephrectomy and radical prostatectomy wore the monocular see-through-type head mounted display (AiRScouter; Brother Industries Ltd, Nagoya, Japan) displaying the instruction of the operation procedure through a crystal panel in front of the eye. Following the operation, the participants completed an anonymous questionnaire, which evaluated the image quality of the head-mounted display, the helpfulness of the head-mounted display to understand the operation procedure, and adverse effects caused by the head-mounted display. Fifteen nurses were eligible for the analysis. The intraoperative use of the head-mounted display could help scrub nurses to understand the surgical procedure and to hand out the instruments for the operation with no major head-mounted-display wear-related adverse event. This novel approach to support scrub nurses will help facilitate technical and nontechnical skills during surgery. PMID- 26018577 TI - Reliability of photographic analysis of wound epithelialization assessed in human skin graft donor sites and epidermolysis bullosa wounds. AB - BACKGROUND: In many clinical trials on cutaneous healing, wound closure is the primary endpoint and single most important outcome parameter, making precise assessment of this time point one of utmost importance. The assessment of wound closure can be performed either by subjective clinical inspection or with a variety of methodologies anticipated to provide more objective data. The aim of this study was to examine intra- and interrater variability of blinded photographic analysis of wound closure of human partial thickness wounds, as well as the reliability of remote photographic analysis of wounds with that of direct clinical assessment. METHODS: Two plastic surgeons, a dermatologist, and a maxillofacial surgeon constituted our rater panel. High-resolution images of patient wounds derived from two randomized controlled clinical trials (EU Clinical Trials Register numbers EudraCT 2009-017418-56 (registered 12 January 2010) and EudraCT 2010-019945-24 (registered 13 July 2010)) were individually assessed by the blinded, experienced study raters. The reliability of photographic image analysis was tested using intraclass and interclass correlation. The validity of photographic image analysis was correlated with clinical assessments of documented time to heal from the study centers' files. RESULTS: The results demonstrated that the mean intraclass correlation coefficient of all four examiners was excellent (r = 0.79; 95% confidence interval (CI), 0.61, 1.00)). The interrater correlation coefficient was good (r = 0.67; 95% CI, 0.57, 1.00)) and therefore acceptable. The agreement between remote visual assessment and clinical assessment at the time of healing was good (r = 0.64; 95% CI, 0.52, 0.76)) with an overall difference of about 1 day. CONCLUSIONS: Remote photographic analysis of cutaneous wounds is a feasible instrument in clinical open-label studies to evaluate time to wound closure. We found that it was a reliable method of measuring wound closure that correlated satisfactorily with clinical judgment, bolstering the potential relevance in the current era of evolving application and dependency in the field of telemedicine. TRIAL REGISTRATION: EU Clinical Trials Register EudraCT numbers 2009-017418-56 (date of registration: 12 January 2010) and 2010-019945-24 (date of registration: 13 July 2010). PMID- 26018578 TI - Isolated fracture of the humeral trochlea: a case report and review of the literature. AB - INTRODUCTION: Isolated fracture of the trochlea is a rarely reported entity. To the best of our knowledge, only 15 cases have been published. We report the case of a patient with an isolated fracture of the trochlea and discuss through a literature review the underlying mechanisms and the clinical, radiological and therapeutic features of this lesion. This work will significantly advance our understanding of this particular fracture. CASE PRESENTATION: A 21-year-old Caucasian man received an elbow injury. An anteroposterior radiograph showed only an irregularity of the medial joint space, but a lateral radiograph showed an intra-articular half-moon-shaped fragment that had moved up and forward. A computed tomography scan confirmed an isolated fracture of his trochlea. Open reduction and internal fixation were performed with a good outcome. CONCLUSION: An isolated fracture of the trochlea is rare. The mechanisms generating this fracture are complex. As with other front-line fractures of the distal end of the humerus, such as the capitulum, we recommend open reduction and internal fixation for displaced fractures, with excision of the small osteochondral fragments that do not permit any osteosynthetic repair. PMID- 26018579 TI - iStent as a Solo Procedure for Glaucoma Patients: A Systematic Review and Meta Analysis. AB - BACKGROUND: Glaucoma is a leading cause of irreversible blindness. It is firmly entrenched in the traditional treatment paradigm to start with pharmacotherapy. However, pharmacotherapy is not benign and has been well documented to have a number of significant challenges. Minimally invasive glaucoma surgery (MIGS) that targets the outflow pathway with minimal to no scleral dissection has resulted in the need to reconsider the glaucoma treatment paradigm. PURPOSE: To perform a systematic review and meta-analysis to evaluate and quantify the effect on post operative intraocular pressure (IOP) and number of topical glaucoma medications, in patients receiving the iStent MIGS device as the solo procedure without concurrent cataract surgery. METHODS: A systematic review was conducted by searching various databases between January 1, 2000, and June 30, 2014. Studies reporting up to a maximum follow-up period of 24 months were retrieved and screened using the EPPI-Reviewer 4 gateway. Percentage reduction in IOP (IOPR%), and mean reduction in topical glaucoma medications after surgery were computed. Meta-analysis was performed using STATA v. 13.0. The standardized mean difference (SMD) was calculated as the effect size for continuous scale outcomes. Heterogeneity was determined using the I2 statistics, Z-value, and chi2 statistics. Fixed-effect and random-effect models were developed based on heterogeneity. Sub-group analysis was performed based on the number of iStents implanted and the follow-up period. The outcome measures were changes in the IOP and number of glaucoma medications. RESULTS: The search strategy identified 105 records from published literature and 9 records from the grey literature. Five studies with 248 subjects were included for quantitative synthesis. A 22% IOP reduction (IOPR%) from baseline occurred at 18-months after one iStent implant, 30% at 6-months after two iStents implantations, and 40% at 6-months after implantation of three iStents. A mean reduction of 1.2 bottles per patient of topical glaucoma medications occurred at 18-months after one iStent implant, 1.45 bottles per patient at 6-months after two iStents, and one bottle of medication per patient was reduced at 6-months following placement of three iStents implants. Meta-analysis results showed a significant reduction in the IOP after one iStent (SMD = -1.68, 95% CI: [-2.7, -0.61]), two iStents (SMD = -1.88, 95% CI: [-2.2, -1.56]), and three iStents (SMD = -2, 95% CI: [-2.62, -1.38]) implantation. Results showed a significant drop in the topical glaucoma medications after one iStent (SMD = -2.11, CI: [-3.95, -0.27]), two iStent (SMD = -1.88, CI: [-2.20, -1.56]), and three iStents (SMD = -2.00, CI: [-2.62, -1.38]) implantation. The maximum reduction in IOP occurred at 12-months (SMD = -2.21, CI: [-2.53, -1.88]) and a significant reduction in post-operative topical glaucoma medications occurred even after 18-months of iStent implantation (SMD = 0.71, CI: [-1.15, -0.26]). CONCLUSION: iStent implantation as a solo procedure without concurrent cataract extraction does lower IOP, and reduces the dependency on glaucoma medications. This effect seems to last at least 18 months. PMID- 26018580 TI - Concurrent host-pathogen gene expression in the lungs of pigs challenged with Actinobacillus pleuropneumoniae. AB - BACKGROUND: Actinobacillus pleuropneumoniae causes pleuropneumonia in pigs, a disease which is associated with high morbidity and mortality, as well as impaired animal welfare. To obtain in-depth understanding of this infection, the interplay between virulence factors of the pathogen and defense mechanisms of the porcine host needs to be elucidated. However, research has traditionally focused on either bacteriology or immunology; an unbiased picture of the transcriptional responses can be obtained by investigating both organisms in the same biological sample. RESULTS: Host and pathogen responses in pigs experimentally infected with A. pleuropneumoniae were analyzed by high-throughput RT-qPCR. This approach allowed concurrent analysis of selected genes encoding proteins known or hypothesized to be important in the acute phase of this infection. The expression of 17 bacterial and 31 porcine genes was quantified in lung samples obtained within the first 48 hours of infection. This provided novel insight into the early time course of bacterial genes involved in synthesis of pathogen-associated molecular patterns (lipopolysaccharide, peptidoglycan, lipoprotein) and genes involved in pattern recognition (TLR4, CD14, MD2, LBP, MYD88) in response to A. pleuropneumoniae. Significant up-regulation of proinflammatory cytokines such as IL1B, IL6, and IL8 was observed, correlating with protein levels, infection status and histopathological findings. Host genes encoding proteins involved in iron metabolism, as well as bacterial genes encoding exotoxins, proteins involved in adhesion, and iron acquisition were found to be differentially expressed according to disease progression. By applying laser capture microdissection, porcine expression of selected genes could be confirmed in the immediate surroundings of the invading pathogen. CONCLUSIONS: Microbial pathogenesis is the product of interactions between host and pathogen. Our results demonstrate the applicability of high-throughput RT-qPCR for the elucidation of dual-organism gene expression analysis during infection. We showed differential expression of 12 bacterial and 24 porcine genes during infection and significant correlation of porcine and bacterial gene expression. This is the first study investigating the concurrent transcriptional response of both bacteria and host at the site of infection during porcine respiratory infection. PMID- 26018581 TI - A comparison of inpatient with outpatient balloon catheter cervical ripening: a pilot randomized controlled trial. AB - BACKGROUND: One in four Australian births are induced. If cervical ripening using a prostaglandin is required, a pre-labour overnight hospitalisation and separation from family and support companions is necessary. Recent evidence shows that balloon catheter cervical ripening is just as effective as prostaglandins, but does not cause uterine stimulation. For women with low risk pregnancies, this offers the possibility of undergoing the overnight ripening process in their own home. We conducted a pilot randomised trial to assess the outcomes, clinical pathways and acceptability to both women and clinicians of outpatient balloon catheter ripening compared with usual inpatient care. METHODS: Forty-eight women with low risk term pregnancies were randomised (2:1) to either outpatient (n = 33) or inpatient double-balloon catheter (n = 15) cervical ripening. Although not powered for statistically significant differences, the study explored potential direction of effect for key clinical outcomes such as oxytocin use, caesarean section and morbidities. Feedback on acceptability was sought from women at catheter insertion and 4 weeks after the birth, and from midwives and doctors, at the end of the study. RESULTS: Clinical and perinatal outcomes were similar. Most women required oxytocin (77 %). The outpatient group were 24 % less likely to require oxytocin (risk difference -23.6 %, 95 % CI -43.8 to -3.5). There were no failed inductions, infections or uterine hyperstimulation attributable to the catheter in either group. Most women in both groups reported discomfort with insertion and wearing the catheter, but were equally satisfied with their care and felt the baby was safe (91 % both groups). Outpatient women reported feeling less isolated or emotionally alone. Most midwives and doctors (n = 90) agreed that they are more comfortable in sending home a woman with a catheter than prostaglandins and 90 % supported offering outpatient ripening to eligible women. CONCLUSIONS: Outpatient balloon catheter ripening should be further investigated as an option for women in an adequately powered randomised trial. TRIAL REGISTRATION: Prospectively registered, Australian New Zealand Clinical Trials Registry ACTRN12612001184864 . PMID- 26018586 TI - Anterior migration of lateral plate mesodermal cells during embryogenesis of the pufferfish Takifugu niphobles: insight into the rostral positioning of pelvic fins. AB - In vertebrates, paired appendages (limbs and fins) are derived from the somatic mesoderm subsequent to the separation of the lateral plate mesoderm into somatic and splanchnic layers. This is less clear for teleosts, however, because the developmental processes of separation into two layers and of extension over the yolk have rarely been studied. During teleost evolution, the position of pelvic fins has generally shifted rostrally (Rosen; Nelson, 1982, 1994), although at the early embryonic stage the presumptive pelvic fin cells are initially located near the future anus region - the anterior border of hoxc10a expression in the spinal cord - regardless of their final destination. Our previous studies in zebrafish (abdominal pelvic fins) and Nile tilapia (thoracic pelvic fins) showed that the presumptive pelvic fin cells shift their position with respect to the body trunk after its protrusion from the yolk surface. Furthermore, in Nile tilapia, presumptive pelvic fin cells migrate anteriorly on the yolk surface. Here, we examined the embryonic development of the lateral plate mesoderm at histological levels in the pufferfish Takifugu niphobles, which belongs to the highly derived teleost order Tetraodontiformes, and lacks pelvic fins. Our results show that, in T. niphobles, the lateral plate mesoderm bulges out as two separate layers of cells alongside the body trunk prior to its further extension to cover the yolk sphere. Once the lateral plate mesoderm extends laterally, it rapidly covers the surface of the yolk. Furthermore, cells located near the anterior border of hoxc10a expression in the spinal cord reach the anterior-most region of the yolk surface. In light of our previous and current studies, we propose that anterior migration of presumptive pelvic fin cells might be required for them to reach the thoracic or more anterior positions as is seen in other highly derived teleost groups. PMID- 26018585 TI - Developmental-stage-dependent transcriptional response to leukaemic oncogene expression. AB - Acute myeloid leukaemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation that gives rise to the RUNX1-ETO fusion protein and initiates the most common form of human AML. Here we study the differentiation of mouse embryonic stem cells expressing an inducible RUNX1-ETO gene into blood cells as a model, combined with genome-wide analyses of transcription factor binding and gene expression. RUNX1-ETO interferes with both the activating and repressive function of its normal counterpart, RUNX1, at early and late stages of blood cell development. However, the response of the transcriptional network to RUNX1-ETO expression is developmental stage specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit. PMID- 26018587 TI - Selection and pilot implementation of a mobile image viewer: a case study. AB - BACKGROUND: For health care providers, mobile image viewing increases image accessibility, which could lead to faster interpretation/consultations and improved patient outcomes. OBJECTIVE: We explored the technical requirements and challenges associated with implementing a commercial mobile image viewer and conducted a small study testing the hypothesis that the mobile image viewer would provide faster image access. METHODS: A total of 19 clinicians (9 radiologists, 3 surgeons, 4 neurologists, and 3 physician assistants) evaluated (1) a desktop commercial picture archiving and communication system (PACS) viewer, (2) a desktop viewer developed internally over 20 years and deployed throughout the enterprise (ENTERPRISE viewer) and (3) a commercial Food and Drug Administration class II-cleared mobile viewer compatible with Web browsers, tablets, and mobile phones. Data were collected during two separate 7-day periods, before and after mobile image viewer deployment. Data included image viewer chosen, time to view first image, technical issues, diagnostic confidence, and ease of use. RESULTS: For 565 image-viewing events, ease of use was identical for PACS and mobile viewers (mean 3.6 for all scores of a possible 4.0), and significantly worse for the enterprise viewer (mean 2.9, P=.001). Technical issues were highest with the enterprise viewer (26%, 56/215) compared with the mobile (7%,19/259, P=.001) and PACS (8%, 7/91, P=.003) viewers. Mean time to first image for the mobile viewer (2.4 minutes) was significantly faster than PACS (12.5 minutes, P=.001) and the enterprise viewer (4.5 minutes, P=.001). Diagnostic confidence was similar for PACS and mobile viewers and worst for enterprise viewer. Mobile image viewing increased by sixfold, from 14% (37/269, before the deployment) to 88.9% (263/296, after the deployment). CONCLUSIONS: A mobile viewer provided faster time to first image, improved technical performance, ease of use, and diagnostic confidence, compared with desktop image viewers. PMID- 26018588 TI - Optoacoustic imaging enabled biodistribution study of cationic polymeric biodegradable nanoparticles. AB - Nanosized contrast agents for molecular imaging have attracted widespread interest for diagnostic applications with high resolution in medicine. However, many solid nanoparticles exhibit a great potential to induce toxicity, hindering their use for clinical applications. On the other hand, near-infrared (NIR) dyes have also been used for extensive biological applications, but show some limitations due to their poor aqueous stability, tendency to aggregation and rapid elimination from the body. An alternative proposed in this work to overcome these limitations is the use of NIR dye-loaded nanoparticles. Here we introduce nanoparticles constructed with poly(D,L-lactide-co-glycolic acid) (PLGA), a biodegradable and biocompatible polymer widely used for biomedical applications, attached to the polycation polyethyleneimine (PEI) to obtain positively charged nanoparticles. The in vivo biodistribution of the cationic PEI-PLGA nanoparticles was investigated after administration through three different routes (intravenous, intraperitoneal and subcutaneous) using multispectral optoacoustic tomography (MSOT). The prepared nanoparticles exhibited good colloidal stability and adequate optical properties for optoacoustic imaging. The in vivo biodistribution assays indicated a strong accumulation of the particles in the liver and spleen, and retention in these organs for at least 24 h. Therefore, these nanoparticles could find promising applications in MSOT due to a sharp and characteristic optoacoustic spectrum and high optoacoustic signal generation, and become a promising building block for theranostic strategies. PMID- 26018589 TI - Detection of polycyclic aromatic hydrocarbons in smoked buffalo mozzarella cheese produced in Campania Region, Italy. AB - BACKGROUND: Smoked mozzarella is obtained through traditional smoking techniques or the use of liquid smoke. Polycyclic aromatic hydrocarbons (PAHs) may be produced during the organic matrix combustion. The aim of this study was to evaluate benzo[a]pyrene (B(a)P), benzo[a]anthracene (B(a)A), benzo[b]fluoranthene (B(b)FA), benzo[k]fluoranthene (B(k)FA), benzo[ghi]perylene (B(g,h,i)PE), chrysene (CHR), dibenz[a,h]anthracene (DB(a,h)A) and indeno[1,2,3-cd]pyrene (IP) in smoked buffalo mozzarella produced in Campania, evaluating also the influence of the different smoking techniques. Milk and mozzarella of the same batch, before and after smoking, were collected. The detection method was basic hydrolysis, clean-up with silica and detection by HPLC equipped with a fluorescence detector. RESULTS: For milk, only 30% was contaminated. In non smoked products the medians were >LODs only for B(a)A and CHR. In smoked mozzarellas the highest median was 0.37 ng g(-1) wet weight (CHR). CONCLUSION: It was found that the consumption of this typical food of Campania does not represent a risk for consumers, considering that the incidences on EFSA dietary intake were always lower than 1.5% for mozzarella cheese and lower than 3% for smoked mozzarella cheese. PMID- 26018590 TI - Effectiveness of egg yolk immunoglobulin against the intracellular salmonid pathogen Piscirickettsia salmonis. AB - AIMS: To produce and characterize egg yolk immunoglobulin (IgY) against the fish intracellular pathogen Piscirickettsia salmonis as well as to evaluate the antibacterial activity of IgY in vitro and the availability in the serum of fish immunized orally. METHODS AND RESULTS: Specific IgY was produced by immunizing hens with P. salmonis proteins. The IgY was obtained from egg yolks using the ammonium sulphate precipitation method and it was characterized by SDS-PAGE, Western-blot and ELISA, demonstrating that anti-P. salmonis IgY strongly reacted specifically against P. salmonis proteins. In an in vitro neutralization assay, IgY inhibited the growth of P. salmonis in liquid medium at concentrations ranging from 128 to 256 MUg ml(-1) in a dose-dependent manner. Interestingly, IgY against P. salmonis also generates a strong protective effect on the infection of P. salmonis in salmon head kidney-1 cells. In addition, the bacteriostatic function of IgY appears to result possibly from agglutination by the interaction of IgY with surface components of the pathogen. Finally, to confirm this IgY as an alternative for salmonid treatment, Atlantic salmon (Salmo salar) specimens were orally inoculated with IgY. The analysis of the sera demonstrates that IgY was effectively transported by fish intestine and that this immunoglobulins maintains its properties and recognizes several proteins of P. salmonis up to 12 h after inoculation of IgY against P. salmonis. CONCLUSIONS: Specific IgY effectively inhibited the growth of P. salmonis and this immunoglobulin can be released in the Atlantic salmon sera when administered orally to fish. SIGNIFICANCE AND IMPACT OF THE STUDY: We propose that this specific IgY against this fastidious micro-organism could be a useful strategy for the treatment of piscirickettsiosis. PMID- 26018591 TI - Development of an HIV-1 Subtype Panel in China: Isolation and Characterization of 30 HIV-1 Primary Strains Circulating in China. AB - BACKGROUND: The complex epidemic and significant diversity of HIV-1 strains in China pose serious challenges for surveillance and diagnostic assays, vaccine development and clinical management. There is a lack of HIV-1 isolates in current canonical HIV-1 subtype panels that can represent HIV-1 diversity in China; an HIV-1 subtype panel for China is urgently needed. METHODS: Blood samples were collected from HIV-1 infected patients participating in the drug-resistance surveillance program in China. The samples were isolated, cultured and stored as neat culture supernatant. The HIV-1 isolates were fully characterized. The panel was used to compare 2 viral load assays and 2 p24 assays as the examples of how this panel could be used. RESULTS: An HIV-1 subtype panel for China composed of 30 HIV-1 primary strains of four subtypes (B [including Thai-B], CRF01_AE, CRF07_BC and G) was established. The samples were isolated and cultured to a high titer (10(6)-10(9) copies/ml)/high-volume (40 ml). The HIV-1 isolates were fully characterized by the final viral load, p24 concentration, gag-pol and envC2V3 sequencing, co-receptor prediction, determination of the four amino acids at the tip of the env V3-loop, glycosylation sites in the V3 loop and the drug resistance mutations. The comparison of two p24 assays and two viral load assays on the isolates illustrated how this panel may be used for the evaluation of diagnostic assay performance. The Pearson value between p24 assays were 0.938. The viral load results showed excellent concordance and agreement for samples of Thai-B, but lower correlations for samples of CRF01_AE. CONCLUSION: The current panel of 30 HIV-1 isolates served as a basis for the development of a comprehensive panel of fully characterized viral isolates, which could reflect the current dynamic and complex HIV-1 epidemic in China. This panel will be available to support HIV-1 research, assay evaluation, vaccine and drug development. PMID- 26018592 TI - Can neural activation in dorsolateral prefrontal cortex predict responsiveness to information? An application to egg production systems and campaign advertising. AB - Consumers prefer to pay low prices and increase animal welfare; however consumers are typically forced to make tradeoffs between price and animal welfare. Campaign advertising (i.e., advertising used during the 2008 vote on Proposition 2 in California) may affect how consumers make tradeoffs between price and animal welfare. Neuroimaging data was used to determine the effects of brain activation in dorsolateral prefrontal cortex (dlPFC) on choices making a tradeoff between price and animal welfare and responsiveness to campaign advertising. Results indicated that activation in the dlPFC was greater when making choices that forced a tradeoff between price and animal welfare, compared to choices that varied only by price or animal welfare. Furthermore, greater activation differences in right dlPFC between choices that forced a tradeoff and choices that did not, indicated greater responsiveness to campaign advertising. PMID- 26018593 TI - Freezing of gait: a practical approach to management. AB - Freezing of gait is a common and disabling symptom in patients with parkinsonism, characterised by sudden and brief episodes of inability to produce effective forward stepping. These episodes typically occur during gait initiation or turning. Treatment is important because freezing of gait is a major risk factor for falls in parkinsonism, and a source of disability to patients. Various treatment approaches exist, including pharmacological and surgical options, as well as physiotherapy and occupational therapy, but evidence is inconclusive for many approaches, and clear treatment protocols are not available. To address this gap, we review medical and non-medical treatment strategies for freezing of gait and present a practical algorithm for the management of this disorder, based on a combination of evidence, when available, and clinical experience of the authors. Further research is needed to formally establish the merits of our proposed treatment protocol. PMID- 26018594 TI - Unfreezing of gait in patients with Parkinson's disease. PMID- 26018595 TI - Difficult Life Events, Selective Migration and Spatial Inequalities in Mental Health in the UK. AB - OBJECTIVE: Research has indicated that people moving towards neighbourhoods with disadvantaged socio-economic status have poor health, in particular mental health, but the reasons for this are unclear. This study aims to assess why people moving towards more socio-economically deprived areas have poor mental health. It focuses upon the role of difficult life events that may both trigger moves and damage mental health. This study investigates how mental health and socio-spatial patterns of mobility vary between people moving following difficult life events and for other reasons. METHODS: Longitudinal analysis of British Household Panel Survey data describing adults' moves between annual survey waves, pooled over ten years, 1996-2006 (N=122,892 observations). Respondents were defined as 'difficult life event movers' if they had experienced relationship breakdown, housing eviction/repossession, or job loss between waves. Respondents were categorised as moving to more or less deprived quintiles using their Census Area Statistic residential ward Carstairs score. Mental health was indicated by self-reported mental health problems. Binary logistic regression models of weighted data were adjusted for age, sex, education and social class. RESULTS: The migration rate over one year was 8.5%; 14.1% of movers had experienced a difficult life event during this time period. Adjusted regression model odds of mental health problems among difficult life event movers were 1.67 (95% CI 1.35 2.07) relative to other movers. Odds of difficult life events movers, compared to other movers, moving to a less deprived area, relative to an area with a similar level of deprivation, were 0.70 (95% CI 0.58-0.84). Odds of mental health problems among difficult life event movers relocating to more deprived areas were highly elevated at 2.40 (95% CI 1.63-3.53), relative to stayers. CONCLUSION: Difficult life events may influence health selective patterns of migration and socio-spatial trajectories, reducing moves to less deprived neighbourhoods among people with mental illness. PMID- 26018596 TI - The Role of Severe Dementia in Nursing Home Report Cards. AB - Health care report cards are intended to improve quality, but there may be considerable heterogeneity in who benefits. In this article, we examine the intended and unintended effects of quality reporting for nursing home residents with severe dementia relative to other residents, using a difference-in differences design to examine selected reported and unreported quality measures. Our results indicate that prior to public reporting, nursing home residents with severe dementia were at significantly higher risk of poor outcomes on most reported quality measures. After public reporting was initiated, outcomes for nursing home residents with severe dementia did not consistently improve or worsen. We see no evidence that individuals with severe dementia are being avoided by nursing homes, despite their potential negative impact on quality scores, but we do find an increase in coding of end-stage disease. Additional risk-adjustment, stratification, or additional quality measures may be warranted. PMID- 26018597 TI - The Mere Co-Presence: Synchronization of Autonomic Signals and Emotional Responses across Co-Present Individuals Not Engaged in Direct Interaction. AB - Existing evidence suggests that in social contexts individuals become coupled in their emotions and behaviors. Furthermore, recent biological studies demonstrate that the physiological signals of interacting individuals become coupled as well, exhibiting temporally synchronized response patterns. However, it is yet unknown whether people can shape each other's responses without the direct, face-to-face interaction. Here we investigated whether the convergence of physiological and emotional states can occur among "merely co-present" individuals, without direct interactional exchanges. To this end, we measured continuous autonomic signals and collected emotional responses of participants who watched emotional movies together, seated side-by-side. We found that the autonomic signals of co-present participants were idiosyncratically synchronized and that the degree of this synchronization was correlated with the convergence of their emotional responses. These findings suggest that moment-to-moment emotional transmissions, resulting in shared emotional experiences, can occur in the absence of direct communication and are mediated by autonomic synchronization. PMID- 26018598 TI - Angiotensin II type 1 receptor-associated protein plays a role in regulating the local renin-angiotensin system in HSC-T6 cells. AB - The aim of the current study was to examine the expression of the angiotensin II type 1 receptor-associated protein (ATRAP) in the rat hepatic stellate cell line HSC-T6 and to determine its interactions with the local renin-angiotensin system (RAS). To achieve this goal, the effect of stimulating HSC-T6 cells with angiotensin II (AngII) and angiotensin-(1-7) [Ang-(1-7)], on the expression of ATRAP, the angiotensin II type I receptor (AT1R), the Mas receptor and the angiotensin converting enzyme 2 (ACE2) 2, 6, 12, 18, 24 and 36 h after stimulation was investigated. Changes in expression were quantified at the gene and protein level using RT-qPCR and western blotting, respectively. A single dose of AngII (1 umol/l) significantly increased the gene expression of ATRAP at 12 h, whereas ACE2 gene expression levels were significantly increased at 6 h and then returned to baseline at 12 h, prior to becoming significantly lower. A single dose of Ang-(1-7) at the same concentration as AngII induced ATRAP gene expression, which became statistically significant at the 6 h time-point, reached a peak at 12 h and remained elevated throughout the experimental time-course. In addition, ACE2 mRNA expression was significantly suppressed by Ang-(1-7) at 6 h, reaching its lowest expression level at 24 h. The expression of AT1R and the Mas receptor were unaffected by stimulation with AngII and Ang-(1-7). The western blotting results were generally consistent with the mRNA expression data. In conclusion, it was identified that ATRAP is endogenously expressed in HSC-T6 cells and therefore, may be critical in regulating the local RAS in these cells. PMID- 26018599 TI - A randomised phase IIb trial to assess the efficacy of ReCharge ice cream in preventing chemotherapy-induced diarrhoea. AB - PURPOSE: Chemotherapy-induced diarrhoea (CID) has a significant impact. A medicinal food product (ReCharge) containing iron-saturated lactoferrin and anhydrous milk fat reduces the detrimental effects of chemotherapy on the gut in animals. We report results of a randomised blinded placebo-controlled phase IIb trial investigating the efficacy and safety of ReCharge in preventing CID. METHODS: Eligible patients were adults due to start the first cycle of a 2- or 3 week-cycle chemotherapy regimen, had an Eastern Cooperative Oncology Group (ECOG) status of 3 or less, had adequate haematological, liver and renal function and provided written informed consent. Patients (197) were randomised to ReCharge or placebo. They consumed 100-g study product for 2 weeks before and 6 weeks after starting chemotherapy, completed daily diaries for 8 weeks and attended clinic visits until 12 weeks (2-week cycles) or 14 weeks (3-week cycles). The primary outcome was days with CID. RESULTS: The mean number of days with diary-recorded CID was marginally but not statistically significantly lower on ReCharge than placebo (-2.0, 95 % CI (-4.7 to 0.7), p = 0.2). The proportion reporting diarrhoea in the previous cycle at the clinic visit was 30 % lower (p = 0.012) on ReCharge. Missing diary data may have contributed to the discrepancy. No significant differences were found in quality of life or other adverse events. CONCLUSIONS: We found no clear evidence that ReCharge reduced CID as measured by patient self-report diary. The converse finding of benefit as recorded at clinic visits and incomplete adherence to diary completion indicates that further research is required into methods for measuring CID. PMID- 26018601 TI - Whole transcriptome analysis with sequencing: methods, challenges and potential solutions. AB - Whole transcriptome analysis plays an essential role in deciphering genome structure and function, identifying genetic networks underlying cellular, physiological, biochemical and biological systems and establishing molecular biomarkers that respond to diseases, pathogens and environmental challenges. Here, we review transcriptome analysis methods and technologies that have been used to conduct whole transcriptome shotgun sequencing or whole transcriptome tag/target sequencing analyses. We focus on how adaptors/linkers are added to both 5' and 3' ends of mRNA molecules for cloning or PCR amplification before sequencing. Challenges and potential solutions are also discussed. In brief, next generation sequencing platforms have accelerated releases of the large amounts of gene expression data. It is now time for the genome research community to assemble whole transcriptomes of all species and collect signature targets for each gene/transcript, and thus use known genes/transcripts to determine known transcriptomes directly in the near future. PMID- 26018600 TI - How it all starts: Initiation of the clotting cascade. AB - The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and procofactors) in the next step of the cascade via limited proteolysis. The ultimate outcome is the polymerization of fibrin and the activation of platelets, leading to a blood clot. This process is protective, as it prevents excessive blood loss following injury (normal hemostasis). Unfortunately, the blood clotting system can also lead to unwanted blood clots inside blood vessels (pathologic thrombosis), which is a leading cause of disability and death in the developed world. There are two main mechanisms for triggering the blood clotting, termed the tissue factor pathway and the contact pathway. Only one of these pathways (the tissue factor pathway) functions in normal hemostasis. Both pathways, however, are thought to contribute to thrombosis. An emerging concept is that the contact pathway functions in host pathogen defenses. This review focuses on how the initiation phase of the blood clotting cascade is regulated in both pathways, with a discussion of the contributions of these pathways to hemostasis versus thrombosis. PMID- 26018602 TI - Acute hemolytic transfusion reaction due to anti-Le(b). AB - BACKGROUND: Anti-Le(b) is usually a clinically insignificant antibody of immunoglobulin M subclass most often found in the sera of pregnant women or individuals that are Le(a-b-). We report a case of an acute hemolytic transfusion reaction due to a hemolytic anti-Le(b) that was not seen in the pretransfusion antibody detection test, but was strongly reactive in posttransfusion testing. CASE REPORT: A 30-year-old African-American woman with metastatic renal cell carcinoma was receiving chemotherapy. She was anemic with hemoglobin (Hb) of 7.2 g/dL and had a negative antibody detection test by the solid-phase red blood cell adherence method. She was transfused with 2 RBC units without incident. Nine days later her Hb was 7.9 g/dL again with a negative antibody detection test. Transfusion of an additional RBC unit was begun. During the transfusion she developed chills, nausea, hypertension, and red-brown urine. The posttransfusion sample plasma was grossly hemolyzed with a strongly positive direct antiglobulin test (DAT) by gel. By comparison the pretransfusion plasma was normal appearing and the DAT was weaker. The eluate was negative on both occasions. Anti-Le(b) was detected in the posttransfusion sample by MTS gel (Ortho Diagnostics). Both RBC units she had received before the RBC unit that caused the reaction were Le(b+) as was the implicated RBC unit. CONCLUSION: This case illustrates that anti-Le(b) which is usually clinically insignificant can occasionally cause severe hemolytic transfusion reactions. Only three other reported cases of anti-Le(b) causing hemolytic transfusion reactions could be found in the literature, two of which were in abstract form only. PMID- 26018604 TI - Exploring the mode of action of dithranol therapy for psoriasis: a metabolomic analysis using HaCaT cells. AB - Psoriasis is a common, immune-mediated inflammatory skin disease characterized by red, heavily scaled plaques. The disease affects over one million people in the UK and causes significant physical, psychological and societal impact. There is limited understanding regarding the exact pathogenesis of the disease although it is believed to be a consequence of genetic predisposition and environmental triggers. Treatments vary from topical therapies, such as dithranol, for disease of limited extent (<5% body surface area) to the new immune-targeted biologic therapies for severe psoriasis. Dithranol (also known as anthralin) is a topical therapy for psoriasis believed to work by inhibiting keratinocyte proliferation. To date there have been no metabolomic-based investigations into psoriasis. The HaCaT cell line is a model system for the epidermal keratinocyte proliferation characteristic of psoriasis and was thus chosen for study. Dithranol was applied at therapeutically relevant doses to HaCaT cells. Following the optimisation of enzyme inactivation and metabolite extraction, gas chromatography-mass spectrometry was employed for metabolomics as this addresses central metabolism. Cells were challenged with 0-0.5 MUg mL(-1) in 0.1 MUg mL(-1) steps and this quantitative perturbation generated data that were highly amenable to correlation analysis. Thus, we used a combination of traditional principal components analysis, hierarchical cluster analysis, along with correlation networks. All methods highlighted distinct metabolite groups, which had different metabolite trajectories with respect to drug concentration and the interpretation of these data established that cellular metabolism had been altered significantly and provided further clarification of the proposed mechanism of action of the drug. PMID- 26018603 TI - Regulation of the Neurodegenerative Process Associated to Parkinson's Disease by CD4+ T-cells. AB - Neuroinflammation constitutes a fundamental process involved in the physiopathology of Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4+ T-cells infiltrate the central nervous system (CNS) in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the neurodegenerative process. Here, we first analysed the pathogenic role of inflammatory phenotypes and the beneficial role of anti inflammatory phenotypes of encephalitogenic CD4+ T-cells involved in the physiopathology of PD. Next, we discussed how alterations of neurotransmitter levels observed in the basal ganglia throughout the time course of PD progression could be strongly affecting the behaviour of encephalitogenic CD4+ T-cells and thereby the outcome of the neuroinflammatory process and the consequent neurodegeneration of dopaminergic neurons. Afterward, we integrated the evidence indicating the involvement of an antigen-specific immune response mediated by T cells and B-cells against CNS-derived self-constituents in PD. Consistent with the involvement of a relevant autoimmune component in PD, we also reviewed the polymorphisms of both, class I and class II major histocompatibility complexes, associated to the risk of PD. Overall, this study gives an overview of how an autoimmune component involved in PD plays a fundamental role in the progression of the neurodegenerative process. PMID- 26018606 TI - Elevated serum levels of heat shock protein 70 are associated with breast cancer. AB - Breast cancer (BC) is the most frequent cause of cancer death in women throughout the world. Thus, it is necessary to establish sensitive screening, diagnosis and treatment methods for BC. Heat shock protein 70 (HSP70) is an important cellular stress response protein that protects cells from apoptosis. Recent studies have shown that serum HSP70 levels may provide clinically important information in various types of cancer. HSP70 is also overexpressed in BC, which is known to be associated with cancer progression, apoptosis and cell proliferation. However, the serum level of HSP70 and its diagnostic and prognostic potential in BC have not been investigated yet. The aim of this study was to determine the usefulness of serum HSP70 level as a diagnostic test and its predictive value in patients with BC. This prospective study consisted of 45 female patients diagnosed with BC and 16 healthy women who were matched for age and body mass index (BMI). Enzyme linked immunosorbent assay (ELISA) technique was used to measure the serum level of HSP70. The serum level of HSP70 was significantly higher in patients with BC than in the healthy control group (5.98 +/- 2.05 vs. 1.49 +/- 0.47 ng/ml, p = 0.001). HSP70 level > 2.41 ng/ml was the best cutoff value to predict BC (97.78% sensitivity and 93.75% specificity). This study shows that HSP70 can be used as an adjunct to other diagnostic tests for BC and may be helpful for identifying patients at increased risk of BC. PMID- 26018605 TI - Intergenerational continuity in high-conflict family environments. AB - In the current study, we examined continuity in conflict across generations and explored potential mediators and moderators that could explain this continuity. We followed 246 targets from adolescence to adulthood and examined family conflict as reported by multiple reporters in targets' family of origin and current families. Results showed that conflict in the current family was strongly correlated with that of the family of origin in women but not in men. Continuity in family conflict across generations was mediated by patterns of elevated adolescent externalizing behavior in members of the second generation (G2). In addition, analyses revealed an interaction between both G2 partners' externalizing behavior such that if one partner in the G2 family demonstrated high levels of externalizing behavior, elevated levels of family conflict resulted. Potential explanations and implications of these findings are considered. PMID- 26018607 TI - Immobilization and orientation-dependent activity of a naturally occurring antimicrobial peptide. AB - A naturally occurring antimicrobial peptide, SMAP-29, was synthesized with an n terminal or c-terminal cysteine, termed c_SMAP and SMAP_c, respectively, for site directed immobilization to superparamagnetic beads. Immobilized SMAP orientation dependent activity was probed against multiple bacteria of clinical interest including Acinetobacter baumannii, Pseudomonas aeruginosa, Bacillus anthracis sterne and Staphylococcus aureus. A kinetic microplate assay was employed to reveal both concentration and time-dependent activity for elucidation of minimum bactericidal concentration (MBC) and sub-lethal effects. Immobilized SMAP activity was equivalent or reduced compared with soluble SMAP_c and c_SMAP regardless of immobilization orientation, with only one exception. A comparison of immobilized SMAP_c and c_SMAP activity revealed a bacteria-specific potency dependent on immobilization orientation, which was contrary to that seen in solution, wherein SMAP_c was more potent against all bacteria than c_SMAP. Sub MBC kinetic studies displayed the influence of peptide exposure to the cells with multiple bacteria exhibiting increased susceptibility and efficacy at lower concentrations upon extended exposure (i.e. MBC enhancement). For instances in which complete killing was not achieved, two predominant effects were evident: retardation of growth rate and an increased lag phase. Both effects, seen independently and concomitantly, indicate some degree of induced cellular damage that can serve as a predictor toward eventual cell death. SMAP_c immobilized on glass through standard silanization chemistry was also investigated to ascertain the influence of substrate on activity against select bacteria. PMID- 26018608 TI - Incarcerated Amyand hernia with simultaneous rupture of an adenocarcinoma in an inguinal hernia sac: a case report. AB - INTRODUCTION: An Amyand's hernia is a rare occurrence of an inguinal hernia, with an estimated prevalence of 1%. The major complications of an Amyand's hernia include necrotizing fasciitis of the anterior abdominal wall and secondary intestinal perforation. Though the incidence of this type of hernia is low, the appendix may easily become initially incarcerated, possibly leading to strangulation and perforation. CASE PRESENTATION: A 92-year-old female patient presented to our emergency department with clinical signs of an incarcerated right inguinal hernia, accompanied by fever. A clinical examination revealed localized abdominal pain, reflecting to the right side of her groin. Laboratory tests showed leukocytosis (13,200/MUL), while an abdominal X-ray showed colon distension with evidence of intestinal obstruction. Ultrasonography was performed and confirmed the presence of an inflamed tubular structure inside her right inguinal canal. Our patient underwent emergency surgery. We started with a right inguinal incision, which revealed an incarcerated right inguinal hernia, containing her ruptured appendix and showing macroscopic evidence of malignancy. A specimen biopsy was immediately performed and the results showed a ruptured cecal adenocarcinoma. The incision was slightly extended upwards, and a right hemicolectomy performed. CONCLUSIONS: Diagnosis of an Amyand's hernia occurs primarily as an incidental finding during surgery and the optimal therapeutic approach must be considered individually for each case. Owing to the rarity of Amyand's hernia and the wide variance of its clinical characteristics, every case provides useful information toward the treatment of this type of hernia. PMID- 26018609 TI - Everyday doings in a nursing home - described by residents and staff. AB - OBJECTIVE: For many groups of elderly people it is important to be active, which can be hindered by disabilities that come with age. Research has progressed in this area but mostly concerns the elderly living at home. The aim of this study was to examine how residents and staff at a nursing home described the residents' everyday doings. METHODS: A nursing home was selected in which 15 of the residents and six of the staff were interviewed about the residents' activities during an ordinary day and week. RESULTS: The material was analysed using qualitative content analysis in which two categories emerged: shared doings and individual doings. The shared doings were important for supporting the residents in their social and physical activities, but participation in these was often hampered by reduced functions. The individual doings, where the residents' own interests can be promoted, were also hampered by their disabilities. Being able to be active and having something to do were emphasized, either continuing with previous activities or participating in shared activities at the nursing home. CONCLUSIONS: Receiving care and being forced to adjust to the context at the nursing home had a significant impact on the residents' daily doings. Most of the residents needed help to be able to continue performing their activities or to find new ones. The social environment consisting of other residents and staff also influenced the residents' activities. PMID- 26018610 TI - Detecting metastatic prostate carcinoma in pelvic lymph nodes following neoadjuvant hormone therapy: the eyes have it! AB - AIMS: Residual cancer morphology in radical prostatectomies (RPs) after neoadjuvant hormone therapy includes inconspicuous cytology, and treated tumour cells can be difficult to identify in lymph nodes. The aim of this study was to evaluate the role of immunohistochemistry (IHC) in identifying occult lymph node metastases following neoadjuvant hormone treatment of prostate cancer. METHODS AND RESULTS: One hundred and twenty-eight lymph nodes from 24 patients treated with neoadjuvant hormone therapy, including abiraterone acetate alone or combined with leuprolide, were stained with antibodies against keratin AE1/AE3, prostate specific antigen (PSA), prostate-specific acid phosphatase (PrAP), androgen receptor (AR), and NKX3.1. IHC slides were scored 'blind', and then retrospectively compared with haematoxylin and eosin (H&E)-stained slides and pathology reports. IHC identified carcinoma in six lymph nodes from three patients. All metastases were positive for NKX3.1 and AR, five of six were positive for AE1/AE3, and three of six were positive for PSA; PrAP was negative in all metastatic foci. All six lymph node metastases had been identified by H&E staining at the time of RP. CONCLUSIONS: These findings suggest that routine use of IHC on lymph nodes from neoadjuvant-treated prostate carcinomas is not necessary. Nevertheless, for suspicious small foci of atypical cells in neoadjuvant-treated lymph nodes, NKX3.1 and AR appear to have the greatest sensitivity. PMID- 26018611 TI - Contextual emergence of mental states. AB - The concept of contextual emergence has been proposed as a non-reductive, yet well-defined relation between different levels of description of physical and other systems. It yields a formally sound and empirically applicable procedure to translate between descriptive levels in an overall consistent fashion. This will be discussed for the contextual emergence of mental states from a neural level of description. PMID- 26018612 TI - Comparative Study on Electronic Structures of Sc and Ti Contacts with Monolayer and Multilayer MoS2. AB - Understanding the nature of the contacts in devices based on MoS2 with metal electrodes is vital to enhancing carrier injection efficiency. In this work, geometric and electronic structures of Sc and Ti contacts with MoS2 have been comparatively studied by first-principles calculations. The analyses of geometric parameters, charge density distributions, and density of states for the Sc and Ti top contacts with monolayer MoS2 (mMoS2) indicate that the interface bonding results in the localization of 4d states of Mo atoms and the consequent metallization of mMoS2. Therefore, the Sc and Ti top contacts with mMoS2 are Ohmic, and electron injections via these contacts are efficient. Because of the formations of the metalized Sc-mMoS2 and Ti-mMoS2 complexes, in the Sc and Ti top contacts with multilayer MoS2, Schottky interfaces may be formed in two contact regions. One is in the edge contacts of the Sc-mMoS2 and Ti-mMoS2 complexes with mMoS2 in the channel region in which Schottky barrier heights of 0.11 and 0.39 eV are extracted, respectively. The other is in the top contacts of these two complexes with mMoS2 under the contacts in which Schottky barrier heights of 0.15 and 0.34 eV are obtained, respectively. Moreover, as the layer number of MoS2 increases in the top contacts, the Schottky barrier heights show decreasing trends. These trends can be understood on the basis of the changes of electron affinity of multilayer MoS2. According to the present results, the device based on MoS2 with Sc electrodes should have better electron injection efficiency and stronger back-gated manipulation of current than the one with Ti electrodes. Furthermore, the electron injection efficiency can be enhanced by using multilayer MoS2. These predictions are generally consistent with recent experimental observations and provide a delicate understanding of the contacts in these devices. PMID- 26018613 TI - Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation. AB - BACKGROUND: We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS: Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS: Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS: We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally. PMID- 26018614 TI - Molecular Interactions of the Min Protein System Reproduce Spatiotemporal Patterning in Growing and Dividing Escherichia coli Cells. AB - Oscillations of the Min protein system are involved in the correct midcell placement of the divisome during Escherichia coli cell division. Based on molecular interactions of the Min system, we formulated a mathematical model that reproduces Min patterning during cell growth and division. Specifically, the increase in the residence time of MinD attached to the membrane as its own concentration increases, is accounted for by dimerisation of membrane-bound MinD and its interaction with MinE. Simulation of this system generates unparalleled correlation between the waveshape of experimental and theoretical MinD distributions, suggesting that the dominant interactions of the physical system have been successfully incorporated into the model. For cells where MinD is fully labelled with GFP, the model reproduces the stationary localization of MinD-GFP for short cells, followed by oscillations from pole to pole in larger cells, and the transition to the symmetric distribution during cell filamentation. Cells containing a secondary, GFP-labelled MinD display a contrasting pattern. The model is able to account for these differences, including temporary midcell localization just prior to division, by increasing the rate constant controlling MinD ATPase and heterotetramer dissociation. For both experimental conditions, the model can explain how cell division results in an equal distribution of MinD and MinE in the two daughter cells, and accounts for the temperature dependence of the period of Min oscillations. Thus, we show that while other interactions may be present, they are not needed to reproduce the main characteristics of the Min system in vivo. PMID- 26018615 TI - Balancing the basal ganglia circuitry: a possible new role for dopamine D2 receptors in health and disease. AB - Current therapies for treating movement disorders such as Parkinson's disease are effective but limited by undesirable and intractable side effects. Developing more effective therapies will require better understanding of what causes basal ganglia dysregulation and why medication-induced side effects develop. Although basal ganglia have been extensively studied in the last decades, its circuit anatomy is very complex, and significant controversy exists as to how the interplay of different basal ganglia nuclei process motor information and output. We have recently identified the importance of an underappreciated collateral projection that bridges the striatal output direct pathway with the indirect pathway. These bridging collaterals are extremely plastic in the adult brain and are involved in the regulation of motor balance. Our findings add a new angle to the classical model of basal ganglia circuitry that could be exploited for the development of new therapies against movement disorders. In this Scientific Perspective, we describe the function of bridging collaterals and other recent discoveries that challenge the simplicity of the classical basal ganglia circuit model. We then discuss the potential implication of bridging collaterals in the pathophysiology of Parkinson's disease and schizophrenia. Because dopamine D2 receptors and striatal neuron excitability have been found to regulate the density of bridging collaterals, we propose that targeting these projections downstream of D2 receptors could be a possible strategy for the treatment of basal ganglia disorders. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 26018616 TI - A bi-filtering method for processing single nucleotide polymorphism array data improves the quality of genetic map and accuracy of quantitative trait locus mapping in doubled haploid populations of polyploid Brassica napus. AB - BACKGROUND: Single nucleotide polymorphism (SNP) markers have a wide range of applications in crop genetics and genomics. Due to their polyploidy nature, many important crops, such as wheat, cotton and rapeseed contain a large amount of repeat and homoeologous sequences in their genomes, which imposes a huge challenge in high-throughput genotyping with sequencing and/or array technologies. Allotetraploid Brassica napus (AACC, 2n = 4x = 38) comprises of two highly homoeologous sub-genomes derived from its progenitor species B. rapa (AA, 2n = 2x = 20) and B. oleracea (CC, 2n = 2x = 18), and is an ideal species to exploit methods for reducing the interference of extensive inter-homoeologue polymorphisms (mHemi-SNPs and Pseudo-simple SNPs) between closely related sub genomes. RESULTS: Based on a recent B. napus 6K SNP array, we developed a bi filtering procedure to identify unauthentic lines in a DH population, and mHemi SNPs and Pseudo-simple SNPs in an array data matrix. The procedure utilized both monomorphic and polymorphic SNPs in the DH population and could effectively distinguish the mHemi-SNPs and Pseudo-simple SNPs that resulted from superposition of the signals from multiple SNPs. Compared with conventional procedure for array data processing, the bi-filtering method could minimize the pseudo linkage relationship caused by the mHemi-SNPs and Pseudo-simple SNPs, thus improving the quality of SNP genetic map. Furthermore, the improved genetic map could increase the accuracies of mapping of QTLs as demonstrated by the ability to eliminate non-real QTLs in the mapping population. CONCLUSIONS: The bi filtering analysis of the SNP array data represents a novel approach to effectively assigning the multi-loci SNP genotypes in polyploid B. napus and may find wide applications to SNP analyses in polyploid crops. PMID- 26018617 TI - Fertility Signaling and Partitioning of Reproduction in the Ant Neoponera apicalis. AB - All individuals in social insect colonies benefit from being informed about the presence and fertility state of reproducers. This allows the established reproductive individuals to maintain their reproductive monopoly without the need for physical control, and the non-reproductive individuals to make appropriate reproductive choices. Here, we studied whether fertility signaling is responsible for the partitioning of reproduction in the ant Neoponera apicalis. This species forms small colonies from one single-mated queen, with workers establishing reproductive hierarchies when hopelessly queenless. Previous studies identified putative fertility signals, particularly the hydrocarbon 13-methylpentacosane (13 MeC25), and have shown that precise status discrimination based on these signals could be involved in the regulation of reproductive activities. Here, we extend these findings and reveal that all individuals, be they queens or workers, differ in their cuticular hydrocarbon profile according to fertility state. Proportions of 13-MeC25 were a strong predictor of an individual's ovarian activity, and could, thus, advertise the established reproducer(s) in both queenright and queenless conditions. Furthermore, this compound might play a key role in the establishment of the reproductive hierarchy, since workers with low fertility at the onset of hierarchy formation already have relatively high amounts of 13 MeC25. Dyadic encounters showed that individuals with experimentally increased amounts of 13-MeC25 triggered less agonistic interactions from top rankers, in accord with them "advertising" higher status. Thus, these bioassays supported the use of 13-MeC25 by competing ants. This simple recognition system potentially allows permanent regulation of partitioning of reproduction in this species. PMID- 26018618 TI - A rare case of spontaneous inguinal faecal fistula as a complication of incarcerated Richter's hernia with brief review of literature. AB - BACKGROUND: Richter's hernia has an early misleading presentation with tendency to strangulation due to common lack of obstructive symptoms which may lead to delay in diagnosis and hence increased mortality. Rarely inguinal Richter's hernia may present with an uncommon complication of spontaneous fistula. The development of spontaneous faecal fistula secondary to incarcerated inguinal hernias is much rarer among the adult population as compared to the paediatric age group. Most of these fistula have been reported from developing countries like India and Nigeria and is usually the result of poverty, lack of knowledge, neglect, late presentation and lack of proper management. CASE PRESENTATION: A 62 years old male presented with chief complaints of multiple openings with faecal discharge in the right groin for last 20 days with no history of constipation, trauma, and urinary or other abdominal complaints. CT scan revealed a small gut loop communicating with anterior abdominal wall. Exploratory laparotomy revealed a loop of distal ileum adherent to the internal inguinal ring which was retrieved back into the abdominal cavity. There was perforation over the loop. Resection of the segment of ileum involved was done with ileo-ileal hand sewn anastomosis and the internal inguinal ring was closed from inside of the peritoneal cavity. The openings in the skin over the inguinal region were communicated with each other and laid open due to cellulitis of the area involved and pus discharge. CONCLUSION: Spontaneous faecal fistula in inguinal region following rupture of strangulated Richter's hernia especially in adults is very rare and can occur even in absence of obstructive symptoms. In presentation of any groin swelling, there is need for an early accurate diagnosis followed by prompt treatment. The delay in its diagnosis and management may result in this rare complication of spontaneous faecal fistula. This reflects the state of health care in the developing world and needs to be addressed by the concerned authorities. PMID- 26018619 TI - In vivo animal study and clinical outcomes of autologous atelocollagen-induced chondrogenesis for osteochondral lesion treatment. AB - BACKGROUND: Collagen acts as a scaffold for healing damaged cartilage. This study evaluated the results of an in vivo animal study and provides short-term clinical results on a mixture of atelocollagen and fibrin glue-enhanced microfracture techniques in patients with osteochondral lesions (OCL) of the talus. METHODS: This paper contains animal in vivo data and clinical outcomes on the effectiveness of atelocollagen. An in vivo animal study was conducted with full thickness cartilage defects created in the femoral condyle of 12 rabbits equally divided into 4 groups evaluated at 2, 4, 8, and 12 weeks. Four chondral lesions were created according to one procedure on each rabbit with each lesion treated as follows: (1) microfracture, (2) microfracture and the lesion covered with atelocollagen, (3) microfracture and the lesion covered with mixture of atelocollagen and fibrin glue, and (4) microfracture and the lesion covered with fibrin glue. In the clinical evaluation, 17 patients were treated with a combination of microfracture and atelocollagen injection for symptomatic full thickness OCL of the talus. They were evaluated by the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS), Hannover Ankle Score System (HSS), visual analog scale (VAS), and magnetic resonance imaging (MRI) at baseline and at 12-months follow-up. Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score of the post-op status was compared with the MOCART score and a modified Anderson's score of the pre-op status. RESULTS: In the animal study, subchondral bone and cartilage were generated completely in groups 2 and 3 microscopically. Hyaline-like cartilage was found in the repair tissue. In the clinical evaluation, mean AOFAS improved from 62 to 88, mean HSS improved from 62 to 87, and mean VAS score improved from 64 to 18, respectively (p <0.001). Fifteen patients (89%) reported good or excellent satisfaction. We defined the improvement of most of the subchondral bone edema and bone cyst as well as a chondral lesion by radiologic evaluation. CONCLUSIONS: Rapid regeneration of cartilage was demonstrated in the in vivo animal study, and patients showed significant clinical improvement. Atelocollagen-enhanced microfracture enabled a reasonable treatment of cartilage defects. PMID- 26018620 TI - Cycloisomerization of Conjugated Trienones and Isomeric 2H-Pyrans: Unified Strategy toward Cyclopenta[b]furans. AB - Conjugated trienones and isomeric 2H-pyrans were found to engage in a novel cycloisomerization cascade toward cyclopenta[b]furan derivatives. Knoevenagel chemistry and pericyclic reactions meet again to expand the polyene-carbonyl manifold. PMID- 26018621 TI - Estrogen and progesterone differentially regulate the levels of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC), and cyclic adenosine mono phosphate (cAMP) in the rat cervix. AB - The consistency of the cervical mucus changes with the reproductive cycle, which we hypothesized involved changing levels of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC), and cyclic adenosine mono-phosphate (cAMP). We therefore measured the abundance of each in the rat cervix under estrogen and progesterone influence to determine if the activity of these components could explain the changes in the consistency of cervical mucus. Ovariectomised adult female rats were treated with three days of either estrogen (1 MUg/kg/day) or progesterone (20 mg/kg/day), or three days of estrogen followed by two days of either vehicle or progesterone or estrogen plus progesterone. In some groups, mifepristone (7 mg/kg/day) was concurrently given with progesterone. Animals were then sacrificed, and the cervix was harvested for protein and mRNA expression analyses by Western blot and real-time PCR, respectively. The distribution of proteins was investigated by immunohistochemistry, and levels of cAMP were determined by enzyme-linked immunosorbent assay (ELISA). Cftr mRNA, AC protein, and cAMP levels in cervical homogenates as well as the tissue distribution of CFTR and AC in endocervical epithelia were highest under estrogen influence; the opposite pattern was seen under progesterone influence. Cervical lumen circumference was highest under estrogen and lowest under progesterone. The effects of progesterone were antagonized by mifepristone. Therefore, increased abundance of CFTR, AC, and cAMP under estrogen influence could account for the increased fluid accumulation within the cervical lumen, which would contribute to lower cervical mucus consistency, whereas progesterone reverses this effect at the molecular and organ level. PMID- 26018624 TI - Time- and energy-efficient solution combustion synthesis of binary metal tungstate nanoparticles with enhanced photocatalytic activity. AB - In the search for stable and efficient photocatalysts beyond TiO2 , the tungsten based oxide semiconductors silver tungstate (Ag2 WO4 ), copper tungstate (CuWO4 ), and zinc tungstate (ZnWO4 ) were prepared using solution combustion synthesis (SCS). The tungsten precursor's influence on the product was of particular relevance to this study, and the most significant effects are highlighted. Each sample's photocatalytic activity towards methyl orange degradation was studied and benchmarked against their respective commercial oxide sample obtained by solid-state ceramic synthesis. Based on the results herein, we conclude that SCS is a time- and energy-efficient method to synthesize crystalline binary tungstate nanomaterials even without additional excessive heat treatment. As many of these photocatalysts possess excellent photocatalytic activity, the discussed synthetic strategy may open sustainable materials chemistry avenues to solar energy conversion and environmental remediation. PMID- 26018626 TI - Applying the prodrug strategy to alpha-phosphonocarboxylate inhibitors of Rab GGTase--synthesis and stability studies. AB - Fourteen novel prodrug-like analogs of two highly ionic phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase were synthesized and preliminary assessment of their chemical and enzymatic stability was evaluated in buffers (pH 6.5 and 7.4) and rat intestinal homogenate (pH 6.5). Both acidic groups in phosphonocarboxylates were subject to modification. Phosphonic acid was protected either as bis(acyloxyalkyl) ester or phosphonodiamidate derived from amino acids. The carboxylic acid group was either left unchanged or was studied as ethyl ester. The compounds exhibited favorable stability in physiologically relevant pH (t1/2 above 18 h), while in intestinal homogenate they showed a large variety of half-lives (from 5 minutes to over 150 hours). LC MS studies have shown that the main product of decomposition under studied conditions resulted from cleavage of one of the ester (for acyloxyalkyl analogs) or amide (for phosphonodiamidate) bonds with phosphorus. PMID- 26018627 TI - Assay for methylmalonyl coenzyme A mutase activity based on determination of succinyl coenzyme A by ultrahigh-performance liquid chromatography tandem mass spectrometry. AB - Methylmalonic acidemia (MMA) is an inherited metabolic disease. In this condition, metabolism from methylmalonyl coenzyme A (CoA) to succinyl-CoA is inhibited because of either low methylmalonyl-CoA mutase (MCM) activity or adenosylcobalamin deficiency owing to altered vitamin B12 metabolism. A high precision assay for detecting MCM activity would facilitate not only MMA diagnosis but also the ability to determine the severity of MMA. We developed an MCM assay method based on ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) that involves the determination of succinyl-CoA, which is formed in an enzyme reaction, using peripheral lymphocytes. Using 0.05, 0.5, and 5 MUmol/L succinyl-CoA, the intra-assay coefficient of variation (CV) was less than 5.2% and the inter-assay CV was less than 8.7%. The MCM activities of five healthy individuals and four patients were investigated with this assay. The MCM activities of the patients were very low in relation to those of healthy individuals. Together, these results show that the UPLC-MS/MS method is useful for a detailed MCM activity assay. PMID- 26018625 TI - Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform. AB - Camelid immunoglobulin variable (IGV) regions were found homologous to their human counterparts; however, the germline V repertoires of camelid heavy and light chains are still incomplete and their therapeutic potential is only beginning to be appreciated. We therefore leveraged the publicly available HTG and WGS databases of Lama pacos and Camelus ferus to retrieve the germline repertoire of V genes using human IGV genes as reference. In addition, we amplified IGKV and IGLV genes to uncover the V germline repertoire of Lama glama and sequenced BAC clones covering part of the Lama pacos IGK and IGL loci. Our in silico analysis showed that camelid counterparts of all human IGKV and IGLV families and most IGHV families could be identified, based on canonical structure and sequence homology. Interestingly, this sequence homology seemed largely restricted to the Ig V genes and was far less apparent in other genes: 6 therapeutically relevant target genes differed significantly from their human orthologs. This contributed to efficient immunization of llamas with the human proteins CD70, MET, interleukin (IL)-1beta and IL-6, resulting in large panels of functional antibodies. The in silico predicted human-homologous canonical folds of camelid-derived antibodies were confirmed by X-ray crystallography solving the structure of 2 selected camelid anti-CD70 and anti-MET antibodies. These antibodies showed identical fold combinations as found in the corresponding human germline V families, yielding binding site structures closely similar to those occurring in human antibodies. In conclusion, our results indicate that active immunization of camelids can be a powerful therapeutic antibody platform. PMID- 26018628 TI - Determination of n-alkanes in C. annuum (bell pepper) fruit and seed using GC-MS: comparison of extraction methods and application to samples of different geographical origin. AB - An efficient extraction and analysis method was developed for the isolation and quantification of n-alkanes from bell peppers of different geographical locations. Five extraction techniques, i.e., accelerated solvent extraction (ASE), ball mill extraction, ultrasonication, rinsing, and shaking, were quantitatively compared using gas chromatography coupled to mass spectrometry (GC MS). Rinsing of the surface wax layer of freeze-dried bell peppers with chloroform proved to be a relatively quick and easy method to efficiently extract the main n-alkanes C27, C29, C31, and C33. A combined cleanup and fractionation approach on Teflon-coated silica SPE columns resulted in clean chromatograms and gave reproducible results (recoveries 90-95 %). The GC-MS method was reproducible (R(2) = 0.994-0.997, peak area standard deviation = 2-5%) and sensitive (LODs, S/N = 3, 0.05-0.15 ng/MUL). The total main n-alkane concentrations were in the range of 5-50 MUg/g dry weight. Seed extractions resulted in much lower total amounts of extracted n-alkanes compared to flesh and surface extractions, demonstrating the need for further improvement of pre-concentration and cleanup. The method was applied to 131 pepper samples from four different countries, and by using the relative n-alkane concentration ratios, Dutch peppers could be discriminated from those of the other countries, with the exception of peppers from the same cultivar. Graphical Abstract Procedure for pepper origin determination. PMID- 26018629 TI - Screening bioactive compounds from Ligusticum chuanxiong by high density immobilized human umbilical vein endothelial cells. AB - High throughput screening methodologies play a very important role in screening bioactive compounds from complex media. In this work, a new strategy for attaching cells onto amino microspheres using human umbilical vein endothelial cells (HUVECs) as a probe was developed. The immobilization depended on the specific affinity between integrin on the cells and the RGD peptide, which was coated on poly[oligo (ethylene glycol) methacrylate] by atom transfer radical polymerization. Validated application of the stationary phase was performed in the analysis of Ligusticum chuanxiong extraction by high performance affinity chromatography-mass spectrometry. Three compounds were screened as the bioactive compounds of Ligusticum chuanxiong. Two of them were identified as 3-butyl hexahydroisobenzofuran-1(3H)-one and tetramethylpyrazine (TMP), whereas the other one remains indistinct. The association constant of vascular endothelial growth factor (VEGF) and TMP binding to VEGF receptor (VEGFR) on HUVECs were calculated to be (1.04 +/- 0.08) * 10(11) M(-1) and (9.84 +/- 1.11) * 10(8) M(-1) by zonal elution. Molecular docking showed that one hydrogen bond was formed between N atom of TMP and 3-N atom of imidazole group in histidine(223) of VEGFR. Both zonal elution and molecular docking indicated that TMP and VEGF bind to the same site of VEGFR on HUVECs. It is possible to become a promising tool for high throughput screening of the bioactive compounds binding to HUVECs through broad application of the stationary phase. PMID- 26018630 TI - Ultrafiltration coupled with high-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry for screening lipase binders from different extracts of Dendrobium officinale. AB - Pancreatic lipase plays essential roles in the digestion, transport, and processing of dietary lipids in humans. Inhibition of pancreatic lipase leading to the decrease of lipid absorption may be used for treating obesity. In the present study, a new approach of ultrafiltration coupled with high-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry was established for rapidly detecting lipase binders from different extracts of medicinal plants. Rutin, a model inhibitor of lipase, was selected to optimize the screening conditions, including ion strength, temperature, pH, and incubation time. Meanwhile, the specificity of the approach was investigated by using denatured lipase and inactive compound emodin. The optimal screening conditions were as follows: ion strength 75 mM, temperature 37 degrees C, pH 7.4, and incubation time 10 min. Furthermore, linearity, accuracy, precision, and matrix effect of the approach were well validated. Finally, lipase binders were screened from different extracts of Dendrobium officinale by applying the established approach and were subsequently subjected to traditional lipase inhibitory assay. Eleven lipase inhibitors were identified, eight of which, namely naringenine, vicenin II, schaftoside, isoschaftoside, isoquercetrin, kaempferol 3-O-beta-D glucopyranoside, vitexin 2"-O-glucoside, and vitexin 2"-O-rhamnoside, were reported for the first time. In addition, docking experiments were performed to determine the preferred binding sites of these new lipase inhibitors. PMID- 26018632 TI - Toward standardized reporting of drug interactions: the READI checklist for anecdotal reports. AB - Anecdotal reports contribute 30% of the literature on adverse drug reactions and interactions. However, the quality of such reports has not been uniformly high. Standardized reporting of clinical studies is of increasing interest, including the CARE guidelines on reporting anecdotal cases in general. Although there are guidelines on evaluating and managing drug-drug interactions, there are none recommending methods for reporting suspected drug interactions. Here, based on published guidelines for reporting suspected adverse drug reactions, I propose a checklist for reporting details of suspected drug interactions, the REporting Anecdotal Drug Interactions (READI) checklist, hoping to stimulate discussion and improve reporting of suspected drug interactions. The checklist includes items relating, among others, to the patient affected, the drugs involved, and the outcome. PMID- 26018631 TI - Advective hydrogel membrane chromatography for monoclonal antibody purification in bioprocessing. AB - Protein A chromatography is widely employed for the capture and purification of monoclonal antibodies (mAbs). Because of the high cost of protein A resins, there is a significant economic driving force to seek new downstream processing strategies. Membrane chromatography has emerged as a promising alternative to conventional resin based column chromatography. However, to date, the application has been limited to mostly ion exchange flow through (FT) mode. Recently, significant advances in Natrix hydrogel membrane has resulted in increased dynamic binding capacities for proteins, which makes membrane chromatography much more attractive for bind/elute operations. The dominantly advective mass transport property of the hydrogel membrane has also enabled Natrix membrane to be run at faster volumetric flow rates with high dynamic binding capacities. In this work, the potential of using Natrix weak cation exchange membrane as a mAb capture step is assessed. A series of cycle studies was also performed in the pilot scale device (> 30 cycles) with good reproducibility in terms of yield and product purities, suggesting potential for improved manufacturing flexibility and productivity. In addition, anion exchange (AEX) hydrogel membranes were also evaluated with multiple mAb programs in FT mode. Significantly higher binding capacity for impurities (support mAb loads up to 10Kg/L) and 40X faster processing speed were observed compared with traditional AEX column chromatography. A proposed protein A free mAb purification process platform could meet the demand of a downstream purification process with high purity, yield, and throughput. PMID- 26018633 TI - Cost-effectiveness of invitation to food supplementation early in pregnancy combined with multiple micronutrients on infant survival: analysis of data from MINIMat randomized trial, Bangladesh. AB - BACKGROUND: Absence of cost-effectiveness (CE) analyses limits the relevance of large-scale nutrition interventions in low-income countries. We analyzed if the effect of invitation to food supplementation early in pregnancy combined with multiple micronutrient supplements (MMS) on infant survival represented value for money compared to invitation to food supplementation at usual time in pregnancy combined with iron-folic acid. METHODS: Outcome data, infant mortality (IM) rates, came from MINIMat trial (Maternal and Infant Nutrition Interventions, Matlab, ISRCTN16581394). In MINIMat, women were randomized to early (E around 9 weeks of pregnancy) or usual invitation (U around 20 weeks) to food supplementation and daily doses of 30 mg, or 60 mg iron with 400 MUgm of folic acid, or MMS with 15 micronutrients including 30 mg iron and 400 MUgm of folic acid. In MINIMat, EMMS significantly reduced IM compared to UFe60F (U plus 60 mg iron 400 MUgm Folic acid). We present incremental CE ratios for incrementing UFe60F to EMMS. Costing data came mainly from a published study. RESULTS: By incrementing UFe60F to EMMS, one extra IM could be averted at a cost of US$907 and US$797 for NGO run and government run CNCs, respectively, and at US$1024 for a hypothetical scenario of highest cost. These comparisons generated one extra life year (LY) saved at US$30, US$27, and US$34, respectively. CONCLUSIONS: Incrementing UFe60F to EMMS in pregnancy seems worthwhile from health economic and public health standpoints. TRIAL REGISTRATION: Maternal and Infant Nutrition Interventions, Matlab; ISRCTN16581394 ; Date of registration: Feb 16, 2009. PMID- 26018635 TI - Perceptions and a measured response. PMID- 26018634 TI - Validation of the Chinese Western Ontario and McMaster Universities Osteoarthritis Index in Patients From Mainland China With Osteoarthritis of the Knee. AB - OBJECTIVE: To establish the reliability, validity, and sensitivity to change of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) among Chinese subjects with osteoarthritis (OA) of the knee, living in mainland China. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel group study was conducted for validation of the electronic personal digital assistant version of the WOMAC Numerical Rating Scale (NRS) 3.1 Index in China. A total of 287 subjects with OA of the knee were randomized to receive either meloxicam (15 mg) or placebo. Psychometric properties of the WOMAC were evaluated by estimating the reliability, validity, and sensitivity to change. Equivalence of the electronic version was also compared with the paper version. RESULTS: Intraclass correlation coefficients for the WOMAC pain, stiffness, and physical function subscales were 0.81, 0.76, and 0.85, respectively, indicating good test retest reliability. Similarly, internal consistency was strong (Cronbach's alpha for the 3 WOMAC subscales was 0.84, 0.86, and 0.96, respectively). Pearson's correlation coefficients for WOMAC pain and Short Form 36 health survey (SF-36) bodily pain, as well as WOMAC physical function and SF-36 physical functioning domains were >0.4, indicating convergent validity, whereas the coefficients for all 3 WOMAC domains with SF-36 mental health and mental health component scores were <0.4, indicating divergent validity. There was strong discriminant validity between healthy volunteers and OA patients. The effect sizes of change from baseline to week 12 in WOMAC subscale scores were large, demonstrating sensitivity to change. Equivalence between paper and electronic versions was very high. CONCLUSION: The culturally and linguistically validated Chinese version of the WOMAC NRS 3.1 for mainland China is psychometrically robust in its validity, reliability, and sensitivity to change for patients with OA of the knee. PMID- 26018636 TI - Coronary stents and non-cardiac surgery: to bridge or not to bridge? PMID- 26018637 TI - Peroral endoscopic myotomy for achalasia cardia: Treatment analysis and follow up of over 200 consecutive patients at a single center. AB - BACKGROUND AND AIM: Peroral endoscopic myotomy (POEM) is a recently introduced technique for the treatment of achalasia cardia (AC). Data regarding safety and efficacy are still emerging. We report our experience of POEM emphasizing its safety, efficacy and follow-up data. METHODS: Patients with AC (220; mean age 39 years, range 9-74 years) underwent POEM from January 2013 to August 2014 for AC. Retrospective analysis of prospectively collected data was done. POEM was carried out by the standard technique of mucosal incision, submucosal tunneling, and myotomy of the esophageal and gastric muscle bundles followed by closure of the mucosal incision by hemoclips. Eckardt score, high-resolution manometry (HRM) and timed barium esophagogram (TBE) were used to evaluate the results. Post-procedure patients were followed up. RESULTS: Technical success rate of POEM was 96%. At 1 year, clinical success rate was 92%. Mean Eckardt score was 7.2 +/- 1.55 prior to POEM and 1.18 +/- 0.74 after POEM (P = 0.001). There was significant improvement of esophageal emptying on TBE (38.4 +/- 14.0 % vs 71.5 +/- 16.1 % (P = 0.001). Pre-procedure and post-procedure mean lower esophageal sphincter pressure was 37.5 +/- 14.5 mmHg and 15.2 +/- 6.3 mmHg, respectively. (P = 0.001) Erosive esophagitis was seen in 16% of patients who underwent POEM. There were no major adverse events. CONCLUSIONS: Study demonstrates excellent safety profile of POEM with significant relief of symptoms, reduced pressure at HRM and improved emptying at TBE. Further prospective studies are required to compare with other treatment modalities. PMID- 26018638 TI - Effects of Differently Coated Silver Nanoparticles on the Photosynthesis of Chlamydomonas reinhardtii. AB - Various factors have been invoked to explain the toxicity of silver nanoparticles (AgNP) to microorganisms including particle size and the nature of stabilizing coatings as well as the amount of dissolved silver occurring in AgNP suspensions. In this study we have assessed the effects of nine differently coated AgNP (chitosan, lactate, polyvinylpyrrolidone, polyethelene glycol, gelatin, sodium dodecylbenzenesulfonate, citrate, dexpanthenol, and carbonate) and AgNO3 on the photosynthesis of the freshwater algae Chlamydomonas reinhardtii. We have thus examined how AgNP effects on algae relate to particle size, measured dissolved silver (Agd), and bioavailable silver (Agbioav). Agbioav was indirectly estimated in toxicity experiments by cysteine-silver complexation at the EC50. The EC50 calculated as a function of measured Agd concentrations showed for some coatings values similar to that of dissolved Ag, whereas other coated AgNP displayed lower EC50 values. In all cases, excess cysteine completely prevented effects on photosynthetic yield, confirming the role of Agd as a cause of the observed effect on the photosynthesis. Toxicity was related neither to particle size nor to the coatings. For all differently coated AgNP suspensions, the EC50 values calculated as a function of Agbioav were comparable to the value of AgNO3. Depending on the coatings Agbioav was comparable to or higher than measured Agd. PMID- 26018639 TI - Strain Engineering of Octahedral Rotations and Physical Properties of SrRuO3 Films. AB - Strain engineering is an effective way to modify functional properties of thin films. Recently, the importance of octahedral rotations in pervoskite films has been recognized in discovering and designing new functional phases. Octahedral behavior of SrRuO3 film as a popular electrode in heterostructured devices is of particular interest for its probable interfacial coupling of octahedra with the functional overlayers. Here we report the strain engineering of octahedral rotations and physical properties that has been achieved in SrRuO3 films in response to the substrate-induced misfit strains of almost the same amplitude but of opposite signs. It shows that the compressively strained film on NdGaO3 substrate displays a rotation pattern of a tetragonal phase whilst the tensilely strained film on KTaO3 substrate has the rotation pattern of the bulk orthorhombic SrRuO3 phase. In addition, the compressively strained film displays a perpendicular magnetic anisotropy while the tensilely strained film has the magnetic easy axis lying in the film plane. The results show the prospect of strain engineered octahedral architecture in producing desired property and novel functionality in the class of perovskite material. PMID- 26018640 TI - How we prevent and manage infection in sickle cell disease. AB - Sickle cell disease (SCD) affects approximately 100,000 people in the US, 12,500 in the UK, and millions worldwide. SCD is typified by painful vaso-occlusive episodes, haemolytic anaemia and organ damage. A secondary complication is infection, which can be bacterial, fungal or viral. Universal newborn screening, routine use of penicillin prophylaxis, availability of conjugated vaccines against S. pneumoniae and comprehensive care programmes instituted during the past few decades in industrialized countries have dramatically reduced childhood mortality and improved life expectancy. Yet patients with SCD remain at increased risk of infection. Unfortunately, the treatment of most bacterial infections that are common in SCD is not based on the results of randomized controlled clinical trials. In their absence, treatment decisions are based on consensus guidelines, clinical experience or adapting treatment applied in other diseases. This leads to wide variation in treatment among institutions and even between treating physicians in a single institution. Prevention of infection, when possible, is most important and we focus on prevention through targeted prophylaxis and vaccination. We will share our management strategies for managing the more common infections in SCD and provide the rationale for our recommendations. PMID- 26018642 TI - Erratum to: Attentional control in the attentional blink is modulated by odor. PMID- 26018643 TI - Capture by colour: evidence for dimension-specific singleton capture. AB - Previous work on attentional capture has shown the attentional system to be quite flexible in the stimulus properties it can be set to respond to. Several different attentional "modes" have been identified. Feature search mode allows attention to be set for specific features of a target (e.g., red). Singleton detection mode sets attention to respond to any discrepant item ("singleton") in the display. Relational search sets attention for the relative properties of the target in relation to the distractors (e.g., redder, larger). Recently, a new attentional mode was proposed that sets attention to respond to any singleton within a particular feature dimension (e.g., colour; Folk & Anderson, 2010). We tested this proposal against the predictions of previously established attentional modes. In a spatial cueing paradigm, participants searched for a colour target that was randomly either red or green. The nature of the attentional control setting was probed by presenting an irrelevant singleton cue prior to the target display and assessing whether it attracted attention. In all experiments, the cues were red, green, blue, or a white stimulus rapidly rotated (motion cue). The results of three experiments support the existence of a "colour singleton set," finding that all colour cues captured attention strongly, while motion cues captured attention only weakly or not at all. Notably, we also found that capture by motion cues in search for colour targets was moderated by their frequency; rare motion cues captured attention (weakly), while frequent motion cues did not. PMID- 26018641 TI - Transcriptional regulation of chemokine genes: a link to pancreatic islet inflammation? AB - Enhanced expression of chemotactic cytokines (aka chemokines) within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required. In this review, we highlight what is known about the signals and mechanisms that govern the transcription of genes encoding specific chemokine proteins in pancreatic islet beta-cells, which include contributions from the NF-kappaB and STAT1 pathways. We further discuss increased chemokine expression in pancreatic islets during autoimmune-mediated and obesity related development of diabetes. PMID- 26018644 TI - Contralateral delay activity tracks the influence of Gestalt grouping principles on active visual working memory representations. AB - Recent studies have demonstrated that factors influencing perception, such as Gestalt grouping cues, can influence the storage of information in visual working memory (VWM). In some cases, stationary cues, such as stimulus similarity, lead to superior VWM performance. However, the neural correlates underlying these benefits to VWM performance remain unclear. One neural index, the contralateral delay activity (CDA), is an event-related potential that shows increased amplitude according to the number of items held in VWM and asymptotes at an individual's VWM capacity limit. Here, we applied the CDA to determine whether previously reported behavioral benefits supplied by similarity, proximity, and uniform connectedness were reflected as a neural savings such that the CDA amplitude was reduced when these cues were present. We implemented VWM change detection tasks with arrays including similarity and proximity (Experiment 1); uniform connectedness (Experiments 2a and 2b); and similarity/proximity and uniform connectedness (Experiment 3). The results indicated that when there was a behavioral benefit to VWM, this was echoed by a reduction in CDA amplitude, which suggests more efficient processing. However, not all perceptual grouping cues provided a VWM benefit in the same measure (e.g., accuracy) or of the same magnitude. We also found unexpected interactions between cues. We observed a mixed bag of effects, suggesting that these powerful perceptual grouping benefits are not as predictable in VWM. The current findings indicate that when grouping cues produce behavioral benefits, there is a parallel reduction in the neural resources required to maintain grouped items within VWM. PMID- 26018645 TI - The effects of simulated vision impairments on the cone of gaze. AB - Detecting the gaze direction of others is critical for many social interactions. We explored factors that may make the perception of mutual gaze more difficult, including the degradation of the stimulus and simulated vision impairment. To what extent do these factors affect the complex assessment of mutual gaze? Using an interactive virtual head whose eye direction could be manipulated by the subject, we conducted two experiments to assess the effects of simulated vision impairments on mutual gaze. Healthy subjects had to demarcate the center and the edges of the cone of gaze-that is, the range of gaze directions that are accepted for mutual gaze. When vision was impaired by adding a semitransparent white contrast reduction mask to the display (Exp. 1), judgments became more variable and more influenced by the head direction (indicative of a compensation strategy). When refractive blur was added (Exp. 1), the gaze cone shrank from 12.9 degrees (no blur) to 11.3 degrees (3-diopter lens), which cannot be explained by a low-level process but might reflect a tightening of the criterion for mutual gaze as a response to the increased uncertainty. However, the overall effects of the impairments were relatively modest. Elderly subjects (Exp. 2) produced more variability but did not differ qualitatively from the younger subjects. In the face of artificial vision impairments, compensation mechanisms and criterion changes allow us to perform better in mutual gaze perception than would be predicted by a simple extrapolation from the losses in basic visual acuity and contrast sensitivity. PMID- 26018647 TI - Attentional blink in children with attention deficit hyperactivity disorder. AB - OBJECTIVE: To explore the temporal mechanism of attention in children with attention deficit hyperactivity disorder (ADHD) and controls using a rapid serial visual presentation (RSVP) task in which two letters (T1 and T2) were presented in close temporal proximity among distractors (attentional blink [AB]). METHOD: Thirty children aged between 9 and 13 years (12 with ADHD combined type and 18 controls) took part in the study. Both groups performed two kinds of RSVP task. In the single task, participants simply had to identify a target letter (T1), whereas in the dual task, they had to identify a target letter (T1) and a probe letter (T2). RESULTS: The ADHD and control groups were equivalent in their single task performance. However, in the dual-task condition, there were significant between-group differences in the rate of detection of the probe letter (T2) at lag + 1 and lag + 4. The ADHD group exhibited a larger overall AB compared with controls. CONCLUSION: Our findings provide support for a link between ADHD and attentional blink. PMID- 26018646 TI - Inhibitory receptors as targets for cancer immunotherapy. AB - Inhibitory receptors expressed on T cells control immune responses while limiting autoimmunity. However, tumors can hijack these "checkpoints" for protection from immune attack. Tumor-specific T cells that exhibit an exhausted, unresponsive phenotype express high levels of inhibitory receptors including CTLA4, PD1, and LAG3, among others. Intratumoral regulatory T cells promote immunosuppression and also express multiple inhibitory receptors. Overcoming this inhibitory receptor mediated immune tolerance has thus been a major focus of recent cancer immunotherapeutic developments. Here, we review how boosting the host's immune system by blocking inhibitory receptor signaling with antagonistic mAbs restores the capacity of T cells to drive durable antitumor immune responses. Clinical trials targeting the CTLA4 and PD1 pathways have shown durable effects in multiple tumor types. Many combinatorial therapies are currently being investigated with encouraging results that highlight enhanced antitumor immunogenicity and improved patient survival. Finally, we will discuss the ongoing identification and dissection of novel T-cell inhibitory receptor pathways, which could lead to the development of new combinatorial therapeutic approaches. PMID- 26018648 TI - Pharmacological treatment and staging in bipolar disorder: evidence from clinical practice. AB - OBJECTIVES: Staging models for medical diseases are widely used to guide treatment and prognosis. Bipolar disorder (BD) is a chronic condition and it is among the most disabling disorders in medicine. The staging model proposed by Kapczinski in 2009 presents four progressive clinical stages of BD. Our aim was to evaluate pharmacological maintenance treatment across these stages in patients with BD. METHODS: One hundred and twenty-nine subjects who met DSM-IV criteria for BD were recruited from the Bipolar Disorders Program at Hospital de Clinicas de Porto Alegre, Brazil. All patients were in remission. The subjects were classified according to the staging model: 31 subjects were classified as stage I, 44 as stage II, 31 as stage III, and 23 as stage IV. RESULTS: Patterns of pharmacological treatment differed among the four stages (p = 0.001). Monotherapy was more frequent in stage I, and two-drug combinations in stage II. Patients at stages III and IV needed three or more medications or clozapine. Impairment in functional status (Functioning Assessment Short Test [FAST] scale scores) correlated positively with the number of medications prescribed. CONCLUSIONS: This study demonstrated differences in pharmacological treatment in patients with stable BD depending on disease stage. Treatment response can change with progression of BD. Clinical guidelines could consider the staging model to guide treatment effectiveness. PMID- 26018649 TI - Quality of life, social functioning, family structure, and treatment history associated with crack cocaine use in youth from the general population. AB - OBJECTIVE: To assess the relationship between crack cocaine use and dimensions of quality of life and social functioning in young adults. METHODS: This was a cross sectional, population-based study involving 1,560 participants in Pelotas, Brazil. Crack cocaine use and abuse were investigated using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) inventory. Outcomes of interest were quality of life, religiosity, and social functioning in terms of education, occupational status, family structure, and medical treatment history. RESULTS: Lifetime crack cocaine use was associated with poor quality of life, worse functioning, impaired academic performance, and lower religious involvement. A greater maternal presence and higher paternal absence were more also more pronounced in crack cocaine users, who were also more likely to seek psychological and psychiatric treatment than the general population. CONCLUSION: Quality of life was severely impacted by crack cocaine use, especially in terms of general and physical health. Social functioning also differed between the general population and crack users, who had lower educational attainment and religious involvement. Maternal presence, paternal absence, and mental health seeking behaviors were also more frequent among crack cocaine users, although these individuals reported lower rates of treatment satisfaction. Crack cocaine users also had significant social impairment, so that interventions involving family management and a greater focus on general health, quality of life, and functioning may make crucial contributions to the recovery of this group. PMID- 26018650 TI - Impact of periodontal conditions on the quality of life of pregnant women: a cross-sectional study. AB - BACKGROUND: Studies have been rarely conducted to provide a comprehensive perspective of pregnant women with the intention to investigate the relationships between periodontal conditions and oral health-related quality of life (OHRQoL). As such, this study aimed to describe the OHRQoL of pregnant women in Shanghai, China and to investigate the relationships between periodontal conditions and OHRQoL of pregnant women. METHODS: A cross-sectional study was conducted amongst pregnant women in all stages of pregnancy in Shanghai, China. Clinical examinations were performed to assess periodontal conditions, including tooth loss, visible plaque index, bleeding on probing, probing pocket depth and clinical attachment level. The OHRQoL of pregnant women was determined using the Oral Health Impact Profile (OHIP-14, Chinese version). Information regarding maternal characteristics, socio-demographic background and health-related behaviours was also obtained from the participants through the structured questionnaires. RESULTS: A total of 512 pregnant women (mean age = 27.3 +/- 4.0 years)participated in the survey,giving a response rate of 91.4 %. The mean gestational age was 19 weeks (SD = 8.2). The mean and the median OHIP-14 scores were 7.92 (SD = 6.84) and 6, respectively. The mean number of negative impact items (extent) was 0.20 (SD = 0.82). Approximately 10 % of pregnant women reported at least one item with 'fairly often' or 'very often' (prevalence). Results of multivariable analyses showed that periodontal conditions was not significantly associated with three scoring formats of OHRQoL (severity, extent and prevalence of impact) after adjustment for pregnancy-related variables and possible confounders (all p > 0.05). However, frequency of nausea-vomiting was found to be significantly associated with severity of impacts (p = 0.012). Utilization of dental services, age and tooth loss were the significant variables to the extent of negative impacts (all p < 0.05). While no significant variable was related with prevalence of negative impacts (p > 0.05). CONCLUSION: Pregnant women with different trimesters showed similar impact of oral disease on their OHRQoL in Shanghai, China. Periodontal health status have no impact on their OHRQoL in the fully adjusted models. Their OHRQoL was associated with early pregnancy reaction, utilisation of dental services, age and tooth loss. PMID- 26018651 TI - Irradiation Can Selectively Kill Tumor Cells while Preserving Erythrocyte Viability in a Co-Culture System. AB - An understanding of how to safely apply intraoperative blood salvage (IBS) in cancer surgery has not yet been obtained. Here, we investigated the optimal dose of 137Cs gamma-ray irradiation for killing human hepatocarcinoma (HepG2), gastrocarcinoma (SGC7901), and colonic carcinoma (SW620) tumor cells while preserving co-cultured erythrocytes obtained from 14 healthy adult volunteers. HepG2, SGC7901, or SW620 cells were mixed into the aliquots of erythrocytes. After the mixed cells were treated with 137Cs gamma-ray irradiation (30, 50, and 100 Gy), tumor cells and erythrocytes were separated by density gradient centrifugation in Percoll with a density of 1.063 g/ml. The viability, clonogenicity, DNA synthesis, tumorigenicity, and apoptosis of the tumor cells were determined by MTT assay, plate colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, subcutaneous xenograft implantation into immunocompromised mice, and annexin V/7-AAD staining, respectively. The ATP concentration, 2,3-DPG level, free Hb concentration, osmotic fragility, membrane phosphatidylserine externalization, blood gas variables, reactive oxygen species levels, and superoxide dismutase levels in erythrocytes were analyzed. We found that 137Cs gamma-ray irradiation at 50 Gy effectively inhibited the viability, proliferation, and tumorigenicity of HepG2, SGC7901, and SW620 cells without markedly damaging the oxygen-carrying ability or membrane integrity or increasing the oxidative stress of erythrocytes in vitro. These results demonstrated that 50 Gy irradiation in a standard 137Cs blood irradiator might be a safe and effective method of inactivating HepG2, SGC7901, and SW620 cells mixed with erythrocytes, which might help to safely allow IBS in cancer surgery. PMID- 26018652 TI - FTO Inhibits Insulin Secretion and Promotes NF-kappaB Activation through Positively Regulating ROS Production in Pancreatic beta cells. AB - FTO (Fat mass and obesity-associated) is associated with increased risk of obesity and type 2 diabetes incurrence. Pancreas islet beta cells dysfunction and insulin resistance are major causes of type 2 diabetes. However, whether FTO plays an important functional role in pancreatic beta cells as well as the related molecular mechanism is still unclear. In the present study, the tissue expression profile of FTO was firstly determined using quantitative PCR and western blot. FTO is widely expressed in various tissues and presented with relative high expression in pancreas tissue, especially in endocrine pancreas. FTO overexpression in MIN6 cells achieved by lentivirus delivery significantly inhibits insulin secretion in the presence of glucose stimulus as well as KCl. FTO silence has no effect on insulin secretion of MIN6 cells. However, FTO overexpression doesn't affect the transcription of insulin gene. Furthermore, reactive oxygen species (ROS) production and NF-kappaB activation are significantly promoted by FTO overexpression. Inhibition of intracellular ROS production by N-acetyl-L-cysteine (NAC) can alleviate NF-kappaB activation and restore the insulin secretion mediated by FTO overexpression. A whole transcript microarray is employed to analyze the differential gene expression mediated by FTO overexpression. The genes which are modulated by FTO are involved in many important biological pathways such as G-protein coupled receptor signaling and NF kappaB signaling. Therefore, our study indicates that FTO may contribute to pancreas islet beta cells dysfunction and the inhibition of FTO activity is a potential target for the treatment of diabetes. PMID- 26018653 TI - An international contrast of rates of placental abruption: an age-period-cohort analysis. AB - BACKGROUND: Although rare, placental abruption is implicated in disproportionately high rates of perinatal morbidity and mortality. Understanding geographic and temporal variations may provide insights into possible amenable factors of abruption. We examined abruption frequencies by maternal age, delivery year, and maternal birth cohorts over three decades across seven countries. METHODS: Women that delivered in the US (n = 863,879; 1979-10), Canada (4 provinces, n = 5,407,463; 1982-11), Sweden (n = 3,266,742; 1978-10), Denmark (n = 1,773,895; 1978-08), Norway (n = 1,780,271, 1978-09), Finland (n = 1,411,867; 1987-10), and Spain (n = 6,151,508; 1999-12) were analyzed. Abruption diagnosis was based on ICD coding. Rates were modeled using Poisson regression within the framework of an age-period-cohort analysis, and multi-level models to examine the contribution of smoking in four countries. RESULTS: Abruption rates varied across the seven countries (3-10 per 1000), Maternal age showed a consistent J-shaped pattern with increased rates at the extremes of the age distribution. In comparison to births in 2000, births after 2000 in European countries had lower abruption rates; in the US there was an increase in rate up to 2000 and a plateau thereafter. No birth cohort effects were evident. Changes in smoking prevalence partially explained the period effect in the US (P = 0.01) and Sweden (P<0.01). CONCLUSIONS: There is a strong maternal age effect on abruption. While the abruption rate has plateaued since 2000 in the US, all other countries show declining rates. These findings suggest considerable variation in abruption frequencies across countries; differences in the distribution of risk factors, especially smoking, may help guide policy to reduce abruption rates. PMID- 26018654 TI - Tributyltin induces disruption of microfilament in HL7702 cells via MAPK-mediated hyperphosphorylation of VASP. AB - Tributyltin (TBT) has been widely used for various industrial purposes, and it has toxic effects on multiple organs and tissues. Previous studies have found that TBT could induce cytoskeletal disruption, especially of the actin filaments. However, the underlying mechanisms remain unclear. The aim of the present study was to determine whether TBT could induce microfilament disruption using HL7702 cells and then to assess for the total levels of various microfilament-associated proteins; finally, the involvement of the MAPK pathway was investigated. The results showed that after TBT treatment, F-actin began to depolymerize and lost its characteristic filamentous structure. The protein levels of Ezrin and Cofilin remained unchanged, the actin-related protein (ARP) 2/3 levels decreased slightly, and the vasodilator-stimulated phosphoprotein (VASP) decreased dramatically. However, the phosphorylation levels of VASP increased 2.5-fold, and the ratio of phosphorylated-VASP/unphosphorylated-VASP increased 31-fold. The mitogen-activated protein kinases (MAPKs) ERK and JNK were discovered to be activated. Inhibition of ERK and JNK not only largely diminished the TBT-induced hyperphosphorylation of VASP but also recovered the cellular morphology and rescued the cells from death. In summary, this study demonstrates that TBT induced disruption of actin filaments is caused by the hyperphosphorylation of VASP through MAPK pathways. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1530-1538, 2016. PMID- 26018655 TI - Urinary iodine concentration of New Zealand adults improves with mandatory fortification of bread with iodised salt but not to predicted levels. AB - PURPOSE: To measure the iodine status and iodine intake of New Zealand adults 18 64 years of age following mandatory fortification of bread with iodine. METHODS: A cross-sectional survey of NZ adults living in Dunedin and Wellington during February-November 2012. Three hundred and one men and women aged 18-64 years randomly selected from the New Zealand Electoral Roll completed a 24-h urine collection, a demographic and iodine-specific food frequency questionnaire (FFQ), and had height and weight measured. Urine collections were analysed for iodine and reported as median urinary iodine concentration (UIC) ug/L and median urinary iodine excretion (UIE) ug/day. The FFQ was used to estimate iodine intake with and without discretionary iodised salt use. RESULTS: The median UIC for all adults was 73 ug/L, indicative of mild iodine deficiency. The mean urinary volume was 2.0 L. As an estimate of iodine intake, the median UIE was 127 ug/day. Estimated iodine intake, using the FFQ which included discretionary iodised salt use, was 132 ug/day. Iodine intakes were associated with UIC (P = 0.040) and UIE (P = 0.003), but not with bread iodine intake and iodised salt use. CONCLUSION: Using the WHO/UNICEF/ICCIDD target for iodine sufficiency (a UIC of >100 ug/L) based on school-aged children with a mean urinary volume of 1.0 L, the iodine status of NZ adults does not reach adequate levels (73 ug/L). A more realistic parameter in a population with a higher urinary volume excretion (2.0 L) is the UIE. A median UIE of 127 ug/day suggests that the iodine status of NZ adults is now likely to be adequate. PMID- 26018657 TI - FDA Regulation of Indoor Tanning Devices and Opportunities for Skin Cancer Prevention. PMID- 26018656 TI - Mid-regional-pro-adrenomedullin plasma levels are increased in obese adolescents. AB - PURPOSE: Recently, adrenomedullin (ADM) was defined as a new member of the adipokine family. ADM secreted by adipocytes, through its vasodilator and antioxidant actions, might be protective against metabolic syndrome-associated cardiovascular complications. The aim of the study was to assess plasma mid regional (MR)-proADM levels in obese adolescents compared to normal-weight subjects and its relation with BMI, body composition and metabolic indices. METHODS: Plasma MR-proADM was measured in 32 healthy adolescents [BMI z-score (mean +/- SEM) = 0.6 +/- 0.09 and 0.8 +/- 0.07 in females and males, respectively] and in 51 age-matched obese adolescents [BMI z-score (mean +/- SEM) = 2.8 +/- 0.12 and 2.9 +/- 0.08 in female and males, respectively] by a time resolved amplified cryptate emission technology assay. RESULTS: Plasma MR-proADM levels resulted significantly higher in obese than in normal-weight adolescents (MR-proADM: 0.33 +/- 0.1 vs 0.40 +/- 0.1 nmol/L, p < 0.0001). Using univariate analysis, we observed that MR-proADM correlated significantly with BMI z-score (p < 0.0001), fat mass (p < 0.0001), circulating insulin (p < 0.004), HOMA-IR (p < 0.005), total cholesterol (p < 0.03) and LDL-cholesterol (p < 0.05). Including MR proADM as response variable and its significant correlates into a multiple regression analysis, we observed that fat mass (p = 0.014) and BMI z-score (p = 0.036) were independent determinants of circulating MR-proADM. CONCLUSIONS: Our study shows for the first time that obese adolescents have higher circulating levels of MR-proADM compared with normal-weight, appropriate controls suggesting its important involvement in obese patients. PMID- 26018658 TI - Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. AB - Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1. PMID- 26018659 TI - A context-aware delayed agglomeration framework for electron microscopy segmentation. AB - Electron Microscopy (EM) image (or volume) segmentation has become significantly important in recent years as an instrument for connectomics. This paper proposes a novel agglomerative framework for EM segmentation. In particular, given an over segmented image or volume, we propose a novel framework for accurately clustering regions of the same neuron. Unlike existing agglomerative methods, the proposed context-aware algorithm divides superpixels (over-segmented regions) of different biological entities into different subsets and agglomerates them separately. In addition, this paper describes a "delayed" scheme for agglomerative clustering that postpones some of the merge decisions, pertaining to newly formed bodies, in order to generate a more confident boundary prediction. We report significant improvements attained by the proposed approach in segmentation accuracy over existing standard methods on 2D and 3D datasets. PMID- 26018660 TI - Lithospermic acid attenuates 1-methyl-4-phenylpyridine-induced neurotoxicity by blocking neuronal apoptotic and neuroinflammatory pathways. AB - BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorders after Alzheimer's disease. The main cause of the disease is the massive degeneration of dopaminergic neurons in the substantia nigra. Neuronal apoptosis and neuroinflammation are thought to be the key contributors to the neuronal degeneration. RESULTS: Both CATH.a cells and ICR mice were treated with 1-methyl 4-phenylpyridin (MPP(+)) to induce neurotoxicity in vitro and in vivo. Western blotting and immunohistochemistry were also used to analyse neurotoxicity, neuroinflammation and aberrant neurogenesis in vivo. The experiment in CATH.a cells showed that the treatment of MPP(+) impaired intake of cell membrane and activated caspase system, suggesting that the neurotoxic mechanisms of MPP(+) might include both necrosis and apoptosis. Pretreatment of lithospermic acid might prevent these toxicities. Lithospermic acid possesses specific inhibitory effect on caspase 3. In mitochondria, MPP(+) caused mitochondrial depolarization and induced endoplasmic reticulum stress via increasing expression of chaperone protein, GRP-78. All the effects mentioned above were reduced by lithospermic acid. In animal model, the immunohistochemistry of mice brain sections revealed that MPP(+) decreased the amount of dopaminergic neurons, enhanced microglia activation, promoted astrogliosis in both substantia nigra and hippocampus, and MPP(+) provoked the aberrant neurogenesis in hippocampus. Lithospermic acid significantly attenuates all of these effects induced by MPP(+). CONCLUSIONS: Lithospermic acid is a potential candidate drug for the novel therapeutic intervention on Parkinson's disease. PMID- 26018661 TI - Temporal Trends and Predictors for Cancer Clinical Trial Availability for Medically Underserved Populations. AB - BACKGROUND: Lack of access to available cancer clinical trials has been cited as a key factor limiting trial accrual, particularly among medically underserved populations. We examined the trends and factors in clinical trial availability within a major U.S. safety-net hospital system. MATERIALS AND METHODS: We identified cancer clinical trials activated at the Harold C. Simmons Cancer from 1991 to 2014 and recorded the characteristics of the trials that were and were not activated at the Parkland Health and Hospital System satellite site. We used univariate and multivariate logistic regression to determine the association between trial characteristics and nonactivation status, and chi-square analysis to determine the association between the trial characteristics and the reasons for nonactivation. RESULTS: A total of 773 trials were identified, of which 152 (20%) were not activated at Parkland. In multivariable analysis, nonactivation at Parkland was associated with trial year, sponsor, and phase. Compared with the 1991-2006 period, clinical trials in the 2007-2014 period were almost eightfold more likely not to be activated at Parkland. The most common reasons for nonactivation at Parkland were an inability to perform the study procedures (27%) and the startup costs (15%). CONCLUSION: Over time, in this single-center setting, a decreasing proportion of cancer clinical trials were available to underserved populations. Trial complexity and costs appeared to account for much of this trend. Efforts to overcome these barriers will be key to equitable access to clinical trials, efficient accrual, and the generalizability of the results. IMPLICATIONS FOR PRACTICE: Despite numerous calls to increase and diversify cancer clinical trial accrual, the present study found that cancer clinical trial activation rates in a safety-net setting for medically underserved populations have decreased substantially in recent years. The principal reasons for study nonactivation were expenses and an inability to perform the study-related procedures, reflecting the increasing costs and complexity of cancer clinical trials. Future efforts need to focus on strategies to mitigate the increasing disparity in access to clinical research and cutting-edge therapies, which also threatens to hinder study accrual, completion rates, and generalizability. PMID- 26018662 TI - Treatment of Metastatic Breast Cancer in a Real-World Scenario: Is Progression Free Survival With First Line Predictive of Benefit From Second and Later Lines? AB - INTRODUCTION: Despite the availability of several therapeutic options for metastatic breast cancer (MBC), no robust predictive factors are available to help clinical decision making. Nevertheless, a decreasing benefit from first line to subsequent lines of treatment is commonly observed. The aim of this study was to assess the impact of benefit from first-line therapy on outcome with subsequent lines. METHODS: We analyzed a consecutive series of 472 MBC patients treated with chemotherapy (CT) and/or endocrine therapy (ET) between 2004 and 2012. We evaluated progression-free survival (PFS) at first (PFS1), second, third, and fourth therapeutic lines, according to treatment (ET and/or CT) and tumor subtypes. RESULTS: In the whole cohort, median overall survival was 34 months, and median PFS1 was 9 months. A 6-month benefit was shown by 289 patients (63.5%) at first line, 128 (40.5%) at second line, 76 (33.8%) at third line, and 34 (23.3%) at fourth line. Not having a 6-month benefit at PFS1 was associated with less chance of benefit at second line (odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.29-0.77, p = .0026) and at any line beyond first (OR: 0.39; 95% CI: 0.24-0.62, p < .0001). In the total series, after stratification for tumor subtypes, a strong predictive effect was observed among HER2-positive tumors (OR: 0.2; 95% CI: 0.05-0.73, p = .0152). CONCLUSION: Our results suggest that the absence of at least a 6-month benefit in terms of PFS with first-line therapy predicts a reduced probability of benefit from subsequent therapeutic lines, especially in HER2-positive disease. IMPLICATIONS FOR PRACTICE: This study supports evidence showing that the absence of a 6-month benefit in terms of progression-free survival with first-line therapy predicts a lack of benefit from subsequent therapeutic lines in metastatic breast cancer. The random distribution of benefit experienced by a subset of the cohort further spurs an interest in identifying predictive factors capable of identifying the most appropriate therapeutic strategy. PMID- 26018664 TI - ? PMID- 26018665 TI - [Diagnostics of Infectious Corneal and Conjunctival Diseases]. PMID- 26018663 TI - Relation of allium vegetables intake with head and neck cancers: evidence from the INHANCE consortium. AB - SCOPE: Only a few studies analyzed the role of allium vegetables with reference to head and neck cancers (HNC), with mixed results. We investigated the potential favorable role of garlic and onion within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. METHODS AND RESULTS: We analyzed pooled individual-level data from eight case-control studies, including 4590 cases and 7082 controls. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between garlic and onion intakes and HNC risk. Compared with no or low garlic use, the ORs of HNC were 0.95 (95% CI 0.71-1.27) for intermediate and 0.74 (95% CI 0.55-0.99) for high garlic use (p for trend = 0.02). The ORs of HNC for increasing categories of onion intake were 0.91 (95% CI 0.68-1.21) for >1 to <=3 portions per week, and 0.83 (95% CI 0.60-1.13) for >3 portions per week (p for trend = 0.02), as compared to <1 portion per week. We found an inverse association between high onion intake and laryngeal cancer risk (OR = 0.69; 95% CI 0.54-0.88), but no significant association for other subsites. CONCLUSION: The results of this pooled-analysis support a possible moderate inverse association between garlic and onion intake and HNC risk. PMID- 26018666 TI - [Chemical Ocular Burns]. PMID- 26018667 TI - Indanes--Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors. AB - The indane (2,3-dihydro-1H-indene) ring system is an attractive scaffold for biologically active compounds due to the combination of aromatic and aliphatic properties fused together in one rigid system. This bicyclic structure provides a wide range of possibilities to incorporate specific substituents in different directionalities, thus being an attractive scaffold for medicinal chemists. Notably, many indane-based compounds are being used in the clinic to treat various diseases, such as indinavir, an HIV-1 protease inhibitor; indantadol, a potent Monoamine Oxidase (MAO)-inhibitor; the amine uptake inhibitor indatraline; and the ultra-long-acting beta-adrenoceptor agonist indacaterol. Given the diversity of targets these drugs act on, one could argue that the indane ring system is a privileged substructure. In the present review, the synthetic and medicinal chemistry of the indane ring system is described. In more detail, it contains a comprehensive overview of compounds bearing the indane substructure with G protein coupled receptor (GPCR) activity, with particular emphasis on their structure-activity relationships (SAR). PMID- 26018668 TI - Lethal interpersonal violence in the Middle Pleistocene. AB - Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin. PMID- 26018669 TI - Charged Termini on the Trp-Cage Roughen the Folding Energy Landscape. AB - We study the energy landscape and thermodynamics of the zwitterionic variant of the widely studied TC5b Trp-cage protein using replica exchange molecular dynamics simulations. We show that the addition of two charge groups at the termini has dramatic consequences to the folding landscape. First, the addition of charged ends increases the equilibration time of the simulation by a factor of 2.5 over a variant with terminal capping. Second, we identify the formation of two long-lived metastable states not present in the capped ends variant structural ensemble. The population of these metastable states is higher at lower temperatures; furthermore, these states are determined to be low energy states, relative to the folded state. The first of the metastable states is a folding intermediate structure which is characterized by a non-native charge pair. The second is characterized by significant beta sheet content. We show through potential of mean force (PMF) calculations that the PMF between two charge groups is a poor predictor of the prevalence of a particular ion pair in the unfolded structural ensemble. Finally, by analyzing the energy differences between the folded state, unfolded states, and the metastable states, we show that the stabilization of these metastable states is not only due to favorable Coulomb interactions but also due to strain in the dihedral angles. Our results show that, even for a simple protein, the folding landscape can be extremely complex and significantly altered by simple changes to the charge states of the sequence. PMID- 26018670 TI - Comparison of Dexmedetomidine Versus Midazolam-Fentanyl Combination for Monitored Anesthesia Care During Burr-Hole Surgery for Chronic Subdural Hematoma. AB - BACKGROUND: Intraoperative movements are marker of inadequate level of sedation and are undesirable during burr-hole surgery under monitored anesthesia care (MAC). It distracts surgeon, hinders surgical procedure, and may lead to iatrogenic complication. Dexmedetomidine has shown to provide excellent analgesia, cooperative sedation with fewer fluctuations in sedation level during MAC. We compared the effect of dexmedetomidine on intraoperative patient movement, postoperative recovery time, and the surgeon and patient satisfaction scores with commonly used midazolam-fentanyl combination. METHODS: Fifty-two patients undergoing burr-hole surgery for chronic subdural hematoma under MAC were randomly assigned to receive either IV dexmedetomidine 1 MUg/kg over 10 minutes followed by continuous infusion 0.03 to 0.07 MUg/kg/h (group D) or IV fentanyl 0.5 MUg/kg and midazolam 0.03 mg/kg over 10 minutes followed by continuous infusion of 0.5 to 1.16 MUg/kg/h fentanyl and 0.03 to 0.07 mg/kg/h midazolam (group M/F) titrated to maintain Ramsay sedation scale 3. Total number of intraoperative patient movements, postoperative recovery time, and patient and surgeon satisfaction scores were recorded. RESULTS: Demographic and baseline characteristics were comparable between the 2 groups. Intraoperative patient movements were significantly less in group D than group M/F (median interquartile range, 1.00 [0.00 to 2.00] vs. 3.00 [1.00 to 3.25], P=0.007). Group D patients showed faster postoperative recovery (mean +/- SD, 7.00 +/- 6.96 vs. 13.69 +/- 6.18 min, P=0.000). Surgeon satisfaction scores were better in group D compared with group M/F (median interquartile range, 1.00 [1.00 to 1.25] vs. 2.00 [1.00 to 2.00], P=0.014). However, patient satisfaction score and hemodynamic parameters were comparable (P>0.05) between both the groups. CONCLUSIONS: Use of dexmedetomidine for MAC is associated with lesser number of intraoperative patient movements, faster postoperative recovery, better surgeon satisfaction score, and comparable patient's satisfaction compared with midazolam-fentanyl combination. PMID- 26018672 TI - Abstracts of EuroPerio8, London, UK, 3-6 June. PMID- 26018671 TI - Comparison of Small Dose Ketamine and Dexmedetomidine Infusion for Postoperative Analgesia in Spine Surgery--A Prospective Randomized Double-blind Placebo Controlled Study. AB - BACKGROUND: High doses of opioids are frequently used to treat postoperative pain after spine surgery. This leads to opioid-related side effects like nausea, vomiting, respiratory depression, etc. The current study is an attempt to find a safe analgesic adjuvant, which will afford opioid sparing property. METHOD: Sixty six patients undergoing spine surgery were randomized into 1 of the 3 groups group K (ketamine bolus 0.25 mg/kg followed by infusion of 0.25 mg/kg/h with midazolam bolus 10 MUg/kg and infusion of 10 MUg/kg/h mixed in the same infusion pump), group D (dexmedetomidine bolus 0.5 MUg/kg followed by 0.3 MUg/kg/h infusion), and group C (normal saline). Study drugs were started in the postoperative period and continued for 24 hours. Pain-free period, pain scores, rescue analgesic (morphine) requirements, and side effects were noted for 48 hours postoperatively. RESULT: Mean pain-free periods in the ketamine group (860 min) and the dexmedetomidine group (580 min) were longer than in the saline group (265 min) (P<0.002) during the observation period of 48 hours. There was a significant decrease in the rescue analgesic requirement in both ketamine and dexmedetomidine group (P<0.05) (cumulative morphine requirement at 24 h-group C 15.64+/-9.31 mg, group D 6.89+/-5.88 mg, group K 2.45+/-2.06 mg; at 48 h-group C 21.09+/-12.88 mg, group D 7.98+/-7.72 mg, group K 2.59+/-1.97 mg). Hemodynamics were maintained within normal range in all the groups. Patients in ketamine and dexmedetomidine groups were sedated, but none required assistance for maintaining airway patency. Few patients in the ketamine group had nausea, dizziness, and diplopia, but the difference was insignificant in comparison with other groups (P>0.05). CONCLUSIONS: Infusion of low-dose ketamine and dexmedetomidine both provide good postoperative analgesia with minimal side effects. Both of the tested analgesic regimes can be used safely and effectively for postoperative pain relief in patients after spine surgery. PMID- 26018674 TI - Skateboarding injuries: An updated review. AB - This in-depth literature review shows that skateboarding has experienced intermittent periods of popularity, with an estimated 6-15 million skateboarders in the US currently involved at all levels of recreational play and competition. Head trauma accounts for ~ 3.5-13.1% of all skateboarding injuries. Injury occurs most often to the upper extremity (55-63%), whereas thoracoabdominal and spine injuries account for 1.5-2.9% of all trauma and lower extremity injuries occur 17 26% of the time. Few fatal injuries (1.1%) have been reported, oftentimes resulting from traumatic head injuries incurred from collisions with motor vehicles. Although skateparks may be perceived as a safer alternative to street skateboarding, injuries still occur when the skateboarder collides with an object or falls from the board. Factors leading to trauma include fatigue and overuse, age and skill level, inadequate medical care, environmental conditions, equipment concerns, lack of fitness and training, and the detrimental behavior of the competitor. Although not all skateboarding injuries are avoidable, numerous opportunities exist to instill safety involving education, instruction, and supervision and the proper use of protective gear to reduce predisposition to trauma. Future research recommendations include a more standardized data collection system, as well as an increased focus on kinetic analysis of the sport. Legislation involving helmet laws and the increased investment in a safer environment for the skateboarder may also assist in reducing injury in this sport. PMID- 26018676 TI - Role of LIMP-2 in the intracellular trafficking of beta-glucosidase in different human cellular models. AB - Acid beta-glucosidase (GCase), the enzyme deficient in Gaucher disease (GD), is transported to lysosomes by the lysosomal integral membrane protein (LIMP)-2. In humans, LIMP-2 deficiency leads to action myoclonus-renal failure (AMRF) syndrome. GD and AMRF syndrome share some clinical features. However, they are different from clinical and biochemical points of view, suggesting that the role of LIMP-2 in the targeting of GCase would be different in different tissues. Besides, the role of LIMP-2 in the uptake and trafficking of the human recombinant (hr)GCase used in the treatment of GD is unknown. Thus, we compared GCase activity and intracellular localization in immortalized lymphocytes, fibroblasts, and a neuronal model derived from multipotent adult stem cells, from a patient with AMRF syndrome, patients with GD, and control subjects. In fibroblasts and neuronlike cells, GCase targeting to the lysosomes is completely dependent on LIMP-2, whereas in blood cells, GCase is partially targeted to lysosomes by a LIMP-2-independent mechanism. Although hrGCase cellular uptake is independent of LIMP-2, its trafficking to the lysosomes is mediated by this receptor. These data provide new insights into the mechanisms involved in the intracellular trafficking of GCase and in the pathogeneses of GD and AMRF syndrome. PMID- 26018675 TI - Inhibition of hyperglycemia-induced angiogenesis and breast cancer tumor growth by systemic injection of microRNA-467 antagonist. AB - Abnormal angiogenesis in multiple tissues is a key characteristic of the vascular complications of diabetes. However, angiogenesis may be increased in one tissue but decreased in another in the same patient at the same time point in the disease. The mechanisms of aberrant angiogenesis in diabetes are not understood. There are no selective therapeutic approaches to target increased neovascularization without affecting physiologic angiogenesis and angiogenesis in ischemic tissues. We recently reported a novel miRNA-dependent pathway that up regulates angiogenesis in response to hyperglycemia in a cell- and tissue specific manner. The goal of the work described herein was to test whether systemic administration of an antagonist of miR-467 would prevent hyperglycemia induced local angiogenesis in a tissue-specific manner. We examined the effect of the antagonist on hyperglycemia-induced tumor growth and angiogenesis and on skin wound healing in mouse models of diabetes. Our data demonstrated that the systemic injection of the antagonist prevented hyperglycemia-induced angiogenesis and growth of mouse and human breast cancer tumors, where the miR-467 pathway was active in hyperglycemia. In tissues where the miR-467-dependent mechanism was not activated by hyperglycemia, there was no effect of the antagonist: the systemic injection did not affect skin wound healing or the growth of prostate tumors. The data show that systemic administration of the miR-467 antagonist could be a breakthrough approach in the treatment and prevention of diabetes-associated breast cancer in a tissue-specific manner without affecting physiologic angiogenesis and angiogenesis in ischemic tissues. PMID- 26018677 TI - Folate- and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor alpha. AB - Deficiency in the methyl donors vitamin B12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor alpha (ER-alpha)/Src tyrosine kinase. The influence of impaired ER-alpha pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-alpha antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2 piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-alpha and subsequent decreased ER-alpha/PPAR-gamma coactivator 1 alpha (PGC-1alpha) interaction in deficiency condition. The impaired ER-alpha pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4' phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4 quinazolinamine, SKI-1, Src-l1) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-alpha pathway. PMID- 26018678 TI - Hydroxysteroid (17beta)-dehydrogenase 1-deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production. AB - Hydroxysteroid (17beta)-dehydrogenase type 1 (HSD17B1) catalyzes the conversion of low active 17-ketosteroids, androstenedione (A-dione) and estrone (E1) to highly active 17-hydroxysteroids, testosterone (T) and E2, respectively. In this study, the importance of HSD17B1 in ovarian estrogen production was determined using Hsd17b1 knockout (HSD17B1KO) mice. In these mice, the ovarian HSD17B enzyme activity was markedly reduced, indicating a central role of HSD17B1 in ovarian physiology. The lack of Hsd17b activity resulted in increased ovarian E1:E2 and A dione:T ratios, but we also observed reduced progesterone concentration in HSD17B1KO ovaries. Accordingly with the altered steroid production, altered expression of Star, Cyp11a1, Lhcgr, Hsd17b7, and especially Cyp17a1 was observed. The ovaries of HSD17B1KO mice presented with all stages of folliculogenesis, while the corpus luteum structure was less defined and number reduced. Surprisingly, bundles of large granular cells of unknown origin appeared in the stroma of the KO ovaries. The HSD17B1KO mice presented with severe subfertility and failed to initiate pseudopregnancy. However, the HSD17B1KO females presented with normal estrous cycle defined by vaginal smears and normal puberty appearance. This study indicates that HSD17B1 is a key enzyme in ovarian steroidogenesis and has a novel function in initiation and stabilization of pregnancy. PMID- 26018679 TI - A Case of Massive Bone Metastases From Lung Cancer Detected Only by 18F-FDG PET/CT. AB - A 74-year-old man was diagnosed with small cell lung carcinoma in the left upper lobe. (18)F-FDG PET/CT showed multifocal strong abnormal uptakes in the axial skeleton and those of the primary lung tumor. CT failed to demonstrate the bony abnormalities. A subsequent (99m)Tc-MDP bone scintigraphy was also almost negative. It is important to note that bone metastasis may be undetectable by both CT and bone scintigraphy even if it is massive. PMID- 26018680 TI - Marked Hematopoiesis Masquerading Multiple Bone Metastasis in a Lung Cancer Patient With Myelodysplastic Syndrome. AB - We diagnosed a 62-year-old man with lung cancer, well-differentiated squamous cell carcinoma, on the right upper lobe and left lower lobe. He had a history of myelodysplastic syndrome and refractory anemia with ringed sideroblasts diagnosed 5 years earlier. The patient's 18F-FDG PET/CT for the clinical staging of lung cancer revealed accumulations of FDG in multiple bones including the rib bones, which strongly suggested multiple bone metastases. He underwent lobectomies and excision of the right fourth and fifth rib bones. The pathological findings of resected rib bones exhibited hypercellular bone marrow without excess of blasts. PMID- 26018681 TI - Pseudomyogenic Hemangioendothelioma Mimicking Multiple Myeloma on 18F-FDG PET/CT, Followed by Spontaneous Regression. AB - Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma is a rare, recently described vascular neoplasm that occurs predominantly in the distal extremities of young to middle aged adult males. In this report, we describe a patient who presented with numerous lytic bone lesions which were intensely 18F FDG avid on PET/CT and presumed to be metastatic. Pathology revealed pseudomyogenic hemangioendothelioma. Follow-up CT showed enlargement and increasing sclerosis of several lesions, believed to represent progression; however, follow-up PET/CT confirmed a spontaneous regression of the disease. PMID- 26018682 TI - Somatostatin Receptors in an Anaplastic Oligodendroglioma Relapse Evidenced By 68Ga DOTANOC PET/CT. AB - Six years ago, a right frontal lobe anaplastic oligodendroglioma negative for AE1/AE3 and HBM-45, positive for 1p/19q deletion, EMA, GFAP, and synaptophysin was excised from a 50-year-old woman. Treatments that followed were radiation therapy, and surgery plus radiation therapy and temozolomide for a relapse with an early partial response, followed by disease progression. In the middle of last year, 68Ga-DOTANOC PET/CT was carried out to evaluate the possibility of treatment with peptide receptor radionuclide therapy. The examination revealed a grossly round-shaped uptake corresponding to the surgical wall, with some smaller uptakes disseminated in different parts of the brain. PMID- 26018683 TI - Incidental Detection of a Hodgkin Lymphoma on 18F-Choline PET/CT and Comparison With 18F-FDG in a Patient With Prostate Cancer. AB - Combined PET/CT scanning with (18)F-FDG is in current use in Hodgkin lymphoma. New tracers have been developed, such as (18)F-choline in prostate cancer. Its use is under investigation in other solid tumors (eg, brain, liver, lung). We report a case of Hodgkin lymphoma incidentally detected on (18)F-choline PET/CT in a prostate cancer patient and show a comparison with (18)F-FDG PET/CT. (18)F choline PET/CT detected more lymph node lesions than the (18)F-FDG PET/CT for this patient. Comparative studies of the 2 tracers might help fine-tune treatments and, in particular, delineate target zones in radiation therapy. PMID- 26018684 TI - 67Ga SPECT/CT in Diagnosis and Follow-up of Acute Bacterial Prostatitis. AB - We report a case of 63-year-old man who had urinary tract infection with septic shock, Klebsiella pneumoniae bacteremia, and bacteriuria. (67)Ga SPECT/CT showed hot uptake in prostate gland, and acute bacterial prostatitis was diagnosed. After antibiotic treatment, follow-up (67)Ga SPECT/CT revealed much less uptake in the prostate gland, suggesting remission of prostatitis. PMID- 26018685 TI - A Clear Cell Variant of Papillary Thyroid Microcarcinoma With Lung, Bone, and Soft Tissue Metastases. AB - A 56-year-old woman presented with a mass lesion on the right occipital bone underwent total resection of the tumor. An adenocarcinoma with immunostaining positive for thyroid transcription factor-1 and thyroglobulin was found. An ultrasound/thyroid scan detected a hot nodule of 9 mm in the right lobe. Fine needle biopsy revealed the similar histological findings with the previous bone resection material. Then, a total thyroidectomy was performed. Histopathologic examination revealed clear cell variant of papillary thyroid microcarcinoma. She received 7.4 GBq of I. On posttherapy scan, metastatic focuses were seen in the left lung and soft tissue between the left paravertebral muscles. PMID- 26018686 TI - Variability of Hepatic 18F-FDG Uptake at Interim PET in Patients With Hodgkin Lymphoma. AB - INTRODUCTION: When evaluating response of Hodgkin lymphoma (HL) to chemotherapy on interim (18)F-FDG-PET/CT, physiological liver uptake is used as reference. Hodgkin lymphoma sites with uptake greater than liver are interpreted as positive. We aimed at examining factors that might influence liver uptake as reference organ. METHODS: Fifty patients with HL who received baseline (18)F-FDG PET/CT (PET1) and interim PET (PET2), usually after 2 cycles of adriamycin bleomycin, vinblastine, and dacarbazine chemotherapy, were included retrospectively. SUVmean normalized for body weight (SUVmean) and for lean body mass (SULmean) were obtained from regions of interest in the right lobe of the liver. RESULTS: On univariate analysis, liver SUVmean on interim PET increased with increasing body mass index (BMI) (P = 0.0453) and were higher in women (P = 0.0401). These factors remained significant on multivariate analysis (P = 0.009 and P = 0.008, respectively). No significant correlation was found with postinjection delay, blood glucose level, and age. Liver SULmean were not affected by the studied variables. Average liver SUVmean in the 50 patients were similar at baseline and interim PET. In 11 patients (22%), however, there was 30% or greater variation in liver SUVmean between PET1 and PET2. No factors explaining intrapatient variation in hepatic uptake between PET1 and PET2 were found on correlation analysis. CONCLUSION: At interim PET in patients with HL, liver SUVmean depends on BMI and sex, but not liver SULmean. Furthermore, our study, conducted with standard clinical procedure, also confirmed the high range of liver uptake values from one patient to another. Caution is required when using liver SUV as reference in patients with high BMI. Intrapatient fluctuation in liver SUVmean should also be expected. PMID- 26018687 TI - 18F-FDG PET/CT of Liver Lymphoepithelioma-like Carcinoma. AB - A 48-year-old woman, chronic hepatitis B virus carrier, was presented with a 3.2 cm hepatic tumor accidentally noted 1 month ago by regular sonography. Serum alpha-fetoprotein level was within reference range, and tumor biopsy showed lymphoepithelioma-like carcinoma. She was referred for F-FDG PET/CT for whole body survey. FDG PET/CT revealed a 3.2-cm FDG PET/CT in S5 to S6 of the liver, as well as lymphadenopathy in the left supraclavicular fossa and between the inferior venous cava and the common bile duct. Lymphoepithelioma-like carcinoma in the liver is extremely rare, and the expression of FDG uptake has never been discussed. PMID- 26018688 TI - Prostate-Specific Membrane Antigen PET/CT in Splenic Sarcoidosis. AB - A 65-year-old man who had prostate cancer presented with slightly progressive prostate-specific antigen values. In this situation of biochemical relapse, prostate-specific membrane antigen (PSMA) PET/CT has proven to be superior to choline PET. The Ga-PSMA PET/CT of our patient revealed PSMA-positive tissue in the spleen. Although the localization was not typical for metastases, metastasis could not be excluded because of the intense focal tracer uptake. A supplementary MRI was performed but also failed to rule out a malignant origin. Finally, biopsy confirmed benign disease in the spleen in the form of granulomatous disease. PMID- 26018689 TI - Clinical Performance of Whole-Body 18F-FDG PET/Dixon-VIBE, T1-Weighted, and T2 Weighted MRI Protocol in Colorectal Cancer. AB - PURPOSE: The aim of this study was to investigate the clinical performance of whole-body (18)F-FDG PET/Dixon-volume-interpolated breath-hold examination (Dixon VIBE), T1-weighted, and T2-weighted MRI protocol in patients with colorectal cancer. PATIENTS AND METHODS: A total of 59 patients with colorectal cancer were enrolled in this study. Each patient had one of the following clinical conditions: initial stage before therapy, stage after neoadjuvant therapy, suspicious colorectal liver metastases, and colorectal liver metastases after chemotherapy. Fourteen patients had primary colorectal cancer, whereas 38 patients had a total of 132 hepatic lesions, 53 lesions existed before chemotherapy, and 79 lesions appeared after chemotherapy. The primary stage and metastases images were obtained using our PET/Dixon-VIBE/T1/T2 MRI protocol and were analyzed by 2 nuclear medicine physicians. Diagnostic accuracy was compared with contrast-enhanced MRI images, which were based on surgical pathology results. RESULTS: The sensitivity of our imaging protocol for primary colorectal cancer was 100% (14/14). T and N stage both showed 92.9% (13/14) accuracy. Of all 132 hepatic lesions, 115 metastatic lesions were analyzed, and 17 benign lesions were excluded (6 were during pretreatment cases, and 11 were during posttreatment cases). In pretreatment metastatic lesions (n = 47), the sensitivities of our protocol and dedicated MRI were 95.7% (45/47) and 100% (47/47), respectively. In posttreatment lesions (n = 68), sensitivities of our protocol and dedicated MRI were 75% (51/68) and 91.2% (62/68), respectively. CONCLUSIONS: Whole-body PET/Dixon-VIBE/T1/T2 MRI protocol is clinically useful for TNM staging and chemonaive hepatic metastasis in colorectal cancer. PMID- 26018690 TI - Targeted Prostate Gland Biopsy With Combined Transrectal Ultrasound, mpMRI, and 18F-FMAU PET/CT. AB - We report on a 61-year-old man with elevated serum prostate-specific antigen level of 10.5 ng/mL who had undergone prior negative standard transrectal ultrasound biopsy at another institution. He was referred to our medical center for evaluation and underwent a clinical 3-T multiparametric MRI and a research protocol PET/CT with the cellular proliferation radiotracer (18)F-FMAU (2'-deoxy 2'-[(18)F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil). The PET/CT and multiparametric MRI were fused with transrectal ultrasound images for real-time hybrid image-based targeting of the biopsy needle. PET/CT with (18)F-FMAU was helpful in localizing the nonstandard biopsy sites that on histopathology revealed suspected tumor deposits. PMID- 26018691 TI - Struma Ovarii in Pregnancy: An Uncommon Cause of Hyperthyroidism. AB - A 28-year-old woman presented with weight loss and tiredness. Investigations revealed hyperthyroidism. She was commenced on treatment and later became pregnant. Her thyroid levels remained raised, and she later underwent an elective cesarean delivery and ovarian cystectomy. Only a partial cystectomy was achieved, and histopathology examination revealed struma ovarii. An isotope uptake scan ((123)I) including her pelvis revealed low uptake in the thyroid gland and an area of high uptake in her pelvis. The cyst was subsequently removed, and within days, her thyroid hormone levels dropped. This case illustrates the importance of considering uncommon causes of hyperthyroidism. PMID- 26018692 TI - Genetic Alterations in Colorectal Cancer Have Different Patterns on 18F-FDG PET/CT. AB - PURPOSE: The aim of this study was to understand the association between various genetic mutation and (18)F-FDG PET-related parameters in patients with colorectal cancer (CRC). METHODS: One hundred three CRC patients who had undergone preoperative PET/CTs were included in this study. Several PET/CT-related parameters, including SUV(max), and various thresholds of metabolic tumor volume, total lesion glycolysis, and PET/CT-based tumor width (TW) were measured. Using high-resolution melting methods for genetic mutation analysis, tumor- and PET/CT related parameters were correlated with various genetic alterations including TP53, KRAS, APC, BRAF, and PIK3CA. Mann-Whitney U test and logistic regression analysis were carried out for this analysis. RESULTS: Genetic alterations in TP53, KRAS, and APC were found in 41 (40%), 34 (33%), and 27 (26%) of tumors, respectively. PIK3CA and BRAF were exhibited by 5 and 4 of the patients with CRC. TP53 mutants exhibited higher SUV(max). The odds ratio was 1.28 (P = 0.04; 95% confidence interval, 1.01-1.61). Tumors with a mutated KRAS had an increased accumulation of FDG using a 40% threshold level for maximal uptake of TW (TW(40%)), whereas the odds ratio was 1.15 (P = 0.001; 95% confidence interval, 1.06-1.24). The accuracy of SUV(max) greater than 10 in predicting TP53 mutation was 60%, whereas that for TW(40%) for KRAS was 61%. CONCLUSIONS: Increased SUV(max) and TW(40%) were associated in CRC tumors with TP53 and KRAS mutations, respectively. Further studies are required because of the low predictive accuracy. PMID- 26018693 TI - 18F-FDG PET/CT for Early Postradiotherapy Assessment in Solitary Bone Plasmacytomas. AB - PURPOSE: The purpose of this study was to evaluate the performance and possible prognostic value of early (18)F-FDG PET/CT (FDG PET/CT) assessment after radiotherapy (RT) in patients with solitary bone plasmacytoma (SBP). METHODS: Twenty-one patients affected by SBP who underwent FDG PET/CT scan for early restaging (<=6 months) postradiotherapy assessment were selected from the PET databases of University College London Hospital of London and San Raffaele Hospital of Milan. Patients with no abnormal uptake were classified as having no pathologic uptake (NPU). A SUV(max) cutoff value of 4 was chosen to discriminate minimal residual uptake (MRU; SUV(max) <= 4) from pathologic uptake (PU, SUV(max) >4). Progression-free survival (PFS) rate was estimated using Kaplan-Meier curves and Cox regression analysis. RESULTS: In 10 of 21 patients restaged by FDG PET/CT, further previous baseline scan was available also at staging, and results showed positive findings at the level of all biopsy-proven disease areas.Considering MRU as PU, FDG PET/CT showed a sensitivity and specificity of 86% and 29%, respectively. Using SUV(max) >4 as the cutoff, sensitivity and specificity were 86% and 93%, respectively. Kaplan-Meier curves revealed a significant difference in PFS probability between patients classified as positive on FDG PET/CT using a cutoff of SUV(max) >4 (PU) and those classified as negative (NPU + MRU) (log-rank, Mantel-Cox, P = 0.009; chi(2) = 6.85). Cox regression analysis of PFS using SUV(max) >4 as cutoff revealed an interesting relation in prediction of progression (HR, 9.458). CONCLUSION: (18)F-FDG PET/CT for early restaging after RT in patients with SBP should be considered carefully in view of the lack of specificity of a low SUV(max) value. The good correlation between a high SUV(max) value and follow-up suggests a possible prognostic role for FDG PET/CT in disease progression at early restaging after RT. PMID- 26018694 TI - Incidental Neurofibroma on 18F-Fluorocholine PET/MR. AB - Neurofibromas are benign peripheral nerve sheath tumors. We described a unique case of recurrent prostate cancer with coexisting neurofibroma diagnosed on F fluorocholine PET/MRI. PMID- 26018695 TI - Radionuclide Salivagram and Gastroesophageal Reflux Scintigraphy in Pediatric Patients: Targeting Different Types of Pulmonary Aspiration. AB - OBJECTIVE: Both gastroesophageal reflux (GER) scintigraphy and radionuclide salivagram are commonly used in the detection of pulmonary aspiration in pediatric patients. This investigation is to compare the diagnostic value of these 2 imaging methods. METHODS: This retrospective study included 4186 pediatric patients (aged 1 week to 16 years; mean age, 28 months) who underwent a GER scintigraphy and/or radionuclide salivagram. Detection rate of pulmonary aspiration by the 2 imaging techniques was compared. RESULTS: The detection rate for pulmonary aspiration in patients undergoing both procedures was 1.9% (5 of 266) for GER scintigraphy and 22.2% (59 of 266) for radionuclide salivagram. Fifty-six of 59 patients with proven aspiration on radionuclide salivagram demonstrated no such findings on GER scintigraphy, whereas 2 of 5 patients with proven aspiration on GER scintigraphy demonstrated no such findings on radionuclide salivagram. In patients who underwent only 1 procedure (either GER scintigraphy or salivagram), the detection rate for pulmonary aspiration was 0.4% (15 of 3551) for GER scintigraphy and 20.3% (75 of 369) for radionuclide salivagram. CONCLUSIONS: Radionuclide salivagram showed a much higher detection rate for pulmonary aspiration compared with GER scintigraphy. However, this may be related to a significantly higher prevalence of antegrade versus retrograde aspiration in our study population. Our results also suggest that not all episodes of retrograde aspiration can be detected by a radionuclide salivagram, and the requested scan should be tailored to the type of suspected aspiration. PMID- 26018696 TI - FDG PET Imaging in Pneumocystis Pneumonia. AB - A 69-year-old woman with rheumatoid arthritis and pleuritis presented with dyspnea. On admission, she was afebrile and had an oxygen saturation of 97% on ambient air. Chest radiography and CT revealed only subtle ground-glass opacities. However, FDG PET revealed pathological uptake in both lungs. A diagnosis of Pneumocystis pneumonia was made based on a positive beta-D-glucan assay and polymerase chain reaction amplification of Pneumocystis jirovecii from the sputum. Posttreatment FDG PET revealed resolution of the previously noted uptake. This case illustrates that FDG PET can be used to diagnose Pneumocystis pneumonia when the CT findings are equivocal. PMID- 26018697 TI - 11C-Choline and 18F-FDG PET/CT in the Detection of Occult Prostate Cancer in the Context of a Paraneoplastic Syndrome. AB - In a 73-year-old man, an occult neoplasm was suspected after 2 consecutive deep venous thrombosis, the latter under anticoagulant therapy and previous axonopathy. After normal CT and MRI findings, a requested (18)F-FDG PET/CT showed a focal uptake in the prostate. Because FDG uptake in the prostate is infrequent, a (11)C-choline PET/CT was indicated revealing a focal uptake in the same location. No other abnormalities were detected in the rest of the body. A guided biopsy by ultrasonography was performed revealing a prostate carcinoma and inflammation in both prostatic lobes. PMID- 26018698 TI - BK Nephritis and Venous Thrombosis in Renal Transplant Recipient Detected by 111In Leukocyte Imaging. AB - Three months after deceased donor kidney transplant, a patient who presented with proteinuric renal dysfunction and fever of undetermined origin was found to have BK viruria by quantitative polymerase chain reaction analysis. An 111In leukocyte scan showed increased renal transplant uptake consistent with nephritis and linear uptake in the knee. Venous duplex ultrasound revealed acute occlusive thrombosis in the superficial right lesser saphenous vein in the area of increased radiolabeled leukocyte uptake. This 111In leukocyte scan performed for fever of undetermined origin demonstrated findings of BK nephritis in a renal transplant patient and associated acute venous thrombosis related to leukocyte colonization. PMID- 26018699 TI - Unusual Adrenal and Brain Metastases From Follicular Thyroid Carcinoma Revealed by 131I SPECT/CT. AB - The adrenal metastasis from differentiated thyroid carcinoma is uncommon. Metastatic involvement of both adrenal and brain in the same patient from differentiated thyroid carcinoma is rare. Here, we described an unusual case with iodine-avid lung, bone, adrenal, liver, and brain metastases from follicular thyroid carcinoma confirmed by 131I SPECT/CT. The utilization of SPECT/CT in thyroid cancer patients can detect the presence of metastases and also exclude potential false-positive lesions. Our case demonstrates that SPECT/CT is helpful in localizing and confirming metastatic lesions from differentiated thyroid carcinoma in rare and unusual sites. PMID- 26018700 TI - Incidental Detection of Shoulder Peripheral T-Cell Lymphoma During the Redistribution Phase of 201Tl Myocardial Perfusion Scintigraphy. AB - A 74-year-old woman underwent Tl myocardial perfusion scan for cardiac symptoms; increased radiotracer accumulation in the left shoulder was found in the redistribution images only, and the shoulder was normal in the stress images. Suspecting septic arthritis subsequent investigations were performed, and peripheral T-cell lymphoma was diagnosed. Attention should also be paid to extracardiac sites in interpreting redistribution images taken as late as 4 hours apart from stress images because some clinically pertinent ancillary findings may be found in redistribution images only. PMID- 26018701 TI - Incidental Finding of Urinary Bladder Retention on the 99mTc-Labeled Red Blood Cells Subcutaneous Radionuclide Venography. AB - We present a case with swelling of the lower extremities, shortness of breath, and hyponatremia. (99m)Tc-labeled red blood cells subcutaneous radionuclide venography was performed to rule out deep vein thrombosis. Disturbed iliac venous flow and a photopenic lesion were noted in the lower abdomen on the planar imaging. SPECT/CT imaging revealed a hypodense lesion in the lower abdomen. Distended urinary bladder and retention were impressed. After approximately 4000 mL of urine was drained, symptoms were dramatically relieved, and improvement of hyponatremia was also observed. PMID- 26018702 TI - Foreign Body Abscess Mimicking a Malignant Peripheral Nerve Sheath Tumor in a Patient With Neurofibromatosis Type 1. AB - We report a case of a 47-year-old man with neurofibromatosis type 1 presenting with a growing and painful lesion within the right thigh, suggesting a malignant peripheral nerve sheath tumor. MRI showed a T2-weighted hyperintense lesion with surrounding edema and contrast enhancement. (18)F-FDG PET/CT demonstrated inhomogeneously increased tracer uptake within the right thigh. Histopathologic evaluation revealed a foreign body with purulent fibroinflammatory reaction. (18)F-FDG PET/CT is a highly sensitive tool for detection of malignant transformation in neurofibromatosis type 1, but false-positive findings may be observed in benign lesions, for example, inflammatory processes. PMID- 26018703 TI - Lymphoscintigraphy in Differentiated Thyroid Cancer. AB - There is considerable variability in the surgical approach to differentiated thyroid cancer regarding the decision to explore and remove central or central and lateral compartment lymph nodes. Much as sentinel lymph node sampling has improved the decision to remove axillary nodes for breast cancer, vital dye and lymphoscintigraphy with lymph node sampling may direct the surgical approach to differentiated thyroid cancer. PMID- 26018704 TI - Time to Reject the Linear-No Threshold Hypothesis and Accept Thresholds and Hormesis: A Petition to the U.S. Nuclear Regulatory Commission. AB - On February 9, 2015, I submitted a petition to the U.S. Nuclear Regulatory Commission (NRC) to reject the linear-no threshold (LNT) hypothesis and ALARA as the bases for radiation safety regulation in the United States, using instead threshold and hormesis evidence. In this article, I will briefly review the history of LNT and its use by regulators, the lack of evidence supporting LNT, and the large body of evidence supporting thresholds and hormesis. Physician acceptance of cancer risk from low dose radiation based upon federal regulatory claims is unfortunate and needs to be reevaluated. This is dangerous to patients and impedes good medical care. A link to my petition is available: http://radiationeffects.org/wp-content/uploads/2015/03/Hormesis-Petition-to-NRC 02-09-15.pdf, and support by individual physicians once the public comment period begins would be extremely important. PMID- 26018705 TI - Epiglottic Squamous Cell Carcinoma Showing Unexpected 18F-FDOPA Uptake on PET/CT Investigation. AB - We report the unexpected findings of 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT performed in a patient with a history of ileal carcinoid. A focally increased 18F-FDOPA uptake was detected in the left side of the epiglottis corresponding to a laryngeal squamous cell carcinoma. Interestingly, uptake of 3 O-methyl-6-18F-fluoro-L-dihydroxyphenylalanine, a metabolite of 18F-FDOPA, has been previously reported in both squamous cell carcinoma cell lines and the corresponding mouse tumor xenograft models. Although 18F-FDOPA is mainly used in patients with neuroendocrine tumors, 18F-FDOPA is not a neuroendocrine tumor specific radiotracer. PMID- 26018706 TI - Liver Trapping of (99m)Tc Macroaggregated Albumin During Ventilation/Perfusion Scintigraphy in a Patient With Superior Vena Cava Stenosis as Demonstrated by SPECT/CT. AB - A 50-year-old woman presented to our institution with a 1-day history of right posterior thoracic pain and dyspnea. She had a previous history of conservative resection of a high-grade basal-like infiltrating ductal carcinoma of the right breast 2 years before, subsequently treated by chemotherapy and radiotherapy. A ventilation and perfusion (VQ) scintigraphy performed for suspected pulmonary embolism showed an abnormal deposition of (99m)Tc macroaggregated albumin ((99m)Tc-MAA) in the left lobe of the liver. This unusual finding prompted additional imaging that demonstrated a superior vena cava stenosis. PMID- 26018707 TI - Herpes Zoster Mimicking Breast Cancer With Axillary Lymph Node Metastasis on PET/CT. AB - Herpes zoster is a reactivated varicella-zoster virus infection and demonstrates typical dermatomal distribution. We herein describe a case of a 41-year-old woman with a history of ovarian cancer. Intense hot uptake in the left breast and enlarged ipsilateral axillary lymph nodes were noted on 18F-FDG PET/CT for adjuvant chemotherapy response evaluation. Blinded to the patient's clinical information, these lesions were interpreted as incidental breast cancer with axillary nodal metastasis. However, clinically she presented with vesicles along the T4 dermatome and palpable enlarged nodes in the left axilla. On 3-month follow-up PET/CT after antiviral treatment, these intense hot uptake areas were no longer visualized. PMID- 26018708 TI - Establish New Formulas for the Calculation of Renal Depth in Both Children and Adults. AB - OBJECTIVE: This study was performed to develop a new formula to estimate the renal depth in both children and adults; then compare the new formula with previously published formulas. METHODS: Renal depth and total thickness (T, cm) of the body at the level of the kidneys were measured by CT in 113 children and 246 adults. Their sex, age, height (H, cm), and weight (W, kg) were recorded. Multiple stepwise linear regression analysis were conducted, using data from children and adults together. The 359 cases were divided into 2 random groups, of which, the first group was used to derive a regressive formula, and the second was used to verify the formula and compare the formula with previously published formulas in different groups. RESULTS: Multiple stepwise linear regression analysis showed that the important variable in estimating the depth of each kidney was the ratio of body weight (W, kg) to body height (H, cm) and the total thickness (T, cm) of the body at the level of the kidneys. The new formula was as follows: for right renal depth (cm) = 0.22 * T + 7.714 * W/H-0.331 (r = 0.95), and for left renal depth (cm) = 0.238 * T + 6.553 * W/H-0.618 (r = 0.95). It is better than the other four formulas in different groups, especially in children and W/H <= 0.30 (in adults) groups. CONCLUSIONS: We first introduced T into renal depth estimation formula and established the new formula. It has a better performance than the other four formulas in different groups. The new formula provided reliable and accurate renal depth and may contribute to improving the methods used to estimate renal function from radionuclide renography. PMID- 26018710 TI - Utility of (99m)Tc RBC Scintigraphy in Diagnosing Parotid Venous Malformations. AB - Venous malformations of the parotid glands are uncommon and can be difficult to confirm on routine anatomical imaging alone because of overlap of imaging features with other more common parotid lesions. (99m)Tc RBC scans combined with SPECT/CT offer a noninvasive way to diagnose parotid venous malformations without the need for biopsy. Combined with anatomical findings of phleboliths (when present), the diagnosis can be reliably determined. We present a case where MRI and biopsy were inconclusive, but the SPECT/CT was used to confirm the suspicion of a benign venous malformation. PMID- 26018709 TI - Ectopic ACTH and CRH Co-secreting Tumor Localized by 68Ga-DOTA-TATE PET/CT. AB - Diagnosis of ectopic adrenocorticotropic hormone (ACTH) and corticotropin releasing hormone (CRH) co-secreting tumors causing Cushing syndrome (CS) is challenging because these tumors are rare and their diagnosis is frequently confused with Cushing disease (CD), caused by the effect of CRH on the pituitary. We report a case of a 21-year-old male patient who was referred to our institution with persistent hypercortisolemia and CS after undergoing unnecessary transsphenoidal surgery (TSS). 68Ga-DOTA-TATE PET/CT revealed increased tracer uptake in the thymus, which was histologically proven to be a neuroendocrine tumor (NET) that stained positive for ACTH and CRH. Imaging with 18F-FDG PET/CT was not diagnostic. PMID- 26018711 TI - Sodium 18F-Fluoride Bone Scintigraphy in Deep Ocean Diver. AB - Sodium 18F-fluoride (NaF) is a diagnostic marker for new bone formation in bone scintigraphy that was approved by US FDA in 1972 but discontinued in 1984. We report a case of a US naval officer who spent time living and working in an oceanic lab, 205 feet below the surface. Plain skeletal films of femurs 4 years later demonstrate bilateral bone infarcts. Corresponding sodium 18F-fluoride bone scintigraphy demonstrates low-normal to decreased tracer activity. This rectilinear scan image is of historical interest. Other bone scintigraphic radiotracers used in the past and present will be briefly discussed. PMID- 26018712 TI - 68Ga-DOTATATE PET/MR Imaging of Urinary Bladder Paraganglioma. AB - Paragangliomas of the urinary bladder are very rare. They are extra-adrenal autonomic nervous system tumors. This report presents a case of a 13-year-old boy with urinary bladder paraganglioma and the role of somatostatin receptor imaging with simultaneous positron emission tomography magnetic resonance (PET/MR). We have also described appearances of iodine-123 metaiodobenzylguanidine ((123)I MIBG) single photon emission computed tomography (SPECT/CT) in comparison to somatostatin receptor imaging. PMID- 26018713 TI - Uptake of 99mTc-DTPA in Bone Metastases from Renal Cancer. AB - A 67-year-old man with left renal cell carcinoma underwent Tc-DTPA renal scintigraphy to evaluate the kidney function. The images incidentally identified a large focus of abnormal activity in the right pelvic region, which corresponded to the site of metastasis in the right ilium revealed on CT image. PMID- 26018714 TI - Is Occipital Cortex a Valid Reference Region in 123I-FP-CIT SPECT Imaging? PMID- 26018715 TI - Talc Pleurodesis With Intense 18F-FDG Activity But No 68Ga-DOTA-TATE Activity on PET/CT. AB - Talc pleurodesis (TP) is a technique, widely employed in the management of patients with persistent pleural effusions or pneumothoraces not amenable to other treatment options. It is well documented that talc deposits produce areas of highly increased F-FDG uptake, because of talc-induced inflammation. We present a case of a patient with history of TP who was evaluated with both F-FDG and Ga-DOTA-TATE. The hypermetabolic area seen on F-FDG-PET-CT in the region of talc placement showed no uptake by Ga-DOTA-TATE, suggesting the potential role of Ga-DOTA-TATE-PET-CT in elucidating F-FDG-postitive lesions in patients with history of both neuroendocrine malignancy and TP. PMID- 26018716 TI - Solitary Retroperitoneal Metastasis as the Initial Site of the Relapse of Osteosarcoma Revealed by FDG PET/CT. AB - Adjuvant and neoadjuvant chemotherapy has altered the metastatic pattern of osteosarcoma. Overwhelming majority of the metastases from osteosarcoma are to the lungs and to the bones. Uncommon metastases to other sites can occur but usually accompany pulmonary and skeletal metastases. Here, we describe an asymptotic 14-year-old boy with solitary retroperitoneal metastasis as the initial relapse of osteosarcoma revealed by FDG PET/CT. PMID- 26018717 TI - FDG PET/CT Findings of Multifocal Epithelioid Hemangioendotheliomas of the Bones. AB - Epithelioid hemangioendothelioma of the bones is very rare. We report a 78-year old patient suffering from epithelioid hemangioendothelioma of multiple pelvic bones and the right femur. FDG PET/CT scan showed intense activity in mainly lytic lesions of these bones. PMID- 26018718 TI - Metabolic Skeletal Superscan on 18F-FDG PET/CT in a Case of Acute Lymphoblastic Leukemia. AB - Superscan is a well-known finding described in skeletal scintigraphy characterized by intense radiotracer uptake in axial skeleton and decreased uptake in soft tissues and kidneys. Metabolic skeletal superscan has also been described in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in various conditions. We describe here a case of 12-year-old boy who presented with a scalp swelling, progressive pallor, easy fatigability, poor appetite, and fever for 6 months. The initial diagnosis was inconclusive. 18F-FDG PET/CT revealed metabolic skeletal superscan and the final histopathological diagnosis was acute lymphoblastic leukemia. PMID- 26018719 TI - The Effect of Electromagnetic Field Generated by a Mobile Phone on the Performance of a SPECT Scanner: A Quantitative Study. AB - PURPOSE: The aim of the current attempt was quantitative investigation of the electromagnetic interference (EMI) of a mobile phone with the function of a SPECT gamma camera during data acquisition. MATERIALS AND METHODS: We tested the effect of a mobile phone, in both ringing mode and standby mode, on one SPECT gamma camera during scanning a cylindrical phantom containing 5.4 mCi (99m)Tc. The experiment was performed for different distances of 10, 12, 14, 16, 18, 20, 25, and 30 cm between mobile phone and head of the scanner, and for different head angles of 0, 30, 60, 90, 120, 150, and 180 degrees. A RF-EMF meter measured strength of electromagnetic field throughout the study. Statistically significant decrease in count number was considered to be electromagnetic interference. RESULTS: There was significant reduction in the recorded counts during ringing of the mobile phone in all studied distances. For gamma camera, fixed at a distance, there was no uniform pattern of reduction of the counts at different angles between two operation modes of the mobile phone. CONCLUSIONS: A mobile phone, at close distance, can be a sensible source of electromagnetic field, disturbing the normal function of a gamma camera. PMID- 26018720 TI - Pituitary 18F-FDG Uptake Correlates With Serum TSH Levels in Subjects With Diffuse Thyroid 18F-FDG Uptake. AB - PURPOSE: This study was to evaluate the relationship among FDG uptake in the pituitary gland (FDGp), FDG uptake in the thyroid gland (FDGt), and serum thyroid stimulating hormone (TSH) levels in patients with diffuse FDGt incidentally noted on positron emission tomography/computed tomography (PET/CT). PATIENTS AND METHODS: We retrospectively reviewed FDG PET/CT scans of 2,945 subjects who underwent health screening. Of these, 44 subjects had diffuse FDGt and available thyroid function tests. FDGt and FDGp were correlated with serum TSH. FDGp in 44 paired control subjects without FDGt and 15 thyroid cancer patients undergoing thyroid hormone withdrawal were additionally measured, and compared with FDGp in the 44 subjects with FDGt divided into 3 groups according to serum TSH levels. RESULTS: In the 44 subjects, there was a strong correlation found between FDGp and TSH (P < 0.001, r = 0.618). As well, there were statistically significant differences in FDGp between the low, normal, and high TSH groups (P < 0.001). FDGp in the paired control subjects was not different from that in the normal TSH group (P = 0.384), and FDGp in the TSH-stimulated thyroid cancer patients was not different from that in the high TSH group (P = 0.463). CONCLUSION: We found a strong positive correlation between pituitary FDG uptake and serum TSH. Pituitary FDG uptake seems to hold an important clue to the functional status of the thyroid in subjects with diffuse thyroid FDG uptake. Furthermore, physiologic FDG uptake in the pituitary gland caused by hypothyroidism should not be confused with pathologic conditions such as macroadenoma or metastases. PMID- 26018721 TI - Cyclic Direct Radionuclide Cystography in the Diagnosis and Characterization of Vesicoureteral Reflux in Children and Adults. AB - PURPOSE: To investigate the influence of cyclic direct radionuclide cystography (RNC) on the diagnosis of vesicoureteral reflux (VUR) in children and adults. PATIENTS AND METHODS: A total of 362 examinations were performed in patients with a mean age of 15.8 +/- 17.2 years (2 months to 76.4 years, 89.5% female). The examinations were divided into 3 groups of age: A, younger than 5 years; B, 5 years and younger than 14 years; and C, older than 14 years. Repeated cycles of bladder filling without removal of the catheter were performed. RESULTS: VUR was diagnosed in 21% of patients based on the first cycle, 5.5% in the second cycle, and 2.5% only in the third cycle. Most examinations showing VUR corresponded to grade II. Reflux occurred in only the filling phase in 10%, only the voiding phase in 27%, and both phases in 63% of patients. There was a higher incidence of reflux in groups A and B than group C after the first cycle. The second cycle was equally effective in diagnosing VUR in all 3 groups. In group A, the third cycle was more effective compared to the other groups. CONCLUSIONS: Performing a second and a third cycle in RNC yielded an additional VUR diagnosis of 35.7%, as compared to performing only 1 cycle. The second cycle showed efficacy in all the groups, whereas the third cycle diagnosed more VUR only in group A. These results confirmed the importance of performing additional cycles in RNC for VUR diagnosis, both in children and adults. PMID- 26018722 TI - 18F-FDG PET/CT Findings in a Splenic Lymphangioma. AB - A 16-year-old girl with abdominal pain for 3 years underwent FDG PET/CT scan for evaluating identifiable origin. The images showed multifocal, subcapsular thin walled low-attenuation masses on CT and focal, slight increased 18F-FDG uptake on PET with an SUV(max) of 3.0. Based on the findings, malignancy cannot be excluded. Then, pathologic examination was performed, and it was identified to be splenic lymphangioma. We herein presented the FDG PET/CT findings of this splenic lymphangioma, which is a rare benign vascular tumor and commonly caused by congenital malformation of the lymphatic vessels. PMID- 26018723 TI - Diet Quality of Young Adults Enrolling in TXT2BFiT, a Mobile Phone-Based Healthy Lifestyle Intervention. AB - BACKGROUND: Young adulthood is associated with poor dietary habits and vulnerability to weight gain. Population studies have revealed that inadequate fruit and vegetable intake, excessive sugar-sweetened beverages, and frequent takeaway food consumption are dietary habits requiring intervention. OBJECTIVE: The aim was to examine the dietary patterns and diet quality of overweight young adults on enrollment into a mobile phone-based healthy lifestyle (mHealth) intervention, TXT2BFiT. METHODS: Baseline diets were analyzed using the online Dietary Questionnaire for Epidemiological Studies version 2. The Healthy Eating Index for Australians (HEIFA) based on the 2013 Dietary Guidelines, was used to rate individual diets according to intake of core foods and deleterious nutrients including sugar, sodium, saturated fat, and alcohol. Findings were compared with the 2011 Australian National Nutrition and Physical Activity Survey (NNPAS). Gender differences were assessed with t tests and chi-square tests. ANOVA models were used to determine linear trends of core and noncore food intake and nutrients across quartiles of HEIFA scores. Associations between HEIFA score, sugar-sweetened beverages, and takeaway food consumption were assessed using linear regression analysis. RESULTS: Diets of 230 participants (females: n=141; males: n=89; body mass index: mean 27.2, SD 2.5 kg/m(2)) were analyzed. The mean diet quality score was 45.4 (SD 8.8, range 21.7-77.0) out of 100 points, with no significant difference between genders. Compared with the NNPAS data for adults aged 19-30 years, this cohort had a lower intake of some core foods and higher intake of alcohol and saturated fat. Better quality diets were associated with higher intakes of fruits, vegetables, and wholegrains (P<.001). Takeaway food (P=.01) and sugar-sweetened beverage consumption (P<.001) were negatively associated with diet quality. CONCLUSIONS: Overweight young adults had poorer diets compared with the reference Australian population within the same age group. This study reinforces that gender-specific interventions are required, as is the current practice in TXT2BFiT, with a need to reduce sodium and alcohol intake in males and sugar intake in females. It also confirms the need to increase fruit and vegetable intake and reduce takeaway food consumption in this population, with additional focus on saturated fat and wholegrain intake. PMID- 26018724 TI - [Masquelet technique for the treatment of large dia- and metaphyseal bone defects]. AB - OBJECTIVE: Treatment of large dia- and metaphyseal bone defects (> 3 cm) with two surgical interventions with an interval of 4-8 weeks. INDICATIONS: Dia- and metaphyseal bone defects predominantly of the lower extremity. CONTRAINDICATIONS: Intraarticular bone defects, persisting bone infection or osteomyelitis, insufficient soft tissue coverage in the region of the bone defect, osteoporosis. SURGICAL TECHNIQUE: First surgical intervention: thorough bone debridement and soft tissue coverage, implantation of a cement spacer into the bone defect for the induction of a synovial foreign-body membrane, internal or external fixation. Second surgical intervention: removal of the cement spacer and filling of the bone defect with autologous cancellous bone graft, optionally internal fixation after initial external fixation. POSTOPERATIVE MANAGEMENT: Partial to full weight bearing after the first surgical intervention depending on pain. Partial weight bearing (max. 15 kg) after the second surgical intervention, until radiological signs of a remodeling of the regenerate bone occur. Usually no implant removal. RESULTS: A total of 6 patients (4 men, 2 women) aged 15-66 years with average bone defects of 7 cm (range 4-10 cm) were treated using the Masquelet technique. There were 2 aseptic femoral nonunions and 4 tibial nonunions (2 septic and 2 aseptic nonunions). One case was a periprosthetic tibial bone defect. Bone stabilization after debridement was performed using ring fixators on the tibia and an intramedullary nail and a locking plate on the femur, respectively. The second surgical intervention was performed after 6-9 weeks. In 3 of the 4 tibial cases, internal fixation was performed during this intervention. The iliac crest and the RIA (reamer-irrigator-aspirator) technique were used for cancellous bone grafting. Amputation after breakage of the plate was necessary in the patient with the periprosthetic bone defect. Nonunion at the docking site required cancellous bone grafting in 1 patient. All 5 patients were able to perform full weight-bearing without pain after 6 months. The Ilizarov fixator was removed 5 months after the second surgical intervention in a 15-year-old patient. None of the other implants were removed. PMID- 26018725 TI - [Percutaneous screw fixation of non- or minimally displaced scaphoid fractures]. AB - OBJECTIVE: Providing stability and reduction of the period of immobilisation of non- or minimally displaced scaphoid fractures using a minimally invasive technique. INDICATIONS: Scaphoid fractures of the types A2, B1 and B2 (Herbert's classification) with no or minimal displacement, along with a patient's request for early functional treatment. CONTRAINDICATIONS: Relative contraindications: significant dislocation of the fracture, scaphoid cyst or a too proximal fracture, concomitant fractures of the wrist. Absolute contraindications: pseudoarthrosis, luxation fractures. SURGICAL TECHNIQUE: Minimally invasive percutaneous screw fixation using a double threaded screw. POSTOPERATIVE MANAGEMENT: Postoperative immobilisation in a plaster cast with a thumb inlay for 1-3 weeks until swelling and pain subside. Followed by active physiotherapeutic exercise, however no pressure on the hand for 6 weeks after surgery. RESULTS: Seventy patients with a non- or a minimally displaced scaphoid fracture were treated between 2005 and 2011. We used percutaneous screw fixation as the therapy technique. A total of 57 patients (81%) presented for follow-up. Four patients (5.7%) had an unhealed fracture 6 months postsurgery confirmed. One patient needed revision surgery because of a screw that was too long. None of the patients had a postsurgical infection, haematoma or a complex regional pain syndrome. Smoking and putting pressure on the hand too early have been identified as possible risk factors for the unhealed fractures. PMID- 26018726 TI - The influence of time interval between preoperative radiation and surgical resection on the development of wound healing complications in extremity soft tissue sarcoma. AB - OBJECTIVE: The aim of this study was to determine the relationship of the time interval between completion of preoperative radiation therapy (RT) and surgical resection on wound complications (WCs) in extremity soft tissue sarcoma (STS). METHODS: Overall, 798 extremity STS patients were managed with preoperative RT and surgery from 1989 to 2013. WCs were defined as requiring secondary operations/invasive procedures for wound care, use of vacuum-assisted closure, prolonged dressing changes, or infection within 120 days of surgery. RESULTS: Mean tumor size was 8.8 cm. A total of 743 (93 %) tumors were primary presentations, 565 (71 %) patients had lower extremity tumors, and 238 patients (30 %) had a prior unplanned excision. Of 242 patients (30 %) who developed a WC, 206 (37 %) had lower extremity tumors and 36 (15 %) had upper extremity tumors. Mean time from RT completion to surgery was 41.3 (range 4-470) days; 42.0 (range 4-470) days for upper extremity cases, and 41.1 (range 4-109) days for lower extremity cases. Similarly, mean time interval for patients who developed a WC was 40.9 (range 4-100) days, and 41.5 (range 4-470) days for those who did not develop a WC (p = 0.69). Thirty-nine cases (5 %) had surgery within 3 weeks of RT; 15 (38 %) patients developed WCs versus 227 (30 %) patients who had their tumors excised after 3 weeks (p = 0.28). One hundred and twenty-nine (16 %) patients had surgery within 4 weeks, and 39 (30 %) patients developed WCs versus 203 (30 %) patients who had their tumors excised after 4 weeks (p = 1.0). A trend towards a higher rate of WCs was seen for those patients who had surgery after 6 weeks (28 % prior vs. 34 % after; p = 0.08). There was no difference in WCs with intensity-modulated RT (IMRT) versus non-IMRT cases (p = 0.6). CONCLUSION: The time interval between preoperative RT and surgical excision in extremity STS had minimal influence on the development of WCs. Four- or 5-week intervals showed equivalent complication rates between the two groups, suggesting an optimal interval to reduce potential WCs. PMID- 26018727 TI - Retroperitoneal sarcoma (RPS) high risk gross tumor volume boost (HR GTV boost) contour delineation agreement among NRG sarcoma radiation and surgical oncologists. AB - PURPOSE: Curative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering "boost doses" of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams. METHODS: Radiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. RESULTS: HRGTV boost volume contour agreement between the seven teams was "substantial" or "moderate" for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection. CONCLUSIONS: Agreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for "individualized" target delineation on the basis of areas deemed at risk and planned resection. PMID- 26018728 TI - Chondrogenic Differentiation of Human Mesenchymal Stem Cells Results in Substantial Changes of Ecto-Nucleotides Metabolism. AB - Mesenchymal stem cells (MSCs) are population of adult stem cells and attractive candidates for cartilage repair due to their chondrogenic potential. Purinergic compounds (purinergic receptors and ecto-enzymes metabolizing nucleotides), together with nucleotides/nucleosides present in the extracellular environment, are known to play a key role in controlling the stem cells biological potential to proliferate and differentiate. Despite the available literature pointing to the importance of purinergic signaling in controlling the fate of MSCs, the research results linking nucleotides and ecto-nucleotidases with MSCs chondrogenic differentiation are indigent. Therefore, the aim of presented study was the characterization of the ecto-nucleotides hydrolysis profile and ecto enzymes expression in human umbilical cord-derived MSCs and chondrogenically induced MSCs. We described substantial changes of ecto-nucleotides metabolism and ecto-enzymes expression profiles resulting from chondrogenic differentiation of human umbilical cord-derived MSCs. The increased rate of ADP hydrolysis, measured by ecto-nucleotidases activity, plays a pivotal role in the regulation of cartilage formation and resorption. Despite the increased level of NTPDase1 and NTPDase3 mRNA expression in chondrogenically induced MSCs, their activity toward ATP remains quite low. Supported by the literature data, we hypothesize that structure-function relationships in chondrogenic lineage dictate the direction of nucleotides metabolism. In early neocartilage tissue, the beneficial role of ATP in improving biomechanical properties of cartilage does not necessitate the high rate of enzymatic ATP degradation. PMID- 26018730 TI - Two-dimensional charge disproportionation of the unusual high valence state Fe(4+) in a layered double perovskite. AB - The crystal and magnetic structures of charge-disproportionated Ca2FeMnO6 were analyzed by neutron powder diffraction. Ca2FeMnO6 is a layered double perovskite oxide with a two-dimensional arrangement of Mn(4+) and unusual high valence Fe(4+) at room temperature. When cooled, the compound shows charge disproportionation followed by magnetic transition. Around 200 K, the Fe(4+) shows the charge disproportionation to Fe(3+) and Fe(5+), which are ordered in a checkerboard pattern in the two-dimensional FeO6 octahedral layers. The magnetic transition occurs at 95 K, which is much lower than the charge disproportionation temperature. The magnetic structure is commensurate but noncollinear, and the antiferromagnetic coupling of Fe(3+) and Fe(5+) spins in the FeO6 octahedral layers gives the ferrimagnetic moments. The unique magnetic structure is described as a result of two-dimensional localization of the ligand holes with effective spins. PMID- 26018729 TI - Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic-neural development. AB - Craniofacial malformations are common congenital defects caused by failed midline inductive signals. These midline defects are associated with exposure of the fetus to exogenous teratogens and with inborn genetic errors such as those found in Down, Patau, Edwards' and Smith-Lemli-Opitz syndromes. Yet, there are no studies that analyze contributions of synchronous neurocranial and neural development in these disorders. Here we present the first in-depth analysis of malformations of the basicranium of a holoprosencephalic (HPE) trisomy 18 (T18; Edwards' syndrome) fetus with synophthalmic cyclopia and alobar HPE. With a combination of traditional gross dissection and state-of-the-art computed tomography, we demonstrate the deleterious effects of T18 caused by a translocation at 18p11.31. Bony features included a single developmentally unseparated frontal bone, and complete dual absence of the anterior cranial fossa and ethmoid bone. From a superior view with the calvarium plates removed, there was direct visual access to the orbital foramen and hard palate. Both the eyes and the pituitary gland, normally protected by bony structures, were exposed in the cranial cavity and in direct contact with the brain. The middle cranial fossa was shifted anteriorly, and foramina were either missing or displaced to an abnormal location due to the absence or misplacement of its respective cranial nerve (CN). When CN development was conserved in its induction and placement, the respective foramen developed in its normal location albeit with abnormal gross anatomical features, as seen in the facial nerve (CNVII) and the internal acoustic meatus. More anteriorly localized CNs and their foramina were absent or heavily disrupted compared with posterior ones. The severe malformations exhibited in the cranial fossae, orbital region, pituitary gland and sella turcica highlight the crucial involvement of transcription factors such as TGIF, which is located on chromosome 18 and contributes to neural patterning, in the proper development of neural and cranial structures. Our study of a T18 specimen emphasizes the intricate interplay between bone and brain development in midline craniofacial abnormalities in general. PMID- 26018731 TI - RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy. AB - Although RIPK1 (receptor [TNFRSF]-interacting protein kinase 1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in cell response to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIPK1 functions as an important prosurvival mechanism in melanoma cells undergoing pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG) through activation of autophagy. While treatment with TM or TG upregulated RIPK1 and triggered autophagy in melanoma cells, knockdown of RIPK1 inhibited autophagy and rendered the cells sensitive to killing by TM or TG, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIPK1 enhanced induction of autophagy and conferred resistance of melanoma cells to TM- or TG induced cell death. Activation of MAPK8/JNK1 or MAPK9/JNK2, which phosphorylated BCL2L11/BIM leading to its dissociation from BECN1/Beclin 1, was involved in TM- or TG-induced, RIPK1-mediated activation of autophagy; whereas, activation of the transcription factor HSF1 (heat shock factor protein 1) downstream of the ERN1/IRE1-XBP1 axis of the unfolded protein response was responsible for the increase in RIPK1 in melanoma cells undergoing pharmacological ER stress. Collectively, these results identify upregulation of RIPK1 as an important resistance mechanism of melanoma cells to TM- or TG-induced ER stress by protecting against cell death through activation of autophagy, and suggest that targeting the autophagy-activating mechanism of RIPK1 may be a useful strategy to enhance sensitivity of melanoma cells to therapeutic agents that induce ER stress. PMID- 26018732 TI - Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma. AB - Survivin is ubiquitously expressed in patients with head neck squamous cell carcinoma (HNSCC) and is associated with poor survival and chemotherapy resistance. Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. However, the curative effects and underlying mechanisms of YM155 in HNSCC remain unclear. This study showed that survivin overexpression positively correlated with p-S6, p-Rb and LAMP2 but negatively correlated with the autophagic marker LC3 in human HNSCC tissues. In vitro studies revealed that YM155 triggered apoptosis of HNSCC cells in mitochondria and death receptor dependent manner. The treatment also significantly enhanced autophagy by upregulating Beclin1, which led to cell death. YM155 not only downregulated the expression of survivin but also remarkably suppressed the activation of the mTOR signaling pathway in vitro and in vivo. YM155 displayed potent antitumor activities in both CAL27 xenograft and transgenic HNSCC mice models by delaying tumor onset and suppressing tumor growth. Furthermore, YM155 combined with docetaxel promoted tumor regression better than either treatment alone without causing considerable body weight loss in the HNSCC xenograft models. Overall, targeting survivin by YM155 can benefit HNSCC therapy by increasing apoptotic and autophagic cell death, and suppressing prosurvival pathways. PMID- 26018733 TI - Co-receptors are dispensable for tethering receptor-mediated phagocytosis of apoptotic cells. AB - During efferocytosis, phagocytic cells recognize dying cells by receptors binding to ligands specifically exposed on apoptotic cells. Multiple phagocytic receptors and some of their signaling pathways have been identified. However, the downstream pathways of tethering receptors that secure apoptotic cells remain elusive. It is generally assumed that tethering receptors induce signaling to mediate engulfment via interacting with co-receptors or other engulfment receptors located nearby. However, it is poorly understood whether co-receptors for tethering receptors exist during efferocytosis, and, if they do, whether they are indispensable for this process. Here, we address this issue using glycophosphatidylinositol (GPI)-anchored annexin A5 (Anxa5-GPI), an artificial tethering receptor without a putative co-receptor. Phagocytes expressing Anxa5 GPI exhibited enhanced binding of apoptotic cells, resulting in promoted ingestion of apoptotic cells in a phosphatidylserine-dependent manner. Anxa5-GPI induced phagocytosis of apoptotic cells relied on the known cytoskeletal engulfment machinery but partially depended on the Elmo-Dock-Rac module or the integrin pathway. In addition, Anxa5-GPI-mediated efferocytosis provoked anti inflammatory responses. Taken together, our work suggests that co-receptors are dispensable for tethering receptor-induced efferocytosis and that tethering receptors mediate the engulfment of apoptotic cells through multiple engulfment signaling pathways. PMID- 26018734 TI - CD59 signaling and membrane pores drive Syk-dependent erythrocyte necroptosis. AB - Mature erythrocytes (red blood cells (RBCs)) undergo the programmed cell death (PCD) pathway of necroptosis in response to bacterial pore-forming toxins (PFTs) that target human CD59 (hCD59) but not hCD59-independent PFTs. Here, we investigate the biochemical mechanism of RBC necroptosis with a focus on the mechanism of induction and the minimal requirements for such RBC death. Binding or crosslinking of the hCD59 receptor led to Syk-dependent induction of vesiculated morphology (echinocytes) that was associated with phosphorylation of Band 3 and was required for Fas ligand (FasL) release. FasL-dependent phosphorylation of receptor-interacting protein kinase 1 (RIP1) in combination with plasma membrane pore formation was required for execution of RBC necroptosis. RIP1 phosphorylation led to the phosphorylation of RIP3, which was also critical for RBC necroptosis. Notably, RBC necroptosis was mediated by FasL and not by other candidate inducers, including tumor necrosis factor alpha (TNF alpha) and TNF-related apoptosis-inducing ligand (TRAIL). Other types of RBC damage, such as eryptotic damage, failed to induce necroptosis when combined with hCD59 crosslinking. This work sheds light on the requirements for this recently discovered PCD in RBCs and provides a clear picture of the biochemical mechanism of induction of RBC necroptosis. PMID- 26018735 TI - Cross talk between EBV and telomerase: the role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus. AB - Epstein-Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose dependent manner. We also found that NF-kappaB pathway is involved in TERT induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies. PMID- 26018736 TI - Older adults' influence in family care: how do daughters and aging parents navigate differences in care goals? AB - OBJECTIVE: This study seeks to address how older adults influence their daily care when their preferences conflict with those of their adult daughter caregivers. METHOD: Using a sample of 10 dyads (N = 20) of an older adult and adult daughter, we utilize content analysis strategies to analyze in-depth, semi structured interview data with QSR NVIVO to investigate how older adults influence their care, how daughters respond to such efforts of influence, and how dyads navigate differences in care goals. RESULTS: When there is agreement in goals, dyads report tasks going well and both individuals' requests are honored. When there are differences in care goals, daughters most frequently reason with their older parents, while parents walk away or 'let go' of their requests. Daughters report making decisions for their parents for health or safety-related needs. However, all dyads discuss differences in care goals, whereby parents are perceived as insisting, resisting, or persisting in care. CONCLUSION: Findings illustrate complex patterns of responses by families when navigating differences in daily care goals that carry important implications for research and the development of dyadic-based family interventions. PMID- 26018737 TI - Erosive rhinitis resembling granulomatosis with polyangiitis (Wegener's granulomatosis) in an Anatolian shepherd dog. AB - Granulomatosis with polyangiitis (Wegener's granulomatosis) is one of the idiopathicimmune-mediated small-vessel vasculitides described in humans which are characterised by the presence of circulating antineutrophil cytoplasmic antibodies. It most commonly involves capillaries, venules and arterioles of the ear, nose and throat, lungs and glomeruli. A case of destructive haemopurulent rhinitis associated with relapsing periods of pyrexia, lethargy and stiffness as well as generalised pulmonary infiltrates in a young Anatolian shepherd dog is presented that closely resembles granulomatosis with polyangiitis (GPA) as reported in humans. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) were detected in the dog's serum. Signs resolved promptly and completely once immunosuppressive doses of prednisone were administered, and have not recurred. This is the first report onthe use of pANCA to investigate rhinitis in dogs. It is also, to the authors' knowledge, the first description of a relapsing haemopurulent lytic rhinitis in this species. The concurrent manifestations of erosive haemopurulent rhinitis, ground-glass opacities on pulmonary computed tomography, pyrexia and listlessness resemble GPA as described in humans. PMID- 26018739 TI - Morphology-Control Synthesis of a Core-Shell Structured NiCu Alloy with Tunable Electromagnetic-Wave Absorption Capabilities. AB - In this work, dendritelike and rodlike NiCu alloys were prepared by a one-pot hydrothermal process at various reaction temperatures (120, 140, and 160 degrees C). The structure and morphology were analyzed by scanning electron microscopy, energy-dispersive spectrometry, X-ray diffraction, and transmission electron microscopy, which that demonstrate NiCu alloys have core-shell heterostructures with Ni as the shell and Cu as the core. The formation mechanism of the core shell structures was also discussed. The uniform and perfect dendritelike NiCu alloy obtained at 140 degrees C shows outstanding electromagnetic-wave absorption properties. The lowest reflection loss (RL) of -31.13 dB was observed at 14.3 GHz, and the effective absorption (below -10 dB, 90% attenuation) bandwidth can be adjusted between 4.4 and 18 GHz with a thin absorber thickness in the range of 1.2-4.0 mm. The outstanding electromagnetic-wave-absorbing properties are ascribed to space-charge polarization arising from the heterogeneous structure of the NiCu alloy, interfacial polarization between the alloy and paraffin, and continuous micronetworks and vibrating microcurrent dissipation originating from the uniform and perfect dendritelike shape of NiCu prepared at 140 degrees C. PMID- 26018738 TI - Impaired decision making and delayed memory are related with anxiety and depressive symptoms in acromegaly. AB - Evaluation of cognitive function in acromegaly has revealed contradictory findings; some studies report normal cognition in patients with long-term cured acromegaly, while others show attention and memory deficits. Moreover, the presence of affective disorders in these patients is common. Our aim was to evaluate memory and decision making in acromegalic patients and explore their relationship with affective disorders like anxiety and depressive symptoms. Thirty-one patients with acromegaly (mean age 49.5 +/- 8.5 years, 14 females and 17 males) and thirty-one healthy controls participated in this study. The Iowa Gambling Task (IGT), Rey Auditory Verbal Learning Test, State-Trait Anxiety Inventory, and Beck Depression Inventory-II (BDI-II) were used to evaluate decision making, verbal memory, anxiety, and depressive symptoms, respectively. Acromegalic patients showed impairments in delayed verbal memory (p < 0.05) and more anxiety and depressive symptoms (p < 0.05) than controls. In the IGT, acromegalic patients presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards (p < 0.05) and higher number of the riskier cards (p < 0.05). Moreover, multiple correlations between anxiety and depressive symptoms and performance in memory and decision making were found. Impaired delayed memory and decision making observed in acromegalic patients are related to anxiety and depressive symptoms. Providing emotional support to the patients could improve their cognitive function. A key clinical application of this research is the finding that depressive symptoms and anxiety are essentially modifiable factors. PMID- 26018740 TI - Malignant gastrointestinal neuroectodermal tumour of the oesophagus with pulmonary metastasis and protracted survival. PMID- 26018741 TI - Dentistry and the dental industry. PMID- 26018745 TI - Activation of autophagy in rat brain cells following focal cerebral ischemia reperfusion through enhanced expression of Atg1/pULK and LC3. AB - The present study aimed to investigate the activation of Atg1/pULK, and LC3 in the cerebral cortex following focal cerebral ischemia reperfusion (CIR) injury, thereby examining its effect on autophagy in brain cells. Rat CIR models were established using the technique of middle cerebral artery occlusion. The neurological function score, TTC staining and the water content of brain tissue were used to evaluate the CIR model. Levels of autophagy in the brain cells were examined at different time-points following CIR damage using electron microscopy. Immunohistochemistry and western blot analysis were also used for the qualitative and quantitative detection of levels of Atg1/pULK and LC3 in the cerebral cortex. Autophagy was observed in the early stage of CIR, and the expression of Atg1/pULK and LC3 were observed 1 h following CIR in the rats and reached peak expression levels after12 h, which following which the they gradually decreased. These results suggested Atg1/pULK and LC3 are key in the regulation of autophagy following CIR in the rat brain. PMID- 26018746 TI - Quality of life of institutionalized older adults by dementia severity. AB - BACKGROUND: The goal of the study was to analyze the factors associated with quality of life (QoL) in institutionalized older adults with dementia, based on self and proxy ratings, and if these characteristics differ by dementia severity. METHODS: Cross-sectional study of 525 people with dementia (PwD) and their caregivers (professional or family caregivers). Two different QoL questionnaires, leading to three measures, were used: QoL in Alzheimer's disease scale (QOL-AD), self and proxy-rated, and QoL in late-stage dementia scale (QUALID), proxy-rated. Multivariate linear regression models were tested for each QoL measure and for mild/moderate and severe stages of dementia. RESULTS: Multiple regression analyses showed a significant association between the three QoL measures and depression. Functional ability was significantly associated with QoL when assessed by proxy. Other factors such as education level, leisure activities and frequency of visits were significantly related with QOL-AD by proxy. The associated factors that differed by dementia severity were education level for moderate dementia, and frequency of visits and who answered the questionnaire (professional vs. family member) for severe dementia. CONCLUSIONS: QoL was consistently associated with depressive symptoms independently of the measures as well as functional ability and social leisure activities when the QoL questionnaire was rated by proxy. Treating depressive symptoms, increasing social activities and maintaining the functional ability may decrease the deterioration of QoL in institutionalized older adults with dementia. PMID- 26018747 TI - 1-Naphthol as an ESPT fluorescent molecular probe for sensing thermotropic microenvironmental changes of pluronic F127 in aqueous media. AB - Thermotropic microenvironmental changes and the level of hydration in different microenvironments of pluronic F127 (PF127), (PEO106 PPO70 PEO106, average molar mass 13 000) in aqueous media have been studied using 1-naphthol, which is an ESPT fluorescent molecular probe. The appearance of 1-naphthol neutral form fluorescence in aqueous PF127 (10% w/v) solution indicates the ability of 1 naphthol to sense hydrophobic domains in micellar aggregations. There is a marked enhancement of the neutral form fluorescence at and above the gelation temperature (20 degrees C), which shows that the probe can accurately sense the sol-gel transition. In the temperature range of 10-40 degrees C, with increase in temperature there is a progressive enhancement of the neutral form fluorescence and the blue shift of the neutral and anionic form fluorescence; a decrease in the deprotonation rate constant (kpt) indicates that the water polymer interfacial region is progressively dehydrated. Because kpt is related to the availability of proton-accepting water in the microenvironment of 1-naphthol, the reduction of kpt indicates progressive dehydration. The thermotropic response of the I1/I3 vibronic band ratio of pyrene-1-butyric acid fluorescence shows a progressive increase in the non-polarity of the interfacial domain with increasing temperature. The increase in non-polarity and the decrease of the hydration level are strongly correlated. PMID- 26018748 TI - Phenotypic Variability and Newly Identified Mutations of the IVD Gene in Japanese Patients with Isovaleric Acidemia. AB - Isovaleric acidemia (IVA) is an autosomal recessive inborn error affecting leucine metabolism. It is caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme that catalyzes the oxidation of isovaleryl CoA to 3-methylcrotonyl-CoA. IVD is a FAD-containing enzyme, consisting of four identical subunits. Clinical features of IVA include poor feeding, vomiting, lethargy, developmental delay, metabolic acidosis, and a characteristic "sweaty foot" odor. IVA is one of the target disorders for newborn screening by tandem mass spectrometry (MS/MS). The human IVD gene is located on chromosome 15q. To date, over 50 disease-causing mutations have been reported worldwide. In this study, we searched for IVD mutations in five Japanese patients with IVA (neonatal type, two patients; chronic intermittent type, two patients; and mild biochemical type, one patient). The diagnosis of IVA was confirmed by urinary organic acid analysis using gas chromatography and mass spectrometry. All coding exons and the flanking introns in the IVD gene were amplified by PCR and were directly sequenced. We thus identified six hitherto unknown mutations (p.G94D, p.E116K, p.M167T, p.L243P, p.L246P, and c.696+1G>T) and four previously reported (p.R53P, p.R395C, p.Y403C, and p.E411K) pathogenic mutations. All patients were compound heterozygotes, and each mutation was identified in a single patient. Pathogenicity of newly identified mutations was validated using computational programs. Among them, the p.M167T is believed to influence FAD binding, as the position 167 is present in one of the FAD-binding sites. Our results have illustrated the heterogeneous mutation spectrum and clinical presentation of IVA in the Japanese patients. PMID- 26018749 TI - Competency in managing cardiac arrest: A scenario-based evaluation of dental students. AB - OBJECTIVE: Advanced Cardiovascular Life Support (ACLS) in life-threatening situations is perceived as a basic skill for dental professionals. However, medical emergency training in dental schools is often not standardized. The dental students' knowledge transfer to an ACLS setting thus remains questionable. The aim of the study was to evaluate dental pre-doctorate students' practical competence in ACLS in a standardized manner to enable the curriculum to be adapted to meet their particular needs. MATERIALS AND METHODS: Thirty dental students (age 25.47 +/- 1.81; 16 male/14 female) in their last year of dental studies were randomly assigned to 15 teams. Students' ability to successfully manage ACLS was assessed by a scenario-based approach (training module: Laerdal(r) ALS Skillmaster). Competence was assessed by means of (a) an observation chart, (b) video analysis and (c) training module analysis (Laerdal HeartSim(r)4000; Version 1.4). The evaluation was conducted by a trained anesthesiologist with regard to the 2010 guidelines of the European Resuscitation Council (ERC). RESULTS: Only five teams (33.3%) checked for all three vital functions (response, breathing and circulation). All teams initiated cardiopulmonary resuscitation (CPR). Only 54.12% of the compressions performed during CPR were sufficient. Four teams stopped the CPR after initiation. In total, 93% of the teams used the equipment for bag-valve-mask ventilation and 53.3% used the AED (Automated external defibrillator). CONCLUSIONS: ACLS training on a regular basis is necessary and, consistent with a close link between dentistry and medicine, should be a standardized part of the medical emergency curriculum for dental students with a specific focus on the deficiencies revealed in this study. PMID- 26018750 TI - Investigation of the molecular similarity in closely related protein systems: The PrP case study. AB - The amyloid conversion is a massive detrimental modification affecting several proteins upon specific physical or chemical stimuli characterizing a plethora of diseases. In many cases, the amyloidogenic stimuli induce specific structural features to the protein conferring the propensity to misfold and form amyloid deposits. The investigation of mutants, structurally similar to their native isoform but inherently prone to amyloid conversion, may be a viable strategy to elucidate the structural features connected with amyloidogenesis. In this article, we present a computational protocol based on the combination of molecular dynamics (MD) and grid-based approaches suited for the pairwise comparison of closely related protein structures. This method was applied on the cellular prion protein (PrP(C)) as a case study and, in particular, addressed to the quali/quantification of the structural features conferred by either E200K mutations and treatment with CaCl(2), both able to induce the scrapie conversion of PrP. Several schemes of comparison were developed and applied to this case study, and made up suitable of application to other protein systems. At this purpose an in-house python codes has been implemented that, together with the parallelization of the GRID force fields program, will spread the applicability of the proposed computational procedure. PMID- 26018751 TI - Natural products with therapeutic potential in melanoma metastasis. AB - Malignant melanoma is the most aggressive form of skin cancer and accounts for about 3% of all cases of malignant tumour. Its incidence is increasing worldwide and it is becoming resistant to current therapeutic agents. Natural products continue to provide lead cytotoxic compounds for cancer treatment but less attention has been given to antimigratory compounds. This paper systematically and critically surveys all natural products with direct in vitro and in vivo pharmacological effects on migration and/or metastasis of melanoma cells and maps the mechanisms of action for these underexploited properties. As a result, over 30 natural active principles are described acting mainly through their antagonistic effects upon the TNF-alpha and EP2 receptors or the suppression of several protein kinases involved in metastatic pathways such as RAS, PI3K, ERK and FAK. Also, some were able to reduce the level of mesenchymal biomarkers such as N-cadherin and/or elevate the expression of other molecules such as E cadherin. Consequently, downstream transcription factors namely NF-kB, AP-1, ATF 2, CREB, and HIF were inactivated leading to diminished production of MMPs, IL-1, IL-6, COX-2, VEGF and GM-CSF. This review also discusses the opportunity of combination therapies based on natural products and approved drugs, such as the combination of EGCG and dacarbazine, or the combination of two natural compounds such as quercetin and sulforaphane. PMID- 26018752 TI - A Novel Coumarin-Based Fluorescent Probe for the Detection of Hydrazine Both in Aqueous Solution and Vapor State. AB - A novel coumarin-based fluorescent probe CF was synthesized for the detection of hydrazine both in aqueous solution and vapor state with high sensitivity and selectivity. Upon addition of hydrazine, the solution of probe CF in MeCN-H2O (3/7, v/v, buffered CH3COOH/CH3COONa) at pH 5.0 exhibited a remarkable change in emission color from pale green to light blue, which could be recognized with naked eyes. Applied in weak acid condition, probe CF could detect hydrazine selectively with large amount of unknown environments according to the competing tests. Besides, with the limit of detection 8.32 ppb (2.6 * 10(-7) M), probe CF could well meet the request (10 ppb) of the U.S. Environmental Protection Agency (EPA). PMID- 26018754 TI - Correction: In Vitro and In Vivo Activity of the Low-Immunogenic Antimesothelin Immunotoxin RG7787 in Pancreatic Cancer. PMID- 26018753 TI - RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma. AB - We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7 dependent upregulation of RacGAP1 in doxorubicin-insensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin. PMID- 26018755 TI - Using visual cues to enhance haptic feedback for palpation on virtual model of soft tissue. AB - This paper explores methods that make use of visual cues aimed at generating actual haptic sensation to the user, namely pseudo-haptics. We propose a new pseudo-haptic feedback-based method capable of conveying 3D haptic information and combining visual haptics with force feedback to enhance the user's haptic experience. We focused on an application related to tumor identification during palpation and evaluated the proposed method in an experimental study where users interacted with a haptic device and graphical interface while exploring a virtual model of soft tissue, which represented stiffness distribution of a silicone phantom tissue with embedded hard inclusions. The performance of hard inclusion detection using force feedback only, pseudo-haptic feedback only, and the combination of the two feedbacks was compared with the direct hand touch. The combination method and direct hand touch had no significant difference in the detection results. Compared with the force feedback alone, our method increased the sensitivity by 5%, the positive predictive value by 4%, and decreased detection time by 48.7%. The proposed methodology has great potential for robot assisted minimally invasive surgery and in all applications where remote haptic feedback is needed. PMID- 26018756 TI - Does a coupling capacitor enhance the charge balance during neural stimulation? An empirical study. AB - Due to their DC-blocking characteristic, coupling capacitors are widely used to prevent potentially harmful charge buildup at the electrode-tissue interface. Although the capacitors can be an effective safety measure, it often seems overlooked that coupling capacitors actually introduce an offset voltage over the electrode-tissue interface as well. This work investigates this offset voltage both analytically and experimentally. The calculations as well as the experiments using bipolar-driven platinum electrodes in a saline solution confirm that coupling capacitors introduce an offset, while they barely contribute to the passive charge balancing. In particular cases, this offset is shown to reach potentially dangerous voltage levels that could induce irreversible electrochemical reactions. This work therefore suggests that when the use of coupling capacitors is required, the offset voltage should be analyzed for all operating conditions to ensure it remains within safe boundaries. PMID- 26018757 TI - A simple and inexpensive test-rig for evaluating the performance of motion sensors used in movement disorders research. AB - Since the advent of electromyogram recording, precise measures of tremor and gait have been used to study movement disorders such as Parkinson's disease. Now, a wide range of accelerometers and other motion-tracking technologies exist to better inform researchers and clinicians, yet such systems are rarely tested for accuracy or suitability before use. Our inexpensive test-rig can produce sinusoidal displacements using a simple cantilever system driven by a subwoofer. Controlled sinusoids were generated using computer software, and the displacement amplitudes of the test-rig were verified with fiducial marker tracking. To illustrate the use of the test-rig, we evaluated an accelerometer and an electromagnetic motion tracker. Accelerometry recordings were accurate to within +/-0.09 g of actual peak-to-peak amplitude with a frequency response close to unity gain between 1 and 20 Hz. The electromagnetic sensor underestimated peak displacement by 2.68 mm, which was largely due to a diminishing gain with increasing frequency. Both sensors had low distortion. Overall sensitivity was limited by noise for the accelerometer and quantisation resolution for the electromagnetic sensor. Our simple and low-cost test-rig can be used to bench test sensors used in movement disorders research. It was able to produce reliable sinusoidal displacements and worked across the 1- to 20-Hz frequency range. PMID- 26018758 TI - Treatments for pregnancy-related lumbopelvic pain: a systematic review of physiotherapy modalities. AB - OBJECTIVE: To explore the effect of physiotherapeutic interventions on pregnancy related lumbopelvic pain. MATERIAL AND METHODS: Data sources: MEDLINE, Cochrane Central Register of Controlled Trials, PEDro, CINAHL, AMED, and SCOPUS databases were searched up to December 2014 for studies written in English, French, German or Scandinavian languages that evaluated physiotherapeutic modalities for preventing and treating pregnancy-related lumbopelvic pain. RESULTS: For lumbopelvic pain during pregnancy, the evidence was strong for positive effects of acupuncture and pelvic belts. The evidence was low for exercise in general and for specific stabilizing exercises. The evidence was very limited for efficacy of water gymnastics, progressive muscle relaxation, a specific pelvic tilt exercise, osteopathic manual therapy, craniosacral therapy, electrotherapy and yoga. For postpartum lumbopelvic pain, the evidence was very limited for clinic-based treatment concepts, including specific stabilizing exercises, and for self management interventions for women with severe disabilities. No specific adverse events were reported for any intervention. No meta-analysis could be performed because of study heterogeneity. CONCLUSIONS: The levels of evidence were strong for a positive effect of acupuncture and pelvic belts, but weak for an effect of specific exercises. Caution should prevail in choosing other interventions for pregnancy-related lumbopelvic pain. PMID- 26018759 TI - Lithium Storage in Microstructures of Amorphous Mixed-Valence Vanadium Oxide as Anode Materials. AB - Constructing three-dimensional (3 D) nanostructures with excellent structural stability is an important approach for realizing high-rate capability and a high capacity of the electrode materials in lithium-ion batteries (LIBs). Herein, we report the synthesis of hydrangea-like amorphous mixed-valence VOx microspheres (a-VOx MSs) through a facile solvothermal method followed by controlled calcination. The resultant hydrangea-like a-VOx MSs are composed of intercrossed nanosheets and, thus, construct a 3 D network structure. Upon evaluation as an anode material for LIBs, the a-VOx MSs show excellent lithium-storage performance in terms of high capacity, good rate capability, and long-term stability upon extended cycling. Specifically, they exhibit very stable cycling behavior with a highly reversible capacity of 1050 mA h g(-1) at a rate of 0.1 A g(-1) after 140 cycles. They also show excellent rate capability, with a capacity of 390 mA h g( 1) at a rate as high as 10 A g(-1) . Detailed investigations on the morphological and structural changes of the a-VOx MSs upon cycling demonstrated that the a-VOx MSs went through modification of the local V?O coordinations accompanied with the formation of a higher oxidation state of V, but still with an amorphous state throughout the whole discharge/charge process. Moreover, the a-VOx MSs can buffer huge volumetric changes during the insertion/extraction process, and at the same time they remain intact even after 200 cycles of the charge/discharge process. Thus, these microspheres may be a promising anode material for LIBs. PMID- 26018760 TI - Abeta42 and Abeta40: similarities and differences. AB - The abnormal accumulation of amyloid-beta (Abeta) peptide in the brain is one of the most important hallmarks of Alzheimer's disease. Abeta is an aggregation prone and toxic polypeptide with 39-43 residues, derived from the amyloid precursor protein proteolysis process. According to the amyloid hypothesis, abnormal accumulation of Abeta in the brain is the primary influence driving Alzheimer's disease pathologies. Among all kinds of Abeta isoforms, Abeta40 and Abeta42 are believed to be the most important ones. Although these two kinds of Abeta differ only in two amino acid residues, recent studies show that they differ significantly in their metabolism, physiological functions, toxicities, and aggregation mechanism. In this review, we mainly summarize the similarities and differences between Abeta42 and Abeta40, recent studies on selective inhibitors as well as probes will also be mentioned. PMID- 26018762 TI - Synthesis of Spirocyclic Pyrazolones by Oxidative C-N Bond Formation. AB - The two-step synthesis of spirocyclic pyrazolone derivatives from simple and commercially available reagents is described. The unusual reaction of 1,3 dicarbonyls with hydrazines and an iodine-mediated oxidative carbon-nitrogen bond formation, joined in a two-step, one-pot reaction, allows the straightforward synthesis of these spirocycles. PMID- 26018761 TI - Low vitamin D levels are associated with higher opioid dose in palliative cancer patients--results from an observational study in Sweden. AB - BACKGROUND: Vitamin D deficiency is common among palliative cancer patients and has been connected to an increased risk for pain, depressions and infections. Therefore we wanted to test the hypothesis that low 25-hydroxyvitamin D (25OHD) levels are associated with higher opioid dose, higher infectious burden and impaired quality of life in palliative cancer patients. The secondary aim was to investigate the association between 25OHD-levels and survival time. METHOD: In this prospective, observational study in palliative cancer-patients (n = 100) we performed univariate and multiple linear regression analysis to assess the association of 25OHD levels with opioid dose, infectious burden (antibiotic consumption), quality of life (Edmonton Symptom Assessment Scale, ESAS) and survival time, controlling for potential confounding factors. RESULTS: The median 25OHD level was 40 nmol/L (range 8-154 nmol/L). There was a significant association between 25OHD levels and opioid dose, beta coefficient -0.67; p=0.02; i.e. a low 25OHD level was associated with a higher opioid dose. This association remained significant after adjustment for stage of the cancer disease in a multivariate analysis, beta coefficient -0.66; p = 0.04. There was no association between 25OHD levels and antibiotic use or quality of life. Univariate cox regression analysis showed a weak correlation between survival time and 25OHD levels (p<0.05). However, decreased albumin levels and increased CRP levels were superior markers to predict survival time; p<0.001 for both analyses. CONCLUSION: Low 25OHD-levels are associated with increased opioid consumption in palliative cancer patients. Future interventional studies are needed to investigate if pain can be reduced by vitamin D supplementation in these patients. In addition, this study confirms previous findings that low albumin and increased CRP levels are useful markers for survival time in palliative cancer patients. PMID- 26018763 TI - Operationalisation of quality of life for adults with severe disabilities. AB - BACKGROUND: The operationalisation of quality of life for people with more severe disabilities has been acknowledged in the published research for more than two decades. This study aims to contribute to our knowledge and understanding of the quality of life of adults with severe disabilities by developing a set of quality of life indicators appropriate to this population using a Delphi method and the eight-domain conceptual model proposed by Schalock & Verdugo (2002). METHOD: The participating panel in the Delphi method included 12 experts who evaluated each proposed item according to four criteria: suitability, importance, observability and sensitivity. Descriptive analyses were used to select the best items in each of the four rounds of this Delphi study, as well as examining the coefficients of concordance that were calculated for the final pool of items. RESULTS: The four rounds of the Delphi study resulted in a final pool of 118 items (91 that were considered valid in the first round plus 27 items proposed, reformulated or discussed in the following rounds). Importance and sensitivity were the criteria that received the highest and lowest ratings, respectively, but also the ones that had the highest and lowest mean coefficients of concordance. Experts showed the strongest agreement for items related to material well-being, while the weakest was found for items related to personal development. CONCLUSIONS: This study further contributes to our understanding of how to operationalise and measure quality of life in adults with severe disabilities. The item pool generated may prove helpful in the development of instruments for the measurement of quality of life-related outcomes in this population. PMID- 26018764 TI - Key genes as stress indicators in the ubiquitous diatom Skeletonema marinoi. AB - BACKGROUND: The dense phytoplankton blooms that characterize productive regions and seasons in the oceans are dominated, from high to low latitudes and from coast line to open ocean, by comparatively few, often cosmopolitan species of diatoms. These key dominant species may undergo dramatic changes due to global climate change. RESULTS: In order to identify molecular stress-indicators for the ubiquitous diatom species Skeletonema marinoi, we tested stress-related genes in different environmental conditions (i.e. nutrient starvation/depletion, CO2 enrichment and combined effects of these stressors) using RT-qPCR. The data show that these stressors impact algal growth rate, inducing early aging and profound changes in expression levels of the genes of interest. CONCLUSIONS: Most analyzed genes (e.g. antioxidant-related and aldehyde dehydrogenases) were strongly down regulated which may indicate a strategy to avoid unnecessary over-investment in their respective proteins. By contrast, key genes were activated (e.g. HSPs, GOX) which may allow the diatom species to better cope with adverse conditions. We propose the use of this panel of genes as early bio-indicators of environmental stress factors in a changing ocean. PMID- 26018766 TI - Effect of Bcl-xL overexpression on sialylation of Fc-fusion protein in recombinant Chinese hamster ovary cell cultures. AB - The sialic acid of glycoproteins secreted by recombinant Chinese hamster ovary (rCHO) cells can be impaired by sialidase under culture conditions which promote the extracellular accumulation of this enzyme. To investigate the effect of Bcl xL overexpression on the sialylation of glycoproteins produced in rCHO cell culture, two rCHO cell lines producing the same Fc-fusion protein, which were derived from DUKX-B11 and DG44, respectively, were engineered to have regulated Bcl-xL overexpression using the Tet-off system. For both cell lines, Bcl-xL overexpression improved cell viability and extended culture longevity in batch cultures. As a result, a maximum Fc-fusion protein titer increased by Bcl-xL overexpression though the extent of titer enhancement differed between the two cell lines. With Bcl-xL overexpression, the sialylation of Fc-fusion protein, which was assessed by isoelectric focusing gel and sialic acid content analyses, decreased more slowly toward the end of batch cultures. This was because Bcl-xL overexpression delayed the extracellular accumulation of sialidase activity by reducing cell lysis during batch cultures. Taken together, Bcl-xL overexpression in rCHO cell culture increased Fc-fusion protein production and also reduced the impairment of sialylation of Fc-fusion protein by maintaining high viability during batch cultures. PMID- 26018765 TI - Evaluating the safety of intraoperative instillation of intravesical chemotherapy at the time of nephroureterectomy. AB - BACKGROUND: Urothelial carcinoma (UC) is a common cancer affecting many patients in the United States. Nephroureterectomy remains the gold standard for the treatment of high grade upper tract disease or low grade tumors that are not amenable to endoscopic management. Recent reports have shown a decrease in UC recurrence in patients who underwent nephroureterectomy and who had Mitomycin C (MMC) instilled into the bladder at the time of catheter removal. At our institution instillation of intravesical MMC at the time of nephroureterectomy has been common for more than 10 years. Given the recent data, we sought to formally describe our experience with and evaluate the safety of intravesical instillation of cytotoxic chemotherapy at the time of nephroureterectomy. METHODS: We retrospectively reviewed 51 patients who underwent intraoperative intravesical instillation of cytotoxic chemotherapy (MMC (n = 48) or adriamycin (n = 3)) at the time of nephroureterectomy (2000-2012). The procedure was performed in a similar fashion by 8 different surgeons from the same institution, with drainage of the bladder prior to management of the bladder cuff. Patient characteristics and perioperative data including complications out to 90 days after surgery were collected. Perioperative complications for all patients were graded using the modified Clavien-Dindo classification. RESULTS: Twenty-four men and 27 women underwent intraoperative intravesical instillation of cytotoxic chemotherapy at the time of nephroureterectomy. Median age at the time of operation was 74 years (range 48-88). Median dwell time was 60 min. Twenty three patients had a total of 45 perioperative complications. The majority (36/45) were Clavien grades I and II. No patients experienced any intraoperative or postoperative complications attributable to MMC or Adriamycin instillation. CONCLUSION: Intraoperative intravesical instillation of cytotoxic chemotherapy at the time of nephroureterectomy is safe and feasible. Multicenter trials to study the efficacy of early cytotoxic chemotherapy administration to prevent recurrence of bladder urothelial carcinoma following nephroureterectomy are warranted. PMID- 26018767 TI - Differential expression patterns of three aromatase genes and of four estrogen receptors genes in the testes of trout (Oncorhynchus mykiss). AB - Estrogens are implicated in male gonad function, although their physiological roles remain uncertain. In the present study, we take advantage of the original model of spatio-temporal organization of trout spermatogenesis to revisit the synthesis and action sites of estrogens in fish testis. Within this system, somatic cell and germ cell development are synchronized due to a strict seasonal spermatogenetic cycle and the cystic organization of gonads. We evaluated the expression patterns and regulation of three aromatase isoforms (cyp19a, cyp19b-I, and cyp19b-II) and four estrogen receptors (esr1a, esr1b, esr2a, and esr2b) by quantitative reverse-transcriptase PCR during testicular maturation and in isolated germ cell populations. Our data demonstrated a reciprocal relationship between cyp19a and cyp19b (I and II) expression during testicular development (cyp19a decreased while cyp19b increased with maturation). Furthermore, cyp19b is significantly expressed in late germ cells. At the protein level, aromatase was immunohistochemically identified in interstitial tissue and in germ cells. Remarkable elevation of esr1a and esr2a was observed during the final stage of spermiation, while esr1b was expressed in an early stage of spermatogenetic development. Estrogen implants reduced testicular cyp19a transcript abundance while up-regulating cyp19b levels, whereas androgens up-regulated testicular esr1a, esr2a, and esr2b. Together, the distinct spatio-temporal expression profiles and regulation of aromatases and estrogen receptors suggest that estrogens have discrete physiological functions during an early step of spermatogenesis and in the final stages of germ cell maturation and/or excretion. PMID- 26018768 TI - Phosphoproteomic analyses of L-02 liver cells exposed to trichloroethylene. AB - Trichloroethylene (TCE) is an environmental and occupational toxicant that has been shown to cause serious hepatotoxicity. However, the mechanisms underlying the hepatotoxicity of TCE remain unclear. Previously, we identified several apoptosis-related proteins in TCE-induced hepatic cytotoxicity. This study is aimed to analyze the changes in phosphoproteins in L-02 liver cells exposed to TCE using iTRAQ labeling, IMAC enrichment and LC-MS/MS. We identified 1878 phosphorylation sites in 107 proteins and found that 20 sites in 16 phosphoproteins were differentially phosphorylated in L-02 cells after TCE treatment. Among these phosphoproteins, 20% were protein localization and formation processes-related proteins, 38% were metabolism-related proteins and 42% were cellular process-related proteins, including transcriptional regulation and biogenesis. Moreover, two phosphoproteins, 4E-BP1 (37T) and MCM2 (139S), were validated as TCE-induced alteration of phosphorylation at specific sites by Western-blot analysis. Taken together, our study demonstrated that TCE exposure changed the levels of multiple phosphoproteins in L-02 liver cells, and the functional analysis suggested that these differentially expressed phosphoproteins might be involved in TCE-induced hepatic cytotoxicity. PMID- 26018769 TI - T1 mapping in myocarditis - headway to a new era for cardiovascular magnetic resonance. AB - Myocarditis is a major cause of cardiac morbidity and mortality, particularly in young patients. A spectrum of challenges besets this condition, from establishing the diagnosis to effective treatment. Endomyocardial biopsy remains the diagnostic gold standard, despite its invasiveness, low diagnostic yield and a paucity of consequential management pathways. Cardiac magnetic resonance by Lake Louise criteria has contested to become the non-invasive diagnostic alternative by providing confirmation of disease. The advent of T1 mapping now allows a high diagnostic accuracy in confirmation and exclusion of disease, discrimination of stages and activity of disease. Alongside the research into the mechanisms and potential therapeutic targets, cardiac magnetic resonance confidently claims a prime role within a modern diagnostic pathway in clinically stable patients with suspected myocarditis. PMID- 26018770 TI - Palladium-catalyzed ortho-acyloxylation of N-nitrosoanilines via direct sp(2) C-H bond activation. AB - The palladium-catalyzed N-nitroso-directed ortho-acyloxylation of N nitrosoanilines has been demonstrated via sp(2) C-H activation with a stoichiometric amount of PhI(OAc)2 as the oxidant and Ac2O/AcOH (1 : 1) or C2H5CO2H as the reaction medium. This protocol can be applied to various N nitrosoanilines with both electron-donating and electron-withdrawing groups. In addition, the products can be further transformed to 2-(methylamino)phenols expediently by a simple reduction method. PMID- 26018771 TI - Acceleration of bone-defect repair by using A-W MGC loaded with BMP2 and triple point-mutant HIF1alpha-expressing BMSCs. AB - BACKGROUND: The goal of this study is to explore the effects of A-W MGC (apatite wollastonite magnetic bioactive glass-ceramic) loaded with BMP2 (bone morphogenetic protein 2)- and HIF1alpha(mu) (hypoxia-inducible factor 1 mutation) expressing BMSCs (bone marrow mesenchymal stem cells) on the bone defect repair. METHODS: (1) BMSCs were infected with viral solution containing BMP2 and HIF1alpha(mu) with the best MOI (multiplicity of infection). The efficiency was observed via hrGFP (human renilla reniformis green fluorescent protein). (2) The cells were divided into five groups (A-E), and ALP (alkaline phosphatase) activity was measured. (3) BMP2 and HIF1alpha (hypoxia-inducible factor 1alpha) protein were measured. (4) A-W MGC was loaded with BMSCs that contain the genes and implanted into the bone defect model. The animals were sacrificed 8 and 12 weeks later. (5) The healing was measured with X-ray, histology, and biomechanics. RESULTS: (1) BMSCs in A-D showed high transfection efficiency. (2) ALP in A and B was higher than the others (p = 0.041 or 0.038); A was higher than B (p = 0.038); (3) BMP2 in A and B was higher than the others (p = 0.014). HIF1alpha in A and C was higher than the others (p = 0.020). (4) 8 and 12 weeks after, an X-ray indicated that bone defect was nearly fully repaired in A and C. (5) 12 weeks after, the bone remodeling was complete in A and C. (6) The flexural strength in A and C was stronger than the others (p = 0.043). CONCLUSION: Engineered A-W MGC with BMP2 and HIF1alpha(mu)-expressing BMSCs exhibits comparable therapeutic effects of bone-defect repair as an autologous bone graft. PMID- 26018772 TI - Antibiotic resistome and its association with bacterial communities during sewage sludge composting. AB - Composting is widely used for recycling of urban sewage sludge to improve soil properties, which represents a potential pathway of spreading antibiotic resistant bacteria and genes to soils. However, the dynamics of antibiotic resistance genes (ARGs) and the underlying mechanisms during sewage sludge composting were not fully explored. Here, we used high-throughput quantitative PCR and 16S rRNA gene based illumina sequencing to investigate the dynamics of ARGs and bacterial communities during a lab-scale in-vessel composting of sewage sludge. A total of 156 unique ARGs and mobile genetic elements (MGEs) were detected encoding resistance to almost all major classes of antibiotics. ARGs were detected with significantly increased abundance and diversity, and distinct patterns, and were enriched during composting. Marked shifts in bacterial community structures and compositions were observed during composting, with Actinobacteria being the dominant phylum at the late phase of composting. The large proportion of Actinobacteria may partially explain the increase of ARGs during composting. ARGs patterns were significantly correlated with bacterial community structures, suggesting that the dynamic of ARGs was strongly affected by bacterial phylogenetic compositions during composting. These results imply that direct application of sewage sludge compost on field may lead to the spread of abundant ARGs in soils. PMID- 26018773 TI - Antioxidant activity of alkyl hydroxytyrosyl ethers in unsaturated lipids. AB - The antioxidant activity of ethyl and octyl hydroxytyrosyl ethers toward lipids was determined using the Rancimat and open cup methods at high temperatures and 50 degrees C, respectively. The effect of the unsaturation of the matrix was evaluated using sunflower, soya, and fish refined oils. The antioxidant activities of alkyl hydroxytyrosyl ethers (HTy ethers), hydroxytyrosyl esters, and free hydroxytyrosol are similar, and are much higher than that of alpha tocopherol at the same millimolar concentration. The relationship between the induction period and the concentration of the HTy ethers is a sigmoidal curve; an accurate concentration of HTy ethers is necessary to achieve maximum activity, as it increases with the level of matrix unsaturation. The presence of tocopherols in commercial oils affects the antioxidant effect of HTy ethers. Thus, the addition of a low concentration of HTy ethers results in a positive effect, whereas the effect of the addition of high amounts of ethers is slightly less than that of the phenol alone. The addition of HTy ethers to commercial refined oils increases the stability of the oils and preserves tocopherols and polyunsaturated fatty acids from oxidation, enabling the oils to maintain their nutritional properties for longer periods of time. PMID- 26018774 TI - A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half life. AB - Immunoglobulin G (IgG) has an unusually long serum half-life in comparison to proteins of a similar size. It is well-known that this phenomenon is due to IgG's ability to bind the neonatal Fc receptor (FcRn) in a pH-dependent manner. FcRn binding properties can vary among IgGs, resulting in altered in vivo half-lives, and therefore it would be beneficial to accurately predict the FcRn binding properties of therapeutic IgG monoclonal antibodies (mAbs). Here we describe the development of an in vitro model capable of predicting the in vivo half-life of human IgG. Using a high-throughput biolayer interferometry (BLI) platform, the human FcRn association rate at acidic pH and subsequent dissociation rate at physiological pH was determined for 5 human IgG1 mAbs. Comparing the combined FcRn association and dissociation rates to the Phase 1 clinical study half-lives of the mAbs resulted in a strong correlation. The correlation was also verified in vivo using mice transgenic for human FcRn. The model was used to characterize various factors that may influence FcRn-mAb binding, including mAb variable region sequence differences and constant region glycosylation patterns. Results indicated that the complementarity-determining regions of the heavy chain significantly influence the mAb's FcRn binding properties, while the absence of glycosylation does not alter mAb-FcRn binding. Development of this high throughput FcRn binding model could potentially predict the half-life of therapeutic IgGs and aid in selection of lead candidates while also serving as a screening tool for the development of mAbs with desired pharmacokinetic properties. PMID- 26018776 TI - Novel retrieval basket for small bile duct stones. PMID- 26018775 TI - Fabrication and cytocompatibility of in situ crosslinked carbon nanomaterial films. AB - Assembly of carbon nanomaterials into two-dimensional (2D) coatings and films that harness their unique physiochemical properties may lead to high impact energy capture/storage, sensors, and biomedical applications. For potential biomedical applications, the suitability of current techniques such as chemical vapor deposition, spray and dip coating, and vacuum filtration, employed to fabricate macroscopic 2D all carbon coatings or films still requires thorough examination. Each of these methods presents challenges with regards to scalability, suitability for a large variety of substrates, mechanical stability of coatings or films, or biocompatibility. Herein we report a coating process that allow for rapid, in situ chemical crosslinking of multi-walled carbon nanotubes (MWCNTs) into macroscopic all carbon coatings. The resultant coatings were found to be continuous, electrically conductive, significantly more robust, and cytocompatible to human adipose derived stem cells. The results lay groundwork for 3D layer-on-layer nanomaterial assemblies (including various forms of graphene) and also opens avenues to further explore the potential of MWCNT films as a novel class of nano-fibrous mats for tissue engineering and regenerative medicine. PMID- 26018777 TI - Folate distribution in barley (Hordeum vulgare L.), common wheat (Triticum aestivum L.) and durum wheat (Triticum turgidum durum Desf.) pearled fractions. AB - BACKGROUND: Wholegrain cereals are an important source of folates. In this study, total folate was analysed in pearled fractions of barley and wheat cultivars employing AOAC Official Method 2004.05. In particular, the distribution of folate in the kernels was evaluated in three barley cultivars (two hulled types and a hulless one as well as two- and six-row types) and in a common and a durum wheat cultivar. RESULTS: A noticeable variation in the folate content was observed between the barley [653-1033 ng g(-1) dry matter (DM)] and wheat cultivars (1024 1119 ng g(-1) DM). The highest folate content was detected in the hulless barley cultivar (1033 ng g(-1) DM). A significant reduction in total folate, from 63% to 86%, was observed in all cultivars from the outermost to the innermost pearled fractions. CONCLUSION: Results proved that folates are mainly present in the germ and in the outer layers of the kernel. This is the first study reporting the folate distribution in kernels of both common and durum wheat and in a hulless barley cultivar. Results suggest that the pearling process could be useful for the selection of intermediate fractions that could be used in order to develop folate-enhanced ingredients and products. PMID- 26018778 TI - Informed decision-making and breast cancer screening. PMID- 26018779 TI - Swiss Medical Board Mammography screening predictions for Switzerland: importance of time-periods. AB - OBJECTIVES: In 2013, the Swiss Medical Board (SMB) concluded that for three breast cancer screens over 13 years in Switzerland, cost-effectiveness was negative, with no additional benefits in quality-adjusted life-years gained. We compared these suggested predicted effects with other estimates. METHODS: We used an extensively validated model on the natural history of breast cancer in Switzerland, comparing a 13-year time frame, a life-time perspective, and a continuous screening programme, per 10,000 Swiss women. Both approaches used the Swedish randomized controlled trials for the theoretical effect. RESULTS: Over 13 years, both approaches yield comparable life-years gained (56 versus 67), but in expectation in 10,000 women's lifetimes 444 life-years are gained, and in a continuous screening programme (instead of three screens) 839 years. The SMB estimate of 56 life-years gained is counterweighted by 57 negative quality of life adjusted years, primarily resulting from a 5% annual loss for 10% of women, being false-positive results. International literature is consistent with more than four times lower losses on false-positives. The estimate of overdiagnosed cases in the 13-year time frame was four times higher than in the long-term perspective. CONCLUSIONS: By restricting life-years gained to a 13-year time frame the SMB prediction on benefits of mammography screening is unrealistically low. Predicting long-term harms and benefits, specifically tailored to observations, regarding the clinical situation before screening commences, and possible data during a screening programme, are crucial for women, professionals, and policymakers. PMID- 26018780 TI - Surface Plasmon Resonance (SPR) for the Evaluation of Shear-Force-Dependent Bacterial Adhesion. AB - The colonization of Escherichia coli (E. coli) to host cell surfaces is known to be a glycan-specific process that can be modulated by shear stress. In this work we investigate whether flow rate changes in microchannels integrated on surface plasmon resonance (SPR) surfaces would allow for investigating such processes in an easy and high-throughput manner. We demonstrate that adhesion of uropathogenic E. coli UTI89 on heptyl alpha-d-mannopyranoside-modified gold SPR substrates is minimal under almost static conditions (flow rates of 10 uL.min-1), and reaches a maximum at flow rates of 30 uL.min-1 (~30 mPa). This concept is applicable to the investigation of any ligand-pathogen interactions, offering a robust, easy, and fast method for screening adhesion characteristics of pathogens to ligand modified interfaces. PMID- 26018781 TI - Individual differences in error tolerance in humans: Neurophysiological evidences. AB - When interacting in error-prone environments, humans display different tolerances to changing their decisions when faced with erroneous feedback information. Here, we investigated whether these individual differences in error tolerance (ET) were reflected in neurophysiological mechanisms indexing specific motivational states related to feedback monitoring. To explore differences in ET, we examined the performance of 80 participants in a probabilistic reversal-learning task. We then compared event-related brain responses (ERPs) of two extreme groups of participants (High ET and Low ET), which showed radical differences in their propensity to maintain newly learned rules after receiving spurious negative feedback. We observed that High ET participants showed reduced anticipatory activity prior to the presentation of incoming feedback, informing them of the correctness of their performance. This was evidenced by measuring the amplitude of the stimulus-preceding negativity (SPN), an ERP component indexing attention and motivational engagement of incoming informative feedback. Postfeedback processing ERP components (the so-called Feedback-Related Negativity and the P300) also showed reduced amplitude in this group (High ET). The general decreased responsiveness of the High ET group to external feedback suggests a higher proneness to favor internal(rule)-based strategies, reducing attention to external cues and the consequent impact of negative evaluations on decision making. We believe that the present findings support the existence of specific cognitive and motivational processes underlying individual differences on error tolerance among humans, contributing to the ongoing research focused on understanding the mental processes behind human fallibility in error-prone scenarios. PMID- 26018783 TI - Pre-harvest cane burning and health: the association between school absences and burning sugarcane fields. AB - The objective of this study was to investigate an association between pre-harvest sugarcane burning and respiratory diseases in children under five years of age. The following data were collected in five schools in the city of Araraquara, SP, Southeastern Brazil, between March and June 2009: daily records of absences and the reasons stated for these absences, total concentration of suspended particulate matter (ug/m3), and air humidity. The relationship between the percentage of school absences due to respiratory problems and the concentration of particulate matter in March and from April to June presented a distinct behavior: absences increased alongside the increase in particulate matter concentration. The use of school absences as indicators of this relationship is an innovative approach. PMID- 26018782 TI - Novel molecular mechanism for generating NK-cell fitness and memory. AB - The mammalian immune system has been traditionally subdivided into two compartments known as the innate and the adaptive. T cells and B cells, which rearrange their antigen-receptor genes using the RAG recombinase, comprise the adaptive arm of immunity. Meanwhile, every other white blood cell has been grouped together under the broad umbrella of innate immunity, including NK cells. NK cells are considered innate lymphocytes because of their rapid responses to stressed cells and their ability to develop without receptor gene rearrangement (i.e. in RAG-deficient mice). However, new findings implicate a critical function for RAG proteins during NK-cell ontogeny, and suggest a novel mechanism by which controlled DNA breaks during NK-cell development dictate the fitness, function, and longevity of these cells. This review highlights recent work describing how DNA break events can impact cellular differentiation and fitness in a variety of cell types and settings. PMID- 26018784 TI - Contextual and individual indicators associated with the presence of teeth in adults. AB - OBJECTIVE The objective of this study was to analyze whether socioeconomic conditions and the period of availability of fluoridated water are associated with the number of teeth present. METHODS This cross-sectional study analyzed data from 1,720 adults between 20 and 59 years of age who resided in Florianopolis, SC, Southern Brazil, in 2009. The outcome investigated was the self-reported number of teeth present. The individual independent variables included gender, age range, skin color, number of years of schooling, and per capita household income. The duration of residence was used as a control variable. The contextual exposures included the period of availability of fluoridated water to the households and the socioeconomic variable for the census tracts, which was created from factor analysis of the tract's mean income, education level, and percentage of households with treated water. Multilevel logistic regression was performed and inter-level interactions were tested. RESULTS Residents in intermediate and poorer areas and those with fluoridated water available for less time exhibited the presence of fewer teeth compared with those in better socioeconomic conditions and who had fluoridated water available for a longer period (OR = 1.02; 95%CI 1.01;1.02). There was an association between the period of availability of fluoridated water, per capita household income and number of years of education. The proportion of individuals in the poorer and less-educated stratum, which had fewer teeth present, was higher in regions where fluoridated water had been available for less time. CONCLUSIONS Poor socioeconomic conditions and a shorter period of availability of fluoridated water were associated with the probability of having fewer teeth in adulthood. Public policies aimed at reducing socioeconomic inequalities and increasing access to health services such as fluoridation of the water supply may help to reduce tooth loss in the future. PMID- 26018785 TI - Consumption of ultra-processed foods and their impact on the diet of young adults. AB - OBJECTIVE To evaluate the consumption of ultra-processed foods, its associated factors, and its influence on nutrient intake in young adults. METHODS In 2004 2005, the individuals belonging to the Pelotas birth cohort of 1982 were identified for a home interview. A total of 4,297 individuals were interviewed and 4,202 individuals were included in the study (follow-up rate of 77.4%). Diet was assessed using a questionnaire on dietary intake and the percentage of daily caloric intake attributed to ultra-processed foods as well as the intake of macro and micronutrients were estimated. The association between cohort characteristics and the consumption of ultra-processed foods was assessed using linear regression. Analysis of variance and Pearson's Chi-square test were used to evaluate the association between the quintiles of the consumption of ultra processed food, nutrient intake and adequacy of nutrient intake, respectively. RESULTS The consumption of ultra-processed foods corresponded to 51.2% of the total caloric intake. The consumption of ultra-processed foods was higher among women, individuals with higher education, and individuals who were never poor and eutrophic. The increased consumption of ultra-processed foods was positively correlated with the consumption of fat, cholesterol, sodium, iron, calcium, and calories (p < 0.001) and was negatively correlated with the consumption of carbohydrates, protein, and dietary fiber (p < 0.001). CONCLUSIONS The high consumption of ultra-processed foods and its positive correlation with the intake of sodium, cholesterol, and fats underscores the need to perform interventions aimed at decreasing the intake of this food group. PMID- 26018786 TI - Risk of dependence associated with health, social support, and lifestyle. AB - OBJECTIVE To analyze the prevalence of individuals at risk of dependence and its associated factors. METHODS The study was based on data from the Catalan Health Survey, Spain conducted in 2010 and 2011. Logistic regression models from a random sample of 3,842 individuals aged >= 15 years were used to classify individuals according to the state of their personal autonomy. Predictive models were proposed to identify indicators that helped distinguish dependent individuals from those at risk of dependence. Variables on health status, social support, and lifestyles were considered. RESULTS We found that 18.6% of the population presented a risk of dependence, especially after age 65. Compared with this group, individuals who reported dependence (11.0%) had difficulties performing activities of daily living and had to receive support to perform them. Habits such as smoking, excessive alcohol consumption, and being sedentary were associated with a higher probability of dependence, particularly for women. CONCLUSIONS Difficulties in carrying out activities of daily living precede the onset of dependence. Preserving personal autonomy and function without receiving support appear to be a preventive factor. Adopting an active and healthy lifestyle helps reduce the risk of dependence. PMID- 26018787 TI - Diabetes burden in Brazil: fraction attributable to overweight, obesity, and excess weight. AB - OBJECTIVE To estimate the burden of type 2 diabetes mellitus and its percentage attributable to overweight and obesity in Brazil. METHODS The burden of diabetes mellitus was described in terms of disability-adjusted life years, which is the sum of two components: years of life lost and years lived with disability. To calculate the fraction of diabetes mellitus attributable to overweight, obesity, and excess weight, we used the prevalence of these risk factors according to sex and age groups (> 20 years) obtained from the 2008 Pesquisa Dimensoes Sociais das Desigualdades (Social Dimensions of Inequality Survey) and the relative risks derived from the international literature. RESULTS Diabetes mellitus accounted for 5.4% of Brazilian disability-adjusted life years in 2008, with the largest fraction attributed to the morbidity component (years lived with disability). Women exhibited higher values for disability-adjusted life years. In Brazil, 49.2%, 58.3%, and 70.6% of diabetes mellitus in women was attributable to overweight, obesity, and excess weight, respectively. Among men, these percentages were 40.5%, 45.4%, and 60.3%, respectively. Differences were observed with respect to Brazilian regions and age groups. CONCLUSIONS A large fraction of diabetes mellitus was attributable to preventable individual risk factors and, in about six years, the contribution of these factors significant increased, particularly among men. Policies aimed at promoting healthy lifestyle habits, such as a balanced diet and physical activity, can have a significant impact on reducing the burden of diabetes mellitus in Brazil. PMID- 26018788 TI - Titanium pyridonates for the homo- and copolymerization of rac-lactide and epsilon-caprolactone. AB - A series of titanium pyridonate complexes have been synthesized under very mild reaction conditions from a common precursor, Ti(NMe2)4. These complexes have been explored as initiators for the ring-opening polymerization of rac-lactide and epsilon-caprolactone and have proven to be competitive with leading titanium initiators. Furthermore, these complexes have been shown to be competent initiators for the synthesis of copolymers (CL-LA block copolymers and random copolymers). Metal complex reactivity trends in both homo- and copolymerization show that poly(lactic acid) is most susceptible to chain scission and transesterification. PMID- 26018789 TI - Surface roughness and wettability of dentin ablated with ultrashort pulsed laser. AB - The aim of this study was to evaluate the surface roughness and wettability of dentin following ultrashort pulsed laser ablation with different levels of fluence and pulse overlap (PO). Twenty-five extracted human teeth crowns were cut longitudinally into slices of approximately 1.5-mm thick and randomly divided into nine groups of five. Samples in groups 1 to 8 were ablated with an ultrashort pulsed laser through a galvanometric scanning system. Samples in group 9 were prepared using a mechanical rotary instrument. The surface roughness of samples from each group was then measured using a three-dimensional profile measurement laser microscope, and wettability was evaluated by measuring the contact angle of a drop of water on the prepared dentin surface using an optical contact angle measuring device. The results showed that both laser fluence and PO had an effect on dentin surface roughness. Specifically, a higher PO decreased dentin surface roughness and reduced the effect of high-laser fluence on decreasing the surface roughness in some groups. Furthermore, all ablated dentin showed a contact angle of approximately 0 deg, meaning that laser ablation significantly improved wettability. Adjustment of ultrashort pulsed laser parameters can, therefore,significantly alter dentin surface roughness and wettability. PMID- 26018790 TI - Effect of motion artifacts and their correction on near-infrared spectroscopy oscillation data: a study in healthy subjects and stroke patients. AB - Functional near-infrared spectroscopy is prone to contamination by motion artifacts (MAs). Motion correction algorithms have previously been proposed and their respective performance compared for evoked rain activation studies. We study instead the effect of MAs on "oscillation" data which is at the basis of functional connectivity and autoregulation studies. We use as our metric of interest the interhemispheric correlation (IHC), the correlation coefficient between symmetrical time series of oxyhemoglobin oscillations. We show that increased motion content results in a decreased IHC. Using a set of motion-free data on which we add real MAs, we find that the best motion correction approach consists of discarding the segments of MAs following a careful approach to minimize the contamination due to band-pass filtering of data from "bad" segments spreading into adjacent "good" segments. Finally, we compare the IHC in a stroke group and in a healthy group that we artificially contaminated with the MA content of the stroke group, in order to avoid the confounding effect of increased motion incidence in the stroke patients. After motion correction, the IHC remains lower in the stroke group in the frequency band around 0.1 and 0.04 Hz, suggesting a physiological origin for the difference. We emphasize the importance of considering MAs as a confounding factor in oscillation-based functional near-infrared spectroscopy studies. PMID- 26018792 TI - Irregular rhythm and atrial metabolism are key for the evolution of proarrhythmic atrial remodeling in atrial fibrillation. PMID- 26018791 TI - Arrhythmia causes lipid accumulation and reduced glucose uptake. AB - Atrial fibrillation (AF) is characterized by irregular contractions of atrial cardiomyocytes and increased energy demand. The aim of this study was to characterize the influence of arrhythmia on glucose and fatty acid (FA) metabolism in cardiomyocytes, mice and human left atrial myocardium. Compared to regular pacing, irregular (pseudo-random variation at the same number of contractions/min) pacing of neonatal rat cardiomyocytes induced shorter action potential durations and effective refractory periods and increased diastolic [Ca(2+)]c. This was associated with the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and AMP-activated protein kinase (AMPK). Membrane expression of fatty acid translocase (FAT/CD36) and (14)C-palmitic acid uptake were augmented while membrane expression of glucose transporter subtype 4 (GLUT 4) as well as (3)H-glucose uptake were reduced. Inhibition of AMPK and CaMKII prevented these arrhythmia-induced metabolic changes. Similar alterations of FA metabolism were observed in a transgenic mouse model (RacET) for spontaneous AF. Consistent with these findings samples of left atrial myocardium of patients with AF compared to matched samples of patients with sinus rhythm showed up-regulation of CaMKII and AMPK and increased membrane expression of FAT/CD36, resulting in lipid accumulation. These changes of FA metabolism were accompanied by decreased membrane expression of GLUT-4, increased glycogen content and increased expression of the pro-apoptotic protein bax. Irregular pacing of cardiomyocytes increases diastolic [Ca(2+)]c and activation of CaMKII and AMPK resulting in lipid accumulation, reduced glucose uptake and increased glycogen synthesis. These metabolic changes are accompanied by an activation of pro-apoptotic signalling pathways. PMID- 26018793 TI - Identification of time-dependent biomarkers and effects of exposure to volatile organic compounds using high-throughput analysis. AB - Volatile organic compounds (VOCs) can be easily taken up by humans, leading to various diseases, such as respiratory system and central nervous system disorders. Environmental risk assessment is generally conducted using traditional tests, which may be time-consuming and technically challenging. Therefore, analysis of the effects of VOCs, such as toluene, ethylbenzene, and xylene, may be improved by use of novel, high-throughput methods, such as microarray analysis. In this study, we examined the effects of VOCs exposure in humans on gene expression and methylation using microarray analysis. We recruited participants who had short-term exposure, long-term exposure, or no exposure. We then analyzed changes in gene expression in blood samples from these participants. A total of 866 genes were upregulated, while 366 genes were downregulated in the short-term exposure group. Similarly, in the long-term exposure group, a total of 852 and 480 genes were up- or downregulated, respectively. Hierarchical clustering analysis was used to divide the clustered genes into nine clusters to investigate the expression of variations in accordance with the exposure period. And the methylation microarray was performed at the same time to see whether this expression variation is related to the epigenetic study. Finally, we have 5 genes that were upregulated and 12 genes that were downregulated, gradually and respectively, so these genes are expected to function as biomarkers of the duration of exposure to VOCs. Further research is required to determine the time-dependent effects of VOCs on epigenetic regulation of gene expression. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1563-1570, 2016. PMID- 26018795 TI - Metasurface Reflector (MSR) Loading for High Performance Small Microstrip Antenna Design. AB - A meander stripline feed multiband microstrip antenna loaded with metasurface reflector (MSR) structure has been designed, analyzed and constructed that offers the wireless communication services for UHF/microwave RFID and WLAN/WiMAX applications. The proposed MSR assimilated antenna comprises planar straight forward design of circular shaped radiator with horizontal slots on it and 2D metasurface formed by the periodic square metallic element that resembles the behavior of metamaterials. A custom made high dielectric bio-plastic substrate (epsilonr = 15) is used for fabricating the prototype of the MSR embedded planar monopole antenna. The details of the design progress through numerical simulations and experimental results are presented and discussed accordingly. The measured impedance bandwidth, radiation patterns and gain of the proposed MSR integrated antenna are compared with the obtained results from numerical simulation, and a good compliance can be observed between them. The investigation shows that utilization of MSR structure has significantly broadened the -10 dB impedance bandwidth than the conventional patch antenna: from 540 to 632 MHz (17%), 467 to 606 MHz (29%) and 758 MHz to 1062 MHz (40%) for three distinct operating bands centered at 0.9, 3.5 and 5.5 GHz. Additionally, due to the assimilation of MSR, the overall realized gains have been upgraded to a higher value of 3.62 dBi, 6.09 dBi and 8.6 dBi for lower, middle and upper frequency band respectively. The measured radiation patterns, impedance bandwidths (S11<-10 dB) and gains from the MSR loaded antenna prototype exhibit reasonable characteristics that can satisfy the requirements of UHF/microwave (5.8 GHz) RFID, WiMAX (3.5/5.5 GHz) and WLAN (5.2/5.8 GHz) applications. PMID- 26018794 TI - Capping protein integrates multiple MAMP signalling pathways to modulate actin dynamics during plant innate immunity. AB - Plants and animals perceive diverse microbe-associated molecular patterns (MAMPs) via pattern recognition receptors and activate innate immune signalling. The actin cytoskeleton has been suggested as a target for innate immune signalling and a key transducer of cellular responses. However, the molecular mechanisms underlying actin remodelling and the precise functions of these rearrangements during innate immunity remain largely unknown. Here we demonstrate rapid actin remodelling in response to several distinct MAMP signalling pathways in plant epidermal cells. The regulation of actin dynamics is a convergence point for basal defence machinery, such as cell wall fortification and transcriptional reprogramming. Our quantitative analyses of actin dynamics and genetic studies reveal that MAMP-stimulated actin remodelling is due to the inhibition of capping protein (CP) by the signalling lipid, phosphatidic acid. In addition, CP promotes resistance against bacterial and fungal phytopathogens. These findings demonstrate that CP is a central target for the plant innate immune response. PMID- 26018796 TI - Anabolic effect of the traditional Chinese medicine compound tanshinone IIA on myotube hypertrophy is mediated by estrogen receptor. AB - Skeletal muscle loss during menopause is associated with a higher risk of developing diabetes type II and the general development of the metabolic syndrome. Therefore, strategies combining nutritional and training interventions to prevent muscle loss are necessary. Danshen Si Wu is a traditional Chinese medicine used for menopausal complains. One of the main compounds of Danshen Si Wu is tanshinone IIA. Physiological effects of tanshinone IIA have been described as being mediated via the estrogen receptor. Therefore, it was the aim of this study to determine its tissue specific ERalpha- and ERbeta-mediated estrogenic activity, to investigate its antiestrogenic properties, and, particularly, to study estrogen receptor-mediated biological responses to tanshinone IIA on skeletal muscle cells. The purity of tanshinone IIA was analyzed by LC-DAD-MS/MS analysis. ERalpha/ERbeta-mediated activity was dose-dependently analyzed in HEK 239 cells transfected with ERalpha or ERbeta expression vectors and respective reporter genes. Androgenic, antiandrogenic, and antiestrogenic properties of tanshinone IIA were analyzed in a yeast reporter gene assay. The effects of tanshinone IIA on proliferation and cell cycle distribution were investigated in ERalpha positive T47D breast cancer cells. The ability of tanshinone IIA to stimulate estrogen receptor-mediated myotube hypertrophy was studied in C2C12 myoblastoma cells. Our data show that tanshinone IIA is quite potent at stimulating ERalpha and ERbeta reporter genes with comparable efficacy. Tanshinone IIA displayed antiestrogenic and also antiandrogenic properties in a yeast reporter gene assay. It inhibited the growth of T47D breast cancer cells by suppressing proliferation and arresting the cells in G0/G1. Tanshinone IIA also stimulated the hypertrophy of C2C12 myotubes via an estrogen receptor-mediated mechanism. Summarizing our results, tanshinone IIA can be characterized as an estrogen receptor partial agonist with antiandrogenic properties. It seems to inhibit ERalpha-mediated cell proliferation but induces ERbeta-related biological responses like hypertrophy of myotubes. These findings are interesting with respect to the treatment of a variety of complains of postmenopausal females, including muscle wasting. PMID- 26018797 TI - Quantitation of Crocins and picrocrocin in saffron by HPLC: application to quality control and phytochemical differentiation from other crocus taxa. AB - A chromatographic method was developed and fully validated for the determination of the major saffron constituents, i.e., picrocrocin and five major crocins. Dried samples (styles of Crocus sativus and other Crocus taxa) were extracted with MeOH : water (1 : 1, v/v), and chromatographic separation of the analytes was achieved by reversed-phase chromatography using a gradient elution. Full validation was performed using spiked samples with analytes, which were isolated, purified, and characterized by MS due to a lack of commercial standards. The method showed a good fit (r2 > 0.999) for all analytes with limit of quantitation values in the range of 1-15 ug/mL, and demonstrated adequate intra- and inter precision (< 15 % RSD) and accuracy (< 7 % RE). The method was applied to the analysis of various commercial saffron samples and of indigenous Crocus taxa and allowed for the first time the absolute quantitation of several Crocus components. PMID- 26018798 TI - Clinicopathological characteristics and treatment outcomes of Chinese patients with genitourinary embryonal rhabdomyosarcoma. AB - BACKGROUND: Genitourinary embryonal rhabdomyosarcoma is rarely reported in China. This retrospective analysis aimed to characterize the clinicopathologic features and treatment outcomes of genitourinary embryonal rhabdomyosarcoma in a sample of Chinese patients. METHODS: Basic demographic and clinical data of 29 patients, who were diagnosed with genitourinary embryonal rhabdomyosarcoma between January 2000 and December 2011, were retrieved and analyzed. RESULTS: In these patients, 25 were males and 4 were females with a median age of 12 years. Paratesticule was the most common lesion site, followed by the prostate, bladder, and vagina. The median tumor size was 5.80 cm. Six patients had clinically positive regional nodes. At the initial diagnosis, patients had a metastatic disease. According to the TNM staging classification for the IRS-IV, phase I lesions were detected in ten cases, phase II lesions in six cases, phase III lesions in four cases, and phase IV lesions in nine cases. The median survival of all patients was 63 (range from 6 to 118) months. The 1-, 3-, and 5-year survival rates for these patients were 93%, 83%, and 52%, respectively. Multivariate analyses demonstrated that staging and anemia were significant predictors of prognosis. CONCLUSIONS: Our findings suggest that metastasis predicts a poor prognosis. Chemotherapy played an important role in comprehensive treatment. Palliative and neo-adjuvant chemotherapy could increase median survival time. PMID- 26018799 TI - Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells. AB - BACKGROUND: P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770. METHODS AND RESULTS: F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR. CONCLUSION: The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials. PMID- 26018800 TI - omega3-polyunsaturated fatty acids suppress lipoprotein-associated phospholipase A2 expression in macrophages and animal models. AB - SCOPE: omega3-polyunsaturated fatty acids (omega3-PUFAs) have beneficial effects on cardiovascular function, and lipoprotein-associated phospholipase A2 (Lp-PLA2 ) is associated with the risk of cardiovascular disease. Here, we investigated the effects of omega3-PUFAs on Lp-PLA2 expression in vitro and in vivo and explored the mechanisms involved. METHODS AND RESULTS: Human monocyticcells (THP 1) were induced into macrophages in an in vitro model. omega3-PUFAs suppressed Lp PLA2 expression; the suppression induced by docosahexaenoic acid (DHA) was related to reduced inflammation. Tumor necrosis factor-alpha (TNF-alpha) was employed to stimulate the phosphorylation of p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappaB (NF-kappaB) p65 and Lp-PLA2 expression in macrophages. The stimulation was inhibited by DHA and the anti-inflammatory drug sodium salicylate. Moreover, the stimulation of Lp-PLA2 expression by TNF-alpha could be suppressed by NF-kappaB and MAPK pathway inhibitors. Then, chronic inflammation was induced in an in vivo mouse model, resulting in an increase in Lp-PLA2 expression in peripheral blood mononuclear cells (PBMCs) and arteries. This increase was suppressed by omega3-PUFAs. Inhibition of Lp-PLA2 transcription in PBMCs was also observed in omega3-PUFA-enriched swine. CONCLUSION: Our results demonstrate that the protective effects of omega3-PUFAs against cardiovascular events may be related to the suppression of Lp-PLA2 levels. PMID- 26018801 TI - Biotransformation and metabolic profile of caudatin-2,6-dideoxy-3-O-methy-beta-d cymaropyranoside with human intestinal microflora by liquid chromatography quadrupole time-of-flight mass spectrometry. AB - In our previous studies, caudatin-2,6-dideoxy-3-O-methy-beta-d- cymaropyranoside (CDMC) was for the first time isolated from Cynanchum auriculatum Royle ex Wightand and was reported to possess a wide range of biological activities. However, the routes and metabolites of CDMC produced by intestinal bacteria are not well understood. In this study, ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technique combined with Metabolynx(TM) software was applied to analyze metabolites of CDMC by human intestinal bacteria. The incubated samples collected for 48 h in an anaerobic incubator and extracted with ethyl acetate were analyzed by UPLC-Q-TOF-MS within 12 min. Eight metabolites were identified based on MS and MS/MS data. The results indicated that hydrolysis, hydrogenation, demethylation and hydroxylation were the major metabolic pathways of CDMC in vitro. Seven strains of bacteria including Bacillus sp. 46, Enterococcus sp. 30 and sp. 45, Escherichia sp. 49A, sp. 64, sp. 68 and sp. 75 were further identified using 16S rRNA gene sequencing owing to their relatively strong metabolic capacity toward CDMC. The present study provides important information about metabolic routes of CDMC and the roles of different intestinal bacteria in the metabolism of CDMC. Moreover, those metabolites might influence the biological effect of CDMC in vivo, which affects the clinical effects of this medicinal plant. PMID- 26018802 TI - An ONIOM and MD Investigation of Possible Monofunctional Activity of Human 8 Oxoguanine-DNA Glycosylase (hOgg1). AB - Since the formation of 8-oxoguanine (OG) is one of the most common DNA-damaging events, cells have evolved efficient repair processes to avoid the mutagenic effects associated with this lesion, including base excision repair (BER) initiated by hOgg1. In the present work, three distinct mechanisms for deglycosylation catalyzed by hOgg1 that represent monofunctional activity were characterized using a combination of molecular dynamics (MD) simulations on the full DNA-enzyme complex and ONIOM calculations on a truncated DNA-protein model. The initial lysine activation step common to all pathways involves proton transfer from (cationic) K249 to (anionic) C253 and subsequent active-site rearrangement to align key amino acids and/or water for the next reaction step. In the first mechanism, K249 initiates deglycosylation as the nucleophile and the resulting DNA-protein cross-link is hydrolyzed to generate an abasic site. In the remaining two mechanisms, an active-site water molecule is the nucleophile, which is activated by either K249 or D268. These latter mechanisms are supported by MD simulations that reveal an abundance of water in the active site that could function as the nucleophile. Our ONIOM model suggests that the most likely mechanism involves water nucleophile activation by K249, which allows the active site aspartate (D268) to electrostatically stabilize the charge buildup on the sugar residue throughout the entire reaction pathway. This newly conjectured mechanism is consistent with the proposed activity of other monofunctional glycosylases. In addition to providing the first atomic level evidence for a monofunctional hOgg1 catalytic pathway, the mechanistic details revealed in the present work can be used to direct future large-scale reaction modeling on the entire DNA-protein complex, which can be coupled with experimental kinetic data to afford a reliable comparison of the potential mono- and bifunctional activity of this crucial enzyme. PMID- 26018803 TI - Influence of extracellular matrix components on the expression of integrins and regeneration of adult retinal ganglion cells. AB - PURPOSE: Retinal ganglion cells (RGCs) are exposed to injury in a variety of optic nerve diseases including glaucoma. However, not all cells respond in the same way to damage and the capacity of individual RGCs to survive or regenerate is variable. In order to elucidate factors that may be important for RGC survival and regeneration we have focussed on the extracellular matrix (ECM) and RGC integrin expression. Our specific questions were: (1) Do adult RGCs express particular sets of integrins in vitro and in vivo? (2) Can the nature of the ECM influence the expression of different integrins? (3) Can the nature of the ECM affect the survival of the cells and the length or branching complexity of their neurites? METHODS: Primary RGC cultures from adult rat retina were placed on glass coverslips treated with different substrates: Poly-L-Lysine (PL), or PL plus laminin (L), collagen I (CI), collagen IV (CIV) or fibronectin (F). After 10 days in culture, we performed double immunostaining with an antibody against betaIII-Tubulin to identify the RGCs, and antibodies against the integrin subunits: alphaV, alpha1, alpha3, alpha5, beta1 or beta3. The number of adhering and surviving cells, the number and length of the neurites and the expression of the integrin subunits on the different substrates were analysed. RESULTS: PL and L were associated with the greatest survival of RGCs while CI provided the least favourable conditions. The type of substrate affected the number and length of neurites. L stimulated the longest growth. We found at least three different types of RGCs in terms of their capacity to regenerate and extend neurites. The different combinations of integrins expressed by the cells growing on different substrata suggest that RGCs expressed predominantly alpha1beta1 or alpha3beta1 on L, alpha1beta1 on CI and CIV, and alpha5beta3 on F. The activity of the integrins was demonstrated by the phosphorylation of focal adhesion kinase (FAK). CONCLUSIONS: Adult rat RGCs can survive and grow in the presence of different ECM tested. Further studies should be done to elucidate the different molecular characteristics of the RGCs subtypes in order to understand the possible different sensitivity of different RGCs to damage in diseases like glaucoma in which not all RGCs die at the same time. PMID- 26018804 TI - Flexibility Correlation between Active Site Regions Is Conserved across Four AmpC beta-Lactamase Enzymes. AB - beta-lactamases are bacterial enzymes that confer resistance to beta-lactam antibiotics, such as penicillins and cephalosporins. There are four classes of beta-lactamase enzymes, each with characteristic sequence and structure properties. Enzymes from class A are the most common and have been well characterized across the family; however, less is known about how physicochemical properties vary across the C and D families. In this report, we compare the dynamical properties of four AmpC (class C) beta-lactamases using our distance constraint model (DCM). The DCM reliably predicts thermodynamic and mechanical properties in an integrated way. As a consequence, quantitative stability/flexibility relationships (QSFR) can be determined and compared across the whole family. The DCM calculates a large number of QSFR metrics. Perhaps the most useful is the flexibility index (FI), which quantifies flexibility along the enzyme backbone. As typically observed in other systems, FI is well conserved across the four AmpC enzymes. Cooperativity correlation (CC), which quantifies intramolecular couplings within structure, is rarely conserved across protein families; however, it is in AmpC. In particular, the bulk of each structure is composed of a large rigid cluster, punctuated by three flexibly correlated regions located at the active site. These regions include several catalytic residues and the Omega-loop. This evolutionary conservation combined with active their site location strongly suggests that these coupled dynamical modes are important for proper functioning of the enzyme. PMID- 26018805 TI - D-Amino Acid Substitution of Peptide-Mediated NF-kappaB Suppression in mdx Mice Preserves Therapeutic Benefit in Skeletal Muscle, but Causes Kidney Toxicity. AB - In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, chronic activation of the classical nuclear factor-kappaB (NF-kappaB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of inhibitor of kappaB kinase (IKK)-mediated NF-kappaB activation using L-isomer NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdx mouse. For our studies, the NBD peptide is synthesized as a fusion peptide with an eight-lysine (8K) protein transduction domain to facilitate intracellular delivery. We hypothesized that the d-isoform peptide could have a greater effect than the naturally occurring L-isoform peptide due to the longer persistence of the D-isoform peptide in vivo. In this study, we compared systemic treatment with low (1 mg/kg) and high (10 mg/kg) doses of L- and D-isomer 8K-wild-type-NBD peptide in mdx mice. Treatment with both L- or D-isoform 8K-wild-type-NBD peptide resulted in decreased activation of NF-kappaB and improved histology in skeletal muscle of the mdx mouse. However, we observed kidney toxicity (characterized by proteinuria), increased serum creatinine, activation of NF-kappaB and pathological changes in kidney cortex that were most severe with treatment with the D-isoform of 8K-wild-type-NBD peptide. The observed toxicity was also seen in normal mice. PMID- 26018807 TI - Inflammatory Myofibroblastic Tumor of the Kidney and Bilateral Lung Nodules in a Child Mimicking Wilms Tumor With Lung Metastases. AB - Renal inflammatory myofibroblastic tumor (IMT) is an extremely rare lesion especially in children. This report describes a case of renal IMT accompanied by multiple lung nodules mimicking Wilms tumor with lung metastasis in a 3-year-old boy. To our knowledge, this is a unique case of IMT which has not been reported in the literature previously. PMID- 26018806 TI - Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL 33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis. AB - The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3(-/-)) and wild-type (LGALS3(+/+)) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3(-/-) mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR gamma, Cd36, Abca-1 and FAS. However, as opposed to LGALS3(-/-) mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b(+)Ly6C(hi) monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1beta and NADPH-oxidase enzymes mRNA expression. Thus, obesity-driven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b(+)IL-13(+) cells, increased levels of IL-33 and IL-13 and up regulated IL-33, ST2 and IL-13 mRNA in liver compared with LGALS3(-/-) mice. IL 33 failed to induce ST2 upregulation and IL-13 production by LGALS3(-/-) peritoneal macrophages in vitro. Administration of IL-33 in vivo enhanced liver fibrosis in HFD-fed mice in both genotypes, albeit to a significantly lower extent in LGALS3(-/-) mice, which was associated with less numerous hepatic IL-13 expressing CD11b(+) cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis. PMID- 26018808 TI - The Safety and Effectiveness of Patient-controlled Analgesia in Outpatient Children and Young Adults With Cancer: A Retrospective Study. AB - BACKGROUND: Patient-controlled analgesia (PCA) is safe and effective in hospitalized children; however, data regarding its use for outpatients are limited. The aims of the study are to determine the safety of outpatient PCA and to compare the standard and proxy PCA groups. METHODS: All patients receiving outpatient PCA over 54 months were included in this retrospective study. Data regarding age, sex, diagnosis, PCA initiation/discontinuation circumstances, patient versus proxy-authorized PCA type, opioid doses, pain scores, and complications were collected. Nonparametric tests (Wilcoxon-Mann-Whitney test for comparing 2 groups or Kruskal-Wallis rank-sum test for comparing >2 groups) were used to compare duration of PCA use, opioid doses, pain scores, and circumstances of initiation and discontinuation of outpatient PCA. RESULTS: Forty-five patients used 69 outpatient PCAs. The complication rate was 0.36%. The starting mean MED (mg/kg/d) was 1.67 when initiation was for an outpatient and 4.04 for those discharged from the hospital with PCA; this difference was not statistically significant (P=0.13). The analysis of mean opioid doses in relationship to the circumstances for the discontinuation of the outpatient PCA revealed a significantly higher dose (mg/kg/d) in the group of patients who died (19.54) than in the group with a change of status to inpatient or transfer to another hospital or hospice (3.70) and in the group in which PCA was discontinued because pain management no longer required a PCA (1.19). The mean opioid daily doses and pain scores were significantly higher at the end of life (P<0.0001). CONCLUSIONS: Outpatient PCA use for children and young adults with cancer is safe. PMID- 26018809 TI - Health-related Quality of Life in Long-term Survivors of Brain Tumors in Childhood and Adolescence: A Serial Study Spanning a Decade. AB - Survivors of brain tumors in childhood experience adverse sequelae that are greater in prevalence and severity than those encountered by survivors of all other forms of cancer in early life, reflected in a burden of morbidity by instruments measuring health-related quality of life (HRQL). However, there are few studies of the change in HRQL over time in such populations. Patients who were above 5 years of age, at least 2 years from completion of therapy, and able to communicate in English were eligible for study of HRQL by the Health Utilities Index HUI2 and HUI3 at study entry, and again 5 and 10 years later. An initial cohort of 40 patients was reduced to 37 and 25 at the second and third time points, respectively, although only 1 death occurred during the study. HRQL showed a progressive decline over the decade, reaching conventional levels of clinical significance for the sizes of the changes. Median scores for HUI2 were 0.93, 0.90, and 0.88; and for HUI3 were 0.88, 0.85, and 0.77 at baseline, 5, and 10 years, respectively. The serial decline in HRQL demands further examination and an exploration of potential targets for therapeutic intervention. PMID- 26018810 TI - White Matter Degeneration in Atypical Alzheimer Disease. AB - PURPOSE: To assess white matter (WM) tract damage in patients with atypical Alzheimer disease (AD), including early-onset AD (EOAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), by using diffusion-tensor magnetic resonance (MR) imaging and to identify similarities and differences across the AD spectrum. MATERIALS AND METHODS: This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. WM tract damage and cortical atrophy were assessed by using diffusion-tensor MR imaging and voxel-based morphometry, respectively, in 28 patients with EOAD, 12 patients with lvPPA, and 13 patients with PCA relative to age- and sex-matched healthy subjects. Conjunction and interaction analyses were used to define overlapping and syndrome-specific patterns of brain damage. RESULTS: Patients with EOAD, lvPPA, and PCA shared a common pattern of WM damage that involved the body of the corpus callosum, fornix, and main anterior-posterior pathways (P < .05). They also shared cortical atrophy of the left temporoparietal regions and precuneus (P < .05, family-wise error corrected). Patients with EOAD also had specific damage to the genu and splenium of the corpus callosum and parahippocampal tract bilaterally (P < .05). In all patients with AD, particularly in the two focal forms (lvPPA and PCA), WM damage was more severe and widely distributed than expected on the basis of cortical atrophy. CONCLUSION: In atypical AD clinical phenotypes, the distribution of WM damage exceeds cortical atrophy and may reflect the pathologic dissemination through structural connections from atrophic to unaffected cortical regions. WM degeneration may be an early marker of AD pathologic changes in EOAD and focal AD forms. PMID- 26018814 TI - Valuing blue carbon: carbon sequestration benefits provided by the marine protected areas in Colombia. AB - Marine protected areas are aimed to protect and conserve key ecosystems for the provision of a number of ecosystem services that are the basis for numerous economic activities. Among the several services that these areas provide, the capacity of sequestering (capturing and storing) organic carbon is a regulating service, provided mainly by mangroves and seagrasses, that gains importance as alternatives for mitigating global warming become a priority in the international agenda. The objective of this study is to value the services associated with the capture and storage of oceanic carbon, known as Blue Carbon, provided by a new network of marine protected areas in Colombia. We approach the monetary value associated to these services through the simulation of a hypothetical market for oceanic carbon. To do that, we construct a benefit function that considers the capacity of mangroves and seagrasses for capturing and storing blue carbon, and simulate scenarios for the variation of key variables such as the market carbon price, the discount rate, the natural rate of loss of the ecosystems, and the expectations about the post-Kyoto negotiations. The results indicate that the expected benefits associated to carbon capture and storage provided by these ecosystems are substantial but highly dependent on the expectations in terms of the negotiations surrounding the extension of the Kyoto Protocol and the dynamics of the carbon credit's demand and supply. We also find that the natural loss rate of these ecosystems does not seem to have a significant effect on the annual value of the benefits. This approach constitutes one of the first attempts to value blue carbon as one of the services provided by conservation. PMID- 26018813 TI - Measurement of C-reactive protein, procalcitonin and neutrophil elastase in saliva of COPD patients and healthy controls: correlation to self-reported wellbeing parameters. AB - BACKGROUND: Saliva is increasingly promoted as an alternative diagnostic bio sample to blood; however its role in respiratory disease requires elucidation. Our aim was to investigate whether C-reactive protein (CRP), procalcitonin (PCT) and neutrophil elastase (NE) could be measured in unstimulated whole saliva, and to explore differences between COPD patients and controls with normal lung function. We also determined the relationship between these salivary biomarkers and self-reported COPD-relevant metrics. METHODS: Salivary CRP, PCT and NE levels were measured at each of 3 visits over a 14-day period alongside spirometry and a daily self-assessment dairy in 143 subjects: 20 never-smokers and 25 smokers with normal spirometry; 98 COPD patients [GOLD Stage I, 16; Stage II, 32; Stage III, 39; Stage IV, 11]. Twenty-two randomly selected subjects provided simultaneous blood samples. RESULTS: Levels of each salivary biomarker could distinguish between the above cohorts. Significant differences remained for salivary CRP and NE (p < 0.05) following adjustment for age, gender, sampling time, gum disease and total co-morbidities; but not for BMI except for salivary NE, which remained higher in smokers compared to non-smokers and stable COPD subjects (p < 0.001). Patients with acute COPD exacerbations had a median increase in all 3 salivary biomarkers (p < 0.001); CRP: median 5.74 ng/ml, [interquartile range (IQR) 2.86 12.25], PCT 0.38 ng/ml, [IQR 0.22-0.94], and NE 539 ng/ml, [IQR 112.25-1264]. In COPD patients, only salivary CRP and PCT levels correlated with breathing scores (r = 0.14, p < 0.02; r = 0.13, p < 0.03 respectively) and sputum features but not with activities of daily living. Salivary CRP and PCT concentrations strongly correlated with serum counterparts [r = 0.82, (95% CI: 0.72-0.87), p < 0.001 by Spearman's; and r = 0.53, (95% CI: 0.33-0.69), p < 0.006 respectively]; salivary NE did not. CONCLUSIONS: CRP, PCT and NE were reliably and reproducibly measured in saliva, providing clinically-relevant information on health status in COPD; additionally NE distinguished smoking status. All 3 salivary biomarkers increased during COPD exacerbations, with CRP and PCT correlating well with patient-derived clinical metrics. These results provide the conceptual basis for further development of saliva as a viable bio-sample in COPD monitoring and exacerbation management. PMID- 26018815 TI - [From the legacy of Carl Koller. Notations on his experiments with cocaine]. AB - The history of local anesthesia began with the discovery of the anesthetic properties of cocaine by the physician Carl Koller from Vienna 130 years ago. After he had realized the options for painless surgery using this substance, he analyzed cocaine in detail from this point of view and evaluated the drug's significance in animal experiments, in self-experiments and in colleagues. The findings of his experiments were accurately recorded by Koller and after his death remained in the possession of the family for a long time until his daughter Hortense Becker-Koller handed these documents over to the Library of Congress in Washington. These recordings were recently studied and will now be presented to the public for the first time ever. PMID- 26018816 TI - Genetic Diversity and Antibiotic Resistance Patterns of Staphylococcus Aureus Isolated from Leaf Vegetables in Korea. AB - Staphylococcus aureus is an important foodborne pathogen on global basis. The current study investigated the genetic patterns in S. aureus isolates from leaf vegetables (n = 53). Additional isolates from livestock (n = 31) and humans (n = 27) were compared with the leaf vegetable isolates. Genes associated with toxins, antibiotic resistance, and pulsed-field gel electrophoresis (PFGE) patterns were analyzed. At least 1 enterotoxin-encoding gene (sea, seb, sec, sed, and see) was detected in 11 of 53 (20.75%) leaf vegetable isolates. When the agr (accessory gene regulator) grouping was analyzed, agr II was the major group, whereas agr IV was not present in leaf vegetable isolates. All S. aureus isolates from leaf vegetables were resistant to more than one of the antibiotics tested. Nineteen of 53 (35.85%) isolates from leaf vegetables exhibited multidrug-resistance, and 11 of these were MRSA (methicillin-resistant S. aureus). A dendrogram displaying the composite types of S. aureus isolates from 3 origins was generated based on the combination of the toxin genes, agr genes, antibiotic resistance, and PFGE patterns. The isolates could be clustered into 8 major composite types. The genetic patterns of S. aureus isolates from leaf vegetables and humans were similar, whereas those from livestock had unique patterns. This suggests some S. aureus isolates from leaf vegetables to be of human origin. PMID- 26018817 TI - Effects of Interventions Based on Health Behavior Models on Breast Cancer Screening Behaviors of Migrant Women in Turkey. AB - BACKGROUND: Antalya is a city receiving internal and external migration in Turkey, including migrant women in need of developing breast cancer screening behaviors. OBJECTIVE: The aim of this study was to develop breast cancer screening behaviors of migrant women through nursing interventions based on the Health Belief Model and the Health Promotion Model. METHODS: This quasi experimental study was conducted with 200 women (100 women in the intervention group, 100 women in the control group) in Antalya. The intervention group received training, consultancy service, and reminders and was followed up at 3 and 6 months after interventions. RESULTS: The rates of breast self-examination, clinical breast examination and mammography were higher at months 3 and 6 in women in the intervention group compared with the women in the control group. In the intervention group, perceptions of susceptibility and barriers decreased after the interventions, and benefit, health motivation, and self-efficacy perceptions increased. According to month 6 data, in the intervention group, the decrease of each unit in perception of barriers increased the rate of breast self examination 0.8 times and the rate of mammography 0.7 times. An increase of each unit in health motivation increased the rate of clinical breast examination 1.3 times and the rate of mammography 1.5 times. CONCLUSION: Interventions based on health behavior models positively affected breast cancer screening behaviors of migrant women. Health motivations and perceptions of barriers are determinants in performing the screening behaviors. IMPLICATIONS FOR PRACTICE: Migrant women should be supported more by healthcare professionals regarding recognition of breast health and disease and in transportation to screening centers in their new location. PMID- 26018818 TI - Identification of Distress in Oncology Patients: A Comparison of the Hospital Anxiety and Depression Scale and a Thorough Clinical Assessment. AB - BACKGROUND: Screening is recommended to identify cancer patients with distress, anxiety, and depression. The ability of current methods to identify distress in oncology patients is of high importance. OBJECTIVE: We compared the Hospital Anxiety and Depression Scale (HADS) with a thorough clinical assessment. Furthermore, we explored the agreement of HADS with clinical assessment outcomes as a function of age, sex, and treatment intention. METHODS: One hundred forty six oncology patients, representing both sexes, different ages (<65/>= 65 years), and treatment intention (curative/palliative), completed the HADS before the clinical assessment. Two study team members (blind to the HADS results) completed clinical assessments of anxiety, depression, and distress analogous to categories used in the HADS. RESULTS: The HADS identified 49 participants and the clinical assessment 71 participants as having anxiety, depression, or distress. The overall agreement between the HADS and the clinical assessment was moderate. The greatest differences were found to be a function of participant sex and age. Agreement between the methods was better for females than for males in relation to distress and anxiety and better for the older (>= 65 years) than younger participants in relation to depression. By treatment intention, agreement was equal for all domains. CONCLUSION: Especially male and young participants appear to have potential problems that the HADS fails to identify. IMPLICATIONS FOR PRACTICE: When the HADS is used for screening, nurses must be aware of psychosocial problems perceived by patients that are not covered by the HADS. Many patients identified as having distress have resources to manage problems without additional support. PMID- 26018819 TI - "Chemo-Knights" and "Radio-Robby": Provision of Information in Pediatric Oncology. AB - BACKGROUND: Information provision is an important step in enabling pediatric patients to participate in healthcare. Storybooks and patient information brochures represent a channel through which children and adolescents with cancer are informed about their illness. However, the use of such written materials has received little academic attention. OBJECTIVE: The aim of this article was to carry out an exploratory analysis of written information resources for pediatric cancer patients. The potential of these to enhance patient participation will be discussed. METHODS: A convenience sample of 16 written resource materials in English and German were chosen for analysis. Thematic coding was carried out to identify major themes. RESULTS: Subthemes were summarized into 3 main categories: information on diagnosis, treatment, and illness experience. Information was provided on, for example, illness name and etiology, diagnostic and treatment procedures, emotions, and coping strategies. CONCLUSIONS: Storybooks and other written resources on cancer contain a broad array of information and describe illness-related issues to a varying extent. They represent an excellent possibility to ease patient participation in healthcare by providing them with necessary information while also inviting further discussion. IMPLICATIONS FOR PRACTICE: Nurses and other healthcare professionals can use written resource materials to engage in discussions with pediatric patients concerning their illness. Nurses should be aware of the information children and adolescents receive in these materials in order to be able to adequately answer questions that may arise or identify misunderstandings as well as lack of information. PMID- 26018820 TI - Oxygen Sensitivity of Placental Trophoblast Connexins 43 and 46: A Role in Preeclampsia? AB - Several gap junction connexins have been shown to be essential for appropriate placental development and function. It is known that the expression and distribution of connexins change in response to environmental oxygen levels. The placenta develops under various oxygen levels, beginning at a low oxygen tension of approximately 2% and increasing to a tension of 8% after the onset of the uteroplacental circulation. Moreover, it has been shown that during preeclampsia (PE) placentas are subjected to chronic hypoxia. Therefore, we investigated oxygen sensitivity of placental connexins 43 and 46. Using the trophoblast cell line Jar, we demonstrated that the expression of connexin43 increased during acute hypoxia but decreased during chronic hypoxia. Chronic hypoxia resulted in the translocation of connexin43 from the membrane to the cytoplasm and in a reduction in its communication properties. In contrast, the expression of connexin46 was down-regulated during chronic hypoxia and was translocated from perinuclear areas to the cell membrane. Hypoxia-inducible factor (HIF) knockdown showed that the translocation of connexin43 but not that of connexin46 was HIF 2alpha dependent and was mediated by phosphoinositide 3-kinase. The up-regulation of connexin43 in combination with the down-regulation of connexin46 was confirmed in placental explants cultivated under low oxygen and in placentas with early onset PE. Taken together, in Jar cells, placental connexins 43 and 46 are regulated during periods of low oxygen in opposite manners. The oxygen sensing of connexins in the trophoblast may play a role in physiological and pathophysiological oxygen conditions and thus may contribute to PE. PMID- 26018821 TI - How Complex, Probable, and Predictable is Genetically Driven Red Queen Chaos? AB - Coevolution between two antagonistic species has been widely studied theoretically for both ecologically- and genetically-driven Red Queen dynamics. A typical outcome of these systems is an oscillatory behavior causing an endless series of one species adaptation and others counter-adaptation. More recently, a mathematical model combining a three-species food chain system with an adaptive dynamics approach revealed genetically driven chaotic Red Queen coevolution. In the present article, we analyze this mathematical model mainly focusing on the impact of species rates of evolution (mutation rates) in the dynamics. Firstly, we analytically proof the boundedness of the trajectories of the chaotic attractor. The complexity of the coupling between the dynamical variables is quantified using observability indices. By using symbolic dynamics theory, we quantify the complexity of genetically driven Red Queen chaos computing the topological entropy of existing one-dimensional iterated maps using Markov partitions. Co-dimensional two bifurcation diagrams are also built from the period ordering of the orbits of the maps. Then, we study the predictability of the Red Queen chaos, found in narrow regions of mutation rates. To extend the previous analyses, we also computed the likeliness of finding chaos in a given region of the parameter space varying other model parameters simultaneously. Such analyses allowed us to compute a mean predictability measure for the system in the explored region of the parameter space. We found that genetically driven Red Queen chaos, although being restricted to small regions of the analyzed parameter space, might be highly unpredictable. PMID- 26018822 TI - Stable Cobalt Nanoparticles and Their Monolayer Array as an Efficient Electrocatalyst for Oxygen Evolution Reaction. AB - Monodisperse cobalt (Co) nanoparticles (NPs) were synthesized and stabilized against oxidation via reductive annealing at 600 degrees C. The stable Co NPs are active for catalyzing the oxygen evolution reaction (OER) in 0.1 M KOH, producing a current density of 10 mA/cm(2) at an overpotential of 0.39 V (1.62 V vs RHE, no iR-correction). Their catalysis is superior to the commercial Ir catalyst in both activity and stability. These Co NPs are also assembled into a monolayer array on the working electrode, allowing the detailed study of their intrinsic OER activity. The Co NPs in the monolayer array show 15 times higher turnover frequency (2.13 s(-1)) and mass activity (1949 A/g) than the NPs deposited on conventional carbon black (0.14 s(-1) and 126 A/g, respectively) at an overpotential of 0.4 V. These stable Co NPs are a promising new class of noble metal-free catalyst for water splitting. PMID- 26018823 TI - Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy. AB - Mitochondria serve as membrane sources and signaling platforms for regulating autophagy. Accumulating evidence has also shown that damaged mitochondria are removed through both selective mitophagy and general autophagy in response to mitochondrial and oxidative stresses. Protein ubiquitination through mitochondrial E3 ligases plays an integrative role in mitochondrial outer membrane protein degradation, mitochondrial dynamics, and mitophagy. Here we showed that MUL1, a mitochondria-localized E3 ligase, regulates selenite-induced mitophagy in an ATG5 and ULK1-dependent manner. ULK1 partially translocated to mitochondria after selenite treatment and interacted with MUL1. We also demonstrated that ULK1 is a novel substrate of MUL1. These results suggest the association of mitochondria with autophagy regulation and provide a new mechanism for the beneficial effects of selenium as a chemopreventive agent. PMID- 26018824 TI - The efficacy of a generic doxycycline tablet in the treatment of canine monocytic ehrlichiosis. AB - The objective of the present study was to evaluate the therapeutic efficacy of a generic doxycycline tablet (DoxyVet) against Ehrlichia canis infection in dogs. Canine monocytic ehrlichiosis is caused by the bacterium E. canis and transmitted by the brown kennel tick (Rhipicephalus sanguineus). Six disease-free and tick free dogs were infested with E. canis infected ticks. Once diagnosed (with polymerase chain reaction [PCR] analysis and platelet counts) as positive for infection, doxycycline tablets were administered orally once a day for 20 consecutive days, at a target dose level of 10 mg/kg. The actual dose administered was calculated as ranging between 10 mg/kg and 11.7 mg/kg. The PCR analysis, 28 days after the first administration of the tablets, failed to detect E. canis in any of the dogs. On Day 56 of the study, four of the dogs were diagnosed with E. canis for the second time and a fifth dog was diagnosed on Day 70. The platelet counts of the sixth dog remained within normal levels and it was discharged from the study on Day 84. Doxycycline tablets were then administered to the remaining five infected dogs for 28 consecutive days. Four of these dogs had no positive PCR results during the following 3 months. The fifth dog was diagnosed with E. canis for the third time 58 days after the last tablets of the second treatment had been administered, after which it was rescue treated (doxycycline for a further 28 days). The results indicate that doxycycline administered in tablet form (DoxyVet) at 10 mg/kg - 11.7 mg/kg body mass once daily for 28 consecutive days clears most dogs of infection. The importance of a concomitant tick-control programme is therefore stressed. PMID- 26018825 TI - Hyperpigmentation mechanism of methyl 3,5-di-caffeoylquinate through activation of p38 and MITF induction of tyrosinase. AB - Methyl 3,5-di-caffeoylquinate (3,5-diCQM) has been used for the treatment of various diseases in oriental medicine, but its effect on melanogenesis has not been reported yet. In this study, the molecular mechanism of 3,5-diCQM-induced melanogenesis was investigated. It was found that 3,5-diCQM induced synthesis of melanin pigments in murine B16F10 melanoma cells in a concentration-dependent manner. Treatment of cells with 3,5-diCQM for 48 h increased extracellular and intracellular melanin production and tyrosinase activity. The expressions of tyrosinase, tyrosinase-related protein 1 (TRP1), and TRP2 were up-regulated in a dose-dependent manner 48 h after 3,5-diCQM treatment. Western blot analysis showed that 3,5-diCQM increased the phosphorylation of p38 mitogen-activated protein kinase and cAMP responsive element binding as well as the expression of microphthalmia-associated transcription factor. In addition, 3,5-diCQM-stimulated cAMP production, and 3,5-diCQM-induced tyrosinase activity and melanin synthesis were attenuated by H89, a protein kinase A inhibitor. These results suggested that 3,5-diCQM-mediated activation of the p38 pathway may represent a novel approach for an effective therapy for vitiligo and hair graying. PMID- 26018826 TI - A Meta-analysis of Randomized Clinical Trials of Chemoradiation Therapy in Locally Advanced Pancreatic Cancer. AB - OBJECTIVES: Pancreatic cancer is the fourth most common cause of cancer deaths in the USA. Despite the fact that the radiotherapy in addition to chemotherapy (CT) is frequently employed, the role of chemoradiation therapy (CRT) in the treatment of locally advanced pancreatic cancer (LAPC) remains controversial. We conducted a systemic review and meta-analysis to evaluate the effect of radiation treatment in addition to CT in patients with LAPC. METHODS: Only randomized controlled trials that compared CRT to CT and reported time to event summary were included in this study. The primary end point was overall survival expressed as hazard ratio (HR). Due to significant heterogeneity, random-effects model statistics were used. RESULTS: Five eligible studies were included with a total of 593 patients (CT, N = 298; CRT, N = 295). Two studies demonstrated statistically significant difference in OS in favor of CRT and the rest of the studies did not demonstrate any significant differences. Meta-analysis demonstrated that there was a non-significant trend toward a survival benefit in the CRT arm; HR 0.913 (95 % CI 0.595-1.400, p = 0.675). No significant differences in overall results were seen with sensitivity analysis. CONCLUSIONS: The addition of radiation therapy to CT in the treatment of LAPC is associated with a non-significant trend toward survival advantage. Larger randomized controlled trials using modern CT regimens and radiation techniques are needed to further clarify the role of radiation in this setting. PMID- 26018827 TI - An Unusual Combination: KRAS and BRAF Co-mutated Metastatic Colorectal Cancer. PMID- 26018829 TI - Erosion Mechanism of MoS2-Based Films Exposed to Atomic Oxygen Environments. AB - The erosion mechanism of magnetron sputtered MoS2 films exposed to the atomic oxygen environment was studied and compared with the Ti-doped MoS2 and MoS2/Ti multilayer films. The compositional and structural changes were investigated as a function of incident fluence by Rutherford back scattering (RBS) and focused ion beam combining with scanning electron microscopy (FIB&SEM). The RBS results indicate that the sulfur atoms are eroded by the incident atomic oxygen atoms and the removed sulfur amount increases but the erosion rate decreases with increasing of incident fluence. For pure MoS2 films the erosion process turns to saturate at the end of investigated fluence of 4.8*10(21) O cm(-2), and for Ti doped and MoS2/Ti multilayer films the saturation of sulfur erosion is much earlier around incident fluence of 5.2*10(19) and 2.6*10(19) O cm(-2), respectively. FIB cross-section results reveal that pores structures present in the as-deposited MoS2 films provide a reaction highway, which allows the incident atomic oxygen to be able to reach and react with the sulfur at bottom. Introducing titanium doping or MoS2/Ti multilayer structures definitely reduce the density of pores and defects in the initial films, consequently, erosion process is suppressed or blocked, and the instinct lubricant properties of MoS2 phases can be well-retained in vacuum sliding conditions. PMID- 26018828 TI - Airway management in patients undergoing emergency Cesarean section. AB - Special care is required for airway management of patients undergoing emergency Cesarean section. Although the incidence of difficult intubation and difficult ventilation is similar between pregnant and non-pregnant women, the severity of complications in pregnant patients would be much greater than in non-pregnant patients, if tracheal intubation is found to be difficult: increased risk of pulmonary aspiration, hypoxia, airway obstruction due to laryngeal edema, and a "sleeping baby" being taken out. Rapid-sequence induction of anesthesia is generally indicated to a patient undergoing emergency Cesarean section under general anesthesia. The technique has been evolving, without losing the key premise of minimizing the period of the airway being not protected from pulmonary aspiration, and of permitting rapid wake up if tracheal intubation fails. In this review, I describe the appropriate airway management, based on the current state of knowledge, in a patient undergoing emergency Cesarean section under general anesthesia. PMID- 26018830 TI - Timing and route of migration of mature female blue crabs in a tidal estuary. AB - Information on migration patterns is critical to using no-take migratory corridors and marine reserves to protect the spawning stock of commercially exploited species. Both active and passive acoustic tracking methods quantified movement of commercially and ecologically important blue crabs in the White Oak River estuary, NC, USA. We targeted post-mating female crabs migrating down estuary to oceanic spawning grounds. Crabs travelled approximately 14.1 km mainly in deeper channels and over 12-26 days from mating areas to spawning grounds. No crabs were detected migrating down-estuary in the autumn and only 30% were detected migrating down-estuary in spring. None of the crabs detected near spawning grounds were detected or recaptured back up-estuary, suggesting that they either (i) do not return to the estuary after a one to two week period in the spawning area or (ii) were captured by fishermen. The results from this study demonstrate that (1) acoustic transmitters coupled with passive acoustic receivers provided reliable and valuable data on migration patterns of mature female blue crabs and (2) mature female blue crabs are capable of migrating primarily within deep channels to spawning grounds shortly after insemination. PMID- 26018831 TI - The sensory ecology of adaptive landscapes. AB - In complex environments, behavioural plasticity depends on the ability of an animal to integrate numerous sensory stimuli. The multidimensionality of factors interacting to shape plastic behaviour means it is difficult for both organisms and researchers to predict what constitutes an adaptive response to a given set of conditions. Although researchers may be able to map the fitness pay-offs of different behavioural strategies in changing environments, there is no guarantee that the study species will be able to perceive these pay-offs. We thus risk a disconnect between our own predictions about adaptive behaviour and what is behaviourally achievable given the umwelt of the animal being studied. This may lead to erroneous conclusions about maladaptive behaviour in circumstances when the behaviour exhibited is the most adaptive possible given sensory limitations. With advances in the computational resources available to behavioural ecologists, we can now measure vast numbers of interactions among behaviours and environments to create adaptive behavioural surfaces. These surfaces have massive heuristic, predictive and analytical potential in understanding adaptive animal behaviour, but researchers using them are destined to fail if they ignore the sensory ecology of the species they study. Here, we advocate the continued use of these approaches while directly linking them to perceptual space to ensure that the topology of the generated adaptive landscape matches the perceptual reality of the animal it intends to study. Doing so will allow predictive models of animal behaviour to reflect the reality faced by the agents on adaptive surfaces, vastly improving our ability to determine what constitutes an adaptive response for the animal in question. PMID- 26018832 TI - Neural mechanisms of infant learning: differences in frontal theta activity during object exploration modulate subsequent object recognition. AB - Investigating learning mechanisms in infancy relies largely on behavioural measures like visual attention, which often fail to predict whether stimuli would be encoded successfully. This study explored EEG activity in the theta frequency band, previously shown to predict successful learning in adults, to directly study infants' cognitive engagement, beyond visual attention. We tested 11-month old infants (N = 23) and demonstrated that differences in frontal theta-band oscillations, recorded during infants' object exploration, predicted differential subsequent recognition of these objects in a preferential-looking test. Given that theta activity is modulated by motivation to learn in adults, these findings set the ground for future investigation into the drivers of infant learning. PMID- 26018833 TI - Frontiers in marine movement ecology: mechanisms and consequences of migration and dispersal in marine habitats. PMID- 26018834 TI - Borrelia burgdorferi sensu lato infection pressure shapes innate immune gene evolution in natural rodent populations across Europe. AB - Although parasite-mediated selection is assumed to be the main driver of immune gene evolution, empirical evidence that parasites induce allele frequency changes at host immune genes in time and/or space remains scarce. Here, I show that the frequency of a protective gene variant of the innate immune receptor Toll-like receptor 2 in natural bank vole (Myodes glareolus) populations is positively associated with the strength of Borrelia burgdorferi sensu lato infection risk across the European continent. Thereby, this study provides rare evidence for the role of spatially variable infection pressures in moulding the vertebrate immune system. PMID- 26018835 TI - Or47b-neurons promote male-mating success in Drosophila. AB - Drosophila performs elaborate well-defined rituals of courtship, which involve several types of sensory inputs. Here, we report that Or47b-neurons promote male mating success. Males with Or47b-neurons silenced/ablated exhibit reduced copulation frequency and increased copulation latency. Copulation latency of Or47b-manipulated flies increased proportionately with size of the assay arena, whereas in controls it remained unchanged. While competing for mates, Or47b ablated males are outperformed by intact controls. These results suggest the role of Or47b-neurons in promoting male-mating success. PMID- 26018836 TI - Investigation of Mechanisms for MK-801-Induced Neurotoxicity Utilizing Metabolomic Approach. AB - Single treatment of rats with the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 induces neuronal cell degeneration and death in the retrosplenial/posterior cingulate cortex (RS/PC) region, along with local cerebral glucose utilization. However, the relationship between this neuronal cell degeneration and death and glucose utilization remains unclear. To investigate the mechanism of MK-801-induced neurotoxicity and its relation to glucose utilization, changes in endogenous metabolites in the RS/PC region of MK 801 treated rats were assessed using metabolomics. Inverse correlation between citrulline and arginine levels suggested increased nitric oxide (NO) production. In addition, decreased levels of purine metabolites suggested enhanced xanthine oxidase activity accompanied with reactive oxygen species (ROS) production. Histopathological analysis confirmed that the production of ROS in the RS/PC region was increased by MK-801 and that the nonspecific NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) prevented MK-801-induced neuronal cell death. These results suggest that NO increases oxidative stress-related cell death. Increased levels of metabolites of glucose metabolism suggested enhanced energy production via glycolysis. To confirm the relationship between NO and glucose utilization, positron emission tomography (PET) imaging with [(18)F] fluoro-2-deoxy-d-glucose ([(18)F] FDG) was conducted. [(18)F] FDG-PET imaging accompanied by co-treatment of L-NAME with MK-801 demonstrated that L-NAME ameliorated MK-801-induced glucose utilization.In conclusion, MK-801 induces NO and ROS production in the RS/PC region, which might subsequently induce oxidative stress and in turn neuronal cell death. In addition, MK-801-induced NO production increased glucose utilization and affected glucose metabolism, the imbalance of which might generate additional oxidative stress related to neuronal cell death. PMID- 26018838 TI - Correlation of electrochromic properties and oxidation states in nanocrystalline tungsten trioxide. AB - Although tungsten trioxide (WO3) has been extensively studied since its electrochromic properties were first discovered, the mechanism responsible for the coloration or bleaching effect is still disputed. New insights into the coloration mechanism of electrochromic, nanocrystalline WO3 are provided in this paper by studying thin WO3 films combining the electrochemical and spectroscopic techniques. By employing in situ UV-Vis transmission spectroscopy at a fixed spectral band pass during electrochemical experiments, such as cyclic voltammetry, a two-step insertion process for both protons and lithium ions is identified, of which one step exhibits a significantly higher coloration efficiency than the other. To obtain a better understanding of the insertion process AxWO3 (A = H, Li,...) thin films were studied at different stages of intercalation using UV-Vis and X-ray photoelectron spectroscopy. The results show that the first step of the intercalation process represents the reduction from initial W(6+) to W(5+) and the second step the reduction of W(5+) to W(4+). We found that the blue coloration of this nanocrystalline tungsten trioxide is mainly due to the presence of W(4+) rather than that of W(5+). PMID- 26018837 TI - Sporadic adult-onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes. AB - AIMS: Adult-onset orthochromatic leucodystrophy, associated with pigmented macrophages and hereditary diffuse leucoencephalopathy with spheroids, are two disorders with similar clinical manifestations, radiological characteristics and neuropathological findings. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene are the hallmark of this spectrum of disease. Furthermore, polycystic membranous lipomembranous osteodysplasia with sclerosing leucoencephalopathy is caused by mutations in two genes, DAP12 and TREM2, which encode proteins involved in the same pathways as CSF1R. We describe a case of sporadic adult-onset orthochromatic leucodystrophy associated with pigmented macrophages diagnosed by biopsy without harbouring mutations in the known targeted genes. METHODS AND RESULTS: A 51-year-old woman, with no familial history of neurological diseases, developed a progressive neurological deterioration showing inappropriate behaviour, ataxia, spasticity, axial dystonia and agitation. Radiological images and a stereotaxic biopsy were conclusive with adult-onset orthochromatic leucodystrophy associated with pigmented macrophages. Genetic analysis did not show mutations in either CSF1R, DAP12 or TREM2. CONCLUSIONS: We add support to the idea that all these entities are closely related diseases linked to a convergent metabolic pathway, but caused by different genes or perhaps by the combination of individually non-pathogenic variations of selected genes. Genetic defects are still barely known in a substantial number of adult leucodystrophies. PMID- 26018839 TI - Restorative materials containing antimicrobial agents: is there evidence for their antimicrobial and anticaries effects? A systematic review. AB - The aim of this systematic literature review was to investigate whether the incorporation of antimicrobial agents into dental restorative materials truly exerts an antimicrobial effect against common cariogenic bacteria (primary outcome), and whether the inclusion of antimicrobial agents is able to prevent caries around restorations (secondary outcome). MEDLINE, via PubMed, was searched for papers published between 1980 and 30 November 2014. A total of 1126 articles were retrieved. After inclusion/exclusion assessment, 147 full text articles were read and included in the review, comprising 130 in vitro, 1 in situ, and 4 in vivo studies, as well as 12 literature reviews. In about 78% of in vitro studies, and in all identified in situ and in vivo studies, a positive antimicrobial effect had been found. However, the anticaries effect had not been tested in any of the selected studies. It was concluded that there is indeed evidence that restorative dental materials containing antimicrobial agents exert an antimicrobial effect, both in laboratory and in clinical studies. However, no evidence has been found regarding the role of these agents in preventing or controlling dental caries, or in preventing caries around restorations. PMID- 26018840 TI - Splicing factor 2/alternative splicing factor contributes to extracellular signal regulated kinase activation in hepatocellular carcinoma cells. AB - The splicing factor is important in cancer development, modulation numerous tumor suppressors and oncogenes, and regulation of multiple signaling pathways. Splicing factor 2/alternative splicing factor (SF2/ASF) is a proto-oncogene, which has been implicated in the development of hepatocellular carcinoma. However, the underlying molecular mechanism remains to be elucidated. In the present study, it was identified that SF2 knockdown had no effect on tumor necrosis factor (TNF)-alpha-induced activation of the c-Jun N-terminal protein kinase (JNK) pathway, the p38 pathway, or the IKK pathway in hepatoma cell lines. However, SF2 knockdown led to reduced levels of basal ERK activation and TNF alpha-induced ERK activation, without changing the protein levels of ERK. Consequently, SF2 knockdown marginally enhanced TNF-alpha-induced cell death. Furthermore, SF2 knockdown and blockade of ERK activation partially suppressed TNF-alpha-induced interleukin-6 expression. As SF2 knockdown exhibited no role in basal Akt activation and serum-induced Akt activation, it is unlikely that SF2 affects ERK activation through modulating the protein levels of certain growth factor receptors. In conclusion, the data suggest that SF2 contributes to the elevated levels of ERK activation in hepatocellular carcinoma cells through modulating key component(s) downstream of growth factor receptors and upstream of ERK. PMID- 26018841 TI - Self-defining memories during exposure to music in Alzheimer's disease. AB - BACKGROUND: Research suggests that exposure to music may enhance autobiographical recall in Alzheimer's Disease (AD) patients. This study investigated whether exposure to music could enhance the production of self-defining memories, that is, memories that contribute to self-discovery, self-understanding, and identity in AD patients. METHODS: Twenty-two mild-stage AD patients and 24 healthy controls were asked to produce autobiographical memories in silence, while listening to researcher-chosen music, and to their own-chosen music. RESULTS: AD patients showed better autobiographical recall when listening to their own-chosen music than to researcher-chosen music or than in silence. More precisely, they produced more self-defining memories during exposure to their own-chosen music than to researcher-chosen music or during silence. Additionally, AD patients produced more self-defining memories than autobiographical episodes or personal semantics during exposure to their own-chosen music. This pattern contrasted with the poor production of self-defining memories during silence or during exposure to researcher-chosen music. Healthy controls did not seem to enjoy the same autobiographical benefits nor the same self-defining memory enhancement in the self-chosen music condition. CONCLUSIONS: Poor production of self-defining memories, as observed in AD, may somehow be alleviated by exposure to self-chosen music. PMID- 26018842 TI - Unique properties of silver cations in solid-acid catalysis by zeolites and heteropolyacids. AB - Ag(+)-exchanged zeolites exhibit unique catalytic properties caused by the combination of their redox and acidic properties. Partial reduction of Ag(+) ions in zeolites with hydrogen leads to the formation of acidic protons and silver metal particles, which can be observed using X-ray powder diffraction patterns (XRD). By simply evacuating hydrogen from the system, the silver metal particles are returned back to Ag(+) ions and at the same time, acidic protons are eliminated. This interconversion of Ag(+) ions and silver metal or gaseous hydrogen and surface protons is reflexed in the catalytic activities of Ag(+) exchanged zeolites for acid-catalyzed reactions: the activity of Ag(+)-exchanged Y zeolite (Ag-Y) reversibly changes with the partial pressure of hydrogen. Furthermore, the activity of Ag-Y in the presence of hydrogen is higher than that of H(+)-exchanged Y zeolite (H-Y). Similar phenomena are also observed for the silver salt of dodecatungstophosphoric acid (Ag3PW12O40). Ag(+)-exchanged ZSM-5 zeolite (Ag-ZSM-5) is a very selective catalyst for aromatization of alkanes, alkenes and methanol. Examination of the activation step of lower alkanes revealed that Ag(+) ions dramatically enhance the dehydrogenation of the alkanes via heterolytic dissociation of the alkanes into carbenium ions and hydride species. Ag(+)-exchanged zeolites can also activate methane. The reaction of methane with ethene and benzene gives propene and toluene, respectively. Ag-ZSM-5 is a very stable catalyst under hydrothermal conditions because of the interconversion properties of Ag(+) ions and silver metal in the zeolite. PMID- 26018844 TI - Effect of maternal periodontitis and low birth weight--a case control study. AB - INTRODUCTION: Since the 1990s, evidence has been raised that there is an association between maternal periodontal disease and undesirable gestational events, for example low birth weight; this issue is controversial. OBJECTIVE: To evaluate whether there is an association between maternal periodontitis and low birth weight (LBW). METHODS: A case-control study was carried out on 951 mothers that had been cared for by the Brazilian Unified Health System in Petrolina-PE and Juazeiro-BA, Brazil. The case group (n = 269) consisted of mothers of newborns with birth weight <2500 g and a control group (n = 682) of mothers of newborns with birth weight >=2500 g. An interview was realized, using a questionnaire as well as a full mouth examination to diagnose the periodontal condition. Women who had at least four teeth with probing depth >=4 mm and clinical attachment loss >=3 mm, with bleeding on probing at the same site, were diagnosed with periodontitis. The birth weight was obtained through the hospital book record. The main association was evaluated using the multivariate regression model, considering confounders. RESULTS: The frequency of periodontitis was 16.4% (case group) and 17.4% (control group). Periodontitis did not show an association with LBW (ORcrude = 0.92; 95% CI = 0.63-1.35), even after adjustment for the following confounders: maternal age, pre-gestational body mass index, number of pre-natal consultations, number of pregnancies, maternal schooling level, smoking habit during pregnancy and hypertension (ORadjusted = 1.00; 95% CI = 0.61-1.68). CONCLUSION: The findings of this study showed no association between maternal periodontal disease and low birth weight, even after appropriate adjustments for confounding factors. PMID- 26018845 TI - Near Misses in Slot Machine Gambling Developed Through Generalization of Total Wins. AB - The purpose of the present study was to evaluate the development of the near miss effect in slot machine gambling as a product of stimulus generalization from total wins. The study was conducted across two experiments. Twelve college students participated in the first experiment, which demonstrated that greater post-reinforcement pauses followed losing outcomes that were formally similar to total wins, relative to losing outcomes that were formally dissimilar [F (5, 7) = 5.24, p = .025] along a generalization gradient (R (2) = .96). Additionally, 11 out of 12 participants showed greater response latencies following near-misses than following total wins. Thirteen college students participated in the second experiment, which demonstrated that symbols that more saliently indicated a loss resulted in lower response latencies than functionally equivalent but visually dissimilar losing symbols [F (3, 10) = 15.50, p = .01]. A generalization gradient was observed across winning symbols (R (2) = .98), and an inverse of the gradient observed across winning symbols was observed across symbols that were the least formally similar (R (2) = .69). The present study replicates and extends previous research on near misses in slot machine gambling, and provides discussion around the clinical utility of such findings on the prevention of problem gambling. PMID- 26018846 TI - Equilibrium transitions between side-chain conformations in leucine and isoleucine. AB - Despite recent improvements in computational methods for protein design, we still lack a quantitative, predictive understanding of the intrinsic probabilities for amino acids to adopt particular side-chain conformations. Surprisingly, this question has remained unsettled for many years, in part because of inconsistent results from different experimental approaches. To explicitly determine the relative populations of different side-chain dihedral angles, we performed all atom hard-sphere Langevin Dynamics simulations of leucine (Leu) and isoleucine (Ile) dipeptide mimetics with stereo-chemical constraints and repulsive-only steric interactions between non-bonded atoms. We determine the relative populations of the different chi(1) and chi(2) dihedral angle combinations as a function of the backbone dihedral angles phi and psi. We also propose, and test, a mechanism for inter-conversion between the different side-chain conformations. Specifically, we discover that some of the transitions between side-chain dihedral angle combinations are very frequent, whereas others are orders of magnitude less frequent, because they require rare coordinated motions to avoid steric clashes. For example, to transition between different values of chi(2), the Leu side-chain bond angles kappa(1) and kappa(2) must increase, whereas to transition in chi(1), the Ile bond angles lambda(1) and lambda(2) must increase. These results emphasize the importance of computational approaches in stimulating further experimental studies of the conformations of side-chains in proteins. Moreover, our studies emphasize the power of simple steric models to inform our understanding of protein structure, dynamics, and design. PMID- 26018847 TI - Towards markerless navigation for percutaneous needle insertions. AB - PURPOSE: Percutaneous needle insertions are increasingly used for diagnosis and treatment of abdominal lesions. The challenging part of computed tomography (CT) guided punctures is the transfer of the insertion trajectory planned in the CT image to the patient. Conventionally, this often results in several needle repositionings and control CT scans. To address this issue, several navigation systems for percutaneous needle insertions have been presented; however, none of them has thus far become widely accepted in clinical routine. Their benefit for the patient could not exceed the additional higher costs and the increased complexity in terms of bulky tracking systems and specialized markers for registration and tracking. METHODS: We present the first markerless and trackerless navigation concept for real-time patient localization and instrument guidance. It has specifically been designed to be integrated smoothly into the clinical workflow and does not require markers or an external tracking system. The main idea is the utilization of a range imaging device that allows for contactless and radiation-free acquisition of both range and color information used for patient localization and instrument guidance. RESULTS: A first feasibility study in phantom and porcine models yielded a median targeting accuracy of 6.9 and 19.4 mm, respectively. CONCLUSIONS: Although system performance remains to be improved for clinical use, expected advances in camera technology as well as consideration of respiratory motion and automation of the individual steps will make this approach an interesting alternative for guiding percutaneous needle insertions. PMID- 26018848 TI - Multimodal image registration with joint structure tensor and local entropy. AB - PURPOSE: Nonrigid registration of multimodal medical images remains a challenge in image-guided interventions. A common approach is to use mutual information (MI), which is robust to the intensity variations across modalities. However, primarily based on intensity distribution, MI does not take into account of underlying spatial and structural information of the images, which might lead to local optimization. To address such a challenge, this paper proposes a two-stage multimodal nonrigid registration scheme with joint structural information and local entropy. METHODS: In our two-stage multimodal nonrigid registration scheme, both the reference image and floating image are firstly converted to a common space. A unified representation in the common space for the images is constructed by fusing the structure tensor (ST) trace with the local entropy (LE). Through the representation that reflects its geometry uniformly across modalities, the complicated deformation field is estimated using L(1) or L(2) distance. RESULTS: We compared our approach to four other methods: (1) the method using LE, (2) the method using ST, (3) the method using spatially weighted LE and (4) the conventional MI-based method. Quantitative evaluations on 80 multimodal image pairs of different organs including 50 pairs of MR images with artificial deformations, 20 pairs of medical brain MR images and 10 pairs of breast images showed that our proposed method outperformed the comparison methods. Student's t test demonstrated that our method achieved statistically significant improvement on registration accuracy. CONCLUSION: The two-stage registration with joint ST and LE outperformed the conventional MI-based method for multimodal images. Both the ST and the LE contributed to the improved registration accuracy. PMID- 26018850 TI - Information Processing in Computer-Assisted Interventions--6th International Conference 2015. Preface. PMID- 26018849 TI - Application of 3D imaging in the real-time US-CT fusion navigation for minimal invasive tumor therapy. AB - PURPOSE: Image-guided minimally invasive treatment (IG-MIT) has been widely used for local therapy of both benign and malignant tumors. However, precise needle targeting is a very important step in the minimally invasive treatment. Nowadays, minimally invasive treatment is usually performed with the guidance of the two dimensional (2D) image. The tip of the puncture needle is difficult to place with precise positioning into the three-dimensional (3D) space of the tumor. This study was an experimental ex vivo study in porcine liver and heart samples with internal targets, focusing on the accuracy with the guidance of the real-time 3D imaging using a self-developed real-time ultrasonography and preoperative computed tomography (CT) fusion navigation system for minimal invasive tumor (liver tumor and uterine fibroid) therapy. METHODS: There are thirty porcine liver samples and thirty porcine heart samples used in the experiments. The average weight of the porcine liver samples was 2216.8 g, and the average weight of the porcine heart samples was 510.5 g. We conducted statistical analysis of the experimental results obtained by five medical students and five interventional radiologists. RESULTS: The puncture precision of the needle placement under the guidance of 3D imaging was significantly higher than that of the other groups, and the assistant function is more obvious for medical students than that for interventional radiologists [Formula: see text]. Assistant function of the US-CT fusion imaging is higher than that of the first group too [Formula: see text]. The precision of the puncture with guidance of the 3D imaging was very satisfied in the fact that it was found that there was a mean discrepancy of [Formula: see text] (medical students) and [Formula: see text] (interventional radiologists) in porcine livers and there was a mean discrepancy of [Formula: see text] (medical students) and [Formula: see text] (interventional radiologists) in porcine hearts. CONCLUSIONS: Experimental results showed that the accuracy of needle targeting can be improved with the guidance of the real-time 3D imaging than that with the guidance of both 2D US images and US-CT fusion images in IG MIT. Assistant function of 3D imaging is obviously for medical students. PMID- 26018851 TI - Neuroleptic malignant syndrome and delirious mania as malignant catatonia in autism: prompt relief with electroconvulsive therapy. PMID- 26018853 TI - Total Synthesis and Antimicrobial Activity of Chlorocatechelin A. AB - Chlorocatechelin A (1) is a structurally unique microbial siderophore containing two units of 4-chloro-2,3-dihydroxybenzoic acid (CDB) and a characteristic acylguanidine structure. Purification from the microbe culture is not an easy task due to the lability of the acylguanidine and its chelating nature. Here we report the first convergent total synthesis and antimicrobial activity of chlorocatechelin A (1). The bis-acylated arginine was constructed using a Schotten-Baumann reaction whereas the CDB component was synthesized from o vanillin (8). Condensation with an ornithine derivative synthesized from 1-benzyl d-glutamate was followed by deprotection in basic and neutral conditions to complete the total synthesis. We examined the antimicrobial activity of chlorocatechelin A (1) and found that this siderophore was active against desferrioxamine B (DFB)-sensitive microbes including the fish pathogen Pasteurella piscicida. PMID- 26018854 TI - A reflection on the significant findings published in Zoological Research over the past 35 years. PMID- 26018855 TI - New observations - with older ones reviewed - on mass migrations in millipedes based on a recent outbreak on Hachijojima (Izu Islands) of the polydesmid diplopod (Chamberlinius hualienensis, Wang 1956): Nothing appears to make much sense. AB - Mass aggregations and migrations of millipedes despite numerous attempts to find causes for their occurrences are still an enigma. They have been reported from both southern and northern hemisphere countries, from highlands and lowlands of both tropical and temperate regions and they can involve species belonging to the orders Julida and Spirobolida, Polydesmida and Glomerida. According to the main suggestions put forward in the past, mass occurrences in Diplopoda occur: (1) because of a lack of food and a population increase beyond sustainable levels; (2) for the purpose of reproduction and in order to locate suitable oviposition sites; (3) to find overwintering or aestivation sites; (4) because of habitat disruption and changes in the local environment; (5) as a consequence of weather conditions the year (or winter and spring) before. A recent outbreak (November 2014) of a mass migration of the polydesmid Chamberlinius hualienensis Wang 1956 on the Japanese Izu Island of Hachijojima 300 km to the south of Tokyo gave this author an opportunity to review the existing literature on millipede mass migrations and to carry out additional observations on the phenomenon in the field as well as the laboratory. Hitherto unreported heavy infestations with phoretic deutonymphs of the mite Histiostoma sp. as well as dense populations of internal rhabditid nematodes (Oscheius cf. necromena and an unidentified species of the genus Fictor), suggest that infestations of this kind could be necromenic and either have been a contributing factor for the mass migration or been a consequence of so many individuals occurring together at close proximity. It is concluded that mass migrations and aggregations in millipedes do not have one common cause, but represent phenomena that often are seasonally recurring events and appear identical in their outcome, but which have evolved as responses to different causes in different millipede taxa and therefore need to be examined on a case-to-case basis. PMID- 26018852 TI - The 30-day metric in acute heart failure revisited: data from IN-HF Outcome, an Italian nationwide cardiology registry. AB - AIMS: Unplanned readmissions early after a discharge from acute heart failure hospitalization are common and have become a reimbursement benchmark and marker of hospital quality. However, the competing risk of short-term post-discharge mortality is substantial. METHODS AND RESULTS: Using data from the prospective, nationwide Registry IN-HF Outcome, we analysed the incidence and predictors of 30 day mortality or readmissions and associated days-alive-out-of-hospital (DAOH) in 1520 patients discharged alive after admission for acute heart failure. Within 30 days after discharge, 94 patients (6.2%) were readmitted (91% for cardiovascular causes; 60% recurrent heart failure) and 42 (2.8%) died, 10 of which occurred during readmission. Overall, 126 patients (8.3%) met the combined endpoint. By multivariable logistic regression, worsening chronic heart failure as clinical presentation [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.21-2.77, P = 0.005), inotropes during admission (OR 2.19, 95% CI 1.40-3.43, P = 0.0006), length of stay (OR 1.02, 95% CI 1.01-1.04, P = 0.002) and renin-angiotensin system inhibitors at discharge (OR 0.52, 95%CI 0.35-0.77, P = 0.001) independently predicted 30-day all-cause mortality and/or readmission (c statistic = 0.695). Per cent 30-day DAOH was lower in patients with in-hospital inotrope use, no renin-angiotensin system inhibitors prescription at discharge, New York Heart Association III-IV class at discharge, and correlated inversely with length of stay and age. CONCLUSION: A clinical and biohumoral profile consistent with chronic advanced heart failure and end-organ damage identifies acute heart failure patients discharged home from cardiology units, who are at highest risk of early death and/or readmission. These findings have practical implications for tailoring specific follow-up. PMID- 26018856 TI - Molecular characterization of an IL-1beta gene from the large yellow croaker (Larimichthys crocea) and its effect on fish defense against Vibrio alginolyticus infection. AB - Interleukin 1beta (IL-1beta), the first interleukin to be characterized, plays a key role in regulating the immune response. In this study, we determined the cDNA and genomic DNA sequences of the IL-1beta gene from the large yellow croaker, Larimichthys crocea. Phylogenetic analysis indicated that the IL-1beta (LcIL 1beta) gene was most closely related to that of European seabass (Dicentrarchus labrax), sharing 67.8% amino acid identity. In healthy large yellow croaker, LcIL 1beta transcription was detected in all tested tissues, with the highest level found in the head kidney. Upon Vibrio alginolyticus infection, LcIL-1beta transcription in all tested tissues was significantly upregulated. Intraperitoneal injection of recombinant LcIL-1beta (rLcIL-1beta) improved the survival rate and reduced the tissue bacterial load after V. alginolyticus infection. In addition, rLcIL-1beta induced monocytes/macrophages (MO/MPhi) chemotaxis and increased phagocytosis and bactericidal activity in vitro. These results suggest that LcIL-1beta plays an important role in the large yellow croaker immune response against V. alginolyticus. PMID- 26018858 TI - Social organization of Shortridge's capped langur (Trachypithecus shortridgei) at the Dulongjiang Valley in Yunnan, China. AB - Non-human primates often live in socially stable groups characterized by bonded relationships among individuals. Social organization can be used to evaluate living conditions and expansion potential. Bisexual group size, ratio of males to females and group composition are essential elements determining the type of social organization. Although the first report on Shortridge's capped langurs (Trachypithecus shortridgei) was in the 1970s, until now, the species only inhabits forests of the Dulongjiang valley in northwest Yunnan, China, with c. 250-370 individuals in 19 populations. To understand its social organization, we collected data from five groups of Shortridge's langurs at Silaluo in the Dulongjiang valley during August 2012-October 2013. Family groups consist of one adult male, 2-3 adult females and up to five young. Group size averaged 8 (7-9) individuals. The ratio of adult males to females (M/F) was 1:2.9, infants to adult females was (I/F) 1:2.2; and ratio of adults to immatures was 1:1.2, indicating the potential of a population increasing. Birth season was during March-July and the inter-birth interval was two years. PMID- 26018857 TI - Selective recruitment of host factors by HSV-1 replication centers. AB - Herpes simplex virus type 1 (HSV-1) enters productive infection after infecting epithelial cells, where it controls the host nucleus to make viral proteins, starts viral DNA synthesis and assembles infectious virions. In this process, replicating viral genomes are organized into replication centers to facilitate viral growth. HSV-1 is known to use host factors, including host chromatin and host transcription regulators, to transcribe its genes; however, the invading virus also encounters host defense and stress responses to inhibit viral growth. Recently, we found that HSV-1 replication centers recruit host factor CTCF but exclude gammaH2A.X. Thus, HSV-1 replication centers may selectively recruit cellular factors needed for viral growth, while excluding host factors that are deleterious for viral transcription or replication. Here we report that the viral replication centers selectively excluded modified histone H3, including heterochromatin mark H3K9me3, H3S10P and active chromatin mark H3K4me3, but not unmodified H3. We found a dynamic association between the viral replication centers and host RNA polymerase II. The centers also recruited components of the DNA damage response pathway, including 53BP1, BRCA1 and host antiviral protein SP100. Importantly, we found that ATM kinase was needed for the recruitment of CTCF to the viral centers. These results suggest that the HSV-1 replication centers took advantage of host signaling pathways to actively recruit or exclude host factors to benefit viral growth. PMID- 26018859 TI - Establishment of HIV-1 model cell line GHOST(3) with stable DRiP78 and NHERF1 knockdown. AB - Chemokine receptors CXCR4 and CCR5 are indispensable co-receptors for HIV-1 entry into host cells. In our previous study, we identified that dopamine receptor interacting protein 78 (DRiP78) and Na(+)-H(+) exchanger regulatory factor 1 (NHERF1) are the CXCR4 and CCR5 homo- or hetero-dimer-interacting proteins. DRiP78 and NHERF1 are able to influence the co-receptor internalization and intracellular trafficking. Over-expression of NHERF1 affects the ligands or HIV-1 gp120-induced CCR5 internalization and HIV-1 production. It is reasonable to speculate that DRiP78 and NHERF1, as well as the signaling pathways involved in viral replication, would probably affect HIV-1 replication through regulating the co-receptors. In this present study, we designed two short hairpin RNAs (shRNAs) targeting the DRiP78 and NHERF1, respectively, and constructed the pLenti6/BLOCK iT-DEST lentiviral plasmids expressing DRiP78 or NHERF1 shRNA. The packaged lentiviruses were used to transduce the widely-applied HIV-1 model cell line GHOST(3). Then, cells with stable knockdown were established through selecting transduced cells with Blasticidin. This study, for the first time, reported the establishment of the GHOST(3) with DRiP78 and NHERF1 knockdown, which is the first stable cell line with HIV-1 co-receptor-interacting molecular defects. PMID- 26018860 TI - Autophagy prevents autophagic cell death in Tetrahymena in response to oxidative stress. AB - Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species (ROS) generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membrane-bound vacuoles characteristic of autophagy followed by autophagic cell death (referred to as cell death with autophagy) after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3 methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena. PMID- 26018861 TI - Purification and characterization of cholecystokinin from the skin of salamander Tylototriton verrucosus. AB - As a group of intestinal hormones and neurotransmitters, cholecystokinins (CCKs) regulate and affect pancreatic enzyme secretion, gastrointestinal motility, pain hypersensitivity, digestion and satiety, and generally contain a DYMGWMDFG sequence at the C-terminus. Many CCKs have been reported in mammals. However, only a few have been reported in amphibians, such as Hyla nigrovittata, Xenopus laevis, and Rana catesbeiana, with none reported in urodele amphibians like newts and salamanders. Here, a CCK called CCK-TV was identified and characterized from the skin of the salamander Tylototriton verrucosus. This CCK contained an amino acid sequence of DYMGWMDF-NH2 as seen in other CCKs. A cDNA encoding the CCK precursor containing 129 amino acid residues was cloned from the cDNA library of T. verrucosus skin. The CCK-TV had the potential to induce the contraction of smooth muscle strips isolated from porcine gallbladder, eliciting contraction at a concentration of 5.0 x 10-11 mol/L and inducing maximal contraction at a concentration of 2.0 x 10-6 mol/L. The EC50 was 13.6 nmol/L. To the best of our knowledge, this is the first report to identify the presence of a CCK in an urodele amphibian. PMID- 26018862 TI - New Record of Lycodon liuchengchaoi in Anhui. AB - One juvenile and one adult female wolf snake (Colubridae: Lycodon) were sampled at Yixian and Fuxi, Huangshan, Anhui, China in the summer of 2011 and 2012, respectively. The two specimens were identified as Lycodon liuchengchaoi based on external morphology and molecular data. This is a new reptile record in Anhui Province. In our laboratory, four eggs were laid and three neonates were hatched successfully. This is the first record of the laying and incubation of L. liuchengchaoi eggs. The five specimens were deposited at the Museum of Huangshan University (HUM20140001) and Guangdong Entomological Institute (HB-lcfsp12613, HB lcfsp-ch1~3). PMID- 26018863 TI - PTPN22 Variant R620W Is Associated With Reduced Toll-like Receptor 7-Induced Type I Interferon in Systemic Lupus Erythematosus. AB - OBJECTIVE: Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is associated with an increased risk of systemic lupus erythematosus (SLE). PTPN22 encodes Lyp, and a disease-associated coding variant bears an R620W substitution (LypW). LypW carriage is associated with impaired production of type I interferon (IFN) by myeloid cells following Toll-like receptor (TLR) engagement. The aim of this study was to investigate the effects of LypW carriage on TLR signaling in patients with SLE. METHODS: Plasma IFNalpha concentrations and whole-blood IFN gene scores were compared in SLE patients who were LypW carriers and those who were noncarriers. TLR-7 agonist R848-stimulated IFNalpha and tumor necrosis factor levels, IFN-dependent gene expression, and STAT-1 activation were determined in peripheral blood mononuclear cells (PBMCs) and/or plasmacytoid dendritic cells (PDCs) obtained from these patients. The effect of LypW expression on the systemic type I IFN response to R848 stimulation in vivo was assessed in transgenic mice. RESULTS: Plasma IFNalpha levels and whole-blood IFN gene signatures were comparable in SLE patients who were LypW carriers and those who were noncarriers. However, PBMCs from LypW carriers produced less IFNalpha and showed reduced IFN-dependent gene up-regulation and STAT-1 activation after R848 stimulation. The frequency of PDCs producing IFNalpha2 and the per-cell IFNalpha2 levels were significantly reduced in LypW carriers. LypW-transgenic mice displayed reduced TLR-7-induced circulating type I IFN responses. CONCLUSION: PDCs from SLE patients carrying the disease-associated PTPN22 variant LypW showed a reduced capacity for TLR-7 agonist-induced type I IFN production, even though LypW carriers displayed systemic type I IFN activation comparable with that observed in noncarriers. LypW carriage identifies SLE patients who may harbor defects in TLR- and PDC-dependent host defense or antiinflammatory functions. PMID- 26018864 TI - Representations of African Americans in the Grief and Mourning Literature from 1998 to 2014: A Systematic Review. AB - The authors examined representations of African Americans in the grief literature to assess (a) frequencies; (b) content; and (c) use of universalist or a contextualized framework. They conducted searches in 3 databases that target the grief literature published in the last 15 years. Fifty-nine articles met the criteria. There are a small number of studies published on African Americans and these tend to focus on homicide. Many studies had incomplete methods. Comparison studies were common and pathological grief outcomes that were validated on White populations were used as outcome variables with African American participants. PMID- 26018865 TI - Venom immunotherapy: clinical efficacy, safety and contraindications. AB - Venom-specific immunotherapy (VIT) is considered for the treatment of patients with IgE-mediated systemic allergic reactions (SARs) after developing a Hymenoptera venom allergy. Tolerance is achieved in a majority of patients after only a few days or even hours of rush immunotherapy. After VIT discontinuation, the allergy returns in up to 15% of patients. During VIT, the majority of patients have local reactions at the site of venom injections. SARs to VIT are much more frequent in honeybee-treated patients than in wasp-treated patients. Increased baseline serum tryptase and increased allergen-specific sensitivity of basophils are other factors that might be associated with systemic reactions (SRs) during VIT. Severe SRs occur mainly during the build-up phase but can also occur in the maintenance phase of the VIT, even in patients with a well-tolerated dose-increase phase. Pre-treatment with humanized anti-IgE antibodies (omalizumab) is effective in patients with repeated SARs; however, this use of omalizumab is off-label. In highly exposed patients with a history of very severe reactions, there are virtually no absolute contraindications for VIT. PMID- 26018866 TI - Direct access to site-specifically phosphorylated-lysine peptides from a solid support. AB - Phosphorylation is a key process for changing the activity and function of proteins. The impact of phospho-serine (pSer), -threonine (pThr) and -tyrosine (pTyr) is certainly understood for some proteins. Recently, peptides and proteins containing N-phosphorylated amino acids such as phosphoarginine (pArg), phosphohistidine (pHis) and phospholysine (pLys) have gained interest because of their different chemical properties and stability profiles. Due to its high intrinsic lability, pLys is the least studied within this latter group. In order to gain insight into the biological role of pLys, chemical and analytical tools, which are compatible with the labile P(=O)-N bond, are highly sought-after. We recently reported an in-solution synthetic approach to incorporate pLys residues in a site-specific manner into peptides by taking advantage of the chemoselectivity of the Staudinger-phosphite reaction. While the in-solution approach allows us to circumvent the critical TFA cleavage, it still requires several transformations and purification steps to finally deliver pLys peptides. Here we report the synthesis of site-specific pLys peptides directly from a solid support by using a base labile resin. This straightforward and highly efficient approach facilitates the synthesis of various site-specific pLys-containing peptides and lays the groundwork for future studies about this elusive protein modification. PMID- 26018867 TI - Effect of Phospholipid on Pyrite Oxidation and Microbial Communities under Simulated Acid Mine Drainage (AMD) Conditions. AB - The effect of phospholipid on the biogeochemistry of pyrite oxidation, which leads to acid mine drainage (AMD) chemistry in the environment, was investigated. Metagenomic analyses were carried out to understand how the microbial community structure, which developed during the oxidation of pyrite-containing coal mining overburden/waste rock (OWR), was affected by the presence of adsorbed phospholipid. Using columns packed with OWR (with and without lipid adsorption), the release of sulfate (SO4(2-)) and soluble iron (FeTot) was investigated. Exposure of lipid-free OWR to flowing pH-neutral water resulted in an acidic effluent with a pH range of 2-4.5 over a 3-year period. The average concentration of FeTot and SO4(2-) in the effluent was >=20 and >=30 mg/L, respectively. In contrast, in packed-column experiments where OWR was first treated with phospholipid, the effluent pH remained at ~6.5 and the average concentrations of FeTot and SO4(2-) were <=2 and l.6 mg/L, respectively. 16S rDNA metagenomic pyrosequencing analysis of the microbial communities associated with OWR samples revealed the development of AMD-like communities dominated by acidophilic sulfide oxidizing bacteria on untreated OWR samples, but not on refuse pretreated with phospholipid. PMID- 26018868 TI - Diabetic foot disease is associated with reduced erythrocyte deformability. AB - The pathogenesis of diabetic foot disease is multifactorial and encompasses microvascular and macrovascular pathologies. Abnormal blood rheology may also play a part in its development. Using a cell flow analyser (CFA), we examined the association between erythrocyte deformability and diabetic foot disease. Erythrocytes from diabetic patients with no known microvascular complications (n = 11) and patients suffering from a diabetic foot ulcer (n = 11) were isolated and their average elongation ratio (ER) as well as the ER distribution curve were measured. Average ER was decreased in the diabetic foot patients compared with the patients with diabetes and no complications (1.64 +/- 0.07 versus 1.71 +/- 0.1; P = 0.036). A significant rise in the percentage of minimally deformable red blood cells RBCs in diabetic foot patients compared with the patients with no complications was observed (37.89% +/- 8.12% versus 30.61% +/- 10.17%; P = 0.039) accompanied by a significant decrease in the percentage of highly deformable RBCs (12.47% +/- 4.43% versus 17.49% +/- 8.17% P = 0.046). Reduced erythrocyte deformability may slow capillary flow in the microvasculature and prolong wound healing in diabetic foot patients. Conversely, it may be the low-grade inflammatory state imposed by diabetic foot disease that reduces erythrocyte deformability. Further study of the rheological changes associated with diabetic foot disease may enhance our understanding of its pathogenesis and aid in the study of novel therapeutic approaches. PMID- 26018869 TI - Ostracism of an albino individual by a group of pigmented catfish. AB - Physiological and behavioural constraints hinder albino individuals. Albino animals are rare in the wild; this trait is associated with easy detection by predators, non-native or damaged environments, and exclusively aphotic environments in total darkness. The social aspect of albinism is reported only for human beings, and the effect is distinguishable in time and space when social benefits, are used to a limited the extent. Thus far, the social consequences of albinism for animals remain unknown. We used socially established groups of the pigmented catfish, (Silurus glanis), to observe space and temporal distance detachment of albino specimens in laboratory conditions. The albino fish were separated at larger distances from the group than pigmented individuals with the same social status determined by familiarity, and this asymmetry also varied in time. Albinism-related ostracism results in a solitary existence, usually followed by enhanced predation risk. The motivation for an individual's exclusion from a group appears to be the avoidance of the predation risk that increases not only for an odd individual but also for conspecifics within a group. Our findings indicate a role for albinism in behavioural processes related to sociality in a group of conspecifics. PMID- 26018870 TI - Ligation-anchored PCR unveils immune repertoire of TCR-beta from whole blood. AB - BACKGROUND: As one of the genetic mechanisms for adaptive immunity, V(D)J recombination generates an enormous repertoire of T-cell receptors (TCRs). With the development of high-throughput sequencing techniques, systematic exploration of V(D)J recombination becomes possible. Multiplex PCR has been previously developed to assay immune repertoire; however, the use of primer pools leads to inherent biases in target amplification. In our study, we developed a "single primer" ligation-anchored PCR method that may amplify the repertoire with much less biases. RESULTS: By utilizing a universal primer paired with a single primer targeting the conserved constant region, we amplified TCR-beta (TRB) variable regions from total RNA extracted from blood. Next-generation sequencing libraries were then prepared for Illumina HiSeq 2500 sequencer, which generates 151-bp read length to cover the entire V(D)J recombination region. We evaluated this approach on blood samples from healthy donors and from patients with malignant and benign meningiomas. Mapping of sequencing data showed that 64% to 96% of mapped TCRV containing reads belong to TRB subtype. An increased usage of specific V segments and V-J pairing were observed in malignant meningiomas samples. The CDR3 sequences of the expanded V-J pairs were distinct in each malignant individual, even for pairing of TRBV7-3 with TRBJ2-2 that showed increased usage in both cases. CONCLUSIONS: We demonstrated the technical feasibility and effectiveness of ligation-anchored PCR approach in capturing the TCR-beta landscapes. Further development of this technology may enable a comprehensive delineation of immune repertoire, including other forms of TCRs as well as immunoglobulins. PMID- 26018871 TI - Anticonvulsive and neuroprotective effects of synergetic combination of phenytoin and gastrodin on the convulsion induced by penicillin in mice. AB - Phenytoin (PHT) is a commonly prescribed first-line antiepileptic drug. However, long-term administration of PHT can cause memory loss and balance disturbance. Gastrodin (GD) is the major bioactive component in Tianma and has sedative, anticonvulsive, memory strengthening, and neuroprotective effects. To combine the two drugs seems attractive; however, little was known about the efficacy of combination therapy. In this study, convulsive attack was successfully induced by penicillin. Isobolographic analysis, memory and balance behavior test, histopathological examination, and Western blot analysis were used to investigate whether the combination therapy of GD and PHT can enhance anticonvulsive effect and reduce the side effects associated with PHT. The GD alone (950.60 mg/kg) and the PHT alone (45.50 mg/kg) could produce an anticonvulsive effect, while comparable effect could be produced by PHT : GD = 1 : 50 (8.59 : 429.27 mg/kg), which reduce the dose of PHT by 81% and GD by 55%. After the chronic anticonvulsive experiments of 16 days, the balance disturbance and short-/long term memory loss were observed in the PHT group, while the PHT + GD therapy can protect the normal balance and memory function. The neuron morphology of hippocampus was preserved, and the number of surviving neurons after combination therapy was more than the model group. The amount of NF-kappaB (p65) expression was increased in combination group. All above suggested the potential of the combination of PHT and GD enhances the anticonvulsive effect and the neuroprotective effect and reduces the PHT-associated memory and balance disturbance. The PHT + GD strategy would provide new possibilities as a novel promising methodology to treat epileptic patients. PMID- 26018872 TI - Recent clinical management of antithrombotic agents for gastrointestinal endoscopy after revision of guidelines in Japan. AB - In 2012, the Japan Gastroenterological Endoscopy Society (JGES) revised guidelines for the management of gastrointestinal endoscopy for patients using antithrombotic agents. The conventional guidelines emphasized reducing the bleeding risk that accompanies gastrointestinal endoscopy, but the present guidelines prioritize reduction of thromboembolism risk during discontinuation of antithrombotic agents, which is consistent with Western guidelines. When the advantages outweigh the disadvantages, the guidelines permit endoscopic biopsy and high-bleeding-risk procedures without discontinuation of selected antithrombotic agents. These guidelines created a paradigm shift that has slowly, but surely, changed clinical daily practice in Japan. As a result, endoscopic biopsy without discontinuation of antithrombotic agents has been widely accepted, although solid evidence for its support is still lacking. Additionally, feasibility of high-bleeding-risk procedures without discontinuation of selected antithrombotic agents is also controversial because evidence newly acquired after publication of the present guidelines is low in evidence level. Consequently, clinical studies with a high evidence level, including randomized controlled studies, are mandatory to establish reliable upcoming guidelines. At the same time, under the present guidelines, the accomplishment of such studies in Japan is expected. PMID- 26018873 TI - Effects of Pu-erh tea aqueous extract (PTAE) on blood lipid metabolism enzymes. AB - Disorders of blood lipid metabolism are the primary risk factors for many diseases. Recently, the effect of Pu-erh tea on blood lipid metabolism has received increasing attention. However, the mechanism underlying its ability to regulate blood lipid metabolism is unclear. We set out to study this through assessing the effects of Pu-erh tea aqueous extract (PTAE) on the central enzymes of blood lipid metabolism, including lipoprotein-associated phospholipase A2 (Lp PLA2), lecithin: cholesterol acyltransferase (LCAT), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and pancreatic lipase (PL). We find that the Lp-PLA2, HMRG and PL activities are inhibited by PTAE in a dose-dependent manner and that the LCAT activity tends to increase with increasing PTAE concentrations. Lineweaver-Burk plot analyses reveal that PTAE acts as a competitive inhibitor for HMGR and PL and as a noncompetitive inhibitor for Lp-PLA2. Moreover, we determine that its active ingredients include catechins, gallic acid, caffeine, free amino acids, and soluble sugar. However, the effect of each ingredient and whether any of them have synergistic effects are still unknown. The results suggest that Pu-erh tea has a potent ability to regulate blood lipid metabolism and knowledge of the mechanisms provides insights into its potential therapeutic application as an alternative hypolipidemic drug. PMID- 26018874 TI - Pictionary-based fMRI paradigm to study the neural correlates of spontaneous improvisation and figural creativity. AB - A novel game-like and creativity-conducive fMRI paradigm is developed to assess the neural correlates of spontaneous improvisation and figural creativity in healthy adults. Participants were engaged in the word-guessing game of Pictionary(TM), using an MR-safe drawing tablet and no explicit instructions to be "creative". Using the primary contrast of drawing a given word versus drawing a control word (zigzag), we observed increased engagement of cerebellum, thalamus, left parietal cortex, right superior frontal, left prefrontal and paracingulate/cingulate regions, such that activation in the cingulate and left prefrontal cortices negatively influenced task performance. Further, using parametric fMRI analysis, increasing subjective difficulty ratings for drawing the word engaged higher activations in the left pre-frontal cortices, whereas higher expert-rated creative content in the drawings was associated with increased engagement of bilateral cerebellum. Altogether, our data suggest that cerebral-cerebellar interaction underlying implicit processing of mental representations has a facilitative effect on spontaneous improvisation and figural creativity. PMID- 26018875 TI - Dietary supplementation of Butyrivibrio fibrisolvens alters fatty acids of milk and rumen fluid in lactating goats. AB - BACKGROUND: Conjugated linoleic acid (CLA) isomers have high health amelioration potential and hence it is of great interest to increase the CLA content in dairy products. The present study was conducted to investigate the effect of administration of high CLA producing Butyrivibrio fibrisolvens In-1 on fatty acid composition of milk and rumen fluid in lactating goats. Four groups (n = 5) of lactating goats were assigned the following treatments: Control (C) (basal diet); T1 (basal diet + linoleic acid source), T2 (basal diet + suspension of Butyrivibrio fibrisolvens In-1, 10(9) CFU head(-1)) and T3 (basal diet + linoleic acid source + suspension of Butyrivibrio fibrisolvens In-1, 10(9) CFU head(-1)). RESULTS: Rumen liquor and milk samples were collected on days 0, 15, 30, 60 and 90 of the experiment and linoleic isomerase enzyme (LA-I) activity and fatty acid profiles were elucidated. Major effects of treatments were seen on day 30 of the experiment. Total CLA content of rumen fluid increased (P < 0.05) by 218.72, 182.26 and 304% whereas total saturated fatty acid (SFA) content was lowered (P < 0.05) by 6.1, 4.44 and 9.55% in T1, T2 and T3, respectively, as compared to control. Vaccenic acid in groups T2 and T3 increased (P < 0.05) by 66.67% and 105.7% as compared to control. In milk, total CLA increased by 2.03, 1.61 and 0.61 folds in T3, T2 and T1, respectively. Total monounsaturated fatty acid and polyunsaturated fatty acid content increased (P < 0.05) in group T3 by 14.15 and 37.44%, respectively. CONCLUSION: Results of the present study indicated that administration of B. fibrisolvens In-1 along with a linoleic acid (LA) source is a useful strategy to alter the biohydrogenation pattern in the rumen that subsequently decreased SFA content while increased CLA and unsaturated fatty acids in ruminant's milk. PMID- 26018877 TI - Response-independent outcomes impact response rates and judgments of control differentially depending on rate of response-dependent outcomes. AB - Two experiments examined the impact of response-independent outcome delivery on human rates of response and judgments of control in an instrumental conditioning task. In Experiment 1, when participants responded on a schedule with a relatively high probability of a response producing an outcome, a random ratio (RR-5), judgments of control declined as rates of response-independent outcomes increased. However, when response-dependent outcomes were delivered with a relatively low probability (RR-15), increasing the rate of response-independent outcomes increased rates of response and judgments of control. Experiment 2 replicated this effect, but also noted a differential effect of response independent outcome and response-independent sensory presentations on response rate and judgments of causal effectiveness. Ratings of the context in which the conditioning occurred suggested these were correlated with total outcome presentation, and that the role of context on response rate and judgments of control may be important to consider. PMID- 26018876 TI - Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK. AB - Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so called "driver mutations") for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. PMID- 26018878 TI - Prognostic role of adjuvant radiotherapy in triple-negative breast cancer: A historical cohort study. AB - The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast-conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23-96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node-negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline-based regimes. In 775 women with T1-2, N0-1, M0 TNBCs, 5-year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8-98.8%), followed by BCT (90.8%, 95% CI: 85.0 94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4-88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3-4, N2-3, M0 TNBCs, BCT was associated with highest 5-year RSR (94.1%, 95% CI: 81.3-99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3-70.1%), and mastectomy only (58.6%, 95% CI: 43.5-71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC. PMID- 26018879 TI - Cardiovascular diseases in Brazil: premature mortality, risk factors and priorities for action. Comments on the preliminary results from the Brazilian National Health Survey (PNS), 2013. PMID- 26018880 TI - Searching for randomized controlled trials and systematic reviews on exercise. A descriptive study. AB - CONTEXT AND OBJECTIVE: The current paradigm of science is to accumulate as much research data as possible, with less thought given to navigation or synthesis of the resulting mass, which hampers locating and using the research. The aim here was to describe the number of randomized controlled trials (RCTs) and systematic reviews (SRs) focusing on exercise, and their journal sources, that have been indexed in PubMed over time. DESIGN AND SETTING: Descriptive study conducted at Bond University, Australia. METHOD: To find RCTs, a search was conducted in PubMed Clinical Queries, using the category "Therapy" and the Medical Subject Headings (MeSH) term "Exercise". To find SRs, a search was conducted in PubMed Clinical Queries, using the category "Therapy", the MeSH term "Exercise" and various methodological filters. RESULTS: Up until 2011, 9,354 RCTs about exercise were published in 1,250 journals and 1,262 SRs in 513 journals. Journals in the area of Sports Science published the greatest number of RCTs and journals categorized as belonging to "Other health professions" area (for example nursing or psychology) published the greatest number of SRs. The Cochrane Database of Systematic Reviews was the principal source for SRs, with 9.8% of the total, while the Journal of Strength and Conditioning Research and Medicine & Science in Sports & Exercise published 4.4% and 5.0% of the RCTs, respectively. CONCLUSIONS: The rapid growth and resulting scatter of RCTs and SRs on exercise presents challenges for locating and using this research. Solutions for this issue need to be considered. PMID- 26018881 TI - Diagnostic accuracy of a noninvasive hepatic ultrasound score for non-alcoholic fatty liver disease (NAFLD) in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - CONTEXT AND OBJECTIVE: Noninvasive strategies for evaluating non-alcoholic fatty liver disease (NAFLD) have been investigated over the last few decades. Our aim was to evaluate the diagnostic accuracy of a new hepatic ultrasound score for NAFLD in the ELSA-Brasil study. DESIGN AND SETTINGS: Diagnostic accuracy study conducted in the ELSA center, in the hospital of a public university. METHODS: Among the 15,105 participants of the ELSA study who were evaluated for NAFLD, 195 individuals were included in this sub-study. Hepatic ultrasound was performed (deep beam attenuation, hepatorenal index and anteroposterior diameter of the right hepatic lobe) and compared with the hepatic steatosis findings from 64 channel high-resolution computed tomography (CT). We also evaluated two clinical indices relating to NAFLD: the fatty liver index (FLI) and the hepatic steatosis index (HSI). RESULTS: Among the 195 participants, the NAFLD frequency was 34.4%. High body mass index, high waist circumference, diabetes and hypertriglyceridemia were associated with high hepatic attenuation and large anteroposterior diameter of the right hepatic lobe, but not with the hepatorenal index. The hepatic ultrasound score, based on hepatic attenuation and the anteroposterior diameter of the right hepatic lobe, presented the best performance for NAFLD screening at the cutoff point >= 1 point; sensitivity: 85.1%; specificity: 73.4%; accuracy: 79.3%; and area under the curve (AUC 0.85; 95% confidence interval, CI: 0.78 0.91)]. FLI and HSI presented lower performance (AUC 0.76; 95% CI: 0.69-0.83) than CT. CONCLUSION: The hepatic ultrasound score based on hepatic attenuation and the anteroposterior diameter of the right hepatic lobe has good reproducibility and accuracy for NAFLD screening. PMID- 26018882 TI - Frequency of obesity and related risk factors among school children and adolescents in a low-income community. A cross-sectional study. AB - CONTEXT AND OBJECTIVE: The frequency of obesity at an early age may contribute to atherosclerosis and cardiovascular disease (CVD) in adults. This study measured the frequency of obesity and cardiovascular risk factors in children and adolescents aged 6 to 17 years. DESIGN AND SETTING: Cross-sectional study in a school located in a region of low income and socioeconomic status in Santa Rita do Sapucai, Minas Gerais, Brazil. METHODS: A total of 175 students were classified using body mass index (BMI) and their waist circumference, blood pressure, number of hours of sedentary behavior and school meals were evaluated. Serum concentrations of fasting blood glucose, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) were analyzed. RESULTS: 37.2% of the students had BMI above the 85th percentile and had significantly lower age, higher prevalence of hypertension, higher serum TC, LDL-C and TG, and greater waist circumference than those with BMI below the 85th percentile. Hypertension was observed in 2.9% of the students; 5.1% presented impaired glucose tolerance, 40% had two risk factors for atherosclerosis and 26.9% had three risk factors. A sedentary lifestyle was significantly less prevalent among subjects with BMI above the 85th percentile and was significantly correlated with serum TC and LDL-C. The school meals were hypoglycemic, hyperproteic and hyperlipidemic. CONCLUSION: One third of the children and adolescents had weights greater than or equal to the age-adjusted weight, and this was associated with greater waist circumference, hypertension and prevalence of dyslipidemia. PMID- 26018883 TI - Pulmonary emphysema induced by methylphenidate: experimental study. AB - CONTEXT AND OBJECTIVE: Methylphenidate is the most widely used drug for treating attention deficit hyperactivity disorder. However, it has important side effects, such as abdominal pain, insomnia, anorexia and loss of appetite, and also some cases of early severe emphysema after drug abuse have been reported. Our aim was to investigate the development of pulmonary emphysema in rats that were subjected to different doses of methylphenidate. DESIGN AND SETTING: Experimental study carried out at the laboratory of a public university. METHODS: Eighteen male Wistar rats were divided into three groups: control (0.9% saline solution); MP 0.8 (methylphenidate, 0.8 mg/kg); MP 1.2 (methylphenidate, 1.2 mg/kg). After 90 days of daily gavage, the animals were sacrificed and lung tissue samples were prepared for analysis on the mean alveolar diameter (Lm). RESULTS: The Lm was greater in MP 0.8 (47.91 +/- 3.13; P < 0.01) and MP 1.2 (46.36 +/- 4.39; P < 0.05) than in the control group (40.00 +/- 3.48). CONCLUSION: Methylphenidate caused an increase in the alveolar diameter of rats, which was compatible with human pulmonary emphysema. PMID- 26018884 TI - Hepatocellular carcinoma may display elevated nestin expression in endothelial cells: experimental study. AB - CONTEXT AND OBJECTIVE: Nestin, a class VI intermediate filament protein, is highly expressed in the portal mesenchyme and sinusoidal endothelium of the human fetal liver, but scarcely expressed in adult portal vessel endothelium. During experimental liver regeneration, an increased number of nestin-positive parenchymal cells have been observed in the zone adjacent to the Hering canals. These parenchymal cells are regarded as hepatic stem cells or hepatoblasts, which may be involved in hepatocellular carcinogenesis. In the light of recent reports describing nestin-positive parenchymal cells in hepatocellular carcinoma, we aimed to use this tumor type as a positive control for immunohistochemical detection of nestin. DESIGN AND SETTING: Experimental study conducted at a university hospital. METHODS: Hepatocellular carcinoma sections from one case were analyzed for nestin expression by immunohistochemistry using confocal microscopy. RESULTS: Surprisingly, a conspicuous pattern resembling liver sinusoid-like cytoarchitecture was observed upon nestin staining of endothelial cells. CONCLUSIONS: This pattern has not been previously described. The preliminary results shown here suggest that nestin-positive endothelial cells are located in niches of immature or proliferative cells. Moreover, nestin expression in endothelial cells of hepatocellular carcinoma enhances the role of angiogenesis in this tumor type, although the prevalence of this immunohistopathological pattern remains to be determined. Finally, hepatocellular carcinoma is an effective positive control for nestin staining in fluorescent immunohistochemistry. PMID- 26018885 TI - The influence of anxiety on quality of life among patients with an indication for cataract surgery. PMID- 26018886 TI - Re-biopsy in lupus nephritis. PMID- 26018887 TI - Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. PMID- 26018888 TI - Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy. PMID- 26018890 TI - Ligament reconstruction with single bone tunnel technique for chronic symptomatic subtle injury of the Lisfranc joint in athletes. AB - INTRODUCTION: Only few procedures for Lisfranc ligaments reconstruction to treat subtle injury of the Lisfranc joint have been reported. We have developed a novel technique for Lisfranc ligaments reconstruction, which was applied to treat chronic symptomatic subtle injuries that had failed to respond to initial treatment or were misdiagnosed. This article describes the technique and its operative outcome in a small case series. METHODS: Between April 2011 and October 2013, 5 (4 male and 1 female) athletes with a mean age of 19.4 (range 17-21) years were diagnosed with chronic subtle injury of the Lisfranc joint and underwent our novel reconstructive operation. In this technique, only a bone tunnel between the medial cuneiform and the second metatarsal bone is needed for near-anatomical reconstruction of the dorsal and interosseous ligaments. All patients were evaluated before and at 1 year after surgery using the American Orthopaedic Foot and Ankle Society (AOFAS) scale for the ankle-midfoot. In addition, the interval between surgery and return to athletic activity, defined as return to near pre-injury performance level, was investigated. RESULTS: Mean duration of postoperative follow-up was 18.8 (range 12-26) months. Mean AOFAS score improved significantly from 74.6 +/- 2.5 (range 71-77) preoperatively to 96.0 +/- 5.5 (range 90-100) at 1 year after the operation (p < 0.01). All patients were able to return to their previous athletic activities and the interval between surgery and return to athletic activity was 16.8 +/- 1.1 (range 15-18) weeks. There was no complication related to the operation. CONCLUSION: The results of this study suggest that our technique of Lisfranc ligaments reconstruction using autologous graft is effective for athletes with chronic subtle injury. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26018891 TI - Call for crop improvement analysis articles. PMID- 26018892 TI - Hypertension linked to PDE3A activation. AB - A new study identifies PDE3A mutations as the cause of brachydactyly type E with hypertension. These mutations alter PDE3A activity by uncovering cryptic sites for phosphorylation by PKA and PKC, leading to enzyme hyperactivation that abnormally lowers cAMP levels. PMID- 26018893 TI - Transposon mutagenesis disentangles osteosarcoma genetic drivers. AB - The genetic drivers of osteosarcoma have been difficult to identify because of the genomic complexity consistently encountered in cancer cells at diagnosis. A new study uses Sleeping Beauty transposon mutagenesis to drive osteosarcomagenesis in the mouse and identify likely drivers of the disease in humans. PMID- 26018894 TI - Massive lineage replacements and cryptic outbreaks of Salmonella Typhi in eastern and southern Africa. AB - A new large-scale study reports the whole-genome sequences of nearly 2,000 Salmonella enterica serovar Typhi (S. Typhi) strains collected from 63 countries. A recent and dominant multidrug-resistant (MDR) lineage originating from South Asia, which is supplanting a bulk of ancestral drug-sensitive strains, is identified; the success of this lineage is likely driven by plasmid acquisitions and the chromosomal integration of resistance-conferring genes. PMID- 26018900 TI - Erratum: the genome and transcriptome of the zoonotic hookworm Ancylostoma ceylanicum identify infection-specific gene families. PMID- 26018901 TI - Corrigendum: analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. PMID- 26018903 TI - Corrigendum: analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance. PMID- 26018902 TI - Corrigendum: a common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. PMID- 26018906 TI - The Power of Influence: School Nurse Stories. AB - School nurses have influence, and this influence is ignited with school nurse stories. School nurses must tell school staff, leaders, families, and students what they do to help students access their education. School boards, city councils, and legislators need to know the knowledge, skills, and judgment school nurses use daily. NASN understands that school nurses benefit from a "how to" kit and has developed tools to empower school nurses in advocating for their important role in supporting the health and learning of students. This article provides an overview this newly developed electronic toolkit while at the same time reinforcing the power of influence when sharing your stories. PMID- 26018904 TI - Discovery and Characterization of Nonpeptidyl Agonists of the Tissue-Protective Erythropoietin Receptor. AB - Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy. Here, we describe the discovery and characterization of the nonpeptidyl compound STS-E412 (2-[2-(4 chlorophenoxy)ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine), which selectively activates the tissue-protective EPO receptor, comprising an EPO receptor subunit (EPOR) and the common beta-chain (CD131). STS-E412 triggered EPO receptor phosphorylation in human neuronal cells. STS-E412 also increased phosphorylation of EPOR, CD131, and the EPO-associated signaling molecules JAK2 and AKT in HEK293 transfectants expressing EPOR and CD131. At low nanomolar concentrations, STS-E412 provided EPO-like cytoprotective effects in primary neuronal cells and renal proximal tubular epithelial cells. The receptor selectivity of STS-E412 was confirmed by a lack of phosphorylation of the EPOR/EPOR homodimer, lack of activity in off-target selectivity screening, and lack of functional effects in erythroleukemia cell line TF-1 and CD34(+) progenitor cells. Permeability through artificial membranes and Caco-2 cell monolayers in vitro and penetrance across the blood-brain barrier in vivo suggest potential for central nervous system availability of the compound. To our knowledge, STS-E412 is the first nonpeptidyl, selective activator of the tissue protective EPOR/CD131 receptor. Further evaluation of the potential of STS-E412 in central nervous system diseases and organ protection is warranted. PMID- 26018907 TI - Simultaneous determination of baicalin, oroxylin A-7-O-glucuronide and wogonoside in rat plasma by UPLC-DAD and its application in pharmacokinetics of pure baicalin, Radix Scutellariae and Yinhuang granule. AB - A novel UPLC-DAD method was developed and validated for the simultaneous determination of baicalin (baicalein-7-glucuronide, BG), oroxylin A-7-O glucuronide (OAG) and wogonoside (WG) in rat plasma using rutin as the internal standard. Plasma samples were precipitated using acetonitrile containing 0.1% formic acid. Separation was performed on an Agilent Eclipse Plus C18 column (2.1 * 50 mm, 1.8 um) using gradient acetonitrile and 0.2% formic acid water solution as mobile phase. The flow-rate was set at 0.4 mL/min and the eluate was detected at 275 nm. The method was linear over the ranges of 0.075-17.50, 0.050-12.60 and 0.056-14.10 ug/mL for BG, OAG and WG, respectively. The intra- and inter-day precisions were respectively <4.8% and 6.4%. All of the limits of detection of three analytes in rat plasma were 0.01 ug/mL, whereas the limits of quantification were, respectively, 0.035, 0.025 and, 0.025 ug/mL. This assay has been successfully applied to pharmacokinetics of BG, OAG and WG in rats after oral administration of Yinhuang granule (YHG) and comparative pharmacokinetics of BG in rats following oral administration of the pure BG, Radix Scutellariae (RS) or YHG. We speculate that some co-existing ingredients in RS or YHG may increase the absorption and elimination of BG in rat. This work may be helpful for the quality control of Yinhuang granule. PMID- 26018905 TI - Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics. AB - Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer. PMID- 26018908 TI - Chordoid glioma: a rare radiologically, histologically, and clinically mystifying lesion. AB - Chordoid glioma (CG) is a rare central nervous system neoplasm (WHO grade II) of uncertain origin whose typical localization is in the anterior part of the third ventricle. Its clinical, radiological, and histological features may vary and furthermore mimic other kind of benign lesions usually associated with a better outcome. We report a case of a 43-year-old female who underwent gross total removal of a lesion of the third ventricle causing hydrocephalus. The imaging studies and the intraoperative examination led at first to a hypothesis of meningioma. Early surgical and neurological outcomes were good. The patient underwent multiple complications related to hypothalamic dysfunctions and thrombohemorragic issues and eventually died because of systemic infections. Definitive examination was of chordoid glioma of the third ventricle. Reviewing literature, we evaluated possible pitfalls in radiological and histological diagnosis as well as in surgical and medical treatment of CGs. Despite their benign presentation, a high incidence of multiple possible severe complications is reported. Early alertness and combined treatment strategies could improve overall CGs treatment strategies. PMID- 26018909 TI - The association of adiponectin gene promoter variations with non-small cell lung cancer in a Han Chinese population. AB - Recently, in vitro studies have demonstrated that adiponectin has antiangiogenic and tumor growth-limiting properties. Additionally, serum adiponectin levels have been associated with the risk of several cancers; specifically, serum adiponectin was significantly lower in lung cancer patients with advanced-stage disease. In this study, we examined the association of adiponectin gene promoter variations associated with adiponectin gene expression and plasma levels in non-small cell lung cancer (NSCLC) in a Han Chinese population. A total of 319 patients with NSCLC and 489 healthy individuals were recruited to evaluate the association of four adiponectin gene promoter single-nucleotide polymorphisms (SNPs) (SNP 12140G>A, SNP-11426A>G, SNP-11391G>A and SNP-11377C>G) with NSCLS risk. Additionally, we constructed haplotypes of these four SNPs and evaluated the association of these haplotypes with NSCLS risk. Our results showed that among these four SNPs, only SNP-12140G>A was associated with NSCLC risk (P<0.05). The haplotype analysis showed that no haplotype was associated with NSCLC after performing a Bonferroni correction (P>0.05). Additionally, an association analysis of the four SNPs stratified into pathologic stages I+II and III+IV showed that these SNPs did not exhibit significant differences between pathologic stages I+II and III+IV. Moreover, we did not observe any differences in allele and genotype frequency for these SNPs between adenocarcinoma and squamous cell carcinoma. Our results indicated that the G allele of SNP-12140 may be a risk factor for NSCLC (OR = 1.516; 95% CI: 1.098-2.094) in this Han Chinese population. PMID- 26018910 TI - Relationship between Body Mass Index and Percent Body Fat in Vietnamese: Implications for the Diagnosis of Obesity. AB - BACKGROUND: The burden of obesity in Vietnam has not been well defined because there is a lack of reference data for percent body fat (PBF) in Asians. This study sought to define the relationship between PBF and body mass index (BMI) in the Vietnamese population. METHODS: The study was designed as a comparative cross sectional investigation that involved 1217 individuals of Vietnamese background (862 women) aged 20 years and older (average age 47 yr) who were randomly selected from the general population in Ho Chi Minh City. Lean mass (LM) and fat mass (FM) were measured by DXA (Hologic QDR 4500). PBF was derived as FM over body weight. RESULTS: Based on BMI >=30, the prevalence of obesity was 1.1% and 1.3% for men and women, respectively. The prevalence of overweight and obesity combined (BMI >=25) was ~24% and ~19% in men and women, respectively. Based on the quadratic relationship between BMI and PBF, the approximate PBF corresponding to the BMI threshold of 30 (obese) was 30.5 in men and 41 in women. Using the criteria of PBF >30 in men and PBF >40 in women, approximately 15% of men and women were considered obese. CONCLUSION: These data suggest that body mass index underestimates the prevalence of obesity. We suggest that a PBF >30 in men or PBF >40 in women is used as criteria for the diagnosis of obesity in Vietnamese adults. Using these criteria, 15% of Vietnamese adults in Ho Chi Minh City was considered obese. PMID- 26018915 TI - Antidiabetic Effects of Aqueous Infusions of Artemisia herba-alba and Ajuga iva in Alloxan-Induced Diabetic Rats. AB - The aqueous infusions of the aerial parts of Artemisia herba-alba Asso and Ajuga iva Schreber, prepared in accordance with the traditional procedure used in the local folk medicine, have been analysed for their composition and content of phytochemical constituents and examined for their antidiabetic effectiveness in alloxan-induced diabetic rats. Oral administration of A. herba-alba and A. iva infusions was studied in normal and alloxan-induced diabetic rats, which were randomly divided into nine groups, each group consisting of six animals. The drug preparations (100, 200, and 300 mg/kg b. w.) of each plant were given orally to the rats of each group twice daily for 15 days. Compositional analysis of the aqueous infusions revealed the presence of several polyphenols as main components. A. herba-alba infusion was characterised by mono- and di cinnamoylquinic acids, with 5-caffeoylquinic (chlorogenic) acid being the main compound, followed by 3,5-dicaffeoylquinic acid. Vicenin-2 (apigenin 6,8-di-C glucoside) appeared to be the most abundant among flavonoids. On the other hand, A. iva showed the exclusive presence of flavonoids, with the flavanone naringin present in relatively high levels together with several apigenin (flavone) derivatives. Oral administration of 300 mg/kg b. w. of the aqueous infusions of A. herba-alba and A. iva exhibited a significant reduction in blood glucose content, showing a much more efficient antidiabetic activity compared to glibenclamide, the oral hypoglycaemic agent used as a positive control in this study. These results suggest that A. herba-alba and A. iva possess significant antidiabetic activity, as they were able to improve the biochemical damage in alloxan-induced diabetes in rats. PMID- 26018916 TI - Antiplasmodial Isoflavanes and Pterocarpans from Apoplanesia paniculata. AB - Bioassay-guided fractionation of an EtOH extract of the roots of the plant Apoplanesia paniculata (Fabaceae) led to the isolation of the three known compounds amorphaquinone (1), pendulone (2), and melilotocarpan C (3), and the two new pterocarpans 4 and 5. Compounds 1 and 2 exhibited good antiplasmodial activity with IC50 values of 5.7 +/- 1.5 and 7.0 +/- 0.8 uM, respectively. Compound 3 exhibited weak antiplasmodial activity (41.8 +/- 5.2 uM), while compounds 4 and 5 were inactive. Compound 6 was synthesized to confirm the structure of 5, and it showed enhanced antiplasmodial activity (15.8 +/- 1.4 uM) compared to its analogues 3-5. PMID- 26018917 TI - Structure-Dependent Deconjugation of Flavonoid Glucuronides by Human beta Glucuronidase - In Vitro and In Silico Analyses. AB - Flavonoid glycosides are extensively metabolized to glucuronidated compounds after oral intake. Recently, a cleavage of quercetin glucuronides by beta glucuronidase has been found. To characterize the deglucuronidation reaction and its structural prerequisites among the flavonoid subtypes more precisely, four flavonol glucuronides with varying glucuronidation positions, five flavone 7-O glucuronides with varying A- and B-ring substitution as well as one flavanone- and one isoflavone-7-O-glucuronide were analyzed in a human monocytic cell line. Investigation of the deglucuronidation rates by HPLC revealed a significant influence of the glucuronidation position on enzyme activity for flavonols. Across the flavonoid subtypes, the C-ring saturation also showed a significant influence on deglucuronidation, whereas A- and B-ring variations within the flavone-7-O-glucuronides did not affect the enzymes' activity. Results were compared to computational binding studies on human beta-glucuronidase. Additionally, molecular modeling and dynamic studies were performed to obtain detailed insight into the binding and cleavage mode of the substrate at the active site of the human beta-glucuronidase. PMID- 26018918 TI - Cardioprotective potential of Irish macroalgae: generation of glycine betaine and dimethylsulfoniopropionate containing extracts by accelerated solvent extraction. AB - Accelerated solvent extraction (ASE(r)) was used to generate 18 macroalgal extracts from Irish seaweeds. The glycine betaine and dimethylsulfoniopriopionate content of the generated ASE(r) extracts were estimated using (1)H-NMR and confirmed for selected extracts using ultra performance liquid chromatography and mass spectrometry. Dimethylsulfoniopriopionate was only identified in the ASE(r) extract generated from Codium fragile ISCG0029. Glycine betaine was identified in the ASE(r) extract generated from Ulva intestinalis ISCG0356 using (1)H-NMR. Mass spectrometry analysis found that the seaweed species Cytoseira nodicaulis ISCG0070, Cytoseira tamariscofolia ISCG0283, and Polysiphonia lanosa ISCG0462 also had a glycine betaine content that ranged from 1.39 ng/ml to 105.11 ng/ml. Generated ASE(r) macroalgal extracts have potential for use as functional food ingredients in food products. PMID- 26018919 TI - Permeation Characteristics of Hypericin across Caco-2 Monolayers in the Absence or Presence of Quercitrin - A Mass Balance Study. AB - Hypericin is a natural polycyclic quinone found in Hypericum perforatum. Although hypericin reportedly has numerous pharmacological activities, only a limited number of studies have been performed on the absorption and transport characteristics of this compound, presumably because hypericin is a highly lipophilic compound that is poorly soluble in a physiological medium. The major aim of this study was to get a detailed understanding of the exposure and fate of hypericin in the Caco-2 cell system under different experimental conditions. The permeation characteristics of hypericin (5 uM) in the absence or presence of the model flavonoid quercitrin (20 uM) were studied in the absorptive direction, without or with the addition of 10 % FBS to the transport buffer apically. Following the application of hypericin to the apical side of the monolayer, only negligible amounts of the compound were found in the basolateral compartment when the experiment was performed with a transport buffer. The amount of hypericin in the basolateral compartment increased in the presence of quercitrin (from 0 to 4 %). The majority of hypericin was found after cell extraction (44 % in the absence and 64 % in the presence of quercitrin). When 10 % FBS was added to the transport buffer in the apical compartment to improve the solubility of hypericin in the aqueous solution, around 68 % of hypericin was bound to the serum proteins. Under these experimental conditions, the amount of hypericin in the cells/cell membrane was only 13 % in the absence and 18 % in the presence of quercitrin. The low recovery and significant amounts of hypericin found after cell extraction and bound to the surface of the culture dish made a correct estimation of permeability constants impossible. Fluorescence microscopy and imaging analysis revealed that hypericin is mainly accumulated in the cell membrane. The precise mechanism through which hypericin might overcome the hydrophobic barrier of cell membranes remains to be elucidated. However, our experiments demonstrated that regardless of the experimental conditions, the permeation characteristics of hypericin improved in the presence of the model flavonoid quercitrin. PMID- 26018920 TI - Effects of the olive tree leaf constituents on myocardial oxidative damage and atherosclerosis. AB - The olive (Olea europaea) leaf is considered an important traditional herbal medicine utilized against infectious diseases, and for the treatment of diabetes and hypertension. Moreover, olive leaf constituents have been related to cardioprotection, probably due to their association with cellular redox modulating effects. The pathogenesis of certain common diseases, including those of the cardiovascular system, involves oxidative stress and tissue inflammation. Olive polyphenolic compounds, such as oleuropein, hydroxytyrosol, or tyrosol, possess antioxidant, anti-inflammatory, antiatherosclerotic, anti-ischemic, and hypolipidemic effects on the myocardium as demonstrated by various in vitro and in vivo studies. In this review article, we summarize the current knowledge on the role of the olive leaf constituents in the prevention of cardiac dysfunction and highlight future perspectives in their use as cardioprotective agents in therapeutics. PMID- 26018921 TI - Plants and their bioactive compounds with the potential to enhance mechanisms of inherited cardiac regeneration. AB - This article reviews the current progress and research indications in the application of natural plant compounds with the potential for the treatment of cardiovascular diseases. Our understanding of how to apply natural plant compounds to enhance mechanisms of inherited cardiac regeneration, which is physiologically pertinent to myocyte turnover or minor cardiac repair, for substantial cardiac regeneration to repair pathological heart injuries is discussed. Although significant progress has been made in the application of natural plant compounds for therapy of heart diseases, the understanding or the application of these compounds specifically for enhancing mechanisms of inherited cardiac regeneration for the treatment of cardiovascular diseases is little. Recent recognition of some natural plant compounds that can repair damaged myocardial tissues through enhancing mechanisms of inherited cardiac regeneration has offered an alternative for clinical translation. Application of natural plant compounds, which show the activity of manipulating gene expressions in such a way to enhance mechanisms of inherited cardiac regeneration for cardiac repair, may provide a promising strategy for the reconstruction of damaged cardiac tissues due to cardiovascular diseases. PMID- 26018922 TI - S-Nitrosylation of p47(phox) enhances phosphorylation by casein kinase 2. AB - OBJECTIVES: Leukocyte NADPH oxidase, which is active in neutrophils, is a membrane-bound enzyme that catalyzes the reduction of oxygen to O2(-) by using NADPH as an electron donor. Previously, we reported that casein kinase 2 (CK2), a ubiquitous and highly conserved Ser/Thr kinase, is responsible for p47(phox) phosphorylation and that phosphorylation of p47(phox) by CK2 regulates the deactivation of NADPH oxidase. METHODS: Here, we report that the residue Cys(196) of p47(phox) is a target of S-nitrosylation by S-nitrosothiol and peroxynitrite and that this modification enhanced phosphorylation of p47(phox) by CK2. RESULTS: S-Nitrosylated p47(phox) enhanced CK2 b subunit binding, presumably due to alterations in protein conformation. DISCUSSION: Taken together, we propose that S-nitrosylation of p47(phox) regulates the deactivation of NADPH oxidase via enhancement of p47(phox) phosphorylation by CK2. PMID- 26018923 TI - "Data safety and monitoring board in non-industry trials: learning it the hard way". PMID- 26018925 TI - Gastrointestinal absorption and metabolism of hesperetin-7-O-rutinoside and hesperetin-7-O-glucoside in healthy humans. AB - SCOPE: Hesperetin-7-O-rutinoside (hesperidin) reduces blood pressure in healthy volunteers but its intestinal absorption and metabolism are not fully understood. Therefore, we aimed to determine sites of absorption and metabolism of dietary flavanone glycosides in humans. METHODS AND RESULTS: Using a single-blind, randomized crossover design, we perfused equimolar amounts of hesperetin-7-O rutinoside and hesperetin-7-O-glucoside directly into the proximal jejunum of healthy volunteers. We assessed the appearance of metabolites in the perfusate, blood and urine, to determine the sites of metabolism and excretion, and compared this to oral administration. The glucoside was rapidly hydrolyzed by brush border enzymes without any contribution from pancreatic, stomach, or other secreted enzymes, or from bacterial enzymes. Only ~3% of the dose was recovered intact in the perfusate, indicating high absorption. A proportion was effluxed directly back into the perfused segment mainly in the form of hesperetin-3'-O-sulfate. In contrast, very little hydrolysis or absorption of hesperetin-7-O-rutinoside was observed with ~80% recovered in the perfusate, no hesperetin metabolites were detected in blood and only traces were excreted in urine. CONCLUSION: The data elucidate the pathways of metabolism of dietary hesperidin in vivo and will facilitate better design of mechanistic studies both in vivo and in vitro. PMID- 26018926 TI - Transportation of children in spica casts in the USA. AB - The aim of this study was to report outcomes of a hospital restraint loaner program for transporting children treated with spica casts. Fifty-two patients were studied. Appropriate restraints were selected by a therapist, consisting of 17 E-Z-On vest, 17 hippo car seat, five spelcast device, four family owned car seat, and nine transported using an ambulance. The cost to the hospital for the restraints ranged from $150 to $750 and $1200 for ambulance transportation. A car seat loaner program is a practical model to provide safe patient care for children in a spica cast. PMID- 26018927 TI - VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study. AB - INTRODUCTION: VEGF-C156S, a lymphangiogenesis-specific form of vascular endothelial growth factor C (VEGF-C), has been considered as a promising candidate for the experimental pro-lymphangiogenic treatment, as it lacks potential angiogenic effects. As a precursor to future clinical trials, the therapeutic efficacy and blood vascular side effects of VEGF-C and VEGF-C156S were compared in a large animal model of secondary lymphedema. Combination of lymphatic growth factor treatment and autologous lymph node transfer was used to normalize the lymphatic anatomy after surgical excision of lymphatic tissue. METHODS: Lymph vessels around the inguinal lymph node of female domestic pigs were destroyed in order to impair the normal lymphatic drainage from the hind limb. Local injections of adenoviruses (Ad) encoding VEGF-C or VEGF-C156S were used to enhance the regrowth of the lymphatic vasculature. AdLacZ (beta galactosidase) and saline injections served as controls. RESULTS: Both VEGF-C and VEGF-C156S induced growth of new lymphatic vessels in the area of excision, although lymphangiogenesis was notably stronger after VEGF-C treatment. Also the transferred lymph nodes were best-preserved in the VEGF-C-treated pigs. Despite the enlargement of blood vessels following the VEGF-C therapy, no signs of sprouting angiogenesis or increased blood vascular permeability in the form of increased wound exudate volumes were observed. CONCLUSIONS: Our results show that VEGF-C provides the preferred alternative for growth factor therapy of lymphedema when compared to VEGF-C156S, due to the superior lymphangiogenic response and minor blood vessel effects. Furthermore, these observations suggest that activation of both VEGFR-2 and VEGFR-3 might be needed for efficient lymphangiogenesis. PMID- 26018928 TI - Genome-wide expression analysis of wounded skin reveals novel genes involved in angiogenesis. AB - Wound healing is a multistage process involving collaborative efforts of different cell types and distinct cellular functions. Among others, the high metabolic activity at the wound site requires the formation and sprouting of new blood vessels (angiogenesis) to ensure an adequate supply of oxygen and nutrients for a successful healing process. Thus, a cutaneous wound healing model was established to identify new factors that are involved in vascular formation and remodeling in human skin after embryonic development. By analyzing global gene expression of skin biopsies obtained from wounded and unwounded skin, we identified a small set of genes that were highly significant differentially regulated in the course of wound healing. To initially investigate whether these genes might be involved in angiogenesis, we performed siRNA experiments and analyzed the knockdown phenotypes using a scratch wound assay which mimics cell migration and proliferation in vitro. The results revealed that a subset of these genes influence cell migration and proliferation in primary human endothelial cells (EC). Furthermore, histological analyses of skin biopsies showed that two of these genes, ALBIM2 and TMEM121, are colocalized with CD31, a well known EC marker. Taken together, we identified new genes involved in endothelial cell biology, which might be relevant to develop therapeutics not only for impaired wound healing but also for chronic inflammatory disorders and/or cardiovascular diseases. PMID- 26018929 TI - Simulation of differential interference contrast microscopy and influence of aberrations. AB - We model differential interference contrast (DIC) for microscopes with residual aberrations. The model presented allows to predict the DIC performance of objectives directly from its bright field point spread function. We numerically simulate partially coherent illumination and discuss the influence of individual aberrations on the image quality. For the recently proposed PlasDIC setup, that comes without any condenser prism, we find that under coherent illumination the contrast reaches the performance of DIC. We present a rule for objective correction to drastically improve PlasDIC contrast also for partially coherent illumination. PMID- 26018930 TI - Rational Design of Chiral Nanostructures from Self-Assembly of a Ferrocene Modified Dipeptide. AB - We report a new paradigm for the rational design of chiral nanostructures that is based on the hierarchical self-assembly of a ferrocene (Fc)-modified dipeptide, ferrocene-L-Phe-L-Phe-OH (Fc-FF). Compared to other chiral self-assembling systems, Fc-FF is unique because of its smaller size, biocompatibility, multiple functions (a redox center), and environmental responsiveness. X-ray and spectroscopic analyses showed that the incorporation of counterions during the hierarchical self-assembly of Fc-FF changed the conformations of the secondary structures from flat beta sheets into twisted beta sheets. This approach enables chiral self-assembly and the formation of well-defined chiral nanostructures composed of helical twisted beta sheets. We identified two elementary forms for the helical twist of the beta sheets, which allowed us to create a rich variety of rigid chiral nanostructures over a wide range of scales. Furthermore, through subtle modulations in the counterions, temperature, and solvent, we are able to precisely control the helical pitch, diameter, and handedness of the self assembled chiral nanostructures. This unprecedented level of control not only offers insights into how rationally designed chiral nanostructures can be formed from simple molecular building blocks but also is of significant practical value for the use in chiroptics, templates, chiral sensing, and separations. PMID- 26018932 TI - Therapeutic effect of double-filtration plasmapheresis combined with methylprednisolone to treat diffuse proliferative lupus nephritis. AB - OBJECTIVE: The efficacy of double-filtration plasmapheresis (DFPP), combined with methylprednisolone, to treat diffuse proliferative lupus nephritis (LN) was studied. METHODS: Twenty-four patients who were admitted to the hospital and diagnosed with diffuse proliferative LN (LN Class IV-G(A)) through renal biopsy from 2011 to 2013 were recruited as the study subjects. The patients' clinical manifestations were nephritic syndrome and/or renal insufficiency. The pathological features were glomerular diffuse proliferative lesions. The patients were divided into two groups: the treatment group and the control group, with 12 patients in each group. The patients in the treatment group were first treated with DFPP combined with methylprednisolone (0.8-1.0 mg/kg/day); subsequently, they were put on methylprednisolone therapy only. The patients in the control group were first put on methylprednisolone pulse therapy (500-1,000 mg) for 3 days; subsequently, they were treated with methylprednisolone (0.8-1.0 mg/kg/day) combined with mycophenolate mofetil (1.5 g/day). The patients were observed for 24 months. Levels of hemoglobin, platelet, albumin, serum creatinine, 24-h urinary protein, serum C3 , antinuclear antibody (ANA), anti-dsDNA, and anti Smith were measured at 0, 3, 6, 12, and 24 months. Complete remission and recurrence standards were established. The total dosages of methylprednisolone were calculated. Repeated renal biopsy was performed on several patients. RESULTS: There was no statistical significance in the baseline conditions of the treatment and the control groups. For the treatment group, no plasmapheresis related complications occurred. The two groups showed no significant difference in complete remission. The patients' edema and serous effusion resolved, urine volume, serum creatinine, and albumin levels returned to normal, urine protein decreased in treatment group more rapidly than the patients in the control group. The mean dose of methylprednisolone received in the treatment group was lower than in the control group. The complement C3 levels in the treatment group were significantly higher than in the control group. The recurrence rate in the treatment group was lower than in the control group. Repeated renal biopsies on several patients in the treatment group indicated that their pathology improved significantly, changing from LN (IV) to LN(II-III). CONCLUSIONS: Appropriate application of DFPP combined with glucocorticoid therapy could accelerate the remission of diffuse proliferative LN, reduce overall glucocorticoid dosage, prevent recurrence, and maintain C3 level in a higher level. J. Clin. Apheresis 31:375-380, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26018933 TI - Metal Ion Dependence of the Matrix Metalloproteinase-1 Mechanism. AB - Matrix metalloproteinase-1 (MMP-1) plays crucial roles in disease-related physiologies and pathological processes in the human body. We report here solution studies of MMP-1, including characterization of a series of mutants designed to bind metal in either the catalytic site or the structural site (but not both). Circular dichroism and fluorescence spectroscopy of the mutants demonstrate the importance of the structural Zn(II) in maintaining both secondary and tertiary structure, while UV-visible, nuclear magnetic resonance, electron paramagnetic resonance, and extended X-ray absorption fine structure show its presence influences the catalytic metal ion's coordination number. The mutants allow us to demonstrate convincingly the preparation of a mixed-metal analogue, Co(C)Zn(S)-MMP-1, with Zn(II) in the structural site and Co(II) in the catalytic site. Stopped-flow fluorescence of the native form, Zn(C)Zn(S)-MMP-1, and the mixed-metal Co(C)Zn(S)-MMP-1 analogue shows that the internal fluorescence of a nearby Trp residue is modulated with catalysis and can be used to monitor reactivity under a number of conditions, opening the door to substrate profiling. PMID- 26018934 TI - Overview of the perceived risk of transboundary pig diseases in South Africa. AB - Pig production is one of the most important animal agricultural activities in South Africa, and plays a definite role in providing food security for certain population groups in the country. As with all animal production systems, it is subject to the risk of outbreak of transboundary diseases. In the present overview, evaluations of the perceived risk of selected transboundary animal diseases of pigs, as collated from the willing participants from the provincial veterinary services of South Africa, are presented. A scenario tree revealed that infected but undetected pigs were the greatest perceived threat. The provincial veterinary services, according to participants in the study, face certain difficulties, including the reporting of disease and the flow of disease information amongst farmers. Perceived strengths in surveillance and disease monitoring include the swiftness of sample despatch to the national testing laboratory, as well as the ease of flow of information between the provincial and national agricultural authorities. The four factors were identified that were perceived to most influence animal health-service delivery: transport, access, livestock policy and resources. African swine fever was perceived to be the most important pig disease in South Africa. Because the decentralisation of veterinary services in South Africa was identified as a potential weakness, it is recommended that national and provincial veterinary services need to work together and interdependently to achieve centrally controlled surveillance systems. Regionally-coordinated surveillance activities for certain transboundary diseases were identified as needing priority for the southern African region. It is proposed that an emergency preparedness document be made available and regularly revised according to the potential risks identified on a continuous basis for South Africa. PMID- 26018935 TI - Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules. AB - Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT. On TCR stimulation of T cells from these mice, proximal signaling and cytokine production was elevated in 2KR versus wild type (WT) LAT mice. Enhanced cytolytic activity as well as T-helper responses were observed on LAT expression, which were further elevated by 2KR LAT expression. Despite greater T-effector function, WT or 2KR LAT expression did not have any effect on clearance of certain pathogens or tumors. Our data support the model that lack of tumor clearance is due to increased differentiation and acquisition of effector phenotype that is associated with suboptimal immunity in an immunotherapy model. Thus, our data further reinforce the role of LAT ubiquitination in TCR signaling and uncovers a novel role for LAT in driving T cell differentiation. PMID- 26018936 TI - Pulsed Radiofrequency Treatment Enhances Dorsal Root Ganglion Expression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in a Rat Model of Neuropathic Pain. AB - Pulsed radiofrequency (PRF) treatment is a minimally invasive technique with multiple therapeutic applications. Hyperpolarization-activated cyclic nucleotide gated (HCN) channel mediating Ih may regulate neuropathic pain signaling. This study aimed to determine whether PRF suppresses neuropathic pain by altering HCN channel expression in dorsal root ganglion (DRG) neurons. Male Sprague Dawley rats with sciatic nerve chronic constriction injury (CCI) were randomly assigned to PRF (n = 60) and sham control (n = 60) groups, respectively. On postoperative day 7 (D07), PRF or sham treatment was delivered to the proximal sciatic nerve for 8 min. Behavioral tests were performed before surgery (D0), on D07, and on D1, D7, and D14 after PRF or sham treatment. HCN1 and HCN2 expression levels in the DRG were examined by immunohistochemistry and Western blot. The results showed that thermal hyperalgesia, mechano-allodynia, and mechano-hyperalgesia were lower, and DRG expression levels of HCN1 and HCN2 higher, in the PRF group compared with sham control animals (all P < 0.05 at D14). In conclusion, PRF can upregulate HCN channel expression in the DRG of rats with sciatic nerve CCI. How this regulation of Ih in nociceptive afferents contributes to the suppression of neuropathic pain by PRF remains to be determined. PMID- 26018937 TI - miR21 is Associated with the Cognitive Improvement Following Voluntary Running Wheel Exercise in TBI Mice. AB - Recent evidences revealed that the alteration of microRNAs (miRNAs) might be associated with neuroplasticity induced by voluntary running wheel (RW) exercise in mice suffered from traumatic brain injury (TBI). In the present study, we explored the possible role of miR21 involved in the cognitive improvement following voluntary RW in TBI mice. Firstly, in situ hybridization and quantitative real-time PCR (qRT-PCR) were employed to determine the hippocampal expression and location of miR21 in TBI mice with or without spontaneous RW. Either miR21-mimics/plenti-miR21 or miR21-agomir/miR21-sponge was employed to regulate the miR21 expression in vivo and in vitro. Acquisition of spatial learning and memory retention was assessed by Morris Water Maze (MWM) test. Golgi stain was also performed to evaluate the alteration of hippocampal dendrite. Our finding confirmed that the elevated miR21 level in hippocampal post-TBI was significantly reduced by spontaneous RW. Overexpression of miR21 in TBI mice with spontaneous RW induced deteriorations in spatial learning and memory retention by significant decreases in the somata size and branch points of the hippocampus neurons. In vitro transduction with miR21 also reduced the neurite extension and the area of cultured hippocampal neuron. However, miR21 down-regulation reversed these effects. The present data strongly suggest that miR21 is an important molecule that has been involved in neuroprotection induced by voluntary RW exercise post-TBI. PMID- 26018938 TI - Polyphosphazenes with Immobilized Dyes as Potential Color Filter Materials. AB - Red, green, and blue dye molecules were linked covalently to polyphosphazenes to generate soluble, film-forming materials appropriate for the formation of patterned tricolor filters for possible use in liquid crystalline and other display devices or in camera sensors. The monofunctional dyes (a red 1-[(E)-(4 nitrophenyl)diazenyl]-2-naphthol, a green tetraphenylporphyrin [5-(4 hydroxyphenyl)-10,15,20-tetraphenylporphyrin], and a toluidine blue dye) were employed as representative chromophores. The cosubstituents employed included 2,2,2-trifluoroethoxy with and without aryloxy groups or cyclopentanoxy groups. The optical densities were varied by adopting several dye-to-cosubstituent side group ratios. These dyes are models for a wide range of different chromophores that can be linked to polyphosphazene chains. PMID- 26018939 TI - Vitamin D levels at birth and risk of type 1 diabetes in childhood: a case control study. AB - AIMS: To assess whether vitamin D levels at birth were associated with risk of having type 1 diabetes up to 10 years of age and the potential modifier effect of ethnic group. METHODS: The Piedmont Diabetes Registry and the Newborn Screening Regional data were linked to identify cases (n = 67 incident children aged <=10 years at diabetes onset, 2002-2012) and up to five controls (n = 236) matched for birthday and ethnic group. Cards with neonatal blood spot were used and 25 hydroxyvitamin D(3) assessed with tandem mass spectroscopy. RESULTS: In conditional logistic regression, OR for unit increment of log vitamin D was 0.78 (95 % CI 0.56-1.10). Vitamin D was significantly lower in migrant than in Italian control newborn babies (p < 0.0001), and interaction between vitamin D and migrant status was statistically significant (p = 0.04). Compared to migrant newborns babies with vitamin D >= 2.14 ng/ml, migrants with lower levels had an OR of 14.02 (1.76-111.70), whereas no association was evident in Italians. CONCLUSIONS: Our case-control study within the Piedmont Diabetes Registry showed no association between vitamin D levels at birth and risk of having type 1 diabetes up to 10 years of age, apart from the subgroup of migrant babies, which might have clinical implications if confirmed. PMID- 26018940 TI - The role of CD5 expression in thymic carcinoma: possible mechanism for interaction with CD5+ lymphoid stroma (microenvironment). AB - AIMS: Most thymic carcinomas express the lymphocyte marker CD5 aberrantly. This study was performed to examine the role of the self-reactive CD5 antigen in thymic carcinoma. METHODS AND RESULTS: We examined CD5 expression in thymic carcinoma in relation to the lymphoid stroma. All cases of thymic carcinoma examined expressed CD5. A number of CD5(+) lymphocytes were also present in the stroma of thymic carcinoma. The CD5(+) tumour areas were predominantly in contact with the lymphoid stroma, and the expression level was significantly lower in tumour cells than lymphocytes. Although p53 and Bcl-2 expression levels were significantly higher in thymic carcinoma than normal thymic epithelial cells (TECs), they did not differ between CD5(+) and CD5(-) areas. E-cadherin expression in thymic carcinoma was comparable with that of normal TECs, and it also did not differ between these areas. In contrast, both Ki-67 index and mitotic activity were significantly higher in thymic carcinoma than normal TECs, and they were significantly higher in CD5(+) than CD5(-) areas. CONCLUSIONS: CD5 may be induced by interaction with CD5(+) lymphoid stroma, and may be related to tumour proliferation. CD5 induction may also be a significant and/or specific effect of the tumour microenvironment of the thymus. PMID- 26018942 TI - Rescue effect of lipid emulsion on bupivacaine-induced cardiac toxicity in cardiomyocytes. AB - The aim of the present study was to investigate the mechanism underlying the rescue effect of lipid emulsion on bupivacaine (BPV)-induced cardiomyocyte toxicity. The inhibitory effects of BPV on H9c2 myoblast cell proliferation were investigated using an MTT assay. The H9c2 myoblast cells were treated with either 1 mM BPV or 1% lipid emulsion (LE) alone, or co-treated with both of the drugs. Cell apoptosis was detected using both Annexin V/propidium iodide staining and a terminal deoxynucleotidyl transferase dUTP assay. The protein expression levels of apoptosis-associated proteins were quantified using western blot analysis, and the mRNA expression levels were quantified by reverse transcription-quantitative polymerase chain reaction. The expression levels of reactive oxidative species, malondialdehyde, superoxide dismutase, and catalase were quantified using the optical density values obtained from a spectrophotometer. In addition, the mechanism underlying the mitochondrial function of the H9c2 myoblast cells was investigated using both JC-1 staining, and cyclosporin A and atractyloside treatment. The results indicated that the H9c2 myoblast cells treated with BPV exhibited significantly higher levels of apoptosis. Furthermore, BPV treatment increased the levels of oxidative stress, and caused mitochondrial dysfunction within the H9c2 myoblast cells. LE treatment reversed the effects of BPV treatment in the H9c2 myoblast cells. PMID- 26018941 TI - Emotion suppression moderates the quadratic association between RSA and executive function. AB - There is uncertainty about whether respiratory sinus arrhythmia (RSA), a cardiac marker of adaptive emotion regulation, is involved in relatively low or high executive function performance. In the present study, we investigated (a) whether RSA during rest and tasks predict both relatively low and high executive function within a larger quadratic association among the two variables, and (b) the extent to which this quadratic trend was moderated by individual differences in emotion regulation. To achieve these aims, a sample of ethnically and socioeconomically diverse women self-reported reappraisal and emotion suppression. They next experienced a 2-min resting period during which electrocardiogram (ECG) was continually assessed. In the next phase, the women completed an array of executive function and nonexecutive cognitive tasks while ECG was measured throughout. As anticipated, resting RSA showed a quadratic association with executive function that was strongest for high suppression. These results suggest that relatively high resting RSA may predict poor executive function ability when emotion regulation consumes executive control resources needed for ongoing cognitive performance. PMID- 26018943 TI - Synthesis and magnetic properties of the chromium-doped iron sulfide Fe1-xCrxS single crystalline nanoplates with a NiAs crystal structure. AB - Single crystalline iron sulfide nanoparticles doped with chromium Fe1-xCrxS (0 <=x<= 0.15) have been successfully prepared by a thermal decomposition method. The particles are self-organized into the single crystalline plates with the accurate hexagonal shape and dimensions up to 1 MU in plane and about 30-40 nm in thickness. The samples have the NiAs-type crystal structure (P63/mmc) at all Cr concentrations up to x = 0.15. Fe(57)-Mossbauer spectroscopy data reveal four nonequivalent iron sites in these nanocrystals related to the different number of cation vacancies in neighboring of the iron atoms. A 2C-type superstructure or a mixture of 2C and 3C superstructures of vacancy ordering can appear in these samples. It was established that in the Fe1-xCrxS series chromium prefers to replace iron in the cation layers containing vacancies at 0.00 < x < 0.10 and Cr atoms occupy both iron and vacant sites at x > 0.10. The specific magnetic properties, which can be tuned by chromium doping, enable potential applications of these nanoparticles in technical devices using the material with thermally activated magnetic memory, for example, switches or storages. PMID- 26018944 TI - Social Attention in 47,XXY (Klinefelter Syndrome): Visual Scanning of Facial Expressions Using Eyetracking. AB - Boys and men with an extra X chromosome (47,XXY, Klinefelter syndrome) are at risk for problems in social functioning and have an increased vulnerability for autism spectrum disorders (ASD). In the search for underlying mechanisms driving this increased risk, this study focused on social attention, that is, spontaneous orientation toward facial expressions. Seventeen adults with 47,XXY and 20 non clinical controls participated in this study. Social attention was measured using an eyetracking method that quantifies the visual scanning patterns of faces expressing different types of emotions (happy, fearful, angry, neutral) and their varying intensity levels (25%, 50%, 75%, 100%). Overall, the group with Klinefelter syndrome fixated less on the eye region of faces when compared to controls (Cohen's d 1.4), and did not show the typical tendency, as was found in the control group, to first fixate on the eyes when presented with a face (Cohen's d 1.0). There was no significant effect of type or intensity of emotion. Shorter looking times toward eyes showed a borderline significant correlation with self-reports of poorer social functioning, with 29% explained variance. These findings suggest a reduced tendency to rapidly and automatically attend to the eyes of others in individuals with 47,XXY. This may have impact on more complex social-cognitive abilities that build upon this. In addition to studies of behaviorally defined disorders such as ASD, studying individuals with Klinefelter syndrome provide insight into mechanisms underlying various "at risk" pathways of social dysfunction and the factors that mediate this risk. PMID- 26018945 TI - Room-temperature ferromagnetism in Co doped MoS2 sheets. AB - Via the hydrothermal method, we synthesized MoS2 nanosheets with varying Co dopant concentrations of 0%, 3%, 7%, using cobaltous acetate as a promoter, and marked as A, B, and C, respectively. We found that the thickness and flatness of the nanosheets increased with the increase of the Co dopant concentrations. Meanwhile, the BET surface area of samples (A, B, and C) decreased with the increase of the Co dopant concentrations. Optical absorption spectroscopy showed that, compared to sample A, the A1 and B1 excitons of samples B and C were 10 and 23 meV redshifted, respectively. Then, we performed magnetization measurement to investigate the effect of Co-doping; the unique result implied that the values of the magnetic moment decreased with the increase of the Co dopant concentrations. We performed DFT computations to address the above magnetic result. The computational result indicated that the value of the magnetic moment decreased with the increase of the Co dopant concentrations, which is in agreement with the results of the experiments described above. PMID- 26018946 TI - Routine therapeutic monitoring of the active metabolite of carbamazepine: Is it really necessary? AB - OBJECTIVES: Carbamazepine (CBZ) is primarily used in the treatment of epilepsy as well as trigeminal neuralgia. It is metabolised by the liver to its pharmacologically active metabolite carbamazepine-10,11-epoxide (CBZ-E), which is potentially toxic. The aim of our study was to measure CBZ and CBZ-E in our patient set and to consider the introduction of CBZ-E to routine therapeutic drug monitoring (TDM). High-performance liquid chromatography (HPLC) and Chemiluminescence Microparticle Immuno Assay (CMIA) methods for the measurement of CBZ were compared. DESIGN AND METHODS: We simultaneously measured serum concentrations of CBZ and CBZ-E using HPLC. Serum concentrations of CBZ were also analysed by CMIA. For the measurements we chose patients (ages 5-67years) on monotherapy (n=51), patients taking CBZ with antiepileptic drugs (AEDs) susceptible to pharmacokinetic interaction including phenytoin, phenobarbital, primidone and valproic acid (n=56) and patients taking other AEDs (n=44). RESULTS: Patient's serum levels of CBZ-E ranged from 1.38-27.79MUmol/L with a mean value of 6.96+/-4.07MUmol/L. The CBZ-E/CBZ ratio increased significantly in patients taking phenytoin, phenobarbital, primidone and valproic acid. CBZ concentrations measured by CMIA were lower than those obtained by HPLC (mean difference of 3.8MUmol/L). The Passing and Bablok regression showed acceptable agreement between these two methods. CONCLUSIONS: Based on our results, we do not consider the introduction of the active metabolite of CBZ to routine TDM to be necessary. However, it might be beneficial in patients taking CBZ with AEDs susceptible to pharmacokinetic interaction to avoid any potential adverse effects. A close correlation between CMIA and HPLC method was found for the measurement of CBZ serum concentrations. PMID- 26018947 TI - EA versus sham acupuncture and no acupuncture for the control of acute and delayed chemotherapy-induced nausea and vomiting: a pilot study. AB - OBJECTIVE: To assess the feasibility of undertaking a high-quality randomised controlled study to determine whether EA gives better control of delayed chemotherapy-induced nausea and vomiting (CINV) than sham EA or standard antiemetic treatment alone. METHODS: Patients having their first cycle of moderately or highly emetogenic chemotherapy were randomised to EA, sham EA or standard care. EA was given for 30 min on day 1 at the time of chemotherapy and on day 3 using standard acupuncture points bilaterally. Sham EA was given to points adjacent to true EA points. All patients received usual care, comprising antiemetics, according to hospital guidelines. The primary outcomes related to study feasibility, and the clinical outcome measure was the change in Functional Living Index Emesis (FLIE) score captured on days 1 and 7. RESULTS: 153 participants were screened between April 2009 and May 2011. Eighteen patients did not meet the inclusion criteria, 37 declined to participate and the absence of an acupuncturist or lack of consent from the treating oncologist excluded a further 38 patients; 60 patients were recruited. The FLIE was completed on day 7 by 49 participants; 33 of 40 patients returned on day 3 for treatment. The nausea and vomiting scores were low in all three arms. Adverse events were generally mild and infrequent. CONCLUSIONS: It was feasible to undertake a randomised EA trial on a busy day oncology unit. As few patients experienced nausea with their first cycle of chemotherapy, it was not possible to determine whether EA improves CINV over standard care. An enriched enrolment strategy is indicated for future studies. A simple numerical rating scale may prove a better objective nausea measure than the FLIE. TRIAL REGISTRATION NUMBER: ACTRN12609001054202. PMID- 26018949 TI - BCL::SAXS: GPU accelerated Debye method for computation of small angle X-ray scattering profiles. AB - Small angle X-ray scattering (SAXS) is an experimental technique used for structural characterization of macromolecules in solution. Here, we introduce BCL::SAXS--an algorithm designed to replicate SAXS profiles from rigid protein models at different levels of detail. We first show our derivation of BCL::SAXS and compare our results with the experimental scattering profile of hen egg white lysozyme. Using this protein we show how to generate SAXS profiles representing: (1) complete models, (2) models with approximated side chain coordinates, and (3) models with approximated side chain and loop region coordinates. We evaluated the ability of SAXS profiles to identify a correct protein topology from a non redundant benchmark set of proteins. We find that complete SAXS profiles can be used to identify the correct protein by receiver operating characteristic (ROC) analysis with an area under the curve (AUC) > 99%. We show how our approximation of loop coordinates between secondary structure elements improves protein recognition by SAchiS for protein models without loop regions and side chains. Agreement with SAXS data is a necessary but not sufficient condition for structure determination. We conclude that experimental SAXS data can be used as a filter to exclude protein models with large structural differences from the native. PMID- 26018952 TI - Learning from The Lancet. PMID- 26018951 TI - Saccharification and hydrolytic enzyme production of alkali pre-treated wheat bran by Trichoderma virens under solid state fermentation. AB - BACKGROUND: In continuation of our previously interest in the saccharification of agriculture wastes by Bacillus megatherium in solid state fermentation (SSF), we wish to report an investigation and comparative evaluation among Trichoderma sp. for the saccharification of four alkali-pretreated agricultural residues and production of hydrolytic enzymes, carboxymethyl cellulase (CMCase), filter paperase (FPase), pectinase (PGase) and xylanase (Xylase) in SSF. The optimization of the physiological conditions of production of hydrolytic enzymes and saccharification content from Trichoderma virens using alkali-pretreated wheat bran was the last goal. METHODS: The physico-chemical parameters of SSF include incubation time, incubation temperature, moisture content of the substrate, incubation pH, supplementation with carbon and nitrogen sources were optimized. RESULTS: Saccharification of different solid state fermentation sources wheat bran, date's seeds, grass and palm leaves, were tested for the production of fermentable sugar by Trichoderma sp. The maximum production of hydrolytic enzymes CMCase, FPase, PGase and Xylase and saccharification content were obtained on wheat bran. Time course, moisture content, optimum temperature, optimum pH, supplementation with carbon and nitrogen sources were optimized to achieve the maximum production of the hydrolytic enzymes, protein and total carbohydrate of T. virens using alkali pre-treated wheat bran. The maximum production of CMCase, FPase, PGase, Xylase, protein and carbohydrate content was recorded at 72 h of incubation, 50-70 % moisture, temperature 25-35 degrees C and pH 5. The influence of supplementary carbon and nitrogen sources was studied. While lactose and sucrose enhanced the activity of PGase from 79.2 to 582.9 and 632.6 U/g, starch inhibited all other enzymes. This was confirmed by maximum saccharification content. Among the nitrogen sources, yeast extract and urea enhanced the saccharification content and CMCase, PGase and Xylase. CONCLUSIONS: The results of this study indicated that alkali pre-treated wheat bran was a better substrate for saccharification and production of hydrolytic enzymes CMCase, FPase, PGase and xylase by T. virens compared to other alkali-pretreated agricultural residues tested. PMID- 26018953 TI - A tribute to Dr. William D. Steers, 1955-2015. PMID- 26018950 TI - Association between Advanced Glycation End Products and Impaired Fasting Glucose: Results from the SALIA Study. AB - Advanced glycation end products (AGEs) may contribute to the development of type 2 diabetes and related complications, whereas their role in the early deterioration of glycaemia is unknown. While previous studies used antibody-based methods to quantify AGEs, data from tandem mass spectrometry coupled liquid chromatography (LC-MS/MS)-based measurements are limited to patients with known diabetes. Here, we used the LC-MS/MS method to test the hypothesis that plasma AGE levels are higher in individuals with impaired fasting glucose (IFG) than in those with normal fasting glucose (NFG). Secondary aims were to assess correlations of plasma AGEs with quantitative markers of glucose metabolism and biomarkers of subclinical inflammation. This study included on 60 women with NFG or IFG (n = 30 each, mean age 74 years) from the German SALIA cohort. Plasma levels of free metabolites (3-deoxyfructose, 3-deoxypentosone, 3-deoxypentulose), two hydroimidazolones, oxidised adducts (carboxymethyllysine, carboxyethyllysine, methionine sulfoxide) and Nepsilon-fructosyllysine were measured using LC-MS/MS. Plasma concentrations of all tested AGEs did not differ between the NFG and IFG groups (all p>0.05). Associations between plasma levels of AGEs and fasting glucose, insulin and HOMA-IR as a measure of insulin resistance were weak (r between -0.2 and 0.2, all p>0.05). The association between 3-deoxyglucosone derived hydroimidazolone with several proinflammatory biomarkers disappeared upon adjustment for multiple testing. In conclusion, plasma AGEs assessed by LC-MS/MS were neither increased in IFG nor associated with parameters of glucose metabolism and subclinical inflammation in our study. Thus, these data argue against strong effects of AGEs in the early stages of deterioration of glucose metabolism. PMID- 26018954 TI - Choline-positron emission tomography/CT in patients with relapsing prostate cancer: to be performed with therapeutic consequences only. PMID- 26018955 TI - To clamp or not to clamp in robotic partial nephrectomy? PMID- 26018956 TI - When normal is not enough. PMID- 26018957 TI - Testing Chemical Safety: What Is Needed to Ensure the Widespread Application of Non-animal Approaches? AB - Scientists face growing pressure to move away from using traditional animal toxicity tests to determine whether manufactured chemicals are safe. Numerous ethical, scientific, business, and legislative incentives will help to drive this shift. However, a number of hurdles must be overcome in the coming years before non-animal methods are adopted into widespread practice, particularly from regulatory, scientific, and global perspectives. Several initiatives are nevertheless underway that promise to increase the confidence in newer alternative methods, which will support the move towards a future in which less data from animal tests is required in the assessment of chemical safety. PMID- 26018958 TI - A Case of Leprosy in Italy: A Multifaceted Disease Which Continues to Challenge Medical Doctors. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae, characterized by a very long incubation period, confounding signs and symptoms and difficulty to establish the onset time. Considering the stigma associated with the diagnosis and the difficulties in detecting asymptomatic leprosy, the incidence and prevalence of this disease are underestimated. In Italy, leprosy is currently included among the rare diseases and can occur as an imported pathology in native individuals or extra-EU immigrants. Currently, given its exceptional appearance in Italy, leprosy is extremely difficult to recognize. In fact, the incomplete knowledge by the medical class of geographical epidemiology and aetiology of tropical diseases including leprosy, often delays the definitive diagnosis. Due to the increasing rate of the migration flows, in Italy and in Europe, leprosy should be considered among the differential diagnosis in patients with cutaneous and neurological signs, especially when originating from endemic countries. PMID- 26018959 TI - Assessing Oral Cancer Awareness Among Rural Latino Migrant Workers. AB - Latino migrant farm workers suffer significant health disparities, including poor oral health. The purpose of this research was to assess Latino migrant farm workers' OC awareness, including knowledge and care-seeking behaviors. A 42-item survey was developed. Trained, bilingual researchers verbally administered the survey to migrant farm workers in Hillsborough County, Florida. Frequencies and descriptive statistics were generated to report baseline data. The sample consisted of 53.7 % female respondents. The mean age for males and females respectively was 38.7 and 39.2. Most respondents had attended grade school; 6.7 % never attended school. Perceptions of cancer susceptibility were present; knowledge of OC risk factors, signs and symptoms was low. Participants were unlikely to seek preventive care. The results contribute to the limited studies regarding Latino migrant farm workers and oral cancer risk factor awareness and knowledge. Findings highlight factors influencing motivation and care-seeking behaviors, as well as provide guidance for development of educational materials. PMID- 26018960 TI - Brunenders: a partially attenuated historic poliovirus type I vaccine strain. AB - Brunenders, a type I poliovirus (PV) strain, was developed in 1952 by J. F. Enders and colleagues through serial in vitro passaging of the parental Brunhilde strain, and was reported to display partial neuroattenuation in monkeys. This phenotype of attenuation encouraged two vaccine manufacturers to adopt Brunenders as the type I component for their inactivated poliovirus vaccines (IPVs) in the 1950s, although today no licensed IPV vaccine contains Brunenders. Here we confirmed, in a transgenic mouse model, the report of Enders on the reduced neurovirulence of Brunenders. Although dramatically neuroattenuated relative to WT PV strains, Brunenders remains more virulent than the attenuated oral vaccine strain, Sabin 1. Importantly, the neuroattenuation of Brunenders does not affect in vitro growth kinetics and in vitro antigenicity, which were similar to those of Mahoney, the conventional type I IPV vaccine strain. We showed, by full nucleotide sequencing, that Brunhilde and Brunenders differ at 31 nucleotides, eight of which lead to amino acid changes, all located in the capsid. Upon exchanging the Brunenders capsid sequence with that of the Mahoney capsid, WT neurovirulence was regained in vivo, suggesting a role for the capsid mutations in Brunenders attenuation. To date, as polio eradication draws closer, the switch to using attenuated strains for IPV is actively being pursued. Brunenders preceded this novel strategy as a partially attenuated IPV strain, accompanied by decades of successful use in the field. Providing data on the attenuation of Brunenders may be of value in the further construction of attenuated PV strains to support the grand pursuit of the global eradication of poliomyelitis. PMID- 26018961 TI - A highly divergent picornavirus in an amphibian, the smooth newt (Lissotriton vulgaris). AB - Genetically highly divergent picornavirus (Newt/2013/HUN, KP770140) was detected using viral metagenomics in faecal samples of free-living smooth newts (Lissotriton vulgaris). Newt picornavirus was identified by reverse transcription polymerase chain reaction (RT-PCR) in six (25 %) of the 24 samples originating from individuals caught in two out of the six investigated natural ponds in Hungary. The first picornavirus in amphibians expands the host range of members of the Picornaviridae, and opens a new research field in picornavirus evolution in lower vertebrates. Newt picornavirus represents a novel species in a novel genus within the family Picornaviridae, provisionally named genus Ampivirus (amphibian picornavirus). PMID- 26018962 TI - Intracellular membrane association of the N-terminal domain of classical swine fever virus NS4B determines viral genome replication and virulence. AB - Classical swine fever virus (CSFV) causes a highly contagious disease in pigs that can range from a severe haemorrhagic fever to a nearly unapparent disease, depending on the virulence of the virus strain. Little is known about the viral molecular determinants of CSFV virulence. The nonstructural protein NS4B is essential for viral replication. However, the roles of CSFV NS4B in viral genome replication and pathogenesis have not yet been elucidated. NS4B of the GPE- vaccine strain and of the highly virulent Eystrup strain differ by a total of seven amino acid residues, two of which are located in the predicted trans membrane domains of NS4B and were described previously to relate to virulence, and five residues clustering in the N-terminal part. In the present study, we examined the potential role of these five amino acids in modulating genome replication and determining pathogenicity in pigs. A chimeric low virulent GPE- derived virus carrying the complete Eystrup NS4B showed enhanced pathogenicity in pigs. The in vitro replication efficiency of the NS4B chimeric GPE- replicon was significantly higher than that of the replicon carrying only the two Eystrup specific amino acids in NS4B. In silico and in vitro data suggest that the N terminal part of NS4B forms an amphipathic alpha-helix structure. The N-terminal NS4B with these five amino acid residues is associated with the intracellular membranes. Taken together, this is the first gain-of-function study showing that the N-terminal domain of NS4B can determine CSFV genome replication in cell culture and viral pathogenicity in pigs. PMID- 26018963 TI - Adsorption of bovine serum albumin onto synthetic Fe-doped geomimetic chrysotile. AB - Synthetic stoichiometric and Fe-doped geomimetic chrysotile nanocrystals represent a reference standard to investigate the health hazard associated with mineral asbestos fibres. Experimental evidence suggests that the generation of reactive oxygen species and other radicals, catalysed by iron ions at the fibre surface, plays an important role in asbestos-induced cytotoxicity and genotoxicity. In this study, structural modification of bovine serum albumin (BSA) adsorbed onto synthetic chrysotile doped with different amounts of Fe has been investigated by Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA) and analytical pyrolysis coupled with gas chromatography-mass spectrometry. FT-IR data evidenced a marked increase in disordered structures like random coil and beta-turn of BSA-nanocrystal adduct with 0.52 wt% of Fe doped. The TGA profile of the BSA revealed that its interaction with the synthetic chrysotile surface was strongly affected by the substitution of Fe into the chrysotile structure. The 2,5-diketopiperazine yields, formed upon thermal degradation of the polypeptide chain (pyrolysis-gas chromatography), changed when the BSA was adsorbed on the nanofibres. In general, results suggested that minute amount (less than 1 wt%) of Fe doping in chrysotile affected the protein-nanofibre interactions, supporting the role that this element may play in asbestos toxicity. The catalytic role of iron and the consequent unfolding of protein due to the structural surface modification of nanofibres were also evaluated. PMID- 26018964 TI - Tissue growth controlled by geometric boundary conditions: a simple model recapitulating aspects of callus formation and bone healing. AB - The shape of tissues arises from a subtle interplay between biochemical driving forces, leading to cell growth, division and extracellular matrix formation, and the physical constraints of the surrounding environment, giving rise to mechanical signals for the cells. Despite the inherent complexity of such systems, much can still be learnt by treating tissues that constantly remodel as simple fluids. In this approach, remodelling relaxes all internal stresses except for the pressure which is counterbalanced by the surface stress. Our model is used to investigate how wettable substrates influence the stability of tissue nodules. It turns out for a growing tissue nodule in free space, the model predicts only two states: either the tissue shrinks and disappears, or it keeps growing indefinitely. However, as soon as the tissue wets a substrate, stable equilibrium configurations become possible. Furthermore, by investigating more complex substrate geometries, such as tissue growing at the end of a hollow cylinder, we see features reminiscent of healing processes in long bones, such as the existence of a critical gap size above which healing does not occur. Despite its simplicity, the model may be useful in describing various aspects related to tissue growth, including biofilm formation and cancer metastases. PMID- 26018965 TI - Tracking employment shocks using mobile phone data. AB - Can data from mobile phones be used to observe economic shocks and their consequences at multiple scales? Here we present novel methods to detect mass layoffs, identify individuals affected by them and predict changes in aggregate unemployment rates using call detail records (CDRs) from mobile phones. Using the closure of a large manufacturing plant as a case study, we first describe a structural break model to correctly detect the date of a mass layoff and estimate its size. We then use a Bayesian classification model to identify affected individuals by observing changes in calling behaviour following the plant's closure. For these affected individuals, we observe significant declines in social behaviour and mobility following job loss. Using the features identified at the micro level, we show that the same changes in these calling behaviours, aggregated at the regional level, can improve forecasts of macro unemployment rates. These methods and results highlight promise of new data resources to measure microeconomic behaviour and improve estimates of critical economic indicators. PMID- 26018966 TI - Diagnostic value of contrast-enhanced cardiac magnetic resonance in patients with acute coronary syndrome with normal coronary arteries. AB - PURPOSE: To evaluate retrospectively the diagnostic value of cardiac magnetic resonance (CMR) in patients with acute coronary syndromes (ACS) with normal coronary arteries, without pre-existing comorbidities. MATERIALS AND METHODS: We retrospectively reviewed the contrast-enhanced (CE) CMR images of 143 patients (70 males and 73 females, mean age 63 years, age range 37-87), within a server of 1590 patients, between January 2012 and January 2014. Only patients with ACS (anginal episode lasting at least 30 min) with normal coronary arteries were included, as well as patients with serologic assay of positive troponin I (TnI) and possible changes in ECG, particularly ST elevation. All patients with a history of ACS, or chronic troponin elevation, dyslipidemia, smoking, patients with cardiomyopathies or preexisting comorbidities such as diabetes, hereditary collagenopathies, amyloidosis, sarcoidosis, hemosiderosis or other infiltrative diseases were excluded to avoid possible bias. RESULTS: The CMR LGE pattern attributable to AMI occurred in 40/143 cases (28 %) and in particular involved only a myocardial segment (60 %). The MR pattern of acute myocarditis occurred in 16/143 (11.2 %); in 6/143 cases, Tako-Tsubo cardiomyopathy was present. Eighty one cases out of 143 presented a CMR with no LGE, parietal edema or morphological alterations (56.6 %). CONCLUSION: In patients with a first episode of ACS with normal coronary arteries, in the absence of pre-existing comorbidities, CMR has a high negative predictive value, often without significant alterations. In particular, the CMR LGE for AMI is infrequent and has predominantly focal distribution. However, further multidisciplinary studies are needed to define the prognostic value of CMR. PMID- 26018968 TI - Two cases of breast carcinoma during pregnancy and review of the literature. AB - Pregnancy-associated breast cancer is the most common solid tumor in pregnancy after cervical carcinoma but still has a low incidence. It has been associated with a poor prognosis; though based on a limited number of retrospective case control studies, some authors have reported no differences from that of non pregnant patients. There is no consensus about the treatment; it requires an interdisciplinary approach and it is necessary to balance between the benefit for the mother and risk for the fetus. Each case requires an individual decision taking into account the stage of disease, patient preferences and gestational age. Above chemotherapy, it is only recommended after the first trimester of pregnancy and anthracyclin-based schemes have the higher evidence, but taxanes are also considered as an alternative in patients who do not respond to anthracyclines or its use is contraindicated. For the time being, there is a lack of data, and clinical decisions are based on small retrospective cohorts, case control studies and case reports. We report two cases of patients being diagnosed with breast cancer while being pregnant and treated with surgery and chemotherapy, including anthracyclines, during the second and third trimester of pregnancy. In both reported cases, childbirth was induced before the 37th week of gestation and only one presented low birth weight with no more complications. The echocardiogram monitorization showed normal cardiac function in mothers and fetus. PMID- 26018969 TI - MED12 is frequently mutated in breast phyllodes tumours: a study of 112 cases. AB - AIM: To determine the frequency of MED12 mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes. METHODS: Phyllodes tumours from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of the MED12 gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out. RESULTS: There were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosing MED12 mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harboured MED12 mutations experienced improved disease-free survivals, with higher recurrence likelihood in those without MED12 mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015). CONCLUSIONS: Similar to fibroadenomas, phyllodes tumours show a high frequency of MED12 mutations, affirming the close biological relationship between these fibroepithelial neoplasms. PMID- 26018967 TI - A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. AB - BACKGROUND: Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) +/- etoposide for patients with relapsed or refractory NB. METHODS AND FINDINGS: Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). CONCLUSIONS: DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. TRIAL REGISTRATION: Clinicaltrials.gov NCT#01059071. PMID- 26018970 TI - Heavy Slow Resistance Versus Eccentric Training as Treatment for Achilles Tendinopathy: A Randomized Controlled Trial. AB - BACKGROUND: Previous studies have shown that eccentric training has a positive effect on Achilles tendinopathy, but few randomized controlled trials have compared it with other loading-based treatment regimens. PURPOSE: To evaluate the effectiveness of eccentric training (ECC) and heavy slow resistance training (HSR) among patients with midportion Achilles tendinopathy. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 58 patients with chronic (>3 months) midportion Achilles tendinopathy were randomized to ECC or HSR for 12 weeks. Function and symptoms (Victorian Institute of Sports Assessment-Achilles), tendon pain during activity (visual analog scale), tendon swelling, tendon neovascularization, and treatment satisfaction were assessed at 0 and 12 weeks and at the 52-week follow-up. Analyses were performed on an intention-to-treat basis. RESULTS: Both groups showed significant (P < .0001) improvements in Victorian Institute of Sports Assessment-Achilles and visual analog scale from 0 to 12 weeks, and these improvements were maintained at the 52-week follow-up. Concomitant with the clinical improvement, there was a significant reduction in tendon thickness and neovascularization. None of these robust clinical and structural improvements differed between the ECC and HSR groups. However, patient satisfaction tended to be greater after 12 weeks with HSR (100%) than with ECC (80%; P = .052) but not after 52 weeks (HSR, 96%; ECC, 76%; P = .10), and the mean training session compliance rate was 78% in the ECC group and 92% in the HSR group, with a significant difference between groups (P < .005). CONCLUSION: The results of this study show that both traditional ECC and HSR yield positive, equally good, lasting clinical results in patients with Achilles tendinopathy and that the latter tends to be associated with greater patient satisfaction after 12 weeks but not after 52 weeks. PMID- 26018971 TI - Intraorbital meningioma: resection through modified orbitozygomatic craniotomy. AB - Intraorbital meningiomas are challenging lesions to excise because of their location and the restricted surgical corridor available due to the presence of important neighboring structures. Lesions located in the posterior one-third of the orbit require skull base approaches for their exposure and safe resection. Frontoorbital and modified orbitozygomatic (OZ) craniotomies may facilitate the exposure and resection of masses in the posterior intraorbital space. Specifically, the one-piece modified OZ craniotomy provides many advantages of the "full" OZ craniotomy (which includes a more extensive zygomatic osteotomy). The modified OZ approach minimizes the extent of frontal lobe retraction and provides ample amount of space for the surgeon to exploit all the working angles to resect the tumor. The following video presentation discusses the nuances of technique for resection of an intraorbital meningioma through modified OZ approach and optic nerve decompression. The nuances of technique will be discussed. The video can be found here: http://youtu.be/fP5X2QNr5qk . PMID- 26018972 TI - Endoscopic endonasal transplanum transtuberculum approach for resection of retrochiasmatic craniopharyngioma. AB - Retrochiasmatic craniopharyngiomas are formidable cranial base tumors to resect because of their intimate relationship with neighboring critical neurovascular structures, particularly the undersurface of the optic chiasm and hypothalamus. Radical resection offers the best chance of minimizing tumor recurrence, although this may be associated with significant surgical morbidity. Although various transcranial approaches have been utilized (transbasal subfrontal, frontobasal interhemispheric, pterional, orbitozygomatic, and petrosal) for resection of retrochiasmatic craniopharyngiomas, each is associated with some degree of brain retraction, and direct visualization of the retrochiasmatic region is often incomplete, therefore resulting in blind dissection. The endoscopic endonasal transplanum transtuberculum approach provides the most direct route to the retrochiasmatic region while affording unmatched visualization of the undersurface of the optic chiasm, third ventricle, and hypothalamus. This advantage allows for direct bimanual tumor dissection off of these critical structures by using microsurgical principles. The endonasal route also has the advantage of avoiding brain retraction and risk of cerebral edema that can be associated with transcranial approaches. In this operative video atlas report, the authors demonstrate their step-by-step techniques for resection of a suprasellar retrochiasmatic craniopharyngioma using a purely endoscopic endonasal transplanum transtuberculum approach. They describe and illustrate the operative nuances and surgical pearls to safely and efficiently perform the approach, tumor resection, and multilayered reconstruction of the cranial base defect. The video can be found here: http://youtu.be/ZIbJvAyRxYU . PMID- 26018973 TI - Expanded endoscopic endonasal transcribriform approach for resection of anterior skull base olfactory schwannoma. AB - Anterior skull base (ASB) schwannomas are extremely rare and can often mimic other pathologies involving the ASB such as olfactory groove meningiomas, hemangiopericytomas, esthesioneuroblastomas, and other malignant ASB tumors. The mainstay of treatment for these lesions is gross-total resection. Traditionally, resection for tumors in this location is performed through a bifrontal transbasal approach that can involve some degree of brain retraction or manipulation for tumor exposure. With the recent advances in endoscopic skull base surgery, various ASB tumors can be resected successfully using an expanded endoscopic endonasal transcribriform approach through a "keyhole craniectomy" in the ventral skull base. This approach represents the most direct route to the anterior cranial base without any brain retraction. Tumor involving the paranasal sinuses, medial orbits, and cribriform plate can be readily resected. In this video atlas report, the authors demonstrate their step-by-step techniques for resection of an ASB olfactory schwannoma using a purely endoscopic endonasal transcribriform approach. They describe and illustrate the operative nuances and surgical pearls to safely and efficiently perform the approach, tumor resection, and multilayered reconstruction of the cranial base defect. The video can be found here: http://youtu.be/NLtOGfKWC6U . PMID- 26018974 TI - Modified one-piece extended transbasal approach for resection of giant anterior skull base sinonasal teratocarcinosarcoma. AB - The transbasal approach is considered the workhorse for removing a variety of benign and malignant tumors of the anterior skull base. In some instances, removal of the supraorbital bar in addition to a standard bifrontal craniotomy (extended transbasal approach) allows for additional basal exposure, thereby minimizing brain retraction. In this operative video atlas report, the authors describe and demonstrate a modified one-piece extended transbasal craniotomy that incorporates the anterior wall of the frontal sinus. The inferior margin of the osteotomy is made as low as possible through the anterior wall of the frontal sinus, starting at the nasofrontal suture and extending laterally over both orbital rims by following the contour of the anterior skull base in the coronal orientation. This modification provides an excellent line of sight to the anterior skull base without any obstruction from bone overhang, which obviates the need for any supraorbital rim removal. Removal of a giant anterior skull base sinonasal teratocarcinosarcoma via the modified one-piece extended transbasal approach is demonstrated in this operative video atlas. The authors describe and illustrate the operative nuances and surgical pearls to safely and efficiently perform the approach, tumor resection, and multilayered reconstruction of the cranial base defect. The video can be found here: http://youtu.be/x1lTtfqKIV0 . PMID- 26018975 TI - Endoscopic endonasal craniopharyngioma resection. AB - The authors present the case of a 21-year-old female with a progressive bitemporal hemianopsia. Cranial MR imaging revealed a large cystic suprasellar, retrochiasmatic lesion consistent with craniopharyngioma. The lesion was fully resected through an endoscopic endonasal transsphenoidal and transplanum approach. Closure of the resultant dural defect was performed with a bilayer fascia lata button and autologous mucoperichondrial nasoseptal flap. Each portion of this procedure was recorded and is presented in an edited high-definition format. The video can be found here: http://youtu.be/i3-qieLlbVk . PMID- 26018976 TI - Endoscopic endonasal repair of spontaneous CSF fistulae. AB - The authors present a fully endoscopic endonasal repair of a spontaneous CSF leak caused by a defect in the anterior fossa floor. Patients were positioned supine in a Mayfield headholder in slight extension. A complete ethmoidectomy was performed to expose the defect. The middle turbinate was removed to increase visualization and allow for more working room. The defect was identified and exposed. A nasoseptal flap was raised and placed over the defect. A free-mucosal graft fashioned from the removed middle turbinate was placed on the nasoseptal donor site. The video can be found here: http://youtu.be/gAN2cvQVXCE . PMID- 26018977 TI - Dorsal variant blister aneurysm repair. AB - Dorsal variant proximal carotid blister aneurysms are treacherous lesions to manage. It is important to recognize this variant on preoperative angiographic imaging, in anticipation of surgical strategies for their treatment. Strategies include trapping the involved segment and revascularization if necessary. Other options include repair of the aneurysm rupture site directly. Given that these are not true berry aneurysms, repair of the rupture site involves wrapping or clip-grafting techniques. The case presented here was a young woman with a subarachnoid hemorrhage from a ruptured dorsal variant blister aneurysm. The technique used is demonstrated in the video and is a modified clip-wrap technique using woven polyester graft material. The patient was given aspirin preoperatively as preparation for the clip-wrap technique. It is the authors' current protocol to attempt a direct repair with clip-wrapping and leaving artery sacrifice with or without bypass as a salvage therapy if direct repair is not possible. Assessment of vessel patency after repair is performed by intraoperative Doppler and indocyanine green angiography. Intraoperative somatosensory and motor evoked potential monitoring is performed in all cases. The video can be found here: http://youtu.be/crUreWGQdGo . PMID- 26018978 TI - Endoscopic endonasal approach for a tuberculum sellae meningioma. AB - The authors present the technical and anatomical nuances needed to perform an endoscopic endonasal removal of a tuberculum sellae meningioma. The patient is a 47-year-old female with headaches and an incidental finding of a small tuberculum sellae meningioma with no vascular encasement, no optic canal invasion, but mild inferior to superior compression of the cisternal segment of the left optic nerve. Neuroophthalmology assessment revealed no visual defects. Treatment options included clinical observation with imaging follow-up studies, radiosurgery, and resection. The patient elected to undergo surgical removal and an endonasal endoscopic approach was the preferred surgical option. Preoperative radiological studies showed the presence of an osseous ring between the left middle and anterior clinoids, the so-called carotico-clinoidal ring. The surgical implications of this finding and its management are illustrated. The surgical anatomy of the suprasellar region is reviewed, including concepts such as the chiasmatic sulcus and limbus sphenoidale, medial and lateral optico-carotid recesses, and the paraclinoidal and supraclinoidal segments of the internal carotid artery. Emphasis is made in the importance of exposing the distal dural ring of the internal carotid artery and the precanalicular segment of the optic nerve for adequate intradural dissection. The endonasal route allows for early coagulation of the tumor meningeal supply and extensive resection of dural attachments, and importantly, provides an inferior to superior access to the infrachiasmatic region that facilitates complete tumor removal without any manipulation of the optic nerve. The lateral limit of dural removal is formed by the distal dural ring, which is gently coagulated after the tumor is resected. A 45 degrees scope is used to inspect for any residual tumor, in particular at the entrance of the optic nerve into the optic canal and at the most anterior margin of the exposure (limbus sphenoidale). The steps for reconstruction are detailed and include intradural placement of dural substitute and extradural placement of the nasoseptal flap. The nuances for proper harvesting, positioning, and reinforcement of the flap are described. No lumbar drain was used. The patient had an uneventful recovery with no CSF leak or any other complications. Imaging follow-up at 6 months showed complete removal of the tumor. The patient had no sinonasal or neurological symptoms, and olfaction was fully preserved. The video can be found here: http://youtu.be/kkuV-yyEHMg . PMID- 26018979 TI - Comparison of hearing results following the use of NiTiBOND versus Nitinol prostheses in stapes surgery: a retrospective controlled study reporting short term postoperative results. AB - The aim of this retrospective study was to compare the 3-month postoperative hearing results following laser stapedotomy with the use of NiTiBOND versus Nitinol prostheses (31 and 39 patients, respectively). The operations were performed between September 2012 and September 2014, and between March 2006 and December 2012 regarding NiTiBOND and Nitinol, respectively. Twenty of the consecutive 31 patients were female and 11 were male for NiTiBOND, while 11 were male and 28 were female for Nitinol. The mean age was 43.8 years (range 22-61) and 46.9 years (range 28-83) for NiTiBOND and Nitinol, respectively. No significant cochlear trauma was documented postoperatively. The mean air-bone gap (ABG) for the frequencies 0.5, 1, 2 and 3 kHz at the 3-month postoperative follow up was 7.6 dB (SD 4.7), and 9.3 dB (SD 4.1) for NiTiBOND and Nitinol, respectively. The differences between the mean pre- (p = 0.179), and postoperative (p = 0.059) ABG of the two groups were not significant. ABG closure within 10 dB was achieved in 77.4 and 59 % for NiTiBOND and Nitinol, respectively, the difference was not significant (p = 0.10). Two cases of delayed facial paralysis occurred, 1 with Nitinol and 1 with the NiTiBOND. All patients attained an ABG <20 dB following surgery. Laser stapedotomy with the application of either heat-memory piston prosthesis allowed an easy and minimally invasive approach with excellent short-term hearing results when the NiTiBOND prosthesis was applied. Laser application allowed manipulation in a bloodless environment and avoided manual crimping of the incus. PMID- 26018981 TI - Reply: To PMID 23215963. PMID- 26018980 TI - Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma. AB - RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression. PMID- 26018982 TI - Methylmercury Bioaccumulation in Stream Food Webs Declines with Increasing Primary Production. AB - Opposing hypotheses posit that increasing primary productivity should result in either greater or lesser contaminant accumulation in stream food webs. We conducted an experiment to evaluate primary productivity effects on MeHg accumulation in stream consumers. We varied light for 16 artificial streams creating a productivity gradient (oxygen production =0.048-0.71 mg O2 L(-1) d( 1)) among streams. Two-level food webs were established consisting of phytoplankton/filter feeding clam, periphyton/grazing snail, and leaves/shredding amphipod (Hyalella azteca). Phytoplankton and periphyton biomass, along with MeHg removal from the water column, increased significantly with productivity, but MeHg concentrations in these primary producers declined. Methylmercury concentrations in clams and snails also declined with productivity, and consumer concentrations were strongly correlated with MeHg concentrations in primary producers. Heterotroph biomass on leaves, MeHg in leaves, and MeHg in Hyalella were unrelated to stream productivity. Our results support the hypothesis that contaminant bioaccumulation declines with stream primary production via the mechanism of bloom dilution (MeHg burden per cell decreases in algal blooms), extending patterns of contaminant accumulation documented in lakes to lotic systems. PMID- 26018983 TI - Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA). AB - In this study, molecular dynamics (MD) simulations and first-principles quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations have been performed to uncover the fundamental reaction pathway of proteasome with a representative inhibitor syringolin A (SylA). The calculated results reveal that the reaction process consists of three steps. The first step is a proton transfer process, activating Thr1-O(gamma) directly by Thr1-N(z) to form a zwitterionic intermediate. The next step is a nucleophilic attack on the olefin carbon of SylA by the negatively charged Thr1-O(gamma) atom. The last step is a proton transfer from Thr1-N(z) to another olefin carbon of SylA to complete the inhibition reaction process. The calculated free energy profile demonstrates that the second step should be the rate-determining step and has the highest free energy barrier of 24.6 kcal mol(-1), which is reasonably close to the activation free energy (~22.4-23.0 kcal mol(-1)) derived from the available experimental kinetic data. In addition, our computational results indicate that no water molecule can assist the rate-determining step, since the second step is not involved in a proton transfer process. The obtained mechanistic insights should be valuable for understanding the inhibition process of proteasome by SylA and structurally related inhibitors at a molecular level, and thus provide a solid mechanistic base and valuable clues for future rational design of novel, more potent inhibitors of proteasome. PMID- 26018984 TI - Relationship of social support and decisional conflict to advance directives attitude in Korean older adults: A community-based cross-sectional study. AB - AIM: The aim of this study was to clarify the relationship between social support, decisional conflict, and attitude towards advance directives, and determine whether decisional conflict mediates the relation between social support and advance directives attitude among older adults in South Korea. METHODS: In total, 209 community-based older adults (mean age, 74.82 years) participated in this cross-sectional study. Demographic characteristics, self perceived health status, social support, decisional conflict, and advance directives attitude were investigated via a structured questionnaire. Data analysis was carried out using Pearson's correlation and path analyses. RESULTS: The mean score of advance directives attitude was 48.01 (range, 35-61). Decisional conflict and social support were both significantly related to advance directives attitude (P < 0.001). Additionally, decisional conflict was a mediator between social support and advance directives attitudes. CONCLUSION: The results confirmed the importance of social support for reducing decisional conflict and encouraging positive attitudes toward advance directives. Future studies are needed to support the development of culturally sensitive educational approaches regarding advance directives for older adults in Korea. PMID- 26018986 TI - Lenticulostriated vasculopathy is a high-risk marker for hearing loss in congenital cytomegalovirus infections. AB - AIM: This study investigated the relationship between lenticulostriated vasculopathy (LSV) and hearing loss in 141 infants with congenital cytomegalovirus (cCMV) infection. METHODS: We included all infants with cCMV infection who were followed in our clinic for more than a year with only LSV signs of brain involvement on initial brain ultrasound. Group one comprised 13 infants with no hearing impairment at birth who were not treated with gan/valganciclovir during 2006-2009. Group two was 51 infants with LSV and no hearing impairment who had been treated since mid-2009. Group three was 25 infants born with LSV and hearing loss, who had been treated from birth. Group four was 52 control infants born during the same period with asymptomatic cCMV. Hearing tests were performed during the neonatal period and every four to six months until four years of age. RESULTS: Hearing deterioration was more extensive in group one (85%) than in group two (0%, p < 0.001) and the asymptomatic group (10%, p < 0.001) and occurred more often in group four (10%) than in group two (0%, p = 0.008). CONCLUSION: Lenticulostriated vasculopathy was common in infants with cCMV infection and may serve as a sign of central nervous system involvement and further hearing deterioration. Antiviral treatment may be prudent in such infants. PMID- 26018987 TI - Detecting the effects of Fabry disease in the adult human brain with diffusion tensor imaging and fast bound-pool fraction imaging. AB - BACKGROUND: To identify quantitative MRI parameters associated with diffusion tensor imaging (DTI) and fast bound-pool fraction imaging (FBFI) that may detect alterations in gray matter and/or white matter in adults with Fabry disease, a lysosomal storage disorder. MATERIALS AND METHODS: Twelve healthy controls (mean age +/- standard deviation: 48.0 +/- 12.4 years) and 10 participants with Fabry disease (46.7 +/- 12.9 years) were imaged at 3.0 Tesla. Whole-brain parametric maps of diffusion tensor metrics (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) and the bound-pool fraction (f) were acquired. Mean voxel values of parametric maps from regions-of-interest within gray and white matter structures were compared between cases and controls using the independent t-test. Spearman's rho was used to identify associations between parametric maps and age. RESULTS: Compared with controls, the left thalamus of Fabry participants had an increase in FA (0.29 +/- 0.02 versus 0.33 +/- 0.05, respectively; P = 0.030) and a trend toward an increase in ADC (0.73 +/- 00.02 versus 0.76 +/- 0.03 MUm(2) /s, respectively; P = 0.082). The left posterior white matter demonstrated a reduction in f (10.45 +/- 0.37 versus 9.00 +/- 1.84%, respectively; P = 0.035), an increase in ADC (0.78 +/- 0.04 versus 0.94 +/- 0.19 MUm(2) /s, respectively; P = 0.024), and a trend toward a reduction in FA (0.42 +/- 0.07 versus 0.36 +/- 0.08, respectively; P = 0.052). Among all parameters, only f measured in the left posterior white matter was significantly associated with age in Fabry participants (rho = -0.71; P = 0.022). CONCLUSION: Parameters derived from DTI and FBFI detect Fabry-related changes in the adult human brain, particularly in the posterior white matter where reductions in myelin density as measured by FBFI appear age related. PMID- 26018988 TI - Anti-Endothelin Receptor Type A Autoantibodies in Systemic Lupus Erythematosus Associated Pulmonary Arterial Hypertension. AB - OBJECTIVE: To investigate the role of autoantibodies against endothelin 1 receptor type A (ETRA) in patients with systemic lupus erythematosus (SLE) associated pulmonary arterial hypertension (PAH) and to examine the possibility that the pathogenesis of this disease is mediated by these autoantibodies. METHODS: ETRA autoantibodies in serum from patients with SLE-associated PAH and serum from controls (SLE patients without PAH) were detected via a human ETRA epitope peptide-based enzyme-linked immunosorbent assay. An exploratory cohort of patients with SLE-associated PAH (n = 76) and an independent validation cohort of patients with SLE-associated PAH confirmed by right-sided heart catheterization (RHC) (n = 82) were enrolled. The clinical relevance of ETRA autoantibodies in SLE-associated PAH was analyzed. The proliferation of vascular smooth muscle cells (SMCs) and the permeability of endothelial cells (ECs) were assessed in vitro in cells stimulated with polyclonal ETRA IgG autoantibodies. Expression of PAH-related markers, i.e., serotonin transporter, platelet-derived growth factor receptor beta, vascular endothelial growth factor A, and platelet-derived growth factor B was measured by quantitative polymerase chain reaction. In addition, a suboptimal dose of monocrotaline was used to induce PAH in rats, and the effect of ETRA autoantibodies in vivo was determined using a right ventricular hypertrophy index, pulmonary angiography, and laboratory parameters. RESULTS: ETRA autoantibodies occurred more frequently in SLE-associated PAH (41.5%) than in controls (17.1%). There was a significant correlation between ETRA autoantibody titers and pulmonary artery systolic pressure measured by echocardiography (r = 0.2978, P = 0.0038) or pulmonary artery systolic pressure measured by RHC (r = 0.2159, P = 0.0257) in SLE-associated PAH. ETRA autoantibodies could promote SMC proliferation, disrupt the endothelial barrier, and up-regulate expression of PAH-related markers, which could be blocked in the presence of an endothelin receptor antagonist. ETRA autoantibodies aggravated right ventricular hypertrophy and vascular remodeling in vivo. CONCLUSION: We identified ETRA autoantibodies as a biomarker of mechanistic relevance in SLE. These autoantibodies may mediate PAH development in SLE. PMID- 26018985 TI - Endoplasmic reticulum quality control and systemic amyloid disease: Impacting protein stability from the inside out. AB - The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking, and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them toward ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion, and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the unfolded protein response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease. PMID- 26018989 TI - [Imaging diagnosis of glomus tumors of the head and neck ]. PMID- 26018990 TI - [Interview with the upcoming DRG-President -- "We have to fight for the organization of radiology"]. PMID- 26018991 TI - [Invitation to the Radiology Congress Ruhr 29. - 31.10.2015 in Bochum]. PMID- 26018994 TI - [Statement of the German Radiological Society e. V. (DRG) on the draft law on combating corruption in the health sector]. PMID- 26018995 TI - Kinks in experimental diffusion profiles of a dissolving semi-crystalline polymer explained by a concentration-dependent diffusion coefficient. AB - The dissolution of polyethylene oxide (PEO) tablets in water has been followed in situ by neutron radiography. When in contact with water, the crystalline phase of semi-crystalline PEO melts once a certain water content is attained. Polymer concentration profiles obtained from the neutron transmission images exhibited a pronounced kink which corresponds to a sharp front in the images and which is related to the melting transition. Sharp diffusion fronts and phase transitions are often linked to non-Fickian behaviour. However, by considering the time evolution of the complete concentration profiles in detail it is shown that the dissolution process can be explained using Fickian diffusion equations with a concentration-dependent diffusion coefficient. PMID- 26018996 TI - Disrupting Virchow's triad: can factor X inhibition reduce risk of adverse outcomes in patients with ischaemic cardiomyopathy? PMID- 26018997 TI - The Challenging Road towards a Unified Animal Research Network in Europe. AB - Animal models are key in biomedical research as a proof of concept to study complex processes in a physiological context. Despite the small yet crucial role animals play in fundamental and applied research, the value of animal research is recurrently undermined. Lack of openness and transparency encourages misconceptions, which can have a dramatic negative impact on science and medicine. Research centres should use all available resources to ensure that relevant details about their use of animals in research are readily accessible. More concerted efforts by professional advocacy groups devoted to informing about the benefits of biomedical animal research are also crucial. The European Animal Research Association acts as an umbrella organisation providing support to national advocacy groups and coordinating actions in countries in which no advocacy group exists. PMID- 26018998 TI - The development of self-regulated learning during the pre-clinical stage of medical school: a comparison between a lecture-based and a problem-based curriculum. AB - Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school. PMID- 26019001 TI - Cavity-Directed Chromism of Phthalein Dyes. AB - Phthalein dyes in the quinone dianion form (pseudo-D3, colored) are transformed into the lactone dianion form (pseudo-T(d), colorless) through encapsulation in a T(d)-symmetric host even under basic conditions (pH ~10). The compatibility in size and symmetry between the lactone and the cavity is essential to the transformation. Upon addition of a guest that strongly binds to the cavity, the encapsulated phenolphthalein is expelled, the color of the basic solution is regained, and the host-guest complexation is thus visualized. PMID- 26018999 TI - A comparison of subjective and objective measures of physical activity from the Newcastle 85+ study. AB - BACKGROUND: Little is known about physical activity (PA) in the very old, the fastest growing age group in the population. We aimed to examine the convergent validity of subjective and objective measures of PA in adults aged over 85 years. METHODS: A total of 484 participants aged 87-89 years recruited to the Newcastle 85+ study completed a purpose-designed physical activity questionnaire (PAQ), which categorised participants as mildly active, moderately active and very active. Out of them, 337 participants wore a triaxial, raw accelerometer on the right wrist over a 5-7-day period to obtain objective measures of rest/activity, PA intensity and PA type. Data from subjective and objective measurement methods were compared. RESULTS: Self-reported PA was significantly associated with objective measures of the daily sedentary time, low-intensity PA and activity type classified as sedentary, activities of daily living and walking. Objective measures of PA were significantly different when low, moderate and high self reported PA categories were compared (all P < 0.001). CONCLUSION: The Newcastle 85+ PAQ demonstrated convergent validity with objective measures of PA. Our findings suggest that this PAQ can be used in the very old to rank individuals according to their level of total PA. PMID- 26019002 TI - Death Anxiety and Education: A Comparison Among Undergraduate and Graduate Students. AB - The present study investigated the association between level of education and self-reported levels of anxiety regarding death of self and others among undergraduate students (n = 149) and graduate students (n = 92). Participants completed the Multidimensional Fear of Death Scale (MFODS) and the Revised Death Anxiety Scale (RDAS). Although undergraduate and graduate students did not differ on Fear of Being Destroyed, graduate students reported lower levels of death anxiety on all remaining measures. Suggestions for future research and implications are discussed. PMID- 26019003 TI - Gastric metastasis from breast cancer visualized by magnifying endoscopy with narrow-band imaging. PMID- 26019004 TI - Modeling error distributions of growth curve models through Bayesian methods. AB - Growth curve models are widely used in social and behavioral sciences. However, typical growth curve models often assume that the errors are normally distributed although non-normal data may be even more common than normal data. In order to avoid possible statistical inference problems in blindly assuming normality, a general Bayesian framework is proposed to flexibly model normal and non-normal data through the explicit specification of the error distributions. A simulation study shows when the distribution of the error is correctly specified, one can avoid the loss in the efficiency of standard error estimates. A real example on the analysis of mathematical ability growth data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-99 is used to show the application of the proposed methods. Instructions and code on how to conduct growth curve analysis with both normal and non-normal error distributions using the the MCMC procedure of SAS are provided. PMID- 26019005 TI - Norms for name agreement, familiarity, subjective frequency, and imageability for 348 object names in Tunisian Arabic. AB - Normative databases for pictorial stimuli are widely used in research on language processing in order to control for a number of psycholinguistic variables in the selected stimuli. Such resources are lacking for Arabic and its dialectal varieties. In the present study, we aimed to provide Tunisian Arabic (TA) normative data for 348 line drawings taken from Cycowicz, Friedman, Rothstein, and Snodgrass (1997), which include Snodgrass and Vanderwart's (1980) 260 pictures. Norms were collected for the following psycholinguistic variables: name agreement, familiarity, subjective frequency, and imageability. Word length data (in numbers of phonemes and syllables) are also listed in the database. We investigated the effects of these variables on word reading in TA. We found that word length and frequency were the best predictors of word-reading latencies in TA. Name agreement was also a significant predictor of word-reading latencies. A particularly interesting finding was that the semantic variables, imageability and familiarity, affected word-reading latencies in TA. Thus, it would seem that TA readers rely on semantics even when reading individual Arabic words that are transparent in terms of orthography-to-phonology mappings. This database represents a precious and much-needed psycholinguistic resource for researchers investigating language processing in Arabic-speaking populations. PMID- 26019006 TI - ROBucket: A low cost operant chamber based on the Arduino microcontroller. AB - The operant conditioning chamber is a cornerstone of animal behavioral research. Operant boxes are used to assess learning and motivational behavior in animals, particularly for food and drug reinforcers. However, commercial operant chambers cost several thousands of dollars. We have constructed the Rodent Operant Bucket (ROBucket), an inexpensive and easily assembled open-source operant chamber based on the Arduino microcontroller platform, which can be used to train mice to respond for sucrose solution or other liquid reinforcers. The apparatus contains two nose pokes, a drinking well, and a solenoid-controlled liquid delivery system. ROBucket can run fixed ratio and progressive ratio training schedules, and can be programmed to run more complicated behavioral paradigms. Additional features such as motion sensing and video tracking can be added to the operant chamber through the array of widely available Arduino-compatible sensors. The design files and programming code are open source and available online for others to use. PMID- 26019007 TI - N-Heterocyclic Carbene-Catalyzed Oxidative Annulations of alpha,beta-Unsaturated Aldehydes with Hydrazones: Selective Synthesis of Optically Active 4,5 Dihydropyridazin-3-ones and Pyridazin-3-ones. AB - A novel and efficient method for the highly enantioselective synthesis of chiral 4,5-dihydropyridazin-3-one derivatives has been developed based on the chiral N heterocyclic carbene-catalyzed oxidative annulation between alpha,beta unsaturated aldehydes and hydrazones. Meanwhile, the selective synthesis of either 4,5-dihydropyridazin-3-ones or pyridazin-3-one derivatives from the same reactants has been achieved by simply varying catalytic and reaction conditions. PMID- 26019008 TI - Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD. AB - Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID- 26019009 TI - Baseline skin information from the foot dorsum is used to control lower limb kinematics during level walking. AB - The aim of the current study was to explore the role of dorsal foot skin on the joint kinematics of gait during level walking. Twelve volunteers experienced sensory perturbations with either reduced dorsal skin feedback using topical anesthetic, reduced visual feedback of the lower visual field, or a combination of both cutaneous and visual reductions (paired). The visual condition was introduced to impose a greater reliance on skin input (goggles occluded lower visual field input). Our results showed that a reduction in skin input, alone, resulted in significant angular position changes at both the ankle and knee joints through swing (increased flexion, p < 0.010), despite preservation of minimal toe clearance (MTC; p = 0.908). Conversely, a reduction in lower visual field input resulted in a greater minimal toe clearance affect (MTC; p < 0.001), a slight increase in dorsiflexion at the ankle (p = 0.046), yet no effect on angular position changes for the knee (p = 0.110). The locomotor changes observed following a reduction in cutaneous feedback from the foot dorsum suggest an important role of the skin over this region for the regulation of level ground walking. Interestingly, it appears that these healthy young adults were able to compensate for the reduced skin information while preserving locomotor efficiency via a maintained ground clearance (MTC). Our data also demonstrated an interaction between skin and visual inputs; vision appears to have a less dominant role compared to skin in controlling the joint positions through swing phase of gait. This work is the first to highlight the influence of reduced cutaneous input from the dorsum of the foot on locomotor strategies. PMID- 26019010 TI - Polymorphism in the u-opioid receptor gene (OPRM1) modulates neural processing of physical pain, social rejection and error processing. AB - Variations of the u-opioid receptor gene OPRM1 have been shown to modulate pain perception with some evidence pointing towards a modulation of not only physical but also "psychological pain". In line with suggestions of a common neural network involved in the processing of physical pain and negative and distressing stimuli, like social rejection as a psychologically harmful event, we examined the influence of the A118G polymorphism on the neural processing of physical and non-physical pain. Using fMRI, we investigated a sample of 23 females with the more frequent AA genotype, and eight females with the relatively rare but more pain-sensitive AG genotype during electrical stimulation to the dorsum of the non dominant hand. Non-physical pain was investigated using Cyberball, a virtual ball tossing game, to induce experiences of non-self-dependent social rejection. A Go/NoGo task with an increased risk of self-dependent erroneous performance was used as a control task to investigate the effects of negative feedback as a more cognitive form of distress. Relative to A118G homozygous A-allele carriers, G allele carriers showed significantly increased activation of the supplementary motor area/superior frontal gyrus and the precentral gyrus during electrical stimulation. Increased activation of the secondary sensorimotor cortex (SII) was found during social exclusion and during negative feedback. We demonstrate that brain regions particularly related to the somatosensory component of pain processing are modulated by variations in OPRM1. Influences were evident for both physical and psychological pain processing supporting the assumption of shared neural pathways. PMID- 26019011 TI - The role of tactile sensation in online and offline hierarchical control of multi finger force synergy. AB - The hand, one of the most versatile but mechanically redundant parts of the human body, must overcome imperfect motor commands and inherent noise in both the sensory and motor systems in order to produce desired motor actions. For example, it is nearly impossible to produce a perfectly consistent note during a single violin stroke or to produce the exact same note over multiple strokes, which we denote online and offline control, respectively. To overcome these challenges, the central nervous system synergistically integrates multiple sensory modalities and coordinates multiple motor effectors. Among these sensory modalities, tactile sensation plays an important role in manual motor tasks by providing hand-object contact information. The purpose of this study was to investigate the role of tactile feedback in individual finger actions and multi-finger interactions during constant force production tasks. We developed analytical techniques for the linear decomposition of the overall variance in the motor system in both online and offline control. We removed tactile feedback from the fingers and demonstrated that tactile sensors played a critical role in the online control of synergistic interactions between fingers. In contrast, the same sensors did not contribute to offline control. We also demonstrated that when tactile feedback was removed from the fingers, the combined motor output of individual fingers did not change while individual finger behaviors did. This finding supports the idea of hierarchical control where individual fingers at the lower level work together to stabilize the performance of combined motor output at the higher level. PMID- 26019012 TI - Cartilage repair by human umbilical cord blood-derived mesenchymal stem cells with different hydrogels in a rat model. AB - This study was carried out to assess the feasibility of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in articular cartilage repair and to further determine a suitable delivering hydrogel in a rat model. Critical sized full thickness cartilage defects were created. The hUCB-MSCs and three different hydrogel composites (hydrogel A; 4% hyaluronic acid/30% pluronic (1:1, v/v), hydrogel B; 4% hyaluronic acid, and hydrogel C; 4% hyaluronic acid/30% pluronic/chitosan (1:1:2, v/v)) were implanted into the experimental knee (right knee) and hydrogels without hUCB-MSCs were implanted into the control knee (left knee). Defects were evaluated after 8 weeks. The hUCB-MSCs with hydrogels composites resulted in a better repair as seen by gross and histological evaluation compared with hydrogels without hUCB-MSCs. Among the three different hydrogels, the 4% hyaluronic acid hydrogel composite (hydrogel B) showed the best result in cartilage repair as seen by the histological evaluation compared with the other hydrogel composites (hydrogel A and C). The results of this study suggest that hUCB-MSCs may be a promising cell source in combination with 4% hyaluronic acid hydrogels in the in vivo repair of cartilage defects. PMID- 26019013 TI - Multiscale mechanobiology: computational models for integrating molecules to multicellular systems. AB - Mechanical signals exist throughout the biological landscape. Across all scales, these signals, in the form of force, stiffness, and deformations, are generated and processed, resulting in an active mechanobiological circuit that controls many fundamental aspects of life, from protein unfolding and cytoskeletal remodeling to collective cell motions. The multiple scales and complex feedback involved present a challenge for fully understanding the nature of this circuit, particularly in development and disease in which it has been implicated. Computational models that accurately predict and are based on experimental data enable a means to integrate basic principles and explore fine details of mechanosensing and mechanotransduction in and across all levels of biological systems. Here we review recent advances in these models along with supporting and emerging experimental findings. PMID- 26019014 TI - Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats. AB - In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORD-expressing putative dopamine neurons in midbrain. In Exp. 3, we used a 'retro-DREADD' dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior. PMID- 26019015 TI - Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder. AB - Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM 1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD 95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer's disease. Graphical Abstract ?. PMID- 26019016 TI - Factors Responsible for Plasma beta-Amyloid Accumulation in Chronic Kidney Disease. AB - Disturbed brain-to-blood elimination of beta-amyloid (Abeta) promotes cerebral Abeta accumulation in Alzheimer's disease. Considering that the kidneys are involved in Abeta elimination from the blood, we evaluated how chronic kidney disease (CKD) affects plasma Abeta. In 106 CKD patients stages 3-5 (including 19 patients on hemodialysis and 15 kidney recipients), 53 control subjects with comparable vascular risk profile and 10 kidney donors, plasma Abeta was determined using electrochemiluminescence immunoassay and gel electrophoresis followed by Western blotting. Plasma Abeta increased with CKD stage (control = 182.98 +/- 76.73 pg/ml; CKD3A = 248.34 +/- 103.77 pg/ml; CKD3B = 259.25 +/- 97.74 pg/ml; CKD4 = 489.16 +/- 154.16 pg/ml; CKD5 = 721.19 +/- 291.69 pg/ml) and was not influenced by hemodialysis (CKD5D = 697.97 +/- 265.91 pg/ml). Renal transplantation reduced plasma Abeta (332.57 +/- 162.82 pg/ml), whereas kidney donation increased it (251.51 +/- 34.34 pg/ml). Gel electrophoresis confirmed stage-dependent elevation namely of Abeta1-40, the most abundant Abeta peptide. In a multivariable regression including age, sex, estimated glomerular filtration rate (eGFR), potassium, hemoglobin, urine urea, and urine total protein, the factors eGFR (beta = -0.42, p < 0.001), hemoglobin (beta = -0.17, p = 0.020), and urine protein (beta = 0.26, p = 0.008) were associated with plasma Abeta. In a regression including age, sex, eGFR, potassium, hemoglobin and the vascular risk factors systolic blood pressure, smoking, LDL, HDL, HbA1c, body mass index, brain derived natriuretic peptide and fibrinogen, the factors eGFR (beta = -0.53, p < 0.001), body mass index (beta = -0.17, p = 0.022), and fibrinogen (beta = 0.18, p = 0.024) were associated with plasma Abeta. Our results demonstrate a stage dependent plasma Abeta increase that is augmented by loss of glomerulotubular integrity, low body weight, and inflammation, demonstrating a multifaceted role of renal dysfunction in Abeta retention. PMID- 26019017 TI - Minimally invasive management of tracheoesophageal fistula with T-tube. PMID- 26019018 TI - Negative linear compressibility. AB - While all materials reduce their intrinsic volume under hydrostatic (uniform) compression, a select few actually expand along one or more directions during this process of densification. As rare as it is counterintuitive, such "negative compressibility" behaviour has application in the design of pressure sensors, artificial muscles and actuators. The recent discovery of surprisingly strong and persistent negative compressibility effects in a variety of new families of materials has ignited the field. Here we review the phenomenology of negative compressibility in this context of materials diversity, placing particular emphasis on the common structural motifs that recur amongst known examples. Our goal is to present a mechanistic understanding of negative compressibility that will help inform a clear strategy for future materials design. PMID- 26019019 TI - Impact of synthetic ghrelin administration for patients with severe body weight reduction more than 1 year after gastrectomy: a phase II clinical trial. AB - PURPOSE: Ghrelin is mainly secreted from the stomach and plays a role in appetite, weight gain, and the promotion of a positive energy balance. The levels of ghrelin decrease immediately after gastrectomy. We herein investigated the effect of the administration of synthetic ghrelin to treat postoperative severe weight loss in a prospective, one-arm clinical trial to develop new strategies for weight gain. METHODS: Ten patients (four distal gastrectomy and six total gastrectomy) received ghrelin treatment. Eligibility criteria included patients who underwent gastrectomy more than 1 year previously and 15 % body weight loss from the preoperative weight or a body mass index under 19. Synthetic human ghrelin (3 MUg/kg) was administered to the patients twice a day for 1 week. Oral intake of calories, appetite [evaluated using the visual analog scale (VAS)], and body weight before and during administration of ghrelin were compared. RESULTS: There was a significant difference in the oral food intake before and during treatment (before treatment: 1236 +/- 409 kcal vs. during treatment: 1398 +/- 365 kcal, p = 0.039), and the VAS for appetite significantly improved with each day of ghrelin administration (p < 0.05). Significant amounts of body weight were gained (39.5 +/- 6.8 vs. 40.1 +/- 6.9, p = 0.037). CONCLUSIONS: The administration of synthetic ghrelin improved the food intake and was effective for treating appetite loss and body weight loss. Synthetic ghrelin may be a promising new therapy for severe body weight loss following gastrectomy. PMID- 26019020 TI - Current status of robotic gastrectomy for gastric cancer. AB - Although over 3000 da Vinci Surgical System (DVSS) devices have been installed worldwide, robotic surgery for gastric cancer has not yet become widely spread and is only available in several advanced institutions. This is because, at least in part, the advantages of robotic surgery for gastric cancer remain unclear. The safety and feasibility of robotic gastrectomy have been demonstrated in several retrospective studies. However, no sound evidence has been reported to support the superiority of a robotic approach for gastric cancer treatment. In addition, the long-term clinical outcomes following robotic gastrectomy have yet to be clarified. Nevertheless, a robotic approach can potentially overcome the disadvantages of conventional laparoscopic surgery if the advantageous functions of this technique are optimized, such as the use of wristed instruments, tremor filtering and high-resolution 3-D images. The potential advantages of robotic gastrectomy have been discussed in several retrospective studies, including the ability to achieve sufficient lymphadenectomy in the area of the splenic hilum, reductions in local complication rates and a shorter learning curve for the robotic approach compared to conventional laparoscopic gastrectomy. In this review, we present the current status and discuss issues regarding robotic gastrectomy for gastric cancer. PMID- 26019021 TI - Magnetic solid-phase extraction for determination of sulpiride in human urine and blood using high-performance liquid chromatography. AB - A novel and efficient sample preconcentration technique based on the Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) coated with silica (SiO2) has been developed for extraction and determination of sulpiride. The functionalized MNPs showed excellent dispersibility in aqueous solution and were applied to magnetic solid phase extraction of sulpiride from human urine and blood prior to high performance liquid chromatography analysis. The separation, preconcentration and desorption procedure was completed in 10 min. Optimal experimental conditions, including sample pH, the amount of the MNPs, eluent type and volume, and the ultrasonication time were studied and established. The method showed good linearity for the determination of sulpiride in the concentration range of 10 1000 ng/mL in urine and blood. The recovery of the method was in the range between 91.2 and 97.5%, and the limit of detection was 2 ng/mL for sulpiride in human blood and urine. The results indicated that the present procedure is a suitable pretreatment method for biological samples. PMID- 26019022 TI - Undergraduate UK nutrition education might not adequately address weight management. AB - OBJECTIVE: Weight management appears to be multidimensional and complex, and registered nutritionists might work to educate, promote and provide weight management services to communities, groups and individuals. However, nutrition education might not adequately reflect the weight-management requirements of individuals and groups. The aim of the present study was to investigate if the Association for Nutrition's undergraduate core competency framework for accredited Nutrition degrees sufficiently reflects the weight-management needs and experiences of individuals. DESIGN: A qualitative investigation, conducted within critical realist ontology, was performed to understand the weight management experiences of dieters and compare these with the Association for Nutrition's accreditation criteria for undergraduate Nutrition degrees. SETTING: Framework analysis was used to identify and explain participants' experiences thematically and to compare these with the Association for Nutrition's core competency criteria. SUBJECTS: Participants (n 8) with weight-loss (n 4) and weight-maintenance experiences (n 4) were interviewed using semi-structured interviews to understand weight management at the agential level. RESULTS: Participants described knowledge, exercise, planning, psychological constructs and behaviour-change techniques, determinants of eating and social support as features of weight management. The competency criteria provided clear guidance on all aspects discussed by the group, apart from psychological constructs and behaviour-change techniques and social support. CONCLUSIONS: Accredited Nutrition courses might not fully reflect the weight-management needs and experiences of individuals. Nutritionists might require greater knowledge of psychology and behaviour change to better understand and accommodate their clients' weight management needs. PMID- 26019023 TI - The effect of plant sterols and different low doses of omega-3 fatty acids from fish oil on lipoprotein subclasses. AB - SCOPE: Consumption of a low-fat spread enriched with plant sterols (PS) and different low doses (<2 g/day) of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil reduces serum triglycerides (TGs) and low-density lipoprotein-cholesterol (LDL-Chol) and thus beneficially affects two blood lipid risk factors. Yet, their combined effects on TG and Chol in various lipoprotein subclasses have been investigated to a limited extent. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled, parallel study, we determined TG and Chol in 13 LP subclasses in fasting serum of 282 hypercholesterolemic subjects, who consumed either a placebo spread or one of the four spreads containing PS (2.5 g/day) and EPA+DHA (0.0, 0.9, 1.3, and 1.8 g/day) for 4 weeks. After PS treatment, total LDL-Chol was reduced, which was not further changed by EPA+DHA. No shift in the LDL-Chol particle distribution was observed. The addition of EPA+DHA to PS dose-dependently reduced VLDL-Chol and VLDL-TG mainly in larger particles. Furthermore, the two highest doses of EPA+DHA increased Chol and TG in the larger HDL particles, while these concentrations were decreased in the smallest HDL particles. CONCLUSION: The consumption of a low-fat spread enriched with both PS and EPA+DHA induced shifts in the lipoprotein distribution that may provide additional cardiovascular benefits over PS consumption alone. PMID- 26019024 TI - Readiness to Implement HIV Testing in African-American Church Settings. AB - HIV and AIDS continue to impact Black Americans at disproportionately high rates. Promotion of HIV testing and linkage to care is a national health imperative for this population. As a pillar in the Black community, the Black Church could have a significant impact on the promotion of HIV testing within their churches and surrounding communities. Churches, however, have varied levels of involvement in testing. Furthermore, little is known about how to assess a church's readiness to integrate HIV testing strategies into its mission, much less how to promote this practice among churches. This qualitative study used interviews and focus groups with pastors and church leaders from four churches with varying levels of involvement in HIV testing to identify key stages in the progression of toward church-based HIV testing and linkage to care. Findings showed that churches progressed through levels of readiness, from refusal of the possibility of HIV interventions to full integration of HIV testing and linkage to care within the church. PMID- 26019025 TI - Functional Assessment in Tibial Hemimelia (Can We Also Save the Foot in Reconstruction?). AB - BACKGROUND: The congenital absence of the tibia is a rare disease, and an orthopaedic surgeon may not encounter such cases during the course of his/her career. This is the largest report to date of the management of such cases by a single surgeon. The foot and leg were persevered in the majority of the cases, and a functional evaluation system was used to report outcomes. METHODS: Thirty six patients with tibial hemimelia, who had been under the direct care of the authors since infancy, were evaluated clinically and radiographically. The patients or their parents filled out the Pediatric Quality of Life and the parents' satisfaction forms. The surgical interventions performed, and their effects on school attendance and, and also the shoe type they wore were documented. RESULTS: Thirty-six patients (19 girls and 17 boys) with 48 tibial deficient limbs (19 right, 5 left, and 12 both right and left sides) were studied. The patients were assessed at 12 years (2.5 to 32.5 y), with a mean follow-up of 9 years (2 to 23 y). The 48 limbs included 14 type I, 16 type II, 11 type IV, and 7 unclassified by using the Jones classification; and 6 type I, 11 type II, 16 type III, 1 type IV, and 14 type VII by using the Weber classification. Primary amputation was performed in 8 patients (10 limbs) and limb preservation surgeries on 38 legs (28 patients). Tibiofibular synostosis, centralization of the ankle, and Ilizarov lengthening were the most common procedures. Nonunion of tibiofibular synostosis (2 cases) and knee stiffness (6 cases) were the main complications. Among the reconstructed limbs, 12 were in regular and 18 in modified shoes. The Pediatric Quality of Life of 68 points in the reconstructed group was a significant achievement, and it was also better than the score of patients who had undergone amputation. CONCLUSION: Reconstruction of tibial hemimelia with foot preservation provides good functional outcome in the majority of cases. LEVEL OF EVIDENCE: Level IV. PMID- 26019027 TI - Growth Disturbance of the Distal Tibia in Patients With Idiopathic Clubfeet: Ankle Valgus and Anteflexion of the Distal Tibia. AB - BACKGROUND: The aim of this study was to evaluate the incidence of deformities of the distal tibia in patients with idiopathic clubfeet who had undergone surgical intervention with a circumferential release through a Cincinnati incision in early infancy. METHODS: A retrospective follow-up evaluation of children with idiopathic clubfoot was conducted. We reviewed children who had undergone surgical treatment by a circumferential release in our department after unsuccessful casting, and who were at least 10 years of age. Main focus was the measurement of anteroposterior and lateral view radiographs for distal tibia deformities. Of 65 patients (93 feet) who had surgery for idiopathic clubfoot from 1998 to 2002, radiographic data of 35 patients (52 feet) were analyzed. RESULTS: An anteflexion deformity was present in 25 of 52 feet (48.1%) and a valgus deformity in 29 of 52 feet (55.8%). A flat-top talus was evident to some degree in all cases. An abnormal lateral talocalcaneal angle was evident in 42.3%. CONCLUSIONS: These results show the importance of conducting follow-up evaluations on patients with idiopathic clubfoot for secondary deformities of the distal tibia. This is the first study, to our knowledge, highlighting the high incidence of distal tibial deformities after surgery for idiopathic clubfoot. It is unclear at this time whether this is also true for clubfeet after conservative treatment. However, patients with clubfeet should have radiographs of the ankle joint between the age of 10 and 12 years to be able to treat possible deformities through guided growth. LEVEL OF EVIDENCE: Level III. PMID- 26019026 TI - Pediatric Nonfracture Acute Compartment Syndrome: A Review of 39 Cases. AB - BACKGROUND: Compartment syndrome in the absence of fracture is rare and poorly described within the pediatric literature. The purpose of this study was to report the varying etiologies, risk factors, and treatment outcomes associated with pediatric nonfracture acute compartment syndrome (NFACS). METHODS: We conducted a retrospective chart review on 37 children who suffered a NFACS and were treated at a single pediatric trauma center between 1997 and 2013. Demographic, diagnostic, treatment, and outcome characteristics were reviewed. Five causal groups were generated: trauma, exercise related (acute presentation after exercise without trauma), infectious, vascular, and postoperative (in the absence of osteotomy). Univariate and multivariate analyses were performed to identify risk factors of NFACS. P-values <0.05 were considered statistically significant. RESULTS: There were 39 cases of NFRCS in 37 children [6 females, 31 males, mean age of 11.7 y (SD+7.2 y)]. The leg was the most commonly involved limb (29 cases, 74%). Diagnosis of NFRCS was made either by compartment pressure monitoring [59%, 23/39 cases, mean pressure 66 mm Hg (SD+28)] or by clinical examination. According to etiology, vascular was most common (11/39, 28%), followed by trauma (10/39, 26%) and postoperative (8/39, 21%), with exertion and infection representing a small proportion (6/39, 15% and 4/39, 10%, respectively). Pain was present in 33 cases (85%), swelling in 28 cases (72%), paresthesias in 13 cases (33%), motor deficit in 12 cases (31%), and poor perfusion in 11 cases (28%). Average time from symptom onset to diagnosis was 48 hours (IQR, 9 to 96 h). At surgery, 21 patients (54%) had evidence of myonecrosis. Children required an average of 3 surgeries for wound closure. The median time to follow-up was 232 days (IQR, 73 to 608 d). A total of 54% made a full recovery, whereas 31% suffered a persistent neurological or functional deficit. CONCLUSIONS: NFACS in children is associated with a delay in diagnosis and a high rate of myonecrosis. Timely assessment with high clinical suspicion is necessary to prevent a delay in diagnosis. LEVEL OF EVIDENCE: Level IV. PMID- 26019029 TI - Inter and intrapatient evolution of hepatitis C virus. AB - Hepatitis C virus (HCV) has a short replication time, high mutation rates and large population sizes, all of which make it an excellent experimental model for evolution studies, because evolution can be visualized in real-time. In this review, we discuss the implications to study HCV evolution at the interpatient and intrapatient levels of infection. The HCV interpatient dynamics is relatively slow, because the generation time is generally long. Then, at population level, the HCV diversity originated by the high mutation and replication rates is modulated by the bottleneck at transmission. Thus, when the virus is transmitted to other hosts, viral diversity is reduced as a result of the founder effect. On the other hand, during intrapatient infection, HCV evolves rapidly, resulting in quasispecies. Accumulated evidence suggests that this quasispecies composition of the HCV population within the same individual may allow the virus to evade the immune response or escape treatment, leading to chronic infection. Thus, a better understanding of the complexities underlying the molecular evolution of HCV in natural populations is needed before accurate predictions of viral evolution can be made. In summary, HCV evolves both within and among patients. Consequently, HCV evolution should be studied at both levels in order to better understand the natural history of the virus and its potential implications in epidemiology, outcome of infection and progression of liver disease. PMID- 26019030 TI - The function of MicroRNA in hepatitis B virus-related liver diseases: from Dim to Bright. AB - MicroRNAs represent a class of non-coding RNA molecules that negatively regulate gene expression either by repressing translation or by inducing degradation of messenger RNA. Studies have shown that, as regulators of gene expression, microRNAs are widely involved in various human diseases, including hepatitis B virus-related liver diseases. By modulating hepatitis B virus replication, regulating extracellular matrix formation, as well as silencing tumor suppressor genes, these small molecules are implicated in the development of chronic hepatitis, liver fibrosis/cirrhosis, and hepatocellular carcinoma caused by hepatitis B virus infection. In addition, current researches indicated a potential role of microRNA as diagnostic markers and therapeutic targets. In conclusion, microRNAs are promising tools in the diagnosis and treatment of hepatitis B virus -related liver diseases. PMID- 26019031 TI - Hypovitaminosis D and its relation to demographic and laboratory data among hepatitis C patients. AB - BACKGROUND: The relationship between 25-hydroxyvitamin D [25(OH)D] serum levels and response to antiviral therapy and laboratory data in HCV infection remains unclear. The aim of this study was to determine pre-treatment 25(OH)D serum level among HCV infected individuals and to evaluate the association between vitamin D status, virological response, and laboratory data. MATERIAL AND METHODS: Baseline serum 25(OH)D levels were measured in 237 chronic HCV infected patients (139 female, age 53.7 +/- 11.2 years) using chemiluminescence immunoassay. Correlations between serum 25(OH)D levels, virological and laboratory data regarding HCV infection as well as sustained virological response (SVR) to antiviral therapy were evaluated. RESULTS: Mean serum values of 25(OH)D was 26.2 +/- 12 ng/mL and prevalence of vitamin D deficiency (< 30 ng/mL) was 66.2%. Advanced age (> 55 years), high mean values of LDL, total cholesterol, HDL and low mean values of alkaline phosphatase and hemoglobin were statistically associated to vitamin D deficiency. Antiviral treatment was underwent by 133 HCV patients and 44.3% of them achieved SVR. Most of individuals that presented SVR also presented 25(OH)D level higher than 30ng/mL (55.9%). SVR was associated to low mean values of LDL, total cholesterol and platelets; high mean values of ALT, AST and low fibrosis grade. CONCLUSIONS: In conclusion, low vitamin D levels were observed among HCV infected patients and was associated to laboratory findings, however baseline 25(OH)D level is not independently associated with SVR. PMID- 26019032 TI - Association of baseline CD4+ cell count and HIV-RNA on sustained virologic response to interferon-ribavirin in HIV/HCV coinfected patients. AB - BACKGROUND AND RATIONALE FOR THE STUDY: We assessed the association of CD4+ T cell counts and HIV-RNA on sustained viral response (SVR) after therapy with pegylated interferon and ribavirin (PR) in HIV/HCV coinfected patients. We examined two large cohorts of coinfected patients treated with PR in Spain between 2000 and 2008. SVR was defined as undetectable HCV-RNA at 24 weeks after the end of PR. RESULTS: We studied 1682 patients, of whom 38% achieved SVR. Baseline factors independently associated with reduced odds of SVR included genotype 1 or 4, HCV-RNA > 500,000 IU/mL, advanced liver fibrosis, CDC clinical category C, and detectable HIV-RNA. By multivariate logistic regression analysis, we found that, in comparison with patients with combination antiretroviral therapy (cART) and undetectable HIV-RNA, the odds ratio [95% confidence interval (CI)] of SVR was 0.56 (0.41-0.78) for cART and detectable HIV-RNA, 0.86 (0.56 2.57) for no-cART and detectable HIV-RNA, and 1.38 (0.74-2.57) for no-cART and undetectable HIV-RNA. CONCLUSIONS: Detectable HIV-RNA, but not CD4+ T-cell count, was associated with reduced odds of SVR. However, this finding was only confirmed for cART and detectable HIV-RNA, raising the question as whether this represents a true association of HIV-RNA on response to PR or a spurious association due to poor adherence to treatment. PMID- 26019033 TI - Detection of hepatitis B activity in HBeAg-negative carriers with normal aminotransferase levels in central Brazil. AB - BACKGROUND AND RATIONALE FOR THE STUDY: Hepatitis B virus (HBV) chronic infection may follow a benign course with low risk of cirrhosis or liver cancer. As differentiation of inactive status from HBeAg-negative chronic hepatitis B is often challenging, monitoring of inactive HBV carriers is important to detect viral relapse or formerly undetected activity. The incidence of hepatitis activity in HBeAg-negative carriers with normal aminotransferases was examined by retrospective analysis of a cohort of carriers who had been followed-up at a hospital in Central Brazil. All patients had remained free of evidence of liver disease and maintained normal aminotransferase levels throughout the first year of follow-up. The incidence density of chronic HBV activity was determined and an incidence curve was constructed using the Kaplan-Meier method. Cox regression models were developed to identify for surrogate markers of activity. RESULTS: Among the 224 patients who comprised the cohort, chronic HBV activity was detected in 30 during followup. The incidence density of activity was 11.8 per 100 person-years (95% confidence interval: 8.3-16.9). The results of Cox regression analysis indicated that chronic HBV activity was associated with entrance in the latter years of the period examined (p = 0.001) and initial normal aspartate aminotransferase (AST) levels close to the upper-normal value (p = 0.022). CONCLUSION: Normal AST levels near the upper-normal value may be an indicator of relapse or previously undetected activity, and should thus be monitored closely in HBeAg-negative HBV carriers, in whom risk of relapse should remain an important managing consideration. PMID- 26019034 TI - High efficacy and safety of triple therapy in HCV genotype 1 and moderate fibrosis: a multicenter study of clinical practice in Spain. AB - BACKGROUND AND RATIONAL: Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220). RESULTS: The mean patient age was 55 years, 67% male. Type of prior response was 22% naive, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%), respectively. Sixty-five percent were non-CC IL28B genotype. Week-12 sustained virologic response (SVR12) was significantly higher among F2-naive patients (78%) compared with F3/F4-naive patients (60%; p = 0.039) and among F2 non-responders (67%) compared with F3/F4 non-responders (42%; p = 0.014). SVR12 among relapsers was remarkably high in both groups (F2:89% vs. F3/F4:78%). Severe anemia and thrombocytopenia were more frequent among patients with F3/F4 than those with F2 (p < 0.01). Overall, 132 patients (22%) discontinued treatment: 58 due to adverse effects, 42 due to the stopping-rule, and 32 due to breakthrough. Premature discontinuation was more frequent among patients with F3/F4 (p = 0.028), especially due to breakthrough (p < 0.001). CONCLUSIONS: This multicenter study demonstrates high efficacy and an acceptable safety profile with regard to TBT in F2-patients in clinical practice. PMID- 26019035 TI - The nuclear receptor FXR, but not LXR, up-regulates bile acid transporter expression in non-alcoholic fatty liver disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Patients with non-alcoholic steatohepatitis (NASH) have increased plasmatic and hepatic concentrations of bile acids (BA), suggesting that they can be associated with the progression of the disease. Hepatic nuclear receptors are known to modulate genes controlling BA metabolism; thus, in this work we aimed to compare the expression of liver nuclear receptors -farnesoid X (FXR), small heterodimer partner (SHP) and liver X alpha (LXRalpha) receptors- and BA transporters -sodium+/taurocholate cotransporting polypeptide (NTCP) and bile salt export pump (BSEP)- in liver biopsy samples of patients with simple steatosis (SS) and NASH. MATERIAL AND METHODS: Forty patients with biopsy-proven NALFD were enrolled between 2009 and 2012; liver biopsies were classified as SS (N = 20) or NASH (N = 20) according to the NAFLD activity score. Gene expression of nuclear FXR, LXRalpha, SHP, NTCP and BSEP was analyzed by real-time reverse transcription polymerase chain reaction and protein level was quantified by western blot. RESULTS: Gene expression of FXR, SHP, NTCP and BSEP was significantly up-regulated in the NASH group in comparison with SS patients (P < 0.05). In contrast, protein level for FXR, SHP and NTCP was decreased in the NASH patients vs. the SS group (P < 0.05). Gene and protein profile of LXRalpha did not show differences between groups. CONCLUSIONS: The results suggest that liver nuclear receptors (FXR and SHP) and BA transporters (NTCP and BSEP) are associated with the progression of NAFLD. PMID- 26019036 TI - DNA methylation markers and serum alpha-fetoprotein level are prognostic factors in hepatocellular carcinoma. AB - INTRODUCTION: Hypermethylation of relevant genes may affect the prognosis of patients with cancer. The purpose of this study was to analyze whether methylation of the promoter regions of cell cycle regulators as well as elevated alpha-Fetoprotein (AFP) levels are useful prognostic factors for patients with hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Nested methylation-specific PCR (nested-MSP) was used to analyze methylation status of the promoter regions of p15, p16, p21, p27, and ras-association domain family 1 (RASSF1A) genes in tumor specimens from 50 patients with HCC. RESULTS: Promoter methylation was most common in the RASSF1A gene (96%), followed by the p16 gene (56%), the p21 gene (44%), the p15 gene (28%), and the p27 gene (2%). Patients with a serum AFP level < 400 ng/mL and an unmethylated p21 promoter had a better prognosis than patients with a serum AFP level >= 400 ng/mL and a methylated p21 promoter (overall survival, p = 0.076; disease-free survival, p = 0.016). In addition, patients with full methylation of the promoter region of RASSF1A had a better prognosis than patients with a partially methylated or unmethylated RASSF1A promoter region if their serum AFP level was >= 400 ng/mL (overall survival, p = 0.028; disease free survival, p = 0.078). CONCLUSION: A partially methylated or unmethylated RASSF1A promoter as well as elevated serum AFP level or methylation of p21 in addition to elevated serum AFP level might be associated with poor prognosis in patients with hepatocellular carcinoma. PMID- 26019037 TI - Comorbidities have a limited impact on post-transplant survival in carefully selected cirrhotic patients: a population-based cohort study. AB - BACKGROUND: Improving estimation of long-term survival of patients with end-stage liver disease after orthotopic liver transplantation (OLT) would optimize decisions on eligibility for transplant. We aimed to externally validate previously derived Charlson Comorbity Index for OLT (CCI-OLT); subsequently, we developed a new model to predict 5-year mortality after transplant. MATERIAL AND METHODS: This single center retrospective cohort study included 524 consecutive adult cirrhotic patients who underwent OLT in 2002-2012. External validation of CCI-OLT used Kaplan-Meier method. Derivation of the new predictive model used Cox proportional hazards regression. RESULTS: One-, 3-, and 5-year cumulative survival after OLT was 89%, 80%, and 73%, respectively. CCI-OLT was not associated with 5-year mortality after transplant (P = 0.34). We derived and internally validated a new predictive model of 5-year mortality after OLT based on six pre-transplant characteristics of patients: age, body mass index, hepatitis C, hepatic encephalopathy, intensive care unit stay at transplant, and live donor (C-index = 0.64). We further developed a nomogram to estimate individual probability of 1-, 3-, and 5-year survival after OLT. CONCLUSIONS: In our cohort, CCI-OLT was not associated with survival following transplant. The new predictive model discriminative capacity was only modest, suggesting that pre transplant characteristics are of limited value in predicting post-transplant outcomes in thoroughly selected patients. PMID- 26019038 TI - Influence of ApoE and FABP2 polymorphisms and environmental factors in the susceptibility to gallstone disease. AB - BACKGROUND: Gallstone disease (GSD) is a common chronic disease in the Western hemisphere, yet environmental and genetic factors may be responsible for the variations in the prevalence of GSD among populations. AIM: To analyze the relationship of the ApoE and FABP2 polymorphisms with diet, physical activity and emotional health in patients with GSD from West Mexico. MATERIAL AND METHODS: A total of 120 patients with GSD and 370 healthy subjects were enrolled. Anthropometric, biochemical, nutritional, clinical and physical activity parameters were measured. ApoE and FABP2 genotypes were assesed by PCR-RFLPs assays. RESULTS: ApoE E3/E4 genotype and the ApoE E4 allele was highly prevalent among the GSD patients compared to the controls (32% vs. 12.0% and 22% vs. 8.4% respectively p < 0.01). Patients with the Apo E4 allele showed an upward trend of cholesterol levels compared to non-Apo E4 allele carriers (E4 186 +/- 30 mg/dL; E3 143 +/- 37 mg/dL; E2 129 +/- 34 mg/dL). High triglyceride levels were associated with patients that were FABP2 Thr54 allele carriers (p < 0.05) but lacked association with GSD. This may be due to changes in dietary fats after GSD diagnosis, masking the clinical course of the disease. Sedentary lifestyle and negative emotions were detected in 83% and 63% of patients, respectively. CONCLUSION: These data suggest that the Apo E4 allele could confer genetic susceptibility for the development of GSD among the Mexican population. The Ala54Thr polymorphism of FABP2 was associated with high triglycerides levels, but not to GSD; suggesting that environmental factors modulate such susceptibility. PMID- 26019039 TI - Prevalence in vulnerable population of liver fibrosis identified by transient elastography. AB - BACKGROUND: Transient elastography (TE) is a useful tool for the assessment of hepatic fibrosis as an alternative to liver biopsy, but it has not been validated as a screening procedure in apparently healthy people. AIM: To determine the prevalence of advanced liver fibrosis diagnosed by TE in a socioeconomically challenged rural population. MATERIAL AND METHODS: We enrolled 299 participants aged over 18 years old from a vulnerable population in Mexico who responded to an open invitation. All participants had their history recorded and underwent a general clinical examination and a liver stiffness measurement, performed by a single operator according to international standards. RESULTS: Overall, 7.35% participants were found to be at high risk for cirrhosis. Three variables correlated with a risk for a TE measure >= 9 kPa and significant fibrosis: history of alcohol intake [7.95 vs. 92.04%, odds ratio (OR) 4.47, 95% confidence interval (CI) 1.45-13.78, P = 0.0167], body mass index (BMI) >= 30 kg/m2 (30.87 vs. 69.12%, OR 4.25, 95%CI 1.04-6.10, P = 0.049), and history of diabetes mellitus (14.87 vs. 85.12%, OR 2.76, 95%CI 1.002-7.63, P = 0.0419). In the multivariate analyses BMI >= 30 kg/m2 was the only significant risk factor for advanced liver fibrosis or cirrhosis (OR 2.54, 95%CI 1.02-6.3, P = 0.0460). CONCLUSION: TE could be useful as a screening process to identify advanced liver fibrosis in the general and apparently healthy population. PMID- 26019040 TI - Management of liver metastases of gastrointestinal stromal tumors (GIST). AB - INTRODUCTION: Liver metastases (LM) are crucial prognostic manifestation of gastrointestinal stromal tumors (GIST). With the advent of tyrosine kinase inhibitors (TKI), management of metastatic GIST has radically changed. Long clinical follow-up provides an increased proportion of GIST patients with LM who are candidates for potentially curative therapy. MATERIAL AND METHODS: Patients who underwent treatment for liver metastases of GIST between 2000-2009 in our department were included in the study. Mean follow-up was 84 months (range 40 145) months. In retrospective analysis we investigated clinical, macro /microscopic and immunohistochemical criteria, surgical, interventional and TKI therapy as well. RESULTS: In 87 GIST-patients we identified 25 (29%) patients with metastatic disease. Of these, 12 patients (14%) suffered from LM with a mean age of 60.5 (range, 35-75) years. Primary GIST were located at stomach (n = 4, 33%) or small intestine (n = 8, 67%); all of them expressed CD117 and/or CD34. LM were multiple (83%), distributed in both lobes (67%). They were detected synchronously with primary tumor in 33% and metachronously in 77%. All patients with liver involvement were considered to treatment with TKI. LM were resected (R0) in 4 patients (33%). In recurrent (2/4) and TKI resistant cases, interventional treatment (radiofrequency ablation) and TKI escalation were carried out. During a median follow-up of 84 months (range 30-152), 2 patients died (16.5%) for progressive disease and one patient for other reasons. Nine patients (75%) were alive. CONCLUSION: Treatment of LM from GIST needs a multimodal approach. TKI-therapy is required at any case. In case of respectability, surgery must be carried out. In unresectable cases or recurrent/progressive disease, interventional treatment or TKI escalation should be considered. Therefore, these patients need to be treated in experienced centres, where multimodal approaches are established. PMID- 26019042 TI - Multiple liver lesions in a patient with Budd-Chiari syndrome secondary to polycythemia vera. AB - Focal nodular hyperplasia and nodular regenerative hyperplasia are occasionally seen in patients with hepatic venous outflow obstruction as a consequence of circulatory stress in the liver. In addition, neoplastic processes such as hepatic adenoma, hepatocellular carcinoma, and metastatic disease may arise in these patients. Histologic evaluation is necessary when imaging modalities are unable to distinguish these lesions. We present a case of multiple hepatic lesions, suspicious for metastases, in a patient with Budd-Chiari syndrome secondary to polycythemia vera. However, the biopsy findings were consistent with focal nodular hyperplasia. Budd-Chiari syndrome may be associated with multiple nodules of focal nodular hyperplasia, which may be difficult to diagnose radiologically. PMID- 26019041 TI - Combined high-fat diet and sustained high sucrose consumption promotes NAFLD in a murine model. AB - BACKGROUND: The study of NAFLD in humans has several limitations. Using murine models helps to understand disease pathogenesis. AIM: Evaluate the impact of 4 different diets in the production of NAFLD with emphasis on a combined high-fat plus sustained high sucrose consumption. MATERIAL AND METHODS: Eight week-old male Wistar rats were divided in four groups and fed for 90 days with the following diets: 1) Control chow diet (C); 2) High-fat cholesterol diet (HFC) + 5% sucrose in drinking water. 3) High-fat cornstarch diet (HFCO) + 5% sucrose in drinking water. 4) Chow diet + 20% sucrose in drinking water (HSD). Metabolic changes, leptin levels, liver histology, hepatic and plasma lipid composition, fasting plasma glucose and insulin and liver gene expression of FAS, SREBP-1 and PPAR-alpha were evaluated. RESULTS: The HFC diet had the highest grade of steatosis (grade 2 of 3) and HSD showed also steatosis (grade 1). Liver weight TG and colesterol concentrations in liver were greater in the HFC diet. There were no increased levels of iron in the liver. Rats in HFC gained significantly more weight (P < 0.001). All experimental groups showed fasting hyperglycemia. HFC had the highest glucose level (158.5 +/- 7 mg/dL) (P < 0.005). The HSD and the HFCO diets developed also hyperglycemia. HSD had significantly higher fasting hyperinsulinemia. Serum leptin was higher in the HFC diet (p = 0.001). In conclusion, the HFC diet with combination of high fat and high sucrose is more effective in producing NAFLD compared with a high sucrose diet only. PMID- 26019043 TI - Successful pregnancy after ileal exclusion in progressive familial intrahepatic cholestasis type 2. AB - Progressive familial intrahepatic cholestasis type 2 (PFIC 2) results from mutations in ABCB11 gene coding bile salt export pump (BSEP). Medical treatment is usually unsuccessful and surgery intervention is necessary. Partial external biliary diversion (PEBD) is regarded as the first choice of surgical treatment. Ileal exclusion (IE) is an alternative operation if external stoma is not tolerated; however, a favorable outcome is uncertain. In chronic liver diseases pregnancy brings additional risk of deterioration of liver function and generally is not recommended. We present the first case report of successful pregnancy in a genetically confirmed PFIC 2 patient after surgical conversion from PEBD to IE. PMID- 26019044 TI - Spontaneous hepatic rupture during pregnancy in a patient with peliosis hepatis. AB - Spontaneous hepatic rupture (SHR) during pregnancy is a rare but well known complication and it usually occurs alongside eclampsia or HELLP syndrome. SHR in uncomplicated pregnancy is extremely rare and can be associated to different undiagnosed pathological conditions. We report the case of a nulliparous woman, 27 weeks pregnant, with a peliosis hepatis, previously unknown, who was admitted to our unit due to SHR and massive hemoperitoneum. The conception was obtained by embryo transfer after multiple attempts of hormone-supported cycles using estrogens and progesterone. After emergency laparotomy the patient was submitted to deliver of the dead foetus and damage control of the hepatic bleeding source. At relaparotomy a right posterior sectionectomy (segments VI and VII) and segmentectomy of segment V were performed. The patient was discharged in good physical conditions after 18 days from admission. If hepatic rupture is suspected in a pregnant patient a collaborative multidisciplinary approach is mandatory. The cornerstones of medical and surgical management are highlighted. At the best of our knowledge this is the first case of SHR in a pregnant woman with peliosis hepatis. A possible correlation of an increased risk for SHR in a pregnant patient who was submitted to several attempts for embryo transfer is discussed. The relevant scientific literature of the possible causative role of the estrogen therapy in inducing politic liver damage is also reviewed. PMID- 26019045 TI - Giant hepatocellular adenoma in a previously obese thirteen-year-old boy. AB - Hepatocellular adenoma is an uncommon neoplasm, especially in the childhood age group. We describe a previously obese 13-year-old male with a giant hepatocellular adenoma requiring an extensive hepatic resection. The related pediatric tumor literature, diagnosis and clinical management is discussed. PMID- 26019046 TI - Colorectal cancer surveillance in primary sclerosing cholangitis and inflammatory bowel disease. PMID- 26019047 TI - Insights in non-alcoholic fatty liver disease pathophysiology with lipidomic analyses. PMID- 26019048 TI - S2k Guidlines for Diverticular Disease and Diverticulitis: Diagnosis, Classification, and Therapy for the Radiologist. AB - Diverticular disease and diverticulitis represent an increasingly common disease especially in patients with advanced age. The German Society of Digestive and Metabolic Diseases (DGVS) as well as the German Society of General and Visceral Surgery (DGAV) in collaboration with the German Radiology Society (DRG) created and published S2k guidelines regarding this topic. Knowledge of the diagnosis and therapy of this common disease is extremely important for the radiologist for the daily clinical routine. In this article we review and discuss the most important clinical situations and algorithms of this disease focusing on radiological topics. Additionally, we introduce the new CCD (classification of diverticular disease) system regarding radiology. KEY POINTS: For the diagnosis of a diverticular disease a sectional imaging method should be performed. First choice should be a "qualified ultrasound examination" followed by CT in uncertain situations or complicated disease. Disease classification should be done according the new CCD (Classification of diverticular disease) algorithm. Based on this new CCD patients can be stratified into outpatient, in-house patient and surgical treatment therapy. PMID- 26019049 TI - Thoracic Pathologies on Scout Views and Bolus Tracking Slices for Computed Tomographic Cerebral Angiography. AB - PURPOSE: To evaluate the incidence of additional thoracic pathologic findings (TPF) detected on scout views and corresponding bolus tracking slices (SVBT) for computed tomographic cerebral angiography (CTCA) and to test the reliability and accuracy of these findings. MATERIALS AND METHODS: The study collective included 505 consecutive patients who underwent multidetector CTCA. Appendant SVBT of all patients were reviewed for any pathologic findings and patient medical reports were analyzed, if any medical treatment was initiated for the detected pathologic findings. In 18 patients thoracic CT scans were performed in the same session. These were additionally reviewed by two blinded observers to test for intra- and interobserver reliability as well as for accuracy of detecting thoracic pathologies on SVBT. RESULTS: TPF were detected in 165 (33%) SVBT. The five most common pathologic findings were: pleural effusion, 12%; pneumonia, 8%; atelectasis/dystelecatsis, 6%; pericardial effusion, 2% and elevated diaphragm, 1%. For 48 % of these findings medical treatment was initiated. SVBT showed a sensitivity of 53%, a specificity of 99%, a positive predictive value of 89%, a negative predictive value of 94% and accuracy of 94% for the detection of TPF. The intraobserver reliability was very good and the interobserver reliability showed moderate agreement. CONCLUSION: SVBT for CTCA should be reviewed with care by radiologists, since additional TPF can affect patient management. Nevertheless, despite a high specificity of SVBT for detecting TPF, an only moderate sensitivity has to be taken into account. KEY POINTS: Thoracic pathologies are frequently found on scout views for cerebral CTA. Reviewing additional bolus trigger slices will improve diagnostic sensitivity. Despite high specificity, scout views and trigger slices offer a moderate sensitivity. Evaluation of scout views and trigger slices can result in medical treatment. PMID- 26019050 TI - [Traumatic plexus lesion with cervicothoracic root avulsions and vertical laceration of the spinal cord]. PMID- 26019051 TI - [Reperfusion of an incidental aneurysm in mechanical stroke treatment with "stent retriever"]. PMID- 26019052 TI - Socioeconomic factors relating to diabetes and its management in India. AB - Diabetes is an escalating problem in India and has major socioeconomic dimensions. Rapid dietary changes coupled with decreased levels of physical activity have resulted in increases in obesity and diabetes in rural and semi urban areas, as well as in urban-based people living in resettlement colonies. Increasing risk has also been recorded in those who suffered from poor childhood nutrition and in rural-to-urban migrants. Social inequity manifests in disparities in socioeconomic status (SES), place of residence, education, gender, and level of awareness and affects prevention, care, and management. All these population subsets have major socioeconomic challenges: low levels of awareness regarding diabetes and prevention, inadequate resources, insufficient allotment of healthcare budgets, and lack of medical reimbursement. Unawareness and delays in seeking medical help lead to complications, resulting in many-fold increased costs in diabetes care. These costs plunge individuals and households into a vicious cycle of further economic hardship, inadequate management, and premature mortality, resulting in more economic losses. At the societal level, these are massive losses to national productivity and the exchequer. Overall, there is an immediate need to strengthen the healthcare delivery system to generate awareness and for the prevention, early detection, cost-effective management, and rehabilitation of patients with diabetes, with a focus on people belonging to the lower SES and women (with a particular focus on nutrition before and during pregnancy). Because of an enhanced awareness campaign spearheaded through the National Program on Prevention of Cardiovascular Disease, Cancer, Diabetes and Stroke (NCPCDS) initiated by Government of India, it is likely that the level of awareness and early detection of diabetes may increase. PMID- 26019053 TI - Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity. AB - Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behavior of the Mecp2(+/-) mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating hypothalamic-pituitary-adrenal axis dysregulation. EE of Mecp2(+/-) mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder. PMID- 26019054 TI - The growing evidence for the use of platelet-rich plasma on diabetic chronic wounds: A review and a proposal for a new standard care. AB - Nonhealing chronic wounds and exposed tendons, bones and joints are very challenging to cure specially for diabetic patients. Plastic surgeons have a new weapon to enhance wound healing with the use of autologous growth factors. Recently, the process of fabrication of platelet-rich plasma (PRP) has been simplified. The goal of this literature review is to summarize the evidenced based body of knowledge regarding the treatment of diabetic chronic wounds by PRP. A PubMed and Cochrane search (1978-2015) was performed and all studies assessing the clinical effect of PRP on the healing of diabetic chronic wounds were included. The screening retrieved 7,555 articles and 12 studies were included. On six randomized studies included, five found significant benefits for the use of PRP on diabetic chronic foot ulcers and the sixth randomized study did not publish a statistical analysis but found favorable outcomes. The two other controlled studies included found significant benefits regarding the healing rate and the four uncontrolled studies included showed high rates of healing with the adjunction of PRP. Regarding the method of use, PRP was applied on the wound as a gel twice a week (41.7% of studies) or once a week (33.3% of studies). In conclusion, 87.5% of controlled studies found a significant benefit for the adjunction of PRP to treat chronic diabetic wounds. As PRP may be beneficial, we suggest using PRP on diabetic ulcers which remain unhealed after standard treatment. PMID- 26019055 TI - Transanal Minimally Invasive Surgery (TAMIS): Standardizing a Reproducible Procedure. AB - BACKGROUND: The recent introduction of transanal minimally invasive surgery (TAMIS) offers a safe and cost-effective method for the local resection of rectal neoplasms. The ability to standardize a technique for TAMIS will lead to the most reproducible outcomes and enable teaching. METHODS: A retrospective, IRB-approved chart review was conducted of 32 patients who underwent the TAMIS procedure at one institution over a 3-year period. RESULTS: TAMIS was performed for 11 benign and 21 malignant lesions. The majority of resections were full thickness (29/32) and all were R0. Average distance from the anal verge was 7.5 +/- 3 cm, defect circumference was 43.7 +/- 10%, operative time was 131 +/- 80 min, and length of stay was 1.1 +/- 1 days. Two patients had morbidities requiring readmission and further treatment for (1) an aspiration pneumonia with CHF exacerbation and (2) a rectal abscess. CONCLUSIONS: This report outlines an operative technique for TAMIS that is reproducible for the excision of rectal lesions, associated with low morbidity. PMID- 26019057 TI - In Clinical Practice, the Term "Central Sensitivity Score" Is More Useful Than the Term "Polysymptomatic Distress Scale": Comment on the Editorial by Wolfe. PMID- 26019058 TI - Discriminating talent-identified junior Australian football players using a video decision-making task. AB - This study examined if a video decision-making task could discriminate talent identified junior Australian football players from their non-talent-identified counterparts. Participants were recruited from the 2013 under 18 (U18) West Australian Football League competition and classified into two groups: talent identified (State U18 Academy representatives; n = 25; 17.8 +/- 0.5 years) and non-talent-identified (non-State U18 Academy selection; n = 25; 17.3 +/- 0.6 years). Participants completed a video decision-making task consisting of 26 clips sourced from the Australian Football League game-day footage, recording responses on a sheet provided. A score of "1" was given for correct and "0" for incorrect responses, with the participants total score used as the criterion value. One-way analysis of variance tested the main effect of "status" on the task criterion, whilst a bootstrapped receiver operating characteristic (ROC) curve assessed the discriminant ability of the task. An area under the curve (AUC) of 1 (100%) represented perfect discrimination. Between-group differences were evident (P < 0.05) and the ROC curve was maximised with a score of 15.5/26 (60%) (AUC = 89.0%), correctly classifying 92% and 76% of the talent-identified and non-talent-identified participants, respectively. Future research should investigate the mechanisms leading to the superior decision-making observed in the talent-identified group. PMID- 26019056 TI - Survival benefit and phenotypic improvement by hamartin gene therapy in a tuberous sclerosis mouse brain model. AB - We examined the potential benefit of gene therapy in a mouse model of tuberous sclerosis complex (TSC) in which there is embryonic loss of Tsc1 (hamartin) in brain neurons. An adeno-associated virus (AAV) vector (serotype rh8) expressing a tagged form of hamartin was injected into the cerebral ventricles of newborn pups with the genotype Tsc1(cc) (homozygous for a conditional floxed Tsc1 allele) SynI cre(+), in which Tsc1 is lost selectively in neurons starting at embryonic day 12. Vector-treated Tsc1(cc)SynIcre(+) mice showed a marked improvement in survival from a mean of 22 days in non-injected mice to 52 days in AAV hamartin vector-injected mice, with improved weight gain and motor behavior in the latter. Pathologic studies showed normalization of neuron size and a decrease in markers of mTOR activation in treated as compared to untreated mutant littermates. Hence, we show that gene replacement in the brain is an effective therapeutic approach in this mouse model of TSC1. Our strategy for gene therapy has the advantages that therapy can be achieved from a single application, as compared to repeated treatment with drugs, and that AAV vectors have been found to have minimal to no toxicity in clinical trials for other neurologic conditions. Although there are many additional issues to be addressed, our studies support gene therapy as a useful approach in TSC patients. PMID- 26019059 TI - Corticosteroids and low bone mineral density affect hip cartilage in systemic lupus erythematosus patients: Quantitative T2 mapping. AB - BACKGROUND: The purpose of this diagnostic study was to quantify the effect of high-dose corticosteroid treatment on hip joint cartilage degeneration in patients with systemic lupus erythematosus (SLE), with and without osteonecrosis, using magnetic resonance imaging (MRI). METHODS: T2 mapping, with a 3.0 Tesla Discovery MR750 (GE Healthcare) MRI scanner, was performed in 12 volunteers without hip pathology (control group, 12 hips), in 11 patients with SLE without osteonecrosis, who were receiving corticosteroid therapy (corticosteroid-ON group, 17 hips), and in 15 patients with SLE receiving corticosteroids, who had noncollapsed and asymptomatic osteonecrosis (corticosteroid+ON group, 26 hips). The distribution of T2 values in the femoral head and acetabular cartilage were compared among the three groups. Step-wise multiple regression analysis was performed to determine the prognostic factors for T2 values indicative of femoral head cartilage degeneration. RESULTS: Mean T2 values of femoral head cartilage were significantly higher in the corticosteroid-ON (40.3 ms) and corticosteroid+ON (35.2 ms) groups than in the control group (30.1 ms, P = 0.001). T2 values of acetabular cartilage were significantly higher in the corticosteroid-ON group (41.8 ms) versus the control (33.4 ms) and the corticosteroid+ON groups (37.0 ms; P = 0.001). Low bone mineral density was a significant prognostic factor for high T2 values of cartilage at the femoral head in patients treated with corticosteroids, regardless of whether they had osteonecrosis. CONCLUSION: T2 mapping suggests that corticosteroid therapy and osteoporosis are independent risk factors for cartilage degeneration at the femoral head in patients with SLE. PMID- 26019063 TI - [Lumboischialgia due to intradural lumbar disc herniation]. PMID- 26019060 TI - Validated spectrofluorimetric method for determination of two phosphodiesterase inhibitors tadalafil and vardenafil in pharmaceutical preparations and spiked human plasma. AB - A valid, sensitive and rapid spectrofluorimetric method has been developed and validated for determination of both tadalafil (TAD) and vardenafil (VAR) either in their pure form, in their tablet dosage forms or spiked in human plasma. This method is based on measurement of the native fluorescence of both drugs in acetonitrile at lambdaem 330 and 470 nm after excitation at 280 and 275 nm for tadalafil and vardenafil, respectively. Linear relationships were obtained over the concentration range 4-40 and 10-250 ng/mL with a minimum detection of 1 and 3 ng/mL for tadalafil and vardenafil, respectively. Various experimental parameters affecting the fluorescence intensity were carefully studied and optimized. The developed method was applied successfully for the determination of tadalafil and vardenafil in bulk drugs and tablet dosage forms. Moreover, the high sensitivity of the proposed method permitted their determination in spiked human plasma. The developed method was validated in terms of specificity, linearity, lower limit of quantification (LOQ), lower limit of detection (LOD), precision and accuracy. The mean recoveries of the analytes in pharmaceutical preparations were in agreement with those obtained from the comparison methods, as revealed by statistical analysis of the obtained results using Student's t-test and the variance ratio F test. PMID- 26019065 TI - [Does outdoor play prevent myopia]. PMID- 26019068 TI - [A small paradise for physician employees]. PMID- 26019073 TI - [How your team should deal with irritable patients]. PMID- 26019076 TI - [ADHD: companion from kindergarten to career]. PMID- 26019077 TI - ["The decisive factor is the motivation of the children"]. PMID- 26019078 TI - [The heart and kidney determine the prognosis]. PMID- 26019080 TI - [Green power for heart and circulation]. PMID- 26019081 TI - [Even after birth mother and child are at risk]. PMID- 26019085 TI - [What are these summertime skin manifestations?]. PMID- 26019086 TI - [Type 2 diabetes is a one way street]. PMID- 26019087 TI - [Reliability of the prick test improves with age]. PMID- 26019088 TI - [Furrowed facial lines and clubbed fingers]. PMID- 26019089 TI - [Memory resides in the hair]. PMID- 26019090 TI - [Antidepressants for esophageal diseases?]. PMID- 26019091 TI - [Health days: drums without reverberation?]. PMID- 26019092 TI - [2 eye lenses fail their function]. PMID- 26019093 TI - [Vegan diet - the ultimate hype]. PMID- 26019094 TI - [Vegetarian/vegan diet - reasonable or dangerous?]. PMID- 26019095 TI - [Vegan nutrition - aspects for the clinical practice]. PMID- 26019096 TI - [Safety of brain dead organ donors]. PMID- 26019097 TI - [Emergency checklist: loss of vision]. PMID- 26019098 TI - [Malaria]. PMID- 26019099 TI - [Asthma and COPD: guidance in the jungle of inhalative drugs]. PMID- 26019100 TI - [Behavioral addictions]. PMID- 26019101 TI - [How to recognize pain in patients with dementia]. PMID- 26019113 TI - Compressive mechanical modulation alters the viability of growth plate chondrocytes in vitro. AB - The aim of this study was to investigate the effect of compressive modulation parameters (mode, magnitude, duration, as well as frequency and amplitude for cyclic modulation) on the viability of growth plate chondrocytes. Swine ulnar growth plate explants (n = 60) were randomly distributed among 10 groups: baseline (n = 1 * 6); culture control (n = 1 * 6); static (n = 3 * 6); and dynamic (n = 5 * 6). Static and dynamic samples were modulated in vitro using a bioreactor. Different compression magnitudes (0.1 MPa or 0.2 MPa), durations (12 h or 24 h), frequencies (0.1 Hz or 1.0 Hz), and amplitudes (30% or 100%) were investigated. Viability was assessed by automatic quantification of number of live/dead cells from confocal images of Live/Dead labeled tissues. Chondrocyte viability was found to be dependent on compression magnitude, duration, frequency, and amplitude in a way that increasing each parameter decreased viability in certain zones of growth plate. More specifically, proliferative and hypertrophic chondrocytes were found to be more sensitive to the applied compression. This study provides an in vitro protocol for studying the effects of compressive modulation on biomechanical and biological responses of growth plate explants, which will be useful in finding efficient and non-detrimental parameters for mechanical modulation of bone growth exploited in scoliosis fusionless treatments. PMID- 26019114 TI - Third trimester fetal heart rate predicts phenotype and mutation burden in the type 1 long QT syndrome. AB - BACKGROUND: Early diagnosis and risk stratification is of clinical importance in the long QT syndrome (LQTS), however, little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype. METHODS AND RESULTS: This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29-41) were lower per added mutation (no mutation, 143+/-5 beats per minute; single mutation, 134+/-8 beats per minute; double mutations, 111+/-6 beats per minute; P<0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122+/-10 versus 137+/-9 beats per minute; P<0.0001). Strong correlations between fetal heart rate and neonatal heart rate (r=0.700; P<0.001), and postnatal QTc (r=-0.762; P<0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (-10 beats per minute per added mutation; P<1.0*10(-23)). Arrhythmia symptoms and intrauterine beta-blocker exposure each predicted -7 beats per minute, P<0.0001. CONCLUSIONS: In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias. PMID- 26019115 TI - Long-term follow-up and epidemiological trends in patients with pretibial myxedema: an 11-year study from a tertiary care center in northern India. AB - INTRODUCTION: Pretibial myxedema (PTM) is a rare manifestation of Graves' disease. There is paucity of data regarding long-term follow-up and response to treatment in PTM. MATERIALS AND METHODS: Retrospective study wherein 30 patients of PTM presenting during 2001-2011 attending dermatology and endocrinology outpatient departments were analyzed. RESULTS: Among 30 patients with PTM, 12 were males and 18 females with a ratio of 1 : 1.5 males/females. Four morphological forms were identified: plaques (18 patients), diffuse non-pitting edema of both lower legs (five), nodules (five), and elephantiasis lesions (two). Eighty percent were diagnosed with hyperthyroidism before the development of dermopathy. Twenty-six patients presented with ophthalmopathy. Fourteen patients with plaque had an excellent response to topical clobetasol propionate ointment and attained complete resolution by 3.6 years. Out of 16 patients treated with combination therapy, which included nine treated with topical corticosteroids/intralesional triamcinolone and seven treated with oral, intralesional, and topical corticosteroids, nine attained complete resolution in the lesions by 3.4 years, and none relapsed anytime during four years of post treatment follow-up. However, the remaining patients (elephantiasis and diffuse forms) failed to achieve complete resolution. CONCLUSIONS: Plaques and nodules are common variants with a favorable clinical response to topical and intralesional corticosteroid; elephantine and diffuse forms responded poorly to therapy. Studies analyzing larger cohorts of patients with PTM and their long term follow-up are limited, hence more such studies are required. PMID- 26019116 TI - Transillumination for needle localization in the larynx. AB - OBJECTIVES/HYPOTHESIS: Transillumination through laryngeal soft tissue may be used to direct percutaneous transcricothyroid membrane subepithelial needle placement in the larynx. STUDY DESIGN: Cadaver simulation (canine and human). METHODS: Lighted devices, including sialendoscopes and fiberoptic cables, were tested as transilluminating obturators in trocars and needles through multiple studies to identify appropriate illumination, monitoring, and equipment for successful localization of needle/trocar tips placed within laryngeal tissue. RESULTS: Lighted 250-micron fiberoptic cables within 23-gauge needles were successfully placed percutaneously through the cricothyroid membrane and maneuvered submucosally into Reinke's space, the midlateral vocal fold, and through the thyroarytenoid gap with monitoring via flexible transnasal laryngoscopy. Technical adaptations in the course of study permitted successful simulation of clinical use in full cadaver study for accurate injection laryngoplasty, confirmed by laryngeal dissection following collagen injection. CONCLUSIONS: Small caliber fiberoptic cables are useful as transilluminating obturators to accurately direct needle position within laryngeal tissue. Clinical application of this new technique is anticipated to improve the accuracy of percutaneous needle localization in the larynx, as well as to assist in directed instrumentation of the larynx from an external approach. LEVEL OF EVIDENCE: N/A. PMID- 26019117 TI - Comparative pharmacokinetic profiles of five poorly soluble pulchinenosides in different formulations from Pulsatilla chinensis saponins extracts for enhanced bioavailability. AB - Pulsatilla chinensis, a traditional Chinese medicine (TCM), has been used for treating amoebic diseases, vaginal trichomoniasis and bacterial infections over a long history. Now growing attention has been attracted to its antitumor activities. The purpose of this work was to compare the pharmacokinetic profiles of pulchinenosides in different formulations and to improve their oral bioavailability. Extracts of P. chinensis saponins were prepared for PRS-Na (salt forming), PRS-HPbetaCD (hydroxypropyl-beta-cyclodextrin inclusion complex), PRS O/W (oil-in-water emulsion) and PRS-silica (micronization), respectively. A simpler and more durable LC-MS/MS method was developed in this study for quantitative analysis of pulsatilla sapoin D, B7, B10, B11 and sapoin PD simultaneously. The four formulations enhanced saponins oral bioavailability to varying degrees, as PRS-HPbetaCD > PRS-silica > PRS-O/W > PRS-Na, which indicated that water-soluble preparations can obviously improve the solubility of saponins, and are helpful to increase bioavailability. In particular, hydroxypropyl-beta cyclodextrin inclusion complex was the most effective way to promote absorption of saponins, raising the F values (bioavailability) >20 times. Therefore, P. chinensis saponin molecules can be slowly released by emulsion and micronization, which can avoid the enormous Cmax appearing in HPbetaCD, considering the pharmacokinetics profiles. However, appropriate pharmacokinetic parameters were observed in PRS-Na, although the F value was minimum among the four preparations. PMID- 26019118 TI - NCoR negatively regulates adipogenic differentiation of mesenchymal stem cells. AB - The nuclear receptor corepressor (NCoR) regulates the activities of gene transcription. Mesenchymal stem cells (MSCs) derived from bone marrow are multipotent cells which can differentiate into osteoblasts and adipocytes. This study was conducted to investigate the effects of NCoR on adipogenic differentiation of MSCs isolated from the rats. The results suggested that rat MSCs could differentiate into adipocytes successfully after cultured in adipogenic medium. NCoR protein determined by Western blot showed a lower expression in MSC-derived adipocytes, indicating that NCoR was involved in adipocyte differentiation of rat MSCs. It further proved that small interfering RNA (siRNA)-mediated knockdown of NCoR could promote cell viability and differentiation and enhance messenger RNA (mRNA) expression of lipoprotein lipase (LPL) and protein expression of CCAAT/enhancer binding protein-alpha (C/EBPalpha) and peroxisome proliferator-activated receptor-gamma (PPARgamma). However, over expression of NCoR exerted its functions in contrary to NCoR knockdown. It indicated that NCoR could negatively regulate adipogenic differentiation of rat MSCs. PMID- 26019119 TI - Effects of mimosine on Wolbachia in mosquito cells: cell cycle suppression reduces bacterial abundance. AB - The plant allelochemical L-mimosine (beta-[N-(3-hydroxy-4-pyridone)]-alpha aminopropionic acid; leucenol) resembles the nonessential amino acid, tyrosine. Because the obligate intracellular alphaproteobacterium, Wolbachia pipientis, metabolizes amino acids derived from host cells, the effects of mimosine on infected and uninfected mosquito cells were investigated. The EC50 for mimosine was 6-7 MUM with Aedes albopictus C7-10 and C/wStr cell lines, and was not influenced by infection status. Mosquito cells responded to concentrations of mimosine substantially lower than those used to synchronize the mammalian cell cycle; at concentrations of 30-35 MUM, mimosine reversibly arrested the mosquito cell cycle at the G1/S boundary and inhibited growth of Wolbachia strain wStr. Although lower concentrations of mimosine slightly increased wStr abundance, concentrations that suppressed the cell cycle reduced Wolbachia levels. PMID- 26019120 TI - Some ferrocenyl chalcones as useful candidates for cancer treatment. AB - Although knowledge of cancer management is extensive, mortality is not currently declining in this area. It is therefore important to implement a long-term strategy that would aim to prevent these serious diseases. Ferrocene-related organometallic compounds are promising candidates for design of new drugs since they can exhibit much greater biological activity than their phenyl analogs. In our work, we focused on investigating the cytotoxic and antiproliferative effects of five ferrocenyl derivatives toward selected tumor cell lines. We found that some of these substances significantly reduced Jurkat cell survival and, to a lesser extent, that of the HeLa, MCF7, A549, and MDA cells. Long-term treatment of HeLa cell cultures with these agents resulted in a significant blockade of formation of tumor cell colonies. We found that one of the mechanisms of action of the compounds is likely to display an effect on the redox state of the mitochondria at a final concentration of 10(-4) and 10(-5) mol l(-1). Of the compounds tested, the indanonyl ferrocene derivative (C) was the most effective, especially via glutathione depletion. Based on the obtained results, it can be concluded that synthetic substances containing iron have potential antitumor activity. PMID- 26019121 TI - Buffalo (Bubalus bubalis) term amniotic-membrane-derived cells exhibited mesenchymal stem cells characteristics in vitro. AB - Recent studies suggested that placentae amniotic membrane is a valuable source of stem cells in human as well as in livestock species. Advantages of amnion over other sources of stem cells included abundant availability, ethically non objectionable and non-invasive source. The aim of the present study was the isolation, culture and characterization of amniotic-membrane-derived mesenchymal stem cells from term placentae collected postpartum in buffalo. We have observed that both presumptive epithelial-like and fibroblast-like cells were cultured and maintained from term amnion. These cells were shown the positive expression of pluripotency markers (OCT-4, SOX-2, NANOG, TERT), mesenchymal stem cell markers (CD29, CD44, CD105) and negative for haematopoietic marker (CD34) genes at different passages. In addition, these cells were also positive for alkaline phosphatase staining. Stem-ness potential of any stem cells is determined by their potential to differentiate into specific lineages of cell type. In the present study, we have successfully differentiated the amniotic-membrane-derived cells into adipogenic, chondrogenic and osteogenic lineages of cells in vitro. In conclusion, the results of this study demonstrate that amniotic-membrane-derived cells expressed pluripotent and mesenchymal stem cells markers and have propensity to differentiate into cells of mesenchymal lineage cell type upon directed differentiation in vitro. PMID- 26019122 TI - COINS Data Exchange: An open platform for compiling, curating, and disseminating neuroimaging data. AB - Neuroimaging data collection is inherently expensive. Maximizing the return on investment in neuroimaging studies requires that neuroimaging data be re-used whenever possible. In an effort to further scientific knowledge, the COINS Data Exchange (DX) (http://coins.mrn.org/dx) aims to make data sharing seamless and commonplace. DX takes a three-pronged approach towards improving the overall state of data sharing within the neuroscience community. The first prong is compiling data into one location that has been collected from all over the world in many different formats. The second prong is curating the data so that it can be stored in one consistent format and so that data QA/QC measures can be assured. The third prong is disseminating the data so that it is easy to consume and straightforward to interpret. This paper explains the concepts behind each prong and describes some challenges and successes that the Data Exchange has experienced. PMID- 26019125 TI - [Harnessing genetic information for health care]. PMID- 26019123 TI - Co-activated yet disconnected-Neural correlates of eye closures when trying to stay awake. AB - Spontaneous eye-closures that herald sleep onset become more frequent when we are sleep deprived. Although these are typically associated with decreased responsiveness to external stimuli, it is less clear what occurs in the brain at these transitions to drowsiness and light sleep. To investigate this, task-free fMRI of sleep-deprived participants was acquired. BOLD activity associated with periods of spontaneously occurring eye closures were marked and analyzed. We observed concurrent and extensive hypnagogic co-activation of the extrastriate visual, auditory, and somatosensory cortices as well as the default mode network, consistent with internal sensory activity without external stimulation. Co activation of fronto-parietal areas known to mediate attentional control could correspond with participants resisting sleep or additional engagement of mental imagery. This constellation of signal changes differed from those elicited by cued eye closures of similar duration and distribution in the same, rested participants. They also differ from signal changes associated with mind-wandering and consolidated light sleep. Concurrent with the observed event-related changes, eye closures elicited additional reduction in functional connectivity within nodes of the DMN and DAN, superposed on already reduced connectivity associated with sleep deprivation. There was concurrent deactivation of the thalamus during eye-closure during the sleep-deprived state but almost similar changes occurred in the well-rested state that may also be relevant. These findings highlight the dynamic shifts in brain activity and connectivity at border between wakefulness and sleep. PMID- 26019126 TI - [Physical activity and physical condition of Icelandic primary and secondary school children with intellectual disability]. AB - INTRODUCTION: Little is known about physical activity, body composition and metabolic risk factors among children with intellectual disability (ID). The purpose of this study was to investigate their physical condition. MATERIAL AND METHODS: Children with ID (n=91) and a randomly selected age-and-gender matched group of 93 typically developed individuals (TDI) participated and the groups were compared on physical activity, fitness, body composition, blood pressure, blood lipids, and glycemic control. RESULTS: Children with ID were shorter (-8.6 cm, p<0.001), had greater skinfolds (p<0.001), diastolic blood pressure (22.7 mm, p=0,006), and body fat percentage (4.0 percentage points, p=0.008) than TDI children. Boys with ID had larger waist circumference than TDI boys (6.3 cm, p=0.009) but no difference was found among the girls. Higher proportion (41%) of children with ID than TDI children (19%) were categorized as obese (p=0.006) based on body fat percentage. No children with ID reached the recommended daily 60 minutes of moderate- to vigorous physical activity compared to 40% of the TDI children. Only 25% of children with ID achieved the recommended levels for fitness, whereas the same proportion was 75% among TDI children. Over 20% of the children with ID had elevated waist circumference, 34% elevated blood pressure, 13-21% elevated metabolic risk factors in the blood, and 7% were diagnosed with metabolic syndrome. These prevalences were lower among the TDI children. CONCLUSION: Physical condition of children with ID is poor and inferior to their TDI peers. Further studies are needed to investigate the reasons underlying the poor physical health among children with ID and how it can most effectively be enhanced. PMID- 26019127 TI - [Eating Disorder Treatment in Iceland - Treatment adherence, psychiatric co morbidities and factors influencing drop-out]. AB - OBJECTIVE: Treatment adherence in patients with eating disorders (ED) in Iceland is unknown. The aim of the study was to investigate treatment drop-out and explore factors that influence premature termination of treatment in a specialized ED treatment unit, at the University Hospital of Iceland, during the period of September 1, 2008 - May 1, 2012. MATERIAL AND METHODS: The study is retrospective and naturalistic. Hospital records of referred patients were examined. Those meeting the ICD 10 criteria of anorexia nervosa (AN) (F50.0, F50.1), bulimia nervosa (BN) (F50.2, F50.3) and eating disorder not otherwise specified (EDNOS) (F50.9) were included. The total sample was 260 and 182 patients met inclusion criteria. No-shows were 7%. Drop-out was defined as premature termination of treatment without formal discharge. RESULTS: The sample consisted of 176 women and 6 men, mean age 26.3 years. BN was diagnosed in 52.7% of patients, EDNOS in 36.8% AN in 10.4%. 74.7% had one or more co-morbid psychiatric diagnosis. Anxiety- and/or depression were diagnosed in 72.5%, Attention hyperactivity deficiency disorder in 15.4% and personality disorders in 8.2%. Lifetime prevalence of substance use disorders (SUDs) was 30.8%. Drop-out from treatment occurred in 54.4% of cases (with approximately 1/3 returning to treatment), 27.5% finished treatment and 18.1% were still in treatment at the end of the follow up period. Treatment adherence was significantly higher in patients who had a university degree, in those who had themselves taken the initiative to seek ED treatment and in those with higher anxiety scores at assessment. AN patients did better than other ED patients while patients with SUDs showed a tendency for higher drop-out (p=0.079). CONCLUSION: The drop-out rates were similar to what has been reported from other western countries. Follow-up time was longer and AN patient did better than expected. Higher education, initiative in seeking treatment and higher anxiety scores on questionnaires were protective. PMID- 26019128 TI - The W620 Polymorphism in PTPN22 Disrupts Its Interaction With Peptidylarginine Deiminase Type 4 and Enhances Citrullination and NETosis. AB - OBJECTIVE: A C-to-T single-nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase PTPN22 complementary DNA carries the highest risk of rheumatoid arthritis (RA) among all non-HLA genetic variants. This C1858T SNP converts an arginine (R620) to a tryptophan (W620), but it is unclear why it has such a strong impact on RA, a disease characterized by anti citrullinated protein antibodies. The aim of this study was to test the hypothesis that PTPN22 regulates protein citrullination. METHODS: The level of citrullinated proteins in immune cells was quantified by Western blotting. The physical interaction between PTPN22 and peptidyl arginine deiminase type 4 (PAD 4), which is one of the enzymes that catalyzes protein citrullination, was examined by coimmunoprecipitation. Neutrophils were collected from healthy donors carrying the C1858T SNP and healthy donors not carrying this SNP. The formation of neutrophil extracellular traps (NETs) was examined by immunocytochemistry. RESULTS: PTPN22 physically interacted with PAD-4, and a deficiency in PTPN22 enhanced protein citrullination. This abnormality was reversed by exogenous wild type PTPN22 or catalytically dead mutant PTPN22. The R-to-W conversion rendered PTPN22 unable to interact with PAD-4 and suppress citrullination. The C1858T SNP was associated with hypercitrullination in peripheral blood mononuclear cells and a heightened propensity for spontaneous formation of NETs, which is a PAD-4 dependent process. CONCLUSION: PTPN22 is an inhibitor of PAD-4 and protein citrullination. This function of PTPN22 is independent of its phosphatase activity but requires R620. Our data not only establish a molecular link between PTPN22 and PAD-4, but also suggest that the C1858T SNP increases the risk of RA by enhancing protein citrullination and spontaneous formation of NETs. PMID- 26019129 TI - CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. AB - BACKGROUND: The role of the CYP2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss-of function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel. METHODS AND RESULTS: CYP2C19*2 and CYP2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes (SPS3) study. CYP2C19 metabolizer status was inferred from genotype, and associations with the risk of recurrent stroke and major bleeding were assessed in the overall cohort and by race/ethnic group with logistic regression modeling. In the overall cohort, there were no differences in outcomes by CYP2C19 metabolizer status (recurrent stroke, odds ratio 1.81 [95% CI 0.76 to 4.30]; major bleeding, odds ratio 0.67 [95% CI 0.22 to 2.03]). In white participants, those with CYP2C19 intermediate or poor metabolizer status had higher odds of recurrent stroke (odds ratio 5.19 [95% CI 1.08 to 24.90]) than those with extensive or ultrarapid metabolizer status, but there was no evidence of difference in major bleeding. CONCLUSIONS: There were significant differences in recurrent stroke by CYP2C19 genotype-inferred metabolizer status in white subcortical stroke patients receiving dual antiplatelet therapy with aspirin and clopidogrel, consistent with cardiovascular studies on CYP2C19 and clopidogrel; however, the bleeding risk that led to early termination of the antiplatelet arm of the SPS3 trial does not appear to be explained by CYP2C19 genotype. This study was relatively underpowered; therefore, these findings should be interpreted with caution and warrant replication. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00059306. PMID- 26019130 TI - The impact of lifecourse socioeconomic position on cardiovascular disease events in African Americans: the Jackson Heart Study. AB - BACKGROUND: Few studies have examined the impact of lifecourse socioeconomic position (SEP) on cardiovascular disease (CVD) risk among African Americans. METHODS AND RESULTS: We used data from the Jackson Heart Study (JHS) to examine the associations of multiple measures of lifecourse SEP with CVD events in a large cohort of African Americans. During a median of 7.2-year follow-up, 362 new or recurrent CVD events occurred in a sample of 5301 participants aged 21 to 94. Childhood SEP was assessed by using mother's education, parental home ownership, and childhood amenities. Adult SEP was assessed by using education, income, wealth, and public assistance. Adult SEP was more consistently associated with CVD risk in women than in men: age-adjusted hazard ratios for low versus high income (95% CIs), 2.46 (1.19 to 5.09) in women and 1.50 (0.87 to 2.58) in men, P for interaction=0.1244, and hazard ratio for low versus high wealth, 2.14 (1.39 to 3.29) in women and 1.06 (0.62 to 1.81) in men, P for interaction=0.0224. After simultaneous adjustment for all adult SEP measures, wealth remained a significant predictor of CVD events in women (HR=1.73 [1.04, 2.85] for low versus high). Education and public assistance were less consistently associated with CVD. Adult SEP was a stronger predictor of CVD events in younger than in older participants (HR for high versus low summary adult SEP score 3.28 [1.43, 7.53] for participants <=50 years, and 1.90 (1.36 to 2.66) for participants >50 years, P for interaction 0.0846). Childhood SEP was not associated with CVD risk in women or men. CONCLUSIONS: Adult SEP is an important predictor of CVD events in African American women and in younger African Americans. Childhood SEP was not associated with CVD events in this population. PMID- 26019131 TI - Geographic variations in cardiovascular health in the United States: contributions of state- and individual-level factors. AB - BACKGROUND: Improving cardiovascular health (CVH) of all Americans by 2020 is a strategic goal of the American Heart Association. Understanding the sources of variation and identifying contextual factors associated with poor CVH may suggest important avenues for prevention. METHODS AND RESULTS: Cross-sectional data from the Behavioral Risk Factor Surveillance System for the year 2011 were linked to state-level coronary heart disease and stroke mortality data from the National Vital Statistics System and to state-level measures of median household income, income inequality, taxes on soda drinks and cigarettes, and food and physical activity environments from various administrative sources. Poor CVH was defined according to the American Heart Association definition using 7 self-reported CVH metrics (current smoking, physical inactivity, obesity, poor diet, hypertension, diabetes, and high cholesterol). Linked micromap plots and multilevel logistic models were used to examine state variation in poor CVH and to investigate the contributions of individual- and state-level factors to this variation. We found significant state-level variation in the prevalence of poor CVH (median odds ratio 1.32, P<0.001). Higher rates of poor CVH and cardiovascular disease mortality were clustered in the southern states. Minority and low socioeconomic groups were strongly associated with poor CVH and explained 44% of the state level variation in poor CVH; state-level factors explained an additional 28%. State-level median household income (odds ratio 0.89; 95% CI 0.84-0.94), taxes on soda drinks (odds ratio 0.94; 95% CI 0.89-0.99), farmers markets (odds ratio 0.91; 95% CI 0.85-0.98), and convenience stores (odds ratio 1.09; 95% CI 1.01 1.17) were predictive of poor CVH even after accounting for individual-level factors. CONCLUSIONS: There is significant state-level variation in poor CVH that is partly explained by individual- and state-level factors. Additional longitudinal research is warranted to examine the influence of state-level policies and food and physical activity environments on poor CVH. PMID- 26019133 TI - Simulation Activity in Otolaryngology Residencies. AB - OBJECTIVES: Simulation has become a valuable tool in medical education, and several specialties accept or require simulation as a resource for resident training or assessment as well as for board certification or maintenance of certification. This study investigates current simulation resources and activities in US otolaryngology residency programs and examines interest in advancing simulation training and assessment within the specialty. STUDY DESIGN: Web-based survey. SETTING: US otolaryngology residency training programs. SUBJECTS AND METHODS: An electronic web-based survey was disseminated to all US otolaryngology program directors to determine their respective institutional and departmental simulation resources, existing simulation activities, and interest in further simulation initiatives. Descriptive results are reported. RESULTS: Responses were received from 43 of 104 (43%) residency programs. Simulation capabilities and resources are available in most respondents' institutions (78.6% report onsite resources; 73.8% report availability of models, manikins, and devices). Most respondents (61%) report limited simulation activity within otolaryngology. Areas of simulation are broad, addressing technical and nontechnical skills related to clinical training (94%). Simulation is infrequently used for research, credentialing, or systems improvement. The majority of respondents (83.8%) expressed interest in participating in multicenter trials of simulation initiatives. CONCLUSION: Most respondents from otolaryngology residency programs have incorporated some simulation into their curriculum. Interest among program directors to participate in future multicenter trials appears high. Future research efforts in this area should aim to determine optimal simulators and simulation activities for training and assessment as well as how to best incorporate simulation into otolaryngology residency training programs. PMID- 26019132 TI - Chlorogenic Acid Activates CFTR-Mediated Cl- Secretion in Mice and Humans: Therapeutic Implications for Chronic Rhinosinusitis. AB - OBJECTIVES: Salubrious effects of the green coffee bean are purportedly secondary to high concentrations of chlorogenic acid. Chlorogenic acid has a molecular structure similar to bioflavonoids that activate transepithelial Cl(-) transport in sinonasal epithelia. In contrast to flavonoids, the drug is freely soluble in water. The objective of this study is to evaluate the Cl(-) secretory capability of chlorogenic acid and its potential as a therapeutic activator of mucus clearance in sinus disease. STUDY DESIGN: Basic research. SETTING: Laboratory. SUBJECTS AND METHODS: Chlorogenic acid was tested on primary murine nasal septal epithelial (MNSE) (CFTR(+/+) and transgenic CFTR(-/-)) and human sinonasal epithelial (HSNE) (CFTR(+/+) and F508del/F508del) cultures under pharmacologic conditions in Ussing chambers to evaluate effects on transepithelial Cl(-) transport. Cellular cyclic adenosine monophosphate (cAMP), phosphorylation of the CFTR regulatory domain (R-D), and CFTR mRNA transcription were also measured. RESULTS: Chlorogenic acid stimulated transepithelial Cl(-) secretion (change in short-circuit current [DeltaISC = uA/cm(2)]) in MNSE (13.1 +/- 0.9 vs 0.1 +/- 0.1; P < .05) and HSNE (34.3 +/- 0.9 vs 0.0 +/- 0.1; P < .05). The drug had a long duration until peak effect at 15 to 30 minutes after application. Significant inhibition with INH-172 as well as absent stimulation in cultures lacking functional CFTR suggest effects are dependent on CFTR-mediated pathways. However, the absence of elevated cellular cAMP and phosphorylation the CFTR R-D indicates chlorogenic acid does not work through a PKA-dependent mechanism. CONCLUSION: Chlorogenic acid is a water-soluble agent that promotes CFTR-mediated Cl(-) transport in mouse and human sinonasal epithelium. Translating activators of mucociliary transport to clinical use provides a new therapeutic approach to sinus disease. Further in vivo evaluation is planned. PMID- 26019134 TI - Reflections: Service to Our Nation. AB - Service to others is something that physicians understand and undertake on a daily basis. Military physicians are in a unique role of serving both our patients and our nation. Millions of Americans have answered the call to military service since the attacks of September 11, 2001. As otolaryngologists, we will increasingly care for veterans of the Global War on Terror. Service to our nation is a mutual goal that brings together people from very different walks of life. PMID- 26019135 TI - Incidental Parotid Neoplasms: Pathology and Prevalence. AB - OBJECTIVE: To better characterize parotid masses incidentally identified on imaging. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: Medical records were reviewed for 771 patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients were stratified into 2 groups: those with tumors identified solely on imaging (parotid incidentalomas [PIs]) and those with palpable masses, pain, facial nerve dysfunction, or other reasons their mass was identified (nonincidentals [NIs]). A chi(2) test was employed to compare the prevalence of malignancy in PIs compared with NIs. Trend analysis was performed to determine the prevalence of PIs over the 20-year period. RESULTS: Of the 771 patients, 67 (8.7%) had their mass discovered incidentally on imaging (PIs). There was a significant difference in the rate of malignancy in the NI (32.7%) compared with the PI group (6.0%) (P < .01). During the 1994 to 2003 time period, 4.0% of all parotoidectomies performed were for PIs, while during the second decade (2004 2013), this proportion increased to 10.2%. This represents a 155.0% increase in the percentage of parotidectomies carried out for PIs between these 2 periods. CONCLUSION: In this study, the rate of malignancy in PIs was significantly lower than the rate of malignancy in patients with NIs. The occurrence of PIs has increased over time and now represents greater than 10.0% of all parotidectomies performed at the University of Wisconsin. This information is important to consider when consenting a patient for resection of a PI. PMID- 26019136 TI - MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4. AB - BACKGROUND: Aim to determine the clinicopathological and prognostic role of miR 301a-3p in pancreatic ductal adenocarcinoma(PDAC), to investigate the biological mechanism of miR-301a-3p in vitro and in vivo. METHODS: By tissue microarray analysis, we studied miR-301a-3p expression in PDAC patients and its clinicopathological correlations as well as prognostic significance. qRT-PCR was used to test miR-301a-3p expression in PDAC tissues and cell lines. Functional experiments including in vitro and in vivo were performed. RESULTS: Significantly higher expression of miR-301a-3p were found in PDAC patients with lymph node metastasis and advanced pathological stages and identified as an independent prognostic factor for worse survival. In PDAC samples and cell lines, miR-301a-3p was significantly up-regulated compared with matched non-tumor tissues and normal pancreatic ductal cells, respectively. Overexpression of miR-301a-3p enhanced PDAC cells colony, invasion and migration abilities in vitro as well as tumorigenicity in vivo. Furthermore, SMAD4 was identified as a target gene of miR 301a-3p by cell as well as mice xenograft experiments. In PDAC tissue microarray, a significantly inverse correlation between miR-301a-3p ISH scores and SMAD4 IHC scores were observed in both tumor and corresponding non-tumor tissues. CONCLUSIONS: MiR-301a-3p functions as a novel oncogene in PDAC and the oncogenic activity may involve its inhibition of the target gene SMAD4. PMID- 26019137 TI - FGF23 promotes prostate cancer progression. AB - Prostate cancer is the most common cancer in US men and the second leading cause of cancer deaths. Fibroblast growth factor 23 (FGF23) is an endocrine FGF, normally expressed by osteocytes, which plays a critical role in phosphate homeostasis via a feedback loop involving the kidney and vitamin D. We now show that FGF23 is expressed as an autocrine growth factor in all prostate cancer cell lines tested and is present at increased levels in prostate cancer tissues. Exogenous FGF23 enhances proliferation, invasion and anchorage independent growth in vitro while FGF23 knockdown in prostate cancer cell lines decreases these phenotypes. FGF23 knockdown also decreases tumor growth in vivo. Given that classical FGFs and FGF19 are also increased in prostate cancer, we analyzed expression microarrays hybridized with RNAs from of LNCaP cells stimulated with FGF2, FGF19 or FGF23. The different FGF ligands induce overlapping as well as unique patterns of gene expression changes and thus are not redundant. We identified multiple genes whose expression is altered by FGF23 that are associated with prostate cancer initiation and progression. Thus FGF23 can potentially also act as an autocrine, paracrine and/or endocrine growth factor in prostate cancer that can promote prostate cancer progression. PMID- 26019139 TI - Evaluation of postural steadiness in below-knee amputees when wearing different prosthetic feet during various sensory conditions using the Biodex(r) Stability System. AB - In recent years, computerized posturography has become an essential tool in quantitative assessment of postural steadiness in the clinical settings. The purpose of this study was to explore the ability of the Biodex((r)) Stability System (BSS) to quantify postural steadiness in below-knee amputees. A convenience sample of 10 below-knee amputees participated in the study. The overall (OSI), anterior-posterior (APSI) and medial-lateral (MLSI) stability indexes as well as the percentage of time spent in left and right quadrants and four concentric zones were measured under altered sensory conditions while standing with solid ankle cushion heel (SACH), single-axis (SA) and energy storage and release (ESAR) feet. Significant difference was found between sensory conditions in SACH and ESAR feet for OSI (SACH, p = 0.002; ESAR, p = 0.005), APSI (SACH, p = 0.036; ESAR, p = 0.003) and MLSI (SACH, p = 0.008; ESAR, p = 0.05) stability indexes. The percentage of time spent in Zone A (0 degrees -5 degrees ) was significantly greater than the other three concentric zones (p < 0.01). The loading time percentage on their intact limb (80%-94%) was significantly longer than the amputated limb (20%-6%) in all conditions for all three prosthetic feet. Below-knee amputees showed compromised postural steadiness when visual, proprioceptive or vestibular sensory input was altered. The findings highlight that the characteristics of postural stability in amputees can be clinically assessed by utilizing the outcomes produced by the BSS. PMID- 26019141 TI - Correction. PMID- 26019140 TI - Fabrication of three-dimensional bioplotted hydrogel scaffolds for islets of Langerhans transplantation. AB - In clinical islet transplantation, allogeneic islets of Langerhans are transplanted into the portal vein of patients with type 1 diabetes, enabling the restoration of normoglycemia. After intra-hepatic transplantation several factors are involved in the decay in islet mass and function mainly caused by an immediate blood mediated inflammatory response, lack of vascularization, and allo and autoimmunity. Bioengineered scaffolds can potentially provide an alternative extra-hepatic transplantation site for islets by improving nutrient diffusion and blood supply to the scaffold. This would ultimately result in enhanced islet viability and functionality compared to conventional intra portal transplantation. In this regard, the biomaterial choice, the three-dimensional (3D) shape and scaffold porosity are key parameters for an optimal construct design and, ultimately, transplantation outcome. We used 3D bioplotting for the fabrication of a 3D alginate-based porous scaffold as an extra-hepatic islet delivery system. In 3D-plotted alginate scaffolds the surface to volume ratio, and thus oxygen and nutrient transport, is increased compared to conventional bulk hydrogels. Several alginate mixtures have been tested for INS1E beta-cell viability. Alginate/gelatin mixtures resulted in high plotting performances, and satisfactory handling properties. INS1E beta-cells, human and mouse islets were successfully embedded in 3D-plotted constructs without affecting their morphology and viability, while preventing their aggregation. 3D plotted scaffolds could help in creating an alternative extra-hepatic transplantation site. In contrast to microcapsule embedding, in 3D plotted scaffold islets are confined in one location and blood vessels can grow into the pores of the construct, in closer contact to the embedded tissue. Once revascularization has occurred, the functionality is fully restored upon degradation of the scaffold. PMID- 26019142 TI - Surgical versus percutaneous coronary revascularization for multivessel disease in diabetic patients with non-ST-segment-elevation acute coronary syndrome: analysis from the Acute Catheterization and Early Intervention Triage Strategy trial. AB - BACKGROUND: The preferred revascularization strategy for diabetic patients with acute coronary syndromes and multivessel coronary artery disease is uncertain. We evaluated the outcomes of diabetic patients with moderate and high-risk acute coronary syndrome and multivessel disease managed with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). METHODS AND RESULTS: Among 13 819 moderate and high-risk acute coronary syndrome patients enrolled in the Acute Catheterization and Early Intervention Triage Strategy (ACUITY) trial, 1772 diabetic patients had multivessel disease with left anterior descending artery involvement and were managed by PCI (n=1349) or CABG (n=423). Propensity scoring was applied to adjust for differences in baseline clinical and angiographic characteristics, yielding a total of 326 matched patients (163 managed by PCI and 163 managed by CABG). At 30 days, treatment with PCI compared with CABG was associated with lower rates of major bleeding (15.3% versus 55.6%; P<0.0001), blood transfusions (9.2% versus 43.2%; P<0.0001), and acute kidney injury (13.4% versus 33.6%; P<0.0001), but more unplanned revascularization procedures (6.9% versus 1.9%; P=0.03). At 1 year PCI was associated with higher rates of repeat revascularization procedures (19.5% versus 5.2%; P=0.0001), with nonsignificantly different rates of myocardial infarction, stroke, and death at either 30 days or 1 year. CONCLUSIONS: In the large-scale ACUITY trial, diabetic patients with acute coronary syndrome and multivessel disease treated with PCI rather than CABG had less bleeding and acute kidney injury, greater need for repeat revascularization procedures, and comparable rates of myocardial infarction, stroke, and death through 1-year follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00093158. PMID- 26019143 TI - Vascular flow reserve immediately after infrapopliteal intervention as a predictor of wound healing in patients with foot tissue loss. AB - BACKGROUND: The purpose of this study was to verify whether the concept of coronary blood flow reserve can be applied to patients with critical limb ischemia who are undergoing endovascular treatment (EVT) for isolated infrapopliteal lesions. METHODS AND RESULTS: Forty patients diagnosed with critical limb ischemia (Rutherford category 5) who were undergoing EVT for isolated infrapopliteal lesions were prospectively enrolled. All lesions were treated with conventional balloon angioplasty without stent placement. After successful EVT, a pressure/temperature sensor-tipped guidewire was positioned in the proximal popliteal artery. Using the thermodilution technique, the mean transit time (Tmn) was determined after bolus injections of 3-mL saline at baseline and at the onset of intra-arterial papaverine induced maximum hyperemia. Vascular flow reserve (VFR) was calculated as resting Tmn divided by hyperemic Tmn. Complete epithelialization of the reference wound (wound healing) was completely closed by either surgical or secondary intervention within 3 months after EVT. Wound healing was achieved in 22 patients after EVT (healing group) but was not achieved in 18 patients (nonhealing group). Postprocedural VFR was significantly lower in the nonhealing group than in the healing group (2.40; interquartile range, 2.00-3.08 versus 4.05; interquartile range, 3.60-4.60; P<0.0001). Receiver operating characteristic analysis revealed postprocedural VFR >3.6 as the best threshold value for complete wound healing after EVT. Univariate analysis revealed that postprocedural VFR >3.6 was a predictor of wound healing (P=0.0002). CONCLUSIONS: Advanced lower limb clinical setting may be caused by a poor capability of microvasculature. VFR, which is easily assessable, is useful in clinical risk stratification for patients with critical limb ischemia after EVT in the catheterization laboratory. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000009313. PMID- 26019144 TI - A three-dimensional model of primary bovine endometrium using an electrospun scaffold. AB - Endometrial stromal and epithelial cell function is typically studied in vitro using standard two-dimensional monocultures, but these cultures fail to reflect the complex three-dimensional (3D) architecture of tissue. A 3D model of bovine endometrium that reflects the architectural arrangement of in vivo tissue would beneficially assist the study of tissue function. An electrospun polyglycolide (PGA) scaffold was selected to grow a 3D model of primary bovine endometrial epithelial and stromal cells, that reflects the architecture of the endometrium for the study of pathophysiology. Electrospun scaffolds were seeded with stromal and epithelial cells, and growth was assessed using histological techniques. Prostaglandin E2 and prostaglandin F2alpha responsiveness of endometrial scaffold constructs was tested using oxytocin plus arachidonic acid (OT + AA) or lipopolysaccharide (LPS). Stromal and epithelial cells growing on the electrospun scaffold had an architectural arrangement that mimicked whole tissue, deposited fibronectin, had appropriate expression of vimentin and cytokeratin and were responsive to OT + AA and LPS, as measured by prostaglandin accumulation. In conclusion, a functional 3D model of stromal and epithelial cells was developed using a PGA electrospun scaffold which may be used to study endometrial pathophysiology. PMID- 26019145 TI - Unsaturated fatty acids-dependent linkage between respiration and fermentation revealed by deletion of hypoxic regulatory KlMGA2 gene in the facultative anaerobe-respiratory yeast Kluyveromyces lactis. AB - In the yeast Kluyveromyces lactis, the inactivation of structural or regulatory glycolytic and fermentative genes generates obligate respiratory mutants which can be characterized by sensitivity to the mitochondrial drug antimycin A on glucose medium (Rag(-) phenotype). Rag(-) mutations can occasionally be generated by the inactivation of genes not evidently related to glycolysis or fermentation. One such gene is the hypoxic regulatory gene KlMGA2. In this work, we report a study of the many defects, in addition to the Rag(-) phenotype, generated by KlMGA2 deletion. We analyzed the fermentative and respiratory metabolism, mitochondrial functioning and morphology in the Klmga2Delta strain. We also examined alterations in the regulation of the expression of lipid biosynthetic genes, in particular fatty acids, ergosterol and cardiolipin, under hypoxic and cold stress and the phenotypic suppression by unsaturated fatty acids of the deleted strain. Results indicate that, despite the fact that the deleted mutant strain had a typical glycolytic/fermentative phenotype and KlMGA2 is a hypoxic regulatory gene, the deletion of this gene generated defects linked to mitochondrial functions suggesting new roles of this protein in the general regulation and cellular fitness of K. lactis. Supplementation of unsaturated fatty acids suppressed or modified these defects suggesting that KlMga2 modulates membrane functioning or membrane-associated functions, both cytoplasmic and mitochondrial. PMID- 26019146 TI - Specific phosphoantibodies reveal two phosphorylation sites in yeast Pma1 in response to glucose. AB - Glucose triggers post-translational modifications of the Saccharomyces cerevisiae plasma membrane H(+)-ATPase (Pma1) that lead to an increase in enzyme activity. The activation results from changes in two kinetic parameters: an increase in the affinity of the enzyme for ATP, depending on Ser899, and an increase in the Vmax involving Ser911/Thr912. Using phosphospecific antibodies, we show that Ser899 and Ser911/Thr912 are phosphorylated in vivo during glucose activation and that protein phosphatase Glc7 is involved in the dephosphorylation of Ser899 upon glucose starvation. PMID- 26019147 TI - Zygosaccharomyces rouxii Trk1 is an efficient potassium transporter providing yeast cells with high lithium tolerance. AB - Zygosaccharomyces rouxii is an osmotolerant yeast growing in the presence of high concentrations of salts and/or sugars. The maintenance of intracellular potassium homeostasis is essential for osmostress adaptation. Zygosaccharomyces rouxii is endowed with only one typical potassium transporter (ZrTrk1). We characterized ZrTrk1 activity and its contribution to various physiological parameters in detail. Our results show that ZrTrk1 is a high-affinity K(+) transporting system efficiently discriminating between K(+) and Li(+) and indicate the presence of another, currently unknown K(+) importing system with a low affinity in Z. rouxii cells. Upon ZrTrk1 heterologous expression in Saccharomyces cerevisiae, it confers cells with a remarkably high lithium tolerance (even to wild-type strains) due to preventing Li(+) influx into cells, and is able to complement a plasma-membrane hyperpolarization and cell sensitivity to cationic compounds caused by the lack of endogenous K(+) transporters. Intracellular pH measurements with pHluorin, whose coding sequence was integrated into the genome, showed that the expression of ZrTrk1 also complements a decrease in intracellular pH in S. cerevisiae trk1Delta trk2Delta cells. Our data corroborate a tight connection between potassium and proton transporters in yeasts and provide new insights into Z. rouxii cation homeostasis and the basis of its high osmotolerance. PMID- 26019148 TI - Involvement of acyl-CoA synthetase genes in n-alkane assimilation and fatty acid utilization in yeast Yarrowia lipolytica. AB - Here, we investigated the roles of YAL1 (FAA1) and FAT1 encoding acyl-CoA synthetases (ACSs) and three additional orthologs of ACS genes FAT2-FAT4 of the yeast Yarrowia lipolytica in the assimilation or utilization of n-alkanes and fatty acids. ACS deletion mutants were generated to characterize their function. The FAT1 deletion mutant exhibited decreased growth on n-alkanes of 10-18 carbons, whereas the FAA1 mutant showed growth reduction on n-alkane of 16 carbons. However, FAT2-FAT4 deletion mutants did not show any growth defects, suggesting that FAT1 and FAA1 are involved in the activation of fatty acids produced during the metabolism of n-alkanes. In contrast, deletions of FAA1 and FAT1-FAT4 conferred no defect in growth on fatty acids. The wild-type strain grew in the presence of cerulenin, an inhibitor of fatty acid synthesis, by utilizing exogenously added fatty acid or fatty acid derived from n-alkane when oleic acid or n-alkane of 18 carbons was supplemented. However, the FAA1 deletion mutant did not grow, indicating a critical role for FAA1 in the utilization of fatty acids. Fluorescent microscopic observation and biochemical analyses suggested that Fat1p is present in the peroxisome and Faa1p is localized in the cytosol and to membranes. PMID- 26019149 TI - Artificial design for new ferroelectrics using nanosheet-architectonics concept. AB - Control over the emergence of ferroelectric order remains a fundamental challenge for the rational design of artificial materials with novel properties. Here we report a new strategy for artificial design of layered perovskite ferroelectrics by using oxide nanosheets (high-k dielectric Ca2Nb3O10 and insulating Ti0.87O2) as a building block. We approached the preparation of superlattice films by a layer-by-layer assembly involving Langmuir-Blodgett deposition. The artificially fabricated (Ti0.87O2/Ca2Nb3O10)2(Ti0.87O2) superlattices are structurally unique, which is not feasible to create in the bulk form. By such an artificial structuring, we found that (Ti0.87O2/Ca2Nb3O10)2(Ti0.87O2) superlattices possess a new form of interface coupling, which gives rise to ferroelectricity with a good fatigue-free characteristic. Considering the flexibility of self-assembled nanosheet interfaces, this technique provides a route to synthesize a new kind of layered ferroelectric oxides. PMID- 26019150 TI - Reducing error rates in straintronic multiferroic nanomagnetic logic by pulse shaping. AB - Dipole-coupled nanomagnetic logic (NML), where nanomagnets (NMs) with bistable magnetization states act as binary switches and information is transferred between them via dipole-coupling and Bennett clocking, is a potential replacement for conventional transistor logic since magnets dissipate less energy than transistors when they switch in a logic circuit. Magnets are also 'non-volatile' and hence can store the results of a computation after the computation is over, thereby doubling as both logic and memory-a feat that transistors cannot achieve. However, dipole-coupled NML is much more error-prone than transistor logic at room temperature [Formula: see text] because thermal noise can easily disrupt magnetization dynamics. Here, we study a particularly energy-efficient version of dipole-coupled NML known as straintronic multiferroic logic (SML) where magnets are clocked/switched with electrically generated mechanical strain. By appropriately 'shaping' the voltage pulse that generates strain, we show that the error rate in SML can be reduced to tolerable limits. We describe the error probabilities associated with various stress pulse shapes and discuss the trade off between error rate and switching speed in SML.The lowest error probability is obtained when a 'shaped' high voltage pulse is applied to strain the output NM followed by a low voltage pulse. The high voltage pulse quickly rotates the output magnet's magnetization by 90 degrees and aligns it roughly along the minor (or hard) axis of the NM. Next, the low voltage pulse produces the critical strain to overcome the shape anisotropy energy barrier in the NM and produce a monostable potential energy profile in the presence of dipole coupling from the neighboring NM. The magnetization of the output NM then migrates to the global energy minimum in this monostable profile and completes a 180 degrees rotation (magnetization flip) with high likelihood. PMID- 26019151 TI - Discharge Hospice Referral and Lower 30-Day All-Cause Readmission in Medicare Beneficiaries Hospitalized for Heart Failure. AB - BACKGROUND: Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all cause readmission remains unknown. METHODS AND RESULTS: Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998-2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06-0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04-0.21) and 0.17 (0.08-0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice eligible patients). CONCLUSIONS: A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral. PMID- 26019152 TI - Clinical Management of Catecholaminergic Polymorphic Ventricular Tachycardia: The Role of Left Cardiac Sympathetic Denervation. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. beta-Betalockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. METHODS AND RESULTS: We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had >=1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% (P<0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year (P<0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P<0.01) than those with a complete LCSD. CONCLUSIONS: LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks. PMID- 26019153 TI - Sympathectomy for Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: Should We Have the Nerve? PMID- 26019154 TI - Niche and metabolic principles explain patterns of diversity and distribution: theory and a case study with soil bacterial communities. AB - The causes of biodiversity patterns are controversial and elusive due to complex environmental variation, covarying changes in communities, and lack of baseline and null theories to differentiate straightforward causes from more complex mechanisms. To address these limitations, we developed general diversity theory integrating metabolic principles with niche-based community assembly. We evaluated this theory by investigating patterns in the diversity and distribution of soil bacteria taxa across four orders of magnitude variation in spatial scale on an Antarctic mountainside in low complexity, highly oligotrophic soils. Our theory predicts that lower temperatures should reduce taxon niche widths along environmental gradients due to decreasing growth rates, and the changing niche widths should lead to contrasting alpha- and beta-diversity patterns. In accord with the predictions, alpha-diversity, niche widths and occupancies decreased while beta-diversity increased with increasing elevation and decreasing temperature. The theory also successfully predicts a hump-shaped relationship between alpha-diversity and pH and a negative relationship between alpha diversity and salinity. Thus, a few simple principles explained systematic microbial diversity variation along multiple gradients. Such general theory can be used to disentangle baseline effects from more complex effects of temperature and other variables on biodiversity patterns in a variety of ecosystems and organisms. PMID- 26019155 TI - Composite collective decision-making. AB - Individual animals are adept at making decisions and have cognitive abilities, such as memory, which allow them to hone their decisions. Social animals can also share information. This allows social animals to make adaptive group-level decisions. Both individual and collective decision-making systems also have drawbacks and limitations, and while both are well studied, the interaction between them is still poorly understood. Here, we study how individual and collective decision-making interact during ant foraging. We first gathered empirical data on memory-based foraging persistence in the ant Lasius niger. We used these data to create an agent-based model where ants may use social information (trail pheromones), private information (memories) or both to make foraging decisions. The combined use of social and private information by individuals results in greater efficiency at the group level than when either information source was used alone. The modelled ants couple consensus decision making, allowing them to quickly exploit high-quality food sources, and combined decision-making, allowing different individuals to specialize in exploiting different resource patches. Such a composite collective decision-making system reaps the benefits of both its constituent parts. Exploiting such insights into composite collective decision-making may lead to improved decision-making algorithms. PMID- 26019156 TI - Minimal effects of latitude on present-day speciation rates in New World birds. AB - The tropics contain far greater numbers of species than temperate regions, suggesting that rates of species formation might differ systematically between tropical and non-tropical areas. We tested this hypothesis by reconstructing the history of speciation in New World (NW) land birds using BAMM, a Bayesian framework for modelling complex evolutionary dynamics on phylogenetic trees. We estimated marginal distributions of present-day speciation rates for each of 2571 species of birds. The present-day rate of speciation varies approximately 30-fold across NW birds, but there is no difference in the rate distributions for tropical and temperate taxa. Using macroevolutionary cohort analysis, we demonstrate that clades with high tropical membership do not produce species more rapidly than temperate clades. For nearly any value of present-day speciation rate, there are far more species in the tropics than the temperate zone. Any effects of latitude on speciation rate are marginal in comparison to the dramatic variation in rates among clades. PMID- 26019157 TI - Links between language diversity and species richness can be confounded by spatial autocorrelation. PMID- 26019158 TI - Asexual queen succession in the higher termite Embiratermes neotenicus. AB - Asexual queen succession (AQS), in which workers, soldiers and dispersing reproductives are produced sexually while numerous non-dispersing queens arise through thelytokous parthenogenesis, has recently been described in three species of lower termites of the genus Reticulitermes. Here, we show that AQS is not an oddity restricted to a single genus of lower termites, but a more widespread strategy occurring also in the most advanced termite group, the higher termites (Termitidae). We analysed the genetic structure in 10 colonies of the Neotropical higher termite Embiratermes neotenicus (Syntermitinae) using five newly developed polymorphic microsatellite loci. The colonies contained one primary king accompanied either by a single primary queen or by up to almost 200 neotenic queens. While the workers, the soldiers and most future dispersing reproductives were produced sexually, the non-dispersing neotenic queens originated through thelytokous parthenogenesis of the founding primary queen. Surprisingly, the mode of thelytoky observed in E. neotenicus is most probably automixis with central fusion, contrasting with the automixis with terminal fusion documented in Reticulitermes. The occurrence of AQS based on different mechanisms of ploidy restoration raises the hypothesis of an independent evolutionary origin of this unique reproductive strategy in individual lineages of lower and higher termites. PMID- 26019159 TI - Migration and the evolution of sexual dichromatism: evolutionary loss of female coloration with migration among wood-warblers. AB - The mechanisms underlying evolutionary changes in sexual dimorphism have long been of interest to biologists. A striking gradient in sexual dichromatism exists among songbirds in North America, including the wood-warblers (Parulidae): males are generally more colourful than females at northern latitudes, while the sexes are similarly ornamented at lower latitudes. We use phylogenetically controlled comparative analysis to test three non-mutually exclusive hypotheses for the evolution of sexual dichromatism among wood-warblers. The first two hypotheses focus on the loss of female coloration with the evolution of migration, either owing to the costs imposed by visual predators during migration, or owing to the relaxation of selection for female social signalling at higher latitudes. The third hypothesis focuses on whether sexual dichromatism evolved owing to changes in male ornamentation as the strength of sexual selection increases with breeding latitude. To test these hypotheses, we compared sexual dichromatism to three variables: the presence of migration, migration distance, and breeding latitude. We found that the presence of migration and migration distance were both positively correlated with sexual dichromatism, but models including breeding latitude alone were not strongly supported. Ancestral state reconstruction supports the hypothesis that the ancestral wood-warblers were monochromatic, with both colourful males and females. Combined, these results are consistent with the hypotheses that the evolution of migration is associated with the relaxation of selection for social signalling among females and that there are increased predatory costs along longer migratory routes for colourful females. These results suggest that loss of female ornamentation can be a driver of sexual dichromatism and that social or natural selection may be a stronger contributor to variation in dichromatism than sexual selection. PMID- 26019160 TI - A test of genetic models for the evolutionary maintenance of same-sex sexual behaviour. AB - The evolutionary maintenance of same-sex sexual behaviour (SSB) has received increasing attention because it is perceived to be an evolutionary paradox. The genetic basis of SSB is almost wholly unknown in non-human animals, though this is key to understanding its persistence. Recent theoretical work has yielded broadly applicable predictions centred on two genetic models for SSB: overdominance and sexual antagonism. Using Drosophila melanogaster, we assayed natural genetic variation for male SSB and empirically tested predictions about the mode of inheritance and fitness consequences of alleles influencing its expression. We screened 50 inbred lines derived from a wild population for male male courtship and copulation behaviour, and examined crosses between the lines for evidence of overdominance and antagonistic fecundity selection. Consistent variation among lines revealed heritable genetic variation for SSB, but the nature of the genetic variation was complex. Phenotypic and fitness variation was consistent with expectations under overdominance, although predictions of the sexual antagonism model were also supported. We found an unexpected and strong paternal effect on the expression of SSB, suggesting possible Y-linkage of the trait. Our results inform evolutionary genetic mechanisms that might maintain low but persistently observed levels of male SSB in D. melanogaster, but highlight a need for broader taxonomic representation in studies of its evolutionary causes. PMID- 26019161 TI - Behaviour in captivity predicts some aspects of natural behaviour, but not others, in a wild cricket population. AB - Examining the relevance of 'animal personality' involves linking consistent among and within-individual behavioural variation to fitness in the wild. Studies aiming to do this typically assay personality in captivity and rely on the assumption that measures of traits in the laboratory reflect their expression in nature. We examined this rarely tested assumption by comparing laboratory and field measurements of the behaviour of wild field crickets (Gryllus campestris) by continuously monitoring individual behaviour in nature, and repeatedly capturing the same individuals and measuring their behaviour in captivity. We focused on three traits that are frequently examined in personality studies: shyness, activity and exploration. All of them showed repeatability in the laboratory. Laboratory activity and exploration predicted the expression of their equivalent behaviours in the wild, but shyness did not. Traits in the wild were predictably influenced by environmental factors such as temperature and sunlight, but only activity showed appreciable within-individual repeatability. This suggests that some behaviours typically studied as personality traits can be accurately assayed in captivity, but the expression of others may be highly context-specific. Our results highlight the importance of validating the relevance of laboratory behavioural assays to analogous traits measured in the wild. PMID- 26019162 TI - Bony labyrinth morphometry indicates locomotor adaptations in the squirrel related clade (Rodentia, Mammalia). AB - The semicircular canals (SCs) of the inner ear detect angular acceleration and are located in the bony labyrinth of the petrosal bone. Based on high-resolution computed tomography, we created a size-independent database of the bony labyrinth of 50 mammalian species especially rodents of the squirrel-related clade comprising taxa with fossorial, arboreal and gliding adaptations. Our sampling also includes gliding marsupials, actively flying bats, the arboreal tree shrew and subterranean species. The morphometric anatomy of the SCs was correlated to the locomotion mode. Even if the phylogenetic signal cannot entirely be excluded, the main significance for functional morphological studies has been found in the diameter of the SCs, whereas the radius of curvature is of minor interest. Additionally, we found clear differences in the bias angle of the canals between subterranean and gliding taxa, but also between sciurids and glirids. The sensitivity of the inner ear correlates with the locomotion mode, with a higher sensitivity of the SCs in fossorial species than in flying taxa. We conclude that the inner ear of flying and gliding mammals is less sensitive due to the large information flow into this sense organ during locomotion. PMID- 26019163 TI - Alarmingly High Segregation Frequencies of Quinolone Resistance Alleles within Human and Animal Microbiomes Are Not Explained by Direct Clinical Antibiotic Exposure. AB - Antibiotic resistance poses a major threat to human health. It is therefore important to characterize the frequency of resistance within natural bacterial environments. Many studies have focused on characterizing the frequencies with which horizontally acquired resistance genes segregate within natural bacterial populations. Yet, very little is currently understood regarding the frequency of segregation of resistance alleles occurring within the housekeeping targets of antibiotics. We surveyed a large number of metagenomic datasets extracted from a large variety of host-associated and non host-associated environments for such alleles conferring resistance to three groups of broad spectrum antibiotics: streptomycin, rifamycins, and quinolones. We find notable segregation frequencies of resistance alleles occurring within the target genes of each of the three antibiotics, with quinolone resistance alleles being the most frequent and rifamycin resistance alleles being the least frequent. Resistance allele frequencies varied greatly between different phyla and as a function of environment. The frequency of quinolone resistance alleles was especially high within host-associated environments, where it averaged an alarming ~ 40%. Within host-associated environments, resistance to quinolones was most often conferred by a specific resistance allele. High frequencies of quinolone resistance alleles were also found within hosts that were not directly treated with antibiotics. Therefore, the high segregation frequency of quinolone resistance alleles occurring within the housekeeping targets of antibiotics in host-associated environments does not seem to be the sole result of clinical antibiotic usage. PMID- 26019164 TI - Complete Genome Sequence and Transcriptomic Analysis of the Novel Pathogen Elizabethkingia anophelis in Response to Oxidative Stress. AB - Elizabethkingia anophelis is an emerging pathogen that can cause life-threatening infections in neonates, severely immunocompromised and postoperative patients. The lack of genomic information on E. anophelis hinders our understanding of its mechanisms of pathogenesis. Here, we report the first complete genome sequence of E. anophelis NUHP1 and assess its response to oxidative stress. Elizabethkingia anophelis NUHP1 has a circular genome of 4,369,828 base pairs and 4,141 predicted coding sequences. Sequence analysis indicates that E. anophelis has well developed systems for scavenging iron and stress response. Many putative virulence factors and antibiotic resistance genes were identified, underscoring potential host-pathogen interactions and antibiotic resistance. RNA-sequencing based transcriptome profiling indicates that expressions of genes involved in synthesis of an yersiniabactin-like iron siderophore and heme utilization are highly induced as a protective mechanism toward oxidative stress caused by hydrogen peroxide treatment. Chrome azurol sulfonate assay verified that siderophore production of E. anophelis is increased in the presence of oxidative stress. We further showed that hemoglobin facilitates the growth, hydrogen peroxide tolerance, cell attachment, and biofilm formation of E. anophelis NUHP1. Our study suggests that siderophore production and heme uptake pathways might play essential roles in stress response and virulence of the emerging pathogen E. anophelis. PMID- 26019165 TI - As Clear as Mud? Determining the Diversity and Prevalence of Prophages in the Draft Genomes of Estuarine Isolates of Clostridium difficile. AB - The bacterium Clostridium difficile is a significant cause of nosocomial infections worldwide. The pathogenic success of this organism can be attributed to its flexible genome which is characterized by the exchange of mobile genetic elements, and by ongoing genome evolution. Despite its pathogenic status, C. difficile can also be carried asymptomatically, and has been isolated from natural environments such as water and sediments where multiple strain types (ribotypes) are found in close proximity. These include ribotypes which are associated with disease, as well as those that are less commonly isolated from patients. Little is known about the genomic content of strains in such reservoirs in the natural environment. In this study, draft genomes have been generated for 13 C. difficile isolates from estuarine sediments including clinically relevant and environmental associated types. To identify the genetic diversity within this strain collection, whole-genome comparisons were performed using the assemblies. The strains are highly genetically diverse with regards to the C. difficile "mobilome," which includes transposons and prophage elements. We identified a novel transposon-like element in two R078 isolates. Multiple, related and unrelated, prophages were detected in isolates across ribotype groups, including two novel prophage elements and those related to the transducing phage phiC2. The susceptibility of these isolates to lytic phage infection was tested using a panel of characterized phages found from the same locality. In conclusion, estuarine sediments are a source of genetically diverse C. difficile strains with a complex network of prophages, which could contribute to the emergence of new strains in clinics. PMID- 26019166 TI - Genome-Wide Search Identifies 1.9 Mb from the Polar Bear Y Chromosome for Evolutionary Analyses. AB - The male-inherited Y chromosome is the major haploid fraction of the mammalian genome, rendering Y-linked sequences an indispensable resource for evolutionary research. However, despite recent large-scale genome sequencing approaches, only a handful of Y chromosome sequences have been characterized to date, mainly in model organisms. Using polar bear (Ursus maritimus) genomes, we compare two different in silico approaches to identify Y-linked sequences: 1) Similarity to known Y-linked genes and 2) difference in the average read depth of autosomal versus sex chromosomal scaffolds. Specifically, we mapped available genomic sequencing short reads from a male and a female polar bear against the reference genome and identify 112 Y-chromosomal scaffolds with a combined length of 1.9 Mb. We verified the in silico findings for the longer polar bear scaffolds by male specific in vitro amplification, demonstrating the reliability of the average read depth approach. The obtained Y chromosome sequences contain protein-coding sequences, single nucleotide polymorphisms, microsatellites, and transposable elements that are useful for evolutionary studies. A high-resolution phylogeny of the polar bear patriline shows two highly divergent Y chromosome lineages, obtained from analysis of the identified Y scaffolds in 12 previously published male polar bear genomes. Moreover, we find evidence of gene conversion among ZFX and ZFY sequences in the giant panda lineage and in the ancestor of ursine and tremarctine bears. Thus, the identification of Y-linked scaffold sequences from unordered genome sequences yields valuable data to infer phylogenomic and population-genomic patterns in bears. PMID- 26019167 TI - A New Class of SINEs with snRNA Gene-Derived Heads. AB - Eukaryotic genomes are colonized by various transposons including short interspersed elements (SINEs). The 5' region (head) of the majority of SINEs is derived from one of the three types of RNA genes--7SL RNA, transfer RNA (tRNA), or 5S ribosomal RNA (rRNA)--and the internal promoter inside the head promotes the transcription of the entire SINEs. Here I report a new group of SINEs whose heads originate from either the U1 or U2 small nuclear RNA gene. These SINEs, named SINEU, are distributed among crocodilians and classified into three families. The structures of the SINEU-1 subfamilies indicate the recurrent addition of a U1- or U2-derived sequence onto the 5' end of SINEU-1 elements. SINEU-1 and SINEU-3 are ancient and shared among alligators, crocodiles, and gharials, while SINEU-2 is absent in the alligator genome. SINEU-2 is the only SINE family that was active after the split of crocodiles and gharials. All SINEU families, especially SINEU-3, are preferentially inserted into a family of Mariner DNA transposon, Mariner-N4_AMi. A group of Tx1 non-long terminal repeat retrotransposons designated Tx1-Mar also show target preference for Mariner N4_AMi, indicating that SINEU was mobilized by Tx1-Mar. PMID- 26019170 TI - Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer. AB - PURPOSE: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression and its regulation in NSCLC positive for the EML4-ALK fusion gene. EXPERIMENTAL DESIGN: The expression of PD L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis. RESULTS: The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNAi with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD L1 was positively associated with the presence of EML4-ALK in NSCLC specimens. CONCLUSIONS: Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression. PMID- 26019171 TI - MR-Guided Near-Infrared Spectral Tomography Increases Diagnostic Performance of Breast MRI. AB - PURPOSE: The purpose of this study was to determine the diagnostically most important molecular biomarkers quantified by magnetic resonance-guided (MR) near infrared spectral tomography (NIRST) that distinguish malignant breast lesions from benign abnormalities when combined with outcomes from clinical breast MRI. EXPERIMENTAL DESIGN: The study was HIPAA compliant and approved by the Dartmouth Institutional Review Board, the NIH, the United States State Department, and Xijing Hospital. MR-guided NIRST evaluated hemoglobin, water, and lipid content in regions of interest defined by concurrent dynamic contrast-enhanced MRI (DCE MRI) in the breast. MRI plus NIRST was performed in 44 subjects (median age, 46, age range, 20-81 years), 28 of whom had subsequent malignant pathologic diagnoses, and 16 had benign conditions. A subset of 30 subject examinations yielded optical data that met minimum sensitivity requirements to the suspicious lesion and were included in the analyses of diagnostic performance. RESULTS: In the subset of 30 subject examinations meeting minimum optical data sensitivity criterion, the MR-guided NIRST separated malignant from benign lesions using total hemoglobin (HbT; P < 0.01) and tissue optical index (TOI; P < 0.001). Combined MRI plus TOI data caused one false positive and 1 false negative, and produced the best diagnostic performance, yielding an AUC of 0.95, sensitivity of 95%, specificity of 89%, positive predictive value of 95%, and negative predictive value of 89%, respectively. CONCLUSIONS: MRI plus NIRST results correlated well with histopathologic diagnoses and could provide additional information to reduce the number of MRI-directed biopsies. PMID- 26019172 TI - Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models. AB - PURPOSE: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. EXPERIMENTAL DESIGN: We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. RESULTS: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and/or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. CONCLUSIONS: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab. PMID- 26019173 TI - Cancer Immunotherapy: More Is (Much) Better. AB - Although antibodies against EGFR and HER2 are used to treat cancer, only some patients respond and resistance often emerges. Jacobsen and colleagues present in this issue experimental evidence favoring replacement of the currently applied monoclonal antibodies with oligoclonal mixtures of six synergistic antibodies, simultaneously engaging EGFR, HER2, and also HER3. PMID- 26019174 TI - A localized nucleolar DNA damage response facilitates recruitment of the homology directed repair machinery independent of cell cycle stage. AB - DNA double-strand breaks (DSBs) are repaired by two main pathways: nonhomologous end-joining and homologous recombination (HR). Repair pathway choice is thought to be determined by cell cycle timing and chromatin context. Nucleoli, prominent nuclear subdomains and sites of ribosome biogenesis, form around nucleolar organizer regions (NORs) that contain rDNA arrays located on human acrocentric chromosome p-arms. Actively transcribed rDNA repeats are positioned within the interior of the nucleolus, whereas sequences proximal and distal to NORs are packaged as heterochromatin located at the nucleolar periphery. NORs provide an opportunity to investigate the DSB response at highly transcribed, repetitive, and essential loci. Targeted introduction of DSBs into rDNA, but not abutting sequences, results in ATM-dependent inhibition of their transcription by RNA polymerase I. This is coupled with movement of rDNA from the nucleolar interior to anchoring points at the periphery. Reorganization renders rDNA accessible to repair factors normally excluded from nucleoli. Importantly, DSBs within rDNA recruit the HR machinery throughout the cell cycle. Additionally, unscheduled DNA synthesis, consistent with HR at damaged NORs, can be observed in G1 cells. These results suggest that HR can be templated in cis and suggest a role for chromosomal context in the maintenance of NOR genomic stability. PMID- 26019168 TI - Mechanisms and ecological consequences of plant defence induction and suppression in herbivore communities. AB - BACKGROUND: Plants are hotbeds for parasites such as arthropod herbivores, which acquire nutrients and energy from their hosts in order to grow and reproduce. Hence plants are selected to evolve resistance, which in turn selects for herbivores that can cope with this resistance. To preserve their fitness when attacked by herbivores, plants can employ complex strategies that include reallocation of resources and the production of defensive metabolites and structures. Plant defences can be either prefabricated or be produced only upon attack. Those that are ready-made are referred to as constitutive defences. Some constitutive defences are operational at any time while others require activation. Defences produced only when herbivores are present are referred to as induced defences. These can be established via de novo biosynthesis of defensive substances or via modifications of prefabricated substances and consequently these are active only when needed. Inducibility of defence may serve to save energy and to prevent self-intoxication but also implies that there is a delay in these defences becoming operational. Induced defences can be characterized by alterations in plant morphology and molecular chemistry and are associated with a decrease in herbivore performance. These alterations are set in motion by signals generated by herbivores. Finally, a subset of induced metabolites are released into the air as volatiles and function as a beacon for foraging natural enemies searching for prey, and this is referred to as induced indirect defence. SCOPE: The objective of this review is to evaluate (1) which strategies plants have evolved to cope with herbivores and (2) which traits herbivores have evolved that enable them to counter these defences. The primary focus is on the induction and suppression of plant defences and the review outlines how the palette of traits that determine induction/suppression of, and resistance/susceptibility of herbivores to, plant defences can give rise to exploitative competition and facilitation within ecological communities "inhabiting" a plant. CONCLUSIONS: Herbivores have evolved diverse strategies, which are not mutually exclusive, to decrease the negative effects of plant defences in order to maximize the conversion of plant material into offspring. Numerous adaptations have been found in herbivores, enabling them to dismantle or bypass defensive barriers, to avoid tissues with relatively high levels of defensive chemicals or to metabolize these chemicals once ingested. In addition, some herbivores interfere with the onset or completion of induced plant defences, resulting in the plant's resistance being partly or fully suppressed. The ability to suppress induced plant defences appears to occur across plant parasites from different kingdoms, including herbivorous arthropods, and there is remarkable diversity in suppression mechanisms. Suppression may strongly affect the structure of the food web, because the ability to suppress the activation of defences of a communal host may facilitate competitors, whereas the ability of a herbivore to cope with activated plant defences will not. Further characterization of the mechanisms and traits that give rise to suppression of plant defences will enable us to determine their role in shaping direct and indirect interactions in food webs and the extent to which these determine the coexistence and persistence of species. PMID- 26019176 TI - RNAiFold 2.0: a web server and software to design custom and Rfam-based RNA molecules. AB - Several algorithms for RNA inverse folding have been used to design synthetic riboswitches, ribozymes and thermoswitches, whose activity has been experimentally validated. The RNAiFold software is unique among approaches for inverse folding in that (exhaustive) constraint programming is used instead of heuristic methods. For that reason, RNAiFold can generate all sequences that fold into the target structure or determine that there is no solution. RNAiFold 2.0 is a complete overhaul of RNAiFold 1.0, rewritten from the now defunct COMET language to C++. The new code properly extends the capabilities of its predecessor by providing a user-friendly pipeline to design synthetic constructs having the functionality of given Rfam families. In addition, the new software supports amino acid constraints, even for proteins translated in different reading frames from overlapping coding sequences; moreover, structure compatibility/incompatibility constraints have been expanded. With these features, RNAiFold 2.0 allows the user to design single RNA molecules as well as hybridization complexes of two RNA molecules. AVAILABILITY: the web server, source code and linux binaries are publicly accessible at http://bioinformatics.bc.edu/clotelab/RNAiFold2.0. PMID- 26019175 TI - PDGFRalpha signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. AB - Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRalpha signaling in perivascular cells causes them to transition into ECM synthesizing profibrotic cells. Before this transition occurs, PDGFRalpha signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP(+) cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFRalpha signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFRalpha targets progenitor cell plasticity as a profibrotic mechanism. PMID- 26019177 TI - INGA: protein function prediction combining interaction networks, domain assignments and sequence similarity. AB - Identifying protein functions can be useful for numerous applications in biology. The prediction of gene ontology (GO) functional terms from sequence remains however a challenging task, as shown by the recent CAFA experiments. Here we present INGA, a web server developed to predict protein function from a combination of three orthogonal approaches. Sequence similarity and domain architecture searches are combined with protein-protein interaction network data to derive consensus predictions for GO terms using functional enrichment. The INGA server can be queried both programmatically through RESTful services and through a web interface designed for usability. The latter provides output supporting the GO term predictions with the annotating sequences. INGA is validated on the CAFA-1 data set and was recently shown to perform consistently well in the CAFA-2 blind test. The INGA web server is available from URL: http://protein.bio.unipd.it/inga. PMID- 26019179 TI - sRNAtoolbox: an integrated collection of small RNA research tools. AB - Small RNA research is a rapidly growing field. Apart from microRNAs, which are important regulators of gene expression, other types of functional small RNA molecules have been reported in animals and plants. MicroRNAs are important in host-microbe interactions and parasite microRNAs might modulate the innate immunity of the host. Furthermore, small RNAs can be detected in bodily fluids making them attractive non-invasive biomarker candidates. Given the general broad interest in small RNAs, and in particular microRNAs, a large number of bioinformatics aided analysis types are needed by the scientific community. To facilitate integrated sRNA research, we developed sRNAtoolbox, a set of independent but interconnected tools for expression profiling from high throughput sequencing data, consensus differential expression, target gene prediction, visual exploration in a genome context as a function of read length, gene list analysis and blast search of unmapped reads. All tools can be used independently or for the exploration and downstream analysis of sRNAbench results. Workflows like the prediction of consensus target genes of parasite microRNAs in the host followed by the detection of enriched pathways can be easily established. The web-interface interconnecting all these tools is available at http://bioinfo5.ugr.es/srnatoolbox. PMID- 26019178 TI - Multivalent ion-mediated nucleic acid helix-helix interactions: RNA versus DNA. AB - Ion-mediated interaction is critical to the structure and stability of nucleic acids. Recent experiments suggest that the multivalent ion-induced aggregation of double-stranded (ds) RNAs and DNAs may strongly depend on the topological nature of helices, while there is still lack of an understanding on the relevant ion mediated interactions at atomistic level. In this work, we have directly calculated the potentials of mean force (PMF) between two dsRNAs and between two dsDNAs in Co(NH3)6 (3+) (Co-Hex) solutions by the atomistic molecular dynamics simulations. Our calculations show that at low [Co-Hex], the PMFs between B-DNAs and between A-RNAs are both (strongly) repulsive. However, at high [Co-Hex], the PMF between B-DNAs is strongly attractive, while those between A-RNAs and between A-DNAs are still (weakly) repulsive. The microscopic analyses show that for A form helices, Co-Hex would become 'internal binding' into the deep major groove and consequently cannot form the evident ion-bridge between adjacent helices, while for B-form helices without deep grooves, Co-Hex would exhibit 'external binding' to strongly bridge adjacent helices. In addition, our further calculations show that, the PMF between A-RNAs could become strongly attractive either at very high [Co-Hex] or when the bottom of deep major groove is fixed with a layer of water. PMID- 26019180 TI - Bacteriophage strain typing by rapid single molecule analysis. AB - Rapid characterization of unknown biological samples is under the focus of many current studies. Here we report a method for screening of biological samples by optical mapping of their DNA. We use a novel, one-step chemo-enzymatic reaction to covalently bind fluorophores to DNA at the four-base recognition sites of a DNA methyltransferase. Due to the diffraction limit of light, the dense distribution of labels results in a continuous fluorescent signal along the DNA. The amplitude modulations (AM) of the fluorescence intensity along the stretched DNA molecules exhibit a unique molecular fingerprint that can be used for identification. We show that this labelling scheme is highly informative, allowing accurate genotyping. We demonstrate the method by labelling the genomes of lambda and T7 bacteriophages, resulting in a consistent, unique AM profile for each genome. These profiles are also successfully used for identification of the phages from a background phage library. Our method may provide a facile route for screening and typing of various organisms and has potential applications in metagenomics studies of various ecosystems. PMID- 26019181 TI - Caffeine inhibits gene conversion by displacing Rad51 from ssDNA. AB - Efficient repair of chromosomal double-strand breaks (DSBs) by homologous recombination relies on the formation of a Rad51 recombinase filament that forms on single-stranded DNA (ssDNA) created at DSB ends. This filament facilitates the search for a homologous donor sequence and promotes strand invasion. Recently caffeine treatment has been shown to prevent gene targeting in mammalian cells by increasing non-productive Rad51 interactions between the DSB and random regions of the genome. Here we show that caffeine treatment prevents gene conversion in yeast, independently of its inhibition of the Mec1(ATR)/Tel1(ATM)-dependent DNA damage response or caffeine's inhibition of 5' to 3' resection of DSB ends. Caffeine treatment results in a dosage-dependent eviction of Rad51 from ssDNA. Gene conversion is impaired even at low concentrations of caffeine, where there is no discernible dismantling of the Rad51 filament. Loss of the Rad51 filament integrity is independent of Srs2's Rad51 filament dismantling activity or Rad51's ATPase activity and does not depend on non-specific Rad51 binding to undamaged double-stranded DNA. Caffeine treatment had similar effects on irradiated HeLa cells, promoting loss of previously assembled Rad51 foci. We conclude that caffeine treatment can disrupt gene conversion by disrupting Rad51 filaments. PMID- 26019183 TI - Controlled Cannabis Vaporizer Administration: Blood and Plasma Cannabinoids with and without Alcohol. AB - BACKGROUND: Increased medical and legal cannabis intake is accompanied by greater use of cannabis vaporization and more cases of driving under the influence of cannabis. Although simultaneous Delta(9)-tetrahydrocannabinol (THC) and alcohol use is frequent, potential pharmacokinetic interactions are poorly understood. Here we studied blood and plasma vaporized cannabinoid disposition, with and without simultaneous oral low-dose alcohol. METHODS: Thirty-two adult cannabis smokers (>=1 time/3 months, <=3 days/week) drank placebo or low-dose alcohol (target approximately 0.065% peak breath-alcohol concentration) 10 min before inhaling 500 mg placebo, low-dose (2.9%) THC, or high-dose (6.7%) THC vaporized cannabis (6 within-individual alcohol-cannabis combinations). Blood and plasma were obtained before and up to 8.3 h after ingestion. RESULTS: Nineteen participants completed all sessions. Median (range) maximum blood concentrations (Cmax) for low and high THC doses (no alcohol) were 32.7 (11.4-66.2) and 42.2 (15.2-137) MUg/L THC, respectively, and 2.8 (0-9.1) and 5.0 (0-14.2) MUg/L 11-OH THC. With alcohol, low and high dose Cmax values were 35.3 (13.0-71.4) and 67.5 (18.1-210) MUg/L THC and 3.7 (1.4-6.0) and 6.0 (0-23.3) MUg/L 11-OH-THC, significantly higher than without alcohol. With a THC detection cutoff of >=1 MUg/L, >=16.7% of participants remained positive 8.3 h postdose, whereas <=21.1% were positive by 2.3 h with a cutoff of >=5 MUg/L. CONCLUSIONS: Vaporization is an effective THC delivery route. The significantly higher blood THC and 11-OH-THC Cmax values with alcohol possibly explain increased performance impairment observed from cannabis-alcohol combinations. Chosen driving-related THC cutoffs should be considered carefully to best reflect performance impairment windows. Our results will help facilitate forensic interpretation and inform the debate on drugged driving legislation. PMID- 26019182 TI - Caffeine impairs resection during DNA break repair by reducing the levels of nucleases Sae2 and Dna2. AB - In response to chromosomal double-strand breaks (DSBs), eukaryotic cells activate the DNA damage checkpoint, which is orchestrated by the PI3 kinase-like protein kinases ATR and ATM (Mec1 and Tel1 in budding yeast). Following DSB formation, Mec1 and Tel1 phosphorylate histone H2A on serine 129 (known as gamma-H2AX). We used caffeine to inhibit the checkpoint kinases after DSB induction. We show that prolonged phosphorylation of H2A-S129 does not require continuous Mec1 and Tel1 activity. Unexpectedly, caffeine treatment impaired homologous recombination by inhibiting 5' to 3' end resection, independent of Mec1 and Tel1 inhibition. Caffeine treatment led to the rapid loss, by proteasomal degradation, of both Sae2, a nuclease that plays a role in early steps of resection, and Dna2, a nuclease that facilitates one of two extensive resection pathways. Sae2's instability is evident in the absence of DNA damage. A similar loss is seen when protein synthesis is inhibited by cycloheximide. Caffeine treatment had similar effects on irradiated HeLa cells, blocking the formation of RPA and Rad51 foci that depend on 5' to 3' resection of broken chromosome ends. Our findings provide insight toward the use of caffeine as a DNA damage-sensitizing agent in cancer cells. PMID- 26019184 TI - Human Aging Is a Metabolome-related Matter of Gender. AB - A molecular description of the mechanisms by which aging is produced is still very limited. Here, we have determined the plasma metabolite profile by using high-throughput metabolome profiling technologies of 150 healthy humans ranging from 30 to 100 years of age. Using a nontargeted approach, we detected 2,678 metabolite species in plasma, and the multivariate analyses separated perfectly two groups indicating a specific signature for each gender. In addition, there is a set of gender-shared metabolites, which change significantly during aging with a similar tendency. Among the identified molecules, we found vitamin D2-related compound, phosphoserine (40:5), monoacylglyceride (22:1), diacylglyceride (33:2), and resolvin D6, all of them decreasing with the aging process. Finally, we found three molecules that directly correlate with age and seven that inversely correlate with age, independently of gender. Among the identified molecules (6 of 10 according to exact mass and retention time), we found a proteolytic product (l gamma-glutamyl-l-leucine), which increased with age. On the contrary, a hydroxyl fatty acid (25-hydroxy-hexacosanoic), a polyunsaturated fatty acid (eicosapentaenoic acid), two phospholipids (phosphocholine [42:9]and phosphoserine [42:3]) and a prostaglandin (15-keto-prostaglandin F2alpha) decreased with aging. These results suggest that lipid species and their metabolism are closely linked to the aging process. PMID- 26019185 TI - Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. AB - BACKGROUND: This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma. METHODS: Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d.), in combination with 200 mg/m(2) TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m(2) TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response. RESULTS: The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade >=3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%. CONCLUSIONS: Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition. PMID- 26019186 TI - Sinus thrombectomy for purulent cerebral venous sinus thrombosis utilizing a novel combination of the Trevo stent retriever and the Penumbra ACE aspiration catheter: the stent anchor with mobile aspiration technique. AB - Intracranial complications of sinusitis are rare but life threatening. We present a case of a 17-year-old woman with sinusitis who deteriorated over the course of 12 days from subdural empyema and global purulent cerebral venous sinus thrombosis. The patient was managed with surgery and mechanical thrombectomy utilizing a novel 'stent anchor with mobile aspiration technique', in which a Trevo stent retriever (Stryker) was anchored in the superior sagittal sinus (SSS) while a 5 MAX ACE reperfusion catheter (Penumbra) was passed back and forth from the SSS to the sigmoid sinus with resultant dramatic improvement in venous outflow. The patient was extubated on postoperative day 3 and was discharged with minimal lower extremity weakness on postoperative day 11. This is the first report using the Trevo stent retriever for sinus thrombosis. It is important to keep these rare complications in mind when evaluating patients with oral and facial infections. PMID- 26019187 TI - Accuracy of Predicted Genomic Breeding Values in Purebred and Crossbred Pigs. AB - Genomic selection has been widely implemented in dairy cattle breeding when the aim is to improve performance of purebred animals. In pigs, however, the final product is a crossbred animal. This may affect the efficiency of methods that are currently implemented for dairy cattle. Therefore, the objective of this study was to determine the accuracy of predicted breeding values in crossbred pigs using purebred genomic and phenotypic data. A second objective was to compare the predictive ability of SNPs when training is done in either single or multiple populations for four traits: age at first insemination (AFI); total number of piglets born (TNB); litter birth weight (LBW); and litter variation (LVR). We performed marker-based and pedigree-based predictions. Within-population predictions for the four traits ranged from 0.21 to 0.72. Multi-population prediction yielded accuracies ranging from 0.18 to 0.67. Predictions across purebred populations as well as predicting genetic merit of crossbreds from their purebred parental lines for AFI performed poorly (not significantly different from zero). In contrast, accuracies of across-population predictions and accuracies of purebred to crossbred predictions for LBW and LVR ranged from 0.08 to 0.31 and 0.11 to 0.31, respectively. Accuracy for TNB was zero for across population prediction, whereas for purebred to crossbred prediction it ranged from 0.08 to 0.22. In general, marker-based outperformed pedigree-based prediction across populations and traits. However, in some cases pedigree-based prediction performed similarly or outperformed marker-based prediction. There was predictive ability when purebred populations were used to predict crossbred genetic merit using an additive model in the populations studied. AFI was the only exception, indicating that predictive ability depends largely on the genetic correlation between PB and CB performance, which was 0.31 for AFI. Multi population prediction was no better than within-population prediction for the purebred validation set. Accuracy of prediction was very trait-dependent. PMID- 26019188 TI - The Wukong Terminal-Repeat Retrotransposon in Miniature (TRIM) Elements in Diverse Maize Germplasm. AB - TRIMs (terminal-repeat retrotransposons in miniature), which are characterized by their small size, have been discovered in all investigated vascular plants and even in animals. Here, we identified a highly conservative TRIM family referred to as Wukong elements in the maize genome. The Wukong family shows a distinct pattern of tandem arrangement in the maize genome suggesting a high rate of unequal crossing over. Estimation of insertion times implies a burst of retrotransposition activity of the Wukong family after the allotetraploidization of maize. Using next-generation sequencing data, we detected 87 new Wukong insertions in parents of the maize NAM population relative to the B73 reference genome and found abundant insertion polymorphism of Wukong elements in 75 re sequenced maize lines, including teosinte, landraces, and improved lines. These results suggest that Wukong elements possessed a persistent retrotransposition activity throughout maize evolution. Moreover, the phylogenetic relationships among 76 maize inbreds and their relatives based on insertion polymorphisms of Wukong elements should provide us with reliable molecular markers for biodiversity and genetics studies. PMID- 26019190 TI - Effect of comorbidity on mortality in multiple sclerosis. AB - OBJECTIVE: We aimed to compare survival in the multiple sclerosis (MS) population with a matched cohort from the general population, and to evaluate the association of comorbidity with survival in both populations. METHODS: Using population-based administrative data, we identified 5,797 persons with MS and 28,807 controls matched on sex, year of birth, and region. We estimated annual mortality rates. Using Cox proportional hazards regression, we evaluated the association between comorbidity status and mortality, stratifying by birth cohort, and adjusting for sex, socioeconomic status, and region. We compared causes of death between populations. RESULTS: Median survival from birth in the MS population was 75.9 years vs 83.4 years in the matched population. MS was associated with a 2-fold increased risk of death (adjusted hazard ratio 2.40; 95% confidence interval: 2.24-2.58). Several comorbidities were associated with increased hazard of death in both populations, including diabetes, ischemic heart disease, depression, anxiety, and chronic lung disease. The magnitude of the associations of mortality with chronic lung disease, diabetes, hypertension, and ischemic heart disease was lower in the MS population than the matched population. The most common causes of death in the MS population were diseases of the nervous system and diseases of the circulatory system. Mortality rates due to infectious diseases and diseases of the respiratory system were higher in the MS population. CONCLUSION: In the MS population, survival remained shorter than expected. Within the MS population, comorbidity was associated with increased mortality risk. However, comorbidity did not preferentially increase mortality risk in the MS population as compared with controls. PMID- 26019189 TI - Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. AB - Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials. PMID- 26019191 TI - Longitudinal patient-oriented outcomes in neuropathy: Importance of early detection and falls. AB - OBJECTIVE: To evaluate longitudinal patient-oriented outcomes in peripheral neuropathy over a 14-year time period including time before and after diagnosis. METHODS: The 1996-2007 Health and Retirement Study (HRS)-Medicare Claims linked database identified incident peripheral neuropathy cases (ICD-9 codes) in patients >=65 years. Using detailed demographic information from the HRS and Medicare claims, a propensity score method identified a matched control group without neuropathy. Patient-oriented outcomes, with an emphasis on self-reported falls, pain, and self-rated health (HRS interview), were determined before and after neuropathy diagnosis. Generalized estimating equations were used to assess differences in longitudinal outcomes between cases and controls. RESULTS: We identified 953 peripheral neuropathy cases and 953 propensity-matched controls. The mean (SD) age was 77.4 (6.7) years for cases, 76.9 (6.6) years for controls, and 42.1% had diabetes. Differences were detected in falls 3.0 years before neuropathy diagnosis (case vs control; 32% vs 25%, p = 0.008), 5.0 years for pain (36% vs 27%, p = 0.002), and 5.0 years for good to excellent self-rated health (61% vs 74%, p < 0.0001). Over time, the proportion of fallers increased more rapidly in neuropathy cases compared to controls (p = 0.002), but no differences in pain (p = 0.08) or self-rated health (p = 0.9) were observed. CONCLUSIONS: In older persons, differences in falls, pain, and self-rated health can be detected 3-5 years prior to peripheral neuropathy diagnosis, but only falls deteriorates more rapidly over time in neuropathy cases compared to controls. Interventions to improve early peripheral neuropathy detection are needed, and future clinical trials should incorporate falls as a key patient-oriented outcome. PMID- 26019192 TI - B cell signature contributes to the prediction of RA development in patients with arthralgia. PMID- 26019193 TI - Evaluation of BD Max StaphSR and BD Max MRSAXT Assays Using ESwab-Collected Specimens. AB - The BD Max MRSAXT and the BD Max StaphSR assays were validated for the detection of methicillin-resistant Staphylococcus aureus (MRSA) in ESwab samples. In addition, the BD Max StaphSR assay was evaluated for its ability to detect and differentiate S. aureus and MRSA in the same sample. A total of 255 ESwab samples collected from the anterior nares of patients were tested by each of three BD Max assays, including the BD Max MRSA first-generation assay. The results were compared to those of direct and enrichment culture. Additionally, a challenge panel comprising 14 control strains was evaluated to determine the ability of these assays to correctly identify MRSA and also appropriately differentiate S. aureus by the BD Max StaphSR assay. Out of 255 clinical samples tested, 161 were negative and 30 were positive for MRSA, and 45 were positive for S. aureus (by BD Max StaphSR) and negative for MRSA by all three PCR assays and culture. Nineteen samples had discrepant results; all of them were retested by additional laboratory testing. All strains from the challenge panel were correctly identified or excluded by the BD Max MRSAXT and BD Max StaphSR assays. The results showed that the BD Max StaphSR and the BD MRSAXT assays have excellent sensitivity (94.3%) and specificity (97.7%) for detecting MRSA. The BD Max StaphSR assay demonstrated excellent sensitivity (96.4%) and specificity (93.6%) for detecting S. aureus. PMID- 26019194 TI - Analysis of Vancomycin Susceptibility Testing Results for Presumptive Categorization of Telavancin. AB - Scattergrams between vancomycin and telavancin demonstrated susceptibility agreement rates of 99.96, 99.65, and 100.00% for Staphylococcus aureus, Enterococcus faecalis, and streptococci, respectively. A single very major error was obtained against E. faecalis, while vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant and teicoplanin-susceptible (VanB phenotype) E. faecalis were responsible for major and minor errors. These results support the use of vancomycin to infer telavancin susceptibility among indicated pathogens, except VISA, which should be tested for telavancin susceptibility. PMID- 26019195 TI - Rapid Detection of KPC, NDM, and OXA-48-Like Carbapenemases by Real-Time PCR from Rectal Swab Surveillance Samples. AB - We describe a multiplex real-time PCR assay for use on the ABI 7500 Fast TaqMan platform to detect all currently described Klebsiella pneumoniae carbapenemases (KPC), New Delhi metallo-beta-lactamases (NDM), and the OXA-48-like family of carbapenemases from bacterial culture lysates or sample enrichment broth lysates. PMID- 26019196 TI - First Case of Human Cerebral Taenia martis Cysticercosis. AB - Taenia martis is a tapeworm affecting mustelids, with rodents serving as intermediate hosts. The larval stage (cysticercus) has been found before only rarely in humans or primates. We hereby describe a case of cerebral T. martis cysticercosis in a French immunocompetent patient, confirmed by DNA analyses of biopsy material. PMID- 26019197 TI - Rapid High-Resolution Melt Analysis of Cytauxzoon felis Cytochrome b To Aid in the Prognosis of Cytauxzoonosis. AB - Cytauxzoon felis is a virulent, tick-transmitted, protozoan parasite that infects felines. Cytauxzoonosis was previously thought to be uniformly fatal in domestic cats. Treatment combining atovaquone and azithromycin (A&A) has been associated with survival rates of over 60%. Atovaquone, a ubiquinone analogue, targets C. felis cytochrome b (cytb), of which 30 unique genotypes have been identified. The C. felis cytb genotype cytb1 is associated with increased survival rates in cats treated with A&A. The purpose of this study was to design a PCR panel that could distinguish C. felis cytb1 from other cytochrome b genotypes. Primer pairs were designed to span five different nucleotide positions at which single-nucleotide polymorphisms in the C. felis cytb gene had been identified. Through the use of high-resolution melt analysis, this panel was predicted to distinguish cytb1 from other cytb genotypes. Assays were validated using samples from 69 cats with cytauxzoonosis for which the C. felis cytb genotypes had been characterized previously. The PCR panel identified C. felis cytb1 with 100% sensitivity and 98.2% specificity. High-resolution melt analysis can rapidly provide prognostic information for clients considering A&A treatment in cats with cytauxzoonosis. PMID- 26019198 TI - Application of Multiplex PCR Coupled with Matrix-Assisted Laser Desorption Ionization-Time of Flight Analysis for Simultaneous Detection of 21 Common Respiratory Viruses. AB - Respiratory infections continue to pose a significant threat to human health. It is important to accurately and rapidly detect respiratory viruses. To compensate for the limits of current respiratory virus detection methods, we developed a 24 plex analysis (common respiratory virus-mass spectrometry [CRV-MS]) that can simultaneously detect and identify 21 common respiratory viruses based on a matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry system. To evaluate the efficacy of the CRV-MS method, we used 102 samples that were confirmed positive for these common respiratory viruses. All tests using the CRV-MS method were effective, with no cross-reactivity observed with other common respiratory viruses. To confirm the usefulness of the CRV-MS method, we screened 336 nasal and throat swabs that were collected from adults or children with suspected viral acute respiratory tract infections using the CRV-MS method and consensus PCR/reverse transcription-PCR (RT-PCR) methods. Excluding four RNase P-negative samples, the CRV-MS and consensus PCR/RT-PCR methods detected respiratory viruses in 92.5% (307/332) and 89.5% (297/332) of the samples, respectively. The two methods yielded identical results for 306 (92.2%) samples, including negative results for 25 samples (7.5%) and positive results for 281 samples (84.6%). Differences between the two methods may reflect their different sensitivities. The CRV-MS method proved to be sensitive and robust, and it can be used in large-scale epidemiological studies of common respiratory virus infections. PMID- 26019199 TI - Clinical and Analytical Evaluation of a Single-Vial Stool Collection Device with Formalin-Free Fixative for Improved Processing and Comprehensive Detection of Gastrointestinal Parasites. AB - Microscopic examination of feces is a standard laboratory method for diagnosing gastrointestinal parasite infections. In North America, the ovum and parasite (O&P) examination is typically performed using stool that is chemically fixed in polyvinyl alcohol (PVA) and formalin, after which the stool is concentrated by filtration to enhance sensitivity. Mini Parasep solvent-free (SF) tubes allow collection and concentration within a single collection vial. The goal of the study was to determine whether consolidated processing and concentration with the Parasep tubes using an alcohol-based fixative (Alcorfix) provide O&P examinations equivalent to or better than those done by processing of PVA-formalin-fixed stool using a SpinCon concentration device. Parasep tubes revealed filtration performance equivalent to that of the SpinCon concentration device using PVA formalin-fixed stool containing protozoa. Specimens cocollected in Parasep tubes containing PVA-formalin and Alcorfix revealed comparable morphology and staining for various protozoa. Alcorfix effectively fixed live Cryptosporidium and microsporidia such that morphology and staining were conserved for modified acid fast and modified trichrome stains. A work flow analysis revealed significant time savings for batches of 10 or 30 O&P specimens in tubes with Alcorfix compared to the amount of time that it took to analyze the same number of specimens in tubes with PVA-formalin. The direct hands-on time savings with Mini Parasep tubes were 17 min and 41 s and 32 min and 1 s for batches of 10 and 30 specimens, respectively. Parasep tubes containing Alcorfix provide significant work flow advantages to laboratories that process medium to high volumes of O&P specimens by streamlining processing and converting to a single tube. These improvements in work flow, reduction of the amount of formalin used in the laboratory, and equivalent microscopy results are attractive advancements in O&P testing for North American diagnostic parasitology laboratories. PMID- 26019200 TI - Evaluation of the FilmArray Blood Culture ID Panel on Biofilms Dislodged from Explanted Arthroplasties for Prosthetic Joint Infection Diagnosis. PMID- 26019201 TI - Defining the Core Genome of Salmonella enterica Serovar Typhimurium for Genomic Surveillance and Epidemiological Typing. AB - Salmonella enterica serovar Typhimurium is the most common Salmonella serovar causing foodborne infections in Australia and many other countries. Twenty-one S. Typhimurium strains from Salmonella reference collection A (SARA) were analyzed using Illumina high-throughput genome sequencing. Single nucleotide polymorphisms (SNPs) in 21 SARA strains ranged from 46 to 11,916 SNPs, with an average of 1,577 SNPs per strain. Together with 47 strains selected from publicly available S. Typhimurium genomes, the S. Typhimurium core genes (STCG) were determined. The STCG consist of 3,846 genes, a set that is much larger than that of the 2,882 Salmonella core genes (SCG) found previously. The STCG together with 1,576 core intergenic regions (IGRs) were defined as the S. Typhimurium core genome. Using 93 S. Typhimurium genomes from 13 epidemiologically confirmed community outbreaks, we demonstrated that typing based on the S. Typhimurium core genome (STCG plus core IGRs) provides superior resolution and higher discriminatory power than that based on SCG for outbreak investigation and molecular epidemiology of S. Typhimurium. STCG and STCG plus core IGR typing achieved 100% separation of all outbreaks compared to that of SCG typing, which failed to separate isolates from two outbreaks from background isolates. Defining the S. Typhimurium core genome allows standardization of genes/regions to be used for high-resolution epidemiological typing and genomic surveillance of S. Typhimurium. PMID- 26019202 TI - Pediatric Staphylococcus aureus Isolate Genotypes and Infections from the Dawn of the Community-Associated Methicillin-Resistant S. aureus Epidemic Era in Chicago, 1994 to 1997. AB - Widespread infections with community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) have occurred in the United States with the dissemination of the USA300 strain beginning in 2000. We examined 105 isolates obtained from children treated at the University of Chicago from 1994 to 1997 (75 methicillin-susceptible S. aureus [MSSA] and 30 MRSA isolates) in order to investigate for possible evidence of USA300 during this period. Infections were defined epidemiologically based on medical record review. The isolates underwent multilocus sequence typing (MLST), as well as assays for the Panton-Valentine leukocidin (PVL) genes, the protein A gene (spa), and arcA and opp3, proxy markers for the arginine catabolic mobile element (ACME), characteristic of USA300 MRSA. MRSA isolates also underwent staphylococcal cassette chromosome mec (SCCmec) typing and pulsed-field gel electrophoresis (PFGE) subtyping. MSSA isolates belonged to 17 sequence type (ST) groups. The 12 epidemiologically defined CA-MRSA infection isolates were either ST1 (n = 4) or ST8 (n = 8). They belonged to 3 different PFGE types: USA100 (n = 1), USA400 (n = 5), and USA500 (n = 6). Among the CA-MRSA infection isolates, 8 (67%) were PVL(+). None of the MRSA or MSSA isolates contained arcA or opp3. Only one MRSA isolate was USA300 by PFGE. This was a health care-associated (HA) MRSA isolate, negative for PVL, that carried SCCmec type II. USA300 with its characteristic features was not identified in the collection from the years 1994 to 1997. PMID- 26019203 TI - Direct DNA Extraction from Mycobacterium tuberculosis Frozen Stocks as a Reculture-Independent Approach to Whole-Genome Sequencing. AB - Culturing before DNA extraction represents a major time-consuming step in whole genome sequencing of slow-growing bacteria, such as Mycobacterium tuberculosis. We report a workflow to extract DNA from frozen isolates without reculturing. Prepared libraries and sequence data were comparable with results from recultured aliquots of the same stocks. PMID- 26019204 TI - Testing Pooled Sputum with Xpert MTB/RIF for Diagnosis of Pulmonary Tuberculosis To Increase Affordability in Low-Income Countries. AB - Tuberculosis (TB) is a global public health problem, with the highest burden occurring in low-income countries. In these countries, the use of more sensitive diagnostics, such as Xpert MTB/RIF (Xpert), is still limited by costs. A cost saving strategy to diagnose other diseases is to pool samples from various individuals and test them with single tests. The samples in positive pool samples are then retested individually to identify the patients with the disease. We assessed a pooled testing strategy to optimize the affordability of Xpert for the diagnosis of TB. Adults with presumptive TB attending hospitals or identified by canvassing of households in Abuja, Nigeria, were asked to provide sputum for individual and pooled (4 per pool) testing. The agreement of the results of testing of individual and pooled samples and costs were assessed. A total of 738 individuals submitted samples, with 115 (16%) being Mycobacterium tuberculosis positive. Valid Xpert results for individual and pooled samples were available for 718 specimens. Of these, testing of pooled samples detected 109 (96%) of 114 individual M. tuberculosis-positive samples, with the overall agreement being 99%. Xpert semiquantitative M. tuberculosis levels had a positive correlation with the smear grades, and the individual sample-positive/pooled sample-negative results were likely due to the M. tuberculosis concentration being below the detection limit. The strategy reduced cartridge costs by 31%. Savings were higher with samples from individuals recruited in the community, where the proportion of positive specimens was low. The results of testing of pooled samples had a high level of agreement with the results of testing of individual samples, and use of the pooled testing strategy reduced costs and has the potential to increase the affordability of Xpert in countries with limited resources. PMID- 26019205 TI - Fatal Case of Polymicrobial Meningitis Caused by Cryptococcus liquefaciens and Mycobacterium tuberculosis Complex in a Human Immunodeficiency Virus-Infected Patient. AB - We describe a fatal case of polymicrobial meningitis in a human immunodeficiency virus-infected patient from Guatemala caused by Cryptococcus liquefaciens and Mycobacterium tuberculosis complex. Central nervous system infections caused concurrently by these species are extremely rare. This is also the first report of disseminated disease caused by C. liquefaciens. PMID- 26019206 TI - Clinical and Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus in a Neonatal Intensive Care Unit in the Decade following Implementation of an Active Detection and Isolation Program. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent source of infection in the neonatal intensive care unit (NICU), often associated with significant morbidity. Active detection and isolation (ADI) programs aim to reduce transmission. We describe a comprehensive analysis of the clinical and molecular epidemiology of MRSA in an NICU between 2003 and 2013, in the decade following the implementation of an MRSA ADI program. Molecular analyses included strain typing by pulsed-field gel electrophoresis, mec and accessory gene regulator group genotyping by multiplex PCR, and identification of toxin and potential virulence factor genes via PCR-based assays. Of 8,387 neonates, 115 (1.4%) had MRSA colonization and/or infection. The MRSA colonization rate declined significantly during the study period from 2.2 to 0.5/1,000 patient days (linear time, P = 0.0003; quadratic time, P = 0.006). There were 19 cases of MRSA infection (16.5%). Few epidemiologic or clinical differences were identified between MRSA-colonized and MRSA-infected infants. Thirty-one different strains of MRSA were identified with a shift from hospital-associated to combined hospital- and community-associated strains over time. Panton-Valentine leukocidin-positive USA300 strains caused 5 of the last 11 infections. Staphylococcal cassette chromosome mec (SCCmec) types II and IVa and agr groups 1 and 2 were most predominant. One isolate possessed the gene for toxic shock syndrome toxin; none had genes for exfoliative toxin A or B. These results highlight recent trends in MRSA colonization and infection and the corresponding changes in molecular epidemiology. Continued vigilance for this invasive pathogen remains critical, and specific attention to the unique host, the neonate, and the distinct environment, the NICU, is imperative. PMID- 26019207 TI - Rapid, Sensitive, and Specific Escherichia coli H Antigen Typing by Matrix Assisted Laser Desorption Ionization-Time of Flight-Based Peptide Mass Fingerprinting. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has gained popularity in recent years for rapid bacterial identification, mostly at the genus or species level. In this study, a rapid method to identify the Escherichia coli flagellar antigen (H antigen) at the subspecies level was developed using a MALDI-TOF MS platform with high specificity and sensitivity. Flagella were trapped on a filter membrane, and on filter trypsin digestion was performed. The tryptic digests of each flagellin then were collected and analyzed by MALDI-TOF MS through peptide mass fingerprinting. Sixty-one reference strains containing all 53 H types and 85 clinical strains were tested and compared to serotyping designations. Whole genome sequencing was used to resolve conflicting results between the two methods. It was found that DHB (2,5-dihydroxybenzoic acid) worked better than CHCA (alpha-cyano-4-hydroxycinnamic acid) as the matrix for MALDI-TOF MS, with higher confidence during protein identification. After method optimization, reference strains representing all 53 E. coli H types were identified correctly by MALDI-TOF MS. A custom E. coli flagellar/H antigen database was crucial for clearly identifying the E. coli H antigens. Of 85 clinical isolates tested by MALDI-TOF MS-H, 75 identified MS-H types (88.2%) matched results obtained from traditional serotyping. Among 10 isolates where the results of MALDI-TOF MS-H and serotyping did not agree, 60% of H types characterized by whole-genome sequencing agreed with those identified by MALDI-TOF MS-H, compared to only 20% by serotyping. This MALDI-TOF MS-H platform can be used for rapid and cost-effective E. coli H antigen identification, especially during E. coli outbreaks. PMID- 26019208 TI - Mupirocin Resistance in Isolates of Staphylococcus spp. from Nasal Swabs in a Tertiary Hospital in France. AB - Mupirocin is a topical antibiotic largely used to eradicate staphylococcal nasal carriage. Here, we investigated the prevalence of mupirocin-resistant Staphylococcus aureus and coagulase-negative staphylococcal isolates recovered from patients in different wards in a hospital (Lyon, France), which were determined both phenotypically with an Epsilometer test (Etest) and genetically by PCR for mupA and mupB. PMID- 26019209 TI - Performance Characteristics of Xpert Flu/RSV XC Assay. AB - The Xpert Flu/RSV XC assay was compared to laboratory-developed tests (LDTs) (n = 207) and the Xpert Flu assay (n = 147) using archived nasopharyngeal swabs. The percentages of positive agreements with LDTs were 97.8% for influenza A, 97.2% for influenza B, and 89.3% for RSV. The sensitivity of influenza detection was improved with the Xpert Flu/RSV XC assay compared to the Xpert Flu assay. PMID- 26019211 TI - Standard Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Reagents May Inactivate Potentially Hazardous Bacteria. PMID- 26019210 TI - Development and Evaluation of Novel Real-Time Reverse Transcription-PCR Assays with Locked Nucleic Acid Probes Targeting Leader Sequences of Human-Pathogenic Coronaviruses. AB - Based on findings in small RNA-sequencing (Seq) data analysis, we developed highly sensitive and specific real-time reverse transcription (RT)-PCR assays with locked nucleic acid probes targeting the abundantly expressed leader sequences of Middle East respiratory syndrome coronavirus (MERS-CoV) and other human coronaviruses. Analytical and clinical evaluations showed their noninferiority to a commercial multiplex PCR test for the detection of these coronaviruses. PMID- 26019212 TI - Head-to-Head Comparison of the RNA-Based Aptima Human Papillomavirus (HPV) Assay and the DNA-Based Hybrid Capture 2 HPV Test in a Routine Screening Population of Women Aged 30 to 60 Years in Germany. AB - Testing for E6/E7 mRNA in cells infected with high-risk (HR) human papillomavirus (HPV) might improve the specificity of HPV testing for the identification of cervical precancerous lesions. Here we compared the RNA-based Aptima HPV (AHPV) assay (Hologic) and the DNA-based Hybrid Capture 2 (HC2) HPV test (Qiagen) to liquid-based cytology (LBC) for women undergoing routine cervical screening. A total of 10,040 women, 30 to 60 years of age, were invited to participate in the study, 9,451 of whom were included in the analysis. Specimens were tested centrally by LBC, the AHPV test, and the HC2 test, and women who tested positive on any test were referred for colposcopy. Genotyping was performed on all HR-HPV positive samples. Test characteristics were calculated based on histological review. As a result, we identified 90 women with cervical intraepithelial neoplasia grade 2+ (CIN2+), including 43 women with CIN3+. Sensitivity differences between the AHPV test and the HC2 test in detecting CIN2+ (P = 0.180) or CIN3+ (P = 0.0625) lesions were statistically nonsignificant. Of three CIN3 cases that were missed with the AHPV test, two cases presented lesion-free cones and one had a non-HR HPV67 infection. The specificity (=30 years of age. PMID- 26019214 TI - Engineering precision. PMID- 26019215 TI - Erratum for the research article: "Interferon-lambda restricts West Nile virus neuroinvasion by tightening the blood-brain barrier" by H. M. Lazear, B. P. Daniels, A. K. Pinto, A. C. Huang, S. C. Vick, S. E. Doyle, M. Gale Jr., R. S. Klein, M. S. Diamond. PMID- 26019213 TI - POU2F2-oriented network promotes human gastric cancer metastasis. AB - BACKGROUND AND AIMS: Aberrant upregulation of POU2F2 expression has been discovered in metastatic gastric cancer (GC). However, the mechanisms underlying the aberrant upregulation and the potential functions of POU2F2 remain uncertain. DESIGN: The role and mechanism of POU2F2 in GC metastasis were investigated in gastric epithelial cells, GC cell lines and an experimental metastasis animal model by gain of function and loss of function. Upstream and downstream targets of POU2F2 were selected by bioinformatics and identified by luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation PCR. The influence of miR-218 on its putative target genes (POU2F2, ROBO1 and IKK beta) and GC metastasis was further explored via in vitro and in vivo approaches. RESULTS: Increased POU2F2 expression was detected in metastatic GC cell lines and patient samples. POU2F2 was induced by the activation of nuclear factor (NF) kappaB and, in turn, regulated ROBO1 transcription, thus functionally contributing to GC metastasis. Finally, miR-218 was found to suppress GC metastasis by simultaneously mediating multiple molecules in the POU2F2-oriented network. CONCLUSIONS: This study demonstrated that NF-kappaB and the SLIT2/ROBO1 interaction network with POU2F2 as the central part may exert critical effects on tumour metastasis. Blocking the activation of the POU2F2-oriented metastasis network using miR-218 precursors exemplified a promising approach that sheds light on new strategies for GC treatment. PMID- 26019216 TI - Research in academic medical centers: two threats to sustainable support. AB - Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine. PMID- 26019217 TI - Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3+ Tregs. AB - Antigen (Ag)-specific tolerance in type 1 diabetes (T1D) in human has not been achieved yet. Targeting lentiviral vector (LV)-mediated gene expression to hepatocytes induces active tolerance toward the encoded Ag. The insulin B chain 9 23 (InsB9-23) is an immunodominant T cell epitope in nonobese diabetic (NOD) mice. To determine whether auto-Ag gene transfer to hepatocytes induces tolerance and control of T1D, NOD mice were treated with integrase-competent LVs (ICLVs) that selectively target the expression of InsB9-23 to hepatocytes. ICLV treatment induced InsB9-23-specific effector T cells but also FoxP3(+) regulatory T cells (Tregs), which halted islet immune cell infiltration, and protected from T1D. Moreover, ICLV treatment combined with a single suboptimal dose of anti-CD3 monoclonal antibody (mAb) is effective in T1D reversal. Splenocytes from LV.InsB9 23-treated mice, but not from LV.OVA (ovalbumin)-treated control mice, stopped diabetes development, demonstrating that protection is Ag-specific. Depletion of CD4(+)CD25(+)FoxP3(+) T cells led to diabetes progression, indicating that Ag specific FoxP3(+) Tregs mediate protection. Integrase-defective LVs (IDLVs).InsB9 23, which alleviate the concerns for insertional mutagenesis and support transient transgene expression in hepatocytes, were also efficient in protecting from T1D. These data demonstrate that hepatocyte-targeted auto-Ag gene expression prevents and resolves T1D and that stable integration of the transgene is not required for this protection. Gene transfer to hepatocytes can be used to induce Ag-specific tolerance in autoimmune diseases. PMID- 26019218 TI - A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. AB - Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may benefit from targeted immunotherapy approaches. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule that binds T lymphocytes and cells expressing CD123, an antigen up-regulated in several hematological malignancies including AML. MGD006 mediates blast killing in AML samples, together with concomitant activation and expansion of residual T cells. MGD006 is designed to be rapidly cleared, and therefore requires continuous delivery. In a mouse model of continuous administration, MGD006 eliminated engrafted KG-1a cells (an AML-M0 line) in human PBMC (peripheral blood mononuclear cell)-reconstituted NSG/beta2m(-/-) mice at doses as low as 0.5 MUg/kg per day for ~7 days. MGD006 binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123 expressing target cells. MGD006 was well tolerated in monkeys continuously infused with 0.1 MUg/kg per day escalated weekly to up to 1 MUg/kg per day during a 4-week period. Depletion of circulating CD123-positive cells was observed as early as 72 hours after treatment initiation and persisted throughout the infusion period. Cytokine release, observed after the first infusion, was reduced after subsequent administrations, even when the dose was escalated. T cells from animals with prolonged in vivo exposure exhibited unperturbed target cell lysis ex vivo, indicating no exhaustion. A transient decrease in red cell mass was observed, with no neutropenia or thrombocytopenia. These studies support clinical testing of MGD006 in hematological malignancies, including AML. PMID- 26019219 TI - Detection of pathological biomarkers in human clinical samples via amplifying genetic switches and logic gates. AB - Whole-cell biosensors have several advantages for the detection of biological substances and have proven to be useful analytical tools. However, several hurdles have limited whole-cell biosensor application in the clinic, primarily their unreliable operation in complex media and low signal-to-noise ratio. We report that bacterial biosensors with genetically encoded digital amplifying genetic switches can detect clinically relevant biomarkers in human urine and serum. These bactosensors perform signal digitization and amplification, multiplexed signal processing with the use of Boolean logic gates, and data storage. In addition, we provide a framework with which to quantify whole-cell biosensor robustness in clinical samples together with a method for easily reprogramming the sensor module for distinct medical detection agendas. Last, we demonstrate that bactosensors can be used to detect pathological glycosuria in urine from diabetic patients. These next-generation whole-cell biosensors with improved computing and amplification capacity could meet clinical requirements and should enable new approaches for medical diagnosis. PMID- 26019220 TI - Programmable probiotics for detection of cancer in urine. AB - Rapid advances in the forward engineering of genetic circuitry in living cells has positioned synthetic biology as a potential means to solve numerous biomedical problems, including disease diagnosis and therapy. One challenge in exploiting synthetic biology for translational applications is to engineer microbes that are well tolerated by patients and seamlessly integrate with existing clinical methods. We use the safe and widely used probiotic Escherichia coli Nissle 1917 to develop an orally administered diagnostic that can noninvasively indicate the presence of liver metastasis by producing easily detectable signals in urine. Our microbial diagnostic generated a high-contrast urine signal through selective expansion in liver metastases (10(6)-fold enrichment) and high expression of a lacZ reporter maintained by engineering a stable plasmid system. The lacZ reporter cleaves a substrate to produce a small molecule that can be detected in urine. E. coli Nissle 1917 robustly colonized tumor tissue in rodent models of liver metastasis after oral delivery but did not colonize healthy organs or fibrotic liver tissue. We saw no deleterious health effects on the mice for more than 12 months after oral delivery. Our results demonstrate that probiotics can be programmed to safely and selectively deliver synthetic gene circuits to diseased tissue microenvironments in vivo. PMID- 26019221 TI - Shaping mycolactone for therapeutic use against inflammatory disorders. AB - Inflammation adversely affects the health of millions of people worldwide, and there is an unmet medical need for better anti-inflammatory drugs. We evaluated the therapeutic interest of mycolactone, a polyketide-derived macrolide produced by Mycobacterium ulcerans. Bacterial production of mycolactone in human skin causes a combination of ulcerative, analgesic, and anti-inflammatory effects. Whereas ulcer formation is mediated by the proapoptotic activity of mycolactone on skin cells via hyperactivation of Wiskott-Aldrich syndrome proteins, analgesia results from neuronal hyperpolarization via signaling through angiotensin II type 2 receptors. Mycolactone also blunts the capacity of immune cells to produce inflammatory mediators by an independent mechanism of protein synthesis blockade. In an attempt to isolate the structural determinants of mycolactone's immunosuppressive activity, we screened a library of synthetic subunits of mycolactone for inhibition of cytokine production by activated T cells. The minimal structure retaining immunosuppressive activity was a truncated version of mycolactone, missing one of the two core-branched polyketide chains. This compound inhibited the inflammatory cytokine responses of human primary cells at noncytotoxic doses and bound to angiotensin II type 2 receptors comparably to mycolactone in vitro. Notably, it was considerably less toxic than mycolactone in human primary dermal fibroblasts modeling ulcerative activity. In mouse models of human diseases, it conferred systemic protection against chronic skin inflammation and inflammatory pain, with no apparent side effects. In addition to establishing the anti-inflammatory potency of mycolactone in vivo, our study therefore highlights the translational potential of mycolactone core-derived structures as prospective immunosuppressants. PMID- 26019222 TI - SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. AB - Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures. PMID- 26019223 TI - Early Marketplace Enrollees Were Older And Used More Medication Than Later Enrollees; Marketplaces Pooled Risk. AB - Little is known about the health status of the 7.3 million Americans who enrolled in insurance plans through the Marketplaces established by the Affordable Care Act in 2014. Medication use may provide an early indicator of the health needs and access to care among Marketplace enrollees. We used data from January September 2014 on more than one million Marketplace enrollees from Express Scripts, the largest pharmacy benefit management company in the United States. We compared the characteristics and medication use between early and late Marketplace enrollees and between all Marketplace enrollees and enrollees with employer-sponsored insurance. Among Marketplace enrollees, we found that those who enrolled earlier (October 2013-February 2014) were older and used more medication than later enrollees. Marketplace enrollees, as a whole, had lower average drug spending and were less likely to use most medication classes than the employer-sponsored comparison group. However, Marketplace enrollees were more likely to use medicines for hepatitis C and particularly for HIV. PMID- 26019224 TI - Physical activity is associated with a reduced risk of atrial fibrillation in middle-aged and elderly women. AB - OBJECTIVE: Previous studies have found that regular participation in intense physical activity increases the risk of developing atrial fibrillation (AF) in men, but it remains unclear how physical activity influences the risk of AF in women. We aimed to examine whether physical activity of different types and at different ages influences the development of AF in women. METHODS: In the population-based Swedish Mammography Cohort, information about physical activity was obtained from 36 513 AF-free women (49-83 years old, median age 60 years) who had completed a questionnaire at study entry (1997). Participants reported their time spent on leisure-time exercise and on walking or bicycling throughout their lifetime (at study entry, and at 30 and 50 years of age). We used the Swedish National Inpatient Register (IPR) to determine whether the participants were diagnosed with AF. Cox proportional hazards regression models were used to estimate relative risks (RR) with 95% CI, adjusted for potential confounders. RESULTS: During a median follow-up of 12 years (10th percentile 7.5 years, 90th percentile 12.0 years), 2915 cases of AF were diagnosed. The risk of AF decreased with increasing levels of leisure-time exercise at study entry (RR 0.85, 95% CI 0.75 to 0.95 for >=4 h/week vs <1 h/week) and walking/bicycling (RR 0.81, 95% CI 0.72 to 0.92, for >=40 min/day vs almost never). CONCLUSIONS: Physical activity is associated with a reduced risk of AF in women. Moderate amount of physical activity was sufficient to significantly reduce AF risk. PMID- 26019225 TI - CD15 Expression Does Not Identify a Phenotypically or Genetically Distinct Glioblastoma Population. AB - : Recent research has focused on the hypothesis that the growth and regeneration of glioblastoma (GB) is sustained by a subpopulation of self-renewing stem-like cells. This has led to the prediction that molecular markers for cancer stem cells in GB may provide a treatment target. One candidate marker is CD15: we wanted to determine if CD15 represented a credible stem cell marker in GB. We first demonstrated that CD15-positive (CD15+) cells were less proliferative than their CD15-negative (CD15-) counterparts in 10 patient GB tumors. Next we compared the proliferative activity of CD15+ and CD15- cells in vitro using tumor initiating primary GB cell lines (TICs) and found no difference in proliferative behavior. Furthermore, TICs sorted for CD15+ and CD15- were not significantly different cytogenetically or in terms of gene expression profile. Sorted single CD15+ and CD15- cells were equally capable of reconstituting a heterogeneous population containing both CD15+ and CD15- cells over time, and both CD15+ and CD15- cells were able to generate tumors in vivo. No difference was found in the phenotypic or genomic behavior of CD15+ cells compared with CD15- cells from the same patient. Moreover, we found that in vitro, cells were able to interconvert between the CD15+ and CD15- states. Our data challenge the utility of CD15 as a cancer stem cell marker. SIGNIFICANCE: The data from this study contribute to the ongoing debate about the role of cancer stem cells in gliomagenesis. Results showed that CD15, a marker previously thought to be a cancer stem-like marker in glioblastoma, could not isolate a phenotypically or genetically distinct population. Moreover, isolated CD15-positive and -negative cells were able to generate mixed populations of glioblastoma cells in vitro. PMID- 26019226 TI - Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates. AB - : Previous studies have demonstrated that neural stem/progenitor cells (NS/PCs) promote functional recovery in rodent animal models of spinal cord injury (SCI). Because distinct differences exist in the neuroanatomy and immunological responses between rodents and primates, it is critical to determine the effectiveness and safety of allografted embryonic stem cell (ESC)-derived NS/PCs (ESC-NS/PCs) in a nonhuman primate SCI model. In the present study, common marmoset ESC-NS/PCs were grafted into the lesion epicenter 14 days after contusive SCI in adult marmosets (transplantation group). In the control group, phosphate-buffered saline was injected instead of cells. In the presence of a low dose of tacrolimus, several grafted cells survived without tumorigenicity and differentiated into neurons, astrocytes, or oligodendrocytes. Significant differences were found in the transverse areas of luxol fast blue-positive myelin sheaths, neurofilament-positive axons, corticospinal tract fibers, and platelet endothelial cell adhesion molecule-1-positive vessels at the lesion epicenter between the transplantation and control groups. Immunoelectron microscopic examination demonstrated that the grafted ESC-NS/PC-derived oligodendrocytes contributed to the remyelination of demyelinated axons. In addition, some grafted neurons formed synaptic connections with host cells, and some transplanted neurons were myelinated by host cells. Eventually, motor functional recovery significantly improved in the transplantation group compared with the control group. In addition, a mixed lymphocyte reaction assay indicated that ESC-NS/PCs modulated the allogeneic immune rejection. Taken together, our results indicate that allogeneic transplantation of ESC-NS/PCs from a nonhuman primate promoted functional recovery after SCI without tumorigenicity. SIGNIFICANCE: This study demonstrates that allogeneic embryonic stem cell (ESC)-derived neural stem/progenitor cells (NS/PCs) promoted functional recovery after transplantation into the injured spinal cord in nonhuman primates. ESC-NS/PCs were chosen because ESC-NS/PCs are one of the controls for induced pluripotent stem cell-derived NS/PCs and because ESC derivatives are possible candidates for clinical use. This translational research using an allograft model of a nonhuman primate is critical for clinical application of grafting NS/PCs derived from various allogeneic pluripotent stem cells, especially induced pluripotent stem cells, into injured spinal cord at the subacute phase. PMID- 26019227 TI - Body Management: Mesenchymal Stem Cells Control the Internal Regenerator. AB - SummaryIt has been assumed that adult tissues cannot regenerate themselves. With the current understanding that every adult tissue has its own intrinsic progenitor or stem cell, it is now clear that almost all tissues have regenerative potential partially related to their innate turnover dynamics. Moreover, it appears that a separate class of local cells originating as perivascular cells appears to provide regulatory oversight for localized tissue regeneration. The management of this regeneration oversight has a profound influence on the use of specific cells for cell therapies as a health care delivery tool set. The multipotent mesenchymal stem cell (MSC), now renamed the medicinal signaling cell, predominantly arises from pericytes released from broken and inflamed blood vessels and appears to function as both an immunomodulatory and a regeneration mediator. MSCs are being tested for their management capabilities to produce therapeutic outcomes in more than 480 clinical trials for a wide range of clinical conditions. Local MSCs function by managing the body's primary repair and regeneration activities. Supplemental MSCs can be provided from either endogenous or exogenous sources of either allogeneic or autologous origin. This MSC-based therapy has the potential to change how health care is delivered. These medicinal cells are capable of sensing their surroundings. Also, by using its complex signaling circuitry, these cells organize site-specific regenerative responses as if these therapeutic cells were well-programmed modern computers. Given these facts, it appears that we are entering a new age of cellular medicine. SIGNIFICANCE: This report is a perspective from an active scientist and an active entrepreneur and commercial leader. It is neither a comprehensive review nor a narrowly focused treatise. The broad themes and the analogy to the working component of a computer and that of a cell are meant to draw several important scientific principles and health care themes together into the thesis that regenerative medicine is a constant throughout life and its management is the next frontier of health care. Mesenchymal stem cells are used as the central connection in the broad theme, not as multipotent progenitors but rather as an important control element in the natural local regeneration process. PMID- 26019228 TI - Using an optimality model to understand medium and long-term responses of vegetation water use to elevated atmospheric CO2 concentrations. AB - Vegetation has different adjustable properties for adaptation to its environment. Examples include stomatal conductance at short time scale (minutes), leaf area index and fine root distributions at longer time scales (days-months) and species composition and dominant growth forms at very long time scales (years-decades centuries). As a result, the overall response of evapotranspiration to changes in environmental forcing may also change at different time scales. The vegetation optimality model simulates optimal adaptation to environmental conditions, based on the assumption that different vegetation properties are optimized to maximize the long-term net carbon profit, allowing for separation of different scales of adaptation, without the need for parametrization with observed responses. This paper discusses model simulations of vegetation responses to today's elevated atmospheric CO2 concentrations (eCO2) at different temporal scales and puts them in context with experimental evidence from free-air CO2 enrichment (FACE) experiments. Without any model tuning or calibration, the model reproduced general trends deduced from FACE experiments, but, contrary to the widespread expectation that eCO2 would generally decrease water use due to its leaf-scale effect on stomatal conductance, our results suggest that eCO2 may lead to unchanged or even increased vegetation water use in water-limited climates, accompanied by an increase in perennial vegetation cover. PMID- 26019229 TI - Intrusive growth of primary and secondary phloem fibres in hemp stem determines fibre-bundle formation and structure. AB - Plant fibres-cells with important mechanical functions and a widely used raw material-are usually identified in microscopic sections only after reaching a significant length or after developing a thickened cell wall. We characterized the early developmental stages of hemp (Cannabis sativa) stem phloem fibres, both primary (originating from the procambium) and secondary (originating in the cambium), when they still had only a primary cell wall. We gave a major emphasis to the role of intrusive elongation, the specific type of plant cell growth by which fibres commonly attain large cell length. We could identify primary phloem fibres at a distance of only 1.2-1.5 mm from the shoot apical meristem when they grew symplastically with the surrounding tissues. Half a millimeter further downwards along the stem, fibres began their intrusive elongation, which led to a sharp increase in fibre numbers visible within the stem cross-sections. The intrusive elongation of primary phloem fibres was completed within the several distal centimetres of the growing stem, before the onset of their secondary cell wall formation. The formation of secondary phloem fibres started long after the beginning of secondary xylem formation. Our data indicate that only a small portion of the fusiform cambial initials (<10 %) give rise directly or via their derivatives to secondary phloem fibres. The key determinant of final bundle structure, both for primary and secondary phloem fibres, is intrusive growth. Through bi-directional elongation, fibres join other fibres initiated individually in other stem levels, thus forming the bundles. Our results provide the specific developmental basis for further biochemical and molecular-genetic studies of phloem fibre development in hemp, but may be applied to many other species. PMID- 26019230 TI - Disentangling root system responses to neighbours: identification of novel root behavioural strategies. AB - Plants live in a social environment, with interactions among neighbours a ubiquitous aspect of life. Though many of these interactions occur in the soil, our understanding of how plants alter root growth and the patterns of soil occupancy in response to neighbours is limited. This is in contrast to a rich literature on the animal behavioural responses to changes in the social environment. For plants, root behavioural changes that alter soil occupancy patterns can influence neighbourhood size and the frequency or intensity of competition for soil resources; issues of fundamental importance to understanding coexistence and community assembly. Here we report a large comparative study in which individuals of 20 species were grown with and without each of two neighbour species. Through repeated root visualization and analyses, we quantified many putative root behaviours, including the extent to which each species altered aspects of root system growth (e.g. rooting breadth, root length, etc.) in response to neighbours. Across all species, there was no consistent behavioural response to neighbours (i.e. no general tendencies towards root over proliferation nor avoidance). However, there was a substantial interspecific variation showing a continuum of behavioural variation among the 20 species. Multivariate analyses revealed two novel and predominant root behavioural strategies: (i) size-sensitivity, in which focal plants reduced their overall root system size in response to the presence of neighbours, and (ii) location sensitivity, where focal plants adjusted the horizontal and vertical placement of their roots in response to neighbours. Of these, size-sensitivity represents the commonly assumed response to competitive encounters-reduced growth. However, location sensitivity is not accounted for in classic models and concepts of plant competition, though it is supported from recent work in plant behavioural ecology. We suggest that these different strategies could have important implications for the ability of a plant to persist in the face of strong competitors, and that location sensitivity may be a critical behavioural strategy promoting competitive tolerance and coexistence. PMID- 26019231 TI - Barriers to seed and seedling survival of once-common Hawaiian palms: the role of invasive rats and ungulates. AB - Mammalian herbivores can limit plant recruitment and affect forest composition. Loulu palms (Pritchardia spp.) once dominated many lowland ecosystems in Hawai'i, and non-native rats (Rattus spp.), ungulates (e.g. pigs Sus scrofa, goats Capra hircus) and humans have been proposed as major causes of their decline. In lowland wet forest, we experimentally determined the vulnerability of seeds and seedlings of two species of Pritchardia, P. maideniana and P. hillebrandii, by measuring their removal by introduced vertebrates; we also used motion-sensing cameras to identify the animals responsible for Pritchardia removal. We assessed potential seed dispersal of P. maideniana by spool-and-line tracking, and conducted captive-feeding trials with R. rattus and seeds and seedlings of both Pritchardia species. Seed removal from the forest floor occurred rapidly for both species: >50 % of Pritchardia seeds were removed from the vertebrate-accessible stations within 6 days and >80 % were removed within 22 days. Although rats and pigs were both common to the study area, motion-sensing cameras detected only rats (probably R. rattus) removing Pritchardia seeds from the forest floor. Captive-feeding trials and spool-and-line tracking revealed that vertebrate seed dispersal is rare; rats moved seeds up to 8 m upon collection and subsequently destroyed them (100 % mortality in 24-48 h in captivity). Surprisingly, seedlings did not suffer vertebrate damage in field trials, and although rats damaged seedlings in captivity, they rarely consumed them. Our findings are consistent with the hypothesis generated from palaeoecological studies, indicating that introduced rats may have assisted in the demise of native insular palm forests. These findings also imply that the seed stage of species in this Pacific genus is particularly vulnerable to rats; therefore, future conservation efforts involving Pritchardia should prioritize the reduction of rat predation on the plant recruitment stages preceding seedling establishment. PMID- 26019232 TI - Developing and testing accelerated partner therapy for partner notification for people with genital Chlamydia trachomatis diagnosed in primary care: a pilot randomised controlled trial. AB - BACKGROUND: Accelerated partner therapy (APT) is a promising partner notification (PN) intervention in specialist sexual health clinic attenders. To address its applicability in primary care, we undertook a pilot randomised controlled trial (RCT) of two APT models in community settings. METHODS: Three-arm pilot RCT of two adjunct APT interventions: APTHotline (telephone assessment of partner(s) plus standard PN) and APTPharmacy (community pharmacist assessment of partner(s) plus routine PN), versus standard PN alone (patient referral). Index patients were women diagnosed with genital chlamydia in 12 general practices and three community contraception and sexual health (CASH) services in London and south coast of England, randomised between 1 September 2011 and 31 July 2013. RESULTS: 199 women described 339 male partners, of whom 313 were reported by the index as contactable. The proportions of contactable partners considered treated within 6 weeks of index diagnosis were APTHotline 39/111 (35%), APTPharmacy 46/100 (46%), standard patient referral 46/102 (45%). Among treated partners, 8/39 (21%) in APTHotline arm were treated via hotline and 14/46 (30%) in APTPharmacy arm were treated via pharmacy. CONCLUSIONS: The two novel primary care APT models were acceptable, feasible, compliant with regulations and capable of achieving acceptable outcomes within a pilot RCT but intervention uptake was low. Although addition of these interventions to standard PN did not result in a difference between arms, overall PN uptake was higher than previously reported in similar settings, probably as a result of introducing a formal evaluation. Recruitment to an individually randomised trial proved challenging and full evaluation will likely require service-level randomisation. TRIAL REGISTRATION NUMBER: Registered UK Clinical Research Network Study Portfolio id number 10123. PMID- 26019233 TI - Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci?. AB - Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes. PMID- 26019234 TI - Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle. AB - Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion-fission machinery and manifesting with upregulated mitochondrial fusion associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways. PMID- 26019236 TI - Superior Sulcus Volumetric Rejuvenation Utilizing Dermis Fat Grafting. PMID- 26019235 TI - Epigenetic changes as a common trigger of muscle weakness in congenital myopathies. AB - Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorders. PMID- 26019237 TI - Nationwide incidence, cost, and epidemiologic trends in facial rhytidectomy: an examination of inpatient facelifts using the Nationwide Inpatient Sample (NIS) database. PMID- 26019238 TI - The "weekend effect" in plastic surgery: analyzing weekday versus weekend admissions in body contouring procedures from 2000 to 2010. AB - BACKGROUND: Body contouring operations are a quickly becoming the most commonly performed operations by American plastic surgeons, mirroring the increase in bariatric surgery in the US over the last decade. Despite previous studies showing worse patient outcomes on weekend admissions for non-emergent cases (spine, breast, and hernia), there is no comparative data reported regarding body contouring procedures. OBJECTIVE: The authors aimed to determine whether body contouring surgery results in worse outcomes when performed on weekends versus weekdays. METHODS: A serial cross-sectional study of body contouring patients was performed using the Nationwide Inpatient Sample database from 2000 to 2010. Data were gathered using international classification of diseases, ninth revision codes for liposuction and reduction of adipose tissue (86.83) for weekday and weekend admissions, including demographics, hospital charges, and patient outcomes. RESULTS: A total of 50,346 hospital admission cases of inpatient body contouring were examined over the 11-year period, 98% of which were on a weekday. When compared to weekday admissions, weekend admissions were associated with a statistically significant increase in hospitalization costs ($35,481, p < 0.000) and in hospital length of stay (5.68 days, p < 0.000). Mortality rates were found to be higher on weekend admissions (3.7%) versus weekdays (0.5%) as well. CONCLUSIONS: Although outcomes are multifactorial, in body contouring patients, weekday admission is associated with favorable outcomes in terms of length of stay and hospital charges. LEVEL OF EVIDENCE: 4 Risk. PMID- 26019241 TI - Outcomes of unconventional utilization of BI-RADS category 3 assessment at opportunistic screening. AB - Background An important difficulty regarding the Breast Imaging Reporting and Data System (BI-RADS) category 3 assessment is the need for extensive diagnostic workup and an additional 6-month follow-up study. Purpose To evaluate the feasibility of the BI-RADS category 3 assessments at opportunistic screening. Material and Methods Mammography charts of 9062 screening patients in a major teaching hospital situated in an urban setting of a developing country were evaluated retrospectively (1997-2010). BI-RADS category 3 patients, called for a 6-month follow-up, which comprised a single-view spot or magnification mammogram. The length of follow-up period, compliance to periodic mammographic surveillance, cancer detection rate, and negative predictive values of category 3 assessments were calculated. Results Of the screened population, 9.2% were assigned BI-RADS category 3, and 31.2% of these cases were lost to follow-up. The mean follow-up period for 606 patients was 36.9 months. The negative predictive values for 6 month, 12-month, and final control studies were 90.9%, 87.5%, and 100%, respectively. Patient compliance for 6 months, 12 months, and any control evaluations beyond 12 months was low (50.0%, 29.8%, and 47.5%, respectively). Cancer detection rate was 0.8%. Conclusion Results of the study supports the feasibility of the BI-RADS category 3 assessments at opportunistic screening without any additional diagnostic workup. The practice of category 3 assessment following screening mammograms may be a more cost-effective method for developing countries with high recall rates and low resources in eliminating the maximum risk with minimum cost within the limits of available resources. PMID- 26019240 TI - GC3-biased gene domains in mammalian genomes. AB - MOTIVATION: Synonymous codon usage bias has been shown to be correlated with many genomic features among different organisms. However, the biological significance of codon bias with respect to gene function and genome organization remains unclear. RESULTS: Guanine and cytosine content at the third codon position (GC3) could be used as a good indicator of codon bias. Here, we used relative GC3 bias values to compare the strength of GC3 bias of genes in human and mouse. We reported, for the first time, that GC3-rich and GC3-poor gene products might have distinct sub-cellular spatial distributions. Moreover, we extended the view of genomic gene domains and identified conserved GC3 biased gene domains along chromosomes. Our results indicated that similar GC3 biased genes might be co translated in specific spatial regions to share local translational machineries, and that GC3 could be involved in the organization of genome architecture. AVAILABILITY AND IMPLEMENTATION: Source code is available upon request from the authors. CONTACT: zhaozh@nic.bmi.ac.cn or zany1983@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26019242 TI - Bosniak classification system: a prospective comparison of CT, contrast-enhanced US, and MR for categorizing complex renal cystic masses. AB - Background The Bosniak classification was originally based on computed tomographic (CT) findings. Magnetic resonance (MR) and contrast-enhanced ultrasonography (CEUS) imaging may demonstrate findings that are not depicted at CT, and there may not always be a clear correlation between the findings at MR and CEUS imaging and those at CT. Purpose To compare diagnostic accuracy of MR, CEUS, and CT when categorizing complex renal cystic masses according to the Bosniak classification. Material and Methods From February 2011 to June 2012, 46 complex renal cysts were prospectively evaluated by three readers. Each mass was categorized according to the Bosniak classification and CT was chosen as gold standard. Kappa was calculated for diagnostic accuracy and data was compared with pathological results. Results CT images found 27 BII, six BIIF, seven BIII, and six BIV. Forty-three cysts could be characterized by CEUS, 79% were in agreement with CT (kappa = 0.86). Five BII lesions were upgraded to BIIF and four lesions were categorized lower with CEUS. Forty-one lesions were examined with MR; 78% were in agreement with CT (kappa = 0.91). Three BII lesions were upgraded to BIIF and six lesions were categorized one category lower. Pathologic correlation in six lesions revealed four malignant and two benign lesions. Conclusion CEUS and MR both up- and downgraded renal cysts compared to CT, and until these non radiation modalities have been refined and adjusted, CT should remain the gold standard of the Bosniak classification. PMID- 26019243 TI - Galacto-oligosaccharides Protect the Intestinal Barrier by Maintaining the Tight Junction Network and Modulating the Inflammatory Responses after a Challenge with the Mycotoxin Deoxynivalenol in Human Caco-2 Cell Monolayers and B6C3F1 Mice. AB - BACKGROUND: The integrity of the epithelial layer in the gastrointestinal tract protects organisms from exposure to luminal antigens, which are considered the primary cause of chronic intestinal inflammation and allergic responses. The common wheat-associated fungal toxin deoxynivalenol acts as a specific disruptor of the intestinal tight junction network and hence might contribute to the pathogenesis of inflammatory bowel diseases. OBJECTIVE: The aim of the current study was to assess whether defined galacto-oligosaccharides (GOSs) can prevent deoxynivalenol-induced epithelial dysfunction. METHODS: Human epithelial intestinal Caco-2 cells, pretreated with different concentrations of GOSs (0.5%, 1%, and 2%) for 24 h, were stimulated with 4.2-MUM deoxynivalenol (24 h), and 6/7 wk-old male B6C3F1 mice were fed a diet supplemented with 1% GOSs for 2 wk before being orally exposed to deoxynivalenol (25 mg/kg body weight, 6 h). Barrier integrity was determined by measuring transepithelial electrical resistance (TEER) and intestinal permeability to marker molecules. A calcium switch assay was conducted to study the assembly of epithelial tight junction proteins. Alterations in tight junction and cytokine expression were assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, or ELISA, and their localization was visualized by immunofluorescence microscopy. Sections of the proximal and distal small intestine were stained with hematoxylin/eosin for histomorphometric analysis. RESULTS: The in vitro data showed that medium supplemented with 2% GOSs improved tight junction assembly reaching an acceleration of 85% after 6 h (P < 0.05). In turn, GOSs prevented the deoxynivalenol-induced loss of epithelial barrier function as measured by TEER (114% of control), and paracellular flux of Lucifer yellow (82.7% of prechallenge values, P < 0.05). Moreover, GOSs stabilized the expression and cellular distribution of claudin3 and suppressed by >50% the deoxynivalenol-induced synthesis and release of interleukin-8 [IL8/chemokine CXC motif ligand (CXCL8)] (P < 0.05). In mice, GOSs prevented the deoxynivalenol-induced mRNA overexpression of claudin3 (P = 0.022) and CXCL8 homolog keratinocyte hemoattractant (Kc) (Cxcl1) (P = 0.06) as well as the deoxynivalenol-induced morphologic defects. CONCLUSIONS: The results demonstrate that GOSs stimulate the tight junction assembly and in turn mitigate the deleterious effects of deoxynivalenol on the intestinal barrier of Caco-2 cells and on villus architecture of B6C3F1 mice. PMID- 26019244 TI - Using 2 Assessment Methods May Better Describe Dietary Supplement Intakes in the United States. AB - BACKGROUND: One-half of US adults report using a dietary supplement. NHANES has traditionally assessed dietary supplement use via a 30-d questionnaire but in 2007 added a supplement module to the 24-h dietary recall (24HR). OBJECTIVE: We compared these 2 dietary assessment methods, examined potential biases in the methods, and determined the effect that instrument choice had on estimates of prevalence of multivitamin/multimineral dietary supplement (MVMM) use. METHODS: We described prevalence of dietary supplement use by age, sex, and assessment instrument in 12,285 adults in the United States (>19 y of age) from NHANES 2007 2010. RESULTS: When using data from the questionnaire alone, 29.3% +/- 1.0% of men and 35.5% +/- 1.0% of women were users of MVMMs, whereas data from the 24HR only produced prevalence estimates of 26.3% +/- 1.1% for men and 33.2% +/- 1.0% for women. When using data from both instruments combined, 32.3% +/- 1.2% of men and 39.5% +/- 1.1% of women were classified as MVMM users. Prevalence estimates were significantly higher by 2-9% in all age-sex groups when using information from both instruments combined than when using data from either instrument individually. A digit preference bias and flattened slope phenomenon were observed in responses to the dietary supplement questionnaire. A majority (67%) of MVMMs were captured on both instruments, whereas 19% additional MVMMs were captured on the questionnaire and 14% additional on the 24HR. Of those captured only on the 24HR, 26% had missing label information, whereas only 12% and 9% of those captured on the questionnaire or both, respectively, had missing information. CONCLUSIONS: Use of both the dietary supplement questionnaire and the 24HR can provide advantages to researchers over the use of a single instrument and potentially capture a larger fraction of dietary supplement users. PMID- 26019245 TI - Calcium Plus Vitamin D Supplementation During the Third Trimester of Pregnancy in Adolescents Accustomed to Low Calcium Diets Does Not Affect Infant Bone Mass at Early Lactation in a Randomized Controlled Trial. AB - BACKGROUND: Pregnancy and lactation in adolescents with low calcium intake may impair fetal growth and infant bone mass. OBJECTIVE: We investigated the effects of calcium plus vitamin D supplementation during pregnancy in Brazilian adolescent mothers consuming low calcium diets (~600 mg/d) on fetal biometry and infant bone mass, and the relation between infant and maternal bone mass during early lactation. METHODS: Infants of mothers who received calcium (600 mg/d) plus cholecalciferol (200 IU/d) supplementation (n = 30) or placebo (n = 26) from 26 wk of gestation until parturition were studied. Fetal biometric measurements at 23 and 36 wk of gestation were obtained from medical records. Infant anthropometric and total body bone measurements [bone mineral content (BMC), bone area (BA), and bone mineral density (BMD)] at 5 wk postpartum were assessed by dual-energy X-ray absorptiometry. Maternal BMD z scores for total body, lumbar spine, total hip, and femoral neck at 5 wk postpartum were obtained. Group comparisons were adjusted for significant covariates. RESULTS: Maternal mean serum 25-hydroxyvitamin D was 59 nmol/L at baseline in both groups. No differences in fetal measurements at 36 wk of gestation were observed between the groups, except for body weight and its increment from 23 to 36 wk, which were higher in the supplemented group (6.8%, P = 0.014 and 10.5%, P = 0.07, respectively). Infant BMC (61.1 +/- 21.7 g), BA (167 +/- 79 cm(2)), and BMD (0.385 +/- 0.069 g/cm(2)) did not significantly differ between the groups. In the placebo group, infant BMC and BA were negatively correlated with maternal BMD z scores for total body (r = -0.40 and r = -0.47; P < 0.05) and hip (r = -0.41 and r = -0.46; P < 0.05). In contrast, no correlations were observed in the supplemented group. CONCLUSIONS: Calcium and vitamin D supplementation of the adolescents studied resulted in higher fetal body weight at 36 wk of gestation and had no effect on infant bone mass at 5 wk postpartum. Because correlations between maternal and infant bone mass were evident only in the placebo group, infant bone mass appeared to be more dependent on maternal skeletal mass when calcium intake was low. This trial was registered at clinicaltrials.gov as NCT01732328. PMID- 26019246 TI - Higher Protein Intake Is Associated with Higher Lean Mass and Quadriceps Muscle Strength in Adult Men and Women. AB - BACKGROUND: The impact of dietary protein intake on lower extremity lean mass and strength in community-dwelling adult Americans is not fully understood. OBJECTIVES: The objective was to determine the associations between total protein (TP), animal protein (AP), and plant protein (PP) intakes and lean mass of the legs and quadriceps muscle strength. We further examined whether the associations with quadriceps strength may be explained by lean mass of the legs. METHODS: This cross-sectional study included men (n = 1166) and women (n = 1509) from the Framingham Offspring Cohort in Massachusetts. Protein intake in grams per day was measured in either 1995-1998 or 1998-2001. Leg lean mass and isometric quadriceps strength, both in kilograms, were measured in 1996-2001. Multilinear regression models estimated adjusted least squares means of each of the muscle measures by quartile categories of protein intake, adjusting for relevant confounders and covariates. RESULTS: Mean age was 59 +/- 9 y (range: 29-86 y) and TP intake was 80 +/- 27 g/d in men and 76 +/- 26 g/d in women. In men and women, leg lean mass was higher in participants in the highest quartiles of TP and AP intake compared with those in the lowest quartiles of intake [least squares means (kg): TP-17.6 vs. 17.1 in men, P-trend: 0.005, and 11.7 vs. 11.4 in women, P-trend: 0.006; AP 17.6 vs. 17.1 in men, P-trend: 0.002, and 11.7 vs. 11.4 in women, P-trend: 0.003]. PP intake was not associated with lean mass in either sex. In men and women, quadriceps strength was higher in participants in the highest quartile of PP intake compared with those in the lowest quartile [least squares means (kg): 22.9 vs. 21.7 in men, P-trend: 0.01, and 19.0 vs. 18.2 in women, P-trend: 0.01]; this association was no longer significant after adjustment for fruit and vegetable intake (P-trend: 0.06 in men and 0.10 in women). Although no significant association was observed for AP intake in either sex, nonsignificant protective trends were observed for TP intake (P-trend: 0.08 in men and 0.10 in women). CONCLUSIONS: Our findings suggest that maintaining adequate protein intake with age may help preserve muscle mass and strength in adult men and women. Dietary protein types may differentially affect muscle mass and strength. Whether PP is a marker of dietary quality or has a direct effect on muscle strength (independent of lean mass) needs to be further clarified. PMID- 26019247 TI - Bovine Colostrum Modulates Myeloablative Chemotherapy-Induced Gut Toxicity in Piglets. AB - BACKGROUND: Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown. OBJECTIVE: We hypothesized that the severity of chemotherapy-induced gut toxicity in early life is diet-dependent, and that intake of bovine colostrum (BC) provides better gut protection than an artificial milk replacer (MR). METHODS: A total of 37 3-d-old pigs received for 6 d either intravenous saline control or myeloablative treatment with busulfan and cyclophosphamide, and were fed either BC or MR, resulting in the following 4 treatments (n = 8-10/group): bovine colostrum plus saline control (Ctr-BC), milk replacer plus saline control (Ctr-MR), bovine colostrum plus busulfan and cyclophosphamide chemotherapy (BUCY-BC), and milk replacer plus busulfan and cyclophosphamide chemotherapy (BUCY-MR). The gut was collected for analysis 11 d after the start of chemotherapy. RESULTS: Relative to the control groups, both busulfan and cyclophosphamide chemotherapy (BUCY) groups showed signs of gut toxicity, with oral ulcers, reduced intestinal dimensions, and hematologic toxicity. Diet type did not affect mucosal structure on day 11, but BUCY-BC pigs had less vomiting than BUCY-MR pigs (1 of 10 vs. 10 of 10, P < 0.05). Markers of intestinal function were higher (up to 20-fold greater galactose absorption and 2 3-fold greater brush border enzyme activity, all P < 0.05), and tissue inflammatory cytokine concentrations and serum liver enzyme values were lower in BUCY-BC than in BUCY-MR pigs (30-50% reductions in interleukin 6 and 8, aminotransferase, and bilirubin concentrations, P < 0.05). Gut colonization was not significantly affected except that BUCY pigs had lower microbial diversity with a higher abundance of Lactobacilli. CONCLUSION: BC may reduce gut toxicity during myeloablative chemotherapy in piglets by preserving intestinal function and reducing inflammation. Whether similar effects occur in children remains to be tested. PMID- 26019248 TI - Ingestion of Casein in a Milk Matrix Modulates Dietary Protein Digestion and Absorption Kinetics but Does Not Modulate Postprandial Muscle Protein Synthesis in Older Men. AB - BACKGROUND: The slow digestion and amino acid absorption kinetics of isolated micellar casein have been held responsible for its relatively lower postprandial muscle protein synthetic response compared with rapidly digested proteins such as isolated whey. However, casein is normally consumed within a milk matrix. We hypothesized that protein digestion and absorption kinetics and the subsequent muscle protein synthetic response after micellar casein ingestion are modulated by the milk matrix. OBJECTIVE: The aim of this study was to determine the impact of a milk matrix on casein protein digestion and absorption kinetics and postprandial muscle protein synthesis in older men. METHODS: In a parallel-group design, 32 healthy older men (aged 71 +/- 1 y) received a primed continuous infusion of L-[ring-(2)H5]-phenylalanine, L-[ring-3,5-(2)H2]-tyrosine, and L-[1 (13)C]-leucine, and ingested 25 g intrinsically L-[1-(13)C]-phenylalanine and L [1-(13)C]-leucine labeled casein dissolved in bovine milk serum (Cas+Serum) or water (Cas). Plasma samples and muscle biopsies were collected in the postabsorptive state and for 300 min in the postprandial period to examine whole body and skeletal muscle protein metabolism. RESULTS: Casein ingestion increased plasma leucine and phenylalanine concentrations and L-[1-(13)C]-phenylalanine enrichments, with a more rapid rise after Cas vs. Cas+Serum. Nonetheless, dietary protein-derived phenylalanine availability did not differ between Cas+Serum (47 +/- 2%, mean +/- SEM) and Cas (46 +/- 3%) when assessed over the 300-min postprandial period (P = 0.80). The milk matrix did not modulate postprandial myofibrillar protein synthesis rates from 0 to 120 min (0.038 +/- 0.005 vs. 0.031 +/- 0.007%/h) or from 120 to 300 min (0.052 +/- 0.004 vs. 0.067 +/- 0.005%/h) after Cas+Serum vs. Cas. Similarly, no treatment differences in muscle protein bound L-[1-(13)C]-phenylalanine enrichments were observed at 120 min (0.003 +/- 0.001 vs. 0.002 +/- 0.001) or 300 min (0.015 +/- 0.002 vs. 0.016 +/- 0.002 mole percent excess) after Cas+Serum vs. Cas. CONCLUSIONS: Casein ingestion in a milk matrix delays protein digestion and absorption but does not modulate postprandial muscle protein synthesis when compared to the ingestion of micellar casein only in healthy older men. This trial was registered at Nederlands Trial Register as NTR4429. PMID- 26019249 TI - Fermented Infant Formula Increases Ileal Protein Digestibility and Reduces Ileal Proteolytic Activity Compared with Standard and Hydrolyzed Infant Formulas in Piglets. AB - BACKGROUND: An infant formula that contained milk fermented by the bacteria Bifidobacterium breve and Streptococcus thermophilus (Lactofidus) was reported to alleviate functional digestive symptoms in infants. It was hypothesized that improved protein digestibility of the fermented infant formula could contribute to this effect. OBJECTIVE: The aim of this study was to evaluate the protein digestibility of a specific fermented (FF), a standard (SF), and an extensively hydrolyzed protein (HF) formula. METHODS: Four-week-old piglets (n = 7) were fitted with a T-cannula at the terminal ileum and received each formula in a Latin square design. FF, SF, and HF contained 11.7%, 9.3%, and 11.9% (w/w) crude protein; 1.5%, 5.4%, and 5.6% (w/w) fiber; and had a casein/whey ratio of 60:40, 50:50, and 0:100 per kilogram of powder, respectively. Ileal digesta were collected and analyzed for amino acids and proteolytic activity. RESULTS: FF had a significantly higher apparent ileal crude protein digestibility (92.1% +/- 1.0%) than SF and HF (84.4% +/- 1.0% and 83.9% +/- 0.9%, respectively). FF also had a significantly higher dry matter digestibility than SF and HF. The ileal crude protein flow of FF was significantly lower than that of SF and HF. The ileal flow of FF total proteolytic activity was significantly lower than that of SF but not significantly different from that of HF (412 +/- 163 kU/8 h vs. 1530 +/- 163 and 703 +/- 156 kU/8 h, respectively). CONCLUSIONS: The FF in piglets had a significantly higher apparent ileal crude protein digestibility than the SF and HF and displayed lower ileal proteolytic activity than the SF. Both effects may contribute to the alleviation of functional gastrointestinal symptoms reported in infants fed fermented infant milk formula. PMID- 26019250 TI - Citrulline Supplementation Induces Changes in Body Composition and Limits Age Related Metabolic Changes in Healthy Male Rats. AB - BACKGROUND: Aging is associated with profound metabolic disturbances, and citrulline may be of use to limit them. OBJECTIVE: The aim of this work was to evaluate the long-term effect of citrulline supplementation on metabolism in healthy aged rats. METHODS: Twenty-month-old male rats were randomly assigned to be fed (ad libitum) for 12 wk with either a citrulline-enriched diet (1 g ? kg( 1) ? d(-1)) or a standard diet [rendered isonitrogenous by addition of nonessential amino acids (NEAAs)]. Motor activity and muscle strength were measured, body composition was assessed, and muscle metabolism (protein structure, mitochondrial exploration, and transductional factors) and lipid metabolism (lipoprotein composition and sensitivity to oxidative stress) were explored. RESULTS: Compared with the NEAA-treated group, citrulline supplementation was associated with lower mortality (0% vs. 20%; P = 0.05), 9% higher lean body mass (P < 0.05), and 13% lower fat mass (P < 0.05). Compared with the NEAA-treated group, citrulline-treated rats had greater muscle mass (+14 48% depending on type of muscle; P < 0.05 for tibialis, gastrocnemius, and plantaris). Susceptibility to oxidation of lipoproteins, as measured by the maximal concentration of 7-ketocholesterol after copper-induced VLDL and LDL oxidation, was lower in citrulline-treated rats than in NEAA-treated rats (187 +/ 8 MUmol/L vs. 243 +/- 7 MUmol/L; P = 0.0005). CONCLUSIONS: Citrulline treatment in male aged rats favorably modulates body composition and protects against lipid oxidation and, thus, emerges as an interesting candidate to help prevent the aging process. PMID- 26019252 TI - The importance of localized auxin production for morphogenesis of reproductive organs and embryos in Arabidopsis. AB - Plant sexual reproduction involves highly structured and specialized organs: stamens (male) and gynoecia (female, containing ovules). These organs synchronously develop within protective flower buds, until anthesis, via tightly coordinated mechanisms that are essential for effective fertilization and production of viable seeds. The phytohormone auxin is one of the key endogenous signalling molecules controlling initiation and development of these, and other, plant organs. In particular, its uneven distribution, resulting from tightly controlled production, metabolism and directional transport, is an important morphogenic factor. In this review we discuss how developmentally controlled and localized auxin biosynthesis and transport contribute to the coordinated development of plants' reproductive organs, and their fertilized derivatives (embryos) via the regulation of auxin levels and distribution within and around them. Current understanding of the links between de novo local auxin biosynthesis, auxin transport and/or signalling is presented to highlight the importance of the non-cell autonomous action of auxin production on development and morphogenesis of reproductive organs and embryos. An overview of transcription factor families, which spatiotemporally define local auxin production by controlling key auxin biosynthetic enzymes, is also presented. PMID- 26019253 TI - Genetic evidence for differential selection of grain and embryo weight during wheat evolution under domestication. AB - Wheat is one of the Neolithic founder crops domesticated ~10 500 years ago. Following the domestication episode, its evolution under domestication has resulted in various genetic modifications. Grain weight, embryo weight, and the interaction between those factors were examined among domesticated durum wheat and its direct progenitor, wild emmer wheat. Experimental data show that grain weight has increased over the course of wheat evolution without any parallel change in embryo weight, resulting in a significantly reduced (30%) embryo weight/grain weight ratio in domesticated wheat. The genetic factors associated with these modifications were further investigated using a population of recombinant inbred substitution lines that segregated for chromosome 2A. A cluster of loci affecting grain weight and shape was identified on the long arm of chromosome 2AL. Interestingly, a novel locus controlling embryo weight was mapped on chromosome 2AS, on which the wild emmer allele promotes heavier embryos and greater seedling vigour. To the best of our knowledge, this is the first report of a QTL for embryo weight in wheat. The results suggest a differential selection of grain and embryo weight during the evolution of domesticated wheat. It is argued that conscious selection by early farmers favouring larger grains and smaller embryos appears to have resulted in a significant change in endosperm weight/embryo weight ratio in the domesticated wheat. Exposing the genetic factors associated with endosperm and embryo size improves our understanding of the evolutionary dynamics of wheat under domestication and is likely to be useful for future wheat-breeding efforts. PMID- 26019251 TI - Cytokinin as a positional cue regulating lateral root spacing in Arabidopsis. AB - The root systems of plants have developed adaptive architectures to exploit soil resources. The formation of lateral roots (LRs) contributes to root system architecture. Roots of plants with a lower cytokinin status form LR primordia (LRP) in unusually close proximity, indicating a role for the hormone in regulating the positioning of LRs along the main root axis. Data obtained from cytokinin-synthesis mutants of Arabidopsis thaliana combined with gene expression analysis indicate that cytokinin synthesis by IPT5 and LOG4 occurring early during LRP initiation generates a local cytokinin signal abbreviating LRP formation in neighbouring pericycle cells. In addition, IPT3, IPT5, and IPT7 contribute to cytokinin synthesis in the vicinity of existing LRP, thus suppressing initiation of new LRs. Interestingly, mutation of CYP735A genes required for trans-zeatin biosynthesis caused strong defects in LR positioning, indicating an important role for this cytokinin metabolite in regulating LR spacing. Further it is shown that cytokinin and a known regulator of LR spacing, the receptor-like kinase ARABIDOPSIS CRINKLY4 (ACR4), operate in a non hierarchical manner but might exert reciprocal control at the transcript level. Taken together, the results suggest that cytokinin acts as a paracrine hormonal signal in regulating root system architecture. PMID- 26019254 TI - Changing the spatial pattern of TFL1 expression reveals its key role in the shoot meristem in controlling Arabidopsis flowering architecture. AB - Models for the control of above-ground plant architectures show how meristems can be programmed to be either shoots or flowers. Molecular, genetic, transgenic, and mathematical studies have greatly refined these models, suggesting that the phase of the shoot reflects different genes contributing to its repression of flowering, its vegetativeness ('veg'), before activators promote flower development. Key elements of how the repressor of flowering and shoot meristem gene TFL1 acts have now been tested, by changing its spatiotemporal pattern. It is shown that TFL1 can act outside of its normal expression domain in leaf primordia or floral meristems to repress flower identity. These data show how the timing and spatial pattern of TFL1 expression affect overall plant architecture. This reveals that the underlying pattern of TFL1 interactors is complex and that they may be spatially more widespread than TFL1 itself, which is confined to shoots. However, the data show that while TFL1 and floral genes can both act and compete in the same meristem, it appears that the main shoot meristem is more sensitive to TFL1 rather than floral genes. This spatial analysis therefore reveals how a difference in response helps maintain the 'veg' state of the shoot meristem. PMID- 26019255 TI - Characterizing root response phenotypes by neural network analysis. AB - Roots play an immediate role as the interface for water acquisition. To improve sustainability in low-water environments, breeders of major crops must therefore pay closer attention to advantageous root phenotypes; however, the complexity of root architecture in response to stress can be difficult to quantify. Here, the Sholl method, an established technique from neurobiology used for the characterization of neural network anatomy, was adapted to more adequately describe root responses to osmotic stress. This method was used to investigate the influence of in vitro osmotic stress on early root architecture and distribution in drought-resistant and -susceptible genotypes of winter oilseed rape. Interactive changes in root architecture can be easily captured by individual intersection profiles generated by Sholl analysis. Validation using manual measurements confirmed that the number of lateral roots decreased, while mean lateral root length was enhanced, under osmotic stress conditions. Both genotypes reacted to osmotic stress with a shift in their intersection patterns measured with Sholl analysis. Changes in interactive root architecture and distribution under stress were more pronounced in the drought-resistant genotype, indicating that these changes may contribute to drought resistance under mild osmotic stress conditions. The Sholl methodology is presented as a promising tool for selection of cultivars with advantageous root phenotypes under osmotic stress conditions. PMID- 26019257 TI - Effect of herbicide resistance endowing Ile-1781-Leu and Asp-2078-Gly ACCase gene mutations on ACCase kinetics and growth traits in Lolium rigidum. AB - The rate of herbicide resistance evolution in plants depends on fitness traits endowed by alleles in both the presence and absence (resistance cost) of herbicide selection. The effect of two Lolium rigidum spontaneous homozygous target-site resistance-endowing mutations (Ile-1781-Leu, Asp-2078-Gly) on both ACCase activity and various plant growth traits have been investigated here. Relative growth rate (RGR) and components (net assimilation rate, leaf area ratio), resource allocation to different organs, and growth responses in competition with a wheat crop were assessed. Unlike plants carrying the Ile-1781 Leu resistance mutation, plants homozygous for the Asp-2078-Gly mutation exhibited a significantly lower RGR (30%), which translated into lower allocation of biomass to roots, shoots, and leaves, and poor responses to plant competition. Both the negligible and significant growth reductions associated, respectively, with the Ile-1781-Leu and Asp-2078-Gly resistance mutations correlated with their impact on ACCase activity. Whereas the Ile-1781-Leu mutation showed no pleiotropic effects on ACCase kinetics, the Asp-2078-Gly mutation led to a significant reduction in ACCase activity. The impaired growth traits are discussed in the context of resistance costs and the effects of each resistance allele on ACCase activity. Similar effects of these two particular ACCase mutations on the ACCase activity of Alopecurus myosuroides were also confirmed. PMID- 26019256 TI - Arabidopsis seed-specific vacuolar aquaporins are involved in maintaining seed longevity under the control of ABSCISIC ACID INSENSITIVE 3. AB - The tonoplast intrinsic proteins TIP3;1 and TIP3;2 are specifically expressed during seed maturation and localized to the seed protein storage vacuole membrane. However, the function and physiological roles of TIP3s are still largely unknown. The seed performance of TIP3 knockdown mutants was analysed using the controlled deterioration test. The tip3;1/tip3;2 double mutant was affected in seed longevity and accumulated high levels of hydrogen peroxide compared with the wild type, suggesting that TIP3s function in seed longevity. The transcription factor ABSCISIC ACID INSENSITIVE 3 (ABI3) is known to be involved in seed desiccation tolerance and seed longevity. TIP3 transcript and protein levels were significantly reduced in abi3-6 mutant seeds. TIP3;1 and TIP3;2 promoters could be activated by ABI3 in the presence of abscisic acid (ABA) in Arabidopsis protoplasts. TIP3 proteins were detected in the protoplasts transiently expressing ABI3 and in ABI3-overexpressing seedlings when treated with ABA. Furthermore, ABI3 directly binds to the RY motif of the TIP3 promoters. Therefore, seed-specific TIP3s may help maintain seed longevity under the expressional control of ABI3 during seed maturation and are members of the ABI3 mediated seed longevity pathway together with small heat shock proteins and late embryo abundant proteins. PMID- 26019258 TI - Synchrotron-based X-ray absorption near-edge spectroscopy imaging for laterally resolved speciation of selenium in fresh roots and leaves of wheat and rice. AB - Knowledge of the distribution of selenium (Se) species within plant tissues will assist in understanding the mechanisms of Se uptake and translocation, but in situ analysis of fresh and highly hydrated plant tissues is challenging. Using synchrotron-based fluorescence X-ray absorption near-edge spectroscopy (XANES) imaging to provide laterally resolved data, the speciation of Se in fresh roots and leaves of wheat (Triticum aestivum L.) and rice (Oryza sativa L.) supplied with 1 MUM of either selenate or selenite was investigated. For plant roots exposed to selenate, the majority of the Se was efficiently converted to C-Se-C compounds (i.e. methylselenocysteine or selenomethionine) as selenate was transported radially through the root cylinder. Indeed, even in the rhizodermis which is exposed directly to the bulk solution, only 12-31% of the Se was present as uncomplexed selenate. The C-Se-C compounds were probably sequestered within the roots, whilst much of the remaining uncomplexed Se was translocated to the leaves-selenate accounting for 52-56% of the total Se in the leaves. In a similar manner, for plants exposed to selenite, the Se was efficiently converted to C-Se C compounds within the roots, with only a small proportion of uncomplexed selenite observed within the outer root tissues. This resulted in a substantial decrease in translocation of Se from the roots to leaves of selenite-exposed plants. This study provides important information for understanding the mechanisms responsible for the uptake and subsequent transformation of Se in plants. PMID- 26019259 TI - Mathematical modelling of WOX5- and CLE40-mediated columella stem cell homeostasis in Arabidopsis. AB - The root meristem of Arabidopsis thaliana harbours a pool of stem cells, which divide to give rise to the differentiated cells of the various root tissues. Regulatory networks of inter-cellular signalling molecules control the homeostasis of stem cell number and position so that both stem and differentiated cells are consistently available. This work focuses on the transcription factor WUSCHEL-RELATED HOMEOBOX 5 (WOX5), the signalling peptide CLAVATA3/EMBRYO SURROUNDING REGION 40 (CLE40) and the feedback loops involving them, which maintain the columella stem cells (CSCs). WOX5 signals from the quiescent centre (QC) to promote stem cell fate, while CLE40 is secreted from the differentiated columella cells (CCs) to promote differentiation. Our analyses of mathematical models of this network show that, when cell fate is controlled primarily by antagonistic factors, homeostasis requires a spatial component and inter-cellular signalling. We have also found that WOX5 contributes to, but is not absolutely necessary for, CSC maintenance. Furthermore, our modelling led us to postulate an additional signalling molecule that promotes CSC maintenance. We propose that this WOX5-independent signal originates in the QC, is targeted by CLE40 signalling and is capable of maintaining CSCs. PMID- 26019262 TI - Education Intervention "Caregivers Like Me" for Latino Family Caregivers Improved Attitudes Toward Professional Assistance at End-of-life Care. AB - OBJECTIVE: This study explores the ability of a culturally sensitive and case based education intervention, Caregivers Like Me, to improve knowledge and attitudes regarding end-of-life (EOL) resources among Latino caregivers. METHODS: A multicentered, cross-sectional study of Latino communities from different geographical regions and cultural backgrounds. An educational intervention was administered to family caregivers of Latino elders using a case-based video "telenovela" and pretest-posttest questionnaires. RESULTS: Participants (N = 145) were mostly females (79%) with mean age of 56 +/- 15 years. They reported active learning from intervention (91%) and high satisfaction (92%) with educational experience. Both caregiver stress self-awareness and willingness to accept professional help improved significantly from pretest to posttest. CONCLUSION: A culturally sensitive educational intervention increased Latino caregivers' self awareness about caregiver stress and the need to consider professional assistance for EOL care. PMID- 26019261 TI - Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells. AB - Testosterone production by Leydig cells is a tightly regulated process requiring synchronized expression of several steroidogenic genes by numerous transcription factors. Myocyte enhancer factor 2 (MEF2) are transcription factors recently identified in somatic cells of the male gonad. In other tissues, MEF2 factors are essential regulators of organogenesis and cell differentiation. So far in the testis, MEF2 factors were found to regulate Leydig cell steroidogenesis by controlling Nr4a1 and Star gene expression. To expand our understanding of the role of MEF2 in Leydig cells, we performed microarray analyses of MEF2-depleted MA-10 Leydig cells, and the results were analyzed using Partek and Ingenuity Pathway Analysis software. Several genes were differentially expressed in MEF2 depleted Leydig cells, and 16 were validated by quantitative RT-PCR. A large number of these genes are known to be involved in fertility, gonad morphology, and steroidogenesis. These include Ahr, Bmal1, Cyp1b1, Hsd3b1, Hsd17b7, Map2k1, Nr0b2, Pde8a, Por, Smad4, Star, and Tsc22d3, which were all downregulated in the absence of MEF2. In silico analyses revealed the presence of MEF2-binding sites within the first 2 kb upstream of the transcription start site of the Por, Bmal1, and Nr0b2 promoters, suggesting direct regulation by MEF2. Using transient transfections in MA-10 Leydig cells, small interfering RNA knockdown, and a MEF2 Engrailed dominant negative, we found that MEF2 activates the Por, Bmal1, and Nr0b2 promoters and that this requires an intact MEF2 element. Our results identify novel target genes for MEF2 and define MEF2 as an important regulator of Leydig cell function and male reproduction. PMID- 26019260 TI - Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice. AB - Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms. PMID- 26019263 TI - Patients' and Family Members' Decision-Making and Information Disclosure Preferences in a Single-Center Survey in China: A Pilot Study. AB - BACKGROUND: Understanding the medical decision-making and information disclosure preferences is important for care quality. OBJECTIVES: To examine the feasibility of using the questionnaires and to identify modifications needed in the following study. DESIGN: Thirty-three pairs of patients with advanced cancers and their caregivers were asked to complete the questionnaires. RESULTS: More than 60% of patients and caregivers had an educational level of middle school and below. The active, passive, or shared decision-making preferences for patients were 33.3%, 39.4%, and 27.3%, respectively. Twenty of 33 patients and 24 of 33 caregivers misunderstood the questions. CONCLUSIONS: Low educational levels may be the reason for poor understanding imprecision. It is necessary to use the modification version of the questionnaires in developing countries. PMID- 26019264 TI - Predicting recurrent shoulder instability. PMID- 26019265 TI - Blood, sweat and tears: reclaiming the ethical high ground in sports physiotherapy. PMID- 26019266 TI - Statin Intolerance From a Clinician's Perspective. PMID- 26019267 TI - Proteomic and Epigenetic Analyses of Lotus (Nelumbo nucifera) Petals Between Red and White cultivars. AB - Lotus is a vital aquatic ornamental plant with different flower colors. To explore the flower coloration mechanism in lotus, the constituents and contents of pigments in two lotus cultivars with red and white flowers were analyzed. Although flavones and flavonols were detected in both cultivars, anthocyanins could only be detected in the red cultivar. A comparative proteomics analysis on the flower petals between these two cultivars was conducted. A total of 88 differentially expressed proteins were identified with 36 more abundant and 52 less abundant in the red than in the white cultivar. Among them, four enzymes involved in the anthocyanin pathway were identified, i.e. flavanone 3 hydroxylase, anthocyanidin synthase, anthocyanidin 3-O-glucosyltransferase and glutathione S-transferase. Analysis of the expression patterns of anthocyanin biosynthetic genes indicated that the anthocyanindin synthase (ANS) gene might be the critical gene determining anthocyanin biosynthesis and accumulation in lotus flower. Further analysis showed that different methylation intensities on the promoter sequence of the ANS gene might result in the different flower coloration in the red and white cultivar. This study provides new insights into the mechanism of flower coloration in lotus, and may be helpful in its breeding and germplasm enhancement. PMID- 26019268 TI - SNARE Molecules in Marchantia polymorpha: Unique and Conserved Features of the Membrane Fusion Machinery. AB - The membrane trafficking pathway has been diversified in a specific way for each eukaryotic lineage, probably to fulfill specific functions in the organisms. In green plants, comparative genomics has supported the possibility that terrestrialization and/or multicellularization could be associated with the elaboration and diversification of membrane trafficking pathways, which have been accomplished by an expansion of the numbers of genes required for machinery components of membrane trafficking, including soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. However, information regarding membrane trafficking pathways in basal land plant lineages remains limited. In the present study, we conducted extensive analyses of SNARE molecules, which mediate membrane fusion between target membranes and transport vesicles or donor organelles, in the liverwort, Marchantia polymorpha. The M. polymorpha genome contained at least 34 genes for 36 SNARE proteins, comprising fundamental sets of SNARE proteins that are shared among land plant lineages with low degrees of redundancy. We examined the subcellular distribution of a major portion of these SNARE proteins by expressing Citrine-tagged SNARE proteins in M. polymorpha, and the results showed that some of the SNARE proteins were targeted to different compartments from their orthologous products in Arabidopsis thaliana. For example, MpSYP12B was localized to the surface of the oil body, which is a unique organelle in liverworts. Furthermore, we identified three VAMP72 members with distinctive structural characteristics, whose N-terminal extensions contain consensus sequences for N-myristoylation. These results suggest that M. polymorpha has acquired unique membrane trafficking pathways associated with newly acquired machinery components during evolution. PMID- 26019269 TI - Identification of a Highly Specific Isoflavone 7-O-glucosyltransferase in the soybean (Glycine max (L.) Merr.). AB - Isoflavone conjugates [7-O-beta-D-glucosides and 7-O-(6"-malonyl-beta-D glucosides) of daidzein and genistein] accumulate in soybean roots and serve as the stored precursors of isoflavones (aglycons), which play very important roles in the rhizobia-mediated nodulation of this plant. Thus far, the isoflavone 7-O glucosyltransferase (GmIF7GT or GmUGT1) has been biochemically characterized and is believed to be involved in isoflavone conjugate biosynthesis. The soybean genome encodes many other glycosyltransferase homologs (GmUGTs) that are related to GmUGT1; however, their catalytic properties, substrate specificities, and role(s) in isoflavone conjugation are unknown. In this study, nine different GmUGT1-related GmUGT cDNAs were isolated; six of these cDNAs belonged to two distinct phylogenetic subgroups (A and B), and these six were functionally characterized. The results showed that GmUGT4, a representative of subgroup A, encoded a UGT that was highly specific for isoflavones showing kcat and kcat/Km values for daidzein of 5.89 +/- 0.65 s(-1) and 2.91 * 10(5) s(-1)M(-1), respectively. Moreover, GmUGT4 was expressed in the roots (mainly in lateral roots) of the 7-day-old seedlings and seeds, both of which contained abundant amounts of isoflavone conjugates. By contrast, GmUGT1 and GmUGT7, which were subgroup B members, encoded enzymes with broad glucosyl-acceptor specificities and were mainly expressed in the aerial portions (cotyledons and hypocotyls) of the seedlings. In the present study, we proposed that the role of isoflavone glucosylation in a soybean plant is assigned to different GmUGT members in an organ/tissue-dependent manner. We also established the functional importance of GmUGT4 in the biosynthesis of isoflavone conjugates in lateral roots that make a major contribution to overall N2 fixation. PMID- 26019270 TI - Different STAT Transcription Complexes Drive Early and Delayed Responses to Type I IFNs. AB - IFNs, which transduce pivotal signals through Stat1 and Stat2, effectively suppress the replication of Legionella pneumophila in primary murine macrophages. Although the ability of IFN-gamma to impede L. pneumophila growth is fully dependent on Stat1, IFN-alphabeta unexpectedly suppresses L. pneumophila growth in both Stat1- and Stat2-deficient macrophages. New studies demonstrating that the robust response to IFN-alphabeta is lost in Stat1-Stat2 double-knockout macrophages suggest that Stat1 and Stat2 are functionally redundant in their ability to direct an innate response toward L. pneumophila. Because the ability of IFN-alphabeta to signal through Stat1-dependent complexes (i.e., Stat1-Stat1 and Stat1-Stat2 dimers) has been well characterized, the current studies focus on how Stat2 is able to direct a potent response to IFN-alphabeta in the absence of Stat1. These studies reveal that IFN-alphabeta is able to drive the formation of a Stat2 and IFN regulatory factor 9 complex that drives the expression of a subset of IFN-stimulated genes, but with substantially delayed kinetics. These observations raise the possibility that this pathway evolved in response to microbes that have devised strategies to subvert Stat1-dependent responses. PMID- 26019271 TI - Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System. AB - M-CSF (or CSF-1) and GM-CSF can regulate the development and function of the mononuclear phagocyte system (MPS). To address some of the outstanding and sometimes conflicting issues surrounding this biology, we undertook a comparative analysis of the effects of neutralizing mAbs to these CSFs on murine MPS populations in the steady-state and during acute inflammatory reactions. CSF-1 neutralization, but not of GM-CSF, in normal mice rapidly reduced the numbers of more mature Ly6C(-) monocytes in blood and bone marrow, without any effect on proliferating precursors, and also the numbers of the resident peritoneal macrophages, observations consistent with CSF-1 signaling being essential only at a relatively late state in steady-state MPS development; in contrast, GM-CSF neutralization had no effect on the numbers of these particular populations. In Ag-induced peritonitis (AIP), thioglycolate-induced peritonitis, and LPS-induced lung inflammation, CSF-1 neutralization lowered inflammatory macrophage number; in the AIP model, this reduced number was not due to suppressed proliferation. More detailed studies with the convenient AIP model indicated that CSF-1 neutralization led to a relatively uniform reduction in all inflammatory cell populations; GM-CSF neutralization, in contrast, was more selective, resulting in the preferential loss among the MPS populations of a cycling, monocyte-derived inflammatory dendritic cell population. Some mechanistic options for the specific CSF-dependent biologies enumerated are discussed. PMID- 26019272 TI - Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide. AB - Dual-specificity phosphatase (DUSP) 1 dephosphorylates and inactivates members of the MAPK superfamily, in particular, JNKs, p38alpha, and p38beta MAPKs. It functions as an essential negative regulator of innate immune responses, hence disruption of the Dusp1 gene renders mice extremely sensitive to a wide variety of experimental inflammatory challenges. The principal mechanisms behind the overexpression of inflammatory mediators by Dusp1(-/-) cells are not known. In this study, we use a genetic approach to identify an important mechanism of action of DUSP1, involving the modulation of the activity of the mRNA destabilizing protein tristetraprolin. This mechanism is key to the control of essential early mediators of inflammation, TNF, CXCL1, and CXCL2, as well as the anti-inflammatory cytokine IL-10. The same mechanism also contributes to the regulation of a large number of transcripts induced by treatment of macrophages with LPS. These findings demonstrate that modulation of the phosphorylation status of tristetraprolin is an important physiological mechanism by which innate immune responses can be controlled. PMID- 26019274 TI - Photosensitizer and Light Pave the Way for Cytosolic Targeting and Generation of Cytosolic CD8 T Cells Using PLGA Vaccine Particles. AB - The generation of CTLs is crucial in the immunological fight against cancer and many infectious diseases. To achieve this, vaccine Ags need to be targeted to the cytosol of dendritic cells, which can activate CD8 T cells via MHC class I (MHCI). Therefore, such targeting has become one of the major objectives of vaccine research. In this study, we aimed to bypass the unwanted and default MHC class II Ag presentation and trigger MHCI presentation by using a photosensitizer that, upon light activation, would facilitate cytosolic targeting of codelivered Ag. Poly(lactide-co-glycolide) microparticles ~1 MUm size were loaded with OVA and the photosensitizer tetraphenyl chlorine disulphonate (TPCS2a) and administered intradermally in mice, which were illuminated 1 d later for activation of the photosensitizer. Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-gamma, TNF-alpha, and IL-2, and prevention of tumor growth. Cytotoxicity was demonstrated by granzyme B production in vitro and by in vivo killing of CFSE-labeled targets. CD4-dependent Ab responses were abrogated in mice immunized with TPCS2a-containing particles, suggesting that photosensitization facilitated a shift from default MHC class II toward MHCI Ag presentation. Hence, vaccine particles with Ag and photosensitizers proved an effective vehicle or adjuvant for stimulation of CTLs, and they may find potential application in therapeutic cancer vaccination and in prophylactic and therapeutic vaccination against intracellular infections. PMID- 26019273 TI - Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators. AB - Proper regulation of microbial-induced cytokines is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, chronic NOD2 stimulation in macrophages decreases cytokines upon pattern recognition receptor (PRR) restimulation; cytokine attenuation to PRR stimulation is similarly observed in intestinal macrophages. The role for the transcriptional repressors Twist1 and Twist2 in regulating PRR-induced cytokine outcomes is poorly understood and has not been reported for NOD2. We found that Twist1 and Twist2 were required for optimal cytokine downregulation during acute and, particularly, chronic NOD2 stimulation of human macrophages. Consistently, Twist1 and Twist2 expression was increased after chronic NOD2 stimulation; this increased expression was IL-10 and TGF-beta dependent. Although Twist1 and Twist2 did not coregulate each other's expression, they cooperated to enhance binding to cytokine promoters after chronic NOD2 stimulation. Moreover, Twist1 and Twist2 contributed to enhance expression and promoter binding of the proinflammatory inhibitor c-Maf and the transcriptional repressor Bmi1. Restoring c-Maf and Bmi1 expression in Twist-deficient macrophages restored NOD2-induced cytokine downregulation. Furthermore, with chronic NOD2 stimulation, Twist1 and Twist2 contributed to the decreased expression and cytokine promoter binding of the transcriptional activators activating transcription factor 4, C/EBPalpha, Runx1, and Runx2. Knockdown of these transcriptional activators in Twist-deficient macrophages restored cytokine downregulation after chronic NOD2 stimulation. Finally, NOD2 synergized with additional PRRs to increase Twist1 and Twist2 expression and Twist-dependent pathways. Therefore, after chronic NOD2 stimulation Twist1 and Twist2 coordinate the regulation of both transcriptional activators and repressors, thereby mediating optimal cytokine downregulation. PMID- 26019275 TI - A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPepsilon Leads to Neutrophil-Specific Granule Deficiency. AB - Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid specific transcription factor, CCAAT/enhancer binding protein-epsilon (C/EBPepsilon), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55 y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (DeltaRS) in the leucine zipper domain of the C/EBPepsilon gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the DeltaRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The DeltaRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the DeltaRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPepsilon for its essential function, and indicate that multiple molecular mechanisms lead to SGD. PMID- 26019276 TI - Central nervous system medication use in older adults with intellectual disability: Results from the successful ageing in intellectual disability study. AB - OBJECTIVE: Information on the rates and predictors of polypharmacy of central nervous system medication in older people with intellectual disability is limited, despite the increased life expectancy of this group. This study examined central nervous system medication use in an older sample of people with intellectual disability. METHODS: Data regarding demographics, psychiatric diagnoses and current medications were collected as part of a larger survey completed by carers of people with intellectual disability over the age of 40 years. Recruitment occurred predominantly via disability services across different urban and rural locations in New South Wales and Victoria. Medications were coded according to the Monthly Index of Medical Specialties central nervous system medication categories, including sedatives/hypnotics, anti-anxiety agents, antipsychotics, antidepressants, central nervous system stimulants, movement disorder medications and anticonvulsants. The Developmental Behaviour Checklist for Adults was used to assess behaviour. RESULTS: Data were available for 114 people with intellectual disability. In all, 62.3% of the sample was prescribed a central nervous system medication, with 47.4% taking more than one. Of those who were medicated, 46.5% had a neurological diagnosis (a seizure disorder or Parkinson's disease) and 45.1% had a psychiatric diagnosis (an affective or psychotic disorder). Linear regression revealed that polypharmacy was predicted by the presence of neurological and psychiatric diagnosis, higher Developmental Behaviour Checklist for Adults scores and male gender. CONCLUSION: This study is the first to focus on central nervous system medication in an older sample with intellectual disability. The findings are in line with the wider literature in younger people, showing a high degree of prescription and polypharmacy. Within the sample, there seems to be adequate rationale for central nervous system medication prescription. Although these data do not indicate non-adherence to guidelines for prescribing in intellectual disability, the high rate of polypharmacy and its relationship to Developmental Behaviour Checklist for Adults scores reiterate the importance of continued medication review in older people with intellectual disability. PMID- 26019277 TI - 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. AB - Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have been reported, coding mutations are scarcer. It is thus of great interest that patients have recently been described with microdeletions encompassing BCL11A. These patients display neurodevelopmental abnormalities, but whether they show increased HbF has not been reported. We have examined the hematological phenotype, HbF levels, and erythroid BCL11A expression in 3 such patients. Haploinsufficiency of BCL11A induces only partial developmental gamma-globin silencing. Of greater interest is that a patient with a downstream deletion exhibits reduced BCL11A expression and increased HbF. Novel erythroid-specific regulatory elements in this region may be required for normal erythroid BCL11A expression, whereas loss of separate elements in the developing brain may explain the neurological phenotype. PMID- 26019278 TI - Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. AB - Hemolysis and consequent release of cell-free hemoglobin (CFHb) impair vascular nitric oxide (NO) bioavailability and cause oxidative and inflammatory processes. Hydroxyurea (HU), a common therapy for sickle cell disease (SCD), induces fetal Hb production and can act as an NO donor. We evaluated the acute inflammatory effects of intravenous water-induced hemolysis in C57BL/6 mice and determined the abilities of an NO donor, diethylamine NONOate (DEANO), and a single dose of HU to modulate this inflammation. Intravenous water induced acute hemolysis in C57BL/6 mice, attaining plasma Hb levels comparable to those observed in chimeric SCD mice. This hemolysis resulted in significant and rapid systemic inflammation and vascular leukocyte recruitment within 15 minutes, accompanied by NO metabolite generation. Administration of another potent NO scavenger (2-phenyl 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) to C57BL/6 mice induced similar alterations in leukocyte recruitment, whereas hemin-induced inflammation occurred over a longer time frame. Importantly, the acute inflammatory effects of water induced hemolysis were abolished by the simultaneous administration of DEANO or HU, without altering CFHb, in an NO pathway-mediated manner. In vitro, HU partially reversed the Hb-mediated induction of endothelial proinflammatory cytokine secretion and adhesion molecule expression. In summary, pathophysiological levels of hemolysis trigger an immediate inflammatory response, possibly mediated by vascular NO consumption. HU presents beneficial anti-inflammatory effects by inhibiting rapid-onset hemolytic inflammation via an NO-dependent mechanism, independently of fetal Hb elevation. Data provide novel insights into mechanisms of hemolytic inflammation and further support perspectives for the use of HU as an acute treatment for SCD and other hemolytic disorders. PMID- 26019280 TI - Teenage obesity is linked to bowel cancer in later life. PMID- 26019279 TI - Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. AB - Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF. PMID- 26019281 TI - Delaying cord clamping is linked to improvements in fine motor skills. PMID- 26019282 TI - The Solid Component of Radiographically Non-Growing, Post-Radiated Vestibular Schwannoma Retains Proliferative Capacity: Implications for Patient Counseling. AB - OBJECTIVE: Nearly all radiated vestibular schwannomas (VS) have solid tissue remaining at the radiation bed. The viability and proliferation capacity of this tissue has never been objectively assessed. The goals of our study were to (1) determine whether this tissue retains the morphological and immunohistochemical features of VS and (2) evaluate whether the tissue is capable of proliferation in cell culture. METHODS: Case history, magnetic resonance imaging (MRI), cell culture, histology, and immunohistochemistry. RESULTS: We report the first case of a post-radiated, sporadic VS patient whose non-growing, residual MR-enhancing solid tissue was examined histologically and in cell culture. These cells were architecturally identical to non-radiated VS, had a Ki67 proliferative index similar to non-radiated sporadic and NF2-associated VS, were S100 positive, and grew in culture with kinetics comparable to non-radiated VS. CONCLUSION: The long term risk for delayed tumor growth and/or secondary malignancy in radiated VS patients is unknown. Because the average life span in the United States is nearly 80 years, patients should be informed that (1) residual VS cells are viable even when tumors appear to be non-growing on MRI, (2) post-radiation surveillance imaging is required indefinitely, and (3) radiation may incur more risk in those patients with life expectancy>20-25 years. PMID- 26019283 TI - Hemoglobin C Trait Provides Protection From Clinical Falciparum Malaria in Malian Children. AB - BACKGROUND: Hemoglobin C trait, like hemoglobin S trait, protects against severe malaria in children, but it is unclear whether hemoglobin C trait also protects against uncomplicated malaria. We hypothesized that Malian children with hemoglobin C trait would have a lower risk of clinical malaria than children with hemoglobin AA. METHODS: Three hundred children aged 0-6 years were enrolled in a cohort study of malaria incidence in Bandiagara, Mali, with continuous passive and monthly active follow-up from June 2009 to June 2010. RESULTS: Compared to hemoglobin AA children (n = 242), hemoglobin AC children (n = 39) had a longer time to first clinical malaria episode (hazard ratio [HR], 0.19; P = .001; 364 median malaria-free days vs 181 days), fewer episodes of clinical malaria, and a lower cumulative parasite burden. Similarly, hemoglobin AS children (n = 14) had a longer time to first clinical malaria episode than hemoglobin AA children (HR, 0.15; P = .015; 364 median malaria-free days vs 181 days), but experienced the most asymptomatic malaria infections of any group. CONCLUSIONS: Both hemoglobin C and S traits exerted a protective effect against clinical malaria episodes, but appeared to do so by mechanisms that differentially affect the response to infecting malaria parasites. PMID- 26019285 TI - Focal Screening to Identify the Subpatent Parasite Reservoir in an Area of Low and Heterogeneous Transmission in the Kenya Highlands. AB - BACKGROUND: Mass screening and treatment currently fails to identify a considerable fraction of low parasite density infections, while mass treatment exposes many uninfected individuals to antimalarial drugs. Here we test a hybrid approach to screen a sentinel population to identify clusters of subpatent infections in the Kenya highlands with low, heterogeneous malaria transmission. METHODS: Two thousand eighty-two inhabitants were screened for parasitemia by nested polymerase chain reaction (nPCR). Children aged <= 15 years and febrile adults were also tested for malaria by rapid diagnostic test (RDT) and served as sentinel members to identify subpatent infections within the household. All parasitemic individuals were assessed for multiplicity of infections by nPCR and gametocyte carriage by nucleic acid sequence-based amplification. RESULTS: Households with RDT-positive individuals in the sentinel population were more likely to have nPCR-positive individuals (odds ratio: 1.71, 95% confidence interval, 1.60-1.84). The sentinel population identified 64.5% (locality range: 31.6%-81.2%) of nPCR-positive households and 77.3% (locality range: 24.2%-91.0%) of nPCR-positive individuals. The sensitivity of the sentinel screening approach was positively associated with transmission intensity (P = .037). CONCLUSIONS: In this low endemic area, a focal screening approach with RDTs prior to the high transmission season was able to identify the majority of the subpatent parasite reservoirs. PMID- 26019286 TI - David Nutt: Champions off-licence prescribing. PMID- 26019284 TI - Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production. AB - The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG 3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4(+) and CD8(+) T cells. Higher frequencies of CD4(+) express more than 1 regulatory molecule compared to CD8(+) T cells. Moreover, lower proportions of CD4(+) T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin-3 signaling restores the cytokine production by antigen specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function. PMID- 26019287 TI - Hypochondriasis: treatment options for a diagnostic quagmire. AB - OBJECTIVE: This article presents the conceptual and diagnostic conundrums surrounding hypochondriasis and reviews current treatment options for this disorder. CONCLUSIONS: The removal of hypochondriasis from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and its replacement with two new diagnostic entities have been controversial. It appears that the Eleventh Revision of the International Classification of Diseases will take a more cautious approach and emphasise the links between hypochondriasis, obsessive compulsive disorder and other anxiety disorders. The cornerstone of any treatment approach to hypochondriasis is establishing a good therapeutic relationship with the patient. Psychological treatments, especially cognitive-behavioural therapy, have been more useful than pharmacotherapy, but there is much room for improving treatment outcomes. PMID- 26019288 TI - Assessment and treatment of hoarding disorder. AB - OBJECTIVES: To provide a brief selective review of the current literature regarding Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Hoarding Disorder, with an emphasis on its associated risks, assessment and management approaches. CONCLUSIONS: Hoarding disorder is defined by clear diagnostic criteria. It can be a severe and disabling disorder that can pose significant safety risks to the individual and to others. Management is often challenging, due to the poor level of insight that people with hoarding disorder often have. Psychological approaches tend to adapt cognitive-behavioural approaches, in order to specifically target areas such as impaired decision making and motivation. Several trials of pharmacological agents have been conducted, but the limitations of these studies call for further research. PMID- 26019289 TI - Afterhyperpolarization (AHP) regulates the frequency and timing of action potentials in the mitral cells of the olfactory bulb: role of olfactory experience. AB - Afterhyperpolarization (AHP) is a principal feedback mechanism in the control of the frequency and patterning of neuronal firing. In principal projection neurons of the olfactory bulb, the mitral cells (MCs), the AHP is produced by three separate components: classical potassium-mediated hyperpolarization, and the excitatory and inhibitory components, which are generated by the recurrent dendrodendritic synaptic transmission. Precise spike timing is involved in olfactory coding and learning, as well as in the appearance of population oscillatory activity. However, the contribution of the AHP and its components to these processes remains unknown. In this study, we demonstrate that the AHP is developed with the MC firing frequency and is dominated by the potassium component. We also show that recurrent synaptic transmission significantly modifies MC AHP and that the strength of the hyperpolarization produced by the AHP in the few milliseconds preceding the action potential (AP) emission determines MC firing frequency and AP timing. Moreover, we show that the AHP area is larger in younger animals, possibly owing to increased Ca(2+) influx during MC firing. Finally, we show that olfactory experience selectively reduces the early component of the MC AHP (under 25 msec), thus producing a modification of the AP timing limited to the higher firing frequency. On the basis of these results, we propose that the AHP, and its susceptibility to be selectively modulated by the recurrent synaptic transmission and olfactory experience, participate in odor coding and learning by modifying the frequency and pattern of MC firing. PMID- 26019290 TI - Effect of antecedent moderate-intensity exercise on the glycemia-increasing effect of a 30-sec maximal sprint: a sex comparison. AB - This study investigated whether a prior bout of moderate-intensity exercise attenuates the glycemia-increasing effect of a maximal 30-sec sprint. A secondary aim was to determine whether the effect of antecedent exercise on the glucoregulatory response to sprinting is affected by sex. Participants (men n = 8; women n = 7) were tested on two occasions during which they either rested (CON) or cycled for 60-min at a moderate intensity of ~65% V O 2 peak (EX) before performing a 30-sec maximal cycling effort 195 min later. In response to the sprint, blood glucose increased to a similar extent between EX and CON trials, peaking at 10 min of recovery, with no difference between sexes (P > 0.05). Blood glucose then declined at a faster rate in EX, and this was associated with a glucose rate of disappearance (R d) that exceeded the glucose rate of appearance (R a) earlier in EX compared with CON, although the overall glucose R a and R d profile was higher in men compared with women (P < 0.05). The response of growth hormone was attenuated during recovery from EX compared with CON (P < 0.05), with a lower absolute response in women compared with men (P < 0.05). The response of epinephrine and norepinephrine was also lower in women compared with men (P < 0.05) but similar between trials. In summary, a prior bout of moderate-intensity exercise does not affect the magnitude of the glycemia increasing response to a 30-sec sprint; however, the subsequent decline in blood glucose is more rapid. This blood glucose response is similar between men and women, despite less pronounced changes in glucose R a and R d, and a lower response of plasma catecholamines and growth hormone to sprinting in women. PMID- 26019291 TI - An investigation into the relationship between small intestinal fluid secretion and systemic arterial blood pressure in the anesthetized rat. AB - The effects of changes in the steady level of diastolic blood pressure on fluid flux across the jejunum has been investigated in the anesthetized rat during perfusion with a nutrient-free and Na(+)-free solution. Diastolic blood pressure was manipulated by intravenous infusions, during the jejunal perfusions, of vasodilators (vasoactive intestinal polypeptide, acetyl-beta-methylcholine, and phentolamine) and a vasoconstrictor (arginine vasopressin), each of which acts through a different cellular mechanism. The outcome was that fluid flux was related by a parabolic relationship with diastolic blood pressure in which net secretion occurred over the range 40-100 mmHg, whereas net absorption was recorded at diastolic pressures exceeding 100 mmHg and below 40 mmHg. Against a background of normal absorption promoted by perfusion with 145 mmol L(-1) Na(+)/5 mmol L(-1) glucose solution, reductions in diastolic blood pressure markedly reduced the mean rate of fluid absorption by 58% overall, whereas the rate of glucose absorption remained unchanged. Our results were explained on the basis that vasodilatation led to increased capillary pressure and then to net filtration of fluid from the mesenteric capillary bed. Experiments in which Escherichia coli heat-stable toxin was added to the jejunal perfusate confirmed the absence of a secretory response, which was consistent with the absence of effect of the toxin on diastolic blood pressure. PMID- 26019292 TI - Validity and reproducibility of a novel method for time-course evaluation of diet induced thermogenesis in a respiratory chamber. AB - We developed a novel method for computing diet-induced thermogenesis (DIT) in a respiratory chamber and evaluated the validity and reproducibility of the method. We hypothesized that DIT may be calculated as the difference between postprandial energy expenditure (EE) and estimated EE (sum of basal metabolic rate and physical activity (PA)-related EE). The estimated EE was derived from the regression equation between EE from respiration and PA intensity in the fasting state. It may be possible to evaluate the time course of DIT using this novel technique. In a validity study, we examined whether DIT became zero (theoretical value) for 6 h of fasting in 11 subjects. The mean value of DIT calculated by the novel and traditional methods was 22.4 +/- 13.4 and 3.4 +/- 31.8 kcal/6 h, respectively. In the reproducibility study, 15 adult subjects lived in the respiratory chamber for over 24 h on two occasions. The DIT over 15 h of postprandial wake time was calculated. There were no significant differences in the mean values of DIT between the two test days. The within-subject day-to-day coefficient of variation for calculated DIT with the novel and traditional methods was approximately 35% and 25%, respectively. The novel method did not have superior reproducibility compared with that of the traditional method. However when comparing the smaller variation in the fasting state than the theoretical value (zero), the novel method may be better for evaluating interindividual differences in DIT than the traditional method and also has the ability to evaluate the time-course. PMID- 26019293 TI - Sympathetic vasomotor outflow and blood pressure increase during exercise with expiratory resistance. AB - The purpose of the present study was to elucidate the effect of increasing expiratory muscle work on sympathetic vasoconstrictor outflow and arterial blood pressure (BP) during dynamic exercise. We hypothesized that expiratory muscle fatigue would elicit increases in sympathetic vasomotor outflow and BP during submaximal exercise. The subjects performed four submaximal exercise tests; two were maximal expiratory pressure (PE max) tests and two were muscle sympathetic nerve activity (MSNA) tests. In each test, the subjects performed two 10-min exercises at 40% peak oxygen uptake using a cycle ergometer in a semirecumbent position [spontaneous breathing for 5 min and voluntary hyperpnoea with and without expiratory resistive breathing for 5 min (breathing frequency: 60 breaths/min, inspiratory and expiratory times were set at 0.5 sec)]. PE max was estimated before and immediately after exercises. MSNA was recorded via microneurography of the right median nerve at the elbow. PE max decreased following exercise with expiratory resistive breathing, while no change was found without resistance. A progressive increase in MSNA burst frequency (BF) appeared during exercise with expiratory resistance (MSNA BF, without resistance: +22 +/- 5%, with resistance: +44 +/- 8%, P < 0.05), accompanied by an augmentation of BP (mean BP, without resistance: +5 +/- 2%, with resistance: +29 +/- 5%, P < 0.05). These results suggest that an enhancement of expiratory muscle activity leads to increases in sympathetic vasomotor outflow and BP during dynamic leg exercise. PMID- 26019294 TI - Control of IFN-gamma production and regulatory function by the inducible nuclear protein IkappaB-zeta in T cells. AB - The transcriptional regulator IkappaB-zeta is important for the control of apoptosis in keratinocytes. Thus, IkappaB-zeta-deficient mice develop autoimmune diseases, such as Sjogren's syndrome. However, T cells also play a pivotal role in Sjogren's syndrome. To study the role of IkappaB-zeta in T cells, we generated T cell-specific, IkappaB-zeta-deficient mice. We observed increased numbers of peripheral effector/memory CD4(+) cells and IFN-gamma-producing CD4(+) cells in 3 week-old mice. We found that IkappaB-zeta can be up-regulated by TGF-beta1 in naive CD4(+) T cells and that it negatively regulates IFN-gamma expression. In addition, we generated Treg-specific, IkappaB-zeta deficient mice and found that IkappaB-zeta is dispensable for the plasticity and stability of Tregs. However, Tregs from T cell-specific, IkappaB-zeta-deficient mice have reduced immunoregulatory function. Thus, our data reveal a previously unappreciated role for IkappaB-zeta in IFN-gamma production in T cells and the immunoregulatory function of Tregs. PMID- 26019296 TI - Fluorescent Ly6G antibodies determine macrophage phagocytosis of neutrophils and alter the retrieval of neutrophils in mice. AB - Fluorescently labeled Ly6G antibodies enable the tracking of neutrophils in mice, whereas purified anti-Ly6G rapidly depletes neutrophils from the circulation. The mechanisms underlying neutrophil depletion are still under debate. Here, we examined how identical Ly6G antibodies coupled to different fluorochromes affect neutrophil fate in vivo. BM cells stained with Ly6G antibodies were injected into mice. The number of retrieved anti-Ly6G-FITC(+) cells was reduced significantly in comparison with anti-Ly6G-APC(+) or anti-Ly6G-PE(+) cells. Flow cytometry and multispectral imaging flow cytometry analyses revealed that anti-Ly6G-FITC(+) neutrophils were preferentially phagocytosed by BMMs in vitro and by splenic, hepatic, and BM macrophages in vivo. Direct antibody injection of anti-Ly6G-FITC but not anti-Ly6G-PE depleted neutrophils to the same degree as purified anti Ly6G, indicating that the FITC-coupled antibody eliminates neutrophils by a similar mechanism as the uncoupled antibody. With the use of a protein G-binding assay, we demonstrated that APC and PE but not FITC coupling inhibited access to interaction sites on the anti-Ly6G antibody. We conclude the following: 1) that neutrophil phagocytosis by macrophages is a central mechanism in anti-Ly6G induced neutrophil depletion and 2) that fluorochrome-coupling can affect functional properties of anti-Ly6G antibodies, thereby modifying macrophage uptake of Ly6G-labeled neutrophils and neutrophil retrieval following adoptive cell transfer or injection of fluorescent anti-Ly6G. PMID- 26019295 TI - Shedding of TNF receptor 2 by effector CD8+ T cells by ADAM17 is important for regulating TNF-alpha availability during influenza infection. AB - Elevated levels of solTNFR2 are observed in a variety of human pathophysiological conditions but regulation of TNFR2 levels during disease is not well understood. We found that solTNFR2 levels were increased following influenza infection or live-attenuated influenza virus challenge in mice and humans, respectively. As influenza-specific CD8(+) T cells up-regulated expression of TNFR2 after infection in mice, we hypothesized that CD8(+) T cells contributed, in part, to solTNFR2 production after influenza infection and were interested in the mechanisms by which CD8(+) T cells regulate TNFR2 shedding. Activation of these cells by TCR stimulation resulted in enhanced shedding of TNFR2 that required actin remodeling and lipid raft formation and was dependent on MAPK/ERK signaling. Furthermore, we identified ADAM17 as the protease responsible for TNFR2 shedding by CD8(+) T cells, with ADAM17 and TNFR2 required in "cis" for shedding to occur. We observed similar activation thresholds for TNF-alpha expression and TNFR2 shedding, suggesting that solTNFR2 functioned, in part, to regulate solTNF-alpha levels. Production of solTNFR2 by activated CD8(+) T cells reduced the availability of solTNF-alpha released by these cells, and TNFR2 blockade during influenza infection in mice enhanced the levels of solTNF-alpha, supporting this hypothesis. Taken together, this study identifies critical cellular mechanisms regulating TNFR2 shedding on CD8(+) T cells and demonstrates that TNFR2 contributes, in part, to the regulation of TNF-alpha levels during infection. PMID- 26019297 TI - Are clinical trials units essential for a successful trial? PMID- 26019298 TI - Correction to "Evidence for the Criterion Validity and Clinical Utility of the Pathological Narcissism Inventory". AB - In our article "Evidence for the Criterion Validity and Clinical Utility of the Pathological Narcissism Inventory" (2012), we provided incorrect values for the r(contrast-cv) coefficients we presented in Table 1. In the current report, we provide correct r(contrast-cv) values in Table 1 and discuss the implications of our updated results, particularly with respect to how these results differ from our initial report. PMID- 26019299 TI - Briefly Assessing Repetitive Thought Dimensions: Valence, Purpose, and Total. AB - Discrete forms of repetitive thought (RT), such as worry and reflection, can be characterized along basic dimensions of valence (positive vs. negative) and purpose (searching vs. solving). In addition, people can be characterized as high or low in their tendency to engage in RT. This dimensional model has been demanding to assess, and a smaller number of items that could stand in for a large battery would make measurement more accessible. Using four samples (N = 1,588), eight items that assess RT valence, purpose, and total in a circumplex model were identified. Across these and other samples, the dimensions were adequately reliable and valid with regard to assessment via large RT battery, other measures of RT, and depressive symptoms. The accessibility of dimensional assessment of RT using this smaller number of items should facilitate work on questions about the qualities of RT that predict mental and physical health. PMID- 26019300 TI - Germination Potential of Dormant and Nondormant Arabidopsis Seeds Is Driven by Distinct Recruitment of Messenger RNAs to Polysomes. AB - Dormancy is a complex evolutionary trait that temporally prevents seed germination, thus allowing seedling growth at a favorable season. High-throughput analyses of transcriptomes have led to significant progress in understanding the molecular regulation of this process, but the role of posttranscriptional mechanisms has received little attention. In this work, we have studied the dynamics of messenger RNA association with polysomes and compared the transcriptome with the translatome in dormant and nondormant seeds of Arabidopsis (Arabidopsis thaliana) during their imbibition at 25 degrees C in darkness, a temperature preventing germination of dormant seeds only. DNA microarray analysis revealed that 4,670 and 7,028 transcripts were differentially abundant in dormant and nondormant seeds in the transcriptome and the translatome, respectively. We show that there is no correlation between transcriptome and translatome and that germination regulation is also largely translational, implying a selective and dynamic recruitment of messenger RNAs to polysomes in both dormant and nondormant seeds. The study of 5' untranslated region features revealed that GC content and the number of upstream open reading frames could play a role in selective translation occurring during germination. Gene Ontology clustering showed that the functions of polysome-associated transcripts differed between dormant and nondormant seeds and revealed actors in seed dormancy and germination. In conclusion, our results demonstrate the essential role of selective polysome loading in this biological process. PMID- 26019301 TI - Transcriptional Activity of the MADS Box ARLEQUIN/TOMATO AGAMOUS-LIKE1 Gene Is Required for Cuticle Development of Tomato Fruit. AB - Fruit development and ripening entail key biological and agronomic events, which ensure the appropriate formation and dispersal of seeds and determine productivity and yield quality traits. The MADS box gene Arlequin/tomato Agamous like1 (hereafter referred to as TAGL1) was reported as a key regulator of tomato (Solanum lycopersicum) reproductive development, mainly involved in flower development, early fruit development, and ripening. It is shown here that silencing of the TAGL1 gene (RNA interference lines) promotes significant changes affecting cuticle development, mainly a reduction of thickness and stiffness, as well as a significant decrease in the content of cuticle components (cutin, waxes, polysaccharides, and phenolic compounds). Accordingly, overexpression of TAGL1 significantly increased the amount of cuticle and most of its components while rendering a mechanically weak cuticle. Expression of the genes involved in cuticle biosynthesis agreed with the biochemical and biomechanical features of cuticles isolated from transgenic fruits; it also indicated that TAGL1 participates in the transcriptional control of cuticle development mediating the biosynthesis of cuticle components. Furthermore, cell morphology and the arrangement of epidermal cell layers, on whose activity cuticle formation depends, were altered when TAGL1 was either silenced or constitutively expressed, indicating that this transcription factor regulates cuticle development, probably through the biosynthetic activity of epidermal cells. Our results also support cuticle development as an integrated event in the fruit expansion and ripening processes that characterize fleshy-fruited species such as tomato. PMID- 26019302 TI - Visfatin, a novel adipokine, stimulates glucose uptake through the Ca2 + dependent AMPK-p38 MAPK pathway in C2C12 skeletal muscle cells. AB - Visfatin is a novel adipocytokine produced by visceral fat. In the present study, visfatin increased AMP-activated protein kinase (AMPK) phosphorylation in mouse C2C12 skeletal muscle cells. It also increased phosphorylation of the insulin receptor, whose knockdown blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin stimulated glucose uptake in differentiated skeletal muscle cells. However, inhibition of AMPKalpha2 with an inhibitor or with knockdown of AMPKalpha2 using siRNA blocked visfatin-induced glucose uptake, which indicates that visfatin stimulates glucose uptake through the AMPKalpha2 pathway. Visfatin increased the intracellular Ca(2) (+) concentration. STO-609, a calmodulin-dependent protein kinase kinase inhibitor, blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin-mediated activation of p38 MAPK was AMPKalpha2-dependent. Furthermore, both inhibition and knockdown of p38 MAPK blocked visfatin-induced glucose uptake. Visfatin increased glucose transporter type 4 (GLUT4) mRNA and protein levels. In addition, visfatin stimulated the translocation of GLUT4 to the plasma membrane, and this effect was suppressed by AMPKalpha2 inhibition. The present results indicate that visfatin plays an important role in glucose metabolism via the Ca(2) (+)-mediated AMPK-p38 MAPK pathway. PMID- 26019303 TI - Common Characteristics of Improvisational Approaches in Music Therapy for Children with Autism Spectrum Disorder: Developing Treatment Guidelines. AB - BACKGROUND: Improvisational methods of music therapy have been increasingly applied in the treatment of individuals with autism spectrum disorder (ASD) over the past decades in many countries worldwide. OBJECTIVE: This study aimed at developing treatment guidelines based on the most important common characteristics of improvisational music therapy (IMT) with children affected by ASD as applied across various countries and theoretical backgrounds. METHODS: After initial development of treatment principle items, a survey among music therapy professionals in 10 countries and focus group workshops with experienced clinicians in three countries were conducted to evaluate the items and formulate revised treatment guidelines. To check usability, a treatment fidelity assessment tool was subsequently used to rate therapy excerpts. RESULTS: Survey findings and feedback from the focus groups corroborated most of the initial principles for IMT in the context of children with ASD. Unique and essential principles include facilitating musical and emotional attunement, musically scaffolding the flow of interaction, and tapping into the shared history of musical interaction between child and therapist. Raters successfully used the tool to evaluate treatment adherence and competence. CONCLUSIONS: Summarizing an international consensus about core principles of improvisational approaches in music therapy for children with ASD, these treatment guidelines may be applied in diverse theoretical models of music therapy. They can be used to assess treatment fidelity, and may be applied to facilitate future research, clinical practice, and training. PMID- 26019304 TI - Let's talk about it: Peer victimization experiences as reported by adolescents with autism spectrum disorder. AB - Individuals with autism spectrum disorder experience high rates of peer victimization; yet, their personal experiences and perceptions of such victimization are not well understood. In this qualitative investigation, responses to questions about bullying and teasing were examined to gain insight into the perception of peer victimization as reported by adolescents with autism spectrum disorder. While the majority of participants provided examples of peer victimization, their situations differed from items typically assessed on bullying questionnaires. Participants were also able to provide explanations for why they believe they are targets and descriptions of their reactions to bullying. Findings from the interviews are used to provide suggestions for the development of more informative bullying assessments and prevention programs for students with autism spectrum disorder. PMID- 26019305 TI - Perceived self-efficacy in parents of adolescents and adults with autism spectrum disorder. AB - Many parents of adolescents and adults with autism spectrum disorder experience difficulty accessing appropriate services for their children, and may report low levels of parent self-efficacy. In an effort to identify the factors that contribute to the difficulties these families face, this study examined the role of demographic, systemic, and clinical need variables as they relate to parents' experience of self-efficacy. Participants included 324 parents of individuals with autism spectrum disorder, 12-25 years of age. Results suggest that parent self-efficacy is related to a number of variables and not simply a child's clinical situation, including child age, parent immigrant status, barriers to service access, and caregiver burden. Given the crucial role that parents often play in the lives of individuals with autism spectrum disorder across the lifespan, it is important that service providers support the efforts of parents who provide and access care for their children. PMID- 26019306 TI - Longitudinal patterns of employment and postsecondary education for adults with autism and average-range IQ. AB - This study examined correlates of participation in postsecondary education and employment over 12 years for 73 adults with autism spectrum disorders and average range IQ whose families were part of a larger, longitudinal study. Correlates included demographic (sex, maternal education, paternal education), behavioral (activities of daily living, maladaptive behaviors, autism symptoms), and family (size of maternal social network; maternal depressive symptoms, anxiety, and pessimism) factors. Although two-thirds of adults with autism spectrum disorder participated in competitive employment/postsecondary education during the study, fewer than 25% maintained these activities over the study period. Behavioral characteristics distinguished those who never had competitive employment/postsecondary education from those who sometimes or consistently participated in these activities. Women were considerably less likely than men to maintain employment/postsecondary education over time. PMID- 26019307 TI - Further understanding of complex information processing in verbal adolescents and adults with autism spectrum disorders. AB - More than 20 years ago, Minshew and colleagues proposed the Complex Information Processing model of autism in which the impairment is characterized as a generalized deficit involving multiple modalities and cognitive domains that depend on distributed cortical systems responsible for higher order abilities. Subsequent behavioral work revealed a related dissociation between concept formation and concept identification in autism suggesting the lack of an underlying organizational structure to manage increases in processing loads. The results of a recent study supported the impact of this relative weakness in conceptual reasoning on adaptive functioning in children and adults with autism. In this study, we provide further evidence of the difficulty relatively able older adolescents and adults with autism have with conceptual reasoning and provide evidence that this characterizes their difference from age- and ability matched controls with typical development better than their differences in language. For verbal adults with autism, language may serve as a bootstrap or compensatory mechanism for learning but cannot overcome an inherent weakness in concept formation that makes information processing challenging as task demands increase. PMID- 26019310 TI - Five key factors determining pairwise correlations in visual cortex. AB - The responses of cortical neurons to repeated presentation of a stimulus are highly variable, yet correlated. These "noise correlations" reflect a low dimensional structure of population dynamics. Here, we examine noise correlations in 22,705 pairs of neurons in primary visual cortex (V1) of anesthetized cats, during ongoing activity and in response to artificial and natural visual stimuli. We measured how noise correlations depend on 11 factors. Because these factors are themselves not independent, we distinguished their influences using a nonlinear additive model. The model revealed that five key factors play a predominant role in determining pairwise correlations. Two of these are distance in cortex and difference in sensory tuning: these are known to decrease correlation. A third factor is firing rate: confirming most earlier observations, it markedly increased pairwise correlations. A fourth factor is spike width: cells with a broad spike were more strongly correlated amongst each other. A fifth factor is spike isolation: neurons with worse isolation were more correlated, even if they were recorded on different electrodes. For pairs of neurons with poor isolation, this last factor was the main determinant of correlations. These results were generally independent of stimulus type and timescale of analysis, but there were exceptions. For instance, pairwise correlations depended on difference in orientation tuning more during responses to gratings than to natural stimuli. These results consolidate disjoint observations in a vast literature on pairwise correlations and point towards regularities of population coding in sensory cortex. PMID- 26019309 TI - Perceptual decision related activity in the lateral geniculate nucleus. AB - Fundamental to neuroscience is the understanding of how the language of neurons relates to behavior. In the lateral geniculate nucleus (LGN), cells show distinct properties such as selectivity for particular wavelengths, increments or decrements in contrast, or preference for fine detail versus rapid motion. No studies, however, have measured how LGN cells respond when an animal is challenged to make a perceptual decision using information within the receptive fields of those LGN cells. In this study we measured neural activity in the macaque LGN during a two-alternative, forced-choice (2AFC) contrast detection task or during a passive fixation task and found that a small proportion (13.5%) of single LGN parvocellular (P) and magnocellular (M) neurons matched the psychophysical performance of the monkey. The majority of LGN neurons measured in both tasks were not as sensitive as the monkey. The covariation between neural response and behavior (quantified as choice probability) was significantly above chance during active detection, even when there was no external stimulus. Interneuronal correlations and task-related gain modulations were negligible under the same condition. A bottom-up pooling model that used sensory neural responses to compute perceptual choices in the absence of interneuronal correlations could fully explain these results at the level of the LGN, supporting the hypothesis that the perceptual decision pool consists of multiple sensory neurons and that response fluctuations in these neurons can influence perception. PMID- 26019311 TI - Opioids potentiate electrical transmission at mixed synapses on the Mauthner cell. AB - Opioid receptors were shown to modulate a variety of cellular processes in the vertebrate central nervous system, including synaptic transmission. While the effects of opioid receptors on chemically mediated transmission have been extensively investigated, little is known of their actions on gap junction mediated electrical synapses. Here we report that pharmacological activation of mu-opioid receptors led to a long-term enhancement of electrical (and glutamatergic) transmission at identifiable mixed synapses on the goldfish Mauthner cells. The effect also required activation of both dopamine D1/5 receptors and postsynaptic cAMP-dependent protein kinase A, suggesting that opioid-evoked actions are mediated indirectly via the release of dopamine from varicosities known to be located in the vicinity of the synaptic contacts. Moreover, inhibitory inputs situated in the immediate vicinity of these excitatory synapses on the lateral dendrite of the Mauthner cell were not affected by activation of mu-opioid receptors, indicating that their actions are restricted to electrical and glutamatergic transmissions co-existing at mixed contacts. Thus, as their chemical counterparts, electrical synapses can be a target for the modulatory actions of the opioid system. Because gap junctions at these mixed synapses are formed by fish homologs of the neuronal connexin 36, which is widespread in mammalian brain, it is likely that this regulatory property applies to electrical synapses elsewhere as well. PMID- 26019312 TI - No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients. AB - Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. PMID- 26019313 TI - Direct-effects and after-effects of visuomotor adaptation with one arm on subsequent performance with the other arm. AB - Adapting to a novel sensorimotor condition is generally thought to result in the formation of an internal representation associated with the novel sensorimotor transform. While the presence of after-effects following sensorimotor adaptation is taken as evidence that such an internal representation was developed as a result of adaptation, it remains unclear whether the absence of after-effects following sensorimotor adaptation indicates that no internal representation was developed. In the present study, we examined this question by having individuals adapt to a 30 degrees visual rotation with one arm first and testing 1) how the initial adaptation would influence subsequent performance with the other arm under the same visual condition (called direct-effects) or under a normal visual condition (called after-effects); or 2) how the initial adaptation that occurred at one workspace location would influence subsequent performance at another location with the same arm under the same or a normal visual condition. Results indicated that initial adaptation with one arm significantly influenced subsequent performance with the other in terms of direct- but not after-effects and that initial adaptation at one workspace location significantly influenced subsequent performance at a new location with the same arm in terms of both direct- and after-effects, but to different extents. These findings indicate that formation of a neural representation associated with a novel visuomotor transform does not always result in after-effects and suggest that visuomotor adaptation may involve multiple aspects of a neural representation, some of which are effector independent and some of which are effector dependent. PMID- 26019314 TI - Experimental muscle pain increases variability of neural drive to muscle and decreases motor unit coherence in tremor frequency band. AB - It has been observed that muscle pain influences force variability and low frequency (<3 Hz) oscillations in the neural drive to muscle. In this study, we aimed to investigate the effect of experimental muscle pain on the neural control of muscle force at higher frequency bands, associated with afferent feedback (alpha band, 5-13 Hz) and with descending cortical input (beta band, 15-30 Hz). Single-motor unit activity was recorded, in two separate experimental sessions, from the abductor digiti minimi (ADM) and tibialis anterior (TA) muscles with intramuscular wire electrodes, during isometric abductions of the fifth finger at 10% of maximal force [maximum voluntary contraction (MVC)] and ankle dorsiflexions at 25% MVC. The contractions were repeated under three conditions: no pain (baseline) and after intramuscular injection of isotonic (0.9%, control) and hypertonic (5.8%, painful) saline. The results showed an increase of the relative power of both the force signal and the neural drive at the tremor frequency band (alpha, 5-13 Hz) between the baseline and hypertonic (painful) conditions for both muscles (P < 0.05) but no effect on the beta band. Additionally, the strength of motor unit coherence was lower (P < 0.05) in the hypertonic condition in the alpha band for both muscles and in the beta band for the ADM. These results indicate that experimental muscle pain increases the amplitude of the tremor oscillations because of an increased variability of the neural control (common synaptic input) in the tremor band. Moreover, the concomitant decrease in coherence suggests an increase in independent input in the tremor band due to pain. PMID- 26019315 TI - Smooth pursuit preparation modulates neuronal responses in visual areas MT and MST. AB - Primates are able to track small moving visual targets using smooth pursuit eye movements. Target motion for smooth pursuit is signaled by neurons in visual cortical areas MT and MST. In this study, we trained monkeys to either initiate or withhold smooth pursuit in the presence of a moving target to test whether this decision was reflected in the relative strength of "go" and "no-go" processes. We found that the gain of the motor response depended strongly on whether monkeys were instructed to initiate or withhold pursuit, thus demonstrating voluntary control of pursuit initiation. We found that the amplitude of the neuronal response to moving targets in areas MT and MST was also significantly lower on no-go trials (by 2.1 spikes/s on average). The magnitude of the neural response reduction was small compared with the behavioral gain reduction. There were no significant differences in neuronal direction selectivity, spatial selectivity, or response reliability related to pursuit initiation or the absence thereof. Variability in eye speed was negatively correlated with firing rate variability after target motion onset during go trials but not during no-go trials, suggesting that MT and MST activity represents an error signal for a negative feedback controller. We speculate that modulation of the visual motion signals in areas MT and MST may be one of the first visual cortical events in the initiation of smooth pursuit and that the small early response modulation may be amplified to produce an all-or-none motor response by downstream areas. PMID- 26019316 TI - Modulation of inhibitory and excitatory fast neurotransmission in the rat CNS by heavy water (D2O). AB - The effects of heavy water (deuterium oxide, D2O) on GABAergic and glutamatergic spontaneous and evoked synaptic transmission were investigated in acute brain slice and isolated "synaptic bouton" preparations of rat hippocampal CA3 neurons. The substitution of D2O for H2O reduced the frequency and amplitude of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration dependent manner but had no effect on glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, for evoked synaptic responses in isolated neurons, the amplitude of both inhibitory and excitatory postsynaptic currents (eIPSCs and eEPSCs) was decreased in a concentration-dependent manner. This was associated with increases of synaptic failure rate (Rf) and paired-pulse ratio (PPR). The effect was larger for eIPSCs compared with eEPSCs. These results clearly indicate that D2O acts differently on inhibitory and excitatory neurotransmitter release machinery. Furthermore, D2O significantly suppressed GABAA receptor-mediated whole cell current (IGABA) but did not affect glutamate receptor-mediated whole cell current (IGlu). The combined effects of D2O at both the pre- and postsynaptic sites may explain the greater inhibition of eIPSCs compared with eEPSCs. Finally, D2O did not enhance or otherwise affect the actions of the general anesthetics nitrous oxide and propofol on spontaneous or evoked GABAergic and glutamatergic neurotransmissions, or on IGABA and IGlu. Our results suggest that previously reported effects of D2O to mimic and/or modulate anesthesia potency result from mechanisms other than modulation of GABAergic and glutamatergic neurotransmission. PMID- 26019317 TI - Optogenetic cholinergic modulation of the mouse superior colliculus in vivo. AB - The superior colliculus (SC) plays a critical role in orienting movements, in part by integrating modulatory influences on the sensorimotor transformations it performs. Many species exhibit a robust brain stem cholinergic projection to the intermediate and deep layers of the SC arising mainly from the pedunculopontine tegmental nucleus (PPTg), which may serve to modulate SC function. However, the physiological effects of this input have not been examined in vivo, preventing an understanding of its functional role. Given the data from slice experiments, cholinergic input may have a net excitatory effect on the SC. Alternatively, the input could have mixed effects, via activation of inhibitory neurons within or upstream of the SC. Distinguishing between these possibilities requires in vivo experiments in which endogenous cholinergic input is directly manipulated. Here we used anatomical and optogenetic techniques to identify and selectively activate brain stem cholinergic terminals entering the intermediate and deep layers of the awake mouse SC and recorded SC neuronal responses. We first quantified the pattern of the cholinergic input to the mouse SC, finding that it was predominantly localized to the intermediate and deep layers. We then found that optogenetic stimulation of cholinergic terminals in the SC significantly increased the activity of a subpopulation of SC neurons. Interestingly, cholinergic input had a broad range of effects on the magnitude and timing of SC responses, perhaps reflecting both monosynaptic and polysynaptic innervation. These findings begin to elucidate the functional role of this cholinergic projection in modulating the processing underlying sensorimotor transformations in the SC. PMID- 26019321 TI - Enhancing diversity among geriatric nurse scientists. PMID- 26019318 TI - The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia. AB - Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD. PMID- 26019322 TI - Insights into the role of postsynaptic cJun and CREB2 in persistent long-term synaptic facilitation. PMID- 26019323 TI - Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving. AB - One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0.75 mg/kg, 6 h/d, 10 d), and cue-induced cocaine-seeking was examined in an extinction test after 1 or 30 d of withdrawal. We show that the withdrawal periods, as well as cue-induced cocaine seeking, are associated with broad, time-dependent enhancement of DNA methylation alterations in the nucleus accumbens (NAc). These gene methylation alterations were partly negatively correlated with gene expression changes. Furthermore, intra-NAc injections of a DNA methyltransferase inhibitor (RG108, 100 MUm) abolished cue-induced cocaine seeking on day 30, an effect that persisted 1 month, whereas the methyl donor S-adenosylmethionine (500 MUm) had an opposite effect on cocaine seeking. We then targeted two proteins whose genes were demethylated by RG108-estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with an intra-NAc injection of the ESR1 agonist propyl pyrazole triol (10 nm) or the CDK5 inhibitor roscovitine (28 MUm) on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results demonstrate a role for NAc DNA methylation, and downstream targets of DNA demethylation, in incubation of cocaine craving. PMID- 26019324 TI - Strong motion deficits in dyslexia associated with DCDC2 gene alteration. AB - Dyslexia is a specific impairment in reading that affects 1 in 10 people. Previous studies have failed to isolate a single cause of the disorder, but several candidate genes have been reported. We measured motion perception in two groups of dyslexics, with and without a deletion within the DCDC2 gene, a risk gene for dyslexia. We found impairment for motion particularly strong at high spatial frequencies in the population carrying the deletion. The data suggest that deficits in motion processing occur in a specific genotype, rather than the entire dyslexia population, contributing to the large variability in impairment of motion thresholds in dyslexia reported in the literature. PMID- 26019325 TI - Nonlinear transfer of signal and noise correlations in cortical networks. AB - Signal and noise correlations, a prominent feature of cortical activity, reflect the structure and function of networks during sensory processing. However, in addition to reflecting network properties, correlations are also shaped by intrinsic neuronal mechanisms. Here we show that spike threshold transforms correlations by creating nonlinear interactions between signal and noise inputs; even when input noise correlation is constant, spiking noise correlation varies with both the strength and correlation of signal inputs. We characterize these effects systematically in vitro in mice and demonstrate their impact on sensory processing in vivo in gerbils. We also find that the effects of nonlinear correlation transfer on cortical responses are stronger in the synchronized state than in the desynchronized state, and show that they can be reproduced and understood in a model with a simple threshold nonlinearity. Since these effects arise from an intrinsic neuronal property, they are likely to be present across sensory systems and, thus, our results are a critical step toward a general understanding of how correlated spiking relates to the structure and function of cortical networks. PMID- 26019326 TI - Interactions between the salience and default-mode networks are disrupted in cocaine addiction. AB - Cocaine dependence is a complex neuropsychiatric disorder manifested as dysregulation of multiple behavioral, emotional, and cognitive constructs. Neuroimaging studies have begun to identify specific neurobiological circuit impairments in cocaine-dependent (CD) individuals that may underlie these symptoms. However, whether, where, and how the interactions within and between these circuits are disrupted remain largely unknown. We used resting-state fMRI and modularity network analysis to identify brain modules of a priori interest (default-mode network [DMN], salience network [SN], executive control network [ECN], medial temporal lobe [MTL], and striatum) in 47 CD and 47 matched healthy control (HC) participants and explored alterations within and between these brain modules as a function of addiction. At the module level, intermodule connectivity decreased between DMN and SN in CD. At the nodal level, several regions showed decreased connections with multiple modules in CD: the rostral anterior cingulate connection strength was reduced with SN and MTL; the posterior cingulate had reduced connections with ECN; and the bilateral insula demonstrated decreased connections with DMN. Furthermore, alexithymia, a personality trait previously associated with addiction, correlated negatively with intramodule connectivity within SN only in cocaine users. Our results indicate that cocaine addiction is associated with disrupted interactions among DMN, MTL, and SN, which have been implicated, respectively, in self-referential functions, emotion and memory, and coordinating between internal and external stimuli, providing novel and important insights into the neurobiological mechanisms of cocaine addiction. PMID- 26019327 TI - A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. AB - Niemann-Pick Type C1 (NPC1) disease is a rare neurovisceral, cholesterol sphingolipid lysosomal storage disorder characterized by ataxia, motor impairment, progressive intellectual decline, and dementia. The most prevalent mutation, NPC1(I1061T), encodes a misfolded protein with a reduced half-life caused by ER-associated degradation. Therapies directed at stabilization of the mutant NPC1 protein reduce cholesterol storage in fibroblasts but have not been tested in vivo because of lack of a suitable animal model. Whereas the prominent features of human NPC1 disease are replicated in the null Npc1(-/-) mouse, this model is not amenable to examining proteostatic therapies. The objective of the present study was to develop an NPC1 I1061T knock-in mouse in which to test proteostatic therapies. Compared with the Npc1(-/-) mouse, this Npc1(tm(I1061T)Dso) model displays a less severe, delayed form of NPC1 disease with respect to weight loss, decreased motor coordination, Purkinje cell death, lipid storage, and premature death. The murine NPC1(I1061T) protein has a reduced half-life in vivo, consistent with protein misfolding and rapid ER-associated degradation, and can be stabilized by histone deacetylase inhibition. This novel mouse model faithfully recapitulates human NPC1 disease and provides a powerful tool for preclinical evaluation of therapies targeting NPC1 protein variants with compromised stability. PMID- 26019328 TI - Phrenic long-term facilitation requires PKCtheta activity within phrenic motor neurons. AB - Acute intermittent hypoxia (AIH) induces a form of spinal motor plasticity known as phrenic long-term facilitation (pLTF); pLTF is a prolonged increase in phrenic motor output after AIH has ended. In anesthetized rats, we demonstrate that pLTF requires activity of the novel PKC isoform, PKCtheta, and that the relevant PKCtheta is within phrenic motor neurons. Whereas spinal PKCtheta inhibitors block pLTF, inhibitors targeting other PKC isoforms do not. PKCtheta is highly expressed in phrenic motor neurons, and PKCtheta knockdown with intrapleural siRNAs abolishes pLTF. Intrapleural siRNAs targeting PKCzeta, an atypical PKC isoform expressed in phrenic motor neurons that underlies a distinct form of phrenic motor plasticity, does not affect pLTF. Thus, PKCtheta plays a critical role in spinal AIH-induced respiratory motor plasticity, and the relevant PKCtheta is localized within phrenic motor neurons. Intrapleural siRNA delivery has considerable potential as a therapeutic tool to selectively manipulate plasticity in vital respiratory motor neurons. PMID- 26019329 TI - Progressive functional impairments of hippocampal neurons in a tauopathy mouse model. AB - The age-dependent progression of tau pathology is a major characteristic of tauopathies, including Alzheimer's disease (AD), and plays an important role in the behavioral phenotypes of AD, including memory deficits. Despite extensive molecular and cellular studies on tau pathology, it remains to be determined how it alters the neural circuit functions underlying learning and memory in vivo. In rTg4510 mice, a Tau-P301L tauopathy model, hippocampal place fields that support spatial memories are abnormal at old age (7-9 months) when tau tangles and neurodegeneration are extensive. However, it is unclear how the abnormality in the hippocampal circuit function arises and progresses with the age-dependent progression of tau pathology. Here we show that in young (2-4 months of age) rTg4510 mice, place fields of hippocampal CA1 cells are largely normal, with only subtle differences from those of age-matched wild-type control mice. Second, high frequency ripple oscillations of local field potentials in the hippocampal CA1 area are significantly reduced in young rTg4510 mice, and even further deteriorated in old rTg4510 mice. The ripple reduction is associated with less bursty firing and altered synchrony of CA1 cells. Together, the data indicate that deficits in ripples and neuronal synchronization occur before overt deficits in place fields in these mice. The results reveal a tau-pathology-induced progression of hippocampal functional changes in vivo. PMID- 26019330 TI - Purification of neural precursor cells reveals the presence of distinct, stimulus specific subpopulations of quiescent precursors in the adult mouse hippocampus. AB - The activity of neural precursor cells in the adult hippocampus is regulated by various stimuli; however, whether these stimuli regulate the same or different precursor populations remains unknown. Here, we developed a novel cell-sorting protocol that allows the purification to homogeneity of neurosphere-forming neural precursors from the adult mouse hippocampus and examined the responsiveness of individual precursors to various stimuli using a clonal assay. We show that within the Hes5-GFP(+)/Nestin-GFP(+)/EGFR(+) cell population, which comprises the majority of neurosphere-forming precursors, there are two distinct subpopulations of quiescent precursor cells, one directly activated by high-KCl depolarization, and the other activated by norepinephrine (NE). We then demonstrate that these two populations are differentially distributed along the septotemporal axis of the hippocampus, and show that the NE-responsive precursors are selectively regulated by GABA, whereas the KCl-responsive precursors are selectively modulated by corticosterone. Finally, based on RNAseq analysis by deep sequencing, we show that the progeny generated by activating NE-responsive versus KCl-responsive quiescent precursors are molecularly different. These results demonstrate that the adult hippocampus contains phenotypically similar but stimulus-specific populations of quiescent precursors, which may give rise to neural progeny with different functional capacity. PMID- 26019331 TI - Reinforcement learning in multidimensional environments relies on attention mechanisms. AB - In recent years, ideas from the computational field of reinforcement learning have revolutionized the study of learning in the brain, famously providing new, precise theories of how dopamine affects learning in the basal ganglia. However, reinforcement learning algorithms are notorious for not scaling well to multidimensional environments, as is required for real-world learning. We hypothesized that the brain naturally reduces the dimensionality of real-world problems to only those dimensions that are relevant to predicting reward, and conducted an experiment to assess by what algorithms and with what neural mechanisms this "representation learning" process is realized in humans. Our results suggest that a bilateral attentional control network comprising the intraparietal sulcus, precuneus, and dorsolateral prefrontal cortex is involved in selecting what dimensions are relevant to the task at hand, effectively updating the task representation through trial and error. In this way, cortical attention mechanisms interact with learning in the basal ganglia to solve the "curse of dimensionality" in reinforcement learning. PMID- 26019332 TI - Segmental organization of vestibulospinal inputs to spinal interneurons mediating crossed activation of thoracolumbar motoneurons in the neonatal mouse. AB - Vestibulospinal pathways activate contralateral motoneurons (MNs) in the thoracolumbar spinal cord of the neonatal mouse exclusively via axons descending ipsilaterally from the vestibular nuclei via the lateral vestibulospinal tract (LVST; Kasumacic et al., 2010). Here we investigate how transmission from the LVST to contralateral MNs is mediated by descending commissural interneurons (dCINs) in different spinal segments. We test the polysynaptic nature of this crossed projection by assessing LVST-mediated ventral root (VR) response latencies, manipulating synaptic responses pharmacologically, and tracing the pathway transynaptically from hindlimb extensor muscles using rabies virus (RV). Longer response latencies in contralateral than ipsilateral VRs, near-complete abolition of LVST-mediated calcium responses in contralateral MNs by mephenesin, and the absence of transsynaptic RV labeling of contralateral LVST neurons within a monosynaptic time window all indicate an overwhelmingly polysynaptic pathway from the LVST to contralateral MNs. Optical recording of synaptically mediated calcium responses identifies LVST-responsive ipsilateral dCINs that exhibit segmental differences in proportion and dorsoventral distribution. In contrast to thoracic and lower lumbar segments, in which most dCINs are LVST responsive, upper lumbar segments stand out because they contain a much smaller and more ventrally restricted subpopulation of LVST-responsive dCINs. A large proportion of these upper lumbar LVST-responsive dCINs project to contralateral L5, which contains many of the hindlimb extensor MNs activated by the LVST. A selective channeling of LVST inputs through segmentally and dorsoventrally restricted subsets of dCINs provides a mechanism for targeting vestibulospinal signals differentially to contralateral trunk and hindlimb MNs in the mammalian spinal cord. PMID- 26019333 TI - Computational substrates of social value in interpersonal collaboration. AB - Decisions to engage in collaborative interactions require enduring considerable risk, yet provide the foundation for building and maintaining relationships. Here, we investigate the mechanisms underlying this process and test a computational model of social value to predict collaborative decision making. Twenty-six participants played an iterated trust game and chose to invest more frequently with their friends compared with a confederate or computer despite equal reinforcement rates. This behavior was predicted by our model, which posits that people receive a social value reward signal from reciprocation of collaborative decisions conditional on the closeness of the relationship. This social value signal was associated with increased activity in the ventral striatum and medial prefrontal cortex, which significantly predicted the reward parameters from the social value model. Therefore, we demonstrate that the computation of social value drives collaborative behavior in repeated interactions and provide a mechanistic account of reward circuit function instantiating this process. PMID- 26019334 TI - Serotonin reuptake inhibitors and serotonin transporter genotype modulate performance monitoring functions but not their electrophysiological correlates. AB - Serotonin (5-HT) has been hypothesized to be implicated in performance monitoring by promoting behavioral inhibition in the face of aversive events. However, it is unclear whether this is restricted to external (punishment) or includes internal (response errors) events. The aim of the current study was to test whether higher 5-HT levels instigate inhibition specifically in the face of errors, measured as post-error slowing (PES), and whether this is represented in electrophysiological correlates of error processing, namely error-related negativity (ERN) and positivity. Therefore, from a large sample of human subjects (n = 878), two extreme groups were formed regarding hypothesized high and low 5-HT transporter (5-HTT) expression based on 5-HTTLPR and two additional single nucleotide polymorphisms (rs25531, rs25532). Seventeen higher (LL) and 15 lower (SS) expressing Caucasian subjects were administered the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg) intravenously in a double-blind crossover design. We found pharmacogenetic evidence for a role of 5-HT in mediating PES: SSRI administration increased PES in both genetic groups, and SS subjects displayed higher PES. These effects were absent on post-conflict slowing. However, ERN and error positivity were unaffected by pharmacogenetic factors, but ERN was decoupled from behavioral adaptation by SSRI administration in the LL group. Thus, pharmacogenetic evidence suggests that increased 5-HT levels lead to behavioral inhibition in the context of internal aversive events, but electrophysiological correlates of performance monitoring appear unrelated to the 5-HT system. Therefore, our findings are consistent with theories suggesting that 5-HT mediates the link between aversive processing and inhibition. PMID- 26019335 TI - Cross-hemispheric collaboration and segregation associated with task difficulty as revealed by structural and functional connectivity. AB - Although it is known that brain regions in one hemisphere may interact very closely with their corresponding contralateral regions (collaboration) or operate relatively independent of them (segregation), the specific brain regions (where) and conditions (how) associated with collaboration or segregation are largely unknown. We investigated these issues using a split field-matching task in which participants matched the meaning of words or the visual features of faces presented to the same (unilateral) or to different (bilateral) visual fields. Matching difficulty was manipulated by varying the semantic similarity of words or the visual similarity of faces. We assessed the white matter using the fractional anisotropy (FA) measure provided by diffusion tensor imaging (DTI) and cross-hemispheric communication in terms of fMRI-based connectivity between homotopic pairs of cortical regions. For both perceptual and semantic matching, bilateral trials became faster than unilateral trials as difficulty increased (bilateral processing advantage, BPA). The study yielded three novel findings. First, whereas FA in anterior corpus callosum (genu) correlated with word matching BPA, FA in posterior corpus callosum (splenium-occipital) correlated with face-matching BPA. Second, as matching difficulty intensified, cross hemispheric functional connectivity (CFC) increased in domain-general frontopolar cortex (for both word and face matching) but decreased in domain-specific ventral temporal lobe regions (temporal pole for word matching and fusiform gyrus for face matching). Last, a mediation analysis linking DTI and fMRI data showed that CFC mediated the effect of callosal FA on BPA. These findings clarify the mechanisms by which the hemispheres interact to perform complex cognitive tasks. PMID- 26019336 TI - Abnormal contrast responses in the extrastriate cortex of blindsight patients. AB - When the human primary visual cortex (V1) is damaged, the dominant geniculo striate pathway can no longer convey visual information to the occipital cortex. However, many patients with such damage retain some residual visual function that must rely on an alternative pathway directly to extrastriate occipital regions. This residual vision is most robust for moving stimuli, suggesting a role for motion area hMT+. However, residual vision also requires high-contrast stimuli, which is inconsistent with hMT+ sensitivity to contrast in which even low contrast levels elicit near-maximal neural activation. We sought to investigate this discrepancy by measuring behavioral and neural responses to increasing contrast in patients with V1 damage. Eight patients underwent behavioral testing and functional magnetic resonance imaging to record contrast sensitivity in hMT+ of their damaged hemisphere, using Gabor stimuli with a spatial frequency of 1 cycle/ degrees . The responses from hMT+ of the blind hemisphere were compared with hMT+ and V1 responses in the sighted hemisphere of patients and a group of age-matched controls. Unlike hMT+, neural responses in V1 tend to increase linearly with increasing contrast, likely reflecting a dominant parvocellular channel input. Across all patients, the responses in hMT+ of the blind hemisphere no longer showed early saturation but increased linearly with contrast. Given the spatiotemporal parameters used in this study and the known direct subcortical projections from the koniocellular layers of the lateral geniculate nucleus to hMT+, we propose that this altered contrast sensitivity in hMT+ could be consistent with input from the koniocellular pathway. PMID- 26019337 TI - Dynamics of multistable states during ongoing and evoked cortical activity. AB - Single-trial analyses of ensemble activity in alert animals demonstrate that cortical circuits dynamics evolve through temporal sequences of metastable states. Metastability has been studied for its potential role in sensory coding, memory, and decision-making. Yet, very little is known about the network mechanisms responsible for its genesis. It is often assumed that the onset of state sequences is triggered by an external stimulus. Here we show that state sequences can be observed also in the absence of overt sensory stimulation. Analysis of multielectrode recordings from the gustatory cortex of alert rats revealed ongoing sequences of states, where single neurons spontaneously attain several firing rates across different states. This single-neuron multistability represents a challenge to existing spiking network models, where typically each neuron is at most bistable. We present a recurrent spiking network model that accounts for both the spontaneous generation of state sequences and the multistability in single-neuron firing rates. Each state results from the activation of neural clusters with potentiated intracluster connections, with the firing rate in each cluster depending on the number of active clusters. Simulations show that the model's ensemble activity hops among the different states, reproducing the ongoing dynamics observed in the data. When probed with external stimuli, the model predicts the quenching of single-neuron multistability into bistability and the reduction of trial-by-trial variability. Both predictions were confirmed in the data. Together, these results provide a theoretical framework that captures both ongoing and evoked network dynamics in a single mechanistic model. PMID- 26019338 TI - Incubation of methamphetamine craving is associated with selective increases in expression of Bdnf and trkb, glutamate receptors, and epigenetic enzymes in cue activated fos-expressing dorsal striatal neurons. AB - Cue-induced methamphetamine seeking progressively increases after withdrawal (incubation of methamphetamine craving), but the underlying mechanisms are largely unknown. We determined whether this incubation is associated with alterations in candidate genes in dorsal striatum (DS), a brain area implicated in cue- and context-induced drug relapse. We first measured mRNA expression of 24 candidate genes in whole DS extracts after short (2 d) or prolonged (1 month) withdrawal in rats following extended-access methamphetamine or saline (control condition) self-administration (9 h/d, 10 d). We found minimal changes. Next, using fluorescence-activated cell sorting, we compared gene expression in Fos positive dorsal striatal neurons, which were activated during "incubated" cue induced drug-seeking tests after prolonged withdrawal, with nonactivated Fos negative neurons. We found significant increases in mRNA expression of immediate early genes (Arc, Egr1), Bdnf and its receptor (Trkb), glutamate receptor subunits (Gria1, Gria3, Grm1), and epigenetic enzymes (Hdac3, Hdac4, Hdac5, GLP, Dnmt3a, Kdm1a) in the Fos-positive neurons only. Using RNAscope to determine striatal subregion and cell-type specificity of the activated neurons, we measured colabeling of Fos with Drd1 and Drd2 in three DS subregions. Fos expression was neither subregion nor cell-type specific (52.5 and 39.2% of Fos expression colabeled with Drd1 and Drd2, respectively). Finally, we found that DS injections of SCH23390 (C17H18ClNO), a D1-family receptor antagonist known to block cue-induced Fos induction, decreased incubated cue-induced methamphetamine seeking after prolonged withdrawal. Results demonstrate a critical role of DS in incubation of methamphetamine craving and that this incubation is associated with selective gene-expression alterations in cue-activated D1- and D2-expressing DS neurons. PMID- 26019339 TI - Astrocyte contributions to flow/pressure-evoked parenchymal arteriole vasoconstriction. AB - Basal and activity-dependent cerebral blood flow changes are coordinated by the action of critical processes, including cerebral autoregulation, endothelial mediated signaling, and neurovascular coupling. The goal of our study was to determine whether astrocytes contribute to the regulation of parenchymal arteriole (PA) tone in response to hemodynamic stimuli (pressure/flow). Cortical PA vascular responses and astrocytic Ca(2+) dynamics were measured using an in vitro rat/mouse brain slice model of perfused/pressurized PAs; studies were supplemented with in vivo astrocytic Ca(2+) imaging. In vitro, astrocytes responded to PA flow/pressure increases with an increase in intracellular Ca(2+). Astrocytic Ca(2+) responses were corroborated in vivo, where acute systemic phenylephrine-induced increases in blood pressure evoked a significant increase in astrocytic Ca(2+). In vitro, flow/pressure-evoked vasoconstriction was blunted when the astrocytic syncytium was loaded with BAPTA (chelating intracellular Ca(2+)) and enhanced when high Ca(2+) or ATP were introduced to the astrocytic syncytium. Bath application of either the TRPV4 channel blocker HC067047 or purinergic receptor antagonist suramin blunted flow/pressure-evoked vasoconstriction, whereas K(+) and 20-HETE signaling blockade showed no effect. Importantly, we found TRPV4 channel expression to be restricted to astrocytes and not the endothelium of PA. We present evidence for a novel role of astrocytes in PA flow/pressure-evoked vasoconstriction. Our data suggest that astrocytic TRPV4 channels are key molecular sensors of hemodynamic stimuli and that a purinergic, glial-derived signal contributes to flow/pressure-induced adjustments in PA tone. Together our results support bidirectional signaling within the neurovascular unit and astrocytes as key modulators of PA tone. PMID- 26019341 TI - Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion at the mouse calyx of held synapse. AB - Complexins (Cplxs) are small synaptic proteins that cooperate with SNARE complexes in the control of synaptic vesicle (SV) fusion. Studies involving genetic mutation, knock-down, or knock-out indicated two key functions of Cplx that are not mutually exclusive but cannot easily be reconciled, one in facilitating SV fusion, and one in "clamping" SVs to prevent premature fusion. Most studies on the role of Cplxs in mammalian synapse function have relied on cultured neurons, heterologous expression systems, or membrane fusion assays in vitro, whereas little is known about the function of Cplxs in native synapses. We therefore studied consequences of genetic ablation of Cplx1 in the mouse calyx of Held synapse, and discovered a developmentally exacerbating phenotype of reduced spontaneous and evoked transmission but excessive asynchronous release after stimulation, compatible with combined facilitating and clamping functions of Cplx1. Because action potential waveforms, Ca(2+) influx, readily releasable SV pool size, and quantal size were unaltered, the reduced synaptic strength in the absence of Cplx1 is most likely a consequence of a decreased release probability, which is caused, in part, by less tight coupling between Ca(2+) channels and docked SV. We found further that the excessive asynchronous release in Cplx1 deficient calyces triggered aberrant action potentials in their target neurons, and slowed-down the recovery of EPSCs after depleting stimuli. The augmented asynchronous release had a delayed onset and lasted hundreds of milliseconds, indicating that it predominantly represents fusion of newly recruited SVs, which remain unstable and prone to premature fusion in the absence of Cplx1. PMID- 26019340 TI - Amphetamine action at the cocaine- and antidepressant-sensitive serotonin transporter is modulated by alphaCaMKII. AB - Serotonergic neurotransmission is terminated by reuptake of extracellular serotonin (5-HT) by the high-affinity serotonin transporter (SERT). Selective 5 HT reuptake inhibitors (SSRIs) such as fluoxetine or escitalopram inhibit SERT and are currently the principal treatment for depression and anxiety disorders. In addition, SERT is a major molecular target for psychostimulants such as cocaine and amphetamines. Amphetamine-induced transport reversal at the closely related dopamine transporter (DAT) has been shown previously to be contingent upon modulation by calmodulin kinase IIalpha (alphaCaMKII). Here, we show that not only DAT, but also SERT, is regulated by alphaCaMKII. Inhibition of alphaCaMKII activity markedly decreased amphetamine-triggered SERT-mediated substrate efflux in both cells coexpressing SERT and alphaCaMKII and brain tissue preparations. The interaction between SERT and alphaCaMKII was verified using biochemical assays and FRET analysis and colocalization of the two molecules was confirmed in primary serotonergic neurons in culture. Moreover, we found that genetic deletion of alphaCaMKII impaired the locomotor response of mice to 3,4 methylenedioxymethamphetamine (also known as "ecstasy") and blunted d fenfluramine-induced prolactin release, substantiating the importance of alphaCaMKII modulation for amphetamine action at SERT in vivo as well. SERT mediated substrate uptake was neither affected by inhibition of nor genetic deficiency in alphaCaMKII. This finding supports the concept that uptake and efflux at monoamine transporters are asymmetric processes that can be targeted separately. Ultimately, this may provide a molecular mechanism for putative drug developments to treat amphetamine addiction. PMID- 26019342 TI - Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo. AB - GABA(A) receptors form Cl(-) permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K(+)/Cl(-) cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl(-) levels, which is thought to enable GABAergic inhibitory control of neuronal activity. However, the widely used KCC2 inhibitor furosemide is nonselective with antiseizure efficacy in slices and in vivo, leading to a conflicting scheme of how KCC2 influences GABAergic control of neuronal synchronization. Here we used the selective KCC2 inhibitor VU0463271 [N-cyclopropyl-N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3 pyridazinyl)thio]acetamide] to investigate the influence of KCC2 function. Application of VU0463271 caused a reversible depolarizing shift in E(GABA) values and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg(2+) conditions induced unremitting recurrent epileptiform discharges. Finally, microinfusion of VU0463271 alone directly into the mouse dorsal hippocampus rapidly caused epileptiform discharges. Our findings indicated that KCC2 function was a critical inhibitory factor ex vivo and in vivo. PMID- 26019343 TI - Skipped-stimulus approach reveals that short-term plasticity dominates synaptic strength during ongoing activity. AB - All synapses show activity-dependent changes in strength, which affect the fidelity of postsynaptic spiking. This is particularly important at auditory nerve synapses, where the presence and timing of spikes carry information about a sound's structure, which must be passed along for proper processing. However, it is not clear how synaptic plasticity influences spiking during ongoing activity. Under these conditions, conventional analyses erroneously suggest that synaptic plasticity has no influence on EPSC amplitude or spiking. Therefore, we developed new approaches to study how ongoing activity influences synaptic strength, using voltage- and current-clamp recordings from bushy cells in brain slices from mouse anteroventral cochlear nucleus. We applied identical trains of stimuli, except for one skipped stimulus, and found that EPSC amplitude was affected for 60 ms following a skipped stimulus. We further showed that the initial probability of release, calcium-dependent mechanisms of recovery, and desensitization all play a role even during ongoing activity. Current-clamp experiments indicated that these processes had a significant effect on postsynaptic spiking, as did the refractory period to a smaller extent. Thus short-term plasticity has real, important functional consequences. PMID- 26019344 TI - Role of hippocampal beta-adrenergic and glucocorticoid receptors in the novelty induced enhancement of fear extinction. AB - Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the beta-adrenergic receptor (betaAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal betaAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not betaAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal betaAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction. PMID- 26019345 TI - Sensorimotor processing in the newborn rat red nucleus during active sleep. AB - Sensory feedback from sleep-related myoclonic twitches is thought to drive activity-dependent development in spinal cord and brain. However, little is known about the neural pathways involved in the generation of twitches early in development. The red nucleus (RN), source of the rubrospinal tract, has been implicated in the production of phasic motor activity during active sleep in adults. Here we hypothesized that the RN is also a major source of motor output for twitching in early infancy, a period when twitching is an especially abundant motor behavior. We recorded extracellular neural activity in the RN during sleep and wakefulness in 1-week-old unanesthetized rats. Neurons in the RN fired phasically before twitching and wake movements of the contralateral forelimb. A subpopulation of neurons in the RN exhibited a significant peak of activity after forelimb movement onset, suggesting reafferent sensory processing. Consistent with this observation, manual stimulation of the forelimb evoked RN responses. Unilateral inactivation of the RN using a mixture comprising GABAA, GABAB, and glycine receptor agonists caused an immediate and temporary increase in motor activity followed by a marked and prolonged decrease in twitching and wake movements. Altogether, these data support a causal role for the RN in infant motor behavior. Furthermore, they indicate that twitching, which is characterized by discrete motor output and reafferent input, provides an opportunity for sensorimotor integration and activity-dependent development of topography within the newborn RN. PMID- 26019346 TI - Orbitofrontal cortex encodes memories within value-based schemas and represents contexts that guide memory retrieval. AB - There are a substantial number of studies showing that the orbitofrontal cortex links events to reward values, whereas the hippocampus links events to the context in which they occur. Here we asked how the orbitofrontal cortex contributes to memory where context determines the reward values associated with events. After rats learned object-reward associations that differed depending on the spatial context in which the objects were presented, neuronal ensembles in orbitofrontal cortex represented distinct value-based schemas, each composed of a systematic organization of the representations of objects in the contexts and positions where they were associated with reward or nonreward. Orbitofrontal ensembles also represent the different spatial contexts that define the mappings of stimuli to actions that lead to reward or nonreward. These findings, combined with observations on complementary memory representation within the hippocampus, suggest mechanisms through which prefrontal cortex and the hippocampus interact in support of context-guided memory. PMID- 26019349 TI - Retraction: Tremere et al, "Mechanistic basis and functional roles of long-term plasticity in auditory neurons induced by a brain-generated estrogen". PMID- 26019347 TI - Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain. AB - Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and >15 years of age to examine the expression of Parkin, PINK1, and alpha-synuclein, which are known to cause PD via loss- or gain-of-function mechanisms. We found that alpha-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of alpha synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant alpha-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age dependent pathological and molecular changes that could contribute to the age dependent neuropathology in PD. PMID- 26019350 TI - Fluid resuscitation in severe sepsis and septic shock: Shifting goalposts. PMID- 26019348 TI - Exclusion of integrins from CNS axons is regulated by Arf6 activation and the AIS. AB - Integrins are adhesion and survival molecules involved in axon growth during CNS development, as well as axon regeneration after injury in the peripheral nervous system (PNS). Adult CNS axons do not regenerate after injury, partly due to a low intrinsic growth capacity. We have previously studied the role of integrins in axon growth in PNS axons; in the present study, we investigate whether integrin mechanisms involved in PNS regeneration may be altered or lacking from mature CNS axons by studying maturing CNS neurons in vitro. In rat cortical neurons, we find that integrins are present in axons during initial growth but later become restricted to the somato-dendritic domain. We investigated how this occurs and whether it can be altered to enhance axonal growth potential. We find a developmental change in integrin trafficking; transport becomes predominantly retrograde throughout axons, but not dendrites, as neurons mature. The directionality of transport is controlled through the activation state of ARF6, with developmental upregulation of the ARF6 GEF ARNO enhancing retrograde transport. Lowering ARF6 activity in mature neurons restores anterograde integrin flow, allows transport into axons, and increases axon growth. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational modifications of tubulin with taxol also allows integrins into the proximal axon. The experiments suggest that the developmental loss of regenerative ability in CNS axons is due to exclusion of growth-related molecules due to changes in trafficking. PMID- 26019351 TI - Perils of paediatric anaesthesia and novel molecular approaches: An evidence based review. AB - Evolution of anaesthesia has been largely helped by progress of evidence-based medicine. In spite of many advancements in anaesthesia techniques and availability of newer and safer drugs, much more needs to be explored scientifically for the development of anaesthesia. Over the last few years, the notion that the actions of the anaesthesiologist have only immediate or short term consequences has largely been challenged. Evidences accumulated in the recent years have shown that anaesthesia exposure may have long-term consequences particularly in the extremes of ages. However, most of the studies conducted so far are in vitro or animal studies, the results of which have been extrapolated to humans. There have been confounding evidences linking anaesthesia exposure in the developing brain with poor neurocognitive outcome. The results of animal studies and human retrospective studies have raised concern over the potential detrimental effects of general anaesthetics on the developing brain. The purpose of this review is to highlight the long-term perils of anaesthesia in the very young and the potential of improving anaesthesia delivery with the novel molecular approaches. PMID- 26019352 TI - A comparative study of pharmacological myocardial protection between sevoflurane and desflurane at anaesthestic doses in patients undergoing off pump coronary artery bypass grafting surgery. AB - BACKGROUND AND AIMS: Perioperative myocardial ischaemia (PMI) is one of the known complications during off pump coronary artery bypass (OPCAB) surgeries. The length of hospital stay is considerably prolonged in patients with PMI. Myocardial protection is an area which is being widely researched currently to prevent or reduce the incidence of PMI. Over the last decade it has become clear that volatile anaesthetic agents are protective in the setting of PMI and reperfusion. Hence, we planned to study the effect of two different volatile anaesthetics as myocardial protective agents in OPCAB surgery. METHODS: A total of 40 patients were enrolled for the study; Group A (sevoflurane, n = 20) and Group B (desflurane, n = 20). All patients had a baseline measurement of Trop-T, creatine phosphokinase-MB (CPKMB) and myocardial performance index (MPI) pre operatively, which was repeated 4 h after the surgery. Chi-square/Fisher test was used to find the significance of the differences between the two agents. RESULTS: Patients were comparable in demographic, baseline, biochemical and echo criteria. Post-operative CPKMB levels (desflurane - 30.85 +/- 2.69 u/L; sevoflurane - 29.05 +/- 5.26 u/L, P = 0.7) and number of Trop-T positive patients (Sevoflurane - 9; desflurane - 6, P >= 0.05) were comparable. Post-operative MPI indicated decreased left ventricular function in sevoflurane group as compared to desflurane group (P <= 0.03). CONCLUSION: Desflurane exerts better cardioprotective effect than sevoflurane as indicated by better MPI in OPCAB surgeries. PMID- 26019353 TI - Comparative evaluation of propofol, sevoflurane and desflurane for neuroanaesthesia: A prospective randomised study in patients undergoing elective supratentorial craniotomy. AB - BACKGROUND AND AIMS: Both inhalational and intravenous anaesthetic agents are being used for neuroanaesthesia. Clinical trials comparing "propofol and sevoflurane" and "desflurane and sevoflurane" have been published. However, the comparison of all the three anaesthetics in neurosurgical patients has not been done. A randomised clinical study was carried out comparing propofol, sevoflurane and desflurane to find the ideal neuroanaesthetic agent. METHODS: A total of 75 adult patients undergoing elective craniotomy for supratentorial tumours were included in the study. The patients were induced with morphine 0.1 mg/kg and thiopentone 4-6 mg/kg. Neuromuscular blockade was facilitated with vecuronium. The patients were randomised to receive propofol, sevoflurane or desflurane along with nitrous oxide in oxygen for maintenance of anaesthesia. The neuromuscular blockade was reversed following the surgery once the patients opened eyes or responded to verbal commands. The three anaesthetics were compared for their effects on haemodynamics, brain relaxation and emergence characteristics. RESULTS: The mean arterial blood pressure during anaesthesia was comparable among the groups. The patients receiving sevoflurane had faster heart rates intraoperatively when compared to desflurane (P < 0.05). The brain relaxation scores at various intraoperative time frames were comparable among the three groups (P > 0.05). The time to response to verbal commands were significantly prolonged with use of sevoflurane (8.0 +/- 2.9 min) when compared to propofol (5.3 +/- 2.9 min) and desflurane (5.2 +/- 2.6 min) (P = 0.003). However, the time to emergence and the number of patients who had early emergence (<15 min) were comparable among the groups (P > 0.05). The quality of emergence (coughing and emergence agitation), as well as postoperative complications, were also comparable among the three groups. CONCLUSIONS: All the three anaesthetic agents propofol, sevoflurane and desflurane appear comparable and acceptable with regard to their clinical profile during anaesthesia in patients undergoing elective supratentorial surgeries. PMID- 26019354 TI - Estimation of effect-site concentration of propofol for laryngeal mask airway insertion using fentanyl or morphine as adjuvant. AB - BACKGROUND AND AIMS: Insertion of laryngeal mask airway (LMA) requires adequate depth of anaesthesia, which provides jaw relaxation and suppression of upper airway reflexes. Propofol can provide these conditions especially when combined with narcotics. This study had been designed to find out the effect-site concentration (EC50) of propofol using target controlled infusion (TCI) when fentanyl or morphine is added as an adjuvant. METHODS: Patients satisfying inclusion criteria were divided into fentanyl and morphine groups. Intravenous glycopyrrolate 0.2 mg was given 15 min before induction. Patients were given either intravenous fentanyl (1 MUg/kg) or morphine (0.1 mg/kg) before propofol infusion depending on the group. Patients in either groups were induced by continuous infusion of propofol at an EC of 6 MUg/mL by TCI with Schneider pharmacokinetic model. The LMA supreme of appropriate size was inserted 1 min after achieving target concentration. Patient movement at LMA insertion or within 1 min of insertion was classified as failure. For subsequent patients, the target EC was increased/decreased depending on previous patients' response. Dixons up and down method was used to determine the EC50. The EC50 is defined as the mean of crossover midpoints in each pair of failure to success. RESULTS: The EC50 of propofol in the fentanyl group for LMA insertion was 5.95 +/- 0.6 MUg/ml and morphine group was 5.75 +/- 0.8 MUg/ml. No significant difference in insertion conditions was noticed between the two groups (P = 0.3). CONCLUSION: We conclude that there was no significant difference in propofol EC50 for insertion of LMA and insertion conditions were similar when fentanyl or morphine was used as an adjuvant drug. PMID- 26019355 TI - Anaesthesia for awake craniotomy: A retrospective study of 54 cases. AB - BACKGROUND AND AIMS: The anaesthetic challenge of awake craniotomy is to maintain adequate sedation, analgesia, respiratory and haemodynamic stability in an awake patient who should be able to co-operate during intraoperative neurological assessment. The current literature, sharing the experience on awake craniotomy, in Indian context, is minimal. Hence, we carried out a retrospective study with the aim to review and analyse the anaesthetic management and perioperative complications in patients undergoing awake craniotomy, at our centre. METHODS: Medical records of 54 patients who underwent awake craniotomy for intracranial lesions over a period of 10 years were reviewed, retrospectively. Data regarding anaesthetic management, intraoperative complications and post-operative course were recorded. RESULTS: Propofol (81.5%) and dexmedetomidine (18.5%) were the main agents used for providing conscious sedation to facilitate awake craniotomy. Hypertension (16.7%) was the most commonly encountered complication during intraoperative period, followed by seizures (9.3%), desaturation (7.4%), tight brain (7.4%), and shivering (5.6%). The procedure had to be converted to general anaesthesia in one of patients owing to refractory brain bulge. The incidence of respiratory and haemodynamic complications were comparable in the both groups (P > 0.05). There was less incidence of intraoperative seizures in patients who received propofol (P = 0.03). In post-operative period, 20% of patients developed new motor deficit. Mean intensive care unit stay was 2.8 +/- 1.9 day (1-14 days) and mean hospital stay was 7.0 +/- 5.0 day (3-30 days). CONCLUSIONS: 'Conscious sedation' was the technique of choice for awake craniotomy, at our institute. Fentanyl, propofol, and dexmedetomidine were the main agents used for this purpose. Patients receiving propofol had less incidence of intraoperative seizure. Appropriate selection of patients, understanding the procedure of surgery, and judicious use of sedatives or anaesthetic agents are key to the success for awake craniotomy as a procedure. PMID- 26019356 TI - Attenuation of the haemodynamic responses to tracheal intubation with gabapentin, fentanyl and a combination of both: A randomised controlled trial. AB - BACKGROUND AND AIMS: We conducted a prospective, randomised, double-blind, controlled clinical trial to examine (1) whether a single preoperative dose of 800 mg gabapentin would be as effective as 2 MUg/kg of intravenous (IV) fentanyl in blunting the haemodynamic response to tracheal intubation and (2) whether a combination of both would be more effective in this regard. METHODS: Seventy-five patients (American Society of Anaesthesiologists physical status I), aged 20-50 years were allocated into one of three groups: 2 MUg/kg IV fentanyl, 800 mg oral gabapentin or a combination of both. Gabapentin was administered 2 h and fentanyl 5 min before induction of anaesthesia, which was achieved with 5 mg/kg thiopentone, and tracheal intubation facilitated with 0.1 mg/kg vecuronium. Laryngoscopy lasting a maximum of 30 s was attempted 3 min after administration of the induction agents. Serial values of mean arterial pressure (MAP) and heart rate (HR) were compared among the three groups and with the respective preinduction measurements. RESULTS: Patients receiving gabapentin 800 mg alone showed remarkable increases in HR and MAP in response to tracheal intubation (P < 0.05). The increases were similar for the other two regimens. These haemodynamic changes were lesser in patients receiving fentanyl and the combination of gabapentin and fentanyl. CONCLUSION: Oral gabapentin does not produce significant reduction in laryngoscopy and tracheal intubation induced sympathetic responses as compared to IV fentanyl or the combination of gabapentin and fentanyl. PMID- 26019357 TI - Dyskeratosis congenita induced cirrhosis for liver transplantation-perioperative management. AB - Dyskeratosis congenita (DC) is an inherited disorder with progressive multisystem involvement. End stage liver disease (ESLD) in patients with DC is rare. We describe the perioperative management of a patient with DC induced ESLD and severe hepatopulmonary syndrome for living donor liver transplantation. PMID- 26019358 TI - Myxoedema coma in adults: Experience from a tertiary referral hospital intensive care unit. PMID- 26019359 TI - Glycine induced acute transient postoperative visual loss. PMID- 26019360 TI - Dexmedetomidine for anaesthetic management of phaeochromocytoma in a child with von Hippel-Lindau type 2 syndrome. PMID- 26019361 TI - Anaesthetic management of a patient with Jarcho-Levin syndrome. PMID- 26019362 TI - Cisatracurium degradation: Intravenous fluid warmer the culprit? PMID- 26019363 TI - The successful use of sugammadex and uneventful recovery from general anaesthesia in a patient with myotonic dystrophy. PMID- 26019364 TI - A patient with VACTERL association for caesarean delivery. PMID- 26019365 TI - Massive hydrothorax following supracostal percutaneous nephrolithotomy. PMID- 26019366 TI - Central anticholinergic syndrome in a neonate operated for tracheoesophageal fistula. PMID- 26019367 TI - Self-knotting of a nasogastric tube passed through i-gelTM. PMID- 26019368 TI - Snake bite and brain death - handle with care. PMID- 26019369 TI - Coiling of guidewire in the internal jugular vein: Putting some caveats. PMID- 26019370 TI - Synthesis of a polymerizable, bivalent glycan mimetic of the HIV envelope spike gp120. AB - A synthetic study on the creation of a bivalent, ROMP capable monomer has the ability to be polymerized into the corresponding neo-glycopolymer mimetic of the surface glycans on gp120 envelope spike of the HIV virus. In our approach, we have developed a new strategy for orthogonally attaching both the terminal Manalpha1-2Man disaccharide unit of the D1 arm of Man9GlcNAc2 of HIV gp120 and the terminal Manalpha1-2 unit of its D2 arm to a bivalent scaffold to produce the corresponding polymerizable monomer. The Manalpha1-2 saccharide moieties were assembled using a nickel catalyst, Ni(4-F-PhCN)4(OTf)2, to activate trihaloacetimidate donors under mild and operationally simple procedure. PMID- 26019371 TI - Tailored fragments of roseophilin selectively antagonize Mcl-1 in vitro. AB - We have discovered a fragment of the natural product roseophilin, a member of the prodiginine family, that antagonizes Mcl-1 functions in a liposome-based assay for mitochondrial membrane permeabilization. By tailoring this substance such that it can participate in salt bridging with the protein surface, we have prepared the first prodiginine inspired structure that shows direct, saturable binding to a recombinant Bcl-2 family member in vitro. PMID- 26019372 TI - Immunohistochemical and morphofunctional studies of skeletal muscle tissues with electric nerve stimulation by in vivo cryotechnique. AB - In this study, morphological and immunohistochemical alterations of skeletal muscle tissues during persistent contraction were examined by in vivo cryotechnique (IVCT). Contraction of gastrocnemius muscles was induced by sciatic nerve stimulation. The IVCT was performed immediately, 3 min or 10 min after the stimulation start. Prominent ripples of muscle fibers or wavy deformation of sarcolemma were detected immediately after the stimulation, but they gradually diminished to normal levels during the stimulation. The relative ratio of sarcomere and A band lengths was the highest in the control group, but it immediately decreased to the lowest level and then gradually recovered at 3 min or 10 min. Although histochemical intensity of PAS reaction was almost homogeneous in muscle tissues of the control group or immediately after the stimulation, it decreased at 3 min or 10 min. Serum albumin was immunolocalized as dot-like patterns within some muscle fibers at 3 min stimulation. These patterns became more prominent at 10 min, and the dots got larger and saccular in some sarcoplasmic regions. However, IgG1 and IgM were immunolocalized in blood vessels under nerve stimulation conditions. Therefore, IVCT was useful to capture the morphofunctional and metabolic changes of heterogeneous muscle fibers during the persistent contraction. PMID- 26019373 TI - Localization of Rod Bipolar Cells in the Mammalian Retina Using an Antibody Against the alpha1c L-type Ca(2+) Channel. AB - Bipolar cells transmit stimuli via graded changes in membrane potential and neurotransmitter release is modulated by Ca(2+) influx through L-type Ca(2+) channels. The purpose of this study was to determine whether the alpha1c subunit of L-type voltage-gated Ca(2+) channel (alpha1c L-type Ca(2+) channel) colocalizes with protein kinase C alpha (PKC-alpha), which labels rod bipolar cells. Retinal whole mounts and vertical sections from mouse, hamster, rabbit, and dog were immunolabeled with antibodies against PKC-alpha and alpha1c L-type Ca(2+) channel, using fluorescein isothiocyanate (FITC) and Cy5 as visualizing agents. PKC-alpha-immunoreactive cells were morphologically identical to rod bipolar cells as previously reported. Their cell bodies were located within the inner nuclear layer, dendritic processes branched into the outer plexiform layer, and axons extended into the inner plexiform layer. Immunostaining showed that alpha1c L-type Ca(2+) channel colocalized with PKC-alpha in rod bipolar cells. The identical expression of PKC-alpha and alpha1c L-type Ca(2+) channel indicates that the alpha1c L-type Ca(2+) channel has a specific role in rod bipolar cells, and the antibody against the alpha1c L-type Ca(2+) channel may be a useful marker for studying the distribution of rod bipolar cells in mouse, hamster, rabbit, and dog retinas. PMID- 26019374 TI - Characteristics of the Localization of Connexin 43 in Satellite Cells during Skeletal Muscle Regeneration In Vivo. AB - For myogenesis, new myotubes are formed by the fusion of differentiated myoblasts. In the sequence of events for myotube formation, intercellular communication through gap junctions composed of connexin 43 (Cx43) plays critical roles in regulating the alignment and fusion of myoblasts in advances of myotube formation in vitro. On the other hand, the relationship between the expression patterns of Cx43 and the process of myotube formation in satellite cells during muscle regeneration in vivo remains poorly understood. The present study investigated the relationship between Cx43 and satellite cells in muscle regeneration in vivo. The expression of Cx43 was detected in skeletal muscles on day 1 post-muscle injury, but not in control muscles. Interestingly, the expression of Cx43 was not localized on the inside of the basement membrane of myofibers in the regenerating muscles. Moreover, although the clusters of differentiated satellite cells, which represent a more advanced stage of myotube formation, were observed on the inside of the basement membrane of myofibers in regenerating muscles, the expression of Cx43 was not localized in the clusters of these satellite cells. Therefore, in the present study, it was suggested that Cx43 may not directly contribute to muscle regeneration via satellite cells. PMID- 26019375 TI - SCGB3A2 Inhibits Acrolein-Induced Apoptosis through Decreased p53 Phosphorylation. AB - Chronic obstructive pulmonary disease (COPD), a major global health problem with increasing morbidity and mortality rates, is anticipated to become the third leading cause of death worldwide by 2020. COPD arises from exposure to cigarette smoke. Acrolein, which is contained in cigarette smoke, is the most important risk factor for COPD. It causes lung injury through altering apoptosis and causes inflammation by augmenting p53 phosphorylation and producing reactive oxygen species (ROS). Secretoglobin (SCGB) 3A2, a secretory protein predominantly present in the epithelial cells of the lungs and trachea, is a cytokine-like small molecule having anti-inflammatory, antifibrotic, and growth factor activities. In this study, the effect of SCGB3A2 on acrolein-related apoptosis was investigated using the mouse fibroblast cell line MLg as the first step in determining the possible therapeutic value of SCGB3A2 in COPD. Acrolein increased the production of ROS and phosphorylation of p53 and induced apoptosis in MLg cells. While the extent of ROS production induced by acrolein was not affected by SCGB3A2, p53 phosphorylation was significantly decreased by SCGB3A2. These results demonstrate that SCGB3A2 inhibited acrolein-induced apoptosis through decreased p53 phosphorylation, not altered ROS levels. PMID- 26019376 TI - Histochemical Analysis of Laminin alpha Chains in Diethylstilbestrol-Induced Prolactinoma in Rats. AB - Laminin, a major basement membrane component, is important in structural support and cell proliferation and differentiation. Its 19 isoforms are assemblies of alpha, beta, and gamma chains, and the alpha chains (alpha1-5) determine the isoform characteristics. Although our previous studies showed alterations in alpha chain expressions during anterior pituitary development, their expressions in pituitary tumors yet to be determined. The present study used a rat model of diethylstilbestrol (DES)-induced prolactinoma to examine alpha chain expressions during prolactinoma tumorigenesis (0-12 weeks of DES treatment) by in situ hybridization and immunohistochemistry. mRNA of alpha1, alpha3, and alpha4 chains was detected in control and after 4 weeks of DES treatment. These expressions were undetectable after 8 weeks of DES treatment and in prolactinoma (12 weeks of DES treatment). Immunohistochemistry showed that the alpha1 chain was localized in some anterior pituitary cells in control and after 4 weeks of treatment and in endothelial cells after 8 weeks of treatment. The alpha3 and alpha4 chains were expressed in endothelial cells, and immunoreactivity and the number of immunopositive cells decreased during DES treatment. These findings suggest that alteration of laminin alpha chains is related to abnormal cell proliferation and neovascularization during development of DES-induced prolactinoma. PMID- 26019377 TI - Limitation of therapeutic effort: When less is more. PMID- 26019378 TI - Dengue in an area of the Colombian Caribbean. AB - BACKGROUND: In Colombia, dengue is an endemic disease and the four serotypes have been reported. OBJECTIVE: To describe the frequency and severity of dengue in an area of the Colombian Caribbean (Department of Cordoba). METHODS: A retrospective study was conducted. Two data sources were analysed: The database from the Direction of Health in Cordoba, and clinical registers of patients diagnosed with haemorrhagic fevers and fevers of unknown origin in reference hospitals. RESULTS: The mean incidence of dengue between 2003-2010 was 36.5 cases/10(5) inhabitants (CI95%: 34.3-37.5) and adjusted for sub-reporting, could be between 178.5 and 521.6. The mean incidence of severe dengue was 4.7 cases/10(5) inhabitants (CI95%: 4.3-5.0). Mean mortality rate due to dengue was 0.3 cases/10(5) inhabitants. The fatality rate was below 1%. The mean total leukocyte count in patients with dengue was 6,181 mm(3) (CI95%: 5,973-6,389) and with severe Dengue was 4,729 mm(3) (CI95%: 4,220-5,238). The average platelet count in patients with Dengue was 118,793/mm(3) (CI95%: 107,255-130,331) and in patients with Severe Dengue 77,655 (CI95%: 59,640-95,670). Both differences were statistically significant (p <0.05). The frequency of laboratories test per patient in patients with Dengue and severe Dengue were different. CONCLUSION: The department of Cordoba is a highly endemic zone of Dengue and severe Dengue in the Colombian Caribbean. Moreover, the results show significant differences between dengue and severe dengue so much in tests as in frequency of use of healthcare services. PMID- 26019379 TI - An experience of liver transplantation in Latin America: a medical center in Colombia. AB - OBJECTIVES: Liver transplantation is the treatment of choice for acute and chronic liver failure, for selected cases of tumors, and for conditions resulting from errors in metabolism. This paper reports the experience of a medical center in Latin America. METHODS: Were conducted 305 orthotopic liver transplantations on 284 patients between 2004 and 2010. Of these patients, 241 were adults undergoing their first transplantation. RESULTS: The average age of patients was 52 years old, and 62% of the individuals were male. The most common indication was alcoholic cirrhosis. The rate of patient survival after 1 and 5 years was 82 and 72% respectively. The rate of liver graft survival after 1 and 5 years was 78 and 68% respectively. The main cause of death was sepsis. Complications in the hepatic artery were documented for 5% of the patients. Additionally, 14.5% of the patients had complications in the biliary tract. Infections were found in 41% of the individuals. Acute rejection was observed in 30% of the subjects, and chronic rejection in 3%. CONCLUSION: In conclusion, liver transplantation at our medical center in Colombia offers good mid-term results, with a complication rate similar to that reported by other centers around the world. PMID- 26019380 TI - Early diagnosis of diabetic retinopathy in primary care. AB - OBJECTIVE: To evaluate the impact of a strategy for early detection of diabetic retinopathy in patients with type 2 diabetes mellitus (DMT2) in Quintana Roo, Mexico. METHODS: Study transversal, observational, prospective, analytical, eight primary care units from Mexican Social Security Institute in the northern delegation of the State of Quintana Roo, Mexico were included. A program for early detection of diabetic retinopathy (DR) in adult 376,169 was designed. Were diagnosed 683 cases of type 2 diabetes, in 105 patients randomized was conducted to direct ophthalmoscopy were subjected to a secondary hospital were assigned. Will determine the degree of diabetic retinopathy and macular edema was performed. RESULTS: In population were 55.2% female, mean age 48+11.1 years, 23.8 % had some degree of DR, 28.0% with mild non- proliferative diabetic retinopathy 48.0 % moderate 16.0% and severe and 8.0% showed proliferative diabetic retinopathy. Those over age 30 are 2.8 times more risk of developing DR, OR= 2.8; 95%CI: 0.42-18.0, and OR= 1.7; 95%CI: 1.02-2.95 women. CONCLUSIONS: The implementation of programs aimed at the early detection of debilitating conditions such as diabetic retinopathy health impact beneficiaries, effective links between primary care systems and provide second level positive health outcomes for patient diseases. PMID- 26019381 TI - Human prefrontal layer II interneurons in areas 46, 10 and 24. AB - BACKGROUND: Prefrontal cortex (PFC) represents the highest level of integration and control of psychic and behavioral states. Several dysfunctions such as autism, hyperactivity disorders, depression, and schizophrenia have been related with alterations in the prefrontal cortex (PFC). Among the cortical layers of the PFC, layer II shows a particular vertical pattern of organization, the highest cell density and the biggest non-pyramidal/pyramidal neuronal ratio. We currently characterized the layer II cytoarchitecture in human areas 10, 24, and 46. OBJECTIVE: We focused particularly on the inhibitory neurons taking into account that these cells are involved in sustained firing (SF) after stimuli disappearance. METHODS: Postmortem samples from five subjects who died by causes different to central nervous system diseases were studied. Immunohistochemistry for the neuronal markers, NeuN, parvalbumin (PV), calbindin (CB), and calretinin (CR) were used. NeuN targeted the total neuronal population while the rest of the markers specifically the interneurons. RESULTS: Cell density and soma size were statically different between areas 10, 46, 24 when using NeuN. Layer II of area 46 showed the highest cell density. Regarding interneurons, PV+-cells of area 46 showed the highest density and size, in accordance to the proposal of a dual origin of the cerebral cortex. Interhemispheric asymmetries were not identified between homologue areas. CONCLUSION: First, our findings suggest that layer II of area 46 exhibits the most powerful inhibitory system compared to the other prefrontal areas analyzed. This feature is not only characteristic of the PFC but also supports a particular role of layer II of area 46 in SF. Additionally, known functional asymmetries between hemispheres might not be supported by morphological asymmetries. PMID- 26019382 TI - Microarray analysis of the in vitro granulomatous response to Mycobacterium tuberculosis H37Ra. AB - BACKGROUND: The hallmark of tuberculosis is the granuloma, an organized cellular accumulation playing a key role in host defense against Mycobacterium tuberculosis. These structures sequester and contain mycobacterial cells preventing active disease, while long term maintenance of granulomas leads to latent disease. Clear understanding on mechanisms involved in granuloma formation and maintenance is lacking. OBJECTIVE: To monitor granuloma formation and to determine gene expression profiles induced during the granulomatous response to M. tuberculosis (H37Ra). METHODS: We used a previously characterized in vitro human model. Cellular aggregation was followed daily with microscopy and Wright staining for 5 days. Granulomas were collected at 24 h, RNA extracted and hybridized to Affymetrix human microarrays. RESULTS: Daily microscopic examination revealed gradual formation of granulomas in response to mycobacterial infection. Granulomatous structures persisted for 96 h, and then began to disappear. CONCLUSIONS: Microarray analysis identified genes in the innate immune response and antigen presentation pathways activated during the in vitro granulomatous response to live mycobacterial cells, revealing very early changes in gene expression of the human granulomatous response. PMID- 26019383 TI - Evidence-based practice: beliefs, attitudes, knowledge, and skills among Colombian physical therapists. AB - OBJECTIVE: The main purpose of this study was to describe a group of Colombian physical therapists' beliefs and attitudes towards Evidence-Based Practice (EBP), their education, knowledge and skills for implementing EBP, the use of relevant literature in clinical practice, access to and availability of scientific information and perceived barriers to including EBP in practice. METHODS: This was a cross-sectional study which involved 1,064 Colombian physical therapists. The study used a 50-item screening questionnaire EBP developed to estimate attitudes, beliefs, knowledge and skills regarding. This instrument has been adapted and was validated previously in Colombia by Florez-Lopez et al. RESULTS: The population mostly consisted of young females (77.2%) aged 22 to 29 years old (79.4%). Most respondents had an undergraduate degree (87.7%). The physical therapists stated that they had positive attitudes and beliefs regarding EBP, most of them answering that they agreed or strongly agreed that EBP is necessary (71.6%), the relevant literature is useful for practice (61.3%), EBP improves the quality of patient care (64.1%) and evidence helps in decision-making (44.5%). Forty-one percent of the respondents indicated that a lack of research skills was the most important barrier to the use of evidence in practice. CONCLUSION: The physical therapists reported that they had a positive attitude to EBP and were interested in learning about or improving the skills necessary to adopt EBP in their clinical practice. PMID- 26019384 TI - Identification of coronary heart disease in asymptomatic individuals with diabetes mellitus: to screen or not to screen. AB - Coronary heart disease (CHD) is highly prevalent in patients with diabetes mellitus (DM), and remains the single most common cause of death among this population. Regrettably, a significant percentage of diabetics fail to perceive the classic symptoms associated with myocardial ischemia. Among asymptomatic diabetics, the prevalence of abnormal cardiac testing appears to be high, ranging between 10% and 62%, and mortality is significantly higher in those with abnormal scans. Hence, the potential use of screening for CHD detection among asymptomatic DM individuals is appealing and has been recommended in certain circumstances. However, it was not until recently, that this question was addressed in clinical trials. Two studies randomized a total of 2,023 asymptomatic diabetics to screening or not using cardiac imaging with a mean follow up of 4.4 +/- 1.4 years. In combination, both trials showed lower than expected annual event rates, and failed to reduce major cardiovascular events in the screened group compared to the standard of care alone. The results of these trials do not currently support the use of screening tools for CHD detection in asymptomatic DM individuals. However, these studies have important limitations, and potential explanations for their negative results that are discussed in this manuscript. PMID- 26019387 TI - ESTIMATING MEAN SURVIVAL TIME: WHEN IS IT POSSIBLE? AB - For right censored survival data, it is well known that the mean survival time can be consistently estimated when the support of the censoring time contains the support of the survival time. In practice, however, this condition can be easily violated because the follow-up of a study is usually within a finite window. In this article we show that the mean survival time is still estimable from a linear model when the support of some covariate(s) with nonzero coefficient(s) is unbounded regardless of the length of follow-up. This implies that the mean survival time can be well estimated when the support of linear predictor is wide in practice. The theoretical finding is further verified for finite samples by simulation studies. Simulations also show that, when both models are correctly specified, the linear model yields reasonable mean square prediction errors and outperforms the Cox model, particularly with heavy censoring and short follow-up time. PMID- 26019386 TI - Erratum: Cancer survival in Cali, Colombia: A population-based study, 1995-2004. PMID- 26019385 TI - Disseminated bronchiectasis in an adult with common variable immunodeficiency. AB - Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow up. Common Variable Immunodeficiency (CVID) diagnosis was made. PMID- 26019388 TI - Obstructive sleep apnoea syndrome: a new paradigm by chronic nocturnal intermittent hypoxia and sleep disruption. AB - Obstructive sleep apnoea syndrome (OSAS) is associated with severe cerebro cardiovascular morbidity and mortality. It is an independent risk factor for atherosclerosis, arterial thrombosis and metabolic syndrome, and recently has been associated with an increased incidence of cancer and death. A causal link between OSAS and atherosclerosis has been partially established. Recent research on atherosclerosis in OSAS has focused on thrombotic tendency and blood viscosity, providing new insight into disease mechanisms. Hypoxia is a critical pathophysiological element in OSAS that leads to intensive sympathetic activity, in association with inflammation, oxidative stress and procoagulant activity. Hypoxia and the induction of oxidative stress can simultaneously represent an underlying mechanism in the pathogenesis of cancer development and progression. This mini-review will discuss the latest findings on the association and potential relationship between OSA and pathological vascular sequelae. PMID- 26019389 TI - Long-term treatment outcomes of juvenile nasopharyngeal angiofibroma treated with radiotherapy. AB - Juvenile nasopharyngeal angiofibroma (JNA) is a disease of adolescent males characterised by high vascularity with local aggressiveness. This analysis was intended to see the effectiveness of radiation in locally advanced JNA. We included patients treated from 1990-2012. A total of 31 patients met study criteria. Median age was 16 years (range: 12-33 years). Radiation was used for refractory, residual or unresectable locally advanced disease. The median radiation dose was 30 Gy (range: 30-45 Gy). Median follow-up was 36 months (Range: 1-271 months). The median progression-free survival [PFS] was not reached. PFS at 3, 5 and 10 years was 91.7, 70.7 and 70.7% respectively. Three patients progressed at 38, 43 and 58 months after completion of treatment and opted for alternative therapy. One patient developed squamous cell carcinoma of the nasal ale 15 years after radiation. PMID- 26019390 TI - Benign tumours affecting the deep lobe of the parotid gland: how to select the optimal surgical approach. AB - Many types of approaches allow extra-capsular dissection in the deep parotid parenchyma in the treatment of benign tumours. A transcervical approach (TCA), transparotid approach (TPA) and a combined transcervical-transparotid approach (TPTCA) are the three main procedures performed to expose the deep parenchyma. We conducted a retrospective chart review enrolling 24 consecutive patients treated for benign tumours affecting the deep lobe of the parotid. Review of the surgical data was accompanied by careful follow-up to establish surgical morbidity, functional (Frey's Syndrome and first-bite syndrome) and aesthetical outcomes. A TPA was performed in the majority of cases; in 26% superficial parotidectomy was not required (selective deep parotidectomy). Minor's test showed a low rate of Frey's syndrome (3 cases of 23, 13%). No long-lasting first-bite syndrome was reported. Some additional procedures were easily performed in order to improve aesthetical results (rotational flap of sternocleidomastoid muscle, free abdominal fat transfer); these had the same results as selective deep parotidectomy. TCA (or TPTCA) ensures the best control of the facial nerve, providing good exposure and good functional and aesthetical results (without sparing the superficial parenchyma if additional techniques are performed with the aim of reducing skin depression in the treated area). The choice of the approach should have only the aim of safe resection and should not be influenced by aesthetical outcome; the craniocaudal level of the tumour seems to be the best indicator of the feasibility of the procedure also considering the branches of the facial nerve. In our experience, mandibulotomy can always be avoided. PMID- 26019391 TI - Cervical paragangliomas: single centre experience with 44 cases. AB - Paragangliomas (PGL) are rare lesions of the neuroendocrine system; in the neck, they usually affect the carotid glomus (carotid body tumours-CBT). This retrospective analysis reports our experience in management of these lesions in patients treated by surgical resection. Between 2000 and 2014, 33 patients were surgically treated at our institution, obtaining a series of 44 cervical PGLs. Tumour characteristics, family history, diagnostic procedures, surgical treatment, short- and long-term outcomes were reviewed. A female prevalence was found (76% of cases). Familial cases occurred in 9 patients (20%); 6 presented with bilateral lesions and 1 had multiple paragangliomas. Lymph node metastasis was not found in any patient. All lesions were classified into three groups according to the latero-lateral diameter. Complete resection of the PGL was performed in all patients. Mortality was null; transitory cranial nerve deficit occurred in 20% of cases with permanent palsy in 6.7%. No perioperative stroke/TIA were observed. Surgical resection of PGL should be considered as the only therapeutic option because it can ensure complete removal of the disease. Patients with bilateral lesions and positive family history should be referred for genetic analysis. Preoperative planning of the surgical procedure by integrated diagnostic imaging and a full mastery of vascular surgery techniques are mandatory to minimise the risk of the most common postoperative complications. Long-term follow-up is recommended, particularly in patients with familial disease or sporadic lesions treated in an advanced stage. PMID- 26019392 TI - Maxillary fungus ball: zinc-oxide endodontic materials as a risk factor. AB - The objective of this study was to demonstrate the correlation between endodontic treatment on maxillary teeth and fungus ball with inductively coupled plasma mass spectrometry measurement of zinc and other metals (barium, lead and copper) in fungus ball samples. Samples of normal maxillary mucosa were used as comparison. Metal concentration was also measured in several endodontic materials. A significant difference was found between the concentration of zinc and copper in fungus ball compared to normal mucosa. Metal distribution was more similar in fungus ball and in the endodontic materials tested than normal mucosa. The similar metal concentration in the endodontic materials and fungus ball suggests that endodontic materials play a role in the pathogenesis of fungus ball. Endodontic materials accidentally pushed into the maxillary sinus during endodontic treatments may play a crucial role. Dentists should be as careful as possible when treating maxillary teeth to avoid perforating the maxillary sinus floor; the use of zinc-free endodontic materials, as zinc is a metal that plays a pivotal role in fungus growth, should be encouraged. PMID- 26019393 TI - Magnetic nanoparticles: a new tool for antibiotic delivery to sinonasal tissues. Results of preliminary studies. AB - Herein we examined the toxicity, penetration properties and ability of Fe2O3.nH2O magnetic nanoparticles extracted from silt of the Borovoye Lake (Krasnoyarsk, Russia) to bind an antibiotic. Experimental studies were carried out using magnetic nanoparticles alone and after antibiotic exposure in tissue samples from nasal mucosa, cartilage and bone (in vitro). Toxicity of particles was studied in laboratory animals (in vivo). Tissues removed at endonasal surgery (nasal mucosa, cartilage and bone of the nasal septum) were placed in solution containing nanoparticles and exposed to a magnetic field. Distribution of nanoparticles was determined by Perls' reaction. After intravenous injection, possible toxic effects of injected nanoparticles on the organs and tissues of rats were evaluated by histological examination. Binding between the nanoparticles and antibiotic (amoxicillin clavulanate) was studied using infrared spectroscopy. In 30 in vitro experiments, magnetisation of Fe2O3.nH2O nanoparticles resulted in their diffuse infiltration into the mucosa, cartilage and bone tissue of the nose and paranasal sinuses. Intravenous injection of 0.2 ml of magnetic nanoparticles into the rat's tail vein did not result in any changes in parenchymatous organs, and the nanoparticles were completely eliminated from the body within 24 hours. The interaction of nanoparticles with amoxicillin clavulanate was demonstrated by infrared spectroscopy. Positive results of experimental studies provide a basis for further clinical investigations of these magnetic nanoparticles and their use in otorhinolaryngology. PMID- 26019394 TI - Idiopathic sudden sensorineural hearing loss: cardiovascular risk factors do not influence hearing threshold recovery. AB - Previous studies have suggested that risk factors for ischaemic vascular disease, such as cigarette smoking, hypertension and hyperlipidaemia, can also be considered risk factors for the development of idiopathic sudden sensorineural hearing loss (ISSNHL). In this study, we have evaluated the hypothesis that these factors can influence hearing threshold recovery in patients affected by ISSNHL. A total of 141 subjects who suffered an episode of ISSNHL were included. All subjects were assessed with tonal audiometry, auditory brainstem responses and MRI to exclude retrocochlear pathology. Hearing tests were conducted at ISSNHL onset (t = 0) and after 30 days. Patients were divided into three classes according to the presence/absence of one or more cardiovascular risk factors including: history of smoking, total serum cholesterol/triglycerides, history of hypertension and diabetes mellitus. Values of hearing threshold recovery were estimated and comparisons were conducted across the three risk factor classes. 75% of patients affected by ISSNHL showed a threshold recovery. However, the threshold recovery was found to be class-independent (average recovery value of 18 dB HL per classes) and also independent of age and gender. Even if cardiovascular risk factors have been found to be involved in the pathogenesis of ISSNHL, the present study suggests that these factors do not have any significant influence on the threshold recovery in ISSNHL. PMID- 26019395 TI - Validity of the Italian version of Khalfa's questionnaire on hyperacusis. AB - The present study aims to evaluate and validate the Italian version of Khalfa's questionnaire on hyperacusis (HQ). We recruited 117 patients (64 men, 53 women, mean age 53 years, range 14-88) with tinnitus for at least 3 months as a primary disorder. All patients completed the THI and the Italian version of the HQ and underwent audiometry, pitch and loudness tinnitus matching, otoacoustic emissions with distortion products (DPOAE) and uncomfortable loudness level (ULL). The overall performance of the tests was evaluated and compared using the area under the RO C curve (AUC) relative to the tests. The cut-off of the HQ was calculated. We also assessed the Cronbach's alpha (alphaC) for the HQ and its three major dimensions (attentional - alphaC1, emotional - alphaC2 and social - alphaC3). Statistical analysis showed no correlation between DPOAE, audiometry, ULL and gender. We observed a high correlation (p < 0.05) between hyperacusis and ULL described by the Spearman's rho index (rs = 0.72). We found a cut-off of 16 indicative of hyperacusis comparing the area under the RO C curve (AUC) of HQ and audiometry, taken as a diagnostic reference, (sensitivity = 67.9% and specificity = 72.2%). The reliability of HQ was confirmed by a high alphaC = 0.89. The alphaC for the single dimensional scales were, respectively, alphaC1 = 0.73, alphaC2 = 0.72 and alphaC3 = 0.81. The Italian version of the HQ is recommended for proper and complete classification of patients with tinnitus and hyperacusis. From our study, we found a cut-off of 16 instead of the cut-off of 28 described as very high by other authors. Moreover, ULL was an important variable and can be discriminating in the evaluation of hyperacusis. PMID- 26019396 TI - Canal switch and re-entry phenomenon in benign paroxysmal positional vertigo: difference between immediate and delayed occurrence. AB - This prospective study was designed to evaluate the differences between immediate and delayed canal re-entry of otoliths after therapeutic manoeuvres in patients with benign paroxysmal positional vertigo (BPPV). A total of 196 patients with BPPV were visited and 127 matched our inclusion criteria. The mean age was 54.74 years. The horizontal semicircular canal (HSC) was involved in 30 cases and the posterior semicircular canal (PSC) in 97 patients. Patients with hearing loss in the ear affected by BPPV have a more recurrent form, compared to those with normal hearing. An immediate canal re-entry was recorded in 3 patients with HSC BPPV, all with geotropic nystagmus. In 7 patients with PSC BPPV, the immediate canal re-entry was detected and the delayed form was noted in 5 patients. The patients with the delayed canal re-entry underwent more than 2 previous manoeuvres. The canal re-entry was not related to the manoeuvre performed. The timing of the Dix-Hallpike test to verify the resolution of the BPPV had a significant role in immediate canal re-entry. A recurrence in the follow-up at least one month after treatment was recorded in 20 patients and was more frequent in patients that had canal re-entry. The canal re-entry or canal switch is a clinical entity that should be kept in mind of the neurotologist when approaching BPPV patients. It is important to distinguish it from recurrence when delayed and from manoeuvre failure when immediate. The timing of manoeuvre performing, in particular the final verification test after therapeutic sessions, is important to prevent the immediate reflux of particles into canals. PMID- 26019397 TI - Supraclavicular artery island flap reconstruction of a contralateral partial laryngopharyngeal defect. AB - Oncologic resection of head and neck cancers often results in complex reconstructive problems that can require local, regional, or free flaps. Herein, we present a case of a 67-year-old female with a history of floor of mouth cancer who had a second primary carcinoma in the left side of pharynx, 9 years after initial therapy. She underwent a wide oncologic resection requiring laryngopharyngeal reconstruction. Significant scar formation on the left side, due to previous surgery and radiotherapy, prevented us from harvesting an ipsilateral flap. Therefore, we used a right sided supraclavicular artery island flap for reconstruction of the contralateral defect. The patient healed completely with hyperbaric oxygen therapy and conservative local wound care. Supraclavicular artery island flap is a viable option for poor microvascular surgical candidates. It is easy and quick to harvest, and significantly decreases operative times. It is thus a versatile option for contralateral laryngopharyngeal reconstruction. PMID- 26019398 TI - Two new cases of chronic tuberculous otomastoiditis in children. AB - This report focuses on tuberculous otomastoiditis treated at a third level Italian paediatric hospital. We reviewed the clinical charts of 4077 children who underwent middle ear surgery at the Audiology and Otology Unit of the Institution's ENT Department from January 1995 to December 2011. A tubercular aetiology was identified in 2 cases: a 4-year old boy who presented with primary ear involvement, i.e. with no other infected sites but the middle ear, and a 5 year old girl with secondary tuberculous otomastoidits, who was treated for pulmonary and mediastinal tuberculosis at the age of 7 months. PMID- 26019399 TI - Simultaneous nasopharyngeal and parotid gland Warthin's tumour: a case report. AB - Herein, a rare case of synchronous cystoadenolymphoma (Warthin's tumour) of the right parotid gland and the nasopharyngeal space is described. Although Warthin's tumour (WT) of the parotid gland is a common benign pathology, the occurrence of extra-parotid cystoadenolymphoma is rare. Extra-parotid WT have been mainly localised in the submandibular gland, periparotid region and occasionally in other sites, such as the oral cavity, hard palate and nasopharynx. The simultaneous occurrence of an intra-parotid and extra-parotid WT localisation, as in the case presented, is extremely uncommon. PMID- 26019400 TI - Treatment situation of male hypogonadotropic hypogonadism in pediatrics and proposal of testosterone and gonadotropins replacement therapy protocols. AB - Male hypogonadotropic hypogonadism (MHH), a disorder associated with infertility, is treated with testosterone replacement therapy (TRT) and/or gonadotropins replacement therapy (GRT) (TRT and GRT, together with HRT hormone replacement therapy). In Japan, guidelines have been set for treatment during adolescence. Due to the risk of rapid maturation of bone age, low doses of testosterone or gonadotropins have been used. However, the optimal timing and methods of therapeutic intervention have not yet been established. The objective of this study was to investigate the current situation of treatment for children with MHH in Japan and to review a primary survey involving councilors of the Japanese Society for Pediatric Endocrinology and a secondary survey obtained from 26 facilities conducting HRT. The subjects were 55 patients with MHH who reached their adult height after HRT. The breakdown of the patients is as follows: 7 patients with Kallmann syndrome, 6 patients with isolated gonadotropin deficiency, 18 patients with acquired hypopituitarism due to intracranial and pituitary tumor, 22 patients with classical idiopathic hypopituitarism due to breech delivery, and 2 patients with CHARGE syndrome. The mean age at the start of HRT was 15.7 yrs and mean height was 157.2 cm. The mean age at reaching adult height was 19.4 yrs, and the mean adult height was 171.0 cm. The starting age of HRT was later than the normal pubertal age and showed a significant negative correlation with pubertal height gain, but it showed no correlation with adult height. As for spermatogenesis, 76% of the above patients treated with hCG-rFSH combined therapy showed positive results, though ranging in levels; impaired spermatogenesis was observed in some with congenital MHH, and favorable spermatogenesis was observed in all with acquired MHH. From the above, we propose the establishment of a treatment protocol for the start low-dose testosterone or low-dose gonadotropins by dividing subjects into two groups to determine different treatment protocols, acquired and congenital MHH, and to conduct them at a timing closer to the onset of puberty, namely, at a timing near entrance to junior high school. We also propose a new HRT protocol using preemptive FSH therapy prior to GRT aimed at achieving future fertility in patients with congenital MHH. PMID- 26019401 TI - Clinical spectrum and outcome of invasive filamentous fungal infections in children with Type 1 diabetes: North Indian experience. AB - There is scarcity of data on spectrum and outcome of invasive filamentous fungal infections (IFIs) in children with Type 1 diabetes (T1D) from developing countries. A retrospective review of medical records of children with T1D hospitalized with IFI over the past decade at the Pediatric Endocrinology and Diabetes Unit of a large tertiary care hospital of North India was performed with an aim to study their clinical spectrum, hospital course and final outcome. Of the 10 patients studied, nasal/paranasal involvement was seen in 6 and pulmonary involvement in 5 patients. One patient developed disseminated disease. Majority of the identified mycoses belonged to Class Zygomycetes Order Mucorales. Early surgery along with antifungal therapy helped limit the extension of infection and achieve a good outcome in majority of patients. Two patients died; one with a late diagnosis of pulmonary mucormycosis and the other with disseminated disease. The longterm morbidity in the survivors was minimal. In conclusion, rapid diagnosis followed by a multimodal approach involving aggressive surgical debridement, appropriate antifungal therapy and control of hyperglycemic state is the key to good outcome in this otherwise lethal infection. PMID- 26019402 TI - Advanced maternal age in Indian children with thyroid dysgenesis. AB - A retrospective review of medical records of 80 children with thyroid dysgenesis (TD) was conducted to determine the association of gender and maternal age with TD. The study subjects were attending the Pediatric Endocrinology Clinic of our hospital which is a large tertiary care Multispecialty Pediatric Center located in Chandigarh, Northwest India. There were no gender differences (boys to girls' ratio 1:1). Mean maternal age of 25.87 +/- 4.17 yrs (range 19-35 yrs) was significantly higher as compared to the mean maternal age of 23.87 +/- 3.34 yrs (range 18-39 yrs) of a reference group (p < 0.0001). Odds of being older than 30 yrs were higher in mothers of children with TD as compared to mothers of normal children (OR 3.23; 95% CI: 1.54-6.44) (p-value 0.0003). In conclusion, our data shows that advanced maternal age is more prevalent in children with TD. PMID- 26019403 TI - Hyperthyroidism in children: treatment outcomes and preferences in Eastern India. PMID- 26019404 TI - Erratum: Onset of puberty and near adult height in short children born small for gestational age and treated with GH: Interim analysis of up to 10 years of treatment in Japan. PMID- 26019405 TI - The vibrational and configurational entropy of disordering in Cu3Au. AB - The thermodynamics of disordering in Cu3Au have been investigated by measuring the heat capacity of samples with different degrees of long- and short-range order between T = 5 and 720 K using relaxation and differential scanning calorimetry. The heat capacities of L12-ordered and fcc-disordered samples show similar behaviour at low temperatures (<300 K). They deviate positively from the linear combination of the end-member heat capacities between ~30 and 160 K. However, small differences between the two samples exist, as the disordered sample has a larger heat capacity producing a vibrational entropy of disordering of ~0.05 R. At temperatures higher than 300 K, the heat capacity of the ordered sample shows a prominent lambda-type anomaly at 675 K due to the diffusive L12 fcc phase transition. When starting these measurements with disordered samples, ordering effects are observed between 400 and 620 K, and the disordering reaction is observed at 660 K. Evaluation of the data gives an enthalpy and entropy of disordering at 683 K of 2.0 kJ mol-1 and 0.39 R, respectively. However, these values increase with increasing temperature, thereby reducing the short-range order. Because the vibrational and configurational disordering effects become active at different temperature regimes, i.e., the vibrational effects at low temperatures (T ? 300 K) and the sum of both effects at higher temperatures (T > 300 K), they have been successfully separated. PMID- 26019406 TI - Mass-based condition measures and their relationship with fitness: in what condition is condition? AB - Mass or body-size measures of 'condition' are of central importance to the study of ecology and evolution, and it is often assumed that differences in condition measures are positively and linearly related to fitness. Using examples drawn from ecological studies, we show that indices of condition frequently are unlikely to be related to fitness in a linear fashion. Researchers need to be more explicit in acknowledging the limitations of mass-based condition measures and accept that, under some circumstances, they may not relate to fitness as traditionally assumed. Any relationship between a particular condition measure and fitness should first be empirically validated before condition is used as a proxy for fitness. In the absence of such evidence, researchers should explicitly acknowledge that assuming such a relationship may be unrealistic. PMID- 26019407 TI - Association between myasthenia gravis and cognitive function: A systematic review and meta-analysis. AB - The course of myasthenia gravis (MG) is complicated by increased reports of cognitive defects in both human and animal models, which suggests potential central nervous system (CNS) damage. We conducted a systematic review of the relationships between MG and cognitive function. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Major databases were searched to examine the neuropsychological studies of adults with MG. Weighted effect sizes were pooled by cognitive domain. Eight studies representing 300 subjects were included. Eight cognitive domain categories were identified: (i) Mini-Mental State Examination (MMSE), (ii) language, (iii) processing speed, (iv) verbal learning and memory, (v) visual learning and memory, (vi) attention span, (vii) response fluency, and (viii) motor performance. Nine (cognitive domain categories, MMSE, language, processing speed, verbal learning and memory (except for delayed recall memory), and motor performance) of 16 cognitive tasks revealed significant moderate effect sizes. Verbal logical-delayed memory, finger tapping with the preferred hand, and the Symbol Digit Modalities Test showed a greater magnitude relationship to cognitive function than did other specific cognitive domains. Verbal learning and memory seems to be the most significant affected according to cognitive domain categories. For MG, the ability of attention, response fluency, visual learning, and memory seems to be reserved. The MG patients seem to perform significantly worse than the non-MG controls in a range of cognitive domains. Our findings should be interpreted with caution because of the clinical and methodological heterogeneity of included studies. PMID- 26019408 TI - Toxic species in amyloid disorders: Oligomers or mature fibrils. AB - Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization) disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov) and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer's Disease, Parkinson's Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer's Disease and Parkinson's Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils) in amyloid cascade are also described. PMID- 26019409 TI - A practical approach to management of focal hand dystonia. AB - Dystonia can be focal, segmental, multifocal, generalized, or hemidystonia. Focal dystonia is localized to a specific part of the body. Overall upper limb is more commonly involved in focal dystonia than lower limb and since it starts from hand, focal hand dystonia (FHD) is a more accepted terminology. Writer's cramp and musician dystonia are commonest types of FHD. Typically this dystonia is task specific, but in some patients this specificity may be lost over a period of time. Segmental or generalized dystonia may also start as FHD, so a detailed clinical assessment is required, which should be supplemented by relevant investigations. Treatment includes oral medications, injection botulinum toxin, neurosurgery including neurostimulation, and rehabilitation. Role of injection botulinum toxin has been extensively studied in writer's cramp patients and found to be effective; however, selection of muscles and techniques of injection are crucial in getting best results. PMID- 26019410 TI - Lhermitte's Sign: The Current Status. AB - Lhermitte's sign was described by Marie and Chatelin and named after Jean Lhermitte. This sign is mostly described as an electric shock like condition by some patients of multiple sclerosis. This sensation occurs when the neck is moved in a wrong way or rather flexed. It can also travel down to the spine, arms, and legs, and sometimes the trunk. Demyelination and hyperexcitability are the main pathophysiological reasons depicted for the Lhermitte's sign. Other causes for Lhermitte's sign include transverse myelitis, behcet's disease, trauma, etc. This article reviews the Lhermitte's sign, its history, and its etiopathophysiology. Very few studies are available on Lermitte's sign and more research need to be done on the same to ensure its sensitivity and specificity. PMID- 26019411 TI - Famous people with Tourette's syndrome: Dr. Samuel Johnson (yes) & Wolfgang Amadeus Mozart (may be): Victims of Tourette's syndrome? AB - Tourette's syndrome is a clinical condition characterized by multiple motor tics and vocal tics which occurs in the age range 5-25 years and the intensity of the symptoms changes with time. It is felt that at least two remarkable personalities namely, Dr. Samuel Johnson from England, a man of letters and the compiler of the first ever English dictionary, and Wolfgang Amadeus Mozart from Austria, one of the greatest musical genius of all time, possibly suffered from this condition. Tourette's syndrome is often described as the classical borderzone between neurology and psychiatry and every neurologist wonders at the curious and fascinating clinical features of this condition. It seems that at least two remarkable personalities, Dr. Samuel Johnson, a man of letters and the first person to compile an English dictionary, and Wolfgang Amadeus Mozart, arguably the most creative musical composer of all time, were possibly afflicted with this condition. PMID- 26019412 TI - Factors delaying hospital arrival of patients with acute stroke. AB - BACKGROUND: Low rates of thrombolysis for ischemic stroke in India and other developing countries have been attributed to delays in presentation to the hospital. MATERIALS AND METHODS: A prospective study was carried out during a 12 month period ending December 2012 in the department of Neurology, Malabar Institute of Medical Sciences, Kerala, India, to look for the factors contributing to delay in hospital arrival of patients with acute stroke. Patients and or their relatives were interviewed within 48 hours of admission using a structured questionnaire. RESULTS: A total of 264 patients attending the emergency department were included. There were 170 men and 94 women. The mean age was 61.5 +/- 12.4 years. A total of 67 (25%) patients presented within 4 hours of stroke onset. Factors associated with early arrival (multivariate logistic regression analysis) were distance 15 km or less from hospital (P 0.03, odds ratio (OR) 2.7), directly reaching the stroke department (P < 0.001, OR 9.7), history of coronary artery disease (P 0.001, OR 3.84), higher educational status (P 0.001, OR 3.7), and presence of hemiplegia (P 0.001, OR 5.5). CONCLUSIONS: We found a considerable delay in the early arrival of patients to our stroke department. Health promotion strategies to improve community awareness of early symptoms of stroke, education of local physicians about the importance of early referrals to the stroke centers, and wider availability and use of ambulance services are promising methods to help expedite presentation to hospital post stroke and thereby improve the management of stroke in India. PMID- 26019413 TI - Ambulation following spinal cord injury and its correlates. AB - OBJECTIVES: To assess walking ability of spinal cord injury (SCI) patients and observe its correlation with functional and neurological outcomes. PATIENTS AND METHODS: The present prospective, observational study was conducted in a tertiary research hospital in India with 66 patients (46 males) between January 2012 and December 2013. Mean age was 32.62 +/- 11.85 years (range 16-65 years), mean duration of injury was 85.3 +/- 97.6 days (range 14-365 days) and mean length of stay in the rehabilitation unit was 38.08 +/- 21.66 days (range 14-97 days) in the study. Walking Index for spinal cord injury (WISCI II) was used to assess ambulation of the SCI patients. Functional recovery was assessed using Barthel Index (BI) and Spinal Cord Independence Measures (SCIM). Neurological recovery was assessed using ASIA impairment scale (AIS). We tried to correlate ambulatory ability of the patients with functional and neurological recovery. RESULTS: Ambulatory ability of the patients improved significantly using WISCI II (P < 0.001) when admission and discharge scores were compared (1.4 +/- 3.5 vs 7.6 +/- 6.03). Similarly, functional (BI: 31.7 +/- 20.5 vs 58.4 +/- 23.7 and SCIM: 29.9 +/- 15.1 vs 56.2 +/- 20.6) and neurological recovery were found to be very significant (P < 0.001) when admission vs discharge scores were compared. Improvement in WISCI II scores was significantly correlated with improvement in neurological (using AIS scores) and functional status (using BI and SCIM scores) (P < 0.001). CONCLUSIONS: Significant improvement was seen in WISCI II, BI, and SCIM scores after in-patient rehabilitation. Improvement in WISCI II scores also significantly correlated with functional and neurological recovery. PMID- 26019414 TI - Neurological associations in auditory neuropathy spectrum disorder: Results from a tertiary hospital in South India. AB - AIMS: To find out the prevalence and types of neurological abnormalities associated in auditory neuropathy spectrum disorder in a large tertiary referral center. SETTINGS AND DESIGN: A prospective clinical study was conducted on all patients diagnosed with auditory neuropathy spectrum disorder in the ear, nose, and throat (ENT) and neurology departments during a 17-month period. Patients with neurological abnormalities on history and examination were further assessed by a neurologist to determine the type of disorder present. RESULTS: The frequency of auditory neuropathy spectrum disorder was 1.12%. Sixty percent were found to have neurological involvement. This included cerebral palsy in children, peripheral neuropathy (PN), spinocerebellar ataxia, hereditary motor-sensory neuropathy, spastic paresis, and ponto-bulbar palsy. Neurological lesions did not present simultaneously with hearing loss in most patients. Sixty-six percent of patients with auditory neuropathy spectrum disorder were born of consanguineous marriages. CONCLUSIONS: There is a high prevalence of neurological lesions in auditory neuropathy spectrum disorder which has to be kept in mind while evaluating such patients. Follow-up and counselling regarding the appearance of neuropathies is therefore important in such patients. A hereditary etiology is indicated in a majority of cases of auditory neuropathy spectrum disorder. PMID- 26019415 TI - Neuropsychological markers of mild cognitive impairment: A clinic based study from urban India. AB - BACKGROUND: Mild cognitive impairment (MCI) is a transitional stage between normal aging and dementia. Persons with MCI are at higher risk to develop dementia. Identifying MCI from normal aging has become a priority area of research. Neuropsychological assessment could help to identify these high risk individuals. OBJECTIVE: To examine clinical utility and diagnostic accuracy of neuropsychological measures in identifying MCI. MATERIALS AND METHODS: This is a cross-sectional study of 42 participants (22 patients with MCI and 20 normal controls [NC]) between the age of 60 and 80 years. All participants were screened for dementia and later a detailed neuropsychological assessment was carried out. RESULTS: Persons with MCI performed significantly poorer than NC on word list (immediate and delayed recall), story recall test, stick construction delayed recall, fluency and Go/No-Go test. Measures of episodic memory especially word list delayed recall had the highest discriminating power compared with measures of semantic memory and executive functioning. CONCLUSION: Word list learning with delayed recall component is a possible candidate for detecting MCI from normal aging. PMID- 26019416 TI - External validation of the SEDAN score: The real world practice of a single center. AB - BACKGROUND AND PURPOSE: Symptomatic intracranial hemorrhage (sICH) is the most serious adverse event in stroke patients who received i.v. rt-PA and is usually associated with poor outcomes. The SEDAN score is built up to predict sICH. We aim to externally validate the SEDAN score in Thai patients from single center in the real world practice. MATERIALS AND METHODS: The SEDAN score of stroke patients treated with intravenous rt-PA at Thammasat University Hospital from January 2010 to June 2012 was calculated. Patients were divided into three groups including symptomatic intracranial hemorrhage (sICH), asymptomatic intracranial hemorrhage (AsICH) and no intracerebral hemorrhage (NoICH). The primary outcome of analyses was sICH. Each parameter of the SEDAN score and correlation between score and sICH were analyzed with univariate and multivariate model. RESULTS: 295 patients (18.6% of stroke admission) were treated with i.v. rt-PA. 13 patients (4.4%) had sICH and 31 patients (10.4%) had AsICH. Baseline blood sugar >12 mmol/l, early infarction, hyperdense cerebral artery, age >75 years-old and NIHSS >=10(SEDAN) were associated with sICH by univariate analysis (P value = 0.018, <0.001, <0.001, 0.002 and 0.027 respectively). The rate of sICH occurrence was increased in accordance with the increasing of the SEDAN score. By multivariate analysis, odds ratio of baseline blood sugar >12 mmol/l, early infarction, hyperdense cerebral artery, age >75 years-old and NIHSS >=10 were 1.248, 2.503, 1.107, 1.532 and 1.263 respectively. CONCLUSIONS: The SEDAN score was practical to use and predictive in Thai population. Each parameter of the SEDAN score was an independent risk factor for sICH after treatment with i.v. rt-PA. PMID- 26019417 TI - Preservative solution for skeletal muscle biopsy samples. AB - CONTEXT: Muscle biopsy samples must be frozen with liquid nitrogen immediately after excision and maintained at -80 degrees C until analysis. Because of this requirement for tissue processing, patients with neuromuscular diseases often have to travel to centers with on-site muscle pathology laboratories for muscle biopsy sample excision to ensure that samples are properly preserved. AIM: Here, we developed a preservative solution and examined its protectiveness on striated muscle tissues for a minimum of the length of time that would be required to reach a specific muscle pathology laboratory. MATERIALS AND METHODS: A preservative solution called Kurt-Ozcan (KO) solution was prepared. Eight healthy Sprague-Dawley rats were sacrificed; striated muscle tissue samples were collected and divided into six different groups. Muscle tissue samples were separated into groups for morphological, enzyme histochemical, molecular, and biochemical analysis. STATISTICAL METHOD USED: Chi-square and Kruskal Wallis tests. RESULTS: Samples kept in the KO and University of Wisconsin (UW) solutions exhibited very good morphological scores at 3, 6, and 18 hours, but artificial changes were observed at 24 hours. Similar findings were observed for the evaluated enzyme activities. There were no differences between the control group and the samples kept in the KO or UW solution at 3, 6, and 18 hours for morphological, enzyme histochemical, and biochemical features. The messenger ribonucleic acid (mRNA) of beta-actin gene was protected up to 6 hours in the KO and UW solutions. CONCLUSION: The KO solution protects the morphological, enzyme histochemical, and biochemical features of striated muscle tissue of healthy rats for 18 hours and preserves the mRNA for 6 hours. PMID- 26019418 TI - Clinico pathological study of adult dermatomyositis: Importance of muscle histology in the diagnosis. AB - AIMS: To study the histological features on muscle biopsy and correlate them with clinical features, other laboratory data in adult patients to make a diagnosis of dermatomyositis (DM), applying the European Neuromuscular center (ENMC) criteria. MATERIALS AND METHODS: Adult patients who fulfilled clinical, laboratory, and muscle biopsy findings according to ENMC criteria for DM during the period 2010 2013 were included in the study. Cryostat sections of muscle biopsy were reviewed with emphasis on Perifascicular atrophy (PFA), perivascular/endomysial inflammation. Muscular dystrophies and metabolic myopathies were excluded by appropriate immunohistochemistry and special stains. RESULTS: The diagnosis of adult DM was made in 45 patients out of 170 clinically suspected idiopathic inflammatory myopathies. These included 33 definite, 4 probable, 7 possible sine dermatitis, and 1 amyopathic DM. All patients with definite DM had typical rash and proximal muscle weakness and muscle biopsy showed PFA with or without inflammation. Thirteen patients had quadriparesis, neck muscle weakness, dysphagia/dysphonia at presentation. Patients with probable DM had rash and showed perivascular/endomysial inflammation with no PFA. Possible DM sine dermatitis showed PFA with perivascular/endomysial infiltrates. One patient of amyopathic DM had typical heliotrope rash and characteristic skin biopsy. CONCLUSIONS: Histological features are important for the diagnosis of DM. Relying on PFA for diagnosis of definite DM underestimates the true frequency of DM. PMID- 26019419 TI - Cognitive profiles in Mild Cognitive Impairment (MCI) patients associated with Parkinson's disease and cognitive disorders. AB - BACKGROUND: Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly and represents an heterogeneous clinical syndrome that can be ascribed to different etiologies; the construct of MCI in Parkinson's disease (PD) (MCI-PD) is more recent but the range of deficits is still variable. Early recognition and accurate classification of MCI-PD could offer opportunities for novel therapeutic interventions to improve the natural pathologic course. OBJECTIVE: To investigate the clinical phenotype of amnestic mild cognitive impairment (aMCI) and in patients with PD and MCI (MCI-PD). MATERIALS AND METHODS: Seventy-three patients with aMCI and in 38 patients with MCI-PD were enrolled. They all underwent Mini mental State Examination (MMSE), the Rey auditory-verbal learning test and the immediate visual memory (IVM) item of the Mental Deterioration Battery, the Rey auditory-verbal learning test included the Rey-immediate (Rey-I), and the delayed recall of the word list (Rey test deferred, Rey-D). The Geriatric Depression Scale (GDS) was used for mood assessment. RESULTS: The results of the Rey-I and Rey-D and of the IVM item showed statistically significant differences between the aMCI and the MCI-PD group. The mean Rey-I and Rey-D score was significantly lower as well as the IVM score was higher in patients with aMCI than in those with MCI-PD, aMCI patients showed greater impairment in long-term memory, whereas more aMCI than MCI-PD patients had preserved attention, computation, praxis, and conceptualization. CONCLUSIONS: Our findings demonstrate that the cognitive deficit profile is specific for each of the two disorders: Memory impairment was a typical feature in aMCI patients while MCI-PD patients suffered from executive functions and visuospatial attention deficits. PMID- 26019420 TI - Methotrexate-induced chemical meningitis in patients with acute lymphoblastic leukemia/lymphoma. AB - BACKGROUND: Intrathecal methotrexate (ITMTX) is an important component in the treatment as well as prophylaxis of leukemia/lymphoma. ITMTX can cause chemical meningitis characterized by vomiting, headache, and fever lasting 2-5 days with spontaneous resolution of symptoms which differentiates this syndrome from bacterial meningitis. OBJECTIVE: This prospective observational study was carried out to determine incidence of post-ITMTX syndrome in patients receiving prophylactic ITMTX as part of Berlin-Frankfurt-Munster (BFM) protocol. MATERIALS AND METHODS: Patients aged 15-50 years receiving BFM 90 or BFM 95 protocol for acute lymphoblastic leukemia or lymphoblastic lymphoma were followed up for post ITMTX syndrome, defined as vomiting, headache and fever between 38 degrees and 39 degrees C following ITMTX. RESULTS: Thirty-three patients received a total of 297 courses of ITMTX. Of the 297 doses of ITMTX, 20 episodes (6.7%) of post-ITMTX syndrome were observed. The incidence of post-ITMTX syndrome was highest after the second dose of ITMTX (24%). The most common symptom of post-ITMTX syndrome was headache which was seen in 17 (85%) patients. Seventeen (85%) patients had vomiting, 10 (50%) patients had fever, and 4 (20%) patients had backache. Meningeal signs were present in 2 (10%) patients. CONCLUSIONS: Post-ITMTX syndrome is not uncommon in adult patients receiving prophylactic ITMTX for treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Patients develop a toxic syndrome closely mimicking acute bacterial meningitis but spontaneous recovery is seen without any neurological sequelae. PMID- 26019421 TI - Utility of cerebrospinal fluid cortisol level in acute bacterial meningitis. AB - BACKGROUND: Meningitis remains a serious clinical problem in developing as well as developed countries. Delay in diagnosis and treatment results in significant morbidity and mortality. The role and levels of intrathecal endogenous cortisol is not known. OBJECTIVE: To study the cerebrospinal fluid (CSF) cortisol levels and to evaluate its role as a diagnostic and therapeutic marker in acute bacterial meningitis. MATERIALS AND METHODS: Thirty patients with acute bacterial meningitis with no prior treatment were evaluated. Cortisol levels were compared with 20 patients with aseptic (viral) meningitis and 25 control subjects. RESULTS: Mean CSF cortisol level was 13.85, 3.47, and 1.05 in bacterial meningitis, aseptic meningitis, and controls, respectively. Mean CSF cortisol level in bacterial meningitis was significantly higher as compared to controls (P < 0.001). There was significant difference in CSFcortisol levels in bacterial and aseptic meningitis (P < 0.001). CONCLUSIONS: Cortisol levels in CSF are highly elevated in patients with acute bacterial meningitis. This suggests that intrathecalcortisol may serve as a valuable, rapid, relatively inexpensive diagnostic marker in discriminatingbetween bacterial and aseptic meningitis. This helps in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality. PMID- 26019422 TI - Guillain-Barre syndrome complicating pregnancy and correlation with maternal and fetal outcome in North Eastern India: A retrospective study. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is rare in pregnancy with an estimated incidence between 1.2 and 1.9 cases per 100,000 people annually, and it is generally accepted that it carries a high maternal risk. Most reports of GBS with pregnancy are case reports only. AIM: Purpose of this retrospective study was to find the correlation between pregnancy and GBS. SETTINGS AND DESIGN: Records of patients admitted in neurology division were analyzed in a tertiary care teaching hospital in the northeastern Indian pregnant female population with GBS between 15-49 years during the period of 2009-2013. MATERIALS AND METHODS: We analyzed the records of 47 patients with pregnancy and GBS, evaluated and treated in our institute from August 2009 to December 2013. This is retrospective observational study done in North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), India. RESULT: Predominant form of GBS was acute inflammatory demyelinating polyneuropathy (AIDP). The weakness started from the lower limbs in majority of patients. Ten percent of women had bifacial weakness. Most of patients had good maternal and fetal outcome. Two patients received intravenous immunoglobulin (IVIG). Only two patient required ventilator supports and one patient had intrauterine death (IUD) and died due to respiratory failure. CONCLUSION: Our results indicate that risk of GBS increases in third trimester and first 2 weeks after delivery. Demyelinating variety of GBS was common in our population. GBS natural course during pregnancy is mild and showed quick recovery. Maternal and perinatal outcome was good. PMID- 26019423 TI - Comparison of high-resolution sonography and electrophysiology in the diagnosis of carpal tunnel syndrome. AB - BACKGROUND: The diagnostic accuracy of high-resolution ultrasonography (HRUS) in comparison to electro-diagnostic testing (EDX) in carpal tunnel syndrome (CTS) is debatable. OBJECTIVE: The aim of this study was to compare the diagnostic accuracy of HRUS with EDX in patients with various grades of CTS and CTS associated with peripheral neuropathy (CTS + PNP). MATERIALS AND METHODS: A prospective cohort of 57 patients with possible CTS was studied along with matched controls. The cross-sectional area (CSA) of the median nerve at the inlet of carpal tunnel was assessed by a sonologist blinded to the clinical and EDX data. Palm wrist distal sensory latency difference (PWDSLD), second lumbrical interosseus distal motor latency difference (2LIDMLD) and CSA were compared in patients with different grades of severity of CTS and CTS+PNP. RESULTS: Total 92 hands of 57 patients met the clinical criteria for CTS. Mean CSA at the inlet of carpal tunnel was 0.11 +/- 0.0275 cm(2). It had the sensitivity, specificity, positive predictive value and negative predictive values of 76.43%, 72.72%, 89.47% and 68%, respectively (P < 0.0001). Overall, HRUS had good correlation with PWDSLD and 2LIDMLD electro-diagnostic studies in all grades of CTS and CTS + PNP. CONCLUSION: HRUS can be used as a complementary screening tool to EDX. However, EDX has been found to be more sensitive and specific in mild CTS. PMID- 26019424 TI - Mild serotonin syndrome: A report of 12 cases. AB - Serotonin syndrome (SS) is an under diagnosed and under reported condition. Mild SS is easily overlooked by physicians. Every patient with mild SS is a potential candidate for developing life-threatening severe SS because of inadvertent overdose or the addition of the second serotonergic drug. Herein, we describe 12 patients with mild SS observed over 12 months in neurology outpatient clinic. It is a retrospective chart review of 12 consecutive patients who had hyperreflexia with tremor (defined as mild SS Hunter's criteria) and had received serotonergic agents in the past 5 weeks. Only four patients (33%) reported tremor as a presenting or main feature. The presenting features in another eight patients were: Dizziness, generalized body pain, headache, and seizure. Five patients responded to the removal of the offending agents and got a complete response in 2 7 days. There were no or minimal responses in another seven patients to the removal of the serotonergic drugs. Cyproheptadine was started in these patients, at the dose of 8 mg three times daily. Response started within 1-3 days of initiation of the drug and the complete responses were noted in 5-14 days. There were no side effects from cyproheptadine in any patient. We suggest that any patient on serotonergic drug developing new symptoms should be examined for the presence of tremor, hypertonia, hyperreflexia, and clonus to look for mild SS. In addition, every patient on any serotonergic drug should be examined for the presence of mild SS before escalating the dose or before adding a new one. PMID- 26019425 TI - Gentle giant. PMID- 26019426 TI - Mineralizing angiopathy with basal ganglia stroke in an infant. AB - Basal ganglia stroke is known following trivial head trauma. Recently a distinct clinic-radiological entity termed 'mineralizing angiopathy' was described. We report an infant who developed basal ganglia stroke following trivial fall. His clinic-radiological features are described. PMID- 26019427 TI - Utilization behavior. AB - Utilisation Behaviour (UB) denotes the appropriate usage of an object by a patient, however at an inappropriate situation. Patients are compelled by the visual, visual-tactile presentation to grasp and use the object kept in front of them. UB is observed in patients having unilateral or bilateral frontal lesions. It is considered to be an extension of magnetic apraxia, which is defined as bilateral manual grasping behavior. The proposed hypothesis is that in frontal lesions there is suppression of the inhibitory effect of frontal lobe on parietal lobe. Neurological models to explain this phenomenon to occur as a result of loss of inhibitory biological system within the brain. A disturbance of balance between the patient's dependence on and independence from the outside world is believed to be present in such cases. From a cognitive point of view, three models have been described. Since its first description by Lhermitte in 1983, UB remains to be an interesting neurological phenomenon. We present a case of UB in a patient of fronto-temporal dementia and also summarise the neurological and cognitive models that explain this behaviour. PMID- 26019428 TI - Encephalitis due to antibodies to voltage gated potassium channel (VGKC) with cerebellar involvement in a teenager. AB - Encephalitis due to antibodies to voltage gated potassium channel (VGKC) typically presents with limbic encephalitis and medial temporal lobe involvement on neuroimaging. We describe a case of 13 year girl female with encephalitis due to antibodies to VGKC with signal changes in the cerebellar dentate nuclei bilaterally and clinical features that suggested predominant cerebellar involvement. These have never been reported previously in the literature. Our case expands the phenotypic spectrum of this rare condition. PMID- 26019429 TI - Polyneuritis cranialis with generalized hyperreflexia as a presenting manifestation of thyrotoxicosis. AB - A 22-year-old male student with no past medical illness, presented with acute onset dysarthria, binocular diplopia, and dysphagia over 10 hours. On examination, he had tachycardia, hypertension, generalized hyper-reflexia, and bilateral pupil sparing oculomotor, troclear, abducens, trigeminal, facial, glossopharyngeal, and vagus nerve palsy. Rest examination was unremarkable. Facial nerve conduction study (NCS) showed decreased amplitude bilaterally and neurogenic pattern on electromyography. Limb NCS, repetitive nerve stimulation, neostigmine test, brain magnetic resonance imaging, cerebrospinal fluid, and biochemical tests were normal. Only positive tests were low thyroid-stimulating hormone (TSH) (<0.01), high free T3 (19.2 pmol/L), and high free T4 (39.2 pmol/L). Thyroid ultrasonography, anti-thyroid peroxidase, and anti-thyroglobulin antibody were normal. Patient was treated with anti-thyroid drugs, with which he completely recovered in 2 months. Though many cases with thyrotoxic myopathy have been reported, only few mention neuropathic cause of dysphagia or polyneuritis cranialis. Getting done thyroid function tests may be helpful in patients with polyneuritis cranialis of uncertain etiology. PMID- 26019430 TI - Limbic encephalitis with antibodies to glutamic acid decarboxylase presenting with brainstem symptoms. AB - Limbic encephalitis (LE) is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. LE associated with glutamic acid decarboxylase antibodies (anti-GAD) is rare in children. Here, we characterized the clinical and laboratory features of a patient presenting with brainstem involvement with non-paraneoplastic LE associated with anti-GAD antibodies. In our patient, after plasma exchange, we determined a dramatic improvement of the neurological deficits. PMID- 26019431 TI - Mirror movements in progressive hemifacial atrophy. AB - Mirror movements are simultaneous, involuntary, identical movements occurring during contralateral voluntary movements. These movements are considered as soft neurologic signs seen uncommonly in clinical practice. The mirror movements are described in various neurological disorders which include parkinsonism, cranio veretebral junction anamolies, and hemiplegic cerebral palsy. These movements are intriguing and can pose significant disability. However, no such observation regarding mirror movements in progressive hemifacial atrophy have been reported previously. We are reporting a teenage girl suffering from progressive hemifacial atrophy and epilepsy with demonstrable mirror movements in hand. PMID- 26019432 TI - Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy. AB - Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term "minipolyfasciculations" may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID- 26019433 TI - Cerebral fat embolism: Use of MR spectroscopy for accurate diagnosis. AB - Cerebral fat embolism (CFE) is an uncommon but serious complication following orthopedic procedures. It usually presents with altered mental status, and can be a part of fat embolism syndrome (FES) if associated with cutaneous and respiratory manifestations. Because of the presence of other common factors affecting the mental status, particularly in the postoperative period, the diagnosis of CFE can be challenging. Magnetic resonance imaging (MRI) of brain typically shows multiple lesions distributed predominantly in the subcortical region, which appear as hyperintense lesions on T2 and diffusion weighted images. Although the location offers a clue, the MRI findings are not specific for CFE. Watershed infarcts, hypoxic encephalopathy, disseminated infections, demyelinating disorders, diffuse axonal injury can also show similar changes on MRI of brain. The presence of fat in these hyperintense lesions, identified by MR spectroscopy as raised lipid peaks will help in accurate diagnosis of CFE. Normal brain tissue or conditions producing similar MRI changes will not show any lipid peak on MR spectroscopy. We present a case of CFE initially misdiagnosed as brain stem stroke based on clinical presentation and cranial computed tomography (CT) scan, and later, MR spectroscopy elucidated the accurate diagnosis. PMID- 26019434 TI - Refractory status epilepticus from NMDA receptor encephalitis successfully treated with an adjunctive ketogenic diet. PMID- 26019435 TI - Author's response on "Neuropsychiatric profiles in patients with Alzheimer's disease and vascular dementia". PMID- 26019436 TI - Early detection of adult onset Susac's syndrome in a South Indian female. PMID- 26019437 TI - Issues with normative data of hippocampal volumetry in Indian population. PMID- 26019438 TI - Author's Reply: Regarding issues with article on hippocampal volumetry. PMID- 26019439 TI - Sphincter of Oddi dysfunction Type III: New studies suggest new approaches are needed. AB - Sphincter of Oddi dysfunction (SOD) has been classified into three types based upon the presence or absence of objective findings including liver test abnormalities and bile duct dilatation. Type III is the most controversial and is classified as biliary type pain in the absence of any these objective findings. Many prior studies have shown that the clinical response to endoscopic therapy is higher based upon the presence of these objective criteria. However, there has been variable correlation of the manometry findings to outcome after endoscopic therapy. Nevertheless, manometry and sphincterotomy has been recommended for Type III patients given the overall response rate of 33%, although the reported response rates are highly variable. However, all of the prior data was non blinded and non-randomized with variable follow-up. The evaluating predictors in SOD study - a prospective randomized blinded sham controlled one year outcome study showed no correlation between manometric findings and outcome after sphincterotomy. Furthermore, patients receiving sham therapy had a statistically significantly better outcome than those undergoing biliary or dual sphincterotomy. This study calls into question the whole concept of SOD Type III and, based upon prior physiologic studies, one can suggest that SOD Type III likely represents a right upper quadrant functional abdominal pain syndrome and should be treated as such. PMID- 26019440 TI - Changes in the esophageal mucosa of patients with non erosive reflux disease: How far have we gone? AB - The normal esophageal mucosa creates a protective epithelial barrier that constrains the acidic reflux in the esophageal lumen. Microscopic findings and functional studies indicate that this barrier might be impaired in patients with non erosive reflux disease (NERD) but not in patients with functional heartburn (FH). Whereas endoscopy and pH monitoring are the most important diagnostic tools in the diagnosis of NERD, recent studies suggest that esophageal biopsies might have a complementary role. Particularly in the differential diagnosis between NERD and FH, the application of histological severity scores showed very promising results. Further evaluation of the scores could lead to routine application of histology in specific NERD populations. PMID- 26019441 TI - Hepatitis C: New challenges in liver transplantation. AB - In an era of great achievements in liver transplantation, hepatitis C viral infection (HCV) remains an unsolved problem. As a leading indication for liver transplantation in Western countries, HCV poses a significant burden both before and after transplantation. Post-transplant disease recurrence occurs in nearly all patients with detectable pretransplant viremia, compromising the lifesaving significance of transplantation. Many factors involving the donor, recipient and virus have been evaluated throughout the literature, although few have been fully elucidated and implemented in actual clinical practice. Antiviral therapy has been recognized as a cornerstone of HCV infection control; however, experience and success are diminished following transplantation in a challenging cohort of patients with liver cirrhosis. Current therapeutic protocols surpass those used previously, both in sustained viral response and side-effect profile. In this article we review the most relevant and contemporary scientific evidence regarding hepatitis C infection and liver transplantation, with special attention dedicated to novel, more efficient and safer antiviral regimens. PMID- 26019442 TI - Gastric cancer and the epoch of immunotherapy approaches. AB - The incidence of gastric cancer (GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancer-related deaths with a case fatality GC ratio higher than other common malignancies. Surgical resection is the primary curative treatment for GC though the overall 5-year survival rate remains poor (approximately 20%-25%). To improve the outcome of resectable gastric cancer, different treatment strategies have been evaluated such as adjuvant or perioperative chemotherapy. In resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit. Moreover, in metastatic patients, chemotherapy is the mainstay of palliative therapy with a median overall survival of 8-10 mo and objective response rates of merely 20%-40%. Therefore, the potential for making key beneficial progress is to investigate the GC molecular biology to realize innovative therapeutic strategies, such as specific immunotherapy. In this review, we provide a panoramic view of the different immune-based strategies used for gastric cancer treatment and the results obtained in the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell based immunotherapies. PMID- 26019443 TI - Pathophysiology after pancreaticoduodenectomy. AB - Pancreaticoduodenectomy (PD) will result in removal of important multiorgans in upper intestinal tract and subsequently secondary physiologic change. In the past, surgeons just focused on the safety of surgical procedure; however, PD is regarded as safe and widely applied to treatment of periampullary lesions. Practical issues after PD, such as, effect of duodenectomy, metabolic surgery like effect, alignment effect of gastrointestinal continuity, and non-alcoholic fatty liver disease were summarized and discussed. PMID- 26019444 TI - Incidence and treatment of brain metastasis in patients with esophageal carcinoma. AB - Brain metastasis from esophageal carcinoma (BMEC) is very rare, but its incidence has increased in the United States, Japan, China and other counties. Reports on BMEC have largely been focused on examining whether adjuvant therapy for esophageal cancer influences the survival duration of BMEC patients and on the imaging characteristics of BMEC determined using new medical equipment. The difference between different pathological types of esophageal cancer, especially adenocarcinoma and squamous cell carcinoma, is one important factor used to assess the influence of BMEC. Adjuvant therapy, including radiotherapy and chemotherapy, for esophageal cancer with different characteristics in different countries may affect BMEC treatment outcomes. The degree of popularization of advanced medical equipment is a major concern related to the prevalence of BMEC. Furthermore, targeted BMEC treatment is under development in developed countries. In this article, we reviewed the debate surrounding BMEC and analyzed BMEC studies from different perspectives. PMID- 26019445 TI - Liver involvement in pediatric celiac disease. AB - Celiac disease (CD) is an intestinal inflammatory disease that manifests in genetically susceptible individuals when exposed to dietary gluten. It is a common chronic disorder, with a prevalence of 1% in Europe and North America. Although the disease primarily affects the gut, the clinical spectrum of CD is remarkably varied, and the disease can affect many extraintestinal organs and systems, including the liver. The hepatic dysfunction presenting in CD ranges from asymptomatic liver enzyme elevations or nonspecific reactive hepatitis (cryptogenic liver disorders), to chronic liver disease. In this article, we review the clinical presentations and possible mechanisms of CD-related liver injury to identify strategies for the diagnosis and treatment of these disorders in childhood. PMID- 26019446 TI - Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease. AB - Inflammatory bowel diseases (IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis. These idiopathic diseases have environmental, genetic, immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type (Th) 1 and Th2 immune responses, other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin, microRNAs, and serum proinflammatory cytokines. An efficient strategy for IBD therapy is represented by the combination of IL-17A and IL-17F in acute IL-17A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17F knockout, DSS-induced colitis have been observed. Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused review in order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation. PMID- 26019447 TI - Magnetic resonance imaging of the pancreas in streptozotocin-induced diabetic rats: Gadofluorine P and Gd-DOTA. AB - AIM: To investigate the performance of Gadofluorine P-enhanced magnetic resonance imaging (MRI) on the diagnosis of diabetes in a streptozotocin (STZ) -induced diabetic rat model. METHODS: Fischer 344 rats were treated with STZ. Rats not treated with STZ served as controls. T1-weighted MRI was performed using a 3T scanner before and after the injection of Gd-DOTA or Gadofluorine P (6 diabetic rats, 5 controls). The normalized signal intensity (SI) and the enhancement ratio (ER) of the pancreas were measured at each time point, and the values were compared between the normal and diabetic rats using the Mann-Whitney test. In addition, the values were correlated with the mean islet number. Optimal cut-off values were calculated using a positive test based on receiver operating characteristics. Intrapancreatic Gd concentration after the injection of each contrast media was measured using laser ablation-inductively coupled plasma-mass spectrometry in a separate set of rats (4 diabetic rats, 4 controls for Gadofluorine P; 2, 2 for Gd-DOTA). RESULTS: The normalized SI and ER of the pancreas using Gd-DOTA were not significantly different between diabetic rats and controls. With Gadofluorine P, the values were significantly higher in the diabetic rats than in the control rats 30 min after injection (P < 0.05). The area under the receiver operating characteristic curve that differentiated diabetic rats from the control group was greater for Gadofluorine P than for Gd DOTA (0.967 vs 0.667, P = 0.085). An increase in normalized SI 30 min after Gadofluorine P was correlated with a decrease in the mean number of islets (r (2) = 0.510, P = 0.014). Intra-pancreatic Gd was higher in rats with Gadofluorine P injection than Gd-DOTA injection (Gadofluorine P vs Gd-DOTA, 7.37 vs 0.00, P < 0.01). A significant difference in the concentration of intrapancreatic Gd was observed between the control and diabetic animals that were sacrificed 30 min after Gadofluorine P injection (control vs diabetic, 3.25 ng/g vs 10.55 ng/g, P < 0.05) CONCLUSION: In this STZ-induced diabetes rat model, Gadofluorine P-enhanced MRI of the pancreas showed high accuracy in the diagnosis of diabetes. PMID- 26019448 TI - Expression profile of microRNAs in gastrointestinal stromal tumors revealed by high throughput quantitative RT-PCR microarray. AB - AIM: To investigate the microRNA (miRNA) expression profile in gastrointestinal stromal tumor (GIST) tissues that could serve as a novel diagnostic biomarker for GIST detection. METHODS: We performed a quantitative real-time quantitative reverse transcriptase polymerase chain reaction assay to analyze the expression of 1888 miRNAs in a sample set that included 54 GIST tissue samples. RESULTS: We found that dysregulation of several miRNAs may be related to the malignant potential of GISTs. Six of these miRNAs, hsa-let-7c, miR-218, miR-488#, miR-4683, miR-34c-5p and miR-4773, were selected as the final list of biomarkers to separate the malignant GISTs (M group) from the benign GISTs (B group). In addition, MiR-29b-2#, hsa-let-7c, miR-891b, miR-218, miR-204, miR-204-3p, miR-628 5p, miR-744, miR-29c#, miR-625 and miR-196a were used to distinguish between the borderline (BO group) and M groups. There were 11 common miRNAs selected to separate the benign and borderline (BB) group from the M group, including hsa-let 7c, miR-218, miR-628-5p, miR-204-3p, miR-204, miR-891b, miR-488#, miR-145, miR 891a, miR-34c-5p and miR-196a. CONCLUSION: The identified miRNAs appear to be novel biomarkers to distinguish malignant from benign GISTs, which may be helpful to understand the mechanisms of GIST oncogenesis and progression, and to further elucidate the characteristics of GIST subtypes. PMID- 26019449 TI - Hepatocyte nuclear factor 4alpha induces a tendency of differentiation and activation of rat hepatic stellate cells. AB - AIM: To investigate the effect of hepatocyte nuclear factor 4alpha (HNF4alpha) on the differentiation and transformation of hepatic stellate cells (HSCs). METHODS: By constructing the recombinant adenovirus vector expressing HNF4alpha and HNF4alpha shRNA vector, and manipulating HNF4alpha expression in HSC-T6 cells, we explored the influence of HNF4alpha and its induction capacity in the differentiation of rat HSCs into hepatocytes. RESULTS: With increased expression of HNF4alpha mediated by AdHNF4alpha, the relative expression of Nanog was downregulated in HSC-T6 cells (98.33 +/- 12.33 vs 41.33 +/- 5.67, P < 0.001). Consequently, the expression of G-P-6 and PEPCK was upregulated (G-P-6: 14.34 +/- 3.33 vs 42.53 +/- 5.87, P < 0.01; PEPCK: 10.10 +/- 4.67 vs 56.56 +/- 5.25, P < 0.001), the expression of AFP and ALB was positive, and the expression of Nanog, Type I collagen, alpha-SMA, and TIMP-1 was significantly decreased. HNF4alpha also downregulated vimentin expression and enhanced E-cadherin expression. The ultrastructure of HNF4alpha-induced cells had more mitochondria and ribosomes compared with the parental cells. After silencing HNF4alpha expression, EPCK, E cadherin, AFP, and ALB were downregulated and alpha-SMA and vimentin were upregulated. CONCLUSION: HNF4alpha can induce a tendency of differentiation of HSCs into hepatocyte-like cells. These findings may provide an effective way for the treatment of liver diseases. PMID- 26019450 TI - MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. AB - AIM: To investigate the underlying molecular mechanisms of miR-451 to inhibit proliferation of esophageal carcinoma cell line EC9706. METHODS: Assays for cell growth, apoptosis and invasion were used to evaluate the effects of miR-451 expression on EC cells. Luciferase reporter and Western blot assays were used to test whether cyclin-dependent kinase inhibitor 2D (CDKN2D) and MAP3K1 act as major targets of miR-451. RESULTS: The results showed that CDKN2D and MAP3K1 are direct targets of miR-451. CDKN2D and MAP3K1 overexpression reversed the effect of miR-451. MiR-451 inhibited the proliferation of EC9706 by targeting CDKN2D and MAP3K1. CONCLUSION: These findings suggest that miR-451 might be a novel prognostic biomarker and a potential target for the treatment of esophageal squamous cell carcinoma in the future. PMID- 26019451 TI - Effect of nuclear factor-kappaB and angiotensin II receptor type 1 on the pathogenesis of rat non-alcoholic fatty liver disease. AB - AIM: To investigate the roles of nuclear factor (NF)-kappaB and angiotensin II receptor type 1 (AT1R) in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). METHODS: Forty-two healthy adult male Sprague-Dawley rats were randomly divided into three groups: the control group (normal diet), the model group, and the intervention group (10 wk of a high-fat diet feeding, followed by an intraperitoneal injection of PDTC); 6 rats in each group were sacrificed at 6, 10, and 14 wk. After sacrifice, liver tissue was taken, paraffin sections of liver tissue specimens were prepared, hematoxylin and eosin (HE) staining was performed, and pathological changes in liver tissue (i.e., liver fibrosis) were observed by light microscopy. NF-kappaB expression in liver tissue was detected by immunohistochemistry, and the expression of AT1R in the liver tissue was detected by reverse transcription-polymerase chain reaction (RT-PCR). The data are expressed as mean +/- SD. A two-sample t test was used to compare the control group and the model group at different time points, paired t tests were used to compare the differences between the intervention group and the model group, and analysis of variance was used to compare the model group with the control group. Homogeneity of variance was analyzed with single factor analysis of variance. H variance analysis was used to compare the variance. P < 0.05 was considered statistically significant. RESULTS: The NAFLD model was successful after 6 wk and 10 wk. Liver fibrosis was found in four rats in the model group, but in only one rat in the intervention group at 14 wk. Liver steatosis, inflammation, and fibrosis were gradually increased throughout the model. In the intervention group, the body mass, rat liver index, serum lipid, and transaminase levels were not increased compared to the model group. In the model group, the degree of liver steatosis was increased at 6, 10, and 14 wk, and was significantly higher than in the control group (P < 0.01). In the model group, different degrees of liver cell necrosis were visible and small leaves, punctated inflammation, focal necrosis, and obvious ballooning degeneration were observed. Partial necrosis and confluent necrosis were observed. In the model group, liver inflammatory activity scores at 6, 10, and 14 wk were higher than in the control group (P < 0.01). Active inflammation in liver tissue in the intervention group was lower than in the model group (P < 0.05). HE staining showed liver fibrosis only at 14 wk in 4/6 rats in the model group and in 1/6 rats in the intervention group. NF-kappaB positive cells were stained yellow or ensemble yellow, and NF-kappaB was localized in the cytoplasm and/or nucleus. The model group showed NF-kappaB activation at 6, 10, and 14 wk in liver cells; at the same time points, there were statistically significant differences in the control group (P < 0.01). Over time, NF-kappaB expression increased; this was statistically lower (P < 0.05) at 14 weeks in the intervention group compared to the model group, but significantly increased (P < 0.05) compared with the control group; RT-PCR showed that AT1R mRNA expression increased gradually in the model group; at 14 wk, the expression was significantly different compared with expression at 10 weeks as well as at 6 weeks (P < 0.05). In the model group, AT1R mRNA expression was significantly higher than at the same time point in the control group (P < 0.01). CONCLUSION: With increasing severity of NAFLD, NF-kappaB activity is enhanced, and the inhibition of NF-kappaB activity may reduce AT1R mRNA expression in NAFLD. PMID- 26019452 TI - Effect of microRNA-1 on hepatocellular carcinoma tumor endothelial cells. AB - AIM: To investigate the effect of microRNA-1 (miR-1) on tumor endothelial cells (TECs) of human hepatocellular carcinoma (HCC). METHODS: MiR-1 specific short hairpin RNA (shRNA) was synthesized and cloned into a recombinant lentiviral vector. TECs were then infected by the miRNA-1-shRNA recombinant lentivirus. TECs were divided into three groups: a control (CON) group consisting of normal TECs without lentiviral infection, a negative control (NC) group consisting of normal TECs infected with a negative control virus, and a micro-down (MD) group consisting of normal TECs infected with the miR-1-inhibition virus containing the target gene. Silencing of miR-1 expression was quantified via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The proliferation of TECs was detected using MTT (Thiazolyl Blue Tetrazolium Bromide) assay; the observations were continued for 5 d, and the optical density value at 490 nm was detected every day. Apoptosis was detected via flow cytometry using Annexin V-APC single staining. The migration and invasion of TECs were detected using transwell assays. RESULTS: Lentiviral miR-1 shRNA was successfully transduced into TECs, and specifically silenced the expression of miR-1. The results of qRT-PCR showed that the expression of miR-1 was significantly decreased in the MD group (2( DeltaDeltaCt) = 0.57 +/- 0.14) compared with the CON group (2(-DeltaDeltaCt) = 1) and the NC group (2(-DeltaDeltaCt) = 1.05 +/- 0.13) (P < 0.01). The results of MTT assay showed that the cell proliferation was all significantly inhibited in the MD group in the 5 days compared with the CON and NC groups (P < 0.01). The results of flow cytometry showed that the apoptosis was significantly increased in the MD group (6.32% +/- 0.33%) compared with the CON group (2.03% +/- 0.30%) and the NC group (2.18% +/- 0.15%) (P < 0.01). The ability of cell migration was significantly inhibited in the MD group (62.0 +/- 5.48) compared with the CON group (99.8 +/- 3.11) and the NC group (97.2 +/- 3.70) (P < 0.01). The ability of invasion of TECs was also significantly inhibited in the MD group (29.8 +/- 2.39) compared with the CON group (44.6 +/- 3.36) and the NC group (44.4 +/- 5.17) (P < 0.01). CONCLUSION: MiR-1 might be a potential tumor activator. Inhibiting its expression could decrease proliferation, induce apoptosis, and inhibit the migration and invasion of TECs of human HCC. PMID- 26019453 TI - Validation of aspartate aminotransferase to platelet ratio for diagnosis of liver fibrosis and prediction of postoperative prognosis in infants with biliary atresia. AB - AIM: To validate the value of aspartate aminotransferase to platelet ratio index (APRI) in assessment of liver fibrosis and prediction of postoperative prognosis of biliary atresia (BA) infants from Mainland China. METHODS: Medical records of 153 BA infants who were hospitalized from January 2010 to June 2013 were reviewed. The efficacy of APRI for diagnosis of liver fibrosis was assessed using the receiver operator characteristic (ROC) curve compared to the pathological Metavir fibrosis score of the liver wedge specimens of 91 BA infants. The prognostic value of preoperative APRI for jaundice persistence, liver injury, and occurrence of cholangitis within 6 mo after KP was studied based on the follow-up data of 48 BA infants. RESULTS: APRI was significantly correlated with Metavir scores (rs = 0.433; P < 0.05). The mean APRI value was 0.76 in no/mild fibrosis group (Metavir score F0-F1), 1.29 in significant fibrosis group (F2-F3), and 2.51 in cirrhosis group (F4) (P < 0.001). The area under the ROC curve (AUC) of APRI for diagnosing significant fibrosis and cirrhosis was 0.75 (P < 0.001) and 0.81 (P = 0.001), respectively. The APRI cut-off of 0.95 was 60.6% sensitive and 76.0% specific for significant fibrosis diagnosis, and a threshold of 1.66 was 70.6% sensitive and 82.7% specific for cirrhosis. The preoperative APRI in infants who maintained jaundice around 6 mo after KP was higher than that in those who did not (1.86 +/- 2.13 vs 0.87 +/- 0.48, P < 0.05). The AUC of APRI for prediction of postoperative jaundice occurrence was 0.67. A cut-off value of 0.60 showed a sensitivity of 66.7% and a specificity of 83.3% for the prediction of jaundice persistence. Preoperative APRI had no significant association with later liver injury or occurrence of cholangitis. CONCLUSION: Our study demonstrated that APRI could diagnose significant liver fibrosis, especially cirrhosis in BA infants, and the elevated preoperative APRI predicts jaundice persistence after KP. PMID- 26019454 TI - Prognostic value and clinical correlations of 18-fluorodeoxyglucose metabolism quantifiers in gastric cancer. AB - AIM: To investigate the correlations of pre-treatment positron emission tomography-computer tomography (PET-CT) metabolic quantifiers with clinical data of unstratified gastric cancer (GC) patients. METHODS: Forty PET-CT scans utilising 18-fluorodeoxyglucose in patients who received no prior treatment were analysed. Analysis involved measurements of maximum and mean standardised uptake volumes (SUV), coefficient of variation (COV), metabolic tumour volumes and total lesion glycolysis of different thresholds above which the tumor volumes were identified. The threshold values were: SUV absolute value of 2.5, 30% of SUVmax, 40% of SUVmax, and liver uptake-based (marked 2.5, 30, 40 and liv, respectively). Clinical variables such as age, sex, clinical stage, performance index, weight loss, tumor histological type and grade, and CEA and CA19.9 levels were included in survival analysis. Patients received various treatment modalities appropriate to their disease stage and the outcome was defined by time to metastasis (TTM) and overall survival (OS). Clinical and metabolic parameters were evaluated by analysis of variance, receiver operating characteristics, univariate Kaplan Meier, and multivariate Cox models. P < 0.05 was considered statistically significant. RESULTS: Significant differences were observed between initially disseminated and non-disseminated patients in mean SUV (6.05 vs 4.13, P = 0.008), TLG2.5 (802 cm(3) vs 226 cm(3); P = 0.031), and TLG30 (436 cm(3) vs 247 cm(3), P = 0.018). Higher COV was associated with poor tumour differentiation (0.47 for G3 vs 0.28 for G1 and G2; P = 0.03). MTV2.5 was positively correlated to patient weight loss (< 5%, 5%-10% and > 10%: 40.4 cm(3) vs 123.6 cm(3) vs 181.8 cm(3), respectively, P = 0.003). In multivariate Cox analysis, TLG30 was prognostic for OS (HR = 1.001, 95%CI: 1.0009-1.0017; P = 0.047) for the whole group of patients. In the same model yet only including patients without initial disease dissemination TLG30 (HR = 1.009, 95%CI: 1.003-1.014; P = 0.004) and MTV2.5 (HR = 1.02, 95%CI: 1.002-1.036; P = 0.025) were prognostic for OS; for TTM TLG30 was the only significant prognostic variable (HR = 1.006, 95%CI: 1.001-1.012; P = 0.02). CONCLUSION: PET-CT in GC may represent a valuable diagnostic and prognostic tool that requires further evaluation in highly standardised environments such as randomised clinical trials. PMID- 26019455 TI - Risk factors causing structural sequelae after anastomotic leakage in mid to low rectal cancer. AB - AIM: To investigate the risk factors causing structural sequelae after anastomotic leakage in patients with mid to low rectal cancer. METHODS: Prospectively collected data of consecutive subjects who had anastomotic leakage after surgical resection for rectal cancer from March 2006 to May 2013 at Korea University Anam Hospital were retrospectively analyzed. Two subgroup analyses were performed. The patients were initially divided into the sequelae (stricture, fistula, or sinus) and no sequelae groups and then divided into the permanent stoma (PS) and no PS groups. Univariate and multivariate analyses were performed to identify the risk factors of structural sequelae after anastomotic leakage. RESULTS: Structural sequelae after anastomotic leakage were identified in 29 patients (39.7%). Multivariate analysis revealed that diversion ileostomy at the first operation increases the risk of structural sequelae [odds ratio (OR) = 6.741; P = 0.017]. Fourteen patients (17.7%) had permanent stoma during the follow-up period (median, 37 mo). Multivariate analysis showed that the tumor level from the dentate line was associated with the risk of permanent stoma (OR = 0.751; P = 0.045). CONCLUSION: Diversion ileostomy at the first operation increased the risk of structural sequelae of the anastomosis, while lower tumor location was associated with the risk of permanent stoma in the management of anastomotic leakage. PMID- 26019456 TI - Needle-knife fistulotomy vs double-guidewire technique in patients with repetitive unintentional pancreatic cannulations. AB - AIM: To compare the success rates and adverse events of early needle-knife fistulotomy (NKF) and double-guidewire technique (DGT) in patients with repetitive unintentional pancreatic cannulations. METHODS: From a total of 1650 patients admitted for diagnostic or therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at a single tertiary care hospital (Pusan National University Yangsan Hospital, Yangsan, South Korea) between January 2009 and December 2012, 134 (8.1%) patients with unsuccessful biliary cannulation after 5 min trial of conventional methods, together with 5 or more repetitive unintentional pancreatic cannulations, were enrolled in the study. Early NKF and DGT groups were assigned 67 patients each. In the DGT group, NKF was performed for an additional 7 min if successful cannulation was not achieved. RESULTS: The success rates with early NKF and the DGT were 79.1% (53/67) and 44.8% (30/67) (P < 0.001), respectively. The incidence of post-ERCP pancreatitis (PEP) was lower in the early NKF group than in the DGT group [4.5% (3/67) vs 14.9% (10/67), P = 0.041]. The mean cannulation times in the early NKF and DGT groups after assignment were 257 s and 312 s (P = 0.013), respectively. CONCLUSION: Our data suggest that early NKF should be considered as the first approach to selective biliary cannulation in patients with repetitive unintentional pancreatic cannulations. PMID- 26019457 TI - Risk scoring system and predictor for clinically relevant pancreatic fistula after pancreaticoduodenectomy. AB - AIM: To establish a scoring system to predict clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). METHODS: The clinical records of 921 consecutive patients who underwent PD between 2008 and 2013 were reviewed retrospectively. Postoperative pancreatic fistula (POPF) was defined and classified by the international study group of pancreatic fistula (ISGPF). We used a logistic regression model to determine the independent risk factors of CR-POPF and developed a scoring system based on the regression coefficient of the logistic regression model. The optimal cut-off value to divide the risk strata was determined by the Youden index. The patients were divided into two groups (low risk and high risk). The independent sample t test was used to detect differences in the means of drain amylase on postoperative day (POD) 1, 2 and 3. The optimal cut-off level of the drain amylase to distinguish CR-POPF from non-clinical POPF in the two risk strata groups was determined using the receiver operating characteristic (ROC) curves. RESULTS: Grade A POPF occurred in 106 (11.5%) patients, grade B occurred in 57 (6.2%) patients, and grade C occurred in 32 (3.5%) patients. A predictive scoring system for CR-POPF (0-6 points) was constructed using the following four factors: 1 point for each body mass index >= 28 [odds ratio (OR) = 3.86; 95% confidence interval (CI): 1.92 7.75, P = 0.00], soft gland texture (OR = 4.50; 95%CI, 2.53-7.98, P = 0.00), and the difference between the blood loss and transfusion in operation >= 800 mL (OR = 3.45; 95%CI, 1.92-7.75, P = 0.00); and from 0 points for a 5 mm or greater duct diameter to 3 points for a less than 2 mm duct (OR = 8.97; 95%CI: 3.70-21.77, P = 0.00). The ROC curve showed that the area under the curve of this score was 0.812. A score of 3 points was suggested to be the best cut-off value (Youden index = 0.485). In the low risk group, a drain amylase level >= 3600 U/L on POD3 could distinguish CR-POPF from non-clinical POPF (the sensitivity and specificity were 75% and 85%, respectively). In the high risk group, the best cut-off was a drain amylase level of 1600 (the sensitivity and specificity were 77 and 63%, respectively). CONCLUSION: A 6-point scoring system accurately predicted the occurrence of CR-POPF. In addition, a drain amylase level on POD3 might be a predictor of this complication. PMID- 26019458 TI - Factors associated with early recurrence after curative surgery for gastric cancer. AB - AIM: To characterize patterns of gastric cancer recurrence and patient survival and to identify predictors of early recurrence after surgery. METHODS: Clinicopathological data for 417 consecutive patients who underwent curative resection for gastric cancer were retrospectively analyzed. Tumor and node status was reclassified according to the 7(th) edition of the American Joint Committee on Cancer tumor-node-metastasis classification for carcinoma of the stomach. Survival data came from both the patients' follow-up records and telephone follow ups. Recurrent gastric cancer was diagnosed based on clinical imaging, gastroscopy with biopsy, and/or cytological examination of ascites, or intraoperative findings in patients who underwent reoperation. Predictors of early recurrence were compared in patients with pT1 and pT2-4a stage tumors. Pearson's chi (2) test and Fisher's exact test were used to compare differences between categorical variables. Survival curves were constructed using the Kaplan Meier method and compared via the log-rank test. Variables identified as potentially important for early recurrence using univariate analysis were determined by multivariate logistic regression analysis. RESULTS: Of 417 gastric cancer patients, 80 (19.2%) were diagnosed with early gastric cancer and the remaining 337 (80.8%) were diagnosed with locally advanced gastric cancer. After a median follow-up period of 56 mo, 194 patients (46.5%) experienced recurrence. The mean time from curative surgery to recurrence in these 194 patients was 24 +/ 18 mo (range, 1-84 mo). Additionally, of these 194 patients, 129 (66.5%) experienced recurrence within 2 years after surgery. There was no significant difference in recurrence patterns between early and late recurrence (P < 0.05 each). For pT1 stage gastric cancer, tumor size (P = 0.011) and pN stage (P = 0.048) were associated with early recurrence of gastric tumors. Patient age, pT stage, pN stage, Lauren histotype, lymphovascular invasion, intraoperative chemotherapy, and postoperative chemotherapy were independent predictors of early recurrence in patients with pT2-4a stage gastric cancer (P < 0.05 each). CONCLUSION: Age, pT stage, pN stage, Lauren histotype, lymphovascular invasion, intraoperative chemotherapy, and postoperative chemotherapy are independent factors influencing early recurrence of pT2-4a stage gastric cancer. PMID- 26019459 TI - Laparoscopic vs computerized tomography-guided radiofrequency ablation for large hepatic hemangiomas abutting the diaphragm. AB - AIM: To compare safety and therapeutic efficacy of laparoscopic radiofrequency (RF) ablation vs computed tomography (CT)-guided RF ablation for large hepatic hemangiomas abutting the diaphragm. METHODS: We retrospectively reviewed our sequential experience of treating 51 large hepatic hemangiomas abutting the diaphragm in 51 patients by CT-guided or laparoscopic RF ablation due to either the presence of symptoms and/or the enlargement of hemangioma. Altogether, 24 hemangiomas were ablated via a CT-guided percutaneous approach (CT-guided ablation group), and 27 hemangiomas were treated via a laparoscopic approach (laparoscopic ablation group). RESULTS: The mean diameter of the 51 hemangiomas was 9.6 +/- 1.8 cm (range, 6.0-12.0 cm). There was no difference in the diameter of hemangiomas between the two groups (P > 0.05). RF ablation was performed successfully in all patients. There was no difference in ablation times between groups (P > 0.05). There were 23 thoracic complications in 17 patients: 15 (62.5%, 15/24) in the CT-guided ablation group and 2 (7.4%, 2/27) in the laparoscopic ablation group (P < 0.05). According to the Dindo-Clavien classification, two complications (pleural effusion and diaphragmatic rupture grade III) were major in two patients. All others were minor (grade I). Both major complications occurred in the CT-guided ablation group. The minor complications were treated successfully with conservative measures, and the two major complications underwent treatment by chest tube drainage and thoracoscopic surgery, respectively. Complete ablation was achieved in 91.7% (22/24) and 96.3% (26/27) in the CT-guided and the laparoscopic ablation groups, respectively (P > 0.05). CONCLUSION: Laparoscopic RF ablation therapy should be used as the first line treatment option for large hepatic hemangiomas abutting the diaphragm. It avoids thermal injury to the diaphragm and reduces thoracic complications. PMID- 26019460 TI - Endoscopic treatment for pancreatic diseases: Needle-knife-guided cannulation via the minor papilla. AB - AIM: To determine the efficacy and safety of meticulous cannulation by needle knife. METHODS: Three needle-knife procedures were used to facilitate cannulation in cases when standard cannulation techniques failed. A total of 104 cannulations via the minor papilla attempted in 74 patients at our center between January 2008 and June 2014 were retrospectively reviewed. RESULTS: Standard methods were successful in 79 cannulations. Of the 25 cannulations that could not be performed by standard methods, 19 were performed by needle-knife, while 17 (89.5%) were successful. Needle-knife use improved the success rate of cannulation [76.0%, 79/104 vs 92.3%, (79 + 17)/104; P = 0.001]. When the 6 cases not appropriate for needle-knife cannulation were excluded, the success rate was improved further (80.6%, 79/98 vs 98.0%, 96/98; P = 0.000). There were no significant differences in the rates of post-endoscopic retrograde cholangiopancreatography adverse events between the group using standard methods alone and the group using needle knife after failure of standard methods (4.7% vs 10.5%, P = 0.301). CONCLUSION: The needle-knife procedure may be an alternative method for improving the success rate of cannulation via the minor papilla, particularly when standard cannulation has failed. PMID- 26019461 TI - Novel immunological and nutritional-based prognostic index for gastric cancer. AB - AIM: To assess the prognostic significance of immunological and nutritional-based indices, including the prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio in gastric cancer. METHODS: We retrospectively reviewed 632 gastric cancer patients who underwent gastrectomy between 1998 and 2008. Areas under the receiver operating characteristic curve were calculated to compare the predictive ability of the indices, together with estimating the sensitivity, specificity and agreement rate. Univariate and multivariate analyses were performed to identify risk factors for overall survival (OS). Propensity score analysis was performed to adjust variables to control for selection bias. RESULTS: Each index could predict OS in gastric cancer patients in univariate analysis, but only PNI had independent prognostic significance in multivariate analysis before and after adjustment with propensity scoring (hazard ratio, 1.668; 95% confidence interval: 1.368-2.035). In subgroup analysis, a low PNI predicted a significantly shorter OS in patients with stage II-III disease (P = 0.019, P < 0.001), T3-T4 tumors (P < 0.001), or lymph node metastasis (P < 0.001). Canton score, a combination of PNI, NLR, and platelet, was a better indicator for OS than PNI, with the largest area under the curve for 12-, 36-, 60-mo OS and overall OS (P = 0.022, P = 0.030, P < 0.001, and P = 0.024, respectively). The maximum sensitivity, specificity, and agreement rate of Canton score for predicting prognosis were 84.6%, 34.9%, and 70.1%, respectively. CONCLUSION: PNI is an independent prognostic factor for OS in gastric cancer. Canton score can be a novel preoperative prognostic index in gastric cancer. PMID- 26019462 TI - Clinicopathologic features of remnant gastric cancer over time following distal gastrectomy. AB - AIM: To investigate remnant gastric cancer (RGC) at various times after gastrectomy, and lay a foundation for the management of RGC. METHODS: Sixty-five patients with RGC > 2 years and < 10 years after gastrectomy (RGC I) and forty nine with RGC > 10 years after gastrectomy (RGC II) who underwent curative surgery were enrolled in the study. The clinicopathologic factors, surgical outcomes, and prognosis were compared between RGC I and RGC II. RESULTS: There was no significant difference in surgical outcomes between RGC I and RGC II. For patients reconstructed with Billroth II, significantly more patients were RGC II compared with RGC (71.9% vs 21.2%, P < 0.001), and more RGC II patients had anastomotic site locations compared to RGC I (31.0% vs 56.3%, P = 0.038). The five-year survival rates for the patients with RGC I and RGC II were 37.6% and 47.9%, respectively, but no significant difference was observed. Borrmann type and tumor stage were confirmed to be independent prognostic factors in both groups. CONCLUSION: RGC II is located on the anastomotic site in higher frequency and more cases develop after Billroth II reconstruction than RGC I. PMID- 26019463 TI - Phase I trial of combination chemotherapy with gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer. AB - AIM: To evaluate the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) and recommended dose (RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer. METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine (mg/m(2)), cisplatin (mg/m(2)), and S-1 (mg/m(2) per day) were as follows: level -1, 800/20/60; level 0, 800/25/60; level 1, 1000/25/60; and level 2, 1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15, and S 1 was administered orally twice daily on days 1 to 7 and days 15 to 21, every 4 wk. RESULTS: Twelve patients were enrolled, and level 0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs (grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1. We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase II study. CONCLUSION: The RD was defined as gemcitabine 1000 mg/m(2) (days 1, 15), cisplatin 25 mg/m(2) (days 1, 15), and S-1 80 mg/m(2) per day (days 1-7, 15-21), every 4 weeks. A phase II study is planned to evaluate the effectiveness of combination chemotherapy with gemcitabine, cisplatin, and S-1 in advanced biliary tract cancer. PMID- 26019464 TI - Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis. AB - AIM: To evaluate the effectiveness of probiotic therapy for suppressing relapse in patients with inactive ulcerative colitis (UC). METHODS: Bio-Three tablets, each containing 2 mg of lactomin (Streptococcus faecalis T-110), 10 mg of Clostridium butyricum TO-A, and 10 mg of Bacillus mesentericus TO-A, were used as probiotic therapy. Sixty outpatients with UC in remission were randomly assigned to receive 9 Bio-Three tablets/day (Bio-Three group) or 9 placebo tablets/day (placebo group) for 12 mo in addition to their ongoing medications. Clinical symptoms were evaluated monthly or on the exacerbation of symptoms or need for additional medication. Fecal samples were collected to analyze bacterial DNA at baseline and 3-mo intervals. Terminal restriction fragment length polymorphism and cluster analyses were done to examine bacterial components of the fecal microflora. RESULTS: Forty-six patients, 23 in each group, completed the study, and 14 were excluded. The relapse rates in the Bio-Three and placebo groups were respectively 0.0% vs 17.4% at 3 mo (P = 0.036), 8.7% vs 26.1% at 6 mo (P = 0.119), and 21.7% vs 34.8% (P = 0.326) at 9 mo. At 12 mo, the remission rate was 69.5% in the Bio-Three group and 56.6% in the placebo group (P = 0.248). On cluster analysis of fecal flora, 7 patients belonged to cluster I, 32 to cluster II, and 7 to cluster III. CONCLUSION: Probiotics may be effective for maintaining clinical remission in patients with quiescent UC, especially those who belong to cluster I on fecal bacterial analysis. PMID- 26019465 TI - Efficacy and safety of a patient-positioning device (EZ-FIX) for endoscopic retrograde cholangiopancreatography. AB - AIM: To assess the efficacy and safety of a patient-positioning device (EZ-FIX) for endoscopic retrograde cholangiopancreatography (ERCP). METHODS: A total of 105 patients were randomized to the EZ-FIX (n = 53) or non-EZ-FIX (n = 52) group in this prospective study. Midazolam and propofol, titrated to provide an adequate level of sedation during therapeutic ERCP, were administered by trained registered nurses under endoscopist supervision. Primary outcome measures were the total dose of propofol and sedative-related complications, including hypoxia and hypotension. Secondary outcome measures were recovery time and sedation satisfaction of the endoscopist, nurses, and patients. RESULTS: There was no significant difference in the rate of hypoxia, but there was a statistical trend (EX-FIX group; n = 4, 7.55%, control group; n = 6, 11.53%, P = 0.06). The mean total dose of propofol was lower in the EZ-FIX group than in the non-EZ-FIX group (89.43 +/- 49.8 mg vs 112.4 +/- 53.8 mg, P = 0.025). In addition, the EZ-FIX group had a shorter mean recovery time (11.23 +/- 4.61 mg vs 14.96 +/- 5.12 mg, P < 0.001). Sedation satisfaction of the endoscopist and nurses was higher in the EX-FIX group than in the non-EZ-FIX group. Technical success rates of the procedure were 96.23% and 96.15%, respectively (P = 0.856). Procedure-related complications did not differ by group (11.32% vs 13.46%, respectively, P = 0.735). CONCLUSION: Using EZ-FIX reduced the total dose of propofol and the recovery time, and increased the satisfaction of the endoscopist and nurses. PMID- 26019466 TI - Assessment of disease specific knowledge and health-related quality of life among United States military veterans with inflammatory bowel disease. AB - AIM: To evaluate the association between patient disease knowledge of inflammatory bowel disease (IBD) and health related quality of life (HRQoL) and identify patient and disease related predictors of patient knowledge of IBD. METHODS: We performed a cross-sectional study of IBD patients with an established diagnosis of IBD longer than 3 mo prior to enrollment. The Crohn's and colitis knowledge score (CCKNOW) and short inflammatory bowel disease questionnaire (SIBDQ) were self-administered to assess patient knowledge of IBD and HRQoL, respectively. Demographic and disease characteristics were abstracted from the electronic medical record. The correlation between CCKNOW and SIBDQ scores was assessed by a linear regression model. Associations of patient knowledge and the variables of interest were calculated using ANOVA. RESULTS: A total of 101 patients were recruited. Caucasian race, younger age at diagnosis, and having a college or post-graduate degree were significantly associated with higher CCKNOW scores. Patients with CD had higher CCKNOW scores compared to patients with ulcerative colitis and inflammatory bowel disease type unclassified, P < 0.01. There was no significant correlation between overall CCKNOW and SIBDQ scores (r (2) = 0.34, P = 0.13). The knowledge sub-domain of diet in CCKNOW was negatively correlated with HRQoL (r (2) = 0.69, P < 0.01). CONCLUSION: IBD diagnosis at a younger age in addition to Caucasian race and higher education were significantly associated with higher knowledge about IBD. However, patient knowledge of IBD was not correlated with HRQoL. Further studies are required to study the effect of patient knowledge of IBD on other clinical outcomes. PMID- 26019467 TI - Risk of venous congestion in live donors of extended right liver graft. AB - AIM: To investigate middle hepatic vein (MHV) management in adult living donor liver transplantation and safer remnant volumes (RV). METHODS: There were 59 grafts with and 12 grafts without MHV (including 4 with MHV-5/8 reconstructions). All donors underwent our five-step protocol evaluation containing a preoperative protocol liver biopsy Congestive vs non-congestive RV, remnant-volume-body-weight ratios (RVBWR) and postoperative outcomes were evaluated in 71 right graft living donors. Dominant vs non-dominant MHV anatomy in total liver volume (d-MHV/TLV vs nd-MHV/TLV) was constellated with large/small congestion volumes (CV-index). Small for size (SFS) and non-SFS remnant considerations were based on standard cut-off- RVBWR and RV/TLV. Non-congestive RVBWR was based on non-congestive RV. RESULTS: MHV and non-MHV remnants showed no significant differences in RV, RV/TLV, RVBWR, total bilirubin, or INR. SFS-remnants with RV/TLV < 30% and non SFS-remnants with RV/TLV >= 30% showed no significant differences either. RV and RVBWR for non-MHV (n = 59) and MHV-containing (n = 12) remnants were 550 +/- 95 mL and 0.79 +/- 0.1 mL vs 568 +/- 97 mL and 0.79 +/- 0.13, respectively (P = 0.423 and P = 0.919. Mean left RV/TLV was 35.8% +/- 3.9%. Non-MHV (n = 59) and MHV-containing (n = 12) remnants (34.1% +/- 3% vs 36% +/- 4% respectively, P = 0.148. Eight SFS-remnants with RVBWR < 0.65 had a significantly smaller RV/TLV than 63 non-SFS-remnants with RVBWR >= 0.65 [SFS: RV/TLV 32.4% (range: 28%-35.7%) vs non-SFS: RV/TLV 36.2% (range: 26.1%-45.5%), P < 0.009. Six SFS-remnants with RV/TLV < 30% had significantly smaller RVBWR than 65 non-SFS-remnants with RV/TLV >= 30% (0.65 (range: 0.6-0.7) vs 0.8 (range: 0.6-1.27), P < 0.01. Two (2.8%) donors developed reversible liver failure. RVBWR and RV/TLV were concordant in 25%-33% of SFS and in 92%-94% of non-SFS remnants. MHV management options including complete MHV vs MHV-4A selective retention were necessary in n = 12 vs n = 2 remnants based on particularly risky congestive and non-congestive volume constellations. CONCLUSION: MHV procurement should consider individual remnant congestive- and non-congestive volume components and anatomy characteristics, RVBWR-RV/TLV constellation enables the identification of marginally small remnants. PMID- 26019468 TI - Vascular endothelial growth factor and tryptase changes after chemoembolization in hepatocarcinoma patients. AB - AIM: To evaluate vascular endothelial growth factor (VEGF) and tryptase in hepatocellular cancer (HCC) before and after trans-arterial chemoembolization (TACE). METHODS: VEGF and tryptase serum concentrations were assessed from 71 unresectable HCC patients before and after hepatic TACE performed by binding DC Beads((r)) to doxorubicin. VEGF levels were examined for each serum sample using the Quantikine Human VEGF-enzyme-linked immuno-absorbent assay (ELISA), whereas tryptase serum concentrations were assessed for each serum sample by means of fluoro-enzyme immunoassay (FEIA) using the Uni-CAP100 tool. Differences between serum VEGF and tryptase values before and after TACE were evaluated using Student t test. Person's correlation was used to assess the degree of association between the two variables. RESULTS: VEGF levels and serum tryptase in HCC patients before TACE had a mean value and standard deviation (SD) of 114.31 +/- 79.58 pg/mL and 8.13 +/- 3.61 MUg/L, respectively. The mean levels and SD of VEGF levels and serum tryptase in HCC patients after TACE were 238.14 +/- 109.41 pg/mL and 4.02 +/- 3.03 MUg/L. The changes between the mean values of concentration of VEGF and tryptase before treatment and after treatment was statistically significant (P < 0.000231 and P < 0.00124, by Wilcoxon-Mann-Whitney respectively). A significant correlation between VEGF levels before and after TACE and between tryptase levels before and after TACE was demonstrated (r = 0.68, P = 0.003; r = 0.84, P = 0.000 respectively). CONCLUSION: Our pilot results suggest that the higher serum VEGF levels and the lower tryptase levels following TACE may be potential biomarkers changing in response to therapy. PMID- 26019469 TI - Association of type 2 diabetes mellitus and the risk of colorectal cancer: A meta analysis and systematic review. AB - AIM: To provide a quantitative assessment of the association between type 2 diabetes mellitus (T2DM) and the risk of colorectal cancer (CRC). METHODS: Systematic review was conducted thorough MEDLINE, EMBASE, Cochrane Library, and ISI Web of knowledge databases till 31(st) January 2014. This meta-analysis included the cohort studies that illustrated relative risk (RR) or odds ratio estimates with 95%CI for the predictive risk of CRC by T2DM. Summary relative risks with 95%CI were analyzed by using an effects summary ratio model. Heterogeneity among studies was assessed by the Cochran's Q and I (2) statistics. RESULTS: The meta analysis of 8 finally selected studies showed a positive correlation of T2DM with the risk of CRC as depicted by effects summary RR of 1.21 (95%CI: 1.02-1.42). Diabetic women showed greater risk of developing CRC as their effect summary RR of 1.22 (95%CI: 1.01-49) with significant overall Z test at 5% level of significance was higher than the effect summary RR of 1.17 (95%CI: 1.00-1.37) of men showing insignificant Z test. The effect summary RR of 1.19 with 95%CI of 1.07-1.33 indicate a positive relationship between DM and increased risk of CRC with significant heterogeneity (I (2) = 92% and P-value < 0.05). CONCLUSION: Results from this systematic review and meta-analysis report that diabetic people have an increased risk of CRC as compared to non-diabetics. PMID- 26019470 TI - Endoscopic submucosal dissection for early gastric cancer with undifferentiated type histology: A meta-analysis. AB - AIM: To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) with undifferentiated-type histology. METHODS: A systematic literature review was conducted using the core databases. Complete resection, curative resection, en bloc resection, recurrence and adverse event rate were extracted and analyzed. A random effect model was applied. The methodological quality of the enrolled studies was assessed using the Newcastle Ottawa Scale. Publication bias was evaluated using a funnel plot, the trim and fill method, Egger's test, and a rank correlation test. RESULTS: Fourteen retrospective studies between 2009 and 2014 were identified (972 EGC lesions with undifferentiated-type histology). The total en bloc and complete resection rates were estimated as 92.1% (95%CI: 87.4%-95.2%) and 77.5% (95%CI: 69.3%-84%), respectively. The total curative resection rate was 61.4% (95%CI: 44.5%-75.9%). The overall recurrence rate was 7.6% (95%CI: 3.4%-16%). Limited to histologically diagnosed expanded-criteria lesions, the en bloc and complete resection rates were 91.2% and 85.6%, respectively. The curative resection rate was 79.8%. CONCLUSION: In this analysis, ESD is a technically feasible treatment modality for EGC with undifferentiated-type histology. Long-term studies are needed to confirm these therapeutic outcomes. PMID- 26019472 TI - Associations between CD24 gene polymorphisms and inflammatory bowel disease: A meta-analysis. AB - AIM: To evaluate the relationships between CD24 gene polymorphisms and the risk of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). METHODS: The PubMed, Web of Science and Cochrane Library databases were searched (up to May 30, 2014). The search terms "CD24", "inflammatory bowel disease", "Crohn's disease", "Ulcerative colitis", "IBD", "CD" or "UC"; and "polymorphism", "mutation" or "variant" were used. Association studies were limited to the English language, but no limitations in terms of race, ethnicity or geographic area were employed. Stata SE12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. The information was independently extracted from each eligible study by two investigators. Two common polymorphisms, C170T (rs8734) and TG1527del (rs3838646), in the CD24 gene were assessed. RESULTS: A total of three case-control studies including 2342 IBD patients and 1965 healthy controls were involved in this meta-analysis. The patients and controls were from Caucasian cohorts. The three articles included in this meta-analysis all conformed to Hardy-Weinberg equilibrium. This meta analysis revealed that there were no significant associations between the two CD24 polymorphisms and the risk for IBD (all P > 0.05). However, in a disease subgroup analysis, we found that the CD24 C170T polymorphism was associated with an increased risk of UC in a dominant model (OR = 1.79, 95%CI: 1.15-2.77, P = 0.009) and an additive model (OR = 1.87, 95%CI: 1.19-2.93, P = 0.007), but this relationship was not present for CD. The CD24 TG1570del polymorphism was significantly associated with CD in the additive model (OR = 1.24, 95%CI: 1.01 1.52, P = 0.037). CONCLUSION: Our findings provide evidence that the CD24 C170T polymorphism might contribute to the susceptibility to UC, and the CD24 TG1527del polymorphism might be associated with the risk of CD. PMID- 26019471 TI - Infliximab is superior to other biological agents for treatment of active ulcerative colitis: A meta-analysis. AB - AIM: To compare the efficacy and safety of biological agents for the treatment of active ulcerative colitis (UC). METHODS: PubMed, MEDLINE, EMBASE and the Cochrane library were searched to screen relevant articles from January 1996 to August 2014. The mixed treatment comparison meta-analysis within a Bayesian framework was performed using WinBUGS14 software. The proportions of patients reaching clinical response, clinical remission and mucosal healing in induction and maintenance phases were analyzed as efficacy indicators. Serious adverse events in maintenance phase were analyzed as safety indicators. RESULTS: The meta analysis results showed that biological agents achieved better clinical response, clinical remission and mucosal healing than placebo. Indirect comparison indicated that in induction phase, infliximab was more effective than adalimumab in inducing clinical response (OR = 0.41, 95%CI: 0.29-0.57), clinical remission (OR = 0.33, 95%CI: 0.19-0.56) and mucosal healing (OR = 0.33, 95%CI: 0.19-0.56), and golimumab in inducing clinical response (OR = 0.66, 95%CI: 0.39-2.33) and mucosal healing (OR = 2.15, 95%CI: 1.18-4.22). No significant difference was found between placebo and biological agents regarding their safety. CONCLUSION: All biological agents were superior to placebo for UC treatment in both induction and maintenance phases with a similar safety profile, and infliximab had a better clinical effect than the other biological agents. PMID- 26019473 TI - Fulminant ulcerative colitis in a healthy pregnant woman. AB - This case report concerns a 25-year-old patient with 6-7 bloody stools/d, abdominal pain, tachycardia, and weight loss occurring during the third trimester of pregnancy. Severe ulcerative colitis complicated by toxic megacolon and gravidic sepsis was diagnosed by clinical evaluation, colonoscopy, and rectal biopsy that were performed safely without risk for the mother or baby. The patient underwent a cesarean section at 28+6 wk gestation. The baby was transferred to the neonatal intensive care unit of our hospital and survived without complications. Fulminant colitis was managed conservatively by combined colonoscopic decompression and medical treatment. Although current European guidelines describe toxic megacolon as an indication for emergency surgery for both pregnant and non-pregnant women, thanks to careful monitoring, endoscopic decompression, and intensive medical therapy with nutritional support, we prevented the woman from having to undergo emergency pancolectomy. Our report seems to suggest that conservative management may be a helpful tool in preventing pancolectomy if the patient's condition improves quickly. Otherwise, surgery is mandatory. PMID- 26019474 TI - Fecal stream diversion and mucosal cytokine levels in collagenous colitis: A case report. AB - In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a 46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs: loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin (IL)-1beta, IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-gamma, IL-4, IL-5, IL-10 and IL-13 were all higher during active disease and decreased to non detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction, the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in collagenous colitis. PMID- 26019475 TI - Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn's disease. AB - Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohn's disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohn's disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease. PMID- 26019476 TI - Surgical repair of intractable chylous ascites following laparoscopic anterior resection. AB - Chylous ascites is the accumulation of a milk-like peritoneal fluid rich in triglycerides and it is an unusual complication following surgical treatment of colorectal cancer. Conservative management is usually sufficient in patients with chylous ascites after surgery. However, we describe a patient with intractable chylous ascites after laparoscopic anterior resection for sigmoid colon cancer who failed initial conservative treatment. This patient was successfully managed by surgery. PMID- 26019477 TI - Severe Henoch-Schonlein purpura with infliximab for ulcerative colitis. AB - Infliximab (IFX) is an anti-tumor necrosis factor chimeric antibody that is effective for treatment of autoimmune disorders such as Crohn's disease and ulcerative colitis (UC). IFX is well tolerated with a low incidence of adverse effects such as infections, skin reactions, autoimmunity, and malignancy. Dermatological manifestations can appear as infusion reaction, vasculitis, cutaneous infections, psoriasis, eczema, and skin cancer. Here, we present an unusual case of extensive and sporadic subcutaneous ecchymosis in a 69-year-old woman with severe UC, partial colectomy and cecostomy, following her initial dose of IFX. The reaction occurred during infliximab infusion, and withdrawal of IFX led to gradual alleviation of her symptoms. We concluded that Henoch-Schonlein purpura, a kind of leukocytoclastic vasculitis, might have contributed to the development of the bruising. Although the precise mechanisms of the vasculitis are still controversial, such a case highlights the importance of subcutaneous adverse effects in the management of UC with IFX. PMID- 26019479 TI - Optical coherence tomography for the diagnosis and evaluation of human otitis media. PMID- 26019478 TI - Primary hepatic angiosarcoma: A report of two cases and literature review. AB - Primary hepatic angiosarcoma (PHA) is a rare malignancy that carries a poor prognosis. Of 1500 patients who underwent hepatectomy for primary hepatic tumors between 1994 and 2013 at our center, two patients were pathologically diagnosed with PHA. Clinical characteristics, treatment modalities, and outcomes of the two patients were collected and analyzed. Both patients underwent hepatectomy and had a postoperative survival time of 8 and 16 mo, respectively. A search of PubMed yielded eight references reporting 35 cases of PHA published between 2004 and 2013. On the basis of the presented cases and review of the literature, we endorse complete surgical resection as the mainstay definitive treatment of PHA, with adjuvant postoperative chemotherapy potentially improving survival. Palliative chemotherapy is an option in advanced hepatic angiosarcoma. PMID- 26019480 TI - Aqueous humor TGF-beta2 levels in patients with open-angle glaucoma: A meta analysis. AB - INTRODUCTION: Elevated intraocular pressure (IOP) in glaucomatous eyes is often due to increased resistance to aqueous outflow. Previous studies have shown that increased extracellular material deposition in outflow pathways leads to increased resistance to aqueous outflow, and transforming growth factor (TGF) beta seems to play a role in the deposition of extracellular material. TGF-beta2 is the predominant isoform in ocular tissue. Hence, comparison of the aqueous humor TGF-beta2 level between patients with open-angle glaucoma (OAG) and controls would provide direct evidence for the role of TGF-beta2 in the etiology of OAG. Hence, we performed this meta-analysis to develop an accurate estimate of the changes in aqueous humor TGF-beta2 levels among OAG patients. METHODS: We undertook the meta-analysis of data from all available studies that had a case control design and investigated the aqueous humor levels of TGF-beta2 (total, active, or both) in OAG patients. OAG included primary OAG (POAG), secondary glaucoma, pseudoexfoliation syndrome, and exfoliation glaucoma (EXG). RESULTS: We selected a total of eight studies that measured TGF-beta2 levels in the aqueous humor of glaucomatous eyes. The studies included in this meta-analysis clearly demonstrated that in OAG eyes, total TGF-beta2 levels are significantly elevated, whereas in POAG eyes, both the total and active TGF-beta2 levels are significantly higher than in controls. CONCLUSIONS: The analysis of pooled data showed that aqueous humor TGF-beta2 levels are elevated in patients with OAG and POAG. PMID- 26019481 TI - Assumption-free estimation of the genetic contribution to refractive error across childhood. AB - PURPOSE: Studies in relatives have generally yielded high heritability estimates for refractive error: twins 75-90%, families 15-70%. However, because related individuals often share a common environment, these estimates are inflated (via misallocation of unique/common environment variance). We calculated a lower-bound heritability estimate for refractive error free from such bias. METHODS: Between the ages 7 and 15 years, participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent non-cycloplegic autorefraction at regular research clinics. At each age, an estimate of the variance in refractive error explained by single nucleotide polymorphism (SNP) genetic variants was calculated using genome-wide complex trait analysis (GCTA) using high-density genome-wide SNP genotype information (minimum N at each age=3,404). RESULTS: The variance in refractive error explained by the SNPs ("SNP heritability") was stable over childhood: Across age 7-15 years, SNP heritability averaged 0.28 (SE=0.08, p<0.001). The genetic correlation for refractive error between visits varied from 0.77 to 1.00 (all p<0.001) demonstrating that a common set of SNPs was responsible for the genetic contribution to refractive error across this period of childhood. Simulations suggested lack of cycloplegia during autorefraction led to a small underestimation of SNP heritability (adjusted SNP heritability=0.35; SE=0.09). To put these results in context, the variance in refractive error explained (or predicted) by the time participants spent outdoors was <0.005 and by the time spent reading was <0.01, based on a parental questionnaire completed when the child was aged 8-9 years old. CONCLUSIONS: Genetic variation captured by common SNPs explained approximately 35% of the variation in refractive error between unrelated subjects. This value sets an upper limit for predicting refractive error using existing SNP genotyping arrays, although higher-density genotyping in larger samples and inclusion of interaction effects is expected to raise this figure toward twin- and family-based heritability estimates. The same SNPs influenced refractive error across much of childhood. Notwithstanding the strong evidence of association between time outdoors and myopia, and time reading and myopia, less than 1% of the variance in myopia at age 15 was explained by crude measures of these two risk factors, indicating that their effects may be limited, at least when averaged over the whole population. PMID- 26019483 TI - Cytogenetic and molecular identification of small-segment chromosome translocation lines from wheat-rye substitution lines to create wheat germplasm with beneficial traits. AB - Intergeneric crop plant hybrid lines with small-segment chromosome translocations are very useful in plant genetic research and breeding. In this study, to create small-segment chromosome translocations with beneficial agronomic characters, the progeny of wheat-rye substitution lines 5R/5A and 6R/6A were selected from generations F2 to F5 for rye-specific characteristics. A PCR primer and specific simple sequence repeat marker for rye were used in F5 populations to detect rye chromatin and to amplify a specific chromosome band in six translocation lines (06-6-5, 06-6-6, 06-6-9, 6-26-1, 7-23, and 7-33). Fragment pSc119.1 cloned from 7 33 had 99% homology with the big ear gene sequence (GenBank AF512607.1) in wheat. The six lines were further characterized via pollen mother cell meiosis analysis for genetic stability, and chromosome C-banding and genomic in situ hybridization for rye chromatin. The results show that line 7-33 was still within the 5R/5A substitution lines and possessed the big ear gene. The other lines all contained small-segment rye chromosome translocations. The results indicated that substitution line hybridization is an effective method for creating small-segment chromosome translocations with useful agronomic traits. Trials for these six wheat-rye translocation lines are justified because they possess many important stably-inherited agronomic characters, including disease resistance and improved yield. PMID- 26019484 TI - Differentiation of grapevine (Vitis vinifera L.) conculta members based on molecular tools. AB - Twenty-seven grapevine (Vitis vinifera L.) varieties within 12 putative berry colour variation groups (conculta) were genotyped with 14 highly polymorphic microsatellite (simple sequence repeats (SSR)) markers. Three additional oligonucleotide primers were applied for the detection of the Gret1 retroelement insertion in the promoter region of VvMybA1 transcription factor gene regulating the UFGT (UDP-glucose: flavonoid 3-O-glucosyltransferase) activity. UFGT is the key enzyme of the anthocyanin biosynthetic pathway. SSR results proved that the analysed cultivars can be grouped only into nine concultas, the other three putative berry colour variant groups consist of homonyms as a consequence of misnaming. In the case of Sarfeher-Sarpiros, Delaware red-Delaware white and Jardovany fekete-Jardovany feher, it was attested that they are not bud sports, but homonyms. Some conculta members could be differentiated according to the presence or the absence of the Gret1 retroelement (Chasselas, Furmint and Lisztes), while others, Bajor, Bakator, Goher and Traminer conculta members, remained indistinguishable either by the microsatellites or the Gret1-based method. PMID- 26019485 TI - Establishment of efficient regeneration protocol for three rapeseed cultivars. AB - Economically, rapeseed is one of the most important crops in the world. Over the past decades, rapeseed research has been focused on improving biotechnological methods to facilitate breeding. The effectiveness of these methods depends on efficient tissue culture techniques. The aim of the present study was to establish an efficient protocol for regeneration of rapeseed. It was conducted in three stages. The first stage was to determine the effect of different concentrations (10%, 20%, 30% and 40%) of sodium hypochlorite solutions on seedling growth parameters. In the second stage, the effects of different growth media (Murashige and Skoog, MS, and Gamborg) and plant growth regulators (6 benzylaminopurine, 1-naphthaleneacetic acid and thidiazuron) at different concentrations on the regeneration capacity of stem explants of three rapeseed cultivars were investigated. In the last stage, the shoots of 'Spok' were cultured for three weeks on MS medium containing 1.5, 3 and 4.5 mg L-1 of indol butyric acid for rooting. The best results in germination, seedling growth and root length were obtained by using 10% disinfectant concentration for 25 minutes. The highest values for shoot regeneration were obtained from the stem explant cultured on MS medium containing 3 mg L-1 BAP and 0.2 mg L-1 NAA. It was found that MS containing 1.5 mg L-1 IBA was the most efficient medium for root formation. PMID- 26019482 TI - What's your poison? Impact of individual repair capacity on the outcomes of genotoxic therapies in cancer. Part II - information content and validity of biomarkers for individual repair capacity in the assessment of outcomes of anticancer therapy. AB - The individual variance in the efficiency of repair of damage induced by genotoxic therapies may be an important factor in the assessment of eligibility for different anticancer treatments, the outcomes of various treatments and the therapy-associated complications, including acute and delayed toxicity and acquired drug resistance. The second part of this paper analyses the currently available information about the possibilities of using experimentally obtained knowledge about individual repair capacity for the purposes of personalised medicine and healthcare. PMID- 26019486 TI - Ammonia stimulates growth and nitrite-oxidizing activity of Nitrobacter winogradskyi. AB - The aim of this study was to obtain a nitrite-oxidizing bacterium with high nitrite oxidation activity for controlling nitrite levels. A nitrite-oxidizing bacterium, ZS-1, was isolated from the water of a coastal Pseudosciaena crocea rearing pond. The strain was identified as Nitrobacter winogradskyi based on the phylogenetic analyses of the 16S ribosomal ribonucleic acid gene and nxrA sequence of ZS-1. Under aerobic condition, the nitrite-oxidizing activity of ZS-1 did not change considerably in the range of pH 7-9, but was strongly inhibited by lower (pH = 6) and higher (pH = 10) pH values. The optimum temperature range is 25-32 degrees C. Lower temperature made the adaptive phase of ZS-1 longer but did not affect its maximum nitrite oxidization rate. The nitrite-oxidizing activity of ZS-1 started to be inhibited by ammonia and nitrate when the concentrations of ammonia and nitrate reached 25 mg L-1 and 100 mg L-1, respectively. The inhibition was stronger with higher concentration of ammonia or nitrate. The nitrite-oxidizing activity of ZS-1, however, was not inhibited by high concentration of nitrite (500 mg L-1). The nitrite-oxidizing activity of ZS 1 was increased by low ammonia concentration (1 mg L-1 to 10 mg L-1). PMID- 26019487 TI - Detergent-like stressor and nutrient in metabolism of Penicillium chrysogenum. AB - The influence of detergents on the metabolism of Penicillium chrysogenum from two aspects, as a stress factor and potential nutrient, was studied. The fungus was isolated from the river bed Lepenica, Kragujevac, at a place where sewage domestic wastewater discharged into the river. The fungus was grown in a liquid nutrient medium according to Czapek with and without addition of commercial detergent (MERIX, Henkel, Serbia) at a concentration of 0.3% and 0.5%. The biochemical changes of pH, redox potential, free and total organic acids, total dry weight biomass, activity of alkaline and acid invertase and alkaline phosphatase were evaluated from day 3 to day 16 of the fungus growth. At the same time, detergent disappearance in terms of methylene blue active substances in the medium was measured. The detergent at a concentration of 0.5% showed a fungicide effect. In the medium with 0.3% of detergent, there was increased pH and concentration of organic acids, but decreased redox potential and total dry weight biomass. The detergent also showed an inhibitory effect on invertase and phosphatase activity. P. chrysogenum decomposed 50.2% of the total detergent concentration for an experimental period of 16 days. PMID- 26019488 TI - Comparison of the performances of four hydrophilic polymers as supports for lipase immobilisation. AB - Four hydrophilic polymers in the form of beads - chitosan, alginate, alginate/polyvinyl alcohol (PVA), and chitosan-coated alginate - were used as supports for lipase immobilisation. Hydrogel beads were characterised by bead size-distribution estimation, surface morphology studies, and polymer interactions assessment. Matrix performances - loading efficiency, immobilisation yield, enzyme activity, and stability retention - were evaluated and compared. Although the loading efficiency of the chitosan-coated Ca-alginate beads (79.8%) was inferior to that of the Ca-alginate (87%) and of the Ca-alginate/PVA beads (81.3%), their enzyme immobilisation yield (63.96%) was the most important. Moreover, lipase encapsulated in chitosan-coated Ca-alginate beads demonstrated better pH, thermal, and storage (89% residual activity after 30 days) stabilities. Immobilised lipase activity also increased in the order: alginate/PVA > chitosan > alginate > alginate/chitosan, and displayed a maximum at pH 8 and at temperatures of 45 degrees C (chitosan and Ca-alginate/PVA beads) and 50 degrees C (Ca-alginate and chitosan-coated Ca-alginate beads). Thus, chitosan-coated Ca-alginate beads could be considered as a suitable support for lipase immobilisation. PMID- 26019489 TI - Maximum parsimony based resolution of inter-species phylogenetic relationships in Citrus L. (Rutaceae) using ITS of rDNA. AB - The present study aims to analyse phylogenetic relationships, using internal transcribed spacer sequence data of ribosomal DNA (rDNA), across 24 Citrus species and close relatives by the evaluation of several parameters such as nucleotide substitution (r), nucleotide diversity (pi) and the estimated values of transition/transversion bias (R). The observed results indicated the presence of a wide divergence pattern of rDNA in subfamily Aurantioideae. Maximum parsimony (MP) analysis inferred divergence pattern in the Citrus genus. We observed seven strongly supported clades among the subfamily Aurantioideae. We postulate that the present investigation provides a more robust topology of Citrus and its close relatives, which can significantly prove as an additional support to resolve the phylogenetic relationships in Citrus genera. Therefore, sequences of noncoding regions should exhibit more phylogenetically informative sites than the coding regions do, which is in accordance with the present study. PMID- 26019490 TI - Assessment of genetic variation in Bulgarian tomato (Solanum lycopersicum L.) genotypes, using fluorescent SSR genotyping platform. AB - Genetic variability in modern crops is limited due to domestication and selection processes. Genetic variation in eight Bulgarian tomato varieties and breeding lines (variety Plovdivska karotina, variety IZK Alya, L21beta, L53beta, L1140, L1116, L975, L984) differing in their morphological and biochemical composition was assessed using a highly efficient and low-cost fluorescent simple sequence repeat (SSR) genotyping platform. Genotyping was conducted with 165 publicly available microsatellite markers developed from different research groups under a number of projects in tomato (SOL Genomics SSRs, Kazusa TGS and TES, SLM, TMS and LEMDDNa) among which only five (3.03%) failed to amplify the expected PCR fragments. Of the remaining markers, 81 (50.62%) were polymorphic in the whole collection of eight genotypes. Among the marker groups used, SLM markers were most polymorphic, followed by TMS and SOL Genomics SSR markers. The total number of amplified alleles was 299, with a mean of 1.869; and the average polymorphic information content (PIC) was 0.196. The genetic diversity within the collection was relatively low (0.2222). Nei's genetic distance varied from 0.0953 to 0.3992. Cluster analysis using the un-weighted pair group method with arithmetic mean (UPGMA) method indicated that the studied tomato genotypes are grouped in four main clusters, which is to some extent consistent with the morpho- and hemo-types of the studied tomatoes. Variety IZK Alya (cherry type) and two of the breeding lines (L1140, L1116) formed three separate and more distant clusters. The fourth cluster includes the other five genotypes. The observed grouping of these genotypes in two sub-clusters reflects their similar morphological and biochemical composition. The genetic distance information from this study might be useful for further implementation of breeding strategies and crosses among these inbred lines. PMID- 26019491 TI - Genetic diversity of Albanian goat breeds revealed by mtDNA sequence variation. AB - Albanian farmers have a long tradition in goat farming. Recently, several studies were carried out to determine genetic diversity of local goat populations, using molecular markers such as SNP (Single Nucleotide Polymorphisms), microsatellites and AFLP (Amplified Fragment Length Polymorphism). In the present study 77 mtDNA D-loop sequences from six different goat breeds were analysed. The results revealed 67 different haplotypes, with haplotype diversity ranging from 0.864 to 1 and nucleotide diversity values ranging from 0.016 to 0.106. The results showed that the studied breed grouped only in lineage A. The FST analysis indicated that 98.7% of the variation was found within the goat breeds and only 1.3% among them. PMID- 26019492 TI - Ecological status assessment of Skalenski Lakes (Bulgaria). AB - Over the past decade new ecological indices based on phytoplankton and macrophytes were developed as part of the tools for assessment of the ecological status of water bodies. This study demonstrates the applicability of two of them (Assemblage index /Q/ and Algae Group Index /AGI/) for evaluation of water bodies from a lake type L4 as well as their comparability. Assessment of the ecological status of two lake ecosystems was performed in order to ensure successful protection, enhancement and management of lowland and semi-mountain lakes in Bulgaria. Data on the aquatic flora from Golyamo Skalensko Lake and Malko Skalensko Lake over a period of two years were used to assess their ecological status. In addition, the toxic potential of the established dominant cyanoprokaryotic species was also evaluated. Phytoplankton- and macrophyte-based metrics resulted in complementary evaluation of temporary and long-term environmental conditions. Despite the hydraulic connection and proximity between the two lakes, Golyamo Skalensko Lake and Malko Skalensko Lake appear as completely different ecosystems, according to the phytoplankton structure (species composition, number of species, abundance, seasonal succession), macrophytes and ecological status. PMID- 26019493 TI - Determination of the effects of initial glucose on the production of alpha amylase from Penicillium sp. under solid-state and submerged fermentation. AB - The effects of catabolite repression of initial glucose on the synthesis of alpha amylase from Penicillium chrysogenum and Penicillium griseofulvum were investigated under solid-state fermentation (SSF) and submerged fermentation (SmF) systems. The results obtained from either fermentation were compared with each other. In the SmF system, initial glucose concentration above 10 mg/mL completely repressed the production of alpha-amylase from P. chrysogenum and P. griseofulvum. However, the repression in the SSF system was not complete, even when the glucose level was raised to 160 mg/g. PMID- 26019494 TI - Mutagenetic study of a novel inosine monophosphate dehydrogenase from Bacillus amyloliquefaciens and its possible application in guanosine production. AB - In this study, the amino acid sequence of inosine monophosphate dehydrogenase (IMPDH) from a guanosine-overproducing strain Bacillus amyloliquefaciens TA208 was found to be highly conserved comparing to its analogue in B. amyloliquefaciens FZB42, only with two substitutions of serine 166 to proline and glutamic acid 481 to lysine. To speculate on the effects of these variation sites, two reverse site-directed mutants P166S and K481E, as well as one deletion mutant IMPDHDeltaCBS, were characterised. According to the kinetic analysis of these enzymes, site-481 is a key mutation site to affect the nicotinamide adenine dinucleotide (NAD+) affinity, which accounted for the higher catalytic efficiency of IMPDH. On the contrary, mutants P166S and IMPDHDeltaCBS did not show better catalytic activity compared to normal IMPDH. Moreover, the overexpression of IMPDH-encoding gene guaB in B. amyloliquefaciens TA208 could improve the total production of guanosine up to 13.5 g L-1, which was 20.02% higher than that of the original strain. PMID- 26019495 TI - Genotyping of Listeria monocytogenes isolates from poultry carcasses using high resolution melting (HRM) analysis. AB - An outbreak situation of human listeriosis requires a fast and accurate protocol for typing Listeria monocytogenes. Existing techniques are either characterized by low discriminatory power or are laborious and require several days to give a final result. Polymerase chain reaction (PCR) coupled with high resolution melting (HRM) analysis was investigated in this study as an alternative tool for a rapid and precise genotyping of L. monocytogenes isolates. Fifty-five isolates of L. monocytogenes isolated from poultry carcasses and the environment of four slaughterhouses were typed by HRM analysis using two specific markers, internalin B and ssrA genes. The analysis of genotype confidence percentage of L. monocytogenes isolates produced by HRM analysis generated dendrograms with two major groups and several subgroups. Furthermore, the analysis of the HRM curves revealed that all L. monocytogenes isolates could easily be distinguished. In conclusion, HRM was proven to be a fast and powerful tool for genotyping isolates of L. monocytogenes. PMID- 26019496 TI - Novel glass slide preparation system for single DNA molecules analysis. AB - Here we propose an easy to build up and apply glass slide preparation system for single DNA molecules stretching. It is based on fast and simple coating of a solid glass with a cocktail of acrylic monomers that are easily polymerized via ultraviolet illumination. The acrylated slides are used to successfully stretch DNA molecules in a broader pH range compared to that of the commonly used amino silanes. Moreover, the single DNA molecules that are stretched on the acrylated slides give a brighter and more photostable signal when visualized under a fluorescent microscope. PMID- 26019497 TI - Examination of extremely low frequency electromagnetic fields on orthodontic tooth movement in rats. AB - The purpose of this study was to evaluate whether 50 Hz extremely low frequency electromagnetic fields (ELF-EMFs) affect the amount of orthodontic tooth movement in rats. The experiments were performed on 18 male Sprague-Dawley rats. The rats were randomly divided into three groups (n = 6): cage-control (Cg-Cnt) group (n = 6); sinusoidal electromagnetic field (SEMF) group (n = 6); and pulsed electromagnetic field (PEMF) group (n = 6). In SEMF and PEMF groups, rats were subjected to 1.5 mT EMF exposure eight hours per day for eight days. In order to obtain tooth movement, holes were drilled on the right and left maxillary central incisors of the rats at a distance 1.5-2 mm away from the gingiva and 20 g of orthodontic forces were applied to the teeth. Generated linear model for repeated measures and Bonferroni tests were used to evaluate the differences between the groups. Interactions among groups by days were found by using Pillai's trace multivariate test. The results showed that significant differences were present among the groups (F = 5.035; p = 0.03) according to the extent of tooth movement. Significant differences between the amount of tooth movements were determined especially after the fifth day and the following days six, seven and eight (p < 0.001). Within the limitations, according to the results of the present study, the application of ELF-EMF accelerated the orthodontic tooth movement in rats. PMID- 26019499 TI - Gene cloning and expression of MAP30 in Pichia pastoris. AB - MAP30, a single-stranded type-I ribosome inactivating protein found in Momordica charantia, shows anti-HIV and anti-tumour activity. It could significantly inhibit the HIV-1 and herpes simplex virus infection. In this study, we tried a safe and convenient expression system supplying MAP30 protein for medical practice. The gene encoding MAP30 was cloned into pMD18-T vector. The pMD18-MAP30 plasmid was transformed into competent Escherichia coli JM109 by a chemical method. The MAP30 gene was obtained from the pMD18-MAP30 plasmid digested with NotI and SnaBI and the MAP30 gene was ligated into pGAPHalpha. Then, pGAPHalpha MAP30 was transformed into Pichia pastoris GS115 by electroporation. GS115 transformants were analysed by sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) and Western blot. SDS-PAGE revealed an extra band of approximately 32 kDa in the supernatant protein of the GS115 transformants and in their intracellular protein fraction. The result of Western-blot analysis showed that the supernatant and the cell pellet from GS115 with pGAPHalpha-MAP30 could specially bind to monoclonal antibodies against His in the 32 kDa site. These results demonstrated that the expression of MAP30 in P. pastoris was successful; the process of the expression did not need methanol induction or introduction of an antibiotic-resistance gene. The study may provide a new way for MAP30 synthesis. Owing to its safety, this new approach is expected to be widely used in the medical field. PMID- 26019498 TI - Novel insights into amylin aggregation. AB - Amylin is a peptide that aggregates into species that are toxic to pancreatic beta cells, leading to type II diabetes. This study has for the first time quantified amylin association and dissociation kinetics (association constant (ka ) = 28.7 +/- 5.1 L mol-1 s-1 and dissociation constant (kd ) = 2.8 +/- 0.6 *10-4 s-1) using surface plasmon resonance (SPR). Thus far, techniques used for the sizing of amylin aggregates do not cater for the real-time monitoring of unconstrained amylin in solution. In this regard we evaluated recently innovated nanoparticle tracking analysis (NTA). In addition, both SPR and NTA were used to study the effect of previously synthesized amylin derivatives on amylin aggregation and to evaluate their potential as a cell-free system for screening potential inhibitors of amylin-mediated cytotoxicity. Results obtained from NTA highlighted a predominance of 100-300 nm amylin aggregates and correlation to previously published cytotoxicity results suggests the toxic species of amylin to be 200-300 nm in size. The results seem to indicate that NTA has potential as a new technique to monitor the aggregation potential of amyloid peptides in solution and also to screen potential inhibitors of amylin-mediated cytotoxicity. PMID- 26019500 TI - Protective effects of traditional Chinese medicine formula NaoShuanTong capsule on haemorheology and cerebral energy metabolism disorders in rats with blood stasis. AB - NaoShuanTong capsule (NSTC), an oral traditional Chinese medicine formula, is composed of Pollen Typhae, Radix Paeoniae Rubra, Rhizoma Gastrodiae, Radix Rhapontici and Radix Curcumae. It has been widely used to treat ischemic stroke in clinic for many years in China. In addition to neuronal apoptosis, haemorheology and cerebral energy metabolism disorders also play an important role in the pathogenesis and development of ischemic stroke. The present study was designed to evaluate the in vivo protective effects of NSTC on haemorheology and cerebral energy metabolism disorders in rats with blood stasis. Sixty specific pathogen-free sprague-dawley rats, male only, were randomly divided into six groups (control group, model group, aspirin (100 mg/kg/d) group, NSTC low dose (400 mg/kg/d) group, NSTC intermediate-dose (800 mg/kg/d) group, NSTC high dose (1600 mg/kg/d) group) with 10 animals in each. The rats except those in the control group were placed in ice-cold water (0-4 degrees C) for 5 min during the time interval (4 h) of two adrenaline hydrochloride injections (0.8 mg/kg) to induce blood stasis. After treatment, whole blood viscosity at three shear rates, plasma viscosity and erythrocyte sedimentation rate significantly decreased in NSTC intermediate- and high-dose groups; erythrocyte aggregation index and red corpuscle electrophoresis index significantly decreased in all the three dose NSTC groups. Moreover, treatment with high-dose NSTC could significantly improve Na+-K+ adenosine triphosphatase (ATPase) and Ca2+ ATPase activity, as well as lower lactic acid level in brain tissues. These results demonstrated the protective effects of NSTC on haemorheology and cerebral energy metabolism disorders, which may provide scientific information for the further understanding of mechanism(s) of NSTC as a clinical treatment for ischemic stroke. Furthermore, the protective effects of activating blood circulation as observed in this study might create valuable insight for the utilisation of NSTC to be a feasible alternative therapeutic agent for patients with blood stasis. PMID- 26019501 TI - Low cytotoxicity and clastogenicity of some polymeric aminophosphonate derivatives. AB - Poly(oxyethylene aminophosphonate)s synthesized on the basis of biodegradable poly(phosphorester)s and Schiff bases were tested in vitro for antitumor activity against a panel of six human epithelial cancer cell lines, for cytotoxicity to mouse fibroblast cells and in vivo for clastogenicity and antiproliferative effects. The polymers showed lower cytotoxicity, both in vivo and in vitro and lower clastogenicity in vivo than the corresponding low-molecular aminophosphonates. The biological activities of the tested polymers correlate with their low in vitro antitumor activity. PMID- 26019502 TI - Pharmacological investigations of new galantamine peptide esters. AB - Galantamine hydrobromide (GAL) is a reversible acetylcholinesterase inhibitor, with properties to increase the concentration of acetylcholine in several brain structures. The aim of this study is to determine the effect of new galantamine peptide esters: 3,4-dichlorophenyl-alanil-leucil-glycine-galantamine (GAL-LEU) and 3,4-dichlorophenyl-alanil-valil-glycine-galantamine (GAL-VAL), on locomotor activity in mice and cognitive processes in experimental model of learning and memory in rats. The results showed that per oral administration of GAL-LEU in a dose of 3 mg per kg improved the cognitive processes by increasing the conditional avoidances and learning ability after the 5th day of application and preserved the memory at the 12th day of the study. PMID- 26019503 TI - Deregulation of the circadian clock constitutes a significant factor in tumorigenesis: a clockwork cancer. Part I: clocks and clocking machinery. AB - Many physiological processes occur in a rhythmic fashion, consistent with a 24-h cycle. The central timing of the day/night rhythm is set by a master clock, located in the suprachiasmatic nucleus (a tiny region in the hypothalamus), but peripheral clocks exist in different tissues, adjustable by cues other than light (temperature, food, hormone stimulation, etc.), functioning autonomously to the master clock. Presence of unrepaired DNA damage may adjust the circadian clock so that the phase in which checking for damage and DNA repair normally occurs is advanced or extended. The expression of many of the genes coding for proteins functioning in DNA damage-associated response pathways and DNA repair is directly or indirectly regulated by the core clock proteins. Setting up the normal rhythm of the circadian cycle also involves oscillating changes in the chromatin structure, allowing differential activation of various chromatin domains within the 24-h cycle. PMID- 26019505 TI - Exogenous spermine pretreatment confers tolerance to combined high-temperature and drought stress in vitro in trifoliate orange seedlings via modulation of antioxidative capacity and expression of stress-related genes. AB - Spermine (Spm) is thought to play an important role in drought or high temperature (HT) tolerance. However, it is not clear whether Spm confers similar resistance in the presence of both drought and HT, which often occur simultaneously. In the present study, the trifoliate orange (Poncirus trifoliata (L.) Raf.) seedlings were pretreated with 1 mmol L-1 Spm to evaluate their tolerance to combined drought and HT (45 oC) stress. Spm-pretreated seedlings showed less leaf wilting, less water loss and less electrolyte leakage than control leaves not treated with Spm within 180 min of treatment. Histochemical staining with diaminobenzidine and nitro blue tetrazolium showed that Spm pretreated seedlings accumulated less hydrogen peroxide and superoxide than those of control plants 60, 120 and 180 min after treatment when exposed to both drought and HT (45 oC). However, superoxide dismutase, peroxidase and catalase were significantly more active in Spm-pretreated seedlings than in control seedlings. In addition, Spm-pretreated seedlings showed significantly higher expression of heat shock proteins, abscisic acid (ABA)-responsive element binding factor and 9-cis-epoxycarotenoid dioxygenase 3 than controls either before (0 min) or after (60, 120 and 180 min) combined drought and HT treatment. All of these data suggest that exogenous Spm pretreatment confers tolerance to simultaneously occurring drought and HT stresses. Spm may influence this by activating antioxidant enzymes, increasing the effectiveness of scavenging of reactive oxygen species. It may also increase the expression levels of stress related genes that protect trifoliate orange seedlings from stress damage. PMID- 26019504 TI - Current state of the opportunities for derivation of germ-like cells from pluripotent stem cells: are you a man, or a mouse? AB - The concept of pluripotency as a prerogative of cells of early mammal embryos and cultured embryonic stem cells (ESC) has been invalidated with the advent of induced pluripotent stem cells. Later, it became clear that the ability to generate all cell types of the adult organism is also a questionable aspect of pluripotency, as there are cell types, such as germ cells, which are difficult to produce from pluripotent stem cells. Recently it has been proposed that there are at least two different states of pluripotency; namely, the naive, or ground state, and the primed state, which may differ radically in terms of timeline of existence, signalling mechanisms, cell properties, capacity for differentiation into different cell types, etc. Germ-like male and female rodent cells have been successfully produced in vitro from ESC and induced pluripotent stem cells. The attempts to derive primate primordial germ cells (PGC) and germ cells in vitro from pluripotent stem cells, however, still have a low success rate, especially with the female germline. The paper reviews the properties of rodent and primate ESC with regard to their capacity for differentiation in vitro to germ-like cells, outlining the possible caveats to derivation of PGC and germ cells from primate and human pluripotent cells. PMID- 26019506 TI - Agrobacterium tumefaciens-mediated transformation of corn (Zea mays L.) multiple shoots. AB - An Agrobacterium tumefaciens-mediated corn transformation method based on multiple shoot tissue cultures was developed, which is effective with a variety of corn inbred lines and standard binary vectors. Six factors that affected the success of corn transformation were tested, including A. tumefaciens strain, corn genotype, tissue culture growth stage, medium composition, co-culture temperature and surfactant treatment. Agropine-type bacteria (EHA 101 and AGL 1) were eightfold more effective than octopine-type strain for corn multi-shoot tissues transformation. The average frequency of Glucuronidase (GUS)-positive explants obtained from 14 corn genotypes ranged from 36% to 76%. L-proline (0.7 g L-1) in the co-culture medium apparently improved the frequency of transformation. The newly initiated multi-shoot tissues were most responsive to Agrobacterium infection. A positive correlation was found between multi-shoot tissue susceptibility to Agrobacterium and the proportion of cells in G1 phase. Transformants were identified by reverse transcription Polymerase Chain Reaction (PCR) and by southern blot hybridization assays. The frequency of transformants was approximately 2% based on the number of multi-shoot explants co-cultivated with Agrobacterium. PMID- 26019507 TI - SSR and SRAP marker-based linkage map of Vitis vinifera L. AB - An F1 population was created by the cross '87-1' * '9-22'. The female parent '87 1' was an extremely early maturing cultivar with strong flavour. The male parent was an excellent breeding line producing large berries maturing late. The mapping population included 149 randomly chosen individuals. Molecular genetic map for each parent and the consensus map were constructed using simple sequence repeat and sequence-related amplified polymorphism markers by software JoinMap 3.0. The '87-1' map covers a total length of 1272.9 cM distributed in 21 linkage groups and consists of 163 molecular markers with an average distance between adjacent markers of 8.9 cM. The '9-22' map covers a total length of 1267.4 cM distributed in 20 linkage groups and consists of 158 molecular markers with an average distance between adjacent markers of 9.1 cM. The consensus map covers a total length of 1537.1 cM distributed in 21 linkage groups and one doublet and consists of 217 molecular markers with an average distance of 7.8 cM between adjacent markers. The length of the linkage groups is 69.8 cM on average. The map covers the 19 chromosomes of the Vitis genome and can lay a solid foundation for further studies such as quantative trait loci (QTL) mapping of correlated traits and marker-assisted selection. PMID- 26019508 TI - Genetic diversity and genetic relationships of japonica rice varieties in Northeast Asia based on SSR markers. AB - Genetic diversity and the relationship among nine japonica rice groups consisting of 288 landraces and varieties in different geographical origins of Northeast Asia (China, Japan, Korea, Democratic People's Republic of Korea) and the Russian Far East district of the Russian Federation were evaluated with 154 simple sequence repeat (SSR) markers. A total of 823 alleles were detected. The observed allele numbers (Na) per locus, Nei's gene diversity (He) and the polymorphism information content (PIC) ranged from 2 to 9, 0.061 to 0.869 and 0.060 to 0.856, with an average of 5.344, 0.624 and 0.586, respectively. Five SSR loci, RM1350, RM1369, RM257, RM336 and RM1374, provided the highest PIC values and are potential for exploring the genetic diversity of rice cultivars in Northeast Asia. Molecular variance analysis showed that a significant difference existed both among groups (91.6%) and within each group (8.4%). The low genetic variation within each group indicated that the gene pool is narrow and alien genetic variation should be introduced into the rice breeding program in Northeast Asia. Based on the He and PIC values, the nine groups were ranked in a descending order: Heilongjiang landraces, Jilin landraces, Japanese improved varieties, Heilongjiang improved varieties, Russian Far East district of the Russian Federation improved varieties, Liaoning improved varieties, Jilin improved varieties, Korean improved varieties and Democratic People's Republic of Korea improved varieties. The nine groups were further divided into three subgroups and the 288 varieties into five clusters. This study provided information for parent selection in order to broaden the gene pool of the japonica rice germplasm in Northeast Asia. PMID- 26019509 TI - The RT-PCR identification and sequence analysis of Apple chlorotic leaf spot virus from apple cultivars in Jiaodong Peninsula, China. AB - A set of specific primer pairs was utilized to detect Apple chlorotic leaf spot virus (ACLSV) from seven different apple cultivars in Jiaodong Peninsula via reverse transcription polymerase chain reaction (RT-PCR), and the sequence of ACLSV genome was analysed. The results indicate that: (1) High-purity total RNA could be successfully isolated using plant RNA rapid extraction kit. The ratios of A260/A280 varied between 1.8 and 2.1. The fragmentation in agarose gel was good and the 28S and 16S bands were clear, which suggested that the extracted RNA had better quality and could be used for RT-PCR. (2) The amplified products by RT PCR were approximately 220 bp, which showed the tested samples were infected by ACLSV in this study. (3) Sequencing analysis showed that the lengths of the target fragments were 217 bp, and the sequence identity rate ranged from 85.7% to 99.1% at the nucleotide level aligned with the corresponding sequences of other ACLSV strains in National Center for Biotechnology Information. PMID- 26019510 TI - Heterologous expression and characterization of laccase 2 from Coprinopsis cinerea capable of decolourizing different recalcitrant dyes. AB - The gene (CcLcc2) encoding laccase from the basidiomycete Coprinopsis cinerea Okayama-7 #130 was synthesized by polymerase chain reaction-based two-step DNA synthesis, and heterologously expressed in Pichia pastoris. The recombinant protein was purified by ammonium sulphate precipitation and nickel nitrilotriacetic acid chromatography. The molecular mass of CcLcc2 was estimated to be 54 kDa by denaturing polyacrylamide gel electrophoresis. The optimum pH and temperature for laccase catalysis for the oxidation of 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonate) (ABTS) were 2.6 and 45 degrees C, respectively. The Km values of the enzyme towards the substrates ABTS, 2,6 dimethoxyphenol (2,6-DMP) and guaiacol were 0.93, 1.02 and 28.07 mmol.L-1, respectively. The decolourization of methyl orange, crystal violet and malachite green, commonly used in the textile industry, was assessed. The decolourization percentage of crystal violet and malachite green was 80% after 4 h of reaction, and that of methyl orange was 50% at 4 h. These results show that the CcLcc2 has enormous potential for the decolourization of highly stable triphenylmethane dyes. PMID- 26019511 TI - Bisorption of chromium(VI) from aqueous solutions by Sargassum thunbergii Kuntze. AB - The potential to remove Cr(VI) from aqueous solutions through biosorption using dried Sargassum thunbergii Kuntze was investigated with respect to initial pH, amount of biosorbent, initial Cr(VI) concentrations and temperature. Cr(VI) removal efficiency was influenced significantly by the variation of pH, and the optimum pH was about 2.0. Moreover, the biosorption kinetics followed the pseudo second-order model. The adsorption equilibrium was well described by the Langmuir and Freundlich isotherm models. The maximum adsorption capacity was 1.855 mmol/g at 318 K and pH 2.0. The adsorption processes were endothermic and the biosorption heat was 15.8 kJ/mol. Furthermore, the Fourier transform infrared spectroscopy suggested that amido-, hydroxyl-, C = O and C-O groups were involved in the biosorption of Cr(VI) onto S. thunbergii. PMID- 26019512 TI - Encapsulation of brewing yeast in alginate/chitosan matrix: lab-scale optimization of lager beer fermentation. AB - Two mathematical models were developed for studying the effect of main fermentation temperature (TMF), immobilized cell mass (MIC) and original wort extract (OE) on beer fermentation with alginate-chitosan microcapsules with a liquid core. During the experiments, the investigated parameters were varied in order to find the optimal conditions for beer fermentation with immobilized cells. The basic beer characteristics, i.e. extract, ethanol, biomass concentration, pH and colour, as well as the concentration of aldehydes and vicinal diketones, were measured. The results suggested that the process parameters represented a powerful tool in controlling the fermentation time. Subsequently, the optimized process parameters were used to produce beer in laboratory batch fermentation. The system productivity was also investigated and the data were used for the development of another mathematical model. PMID- 26019513 TI - The 656C and 725C are two important sites in gene STGC3 for its negative regulation on cell growth. AB - The aim of this study was to analyze the functional sites of the nasopharyngeal candidate tumour suppressor gene STGC3. Recombinant plasmid pcDNA3.1TM/myc-His B STGC3 was constructed. Site-directed mutagenesis of pcDNA3.1TM/myc-His B-STGC3 plasmid at sites of C656G, C725T and T913G was induced by the Stratagene mutagenesis method. Recombinant plasmids with point mutations at C656G, C725T and T913G of gene STGC3 were named as STGC3-C656G, STGC3-C725T and STGC3-T913G, respectively. CNE2 cell lines stably expressing wild and mutant STGC3 genes were established. STGC3 expression was detected by Western Blotting and immunocytochemistry. Cell proliferation was analyzed by 3-(4, 5-Dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue staining. Flow cytometry analysis was used to assess apoptosis of CNE2 cells. Bax protein expression was detected by Western Blotting. Proteins of wild-type and mutant STGC3 genes were expressed in the cytoplasm and nucleus of CNE2 cells. Compared with the control groups, in cells stably expressing wild-type STGC3 and STGC3 T913G genes, cell proliferation was significantly inhibited, whereas levels of apoptosis and Bax protein expression were significantly increased. However, the cell proliferation, apoptosis and Bax protein expression in cells stably expressing STGC3-C656G and STGC3-C725T genes were not significantly different from those in the control groups. Our results suggest that mutations at 656C and 725C, but not 913T, abolished the effects of the wild-type STGC3 gene on CNE2 cells and that the 656C and 725C were important sites in gene STGC3 for its negative regulation on cell growth. PMID- 26019514 TI - Differentiation of mixed biological traces in sexual assaults using DNA fragment analysis. AB - During the investigation of sexual abuse, it is not rare that mixed genetic material from two or more persons is detected. In such cases, successful profiling can be achieved using DNA fragment analysis, resulting in individual genetic profiles of offenders and their victims. This has led to an increase in the percentage of identified perpetrators of sexual offenses. The classic and modified genetic models used, allowed us to refine and implement appropriate extraction, polymerase chain reaction and electrophoretic procedures with individual assessment and approach to conducting research. Testing mixed biological traces using DNA fragment analysis appears to be the only opportunity for identifying perpetrators in gang rapes. PMID- 26019515 TI - Synthesis and in vitro activity of platinum(II) complexes of two fluorenylspirohydantoins against a human tumour cell line. AB - This paper presents a method for synthesis and cytotoxicity of new platinum(II) complexes of (9'-fluorene)-spiro-5-hydantoin (L1) and (9'-fluorene)-spiro-5-(2 thiohydantoin) (L2). The new obtained complexes were studied by elemental analysis: ultraviolet-visible, attenuated total reflection Fourier transform infrared (ATR-FTIR), and 1H- and 13C-NMR for Pt(II) compounds and additionally Raman spectroscopy for free ligands. Based on the experimental data, the most probable structure of the complexes is suggested. In the present study, we have examined cytotoxic activity of (9'-fluorene)-spiro-5-hydantoin (L1) and (9' fluorene)-spiro-5-(2-thiohydantoin) (L2) and their Pt(II) complexes on the retinoblastoma cell line WERI-Rb-1. PMID- 26019516 TI - Chinese medicinal formula Fufang Xueshuantong capsule could inhibit the activity of angiotensin converting enzyme. AB - Fufang Xueshuantong (FXST) capsule, a Chinese medicinal formula composed of four herbals - Panax notoginseng, Radix Astragali, Radix Salvia Miltiorrhizae and Radix Scrophulariaceae, has been used to treat cardiovascular diseases for many years, but the pharmacological mechanisms underlying its effects has not been clarified. This study investigates if a connection between FXST and angiotensin converting enzyme (ACE) might be an explanation for its pharmacological effects. ACE inhibition assay was performed on FXST capsule, 50% ethanol extracts from the four herbals and three selected saponins most abundant in P. notoginseng (Ginsenoside Rg1, Ginsenoside Rb1 and Notoginsenoside R1) using a biochemical test. Reversed-phase high-performance liquid chromatography of liberated hippuric acid from the ACE assay was conducted to determine the inhibitory effect. As a result, FXST and extracts from P. notoginseng showed a significant and dose dependent inhibition on ACE activity with the IC50 values of 115 MUg/ml and 179 MUg/ml, respectively. But extracts from the other three herbals and the three selected saponins had no significant effect on ACE inhibition. Compared to other reported plant extracts, FXST could be considered as an effective ACE inhibitor. The inhibition of ACE activity supports the traditional use of FXST on blood circulation and the inhibitory property of FXST is mainly caused by P. notoginseng. PMID- 26019517 TI - Antimicrobial action of an endophytic fungi from Sophor flavescens and structure identification of its active constituent. AB - Endophytic fungus BS002 was isolated and characterized from Sophora flavescens by plate method, which has broad antimicrobial activity. Isolation and trace of a new bioactive compound from the fungus' culture extracts with the method of column chromatography and TLC biological autoradiography was conducted. Finally, it was identified as 6,7-(2'E) dibutenyl-5,8-dihydroxy-(Z)-cyclooct-2-ene-1,4 dione by nuclear magnetic resonance, infrared and liquid chromatography-mass spectrometry. The compound presented strong antifungal activities for example: Botryosphaeria berengriana f.sp. piricola, Physalospora piricola, Cladosporium cucumerinum Ell. Arthur., Fusarium oxysporum f.sp. cucumerinum, Fusarium moniliforme. The inhibition to Physalospora piricola was the strongest with an antibacterial diameter of 45 mm. This paper is the first report of the antimicrobial activity of endophytic fungi BS002 that was the secondary metabolites extracted from the seeds of Sophora flavescens. The results provide a broad foreground for biopharmaceuticals and biopesticide. PMID- 26019518 TI - Binding of dihydromyricetin and its metal ion complexes with bovine serum albumin. AB - The binding mechanisms of the interaction of three dihydromyricetin (DMY)-metal complexes (DMY-Cu (II) complex, DMY-Mn (II) complex, DMY-Zn (II) complex) and DMY with bovine serum albumin (BSA) were investigated using fluorescence and ultraviolet spectroscopy at different temperatures. The results indicated some differences in the binding process between different DMY-metal complexes and BSA compared with that of free DMY. All of the complexes and DMY quenched the fluorescence of BSA based on static mode combined with radiationless energy transfer, yet having different binding distance based on the Forster theory. Different DMY-metal complexes can change the binding constants. The binding constants increase for DMY-Cu (II) and DMY-Mn (II) complexes, whereas the opposite is true for the DMY-Zn (II) complex compared to the one with free DMY. The DMY-metal complexes can also affect the types of the interaction. The van der Waals forces and hydrogen bonding may play a major role in the interaction of free DMY with BSA, while for the three complexes, the nature of the binding forces lies in hydrophobic forces and hydrogen bonding based on the thermodynamic parameters. PMID- 26019519 TI - Influence of terpenoids and acarbose on glycosyltransferases produced by strain Leuconostoc mesenteroides URE 13. AB - A study of the influence of different plant terpenoids and amino sugar derivate acarbose on the activity of glycosyltransferase complex and purified dextransucrase from Leuconostoc mesenteroides URE 13 strain was carried out. All the tested terpenoids showed an inhibitory effect on glycosyltransferases from strain URE 13 at concentration 0.34 mmol. Out of all studied diterpenoids splendidin showed the strongest inhibitory effect decreasing the activity of both glycosyltransferase complex and dextransucrase with 70% and 90%, respectively. The triterpenoid ursolic showed the second strongest inhibitory effect as the enzyme complex and dextransucrase from strain URE 13 retain 27% and 13% of their initial enzyme activity. Despite the higher degree of inhibition of purified dextransucrase, compared to the enzyme complex, a complete inhibition of the enzyme was not observed at the highest used terpenoid concentration (3.42 mmol). When acarbose was used as an inhibitor, a complete inhibition of dextransucrase was observed at concentration of 6.9 mmol, while the enzyme complex retained 8% of its enzyme activity. Ki values of 0.28 mmol for splendidin, 0.37 mmol for ursolic acid and 0.29 mmol for acarbose were determined from the kinetic studies of purified dextransucrase. PMID- 26019520 TI - Poly-gamma-glutamic acid enhances the quality of recombant erythropoietin produced by CHO cells. AB - The effect of poly-gamma-glutamic acid (gammaPGA), which is produced by Bacillus sp., on the production of recombinant erythropoietin (rEPO) by Chinese hamster ovary (CHO) cells in suspension culture was evaluated. The growth, viability, and productivity of recombinant CHO cells were investigated in a chemically defined medium with 50 and 500 kD gammaPGAs at 0.075% or with Pluronic F68. Cell growth with the two gammaPGAs was lower than that with Pluronic F68 but significantly higher than that without any additive (control). The effect of additives on rEPO productivity was 50 kDa gammaPGA > 500 kDa gammaPGA > Pluronic F68 > control. Using EPO-dependent F-36E cells, we found that the effect of additives on rEPO quality was 500 kDa gammaPGA > 50 kDa gammaPGA > control > Pluronic F68. gammaPGA has an enhancement effect on the quality of rEPO produced by CHO cells. PMID- 26019521 TI - Marketing approaches for OTC analgesics in Bulgaria. AB - The marketing management includes analysis of market opportunities, selection of target markets, planning, developing and implementing of marketing strategies, monitoring and result control. The object of the present study was to analyse the marketing approaches applied for non-steroidal anti-inflammatory drugs (NSAIDs) in Bulgaria. The performed SWOT(planning method used to evaluate the strengths, weaknesses, opportunities, and threats) analysis for one of the leading Bulgarian manufacturers marked the complex corporative strategy for stimulating the sales of NSAIDs. The study results show that the legislation frame in the country gives an opportunity for regulation of the NSAID market in order that incorrect marketing approaches such as disloyal competition are avoided. PMID- 26019522 TI - Economic consequences of the vaccination against hepatitis A in the Bulgarian healthcare setting. AB - The purpose of the present analysis is to calculate and compare the costs and results of the implication of the inactivated vaccine against hepatitis A virus (HAV) in the Bulgarian healthcare setting in the period of 2002-2012. A combined pharmacoeconomic and epidemiological study was performed on the basis of the prevalence of hepatitis A infection in this 10-year period. The investments in the vaccination were considered as costs and the avoided costs in the case of vaccination of all one-year old children in the population - as benefits. The results show that the vaccination of one-year-old children would be cost effective to the healthcare system in the years with an epidemiologic outbreak, as in these years the total cost of treatment of patients with hepatitis A infection exceeds the cost for vaccination of the whole one-year-old cohort. The critical threshold is 4600 infected patients per year that equalize the benefits to costs. The inclusion of HAV vaccine in the National Immunization Calendar would be cost effective for the healthcare system when the vaccination is performed in certain risk groups and could help to decrease the circulation of the virus in the general population. PMID- 26019523 TI - ISO 9001 certification for hospitals in Bulgaria: does it help service? AB - The aim of our study is to review the published literature on establishment and implementation of ISO 9001 QMS in European hospitals, to study the availability of International Organization for Standardization (ISO) quality management systems (QMS) in Bulgarian hospitals and to outline the main advantages of ISO implementation in the hospitals in Bulgaria. The information on availability of ISO QMS in the hospitals in Bulgaria was gathered via Bulgarian certification register, the registries of various quality associations, websites of hospitals and certification companies presented in Bulgaria. A total number of 312 hospitals in Bulgaria were screened for the availability of QMS certified against the ISO 9001 requirements. The experience of European hospitals that implemented QMS is positive and the used approaches to improve the processes and the demonstrated effects from ISO implementation are analysed by the researchers. Unlike other European Union member states, the establishment of quality management systems in Bulgaria is not compulsory. However, our study revealed that 14.42% of the hospitals in Bulgaria have implemented and have certified quality systems against the requirements of ISO 9001. Our study confirmed that a quality management system using the ISO 9001 standard is useful for the hospitals as it can help to increase the operational efficiencies, to reduce errors, improve patient safety and produce a more preventive approach instead of a reactive environment. PMID- 26019524 TI - Deregulation of the circadian clock constitutes a significant factor in tumorigenesis: a clockwork cancer. Part II. In vivo studies. AB - The uneventful progression through the cell cycle is closely associated with the rhythm set by the circadian clock machinery, with the S-phase of the cell cycle typically occurring at night. Presence of unrepaired DNA damage may reset the phase of the circadian clock, providing opportunities for damage assessment, repair and/or the induction of pro-apoptotic pathways. The core proteins of the circadian clock regulate directly or indirectly a significant number of genes coding for proteins involved in checkpoint transition, cell proliferation and programmed cell death. Disruption of the circadian rhythm may increase the risk for some multifactorial diseases and conditions, including glucose intolerance, cardiovascular disease and various common cancers. In patients with cancer, chronic circadian misalignment may stimulate the growth of tumours and may modify the outcomes of anticancer therapy. Knowledge about the role of physiological rhythms in human disease may contribute to the field of individualized medicine, specifically, in risk assessment and prognostication of the outcomes in patients with multifactorial disease. PMID- 26019525 TI - Quality control and safety assessment of BCG vaccines in the post-genomic era. AB - A hundred and five years ago, Albert Calmette and Camille Guerin began a daunting task, which is unmatched even today, that led to the most widely used vaccine in human history. Despite a century of scientific advances, BCG (an acronym for Bacillus Calmette-Guerin) remains the only vaccine for prevention of tuberculosis. Due to the fact that the use of BCG vaccines will continue, either as a stand-alone or as a prime vaccine in prime-boost immunization strategies, the World Health Organization (WHO) has underlined the necessity for further work toward better characterization, evaluation and quality control of the BCG vaccine, taking into account recent advances in genetics and molecular biology. The potential benefit of such improved characterization could be addressed to better and easier differentiation between sub-strains used by different manufacturers. It may help to ensure consistency of production in terms of genetic stability and it may also help the clinical evaluation of new antituberculosis vaccines. Last but not least, the state-of-the-art technologies could facilitate the quality control performed by the manufacturers and by National Control Authorities as well. PMID- 26019526 TI - Detection of Potato spindle tuber viroid sequence variants derived from PSTVd infected Phelipanche ramosa in flower organs of tomato plants. AB - Potato spindle tuber viroid (PSTVd) is an infectious small, circular, non-coding single-stranded RNA that induces disease on many crop species, ornamental plants, weeds and parasitic plants. PSTVd propagate in their host as a population of closely related but non-identical RNA variants referred to as quasispecies. Recently, we have described three de novo arising PSTVd variants in the parasitic plant Phelipanche ramosa after mechanical inoculation with the PSTVd KF440-2 isolate. These P. ramosa derived mutants were designated as G241-C, C208-U and C227-U PSTVd variants. Each of these variants carries a single-nucleotide substitution compared to the PSTVd KF440-2 sequence from which they are considered to have evolved. Here we complement our previous studies on these mutants by exploring their potential to infect the floral organs of tomato plants. We found that the PSTVd G241-C and C208-U variants were able to replicate in systemic leaves and floral organs of tomato plants, while the PSTVd C227-U variant did not develop systemic infection. Furthermore, we analysed the progeny of these PSTVd variants in sepals and petals of tomato plants for retention of the specific mutations. PMID- 26019527 TI - The lectin from Musa paradisiaca binds with the capsid protein of tobacco mosaic virus and prevents viral infection. AB - It has been demonstrated that the lectin from Musa paradisiaca (BanLec-1) could inhibit the cellular entry of human immunodeficiency virus (HIV). In order to evaluate its effects on tobacco mosaic virus (TMV), the banlec-1 gene was cloned and transformed into Escherichia coli and tobacco, respectively. Recombinant BanLec-1 showed metal ions dependence, and higher thermal and pH stability. Overexpression of banlec-1 in tobacco resulted in decreased leaf size, and higher resistance to TMV infection, which includes reduced TMV cellular entry, more stable chlorophyll contents, and enhanced antioxidant enzymes. BanLec-1 was found to bind directly to the TMV capsid protein in vitro, and to inhibit TMV infection in a dose-dependent manner. In contrast to limited prevention in vivo, purified rBanLec-1 exhibited more significant effects on TMV infection in vitro. Taken together, our study indicated that BanLec-1 could prevent TMV infection in tobacco, probably through the interaction between BanLec-1 and TMV capsid protein. PMID- 26019528 TI - Genetic relationship in mulberry (Morus L.) inferred through PCR-RFLP and trnD trnT sequence data of chloroplast DNA. AB - Ten universal primer pairs of the plant chloroplast genome were used to amplify the chloroplast DNA (cpDNA) non-coding regions in eight mulberry (Morus spp.) genotypes, including M. mongolica, M. bombycis, M. alba, M. atropurpurea and M. multicaulis. Subsequently, the polymerase chain reaction (PCR) products were digested by seven restriction enzymes and the trnD-trnT fragment for sequence alignment, and the variations were expected to provide the genetic information for system classification. The results from this study showed that: (1) 10 cpDNA primer pairs could be used for successful amplification in the tested materials, with approximately 17.1 kb of the chloroplast genome analysed. The 152 marker loci were detected by 70 primer/restriction endonuclease combinations, among which the trnD-trnT non-coding region digested by AluI, HinfI, MvaI and RsaI was detected by visible fragment length variation in different genotypes of the genus Morus. (2) eight Morus L. genotypes were divided into two groups based on the digesting pattern discrepancy through cpDNA. The M. multicaulis genotypes displayed diversity on an intraspecies level. 'Nongsang No.12' was identical with the female parent 'Beiqu No.1' (M. atropurpurea) in the surveyed sequence, but different from the male parent 'Tongxiangqing' (M. multicaulis), suggesting that the cpDNA was maternal inheritance in Morus L. (3) There were two deletion fragments (451-456 bp; 840-863bp) and six base point mutations in the trnD-trnT region based on homologous sequence alignment. The sequence of trnD-trnT in the cpDNA of mulberry could provide more genetic information for phylogenetic analysis and pedigree identification. PMID- 26019529 TI - Reverse transcriptase domain sequences from tree peony (Paeonia suffruticosa) long terminal repeat retrotransposons: sequence characterization and phylogenetic analysis. AB - Tree peony is an important horticultural plant worldwide of great ornamental and medicinal value. Long terminal repeat retrotransposons (LTR-retrotransposons) are the major components of most plant genomes and can substantially impact the genome in many ways. It is therefore crucial to understand their sequence characteristics, genetic distribution and transcriptional activity; however, no information about them is available in tree peony. Ty1-copia-like reverse transcriptase sequences were amplified from tree peony genomic DNA by polymerase chain reaction (PCR) with degenerate oligonucleotide primers corresponding to highly conserved domains of the Ty1-copia-like retrotransposons in this study. PCR fragments of roughly 270 bp were isolated and cloned, and 33 sequences were obtained. According to alignment and phylogenetic analysis, all sequences were divided into six families. The observed difference in the degree of nucleotide sequence similarity is an indication for high level of sequence heterogeneity among these clones. Most of these sequences have a frame shift, a stop codon, or both. Dot-blot analysis revealed distribution of these sequences in all the studied tree peony species. However, different hybridization signals were detected among them, which is in agreement with previous systematics studies. Reverse transcriptase PCR (RT-PCR) indicated that Ty1-copia retrotransposons in tree peony were transcriptionally inactive. The results provide basic genetic and evolutionary information of tree peony genome, and will provide valuable information for the further utilization of retrotransposons in tree peony. PMID- 26019530 TI - Efficacious rat model displays non-toxic effect with Korean beechwood creosote: a possible antibiotic substitute. AB - Wood creosote, an herbal anti-diarrheal and a mixture of major volatile compounds, was tested for its non-toxicological effects, using a rat model, with the objective to use the creosote as an antibiotic substitute. A total of 30 Sprague-Dawley rats were studied to form five groups with 6 rats each. Korea beechwood creosote was supplemented into three test groups with 0.03 g/kg, 0.07 g/kg and 0.1 g/kg body weight/day without antibiotic support, along with a positive control of Apramycin sulphate (at 0.5% of the daily feed) and a negative control. Korean beechwood creosote supplementation showed no negative effect on the body weight gain in comparison to the negative and the positive control groups and the feed conversion ratio was also comparable with that of the control groups. The clinical pathology parameters studied were also under the umbrella of normal range, including liver specific enzymes, blood glucose, total protein, blood urea nitrogen (BUN), which indicated no toxic effect of creosote at the given doses. The non-hepatotoxic effect was also confirmed using hepatic damage specific molecular markers like Tim-p1, Tim-p2 and Tgf-beta1. The results suggested that Korean beechwood may be used as antibiotic substitute in weanling pigs feed without any toxic effect on the body. Although the antimicrobial properties of creosote were not absolutely similar to those of apramycin sulphate, they were comparable. PMID- 26019531 TI - Long-term assessment of the self-purification potential of a technologically managed ecosystem: the Middle Iskar cascade. AB - The Middle Iskar cascade is situated along the middle course of the Iskar River (Bulgaria) after the capital city Sofia and has three small hydroelectric power plants that were put into operation by the end of 2012. The aim of this study was to evaluate the self-purification potential of water in the reservoirs of these plants as an important and necessary condition for their ecological functioning. The assessment was made by hydrochemical parameters (dissolved suspended solids, insoluble suspended solids, total suspended solids, nitrites, nitrates, ammonium, phosphates, chemical oxygen demand, dissolved oxygen) and microbiological parameters (aerobic heterotrophic bacteria and bacteria growing in an Endo medium) and covered a period of three years (2010, 2011 and 2012). Standard methods were applied, mainly colorimetric and microbiological cultivation methods. The obtained results showed high levels of some of the tested indicators during 2012. In the section of the Middle Iskar cascade a high self-purification potential was observed in the reservoirs which maintain good water quality. PMID- 26019532 TI - Effect of different carbon sources on the biological phosphorus removal by a sequencing batch reactor using pressurized pure oxygen. AB - The effect of different carbon source on the efficiency of enhanced biological phosphorus removal (EBPR) from synthetic wastewater with acetate and two ratios of acetate/starch as a carbon source was investigated. Three pressurized pure oxygen sequencing batch reactor (POSBR) experiments were operated. The reactors (POSBR1, POSBR2 and POSBR3) were developed and studied at different carbon source ratios of 100% acetate, 75% acetate plus 25% starch and 50% acetate plus 50% starch, respectively. The results showed that POSBR1 had a higher phosphate release-to-uptake ratio and, respectively, in a much higher phosphorus removal efficiency (93.8%) than POSBR2 (84.7%) and POSBR3 (77.3%) within 30 days of operation. This indicated that the phosphorus removal efficiency decreased the higher the starch concentration was. It was also found that POSBR1 produced more polyhydroxyalkanoates (PHAs) than the other reactors. Based on the effect of the carbon source on the PHA concentration and consumption, the conditions of POSBR1 were favourable for the growth of polyphosphate-accumulating organisms and therefore, beneficial for the biological phosphorus removal process. PMID- 26019533 TI - Decolourization of azo dyes by a newly isolated Klebsiella sp. strain Y3, and effects of various factors on biodegradation. AB - In this study, we isolated and characterized a new strain of Klebsiella sp. Y3, which was capable of decolourizing azo dyes under anaerobic conditions. The effects of physico-chemical parameters on the Methyl Red degradation by the strain were determined. The results indicated that strain Y3 exhibited a good decolourization ability in the range of pH from 4 to 9, temperature from 30 degrees C to 42 degrees C and salinity from 1% to 4%. A broad spectrum of azo dyes with different structures could be decolourized by the strain. The isolate decolourized Methyl Red, Congo Red, Orange I and Methyl Orange by almost 100% (100 mg/L) in 48 h. The culture exhibited an ability to decolourize repeated additions of dye, showing that the strain could be used for multiple cycles of biodegradation. Azo dyes at high concentrations could be tolerated and degraded by Y3. An almost complete mineralization of Methyl Red and Congo Red at the concentration of 800 mg/L was observed within 48 h. The high degradation potential of this bacterium supports its use in the treatment of industrial wastewater containing azo dyes. PMID- 26019534 TI - Examination of the technological properties of newly isolated strains of the genus Lactobacillus and possibilities for their application in the composition of starters. AB - The ability of four Lactobacillus strains - Lactobacillus brevis LBRZ7 (isolated from fermented cabbage), Lactobacillus plantarum LBRZ12 (isolated from fermented cabbage), Lactobacillus fermentum LBRH9 (of human origin) and Lactobacillus casei ssp. rhamnosus LBRC11 (isolated from home-made cheese) - to grow in flour/water environment and to accumulate high concentrations of viable cells was examined. Two starters for sourdough were created for lab-scale production of wheat bread: a two-strain starter and a four-strain starter. Wheat bread with improved properties - greater loaf volume, enhanced flavour and softer and brighter crumb was obtained from the 7% four-strain starter sourdough. The addition of sourdough in the production of wheat bread affected positively the technological and organoleptic characteristics of the final bread by inhibiting the growth of wild yeasts and mold and Bacillus spores without the addition of preservatives. The inclusion of 15% of the four-strain starter sourdough in the bread-making process led to enhanced safety and longer shelf life of the baked bread. PMID- 26019535 TI - High-level production of L-threonine by recombinant Escherichia coli with combined feeding strategies. AB - The process of L-threonine production using Escherichia coli TRFC was investigated, and the result showed that there was a large amount of acetic acid in the broth. The effects of acetic acid, which is a known inhibitory metabolite in E. coli cultivation, on L-threonine production by recombinant E. coli TRFC were evaluated, and the result indicated that the growth of E. coli TRFC and L threonine formation were significantly inhibited in the presence of acetic acid. Two combined feeding strategies were applied to L-threonine fed-batch fermentation in order to investigate the effects of the feeding strategy on L threonine fermentation. The results showed that using the combined feeding strategy of pseudo-exponential feeding and glucose-stat feeding resulted in high cell density (36.67 g L-1) and L-threonine production (124.57 g L-1) as well as low accumulation of by-products. This work provides a useful approach for large scale production of L-threonine. PMID- 26019536 TI - Evaluation of prognostic utility of MIB-1 and p53 expression in pituitary adenomas: correlations with clinical behaviour and follow-up results. AB - Pituitary adenomas (PAs) show a broad clinicomorphological spectrum. The proliferation activity, evaluated by MIB-1 labelling index (LI), and p53 expression have been pointed as predictive markers for invasiveness and progression. The aim of this study was to evaluate the proliferation rate and p53 expression and to look for any relationships with the clinical behaviour and follow-up results in a series of Bulgarian patients with PAs. A total of 93 patients with PAs (81 hormone-secreting, 12 non-functioning), who were operated on and followed up for a period of five years, were included. The MIB-1 LI and p53 expressions were determined by immunohistochemistry and correlated with various clinical and tumour variables. The whole group of PAs showed a low proliferation rate with evident variations in a small number of cases (MIB-1 LI - 0.50 +/- 0.56, from 0.1 to 3.30). MIB-1 LI correlated with tumour size (p = 0.012) and was positively related with male gender (p = 0.23) and partial surgical resection (p = 0.036). We found no significant differences regarding the age, functional activity, invasion (n = 33), expansion (n = 37) and tumour recurrences (seven cases). Only 10 cases (10.8%) showed a focal, nuclear p53 immunoreactivity. The p53 positive tumours had higher proliferation rate (p = 0.0001) but no relationship with the other clinical and tumour variables. Among all cases, there was only one case with higher MIB-1 LI (3.3%), positive p53 expression and tumour recurrence after surgery. Our results show that most PAs have a low proliferation rate and lack of p53 expression, as well as no relationship with tumour invasion or postsurgical progression. PMID- 26019537 TI - VEGF expression, microvessel density and dendritic cell decrease in thyroid cancer. AB - Thyroid cancer is one of the five most common cancers in the age between 20 and 50 years. Many factors including the potent angiogenic vascular endothelial growth factor (VEGF) and different dendritic cell types are known to be related to thyroid tumourogenesis. The study was performed to address the expression of VEGF and microvessel density in thyroid cancers and to evaluate the effect of VEGF expression in thyroid tumour cells on the dendritic cells. We investigated 65 patients with different types of thyroid carcinomas: papillary (PTC), oncocytic (OTC), follicular (FTC) and anaplastic (ATC), immunohistochemically with antibodies against VEGF, CD1a, CD83, S100 and CD31. Our results suggest that the expression of VEGF is significantly more often in PTC than ATC (92.3% vs. 60.0%, p = 0.025). The microvessel density marked with CD31 in the tumour border of PTC was significantly higher as compared to FTC (p = 0.039), but not to ATC and OTC (p = 0.337 and 0.134). We found that CD1a- and CD83-positive cells were dispersed with variable density and in OC CD31+ vessel numbers were positively correlated with CD83+ dendritic cells in tumour stroma (R = 0.847, p = 0.016). We did not find statistically significant associations of the survival of patients with PTC after the surgical therapy with VEGF expression and MVD. In conclusion we may state that VEGF expression in tumour cells of thyroid cancer can induce neovascularization and suppress dendritic cells. PMID- 26019538 TI - Whole genome methylation analyses of schizophrenia patients before and after treatment. AB - The aetiology of schizophrenia is still unknown but it involves both heritable and non-heritable factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. It takes part in the regulation of neurodevelopment and may be a contributing factor to the pathogenesis of brain diseases. It was found that many of the antipsychotic drugs may lead to epigenetic modifications. We have performed 42 high-resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands. Differentially methylated regions were studied with samples from 20 Bulgarian individuals divided in four groups according to their gender (12 males/8 females) and their treatment response (6 in complete/14 in incomplete remission). They were compared to two age and sex matched control pools (110 females in female pool/110 males in male pool) before and after treatment. We found significant differences in the methylation profiles between male schizophrenia patients with complete remission and control male pool before treatment (C16orf70, CST3, DDRGK1, FA2H, FLJ30058, MFSD2B, RFX4, UBE2J1, ZNF311) and male schizophrenia patients with complete remission and control male pool after treatment (AP1S3, C16orf59, KCNK15, LOC146336, MGC16384, XRN2) that potentially could be used as target genes for new therapeutic strategies as well as markers for good treatment response. Our data revealed major differences in methylation profiles between male schizophrenia patients in complete remission before and after treatment and healthy controls which supports the hypothesis that antipsychotic drugs may play a role in epigenetic modifications. PMID- 26019539 TI - Analysis of stress distribution around total hip stems custom-designed for the standardized Asian femur configuration. AB - In total hip replacement (THR), bone resorption related to the foreign body reaction around the implant causes bonding failure at the bone-prosthesis interface and adversely affects the function and longevity of femoral implants. Stress shielding is thought to be one of the possible biomechanical factors that causes bone resorption, and is related to prosthesis design. We therefore investigated stress distribution at the bone-implant interface of implant models custom-fitted to Asian individuals, using a finite-element method. Based on the standard geometry of Asian femurs, we designed four different custom-fitted implant stems and applied boundary conditions, including a stationary loading of 1750 N. Even though stress shielding was observed for all four different prostheses, the custom-designed implant with a stepped groove in the proximal medial region had the largest maximum principal stress distribution along paths on the bone-implant interface. This implant type also showed the highest maximum principal stress distribution at the proximal (0.308 MPa), mid (0.872 MPa) and distal (12.981 MPa) regions of the cortical surface of the femur. In conclusion, the implant design with a stepped groove in the proximal-medial region showed an overall increase in stress distribution due to minimization of stress shielding afforded by the reduced effective area in the bone-implant interface. Therefore, this hip implant type could be a possible geometry to remain functional over the long term in THR patients. PMID- 26019540 TI - Radioprotective effect of Rapana thomasiana hemocyanin in gamma induced acute radiation syndrome. AB - The radioprotective effect of Rapana thomasiana hemocyanin (RtH) against radiation-induced injuries (stomach ulcers, survival time and endogenous haemopoiesis) and post-radiation recovery was investigated in male albino mice (C3H strain). Radiation course was in a dose of 7.5 Gy (LD 100/30 - dose that kills 100% of the mice at 30 days) from 137Cs with a dose of 2.05 Gy/min. Radiation injuries were manifested by inducing a hematopoietic form of acute radiation syndrome. RtH was administered intraperitoneally in a single dose of 50, 100, 150 and 200 mg/kg body weight (b. w.) once a day for five consecutive days before irradiation. The results obtained showed that radiation exposure led to (1) 100% mortality rate, (2) ulceration in the stomach mucosa and (3) decrease formation of spleen colonies as a marker of endogenous haemopoiesis. Administration of RtH at a dose of 200 mg/kg provided better protection against radiation-induced stomach ulceration, mitigated the lethal effects of radiation exposure and recovered endogenous haemopoiesis versus irradiated but not supplemented mice. It could be expected that RtH will find a use in mitigating radiation induced injury and enhanced radiorecovery. PMID- 26019541 TI - Seroprevalance of Crimean-Congo haemorrhagic fever in Bulgarian livestock. AB - Crimean-Congo haemorrhagic fever (CCHF) is a tick-borne zoonotic disease. Over the past decade, CCHF cases in humans have emerged in Turkey and reemerged in the Balkan countries, Ukraine and Tajikistan. Occupational contact with infected livestock has been recognized as a common cause of the disease. A cross-sectional seroprevalence study in livestock was conducted in farming communities of an endemic area in Bulgaria, southeastern Europe. Overall, 72% of the tested animals were positive for IgG antibodies to CCHF virus. By the time the animals were one year old almost 50% had serologic evidence of CCHF infection, and by two years already 80% of them had been infected. The data obtained in this study reflect current situation of CCHF virus infection among livestock in Bulgaria. The results showed active CCHF virus circulation that poses risk for humans to be infected during contacts with animals and requires public health awareness. PMID- 26019542 TI - Metal Zn(II), Cu(II), Ni (II) complexes of ursodeoxycholic acid as putative anticancer agents. AB - The aim of the study was to evaluate the influence of metal [Zn(II), Cu(II), Ni(II)] complexes with ursodeoxycholic acid (UDCA) on the viability and proliferation of tumour and non-tumour cells. Cell lines established from retrovirus-transformed chicken hepatoma (LSCC-SF-Mc29) and rat sarcoma (LSR-SF SR) as well as from human cancers of the breast (MCF-7), uterine cervix (HeLa), lung (A549) and liver (HepG2) were used as model systems. Non-tumour human embryo (Lep-3) cells were also included in some of the experiments. The investigations were carried out by the thiazolyl blue tetrazolium bromide (MTT) test, neutral red uptake cytotoxicity assay, crystal violet staining, double staining with acridine orange and propidium iodide and the colony-forming method. The results obtained revealed that: (1) UDCA and its metal complexes in the tested concentrations decreased (to a varying degree) the viability and proliferation of the treated cells in a time- and concentration-dependent manner; (2) chicken hepatoma (LSCC-SF-Mc29) cells were most sensitive to the cytotoxic and antiproliferative action of the compounds tested, followed by rat sarcoma (LSR-SF SR) cells; (3) Cu-UDCA and Ni-UDCA were more effective against animal LSCC-SF Mc29 and LSR-SF-SR cells, while Zn-UDCA significantly decreased the viability and proliferation of human tumour cell lines; (4) applied independently, UDCA expressed lower cytotoxic/cytostatic activity as compared to metal complexes; and (5) the sensitivity of the non-tumour embryonic Lep-3 cells to the effects of UDCA and its metal complexes was comparable or even higher than those of the human tumour cells. PMID- 26019543 TI - Production of a new non-specific nuclease from Yersinia enterocolitica subsp. palearctica: optimization of induction conditions using response surface methodology. AB - A new non-specific nuclease from Yersinia enterocolitica subsp. palearctica (Y. NSN) was expressed in Escherichia coli (E. coli) BL 21 StarTM (DE3)plysS. Induction conditions, including isopropyl-beta-D-thiogalactoside (IPTG) concentration, cell density (OD600), induction time and induction temperature, were optimized using response surface methodology. Statistical analysis of the results revealed that induction temperature and all the quadratic terms of variables had significant effects on enzyme activity of Y. NSN. The optimal induction conditions were as follows: 1.5 mmol/L IPTG, OD600 of 0.80, induction time of 20.5 h, and induction temperature of 32 degrees C. Under the optimized conditions, the highest enzyme activity could be obtained. PMID- 26019544 TI - Adjusting the input ultrasound image data and the atherosclerotic plaque detection in the carotid artery by the FOTOMNG system. AB - Stroke is the third most frequent cause of death. Specifically, ischemic stroke accounts for the largest group of this kind of cases. Despite all the advances in medical therapeutic methods, no methods that would reliably reduce mortality from ischemic stroke have been found. Prevention is still the most significant way to combat stroke. When the frequent cause of ischemic stroke is atherosclerotic plaque in the carotid artery, its exploration can help to determine the development of the disease. These problems were very extensively discussed in October 2013 during the XVI International Neurosonology Congress in Sofia organized under the auspices of World Research Neurosonology Group, Bulgarian Neurosonology and Cerebral Hemodynamics Association. Our goal was to develop special modules for carotid artery picture processing (AVI file processing, reparation and reconstruction) and modules containing tools for automated carotid artery plaque detection; and to solve its measurement and three-dimensional modelling of the carotid artery and the plaque. New modules were implemented into the FOTOMNG system and tested on appropriate input data files, which verified their functionality and applicability. PMID- 26019545 TI - Humanistic and economic aspects of haemophilia treatment in Bulgaria. Comparison between two therapeutic approaches: prophylactic vs. on-demand treatment. AB - The aim of the present study was to calculate the cost-effectiveness of on-demand and prophylactic treatments of severe haemophilia A for Bulgarian patients. The point of view is that of all patients suffering from severe haemophilia A. An epidemiological model was created, which includes data regarding the number of patients divided into age groups up to 74 years. In the model, the transition age from prophylactic to on-demand treatment was gradually increased to up to 40 years. Costs of blood clotting factor, hospitalization, major surgery and indirect costs were considered; incremental cost-effectiveness ratio was calculated. The results showed that despite the increase in the costs for factor VIII with 20 million BGN, the saving obtained from other health services and indirect expenses reduce the overall expenses with 5.3 million BGN. If there is a gradual increase in the age when patients are transferred from a prophylactic to an on-demand regimen, the costs for factor VIII would increase from 10.4 million to 19.7 million BGN, but due to a decrease in indirect costs as well as other health service costs, the total costs would decrease. The sensitivity analysis showed that the costs for clotting factor VIII are what influences the cost effectiveness in both regimes. This indicates that decreases in the factor VIII cost will increase the overall efficiency in both regimes. In conclusion, the application of the prophylactic regime for patients up to 40 years of age will provide better treatment, increase the quality of life and decrease the incremental costs. PMID- 26019547 TI - Sub-species diversity of Xanthomonas euvesicatoria Bulgarian and Macedonian strains from pepper. AB - Sub-species diversity of pepper populations of Xanthomonas euvesicatoria in Bulgaria and Macedonia in 2012 was the object of this study. Species determination of 44 strains was performed by molecular methods using two pairs of species-specific primers and RFLP (restriction fragment length polymorphism) analysis of the 16S-23S ITS region with HpaII. The populations were characterized by genotypic and phenotypic properties. The genotypic diversity of the strains was evaluated by RAPD (random amplified polymorphic DNA) technique. Primer CUGEA 6 differentiated the strains in two groups, one of which included only Bulgarian strains and revealed a mixed profile of the type strain. BiologTM metabolite profiles separated the strains in four groups: two of which were composed only of Bulgarian or Macedonian strains. Correlation between the RAPD and the metabolic profiles was observed. Twelve antibiotics and copper ions in five concentrations (1-5 g kg-1) were tested for biological activity. The inhibition zones of the Bulgarian strains were statistically proven to be considerably larger than the Macedonian ones in the tests with kanamycin, streptomycin, polymyxin B sulphate, tetracycline and vankomycin. The inhibition zones of the Bulgarian strains were statistically proven to be relatively larger than the Macedonian ones in the copper tests. Based on our studies the Macedonian population of X. euvesicatoria manifested a relative homogeneity while a greater diversity was observed in the Bulgarian population. PMID- 26019546 TI - Molecular detection of bacteria in plant tissues, using universal 16S ribosomal DNA degenerated primers. AB - Highly specific, sensitive and rapid tests are required for the detection and identification of covert bacterial contaminations in plant tissue cultures. Current methods available for this purpose are tedious, time consuming, highly error prone, expensive, require advanced technical expertise and are sometimes ineffective. We report here the development of a sensitive polymerase chain reaction (PCR) based method for the rapid detection and identification of bacteria occurring in plant tissue cultures. A total of 121 16S ribosomal DNA (rDNA) coding regions from 14 different groups of bacteria, algae and plants, available in the Gene Bank/European Molecular Biology Laboratory databases, were aligned and several conserved DNA sequences of bacterial origin were identified. From those, five degenerated primers were designed in order to amplify only the bacterial DNA present in mixed plant/bacteria genomic DNA extracts. A known amount of bacterial suspension of either covert Pseudomonas or covert Bacillus were added to in vitro plant leaves and total plant/bacterial DNA extracted using three different methods to determine the lowest number of bacteria required to be present in order to allow their detection. The highest sensitivity of the bacterial cell detection was 2.5 * 106 cells of both Bacillus and Pseudomonas inoculums, using template DNA prepared by the MiniPrep method. Generation of PCR amplification fragments was achieved only for the 16S rDNA bacterial gene by using four combinations of degenerated primers. Successive sequence analysis of these amplified fragments led to the rapid detection and molecular identification of bacteria covertly associated with plants. PMID- 26019548 TI - Changes in protein thiols in response to salt stress in embryogenic suspension cultures of Dactylis glomerata L. AB - The aim of the present study is to assess the rate of protein disulphide formation and the activity of NADPH-dependent thioredoxin and glutaredoxin systems, responsible for the reverse reduction of protein and mixed protein glutathione disulphides, in embryogenic suspension cultures of Dactylis glomerata, subjected to salt stress. Two concentrations of NaCl previously established as enhancing (0.085 mol/L) and inhibiting (0.17 mol/L) somatic embryogenesis were used. The quantitative (by colour reaction with Ellman's reagent) and qualitative (by diagonal gel electrophoresis) analyses showed a significant increase in protein disulphide formation in salt-treated cultures compared to controls. The ratio of disulphides to free thiols is higher in 0.17 mol/L NaCl-treated cultures. The activity of the thioredoxin-thioredoxin reductase system has been increased accordingly in 0.085 mol/L NaCl-treated cultures but decreased at the higher salt concentration. The activity of glutaredoxins was also estimated, by using glutathionylated bovine serum albumin as substrate and following the decrease of NADPH absorbance at 340 nm in the presence of glutathione and glutathione reductase. Mild salt (0.085 mol/L NaCl) treated cultures again showed the highest activity compared to controls and 0.17 mol/L NaCl-treated cultures. Based on these observations it was suggested that salt treatment resulted in increased protein disulphide formation and thioredoxin and glutaredoxin systems are important regulators of this process, strongly involved in salt stress response. The highest activity at 0.085 mol/L NaCl may be also related to the regulatory mechanisms, involved in the potentiating of somatic embryogenesis at this salt concentration. PMID- 26019549 TI - Gene cloning of an important eukaryotic translation initiation factor family, eIF2A gene in halophytic Leymus chinensis (Trin.). AB - Eukaryotic initiation factors eIF2A and eIF2 both play important roles in the mRNA translation of protein synthesis, whereas the functions of eIF2A are usually overlooked, as both functions of binding methyionly-tRNAi (Met-tRNAi) to 40S are similar under the same complementary factor and nucleotide requirements. Recently, the functions of eIF2A were reported to differ from those of eIF2 in manners when binding Met-tRNAi to 40S. Given that eukaryotic initiation factor eIF2 has been well known, eIF2A was still deficient in understanding of its sequence, structure and functions. In this work, we collected a high salt tolerant grass Leymus chinensis (Trin.) as the object of study, and cloned and sequenced the eIF2A gene from this species. Based on the DNA alignment and analysis of eIF2A gene sequences from other organisms, an effective primer set was newly designed. Using this primer set, a DNA fragment with length of about 500 bp was obtained, and we have submitted this sequencing result to NCBI GenBank database (accession number: KF279515). The Basic Local Alignment Search Tool (BLAST) result showed that our sequence is highly identical to eIF2A gene sequences that existed in NCBI GenBank database. This work would help to further understand the function of eIF2A, and provide more potential target genes for studying their functions in relation to stress tolerance mechanisms. PMID- 26019550 TI - Lactic acid microflora of the gut of snail Cornu aspersum. AB - The intestinal lactic acid microflora of the edible snail Cornu aspersum was studied by culture-based methods and was phenotypically and molecularly characterized. The antibacterial activity of lactic acid bacteria (LAB) isolates was investigated. Snails in different stages of development were collected from farms located in several regions of Bulgaria. One hundred twenty-two isolates, belonging to the group of LAB, were characterized morphologically and were divided into four groups. Representative isolates from each morphological type were subjected to phenotypic characterization and molecular identification. The snail gut lactic acid microflora was composed by Enterococcus (17 isolates), Lactococcus (12 isolates), Leuconostoc (7 isolates), Lactobacillus (18 isolates) and Weissella (1 isolate). The species affiliation of Lactococcus lactis (12), Leuconostoc mesenteroides (4) and Lactobacillus plantarum (2) was confirmed by species-specific primers. The Lactobacillus isolates were identified by sequence analysis of 16S rDNA as Lactobacillus brevis (12), L. plantarum (2), Lactobacillus graminis (1) and Lactobacillus curvatus (3). The species L. brevis, L. graminis and L. curvatus were found in snails in a phase of hibernation, whereas L. plantarum was identified both in active and hibernation phases. Antibacterial activity (bacteriocine-like) was shown only by one strain of L. mesentereoides P4/8 against Propionibacterium acnes. The present study showed that the LAB are a component of the microbial communities in the snail digestive system. This is the first report on Lactobacillus strains detected in the gut of C. aspersum. PMID- 26019551 TI - Microbial community development of biofilm in Amaranth decolourization technology analysed by FISH. AB - The aim of this study was to elucidate the role, the space distribution and the relationships of the bacteria from the genus Pseudomonas in a biofilm community during semi-continuous Amaranth decolourization process in model sand biofilters. The examined parameters of the process were as follows: technological parameters; key enzyme activities (azoreductase, succinate dehydrogenase, catechol-1,2 dioxygenase, catechol-2,3-dioxygenase); the number of azo-degrading bacteria and the bacteria from genus Pseudomonas (plate count technique); the amount and the location of Pseudomonas sp. using fluorescent in situ hybridization (FISH). The results showed that the increase of the Amaranth removal rate with 120% was accompanied with increase of the enzyme activities of the biofilm (azoreductase activity - with 25.90% and succinate dehydrogenase - with 10.61%). The enzyme assays showed absence of activity for satechol-1,2-dioxygenase and catechol-2,3 dioxygenase at the early phase and high activities of the same oxygenases at the late phase (2.76 and 1.74 MUmol/min mg protein, respectively). In the beginning of the process (0-191 h), the number of the culturable microorganisms from genus Pseudomonas was increased with 48.76% but at the late phase (191-455 h) they were decreased with 15.25% while the quantity of the non-culturable bacteria from this genus with synergetic relationships was increased with 23.26%. The dominant microbial factors were identified in the structure of the biofilm during the azo degradation process by using FISH analysis. Furthermore, the inner mechanisms for increase of the rate and the range of the detoxification were revealed during the complex wastewater treatment processes. PMID- 26019552 TI - Heavy metal accumulation in the bark and leaves of Juglans regia planted in Artvin City, Turkey. AB - The aim of this study was to determine the level of heavy metals such as copper, iron, manganese, zinc, lead, nickel, cadmium and chromium concentrated in Juglans regia bark and leaf samples from different localities in Artvin, Turkey. Analysis of the heavy metals Cu, Fe, Mn, Zn, Pb, Ni, Cd and Cr in samples was carried out by inductively coupled plasma optical emission spectroscopy (ICP-OES; Perkin Elmer, Optima 8000 DV). Statistical significance was determined by analysis of variance (ANOVA). The comparisons were performed in order to determine whether there were any differences between J. regia bark and leaf samples in terms of average heavy metal accumulation levels. As a result of this study, the following mean concentrations were determined for J. regia bark samples: the contents of Cu, Fe, Mn, Zn, Pb, Ni, Cd and Cr (MUg g-1, dry weight) ranged from 72.46 to 88.14, 14.40 to 628.0, 0.896 to 67.71, 7.000 to 28.52, 0.040 to 0.905, 1.031 to 2.744, 0.011 to 0.158 and 1.192 to 3.134, respectively. On the other hand, for J. regia leaf samples, the contents of Cu, Fe, Mn, Zn, Pb, Ni, Cd and Cr (MUg g-1, dry weight) ranged from 0.339 to 13.80, 12.72 to 698.2, 1.001 to 204.6, 7.362 to 56.03, 0.158 to 0.665, 0.130 to 2.744, 0.041 to 0.114 and 0.508 to 2.767, respectively. In the statistical analysis, heavy metal accumulation values of J. regia bark and leaf samples for Cu, Ni and Cr were significantly different (P < 0.05). PMID- 26019553 TI - Protective effects of ethyl pyruvate in cisplatin-induced nephrotoxicity. AB - This study was performed to investigate the effect of ethyl pyruvate on changes in renal functions and oxidative stress related renal injury caused by cisplatin (cis-dichlorodiammine platinum-II; CDDP). Male Wistar albino rats were divided into four groups (n = 8): (1) control group (1 ml Ringer's lactate solution i.p.); (2) ethyl pyruvate (EP) group (50 mg/kg Ringer's EP solution (REPS) i.p.); (3) cisplatin group (a single dose of cisplatin (5 mg/kg, i.p.); and (4) cisplatin + EP group (a single dose of cisplatin (5 mg/kg, i.p.) + REPS 50 mg/kg/day, i.p.) for five days. At the sixth day, kidneys of rats were mounted to a Langendorff apparatus. Renal perfusion pressures were recorded. Blood samples were taken for serum urea, creatinine, total oxidant status (TOS), total antioxidant status (TAS) and oxidative stres index (OSI) evaluations. Kidney tissues were obtained for malondialdehyde (MDA) analyses and histopathological examination. Perfusion pressures, serum urea, creatinine, TOS, OSI and tissue MDA levels were found significantly higher, whereas TAS was notably lower in cisplatin group. Histopathological examination showed apparent renal paranchymal injury in cisplatin group. In cisplatin + REPS group, perfusion pressures, serum urea, creatinine and tissue MDA levels were decreased. Moreover, EP co administration provided less inflammatory cell infiltration, tubular dilatation, whereas TOS, TAS and OSI improved significantly versus cisplatin group. These findings show that EP has protective effects against cisplatin nephrotoxicity. PMID- 26019554 TI - Antiviral activity of Bifidobacterium adolescentis SPM1605 against Coxsackievirus B3. AB - Bifidobacteria are considered one of the most beneficial probiotics and have been widely studied for their effects against specific pathogens. The present study investigated the antiviral activity of probiotics isolated from Koreans against Coxsackievirus B3 (CVB3). The effect of probiotic isolates against CVB3 was measured by the plaque assay and cellular toxicity of bifidobacteria in HeLa cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among 13 probiotic isolates, 3 Bifidobacterium adolescentis, 2 Bifidobacterium longum and 1 Bifidobacterium pseudocatenulatum had an antiviral effect against CVB3, while the others did not show such effect. B. adolescentis SPM1605 showed the greatest inhibitory properties against CVB3. When the threshold cycle (CT) values for the treated B. adolescentis SPM1605 samples were compared to the results for the non-treated samples, it was shown that the amplified viral sequences from the CVB3 had their copy number lowered by B. adolescentis SPM1605. Moreover, the gene expression in infected HeLa cells was also inhibited by 50%. The results suggest that B. adolescentis SPM1605 suppresses CVB3 and could be used as an alternative therapy against infectious diseases caused by coxsackieviruses. PMID- 26019555 TI - Effect of recombinant Hepatitis B virus on human glomerular mesangial cell apoptosis. AB - The aim of this study was to investigate the expression of recombinant Hepatitis B virus (HBV) in normal human glomerular mesangial cells (NHMC) and its effect on cell apoptosis. Cell transfection was conducted by the liposome method. The levels of HBsAg and HBeAg in the culture supernatant were detected by electrochemiluminescence. Morphological changes were observed by light and fluorescence microscopy. Cell proliferation was analysed by the methyl thiazole tetrazolium (MTT) assay and cell apoptosis, by flow cytometry. The expression level of Bax and Bcl-2 mRNA was measured by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Caspase-3 activity was detected by a Caspase-3 activity detection kit. The results showed high expression levels of HBsAg and HBeAg in NHMC cells transfected with recombinant full-length C genotype HBV (PHY106-CHBV). Typical apoptotic morphology was observed at 48 h after PHY106-CHBV transfection. Cell proliferation was inhibited. The percentage of apoptotic cells and the expression level of Bax mRNA were significantly higher in the PHY106-CHBV group than those in the blank control group and the PHY106 group. There was no significant difference in the expression level of Bcl-2 mRNA among the three groups. Caspase-3 was significantly activated after PHY106-CHBV transfection. The results demonstrate that recombinant HBV can be expressed in NHMC and its expression induces NHMC apoptosis. PMID- 26019556 TI - Antibacterial potential of streptomycete strains from Antarctic soils. AB - The exploration of habitats with unusual environment and poorly explored areas such as Antarctica is one of the strategies for discovery of new biologically active substances and/or new producers. The aim of this study was to identify the actinomycetes isolated from the soils of the island Livingston - Antarctica and to investigate their potential to synthesize antibacterial agents against phytopathogens. Twenty-three actinomycete strains were the object of this study. Using PCR (polymerase chain reaction) amplification all strains were affiliated to genus Streptomyces. The sequencing of the 16S rRNA for three of the strains showed greatest similarity to Streptomyces tendae for one of them, and revealed that the other strains had closest relations to streptomycetes isolated from anthropogenically unaltered regions including Antarctica. The isolates were studied for production of antibacterial substances both by molecular and culture methods. PCR targeting specific biosynthetic genes involved in the production of some groups of antibiotics was performed. The screening showed that all strains possessed the gene for Type-II polyketide synthase, 11 strains - for non ribosomal peptide synthetase; 6 strains - for polyene antibiotics; and 4 strains for glycopeptide antibiotics. The production of antibacterial substances by the strains was tested in vitro against phytopathogenic bacteria. The strains differed in the number of inhibited test - bacteria and in their spectrum of action. Four strains showed a wide range of activity against Gram-positive and Gram-negative phytopathogens. The results obtained revealed that the Antarctic soils are potential source for isolation of streptomycetes producing antibiotics from different groups. PMID- 26019557 TI - Comparative study of cytotoxicity of detonation nanodiamond particles with an osteosarcoma cell line and primary mesenchymal stem cells. AB - Recently, nanodiamonds (NDs) have attracted great interest due to their unique physical and chemical properties that could be used in various biological applications. However, depending on the origin, NDs often contain different impurities which may affect cellular functions and viability. Therefore, before their biomedical application, the cytotoxicity of newly produced NDs should be assessed. In the present study, we have evaluated cytotoxicity of four types of ND particles with two cell models: a human osteosarcoma cell line, MG-63, and primary rat mesenchymal stem cells (rMSCs). Detonation-generated nanodiamond (DND) particles were purified with different acid oxidizers and impurities' content was determined by elemental analysis. The particles size distribution was measured revealing that the DND particles have an average size in the range of 51 233 nm. Cytotoxicity was assessed by optical microscopy and proliferation assay after 72 hours exposure of the cells to nanoparticles. We observed cell-specific and material-specific toxicity for all tested particles. Primary stem cells demonstrated higher sensitivity to DND particles than osteosarcoma cells. The most toxic were the DND particles with the smallest grain size and slight content of non-diamond carbon, while DNDs with higher grain size and free from impurities had no significant influence on cell proliferation and morphology. In addition, the smaller DND particles were found to form large aggregates mainly during incubation with rMSCs. These results demonstrate the role of the purification method on the properties of DND particles and their cytotoxicity as well as the importance of cell types used for evaluation of the nanomaterials. PMID- 26019558 TI - Evaluation of different pretreatments on microbial transformation of saponins in Dioscorea zingiberensis for diosgenin production. AB - In order to evaluate the effects of different pretreatments on microbial transformation of saponins in Dioscorea zingiberensis (DZW), various methods have been systematically studied on a large scale. Five pretreatments, including physical separation, catalytic solvent extraction, ultrasonic fermentation, complex enzymatic hydrolyzation and enzymatic saccharification, were performed on DZW. Compared with other methods, complex enzymatic hydrolyzation significantly improved the efficiency of microbial transformation. Due to the pretreatment, a diosgenin yield of 92.6%, and diosgenin accumulation of 27.3 mg/g DZW were achieved. The high efficiency of this method was attributed to the separation of 84.3% starch and 76.5% fibre from DZW in the form of a sugar. Analysis of saponins in this microbial transformation process showed that the residual rates of the intermediate products were much lower than those obtained from other pretreatments. The results demonstrate that complex enzymatic hydrolyzation is a practical and effective pretreatment method for production of diosgenin from DZW in a microbial transformation way. PMID- 26019559 TI - GECluster: a novel protein complex prediction method. AB - Identification of protein complexes is of great importance in the understanding of cellular organization and functions. Traditional computational protein complex prediction methods mainly rely on the topology of protein-protein interaction (PPI) networks but seldom take biological information of proteins (such as Gene Ontology (GO)) into consideration. Meanwhile, the environment relevant analysis of protein complex evolution has been poorly studied, partly due to the lack of high-precision protein complex datasets. In this paper, a combined PPI network is introduced to predict protein complexes which integrate both GO and expression value of relevant protein-coding genes. A novel protein complex prediction method GECluster (Gene Expression Cluster) was proposed based on a seed node expansion strategy, in which a combined PPI network was utilized. GECluster was applied to a training combined PPI network and it predicted more credible complexes than peer methods. The results indicate that using a combined PPI network can efficiently improve protein complex prediction accuracy. In order to study protein complex evolution within cells due to changes in the living environment surrounding cells, GECluster was applied to seven combined PPI networks constructed using the data of a test set including yeast response to stress throughout a wine fermentation process. Our results showed that with the rise of alcohol concentration, protein complexes within yeast cells gradually evolve from one state to another. Besides this, the number of core and attachment proteins within a protein complex both changed significantly. PMID- 26019560 TI - Insights into 3-hydroxypropionic acid biosynthesis revealed by overexpressing native glycerol dehydrogenase in Klebsiella pneumoniae. AB - In Klebsiella pneumoniae, glycerol dissimilation involves parallel oxidation and reduction pathways. Oxidation pathway provides adenosine triphosphate (ATP) and cofactors to sustain cell growth, while reduction pathway presents 3 hydroxypropionic acid (3-HP) and 1,3-propanediol(1,3-PDO), which are commercially attractive platform chemicals. Previous metabolic engineering of K. pneumoniae focused on the intensification of reduction pathway; however, it failed to overproduce 3-HP or 1,3-PDO. Contrary to this strategy, here we show that overexpression of glycerol dehydrogenase (dhaD), the first functional enzyme in oxidation pathway, can efficiently stimulate cell growth and facilitate 3-HP accumulation. Under microaerobic conditions, although metabolic burden arising from plasmid replication, the recombinant K. pneumoniae overexpressing dhaD grew actively and showed 60% enhancement of 3-HP compared to the control. In particular, overexpression of dhaD increased the activity of glycerol dehydratase, indicating the concerted action of two enzymes and the interdependence between glycerol oxidation and reduction pathways. Moreover, the strain overexpressing dhaD produced more lactic acid yet less acetic acid than the control, implying the interplay between dhaD expression and the formation of byproducts. Together, not only showing that intensifying glycerol oxidation pathway is beneficial to 3-HP production, this study also reveals the structural rigidity of dha operon that mediates glycerol dissimilation in K. pneumoniae. PMID- 26019561 TI - Comparison of health-related quality-of-life measurement instruments in diabetic patients. AB - The objective of the study was to compare three different questionnaires (Short Form (SF)-6D, EuroQuol (EQ)-5D and WHO-5) to establish which one is more sensitive and which one gives an adequate assessment of the quality of life in patients with diabetes. In an observational and transversal study with duration of 4 months, in 5 Bulgarian cities, 146 patients were randomly selected. The following quality-of-life measuring instruments were applied: 146 questionnaires SF-6D, 146 questionnaires EQ-5D and 103 questionnaires of WHO-5. Descriptive statistics, chi-Square and correlation coefficients were used for data analysis. The study assessed the quality of life of patients suffering from diabetes mellitus with a mean age of 57.39 years (standard deviation (SD) 17.087); 95% confidence interval (CI) 54.60-60.19; 76% of the patients had diabetes type 2. The patients received a mean SF-6D score of 0.6290, an EQ-5D score of 0.6272, a visual analogue scale score of 0.7158 and a WHO-5 score of 0.4635. Preferences measured by the SF-6D and by the EQ-5D showed significant correlations with one another, and the Pearson coefficient was r = 0.906 (p < 0.01). The most current version of SF-6D, based on the 2002 model, was found to be valid and reliable when compared to the EQ-5D and is a questionnaire alternative to assess preferences in economic analysis carried out in health care. PMID- 26019563 TI - Development of a core collection for ramie by heuristic search based on SSR markers. AB - There are more than 2000 ramie germplasms in the National Ramie Germplasm Nursery affiliated with the Institute of Bast Fiber Crops, Chinese Academy of Agricultural Science, China. As it is difficult to perform effective conservation, management, evaluation, and utilization of redundant genetic resources, it is necessary to construct a core collection by using molecular markers. In this study, a core collection of ramie consisting of 22 germplasms was constructed from 108 accessions by heuristic search based on 21 Simple Sequence Repeat (SSR) marker combinations. The results showed that there is a poor relationship between the core collection and the geographic distribution. The number of amplification bands for the core collection was the same as that for the entire collection. Shannon's index for three of the SSR primers (14%) and Nei's index for nine of the SSR primers (19%) were lower in the core collection than in the entire collection. The true core collection had wider genetic diversity compared with the random core collection. Collectively, the core collection constructed in this study is reliable and represents the genetic diversity of all the 108 accessions. PMID- 26019562 TI - Osmoregulation capacity in Bulgarian durum wheat. AB - The phenotypic variation in osmotic adjustment (OA) capacity of five Bulgarian winter durum wheat genotypes and their progenies was determined using a modified method based on the measurement of seedling growth suppression after three-day exposure to osmotic stress induced by 1 mol/L sucrose. The genetic parameters of the studied trait in a diallel crossing scheme, including the selected genotypes and the microsatellite polymorphism at 43 loci, were determined. The old Bulgarian cultivar Apulicum 233 and all hybrid combinations involving this genotype showed higher OA. In the heritability of osmoregulation ability, the non additive gene effects (specific combining ability) strongly predominated over the additive ones and had a significant impact on the observed high heterosis effect. Distinct polymorphisms were identified between the studied genotypes. Cluster analysis of the phenotypic data obtained from a multiyear test under water limited conditions and the molecular data, both based on Euclidean distance, showed similar grouping of the genotypes with specific separation of cultivar Apulicum 233 (high OA) in a single cluster. Principal component analysis revealed not only interrelationships between the important agronomic and morpho physiological traits in Bulgarian durum wheat under water-limited conditions, but also presence of relations between them and some microsatellite loci located near or within known quantitative trait loci (QTLs) for these traits. Further studies based on segregating population between genotypes with contrasting levels of OA will allow mapping QTLs for phenotypic traits expressed under water deficit and isolation of genes that can be used as potential markers in marker-assisted selection for drought tolerance. PMID- 26019564 TI - Molecular characterization of three common olive (Olea europaea L.) cultivars in Palestine, using simple sequence repeat (SSR) markers. AB - Eight accessions of olive trees from three common varieties in Palestine, Nabali Baladi, Nabali Mohassan and Surri, were genetically evaluated using five simple sequence repeat (SSR) markers. A total of 17 alleles from 5 loci were observed in which 15 (88.2%) were polymorphic and 2 (11.8%) were monomorphic. An average of 3.4 alleles per locus was found ranging from 2.0 alleles with the primers GAPU 103 and DCA-9 to 5.0 alleles with U9932 and DCA-16. The smallest amplicon size observed was 50 bp with the primer DCA-16, whereas the largest one (450 bp) with the primer U9932. Cluster analysis with the unweighted pair group method with arithmetic average (UPGMA) showed three clusters: a cluster with four accessions from the 'Nabali Baladi' cultivar, another cluster with three accessions that represents the 'Nabali Mohassen' cultivar and finally the 'Surri' cultivar. The similarity coefficient for the eight olive tree samples ranged from a maximum of 100% between two accessions from Nabali Baladi and also in two other samples from Nabali Mohassan, to a minimum similarity coefficient (0.315) between the Surri and two Nabali Baladi accessions. The results in this investigation clearly highlight the genetic dissimilarity between the three main olive cultivars that have been misidentified and mixed up in the past, based on conventional morphological characters. PMID- 26019565 TI - Characterization of two acetyltransferase genes in the pyripyropene biosynthetic gene cluster from Penicillium coprobium. AB - Pyripyropenes potently and selectively inhibit acyl-CoA:cholesterol acyltransferase 2 (ACAT-2). Among multiple isomers of pyripyropene (A to R), pyripyropene A (PyA) has insecticidal properties in addition to its growth inhibition properties against human umbilical vein endothelial cells. Based on the predicted biosynthetic gene cluster of pyripyropene A, two genes (ppb8 and ppb9) encoding two acetyltransferases (ATs) were separately isolated and introduced into the model fungus Aspergillus oryzae, using the protoplast polyethylene glycol method. The bioconversion of certain predicted intermediates in the transformants revealed the manner by which acetylation occurred in the biosynthetic pathway by the products expressed by these two genes (AT-1 and AT 2). The acetylated products detected by high-performance liquid chromatography (HPLC) in the extracts from AT-1 and AT-2 transformant clones were not present in the extract from the transformant clone with an empty vector. The HLPC charts of each bioconversion study exhibited high peaks at 12, 10.5 and 9 min, respectively. Further ultraviolet absorption and mass spectrometry analyses identified the products as PyE, PyO and PyA, respectively. AT-1 acetylated the C 1 of deacetyl-pyripyropene E (deAc-PyE), while AT-2 played an active role in acetylating the C-11 of 11-deAc-PyO and C-7 of deAc-PyA at two different steps of the biosynthetic pathway. PMID- 26019566 TI - Genetic characterization of MHC class II DQB exon 2 variants in gayal (Bos frontalis). AB - In the present study, exon 2 of major histocompatibility complex (MHC) class II DQB gene from 39 gayals (Bos frontalis) was isolated, characterized and compared with previously reported patterns for other bovidae. It was revealed by sequence analyses that there are 36 DQB exon 2 variants among 39 gayals. These variants exhibited a high degree of nucleotide and amino acid substitutions with most amino acid variations occurring at positions forming the peptide-binding sites (PBS). The DQB loci were analysed for patterns of synonymous (dS) and non synonymous (dN) substitution. The gayals were observed to be under strong balancing selection in the DQB exon 2 PBS (dN = 0.094, P = 0.001). It appears that this variability among gayals could confer the ability to mount immune responses to a wide variety of peptides or pathogens. PMID- 26019567 TI - Immobilization of Pseudomonas sp. DG17 onto sodium alginate-attapulgite-calcium carbonate. AB - A strain of Pseudomonas sp. DG17, capable of degrading crude oil, was immobilized in sodium alginate-attapulgite-calcium carbonate for biodegradation of crude oil contaminated soil. In this work, proportion of independent variables, the laboratory immobilization parameters, the micromorphology and internal structure of the immobilized granule, as well as the crude oil biodegradation by sodium alginate-attapulgite-calcium carbonate immobilized cells and sodium alginate attapulgite immobilized cells were studied to build the optimal immobilization carrier and granule-forming method. The results showed that the optimal concentrations of sodium alginate-attapulgite-calcium carbonate and calcium chloride were 2.5%-3.5%, 0.5%-1%, 3%-7% and 2%-4%, respectively. Meanwhile, the optimal bath temperature, embedding cell amount, reaction time and multiplication time were 50-60 degrees C, 2%, 18 h and 48 h, respectively. Moreover, biodegradation was enhanced by immobilized cells with a total petroleum hydrocarbon removal ranging from 33.56% +/- 3.84% to 56.82% +/- 3.26% after 20 days. The SEM results indicated that adding calcium carbonate was helpful to form internal honeycomb-like pores in the immobilized granules. PMID- 26019568 TI - Conversion of yellow wine lees into high-protein yeast culture by solid-state fermentation. AB - This study is focussed on the possibility of producing a yeast culture with yellow wine lees as a substrate by solid-state fermentation (SSF). Results showed that a yeast count of 1.58 * 109 CFU/g was achieved by signal factor and orthogonal experiments. After fermentation, the starch content in the yeast culture reduced from 32.2% +/- 0.5% to 7.5% +/- 0.2%, and the contents of crude protein and peptide increased from 36.1% +/- 0.8% to 48.0% +/- 1.0% and 3.9% +/- 0.2% to 7.2% +/- 0.4%, respectively. Additionally, large amounts of short peptides and free amino acids were detected by fast protein liquid chromatography (FPLC). These results suggest that yellow wine lees are a suitable substrate for the production of yeast cultures. It can serve as a growth-promoting factor and help reduce the shortage of protein feed in the animal industry. This research provides a potential way for the utilization of agro-industrial residues. PMID- 26019569 TI - Effect of multiple short highly energetic X-ray pulses on the synthesis of endoglucanase by a mutant strain of Trichoderma reesei-M7. AB - Bioconversion of cellulose-containing substrate to glucose represents an important area of modern biotechnology. Enzymes for the degradation of the polysaccharide part of biomass have been produced, mostly by fungi belonging to genus Trichoderma. Studies were carried out with the mutant strain Trichoderma reesei-M7, a cellulase producer. Spores of the enzyme producer were irradiated with different doses of characteristic X-ray radiation from metallic tungsten (mainly the W Kalpha1 and Kalpha2 lines) with a high dose rate. The latter is a specific property of the dense plasma focus (DPF) device, which has pulsed operation and thus gives short and highly energetic pulses of multiple types of rays and particles. In this case, we focused our study on the influence of hard X rays. The doses of X-rays absorbed by the spores varied in the range of approximately 5-11,000 mSv measured with thermoluminescent dosimeters (TLD). The influence of the applied doses in combination with exceptionally high dose rates (in the order of tens of millisieverts per microsecond) on the activity of the produced endoglucanase, amount of biomass and extra-cellular protein, was studied in batch cultivation conditions. In the dose range of 200-1200 mSv, some enhancement of endoglucanase activity was obtained: around 18%-32%, despite the drop of the biomass amount, compared with the untreated material. PMID- 26019571 TI - Phytoplankton abundance and structural parameters of the critically endangered protected area Vaya Lake (Bulgaria). AB - Vaya (Ramsar site, protected area and Natura 2000 site) is the biggest natural lake in Bulgaria and the shallowest Black Sea coastal lake, which during the last decades has undergone significant changes and was included as critically endangered in the Red List of Bulgarian Wetlands. Our studies were conducted during the summer and autumn months of three years - 2004-2006. The paper presents results on the phytoplankton abundance (numbers, biomass and carbon content) in combination with the indices of species diversity, evenness and dominance. Phytoplankton abundance was extremely high (average values of 1135 * 106 cells/L for the quantity and of 46 mg/L for the biomass) and increased in the end of the studied period (years 2005-2006), when decrease of species diversity and increase of the dominance index values were detected. The carbon content of the phytoplankton was at an average value of 9.7 mg/L and also increased from 2004 to 2006. Cyanoprokaryota dominated in the formation of the total carbon content of the phytoplankton, in its numbers (88%-97.8%), and in the biomass (62% 87.9%). All data on phytoplankton abundance and structural parameters in Vaya confirm the hypertrophic status of the lake and reflect the general negative trend in its development. PMID- 26019570 TI - The oxidative stress response of the filamentous yeast Trichosporon cutaneum R57 to copper, cadmium and chromium exposure. AB - Despite the intensive research in the past decade on the microbial bioaccumulation of heavy metals, the significance of redox state for oxidative stress induction is not completely clarified. In the present study, we examined the effect of redox-active (copper and chromium) and redox-inactive (cadmium) metals on the changes in levels of oxidative stress biomarkers and antioxidant enzyme defence in Trichosporon cutaneum R57 cells. This filamentous yeast strain showed significant tolerance and bioaccumulation capability of heavy metals. Our findings indicated that the treatment by both redox-active and redox-inactive heavy metal induced oxidative stress events. Enhanced concentrations of Cu2+, Cr6+ and Cd2+ caused acceleration in the production of reactive oxygen species (ROS), increase in the level of oxidatively damaged proteins and accumulation of reserve carbohydrates (glycogen and trehalose). Cell response against heavy metal exposure also includes elevation in the activities of antioxidant enzymes, superoxide dismutase and catalase, which are key enzymes for directly scavenging of ROS. Despite the mentioned changes in the stress biomarkers, T. cutaneum did not show a significant growth diminution. Probably, activated antioxidant defence contributes to the yeast survival under conditions of heavy metal stress. PMID- 26019572 TI - Intraspecific protoplast fusion of Brettanomyces anomalus for improved production of an extracellular beta-glucosidase. AB - Improvement of production of an extracellular beta-glucosidase with high activity by Brettanomyces anomalus PSY-001 was performed by using recursive protoplast fusion in a genome-shuffling format. The initial population was generated by ultraviolet irradiation, ultrasonic mutagenesis and, then, subjected to recursive protoplast fusion. Mutant strains exhibiting significantly higher beta glucosidase activities in liquid media were isolated. The best mutant strain showed increased cell growth in a flask culture, as well as increased beta glucosidase production. A recombinant strain, F3-25, was obtained after three rounds of genome shuffling and its production of beta-glucosidase activity reached 4790 U L-1, which was a nearly eightfold increase compared to the original strain B. anomalus PSY-001. The subculture experiments indicated that F3 25 was genetically stable. PMID- 26019573 TI - Identification of pork in meat products using real-time loop-mediated isothermal amplification. AB - In this study, a one-step, real-time, loop-mediated isothermal amplification (RealAmp) assay was developed, for the highly specific detection of pork DNA. For the assay, the mtDNA of cytochrome b (cytb) gene was amplified at 63 degrees C using SYBR Green I for 45 min with a Real-Time Polymerase Chain Reaction (PCR) System that measured the fluorescent signal at one-minute intervals. As little as 1 pg of template DNA could be detected, without any cross-reactivity with non target species. Meat mixtures, heat-treated at 100 degrees C for 15 min, prepared by mixing pork meat with beef at different ratios (0.01%-10%) were tested, and the RealAmp assays allowed the detection of as little as 0.01% pork in the meat mixtures. Thus, this work showed that RealAmp could be used for specific identification and sensitive quantification of meat species, even for heat-treated meat products. PMID- 26019574 TI - Production of wheat bread without preservatives using sourdough starters. AB - In order for the beneficial effects of sourdough application in breadmaking to take place a proper selection of lactic acid bacteria species and strains, an appropriate technology and effective control of the purity and activity of the selected cultures. Four symbiotic starters for sourdough for the production of bread were developed and probated in a production laboratory using the selected strains Lactobacillus brevis LBRZ7, L. buchneri LBRZ6, L. plantarum X2, L. paracasei RN5, L. sanfranciscensis R and L. fermentum LBRH10 and the probiotic strain Propionibacterium freudenreichii ssp. shermanii NBIMCC 327. The starter sourdoughs that include Propionibacterium freudenreichii ssp. shermanii NBIMCC 327 had greater antimicrobial activity against saprophytic microorganisms: Bacillus subtilis, B. mesentericus, Aspergillus niger, Penicillium sp. and Rhizopus sp., but none of them inhibited the growth of bakery yeasts Saccharomyces cerevisiae. It was established that in order to prevent bacterial spoilage 10% of the selected starter sourdoughs had to be added in the breadmaking process, while for prevention of mold spoilage the necessary amount of starter sourdough had to be between 15% and 20%.The application of the developed starters for the production of wheat bread guarantees longer shelf life and no adverse alterations in the features of the final bread. PMID- 26019575 TI - Selection and characterization of naturally occurring high acidification rate Streptococcus thermophilus strains. AB - Among Streptococcus thermophilus cultures, the principle component of yoghurt and cheese starters, a minority of strains forms the group of 'H'-strains which show an unusually high acidification rate, grow faster and coagulate milk 3-5 hours earlier than the typical S. thermophilus cultures. A large-scale screening study was performed to select 'H'-strains of S. thermophilus from more than 100 samples of home-made yoghurt, industrial yoghurt starters and single cultures, maintained in the LBB culture collection. Only four strains - LBB.TN1, LBB.M23, LBB.M34 and LBB.M60 - were isolated/selected due to their ability to form large yellowish colonies on milk agar, supplemented with beta-glycerophosphate and bromocresol purple. While in general S. thermophilus is described as a species with limited proteolytic capacity and in contrast to all other tested S. thermophilus cultures, the four selected strains invariably gave positive amplification product with the polymerase chain reaction when primers, specific for the membrane proteinase-coding gene prtS were used. The macrorestriction profiles of the genomic DNA of the four strains confirmed that they are non-isogenic and not related to each other. When grown in milk and compared to the control industrial strain LBB.A, the four strains showed a dramatically faster acidification, coagulating milk within four hours. The application of strain TN1 or M23 as adjunct culture to industrial yoghurt starter LBB.BY5-12 resulted in shortening the fermentation time with more than 30 min. PMID- 26019576 TI - Investigation of the role of MMP3 -1171insA polymorphism in cutaneous malignant melanoma - a preliminary study. AB - Coetaneous malignant melanoma is the most aggressive cancer of the skin with a high rate of mortality worldwide. Degradation of basement membranes and extracellular matrix is an essential step in cancer invasion and metastasis. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles in this step. MMP-3 also called stromelysin-1 was one of the first proteinases found to be associated with cancer. In the gene of MMP-3 (MMP3), an insertion/deletion of an A nucleotide at position -1171 in promoter region has been identified and shown to effect the expression activity of the gene. The present study was conducted to investigate the relation of MMP3 -1171insA polymorphism with skin malignant melanoma risk in a pilot case-control study of Bulgarian patients (n = 26) and unaffected controls (n = 172). The genotypes of controls and melanoma patients were in Hardy-Weinberg equilibrium. The results showed no statistically significant difference both in genotype and allele frequencies of MMP3 -1171insA polymorphism between melanoma patients and healthy controls either in crude analyses (p = 0.360 and 0.790, c2-test) or after adjustment for age and sex. The comparison of some clinical characteristics between the patients with different genotypes showed a trend for longer survival of patients with 6A/6A genotype compared to the carriers of 5A allele (5A/5A+5A/6A genotypes, p = 0.118, Log rank test). The results of our current preliminary study do not provide evidence for the role of the promoter polymorphism -1171insA in MMP3 as a risk factor for development of coetaneous melanoma, but suggest its implication in progression of the diseases. PMID- 26019577 TI - Colorectal cancer severity and survival in correlation with tumour necrosis factor-alpha. AB - Colorectal cancer (CRC) development is strongly associated with innate immune mechanisms and intestinal inflammation. The aim of the study was to investigate the pre-operative serum levels of TNF-alpha and its correlation with cancer progression and survival in CRC patients taking into account the genotype of 308G/A promoter polymorphism in TNF-alpha gene (rs1800629). TNF-alpha -308G/A genotypes of 119 CRC cases and 177 no CRC controls were determined by restriction fragment length polymorphism assay (RFLP-PCR). TNF-alpha serum levels were measured by enzyme-linked immunosorbent assay (ELISA). Although no significant differences in allele and genotype frequencies between CRC and controls were observed, it should be noted that the minor allele-A and its homozygous genotype were overrepresented among CRC. In addition, allele-A was more frequent in early CRC patients compared to advanced cases. TNF-alpha serum level was significantly higher in CRC patients than in controls (36.1 +/- 8.4 pg/mL vs. 18.66 +/- 11 pg/mL; p = 0.0000001). In the subgroup analysis by tumour-node-metastasis stages, the highest TNF-alpha level was found in stage IV (42.7 +/- 12.5 pg/mL) and was significantly elevated compared to earlier stages of CRC and controls. The survival rate of CRC patients with low TNF-alpha serum level, estimated as median survival, was significantly higher than that of patients with high levels of TNF alpha (38.4 vs. 7.761 months; log rank test p = 0.00015) In conclusion, we can affirm that TNF-alpha affects tumour development along with disease progression which has an impact on the survival of CRC. PMID- 26019578 TI - Interactions of pharmacologically active snake venom sPLA2 with different cell lines. AB - Secreted Phospholipases A2 (sPLA2s) represent a large family of structurally related enzymes, which target different tissues and organs and induce numerous pharmacological effects based on their catalytic specificity - hydrolysis of the sn-2 ester bond of glycerophospholipids. The neurotoxin vipoxin, isolated from the venom of Vipera ammodytes meriodionalis, is a heterodimeric postsynaptic ionic complex composed of two protein subunits - a basic and toxic His48 sPLA2 enzyme and an acidic, enzymatically inactive and non-toxic component. In this paper, for the first time, we demonstrate that vipoxin sPLA2 enzyme affects cell integrity and viability of four cell types and causes different cell responses. The most dramatic local tissue effects were observed with RPE-1 (retinal pigment epithelial) cells followed by A549 (adenocarcinomic human alveolar epithelial) cells and MDCK (Madin-Darby Canine Kidney epithelial) cells. Products of the enzymatic reaction, lysophospholipids and unsaturated free fatty acids, act as lipid mediators that can induce membrane damaging or can stimulate cell proliferation. Our preliminary results on the cytotoxic effect of vipoxin sPLA2 on A549 cells are promising in searching of its eventual anticancer potential. PMID- 26019579 TI - Angelica sinensis is effective in treating diffuse interstitial pulmonary fibrosis in rats. AB - The aim of this study was to investigate the therapeutic effect of Angelica sinensis on a rat model of diffuse interstitial pulmonary fibrosis induced by bleomycin A5. The mechanism by which A. sinensis exerts its effect is also discussed. A diffuse interstitial pulmonary fibrosis model was established in 36 male Wistar rats by an endotracheal injection of bleomycin A5 (5 mg/kg). Then, these rats were randomly divided into the model group (n = 18) and the treatment group (treated with A. sinensis after modelling, n = 18). Control rats (n = 6) received an equal volume of saline. Hematoxylin-eosin (HE) staining was performed to analyse alveolitis and Masson staining, to observe pulmonary fibrosis. Collagen content was determined by hydroxyproline assay. Nuclear factor kappa B (NF-kappaB) activity was measured by electrophoretic mobility shift assay. Transforming growth factor-beta (TGF-beta) expression at mRNA level was detected by northern blotting and at protein level by enzyme-linked immunosorbent assay. The results obtained showed that the alveolitis and pulmonary fibrosis of the rats treated with A. sinensis was significantly alleviated compared with that of the rats in the model group. Treatment with A. sinensis also lowered the content of collagen, decreased NF-kappaB activity in alveolar macrophages and reduced the TGF-beta expression at the mRNA and protein level. These results indicated that A. sinensis is effective in treating and alleviating interstitial pulmonary fibrosis, possibly by lowering collagen, inhibiting the activity of NF-kappaB and reducing the TGF-beta expression. PMID- 26019580 TI - Clinical assessment of the therapeutic effect of low-level laser therapy on chronic recurrent aphthous stomatitis. AB - The aim of this study was to clinically assess the therapeutic effect of low level laser therapy (LLLT) on chronic recurrent aphthous stomatitis (RAS) using a protocol we developed especially for the purpose. The study included 180 patients: group 1 (the study group) - 90 patients who received LLLT using a laser operating in the red spectrum (658 nm; in a non-contact mode; power output P = 27 mW; frequency f1 = 5.8 Hz, f2 - continuous waveform; time T = 1.14 min; dosage of 2 J/cm2 once daily); group 2 (controls) - 90 patients who received pharmacotherapy (Granofurin and solcoseryl given twice daily). The indices we assessed were pain intensity, erythema dynamics and epithelization time. Pain was completely managed in 55.6% of group 1 patients one day after therapy began, while it took three days to alleviate pain for 11.1% of the patients in group 2. The erythema was managed entirely in 24.4% of group 1 patients after the first session, while it did not change in any of the group 2 patients. Pain intensity and erythema had similar dynamics for both groups. In 5 days, 75.6% of group 1 patients showed complete epithelization, while in group 2 the process was completed in only 37.8% of patients. As a whole, the results we obtained using LLLT to treat chronic RAS were better than those obtained in the group receiving pharmacotherapy. Pain and inflammation were very effectively managed with LLLT with the parameters we used and epithelization was considerably accelerated. PMID- 26019581 TI - Fungal biotransformation of ezetimibe. AB - Structural transformation of ezetimibe was performed by fungi Beauvaria bassiana and Cunninghamella blakesleeana. The metabolites were identified by different spectroscopic techniques as (3R,4S)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl) allyl)-4-(4-hydroxyphenyl) azetidin-2-one (2), (3R, 4S)-1-(4-fluorophenyl)-3-(3 (4fluorophenyl)-3-oxopropyl)-4-(4-hydroxyphenyl) azetidin-2-one (3), (3R,4S) 1-(4 fluorophenyl)-3-(3-(4-fluorophenyl) propyl)-4-(4-hydroxyphenyl) azetidin-2-one (4) and (2R,5S)-N, 5-bis (4-fluorophenyl)-5-hydroxy-2-(4-hydroxybenzyl) pentanamide (5). This study displays two important features of these fungi, viz., their ability to metabolize halogenated compounds, and their capacity to metabolize drugs that are targets of the UDP-Glucuronyl Transferase System, a phenomenon not commonly observed. PMID- 26019582 TI - Gene expression of enzymes involved in utilization of xylooligosaccharides by Lactobacillus strains. AB - Prebiotics are defined as food components that confer health benefits on the host through modulation of the microbiota. Xylooligosaccharides (XOS) are non digestible oligosaccharides that have recently received increasing attention as potential prebiotic candidates. XOS are sugar oligomers composed of 1,4-linked xylopyranosyl backbone and are obtained by either chemical or, more commonly, enzymatic hydrolysis of xylan polysaccharides, extracted from the plant cell wall. The bifidogenic effect of XOS was demonstrated by both in vitro studies and small-scale in vivo human studies. Some intestinal bacterial strains are able to grow on XOS, yet numerous studies have demonstrated that the ability to utilize these oligosaccharides varies considerably among these bacteria. The aim of this study is to investigate the ability of several strains Lactobacillus to use XOS. Fifteen Lactobacillus strains, allifiated to L. plantarum, L. brevis and L. sakei, were studied. Screening procedure was performed for the ability of the strains to utilize XOS as an alternative carbon source. Only some of them utilize XOS. The growth kinetics show the presence of two lag phases, indicating that these bacteria utilize probably some monosaccharides present in the used XOS. XOS were fermented with high specificity by Bifidobacteria strains, but Lactobacilli did not metabolize XOS efficiently. PMID- 26019583 TI - Interactions of non-natural halogenated substrates with D-specific dehalogenase (DehD) mutants using in silico studies. AB - The D-2-haloacid dehalogenase of D-specific dehalogenase (DehD) from Rhizobium sp. RC1 catalyses the hydrolytic dehalogenation of D-haloalkanoic acids, inverting the substrate-product configuration and thereby forming the corresponding L-hydroxyalkanoic acids. Our investigations were focused on DehD mutants: R134A and Y135A. We examined the possible interactions between these mutants with haloalkanoic acids and characterized the key catalytic residues in the wild-type dehalogenase, to design dehalogenase enzyme(s) with improved potential for dehalogenation of a wider range of substrates. Three natural substrates of wild-type DehD, specifically, monochloroacetate, monobromoacetate and D,L-2,3-dichloropropionate, and eight other non-natural haloalkanoic acids substrates of DehD, namely, L-2-chloropropionate; L-2-bromopropionate; 2,2 dichloropropionate; dichloroacetate; dibromoacetate; trichloroacetate; tribromoacetate; and 3-chloropropionate, were docked into the active site of the DehD mutants R134A and Y135A, which produced altered catalytic functions. The mutants interacted strongly with substrates that wild-type DehD does not interact with or degrade. The interaction was particularly enhanced with 3 chloropropionate, in addition to monobromoacetate, monochloroacetate and D,L-2,3 dichloropropionate. In summary, DehD variants R134A and Y135A demonstrated increased propensity for binding haloalkanoic acid and were non-stereospecific towards halogenated substrates. The improved characteristics in these mutants suggest that their functionality could be further exploited and harnessed in bioremediations and biotechnological applications. PMID- 26019584 TI - Towards computational improvement of DNA database indexing and short DNA query searching. AB - In order to facilitate and speed up the search of massive DNA databases, the database is indexed at the beginning, employing a mapping function. By searching through the indexed data structure, exact query hits can be identified. If the database is searched against an annotated DNA query, such as a known promoter consensus sequence, then the starting locations and the number of potential genes can be determined. This is particularly relevant if unannotated DNA sequences have to be functionally annotated. However, indexing a massive DNA database and searching an indexed data structure with millions of entries is a time-demanding process. In this paper, we propose a fast DNA database indexing and searching approach, identifying all query hits in the database, without having to examine all entries in the indexed data structure, limiting the maximum length of a query that can be searched against the database. By applying the proposed indexing equation, the whole human genome could be indexed in 10 hours on a personal computer, under the assumption that there is enough RAM to store the indexed data structure. Analysing the methodology proposed by Reneker, we observed that hits at starting positions [Formula: see text] are not reported, if the database is searched against a query shorter than [Formula: see text] nucleotides, such that [Formula: see text] is the length of the DNA database words being mapped and [Formula: see text] is the length of the query. A solution of this drawback is also presented. PMID- 26019585 TI - Neuro-fuzzy based model of batch fermentation of Kluyveromyces marxianus var. lactis MC5. AB - In this work a neuro-fuzzy based model of a whey batch fermentation process by a strain Kluyveromyces marxianus var. lactis MC5 is presented. A three-layered neuro-fuzzy network is realized. The simulation results are compared with conventional models (based on mass balance and differential equations). The neuro fuzzy model provides a better fitness and allows inclusion of linguistic variables (such as colour, smell, taste, morphophysiology, etc.). The accuracy is approximately equal to this achieved by a conventional neural network. The proposed approach is flexible (with regard to the process model) and quite robust (with regard to the possible uncertainties and to the optimization surface). Future work will focus on applying this approach for modelling of different biotechnological processes. PMID- 26019586 TI - Recent developments in the catalytic conversion of cellulose. AB - The increasing demand for energy has led to the development of biomass conversion technologies. As the most abundant biomass on Earth, cellulose is generally chosen as the primary research target for biomass conversion. In this review, gasification and pyrolysis of cellulose are briefly discussed and hydrolysis is then considered in detail. Moreover, many new developments and applications are introduced in cellulose conversion in recent years. Among these technologies, heterogeneous catalysis, hydrolysis in ionic liquid and hydrolysis by hot compressed water exhibit a promising potential in cellulose conversion. Therefore, they are well recognized as powerful, fast and efficient techniques, becoming the focus of intensive research. PMID- 26019587 TI - A simple method for RNA isolation from various tissues of the tree Neolamarckia cadamba. AB - Plant tissues contain abundant polysaccharides, phenolic compounds and other metabolites, which makes it difficult to isolate high-quality RNA from them. In addition, Neolamarckia cadamba contains large quantities of other components, particularly RNA-binding alkaloids, which makes the isolation even more challenging. Here, we describe a concise and efficient RNA isolation method that combines the cetyltrimethyl ammonium bromide (CTAB) and Plant RNA Kit (Omega) protocols. Gel electrophoresis showed that RNA extracted from all tissues, using this protocol, was of good integrity and without DNA contamination. Furthermore, the isolated RNA was of high purity, with an A260/A280 ratio of 2.1 and an A260/A230 ratio of >2.0. The isolated RNA was also suitable for downstream applications, such as reverse transcription-polymerase chain reaction (RT-PCR) and quantitative RT-PCR (RT-qPCR). The RNA isolation method was also efficient for recalcitrant plant tissues. PMID- 26019588 TI - Influence of protoplast fusion between two Trichoderma spp. on extracellular enzymes production and antagonistic activity. AB - Biological control plays a crucial role in grapevine pathogens disease management. The cell-wall degrading enzymes chitinase, cellulase and beta glucanase have been suggested to be essential for the mycoparasitism activity of Trichoderma species against grapevine fungal pathogens. In order to develop a useful strain as a single source of these vital enzymes, it was intended to incorporate the characteristics of two parental fungicides tolerant mutants of Trichoderma belonging to the high chitinase producing species T. harzianum and the high cellulase producing species T. viride, by fusing their protoplasts. The phylogeny of the parental strains was carried out using a sequence of the 5.8S ITS region. The BLAST of the obtained sequence identified these isolates as T. harzianum and T. viride. Protoplasts were isolated using lysing enzymes and were fused using polyethylene glycol. The fused protoplasts have been regenerated on protoplast regeneration minimal medium supplemented with two selective fungicides. Among the 40 fast growing fusants, 17 fusants were selected based on their enhanced growth on selective media for further studies. The fusant strains were growing 60%-70% faster than the parents up to third generation. All the 17 selected fusants exhibited morphological variations. Some fusant strains displayed threefold increased chitinase enzyme activity and twofold increase in beta-glucanase enzyme activity compared to the parent strains. Most fusants showed powerful antagonistic activity against Macrophomin aphaseolina, Pythium ultimum and Sclerotium rolfsii pathogens. Fusant number 15 showed the highest inhibition percentage (92.8%) against M. phaseolina and P. ultimum, while fusant number 9 showed the highest inhibition percentage (98.2%) against the growth of S. rolfsii. A hyphal intertwining and degradation phenomenon was observed by scanning electron microscope. The Trichoderma antagonistic effect against pathogenic fungal mycelia was due to the mycoparasitism effect of the extracellular enzymes. PMID- 26019589 TI - Biotransformation of steroidal saponins in sisal (Agave sisalana Perrine) to tigogenin by a newly isolated strain from a karst area of Guilin, China. AB - A rod-shaped bacterium was isolated from the soil in a karst area of Guilin, China and its biotransformation of steroidal saponins in sisal (Agave sisalana Perrine) to tigogenin was presented for the first time. A total of 22 strains for the degradation of steroidal saponins in sisal were isolated from 48 soil samples, and the isolated rod-shaped, bacterial strain ZG-21 was used for the production of tigogenin due to its highest degradation efficiency of steroidal saponins in sisal. The parameters affecting biotransformation by strain ZG-21 were optimized. Under the optimized conditions of temperature (30 degrees C), pH (6), time (5 days) and substrate concentration (5 mg/mL), a maximum tigogenin yield of 26.7 mg/g was achieved. Compared with the conventional method of acid hydrolysis, the biotransformation method provided a clean and eco-friendly alternative for the production of tigogenin. PMID- 26019590 TI - Succinic acid production from xylose mother liquor by recombinant Escherichia coli strain. AB - Succinic acid (1,4-butanedioic acid) is identified as one of important building block chemicals. Xylose mother liquor is an abundant industrial residue in xylitol biorefining industry. In this study, xylose mother liquor was utilized to produce succinic acid by recombinant Escherichia coli strain SD121, and the response surface methodology was used to optimize the fermentation media. The optimal conditions of succinic acid fermentation were as follows: 82.62 g L-1 total initial sugars, 42.27 g L-1 MgCO3 and 17.84 g L-1 yeast extract. The maximum production of succinic acid was 52.09 +/- 0.21 g L-1 after 84 h with a yield of 0.63 +/- 0.03 g g-1 total sugar, approaching the predicted value (53.18 g L-1). It was 1.78-fold of the production of that obtained with the basic medium. This was the first report on succinic acid production from xylose mother liquor by recombinant E. coli strains with media optimization using response surface methodology. This work suggested that the xylose mother liquor could be an alternative substrate for the economical production of succinic acid by recombinant E. coli strains. PMID- 26019591 TI - Water quality assessment of aquatic ecosystems using ecological criteria - case study in Bulgaria. AB - Four aquatic ecosystems (two rivers and two dams) situated in the western part of Bulgaria were investigated over a three years' period. The River Egulya and Petrohan dam are situated in mountainous regions at about 1000 m altitude, and are not influenced by any anthropogenic sources. Petrohan dam is a site for long term ecosystem research as a part of Bulgarian long-term ecological research network. The other two systems belong to populated industrial areas. The River Martinovska flows through a region with former long-term mining activity, while Ogosta dam is near a battery production factory. Both the geochemical and geographical ecosystems' conditions are different, and their social usage as well. Ogosta dam water is used for irrigation and Petrohan dam for electric supply. The ecosystem sensitivity to heavy metals was evaluated by a critical load approach. Two criteria were used for risk assessment: critical load exceedance and microbial toxicity test. All studied ecosystems were more sensitive to cadmium than to lead deposition. The potential risk of Cd damage is higher for Petrohan dam and the River Egulya, where critical load exceedance was calculated for two years. Pseudomonas putida growth inhibition test detected a lack of toxicity for all studied ecosystems at the time of investigation with the exception of the low water September sample of the River Martinovska. The fast bacterial test is very suitable for a regular measurement of water toxicity because of its simplicity, lack of sophisticated equipment and clear results. PMID- 26019592 TI - A new approach to determine the capture conditions of bark beetles in pheromone baited traps. AB - Forests form an organic unity with a great number of organic and inorganic components and tend to maintain the sustainability of their existing balance. However, some factors which adversely affect the balance of nature may interrupt this sustainability. The epidemic which is formed by bark beetles in their spreading region, due to various factors, changes the stability so much that interference is required. One of the most common methods used to monitor these beetles is pheromone-baited traps. The recognition of parameters, such as date (day/month/year), temperature and humidity, when bark beetles are captured in pheromone-baited traps, especially those used for monitoring will help to increase the trap efficiency on land and to develop an effective strategy for combating pests. In this study, an electronic control unit was added to pheromone baited traps in order to obtain all of the above mentioned parameters. This unit operates with microcontrollers and data related to the parameters is saved in a storage unit. This is triggered by the beetle at the moment it is captured in the trap. A photovoltaic system was used to meet the energy needed for the system functioning and to complete the counting process in due time. PMID- 26019593 TI - Proteolytic and antimicrobial activity of lactic acid bacteria grown in goat milk. AB - We examined 62 strains and 21 trade starter cultures from the collection of LB Bulgaricum PLC for proteolytic and antimicrobial activity of lactic acid bacteria (LAB) grown in goat milk. The aim of this study was to investigate the fermentation of caseins, alpha-lactalbumin and beta-lactoglobulin by LAB, using the o-phthaldialdehyde (OPA) spectrophotometric assay and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The proteolysis targeted mainly caseins, especially beta-casein. Whey proteins were proteolyzed, essentially beta lactoglobulin. The proteolytic activity of Lactococcus lactis l598, Streptococcus thermophilus t3D1, Dt1, Lactobacillus lactis 1043 and L. delbrueckii subsp. bulgaricus b38, b122 and b24 was notably high. The proteolysis process gave rise to medium-sized peptide populations. Most of the examined strains showed antimicrobial activity against some food pathogens, such as Escherichia coli, Staphylococcus aureus, Salmonella cholere enteridis, Listeria monocytogenes, Listeria innocua and Enterobacter aerogenes. The most active producers of antimicrobial-active peptides were strains of L. delbrueckii subsp. bulgaricus and S. thermophilus, which are of practical importance. The starter cultures containing the examined species showed high proteolytic and antimicrobial activity in skimmed goat milk. The greatest antimicrobial activity of the cultures was detected against E. aerogenes. The obtained results demonstrated the significant proteolytic potential of the examined strains in goat milk and their potential for application in the production of dairy products from goat's milk. The present results could be considered as the first data on the proteolytic capacity of strains and starter cultures in goat milk for the purposes of trade interest of LB Bulgaricum PLC. PMID- 26019594 TI - In vitro characterization of the adhesive factors of selected probiotics to Caco 2 epithelium cell line. AB - The aim of the present study was to analyse the type of adhesive factors of selected probiotic strains. A large number of lactic acid bacteria with intestinal and dairy origin were collected and assessed for adhesion on Caco-2 cell line. From the best adherent bacteria, four strains were selected for further research: Lactobacillus gasseri G7, L. plantarum F1, L. helveticus AC and L. delbrueckii subsp. bulgaricus B14. The average number of adhered bacteria was 17 per one Caco-2 cell in the case of L. gasseri G7 and 21 per cell in the case of L. plantarum F1. Treatment with ethylenediaminetetraacetic acid (EDTA), trypsin and metaperiodic acid in separate assays revealed that cell-bonded extracellular proteins were responsible for the adhesion of the selected L. gasseri, L. plantarum and L. helveticus strains, in contrast to the L. delbrueckii subsp. bulgaricus strain, whose adhesive factors were identified as cell-bonded exopolysaccharides. The cell-wall proteins from the first three strains were isolated, fractionated and assessed for adhesion to Caco-2 cells. Based on the attachment properties of the purified proteins towards Caco-2 cells, it was clearly proved exactly which proteins are involved in the adherence. L. plantarum F1 strain contains two adhesive proteins in contrast to the other selected strains containing one adhesive protein each. The determination of the factors mediating the adhesive abilities of the selected strains provides important information about the possible ways to preserve and increase adhesive properties towards epithelium cells. PMID- 26019595 TI - Panton-Valentine leukocidin in community and hospital-acquired Staphylococcus aureus strains. AB - Staphylococcus aureus causes serious hospital-acquired (HA) and community acquired (CA) infections. Skin and soft-tissue infections especially are sometimes caused by strains harbouring Panton-Valentine leukocidin (PVL). PVL belongs to a family of bi-component leukocidal toxins produced by staphylococci. It is a pore-forming toxin encoded by lukF-PV and lukS-PV. A total of 70 S. aureus strains: 38 (54%) methicillin-resistant (MRSA) and 32 (46%) methicillin susceptible (MSSA), were isolated from patients admitted to Dicle University Hospital (Turkey). Identification of S. aureus and antibiotics-susceptibility testing were performed with PHOENIX 100. PVL genes and mecA genes were detected by polymerase chain reaction. Of the 70 studied strains, 36 ones (51%) were community acquired and 34 ones (49%) were hospital acquired . A total of 38 (54%) strains were positive for mecA (mecA+), of which 32 ones (84%) were HA. Of the mecA- strains, 30 (94%) were CA. Of the 70 studied strains, 12 (17%) strains were PVL+: 8 (22%) of the 36 CA strains and 4 (12%) of the 34 HA strains. Of the 12 PVL+ strains, 4 strains were mecA+. The PVL positivity rate was 25% in MSSA, whereas 10.5% in MRSA. Of the overall PVL+ strains, seven strains were obtained from wounds; four ones from skin abscess; and one from blood culture. Taken together, the obtained results showed a substantial level of PVL genes in the studied region. Although PVL is known as a common virulence factor of CA MRSA, HA MRSA isolates in our study showed a considerable rate of PVL positivity. PMID- 26019596 TI - Detection of Human parvovirus B19 (HPVB19) in serum samples from fever-rash ill individuals during the rubella outbreak (2005) in Bulgaria. AB - The present study aimed to determine the involvement of the parvovirus B19 (HPVB19) as an etiological agent in individuals with fever-rash infections but not infected with rubella during the rubella outbreak (2005) in Bulgaria. A total of 194 serum samples with negative results for measles and rubella-specific IgM antibodies were tested in the National Reference Laboratory. The individuals aged 5-52 years (mean age 17.2 +/- 10.15) were divided into four age groups: 5-14; 15 24; 25-34; and 35+ years old. Serological (indirect enzyme immunoassay - EIA) and molecular (extraction and detection of HPVB19-DNA) methods were used. A genotyping assay of the NS1-PCR product was proceeded with the MfeI restriction enzyme. Out of the total number of samples, 95 samples (48.97%) tested positive for HPVB19-IgM and 109 (56.18%) for HPVB19-DNA. The results from the genotyping assay revealed that genotype 1 (prototype B19) was dominant in 106 from 109 samples (97.25%), while genotype 3 (prototype V9) was detected in only 3 (2.75%). Subjects whose sera tested positive for IgM and had a positive PCR result formed a group that was most frequently linked (in 40% of cases) to acute infection. The highest prevalence was established in the group of the school-age children (5-14 years). The combined application of serological and molecular methods confirms the etiological role of HPVB19, and including virus genotyping, confirms the involvement of HPVB19 in the etiological palette of febrile rash diseases and provides a correct differential diagnostic approach. PMID- 26019597 TI - Association of single nucleotide polymorphism at position -308 of the tumor necrosis factor-alpha gene with ankylosing spondylitis and rheumatoid arthritis. AB - In this study, we analyzed the putative association between the -308 G/A polymorphism in the promoter region of the tumor necrosis factor (TNF) alpha gene (rs1800629) and chronic inflammatory arthritis in the Bulgarian population. A case-control study was carried out on 58 patients with ankylosing spondylitis (AS), 108 rheumatoid arthritis (RA) patients and 177 healthy subjects. -308 G/A TNF-alpha genotypes of patients and controls were determined by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). No significant association between the rs1800629 polymorphism and RA risk in the study cohort was observed. However, there were significant differences in the genotype and allele frequencies of the -308 G/A TNF-alpha polymorphism between AS patients and the healthy subjects. In logistic regression analysis, the presence of the TNF alpha -308A allele in the genotype (AA + AG vs. GG) was associated with a 3.298 times lower risk of developing AS. In addition, in AS, there were associations for age at disease onset (<29 years; odds ratio (OR) = 0.222), disease severity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score > 4; OR = 0.152) and response to anti-TNF treatment (OR = 2.25) under a dominant model (AA + AG vs. GG). In conclusion, our results suggested that the promoter polymorphism -308 G/A in the TNF-alpha gene had no significant effect on RA development, but could play a role in AS development and in determining the age of disease onset, disease severity and therapeutic outcome of AS in the Bulgarian patients who participated in our study. PMID- 26019598 TI - Endothelial nitric oxide synthase intron 4a/b polymorphism in coronary artery disease in Thrace region of Turkey. AB - Coronary artery disease (CAD) is one of the frequent cardiovascular mortality causes in the world. Common risk factors explain only about half the risk of CAD. The healthy familial predisposition to CAD, combined with advances in genetic analysis, has led to a number of studies in recent years making an effort to identify the genetic factors that influence the risk. The approach taken by most studies was to examine the association of naturally occurring genetic polymorphisms in candidate genes with risk of or severity of CAD. Endothelial nitric oxide synthase (eNOS) is important for vascular and tissue protection and is found in endothelial cells that encompass the entire vasculature, including the vessels in the heart. Nitric oxide (NO) is produced in a catabolic reaction in the endothelial cells, neurons, glia and macrophages by nitric oxide synthase (NOS) isoenzymes. eNOS is a subgroup of this family of enzymes that catalyses the production of nitric oxide (NO) from L-arginine and oxygen, which leads to vascular relaxation by activating the guanylate cyclase. This finally induces smooth muscle relaxation. The aim of this study was to investigate the allelic frequency and the genotypic distribution of the variable number of tandem repeat 27 (27 VNTR) gene polymorphism in intron 4 of the eNOS (eNOS 4a/b) gene in Thrace region, to compare CAD patients with appropriate healthy controls and to correlate the genetic findings with CAD subtypes. The study group included 281 (153 subjects with CAD and 128 controls) patients. The eNOS polymorphism was identified with a polymerase chain reaction. Genotypes were defined as aa, ab and bb according to the presence of a and b alleles. In this case-control study, we found that there was sensible correlation between eNOS gene intron 4a/b VNTR polymorphism and the risk of CAD in Thrace region of Turkey. However, there was no major difference for the genotype distribution and the allelic frequency among the CAD subtypes. Further studies on the interaction of such genes are needed to clarify the association between eNOS 4a/b polymorphism and CAD patients. PMID- 26019599 TI - Adjacent vessel sign and breast imaging reporting and data system are valuable for diagnosis of benign and malignant breast lesions. AB - The purpose of this study is to investigate whether an adjacent vessel sign (AVS) observed on the maximum intensity projections (MIPs) from the subtracted images can help distinguish between malignant and benign breast lesions and to test whether the combination of breast imaging reporting and data system (BI-RADS) category and AVS can increase the specificity and diagnostic accuracy of breast magnetic resonance imaging (MRI). The study included 63 histologically verified lesions which underwent dynamic breast MRI before biopsy. All magnetic resonance (MR) images were evaluated by two radiologists in consensus, who were unaware of the histopathological outcome. The MR images of all cases were analyzed according to BI-RADS-MRI assessment category. Levels of suspicion were reported as categories of I-V. The presence of vessels either entering the enhancing lesion or in contact with the lesion edge on MIP images was considered as the presence of AVS. Final analysis of 63 masses revealed 41 malignant lesions (65.1%) and 22 benign lesions (34.9%). Thirty seven out of 41 malignant lesions and 3 out of 22 benign lesions were associated with adjacent vessel, with highly significant difference between benign and malignant lesions (P < 0.001), especially for lesions smaller than 2.0 cm. The corresponding specificity, sensitivity and accuracy of contrast-enhanced 3.0-T breast were 86.4%, 82.9% and 84.1%, respectively. Based on BI-RADS-MRI category, the specificity, sensitivity and accuracy of breast MRI were 54.5%, 100% and 84.1%, respectively. After combining BI-RADS category and AVS, the specificity, sensitivity and accuracy of breast MRI were 90.9%, 82.9% and 85.7%, respectively. AVS can help differentiate malignant from benign breast lesions, especially for the lesions smaller than 2.0 cm. The combination of BI-RADS category and AVS can increase the specificity and the diagnostic accuracy of breast MRI. PMID- 26019600 TI - Denosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment. AB - Osteoporosis is a key health problem in postmenopausal women with high social and economic impact. Decreased bone mineral density (BMD) and deterioration of bone microarchitecture may occur also as a result of long-term glucocorticoid treatment (GCT) of autoimmune or inflammatory conditions. Denosumab specifically inhibits the binding of the receptor activator of nuclear factor-kappaB to its ligand, thus preventing osteoclast activation and bone resorption. The efficacy and safety of denosumab, administered subcutaneously as 60 mg, once every six months for 12 months, were evaluated in 60 patients with postmenopausal osteoporosis (PMO) divided into two groups. The GCT group included 30 patients receiving concomitant glucocorticoid therapy and the non-GCT group included 30 patients that did not receive GCT. In the non-GCT group, the 12-month treatment with denosumab resulted in BMD increase of 6.1% and 2.8% in lumbar spine and hip, respectively. T-score increased by 13.1% and 5.6% in both, the lumbar spine and hip. A slight rise in the Trabecular Bone Score (TBS) of 0.3% was observed. Bone pain was markedly reduced by 56.2%. In the GCT group, denosumab therapy increased BMD with 5.8% and 2.3% in lumbar spine and hip, respectively. T-score of lumbar spine and hip significantly increased by 14.0% and 4.4%, and the TBS rose by 5%. Bone pain was reduced by 53.6%. These data confirm the available knowledge on denosumab efficacy and safety in women with PMO and also provide new insights into its therapeutic potential in patients with osteoporosis related to a long term corticosteroid treatment. PMID- 26019602 TI - Risk factors for development of chronic periodontitis in Bulgarian patients (pilot research). AB - The aim of this work was to assess the risks and analyse the risk factors for development of chronic periodontitis in Bulgarian patients. The quality of life was investigated in a cohort of 228 patients with chronic periodontitis. Within the frame of this study, pilot research (a case-control study) was conducted among 80 patients (20 cases and 60 control patients without periodontitis) to evaluate the risk for development of chronic periodontitis. The minimum sample size of patients was determined based on power analysis for sample-size calculation. The mean age of participants in the control group was 31.33 +/- 9.38 years and in the case group, 33.00 +/- 11.52. Data were accumulated by clinical and sociological methods. Descriptive statistics and multi-factor logistic regression analysis (Backward Conditional procedure) were used. One-factor dispersion analysis showed that, of the 12 studied risk factors, the following variables were significant: stress, diabetes, presence of calculus, overlapping and misaligned teeth (P < 0.05). Multiple logistic regressions were applied to evaluate the association between the variables. Three predictors were selected in the final logistic regression equation: diabetes (B = 4.195; P = 0.001), crooked and overlapping teeth (B = 3.022; P = 0.010) and stress (B = 2.882; P = 0.014). The logistic risk assessment model for development of periodontitis has a predictive value of 93.80% (chi2 = 63.91; P = 0.000). Our results confirmed some proven risk factors for periodontal disease. In the studied population, diabetes was the single, most important predictor for development of periodontitis. PMID- 26019601 TI - Prognostic value of matrix metalloproteinases in oral squamous cell carcinoma. AB - The aim of this study was to investigate whether there is a correlation between the expressions of four matrix metalloproteinases (MMPs): MMP-2, MMP-7, MMP-9 and MMP-13, and the TNM (tumour-node-metastasis) stages of oral squamous cell carcinoma (OSCC); and to explore the implication of these MMPs in OSCC dissemination. Samples from 61 patients diagnosed with oropharyngeal tumour were studied by immunohistochemistry against MMP-2, MMP-7, MMP-9 and MMP-13. The assessment of immunoreactivity was semi-quantitative. The results showed that MMP 2 and MMP-9 had similar expression patterns in the tumour cells with no changes in the immunoreactivity during tumour progression. MMP-9 always had the highest expression, whereas that of MMP-2 was moderate. MMP-7 showed a significant decrease in expression levels during tumour evolution. MMP-13 had constant expression levels within stage T2 and T3, but showed a remarkable decline in immunoreactivity in stage T4. No significant differences in the MMPs immunoreactivity between tumour cells and stroma were observed. Although strong evidence for the application of MMPs as reliable predictive markers for node metastasis was not acquired, we believe that combining patients' MMPs expression intensity and clinical features may improve the diagnosis and prognosis. Strong evidence for the application of MMPs as reliable predictive markers for node metastasis was not acquired. Application of MMPs as prognostic indicators for the malignancy potential of OSCC might be considered in every case of tumour examination. We believe that combining patients' MMPs expression intensity and clinical features may improve the process of making diagnosis and prognosis. PMID- 26019603 TI - Synthesis and antioxidant activity of some 1-aryl/aralkyl piperazine derivatives with xanthine moiety at N4. AB - Piperazine nucleus is one of the most important heterocyclic systems exhibiting remarkable pharmacological activities. Thus, in the current study six new aryl/aralkyl substituted piperazine derivatives, containing methylxanthine moiety were synthesized and their structures were confirmed by IR and 1H NMR analysis. All compounds were in vitro screened for their activity as antioxidants using DPPH (2,2'-Diphenyl-1-picrylhydrazyl), ABTS (2,2'-azinobis-(3-ethylbenzo thiazine 6-sulfonic acid)) and FRAP (ferric reducing/antioxidant power) methods. The antioxidant activity of the studied compounds against lipid peroxidation was also measured. The highest antioxidant activity was demonstrated by compound 3c. It is obvious that the presence of a hydroxyl group in the structure is essential for the antioxidant properties and should be taken into consideration in further design of structures with potential antioxidant properties. PMID- 26019604 TI - Biological evaluation of new potential anticancer agent for tumour imaging and radiotherapy by two methods: 99mTc-radiolabelling and EPR spectroscopy. AB - Recently, a new class of in vitro and ex vivo radiotracers/radioprotectors, the nitroxyl-labelled agent 1-ethyl-1-nitroso-3-[4-(2,2,6,6-tetramethylpiperidine-1 oxyl)]-urea (SLENU), has been discovered. Our previous investigations demonstrated that SLENU is a low-molecular-weight stable free radical which is freely membrane permeable, easily crosses the blood brain barrier and exhibited in/ex vivo the lowest general toxicity and higher anticancer activity against some experimental tumour models. Further investigation was aimed to develop a 99mTc-labelled SLENU (97%) as a chelator and evaluate its labelling efficiency and potential use as a tumour seeking agent and for early diagnosis. Tissue biodistribution of 99mTc-SLENU was determined in normal mice at 1, 2 and 24 h (n = 4/time interval, route of administration i.v.). The distribution data were compared using male albino non-inbred mice and electron paramagnetic resonance investigation. The imaging characteristics of 99mTc-SLENU conjugate examined in BALB/c mice grafted with Ehrlich Ascitis tumour in the thigh of hind leg demonstrated major accumulation of the radiotracer in the organs and tumour. Planar images and auto-radiograms confirmed that the tumours could be visualized clearly with 99mTc-SLENU. Blood kinetic study of radio-conjugate showed a bi exponential pattern, as well as quick reduced duration in the blood circulation. This study establishes nitroxyls as a general class of new spin-labelled diagnostic markers that reduce the negative lateral effects of radiotherapy and drug damages, and are appropriate for tumour-localization. PMID- 26019605 TI - Health technology assessment in the Balkans: opportunities for a balanced drug assessment system. AB - Countries in the Balkan region use pharmaco-economic data for decisions about the inclusion of new pharmaceuticals into their positive drug lists, but no predefined frameworks are used and resources for health technology assessment (HTA) are limited. The goal of this analysis is to investigate into possible development directions for the HTA system in the region, and provide some practical recommendations for a sustainable model. For this purpose, the main factors currently influencing HTA in Balkan countries are briefly presented, and possible development strategies are compared. A resource-saving balanced assessment approach is proposed. It is aligned with available resources and capabilities, and helps access to new pharmaceuticals while ensuring the transparency of decision-making processes and the stability of the pharmaceutical budget. PMID- 26019606 TI - Effect of Ca-Al-Si-O common glass on dielectric properties of low-temperature co fired ceramic materials with different fillers. AB - High-density integration in single component used for mobile communication is highly demanded with the miniaturization trend in multi-functional light-weighted mobile communication devices. Embedding passive components into multi-layered ceramic chips is also increasingly needed for high integrity. The need for high strength materials to be used in handheld devices has also increased. To this end, many attempts to join different low-temperature co-fired ceramics (LTCC) materials with different dielectric constants have been made, but failed with de laminations or internal cracks mainly due to difference of thermal expansion coefficients. It is thought that this difference could be minimized with the use of common glass in different LTCC materials. In this study, several candidates of common glass were mixed with various fillers of LTCC to have various dielectric constants in the radio-frequency, and to minimize the mismatch in joining. Ca-Al Si-O glass was mixed with 1.3MgO-TiO2, cordierite and CaTiO3. Mixtures were tape cast and sintered to be compared with their micro-structures, dielectric properties and thermo-mechanical characteristics. When 1.3MgO-TiO2 with volumetric ratio of 30% was mixed with Ca-Al-Si-O glass, the measured dielectric constant was 7.9, the quality factor was 3708. With 45 volumetric percent of cordierite, the dielectric constant was 5 and the quality factor was 1052. PMID- 26019607 TI - Improvement of voice quality and prevention of deafness by a bone-conduction device. AB - In modern society, people are involuntarily being exposed to various noises in their everyday-life environments. The increasing use of mobile phones and other portable devices as a primary means of communication outside of homes makes the current noise condition even worse. During the exchange of information on these devices, the volume is usually set 15 dB higher than the surrounding noise in order for the sound to be perceived more clearly. Hence, the sum of noise on these devices is usually estimated to be around 110 dB. This level of noise can cause noise-induced hearing impairment or even hearing loss to users when continued for a long time. A bone-conduction system can be a possible solution to reducing the noise while enhancing the quality of voice signals in mobile phones. In this study, we suggest that the implementation of the bone-conduction feedback system in mobile phones will raise the ratio of signal to noise with about 17 dB, enhancing the quality of voice signals. PMID- 26019608 TI - Implementation of the remote measuring system for addiction patients in rehabilitation applying vital sensor. AB - Recently, with the rapid development of related ubiquitous industries, ubiquitous Zone (u-Zone) development is being promoted to build a ubiquitous environment within a specific area. From a health care system perspective, in particular, u Zone is expected to contribute to reducing cost and effort to manage patients' condition such as in-patients, addiction patients and mental patients. In contrast, the current health care system only targets specific persons or continues to expand the internal system of hospitals. As addiction patients are on the rise in terms of drug addiction, including alcohol and narcotics, behavioural addiction attributable to the exposure to games, gambling, Internet and mobile communications and shopping is also becoming a problem. That is why it is difficult to collect data for the daily addiction status, which causes difficulties in systematic management and accurate diagnosis. Therefore, this paper suggests a remote measuring system to collect continuous condition data, which monitors the addiction patients via the vital sign measuring sensor within u-Zone. That is, the system collects their condition information from the sensors measuring heart rate, body temperature and acceleration, based on which the specialists determine the patient's emotional state. These data are expected to become the basis of diagnosing and managing addiction patients. PMID- 26019609 TI - A spot-matching method using cumulative frequency matrix in 2D gel images. AB - A new method for spot matching in two-dimensional gel electrophoresis images using a cumulative frequency matrix is proposed. The method improves on the weak points of the previous method called 'spot matching by topological patterns of neighbour spots'. It accumulates the frequencies of neighbour spot pairs produced through the entire matching process and determines spot pairs one by one in order of higher frequency. Spot matching by frequencies of neighbour spot pairs shows a fairly better performance. However, it can give researchers a hint for whether the matching results can be trustworthy or not, which can save researchers a lot of effort for verification of the results. PMID- 26019610 TI - Clustering performance comparison using K-means and expectation maximization algorithms. AB - Clustering is an important means of data mining based on separating data categories by similar features. Unlike the classification algorithm, clustering belongs to the unsupervised type of algorithms. Two representatives of the clustering algorithms are the K-means and the expectation maximization (EM) algorithm. Linear regression analysis was extended to the category-type dependent variable, while logistic regression was achieved using a linear combination of independent variables. To predict the possibility of occurrence of an event, a statistical approach is used. However, the classification of all data by means of logistic regression analysis cannot guarantee the accuracy of the results. In this paper, the logistic regression analysis is applied to EM clusters and the K means clustering method for quality assessment of red wine, and a method is proposed for ensuring the accuracy of the classification results. PMID- 26019611 TI - A new posture-correcting system using a vector angle model for preventing forward head posture. AB - In modern society many people are afflicted with muscle pain in the neck and shoulders mainly caused by incorrect posture. The number of patients having neck pain is increasing as usage of digital devices becomes more frequent. If patients could be notified how inappropriate their postures are in real time, the number of patients could be lower. Unfortunately, there is no digitized standard way of diagnosis for forward head posture. This study applies a concept based on a vector related to two angles which are acquired from the neck and the head, so that a device can diagnose the posture by measuring and analysing the angles. To obtain the vector, integral calculations of displacement of the head are needed. As a result, with this device, patients' faulty posture can be easily detected. PMID- 26019612 TI - Possible effect of biotechnology on plant gene pools in Turkey. AB - The recent rapid developments in biotechnology have made great contributions to the study of plant gene pools. The application of in vitro methods in freeze storage and DNA protection techniques in fast production studies has made major advances. From that aspect, biotechnology is an indispensable means for the protection of plant gene pools, which includes the insurance of sustainable agriculture and development of species. Besides all the positive developments, one of the primary risks posed by the uncontrolled spreading of genetically modified organisms is the possibility for other non-target organisms to be negatively affected. Genes of plant origin should be given priority in this type of studies by taking into consideration such negative effects that may result in disruption of ecological balance and damage to plant genetic pools. Turkey, due to its ecological conditions and history, has a very important position in terms of plant gene pools. This richness ought to be protected without corrupting its natural quality and natural evolution process in order to provide the sources of species that will be required for future sustainable agricultural applications. Thus, attention should be paid to the use of biotechnological methods, which play an important role especially in the protection and use of local and original plant gene pools. PMID- 26019613 TI - Impacts of drought stress on soluble carbohydrates and respiratory enzymes in fruit body of Auricularia auricula. AB - In order to study the survival mechanisms to drought stress for fruit body of Auricularia auricula, soluble carbohydrates and respiratory enzymes were investigated. Fruit bodies were exposed to sunlight and were naturally dehydrated. Samples were taken at different levels of water loss (0%, 10%, 30%, 50% and 70%) to measure the content of soluble sugars and polysaccharides. The activities of phosphoglucose isomerase (PGI), combined glucose-6-phosphate dehydrogenase (G-6-PDH) and 6-phosphogluconate dehydrogenase (6-PGDH), and malate dehydrogenase (MDH), were also determined. The results showed that with the increase in water loss, soluble sugars and MDH activity declined, whereas the activities of G-6-PDH and 6-PGDH increased. Soluble polysaccharides content and PGI activity decreased with water loss up to 30% and increased afterwards. These results suggested that the pentose phosphate pathway (PPP), as demonstrated by activities of G-6-PDH and 6-PGDH, could be one of the mechanisms for survival during drought stress in the fruit body of A. auricula. Moreover, soluble polysaccharides may play a part in protecting the fruit body in further drought stress. PMID- 26019614 TI - Genetic diversity assessment of Vitis ficifolia Bge. populations from Henan province of China by SRAP markers. AB - Eighteen sequence-related amplified polymorphism (SRAP) primer combinations were used to assess the genetic diversity of 126 individuals from five different geographical populations of Vitis ficifolia Bge. The numbers of bands scored per primer combination ranged from 8 to 27, with an average of 18.6 bands. At the population level, the percentage of polymorphic bands (PPB), Nei's gene diversity index (H) and Shannon's information index (I) were the highest in the Shihe (Xinyang) population (77.31%, 0.1987, 0.2805) and the lowest in the Linzhou (Anyang) population (55.82%, 0.1112, 0.1727). At the species level, PPB, H and I were 80.56%, 0.2129 and 0.3075, respectively. The genetic differentiation coefficient (GST) was 0.2055 and the gene flow (Nm ) was 1.9328, indicating strong intra-population genetic differentiation. Based on the unweighted pair group method based arithmetic average clustering diagram, the five studied populations may be divided into three groups. The clustering results were almost in accordance with the populations' geographical distribution. PMID- 26019615 TI - Induction of resistance to potato virus Y strain NTN in potato plants through RNAi. AB - Potato viruses cause enormous economic loss in agriculture production. Potatoes can be infected by a number of different viruses that affect negatively the harvest and the tuber quality. Direct and effective drugs against plant virus diseases are still not available and control is only applied as agricultural measures and pesticides against virus vectors. Potato virus Y (PVY) is transmitted by aphids in non-persistent manner and on that account using insecticides to prevent spread of the infection is useless. Breeding of resistant plant cultivars proved to be not always a solution of the problem because of the fast evolution of the virus strains and the constantly growing group of recombinants. In this study, we have proposed a new way of controlling the virus by blocking replication and transmission through the plant by RNAi-based vaccination of potato seedlings with specific to viral HC-Pro gene siRNAs. Thus, PVY replication is decreased without altering the valuable qualities of the sensitive to the virus potato cultivars like Agria. PMID- 26019616 TI - Ex situ conservation of Ruscus aculeatus L. - ruscogenin biosynthesis, genome size stability and propagation traits of tissue-cultured clones. AB - Ruscus aculeatus L. is a perennial semi-shrub with distinctive leaf-like branches (cladodes). Rhizomes and roots contain steroidal saponins (ruscogenins) that are used in medicine and cosmetics for their anti-inflammatory, venotonic and antihaemorroidal activity. Problematic cultivation of the species causes in many countries unsustainable over-collection from the wild. Tissue culture propagation of R. aculeatus was carried out for conservation and propagation purposes. The impact of the clonal origin (genotype) on the ruscogenin biosynthesis, genome size stability and propagation traits and morpho-physiological response to long term cultivation in vitro was studied. Production of ruscogenins in fully developed regenerants was quantified by high-performance liquid chromatography (HPLC). Genome-size stability of the clones was assessed by flow cytometry. Slow growth and prolonged lag-phase were characteristic for the whole propagation cycle. Produced plantlets with well-defined organs were suitable for direct ex vitro planting. Genome DNA content of all clones was stable and comparable to native plants. Ruscogenin biosynthesis was clone-specific, presenting distinctive profiles of the cultures. Our results imply that clone origin and culture type might influence saponin biosynthesis in Ruscus. These traits should be considered in the ex situ conservation of the genetic diversity of this species and by production of planting material as well. PMID- 26019617 TI - Isolation and cDNA characteristics of MHC-DRA genes from gayal (Bos frontalis) and gaytle (Bos frontalis * Bos taurus). AB - The mammalian major histocompatibility complex (MHC) plays important roles in pathogen recognition and disease resistance. In the present study, the coding sequence and the 5'- and 3'-untranslated regions of MHC class II DR alpha chain (the DRA gene) from rare gayal and gaytle were cloned and analyzed to dissect structural and functional variations. The nucleotide and amino acid sequences for the DRA genes in gayal (Bofr-DRA) and gaytle (Bofr * BoLA-DRA) were almost identical to those for cattle and yak (99%). Compared to yak, two amino acids substitutions in the signal peptide (SP) domain for gayal were found within all Bos animals. Except for only one replacement in the amino acid within the alpha2 domain of the DRA protein in gayal, the additional residues were highly conserved across the species investigated. The 20 peptide-binding sites (PBS) of Bofr-DRA and Bofr * BoLA-DRA were essentially reserved in the alpha1 domain among all species investigated. The lesser degree of substitution in Bofr-DRA is concordant with the concept that the DRA gene is highly conserved among all mammals. The very high degree of conservativity of the DRA gene among ruminants, including gayal, suggests its recent evolutionary separation. PMID- 26019618 TI - Optimization of permeabilization process of yeast cells for catalase activity using response surface methodology. AB - Biotransformation processes accompanied by whole yeast cells as biocatalyst are a promising area of food industry. Among the chemical sanitizers currently used in food technology, hydrogen peroxide is a very effective microbicidal and bleaching agent. In this paper, permeabilization has been applied to Saccharomyces cerevisiae yeast cells aiming at increased intracellular catalase activity for decomposed H2O2. Ethanol, which is non-toxic, biodegradable and easily available, has been used as permeabilization factor. Response surface methodology (RSM) has been applied in determining the influence of different parameters on permeabilization process. The aim of the study was to find such values of the process parameters that would yield maximum activity of catalase during decomposition of hydrogen peroxide. The optimum operating conditions for permeabilization process obtained by RSM were as follows: 53% (v/v) of ethanol concentration, temperature of 14.8 degrees C and treatment time of 40 min. After permeabilization, the activity of catalase increased ca. 40 times and its maximum value equalled to 4711 U/g. PMID- 26019619 TI - Selected adjunct cultures remarkably increase the content of bioactive peptides in Bulgarian white brined cheese. AB - Some lactic acid bacteria strains in milk media are capable of releasing bioactive peptides. In this study, we evaluated the angiotensin-converting enzyme (ACE)inhibitory activity of 180 lactic acid bacteria and selected several Lactobacillus helveticus, L. delbrueckii subsp. bulgaricus and L. casei strains that demonstrated strong ACE-inhibitory activity. The aim was to carry out a molecular study on the bioactive peptides released by the strains with the best ACE-inhibitory properties and by the strains demonstrating a calcium-binding effect. To the best of our knowledge, this is the first study of bioactive peptides in Bulgarian white cheese. Peptides with the strongest ACE-inhibitory activity were purified and sequenced. The strains were assessed for production of peptides with calcium-binding properties. These peptides were isolated, purified and sequenced. Two strains releasing bioactive peptides with the strongest ACE inhibitory and calcium-binding activities were selected for development of cheese starters. The strain with the best ACE-inhibitory activity was L. helveticus A1, which releases the peptide Ala-Leu-Pro-Met as a main contributor to the ACE inhibition. The strain with the best calcium-binding activity was L. casei C3 releasing the peptide SpLSpSpSpE (fraction 15-20 of beta-casein) as a main contributor to calcium binding. After pilot production of cheeses with the developed starters, the ACE-inhibitory and calcium-binding effects were confirmed during the cheese ripening. The addition of the two selected adjunct cultures led to increased production of bioactive peptides in the cheese. In this way, it is possible to increase the functional properties of Bulgarian white brined cheese. PMID- 26019620 TI - Antimicrobial activity and antibiotic susceptibility of Lactobacillus and Bifidobacterium spp. intended for use as starter and probiotic cultures. AB - Antimicrobial activity and antibiotic susceptibility were tested for 23 Lactobacillus and three Bifidobacterium strains isolated from different ecological niches. Agar-well diffusion method was used to test the antagonistic effect (against Staphylococcus aureus, Escherichia coli, Bacillus cereus and Candida albicans) of acid and neutralized (pH 5.5) lyophilized concentrated supernatants (cell-free supernatant; CFS) and whey (cell-free whey fractions; CFW) from de Man-Rogosa-Sharpe/trypticase-phytone-yeast broth and skim milk. Acid CFS and CFW showed high acidification rate-dependent bacterial inhibition; five strains were active against C. albicans. Neutralized CFS/CFW assays showed six strains active against S. aureus (L. acidophilus L-1, L. brevis 1, L. fermentum 1, B. animalis subsp. lactis L-3), E. coli (L. bulgaricus 6) or B. cereus (L. plantarum 24-4V). Inhibition of two pathogens with neutralized CFS (L. bulgaricus 6, L. helveticus 3, L. plantarum 24-2L, L. fermentum 1)/CFW (L. plantarum 24-5D, L. plantarum 24-4V) was detected. Some strains maintained activity after pH neutralization, indicating presence of active substances. The antibiotics minimum inhibitory concentrations (MICs) were determined by the Epsilometer test method. All strains were susceptible to ampicillin, gentamicin, erythromycin and tetracycline. Four lactobacilli were resistant to one antibiotic (L. rhamnosus Lio 1 to streptomycin) or two antibiotics (L. acidophilus L-1 and L. brevis 1 to kanamycin and clindamycin; L. casei L-4 to clindamycin and chloramphenicol). Vancomycin MICs > 256 MUg/mL indicated intrinsic resistance for all heterofermentative lactobacilli. The antimicrobially active strains do not cause concerns about antibiotic resistance transfer and could be used as natural biopreservatives in food and therapeutic formulations. PMID- 26019621 TI - Nitroxidergic modulation of behavioural, cardiovascular and immune responses, and brain NADPH diaphorase activity upon morphine tolerance/dependence in rats. AB - Opioid and non-opioid effects of acute and chronic morphine administration on behaviour, cardiovascular responses, cell proliferation and apoptosis and nitric oxide synthase (NOS) activity were studied in rats. A novel score-point scale was introduced to quantify the signs of opioid withdrawal syndrome. NOS inhibitor L NAME (NG-nitro-L-arginine methyl ester) was applied to reveal the role of NOS/NO pathway in the modulation of morphine-induced in vivo and in vitro responses. The obtained data showed that chronic co-administration of L-NAME drastically attenuated naloxone-precipitated withdrawal syndrome and prevented the development of morphine tolerance to cardiovascular action of morphine. The apoptotic process was very much restricted by L-NAME supplementation of chronic morphine treatment, which resulted in few apoptotic cells, less low molecular weight genomic DNA and preservation of high molecular weight non-fragmented genomic DNA. The study provides new data for nitroxidergic modulation of opioid tolerance and dependence. PMID- 26019622 TI - Transepithelial resistance in human bestrophin-1 stably transfected Madin-Darby canine kidney cells. AB - Bestrophin-1 (Best1) is a transmembrane protein, found in the basolateral plasma membrane of retinal pigmented epithelial cells. The exact structure and functions of Best1 protein are still unclear. The protein is thought to be a regulator of ion channels, or an ion channel itself: it was shown to be permeable for chloride, thiocyanate, bicarbonate, glutamate and gamma-aminobutyric acid (GABA). Mutations in the gene for Best1 are leading to best vitelliform macular dystrophy (BVMD) and are found in several other types of maculopathy. In order to obtain additional information about Best1 protein, we determined cell polarization of a stably transfected Madin-Darby canine kidney cell line II (MDCK II) cell line, expressing human Best1. We measured the transepithelial resistance of transfected and non-transfected MDCK cells by voltmeter EVOM, over 10 days at 24 hour intervals. The first few days (first-fourth day) both cell lines showed the same or similar values of transmembrane resistance. As expected, on the fifth day the non-transfected cells showed maximum value of epithelial resistance, corresponding to the forming of monolayer. The transfected cells showed maximum value of transepithelial resistance on the ninth day of their cultivation. Phalloidin staining of actin demonstrated the difference in actin arrangements between transfected and non-transfected cells due to Best1. As a consequence of actin rearrangement, Best1 strongly affects the transepithelial resistance of polarizing stably transfected MDCK cells. Our results suggest that Best1 protein has an effect on transepithelial resistance and actin rearrangements of polarized stably transfected MDCK cells. PMID- 26019623 TI - Whole genome microarray analysis in non-small cell lung cancer. AB - Lung cancer is a serious health problem, since it is one of the leading causes for death worldwide. Molecular-cytogenetic studies could provide reliable data about genetic alterations which could be related to disease pathogenesis and be used for better prognosis and treatment strategies. We performed whole genome oligonucleotide microarray-based comparative genomic hybridization in 10 samples of non-small cell lung cancer. Trisomies were discovered for chromosomes 1, 13, 18 and 20. Chromosome arms 5p, 7p, 11q, 20q and Xq were affected by genetic gains, and 1p, 5q, 10q and 15q, by genetic losses. Microstructural (<5 Mbp) genomic aberrations were revealed: gains in regions 7p (containing the epidermal growth factor receptor gene) and 12p (containing KRAS) and losses in 3p26 and 4q34. Based on high amplitude of alterations and small overlapping regions, new potential oncogenes may be suggested: NBPF4 (1p13.3); ETV1, AGR3 and TSPAN13 (7p21.3-7p21.1); SOX5 and FGFR1OP2 (12p12.1-12p11.22); GPC6 (13q32.1). Significant genetic losses were assumed to contain potential tumour-suppressor genes: DPYD (1p21.3); CLDN22, CLDN24, ING2, CASP3, SORBS2 (4q34.2-q35.1); DEFB (8p23.1). Our results complement the picture of genomic characterization of non small cell lung cancer. PMID- 26019624 TI - Correlation between vascular endothelial growth factor levels and prognosis of hepatocellular carcinoma patients receiving radiofrequency ablation. AB - This study is aimed to investigate the effect of serum vascular endothelial growth factor (VEGF) levels on prognosis of hepatocellular carcinoma (HCC) patients receiving radiofrequency ablation (RFA). The 110 HCC patients who received computed tomography (CT) guided RFA were enrolled in this study. The levels of serum VEGF were determined before and after RFA by enzyme-linked immunosorbent assay (ELISA). According to the ELISA results, the patients were divided into the negative group and the positive group. The patient's progression free survival time was determined. It was demonstrated that the serum VEGF had no significant correlation with ages, sex and tumour size. There were no significant peripheral blood supplies around tumour necrosis. The results showed that higher levels of serum VEGF had a worse prognosis when compared to the patients with lower levels of serum VEGF. The difference between the area under the receiver operating characteristic curve and those when area under curves equalled 0.5 was statistically significant (P < 0.05). The serum VEGF level in liver cancer patients can be used as a prognostic indicator for evaluating the efficacy of RFA treatments. PMID- 26019625 TI - Tetramethylpyrazine inhibits CTGF and Smad2/3 expression and proliferation of hepatic stellate cells. AB - To study the effects of tetramethylpyrazine (TMP) on the proliferation of hepatic stellate cells-T6 (HSC-T6), and the expression of connective tissue growth factor (CTGF) and Smad2/3 in these cells, HSC-T6 cells were cultured with TMP at different concentrations after transforming growth factor-beta1 (TGF-beta1) stimulation. MTT assay was used to assess the cell proliferation. Cells were divided into the control group, TGF-beta1-treated group and TMP-treated groups, which were treated with different concentrations of TMP. Immunocytochemistry and western blot were performed to detect the expression levels of CTGF and Smad2/3 in HSC-T6 cells. MTT analysis indicated that TMP significantly inhibited the proliferation of HSC-T6 cells, in dose-dependent and time-dependent manners. Immunocytochemistry detection and western blot showed that TMP could diminish TGF beta1-induced CTGF over-expression in HSC-T6 cells. Similarly, the enhancing effects of TGF-beta1 on Smad2/3 expressions in HSC-T6 cells could also be counteracted by TMP treatment. Nuclear translocation of Smad2/3 was blocked by TMP treatment. Correlation analysis suggested a positive correlation between CTGF and Smad2/3 expression levels in HSC-T6 cells. TMP exerts anti-hepatic fibrosis effect through decreasing the expression of CTGF and Smad2/3, as well as inhibiting the proliferation of HSC-T6 cells. Our study provides cellular and molecular bases for further application of TMP in the clinical treatment for hepatic fibrosis. PMID- 26019626 TI - A polysaccharide from Dendrobium huoshanense prevents hepatic inflammatory response caused by carbon tetrachloride. AB - Dendrobium huoshanense is a precious herbal medicine in China, which exhibits a variety of restorative and therapeutic effects. This study aimed at investigating the hepatoprotective effects of a polysaccharide (DHP1A) isolated from D. huoshanense via water extraction, diethylaminoethyl (DEAE) cellulose anion exchange and size exclusion chromatography. The animal experiment indicated that the oral administration of DHP1A obviously reduced the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and 8-hydroxy 2'-deoxyguanosine in the serum of mice treated with carbon tetrachloride (CCl4), suggesting the hepatoprotective potential of this polysaccharide. Moreover, DHP1A decreased the expressions of tumor necrosis factor-alpha, interleukin-1beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, CD68 and phosphorylated IkappaBalpha (p-IkappaBalpha) in the CCl4-treated mice. These results revealed that the hepatoprotective effect of DHP1A was partly attributed to its anti-inflammatory action. PMID- 26019627 TI - Combination of Tripterygium wilfordii Hook F and angiotensin receptor blocker synergistically reduces excretion of urinary podocytes in patients with type 2 diabetic kidney disease. AB - The aim of this study was to investigate whether Tripterygium wilfordii Hook F (TwHF) and irbesartan could synergistically affect the urinary excretion of podocytes and proteins in type 2 diabetic kidney disease (DKD) patients and the underlying mechanisms. Forty DKD patients were divided into a DI group (DKD patients treated with irbesartan alone) and a DTI group (DKD patients treated with Tripterygium wilfordii Hook F and irbesartan). Urinary podocytes were observed by immunofluorescence. Urinary levels of connective tissue growth factor (CTGF) and transforming growth factor-beta1 (TGF-beta1) were detected by enzyme linked immunosorbent assay. Immunofluorescence indicated that shed podocytes were not detected in urine samples of normal controls, whereas the detection rate of urinary podocytes was 82.5% in DKD patients. Urinary CTGF and TGF-beta1 levels were significantly higher in urinary podocyte-positive DKD patients than in urinary podocyte-negative patients. Furthermore, urinary podocyte excretion was closely correlated with urinary protein excretion and urinary CTGF/TGF-beta1 levels. Treatments with TwHF and irbesartan significantly reduced the urinary excretion of proteins and podocytes, and decreased the urinary levels of CTGF and TGF-beta1. Our results suggest that urinary podocyte excretion might serve as a predictor for DKD progression. TwHF/irbesartan combination could reduce the urinary excretion of proteins and podocytes synergistically in DKD patients, which might result from the synergistic inhibition of CTGF and TGF-beta1 in urine. PMID- 26019628 TI - Cystathionine gamma-lyase of perivascular adipose tissue with reversed regulatory effect in diabetic rat artery. AB - The aim of this study is to reveal the regulatory role of cystathionine gamma lyase (CSE), the main source of hydrogen sulphide (H2S) in perivascular adipose tissue (PVAT), of diabetic rats. Diabetes was induced in male rats by a single intraperitoneal injection of streptozotocin. Animals with glucose levels above 20 mmol/L were determined as diabetic. The rat gracilis arteries (a. gracilis) were dissected with or without PVAT. In all in vitro experiments endothelium-denuded preparations were used for isometric contraction measurements. Increasing concentrations of 5-hydroxytryptamine (5-HT) from 10-10 to 10-5 mol/L were applied to induce gradual increase in force of contractions of circular artery segments. The relaxing effect of CSE was inhibited by DL-propargyl glycine (PGG). The presence of PVAT decreases the contractile response to 5-HT of a. gracilis from control rats. This response is reversed in contraction studies in the same rat artery from diabetic rats. DL-PPG (1 mmol/L) induced significant increase of the force of contraction in artery preparations with PVAT from control rats in the whole range of 5-HT. In contrast, PGG had a relaxing effect in high concentrations of 5-HT (10-6 and 10-5 mol/L) in diabetic rat arteries with PVAT. It is concluded that in skeletal muscle artery from diabetic rats, a mediator related to H2S is released from PVAT. This paracrine mediator increases the maximal force of contraction of endothelium-denuded preparations at higher concentrations of 5-HT. PMID- 26019629 TI - Rapid identification of Pseudomonas aeruginosa by pulsed-field gel electrophoresis. AB - Twenty clinical Pseudomonas aeruginosa isolates recovered from patients admitted to The General Hospital in Ismailia Governorate (Egypt) were examined in this study. We analysed P. aeruginosa ATCC 9027 (as a control strain) and 19 of the isolates after digestion with SpeI restriction endonuclease. After this we conducted a pulsed-field gel electrophoresis (PFGE) and typed the obtained 10 unique patterns, designated as A, A1, B, B1, C, C1, D, D1, E and F. We evaluated the genetic relatedness between all strains, based on >=87% band identity. As a result, the isolates were grouped in the 10 clusters as follows: patterns A, A1, B, B1, C contained two strains each and patterns C1, D, D1, E contained a single strain each; the five remaining strains were closely related (genomic pattern F). One isolate belonged to antibiotype 'b'. The genotype patterns of the P. aeruginosa ATCC 9027 control strain and isolate no. 11 were closely related and had two different antibiotypes 'd' and 'c', respectively. PMID- 26019630 TI - Delivery of size-controlled long-circulating polymersomes in solid tumours, visualized by quantum dots and optical imaging in vivo. AB - The present study was designed to investigate whether poly-ion complex hollow vesicles (polymersomes), based on chemically modified chitosan, are appropriate for passive tumour targeting in the context of their application as drug carriers. The experiments were performed on colon cancer-grafted mice. The mice were subjected to anaesthesia and injected intravenously with water-soluble nanoparticles: (1) QD705-labelled polymersomes (average size ~120 nm; size distribution ~10%) or (2) native QD705. The optical imaging was carried out on Maestro EX 2.10 In Vivo Imaging System (excitation filter 435-480 nm; emission filter 700 nm, longpass). In the case of QD705, the fluorescence appeared in the tumour area within 1 min after injection and disappeared completely within 60 min. A strong fluorescent signal was detected in the liver on the 30th minute. The visualization of tumour using QD705 was based only on angiogenesis. In the case of QD705-labelled polymersomes, the fluorescence appeared in the tumour area immediately after injection with excellent visualization of blood vessels in the whole body. A strong fluorescent signal was detected in the tumour area within 16 hours. This indicated that QD705-labelled polymersomes were delivered predominantly into the tumour due to their long circulation in the bloodstream and enhanced permeability and retention effect. A very weak fluorescent signal was found in the liver area. The data suggest that size-controlled long circulating polymersomes are very promising carriers for drug delivery in solid tumours, including delivery of small nanoparticles and contrast substances. PMID- 26019631 TI - Changes in the functional characteristics of tumor and normal cells after treatment with extracts of white dead-nettle. AB - Lamium album L. is a perennial herb widely used in folk medicine. It possesses a wide spectrum of therapeutic activities (anti-inflammatory, astringent, antiseptic, antibiotic, antispasmodic, antioxidant and anti-proliferative). Preservation of medicinal plant could be done by in vitro propagation to avoid depletion from their natural habitat. It is important to know whether extracts from L. album plants grown in vitro possess similar properties as extracts from plants grown in vivo. For these reasons, it is important to examine changes in the composition of secondary metabolites during in vitro cultivation of the plant and how they affect the biological activity. We used A549 human cancer cell line and normal kidney epithelial cells MDCKII (Madin-Darby canine kidney cells II) as controls in assessing the anti-cancer effect of plant extracts. To elucidate changes in some key functional characteristics, adhesion test, MTT (3-(4,5 dimethylthiazol-2-yl)-2-5-diphenyl tetrazolium bromide), transepithelial resistance (TER), immunofluorescence staining and trypan blue exclusion test were performed. Methanol and chloroform extracts of in vivo and in vitro propagated plants affected differently cancerous and non-cancerous cells. The most pronounced differences were observed in the morphological analysis and in the cell adhesive properties. We also detected suppressed epithelial transmembrane electrical resistance of MDCK II cells, by treatment with plant extracts, compared to non-treated MDCK II cells. A549 cells did not polarize under the same conditions. Altered organization of actin filaments in both cell types were noticed suggesting that extracts from L. album L. change TER and actin filaments, and somehow may block cell mechanisms, leading to the polarization of MDCK II cells. PMID- 26019632 TI - Biological evaluation of synthesized allicin and its transformation products obtained by microwaves in methanol: antioxidant activity and effect on cell growth. AB - Allicin is the most biologically active substance present in garlic. It can be synthesized or obtained by extraction of fresh garlic. Transformation products of allicin are also biologically active. The aim of this study was to examine the antioxidant activity of synthesized allicin and its transformation products obtained using microwaves in methanol at 55 degrees C as well as their effect on HeLa cells growth. The antioxidant activity was determined by DPPH (2,2-diphenyl 1-picrylhydrazyl radical) test. The effect on HeLa cells growth was determined by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) test. For MTT test, allicin and its transformation products were dispersed in carmellose sodium solution and examined in concentrations ranging from 0.3 MUg/mL to 3 mg/mL. Allicin showed stronger antioxidant activity than the transformation products. A maximum degree of neutralization of DPPH radicals, about 90%, was reached when the concentration of allicin was 2 mg/mL, with an EC50 (concentration of sample which is required for reduction of the initial concentration DPPH radicals to 50%) value of 0.37 mg/mL. In our study, allicin and its transformation products were not cytotoxic to HeLa cells under the examined conditions. The highest concentration of allicin and its transformation products had a slight antiproliferative effect, with a more pronounced effect of allicin, which reflected on the morphology of HeLa cells. The examined substances are safe to use on epithelial cells at concentrations up to 3 mg/mL when applied in carmellose sodium solution. Using carmellose sodium as a dispersing agent could be recommended as a good approach for testing liposoluble substances in liquid cell cultures. PMID- 26019633 TI - Time lag model for batch bioreactor simulation accounting the effect of micro organism mortality. AB - In the present work, a generalization of the classical model of Monod accounting the influence of both delayed and instant mortalities on the dynamics of the micro-organism population is proposed. The model was analysed and compared with respect to its quality and applicability for simulation of the cultivation process of micro-organisms. Existence of a unique global positive solution of the Cauchy problem for the proposed model is proved and explicit relations between the decay parameters and the nutrition substrate concentration are obtained. These mathematical results allow us to calculate the nutrient substrate concentration which guarantees that the biomass concentration is maximal for every specific type of taxonomic groups of micro-organisms (bacteria, yeasts). PMID- 26019634 TI - Assessment of food habits in children aged 6-12 years and the risk of caries. AB - Food is necessary for the proper growth and development of children. The excessive intake of low-molecular carbohydrates constitutes a serious health issue, which has an unfavourable impact on the dental health status. The aim of this study was to assess the food habits in healthy children aged 6-12 years and the effect on their oral risk profile. The study included 100 children. The assessment of their nutrition was done with the help of a seven-day reproduction of the food intake and a survey used to determine their underlying food habits and preferences. The results revealed unbalanced nutrition of the children and increased intake of simple sugar, which will increase the risk of development of dental caries. The observed high levels of DMFT (number of decayed, missing and filled teeth) in 54% of the children is a logical result of the frequent intake of sugary foods and beverages for a long period of time, as this will increase the acid production by microorganisms in dental plaque, which is one of the leading etiologic factors for the development of caries. It is necessary for dentists to administer control over the carbohydrate intake and the food habits of children, as well as to encourage non-cariogenic diet in order to keep their good oral health. PMID- 26019635 TI - An overview of technologies for immobilization of enzymes and surface analysis techniques for immobilized enzymes. AB - The current demands of sustainable green methodologies have increased the use of enzymatic technology in industrial processes. Employment of enzyme as biocatalysts offers the benefits of mild reaction conditions, biodegradability and catalytic efficiency. The harsh conditions of industrial processes, however, increase propensity of enzyme destabilization, shortening their industrial lifespan. Consequently, the technology of enzyme immobilization provides an effective means to circumvent these concerns by enhancing enzyme catalytic properties and also simplify downstream processing and improve operational stability. There are several techniques used to immobilize the enzymes onto supports which range from reversible physical adsorption and ionic linkages, to the irreversible stable covalent bonds. Such techniques produce immobilized enzymes of varying stability due to changes in the surface microenvironment and degree of multipoint attachment. Hence, it is mandatory to obtain information about the structure of the enzyme protein following interaction with the support surface as well as interactions of the enzymes with other proteins. Characterization technologies at the nanoscale level to study enzymes immobilized on surfaces are crucial to obtain valuable qualitative and quantitative information, including morphological visualization of the immobilized enzymes. These technologies are pertinent to assess efficacy of an immobilization technique and development of future enzyme immobilization strategies. PMID- 26019636 TI - Myconanoparticles: synthesis and their role in phytopathogens management. AB - Nanotechnology can offer green and eco-friendly alternatives for plant disease management. Apart from being eco-friendly, fungi are used as bio-manufacturing units, which will provide an added benefit in being easy to use, as compared to other microbes. The non-pathogenic nature of some fungal species in combination with the simplicity of production and handling will improve the mass production of silver nanoparticles. Recently, a diverse range of fungi have been screened for their ability to create silver nanoparticles. Mycosynthesis of gold, silver, gold-silver alloy, selenium, tellurium, platinum, palladium, silica, titania, zirconia, quantum dots, usnic acid, magnetite, cadmium telluride and uraninite nanoparticles has also been reported by various researchers. Nanotechnological application in plant pathology is still in the early stages. For example, nanofungicides, nanopesticides and nanoherbicides are being used extensively in agriculture practices. Remote activation and monitoring of intelligent nano delivery systems can assist agricultural growers of the future to minimize fungicides and pesticides use. Nanoparticle-mediated gene transfer would be useful for improvement of crops resistant to pathogens and pest. This review critically assesses the role of fungi in the synthesis of nanoparticles, the mechanism involved in the synthesis, the effect of different factors on the reduction of metal ions in developing low-cost techniques for the synthesis and recovery of nanoparticles. Moreover, the application of nanoparticles in plant disease control, antimicrobial mechanisms, and nanotoxicity on plant ecosystem and soil microbial communities has also been discussed in detail. PMID- 26019637 TI - Marker-assisted backcrossing: a useful method for rice improvement. AB - The world's population is increasing very rapidly, reducing the cultivable land of rice, decreasing table water, emerging new diseases and pests, and the climate changes are major issues that must be addressed to researchers to develop sustainable crop varieties with resistance to biotic and abiotic stresses. However, recent scientific discoveries and advances particularly in genetics, genomics and crop physiology have opened up new opportunities to reduce the impact of these stresses which would have been difficult if not impossible as recently as the turn of the century. Marker assisted backcrossing (MABC) is one of the most promising approaches is the use of molecular markers to identify and select genes controlling resistance to those factors. Regarding this, MABC can contribute to develop resistant or high-yielding or quality rice varieties by incorporating a gene of interest into an elite variety which is already well adapted by the farmers. MABC is newly developed efficient tool by which using large population sizes (400 or more plants) for the backcross F1 generations, it is possible to recover the recurrent parent genotype using only two or three backcrosses. So far, many high yielding, biotic and abiotic stresses tolerance, quality and fragrance rice varieties have been developed in rice growing countries through MABC within the shortest timeframe. Nowadays, MABC is being used widely in plant breeding programmes to develop new variety/lines especially in rice. This paper reviews recent literature on some examples of variety/ line development using MABC strategy. PMID- 26019638 TI - Molecular cloning, sequence characterization and expression pattern of Rab18 gene from watermelon (Citrullus lanatus). AB - The complete mRNA sequence of watermelon Rab18 gene was amplified through the rapid amplification of cDNA ends (RACE) method. The full-length mRNA was 1010 bp containing a 645 bp open reading frame, which encodes a protein of 214 amino acids. Sequence analysis revealed that watermelon Rab18 protein shares high homology with the Rab18 of cucumber (99%), muskmelon (98%), Morus notabilis (90%), tomato (89%), wine grape (89%) and potato (88%). Phylogenetic analysis revealed that watermelon Rab18 gene has a closer genetic relationship with Rab18 gene of cucumber and muskmelon. Tissue expression profile analysis indicated that watermelon Rab18 gene was highly expressed in root, stem and leaf, moderately expressed in flower and weakly expressed in fruit. PMID- 26019639 TI - Frequent problems and their resolutions by using thermal asymmetric interlaced PCR (TAIL-PCR) to clone genes in Arabidopsis T-DNA tagged mutants. AB - T-DNA insertional mutagenesis is a powerful tool in Arabidopsis functional genomics research. Previous studies have developed thermal asymmetric interlaced polymerase chain reaction (TAIL-PCR) as an efficient strategy in isolation of DNA sequences adjacent to known sequences in T-DNA tagged mutants. However, a number of problems are encountered when attempts are made to clone flanking sequences in T-DNA tagged mutants. Therefore, it is necessary to improve the efficiency of cloning mutagenesis. Here, we present the most frequent problems and provide an improved method to increase TAIL-PCR efficiency. Even then, it is not always possible to successfully obtain flanking sequences; in such cases, we recommend using high-throughput sequencing to determine the mutations. PMID- 26019640 TI - Geneticin (G418) resistance and electroporation-mediated transformation of Fusarium graminearum and F. culmorum. AB - Fusarium graminearum and F. culmorum are phytopathogenic species causing scab and root rot diseases in all small grain cereals worldwide including Turkey. In this study, resistance levels to geneticin (G418) of 14 F. graminearum and 24 F. culmorum isolates collected from cereals were determined. Fungal cultures were grown on potato dextrose agar medium supplemented with 0, 25, 50, 75 and 100 ug/mL of G418. Minimum inhibitory concentration was determined as 25 ug/mL. As a result, it was concluded that all isolates were highly sensitive to G418. Plasmid pFA6-kanmx4 containing geneticin resistance gene (kanmx) was introduced singly or co-electroporated with pEGFP75 plasmid, containing GFP gene, into fungal protoplast cultures obtained with lytic enzyme. Transformants were grown in media including 25 ug/mL G418. Transformation frequencies were 2.8 and 1.8 transformant per ug plasmid for F. graminearum and F. culmorum isolates, respectively. Transformation process was also confirmed by spectrofluorimetric assay. Relative fluorescence unit values in co-transformants were calculated as 1.87 +/- 0.04 for F. graminearum and 2.26 +/- 0.08 for F. culmorum. The results obtained from the study gave information about antibiotic resistance levels of two Fusarium species in Turkey. Moreover, it was shown that pFA6-kanmx4 plasmid was a suitable vector, which can be used in genetic manipulation studies of these two fungal species in particular suppression of endogenous and/or the expression of exogenous genes. PMID- 26019641 TI - Antibiotic resistance of Gram-negative benthic bacteria isolated from the sediments of Kardzhali Dam (Bulgaria). AB - The aim of the present study was to carry out a preliminary assessment for the occurrence of bacterial strains resistant to frequently used antibiotics in the sediments beneath the sturgeon cage farm in Kardzhali Dam (Bulgaria). Samples were taken from the top 2 cm of sediments under a fish farm and from a control station in the aquatory of the reservoir in the period July-October 2011. Surveillance of bacterial susceptibility to 16 antimicrobial agents was performed for 160 Gram-negative strains (Pseudomonas mandelii - 100 strains; Hafnia alvei - 30 strains; and Raoultella ornithinolytica - 30 strains). No significant differences in the resistance to the tested antibiotics were observed between the strains isolated from the two stations (analysis of variance, P > 0.05). Widespread resistance to penicillins and certain cephalosporin antibiotics was observed in both stations. None of the studied strains showed resistance to the aminoglycoside antibiotics gentamicin and amikacin, or to ciprofloxacin. Minimal Inhibitory Concentrations (MIC) were determined for five of the tested antimicrobial agents by the microdilution antibiotic sensitivity assay. The data indicate that amikacin, tetracycline and ciprofloxacin effectively suppress the growth of the tested micro-organisms. The isolates from genus Pseudomonas showed the highest MIC and were characterized by the highest percentage of antibiotic resistance. PMID- 26019642 TI - Screening for antibacterial activity of some Turkish plants against fish pathogens: a possible alternative in the treatment of bacterial infections. AB - The antibacterial activity of ethanolic and aqueous crude extracts from 36 plants in Turkey, including seven endemic species, against fish pathogens was studied using the disc diffusion assay. The extract that was most active against all microbial strains, except Aeromonas salmonicida, was that of Dorycnium pentaphyllum. Some of the extracts also showed a very broad spectrum of potent antimicrobial activity. The extract of Anemone nemorosa showed the highest antimicrobial activity against Vibrio anguillarum. V. anguillarum, a Gram negative bacterium, appeared to be the most susceptible to the plant extracts used in this experiment. To the best of our knowledge, this is the first report on the antimicrobial activity of 11 of the studied plants. The preliminary screening assay indicated that some of the Turkish plants with antibacterial properties may offer alternative therapeutic agents against bacterial infections in aquaculture industry. PMID- 26019643 TI - The effects of composite photosynthetic bacterial inoculant PS21 on the biochemical characteristics of wheat seedlings under tetrabromobisphenol A stress. AB - The aim of this study was to investigate whether the composite photosynthetic bacterial inoculant PS21 alleviate the damage inflicted on wheat seedlings by tetrabromobisphenol A (TBBPA). The biochemical characteristics of wheat seedlings were analysed through laboratory simulation after co-treating seedlings with PS21 and 0, 5, 10, 20, 40, 80 and 100 mg kg-1 TBBPA, respectively. The results showed that TBBPA reduced the total chlorophyll content and increased the malondialdehyde (MDA) content. TBBPA increased the soluble sugar content, soluble protein content and activate superoxide dismutase (SOD; EC: 1.15.1.1), catalase (CAT; EC: 1.11.1.6) and peroxidase (POD; EC: 1.11.1.7) at low concentrations, while it reduced soluble sugar content, soluble protein content and decreased the activities of SOD, CAT and POD at high concentrations. At the concentration of 107 CFU mL-1, PS21 could markedly relieve the toxicity of different concentrations of TBBPA on wheat seedlings. Wheat seedlings treated with both TBBPA and PS21 showed a higher soluble sugar content, higher soluble protein content, higher SOD, CAT and POD activities, and a lower MDA content as compared to those treated only with TBBPA. The composite photosynthetic bacterial inoculant PS21 significantly alleviates the damage inflicted on wheat seedlings by TBBPA. PMID- 26019644 TI - Light-emitting diodes and their potential in callus growth, plantlet development and saponin accumulation during somatic embryogenesis of Panax vietnamensis Ha et Grushv. AB - In recent years, LED (light-emitting diode) has been the subject of research within the field of plant growth and development. However, there has been little discussion about using LED in vitro cultures of Panax vietnamensis, one of the important medicinal plants belonging to the Panax genus. This study examines the influence of various LED lamps on callus growth and plant formation of P. vietnamensis. Results show significant differences in growth and development, as various light conditions were suitable for different stages. Callus of 70 mg in fresh weight cultured under yellow LEDs resulted in growth of 1197 mg in fresh weight and 91.7 mg of dry weight, within a period of three months. The most effective plant formation was obtained when embryogenic calli were cultured under the combination of 60% red LED and 40% blue LED with an average of 11.21 plantlets per explant; the shoot clump fresh weight and dry weight were of 1147 and 127 mg, respectively, and the average plant height was 3.1 cm. It was also shown that this light condition was the most efficient for P. vietnamensis in vitro plant growth and development. This study provided additional evidence regarding the influence of different LEDs on ginsenoside production applying high performance liquid chromatography (HPLC) analysis with photo-diode array (PDA) detection at ultraviolet (UV) wavelength 203 nm. The highest MR2 content was recorded when plants maintained under 20% red LED combined with 80% blue LED. However, the highest Rg1 and Rb1 content was found under fluorescent light. The results presented might provide new strategies using LEDs for adequate micropropagation protocols of P. vietnamensis. PMID- 26019645 TI - Assessment of genetic characteristics of Aconitum germplasms in Xinjiang Province (China) by RAPD and ISSR markers. AB - Aconitum is a medicinal treasure trove that grows extensively on fertile pastures in Xinjiang Province (China); however, its molecular genetic characteristics are still poorly studied. We studied Aconitum kusnezoffii Reichb., Aconitum soongaricum Stapf., Aconitum carmichaelii Debx. and Aconitum leucostomum Worosch, using random amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR) techniques, to evaluate their genetic relationship and potential medicinal value. Our results showed that A.kusnezoffii Reichb. and A.soongaricum Stapf. have close genetic relationship and cluster together. Polymorphism rates of 97.25% and 98.92% were achieved by using 15 RAPD and 15 ISSR primers, respectively. Based on Nei's gene diversity (H) and Shannon's index (I), the inter-population diversity (Hs ) was higher when compared with the intra population diversity (Hp ). Among the three Aconitum populations, the coefficient of gene differentiation (Gst ) was 0.4358 when evaluated by RAPD and 0.5005 by ISSR. The genetic differentiation among the three Aconitum populations was highly significant, suggesting low gene flow (Nm ). This was confirmed by the estimates of gene flow (Nm = 0.6473 and Nm = 0.4991, based on ISSR and RAPD data, respectively). Comparing the RAPD and ISSR results, the two DNA markers proved similarly effective in the assessment of the genetic characteristics of the studied Aconitum populations and could be used for reliable fingerprinting and mapping in studies on Aconitum diversity in view of Aconitum suitability for development and protection. PMID- 26019646 TI - Optimization and purification of mannanase produced by an alkaliphilic thermotolerant Bacillus cereus N1 isolated from Bani Salama Lake in Wadi El Natron. AB - An alkaliphilic-thermotolerant Bacillus cereus N1 isolated from Bani Salama Lake, Wadi El-Natron, Egypt, was proved to produce mannanase enzyme. Optimization of the fermentation medium components using Plackett-Burman design was applied. Glucose and inoculum size were found to be the most significant factors enhancing the production of the enzyme. On applying optimized medium in the fermentation process, an enzyme productivity of 42.2 UmL-1 was achieved with 6.4 fold increase compared to the basal one. Mannanase was also extracted and purified using chromatography such as ion-exchange chromatographic and gel filtration methods. It was indicated that, the mannanase activity extracted and purified from the isolate B. cereus N1 was reduced to 321.6 U (about 36% of the whole mannanase in the culture filtrate) in comparison with the initial mannanase activity (900 U) and the total protein content reduced to 52 mg (the initial total protein content was 220 mg). However, the specific activity for the mannanase from B. cereus N1 at the end of the purification steps was found to be about 628 Umg-1 compared to 4.2 Umg-1 at the initial culture filtrate. It was also indicated that the mannanase enzyme was purified almost 149-fold. PMID- 26019647 TI - Toxigenic profiles and trinucleotide repeat diversity of Fusarium species isolated from banana fruits. AB - Infesting Fusarium species isolated from banana fruit samples were identified and quantified by morphological, mycotoxicological and molecular tools. A total of 19 Fusarium isolates were obtained: F. semitectum was most predominant (26%), followed by F. proliferatum (16%), F. circinatum (16%), F. chlamydosporum (10.5%), F. solani (10.5%), F. oxysporum (10.5%) and F. thapsinum (5%). Fumonisin B1, deoxynivalenol and zearalenone contents were assayed by high-performance liquid chromatography (HPLC). Seventeen isolates, belonging to F. chlamydosporum, F. circinatum, F. semitectum, F. solani, F. thapsinum, F. proliferatum and Fusarium spp., produced mycotoxins when cultured on rice medium. Fumonisin was produced by all of the studied Fusarium isolates, except F. oxysporum, at a concentration of over 1 MUg/mL. F. citrinium isolates 4 and 5 and F. solani isolate 3 were the most potent producers of deoxynivalenol. We compared the 19 Fusarium isolates based on the bands amplified by 10 microsatellite primers. Of these, seven primers, (TCC)5, (TGG)5, (GTA)5, (ATG)5, (TAC)5, (TGC)5 and (TGT)5, yielded a high number of bands and different mean number of alleles. The similarity level between isolates was calculated using a simple matching coefficient. Dendrograms were constructed by the unweighted pair-group method with arithmetical averages (UPGMA). Two main clusters were observed. The interspecific genetic similarity between Fusarium spp. isolates was between 40% and 58% and the intraspecific similarity from 58% to 100%, indicating a high degree of genetic diversity in the tested isolates. Some unexpected genetic similarities were observed among the isolates, indicating non-agreement between morphological and molecular identification of the isolates. PMID- 26019648 TI - Relationship between vitamin D status and immunosuppressive therapy in kidney transplant recipients. AB - There is a growing body of evidence for the protective role of vitamin D in diabetes mellitus (DM), infection, cancer, cardiovascular disease, immune disorders and kidney function. Considering the reported high prevalence of vitamin D insufficiency among kidney transplant recipients (KTRs), the aim of this study was to assess the influence of immunosuppressive therapy and other factors on vitamin D status in such patients. The study included 289 KTRs (189 males and 100 females) who consented to participate. The first test for 25 hydrohyvitamin D [25(OH)D] was performed by a validated liquid chromatography tandem mass spectrometry method. Influence of immunosuppressive drugs and previously reported predictors on vitamin D status was assessed by descriptive statistics, univariate and multivariate regression. Our results showed that only 53 patients (18.34%) of the studied KTRs were vitamin D sufficient. In addition to a well expected positive association between serum 25(OH)D and summer blood sampling (p < 0.05) and inverse relationship between vitamin D status and DM, gender (female) and body mass index, serum 25(OH)D was found to be inversely associated with calcineurin inhibitors (CNI) (p < 0.05) and unaffected by other immunosuppressive agents. Our study demonstrated high prevalence of vitamin D insufficiency after kidney transplantation in the studied cohort of patients. Apart from female gender, winter months, DM and overweight, the use of CNI could be considered an additional significant predictor of lower 25(OH)D in Bulgarian KTRs. PMID- 26019649 TI - Effect of BMP-6 on development and maturation of mouse preantral follicles in vitro. AB - The aim of this study was to investigate the effect and mechanism of bone morphogenetic protein-6 (BMP-6) on the growth and maturation of mouse follicles in vitro. Preantral follicles isolated from mice were incubated with recombinant human BMP-6 (rhBMP-6) before analysis. BMP-6 expression was detected by immunofluorescence and western blot. Maturation of oocytes was observed microscopically. Estradiol (E2) and progesterone (P4) levels were measured by enzyme-linked immunosorbent assay. Expression of steroidogenesis-related genes was detected by reverse transcription quantitative polymerase chain reaction. There was a marked increase in the preantral follicles maturation in cells incubated with 50 ng/mL of rhBMP-6 for eight days, compared with the control. The levels of E2, P4 and steroidogenesis-related genes were also significantly increased in granulosa cells and theca cells cultured for 6, 10 and 11 days, respectively. Conversely, the preantral follicle maturing rate was remarkably decreased in cells incubated with 50 ng/mL of rhBMP-6 for day 11, accompanied with reduction in E2, P4 levels and steroidogenesis-related genes levels. Meanwhile, compared with the control, the maturing rate was not significantly different in cells incubated with 100 ng/mL of rhBMP-6 for day 8 or day 11. However, the E2 levels and its relevant regulation gene expression all increased significantly, while the P4 content and its relevant regulation gene expression decreased. The results indicate that BMP-6 can promote the maturation of preantral follicles in vitro in a concentration and time-dependent manner and may play a role in the regulation of steroid hormone synthesis and/or secretion. PMID- 26019650 TI - Severe pre-eclampsia complicated by HELLP syndrome alterations in the structure of the umbilical cord (morphometric and immunohistochemical study). AB - The aim of this study was to evaluate the morphometric and immunohistochemistry in umbilical cords from patients with severe pre-eclampsia with and without haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. The patient and control groups were similar according to baseline obstetric characteristics. White blood cell count in patients with HELLP syndrome and the control group was significantly increased among patients with HELLP syndrome (p < 0.001). Morphometric examination and endothelial core length were significantly different between the groups. In the umbilical cord cross-section of the HELLP group, endothelial cell degeneration in the vessel wall and basement membrane thickening were observed. In the muscle layer of blood vessels, the following disorders were found: increased collagen fibres in the muscle cell, hyperplasia and separation of muscle fibres as well as edema in the intermediate connective tissue. Immunohistochemical analysis showed that endothelial cells, basal membrane and fibroblast cells in the HELLP group expressed high levels of CD44. Vessel wall and amniotic epithelial basement membrane thickening were observed in the HELLP group. Matrix metalloproteinase 9 (MMP9) was expressed. Fibroblast and smooth muscle cells were fusiform and showed a positive reaction to immunohistochemical staining of alpha-actin smooth muscle. PMID- 26019651 TI - Frequency of the common promoter polymorphism MMP2 -1306 C>T in a population from central Bulgaria. AB - Matrix metalloproteinases (MMPs) are a family of highly homologous extracellular Zn2+-dependent endopeptidases, also known as matrixins. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are considered to play a key role in a variety of physiological processes as well as in the development and progression of a vast majority of pathological conditions. Most of the genes encoding MMPs, including MMP-2, are highly polymorphic. One of the single nucleotide polymorphisms with functional activity in the promoter region of MMP2 is the transition MMP2 1306C>T (rs243865). The aim of the present study was to evaluate the genotype and allele frequencies of the common promoter polymorphism -1306C>T in MMP2 in 75 individuals from central Bulgaria and to compare our results with those of other population studies. We found that 76.0% of the randomly enrolled individuals are carriers of the CC genotype, 17.3% of CT, and 6.7% of the TT genotype. The minor allele frequency (MAF) was 15.3%. Interestingly, the obtained genotype frequencies appeared to differ from those of some other Caucasian populations (USA - 55/38/7, MAF 26%; The Netherlands - 52.8/40.5/6.7, MAF 26.9%; Austria - 55.6/35.5/8.9, MAF 27.2%), but were closer to the values of the reported global genotype distribution (75.3/21.3/3.4, MAF 14%). PMID- 26019652 TI - Distribution patterns of carbohydrates in murine glycocalyx. AB - Enterocytes are unique cells governing an array of processes. They are covered by the gut glycocalyx, which is an extraneous carbohydrate-rich coat and an integral part of the plasma membrane. The intestinal glycocalyx and secreted mucins constitute a glycosylated milieu which has a number of physiological and protective functions. One of the important functions of the glycocalyx is its barrier function against microbial adherence to different membrane glycolipids. Thus, the glycocalyx is an important part of the mucosal immune system in newborns. The aim of our study was to identify the carbohydrates in the small bowel glycocalyx of Balb/c mice at different ages. We used plant lectins with different sugar specificities. Fluorescein-labelled lectins binding different carbohydrate moieties were detected using confocal laser scanning microscopy. Biotinilated lectins were used for transmission electron microscopy observations of the constituents of the gut glycocalyx at different periods of postnatal development in mice. Different carbohydrate moieties that were identified in the murine intestinal glycocalyx followed different distribution patterns and characteristics. Carbohydrates present on the mucus surface depended on tissue localization, cell type and stage of development. The distribution and mucins glycosylation could be of interest in analysing the response of the mucosal barrier to intestinal pathogens causing infection or inflammation. PMID- 26019653 TI - Resin cementation of zirconia ceramics with different bonding agents. AB - The aim of this study was to evaluate the effects of sandblasting and different chemical bonding agents on shear bond strength of zirconia and conventional resin cement. In this study, 35 zirconia specimens were treated as follows: Group I: control; Group II: sandblasting; Group III: sandblasting + Monobond S; Group IV: sandblasting + Monobond Plus; Group V: sandblasting + Z-Prime Plus. The specimens in each group were bonded with conventional composite resin cement Variolink II. After cementation, specimens were stored in distilled water (at 37 degrees C) for 24 h and shear test was performed. The highest shear bond strength values were observed in Groups IV and V. The lowest shear bond strength values were observed in Group I. Using 10-methacryloyloxy-decyl dihydrogenphosphate monomer containing priming agents, e.g. Monobond Plus and Z-PRIME Plus, combined with sandblasting can be an effective method for resin bonding of zirconia restorations. PMID- 26019654 TI - Evaluation of dentinal defect formation after root canal preparation with two reciprocating systems and hand instruments: an in vitro study. AB - The purpose of this study was to evaluate the presence of dentinal defects after root canal preparation with hand instruments and two different reciprocating instruments. Sixty freshly extracted mandibular incisor teeth were selected for this in vitro study. On the basis of root length, mesiodistal and buccolingual dimensions, the teeth were allocated into three identical experimental groups (n = 15) and one control group (n = 15). The teeth in the control group were left unprepared. The other groups were: stainless steel hand instruments, WaveOne(r) Primary instruments and RECIPROC(r) R25 instruments. The reciprocating instruments were used with a reciprocating gentle in-and-out motion in a torque limited electric motor at the appropriate preset mode. Horizontal sections were made 3, 6 and 9 mm from the apex. Samples were stained with methylene blue and viewed through a stereomicroscope. The presence of dentinal defects (fractures, incomplete cracks and craze lines) and their locations were investigated by two endodontists. These data were analysed statistically by Fisher's exact and chi square tests. No defects were observed in the unprepared group. All instruments caused dentinal defects, with no significant differences between the instrument systems. All experimental groups demonstrated significantly more defects at the 3 mm level in comparison with the unprepared group (p = 0.032). At the other levels, there was no significant difference between the experimental groups and the control group. The use of hand or reciprocating instruments could induce the formation of dentinal defects during root canal preparation. PMID- 26019655 TI - Optimization of carbon source and glucose feeding strategy for improvement of L isoleucine production by Escherichia coli. AB - Fed-batch cultivations of L-isoleucine-producing Escherichia coli TRFP (SGr, alpha-ABAr, with a pTHR101 plasmid containing a thr operon and ilvA) were carried out on different carbon sources: glucose, sucrose, fructose, maltose and glycerol. The results indicated that sucrose was the best initial carbon source for L-isoleucine production and then sucrose concentration of 30 g.L-1 was determined in the production medium. The results of different carbon sources feeding showed that the glucose solution was the most suitable feeding media. The dissolved oxygen (DO) of L-isoleucine fermentation was maintained at 5%, 15% and 30% with DO-stat feeding, respectively. The results indicated that when the DO level was maintained at 30%, the highest biomass and L-isoleucine production were obtained. The accumulation of acetate was decreased and the production of L isoleucine was increased markedly, when the glucose concentration was maintained at 0.15 g.L-1 by using glucose-stat feeding. Finally, the glucose concentration was maintained at 0.10 g.L-1 and the DO level was controlled at approximately 30% during the whole fermentation period, using the combined feeding strategy of glucose-stat feeding and DO feedback feeding. The acetate accumulation was decreased to 7.23 g.L-1, and biomass and production of L-isoleucine were increased to 46.8 and 11.95 g.L-1, respectively. PMID- 26019656 TI - The positive effects of Mn2+ on nitrogen use and surfactin production by Bacillus subtilis ATCC 21332. AB - Surfactin, one of the most effective biosurfactants, has great potential in commercial applications. Studies on effective methods to reduce surfactin's production cost are always a hotspot in the research field of biosurfactants. The aim of this study was to reveal the role of Mn2+ in promoting the biosynthesis of surfactin by Bacillus subtilis ATCC 21332, which could arise more targeted suggestions on surfactin yield promotion. In this study, B.subtilis was cultivated in media containing different Mn2+ concentrations. The obtained results showed that the yield of surfactin gradually increased upon Mn2+ addition (0.001 to 0.1 mmol/L) and achieved the maximal production of 1500 mg/L, which reached 6.2-fold of the yield obtained in media without Mn2+ addition. Correspondingly, the usage ratios of ammonium nitrate were improved. When the Mn2+ concentration was higher than 0.05 mmol/L, nitrate became the main nitrogen source, instead of ammonium, indicating that the nitrogen utilization pattern was also changed. An increase in nitrate reductase activity was observed and the increase upon Mn2+ dosage had a positive correlate with nitrate use, and then stimulated secondary metabolic activity and surfactin synthesis. On the other hand, Mn2+ enhanced the glutamate synthase activity, which increased nitrogen absorption and transformation and provided more free amino acids for surfactin synthesis. PMID- 26019657 TI - Effect of hydrophilic polymers on the wettability, static and dynamic, of solid substrate covered by confluent monolayer of air-damaged SIRC cells. AB - The aim of this study was to evaluate the possible implementation of hydrophilic polymers as recovery agents in air-damaged corneal cells. The sessile bubble technique was implemented to measure the wetting properties of four selected polymers: hydroxyethyl cellulose (HEC), sodium chondroitin sulphate (SCS), hydroxypropyl-methylcellulose (HPMC) and poloxamer F127 (PO12), at equilibrium conditions and in the case of advancing and receding contact angle. For testing the wetting properties of the polymers, glass slides covered with a confluent monolayer of Statens Seruminstitut rabbit cornea (SIRC) cells were used. HEC showed best properties for a broad concentration range, as the polymer showed capability to maintain low values of the static (equilibrium) contact angle (average static contact angle - 36.07, compared to average static compact angles of HPMC - 38.44, PO12 - 38.92 and SCS - 37.85), i.e. better wettability. Sessile bubble technique provides quick, relatively simple and reliable approach for testing surface properties of the listed polymers. The nature of the surface damage produced by the exposition of SIRC cells was used as a plausible model of evaporative dry eye syndrome, and thus the results may have clinical implementation. PMID- 26019658 TI - De novo transcriptome analysis of a medicinal fungi Phellinus linteus and identification of SSR markers. AB - The aim of this study was to facilitate gene discovery for functional genome studies and to identify simple sequence repeat (SSR) markers for molecular assisted selection in Phellinus linteus. The transcriptome of Phellinus linteus was sequenced using a high-throughput RNA sequencing system - the Illumina Hiseq 2000. A total of 16,383,818 clean sequencing reads, 35,532 contigs and 25,811 unigenes were postulated. Based on similarity searches with known proteins, 19,350 genes (74.97% of the unigenes) were annotated. In the present research, 19,266, 10,978 and 7831 unigenes were mapped in Nr, Swiss-Prot and clusters of orthologous groups (COG) classifications, respectively. Of all unigenes, 6845 were categorized into three functional groups, namely biological process, cellular components and molecular function and 11,088 were annotated to 108 pathways by searching the Kyoto Encyclopedia of Genes and Genomes pathway database. A total of 1129 SSRs were identified in these unigenes. In addition, 23 candidate genes, potentially involved in sterol biosynthesis, were identified and were worthy of further investigation. PMID- 26019659 TI - Research into acetone removal from air by biofiltration using a biofilter with straight structure plates. AB - The biological air treatment method is based on the biological destruction of organic compounds using certain cultures of microorganisms. This method is simple and may be applied in many branches of industry. The main element of biological air treatment devices is a filter charge. Tests were carried out using a new generation laboratory air purifier with a plate structure. This purifier is called biofilter. The biofilter has a special system for packing material humidification which does not require additional energy inputs. In order to extend the packing material's durability, it was composed of thermally treated birch fibre. Pollutant (acetone) biodegradation occurred on thermally treated wood fibre in this research. According to the performed tests and the received results, the process of biodestruction was highly efficient. When acetone was passed through biofilter's packing material at 0.08 m s-1 rate, the efficiency of the biofiltration process was from 70% up to 90%. The species of bacteria capable of removing acetone vapour from the air, i.e. Bacillus (B. cereus, B. subtilis), Pseudomonas (P. aeruginosa, P. putida), Stapylococcus (S. aureus) and Rhodococcus sp., was identified in this study during the process of biofiltration. Their amount in the biological packing material changed from 1.6 * 107 to 3.7 * 1011 CFU g-1. PMID- 26019660 TI - Cherax (Astaconephrops) pulcher, a new species of freshwater crayfish (Crustacea, Decapoda, Parastacidae) from the Kepala Burung (Vogelkop) Peninsula, Irian Jaya (West Papua), Indonesia. AB - A new species, Cherax (Astaconephrops) pulchersp. n., from Hoa Creek, close to the village Teminabuan in the southern-central part of the Kepala Burung (Vogelkop) Peninsula, West Papua, Indonesia, is described, figured and compared with the morphologically closest species, Cheraxboesemani Lukhaup & Pekny, 2008. PMID- 26019661 TI - Significance of hind wing morphology in distinguishing genera and species of cantharid beetles with a geometric morphometric analysis. AB - There remain some difficulties in delimitation of related genera or sibling species for cantharid beetles, because the traditionally taxonomic method and morphological characters have not been updated or introduced. In the present study, we firstly use the landmark-based geometric morphometrics to analyze and compare the hind wings of nine species belonging to three genera of Cantharinae to ascertain whether this approach may be used as a reliable method in the study of the taxonomy of this group. The results show that the shape differences of the hind wings among genera seem more variable than that within each genus, and the variations for each species are different from one another, as shown in the principal component analyses. And the canonical variates analyses show that there are significant differences among the genera and the species of each genus, which demonstrates that the hind wing shape can be diagnostic for both generic and specific identification of the cantharid beetles. This study sheds new light into clarifying the taxonomic uncertainties of Cantharidae, and lays a foundation for further studies on the evolution of the cantharid hind wing shape. PMID- 26019662 TI - A new species of the brown lacewing genus Zachobiella Banks from China (Neuroptera, Hemerobiidae) with a key to species. AB - The genus Zachobiella Banks, 1920 is reviewed and a new species Zachobiellayunanica sp. n. described from China. All species found in China are redescribed, and Zachobiellasubmarginata Esben-Petersen, 1929 is recorded from China for the first time. A key to the adults of Zachobiella is provided. PMID- 26019663 TI - Revision of the genus Trypogeus Lacordaire, 1869 (Cerambycidae, Dorcasominae). AB - The ten species of the genus Trypogeus Lacordaire are revised. Trypogeusapicalis Fisher, 1936, is proposed as a new synonym of Trypogeusjavanicus Aurivillius, 1925. A neotype for Trypogeussericeus (Gressitt, 1951) and lectotypes for Toxotusfuscus Nonfried, 1894 and Trypogeusjavanicus are designated. Trypogeusfuscus auct. nec Nonfried is a misidentification of Philusophthalmicus Pascoe. All the species are described and keys are given for distinguishing the species. Photographs of the types of all the Trypogeus species are published for the first time. PMID- 26019664 TI - A taxonomic review of Korean species of the AthetaThomsonsubgenusMicrodota Mulsant & Rey, with descriptions of two new species (Coleoptera, Staphylinidae, Aleocharinae). AB - A taxonomic review of the AthetaThomsonsubgenusMicrodota Mulsant & Rey in Korea is presented. The subgenus is represented in Korea by 15 species including two new species, Atheta (Microdota) jangtaesanensis Lee & Ahn, sp. n. and Atheta (Microdota) pasniki Lee & Ahn, sp. n. Four species [Atheta (Microdota) kawachiensis Cameron, Atheta (Microdota) muris Sawada, Atheta (Microdota) spiniventris Bernhauer, and Atheta (Microdota) spinula (Sawada)] are new to the Korean Peninsula and two [Atheta (Microdota) formicetorum Bernhauer and Atheta (Microdota) subcrenulata Bernhauer] to South Korea. Two other species [Atheta (Microdota) kobensis Cameron and Atheta (Microdota) scrobicollis (Kraatz)] previously recorded in North Korea had been identified incorrectly. A key, descriptions, habitus photographs and illustrations of the diagnostic features are provided. Species distributions and diversity in East Asia are discussed. PMID- 26019665 TI - The Tetramoriumsquaminode species group (Hymenoptera, Formicidae) in the Arabian Peninsula, with a new record from the Kingdom of Saudi Arabia and keys to Arabian species. AB - The Arabian species of the Tetramoriumsquaminode-group are treated. Tetramoriumsquaminode Santschi, 1911 is recorded for the first time from the Kingdom of Saudi Arabia and the Arabian Peninsula. Keys to the two Arabian species of the Tetramoriumsquaminode-group, Tetramoriumlatinode Collingwood & Agosti, 1996 and Tetramoriumsquaminode, based on worker and queen castes, are given and a regional distribution map is provided. Notes on habitats of Tetramoriumsquaminode are presented. PMID- 26019666 TI - Two new species of Tribonium Saussure, 1862 (Blattodea, Blaberidae, Zetoborinae), with a key to males of the genus. AB - This contribution describes and illustrates the male genitalia of two new species of Blaberidae collected in the state of Minas Gerais, Brazil: Triboniumcaldensis sp. n. resembles Triboniumneospectrum Lopes, 1978, differing in the coloration, size and genitalia; and Triboniummorroferrensis sp. n., which resembles Triboniumguttulosum (Walker, 1868) but also differs in the size and coloration of specimen and genital pieces morphology. The genital plates were removed after dissection of the posterior part of the abdomen, and were stored in microvials containing glycerin, attached to the respective exemplar in the collection of the Museu Nacional of Rio de Janeiro, Brazil. A key to males of the species of the genus is also presented. Illustrations of Triboniumneospectrum and Triboniumguttulosum are provided to clarify the comparisons with the new species described here. PMID- 26019667 TI - Three new species of the genus Ripipteryx from Colombia (Orthoptera, Ripipterygidae). AB - Three new species of Ripipteryx Newman (Orthoptera: Tridactyloidea: Ripipterygidae) are described from Colombia; namely Ripipteryxdiegoi sp. n. (Forceps Group) and Ripipteryxguacharoensis sp. n. (Marginipennis Group) from Parque Nacional Natural Cueva de los Guacharos in Huila, and Ripipteryxgorgonaensis sp. n. (Crassicornis Group) from Parque Nacional Natural Gorgona in Cauca. Ripipteryxdiegoi sp. n. is characterized by the antennae black with white spots on flagellomeres 3-7, male subgenital plate with median ridge forming a bilobed setose process, epiproct produced laterally near its base and phallic complex with virga thickened distally and not reaching beyond the membrane. Ripipteryxguacharoensis sp. n. is characterized by the antennae thick with white spots present dorsally on flagellomeres 1-4 and 8, epiproct narrow and triangular, uncus reduced and lacking a distal hook, phallic complex with a concave ventral plate and a dorsal elevation in the middle extended to the virga, and the virga itself with two small projections basally. Ripipteryxgorgonaensis sp. n. is characterized by the epiproct with a lateral notch, antennae with a white dorsal spot on flagellomere 1 and flagellomeres 4-7 entirely white. The antennal color pattern of Ripipteryxgorgonaensis sp. n. strongly resembles that of Ripipteryxatra but differs from the latter in the absence of any significant morphological modification of the flagellomeres. PMID- 26019668 TI - Meteoronakishinouyei, a new family, genus and species (Cnidaria, Cubozoa, Chirodropida) from Japanese Waters. AB - A new family, genus and species of cubozoan box jellyfish belonging to the order Chirodropida is reported from the eastern Japan. Meteoronakishinouyei gen. et sp. n. possesses the following unique morphological characters with respect to other known species in the Chirodropida: having one tentacle per scalpel-like unbranched pedalium and slightly raised unbranched gastric saccules. A comparative table of the primary diagnostic characters of genus and order in the Chirodropida is given. The order Chirodropida is redefined. The family Chiropsellidae is established. Discussion is provided on the implications for these findings on our current understanding of Cubozoan systematics. PMID- 26019669 TI - Description of a new species of Potamonautes MacLeay, 1838, from the iSimangaliso Wetland Park, South Africa. AB - A new species of freshwater crab, Potamonautesisimangaliso sp. n., is described from the western shores of False Bay, Hluhluwe, within the iSimangaliso Wetland Park, South Africa. While bearing a superficial resemblance to Potamonauteslividus, the new species has been found to be genetically distinct, diverging from the former by 7.4-7.8% in mtDNA. Potamonautesisimangaliso most closely resembles Potamonauteslividus, but is distinguished by a unique suite of carapace characters, colouration, and size. The new species also lives in close association with oxygen-poor, fresh ephemeral pans, while the habitat of Potamonauteslividus is well above the surface water line of the closest water body. An updated identification key for the Potamonautes species of South Africa is provided. PMID- 26019670 TI - Two new species of Edmockfordia Garcia Aldrete (Psocodea, 'Psocoptera', Epipsocidae), from Valle del Cauca, Colombia, and description of the female E.chiquibulensis Garcia Aldrete. AB - Two new species of Edmockfordia Garcia Aldrete, from Valle del Cauca, Colombia, and the female of Edmockfordiachiquibulensis Garcia Aldrete, are described and illustrated. A key to the species of Edmockfordia is included; the genus was previously known only from Belize. The genus is re-diagnosed to include female characters. The distribution of the genus is considerably widened, from Belize to northeastern South America. PMID- 26019671 TI - Updated list of Collembola species currently recorded from South Africa. AB - Understanding the abundance and richness of species is one of the most fundamental steps in effecting their conservation. Despite global recognition of the significance of the below-ground component of diversity for ecosystem functioning, the soil remains a poorly studied terrestrial ecosystem. In South Africa, knowledge is increasing for a variety of soil faunal groups, but many still remain poorly understood. We have started to address this gap in the knowledge of South African soil biodiversity by focusing on the Collembola in an integrated project that encompasses systematics, barcoding and ecological assessments. Here we provide an updated list of the Collembola species from South Africa. A total of 124 species from 61 genera and 17 families has been recorded, of which 75 are considered endemic, 24 widespread, and 25 introduced. This total number of species excludes the 36 species we consider to be dubious. From the published data, Collembola species richness is high compared to other African countries, but low compared to European countries. This is largely a consequence of poor sampling in the African region, as our discovery of many new species in South Africa demonstrates. Our analyses also show that much ongoing work will be required before a reasonably comprehensive and spatially explicit picture of South Africa's springtail fauna can be provided, which may well exceed 1000 species. Such work will be necessary to help South Africa meet its commitments to biodiversity conservation, especially in the context of the 2020 Aichi targets of the Convention on Biological Diversity. PMID- 26019672 TI - Alpha taxonomy of the genus Kessleria Nowicki, 1864, revisited in light of DNA barcoding (Lepidoptera, Yponomeutidae). AB - The taxonomy of Kessleria, a highly specialized montane genus of Yponomeutidae with larval host restriction to Saxifragaceae and Celastraceae (Saxifraga spp. - subgenus Kessleria; Saxifraga spp. and Parnassia spp. - subgenus Hofmannia), is revised based on external morphology, genitalia and DNA barcodes. An integrative taxonomic approach supports the existence of 29 species in Europe (the two known species from Asia and North America are not treated herein). A full 658 bp fragment of COI was obtained from 135 specimens representing 24 species, a further seven sequences are >560 bp. Five new species are described: Kessleriacottiensis sp. n. (Prov. Torino, Italy; Dep. Hautes Alpes, France), Kessleriadimorpha sp. n. (Dep. Alpes-de-Haute-Provence, France), Kessleriaalpmaritimae sp. n. (Dep. Alpes-Maritimes, France), Kessleriaapenninica sp. n. (Prov. Rieti, Prov. L'Aquila, Italy), and Kessleriaorobiae sp. n. (Prov. Bergamo, Italy). PMID- 26019673 TI - Taxonomic status and redescription of Magneuptychianebulosa (Butler, 1867) (Lepidoptera, Nymphalidae, Satyrinae) with a lectotype designation. AB - A redescription of Magneuptychianebulosa (Butler, 1867), a poorly known euptychiine butterfly, is given here, and accurate distributional data are provided for the first time. Taxonomic status of this taxon has been discussed by comparing its morphology against its possible congeners. In addition, lectotype designation for Magneuptychianebulosa is provided in order to objectively establish the identity of this taxon and consequently stabilize the nomenclature. PMID- 26019674 TI - East Weddell Sea echinoids from the JR275 expedition. AB - Information regarding the echinoids in this dataset is based on the Agassiz Trawl (AGT) and epibenthic sledge (EBS) samples collected during the British Antarctic Survey cruise JR275 on the RRS James Clark Ross in the austral summer 2012. A total of 56 (1 at the South Orkneys and 55 in the Eastern Weddell Sea) Agassiz Trawl and 18 (2 at the South Orkneys and 16 in the Eastern Weddell Sea) epibenthic sledge deployments were performed at depths ranging from ~280 to ~2060 m. This presents a unique collection for the Antarctic benthic biodiversity assessment of an important group of benthic invertebrates. In total 487 specimens belonging to six families, 15 genera, and 22 morphospecies were collected. The species richness per station varied between one and six. Total species richness represents 27% of the 82 echinoid species ever recorded in the Southern Ocean (David et al. 2005b, Pierrat et al. 2012, Saucede et al. 2014). The Cidaridae (sub-family Ctenocidarinae) and Schizasteridae are the two most speciose families in the dataset. They comprise seven and nine species respectively. This is illustrative of the overall pattern of echinoid diversity in the Southern Ocean where 65% of Antarctic species belong to the families Schizasteridae and Cidaridae (Pierrat et al. 2012). PMID- 26019675 TI - Status of Exosphaeromaamplicauda (Stimpson, 1857), E.aphrodita (Boone, 1923) and description of three new species (Crustacea, Isopoda, Sphaeromatidae) from the north-eastern Pacific. AB - Exosphaeromaamplicauda (Stimpson, 1857) from the west coast of North America is reviewed and redescribed and revealed to be a group of closely related species. A neotype is designated and the species redescribed based on the neotype and topotypic specimens. Exosphaeromaamplicauda is known only from the coast of California, at Marin, Sonoma and San Mateo Counties. Exosphaeromaaphrodita (Boone, 1923), type locality La Jolla, California and previously considered nomen dubium is taken out of synonymy and re-validated. A further three species: Exosphaeromapaydenae sp. n., Exosphaeromarussellhansoni sp. n., and Exosphaeromapentcheffi sp. n. are described herein. Sphaeromaoctonctum Richardson, 1899 is placed into junior synonymy with Exosphaeromaamplicauda. A key to the Pacific West Coast Exosphaeroma is provided. PMID- 26019676 TI - Redescription of Brochopeltismjoebergi Verhoeff, 1924 and description of a second Brochopeltis species from Australia (Diplopoda, Polydesmida, Paradoxosomatidae). AB - Brochopeltismjoebergi Verhoeff, 1924 is redescribed from type and new material, a lectotype is designated and Brochopeltismjoebergiqueenslandica Verhoeff, 1924 is synonymised with Brochopeltismjoebergi. Brochopeltismediolocus sp. n. is the first native paradoxosomatid described from Australia's Northern Territory. PMID- 26019677 TI - The male of Megacormusgranosus (Gervais, 1844) with comments on its hemispermatophore (Scorpiones, Euscorpiidae). AB - The male of Megacormusgranosus is described for the first time and the female redescribed. A homology scheme proposed recently is applied to hemispermatophore structures. The specimens were collected in an oak forest from Pico de Orizaba Volcano at an average altitude of 2340 m. All adult males were collected by pitfall traps, whereas all adult females and both sex immatures were collected using Berlese funnels, suggesting that males are comparatively more mobile within the leaf litter layer, probably due to mating season. PMID- 26019678 TI - Thysanoptera of bulgaria. AB - The present checklist includes data on the species composition, geographic distribution and feeding preferences of thrips species in Bulgaria. In total, 155 species in 48 genera are listed. Of these, 125 species belong to suborder Terebrantia and include 103 species of 33 genera in family Thripidae, 14 species of two genera in Aeolothripidae, seven species of two genera in Melanthripidae and one species in Fauriellidae. In suborder Tubulifera, 30 species of 10 genera in the single family Phlaeothripidae are listed. Of the 155 Bulgarian thrips species, 87.7% are phytophagous, 4.5% are obligate predators, 5.8% are mycophagous and 1.9% are with unknown feeding preferences. Fourteen pest species are listed for Bulgaria, of which Frankliniellaoccidentalis, Thripstabaci and Haplothripstritici are of economic importance. The list provides detailed information on the horizontal and vertical distribution of Thysanoptera in 5 regions and 45 subregions of Bulgaria. The present paper also includes an evaluation of the biodiversity of Thysanoptera and the extent to which each region of the country has been studied. PMID- 26019679 TI - Two new species of the genus Comidoblemmus Storozhenko & Paik from China (Orthoptera, Gryllidae). AB - Two new species of Comidoblemmus Storozhenko & Paik, 2009 are described and illustrated, Comidoblemmussororius sp. n. (CHINA, Zhejiang) and Comidoblemmusexcavatus sp. n. (CHINA, Guizhou). A key and a distribution map of all species in the world are presented. PMID- 26019680 TI - A new species of the genus Anteon Jurine (Hymenoptera, Dryinidae) from Thailand. AB - A new species of Anteon Jurine, 1807 is described from Thailand, Nan Province: Anteonhuettingeri sp. n. Morphologically the new species is similar to Anteonborneanum Olmi, 1984, Anteonjurineanum Latreille, 1809, Anteoninsertum Olmi, 1991, Anteonyasumatsui Olmi, 1984, Anteonsarawaki Olmi, 1984, Anteonthai Olmi, 1984 and Anteonkrombeini Olmi, 1984, but it is clearly different for the numerous sensorial processes present on the inner side of the paramere; these processes are absent in the other above species. Published identification keys to the Oriental species of Anteon are modified to include the new species. PMID- 26019681 TI - First record of Closteroceruschamaeleon, parasitoid of the Eucalyptus Gall Wasp Ophelimusmaskelli (Hymenoptera, Chalcidoidea, Eulophidae), in the New World. AB - The uniparental parasitoid Closteroceruschamaeleon (Girault) is discovered to be fortuitously present on a population of the invasive Eucalyptus Gall Wasp Ophelimusmaskelli (Ashmead) in Riverside, California. This is the first report from the New World of Closteroceruschamaeleon, which has proven to be a highly effective natural enemy of Ophelimusmaskelli in the Mediterranean Basin. The taxonomy and identification of Closteroceruschamaeleon is discussed. PMID- 26019682 TI - Corrigenda: Martinsson S, Rota E, Erseus C (2015) On the identity of Chamaedrilusglandulosus (Michaelsen, 1888) (Clitellata, Enchytraeidae), with the description of a new species. ZooKeys 501: 1-14. doi: 10.3897/zookeys.501.9279. AB - [This corrects the article DOI: 10.3897/zookeys.501.9279.]. PMID- 26019683 TI - Temporomandibular Disorders in Psoriasis Patients with and without Psoriatic Arthritis: An Observational Study. AB - AIMS: Psoriasis is a chronic, remitting and relapsing inflammatory disorder, involving the skin, nails, scalp and mucous membranes, that impairs patients' quality of life to varying degrees. Psoriatic arthritis is a chronic seronegative, inflammatory arthritis, usually preceded by psoriasis. Temporomandibular disorders is a generic term referred to clinical conditions involving the jaw muscles and temporomandibular joint. The aim of this study was to assess symptoms and signs of temporomandibular disorders in psoriasis patients with and without psoriatic arthritis. METHODS: The study group included 112 patients (56 men, 56 women; median age 49.7+/-12 years) with psoriasis, 25 of them were affected by psoriatic arthritis. A group of 112 subjects without psoriasis (56 men, 56 women; median age 47.7+/-17 years) served as controls. Signs and symptoms of temporomandibular disorders were evaluated according to the standardized Research Diagnostic Criteria for Temporomandibular Disorders. Psoriasis patients were subgrouped according to the presence/absence of psoriatic arthritis and by gender, to assess the prevalence of traditional symptoms and signs of temporomandibular disorders. RESULTS: Patients with psoriasis, and to an even greater extent those with psoriatic arthritis, were more frequently affected by symptoms and signs of temporomandibular disorders, including an internal temporomandibular joint opening derangement than healthy subjects. A statistically significant increase in symptoms of temporomandibular disorders, in opening derangement, bruxism and sounds of temporomandibular joint was found in patients with psoriatic arthritis as compared with psoriasis patients without arthritis and controls. CONCLUSIONS: psoriasis seems to play a role in temporomandibular joint disorders, causing an increase in orofacial pain and an altered chewing function. PMID- 26019684 TI - PIK3CA Amplification Is Common in Left Side-Tubular Adenomas but Uncommon Sessile Serrated Adenomas Exclusively with KRAS Mutation. AB - Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and sessile serrated adenomas (SSAs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SSAs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR and pyrosequencing. PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs, respectively. KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs. In TAs, PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation. PMID- 26019686 TI - Comparison of time-motion analysis of conventional stool culture and the BD MAXTM Enteric Bacterial Panel (EBP). AB - BACKGROUND: Conventional bacterial stool culture is one of the more time consuming tests in a routine clinical microbiology laboratory. In addition, less than 5 % of stool cultures yield positive results. A molecular platform, the BD MAXTM System (BD Diagnostics, Sparks, MD) offers the potential for significantly more rapid results and less hands-on time. Time-motion analysis of the BD MAX Enteric Bacterial Panel (EBP) (BD Diagnostics, Quebec, Canada) on the BD MAX System was compared to conventional stool culture in the microbiology laboratory of a tertiary care pediatric hospital. METHODS: The process impact analysis of time-motion studies of conventional cultures were compared to those of EBP with 86 stool specimens. Sample flow, hands-on time, processing steps, and overall turnaround time were determined and analyzed. Data were obtained and analyzed from both standard operating procedures and direct observation. A regression analysis was performed to ensure consistency of measurements. Time and process measurements started when the specimens were logged into the accessioning area of the microbiology laboratory and were completed when actionable results were generated. RESULTS: With conventional culture, negative culture results were available from 41:14:27 (hours:minutes:seconds) to 54:17:19; with EBP, positive and negative results were available from 2:28:40 to 3:33:39. CONCLUSIONS: This study supports the suggestion that use of the EBP to detect commonly encountered stool pathogens can result in significant time savings and a shorter time-to result for patients with acute bacterial diarrhea. PMID- 26019685 TI - Predicting one-year mortality in peritoneal dialysis patients: an analysis of the China Peritoneal Dialysis Registry. AB - This study aims to investigate basic clinical features of peritoneal dialysis (PD) patients, their prognostic risk factors, and to establish a prognostic model for predicting their one-year mortality. A national multi-center cohort study was performed. A total of 5,405 new PD cases from China Peritoneal Dialysis Registry in 2012 were enrolled in model group. All these patients had complete baseline data and were followed for one year. Demographic and clinical features of these patients were collected. Cox proportional hazards regression model was used to analyze prognostic risk factors and establish prognostic model. A validation group was established using 1,764 new PD cases between January 1, 2013 and July 1, 2013, and to verify accuracy of prognostic model. Results indicated that model group included 4,453 live PD cases and 371 dead cases. Multivariate survival analysis showed that diabetes mellitus (DM), residual glomerular filtration rate (rGFR), , SBP, Kt/V, high PET type and Alb were independently associated with one year mortality. Model was statistically significant in both within-group verification and outside-group verification. In conclusion, DM, rGFR, SBP, Kt/V, high PET type and Alb were independent risk factors for short-term mortality in PD patients. Prognostic model established in this study accurately predicted risk of short-term death in PD patients. PMID- 26019687 TI - The role of a clinical nurse consultant in an Australian Health District: a quantitative survey. AB - BACKGROUND: This study replicates previous research undertaken in 2013 that explored the role of the Clinical Nurse Consultant in a metropolitan health district in Sydney, Australia. METHODS: A descriptive survey, using Likert scales, was used to collect data from Clinical Nurse Consultants. RESULTS: Clinical Nurse Consultants are well informed about the domains and functions of their role, as stipulated in the relevant award. They identified clinical service and consultancy as the area in which they predominantly practice. CONCLUSION: Despite the clarity of the domains and functions as outlined in the relevant legislated award, the activities undertaken by these clinical nurses are institutionally, individually and contextually constructed. PMID- 26019688 TI - Inhibitor of caspase-activated DNase expression enhances caspase-activated DNase expression and inhibits oxidative stress-induced chromosome breaks at the mixed lineage leukaemia gene in nasopharyngeal carcinoma cells. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is commonly found in Asia, especially among the Chinese ethnic group. Chromosome rearrangements are common among NPC patients. Although the mechanism underlying the chromosome rearrangements in NPC is unclear, various mechanisms including activation of caspase-activated DNase (CAD) were proposed to contribute to chromosome rearrangements in leukaemia. Activation of CAD can be initiated by multiple agents, including oxidative stress, which is well implicated in carcinogenesis. CAD is the main enzyme that causes DNA fragmentation during apoptosis, and CAD is also implicated in promoting cell differentiation. In view of the role of oxidative stress in carcinogenesis and CAD activation, and since CAD was suggested to contribute to chromosome rearrangement in leukaemia, we hypothesise that oxidative stress induced CAD activation could be one of the mechanisms that leads to chromosome rearrangements in NPC. METHODS: SUNEI cells were treated with various concentrations of H2O2 for different period of time to ensure that cells undergo H2O2-induced MLL gene cleavage. Transfections with hCAD, mCAD, mutant hCAD, or cotransfection with hCAD and mICAD, and cotransfection with mutant hCAD and mICAD were performed. Gene expression was confirmed by Western blotting and MLL gene cleavage was assessed by inverse polymerase chain reaction (IPCR). RESULTS: Treatment with H2O2 clearly induces cleavages within the MLL gene which locates at 11q23, a common deletion site in NPC. In order to investigate the role of CAD, CAD was overexpressed in SUNE1 cells, but that did not result in significant changes in H2O2-induced MLL gene cleavage. This could be because CAD requires ICAD for proper folding. Indeed, by overexpressing ICAD alone or co-expressing ICAD with CAD, Western blotting showed that CAD was expressed. In addition, ICAD overexpression also suppressed H2O2-induced MLL gene cleavage, suggesting a possible role of CAD in initiating chromosome cleavage during oxidative stress. CONCLUSIONS: Oxidative stress mediated by H2O2 induces cleavage of the MLL gene, most likely via the caspase-activated DNase, CAD, and CAD expression requires ICAD. Since the MLL gene is located at 11q23, a common deletion site in NPC, thus stress-induced CAD activation may represent one of the mechanisms leading to chromosome rearrangement in NPC. PMID- 26019689 TI - The prevalence and burden of systemic lupus erythematosus in a medicare population: retrospective analysis of medicare claims. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder which can affect multiple organs of the body, requiring ongoing disease management and healthcare resource utilization. The economic impact of SLE has not been evaluated in a Medicare population to date. This study was conducted to assess the prevalence of SLE and its burden in terms of healthcare resource utilization and costs in a US Medicare population. METHODS: This was a retrospective observational study using Medicare medical claims data (5% random sample) for the period spanning 2003 to 2007. SLE patients were identified by having >=2 medical claims with a primary or secondary diagnosis of ICD-9 code 710.0X. The earliest quarter of SLE diagnosis was defined as the index quarter. Prevalence of SLE, the proportion of SLE cases on disability benefits, and the contribution of SLE to new disability cases were evaluated. Healthcare resource utilization and direct medical costs (2008 US dollars) over 12 months were compared between a cohort of patients with SLE and a cohort without SLE matched on key demographics. Differences in outcomes between cohorts were assessed using McNemar's test for dichotomous variables and paired t-tests for continuous variables. RESULTS: A total of 13,348 patients with SLE were identified. The prevalence of SLE was approximately 3 per 1000 Medicare beneficiaries. After matching, the sample consisted of 6,707 SLE and 13,414 non-SLE patients. On average, the SLE cohort compared with the non-SLE cohort had 2.4 times more physician visits, 2.7 times more hospitalizations, 2.2 times more outpatient visits, and 2.1 times more emergency room visits. A medical cost surplus of approximately $10,229 per patient per year in the SLE cohort relative to the non SLE cohort was driven largely by inpatient hospitalization costs (p < 0.001). CONCLUSIONS: SLE prevalence was 3 per 1,000 Medicare patients. Patients with SLE consumed significantly more health care resources with significantly greater costs compared with those without SLE. Added costs were largely attributable to inpatient hospitalizations. The Medicare population is an important target for efforts to improve SLE disease management and reduce costs. PMID- 26019690 TI - Review of disability weight studies: comparison of methodological choices and values. AB - INTRODUCTION: The disability-adjusted life year (DALY) is widely used to assess the burden of different health problems and risk factors. The disability weight, a value anchored between 0 (perfect health) and 1 (equivalent to death), is necessary to estimate the disability component (years lived with disability, YLDs) of the DALY. After publication of the ground-breaking Global Burden of Disease (GBD) 1996, alternative sets of disability weights have been developed over the past 16 years, each using different approaches with regards to the panel, health state description, and valuation methods. The objective of this study was to review all studies that developed disability weights and to critically assess the methodological design choices (health state and time description, panel composition, and valuation method). Furthermore, disability weights of eight specific conditions were compared. METHODS: Disability weights studies (1990?2012) in international peer-reviewed journals and grey literature were identified with main inclusion criteria being that the study assessed DALY disability weights for several conditions or a specific group of illnesses. Studies were collated by design and methods and evaluation of results. RESULTS: Twenty-two studies met the inclusion criteria of our review. There is considerable variation in methods used to derive disability weights, although most studies used a disease-specific description of the health state, a panel that consisted of medical experts, and nonpreference-based valuation method to assess the values for the majority of the disability weights. Comparisons of disability weights across 15 specific disease and injury groups showed that the subdivision of a disease into separate health states (stages) differed markedly across studies. Additionally, weights for similar health states differed, particularly in the case of mild diseases, for which the disability weight differed by a factor of two or more. CONCLUSIONS: In terms of comparability of the resulting YLDs, the global use of the same set of disability weights has advantages, though practical constraints and intercultural differences should be taken into account into such a set. PMID- 26019691 TI - Modeling contextual effects using individual-level data and without aggregation: an illustration of multilevel factor analysis (MLFA) with collective efficacy. AB - Population health scientists increasingly study how contextual-level attributes affect individual health. A major challenge in this domain relates to measurement, i.e., how best to measure and create variables that capture characteristics of individuals and their embedded contexts. This paper presents an illustration of multilevel factor analysis (MLFA), an analytic method that enables researchers to model contextual effects using individual-level data without using derived variables. MLFA uses the shared variance in sets of observed items among individuals within the same context to estimate a measurement model for latent constructs; it does this by decomposing the total sample variance-covariance matrix into within-group (e.g., individual-level) and between-group (e.g., contextual-level) matrices and simultaneously modeling distinct latent factor structures at each level. We illustrate the MLFA method using items capturing collective efficacy, which were self-reported by 2,599 adults in 65 census tracts from the Los Angeles Family and Neighborhood Survey (LAFANS). MLFA identified two latent factors at the individual level and one factor at the neighborhood level. Indicators of collective efficacy performed differently at each level. The ability of MLFA to identify different latent factor structures at each level underscores the utility of this analytic tool to model and identify attributes of contexts relevant to health. PMID- 26019694 TI - The effects of acute garlic supplementation on the fibrinolytic and vasoreactive response to exercise. AB - BACKGROUND: The purpose of this project was to examine the effects of acute garlic supplementation on fibrinolysis and vasoreactivity both at rest and following maximal exercise. METHODS: Eighteen healthy trained males (20.9 +/- 2.2 years, 178 +/- 7.7 cm, 75.5 +/- 9.6 kg, VO2max = 59.8 +/- 6.7 ml * kg(-1) * min( 1)) performed a graded treadmill test to volitional exhaustion. Blood samples were taken at rest, within two minutes post-exercise, and one hour post-exercise. Eleven of the subjects also had a brachial vasoreactivity test performed immediately after the blood sample to assess flow-mediated dilation (FMD) of the brachial artery. Participants were randomly assigned to ingest either 900 mg of powdered garlic or a placebo three hours before the exercise session. The supplement was distributed in a double-blind, crossover fashion. Participants repeated the protocol with the other treatment after a 14-day washout period. Paired t-tests were used to compare VO2max between the two trials. A two-factor (treatment and time) repeated measures analysis of variance (ANOVA) was used to assess changes in FMD, tPA activity, tPA antigen, and PAI-1 activity. A priori statistical significance was set at P <0.05. RESULTS: VO2max was greater for the garlic treatment trial vs. placebo (Placebo = 59.8 +/- 6.7 ml * kg(-1) * min(-1); Garlic = 61.4 +/- 6.6 ml * kg(-1) * min(-1)). There was no main effect for treatment and no treatment x time interaction for FMD or any fibrinolytic variables examined. CONCLUSION: Acute garlic supplementation does not alter vasoreactivity, fibrinolytic potential or the fibrinolytic response to exercise in young healthy trained males. Acute garlic supplementation does, however, cause a small but statistically significant increase in VO2max. It remains unclear if this increase in VO2max is of functional importance. PMID- 26019695 TI - An evidence-based review of edoxaban and its role in stroke prevention in patients with nonvalvular atrial fibrillation. AB - Atrial fibrillation is the most common arrhythmia in the elderly. It is responsible for significant morbidity and mortality from cardioembolic complications like stroke. As a result, atrial fibrillation patients are risk stratified using the CHADS2 or CHA2DS2-VASc scoring systems. Those at intermediate-to-high risk have traditionally been treated with therapeutic anticoagulation with warfarin for stroke prevention. Although effective, warfarin use is fraught with multiple concerns, such as a narrow therapeutic window, drug drug and drug-food interactions, and excessive bleeding. Novel oral anticoagulant agents have recently become available as viable alternatives for warfarin therapy. Direct thrombin inhibitor dabigatran and factor Xa inhibitors like rivaroxaban and apixaban have already been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation. Edoxaban is the latest oral direct factor Xa inhibitor studied in the largest novel oral anticoagulant trial so far: ENGAGE AF-TIMI 48. Treatment with a 30 mg or 60 mg daily dose of edoxaban was found to be noninferior to dose adjusted warfarin in reducing the rate of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a lower incidence of bleeding complications and cardiovascular deaths. Edoxaban was recently reviewed by an FDA advisory committee and recommended as a stroke-prophylaxis agent. Once approved, it promises to provide another useful alternative to warfarin therapy. PMID- 26019696 TI - Ag nanoparticle-deposited TiO2 nanotube arrays for electrodes of Dye-sensitized solar cells. AB - ABSTRACT: Dye-sensitized solar cells composed of a photoanode of Ag nanoparticle (NP)-deposited TiO2 nanotube (TNT) arrays were fabricated. The TNT arrays were prepared by anodizing Ti films on fluorine-doped tin oxide (FTO)-coated glass substrates. Efficient charge transportation through the ordered nanostructure of TNT arrays should be carried out compared to conventional particulate TiO2 electrodes. However, it has been a big challenge to grow TNT arrays on FTO glass substrates with the lengths needed for sufficient light-harvesting (tens of micrometers). In this work, we deposited Ag nanoparticles (NPs) on the wall of TNT arrays to enhance light-harvesting property. Dye-sensitized solar cells with these Ag NP-deposited TNT arrays yielded a higher power conversion efficiency (2.03 %) than those without Ag NPs (1.39 %). PACS CODES: 06.60.Ei Sample preparation, 81.05.Bx Metals, Semimetals, Alloys, 81.07.De Nanotubes. PMID- 26019693 TI - Microtubules in plants. AB - Microtubules (MTs) are highly conserved polar polymers that are key elements of the eukaryotic cytoskeleton and are essential for various cell functions. alphabeta-tubulin, a heterodimer containing one structural GTP and one hydrolysable and exchangeable GTP, is the building block of MTs and is formed by the sequential action of several molecular chaperones. GTP hydrolysis in the MT lattice is mechanistically coupled with MT growth, thus giving MTs a metastable and dynamic nature. MTs adopt several distinct higher-order organizations that function in cell division and cell morphogenesis. Small molecular weight compounds that bind tubulin are used as herbicides and as research tools to investigate MT functions in plant cells. The de novo formation of MTs in cells requires conserved gamma-tubulin-containing complexes and targeting/activating regulatory proteins that contribute to the geometry of MT arrays. Various MT regulators and tubulin modifications control the dynamics and organization of MTs throughout the cell cycle and in response to developmental and environmental cues. Signaling pathways that converge on the regulation of versatile MT functions are being characterized. PMID- 26019697 TI - Scalability of the Heat and Current Treatment on SWCNTs to Improve their Crystallinity and Thermal and Electrical Conductivities. AB - We have investigated the scalability of our post-synthesis graphitization process for single-walled carbon nanotubes (SWCNTs), which applies heat and current to SWCNTs to improve the thermal and electrical conductivities. This investigation was performed by examining the relationship between the processing conditions and the amount of treated SWCNTs. Characterization of all cases of treated SWCNTs showed the same level of improvement of ~3 times to both the thermal and electrical conductivities and that the SWCNTs remained SWCNTs, i.e., no change in diameter or wall number. These results provided evidence that the ability to improve the crystallinity of the SWCNTs was independent of the treatment amount. Further, our results showed that an increase in SWCNT amount required increased applied current density or increased in applied temperature to achieve optimum property improvement. Finally, we found a trade-off between the current density and temperature indicating that either a high current or high temperature was required to achieve the optimum process conditions. These results demonstrated that our heat and current SWCNT treatment was fundamentally scalable and applied towards larger scale (i.e., gram-level or more) amounts of SWCNT. PMID- 26019698 TI - Flexible conducting polymer/reduced graphene oxide films: synthesis, characterization, and electrochemical performance. AB - In this paper, we demonstrate the preparation of a flexible poly (3,4 ethylenedioxythiophene) -poly (styrenesulfonate)/reduced graphene oxide (PEDOT PSS/RGO) film with a layered structure via a simple vacuum filtered method as a high performance electrochemical electrode. The PEDOT-PSS/RGO films are characterized by scanning electron microscopy (SEM), X-ray diffraction, Raman spectroscopy, and Fourier transform infrared (FT-IR) spectrometry. The results indicate that a layer-ordered structure is constructed in this nanocomposite during the vacuum filtering process. The electrochemical performances of the flexible films are characterized by electrochemical impedance spectroscopy, cyclic voltammetry, and galvanostatic charge/discharge. The results reveal that a 193.7 F/g highly specific capacitance of nanocomposite film is achieved at a current density of 500 mA/g. This flexible and self-supporting nanocomposite film exhibits excellent cycling stability, and the capacity retention is 90.6 % after 1000 cycles, which shows promising application as high-performance electrode materials for flexible energy-storage devices. PMID- 26019699 TI - A Unique Approach to Generate Self-Aligned SiO2/Ge/SiO2/SiGe Gate-Stacking Heterostructures in a Single Fabrication Step. AB - We report a first-of-its-kind, unique approach for generating a self-aligned, gate-stacking heterostructure of Ge quantum dot (QD)/SiO2/SiGe shell on Si in a single fabrication step. The 4-nm-thick SiO2 layer between the Ge QD and SiGe shell fabricated during the single-step process is the result of an exquisitely controlled dynamic balance between the fluxes of oxygen and silicon interstitials. The high-quality interface properties of our "designer" heterostructure are evidenced by the low interface trap density of as low as 2-4 * 10(11) cm(-2) eV(-1) and superior transfer characteristics measured for Ge based metal-oxide-semiconductor field-effect transistors (MOSFETs). Thanks to the very thin interfacial SiO2 layer, carrier storage within the Ge QDs with good memory endurance was established under relatively low-voltage programming/erasing conditions. We hope that our unique self-aligned, gate-stacking heterostructure provides an effective approach for the production of next-generation, high performance Ge gate/SiO2/SiGe channel MOSFETs. PMID- 26019700 TI - Application of quantitative proteomics to the integrated analysis of the ubiquitylated and global proteomes of xenograft tumor tissues. AB - BACKGROUND: Post-translational modification by ubiquitin is a fundamental regulatory mechanism that is implicated in many cellular processes including the cell cycle, apoptosis, cell adhesion, angiogenesis, and tumor growth. The low stoichiometry of ubiquitylation presents an analytical challenge for the detection of endogenously modified proteins in the absence of enrichment strategies. The recent availability of antibodies recognizing peptides with Lys residues containing a di-Gly ubiquitin remnant (K-epsilon-GG) has greatly improved the ability to enrich and identify ubiquitylation sites from complex protein lysates via mass spectrometry. To date, there have not been any published studies that quantitatively assess the changes in endogenous ubiquitin modification protein stoichiometry status at the proteome level from different tissues. RESULTS: In this study, we applied an integrated quantitative mass spectrometry based approach using isobaric tags for relative and absolute quantitation (iTRAQ) to interrogate the ubiquitin-modified proteome and the cognate global proteome levels from luminal and basal breast cancer patient derived xenograft tissues. Among the proteins with quantitative global and ubiquitylation data, 91 % had unchanged levels of total protein relative abundance, and less than 5 % of these proteins had up- or down-regulated ubiquitylation levels. Of particular note, greater than half of the proteins with observed changes in their total protein level also had up- or down-regulated changes in their ubiquitylation level. CONCLUSIONS: This is the first report of the application of iTRAQ-based quantification to the integrated analysis of the ubiquitylated and global proteomes at the tissue level. Our results underscore the importance of conducting integrated analyses of the global and ubiquitylated proteomes toward elucidating the specific functional significance of ubiquitylation. PMID- 26019701 TI - Patient blood management: it is time to streamline targeted therapy options. PMID- 26019692 TI - Mechanism of cytoplasmic mRNA translation. AB - Protein synthesis is a fundamental process in gene expression that depends upon the abundance and accessibility of the mRNA transcript as well as the activity of many protein and RNA-protein complexes. Here we focus on the intricate mechanics of mRNA translation in the cytoplasm of higher plants. This chapter includes an inventory of the plant translational apparatus and a detailed review of the translational processes of initiation, elongation, and termination. The majority of mechanistic studies of cytoplasmic translation have been carried out in yeast and mammalian systems. The factors and mechanisms of translation are for the most part conserved across eukaryotes; however, some distinctions are known to exist in plants. A comprehensive understanding of the complex translational apparatus and its regulation in plants is warranted, as the modulation of protein production is critical to development, environmental plasticity and biomass yield in diverse ecosystems and agricultural settings. PMID- 26019702 TI - Utilisation of blood components in cardiac surgery: a single-centre retrospective analysis with regard to diagnosis-related procedures. AB - BACKGROUND: More blood components are required in cardiac surgery than in most other medical disciplines. The overall blood demand may increase as a function of the total number of cardiothoracic and vascular surgical interventions and their level of complexity, and also when considering the demographic ageing. Awareness has grown with respect to adverse events, such as transfusion-related immunomodulation by allogeneic blood supply, which can contribute to morbidity and mortality. Therefore, programmes of patient blood management (PBM) have been implemented to avoid unnecessary blood transfusions and to standardise the indication of blood transfusions more strictly with aim to improve patients' overall outcomes. METHODS: A comprehensive retrospective analysis of the utilisation of blood components in the Department of Cardiac Surgery at the University Hospital of Munster (UKM) was performed over a 4-year period. Based on a medical reporting system of all medical disciplines, which was established as part of a PBM initiative, all transfused patients in cardiac surgery and their blood components were identified in a diagnosis- and medical procedure-related system, which allows the precise allocation of blood consumption to interventional procedures in cardiac surgery, such as coronary or valve surgery. RESULTS: This retrospective single centre study included all in-patients in cardiac surgery at the UKM from 2009 to 2012, corresponding to a total of 1,405 1,644 cases per year. A blood supply was provided for 55.6-61.9% of the cardiac surgery patients, whereas approximately 9% of all in-patients at the UKM required blood transfusions. Most of the blood units were applied during cardiac valve surgery and during coronary surgery. Further surgical activities with considerable use of blood components included thoracic surgery, aortic surgery, heart transplantations and the use of artificial hearts. Under the measures of PBM in 2012 a noticeable decrease in the number of transfused cases was observed compared to the period from 2009 to 2011 before implementation of the PBM initiative (red blood cells p < 0.002; fresh frozen plasma p < 0.0006; platelets p < 0.00006). CONCLUSION: Until now, cardiac surgery comes along with a significant blood supply. By using a case-related data evaluation programme, the consumption of each blood component can be linked to clinical performance groups and, if necessary, to individual patients. Based on the results obtained from this retrospective analysis, prospective studies are underway to begin conducting target / actual performance comparisons to better understand the individual decision-making by the attending physicians with respect to transfusions. PMID- 26019703 TI - Utilisation of Blood Components in Trauma Surgery: A Single-Centre, Retrospective Analysis before and after the Implementation of an Educative PBM Initiative. AB - BACKGROUND: The aim of our single-centre retrospective study presented here is to further analyse the utilisation of allogeneic blood components within a 5-year observation period (2009-2013) in trauma surgery (15,457 patients) under the measures of an educational patient blood management (PBM) initiative. METHODS: After the implementation of the PBM initiative in January 2012, the Institute of Transfusion Medicine und Transplantation Immunology educates surgeons and nurses at the Department of Trauma Surgery to avoid unnecessary blood transfusions. A standardised reporting system was used to document the utilisation of blood components carefully for the most frequent diagnoses and surgical interventions in trauma surgery. These measures served as basis for the implementation of an interdisciplinary systematic exchange of information to foster decision-making processes in favour of patient blood management. RESULTS: Since January 2012, the proportion of patients who received a transfusion as well as the number of transfused red blood cell (RBC) (7.3%/6.4%; p = 0.02), fresh frozen plasma (FFP) (1.7%/1.3%; p < 0.05) and platelet (PLT) (1.0%/0.5%; p < 0.001) units were reduced as a result of our PBM initiative. However, among the transfused patients, the number of administered RBC, FFP and PLT units did not decrease significantly. Overall, patients who did not receive transfusions were younger than transfused patients (p = 0.001). The subgroup with the highest probability of blood transfusion administered included patients with intensive care and long term ventilation (before/after implementation of PBM: RBC 81.5%/75.9%; FFP 33.3%/20.4%; PLT 24.1%/13.0%). Only a total of 60 patients of 531 patients suffering multiple traumas were massively transfused (before/after implementation of PBM: RBC 55.6%/49.8%; FFP 28.4%/20.4%; PLT 17.6%/8.9%). CONCLUSION: According to our educational PBM initiative, at least the proportion of trauma patients who received allogeneic blood transfusions could be reduced significantly. However, in case of blood transfusions, the total consumption of RBC, FFP and PLT units remained stable in both time periods. This phenomenon might indicate that the actual need of blood transfusions rather depends on the severity of trauma related blood loss, the coagulopathy rates or the complexity of the surgical intervention which mainly determines the intra-operative blood loss. Taken together, educational training sessions and systematic reporting systems are suitable measures to avoid unnecessary allogeneic blood transfusions and to continuously improve their restrictive application. PMID- 26019704 TI - Patient blood management implementation strategies and their effect on physicians' risk perception, clinical knowledge and perioperative practice - the frankfurt experience. AB - INTRODUCTION: A multicomponent, evidence-based and interdisciplinary Patient Blood Management (PBM) program was introduced at the University Hospital Frankfurt in July 2013. The implementation strategy included practical and tactical components aimed to increase knowledge on the risks of preoperative anemia, to standardize hemotherapy, and to facilitate PBM components. METHODS: This article analyzes barriers to PBM implementation and outlines a strategy to introduce and manifest PBM. The effects in Frankfurt were measured in a before and after questionnaire study distributed among groups of physicians immediately before and 1 year after PBM implementation. RESULTS: 142 clinicians completed the questionnaire in July 2013 and 101 clinicians in August 2014. Absolute certainty that the treatment of preoperative anemia favorably influences morbidity and mortality rose from 25 to 37%. Transfusion behavior seems to have been affected: In 2014, 56% of clinicians stated that they clinically reassess the patient and analyze hemoglobin following each single red blood cell unit compared to only 38% stating this in 2013. CONCLUSION: These results show that our implementation strategy was effective in changing physicians' risk perception, attitude, and knowledge on PBM principles. Our experience highlights key success factors for the implementation of a comprehensive PBM program. PMID- 26019705 TI - Preoperative Thromboelastometry as a Predictor of Transfusion Requirements during Adult Living Donor Liver Transplantation. AB - BACKGROUND: The ability to predict transfusion requirements may improve perioperative bleeding management as an integral part of a patient blood management program. Therefore, the aim of our study was to evaluate preoperative thromboelastometry as a predictor of transfusion requirements for adult living donor liver transplant recipients. METHODS: The correlation between preoperative thromboelastometry variables in 100 adult living donor liver transplant recipients and intraoperative blood transfusion requirements was examined by univariate and multivariate linear regression analysis. Thresholds of thromboelastometric parameters for prediction of packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate transfusion requirements were determined with receiver operating characteristics analysis. The attending anesthetists were blinded to the preoperative thromboelastometric analysis. However, a thromboelastometry-guided transfusion algorithm with predefined trigger values was used intraoperatively. The transfusion triggers in this algorithm did not change during the study period. RESULTS: Univariate analysis confirmed significant correlations between PRBCs, FFP, platelets or cryoprecipitate transfusion requirements and most thromboelastometric variables. Backward stepwise logistic regression indicated that EXTEM coagulation time (CT), maximum clot firmness (MCF) and INTEM CT, clot formation time (CFT) and MCF are independent predictors for PRBC transfusion. EXTEM CT, CFT and FIBTEM MCF are independent predictors for FFP transfusion. Only EXTEM and INTEM MCF were independent predictors of platelet transfusion. EXTEM CFT and MCF, INTEM CT, CFT and MCF as well as FIBTEM MCF are independent predictors for cryoprecipitate transfusion. Thromboelastometry-based regression equation accounted for 63% of PRBC, 83% of FFP, 61% of cryoprecipitate, and 44% of platelet transfusion requirements. CONCLUSION: Preoperative thromboelastometric analysis is helpful to predict transfusion requirements in adult living donor liver transplant recipients. This may allow for better preparation and less cross-matching prior to surgery. The findings of our study need to be re-validated in a second prospective patient population. PMID- 26019706 TI - Evidence base for restrictive transfusion triggers in high-risk patients. AB - Liberal versus restrictive red blood cell (RBC) transfusion triggers have been debated for years. This review illustrates the human body's physiologic response to acute anemia and summarizes the evidence from prospective randomized trials (RCTs) for restrictive use of RBC transfusions in high-risk patients. During progressive anemia, the human body maintains the oxygen delivery to the tissues by an increase in cardiac output and peripheral oxygen extraction. Seven RCTs with a total of 5,566 high-risk patients compared a restrictive hemoglobin (Hb) transfusion trigger (Hb < 70 or < 80 g/l) with a liberal Hb transfusion trigger (Hb < 90 or < 100 g/l). Unanimously these studies show non-inferiority, safety, and a significant reduction in RBC transfusions in the restrictive groups. In one RCT mortality was higher in the liberal Hb transfusion group, and in two additional RCTs mortality of subgroups or after risk adjustment was significantly higher in the liberal Hb transfusion trigger groups. CONCLUSION: Strong RCT evidence suggests the safety of restrictive transfusion triggers. As a consequence, an Hb transfusion trigger of <70 g/l is recommended for high risk patients. PMID- 26019708 TI - Static image analysis as new approach for the characterization of tumor cell lysate used in dendritic cell vaccine preparation. AB - BACKGROUND: Safety is an important consideration for the clinical application of dendritic cells (DC) loaded with autologous tumor lysate (TL). Thus, avitalization of TL from living autologous tumor tissue has to be guaranteed. METHODS: Composition of TL was investigated by static image analysis (SIA) with the Morphologi G3 device, which simultaneously measures size and shape of up to 100,000 particles within one sample run. This approach was compared with sample characterization by high-resolution automated cell counting, trypan blue staining, and ATP quantification. RESULTS: Using SIA, we only detected fragmented, non-cellular structures in completely avitalized TL, indicating complete destruction of living cells. Analysis of particle size distribution by SIA as well as CASY cell counter showed that 95% of particles had a diameter of <10 um as a sign of cell fragmentation. Complete avitalization of TL was confirmed with trypan blue staining and ATP analysis. CONCLUSION: Regarding generation of DC vaccines, the proof of avitality of TL from living tumor tissue can clearly be achieved by SIA alone or in combination with standard assays. Our data show that SIA is a highly precise method for TL characterization. The SIA device complies with FDA regulation and, therefore, might be suitable for characterization of cellular therapy medicinal products. PMID- 26019707 TI - Point of care and factor concentrate-based coagulation algorithms. AB - In the last years it has become evident that the use of blood products should be reduced whenever possible. There is increasing evidence regarding serious adverse events, including higher mortality and morbidity, related to transfusions. The use of point of care (POC) devices integrated in algorithms is one of the important mechanisms to limit blood product exposure. Any type of algorithm, especially the POC-based ones, allows goal-directed transfusions of blood products and even better targeted factor concentrate substitutions. Different types of algorithms in different surgical settings (cardiac surgery, trauma, liver surgery etc.) have been established with growing interest in their use as they offer objective therapy for management and reduction of blood product use. The use of POC devices with evidence-based algorithms is important in the bleeding patient independent of its origin (traumatic vs. surgical). The use of factor concentrates compared to the classical blood products can be cost-saving, beneficial for the patient, and in agreement with the WHO-requested standard of care. The empiric and uncontrolled use of blood products such as fresh frozen plasma, red blood cells, and platelets without POC monitoring should no longer be followed with regard to actual evidence in literature. Furthermore, the use of factor concentrates may provide better outcomes and potential for cost saving. PMID- 26019709 TI - Management of a pregnant woman with anti-holley alloantibody. AB - BACKGROUND: Holley (Hy) is a high-incidence antigen of the Dombrock blood group system (ISBT 014), present in almost 100% of most populations and more than 99% of Blacks. Since anti-Hy is an extremely rare antibody, data on its clinical relevance and in particular on a possible hemolytic disease of the fetus and newborn (HDFN) are scarce. CASE REPORT: The pregnant patient underwent two autologous whole blood collections at weeks 17 and 19 of gestation with cryopreservation. In our case autologous whole blood collection was well tolerated. There were no signs of HDFN in the healthy newborn. CONCLUSION: Our case improves our understanding of anti-Hy alloantibodies during pregnancy. Additionally, autologous whole blood collection of RBC units with cryopreservation is a safe and feasible way to manage pregnancies in women with rare alloantibodies, when no compatible donor can be found. PMID- 26019710 TI - The development of carotid stent material. AB - Endovascular angioplasty with stenting is a promising option for treating carotid artery stenosis. There exist a rapidly increasing number of different stent types with different materials. The bare-metal stent is the most commonly used stent with acceptable results, but it leaves us with the problems of thrombosis and restenosis. The drug-eluting stent is a breakthrough as it has the ability to reduce the restenosis rate, but the problem of late thrombosis still has to be addressed. The biodegradable stent disappears after having served its function. However, restenosis and degradation rates remain to be studied. In this article, we review every stent material with its characteristics, clinical results and complications and point out the standards of an ideal carotid stent. PMID- 26019711 TI - High-flow carotid cavernous fistula and the use of a microvascular plug system: initial experience. AB - PURPOSE: We report our initial experience using a detachable microvascular plug system to occlude the internal carotid artery during endovascular treatment of high-flow carotid cavernous fistula. CASE AND TECHNIQUE: An 87-year-old patient was admitted for acute-onset double vision with associated right-eye ptosis. Exam revealed a pupil-sparing, partial right third cranial nerve palsy. MRI showed a carotid cavernous fistula with high-flow drainage. Digital subtraction angiography showed a high-flow, right-sided, direct carotid cavernous fistula with flow from the proximal right internal carotid artery. The ophthalmic artery, posterior communicating artery and anterior communicating arteries supplied retrograde flow to the fistula through the internal carotid artery. Obliteration of the fistula was achieved through coil embolization in combination with proximal and distal microvascular plugs (Reverse Medical, Irvine, Calif., USA). CONCLUSION: The microvascular plug is a new addition to current endovascular embolization devices for the treatment of high-flow, direct carotid cavernous fistulas. This technique offers easy navigability through tortuous arteries, precise localization and immediate occlusion, which may allow shorter procedure and fluoroscopy times and increased cost-effectiveness. Larger case series are needed to support our observation. PMID- 26019712 TI - Implementation of Intraoperative Neurophysiological Monitoring during Endovascular Procedures in the Central Nervous System. AB - BACKGROUND AND OBJECTIVE: Intraoperative monitoring (IOM) has been used in different surgical disciplines since the 1980s. Nonetheless, regular routine use of IOM in interventional neuroradiology units has only been reported in a few centers. The aim of this study is to report our experience, 1 year after deciding to implement standardized IOM during endovascular treatment of vascular abnormalities of the central nervous system. METHODS: Basic recordings included somatosensory-evoked potentials (SEPs) and motor-evoked potentials (MEPs). Corticobulbar motor-evoked potentials and flash-visual-evoked potentials were also recorded depending on the topography of the lesion. Intra-arterial provocative tests (PTs) with amobarbital and lidocaine were also performed. All patients except 1 were under total intravenous anesthesia. Clinical outcome was assessed prospectively and correlated with IOM events. RESULTS: Twelve patients and 15 procedures were monitored during the inclusion period. Significant IOM events were detected during 3 of the 15 procedures (20%). We observed temporary MEP changes in 2 cases which resolved after interruption of the embolization or application of corrective measures, leaving no postoperative neurological deficits. In 1 case, persistent SEP and MEP deterioration was detected secondary to a frontal hematoma, resulting in mild sensory-motor deficit in the right upper extremity after the procedure. Overall, 12 PTs (4 spinal cord and 8 brain abnormalities) were performed using lidocaine and sodium amytal injections. One positive result occurred after the injection of lidocaine. No false negatives were detected. CONCLUSIONS: IOM may provide continuous real-time data about the functional status of eloquent areas and pathways of the central nervous system in patients under general anesthesia. It therefore allows us to detect early neurological damage in time to perform specific actions that may prevent irreversible neurological deficits. PMID- 26019713 TI - Thrombolysis in chinese ischemic stroke patients with renal dysfunction. AB - BACKGROUND: Current data concerning the relationship between renal function and clinical outcome among stroke patients treated with intravenous thrombolytic therapy are conflicting. Our aim is to analyze whether the clinical outcome of Chinese ischemic stroke patients treated with thrombolytic therapy is affected by the presence of renal dysfunction. METHODS: Chinese patients who received intravenous thrombolytic therapy for acute ischemic stroke were recruited. Renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m(2). The primary outcome was independent function (modified Rankin Scale, mRS, 0-2) at 3 months, while secondary outcomes included early improvement of the National Institute of Health Stroke Scale (NIHSS) score of >=4 points at 24 h, symptomatic intracerebral hemorrhage (ICH) within 36 h of treatment and 30 day mortality. RESULTS: A total of 199 patients were recruited, of whom 51.3% had renal dysfunction. There were no significant differences in functional independence at 3 months, NIHSS improvement at 24 h post-thrombolysis and 30-day mortality between patients with or without renal dysfunction. Multivariate analysis showed that eGFR as a continuous variable was not an independent risk factor for symptomatic ICH. CONCLUSION: Chinese ischemic stroke patients with renal dysfunction who received thrombolytic therapy had clinical outcomes similar to those without renal dysfunction. PMID- 26019714 TI - Periprocedural cost-effectiveness analysis of mechanical thrombectomy for acute ischemic stroke in the stent retriever era. AB - BACKGROUND: Early reperfusion is critical for favorable outcomes in acute ischemic stroke (AIS). Stent retrievers lead to faster and more complete reperfusion than previous technologies. Our aim is to compare the cost effectiveness of stent retrievers to the previous mechanical thrombectomy devices. METHODS: Retrospective review of endovascularly treated large-vessel AIS. Data from all consecutive patients who underwent thrombectomy from January 2012 through November 2012 were collected. Baseline characteristics, the total procedural cost, the rates of successful recanalization [modified thrombolysis in cerebral ischemia (mTICI) scores of 2b or 3], and the length of stay at the hospital were compared between the stent retriever (SR) and the non-stent retriever (NSR) groups. RESULTS: After excluding the patients who underwent concomitant extracranial stenting (n = 22) or received intra-arterial tissue plasminogen activator only (n = 6), the entire cohort included 150 patients. The cost of the reperfusion procedure was significantly higher in the SR compared to the NSR group (USD 13,419 vs. 9,308, p <0.001). We were unable to demonstrate a statistically significant difference in the rates of mTICI 2b/3 reperfusion (81 vs. 74%, p = 0.337) or the length of stay (11.1 +/- 9.1 vs. 12.8 +/- 9.6 days, p = 0.260) amongst the SR and the NSR patients. CONCLUSION: The procedural costs of thrombectomy for AIS are increasing and account for the bulk of hospitalization reimbursement. The impact of these expenditures in the long-term sustainability of stroke centers deserves greater consideration. While it is likely that the SR technology results in higher rates of optimal reperfusion, better clinical outcomes, and shorter lengths of stay, larger studies are needed to prove its cost-effectiveness. PMID- 26019715 TI - TRiP: Tracking Rhythms in Plants, an automated leaf movement analysis program for circadian period estimation. AB - BACKGROUND: A well characterized output of the circadian clock in plants is the daily rhythmic movement of leaves. This process has been used extensively in Arabidopsis to estimate circadian period in natural accessions as well as mutants with known defects in circadian clock function. Current methods for estimating circadian period by leaf movement involve manual steps throughout the analysis and are often limited to analyzing one leaf or cotyledon at a time. RESULTS: In this study, we describe the development of TRiP (Tracking Rhythms in Plants), a new method for estimating circadian period using a motion estimation algorithm that can be applied to whole plant images. To validate this new method, we apply TRiP to a Recombinant Inbred Line (RIL) population in Arabidopsis using our high throughput imaging platform. We begin imaging at the cotyledon stage and image through the emergence of true leaves. TRiP successfully tracks the movement of cotyledons and leaves without the need to select individual leaves to be analyzed. CONCLUSIONS: TRiP is a program for analyzing leaf movement by motion estimation that enables high-throughput analysis of large populations of plants. TRiP is also able to analyze plant species with diverse leaf morphologies. We have used TRiP to estimate period for 150 Arabidopsis RILs as well as 5 diverse plant species, highlighting the broad applicability of this new method. PMID- 26019716 TI - Comorbidity Among Dimensions of Childhood Psychopathology: Converging Evidence from Behavior Genetics. AB - In this article, we review evidence from recent behavior genetic studies that examined the covariance among common childhood psychopathological conditions and tested specific hypotheses regarding common and broadband-specific underlying features of childhood psychopathology. Specifically, we review the distinction between internalizing and externalizing disorders, the support for the generalist genes and specialist environments model, negative emotionality as a heritable underlying feature common to both internalizing and externalizing disorders, and daring as a heritable broadband-specific underlying feature that distinguishes externalizing disorders from internalizing disorders. We also discuss the implications of research in the search for specific genes that influence childhood psychopathology and suggest avenues for new research. PMID- 26019717 TI - Development of Maladaptive Coping: A Functional Adaptation to Chronic, Uncontrollable Stress. AB - Health disparities are rooted in childhood and stem from adverse early environments that damage physiologic stress-response systems. Developmental psychobiological models of the effects of chronic stress account for both the negative effects of a stress-response system calibrated to a dangerous and unpredictable environment from a health perspective, and the positive effects of such an adaptively calibrated stress response from a functional perspective. Our research suggests that contexts that produce functionally adapted physiologic responses to stress also encourage a functionally adapted coping response-coping that can result in maladjustment in physical and mental health, but enables children to grow and develop within those contexts. In this article, I highlight the value of reframing maladaptive coping as functional adaptation to understand more completely the development of children's coping in different contexts, and the value of such a conceptual shift for coping-based theory, research, and intervention. PMID- 26019718 TI - Bilingualism and the Development of Executive Function: The Role of Attention. AB - This paper reviews research examining the effect of bilingualism on children's cognitive development, and in particular, executive function. Studies reporting bilingual advantages in various tasks are described with the purpose of identifying the process or executive function component that might be responsible for this bilingual advantage. Several possibilities are discussed, such as inhibitory control. Finally, the role of attention is proposed as a fundamental process that initiates developmental differences in bilingual children from as early as infancy. PMID- 26019719 TI - Social and psychological factors of the suicidal tendencies of Chinese medical students. AB - BACKGROUND: Over the past few decades, concern about suicide by college students has been on the rise worldwide, in general and in China particularly. The main objective of this study is to investigate the effects of social and psychological factors on the suicidal tendencies of Chinese medical students. FINDINGS: Of the 540 students surveyed, 48 had a suicidal tendency to some extent. The highest rate of suicide was observed for fourth-year students, followed by the fifth year, first-year, third-year, and second-year students. Female students and students not satisfied with their major had a higher rate of suicidal tendency. However, mature coping strategies had a protective effect on suicide. The stepwise regression analysis shows that academic burden, grade, and introversion/extraversion are the most significant risk factors for the suicidal tendency of Chinese medical students. CONCLUSION: Suicide is affected by demographic risk factors as well as psychological factors. Our results lend support to a multi-factorial approach to the understanding and prevention of suicide by college students. PMID- 26019720 TI - The effect of cognitive appraisal for stressors on the oral health-related QOL of dry mouth patients. AB - BACKGROUND: Dry mouth is very common symptom, and psychological factors have an influence on this symptom. Although the influence of emotional factor related to patients with oral dryness has been examined in previous studies, the cognitive factors have not been examined thus far. OBJECTIVE: The purpose of this study was to examine the influence of cognitive factors on patients with oral dryness. METHODS: The participants were 106 patients complaining of oral dryness. They were required to complete a questionnaire measuring subjective oral dryness, oral related QOL, cognition for stressors, and mood state. RESULTS: Correlational analyses revealed that OHIP-14 is significantly related to oral dryness, appraisal for effect, appraisal for threat, and commitment. These correlations were maintained even after controlling for the influence of depression and anxiety. Using oral dryness, appraisal for effect, appraisal for threat, and commitment, cluster analysis was done and three clusters (cluster-1, severe oral dryness; cluster-2, positive cognitive style: cluster-3, negative cognitive style) were extracted. The results of ANOVA showed that the group with severe oral dryness (cluster-1) had a significantly higher score on OHIP-14 than the other two groups. There was no significant difference between the groups with positive (cluster-2) and negative (cluster-3) cognitive style. CONCLUSION: Although the group of patients with positive cognitive style complained of more severe oral dryness than the group with negative cognitive style, no significant difference was observed between these two groups in OHIP-14. These results indicate that cognitive factors would be a useful therapeutic target for the improvement of the oral-related QOL of patients with oral dryness. PMID- 26019721 TI - Depression, anxiety and major adverse cardiovascular and cerebrovascular events in patients following coronary artery bypass graft surgery: a five year longitudinal cohort study. AB - BACKGROUND: Although depression and anxiety have been implicated in risk for major adverse cardiovascular and cerebrovascular events (MACCE), a theoretical approach to identifying such putative links is lacking. The objective of this study was to examine the association between theoretical conceptualisations of depression and anxiety with MACCE at the diagnostic and symptom dimension level. METHODS: Before coronary artery bypass graft (CABG) surgery, patients (N = 158; 20.9 % female) underwent a structured clinical interview to determine caseness for depression and anxiety disorders. Depression and anxiety disorders were arranged into the distress cluster (major depression, dysthymia, generalized anxiety disorder, post-traumatic stress disorder) and fear cluster (panic disorder, agoraphobia, social phobia). Patients also completed the self-report Mood and Anxiety Symptom Questionnaire, measuring anhedonia, anxious arousal and general distress/negative affect symptom dimensions. Incident MACCE was defined as fatal or non-fatal; myocardial infarction, unstable angina pectoris, repeat revascularization, heart failure, sustained arrhythmia, stroke or cerebrovascular accident, left ventricular failure and mortality due to cardiac causes. Time-to MACCE was determined by hazard modelling after adjustment for EuroSCORE, smoking, body mass index, hypertension, heart failure and peripheral vascular disease. RESULTS: In the total sample, there were 698 cumulative person years of survival for analysis with a median follow-up of 4.6 years (interquartile range 4.2 to 5.2 years) and 37 MACCE (23.4 % of total). After covariate adjustment, generalized anxiety disorder was associated with MACCE (hazard ratio [HR] = 2.79, 95 % confidence interval [CI] 1.00-7.80, p = 0.049). The distress disorders were not significantly associated with MACCE risk (HR = 2.14; 95 % CI .92-4.95, p = 0.077) and neither were the fear-disorders (HR = 0.24, 95 % CI .05-1.20, p = 0.083). None of the symptom dimensions were significantly associated with MACCE. CONCLUSIONS: Generalized anxiety disorder was significantly associated with MACCE at follow-up after CABG surgery. The findings encourage further research pertaining to generalized anxiety disorder, and theoretical conceptualizations of depression, general distress and anxiety in persons undergoing CABG surgery. PMID- 26019722 TI - Diverse models for anti-HIV activity of purine nucleoside analogs. AB - BACKGROUND: Purine nucleoside analogs (PNAs) constitute an important group of cytotoxic drugs for the treatment of neoplastic and autoimmune diseases. In the present study, classification models have been developed for the prediction of the anti-HIV activity of purine nucleoside analogs. RESULTS: The topochemical version of superaugmented pendentic index-4 has been proposed and successfully utilized for the development of models. A total of 60 2D and 3D molecular descriptors (MDs) of diverse nature were selected for building the classification models using decision tree (DT), random forest (RF), support vector machine (SVM), and moving average analysis (MAA). The values of most of these descriptors for each of the analogs in the dataset were computed using the Dragon software (version 5.3). An in-house computer program was also employed to calculate additional MDs which were not included in the Dragon software. DT, RF, and SVM correctly classified the analogs into actives and inactives with an accuracy of 89 %, 83 %, and 78 %, respectively. MAA-based models predicted the anti-HIV activity of purine nucleoside analogs with a non-error rate up to 98 %. Therapeutic active spans of the suggested MAA-based models not only showed more potency but also exhibited enhanced safety as revealed by comparatively high values of selectivity index (SI). The statistical importance of the developed models was appraised via intercorrelation analysis, specificity, sensitivity, non error rate, and Matthews correlation coefficient. CONCLUSIONS: High predictability of the proposed models clearly indicates an immense potential for developing lead molecules for potent but safe anti-HIV purine nucleoside analogs. PMID- 26019723 TI - Whole genome prediction for preimplantation genetic diagnosis. AB - BACKGROUND: Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD). METHODS: We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha thalassemia. RESULTS: Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent. CONCLUSIONS: Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos. PMID- 26019724 TI - JAFFA: High sensitivity transcriptome-focused fusion gene detection. AB - Genomic instability is a hallmark of cancer and, as such, structural alterations and fusion genes are common events in the cancer landscape. RNA sequencing (RNA Seq) is a powerful method for profiling cancers, but current methods for identifying fusion genes are optimised for short reads. JAFFA (https://github.com/Oshlack/JAFFA/wiki) is a sensitive fusion detection method that outperforms other methods with reads of 100 bp or greater. JAFFA compares a cancer transcriptome to the reference transcriptome, rather than the genome, where the cancer transcriptome is inferred using long reads directly or by de novo assembling short reads. PMID- 26019726 TI - Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences. AB - Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online 'TB Profiler' tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing. PMID- 26019727 TI - Substrate Stiffness Affects Human Keratinocyte Colony Formation. AB - Restoration of epidermal organization and function in response to a variety of pathophysiological insults is critically dependent on coordinated keratinocyte migration, proliferation, and stratification during the process of wound healing. These processes are mediated by the reconfiguration of both cell-cell (desmosomes, adherens junctions) and cell-matrix (focal adhesions, hemidesmosomes) junctions and the cytoskeletal filament networks that they serve to interconnect. In this study, we investigated the role of substrate elasticity (stiffness) on keratinocyte colony formation in vitro during the process of nascent epithelial sheet formation as triggered by the calcium switch model of keratinocyte culture. Keratinocytes cultured on pepsin digested type I collagen coated soft (nominal E = 1.2 kPa) polyacrylamide gels embedded with fluorescent microspheres exhibited (i) smaller spread contact areas, (ii) increased migration velocities, and (iii) increased rates of colony formation with more cells per colony than did keratinocytes cultured on stiff (nominal E = 24 kPa) polyacrylamide gels. As assessed by tracking of embedded microsphere displacements, keratinocytes cultured on soft substrates generated large local substrate deformations that appeared to recruit adjacent keratinocytes into joining an evolving colony. Together with the observed differences in keratinocyte kinematics and substrate deformations, we developed two ad hoc analyses, termed distance rank (DR) and radius of cooperativity (RC), that help to objectively ascribe what we perceive as increasingly cooperative behavior of keratinocytes cultured on soft versus stiff gels during the process of colony formation. We hypothesize that the differences in keratinocyte colony formation observed in our experiments could be due to cell-cell mechanical signaling generated via local substrate deformations that appear to be correlated with the increased expression of beta4 integrin within keratinocytes positioned along the periphery of an evolving cell colony. PMID- 26019725 TI - RNA interference approaches for treatment of HIV-1 infection. AB - HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery. PMID- 26019728 TI - Impulsive Enzymes: A New Force in Mechanobiology. AB - We review studies that quantify newly discovered forces from single enzymatic reactions. These forces arise from the conversion of chemical energy to kinetic energy, which can be harnessed to direct diffusion of the enzyme up a concentration gradient of substrate, a novel phenomenon of molecular chemotaxis. When immobilized, enzymes can move fluid around them and perform directional pumping in microfluidic chambers. Because of the extensive array of enzymes in biological cells, we also develop three new hypotheses: that enzymatic self diffusion can assist in organizing signaling pathways in cells, can assist in pumping of fluid in cells, and can impose biologically significant forces on organelles, which will be manifested as stochastic motion not explained by thermal forces or myosin II. Such mechanochemical phenomena open up new directions in research in mechanobiology in which all enzymes, in addition to their primary function as catalysts for reactions, may have secondary functions as initiators of mechanosensitive transduction pathways. PMID- 26019729 TI - Resin infiltration into differentially extended experimental carious lesions. AB - Resin infiltration of initial caries lesions is a novel method of caries therapy. However, it has some limitations. Therefore, further experimental studies are needed to improve resin infiltration. It was the aim of this investigation to study resin infiltra-tion into different experimental carious lesions. Caries free extracted human molars and premolars were demineralized for 3, 6, 9 and 12 days and infiltrated with resin. Prior to infiltration, the teeth were incubated with sodium fluorescein. After em-bedding, serial sections were cut through the experimental lesions, and the penetration of the resin was measured with fluo rescence microscopy. Two infiltrated teeth from each time interval were not embedded and cut. Infiltration of the resin was then studied with EDS element analysis. The results showed that with increasing demineralization time, the lesion expansion was also increasing, and the resin infiltration was always almost complete. From these results it can be concluded that artifi-cial standardized caries-like lesions are suitable for experimental studies of resin infiltration. PMID- 26019730 TI - Combining Wireless Neural Recording and Video Capture for the Analysis of Natural Gait. AB - Neural control of movement is typically studied in constrained environments where there is a reduced set of possible behaviors. This constraint may unintentionally limit the applicability of findings to the generalized case of unconstrained behavior. We hypothesize that examining the unconstrained state across multiple behavioral contexts will lead to new insights into the neural control of movement and help advance the design of neural prosthetic decode algorithms. However, to pursue electrophysiological studies in such a manner requires a more flexible framework for experimentation. We propose that head-mounted neural recording systems with wireless data transmission, combined with markerless computer-vision based motion tracking, will enable new, less constrained experiments. As a proof of-concept, we recorded and wirelessly transmitted broadband neural data from 32 electrodes in premotor cortex while acquiring single-camera video of a rhesus macaque walking on a treadmill. We demonstrate the ability to extract behavioral kinematics using an automated computer vision algorithm without use of markers and to predict kinematics from the neural data. Together these advances suggest that a new class of "freely moving monkey" experiments should be possible and should help broaden our understanding of the neural control of movement. PMID- 26019731 TI - Ethanol-induced hepatic autophagy: Friend or foe? AB - Excessive alcohol intake may induce hepatic apoptosis, steatosis, fibrosis, cirrhosis and even cancer. Ethanol-induced activation of general or selective autophagy as mitophagy or lipophagy in hepatocytes is generally considered a prosurvival mechanism. On the other side of the coin, upregulation of autophagy in non-hepatocytes as stellate cells may stimulate fibrogenesis and subsequently induce detrimental effects on the liver. The autophagic response of other non hepatocytes as macrophages and endothelial cells is unknown yet and needs to be investigated as these cells play important roles in ethanol-induced hepatic steatosis and damage. Selective pharmacological stimulation of autophagy in hepatocytes may be of therapeutic importance in alcoholic liver disease. PMID- 26019732 TI - Hepatocellular carcinoma: Advances in diagnosis, management, and long term outcome. AB - Hepatocellular carcinoma (HCC) remains a common and lethal malignancy worldwide and arises in the setting of a host of diseases. The incidence continues to increase despite multiple vaccines and therapies for viruses such as the hepatitis B and C viruses. In addition, due to the growing incidence of obesity in Western society, there is anticipation that there will be a growing population with HCC due to non-alcoholic fatty liver disease. Due to the growing frequency of this disease, screening is recommended using ultrasound with further imaging using magnetic resonance imaging and multi-detector computed tomography used for further characterization of masses. Great advances have been made to help with the early diagnosis of small lesions leading to potential curative resection or transplantation. Resection and transplantation maybe used in a variety of patients that are carefully selected based on underlying liver disease. Using certain guidelines and clinical acumen patients may have good outcomes with either resection or transplantation however many patients are inoperable at time of presentation. Fortunately, the use of new locoregional therapies has made down staging patients a potential option making them potential surgical candidates. Despite a growing population with HCC, new advances in viral therapies, chemotherapeutics, and an expanding population of surgical and transplant candidates might all contribute to improved long-term survival of these patients. PMID- 26019733 TI - Hepatocellular carcinoma: Surgeon's view on latest findings and future perspectives. AB - Hepatocellular carcinoma (HCC) is the most common liver-derived malignancy with a high fatality rate. Risk factors for the development of HCC have been identified and are clearly described. However, due to the lack of tumor-specific symptoms, HCC are diagnosed at progressed tumor stages in most patients, and thus curative therapeutic options are limited. The focus of this review is on surgical therapeutic options which can be offered to patients with HCC with special regard to recent findings, not exclusively focused on surgical therapy, but also to other treatment modalities. Further, potential promising future perspectives for the treatment of HCC are discussed. PMID- 26019734 TI - Intermediate hepatocellular carcinoma: How to choose the best treatment modality? AB - Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is "a priori" preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be "patient-tailored" and made by a multidisciplinary team. PMID- 26019737 TI - Chronic hepatitis B infection in pregnancy. AB - There are no standard guidelines to follow when a patient with chronic hepatitis B infection becomes pregnant or desires pregnancy. Topics to consider include which patients to treat, when to start treatment, what treatment to use and when to stop treatment. Without any prophylaxis or antiviral therapy, a hepatitis B surface antigen and E antigen positive mother has up to a 90% likelihood of vertical transmission of hepatitis B virus (HBV) to child. Standard of care in the United States to prevent perinatal transmission consists of administration of hepatitis B immune globulin and HBV vaccination to the infant. The two strongest risk factors of mother to child transmission (MTCT) of HBV infection despite immunoprophylaxis are high maternal HBV viral load and high activity of viral replication. The goal is to prevent transmission of HBV at birth by decreasing viral load and/or decreasing activity of the virus. Although it is still somewhat controversial, most evidence shows that starting antivirals in the third trimester is effective in decreasing MTCT without affecting fetal development. There is a growing body of literature supporting the safety and efficacy of antiviral therapies to reduce MTCT of hepatitis B. There are no formal recommendations regarding which agent to choose. Tenofovir, lamivudine and telbivudine have all been proven efficacious in decreasing viral load at birth without known birth defects, but final decision of which antiviral medication to use will have to be determined by physician and patient. The antivirals may be discontinued immediately if patient is breastfeeding, or within first four weeks if infant is being formula fed. PMID- 26019735 TI - Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries. AB - Heterogeneity in clinical presentation, histological severity, prognosis and therapeutic outcomes characteristic of non-alcoholic fatty liver disease (NAFLD) necessitates the development of scientifically sound classification schemes to assist clinicians in stratifying patients into meaningful prognostic subgroups. The need for replacement of invasive liver biopsies as the standard method whereby NAFLD is diagnosed, graded and staged with biomarkers of histological severity injury led to the development of composite prognostic models as potentially viable surrogate alternatives. In the present article, we review existing scoring systems used to (1) confirm the presence of undiagnosed hepatosteatosis; (2) distinguish between simple steatosis and NASH; and (3) predict advanced hepatic fibrosis, with particular emphasis on the role of NAFLD as an independent cardio-metabolic risk factor. In addition, the incorporation of functional genomic markers and application of emerging imaging technologies are discussed as a means to improve the diagnostic accuracy and predictive performance of promising composite models found to be most appropriate for widespread clinical adoption. PMID- 26019738 TI - Anticoagulation and antiplatelets as prophylaxis for hepatic artery thrombosis after liver transplantation. AB - Hepatic artery thrombosis (HAT) is the most serious vascular complication after liver transplantation. Multiple risk factors have been identified to impact its development. Changes in haemostasis associated with end stage liver disease and the disturbance of the coagulation and anticoagulation cascades play an important role in development of this lethal complication. Early recognition and therapeutic intervention is mandatory to avoid its consequences. Pharmacological prophylaxis, by the use of antiplatelet or anticoagulant agents, is an important tool to reduce its incidence and prevent graft loss. Only a few studies have shown a clear benefit of antiplatelet agents in reducing HAT occurrence, however, these studies are limited by being retrospective and by inhomogeneous populations. The use of anticoagulants such as heparin is associated with an improvement in the outcomes mainly when used for a high-risk patients like living related liver recipients. The major concern when using these agents is the tendency to increase bleeding complications in a setting of already unstable haemostasis. Hence, monitoring of their administration and careful selection of patients to be treated are of great importance. Well-designed clinical studies are still needed to further explore their effects and to formulate proper protocols that can be implemented safely. PMID- 26019736 TI - Traditional Chinese medicine for prevention and treatment of hepatocarcinoma: From bench to bedside. AB - Traditional Chinese medicine (TCM) has played a positive role in the management of hepatocarcinoma. Hepatocarcinoma patients may present Qi-stagnation, damp heat, blood stasis, Qi-deficiency, Yin-deficiency and other TCM syndromes (Zheng). Modern treatments such as surgery, transarterial chemoembolization (TACE) and high intensity focus ultrasound treatment would influence the manifestation of TCM syndromes. Herbs with traditional efficacy of tonifying Qi, blood and Yin, soothing liver-Qi stagnation, clearing heat and detoxifying and dissolving stasis, have been demonstrated to be potent to prevent hepatocarcinogenesis. TCM has been widely used in all aspects of integrative therapy in hepatocarcinoma, including surgical resection, liver transplantation, TACE, local ablative therapies and even as monotherapy for middle-advanced stage hepatocarcinoma. Clinical practices have confirmed that TCM is effective to alleviate clinical symptoms, improve quality of life and immune function, prevent recurrence and metastasis, delay tumor progression, and prolong survival time in hepatocarcinoma patients. The effective mechanism of TCM against hepatocarcinoma is related to inducing apoptosis, autophagy, anoikis and cell senescence, arresting cell cycle, regulating immune function, inhibiting metastasis and angiogenesis, reversing drug resistance and enhancing effects of chemotherapy. Along with the progress of research in this field, TCM will contribute more to the prevention and treatment of hepatocarcinoma. PMID- 26019739 TI - New prognostic markers in liver cirrhosis. AB - Determining the prognosis of cirrhotic patients is not an easy task. Prognostic scores, like Child-Pugh and Model of End-stage Liver Disease scores, are commonly used by hepatologists, but do not always reflect superimposed events that may strongly influence the prognosis. Among them, bacterial intestinal translocation is a key phenomenon for the development of cirrhosis-related complications. Several biological variables (C-reactive protein, serum free cortisol, copeptin, von Willebrand factor antigen) are surrogates of "inflammatory stress" and have recently been identified as potential prognostic markers in cirrhotic patients. Most of these above mentioned markers were investigated in pilot studies with sometimes a modest sample size but allow us to catch a glimpse of the pathophysiological mechanisms leading to the worsening of cirrhosis. These new data should generate further well-designed studies to better assess the benefit for liver function of preventing intestinal bacterial translocation and microvascular thrombosis. The control of infection is vital and among all actors of immunity, vitamin D also appears to act as an anti-infective agent and therefore has probably a prognostic value. PMID- 26019740 TI - Valproic acid and nonalcoholic fatty liver disease: A possible association? AB - Valproic acid (VPA) is one of the most prescribed drugs in children with newly diagnosed epilepsy. Weight gain and obesity have been observed as side effects of VPA. These are often linked with other metabolic disturbances such as development of insulin resistance, dyslipidemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD). NAFLD refers to a group of liver disorders with marked hepatic steatosis. It is associated with an increased incidence of cardiovascular diseases and overall reduced life expectancy. NAFLD occurs in 20%-25% of the general population and it is known to be the most common cause of chronic liver disease. NAFLD therefore represents a major public health issue worldwide. This study reviews and summarizes relevant literature that supports the existence of an association between VPA therapy and the development of NAFLD in children. Long-term VPA-therapy appears to be associated with an increased risk of developing NAFLD. Further studies are needed to clarify the pathogenic mechanisms that lie behind this association and to standardize the options for the use of this drug in overweight patients and in those with risks for developing MetS and NAFLD. PMID- 26019741 TI - Bone changes in alcoholic liver disease. AB - Alcoholism has been associated with growth impairment, osteomalacia, delayed fracture healing, and aseptic necrosis (primarily necrosis of the femoral head), but the main alterations observed in the bones of alcoholic patients are osteoporosis and an increased risk of fractures. Decreased bone mass is a hallmark of osteoporosis, and it may be due either to decreased bone synthesis and/or to increased bone breakdown. Ethanol may affect both mechanisms. It is generally accepted that ethanol decreases bone synthesis, and most authors have reported decreased osteocalcin levels (a "marker" of bone synthesis), but some controversy exists regarding the effect of alcohol on bone breakdown, and, indeed, disparate results have been reported for telopeptide and other biochemical markers of bone resorption. In addition to the direct effect of ethanol, systemic alterations such as malnutrition, malabsorption, liver disease, increased levels of proinflammatory cytokines, alcoholic myopathy and neuropathy, low testosterone levels, and an increased risk of trauma, play contributory roles. The treatment of alcoholic bone disease should be aimed towards increasing bone formation and decreasing bone degradation. In this sense, vitamin D and calcium supplementation, together with biphosphonates are essential, but alcohol abstinence and nutritional improvement are equally important. In this review we study the pathogenesis of bone changes in alcoholic liver disease and discuss potential therapies. PMID- 26019742 TI - Hepatitis B among Inuit: A review with focus on Greenland Inuit. AB - Hepatitis B virus (HBV) infection is a disease with a highly variable course. Chronic HBV infection may cause end-stage liver disease including cirrhosis and hepatocellular carcinoma, which is the 3(rd) most common cause of cancer related death due to the poor prognosis. The prevalence of HBV infection is low in many countries. Still, it remains important due to the potential consequences of the disease. HBV is endemic in the Arctic with serologic markers of chronic HBV infection in up to 29% of the population in some areas in Greenland. Interestingly, Inuit populations rarely show signs of liver disease despite the fact that around half of all Inuit has been exposed to HBV and around 8% of Inuit are chronically infected with HBV. These findings have been consistent in surveys conducted for more than four decades among Arctic Inuit. We thus review HBV infection in the Arctic with focus on Greenland Inuit and compared with Inuit in Canada, Alaska and Siberia. The aspects described include epidemiology and monitoring of the disease, as well as treatment and the risk of liver cancer. PMID- 26019743 TI - Search for a cure for chronic hepatitis B infection: How close are we? AB - Chronic hepatitis B (CHB) remains a significant unmet medical need, with 240 million chronically infected persons worldwide. It can be controlled effectively with either nucleoside/nucleotide-based or interferon-based therapies. However, most patients receiving these therapies will relapse after treatment withdrawal. During recent years, the advances in molecular biology and immunology have enabled a better understanding of the viral-host interaction and inspired new treatment approaches to achieve either elimination of the virus from the liver or durable immune control of the infection. This review aims to provide a brief overview on the potential new therapies that may overcome the challenge of persistent CHB infection in the near future. PMID- 26019744 TI - Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma. AB - Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). The HBV mutations, which include point mutation, deletion, insertion and truncation mutation of HBV gene in 4 open reading frames (S, C, P, X), are closely associated with HCC pathogenesis. Some mutations accumulated during chronic HBV infection could be regarded as a biomarker to predict the occurrence of HCC. The detection of the mutations in clinical practice could be helpful for defining better preventive and therapeutic strategies and, moreover, predicting the progression of liver disease. PMID- 26019745 TI - Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant. AB - AIM: To characterize management of telaprevir (TVR)-based triple therapy of hepatitis C virus (HCV) reinfection after liver transplantation (LT). METHODS: We retrospectively analyzed safety and efficacy of telaprevir - based triple therapy in a single center cohort of 19 patients with HCV genotype (GT) 1 recurrence after LT, with respect to factors possibly predicting sustained viral response (SVR) or non-SVR. All patients were treated with TVR, pegylated (PEG) and ribavirine (RBV) for 12 wk followed by a dual phase with PEG/RBV for 12 wk in 7 patients and for 36 wk in 5 patients. RESULTS: In total 11/19 (58%) of patients achieved a sustained response. All (11/11) SVR patients showed a rapid viral response at treatment weeks 4 and 11/14 rapid virological response (RVR) patients achieved SVR. Notably, all (7/7) patients who completed 48 wk of therapy and 80% (4/5) patients who completed 24 wk of therapy achieved SVR24. Treatment failure was significantly (P > 0.049) more frequent in GT1a infection (5/7) compared to GT1b (3/12) infection and was associated with emergence of resistance-associated mutations in the NS3 protease domain. Bilirubin level at baseline is also related to SVR (P > 0.030). None of the patients had to discontinue treatment due to side effects. CONCLUSION: RVR, GT and bilirubin are clearly related to achievement of SVR. Providing a thorough patient selection and monitoring, a full course of TVR based triple therapy in LT patients is feasible and achieves high SVR rates. PMID- 26019746 TI - The prevalence of parasitic infestation of small ruminant farms in perak, malaysia. AB - Helminthiasis due to strongyles such as Haemonchus contortus, coccidiosis caused by Eimeria sp. and blood parasite diseases such as theileriosis by Theileria sp. have been reported to cause severe morbidity and mortality annually in small ruminants in Malaysia. The aims of this study were to investigate the prevalence of helminthiasis, coccidiosis and theileriosis and to determine the packed cell volume (PCV) value of small ruminants in Perak, Malaysia. Blood and faecal samples were obtained from a total of 175 animals from 7 small ruminant farms in Kampar, Larut Matang and Selama, Kuala Kangsar and Manjung districts in Perak; the samples were examined for parasitic infestations from April to July 2011. The results of this study show that H. contortus was found in 152 (86.86%) animals, Eimeria sp. was found in 162 (92.57%) animals and the blood protozoa Theileria sp. was found in 25 (14.30%) animals. The PCV values of all of these animals were recorded between 7% and 44%. A total of 42 (24%) animals were anaemic, with a PCV of less than 21%. Continuous monitoring of small ruminant farms will provide important information for assisting farmers with managing the spread of parasitic infections and maintaining the productivity of animals. PMID- 26019747 TI - Possible food sources of macrozoobenthos in the manko mangrove ecosystem, okinawa (Japan): a stable isotope analysis approach. AB - Identifying potential food sources in mangrove ecosystems is complex because of the multifarious inputs from both land and sea. This study, which was conducted in the Manko mangrove ecosystem of Okinawa, Japan, determined the composition of the stable isotopes delta(13)C and delta(15)N in primary producers and macrozoobenthos to estimate the potential food sources assimilated and to elucidate the target trophic levels of the macrozoobenthos. We measured the two stable isotope signatures of three gastropods (Cerithidea sp., Cassidula mustelina, Peronia verruculata), two crabs (Grapsidae sp., Uca sp.), mangrove tree (Kandelia candel) leaves, and sediment from the mangrove ecosystem. The respective carbon and nitrogen isotope signature results were as follows: 22.40/00 and 8.60/00 for Cerithidea sp., -25.060/00 and 80/00 for C. mustelina, 22.580/00 and 80/00 for P. verruculata, -24.30/00 and 10.60/00 for unidentified Grapsidae, -21.87 0/00 and 11.5 0/00 for Uca sp., -29.810/00 and 110/00 for K. candel, and -24.230/00 and 7.20/00 for the sediment. The stable isotope assimilation signatures of the macrozoobenthos indicated sediment as their food source. Considering the trophic levels, the stable isotope values may also indicate that the five macrozoobenthos species were secondary or higher consumers. PMID- 26019748 TI - Reproductive Biology of the Blue Swimming Crab Portunus pelagicus (Brachyura: Portunidae) in East Lampung Waters, Indonesia: Fecundity and Reproductive Potential. AB - The blue swimming crab Portunus pelagicus is an important catch species for many coastal villages along the Java Sea coastline, but little is known regarding its reproductive biology or stock status. We examined the batch fecundity of female crabs that were collected monthly at landing sites from June 2011 to May 2012, calculated the relationships with body size, egg mass and month of the year, and determined the size at which females became potentially reproductive in the population inhabiting East Lampung waters (western Java Sea). Fecundity values ranged from 229,468 to 2,236,355 (mean = 926,638+/-30,975 [+/-SE]). The fecundity was positively and linearly correlated with carapace width (CW), but the relationships with body weight and egg mass were best described by logarithmic regression. A peaked, temporally cyclical pattern in fecundity was observed, with a peak period that was significantly different (F = 226.36; df = 22, p<0.05) from March to May 2012. Reproductive females were within the 111.0-155.9 mm CW size range; significantly higher reproductive potentials (F = 14.59; df = 30, p<0.05) were found in females within the 126.0-130.9 mm CW size group. The current minimum legal size (MLS = 100 mm CW) is not an appropriate limit reference point, and a precautionary approach is needed for a sustainable harvesting strategy. Resetting the MLS to 115 mm CW would potentially provide adequate protection for spawning females and increase total egg production, thereby maintaining population productivity and enhancing resilience in the face of current fishing pressures. PMID- 26019749 TI - Stem cell research in pakistan; past, present and future. AB - BACKGROUND AND OBJECTIVES: Stem cells have proved to have great therapeutic potential as stem cell treatment is replacing traditional ways of treatment in different disorders like cancer, aplastic anemia, stroke, heart disorders. The developed and developing countries are investing differently in this area of research so research output and clinical translation of research greatly vary among developed and developing countries. Present study was done to investigate the current status of stem cells research in Pakistan and ways to improve it. RESULTS: Many advanced countries (USA, UK and Canada etc.) are investing heavily in stem cell research and treatment. Different developing countries like Iran, Turkey and India are also following the developed countries and investing a lot in stem cells research. Pakistan is also making efforts in establishing this field to get desired benefits but unfortunately the progress is at very low pace. If Government plays an active role along with private sector, stem cell research in Pakistan can be boosted up. The numbers of publications from Pakistan are very less compared to developed and neighboring countries and Pakistan also has very less number of institutes working in this area of research. CONCLUSIONS: Stem cells research is at its initial stages in Pakistan and there is great need to bring Government, academia and industry together so they could make serious efforts to promote research in this very important field. This will help millions of patients suffering from incurable disorders and will also reduce economic loss. PMID- 26019750 TI - The contribution of resident vascular stem cells to arterial pathology. AB - Intimal accumulation of smooth muscle cells contributes to the development and progression of atherosclerotic lesions and restenosis following endovascular procedures. Arterial smooth muscle cells display heterogeneous phenotypes in both physiological and pathological conditions. In response to injury, dedifferentiated or synthetic smooth muscle cells proliferate and migrate from the tunica media into the intima. As a consequence, smooth muscle cells in vascular lesions show a prevalent dedifferentiated phenotype compared to the contractile appearance of normal media smooth muscle cells. The discovery of abundant stem antigen-expressing cells in vascular lesions also rarely detected in the tunica media of normal adult vessels stimulated a great scientific debate concerning the possibility that proliferating vascular wall-resident stem cells accumulate into the neointima and contribute to the progression of lesions. Although several experimental studies support this hypothesis, others researchers suggest a positive effect of stem cells on plaque stabilization. So, the real contribute of vascular wall-resident stem cells to pathological vascular remodelling needs further investigation. This review will examine the evidence and the contribution of vascular wall-resident stem cells to arterial pathobiology, in order to address future investigations as potential therapeutic target to prevent the progression of vascular diseases. PMID- 26019751 TI - Hormonal regulation of hematopoietic stem cells and their niche: a focus on estrogen. AB - Self-renewal and differentiation are hallmarks of stem cells and controlled by various intrinsic and extrinsic factors. Increasing evidence indicates that estrogen (E2), the primary female sex hormone, is involved in regulating the proliferation and lineage commitment of adult and pluripotent stem cells as well as modulating the stem cell niche. Thus, a detailed understanding of the role of E2 in behavior of stem cells may help to improve their therapeutic potential. Recently, it has been reported that E2 promotes cell cycle activity of hematopoietic stem and progenitor cells and induces them to megakaryocyte erythroid progenitors during pregnancy. This study paves the way towards a previously unexplored endocrine mechanism that controls stem cell behavior. In this review, we will focus on the scientific findings regarding the regulatory effects of E2 on the hematopoietic system including its microenvironment. PMID- 26019752 TI - Regulation of Stem Cell Fate by ROS-mediated Alteration of Metabolism. AB - Stem cells have attracted much attention due to their distinct features that support infinite self-renewal and differentiation into the cellular derivatives of three lineages. Recent studies have suggested that many stem cells both embryonic and adult stem cells reside in a specialized niche defined by hypoxic condition. In this respect, distinguishing functional differences arising from the oxygen concentration is important in understanding the nature of stem cells and in controlling stem cell fate for therapeutic purposes. ROS act as cellular signaling molecules involved in the propagation of signaling and the translation of environmental cues into cellular responses to maintain cellular homeostasis, which is mediated by the coordination of various cellular processes, and to adapt cellular activity to available bioenergetic sources. Thus, in this review, we describe the physiological role of ROS in stem cell fate and its effect on the metabolic regulation of stem cells. PMID- 26019753 TI - Cell sources, liver support systems and liver tissue engineering: alternatives to liver transplantation. AB - The liver is the largest organ in the body; it has a complex architecture, wide range of functions and unique regenerative capacity. The growing incidence of liver diseases worldwide requires increased numbers of liver transplant and leads to an ongoing shortage of donor livers. To meet the huge demand, various alternative approaches are being investigated including, hepatic cell transplantation, artificial devices and bioprinting of the organ itself. Adult hepatocytes are the preferred cell sources, but they have limited availability, are difficult to isolate, propagate poor and undergo rapid functional deterioration in vitro. There have been efforts to overcome these drawbacks; by improving culture condition for hepatocytes, providing adequate extracellular matrix, co-culturing with extra-parenchymal cells and identifying other cell sources. Differentiation of human stem cells to hepatocytes has become a major interest in the field of stem cell research and has progressed greatly. At the same time, use of decellularized organ matrices and 3 D printing are emerging cutting-edge technologies for tissue engineering, opening up new paths for liver regenerative medicine. This review provides a compact summary of the issues, and the locations of liver support systems and tissue engineering, with an emphasis on reproducible and useful sources of hepatocytes including various candidates formed by differentiation from stem cells. PMID- 26019754 TI - Cell Therapy and Tissue Engineering Approaches for Cartilage Repair and/or Regeneration. AB - Articular cartilage injuries caused by traumatic, mechanical and/or by progressive degeneration result in pain, swelling, subsequent loss of joint function and finally osteoarthritis. Due to the peculiar structure of the tissue (no blood supply), chondrocytes, the unique cellular phenotype in cartilage, receive their nutrition through diffusion from the synovial fluid and this limits their intrinsic capacity for healing. The first cellular avenue explored for cartilage repair involved the in situ transplantation of isolated chondrocytes. Latterly, an improved alternative for the above reparative strategy involved the infusion of mesenchymal stem cells (MSC), which in addition to a self-renewal capacity exhibit a differentiation potential to chondrocytes, as well as a capability to produce a vast array of growth factors, cytokines and extracellular matrix compounds involved in cartilage development. In addition to the above and foremost reparative options up till now in use, other therapeutic options have been developed, comprising the design of biomaterial substrates (scaffolds) capable of sustaining MSC attachment, proliferation and differentiation. The implantation of these engineered platforms, closely to the site of cartilage damage, may well facilitate the initiation of an 'in situ' cartilage reparation process. In this mini-review, we examined the timely and conceptual development of several cell-based methods, designed to repair/regenerate a damaged cartilage. In addition to the above described cartilage reparative options, other therapeutic alternatives still in progress are portrayed. PMID- 26019756 TI - Bone Marrow Mesenchymal Stem Cell Transplantation in a Rabbit Corneal Alkali Burn Model (A Histological and Immune Histo-chemical Study). AB - BACKGROUND: Alkali-burned corneas can seldom heal properly to restore corneal transparency. Treatment of this severe disorder of the ocular surface remains a challenge. AIM OF THE WORK: was to investigate whether systemically transplanted bone marrow mesenchymal stem cells (BM-MSCs) can promote corneal wound healing after alkali burn. MATERIAL AND METHODS: Thirty five male New Zealand rabbits were used in this study. The animals were divided into three groups. Group I; the control group was sham operated. Group II; corneal alkali burn was created. Group III; underwent corneal alkali burn then treated with BM-MSCs. All corneas were collected after fourteen and twenty eight days. Evaluation using H&E, PAS & alkaline phosphatase reaction was carried out. Immune histo-chemical staining for CD44 and vimentin was performed as well. RESULTS: the corneal epithelium of (Group II) showed marked alterations. Vascularization, cellular infiltration and irregularity of the collagen fibers were also seen in the substantia propria. Increase in the thickness of the Descemet's membrane was noticed as well. On the other hand, at the time of 28 days, Group III rabbits showed best histological results with nearly healed corneas compared to other groups. Meanwhile, vimentin was more strongly expressed in Group III assessing the differentiating ability of BM-MSCs. CONCLUSION: BM-MSCs could effectively promote corneal alkali burn healing. PMID- 26019755 TI - New strategies for overcoming limitations of mesenchymal stem cell-based immune modulation. AB - Mesenchymal stem cells (MSCs) have rapidly been applied in a broad field of immune-mediated disorders since the first successful clinical use of MSCs for treatment of graft-versus-host disease. Despite the lack of supporting data, expectations that MSCs could potentially treat most inflammatory conditions led to rushed application and development of commercialized products. Today, both pre clinical and clinical studies present mixed results for MSC therapy and the discrepancy between expected and actual efficacy of MSCs in various diseases has evoked a sense of discouragement. Therefore, we believe that MSC therapy may now be at a critical milestone for re-evaluation and re-consideration. In this review, we summarize the current status of MSC-based clinical trials and focus on the discrepancy between expected and actual outcome of MSC therapy from bench to bedside. Importantly, we discuss the underlying limitations of MSCs and suggest a new guideline for MSC therapy in hopes of improving their therapeutic efficacy. PMID- 26019757 TI - Epigenetic Alterations of IL-6/STAT3 Signaling by Placental Stem Cells Promote Hepatic Regeneration in a Rat Model with CCl4-induced Liver Injury. AB - BACKGROUND: Human chorionic plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta have been reported to demonstrate therapeutic effects in animal models of liver injury; however, the underlying epigenetic mechanism of this effect has not been elucidated. Thus, we investigated whether CP-MSCs influence epigenetic processes during regeneration of the injured liver. METHODS: CP-MSCs were engrafted into a carbon tetrachloride (CCl4)-injured rat model through direct transplantation into the liver (DTX), intrasplenic transplantation (STX), and intravenous transplantation via the tail vein (TTX). Non-transplanted (NTX) rats were maintained as sham controls. Liver tissues were analyzed after transplantation using immunohistochemistry, western blot analysis, and quantitative methylation-specific polymerase chain reaction. Proliferation and human interleukin-6 (hIL-6) enzyme-linked immunosorbent assays were performed using CCl4-treated hepatic cells that were co-cultured with CP-MSCs. RESULTS: The Ki67 labeling index, cell cyclins, albumin, IL-6, and gp130 levels were elevated in the CP-MSC transplantation groups. The concentration of hIL-6 in supernatants and the proliferation of CCl4-treated rat hepatic cells were enhanced by co culturing with CP-MSCs (p<0.05), while the methylation of IL-6/IL-6R and STAT3 by CP-MSC transplantation decreased. CONCLUSION: These results suggest that administration of CP-MSCs promotes IL-6/STAT3 signaling by decreasing the methylation of the IL-6/SATA3 promoters and thus inducing the proliferation of hepatic cells in a CCl4-injured liver rat model. These data advance our understanding of the therapeutic mechanisms in injured livers, and can facilitate the development of cell-based therapies using placenta-derived stem cells. PMID- 26019758 TI - Attachment and Differentiation of Human Umbilical Cord Stem Cells on to the Tooth Root Surface with and without the Use of Fibroblast Growth Factor-An In Vitro Study. AB - BACKGROUND AND OBJECTIVES: The purpose of this first of its kind study was to analyse the growth, development and attachment of cultured human umbilical cord stem cells alone or supplemented with basic Fibroblast Growth Factor (bFGF) on both healthy and periodontally diseased tooth surfaces in vitro. METHODS: Four groups of 12 root surface scaffolds each were classified as Group I- healthy root surfaces; Group II- periodontally diseased; Group III- Healthy with bFGF and Group IV- periodontally diseased root with bFGF. bFGF was applied in the concentration of 8 ng/ml on to the surface followed by incubation of cultured human umbilical cord stem cells (hUCMSCs) on the scaffolds. Scanning electron microscopy observations were made on 14(th) and 21(st) days to assess the proliferation and morphology of cells attached on the tooth surface. RESULTS: Cultured hUCMSCs demonstrated adhesion to tooth root scaffold. All the groups showed a significant increase in the number of cell attachment from 14(th) day to 21(st) day. The groups with bFGF showed a significant increase in attachment of cells when compared to the groups without bFGF. The cells showed an increase in number of flat cells from 14th day to 21st day in all the groups indicating an increased maturity of cells. Periodontally diseased groups had less maturity of cells than healthy groups. The groups supplemented with bFGF, had more mature cells than the groups without bFGF. CONCLUSIONS: hUCMSCs have the propensity to differentiate into cells that have the capacity to bind to root surfaces. hUCMSCs incubated with bFGF showed better proliferation and attachment to tooth root surfaces. The role of hUCMSCs can be further explored for periodontal regeneration. PMID- 26019759 TI - Combination cell therapy with mesenchymal stem cells and neural stem cells for brain stroke in rats. AB - OBJECTIVES: Brain stroke is the second most important events that lead to disability and morbidity these days. Although, stroke is important, there is no treatment for curing this problem. Nowadays, cell therapy has opened a new window for treating central nervous system disease. In some previous studies the Mesenchymal stem cells and neural stem cells. In this study, we have designed an experiment to assess the combination cell therapy (Mesenchymal and Neural stem cells) effects on brain stroke. METHOD AND MATERIALS: The Mesenchymal stem cells were isolated from adult rat bone marrow and the neural stem cells were isolated from ganglion eminence of rat embryo 14 days. The Mesenchymal stem cells were injected 1 day after middle cerebral artery occlusion (MCAO) and the neural stem cells transplanted 7 day after MCAO. After 28 days, the neurological outcomes and brain lesion volumes were evaluated. Also, the activity of Caspase 3 was assessed in different groups. RESULT: The group which received combination cell therapy had better neurological examination and less brain lesion. Also the combination cell therapy group had the least Caspase 3 activity among the groups. CONCLUSIONS: The combination cell therapy is more effective than Mesenchymal stem cell therapy and neural stem cell therapy separately in treating the brain stroke in rats. PMID- 26019760 TI - Direct differentiation of adult ocular progenitors into striatal dopaminergic neurons. AB - Parkinson's disease, characterized by motor dysfunction due to the loss of nigrostriatal dopaminergic neurons, is one of the most prevalent age-related neurodegenerative disorders. Given there is no current cure, the stem cell approach has emerged as a viable therapeutic option to replace the dopaminergic neurons that are progressively lost to the disease. The success of the approach is likely to depend upon accessible, renewable, immune compatible, and non tumorigenic sources of neural progenitors from which stable dopaminergic neurons can be generated efficaciously. Here, we demonstrate that neural progenitors derived from limbus, a regenerative and accessible ocular tissue, represent a safe source of dopaminergic neurons. When the limbus-derived neural progenitors were subjected to a well-established protocol of directed differentiation under the influence of Shh and FGF8, they acquired the biochemical and functional phenotype of dopaminergic neurons that included the ability to synthesize dopamine. Their intrastriatal transplantation in the rat model of hemi Parkinsonism was associated with a reduction in the amphetamine-induced rotation. No tumor formation was observed 6 weeks post-transplantation. Together, these observations posit limbus-derived neural progenitors as an accessible and safe source of dopaminergic neurons for a potential autologous ex-vivo stem cell approach to Parkinson's disease. PMID- 26019761 TI - Establishing a Personal Health Record System in an Academic Hospital: One Year's Experience. AB - BACKGROUND: Personal health records (PHRs) are web based tools that help people to access and manage their personalized medical information. Although needs for PHR are increasing, current serviced PHRs are unsatisfactory and researches on them remain limited. The purpose of this study is to show the process of developing Seoul National University Bundang Hospital (SNUBH)'s own PHR system and to analyze consumer's use pattern after providing PHR service. METHODS: Task force team was organized to decide service range and set the program. They made the system available on both mobile application and internet web page. The study enrolled PHR consumers who assessed PHR system between June 2013 and June 2014. We analyzed the total number of users on a monthly basis and the using pattern according to each component. RESULTS: The PHR service named Health4U has been provided from June 2013. Every patient who visited SNUBH could register Health4U service and view their medical data. The PHR user has been increasing, especially they tend to approach via one way of either web page or mobile application. The most frequently used service is to check laboratory test result. CONCLUSION: For paradigm shift toward patient-centered care, there is a growing interest in PHR. This study about experience of establishing and servicing the Health4U would contribute to development of interconnected PHR. PMID- 26019762 TI - Prevalence of chronic obstructive lung disease in Korea using data from the fifth Korea national health and nutrition examination survey. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death worldwide. The awareness and treatment rate of the disease are low despite its relatively high prevalence. With the added data, this study aimed to identify changes in prevalence and risk factors of COPD using the data from the 5th KNHNES. METHODS: The subjects of this study were 8,969 individuals aged 40 and older who satisfied suitability and reproducibility for pulmonary function tests. The prevalence, awareness and risk factors of COPD were predicted based on the questionnaires on gender, age, educational level, income level, smoking history, body mass index (BMI) and other COPD related questions. RESULTS: Diagnosis of COPD was based on the airflow limitation (forced expiratory volume in one second/forced vital capacity <0.7) of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. The prevalence of COPD from 2010 to 2012 was 13.7%, of which 23.3% was men and 6.5% women. The prevalence was on the rise, with 12.2% in 2010, 13.2% in 2011, and 15.5% in 2012. In GOLD stage 1, the percentages of those who had cough or sputum and smoking history were 12.1% and 75.5%, respectively, but only 0.1% was diagnosed with COPD. Even after adjusting for asthma and tuberculosis, men, old age, larger amount of smoking were linked with a higher prevalence of COPD, and obese and higher educational level were associated with a lower prevalence of COPD. CONCLUSION: The prevalence of COPD in Korea has been increasing every year, and a higher prevalence was associated with male, older age, more amount of smoking, lower educational level and lower BMI. PMID- 26019763 TI - Validity and reliability of the korean version of neighborhood physical activity questionnaire. AB - BACKGROUND: Given that a substantial number of daily activities take place in neighborhoods, a convenient and effective method for measuring the physical activity of individuals is needed. Therefore, we tested the validity and reliability of the Korean version of the Neighborhood Physical Activity Questionnaire (K-NPAQ), which was developed through translation and back translation of the NPAQ. METHODS: The K-NPAQ was administered twice, with a 1 week interval, to participants in the study who were recruited at a health promotion center. We assessed energy expenditure and compliance using an accelerometer and an activity diary. The Kappa statistic and Spearman correlation coefficient were used to evaluate the test-retest reliability of the K-NPAQ, and the Spearman rank correlation was used to assess the validity. RESULTS: Of the 122 participants, 43 were excluded owing to a lack of compliance. The Kappa values for all items that were used to assess walking or cycling within or outside the neighborhood were >0.424; 0.251-0.902 for 5 items related to the purpose of the physical activity; 0.232-0.912 for most items related to the number of times and the duration for each types of physical activity. The total energy expenditure and the energy expenditure in the neighborhood were significantly correlated with the K-NPAQ and the accelerometer, with correlation coefficients of 0.192-0.264. CONCLUSION: The K-NPAQ is a valid and reliable tool for measuring physical activity in the neighborhood, and it can be used for individual education and counseling in order to augment physical activity in specific neighborhood environments. PMID- 26019764 TI - Generalized Joint Laxity is Associated with Primary Occurrence and Treatment Outcome of Lumbar Disc Herniation. AB - BACKGROUND: We investigated relationships between generalized joint laxity and primary lumbar disc herniation occurrence and compared clinical outcomes after conservative treatment in lumbar disc herniation patients with and without generalized joint laxity. METHODS: The study group included 128 men, and the control group included 276 men matched for age and body mass index with the study group. The primary outcome measure was the presence or absence of generalized joint laxity using the Beighton scale. Clinical outcomes measured by the visual analog scale and the Oswestry disability index 2 years after conservative treatment were the secondary outcome measure. RESULTS: Generalized joint laxity prevalence was 13.2% in the study group and 5.1% in the control group, a significant difference (P=0.01). Spearman correlation analysis revealed that weight (r=0.162, P=0.03), body mass index (r=0.131, P=0.03), and generalized joint laxity (r=0.372, P<0.01) significantly correlated with lumbar disc herniation occurrence. In multivariate regression analysis, generalized joint laxity was the only significant lumbar disc herniation predictor (P=0.002; 95% confidence interval, 1.08 to 5.26). Generalized joint laxity in lumbar disc herniation patients was associated with worse clinical outcomes after conservative treatment measured by visual analog scale scores for lower extremity pain (P=0.02), lower back pain (P=0.03), and Oswestry disability index scores (P=0.03). CONCLUSION: Generalized joint laxity might be associated with lumbar disc herniation occurrence and might also be a negative predictor of worse clinical outcomes after conservative treatment. PMID- 26019765 TI - Advanced erosive gout as a cause of Fever of unknown origin. AB - A 61-year-old man was referred to our hospital due to a 3-month history of fever of unknown origin, and with right knee and ankle joint pains. At another hospital, extensive investigations had produced negative results, including multiple sterile cultures of blood and joint fluids, and negative autoantibodies. His serum uric acid level was not elevated. However, after admission to our hospital, we performed right knee arthrocentesis, which revealed uric acid crystals. These findings, combined with the results of imaging tests, which showed joint degeneration, led to a diagnosis of advanced erosive gout. After receiving a therapeutic non-steroidal anti-inflammatory drug and a maintenance dose of colchicine for prophylaxis against recurrence, the patient's symptoms subsided and did not return. Advanced erosive gout should be considered a possible cause of fever of unknown origin and diagnostic arthrocentesis should be performed in patients with unexplained arthritis. PMID- 26019766 TI - Virilizing adrenocortical carcinoma advancing to central precocious puberty after surgery. AB - Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8 year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was ACC. Two months after surgical removal of the mass, he subsequently developed central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist to delay further pubertal progression. In patients with functioning ACC and surgical removal, clinical follow-up and hormonal marker examination for the secondary effects of excessive hormone secretion may be a useful option at least every 2 or 3 months after surgery. PMID- 26019767 TI - Comments on statistical issues in may 2015. PMID- 26019768 TI - Relationship between Neck Length, Sleep, and Psychiatric Disorders: A Psychiatric Aspect. PMID- 26019769 TI - Congenital hypothyroidism screening program in iran; a systematic review and metaanalysis. AB - OBJECTIVE: Unrecognized congenital hypothyroidism (CH) leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. In this systematic review, the local results of the national CH screening program in different provinces in Iran are reviewed and evaluated. METHODS: Literature on the CH screening, the national databases including SID, Medlib, Iran Medex, Magiran as well as international databases including PubMed/Medline, ISI Web of Knowledge and web of science, EMBASE, SCOPUS and Google Scholar. Appraisal was guided by a checklist assessing clarity of aims and research questions. The 95% confidence intervals were calculated by I-square models. Meta regression was introduced to explore the heterogeneity between studies. FINDINGS: We identified 25 samples including 1425124 neonates in our country. Data were Meta analyzed using random-effects models, and we found a TSH levels of 19633 babies in the first sampling were greater than the cut-off level (TSH >=5mIU/L). The pooled recall rate was 0.014 (95 % CI: 0.013 - 0.015). According to Meta analysis the overall incidence of CH was 2/1000 (95% CI: .002 - .002). The incidence of CH did not appear to be increasing over time (P=0.08). CONCLUSION: Considering TSH >=5mIU/L as a cut-off point for recalling neonates and low positive predictive value (14%) of this point shows that more investigation and research is needed for establishing accurate level of TSH as a criterion for recalling patients. PMID- 26019770 TI - 3-Day versus 5-Day Course of Intravenous Antibiotics for Suspected Early Onset Neonatal Sepsis: A Randomized Controlled Trial. AB - OBJECTIVE: The objective of this randomized controlled trial was to compare the treatment failure of suspected early onset neonatal sepsis with either 3-day or 5 day course of empirical antibiotic therapy. METHODS: Infants with birth weight over 1500 g and/or gestational age over 34 weeks within 7 days postnatal age with clinical symptoms of neonatal sepsis received empirical antibiotics (Ampicillin + Amikacin) in two neonatal intensive care units. After 72 hours if the result of blood culture was negative and symptoms resolved they were randomly allocated to 3-day or 5-day groups. The main outcome was treatment failure which was defined as reappearance of symptoms of sepsis within two weeks after discontinuation of antibiotics. Infants with congenital anomalies, localized infections, asphyxia, those undergoing surgery or when serum C-reactive protein levels remained abnormal despite treatment, were not included. Randomization was accomplished with simple randomization procedure. FINDINGS: Sixty patients were randomized in a 1:1 ratio to either group. Baseline characteristics were similar between two groups. The follow-up period was 2 weeks with no lost to follow-up. One infant in 3-day group had treatment failure compared with no treatment failure in 5-day group (P=0.5). No serious harm was observed due to our empirical antibiotic regimen. CONCLUSION: The results of this study indicated no evidence that treatment failure differs between 3-day and 5-day course antibiotic therapy for suspected early onset uncomplicated neonatal sepsis in late preterm and term newborns. PMID- 26019771 TI - Do term newborns respond similarly to different painful procedures? AB - OBJECTIVE: Although many methods for pain assessment in newborns are available, none of them are widely accepted. Our aim was to answer the question: do newborns respond similarly to different painful procedures? METHODS: Sixty term newborns were involved in non-randomized prospective study. They were classified into 2 groups: Group A (n=30) who needed intubation and Group B (n=30) who necessitated umbilical vein catheterization. Close observation prior to and 10 minutes after the painful procedures was performed for recording of physiological and behavioral indicators. Plasma renin activity (PRA) was measured before and 10 minutes after the painful procedures. FINDINGS: There was statistically significant difference between the 2 groups as regards physiological and hormonal responses to pain (P<0.05). Apart from palmar sweating and crying, there was no significant difference in behavioral response (P>0.05). The median pre- and post intubation levels of PRA were 3.04 and 12.05 ng/ml/hour, respectively. There was significant (P<0.001) increase of PRA after intubation. On the other hand, the median pre- and post-catheterization levels of PRA were 5.21 and 9.19 ng/ml/hour, respectively. There was significant (P<0.001) increase of PRA after umbilical vein catheterization. We found that PRA was the only indicator of pain in group A (P=0.047). On the other hand, we did not find any indicator of pain in group B. CONCLUSION: We concluded that full-term newborns vary in their physiological and hormonal responses to different painful procedures but their behavioral response is the same. PMID- 26019772 TI - Validation of simple epidemiological or clinical methods for the measurement of body composition in young children. AB - OBJECTIVE: The present study aimed to determine the validity of simple epidemiological and clinical methods for the assessment of body fatness in preschool children. METHODS: In 89 children (42 boys, 47 girls; mean age 4.1 SD 1.3y) measures of body fatness were made using total body water (TBW), dual energy x-ray absorptiometry (DXA), air displacement plethysmography (BODPOD) and skinfold thickness. Methods were compared by Bland-Altman analysis using TBW as the reference method, and by paired comparisons and rank order correlations. FINDINGS: Bias for DXA was +1.8% body fat percentage units (limits of agreement +15.5% to -11.9%), bias for BODPOD was -3.5% (limits of agreement +18.9% to 5.9%) and bias for skinfolds using the Slaughter equations was -6.5% (limits of agreement +10.0% to -23.1%). Significant rank order correlations with TBW measures of fatness were obtained for DXA estimates of fatness (r=0.54, P=0.01), but not for estimates of fat by skinfold thickness (r=0.20, P=0.2) or BODPOD (r=0.25, P=0.1). Differences between both DXA and BODPOD and the reference TBW estimates of body fatness were not significant (P=0.06 and P=0.1 respectively); however, the difference in estimated body fatness between skinfold thickness and TBW was significant (P<0.001). CONCLUSION: Estimates of body fatness in preschool children were inaccurate at the level of the individual child using all the methods, but DXA might provide unbiased estimates and a means of making relative assessments of body fatness. PMID- 26019773 TI - Breast milk concentration of rubidium in lactating mothers by instrumental neutron activation analysis method. AB - OBJECTIVE: Relatively little is known about the trace elements content of human milk from different countries. This has not been fully investigated especially among Iranian women. This study aimed to assess the concentration of Rubidium (Rb) as a poisonous trace element in transitional breast milk of lactating mothers living in Mashhad. METHODS: Forty nursing mothers in early lactation 3 days to 15 days postpartum, free from any medical disorder and/or medication were randomly selected. We have applied Instrumental Neutron Activation Analysis (INAA) to assess the long-lived isotope trace element Rb in transitional milk of these economically moderate 18-39 year old Iranian women. FINDINGS: The average concentration level of Rb was 32.176 ppm dry weight (min 8.660, max 107.210 ppm). No significant correlation was observed between Rb concentration and maternal weight and age (P=0.06, P=0.05 respectively) and newborns' weight, age and sex (P=0.07, P=0.2, P=0.2 respectively). CONCLUSION: Although the Rubidium concentration found in this study is among the highest reported in the literature, it could not be compared to other studies because of differences in analytical performance, state of lactation, and unavailable reference ranges, so this finding needs further investigations. PMID- 26019774 TI - The Evaluation of Red Reflex Sensitivity and Specificity Test among Neonates in Different Conditions. AB - OBJECTIVE: Red reflex test is an effective screening tool in the early diagnosis of neonatal eye abnormalities. The aim of this study was to detect the sensitivity and specificity of red reflex assessment in neonates, performed by pediatricians (or other care providers) in comparison with ophthalmologists. Also association between red reflex findings and neonatal variables is evaluated. METHODS: By a prospective study all neonates born from July 2011 until March 2012 in Mustafa Hospital, a general teaching hospital in Ilam city, Iran, were evaluated. Neonates were firstly investigated by pediatrician in substandard conditions at the first day of birth and several days later by ophthalmologist in standard conditions. FINDINGS: Totally 255 neonates including 141 boys and 114 girls were investigated, 144 of whom were born by cesarean section. There was a significant relationship between method of childbirth (72.9% disorders in CS vs 56.8% in vaginal delivery (P<0.007)), duration of delivery (disorders in prolonged: 100% and 11.8% vs no prolonged: 56.8% and 6.3% in standard and non standard conditions respectively (P<0.0001)), difficult delivery (98.6% disorders vs 6.5% in standard and non standard conditions respectively (P<0.01)) and increase or decrease of red reflex sensitivity test. A significant difference (identification of ophthalmic problems) was seen among neonates' inspections in primary hours and substandard conditions compared to further inspections in standard conditions particularly from 3(rd) day of birth. CONCLUSION: Due to a considerable difference between the results of ophthalmic examination of neonates in different conditions, red reflex examination by pediatricians is suggested for all neonates to early identification of ophthalmic problems at the first step. It is also suggested a red reflex screening for all neonates before being discharged from hospital as well as 6 weeks later and in case of any problem to be referred to ophthalmologist. PMID- 26019775 TI - Analysis of Genomic Diversity among Helicobacter pylori Strains Isolated from Iranian Children by Pulsed Field Gel Electrophoresis. AB - OBJECTIVE: Presence of genomic diversity among Helicobacter pylori (H. pylori) strains have been suggested by numerous investigators. Little is known about diversity of H. pylori strains isolated from Iranian children and their association with virulence of the strains. Our purpose was to assess the degree of genomic diversity among H. pylori strains isolated from Iranian-children, on the basis of vacA genotype, cagA status of the strains, sex, age as well as the pathological status of the patients. METHODS: Genomic DNA from 44 unrelated H. pylori strains isolated during 1997-2009, was examined by pulse-field gel electrophoresis (PFGE). Pathological status of the patients was performed according to the modified Sydney-system and genotype/status of vacA/cagA genes was determined by PCR. PFGE was performed using XbaI restriction-endonuclease and the field inversion-gel electrophoresis system. FINDINGS: No significant relationship was observed between the patterns of PFGE and the cagA/vacA status/genotype. Also no relationship was observed between age, sex, and pathological status of the children and the PFGE patterns of their isolates. Similar conclusion was obtained by Total Lab software. However, more relationship was observed between the strains isolated in the close period (1997-2009, 2001 2003, 2005-2007, and 2007-2009) and more difference was observed among those obtained in the distant periods (1997 and 2009). CONCLUSION: H. pylori strains isolated from children in Iran are extremely diverse and this diversity is not related to their virulence characteristics. Occurrence of this extreme diversity may be related to adaptation of H. pylori strains to variable living conditions during transmission between various host individuals. PMID- 26019776 TI - Relationship between Vitamin D and Childhood Asthma: A Case-Control Study. AB - OBJECTIVE: Studies determining the relationship between serum vitamin D status and childhood asthma have yielded controversial results. Findings indicated that vitamin D deficiency is associated with asthma and airway hyper responsiveness. The aim of this study was to assess the relationship between serum vitamin D status and childhood asthma. METHODS: Data were obtained from 200 asthmatic children (age 3-12 years) and 200 healthy controls. Serum levels of 25(OH) vitamin D, total IgE, calcium, phosphorus, parathormone (PTH) and eosinophil count were measured in both asthmatic children and healthy controls. Also, the mean values of 25(OH) vitamin D were compared with asthma symptom severities. FINDINGS: There was a significant decrease in the concentration of serum 25(OH) vitamin D in the asthmatic patients as compared with the controls (20.34+/-2.8 vs 25.39+/-4.1 ng/mL, 95%CI: 1.46-3.86, P=0.01). Out of total asthmatic subjects, 40 (20%) were vitamin D sufficient, 48 (24%) were insufficient, and 112 (56%) were deficient. Total IgE concentration was also significantly higher in asthmatic patients having vitamin D deficiency (132.4+/-20.1 IU/ml, 95%CI: 1.38-3.75, P=0.03). Comparing asthmatic patients with healthy controls, odds of having vitamin D level less than 20ng/mL was 2.47. CONCLUSION: Our findings suggest that vitamin D deficiency or insufficiency may be positively related to the prevalence of asthma in children. PMID- 26019777 TI - Presepsin (scd14) as a marker of serious bacterial infections in chemotherapy induced severe neutropenia. AB - OBJECTIVE: Timely detection of serious bacterial infections or prediction of sepsis and death is of paramount importance in neutropenic patients especially in oncology settings. The aim of this study was to determine a rapid and secure predictor of sepsis in severe neutropenic cancer children. METHODS: In addition to blood culture, we have evaluated serum soluble CD14 on this role and measured it in 39 neutropenic episodes in Mahak pediatric oncology center from September 2012 to January 2013. Fifteen episodes had positive bacterial cultures and 18 had fever. The mean sCD14 values were compared in the presence or absence of fever, positive blood culture and other clinical conditions. Also, mean levels compared in different white cell counts and different four combination settings of fever and blood culture. FINDINGS: It was statistically higher in febrile episodes, in the presence of oral mucositis, indwelling catheter infection, otitis media, and post toxic epidermal necrolysis sepsis and in instances of death within 15 days. Leukocyte count did not affect sCD14 level and in combinations of fever and blood culture, mean sCD14 values were ranked as follow: febrile culture negatives, febrile culture positives, afebrile culture positives and afebrile culture negatives. CONCLUSION: Although sCD14 was not sensitive in detection of bacteremia, in the absence of clinically detectable source of infection, it was significantly higher in culture positives. PMID- 26019778 TI - Prevalence of Celiac Disease in Children with Autoimmune Hepatitis and vice versa. AB - OBJECTIVE: Celiac disease is an autoimmune disorder in which the risk of autoimmune liver disease is high. Autoimmune hepatitis is a chronic and progressive entity and the risk of its being associated with other autoimmune disorders such as celiac disease is high also. The aim of this study was to determine the prevalence of celiac disease in patients with autoimmune hepatitis and vice versa. METHODS: In a cross-sectional study children with autoimmune hepatitis underwent serological screening and endoscopy for celiac disease. In patients with celiac disease, serum aminotransferases were measured and, if abnormal, autoantibodies related to autoimmune hepatitis were checked and needle liver biopsy was performed. FINDINGS: Of the 96 patients, 64 had autoimmune hepatitis and 32 celiac disease. Among patients with autoimmune hepatitis only three (4.7%) were compatible with celiac disease. In the group of patients with celiac disease, autoimmune hepatitis was confirmed in four (12.5%) cases. We consider important to state that 3.1% of this group had celiac hepatitis. CONCLUSION: Autoimmune liver disease is sometimes associated with latent celiac disease. Serological screening for celiac disease should be routinely done in patients with abnormal serum aminotransferases, particularly those with chronic liver disease. On the other hand, celiac disease is often accompanied by other autoimmune diseases, including autoimmune hepatitis. PMID- 26019779 TI - Factors Creating Trust in Hospitalized Children's Mothers towards Nurses. AB - OBJECTIVE: Trust is proposed as the necessary foundation to achieve better performance in the nursing of children. In this regard, Pediatric nurses need to achieve a deeper understanding of parents' experiences, and find out how these experiences are being related to the nursing practice. So to increase nurses' understanding of this concept based on the experiences of the recipients of nursing, the present study aims to express the factors that affect the formation of trust in mothers of hospitalized children towards the nurses. METHODS: In this study, a qualitative design, conventional content analysis, was used. Pediatric Ward of hospitals in Yazd, Iran were the research environment. 14 mothers whose children were hospitalized in pediatric wards were selected through purposive sampling. They were deeply interviewed and data was analyzed with conventional content analysis. FINDINGS: Data analysis led to emerging a major category "nurses' attempt for professional nursing" which includes sub-categories of commitment and empathetic caring, skill in performing duties, mothers' participation in the process of caring, being interested in pediatric nursing and establishing effective communication. CONCLUSION: Findings from the study showed that mothers know different factors involved in establishing confidence in nurses. Managers and people in charge in the field of nursing - regarding these findings - can design and perform necessary training programs to increase knowledge and skills for pediatric nursing, to win the trust of mothers and children in hospital for an effective step towards providing a better nursing care. PMID- 26019780 TI - Diagnostic value of serum procalcitonin level in differentiating bacterial from nonbacterial meningitis in children. AB - OBJECTIVE: Acute bacterial meningitis in pediatrics remains a serious and potentially lethal disease. Its prognosis is critically dependent on rapid diagnosis and treatment. The use of biological markers, like procalcitonin, has been proposed to facilitate the accuracy of the initial diagnosis of bacterial meningitis. The aim of this study was assessment the diagnostic values of serum procalcitonin (PCT) assay in the diagnosis and differentiation of acute bacterial from non bacterial meningitis. METHODS: 45 patients with suspicion of meningitis were enrolled in the study and were clinically evaluated and investigated by lumbar punctures for cerebrospinal fluid analysis, C-reactive protein and differential leukocyte count. Patients with clinical and laboratory suggestion of bacterial causes were regarded as bacterial meningitis group (29 patients), and those who were suggestive of nonbacterial causes were regarded as nonbacterial group (16 patients). FINDINGS: Serum procalcitonin levels were significantly higher in bacterial meningitis group (637+/-325 pg/ml) compared with non bacterial meningitis (380+/-170 pg/ml); P<0.001. Procalcitonin levels were more sensitive and specific (79%, 81%) than C-reactive protein (76%, 75%) and white blood cell count (72%, 75%) in the diagnosis of bacterial meningitis. CONCLUSION: Elevated serum procalcitonin level could be a predictor of bacterial causes of meningitis and is more sensitive and specific than other diagnostic predictors. PMID- 26019781 TI - Breastfeeding and Helicobacter pylori Infection in Early Childhood: a Continuing Dilemma. AB - OBJECTIVE: Helicobacter pylori (H. pylori) is the most common chronic bacterial infection in humans. Chronic colonization increases the risk of duodenal ulcer and gastric cancer. The risk factors for acquiring the infection have been extensively studied. However, there are conflicting results on the role of breastfeeding in the prevention of H. pylori infection. We conducted a study to evaluate the effects of breastfeeding on the H. Pylori infection in Kurdish children in Sanandaj, IR Iran. METHODS: A historical cohort study was carried out from January 2011 through December 2012. Totally 221 children who were going to attain 2 years old during the study period were randomly enrolled. They were divided into two groups, i.e. breastfed and non-breastfed. We used H. pylori stool antigen test to detect infection in the selected group of children after age of 2 years and cessation of breastfeeding. Each group was subdivided into two subgroups, infected and non-infected. The associations of breastfeeding with H. pylori infection was assessed using statistical software. FINDINGS: We found no difference in the odds of infection between breastfed and non-breastfed groups (OR=0.809, 95% CI [0.453-1.444]). An association between age and the prevalence of infection was found (P=0.008). There was an increase in the odds of infection as the family size grew (OR=1.93, 95% CI [1.04-3.6]) as well as increasing housing density (OR=2.12, 95% CI [1.10-4.10]). CONCLUSION: The data suggests that breastfeeding in infancy does not protect against H. pylori infection for long duration among studied children in Iran. The protective effects of breastfeeding, if any, are at most transient. PMID- 26019782 TI - Beneficial effect of cyproheptadine on body mass index in undernourished children: a randomized controlled trial. AB - OBJECTIVE: Cyproheptadine hydrochloride (CH) is a first-generation antihistamine which is used as an appetite stimulant. This study was designed to identify the role of CH therapy on weight gain, linear growth and body mass index in children with mild to moderate undernutrition. METHODS: Eighty-nine patients were enrolled. The present randomized, double-blinded controlled trial included 77 evaluable patients, aged 24-64 months with undernutrition. The patients were randomized to receive cyproheptadine with multivitamin, or multivitamin over a period of four weeks. The weight, height and body mass index were measured at the baseline, four weeks after intervention and four weeks after discontinuation. FINDINGS: A significant higher body mass index was observed among CH-treated patients after 8 weeks intervention with cyproheptadine compared with the control group (P<0.041). Mean weight gain after eight weeks was 0.11 kg in the control group and 0.60 kg in the CH group. There were no significant differences in changes of weight and height velocity across the study between CH-treated and control group at the end of study. CONCLUSION: In our study, cyproheptadine promotes increase in body mass index in children with mild to moderate undernutrition after four weeks treatment. PMID- 26019783 TI - Effects of Maternal Cervical Incompetence on Morbidity and Mortality of Preterm Neonates with Birth weight Less than 2000g. AB - OBJECTIVE: This study aimed to determine the impact of maternal cervical incompetence (with or without McDonald cerclage) on mortality and morbidity of preterm infant with birth weight <2000g. METHODS: 581 neonates were eligible for this study, 79 with cervical incompetence and 502 without it (control). Incidences of neonatal respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), neonatal necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), periventricular leukomalacia (PVL), severe asphyxia, small for gestational age (SGA), early-onset sepsis (EOS), and mortality were compared between the two groups. FINDINGS: Mean gestational age was earlier in cervical incompetence group than in control (30.2+/-2.1 vs 30.7+/-1.9, P<0.05). Except lower frequency of SGA, there were no significant differences in the incidences of RDS, BPD, ROP, PVL, IVH, NEC, EOS, severe asphyxia and mortality between the two groups. Infants with no cerclage had a higher prevalence of RDS (21/66 vs 9/13, P<0.05) compared to cerclage group due to lower mean gestational age (30.68+/-2.1 vs 28.6+/-1.4, P<0.01) and birth weight (1519.5+/-274.6 vs 1205.8+/-204.4, P<0.001), and clinical neonatal outcomes of the elective cerclage were similar to emergency cerclage in cervical incompetence groups. CONCLUSION: Maternal cervical incompetence was not associated with postnatal adverse neonatal outcomes. Lower mean gestational age was a major risk associated with higher prevalence of RDS in preterm neonates with no McDonald cerclage, and emergency cerclage did not predict poor clinical neonatal outcomes. PMID- 26019784 TI - Usefulness of serum brain natriuretic Peptide level for screening hemodynamically significant patent ductus arteriosus in preterm neonates. AB - OBJECTIVE: We studied usefulness of serum B-type natriuretic peptide level as a screening tool for detecting hemodynamically significant patent ductus arteriosus in the preterm neonates. METHODS: Sixty admitted preterm neonates with gestational age <=34 weeks, birth weight <=2500 gr, and age of >3 days have been enrolled in this study. We measured serum B-type natriuretic peptide levels at the beginning and after completion of drug therapy for ductus occlusion. FINDINGS: Mean+/-SD gestational age and weight was 31+/-1.9 weeks and 1680+/-350 gr, respectively. The peptide levels in the neonates with significant duct (n=13) were significantly higher than in those with insignificant duct (n=17) or no duct (n=30) (1667+/-821 pg/ml versus 667+/-666 and 309+/-171, respectively). The peptide level dropped significantly after ibuprofen administration in the neonates with significant PDA (n=13), (1667+/-1165 pg/ml to 429+/-386). CONCLUSION: At a cutoff point of 450 pg/ml, B-type natriuretic peptide level had a sensitivity of 92% and specificity of 87%, the negative predictive value of 98.5%, the positive likelihood ratio of 6.92 and the negative likelihood ratio of 0.089 for detecting significant patent duct. Levels below this can eliminate the need for echocardiography. PMID- 26019785 TI - Caseous granuloma: tuberculosis or chronic recurrent multifocal osteomyelitis? AB - BACKGROUND: Chronic recurrent multifocal osteomyelitis (CREMO) is one of the autoinflammatory bone disorders due to disturbance in innate immune system. Up to now, there is no reported case of caseous granulomas in the CREMO. We report a boy with sterile granolumatous osteomyelitis. CASE PRESENTATION: A four-year-old boy presented with swelling and pain in the left wrist, malaise and bilateral erythematous pustulosis on the palmar region which had resolved spontaneously after about 7 days. The histopathology of the lesions showed severe acute and chronic inflammatory process and chronic granulomatous reaction with caseating necrosis (granulomatous osteomyelitis). The direct smear, culture and PCR for the mycobacterium tuberculosis and atypical mycobacteria were negative. About five months after initiation of the anti-mycobacterial treatment, he was referred to the rheumatology clinic with left elbow pain, effusion and decreased range of motion, and bilateral erythematous palmar pustulosis. He was diagnosed as CREMO based on two exacerbations, repeatedly negative cultures, and concomitant acute and chronic lesions in the histopathology and X-ray. Naproxen and pamidronate every 3 months were started and all other medications were stopped. Two months after the first dose of pamidronate, he became symptom-free and forearm X-ray showed disappearance of the osteolytic lesions and periosteal reactions. CONCLUSION: The diagnosis of CREMO should be considered in the patients with lytic bone lesions. In addition, the clinicians should be aware of the possibility of caseating granuloma in the cases with possible diagnosis of CREMO. PMID- 26019786 TI - Infantile Systemic Hyalinosis: Report of 17-year Experience. AB - BACKGROUND: Infantile Systemic Hyalinosis (ISH) is a very rare autosomal recessive disorder characterized by connective tissue involvement as hyaline deposition in skin, gastrointestinal tract, muscles, glands and other organs. CASES PRESENTATION: We report eight Iranian children (4 male and 4 female) with ISH referred to our hospital from 1996 to 2013. The illness had been diagnosed by clinical manifestations and disease progression. Six of them died and two are alive but very sick. CONCLUSION: ISH is a very rare disorder with poor prognosis. Seventy five percent of our 8 patients died before 2 years old due to severe diarrhea, malabsorption and/or infection. PMID- 26019787 TI - Diagnosis of an abnormality in brain MRI. PMID- 26019788 TI - Kidney tubular cell protection; recent findings. PMID- 26019789 TI - Extramedullary hematopoiesis in adrenal gland. An uncommon cause of adrenal incidentaloma in sickle cell disease. PMID- 26019790 TI - Chicken meat anaphylaxis in a child with no allergies to eggs or feathers. PMID- 26019791 TI - Unusual presentation of congenital neuroblastoma as persistent respiratory distress and Fever from age of 13 days in an infant: a case report. PMID- 26019792 TI - The frequency of CCR5 promoter polymorphisms and CCR5 Delta 32 mutation in Iranian populations. AB - Evidence showed that chemokines serve as pro-migratory factors for immune cells. CCL3, CCL4 and CCL5, as the main CC chemokines subfamily members, activate immune cells through binding to CC chemokine receptor 5 or CCR5. Macrophages, NK cells and T lymphocytes express CCR5 and thus, affected CCR5 expression or functions could be associated with altered immune responses. Deletion of 32 base pairs (Delta 32) in the exon 1 of the CCR5 gene, which is known as CCR5 Delta 32 mutation causes down regulation and malfunction of the molecule. Furthermore, it has been evidenced that three polymorphisms in the promoter region of CCR5 modulate its expression. Altered CCR5 expression in microbial infection and immune related diseases have been reported by several researchers but the role of CCR5 promoter polymorphisms and CCR5 Delta 32 mutation in Iranian patients suffering from these diseases are controversial. Due to the fact that Iranian people have different genetic backgrounds compared to other ethnics, hence, CCR5 promoter polymorphisms and CCR5 32 mutation association with the diseases may be different in Iranian patients. Therefore, this review addresses the most recent information regarding the prevalence as well as association of the mutation and polymorphisms in Iranian patients with microbial infection and immune related diseases as along with normal population. PMID- 26019793 TI - Biochemical and morphological changes in bone marrow mesenchymal stem cells induced by treatment of rats with p-Nonylphenol. AB - OBJECTIVES: In previous investigations, we have shown para-nonylphenol (p-NP) caused significant reduction of proliferation and differentiation of rat bone marrow mesenchymal stem cells (MSCs) in vitro. In this study, we first treat the rats with p-NP, then carried out the biochemical and morphological studies on MSCs. MATERIALS AND METHODS: Proliferation property of cells was evaluated with the help of MTT assay, trypan blue, population doubling number, and colony forming assay. Differentiation property was evaluated with quantitative alizarin red assay, measurement of alkaline phosphatase (ALP) activity as well as intracellular calcium content. In addition; morphological study, TUNEL test, activated caspase assay, and comet assay were performed to evaluate the mechanism of the cell death. RESULTS: The results showed significant reduction in the colony-forming-ability and population-doubling-number of extracted cells when compared to control ones. In addition, it was revealed that the p-NP treatment of rats caused significant reduction in nuclear diameter, cytoplasm shrinkage, and induction of caspase-dependent-apoptosis. Also there was significant reduction in ALP activity, intracellular calcium content, and intracellular matrix following osteogenic differentiation. CONCLUSION: As MSCs are the cellular back up for bone remodeling and repair, we suggest more investigations to be conducted regarding the correlation between the increasing number of patients suffering from osteoporosis and p-NP toxicity. Also, we strongly recommend WHO and local health organization to prevent industries of using p-NP in formulation of industrial products which may cause changes in proliferation and differentiation properties of stem cells. PMID- 26019794 TI - Male germ-like cell differentiation potential of human umbilical cord Wharton's jelly-derived mesenchymal stem cells in co-culture with human placenta cells in presence of BMP4 and retinoic acid. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) derived from Wharton's jelly (WJ-MSCs) are now much more appealing for cell-based infertility therapy. Hence, WJ-MSCs differentiation toward germ layer cells for cell therapy purposes is currently under intensive study. MATERIALS AND METHODS: MSCs were isolated from human Wharton's jelly and treated with BMP4, retinoic acid (RA) or co-cultured on human amniotic epithelial (HAE) and chorionic plate (HCP) placenta feeder cells. profile of POU5F1, Fragilis, Plzf, DDX4, Piwil2, Stra8, Dazl, beta1- and alpha6 integrins (ITBeta1, ITA6) genes expression as germ cell markers were analyzed using RT-PCR and real-time PCR. Immunocytochemistry of surface markers were conducted. RESULTS: After 3 weeks treatment with different reagents and co culture system, morphology of WJ-MSCs changed to shiny clusters and germ cell specific markers in mRNA were up-regulated in both placental feeder + RA and BMP4 + RA. Induction of hWJ-MSCs with BMP4 in presence of RA resulted in significant up-regulation (P<=0.05) of all germ cell specific genes (c-Kit; 2.84+/-0.59, DDX4; 1.69+/-0.39, Piwil2; 1.14+/-0.21, Dazl; 0.65+/-0.25, alpha6 integrin; 1.26+/-0.53, beta1 integrins; 1.18+/-0.65) compared to control and placental feeder cells + RA. Our results indicated that HAE and HCP followed by RA treatment were involved in human germ cell development. CONCLUSION: We demonstrated that under the right conditions, hWJ-MSCs have the ability to differentiate to germ cells and this provides an excellent pattern to study infertility cause and treatment. PMID- 26019795 TI - Effects of berberine on proliferation, cell cycle distribution and apoptosis of human breast cancer T47D and MCF7 cell lines. AB - OBJECTIVES: Berberine, a naturally occurring isoquinoline alkaloid, has shown antitumor properties in some in vitro systems. But the effect of berberine on breast cancer has not yet been completely studied. In this study, we evaluated anticancer properties of berberine in comparison to doxorubicin. MATERIALS AND METHODS: The antiproliferative effects of berberine and doxorubicin alone and in combination were evaluated in T47D and MCF7 cell lines using MTT cytotoxicity assay. In addition, flow cytometry analysis was performed to evaluate the cell cycle alteration and apoptosis induction in these cell lines following exposure to berberine and doxorubicin alone and in combination. RESULTS: The IC50 of berberine was determined to be 25 uM after 48 hr of treatment in both cell lines but for doxorubicin it was 250 nM and 500 nM in T47D and MCF-7 cell lines, respectively. Co-treatment with berberine and doxorubicin increased cytotoxicity in T47D cells more significantly than in MCF-7 cells. Flow cytometry results demonstrated that berberine alone or in combination with doxorubicin induced G2/M arrest in the T47D cells, but G0/G1 arrest in the MCF-7 cells. Doxorubicin alone induced G2/M arrest in both cell lines. Furthermore, berberine and doxorubicin alone or in combination significantly induced apoptosis in both cell lines. CONCLUSION: Berberine alone and in combination with doxorubicin inhibited cell proliferation, induced apoptosis and altered cell cycle distribution of breast cancer cells. Therefore, berberine showed to be a good candidate for further studies as a new anticancer drug in the treatment of human breast cancer. PMID- 26019796 TI - The prevention and treatment effects of egg yolk high density lipoprotein on the formation of atherosclerosis plaque in rabbits. AB - OBJECTIVES: Atherosclerosis is the main leading cause of cardiovascular diseases. The purpose of this study was to assess the potential preventive effect of egg yolk HDL on the atherosclerosis plaque formation. MATERIALS AND METHODS: Thirty rabbits were divided into five groups: A; normal diet, B; hyper-cholesterolemic diet, C; hypercholesterolemic + 400 mg/kg egg yolk HDL D; hypercholesterolemic +100 mg/kg egg yolk HDL and E; 200 mg/kg egg yolk HDL. At the end of the experiment, the lipid profiles were measured by spectrophotometric method. The histological sections of thoracic aorta also were taken and analyzed under light microscope. RESULTS: At the end of the 2(nd) and the 4(th) weeks, there was a significant increase of cholesterol level in groups B, C, and D compared to group A (P<0.05). Following HDL treatment, triglyceride (TG) levels increased significantly versus group A and also the TG level decreased significantly in group C, D, and E versus group B (P<0.01). Egg yolk HDL significantly increased HDL-C in groups C, D, and E (P<0.01) compared to groups A and B (P<0.05). The surface area of the atherosclerotic plaque was increased significantly in group B versus group A (P<0.001). Egg yolk HDL consumption reduced the plaque size significantly (P<0.001). CONCLUSION: Our findings indicated that treatment with egg yolk HDL increased serum HDL-C and decreased atherosclerotic plaque size in rabbits. Thus, egg yolk HDL may be considered as an anti-atherosclerotic treatment for cardiovascular diseases. PMID- 26019797 TI - Immune reactivity of sera obtained from brucellosis patients and vaccinated rabbits to a fusion protein from Brucella melitensis. AB - OBJECTIVES: Brucella spp. are facultative intracellular pathogens which can stay alive and multiply in professional and nonprofessional phagocytes. Immunity against Brucella melitensis involves antigen-specific CD4(+) and CD8(+) T-cells activation and humoral immune responses. Due to negative aspects of live attenuated vaccines, much attention has been focused on finding Brucella protective antigens to introduce them as potential subunit vaccine candidates. MATERIALS AND METHODS: A chimeric gene encoding trigger factor (TF), Omp31(48-74) and BP26(87-111) fragments (TOB) from B. melitensis was successfully cloned, expressed in Escherichia coli BL21-DE3 and purified by Ni-NTA agarose column. Antibodies to recombinant TOB (rTOB) have been investigated in Brucella-infected human sera and a pool serum prepared from B. melitensis-vaccinated rabbits. RESULTS: Our results showed that the immunized rabbit pool serum strongly reacted with rTOB. In addition, antibodies against rTOB were detectable in 76.5% of sera obtained from infected patients. CONCLUSION: These findings suggest that rTOB may provide a potential immunogenic candidate which could be considered in future vaccine studies. PMID- 26019798 TI - Neuroprotective effect of p-coumaric acid in rat model of embolic cerebral ischemia. AB - OBJECTIVES: Stroke poses a crucial risk for mortality and morbidity. Our study aimed to investigate the effect of p-coumaric acid on focal cerebral ischemia in rats. MATERIAL AND METHODS: Rats were randomly divided into four groups, namely Group I (control rats), Group II (ischemia rats), Group III (6 hr ischemia + p coumaric acid rats) and Group IV (24 hr ischemia + p-coumaric acid rats). Cerebral ischemia was induced via intraluminal monofilament occlusion model. In all groups, the brain was removed after the procedure and rats were sacrificed. Malondialdehyde, superoxide dismutase and nuclear respiratory factor-1 were measured in the ischemic hemisphere. The histopathological changes were observed in the right hemisphere within the samples. Functional assessment was performed for neurological deficit scores. RESULTS: Following the treatment, biochemical factors changed significantly. Histopathologically, it was shown that p-coumaric acid decreased the oxidative damage. The neurological deficit scores of p coumaric acid-treated rats were significantly improved after cerebral ischemia. CONCLUSION: Our results showed that p-coumaric acid is a neuroprotective agent on account of its strong anti-oxidant and anti-apoptotic features. Moreover, p coumaric acid decreased the focal ischemia. Extra effort should be made to introduce p-coumaric acid as a promising therapeutic agent to be utilized for treatment of human cerebral ischemia in the future. PMID- 26019799 TI - Comparison of acute effects of heroin and Kerack on sensory and motor activity of honey bees (Apis mellifera). AB - OBJECTIVES: Previous studies demonstrated a functional similarity between vertebrate and honey bee nervous systems. The aim of the present study was to compare the effects of heroin and Iranian street Kerack, a combination of heroin and caffeine, on sensory threshold and locomotor activity in honey bees. MATERIALS AND METHODS: All drugs were given orally to honey bees 30 min before each experiment. The levels of these drugs and their metabolites in brain samples of honey bees were determined by GC/MS. The sucrose sensitivity test was used for evaluation of changes in honey bees' sensory threshold. Following the administration of both drugs, the honey bees' locomotor activity changes were evaluated in open fields. RESULTS: 6-acetylmorphine had a higher concentration in comparison with other heroin metabolites in honey bees' brains. Concentration of the compound in the brain was directly proportional to the amount ingested. Heroin reduced the sensory threshold of honey bees, but Kerack increased it in the same doses. Locomotor activity of honey bee in open field was enhanced after the administration of both drugs. However, immobility time of honey bees was only affected by high doses of heroin. CONCLUSION: Acute effects of heroin andKerack on the sensory and motor functions of honey bees were different. Findings of this research suggest that these differences originated from the activation of different neurotransmitter systems by caffeine together with activation of opioid receptors by heroin. PMID- 26019800 TI - Protective effect of royal jelly in 2,4,6 trinitrobenzene sulfonic acid-induced colitis in rats. AB - OBJECTIVES: In the present study, we evaluated immunological and immunomodulatory properties of royal jelly (RJ) in 2,4,6 trinitrobenzene sulfonic acid (TNBS) induced colitis in rats. MATERIALS AND METHODS: Eighteen adult female Wistar albino rats were divided into three groups of six animals each: a control group that received only saline solution, a TNBS-induced colitis group, and a TNBS colitis+RJ group that received 250 mg/kg/day of RJ for seven days before the induction of colitis, following by the same treatment for an additional seven days. At the end of the experiment, cardiac blood and colon samples were obtained under deep anaesthesia from the animals in all groups. Serum interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and IL-10 levels were analyzed with an enzyme-linked immunosorbent assay (ELISA). Five-micrometre-thick sections were stained with haematoxylin-eosin (H&E) for microscopic evaluations. For immunohistochemical evaluations, the paraffin sections were stained with anti CD3 (cluster of differentiation), anti-CD5, anti-CD8 and anti-CD45. RESULTS: The results showed that the oral RJ treatment inhibited proinflammatory cytokines, IL 1beta and TNF-alpha secretion, while increasing anti-inflammatory cytokine IL-10 production in the TNBS-induced colitis+RJ group compared with the colitis group not treated with RJ. The colitis was not as severe in the colitis+RJ group, with ulcerative damage, weight loss and inflammatory scores suggesting that impaired CD3-, CD5-, CD8- and CD45-positive T cell immune responses likely mediated the anti-inflammatory effect. CONCLUSION: The antioxidant and anti-inflammatory properties of RJ protected colon mucosa against TNBS-induced colitis in rats orally treated with RJ. PMID- 26019801 TI - Expression analysis of CD44 isoforms S and V3, in patients with esophageal squamous cell carcinoma. AB - OBJECTIVES: CD44 is a member of the cell adhesion molecules family. Naturally, CD44S, along with CD44V3 influence the cell motility, migration, and adhesion, while in tumor cells they lead to tumor invasion, progression, and metastasis. The purpose of this research is to evaluate the CD44S and CD44V3 expression in Esophageal Squamous Cell Carcinoma (ESCC) and to reveal their correlations with clinicopathological features of patients. MATERIALS AND METHODS: Fresh tumoral and distant tumor-free esophageal tissues were obtained from 50 patients with ESCC. Using quantitative real-time PCR, the expression levels of CD44S and CD44V3 were quantified and compared in both groups of cells. The patients had not received any therapeutic interference, such as chemotherapy or radiation, prior to sampling. RESULTS: Significant overexpression of CD44S and CD44V3 mRNA was observed in 13 (26.0%, P=0.03) and 11 (22.0%, P=0.007) tumor specimens, respectively. The expression of the genes were significantly correlated not only with each other (P=0.0001), but also with differentiation grade of tumor (P=0.033), stage of tumor progression (P=0.003), and depth of tumor invasion (P=0.00). In addition, low level of CD44V3 mRNA expression was attended to be associated with tumor invasion. CONCLUSION: There is no correlation between CD44S expression with clinicopathological features of patients; however, simultaneous expression of these genes has an important effect on tumorigenesis. PMID- 26019802 TI - Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer. AB - OBJECTIVES: P-glycoprotein (P-gp) is an efflux protein, the overexpression of which has been associated with multidrug resistance in various cancers. Although siRNA delivery to reverse P-gp expression may be promising for sensitizing of tumor cells to cytotoxic drugs, the therapeutic use of siRNA requires effective carriers that can deliver siRNA intracellularly with minimal toxicity on target cells. We investigated a special class of PEGylated lipid-based nanoparticles (NP), named nanolipoparticles (NLPs), for siRNA-mediated P-gp downregulation. MATERIALS AND METHODS: NLPs were prepared based on low detergent dialysis method. After characterization, we evaluated the effect of NLPs on siRNA delivery, and P gp downregulation compared to oligofectamineTM (OFA) in vitro and in vivo. RESULTS: Our results showed a significant decrease in P-gp expression and subsequent enhancement of chemosensitivity to doxorubicin in vitro. Although the effectiveness of NLPs for in vitro siRNA delivery compared to OFA was limited, the results of in vivo studies showed noticeable effectiveness of NLPs for systemic siRNA delivery. siRNA delivery using NLPs could downregulate MDR1 in tumor cells more than 80%, while OFA had a reverse effect on MDR1 expression in vivo. CONCLUSION: The results indicated that the prepared NLPs could be suitable siRNA delivery systems for tumor therapy. PMID- 26019803 TI - Activation of calcium/calmodulin-dependent kinase II following bovine rotavirus enterotoxin NSP4 expression. AB - OBJECTIVES: The rotavirus nonstructural protein 4 (NSP4) is responsible for the increase in cytoplasmic calcium concentration through a phospholipase C-dependent and phospholipase C-independent pathways in infected cells. It is shown that increasing of intracellular calcium concentration in rotavirus infected cells is associated with the activation of some members of protein kinases family such as calcium/calmodulin-dependent kinase II, which plays a crucial role in replication and pathogenesis of the virus. The aim of this study was to expression bovine rotavirus NSP4 gene in HEK293 cell and evaluation of its biological effect related to activation of calcium/calmodulin-dependent kinase II in cell culture. MATERIALS AND METHODS: MA104 cells was used as a sensitive cell for propagation of virus and defined as a positive control. The NSP4 gene was amplified and inserted into an expression vector, and introduced as a recombinant plasmid into HEK293T cells. Western blot analysis was performed as a confirmation test for both expression of NSP4 protein and activation of calcium/calmodulin-dependent kinase II. RESULTS: Expression of NSP4 and activated form of calcium/calmodulin dependent kinase II were demonstrated by western blotting. CONCLUSION: It was shown that the expression of biologically active full- length NSP4 protein in HEK293T cells may be associated with some biological properties such as calcium calmodulin kinase II activation, which was indicator of rotaviruses replication and pathogenesis. PMID- 26019804 TI - Interaction between the antioxidant activity of curcumin and cholinergic system on memory retention in adult male Wistar rats. AB - OBJECTIVES: The cholinergic system plays an important role in learning and memory. This study investigated the effects of curcumin (turmeric extract) and the cholinergic system and their interaction on memory retention of passive avoidance learning in adult male Wistar rats. MATERIALS AND METHODS: At first, an injection cannula was implanted in right ventricles of the animals. One week after the surgery, the animals were trained with a shuttle box set up. Post training, injections were performed in all experiments. Administration of curcumin increased memory retention. Also administrations of nicotine and pilocarpine, the cholinergic receptor agonists, increased memory retention, while it is decreased by succinylcholine and scopolamine, the cholinergic receptor antagonists. Then co-administration of curcumin and cholinergic drugs were performed. Intraperitoneal and intracerebroventricular injections were applied for the curcumin and cholinergic drugs, respectively. RESULTS: Co-administration of curcumin (45 mg/kg) with a low dose of nicotine (0.1 ug/rat) or pilocarpine (0.5 ug/rat) increased memory retention significantly. Effects of succinylcholine (0.01, 0.1 and 0.5 ug/rat) or scopolamine (0.1, 1 and 5 ug/rat) were attenuated by curcumin markedly (45 mg/kg). CONCLUSION: The results suggest that curcumin has a close interaction with cholinergic system in memory retention process. PMID- 26019805 TI - Modulation of IKKbeta/NF-kappaB and TGF-beta1/Smad via Fuzheng Huayu recipe involves in prevention of nutritional steatohepatitis and fibrosis in mice. AB - OBJECTIVES: Fuzheng Huayu recipe (FZHY) exerts significant protective effects against liver fibrosis by strengthening the body's resistance and removing blood stasis. However, the molecular mechanisms through which FZHY affects liver fibrosis are still unclear. In this study, we examined the expression levels of factors involved in the inhibitor kappaB kinase-beta (IKK-beta)/nuclear factor kappaB (NF-kappaB) and transforming growth factor beta 1 (TGF-beta1)/Smad signaling pathways to elucidate whether FZHY could attenuate nutritional steatohepatitis and fibrosis in mice. MATERIALS AND METHODS: C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. FZHY and/or heme oxygenase-1 (HO-1) chemical inducer (hemin) were administered to mice. The effects of FZHY alone and in combination with hemin were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells (HSCs), and the expression of oxidative stress, inflammation and fibrogenesis related genes. RESULTS: Administration of FZHY, hemin and FZHY plus hemin significantly ameliorated liver injury. Additionally, our analysis indicated that administration of these agents significantly attenuated oxidative stress, downregulated the expression of pro-inflammatory and pro-fibrotic genes, including IKK-beta, NF-kappaB, monocyte chemoattractant protein-1 (MCP-1), alpha-smooth muscle actin (alpha-SMA), TGF-beta1, Smad3 and Smad4, and upregulated the expression of the antifibrogenic gene Smad7 (P< 0.001). CONCLUSION: FZHY-containing therapies prevented nutritional steatohepatitis and fibrosis through modulating the expression of factors associated with the IKKbeta/NF-kappaB and TGF-beta1/Smad signaling pathways and oxidative stress related genes. PMID- 26019806 TI - Nephroprotective potential of Graptophyllum pictum against renal injury induced by gentamicin. AB - OBJECTIVES: To evaluate the effect of Graptophyllum pictum on lipid peroxidation and tissue antioxidant enzymes in liver and kidney of gentamicin induced nephrotoxic rats. MATERIALS AND METHODS: Animals were grouped into 6: Group 1 received gum acacia, Group 2 received G. pictum ethanol extract (300 mg/kg), Group 3 received gentamicin, Groups 4, 5, 6 received gentamicin along with G. pictum at 300, 150, 75 mg/kg, respectively. Nephroprotective activity was evaluated by measuring thiobarbituric acid-reactive substances (TBARS), biochemical markers Glutathione (GSH), Glutathione-S Transferase(GST), Superoxide dismutase (SOD), Catalase (CAT), serum urea and creatinine levels. RESULTS: Results obtained showed that gentamicin induced nephrotoxic rats exhibited lower activities of biochemical markers and raised levels of TBARS, serum creatinine and urea. Remarkably, after treatment with G. pictum extract, anomalous levels of biochemical markers, lipid peroxidation and serum creatinine were returned to normal. CONCLUSION: The results propose that G. pictum has nephroprotective effects, and can be a promising natural source against gentamicin induced nephrotoxicity. PMID- 26019807 TI - Hypoglycemic and hypolipidemic activities of Salvia hydrangea in streptozotocin induced diabetes in rats. AB - OBJECTIVES: This study was to investigate the potential anti-diabetic effects of alcoholic extract of Salvia hydrangea in rats. MATERIALS AND METHODS: Thirty five male Wistar rats were divided into five groups namely non-diabetic control, diabetic control, and three experimental diabetic that received either Salvia hydrangea extract for 21 days at the doses of 100 and 200 or glibenclamide at the dose of 10 mg/kg through gavage feeding. To induce diabetes, streptozotocin was injected intraperitoneally. RESULTS: Insulin and HDL levels in the group receiving the high dose of the extract showed significant increase, whereas the amount of cholesterol in rats that received glibenclamide and the extract showed a significant decrease as compared to the diabetic control group (P<0.05). The blood glucose levels showed significant reduction in all experimental groups (P<0.05). CONCLUSION: Consumption of the extract of the aerial parts of S. hydrangea which reduces blood fat and increases insulin may have beneficial effects on the symptoms of diabetes and hyperlipidemia. PMID- 26019808 TI - Elucidating the cellular actions of demineralised dentine matrix extract on a clonal dental pulp stem cell population in orchestrating dental tissue repair. AB - Bioactive growth factors identified within the extracellular matrix of dentine have been proposed roles in regulating the naturally inherent regenerative dentine formation seen in teeth in response to trauma and infection, which may also be harnessed for novel clinical treatments in augmenting mineralised tissue repair. This study examined the specific biological action of demineralised dentine matrix extract on a clonal population of dental pulp stem cells in stimulating the prerequisite stages of wound healing associated with mineralised tissue repair. A clonal dental pulp stem cell population with sustained proliferative capacity and multi-potentiality towards osteogenic, adipogenic and chondrogenic lineages was isolated from the pulp of human third molars. Dentine was collected from human healthy teeth, powdered and treated with ethylenediaminetetraacetic acid to obtain a solubilised DDM protein extract. The influence of DDM on the DPSC clonal population was assessed in vitro. Exposure of cells to proteolytically degraded DDM or unsupplemented media served as controls. Compared to controls, DDM stimulated cell expansion, reduced apoptotic marker caspase 3, increased cell survival marker Akt1 and enhanced mineralised matrix deposition as determined by mineral deposition and increased expression of bone related markers, alkaline phosphatase and osteopontin. Dental pulp stem cells successfully migrated into collagen gels supplemented with demineralised dentine matrix, with cells remaining viable and expanding in numbers over a 3-day period. Collectively, the results provide evidence that soluble proteins extracted from dentine matrix are able to exert a direct biological effect on dental pulp stem cells in promoting mineralised tissue repair mechanisms. PMID- 26019809 TI - The use of self-quantification systems for personal health information: big data management activities and prospects. AB - BACKGROUND: Self-quantification is seen as an emerging paradigm for health care self-management. Self-quantification systems (SQS) can be used for tracking, monitoring, and quantifying health aspects including mental, emotional, physical, and social aspects in order to gain self-knowledge. However, there has been a lack of a systematic approach for conceptualising and mapping the essential activities that are undertaken by individuals who are using SQS in order to improve health outcomes. In this paper, we propose a new model of personal health information self-quantification systems (PHI-SQS). PHI-SQS model describes two types of activities that individuals go through during their journey of health self-managed practice, which are 'self-quantification' and 'self-activation'. OBJECTIVES: In this paper, we aimed to examine thoroughly the first type of activity in PHI-SQS which is 'self-quantification'. Our objectives were to review the data management processes currently supported in a representative set of self quantification tools and ancillary applications, and provide a systematic approach for conceptualising and mapping these processes with the individuals' activities. METHOD: We reviewed and compared eleven self-quantification tools and applications (Zeo Sleep Manager, Fitbit, Actipressure, MoodPanda, iBGStar, Sensaris Senspod, 23andMe, uBiome, Digifit, BodyTrack, and Wikilife), that collect three key health data types (Environmental exposure, Physiological patterns, Genetic traits). We investigated the interaction taking place at different data flow stages between the individual user and the self quantification technology used. FINDINGS: We found that these eleven self quantification tools and applications represent two major tool types (primary and secondary self-quantification systems). In each type, the individuals experience different processes and activities which are substantially influenced by the technologies' data management capabilities. CONCLUSIONS: Self-quantification in personal health maintenance appears promising and exciting. However, more studies are needed to support its use in this field. The proposed model will in the future lead to developing a measure for assessing the effectiveness of interventions to support using SQS for health self-management (e.g., assessing the complexity of self-quantification activities, and activation of the individuals). PMID- 26019810 TI - Successful management of severe hyponatraemia during continuous renal replacement therapy. AB - Rapid correction of chronic hyponatraemia can lead to osmotic demyelination syndrome. Ensuring a gradual correction can be difficult, especially in patients on renal replacement therapy (RRT). A 43-year-old renal transplant patient presented with severe chronic hyponatraemia. She required continuous RRT. The hyponatraemia was corrected successfully by manually adjusting sodium concentration in the dialysate. Our case describes an effective method to ensure severe hyponatraemia is corrected safely during continuous RRT. PMID- 26019811 TI - Fabry disease: the many faces of a single disorder. PMID- 26019812 TI - Heavy-chain deposition disease: a morphological, immunofluorescence and ultrastructural assessment. AB - Heavy-chain deposition disease (HCDD) is the least common of the monoclonal immunoglobulin deposition diseases with only 24 reported cases in English literature, including the present case. The rarity of this disease merits its documentation. We present a case of HCDD from our archival material, who presented with rapidly progressive renal failure and nephrotic syndrome and was found to have nodular glomerulosclerosis on renal biopsy which on immunofluorescence and electron microscopy confirmed HCDD of immunoglobulin G1 type without any light-chain deposition. We also present an in-depth literature review on HCDD. PMID- 26019813 TI - Acute kidney injury in dengue virus infection. AB - BACKGROUND: Dengue is a growing public health problem in Pakistan and acute kidney injury (AKI) is one of the least studied complications of dengue virus infection (DVI). The aim of this study was to determine the frequency, severity and predictors of AKI in patients with DVI and to study the impact of AKI on the length of hospital stay and mortality. METHODS: We retrospectively reviewed medical records of patients aged >=14 years hospitalized with a primary diagnosis of DVI at Aga Khan University Hospital Karachi between January 2008 and December 2010. Binary logistic regression models were constructed to identify factors associated with the development of AKI and to study the impact of AKI on hospital stays of more than 3 days. RESULTS: Out of 532 patients, AKI was present in 13.3% (71/532). Approximately two-thirds (64.8%) of these patients had mild AKI and a third (35.2%) had moderate to severe AKI. Independent predictors for AKI were male gender [odds ratio (OD) 4.43; 95% CI 1.92-10.23], presence of dengue hemorrhagic and dengue shock syndrome (DSS, OD 2.14; 95% CI 1.06-4.32), neurological involvement (OD 12.08; 95% CI 2.82-51.77) and prolonged activated partial thromboplastin time (aPTT, OD 1.81; 95% CI 1.003-3.26). AKI was associated with a length of stay >=3 days when compared with those who did not have AKI (OD 2.98; 95% CI 1.66-5.34). Eight patients (11.3%) with AKI died whereas there were no mortalities in patients without AKI (P < 0.001). Only 5 patients (7%) had persistent kidney dysfunction at discharge. CONCLUSIONS: AKI in DVI is associated with neurological involvement, prolongation of aPTT, greater length of hospital stay and increased mortality. PMID- 26019814 TI - Broad spectrum of Fabry disease manifestation in an extended Spanish family with a new deletion in the GLA gene. AB - BACKGROUND: Fabry disease (FD) is an X-linked inherited disease based on the absence or reduction of lysosomal-galactosidase (Gla) activity. The enzymatic defect results in progressive impairment of cerebrovascular, renal and cardiac function. Normally, female heterozygote mutation carriers are less strongly affected than male hemizygotes aggravating disease diagnosis. METHOD: Close examination of the patients by renal biopsy, echo- and electrocardiography and MRI. Blood work and subsequent DNA analysis were carried out utilizing approved protocols for PCR and Sequencing. MLPA analysis was done to unveil deletions within the GLA gene locus. Quantitative detection of Glycolipids in patient plasma and urine were carried out using HPLC/MS-MS and ESI-MS. RESULTS: In the presented case, a female index patient led to the examination of three generations of a Spanish family. She presented with severe oto-cochlear symptoms and covert renal and cardiac involvement. While conventional sequencing failed to detect a causative mutation, MLPA analysis revealed a deletion within the GLA gene locus, which we were able to map to a region spanning exon 2 and adjacent intronic parts. The analysis of different biomarkers revealed elevated lyso-Gb3 levels in all affected family members. CONCLUSION: Our findings highlight the broad intrafamilial spectrum of symptoms of FD and emphasise the need to use MLPA screening in symptomatic females without conclusive sequencing result. Finally, plasma lyso-Gb3 proved to be a reliable biomarker for the diagnosis of FD. PMID- 26019815 TI - An analysis of functional activity via the three complement pathways during hemodialysis sessions: a new insight into the association between the lectin pathway and C5 activation. AB - BACKGROUND: We have recently demonstrated that hemodialysis (HD) patients have significantly higher levels of functional complement activity (FCA) in all three pathways, i.e. the classical pathway, alternative pathway and lectin pathway (LP), than in age-matched controls, though the role of FCA during HD still remains unknown. METHODS: Serial plasma or serum samples were obtained from five patients during HD in order to investigate the kinetics of complement components. The levels of the C5b-9 complex, the FCA of the three pathways, a derivative of C3a (C3a desArg) and a derivative of C5a (C5a desArg) in the samples were analyzed. RESULTS: The levels of the C5b-9 complex at 60 min were significantly increased when compared with those at 0 min. Functional activities for all three pathways showed different patterns so the same tendency between pathways was not observed. The levels of C3a desArg and C5a desArg at 60 min were markedly increased when compared with those at 0 min. A Spearman's rho test showed a strong positive correlation between functional LP activity and C5a desArg. CONCLUSIONS: These findings lead to new insights into the FCA during HD and suggest that functional LP activity has an important role in C5 activation. PMID- 26019816 TI - Growth of arachnoid cysts in patients with autosomal dominant polycystic kidney disease: serial imaging and clinical relevance. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder that results in the growth of cysts in the kidneys and other organs. Multisystemic involvement is common including affection of the central nervous system with cerebral aneurysms and arachnoid cysts. METHODS: This is a prospective cohort study to investigate the prevalence and growth rate of arachnoid cysts in ADPKD patients. Participants enrolled in the SUISSE ADPKD cohort were offered cranial imaging for the detection of intracranial alterations. In the case of identified arachnoid cysts, patients were suggested to undergo follow-up imaging to assess the growth rate of the cysts. Volume of arachnoid cysts at the baseline and at follow-up visits was assessed by manual segmentation on a dedicated workstation. RESULTS: A total of 109 ADPKD patients agreed to undergo cranial imaging. In 14 (12.8%) patients (9 males and 5 females), 18 singular arachnoid cysts were identified. The baseline volumes of individual cysts ranged from 1.8 to 337.6 cm(3). During a mean follow-up period of 24 months, the volume changes of 12 individual arachnoid cysts of nine patients ranged from -3.1 to 3.7 cm(3). Cystic lesions were mostly localized in the middle fossa. All affected patients were clinically asymptomatic. CONCLUSIONS: We found a higher prevalence of arachnoid cysts in ADPKD patients with more advanced disease. There was a large variability in size and growth. These arachnoid cysts were clinically silent and their growth pattern was subtle and unpredictable, in contrast to the much more foreseeable growth of the renal cysts. PMID- 26019817 TI - Solid renal tumours of collecting duct origin in patients on chronic lithium therapy. AB - BACKGROUND: Lithium (Li) is an invaluable drug for the treatment of bipolar disorder. Long-term Li use is associated with renal complications including the formation of uncomplicated renal cysts caused by proliferation and expansion of collecting duct (CD) cells. We report six patients with complicated renal cysts in the context of Li nephropathy. METHODS: Over a time period of 15 years, we have identified six patients with one or more solid renal tumours in our population of approximately 50 patients with chronic Li nephropathy. In this study we describe the clinical and pathological characteristics of these Li related tumours. RESULTS: All patients were on Li therapy for over 10 years and suffered from varying degrees of Li nephropathy. The tumours were all of CD origin and comprised both oncocytomas and collecting duct carcinomas. The CD carcinomas differed from the very rare "classical" CD cell carcinomas in histological appearance, multifocal presentation and non-aggressive clinical behaviour. CONCLUSIONS: The increased incidence of CD derived tumours and atypical presentation of CD cell carcinomas in patients with chronic Li nephropathy suggests that Li predisposes to the development of these tumours. We hypothesize that prolonged stimulation of CD cell proliferation and expansion by Li not only causes cyst formation, but can eventually induce the formation of adenomas and carcinomas. Increased awareness of a possible relationship between chronic Li therapy and renal neoplasms, will enhance the knowledge on epidemiology, clinical behavior and optimal therapy for the Li-related renal neoplasms. PMID- 26019818 TI - Renal variant of Fabry disease with sporadic GLA gene mutation: role of early renal biopsy. AB - Fabry disease (FD) is a rare, X-linked inherited disease of glycosphingolipid metabolism due to deficiency of lysosomal alpha-galactosidase A activity. Scarce activity of lysosomal alpha-galactosidase A results in progressive accumulation of globotriaosylceramide (Gb3) within lysosomes, believed to trigger a flow of cellular changes that lead to the clinical manifestation of the disease. We present a 23-year-old male with renal variant of FD who was born from non affected parents, which, to the best of our knowledge, has not been reported in the literature so far. In conclusion, FD can occur due to sporadic GLA gene mutation. Pure renal involvement might be associated with progressive disease which leads to end-stage renal disease within a short period. Physicians should have a high index of suspicion for FD especially in male cases with unexplained renal failure that are slowly progressive in nature, even in the absence of a clear hereditary component. Early renal biopsy is recommended in any progressive renal impairment. PMID- 26019819 TI - Minimal-change disease secondary to etanercept. AB - Etanercept is a soluble tumor necrosis factor alpha (TNFalpha) receptor which is widely used in the treatment of rheumatoid arthritis, psoriasis and other autoimmune inflammatory disorders. It is known for its relative lack of nephrotoxicity; however, there are reports on the development of nephrotic syndrome associated with the treatment with TNFalpha antagonists. Here, we describe a patient with psoriasis who developed biopsy-proven minimal-change disease (MCD) shortly after initiating etanercept. Our case is unique in that the MCD resolved after discontinuation of this medication, notably without the use of corticosteroids, strongly suggesting a drug-related phenomenon. PMID- 26019820 TI - Indolent systemic mastocytosis associated with light chain deposition disease. AB - Systemic mastocytosis (SM) is characterized by infiltration of neoplastic mast cells in one or more organ systems. SM in association with plasma cell dyscrasia is very rare. We report a first case of indolent SM (ISM) associated with light chain deposition disease (LCDD) in a kidney biopsy from a 59-year-old female presenting with skin rash, elevated serum creatinine, hematuria and mild proteinuria. Subsequent workup demonstrated IgG kappa monoclonal protein in serum and urine. A bone marrow biopsy revealed neoplastic mast cells involving bone marrow without evidence of clonal myeloid or lymphoid proliferation. Kidney biopsy demonstrated modest mesangial expansion detected by light microscopy and unequivocal evidence of monoclonal kappa light chain deposition within glomerular capillaries, tubular basement membranes and vascular walls detected by immunofluorescence and/or electron microscopy, along with equivocal evidence of light chain cast nephropathy. Despite treatment with bortezomib and dexamethasone, her renal function was progressively declined over the next 6 months. This case is a reminder that SM can coincide with LCDD, which requires clinical suspicion and multimodality workup on a kidney biopsy including immunofluorescence and electron microscopy to reach the correct diagnosis. PMID- 26019821 TI - Complete renal recovery from severe acute renal failure after thrombolysis of bilateral renal vein thrombosis. AB - A previously healthy young man presented with acute renal failure due to extensive spontaneous deep vein thrombosis, including the inferior vena cava (IVC) and both renal veins. The patient was treated with selectively delivered thrombolytic therapy over a 7-day-period, which resulted in renal vein patency and complete recovery of renal function. A stent was placed over a segment stenosis of the IVC. No thrombophilic factors were identified. Bilateral renal vein thrombosis in young fit individuals is an unusual cause of acute renal failure. Thrombolytic therapy, even with delay, can completely restore renal function. PMID- 26019822 TI - Acute kidney injury in a preterm infant homozygous for the C3435T polymorphism in the ABCB1 gene given oral morphine. AB - A 34-week infant born from a mother with a history of drug abuse developed neonatal abstinence syndrome (NAS) in the first hours of life. Urine drug screening was positive for cocaine and heroin. The infant developed acute kidney injury and bilateral hydronephrosis while receiving oral morphine for control of NAS. Cessation of morphine therapy and urinary catheterization resulted in a rapid and complete resolution of the symptoms. Our patient was homozygous for the C3435T polymorphism in the ABCB1 gene, a polymorphism previously associated with impaired P-glycoprotein activity. We hypothesize that acute renal toxicity was related to accumulation of morphine within urothelial cells due to genetically determined impaired P-glycoprotein activity. PMID- 26019823 TI - Discrete renal deposition of IgM heavy chain and kappa light chain in Waldenstrom macroglobulinemia (IgM-kappa). AB - We report previously undescribed renal lesions associated with monoclonal gammopathy in a 59-year-old man with Waldenstrom macroglobulinemia (IgM-kappa). Light microscopy showed mesangial proliferation and thickening of glomerular basement membranes (GBMs) and tubular basement membranes (TBMs). Neither intraglomerular thrombi nor nodular glomerulosclerosis was observed. Immunofluorescence studies disclosed essentially discrete localization of IgM heavy chain within the mesangial area and kappa light chain along GBMs and TBMs. Electron microscopy showed continuous linear deposits of finely granular electron dense material along the inner aspect of GBMs and TBMs. Repeated rituximab treatment and chemotherapy (melphalan and prednisolone) led to the improvement of proteinuria. PMID- 26019824 TI - Progressive chronic kidney disease secondary to tubulointerstitial nephritis in primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by the presence of anti-mitochondrial antibodies (AMA). Whilst asymptomatic distal tubular acidosis (DTA) is the commonest renal lesion reported in PBC, tubulointerstitial nephritis (TIN) has also been reported as a rare association. Although PBC could be a familial disorder, there have been no previous reports of familial chronic TIN in association with PBC. We report a case of progressive chronic kidney disease (CKD) due to TIN in a mother and daughter known to suffer from PBC and review the previously reported literature. Both showed good response to steroids. PMID- 26019825 TI - Idiopathic nodular glomerulosclerosis in a never-smoking, normotensive, non obese, normal-glucose-tolerant middle-aged woman. AB - A 53-year-old woman with a history of dyslipidemia presented with medium-grade proteinuria and several years of progressive renal dysfunction. Renal biopsy showed diffuse and global Kimmelstiel-Wilson nodule like nodular mesangial sclerosis, but she had no history of diabetes mellitus, no diabetic retinopathy and normal oral glucose tolerance. Congo red staining was negative, and immunofluorescence staining showed no immunoglobulin deposition including kappa or lambda light chains. Electron microscopy showed no electron dense deposits or organized deposits. Thus, we diagnosed idiopathic nodular glomerulosclerosis (ING). ING is a recently established clinicopathologic disease entity linked to longstanding cigarette smoking and hypertension. Obesity is also listed as a contributing factor. However, none of these factors was documented in this case. This is a valuable case of ING that suggests the existence of as-yet unknown causative factors of ING other than smoking, hypertention or obesity. PMID- 26019826 TI - Successful treatment of massive proteinuria and severe chyluria by inhibition of cholesterol absorption with ezetimibe in a patient with filariasis. AB - We describe a case of filariasis presenting with severe chyluria and nephrotic range proteinuria. There were no obvious findings of glomerulonephritis in the renal biopsy. Technetium-99m-human serum albumin (Tc-99m-HSA) lymphoscintigraphy revealed the presence of communications between lymphatic channels and the urinary tract. Ezetimibe (10 mg/day) was administered during hospitalization. Chyluria was decreased within a few days following the administration of ezetimibe. Moreover, a remission was obtained from nephrotic-range proteinuria. Tc-99m-HSA lymphoscintigraphy showed a reduction of lymph flow to the urinary tract three months later. In our patient, therapeutic intervention by ezetimibe may have resulted in a reduction of chylous lymph absorption from the intestine and the prevention of mucosal rupture into the renal pelvis and calyx via reduced intralymphatic pressure. Ezetimibe may be an effective and safe treatment for this indication, and should be considered when filarial patients present with chyluria and massive proteinuria before employing invasive surgical procedures. PMID- 26019827 TI - Cowden disease and multicystic dysplastic kidney: increased risk of renal cancer? AB - Unilateral multicystic dysplastic kidney is one of the most frequently identified urinary tract abnormalities in children. Although it can be an isolated finding, it is often associated with other anomalies of the kidney and urinary tract. It has also been described in association with other multisystemic disorders of known genetic aetiologies. Cowden disease (CD) is a rare autosomal-dominant disorder with age-related penetrance characterized by benign and malignant hamartomatous lesions affecting derivatives of all three germ cell layers. Hamartomas can emerge in virtually every organ, but are mostly found in the skin and gastrointestinal tract. We report a 7-year-old patient presenting with unilateral multicystic dysplastic kidney and CD, a hitherto unknown association in paediatrics, which raises the question of an increased risk of renal cancer. PMID- 26019828 TI - Pulmonary hemorrhage with hematuria: do not forget IgA nephropathy. AB - IgA nephropathy is the commonest cause of glomerulonephritis worldwide, and is usually a renal-limited disease. In rare cases, IgA nephropathy may also present with a pulmonary-renal syndrome in which pulmonary hemorrhage is a critical feature. Patients presenting with IgA nephropathy and pulmonary hemorrhage have high morbidity and are at high risk for mortality unless rapid immunosuppressive therapy is instituted. We present a case of IgA nephropathy complicated by pulmonary hemorrhage in which immunosuppressive therapy led to a good outcome, and review the literature on similar cases and the outcome of therapy. PMID- 26019829 TI - A transplant patient with a swollen leg. PMID- 26019830 TI - JC viraemia in kidney transplant recipients: to act or not to act? PMID- 26019831 TI - Night blindness in a haemodialysed ADPKD patient receiving octreotide. PMID- 26019832 TI - Primary renal lymphoma: an uncommon diagnosis for acute kidney failure. PMID- 26019833 TI - What's in a name? Bence Jones protein. PMID- 26019834 TI - Immunoadsorption for paediatric post-diarrhoea haemolytic-uraemic syndrome with severe neurological involvement. PMID- 26019835 TI - ANCA-positive pauci-immune glomerulonephritis and febuxostat treatment. PMID- 26019836 TI - Anti-TNF-alpha therapy in membranous glomerulonephritis. PMID- 26019837 TI - Uraemia-associated cardiovascular and lung injury. PMID- 26019838 TI - Reply. PMID- 26019839 TI - Of mites and men: scabies in patients with kidney disease. PMID- 26019840 TI - Management of hyperphosphataemia in chronic kidney disease-challenges and solutions. AB - Hyperphosphataemia is a clinical consequence of the advanced stages of chronic kidney disease (CKD). Considerable evidence points to a role of hyperphosphataemia in the pathogenesis of CKD-associated cardiovascular (CV) complications, including vascular calcification, and with increased all-cause and CV mortality. These observations place management of hyperphosphataemia at the centre of CKD treatment. Although our increased understanding of the physiological role of FGF-23 may provide a long-term alternative biomarker of phosphate load and underlying disease progression, regular determination of serum phosphate is currently the most frequently used parameter to evaluate phosphate load in clinical practice. This review considers the challenges physicians and patients face in trying to control hyperphosphataemia. Amongst these are the limitations of dietary phosphate restriction, giving rise to the need for phosphate binder therapy to maintain serum phosphate control. Once the decision to use phosphate binders has been made, considerations include the relative efficacy, different potential side effects and pill burden associated with various phosphate binders. Although a number of phosphate binders are available, adherence poses a major obstacle to effective treatment. This emphasizes that further improvements to phosphate binder therapy can be made. Evaluation of novel agents and their potential role in the clinic should continue. PMID- 26019841 TI - QT interval in CKD and haemodialysis patients. AB - Cardiovascular (CV) disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD) patients. Although about half of the deaths are due to CV causes, only a minority are directly linked to myocardial infarction and it is estimated that cardiac arrest or cardiac arrhythmias account for about a quarter of all deaths registered in dialysis patients. Thus, simple non-invasive tools such as electrocardiogram (ECG) may detect those patients at increased risk for arrhythmias. The QT interval on the standard 12-lead ECG is the time from ventricular depolarization (Q wave onset) to cardiac repolarization completion (end of the T wave) and represents a marker of cardiac repolarization defects. Numerous studies suggest a direct association between QT abnormalities and poor prognosis in the general population, CKD patients and dialysis patients. Of note, multivariable adjustments for different traditional and CKD-specific risk factors for CV events attenuate but do not cancel these associations. We herein review the clinical significance of simple non-invasive tools such as the QT tract on ECG for detecting those patients at increased risk of CV event and possibly for treatment individualization. PMID- 26019842 TI - Congenital anomalies of kidney and hand: a review. AB - 'Acro-renal syndrome' refers to co-occurrence of congenital renal and limb anomalies. The term acro-renal syndrome was coined by Curran et al. in 1972 though Dieker and Opitz were the first to report this phenomenon in three male patients in 1969. The common limb defects include oligodactyly, ectrodactyly, syndactyly or brachydactyly anomalies of the carpal and tarsal bones and the common renal anomalies observed are unilateral renal agenesis (URA), bilateral renal hypoplasia, ureteric hypoplasia, hydroureteronephrosis and duplication abnormalities. The acro-renal syndrome as originally described is rare, reported only in ~20 patients in the international literature. We report a 23-year-old male patient with renal anomalies in the form of absent right kidney, left-sided vesicoureteric reflux (VUR) and skeletal anomalies viz short radius, absent first metacarpal ray in left hand and left undescended testis, consistent with Dieker's type acro-renal syndrome. Apart from the classical acro-renal syndrome, several anomalies of acro-renal patterns and the abnormal gene loci involved are described in the literature. This article is a comprehensive review of the development of kidneys, types of acro-renal syndromes, congenital anomalies of the kidney and urinary tract (CAKUT), syndromes associated with combined limb and renal anomalies, and anomalies associated with URA. PMID- 26019843 TI - Changing epidemiology of community-acquired acute kidney injury in developing countries: analysis of 2405 cases in 26 years from eastern India. AB - BACKGROUND: The epidemiology of acute kidney injury (AKI) differs from country to country and varies from center to center within a country. Owing to the absence of a central registry, data on overall epidemiology of AKI are scanty from India. METHODS: This study aimed at describing changes in epidemiology of community acquired AKI (CAAKI) over a time span of 26 years in two study periods, namely, 1983-95 and 1996-2008. RESULTS: We studied 2405 (1375 male and 1030 female) cases of AKI in the age range 1-95 (mean: 40.32) years. The incidence of CAAKI in 1983 95 and 1996-2008 was 1.95 and 4.14 per 1000 admission, respectively (P < 0.01). Obstetrical AKI has decreased because of the declining number of post-abortal AKI. Surgical AKI decreased from 13.8% in 1983-95 to 9.17% in 1996-2008(P < 0.01). Malarial AKI increased significantly from 4.7% in the first half of the study to 17% in the later period (P < 0.01). Diarrhea-associated AKI had significantly decreased from 36.83% in 1983-95 to 19% in 1996-2008 (P < 0.01). Sepsis-related AKI had increased from 1.57% in 1983-95 to 11.43% in 1996-2008 (P < 0.01). Nephrotoxic AKI showed an increasing trend in recent years (P < 0.01) and mainly caused by rifampicin and NSAIDs. Liver disease-related AKI increased from 1.73% in 1983-95 to 3.17% in 1996-2008 (P < 0.01). Myeloma-associated acute renal failure (ARF) accounted for 1.25% of the total number of ARF cases in the period 1996-2008. HIV infection contributed to 1.65% of ARF of the total number of AKI cases in the second period (1996-2008). Incidence of renal cortical necrosis (RCN) decreased significantly from 5.8% in 1983-95 to 1.3% in 1996-2008 of the total number of ARF cases (P < 0.01). However, during the same period ARF due to acute tubular necrosis, acute glomerulonephritis and acute interstitial nephritis remained unchanged. The mortality rate from AKI decreased significantly from 20% in 1983-95 to 10.98% in 1996-2008 (P < 0.01). CONCLUSIONS: The epidemiological characteristics of CAAKI have changed over the past three decades. There has been an increase in the overall incidence of ARF with the changing etiology of AKI in recent years. Incidences of obstetrical, surgical and diarrheal AKI have decreased significantly, whereas those of AKI associated with malaria, sepsis, nephrotoxic drugs and liver disease have increased. RCN has decreased significantly. In contrast to developed nations, community-acquired AKI is more common in developing countries. It often affects younger individuals and is caused by single and preventable diseases. PMID- 26019844 TI - Clinical profile and post-transplant anaemia in renal transplant recipients restarting dialysis after a failed graft: changing trends between 2001 and 2009. AB - BACKGROUND: The aim of this study was to compare the clinical profile, outcome and the prevalence and management of anaemia between two cohorts of renal transplant patients with graft failure restarting dialysis in 2001 and 2009. METHODS: Cross-sectional, observational, retrospective and multicentre study of 397 patients in the 2001 cohort and 222 in the 2009 cohort. Data were recorded at 0, 3, 6, 9 and 12 months before the onset of dialysis resumption and during the first 90 days after restarting dialysis (mortality and hospital admission). RESULTS: Patients in the 2009 cohort were older at the time of inclusion in the study and transplantation, and restarted dialysis therapy with a significantly better glomerular filtration rate. In both cohorts, there was a rapid deterioration of renal function with statistically significant differences in serum creatinine and glomerular filtration rate between the monthly intervals -12 and 0. The mean haemoglobin value at -12 months was 11.6 g/dL [7.2 mmol/L] in the 2001 cohort when compared with 12.3 g/dL [7.6 mmol/L] in the 2009 cohort, and at the time of restarting dialysis 9.6 g/dL [6.0 mmol/L] versus 10.6 g/dL [6.6 mmol/L]. The percentage of patients treated with erythropoiesis-stimulating agents, at any time during the 12 months before readmission to dialysis, increased significantly from 61.5% in the 2001 cohort to 96% in the 2009 cohort. There were no significant differences between the 2001 and 2009 cohorts in mortality rate (8.8 versus 9.0%) or hospital admission (31.5 versus 31.1%) during the study time. CONCLUSIONS: At restarting dialysis, the proportion of patients with anaemia (and its severity) due to progressive graft nephropathy decreased over the past 8 years, increasing significantly the percentage of patients treated with erythropoietin. Differences in morbimortality after dialysis resumption were not observed, this is probably due to an increase in the age of donors and recipients. PMID- 26019845 TI - Treatment with oral paricalcitol in daily clinical practice for patients with chronic kidney disease stage 3-4: a preliminary study. AB - BACKGROUND: Active vitamin D is an effective treatment for secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients often complicated by hypercalcaemia and hyperphosphataemia. Treatment with paricalcitol, a selective vitamin D receptor activator, has shown benefits by adequately reducing parathyroid hormone (PTH) levels with minimal changes in serum calcium (Ca) and phosphorus (P). The purpose of this study is to present data on the use of oral paricalcitol in real-life clinical practice in patients with CKD stage 3-4 and SHPT. METHODS: We studied 43 patients, M/F: 25/18, median age: 74 years (47-87), CKD stage 3/4: 16/27, with SHPT, who were prescribed oral paricalcitol at recommended doses for 6 months. Monthly measurements of serum intact PTH (iPTH), Ca, P, alkaline phosphatase (ALP), haemoglobin, albumin (ALB), lipid profile, proteinuria and 24-h urine creatinine clearance were performed 3 months before and 6 months after treatment initiation. RESULTS: Paricalcitol induced a significant, early and sustained, through the end of follow-up period, decrease in iPTH and ALP levels and an increase in serum ALB. No significant increase in Ca and P levels as well as in Ca * P product was observed during the study period. No significant changes were found in protein excretion, kidney function and the other measured parameters between baseline and last evaluation. Paricalcitol final median dose was 5 MUg/week ranging between 3 and 7 MUg/week. CONCLUSIONS: In the context of real-life clinical practice, oral paricalcitol for 6 months is an effective, well-tolerated treatment of SHPT in CKD stage 3-4 with minimal effects on calcium and phosphorus metabolism. PMID- 26019846 TI - Vascular access and infection prevention and control: a national survey of routine practices in Irish haemodialysis units. AB - BACKGROUND: National and international guidelines recommend the use of effective vascular access (VA) and infection prevention and control practices within the haemodialysis environment. Establishing an arterio-venous fistula (AVF) and preventing central venous catheter (CVC)-related infections are ongoing challenges for all dialysis settings. We surveyed VA and routine infection prevention and control practices in dialysis units, to provide national data on these practices in Ireland. METHODS: A descriptive survey was emailed to nurse managers at all adult (n = 19) and children (n = 1) outpatient haemodialysis units in the Republic of Ireland. Data collected included AVF formation, CVC insertion and maintenance practices, VA use and surveillance of infection and screening protocols. Nineteen of the 20 units responded to the survey. RESULTS: The AVF prevalence was 49% for 1370 patients in 17 units who provided these data [mean prevalence per unit: 45.7% (SD 16.2)]; the CVC mean prevalence per unit was 52.5% (SD 16.0). Fourteen dialysis units experienced inadequate access to vascular surgical procedures either due to a lack of dedicated theatre time or hospital beds. Six units administered intravenous prophylactic antimicrobials prior to CVC insertion with only two units using a CVC insertion checklist at the time of catheter insertion. CONCLUSION: In general, dialysis units in Ireland show a strong adherence to national guidelines. Compared with the 12 countries participating in the Dialysis Outcomes Practice Patterns Study (DOPPS 4), in 2010, AVF prevalence in Irish dialysis units is the second lowest. Recommendations include establishing an AVF national prevalence target rate, discontinuing the administration of intravenous prophylactic antimicrobials prior to CVC insertion and promoting the use of CVC insertion checklists. PMID- 26019847 TI - Glomerular involvement in the arthrogryposis, renal dysfunction and cholestasis syndrome. AB - BACKGROUND: Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a multisystem autosomal-recessive disorder caused by defects in the VPS33B and VIPAR genes, involved in localization of apical membrane proteins. Affected children usually die by 1 year of age, often secondary to infective complications. The classic renal manifestation previously described in ARC syndrome is proximal-tubular dysfunction. The aim of this study is to gain further insight into the renal manifestations of this syndrome. METHODS: Clinical review of three cases of ARC syndrome presenting to a tertiary centre. Together with measurement of VPS33B and VIPAR protein expression in the human glomerulus. RESULTS: The cases demonstrated severe failure to thrive and in addition to commonly described features profound proteinuria and albuminuria, together with hypoalbuminaemia, suggesting glomerular involvement of this syndrome. Western blotting of conditionally immortalized human glomerular cells and ex vivo immunofluorescent analysis of the human glomerulus revealed that VPS33B and VIPAR were highly expressed in glomerular endothelium, and podocytes, but not in the mesangium. CONCLUSIONS: ARC syndrome affects the glomerulus as well as the proximal tubule in the kidney. Our molecular studies suggest that both cell types that constitute the glomerular filtration barrier are affected in this condition, providing an explanation for the albuminuria that we have observed in our cases. PMID- 26019848 TI - Hereditary renal amyloidosis caused by a heterozygous G654A gelsolin mutation: a report of two cases. AB - Finnish-type familial amyloidosis (FAF) is a rare hereditary systemic amyloidosis that mainly exhibits cranial neuropathy. We describe a Japanese family with FAF manifested predominantly as renal amyloidosis. The proband was a 42-year-old woman with a 21-year history of proteinuria due to renal amyloidosis. Her mother was subsequently diagnosed with a similar disorder. After the first renal biopsy, both patients were followed up routinely for a period of 14 years. Genetic analysis of DNA samples revealed a heterozygous G654A gelsolin mutation. Severe renal involvement has not been reported previously in patients with FAF bearing a heterozygous gelsolin mutation. PMID- 26019849 TI - Enigmatic pruritus in a kidney transplant patient. AB - Pruritus is a common problem following a kidney transplant and is usually attributable to new medications related to transplantation. We present an unusual case of pruritus that began several months after kidney transplantation. After changing several immunosuppressive medications, numerous clinical visits and consideration by the patient of stopping immunosuppression, scabies was diagnosed as the cause. Treatment with oral ivermectin and topical permethrin resulted in complete resolution of symptoms within 1 week. Transplant physicians should consider common causes of pruritus unrelated to transplantation; diagnostic skin lesions of scabies may be absent. PMID- 26019850 TI - A cardiorenal-pulmonary-cutaneous-muscle syndrome. AB - Anti-synthetase syndrome is a relatively recently described auto-immune disease characterized by auto-antibodies to enzymes that acetylate transfer RNA (tRNA). Interstitial pulmonary disease and inflammatory myopathy are regular findings. Our patient also exhibited a lupus-like glomerulonephritis. An important clue was the presence of 'mechanics' hands. Nephrologists need to be aware of this syndrome. PMID- 26019851 TI - Acute kidney injury by cantharidin poisoning following a silly bet on an ugly beetle. AB - Cantharidin is a poisonous substance secreted by blister beetles, including the 'Spanish fly'. Historically, cantharidin was used as an aphrodisiac, vesicant and abortifacient. Symptoms of poisoning include gastrointestinal and genitourinary mucosal irritation along with renal dysfunction. We present the case of a reckless 23-year-old soldier who accepted the challenge of eating a beetle (Berberomeloe majalis). Six hours later he was admitted to the emergency room with abdominal pain, dysuria, gross haematuria with clots, hypotension, fever and renal insufficiency. With intravenous fluid therapy, he recovered clinically. Laboratory parameters returned to normal within 1 week. PMID- 26019852 TI - Osteoclastomas ('brown tumours') and spinal cord compression: a review. AB - Brown tumours are an uncommon manifestation of primary and secondary hyperparathyroidism. There are numerous case reports of brown tumours arising in various parts of the skeleton. They can therefore present a wide range of clinical manifestations. A recent case highlighted the need for heightened awareness of the diagnosis and prompted a literature review. PMID- 26019853 TI - Donor transmission of Cryptococcus neoformans presenting late after renal transplantation. PMID- 26019854 TI - Unexpected deterioration of graft function after combined kidney and pancreas transplantation. PMID- 26019855 TI - Peculiarly progressive tetraplegia. PMID- 26019856 TI - Macrophages at work: phagocytosis of urinary fungi. PMID- 26019857 TI - Diffusion-weighted magnetic resonance imaging as a new diagnostic tool of subclinical IgG4-related acute tubulointerstitial nephritis. PMID- 26019858 TI - Parapelvic cyst misdiagnosed as hydronephrosis. PMID- 26019859 TI - Joint pain, digital necrosis and acute kidney failure in small-vessel autoimmune disease. PMID- 26019860 TI - Post-partum atypical haemolytic-uraemic syndrome treated with eculizumab: terminal complement activity assessment in clinical practice. PMID- 26019861 TI - Prolonged hypocalcaemia following a single dose of 60 mg denosumab in two patients with CKD 4/5 on cinacalcet treatment for tertiary hyperparathyroidism. PMID- 26019862 TI - The 50th anniversary of haemodialysis in Krakow, Poland. PMID- 26019863 TI - A short history of 'glomerulus'. PMID- 26019864 TI - The application of antimicrobial peptides as growth and health promoters for swine. AB - With the widespread ban on the use of antibiotics in swine feed, alternative measures need to be sought to maintain swine health and performance. Antimicrobial peptides (AMPs) are part of the nonspecific defense system and are natural antibiotics produced by plants, insects, mammalians, and micro-organisms as well as by chemical synthesis. Due to their broad microbicidal activity against various fungi, bacteria and enveloped viruses, AMPs are a potential alternative to conventional antibiotics for use in swine production. This review focuses on the structure and mechanism of action of AMPs, as well as their effects on performance, immune function and intestinal health in pigs. The aim is to provide support for the application of AMPs as feed additives replacing antibiotics in swine nutrition. PMID- 26019865 TI - The nucleus accumbens: a target for deep brain stimulation in resistant major depressive disorder. AB - OBJECTIVE: This review aimed to investigate the therapeutic potential of Deep Brain Stimulation (DBS) for treating resistant Major Depressive Disorder (MDD). We explored the role of Nucleus accumbens (Nac) as a target for treatment. METHOD: We made a systematic review of all studies examining the mechanisms of action of high frequency brain stimulation and the pathophysiology of MDD. We also reported all the studies exploring the therapeutic potential of DBS in MDD. RESULTS: As a central relay-structure, the Nac seems to play a central role in MDD symptomatology. We investigated its role as a primary target for DBS in depressed patients. Anatomically the Nac is at the centre of the interactions between dopaminergic, serotoninergic and glutamatergic systems. Functionally, the Nac is involved in both normal and abnormal reward processes and in anhedonia and loss of motivation. Due to its central location between the emotional system, the cognitive system and motor control system, the Nac seems to have a central role in mood and feeling regulation. CONCLUSION: According to encouraging recent studies, DBS seems to be a promising technique in resistant MDD treatment. PMID- 26019867 TI - Behavioral disorders and cognitive impairment associated with cerebellar lesions. AB - In the last decade evidence has accumulated that suggests that the cerebellum is involved not only in motor but also in behavioral and cognitive functions. A myriad of anatomical, clinical and imaging studies support that assumption. The lengthened survival of patients with cerebellar tumors has also brought an increased awareness of neurocognitive deficits to the neurooncological community. Although evidence from neurosurgical case series exists that clearly demonstrates that patients afflicted from posterior fossa tumors are at high risk for long term cognitive or adaptive deficits, there is still a lack of systematic translational review on this issue. Accordingly a systematic review was conducted to summarize the impact of cerebellar lesions on behavior and cognition. The findings and clinical implications are discussed in the light of the recent advances in neuroimaging techniques. PMID- 26019866 TI - Astrocytes reassessment - an evolving concept part one: embryology, biology, morphology and reactivity. AB - The goal of this review is to integrate - in its two parts - the considerable amount of information that has accumulated during these recent years over the morphology, biology and functions of astrocytes - first part - and to illustrate the active role of these cells in pathophysiological processes implicated in various psychiatric and neurologic disorders - second part. PMID- 26019868 TI - Time to restore body weight in adults and adolescents receiving cognitive behaviour therapy for anorexia nervosa. AB - BACKGROUND: The aim of the present study was to provide benchmark data on the duration of treatment required to restore body weight (to BMI >=18.5 or a corresponding BMI centile) in adolescents and adults with anorexia nervosa treated with outpatient cognitive behaviour therapy. METHODS: Ninety-five participants (46 adolescents and 49 adults) were recruited from consecutive referrals to a specialist eating disorder clinic. Each was offered 40 sessions of enhanced cognitive behaviour therapy (CBT-E) over 40 weeks, the conventional length of this treatment. RESULTS: Twenty-nine (63.1%) of the adolescents and 32 (65.3%) of the adults completed all 40 sessions of treatment (P = 0.818). Significantly more adolescents reached the goal BMI than adults (65.3% vs. 36.5%; P = 0.003). The mean time required by the adolescents to restore body weight was about 15 weeks less than that for the adults (14.8 (SE = 1.7) weeks vs. 28.3 (SE = 2.0) weeks, log-rank = 21.5, P < 0.001). CONCLUSIONS: The findings indicate that adolescent patients receiving CBT-E are able to regain weight more successfully than adults and at a faster rate. If these findings are replicated and extend to eating disorder psychopathology, then their treatment could be shorter than that of adults. PMID- 26019869 TI - Weight loss intervention for individuals with high internal disinhibition: design of the Acceptance Based Behavioral Intervention (ABBI) randomized controlled trial. AB - BACKGROUND: Obesity is public health problem associated with significant health risks and healthcare costs. Behavioral weight control programs produce clinically meaningful weight losses, however outcomes have high variability and maintenance continues to be a problem. The current study is an NIH-funded randomized clinical trial testing a novel approach, Acceptance-Based Behavioral Intervention (ABBI), that combines techniques from standard behavioral treatment (SBT) and Acceptance and Commitment Therapy (ACT). We test this approach among individuals reporting high internal disinhibition who typically respond poorly to standard interventions and appear to benefit from ACT components. METHODS/DESIGN: The ABBI study targets recruitment of 160 overweight or obese adults (BMI of 25-50) who report that they overeat in response to negative emotional states. These individuals are randomly assigned to either (1) ABBI or (2) SBT. Both interventions involve weekly meetings for 22 sessions, bi-weekly for 6 sessions, and then monthly for 3 sessions and both receive the same calorie intake target (1200-1800, depending on starting weight), exercise goal (work up to 250 min per week), and self-monitoring skills training. SBT incorporates current best practice interventions for addressing problematic thoughts and emotions, sometimes called "change" or "control" strategies. ABBI uses acceptance-based techniques based on ACT. Full assessments occur at baseline, 6, 12, and 18 months. Weight loss from baseline to 18 months is the primary outcome. DISCUSSION: The ABBI study is unique in its focus on integrating acceptance-based techniques into a SBT intervention and targeting a group of individuals with problems with emotional overeating who might experience particular benefit from this novel approach. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01461421 (registered October 25, 2011). PMID- 26019870 TI - Windscapes shape seabird instantaneous energy costs but adult behavior buffers impact on offspring. AB - BACKGROUND: Windscapes affect energy costs for flying animals, but animals can adjust their behavior to accommodate wind-induced energy costs. Theory predicts that flying animals should decrease air speed to compensate for increased tailwind speed and increase air speed to compensate for increased crosswind speed. In addition, animals are expected to vary their foraging effort in time and space to maximize energy efficiency across variable windscapes. RESULTS: We examined the influence of wind on seabird (thick-billed murre Uria lomvia and black-legged kittiwake Rissa tridactyla) foraging behavior. Airspeed and mechanical flight costs (dynamic body acceleration and wing beat frequency) increased with headwind speed during commuting flights. As predicted, birds adjusted their airspeed to compensate for crosswinds and to reduce the effect of a headwind, but they could not completely compensate for the latter. As we were able to account for the effect of sampling frequency and wind speed, we accurately estimated commuting flight speed with no wind as 16.6 ms(?1) (murres) and 10.6 ms(?1) (kittiwakes). High winds decreased delivery rates of schooling fish (murres), energy (murres) and food (kittiwakes) but did not impact daily energy expenditure or chick growth rates. During high winds, murres switched from feeding their offspring with schooling fish, which required substantial above water searching, to amphipods, which required less above-water searching. CONCLUSIONS: Adults buffered the adverse effect of high winds on chick growth rates by switching to other food sources during windy days or increasing food delivery rates when weather improved. PMID- 26019871 TI - The intensity of horizontal and vertical search in a diving forager: the harbour seal. AB - BACKGROUND: Free ranging foraging animals can vary their searching intensity in response to the profitability of the environment by modifying their movements. Marine diving animals forage in a three dimensional space and searching intensity can be varied in both the horizontal and vertical planes. Therefore understanding the relationship between the allocation of searching effort in these two spaces can provide a better understanding of searching strategies and a more robust identification of foraging behaviour from the multitude of foraging indices (FIs) available. We investigated the movement of a widespread marine coastal predator, the harbour seal (Phoca vitulina), and compared two sets of foraging indices reflecting searching intensity respectively in the horizontal plane (displacement speed, extensive vs. intensive movement types, residence time) and in the vertical dimension (time at the bottom of a dive). We then tested how several factors (dive depth, direction of the trip with respect to haul-out site, different predatory tactics, the presence of factors confounding the detection of foraging, and temporal resolution of the data) affected their relationships. RESULTS: Overall the indices only showed a very weak positive correlation across the two spaces. However controlling for various factors strengthened the relationships. Resting at sea, a behaviour intrinsically static in the horizontal plane, was found to be strongly negatively related to the time spent at the bottom of the dives, indirectly weakening the relationship between horizontal and vertical foraging indices. Predatory tactic (benthic vs. pelagic) was found to directly affect the relationship. In benthic (as opposed to pelagic) foraging a stronger positive relationship was found between vertical and horizontal indices. CONCLUSIONS: Our results indicated that movement responses, leading to an intensification of search, are similar in the two spaces (positive relationship), but additional factors need to be taken into account for this relationship to emerge. Foraging indices measuring residence in the horizontal plane tend to be inflated by resting events at sea, while vertical indices tend to distinguish mainly between periods of activity and inactivity, or of benthic and pelagic foraging. The simultaneous consideration of horizontal and vertical movements, as well as topographic information, allows additional behavioural states to be inferred, providing greater insight into the interpretation of foraging activity. PMID- 26019872 TI - Familial hypocalciuric hypercalcemia with a de novo heterozygous mutation of calcium-sensing receptor. AB - A de novo heterozygous inactivating mutation of calcium-sensing receptor (CASR) gene typically causes neonatal hyperparathyroidism (NHPT) with moderate hypercalcemia and hyperparathyroid bone disease. We present a case of asymptomatic hypocalciuric hypercalcemia with a de novo heterozygous mutation in CASR, S591C, which is primarily reported to be responsible for NHPT. A 54-year old female was referred for investigation of asymptomatic hypercalcemia that was initially found in the 1980s but without a history of bone disease during the perinatal period. She had moderate hypercalcemia (12.4 mg/dl) and relative hypocalciuria (fractional extraction of calcium 1.07%) but normal intact parathyroid hormone and serum 1,25-dihydroxyvitamin D3. Pedigree analysis revealed that she carried a de novo heterozygous mutation of S591C, which she transmitted to an affected child with moderate hypercalcemia but not to other children, who had normal serum calcium levels. A de novo heterozygous CASR mutation that is responsible for NHPT may also present in individuals with asymptomatic hypocalciuric hypercalcemia. Caution is required when predicting course and outcome in a pedigree with CASR mutation, as well as incidental hypercalcemia, because of its variable phenotypes. LEARNING POINTS: The phenotype and severity of CASR mutations are thought to be dependent on genotypes.We report an asymptomatic case of the de novo heterozygous S591C mutation in CASR, which has previously been reported as a responsible mutation of NHPT with bone diseases.Variable phenotypes of CASR raise a cautionary note about predicting outcome by genotyping in a pedigree with CASR mutation. PMID- 26019873 TI - Changes in transition times in 'Ironman Hawaii' between 1998 and 2013. AB - BACKGROUND: Recent findings showed that elite Ironman triathletes competing in 'Ironman Hawaii' improved both split and overall race times. The present study investigated whether elite athletes also improved in transition time (i.e. time needed between disciplines for changing clothes and equipment). METHODS: Changes in split times, overall race times and transition times (i.e. expressed in absolute and relative terms) in the annual fastest competing in 'Ironman Hawaii' were investigated using linear, non-linear and multi-level regression analyses. To detect a potential difference in transition times between different race distances, we compared transition times in 'Ironman Hawaii' to transition times in the World Championships 'Ironman 70.3' covering the half distance of the Ironman distance triathlon. RESULTS: In 'Ironman Hawaii', transition times remained unchanged for the annual fastest women but increased linearly for the annual fastest men. For the annual ten fastest, transition times increased linearly for women and men in both absolute and relative terms. The sex difference in transition times remained unchanged for the annual fastest, but decreased linearly for the annual ten fastest. In 'Ironman 70.3', transition times remained unchanged for the annual fastest. For the annual ten fastest, transition times decreased linearly for both women and men in absolute and relative terms. The sex difference in transition times remained unchanged for both the annual fastest and the annual ten fastest. Transition times were faster in 'Ironman 70.3' for women in 2011 and for men in 2006, 2007, and 2010-2013. In relative terms, transition times were faster in 'Ironman 70.3'compared to 'Ironman Hawaii' during 2006-2013. The sex difference in transition times remained unchanged. CONCLUSIONS: In 'Ironman Hawaii', transition times increased for both women and men whereas the sex difference decreased. In 'Ironman 70.3', transition times decreased for both women and men whereas the sex difference remained unchanged. Generally, transition times were slower in 'Ironman Hawaii' compared to 'Ironman 70.3'. PMID- 26019874 TI - Modelling of aflatoxin G1 reduction by kefir grain using response surface methodology. AB - Aflatoxin G1 (AFG1) is one of the main toxic contaminants in pistachio nuts and causes potential health hazards. Hence, AFG1 reduction is one of the main concerns in food safety. Kefir-grains contain symbiotic association of microorganisms well known for their aflatoxin decontamination effects. In this study, a central composite design (CCD) using response surface methodology (RSM) was applied to develop a model in order to predict AFG1 reduction in pistachio nuts by kefir-grain (already heated at 70 and 110 degrees C). The independent variables were: toxin concentration (X1: 5, 10, 15, 20 and 25 ng/g), kefir-grain level (X2: 5, 10, 20, 10 and 25%), contact time (X3: 0, 2, 4, 6 and 8 h), and incubation temperature (X4: 20, 30, 40, 50 and 60 degrees C). There was a significant reduction in AFG1 (p < 0.05) when pre-heat-treated kefir-grain used. The variables including X1, X3 and the interactions between X2-X4 as well as X3 X4 have significant effects on AFG1 reduction. The model provided a good prediction of AFG1 reduction under the assay conditions. Optimization was used to enhance the efficiency of kefir-grain on AFG1 reduction. The optimum conditions for the highest AFG1 reduction (96.8%) were predicted by the model as follows: toxin concentration = 20 ng/g, kefir-grain level = 10%, contact time = 6 h, and incubation temperature = 30 degrees C which validated practically in six replications. PMID- 26019875 TI - Influenza vaccination for NHS staff: attitudes and uptake. AB - OBJECTIVES: Annual vaccination against influenza (flu) is recommended for all UK National Health Service (NHS) staff to help reduce the risk of contracting the virus and transmitting it to patients. However, despite flu campaigns and vaccination promotion, uptake remains low. The aim of this study was to investigate staff attitudes to flu vaccination to see how this may influence their decision to be vaccinated. METHODS: An online survey was sent to staff members across 6 NHS trusts, asking if staff had been vaccinated in the preceding flu season (2013-2014); the survey included questions about beliefs and attitudes to the vaccination, scored on a 5-point Likert scale. RESULTS: 3059 NHS staff members responded to the survey (86% in the 26-59 age group, 77% female and 84% hospital based). 68% of respondents reported being vaccinated in the preceding year. Using a stepwise regression model, the survey response retained as a positive predictor of having been vaccinated was 'people working in healthcare should have the flu vaccination every year' (p<0.001), and the responses retained as negative predictors were 'the flu vaccination will make me unwell' (p<0.001) and 'the flu vaccination was too much trouble for me' (p<0.001). Analysis by staff group showed a significant difference in the response to 'the flu vaccination will make me unwell' between groups (p=0.01), with doctors having a greater tendency to disagree with this statement than other staff members. CONCLUSIONS: These results suggest that addressing NHS staff beliefs around the need for vaccination, while ensuring that practical barriers to having the vaccination are removed, may help to increase uptake. An emphasis on alleviating the concerns of particular staff groups regarding adverse effects of the vaccine may also be of benefit in improving uptake, to protect patients as well as staff. PMID- 26019876 TI - British Thoracic Society community acquired pneumonia guideline and the NICE pneumonia guideline: how they fit together. AB - The British Thoracic Society (BTS) guideline for the management of adults with community acquired pneumonia (CAP) published in 2009 was compared with the 2014 National Institute for Health and Care Excellence (NICE) Pneumonia Guideline. Of the 36 BTS recommendations that overlapped with NICE recommendations, no major differences were found in 31, including those covering key aspects of CAP management: timeliness of diagnosis and treatment, severity assessment and empirical antibiotic choice. Of the five BTS recommendations where major differences with NICE were identified, one related to antibiotic duration in low and moderate severity CAP, two to the timing of review of patients and two to legionella urinary antigen testing. PMID- 26019877 TI - Association of severe hypoglycemia with depressive symptoms in patients with type 2 diabetes: the Fukuoka Diabetes Registry. AB - OBJECTIVE: Although many studies have investigated the clinical characteristics of patients with diabetes with depression in Western populations, there is a lack of information regarding other ethnicities. We studied the association between clinical characteristics and depressive symptoms in Japanese patients with type 2 diabetes. METHODS: A total of 4218 Japanese patients with type 2 diabetes who were not taking antidepressants were divided into four groups according to the Center for Epidemiologic Studies Depression Scale (CES-D) score. The relationship between the severity of depressive symptoms and clinical parameters was examined cross-sectionally. RESULTS: After multivariate adjustments, the severity of depressive symptoms was significantly associated with body mass index, leisure time physical activity, current smoking, sleep duration, sucrose intake, skipping breakfast, insulin use, severe hypoglycemia, dysesthesia of both feet, history of foot ulcer, photocoagulation, ischemic heart disease, and stroke. ORs for severe hypoglycemia increased significantly with the CES-D score in 2756 sulfonylurea and/or insulin-treated patients after multivariate adjustment including age, sex, duration of diabetes, glycated hemoglobin, insulin use, self-monitoring of blood glucose, leisure-time physical activity, skipping breakfast, dysesthesia of both feet, ischemic heart disease, and stroke (CES-D score <=9, referent; 10-15, OR 1.64; 16-23, OR 2.09; >=24, OR 3.66; p for trend <0.01). CONCLUSIONS: Severe hypoglycemia was positively associated with the severity of depressive symptoms in Japanese patients with type 2 diabetes independent of glycemic control, insulin therapy, lifestyle factors, and diabetic complications. As both severe hypoglycemia and depression are known risk factors for morbidity and mortality in patients with diabetes, clinicians should be aware of this association. UMIN CLINICAL TRIAL REGISTRY: 000002627. PMID- 26019878 TI - Insulin therapy and dietary adjustments to normalize glycemia and prevent nocturnal hypoglycemia after evening exercise in type 1 diabetes: a randomized controlled trial. AB - INTRODUCTION: Evening-time exercise is a frequent cause of severe hypoglycemia in type 1 diabetes, fear of which deters participation in regular exercise. Recommendations for normalizing glycemia around exercise consist of prandial adjustments to bolus insulin therapy and food composition, but this carries only short-lasting protection from hypoglycemia. Therefore, this study aimed to examine the impact of a combined basal-bolus insulin dose reduction and carbohydrate feeding strategy on glycemia and metabolic parameters following evening exercise in type 1 diabetes. METHODS: Ten male participants (glycated hemoglobin: 52.4+/-2.2 mmol/mol), treated with multiple daily injections, completed two randomized study-days, whereby administration of total daily basal insulin dose was unchanged (100%), or reduced by 20% (80%). Participants attended the laboratory at ~08:00 h for a fasted blood sample, before returning in the evening. On arrival (~17:00 h), participants consumed a carbohydrate meal and administered a 75% reduced rapid-acting insulin dose and 60 min later performed 45 min of treadmill running. At 60 min postexercise, participants consumed a low glycemic index (LGI) meal and administered a 50% reduced rapid-acting insulin dose, before returning home. At ~23:00 h, participants consumed a LGI bedtime snack and returned to the laboratory the following morning (~08:00 h) for a fasted blood sample. Venous blood samples were analyzed for glucose, glucoregulatory hormones, non-esterified fatty acids, beta-hydroxybutyrate, interleukin 6, and tumor necrosis factor alpha. Interstitial glucose was monitored for 24 h pre-exercise and postexercise. RESULTS: Glycemia was similar until 6 h postexercise, with no hypoglycemic episodes. Beyond 6 h glucose levels fell during 100%, and nine participants experienced nocturnal hypoglycemia. Conversely, all participants during 80% were protected from nocturnal hypoglycemia, and remained protected for 24 h postexercise. All metabolic parameters were similar. CONCLUSIONS: Reducing basal insulin dose with reduced prandial bolus insulin and LGI carbohydrate feeding provides protection from hypoglycemia during and for 24 h following evening exercise. This strategy is not associated with hyperglycemia, or adverse metabolic disturbances. CLINICAL TRIALS NUMBER: NCT02204839, ClinicalTrials.gov. PMID- 26019879 TI - In-hospital treatment and outcomes of heart failure in specialist and non specialist services: a retrospective cohort study in the elderly. AB - BACKGROUND: Heart failure is common in the elderly and is associated with high rates of hospitalisation, readmission and mortality. International guidelines however are not frequently implemented in this population. METHODS: We retrospectively studied the clinical profile, investigations, treatment on discharge, length of hospital stay, readmission rate and mortality in 261 patients, aged >=75 years, with a discharge diagnosis of heart failure. Clinical frailty was estimated using the Canadian Study of Health and Aging clinical frailty scale. RESULTS: Hypertension (64%), atrial fibrillation (50.6%) and ischaemic heart disease (46%) were common, and 75.6% of patients were clinically vulnerable or frail. 23.5% of admitters had an inpatient echocardiogram and 20% of patients had at least one readmission episode for heart failure. On discharge, 64.6% of admissions were treated with an ACE inhibitor or angiotensin II receptor antagonist, 49.3% with a beta blocker and 28.7% with an aldosterone receptor antagonist (ARA). Patients discharged from cardiology wards were more likely to receive a beta blocker (p<0.05) versus care of elderly (COE) wards and readmitters were more likely to receive an ARA (p<0.05) versus patients with a single admission. In total, 34 inpatient deaths were recorded (13%) and 80 deaths (30.7%) were recorded long-term (median follow-up 337 days). Long-term mortality was significantly lower in single admitters versus readmitters (p<0.0001) and in those managed on cardiology wards versus COE wards (p<0.05). CONCLUSIONS: Compared with patients hospitalised on geriatric wards, those admitted to cardiology units were discharged more frequently with recommended medications and had a lower long-term mortality. PMID- 26019880 TI - Routine issuance of clinical magnets to patients receiving implantable defibrillators: retention of information and appropriateness of use. AB - BACKGROUND: The application of a clinical magnet over an implantable cardioverter defibrillator (ICD) can be used to suspend tachycardia therapies in patients receiving recurrent or inappropriate shocks. In our institution, they have been routinely issued to patients undergoing ICD implantation during the past 5 years. The purpose of this survey was to investigate how well information concerning their use had been retained, and in what circumstances the magnets had been used. METHODS: We sent a questionnaire to 476 patients, and received a response from 343 (72%). Data was collated using 'Microsoft Excel', cross-referenced against our own pacing database, and analysed using basic statistical methods. RESULTS: 256 (74.6%) patients recalled being issued with a magnet. 48% of these were still in possession of their written information leaflet at the time of survey; 62% felt that they were able to remember when and how to use the magnet-with patients who had received written instructions and verbal reinforcement demonstrating the best recall. 8% of patients had used their magnets and the most common reason for use was multiple or inappropriate shocks. In addition, almost half of the patients who had suffered inappropriate shocks had been able to successfully use their magnets. No cases of harm related to magnet use were identified. CONCLUSIONS: The results of our survey suggest that routinely issuing clinical magnets to ICD patients is a safe and effective practice, and a small but significant number of patients were able to utilise their magnets in clinically important situations. PMID- 26019881 TI - Observer variability in the assessment of CT coronary angiography and coronary artery calcium score: substudy of the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial. AB - INTRODUCTION: Observer variability can influence the assessment of CT coronary angiography (CTCA) and the subsequent diagnosis of angina pectoris due to coronary heart disease. METHODS: We assessed 210 CTCAs from the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial for intraobserver and interobserver variability. Calcium score, coronary angiography and image quality were evaluated. Coronary artery disease was defined as none (<10%), mild (10-49%), moderate (50-70%) and severe (>70%) luminal stenosis and classified as no (<10%), non-obstructive (10-70%) or obstructive (>70%) coronary artery disease. Post-CTCA diagnosis of angina pectoris due to coronary heart disease was classified as yes, probable, unlikely or no. RESULTS: Patients had a mean body mass index of 29 (28, 30) kg/m(2), heart rate of 58 (57, 60)/min and 62% were men. Intraobserver and interobserver agreements for the presence or absence of coronary artery disease were excellent (95% agreement, kappa 0.884 (0.817 to 0.951) and good (91%, 0.791 (0.703 to 0.879)). Intraobserver and interobserver agreement for the presence or absence of angina pectoris due to coronary heart disease were excellent (93%, 0.842 (0.918 to 0.755) and good (86%, 0.701 (0.799 to 0.603)), respectively. Observer variability of calcium score was excellent for calcium scores below 1000. More segments were categorised as uninterpretable with 64-multidetector compared to 320-multidetector CTCA (10.1% vs 2.6%, p<0.001) but there was no difference in observer variability. CONCLUSIONS: Multicentre multidetector CTCA has excellent agreement in patients under investigation for suspected angina due to coronary heart disease. TRIAL REGISTRATION NUMBER: NCT01149590. PMID- 26019882 TI - Serial assessment of the index of microcirculatory resistance during primary percutaneous coronary intervention comparing manual aspiration catheter thrombectomy with balloon angioplasty (IMPACT study): a randomised controlled pilot study. AB - OBJECTIVE: Utilising a novel study design, we evaluated serial measurements of the index of microcirculatory resistance (IMR) in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) to assess the impact of device therapy on microvascular function, and determine what proportion of microvascular injury is related to the PPCI procedure, and what is an inevitable consequence of STEMI. DESIGN: 41 patients undergoing PPCI for STEMI were randomised to balloon angioplasty (BA, n=20) or manual thrombectomy (MT, n=21) prior to stenting. Serial IMR measurements, corrected for collaterals, were recorded at baseline and at each stage of the procedure. Microvascular obstruction (MVO) and infarct size at 24 h and 3 months were measured by troponin and cardiac MRI (CMR). RESULTS: IMR did not change significantly following PPCI, but patients with lower IMR values (<32, n=30) at baseline had a significant increase in IMR following PPCI (baseline: 21.2+/-7.9 vs post-stent: 33.0+/-23.7, p=0.01) attributable to prestent IRA instrumentation (baseline: 21.7+/-8.0 vs post-BA or MT: 36.9+/-25.9, p=0.006). Post-stent IMR correlated with early MVO on CMR (p=0.01). There was no significant difference in post-stent IMR, presence of early MVO or final infarct size between patients with BA and patients treated with MT. CONCLUSIONS: Patients with STEMI and less microcirculatory dysfunction may be susceptible to acute iatrogenic microcirculatory injury from prestent coronary devices. MT did not appear to be superior to BA in maintaining microcirculatory integrity when the guide wire partially restores IRA flow during PPCI. TRIAL REGISTRATION NUMBER: ISRCTN31767278. PMID- 26019883 TI - Organisation of reperfusion therapy for STEMI in a developing country. AB - OBJECTIVE: Routine evaluation of performance measures for the system of care for patients with ST-elevation myocardial infarction (STEMI) is needed to improve the STEMI network. We sought to evaluate the current status of reperfusion therapy for STEMI in the capital city of a developing country where a STEMI network was introduced in 2010. METHODS: Data were obtained from a local registry. A total of 28 812 patients admitted to the emergency department of a national cardiovascular hospital in three different periods (2007, 2010 and 2013) were retrospectively analysed; there were 2703 patients with STEMI. RESULTS: In 2013 compared with 2007, there was a major increase in the number of primary percutaneous coronary interventions (PCIs) (35% vs 24%, p<0.001), and the proportion of non-reperfused patients fell (62.8% vs 67.7%, p<0.001). An improvement in the overall STEMI mortality rate was also observed (7.5% vs 11.7%, p<0.001). CONCLUSIONS: Implementation of a regional system of care for STEMI may improve utilisation of primary PCI. Future organisation of reperfusion therapy in a developing country such as Indonesia strongly calls for a strategy that focuses on prehospital care to minimise delay from the first medical contact to reperfusion therapy, and this may reduce the proportion of non-reperfused patients. These strategies are in concordance with guideline recommendations and may reduce or eliminate gaps in healthcare in developing countries, particularly the underutilisation of evidence based therapies for patients with STEMI. TRIAL REGISTRATION NUMBER: NCT 02319473, Clinicaltrials.gov. PMID- 26019884 TI - Metastatic transitional cell carcinoma of the skin presenting as painful zosteriform eruptions. AB - Metastatic skin disease is an uncommon manifestation of visceral malignancies and failure to diagnose this early may result in incorrect treatment. Here, we report a 65-year-old man with bilateral painful eruptions on the abdominal skin and a past history of transitional cell carcinoma of urinary bladder. PMID- 26019885 TI - Cerebral venous sinus thrombosis in heterozygous prothrombin G20210A mutation in Egyptian child, with an excellent outcome. AB - Prothrombin gene G20210A mutation is a risk factor for the development of deep vein thrombosis. We present a 6-year-old Egyptian boy who had vomiting associated with headache and dizziness. His conscious level was normal, with neither focal neurological signs nor papilledema. Brain computed tomographic scan, magnetic resonance imaging and magnetic resonance venography (MRV) revealed thrombosis of the superior sagittal and left transverse sinuses. The patient was heterozygous for prothrombin gene G20210A mutation. He received enoxaparin and warfarin. Brain imaging follow-up, after 1 month, showed complete resolution of the thrombus. The child was followed up for 1 year, and he was very healthy. Cerebral venous thrombosis must be considered in the differential diagnosis of any neurological symptoms, even mild symptoms, and prothrombin gene G20210A mutation must be considered in the screening of Egyptian children. Early diagnosis and treatment can be a good prognostic index. PMID- 26019886 TI - Multilevel lumbar transverse process fractures in a professional association football player: a case report. AB - We present a case of multilevel lumbar transverse process fracture in a professional association football player, incurred after a fall from height during competitive play. Traditionally associated with high impact trauma in the general population, this injury is relatively rare in the context of professional football where it is more likely to be associated with lower impact trauma. We outline our experience of mechanism of injury, treatment options and recovery time serving as a guide for fellow clinicians when treating this condition in practice. In this particular case, the return to play time was 68 days. PMID- 26019887 TI - Validation of kidney transplantation using administrative data. AB - BACKGROUND: Administrative data are increasingly being used to assess outcomes in kidney transplant recipients. OBJECTIVE: To assess the validity of transplant data in healthcare administrative databases compared to the reference standard of information collected directly from transplant centres. DESIGN: Retrospective cohort study. SETTING: One of three major transplant centres in Ontario (Toronto General Hospital, University Hospital - London, and Ottawa Hospital). PATIENTS: Recipients who received a kidney-only transplant between 2008 and 2011. MEASUREMENTS: For each data source, we identified kidney transplants performed. We calculated the sensitivity and positive predictive value (PPV) of the administrative data for the reference standard data. METHODS: The data collected from transplant centres were compared with data from the Canadian Organ Replacement Register (CORR) database, a hospital procedural code from the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD), and provincial physician billing claims from the Ontario Health Insurance Plan (OHIP) database. RESULTS: During the study period, the three centres reported a total of 1112 kidney transplants performed. The probability of identifying kidney transplant recipients in CORR, CIHI, and OHIP, given they were identified by the transplant centres (sensitivity), was 96%, 98%, and 98% respectively. The probability that the database code correctly identified a transplant recipient (positive predictive value) in CORR, CIHI, and OHIP was 98%, 98%, and 96% respectively. LIMITATIONS: We validated the information from 2008 to 2011 and cannot attest to the reliability of the data beyond the study period. Specifically, we would not regard this as evidence that applies to the earlier years, shortly after the inception of the databases. Secondly, we were unable to distinguish between first and repeat transplantation. CONCLUSIONS: Codes in CORR, CIHI, and OHIP each operate well in the detection of kidney transplant recipients. These data sources can be used to efficiently identify and follow kidney transplant recipients for post-transplant outcomes. PMID- 26019888 TI - PTHrP-related Hypercalcaemia in Infancy and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). AB - BACKGROUND: Severe hypercalcaemia is a rare but clinically significant condition in infancy and childhood. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcaemia resulting from a malignancy is rare and only a handful of case reports have outlined its incidence alongside a benign condition. OBJECTIVES: To describe the diagnostic workup and management of an infant with hypercalcaemia, renal dysplasia, and elevated PTHrP levels. DESIGN: Case report. SETTING: The Victoria Hospital campus of the London Health Sciences Centre in London, Ontario, Canada. PATIENTS: A child with congenital anomalies of the kidneys and urinary tract (CAKUT), stage 2 chronic kidney disease (CKD), and renal dysplasia who presented with severe hypercalcaemia. MEASUREMENTS: Weight, renal ultrasound, creatinine, cystatin C, eGFR, calcium, urea, bicarbonate, serum sodium, fractional sodium excretion, urine calcium to creatinine ratio, PTH, TSH, Free T4, AM cortisol, HMA, VMA, 25-vitamin D, 1,25 dihydroxy-vitamin D, calcitriol, vitamin A, ACE levels, skull and chest x-rays, alkaline phosphatase, CBC, tumour lysis profile, catecholamine breakdown, whole-body MRI, PTHrP. METHODS: Full diagnostic workup and patient management. Patient treated with intravenous hydration, furosemide, calcitonin and CalciLo. RESULTS: PTHrP was elevated and no evidence of a malignancy was found. Treatment consisting of a low-calcium CalciLo diet (in place of breast milk) adequately controlled the patient's hypercalcaemia. Hypercalcaemia associated with CAKUT in infancy is not all that uncommon and was reported in 15/99 infants in another study, most of whom had a suppressed PTH similar to that of our patient. PTHrP was not measured in these cases and may have also been elevated. LIMITATIONS: The study is limited in that it is a description of a single patient case. Future measurement of PTHrP in similar patients is necessary to confirm our results. CONCLUSIONS: The possibility of elevated PTHrP levels must be considered in patients with known renal dysplasia who are differentially diagnosed with hypercalcaemia. PMID- 26019889 TI - Correlative imaging of cystic lymphangiomas: ultrasound, CT and MRI comparison. AB - BACKGROUND: Cystic lymphangioma is a rare benign lesion derived from the detachment of the lymph sacs from venous drainage systems; the treatment of choice is a surgical excision and the final diagnosis is of histological type. PURPOSE: To compare the results of ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) in patients with cystic lymphangioma to clearly evaluate the anatomic as well as the structural lesion features necessary for differential diagnosis and for the patient treatment planning. MATERIAL AND METHODS: We analyzed the imaging results of six patients admitted in our department to evaluate cyst-like tumor masses clinically palpable or detected by US. All the patients underwent US, CT, and MRI. The pathology reports demonstrated a mesenterial cystic lymphangioma in five cases underwent surgical resection and in the last case a chest cystic lymphangioma underwent a fine needle aspiration biopsy (FNAB). RESULTS: In all the cases, the results of US, CT, and MRI were concordant showing cyst-like tumor masses in the abdomen (n = 5) and chest (n = 1) ranging in size from 3.5 to 15 cm. CONCLUSION: According to our experience, we suggest that the appropriate diagnostic imaging protocol in patients with cystic lymphangioma should initially include the US study and followed by a MRI scan with contrast administration. CT should be avoided because of radiation exposure. US and MRI may also be useful in the follow-up of patients who refuse surgical resection or in whom surgery is contraindicated or postponed as well as to early detect a possible disease relapse. PMID- 26019890 TI - Non-contrast-enhanced MR portography and hepatic venography with time-spatial labeling inversion pulses: comparison at 1.5 Tesla and 3 Tesla. AB - BACKGROUND: A 3 Tesla (3 T) magnetic resonance (MR) scanner is a promising tool for upper abdominal MR angiography. However, there is no report focused on the image quality of non-contrast-enhanced MR portography and hepatic venography at 3 T. PURPOSE: To compare and evaluate images of non-contrast-enhanced MR portography and hepatic venography with time-spatial labeling inversion pulses (Time-SLIP) at 1.5 Tesla (1.5 T) and 3 T. MATERIAL AND METHODS: Twenty-five healthy volunteers were examined using respiratory-triggered three-dimensional balanced steady-state free-precession (bSSFP) with Time-SLIP. For portography, we used one tagging pulse (selective inversion recovery) and one non-selective inversion recovery pulse; for venography, two tagging pulses were used. The relative signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were quantified, and the quality of visualization was evaluated. RESULTS: The CNRs of the main portal vein, right portal vein, and left portal vein at 3 T were better than at 1.5 T. The image quality scores for the portal branches of segment 4, 5, and 8 were significantly higher at 3 T than at 1.5 T. The CNR of the right hepatic vein (RHV) at 3 T was significantly lower than at 1.5 T. The image quality scores of RHV and the middle hepatic vein were higher at 1.5 T than at 3 T. For RHV visualization, the difference was statistically significant. CONCLUSION: Non-contrast-enhanced MR portography with Time-SLIP at 3 T significantly improved visualization of the peripheral branch in healthy volunteers compared with1.5 T. Non-contrast-enhanced MR hepatic venography at 1.5 T was better than at 3 T. PMID- 26019891 TI - Unusual growth of upper lip squamous cell carcinoma: a case report. AB - INTRODUCTION: Squamous cell carcinoma is the most common type of lip and oral cavity cancers. In majority of cases it follows quite common course, and after the surgery it does not produce any harm. This case presents unusual and unexpected growth of upper lip squamous cell carcinoma with severe cosmetic problems, and possible health threats. CASE PRESENTATION: A 46-year-old woman noticed on her upper lip "a spot, the size of a wheat grain", which grew rapidly and reached the size of 0.6 cm during a two-week period. The lesion was red, hard and painful, attached to the skin. It was surgically removed, and primary histopathological finding was follicular keratosis. Recurrent tumor appeared seven days after the operation, with the extreme swelling of the upper lip. The patient was sent to a tertiary hospital, where fungal or bacterial infection was excluded. The change on the patient's upper lip reached the size of 5 * 2 cm, as soft, reddish nodular tumor. Squamous cell carcinoma was diagnosed after the histopathological audit. With the second surgical intervention the tumor was removed and the defect reconstructed. CONCLUSIONS: Prognosis of this type of tumor, apart from its size and differentiation level, depends on infiltration in tumor-surrounding tissue, perineural and perivascular spread. Therefore, it is always necessary to analyze the removed skin especially on margins. PMID- 26019892 TI - Effect of Sample Storage Temperature and Time Delay on Blood Gases, Bicarbonate and pH in Human Arterial Blood Samples. AB - BACKGROUND: Results of arterial blood gas analysis can be biased by pre analytical factors, such as time interval before analysis, temperature during storage and syringe type. OBJECTIVES: To investigate the effects of samples storage temperature and time delay on blood gases, bicarbonate and PH results in human arterial blood samples. PATIENTS AND METHODS: 2.5 mL arterial blood samples were drawn from 45 patients via an indwelling Intraarterial catheter. Each sample was divided into five equal samples and stored in multipurpose tuberculin plastic syringes. Blood gas analysis was performed on one of five samples as soon as possible. Four other samples were divided into two groups stored at 22 degrees C and 0 degrees C. Blood gas analyses were repeated at 30 and 60 minutes after sampling. RESULTS: PaO2 of the samples stored at 0 degrees C was increased significantly after 60 minutes (P = 0.007). The PaCO2 of the samples kept for 30 and 60 minutes at 22 degrees C was significantly higher than primary result (P = 0.04, P < 0.001). In samples stored at 22 degrees C, pH decreased significantly after 30 and 60 minutes (P = 0.017, P = 0.001). There were no significant differences in other results of samples stored at 0 degrees C or 22 degrees C after 30 or 60 minutes. CONCLUSIONS: In samples stored in plastic syringes, overestimation of PaO2 levels should be noted if samples cooled before analysis. In samples stored in plastic syringes, it is not necessary to store samples in iced water when analysis delayed up to one hour. PMID- 26019893 TI - Incidence of self-reported interpersonal violence related physical injury in iran. AB - BACKGROUND: Violence is the cause of death for 1.5 million people in a year. OBJECTIVES: Our study aimed to estimate the incidence rate of self-reported interpersonal violence related physical injury (VRPI) and its associated factors in Iran. PATIENTS AND METHODS: The sample included people ranged from 15 to 64 years old who were residing in Iran. A total of 1525 clusters were selected from the whole country. Six families were selected from each cluster via a systematic random sampling method. Then, the residential units were identified and the interviewers contacted the inhabitants. In the next step, one of the family members was selected by using Kish grid method. The instrument was a researcher made questionnaire and consisted of two sections; demographics and project related data. Face validity and content validity of our questionnaire were investigated based on expert opinions and the reliability was confirmed by a pilot study, as well. The inclusion criteria were considered for choosing the interviewers. An interviewer was assigned for each 42 participants (7 clusters). An educational seminar was held for the administrative managers (54 persons) and interviewers (230 persons) for a week. The field work was distributed among all 46 Medical Sciences universities in Iran. In each university, administrative issues were related to an executive director. Mann-Whitney U test and odds ratio were used to analyze the data with 95% confidence interval. alpha value was considered less than 5%. RESULTS: The frequency of VRPI among 7886 participants was 24 during the last three months. The incidence rate of interpersonal VRPI was estimated at 3.04 per 1000 population (95% CI: 2.66-3.42) during a three-month interval in Iran. The incidence was 4.72 per 1000 population (95% CI: 4.01-5.43) for males and 1.78 per 1000 population (95% CI: 1.39-2.17) for females during a three-month interval. The mean (SD) of age of the participants with and without a history of VRPI were 26.5 (7.21) and 33.05 (12.05) years, respectively (P = 0.008). Considering the participants' gender, 66.7% were males (OR = 2.66, 95% CI: 1.14-6.23). Khuzestan Province had the most VRPIs (25% of all VRPIs). Streets and roads were the places with the highest frequency of injury (50%). The most frequent injured organ was the upper limb (54.17%). The most prevalent type of injury was a superficial wound (50%). Finally, the most common place of treatment was home (45.83%). CONCLUSIONS: We determined the incidence rate of self-reported interpersonal VRPI for the first time in Iran based on a national survey. The injuries were more common among young men. We suggest consecutive national surveys with different data gathering methods and more sample sizes. PMID- 26019894 TI - Acute hepatorenal failure in a patient following consumption of mushrooms: a case report. AB - INTRODUCTION: One of the highly toxic mushrooms that are common in the northwest region of Iran is Amanita phalloides, which might result in renal or liver failure. CASE PRESENTATION: This is a case report of a patient referred a few days after consumption of wild mushrooms to emergency department having gastrointestinal complaint whose experiments indicated liver and renal failure. The supportive treatment was given to the patient prescribing N-acetyl cysteine (NAC) and Livergol (silymarin) along with hemodialysis. A few days after admission to the hospital, the patient died due to severe clinical symptoms. CONCLUSIONS: The patient was poisoned by A. phalloides complaining gastrointestinal symptoms including nausea; vomiting and watery diarrhea about six hours after consumption and then, amatoxin in the mushroom caused damage to hepatocytes and renal cells and finally led to hepatorenal failure. Deaths caused by this type of mushroom are extremely high and necessary trainings should be provided to the people by the health system not to consume wild mushrooms, especially in spring and summer. PMID- 26019895 TI - Cardiopulmonary resuscitation, chest compression only and teamwork from the perspective of medical doctors, surgeons and anesthesiologists. AB - BACKGROUND: New resuscitation guidelines that were proposed by the European Resuscitation Council in 2010 have introduced a new method of cardiopulmonary resuscitation (CPR) by chest compressions only for untrained individuals. OBJECTIVES: We conducted this study to evaluate differences in attitudes towards CPR among medical doctors, surgeons and anesthesiologists in Osijek University Hospital. A call for help, chest-compression-only resuscitation, mouth-to-mouth ventilation and team-work were recognized as critical points that may influence the outcome. Unfamiliarity with these methods may be indicative of a lack of education in resuscitation and may result in poor outcomes for victims. PATIENTS AND METHODS: An anonymous survey was conducted on 190 medical professionals: 93 medical doctors, 70 surgeons, and 27 anesthesiologists during year 2012 (mean age 41.9 years). The questions were related to previous education in resuscitation, current resuscitation practices and attitudes towards cardiopulmonary resuscitation. Data were analyzed using ANOVA and Fisher exact test. A P value of < 0.05 was considered statistically significant. RESULTS: The only difference between groups was regarding the male and female ratio, with more male surgeons (45, 55, and 11, P < 0.001). All doctors considered CPR as important, but only anesthesiologists knew how often guidelines in CPR change. Approximately 45% of medical doctors, 48% of surgeons and 77% of anesthesiologists reported that they have renewed their knowledge in CPR within the last five years, whereas 34%, 25% and 22% had never renewed their knowledge in the CPR (P = 0.01 between surgeons anesthesiologists). Furthermore, chest-compression-only was recognized as a valuable CPR technique by 25.8% of medical doctors, 14.3% of surgeons and 59.3% of anesthesiologists (P < 0.001). Anesthesiologists estimated a high risk of infection transmission (62%) and were more likely to refuse mouth-to-mouth ventilation when compared to surgeons (25% vs.10%, P = 0.01). Anesthesiologists are most often called for help by their colleagues, only rarely surgeons call their departmental colleagues and nurses to help in CPR. CONCLUSIONS: An insufficient formal education in CPR was registered for all groups, reflecting the lack of familiarity with new CPR methods. A team education, involving doctors and nurses may improve familiarity with CPR and patient outcomes. PMID- 26019896 TI - Factors predicting nutrition and physical activity behaviors due to cardiovascular disease in tehran university students: application of health belief model. AB - BACKGROUND: Disease preventing methods focus mostly on lifestyle factors such as physical activity, healthy diet and not smoking. Previous studies verified using theory and models to change unhealthy behaviors, so that health belief model (HBM) is a useful framework for describing the healthy nutrition behavior. OBJECTIVES: This study aimed to predict factors related to unhealthy nutrition and inactive life in students of Tehran University, Tehran, Iran based on the Health Belief Model (HBM). PATIENTS AND METHODS: In this cross sectional study, proportional quota sampling from three different educational levels was conducted from October to December 2012. A self-administered validated instrument based on the Health Belief Model (HBM) with 69 items and four sections was used to collect data. In this study through using linear and logistic regression, the effect of body mass index, age, gender, marriage, self-efficacy, cues to action, knowledge, perceived severity, susceptibility, benefits and barriers on nutrition and physical activity behavior were assessed. SPSS version 18 was used to analyze data. RESULTS: Totally, 368 students including 318 female students (86.4%) and 50 male students (13.6%) with a mean age of 24.9 years (SD = 4.55) took part in the study. Among all independent variables, gender (P < 0.001), knowledge (P = 0.023) and perceived barriers (P = 0.004) predicted nutrition behavior. In case of physical activity, knowledge (P = 0.011), perceived severity (P = 0.009), perceived barriers (P = 0.019) and self-efficacy (P = 0.033) had significance association with physical activity behavior. CONCLUSIONS: This study indicated that health belief model contrasts could predict the risky behavior of university students due to heart disease. However, more researches are needed to verify the predictors of high risky behaviors in students. PMID- 26019897 TI - Empowerment and coping strategies in menopause women: a review. AB - CONTEXT: Menopause is described as a period of psychological difficulties that changes the lifestyle of women in multiple ways. Menopausal women require more information about their physical and psychosocial needs. Empowerment during the menopause can contribute to improving the perception of this stage and the importance of self-care. It is essential to increase women's awareness and adaptation to menopause, using empowerment programs. The aim of this study was to review the empowerment and coping strategies in menopause women. EVIDENCE ACQUISITION: In this review, PubMed, EMBASE, ISI, and Iranian databases were scanned for relevant literature. A comprehensive search was performed, using the combinations of the keywords "empowerment, menopause, coping with" to review relevant literature and higher education journals. RESULTS: Most interventions for menopause women have focused on educational intervention, physical activity/exercise, healthy diet, stress management, healthy behaviors, preventing certain diseases and osteoporosis. Health education intervention strategy is one of the alternative strategies for improving women's attitudes and coping with menopause symptoms, identified as severalof the subcategories of health promotion programs. CONCLUSIONS: Empowerment of menopausal women will guarantee their health during the last third of their life. It will also help them benefit from their final years of reproductive life. The results of the present study can pave the way for future research about women's health promotion and empowerment. PMID- 26019898 TI - Developing of the appropriateness evaluation protocol for public hospitals in iran. AB - BACKGROUND: Employment of utilization review instruments is a method for managing costs and efficiency in the healthcare systems. OBJECTIVES: This study developed an instrument for measuring the level of inappropriate acute hospital admissions and days of care in Iran. PATIENTS AND METHODS: The American version of the Appropriateness Evaluation Protocol (AEP) was modified, using the agreement method, by a multidisciplinary group of physicians. We conducted a retrospective descriptive study of 273 randomly selected patients admitted to Imam Khomeini Hospital of Tehran University of Medical Sciences in Tehran, Iran. For the reliability study, two nurses were asked to review patients' medical records using the instrument. Validity was appraised by pairs of clinicians, including two general surgeons, two internists and two gynecologists. The degree of consensus between the three pairs of clinicians was compared with that of the nurses. RESULTS: Inter-rater and intra-rater reliability testing revealed an excellent level of consensus between the two nurses employing the AEP in all the studied departments. Overall agreement was > 92%, while the specific appropriate agreement and specific inappropriate agreement were > 88% and > 83%, respectively. External validity testing of the instrument yielded a sensitivity > 0.785, specificity > 0.55, and positive and negative predictive values > 0.775 and > 0.555, respectively. The kappa statistic for the nurses who applied the AEP and clinicians using personal judgment were perfect (k > 0.85) and substantial (k > 0.68), respectively. CONCLUSIONS: The results illustrate that the Iranian version of the AEP (IR-AEP) could be a reliable and valid instrument for assessing the level of inappropriate acute hospital admissions and days of care in the Iranian context. PMID- 26019899 TI - Tessier number 30 clefts with congenital heart defects. AB - INTRODUCTION: Midline cleft of mandible, classified as Tessier 30 clefts is extremely rare, with less than 100 reported cases in the latest studies. Variations in severity and associated malformations have been reported before. CASE PRESENTATION: In this report, we present the first documented Iranian case of Tessier 30 with median cleft of lower lip and bifid tongue concomitant with congenital heart defects. CONCLUSIONS: We explain embryologic origin, differential diagnosis, other associated anomalies and its treatment by reviewing literature. PMID- 26019900 TI - Evaluating glucocorticoid administration on biomechanical properties of rats' tibial diaphysis. AB - BACKGROUND: Osteoporosis is a disease, which causes bone loss and fractures. Although glucocorticoids effectively suppress inflammation, their chronic use is accompanied by bone loss with a tendency toward secondary osteoporosis. OBJECTIVES: This study took into consideration the importance of cortical bone in the entire bone's mechanical competence. Hence, the aim of this study was to assess the effects of different protocols of glucocorticoid administration on the biomechanical properties of tibial bone diaphysis in rats compared to control and low-level laser-treated rats. MATERIALS AND METHODS: This experimental study was conducted at Shahid Beheshti University of Medical Sciences, Tehran, Iran. We used systematic random sampling to divide 40 adult male rats into 8 groups with 5 rats in each group. Groups were as follows: 1) control, 2) dexamethasone (7 mg/week), 3) dexamethasone (0.7 mg/week), 4) methylprednisolone (7 mg/kg/week), 5) methylprednisolone (5 mg/kg twice weekly), 6) dexamethasone (7 mg/kg three times per week), 7) dexamethasone (0.7 mg/kg thrice per week), and 8) low-level laser-treated rats. The study periods were 4-7 weeks. At the end of the treatment periods, we examined the mechanical properties of tibial bone diaphysis. Data were analyzed by statistical analyses. RESULTS: Glucocorticoid-treated rats showed weight loss and considerable mortality (21%). The biomechanical properties (maximum force) of glucocorticoid-treated rats in groups 4 (62 +/- 2.9), 6 (63 +/ 5.1), and 7 (60 +/- 5.3) were comparable with the control (46 +/- 1.5) and low level laser-treated (57 +/- 3.2) rats. CONCLUSIONS: In contrast to the findings in humans and certain other species, glucocorticoid administration caused anabolic effect on the cortical bone of tibia diaphysis bone in rats. PMID- 26019901 TI - Longitudinal discriminant analysis of hemoglobin level for predicting preeclampsia. AB - BACKGROUND: Preeclampsia is one of the most serious complications during pregnancy with important effects on health of mother and fetus that causes maternal and fetal morbidity and mortality. This study was performed to evaluate whether high levels of hemoglobin may increase the risk of preeclampsia. OBJECTIVES: The present study aimed to predict preeclampsia by the hemoglobin profiles through longitudinal discriminant analysis and comparing the error rate of discrimination in longitudinal and cross sectional data. PATIENTS AND METHODS: In a prospective cohort study from October 2010 to July 2011, 650 pregnant women referred to the prenatal clinic of Milad Hospital in Tehran were evaluated in 3 stages. The hemoglobin level of each woman was measured in the first, second, and third trimester of pregnancy by an expert technician. The subjects were followed up to delivery and preeclampsia was the main outcome under study. The covariance pattern and linear-mixed effects models are common methods that were applied for discriminant analysis of longitudinal data. Also Student t, Mann-Whitney U, and chi-square tests were used for comparing the demographic and clinical characteristics between two groups. Statistical analyses were performed using the SAS software version 9.1. RESULTS: The prevalence rate of preeclampsia was 7.2% (47 women). The women with preeclampsia had a higher mean of hemoglobin values and the difference was 0.46 g/dL (P = 0.003). Also the mean of hemoglobin in the first trimester was higher than that of the second trimester, and was lower than that of the third trimester and the differences were significant (P = 0.015 and P < 0.001, respectively). The sensitivity for longitudinal data and cross-sectional data in three trimesters was 90%, 67%, 72%, and 54% and the specificity was 88%, 55%, 63%, and 50%, respectively. CONCLUSIONS: The levels of hemoglobin can be used to predict preeclampsia and monitoring the pregnant women and its regular measure in 3 trimesters help us to identify women at risk for preeclampsia. PMID- 26019902 TI - Factors affecting the communication competence in Iranian nursing students: a qualitative study. AB - BACKGROUND: Communication competence in nursing students is one of the nursing education requirements, especially during the internship period, the final stage of the bachelor nursing education in Iran. Several factors can influence this competence and identifying them could help provide safe care by nursing students in the future. OBJECTIVES: This study aimed to investigate factors that influence nursing students' communication competence. PATIENTS AND METHODS: A purposeful sampling technique was used to select 18 nursing students who had completed their internship. Semi-structured interviews were conducted and data were analyzed by the conventional qualitative content analysis method. RESULTS: After data analysis, three main categories were achieved: organizational factors, humanistic factors and socio-cultural factors. The main and latent theme that affected the students' communication competence was not being accepted as a caregiver in the clinical environment. CONCLUSIONS: With regards to students not being accepted in health care environments, it is recommended to plan special programs for empowering students to acquire better social state and acceptance by the health care team. PMID- 26019903 TI - Quality of life of postmenopausal women and their spouses: a community-based study. AB - BACKGROUND: Most women spend more than one-third of their lives after menopause. Due to physiologic changes in that period, menopause can cause a series of symptoms such as vasomotor symptoms, psychologic problems, and sexual dysfunction, which can affect the women's quality of life (QoL) and other family members, especially their spouse. OBJECTIVES: The present study aimed to determine the association between the QoL of postmenopausal women and their husbands. PATIENTS AND METHODS: This descriptive-inferential cross-sectional study was conducted according to the census of 2006 in Iran. A total of 400 postmenopausal women aging 50 to 59 years and their spouses in 80 cluster heads of Ilam City residents were selected and studied in collaboration with the Statistical Center of Iran. The required data were gathered using the short-form health survey (SF-36) questionnaire and demographic questionnaire developed by the researcher-trained interviewers. Data were analyzed by SPSS 18 through Kruskal Wallis test, Wilcoxon signed ranks test, and correlation. RESULTS: The participants' mean age was 54.2 +/- 2.8 years for women and 61.1 +/- 6.1 years for their spouses. More than half of the women (57%) and about one-third of men (32.8%) were illiterate. The employed educated women aging 50 to 54 years had a higher mean score of SF-36 domains. The difference in education was significant in all domains except for mental health. There was a significant difference in age in all domains except in general health. The mean score of all domains of QoL was significantly less in the illiterate men than in the literate ones (P < 0.05). The results of the present study showed a significant correlation (P < 0.05) between the couples' QoL, vasomotor symptoms, and aging. Spearman test showed a significant positive correlation in all domains of QoL between postmenopausal women and their spouses (correlation coefficient, 0.48-0.63). CONCLUSIONS: Based on the results of the present study and other performed studies in this regard, menopause, aging, vasomotor symptoms, and education had significant association with the QoL of postmenopausal women. The reduced QoL in postmenopausal women could eventually lead to the reduced QoL of their spouses. Therefore, it is necessary to plan for the education of these women and their husbands to broaden their understanding of the changes of menopause and ways to improve their QoL. PMID- 26019904 TI - Prevalence of trichomoniasis among women in kermanshah, iran. AB - BACKGROUND: Trichomoniasis, caused by Trichomonas vaginalis, is the most common sexually transmitted disease (STD) in the world with estimates of 7-8 million infections annually in the United States and 180 million globally. OBJECTIVES: This study aimed to determine the prevalence and risk factors for T. vaginalis infection in women who attended the Clinic of Obstetrics and Gynecology in Kermanshah, Iran. PATIENTS AND METHODS: This cross-sectional study was performed on all women aged 15 to 65 years who attended the clinic of obstetrics and gynecology, Imam Reza Hospital, Kermanshah, west of Iran, between September 2011 and July 2012. Vaginal secretion samples were examined by the Dorset culture medium and wet-mount methods. Demographic and personal information were also collected via questionnaires and the data were analyzed using chi-square and Fisher exact tests. RESULTS: A total of 600 women were screened for T. vaginalis infection and this infection was diagnosed in 9 (1.5%) and 13 cases (2.1%) using the wet mount and culture methods, respectively. The age and husband occupation were significantly associated with an increased risk of trichomoniasis in the infected cases (P < 0.05 and P < 0.001, respectively); other variables, including the patients' occupation and education level appeared to be positively (but not significantly) correlated with infection (P > 0.05). CONCLUSIONS: The prevalence of T. vaginalis infection in the study population was low. Diagnosis of trichomoniasis based on only clinical symptoms is not efficient for treatment decision. Based on our results, we suggest using the culture method on all the suspected cases even if the wet smear is negative. PMID- 26019905 TI - Ambivalence towards childbirth in a medicalized context: a qualitative inquiry among Iranian mothers. AB - BACKGROUND: Today, pregnant women are treated as individuals requiring medical care. Every day, more and more technologies, surgical procedures and medications are used even for low-risk childbirths. These interventions can save mothers' lives in threatening situations, although they might be risky for mothers and neonates in low-risk deliveries. Despite the increasing interest in medical care for childbirth, our knowledge about underlying factors for development of medicalized childbirth is limited in Iran. OBJECTIVES: The purpose of this study was to provide a broad description of medicalized childbirth in Iran. MATERIALS AND METHODS: In this study, a qualitative approach was applied and data was gathered via in-depth interviews. The subjects were selected via purposive sampling. Overall, 27 pregnant and postpartum women were enrolled in this study. Participants were selected from public health centers, hospitals and offices. Data analysis was performed using conventional qualitative content analysis. RESULTS: As the results indicated, mothers preferred medicalized childbirth under the supervision of obstetricians. The subjects mostly opted for elective cesarean section; this choice led to an increase in physicians' authority and restricted midwives' role in childbirth. Consequently, mothers' preference for cesarean section led to the expansion of medicalization and challenged the realization of natural childbirth. Mothers also had a strong tendency toward natural childbirth. CONCLUSIONS: Generally, many Iranian mothers choose the medicalized approach, despite their inclination to comply with the natural mode of delivery. It seems that mothers have an ambivalent attitude toward childbirth. Health authorities can prevent the adverse effects of medicalized birth and encourage natural childbirth among women using the obtained findings. PMID- 26019906 TI - A New 2D-Based Method for Carotid Intima-Media Thickness Quantification From Ultrasound Sequences. AB - BACKGROUND: Ultrasound measurement of carotid Intima-Media Thickness (IMT) is a suitable method to evaluate subclinical arteriosclerosis. OBJECTIVES: The current study aimed to present a new computerized algorithm to detect instantaneous changes of the IMT to Common Carotid Artery (CCA) of IMT in sequential ultrasound images by applying the maximum gradient and the dynamic programming. PATIENTS AND METHODS: In a cross-sectional design, an examination was performed on thirty healthy human subjects with the mean age of 44 +/- 6 years from April 2013 to June 2013 in Beheshti Hospital, Kashan, Iran. In all individuals, the instantaneous changes of the far wall IMT on the CCA were extracted. Local measurements of vessel intensity, intensity gradient, and boundary continuity were extracted for all of the sequential ultrasonic 2D-frames throughout three cardiac cycles. The Pearson correlation coefficients and Bland-Altman analysis were performed to assess the relationship and agreement between IMT measured by the proposed and conventional manual methods. RESULTS: There was no significant difference between the proposed and manual methods with paired t-test analysis (in systole: 0.57 +/- 0.10 vs. 0.56 +/- 0.10 mm; P = 0.188 and in diastole: 0.63 +/- 0.16 vs. 0.62 +/- 0.10 mm; P = 0.122 for the manual and proposed methods, respectively). The Pearson correlation coefficients were r = 0.94 and r = 0.93 for IMTs and IMTd, respectively (both P < 0.001). Limit of agreements were narrow and considerable agreement was found between the two methods. CONCLUSIONS: The present study demonstrated that the proposed computerized analyzing method can provide accurate measurements of the IMT of the CCA in sequential 2D ultrasonic images. PMID- 26019907 TI - The effect of equisetum arvense (horse tail) ointment on wound healing and pain intensity after episiotomy: a randomized placebo-controlled trial. AB - BACKGROUND: Episiotomy, a common surgical practice in midwifery, is accompanied with high levels of pain and discomfort for mothers. The importance of medicinal herbs and traditional medicine in wound healing cannot be neglected. OBJECTIVES: Considering the positive effects and easy accessibility of Equisetum arvense, this study examined the effectiveness of topical application of Equisetum arvense ointment in wound healing, reduction of inflammation and pain relief after episiotomy in nulliparous mothers. PATIENTS AND METHODS: This double-blind clinical trial was performed on 108 postpartum nulliparous mothers (54 women in horsetail group and 54 women in placebo group) in Alzahra Educational-Medical Center (Tabriz, Iran). About 5 +/- 1 and 10 +/- 1 days after the childbirth, the primary outcomes of episiotomy, i.e. wound healing and pain intensity, were assessed based on redness, edema, ecchymosis, discharge and approximation of the edges (REEDA) scale and a visual analogue scale (VAS), respectively. The secondary outcomes evaluated in the current research were the number of used painkillers and the adverse events during the 10-day period of the study. Data was analyzed using independent t and Mann-Whitney U tests. RESULTS: The case and control groups had no significant differences in for the mean wound healing score (5.0 +/- 1.6 vs. 4.1 +/- 1.6) and mean pain intensity (5.7 +/- 2.4 vs. 5.3 +/- 2.2) at baseline. During both follow-up sessions (5 +/- 1 and 10 +/- 1days after delivery), the mean scores were significantly lower in the case group than the control group. The adjusted pain score difference (MD) after 5 +/- 1 and 10 +/- 1 days was -2.3 (95% CI: -3.2 to -1.3) and 3.8 (95% CI: -4.7 to -3.0), respectively. The mean numbers of acetaminophen pills used in the control and case groups during the 10-day period of the study were 6.8 +/- 4.4 and 11.6 +/- 7.1, respectively (P < 0.001). CONCLUSIONS: According to our findings, 3% Equisetum arvense ointment promoted wound healing and relieved pain during the 10 day period after episiotomy. Since this study was the first to assess the effects of Equisetum arvense ointment on wound healing and pain intensity following episiotomy in humans, further research is warranted to fully clarify the beneficial effects of prepared ointment. PMID- 26019908 TI - Acupressure and anxiety in cancer patients. AB - BACKGROUND: Anxiety has negative effects on mental and physical performance, quality of life, duration of hospitalization, and even on the treatment of patients with cancer. OBJECTIVES: Today acupressure is widely used to treat anxiety. Thus, the present study aimed to investigate the effects of acupressure on anxiety in patients with cancer. PATIENTS AND METHODS: A double-blind randomized clinical trial was conducted on 85 patients hospitalized with 3 groups including acupressure group (n = 27), sham group (n = 28), and control group (n = 30) in the hematologic ward of Shahid Beheshti Hospital of Hamadan, Iran, in 2013. The sampling permuted-block randomization with triple block was used. The anxiety of the patients in the experimental, sham, and control groups were measured with Spielberger's State-Trait Anxiety Inventory (STAI). Then, real acupressure was performed in the experimental group and fake acupressure in the sham group, and only routine care was provided for the control group. Anxiety of the patients was also assessed at 5 and 10 days after the intervention. Statistical analysis of the data was performed by SPSS software using repeated measures analysis of variance (ANOVA) and post hoc least significant difference (LSD) test. RESULTS: According to the findings, the mean level of anxiety before the intervention between groups were matched (P > 0.05). Acupressure had a significant influence on the anxiety in the experimental group at 5 (45.30 +/- 7.14) and 10 days (43.48 +/- 6.82) after the intervention (P < 0.05). However, it did not have a significant impact on their covert anxiety (45.48 +/- 7.92 at 5(th) day vs 45.63 +/- 8.08 at 10th day, P > 0.05). No significant differences were observed in the fake points regarding overt and covert anxiety of patients in the sham group (overt anxiety; 47.57 +/- 7.85 at 5(th) day vs. 46.71 +/- 7.32 at 10(th) day, P > 0.05) (covert anxiety; 47.96 +/- 6.33 at 5(th) day vs. 46.89 +/- 6.94 at 10(th) day, P > 0.05). Moreover, the routine care provided for the control group did not have any effect on the overt and covert anxiety of the patients (P > 0.05). CONCLUSIONS: Acupressure is recommended as a complementary therapy to reduce anxiety in patients with cancer because of its low cost, safety, and simplicity. PMID- 26019909 TI - At what age range should children be circumcised? AB - BACKGROUND: Although male circumcision is a surgical intervention that is frequently performed in children, there is no consensus about the age at which it should be performed. OBJECTIVES: The purpose of this study was to determine the best age range for routine male circumcision with respect to a child's health and the cost. PATIENTS AND METHODS: This clinical trial was conducted in the affiliated hospital of the Erzincan University of Medical Sciences, Turkey, in 2014. The circumcised children were evaluated in 3 groups: < 1 year old (Group 1), 1-7 years old (Group 2), and > 7 years old (Group 3). To obtain a satisfactory Wilton sedation score, midazolam 0.1 mg/kg IV was administered first. If adequate sedation was not achieved, ketamine 2 mg/kg IV was also administered. If adequate sedation was still not achieved, general anesthesia was administered via a laryngeal mask. At the end of the surgery, the groups were compared in terms of post-anesthesia recovery duration, complications, discharging duration, and cost. RESULTS: A total of 603 children were circumcised, 374 in Group 1, 94 in Group 2, and 135 in Group 3. Midazolam was sufficient for sedation in 364 Group 1 patients (97.3%), 6 Group 2 patients (6.3%), and 38 Group 3 patients (28.1%). The shortest post-anesthesia recovery duration after surgical intervention and time until discharge, the lowest cost, and the fewest anesthesia complications were observed in Group 1 (P < 0.05 for all). CONCLUSIONS: Although almost all of the < 1 year-old children could be sedated with midazolam alone, most of the > 1 year-old children required ketamine or general anesthesia. Performing circumcision when children are less than 1 year old decreases the risk of complications due to anesthesia and lowers the costs compared with performing the procedure on older children. PMID- 26019910 TI - Cross cultural adaptation, validity, and reliability of the farsi breastfeeding attrition prediction tools in Iranian pregnant women. AB - BACKGROUND: The rate of exclusive breastfeeding in Iran is decreasing. The breastfeeding attrition prediction tools (BAPT) have been validated and used in predicting premature weaning. OBJECTIVES: We aimed to translate the BAPT into Farsi, assess its content validity, and examine its reliability and validity to identify exclusive breastfeeding discontinuation in Iran. MATERIALS AND METHODS: The BAPT was translated into Farsi and the content validity of the Farsi version of the BAPT was assessed. It was administered to 356 pregnant women in the third trimester of pregnancy, who were residents of a city in northeast of Iran. The structural integrity of the four-factor model was assessed in confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Reliability was assessed using Cronbach's alpha coefficient and item-subscale correlations. Validity was assessed using the known-group comparison (128 with vs. 228 without breastfeeding experience) and predictive validity (80 successes vs. 265 failures in exclusive breastfeeding). RESULTS: The internal consistency of the whole instrument (49 items) was 0.775. CFA provided an acceptable fit to the a priori four-factor model (Chi-square/df = 1.8, Root Mean Square Error of Approximation (RMSEA) = 0.049, Standardized Root Mean Square Residual (SRMR) = 0.064, Comparative Fit Index (CFI) = 0.911). The difference in means of breastfeeding control (BFC) between the participants with and without breastfeeding experience was significant (P < 0.001). In addition, the total score of BAPT and the score of Breast Feeding Control (BFC) subscale were higher in women who were on exclusive breastfeeding than women who were not, at four months postpartum (P < 0.05). CONCLUSIONS: This study validated the Farsi version of BAPT. It is useful for researchers who want to use it in Iran to identify women at higher risks of Exclusive Breast Feeding (EBF) discontinuation. PMID- 26019911 TI - Editorial: Special issue on teaching and training. PMID- 26019912 TI - What do I want from my urology training? AB - INTRODUCTION: The basic aims of a urology trainee are broadly similar, with the need to be trained to a competent level of surgical and clinical skill being a general theme. AIM: In this article I provide a short list of what I felt were and are the most important elements in my training as I enter my final 5 years of specialist registrar training, having completed 3 years of research for an MD, 3 years as a surgery/urology Senior House Officer, a year as a House Officer and 6 years in medical school. Some of the points will, of course, be more personal, but hopefully this will give some perspective to the exciting early years in a young urologist's career. PMID- 26019913 TI - Urology training in the developing world: The trainees' perspective in Kurdistan, Iraq. AB - OBJECTIVE: To analyse the advanced systems of urology residency in the developed world, to compare them to a system in the developing world, and thereby identify the shortcomings and make recommendations to improve residency programmes for urology in the Kurdistan Region of Iraq. METHODS: A survey was conducted amongst the urology Residents (55) in the three governorates of the Kurdistan Region of Iraq, to assess the accessibility of the training programme, the types of the residency programmes, skills acquisition, the use of modern technology for teaching and assessment, the environment of the settings of practice, and the status of research in their training. RESULTS: An overwhelming majority (88%) of trainees reported difficulty in securing a training position. A high proportion (43%) felt disappointed at the beginning of their training. There is no unified curriculum of training, and more than two-thirds of the respondents reported a lack of a proper evidence-based medical education. There is no formal subspecialty training programme. Of the respondents, 65% referred to the difficulties in the environment for training, and that there was a low level of research involvement (12%). CONCLUSIONS: Urology training is not easily accessible, there is no unified programme of residency, there are limited facilities, and a minimal assessment of practical skills. The environment for practice needs enormous improvements and a strong foundation for research should be created. PMID- 26019914 TI - How to conduct a successful workshop: The trainees' perspective. AB - OBJECTIVES: To define the success of a medical workshop from the trainees' perspective, where a medical workshop is a scientific event with the aim of presenting updated knowledge and to teach medical skills to the participants. In surgical specialties, it contributes to the development and maintenance of surgical skills. METHODS: Medline was searched for the previous 4 months to identify articles with combinations of the keywords 'workshops', 'training', 'simulators', and 'virtual reality'. Further articles were obtained by manually searching the reference lists of identified papers. We also obtained information and critical aspects of view from other trainees. RESULTS: Based on 30 articles from the Medline search, and mostly from the trainees' perspective, we present the basic characteristics of a successful workshop. The objective of the workshop, appropriate faculty members and presenters, highly motivated participants, the use of simulators and evaluation sheets, the venue and the registration fees all have a major role in the success of a workshop. CONCLUSIONS: A successful workshop is that from which trainees have grasped most of the knowledge and skills imparted to them, with a positive progression reflected on their learning curve. Workshops are a current necessity and all efforts should be made to achieve the desired result from the trainees' perspective. PMID- 26019915 TI - Bringing excellence into urology: How to improve the future training of residents? AB - THE PROBLEM: The demographic development of society leads to an increased demand for physicians. Particularly in the surgical disciplines, there is a noticeably declining interest among graduates from medical schools worldwide. For reasons discussed in detail, this applies especially to urology. SOLUTIONS: We indicate possibilities on how to counteract this trend, by improving the training for urology residents. Whereas some major changes for the better have already been introduced into the curricula in some countries, others will have to be further specified in the future. This article gives an overview of the requirements of a specific training programme, from a planning phase to its certification. Aspects such as the selection of candidates, the goals of a good training programme, and an implementation strategy are presented. Essential elements of a urology resident programme for effective coaching, improving medical skills (e.g. in surgical laboratories), knowledge revision, progress evaluation, and retrospection are discussed critically, giving an understanding of the crucial requirements of a good and attractive education in urology. CONCLUSION: A structured and well organised training programme might attract additional medical students towards urology and contribute significantly to the further development of the speciality. This can be seen as an initiative to counteract the decline of urology as an attractive field of interest to upcoming generations of physicians, and therefore to ensure urological care of the highest quality that patients deserve. PMID- 26019916 TI - Is there a place for a holistic approach in surgical training? AB - INTRODUCTION: The holistic approach in medicine is a framework that considers and treats all aspects of a patient's needs, as it relates to their health. The goal of such an approach is to prevent illness, and to maximise the well-being of individuals and families. Holistic medicine is also referred to as integrative, which has been interpreted by some professionals as the combination of evidence based medicine and complementary medicine. THE PROBLEM: The speciality of Family Medicine (FM) is often referred to as General Practice (GP), a terminology which emphasises the holistic nature of that discipline. Furthermore, GP/FM professional bodies in some countries have incorporated the holistic and integrative approach into curricula and guidelines for doctors in training, which reflects its acceptance as a component of medical training. However, despite this validation, and despite research showing the effectiveness of such strategies in enhancing the outcomes of surgery, a holistic framework or integrative approach has not been equally integrated into speciality training for would-be surgeons. CONCLUSION: We argue that it would be advisable to include holistic approaches into surgical training and help surgeons to recognise their role in the continuum of care. PMID- 26019917 TI - Attrition in surgical residency programmes: Causes and effects. AB - OBJECTIVE: To determine the rate and trend of attrition from a surgical residency programme and to identify the reasons for attrition. METHODS: A questionnaire based survey was conducted at a university hospital. Separate questionnaires were designed for residents and programme directors (PDs). The residents who left the training voluntarily from one of the five surgical residency programmes (i.e., general surgery, orthopaedics, neurosurgery, otorhinolaryngology and urology) during the academic years 2005-2011 were identified from a departmental database. The residents who did not respond after three attempts at contact, or those who refused to participate, were excluded. RESULTS: During the last 6 years, 106 residents were recruited; 84 (78%) were men, of whom 34.5% left the programme voluntarily. Of 22 women, half (54%) left the programme voluntarily (P = 0.07). The overall 6-year attrition rate was 39%. The reasons identified for attrition, in descending order, were personal reasons, attitude of senior residents or faculty, and change of specialty. None of the residents cited an excess workload as a reason for their leaving the programme. About 40% rejoined the same specialty after leaving, while 35% chose a different specialty (80% chose a different surgical subspecialty and 20% chose medicine). There was a significant discrepancy in the perspective of residents and PDs about the reasons for attrition. CONCLUSION: Attrition among surgical residents, in particular woman residents, is high. Personal reasons and interpersonal relations were the most commonly cited reasons. Programme managers and residents have significantly different perspectives, again an indication of a communication gap. PMID- 26019918 TI - The Consultant urological surgeon: Surviving the first few years. PMID- 26019919 TI - Pilot training: What can surgeons learn from it? AB - OBJECTIVE: To provide healthcare professionals with an insight into training in aviation and its possible transfer into surgery. METHODS: From research online and into company archives, relevant publications and information were identified. RESULTS: Current airline pilot training consists of two categories, basic training and type-rating. Training methods comprise classroom instruction, computer-based training and practical training, in either the aircraft or a flight-training device, which ranges from a fixed-base flight-training device to a full flight simulator. Pilot training not only includes technical and procedural instruction, but also training in non-technical skills like crisis management, decision-making, leadership and communication. Training syllabuses, training devices and instructors are internationally standardized and these standards are legally binding. Re-qualification and recurrent training are mandatory at all stages of a pilot's and instructor's career. CONCLUSION: Surgeons and pilots have much in common, i.e., they work in a 'real-time' three dimensional environment under high physiological and psychological stress, operating expensive equipment, and the ultimate cost for error is measured in human lives. However, their training differs considerably. Transferring these well-tried aviation methods into healthcare will make surgical training more efficient, more effective and ultimately safer. PMID- 26019920 TI - Pilot training: What can surgeons learn from it? PMID- 26019921 TI - Lessons that cross the surgical drapes. AB - BACKGROUND: Modern medicine has created a need for innovative methods of training that create safe, proficient specialists with adequate experience, and who are fit for purpose in this new system. Patient safety and patient-focused care are central to current practice and promoted by the use of simulation, human factors, team-based, multidisciplinary and interspecialty training. An acknowledgement that postgraduate training occurs within the work environment underlies the need to create systems that support learning within the workplace. Supervision, protected time for adequate induction and the opportunity to be involved in workplace learning are the key. It is also important that robust mechanisms to assure the quality of postgraduate education are in place. METHODS: Available reports were researched, and the particularities of anaesthetic training were outlined and summarised. Then, in a translational approach, we examined how to apply the lessons learned from anaesthesiological training to surgical training. RESULTS: The trend towards reducing the working hours of junior doctors, whilst still providing excellent training, creates a need for innovative, efficient, concentrated training programmes, where trainers and trainees are engaged in a seamless, constant educational endeavour. CONCLUSION: Within this review we offer the system of anaesthetic training in the UK, and some of its recent changes, as a template to highlight themes in postgraduate education that exemplify this innovation and are transferable not only to surgery but across different specialties. PMID- 26019922 TI - Training in ureteroscopy for urolithiasis. AB - OBJECTIVES: To provide an insight into the current status of semi-rigid and flexible ureteroscopy, following new curricula for training methods, including training with models, virtual reality and active mentoring. METHODS: We systematically reviewed previous reports, including articles in English identified using the following strategy: ('ureteroscopy'[Mesh]) or ('urolithiasis'[Mesh]) AND ('education'[Mesh]), or ('teaching'[Mesh]). Abstracts submitted at congresses were not included. Relevant articles that were identified as references in the retrieved articles were also included. RESULTS: The terms ('urolithiasis'[Mesh] AND 'education'[Mesh]) retrieved 106 articles, of which five were included. The terms ('urolithiasis'[Mesh] AND 'teaching'[Mesh]) retrieved six articles, of which three were included. The terms ('ureteroscopy'[Mesh] AND 'education'[Mesh]) retrieved 29 articles, of which 21 were included. The terms ('ureteroscopy'[Mesh] AND 'teaching'[Mesh]) retrieved eight articles, of which seven were included. Remaining articles were found in the reference section of retrieved articles. Finally, 43 articles were included. Four randomised controlled trials with level 1b evidence were included. Currently there is no standard teaching method for ureteroscopy and the number of cases to reach competence has not yet been defined. However, simulation-based training has been shown to be effective, cost-effective, and to increase patient safety. CONCLUSIONS: Simulators lead to a more rapid acquisition of skills in ureteroscopy than do conventional training methods, and improve the performance of future surgeons. Flexible ureteroscopy simulators are a promising tool for training, and have the advantage of minimising the need for learning the procedures on patients. A didactic and clinical curriculum, including surgical videotape reviews as well as operative mentoring, enables a rapid progression in already experienced endourologists. However, there are few reports specifically addressing the skills necessary for training. PMID- 26019923 TI - Training the resident in percutaneous nephrolithotomy. AB - OBJECTIVE: From the trainers' perspective percutaneous nephrolithotomy (PCNL) is one of the most challenging endourological procedures. In this review we examine the problems arising when training residents in PCNL, and how to facilitate this process. METHODS: The recommendations are derived from discussions and consensus during the First European Urolithiasis Society (EULIS) meeting held in London in September 2011. In addition, we searched Medline for articles identified using the keywords 'training', 'percutaneous surgery', 'renal calculi', 'PCNL', 'virtual reality' and 'simulators'. We also assessed the effect of modern technology, including the availability of virtual reality models vs. operating room training, and how international organisations like EULIS and European Urological Association can help. RESULTS: The difficulty of training residents in PCNL is partly due to the complexity of obtaining a safe access to the kidney for lithotripsy. The most common way of obtaining access is guided by imaging only, and usually only fluoroscopic imaging is available. This has the potential for injuring structures from the skin to the renal capsule. Minor vascular injuries are relatively common, although most are self-limiting. Visceral injuries that are particularly important are pleural and less commonly colonic injuries, but they are more complex and often require additional procedures. CONCLUSIONS: Teaching the skills is more challenging than performing PCNL. In most urological training programmes it is difficult to incorporate teaching and training skills when performing PCNL. To train an academic stone doctor, proficiency in the safe conduct of PCNL is mandatory. PMID- 26019924 TI - Training in percutaneous nephrolithotomy: The learning curve and options. AB - OBJECTIVE: To review the current approach to training and the learning curve for percutaneous nephrolithotomy (PCNL), and to formulate a recommendation for structured PCNL training for the urologist in-training. METHODS: Publications related to PCNL training, simulator training, surgical training and working-hour restrictions on surgical training were reviewed. RESULTS: The key components for a successful PCNL training programme should include stages for acquiring basic knowledge related to the procedure, acquiring basic skill in various training models, and acquiring clinical experience under supervised clinical practice. Lastly, life-long continuous learning would be important to maintain the practising standard. CONCLUSION: Despite being one of the main endoscopic procedures for managing stones, PCNL remains a difficult procedure with a long period of learning. Facing the challenge of working-hour restrictions on training, a more structured training programme, together with the use of models, would improve the learning curve for PCNL. PMID- 26019925 TI - Training in robotics: The learning curve and contemporary concepts in training. AB - OBJECTIVE: To define the learning curve of robot-assisted laparoscopic surgery for prostatectomy (RALP) and upper tract procedures, and show the differences between the classical approach to training and the new concept of parallel learning. METHODS: This mini-review is based on the results of a Medline search using the keywords 'da Vinci', 'robot-assisted laparoscopic surgery', 'training', 'teaching' and 'learning curve'. RESULTS: For RALP and robot-assisted upper tract surgery, a learning curve of 8-150 procedures is quoted, with most articles proposing that 30-40 cases are needed to carry out the procedure safely. There is no consensus about which endpoints should be measured. In the traditional proctored training model, the surgeon learns the procedure linearly, following the sequential order of the surgical steps. A more recent approach is to specify the relative difficulty of each step and to train the surgeon simultaneously in several steps of equal difficulty. The entire procedure is only performed after all the steps are mastered in a timely manner. Recently, a 'warm-up' before robotic surgery has been shown to be beneficial for successful surgery in the operating room. CONCLUSION: There is no clear definition of the duration of the effective learning curve for RALP and robotic upper tract surgery. The concept of stepwise, parallel learning has the potential to accelerate the learning process and to make sure that initial cases are not too long. It can also be assumed that a preoperative 'warm up' could help significantly to improve the progress of the trainee. PMID- 26019926 TI - How to train your surgeon! Experience of a patient side assistant. PMID- 26019927 TI - Urology training in the developing world: The trainers' perspective. AB - CONTEXT: Despite producing some of the leading urologists in the world, urological training in the developing world is marred by inconsistency, and a lack of structure and focus on evidence-based practice. In this review we address these issues from the trainers' perspective. INTRODUCTION: Teaching the art and science of urological practice is a demanding task. It not only involves helping the resident to develop the depth of cognitive knowledge, but also to have an appropriate surgical judgement, and an ability to act quickly but thoughtfully and, when necessary, decisively. DISCUSSION: The surgeon must have compassion, communication skills, be perceptive and dedicated. Most importantly, however, he or she should have the ability to cut and suture. Not all of these can be inculcated in the training programme, even with the best of efforts. The selection of an appropriate candidate therefore becomes an issue of pivotal importance. The changing focus of urological training incorporates research and evidence-based practice as essential components. It is particularly important in the developing world, as there is a dearth of standardised practice models across the healthcare system. Encouraging female residents can be done by improving and tailoring the working conditions. The 'brain drain' is a major problem in the developing world, and bureaucracy and government need to take appropriate measures to provide high-quality healthcare facilities with room for professional growth. CONCLUSIONS: The future of urology will depend on improved education and training, leading to high-quality urological care, and to developing a service that is patient focused. PMID- 26019928 TI - Why should I do research? Is it a waste of time? AB - OBJECTIVES: To answer the questions 'Why should I do research? Is it a waste of time?' and present relevant issues. METHODS: Medline was used to identify relevant articles published from 2000 to 2013, using the following keywords 'medicine', 'research', 'purpose', 'study', 'trial', 'urology'. RESULTS: Research is the most important activity to achieve scientific progress. Although it is an easy process on a theoretical basis, practically it is a laborious process, and full commitment and dedication are of paramount importance. Currently, given that the financial crisis has a key influence in daily practice, the need to stress the real purpose of research is crucial. CONCLUSION: Research is necessary and not a waste of time. Efforts to improving medical knowledge should be continuous. PMID- 26019929 TI - How to write a medical original article: Advice from an Editor. AB - OBJECTIVES: To provide guidelines for potential authors on how to increase the chances of their manuscript being accepted, with a review focusing on writing an original medical article. METHODS: This review reflects the personal experience of the present author, who has extensive experience as an author, reviewer and editor. RESULTS: To write an original article successfully, there are three essential requirements, the 'basic triad' of an original article. These are subjects worth reporting, knowledge of the basic structure of an article, and knowledge of the essential mechanics of good writing. This review details each of the three items. CONCLUSIONS: Writing, like every other art, cannot be learned wholly from books or lectures, but can be learned largely by experience. The best training is to start the task and persevere. The act of writing, like surgical techniques, must be learned the hard way, by practice and perseverance. Anyone can start writing but only a good writer can finish the task. PMID- 26019930 TI - Academic development for urologists in the Kurdistan region of Iraq. AB - OBJECTIVES: Continuous education is mandatory for all urologists, and undertaking cooperative research is a very effective means for this. We describe the experience and possibilities for continuing education for urologists in the Kurdistan region of Iraq. We hope to provide a framework for stimulating urological education and research in other countries where urologists face the same obstacles. METHODS: Data were obtained from the perspective of two academics who co-operate with urologists from Iraq, and from the perspective of two officials from the Ministry of Higher education of the Kurdistan Regional Government who are responsible for stimulating continuous education. RESULTS: Based on a co-operative and supportive attitude of both Government and Academics, urologists in the Kurdistan region of Iraq have brought the standards of education and cooperative research to an internationally competitive level. CONCLUSION: The authors hope that the examples given here can stimulate urologists from Arab countries to fully engage in new urological developments, despite the obstacles that they perceive. PMID- 26019931 TI - Revalidation: A world first in medical regulation. AB - The revalidation of doctors was introduced in the UK in December 2012, and means that all licensed doctors must demonstrate periodically that they are up-to-date and fit to practise. Regular appraisals, based on the General Medical Council's core guidance for doctors, will be used by responsible officers to evaluate a doctor's practice based on six types of supporting information, including feedback from patients and colleagues. In this commentary, as the Chair of the General Medical Council and Consultant Physician, I provide an overview of the history of revalidation and discuss the role of the new system of checks (which is being watched with interest by regulators around the world) ensuring that medical practice is of a high quality, that doctors are supported in their professional development and, most importantly, that patients can have confidence in the doctors they consult. PMID- 26019932 TI - Lifelong learning: Established concepts and evolving values. AB - OBJECTIVE: To summarise the concepts critical for understanding the content and value of lifelong learning (LL). METHODS: Ideas generated by personal experience were combined with those of philosophers, social scientists, educational institutions, governments and UNESCO, to facilitate an understanding of the importance of the basic concepts of LL. RESULTS: Autopoietic, continuous, self determined, informal, vicarious, biographical, lifelong reflexive learning, from and for society, when supported by self-chosen formal courses, can build capacities and portable skills that allow useful responses to challenges and society's new structures of governance. The need for LL is driven by challenges. LL flows continuously in pursuit of one agenda, which could either be citizenship, as is conventional, or as this article proposes, health. LL cannot be wholly centred on vocation. Continuous medical education and continuous professional development, important in their own right, cannot supply all that is needed. LL aids society with its learning, and it requires an awareness of the environment and structures of society. It is heavily vicarious, draws on formal learning and relies for effectiveness on reflection, self-assessment and personal shaping of views of the world from different perspectives. CONCLUSION: Health is critical to rational thought and peace, and determines society's capacity to govern itself, and improve its health. LL should be reshaped to focus on health not citizenship. Therefore, embedding learning in society and environment is critical. Each urologist must develop an understanding of the numerous concepts in LL, of which 'biographicisation' is the seed that will promote innovative strategies. PMID- 26019933 TI - The management of genitourinary fistula in the third millennium. AB - BACKGROUND: A vesicovaginal fistula (VVF) is an abnormal fistulous tract between the bladder and vagina, causing continuous loss of urine via the vagina. VVF is a relatively uncommon condition, but there is a drastically higher prevalence in the developing world. Furthermore, iatrogenic postoperative VVF is most common in developed countries, compared to mainly obstetric trauma in developing countries. In this review we focus on the development of current management techniques for VVF. METHODS: Medline was searched to identify articles related to urogenital fistulae, including VVF. Based on these reports we focus on the aetiology, clinical presentation, diagnosis and management of VVF. This in-depth review includes the optimal surgical timing, different surgical approaches (including minimally invasive techniques such as laparoscopic and robotic surgery), recommendations for postoperative care, surgical complications, and the need for further research in the use of robotic surgery to treat this condition. RESULTS: In all, 60 articles were identified and included in this review; eight were related to the aetiology, 12 to diagnosis, and 40 to the management of VVF. A thorough evaluation of VVF is imperative for planning the repair. Although the surgeonis experience typically influences the surgical approach, special situations will dictate the best approach. CONCLUSION: The treatment of genitourinary fistulae with robotic assistance continues to develop, but further research is necessary to fully understand the use of this technology. PMID- 26019934 TI - Emphysematous pyelonephritis: Time for a management plan with an evidence-based approach. AB - INTRODUCTION: Emphysematous pyelonephritis (EPN) is a life-threatening necrotising kidney infection, but there is no consensus on the best management. METHODS: We systematically reviewed previous articles published from 1980 to 2013 that included studies reporting on EPN, and applying the Cochrane guidelines, we conducted a meta-analysis of the results. RESULTS: In all, 32 studies were included, with results for 628 patients (mean age 56.6 years, range 33.8-79.9). There were 462 women, outnumbering men by 3:1. Diabetes was present in 85% of the cases. Fevers and rigor (74.7%), pyuria (78.2%) and pain (70.4%) were the most common symptoms. Shock was associated with 54.4% of deaths while obstructive uropathy was associated with 15.1% of deaths. Computed tomography was diagnostic in all the cases. Percutaneous drainage (PCD) and medical management (MM) alone were associated with a significantly lower mortality rate than was emergency nephrectomy (EN), with an odds ratio (95% confidence interval) for PCD vs. EN of 3.13 (1.89-5.16; P < 0.001), for EN vs. MM of 2.84 (1.62-4.99; P = 0.001), and of 0.91 (0.53-1.56; P = 0.73, i.e., no difference) for PCD vs. MM. Open drainage also had a significantly lower mortality rate than EN, with a ratio of 0.12 (0.02 0.91; P < 0.04). CONCLUSION: The overall mortality rate was ~18%; shock was associated with a high mortality rate and therefore should be managed aggressively. PCD and MM were associated with significantly higher survival rates than EN, and therefore EN should only be considered if the patient does not improve despite other treatments. PMID- 26019935 TI - Distal extension of the midline urethral-plate incision in the Snodgrass hypospadias repair: An objective assessment of the functional and cosmetic outcomes. AB - OBJECTIVES: To objectively assess the functional and cosmetic outcomes of a modified tubularised incised-plate (TIP) urethroplasty (Snodgrass) technique, with particular attention to the uroflowmetry study and Hypospadias Objective Scoring Evaluation (HOSE) score. PATIENTS AND METHODS: In a prospective case series study, 43 consecutive patients with primary distal hypospadias were evaluated. The modified Snodgrass technique included an extension of the midline relaxing incision of the urethral plate from within the hypospadiac meatus to the very tip of the glans. The neourethra was tubularised starting at the neomeatus and proceeding proximally. The neourethra was covered with either a single or double dartos flap. In toilet-trained boys, at least 3 months after surgery, the flow pattern, maximum (Q max), and mean urinary flow rate (Q ave) were recorded, and the results plotted against a recently published flow-rate nomogram from normal children. The postvoid residual urine volume was measured using ultrasonography. The cosmetic outcome was assessed using the HOSE system. RESULTS: The native meatus was coronal in 11 (26%), subcoronal in 23 (53%) and distal penile in nine (21%) of the patients. The median (range) age was 4.2 (0.5 14) years. The neourethra was covered by a single dorsal dartos flap in 25 and a double dartos flap in 18 patients. At a median (range) follow-up of 6 (3-24) months, the uroflowmetry findings in 26 uncomplicated toilet-trained boys with a median (range) age of 5.2 (3.3-14) years showed an abnormal Q max below the fifth percentile in four (15%), with the Q ave above the fifth percentile in all. The flow pattern was bell-shaped in nine boys (35%), interrupted/intermittent in five (19%), slightly flattened in 10 (39%) and a plateau in two (8%). A vertical slit like meatus located at the distal glans was created in 39 (91%) boys, and at the proximal glans in four (9%). The urinary stream was single and straight in 39 and angled in four patients. A straight erection was observed in 42 (98%) boys. Four patients had preoperative mild penile torsion of <45 degrees , that was corrected by surgery. The mean (SD, range) HOSE score was 15.8 (0.6, 13-16). Two patients had a small, single subcoronal fistula. CONCLUSION: Extending the midline urethral plate-incision in the modified Snodgrass repair to the apical part of the glans can be done safely with a high rate of locating the neomeatus at the glans tip, with no resultant meatal stenosis. The functional and cosmetic results of the procedure are good, but long-term data and comparative studies are required to confirm these results. PMID- 26019936 TI - The management of moderate and severe congenital penile torsion associated with hypospadias: Urethral mobilisation is not a panacea against torsion. PMID- 26019937 TI - Prepubertal testicular tumours: Should testicular-sparing surgery be considered? A single-institution experience and review of the literature. AB - OBJECTIVES: To review our 10-year experience with uncommon testicular tumours in children (prepubertal testicular and paratesticular), to review previous reports, and to determine the appropriate management of these rare tumours, specifically the role of testicular-sparing surgery. PATIENTS AND METHODS: We retrospectively reviewed all cases of testicular tumours managed at our institution between 1999 and 2009. Boys aged <16 years were included in the study. The patients' characteristics, presentation, the diagnostic tools, tumour markers, mode of treatment, pathological findings and outcome were assessed. We reviewed previous reports that addressed testicular and paratesticular tumours in prepubertal boys, using a Medline/PubMed search. RESULTS: From 80 patients, 13 boys (median age 8.7 years) presented with testicular tumours (16%) and were included in the study. Two boys presented with precocious puberty and one with gynaecomastia. The level of alpha-fetoprotein was high in three boys, and the human chorionic gonadotrophin level was elevated in one, and both markers were high in one. Testicular-sparing surgery was performed in three boys. Six of the 13 tumours were malignant and seven were benign. None of the patients developed a recurrence or testicular atrophy after testicular-sparing surgery. From the review of previous reports we devised an evidence-based algorithm for managing prepubertal testicular tumours. CONCLUSIONS: Paediatric testicular tumours are rare but they require an inguinal approach for either orchidectomy or testicular-sparing surgery; we recommend the latter option as long as frozen sections are analysed and a safety margin is maintained. PMID- 26019938 TI - Variables affecting adolescent renal function in patients born with vesico ureteric reflux. AB - OBJECTIVE: To examine whether factors in a child's perinatal history influence renal function in adolescence, using a cross-sectional study, as during the past two decades researchers have tried to ascertain whether factors such as low birth weight might be related to a decline in kidney function in adolescence, although published data for children born with vesico-ureteric reflux (VUR) remain insufficient. PATIENTS AND METHODS: Sixty-one children (20 boys and 41 girls), born between 1985 and 1989 in Greece and diagnosed with VUR, were assessed. A detailed personal and family history was taken and basic anthropometric variables were measured. Kidney function was calculated from serum creatinine levels, and the glomerular filtration rate (GFR), fractional excretion of sodium, albumin levels in urine, creatinine clearance, cystatin C level and the dimensions of each kidney were measured. RESULTS: The results showed a positive relationship of birth weight (P = 0.01) with blood pressure in adolescence in children diagnosed with any degree of VUR. Renal function seemed to be intact whatever the cause of VUR, the volume of the kidneys in adolescence (P = 0.386 and 0.483, respectively, for the right and left kidney) and the values of GFR (P = 0.105), creatinine clearance (P = 0.213) and cystatin C (P = 0.055). CONCLUSIONS: These results showed that although there is a positive association between blood pressure in adolescence and birth weight, in children born with VUR there was no deterioration in renal function. Kidneys seem to function normally regardless of the gestational age at birth. PMID- 26019939 TI - Radical retropubic and perineal prostatectomy for clinically localised prostate cancer in renal transplant recipients. AB - OBJECTIVE: To analyse the functional and oncological outcome of consecutive renal transplant recipients (RTRs) with clinically localised prostate cancer who underwent radical retropubic (RRP) or perineal (RPP) prostatectomy. PATIENTS AND METHODS: Between January 2000 and July 2011 16 patients underwent RRP (group 1) and seven RPP (group 2). In all, 200 consecutive non-RTRs served as the control group, of whom 100 each underwent RRP and RPP, respectively. The mean (range) interval between renal transplantation and RP was 95 (24-206) months, the PSA at the time of diagnosis was 4.5 (3.0-17.5) ng/mL, and the mean patient age was 64 (59-67) years. RESULTS: The mean follow-up was 39 (RRP) and 48 months (RPP). There was no deterioration in graft function. In group 1, 13 and three patients had pT2a-cpN0 and pT3a-bpN0 prostate cancer, respectively, with a Gleason score of 6, 7 and 8 in 11, three and one patients, respectively. In group 2, three and four patients had pT2a-c and pT3a-b disease, respectively, with a Gleason score of 6 and 7 in two and five, respectively. In both groups one patient had a positive surgical margin and was followed expectantly, and all patients have no evidence of disease. Wound infections developed more often in the RPP group (29% vs. 7%), but there were no Clavien grade III-V complications. All patients achieved good continence, and two need one pad/day. CONCLUSIONS: RRP and RPP are suitable surgical treatments for prostate cancer in RTRs. RRP might be preferable, as it has the advantage of simultaneous pelvic lymphadenectomy and a lower risk of infectious complications. PMID- 26019940 TI - Urethral and penile war injuries: The experience from civil violence in Iraq. AB - OBJECTIVE: To determine the incidence, mechanism of injury, wounding pattern and surgical management of urethral and penile injuries sustained in civil violence during the Iraq war. PATIENTS AND METHODS: In all, 2800 casualties with penetrating trauma to the abdomen and pelvis were received at the Al-Yarmouk Hospital, Baghdad, from January 2004 to June 2008. Of these casualties 504 (18%) had genitourinary trauma, including 45 (8.9%) with urethral and/or penile injuries. RESULTS: Of 45 patients, 29 (64%) were civilians and 16 (36%) were Iraqi military personnel. The injury was caused by an improvised explosive device (IED) in 25 (56%) patients and by individual firearms in 20 (44%). Of the patients, 24 had penile injuries, 15 had an injury to the bulbar urethra and six had an injury to the posterior urethra. Anterior urethral injuries were managed by primary repair, while posterior urethral injuries were managed by primary realignment in five patients and by a suprapubic cystostomy alone in one. An associated injury to major blood vessels was the cause of death in eight of nine patients who died soon after surgery (P < 0.001). CONCLUSION: Urethral and penile injuries were caused by IEDs and individual firearms with a similar frequency. Most of the casualties were civilians and a minority were military personnel. Injuries to the anterior urethra can be managed by primary repair, while injuries to the posterior urethra can be managed by primary realignment. An associated trauma to major blood vessels was the leading cause of death in these casualties. PMID- 26019941 TI - The success of extracorporeal shock-wave lithotripsy based on the stone attenuation value from non-contrast computed tomography. AB - OBJECTIVE: To determine the utility of the urinary stone-attenuation value (SAV, in Hounsfield units, HU) from non-contrast computed tomography (NCCT) for predicting the success of extracorporeal shock-wave lithotripsy (ESWL). PATIENTS AND METHODS: The study included 305 patients with renal calculi of ?30 mm and upper ureteric calculi of ?20 mm. The SAV was measured using NCCT. Numerical variables were compared using a one-way analysis of variance with posthoc multiple two-group comparisons. Univariate and multivariate regression analysis models were used to test the preferential effect of the independent variable(s) on the success of ESWL. RESULTS: Patients were grouped according to the SAV as group 1 (?500 HU, 81 patients), group 2 (501-1000 HU, 141 patients) and group 3 (>1000 HU, 83 patients). ESWL was successful in 253 patients (83%). The rate of stone clearance was 100% in group 1, 95.7% (135/141) in group 2 and 44.6% (37/83) in group 3 (P = 0.001). CONCLUSIONS: The SAV value is an independent predictor of the success of ESWL and a useful tool for planning stone treatment. Patients with a SAV ?956 HU are not ideal candidates for ESWL. The inclusion criteria for ESWL of stones with a SAV <500 HU can be expanded with regard to stone size, site, age, renal function and coagulation profile. In patients with a SAV of 500-1000 HU, factors like a body mass index of >30 kg/m(2) and a lower calyceal location make them less ideal for ESWL. PMID- 26019942 TI - Multislice computed tomography vs. intravenous urography for planning supine percutaneous nephrolithotomy: A randomised clinical trial. AB - OBJECTIVE: To compare the outcome of treatment planning using multislice computed tomography (CT) or intravenous urography (IVU) for supine percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: The study included 60 patients with renal stones, all treated by supine PCNL, between March 2011 and October 2012. The patients were divided randomly into two equal groups; in group 1 30 patients had the PCNL access planned based on IVU findings, and in group 2 the PCNL access was planned based on multislice CT images. All patients were suitable for PCNL, based on a plain abdominal film and ultrasonography, and with a body mass index of <30 kg/m(2). The exclusion criteria were renal anomalies and bleeding diathesis. All data from both groups for the mean time taken to gain percutaneous access, operative duration, fluoroscopic time, access difficulty, stone-free rate and intraoperative morbidity were collected and analysed statistically. RESULTS: The mean (SD) time taken to gain percutaneous access was longer in group 1 than group 2, at 22.2 (1.76) vs. 13.1 (1.62) min (P < 0.001), as were the operative duration, at 81.9 (14.9) vs. 58.8 (7.6) min (P < 0.001), and fluoroscopic time, at 3.5 (1.7) vs. 2.2 (1.3) min (P = 0.002). In group 1 there were four cases (13%) in which there were difficulties in establishing percutaneous access, while in group 2 there were none (P = 0.003). There was intraoperative morbidity in three patients (10%) in group 1 and two (7%) in group 2. CONCLUSION: Multislice CT is a safer, more accurate and noninvasive imaging technique than IVU for mapping the pelvicalyceal system. It saves time and is essential in choosing the optimal percutaneous access into the pelvicalyceal system for a safe and successful PCNL. PMID- 26019943 TI - The development of ureteric strictures after ureteroscopic treatment for ureteric calculi: A long-term study at two academic centres. AB - OBJECTIVE: To determine the incidence of symptomatic and 'silent' obstruction after ureteroscopic procedures. PATIENTS AND METHODS: In all, 1980 patients underwent ureteroscopy for ureteric calculi in two large centres. The methods of disintegration, auxiliary procedures used and type of stenting were considered. Intraoperative complications, in addition to the size and site of the stone, were assessed in relation to postoperative obstruction. The mean (range) follow-up was 42 (12-68) months, with patients assessed after 3-6 months and yearly thereafter. The postoperative evaluation included an assessment of pain, renal ultrasonography, a plain abdominal film, intravenous urography, and a diuretic renal scan in some cases to confirm obstruction. RESULTS: The success rate of stone removal was 98.5%. The failures were related to the size of the stone (>2 cm; P < 0.001). In eight patients there was a ureteric perforation, and six of these developed a ureteric stricture. A stricture also occurred in 12 patients (0.6%) during the follow-up; these included nine of 204 with stones of >2 cm (4.4%), compared to three (0.17%) of 1746 patients with stones of <2 cm (P < 0.001). Fourteen patients presented with pain (0.7%), and five had no obstruction, while in nine (0.46%) the pain was associated with obstruction. There was silent obstruction in three cases (0.15%). The negative and positive predictive values for pain were 99.8% and 64.3%, respectively. CONCLUSIONS: Radiographic surveillance for stricture formation and obstruction is mandatory in patients who are symptomatic after ureteroscopy, and for up to 18 months in patients with intraoperative complications or with a stone of >2 cm in the proximal ureter. PMID- 26019944 TI - The laparoscopic management of symptomatic renal cysts: A single-centre experience. AB - OBJECTIVES: To present our experience of treating symptomatic renal cysts by different techniques of laparoscopic decortication, as there are many treatment options for such cysts, each of them with advantages and drawbacks. PATIENTS AND METHODS: Between January 2002 and December 2012, 51 patients underwent laparoscopic renal-cyst decortication; 15 of them had recurrent cysts after percutaneous aspiration. A retroperitoneal approach was adopted in 44 cases, transperitoneal in four and laparo-endoscopic single-site surgery (LESS) cyst decortication in three (two of them had bilateral renal cyst decortications in the same session). All patients were diagnosed by ultrasonography and computed tomography to determine the Bosniak classification of the cyst. Pain and cyst recurrence were assessed during the follow-up. RESULTS: All procedures were completed successfully, with no major intraoperative complications. The mean (range) operative duration was 56 (35-125) min, affected by the site and number of cysts unroofed. All patients were symptom-free except one, who had a recurrent large cyst, anteriorly located, and who underwent open cyst decortication. CONCLUSIONS: Laparoscopic decortication of symptomatic renal cysts should be the standard of care, especially after failed percutaneous aspiration or decortication. LESS cyst decortication is a promising technique, especially with bilateral pathology. It is feasible with conventional laparoscopic instruments and gives a better cosmetic outcome. PMID- 26019945 TI - Galectin 3 for the diagnosis of bladder cancer. AB - OBJECTIVE: To evaluate serum levels of galectin-3 (G-3) in patients with bladder cancer and a control group, as a potential diagnostic and prognostic serum tumour marker. PATIENTS AND METHODS: Between November 2012 and January 2013, 55 patients (median age 58 years) were enrolled into three groups, i.e., a control, those with transitional cell carcinoma (TCC) or those with squamous cell carcinoma (SCC). The serum G-3 level was measured the night before cystoscopy. The levels of G-3 levels were correlated with tumour type, stage and grade, and in relation to levels in normal urothelium. The results were analysed statistically using the Mann-Whitney U-test, the Kruskal-Wallis test and the receiver operating characteristic curve, as appropriate. RESULTS: The median serum G-3 level was 100, 720 and 920 pg/mL in the control, TCC and SCC groups, respectively, with very significantly greater G-3 levels in both the TCC and SCC groups than in the control group. Patients with high-grade TCC had a statistically significantly greater serum G-3 level than those with low-grade tumours, as did those with muscle-invasive TCC than those with Ta tumours. CONCLUSIONS: The level of G-3 can aid as a diagnostic marker in patients with either TCC or SCC of the bladder, but the prognostic significance of G-3 remains to be confirmed. PMID- 26019946 TI - Live surgery at conferences - Clinical benefits and ethical dilemmas. AB - Live surgical broadcasts (LSBs) are becoming increasingly popular in urological conferences. These activities can provide excellent training opportunities, as they allow the audience to view an operation conducted by world-renowned surgeons, and have the ability to interact with them in real time. However, several ethical considerations have been raised with this practice, which the participating surgeons and conference organisers must appreciate and address carefully. In this article we highlight the ethical considerations related to LSBs and advise on how these should be addressed. We also present the latest recommendations made by the European Association of Urology Live Surgery Committee and discuss alternatives to LSB. PMID- 26019947 TI - An early-detection programme for prostate cancer in Saudi men: A call from a tertiary-care centre in the Eastern province. AB - OBJECTIVE: To review the mode of presentation and clinical course of patients with prostate cancer during a specified period, as the detection rate is tending to increase, with most patients presenting at an advanced stage, and yet the overall incidence and prevalence rates are low. PATIENTS AND METHODS: We retrospectively reviewed all aspects of care for patients who were diagnosed between May 2006 and July 2010. RESULTS: In all, 76 men had a histologically confirmed prostatic adenocarcinoma diagnosed between May 2006 and July 2010 (mean age 71.1 years, SD 8). The median (range) prostate-specific antigen level at diagnosis was 52 (1.2-16,230) ng/mL. Of the patients, 74% had a Gleason grade of ? 7 on diagnosis, and 64% had extraprostatic disease on presentation. Active surveillance was adopted in four patients, and four others were maintained on watchful waiting. Six patients had a radical prostatectomy, in one of whom it was a salvage procedure. Six patients received external-beam radical radiotherapy, five of whom had neoadjuvant, concurrent and adjuvant hormonal therapy. All remaining patients were treated primarily with androgen-deprivation therapy (ADT). Of the patients on hormonal manipulation, in 56% the cancer became castrate-resistant within the mean (SD) follow-up of 17.2 (15) months. Of patients treated primarily with ADT, 34% died. The death rate among the whole group was 23%. Both percentages include both prostate cancer-specific and non specific mortality. CONCLUSION: An advanced stage of disease at presentation mandates an early-detection, hospital-based screening programme. Further research should include many more patients and be based in several centres. PMID- 26019948 TI - Clinical evaluation of patients treated with a detubularised isolated ureterosigmoidostomy diversion after radical cystectomy. AB - OBJECTIVES: To assess the emptying pattern and patient satisfaction after constructing a detubularised isolated ureterosigmoidostomy (DIUS) following a cystectomy, introduced to overcome the poor outcome of conventional ureterosigmoidostomy, to improve the emptying pattern and accordingly patients' quality of life. PATIENTS AND METHODS: The study included 122 patients who were treated with a DIUS diversion after cystectomy. The minimum follow-up of the patients was 6 months. The frequency of emptying and continence during the day and night were recorded. The ability of the patients to discriminate between urine and stool was assessed. The patients' overall satisfaction with the outcome was categorised as fully satisfied, moderately satisfied or not satisfied. RESULTS: In all, 95 patients were available for this evaluation; all patients were completely continent during the day and night. The mean emptying frequency was 3.9 during the day and 1.7 during the night. All patients were able to feel the desire to empty and the mean holding time was 35 min. Fifty-two patients (55%) could pass solid stools once per day, with minimal urine at the end of voiding, and the remaining evacuations were of clear urine only. Thirty-two patients (34%) were able to differentiate between urine and stool sensation before emptying. For satisfaction, 82 patients reported full satisfaction, 13 were moderately satisfied, and none regretted the diversion. CONCLUSIONS: The DIUS diversion provides continence during the day and night, with a satisfactory emptying habit. Patients with a DIUS diversion can tolerate a full pouch comfortably, with no leakage, and they can discriminate between urine and stool evacuations. PMID- 26019949 TI - Detubularised isolated ureterosigmoidostomy (Atta pouch): Manometric and radiological studies in a sample of patients. AB - OBJECTIVES: To assess whether the detubularised isolated ureterosigmoidostomy (DIUS) technique is safe for urinary diversion after radical cystectomy. PATIENTS AND METHODS: The study included 10 patients (mean age 61.8 years) with invasive bladder tumour, operated at the Alexandria University, Egypt. The diversion in all patients was through a DIUS, with ureteric reimplantation by an antirefluxing procedure, using an embedded-nipple technique. The patients were evaluated before and after surgery using radiological and manometric studies, and the results analysed statistically using Student's t-test. RESULTS: Nine of the 10 patients could differentiate between urinary and stool sensation, and evacuate them separately. The mean (range) daytime frequency was 4.1 (3-5) and the mean night time frequency was 0.5 (0-1). Before and after surgery, the respective mean resting anal pressure was 71 and 74 cm H2O (P = 0.004), the volume at first desire to defecate was 54 and 72 mL (P = 0.004) and the maximum tolerable volume was 140 and 160 mL (P < 0.001). The anorectal inhibitory reflex was lost in all patients after surgery. The mean (SD, range) basal pouch pressure was 5 (3.33, 0 10) cmH2O, and the end pressure was 13.2 (4.42, 9-20) cmH2O. CONCLUSION: Although the Mainz II pouch has a documented efficacy for urinary diversion after radical cystectomy, the modifications we applied to the DIUS improved that method of diversion, by separating urine and stool evacuation, maintaining continence, and with a low frequency and better protection of the upper urinary tracts, resulting in an improvement in the patients' quality of life. PMID- 26019950 TI - The first Iraqi experience with the rectus fascia sling and transobturator tape for female stress incontinence: A randomised trial. AB - OBJECTIVES: To present the first experience in Iraq of autologous rectus fascia sling (RFS) procedures and transobturator tape (TOT) for treating female stress urinary incontinence (SUI), and to review the validity of the RFS in the era of synthetic tapes. PATIENTS AND METHODS: From December 2004 to July 2012, 80 female patients with SUI were enrolled in the study, and randomly assigned into two types of surgery, with 40 treated by RFS (retropubic route) and 40 by TOT. The surgical results were compared between the groups and with those from previous studies. RESULTS: The mean operative duration was 80 min for RFS vs. 20 min for TOT. The early cure rate was 98% for RFS (with one failure due to prolonged urinary retention) and 95% for TOT (with two failures due to persistent incontinence). The early complications were mainly abdominal wound problems (20%) for RFS, and groin and upper thigh pain (13%) for TOT. The late complications were the development of postvoid residual urine (8% in RFS vs. 5% in TOT) and de novo detrusor overactivity (5% in each group). There were no vaginal or urethral erosions up to the end of the study. CONCLUSIONS: RFS and TOT have comparable efficacy and safety in treating SUI. Nevertheless RFS, with its more invasive nature and long operative duration, should only be used when synthetic tapes are not available or not preferable. PMID- 26019951 TI - The accuracy of three-dimensional bladder ultrasonography in determining the residual urinary volume compared with conventional catheterisation. AB - OBJECTIVE: To determine the accuracy of three-dimensional bladder ultrasonography (US, using the BVI 3000, Verathon, WA, USA) for determining the residual urinary volume, compared with the conventional catheterisation method. PATIENTS AND METHODS: We conducted a cross-sectional study at day-care unit of a University hospital after obtaining approval from the Ethics Review Committee of the hospital. Thirty-four patients with lower urinary tract symptoms requiring cystometrography were included. The postvoid volume was measured by bladder US, with three readings taken, and then patient was catheterised using a 12-F Nelaton catheter to measure the urinary volume. The mean of the three readings was compared with the catheterisation volume. RESULTS: The mean (SD) urinary volumes by US and catheterisation were 261 (186) and 260 (175) mL, respectively, and the correlation (r (2)) was 0.97. There was no effect of age, gender or body mass index on the accuracy of bladder US, which was accurate even when the urinary volume was ?100 mL. CONCLUSION: The bladder US estimate is as accurate as catheterisation for determining the postvoid residual urinary volume. Its accuracy was also comparable when the urinary volume is <100 mL, and there was no significant effect of age, gender and body mass index. This system could replace the more invasive catheterisation, and with excellent accuracy. PMID- 26019952 TI - Factors determining the amount of residual urine in men with bladder outlet obstruction: Could it be a predictor for bladder contractility? AB - OBJECTIVE: To determine from urodynamic data what causes an increased postvoid residual urine volume (PVR) in men with bladder outlet obstruction (BOO), urethral resistance or bladder failure, and to determine how to predict bladder contractility from the PVR. PATIENTS AND METHODS: We analysed retrospectively the pressure-flow studies (PFS) of 90 men with BOO. Nine patients could not void and the remaining 81 were divided into three groups, i.e. A (30 men, PVR < 100 mL), B (30 men, PVR 100-450 mL) and C (21 men, PVR > 450 mL). The division was made according to a receiver operating characteristic curve, showing that using a threshold PVR of 450 mL had the best sensitivity and specificity for detecting the start of bladder failure. RESULTS: The filling phase showed an increase in bladder capacity with the increase in PVR and a significantly lower incidence of detrusor overactivity in group C. The voiding phase showed a significant decrease in voided volume and maximum urinary flow rate (Q max) as the PVR increased, while the urethral resistance factor (URF) increased from group A to B to C. The detrusor pressure at Q max (PdetQ max) and opening pressure were significantly higher in group B, which had the highest bladder contractility index (BCI) and longest duration of contraction. Group C had the lowest BCI and the lowest PdetQ max. CONCLUSIONS: In men with BOO, PVR results from increasing outlet resistance at the start and up to a PVR of 450 mL, where the bladder reaches its maximum compensation. At volumes of >450 mL, both the outlet resistance and bladder failure are working together, leading to detrusor decompensation. PMID- 26019953 TI - Single-step renal dilatation in percutaneous nephrolithotomy: A prospective randomised study. AB - OBJECTIVE: To perform an economical single-step renal dilatation (RD) during percutaneous nephrolithotomy (PCNL), using directly a 30-F Amplatz dilator over the central Alken dilator, in a trial to reduce the operative duration and radiation exposure during RD while avoiding an exchange of dilators that might increase the risk of blood loss. PATIENTS AND METHODS: In a prospective randomised study including 49 patients divided into two groups, the first had RD before PCNL using the standard metallic telescopic dilators (Alken), and the second had RD using the 30-F Amplatz dilator over the central Alken dilator. The operative duration, with X-ray exposure, was calculated. The procedure outcome in terms of complications, stone-free rates and hospital stay was evaluated statistically. RESULTS: The tract was dilated correctly in all cases. The operative duration and X-ray exposure was shorter in patients undergoing single step RD (P < 0.05). There were perioperative complications, according to the Clavien grading system, in 17 (34%) patients but there was no statistically significant difference between the groups. The stone-free rates were comparable in both groups. CONCLUSION: A single-step RD during PCNL is feasible, with a shorter operative duration and X-ray exposure. The outcomes were comparable with those of a standard metallic telescopic RD. PMID- 26019954 TI - 'Minimum-incision' endoscopically assisted transvesical prostatectomy: Surgical technique and early outcomes. AB - OBJECTIVE: To describe the surgical technique and report the early outcomes of a 'minimum-incision' endoscopically assisted transvesical prostatectomy (MEATP) for managing benign prostatic obstruction secondary to a large (>80 g) prostate. PATIENTS AND METHODS: In a prospective feasibility trial, 60 men with large benign prostates underwent MEATP. The baseline and postoperative evaluation included the International Prostate Symptom Score (IPSS), a measurement of maximum urinary flow rate (Q max), and the postvoid residual (PVR) urine volume. The adenoma was enucleated digitally through a 3-cm suprapubic skin incision, and haemostasis was completed with endoscopic coagulation of the prostatic fossa. Perioperative complications were recorded and stratified according to the modified Clavien-Dindo score. RESULTS: The mean (SD, range) prostate weight estimated by ultrasonography was 102.9 (15.4, 80-160) g, the operative duration was 52 (8, 40-65) min, the haemoglobin loss was 2.1 (1, 0.4-5) g/dL, the catheterisation time was 5.2 (1.3, 4-9) days, and the hospital stay was 6.2 (1.4, 5-10) days. There were 21 complications recorded in 16 (27%) patients, and most (86%) were of grades 1 and 2. The most frequent complications were bleeding requiring a blood transfusion (8%), and prolonged drainage (5%). There was a significant improvement at 3 months after surgery in the IPSS (8.6 vs. 21.6, P < 0.001), Q max (19.5 vs. 7.7, P < 0.001), and PVR (15.8 vs. 83.9 mL, P < 0.001). CONCLUSION: MEATP is feasible, safe and effective. Comparative studies and long term data are required to determine its role in the surgical treatment of large volume BPH. PMID- 26019955 TI - Laparo-endoscopic single-site radical cystectomy with orthotopic urinary diversion: Technique, feasibility, and the 3-year follow-up. AB - OBJECTIVES: To assess the feasibility, operative morbidity and oncological outcome of laparoendoscopic single-site (LESS) radical cystectomy. PATIENTS AND METHODS: Ten patients with clinical stage T1-T2 bladder cancer underwent a LESS radical cystectomy. The mean (SD) age of the patients was 64.8 (8.6) years and their mean body mass index was 25.9 (2.7) kg/m(2). The procedure was done via a single-incision laparoscopic surgery port using a rigid 5-mm 30 degrees long shaft laparoscope in addition to the two working instruments. A 7-cm Pfannenstiel incision was made to remove the specimens and to allow the creation of an ileal neobladder with hand assistance. RESULTS: In eight patients the LESS radical cystectomy was completed as scheduled, with the other two requiring a conversion, one to an open procedure due to locally advanced disease, and the other to conventional laparoscopy due to gas leakage. The mean (SD) operative duration was 236 (49) min, with a mean estimated blood loss of 575 (113) mL, and a mean hospital stay of 5.5 (0.7) days. No postoperative analgesic medications were prescribed and patients returned to normal activity after a mean (SD) of 17.6 (2.6) days. The pathological examination showed negative surgical margins for the bladder specimens, with a mean (SD) of 14 (1.9) lymph nodes retrieved. Seven patients were cancer-free within a mean (SD, range) follow-up of 37 (6, 29-44) months. CONCLUSIONS: LESS radical cystectomy is technically feasible, with a favourable course and convalescence, and it has an acceptable oncological outcome. PMID- 26019956 TI - The assessment of sexual dysfunction in Egyptian women with lower urinary tract symptoms. AB - INTRODUCTION: Female sexual dysfunction (FSD) has been reported in 46% of women with lower urinary tract symptoms (LUTS). FSD is a common health problem that remains under-investigated, especially in Eastern communities, where discussion of the issue is considered a taboo. In this study we determined the prevalence of various subtypes of FSD in relation to LUTS in women in Ismailia, Egypt. PATIENTS AND METHODS: This was a case-control study to assess FSD in women with LUTS in comparison to normal women. In all, 101 women patients attending the Urology clinic at our institution were divided into two groups, a study group of 52 with LUTS and a control group of 49 with no LUTS. Validated Arabic versions of the FSD index and the Bristol questionnaire were used to assess the participants, and the data analysed statistically. RESULTS: FSD was diagnosed in 75 of the 101 patients (74%); 87 (86%) reported hypoactive sexual desire, 61 (60%) reported sexual arousal disorder, 56 (55%) had lubrication disorders, 65 (64%) complained of orgasmic deficiency, 36 (36%) had satisfaction disorder, and 59 (58%) had sexual pain disorder (e.g., dyspareunia or non-coital genital pain). Arousal, satisfaction, orgasmic and lubrication disorders were more common in the women with LUTS. There was no statistically significant difference in desire disorders between the groups. CONCLUSIONS: FSD and its subtypes are more prevalent in women with LUTS in this sample of Egyptian women. PMID- 26019957 TI - The management of the persistent Mullerian duct syndrome. AB - OBJECTIVES: To report the findings and management of patients with persistent Mullerian duct syndrome (PMDS). PATIENTS AND METHODS: Nineteen phenotypically male patients (aged 8 months to 27 years) presented with testicular maldescent. All of them had normal male external genitalia. Two of them had had a previous diagnosis of persistent Mullerian structures. All patients were karyotyped, and had a hormonal profile, diagnostic laparoscopy, retrograde urethrocystogram, gonadal biopsies, and surgical management according to the findings. The follow up was based on a clinical examination, abdominal ultrasonography (US) and scrotal colour-Doppler US at 3 and 6 months after surgery, and every 6 months thereafter. RESULTS: Diagnostic laparoscopy showed the presence of persistent Mullerian structures in all 19 patients. All patients had a normal male karyotype (46XY). Ten patients had a laparoscopic excision of their Mullerian structures while the remaining nine patients had their Mullerian structures left in place. No malignant changes were found in the excised Mullerian tissues. Of the 37 gonadal biopsies taken, 31 (84%) indicated normal testes. CONCLUSIONS: The incidence and prevalence of PMDS are not well estimated. Mullerian structures should be removed whenever possible to avoid the risk of malignant transformation. The early diagnosis of PMDS makes possible the excision of Mullerian structures and a primary orchidopexy. A long-term follow-up is needed for patients with intact Mullerian structures and magnetic resonance imaging might be a better method than US for that purpose. Most of the patients had normal testicular histology, which might allow fertility. PMID- 26019958 TI - Diode laser vaporisation of the prostate vs. diode laser under cold irrigation: A randomised control trial. AB - OBJECTIVE: To compare the perioperative morbidity and early follow-up after diode laser vaporisation of the prostate (LVP) and its modification, diode laser under cold irrigation (LUCI) in patients with symptomatic benign prostatic hyperplasia, as the main disadvantages of LVP are the postoperative pain, dysuria and storage urinary symptoms. PATIENTS AND METHODS: This was a single-centre prospective randomised control trial in which 100 patients were randomised to receive LVP (50) or LUCI (50) from June 2011 until July 2012. LUCI is similar to LVP except that it is done under normal irrigation with saline at 4 degrees C instead of saline at room temperature. The primary outcome measures were the International Prostate Symptom Score (IPSS), IPSS-Dysuria, a pain scale (PS), maximum flow rate (Q max), a quality-of-life (QoL) score and the postvoid residual urine volume (PVR) after 1 month, then the IPSS, Q max, QoL, and PVR at 3 and 12 months. Secondary outcomes included intraoperative surgical variables, e.g., the decline in core temperature, bleeding, peri- and postoperative morbidity. RESULTS: The baseline characteristics of both groups were similar. For the primary outcome measures, there was a statistically significant difference between the groups in all variables except Q max after 1 month, in favour of LUCI. The mean (SD) IPSS at 1 month in the LVP group was 8.97 (1.68), statistically significantly different from that after LUCI, of 6.89 (1.5) (P < 0.05). The mean IPSS-Dysuria at 1 month was also significantly, at -2.32 (0.91) for LVP and 3.54 (1.07) for LUCI (P < 0.05). The respective mean PS at 1 month was 7.84 (2.92) and 5.7 (2.1) (P < 0.05). The QoL and PVR at 1 month were also significantly different. Within the first month 17% of patients in the LVP group and 4% in the LUCI group complained of transient urgency or stress incontinence, and this difference was statistically significant (P < 0.05). There was no significant bleeding in either group. The mean operative time or applied energy of LVP was not statistically significant from that of LUCI, and there was no significant difference in the decline in core temperature between the groups (P > 0.05). CONCLUSION: LUCI is a good modification for reducing the pain, dysuria and storage symptoms associated with LVP. The procedure appears to be safe, with no significant decrease in core temperature in either group. PMID- 26019959 TI - Predicting the resected tissue weight from a digital rectal examination and total prostate specific antigen level before transurethral resection of the prostate. AB - OBJECTIVE: To determine the use of the prostate specific antigen (PSA) level and digital rectal examination (DRE) findings to estimate the resected tissue weight (RTW) before transurethral resection of the prostate (TURP). PATIENTS AND METHODS: We retrospectively analysed 983 patients who underwent TURP between December 2006 and December 2012. The primary outcome was the RTW required for clinical improvement, and was not associated with re-intervention. Age, PSA level, body mass index (BMI) and DRE findings were correlated and modelled with the RTW. The DRE result was defined as DREa (small vs. large) or DREb (small vs. moderate vs. large) according to the surgeon's report. Equations to calculate RTW were developed and tested using receiver operating characteristic (ROC) curve analyses. RESULTS: There were significant correlations between PSA level (r = 0.4, P < 0.001) and RTW, whilst BMI and age showed weak correlations. The median (range) RTW was 45 (7-60) vs. 15 (6-60) g for small vs. large prostates (DREa) (P < 0.001), respectively. Similarly, the median (range) RTW was 11 (6-59) vs. 26.2 (6-60) vs. 42 (7-60) g in small vs. moderate vs. large prostates (DREb) (P < 0.001), respectively. Using PSA level and DREb (model 3) there was a significantly better ability to estimate RTW than using PSA and DREa (model 2) or PSA alone (model 1) based on ROC curve analyses. The equation developed by model 3 (RTW = 1.2 + (1.13 * PSA) + (DREb * 9.5)) had a sensitivity and specificity of 82% and 71% for estimating a RTW of >30 g, and 84% and 63% for estimating a RTW of >40 g, respectively. CONCLUSIONS: The PSA level and DRE findings can be used to predict the RTW before TURP. PMID- 26019960 TI - Prostatic abscess: Objective assessment of the treatment approach in the absence of guidelines. AB - OBJECTIVE: To assess the outcome of the drainage procedure used for treating a prostatic abscess, and to propose a treatment algorithm to reduce the morbidity and the need for re-treatment. Patients and methods We retrospectively reviewed patients who were admitted and received an interventional treatment for a prostatic abscess. All baseline relevant variables were reviewed. Details of the intervention, laboratory data, duration of hospital stay, follow-up data and re admissions were recorded. RESULTS: A prostatic abscess was diagnosed in 42 patients; 30 were treated by transurethral deroofing and 12 by transrectal needle aspiration. The median (range) size of the abscess was 4.5 (2-23) mL and 2.7 (1.5 7.1) mL in the deroofing and aspiration groups, respectively (P = 0.2). In half of the cases multiple abscesses were evident on imaging before the intervention. The median (range) hospital stay after deroofing and aspiration was 2 (1-11) and 1 (1-19) days, respectively (P = 0.04). Perioperative complications occurred only in the deroofing group, in which two patients developed septic shock requiring intensive care (Clavien 4) and one developed epididymo-orchitis (Clavien 2). There were two late complications in the deroofing group, in which one patient developed a urethral stricture that required endoscopic urethrotomy (Clavien 3a) and one developed a urethral diverticulum and urinary incontinence that required diverticulectomy and a bulbo-urethral sling procedure (Clavien 3b). A urethro rectal fistula developed after aspiration in one patient. Re-treatment for the abscess was indicated in two (7%) patients in the deroofing group, which was treated by aspiration. CONCLUSION: Transrectal needle aspiration for a prostatic abscess, when done for properly selected cases, could minimise the morbidity of the drainage procedure. PMID- 26019961 TI - Urinary incontinence in Qatar: A study of the prevalence, risk factors and impact on quality of life. AB - OBJECTIVE: To study the prevalence of and risk factors for urinary incontinence (UI) in Qatar, and its impact on quality of life (QoL). PATIENTS AND METHODS: This study was conducted in two phases, as phase 1 from 2010 to 2011 and phase 2 from 2011 to 2012. In phase 1 we calculated the prevalence of UI in Qatar and its risk factors. In phase 2 we determined the frequency and severity of different types of UI and its impact on QoL, by using the International Consultation Incontinence Questionnaire - Short Form (ICIQ-SF). RESULTS: The total of women included in phase 1 was 521, among whom 108 (20.7%) confirmed that they had experienced UI during the previous 4 weeks, whilst 413 (79.3%) denied any type of UI. Women with UI were older and less educated. Bronchial asthma was the only statistically significant factor affecting UI. In phase 2, 1085 patients with UI were enrolled, of whom 454 (41.9%) had urge UI (UUI), 484 (44.5%) had stress UI (SUI) and 148 (13.6%) had mixed UI (MUI). This phase also showed a distribution of the type of UI according to the age of the patients. UUI was predominant in women aged <40 years, SUI in those aged <70 years and MUI in those aged 40-70 years. Of these women, 86% had a small amount of urinary leakage (requiring 1-2 pads per day) but this had a significant effect on their QoL. CONCLUSION: In Qatar, 21% of women have UI, but bronchial asthma was a significant risk factor influencing the occurrence of UI. Social and religious factors have a significant effect on the QoL of incontinent women. A well-designed national health programme for both women in general and for those with UI, and for physicians and nurses in primary health centres, is highly recommended. PMID- 26019962 TI - 3-year results of transvaginal cystocele repair with transobturator four-arm mesh: A prospective study of 105 patients. AB - OBJECTIVES: To evaluate the long-term efficacy and safety of transobturator four arm mesh for treating cystoceles. PATIENTS AND METHODS: In this prospective study, 105 patients had a cystocele corrected between January 2004 and December 2008. All patients had a symptomatic cystocele of stage ?2 according to the Baden Walker halfway stratification. We used only the transobturator four-arm mesh kit (Surgimesh(r), Aspide Medical, France). All surgical procedures were carried out by the same experienced surgeon. The patients' characteristics and surgical variables were recorded prospectively. The anatomical outcome, as measured by a physical examination and postoperative stratification of prolapse, and functional outcome, as assessed by a questionnaire derived from the French equivalents of the Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire and the Pelvic Organ Prolapse-Urinary Incontinence-Sexual Questionnaire, were considered as the primary outcome measures. Peri- and postoperative complications constituted the secondary outcome measures. RESULTS: At 36 months after surgery the anatomical success rate (stage 0 or 1) was 93%. On a functional level, all the scores of quality of life and sexuality were improved. The overall satisfaction score (visual analogue scale) was 71.4%. There were no perioperative adverse events. Mesh erosion was reported in 7.6% and mesh retraction in 5.7% of the patients. CONCLUSIONS: If the guidelines and precautions are followed, vaginal prosthetic surgery for genitourinary prolapse has shown long-term benefits. It provides excellent results both anatomically and functionally. However, complications are not negligible and some are specific to prosthetic surgery. PMID- 26019963 TI - The reliability and reproducibility of ultrasonography for measuring the residual urine volume in men with lower urinary tract symptoms. AB - OBJECTIVE: To assess the reliability and reproducibility of abdominal ultrasonography (US) for measuring the postvoid residual urine volume (PVR), and to compare measurements by a radiologist and urologist, in men with lower urinary tract symptoms (LUTS), as a significant PVR is common in patients with LUTS and an assessment of the PVR could protect patients from unnecessary catheterisation. PATIENTS AND METHODS: This was a prospective comparative study of 45 men aged ?45 years with LUTS attending a urological outpatient clinic from July 2011 to May 2012. A detailed history was taken, with an assessment of LUTS using the Arabic Validated International Prostate Symptom Score (IPSS) and complete general and local examination. The PVR was measured by US twice by a radiologist and urologist, and then repeated after 1 week. Within ?2 min after US a urethral catheter was used to measure the PVR. RESULTS: The mean (range) age of the patients was 63.8 (45-88) years and the mean IPSS was 16.18. Reliability testing between the PVR measured by US and the catheterised measure of PVR showed that US was not reliable (Cronbach's alpha < 0.7). The US measurement was reproducible for both single examiner over two sessions, and with two examiners in one session. The PVR obtained by the urethral catheter was significantly higher than the US measurement (P < 0.05). CONCLUSIONS: The measurement of PVR by US is reproducible by either a urologist or radiologist, but it is not reliable, as the urethral catheter estimate gives a significantly higher PVR. PMID- 26019964 TI - Validation of the Arabic linguistic version of the Ureteral Stent Symptoms Questionnaire. AB - OBJECTIVE: To validate the Arabic version of the Ureteral Stent Symptoms Questionnaire (USSQ). PATIENTS AND METHODS: The English version of the USSQ was translated into Arabic using a multi-step process by three urologists and two independent translators. The Arabic version was validated by asking 37 patients with temporary unilateral ureteric stents to complete the questionnaire at 2 weeks after stent insertion. The second group included 53 healthy individuals who agreed to complete the Arabic version of the questionnaire. The reliability of the Arabic version was evaluated for internal consistency using Cronbach's alpha test. Domain structures were examined by interdomain (section) associations using Spearman's correlation coefficient (r). The discrimination validity was evaluated by comparing the scores of patients with those of healthy individuals, using the Mann-Whitney test. RESULTS: Internal consistency was high for the sexual index and intermediate for urinary, pain and general health indices. There were good correlations of urinary symptoms with body pain (r = 0.596) and general health (r = 0.690). There was also a good correlation between body pain and general health (r = 0.681). For discrimination validity, there were significant changes in all domain scores when comparing patients with ureteric stents and healthy individuals (P < 0.001). CONCLUSION: The Arabic version of the USSQ is a reliable and valid instrument that can be used to evaluate symptoms and health-related quality of life in Arabic patients with ureteric stents. PMID- 26019965 TI - Ethanolamine oleate vs. absolute ethanol as sclerosing agents for treating symptomatic simple renal cysts. AB - OBJECTIVES: To compare the efficacy and safety of ethanolamine oleate (EO) as a sclerosing agent, vs. absolute ethanol (AE), in the treatment of symptomatic simple renal cysts. PATIENTS AND METHODS: Between November 2009 and October 2012, 46 patients were prospectively randomised into two groups. All patients presented with a simple renal cyst underwent ultrasonographic aspiration and injection of a sclerosing agent. In group 1, 25 patients had the cyst injected with EO, and in group 2, 21 were treated with AE. One injection was used in cysts of <200 mL and two injections were used in larger cysts. Complete and partial success were defined as complete cyst ablation or a >50% reduction in cyst volume with symptomatic relief, respectively. Patients were followed up using semi-annual ultrasonography and computed tomography for 2 years. RESULTS: Sclerotherapy was technically successful in all patients. There was no significant difference in cyst volume between the groups. After ~2 years of follow-up there was complete symptomatic relief in both groups, and the overall radiological success rate was 100% of both groups, at 79% complete and 21% partial in group 1, and 83% complete and 17% partial in group 2. The frequency of transient complications in the form of microscopic haematuria was 7% and 13%, and of low-grade fever in 4% and 10% in groups 1 and 2, respectively. CONCLUSION: EO can replace AE as a sclerosing agent for symptomatic simple renal cysts, as it has comparable efficacy with higher safety and tolerance. PMID- 26019966 TI - Definitive ureteroscopy and intracorporeal lithotripsy in treatment of ureteral calculi during pregnancy. AB - OBJECTIVE: To evaluate the outcome of using semi-rigid ureteroscopy with or without intracorporeal pneumatic lithotripsy vs. temporary ureteric JJ stenting in the management of obstructing ureteric calculi in pregnant women. PATIENTS AND METHODS: This prospective comparative study comprised 43 pregnant women with obstructing ureteric calculi. The diagnosis was based on the acute flank pain as the main symptom, microscopic haematuria, and unilateral hydronephrosis on abdominal ultrasonography (US). The patients were randomly divided into two groups; those in group 1 (22 patients) were treated by temporary ureteric JJ stenting until after delivery, and those in group 2 (21) were treated definitively by ureteroscopic stone extraction with intracorporeal pneumatic lithotripsy. Postoperative complications and the degree of patient satisfaction were reported. RESULTS: An obstructing ureteric stone was identified by US in 68% and 76% of groups 1 and 2, respectively. In group 1, nine patients had mid ureteric stones and 13 had stones in the lower ureter. In group 2, seven patients had mid-ureteric stones, whilst the stones were in the distal ureter in 14. No perioperative foetal complications were detected in any group and all patients completed the full term of pregnancy. In group 1, four patients had a postoperative urinary tract infection (UTI), and the JJ stent was exchanged in seven. Two patients in group 2 had a postoperative UTI. CONCLUSIONS: Definitive ureteroscopy, even with intracorporeal pneumatic lithotripsy, is an effective and safe treatment for pregnant women with obstructing ureteric calculi. It has a better outcome and is more satisfactory for the patients than a temporary JJ stent. PMID- 26019967 TI - Indications for adrenalectomy during radical nephrectomy for renal cancer. AB - OBJECTIVES: To determine if the selection criteria for ipsilateral adrenalectomy during laparoscopic radical nephrectomy (RN) can be further restricted, with the goal of sparing more patients unnecessary adrenalectomy while preserving the removal of adrenal glands containing malignancy, as recent evidence suggests that adrenalectomy in association with RN for renal cancer can be limited to patients with abnormalities on adrenal imaging or large upper-pole renal tumours. PATIENTS AND METHODS: The cohort consisted of two data sets, each from one institution, i.e., a training set and a validation set. All patients underwent RN for radiographically localised disease. Removal of the adrenal gland was based on the surgeon's preference, related to the presence of a suspect adrenal lesion on preoperative imaging, suspicion for involvement of the adrenal gland intraoperatively, location of the tumour, size of the tumour and local tumour stage. RESULTS: Of 159 patients in the training cohort, three (2%) had metastatic renal cancer in the ipsilateral adrenal gland. All three patients had tumours of >7 cm and either an abnormal radiographic appearance of the adrenal gland or suspect intraoperative findings. In the validation cohort of 74 patients, seven (10%) had adrenal metastasis, of which one had a tumour of <7 cm and the indication for adrenalectomy was the high intraoperative suspicion. CONCLUSION: We recommend performing ipsilateral adrenalectomy in association with RN for renal cancer when there is either abnormal radiographic appearance of the adrenal gland or suspect intraoperative findings, with no regard for primary tumour size. PMID- 26019969 TI - Editorial. PMID- 26019968 TI - The influence of antisperm antibodies, intratesticular haemodynamics and the surgical approach to varicocelectomy on seminal variables. AB - OBJECTIVE: To evaluate the effect of antisperm antibodies (ASAs), hormonal levels, intratesticular haemodynamics and the surgical approach on the outcomes of varicocelectomy in infertile men, as assessed by seminal variables. PATIENTS AND METHODS: In a prospective case-series study, 82 infertile men with varicocele (35 left and 47 bilateral) were evaluated. The preoperative assessment included a physical examination, semen analysis, assessment of ASAs in seminal plasma, hormonal levels (follicle-stimulating hormone (FSH), luteinising hormone and testosterone), and scrotal colour Doppler ultrasonography (CDUS) to measure the peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI) and pulsatility index. Patients were scheduled for varicocelectomy, with high ligation (Palomo) used in 40 patients (18, 45%, with left and 22, 55%, with bilateral varicocele), or an inguinal approach (Ivanissivich) with loupe magnification used in 42 (17, 40%, with left and 25, 60%, with bilateral varicocele). The men were reassessed at ?3 months after surgery and according to the improvement in seminal variables (expressed as a ?50% increase in total motile sperm count, TMSC), patients were further categorised into 'improved' or 'unimproved'. Binary logistic regression analysis was used to investigate the predictors of improvement. RESULTS: Before surgery the ASAs were positive in 17 men (21%). There was no significant difference between the right and left sides in intratesticular haemodynamics. The TMSC was improved in 52 (63%) patients who had a significant improvement in the haemodynamic variables. Intratesticular haemodynamics, serum FSH and testosterone levels differed significantly between the improved and unimproved patients. Positivity for ASAs, the surgical approach and laterality of the varicocele were not significantly different, although the ASA-positive cases were characterised by a significant decrease in motility. Logistic regression analysis showed that the EDV, PSV, FSH, testosterone level and bilateral testicular volume (BTV) were significant predictors of improvement. CONCLUSION: Positivity for ASAs is not a predictor of the outcome after varicocelectomy but affects only the motile fraction in positive cases, despite the improvement in other seminal variables and testicular haemodynamics, and regardless of the surgical approach. The EDV, PSV, FSH, testosterone and BTV were significant predictors of a successful outcome. PMID- 26019970 TI - The incidence, causes, mechanism, risk factors, classification, and diagnosis of pelvic fracture urethral injury. AB - BACKGROUND: Pelvic fracture urethral injury (PFUI) is an uncommon but potentially devastating result of pelvic fracture. It ranges in severity based on the cause and the mechanism of injury. METHODS: We reviewed previous reports to identify the incidence, causes, mechanisms of injury and risk factors of PFUI. In addition, we reviewed the current classification systems and diagnostic methods that have been described to assess the severity of PFUI, to identify optimal management strategies and evaluate outcomes. RESULTS: PFUI occurs more commonly in men, but is more likely to be severe in children. The most common cause is motor vehicle collisions, and the mechanism is typically a ligament rupture at the attachment to the urethra. There is no reliable classification system to differentiate partial and complete PFUI. Retrograde urethrography is the standard imaging method but it has its limitations. CONCLUSIONS: Despite many reports describing this injury, there is still a need to further clarify the incidence, aetiology and mechanism of injury to better determine optimal management strategies and evaluate outcomes. Consensus in the diagnosis of PFUI is lacking, and outcomes of primary realignment and the role of flexible cystoscopy as a diagnostic method are still to be determined. PMID- 26019971 TI - The management of the acute setting of pelvic fracture urethral injury (realignment vs. suprapubic cystostomy alone). AB - BACKGROUND: In patients with pelvic fracture urethral injury there are two options for management: First, to realign as an early primary realignment over a catheter; and second, to place a suprapubic tube with delayed urethroplasty of the inevitable stricture. METHODS: We reviewed previous reports from 1990 to the present, comparing early endoscopic realignment, early open realignment and suprapubic tube placement, to determine the rates of incontinence, erectile dysfunction and stricture formation. RESULTS: Twenty-nine articles were identified. The rates of erectile dysfunction, incontinence, and stricture formation, respectively, were: for early endoscopic realignment, 20.5%, 5.8% and 43.8%; for open realignment over a catheter, 16.7%, 4.7% and 48.9%; and for a suprapubic tube and delayed urethroplasty 13.7%, 5.0%, and 89.0%. A one-way anova showed no difference in the mean rate of erectile dysfunction (P = 0.53) or incontinence (P = 0.73), and only stricture formation was significantly different (P < 0.1). CONCLUSION: The rates of incontinence and erectile dysfunction are similar between the groups. Only the rate of stricture formation was higher in the suprapubic tube and delayed urethroplasty group. PMID- 26019972 TI - The case against primary endoscopic realignment of pelvic fracture urethral injuries. AB - OBJECTIVES: To review previous reports and present our experience on the outcomes after treating pelvic fracture urethral injuries (PFUIs) with primary endoscopic realignment (PER) vs. placing a suprapubic tube (SPT) with elective bulbomembranous anastomotic urethroplasty (BMAU). METHODS: We reviewed previous reports and identified articles that reported outcomes after PER vs. SPT and elective BMAU for patients who sustained PFUIs. We also present our institutional experience of treating patients who were referred after undergoing either form of treatment. RESULTS: The success rates for PER after PFUI are wide-ranging (11 86%), with variable definitions for a successful outcome. At our institution, for patients treated by SPT/BMAU, the mean time to a definitive resolution of stenosis was dramatically shorter (6 months, range 3-15) than for those treated with PER (122 months, range 4-574; P < 0.01). The vast majority of patients treated by PER required multiple endoscopic urethral interventions (median 4, range 1-36;P < 0.01) and/or had various other adverse events that were rare among the SPT/BMAU group (14/17, 82%, vs. 2/23, 9%;P < 0.05). CONCLUSION: While PER occasionally results in urethral patency with no need for further intervention, the risk of delay in definitive treatment and the potential for adverse events have led to a preference for SPT and elective BMAU at our institution. PMID- 26019973 TI - Simple perineal and elaborated perineal posterior urethroplasty. AB - A pelvic fracture urethral distraction defect (PFUDD) can present in varying lengths and degrees of complexity. In recent decades the repair of PFUDD has developed into a reliance on a perineal anastomotic approach for all but the most complex cases, which might still require an abdominal transpubic approach, or rarely a staged skin-inlay procedure. There is now controversy about the extent to which the perineal repair needs to be elaborated in individual patients. As originally described, the elaborated perineal approach comprises four steps that are used sequentially, as required, depending on the magnitude of the urethral defect. These steps are urethral mobilisation, corporal body separation, inferior wedge pubectomy and supra-crural urethral re-routing to the anastomosis. We present a review of the progressive repair, its reported use and outcomes and our recommendations for its continued use. PMID- 26019974 TI - The combined perineo-abdominal transpubic urethroplasty. AB - Research pertaining to transpubic urethral surgery is described. The operative technique of the perineo-abdominal transpubic approach for pelvic fracture urethral injury (PFUI) is reported in detail. Under all circumstances the operation should be started by a perineal exposure and liberal circumferential mobilisation of the bulbar urethra. The operation proceeds to an abdominal exposure only when a tension-free urethral anastomosis cannot be made from the perineal approach. An omental wrap of the urethral anastomosis is mandatory to guard against the surrounding fibrosis and callus formation. The operation might be indicated for PFUI with a long urethral gap when the urethral anastomosis cannot be made from the perineal approach, and in complex PFUI associated with an intra-abdominal complication. The combined perineo-abdominal transpubic procedure provides a wide and excellent exposure for an easy and neat bulboprostatic urethral anastomosis. Success rates are usually 98-100% and are sustained in the long term. PMID- 26019975 TI - Optimising the outcome after anastomotic posterior urethroplasty. AB - OBJECTIVES: To develop a plan that would optimise the outcome after an anastomotic repair of a pelvic fracture urethral injury (PFUI). METHODS: Data on the delayed repair of PFUI from reports in English were critically reviewed. The search criteria included reports by high-volume surgeons and those from tertiary centres of reconstructive urethral surgery. RESULTS: The delayed repair of a PFUI should not be attempted within 4-6 months of the initial trauma. A tension-free, scar-free and mucosa-to-mucosa urethral anastomosis is critically important for a successful outcome. Urethral defects shorter than a third of the bulbar urethral length can usually be repaired by a simple perineal operation, while longer defects usually need an elaborated perineal or perineo-abdominal transpubic procedure. The finest suture that provides adequate strength should always be used for a urethral anastomosis, generally 3/0 polyglactin 910 for adult patients and 4/0 for children. In transpubic urethroplasty, an omental wrapping of the intra-abdominal segment of the bulbar urethra and the site of anastomosis is mandatory. CONCLUSIONS: Anastomotic repair of a PFUI entails various surgical components, and the importance of each of these should not be underestimated. Careful attention to these surgical components is mandatory for a successful outcome after repair. PMID- 26019976 TI - The spectrum of pelvic fracture urethral injuries and posterior urethroplasty in an Italian high-volume centre, from 1980 to 2013. AB - OBJECTIVE: To describe the emergency and delayed treatment of patients with pelvic fracture urethral injuries (PFUI) presenting to an Italian high-volume centre. PATIENTS AND METHODS: In a retrospective, observational study we evaluated the spectrum of PFUI and posterior urethroplasty in an Italian high volume centre, from 1980 to 2013. Patients requiring emergency treatment for PFUI and delayed treatment for pelvic fracture urethral defects (PFUD) were included. Patients with incomplete clinical records were excluded from the study. Descriptive statistical methods were applied. RESULTS: In all, 159 male patients (median age 35 years) were included in the study. A traffic accident was the most frequent (42.8%) cause of PFUI, and accidents at work were reported as the cause of trauma in 34% of patients. Agricultural accidents decreased from 24.4% to 6.2% over the course of the survey. A suprapubic cystostomy was the most frequent (49%) emergency treatment in patients with PFUI. The use of surgical realignment decreased from 31.7% to 6.2%, and endoscopic realignment increased from 9.7% to 35.3%. A bulbo-prostatic anastomosis was the most frequent (62.9%) delayed treatment in patients with PFUD. The use of the Badenoch pull-through decreased from 19.5% to 2.6%, and endoscopic holmium laser urethrotomy increased from 4.9% to 32.7%. CONCLUSIONS: The spectrum of PFUI and subsequent treatment of PFUD has changed greatly over the last 10 years at our centre. These changes involved patient age, aetiology, emergency and delayed treatments, and were found to be related to changes in the economy and lifestyle of the Italian patients. PMID- 26019977 TI - Pelvic-fracture urethral injury in children. AB - OBJECTIVE: To review paediatric posterior urethral injuries and the current potential management options; because urethral injury due to pelvic fracture in children is rare and has a low incidence, the management of this type of trauma and its complications remains controversial. METHODS: We reviewed previous reports identified by searching the PubMed Medline electronic database for clinically relevant articles published in the past 25 years. The search was limited to the keywords 'pediatric', 'pelvic fracture', 'urethral injury', 'stricture', 'trauma' and 'reconstruction'. RESULTS: Most paediatric urethral injuries are a result of pelvic fractures after high-impact blunt trauma. After the diagnosis, immediate bladder drainage via a suprapubic cystotomy, or urethral realignment, are the initial management options, except for a possible immediate primary repair in girls. The common complications of pelvic fracture-associated urethral injury include urethral stricture formation, incontinence and erectile dysfunction. Excellent results can be achieved with delayed urethroplasty for pelvic fracture-associated urethral injuries. CONCLUSION: Traumatic injury to the paediatric urethra is rare and calls for an immediate diagnosis and management. These devastating injuries have a high complication rate and therefore a close follow-up is warranted to assure adequate delayed repair by a reconstructive urologist. PMID- 26019978 TI - Complex posterior urethral injury. AB - OBJECTIVE: To assess treatment strategies for seven different scenarios for treating complex pelvic fracture urethral injury (PFUI), categorised as repeat surgery for PFUI, ischaemic bulbar urethral necrosis (BUN), repair in boys and girls aged ?12 years, in patients with a recto-urethral fistula, or bladder neck incontinence, or with a double block at the bulbomembranous urethra and bladder neck/prostate region. PATIENTS AND METHODS: We retrospectively reviewed the success rates and surgical procedures of these seven complex scenarios in the repair of PFUI at our institution from 2000 to 2013. RESULTS: In all, >550 PFUI procedures were performed at our centre, and 308 of these patients were classified as having a complex PFUI, with 225 patients available for follow-up. The overall success rates were 81% and 77% for primary and repeat procedures respectively. The overall success rate of those with BUN was 76%, using various methods of novel surgical techniques. Boys aged ?12 years with PFUI required a transpubic/abdominal approach 31% of the time, compared to 9% in adults. Young girls with PFUI also required a transpubic/abdominal urethroplasty, with a success rate of 66%. In patients with a recto-urethral fistula the success rate was 90% with attention to proper surgical principles, including a three-stage procedure and appropriate interposition. The treatment of bladder neck incontinence associated with the tear-drop deformity gave a continence rate of 66%. Children with a double block at the bulbomembranous urethra and at the bladder neck-prostate junction were all continent after a one-stage transpubic/abdominal procedure. CONCLUSION: An understanding of complex pelvic fractures and their appropriate management can provide successful outcomes. PMID- 26019979 TI - Evaluation of the outcomes after posterior urethroplasty. AB - Posterior urethral injury is a clinically significant complication of pelvic fractures. The management is complicated by the associated organ injuries, distortion of the pelvic anatomy and the ensuing fibrosis that occurs with urethral injury. We report a review of the outcomes after posterior urethroplasty in the context of pelvic fracture urethral injury. PMID- 26019980 TI - Unsuccessful outcomes after posterior urethroplasty. AB - Posterior urethroplasty is the most common strategy for the treatment of post traumatic urethral injuries. Especially in younger patients, post-traumatic injuries are a common reason for urethral strictures caused by road traffic accidents, with pelvic fracture or direct trauma to the perineum. In many cases early endoscopic realignment is the first attempt to restore the junction between proximal and distal urethra, but in some cases primary realignment is not possible or not enough to treat the urethral injury. In these cases suprapubic cystostomy alone and delayed repair by stricture excision and posterior urethroplasty is an alternative procedure to minimise the risk of stricture recurrence. PMID- 26019981 TI - The mechanism of continence after posterior urethroplasty. AB - The standard of care after a pelvic fracture urethral injury is a repair via a one-stage anastomotic posterior urethroplasty using a step-wise perineal approach. The initial injury, immediate postoperative management, and surgical repair can all affect urinary continence in these patients. Proximal continence mechanisms, particularly the bladder neck, are particularly important in maintaining urinary continence in these patients. Patients with bladder neck dysfunction should be counselled about the greater risk of urinary incontinence. PMID- 26019982 TI - Bladder neck incompetence at posterior urethroplasty. AB - The finding of an incompetent bladder neck (BN) at the time of posterior urethroplasty will necessarily exacerbate the already difficult situation. In such cases the aim of the treatment is not only to restore urethral continuity by end-to-end urethral anastomosis, but also to restore the function of the BN to maintain urinary continence. Fortunately, the incidence of incompetence of the BN at posterior urethroplasty is uncommon, usually ~4.5%. It seems that pelvic fracture-related BN injuries, in contrast to urethral injuries which result from a shearing force, are due to direct injury by the sharp edge of the fractured and displaced pubic bone. The risk of injuries to the BN is greater in children, in patients with a fracture involving both superior and inferior pubic rami on the same side, and in those managed initially by primary realignment. An incompetent BN is suspected by finding an open rectangular BN on cystography, and a fixedly open BN on suprapubic cystoscopy. An incompetent BN can be treated either subsequent to or concomitant with the urethral repair, according to whether a perineal or a perineo-abdominal urethroplasty is used, respectively. Several options have been reported to treat pelvic fracture-related BN incompetence, including reconstructing the BN, forming a new sphincter by tubularisation of a rectangular flap of the anterior bladder wall, and mechanical occlusion by an artificial sphincter or collagen injection. Reconstruction of the BN by the Young Dees-Leadbetter** procedure probably provides the most successful results. PMID- 26019983 TI - The incidence of erectile dysfunction after pelvic fracture urethral injury: A systematic review and meta-analysis. AB - BACKGROUND: Pelvic fracture urethral injury (PFUI) is associated with a high risk of erectile dysfunction (ED). The effect of the type of posterior urethral disruption repair on erectile function has not been clearly established. We systematically reviewed and conducted a meta-analysis of the proportion of patients with ED at (i) baseline after pelvic fracture with PFUI, (ii) after immediate primary realignment, and (iii) after delayed urethroplasty. METHODS: Using search terms for primary realignment or urethroplasty and urethral disruption, we systematically reviewed PubMed and EMBASE. A meta-analysis of the proportion of patients with ED was conducted assuming a random-effects model. RESULTS: Of 734 articles found, 24 met the inclusion criteria. The estimate of the proportion (95% confidence interval) of patients with ED after (i) PFUI was 34 (25-45)%, after (ii) immediate primary realignment was 16 (8-26)%, and after (iii) delayed urethroplasty was an additional 3 (2-5)% more than the 34% after pelvic fracture in this cohort. CONCLUSIONS: After pelvic fracture, 34% of patients had ED. After primary endoscopic alignment, patients had a lower reported rate of ED (16%). Delayed urethroplasty conferred an additional 3% risk above the 34% associated with PFUI alone, with 37% of patients having de novo ED. The difference in de novo ED after primary endoscopic alignment vs. delayed urethroplasty is probably due to reporting differences in ED and/or patients with less severe injury undergoing primary realignment. PMID- 26019984 TI - Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia. AB - BACKGROUND: Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm classified in the myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category. Molecular abnormalities are reported in about 90 % of patients with CMML. ASXL1 and SETBP1 mutations, but not TET2 or SFRS2 mutations are reported to be associated with prognosis. METHODS: We studied frequency of TET2, SRSF2, ASXL1 and SETBP1 mutations in 145 patients with CMML using Sanger sequencing, and determined the prognostic factors for OS. We also identified the predictive value of ASXL1 mutations (frameshift and nonsense mutations) through comparing the Mayo Prognostic Model with the Mayo Molecular Model. RESULTS: Forty-seven (32 %) had a mutation in TET2, 42 (29 %), a mutation in SRSF2, 65 (45 %), a mutation (nonsense and frame-shift) in ASXL1 and 26 (18 %), a mutation in SETBP1. Significant variables in multivariable analysis of survival included ASXL1 (HR = 1.99 [1.20 3.28]; P = 0.007), hemoglobin <100 g/L (HR = 2.42 [1.40-4.19]; P = 0.002) and blood immature myeloid cells (IMCs) (HR = 2.08 [1.25-3.46]; P = 0.005). When our patients were analyzed using the Mayo Prognostic Model median OS were not reached, 26 months and 15 months (P = 0.014). An analysis using the Mayo Molecular Model identified 4 cohorts with median OS of not reached, 70 months, 26 months and 11 months (P < 0.001). Data fitting using our patients suggest the Molecular Mayo Model has significantly higher survival predictive power compared with Mayo Prognostic Model (P < 0.001, -2 log-likelihood ratios of 538.070 and 552.260). CONCLUSIONS: There were high frequencies of mutations in TET2, SRSF2, ASXL1 and SETBP1 in patients with CMML. With the addition of ASXL1 frameshift and nonsense mutations, the Mayo Molecular Model fitted better than Mayo Prognostic Model of our patients. PMID- 26019985 TI - Translational research education and training needs in Hawai'i. AB - The purpose of this needs assessment was to identify the translational research education and training needs of researchers and administrators working in Hawai'i's communities and to use the finding to develop an education and training plan. The assessment was led by a community advisory board with members from community health centers, social agencies, hospitals, and academia on O'ahu. The survey, developed with input of the community advisory board, was sent to 94 administrators and researchers involved or affiliated with research being conducted in Hawai'i. Forty-one respondents (43%) completed the survey. Respondents wanted education and training in research processes, specific research-related skills, and facilitating interactions between community and academic researchers. Sixty-one percent were interested in training related to community-engaged research and yearly seminars on "collaborative mentoring." Popular topics of interest were related to data monitoring, networking with different cultural groups, statistics, and human subjects review. A majority of respondents wanted to attend workshops, seminars, and presentations rather than take a class. Approximately 50% of the respondents wanted to gain information through on-line training. Findings guided the development of a translational research education and training plan for the University of Hawai'i National Institute of Health (NIH) Research Centers in Minority Institutions Multidisciplinary and Translational Research Infrastructure Expansion (RMATRIX) grant. PMID- 26019986 TI - Medicare reimbursement to ophthalmologists: a comparison of Hawai'i to other states. AB - When Medicare publically released data on payments made to specific physicians in April of 2014, it quickly became apparent that a large portion of 2012 Medicare reimbursements went to ophthalmologists. Part of the reason for this unusually high level of reimbursement was thought to be the cost of injectable drugs such as ranibizumab (brand name Lucentis). This study was designed to compare Hawai'i ophthalmologists' Medicare reimbursements with those of other states. In 2012, Medicare payment to ophthalmologists in Hawai'i was $18.2 million. Hawai'i ranked third in the nation in terms of percentage of total reimbursement going to ophthalmologists at 11.1% and 34th (8.2%) in percentage of ophthalmologist reimbursements going to injectable biological products. Hence, the high percentage of reimbursement going to ophthalmologists in Hawai'i is unlikely due to high use of injectable medications. Further research, based on a more detailed analysis of clinical data, is needed to determine how to slow the growth of health care costs while promoting high-value, effective care, not only for ophthalmic services but in other high-cost areas as well. PMID- 26019987 TI - Emergence of Raoultella ornithinolytica on O'ahu: a case of community-acquired R. ornithinolytica urinary tract infection. AB - Human infection with Raoultella ornithinolytica is rare, with only ten cases having been reported previously. This case report describes a local patient diagnosed with community-acquired R. ornithinolytica urinary tract infection in 2014. PMID- 26019988 TI - Medical school hotline: tropical cyclone Haiyan/Yolanda medical relief mission: perspectives of John A. Burns School of Medicine 2nd year medical students. PMID- 26019989 TI - Insights in public health: a tale of two polities: health in Independent and American Samoa. AB - Independent and American Samoa have a shared cultural, genetic, ethnolinguistic, and historical background but have been politically separated since 1899. In this essay, we examine the health of these two polities and identify two key health patterns that have emerged even as American Samoa has achieved a higher per capita income than Independent Samoa. Whereas the gender gap in life expectancy at birth has narrowed in Independent Samoa, this gap has not narrowed in American Samoa and its male life expectancy now lags behind that of Independent Samoa. Neonatal mortality rates in American Samoa are slightly higher than in Independent Samoa. These patterns may be linked to the higher rates of obesity and urbanization observed in American Samoa compared to Independent Samoa, as well as the differing political and institutional arrangements of the two polities. Limited data remains a persistent challenge to conducting analysis of public health in the Pacific islands, particularly in American Samoa. PMID- 26019990 TI - The Daniel K. Inouye College of Pharmacy Scripts: pharmacy school graduates continue training in postgraduate residency programs. AB - Residency training is designed to provide recent pharmacy school graduates who have the profession's terminal Doctor of Pharmacy (PharmD) degree with accelerated growth beyond entry-level professional competence. Placement into residency programs is highly competitive through an application and match process. These programs provide additional training in patient-centered care with advancement of skills in clinical judgment, pharmacy operations, clinical research, project management, and leadership. Approximately 20% of a pharmacy graduating class will apply for a residency. With increasing numbers of pharmacy schools across the country, the availability of residency programs is falling behind applicants. The establishment of the Daniel K. Inouye College of Pharmacy (DKICP) has addressed the shortage of pharmacists within the state. In recent years, resident positions in Hawai'i have doubled to a total of ten first year residency (PGY1) and two second year (PGY2) specialty residencies. Given the limited availability of positions in Hawai'i, graduates continue to return to the continental US to seek positions, thus increasing the likelihood of them not returning to practice in Hawai'i. Establishing residency programs is essential to elevate the level of pharmacy practice toward innovation and adherence to best practices, academia/teaching and scholarly research. This descriptive paper will detail the general components and types of pharmacy practice residency, the unique components of the Hawai'i programs, the career placement of Hawai'i's programs graduates and future challenges. PMID- 26019992 TI - Replicability of sight word training and phonics training in poor readers: a randomised controlled trial. AB - Given the importance of effective treatments for children with reading impairment, paired with growing concern about the lack of scientific replication in psychological science, the aim of this study was to replicate a quasi randomised trial of sight word and phonics training using a randomised controlled trial (RCT) design. One group of poor readers (N = 41) did 8 weeks of phonics training (i.e., phonological decoding) and then 8 weeks of sight word training (i.e., whole-word recognition). A second group did the reverse order of training. Sight word and phonics training each had a large and significant valid treatment effect on trained irregular words and word reading fluency. In addition, combined sight word and phonics training had a moderate and significant valid treatment effect on nonword reading accuracy and fluency. These findings demonstrate the reliability of both phonics and sight word training in treating poor readers in an era where the importance of scientific reliability is under close scrutiny. PMID- 26019993 TI - Synthetic neuronal datasets for benchmarking directed functional connectivity metrics. AB - Background. Datasets consisting of synthetic neural data generated with quantifiable and controlled parameters are a valuable asset in the process of testing and validating directed functional connectivity metrics. Considering the recent debate in the neuroimaging community concerning the use of these metrics for fMRI data, synthetic datasets that emulate the BOLD signal dynamics have played a central role by supporting claims that argue in favor or against certain choices. Generative models often used in studies that simulate neuronal activity, with the aim of gaining insight into specific brain regions and functions, have different requirements from the generative models for benchmarking datasets. Even though the latter must be realistic, there is a tradeoff between realism and computational demand that needs to be contemplated and simulations that efficiently mimic the real behavior of single neurons or neuronal populations are preferred, instead of more cumbersome and marginally precise ones. Methods. This work explores how simple generative models are able to produce neuronal datasets, for benchmarking purposes, that reflect the simulated effective connectivity and, how these can be used to obtain synthetic recordings of EEG and fMRI BOLD signals. The generative models covered here are AR processes, neural mass models consisting of linear and nonlinear stochastic differential equations and populations with thousands of spiking units. Forward models for EEG consist in the simple three-shell head model while the fMRI BOLD signal is modeled with the Balloon-Windkessel model or by convolution with a hemodynamic response function. Results. The simulated datasets are tested for causality with the original spectral formulation for Granger causality. Modeled effective connectivity can be detected in the generated data for varying connection strengths and interaction delays. Discussion. All generative models produce synthetic neuronal data with detectable causal effects although the relation between modeled and detected causality varies and less biophysically realistic models offer more control in causal relations such as modeled strength and frequency location. PMID- 26019994 TI - Continued Dispensing: what medications do patients believe should be available? AB - Background. Continued Dispensing (CD) is a new medication supply method for certain medications in Australia. It aims to prevent treatment interruption as a result of patients' inability to obtain a new valid prescription. The only currently eligible patients for this service are statin and/or oral contraceptives users who have been using these medications for 6 months or more, have not utilized the CD method during the last 12 months, and cannot obtain an immediate appointment with the prescriber in order to get a new prescription. This study aimed to investigate patients' attitudes towards potential extension and expansion of this medication supply method. Methods. A randomly selected 301 users of these medications from all Australian States were recruited using Computer Assisted Telephone Interview (CATI). Result. The response rate was 79%. The majority of the participants (73.3%) did not agree with current restriction on CD utilization frequency. They also supported, to varying degrees, inclusion of all the proposed medications (support ranged from 44.2-78.4%). In this regard, participants who suffered from a specific disease did not differ significantly from those without the disease except in case of patients with depression (p = 0.001). Conclusions. Participants of this study strongly supported both CD extension and expansion. A future critical review of the current version of CD is highly recommended in order to enhance CD capability to achieve its goals. PMID- 26019995 TI - Seasonal trends in the condition of nesting females of a solitary bee: wing wear, lipid content, and oocyte size. AB - During the nesting season, adult females of the solitary bee Megachile rotundata (F.) face considerable physical and energy demands that could include increasing wear and tear on their bodies and decreasing lipid reserves. Consequently, their reproductive performance may be affected not only by extrinsic factors (e.g., weather and floral resource availability), but intrinsic changes in their own bodies. Because of the potential fitness effects of seasonal changes in body condition, our objectives were to determine how wing wear, lipid reserves, and oocyte sizes vary during nesting seasons, beginning when females emerge as adults. As nesting progressed, females in two populations experienced a steady increase in wing wear, which is known to reduce foraging efficiency and increase risk of mortality in other bees. Soon after emergence, females exhibited sharp declines in lipid content which remained low for the remainder of the season. Newly-emerged females ingested pollen, an activity known to be correlated with the initiation of egg maturation in this species. Additionally, the early summer drop in lipid stores was correlated with an increase in the size of the oocytes carried. However, by ~6 weeks after emergence, oocytes began to decrease in length and volume, perhaps due to nutrient deficiencies related to loss of stored lipids. Our results suggest management of M. rotundata should include rearing bees at temperatures that maximize stored lipid reserves in adults and timing bee release so that significant pollen resources are available for both adults and offspring. PMID- 26019996 TI - Thylacinus (Marsupialia: Thylacinidae) from the Mio-Pliocene boundary and the diversity of Late Neogene thylacinids in Australia. AB - Thylacinus yorkellus is described as a new, moderately small-bodied species of thylacinid from the latest Miocene or, more likely, earliest Pliocene of South Australia. The new species can be diagnosed by the autapomorphic presence a strongly developed precingulid that terminates in a cuspidule on the anterobuccal face of the paraconid of the lower molars and a tiny basal anterior cuspidule on P 2, P 3 and the lower molars. It is found by cladistic analysis to be the sister species of the recently extinct Th. cynocephalus and distinct from the approximately coeval Th. megiriani from the Northern Territory. New dentary material is described and referred to Th. megiriani. These add character data and allow this species to be re-diagnosed based on autapomorphic character traits. Each of the three known late Miocene to early Pliocene Thylacinus species (Th. potens, Th. megiriani and Th. yorkellus) suggest that, instead of declining, there was a modest radiation of Thylacinus in the late Miocene. PMID- 26019997 TI - GFVO: the Genomic Feature and Variation Ontology. AB - Falling costs in genomic laboratory experiments have led to a steady increase of genomic feature and variation data. Multiple genomic data formats exist for sharing these data, and whilst they are similar, they are addressing slightly different data viewpoints and are consequently not fully compatible with each other. The fragmentation of data format specifications makes it hard to integrate and interpret data for further analysis with information from multiple data providers. As a solution, a new ontology is presented here for annotating and representing genomic feature and variation dataset contents. The Genomic Feature and Variation Ontology (GFVO) specifically addresses genomic data as it is regularly shared using the GFF3 (incl. FASTA), GTF, GVF and VCF file formats. GFVO simplifies data integration and enables linking of genomic annotations across datasets through common semantics of genomic types and relations. Availability and implementation. The latest stable release of the ontology is available via its base URI; previous and development versions are available at the ontology's GitHub repository: https://github.com/BioInterchange/Ontologies; versions of the ontology are indexed through BioPortal (without external class /property-equivalences due to BioPortal release 4.10 limitations); examples and reference documentation is provided on a separate web-page: http://www.biointerchange.org/ontologies.html. GFVO version 1.0.2 is licensed under the CC0 1.0 Universal license (https://creativecommons.org/publicdomain/zero/1.0) and therefore de facto within the public domain; the ontology can be appropriated without attribution for commercial and non-commercial use. PMID- 26019998 TI - Analgesic effects of lappaconitine in leukemia bone pain in a mouse model. AB - Bone pain is a common and severe symptom in cancer patients. The present study employed a mouse model of leukemia bone pain by injection K562 cells into tibia of mouse to evaluate the analgesic effects of lappacontine. Our results showed that the lappaconitine treatment at day 15, 17 and 19 could effectively reduce the spontaneous pain scoring values, restore reduced degree in the inclined-plate test induced by injection of K562 cells, as well as restore paw mechanical withdrawal threshold and paw withdrawal thermal latency induced by injection of K562 cells to the normal levels. Additionally, the molecular mechanisms of lappaconitine's analgesic effects may be related to affect the expression levels of endogenous opioid system genes (POMC, PENK and MOR), as well as apoptosis related genes (Xiap, Smac, Bim, NF-kappaB and p53). Our present results indicated that lappaconitine may become a new analgesic agent for leukemia bone pain management. PMID- 26019999 TI - Patient understanding of radiation risk from medical computed tomography-A comparison of Hispanic vs. non-Hispanic emergency department populations. AB - Background. Cultural differences and language barriers may adversely impact patients with respect to understanding the risks/benefits of medical testing. Objective. We hypothesized that there would be no difference in Hispanic vs. non Hispanic patients' knowledge of radiation risk that results from CT of the abdomen/pelvis (CTAP). Methods. We enrolled a convenience sample of adults at an inner-city emergency department (ED). Patients provided written answers to rate agreement on a 10-point scale for two correct statements comparing radiation exposure equality between: CTAP and 5 years of background radiation (question 1); CTAP and 200 chest x-rays (question 3). Patients also rated their agreement that multiple CT scans increase the lifetime cancer risk (question 2). Scores of >8 were considered good knowledge. Multivariate logistic regression analyses were performed to estimate the independent effect of the Hispanic variable. Results. 600 patients in the study group; 63% Hispanic, mean age 39.2 +/- 13.9 years. Hispanics and non-Hispanics whites were similar with respect to good knowledge level answers to question 1 (17.3 vs. 15.1%; OR = 1.2; 95% CI [0.74-2.0]), question 2 (31.2 vs. 39.3%; OR = 0.76; 95% CI [0.54-1.1]), and question 3 (15.2 vs. 16.5%; OR = 1.1; 95% CI [0.66-1.8]). Compared to patients who earned <20,000, patients with income >40,000 were more likely to answer question 2 with good knowledge (OR = 1.96; 95% CI [1.2-3.1]). Conclusion. The study group's overall knowledge of radiation risk was poor, but we did not find significant differences between Hispanic vs. non-Hispanic patients. PMID- 26020000 TI - Blood serum and BSA, but neither red blood cells nor hemoglobin can support vitellogenesis and egg production in the dengue vector Aedes aegypti. AB - Aedes aegypti is the major vector of dengue, yellow fever and chikungunya viruses that put millions of people in endemic countries at risk. Mass rearing of this mosquito is crucial for strategies that use modified insects to reduce vector populations and transmission of pathogens, such as sterile insect technique or population replacement. A major problem for vector mosquito mass rearing is the requirement of vertebrate blood for egg production since it poses significant costs as well as potential health hazards. Also, regulations for human and animal use as blood source can pose a significant obstacle. A completely artificial diet that supports egg production in vector mosquitoes can solve this problem. In this study, we compared different blood fractions, serum and red blood cells, as dietary protein sources for mosquito egg production. We also tested artificial diets made from commercially available blood proteins (bovine serum albumin (BSA) and hemoglobin). We found that Ae. aegypti performed vitellogenesis and produced eggs when given whole bovine blood, serum, or an artificial diet containing BSA. Conversely, egg production was impaired after feeding of the red blood cell fraction or an artificial diet containing only hemoglobin. We also found that egg viability of serum-fed mosquitoes were comparable to that of whole blood and an iron supplemented BSA meal produced more viable eggs than a meal containing BSA alone. Our results indicate that serum proteins, not hemoglobin, may replace vertebrate blood in artificial diets for mass mosquito rearing. PMID- 26020001 TI - New insights into the lifestyle of Allosaurus (Dinosauria: Theropoda) based on another specimen with multiple pathologies. AB - Adult large-bodied theropods are often found with numerous pathologies. A large, almost complete, probably adult Allosaurus specimen from the Howe Stephens Quarry, Morrison Formation (Late Kimmeridgian-Early Tithonian), Wyoming, exhibits multiple pathologies. Pathologic bones include the left dentary, two cervical vertebrae, one cervical and several dorsal ribs, the left scapula, the left humerus, the right ischium, and two left pedal phalanges. These pathologies can be classified as follows: the fifth cervical vertebra, the scapula, several ribs and the ischium are probably traumatic, and a callus on the shaft of the left pedal phalanx II-2 is probably traumatic-infectious. Traumatically fractured elements exposed to frequent movement (e.g., the scapula and the ribs) show a tendency to develop pseudarthroses instead of a callus. The pathologies in the lower jaw and a reduced extensor tubercle of the left pedal phalanx II-2 are most likely traumatic or developmental in origin. The pathologies on the fourth cervical are most likely developmental in origin or idiopathic, that on the left humerus could be traumatic, developmental, infectious or idiopathic, whereas the left pedal phalanx IV-1 is classified as idiopathic. With exception of the ischium, all as traumatic/traumatic-infectious classified pathologic elements show unambiguous evidences of healing, indicating that the respective pathologies did not cause the death of this individual. Alignment of the scapula and rib pathologies from the left side suggests that all may have been caused by a single traumatic event. The ischial fracture may have been fatal. The occurrence of multiple lesions interpreted as traumatic pathologies again underlines that large bodied theropods experienced frequent injuries during life, indicating an active predatory lifestyle, and their survival perhaps supports a gregarious behavior for Allosaurus. Alternatively, the frequent survival of traumatic events could be also related to the presence of non-endothermic metabolic rates that allow survival based on sporadic food consumption or scavenging behavior. Signs of pathologies consistent with infections are scarce and locally restricted, indicating a successful prevention of the spread of pathogens, as it is the case in extant reptiles (including birds). PMID- 26020002 TI - Measures of skin conductance and heart rate in alcoholic men and women during memory performance. AB - We examined abnormalities in physiological responses to emotional stimuli associated with long-term chronic alcoholism. Skin conductance responses (SCR) and heart rate (HR) responses were measured in 32 abstinent alcoholic (ALC) and 30 healthy nonalcoholic (NC) men and women undergoing an emotional memory task in an MRI scanner. The task required participants to remember the identity of two emotionally-valenced faces presented at the onset of each trial during functional magnetic resonance imaging (fMRI) scanning. After viewing the faces, participants saw a distractor image (an alcoholic beverage, nonalcoholic beverage, or scrambled image) followed by a single probe face. The task was to decide whether the probe face matched one of the two encoded faces. Skin conductance measurements (before and after the encoded faces, distractor, and probe) were obtained from electrodes on the index and middle fingers on the left hand. HR measurements (beats per minute before and after the encoded faces, distractor, and probe) were obtained by a pulse oximeter placed on the little finger on the left hand. We expected that, relative to NC participants, the ALC participants would show reduced SCR and HR responses to the face stimuli, and that we would identify greater reactivity to the alcoholic beverage stimuli than to the distractor stimuli unrelated to alcohol. While the beverage type did not differentiate the groups, the ALC group did have reduced skin conductance and HR responses to elements of the task, as compared to the NC group. PMID- 26020003 TI - The diversity of membrane transporters encoded in bacterial arsenic-resistance operons. AB - Transporter-facilitated arsenite extrusion is the major pathway of arsenic resistance within bacteria. So far only two types of membrane-bound transporter proteins, ArsB and ArsY (ACR3), have been well studied, although the arsenic transporters in bacteria display considerable diversity. Utilizing accumulated genome sequence data, we searched arsenic resistance (ars) operons in about 2,500 bacterial strains and located over 700 membrane-bound transporters which are encoded in these operons. Sequence analysis revealed at least five distinct transporter families, with ArsY being the most dominant, followed by ArsB, ArsP (a recently reported permease family), Major Facilitator protein Superfamily (MFS) and Major Intrinsic Protein (MIP). In addition, other types of transporters encoded in the ars operons were found, but in much lower frequencies. The diversity and evolutionary relationships of these transporters with regard to arsenic resistance will be discussed. PMID- 26020004 TI - Calcium affinity of human alpha-actinin 1. AB - Due to alternative splicing, the human ACTN1 gene codes for three different transcripts of alpha-actinin; one isoform that is expressed only in the brain and two with a more general expression pattern. The sequence difference is located to the C-terminal domains and the EF-hand motifs. Therefore, any functional or structural distinction should involve this part of the protein. To investigate this further, the calcium affinities of these three isoforms of alpha-actinin 1 have been determined by isothermal calorimetry. PMID- 26020005 TI - Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease? AB - Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat model to serve as an animal model for PD. Commercially available BAC transgenic rats expressing human LRRK2 with the familial PD mutation, R1441G, and their wild-type siblings were tested for deficits in motor function, sensorimotor gating, and higher cognitive function reminiscent of PD through the ages of 3, 6, 9 and 12 months. At 12 months of age, rats were exposed to intraperitoneal injections of the environmental toxin Paraquat or saline. Our results indicate that LRRK2 (R1441G) transgenic rats do not show signs of neurodegeneration and do not develop significant motor or cognitive deficits until the age of 16 months. In addition, LRRK2 (R1441G) transgenic rats did not show increased vulnerability to sub-toxic doses of Paraquat. Gene expression studies indicate that despite genomic presence and initial expression of the transgene, its expression was greatly reduced in our aged rats. We conclude that the transgenic LRRK2 (R1441G) rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models. PMID- 26020006 TI - Male convict cichlid 11-ketotestosterone levels throughout the reproductive cycle: an exploratory profile study in laboratory and field populations. AB - The convict cichlid (Amatitlania nigrofasciata) has been extensively examined in relation to many behavioral topics, such as courtship, pair-bonding, bi-parental care, and territoriality. Recently, this model species has been utilized in studies on genetics, endocrinology, and neuroanatomy, with an ultimate goal of connecting behavior with its underlying mechanisms. The goal of this study was two-fold: (1) profile the circulating levels of plasma 11KT in the male convict cichlid at multiple points during the reproductive cycle and (2) generally compare the hormonal profiles of the widely used laboratory populations and those of a free-living population in the streams of Costa Rica. The results of the field experiment showed that male convict cichlids had higher levels of circulating 11KT during courtship and lower during the parental care and non breeding phases. The profile of the laboratory population was similar to the profile of the free-living individuals, with significantly higher levels of 11KT occurring during courtship than during parental care, though the level of 11KT during non-breeding phase was elevated in the laboratory. The high levels of 11KT during courtship and low levels of 11KT during parental care found in both the field and the laboratory is similar to what has been reported in other species of teleosts, and may suggest an important function of 11KT in the expression of courtship behavior and the subsequent onset of parental behaviors in this model species. PMID- 26020007 TI - The unnatural history of Kane'ohe Bay: coral reef resilience in the face of centuries of anthropogenic impacts. AB - Kane'ohe Bay, which is located on the on the NE coast of O'ahu, Hawai'i, represents one of the most intensively studied estuarine coral reef ecosystems in the world. Despite a long history of anthropogenic disturbance, from early settlement to post European contact, the coral reef ecosystem of Kane'ohe Bay appears to be in better condition in comparison to other reefs around the world. The island of Moku o Lo'e (Coconut Island) in the southern region of the bay became home to the Hawai'i Institute of Marine Biology in 1947, where researchers have since documented the various aspects of the unique physical, chemical, and biological features of this coral reef ecosystem. The first human contact by voyaging Polynesians occurred at least 700 years ago. By A.D. 1250 Polynesians voyagers had settled inhabitable islands in the region which led to development of an intensive agricultural, fish pond and ocean resource system that supported a large human population. Anthropogenic disturbance initially involved clearing of land for agriculture, intentional or accidental introduction of alien species, modification of streams to supply water for taro culture, and construction of massive shoreline fish pond enclosures and extensive terraces in the valleys that were used for taro culture. The arrival by the first Europeans in 1778 led to further introductions of plants and animals that radically changed the landscape. Subsequent development of a plantation agricultural system led to increased human immigration, population growth and an end to traditional land and water management practices. The reefs were devastated by extensive dredge and fill operations as well as rapid growth of human population, which led to extensive urbanization of the watershed. By the 1960's the bay was severely impacted by increased sewage discharge along with increased sedimentation due to improper grading practices and stream channelization, resulting in extensive loss of coral cover. The reefs of Kane'ohe Bay developed under estuarine conditions and thus have been subjected to multiple natural stresses. These include storm floods, a more extreme temperature range than more oceanic reefs, high rates of sedimentation, and exposure at extreme low tides. Deposition and degradation of organic materials carried into the bay from the watershed results in low pH conditions such that according to some ocean acidification projections the rich coral reefs in the bay should not exist. Increased global temperature due to anthropogenic fossil fuel emmisions is now impacting these reefs with the first "bleaching event" in 1996 and a second more severe event in 2014. The reefs of Kane'ohe Bay have developed and persist under rather severe natural and anthropogenic perturbations. To date, these reefs have proved to be very resilient once the stressor has been removed. A major question remains to be answered concerning the limits of Kane'ohe Bay reef resilience in the face of global climate change. PMID- 26020008 TI - Calibrating abundance indices with population size estimators of red back salamanders (Plethodon cinereus) in a New England forest. AB - Herpetologists and conservation biologists frequently use convenient and cost effective, but less accurate, abundance indices (e.g., number of individuals collected under artificial cover boards or during natural objects surveys) in lieu of more accurate, but costly and destructive, population size estimators to detect and monitor size, state, and trends of amphibian populations. Although there are advantages and disadvantages to each approach, reliable use of abundance indices requires that they be calibrated with accurate population estimators. Such calibrations, however, are rare. The red back salamander, Plethodon cinereus, is an ecologically useful indicator species of forest dynamics, and accurate calibration of indices of salamander abundance could increase the reliability of abundance indices used in monitoring programs. We calibrated abundance indices derived from surveys of P. cinereus under artificial cover boards or natural objects with a more accurate estimator of their population size in a New England forest. Average densities/m(2) and capture probabilities of P. cinereus under natural objects or cover boards in independent, replicate sites at the Harvard Forest (Petersham, Massachusetts, USA) were similar in stands dominated by Tsuga canadensis (eastern hemlock) and deciduous hardwood species (predominantly Quercus rubra [red oak] and Acer rubrum [red maple]). The abundance index based on salamanders surveyed under natural objects was significantly associated with density estimates of P. cinereus derived from depletion (removal) surveys, but underestimated true density by 50%. In contrast, the abundance index based on cover-board surveys overestimated true density by a factor of 8 and the association between the cover-board index and the density estimates was not statistically significant. We conclude that when calibrated and used appropriately, some abundance indices may provide cost effective and reliable measures of P. cinereus abundance that could be used in conservation assessments and long-term monitoring at Harvard Forest and other northeastern USA forests. PMID- 26020009 TI - Comparison of methods used to estimate coral cover in the Hawaiian Islands. AB - Nine coral survey methods were compared at ten sites in various reef habitats with different levels of coral cover in Kane'ohe Bay, O'ahu, Hawai'i. Mean estimated coverage at the different sites ranged from less than 10% cover to greater than 90% cover. The methods evaluated include line transects, various visual and photographic belt transects, video transects and visual estimates. At each site 25 m transect lines were laid out and secured. Observers skilled in each method measured coral cover at each site. The time required to run each transect, time required to process data and time to record the results were documented. Cost of hardware and software for each method was also tabulated. Results of this investigation indicate that all of the methods used provide a good first estimate of coral cover on a reef. However, there were differences between the methods in detecting the number of coral species. For example, the classic "quadrat" method allows close examination of small and cryptic coral species that are not detected by other methods such as the "towboard" surveys. The time, effort and cost involved with each method varied widely, and the suitability of each method for answering particular research questions in various environments was evaluated. Results of this study support the finding of three other comparison method studies conducted at various geographic locations throughout the world. Thus, coral cover measured by different methods can be legitimately combined or compared in many situations. The success of a recent modeling effort based on coral cover data consisting of observations taken in Hawai'i using the different methods supports this conclusion. PMID- 26020010 TI - Tactile roughness perception in the presence of olfactory and trigeminal stimulants. AB - Previous research has shown that odorants consistently evoke associations with textures and their tactile properties like smoothness and roughness. Also, it has been observed that olfaction can modulate tactile perception. We therefore hypothesized that tactile roughness perception may be biased towards the somatosensory connotation of an ambient odorant. We performed two experiments to test this hypothesis. In the first experiment, we investigated the influence of ambient chemosensory stimuli with different roughness connotations on tactile roughness perception. In addition to a pleasant odor with a connotation of softness (PEA), we also included a trigeminal stimulant with a rough, sharp or prickly connotation (Ethanol). We expected that-compared to a No-odorant control condition-tactile texture perception would be biased towards smoothness in the presence of PEA and towards roughness in the presence of Ethanol. However, our results show no significant interaction between chemosensory stimulation and perceived tactile surface roughness. It could be argued that ambient odors may be less effective in stimulating crossmodal associations, since they are by definition extraneous to the tactile stimuli. In an attempt to optimize the conditions for sensory integration, we therefore performed a second experiment in which the olfactory and tactile stimuli were presented in synchrony and in close spatial proximity. In addition, we included pleasant (Lemon) and unpleasant (Indole) odorants that are known to have the ability to affect tactile perception. We expected that tactile stimuli would be perceived as less rough when simultaneously presented with Lemon or PEA (both associated with softness) than when presented with Ethanol or Indole (odors that can be associated with roughness). Again, we found no significant main effect of chemosensory condition on perceived tactile roughness. We discuss the limitations of this study and we present suggestions for future research. PMID- 26020011 TI - Impacts of sea level rise and climate change on coastal plant species in the central California coast. AB - Local increases in sea level caused by global climate change pose a significant threat to the persistence of many coastal plant species through exacerbating inundation, flooding, and erosion. In addition to sea level rise (SLR), climate changes in the form of air temperature and precipitation regimes will also alter habitats of coastal plant species. Although numerous studies have analyzed the effect of climate change on future habitats through species distribution models (SDMs), none have incorporated the threat of exposure to SLR. We developed a model that quantified the effect of both SLR and climate change on habitat for 88 rare coastal plant species in San Luis Obispo, Santa Barbara, and Ventura Counties, California, USA (an area of 23,948 km(2)). Our SLR model projects that by the year 2100, 60 of the 88 species will be threatened by SLR. We found that the probability of being threatened by SLR strongly correlates with a species' area, elevation, and distance from the coast, and that 10 species could lose their entire current habitat in the study region. We modeled the habitat suitability of these 10 species under future climate using a species distribution model (SDM). Our SDM projects that 4 of the 10 species will lose all suitable current habitats in the region as a result of climate change. While SLR accounts for up to 9.2 km(2) loss in habitat, climate change accounts for habitat suitability changes ranging from a loss of 1,439 km(2) for one species to a gain of 9,795 km(2) for another species. For three species, SLR is projected to reduce future suitable area by as much as 28% of total area. This suggests that while SLR poses a higher risk, climate changes in precipitation and air temperature represents a lesser known but potentially larger risk and a small cumulative effect from both. PMID- 26020012 TI - Swabs to genomes: a comprehensive workflow. AB - The sequencing, assembly, and basic analysis of microbial genomes, once a painstaking and expensive undertaking, has become much easier for research labs with access to standard molecular biology and computational tools. However, there are a confusing variety of options available for DNA library preparation and sequencing, and inexperience with bioinformatics can pose a significant barrier to entry for many who may be interested in microbial genomics. The objective of the present study was to design, test, troubleshoot, and publish a simple, comprehensive workflow from the collection of an environmental sample (a swab) to a published microbial genome; empowering even a lab or classroom with limited resources and bioinformatics experience to perform it. PMID- 26020013 TI - Individual consistency in the behaviors of newly-settled reef fish. AB - Flexibility in behavior is advantageous for organisms that transition between stages of a complex life history. However, various constraints can set limits on plasticity, giving rise to the existence of personalities that have associated costs and benefits. Here, we document a field and laboratory experiment that examines the consistency of measures of boldness, activity, and aggressive behavior in the young of a tropical reef fish, Pomacentrus amboinensis (Pomacentridae) immediately following their transition between pelagic larval and benthic juvenile habitats. Newly-settled fish were observed in aquaria and in the field on replicated patches of natural habitat cleared of resident fishes. Seven behavioral traits representing aspects of boldness, activity and aggression were monitored directly and via video camera over short (minutes), medium (hours), and long (3 days) time scales. With the exception of aggression, these behaviors were found to be moderately or highly consistent over all time scales in both laboratory and field settings, implying that these fish show stable personalities within various settings. Our study is the first to examine the temporal constancy of behaviors in both field and laboratory settings in over various time scales at a critically important phase during the life cycle of a reef fish. PMID- 26020014 TI - Childhood socioeconomic deprivation, but not current mood, is associated with behavioural disinhibition in adults. AB - There is evidence to suggest that impulsivity is predicted by socioeconomic background, with people from more deprived backgrounds tending to be more impulsive, and by current mood, with poorer mood associated with greater impulsivity. However, impulsivity is not a unitary construct, and previous research in this area has focused on measures of 'waiting' impulsivity rather than behavioural disinhibition. We administered a standard measure of behavioural disinhibition, the stop-signal task, to 58 adult participants from a community sample. We had measured socioeconomic background using participant postcode at age 16, and assigned participants to receive either a neutral or a negative mood induction. We found no effects of mood on behavioural disinhibition, but we found a significant effect of socioeconomic background. Participants who had lived in more deprived postcodes at age 16 showed longer stop-signal reaction times, and hence greater behavioural disinhibition. The pattern was independent of participant age and overall reaction time. Though caution is required inferring causality from correlation, it is possible that that experiencing socioeconomic deprivation in childhood and adolescence may lead to greater behavioural disinhibition in adulthood. PMID- 26020015 TI - Salmonella enterica biofilm-mediated dispersal by nitric oxide donors in association with cellulose nanocrystal hydrogels. AB - Protected by extracellular polymers, microbes within biofilms are significantly more resistant to disinfectants. Current research has been instrumental in identifying nitric oxide donors and hydrogels as potential disinfectant additives. Nitric oxide (NO) donors are considered a very promising molecule as biofilm dispersal agents and hydrogels have recently attracted a lot of interest due to their biocompatible properties and ability to form stable thin films. When the NO donor MAHMA NONOate was dissolved in phosphate saline buffer, it was able to reduce the biomass of well-established biofilms up to 15% for at least 24 h of contact time. Encapsulation of MAHMA NONOate and molsidomine within a hydrogel composed of cellulose nanocrystals (CNC) has shown a synergistic effect in dispersing well-established biofilms: after 2 h of exposure, moderate but significant dispersion was measured. After 6 h of exposure, the number of cells transitioning from the biofilm to the planktonic state was up to 0.6 log higher when compared with non-treated biofilms. To further explore the transport processes of NO donors within hydrogels, we measured the nitric oxide flux from gels, at 25 degrees C for a composite of 0.1 uM MAHMA NONOate-CNC. Nitric oxide diffuses up to 500 um from the hydrogel surface, with flux decreasing according to Fick's law. 60% of NO was released from the hydrogel composite during the first 23 min. These data suggest that the combined treatments with nitric oxide donor and hydrogels may allow for new sustainable cleaning strategies. PMID- 26020016 TI - Elucidation of the recognition mechanisms for hemicellulose and pectin in Clostridium cellulovorans using intracellular quantitative proteome analysis. AB - Clostridium cellulovorans is an anaerobic, cellulolytic bacterium, capable of effectively degrading and metabolizing various types of substrates, including cellulose, hemicellulose (xylan and galactomannan), and pectin. Among Clostridia, this ability to degrade and metabolize a wide range of hemicellulose and pectin substrates is a unique feature; however, the mechanisms are currently unknown. To clarify the mechanisms of hemicelluloses and pectin recognition and metabolism, we carried out a quantitative proteome analysis of C. cellulovorans cultured with these substrates. C. cellulovorans was cultured in the medium of glucose (control), xylan, galactomannan (Locus bean gum, LBG), or pectin for 36 h. Xylan and galactomannan were used to search for the common recognition mechanisms of hemicellulose, and pectin was used to search for unique recognition systems in C. cellulovorans. Using an isobaric tag method and liquid chromatograph/mass spectrometer equipped with a long monolithic silica capillary column, we identified 734 intracellular proteins from all substrates. We performed KEGG analyses and cluster analyses of the resulting proteins. In the KEGG analyses, we found common degradation mechanisms for hemicellulose and pectin. In the cluster analysis corresponding to the genome analysis, we detected substrate-specific clusters that include genes involved in substrate recognition, substrate degradation, and metabolism. Combining the results of the KEGG analyses and cluster analyses, we propose the mechanisms involved in the recognition and metabolism of hemicellulose and pectin in C. cellulovorans. PMID- 26020017 TI - The impact of use of an intraoperative margin assessment device on re-excision rates. AB - Historically there has been a high rate of surgical interventions to obtain clear margins for breast cancer patients undergoing breast conserving local therapy. An intraoperative margin assessment tool (MarginProbe) has been approved for use in the US since 2013. This study is the first compilation of data from routine use of the device, to assess the impact of device utilization on re-excision rates. We present a retrospective, observational, review from groups of consecutive patients, before and after the implementation of intraoperative use of the device during lumpectomy procedures. Lesions were localized by standard methods. The intraoperative margin assessment device was used on all circumferential margins of the main specimen, but not on any additional shavings. A positive reading by the device led to an additional shaving of the corresponding cavity location. Specimens were also, when feasible, imaged intra-operatively by X-ray, and additional shavings were taken if needed based on clinical assessment. For each surgeon, historical re-excision rates were established based on a consecutive set of patients from a time period proximal to initiation of use of the device. From March 2013 to April 2014 the device was routinely used by 4 surgeons in 3 centers. In total, 165 cases lumpectomy cases were performed. Positive margins resulted in additional re-excision procedures in 9.7% (16/165) of the cases. The corresponding historical set from 2012 and 2013 consisted of 186 Lumpectomy cases, in which additional re-excision procedures were performed in 25.8% (48/186) of the cases. The reduction in the rate of re-excision procedures was significant 62% (P < 0.0001). Use of an intraoperative margin assessment device contributes to achieving clear margins and reducing re-excision procedures. As in some cases positive margins were found on shavings, future studies of interest may include an analysis of the effect of using the device on the shavings intra operatively. PMID- 26020018 TI - Genetic variability in the region encompassing reiteration VII of herpes simplex virus type 1, including deletions and multiplications related to recombination between direct repeats. AB - A number of tandemly reiterated sequences are present on the herpes simplex virus type 1 (HSV-1) DNA molecule of 152 kbp. While regions containing tandem reiterations were usually unstable, reiteration VII, which is present within the protein coding regions of gene US10 and US11, was stable; hence, reiteration VII could be used as a genetic marker. In the present study, the nucleotide sequences (159-213 bp) of a region encompassing reiteration VII of 62 HSV-1 isolates were compared with that of strain 17 as the standard strain, and the genetic variability of base substitutions, deletions, and multiplications was revealed. Base substitution was observed in nine residues on the region flanking reiteration VII and sixty-two HSV-1 isolates were classified into twelve groups based on these base substitutions. Deletions, which were present in all sixty-two isolates, were classified into six groups. Multiplications, which were present in 19 isolates having the same deletion (named del-2), were classified into four groups. The sixty-two isolates were classified into twenty patterns based on variations in the region encompassing reiteration VII, and the region encompassing reiteration VII was considered to be useful for studies on the molecular epidemiology and evolution of HSV-1. The lengths of these deletions and multiplications were multiples of 3; thus, a frame-shift mutation was not induced, and a mechanism to maintain the functions of US10 and US11 was suggested. A series of multiplications, which consisted of the duplication, triplication, and tetraplication of the same sequence, were found. Since all isolates with a multiplication had del-2, multiplications were assumed to be generated after the generation of del-2, and an isolate with del-2 was considered to have the ability to generate a multiplication. Recombination between a pair of direct repeats in and around reiteration VII was accountable for the generation of deletions and multiplications, indicating the recombinogenic property of the region encompassing reiteration VII. A correlation was revealed between a set of 20 DNA polymorphisms widely present on the HSV-1 genome and the base substitutions and deletions of the region encompassing reiteration VII, using discriminant analyses. PMID- 26020019 TI - Antihyperglycemic, antihyperlipidemic and antioxidant activity of phenolic rich extract of Brassica oleraceae var gongylodes on streptozotocin induced Wistar rats. AB - Cruciferous vegetables, in particular those included into the Brassica genus, are good sources of a variety of nutrients and health-promoting phytochemicals. Phenolic compounds are the major antioxidants of Brassica; hence the contribution of Brassica vegetables to health improvement has largely been associated to their antioxidant capacity. This study aimed to assess anti-diabetic, antilipidemic, and antioxidant activity of phenolic rich extract of Brassica oleraceae var gongylodes (BOvG) in Wistar rats. The findings revealed that the administration of BOvG extract to diabetic rats significantly reduced fasting blood glucose by 64% within 7 days of treatment. Additionally, BOvG extract was also observed to normalize the diabetic rats' lipid profile and HbA1c (Glycated hemoglobin). BOvG extract also showed protection of liver- kidney functions, which was evidenced by the significant decrease in Blood Urea Nitrogen (BUN), Serum glutamic oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT). The treatment also improved the antioxidant status of the diabetic rats where the enzymatic activities of Catalase (CAT) and Super Oxide Dismutase (SOD) were significantly increased. Furthermore, RP-HPLC analysis detected chlorogenic acid, rutin, and sinapic acid against known standards in BOvG extract. Hence, the present investigation suggests that BOvG phenolic rich extract (as a multi-component therapy) exhibited anti-diabetic, antilipidemic and antioxidant properties in STZ induced diabetic rats. PMID- 26020020 TI - Inclusion complexes of trihexyphenidyl with natural and modified cyclodextrins. AB - The solubility of trihexyphenidyl (Thp) was improved by its combination with beta cyclodextrin (beta-CD) and modified beta-CDs. The solubility of Thp was found to be increased in the presence of beta-CD, hydroxypropyl-beta-cyclodextrin (HP-beta CD), methyl-beta-cyclodextrin (Me-beta-CD) and sulfobutylether-beta-cyclodextrin (SBE-beta-CD). In particular, the solubility of Thp in conjunction with SBE-beta CD was increased by a factor of 11. The formation constant (K c ) for the Thp/SBE beta-CD inclusion complex was determined to be 2300 L/mol based on fluorometry data. The structure of the Thp/SBE-beta-CD complex in aqueous solution was examined by (1)H-(1)H rotating frame nuclear Overhauser effect spectroscopy (ROESY) NMR, and the phenyl moiety of the Thp was found to coordinate with the secondary hydroxyl face of the SBE-beta-CD. A solid Thp/SBE-beta-CD inclusion complex was prepared by freeze-drying. PMID- 26020021 TI - Efficient hash tables for network applications. AB - Hashing has yet to be widely accepted as a component of hard real-time systems and hardware implementations, due to still existing prejudices concerning the unpredictability of space and time requirements resulting from collisions. While in theory perfect hashing can provide optimal mapping, in practice, finding a perfect hash function is too expensive, especially in the context of high-speed applications. The introduction of hashing with multiple choices, d-left hashing and probabilistic table summaries, has caused a shift towards deterministic DRAM access. However, high amounts of rare and expensive high-speed SRAM need to be traded off for predictability, which is infeasible for many applications. In this paper we show that previous suggestions suffer from the false precondition of full generality. Our approach exploits four individual degrees of freedom available in many practical applications, especially hardware and high-speed lookups. This reduces the requirement of on-chip memory up to an order of magnitude and guarantees constant lookup and update time at the cost of only minute amounts of additional hardware. Our design makes efficient hash table implementations cheaper, more predictable, and more practical. PMID- 26020022 TI - Towards an understanding of the control of 'crumbly' fruit in red raspberry. AB - The genetic disorder known as 'crumbly' fruit is becoming a serious problem in the European raspberry industry. The study set out to examine the crumbly phenotype in a red raspberry mapping population under two environments (field and polytunnel) across six seasons in an effort to understand variability of the syndrome and to examine whether genetic factors were important and if so, whether QTL associated with the phenotype could be identified. This highlighted that seasonal, environmental (field or polytunnel) and genetic factors all influence the condition. Two QTL that are important for the genetic control of the condition have been located on linkage groups one and three, and an association with ripening time has been identified. PMID- 26020023 TI - Evenness indices once again: critical analysis of properties. AB - Various properties have been advocated for biological evenness indices, with some properties being clearly desirable while others appear questionable. With a focus on such properties, this paper makes a distinction between properties that are clearly necessary and those that appear to be unnecessary or even inappropriate. Based on Euclidean distances as a criterion, conditions are introduced in order for an index to provide valid, true, and realistic representations of the evenness characteristic (attribute) from species abundance distributions. Without such value-validity property, it is argued that a measure or index provides only limited information about the evenness and results in misleading interpretations and evenness comparisons and incorrect results and conclusions. Among the overabundant variety of evenness indices, each of which is typically derived by rescaling a diversity measure to the interval from 0 to 1 and thereby controlling or adjusting for the species richness, most are found to lack the value-validity property and some lack the property of strict Schur-concavity. The most popular entropy-based index reveals an especially poor performance with a substantial overstatement of the evenness characteristic or a large positive value bias. One evenness index emerges as the preferred one, satisfying all properties and conditions. This index is based directly on Euclidean distances between relevant species abundance distributions and has an intuitively meaningful interpretation in terms of relative distances between distributions. The value validity of the indices is assessed by using a recently introduced probability distribution and from the use of computer-generated distributions with randomly varying species richness and probability (proportion) components. PMID- 26020024 TI - Malignant transformation of hepatocellular adenoma: how frequently does it happen? PMID- 26020025 TI - Yttrium-90 microspheres: a review of its emerging clinical indications. AB - BACKGROUND: Many patients with liver malignancies are not candidates for resection, and systemic therapies are often not effective. Radioembolization (RE) is an alternative treatment for this group of patients. The safety and efficacy of RE with yttrium 90 (Y90) in patients with hepatocellular carcinoma (HCC) or metastatic colon cancer to the liver have been proven in several studies. However, fewer studies have focussed on the safety and efficacy of RE with Y90 in other extrahepatic primary and secondary liver cancers. The effect on outcomes of concomitant use of Y90 with a systemic therapy is still currently under investigation. SUMMARY: A review of the published data on the use of RE as stand alone, concomitant or sequential with other treatment modalities in HCC and other primary and secondary liver cancer is reported here. KEY MESSAGE: RE for the treatment of HCC and other extrahepatic, primary and secondary liver cancer has reasonable efficacy and acceptable toxicities. Definitive studies to establish the role of RE in the treatment of such malignancies are warranted. PMID- 26020026 TI - Yttrium-90 microsphere radioembolization for hepatocellular carcinoma. AB - Yttrium-90 (Y90) radioembolization is an emerging strategy to treat liver malignancies, and clinical data supporting its use have accumulated in recent years. Y90-radioembolization has shown clinical effectiveness in intermediate and advanced hepatocellular carcinoma, with a favorable safety profile. Retrospective data show similar levels of effectiveness to transarterial chemoembolization in intermediate hepatocellular carcinoma, with some evidence of better tolerance. While phase 3 studies comparing Y90-radioembolization to chemoembolization in intermediate hepatocellular carcinoma would be difficult to conduct, studies comparing or combining Y90-radioembolization with sorafenib are under way. Questions also remain about the most suitable modalities for defining the dose to administer. Phase 3 studies are under way to clarify the place of Y90 radioembolization in the algorithm of HCC treatment. PMID- 26020027 TI - Insufficient ablative margin determined by early computed tomography may predict the recurrence of hepatocellular carcinoma after radiofrequency ablation. AB - Tumor recurrence in hepatocellular carcinoma (HCC) patients after radiofrequency ablation (RFA) remains common; some studies have reported that insufficient ablative margin after RFA might contribute to HCC recurrence. The aim of this study was to investigate whether insufficient ablative safety margins determined by early computed tomography (CT) predicts HCC recurrence after RFA. This retrospective study recruited patients with a single HCC lesion after RFA in our department between May 2013 and March 2014. Early follow-up CT was performed within 7 days after RFA. An adequate ablative margin assessed by follow-up CT was defined as (maximum post-RFA CT radius)(3)/(maximum pre-RFA CT radius + 5 mm)(3)> 1. All patients in whom complete ablation was achieved underwent a CT scan every 3 months for early detection of HCC recurrence. In total, 72 patients (48 male, mean age 69.4 years) were analyzed. Of these, eight patients had local tumor progression, four had intra-hepatic distant recurrence, and two had extra-hepatic metastasis. Insufficient ablative margin, defined as an ablative volume with a safety margin of less than 5 mm, was an important predictor of local tumor progression (LTP) (p = 0.015) and overall recurrence (p = 0.012). The sensitivity, specificity, and positive and negative predictive values of an insufficient ablative margin for predicting LTP and overall recurrence were 36.4%, 97.2%, 50.0%, and 87.9%, and 46.2%, 89.7%, 42.9%, and 87.9%, respectively. An ablative volume with an ablative margin of less than 5 mm is associated with higher rates of both LTP and overall recurrence in HCC after RFA. PMID- 26020028 TI - Surveillance, diagnosis, treatment, and outcome of liver cancer in Japan. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third leading cause of cancer-related death worldwide. HCC is most common in Asia, but its prevalence is rapidly increasing in Western countries; consequently, HCC is a global medical issue that urgently needs to be addressed. Japan is the only developed country that has experienced both hepatitis B-related and hepatitis C-related HCC and has a long history of innovation when it comes to new diagnostic and therapeutic modalities, such as computed tomography angiography, anatomical resection, ablation, and transarterial chemoembolization. Among these innovations, a nationwide surveillance program was well established by the 1980s, and such a long-term national program does not exist anywhere else in the world. SUMMARY: More than 60% of the initially detected HCCs in Japan are Barcelona Clinic Liver Cancer stage 0 or A, which can undergo curative therapies such as resection, ablation, or transplantation. The recent 5-year survival rate of HCC patients in Japan was 43% and the median survival time was 50 months. In addition, both incidence and mortality rates are drastically declining as a result of the successful surveillance program, careful diagnostic flow, and extensive repeated treatments. KEY MESSAGE: Japan's successful model in the surveillance, diagnosis, and treatment of HCC should be adopted as widely as possible to improve the survival of HCC patients worldwide. PMID- 26020030 TI - Treatment of hepatocellular carcinoma in the community: disparities in standard therapy. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) incidence is expected to rise dramatically over the next decades because of increasing hepatitis C infections and obesity-related comorbidities. However, little information exists regarding the treatment of patients with HCC in the community setting. The purpose of this article was to characterize patterns of diagnosis, treatment, and survival for HCC in the community. METHODS: We identified 946 HCC patients in the 2007 National Cancer Institute's Patterns of Care study. Chi-square analyses and multivariable regression were used to examine patient and provider factors associated with treatment and survival by stage at diagnosis. RESULTS: Our primary findings indicate that liver transplants, embolization, or radiofrequency ablation for Barcelona Clinic Liver Cancer stage A patients were performed significantly less often for non-Hispanic blacks, Hispanics, patients in the highest income quartile, and patients with Medicaid. Patients with stage D disease were less likely to receive cancer therapy if they had Medicaid insurance compared to private insurance (p<0.001 for all). In multivariable analyses, all cause mortality was associated with treatment in a hospital without a residency training program (hazard ratio [HR] 1.4 [1.1,1.9]), more advanced stage (HR: 10.6 [5.7, 19.5] stage D vs. A), and lack of appropriate treatment (HR: 2.4 [1.9,3.2]). CONCLUSIONS: This is the first population-based study to evaluate therapy provided for HCC in the community. Current therapy depended on patients' HCC stage at diagnosis and other clinical and demographic factors. Overall, our study identifies those least likely to receive specific therapies in a variety of health care settings and can inform strategies for promoting appropriate therapy now and as new agents are developed. PMID- 26020031 TI - Clinical Practice Guidelines for Hepatocellular Carcinoma Differ between Japan, United States, and Europe. PMID- 26020029 TI - Hong Kong consensus recommendations on the management of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is particularly prevalent in Hong Kong because of the high prevalence of chronic hepatitis B (CHB) infection; HCC is the fourth commonest cancer in men and the seventh commonest in women, and it is the third leading cause of cancer death in Hong Kong. The full spectrum of treatment modalities for HCC is available locally; however, there is currently no local consensus document detailing how these modalities should be used. SUMMARY: In a series of meetings held between May and October 2013, a multidisciplinary group of Hong Kong clinicians - liver surgeons, medical oncologists, clinical oncologists, hepatologists, and interventional radiologists - convened to formulate local recommendations on HCC management. These recommendations consolidate the most current evidence pertaining to HCC treatment modalities, together with the latest thinking of practicing clinicians engaged in HCC management, and give detailed guidance on how to deploy these modalities effectively for patients in various disease stages. KEY MESSAGES: Distinct from other regional guidelines, these recommendations provide guidance on the use of antiviral therapy to reduce the incidence of HCC in CHB patients with cirrhosis and to reduce recurrence of CHB-related HCC. PMID- 26020032 TI - Consensus Development from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014). AB - A key mission of the Asia-Pacific Primary Liver Cancer Expert (APPLE) Association is to ensure a coherent view for management of hepatocellular carcinoma (HCC) and to advance new treatment for this difficult disease. At the 5th APPLE meeting, held in July 2014 in Taipei, Taiwan, an APPLE consensus development program was established to facilitate discussion among experts in the Asia-Pacific region on pertinent issues for HCC management, including (1) surgery for intermediate/advanced-stage disease, (2) prevention of HCC recurrence after curative treatment, (3) optimizing imaging diagnosis, (4) radiotherapy: current practice and future clinical trials, and (5) the role of cytotoxic chemotherapy. A pre-congress questionnaire was undertaken with the consensus development committee members to help understand the current practice patterns for HCC in the Asia-Pacific region and to identify issues relating to optimal patient care and further clinical trials for which consensus needs to be developed. In this report, the results of the questionnaire are presented, and the pertinent issues identified by each consensus group for further discussion and consensus development are summarized. PMID- 26020033 TI - Phase I trial of sorafenib following liver transplantation in patients with high risk hepatocellular carcinoma. AB - Liver transplantation offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who fall within established criteria. For those outside such criteria, or with high-risk pathologic features in the explant, HCC recurrence rates are higher. We conducted a multicenter phase I trial of sorafenib in liver transplantation patients with high-risk HCC. Subjects had HCC outside the Milan criteria (pre- or post-transplant), poorly differentiated tumors, or vascular invasion. We used a standard 3+3 phase I design with a planned duration of treatment of 24 weeks. Correlative studies included the number of circulating endothelial cells (CECs), plasma biomarkers, and tumor expression of p-Erk, p-Akt, and c-Met in tissue micro-arrays. We enrolled 14 patients with a median age of 63 years. Of these, 93% were men and 71% had underlying hepatitis C virus (HCV) and 21% had HBV. The maximum tolerated dose of sorafenib was 200 mg BID. Grade 3-4 toxicities seen in >10% of subjects included leukopenia (21%), elevated gamma-glutamyl transferase (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, one patient died and four recurred. The mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean soluble vascular endothelial growth factor receptor-2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression to correlate with increased risk of recurrence. Post-transplant sorafenib was found to be feasible and tolerable at 200 mg PO BID. The effect of post-transplant sorafenib on recurrence-free survival is potentially promising but needs further validation in a larger study. PMID- 26020034 TI - Tumor Markers for Hepatocellular Carcinoma: Simple and Significant Predictors of Outcome in Patients with HCC. AB - BACKGROUND: The effectiveness of tumor markers in evaluating outcomes of patients with hepatocellular carcinoma (HCC) remains to be clarified. SUMMARY: The usefulness of the HCC tumor markers, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), and des-gamma-carboxy prothrombin (DCP) was reviewed. Elevations in these tumor markers at the time of HCC diagnosis correlate with disease progression as assessed by both imaging studies and pathologic examinations. The combination of these three tumor markers results in good predictive ability for patient survival after diagnosis. In addition, combination at the time of HCC diagnosis of these three tumor markers (as a measure of tumor progression) and serum albumin and bilirubin levels (as indicators of remnant liver function) can be used for HCC staging and further predicts prognosis in patients with HCC. KEY MESSAGE: The prognosis of patients with HCC can be well discriminated based solely on serum markers. Staging of HCC with serum markers is objective; if stored serum samples are available, HCC stages can be standardized across different countries and time periods. PMID- 26020035 TI - Dry eye disease in type 2 diabetes mellitus; comparison of the tear osmolarity test with other common diagnostic tests: a diagnostic accuracy study using STARD standard. AB - BACKGROUND: To determine the diagnostic performance of tear osmolarity in diagnosis of dry eye disease by using tear lab osmolarity system in people with type 2 diabetes, and to compare it with common diagnostic tests already available in clinical practice. METHODS: Two hundreds forty three people with type 2 diabetes were included. Tear osmolarity was measured with the tear osmolarity system. The 308 mOsm/L cutoff was used to diagnose dry eye disease. The following tests were also performed: Ocular Surface Disease Index (OSDI) questionnaire, Tear Film Break up Time (TFBUT), Schirmer I test, Rose Bengal and Fluorescein staining. The results of these tests were compared to the tear osmolarity measurement. RESULTS: The prevalence of dry eye disease detected by the tear osmolarity test was 27.7%. It was as follows for the other common diagnostic tests: OSDI (17.7%), Schirmer I test (33%), TFBUT (41%), Rose Bengal (11%), and Fluorescein staining (4%). Fluorescein staining had the highest specificity (97%). With the cutoff score >12, the positive likelihood ratio for the OSDI questionnaire was the highest (1.78). The sensitivity was poor for all common diagnostic tests. ROC curve analysis could not determine optimal cut offs for the common diagnostic tests. CONCLUSIONS: The available common diagnostic tests underestimate the presence of dry eye disease in people with type 2 diabetes. Moreover, they could not discriminate tear hyperosmolarity from normal. Tear osmolarity could be considered as the best single test for detection of dry eye disease in people with type2 diabetes. PMID- 26020036 TI - Effect of multiple debonding sequences on shear bond strength of new stainless steel brackets. AB - OBJECTIVES: This in-vitro study aimed at evaluating the effect of three debonding sequences on the shear bond strength (SBS) of new stainless steel (SS) brackets. MATERIALS AND METHODS: Stainless steel twin brackets (0.022-inch, American Orthodontics, Sheboygan, WI, USA) were bonded with light cure adhesive (Transbond XT, 3M Unitek, St. Paul, MN, USA) to 80 newly extracted human premolars after acid etching with 37% phosphoric acid (30 s). Brackets were debonded with a universal testing machine, and new brackets were bonded to teeth using the same adhesive and same manner. This process was repeated twice, and brackets were debonded within 24 h after bonding. The longitudinal changes of average SBS were assessed with the repeated measures ANOVA. Post-hoc tests using the Bonferroni correction were also used to compare the average SBS at three debonding sequences. RESULT: The mean SBS decreased significantly after each debonding sequence (P < 0.01). The corresponding mean values (standard deviation, 95% CI) after the first, second, and third debonding sequences were 22.88 MPa (4.08, 21.97-22.79), 19.36 MPa (4.54, 18.62-20.64), and 16.67 MPa (4.27, 15.72-17.62), respectively. There was no significant difference among the adhesive remnant index (ARI) scores of three debonding sequences (chi(2)= 5.067, df = 6, P = 0.53). CONCLUSION: Average SBS after three debonding sequences was significantly decreased, but was above the recommended 5.9-7.8 MPa. In-vivo studies are required to validate the finding of this study. PMID- 26020037 TI - In vitro evaluation of frictional forces of two ceramic orthodontic brackets versus a stainless steel bracket in combination with two types of archwires. AB - PURPOSE: The aim of this study was to compare frictional forces between monocrystalline alumina (MA), polycrystalline alumina (PA), and stainless steel (SS) brackets with two SS wires: Rectangular and round. MATERIALS AND METHODS: In this in vitro study, 60 0.022 brackets [20 PA (0 degrees torque, Forestadent, Germany) and 20 MA (0 degrees torque, Ormco, California, USA)] brackets plus 20 SS brackets (0 degrees torque, Foretadent, Germany) and 60 SS archwires (30 rectangular 0.019 *0.025 archwires and 30 round 0.018 archwires, Ortho Technology, USA) were used in subgroups of 10 from the combination of all brackets and all archwires. A universal testing machine (Instron, Model STM 250, Germany) was used to investigate the static frictional resistance. The angulation between the bracket and wire was 0 degrees , and the wires were pulled through the slots at a crosshead speed of 10 mm/min. Two-way and one-way analyses of variance (ANOVA) and Tukey tests were used to analyze the data. RESULTS: Mean (SD) static frictional force for each group was as follows: MA + round: 3.47 (0.38); MA + rectangular: 4.05 (0.47); PA + round: 4.14 (0.37); PA + rectangular: 4.45 (0.65); SS + round: 3.28 (0.22); and SS + rectangular: 4.22 (0.61). Significant effects of bracket types (P = 0.001) and archwire types (P = 0.000) on the friction force were detected using ANOVA. Tukey test indicated significant differences between PA brackets with both SS and MA brackets (P < 0.05), but not between SS and MA brackets. The two archwires as well had significantly different effects (Tukey P = 0.000). CONCLUSIONS: Based on the present in-vitro study, the PA brackets might create higher frictional forces compared to both SS and MA brackets. The rectangular 0.019 *0.025 archwire might create greater forces than round 0.018 archwire. PMID- 26020038 TI - Orthodontic treatment need among special health care needs school children in Dharwad, India: A comparative study. AB - OBJECTIVES: The aim was to assess and compare the prevalence of orthodontic treatment need among various special health care needs (SHCN) schoolchildren and adolescents in Dharwad, India. MATERIALS AND METHODS: This cross-sectional study was carried out among 492 subjects in age group of 12-19 years (mean age 14.02 +/ 1.84 standard deviation [SD]) who were examined for occlusal anomalies using dental aesthetic index (DAI). They were classified into five groups as: Visual impairment, speech and hearing disability (SH), physical disability, mentally subnormal and multiple disabilities (MD). Chi-square test was used to compare the orthodontic treatment need among various SHCN groups. One-way ANOVA and ANCOVA were performed to test any significant differences in mean DAI scores among the SHCN groups. RESULTS: None of the children were undergoing or had undergone orthodontic treatment for malocclusion. Mean DAI score was 28.81 +/- 11.64 (SD). Orthodontic treatment was indicated in 50.2% of study population who had DAI scores of 26 and above. Mandatory orthodontic treatment (DAI >=36) was required in as high as 29% of MD individuals when compared to only 10% of SH individuals. Significant differences in DAI scores were found between the SHCN groups. CONCLUSIONS: The need for orthodontic treatment among SHCN individuals was found to be high. Yet, absence of any orthodontic treatment for any child points out to the fact that the dental services are highly needed in these individuals. PMID- 26020039 TI - An in vitro assessment of the mechanical characteristics of nickel-titanium orthodontic wires in Fluoride solutions with different acidities. AB - OBJECTIVES: The aim was to evaluate the in vitro effects of fluoride solutions with different acidities on load-deflection characteristics of nickel-titanium (NiTi) orthodontic wires. MATERIALS AND METHODS: In this study, which lasted 30 days, 36 (3 cm long, 0.016 * 0.022 inches, SENT 1622, G & H wire Company, Greenwood, Indiana, USA) NiTi wires, were divided into three experimental groups of 12 each. Two groups were subjected to 0.05 topical fluoride mouthwash with different acidities (G1, pH 4; G2, pH 6.6) for 90 s, twice a day, and kept in normal saline after that. The third group (G3, the control group) was kept in normal saline only. Load and unload forces were measured with three bracket bending test in a universal testing machine (Testometric Co, Rochdale, UK). Loading and unloading plateaus and hysteresis were also recorded. Data were then analyzed using analysis of variance and honestly significant difference Tukey at P < 0.05. RESULTS: During the loading phase, there was a significant difference between deflections (P < 0.001); but there was no interaction effect (P = 0.191) and no significant difference among three groups (P = 0.268). In the unloading phase, there was a significant difference between deflections (P < 0.001) and an interaction effect was also observed (P = 0.008). Further, significant differences noted among three groups (P = 0.037). Only in the unloading phase, at deflections of 2.2 through 0.2 mm, significant differences between the mean force values of the G1 and G3 groups were observed (P = 0.037). CONCLUSION: Based on this in-vitro study, compared to neutral fluoride solution, daily mouthwash with a fluoride solution with more acidic pH of 4 affected the NiTi wires load deflection characteristics during the unloading phase. This finding may have clinical implications and can be further validated by in-vivo studies. PMID- 26020040 TI - Preoperative endoscopic ultrasound-guided fine needle aspiration for diagnosis of pancreatic cancer in potentially resectable patients: Is this safe? PMID- 26020041 TI - Endoscopic ultrasound-guided liver biopsy. AB - Liver biopsy remains the cornerstone in the diagnosis and management of liver disorders. Results of liver biopsy can often drive therapeutic decision-making. Unfortunately, studies have shown conventional biopsy techniques to carry significant sampling variability that can potentially impact patient care. Endoscopic ultrasound (EUS) is gaining traction as an alternative method of biopsy. For parenchymal disease, it can decrease sampling variability. It offers a more targeted approach for focal lesions. Its diagnostic yield and limited adverse event profile make it a promising approach for liver biopsy. PMID- 26020042 TI - Nonfluoroscopic endoscopic ultrasound-guided transmural drainage of pseudocysts: A pictorial technical review. AB - Pancreatic pseudocysts (PP) are one of the important local complications of pancreatitis and can be treated by surgical, laparoscopic, percutaneous, or endoscopic methods. The endoscopic methods of drainage include transpapillary or transmural drainage or a combination of these two routes. The transmural drainage can be done using conventional duodenoscope without endoscopic ultrasound (EUS) guidance or under EUS guidance. The EUS-guided transmural drainage of PP is done under EUS and fluoroscopic guidance. We have earlier reported nonfluoroscopic EUS guided transmural drainage of walled-off pancreatic necrosis. In this pictorial technical review, we will discuss in detail this method of nonfluoroscopic EUS guided drainage of PP. PMID- 26020043 TI - Techniques of imaging of the aorta and its first order branches by endoscopic ultrasound (with videos). AB - Endoscopic ultrasonography (EUS) is a useful modality for imaging of the blood vessels of the mediastinum and abdomen. The aorta acts as an important home base during EUS imaging. The aorta and its branches are accessible by standard angiographic methods, but endosonography also provides a unique opportunity to evaluate the aorta and its branches. This article describes the techniques of imaging of different part of the aorta by EUS. PMID- 26020044 TI - High risk of acute pancreatitis after endoscopic ultrasound-guided fine needle aspiration of side branch intraductal papillary mucinous neoplasms. AB - BACKGROUND AND OBJECTIVES: Data on the risk of acute pancreatitis following endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic cystic lesions are limited. The aim of our study was to evaluate the frequency of acute pancreatitis after EUS-FNA of pancreatic cysts and solid lesions, and determine whether there was a difference in pancreatitis risk in patients with side branch intraductal papillary mucinous neoplasms (SB-IPMN). PATIENTS AND METHODS: A retrospective review of patients who underwent EUS-FNA of pancreatic cysts and solid lesions was performed. The primary outcome measure was development of acute pancreatitis after EUS-FNA. Factors associated with acute pancreatitis were examined by statistical analysis to determine independent predictors of acute pancreatitis. Statistical significance was determined at a P <= 0.05. RESULTS: We identified 186 patients with pancreatic cystic lesions and 557 with solid lesions in which EUS-FNA was performed. The median size of the cysts was 19 mm (range: 10-66 mm). There were 37 IPMNs, 33 mucinous cystic neoplasms, 58 serous cysts and 46 pseudocysts and 12 solid-cystic ductal carcinomas. The majority of patients (75%) with solid lesions were diagnosed with adenocarcinoma. Patients with pancreatic cysts had a statistically greater frequency of developing pancreatitis after EUS-FNA when compared to those with solid lesions (2.6% vs. 0.36% respectively; P = 0.13). In patients with cysts, there were no statistically significant differences between the two groups (with and without pancreatitis) with regard to a cyst location, size of the cyst, and number of needle passes or trainee involvement. Patients with SB-IPMN had a statistically higher frequency of pancreatitis after EUS-FNA compared to those with other cyst types (8% vs. 1.3% respectively; odds ratio = 6.4, 95% confidence intervals = 1.0-40.3, P = 0.05). DISCUSSION: Patients with SB-IPMN are at a higher risk of developing acute pancreatitis after a EUS-FNA. Alternative means of diagnosis such as magnetic resonance cholangiopancreatogram might be necessary to avoid risk of EUS-FNA. PMID- 26020045 TI - Comparison of cytologic accuracy of endobronchial ultrasound transbronchial needle aspiration using needle suction versus no suction. AB - BACKGROUND AND OBJECTIVES: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a relatively new procedure initially used for lung cancer diagnosis, staging and re-staging and extended to benign diseases such as sarcoidosis and other mediastinal lesions. Previously, multiple studies evaluated the use of needle biopsy with no aspiration that did not change the diagnostic accuracy compared with needle biopsy aspiration. MATERIALS AND METHODS: All adult subjects who were scheduled to undergo EBUS-TBNA to sample mediastinal lesions were eligible. We evaluated two methods of sampling mediastinal lesions. The first method was the application of negative pressure syringe for needle suction aspiration. The second was with no suction. For every patient and every biopsy site in the same patient, we had two samples using each method. RESULTS: Among the 26 participants, 24 patients had adequate tissue using both methods (92.3%, P = 1.00). Among the 24 patients with adequate tissue using both methods, 14 patients (58.3%) had benign pathology using both methods, whereas ten patients (41.7%) had malignant pathology using both methods (P = 1.00). Among the 32 sites that were sampled, 30 sites had adequate tissue using both methods (93.8%, P = 1.00). Among the thirty sites with adequate tissue using both methods, 17 (56.7%) had benign pathology using both methods; 12 (40.0%) had malignant pathology using both methods; and one site (3.3%) had malignant pathology using suction, but benign pathology using no suction (P = 1.00). CONCLUSION: In patients undergoing EBUS-TBNA to sample mediastinal lesions, the diagnostic yield with the application of suction to needle biopsy was not statistically significant compared to no suction. PMID- 26020046 TI - Clinical evaluation of endoscopic ultrasonography-guided drainage using a novel flared-type biflanged metal stent for pancreatic fluid collection. AB - BACKGROUND AND OBJECTIVES: Endoscopic ultrasonography (EUS)-guided transluminal drainage for pancreatic fluid collections (PFCs) has become the standard therapy worldwide as a minimally invasive therapy compared with surgical drainage. Recently, a novel flared-type biflanged metal stent (BFMS) designed specifically for the treatment of PFCs has been developed. The aim of this study was to retrospectively assess the feasibility and safety of EUS-guided drainage and direct endoscopic necrosectomy (DEN) for PFCs using the novel flared-type BFMS. PATIENTS AND METHODS: Twenty-one patients were treated by EUS-guided drainage using a flared-type BFMS for PFCs (pancreatic pseudocyst, 2 patients; walled-off necrosis, 19 patients). RESULTS: The present study showed a technical success rate of 100%, a final clinical success rate of 100%, a procedure-related adverse event (AE) rate of 0%, an early AE rate of 28.6% (moderate and severe AE rate of 9.5%), a mortality rate of 0%, and a recurrence rate of 9.5%. DEN (mean, 2.3 sessions) was required in 38% of the patients. CONCLUSION: The present study clarified that the EUS-guided drainage using the flared-type BFMS is an effective and safe treatment approach for PFCs. Further studies using randomized controlled multicenter trials are warranted. PMID- 26020047 TI - The application of linear endoscopic ultrasound in the patients with esophageal anastomotic strictures. AB - OBJECTIVES: To evaluate the role of linear endoscopic ultrasound (EUS) in the diagnosis and treatment of the anastomotic stricture after esophagectomy for locally advanced esophageal cancer (EC). MATERIALS AND METHODS: A retrospective analysis was performed in patients undergone EUS assessment and endoscopic treatment for anastomotic stricture after esophagectomy for locally advanced EC from January 2010 to December 2014 at Shengjing Hospital. The linear EUS was performed in all the patients to assess the thickness of the esophageal wall, the length and width of the lesion, and to evaluate the severity of anastomotic stricture. According to the EUS features of the lesion, different endoscopic therapy were performed. RESULTS: There were 92 patients enrolled in this study. All the lesions of the patients were assessed by EUS. Eighty-six patients had cicatricial stricture of the esophagus confirmed by EUS, and were treated by endoscopic balloon dilation. Five patients were suspected to have tumor relapses, and the other one had lymphatic metastasis. All the six patients were undergone endoscopic metal stent implantation. The EUS diagnoses of all the patients were confirmed by pathological biopsy. CONCLUSION: Linear EUS is safe and effective for distinguishing the nature of the anastomotic stricture, and should be performed before endoscopic or surgical treatment. PMID- 26020048 TI - Role of endoscopic ultrasound-guided fine needle aspiration and ultrasound-guided fine-needle aspiration in diagnosis of cystic pancreatic lesions. AB - BACKGROUND AND OBJECTIVE: The addition of fine-needle aspiration (FNA) to different imaging modalities has raised the accuracy for diagnosis of cystic pancreatic lesions. We aim to differentiate benign from neoplastic pancreatic cysts by evaluating cyst fluid carcinoembryonic antigen (CEA), carbohydrate antigen (CA19-9), and amylase levels and cytopathological examination, including mucin stain. PATIENTS AND METHODS: This prospective study included 77 patients with pancreatic cystic lesions. Ultrasound-FNA (US-FNA) or endoscopic ultrasound FNA (EUS-FNA) was done according to the accessibility of the lesion. The aspirated specimens were subjected to cytopathological examination (including mucin staining), tumor markers (CEA, CA19-9), and amylase level. RESULTS: Cyst CEA value of 279 or more showed high statistical significance in differentiating mucinous from nonmucinous lesions with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 73%, 60%, 50%, 80%, and 65%, respectively. Cyst amylase could differentiate between neoplastic and nonneoplastic cysts at a level of 1043 with sensitivity of 58%, specificity of 75%, PPV of 73%, NPV of 60%, and accuracy of 66%. CA19-9 could not differentiate between neoplastic and nonneoplastic cysts. Mucin examination showed a sensitivity of 85%, specificity of 95%, PPV of 92%, NPV of 91%, and accuracy of 91% in differentiating mucinous from non-mucinous lesions. Cytopathological examination showed a sensitivity of 81%, specificity of 94%, PPV of 94%, NPV of 83%, and accuracy of 88%. CONCLUSION: US or EUS-FNA with analysis of cyst CEA level, CA19-9, amylase, mucin stain, and cytopathological examination increases the diagnostic accuracy of cystic pancreatic lesions. PMID- 26020049 TI - Utility of EUS following endoscopic polypectomy of high-risk rectosigmoid lesions. AB - BACKGROUND: The utility of endoscopic ultrasound (EUS) compared with standard white light endoscopy (WLE) following recent polypectomy of high-risk colorectal polyps is unknown. OBJECTIVE: To assess the incremental yield of EUS after endoscopic polypectomy of a high-risk rectal lesion. DESIGN: Retrospective cohort. SETTING: Tertiary referral center. MATERIALS AND METHODS: Patients referred for EUS following attempted endoscopic resection of a high-risk rectal neoplasm, defined as a tubulovillous adenoma, tubular adenoma with high-grade dysplasia, carcinoid, carcinoma in-situ or adenocarcinoma (CA). INTERVENTIONS: Sigmoidoscopy +/- mucosal biopsy and EUS +/- fine-needle aspiration (FNA) to evaluate for: (1) Residual polyp/tumor in the rectal wall or (2) peritumoral adenopathy. MAIN OUTCOME: Sensitivity and specificity for detection of residual neoplasia for WLE +/- biopsy (WLE/BX) and EUS +/- FNA for cancer (CA group) or benign disease (non-CA group). The incremental yield of EUS defined as: (1) Residual intramural neoplasia not present on WLE +/- BX and; (2) abnormal peritumoral adenopathy. RESULTS: A total of 70 patients (mean age 64 +/- 11 years, 61% male) with a final diagnosis of CA (n = 38) and non-CA (n = 32) were identified. There was no difference between the sensitivity and specificity of WLE alone (65% and 84%), WLE with biopsy (71% and 95%), and EUS (59% and 84%), for the detection of residual neoplasia (P > 0.05 for all). EUS identified 3 masses missed by WLE, all in the CA group. A malignant (n = 2) or benign (n = 3) node was identified in 5 (13%) CA patients; EUS-FNA in two showed residual malignancy in one and a reactive lymph node (LN) in one. No LNs were identified in the non-CA patients. LIMITATIONS: Retrospective design, incomplete follow-up in some patients. CONCLUSION: Following endoscopic polypectomy of high-risk rectal neoplasia, the incremental yield of EUS compared with WLE/BX for evaluation of residual disease appears limited, especially in patients with benign disease. PMID- 26020050 TI - Multiple pancreatic metastases from malignant melanoma: Conclusive diagnosis with endoscopic ultrasound-guided fine needle aspiration. AB - Pancreatic metastases are rare, ranging from 2% to 5% of pancreatic malignancies. Differentiating a primary pancreatic malignancy from a metastasis can be difficult due to similarities on imaging findings, but is crucial to ensure proper treatment. Although transabdominal ultrasound, computed tomography, and magnetic resonance imaging provide useful images, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is often needed to provide a cytologic diagnosis. Here, we present a unique case of malignant melanoma with pancreatic metastases. It is important for clinicians to recognize the possibility of melanoma metastasizing to the pancreas and the role of EUS with FNA in providing cytological confirmation. PMID- 26020051 TI - Gossypiboma diagnosed by a forward-view endoscopic ultrasound fine-needle aspiration out of the sigmoid colon. AB - Gossypiboma is a term used to describe a foreign mass within the body that is composed of a cotton matrix. Gossypiboma can cause infection or abscess formation from an early stage, or it can remain clinically silent for many years. Gossypiboma can be diagnosed using several methods including abdominal X-ray films, US of the abdomen, contrast-enhanced computed tomography of the abdomen, and during surgery. However, the variable appearance of gossypiboma can lead to diagnostic misinterpretations. Here, we report a successful diagnosis of gossypiboma using a novel method, that is, endoscopic ultrasound-fine-needle aspiration. PMID- 26020052 TI - Endoscopic ultrasound-assisted cholecystogastrostomy by a novel fully covered metal stent for the treatment of gallbladder stones. AB - An 85-year-old male patient with common bile duct stones and gallbladder stone was admitted to the hospital. Endoscopic ultrasound (EUS)-guided cholecystogastrostomy and the placement of a novel covered mental stent was performed after the endoscopic sphincter ectomy procedure. Two weeks later the stents were removed, and an endoscope was advanced into the gallbladder via the fistula, and cholecystolithotomy was performed. For weeks later gallbladder was assessed by abdominal ultrasound. EUS-guided cholecystogastrostomy with mental stent deployment was successfully performed. Two weeks after the procedure, the fistulas had formed, and the stent were removed. Endoscopic cholecystolithotomy was successfully performed through the fistula. The ultrasound exam of gallbladder 4 weeks later showed no stone remain and satisfactory function. The EUS-guided placement of a novel metal stent was a safe and simple approach to performing an endoscopic cholecystogastrostomy, which can subsequently allow procedures for treating biliary disease, including cholecystolithotomy. PMID- 26020053 TI - Convex probe endobronchial ultrasound placement of fiducial markers for central lung nodule (with video). PMID- 26020054 TI - Pancreatic cancer with portal vein invasion diagnosed by endoscopic ultrasound. PMID- 26020055 TI - Contrast-enhanced harmonic endoscopic ultrasound in the diagnosis of primary pancreatic B-cell non-Hodgkin's lymphoma. PMID- 26020056 TI - Pericardial recess through the eyes of endobronchial ultrasound. PMID- 26020057 TI - Formation of Mercury(II)-Glutathione Conjugates Examined Using High Mass Accuracy Mass Spectrometry. AB - Maternal exposure to Hg(II) during pregnancy has been identified as a potential causal factor in the development of severe neurobehavioral disorders. Children with autism have been identified with lower reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios, and GSH is known to strongly bind Hg(II). In order to gain insight into the mechanism by which GSH binds Hg(II), high resolution mass spectrometry coupled with tandem mass spectrometry was utilized to examine the conjugation process. While the 1:1 Hg(II):GSH conjugate is not formed immediately upon mixing aqueous solutions of Hg(II) and GSH, two species containing Hg(II) are observed: the 1:2 Hg(II):GSH conjugate, [(GS)2Hg + H+], and a second Hg(II) containing species around m/z 544. Interestingly, this species at m/z 544 decreases in time while the presence of the 1:1 Hg(II):GSH conjugate increases, suggesting that m/z 544 is an intermediate in the formation of the 1:1 conjugate. Experiments using the high mass accuracy capability of Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry coupled to an electrospray ionization source indicate that the intermediate species is [GSH + HgCl]+, and not the 1:1 conjugate [Hg(GSH) - H + 2H2O]+ postulated in previous literature. Further confirmation of [GSH + HgCl]+ is supported by collision of induced dissociation experiments, which show neutral loss of HCl from the intermediate and loss of the N- and C-terminal amino acids, indicating binding of Hg(II) at the Cys residue. PMID- 26020058 TI - Does Nrf2 help nerves to survive? PMID- 26020059 TI - Expanding spectrum of neurologic manifestations in patients with NLRP3 low penetrance mutations. AB - OBJECTIVE: To evaluate the frequency of the cryoporin/NLRP3 low-penetrance mutations V198M and Q703K in patients who reported at least 2 symptoms compatible with cryopyrin-associated periodic syndromes (CAPS) and to characterize the phenotype in mutation-positive patients. METHODS: The frequency of the V198M and Q703K mutations was investigated in a selected cohort of 108 patients from our neuroimmunology department. We describe the clinical, neurologic, immunologic, and neuroradiologic features of the mutation carriers. RESULTS: Seventeen patients (16%) tested positive for either of the 2 mutations (V198M: n = 2; Q703K: n = 15). Eleven patients (65%) had severe headache syndromes. Six of these 11 patients were diagnosed with migraine. Nine patients (53%) had a concomitant diagnosis of multiple sclerosis (MS). In 3 patients, we identified additional family members with the respective mutation as well as the diagnosis of MS. Severe recurrent cranial nerve (CN) affection was the hallmark feature in 7 of the 8 (88%) non-MS mutation carriers. Brain MRI showed abnormalities in all but 2 patients (88%) and detected CN inflammation in 4 patients. Interleukin-6 was elevated in the CSF of 2 patients in the non-MS cohort during acute CAPS episodes with severe CNS inflammation. 5 of 9 treated patients (56%) responded to anti interleukin-1 therapy. CONCLUSION: CAPS constitute rare but treatable and commonly misdiagnosed autoinflammatory syndromes. Our data expand the spectrum of CAPS-associated neurologic manifestations. They also broaden our concept of autoimmunity and autoinflammation by linking CAPS and MS. PMID- 26020060 TI - F10 Inhibits Growth of PC3 Xenografts and Enhances the Effects of Radiation Therapy. AB - Chemotherapy remains of limited use for the treatment of prostate cancer with only one drug, docetaxel, demonstrating a modest survival advantage for treatment of late-stage disease. Data from the NCI 60 cell line screen indicated that the castration-resistant prostate cancer cell lines PC3 and DU145 were more sensitive than average to the novel polymeric fluoropyrimidine (FP), F10, despite displaying less than average sensitivity to the widely-used FP, 5FU. Here, we show that F10 treatment of PC3 xenografts results in a significant survival advantage (treatment to control ratio (T/C) days = 18; p < 0.001; n = 16) relative to control mice treated with saline. F10 (40 mg/kg/dose) was administered via jugular vein catheterization 3-times per week for five weeks. This aggressive dosing regimen was completed with no drug-induced weight loss and with no evidence of toxicity. F10 was also shown to sensitize PC3 cells to radiation and F10 was also shown to be a potent radiosensitizer of PC3 xenografts in vivo with F10 in combination with radiation resulting in significantly greater regression of PC3 xenografts than radiation alone. The results indicate that F10 in this pre-clinical setting is an effective chemotherapeutic agent and possesses significant radiosensitizing properties. PMID- 26020061 TI - Identification of proteins associated with Mycobacterium tuberculosis virulence pathway by their polar profile. AB - With almost one third of the world population infected, tuberculosis is one of the most devastating diseases worldwide and it is a major threat to any healthcare system. With the mathematical-computational method named "Polarity Index Method", already published by this group, we identified, with high accuracy (70%), proteins related to Mycobacterium tuberculosis bacteria virulence pathway from the Tuberculist Database. The test considered the totality of proteins cataloged in the main domains: fungi, bacteria, and viruses from three databases: Antimicrobial Peptide Database (APD2), Tuberculist Database, Uniprot Database, and four antigens of Mycobacterium tuberculosis: PstS-1, 38-kDa, 19-kDa, and H37Rv ORF. The method described was calibrated with each database to achieve the same performance, showing a high percentage of coincidence in the identification of proteins associated with Mycobacterium tuberculosis bacteria virulence pathway located in the Tuberculist Database, and identifying a polar pattern regardless of the group studied. This method has already been used in the identification of diverse groups of proteins and peptides, showing that it is an effective discriminant. Its metric considers only one physico-chemical property, i.e. polarity. PMID- 26020062 TI - Association between UBE2E2 variant rs7612463 and type 2 diabetes mellitus in a Chinese Han population. AB - UBE2E2 encodes ubiquitin-conjugating enzyme E2E2, which plays an important role in the synthesis and secretion of insulin. Two previous studies indicated that SNPs in UBE2E2 were associated with risk for type 2 diabetes mellitus (T2DM) in the Japanese and Korean populations, respectively. We examined the association of one SNP in this gene, rs7612463, with the risk of T2DM in 1957 Han participants in northeastern China, using an SNPscan(TM) Kit. rs7612463 genotype was significantly associated with risk for T2DM under various genetic models, including an additive model (P = 0.004), a dominant model (P = 0.024), and a recessive model (P = 0.008). The AA genotype was associated with a significantly decreased risk for T2DM (P = 0.004, OR = 0.513, 95% CI = 0.325-0.810) after adjustment for age, gender, and BMI. The heterozygous genotype, AC, was associated with increased risk for total cholesterol (mmol l-1; P = 0.031) and triglycerides (mmol l-1; P = 0.039) in control individuals. Our results show that rs7612463 is associated with T2DM, with homozygotes of the AA genotype at decreased risk for T2DM in the Chinese population. Additionally, heterozygotes may have decreased risk of T2DM due to insulin resistance. PMID- 26020063 TI - Human neutrophil peptide 3 could be functionally expressed in Rhodobacter sphaeroides. AB - Human neutrophil peptides (HNPs) possess high antimicrobial activities against a broad spectrum of microorganisms. Rhodobacter sphaeroides is the best characterized photosynthetic bacterium and exhibits potential as a novel expression system. Up to date, no literature has been reported regarding expression of HNP3 in Rb. sphaeroides. In the present study, the HNP3 gene fragment was amplified by SOE PCR and ligated into photosynthetic bacteria light harvesting complex 2 (LH2) expression vector leading to HNP3 fusion protein expression vector. The HNP3 fusion protein was successfully expressed as rapidly evaluated by the LH2 characteristic peaks at ~800 nm and ~850 nm before purification and SDS/PAGE. Subsequently, the HNP3 fusion protein was purified by one-step affinity chromatography, and could be rapidly detected by the color and the spectral absorption at ~800 nm and ~850 nm before SDS/PAGE. Antimicrobial activity assay suggested that the HNP3 fusion protein exhibited high antimicrobial activity towards E. coli. The present study may supply an insight into employing the novel Rb. sphaeroides expression system, exhibiting dramatic advantages over currently used commercial expression system, to heterologously express human neutrophil peptides. PMID- 26020064 TI - Apatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors. AB - Aberrant proangiogenic pathways have long been implicated in tumorigenesis and metastasis. Antiangiogenic therapies have shown efficacy in the treatment of a variety of solid tumors including lung, breast, colon, glioblastomas, and other solid tumor types. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), is an orally bioavailable agent currently being studied in multiple tumor types. Apatinib has shown a survival benefit in gastric cancer in a phase III trial and non-small cell lung cancer in a phase II trial. With a favorable side effect profile and improved outcomes, apatinib has demonstrated a substantial potential to augment therapeutic options in a variety of tumor types. PMID- 26020065 TI - Blinatumomab for the treatment of adult acute lymphoblastic leukemia. AB - The marker CD19 is frequently expressed on the surface of malignant B cells including non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL), which makes it an attractive target for antineoplastic therapy (1). T cells are part of the immune surveillance system for malignant cells (2). Blinatumomab is a bispecific T cell engager (BiTE((r))) antibody that binds both CD3-positive T cells and CD19-positive B cells via its two variable antigen-binding domains. Once bound to both the T and B cell, blinatumomab induces T-cell activation and subsequently perforin-mediated malignant B-cell death. It has shown efficacy in ALL with minimal residual disease, relapsed/refractory ALL, and NHL in phase I and II clinical trials. With a favorable safely profile and promising results, blinatumomab was granted accelerated FDA approval to treat B-cell ALL in December 2014. Herein, we will review the most relevant data related to blinatumomab in ALL. PMID- 26020066 TI - The treatment of rosacea with topical ivermectin. AB - The treatment of rosacea is challenging because several pathophysiologic processes may be involved, including neurovascular dysregulation and alterations in innate immune status. Demodex mites may play a role in the latter mechanism. Topical ivermectin is a new therapeutic modality which demonstrates antiparasitic and anti-inflammatory properties. This article reviews published evidence related to the efficacy and safety of topical ivermectin. PubMed was utilized to search for key words "topical ivermectin", "ivermectin cream" and "rosacea". Three clinical trials were found that studied topical ivermectin as a treatment option for rosacea. Ivermectin was effective, safe and well tolerated. PMID- 26020067 TI - A report from the 73rd Annual Meeting of the American Academy of Dermatology (March 20-24 - San Francisco, California, USA). AB - With five late-breaking research in dermatology forums, a very intensive program of other forum sessions and a popular electronic poster session with a wealth of new clinical and preclinical research, many of which reflecting advances in the management of skin and skin structure diseases that either endanger the lives of patients or severely limit their quality of life and psychological wellbeing, the American Academy of Dermatology meeting gathered attendees from all around the world to its annual meeting in San Francisco. The following report highlights some of the most relevant new findings directly related with therapy for conditions such as psoriasis, nonmelanoma skin cancer, and other inflammatory, immunological and infectious diseases of the skin. PMID- 26020068 TI - A report from the European Association for the Study of the Liver's 50th International Liver Congress (April 22-26 - Vienna, Austria). AB - While Vienna's Prater park offers a varied selection of options, from theme parks to lush gardens and prairies to enjoy the sun, the nearby Messe Wien convention center was the focus of attention in April 2015 for all the scientists, researchers and clinicians interested in viral hepatitis, nonalcoholic steatohepatitis, hepatocellular carcinoma and a variety of other liver diseases. Treatments and potential new therapeutic strategies for these hepatopathies were discussed during the 50th International Liver Congress organized by the European Association for the Study of the Liver. Echoing epidemiological facts and a high social interest for hepatitis C virus infection, new findings with investigational and potential new therapies for the disease centered much of the attention at the conference. Nevertheless, new research was also reported related to potential improvements in how other liver diseases, particularly hepatitis B virus infection, hepatocellular carcinoma and a range of inflammatory and immune mediated liver diseases, including rare hereditary diseases that should never be forgotten. PMID- 26020069 TI - The author responds. PMID- 26020070 TI - The author responds. PMID- 26020071 TI - Demographics of the profession. PMID- 26020072 TI - Imaging fibrosis in pancreatic cancer using second harmonic generation. PMID- 26020074 TI - Proceedings of the International Cow Fertility Conference 'New Science - New Practices' , 2014, Westport, Ireland. PMID- 26020073 TI - Pancreatic ductal calculous leading to gastric fistulization. PMID- 26020075 TI - Special issue dedicated to Emmet Keeffe. PMID- 26020076 TI - [Cefazolin: a well-tolerated treatment for methicillin-susceptible Staphylococcus aureus complicated bacteremia]. PMID- 26020077 TI - [Dengue vaccine: the onset of success?]. PMID- 26020078 TI - A safe hospital should be... PMID- 26020079 TI - Proceedings of the 2nd European Conference on the Biology of Hydrogen Sulfide, September 8-11, 2013, Exeter, England. PMID- 26020080 TI - "Inspirom"--overview of the relationship between the pulmonologist and the COPD patient in Romania. AB - The aim of the study was to provide an insight of the investigation related to multiple clinical and care problems encountered by COPD patients in relations with the practitioner. In a 6 month prospective observational study (sponsored by Servier Pharmaceutical Company), started in 2012 and completed in 2013, in out patient settings, we involved 39 doctors (from different pneumology centers of the country) and assessed the involvement of both doctors and 1,131 patients in their observance of the therapeutic indications, as well as patients' compliance with the medical instructions, 2 months after the therapeutic indication. In this observational study we analyzed through the new GOLD classification the COPD patients at the time of recruitment until the next monitoring visit in two months. We applied for the first time this new GOLD classification for Romanian COPD patients as an overview in a period of follow-up. Results showed that at detection time, 56% patients had mild and moderate obstruction (stage 1-2 GOLD) and 44% patients are in old GOLD stage 3-4. When we used new GOLD classification, 46.4% patients are in GOLD C and D stages, with 35% having CAT over 20 and 25% an mMRC over 2. There findings can be alarm signals related to the large number of smokers, the lack of involvement of doctors in fighting tobacco consumption, and over-assessment of mild stages of the disease. All these elements can guide future prevention programs and actions of active screening for this disease. PMID- 26020081 TI - The Conference of Interns in Pneumology 2014--a breath of fresh air for Romanian pneumology. PMID- 26020082 TI - Austin, Texas, USA: CHEST 2014--a different kind of pneumology Congress. PMID- 26020083 TI - What every renal care professional should know about transplantation. PMID- 26020084 TI - [Sequence analysis of 16S rDNA and pmoCAB gene cluster of trichloroethylene degrading methanotroph]. AB - Methanotrophs could degrade methane and various chlorinated hydrocarbons. The analysis on methane monooxygenase gene cluster sequence would help to understand its catalytic mechanism and enhance the application in pollutants biodegradation. The methanotrophs was enriched and isolated with methane as the sole carbon source in the nitrate mineral salt medium. Then, five chlorinated hydrocarbons were selected as cometabolic substrates to study the biodegradation. The phylogenetic tree of 16S rDNA using MEGE5.05 software was constructed to identify the methanotroph strain. The pmoCAB gene cluster encoding particulate methane monooxygenase (pMMO) was amplified by semi-nested PCR in segments. ExPASy was performed to analyze theoretical molecular weight of the three pMMO subunits. As a result, a strain of methanotroph was isolated. The phylogenetic analysis indicated that the strain belongs to a species of Methylocystis, and it was named as Methylocystis sp. JTC3. The degradation rate of trichloroethylene (TCE) reached 93.79% when its initial concentration was 15.64 MUmol/L after 5 days. We obtained the pmoCAB gene cluster of 3 227 bp including pmoC gene of 771 bp, pmoA gene of 759 bp, pmoB gene of 1 260 bp and two noncoding sequences in the middle by semi-nested PCR, T-A cloning and sequencing. The theoretical molecular weight of their corresponding gamma, beta and alpha subunit were 29.1 kDa, 28.6 kDa and 45.6 kDa respectively analyzed using ExPASy tool. The pmoCAB gene cluster of JTC3 was highly identical with that of Methylocystis sp. strain M analyzed by Blast, and pmoA sequences is more conservative than pmoC and pmoB. Finally, Methylocystis sp. JTC3 could degrade TCE efficiently. And the detailed analysis of pmoCAB from Methylocystis sp. JTC3 laid a solid foundation to further study its active sites features and its selectivity to chlorinated hydrocarbon. PMID- 26020095 TI - Sleep Management Strategy and Performance in an Extreme Mountain Ultra-marathon. AB - We intended to assess the relationship between sleep strategies and performance during the North-Face Ultra-Trail du Mont-Blanc 2013, to test the hypothesis that sleep management can influence athletic performance. Almost all runners specifically adopted sleep management strategies before the race. Among the finishers 72% didn't sleep at all during the race and 28% took a least one break for sleep. Non-sleepers completed the race faster than the sleepers (P = 0.0008). Race time was positively correlated with drowsiness (P < 0.0001) and negatively correlated with the number participations in this race (P = 0.0039). Runners who adopted a sleep management strategy based on increased sleep time before the race completed the race faster (P = 0.0258). Most finishers seemed to be aware of the importance of developing sleep management strategies and increasing sleep time some nights before the race appeared to be the most relevant strategy to improve performance. PMID- 26020096 TI - A novel lead design enables selective deep brain stimulation of neural populations in the subthalamic region. AB - OBJECTIVE: The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) as a treatment for Parkinson's disease are sensitive to the location of the DBS lead within the STN. New high density (HD) lead designs have been created which are hypothesized to provide additional degrees of freedom in shaping the stimulating electric field. The objective of this study is to compare the performances of a new HD lead with a conventional cylindrical contact (CC) lead. APPROACH: A computational model, consisting of a finite element electric field model combined with multi-compartment neuron and axon models representing different neural populations in the subthalamic region, was used to evaluate the two leads. We compared ring-mode and steering-mode stimulation with the HD lead to single contact stimulation with the CC lead. These stimulation modes were tested for the lead: (1) positioned in the centroid of the STN, (2) shifted 1 mm towards the internal capsule (IC), and (3) shifted 2 mm towards the IC. Under these conditions, we quantified the number of STN neurons that were activated without activating IC fibers, which are known to cause side-effects. MAIN RESULTS: The modeling results show that the HD lead is able to mimic the stimulation effect of the CC lead. Additionally, in steering mode stimulation there was a significant increase of activated STN neurons compared to the CC mode. SIGNIFICANCE: From the model simulations we conclude that the HD lead in steering-mode with optimized stimulation parameter selection can stimulate more STN cells. Next, the clinical impact of the increased number of activated STN cells should be tested and balanced across the increased complexity of identifying the optimized stimulation parameter settings for the HD lead. PMID- 26020097 TI - Special issue of Platelets in celebration of Stan Heptinstall, founder and Editor in-Chief (1990-2015). PMID- 26020098 TI - Rhenium and Technetium Complexes with Pentadentate Thiocarbamoylbenzamidines: Steps toward Bioconjugation. AB - Thiocarbamoylbenzimidoyl chlorides, PhC(Cl)?N-(C?S)-NR(1)R(2), react with 2 (iminodiacetic acid)benzylamine under formation of the potentially pentadentate ligands H3L (R(1), R(2) = Et) and H3L-COOEt (R(1) = Me, R(2) = C6H4-4-COOEt) in high yields. Hydrolysis of H3L-COOEt in NaOH/MeOH gives quantitatively another benzamidine ligand H3L-COOH. The novel ligands readily react with (NBu4)[MOCl4] (M = Re, Tc) under formation of stable complexes with the general composition [MO(L)], in which they are triply deprotonated and fully occupy the remaining five coordination positions of the {MO}(3+) cores. In a "proof-of-principle" reaction for possible bioconjugations, the complex [ReO(L-COOH)] has been labeled with triglycine ethyl ester in high yields. PMID- 26020099 TI - Ab Initio Anharmonic Analysis of Vibrational Spectra of Uracil Using the Numerical-Analytic Implementation of Operator Van Vleck Perturbation Theory. AB - The numerical-analytic implementation of the operator version of the canonical Van Vleck second-order vibrational perturbation theory (CVPT2) is employed for a purely ab initio prediction and interpretation of the infrared (IR) and Raman anharmonic spectra of a medium-size molecule of the diketo tautomer of uracil (2,4(1H,3H)-pyrimidinedione), which has high biological importance as one of the four RNA nucleobases. A nonempirical, semidiagonal quartic potential energy surface (PES) expressed in normal coordinates was evaluated at the MP2/cc-pVTZ level of theory. The quality of the PES was improved by replacing the harmonic frequencies with the "best" estimated CCSD(T)-based values taken from the literature. The theoretical method is enhanced by an accurate treatment of multiple Fermi and Darling-Dennison resonances with evaluation of the corresponding resonance constants W and K (CVPT2+WK method). A prediction of the anharmonic frequencies as well as IR and Raman intensities was used for a detailed interpretation of the experimental spectra of uracil. Very good agreement between predicted and observed vibrational frequencies has been achieved (RMSD ~4.5 cm(-1)). The model employed gave a theoretically robust treatment of the multiple resonances in the 1680-1790 cm(-1) region. Our new analysis gives the most reliable reassignments of IR and Raman spectra of uracil available to date. PMID- 26020100 TI - "Smart" Nanoparticles Enhance the Cytoplasmic Delivery of Anti-RhoC Silencing RNA and Inhibit the Migration and Invasion of Aggressive Breast Cancer Cells. AB - Rho-GTPases are small GTP-binding proteins that contribute to the epithelial-to mesenchymal transition by regulating several cellular processes including organization of the actin cytoskeleton, cell motility, transcription, and cell proliferation. Overexpression of RhoC-GTPases (RhoC) in breast cancer has been implicated in poor disease prognosis due to increased cancer cells invasion, migration, and motility, which warranted its consideration as a therapeutic target for inhibiting breast cancer metastasis. Using silencing RNA (siRNA) molecules to knockdown RhoC expression is a promising approach to inhibit breast cancer metastases. However, transforming anti-RhoC siRNA molecules into a viable therapy remains a challenge due to the lack of a biocompatible carrier that can selectively deliver the RNA cargo into breast cancer cells. We report the use of a degradable, pH-sensitive, beta-cyclodextrin (betaCD)-based polymeric carrier that condenses anti-RhoC siRNA forming "smart" particles. These smart anti-RhoC particles were efficiently internalized, successfully escaped the endosome, and delivered the RNA cargo into the cytoplasm of SUM149 and MDA-MB-231 breast cancer cells. Our results show that anti-RhoC particles used at a low N/P ratio of 2.5/1 suppressed RhoC protein levels by 100% and 90% in SUM149 and MDA-MB-231 cells, respectively. Further, anti-RhoC particles inhibited the invasion, motility, and migration of SUM149 and MDA-MB-231 cells by 40-47%, 57-60%, and 61.5-73%, respectively. Smart particles encapsulating the scrambled siRNA sequence did not affect RhoC protein expression or the invasion, motility, and migration of SUM149 and MDA-MB-231 cells, which indicate the biocompatibility of the polymeric carrier and selectivity of the observed RhoC knockdown. These results collectively indicate the therapeutic potential of smart anti-RhoC particles in arresting the metastatic spread of breast cancer cells. PMID- 26020102 TI - Gas Transfer in Cellularized Collagen-Membrane Gas Exchange Devices. AB - Chronic lower respiratory disease is highly prevalent in the United States, and there remains a need for alternatives to lung transplant for patients who progress to end-stage lung disease. Portable or implantable gas oxygenators based on microfluidic technologies can address this need, provided they operate both efficiently and biocompatibly. Incorporating biomimetic materials into such devices can help replicate native gas exchange function and additionally support cellular components. In this work, we have developed microfluidic devices that enable blood gas exchange across ultra-thin collagen membranes (as thin as 2 MUm). Endothelial, stromal, and parenchymal cells readily adhere to these membranes, and long-term culture with cellular components results in remodeling, reflected by reduced membrane thickness. Functionally, acellular collagen membrane lung devices can mediate effective gas exchange up to ~288 mL/min/m(2) of oxygen and ~685 mL/min/m(2) of carbon dioxide, approaching the gas exchange efficiency noted in the native lung. Testing several configurations of lung devices to explore various physical parameters of the device design, we concluded that thinner membranes and longer gas exchange distances result in improved hemoglobin saturation and increases in pO2. However, in the design space tested, these effects are relatively small compared to the improvement in overall oxygen and carbon dioxide transfer by increasing the blood flow rate. Finally, devices cultured with endothelial and parenchymal cells achieved similar gas exchange rates compared with acellular devices. Biomimetic blood oxygenator design opens the possibility of creating portable or implantable microfluidic devices that achieve efficient gas transfer while also maintaining physiologic conditions. PMID- 26020101 TI - Safety, reactogenicity and immunogenicity of 2-dose catch-up vaccination with 10 valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Malian children in the second year of life: Results from an open study. AB - Pneumonia is still the leading cause of death among African children with pneumococcal serotypes 1 and 5 being dominant in the below 5 y of age group. The present study assessed the safety, reactogenicity and immunogenicity of a 2-dose catch-up vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) in Malian children. This phase III, open-label study (NCT00985465) was conducted in Ouelessebougou, Mali, between November 2009 and July 2010. The study population consisted of PHiD-CV unprimed Malian children previously enrolled in the control group of study NCT00678301 receiving a 2-dose catch-up vaccination with PHiD-CV in the second year of life. Adverse events were recorded following each PHiD-CV dose. Antibody responses and opsonophagocytic activity (OPA) were measured pre-vaccination and after the second PHiD-CV catch-up dose. Swelling and fever (axillary temperature >= 37.5 degrees C) were the most frequently reported solicited symptoms following either PHiD-CV dose. Few grade 3 solicited symptoms were reported. Large swelling reactions and serious adverse events were not reported. Post-catch-up vaccination, for each vaccine pneumococcal serotype, at least 94.7% of subjects had antibody concentrations >= 0.2 MUg/ml, except for serotypes 6B (82.5%) and 23F (87.7%). At least 94.0% of subjects had OPA titres >= 8, except for serotype 19F (89.4%). The geometric mean concentration for antibodies against protein D was 839.3 (95% CI: 643.5-1094.6) EL.U/ml. Two-dose PHiD-CV catch-up regimen in the second year of life was well-tolerated and immunogenic for all vaccine pneumococcal serotypes and NTHi protein D when administered to Malian children. PMID- 26020103 TI - Direct Dehydroxylative Coupling Reaction of Alcohols with Organosilanes through Si-X Bond Activation by Halogen Bonding. AB - The combined use of a halogen bond (XB) donor with trimethylsilyl halide was found to be an efficient cocatalytic system for the direct dehydroxylative coupling reaction of alcohol with various nucleophiles, such as allyltrimethylsilane and trimethylcyanide, to give the corresponding adduct in moderate to excellent yields. Detailed control experiments and mechanistic studies revealed that the XB interaction was crucial for the reaction. The application of this coupling reaction is also described. PMID- 26020104 TI - Assessment of Modification of Diet in Renal Disease Equation to Predict Reference Serum Creatinine Value in Severe Trauma Patients: Lessons From an Observational Study of 775 Cases. AB - OBJECTIVE: We assessed the Modification of Diet in Renal Disease (MDRD) performance to predict serum creatinine (SCr) in severe trauma population and determined the best theoretical glomerular filtration rate (GFR) to use in this estimation. BACKGROUND: Baseline SCr may be misestimated in severe trauma patients because of their specific demographic characteristics including renal hyperfiltration. However, the back-calculated MDRD equation is supposed to estimate SCr using a predetermined GFR of 75 mL/min/1.73 m. METHODS: All severe trauma patients with a normal SCr were retrospectively included between January 2005 and January 2011. For each patient, the lowest SCr (oSCr) observed during the first week was used to estimate the GFR. The median GFR in period 1 (2005 2006) was determined. The back-calculated MDRD performance was assessed in period 2 (2007-2011) to predict oSCr by agreement, precision, and accuracy using a GFR of 75 mL/min/1.73 m (eSCr75-MDRD) or the median GFR observed in period 1 (eSCrTRAUMA-MDRD). RESULTS: A total of 775 patients were studied: mean age, 37.7 +/- 17 years; mean Injury Severity Score, 19 +/- 11; 75% of male. In period 1 (n = 243), median GFR was 121 mL/min/1.73 m. In period 2 (n = 532), eSCrTRAUMA-MDRD demonstrated better agreement in predicting oSCr than eSCr75-MDRD (mean bias 2 vs 35 MUmol/L; P < 0.001). Both precision (14 vs 39 MUmol/L, respectively) and accuracy were significantly improved with eSCrTRAUMA-MDRD. Proportion of estimated SCr values that deviated less than 15%, 30%, or 50% was also higher with eSCrTRAUMA-MDRD (P < 0.001). CONCLUSIONS: The eSCr75-MDRD equation systematically overestimates oSCr of severe trauma patients. The eSCrTRAUMA-MDRD equation determined was statistically superior allowing more accurate qualification of acute kidney injury. PMID- 26020105 TI - Reliable Detection of Somatic Mutations in Fine Needle Aspirates of Pancreatic Cancer With Next-generation Sequencing: Implications for Surgical Management. AB - OBJECTIVE: To determine the feasibility of genotyping pancreatic tumors via fine needle aspirates (FNAs). BACKGROUND: FNA is a common method of diagnosis for pancreatic cancer, yet it has traditionally been considered inadequate for molecular studies due to the limited quantity of DNA derived from FNA specimens and tumor heterogeneity. METHODS: In vitro mixing studies were performed to deduce the minimum cellularity needed for genetic analysis. DNA from both simulated FNAs and clinical FNAs was sequenced. Mutational concordance was determined between simulated FNAs and that of the resected specimen. RESULTS: Limiting dilution studies indicated that mutations present at allele frequencies as low as 0.12% are detectable. Comparison of simulated FNAs and matched tumor tissue exhibited a concordance frequency of 100% for all driver genes present. In FNAs obtained from 17 patients with unresectable disease, we identified at least 1 driver gene mutation in all patients including actionable somatic mutations in ATM and MTOR. The constellation of mutations identified in these patients was different than that reported for resectable pancreatic cancers, implying a biologic basis for presentation with locally advanced pancreatic cancer. CONCLUSIONS: FNA sequencing is feasible and subsets of patients may harbor actionable mutations that could potentially impact therapy. Moreover, preoperative FNA sequencing has the potential to influence the timing of surgery relative to systemic therapy. FNA sequencing opens the door to clinical trials in which patients undergo neoadjuvant or a surgery-first approach based on their tumor genetics with the goal of utilizing cancer genomics in the clinical management of pancreatic cancer. PMID- 26020106 TI - Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5. AB - OBJECTIVES: To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. BACKGROUND: Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival. METHODS: Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. RESULTS: Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-kappaB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon alpha mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves). CONCLUSIONS: These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs. PMID- 26020111 TI - Variation in Transfusion Practices and the Effect on Outcomes After Noncardiac Surgery. AB - OBJECTIVES: To identify the patient-level effects of blood transfusion on postoperative outcomes and to estimate the effects of different transfusion practices on hospital-level risk-adjusted outcomes. BACKGROUND: Postoperative transfusion practices and their effects on short-term outcomes in patients undergoing noncardiac surgery are not well understood. METHODS: Demographic, operative, and outcomes data for 48,720 patients undergoing general or vascular surgery at 52 hospitals between July 2012 and April 2014 were obtained. The main exposure variable was receipt of any blood transfusion within 72 hours after surgery. Thirty-day mortality, any morbidity, infectious complications, and postoperative myocardial infarction were the outcomes of interest. Propensity score matching was used to minimize confounding by indication. Hospitals were categorized as having a restrictive, average, or liberal transfusion practice based on average trigger hemoglobin values. RESULTS: A total of 2243 (4.6%) patients received a postoperative blood transfusion. After propensity matching, a postoperative transfusion was associated with increased 30-day mortality (3.6% excess absolute risk), any morbidity (4.4% excess absolute risk), and infectious morbidity (1.0% excess absolute risk). However, a transfusion was associated with 3.5% absolute risk reduction in postoperative myocardial infarction. At the hospital level, there was a wide variation in transfusion practices. Hospitals with liberal practices were twice as likely to transfuse patients and had higher risk-adjusted mortality rates than restrictive hospitals (3.1% vs 2.2%; P = 0.002). CONCLUSIONS AND RELEVANCE: Postoperative transfusions after noncardiac surgery are associated with increased adverse postoperative outcomes, with the exception of postoperative myocardial infarction. Hospitals that are liberal in their transfusion practices have higher 30-day mortality rates, suggesting potential interventions for quality improvement. PMID- 26020107 TI - Multicenter Prospective Comparative Study of Robotic Versus Laparoscopic Gastrectomy for Gastric Adenocarcinoma. AB - OBJECTIVE: To compare short-term surgical outcomes including financial cost of robotic and laparoscopic gastrectomy. BACKGROUND: Despite a lack of supporting evidence, robotic surgery has been increasingly adopted as a minimally invasive modality for the treatment of gastric cancer because of its assumed technical superiority over conventional laparoscopy. METHODS: A prospective, multicenter comparative study was conducted. Patients were matched according to the surgeon, extent of gastric resection, and sex. The primary endpoint was morbidity and mortality. Outcomes were analyzed on an intention-to-treat and per-protocol basis. RESULTS: A total of 434 patients were enrolled for treatment with either robotic (n = 223) or laparoscopic (n = 211) gastrectomy for intention-to-treat analysis, and a total of 370 patients (n = 185 per treatment) were compared in per-protocol analysis. Results were similar between both analyses. In per protocol analysis, both groups showed similar overall complication rates (robotic = 11.9% vs laparoscopic = 10.3%) and major complication rates (robotic = 1.1% vs laparoscopic = 1.1%) with no operative mortality in either group. Patients treated with robotic surgery showed significantly longer operative time (robotic = 221 minutes vs laparoscopic = 178 minutes; P < 0.001) and significantly higher total costs (robotic = US$13,432 vs laparoscopic = US$8090; P < 0.001), compared with those who underwent laparoscopic gastrectomy. No significant differences between groups were noted in estimated blood loss, rates of open conversion, diet build-up, or length of hospital stay. CONCLUSIONS: The use of robotic systems is assumed to provide a technically superior operative environment for minimally invasive surgery. However, our analysis of perioperative surgical outcomes indicated that robotic gastrectomy is not superior to laparoscopic gastrectomy. Clinical trials identification: NCT01309256. PMID- 26020112 TI - Blood Transfusion Strategy and Clinical Outcomes. PMID- 26020113 TI - The Association of Insurance Status and Race With Transfers of Patients With Traumatic Brain Injury Initially Evaluated at Level III and IV Trauma Centers. AB - OBJECTIVE: To investigate the association of lack of insurance and African American race with the probability of transfer to level I/II trauma centers after evaluation in the emergency department of level III/IV trauma centers for traumatic brain injury (TBI). BACKGROUND: The influence of nonmedical factors on the disposition of TBI patients initially seen in less specialized institutions is debated. METHODS: We conducted a retrospective cohort study involving TBI patients who were registered in the National Trauma Data Bank between 2009 and 2011. Regression methods were used to investigate the association of insurance status and race with the disposition of TBI patients evaluated in less specialized trauma centers. RESULTS: During the study period, there were 26,031 TBI patients who were registered in the National Trauma Data Bank and met inclusion criteria. Of these, 10,572 (35.9%) were transferred to a higher level of care institution. Multivariable logistic regression after coarsened exact matching demonstrated an association of uninsured patients with an increased possibility of transfer (odds ratio [OR] = 1.22; 95% confidence interval [CI], 1.05-1.42). On the contrary, there was no association of African Americans with transfers (OR = 1.27; 95% CI, 0.99-1.62). Those with Glasgow Coma Scale score above 8 (OR = 1.22; 95% CI, 1.08-1.39) or Injury Severity Score below 16 (OR = 1.33; 95% CI, 1.13-1.56) had a higher possibility of transfer. CONCLUSIONS: In TBI patients, lack of insurance was associated with an increased possibility of transfer to higher level of care institutions after evaluation in a level III or IV trauma center emergency department. Regardless of insurance status, this transfer pattern was also observed for African Americans, but only for those with milder injuries. PMID- 26020114 TI - Insurance Status and Trauma Patient Transfer: "Deja vu All Over Again" Yogi Berra Baseball Hall of Famer and Street Corner Philosopher, circa 1960s. PMID- 26020115 TI - Commentary on "Simultaneous Resection of High-risk Liver Tumors and Pulmonary Metastases in Children". PMID- 26020116 TI - The RAPID Concept-Novel Idea or a Bridge Too Far? PMID- 26020118 TI - Copper-Catalyzed Aerobic Oxidations of Organic Molecules: Pathways for Two Electron Oxidation with a Four-Electron Oxidant and a One-Electron Redox-Active Catalyst. AB - Selective oxidation reactions have extraordinary value in organic chemistry, ranging from the conversion of petrochemical feedstocks into industrial chemicals and polymer precursors to the introduction of heteroatom functional groups into pharmaceutical and agrochemical intermediates. Molecular oxygen (O2) would be the ideal oxidant for these transformations. Whereas many commodity-scale oxidations of simple hydrocarbon feedstocks employ O2 as an oxidant, methods for selective oxidation of more complex molecules bearing diverse functional groups are often incompatible with existing aerobic oxidation methods. The latter limitation provides the basis for our interest in the development of new catalytic transformations and the elucidation of mechanistic principles that underlie selective aerobic oxidation reactions. One challenge inherent in such methods is the incommensurate redox stoichiometry associated with the use of O2, a four electron oxidant, in reactions that achieve two-electron oxidation of organic molecules. This issue is further complicated by the use of first-row transition metal catalysts, which tend to undergo facile one-electron redox steps. In recent years, we have been investigating Cu-catalyzed aerobic oxidation reactions wherein the complexities just noted are clearly evident. This Account surveys our work in this area, which has emphasized three general classes of reactions: (1) single-electron-transfer reactions for oxidative functionalization of electron rich substrates, such as arenes and heterocycles; (2) oxidative carbon-heteroatom bond-forming reactions, including C-H oxidations, that proceed via organocopper(III) intermediates; and (3) methods for aerobic oxidation of alcohols and amines that use Cu(II) in combination with an organic redox-active cocatalyst to dehydrogenate the carbon-heteroatom bond. These reaction classes demonstrate three different pathways to achieve two-electron oxidation of organic molecules via the cooperative involvement of two one-electron oxidants, either two Cu(II) species or Cu(II) and a nitroxyl cocatalyst. They show the ability of Cu to participate in traditional organometallic steps commonly associated with precious-metal catalysts, such as C-H activation and reductive elimination, but also demonstrate the accessibility of reaction steps not typically associated with precious-metal catalysts, such as single-electron transfer. Many of the Cu catalyzed reactions offer advantages over analogous two-electron oxidation reactions mediated by palladium or other noble metals. For example, carbon heteroatom oxidative coupling reactions in the first two reaction classes noted above are capable of using O2 as the terminal oxidant, while analogous reactions with Pd commonly require less desirable oxidants, such as hypervalent iodine or electrophilic halogen sources. In addition, the alcohol and amine oxidations in the third reaction class are significantly more efficient and show much broader scope and functional group tolerance than related Pd-catalyzed reactions. The mechanistic basis for these differences are described herein. PMID- 26020117 TI - Identification of a distinct population of CD133(+)CXCR4(+) cancer stem cells in ovarian cancer. AB - CD133 and CXCR4 were evaluated in the NCI-60 cell lines to identify cancer stem cell rich populations. Screening revealed that, ovarian OVCAR-3, -4 and -5 and colon cancer HT-29, HCT-116 and SW620 over expressed both proteins. We aimed to isolate cells with stem cell features sorting the cells expressing CXCR4(+)CD133(+) within ovarian cancer cell lines. The sorted population CD133(+)CXCR4(+) demonstrated the highest efficiency in sphere formation in OVCAR 3, OVCAR-4 and OVCAR-5 cells. Moreover OCT4, SOX2, KLF4 and NANOG were highly expressed in CD133(+)CXCR4(+) sorted OVCAR-5 cells. Most strikingly CXCR4(+)CD133(+) sorted OVCAR-5 and -4 cells formed the highest number of tumors when inoculated in nude mice compared to CD133(-)CXCR4(-), CD133(+)CXCR4(-), CD133(-)CXCR4(+) cells. CXCR4(+)CD133(+) OVCAR-5 cells were resistant to cisplatin, overexpressed the ABCG2 surface drug transporter and migrated toward the CXCR4 ligand, CXCL12. Moreover, when human ovarian cancer cells were isolated from 37 primary ovarian cancer, an extremely variable level of CXCR4 and CD133 expression was detected. Thus, in human ovarian cancer cells CXCR4 and CD133 expression identified a discrete population with stem cell properties that regulated tumor development and chemo resistance. This cell population represents a potential therapeutic target. PMID- 26020119 TI - Leuco-crystal-violet micelle gel dosimeters: II. Recipe optimization and testing. AB - In this study, recipe optimization of Leuco Crystal Violet (LCV) micelle gels made with the surfactant Cetyl Trimethyl Ammonium Bromide (CTAB) and the chemical sensitizer 2,2,2-trichloroethanol (TCE) was aided by a two-level three-factor designed experiment. The optimized recipe contains 0.75 mM LCV, 17.0 mM CTAB, 120 mM TCE, 25.0 mM tri-chloro acetic acid (TCAA), 4 wt% gelatin and ~96 wt% water. Dose sensitivity of the optimized gel is 1.5 times higher than that of Jordan's standard LCV micelle gel. Spatial integrity of the 3D dose distribution information in 1L phantoms filled with this recipe is maintained for >120 d. Unfortunately, phantoms made using the optimized recipe showed dose-rate dependence (14% difference in optical attenuation at the peak dose using electron beam irradiations at 100 and 400 MU min(-1)). Further testing suggests that the surfactant CTAB is the cause of this dose rate behaviour. PMID- 26020120 TI - The effect of composition on diffusion of macromolecules in a crowded environment. AB - We study diffusion of macromolecules in a crowded cytoplasm-like environment, focusing on its dependence on composition and its crossover to the anomalous subdiffusion. The crossover and the diffusion itself depend on both the volume fraction and the relative concentration of macromolecules. In accordance with previous theoretical and experimental studies, diffusion slows down when the volume fraction increases. Contrary to expectations, however, the diffusion is also strongly dependent on the molecular composition. The crossover time decreases and diffusion slows down when the smaller macromolecules start to dominate. Interestingly, diffusion is faster in a cytoplasm-like (more polydisperse) system than it is in a two-component system, at comparable packing fractions, or even when the cytoplasm packing fraction is larger. PMID- 26020121 TI - SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid. AB - OBJECTIVE: Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1 gene) is a hepatic uptake transporter, and its genetic variability is associated with pharmacokinetics and muscle toxicity risk of simvastatin. We examined the possible effects of variations in the SLCO1B1 gene on the pharmacokinetics of lovastatin in a prospective genotype panel study. PARTICIPANTS AND METHODS: Seven healthy volunteers with the SLCO1B1*1B/*1B genotype, five with the SLCO1B1*5/*15 or *15/*15 genotype, and 15 with the SLCO1B1*1A/*1A genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of lovastatin. Plasma concentrations of lovastatin (inactive lactone) and its active metabolite lovastatin acid were measured up to 24 h. RESULTS: In the SLCO1B1*5/*15 or *15/*15 genotype group, the geometric mean Cmax and AUC0-24 of lovastatin acid were 340 and 286% of the corresponding values in the SLCO1B1*1A/*1A (reference) genotype group (P<0.005). In contrast, the AUC0 24 of lovastatin acid in the SLCO1B1*1B/*1B genotype group was only 68% of that in the reference genotype group (P=0.03). No statistically significant association was observed between the SLCO1B1 genotype and the pharmacokinetics of lovastatin lactone. CONCLUSION: SLCO1B1*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on lovastatin lactone, similar to their effects on simvastatin and simvastatin acid. Accordingly, it is probable that the risk of muscle toxicity during lovastatin treatment is increased in individuals carrying the SLCO1B1*5 or *15 allele. The SLCO1B1*1B/*1B genotype is associated with reduced lovastatin acid concentrations, consistent with enhanced hepatic uptake. PMID- 26020122 TI - The Structural Relationship Between Two Motor Sequences Practiced Close in Time Impacts Offline Facilitation. AB - Robust offline gains occur during explicit motor sequence learning. However practice of a motor sequence, other than the target sequence, within 4-6 hr after initial practice interferes with these gains. This work assessed if experiencing supplemental practice of spatially or motorically similar sequences influenced the extent of offline gain. A contemporary model of sequence learning assumes that exposure to a spatially but not motor-related sequence would not compromise stabilization of the memory for the target sequence, thus, would have minimal impact on the resultant offline gain and possibly amplify overnight gains. As anticipated, a reliable offline improvement was observed for the target motor sequence in the absence of practice with an alternative motor sequence. This gain was significantly reduced when the learner experienced additional practice with either a novel or motorically similar sequence. There was no evidence of heightened overnight gain for the target sequence from intervening practice with a spatially similar sequence. Thus, the expression of offline improvement is not necessarily eliminated if practice of an alternative motor sequence is encountered shortly after a target sequence. However, the structure of the motor sequence faced during intervening practice can impact the resultant postpractice consolidation processes reflected in the eventual expression of offline facilitation. PMID- 26020124 TI - Combination Treatment with All-Trans Retinoic Acid Prevents Cisplatin-Induced Enrichment of CD133+ Tumor-Initiating Cells and Reveals Heterogeneity of Cancer Stem Cell Compartment in Lung Cancer. AB - The existence of specific cellular subpopulations within primary tumors with increased tumorigenic potential and chemotherapy resistance (tumor-initiating cells, TICs) holds great therapeutic implications. Resistant cells can remain quiescent for long periods and be responsible for local relapses and metastasis. We and others have previously described in non-small-cell lung cancer the presence of cisplatin-resistant CD133+ cells with tumor-initiating potential and co-expression of CXCR4 as possible indicator of TICs with disseminating potential. In this study, we report, by in vitro cell fate tracing systems, heterogeneity within the TIC compartment with a highly quiescent pool and a slowly dividing subpopulation, both containing CD133+ cells but respectively enriched for CD133+/CXCR4- and CD133+/CXCR4+ cells. Pretreatment with differentiating agent all-trans retinoic acid counteracts cisplatin resistance specifically of the slowly dividing compartment indicating effect on CD133+/CXCR4+ cells. The same effects are appreciable also in vivo in patient derived xenografts, where several cycles of all-trans retinoic acid and cisplatin treatment are able to stably reduce this fraction of TICs and tumor dissemination. Thus, partially affecting the heterogeneous TICs compartment, differentiating therapy has promising effects in counteracting cisplatin resistance of CD133+ cells, reducing both local tumor growth and dissemination. In addition, our approach discloses a further level of complexity of chemotherapy resistant CD133+ TICs, revealing phenotypical and functional heterogeneity of the cancer stem cell compartment in lung cancer. PMID- 26020125 TI - Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors. AB - INTRODUCTION: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies. METHODS: This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy. The study comprised two parts: dose escalation and dose expansion. Ceritinib (single dose) was administered orally in the 3-day PK run-in period, then once daily, in 21-day cycles. Adaptive dose escalations were guided by a Bayesian model. RESULTS: Twenty patients (80% with ALKi treatment history [ALKi-pretreated]; 19 NSCLC; one inflammatory myofibroblastic tumor) received ceritinib 300 to 750 mg (19 during dose escalation, one in dose expansion). Two dose-limiting toxicities occurred: grade 3 lipase increase (600 mg); grade 3 drug-induced liver injury (750 mg). The most common adverse events were gastrointestinal (nausea: 95%; diarrhea, vomiting: 75%). Ceritinib PK profile was dose proportional across 300 to 750 mg dosages; steady state was reached by day 15. Overall response rate was 55% (11 of 20 patients). Among patients with NSCLC, partial response was observed in two of four ALKi-naive patients, five of nine crizotinib-pretreated patients, two of four alectinib-pretreated patients, and one of two crizotinib and alectinib/ASP3026 pretreated patients. The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response. CONCLUSIONS: Ceritinib maximum-tolerated dose was 750 mg once daily in Japanese patients. Antitumor activity was observed irrespective of prior ALKi treatment history. Dose expansion, examining the activity of ceritinib in alectinib-resistant patients, is ongoing. PMID- 26020126 TI - Fibroblast Growth Factor Receptor 1 and Related Ligands in Small-Cell Lung Cancer. AB - INTRODUCTION: Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been understudied for novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor has recently emerged as a contributing factor in the pathogenesis and progression of non-small-cell lung cancer. In this study, we evaluated fibroblast growth factor receptor 1 (FGFR1) and ligand expression in primary SCLC samples. METHODS: FGFR1 protein expression, messenger RNA (mRNA) levels, and gene copy number were determined by immunohistochemistry (IHC), mRNA in situ hybridization, and silver in situ hybridization, respectively, in primary tumors from 90 patients with SCLC. Protein and mRNA expression of the FGF2 and FGF9 ligands were determined by IHC and mRNA in situ hybridization, respectively. In addition, a second cohort of 24 SCLC biopsy samples with known FGFR1 amplification by fluorescence in situ hybridization was assessed for FGFR1 protein expression by IHC. Spearman correlation analysis was performed to evaluate associations of FGFR1, FGF2 and FGF9 protein levels, respective mRNA levels, and FGFR1 gene copy number. RESULTS: FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 mRNA levels (p < 0.0001) and FGFR1 gene copy number (p = 0.03). The prevalence of FGFR1 mRNA positivity was 19.7%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.002) mRNA levels, as well as with FGF2 (p = 0.01) and FGF9 (p = 0.001) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. In the second cohort of specimens with known FGFR1 amplification by fluorescence in situ hybridization, 23 of 24 had adequate tumor by IHC, and 73.9% (17 of 23) were positive for FGFR1 protein expression. CONCLUSIONS: A subset of SCLCs is characterized by potentially activated FGF/FGFR1 pathways, as evidenced by positive FGF2, FGF9, and FGFR1 protein and/or mRNA expression. FGFR1 protein expression is correlated with FGFR1 mRNA levels and FGFR1 gene copy number. Combined analysis of FGFR1 and ligand expression may allow selection of patients with SCLC to FGFR1 inhibitor therapy. PMID- 26020127 TI - Manganese-Cycling Microbial Communities Inside Deep-Sea Manganese Nodules. AB - Polymetallic nodules (manganese nodules) have been formed on deep sea sediments over millions of years and are currently explored for their economic potential, particularly for cobalt, nickel, copper, and manganese. Here we explored microbial communities inside nodules from the northeastern equatorial Pacific. The nodules have a large connected pore space with a huge inner surface of 120 m(2)/g as analyzed by computer tomography and BET measurements. X-ray photoelectron spectroscopy (XPS) and electron microprobe analysis revealed a complex chemical fine structure. This consisted of layers with highly variable Mn/Fe ratios (<1 to >500) and mainly of turbostratic phyllomanganates such as 7 and 10 A vernadites alternating with layers of Fe-bearing vernadite (delta-MnO2) epitaxially intergrown with amorphous feroxyhyte (delta-FeOOH). Using molecular 16S rRNA gene techniques (clone libraries, pyrosequencing, and real-time PCR), we show that polymetallic nodules provide a suitable habitat for prokaryotes with an abundant and diverse prokaryotic community dominated by nodule-specific Mn(IV) reducing and Mn(II)-oxidizing bacteria. These bacteria were not detected in the nodule-surrounding sediment. The high abundance and dominance of Mn-cycling bacteria in the manganese nodules argue for a biologically driven closed manganese cycle inside the nodules relevant for their formation and potential degradation. PMID- 26020123 TI - Development and validation of a score to predict postoperative respiratory failure in a multicentre European cohort: A prospective, observational study. AB - BACKGROUND: Postoperative respiratory failure (PRF) is the most frequent respiratory complication following surgery. OBJECTIVE: The objective of this study was to build a clinically useful predictive model for the development of PRF. DESIGN: A prospective observational study of a multicentre cohort. SETTING: Sixty-three hospitals across Europe. PATIENTS: Patients undergoing any surgical procedure under general or regional anaesthesia during 7-day recruitment periods. MAIN OUTCOME MEASURES: Development of PRF within 5 days of surgery. PRF was defined by a partial pressure of oxygen in arterial blood (PaO2) less than 8 kPa or new onset oxyhaemoglobin saturation measured by pulse oximetry (SpO2) less than 90% whilst breathing room air that required conventional oxygen therapy, noninvasive or invasive mechanical ventilation. RESULTS: PRF developed in 224 patients (4.2% of the 5384 patients studied). In-hospital mortality [95% confidence interval (95% CI)] was higher in patients who developed PRF [10.3% (6.3 to 14.3) vs. 0.4% (0.2 to 0.6)]. Regression modelling identified a predictive PRF score that includes seven independent risk factors: low preoperative SpO2; at least one preoperative respiratory symptom; preoperative chronic liver disease; history of congestive heart failure; open intrathoracic or upper abdominal surgery; surgical procedure lasting at least 2 h; and emergency surgery. The area under the receiver operating characteristic curve (c-statistic) was 0.82 (95% CI 0.79 to 0.85) and the Hosmer-Lemeshow goodness-of-fit statistic was 7.08 (P = 0.253). CONCLUSION: A risk score based on seven objective, easily assessed factors was able to predict which patients would develop PRF. The score could potentially facilitate preoperative risk assessment and management and provide a basis for testing interventions to improve outcomes.The study was registered at ClinicalTrials.gov (identifier NCT01346709). PMID- 26020130 TI - Novel Guanidinium-Based Ionic Liquids for Highly Efficient SO2 Capture. AB - The application of ionic liquids (ILs) for acidic gas absorption has long been an interesting and challenging issue. In this work, the ethyl sulfate ([C2OSO3](-)) anion has been introduced into the structure of guanidinium-based ILs to form two novel low-cost ethyl sulfate ILs, namely 2-ethyl-1,1,3,3-tetramethylguanidinium ethyl sulfate ([C2(2)(C1)2(C1)2(3)gu][C2OSO3]) and 2,2-diethyl-1,1,3,3 tetramethylguanidinium ethyl sulfate ([(C2)2(2)(C1)2(C1)2(3)gu][C2OSO3]). The ethyl sulfate ILs, together with 2-ethyl-1,1,3,3-tetramethylguanidinium bis(trifluoromethylsulfonyl)imide ([C2(2)(C1)2(C1)2(3)gu][NTf2]) and 2,2-diethyl 1,1,3,3-tetramethylguanidinium bis(trifluoromethylsulfonyl)imide ([(C2)2(2)(C1)2(C1)2(3)gu][NTf2]), are employed to evaluate the SO2 absorption and desorption performance. The recyclable ethyl sulfate ILs demonstrate high absorption capacities of SO2. At a low pressure of 0.1 bar and at 20 degrees C, 0.71 and 1.08 mol SO2 per mole of IL can be captured by [C2(2)(C1)2(C1)2(3)gu][C2OSO3] and [(C2)2(2)(C1)2(C1)2(3)gu][C2OSO3], respectively. The absorption enthalpy for SO2 absorption with [C2(2)(C1)2(C1)2(3)gu][C2OSO3] and [(C2)2(2)(C1)2(C1)2(3)gu][C2OSO3] are -3.98 and -3.43 kcal mol(-1), respectively. While those by [C2(2)(C1)2(C1)2(3)gu][NTf2] and [(C2)2(2)(C1)2(C1)2(3)gu][NTf2] turn out to be only 0.17 and 0.24 mol SO2 per mole of IL under the same conditions. It can be concluded that the guanidinium ethyl sulfate ILs show good performance for SO2 capture. Quantum chemistry calculations reveal nonbonded weak interactions between the ILs and SO2. The anionic moieties of the ILs play an important role in SO2 capture on the basis of the consistently experimental and computational results. PMID- 26020132 TI - Tunneling Electrical Connection to the Interior of Metal-Organic Frameworks. AB - Metal-organic frameworks (MOFs) are typically poor electrical conductors, which limits their uses in sensors, fuel cells, batteries, and other applications that require electrically conductive, high surface area materials. Although metal nanoclusters (NCs) are often added to MOFs, the electrical properties of these hybrid materials have not yet been explored. Here, we show that adding NCs to a MOF not only imparts moderate electrical conductivity to an otherwise insulating material but also renders it photoconductive, with conductivity increasing by up to 4 orders of magnitude upon light irradiation. Because charge transport occurs via tunneling between spatially separated NCs that occupy a small percent of the MOF's volume, the pores remain largely open and accessible. While these phenomena are more pronounced in single-MOF crystals (here, Rb-CD-MOFs), they are also observed in films of smaller MOF crystallites (MIL-53). Additionally, we show that in the photoconductive MOFs, the effective diffusion coefficients of electrons can match the typical values of small molecules diffusing through MOFs; this property can open new vistas for the development of MOF electrodes and, in a wider context, of electroactive and light-harvesting MOFs. PMID- 26020133 TI - Synthesis, Characterization, and Nanoencapsulation of Tetrathiatriarylmethyl and Tetrachlorotriarylmethyl (Trityl) Radical Derivatives-A Study To Advance Their Applicability as in Vivo EPR Oxygen Sensors. AB - Tissue oxygenation plays an important role in the pathophysiology of various diseases and is often a marker of prognosis and therapeutic response. EPR (ESR) is a suitable noninvasive oximetry technique. However, to reliably deploy soluble EPR probes as oxygen sensors in complex biological systems, there is still a need to investigate and improve their specificity, sensitivity, and stability. We reproducibly synthesized various derivatives of tetrathiatriarylmethyl and tetrachlorotriarylmethyl (trityl) radicals. Hydrophilic radicals were investigated in aqueous solution mimicking physiological conditions by, e.g., variation of viscosity and ionic strength. Their specificity was satisfactory, but the oxygen sensitivity was low. To enhance the capability of trityl radicals as oxygen sensors, encapsulation into oily core nanocapsules was performed. Thus, different lipophilic triesters were prepared and characterized in oily solution employing oils typically used in drug formulations, i.e., middle-chain triglycerides and isopropyl myristate. Our screening identified the deuterated ethyl ester of D-TAM (radical 13) to be suitable. It had an extremely narrow single EPR line under anoxic conditions and excellent oxygen sensitivity. After encapsulation, it retained its oxygen responsiveness and was protected against reduction by ascorbic acid. These biocompatible and highly sensitive nanosensors offer great potential for future EPR oximetry applications in preclinical research. PMID- 26020134 TI - Overview on the mechanisms of coffee germination and fermentation and their significance for coffee and coffee beverage quality. AB - Quality of coffee is a complex trait and is influenced by physical and sensory parameters. A complex succession of transformations during the processing of seeds to roasted coffee will inevitably influence the in-cup attributes of coffee. Germination and fermentation of the beans are two bioprocesses that take place during post-harvest treatment, and may lead to significant modifications of coffee attributes. The aim of this review is to address the current knowledge of dynamics of these two processes and their significance for bean modifications and coffee quality. The first part of this review gives an overview of coffee germination and its influence on coffee chemistry and quality. The germination process initiates while these non-orthodox seeds are still inside the cherry. This process is asynchronous and the evolution of germination depends on how the beans are processed. A range of metabolic reactions takes place during germination and can influence the carbohydrate, protein, and lipid composition of the beans. The second part of this review focuses on the microbiota associated with the beans during post-harvesting, exploring its effects on coffee quality and safety. The microbiota associated with the coffee cherries and beans comprise several bacterial, yeast, and fungal species and affects the processing from cherries to coffee beans. Indigenous bacteria and yeasts play a role in the degradation of pulp/mucilage, and their metabolism can affect the sensory attributes of coffee. On the other hand, the fungal population occurring during post-harvest and storage negatively affects coffee quality, especially regarding spoilage, off-tastes, and mycotoxin production. PMID- 26020136 TI - Use of tobacco tax stamps to prevent and reduce illicit tobacco trade--United States, 2014. AB - Tobacco use is the leading cause of preventable disease and death in the United States. Increasing the unit price on tobacco products is the most effective tobacco prevention and control measure. Illicit tobacco trade (illicit trade) undermines high tobacco prices by providing tobacco users with cheaper-priced alternatives. In the United States, illicit trade primarily occurs when cigarettes are bought from states, jurisdictions, and federal reservation land with lower or no excise taxes, and sold in jurisdictions with higher taxes. Applying tax stamps to tobacco products, which provides documentation that taxes have been paid, is an important tool to combat illicit trade. Comprehensive tax stamping policy, which includes using digital, encrypted ("high-tech") stamps, applying stamps to all tobacco products, and working with tribes on stamping agreements, can further prevent and reduce illicit trade. This report describes state laws governing tax stamps on cigarettes, little cigars (cigarette-sized cigars), roll-your-own tobacco (RYOT), and tribal tobacco sales across the United States as of January 1, 2014, and assesses the extent of comprehensive tobacco tax stamping in the United States. Forty-four states (including the District of Columbia [DC]) applied traditional paper ("low-tech") tax stamps to cigarettes, whereas four authorized more effective high-tech stamps. Six states explicitly required stamps on other tobacco products (i.e., tobacco products other than cigarettes), and in approximately one third of states with tribal lands, tribes required tax stamping to address illicit purchases by nonmembers. No U.S. state had a comprehensive approach to tobacco tax stamping. Enhancing tobacco tax stamping across the country might further prevent and reduce illicit trade in the United States. PMID- 26020135 TI - Putative Links Between Sleep Apnea and Cancer: From Hypotheses to Evolving Evidence. AB - In recent years, the potentially adverse role of sleep-disordered breathing in cancer incidence and outcomes has emerged. In parallel, animal models of intermittent hypoxia (IH) and sleep fragmentation (SF) emulating the two major components of OSA have lent support to the notion that OSA may enhance the proliferative and invasive properties of solid tumors. Based on several lines of evidence, we propose that OSA-induced increases in sympathetic outflow and alterations in immune function are critically involved in modifying oncologic processes including angiogenesis. In this context, we suggest that OSA, via IH (and potentially SF), promotes changes in several signaling pathways and transcription factors that coordinate malignant transformation and expansion, disrupts host immunologic surveillance, and consequently leads to increased probability of oncogenesis, accelerated tumor proliferation, and invasion, ultimately resulting in adverse outcomes. PMID- 26020137 TI - Approaches for controlling illicit tobacco trade--nine countries and the European Union. AB - An estimated 11.6% of the world cigarette market is illicit, representing more than 650 billion cigarettes a year and $40.5 billion in lost revenue. Illicit tobacco trade refers to any practice related to distributing, selling, or buying tobacco products that is prohibited by law, including tax evasion (sale of tobacco products without payment of applicable taxes), counterfeiting, disguising the origin of products, and smuggling. Illicit trade undermines tobacco prevention and control initiatives by increasing the accessibility and affordability of tobacco products, and reduces government tax revenue streams. The World Health Organization (WHO) Protocol to Eliminate Illicit Trade in Tobacco Products, signed by 54 countries, provides tools for addressing illicit trade through a package of regulatory and governing principles. As of May 2015, only eight countries had ratified or acceded to the illicit trade protocol, with an additional 32 needed for it to become international law (i.e., legally binding). Data from multiple international sources were analyzed to evaluate the 10 most commonly used approaches for addressing illicit trade and to summarize differences in implementation across select countries and the European Union (EU). Although the WHO illicit trade protocol defines shared global standards for addressing illicit trade, countries are guided by their own legal and enforcement frameworks, leading to a diversity of approaches employed across countries. Continued adoption of the methods outlined in the WHO illicit trade protocol might improve the global capacity to reduce illicit trade in tobacco products. PMID- 26020138 TI - Occupational fatalities during the oil and gas boom--United States, 2003-2013. AB - During 2003-2013, the U.S. oil and gas extraction industry experienced unprecedented growth, doubling the size of its workforce and increasing the number of drilling rigs by 71%. To describe fatal events among oil and gas workers during this period, CDC analyzed data from the Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI), a comprehensive database of fatal work injuries. During 2003-2013, the number of work-related fatalities in the oil and gas extraction industry increased 27.6%, with a total of 1,189 deaths; however, the annual occupational fatality rate significantly decreased 36.3% (p<0.05) during this 11-year period. Two-thirds of all worker fatalities were attributed to transportation incidents (479, [40.3%]) and contact with objects/equipment (308 [25.9%]). More than 50% of persons fatally injured were employed by companies that service wells (615 [51.7%]). It is important for employers to consider measures such as land transportation safety policies and engineering controls (e.g., automated technologies) that would address these leading causes of death and reduce workers' exposure to hazards. PMID- 26020139 TI - Acute rheumatic fever and rheumatic heart disease among children--American Samoa, 2011-2012. AB - Acute rheumatic fever is a nonsuppurative, immune-mediated consequence of group A streptococcal pharyngitis (strep throat). Recurrent or severe acute rheumatic fever can cause permanent cardiac valve damage and rheumatic heart disease, which increases the risk for cardiac conditions (e.g., infective endocarditis, stroke, and congestive heart failure). Antibiotics can prevent acute rheumatic fever if administered no more than 9 days after symptom onset. Long-term benzathine penicillin G (BPG) injections are effective in preventing recurrent acute rheumatic fever attacks and are recommended to be administered every 3-4 weeks for 10 years or until age 21 years to children who receive a diagnosis of acute rheumatic fever. During August 2013, in response to anecdotal reports of increasing rates of acute rheumatic fever and rheumatic heart disease, CDC collaborated with the American Samoa Department of Health and the Lyndon B. Johnson Tropical Medical Center (the only hospital in American Samoa) to quantify the number of cases of pediatric acute rheumatic fever and rheumatic heart disease in American Samoa and to assess the potential roles of missed pharyngitis diagnosis, lack of timely prophylaxis prescription, and compliance with prescribed BPG prophylaxis. Using data from medical records, acute rheumatic fever incidence was calculated as 1.1 and 1.5 cases per 1,000 children aged <=18 years in 2011 and 2012, respectively; 49% of those with acute rheumatic fever subsequently received a diagnosis of rheumatic heart disease. Noncompliance with recommended prophylaxis with BPG after physician-diagnosed acute rheumatic fever was noted for 22 (34%) of 65 patients. Rheumatic heart disease point prevalence was 3.2 cases per 1,000 children in August 2013. Establishment of a coordinated acute rheumatic fever and rheumatic heart disease control program in American Samoa, likely would improve diagnosis, treatment, and patient compliance with BPG prophylaxis. PMID- 26020140 TI - Notes from the field: outbreak of skin lesions among high school wrestlers- Arizona, 2014. AB - Skin infections are a common problem among athletes at all levels of competition; among wrestlers, 8.5% of all adverse events are caused by skin infections. Wrestlers are at risk because of the constant skin-to-skin contact required during practice and competition. The most common infections transmitted among high school wrestlers include fungal infections (e.g., ringworm), the viral infection herpes gladiatorum caused by herpes simplex virus-1 (HSV-1), and bacterial infections (e.g., impetigo) caused by Staphylococcus or Streptococcus species, including methicillin-resistant Staphylococcal aureus (MRSA). On February 7, 2014, the Maricopa County Department of Public Health was notified of multiple wrestlers who reported skin lesions 2 weeks after participating in a wrestling tournament at school A. The tournament was held on January 24-25 and included 168 wrestlers representing 24 schools. The county health department initiated an investigation to identify cases of skin lesion, determine lesion etiology, identify risks associated with lesion development, and provide guidance for preventing additional cases. PMID- 26020141 TI - Immunotherapeutic applications of NK cells. AB - Natural Killer (NK) cells are lymphoid cells that exhibit an innate response against virus-infected cells. These cells are also capable of mounting an immune response against tumor cells after education through major histocompatibility complex (MHC) class I molecules. NK cell regulation is mediated through IFN-gamma and IL-15, important cytokines which can drive NK cell expansion in vivo. Previous studies have shown effective infusion of allogeneic NK cells after lymphodepleting regimens with induction of remission of poor prognosis acute myeloid leukemia (AML). Challenges remain in the expansion of these NK cells once infused and in their education to recognize tumor targets. A principal mechanism of tumor recognition is through KIR mismatch in cells lacking self MHC I molecules. Activating KIRs exist, though their ligands are unknown at this time. Impacting NK cell expansion and education in vivo has been challenging, and thus far clinical applications of NK cells have shown promise in helping to maintain remission in humans, though this remission has not been maintained. Future efforts to utilize NK cells clinically are focusing on developing more consistency in successful expansion of NK cell and educating them to recognize their tumor targets. Additional efforts to utilize novel antibody-based therapy to engage NK cells to their tumor targets are also in development. PMID- 26020142 TI - COUNTERPOINT: Should Oscillometry Be Used to Screen for Airway Disease? No. PMID- 26020144 TI - Hot electron of Au nanorods activates the electrocatalysis of hydrogen evolution on MoS2 nanosheets. AB - Efficient water splitting through electrocatalysis holds great promise for producing hydrogen fuel in modern energy devices. Its real application however suffers from sluggish reaction kinetics due to the lack of high-performance catalysts except noble metals such as platinum. Herein, we report an active system of plasmonic-metal Au nanorods/molybdenum disulfide (MoS2) nanosheets hybrids for the hydrogen evolution reaction (HER). The plasmonic Au-MoS2 hybrids dramatically improve the HER, leading to a ~3-fold increase of current under excitation of Au localized surface plasmon resonance (LSPR). A turnover of 8.76 s(-1) at 300 mV overpotential is measured under LSPR excitation, which by far exceeds the activity of MoS2 catalysts reported recently. The HER enhancement can be largely attributed to the increase of carrier density in MoS2 induced by the injection of hot electrons of Au nanorods. We demonstrate that the synergistic effect of the hole scavengers can further facilitate electron-hole separation, resulting in a decrease of the overpotential of HER at MoS2 to ~120 mV. This study highlights how metal LSPR activates the HER and promises novel opportunities for enhancing intrinsic activities of semiconducting materials. PMID- 26020143 TI - Protein-induced supramolecular disassembly of amphiphilic polypeptide nanoassemblies. AB - Mimicking noncovalent interaction based processes in nature has been an important goal of supramolecular chemistry. Here, we report on amphiphilic polypeptides that self-assemble to form nanoscale supramolecular assemblies and are programmed to disassemble in response to a specific protein. Benzenesulfonamide and carbonic anhydrase have been chosen as the ligand and protein, respectively, to demonstrate this possibility. Since the amphiphilic nanoassembly sequesters hydrophobic guest molecules, the protein-specific disassembly event provides a protein-sensitive molecular release as well. We envision that the binding induced disassembly and guest release might open up new opportunities for the next generation of supramolecular assemblies for protein-specific delivery and diagnostics. PMID- 26020145 TI - Age of onset of a normally timed pubertal growth spurt affects the final height of children. AB - BACKGROUND: The exact nature of the relationship between the age of onset of puberty and final height in normally maturing children is controversial. Some authors have claimed that the age of pubertal onset does not affect final height, and others have claimed the opposite. We hypothesized that both height and the age of onset of the pubertal growth spurt (PGS) are correlated to final height. METHODS: The height measurements of 335 children (162 girls) were analyzed in an observational retrospective study. The age and height at the onset of the PGS were computed from the equations of the Karlberg's infancy-childhood-puberty model. RESULTS: A very low correlation was found between the age of onset of the PGS and final height. However, the correlation became very high when the parameter "height at onset of the PGS" was included in the regression analysis. The model was found reliable when tested on growth data of 60 Israeli children. CONCLUSIONS: Final height is influenced by both height and the age of onset of the PGS in normal maturing children. A normal but early puberty exerts a negative effect on final height. A delayed PGS exerts a positive effect on final height. PMID- 26020147 TI - Mid-arm circumference is a reliable method to estimate adiposity in preterm and term infants. AB - BACKGROUND: Premature birth is associated with increased adipose deposition after birth. Standard anthropometry (body weight, length, and head circumference) may not adequately assess fat deposition. Validated methods to assess adiposity are needed to optimize growth quality in preterm infants. The purpose of this study was to identify covariates of infant body fat. METHODS: Air displacement plethysmography (ADP), standard anthropometry, and body circumferences were measured at hospital discharge in preterm (n = 28; 31-35 wk postmenstrual age (PMA)) and term (n = 28; 38-41 wks PMA) infants. RESULTS: Body weight, length, and head circumference were lower for preterm infants (P < 0.05) at hospital discharge compared with that of term infants. Despite smaller body size and younger PMA, preterm infant percent body fat (%BF) by ADP was 12.33 +/- 4.15% vs. 9.64 +/- 4.01% in term infants (P = 0.01). Mid-arm circumference (MAC) is a covariate of %BF in both preterm and term infants (adjusted R(2) = 0.49; P < 0.001). In preterm infants alone, MAC accounted for 60.4% of the variability of percent body fat (%BF) by ADP (P < 0.01). CONCLUSIONS: Preterm infants have increased body fat deposition as they approach term-corrected age, and MAC is a reliable, low-cost measure for monitoring infant body fat deposition in preterm and term infants. PMID- 26020146 TI - Histologic changes of the fetal membranes after fetoscopic laser surgery for twin twin transfusion syndrome. AB - BACKGROUND: Preterm premature rupture of membranes remains a major complication after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS). We studied the histologic changes of fetal membranes post-FLS and investigated a possible impact of amniotic fluid (AF) dilution. METHODS: Fetal membranes of 31 pregnancies that underwent FLS for TTTS were investigated histologically at delivery at different sites: trocar site of recipient sac and at distance, donor sac, and inter-twin membrane. RESULTS: The trocar insertion site on the recipient sac showed no signs of histologic hallmarks of healing. Wide-spread alteration in collagen organization and higher apoptotic index in the amnion of the recipient sac which were absent in donor's and reference membranes. To explain the mechanisms, we analyzed the AF composition of recipient sacs from TTTS pregnancies vs. GA-matched healthy singleton controls and found glucose, protein and lactate dehydrogenase activity were all significantly lower in TTTS sacs consistent with over-dilution of recipient's AF (~2-fold). In-vitro exposure of healthy amniochorion to analogous dilutional stress conditions recapitulated the histologic changes and induced apoptosis and autophagy. CONCLUSION: Alteration in structural integrity of the recipient's amniochorion, possibly in response to dilution stress, along with ineffective repair mechanisms may explain the increased incidence of preterm birth post-FLS. PMID- 26020148 TI - Impaired cognitive performance in premature newborns with two or more surgeries prior to term-equivalent age. AB - BACKGROUND: Anesthesia in early childhood is associated with adverse neurodevelopmental outcome; however, it is not known if age at exposure affects the risk of adverse outcome. Our objective was to evaluate the association of the number and timing of anesthetic exposures for surgery with cognitive outcome in a cohort of premature newborns. METHODS: A cohort study of exposure to anesthesia for surgery in premature newborns (<33 wk gestation) prospectively evaluated with neonatal magnetic resonance imaging (MRI) and neurodevelopmental testing at 3-6 y was employed. Exposure to anesthesia for surgery was classified as before term equivalent age (TEA, <42 wk postmenstrual age) or after (>=42 wk). Multivariate regression was performed to analyze the association of composite IQ scores with the number of surgeries before and after TEA. RESULTS: Among 137 newborns, 25 (18.2%) had one surgery before TEA and 18 (13.1%) had >=2 surgeries. Two or more surgeries before TEA were associated with significantly reduced composite IQ scores at 4.6 +/- 0.6 y after adjusting for gestational age and illness severity. Neither the number of surgeries after TEA nor sedation for MRI was associated with cognitive outcome. CONCLUSIONS: More than one surgery prior to TEA is independently associated with impaired cognitive performance in premature newborns. PMID- 26020149 TI - Women's Perceptions of Communication in Pregnancy and Childbirth: Influences on Participation and Satisfaction With Care. AB - In this study, 3,531 Queensland women, who had recently given birth, completed a questionnaire that included questions about their participation in decision making during pregnancy, their ratings of client-centered care, and perceived quality of care. These data tested a version of the Linguistic Model of Patient Participation in Care, adapted to the maternity context. The authors investigated how age and education influenced women's perceptions of their participation and quality of care. Hierarchical multiple regressions revealed that women's perceived ability to make decisions, and the extent of client-centered communication with maternity care providers, were the most influential predictors of participation and perceived quality of care. Participation in care predicted perceived quality of care, but the influence of client-centered communication by a care provider and a woman's confidence in decision making were stronger predictors of perceived quality of care. Age and education level were not important predictors. These findings extend and support the use of Linguistic Model of Patient Participation in Care in the maternity context. PMID- 26020150 TI - Correction to "Neutralized Chimeric Avidin Binding at a Reference Biosensor Surface". PMID- 26020155 TI - Cocaine use and buprenorphine compliance. PMID- 26020156 TI - Author's Reply. PMID- 26020157 TI - Methadone and buprenorphine during pregnancy. PMID- 26020158 TI - Author's Reply. PMID- 26020160 TI - Thermostructural behaviour of Ni-Cr materials: modelling of bulk and nanoparticle systems. AB - The thermostructural properties of Ni-Cr materials, as bulk and nanoparticle (NP) systems, have been predicted with a newly developed interatomic potential, for Ni/Cr ratios from 100/0 to 60/40. The potential, which has been fitted using experimental data and further validated using Density Functional Theory (DFT), describes correctly the variation with temperature of lattice parameters and the coefficient of thermal expansion, from 100 K to 1000 K. Using this potential, we have performed Molecular Dynamics (MD) simulations on bulk Ni-Cr alloys of various compositions, for which no experimental data are available. Similarly, NPs with diameters of 3, 5, 7, and 10 nm were studied. We found a very rapid convergence of NP properties with the size of the systems, showing already the 5 nm NPs with a thermostructural behaviour similar to the bulk. MD simulations of two 5 nm NPs show very little sintering and thermally induced damage, for temperatures between 300 K and 1000 K, suggesting that materials formed by agglomeration of Ni-Cr NPs meet the thermostructural stability requirements for catalysis applications. PMID- 26020161 TI - Daptomycin: Physicochemical, Analytical, and Pharmacological Properties. AB - Daptomycin is the first approved member of a new class of antimicrobials, the cyclic lipopeptides, and presents selective action against gram-positive bacteria, including methicillin- and vancomycin-resistant strains. Considering that resistance to daptomycin is rare, the drug has become very important for current clinical practice. This review covers daptomycin's physicochemical characteristics, antibacterial spectrum, mechanism of action, pharmacokinetics, clinical applications, side effects, drug interactions, and the analytical methods used to measure daptomycin in pharmaceutical products and biologic samples. Special attention has been given to therapeutic drug monitoring reports, as studies have shown its highly variable pharmacokinetics in specific circumstances, such as in patients suffering from critical illness, morbid obesity, severe sepsis, and kidney injury. For the same reason, methods described for therapeutic drug monitoring of daptomycin in the special patient population have been reviewed. In addition, the review presents a discussion of environmentally friendly analytical methods for daptomycin, which are necessary to reduce the impact of our activities on the environment. However, it was observed that there is a gap in the literature in this regard and further research involving the development of "green" methodologies for the analysis of daptomycin is necessary. The review will be useful to the clinical community in assisting with the responsible use of daptomycin, which is critical to prevent the emergence of resistant strains. PMID- 26020162 TI - Attitudes Toward Male and Female Sexuality Among Men and Women With Intellectual Disabilities. AB - Studies comparing the sexual attitudes of men and women with intellectual disabilities (ID) have been limited. A mixed-methods approach was employed to explore attitudes toward sexuality among men and women with ID in Taiwan and to ascertain the disparities between attitudes among men and women with ID. First, fifty-six men and forty-four women with mild and moderate ID completed a face-to face interview survey. After this, focus groups were conducted for men and women with ID. Results indicated that women with ID were more likely to have negative attitudes toward parenting and non-reproductive sexual behavior than their male counterparts. Qualitative data indicated that men and women with ID had different sexual attitudes and experiences and were subject to different expectations from people around them. Both men and women with ID had very limited opportunities to develop romantic relationships and a healthy sexual identity. Sexual rights awareness and practice should be matters of concern for this group of adults and women with ID in particular. PMID- 26020163 TI - Long-haul and high-resolution optical time domain reflectometry using superconducting nanowire single-photon detectors. AB - In classical optical time domain reflectometries (OTDRs), for sensing an 200-km long fiber, the optical pulses launched are as wide as tens of microseconds to get enough signal-to-noise ratio, while it results in a two-point resolution of kilometers. To both reach long sensing distance and sub-kilometer resolution, we demonstrated a long-haul photon-counting OTDR using a superconducting nanowire single-photon detector. In a 40-minute-long measurement, we obtained a dynamic range of 46.9 dB, corresponding to a maximum sensing distance of 246.8 km, at a two-point resolution of 0.1 km. The time for measuring fiber after 100 km was reduced to one minute, while the fiber end at 217 km was still distinguished well from noise. After reducing the pulse width to 100 ns, the experimental two-point resolution was improved to 20 m while the maximum sensing distance was 209.47 km. PMID- 26020165 TI - RUMINANT NUTRITION SYMPOSIUM: The impact of the rumen microbiome on nutrition, health, and production. PMID- 26020164 TI - Measurement of neural signals from inexpensive, wireless and dry EEG systems. AB - Electroencephalography (EEG) is challenged by high cost, immobility of equipment and the use of inconvenient conductive gels. We compared EEG recordings obtained from three systems that are inexpensive, wireless, and/or dry (no gel), against recordings made with a traditional, research-grade EEG system, in order to investigate the ability of these 'non-traditional' systems to produce recordings of comparable quality to a research-grade system. The systems compared were: Emotiv EPOC (inexpensive and wireless), B-Alert (wireless), g.Sahara (dry) and g.HIamp (research-grade). We compared the ability of the systems to demonstrate five well-studied neural phenomena: (1) enhanced alpha activity with eyes closed versus open; (2) visual steady-state response (VSSR); (3) mismatch negativity; (4) P300; and (5) event-related desynchronization/synchronization. All systems measured significant alpha augmentation with eye closure, and were able to measure VSSRs (although these were smaller with g.Sahara). The B-Alert and g.Sahara were able to measure the three time-locked phenomena equivalently to the g.HIamp. The Emotiv EPOC did not have suitably located electrodes for two of the tasks and synchronization considerations meant that data from the time-locked tasks were not assessed. The results show that inexpensive, wireless, or dry systems may be suitable for experimental studies using EEG, depending on the research paradigm, and within the constraints imposed by their limited electrode placement and number. PMID- 26020166 TI - RUMINANT NUTRITION SYMPOSIUM: Use of genomics and transcriptomics to identify strategies to lower ruminal methanogenesis. AB - Globally, methane (CH4) emissions account for 40% to 45% of greenhouse gas emissions from ruminant livestock, with over 90% of these emissions arising from enteric fermentation. Reduction of carbon dioxide to CH4 is critical for efficient ruminal fermentation because it prevents the accumulation of reducing equivalents in the rumen. Methanogens exist in a symbiotic relationship with rumen protozoa and fungi and within biofilms associated with feed and the rumen wall. Genomics and transcriptomics are playing an increasingly important role in defining the ecology of ruminal methanogenesis and identifying avenues for its mitigation. Metagenomic approaches have provided information on changes in abundances as well as the species composition of the methanogen community among ruminants that vary naturally in their CH4 emissions, their feed efficiency, and their response to CH4 mitigators. Sequencing the genomes of rumen methanogens has provided insight into surface proteins that may prove useful in the development of vaccines and has allowed assembly of biochemical pathways for use in chemogenomic approaches to lowering ruminal CH4 emissions. Metagenomics and metatranscriptomic analysis of entire rumen microbial communities are providing new perspectives on how methanogens interact with other members of this ecosystem and how these relationships may be altered to reduce methanogenesis. Identification of community members that produce antimethanogen agents that either inhibit or kill methanogens could lead to the identification of new mitigation approaches. Discovery of a lytic archaeophage that specifically lyses methanogens is 1 such example. Efforts in using genomic data to alter methanogenesis have been hampered by a lack of sequence information that is specific to the microbial community of the rumen. Programs such as Hungate1000 and the Global Rumen Census are increasing the breadth and depth of our understanding of global ruminal microbial communities, steps that are key to using these tools to further define the science of ruminal methanogenesis. PMID- 26020167 TI - RUMINANT NUTRITION SYMPOSIUM: How to use data on the rumen microbiome to improve our understanding of ruminant nutrition. AB - Metagenomics and high-throughput sequencing have greatly expanded our knowledge of the rumen microbiome. Surveys of all 4 cellular microbial groups (bacteria, archaea, protozoa, and fungi) reveal profound diversity. Even so, evidence exists for core members to perform key degradative or fermentative roles for the host. Some core members are functionally similar yet taxonomically diverse, and noncore members are particularly diverse and probably vary among diets, animals, and over time after feeding. Gains in functional knowledge are being made and offer much potential not only to improve fiber digestibility, decrease methane emissions, and improve efficiency of nitrogen usage but also to help explain the differences in nutrient digestibility or feed efficiency among animals fed the same diet. Integrated research using metagenomics, bioinformatics, traditional ruminant nutrition, and statistical inferences have provided opportunities for ruminant nutritionists and rumen microbiologists to work synergistically to improve nutrient utilization efficiency while minimizing output of wastes and emissions of methane and ammonia. Examples we highlight include residual feed intake, rumen biohydrogenation of unsaturated fatty acids, and dietary inclusion of ionophores. However, there are still some quantitative limitations in approaches being used. This review addresses knowledge gained and current limitations and challenges that remain. PMID- 26020168 TI - Genetic analysis of within-litter variation in piglets' birth weight using genomic or pedigree relationship matrices. AB - The objective of this study was to estimate the genetic variance for within litter variation of birth weight (BW0) using genomic (GRM) or pedigree relationship matrices (PRM) and to compare the accuracy of estimated breeding values (EBV) for within-litter variation of BW0 using GRM and PRM. The BW0 and residual variance of BW0 were modeled by the double hierarchical generalized linear model using GRM or PRM. Data came from 2 dam lines: Landrace and Large White. After editing, the data set in Landrace consisted of 748 sows with 1,938 litters and 29,430 piglets and in Large White of 989 sows with 3,320 litters and 51,818 piglets. To construct GRM, 46,466 (Landrace) and 44,826 (Large White) single nucleotide polymorphisms were used, whereas to construct PRM, 5 generations of pedigree were used. The accuracy of EBV with GRM was estimated with 8-fold cross-validation and compared to PRM. Estimated variance components were highly similar for GRM and PRM. The maternal genetic variance in residual variance of BW0 in Landrace was 0.05 with GRM and 0.06 with PRM. In Large White these were 0.04 with GRM and 0.05 with PRM. The genetic coefficient of variation (GCV SDe) was about 0.10 in both dam lines. This indicates a change of 10% in residual SD of BW0 when achieving a genetic response of 1 genetic standard deviation. The genetic correlation between birth weight and its residual variance was about 0.6 in both dam lines. The accuracies of selection for within-litter variation of birth weight were 0.35 with GRM and 0.23 with PRM in Landrace and 0.29 with GRM and 0.34 with PRM in Large White. In this case, using GRM did not significantly increase accuracies of selection. Results, however, show good opportunities to select for reduced within-litter variation of BW0. Genomic selection can increase accuracy of selection when reference populations contain at least 2,000 sows. PMID- 26020169 TI - A genomewide association study of feed efficiency and feeding behaviors at two fattening stages in a White Duroc * Erhualian F population. AB - Feeding efficiency is a multifactorial and economically important trait in pigs. Genetic improvement of feeding efficiency will greatly benefit the pig industry. In the past decades, the hog market weight has increased worldwide. However, whether the genetic architecture of feeding efficiency is same or not at early and late fattening periods is unclear. To map genomic regions for feed efficiency and feeding behavior traits at early (n >= 384) and late (n >= 334) growth stages in pigs, we performed genomewide association studies for feed to gain ratio (FCR), residual feed intake (RFI), daily feed intake, daily visit times, daily feeding time (DFT), feed intake per second (FIPS), and feed intake per visit during 3 periods (2 stages and overall) in a White Duroc * Erhualian F2 intercross population. Six chromosomal regions showed significant association with these traits, of which 4 loci were reported for the first time. Our results confirmed the QTL of FCR around 34 Mb on SSC7 and RFI around 134 Mb on SSC12. Of note, 2 regions were associated with more than 1 trait. One was around 36 Mb on SSC7, and there were 47 and 67 SNP associated with FCR from 120 to 210 and from 120 to 240 d, respectively. The top SNP is located in a 2.88-Mb linkage disequilibrium (LD) block that harbors 44 genes. We propose the high mobility group AT-hook 1 gene as a plausible candidate gene in this region. The other was evidenced around 53 Mb on SSC12, which had multiple association signals for DFT and FIPS. The top SNP is located in a 211-kb LD block that harbors only 1 annotated gene, WSCD1, which encodes a protein with sulfotransferase activity and involves the glucose metabolism and, therefore, appears to be a plausible candidate gene. Except the region on SSC12 associated with DFT at both stages, the rest of the regions associated with the traits at only 1 stage, so the genetic architectures of the 2 stages are not same. PMID- 26020170 TI - Correlations between purebred and crossbred body weight traits in Limousin and Limousin-Angus populations. AB - The purpose of this study was to estimate correlations between purebred and F1 crossbred performance to verify the appropriateness of current models used in multibreed selection. Records on birth weight (WB) and weaning weight (WW) from purebred Limousins (LIM) and Limousin * Angus progeny (F1) were used to estimate genetic parameters using a multiple-trait (purebred and F1 weights were different traits) approach. For WB, there were 148,647 records for LIM and 17,981 for F1, and for WW, there were 81,585 records for LIM and 21,778 for F1. The fixed effect in models for LIM and F1 animals was contemporary group. Random effects for LIM animals were direct genetic, maternal genetic, and maternal permanent environment effects. Random effects for F1 were sire and dam. The pedigree for Angus dams used for crossing was unavailable and therefore these dams were assumed unrelated. The direct h2 estimates (SE) for purebred animals were 0.41 (0.05) and 0.24 (0.02) for WB and WW, respectively. For F1, the same estimates were 0.22 (0.09) and 0.32 (0.05). Genetic correlations estimates between purebreds and crossbreds were 0.84 (0.07) and 0.64 (0.18) for WB and WW, respectively. The genetic correlation for WW estimated in this study suggests that F1 and purebred information for this trait should not be treated, genetically, as the same trait due to different genetic effects molding it. However, the genetic correlation for WB was much higher, indicating that this trait in purebreds and F1 is essentially the same trait. PMID- 26020171 TI - Estimation of genetic parameters and breeding values across challenged environments to select for robust pigs. AB - Robustness is an important issue in the pig production industry. Since pigs from international breeding organizations have to withstand a variety of environmental challenges, selection of pigs with the inherent ability to sustain their productivity in diverse environments may be an economically feasible approach in the livestock industry. The objective of this study was to estimate genetic parameters and breeding values across different levels of environmental challenge load. The challenge load (CL) was estimated as the reduction in reproductive performance during different weeks of a year using 925,711 farrowing records from farms distributed worldwide. A wide range of levels of challenge, from favorable to unfavorable environments, was observed among farms with high CL values being associated with confirmed situations of unfavorable environment. Genetic parameters and breeding values were estimated in high- and low-challenge environments using a bivariate analysis, as well as across increasing levels of challenge with a random regression model using Legendre polynomials. Although heritability estimates of number of pigs born alive were slightly higher in environments with extreme CL than in those with intermediate levels of CL, the heritabilities of number of piglet losses increased progressively as CL increased. Genetic correlations among environments with different levels of CL suggest that selection in environments with extremes of low or high CL would result in low response to selection. Therefore, selection programs of breeding organizations that are commonly conducted under favorable environments could have low response to selection in commercial farms that have unfavorable environmental conditions. Sows that had experienced high levels of challenge at least once during their productive life were ranked according to their EBV. The selection of pigs using EBV ignoring environmental challenges or on the basis of records from only favorable environments resulted in a sharp decline in productivity as the level of challenge increased. In contrast, selection using the random regression approach resulted in limited change in productivity with increasing levels of challenge. Hence, we demonstrate that the use of a quantitative measure of environmental CL and a random regression approach can be comprehensively combined for genetic selection of pigs with enhanced ability to maintain high productivity in harsh environments. PMID- 26020172 TI - Genotype * environment interaction for age at first calving, scrotal circumference, and yearling weight in Nellore cattle using reaction norms in multitrait random regression models. AB - The aim of this study was to evaluate the effect of genotype * environment interaction (G*E) on age at first calving (AFC), scrotal circumference (SC), and yearling weight (YW) and to estimate genetic correlations between these traits in Nellore cattle using reaction norms in multitrait random regression models. In this study, 28,871, 41,386, and 89,152 records of Nellore cattle for AFC, SC, and YW, respectively, were used. The data were obtained from farms located in the north, northeast, midwest, and southeast regions of Brazil that participate in the DeltaGen Breeding Program. Environmental levels were defined as a function of contemporary groups, that is, animals born in the same herd and year, from the same management group (from birth to yearling), and of the same sex. Postweaning weight gain was used as a criterion to evaluate the environmental conditions for all traits. For reaction norm analyses, residual variances were modeled with homogeneous and heterogeneous classes. The model for SC and YW included the fixed effects of contemporary group and age of the animal as a covariate as well as random direct additive genetic and residual effects. The same model, excluding the covariate age of the animal, was used for AFC. The heritability estimates were low to high for AFC (0.09 to 0.50), high for SC (0.51 to 0.67), and moderate to high for YW (0.33 to 0.71). The genetic correlations (within each trait) along the environmental levels varied from -0.27 to 1.0 for AFC, from 0.73 to 1.0 for SC, and from 0.26 to 1.0 for YW. The genetic correlations between different traits in different environments varied from -0.14 to -0.60 between AFC and SC, from -0.05 to -0.32 between AFC and YW, and from -0.05 to 0.72 between YW and SC. The genetic correlations have had different magnitudes for AFC, SC, and YW, which could indicate the presence of G*E. The present results should support researchers and farmers in defining selection criteria to improve growth traits and sexual precocity. Our results suggest that animals for breeding have to be selected in the same environment and management conditions as their progeny will be reared. PMID- 26020173 TI - Genetic parameters for yearling weight, carcass traits, and primal-cut yields of Hanwoo cattle. AB - Genetic parameters associated with yearling weight, carcass traits, and primal cut yields of male Hanwoo cattle were investigated using univariate and bivariate animal models. The mean yearling weight (YWT), carcass weight (CWT), longissimus muscle area (LMA), backfat thickness (BFT), and marbling score (MS) were 352.47 +/- 0.40 kg, 337.39 +/- 0.64 kg, 78.28 +/- 0.13 cm2, 8.45 +/- 0.05 mm, and 3.25 +/- 0.03, respectively. Total primal-cut yield (TPC) was 78.95 +/- 0.10% of CWT, of which 42.3% was contributed by the forequarters (chuck, CHK; shoulder, SLD; ribs, RIB; and brisket and flank, BAF). Loins, top round (TRND), and round (RND) were associated with yields of 13.57%, 5.45 +/- 0.01%, and 8.87 +/- 0.02%, respectively. The largest cut studied was ribs (15.67 +/- 0.03%). The estimated heritabilities (h2) of YWT, CWT, LMA, BFT, and MS were 0.18 +/- 0.02, 0.29 +/- 0.04, 0.38 +/- 0.05, 0.45 +/- 0.05, and 0.62 +/- 0.07, respectively. Shoulder yield was highly heritable in Hanwoo steers (0.83 +/- 0.13), followed by the yields of round (0.66 +/- 0.12), striploin (0.64 +/- 0.12), top round (0.62 +/- 0.12), sirloin (0.60 +/- 0.12), and total primal-cut yield (0.52 +/- 0.11). The h2 values of CHK, BAF, RIB, and tenderloin (TLN) ranged from 0.19 +/- 0.09 to 0.41 +/- 0.11. Generally, the genetic CV was low for most traits (2.33%-6.15%), except for CHK, BFT, and MS. The genetic correlation (rg) was strong between YWT and CWT (0.77 +/- 0.06). The greatest positive and negative rg among carcass traits were those between LMA and CWT (0.52 +/- 0.08) and between LMA and BFT ( 0.30 +/- 0.09), respectively. The correlation between CHK and SLD (0.81 +/- 0.14), and those between SLD, TLN, TRND, and RND, were mostly strong (0.77-0.87), but the rg between RIB and other traits were strongly negative. The TPC yield showed moderate to high rg with most primal cuts. The YWT, CWT, and LMA correlated notably with CHK, SLD, and loin yields, especially LMA. However, BFT and MS were negatively correlated with many primal cuts but RIB. Those rg estimates were also opposite of that of LMA and CWT with primal cuts. Phenotypic correlations (rp) were generally weaker than rg estimates. The rp of YWT, CWT, and LMA were either zero or moderately negative compared to those of the BFT and MS with primal cuts. Most primal cuts yielded positive rp estimates among them, except for RIB. Our results suggest that direct selection for YWT, various carcass traits, and primal-cut yields may increase the carcass value of Hanwoo males. PMID- 26020174 TI - Feeding conditions and breed affect the level of DNA methylation of the mitochondrial uncoupling protein 3 gene in chicken breast muscle. AB - To investigate the effects of feed condition and breed on the level of DNA methylation for the uncoupling protein 3 (UCP3) gene, which is an important candidate gene for regulating intramuscular fat (IMF) content in chicken breast muscle, breast muscle of Daninghe (DNH) and Qingjiaoma (QJM) chickens under scatter-feed and captivity-feed conditions was analyzed. Using RNA sequencing, 47 and 113 candidate genes were determined to be related to feed conditions and breed, respectively, and 7 differentially expressed genes were confirmed by real time quantitative PCR, including UCP3. The mRNA levels of UCP3 were significantly different between the 2 feed conditions. The DNA region from bp +1700 to +2459 of the UCP3 gene was studied using the bisulfite sequencing method and contained 46 methylation sites and 3 CpG islands. The results showed that the methylation level of this UCP3 region was lower in DNH chickens (0.77% to 0.88%, P = 0.012) and QJM chickens (0.88% to 0.91%, P = 0.20) under scatter-feed conditions than under captivity-feed conditions. The mean methylation level of UCP3 in DNH chickens was lower than that in QJM chickens under scatter-feed conditions (DNH to QJM, 0.77% to 0.88%, P = 0.007), which suggests that breed affects the mean methylation level of UCP3 under scatter-feed conditions. In summary, our findings suggest that feed condition and breed affect the methylation of UCP3 in chicken breast muscle. PMID- 26020175 TI - The effects of age, weight, and sire on pregnancy rate in cattle. AB - The goal was to estimate the heritabilities and genetic variances for pregnancy rate (PR) and calving date (CD) in Angus cattle along with the effect of weight, age, and sire on PR and CD. The data consisted of 4,999 records on PR and CD. Statistical models included year as a fixed effect; premating/postmating weight and age as covariates; and sire of embryo, maternal grandsire (MGS), and permanent maternal environmental effects as random effects. The models also included the interactions between herd and weight (weight change). Direct and maternal effects on PR and CD were estimated using sire MGS and animal models in REML. Pregnancy rate increased from age 2 to 6 and decreased from age 7 to 11 (P < 0.01) and this effect was independent of the culling strategy. There was a quadratic effect of premating cow weight independent of age on PR, with lower PR for low weights (P < 0.01). Overall, cows with a premating weight of 550 kg had the greatest PR. Cows that lost weight during mating had lower PR (P < 0.01). The maternal additive heritability for PR was 0.001 +/- 0.012 and the direct additive heritability was 0.024 +/- 0.020. The ratio of permanent maternal environmental variance to phenotypic variance was significant (0.048 +/- 0.017; P < 0.01). This demonstrates that permanent maternal environmental effects play a major role in the repeatability of PR (0.049 +/- 0.015; P < 0.01). The maternal additive heritability for CD was 0.040 +/- 0.022, and the direct additive heritability was 0.076 +/- 0.045. The ratio of permanent maternal environmental variance to phenotypic variance was low (0.014 +/- 0.017) and the repeatability for CD was significant (0.0544 +/- 0.0180; P < 0.01). This suggests that maternal genetic effects are as important as direct genetic effects on CD. There was a positive quadratic relationship between premating cow weight and CD with delayed calving for low/high weights (P < 0.01). Cows that lost weight over mating also had a later CD (P < 0.01). Comparisons of a weight-selected herd to the control herd showed differences (P < 0.05) in the optimal premating weight for early calving (control, 480 kg, and weight selected, 615 kg). Calving date was also more sensitive to changes in weight over mating in the weight selection herd (P < 0.05). Therefore, the set point in the weight-fertility axis and the sensitivity of fertility to changes in weight both changed in the weight selection herd. PMID- 26020176 TI - Rainbow trout (Oncorhynchus mykiss) resistance to columnaris disease is heritable and favorably correlated with bacterial cold water disease resistance. AB - Columnaris disease (CD), caused by Flavobacterium columnare, is an emerging disease affecting rainbow trout aquaculture. Objectives of this study were to 1) estimate heritability of CD resistance in a rainbow trout line (ARS-Fp-R) previously selected 4 generations for improved bacterial cold water disease (BCWD) resistance; 2) estimate genetic correlations among CD resistance, BCWD resistance, and growth to market BW; and 3) compare CD resistance among the ARS Fp-R, ARS-Fp-S (selected 1 generation for increased BCWD susceptibility), and ARS Fp-C (selection control) lines. Heritability of CD resistance was estimated using data from a waterborne challenge of 44 full-sib ARS-Fp-R families produced using a paternal half-sib mating design, and genetic correlations were estimated using these data and 5 generations of BCWD resistance, 9-mo BW (approximately 0.5 kg), and 12-mo BW (approximately 1.0 kg) data from 405 ARS-Fp-R full-sib families. The CD and BCWD challenges were initiated at approximately 52 and 84 d posthatch, or approximately 650 and 1,050 degree days ( degrees C * d), respectively. Survival of ARS-Fp-R families ranged from 0 to 48% following CD challenge and heritability estimates were similar between CD (0.17 +/- 0.09) and BCWD (0.18 +/- 0.03) resistance, and the genetic correlation between these 2 traits was favorable (0.35 +/- 0.25). Genetic correlations were small and antagonistic (-0.15 +/- 0.08 to -0.19 +/- 0.24) between the 2 resistance traits and 9- and 12-mo BW. Two challenges were conducted in consecutive years to compare CD resistance among ARS Fp-R, ARS-Fp-C, and ARS-Fp-S families. In the first challenge, ARS-Fp-R families (83% survival) had greater CD resistance than ARS-Fp-C (73.5%; P = 0.02) and ARS Fp-S (68%; P < 0.001) families, which did not differ (P = 0.16). In the second challenge, using an approximately 2.5-fold greater challenge dose, ARS-Fp-R families exhibited greater CD resistance (56% survival) than ARS-Fp-S (38% survival; P = 0.02) families. The favorable genetic correlation between CD and BCWD resistance is supported by greater CD resistance of the ARS-Fp-R line compared to the ARS-Fp-C and ARS-Fp-S lines and suggests that both traits will be improved simultaneously when selection is practiced on only 1 trait. In summary, these data indicate the feasibility of further selective breeding of the BCWD resistant ARS-Fp-R line for increased CD resistance to produce a double pathogen resistant line of rainbow trout. PMID- 26020177 TI - Contributions of the maternal uterine environment and piglet genotype on weaning survivability potential: II. Piglet growth, lactation performance, milk composition, and piglet blood profiles during lactation following reciprocal embryo transfers between Meishan and White crossbred gilts. AB - Crossbreeding studies between Meishan (MS) and Large White (LW) pigs have illustrated that increased piglet growth before weaning is attributed to the maternal genotype of LW dams. The objective of this study was to determine the contributions of the maternal uterine environment (MUE), piglet genotype (PigG), piglet age (PA), and their interactions on piglet growth, lactation performance, milk composition, and piglet blood profiles during lactation following reciprocal embryo transfers between MS and White crossbred (WC) gilts. Twenty-five successful pregnancies were generated by embryo transfer in 2 farrowing years representing all MUE * PigG combinations: MS * MS (n = 4 litters), MS * WC (n = 7 litters), WC * MS (n = 7 litters), and WC * WC (n = 7 litters). At d 1 and 10 and at weaning, piglets (n = 147, n = 96, and n = 94, respectively) were weighed and blood samples were collected and measured for hematocrit, hemoglobin, glucose, nitrogen, NEFA, albumin, lactate, and cortisol. In addition, sows were manually milked from a medial mammary gland to determine milk composition. All data were analyzed by ANOVA using MIXED model procedures with the fixed effects of MUE, PigG, PA, and their interactions. Piglet weight was greater (P < 0.001) in piglets from WC dams compared to MS dams at d 10 and weaning but not at d 1. In addition, ADG were greater (P < 0.05) from piglets from WC dams compared to MS dams throughout lactation. However, milk composition was greater (P < 0.05) for GE and fat content from MS dams compared to WC dams, illustrating differences in milk quality between the breeds. There were significant MUE * PigG * PA interactions for hematocrit and hemoglobin levels in which greater (P < 0.001) levels were observed in MS piglets, irrespective of MUE, at d 1 of lactation and in MS piglets from MS dams at d 10 of lactation. Blood glucose was greater (P = 0.01) at d 1 in piglets from WC dams regardless of PigG but, at weaning, glucose was greater (P = 0.01) in WC piglets regardless of MUE. Serum NEFA levels were greater (P = 0.02) in piglets from MS dams throughout the lactation period. This study demonstrated that WC dams were superior to MS dams for piglet growth during lactation, in agreement with previous crossbreeding studies. However, blood components measured displayed complex interactions between the piglet and maternal breed, which signify possible mechanisms for improved preweaning survivability but slower lactational growth of MS piglets. PMID- 26020178 TI - Feed intake and diet selection in Angus-cross heifers of two frame sizes at two stages of growth. AB - Assessing feed efficiency in pasture-based systems can be challenging due to difficulties in measuring feed intake and diet preference. Furthermore, heifers may modify their intake of a particular forage species depending on its nutritive and physical attributes and on their own physiological status. For instance, heifers growing to larger mature sizes have higher maintenance requirements, which may affect their dietary preferences. The present study was designed to determine the influence of frame size (FS) on feed intake and diet selection at 2 age subclasses: postweaning, at, on average, 313 d of age (317 kg BW for larger FS and 285 kg BW for smaller FS), and as yearlings, at, on average, 403 d of age (391 kg BW for larger FS and 343 kg BW for the smaller FS). Twenty-four Angus cross heifers were evaluated at these ages. They were housed in a drylot equipped with a Broadbent Feeding System and had ad libitum access to cubed red clover and cubed fescue hay in separate buckets. Following 3-wk acclimation periods, DMI of each forage species was assessed daily for 10 d. Body weights were also recorded daily over those 10 d. Larger and smaller FS cattle did not differ in ADG, feed conversion ratio, and Kleiber ratio at either age (P > 0.05). However, heifers from larger FS category had higher total and red clover DMI at both ages (P < 0.05) and higher proportions of red clover in their diet as yearlings (P < 0.001). Cumulative differences between clover and fescue DMI were similar at postweaning in both FS (P > 0.05); however, at yearling age, the larger FS cattle ate consistently and cumulatively more red clover (P < 0.001). The intake and diet selection of heifers across ages were not consistent for either FS category (P = 0.748), suggesting difficulties in predicting lifetime feed efficiencies based on an early measure. Although gains and feed conversion ratios were similar between FS categories, the larger FS heifers ate more. At yearling age, these heifers of larger metabolic size also selected a greater proportion of red clover in their diet. Because the FS and, thereby, BW of cattle affect intakes and diet selections, they also may impact the composition and sustainability of grasslands generally. Therefore, the relationship between FS and pasture usage likely needs to be integrated into descriptions of cow efficiency in pasture-based operations. PMID- 26020179 TI - Responses of hematological parameters, beta-endorphin, cortisol, reactive oxygen metabolites, and biological antioxidant potential in horses participating in a traditional tournament. AB - Several concerns have been raised over the health of animals used in equestrian games that have their origins in historical or religious events and are currently held in many countries. This study investigated physiological stress response and health status of horses participating in the Sartiglia, a historical horse tournament held in the city of Oristano, Italy, which is principally based on the attempts of masked horsemen at a gallop to run a sword through a hole in a suspended silver star. Blood samples were collected from 21 horses the day before the tournament (D0), during the tournament (D1), and the day after the tournament (D2). Samples were analyzed for complete blood count and biochemical, hormonal, and oxidative stress assays. Data were analyzed using the mixed effect model with sampling session as one of the fixed effects. On the whole, blood parameters evidenced an optimal health status of horses at D0. Significant dehydration and increase of circulating glucose, enzymes, cortisol, and beta-endorphin were registered at D1 (P < 0.001) with a complete recovery of physiological values just at D2. The reactive oxygen metabolites (d-ROM), from which the prooxidant activity can be evaluated, showed an increase from D0 to D1 and D2. Concentration of biological antioxidant potential, which measured the antioxidant capacity, was characterized by the maximum level registered during the tournament and counteracted the simultaneous increase of d-ROM. It can be hypothesized that the tournament played an important role in causing high levels of oxidant markers not only because of the physical exercise represented by the gallop but also because the emotional stressors. In conclusion, the tournament caused significant changes of most parameters, which rapidly recovered to baseline values within the day after. These data will certainly be useful for a future implementation of tests in equine medicine and for the improvements of knowledge of changes of blood parameters and health of horses in similar tournaments. PMID- 26020180 TI - Effect of anti-gonadotropin-releasing factor vaccine and band castration on indicators of welfare in beef cattle. AB - Angus crossbred bulls (n = 60; 257 +/- 5.4 d of age; initial BW 358.8 +/- 3.78 kg) were used to study the effect of a vaccine against gonadotropin-releasing factor (GnRF) and band castration on behavioral and physiological indicators of pain. Cattle were randomly assigned to 1 of 3 treatments: bulls, band-castrated calves without pain mitigation (castrated), and immune-vaccinated animals administered an anti-GnRF vaccine (vaccinated). All animals were fitted with a radio frequency ear tag so that individual animal feed intake and feeding behavior were recorded daily over the entire trial using an electronic feed bunk monitoring system. Two doses of anti-GnRF vaccine were administrated on d -35 and 0 and band castration was performed on d 0. Animal BW was recorded weekly starting on d -36 until d 56. Visual analog scores (VAS) were measured on d -36 35, -1, and 0, and salivary cortisol concentration was measured at -30, 0, 30, 60, 120, and 270 min on d -35 and 0 after castration. Saliva and blood were obtained on d 1, 2, 5, and 7 and weekly until d 56 for determination of cortisol and complete blood cell count. Video data were collected for pain, sexual, and aggressive behavior daily the first week and once a week until d 56. Data were analyzed with a mixed-effect model with castration, time, and their interactions as main effects. Vaccinated calves had reduced ADG and intake (P < 0.05 and P < 0.001, respectively) during the first week after vaccination. Band-castrated calves had reduced ADG and intake (P < 0.001) until the end of the study. No differences in salivary cortisol and VAS were observed among groups at d -35 after the first vaccination and before band castration. However, on d 0, castrated cattle had greater cortisol concentrations and VAS (P < 0.05 and P < 0.01, respectively) than bulls and vaccinated animals. Complete blood cell count did not differ (P > 0.05) between treatments on d 0, 1, and 2. At d 56, vaccinated calves had greater (P < 0.05) final BW than band-castrated calves and both had less final BW than bulls. There was no indication that vaccination caused any physiological or behavioral changes indicative of pain. In contrast, band castration resulted in elevated cortisol scores and VAS indicative of a pain response and behavior related to pain (P < 0.001) until d 42 of the study. The present study demonstrates that anti-GnRF vaccine is a viable animal welfare friendly alternative to traditional band castration in beef cattle under North American feedlot practices. PMID- 26020181 TI - Investigation of the efficacy of albumin removal procedures on porcine serum proteome profile. AB - Improving the ability to predict livestock performance using biomarkers will provide a benefit for livestock genetic evaluation and improvement. The most practical biological sample to screen for development of biomarkers is serum due to the ease of collection. However, protein profiles in serum are complex and dynamic. Strategies are needed to manage variation in serum proteins used for biomarker identification. Albumin is the most abundant protein in serum, comprising over 50% of the overall protein content, and has historically been depleted from serum before biomarker identification. The objective of this study was to investigate the use of gel-based proteomic techniques to evaluate the need for porcine albumin depletion in biomarker identification. Albumin is known to bind many proteins in the blood, thus potential biomarkers could be removed during albumin depletion. Using two-dimensional difference in gel electrophoresis (2D-DIGE), we show whole serum can be used for biomarker discovery. The data obtained show that albumin removal methods are effective for porcine sera. Over 85% of the protein spots resolved on at least half of the gels were changed in abundance between whole and albumin depleted sera. Of the 204 protein spots significantly altered in abundance, 59 were changed over 400%. However, albumin removal also altered the serum proteome in an unpredictable manner; in the depleted sera, 86 protein spots were increased in abundance and 118 were decreased. Furthermore, the abundance of 59.4% of the protein spots in the albumin depleted samples had a larger standard error than whole sera. However, the resolution of albumin in 2D-DIGE analysis of whole sera permitted the detection and quantification of substantial numbers of proteins. Thus, it is proposed that whole serum can be used in a gel-based proteomics system for the identification of porcine biomarkers. PMID- 26020182 TI - Diosmectite-zinc oxide composite improves intestinal barrier restoration and modulates TGF-beta1, ERK1/2, and Akt in piglets after acetic acid challenge. AB - The present study evaluated the beneficial effect of diosmectite-zinc oxide composite (DS-ZnO) on improving intestinal barrier restoration in piglets after acetic acid challenge and explored the underlying mechanisms. Twenty-four 35-d old piglets (Duroc * Landrace * Yorkshire), with an average weight of 8.1 kg, were allocated to 4 treatment groups. On d 1 of the trial, colitis was induced via intrarectal injection of acetic acid (10 mL of 10% acetic acid [ACA] solution for ACA, DS-ZnO, and mixture of diosmectite [DS] and ZnO [DS+ZnO] groups) and the control group was infused with saline. Twenty-four hours after challenged, piglets were fed with the following diets: 1) control group (basal diet), 2) ACA group (basal diet), 3) DS-ZnO group (basal diet supplemented with DS-ZnO), and 4) DS+ZnO group (mixture of 1.5 g diosmectite [DS]/kg and 500 mg Zn/kg from ZnO [equal amount of DS and ZnO in the DS-ZnO treatment group]). On d 8 of the trial, piglets were sacrificed. The results showed that DS-ZnO supplementation improved (P < 0.05) ADG, ADFI, and transepithelial electrical resistance and decreased (P < 0.05) fecal scores, crypt depth, and fluorescein isothiocyanate-dextran 4 kDa (FD4) influx as compared with ACA group. Moreover, DS-ZnO increased (P < 0.05) occludin, claudin-1, and zonula occluden-1 expressions; reduced (P < 0.05) caspase-9 and caspase-3 activity and Bax expression; and improved (P < 0.05) Bcl2, XIAP, and PCNA expression. Diosmectite-zinc oxide composite supplementation also increased (P < 0.05) TGF-beta1 expression and ERK1/2 and Akt activation. These results suggest that DS-ZnO attenuates the acetic acid-induced colitis by improving mucosa barrier restoration, inhibiting apoptosis, and improving intestinal epithelial cells proliferation and modulation of TGF-beta1 and ERK1/2 and Akt signaling pathway. PMID- 26020183 TI - Renal mechanisms of calcium homeostasis in sheep and goats. AB - In small ruminants, the renal excretion of calcium (Ca) and phosphate (Pi) is not modulated in response to dietary Ca restriction. Although this lack of adaptation was observed in both sheep and goats, differences in renal function between these species cannot be excluded. Recent studies demonstrated that compared with sheep, goats have a greater ability to compensate for challenges to Ca homeostasis, probably due to a more pronounced increase in calcitriol production. Therefore, the aim of the present study was to examine the effect of 1) dietary Ca restriction, 2) administration of calcitriol, and 3) lactation on Ca and Pi transport mechanisms and receptors as well as enzymes involved in vitamin D metabolism in renal tissues of sheep and goats. Whereas RNA expression of renal transient receptor potential vanilloid channel type 5 was unaffected by changes in dietary Ca content, a significant stimulation was observed with administration of calcitriol in both sheep (P < 0.001) and goats (P < 0.01). Calbindin-D28K was downregulated during dietary Ca restriction in goats (P < 0.05). Expression of the sodium/Ca exchanger type 1 was decreased by low Ca intake in sheep (P < 0.05) and upregulated by calcitriol treatment in goats (P < 0.05). A significant reduction in RNA expression of the cytosolic and the basolateral Ca transporting proteins was also demonstrated for lactating goats in comparison to dried-off animals. Species differences were found for vitamin D receptor expression, which was stimulated by calcitriol treatment in sheep (P < 0.01) but not in goats. As expected, expression of 1alpha-hydroxylase was upregulated by dietary Ca restriction (P < 0.001; P < 0.05) and inhibited by exogenous calcitriol (P < 001; P < 0.05) in both sheep and goats. However, whereas 24-hydroxylase expression was stimulated to the same extent by calcitriol treatment in sheep, irrespective of the diet (P < 0.001), a modulatory effect of dietary Ca supply on 24-hydroxylase induction was observed in goats (P < 0.05). Taken together, our results confirm observations that modulation of renal Ca excretion does not contribute to maintenance of Ca homeostasis in these ruminants during restricted dietary supply, unlike responses in monogastric animals. The interesting species differences related to vitamin D metabolism might explain the greater capacity of goats to compensate for challenges of Ca homeostasis and should be further investigated. PMID- 26020184 TI - Identification of a novel microRNA important for melanogenesis in alpaca (Vicugna pacos). AB - The molecular mechanisms underlying the formation of coat colors in animals are poorly understood. Recent studies have demonstrated that microRNA play important roles in the control of melanogenesis and coat color in mammals. In a previous study, we characterized the miRNA expression profiles in alpaca skin with brown and white coat color and identified a novel miRNA (named lpa-miR-nov-66) that is expressed significantly higher in white skin compared to brown skin. The present study was conducted to determine the functional roles of this novel miRNA in the regulation of melanogenesis in alpaca melanocytes. lpa-miR-nov-66 is predicted to target the soluble guanylate cyclase (sGC) gene based on presence of a binding site in the sGC coding sequence (CDS). Overexpression of lpa-miR-nov-66 in alpaca melanocyes upregulated the expression of sGC both at the mRNA and protein level. Overexpression of lpa-miR-nov-66 in melanocyes also resulted in decreased expression of key melanogenic genes including tyrosinase (TYR), tyrosinase related protein 1 (TYRP1), and microphthalmia transcription factor (MITF). Our ELISA assays showed increased cyclic guanosine monophosphate (cGMP) but decreased cyclic adenosine monophosphate (cAMP) production in melanocytes overexpressing lpa-miR-nov-66. In addition, overexpression of lpa-miR-nov-66 also reduced melanin production in cultured melanocytes. Results support a role of lpa-miR-nov 66 in melanocytes by directly or indirectly targeting , which regulates melanogenesis via the cAMP pathway. PMID- 26020185 TI - The effect of cyclical and severe heat stress on growth performance and metabolism in Afshari lambs. AB - The extent to which reduced feed intake contributes to decreased growth during heat stress (HS) in the ovine model is not clear. To evaluate the impact of decreased DMI on performance, we conducted an experiment on growing lambs experiencing a cyclical but extensive heat load. Sixteen intact male Afshari lambs (40.1 +/- 1.9 kg) were used in a completely randomized design in 2 periods. In period 1, all 16 lambs were housed in thermal neutral (TN) conditions (22.2 +/ 3.1 degrees C and a temperature-humidity index [THI] of 67.9 +/- 3.2) and fed at libitum for 8 d. In period 2 (P2), which lasted 9 d, 8 lambs were subjected to a cyclical HS condition (33.0 to 45.0 degrees C and a THI of more than 80 at least for 24 h/d and more than 90 for 8 h/d). The other 8 lambs were maintained in TN conditions but pair-fed (pair-fed thermal neutral [PFTN]) to the HS lambs. During each period, DMI and water intake were measured daily. Respiration rate, rectal temperature, and skin temperature at the shoulder, rump, and front and rear leg were recorded at 0700 and 1400 h daily. Dry matte intake declined (17.5%; P < 0.01) in HS lambs and, by design, the temporal pattern and magnitude of reduced feed intake was similar in the PFTN controls. Water intake increased (19%; P < 0.05) during P2 in HS but not in the PFTN controls. Heat stress increased the 0700 and 1400 h skin temperature at the shoulder (5 and 9.2%), rump (6.2 and 10.3%), rear (6 and 9.2%), and front leg (6.5 and 9.8%) and respiratory rates (84 and 163% [P < 0.01]at 0700 and 1400 h, respectfully), but only the 1400 h rectal temperature was increased (P < 0.01; 0.65 degrees C) in HS lambs. Neither environment nor period affected blood urea nitrogen and glucose concentrations. However, circulating NEFA and insulin were increased and declined (P < 0.01) in PFTN lambs, respectively, but neither variable was altered in the HS lambs. Growth was reduced in P2 for lambs in both treatments, but despite being on a similar reduced plane of nutrition, the HS lambs' ADG was more than 2-fold greater than the PFTN controls. These results indicate that HS markedly alters the energetics of weight gain during growth and that the effects of HS are dependent on the severity of the heat load. PMID- 26020186 TI - Milk from dams fed an obesogenic diet combined with a high-fat/high-sugar diet induces long-term abnormal mammary gland development in the rabbit. AB - Alterations to the metabolic endocrine environment during early life are crucial to mammary gland development. Among these environmental parameters, the initial nutritional event after birth is the consumption of milk, which represents the first maternal support provided to mammalian newborns. Milk is a complex fluid that exerts effects far beyond its immediate nutritional value. The present study, therefore, aimed to determine the effect of the nutritional changes during the neonatal and prepubertal periods on the adult mammary phenotype. Newborn rabbits were suckled by dams fed a high-fat/high-sugar obesogenic (OD) or a control (CON) diet and then subsequently fed either the OD or CON diets from the onset of puberty and throughout early pregnancy. Mammary glands were collected during early pregnancy (Day 8 of pregnancy). Rabbits fed with OD milk and then subjected to an OD diet displayed an abnormal development of the mammary gland: the mammary ducts were markedly enlarged (P < 0.05) and filled with abundant secretory products. Moreover, the alveolar secretory structures were disorganized, with an abnormal aspect characterized by large lumina. Mammary epithelial cells contained numerous large lipid droplets and exhibited fingering of the apical membrane and abnormally enlarged intercellular spaces filled with casein micelles. Leptin has been shown to be involved in modulating several developmental processes. We therefore analyzed its expression in the mammary gland. Mammary leptin mRNA was strongly expressed in rabbits fed with OD milk and subjected to an OD diet by comparison with the CON rabbits. Leptin transcripts and protein were localized in the epithelial cells, indicating that the increase in leptin synthesis occurs in this compartment. Taken together, these findings suggest that early-life nutritional history, in particular through the milking period, can determine subsequent mammary gland development. Moreover, they highlight the potentially important regulatory role that leptin may play during critical early-life nutritional windows with respect to long-term growth and mammary function. PMID- 26020187 TI - Dietary curcumin supplementation protects against heat-stress-impaired growth performance of broilers possibly through a mitochondrial pathway. AB - A total of 400 1-d-old Arbor Acres broiler chicks were raised at a recommended environmental temperature from d 1 to 20 (experimental day [ED] = ED1 to ED20). On ED21, the chicks were weighed and reallocated into 5 treatment groups, with 8 replicates of 10 birds each. The 5 treatment groups were as follows: the control group, in which chicks were housed at 22 +/- 1 degrees C and fed the basal diet, and the HS, HS-CUR50, HS-CUR100, and HS-CUR200 groups, in which chicks were housed at 34 +/- 1 degrees C for 8 h (0900-1700 h) and 22 +/- 1 degrees C for the rest time and fed the basal diet with 0, 50, 100, and 200 mg/kg curcumin, respectively. From ED21 to ED42, the heat treatment lasted for 20 consecutive days. The results showed that heat-stressed broilers had greater (P < 0.05) average head surface and rectal temperature on ED21 and ED42 than the non-heat stressed broilers. Diets supplied with 50 and 100 mg/kg curcumin increased (P < 0.05) the G:F compared to the heat-stressed groups. Mitochondrial malondialdehyde levels, an index of lipid peroxidation, in the breast muscle were 15.15 and 9.09% higher (P < 0.05) in 50 and 100 mg/kg curcumin supplemented groups than that of the heat-stressed group, respectively. Curcumin supplementation (50, 100, and 200 mg/kg) increased (P < 0.05) mitochondrial glutathione content and glutathione peroxidase, glutathione S-transferase, and manganese superoxide dismutase activities compared to heat-stressed broilers. Curcumin supplementation (50, 100, and 200 mg/kg) resulted in a decrease (P < 0.05) of heat shock protein 70 mRNA levels in the breast muscle. The breast muscle mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and nuclear respiratory factor 1 and 2 in heat-stressed groups was increased (P < 0.05) in response to dietary 100 mg/kg curcumin treatment. Additionally, when compared to the heat stressed group, mitochondrial transcription factor A mRNA levels were increased (P < 0.05) by 17.64% in the 200 mg/kg curcumin supplemented group. In conclusion, dietary curcumin supplementation prevented heat-stress-impaired growth performance, possibly through improving the antioxidant defense system and enhancing the mitochondrial biogenesis. PMID- 26020188 TI - Equations generated to predict iodine value of pork carcass back, belly, and jowl fat. AB - Data from existing literature were used to generate equations to predict finishing pig back, belly, and jowl fat iodine values (IV) and an experiment was conducted to evaluate these equations. The final database included 24, 21, and 29 papers for back, belly, and jowl fat IV, respectively. For experiments that changed dietary fatty acid composition, initial (INT) diets were defined as those fed before the change in diet composition and final (FIN) diets were those fed after. The predictor variables tested were divided into 5 groups: 1) diet fat composition (dietary percent C16:1, C18:1, C18:2, C18:3, EFA, unsaturated fatty acids, and IV product) for both INT and FIN diets, 2) day feeding the INT and FIN diets, 3) ME or NE of the INT and FIN diet, 4) live performance criteria (initial BW, final BW, ADG, ADFI, and G:F), and 5) carcass criteria (HCW and backfat thickness). The PROC MIXED procedure of SAS (SAS Inst., Inc., Cary, NC) was used to develop regression equations. Evaluation of models with significant terms was then conducted based on the Bayesian information criterion. The optimum equations to predict back, belly, and jowl fat IV were backfat IV = 84.83 + (6.87 * INT EFA) - (3.90 * FIN EFA) - (0.12 * INT days) - (1.30 * FIN days) - (0.11 * INT EFA * FIN days) + (0.048 * FIN EFA * INT days) + (0.12 * FIN EFA * FIN days) - (0.0060 * FIN NE) + (0.0005 * FIN NE * FIN days) - (0.26 * backfat depth); belly fat IV = 106.16 + (6.21 * INT EFA) - (1.50 * FIN days) - (0.11 * INT EFA * FIN days) - (0.012 * INT NE) + (0.00069 * INT NE * FIN days) - (0.18 * HCW) - (0.25 * backfat depth); and jowl fat IV = 85.50 + (1.08 * INT EFA) + (0.87 * FIN EFA) - (0.014 * INT days) - (0.050 * FIN days) + (0.038 * INT EFA * INT days) + (0.054 * FIN EFA * FIN days) - (0.0066 * INT NE) + (0.071 * INT BW) - (2.19 * ADFI) - (0.29 * backfat depth). Dietary treatments from the evaluation experiment consisted of a corn-soybean meal control diet with no added fat or a 3 * 3 factorial arrangement with main effects of fat source (4% tallow, 4% soybean oil, or a blend of 2% tallow and 2% soybean oil) and feeding duration (d 0 to 42, 42 to 84, or 0 to 84). The back, belly, and jowl fat IV equations tended to overestimate IV when observed IV were less than approximately 65 g/100 g and underestimate belly fat IV when actual IV are greater than approximately 74 g/100 g or when the fat blend was fed from d 0 to 84 or 42 to 84. Overall, with the exceptions noted, the regression equations were an accurate tool for predicting carcass fat quality based on dietary and pig performance factors. PMID- 26020189 TI - Oral administration of putrescine and proline during the suckling period improves epithelial restitution after early weaning in piglets. AB - Polyamines are necessary for normal integrity and the restitution after injury of the gastrointestinal epithelium. The objective of this study was to investigate the effects of oral administration of putrescine and proline during the suckling period on epithelial restitution after early weaning in piglets. Eighteen neonatal piglets (Duroc * Landrace * Large Yorkshire) from 3 litters (6 piglets per litter) were assigned to 3 groups, representing oral administration with an equal volume of saline (control), putrescine (5 mg/kg BW), and proline (25 mg/kg BW) twice daily from d 1 to weaning at 14 d of age. Plasma and intestinal samples were obtained 3 d after weaning. The results showed that oral administration of putrescine or proline increased the final BW and ADG of piglets compared with the control (P < 0.05). Proline treatment decreased plasma D-lactate concentration but increased the villus height in the jejunum and ileum, as well as the percentage of proliferating cell nuclear antigen (PCNA) positive cells and alkaline phosphatase (AKP) activity in the jejunal mucosa (P < 0.05). The protein expressions for zonula occludens (ZO-1), occludin, and claudin-3 (P < 0.05) but not mRNA were increased in the jejunum of putrescine- and proline-treated piglets compared with those of control piglets. The voltage-gated K+ channel (Kv) 1.1 protein expression in the jejunum of piglets administrated with putrescine and the Kv1.5 mRNA and Kv1.1 protein levels in the ileum of piglets administrated with proline were greater than those in control piglets (P < 0.05). These findings indicate that polyamine or its precursor could improve mucosal proliferation, intestinal morphology, as well as tight junction and potassium channel protein expressions in early-weaned piglets, with implications for epithelial restitution and barrier function after stress injury. PMID- 26020190 TI - Effects of diet mix time and ractopamine hydrochloride on finishing pig growth and carcass performance. AB - Two experiments were completed to determine the effects of diet mix uniformity and ractopamine HCl on finishing pig performance. In Exp. 1, a total of 200 pigs (BW = 90 kg) were used in a 33-d growth assay arranged in a randomized complete block design with 5 pigs/pen and 8 pens/treatment. Treatments were a corn-soybean meal-based control diet mixed for 360 s or the mixed control diet with 10 mg/kg ractopamine added before additional mixing for 0, 30, 120, or 360 s. Chromium was added to the diet and analyzed to determine mix uniformity of the ractopamine. Therefore, this experiment was designed to determine the effects of nutrient utilization from a thoroughly mixed diet with a potentially nonuniform distribution of ractopamine. Pigs fed diets with ractopamine had greater (P < 0.05) ADG, G:F, final BW, HCW, dressing percentage, loin depth, and percentage carcass lean with lower (P = 0.005) 10th rib backfat thickness. Increasing mix time from 0 to 360 s decreased (quadratic, P = 0.001) CV for Cr from 67 to 12% but had no effect on the response to ractopamine for any growth or carcass measurements. In Exp. 2, a total of 160 pigs (BW = 93 kg) were used in a 27-d growth assay arranged in a completely randomized design with 2 pigs/pen and 16 pens/treatment. Treatments were a corn-soybean meal-based control diet mixed for 360 s or the control diet with 10 mg/kg ractopamine mixed for 0, 30, 120, or 360 s. Diet mix uniformity was determined by measuring Cr and using Quantab Cl titrators (low range 0.005 to 0.1% as NaCl; Environmental Test Systems Inc., Elkhart, IN) to measure the concentration of salt. This experiment was designed to determine the combined effects of potentially nonuniform distribution of both nutrients and ractopamine. The use of ractopamine increased (P < 0.05) ADG, G:F, final BW, HCW, dressing percentage, percentage lean, and loin depth. Increasing mix times from 0 to 360 s decreased (quadratic, P = 0.050) CV for salt and Cr from 51 to 12% and 51 to 15%, respectively, with no effect on ADG, ADFI, final BW CV, HCW, dressing percentage, backfat thickness, loin depth, or percentage carcass lean; however, G:F tended to increase (linear, P = 0.07) as mix time increased from 0 to 360 s. In conclusion, increasing mix time of diets from 0 to 360 s did not affect the response of finishing pigs to ractopamine PMID- 26020191 TI - Partitioning of dietary energy of chickens fed maize- or wheat-based diets with and without a commercial blend of phytogenic feed additives. AB - The aim of the study was to investigate the effects of a standardized mixture of a commercial blend of phytogenic feed additives containing 5% carvacrol, 3% cinnamaldehyde, and 2% capsicum on utilization of dietary energy and performance in broiler chickens. Four experimental diets were offered to the birds from 7 to 21 d of age. These included 2 basal control diets based on either wheat or maize that contained 215 g CP/kg and 12.13 MJ/kg ME and another 2 diets using the basal control diets supplemented with the plant extracts combination at 100 mg/kg diet. Each diet was fed to 16 individually penned birds following randomization. Dietary plant extracts improved feed intake and weight gain (P < 0.05) and slightly (P < 0.1) improved feed efficiency of birds fed the maize-based diet. Supplementary plant extracts did not change dietary ME (P > 0.05) but improved (P < 0.05) dietary NE by reducing the heat increment (P < 0.05) per kilogram feed intake. Feeding phytogenics improved (P < 0.05) total carcass energy retention and the efficiency of dietary ME for carcass energy retention. The number of interactions between type of diet and supplementary phytogenic feed additive suggest that the chemical composition and the energy to protein ratio of the diet may influence the efficiency of phytogenics when fed to chickens. The experiment showed that although supplementary phytogenic additives did not affect dietary ME, they caused a significant improvement in the utilization of dietary energy for carcass energy retention but this did not always relate to growth performance. PMID- 26020192 TI - Effects of drought-affected corn and nonstarch polysaccharide enzyme inclusion on nursery pig growth performance. AB - The effectiveness of carbohydrase enzymes has been inconsistent in corn-based swine diets; however, the increased substrate of nonstarch polysaccharides in drought-affected corn may provide an economic model for enzyme inclusion, but this has not been evaluated. A total of 360 barrows (PIC 1050 * 337, initially 5.85 kg BW) were used to determine the effects of drought-affected corn inclusion with or without supplementation of commercial carbohydrases on growth performance and nutrient digestibility of nursery pigs. Initially, 34 corn samples were collected to find representatives of normal and drought-affected corn. The lot selected to represent the normal corn had a test weight of 719.4 kg/m3, 15.0% moisture, and 4.2% xylan. The lot selected to represent drought-affected corn had a test weight of 698.8 kg/m3, 14.3% moisture, and 4.7% xylan. After a 10-d acclimation period postweaning, nursery pigs were randomly allotted to 1 of 8 dietary treatments in a completely randomized design. Treatments were arranged in a 2 * 4 factorial with main effects of corn (normal vs. drought affected) and enzyme inclusion (none vs. 100 mg/kg Enzyme A vs. 250 mg/kg Enzyme B vs. 100 mg/kg Enzyme A + 250 mg/kg Enzyme B). Both enzymes were included blends of beta glucanase, cellulose, and xylanase (Enzyme A) or hemicellulase and pectinases (Enzyme B). Pigs were fed treatment diets from d 10 to 35 postweaning in 2 phases. Feed and fecal samples were collected on d 30 postweaning to determine apparent total tract digestibility of nutrients. The nutrient concentrations of normal and drought-affected corn were similar, which resulted in few treatment or main effects differences of corn type or enzyme inclusion. No interactions were observed (P > 0.10) between corn source and enzyme inclusion. Overall (d 10 to 35), treatments had no effect on ADG or ADFI, but enzyme A inclusion tended to improve (P < 0.10; 0.74 vs. 0.69) G:F, which was primarily driven by the improved feed efficiency (0.76 vs. 0.72; P < 0.05) of pigs fed Enzyme A in Phase 2 (d 10 to 25 postweaning) and was likely a result of improved xylan utilization. In conclusion, drought stress did not alter the nonstarch polysaccharide concentration of corn beyond xylan concentration, so it was not surprising that enzyme inclusion showed little benefit to nursery pig growth performance. However, improved feed efficiency of pigs fed diets containing Enzyme A from d 10 to 25 postweaning warrants further investigation PMID- 26020193 TI - Effects of feeding cracked corn to nursery and finishing pigs. AB - Four experiments were conducted to determine the effects of supplementing cracked corn in nursery and finishing pig diets (PIC TR4 * 1050). In Exp. 1, 144 pigs (7.5 kg BW) were used in a 28-d experiment with 6 pigs per pen and 6 pens per treatment. Treatments were corn-soybean meal based in the form of mash, pellets (PCD), and pellets with 100% of the corn ground (PGr; 618 mm) or cracked (PCr; 3444 mm) and blended into the diet after the rest of the formulation had been pelleted. For d 0 to 28, pigs fed mash had increased (P = 0.042) ADFI compared with those fed the PCD diet. Pigs fed PCD had increased (P < 0.05) ADG and G:F compared with pigs fed PGr and PCr. Pigs fed PCr had decreased (P = 0.004) G:F compared with those fed PGr. For Exp. 2, 224 nursery pigs (7.4 kg BW) were used in a 28-d study with 7 pigs per pen and 8 pens per treatment. Treatments were similar to Exp. 1, with 50% of the corn either ground (445 mm) or cracked (2142 mm). For d 0 to 28, pigs fed mash had greater (P < 0.05) ADFI and G:F than pigs fed the PCD diet. Pigs fed the PCD diet had decreased (P = 0.001) ADFI and increased (P = 0.001) G:F compared to those fed PGr and PCr. For Exp. 3, 208 pigs (62.6 kg BW) were used in a 63-d experiment with 13 pigs per pen and 4 pens per treatment. Treatments were corn-soybean meal based with 0, 10, 20, and 40% cracked corn (3549 um). All treatments were fed in mash form. For d 0 to 63, increasing cracked corn tended to decrease (linear, P = 0.093) G:F and decreased (linear, P = 0.047) carcass yield. Adding up to 40% of cracked corn to a mash diet decreased (P < 0.05) scores for keratinization and ulcers. For Exp. 4, 252 finishing pigs (40 kg BW) were used with 7 pigs per pen and 9 pens per treatment. The treatments were the same as described in Exp. 2. For the 80-d experiment, pigs fed mash had decreased (P < 0.05) ADG, stomach keratinization, and ulcer scores and increased (P < 0.05) yield and loin depth compared with pigs fed the PCD diet. Pigs fed PCD had increased (P < 0.05) ADG and G:F and decreased (P = 0.026) loin depth compared with pigs fed PGr and PCr diets. Pigs fed PCr had increased (P = 0.023) ADG and decreased (P = 0.001) yield compared with pigs fed PGr. Pigs fed PCr had decreased (P < 0.05) stomach keratinization and ulcer scores compared with pigs fed the PCD and PGr diets. In conclusion, pigs fed PCD had the greatest G:F, and PGr and PCr treatments had negative effects on G:F of pigs. Scores for stomach lesions were lowest for pigs fed PCr. PMID- 26020194 TI - Nutrient value of spray field forages fed to pigs and the use of feed enzymes to enhance nutrient digestibility. AB - This study determined the DE, ME, apparent total tract digestibility (ATTD) of N, and N retention of spray field forages (Bermuda grass, forage sorghum, and sweet sorghum) fed to pigs and the effects of the supplemental feed enzymes on energy and N utilization. A basal diet was formulated with 96% corn and 4% amino acids, minerals, and vitamins. Test diets contained 85% basal diet + 15% Bermuda grass, forage sorghum, or sweet sorghum. Allzyme SSF (Alltech, Nicholasville, KY) was used as a feed enzyme, which was composed of cellulase, glucanase, xylanase, phytase, and protease. The basal diet and test diets were evaluated by using 4 sets of 2 * 2 Latin square designs consisting of 2 pigs and 2 periods with a total of 32 barrows (38.7 +/- 7.9 kg). Each period (10-d adjustment and 4-d collection) had 2 Latin squares. The 2 treatments were levels of enzyme supplementation (0 or 200 mg/kg). Pigs received experimental diets twice daily (0700 and 1700 h) at a fixed amount based on BW of pigs (0.09 * BW0.75 kg). On d 10, chromic oxide (0.5%) was added to the diets at 1700 h as an external marker. Fecal and urine samples were collected during 4 consecutive days. The basal diet contained 3,850 kcal DE/kg, 3,769 kcal ME/kg, 86.06% ATTD of N, and 71.10% N retention and was not affected by enzyme supplementation. Bermuda grass contained 893 kcal DE/kg, 845 kcal ME/kg, -16.50% ATTD of N, and -37.49% N retention and tended to be improved by enzyme supplementation to 1,211 kcal DE/kg (P = 0.098), 1,185 kcal ME/kg (P = 0.081), and -10.54% N retention (P = 0.076). The ATTD of N of Bermuda grass increased (P < 0.05) to 0.08% by enzyme supplementation. The forage sorghum contained 1,520 kcal DE/kg, 1,511 kcal ME/kg, -0.72% ATTD of N, and -16.99% N retention. The sweet sorghum contained 1,086 kcal DE/kg, 1,061 kcal ME/kg, -75.47% ATTD of N, and -49.22% N retention. Enzyme supplementation did not improve energy digestibility of forage sorghum and sweet sorghum. Nitrogen in these forages was poorly utilized. In conclusion, spray field forages including Bermuda grass, forage sorghum, and sweet sorghum can partly be utilized in pig feed to provide energy, although N is rather poorly digested. Feed enzymes could enhance both energy and N utilization in Bermuda grass but not sorghum. PMID- 26020195 TI - Forage choice in pasturelands: Influence on cattle foraging behavior and performance. AB - We determined if combinations of adjacent pastures of 3 forage species led to complementary relationships that influenced animal behavior and performance over monocultures. Grazing bouts, behavioral levels of activity, blood urea N (BUN), chemical composition of feces, BW, and herbage biomass before and after grazing were monitored when beef calves strip-grazed 3 replications of 4 treatments from June 14 through August 23, 2013 (9 animals/treatment). Animals grazed monocultures of: 1) tall fescue (TF), 2) alfalfa (ALF), 3) sainfoin (SAN), or 4) a choice of strips of forages TF, ALF, and SAN (CHOICE). The lowest and greatest incidence of foraging bouts occurred for cattle in CHOICE and SAN, respectively (P < 0.01). Animals in CHOICE grazed SAN > ALF > TF (P < 0.01). Animals on TF and CHOICE took greater number of steps than animals grazing a monocultures of either legume (P = 0.01). Calves in TF had lower BUN (P < 0.01) and fecal CP concentration (P < 0.01) than calves grazing the remaining treatments, whereas animals in SAN showed the greatest concentrations of fecal CP (P < 0.01). Fecal NDF concentration was the greatest for animals grazing TF and the lowest for animals grazing SAN (P < 0.01), whereas fecal ADF concentration was greater for animals grazing TF and SAN than for animals grazing CHOICE and ALF (P = 0.02). Calcium, Mg, and Zn concentrations were the lowest in feces from calves grazing TF and the greatest for calves grazing a monoculture of either legume (P < 0.05). When averaging both periods, animals grazing SAN, ALF, or CHOICE gained more BW than animals grazing TF (P < 0.01). Thus, calves in CHOICE incorporated tall fescue into their diets, were more active, and displayed a lower number of grazing bouts than calves grazing monoculture of either legume. Herbage diversity may lead to levels of ADG comparable to legume monocultures with the potential benefit of maintaining plant species diversity in pasturelands. PMID- 26020196 TI - Ruminal pH predictions for beef cattle: Comparative evaluation of current models. AB - This study evaluated 8 empirical models for their ability to accurately predict mean ruminal pH in beef cattle fed a wide range of diets. Models tested that use physically effective fiber (peNDF) as a dependent variable were Pitt et al. (1996, PIT), Mertens (1997, MER), Fox et al. (2004, FOX), Zebeli et al. (2006, ZB6), and Zebeli et al. (2008, ZB8), and those that use rumen VFA were Tamminga and Van Vuuren (1988, TAM), Lescoat and Sauvant (1995, LES), and Allen (1997, ALL). A data set of 65 published papers (231 treatment means) for beef cattle was assembled that included information on animal characteristics, diet composition, and ruminal fermentation and mean pH. Model evaluations were based on mean square prediction error (MSPE), concordance correlation coefficient (CCC), and regression analysis. The prediction potential of the models varied with low root MSPE (RMSPE) values of 4.94% and 5.37% for PIT and FOX, RMSPE values of 9.66% and 12.55% for ZB6 and MER, and intermediate RMSPE values of 5.66% to 6.26% for the other models. For PIT and FOX, with the lowest RMSPE, approximately 96% of MSPE was due to random error, whereas for ZB6 and MER, with the highest RMSPE, 15.85% and 23.42% of MSPE, respectively, was due to linear bias, and 37.19% and 60.12% of the error, respectively, was due to deviation of the regression slope from unity. The CCC was greatest for PIT (0.67) and FOX (0.62), followed by 0.60 for LES and TAM, 0.52 for ZB8, 0.39 for MER, 0.34 for ALL, and 0.22 for ZB6. Residuals plotted against model-predicted values showed linear bias (P < 0.001) for all models except PIT (P = 0.976) and FOX (P = 0.054) and mean bias (P < 0.001) except for FOX (P = 0.293), LES (P = 0.215), and TAM (P = 0.119). The study showed that the empirical models PIT and FOX, based on peNDF, and LES and TAM, based on VFA, are preferred over the others for prediction of mean ruminal pH in beef cattle fed a wide range of diets. Several animal (BW and intake), diet (forage and OM contents), and ruminal (ammonia and acetate concentrations) factors were (P < 0.001) related to the residuals for each model. We conclude that the accuracy of prediction of mean ruminal pH was relatively low for all extant models. Consideration of factors in addition to peNDF and total VFA, as well as the use of data from studies with continuous measurement of ruminal pH over 24 h or more, would be useful in the development of improved models for predicting ruminal pH in beef cattle. PMID- 26020197 TI - Impact of ruminal pH on enteric methane emissions. AB - The objective of this study was to determine the impact of ruminal pH on methane (CH4) emission from beef cattle. Ruminal pH and CH4 data were generated in 2 experiments using 16 beef heifers offered high-forage (55% barley silage) or high grain (92% concentrate; DM basis) diets. Both experiments were designed as a replicated 4 * 4 Latin square with 4 periods and 4 dietary treatments. Methane was measured over 4 consecutive days using open-circuit respiratory chambers with each chamber housing 2 heifers. The ruminal pH of individual heifers was measured using indwelling pH loggers. The mean ruminal pH and CH4 emission (g/h) of 2 heifers in every chamber were summarized in 30-min blocks. Even though rumen methanogens have been described to be inhibited by a pH < 6.0 in vitro, in vivo CH4-production rates (g/h) did not decrease when ruminal pH declined to threshold levels for subacute (5.2 <= pH < 5.5) or acute ruminal acidosis (pH < 5.2; P > 0.05). Daily mean CH4 emission (g/d) and ruminal pH were only mildly correlated (r2 = 0.27; P < 0.05), suggesting that additional factors, such as increased propionate formation or passage rate, account for the lower CH4 emissions from cattle fed high-grain as compared to high-forage diets. Lowering ruminal pH alone is, therefore, not an effective CH4-mitigation strategy. Mechanisms permitting methanogens to survive episodes of low-ruminal pH might include changes in community structure toward more pH-tolerant strains or sequestration into microenvironments within biofilms or protozoa where methanogens are protected from low pH. PMID- 26020198 TI - Effect of a multielement trace mineral injection before transit stress on inflammatory response, growth performance, and carcass characteristics of beef steers. AB - Weaned calves (n = 98; 256 +/- 11.5 kg) were used to evaluate the impact of improving trace mineral (TM) status using a multielement TM injection 28 d before transit on markers of inflammatory and stress responses in response to transit and postshipping growth performance. On d 0 of a 28-d preconditioning program, calves received subcutaneous TM injection (MM; n = 48) containing 15, 10, 5, and 60 mg/mL of Cu, Mn, Se, and Zn, respectively, or physiological saline injection (SAL; n = 48). On d 28, steers were weighed, half of the steers from each treatment were transported for a 20-h transit stress period (SHIP; n = 24 per injection treatment), and half of the steers were returned to their pens for 20 h of feed and water restriction without transit (NOSHIP; n = 24 per injection treatment). The SHIP steers were unloaded on d 29 and all steers (SHIP and NOSHIP) were immediately weighed and sorted into new pens (n = 4 steers per pen) for the growing period. At the start of finishing (d 113), steers received a second MM or SAL, resulting in a 2 * 2 * 2 factorial (n = 12 steers per treatment combination). Samples of blood were collected on d 28, 29, and 34 and liver on d 22 and 40. The initial MM increased liver Cu, Se, and Zn concentrations of cattle (P <= 0.02) but did not affect ADG during preconditioning (P = 0.89) or BW shrink as a result of transit (P >= 0.52). Plasma Fe concentrations were decreased after the transit stress period in SHIP calves (P <= 0.05) relative to NOSHIP calves but recovered 5 d after transit, and serum IL-8 concentrations were greater in SAL-SHIP steers than MM-SHIP steers (P = 0.04). Altering TM status through MM caused steers to have lesser ADG (P = 0.03) during the 14-d period after transit (d 29 through 43) but did not affect growth during the growing period (d 5 through 112; P >= 0.40). Minimal effects on finishing performance and carcass characteristics were noted, but there was a 3-way interaction (P <= 0.02) in which SAL-NOSHIP-MM steers had the greatest yield grade (YG) and smallest ribeye area (REA) and SAL-SHIP-MM steers had the least YG and largest REA. Overall, a MM 28 d before transit or before feed and water restriction did not affect the inflammatory response or plasma TM concentrations but decreased ADG in the 14-d period after transit. Trace mineral injection had limited effects on overall growth performance and carcass characteristics, likely because steer initial TM status was well within the adequate range. PMID- 26020199 TI - Sustained reduction in methane production from long-term addition of 3 nitrooxypropanol to a beef cattle diet. AB - The objective was to evaluate whether long-term addition of 3-nitrooxypropanol (NOP) to a beef cattle diet results in a sustained reduction in enteric CH4 emissions in beef cattle. Eight ruminally cannulated heifers (637 +/- 16.2 kg BW) were used in a completely randomized design with 2 treatments: Control (0 g/d of NOP) and NOP (2 g/d of NOP). Treatments were mixed by hand into the total mixed ration (60% forage, DM basis) at feeding time. Feed offered was restricted to 65% of ad libitum DMI (slightly over maintenance energy intake) and provided once per day. The duration of the experiment was 146 d, including an initial 18-d covariate period without NOP use; a 112-d treatment period with NOP addition to the diet, divided into four 28-d time intervals (d 1 to 28, 29 to 56, 57 to 84, and 85 to 112); and a final 16-d recovery period without NOP use. During the covariate period and at the end of each interval and the end of the recovery period, CH4 was measured for 3 d using whole animal metabolic chambers. The concentration of VFA was measured in rumen fluid samples collected 0, 3, and 6 h after feeding, and the microbial population was evaluated using rumen samples collected 3 h after feeding on d 12 of the covariate period, d 22 of each interval within the treatment period, and d 8 of the recovery period. Average DMI for the experiment was 7.04 +/- 0.27 kg. Methane emissions were reduced by 59.2% when NOP was used (9.16 vs. 22.46 g/kg DMI; P < 0.01). Total VFA concentrations were not affected (P = 0.12); however, molar proportion of acetate was reduced and that for propionate increased when NOP was added (P < 0.01), which reduced the acetate to propionate ratio (3.0 vs. 4.0; P < 0.01). The total copy number of the 16S rRNA gene of total bacteria was not affected (P = 0.50) by NOP, but the copy number of the 16S rRNA gene of methanogens was reduced (P < 0.01) and the copy number of the 18S rRNA gene of protozoa was increased (P = 0.03). The residual effect of NOP for most of the variables studied was not observed or was minimal during the recovery period. These results demonstrated that the addition of NOP to a diet for beef cattle caused a sustained decrease of methanogenesis, with no sign of adaptation, and that these effects were reversed once NOP addition was discontinued PMID- 26020200 TI - Sources of variability in livestock water quality over 5 years in the Northern Great Plains. AB - Concentrated dissolved minerals in naturally occurring water accessible to livestock grazing semiarid landscapes can negatively influence animal productivity and well-being. Twelve indicators of water quality (Ca, Cl, Fe, F, Mg, Mn, Na, nitrate N, pH, SO4, total dissolved solids [TDS], and temperature) were measured at 45 livestock water sites over 5 yr from 2009 through 2013 at the 22,257-ha USDA-ARS Fort Keogh Livestock and Range Research Laboratory (Miles City, MT) to estimate variation. Water was sampled from 4 sources: 1) flowing surface water, 2) groundwater, 3) reservoirs, and 4) springs. The sampled area was classified by 3 cardinal compass bearings (locations): 1) north, 2) southeast, and 3) southwest of the Yellowstone River. Samples were collected twice yearly in 2 seasons, May (wet) and September (dry). Year, location, source, and season and their interactions were analyzed as a 5 * 3 * 4 * 2 factorial arrangement of treatments. A location * year interaction (P < 0.04) was found for Mg, Na, SO4, and TDS. The southwest location had the greatest concentrations in 2012 of Na, SO4, and TDS. A source * year interaction (P < 0.02) was found for Ca, Fe, F, Mg, Mn, Na, SO4, TDS, and temperature. Iron, Mg, and Mn had the greatest concentrations in flowing surface water in 2012. Greater and then lower precipitation in 2011 followed by below-average precipitation in 2012 was associated with elevated mineral concentrations in sources in the southwest location and flowing surface water sources demonstrating sources of water quality variability within time and space at the study site. Average concentrations of Ca, Cl, Mg, and nitrate N and pH levels across sources and locations did not exceed the upper maximum intake level for beef cattle. In contrast, concentrations of F, Fe, Na, SO4, and TDS at times exceeded the upper maximum level for beef cattle, indicating these minerals may negatively impact range beef cattle performance. PMID- 26020201 TI - Contribution of different segments of the gastrointestinal tract to digestion in growing Saanen goats. AB - This study examined mean retention time (MRT) of particulate and liquid matter in different segments of the gastrointestinal tract (GIT) of growing Saanen goats of different sexes and subjected to different levels of feed restriction. In addition, feeding behavior and total tract digestibility were determined for all animals ahead of slaughter. In total, 54 Saanen goats (18 each of females, castrated males, and intact males) with initial BW 15.3 +/- 0.4 kg were used in a 3 * 3 factorial arrangement comprising the 3 sexes and 3 levels of feed restriction (unrestricted/ad libitum, moderate, and severe restriction). Six blocks per sex group, each consisting of 3 goats, were randomly formed and the goats within each block were randomly allocated to 1 of 3 different feed restrictions. The daily amounts of feed offered to animals subjected to moderate and severe feed restriction (approximately 75% and 50% of ad libitum rate, respectively) were determined within block based on the DMI by ad libitum fed goats on the previous day. The MRT of particulate matter was determined either using Yb-labeled diet or indigestible NDF (iNDF) determined in situ as markers. Mean retention time of the liquid phase was determined by Cr-EDTA. Orthogonal polynomial contrasts were used to determine linear and quadratic effect of feed restriction, while the effect of sex was compared by Tukey test. The effects of sex and the interaction between sex and feed restriction were not significant on most of variables evaluated. Eating, ruminating, and total chewing time per g DM and NDF intake increased linearly as feed restriction increased (P <= 0.03). Diet digestibility increased quadratically for DM and OM, and linearly for NDF as feed intake decreased (P <= 0.03). The MRT of iNDF in the reticulorumen, omasum, abomasum, colon, and total GIT increased linearly with increased feed restriction (P <= 0.01). Mean retention time in the cecum varied quadratically, being greatest for animals with moderate feed restriction. The MRT of liquid was quadratically (P <= 0.04) affected by feed restriction in the reticulorumen, cecum, and total GIT, with the greatest MRT observed for animals subjected to moderate feed restriction. In conclusion, the level of feed restriction increased the MRT of particulate and liquid matter. The MRT was an important mechanism to increase nutrient supply when animals were subjected to feed restriction, as indicated by increased total tract digestibility. PMID- 26020202 TI - Effectiveness of nitrate addition and increased oil content as methane mitigation strategies for beef cattle fed two contrasting basal diets. AB - The objectives of this study were to investigate the effects of (1) the addition of nitrate and (2) an increase in dietary oil on methane (CH4) and hydrogen (H2) emissions from 2 breeds (cross-bred Charolais and purebred Luing) of finishing beef cattle receiving 2 contrasting basal diets consisting (grams per kilogram DM) of 500:500 (Mixed) and 80:920 (Concentrate) forage to concentrate ratios. Within each basal diet there were 3 treatments: (i) control treatments (mixed-CTL and concentrate-CTL) contained rapeseed meal as the protein source, which was replaced with either (ii) calcium nitrate (mixed-NIT and concentrate-NIT) supplying 21.5 g nitrate/kg DM, or (iii) rapeseed cake (mixed-RSC and concentrate RSC) to increase dietary oil from 27 (CTL) to 53 g/kg DM (RSC). Following adaption to diets, CH4 and H2 emissions were measured on 1 occasion from each of the 76 steers over a 13-wk period. Dry matter intakes tended (P = 0.051) to be greater for the concentrate diet than the mixed diet; however, when expressed as grams DMI per kilogram BW, there was no difference between diets (P = 0.41). Dry matter intakes for NIT or RSC did not differ from CTL. Steers fed a concentrate diet produced less CH4 and H2 than those fed a mixed diet (P < 0.001). Molar proportions of acetate (P < 0.001) and butyrate (P < 0.01) were lower and propionate (P < 0.001) and valerate (P < 0.05) higher in the rumen fluid from steers fed the concentrate diet. For the mixed diet, CH4 yield (grams per kilogram DMI) was decreased by 17% when nitrate was added (P < 0.01), while H2 yield increased by 160% (P < 0.001). The addition of RSC to the mixed diet decreased CH4 yield by 7.5% (P = 0.18). However, for the concentrate diet neither addition of nitrate (P = 0.65) nor increasing dietary oil content (P = 0.46) decreased CH4 yield compared to concentrate-CTL. Molar proportions of acetate were higher (P < 0.001) and those of propionate lower (P < 0.01) in rumen fluid from NIT treatments compared to respective CTL treatments. Overall, reductions in CH4 emissions from adding nitrate or increasing the oil content of the mixed diet were similar to those expected from previous reports. However, the lack of an effect of these mitigation strategies when used with high concentrate diets has not been previously reported. This study shows that the effect of CH4 mitigation strategies is basal diet-dependent. PMID- 26020203 TI - Quantification of sodium pentobarbital residues from equine mortality compost piles. AB - Sodium pentobarbital, a euthanasia drug, can persist in animal carcasses following euthanasia and can cause secondary toxicosis to animals that consume the remains. This experiment was conducted to observe the effects of composting on euthanized horse carcass degradation and sodium pentobarbital residues in compost material up to 367 d. Six separate compost bins were constructed on pastureland. Three bins served as the control while 3 served as the treatment. The carbonaceous material, or bulking agent, consisted of hardwood chips mixed with yard waste wetted to approximately 50% moisture content. Bulking agent was added to each bin at a depth of 0.46 m, creating the pad. A licensed veterinarian provided 6 horse carcasses for use in the experiment. These horses had required euthanasia for health reasons. All horses were weighed and then sedated with an intravenous injection of 8 mL of xylazine. After sedation the 3 horses in the treatment group were euthanized by intravenous injection of 60 mL of sodium pentobarbital. The 3 control group horses were anesthetized by intravenous injection of 15 mL of ketamine hydrochloride and then humanely euthanized by precise gunshot to the temporal lobe. Following euthanasia, each carcass was placed on the center of the pad and surrounded with 0.6 m of additional bulking agent. Serum and liver samples were obtained immediately following death. Compost samples were obtained on d 7, 14, 28, 56, 84, 129, 233, and 367 while soil samples were obtained on d -1 and 367. Each sample was analyzed for sodium pentobarbital concentration. Compost pile and ambient temperatures were also recorded. Composting successfully degraded soft tissue with only large bones remaining. Data illustrate that sodium pentobarbital was detectable up to 367 d in compost piles with no clear trend of concentration reduction. Drug residues were detected in soil samples indicating that sodium pentobarbital leached from the carcass and through the pad. These findings confirm the persistence of sodium pentobarbital from equine mortality compost piles and emphasize the importance of proper carcass management of animals euthanized with a barbiturate to reduce environmental impact and secondary toxicosis. PMID- 26020204 TI - Large-scale investigation of the parameters in response to Eimeria maxima challenge in broilers. AB - Coccidiosis, a parasitic disease of the intestinal tract caused by members of the genera Eimeria and Isospora, is one of the most common and costly diseases in chicken. The aims of this study were to assess the effect of the challenge and level of variability of measured parameters in chickens during the challenge with Eimeria maxima. Furthermore, this study aimed to investigate which parameters are the most relevant indicators of the health status. Finally, the study also aimed to estimate accuracy of prediction for traits that cannot be measured on large scale (such as intestinal lesion score and fecal oocyst count) using parameters that can easily be measured on all animals. The study was performed in 2 parts: a pilot challenge on 240 animals followed by a large-scale challenge on 2,024 animals. In both experiments, animals were challenged with 50,000 Eimeria maxima oocysts at 16 d of age. In the pilot challenge, all animals were measured for BW gain, plasma coloration, hematocrit, and rectal temperature and, in addition, a subset of 48 animals was measured for oocyst count and the intestinal lesion score. All animals from the second challenge were measured for BW gain, plasma coloration, and hematocrit whereas a subset of 184 animals was measured for intestinal lesion score, fecal oocyst count, blood parameters, and plasma protein content and composition. Most of the parameters measured were significantly affected by the challenge. Lesion scores for duodenum and jejunum (P < 0.001), oocyst count (P < 0.05), plasma coloration for the optical density values between 450 and 490 nm (P < 0.001), albumin (P < 0.001), alpha1-globulin (P < 0.01), alpha2-globulin (P < 0.001), alpha3-globulin (P < 0.01), and beta2-globulin (P < 0.001) were the most strongly affected parameters and expressed the greatest levels of variation. Plasma protein profiles proved to be a new, reliable parameter for measuring response to Eimeria maxima. Prediction of intestinal lesion score and fecal oocyst count using the other parameters measured was not very precise (R2 < 0.7). The study was successfully performed in real raising conditions on a large scale. Finally, we observed a high variability in response to the challenge, suggesting that broilers' response to Eimeria maxima has a strong genetic determinism, which may be improved by genetic selection. PMID- 26020205 TI - Cattle with increased severity of bovine respiratory disease complex exhibit decreased capacity to protect against histone cytotoxicity. AB - Bovine respiratory disease complex (BRDC) is the leading cause of morbidity and mortality in feedlot cattle. Significant inflammation and lesions are often observed in lungs of infected cattle. During acute inflammatory responses, histones contribute to mortality in rodents and humans and serum proteins can protect against histone-induced cytotoxicity. We hypothesized that cattle experiencing chronic or fatal cases of BRDC have reduced ability to protect against cytotoxic effects of histones. Serum samples were collected from 66 bull calves at the time of normal feedlot processing procedures. Animals were retrospectively assigned to groups consisting of calves never treated for BRDC (control [CONT]; n = 10), calves treated with antimicrobials once for BRDC (1T; n = 16), calves treated twice for BRDC (2T; n = 13), calves treated 3 times for BRDC (3T; n = 14), or calves treated 4 times for BRDC (4T; n = 13). Samples were also collected each time animals received antimicrobial treatment; animals within a group were further sorted by calves that recovered and calves that died to test histone cytotoxicity. Bovine kidney cells were cultured in duplicate in 96-well plates and exposed to 0 or 50 MUg/mL of total histones for 18 h with 1% serum from each animal. Cell viability was assessed by the addition of resazurin for 6 h followed by fluorescent quantification. Fluorescent values from serum alone were subtracted from values obtained for histone treatment for each animal. Serum from CONT, 1T, and 2T at initial processing all exhibited a similar (P > 0.10) response to histone treatment with fluorescent values of -312 +/- 557, -1,059 +/- 441, and -975 +/- 489, respectively. However, 3T and 4T demonstrated an impaired capacity (P < 0.05) to protect against histones (-2,778 +/- 471 and -3,026 +/- 489) at initial processing when compared to the other groups. When sorted by mortality within group, calves that were treated twice and recovered (-847 +/- 331) demonstrated a greater (P < 0.05) protective capacity than calves that were treated twice and died (-2,264 +/- 412), indicating that calves that contract BRDC and ultimately die might have reduced protective capacity against histone cytotoxicity. Results suggest that calves that require multiple treatments for BRDC have reduced ability to protect against cytotoxicity of histones. Understanding the primary mechanism responsible for protecting against histone cytotoxicity could lead to improved identification of animals susceptible to severe cases of BRDC, improved focus and use of available resources, or better treatments for severe cases of BRDC PMID- 26020206 TI - Effect of pour-on alphacypermethrin on feed intake, body condition score, milk yield, pregnancy rates, and calving-to-conception interval in buffaloes. AB - The aims of this study were to assess the efficacy of alphacypermethrin (ACYP) on pediculosis due to Haematopinus tuberculatus and to evaluate the influence of the treatment on productive and reproductive performance in buffaloes (Bubalus bubalis) reared in an intensive system. The trial was performed on 56 pluriparous buffaloes at 86.8 +/- 8.1 d in milk. The animals underwent individual louse count and were divided into 2 homogenous groups according to louse count, age, number of lactations, days in milk, live BW, BCS, pregnancy status, and milk yield. Group A (n = 28) was treated by a pour-on formulation of ACYP, and Group S (n = 28) was treated by pour-on saline solution. Individual louse counts were performed weekly on 10 buffaloes in each group. Feed intake was recorded daily and the total mixed ration, individual ingredients, and orts were analyzed to calculate DM ingestion. Individual milk yield was recorded daily and milk samples were analyzed at the beginning of the trial, after 4 wk, and at the end of the trial to assess milk composition. Individual BCS was also evaluated simultaneously. Finally, the animals underwent synchronization of ovulation starting 4 wk after treatment and the pregnancy rate and the calving-conception interval were evaluated. Data were analyzed by the Mann-Whitney test and ANOVA for repeated measures. The infestation was constant in Group S, whereas no lice were present in Group A throughout the study. Daily DMI was similar in the 2 groups (16.7 +/- 0.4 vs. 16.3 +/- 0.3 kg/d in Group A vs. Group S, respectively), although buffaloes in Group A showed higher (P < 0.05) BCS score at the end of the trial (7.39 +/- 0.1 vs. 7.14 +/- 0.1 in Group A vs. Group S, respectively). The average milk yield/buffalo was higher (P < 0.05) in Group A compared to Group S (10.58 +/- 0.1 vs. 10.39 +/- 0.1 kg in Group A vs. Group S, respectively) and this was mainly due to the higher milk production recorded in buffaloes at less than 75 d in milk (11.81 +/- 0.1 vs. 11.45 +/- 0.1 kg in Group A vs. Group S, respectively). Despite of a similar fertility rate (90.5 vs. 80.9% in Group A vs. Group S, respectively), a lower (P < 0.05) calving-conception interval was recorded in Group A compared to Group S (118 +/- 16 vs. 177 +/- 16 d in Group A vs. Group S, respectively). In addition to the pour-on treatment against pediculosis, productive and reproductive performance were also improved. This represents a significant improvement in dairy buffalo herd management. PMID- 26020207 TI - Relationships of milk yield and quality from six breed groups of beef cows to preweaning average daily gain of their calves. AB - Milk yield and quality influence calf preweaning growth and ultimately the sale value of the calf at weaning. This study was conducted to evaluate the relationships of milk production and quality of beef cows to calf preweaning ADG in beef cows sired by Bonsmara, Brangus, Charolais, Gelbvieh, Hereford, and Romosinuano and from Brangus dams to determine whether the relationships were homogeneous across cow breed group. Approximately 50 cows/yr were milked monthly for 6 mo in each of the 7 yr of this study. Milk traits were included in models as linear and quadratic covariates along with interactions of the covariates with sire breed. Tests for curvilinearity and homogeneity of regression coefficients indicated the relationship of calf preweaning ADG to milk yield and quality was quadratic and homogeneous across Charolais and Gelbvieh; linear and homogeneous across Bonsmara, Brangus, and Romosinuano; and linear and different from other sire breeds in Herefords (P < 0.05). Exceptions to this were in the regression of calf preweaning ADG on the natural logarithm of somatic cell count (SCC) and milk urea nitrogen (MUN). The relationship of calf preweaning ADG to SCC was quadratic in Brangus (P < 0.05) and linear in Gelbvieh (P < 0.05) with little evidence (P > 0.05) of a relationship in Bonsmara, Charolais, Hereford, or Romosinuano. There was little evidence (P > 0.05) of a relationship of calf preweaning ADG to MUN in any of the sire breed groups. Results from this study confirmed the importance of the influence of milk yield and quality on calf preweaning growth but indicated this influence can depend on the breed composition of the cow. Furthermore, results suggest that breed origin or adaptation may have influenced the relationships of calf preweaning ADG to cow milk yield and quality. PMID- 26020208 TI - Impact of supplemental protein source offered to primiparous heifers during gestation on I. Average daily gain, feed intake, calf birth body weight, and rebreeding in pregnant beef heifers. AB - A 3-yr study was conducted to determine the effect of supplemental protein source on ADG, feed intake, calf birth BW, and subsequent pregnancy rate in pregnant beef heifers. Crossbred, Angus-based, AI-pregnant heifers (yr 1, n = 38; yr 2, n = 40; and yr 3, n = 36) were stratified by BW (450 +/- 10 kg) and placed in a Calan Broadbent individual feeding system at approximately d 142 of gestation. Following a 25-d adaptation period, an 84-d feeding trial was conducted. Heifers were offered ad libitum grass hay (8 to 11% CP, DM basis) and no supplement (CON), 0.83 kg/d distillers-based supplement (HI), or 0.83 kg/d dried corn gluten based supplement (LO). Supplements were formulated to be isocaloric, isonitrogenous (28% CP, DM basis), and equal in lipid content but differed in RUP, with HI (59% RUP) having greater levels of RUP than LO (34% RUP). Dry matter intake was also calculated based on feed NE values to account for different energy levels of the supplement compared with the control diet. Control heifers tended (P = 0.09) to consume less total DM than either supplement treatment. However, forage-only DMI was greater (P < 0.01) for CON heifers (9.94 +/- 0.12 kg) compared with HI or LO heifers (8.50 and 8.34 +/- 0.12 kg, respectively). Net energy DMI was less (P < 0.01) for CON heifers (4.98 +/- 0.23 kg) compared with HI or LO heifers (5.43 and 5.35 +/- 0.23 kg, respectively). Control heifers gained less (P < 0.01; 0.59 +/- 0.14 kg/d) than either HI (0.82 +/- 0.14 kg/d) or LO heifers (0.78 +/- 0.14 kg/d), resulting in lower (501 +/- 9 kg) BW (P < 0.01) than HI (519 +/- 9 kg) heifers at the end of the feeding period. Calf birth BW was similar (P = 0.99) among treatments. At prebreeding, CON heifers weighed less (P < 0.03) than LO heifers. Cow BW was similar (P = 0.48) among treatments at pregnancy diagnosis, and final pregnancy rate was also similar (87%; P = 0.22). Protein supplementation increased ADG in pregnant heifers; however, calf birth BW and subsequent pregnancy rates were similar. PMID- 26020209 TI - Impact of supplemental protein source offered to primiparous heifers during gestation on II. Progeny performance and carcass characteristics. AB - A 3-yr study using primiparous crossbred beef heifers (n = 114) was conducted to determine the effects of protein supplement during late gestation on progeny performance and carcass characteristics. Pregnant heifers were stratified by heifer development system, initial BW, and AI service sire and placed in an individual feeding system. Heifers were offered meadow hay (8 to 11% CP) from early November to mid-February and provided no supplement (CON; n = 37), 0.83 kg/d (DM basis) of a dried distillers grains with solubles-based supplement (HI; n = 39), or 0.83 kg/d (DM basis) of a dried corn gluten feed-based supplement (LO; n = 38). Supplements were designed to be isonitrogenous (28% CP) and isocaloric but to differ in RUP with HI (59% RUP) having greater levels of RUP than LO (34% RUP). After the individual feeding period, heifers were placed in a drylot for calving. All heifers were bred using a fixed-timed AI protocol and pairs were moved to a commercial ranch in the Nebraska Sandhills for summer grazing. Calf weaning BW did not differ (P = 0.14) based on maternal diet. However, feedlot entry BW was greater (P = 0.03) for HI compared with CON calves. Average daily gain during the initial feedlot phase tended (P = 0.10) to be greatest for calves born to CON dams and lowest for calves born to LO dams. However, overall ADG was similar (P = 0.50) for the entire feedlot period. Residual feed intake during the reimplant and total feeding period was improved in calves born to supplemented dams in yr 2 and 3 compared with calves born to CON dams. There was no difference in final BW among treatments (P = 0.71). Hot carcass weight was similar (P = 0.72) among treatments; however, steers had greater (P < 0.01) HCW than heifers. Furthermore, percent empty body fat and 12th rib fat thickness were lowest (P = 0.05 and P = 0.04) for calves born to LO dams. Tenderness measured by Warner-Bratzler shear force was increased (P = 0.03) in longissimus samples from calves from CON dams compared to calves from LO dams. Similarly, crude fat levels tended to be greater (P = 0.07) for calves from CON dams compared with calves from LO dams. Based on these data, providing RUP supplements, similar to those used in this study, to primiparous heifers in late gestation consuming ad libitum grass hay resulted in increased initial feedlot BW for HI compared to CON calves, improved feed efficiency, and altered carcass characteristics in calves born to supplemented compared with CON dams. PMID- 26020210 TI - Individual variation in eating speed of dry sows. AB - We investigated the variation in eating speed by individual pregnant sows and the influence of feeding dry compared to wet feed. A total of 39 Norwegian Landrace * Yorkshire dry sows, 13 primiparous and 26 multiparous, were included in the experiment. In experimental period 1, each sow was offered 2.2 kg of a standard concentrate feed without added water. In experimental period 2, the sows were offered the same weight of concentrate feed but after mixing with water at a ratio of 1:4, based on weight. The sows were kept in groups of 4 or 5 in pens with individual feeding stalls. The weighed allocations of feed were poured into the troughs before the sows were given access to the food. On d 1, the sows were allowed to eat for 15 min, on d 2 for 10 min, on d 3 for 5 min, on d 4 for 2 min 30 s, and on d 5 for 1 min 15 s. At the designated time, feed troughs were covered, blocking sow access, and residual feed was carefully removed and weighed. Mean consumption rate of dry feed was 183.2 g/min for the first 5 min and 169.7 g/min for the first 10 min. For wet feed, the mean consumption rate was 1,859.8 g/min for the first 5 min and 1,060.7 g/min for the first 10 min. After 5 min, the sows had consumed 41.6% of the dry feed (range 19.5 to 79.1%, CV = 31.0%) and 84.5% of the wet feed (range 54.3 to 99.1%, CV = 14.9%). After 10 min, the sows had consumed 77.1% of the dry feed (range 33.9 to 100.0%, CV = 24.9%) and 5 of the 39 sows had completely ingested their allotted feed. When feed was wet, sows finished 96.4% of the ration (range 72.7 to 99.1%, CV = 6.4%) after 10 min. The speed of eating dry feed was positively correlated with sow weight, both at 5 (R = 0.72, P < 0.001) and 10 min (R = 0.75, P < 0.001), but for wet feed, the correlation was weak at 5 min (R = 0.36, P < 0.05) and there was no correlation at 10 min (R = 0.20, P > 0.10). We conclude that dry feed resulted in larger individual variation in feed consumption rate than wet feed. Furthermore, whereas feed consumption rate was correlated with liveweight of the sow when eating dry feed, the relationship was not significant when sows ate wet feed. PMID- 26020211 TI - Physiological and nonphysiological indicators of body condition score in weaner pigs. AB - The aim of this study was to identify parameters that may be used as objective measures of wellbeing in weaner pigs on farm. Eighty-six weaner pigs were categorized into 3 groups based on their BCS: very compromised (VC, BCS = 1), moderately compromised (MC, BCS = 2), or healthy (HY, BCS >= 3). Nonphysiological and physiological measures were then collected from the pigs. Nonphysiological measures included 3 subjective binary scores that assessed the activity, hairiness, and responsiveness of each pig. Physiological measures included rectal temperature, skin temperature, and 11 blood-based parameters. Each physiological measure was assessed in a ternary manner, with pigs being classed as being above, below, or within the normal physiological range. Fisher's exact tests (FET) were used to identify differences between the numbers of pigs in each BCS category for each variable, and ANOVA of physiological measures was also conducted. Correlations between all variables were also conducted. The FET results identified significant differences for 8 of the measures, with activity, hairiness, responsiveness, rectal temperature, and blood concentrations of glucose, creatinine kinase (CK), albumin, and globulin all differing significantly (all P < 0.05) according to category. Rectal temperature, glucose, and globulin concentrations were significantly different in ANOVA analyses. Of these measures, there were significant correlations between hairiness, rectal temperature, and glucose (all R > 0.30 and P < 0.05). Based on these results, rectal temperature, glucose, and hairiness all warrant further investigation as simple to apply, on-farm measures that can be used in conjunction with body condition and subjective assessment to aid management decisions on pig welfare. PMID- 26020212 TI - Effects of rumen-protected choline supplementation on metabolic and performance responses of transition dairy cows. AB - The objective of this experiment was to compare metabolic and milk production parameters in dairy cows supplemented and nonsupplemented with rumen-protected choline (RPC) during the transition period. Twenty-three nonlactating, multiparous, pregnant Holstein cows were ranked by BW and BCS 21 d before expected date of calving and immediately were assigned to receive (n = 12) or not receive (control; n = 11) RPC until 45 d in milk (DIM). Cows supplemented with RPC received (as-fed basis) 50 and 100 g/d of RPC (18.8% choline) before and after calving, respectively. Before calving, cows were maintained in 2 drylot pens according to treatment with ad libitum access to corn silage, and individually they received (as-fed basis) 3 kg/cow daily of a concentrate. Upon calving, cows were moved to 2 adjacent drylot pens according to treatment, milked twice daily, offered (as-fed basis) 35 kg/cow daily of corn silage, and individually received a concentrate formulated to meet their nutritional requirements after milking. The RPC was individually offered to cows as a topdressing into the morning concentrate feeding. Before calving, cow BW and BCS were recorded weekly, and blood samples were collected every 5 d beginning on d 21 relative to expected calving date. Upon calving and until 45 DIM, BW and BCS were recorded weekly, individual milk production was recorded daily, and milk samples were collected once a week and analyzed for fat, protein, and total solids. Blood samples were collected every other day from 0 to 20 DIM and every 5 d from 20 to 45 DIM. Based on actual calving dates, cows receiving RPC or control began receiving treatments 16.8 +/- 1.7 and 17.3 +/- 2.0 d before calving, respectively. No treatment effects were detected (P >= 0.18) on postpartum concentrate intake, BW and BCS, or serum concentrations of cortisol, beta hydroxybutyrate, NEFA, glucose, and IGF-I. Cows supplemented with RPC had greater (P <= 0.01) mean serum haptoglobin and insulin concentrations compared with control. Cows supplemented with RPC had greater (P < 0.01) milk protein, total solids (P < 0.01), and milk fat concentrations (P = 0.09) compared with control. No treatment effects were detected (P >= 0.43) for milk yield parameters, such as fat-corrected or solids-corrected milk yield. In conclusion, supplementing RPC to transition dairy cows increased haptoglobin and insulin concentrations and benefited milk composition. PMID- 26020213 TI - Wean-to-finish feeder space availability effects on nursery and finishing pig performance and total tract digestibility in a commercial setting when feeding dried distillers grains with solubles. AB - The study objectives were to determine nursery phase feeder space allowance effects on pig performance when double stocked and, second, to determine feeder space allowance and dried distillers grains with solubles (DDGS) inclusion level effects on pig performance and nutrient digestibility during the growing finishing phase. This study was performed on the same group of pigs within a commercial wean-finish system. For the nursery phase, a completely randomized design was used to compare 3 feeder space allowance treatments (2.1, 2.5, and 2.9 cm/pig). A total of 3,720 pigs were randomly allotted to same-sex pens (10 feeders/treatment) housing 62 pigs/pen. Thirty 7-hole, double-sided feeders were utilized in the study. Differing linear feeder space treatments were established by blocking off sections for the nursery and grow-finish portions of this experiment. All pigs were provided equal floor space (0.26 m2/pig). In the grow finish phase, a total of 1,860 pigs (n = 60 pens) were utilized in a 2 * 3 factorial design with 3 feeder space allowances (4.1, 4.9, or 5.7 cm/pig) and 2 dietary DDGS treatments (30% [D30] or 60% [D60]). Fecal and diet samples were collected and analyzed to estimate apparent total tract digestibility percentage (ATTD %). In the nursery portion of the trial, there was no feeder space treatment effect on ADG, ADFI, or feed efficiency (P > 0.10) from weaning to d 56 postweaning or during any weigh period. In the grow-finish portion of the trial, feeder space allowance and DDGS inclusion level did not affect ADG, ADFI, or feed efficiency (P > 0.05) from d 57 postweaning to market. Pigs fed the D30 diet had greater HCW, percent yield, and loin depth than those on the D60 diet (P < 0.05). Pigs fed the D30 treatment had greater (P < 0.05) ATTD for DM and GE for both collection periods compared with those on the D60 treatment. In summary, feeder space allowance did not impact pig performance during the nursery or grow-finish production phases. Inclusion of DDGS at higher levels will decrease ADFI but not ADG or efficiency when isocaloric diets are fed. The inclusion level of DDGS does impact HCW and percent yield because of increasing intestinal weights when pigs are fed diets containing increasing DDGS inclusion rates. Dry matter and energy digestibility were greater in pigs fed the lower DDGS treatment. PMID- 26020214 TI - Daily methane production pattern of Welsh ponies fed a roughage diet with or without a cereal mixture. AB - Methane production from Welsh ponies fed 2 isoenergetic diets (NE basis) at maintenance was studied in a crossover design with 4 mature geldings (230 +/- 10.5 kg BW, mean +/- SE). Treatments included a roughage-only (R) diet (5.1 kg DM/d) or a roughage plus cereal mix (RC) diet (2.5 kg DM hay/d plus 1.1 kg DM cereal mix/d). For both diets, the same grass hay was used (898 g DM/kg and 4.5 MJ NE/kg DM) and a commercial cereal mix was used in the RC diet (890 g DM/kg and 9.6 MJ NE/kg DM). Ponies were housed in pairs in climate-controlled respiration chambers. Carbon dioxide production (CO2), oxygen (O2) consumption, and CH4 production were measured over 3 consecutive days. Heat production (HP) rates were calculated from gaseous exchange. Feces were collected quantitatively to determine dietary nutrient digestibility. Dry matter intake differed between diets (P < 0.0001), but NE intake was equal for both diets (22.3 +/- 0.07 MJ NEm/d). Organic matter digestibility was lower (P = 0.006) for the R diet (47.2%) than the RC diet (55.6%). Methane production was higher (P = 0.014) on the R diet (29.8 L . pony(-1) . d(-1)) compared to the RC diet (23.2 L . pony(-1) . d(-1)). Methane production expressed in liters/kilogram metabolic body weight (BW0.75) per day tended (P = 0.064) to decrease with 21% for the RC group compared with the R group. Heat production, O2 consumption, and CO2 production were not affected by diet. Diurnal patterns of CH4 production and HP were similar for both diets. Methane production increased slightly (P < 0.652) after feeding and was numerically lower for the RC diet for all time points throughout the day. For both diets, HP was higher after feeding than before feeding and decreased again within approximately 3 h after feeding. Isoenergetic replacement of roughage by a cereal mix reduces CH4 production in ponies. No clear diurnal pattern in CH4 emission can be discerned in ponies fed at maintenance. PMID- 26020215 TI - Performance of beef cows and calves fed different sources of rumen-degradable protein when grazing stockpiled limpograss pastures. AB - Two experiments evaluated the effects of different sources of RDP on forage characteristics, animal performance, and ruminal and blood parameters of beef cattle grazing stockpiled limpograss (Hemarthria altissima) from January to May 2011 and 2012. In Exp. 1, 24 mature lactating beef cows and their respective calves were allocated to 8 stockpiled limpograss pastures (3 pairs/pasture). Treatments were 2 different sources of RDP, urea or cottonseed (Gossypium spp.) meal (CSM), distributed in a completely randomized design with 4 replicates. Feather meal and corn (Zea mays) meal were added to the urea treatments to balance RUP and energy. Treatments were mixed in sugarcane (Saccharum officinarum) molasses, which resulted in 3 kg DM/cow per day of supplement. There were no differences (P > 0.10) in herbage mass (HM; 3,200 +/- 400 kg DM/ha), herbage allowance (HA; 1.9 +/- 0.2 kg DM/kg of BW), CP (5.2 +/- 0.2%), and in vitro digestible organic matter (IVDOM; 47 +/- 0.5%) concentrations. There was a decrease (P < 0.10) in HM (from 4,100 to 2,600 kg/ha), IVDOM (from 46 to 39.9%), and HA (from 2.5 to 1.4 kg DM/kg BW) from January to March. Cow ADG (0.23 +/- 0.08 kg/d), BCS (4.6 +/- 0.2), milk yield (7.0 +/- 0.4 kg/d), and plasma urea nitrogen (PUN; 16.1 +/- 0.8 mg/dL) and calf ADG (0.71 +/- 0.05 kg/d) were similar (P > 0.10) among treatments. Sixteen cow-calf pairs were moved to 8 drylot pens after Exp. 1, maintained on the same treatment, and evaluated for forage and total DMI. There was no difference in forage (P = 0.16; 2.1 +/- 0.1% BW) and total DMI (P = 0.12; 2.5 +/- 0.1% BW) between treatments. In Exp. 2, 2 rumen cannulated steers were used in a 2 * 2 Latin square design, replicated in 2011 and 2012, to test the effects of the same treatments on rumen fluid and blood parameters. There was no difference (P > 0.10) in ruminal NH3-N (12.9 +/- 0.3 mg/dL), pH (6.5 +/- 0.1), propionic acid (25 +/- 2.2 mol/100 mol), acetic acid (69.2 +/- 2.9 mol/100 mol), and butyric acid (4.5 +/- 0.5 mol/100 mol) as well as branched-chain VFA (1.3 +/- 2.2 mol/100 mol) concentrations in the rumen. In addition, there was no difference (P = 0.91) in PUN (7.9 +/- 0.3 mg/dL) concentration between treatments. Therefore, urea can be as effective as CSM as the main source of RDP in the molasses-based supplement offered to mature lactating beef cows grazing stockpiled limpograss pastures. PMID- 26020216 TI - Growth promoting hormonal implant pellets coated with a polymeric, porous film promote weight gain by grazing beef heifers and steers for up to 200 days. AB - Two studies evaluated growth promoting effects of implant pellets (IP), each containing 3.5 mg estradiol benzoate (EB) and 25 mg trenbolone acetate (TBA), to which a polymeric, porous coating was applied. Trial 1 evaluated performance of heifers (n = 70/treatment, initial BW = 188 +/- 2.2 kg) and steers (n = 70/treatment, initial BW = 194 +/- 2.2 kg) implanted subcutaneously in the ear with 0 (SC), 2 (2IP), 4 (4IP), or 6 (6IP) pellets that delivered EB/TBA (mg/mg) doses of 0/0, 7/50, 14/100, and 21/150, respectively, over grazing periods of 202 d (heifers) or 203 d (steers). Animals received experimental treatments on d 0 and over the grazing period were managed as single groups by sex in a rotational grazing system. When pasture forage availability became limited, cattle were supplemented with preserved forage but not concentrate supplements. Weight gains by heifers treated with 2IP, 4IP, and 6IP were greater (P < 0.05) than SC heifers but not different from each other. Weight gains by steers treated with 2IP, 4IP, and 6IP were greater than SC steers (P < 0.05), and ADG by steers treated with 6IP was greater (P < 0.05) than steers given 2IP or 4IP. Trial 2 was a multisite grazing study performed with heifers and steers to compare ADG after treatment with one 6-pellet, coated implant delivering 21 mg EB and 150 mg TBA (6IP) to sham treated negative controls (SC) over a grazing period of at least 200 d. A completely random design was used at each site, with the goal to treat 70 cattle per site, treatment, and sex; data were pooled across sites. Heifers (n = 558, initial BW = 229 +/- 16 kg) and steers (n = 555, initial BW = 235 +/- 20 kg) grazed in rotational programs consistent with regional practices for an average of 202 d. When necessary, cattle were supplemented with preserved forage, but no concentrate supplements were fed. Over 202 d, ADG by heifers treated with 6IP was 11.3% greater (P = 0.0035) than SC heifers (0.64 +/- 0.06 kg/d), and ADG by steers treated with 6IP was 17.2% greater (P = 0.0054) than SC steers (0.66 +/- 0.08 kg/d). In neither study was there evidence that concurrent therapeutic treatments or abnormal health observations were influenced by experimental treatments. These studies demonstrated that a 6-pellet implant with a polymeric, porous coating that delivers 21 mg EB and 150 mg TBA improved ADG by grazing heifers and steers for at least 200 d compared to sham-implanted negative controls. PMID- 26020217 TI - Continuous, low-dose oral exposure to sodium chlorate reduces fecal generic Escherichia coli in sheep feces without inducing clinical chlorate toxicosis. AB - Our objectives were to determine an effective, yet safe, daily dose of sodium chlorate for reducing fecal shedding of generic Escherichia coli in mature ewes. In a completely randomized experimental design, 25 Targhee ewes (age ~ 18 mo; BW = 62.5 +/- 7.3 kg, mean +/- SD) were assigned randomly to 1 of 5 sodium chlorate treatments, which were administered in the drinking water for 5 consecutive days. Treatments were control group (no sodium chlorate) and 4 targeted levels of daily sodium chlorate intake: 30, 60, 90, and 120 mg . kg(-1) BW . d(-1) for 5 d. Individual ewe ad libitum intake of water (with treatments) was measured daily, and BW was measured at the beginning of and 15 and 51 d after the 5-d treatment period. Serum chlorate, whole blood methemoglobin and packed-cell volume (PCV), and fecal generic E. coli and general Enterobacteriaceae coliforms were measured from corresponding samples collected at the end of the 5-d treatment period. Average daily intakes of sodium chlorate from drinking water treatments were 95%, 91%, 90%, and 83% of the target treatment intakes of 30, 60, 90, and 120 mg . kg( 1) BW . d(-1), respectively. Daily sodium chlorate intake remained constant for all treatment groups except for ewes offered 120 mg NaClO3 . kg(-1) BW . d(-1), which decreased (quadratic; P = 0.04) over the course of the 5-d treatment period. This decrease in sodium chlorate intake indicated that the 120-mg NaClO3 level may have induced either toxicity and/or an aversion to the drinking water treatment. Serum chlorate concentrations increased (quadratic; P < 0.001) with increasing sodium chlorate intake. At the end of the 5-d treatment period, mean (least squares +/- SEM) serum chlorate concentrations for ewes offered 30, 60, 90, and 120 mg NaClO3 . kg(-1) BW . d(-1) were 15.6 +/- 14.1, 32.8 +/- 15.8, 52.9 +/- 14.1, and 90.3 +/- 14.1 MUg/mL, respectively. Whole blood methemoglobin and PCV were similar (P = 0.31 to 0.81) among the control group and ewes offered sodium chlorate. Likewise, BW was not affected by sodium chlorate (P > 0.27). Ewes consuming approximately 55 mg NaClO3 . kg(-1) BW . d(-1) or more (i.e., ewes offered 60, 90, and 120 mg) had a >1.4 log unit reduction in fecal E. coli and Enterobacteriaceae coliforms compared with control ewes. We suggest that for a short-term, 5-d dosing strategy, 55 to 81 mg NaClO3 . kg(-1) BW . d(-1) is an effective, yet safe, daily oral dose range for mature ewes to achieve a 97% to 99% reduction in fecal shedding of generic E. coli. PMID- 26020218 TI - Changes in hematology, serum biochemistry, and gastrointestinal nematode infection in lambs fed sericea lespedeza with or without dietary sodium molybdate. AB - Sericea lespedeza (SL; Lespedeza cuneata) is a legume rich in condensed tannins that can be grazed or fed to small ruminants for parasite control. Condensed tannins, a secondary plant compound in SL, may lead to unintended consequences such as changes in production. In our preliminary research, there was consistently a reduction in serum and liver concentrations of Mo. The objective of this study was to determine the effect of SL with or without Mo supplementation on changes in BW, hematology, and serum biochemistry in lambs. Thirty ram lambs weaned in May (84 +/- 1.5 d of age; 27 +/- 1.1 kg) were blocked by BW, breed type (full or three-fourths Katahdin), and EBV of parasite resistance and randomly assigned to be fed 900 g of alfalfa-based supplement (CON; n = 10) or SL-based supplement (n = 20) for 103 d. Supplements were formulated to be isonitrogenous and isocaloric and to meet trace mineral requirements. Within the SL diet, half of the lambs received 490 mg sodium molybdate weekly (SLMO). Body condition scores and BW were determined every 14 d and blood and feces collected to determine hematological and serum biochemical profiles and fecal egg counts (FEC). Data were analyzed using a mixed model with repeated measures and orthogonal contrasts. The white blood cell counts tended to be reduced in SL- and SLMO-fed lambs compared with CON-fed lambs (P < 0.06), which was associated with a reduction in neutrophils (P < 0.001). Red blood cell counts were also reduced in SL but not SLMO lambs compared with CON lambs (P < 0.04). There was a reduction in blood packed cell volume (P < 0.04) and serum concentrations of albumin (P < 0.001) and creatinine (P < 0.02) in both SL and SLMO lambs compared with CON lambs. Similarly, concentrations of blood urea nitrogen were reduced in both SL and SLMO lambs, but differences among dietary treatments disappeared after 42 d of feeding (treatment * day, P < 0.004). Serum concentrations of total proteins were reduced only in SLMO lambs compared with other lambs (P < 0.001). Body weight and FEC were similar among dietary treatments. Means of all measurements were within a normal range, even though there were subtle but significant differences between dietary groups. Feeding a diet high in condensed tannin-rich SL did not lead to serious effects on hematology or serum biochemistry in lambs. PMID- 26020219 TI - Manipulation of dietary calcium concentration to potentiate changes in tenderness of beef from heifers supplemented with zilpaterol hydrochloride. AB - Dietary Ca concentrations were manipulated during supplementation of zilpaterol hydrochloride (ZH) to evaluate impact on feedlot performance, carcass characteristics, and beef tenderness using 96 heifers (BW 392 kg +/- 3.2). We hypothesized that temporary depletion followed by repletion of dietary Ca before harvest would increase intracellular Ca concentrations, thus stimulating postmortem activity of Ca-dependent proteases to effect changes in tenderness. Heifers were stratified by initial BW and randomly assigned, within strata (block), to treatments consisting of a finishing diet in which Ca was added in the form of limestone (+Ca) or removed (-Ca) during ZH supplementation. Cattle were fed a common diet, including limestone, before ZH supplementation, and 28 d before slaughter, ZH was added to the diet with and without supplemental Ca. Calcium content of the diets during ZH supplementation was 0.74% or 0.19% (diet DM) for +Ca and -Ca, respectively. Zilpaterol hydrochloride was fed for 25 d then removed from the diet 3 d before harvest. The final 3 d before harvest, all cattle were fed Ca at 0.74% of diet DM. Heifers were housed in concrete-surfaced pens with 8 animals/pen (6 pens/treatment). At the end of the finishing phase, animals were weighed and transported to an abattoir in Holcomb, KS. Severity of liver abscesses and HCW were collected the day of harvest, and after 48 h of refrigeration, USDA yield and quality grades, KPH, LM area, and 12th-rib subcutaneous fat thickness were determined. Boneless loin sections were also collected for Warner-Bratzler shear force determination. Removal of Ca did not affect Warner-Bratzler shear force values (P = 0.64). In addition, ADG, DMI, final BW, and feed efficiency were unaffected by treatment (P > 0.05). Carcass measurements also were unaffected by the temporary decrease in dietary Ca (P > 0.05). In conclusion, temporary depletion of dietary Ca during ZH supplementation did not alter beef tenderness, live animal performance, or carcass measurements. PMID- 26020221 TI - Ixodicide activity of Eysenhardtia polystachya against Rhipicephalus (Boophilus) microplus. AB - The objective of this study was to evaluate the acaricidal effect of 2 compounds extracted from Eysenhardtia polystachya in vitro, namely coatlines and matlalines. Each extract was obtained by aqueous extraction in a nitrogen atmosphere. Engorged adult females of an amitraz-resistant strain of Rhipicephalus (Boophilus) microplus were used to produce larvae and to carry out the adult immersion test (AIT), while larvae were assayed using the larval packet test (LPT). After exposure to coatlines or matlalines, the mortality of larvae and engorged females, as well as the reproductive parameters of adult ticks were assessed. Coatlines were not lethal against larvae and did not decrease reproductive parameters. Conversely, matlalines showed a 90 to 100% efficacy against adults and larvae at all concentrations tested and a reduction of 76.41 to 80.64% oviposition and a 48.02 to 54.86% reduction in egg hatchability. Therefore, the acaricidal activity of matlalines was more efficient. Further studies are required to elucidate both the mode of action of matlalines as well the structure-activity relationships responsible for the observed differential efficacy between these 2 related isoflavans against the cattle tick. PMID- 26020220 TI - Protein expression and oxygen consumption rate of early postmortem mitochondria relate to meat tenderness. AB - Oxygen consumption rate (OCR) of muscle fibers from bovine semimembranosus muscle of 41 animals was investigated 3 to 4 h and 3 wk postmortem. Significant relations (P < 0.05) were found between OCR measurements and Warner-Bratzler shear force measurement. Muscles with high mitochondrial OCR after 3 to 4 h and low nonmitochondrial oxygen consumption gave more tender meat. Tender (22.92 +/- 2.2 N/cm2) and tough (72.98 +/- 7.2 N/cm2) meat samples (4 samples each), separated based on their OCR measurements, were selected for proteomic studies using mitochondria isolated approximately 2.5 h postmortem. Twenty-six differently expressed proteins (P < 0.05) were identified in tender meat and 19 in tough meat. In tender meat, the more prevalent antioxidant and chaperon enzymes may reduce reactive oxygen species and prolong oxygen removal by the electron transport system (ETS). Glycolytic, Krebs cycle, and ETS enzymes were also more abundant in tender meat PMID- 26020222 TI - A compact photometer based on metal-waveguide-capillary: application to detecting glucose of nanomolar concentration. AB - Trace analysis of liquid samples has wide applications in life science and environmental monitor. In this paper, a compact and low-cost photometer based on metal-waveguide-capillary (MWC) was developed for ultra-sensitive absorbance detection. The optical-path can be greatly enhanced and much longer than the physical length of MWC, because the light scattered by the rippled and smooth metal sidewall can be confined inside the capillary regardless of the incident angle. For the photometer with a 7 cm long MWC, the detection limit is improved ~3000 fold compared with that of commercial spectrophotometer with 1 cm-cuvette, owing to the novel nonlinear optical-path enhancement as well as fast sample switching, and detecting glucose of a concentration as low as 5.12 nM was realized with conventional chromogenic reagent. PMID- 26020224 TI - Reporting of IMMPACT-recommended core outcome domains among trials assessing opioids for chronic non-cancer pain. AB - The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has recommended that trialists evaluating treatments for chronic pain should consider reporting 9 patient-important outcome domains. We examined the extent to which clinical trials evaluating the effect of opioids for chronic non cancer pain (CNCP) report outcome domains recommended by IMMPACT. We systematically searched electronic databases for English-language studies that randomized patients with CNCP to receive an opioid or a non-opioid control. In duplicate and independently, reviewers established the eligibility of each identified study and recorded all reported outcome domains from eligible trials. We conducted a priori regression analyses to explore factors that may be associated with IMMPACT-recommended outcome domains. Among 156 eligible trials, reporting of IMMPACT-recommended outcome domains was highly variable, ranging from 99% for pain to 7% for interpersonal functioning. Recently published trials were more likely to report the effect of treatment on physical functioning, emotional functioning, role functioning, sleep and fatigue, and participant disposition. Trials for which the corresponding author was from North America were more likely to report treatment effects on physical functioning and participant ratings of improvement and satisfaction with treatment. Trials published in higher impact journals were more likely to report treatment effects on emotional function, but less likely to report participant ratings of improvement and satisfaction with treatment. Most IMMPACT domains showed an increased rate of reporting over time, although many patient-important outcome domains remained unreported by over half of all trials evaluating the effects of opioids for CNCP. PMID- 26020223 TI - Solid-State Nuclear Magnetic Resonance on the Static and Dynamic Domains of Huntingtin Exon-1 Fibrils. AB - Amyloid-like fibrils formed by huntingtin exon-1 (htt_ex1) are a hallmark of Huntington's disease (HD). The structure of these fibrils is unknown, and determining their structure is an important step toward understanding the misfolding processes that cause HD. In HD, a polyglutamine (polyQ) domain in htt_ex1 is expanded to a degree that it gains the ability to form aggregates comprising the core of the resulting fibrils. Despite the simplicity of this polyQ sequence, the structure of htt_ex1 fibrils has been difficult to determine. This study provides a detailed structural investigation of fibrils formed by htt_ex1 using solid-state nuclear magnetic resonance (NMR) spectroscopy. We show that the polyQ domain of htt_ex1 forms the static amyloid core similar to polyQ model peptides. The Gln residues of this domain exist in two distinct conformations that are found in separate domains or monomers but are relatively close in space. The rest of htt_ex1 is relatively dynamic on an NMR time scale, especially the proline-rich C-terminus, which we found to be in a polyproline II helical and random coil conformation. We observed a similar dynamic C-terminus in a soluble form of htt_ex1, indicating that the conformation of this part of htt_ex1 is not changed upon its aggregation into an amyloid fibril. From these data, we propose a bottlebrush model for the fibrils formed by htt_ex1. In this model, the polyQ domains form the center and the proline-rich domains the bristles of the bottlebrush. PMID- 26020225 TI - Somatosensory nociceptive characteristics differentiate subgroups in people with chronic low back pain: a cluster analysis. AB - The objectives of this study were to explore the existence of subgroups in a cohort with chronic low back pain (n = 294) based on the results of multimodal sensory testing and profile subgroups on demographic, psychological, lifestyle, and general health factors. Bedside (2-point discrimination, brush, vibration and pinprick perception, temporal summation on repeated monofilament stimulation) and laboratory (mechanical detection threshold, pressure, heat and cold pain thresholds, conditioned pain modulation) sensory testing were examined at wrist and lumbar sites. Data were entered into principal component analysis, and 5 component scores were entered into latent class analysis. Three clusters, with different sensory characteristics, were derived. Cluster 1 (31.9%) was characterised by average to high temperature and pressure pain sensitivity. Cluster 2 (52.0%) was characterised by average to high pressure pain sensitivity. Cluster 3 (16.0%) was characterised by low temperature and pressure pain sensitivity. Temporal summation occurred significantly more frequently in cluster 1. Subgroups were profiled on pain intensity, disability, depression, anxiety, stress, life events, fear avoidance, catastrophizing, perception of the low back region, comorbidities, body mass index, multiple pain sites, sleep, and activity levels. Clusters 1 and 2 had a significantly greater proportion of female participants and higher depression and sleep disturbance scores than cluster 3. The proportion of participants undertaking <300 minutes per week of moderate activity was significantly greater in cluster 1 than in clusters 2 and 3. Low back pain, therefore, does not appear to be homogeneous. Pain mechanisms relating to presentations of each subgroup were postulated. Future research may investigate prognoses and interventions tailored towards these subgroups. PMID- 26020226 TI - The disruptive effects of pain on n-back task performance in a large general population sample. AB - Pain captures attention, displaces current concerns, and prioritises escape and repair. This attentional capture can be measured by its effects on general cognition. Studies on induced pain, naturally occurring acute pain, and chronic pain all demonstrate a detrimental effect on specific tasks of attention, especially those that involve working memory. However, studies to date have relied on relatively small samples and/or one type of pain, thus restricting our ability to generalise to wider populations. We investigated the effect of pain on an n-back task in a large heterogeneous sample of 1318 adults. Participants were recruited from the general population and tested through the internet. Despite the heterogeneity of pain conditions, participant characteristics, and testing environments, we found a performance decrement on the n-back task for those with pain, compared with those without pain; there were significantly more false alarms on nontarget trials. Furthermore, we also found an effect of pain intensity; performance was poorer in participants with higher intensity compared with that in those with lower intensity pain. We suggest that the effects of pain on attention found in the laboratory occur in more naturalistic settings. Pain is common in the general population, and such interruption may have important, as yet uninvestigated, consequences for tasks of everyday cognition that involve working memory, such as concentration, reasoning, motor planning, and prospective memory. PMID- 26020228 TI - Cation stoichiometry and electrical transport properties of the NdGaO3/(0 0 1)SrTiO3 interface. AB - The interface formed between two wide band-gap insulators, NdGaO3 and SrTiO3 renders metallic behavior, similar to the LaAlO3/SrTiO3 interface. The interface conductivity depends strongly upon oxygen pressure during growth of the NdGaO3 film and subsequent annealing in oxygen. The conductivity of a (10 uc) NdGaO3/SrTiO3 film, pulsed laser deposited at low (pO2 = 10(-4) mbar) oxygen pressure, vanishes after annealing at 600 degrees C in oxygen atmosphere. For a similar interface formed at high oxygen pressure (pO2 = 0.3 mbar), the metallic conductivity remains also after post annealing. Medium energy ion spectroscopy (MEIS) in random (non-channeling) direction showed that a substantial part of Ga is missing in films deposited at low pressure, while optimal stoichiometry is approached in films deposited at high pressure. Aligned (channeling) MEIS likewise show that the Ga/Nd ratio approaches the stoichiometric value as the pressure is increased from 10(-4) to 0.3 mbar. This is interpreted as due to gallium desorption from a growing film at high temperature and low oxygen pressure while the re-evaporation of gallium is considerably suppressed at higher pressure. We discuss the possible role of stoichiometry on electrical transport properties. PMID- 26020227 TI - Fat intake in children with autism spectrum disorder in the Mediterranean region (Valencia, Spain). AB - OBJECTIVE: Children with autism spectrum disorder (ASD) have been found to have alterations in dietary fat intake and fat quality. The fat intakes of the foods consumed by children with and without ASD were compared, and the deficiency and excess of these nutrients were examined. METHODS: In a matched case-control study, 3-day food diaries were completed by 105 children with ASD and 495 typically developing (TD) 6- to 9-year-old children in Valencia (Spain). We used the probabilistic approach and estimated average requirement cut-point to evaluate the risk of inadequate nutrients intakes. These were compared between groups and with Spanish recommendations using linear and logistic regression, respectively. RESULTS: Groups did not differ significantly in age, total dietary intake, Healthy Eating Index, or food variety score. Children with ASD had lower saturated fatty acids (SFAs) and omega-3 polyunsaturated fatty acids (PUFAs) intakes, but their total PUFAs and (PUFAs + monounsaturated fatty acids (MUFAs)/SFAs, PUFAs/SFAs intakes and omega-6/omega-3 ratios were higher than TD children. The total fat and cholesterol intakes of both groups were slightly above Spanish recommendations. Both groups had low omega-6 intakes, very low omega-3 intakes, and high omega-6/omega-3 ratios. CONCLUSION: Further research is required to clarify associations between ASD symptomatology, fat-eating patterns and health status. PMID- 26020229 TI - Toddler with retinal defects. . .psychomotor regression. Sandhoff disease. PMID- 26020230 TI - Visinets: a web-based pathway modeling and dynamic visualization tool. AB - In this report we describe a novel graphically oriented method for pathway modeling and a software package that allows for both modeling and visualization of biological networks in a user-friendly format. The Visinets mathematical approach is based on causal mapping (CMAP) that has been fully integrated with graphical interface. Such integration allows for fully graphical and interactive process of modeling, from building the network to simulation of the finished model. To test the performance of Visinets software we have applied it to: a) create executable EGFR-MAPK pathway model using an intuitive graphical way of modeling based on biological data, and b) translate existing ordinary differential equation (ODE) based insulin signaling model into CMAP formalism and compare the results. Our testing fully confirmed the potential of the CMAP method for broad application for pathway modeling and visualization and, additionally, showed significant advantage in computational efficiency. Furthermore, we showed that Visinets web-based graphical platform, along with standardized method of pathway analysis, may offer a novel and attractive alternative for dynamic simulation in real time for broader use in biomedical research. Since Visinets uses graphical elements with mathematical formulas hidden from the users, we believe that this tool may be particularly suited for those who are new to pathway modeling and without the in-depth modeling skills often required when using other software packages. PMID- 26020231 TI - Acute Kidney Injury in Severe Sepsis and Septic Shock in Patients with and without Diabetes Mellitus: A Multicenter Study. AB - INTRODUCTION: Whether diabetes mellitus increases the risk of acute kidney injury (AKI) during sepsis is controversial. MATERIALS AND METHODS: We used a case control design to compare the frequency of AKI, use of renal replacement therapy (RRT), and renal recovery in patients who had severe sepsis or septic shock with or without diabetes. The data were from the Outcomerea prospective multicenter database, in which 12 French ICUs enrolled patients admitted between January 1997 and June 2009. RESULTS: First, we compared 451 patients with severe sepsis or septic shock and diabetes to 3,277 controls with severe sepsis or septic shock and without diabetes. Then, we compared 318 cases (with diabetes) to 746 matched controls (without diabetes). Diabetic patients did not have a higher frequency of AKI (hazard ratio [HR], 1.18; P = 0.05]) or RRT (HR, 1.09; P = 0.6). However, at discharge, diabetic patients with severe sepsis or septic shock who experienced acute kidney injury during the ICU stay and were discharged alive more often required RRT (9.5% vs. 4.8%; P = 0.02), had higher serum creatinine values (134 vs. 103 umoL/L; P<0.001) and had less often recovered a creatinine level less than 1.25 fold the basal creatinine (41.1% vs. 60.5%; P<0.001). CONCLUSIONS: In patients with severe sepsis or septic shock, diabetes is not associated with occurrence of AKI or need for RRT but is an independent risk factor for persistent renal dysfunction in patients who experience AKI during their ICU stay. PMID- 26020232 TI - The role of horizontal gene transfer in the evolution of the oomycetes. PMID- 26020234 TI - Modeling the geographic spread of rabies in China. AB - In order to investigate how the movement of dogs affects the geographically inter provincial spread of rabies in Mainland China, we propose a multi-patch model to describe the transmission dynamics of rabies between dogs and humans, in which each province is regarded as a patch. In each patch the submodel consists of susceptible, exposed, infectious, and vaccinated subpopulations of both dogs and humans and describes the spread of rabies among dogs and from infectious dogs to humans. The existence of the disease-free equilibrium is discussed, the basic reproduction number is calculated, and the effect of moving rates of dogs between patches on the basic reproduction number is studied. To investigate the rabies virus clades lineages, the two-patch submodel is used to simulate the human rabies data from Guizhou and Guangxi, Hebei and Fujian, and Sichuan and Shaanxi, respectively. It is found that the basic reproduction number of the two-patch model could be larger than one even if the isolated basic reproduction number of each patch is less than one. This indicates that the immigration of dogs may make the disease endemic even if the disease dies out in each isolated patch when there is no immigration. In order to reduce and prevent geographical spread of rabies in China, our results suggest that the management of dog markets and trades needs to be regulated, and transportation of dogs has to be better monitored and under constant surveillance. PMID- 26020235 TI - Chimps, Humans, and the Hominid Struggle against Viruses. PMID- 26020233 TI - Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature. AB - Differentiation of lung vascular smooth muscle cells (vSMCs) is tightly regulated during development or in response to challenges in a vessel specific manner. Aberrant vSMCs specifically associated with distal pulmonary arteries have been implicated in the pathogenesis of respiratory diseases, such as pulmonary arterial hypertension (PAH), a progressive and fatal disease, with no effective treatment. Therefore, it is highly relevant to understand the underlying mechanisms of lung vSMC differentiation. miRNAs are known to play critical roles in vSMC maturation and function of systemic vessels; however, little is known regarding the role of miRNAs in lung vSMCs. Here, we report that miR-29 family members are the most abundant miRNAs in adult mouse lungs. Moreover, high levels of miR-29 expression are selectively associated with vSMCs of distal vessels in both mouse and human lungs. Furthermore, we have shown that disruption of miR-29 in vivo leads to immature/synthetic vSMC phenotype specifically associated with distal lung vasculature, at least partially due to the derepression of KLF4, components of the PDGF pathway and ECM-related genes associated with synthetic phenotype. Moreover, we found that expression of FBXO32 in vSMCs is significantly upregulated in the distal vasculature of miR-29 null lungs. This indicates a potential important role of miR-29 in smooth muscle cell function by regulating FBXO32 and SMC protein degradation. These results are strongly supported by findings of a cell autonomous role of endogenous miR-29 in promoting SMC differentiation in vitro. Together, our findings suggested a vessel specific role of miR-29 in vSMC differentiation and function by targeting several key negative regulators. PMID- 26020236 TI - Ketamine causes mitochondrial dysfunction in human induced pluripotent stem cell derived neurons. AB - PURPOSE: Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated. METHODS: Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 MUM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy. RESULTS: Twenty-four-hour exposure of iPSC derived neurons to 500 MUM ketamine resulted in a 40% increase in caspase 3/7 activity (P < 0.01), 14% increase in ROS production (P < 0.01), and 81% reduction in mitochondrial membrane potential (P < 0.01), compared with untreated cells. Lower concentration of ketamine (100 MUM) decreased the ATP level (22%, P < 0.01) and increased the NADH/NAD+ ratio (46%, P < 0.05) without caspase activation. Transmission electron microscopy showed enhanced mitochondrial fission and autophagocytosis at the 100 MUM ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation. CONCLUSIONS: We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons. PMID- 26020237 TI - BABA and Phytophthora nicotianae Induce Resistance to Phytophthora capsici in Chile Pepper (Capsicum annuum). AB - Induced resistance in plants is a systemic response to certain microorganisms or chemicals that enhances basal defense responses during subsequent plant infection by pathogens. Inoculation of chile pepper with zoospores of non-host Phytophthora nicotianae or the chemical elicitor beta-aminobutyric acid (BABA) significantly inhibited foliar blight caused by Phytophthora capsici. Tissue extract analyses by GC/MS identified conserved change in certain metabolite concentrations following P. nicotianae or BABA treatment. Induced chile pepper plants had reduced concentrations of sucrose and TCA cycle intermediates and increased concentrations of specific hexose-phosphates, hexose-disaccharides and amino acids. Galactose, which increased significantly in induced chile pepper plants, was shown to inhibit growth of P. capsici in a plate assay. PMID- 26020238 TI - Jaeumganghwa-Tang Induces Apoptosis via the Mitochondrial Pathway and Lactobacillus Fermentation Enhances Its Anti-Cancer Activity in HT1080 Human Fibrosarcoma Cells. AB - Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080 bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly. PMID- 26020239 TI - Analysis of the prevalence and associated risk factors of tinnitus in adults. AB - BACKGROUND: Tinnitus is a common condition in adults; however, the pathophysiology of tinnitus remains unclear, and no large population-based study has assessed the associated risk factors. The aim of this study was to analyze the prevalence and associated risk factors of tinnitus. METHODS: We conducted a cross-sectional study using data from the Korea National Health and Nutrition Examination Survey, with 19,290 participants ranging in age from 20 to 98 years old, between 2009 and 2012. We investigated the prevalence of tinnitus using a questionnaire and analyzed various possible factors associated with tinnitus using simple and multiple logistic regression analysis with complex sampling. RESULTS: The prevalence of tinnitus was 20.7%, and the rates of tinnitus associated with no discomfort, moderate annoyance, and severe annoyance were 69.2%, 27.9%, and 3.0%, respectively. The prevalence of tinnitus and the rates of annoying tinnitus increased with age. The adjusted odds ratio (AOR) of tinnitus was higher for females, those with a smoking history, those reporting less sleep (<= 6 h), those with more stress, those in smaller households, those with a history of hyperlipidemia osteoarthritis, rheumatoid arthritis, asthma, depression, thyroid disease, an abnormal tympanic membrane, unilateral hearing loss, bilateral hearing loss, noise exposure from earphones, noise exposure at the workplace, noise exposure outside the workplace, and brief noise exposure. Additionally, unemployed individuals and soldiers had higher AORs for tinnitus. The AOR of annoying tinnitus increased with age, stress, history of hyperlipidemia, unilateral hearing loss, and bilateral hearing loss. CONCLUSIONS: Tinnitus is very common in the general population and is associated with gender, smoking, stress, sleep, hearing loss, hyperlipidemia, osteoarthritis, rheumatoid arthritis, asthma, depression, and thyroid disease history. PMID- 26020240 TI - Suppression of Abdominal Motor Activity during Swallowing in Cats and Humans. AB - Diseases affecting pulmonary mechanics often result in changes to the coordination of swallow and breathing. We hypothesize that during times of increased intrathoracic pressure, swallow suppresses ongoing expiratory drive to ensure bolus transport through the esophagus. To this end, we sought to determine the effects of swallow on abdominal electromyographic (EMG) activity during expiratory threshold loading in anesthetized cats and in awake-healthy adult humans. Expiratory threshold loads were applied to recruit abdominal motor activity during breathing, and swallow was triggered by infusion of water into the mouth. In both anesthetized cats and humans, expiratory cycles which contained swallows had a significant reduction in abdominal EMG activity, and a greater percentage of swallows were produced during inspiration and/or respiratory phase transitions. These results suggest that: a) spinal expiratory motor pathways play an important role in the execution of swallow, and b) a more complex mechanical relationship exists between breathing and swallow than has previously been envisioned. PMID- 26020241 TI - Phosphatidic acid produced by phospholipase D promotes RNA replication of a plant RNA virus. AB - Eukaryotic positive-strand RNA [(+)RNA] viruses are intracellular obligate parasites replicate using the membrane-bound replicase complexes that contain multiple viral and host components. To replicate, (+)RNA viruses exploit host resources and modify host metabolism and membrane organization. Phospholipase D (PLD) is a phosphatidylcholine- and phosphatidylethanolamine-hydrolyzing enzyme that catalyzes the production of phosphatidic acid (PA), a lipid second messenger that modulates diverse intracellular signaling in various organisms. PA is normally present in small amounts (less than 1% of total phospholipids), but rapidly and transiently accumulates in lipid bilayers in response to different environmental cues such as biotic and abiotic stresses in plants. However, the precise functions of PLD and PA remain unknown. Here, we report the roles of PLD and PA in genomic RNA replication of a plant (+)RNA virus, Red clover necrotic mosaic virus (RCNMV). We found that RCNMV RNA replication complexes formed in Nicotiana benthamiana contained PLDalpha and PLDbeta. Gene-silencing and pharmacological inhibition approaches showed that PLDs and PLDs-derived PA are required for viral RNA replication. Consistent with this, exogenous application of PA enhanced viral RNA replication in plant cells and plant-derived cell-free extracts. We also found that a viral auxiliary replication protein bound to PA in vitro, and that the amount of PA increased in RCNMV-infected plant leaves. Together, our findings suggest that RCNMV hijacks host PA-producing enzymes to replicate. PMID- 26020242 TI - Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling. AB - Unrepaired or inaccurately repaired DNA damage can lead to a range of cell fates, such as apoptosis, cellular senescence or cancer, depending on the efficiency and accuracy of DNA damage repair and on the downstream DNA damage signalling. DNA damage repair and signalling have been studied and modelled in detail separately, but it is not yet clear how they integrate with one another to control cell fate. In this study, we have created an integrated stochastic model of DNA damage repair by non-homologous end joining and of gamma irradiation-induced cellular senescence in human cells that are not apoptosis-prone. The integrated model successfully explains the changes that occur in the dynamics of DNA damage repair after irradiation. Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model. Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence. The integrated model is valuable for studying the processes of DNA damage induced cell fate and predicting the effectiveness of DNA damage related medical interventions at the cellular level. PMID- 26020243 TI - Robust control of burst suppression for medical coma. AB - OBJECTIVE: Medical coma is an anesthetic-induced state of brain inactivation, manifest in the electroencephalogram by burst suppression. Feedback control can be used to regulate burst suppression, however, previous designs have not been robust. Robust control design is critical under real-world operating conditions, subject to substantial pharmacokinetic and pharmacodynamic parameter uncertainty and unpredictable external disturbances. We sought to develop a robust closed loop anesthesia delivery (CLAD) system to control medical coma. APPROACH: We developed a robust CLAD system to control the burst suppression probability (BSP). We developed a novel BSP tracking algorithm based on realistic models of propofol pharmacokinetics and pharmacodynamics. We also developed a practical method for estimating patient-specific pharmacodynamics parameters. Finally, we synthesized a robust proportional integral controller. Using a factorial design spanning patient age, mass, height, and gender, we tested whether the system performed within clinically acceptable limits. Throughout all experiments we subjected the system to disturbances, simulating treatment of refractory status epilepticus in a real-world intensive care unit environment. MAIN RESULTS: In 5400 simulations, CLAD behavior remained within specifications. Transient behavior after a step in target BSP from 0.2 to 0.8 exhibited a rise time (the median (min, max)) of 1.4 [1.1, 1.9] min; settling time, 7.8 [4.2, 9.0] min; and percent overshoot of 9.6 [2.3, 10.8]%. Under steady state conditions the CLAD system exhibited a median error of 0.1 [-0.5, 0.9]%; inaccuracy of 1.8 [0.9, 3.4]%; oscillation index of 1.8 [0.9, 3.4]%; and maximum instantaneous propofol dose of 4.3 [2.1, 10.5] mg kg(-1). The maximum hourly propofol dose was 4.3 [2.1, 10.3] mg kg(-1) h(-1). Performance fell within clinically acceptable limits for all measures. SIGNIFICANCE: A CLAD system designed using robust control theory achieves clinically acceptable performance in the presence of realistic unmodeled disturbances and in spite of realistic model uncertainty, while maintaining infusion rates within acceptable safety limits. PMID- 26020244 TI - Performance of an Optimized Paper-Based Test for Rapid Visual Measurement of Alanine Aminotransferase (ALT) in Fingerstick and Venipuncture Samples. AB - BACKGROUND: A paper-based, multiplexed, microfluidic assay has been developed to visually measure alanine aminotransferase (ALT) in a fingerstick sample, generating rapid, semi-quantitative results. Prior studies indicated a need for improved accuracy; the device was subsequently optimized using an FDA-approved automated platform (Abaxis Piccolo Xpress) as a comparator. Here, we evaluated the performance of the optimized paper test for measurement of ALT in fingerstick blood and serum, as compared to Abaxis and Roche/Hitachi platforms. To evaluate feasibility of remote results interpretation, we also compared reading cell phone camera images of completed tests to reading the device in real time. METHODS: 96 ambulatory patients with varied baseline ALT concentration underwent fingerstick testing using the paper device; cell phone images of completed devices were taken and texted to a blinded off-site reader. Venipuncture serum was obtained from 93/96 participants for routine clinical testing (Roche/Hitachi); subsequently, 88/93 serum samples were captured and applied to paper and Abaxis platforms. Paper test and reference standard results were compared by Bland-Altman analysis. FINDINGS: For serum, there was excellent agreement between paper test and Abaxis results, with negligible bias (+4.5 U/L). Abaxis results were systematically 8.6% lower than Roche/Hitachi results. ALT values in fingerstick samples tested on paper were systematically lower than values in paired serum tested on paper (bias -23.6 U/L) or Abaxis (bias -18.4 U/L); a correction factor was developed for the paper device to match fingerstick blood to serum. Visual reads of cell phone images closely matched reads made in real time (bias +5.5 U/L). CONCLUSIONS: The paper ALT test is highly accurate for serum testing, matching the reference method against which it was optimized better than the reference methods matched each other. A systematic difference exists between ALT values in fingerstick and paired serum samples, and can be addressed by application of a correction factor to fingerstick values. Remote reading of this device is feasible. PMID- 26020245 TI - Identifying bioaccumulative halogenated organic compounds using a nontargeted analytical approach: seabirds as sentinels. AB - Persistent organic pollutants (POPs) are typically monitored via targeted mass spectrometry, which potentially identifies only a fraction of the contaminants actually present in environmental samples. With new anthropogenic compounds continuously introduced to the environment, novel and proactive approaches that provide a comprehensive alternative to targeted methods are needed in order to more completely characterize the diversity of known and unknown compounds likely to cause adverse effects. Nontargeted mass spectrometry attempts to extensively screen for compounds, providing a feasible approach for identifying contaminants that warrant future monitoring. We employed a nontargeted analytical method using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC/TOF-MS) to characterize halogenated organic compounds (HOCs) in California Black skimmer (Rynchops niger) eggs. Our study identified 111 HOCs; 84 of these compounds were regularly detected via targeted approaches, while 27 were classified as typically unmonitored or unknown. Typically unmonitored compounds of note in bird eggs included tris(4-chlorophenyl)methane (TCPM), tris(4-chlorophenyl)methanol (TCPMOH), triclosan, permethrin, heptachloro-1' methyl-1,2'-bipyrrole (MBP), as well as four halogenated unknown compounds that could not be identified through database searching or the literature. The presence of these compounds in Black skimmer eggs suggests they are persistent, bioaccumulative, potentially biomagnifying, and maternally transferring. Our results highlight the utility and importance of employing nontargeted analytical tools to assess true contaminant burdens in organisms, as well as to demonstrate the value in using environmental sentinels to proactively identify novel contaminants. PMID- 26020246 TI - CONSORT item reporting quality in the top ten ranked journals of critical care medicine in 2011: a retrospective analysis. AB - INTRODUCTION: Reporting randomised controlled trials is a key element in order to disseminate research findings. The CONSORT statement was introduced to improve the reporting quality. We assessed the adherence to the CONSORT statement of randomised controlled trials published 2011 in the top ten ranked journals of critical care medicine (ISI Web of Knowledge 2011, Thomson Reuters, London UK). METHODS: Design. We performed a retrospective cross sectional data analysis. Setting. This study was executed at the University Hospital of RWTH, Aachen. Participants. We selected the following top ten listed journals according to ISI Web of Knowledge (Thomson Reuters, London, UK) critical care medicine ranking in the year 2011: American Journal of Respiratory and Critical Care Medicine, Critical Care Medicine, Intensive Care Medicine, CHEST, Critical Care, Journal of Neurotrauma, Resuscitation, Pediatric Critical Care Medicine, Shock and Minerva Anestesiologica. Main outcome measures. We screened the online table of contents of each included journal, to identify the randomised controlled trials. The adherence to the items of the CONSORT Checklist in each trial was evaluated. Additionally we correlated the citation frequency of the articles and the impact factor of the respective journal with the amount of reported items per trial. RESULTS: We analysed 119 randomised controlled trials and found, 15 years after the implementation of the CONSORT statement, that a median of 61,1% of the checklist-items were reported. Only 55.5% of the articles were identified as randomised trials in their titles. The citation frequency of the trials correlated significantly (rs = 0,433; p<0,001 and r = 0,331; p<0,001) to the CONSORT statement adherence. The impact factor showed also a significant correlation to the CONSORT adherence (r = 0,386; p<0,001). CONCLUSION: The reporting quality of randomised controlled trials in the field of critical care medicine remains poor and needs considerable improvement. PMID- 26020247 TI - Maturation of Oral Microbiota in Children with or without Dental Caries. AB - BACKGROUND: The aim of this longitudinal study was to evaluate the oral microbiota in children from age 3 months to 3 years, and to determine the association of the presence of caries at 3 years of age. METHODS AND FINDINGS: Oral biofilms and saliva were sampled from children at 3 months (n = 207) and 3 years (n = 155) of age, and dental caries was scored at 3 years of age. Oral microbiota was assessed by culturing of total lactobacilli and mutans streptococci, PCR detection of Streptococcus mutans and Streptococcus sobrinus, 454 pyrosequencing and HOMIM (Human Oral Microbe Identification Microarray) microarray detection of more then 300 species/ phylotypes. Species richness and taxa diversity significantly increased from 3 months to 3 years. Three bacterial genera, present in all the 3-month-old infants, persisted at 3 years of age, whereas three other genera had disappeared by this age. A large number of new taxa were also observed in the 3-year-olds. The microbiota at 3 months of age, except for lactobacilli, was unrelated to caries development at a later age. In contrast, several taxa in the oral biofilms of the 3-year-olds were linked with the presence or absence of caries. The main species/phylotypes associated with caries in 3-year-olds belonged to the Actinobaculum, Atopobium, Aggregatibacter, and Streptococcus genera, whereas those influencing the absence of caries belonged to the Actinomyces, Bergeyella, Campylobacter, Granulicatella, Kingella, Leptotrichia, and Streptococcus genera. CONCLUSIONS: Thus, during the first years of life, species richness and taxa diversity in the mouth increase significantly. Besides the more prevalent colonization of lactobacilli, the composition of the overall microbiota at 3 months of age was unrelated to caries development at a later age. Several taxa within the oral biofilms of the 3-year-olds could be linked to the presence or absence of caries. PMID- 26020248 TI - National Health Insurance Development in China from 2004 to 2011: Coverage versus Benefits. AB - BACKGROUND: The simultaneous improvement of the security capability of China Health Insurance System and its development in the last decade remains uncertain. This study measures the status and trends of reimbursement levels of the China Health Insurance System, as well as to offer policy advice to subsequent insurance reforms. METHODS: The National Reimbursement Ratio was created to determine the reimbursement level of the national health insurance system based on total health expenditure and the covered population. Chinese total health expenditure data from 2004 to 2011 were extracted from China's Health Statistics according to the standards of the International Classification for Health Accounts by Healthcare Financing. RESULTS: In 2011, the medical expenditure per capita in China was USD 130.95 and the National Reimbursement Ratio was 26.39%. The National Reimbursement Ratio showed an intense transition from 2004 to 2011, with a sharp decrease from 98.51% in 2004 to 22.44% in 2009, and then a small increase to 26.39% in 2011. CONCLUSION: The National Reimbursement Ratio was effective in revealing the reimbursement level of the national health insurance system and in predicting its trends. The challenge to China's healthcare reform is to switch from increasing insurance coverage to guaranteeing a steady increase in government input and building a powerful supervision mechanism. PMID- 26020249 TI - Frequency, suppressive capacity, recruitment and induction mechanisms of regulatory T cells in sinonasal squamous cell carcinoma and nasal inverted papilloma. AB - BACKGROUND: Sinonasal squamous cell carcinoma (SSCC) and nasal inverted papilloma (NIP) represent the predominant type of malignant and benign tumors in sinonasal tract, respectively. CD4+ CD25+ Foxp3+ natural regulatory T (Treg) cells might play critical role(s) in the suppression of anti-tumor immune response and thus shed light on tumor progression from benign to malignant. OBJECTIVE: This study aimed to evaluate the frequency and suppressive capacity of Treg cells in SSCC compared to NIP and further to explore the underlying mechanisms. PATIENTS AND METHODS: Frequencies of Treg, Th1 and Th2 cells were evaluated by flow cytometry in tissue homogenate and peripheral blood from 31 SSCC patients, 32 NIP patients and 35 normal controls. Treg cells were tested for regulatory function by co culture with effector T cells. CCR4 and its ligands, CCL22 and CCL17, were analyzed by flow cytometry and Luminex, respectively. The chemoattractant properties of CCR4/CCL22 and CCR4/CCL17 for Treg cells were assessed using the Boyden chamber technique, to elucidate the potential mechanisms of Treg recruitment in tumor microenvironment. Treg cells induction via TGF-beta was assessed with transwells after local CD4+ Foxp3+ T cells were assessed by immunohistochemistry and TGF-beta concentration was measured by Luminex. RESULTS: Tumor-infiltrating Treg cells increased significantly from normal to NIP to SSCC (P <= 0.001 for normal vs. NIP and P = 0.004 for NIP vs. SSCC). Significantly elevated frequency and enhanced suppression capacity of circulating Treg cells in SSCC were detected compared to NIP and healthy controls, concomitant with Th1 decrease and Th2 increase. Apparently increased CCL22 attracted CCR4-expressing Treg cells to tumor microenvironment in SSCC, compared to NIP. SSCC produced significantly more TGF-beta than NIP and thus possessed greater potential for Treg cell induction. CONCLUSION: Frequency and suppressive capacity of Treg cells enhanced with progression of malignancy from NIP to SSCC. Circulating Treg cells were recruited to tumor tissue via CCR4/CCL22 signalling, whereas tumor synthesised TGF-beta contributed to induction of peripheral Treg cells. PMID- 26020250 TI - Undiagnosed cryptic diversity in small, microendemic frogs (Leptolalax) from the Central Highlands of Vietnam. AB - A major obstacle in prioritizing species or habitats for conservation is the degree of unrecognized diversity hidden within complexes of morphologically similar, "cryptic" species. Given that amphibians are one of the most threatened groups of organisms on the planet, our inability to diagnose their true diversity is likely to have significant conservation consequences. This is particularly true in areas undergoing rapid deforestation, such as Southeast Asia. The Southeast Asian genus Leptolalax is a group of small-bodied, morphologically conserved frogs that inhabit the forest-floor. We examined a particularly small bodied and morphologically conserved subset, the Leptolalax applebyi group, using a combination of molecular, morphometric, and acoustic data to identify previously unknown diversity within. In order to predict the geographic distribution of the group, estimate the effects of habitat loss and assess the degree of habitat protection, we used our locality data to perform ecological niche modelling using MaxEnt. Molecular (mtDNA and nuDNA), acoustic and subtle morphometric differences revealed a significant underestimation of diversity in the L. applebyi group; at least two-thirds of the diversity may be unrecognised. Patterns of diversification and microendemism in the group appear driven by limited dispersal, likely due to their small body size, with several lineages restricted to watershed basins. The L. applebyi group is predicted to have historically occurred over a large area of the Central Highlands of Vietnam, a considerable portion of which has already been deforested. Less than a quarter of the remaining forest predicted to be suitable for the group falls within current protected areas. The predicted distribution of the L. applebyi group extends into unsurveyed watershed basins, each potentially containing unsampled diversity, some of which may have already been lost due to deforestation. Current estimates of amphibian diversity based on morphology alone are misleading, and accurate alpha taxonomy is essential to accurately prioritize conservation efforts. PMID- 26020251 TI - Acupuncture or low frequency infrared treatment for low back pain in Chinese patients: a discrete choice experiment. AB - Acupuncture is a popular but controversial treatment option for low back pain. In China, it is practised as traditional Chinese medicine; other treatment strategies for low back pain are commonly practised as Western medicine. Research on patient preference for low back-pain treatment options has been mainly conducted in Western countries and is limited to a willingness-to-pay approach. A stated-preference, discrete choice experiment was conducted to determine Chinese patient preferences and trade-offs for acupuncture and low frequency infrared treatment in low back pain from September 2011 to August 2012 after approval from the Department of Scientific Research in the study settings. Eight-six adult outpatients who visited the 'traditional medicine department' at a traditional Chinese medicine hospital and the 'rehabilitation department' at a Western medicine hospital in Guangdong Province of China for chronic low back pain during study period participated in an interview survey. A questionnaire containing 10 scenarios (5 attributes in each scenario) was used to ask participants' preference for acupuncture, low frequency infrared treatment or neither option. Validated responses were analysed using a nested-logit model. The decision on whether to receive a therapy was not associated with the expected utility of receiving therapy, female gender and higher out-of-pocket payment significantly decreased chance to receive treatments. Of the utility of receiving either acupuncture or low frequency infrared treatment, the treatment sensation was the most important attribute as an indicator of treatment efficacy, followed by the maximum efficacy, maintenance duration and onset of efficacy, and the out-of pocket payment. The willingness-to-pay for acupuncture and low frequency infrared treatment were about $618.6 and $592.4 USD per course respectively, demonstrated patients' demand of pain management. The treatment sensation was regarded as an indicator of treatment efficacy and the most important attribute for choosing acupuncture or low frequency infrared treatment. The high willingness-to-pay demonstrated patients' demand of pain management. However, there may be other factors influencing patients' preference to receive treatments. PMID- 26020253 TI - Rapid diagnosis. PMID- 26020252 TI - The use of Nanotrap particles in the enhanced detection of Rift Valley fever virus nucleoprotein. AB - BACKGROUND: Rift Valley fever virus (RVFV) is a highly pathogenic arthropod-borne virus that has a detrimental effect on both livestock and human populations. While there are several diagnostic methodologies available for RVFV detection, many are not sensitive enough to diagnose early infections. Furthermore, detection may be hindered by high abundant proteins such as albumin. Previous findings have shown that Nanotrap particles can be used to significantly enhance detection of various small analytes of low abundance. We have expanded upon this repertoire to show that this simple and efficient sample preparation technology can drastically improve the detection of the RVFV nucleoprotein (NP), the most abundant and widely used viral protein for RVFV diagnostics. RESULTS: After screening multiple Nanotrap particle architectures, we found that one particle, NT45, was optimal for RVFV NP capture, as demonstrated by western blotting. NT45 significantly enhanced detection of the NP at levels undetectable without the technology. Importantly, we demonstrated that Nanotrap particles are capable of concentrating NP in a number of matrices, including infected cell lysates, viral supernatants, and animal sera. Specifically, NT45 enhanced detection of NP at various viral titers, multiplicity of infections, and time points. Our most dramatic results were observed in spiked serum samples, where high abundance serum proteins hindered detection of NP without Nanotrap particles. Nanotrap particles allowed for sample cleanup and subsequent detection of RVFV NP. Finally, we demonstrated that incubation of our samples with Nanotrap particles protects the NP from degradation over extended periods of time (up to 120 hours) and at elevated temperatures (at 37oC). CONCLUSION: This study demonstrates that Nanotrap particles are capable of drastically lowering the limit of detection for RVFV NP by capturing, concentrating, and preserving RVFV NP in clinically relevant matrices. These studies can be extended to a wide range of pathogens and their analytes of diagnostic interest. PMID- 26020254 TI - An EPIC Adventure. PMID- 26020255 TI - Can empathy be taught? Reflections from a medical student active-listening workshop. AB - Medical students deserve training in active listening and counseling before they encounter patients in distress. At the Alpert Medical School of Brown University we created and evaluated a workshop that trains first-year medical students to assess patients' emotional states and express empathy in an efficient and effective manner. Using second-year students as near-peer facilitators, we integrated the workshop into the existing preclinical first-year curriculum. We found that students' self-reported comfort in counseling a patient experiencing an emotionally challenging situation increased from 27% to 79% after the 90 minute workshop. PMID- 26020256 TI - This Is Not Your Grandfather's Emergency Department. PMID- 26020257 TI - Emergency Ultrasound: Point-of-care Ultrasound in Emergency Medicine. PMID- 26020258 TI - The emerging science of gender-specific emergency medicine. PMID- 26020259 TI - Concussion: a primer for the physician. PMID- 26020260 TI - The extinction of triage. PMID- 26020261 TI - Scribes: letting doctors do what they do best. PMID- 26020262 TI - A Scribe's Reflection. PMID- 26020263 TI - Reported Behaviors of Prescription-Drug Misuse and Medication Safety among Students Attending a Rhode Island University. AB - OBJECTIVE: College students are at high risk of illicit drug use, where nonmedical use of prescription medications ranks second behind marijuana. Assessment of college students' behaviors regarding prescription medication storage, disposal and sharing tendencies is needed to provide foundation for medication safety education on campuses. METHOD: Students (n = 333) completed a prevalence survey assessing prescription medication use, storage and disposal activities upon obtaining prescription at the University pharmacy. RESULTS: Unsafe student practices of rarely/never storing medications in locked place (77%), improper medication disposal (81%), witnessing (28%) and admitting (27%) medication sharing was reported. Female students were more likely to store medications unlocked (p < 0.001). Students living on-campus were more likely to witness sharing of medications (p = 0.043), and students living off-campus were more likely to have shared prescription medications (p = 0.036). CONCLUSIONS: Campus education is needed regarding safe medication storage, proper disposal of unused medications, and risks associated with sharing medications. PMID- 26020264 TI - Dyspnea on daptomycin: eosinophilic pneumonia. AB - We present a case of drug-induced acute eosinophilic pneumonia with characteristic imaging and bronchioloaveolar lavage (BAL) findings. Although not a common diagnosis, it is important to consider in the right clinical scenario, including a patient with presumed pneumonia that does not respond to typical treatment. Diagnosis is confirmed by bronchoscopy with BAL. For drug-induced types, treatment includes removal of the offending agent. Corticosteroids are used if symptoms are severe and can result in rapid clinical improvement. PMID- 26020265 TI - A twist and a turn. PMID- 26020266 TI - Predictors of non-completion of community-based chronic disease self-management programs: The Rhode Island experience during an economic recession. PMID- 26020267 TI - The impact of power on humanity: self-dehumanization in powerlessness. AB - Power gives people the ability to control themselves and their environment, and this control is considered a fundamental human need. We investigated whether experiencing powerlessness induces the experience of self-dehumanization using three methods: priming, role-playing, and cueing. People in a position of low power viewed themselves (Experiments 1-3) as less human relative to people in a position of high power; furthermore, people with low power believed that they were viewed as less human by others as well (Experiments 2-3). In all of the experiments, human nature traits were most negatively affected by powerlessness in self-perception judgments, and uniquely human traits were most negatively affected by powerlessness in meta-perception judgments. Furthermore, the powerless believed they were viewed as less human not only by the powerful people but also the outside observers of the power dynamic. Self-dehumanization also appears to be a consequence of powerlessness rather than an incidental result of a change in mood or a negative self-view. Our findings are an important extension of previous work on the adverse effects of powerlessness and dehumanization. PMID- 26020268 TI - Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types. AB - Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non-cell autonomous malignancy. PMID- 26020269 TI - Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice. AB - Neonatal white matter injury (nWMI) is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P) 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2-3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFalphaR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life, followed by dysmyelination, abnormal spinal neuron composition, and neuro-motor deficits in adulthood. PMID- 26020270 TI - Laccase-catalyzed decolorization of malachite green: performance optimization and degradation mechanism. AB - Malachite green (MG) was decolorized by laccase (LacA) of white-rot fungus Cerrena sp. with strong decolorizing ability. Decolorization conditions were optimized with response surface methodology. A highly significant quadratic model was developed to investigate MG decolorization with LacA, and the maximum MG decolorization ratio of 91.6% was predicted under the conditions of 2.8 U mL(-1) LacA, 109.9 mg L(-1) MG and decolorization for 172.4 min. Kinetic studies revealed the Km and kcat values of LacA toward MG were 781.9 mM and 9.5 s(-1), respectively. UV-visible spectra confirmed degradation of MG, and the degradation mechanism was explored with liquid chromatography-mass spectrometry (LC-MS) analysis. Based on the LC-MS spectra of degradation products, LacA catalyzed MG degradation via two simultaneous pathways. In addition, the phytotoxicity of MG, in terms of inhibition on seed germination and seedling root elongation of Nicotiana tabacum and Lactuca sativa, was reduced after laccase treatment. These results suggest that laccase of Cerrena was effective in decolorizing MG and promising in bioremediation of wastewater in food and aquaculture industries. PMID- 26020271 TI - Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci. AB - To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology. PMID- 26020272 TI - Association of TERT Polymorphisms with Clinical Outcome of Non-Small Cell Lung Cancer Patients. AB - TERT is of great importance in cancer initiation and progression. Many studies have demonstrated the TERT polymorphisms as risk factors for many cancer types, including lung cancer. However, the impacts of TERT variants on cancer progression and treatment efficacy have remained controversial. This study aimed to investigate the association of TERT polymorphisms with clinical outcome of advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy, including response rate, clinical benefit, progression-free survival (PFS), overall survival (OS), and grade 3 or 4 toxicity. Seven polymorphisms of TERT were assessed, and a total of 1004 inoperable advanced NSCLC patients treated with platinum-based chemotherapy were enrolled. It is exhibited that the variant heterozygote of rs4975605 showed significant association with a low rate of clinical benefit, and displayed a much stronger effect in never-smoking female subset, leading to the clinical benefit rate decreased from 82.9% (C/C genotype) to 56.4% (C/A genotype; adjusted OR, 3.58; P=1.40*10(-4)). It is also observed that the polymorphism rs2736109 showed significant correlation with PFS (log-rank P=0.023). In age > 58 subgroup, patients carrying the heterozygous genotype had a longer median PFS than those carrying the wild-type genotypes (P=0.002). The results from the current study, for the first time to our knowledge, provide suggestive evidence of an effect of TERT polymorphisms on disease progression variability among Chinese patients with platinum-treated advanced NSCLC. PMID- 26020273 TI - Markerless attenuation correction for carotid MRI surface receiver coils in combined PET/MR imaging. AB - The purpose of the study was to evaluate the effect of attenuation of MR coils on quantitative carotid PET/MR exams. Additionally, an automated attenuation correction method for flexible carotid MR coils was developed and evaluated. The attenuation of the carotid coil was measured by imaging a uniform water phantom injected with 37 MBq of 18F-FDG in a combined PET/MR scanner for 24 min with and without the coil. In the same session, an ultra-short echo time (UTE) image of the coil on top of the phantom was acquired. Using a combination of rigid and non rigid registration, a CT-based attenuation map was registered to the UTE image of the coil for attenuation and scatter correction. After phantom validation, the effect of the carotid coil attenuation and the attenuation correction method were evaluated in five subjects. Phantom studies indicated that the overall loss of PET counts due to the coil was 6.3% with local region-of-interest (ROI) errors reaching up to 18.8%. Our registration method to correct for attenuation from the coil decreased the global error and local error (ROI) to 0.8% and 3.8%, respectively. The proposed registration method accurately captured the location and shape of the coil with a maximum spatial error of 2.6 mm. Quantitative analysis in human studies correlated with the phantom findings, but was dependent on the size of the ROI used in the analysis. MR coils result in significant error in PET quantification and thus attenuation correction is needed. The proposed strategy provides an operator-free method for attenuation and scatter correction for a flexible MRI carotid surface coil for routine clinical use. PMID- 26020274 TI - Emergence of phenotype switching through continuous and discontinuous evolutionary transitions. AB - Bacterial persistence (phenotypic tolerance to antibiotics) provides a prime example of bet-hedging, where normally growing cells generate slow-growing but antibiotic-tolerant persister cells to survive through periods of exposure to antibiotics. The population dynamics of persistence is explained by a phenotype switching mechanism that allows individual cells to switch between these different cellular states with different environmental sensitivities. Here, we perform a theoretical study based on an exact solution for the case of a periodic variation of the environment to address how phenotype switching emerges and under what conditions switching is or is not beneficial for long-time growth. Specifically we report a bifurcation through which a fitness maximum and minimum emerge above a threshold in the duration of exposure to the antibiotic. Only above this threshold, the optimal phenotype switching rates are adjusted to the time scales of the environment, as emphasized by previous theoretical studies, while below the threshold a non-switching population is fitter than a switching one. The bifurcation can be of different type, depending on how the phenotype switching rates are allowed to vary. If the switching rates for both directions of the switch are coupled, the transition is discontinuous and results in evolutionary hysteresis, which we confirm with a stochastic simulation. If the switching rates vary individually, a continuous transition is obtained and no hysteresis is found. We discuss how both scenarios can be linked to changes in the underlying molecular networks. PMID- 26020281 TI - An effective method for substance detection using the broad spectrum THz signal with a "terahertz nose". AB - We propose an effective method for the detection and identification of dangerous substances by using the broadband THz pulse. This pulse excites, for example, many vibrational or rotational energy levels of molecules simultaneously. By analyzing the time-dependent spectrum of the THz pulse transmitted through or reflected from a substance, we follow the average response spectrum dynamics. Comparing the absorption and emission spectrum dynamics of a substance under analysis with the corresponding data for a standard substance, one can detect and identify the substance under real conditions taking into account the influence of packing material, water vapor and substance surface. For quality assessment of the standard substance detection in the signal under analysis, we propose time dependent integral correlation criteria. Restrictions of usually used detection and identification methods, based on a comparison between the absorption frequencies of a substance under analysis and a standard substance, are demonstrated using a physical experiment with paper napkins. PMID- 26020282 TI - Hepatic expression levels of interferons and interferon-stimulated genes in patients with chronic hepatitis C: A phenotype-genotype correlation study. AB - IFNL4 is linked to hepatitis C virus treatment response and type III interferons (IFNs). We studied the functional associations among hepatic expressions of IFNs and IFN-stimulated genes (ISGs), and treatment response to peginterferon and ribavirin. Type I IFNs (IFNA1, IFNB1), type II (IFNG), type III (IFNL1, IFNL2/3), IFNL4 and ISG hepatic expressions were measured by qPCR from in 65 chronic hepatitis C (CHC) patients whose IFNL4-associated rs368234815 and IFNL3 associated rs12989760 genotype were determined. There was a robust correlation of hepatic expression within type I and type III IFNs and between type III IFNs and IFNL4 but no correlation between other IFN types. Expression of ISGs correlated with type III IFNs and IFNL4 but not with type I IFNs. Levels of ISGs and IFNL2/3 mRNAs were lower in IFNL3 rs12979860 CC patients compared with non-CC patients, and in treatment responders, compared with nonresponders. IFNL4-DeltaG genotype was associated with high ISG levels and nonresponse. Hepatic levels of ISGs in CHC are associated with IFNL2/3 and IFNL4 expression, suggesting that IFNLs, not other types of IFNs, drive ISG expression. Hepatic IFNL2/3 expression is functionally linked to IFNL4 and IFNL3 polymorphisms, potentially explaining the tight association among ISG expression and treatment response. PMID- 26020284 TI - Introduced and Native Haplotypes of Echinococcus multilocularis in Wildlife in Saskatchewan, Canada. AB - Recent detection of a European-type haplotype of the cestode Echinococcus multilocularis in a newly enzootic region in British Columbia prompted efforts to determine if this haplotype was present elsewhere in wildlife in western Canada. In coyote (Canis latrans) definitive hosts in an urban region in central Saskatchewan (SK), we found a single haplotype of E. multilocularis that was most similar to a haplotype currently established in the core of this parasite's distribution in Europe and to the European-type haplotype found in coyotes and a dog (Canis lupus familiaris) in British Columbia. We found six haplotypes of E. multilocularis from deer mouse (Peromyscus maniculatus) intermediate hosts in southwestern SK that were closely related to, and one haplotype indistinguishable from, a haplotype previously reported in the adjacent north-central US. This is a higher level of diversity than has previously been recognized for this parasite, which suggests that the population native to central North America is well established, rather than a recent introduction from the Arctic. These findings, in combination with recent cases of alveolar hydatid cysts in dogs in Canada, raise concerns that European haplotypes of E. multilocularis may be increasing in distribution within wildlife in Canada. European haplotypes may pose greater risks to veterinary and human health than native haplotypes long established in central North America. PMID- 26020283 TI - Stress-caused anergy of leukocytes towards Staphylococcal enterotoxin B and exposure transcriptome signatures. AB - Leucocytes from soldiers exposed to battlefield-like stress (RASP: Rangers Assessment and Selection Program) were exposed in vitro to Staphylococcal enterotoxin B (SEB). We assayed SEB-induced regulation of gene expression, both in the presence and absence of severe stress, to generate two sets of gene profiles. One set of transcripts and microRNAs were specific to post-RASP SEB exposure, and another set were signatures of SEB exposure common to both the pre- and post-RASP leucocytes. Pathways and upstream regulatory analyses indicated that the post-RASP SEB-signature transcripts were manifestation of the anergic state of post-RASP leucocytes. These were further verified using expression-based predictions of cellular processes and literature searches. Specificity of the second set of transcripts to SEB exposure was verified using machine-learning algorithms on our and four other (Gene Expression Omnibus) data sets. Cell adhesion, coagulation, hypoxia and vascular endothelial growth factor-mediated vascular leakage were SEB-specific pathways even under the background of severe stress. Hsa-miR-155-3p was the top SEB exposure predictor in our data set, and C X-C motif chemokine ligand 9 was SEB specific in all the analyzed data sets. The SEB-signature transcripts (which also showed distinct expression signatures from Yersinia pestis and dengue virus) may serve as potential biomarkers of SEB exposure even under the background of stress. PMID- 26020285 TI - Using Virtual Pets to Promote Physical Activity in Children: An Application of the Youth Physical Activity Promotion Model. AB - A virtual pet was developed based on the framework of the youth physical activity promotion model and tested as a vehicle for promoting physical activity in children. Children in the treatment group interacted with the virtual pet for three days, setting physical activity goals and teaching tricks to the virtual pet when their goals were met. The virtual pet became more fit and learned more sophisticated tricks as the children achieved activity goals. Children in the control group interacted with a computer system presenting equivalent features but without the virtual pet. Physical activity and goal attainment were evaluated using activity monitors. Results indicated that children in the treatment group engaged in 1.09 more hours of daily physical activity (156% more) than did those in the control group. Physical activity self-efficacy and beliefs served as mediators driving this increase in activity. Children that interacted with the virtual pet also expressed higher intentions than children in the control group to continue physical activity in the future. Theoretical and practical potentials of using a virtual pet to systematically promote physical activity in children are discussed. PMID- 26020287 TI - Influence of Gender on Trunk and Lower Limb Biomechanics during Lateral Movements. AB - This study investigates gender differences in lateral trunk lean to confound possible associations with hip and knee joint biomechanics during lateral reactive jumps. Twelve female and 12 male athletes performed lateral reactive jumps while three-dimensional knee, hip and trunk kinematics as well as ground reaction forces and electromyography of selected thigh muscles were recorded. Lateral trunk lean did not differ between genders, while females had greater knee valgus angle than males (-4.9 +/- 3.9 degrees vs. 1.6 +/- 3.2 degrees , p = 0.001). A significant association between the lateral trunk lean and the hip abduction moment (r = 0.55) was found. Moreover, lateral trunk lean and knee abduction moment showed a significant relationship (r = 0.67). The positive association between trunk lean and knee abduction moment suggests that higher lateral trunk lean may increase the risk of knee injury during lateral movements and that the trunk should be trained accordingly in team sports. PMID- 26020286 TI - High-Throughput Screening of Surface Marker Expression on Undifferentiated and Differentiated Human Adipose-Derived Stromal Cells. AB - Adipose tissue contains an abundant source of multipotent mesenchymal cells termed "adipose-derived stromal cells" (ASCs) that hold potential for regenerative medicine. However, the heterogeneity inherent to ASCs harvested using standard methodologies remains largely undefined, particularly in regards to differences across donors. Identifying the subpopulations of ASCs predisposed toward differentiation along distinct lineages holds value for improving graft survival, predictability, and efficiency. Human ASCs (hASCs) from three different donors were independently isolated by density-based centrifugation from adipose tissue and maintained in culture or differentiated along either adipogenic or osteogenic lineages using differentiation media. Undifferentiated and differentiated hASCs were then analyzed for the presence of 242 human surface markers by flow cytometry analysis. By comprehensively characterizing the surface marker profile of undifferentiated hASCs using flow cytometry, we gained novel insights into the heterogeneity underlying protein expression on the surface of cultured undifferentiated hASCs across different donors. Comparison of the surface marker profile of undifferentiated hASCs with hASCs that have undergone osteogenic or adipogenic differentiation allowed for the identification of surface markers that were upregulated and downregulated by osteogenic or adipogenic differentiation. Osteogenic differentiation induced upregulation of CD164 and downregulation of CD49a, CD49b, CD49c, CD49d, CD55, CD58, CD105, and CD166 while adipogenic differentiation induced upregulation of CD36, CD40, CD146, CD164, and CD271 and downregulation of CD49b, CD49c, CD49d, CD71, CD105, and CD166. These results lend support to the notion that hASCs isolated using standard methodologies represent a heterogeneous population and serve as a foundation for future studies seeking to maximize their regenerative potential through fluorescence-activated cell sorting-based selection before therapy. PMID- 26020288 TI - Voxel-Wise Functional Connectomics Using Arterial Spin Labeling Functional Magnetic Resonance Imaging: The Role of Denoising. AB - The objective of this study was to investigate voxel-wise functional connectomics using arterial spin labeling (ASL) functional magnetic resonance imaging (fMRI). Since ASL signal has an intrinsically low signal-to-noise ratio (SNR), the role of denoising is evaluated; in particular, a novel denoising method, dual-tree complex wavelet transform (DT-CWT) combined with the nonlocal means (NLM) algorithm is implemented and evaluated. Simulations were conducted to evaluate the performance of the proposed method in denoising images and in detecting functional networks from noisy data (including the accuracy and sensitivity of detection). In addition, denoising was applied to in vivo ASL datasets, followed by network analysis using graph theoretical approaches. Efficiencies cost was used to evaluate the performance of denoising in detecting functional networks from in vivo ASL fMRI data. Simulations showed that denoising is effective in detecting voxel-wise functional networks from low SNR data and/or from data with small total number of time points. The capability of denoised voxel-wise functional connectivity analysis was also demonstrated with in vivo data. We concluded that denoising is important for voxel-wise functional connectivity using ASL fMRI and that the proposed DT-CWT-NLM method should be a useful ASL preprocessing step. PMID- 26020289 TI - The history of the German platelet meeting and Stan Heptinstall's contribution to create a "European Platelet Spirit". PMID- 26020290 TI - Correction: fMRI reveals neural activity overlap between adult and infant pain. PMID- 26020292 TI - Pro-Environmental Values Matter in Competitive but Not Cooperative Commons Dilemmas. AB - The choice to conserve or be greedy in a commons dilemma may be influenced by the behavior of others and by pro-environmental values. Participants completed a measure of pro-environmental values one week before taking part in an Internet based commons dilemma microworld consisting of a shared fishery with three computer-controlled virtual fishers whom participants believed to be real people. The three virtual fishers either behaved greedily (taking an unsustainable number of fish each season) or sustainably. In the sustainable scenario, virtual fishers left abundant numbers of fish for the participant and, thus, pro-environmental values were not related to harvesting decisions. However, in the greedy scenario, participants' pro-environmental values significantly predicted sustainable behavior, demonstrating that the influence of others' greediness may be overridden by pro-environmental values. PMID- 26020291 TI - Female mice ultrasonically interact with males during courtship displays. AB - During courtship males attract females with elaborate behaviors. In mice, these displays include ultrasonic vocalizations. Ultrasonic courtship vocalizations were previously attributed to the courting male, despite evidence that both sexes produce virtually indistinguishable vocalizations. Because of this similarity, and the difficulty of assigning vocalizations to individuals, the vocal contribution of each individual during courtship is unknown. To address this question, we developed a microphone array system to localize vocalizations from socially interacting, individual adult mice. With this system, we show that female mice vocally interact with males during courtship. Males and females jointly increased their vocalization rates during chases. Furthermore, a female's participation in these vocal interactions may function as a signal that indicates a state of increased receptivity. Our results reveal a novel form of vocal communication during mouse courtship, and lay the groundwork for a mechanistic dissection of communication during social behavior. PMID- 26020293 TI - Sociodemographic Factors Related to Quality of Life Among Premenopausal Women in Ibadan, Nigeria. AB - Quality of life (QoL) of premenopausal women (PW) was assessed using primary data collected between September and December 2011. A 26-item questionnaire (WHO-QoL BREF) was administered to 285 apparently healthy women selected from two local government areas in Ibadan. The scores were categorized into poor (<= 79.53) and good (>79.53) QoL. Multiple logistic regressions were used to study factors associated with QoL. The mean score for the overall QoL (OQoL) was 65.18 +/- 11.35 (range = 81.25). The Cronbach's alpha for all domains as well as the OQoL were within an acceptable range. The proportion of women with good OQoL was significantly higher in the urban areas (18.2 percent) than in the rural areas (9.2 percent) (p < .05). The proportion of respondents with good OQoL was significantly higher for women aged <20 years (37.5 percent) than older women (p < .01). Teenage participants were almost ten times as likely to have a good social relationship than participants above 35 years of age (odds ratio: 9.52; 95% confidence interval: 1.83-49.40). The authors' results suggest that the WHO QoL BREF is a reliable instrument for measuring QoL among PW in Nigeria. Younger PW and women in the urban areas were more likely to have good QoL. PMID- 26020295 TI - Imaging the Effect of Reactant Rotations on the Dynamics of the Cl + CHD3(v1 = 1, |J,K?) Reaction. AB - The effect of the rotational excitations of CHD3(v1 = 1, |J,K?) in reaction with the Cl atom was investigated in a crossed-beam, product-imaging experiment over the collisional energy (Ec) range 1-6 kcal mol(-1). It was found that the initial J- and K-selections affect only the total reactivity, not the more detailed product-state and angular distributions-a surprising result that defies conventional wisdom. Although the higher reactivity with increasing J states could be understood as a result of a wider range of attack angles near the barrier, the observed K-propensity of sigma|J0? < sigma|JJ? for J = 1 at Ec < 2 kcal mol(-1), opposite to that reported previously at higher Ec's, is perplexing and yet to be explained. PMID- 26020294 TI - Middle-aged adults exhibit altered spatial variations in Achilles tendon wave speed. AB - The purpose of this study was to investigate spatial variations in measured wave speed in the relaxed and stretched Achilles tendons of young and middle-aged adults. Wave speed was measured from the distal Achilles tendon, soleus aponeurosis, medial gastrocnemius aponeurosis and medial gastrocnemius muscle in healthy young (n = 15, aged 25 +/- 4 years) and middle-aged (n = 10, aged 49 +/- 4 years) adults in resting, dorsiflexed and plantarflexed postures. In both age groups, Achilles tendon wave speed decreased proximally, with the lowest wave speed measured in the gastrocnemius aponeurosis. Measured wave speed increased with passive dorsiflexion, reflecting the strain-stiffening behavior of tendons. There were no significant aging effects on wave speed in the free tendon or soleus aponeurosis. However, a significant, inverse relationship between gastrocnemius aponeurosis wave speed and age was observed in the dorsiflexed posture. We also observed significantly lower wave speeds in the gastrocnemius muscles of middle-aged adults when compared with young adults. These results suggest that Achilles tendon compliance increases in a distal-to-proximal pattern, with middle-aged adults exhibiting greater compliance in the distal gastrocnemius muscle and tendinous structures. An age-related change in the spatial variation in Achilles tendon compliance could affect localized tissue deformation patterns and injury potential within the triceps surae muscle-tendon units. PMID- 26020297 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Reproductive success in ruminants: a complex interaction among endocrine, metabolic, and environmental factors. PMID- 26020296 TI - Effects of group housing on sow welfare: a review. AB - Factors that have been shown to impact the welfare of group-housed sows are discussed in this review. Floor space allowance markedly affects sow welfare. In addition to quantity of floor space, the quality of space is important: spatial separation between sows can be provided with visual or physical barriers and stalls. Whereas 1.4 m/sow is insufficient, further research is required to examine space effects in the range of 1.8 to 2.4 m/sow in more detail. The period immediately after mixing has the most pronounced effects on aggression and stress, and therefore, well-designed mixing pens offer the opportunity to reduce aggression, injury, and stress while allowing the social hierarchy to quickly form. Because hunger is likely to lead to competition for feed or access to feeding areas, strategies to reduce hunger between meals through higher feeding levels, dietary fiber, or foraging substrate should be examined. However, feeding systems, such as full-body feeding stalls, can also affect aggression and stress by providing protection at feeding, but deriving conclusions on this topic is difficult because research directly comparing floor feeding, feeding stalls, and electronic sow feeder systems has not been conducted. Familiar sows engage in less aggression, so mixing sows that have been housed together in the previous gestation may reduce aggression. Although there is evidence in other species that early experience may affect social skills later in life, there are few studies on the effects of early "socialization" on aggressive behavior of adult sows. Genetic selection has the potential to reduce aggression, and therefore, continued research on the opportunity to genetically select against aggressiveness and its broader implications is required. Most research to date has examined mixing sows after insemination and knowledge on grouping after weaning is limited. PMID- 26020298 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Uterine infection: linking infection and innate immunity with infertility in the high-producing dairy cow. AB - Uterine contamination with bacteria is ubiquitous in the postpartum dairy cow. Nearly one-half of all postpartum dairy cows develop clinical disease resulting in metritis and endometritis, which cause depressed milk production and infertility. The causative links between uterine infection and infertility include a hostile uterine environment, disrupted endocrine signaling, and perturbations in ovarian function and oocyte development. In this review we consider the various mechanisms linking uterine infection with infertility in the dairy cow, specifically 1) innate immune signaling in the endometrium, 2) alteration in endocrine signaling in response to infectious agents, and 3) impacts of infection on ovarian function, oocyte development, and follicular development. Normal ovarian follicular and oocyte development requires a series of temporally and spatially orchestrated events; however, several of the cellular pathways required for ovarian function are also used during the innate immune response to bacterial pathogens. We propose that activation of cellular pathways during this immune response has a negative impact on ovarian physiology, which is manifest as infertility detected after the clearance of the bacteria. This review highlights how new insights into infection and immunity in cattle are linked to infertility. PMID- 26020299 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Cellular and molecular mechanisms of heat stress related to bovine ovarian function. AB - In light of the intensive genetic selection for high milk production and the onset of global warming, it seems that the reduced fertility of lactating cows during the summer will worsen in coming years. Although not entirely clear, the mechanism appears to be multifactorial in nature. It includes alterations in follicular development, depression of follicular dominance, and impairment of steroidogenesis and gonadotropin secretion. Heat-induced perturbations in the physiology of the follicle-enclosed oocyte have also been documented, expressed by impaired cleavage rate and reduced developmental competence. With respect to the oocyte, alterations include an increase in PUFA in the membrane, reactive oxygen species, ceramide formation and caspase activity, and induction of apoptosis via the sphingomyelin and/or mitochondrial pathways. New insight into cellular and molecular alterations has revealed that heat induces perturbations in both nuclear and cytoplasmic maturation events, such as resumption of meiosis, metaphase II plate formation, cytoskeleton rearrangement, and translocation of cortical granules. Alterations in mitochondrial distribution (i.e., low proportion of category I mitochondria) and function (i.e., low membrane potential) have recently been reported for oocytes collected during the summer. These were associated with impaired expression of both nuclear (succinate dehydrogenase subunit [SDHD], adenosine triphosphate [ATP] synthase subunit beta [ATP5B]), mitochondrially NADH dehydrogenase subunit 2 (ND2), and mitochondiral (cytochrome c oxidase subunit II [MT-CO2] and cytochrome b [MT-CYB]) genes that are crucial in the mitochondrial respiratory chain. In addition, season-induced alteration in the stored maternal mRNA has been documented, expressed by reduced transcript levels (oocyte maturation factor MOS [C-MOS], growth differentiation factor 9 [GDF9], POU domain class 5 transcription factor 1 [POU5F1], and glyceraldehyde-3-phosphate dehydrogenase []GAPDH) in metaphase II stage oocytes and embryos before (i.e., 2-, 4-, and 8-cell stages) and after (i.e., 8- to 16 cell stage) embryonic genome activation. Taken together, the findings indicate an association between cellular and molecular modifications and reduced developmental competence during the hot seasons. Such knowledge is essential for the development of new approaches to cope with this unsolved problem. PMID- 26020300 TI - Yield and quality grade outcomes as affected by molecular breeding values for commercial beef cattle. AB - Although genetic tests for many economically important beef cattle traits are commercially available, additional information is needed to help the industry better understand how the results from these tests translate into phenotypic outcomes. This information has important implications for marker-assisted management. The objective of this research was to determine the relationship between molecular breeding values (MBV) characterizing yield grade and marbling and distributions of phenotypic outcomes for yield grade and quality grade. Using data collected from commercially-fed cattle, mixed-model regression equations were estimated for yield grade and quality grade outcomes for both the full sample of commercial cattle (n= 8,995) and a subsample of black-hided steers (n = 4,790). Significant yield grade (P < 0.01) and marbling (P < 0.01) MBV effects were found. However, the yield grade MBV held up better at predicting phenotypic outcomes than the marbling MBV. Estimated conditional probability mass functions of yield and quality grade outcomes for the general population and black-hided steers were similar. Since distributions for black-hided steers were expected to be more applicable from a management perspective, we focused our analysis on these animals. For example, black-hided steers with "low" genetic potential for yield grade and marbling had about a 29% chance of achieving the base price or better on a price grid (yield grade 3 or lower and quality grade Low Choice or better). Increasing genetic potential for marbling increased the likelihood of achieving this same outcome. However, increasing genetic potential for yield grade was unlikely to increase overall carcass quality given its large deleterious effect on quality grade outcomes. Instead, simultaneous improvements in genetic potential for yield grade and marbling offered much more reliable improvements in overall carcass quality. For example, an animal with "moderate" genetic potential for both yield grade and marbling had a 46% chance of achieving the base price or better on a price grid, and an animal with the maximum observed MBV for these traits had a 66% chance of achieving this same outcome. Although the yield grade MBV held up better at predicting phenotypic outcomes, shifts in the distributions of yield grade and quality grade suggested that these increases were largely determined by the marbling MBV. PMID- 26020301 TI - SNP annotation-based whole genomic prediction and selection: an application to feed efficiency and its component traits in pigs. AB - The study investigated genetic architecture and predictive ability using genomic annotation of residual feed intake (RFI) and its component traits (daily feed intake [DFI], ADG, and back fat [BF]). A total of 1,272 Duroc pigs had both genotypic and phenotypic records, and the records were split into a training (968 pigs) and a validation dataset (304 pigs) by assigning records as before and after January 1, 2012, respectively. SNP were annotated by 14 different classes using Ensembl variant effect prediction. Predictive accuracy and prediction bias were calculated using Bayesian Power LASSO, Bayesian A, B, and Cpi, and genomic BLUP (GBLUP) methods. Predictive accuracy ranged from 0.508 to 0.531, 0.506 to 0.532, 0.276 to 0.357, and 0.308 to 0.362 for DFI, RFI, ADG, and BF, respectively. BayesCpi100.1 increased accuracy slightly compared to the GBLUP model and other methods. The contribution per SNP to total genomic variance was similar among annotated classes across different traits. Predictive performance of SNP classes did not significantly differ from randomized SNP groups. Genomic prediction has accuracy comparable to observed phenotype, and use of genomic prediction can be cost effective by replacing feed intake measurement. Genomic annotation had less impact on predictive accuracy traits considered here but may be different for other traits. It is the first study to provide useful insights into biological classes of SNP driving the whole genomic prediction for complex traits in pigs. PMID- 26020302 TI - Identification of a single SNP that affects the promoter activity in the Moroccan prolific D'man breed. AB - Common Moroccan breeds D'man, Sardi, and Timahdite have been found to differ regarding litter size. D'man is known for its high prolificacy (2-7 lambs), whereas Timahdite and Sardi are normally prolific (1-2 lambs). Here, we aimed to identify genetic variants in the beta promoter and to study the promoter activity amongst these breeds using sequencing for the former and the in vitro luciferase assay for the latter. Sequence analysis revealed 16 genetic variants among these common breeds. Luciferase assay analysis demonstrated a higher promoter activity in D'man compared to the Sardi/Timahdite breeds. A small region of 541 bp was further characterized as possessing a high promoter activity. This region contains 2 palindromic sequences and 7 variants. Based on in silico analysis, only 2 variants at position -559 and -568 were found to be informative. These 2 variants were localized within a region rich in transcription factor binding sites including GATA-1/GATA-2, E4/th1, CP2, and c-Ets. Using site-directed mutagenesis, only the variant at position -559 A/G was found to substantially influence the promoter activity. Taken together, differences in the level of beta transcription among highly and minimally prolific Moroccan breeds were demonstrated and a novel single variant was identified that could explain this difference. PMID- 26020303 TI - Gene expression profiles of hair and wool sheep reveal importance of Th2 immune mechanisms for increased resistance to. AB - Management of gastrointestinal parasites is a critical issue for sheep producers worldwide. Increases in the prevalence of drug-resistant worms have complicated parasite control and increased economic losses. Therefore, other methods of parasite control need to be assessed, including the use of genetically resistant animals in breeding programs. Hair sheep breeds such as the St. Croix have greater parasite resistance than conventional wool breeds. However, the immune mechanisms that control parasite resistance in hair or wool breeds have not yet been fully determined, and information on cytokine expression profiles for both wool sheep selected for increased resistance and hair sheep is limited. Our objective was to investigate gene expression differences in 24 parasite-resistant hair and 24 susceptible wool sheep to identify immune effectors associated with resistance to . One-half of the lambs were infected and sacrificed at 3 or 27 d after infection. Remaining lambs were not infected. Breed differences in expression of genes associated with Th1 and Th2 immune responses in lymph nodes and abomasal tissue were determined. Th2-associated genes included IL-4, IL-13, IL-5, IgE, the alpha chain of the IL-4 receptor, and the alpha chain of the high affinity IgE receptor (FcepsilonRI). Th1-associated genes included interferon gamma (IFN-gamma), the p35 subunit of IL-12 (IL-12 p35), and the beta1 and beta2 chains of the IL-12 receptor (IL-12 Rbeta1 and IL-12 Rbeta2, respectively). In both hair and wool sheep, infection with resulted in greater expression of IgE, IL-13, IL-5, and IL-12 p35 and somewhat reduced expression of IFNgamma in lymph nodes. In abomasal tissue, parasite infection resulted in greater IgE, IL-13, FcepsilonRI, and IL-12 p35 expression in infected lambs compared with control lambs. Between breeds, hair sheep had a stronger Th2 response after infection than wool sheep, with increased expression of IgE and IL-13 and decreased expression of IFNgamma in lymph nodes and increased expression of IL-13 and decreased expression of IL-12 p35 in abomasal tissue. Expression of IL-4 in lymph nodes did not differ between hair and wool lambs, and IL-4, IL-5, IL-12 Rbeta1, and IL-12 Rbeta2 expression was too low to measure at the times sampled in abomasal tissue. PMID- 26020304 TI - Differences in mitochondrial DNA inheritance and function align with body conformation in genetically lean and fat sheep. AB - Body weight and adiposity are determined by the balance between energy intake, energy expenditure, and nutrient deposition. We have identified differences in appetite-regulating peptides in sheep selectively bred to be either lean or fat, wherein gene expression for orexin and melanin-concentrating hormone are elevated in the lean group. Despite this, the underlying mechanisms leading to differences in body composition in the lean and fat lines remains unknown. We measured postprandial temperature in adipose tissue and muscle to ascertain whether a difference in thermogenesis is associated with the difference in body composition in genetically lean (n = 8) and fat (n = 12) ewes. Body weight was higher (P < 0.01) but percent fat mass was lower (P < 0.001) in the lean group. The percent lean mass was similar in lean and fat groups. Animals received intracerebroventricular cannulae and temperature probes implanted into the retroperitoneal fat and the hind-limb skeletal muscle (vastus lateralis). Animals were meal fed (1100-1600 h) to entrain postprandial thermogenesis. Food intake was similar between lean and fat animals. Postprandial thermogenesis was greater (P < 0.05) in the retroperitoneal adipose tissue of lean animals but not in skeletal muscle. Intracerebroventricular infusion of leptin reduced (P< 0.05) food intake by an equal extent in both groups. Postprandial expression of UCP1 mRNA was greater (P < 0.05) in retroperitoneal fat of lean animals, with similar UCP3 expression in skeletal muscle. Mitochondrial genome sequencing indicated haplotypic clustering in lean and fat animals within both the encoding and nonencoding regions. This demonstrates that differences in body composition may be underpinned by differences in thermogenesis, specifically within adipose tissue. Furthermore, thermogenic differences may be associated with specific mitochondrial DNA haplotypes, suggesting a strong genetic component inherited through the maternal lineage. PMID- 26020305 TI - Technical note: Isolation and characterization of ovine brown adipocyte precursor cells. AB - Brown adipose tissue (BAT) plays a critical role in regulating body temperature in newborn lambs. Availability of a stable BAT cell line would be invaluable for biochemical studies to elucidate cellular and molecular mechanisms responsible for nutritional regulation of fetal BAT growth and development. Ovine brown adipocyte precursor cells (BAPC) were isolated from fetal lambs at d 90 of gestation and cultured to establish a stable cell line. These cells were characterized by adipogenic differentiation and expression of a hallmark gene, (). The BAPC doubled every 24 h. After a 9-d induction with a serum-free Dulbecco's modified Eagle Ham/F12 medium, BAPC differentiated into brown adipocytes with large lipid droplets. The differentiation medium induced expression of mRNA and protein in BAPC. Furthermore, after BAPC were passaged 30 times, they maintained similar cell morphology, the potential for adipogenic differentiation, and the ability to express . Taken together, we have established a stable ovine BAPC cell line for studying nutritional regulation of BAT growth and development in the fetus. PMID- 26020306 TI - Measuring the efficacy of flunixin meglumine and meloxicam for lame sows using a GAITFour pressure mat and an embedded microcomputer-based force plate system. AB - Pain associated with lameness on farm is a negative affective state and has a detrimental impact on individual farm animal welfare. Animal pain can be managed utilizing husbandry tools and through pharmacological approaches. Nonsteroidal anti-inflammatory drugs including meloxicam and flunixin meglumine are compounds used in many species for pain management because they are easy to administer, long lasting, and cost-effective. Assessing an animal's biomechanical parameters using such tools as the embedded microcomputer-based force plate system and GAITFour pressure mat gait analysis walkway system provides an objective, sensitive, and precise means to detect animals in lame states. The objectives of this study were to determine the efficacy of meloxicam and flunixin meglumine for pain mitigation in lame sows using the embedded microcomputer-based force plate system and GAITFour pressure mat gait analysis walkway system. Lameness was induced in 24 mature mixed-parity sows using a chemical synovitis model and compared 3 treatments: meloxicam (1.0 mg/kg per os), flunixin meglumine (2.2 mg/kg intramuscular) and sterile saline (intramuscular). Weight distribution (kg) for each foot was collected twice per second for a total of 5 min for each time point using the embedded microcomputer-based force plate system. Stride time, stride length, maximum pressure, activated sensors, and stance time were collected using 3 quality walks (readings) for each time point using the GAITFour pressure mat gait analysis walkway system. Sows administered flunixin meglumine or meloxicam tolerated more weight on their lame leg compared with saline sows (P < 0.005). Sows administered flunixin meglumine or meloxicam had smaller differences in stance time, maximum pressure, and activated sensors between the sound and lame legs compared with saline-treated sows between 37 and 60 h after lameness induction (P < 0.03). In conclusion, flunixin meglumine and meloxicam administration mitigated pain sensitivity in sows after lameness induction when pain sensitivity was evaluated with the embedded microcomputer-based force plate system and GAITFour pressure mat gait analysis walkway system. Analgesic drugs may be a key tool to manage negative pain affective states associated with lameness. PMID- 26020307 TI - Progesterone status, parity, body condition, and days postpartum before estrus or ovulation synchronization in suckled beef cattle influence artificial insemination pregnancy outcomes. AB - Our objective was to assess the effects of progesterone before initiating an estrus- or ovulation-synchronization program in addition to the influence of parity, BCS, and days postpartum on resulting pregnancy rates per AI. Experimental data were combined from 73 herd-year studies consisting of more than 8,500 suckled beef cows exposed to variants of the CO-Synch program. Blood was harvested from samples collected at 10 and 0 d before the onset of CO-Synch, and progesterone concentrations of the samples were determined. The progesterone environment preceding synchronization was assessed in 3 ways on the basis of progesterone concentrations measured in the 2 defined blood samples. All binomial logistic regression models used procedure GLIMMIX in SAS and included the fixed effects of program duration, inclusion of progesterone via an intravaginal insert, parity, days postpartum at AI, BCS, and appropriate interactions. In addition, model 1 included 3 categories of progesterone concentrations (low [<1 ng/mL], medium [1.00 to 3.99 ng/mL], and high [>=4.00 ng/mL] concentrations) at 10 and 0 d before synchronization and their interaction. Model 2 included 4 categories defining the stage of the estrous cycle (late diestrus, early diestrus, and proestrus-estrus-metestrus) or anestrus, at which cows started the synchronization program. Model 3 defined cows as cycling or noncycling at the onset of the program. Significant effects of progesterone supplementation, which hormone was used to initiate the timed AI program, parity, BCS, days postpartum, and progesterone status assessed in 3 ways were consistent in nearly all models. Progesterone status at the onset of synchronization was not important to pregnancy outcomes in multiparous cows, whereas pregnancy rate per AI was suppressed in primiparous cows that began in a low-progesterone environment (proestrus, estrus, metestrus, or anestrus). A significant 3-way interaction of parity, BCS, and days postpartum in 2 models reinforced the importance of these factors to AI pregnancy outcomes. Ancillary analyses identified the significant effects of cycling status and BCS as well as days postpartum on luteolytic response to PGF(2alpha). Pregnancy loss of 2.7% to 4.2% was detected to occur between a positive pregnancy diagnosis at 35 d post-AI and later stages of pregnancy. We concluded that progesterone status at the onset of the synchronization program is critical to pregnancy outcomes in primiparous but not multiparous cows. PMID- 26020308 TI - Stress assessment in captive greylag geese (Anser anser). AB - Chronic stress--or, more appropriately, "allostatic overload"--may be physiologically harmful and can cause death in the most severe cases. Animals in captivity are thought to be particularly vulnerable to allostatic overload due to artificial housing and group makeup. Here we attempted to determine if captive greylag geese (Anser anser), housed lifelong in captivity, showed elevated levels of immunoreactive corticosterone metabolites (CORT) and ectoparasites in dropping samples as well as some hematological parameters (hematocrit, packed cell volume, total white blood cell count [TWBC], and heterophil:lymphocyte ratio [H:L]). All of these have been measured as indicators of chronic stress. Furthermore, we correlated the various stress parameters within individuals. Captive geese showed elevated values of CORT and ectoparasites relative to a wild population sampled in the vicinity of the area where the captive flock is held. The elevated levels, however, were by no means at a pathological level and fall well into the range of other published values in wild greylag geese. We found no correlations between any of the variables measured from droppings with any of the ones collected from blood. Among the blood parameters, only the H:L negatively correlated with TWBC. We examine the problem of inferring allostatic overload when measuring only 1 stress parameter, as there is no consistency between various measurements taken. We discuss the different aspects of each of the parameters measured and the extensive individual variation in response to stress as well as the timing at which different systems respond to a stressor and what is actually measured at the time of data collection. We conclude that measuring only 1 stress parameter often is insufficient to evaluate the well-being of both wild and captively housed animals and that collecting behavioral data on stress might be a suitable addition. PMID- 26020309 TI - Transcript profiles in longissimus dorsi muscle and subcutaneous adipose tissue: a comparison of pigs with different postweaning growth rates. AB - Although most pigs recover rapidly from stresses associated with the transition of weaning, a portion of the population lags behind their contemporaries in growth performance. The underlying biological and molecular mechanisms involved in postweaning differences in growth performance are poorly understood. The objective of this experiment was to use transcriptional profiling of skeletal muscle and adipose tissue to develop a better understanding of the metabolic basis for poor weaned-pig transition. A total of 1,054 pigs was reared in commercial conditions and weighed at birth, weaning, and 3 wk postweaning. Transition ADG (tADG) was calculated as the ADG for the 3-wk period postweaning. Nine pigs from both the lowest 10th percentile (low tADG) and the 60th to 70th percentile (high tADG) were harvested at 3 wk postweaning. Differential expression analysis was conducted in longissimus dorsi muscle (LM) and subcutaneous adipose tissue using RNA-Seq methodology. In LM, 768 transcripts were differentially expressed (DE), 327 with higher expression in low tADG and 441 with higher expression in high tADG pigs (q < 0.10). Expression patterns measured in LM by RNA-Seq were verified in 30 of 32 transcripts using quantitative PCR. No DE transcripts were identified in adipose tissue. To identify biological functions potentially underlying the effects of tADG on skeletal muscle metabolism and physiology, functional annotation analysis of the DE transcripts was conducted using DAVID and Pathway Studio analytic tools. The group of DE genes with lower expression in LM of low tADG pigs was enriched in genes with functions related to muscle contraction, glucose metabolism, cytoskeleton organization, muscle development, and response to hormone stimulus (enrichment score > 1.3). The list of DE genes with higher expression in low tADG LM was enriched in genes with functions related to protein catabolism (enrichment score > 1.3). Analysis of known gene-gene interactions identified possible regulators of these differences in gene expression in LM of high and low tADG pigs; these include forkhead box O1 (FOXO1), growth hormone (GH1), and the glucocorticoid receptor (NR3C1). Differences in gene expression between poor transitioning pigs and their contemporaries indicate a shift to decreased protein synthesis, increased protein degradation, and reduced glucose metabolism in the LM of low tADG pigs. PMID- 26020310 TI - Heat stress impairs mitochondria functions and induces oxidative injury in broiler chickens. AB - The objective of this study was to explore the linkage of oxidative stress occurring in mitochondria, skeletal muscles, and plasma in heat stress-challenged broilers. At d 35, 24 broilers were randomly assigned to 2 treatments: rearing at high temperature (32 +/- 1 degrees C; heat stress group) or normal temperature (21 +/- 1.2 degrees C; control) for 7 d. The oxidative damage of lipid, DNA, and protein and the activities of antioxidative enzymes were measured, respectively, in plasma, skeletal muscles (breast and thigh muscles), and skeletal muscle mitochondria. The result showed that heat exposure increased (P < 0.01) plasma concentrations of thiobarbituric acid reacting substances (TBARS) and 8 hydroxydeoxyguanosine (8-OHdG) whereas it deceased total antioxidant capacity (P < 0.05) and ability to inhibit hydroxyl radicals (AIHR; P< 0.001). Protein carbonyl and TBARS levels were increased (P < 0.001) by heat stress in breast and thigh muscles. In skeletal muscle mitochondria, heat stress increased (P < 0.05) 8-OHdG and suppressed AIHR. Plasma activity of superoxide dismutase (SOD) was increased (P< 0.001) whereas glutathione peroxidase (GSH-Px) was suppressed by heat stress (P < 0.001). Heat exposure increased SOD and catalase activities in breast muscle (P < 0.01) but the reverse was true in thigh muscle (P < 0.05). Glutathione peroxidase was increased in thigh muscle (P < 0.001) but was not changed in breast muscle (P > 0.05). Heat stress increased SOD (P < 0.05) and decreased GSH-Px activities (P < 0.05) of mitochondria regardless of muscle types. Plasma allantoin level increased (P < 0.01) correspondingly with urate (P < 0.001) in heat-stressed broilers, indicating that urate could serve as an antioxidant to enhance the antioxidative capacity during stress in a concentration-dependent manner. The activities of respiratory chain complexes I and III were estimated in skeletal muscle mitochondria. Mitochondrial complex I activity was suppressed (P < 0.01) by heat exposure in breast and thigh muscles but complex III activity was elevated only in breast muscle (P < 0.01) of heat stressed broiler. The fatty acid composition in skeletal muscle was not influenced by heat stress. In conclusion, suppressed mitochondrial complex I activity is associated with oxidative stress induced by heat exposure, which, in turn, is linked with the oxidative damages in muscle tissues and plasma. PMID- 26020311 TI - Low-protein amino acid-supplemented diets for growing pigs: effect on expression of amino acid transporters, serum concentration, performance, and carcass composition. AB - Pigs fed protein-bound AA appear to have a higher abundance of AA transporters for their absorption in the jejunum compared with the duodenum. However, there is limited data about the effect of dietary free AA, readily available in the duodenum, on the duodenal abundance of AA transporters and its impact on pig performance. Forty-eight pigs (24.3 kg initial BW) distributed in 4 treatments were used to evaluate the effect of the CP level and form (free vs. protein bound) in which AA are added to diets on the expression of AA transporters in the 3 small intestine segments, serum concentration of AA, and performance. Dietary treatments based on wheat and soybean meal (SBM) were 1) low-CP (14%) diet supplemented with L-Lys, L-Thr, DL-Met, L-Leu, L-Ile, L-Val, L-His, L-Trp, and L Phe (LPAA); 2) as in the LPAA but with added L-Gly as a N source (LPAA+N); 3) intermediate CP content (16%) supplemented with L-Lys HCl, L-Thr, and DL-Met (MPAA); and 4) high-CP (22%) diet (HP) without free AA. At the end of the experiment, 8 pigs from LPAA and HP were sacrificed to collect intestinal mucosa and blood samples and to dissect the carcasses. There were no differences in ADG, ADFI, G:F, and weights of carcass components and some visceral organs between treatments. Weights of the large intestine and kidney were higher in HP pigs (P < 0.01). Expression of b(0,+) in the duodenum was higher in pigs fed the LPAA compared with the HP diet (P= 0.036) but there was no difference in the jejunum and ileum. In the ileum, y+ L expression tended to be higher in pigs fed the LPAA diet (P = 0.098). Expression of b(0,+) in LPAA pigs did not differ between the duodenum and the jejunum, but in HP pigs, the expression of all AA transporters was higher in the jejunum than in the duodenum or ileum (P < 0.05). The serum concentration of Arg, His, Ile, Leu, Phe, and Val was higher but serum Lys and Met were lower in pigs fed the HP diet (P < 0.05). These results indicate that LPAA can substitute up to 8 percentage units of protein in HP wheat-SBM diets without affecting pig performance; nonessential N does not seem to be limiting in very low-protein wheat-SBM diets for growing pigs. Also, the inclusion of free AA in the diet appears to affect their serum concentration and the expression of the AA transporter b0,+ in the duodenum of pigs. PMID- 26020312 TI - Effects of high-protein or conventional canola meal on growth performance, organ weights, bone ash, and blood characteristics of weanling pigs. AB - An experiment was conducted to evaluate effects of 2 high-protein canola meals (canola meal A [CMA]: 45.69% CP and canola meal B [CMB]: 46.97% CP) and a conventional canola meal (CM-CV: 35.10% CP) on growth performance, organ weights, bone ash, and blood parameters of weanling pigs. Inclusion rates of canola meal (CM) in the diets were 10, 20, 30, or 40% for CMA and CM-CV, whereas inclusions were 10, 20, or 30% for CMB. A control diet containing no CM was also formulated. Therefore, 12 diets were used in this experiment. A total of 420 pigs (initial BW: 9.8 +/- 1.1 kg) were divided into 3 blocks and randomly allotted to 1 of the 12 diets with 8 replicate pens per treatment and 4 or 5 pigs per pen. The ADG, ADFI, and G:F were calculated, and at the conclusion of the experiment, 1 pig in each pen was euthanized to allow measurements of organ weights, collection of blood, and collection of the third and fourth metacarpals from the left foot. Results indicate that ADFI was linearly (P < 0.05) decreased if inclusion of CMA, CMB, or CM-CV was increased. Average daily gain for pigs fed CMA tended to increase quadratically with the maximum response observed at 10 or 20% CM inclusion in the diet ( P= 0.06). However, G:F was linearly (P < 0.05) increased by adding CMA or CM-CV to the diets. Liver weights were also linearly (P < 0.05) increased if pigs were fed diets containing CMB, but kidney weights were linearly (P < 0.05) decreased by the addition of CM-CV to the diets. Thyroid gland weights increased linearly (P < 0.05) for pigs fed diets containing CMA. No differences were observed in heart and bone weights if CM was added to the diets. Addition of any of the 3 CM linearly (P < 0.05) increased bone ash percentage in the metacarpals. Inclusion of CMA or CM-CV linearly (P < 0.05) decreased concentrations of serum triiodothyronine, and the inclusion of CMA also linearly (P < 0.05) decreased serum thyroxine concentrations. No differences were observed for complete blood counts or blood urea nitrogen if CM was added to the diets. In conclusion, up to 20% high-protein CM or CM-CV may be included in diets for weanling pigs from 2 wk postweaning without reducing growth performance or negatively affecting organ, bone, or blood parameters. In some instances, it may also be possible to use greater inclusion rates. PMID- 26020313 TI - Quantitative relationships between standardized total tract digestible phosphorus and total calcium intakes and their retention and excretion in growing pigs fed corn-soybean meal diets. AB - An experiment was conducted to determine the quantitative relationships between standardized total tract digestible P (STTD P) and total Ca intakes with their retention and excretion by growing pigs fed corn-soybean meal diets. Forty-eight crossbred barrows (BW = 22.7 +/- 2.9 kg) were allotted to 1 of 8 diets, housed individually in pens for 3 wk, and then moved to metabolism crates and allowed 4 d for adaptation and 5 d for collection of urine and fecal samples. Eight corn soybean meal diets were formulated for similar NE, fat, and AA concentrations but to increase the STTD P from 0.16 to 0.62% using monocalcium phosphate. Dietary treatments were formulated for a constant Ca:STTD P ratio (2.2:1). The STTD P intake increased (P < 0.001) from 64 to 242% of the daily requirement (4.59 g/d of STTD P). Fecal and total excretion of P and Ca were linearly associated with mineral intake (P < 0.001). Constant urinary P excretion of 0.03 g/d P was observed, but at 4.96 g/d of STTD P intake, the urinary P excretion increased (P < 0.001). In contrast, Ca excretion in urine decreased (P < 0.001) with Ca intake, but constant excretion of 0.40 g/d Ca was reached at 17.97 g/d of Ca intake. The daily intakes of STTD P and Ca moderately explained the variation in urinary excretion of P (R2= 0.41) and Ca (R2= 0.64). The absorption and retention of P increased linearly (P< 0.001) with dietary P intake, whereas absorption and retention of Ca showed a quadratic response (P < 0.001). Absorption and retention of P and Ca were highly predictable from the STTD P and Ca intakes, with of 0.87 and 0.90, respectively. The femur mineral content (FMC) increased by 2.71 g with STTD P intake (P < 0.001) but reached a plateau (29.54 g of FMC) at 8.84 g/d of STTD P intake. The FMC was highly predictable from the STTD P intake (R2 = 0.89). The FMC affected the urinary P excretion ( P< 0.01), but moderately (R2= 0.19) explained the variation in urinary P. In conclusion, constant excretion of P in urine was observed but excretion increased linearly at STTD P intake levels above the requirement for maximum growth of growing pigs. The FMC increased with STTD P intake, but a plateau was reached at a STTD P intake level above the requirement. Dietary STTD P was used for growth and accumulated in bones until a plateau was reached and excess was excreted in urine. The predictability of P and Ca excretion in urine from the dietary STTD P and Ca intakes was moderate. PMID- 26020314 TI - Dietary marker effects on fecal microbial ecology, fecal VFA, nutrient digestibility coefficients, and growth performance in finishing pigs. AB - Use of indigestible markers such as Cr2O3, Fe2O3, and TiO2 are commonly used in animal studies to evaluate digesta rate of passage and nutrient digestibility. Yet, the potential impact of indigestible markers on fecal microbial ecology and subsequent VFA generation is not known. Two experiments utilizing a total of 72 individually fed finishing pigs were conducted to describe the impact of dietary markers on fecal microbial ecology, fecal ammonia and VFA concentrations, nutrient digestibility, and pig performance. All pigs were fed a common diet with no marker or with 0.5% Cr2O3, Fe2O3, or TiO2. In Exp. 1, after 33 d of feeding, fresh fecal samples were collected for evaluation of microbial ecology, fecal ammonia and VFA concentrations, and nutrient digestibility, along with measures of animal performance. No differences were noted in total microbes or bacterial counts in pig feces obtained from pigs fed the different dietary markers while Archaea counts were decreased (P = 0.07) in feces obtained from pigs fed the diet containing Fe2O 3compared to pigs fed the control diet. Feeding Cr2O3, Fe2O3, or TiO2 increased fecal bacterial richness (P = 0.03, 0.01, and 0.10; respectively) when compared to pigs fed diets containing no marker, but no dietary marker effects were noted on fecal microbial evenness or the Shannon-Wiener index. Analysis of denaturing gradient gel electrophoresis gels did not reveal band pattern alterations due to inclusion of dietary markers in pig diets. There was no effect of dietary marker on fecal DM, ammonia, or VFA concentrations. Pigs fed diets containing Cr2O3 had greater Ca, Cu, Fe, and P (P <= 0.02), but lower Ti ( P= 0.08) digestibility compared to pigs fed the control diet. Pigs fed diets containing Fe2O3 had greater Ca (P = 0.08) but lower Ti (P = 0.01) digestibility compared to pigs fed the control diet. Pigs fed diets containing TiO2 had greater Fe and Zn (P <= 0.09), but lower Ti ( P= 0.01) digestibility compared to pigs fed the control diet. In Exp. 2, no effect of dietary marker on pig performance was noted. Overall, the data indicate that the inclusion of Cr2O3, Fe2O3, or TiO2 as digestibility markers have little to no impact on microbial ecology, fecal ammonia or VFA concentrations, nutrient digestibility, or pig growth performance indicating they are suitable for use in digestion studies. PMID- 26020315 TI - Evaluation of soluble corn fiber on chemical composition and nitrogen-corrected true metabolizable energy and its effects on in vitro fermentation and in vivo responses in dogs. AB - Dietary fermentable fiber is known to benefit intestinal health of companion animals. Soluble corn fiber (SCF) was evaluated for its chemical composition, nitrogen-corrected true ME (TMEn) content, in vitro digestion and fermentation characteristics, and in vivo effects on nutrient digestibility, fecal fermentation end products, and modulation of the fecal microbiome of dogs. Soluble corn fiber contained 78% total dietary fiber, all present as soluble dietary fiber; 56% was low molecular weight soluble fiber (did not precipitate in 95% ethanol). The SCF also contained 26% starch and 8% resistant starch and had a TMEn value of 2.6 kcal/g. Soluble corn fiber was first subjected to in vitro hydrolytic-enzymatic digestion to determine extent of digestibility and then fermented using dog fecal inoculum, with fermentative outcomes measured at 0, 3, 6, 9, and 12 h. Hydrolytic-enzymatic digestion of SCF was only 7%. In vitro fermentation showed increased (P < 0.05) concentrations of short-chain fatty acids through 12 h, with acetate, propionate, and butyrate reaching peak concentrations of 1,803, 926, and 112 MUmol/g DM, respectively. Fermentability of SCF was higher (P < 0.05) than for cellulose but lower (P < 0.05) than for pectin. In the in vivo experiment, 10 female dogs (6.4 +/- 0.2 yr and 22 +/- 2.1 kg) received 5 diets with graded concentrations of SCF (0, 0.5, 0.75, 1.0, or 1.25% [as-is basis]) replacing cellulose in a replicated 5 * 5 Latin square design. Dogs were first acclimated to the experimental diets for 10 d followed by 4 d of total fecal collection. Fresh fecal samples were collected to measure fecal pH and fermentation end products and permit a microbiome analysis. For microbiome analysis, extraction of DNA was followed by amplification of the V4 to V6 variable region of the 16S rRNA gene using barcoded primers. Sequences were classified into taxonomic levels using a nucleotide basic local alignment search tool (BLASTn) against a curated GreenGenes database. Few changes in nutrient digestibility or fecal fermentation end products or stool consistency were observed, and no appreciable modulation of the fecal microbiome occurred. In conclusion, SCF was fermentable in vitro, but higher dietary concentrations may be necessary to elicit potential in vivo responses. PMID- 26020316 TI - Serum lipid profiles, total tract nutrient digestibility, and gastrointestinal tolerance by dogs of alpha-cyclodextrin. AB - The objectives were to quantify gastrointestinal tolerance, total tract nutrient digestibility, and serum lipid profiles of dogs as affected by alpha-cyclodextrin (ACD) supplementation and to validate the accuracy of fat analyses techniques using novel ACD-fat complexes. The ACD was hydrolyzed and free sugars and hydrolyzed monosaccharides were quantified using high performance liquid chromatography. Known amount of fats were complexed with ACD, and fat content of complexes were determined using the ether extraction and acid-hydrolyzed fat methods. Nine mixed-breed hounds were used in a crossover design with 3 periods of 10 d each, including 6 d for diet adaptation and 4 d for fecal collection. Dogs were fed twice daily a diet with poultry byproduct meal and brewer's rice as the main ingredients, and chromic oxide (0.2%) was included as a digestion marker. Dogs were supplemented with either 0, 3, or 6 g of ACD diluted in 15 mL of water twice per day for a total of 0, 6, and 12 g ACD per day. The ACD had a very low free sugar concentration and, once hydrolyzed, released only glucose, as expected. Average daily food intake, fecal output (DM basis), and fecal scores were not significantly different among treatments. Body weight and condition score and serum triglycerides and cholesterol concentrations remained unaltered throughout the duration of the experiment. Dry matter, OM, and fat digestibility coefficients were lower (P < 0.05) for both treatment groups compared to the control. The acid-hydrolyzed fat method was valid to measure fat that was bound to ACD. Intake of ACD lowered fat digestibility somewhat but not to the extent previously reported, without affecting serum lipid concentrations or outcomes related to tolerance. Therefore, ACD supplementation resulted in a small decrease in fat digestibility, but ACD supplementation might have potential in modifying serum lipid profiles. PMID- 26020317 TI - Energy concentration and amino acid digestibility in high-protein canola meal, conventional canola meal, and soybean meal fed to growing pigs. AB - Two experiments were conducted to determine DE and ME and the standardized ileal digestibility (SID) of CP and AA in 2 sources of high-protein canola meal (CM-HP1 and CM-HP2), conventional canola meal (CM-CV), and soybean meal (SBM) fed to growing pigs. In Exp. 1, 40 barrows (51.5 +/- 4.0 kg initial BW) were housed in metabolism cages and randomly allotted to 1 of 5 diets with 8 replicate pigs per diet. A corn-based diet (97.4% corn) and 4 diets that contained both corn and each of the 3 sources of canola meal or SBM were formulated. Feces and urine were collected for 5 d after a 5-d adaptation period. The DE and ME were 3,347 and 3,268 kcal/kg in corn, 3,312 and 2,893 kcal/kg in CM-HP1, 3,627 and 3,346 kcal/kg in CM-HP2, 2,798 and 2,492 kcal/kg in CM-CV, and 4,000 and 3,796 kcal/kg in SBM, respectively. Values for DE and ME were greater (P< 0.05) in SBM than in all other ingredients, but DE and ME were greater (P < 0.05) in corn and the 2 high protein canola meals than in CM-CV. The DE and ME were also greater (P< 0.05) in CM-HP2 than in CM-HP1. In Exp. 2, 10 barrows (65.3 +/- 10.4 kg initial BW) were equipped with a T-cannula in the distal ileum and randomly allotted to a replicated 5 * 5 Latin square design with 5 diets and 5 periods in each square. A N-free diet and 4 corn starch-based diets that contained CM-HP1, CM-HP2, CM-CV, or SBM as the sole source of AA were formulated. Each period lasted 7 d and ileal digesta were collected on d 6 and 7 of each period. The SID of CP and all AA except Pro were greater (P < 0.05) in SBM than in the 3 sources of canola meal. With the exception of His and Lys, no differences in SID of indispensable AA were observed among the 3 sources of canola meal. The SID of His and Lys were greater (P < 0.05) in CM-HP1 and CM-HP2 than in CM-CV and the SID of CP was greater (P < 0.05) in CM-HP2 than in CM-CV, but no differences in the SID of indispensable AA were observed between CM-HP1 and CM-HP2. In conclusion, the 2 high-protein canola meals used in this experiment have ME values that are not different from corn but greater than in CM-CV. The SID of most AA is greater in SBM than in canola meals, but SID of His and Lys are greater in high-protein canola meals than in CM-CV. As a consequence, high-protein canola meals supply more ME and SID of AA for growing pigs than CM-CV. PMID- 26020318 TI - The optimum ratio of standardized ileal digestible leucine to lysine for 8 to 12 kg female pigs. AB - The objective of the study was to estimate Leu requirement for weaned piglets to balance indispensable AA in reduced CP diets. A dose-response experiment was conducted to estimate the standardized ileal digestible (SID) Leu to Lys ratio required for the maximum growth of young pigs after weaning. In this study, 96 female pigs (initial BW of 8 kg) were allotted to 1 of 6 dietary treatments with 16 individually penned pigs per treatment. Graded levels of crystalline L-Leu were added to a basal diet to provide diets containing 0.70, 0.80, 0.90, 1.00, 1.10, and 1.20 SID Leu:Lys. Lysine was limiting and fulfilled 90% of the current recommendations. The ADFI, ADG, and G:F were determined during a 2 wk experimental period. Blood and urine samples were taken at the end of each wk. The ADFI increased linearly (P < 0.001) from 0.70 to 0.80 SID Leu:Lys and then remained constant from 0.90 to 1.20 SID Leu:Lys. The ADG showed a quadratic increase ( P= 0.02), as the SID Leu:Lys level increased from 0.70 to 0.90 SID Leu:Lys and did not change further from 0.90 to 1.20 SID Leu:Lys. The G:F increased quadratically (P < 0.001) with increasing SID Leu:Lys level, and the greatest G:F was achieved with pigs receiving the diet with 0.80 SID Leu:Lys. Increasing the dietary SID Leu:Lys resulted in a linear increase in plasma Leu concentration (P < 0.001) and quadratic increases (P < 0.001) in plasma Cys concentration. The plasma concentration of most of the other AA was lowest in pigs receiving the diets with 0.90 to 1.00 SID Leu:Lys. The plasma urea nitrogen concentration tended (P = 0.08) to be lowest in pigs receiving 1.00 SID Leu:Lys, suggesting a more balanced AA profile at this level. Using a curvilinear-plateau model, the SID Leu:Lys requirement was estimated at 0.93 to maximize growth in female pigs weighing 8 to 12 kg. PMID- 26020319 TI - Comparison of three patterns of feed supplementation with live Saccharomyces cerevisiae yeast on postweaning diarrhea, health status, and blood metabolic profile of susceptible weaning pigs orally challenged with Escherichia coli F4ac. AB - The development of effective feeding strategies to reduce the detrimental effect of enterotoxigenic F4ac (ETEC) plays a crucial role in reducing the occurrence of therapeutic intervention with antibiotics in livestock. The ability of CNCM I 4407 (SCC), supplied in different patterns to counteract ETEC infection in weaned pigs, was evaluated. Fifty pigs weaned at 24 d were then divided into 5 groups: control (CO), CO + colistin (AB), CO + 5 * 10(10) cfu of SCC/ kg feed, from d 0 to 21 (PR), CO + 5 * 10(10) cfu of SCC/ kg feed from d 7 to 11 (CM), and CO + 1 shot of 2 * 10(11) cfu of SCC when the first diarrhea appeared (CU). On d 7 postweaning, all the pigs were orally challenged with 10(8) cfu of ETEC. Blood samples were taken from the pigs (d 7, 8, 12, and 21) while the fecal excretion of ETEC was assessed on d 7 and 10. Fecal consistency was scored from 12 h before infection to 144 h postinfection (p.i.). On d 21, the pigs were sacrificed. The in vitro adhesion test on the intestinal villi confirmed individual susceptibility to ETEC, excluding the presence of resistant pigs. Growth performance did not differ between the treatments. Mortality was reduced in the AB group (P< 0.01) and, marginally, in the PR group (P = 0.089) when compared to the CO group. The CO group had a higher fecal score than AB in the period of observation (from P = 0.01 to P< 0.001). Yeast administration reduced the fecal score when compared to the CO group 12 and 48 h p.i. (P = 0.04). Total IgA never differed among the treatments, but the ETEC-specific IgA concentration was lower in the AB group than in CO (P = 0.04) at d 12. Four days p.i., the pigs fed live yeast had reduced ETEC excretion compared with the CO pigs (P = 0.05). Blood concentrations of dodecenoyl-L-carnitine (P < 0.01), glutaryl-L carnitine/hydroxyhex!anoyl-L-carnitine, phosphatidylcholine diacyl and phosphatidylcholine diacyl (P = 0.01 and P< 0.01, respectively), and alpha-amino adipic acid (P < 0.01) were reduced in the AB group compared to the CO group; PR + CM reduced the concentration of sphingomyelin-ceramide (P = 0.02) and increased the concentration of decadienyl-L-carnitine (C10:2; P= 0.02) vs. CO. The CM group had an increased concentration of C10:2 (P < 0.01) compared to the PR group. In conclusion, the administration of live yeast, even in concomitance with ETEC infections, reduces pig illness and mortality. The strain of SCC tested did not show a therapeutic effect. PMID- 26020320 TI - Fermentation and addition of enzymes to a diet based on high-moisture corn, rapeseed cake, and peas improve digestibility of nonstarch polysaccharides, crude protein, and phosphorus in pigs. AB - Fluctuating prices of cereals have led to an interest in alternative ingredients for feed. The aim of this study was to evaluate the effect of fermentation and the addition of nonstarch polysaccharide (NSP)-degrading enzymes on the ileal and total tract digestibility of nutrients of a diet based on locally grown crops. Four diets were fed including a nonfermented liquid standard grower diet (Control) and 3 experimental diets based on high-moisture corn, rapeseed cake, and peas fed as nonfermented liquid feed (nFLF), fermented liquid feed (FLF), or FLF supplemented with an enzyme mixture of beta-glucanase + xylanase + pectinase (FLF+Enz). The FLF was prepared by mixing feed and water (1:2.5, wt/wt) and, once daily, replacing 50% of the mixture with an equal amount of fresh feed and water. The diets were fed to 8 ileal cannulated barrows in a double Latin square design. Ileal digesta and feces were collected after an adaption period of 10 d. Results showed microbiologically good-quality fermented diets. The levels of Enterobacteriaceae were 5.1 to 5.4 log cfu/g in FLF and FLF+Enz vs. 6.3 log cfu/g in nFLF in the ileum and 5.1 to 5.2 log cfu/g in FLF and FLF+Enz vs. 6.3 log cfu/g in nFLF in the feces. Apparent total tract digestibility (ATTD) of CP was increased by fermentation (73.2% in FLF vs. 69.0% in nFLF; P = 0.033), and digestibility of P showed a tendency (P = 0.073) toward an increase. Addition of the enzyme mixture resulted in a pronounced reduction of dietary NSP compared with FLF (12.8% total NSP in FLF+Enz vs. 15.9% total NSP in FLF; P< 0.001), which also led to increased apparent ileal digestibility (AID) of total and insoluble NSP (total NSP, 31.1% in FLF+Enz vs. 13.6% in FLF; P = 0.002). The Control did not, in general, show higher digestibility values than the experimental diet. However, in the cases were it did, fermentation and enzyme addition brought the digestibility to the level of the Control. In conclusion, fermentation increased the ATTD of CP and the AID of P, with the same tendency (P <= 0.07) for the ATTD. Addition of NSP-degrading enzymes resulted in a pronounced reduction in the concentration of NSP in the feed along with increased AID of NSP. Hence, the experimental diet seems to be a possible alternative to a traditional diet for pigs. PMID- 26020321 TI - Effect of dietary supplementation with glycitein during late pregnancy and lactation on antioxidative indices and performance of primiparous sows. AB - The objective of the present study was to investigate the effects of dietary supplementation with glycitein, a major soy isoflavone, during late pregnancy (starting on d 85) and lactation on antioxidative indices and performance in primiparous sows. A total of 227 gilts (Yorkshire * Landrace) were used, and after parturition, piglets were cross-fostered within treatment so that each sow suckled 10 piglets. Gilts were randomly divided into 4 groups on d 85 of pregnancy and thereafter fed the basal diets of gestation or lactation (controls) or those supplemented with 15, 30, or 45 mg/kg diet glycitein. Reproductive performance of the sows, growth of litters, concentration of plasma glycitein, milk composition, and antioxidative indices in sows' plasma and milk, such as the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and the content of malondialdehyde (MDA), were measured. Supplementation of the dam's diets with glycitein increased ADG of piglets (linear, P = 0.003) and weaned BW of litters (linear, P = 0.01) and both variables were approximately 10% greater than controls with the 45 mg/kg treatment. The percentage of milk protein was linearly (P < 0.05) increased on d 1 and 7 of lactation, and milk fat content increased on d 7 and 14 (linear, P< 0.05). All other measured indices of performance were unaffected by supplementation with glycitein (P > 0.05). The glycitein concentration in sow's plasma was linearly (P < 0.0001) elevated. During lactation, linear increases occurred in plasma activities of SOD (P < 0.001) and T-AOC (P < 0.05 to P< 0.001), CAT (d 7 to 18 of lactation, P < 0.05) and GSH-Px (d 7 of lactation, P < 0.05), whereas the content of plasma MDA decreased (linear, P < 0.05) throughout lactation with glycitein supplementation. Activities of CAT and T-AOC in milk were not affected by maternal supplementation with glycitein, but increases in SOD on d 18 of lactation (P< 0.001) and GSH-Px in colostrum (P < 0.05) were observed. The content of MDA in milk was decreased (linear, P< 0.05) at all stages of lactation except d 14. Collectively, the results of this study indicate that dietary supplementation with glycitein in sows during late pregnancy and lactation elevated the antioxidative indices, decreased the content of MDA in sow's plasma and milk, improved milk composition, and enhanced the growth performance of the sucking piglets. PMID- 26020322 TI - Effects of microbial phytase on apparent and standardized total tract digestibility of calcium in calcium supplements fed to growing pigs. AB - An experiment was conducted to test the hypothesis that differences in the apparent total tract digestibility (ATTD) and standardized total tract digestibility (STTD) of Ca exist among Ca supplements and that inclusion of microbial phytase increases the ATTD and STTD of Ca. One hundred and four growing barrows (average initial BW of 17.73 +/- 2.53 kg) were allotted to a randomized complete block design with 13 dietary treatments and 8 pigs per treatment. A basal diet containing corn, cornstarch, potato protein isolate, soybean oil, calcium carbonate, monosodium phosphate, vitamins, and minerals was formulated. Five additional diets were formulated by adding monocalcium phosphate (MCP), dicalcium phosphate (DCP), calcium carbonate, Lithothamnium calcareum Ca, or a high-Ca sugar beet co-product to the basal diet at the expense of cornstarch. Six additional diets that were similar to the previous 6 diets with the exception that they also contained 500 units per kilogram of microbial phytase were also formulated. A Ca-free diet was used to determine basal endogenous losses of Ca. Feces were collected using the marker-to-marker approach. Results indicated that regardless of inclusion of microbial phytase, MCP had the greatest (P < 0.05) ATTD and STTD of Ca. The ATTD and STTD of Ca in DCP were greater (P < 0.05) than in calcium carbonate, L. calcareumC a, or in the sugar beet co-product, but no differences were observed among the ATTD and STTD of Ca in calcium carbonate, L. calcareum Ca, or sugar beet co-product. Inclusion of microbial phytase increased (P < 0.05) the ATTD and STTD of Ca in the diets, but this was not the case in the Ca supplements. Regardless of inclusion of microbial phytase, the ATTD of P was greater ( P< 0.05) in pigs fed basal, MCP, or DCP diets than in pigs fed calcium carbonate, L. calcareum Ca, or the sugar beet co-product, but pigs fed calcium carbonate diets had greater ( P< 0.05) ATTD of P than pigs fed L. calcareumCa or the sugar beet co-product. Regardless of Ca source, inclusion of microbial phytase increased (P < 0.001) the ATTD of P. In conclusion, MCP has the greatest ATTD and STTD of Ca among the calcium supplements used in this experiment, followed by DCP. Basal, MCP, and DCP diets had greater ATTD of P than the other diets, and inclusion of microbial phytase increased the ATTD and STTD of Ca and the ATTD of P in the diets. PMID- 26020323 TI - Influence of distillers grains resulting from a cellulosic ethanol process utilizing corn kernel fiber on nutrient digestibility of lambs and steer feedlot performance. AB - Two experiments evaluated the effects on animal performance of traditional wet distillers grains (T-WDG) compared to cellulosic wet distillers grains (C-WDG) from a new process converting corn kernel fiber into cellulosic ethanol. The resulting coproduct has greater CP and decreased starch and ether extract (EE) concentrations (34.0% CP, 1.6% starch, 7.3% EE) compared to T-WDG (32.5% CP, 5.1% starch, 7.7% EE). In Exp. 1, 10 wethers (34.1 +/- 2.35 kg, SD) were used in a replicated 5 * 5 Latin square to evaluate digestibility of DM, fiber, EE, and N. Diets including a corn-based control with 7.5% T-WDG and 7.5% C-WDG (CORN); 30% or 45% inclusion of T-WDG; and 30% or 45% inclusion of C-WDG. Between CORN, 30% T WDG, 45% T-WDG, or 45% C-WDG, DMI was not different (P >= 0.11), but lambs fed 30% C-WDG had decreased (P <= 0.05) DMI compared to other diets. Compared to CORN and 30% T-WDG, DM digestibility was lesser ( P< 0.05) for 45% T-WDG or 30% C-WDG, while 45% C-WDG has lesser (P <= 0.05) DM digestibility than all other treatments. Digestibility of NDF was not affected by treatment (P= 0.13), and ADF digestibility was not different ( 0.21) between CORN, 30% T-WDG, 30% C-WDG, or 45% C-WDG. However, digestibility of ADF tended to differ (P = 0.06) between 30% T-WDG and 45% C-WDG and was greater (P <= 0.05) in lambs fed 45% T-WDG compared to other treatments. In Exp. 2, 168 steers (421 +/- 23.9 kg, SD) were used in a randomized complete block design to determine the impact of C-WDG or T-WDG on growth performance and carcass characteristics. Diets included a corn-based control (CON), 30% T-WDG (TRAD), 30% C-WDG (CEL), and 18% C-WDG and 12% condensed corn distillers solubles (CEL+CCDS; = 7 pens of 6 steers/pen). Steers fed TRAD had improved (P <= 0.01) ADG, G:F, and HCW compared to steers fed the CON diet. No differences (P >= 0.16) in ADG and HCW were noted for steers fed CEL compared to TRAD; however, steers fed CEL had decreased (P = 0.01) G:F due to increased (P = 0.02) DMI compared to TRAD-fed steers. Steers fed CEL or CEL+CCDS did not differ (P = 0.50) in G:F, but CEL+CCDS-fed steers had lesser (P <= 0.01) DMI and ADG likely due to greater S content of the CEL+CCDS diet. Overall, while DM digestibility of lambs fed 30% C-WDG was lesser than 30% T-WDG, performance of steers finished on C-WDG was similar to those fed T-WDG. However, WDG from the secondary fermentation appeared to have lesser energy than T-WDG, while maintaining similar cattle performance to corn-fed controls. PMID- 26020324 TI - Effect of starch-based supplementation level combined with oil on intake, performance, and methane emissions of growing Nellore bulls on pasture. AB - Intake of tropical grass forages alone is generally insufficient to avoid nutrition imbalances and reduced animal performance; therefore, supplementation is often recommended. The hypothesis of the present study is that when combined with fat, soybean hulls (SH) could replace corn as a source of energy, reducing methane production without affecting animal performance. This study evaluated the effects of starch-based supplementation level combined with oil on intake, digestibility, performance, and methane emissions of growing Nellore bulls (P = 44; initial BW = 250.69 +/- 27 kg) fed cv. Xaraes during the rainy season. There were no interactions between starch level and oil supplementation with regard to intake of DM (P = 0.67), forage DM (P = 0.55), supplement DM (P = 0.14), OM (P = 0.66), CP (P = 0.74), NDF (P = 0.50), ether extract (EE; = 0.47), and GE ( P= 0.68). The intake of EE was greater for animals supplemented with oil than those fed supplements without oil (P < 0.01). There were no interactions between starch level and oil supplementation on digestibility of DM (P= 0.18), OM (P = 0.11), NDF (P= 0.42), and EE (P = 0.14). Moreover, there was interaction between starch and oil supplementation on GE (P < 0.01). Independent of starch level used, the addition of oil decreased the digestibility of OM (P = 0.04) and NDF (P = 0.03). There were no main effects of starch level, oil, or interaction between starch and oil for initial BW (P = 0.10), final BW (P = 0.94), ADG (P = 0.40), feed efficiency (P= 0.37), and carcass gain (P = 0.38). There was no interaction between starch-based supplementation level and oil on methane emissions when expressed in grams per day (P = 0.77), kilograms per year (P = 0.77), grams per kilogram DMI (P = 0.53), and grams per kilogram carcass gain (P= 0.31). There was, however, an interaction (P = 0.04) between starch level and oil on methane emissions when corrected for NDF intake. Additionally, oil decreased enteric methane emission for intake of GE (P = 0.04) and EE (P < 0.01) of animals fed with starch level. Soybean hulls have an estimated feeding value similar to that of corn. The use of oil supplementation may be effective to reduce enteric methane emission of Nellore bulls raised on pasture. PMID- 26020325 TI - Impact of sorting before feeding zilpaterol hydrochloride on feedlot performance and carcass characteristics of yearling steers. AB - Two studies evaluated sorting and feeding zilpaterol hydrochloride (ZH) on feedlot performance and carcass characteristics in randomized block-designed finishing trials. In Exp. 1 (initial BW 342 +/- 10 kg, = 1,000), 5 treatments included an unsorted non-ZH fed negative control (-CON), an unsorted ZH fed positive control (+CON), and 3 treatments in which the heaviest 20% within the pen were sorted and marketed 28 d early and the remaining 80% were fed ZH. The 20% were identified at the beginning (EARLY), 100 d from slaughter (MIDDLE), or 50 d from slaughter (LATE). Because of sorting, the remaining steers in sorted treatments were fed 14 d longer than -CON and +CON. Average days on feed for control treatments were 165 and 173 d for the EARLY, MIDDLE, and LATE treatments. In Exp. 2 (initial BW 376 +/- 29 kg, = 1,400), 4 treatments included -CON; +CON; an early weight sort fed ZH (1-SORT) with the heaviest 20% identified at d 1 and sorted 50 d from harvest and marketed 14 d before -CON and +CON, with the remaining 80% of the pen fed 7 d longer than -CON and +CON; and a 4-way sort 50 d from harvest fed ZH (4-SORT) with steers sorted into HEAVY, MID-HEAVY, MID-LIGHT, and LIGHT groups marketed -14, 0, +7, and +28 d from -CON and +CON, respectively. Average days on feed for control treatments were 154 and 157 d for the 1-SORT and 159 d for 4-SORT. Steers were fed Zilmax at 8.3 mg/kg DM for 20 d followed by a 3 d withdrawal. In Exp. 1, steers fed +CON had 13 kg greater (P < 0.01) HCW than steers fed -CON. Steers sorted EARLY, MIDDLE, and LATE had 28, 25, and 24 kg heavier ( P< 0.01) HCW than -CON steers, respectively. Carcass weight SD was greater (P = 0.01) for +CON than -CON but was not different (P = 0.17) between CON and ZH sorted treatments. Percentage of overweight carcasses (454 kg) was greater (P <= 0.05) in sorted treatments than in -CON. In Exp. 2, HCW for +CON was 15 kg heavier (P < 0.01) than that for -CON, and HCW for 4-SORT was greater (P < 0.02) than that for +CON. Carcass weight SD was not different (P > 0.10) between +CON and -CON, whereas carcass weight SD of 4-SORT was reduced (P < 0.01) compared with that of -CON and +CON. Steers fed ZH had a greater percentage of carcasses over 454 kg than steers fed -CON (P < 0.01). Although not statistically different (P = 0.27), the percentage of carcasses over 454 kg was reduced by 28% for 4-SORT compared with +CON. Feeding ZH increases carcass weight, but sorting reduces variation, allowing further increases in carcass weight while minimizing overweight carcasses. PMID- 26020326 TI - Impact of supplementing vitamin C for 56, 90, or 127 days on growth performance and carcass characteristics of steers fed a 0.31 or 0.59% sulfur diet. AB - The objective was to examine differential timing of vitamin C (VC) supplementation during the finishing period (for the first 56, 90, or 127 d) on performance, VC, and glutathione (GSH) concentrations and carcass traits of steers receiving a 0.31 or 0.59% S diet. Angus steers (n = 42) were stratified to pens by initial BW (304 +/- 13 kg) and GeneMax marbling score (4.3 +/- 0.12), and pens were randomly assigned to 1 of 7 treatments (6 steers/pen and 1 pen/treatment), including a high-S (HS; 0.59% S) control (HS CON), HS CON + 10 g VC?steer(-1)?d(-1) for the first 56 d of the finishing period, HS CON + 10 g VC?steer(-1)?d(-1) for the first 90 d of the finishing period, HS CON + 10 g VC?steer(-1)?d(-1) for the entire 127-d finishing period (HS VC127), low-S (LS; 0.31% S) diet + 10 g VC?steer(-1)?d(-1) for the first 56 d of the finishing period (LS VC56), LS diet + 10 g VC?steer(-1)?d(-1) for the first 90 d of the finishing period, or LS diet + 10 g VC?steer(-1)?d(-1) for the entire 127-d finishing period. Jugular blood and ultrasound measures were taken from all steers before feeding on d 0, 56, 90, and 127, and liver biopsies and ruminal hydrogen sulfide measurements were collected on d 121 or 122. Steers (n = 40) were harvested on d 127, and carcass data were collected. Data were analyzed by ANOVA as a completely randomized design with the fixed effect of treatment. Because individual intake data were collected, steer was the experimental unit. Final BW and ADG were greater (P <= 0.03) and DMI tended (P = 0.09) to be greater in the LS steers compared to HS steers, but G:F did not differ (P = 0.41) by treatment. A treatment * time effect (P = 0.04) for DMI was noted, likely due to lesser DMI between d 91 and 127 for all treatments except the HS VC127 and LS VC56. Plasma VC concentrations of LS steers were less (P = 0.05) than the HS steers. Total (P = 0.06) and reduced (P = 0.03) plasma GSH were greater in HS steers supplemented with VC than the HS CON, but liver GSH were not different due to S or VC (P >= 0.13). The ratio of oxidized to reduced liver GSH was greater (P < 0.01) in HS CON than HS steers supplemented with VC. Marbling score, LM area, KPH, and quality grade were not different (P >= 0.19) due to diet, but LS steers had greater (P = 0.05) back fat than HS steers. In conclusion, steers fed a HS diet had poorer live performance and unexpectedly greater plasma ascorbate concentrations than the LS-fed steers. Interestingly, increasing days of VC supplementation across the HS diets increased GSH indices, suggesting that although HS diets may negatively affect antioxidant capacity of cattle, supplementing VC may help correct this. PMID- 26020327 TI - Effect of barley silage chop length and inoculation on growth performance, feeding behavior, and ruminal acidosis in finishing feedlot steers. AB - The objective of this study was to investigate the effects of chop length and inoculation of barley silage on feeding behavior, rumen fermentation, and growth performance of finishing feedlot steers. Barley forage (22-35% DM) was chopped to a theoretical chop length (TCL) of either 1.0 (short chop; SC) or 2.0 cm (long chop; LC) and ensiled without or with an esterase-producing bacterial inoculant in a 2 * 2 factorial arrangement of treatments with TCL and inoculation as the main factors. The resultant silages were then incorporated into 4 finishing diets and fed to 80 feedlot steers (n = 20) housed in feedlot pens equipped with a GrowSafe system. Each pen consisted of 8 intact and 2 cannulated steers. Feeding behavior and ruminal pH were measured continuously using the GrowSafe system and ruminal indwelling pH probes, respectively. On average, inoculated silages had higher acetic acid concentrations and lower NDF concentrations. Increasing the TCL from 1.0 to 2.0 cm increased DMI by 0.5 kg/d (P = 0.001), but intake was unaffected ( P= 0.56) by inoculation. Feed efficiency and ADG were not affected (P >= 0.46) by TCL, inoculation, or TCL * inoculation interaction. Steers fed LC silage exhibited a reduced eating rate compared to those fed SC silage (8.6 vs. 9.2 kg DM/h) and consequently spent more time (77.5 vs. 70.2 min/(visit?d)) at the feed bunk. Inoculation also reduced the area under the curve and duration of ruminal pH below 5.8, 5.5, and 5.2 for steers fed the LC diet but increased (P <= 0.003) these parameters for those fed the SC diet. It was concluded that incorporation of longer chopped silage into a finishing diet increased DMI, with responses of ruminal pH to inoculation differing between SC and LC silage. Increasing the TCL of barley silage from 1.0 to 2.0 cm may have no additional benefits to finishing feedlot operators as it did not improve rumen function or the growth performance of feedlot steers. PMID- 26020328 TI - Impact of adding Saccharomyces strains on fermentation, aerobic stability, nutritive value, and select lactobacilli populations in corn silage. AB - Bacterial inoculants can improve the conservation and nutritional quality of silages. Inclusion of the yeast Saccharomyces in the diet of dairy cattle has also been reported to be beneficial. The present study assessed the ability of silage to be used as a means of delivering Saccharomyces strains to ruminants. Two strains of Saccharomyces cerevisiae (strain 1 and 3)and 1 strain of Saccharomyces paradoxus (strain 2) were inoculated (10(3) cfu/g) individually onto corn forage that was ensiled in mini silos for 90 d. Fermentation characteristics, aerobic stability, and nutritive value of silages were determined and real-time quantitative PCR (RT-qPCR) was used to quantify S. cerevisiae, S.paradoxus, total Saccharomyces, fungal, and bacterial populations. Fermentation characteristics of silage inoculated with S1 were similar to control silage. Although strain 3 inoculation increased ash and decreased OM contents of silage (P = 0.017), no differences were observed in nutrient composition or fermentation profiles after 90 d of ensiling. Inoculation with Saccharomyces had no detrimental effect on the aerobic stability of silage. In vitro DM disappearance, gas production, and microbial protein synthesis were not affected by yeast inoculation.Saccharomyces strain 1 was quantified throughout ensiling, whereas strain 2 was detected only immediately after inoculation. Saccharomyces cerevisiae strain 3 was quantified until d 7 and detectable 90 d after ensiling. All inoculants were detected and quantified during aerobic exposure. Inoculation with Saccharomyces did not alter lactobacilli populations. Saccharomycetales were detected by RT-qPCR throughout ensiling in all silages. Both S. cerevisiae and S. paradoxus populations increased during aerobic exposure, demonstrating that the density of these yeast strains would increase between the time that silage was removed from storage and the time it was fed. PMID- 26020329 TI - Direct-fed microbials containing lactate-producing bacteria influence ruminal fermentation but not lactate utilization in steers fed a high-concentrate diet. AB - Direct-fed microbials (DFM) have been shown to improve gain and growth efficiency and also modulate ruminal fermentation. In Exp. 1,72 beef steers were used to compare a lactate-producing bacterial (LAB) DFM consisting primarily of Lactobacillus acidophilus and Enterococcus faecium,and a lactate-producing and lactate-utilizing (LAB/LU) DFM consisting primarily of L. acidophilus and Propionibacterium both fed at 10(9) cfu/d. Steers were fed a corn-based finishing diet for 153 d and then slaughtered for collection of carcass characteristics. In Exp. 2, 12 ruminally cannulated steers were fed acorn-based finishing diet and treated with 10(9) cfu/d of LAB DFM. Rumen fluid was sampled on d 14 and 28 over a 12-h period. Steers were ruminally dosed with a 2-L solution of neutralized DL lactate (0.56 M)and Cr-EDTA (13.22 M) 3 h postfeeding on d 15 and 29. Ruminal samples were collected at 10- and 20-minintervals for the first and second hour postdosing. No differences (P >= 0.14) between control (CON) and LAB for DMI, ADG, growth efficiency, or carcass characteristics were observed. Dry matter intake was greater (P = 0.04) for LAB/LU than LAB from d 0 to 28 but did not differ (P >= 0.29) thereafter. Average daily gain was greater (P = 0.04) and efficiency tended(P = 0.06) to be greater for LAB than LAB/LU over the entire 153 d. In Exp. 2, total VFA concentration and molar proportions of butyrate were unaffected(P >= 0.24). Molar proportions of acetate exhibited a DFM by hour interaction (P = 0.04); however, on average, molar proportion of acetate was 4.4% greater for DFM. Conversely, DFM did not affect the molar proportion of propionate (P = 0.39). On average,molar proportions of propionate tended to increase(P = 0.07), and acetate tended to decrease (P = 0.07)across days. Mean daily ruminal pH was similar for CON on d 14 and 28, whereas mean pH increased from d 14 to 28 for DFM (DFM * day; P = 0.08).Minimum pH remained unchanged for CON over time but increased from d 14 to 2 for DFM (DFM * day;P = 0.10). Maximum pH decreased from d 14 to 28 in CON but increased over time with DFM (DFM * day;P = 0.05). DL- and L-lactate utilization were unaffected by DFM (P >= 0.33) or day (P >= 0.50). Although the LAB DFM did not impact growth performance, itd id modulate ruminal fermentation, as evidenced by shifts in ruminal VFA profile and pH; however, DFM did not appear to influence ruminal lactate utilization. PMID- 26020330 TI - Mineral requirements for growth and maintenance of F1 Boer * Saanen male kids. AB - The objective of this study was to determine the net requirements of minerals for the growth and maintenance of intact male F1 Boer * Saanen goat kids in the initial phase of growth. The following 2 experiments were performed: Exp. 1 was performed to determine the net growth requirements for Ca, P, Mg, Na, and K by F1 Boer * Saanen goat kids from 5 to 25 kg of BW and Exp. 2 was performed to determine the maintenance requirements of F1 Boer * Saanen goats from 15 to 25 kg BW. In Exp. 1, 32 intact male goat kids were distributed in a completely randomized design and mineral body composition was fit to an allometric equation in the form of a nonlinear model. To determine the mineral requirements for maintenance in Exp. 2, 21 intact male goat kids were distributed in a randomized block design, where the goat kids were subjected to 3 levels of feed restriction (0, 30, and 60% feed restriction). At the onset of Exp. 2, 7 goat kids were harvested and used to estimate the initial body composition (15 kg BW). Initial body composition was used to calculate the retention of minerals. The maintenance requirements were estimated by regressions obtained from the retention of minerals in the empty body and the intake of the mineral. The concentration of Ca, P, Na, and K in the empty BW decreased by 11, 13, 26, and 23% with the increase in BW from 5 to 25 kg (P < 0.01). As a consequence, our results showed that net requirements of Ca, P, Mg, Na, and K for weight gain decreased by 27.5, 27.8, 4.25, 43.2, and 39.7%, respectively, with the increase in BW from 5 to 25 kg (P < 0.01). The net requirements (g/kg of ADG) decreased from 9.7 to 7.0 for Ca, 6.5 to 4.7 for P, 0.38 to 0.36 for Mg, 0.88 to 0.50 for Na, and 1.9 to 1.2 for K when BW increased from 5 to 25 kg. The daily net requirements for maintenance per kilogram of BW were 38 mg of Ca, 42 mg of P, 1.6 mg of Mg, 5.0 mg of Na, and 19 mg of K. These results for the nutritional requirements of minerals may help to formulate more balanced diets for F1 Boer * Saanen goat kids in the initial growth phase. PMID- 26020331 TI - Antioxidant activity in plasma and rumen papillae development in lambs fed fermented apple pomace. AB - The effect of fermented apple pomace (FAP) on animal health, antioxidant activity (AA), hematic biometry (HBm) and the development of ruminal epithelium were investigated in a study with 24 finishing lambs (BW = 25.4 +/- 3.3 Kg). Lambs were grouped by sex (12 male and 12 female) and fed (n = 6 per group of treatment) a basal fattening diet (Control diet, T1) or the basal diet supplemented to include 10.91% of fermented apple pomace (FAP diet, T2). The animals were kept 56 d in individual metabolic cages, with ad libitum access to water and feed. Two blood samples were collected from each animal on d 0, 28, and 56 to determine AA in plasma and hematic biometry (HBm). Four samples of ruminal tissue were taken postmortem to evaluate the development of ruminal epithelium based on the length (LP) and width (WP) of papillae. AA and HBm data were analyzed with a mixed model (fixed effects: diet, sampling, sex, and their interaction; using the experimental unit nested in the effect of the diet as the random effect). LP and WP were analyzed with a hierarchical model, as simple and nested effects in the sampling site, where the fixed effects were the diet and the sex of the animal and their interaction. There was an effect of diet on AA, which was higher (P < 0.06) in T2 vs. T1 at 56 d (24.34 vs. 21.79 mM Fe2). Leukocytes increased (P < 0.05) from 7.52*10(3) +/- 1.29*10/(3)MUL to 9.14*10(3) +/- 1.24*10(3)/MUL in all the animals in the experiment, with a marked increased (P < 0.05) at 28 d after beginning of the feeding period, with values within the normal range for this species and without effect of the diet (P > 0.05) for the other indicators of HBm. Males' LP was higher in T2 than in T1 (P < 0.05). It was concluded that the use of FAP in the diets of finishing sheep reaped benefits on animal health and the development of rumen epithelium by improving antioxidant activity in plasma and stimulating the growth of papillae. PMID- 26020332 TI - Effects of roughage sources produced in a tropical environment on forage intake, and ruminal and microbial parameters. AB - Our objective was to study the effect of different roughage sources produced in a tropical environment on intake, digestibility, and ruminal parameters of crossbred bulls. Five rumen-fistulated 30-mo-old Holstein * Bos indicus bulls (average BW =459 +/- 32.5 kg) were utilized in a 5 * 5 randomized Latin square design. The experiment consisted of five 19-d experimental periods (10 d for adaptation and 9 d for data collection) and 5 treatments. Experimental diets consisted of corn (Zea mays L.) silage (CS), Brachiaria grass (Brachiaria decumbens Stapf.) silage (BGS), elephant grass (Pennisetum purpureum Schumach.) silage(EGS), Tifton 85 (Cynodon spp.) hay (T85), and fresh sugarcane (Saccharum officinarum L.; SC). Diets were formulated to have approximately 11% CP (DM basis)using a mixture of urea and ammonium sulfate (9:1 ratio) that was diluted in water and then mixed with roughage. Intake, ruminal outflow, digestibility coefficients,ruminal pool, intake, passage (kp) and digestion rates, microbial parameters, and pH data were assessed.D ry matter intake was greater (P < 0.01) for CS compared with SC. Among treatments, lesser (P < 0.01)potentially digestible NDF, ash- and protein-free NDF(apNDF), and digestible ash- and protein free NDF intake values were observed for SC. Ruminal outflows of DM and nonfibrous carbohydrates were lesser (P <0.01) for SC compared with other treatments. Dry matter apparent digestibility and ruminal digestibility did not differ (P > 0.27) among treatments. No differences (P = 0.11) were observed for ruminal apNDF pool and ruminal kp of apNDF (P = 0.06) among treatments. No treatment effect (P > 0.28) was observed for DM and nitrogen of rumen-isolated bacteria, and microbial efficiency was greater (P = 0.02) for BGS among treatments.A treatment * time interaction (P < 0.01) was found for ruminal pH, with a quadratic pattern in terms of time for CS, BGS, EGS, and T85, whereas pH values for CA linearly decreased as a function of time. In summary, these roughages, when supplemented with an additional nitrogen sources, show similar overall apparent digestibility and ruminal pool values, but conversely, bulls fed sugarcane had less overall nutrient intake and lower ruminal outflow and digestion rate values. We conclude that fresh-cut sugarcane, when provided with urea, can affect digestion rate and, consequently, impact nutrient intake. PMID- 26020333 TI - Methane production and methanogen levels in steers that differ in residual gain. AB - Methane (CH4) gas released by cattle isa product of fermentation in the digestive tract. The 2 primary sites of CH4 production in ruminants are the reticulum-rumen complex and the cecum. Methane release from cattle represents a 2% to 12% loss of the energy intake. Reducing the proportion of feed energy lost as CH4 has the potential of improving feed efficiency as well as decreasing the contribution of cattle to greenhouse gas production. Feed intake and growth were measured on 132 fall-born steers for 70 d. Seven steers with extreme positive residual gain (RG) and 7 steers with extreme negative RG whose DMI was within 0.32 SD of the mean intake were selected for subsequent measurements. Enteric CH4 production was measured via indirect calorimetry. Rumen, cecum, and rectal contents were obtained from steers at slaughter for measurement of in vitro CH4 production and methanogen 16S rRNA levels. Enteric CH4 production did not differ (P = 0.11) between the positive RG (112 +/- 13 L/d)and the negative RG (74 +/- 13 L/d) steers. In vitro rumen methane production did not differ between positive RG(64.26 * 10(-5) +/- 10.85 * 10(-5) mmol?g(-1) DM?min(-1)) and negative RG (61.49 * 10(-5) +/- 10.85 * 10(-5) mmol?g(-1)DM?min(-1); P = 0.86). In vitro cecum methane production did not differ between positive RG (4.24 *10(-5) +/- 1.90 * 10(-5) mmol?g(-1) DM?min(-1)) and negative RG (4.35 * 10(-5) +/- 1.90 * 10(-5) mmol?g(-1) DM?min(-1); P = 0.97). Methanogen 16S rRNA as a percentage of the total bacteria16S rRNA did not differ between RG groups (P = 0.18). The methanogen 16S rRNA as a percentage of rumen fluid total bacteria 16S rRNA (5.3% +/-3.1%) did not differ from the methanogen 16S rRNA asa percentage of cecum content total bacteria 16S rRNA(11.8% +/- 3.1%; P = 0.14). The methanogen 16S rRNA as a percentage of the rectum content total bacteria 16SrRNA (0.7% +/- 3.1%) was not different from the rumen content (P = 0.29) but was less than the cecum content(P = 0.01). Methanomicrobiales 16S rRNA as a percentage of total methanogen 16S rRNA did not differ across sample sites (P = 0.81); however, steers with positive RG (10.5% +/- 1.6%) were more numerous than steers with negative RG (5.1% +/- 1.6%; P = 0.02). Cattle that differ in RG at the same DMI do not differ in characteristics associated with CH4 production. PMID- 26020334 TI - Role of rumen butyrate in regulation of nitrogen utilization and urea nitrogen kinetics in growing sheep. AB - Butyrate, a major rumen VFA, has been indirectly linked to enhancement of urea recycling on the basis of increased expression of urea transporter in the rumen epithelia of steers fed a rumen butyrate-enhancing diet. Two studies were conducted to quantify the effect of elevated rumen butyrate concentrations on N balance, urea kinetics and rumen epithelial proliferation. Wether sheep (n= 4), fitted with a rumen cannula, were fed a pelleted ration (~165 g CP/kg DM, 10.3 MJ ME/kg DM) at 1.8 * ME requirement. In Exp. 1, sheep were infused intraruminally with either an electrolyte buffer solution (Con-Buf) or butyrate dissolved in the buffer solution (But-Buf) during 8-d periods in a balanced crossover design. In Exp. 2, sheep were infused intraruminally with either sodium acetate (Na-Ac) or sodium butyrate (Na-But) for 9 d. All solutions were adjusted to pH 6.8 and 8.0 in Exp. 1 and 2, respectively, and VFA were infused at 10% of ME intake. [15N2] urea was continuously infused intravenously for the last 5 d of each period, and total urine and feces were collected. In Exp. 1, 2H5-phenylalanine was continuously infused intravenously over the last 12 h, after which a biopsy from the rumen papillae was taken for measurement of fractional protein synthesis rate (FSR). Butyrate infusion treatments increased (P = 0.1 in Exp. 1; P < 0.05 in Exp. 2) the proportion of rumen butyrate, and acetate infusion increased (P < 0.05) rumen acetate. All animals were in positive N balance (4.2 g N/d in Exp. 1; 7.0 g N/d in Exp. 2), but no difference in N retention was observed between treatments. In Exp. 2, urea entry (synthesis) rate was reduced ( < 0.05) by Na But compared with the Na-Ac control. In Exp. 1, although But-Buf infusion increased the FSR of rumen papillae (35.3% +/- 1.08%/d vs. 28.7% +/- 1.08%/d; P < 0.05), urea kinetics were not altered by But-Buf compared with Con-Buf. These studies are the first to directly assess the role of butyrate in urea recycling and its effects on rumen papillae protein turnover in growing lambs. Under the feeding conditions used and the rate of continuous butyrate infusion into the rumen in the present studies, butyrate does not affect overall N retention in growing sheep. However, butyrate may play a role in the redistribution of urea N fluxes in the overall scheme of N metabolism. PMID- 26020335 TI - Effects of encapsulated nitrate on enteric methane production and nitrogen and energy utilization in beef heifers. AB - The objective of this study was to investigate effects of encapsulated nitrate (EN) on enteric methane emission and N and energy utilization in beef heifers. Eight ruminally-cannulated beef heifers (451 +/- 21 kg BW) were used in a replicated 4 * 4 Latin square design. Four experimental diets were prepared and fed once daily for ad libitum intake: control, 1%, 2%, and 3% EN (0.15, 0.9, 1.5, and 2.5% NO3(-) in dietary DM, respectively). The control diet (55% forage and 45% concentrate) included encapsulated urea, which was gradually replaced with EN for the EN diets (iso-nitrogenous; 12.5% CP). In each period, EN was increased stepwise by 1% every 4 d during adaptation. A 7-d washout period (control diet offered to all heifers) was provided between experimental periods. Dry matter intake tended to decrease (10.4 to 10.1 kg/d; linear, P = 0.06) with EN levels. Enteric methane yield was linearly decreased (21.3 to 17.4 g/kg DMI; P < 0.01) by EN, and methane production (g/d) recovered to the level from heifers fed the control diet on the first day when EN was withdrawn from the diet. Apparent total tract digestibility of DM and OM increased (P = 0.03) or tended to increase (P = 0.06), respectively, with EN levels. Starch digestibility tended to be greater (P = 0.07) for EN vs. CONTROL: The concentrations of rumen ammonia-N and plasma urea N decreased linearly (P < 0.01) with EN. Total urinary N and urea-N excretion as proportions of N intake were linearly decreased (46.3 to 41.4%, = 0.09 and 37.1 to 29.9%, P = 0.01, respectively) with EN addition. However, NO3(-)-N excretion in urine increased linearly (P < 0.01) with EN levels. Fecal N excretion was not affected (P = 0.47) by EN, although fecal NO-N excretion increased linearly (P < 0.01) with inclusion of EN (0.09 to 0.88% of total N, P < 0.01). Retained N tended to be increased (percentage of N intake; 16.6 to 21.4%, = 0.08) by the EN. Supplementary EN lowered (6.64 to 5.46% of GE intake [GEI], P < 0.01) energy losses by enteric methane mitigation, which increased ME supply (calculated; 56.5 to 58.8% of GEI, P = 0.01) without changes in calculated heat production (P = 0.24). As a result, retained energy tended to increase (P = 0.07) with EN levels. In conclusion, feeding EN to beef heifers lowered enteric methane production in a dose-response manner, which slightly increased energy supply. Total urinary N excretion was lowered for EN due to lower urinary urea-N excretion. PMID- 26020336 TI - Effects of encapsulated nitrate on eating behavior, rumen fermentation, and blood profile of beef heifers fed restrictively or ad libitum. AB - A slow-release form of nitrate (encapsulated nitrate [EN]) was investigated for effects on risk of toxicity, feed consumption rates, and feed sorting behavior in 2 experiments. In Exp. 1, 5 beef heifers (806 +/- 72 kg BW) were fed once daily at 75% of ad libitum intake. Supplementary EN (85.6% DM; 71.4% NO3(-) on a DM basis) was increased by 1% every 4 d from 0 to 1.0, 2.0, 2.9, 3.9, 4.8, and 5.8% of dietary DM (from 10.3 to 15.6% CP and 0.11 to 4.8% total NO3(-)). During the study, a heifer was removed due to nitrate poisoning with 59% blood methemoglobin (MetHb; % of total hemoglobin) at 2.9% EN and another due to refusal to eat the 2% EN diet. When dietary EN increased from 0 to 5.8%, DMI (8.8 to 7.6 kg/d; P < 0.001) and feed consumption from 0 to 3 h were decreased (70.3 to 48.6% of total feed offered on an as-is basis; P = 0.001) and feed consumption from 12 to 24 h was increased (0.6 to 22.6%; P < 0.001). Blood MetHb at 1% EN was negligible (<1.5% of total hemoglobin). However, MetHb levels were greater (average 9.8 vs. 3.1% and maximum 23.6 vs. 13.6% at 3 h) at 2.0 and 2.9% EN than at 3.9, 4.8, and 5.8% EN. In Exp. 2, 8 beef heifers (451 +/- 21 kg BW) were used in a replicated 4 * 4 Latin square design and fed for ad libitum intake, once daily, diets containing 0, 1, 2, and 3% EN (isonitrogenous, 12.7% CP, and 0.15 to 2.5% total NO3(-) in dietary DM). Each period consisted of 14 d for adaption and 14 d for sampling followed by a 7-d washout. During adaptation, EN was provided to heifers in a stepwise manner (an increase by 1% every 4 d). In Exp. 2 with ad libitum feeding, feed consumption rates were not different (41.8% of total feed consumed from 0 to 3 h; P = 0.56) among EN levels, but DMI tended to decrease linearly (0 to 3% EN; 10.4 to 10.1 kg/d; P = 0.06) and feed was sorted (linear, P < 0.05) against concentrates (containing EN) with EN inclusion. Potential toxicity of nitrate based on blood MetHb was not observed (all samples <2.0% of total hemoglobin). In both studies, ruminal pH increased numerically (Exp. 1) and significantly (Exp. 2; linear, P = 0.04) with EN. In conclusion, studies indicated that the organoleptic properties of diets containing >3% EN may have caused lower feed intake, reduced feed consumption rates, and feed sorting. In addition, feed consumption rate, which was altered by restrictive or ad libitum feeding, was an important factor affecting the potential toxicity of nitrate (e.g., MetHb). Ad libitum feeding minimized risks of nitrate toxicity. PMID- 26020337 TI - Effects of zilpaterol hydrochloride on growth performance, blood metabolites, and fatty acid profiles of plasma and adipose tissue in finishing steers. AB - The effects of zilpaterol hydrochloride (ZH) on blood metabolites and fatty acid profiles of plasma and adipose tissue were evaluated in crossbred finishing steers (n = 18, BW 639 +/- 12.69 kg) that were stratified by BW and randomly assigned, within strata (block), to receive 0 (control) or 8.33 mg/kg diet DM ZH. Cattle were fed once daily ad libitum in individual feeding pens (9 pens/treatment). Zilpaterol hydrochloride was fed for 23 d and withdrawn 3 d before harvest. Blood samples and measures of BW were taken on d 0, 7, 14, and 21. Concentrations of beta-hydroxybutyrate (BHB), glucose, and lactate were determined from whole blood. Nonesterified fatty acids, urea nitrogen (PUN), glucose, lactate, and long-chain fatty acid (LCFA) concentrations were analyzed from plasma. Postharvest, adipose tissue samples (approximately 20 g) from subcutaneous fat covering the lumbar vertebrae were collected after 48 h of refrigeration and analyzed for LCFA profiles. Feeding ZH decreased DMI by 8% (P = 0.03) but did not affect BW gain or efficiency (P = 0.83 and P = 0.56, respectively). Addition of ZH resulted in greater HCW, dressing percentage, and LM area ( P = 0.02, P = 0.08, and P = 0.07, respectively) but did not influence other carcass traits (P > 0.10). A ZH * d interaction was observed for PUN and whole-blood glucose concentrations (P = 0.06), in which concentrations decreased in cattle receiving ZH. Nonesterified fatty acids, BHB, plasma glucose, whole blood, and plasma lactate concentrations were unaffected by ZH (P > 0.10). Zilpaterol hydrochloride increased plasma concentrations of elaidic (P = 0.03), vaccenic (P = 0.006), and docosapentaenoic acids ( P= 0.08), but LCFA concentrations of adipose tissue were unaffected ( P> 0.10), suggesting no preferential oxidation of specific fatty acids. In conclusion, ZH supplementation decreased PUN concentration possibly due to decreased muscle catabolism, but components of blood related to lipid oxidation were unaffected. PMID- 26020338 TI - Effects of different levels of supplementation of a 50:50 mixture of molasses:crude glycerol on performance, Bermuda grass hay intake, and nutrient digestibility of beef cattle. AB - Two experiments were performed to evaluate the effects of different levels of supplementation with a 50:50 (as-fed) mixture of molasses:crude glycerol on animal performance, total tract digestibility of nutrients, and ruminal in situ degradability of nutrients in beef heifers and steers consuming Tifton 85 Bermuda grass (Cynodon spp.) hay. For Exp. 1, 24 Angus crossbred heifers (380 +/- 31 kg BW) were used in a generalized randomized block design. For Exp. 2, 8 ruminally cannulated Angus crossbred steers (323 +/- 42 kg BW) were used in a 4 * 4 duplicated Latin square design. For both experiments, animals were housed in individual pens at the University of Florida Feed Efficiency Facility, had ad libitum access to Tifton 85 Bermuda grass hay, and were randomly assigned to 1 of 4 treatments: 1) CTRL, no supplementation; 2) SUP1, 0.45 kg/d (as fed) of 50:50 mixture; 3) SUP3, 1.36 kg/d (as fed) of 50:50 mixture; and 4) SUP5, 2.27 kg/d (as fed) of a 50:50 mixture. Individual feed intake was recorded. Total DMI increased linearly (P = 0.005) as the level of supplementation increased. Hay intake ranged from 1.36 (CTRL) to 1.23% (SUP5) of BW, and was not affected (P >= 0.10) by liquid supplementation. Final BW was not affected by liquid supplementation ( >= 0.10). There was a linear increase (P = 0.027) in ADG as the liquid supplementation amounts increased. Liquid supplementation did not affect G:F (P >= 0.10). Apparent total tract digestibility of DM, OM, NDF, and ADF increased linearly (P < 0.001), while CP total tract digestibility decreased linearly (P = 0.002) as the level of supplementation increased. Ruminal pH was decreased linearly (P = 0.012) as the level of supplementation increased. No effect (P >= 0.10) of liquid supplementation was detected on lag time for NDF and ADF content of bermudagrass hay; however, rate of degradation (Kd) of NDF tended (P = 0.076) to be affected cubically by liquid supplementation. In addition, liquid supplementation linearly decreased (P < 0.05) ED of OM, CP, NDF, and ADF. In conclusion, supplementing up to 2.27 kg/d of a 50:50 mixture of molasses:crude glycerol may stimulate microbial growth and fermentative activity, thereby increasing nutrient digestibility. Increased fiber digestion, along with energy supplementation, led to increased ADG in heifers consuming Bermuda grass hay. PMID- 26020339 TI - Effect of early grain feeding of beef steers on postabsorptive metabolism. AB - The objective of this study was to determine the effect of early weaning followed by a period of high-grain feeding on plasma acetate kinetics and signaling protein phosphorylation in LM tissue of growing steers. We hypothesized that early grain feeding would result in altered cell signaling and acetate use to support observed improvements in carcass gain and marbling. Fall-born Angus * Simmental steers were weaned at 106 +/- 4 d of age (early weaned [EW]; n = 6) and fed a high-grain diet for 148 d or remained with their dams (normal weaned [NW]; n = 6) on pasture until weaning at 251 +/- 5 d of age. Both treatments were subsequently combined and grazed on mixed summer pasture to 394 +/- 5 d of age followed by a feedlot ration until harvest at 513 +/- 5 d of age. Longissimus muscle tissue biopsies were collected at 253 +/- 5 and 394 +/- 5 d of age and at harvest. Total and phosphorylated forms of 5' adenosine monophosphate-activated protein kinase (AMPK) and downstream proteins of the mammalian target of rapamycin signaling pathway were determined by western blotting. Eight steers were used to assess acetate clearance at different age points via a bolus infusion of acetate (4 mmol/kg of BW). Early weaned steers had greater (P < 0.05) ADG than NW steers during the early grain feeding period. Phosphorylated to total ratios of ribosomal protein S6 (rpS6) and ribosomal protein S6 kinase 1 (S6K1) were significantly different during the early grain feeding period. Phosphorylated to total ratios of S6K1, rpS6, acetyl-CoA carboxylase, and 4E binding protein 1 and the absolute amount of phosphorylated AMPK were correlated with ADG, explaining 46% of the variance. Acetate clearance rates were less (P < 0.05) and synthesis rates were greater (P = 0.06) in EW steers during early grain feeding. Acetate synthesis rates were also greater (P < 0.05) in NW steers at harvest, suggesting a permanent shift in the gut microflora or gut function in response to the treatment. Neither treatment nor acetate infusion significantly affected plasma glucose or insulin concentrations. Plasma beta-hydroxybutyric acid concentrations increased with acetate infusion (P < 0.05). Based on these results, altered cell signaling during the early grain feeding period likely mediated increased protein deposition, leading to increased carcass weights, but observed changes in acetate appearance and clearance rates do not appear to explain the observed differences in intramuscular fat deposition during the terminal feeding period. PMID- 26020340 TI - Acetate and glucose incorporation into subcutaneous, intramuscular, and visceral fat of finishing steers. AB - The objectives of this study were to assess the effects of early grain feeding on acetate and glucose turnover rates and acetate and glucose preference for palmitate synthesis by subcutaneous fat (SCF), intramuscular fat (IMF), and visceral fat (VF) in finishing steers. Sixteen Angus * Simmental steers were used in the study; 8 were early weaned (EW) and fed a high-grain diet immediately after weaning for 100 or 148 d, and 8 remained with their dams on pasture until weaning at 202 +/- 5 or 253 +/- 5 d of age. Normal weaned (NW) and EW animals were combined and grazed to 374 +/- 5 or 393 +/- 5 d of age, when they were placed on a corn silage-based finishing ration until they achieved a SCF thickness of 1.0 to 1.2 cm (494 +/- 17 d of age for EW steers and 502 +/- 12 d of age for NW steers). Immediately before harvest, steers were continuously infused for 12 h with [2H3] acetate (1.63 mmol/min; n = 8) or [U-13C6] glucose (0.07 mmol/min; n = 8). Blood samples were collected before initiation of infusions and at the end of the infusion from 8 animals or at 1-h intervals for the first 11 h and at 15-min intervals for the last hour of infusion for the other 8 animals. Adipose tissue samples from SCF, IMF, and VF depots were collected at harvest, and lipids were extracted. Plasma enrichments of acetate and glucose and palmitate enrichment in each depot were used to calculate plasma turnover rates and fractional synthesis rates (FSR; % per h) of palmitate from each isotope. Early weaned steers had greater marbling scores compared to NW steers ( P< 0.05). Plasma turnover rates and FSR for EW and NW steers were similar except for SCF, where a greater FSR from acetate was observed for EW steers. It is possible the greater FSR for SCF was due to harvesting the animals at a slightly more advanced stage of conditioning as evidenced by the trend for greater 12th rib fat (P = 0.07). Plasma acetate turnover and palmitate FSR from acetate were much greater (P < 0.05) than the corresponding rates from glucose, supporting the primary role of acetate as an energy source and the primary substrate for lipid synthesis across fat depots. However, FSR from acetate and glucose were not different among depots, suggesting that any potential effects of dietary starch on differential deposition of energy in SCF and IMF are not substrate driven. PMID- 26020341 TI - Effect of castration timing and oral meloxicam administration on growth performance, inflammation, behavior, and carcass quality of beef calves. AB - Beef bull calves (n = 62) were assigned randomly, within sire breed, to 1 of 4 treatments at birth. Treatments were 1) surgical castration near birth, 2) surgical castration near birth with oral administration of meloxicam (1 mg/kg BW), 3) surgical castration at weaning (WNG), or 4) surgical castration at weaning with oral administration of meloxicam (1 mg/kg BW; WMX). A subset of calves (n = 7/treatment group) were selected randomly near birth for blood collection, behavioral analyses, and rectal temperature (RT) records for a 7-d postcastration period on d 0 (birth), 1, 3, and 7, and on d 214 (weaning), 214 + 6 h, 215, 217, 221, and 228. Calf standing and lying activity were monitored from the same subsets by recording x- and y-axis positions of an accelerometer attached to the right metatarsus for 7 d postcastration. Calf BW was recorded throughout the entire production cycle, and carcass data were collected at slaughter. For statistical analyses, bulls left intact at birth were considered a positive control (BUL) for observations that occurred before their treatment application at weaning; likewise, bulls castrated at birth were considered a negative control (STR) during postweaning observations. No difference (P > 0.88) occurred in ADG between treatments throughout the preweaning period (d 0 to 214); however, 56-d postweaning ADG was greatest ( P= 0.02) in STR, intermediate in WMX, and least in WNG. At weaning, haptoglobin (Hp) was greater (P <= 0.005) for WNG and WMX compared to STR on d 214+6 h, 215, and 217, and Hp was greater (P = 0.05) in WNG compared to WMX on d 217. Neutrophils increased (P < 0.001) and red blood cells decreased (P <= 0.03) for WNG and WMX on d 214+6 h and 217, respectively. Postweaning behavior observations indicated that STR calves spent the least proportion of time standing (P = 0.002) when compared to WNG and WMX. Furthermore, WMX calves exhibited a greater proportion of time spent standing (P = 0.03) compared to WNG. Grazing and finishing phase ADG and carcass measurements did not differ (P >= 0.24) across treatments. In this study, surgical castration at weaning, but not near birth, altered the acute phase response, behavior, and growth performance. Oral meloxicam reduced serum Hp and improved ADG briefly when administered to calves castrated at weaning. Oral administration of meloxicam may be efficacious for mitigating some of the stress and inflammation associated with castration of weaning-age bull calves. PMID- 26020342 TI - Trace element concentrations and distributions in the main body tissues and the net requirements for maintenance and growth of Dorper * Hu lambs. AB - A comparative slaughter trial was conducted to estimate the trace element concentrations and distributions in the main body tissues and the net requirements for maintenance and growth of Dorper * Hu crossbred lambs. Thirty five lambs of each gender (19.2 +/- 0.36 kg initial BW) were used. Seven lambs of each gender were randomly chosen and slaughtered at approximately 20 kg BW as the baseline group for measuring initial body composition. Another 7 lambs of each gender were also randomly chosen and offered a pelleted mixed diet for ad libitum intake and slaughtered at approximately 28 kg BW. The remaining 21 sheep of each gender were randomly divided into 3 groups with 7 sheep each and assigned to ad libitum or 40 or 70% of ad libitum intake of a pelleted mixed diet (42:58 concentrate:roughage, DM basis). The 3 groups of each gender were slaughtered when the sheep fed ad libitum reached approximately 35 kg BW. Empty body (head + feet, hide, viscera + blood, and carcass) trace element contents were determined after slaughter. The results showed that the trace elements were mainly distributed in viscera (blood included), except for Zn, which was mainly distributed in the muscle and bone tissues. The net requirements were calculated using the comparative slaughter technique. For males and females, the daily net trace element requirements for maintenance were 356.1 and 164.1 MUg Fe, 4.3 and 3.4 MUg Mn, 42.0 and 29.8 MUg Cu, and 83.5 and 102.0 MUg Zn per kilogram empty body weight (EBW), respectively. Net requirements for growth decreased from 65.67 to 57.27 mg Fe, 0.35 to 0.25 mg Mn, and 3.45 to 2.82 mg Cu and increased from 26.36 to 26.65 mg Zn per kilogram EBW gain (EBWG) for males. Net requirements for growth decreased from 30.66 to 22.14 mg Fe, 0.43 to 0.32 mg Mn, 2.86 to 2.18 mg Cu, and 27.71 to 25.83 mg Zn per kilogram EBWG for females from 20 to 35 kg BW. This study indicated that the net trace element requirements for Dorper * Hu crossbred lambs may be different from those of purebred or other genotypes, and more data are needed for sheep in general. PMID- 26020343 TI - Optimum measurement period for evaluating feed intake traits in beef cattle. AB - The Beef Improvement Federation recommends residual feed intake (RFI) be calculated from 70-d tests preceded by a 21-d adjustment period. Individual animal feed intake and gain measurements are expensive and time consuming, which limits the number of animals available for national genetic evaluation of feed intake. If a shorter test period of comparable accuracy could be used, the cost would decrease and more animals could be tested annually. The objective of this study was to determine if data from shortened tests is equally as predictive of average daily DMI (ADMI) and RFI values from 70-d tests. Feed intake and weight measures were collected after weaning from Bos taurus bulls, steers, and heifers (n = 612) during four 70-d performance tests. For each individual, ADMI and RFI were calculated. Residual feed intake was calculated by regressing ADMI on metabolic midweight (MMWT) and ADG with the effect of breed included where appropriate. Based on four 70-d intake tests, ADMI, RFI, ADG, and MMWT were evaluated using shortened test lengths in a post hoc analysis where shortened test lengths were imposed on the full-period tests. The ADMI, RFI, ADG, and MMWT values from the full 70-d test were regressed on ADMI, RFI, ADG, and MMWT values resulting from the constructed shorter data subsets. The 8 subsets ranged from 14 to 56 d in length. The fixed effects of test, breed, animal's origin, and sex were included in each comparison for ADMI, ADG, and MMWT. Estimates for regression coefficients of ADMI values from a full test on various subsets ranged from 0.63 to 1.02. Likewise, estimated coefficients obtained from the regression of full test RFI, ADG, and MMWT values on subsets ranged from 0.50 to 1.00, 0.09 to 0.85, and 0.48 to 1.02, respectively. We conclude that ADMI values from a 42-d test ( < 0.0001) and RFI values from a 56-d test (P < 0.0001) adequately predict ADMI and RFI when compared to a 70-d test. These results suggest that testing periods of 42 d for determining ADMI and 56 d for RFI could ultimately reduce testing costs and result in collection of data on a larger number of animals per year, in turn resulting in more data for genetic evaluation. PMID- 26020344 TI - Impact of sow and litter characteristics on colostrum yield, time for onset of lactation, and milk yield of sows. AB - The aim of the present study was to estimate the concurrent impact of sow and litter characteristics on sow productivity. Sow productivity was defined as colostrum yield (CY), onset of lactation (the time point when milk secretion increased steeply, approximately 31 h postpartum), transition milk yield (MY; 36 60 h postpartum), and the mean MY in wk 1 to 4 of lactation. Therefore, the study investigated how factors related with sow nutrition, litter characteristics, farrowing characteristics, and composition of mammary secreta affected sow productivity. Data obtained from 5 previous sow experiments were used. The variables describing sow productivity were all defined as dependent variables and Pearson coefficient of correlation was used to examine relations among dependent variables. The results showed that CY was positively correlated with transition MY and MY in wk 1 and 2 of lactation (P < 0.05), and time for onset of lactation was positively correlated with transition MY (P < 0.05) but negatively correlated with MY in wk 1, 2, and 4 of lactation (P < 0.05). Multivariate regression analyses with a backward elimination approach were performed for each dependent variable to investigate relations with characteristics of sow nutrition, litter size, farrowing, and composition of mammary secreta (independent variables). Litter size was positively related with both CY and MY in wk 1 to 4 (P < 0.001). Milk protein concentration was negatively correlated with MY in all 4 wk (P < 0.01), which indicated that high yielding sows were unable to maintain milk protein synthesis during lactation. Additionally, mean intake of ME prepartum ( < 0.05) was included in the regression model for transition MY and the BW of the sow on d 3 was included in the regression model for MY in wk 1 ( P< 0.05). Except litter equlization, none of the observed independent variables were related with time for onset of lactation. In conclusion, when maximizing sow productivity in the future, it may be rewarding to pay attention to sow productivity in the colostrum period and around time for onset of lactation, and special attention should be given to dietary supplies of protein and essential AA. PMID- 26020345 TI - High lifetime and reproductive performance of sows on southern European Union commercial farms can be predicted by high numbers of pigs born alive in parity one. AB - Our objectives were 1) to compare reproductive performance across parity and lifetime performance in sow groups categorized by the number of pigs born alive (PBA) in parity 1 and 2) to examine the factors associated with more PBA in parity 1. We analyzed 476,816 parity records and 109,373 lifetime records of sows entered into 125 herds from 2008 to 2010. Sows were categorized into 4 groups based on the 10th, 50th, and 90th percentiles of PBA in parity 1 as follows: 7 pigs or fewer, 8 to 11 pigs, 12 to 14 pigs, and 15 pigs or more. Generalized linear models were applied to the data. For reproductive performance across parity, sows that had 15 or more PBA in parity 1 had 0.5 to 1.8 more PBA in any subsequent parity than the other 3 PBA groups ( P< 0.05). In addition, they had 2.8 to 5.4% higher farrowing rates in parities 1 through 3 than sows that had 7 or fewer PBA (P < 0.05). However, there were no differences between the sow PBA groups for weaning-to-first-mating interval in any parity (P >= 0.37). For lifetime performance, sows that had 15 or more PBA in parity 1 had 4.4 to 26.1 more lifetime PBA than sows that had 14 or fewer PBA (P < 0.05). Also, for sows that had 14 or fewer PBA in parity 1, those that were first mated at 229 d old (25th percentile) or earlier had 2.9 to 3.3 more lifetime PBA than those first mated at 278 d old (75th percentile) or later (P < 0.05). Factors associated with fewer PBA in parity 1 were summer mating and lower age of gilts at first mating (AFM; P < 0.05) but not reservice occurrences (P = 0.34). Additionally, there was a 2-way interaction between mated month groups and AFM for PBA in parity 1 (P < 0.05); PBA in parity 1 sows mated from July to December increased nonlinearly by 0.3 to 0.4 pigs when AFM increased from 200 to 310 d old (P < 0.05). However, the same rise in AFM had no significant effect on the PBA of sows mated between January and June (P >= 0.17). In conclusion, high PBA in parity 1 can be used to predict that a sow will have high reproductive performance and lifetime performance. Also, the data indicate that the upper limit of AFM for mating between July and December should be 278 d old. PMID- 26020346 TI - Cradle-to-farm gate environmental footprints of beef cattle production in Kansas, Oklahoma, and Texas. AB - A comprehensive national assessment of the sustainability of beef is being conducted by the U.S. beef industry. The first of 7 regions to be analyzed is Kansas, Oklahoma, and Texas. A survey and visits conducted throughout the region provided data on common production practices. From these data, representative ranch and feedyard operations were defined and simulated for the varying climate and soil conditions throughout the region using the Integrated Farm System Model. These simulations predicted environmental impacts of each operation including cradle-to-farm gate footprints for greenhouse gas emissions, fossil-based energy use, nonprecipitation water use, and reactive N loss. Individual ranch and feedyard operations were linked to form 28 representative production systems. A weighted average of the production systems was used to determine the environmental footprints for the region where weighting factors were developed based on animal numbers reported in the survey and agricultural statistics data. Along with the traditional beef production systems, Holstein steer and cull cow production from the dairy industry in the region were also modeled and included. The carbon footprint of all beef produced was 18.3 +/- 1.7 kg CO2 equivalents (CO2e)/kg carcass weight (CW) with the range in individual production systems being 13 to 25 kg CO2e/kg CW. Energy use, water use, and reactive N loss were 51 +/- 4.8 MJ/kg CW, 2,470 +/- 455 L/kg CW, and 138 +/- 12 g N/kg CW, respectively. The major portion of each footprint except water use was associated with the cow calf phase; most of the nonprecipitation water use was attributed to producing feed for the finishing phase. These data provide a baseline for comparison as new technologies and strategies are developed and implemented to improve the sustainability of cattle production. Production information also will be combined with processing, marketing, and consumer data to complete a comprehensive life cycle assessment of beef. PMID- 26020347 TI - Energy supplementation and herbage allowance effects on daily intake in lactating mares. AB - Little is known about how to manage grazing horses, including the thresholds under which energy supplementation is required. Here we investigated the effects of daily herbage allowance (DHA) and energy supplementation (ES) on daily herbage intake in lactating mares of light breeds grazing high-quality regrowth during summer. Three contrasting DHA, low (LOW), medium (MED), and high (HIGH), that is, 35.0, 52.5, and 70.0 g DM?kg BW(-1)?d(-1), respectively, were obtained by adjusting pasture strip width. Eighteen Anglo-Arab and French Saddle lactating mares were either supplemented with 2.6 kg DM barley/d (SUP group; n= 9) or left nonsupplemented (NSUP group; n = 9) throughout the experiment. For 3 successive 2 wk periods, 3 groups of SUP mares (n = 3) and 3 groups of NSUP mares (n = 3) grazed each DHA according to a 3 * 3 Latin square design. Pregrazing sward surface height (SSH) was similar between treatments (26.6 cm), but postgrazing SSH differed significantly between each DHA (2.9, 4.4, and 5.7 cm for LOW, MED, and HIGH, respectively; P < 0.001). Herbage DMI (HDMI) increased linearly from 18.5 to 23.4 g DM?kg BW(-1)?d(-1) with increasing DHA (i.e., 0.13 kg DM eaten/kg DM of herbage offered; P < 0.001) independently of ES and with no significant ES * DHA interaction. This increase in HDMI resulted from an increase in grazing time between LOW (961 min/d) and MED and HIGH (1,021 min/d; P < 0.01) and from an increase in intake rate between LOW and MED (11.8 g DM/min) and HIGH (13.6 g DM/min; P < 0.01). Total digestible DMI (TDDMI) and NE intake (NEI) increased linearly from 12.3 to 15.2 g DM?kg BW?(-1)d(-1) and from 136.6 to 165.8 kJ?kg BW( 1)?d (-1)with increasing DHA (P < 0.001), respectively. Total digestible DMI and NEI were significantly lower for NSUP than for SUP mares: 12.5 vs. 14.9 g DM?kg BW(-1)?d(-1) (P < 0.01) and 134.6 vs. 166.5 kJ?kg BW(-1)?d(-1) (P < 0.001), respectively. Whereas SUP mares always met their energy requirements, NSUP mares no longer met theirs when DHA fell below 66 g DM?kg BW(-1)?d(-1) (i.e., 39 kg DM?mare(-1)?d(-1)). PMID- 26020348 TI - Composition and quality characteristics of carcasses from pigs divergently selected for residual feed intake on high- or low-energy diets. AB - The objective was to determine the extent to which feeding low-energy, high-fiber (LEHF) and high-energy, low-fiber (HELF) diets impacts meat quality and carcass composition of pigs divergently selected for residual feed intake (RFI). Two experiments were conducted in the divergently selected Iowa State University RFI lines: Exp. 1 evaluated carcasses of generation (G) 8 pigs fed on commercial feeders; Exp. 2 evaluated composition, pork quality, sensory, and postmortem proteolysis of pigs fed on electronic single-space feeders in G 8 and 9. Pigs (N = 177) in Exp. 1 were randomly assigned a pen (mixed sex and line; N = 8). Groups (n = 3) of pigs were slaughtered at a mean BW of 121.5 kg. Pigs in Exp. 2 (G8: n = 158; G9: n = 157) were randomly assigned to 1 of 6 pens of each diet per G. Pigs from G8 were slaughtered at a mean BW of 122.5 kg and G9 at a mean of 128.4 kg. Data were analyzed using the mixed procedure of SAS. Fixed effects were line, diet, sex, and all appropriate interactions. Random effects were group, pen, litter, and sire and covariate of off-test BW. For Exp. 2, G was added as a fixed effect and sensory day was added as a random effect when applicable. In Exp. 1, carcasses from low RFI (LRFI) pigs were leaner and had less fat depth (P < 0.01). Carcasses from pigs fed the LEHF diet had a lighter HCW and greater estimated percent lean than pigs fed HELF diet (P < 0.01). In Exp. 2, LRFI pigs on the HELF diet had the greatest loin depth (P < 0.01). Chops from HRFI pigs had greater drip loss, color scores, lean tissue a*, and percent lipid and lesser percent moisture than LRFI ( P< 0.05). Chops from pigs on the LEHF diet had lesser muscle L* values and greater percent moisture than chops from pigs fed the HELF diet (P < 0.05). Chops from LRFI pigs were juicer than those from HRFI pigs (P < 0.05). Protein extracted at d 2 postmortem from LRFI pigs on the LEHF diet had a greater 38 kDa desmin degradation product than protein from LRFI pigs fed the HELF diet (P < 0.05). Day 5 postmortem extracted protein from HRFI pigs had greater 38 kDa desmin degradation product than LRFI (P = 0.05). Pigs fed LEHF (P < 0.01) had adipose with a greater iodine value than adipose from HELF fed pigs. Pork sensory quality from pigs differentially selected for residual feed intake was not influenced by energy content of the diet the pigs were fed. PMID- 26020349 TI - Increased prenatal IGF2 expression due to the porcine intron3-G3072A mutation may be responsible for increased muscle mass. AB - A SNP (IGF2 G3072A) within intron 3 of disrupts a binding site for the repressor zinc finger BED-type containing 6 (ZBED6), leading to increased carcass lean yields in pigs. However, the relative contributions of prenatal as opposed to postnatal increased IGF2 expression are unclear. As muscle fiber number is set at birth, prenatal and neonate skeletal muscle development is critical in determining mature growth potential. Therefore, the objectives of this study were to determine the contributions of hyperplasia and hypertrophy to increased muscle mass and to delineate the effect of the mutation on the expression of myogenic genes during prenatal and postnatal growth. Sows (IGF2 A/A) were bred to a single heterozygous (IGF2 A/G) boar. For fetal samples, sows were euthanized at 60 and 90 d of gestation (d60 and d90) to obtain fetuses. Male and female offspring were also euthanized at birth (0d), weaning (21d), and market weight of approximately 130 kg (176d). At each sampling time, the LM, psoas major (PM), and semitendinosus (ST) muscles were weighed. Samples of the LM were used to quantify the expression of IGF family members, myogenic regulatory factors (MRF), myosin heavy chain isoforms, and growth factors, myostatin, and . Liver samples were used to quantify and expression. At 176d, weights of LM, PM, and ST muscles were all increased approximately 8% to 14% (P < 0.01) in pigs with paternal A (A(Pat)) alleles compared with those with paternal G (G(Pat)) alleles. Additionally, total muscle fiber number in the ST at 176d tended to be greater (P = 0.10), whereas muscle fiber cross-sectional area tended to be reduced ( P= 0.08) in A(Pat) pigs compared with G(Pat) pigs. In addition to the expected 2.7- to 4.5-fold increase (P <= 0.02) in expression in the LM in A(Pat) compared with G(Pat) pigs at postnatal sampling times (21d and 176d), IGF2 expression was also increased (P <= 0.06) 1.4- to 1.5-fold at d90 of gestation and at birth. At d90, expression of myogenic factor 5 (MYF5), a MRF expressed in proliferating myoblasts, in the LM was greater (P = 0.01) in A (Pat) pigs than in G(Pat) pigs. Interestingly, at 21d hepatic expression was greater (P = 0.01), whereas expression decreased (P = 0.01) in A(Pat) pigs compared with G(Pat) pigs; however, there were no differences (P >= 0.18) in hepatic expression between genotypes at 0d and 176d. These data suggest that prenatal hyperplasia of muscle fibers stimulated by increased IGF2 expression may contribute to increased muscle mass of A(Pat) pigs. PMID- 26020350 TI - Beef quality of different portions of the biceps femoris muscle in Bos indicus cattle improved by tumbling with brine. AB - The effect of tumbling with brines on different portions of the biceps femoris muscle was evaluated for the quality of beef from cattle older than 30 mo. Six biceps femoris muscles were divided into portions: origin (OP), insertion 1(IP1), and insertion 2 (IP2). The portions were sliced into steaks and were treated with no tumbling (control), tumbling with brine (BR), and tumbling with brine and hydrolyzed soy protein (BR+HSP). The steaks were vacuum packaged and stored for 1 and 12 d and then analyzed for pH, yield, color, cooking loss, and shear force. The control steaks from the OP had higher (P < 0.05) pH and shear force values and lower (P < 0.05) L* values than the control steaks from IP2. The pH and a* and b* values increased (P < 0.05) and the L* values and cooking loss decreased (P < 0.05) when the steaks were tumbled with BR and BR+HSP. Overall, substantial variation was found for the variables among the different portions of the biceps femoris muscle. Based on the lower lightness (low exudation) and greater yellow and red intensity (less oxidation) of the meat, the tumbling with brines improved the meat quality. However, the hydrolyzed soy protein incorporated into the brine did not increase the effect compared with using the brine alone for most of the variables. PMID- 26020351 TI - Effects of duration of vitamin C supplementation during the finishing period on postmortem protein degradation, tenderness, and meat color of the longissimus muscle of calf-fed steers consuming a 0.31 or 0.59% sulfur diet. AB - High-S (HS) diets have been identified as a causative agent in the development of oxidative stress in cattle, which in postmortem muscle can negatively alter meat quality. Vitamin C (VC) is a potent antioxidant produced endogenously by cattle; however, exogenous supplementation of VC may be useful when HS diets are fed to cattle. The objective of this study was to examine the impact of duration of VC supplementation, for the first 56, 90, or 127 d, during the finishing period on meat color and tenderness of the longissimus thoracis (LT) collected from calf fed steers consuming a 0.31 or 0.59% S diet. Angus steers ( n= 42) were stratified to pens by initial BW (304 +/- 13 kg) and GeneMax marbling score (4.3 +/- 0.12), and each pen was randomly assigned to 1 of 7 treatments (6 steers/pen, 1 pen/treatment), including HS (0.59% S, a combination of dried distillers grains plus solubles and sodium sulfate) control (HS CON), HS CON + 10 g VC.steer.(-1)d( 1) for the first 56 d (HS VC56), 90 d (HS VC90), or 127 d (HS VC127), low S (LS; 0.31% S) + 10 g VC.steer.(-1)d(-1) for the first 56 d (LS VC56), 90 d (LS VC90), or 127 d (LS VC127). Steers were harvested (n = 40) and, after a 24-h chill, rib sections (LT) were collected. pH was determined on each rib section before division into 3 sections for determination of 1) 7-d retail display and color and Warner-Bratzler shear force (WBSF), 2) 14-d WBSF determination, and 3) protein degradation and collagen content (2 d postmortem). Data were analyzed by ANOVA as a completely randomized design, with the fixed effect of treatment. Individual feed intake was recorded, and steer was the experimental unit. The HS steers had a greater and lesser percent of the 80- and 76-kDa subunits of calpain-1 (P <= 0.05), respectively, and tended to have less (P = 0.08) troponin T degradation (d2), and more (P = 0.02) collagen than LS steers. Increasing days of VC supplementation decreased (P = 0.05) the percentage of the 80 kDa subunit of calpain-1 in HS steers but actually increased it in LS steers (P= 0.003). Supplementing VC, regardless of dietary S, did not affect meat collagen, WBSF, or color (P >= 0.12). a* and b* values were greater (P <= 0.05) in the LS treatments compared to the HS treatments. Increasing the days of VC supplementation to steers fed a HS diet appears to alleviate the negative effects of the HS diet on calpain-1 but has no effect on muscle tenderness or meat color. PMID- 26020352 TI - The effect of feeding native warm-season grasses during the stocker phase on meat composition, quality characteristics, and sensory properties of loin steaks from forage-finished cattle. AB - The objective of this research was to determine the quality of beef from cattle that were fed native warm-season grass (NWSG) in the stocker phase and forage finished on tall fescue. Seventy-two British crossbred steers were randomly allotted to 9 pasture plots with 3 different forage treatments that included Bermuda grass (BER), Indian grass monoculture (IND), and big bluestem, little bluestem, and Indian grass (MIX) and forage finished on tall fescue. Two steers were randomly selected from each pasture plot for meat quality analyses (n = 18). Carcasses graded 67% Select for IND and 17% for both BER and MIX treatments, respectively. All other carcasses received quality grades of Standard. Steaks from treatments did not differ (P > 0.05) in sensory attributes, average sensory acceptability, color, tenderness, pH, or bacterial counts at each storage time, with limited differences in aroma, flavor, and texture. The IND steaks had lower cooking loss (P < 0.05) than steaks from the MIX and BER treatments. Steaks from the BER treatment had higher thiobarbituric acid reactive substances values (P < 0.05) after 6 d of storage when compared with steaks from the MIX and IND treatments, which indicated a higher susceptibility to lipid oxidation. Cluster analysis was conducted to group consumers on the basis of their preference and liking of steak from the different forage treatments. On the basis of panelists' acceptability scores, consumers were grouped into 4 clusters. The largest group (60% of consumers) liked all treatments between moderately and very much. In addition, 17% of consumers preferred steaks from the IND treatment over the BER treatment, and 11% of consumers preferred steaks from the BER and IND treatments over steaks from the MIX treatment. Overall, results indicate that high-quality forage-fed beef can be produced when cattle are fed mixed NWSG, Indian grass, or Bermuda grass during the stocker phase and then finished on tall fescue. PMID- 26020353 TI - Carcass composition of market weight pigs subjected to heat stress in utero and during finishing. AB - Objectives were to investigate the effects of prolonged gestational and/or postnatal heat stress on performance and carcass composition of market weight pigs. Pregnant gilts were exposed to gestational heat stress (GHS, 28 degrees C to 34 degrees C, diurnal) or thermal neutral (18 degrees C to 22 degrees C, diurnal) conditions during the entire gestation or during the first or second half of gestation. At 14 wk of age (58 +/- 5 kg), barrows were housed in heat stress (32 degrees C, HS) or thermal neutral (21 degrees C, TN) conditions. Feed intake and BW were recorded weekly, and body temperature parameters were monitored twice weekly until slaughter (109 +/- 5 kg). Organs were removed and weighed, and loin eye area (LEA) and back fat thickness (BF) were measured after carcass chilling. Carcass sides were separated into lean, separable fat, bone, and skin components and were weighed. Moisture, lipid, and protein content were determined in the LM at the 10th rib. Data were analyzed using a split plot with random effect of dam nested within gestational treatment. Carcass measurements included HCW as a covariate to control for weight. Planned orthogonal contrast statements were used to evaluate the overall effect of GHS in the first half, second half, or any part of gestation. Gestational heat stress did not alter postnatal performance or most body temperature parameters (P > 0.10). However, ADFI in the finishing period was increased (P < 0.05) in response to GHS, particularly in pigs receiving GHS in the first half of gestation. Gestational heat stress during the first half of gestation decreased head weight as a percent of BW (P = 0.02), whereas GHS in the second half of gestation decreased bone weight as a percent of BW (P = 0.02). Heat stress reduced ADG, BW, and HCW (P < 0.0001). Lean tissue was increased in HS pigs on both a weight and percentage basis (P < 0.0001), but LEA was similar to TN carcasses (P = 0.38). Carcasses from HS barrows also had less carcass separable fat (P < 0.01) and tended to have less BF (P = 0.06) compared with those from TN barrows, even after controlling for HCW. However, percent intramuscular fat did not differ between treatments (P = 0.48). The LM from HS carcasses had a greater moisture to protein ratio (P = 0.04). HS barrows also had decreased heart (P < 0.001) and kidney (P < 0.0001) as a percent of BW compared with TN pigs. In summary, GHS may affect head and bone development, subsequently affecting carcass composition. Chronic HS during finishing results in longer times to reach market weight and a leaner carcass once market weight is achieved. PMID- 26020354 TI - Feeding frequency, but not dietary water content, affects voluntary physical activity in young lean adult female cats. AB - The objective of this study was to investigate whether increased dietary water content and feeding frequency increased voluntary physical activity of young, lean adult female cats. A replicated 4 * 4 Latin square design with a 2 * 2 factorial treatment arrangement (feeding frequency and water content) was used. The 4 treatments consisted of 1 meal daily dry pet food without added water (1D; 12% moisture as is), 1 meal daily dry pet food with added water (1W; 70% total water content), 4 meals daily dry pet food without added water (4D; 12% moisture as is), and 4 meals daily dry pet food with added water (4W; 70% total water content). Eight healthy adult, lean, intact, young, female domestic shorthair cats were used in this experiment. Voluntary physical activity was evaluated using Actical activity monitors placed on collars and worn around the cats' necks for the last 7 d of each experimental period of 14 d. Food anticipatory activity (FAA) was calculated based on 2 h prior to feeding periods and expressed as a percentage of total daily voluntary physical activity. Increased feeding frequency (4 vs. 1 meal daily) resulted in greater average daily activity (P = 0.0147), activity during the light period (P = 0.0023), and light:dark activity ratio (P = 0.0002). In contrast, physical activity during the dark period was not altered by feeding frequency (P > 0.05). Cats fed 4 meals daily had increased afternoon FAA (P= 0.0029) compared with cats fed once daily. Dietary water content did not affect any measure of voluntary physical activity. Increased feeding frequency is an effective strategy to increase the voluntary physical activity of cats. Thus, it may assist in the prevention and management of obesity. PMID- 26020355 TI - Synthesis and Characterization of Rare Earth Corrole-Phthalocyanine Heteroleptic Triple-Decker Complexes. AB - We recently reported the first example of a europium triple-decker tetrapyrrole with mixed corrole and phthalocyanine macrocycles and have now extended the synthetic method to prepare a series of rare earth corrole-phthalocyanine heteroleptic triple-decker complexes, which are characterized by spectroscopic and electrochemical methods. The examined complexes are represented as M2[Pc(OC4H9)8]2[Cor(ClPh)3], where Pc = phthalocyanine, Cor = corrole, and M is Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), or Tb(III). The Y(III) derivative with OC4H9 Pc substituents was obtained in too low a yield to characterize, but for the purpose of comparison, Y2[Pc(OC5H11)8]2[Cor(ClPh)3] was synthesized and characterized in a similar manner. The molecular structure of Eu2[Pc(OC4H9)8]2[Cor(ClPh)3] was determined by single-crystal X-ray diffraction and showed the corrole to be the central macrocycle of the triple-decker unit with a phthalocyanine on each end. Each triple-decker complex undergoes up to eight reversible or quasireversible one-electron oxidations and reductions with E1/2 values being linearly related to the ionic radius of the central ions. The energy (E) of the main Q-band is also linearly related to the radius of the metal. Comparisons are made between the physicochemical properties of the newly synthesized mixed corrole-phthalocyanine complexes and previously characterized double- and triple-decker derivatives with phthalocyanine and/or porphyrin macrocycles. PMID- 26020356 TI - Occupational Embeddedness, Perceived Risk, and the Quality of Reach Motion in Females Aged 7 to 9 Years. AB - The perceived meaning ascribed to objects can influence the motor control efficiency in adults when reaching. However, little is known whether the same phenomenon occurs in pediatric females. Twenty-seven girls aged 7 to 9 years recruited from Girl Scout Brownie troupes and afterschool programs were asked to reach for plastic and porcelain teacups in the context of a "tea party" scenario. No differences were found in most of the motion capture variables (p > .05), and effect sizes were small. It is likely that the perceived meaning of the tea party was so robust that it overwhelmed any perceived differences inherent between the two conditions. Future research is needed to clarify the age at which children can qualitatively discern meaningful differences between objects. PMID- 26020357 TI - Concise Synthesis of the Tricyclic Core of Salimabromide. AB - A concise synthesis of the tricyclic core 2 of the structurally unique marine myxobacterial natural product salimabromide has been developed. Compound 2 contains the tetraline subunit including the two quaternary centers and the eight membered ring of salimabromide. Major features for its synthesis include a Lewis base catalyzed Denmark-crotylation for stereoselective construction of the highly hindered quaternary stereocenter, an innovative iodine/selectfluor induced endo carbocylization, and a unique chemoselective carbonylative lactonization of the eight-membered ring. PMID- 26020358 TI - Nucleation and temperature-driven phase transitions of silicene superstructures on Ag(1 1 1). AB - Silicene grown on Ag(1 1 1) is characterized by several critical parameters. Among them, the substrate temperature plays a key role in determining the morphology during growth. However, an unexpected important role is also equally played by the post-deposition annealing temperature which determines the self organization of silicene domains even in the submonolayer coverage regime and consecutive transitions between silicene with different periodicity. These temperature-driven phase transitions can be exploited to select the desired majority silicene phase, thus allowing for the manipulation of silicene properties. PMID- 26020359 TI - Toward Biofunctional Microneedles for Stimulus Responsive Drug Delivery. AB - Microneedles have recently been adopted for use as a painless and safe method of transdermal therapeutic delivery through physically permeating the stratum corneum. While microneedles create pathways to introduce drugs, they can also act as conduits for biosignal sensing. Here, we explore the development of microneedles as both biosensing and drug delivery platforms. Microneedle sensors are being developed for continuous monitoring of biopotentials and bioanalytes through the use of conductive and electrochemically reactive biomaterials. The range of therapeutics being delivered through microneedle devices has diversified, while novel bioabsorbable microneedles are undergoing first-in-human clinical studies. We foresee that future microneedle platform development will focus on the incorporation of biofunctional materials, designed to deliver therapeutics in a stimulus responsive fashion. Biofunctional microneedle patches will require improved methods of attaching to and conforming to epithelial tissues in dynamic environments for longer periods of time and thus present an assortment of new design challenges. Through the evolution of biomaterial development and microneedle design, biofunctional microneedles are proposed as a next generation of stimulus responsive drug delivery systems. PMID- 26020360 TI - Modeling the Histidine-Phenylalanine Interaction: The NH...pi Hydrogen Bond of Imidazole.Benzene. AB - NH...pi hydrogen bonds occur frequently between the amino acid side groups in proteins and peptides. Data-mining studies of protein crystals find that ~80% of the T-shaped histidine...aromatic contacts are CH...pi, and only ~20% are NH...pi interactions. We investigated the infrared (IR) and ultraviolet (UV) spectra of the supersonic-jet-cooled imidazole.benzene (Im.Bz) complex as a model for the NH...pi interaction between histidine and phenylalanine. Ground- and excited state dispersion-corrected density functional calculations and correlated methods (SCS-MP2 and SCS-CC2) predict that Im.Bz has a Cs-symmetric T-shaped minimum energy structure with an NH...pi hydrogen bond to the Bz ring; the NH bond is tilted 12 degrees away from the Bz C6 axis. IR depletion spectra support the T shaped geometry: The NH stretch vibrational fundamental is red shifted by -73 cm( 1) relative to that of bare imidazole at 3518 cm(-1), indicating a moderately strong NH...pi interaction. While the S0(A1g) -> S1(B2u) origin of benzene at 38 086 cm(-1) is forbidden in the gas phase, Im.Bz exhibits a moderately intense S0 > S1 origin, which appears via the D(6h) -> Cs symmetry lowering of Bz by its interaction with imidazole. The NH...pi ground-state hydrogen bond is strong, De=22.7 kJ/mol (1899 cm-1). The combination of gas-phase UV and IR spectra confirms the theoretical predictions that the optimum Im.Bz geometry is T shaped and NH...pi hydrogen bonded. We find no experimental evidence for a CH...pi hydrogen-bonded ground-state isomer of Im.Bz. The optimum NH...pi geometry of the Im.Bz complex is very different from the majority of the histidine.aromatic contact geometries found in protein database analyses, implying that the CH...pi contacts observed in these searches do not arise from favorable binding interactions but merely from protein side-chain folding and crystal-packing constraints. The UV and IR spectra of the imidazole.(benzene)2 cluster are observed via fragmentation into the Im.Bz+ mass channel. The spectra of Im.Bz and Im.Bz2 are cleanly separable by IR hole burning. The UV spectrum of Im.Bz2 exhibits two 000 bands corresponding to the S0 -> S1 excitations of the two inequivalent benzenes, which are symmetrically shifted by -86/+88 cm(-1) relative to the 000 band of benzene PMID- 26020361 TI - Kinetic Stability of Non-IPR Fullerene Molecular Ions. AB - Many fullerenes that violate the isolated pentagon rule (IPR) form stable metallofullerenes. In general, a fullerene cage is kinetically stabilized by acquiring a given number of electrons. Kinetic stability of negatively charged non-IPR fullerenes, including the recently isolated endohedral metallofullerene with a heptagonal face, was rationalized in terms of bond resonance energy (BRE). Interestingly, molecular anions of conventional fullerenes found in most isolated metallofullerenes are kinetically stable with large positive BREs for all CC bonds. As we pointed out in 1993, the IPR does not apply to charged fullerenes because pi-bonds shared by two five-membered rings are aromatized to varying extents. PMID- 26020362 TI - Comparative Study of Metal Quantification in Neurological Tissue Using Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry Imaging and X-ray Fluorescence Microscopy. AB - Redox-active metals in the brain mediate numerous biochemical processes and are also implicated in a number of neurodegenerative diseases. A number of different approaches are available for quantitatively measuring the spatial distribution of biometals at an image resolution approaching the subcellular level. Measured biometal levels obtained using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS; spatial resolution 15 MUm * 15 MUm) were within the range of those obtained using X-ray fluorescence microscopy (XFM; spatial resolution 2 MUm * 7 MUm) and regional changes in metal concentration across discrete brain regions were replicated to the same degree. Both techniques are well suited to profiling changes in regional biometal distribution between healthy and diseased brain tissues, but absolute quantitation of metal levels varied significantly between methods, depending on the metal of interest. Where all possible variables affect metal levels, independent of a treatment/phenotype are controlled, either method is suitable for examining differences between experimental groups, though, as with any method for imaging post mortem brain tissue, care should be taken when interpreting the total metal levels with regard to physiological concentrations. PMID- 26020363 TI - Metabolic Effect Level Index Links Multivariate Metabolic Fingerprints to Ecotoxicological Effect Assessment. AB - A major goal of ecotoxicology is the prediction of adverse outcomes for populations from sensitive and early physiological responses. A snapshot of the physiological state of an organism can be provided by metabolic fingerprints. However, to inform chemical risk assessment, multivariate metabolic fingerprints need to be converted to readable end points suitable for effect estimation and comparison. The concentration- and time-dependent responsiveness of metabolic fingerprints to the PS-II inhibitor isoproturon was investigated by use of a Myriophyllum spicatum bioassay. Hydrophilic and lipophilic leaf extracts were analyzed with gas chromatography-mass spectrometry (GC-MS) and preprocessed with XCMS. Metabolic changes were aggregated in the quantitative metabolic effect level index (MELI), allowing effect estimation from Hill-based concentration response models. Hereby, the most sensitive response on the concentration scale was revealed by the hydrophilic MELI, followed by photosynthetic efficiency and, 1 order of magnitude higher, by the lipophilic MELI and shoot length change. In the hydrophilic MELI, 50% change compares to 30% inhibition of photosynthetic efficiency and 10% inhibition of dry weight change, indicating effect development on different response levels. In conclusion, aggregated metabolic fingerprints provide quantitative estimates and span a broad response spectrum, potentially valuable for establishing adverse outcome pathways of chemicals in environmental risk assessment. PMID- 26020364 TI - Ultrafast photoinduced electron transfer in green fluorescent protein bearing a genetically encoded electron acceptor. AB - Electron transfer (ET) is widely used for driving the processes that underlie the chemistry of life. However, our abilities to probe electron transfer mechanisms in proteins and design redox enzymes are limited, due to the lack of methods to site-specifically insert electron acceptors into proteins in vivo. Here we describe the synthesis and genetic incorporation of 4-fluoro-3-nitrophenylalanine (FNO2Phe), which has similar reduction potentials to NAD(P)H and ferredoxin, the most important biological reductants. Through the genetic incorporation of FNO2Phe into green fluorescent protein (GFP) and femtosecond transient absorption measurement, we show that photoinduced electron transfer (PET) from the GFP chromophore to FNO2Phe occurs very fast (within 11 ps), which is comparable to that of the first electron transfer step in photosystem I, from P700* to A0. This genetically encoded, low-reduction potential unnatural amino acid (UAA) can significantly improve our ability to investigate electron transfer mechanisms in complex reductases and facilitate the design of miniature proteins that mimic their functions. PMID- 26020365 TI - Synthesis of Cryptophanes with Two Different Reaction Sites: Chemical Platforms for Xenon Biosensing. AB - We report the synthesis of new water-soluble cryptophane host molecules that can be used for the preparation of (129)Xe NMR-based biosensors. We show that the cryptophane-223 skeleton can be modified to introduce a unique secondary alcohol to the propylenedioxy linker. This chemical functionality can then be exploited to introduce a functional group that is different from the six chemical groups attached to the aromatic rings. In this approach, the generation of a statistical mixture when trying to selectively functionalize a symmetrical host molecule is eliminated, which enables the efficient large-scale production of new cryptophanes that can be used as chemical platforms ready to use for the preparation of xenon biosensors. To illustrate this approach, two molecular platforms have been prepared, and the ability of these new derivatives to bind xenon has been investigated. PMID- 26020366 TI - Enhanced cycling stability of hybrid Li-air batteries enabled by ordered Pd3Fe intermetallic electrocatalyst. AB - We report an ordered Pd3Fe intermetallic catalyst that exhibits significantly enhanced activity and durability for the oxygen reduction reaction under alkaline conditions. Ordered Pd3Fe enables a hybrid Li-air battery to exhibit the best reported full-cell cycling performance (220 cycles, 880 h). PMID- 26020367 TI - Accuracy validation of the Microlife 3AS1-2 blood pressure device in a pregnant population with low blood pressure. AB - OBJECTIVE: To assess the accuracy of the Microlife 3AS1-2 blood pressure (BP) device in pregnant women with low BP to investigate suitability for hypotensive detection in low-income and middle-income countries. METHODS: A prospective observational study was carried out evaluating the Microlife 3AS1-2, a hand-held, upper-arm, semiautomated BP device, according to British Hypertension Society (BHS) protocol methods. Thirty (stable) pregnant women with a clinical systolic BP less than 100 mmHg and/or diastolic BP less than 60 mmHg were recruited from antenatal wards and clinics and their BP was measured by three trained observers at a district-level hospital in South Africa. Accuracy was assessed according to the BHS grading criteria (A/B=pass) and the ANSI/AAMI/ISO standard for mean difference and SD (<=5+/-8 mmHg). RESULTS: The device achieved an A/A grade according to the BHS grading criteria. The mean difference+/-SD between the observer and the test device was 0.5+/-6.2 and 1.3+/-5.4 mmHg for systolic and diastolic BP, respectively, fulfilling the standard required by the ANSI/AAMI/ISO protocol. All observer differences were within 4 mmHg. CONCLUSION: According to the BHS protocol, the Microlife 3AS1-2 BP device is accurate in pregnant women with low BP. The device has been validated previously in pregnancy and pre eclampsia and also fulfils the criteria of the WHO for use in a low-resource setting. Although unstable women were not included in this validation (for safety and pragmatic reasons), this device could potentially improve the detection of shock secondary to obstetric haemorrhage or sepsis, as well as being used in pre eclampsia, particularly in low-income and middle-income countries. PMID- 26020368 TI - Antiferromagnetism of two-dimensional electronic gas on light-irradiated SrTiO3 and at LaAlO3/SrTiO3 interfaces. AB - To gain an insight into the origin of tunable two-dimensional (2D) electronic liquid at the interfaces of transition-metal oxides, we address properties of a conducting layer on the light-irradiated surfaces of SrTiO3; the energy spectrum of the latter is known and consists of the titanium dxz/dyz and dxy bands. Recently, Santander-Syro et al (2014 Nature Mater. 13 1085) revealed that the dxy bands actually comprise two chiral branches with the Kramers degeneracy at the zone center lifted in the absence of a magnetic moment. We suggest that interacting electrons on the irradiated SrTiO3 go over into a magnetic phase as the result of one of the instabilities of the 2D Fermi liquid with exchange interactions, and point out the concrete antiferromagnetic order parameter. Large energy scales of the order of Fermi energy ~0.1 eV inherent in this mechanism warrant stability of the magnetic ground state against ever-present effects of disorder. Arguments are given that electrons at the irradiated SrTiO3 surface and at the LaAlO3/SrTiO3 interfaces undergo a kind of first-order transformation into one and the same phase of the 2D electronic Fermi liquid with reduced magnetic symmetry. PMID- 26020369 TI - A Survey of Australian Nurses' Knowledge of Pressure Injury/Pressure Ulcer Management. AB - PURPOSE: Management of hospital-acquired pressure ulcers (PUs) is an essential aspect of nursing practice that requires knowledge of risk assessment, prevention, identification, and treatment strategies. The aim of this study was to assess nurses' knowledge of PU management in order to identify knowledge gaps. SUBJECTS AND SETTING: The study setting was a large Australian health service district employing more than 10,000 nurses in full and part-time roles. A proportional (by facility) and stratified (by nursing grade) sample of 10% of the district population was targeted. Eight hundred twenty-seven participants completed the survey. Most participants had more than 5 years of experience as professional nurses. DESIGN: Cross-sectional survey. INSTRUMENT: A modified version of the Pressure Ulcer Knowledge Test, comprising 49 true/false questions, was used. A cutoff score of 90% of participants answering an item correctly was used to gauge "adequate" knowledge level. METHODS: An opportunity to participate in the research was advertised throughout the different facilities in the district by strategically placed posters, computer screen savers, and e-mails. Most data were collected online, with some collected manually using paper-based questionnaires. All data were collected between April and November 2012. RESULTS: Twenty-six questions (53%) were answered correctly by 90% or more of participants, and 6 questions were answered correctly by 50% or less, identifying important knowledge deficits. The mean Pressure Ulcer Knowledge Test score was 79%; 15 nurses (1.8%) achieved a score of 90% or more, and more than 90% achieved scores more than 70%. There were small but significant positive effects of years of nursing experience and level of nursing grade on the knowledge scores. CONCLUSIONS: Our results identified deficits in PU knowledge and areas where nurses would benefit from focused education strategies. PMID- 26020371 TI - Breast-feeding Duration: Early Weaning-Do We Sufficiently Consider the Risk Factors? AB - OBJECTIVES: Breast-feeding is the recommended form of nutrition for the first 6 months. This target is unmet, however, in most industrialized regions. We evaluated aspects of breast-feeding in a cohort of mother-baby dyads. METHODS: Breast-feeding practices in 555 mother-baby dyads were prospectively studied for 24 months (personal interview at birth and 7 structured telephone interviews). RESULTS: Of the babies, 71.3% were fully breast-fed on discharge from maternity hospitals and 11.9% were partially breast-feed. Median breast-feeding duration was 6.93 (interquartile range 2.57-11.00) months; for full (exclusive) breast feeding 5.62 (interquartile range 3.12-7.77) months; 61.7% received supplemental feedings during the first days of life. Breast-feeding duration in babies receiving supplemental feedings was significantly shorter (median 5.06 months versus 8.21 months, P < 0.001). At 6 months, 9.4% of the mothers were exclusively and 39.5% partially breast-feeding. Risk factors for early weaning were early supplemental feedings (odds ratio [OR] 2.87, 95% CI 1.65-4.98), perceived milk insufficiency (OR 7.35, 95% CI 3.59-15.07), low breast-feeding self-efficacy (a mother's self-confidence in her ability to adequately feed her baby) (OR 3.42, 95% CI 1.48-7.94), lower maternal age (OR 3.89, 95% CI 1.45-10.46), and lower education level of the mother (OR 7.30, 95% CI 2.93-18.20). CONCLUSIONS: The recommended full breast-feeding duration of the first 6 months of life was not reached. Sociodemographic variables and factors directly related to breast feeding practices play an important role on breast-feeding duration/weaning in our region. Understanding risk factors will provide insights to give better support to mothers and prevent short- and long-term morbidity following early weaning. PMID- 26020370 TI - ESPGHAN 2012 Guidelines for Coeliac Disease Diagnosis: Validation Through a Retrospective Spanish Multicentric Study. AB - OBJECTIVES: A large retrospective multicentre study was conducted in Spain to evaluate the efficiency of the new European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criteria for the diagnosis of coeliac disease (CD). METHODS: The study protocol was approved by the ethics committee of Hospital Universitari i Politecnic La Fe (Valencia, Spain). The present study included 2177 children (ages 0.6-15.9 years) with small bowel biopsy (SBB) performed for diagnostic purposes (from 2000 to 2009) and with a minimum 2-year follow-up after biopsy. RESULTS: CD was diagnosed in 2126 patients (97.5%) and excluded in 51 (2.5%). Tissue transglutaminase antibodies (TG2A), anti-endomysial antibodies (EMA), and human leukocyte antigen (HLA) were reported in 751 patients, 640 symptomatic and 111 asymptomatic. TG2A levels >10 times the upper limit of normal, plus positive EMA and HLA DQ2 and/or DQ8 haplotypes, were found in 336 symptomatic patients, all of them with final diagnosis of CD. In 65 of 69 asymptomatic patients, 65 had confirmed CD and 4 did not have CD. According to the 2012 ESPGHAN guidelines, SBB may have been omitted in 52% of the symptomatic patients with CD with serologic and HLA available data. Gluten challenge was performed in 158 children, 75 of them <2 years at first biopsy. Only 1 patient in whom according to the new proposed diagnostic criteria gluten challenge would not have been mandatory did not relapse. CONCLUSIONS: Our results support the new ESPGHAN 2012 guidelines for diagnosis of CD can be safely used without the risk of overdiagnosis. A prospective multicentre study is needed to confirm our results. PMID- 26020373 TI - Pediatric Functional Constipation Gastrointestinal Symptom Profile Compared With Healthy Controls. AB - OBJECTIVES: Patient-reported outcomes are necessary to evaluate the gastrointestinal symptom profile of patients with functional constipation. Study objectives were to compare the gastrointestinal symptom profile of pediatric patients with functional constipation with matched healthy controls with the Pediatric Quality of Life Inventory Gastrointestinal Symptoms and Gastrointestinal Worry Scales and to establish clinical interpretability in functional constipation through identification of minimal important difference (MID) scores. The secondary objective compared the symptom profile of patients with functional constipation with patients with irritable bowel syndrome (IBS). METHODS: Gastrointestinal Symptoms and Worry Scales were completed in a 9-site study by 116 pediatric patients with functional constipation and 188 parents. Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were administered along with Gastrointestinal Worry Scales. A total of 341 families with healthy children and 43 families with patients with IBS completed the scales. RESULTS: A broad profile of gastrointestinal symptoms and worry were reported by patients with functional constipation in comparison with healthy controls (P < 0.001) with large effect sizes (>0.80) across the majority of symptom domains. Patients with IBS manifested a broader symptom profile than functional constipation, with differences for stomach pain, stomach discomfort when eating, and worry about stomachaches, with similar constipation scores. CONCLUSIONS: Pediatric patients with functional constipation report a broad gastrointestinal symptom profile in comparison with healthy controls and only somewhat fewer symptoms than patients with IBS, highlighting the critical need for more efficacious interventions to achieve healthy functioning. PMID- 26020374 TI - Endoscopy Following Pediatric Intestinal Transplant. AB - OBJECTIVES: Biopsies remain the criterion standard in the diagnosis of intestinal transplant (ITx) rejection, and gastrointestinal endoscopy plays a pivotal role in patient management. Herein, we describe a single-center 23-year endoscopic experience in pediatric ITx recipients. METHODS: A retrospective review of endoscopy and pathology reports of all ITx recipients <18 years old transplanted between 1991 and 2013 was performed with the aim of describing the procedural indications, findings, and complications. RESULTS: A total of 1770 endoscopic procedures within 1014 sessions were performed. A combination of esophagogastroduodenoscopy and ileoscopy was the most common procedure (36%). Increased stool output (35%) and surveillance endoscopy (32%) were the most common indications. A total of 162 episodes of biopsy-proven rejection were diagnosed. The first episode of rejection occurred at a median of 1 month after ITx. Of histology-proven rejections, 45% had normal-appearing endoscopies. The rate of procedural complications, including but not limited to bleeding and perforation, was 1.8%. CONCLUSIONS: Endoscopy with biopsy plays a significant role in the care of ITx recipients. Multiple procedures are required for graft surveillance, diagnosis of rejection, subsequent treatment, and follow-up of therapy. The gross endoscopic appearance, particularly in mild to moderate acute cellular rejection, does not correlate well with histology. Complex anatomy, complication rates that are higher than patients with non-ITx pediatric endoscopy, and timely histologic interpretation by experienced pathologists are reasons that these procedures should be performed at centers accustomed to caring for ITx recipients. The field would benefit from the development of a noninvasive biomarker to reliably and efficiently detect rejection. PMID- 26020375 TI - Effect of Ursodeoxycholic Acid on Indirect Hyperbilirubinemia in Neonates Treated With Phototherapy. AB - BACKGROUND: Hyperbilirubinemia is a common neonatal problem. The present study aimed to investigate the effect of ursodeoxycholic acid in reducing indirect hyperbilirubinemia of infants under phototherapy. METHODS: This double-blind randomized clinical trial was conducted on neonates with jaundice, who had received phototherapy in the hospitals affiliated with the Shiraz University of Medical Sciences in 2013. A total of 80 neonates were enrolled in the study and were randomly divided into 2 groups. The intervention group (n = 0) with indirect hyperbilirubinemia received 10 mg . kg(-1) . day(-1) divided every 12 hours Ursobil (capsule 300 mg) in addition to phototherapy, whereas the control group (n = 0) received only phototherapy. Total bilirubin levels were measured every 12 hours until reaching <10 mg/dL, and then phototherapy was disrupted. The duration of phototherapy was measured. The 2 groups were compared regarding total bilirubin levels at different time points and duration of phototherapy using the generalized estimating equation (GEE) test. RESULTS: The mean of total bilirubin in the intervention group was 12 +/- 1.6, 10 +/- 1.1, and 9.8 +/- 0.2 mg/dL 12, 24, and 48 hours after the beginning of phototherapy, respectively. On the contrary, these measures were 14.4 +/- 1.3, 12.5 +/- 1.4, and 10.1 +/- 1.1 mg/dL in the control group, respectively, (P < 0.05). The mean time required for phototherapy to decrease the bilirubin level to < 10 mg/dL was 15.5 +/- 6 and 44.6 +/- 13.3 hours in the case and the control group, respectively, (P = 0.001). CONCLUSIONS: Ursodeoxycholic acid had additive effect with phototherapy in neonates with indirect hyperbilirubinemia. This drug also reduced the time period needed for phototherapy and, consequently, decreased the hospitalization period. PMID- 26020376 TI - Liver and spleen stiffness and other noninvasive methods to assess portal hypertension in cirrhotic patients: a review of the literature. AB - Portal hypertension (PH) is one of the most important causes of morbidity and mortality in patients with chronic liver disease. PH measurement is crucial to stage and predict the clinical outcome of liver cirrhosis. Measurement of hepatic vein pressure gradient is considered the gold standard for assessment of the degree of PH; however, it is an invasive method and has not been used widely. Thus, noninvasive methods have been proposed recently. We critically evaluated serum markers, abdominal ultrasonography, and particularly liver and spleen stiffness measurement, which represent the more promising methods to stage PH degree and to assess the presence/absence of esophageal varices (EV). A literature search was carried out on MEDLINE, EMBASE, Web of Science, and Scopus for articles and abstracts. The search terms used included 'liver cirrhosis', 'portal hypertension', 'liver stiffness', 'spleen stiffness', 'ultrasonography', and 'portal hypertension serum biomarker'. The articles cited were selected on the basis of their relevance to the objective of the review. The results of available studies indicate that individually, these methods have a mild accuracy in predicting the presence of EV, and thus they cannot substitute endoscopy to predict EV. When these tests were used in combination, their accuracy increased. In addition to the PH staging, several serum markers and spleen stiffness measurement can predict the clinical outcome of liver cirrhosis with a good accuracy, comparable to that of hepatic vein pressure gradient. In the future, noninvasive methods could be used to select patients requiring further investigations to identify the best tailored clinical management. PMID- 26020377 TI - Diagnostic utility of interferon gamma-induced protein 10 kDa in spontaneous bacterial peritonitis: single-center study. AB - BACKGROUND AND AIMS: Spontaneous bacterial peritonitis (SBP) is an important cause of mortality and morbidity in cirrhotic patients with ascites. The diagnosis of SBP is mainly made on the basis of a polymorphonuclear leukocyte cell count exceeding 250/MUl in ascitic fluid. However, this procedure is subjective. We aimed to evaluate serum and ascitic fluid interferon-gamma-induced protein (IP-10) as accurate diagnostic markers for detecting SBP. METHODS: A total of 425 consecutive patients with ascites were included. Serum and ascitic fluid of IP-10, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured using an enzyme-linked immunosorbent assay. RESULTS: Patients were divided into an SBP group, including 61 patients, and a non-SBP group, including 364 patients. Serum and ascitic IP-10 were significantly higher in SBP patients than in patients without SBP (1855+/-825 vs. 955+/-510 pg/ml; P<0.001 and 2160+/ 994 vs. 1110+/-623 pg/ml; P<0.001), respectively. There was a significant increase in both serum and ascitic levels of TNF-alpha and IL-6 in SBP patients than in patients without SBP. At a cut-off value of 1915 pg/ml, serum IP-10 had 91% sensitivity and 89% specificity for detecting SBP (area under the curve: 0.912). Also, at a cut-off value of 2355 pg/ml, ascitic IP-10 had 92.5% sensitivity and 87% specificity for detecting SBP (area under the curve: 0.943). Both were correlated with ascitic fluid proteins, polymorphonuclear count, TNF alpha, and IL-6. CONCLUSION: Serum and ascitic IP-10, TNF-alpha, and IL-6 are significantly increased in SBP patients versus patients without SBP. Serum level of IP-10 is more specific and sensitive, such as ascites. Thus, it seems to represent a satisfactory diagnostic marker for the diagnosis of SBP. PMID- 26020378 TI - Downregulated miR-495 [Corrected] Inhibits the G1-S Phase Transition by Targeting Bmi-1 in Breast Cancer. AB - Bmi-1 (B cell-specific Moloney murine leukemia virus integration site 1) is upregulated in breast cancer and was involved in many malignant progressions of breast cells, including cell proliferation, stem cell pluripotency, and cancer initiation. However, the epigenetic regulatory mechanism of Bmi-1 in breast cancer remains unclear. After analysis of the ArrayExpress dataset GSE45666, we comparatively detected the expression levels of miR-495 in 9 examined breast cancer cell lines, normal breast epithelial cells and 8 pairs of fresh clinical tumor samples. Furthermore, to evaluate the effect of miR-495 on the progression of breast cancer, MCF-7 and MDA-MB-231 were transduced to stably overexpress miR 495. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, colony formation assays, 5-Bromo-2-deoxyUridine labeling and immunofluorescence, anchorage-independent growth ability assay, flow cytometry analysis, and luciferase assays were used to test the effect of miR-495 in MCF-7 and MDA-MB-231 cells in vitro. Xenografted tumor model was also used to evaluate the effect of miR-495 in breast cancer. Herein, we found that miR-495, a predicted regulator of Bmi-1, was frequently downregulated in malignant cells and tissues of breast. Upregulation of miR-495 significantly suppressed breast cancer cell proliferation and tumorigenicity via G1-S arrest. Further analysis revealed that miR-495 targeted Bmi-1 through its 3' untranslated region. Moreover, Bmi-1 could neutralize the suppressive effect of miR-495 on cell proliferation and tumorigenicity of breast cancer in vivo. These data suggested that miR-495 could inhibit the G1-S phase transition that leads to proliferation and tumorigenicity inhibition by targeting and suppressing Bmi-1 in breast cancer. PMID- 26020380 TI - New Deep Dermal ADM Incorporates Well in Case Series of Complex Breast Reconstruction Patients. AB - Breast cancer patients with significant comorbidities present reconstructive challenges due to a predictably high complication rate. During expander-based breast reconstruction, human acellular dermal matrix (ADM) is often used to prevent pectoralis muscle retraction, facilitate early expansion, and improve cosmetic outcome. Device infection and chronic seroma have been correlated to the addition of the graft by some large database reports but not others. This study describes the first reported experience with a new deep dermal ADM, FlexHD(r) PliableTM (MTF, Edison, NJ). Sixteen breasts in 10 consecutive patients identified retrospectively and followed prospectively had immediate expander based breast reconstruction utilizing the new ADM. Patient comorbidities were catalogued, complications were recorded, and overall reconstructive success was assessed. At implant exchange, the ADM was examined for tissue ingrowth and biopsied for histologic examination. All 16 breasts had successful reconstructions. Two breasts (12.5%) developed device infection, requiring removal and later replacement of the expander. One breast (6.7%) developed chronic seroma, also requiring expander removal and later replacement. All the complicated patients had significant comorbidities, including obesity in all 3. At expander removal, the FlexHD Pliable showed near-complete visual tissue incorporation in 14 of 16 breasts (88%). This case series demonstrates significant reconstructive success in challenging patients utilizing a novel ADM. Visual and histologic assessment of tissue ingrowth into the graft suggests the high rate of complication may be due to patient comorbidities rather than addition of ADM. Additional experience is needed to confirm and the study is ongoing. PMID- 26020379 TI - An update of the Mayo Clinic cohort of patients with adult primary central nervous system vasculitis: description of 163 patients. AB - Primary central nervous system vasculitis (PCNSV) is an uncommon condition in which lesions are limited to vessels of the brain and spinal cord. Because the clinical manifestations are not specific, the diagnosis is often difficult, and permanent disability and death are frequent outcomes. This study is based on a cohort of 163 consecutive patients with PCNSV who were examined at the Mayo Clinic over a 29-year period from 1983 to 2011. The aim of the study was to define the characteristics of these patients, which represents the largest series in adults reported to date. A total of 105 patients were diagnosed by angiographic findings and 58 by biopsy results. The patients diagnosed by biopsy more frequently had at presentation cognitive dysfunction, greater cerebrospinal fluid total protein concentrations, less frequent cerebral infarcts, and more frequent leptomeningeal gadolinium-enhanced lesions on magnetic resonance imaging (MRI), along with less mortality and disability at last follow-up. The patients diagnosed by angiograms more frequently had at presentation hemiparesis or a persistent neurologic deficit or stroke, more frequent infarcts on MRI and an increased mortality. These differences were mainly related to the different size of the vessels involved in the 2 groups. Although most patients responded to therapy with glucocorticoids alone or in conjunction with cyclophosphamide and tended to improve during the follow-up period, an overall increased mortality rate was observed. Relapses occurred in one-quarter of the patients and were less frequent in patients treated with prednisone and cyclophosphamide compared with those treated with prednisone alone. The mortality rate and degree of disability at last follow-up were greater in those with increasing age, cerebral infarctions on MRI, angiographic large vessel involvement, and diagnosis made by angiography alone, but were lower in those with gadolinium-enhanced lesions on MRI and in those with cerebral amyloid angiopathy. The annual incidence rate of PCNSV was estimated at 2.4 cases per 1,000,000 person-years. PCNSV appears to consist of several subsets defined by the size of the vessels involved, the clinical characteristics at presentation, MRI findings, and histopathological patterns on biopsy. Early recognition and treatment may reduce poor outcomes. PMID- 26020381 TI - Prediction Table and Nomogram as Tools for Diagnosis of Papillary Thyroid Carcinoma: Combined Analysis of Ultrasonography, Fine-Needle Aspiration Biopsy, and BRAF V600E Mutation. AB - Although ultrasonography (US)-guided fine-needle aspiration biopsy (FNAB) is the most reliable diagnostic modality for evaluating thyroid nodules, 10% to 40% of FNAB samples yield indeterminate findings. The BRAF V600E mutation, a highly specific molecular marker for papillary thyroid carcinoma (PTC), well known for its prognostic value, has dubious diagnostic value because of its low sensitivity. Novel strategies are clearly needed to distinguish PTC, which represents the majority of thyroid malignancies, from other thyroid nodules. The records of 3297 patients with surgically proven PTC were retrospectively reviewed. A prediction table and nomogram were designed using a combination of diagnostic parameters for US, FNAB, and the BRAF V600E mutation. For the nomogram, parameters were proportionally assigned 0 to 100 points according to their regression coefficient for PTC. The probability of PTC for thyroid nodules with intermediate-risk (IR) US and atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) FNAB was significantly dependent on BRAF V600E mutation status based on our prediction table (negative, 29.2% vs positive, 87.5%; P < 0.001). By our nomogram, the probability of PTC for thyroid nodules with IR US, AUS/FLUS FNAB, and positive BRAF V600E mutation was approximately 85% to 90%. We strongly recommend preoperative evaluation of the BRAF V600E mutation in indeterminate thyroid nodules. The prediction table and nomogram developed in this study could help clinicians and patients easily assess the probability of PTC in the preoperative period. PMID- 26020382 TI - Blood as a Substitute for Tumor Tissue in Detecting EGFR Mutations for Guiding EGFR TKIs Treatment of Nonsmall Cell Lung Cancer: A Systematic Review and Meta Analysis. AB - Tumor tissues are often absent or insufficient for testing epidermal growth factor receptor (EGFR) mutations to guide EGFR tyrosine kinase inhibitors (TKIs) treatment of patients with nonsmall cell lung cancer (NSCLC). We conducted this systematic review and meta-analysis to assess whether blood can be used as a substitute for tumor tissue in detecting EGFR mutations. MEDLINE, EMBASE, and the Cochrane Library were searched for studies that provided data to estimate the accuracy of blood testing against tissue testing in NSCLC patients and/or those directly compared the efficacy of EGFR TKIs in EGFR mutant and wild-type patients according to sources of specimens. Sensitivity, specificity, and concordance rate were used as measures of the accuracy. Risk ratio (RR) for objective response and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were used as measures for treatment efficacy. We combined the effects by using the fixed-effects model unless there was evidence of heterogeneity, in which case a random-effects mode was used. This systematic review included 25 studies with 2605 patients. The pooled overall sensitivity, specificity, and concordance rate were 0.61, 0.90, and 0.79, respectively. Serum showed lower sensitivity (0.56 vs 0.65) but higher specificity (0.95 vs 0.85) and higher concordance (0.86 vs 0.74) than plasma. EGFR mutations (exon 19 or 21) in blood were significantly associated with objective response (RR: 4.08; 95% confidence interval [CI] 2.48 6.70), PFS (HR: 0.72; 95% CI 0.64-0.80), and OS (HR: 0.71; 95% CI 0.50-0.99). Importantly, the association of the mutations with the 3 clinical outcomes for serum was similar to that for tumor tissue and higher than that for plasma. Blood, in particular serum, is a good substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the absence of blood positivity should not necessarily be construed with confirmed negativity. PMID- 26020383 TI - Clinical and microbiological profile of a retrospective cohort of enteric fever in 2 Spanish tertiary hospitals. AB - Enteric fever in high-income countries is diagnosed mainly in patients returning from endemic countries. We assess the clinical, microbiological, and prognosis aspects of enteric fever in 2 Spanish tertiary hospitals. A retrospective observational study was conducted at Vall d'Hebron University Hospital and Ramon y Cajal University Hospital in Spain. We reviewed medical records of all patients who were diagnosed with enteric fever from January 2000 to January 2014 at these hospitals. We identified 47 patients with enteric fever episodes. According to their travel history, 35 (74.5%) patients had travelled to highly endemic countries. Imported enteric fever was acquired mainly in Asia (70.3%). Imported infections were implicated in travelers (48.6%), visiting friends and relatives (40%) and immigrants (11.4%). We found that 12 patients were diagnosed with enteric fever without a travel history (autochthonous infection). The resistance profile of the isolates showed decreased ciprofloxacin susceptibility in 66.7% of the imported group and 8.3% of the autochthonous group (P = 0.001). Salmonella strains from patients returning from Asia had an increased risk of having decreased ciprofloxacin susceptibility (odds ratio, 52.25; 95% confidence interval: 8.6-317.7). Patients with imported enteric fever are at higher risk for having a Salmonella strain with decreased ciprofloxacin susceptibility, especially in patients returning from Asia. Initial treatment with third generation cephalosporin or azithromycin is strongly recommended until a drug susceptibility test is available. Prevention strategies such as pretravel counseling and immunization before travel may be beneficial. PMID- 26020384 TI - High Levels of Gamma-Glutamyl Transferase and Indocyanine Green Retention Rate at 15 min as Preoperative Predictors of Tumor Recurrence in Patients With Hepatocellular Carcinoma. AB - This study investigated the preoperative independent risk factors associated with survival and recurrence for patients with hepatocellular carcinoma (HCC) who underwent hepatic resection. In total, 384 consecutive patients who underwent curative hepatic resection for single primary HCC were studied. Predictive factors associated with 1-, 3-, and 5-year survival and recurrence-free survival (RFS) were assessed using a univariate log-rank test and multivariate Cox proportional hazards regression model. Gamma-glutamyl transferase (GGT) > 100 U/L was identified as a preoperative independent risk factor affecting 1-, 3-, and 5 year survival whereas GGT > 50 U/L and indocyanine green retention 15 min (ICG R15) > 10% were identified as preoperative independent risk factors affecting 1-, 3-, and 5-year RFS. The 384 patients studied had a 1-, 3-, and 5-year RFS rate of 72.8%, 43.3%, and 27%, respectively. Patients with GGT > 50 U/L had a 1-, 3-, and 5-year RFS rate of 64.5%, 36.0%, and 21.7%. These patients had lower survival rates than did patients with GGT <= 50 U/L (P < 0.05). Patients with GGT > 50 U/L and ICG-R15 > 10% had a 1-, 3-, and 5-year RFS rate of 62.4%, 29.5%, and 14.1%, respectively. These patients had lower survival rates than did patients in the other 2 groups with different levels of GGT and ICG (P < 0.05, respectively). The same was also true for patients with a tumor < 5 cm in size. Combined information in the form of high levels of GGT and ICG-R15 is a preoperative predictor that warrants full attention when evaluating tumor recurrence postoperatively. PMID- 26020385 TI - Clinical and laboratory predictors of distinct histopathogical features of lupus nephritis. AB - The authors aimed to explore whether distinct clinical, serological, and urinalysis findings are associated with specific histological classes of lupus nephritis. Clinical and laboratory features were recorded at the time of clinical diagnosis from 297 consecutive patients with biopsy-confirmed lupus nephritis. Univariate and logistic regression analyses were performed and a risk score was developed to estimate the risk for developing different classes of lupus nephritis. Variables independently associated with class II included absence of malar rash, negative anti-dsDNA, and <=5 urine leucocytes/high power field (hpf); with III/IV: age at nephritis diagnosis <=32 years old, presence of musculoskeletal features, new-onset hypertension, positive anti-dsDNA, >5 urine leucocytes/hpf, creatinine >1.2 mg/dL, cellular casts >1/hpf, and absence of nephrotic range proteinuria; with V: age at nephritis diagnosis >32 years, malar rash, absence of musculoskeletal complaints or serum C3 hypocomplementemia, nephrotic range proteinuria, and <=9 urine erythrocytes/hpf. A risk predictive score of specific histological classes was calculated for each patient. Associations between 2, 3 or more risk factors with specific histological classes were also revealed [Odds ratios (95% confidence interval) (>=2 risk factors) was 6.7 (2.8-17.4) for class II nephritis, 15.6 (5.1-47.8), and 8.2 (3.6-19.0) for classes III/IV and for class V, respectively (>=3 risk factors)]. The identification of independent factors associated with specific classes of lupus nephritis can provide guidance in selecting specific therapeutic modalities, particularly in cases in which renal biopsy is contraindicated. PMID- 26020386 TI - Respiratory Syncytial Virus Bronchiolitis in Children up to 5 Years of Age in Spain: Epidemiology and Comorbidities: An Observational Study. AB - This epidemiological survey in Spain estimates the burden of respiratory syncytial virus (RSV) infection in children up to 5 year of age during a 15-year period (1997-2011). Observational retrospective survey was conducted by reviewing data of the National Surveillance System for Hospital Data, including >98% of Spanish hospitals. All hospitalizations related to RSV infection for children up to 5 years, reported during 1997-2011 period, were analyzed. Codes were selected by using the International Classification of Diseases 9th Clinical Modification 466.0-466.19, 480.1, and 079.6. A total of 326,175 and 286,007 hospital discharges for children up to 5 and 2 years of age were reported during the study period. The annual incidence was 1072 and 2413 patients per 100,000, respectively. The average length of hospital stay was 5.7 (standard deviation 8.2) days. Four hundred forty-six deaths were reported; of those, 403 occurred in children <2 years and 355 (80%) occurred in children <12 months of age. Hospitalization and mortality rates were significantly higher in boys and decrease significantly with age. The higher rate of hospitalization and mortality rates were found in the first year of life. Annual average cost for National Health Care System was ? 47 M with a mean hospitalization cost of ?2162. The average length of hospitalization and costs were significantly higher in high risk children. RSV infections in children up to 5 year of age still pose a significant health threat in Spain, especially in the infants. The development of preventive, diagnostic, and therapeutic guidelines focused in children with comorbidities may help reduce the hospital and economic burden of the disease. PMID- 26020387 TI - Higher risk of myasthenia gravis in patients with thyroid and allergic diseases: a national population-based study. AB - The aim of this study was to determine the risk of myasthenia gravis (MG) in patients with allergic or autoimmune thyroid disease in a large cohort representing 99% of the population in Taiwan. Data from the Taiwan National Health Insurance Database were used to conduct retrospective analyses. The study comprised 1689 adult patients with MG who were 4-fold frequency matched to those without MG by sex, age, and assigned the same index year. Multivariate logistic regression models were used to calculate the odds ratios and 95% confidence intervals for the association between allergic or autoimmune thyroid disease and MG. An increased subsequent risk of MG was observed in the patients with allergic conjunctivitis (AC), allergic rhinitis, Hashimoto thyroiditis, and Graves disease. The adjusted odds ratios (aORs) were 1.93 (1.71-2.18), 1.26 (1.09-1.45), 2.87 (1.18-6.97), and 3.97 (2.71-5.83), respectively. The aORs increased from 1.63 (1.43-1.85) in a patient with only 1 allergic or autoimmune thyroid disease to 2.09 (1.75-2.49) in a patient with 2 thyroid or allergic diseases to 2.82 (2.19-3.64) in a patient with >=3 thyroid or allergic diseases. MG was associated with the cumulative effect of concurrent allergic and autoimmune thyroid disease with combined AC and Hashimoto thyroiditis representing the highest risk (aOR = 15.62 [2.88-87.71]). This population-based case-control study demonstrates the association between allergic or autoimmune thyroid disease and the risk of MG. The highest risk of subsequent MG was associated with combined AC and Hashimoto thyroiditis. PMID- 26020388 TI - Characterization of papillary thyroid microcarcinomas using sonographic features in malignant papillary thyroid cancer: a retrospective analysis. AB - The diagnosis of malignant thyroid nodules is still a clinical challenge. This study aimed to determine the ultrasonographic characteristics of papillary thyroid carcinoma. The ultrasonographic and pathological data of 2453 thyroid nodules in a cohort of 1895 Chinese patients who underwent thyroidectomy from January 2010 to December 2012 were retrospectively reviewed. Anteroposterior and transversal (AP/TR) diameters >=1, solid structure, infiltrative margins, hypoechoic appearance, and microcalcifications were more common in malignant nodules than in benign nodules (P < 0.01). These ultrasonographic features were independent risk factors of malignancy (P < 0.01) as determined by logistic regression analysis. Based on multivariate analysis, these characteristics were also present in large nodules (diameter >10 mm). However, in small nodules (diameter <=10 mm), only AP/TR >=1 and infiltrative margins were independent risk factors of malignancy (P < 0.01). Ultrasonography is of high diagnostic value for malignant thyroid nodules and may help to improve the differential diagnosis. Small and large nodules have distinct ultrasonographic features. PMID- 26020389 TI - Can the ETView VivaSight SL Rival Conventional Intubation Using the Macintosh Laryngoscope During Adult Resuscitation by Novice Physicians?: A Randomized Crossover Manikin Study. AB - The aim of this study was to assess the performance of the ETView VivaSight SL (ETView) single-lumen airway tube with an integrated high-resolution imaging camera in a manikin-simulated cardiopulmonary resuscitation scenario with and without chest compression. This was a randomized crossover manikin trial. Following a brief training session, 107 volunteer novice physicians who were inexperienced with airway management attempted to intubate a manikin using a Macintosh laryngoscope (MAC) and an ETView, with and without chest compressions. The participants were instructed to make 3 attempts in each scenario. In this trial, we compared intubation time, intubation success rates, and glottic visibility using a Cormack & Lehane Grade. Dental compression and ease of use of each device were also assessed. Median intubation times for the ETView and MAC without chest compressions were 17 (IQR, 15-19) s and 27 (IQR, 25-33) s, respectively (P < 0.001). The ETView proved more successful on the first intubation attempt than the MAC, regardless of compressions. Continuation of compressions caused an increase in intubation times for both the ETView (P = 0.27) and the MAC (P < 0.005). The ETView VivaSight SL is an effective tool for endotracheal intubation when used by novice physicians in a manikin-simulated cardiac arrest, both with and without chest compressions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02295618. PMID- 26020390 TI - Intratumoral Heterogeneity of Subcutaneous Nodules in a Never-Smoker Woman of Lung Squamous Cell Carcinoma Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography: A Case Report. AB - Subcutaneous tissue is a rare site of metastasis, accounting for only 1-2% of all lung neoplasms. Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has been reported to increase the diagnostic accuracy of subcutaneous metastasis. A 58-year-old woman presented with complaints of dry coughing, in which three positive subcutaneous nodules were found on 18F-FDG positron emission tomography and computed tomography (PET/CT). Pathologic examination confirmed that each of the nodules contained 1) necrotic fat, 2) small amounts of blood cells and glandular epithelium, and 3) subcutaneous metastasis of moderately differentiated lung squamous cell carcinoma, respectively. Although PET/CT is useful for the detection of subcutaneous metastasis of primary lung cancer, we noted heterogeneous accumulation of 18F-FDG in subcutaneous tumors. This case highlights the importance of obtaining histological confirmation of malignant diseases whenever possible. PMID- 26020391 TI - Whole Cell Therapeutic Vaccine Modified With Hyper-IL6 for Combinational Treatment of Nonresected Advanced Melanoma. AB - Active specific immunotherapy of cancer requires an efficient induction and effector phase. The induction covers potent activation of anti-tumor response, whereas effector breaks the immunosuppression. We report efficacy of therapeutic melanoma vaccine (AGI-101H) used alone in advanced disease as a candidate for further combined treatment. In adjuvant setting in patients with resected metastases AGI-101H combined with surgery of recurring disease demonstrated long term survival. Seventy-seven patients with nonresectable melanoma (8% IIIB, 21% IIIC, 71% IV) were enrolled. AGI-101H was administered 8* every 2 weeks, and then every month. At progression, maintenance was continued or induction was repeated and followed by maintenance. Median follow-up was 139.3 months. The median overall survival (OS) was 17.3 months; in patients with WHO 0-1 was 20.3 months. Complete response (CR) and partial response (PR) were observed in 19.4% and 9% of pts. Disease control rate was 54.5% of pts. The median CR+PR duration was 32 months. Reinduction was performed in 36.3% patients following disease progression with 46.6% of CR+PR. No grade 3/4 adverse events were observed. Treatment with AGI-101H of melanoma patients is safe and effective. AGI-101H is a good candidate for combinatorial treatment with immune check-points inhibitors or tumor hypoxia normalizators. TRIAL REGISTRATION: EudraCT Number 2008-003373-40. PMID- 26020392 TI - Evaluation of Teaching Methods in Mass CPCR Training in Different Groups of the Society, an Observational Study. AB - To determine the efficacy of different methods of cardiopulmonary resuscitation (CPCR) training in 3 different groups of the society. In a prospective and observational study of 2000 individuals in 3 different groups including G1, G2, and G3 4 different protocols of CPCR training were applied and their efficacy was compared between the groups. Also, 12 months after the study course, 460 participants from 3 groups were asked to take apart in a theoretical and practical examination to evaluate the long-term efficacy of the 4 protocols. Among 2000 individuals took a parted in the study, 950 (47.5%) were G1, 600 (30%) were G2, and 450 (22.5%) were G3. G1 in 4 groups were 2.37 and 2.65 times more successful in pretest theoretical and 2.61 and 18.20 times more successful in practical examinations compared with G2 and G3 and gained highest improvement in CPCR skills. Other groups also showed significantly improved CPCR skills. Comparison of different methods of CPCR learning showed that the workshop using interactive lecture as well as human model, educational film, and reference CPCR book has the highest efficacy in all groups. This protocol of CPCR training showed more efficacy in long-term postdelayed evaluation. On the contrary, medical students had better long-term outcomes from the course. Although G1 and G2 obtained better results in learning CPCR skills, in G3 also the theoretical and practical knowledge were improved significantly. This course increased confidence for doing CPCR in all groups of the study. Considering that the most of the bystanders at emergency states are general population, training this group of the society and increasing their confidence about performing CPCR can be so effective and lifesaving at emergency states. (Clinical trial. Gov registration: NCT02120573). PMID- 26020393 TI - Disseminated Mycobacterium abscessus Infection Following Septic Arthritis: A Case Report and Review of the Literature. AB - Mycobacterium abscessus is a rapidly growing mycobacterium found mainly in patients with respiratory or cutaneous infections, but it rarely causes disseminated infections. Little is known about the clinical characteristics, treatment, and prognosis of disseminated M abscessus infection. A 75-year-old Japanese woman who had been treated for 17 years with a corticosteroid for antisynthetase syndrome with antithreonyl-tRNA synthetase antibody developed swelling of her right elbow. X-ray of her right elbow joint showed osteolysis, and magnetic resonance imaging revealed fluid in her right elbow joint. M abscessus grew in joint fluid and blood cultures. She was diagnosed with a disseminated M abscessus infection following septic arthritis. Antimicrobial treatment by clarithromycin, amikacin, and imipenem/cilastatin combined with surgical debridement was administered. Although blood and joint fluid cultures became negative 1 week later, the patient died at 6 weeks from starting antimicrobial treatment. We reviewed 34 cases of disseminated M abscessus infections from the literature. Most of the patients had immunosuppressive backgrounds such as transplantation, use of immunosuppressive agents, hematological malignancy, and end stage renal disease. The duration from onset of symptoms to diagnosis was over 3 months in half of the cases. All fatal cases had positive blood cultures or use of immunosuppressive agents. Clinicians should bear in mind that mycobacterial infections including M abscessus are one of the differential diagnoses in patients with subacute arthritis and soft tissue infections. PMID- 26020394 TI - The role of laparoscopic surgery in the management of children and adolescents with inflammatory bowel disease. AB - Although laparoscopic surgery is readily used in the management of inflammatory bowel disease (IBD) in adults, its role in the surgical treatment of IBD in the pediatric population is not well established. The aim of this narrative review was to analyze the published evidence comparing laparoscopic and open resection in the management of children and adolescents with IBD. The Pubmed and Embase databases were searched using the terms "inflammatory bowel disease," "children," "adolescents," "laparoscopic," and "colectomy." The review identified 10 appropriate studies. Even though laparoscopic surgery generally resulted in longer operating times (between a mean of 40 and 140 min), benefits included reduced postoperative pain (mean duration of opiate use 3 vs 6 days) and reduced length of stay (median length of stay 5-8 vs 10.5-19 days) compared with open surgery. Postoperative complication rates were similar following both approaches. Due to the limited available data and the small sample size of the published series, definite recommendations are not able to be drawn. Nevertheless, current evidence indicates that laparoscopic colorectal resection is safe and feasible in the management of IBD in the paediatric population, with reductions in postoperative pain and length of hospital stay achievable. PMID- 26020395 TI - Surgical treatment of pulsatile tinnitus caused by the sigmoid sinus diverticulum: a preliminary study. AB - The sigmoid sinus diverticulum (SSD) is an increasingly recognized cause of pulsatile tinnitus (PT). Surgical reconstruction of the sigmoid sinus wall has been found to be highly effective for SSD; however, surgical techniques still need to be refined to reduce the incidence of serious postoperative complications. Moreover, scrutinizing more cases of SSD is desirable for establishing the diagnostic criteria and standardizing the surgical technique. This study was retrospectively undertaken in 28 patients who were diagnosed with SSD upon computed tomography angiography (CTA) and digital subtraction angiography findings at Beijing Tongren Hospital in China. A majority of patients (20/28) presented with SSD and accompanying sigmoid sinus wall dehiscence (SSWD). Twenty-five patients opted to undergo sigmoid sinus wall reconstruction, and 3 patients refused surgery. Following surgery, 17 patients experienced complete resolution of PT, 3 patients experienced partial resolution, and 5 patients experienced no change in PT. No serious complications were found postoperatively. A comparative analysis of the preoperative and postoperative CTA findings suggested that completely resolving SSD and the accompanying SSWD resulted in the elimination of PT. In conclusion, SSD is generally accompanied by SSWD. Sigmoid sinus wall reconstruction is a safe and effective approach for the treatment of SSD. During surgery, completely resolving both SSD and SSWD is advisable, and maintaining the normal diameter of the sigmoid sinus is imperative. PMID- 26020397 TI - Acute self-induced poisoning with sodium ferrocyanide and methanol treated with plasmapheresis and continuous renal replacement therapy successfully: a case report. AB - Self-induced poisoning with chemicals is one of the most commonly used suicide methods. Suicide attempts using massive pure sodium ferrocyanide and methanol are rare. This article discusses the management of acute intentional self-poisoning using sodium ferrocyanide and methanol. We present a case of acute self-induced poisoning using sodium ferrocyanide and methanol admitted to our hospital 2 hours after ingestion. He was deeply unconscious and unresponsive to painful stimuli. The laboratory findings showed acute kidney injury and severe metabolic acidosis. We took effective measures including endotracheal intubation and mechanical ventilation to ensure the vital signs were stable. Subsequently, we treated the patient using gastric lavage, bicarbonate, ethanol, plasmapheresis (plasma exchange), and continuous renal replacement therapy (CRRT) successfully. He gradually recovered from poisoning and was discharged without abnormalities on the 6th day. Follow-up for 3 months revealed no sequelae. Blood purification including plasmapheresis and CRRT is an effective method to scavenge toxicants from the body for acute self-poisoning with sodium ferrocyanide and methanol. Treatment strategies in the management of poisoning, multiple factors including the removal efficiency of toxin, the protection of vital organs, and the maintenance of homeostasis must be considered. PMID- 26020396 TI - Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observational study. AB - Rheumatoid arthritis (RA) is characterized by increased insulin resistance, a well-known risk factor for diabetes and cardiovascular diseases. The aim of the present study was to evaluate the effect of abatacept on insulin sensitivity in RA patients with moderate to severe disease despite treatment with methotrexate. Fifteen RA patients were recruited for the present study. Patients were evaluated at time 0 and after 6 months of the treatment with i.v. abatacept at the dosage recommended for weight range. Evaluation included oral glucose tolerance test (OGTT) at both time points. Insulin sensitivity was estimated with insulin sensitivity index (ISI) by Matsuda, a measure of whole-body insulin sensitivity. ISI significantly increased after the treatment with abatacept from 3.7 +/- 2.6 to 5.0 +/- 3.2 (P = 0.003) with a mean difference of 1.23. Analysis of glucose and insulin values during OGTT revealed a reduction of both glucose (303.9 +/- 73.4 mg/dL min versus 269.2 +/- 69.5 mg/dL min, P = 0.009) and insulin (208.4 +/- 119.7 mg/dL min versus 158.0 +/- 95.3 mg/dL min, P = 0.01) area under the curves (AUCs). Accordingly also glycated hemoglobin significantly improved (5.5 +/- 0.4% versus 5.3 +/- 0.3%, P = 0.04). No significant differences were found for measures of beta-cell function insulinogenic index (1.11 +/- 1.19 versus 1.32 +/- 0.82, P = 0.77) and oral disposition index (2.0 +/- 5.4 versus 6.0 +/- 6.0, P = 0.25). Treatment with abatacept seems to be able to improve whole-body insulin sensitivity in RA patients without affecting beta-cell function. PMID- 26020398 TI - Femoral version, neck-shaft angle, and acetabular anteversion in Chinese Han population: a retrospective analysis of 466 healthy adults. AB - Anatomic data regarding femoral version, neck-shaft angle, and acetabular anteversion are still limited in Chinese Han adult population. The aim of this study was to investigate the effects of age, sex, and body laterality on the 3 important anatomic indicators in Chinese Han healthy adults. Measurements were performed independently by 3 experienced observers using the picture archiving and communication system (PACS) in healthy adults who had received imaging tests of the femur and acetabulum between January 2009 and October 2014. Relevant data were measured and analyzed. A total of 466 adults (353 males and 113 females) were included. The mean femoral version, neck-shaft angle, and acetabular anteversion for all were 10.62, 133.02, and18.79, respectively. Age-based analysis showed that adults younger than 60 years had a significantly higher neck shaft angle (P < 0.001) but a significantly lower acetabular anteversion (P < 0.001) than those older than 60 years. Sex-based analysis revealed that females had significantly higher values of femoral version (P < 0.001) and acetabular anteversion (P < 0.001) than males. Laterality-based analysis found the left side had a significantly lower acetabular anteversion (P < 0.001) than the right side. Outcomes of multiple linear regression analysis indicated that femoral version may be associated with sex (P < 0.001) but not age (P = 0.076) or laterality (P = 0.430), neck-shaft angle may be associated with age (P < 0.001) but not sex (P = 0.378) or laterality (P = 0.233), and acetabular anteversion may be associated with age (P < 0.001) and sex (P < 0.001) but not laterality (P = 0.060). In this representative Chinese cohort, neck-shaft angle may decrease, whereas acetabular anteversion may increase with age, females may have higher values of femoral version and acetabular anteversion than males, and the right body side may have a higher value of acetabular anteversion than the left side. PMID- 26020399 TI - The feasibility of venovenous extracorporeal life support to treat acute respiratory failure in adult cancer patients. AB - Venovenous extracorporeal life support (VV-ECLS) is a lifesaving but invasive treatment for acute respiratory failure (ARF) that is not improved with conventional therapy. However, using VV-ECLS to treat ARF in adult cancer patients is controversial. This retrospective study included 14 cancer patients (median age: 58 years [interquartile range: 51-66]; solid malignancies in 13 patients and hematological malignancy in 1 patient) who received VV-ECLS for ARF that developed within 3 months after anticancer therapies. VV-ECLS would be considered in selected patients with a P(a)O2/F(i)O2 ratio <=70 mmHg under advanced mechanical ventilation. Before ECLS, the medians of intubation day, P(a)O2/F(i)O2 ratio, and Sequential Organ Failure Assessment (SOFA) score were 8 (2-12), 62 mmHg (53-76), and 10 (9-14), respectively. The case numbers of bacteremia, thrombocytopenia (platelet count <50000 cells/MUL), and neutropenia (actual neutrophil count <1000 cells/MUL) detected before ECLS were 3 (21%), 2 (14%), and 1 (7%), respectively. After 24 hours of ECLS, a significant improvement was seen in P(a)O2/F(i)O2 ratio but not in SOFA score. Six patients experienced major hemorrhages during ECLS. The median ECLS day, ECLS weaning rate, and hospital survival were 11 (7-16), 50% (n = 7), and 29% (n = 4). The development of dialysis-dependent nephropathy predicted death on ECLS (odds ratio: 36; 95% confidence interval: 1.8-718.7; P = 0.01). With a median follow-up of 11 (6-43) months, half of the survivors died of cancer recurrence and the others were in partial remission. The most prominent benefit of VV-ECLS is to improve the arterial oxygenation and rest the lungs. This may increase the chance of recovery from ARF in selected cancer patients. PMID- 26020401 TI - Association Between Pulmonary Function and Nonalcoholic Fatty Liver Disease in the NHANES III Study. AB - Emerging evidence indicates that nonalcoholic fatty liver disease (NAFLD) is associated with a wide variety of extrahepatic complications. However, the potential association between impaired pulmonary function and NAFLD has been less investigated. This study examined the relationship between pulmonary function and hepatic steatosis in 9976 adults participating in a cross-sectional analysis of the Third National Health and Nutrition Examination Survey (NHANES III). NAFLD was defined as hepatic steatosis presented on ultrasound examinations in the absence of other known liver diseases. The associations between predicted forced expiratory volume in 1 second (FEV1)% or predicted forced vital capacity (FVC)% and NAFLD were examined using multivariable linear regression while controlling for confounders. The association between obstructive or restrictive spirometry patterns and NAFLD was also evaluated using multivariable logistic regression analysis. After adjustment for multiple covariates, predicted FEV1% and FVC% were significantly and inversely associated with the degree of hepatic steatosis (P for trend <0.001 for both). The restrictive lung pattern was significantly related to participants with moderate and severe hepatic steatosis as compared with those without steatosis (OR 1.65, 95% CI 1.14-2.39 and OR 1.85, 95% CI 1.13 2.82), whereas the obstructive lung pattern was not associated with the presence of hepatic steatosis. Individuals with a greater degree of hepatic steatosis were at greater risk for poor pulmonary function, especially in restrictive pattern. These novel findings demonstrate that impaired pulmonary function is also an extrahepatic complication of NAFLD. PMID- 26020400 TI - Genetic Characteristics of CRF01_AE Among Newly Diagnosed HIV-1-Infected 16- to 25-Year Olds in 3 Geographic Regions of Guangxi, China. AB - The aim of this study was to analyze the distribution of clusters and drug resistance of CRF01_AE among newly diagnosed, treatment-naive HIV-infected teenagers and young adults in 3 major HIV-affected geographic regions of Guangxi Province, including the cities of Hezhou, Liuzhou, and Nanning. Samples were sequentially collected from newly diagnosed HIV-infected 16- to 25-year olds in these 3 regions from 2009 to 2013. The viral genome was extracted, and the partial pol gene was amplified and sequenced. Phylogenetic analyses were used to determine HIV-1 subtypes and CRF01_AE clusters. Transmitted drug resistance (TDR) mutations were identified using the 2009 WHO list of TDR mutations. A total of 216 sequences were obtained from CRF01_AE strains, which accounted for 83.1% of the 260 genotyped samples, of which 36 were from Hezhou, 147 from Liuzhou, and 33 in Nanning. Most (83.3%, 180/216) were from heterosexuals, followed by injection drug users (5.6%), homosexuals (4.2%), and unknown risk group (6.9%). Based on phylogenetic analyses by the maximum likelihood method, 5 distinct clusters (cluster 1-5) were identified with 213 (98.6%) sequences, whereas 3 (1.4%) sequences were ungrouped. In Hezhou, 88.9% (32/36) of CRF01_AE infections were caused by cluster 2, and 11.1% (4/36) were caused by cluster 1. In Liuzhou, 83.0% (122/147) of the CRF01_AE strains were found in cluster 1, 11.6% (17/147) from cluster 2, 1.4% (2/147) from cluster 3, 2.7% (4/147) from cluster 4, and 0.7% (1/147) from cluster 5. The distribution of CRF01_AE clusters was more even in Nanning than it was in the other 2 regions, with 18.2% (6/33) from cluster 1, 36.3% (12/33) from cluster 2, 9.1% (3/33) from cluster 3, 18.2% (6/33) from cluster 4, and 12.1% (4/33) from cluster 5. The most frequent TDR mutations were M46I (2) in the protease region and Y181C (2) from the reverse transcriptase fragment. Clusters 1 and 2 of CRF01_AE strains were prevalent in Liuzhou and Hezhou, respectively. However, multiple CRF01_AE clusters existed in Nanning. This can be partially explained by the high mobility of laborers in Nanning, the capital city of Guangxi. The prevalence of TDR was low. PMID- 26020402 TI - Utrogestan as an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. AB - A major cause of cycle cancellation during controlled ovarian hyperstimulation (COH) in women undergoing in vitro fertilization (IVF) is the occurrence of premature luteinizing hormone (LH) surges. Steroidal preparations can modulate the secretion of gonadotropins (Gn); however, few studies using progesterone to inhibit the premature LH surges in COH have been published. The purpose of the study was to evaluate the oral delivery of progesterone soft capsules (Utrogestan) to prevent LH surges from the follicular phase and to compare cycle characteristics as well as to evaluate pregnancy outcomes in subsequent frozen thawed embryo transfer (FET) cycles. A total of 374 patients were enrolled in this retrospective study, among which 187 patients were simultaneously administered Utrogestan and human menopausal gonadotrophin (hMG) from cycle day 3 until the trigger day. A short protocol including 187 controls with comparable age, body mass index (BMI), infertility duration, and antral follicle count was also used. GnRH agonist (0.1 mg) or hCG (3000 IU) was used for a trigger when the dominant follicles matured. Viable embryos were cryopreserved for later transfer in both groups. The primary outcome was the number of oocytes retrieved. The secondary outcomes included the number of mature oocytes, incidence of premature LH surge, and clinical pregnancy outcomes from FET cycles. Consistent LH suppression was achieved during COH, with a range of 0.07 to 8.9 IU/L, and no premature LH surge was detected. The number of oocytes retrieved in the Utrogestan and hMG protocol was comparable with that in the short protocol (10.92 +/- 5.74 vs 10.6 +/- 6.22, P > 0.05), and the dose of hMG was higher than that used in the short protocol (1884.22 +/- 439.47 IU vs 1446.26 +/- 550.48 IU, P < 0.05). No significant between-group difference was observed in the mature oocyte rate (88.88% vs 90.12%), cleavage rate (96.58% vs 96.58%), clinical pregnancy rate (54.27% vs 51.65%), or implantation rate (33.59% vs 34.02%). The study shows that Utrogestan is an effective oral alternative for preventing premature LH surges in women undergoing COH, which will help to establish a convenient user regimen in combination with FET. PMID- 26020403 TI - Pneumoconiosis increases the risk of peripheral arterial disease: a nationwide population-based study. AB - This nationwide population-based retrospective cohort study was used to evaluate the association between pneumoconiosis and peripheral arterial disease (PAD). We identified 3374 patients with pneumoconiosis from the catastrophic illness registry who were newly diagnosed from 2000 to 2005; 13,496 patients without pneumoconiosis from Longitudinal Health Insurance Database 2000 (LHID2000) were randomly frequency matched according to sex, age, and index year and used as a nonpneumoconiosis group. Multivariate Cox proportional hazards regression was used to calculate adjusted hazard ratios (HRs) of PAD in the pneumoconiosis group compared with the nonpneumoconiosis group. The mean follow-up years were 7.44 years in the pneumoconiosis group and 8.17 years in the nonpneumoconiosis group. The incidence density rate of PAD was 1.25 times greater in the pneumoconiosis group than in the nonpneumoconiosis group (8.37 vs 6.70 per 1000 person-years). After adjusting for sex, age, and comorbidities, the adjusted HRs of PAD for the pneumoconiosis group were 1.30 (95% CI = 1.08-1.57), compared with the nonpneumoconiosis group. The combined impacts of patients with pneumoconiosis and diabetes, hyperlipidemia, hypertension, ischemic heart disease, chronic obstructive pulmonary disease, and asthma showed a significant by joint association with PAD risk compared with patients with no pneumoconiosis and no counterpart comorbidity. Patients with pneumoconiosis have an independently higher risk of developing PAD. Physicians should include pneumoconiosis in evaluating PAD risk. PMID- 26020404 TI - Risk factors associated with end-stage renal disease (ESRD) in patients with atherosclerotic renal artery stenosis: a nationwide population-based analysis. AB - The aim of this study was to investigate the risk factors associated with end stage renal disease (ESRD) in patients with atherosclerotic renal artery stenosis (ARAS). Information about the study participants was extracted from the National Health Insurance Research Database of Taiwan for the years 1999 through 2011. We conducted this retrospective cohort study of patients with ARAS to identify the potential risk factors associated with long-term renal outcomes. A total of 2184 patients with ARAS were enrolled, of whom 840 had ESRD and were classified as the study group, and 1344 patients who were without ESRD were included in the comparison cohort. After adjusting for related variables, univariable, and multivariable logistic regression analysis showed that ESRD was associated with higher Charlson-comorbidity index (CCI) score (adjusted odds ratio [OR] = 6.78, 95% CI = 4.59-10.0 for CCI = 2; adjusted OR = 20.0, 95% CI = 13.7-29.2 for CCI >=3), diabetes (adjusted OR = 1.55, 95% CI = 1.24-1.93), hypertension (adjusted OR = 3.66, 95% CI = 2.36-5.66), and age 20 to 49-years old (adjusted OR = 2.14, 95% CI = 1.51-3.03). Moreover, our data showed that renal artery revascularization (RAR) was significantly associated with a lower risk of ESRD in ARAS patients (crude OR = 0.64, 95% CI = 0.50-0.84). Our study is the first to disclose that CCI score was significantly associated with the risk of ESRD in ARAS patients, and comorbid diseases including diabetes mellitus and hypertension significantly affect renal outcomes in patients with ARAS. Of note, our data showed that renal artery revascularization was associated with a lower risk of ESRD in ARAS patients in long-term follow-up. PMID- 26020405 TI - Clinical impact and cost-effectiveness of coronary computed tomography angiography or exercise electrocardiogram in individuals without known cardiovascular disease. AB - It is not clear whether screening by coronary computed tomographic angiography (CCTA) and/or exercise electrocardiogram (ECG) can improve clinical outcomes and reduce costs in individuals without known cardiovascular disease (CVD). In total, 71,811 consecutive individuals without known CVD who underwent general health examinations were enrolled. Using propensity-score matching according to screening tests, 1-year clinical outcomes and 6-month total and coronary artery disease-related medical costs were analyzed in separate groups: group 1 (CCTA [n = 2578] vs no screening [n = 5146]), group 2 (exercise ECG [n = 2898] vs no screening [n = 5796]), and group 3 (CCTA and exercise ECG [n = 2003] vs no screening [n = 4006]). There were no significant differences in the composite outcome of death, myocardial infarction, and stroke in each matched group: group 1 (0.35% vs 0.45%, P = 0.501), group 2 (0.14% vs 0.28%, P = 0.157), and group 3 (0.25% vs 0.27%, P = 0.858). However, revascularization was more frequent in the CCTA screening groups: group 1 (2.02% vs 0.45%, P < 0.001) and group 3 (1.40% vs 0.45%, P < 0.001). Matched screening groups had higher 6-month total and coronary artery disease-related medical costs: group 1 ($777 vs $603, P < 0.001 and $177 vs $39, P < 0.001), group 2 ($544 vs $492, P = 0.045 and $12 vs $15, P = 0.611), and group 3 ($705 vs $627, P = 0.090 and $135 vs $35, P < 0.001). In individuals without known CVD, CCTA screening with or without exercise ECG led to more frequent revascularization at the expense of higher medical costs, but did not decrease the 1-year risk of death, myocardial infarction, and stroke. PMID- 26020406 TI - Disparities of Shigellosis Rates among California Children by Race/Ethnicity and Census Tract Poverty Level, 2000-2010. AB - BACKGROUND: We examined surveillance data for disparities in shigellosis rates among children by census tract (CT) poverty level and race/ethnicity in California. METHODS: We geocoded addresses of 9740 children younger than 15 years of age from 2000-2010 California shigellosis surveillance data and calculated incidence rate (IR) per 100,000 population by age group and race/ethnicity. We linked geocoded cases to 2006-2010 American Community Survey CT-level poverty data and used IR ratios to compare children in the most impoverished CTs with those in the least impoverished CTs. The contribution of socioeconomic inequalities to age-standardized racial and ethnic disparities was explored using Poisson regression. RESULTS: Per 100,000 population, shigellosis IR was highest among California children less than 5 years old (16.4) and of Hispanic ethnicity (15.2). The age-standardized IR was 22.3 per 100,000 person-years in CTs with more than 40% of the population below the poverty line and 4.1 per 100,000 person years in CTs with less than 5% of the population below the poverty line, an IR ratio of 5.8 (95% confidence interval: 5.2, 6.5). CONCLUSIONS: Shigellosis rates among California children were highest among Hispanics and increased with CT poverty. PMID- 26020407 TI - Ebola Knowledge and Attitudes Among Pediatric Providers Before the First Diagnosed Case in the United States. AB - The 2014 Ebola virus disease outbreak triggered concerns about health-care worker (HCW) readiness. Two hundred and forty-five HCWs at a children's hospital were surveyed. Knowledge scores were lower for nurses than physicians (50-61%, P = 0.001). Despite HCWs lacking Ebola virus disease knowledge, their perceived lack of institutional preparedness and their own lack of training, most HCWs wanted to believe that they would be safe and were willing to provide care. PMID- 26020408 TI - Human Rhinovirus Types and Association with Respiratory Symptoms During the First Year of Life. AB - Human rhinoviruses (HRV) cause respiratory infections and are associated with asthma development. We assessed HRV prevalence, types and association with respiratory symptoms in the first year of life in 20 unselected infants. HRV was detected in 32% of 825 weekly nasal swabs. Seventy-four different types of all three species were identified. HRV presence and related respiratory symptoms are highly heterogeneous. PMID- 26020409 TI - Higher Prevalence and Distinct Features of Herpes Zoster Infection in Children than Adults with Systemic Lupus Erythematosus. AB - Herpes zoster infection was significantly more often observed in children (10%, N = 362) than in adults (4%, N = 1830). At herpes zoster infection diagnosis, disease activity score (8 vs. 3, P = 0.002) was higher in children, and fever (43% vs. 12%, P < 0.0001), nephritis (45% vs. 25%, P = 0.038), anti-double stranded DNA autoantibodies (76% vs. 15%, P < 0.0001) and low C4 (48% vs. 22%, P = 0.017) were more often observed in children versus adults. Post herpetic neuralgia was less common in children than adults (3% vs. 24%, P =0.005). PMID- 26020410 TI - Decreased Carriage and Genetic Shifts in the Streptococcus pneumoniae Population After Changing the Seven-valent to the Thirteen-valent Pneumococcal Vaccine in Norway. AB - BACKGROUND: Shifts in the pneumococcal population colonizing healthy children are expected after switching from a 7-valent pneumococcal conjugate vaccine (PCV7) to a 13-valent (PCV13) in the childhood immunization program. We assessed effects of the switch by comparing pneumococcal carriage and serotype and genetic diversity of pneumococci carried by children in the PCV13-era with those carried in the prevaccination-era and PCV7-era. METHODS: Nasopharyngeal swabs were obtained in autumn 2013 from children attending day-care centers (874 swabs, 583 isolates). Serotyping, multilocus sequence typing and antimicrobial susceptibility testing were performed on all isolates. Results were compared with samples from 2006 (610 swabs, 538 isolates) and 2008 (600 swabs, 562 isolates). RESULTS: The carriage prevalence in 2013 was 62 of 100 children (95% confidence intervals: 58-66), a significant decrease from 2006 and 2008. PCV13 serotypes accounted for 7% of isolates in 2013. Non-PCV13 prevalence increased from 2006 to 2008 [prevalence ratio: 1.73 (1.40-2.15)] but remained stable in 2013 [0.99 (0.88-1.12)]. Still, non-PCV13 serotypes 21, 23B, 23A and 22F had increased. In 2013, the serotype and genetic diversity had decreased slightly, and distinct serotype and genetic profiles clustered more within day-care centers compared with the earlier samples. Serotype switch was uncommon. Overall, antimicrobial resistance was limited. CONCLUSIONS: Carriage of PCV13 serotypes has decreased without a coinciding increase in non-PCV13 serotypes. The serotype and genetic shifts among non-PCV13 serotypes suggest that a new equilibrium has not yet been reached. As the few non-PCV13 serotypes that increased have generally a lower invasive capacity than vaccine serotypes, direct and indirect protection of PCV13 on invasive pneumococcal disease can be expected to continue. PMID- 26020411 TI - Pleural Effusion Increases Serum Procalcitonin Values in Children with Community acquired Pneumonia. PMID- 26020412 TI - Data Clustering using Memristor Networks. AB - Memristors have emerged as a promising candidate for critical applications such as non-volatile memory as well as non-Von Neumann computing architectures based on neuromorphic and machine learning systems. In this study, we demonstrate that memristors can be used to perform principal component analysis (PCA), an important technique for machine learning and data feature learning. The conductance changes of memristors in response to voltage pulses are studied and modeled with an internal state variable to trace the analog behavior of the device. Unsupervised, online learning is achieved in a memristor crossbar using Sanger's learning rule, a derivative of Hebb's rule, to obtain the principal components. The details of weights evolution during training is investigated over learning epochs as a function of training parameters. The effects of device non uniformity on the PCA network performance are further analyzed. We show that the memristor-based PCA network is capable of linearly separating distinct classes from sensory data with high clarification success of 97.6% even in the presence of large device variations. PMID- 26020413 TI - Chemoselective reduction and oxidation of ketones in water through control of the electron transfer pathway. AB - The selective synthesis of different products from the same starting materials in water, which is the most abundant solvent in nature, is a crucial issue as it maximizes the utilization of materials. Realizing such reactions for ketones is of considerable importance because numerous organic functionalities can be obtained via nucleophilic addition reactions. Herein, we report chemoselective reduction and oxidation reactions of 1,2-diketones in water, which initiates anionic electron transfer from the inorganic electride [Ca24Al28O64](4+).4e(-), through controlling the pathway of the electrons to substrates. The generation of different radical species for transient intermediates was the key process required to control the reaction selectivity, which was achieved by reacting the anionic electrons with either diketones or O2, leading to the formation of ketyl dianion and superoxide radicals in the reduction and oxidation reactions, respectively. This methodology that utilizes electrides may provide an alternative to the pulse radiolysis of water in synthetic chemistry. PMID- 26020414 TI - Fast simulation and optimization of pulse-train chemical exchange saturation transfer (CEST) imaging. AB - Chemical exchange saturation transfer (CEST) MRI has been increasingly applied to detect dilute solutes and physicochemical properties, with promising in vivo applications. Whereas CEST imaging has been implemented with continuous wave (CW) radio-frequency irradiation on preclinical scanners, pulse-train irradiation is often chosen on clinical systems. Therefore, it is necessary to optimize pulse train CEST imaging, particularly important for translational studies. Because conventional Bloch-McConnell formulas are not in the form of homogeneous differential equations, the routine simulation approach simulates the evolving magnetization step by step, which is time consuming. Herein we developed a computationally efficient numerical solution using matrix iterative analysis of homogeneous Bloch-McConnell equations. The proposed algorithm requires simulation of pulse-train CEST MRI magnetization within one irradiation repeat, with 99% computation time reduction from that of conventional approach under typical experimental conditions. The proposed solution enables determination of labile proton ratio and exchange rate from pulse-train CEST MRI experiment, within 5% from those determined from quantitative CW-CEST MRI. In addition, the structural similarity index analysis shows that the dependence of CEST contrast on saturation pulse flip angle and duration between simulation and experiment was 0.98 +/- 0.01, indicating that the proposed simulation algorithm permits fast optimization and quantification of pulse-train CEST MRI. PMID- 26020415 TI - Vision and Relevant Risk Factor Interventions for Preventing Falls among Older People: A Network Meta-analysis. AB - Our study objective was to determine the effect of vision intervention and combinations of different intervention components on preventing falls and fall related injuries among older people. Six electronic databases were searched to identify seven articles published before May, 2014. We conducted a systematic review of data from seven randomized controlled trails and identified eight regimens: vision intervention alone (V), vision plus exercise (referred to as physical exercise) interventions (V + E), vision plus home hazard interventions (V + HH), vision plus exercise plus home hazard interventions (V + E + HH), vision plus exercise plus sensation interventions (V + E + S), vision plus hearing interventions (V + H), vision plus various risk factor assessment and interventions (V + VRF), and the control group (C, no intervention group). The main outcome was the incidence of falls during the follow-up period. Seven papers included 2723 participants. Network meta-analysis of seven trials, using pairwise comparisons between each intervention, indicated there was no significant difference. However, there was a trend in which intervention incorporating V + VRF had more advantages than any other combination of interventions. In conclusion, V + VRF proves to be more effective than other V combination interventions in preventing falls in older people (>=65 years of age). V alone appears less effective in our network meta-analysis. PMID- 26020416 TI - L-cystathionine inhibits oxidized low density lipoprotein-induced THP-1-derived macrophage inflammatory cytokine monocyte chemoattractant protein-1 generation via the NF-kappaB pathway. AB - This study aimed to explore whether and how L-cystathionine had any regulatory effect on the inflammatory response in THP-1-derived macrophages cultured in vitro under oxidized low-density lipoprotein (ox-LDL) stimulation. The human monocyte line THP-1 cell was cultured in vitro and differentiated into macrophages after 24 hours of PMA induction. Macrophages were pretreated with L cystathionine and then treated with ox-LDL. The results showed that compared with the controls, ox-LDL stimulation significantly upregulated the expression of THP 1-derived macrophage MCP-1 by enhancing NF-kappaB p65 phosphorylation, nuclear translocation and DNA binding with the MCP-1 promoter. Compared with the ox-LDL group, 0.3 mmol/L and 1.0 mmol/L L-cystathionine significantly inhibited the expression of THP-1-derived macrophage MCP-1. Mechanistically, 0.3 mmol/L and 1.0 mmol/L L-cystathionine suppressed phosphorylation and nuclear translocation of the NF-kappaB p65 protein, as well as the DNA binding activity and DNA binding level of NF-kappaB with the MCP-1 promoter, which resulted in a reduced THP-1 derived macrophage MCP-1 generation. This study suggests that L-cystathionine could inhibit the expression of MCP-1 in THP-1-derived macrophages induced by ox LDL via inhibition of NF-kappaB p65 phosphorylation, nuclear translocation, and binding of the MCP-1 promoter sequence after entry into the nucleus. PMID- 26020417 TI - Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. AB - PURPOSE: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder of lipid metabolism caused by mutations in LDLR, APOB, and PCSK9. To fulfill the World Health Organization recommendation, the Portuguese FH Study was established. Here, we report the results of the past 15 years and present practical considerations concerning the genetic diagnosis of FH based on our experience. METHODS: Our approach comprises a biochemical and molecular study and is divided into five phases, including the study of whole APOB and functional assays. RESULTS: A total of 2,122 individuals were enrolled. A putative pathogenic variant was identified in 660 heterozygous patients: LDLR (623), APOB (33), and PCSK9 (4); 8 patients presented with homozygous FH. A detection rate of 41.5% was observed. A stricter biochemical criteria was shown to improve patient identification. Overall, we have identified 3.4% and 80% of all heterozygous and homozygous patients, respectively, estimated to exist in our country. CONCLUSION: The Portuguese FH Study has established the genetic diagnosis of FH in Portugal and is committed to continue the investigation of the genetic complexity of FH. Genetic diagnosis of FH should be expanded to include the study of all coding/flanking regions of APOB and functional in vitro studies, to improve the correct patient identification, and to avoid misdiagnosis.Genet Med 18 4, 316 324. PMID- 26020419 TI - Rebuttal From Dr Berger et al. PMID- 26020418 TI - Age-related macular degeneration: genome-wide association studies to translation. AB - In recent years, genome-wide association studies (GWAS), which are able to analyze the contribution to disease of genetic variations that are common within a population, have attracted considerable investment. Despite identifying genetic variants for many conditions, they have been criticized for yielding data with minimal clinical utility. However, in this regard, age-related macular degeneration (AMD), the most common form of blindness in the Western world, is a striking exception. Through GWAS, common genetic variants at a number of loci have been discovered. Two loci in particular, including genes of the complement cascade on chromosome 1 and the ARMS2/HTRA1 genes on chromosome 10, have been shown to convey significantly increased susceptibility to developing AMD. Today, although it is possible to screen individuals for a genetic predisposition to the disease, effective interventional strategies for those at risk of developing AMD are scarce. Ongoing research in this area is nonetheless promising. After providing brief overviews of AMD and common disease genetics, we outline the main recent advances in the understanding of AMD, particularly those made through GWAS. Finally, the true merit of these findings and their current and potential translational value is examined.Genet Med 18 4, 283-289. PMID- 26020423 TI - Attitudinal Ambivalence as a Protective Factor Against Junk Food Advertisements: A Moderated Mediation Model of Behavioral Intention. AB - This study investigates the role of attitudinal ambivalence in moderating the effects of junk food advertisements on behavioral intentions by tapping different facets of this construct-felt ambivalence, potential ambivalence, and affective cognitive ambivalence. Results based on an online survey of college students indicate that attention to junk food advertisements has an indirect positive effect on intentions to eat junk food through its positive effect on attitudes toward junk food. A moderated mediation model reveals that this indirect effect of junk food advertisements is weakened as respondents' levels of felt ambivalence increase. This moderating role is not observed for the measures of potential ambivalence and affective-cognitive ambivalence. Implications are discussed for health interventions. PMID- 26020424 TI - Blocking tumor growth by targeting autophagy and SQSTM1 in vivo. AB - Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials in response to starvation and maintenance of cellular homeostasis. Dysfunction of autophagy is implicated in a variety of diseases including cancer. In a recent study, we devised a system for inducible deletion of an essential autophagy gene Rb1cc1/Fip200 in established tumor cells in vivo and showed that Rb1cc1 is required for maintaining tumor growth. We further investigated the role of the accumulated SQSTM1 in Rb1cc1-null autophagy deficient tumor cells. To our surprise, the increased SQSTM1 was not responsible for the inhibition of tumor growth, but rather supported the residual growth of tumors (i.e., partially compensated for the defective growth caused by Rb1cc1 deletion). Further analysis indicated that SQSTM1 promoted tumor growth in autophagy-deficient cells at least partially through its activation of the NFKB signaling pathway. A working model is proposed to account for our findings, which suggest that targeting both autophagy and the consequently increased SQSTM1 may be exploited for developing more effective cancer therapies. PMID- 26020425 TI - Comparison based on environmental effects of nitrogen management techniques in a manure digestate case study. AB - Due to climate issues and favourable energy market, biogas is spreading as a manure management technique. Digestate is rich in nutrient and has to be handled in order to respect the 'nitrate directive' that limits nitrogen field application in areas defined as vulnerable. In this study, we compared different nitrogen management scenarios: a non-treatment option, a biological short-cut nitrification, a complete autotrophic process (anammox) and ammonia stripping from membrane filtration concentrate. The environmental effect comparison was obtained with 'Cross media effects analysis' and life cycle assessment (LCA). The results were different in some aspects, especially the impacts on eutrophication. According to cross media, the best process is DENO 2, while LCA shows similar impacts for all techniques and the best solution would be the no-treatment option. The main reason to adopt a digestate treatment technique is the lack of area for a correct disposal. If LCA eutrophication results are multiplied with the hectares necessary for each technology, a result similar to that of cross media is obtained. PMID- 26020426 TI - Improving ED specimen TAT using Lean Six Sigma. AB - PURPOSE: Lean and Six Sigma are continuous improvement methodologies that have garnered international fame for improving manufacturing and service processes. Increasingly these methodologies are demonstrating their power to also improve healthcare processes. The purpose of this paper is to discuss a case study for the application of Lean and Six Sigma tools in the reduction of turnaround time (TAT) for Emergency Department (ED) specimens. This application of the scientific methodologies uncovered opportunities to improve the entire ED to lab system for the specimens. DESIGN/METHODOLOGY/APPROACH: This case study provides details on the completion of a Lean Six Sigma project in a 1,000 bed tertiary care teaching hospital. Six Sigma's Define, Measure, Analyze, Improve, and Control methodology is very similar to good medical practice: first, relevant information is obtained and assembled; second, a careful and thorough diagnosis is completed; third, a treatment is proposed and implemented; and fourth, checks are made to determine if the treatment was effective. Lean's primary goal is to do more with less work and waste. The Lean methodology was used to identify and eliminate waste through rapid implementation of change. FINDINGS: The initial focus of this project was the reduction of turn-around-times for ED specimens. However, the results led to better processes for both the internal and external customers of this and other processes. The project results included: a 50 percent decrease in vials used for testing, a 50 percent decrease in unused or extra specimens, a 90 percent decrease in ED specimens without orders, a 30 percent decrease in complete blood count analysis (CBCA) Median TAT, a 50 percent decrease in CBCA TAT Variation, a 10 percent decrease in Troponin TAT Variation, a 18.2 percent decrease in URPN TAT Variation, and a 2-5 minute decrease in ED registered nurses rainbow draw time. PRACTICAL IMPLICATIONS: This case study demonstrated how the quantitative power of Six Sigma and the speed of Lean worked in harmony to improve the blood draw process for a 1,000 bed tertiary care teaching hospital. The blood draw process is a standard process used in hospitals to collect blood chemistry and hematology information for clinicians. The methods used in this case study demonstrated valuable and practical applications of process improvement methodologies that can be used for any hospital process and/or service environment. ORIGINALITY/VALUE: While this is not the first case study that has demonstrated the use of continuous process improvement methodologies to improve a hospital process, it is unique in the way in which it utilizes the strength of the project focussed approach that adheres more to the structure and rigor of Six Sigma and relied less on the speed of lean. Additionally, the application of these methodologies in healthcare is emerging research. PMID- 26020427 TI - Improving screening for diabetes in cystic fibrosis. AB - PURPOSE: Annual screening for cystic fibrosis-related-diabetes (CFRD) using oral glucose tolerance test (OGTT) is recommended, but national testing rates are low. The purpose of this paper is to implement the quality improvement (QI) initiative to improve cystic fibrosis (CF) annual screening rates among patients at one CF center. DESIGN/METHODOLOGY/APPROACH: To improve screening for CFRD at the CF Center, the authors used the Dartmouth Microsystem Improvement Ramp method and formed a collaborative working group. A process map was created to outline the steps and a fishbone analysis was performed to identify barriers and to utilize resources for implementing new interventions. FINDINGS: Prior to these interventions, 21 percent of eligible patients had completed annual screening and after the intervention, it rose to 72 percent. The initial completion rate with the first prescription was only 50 percent, but it improved steadily to 54/75 (72 percent) in response to reminder letters sent six weeks after the initial script was given. PRACTICAL IMPLICATIONS: Close tracking and reminder letters can improve adherence with annual OGTT screening for CFRD among CF patients, with special emphasis on high-risk patients. ORIGINALITY/VALUE: There should be a special emphasis on screening for CFRD in high-risk CF patients (those with low BMI or higher age). This QI initiative brought about several operational changes in the annual OGTT screening process that have now become the standard operating procedure at the center. PMID- 26020428 TI - Customer perceived service quality, satisfaction and loyalty in Indian private healthcare. AB - PURPOSE: The purpose of this paper is to analyse how perceived service quality and customer satisfaction lead to loyalty towards healthcare service providers. DESIGN/METHODOLOGY/APPROACH: In total, 475 hospital patients participated in a questionnaire survey in five Indian private hospitals. Descriptive statistics, factor analysis, regression and correlation statistics were employed to analyse customer perceived service quality and how it leads to loyalty towards service providers. FINDING: Results indicate that the service seeker-service provider relationship, quality of facilities and the interaction with supporting staff have a positive effect on customer perception. PRACTICAL IMPLICATIONS: Findings help healthcare managers to formulate effective strategies to ensure a better quality of services to the customers. This study helps healthcare managers to build customer loyalty towards healthcare services, thereby attracting and gaining more customers. ORIGINALITY/VALUE: This paper will help healthcare managers and service providers to analyse customer perceptions and their loyalty towards Indian private healthcare services. PMID- 26020429 TI - Agile, a guiding principle for health care improvement? AB - PURPOSE: The purpose of this paper is to contribute to increased understanding of the concept agile and its potential for hospital managers to optimize design of organizational structures and processes to combine internal efficiency and external effectiveness. DESIGN/METHODOLOGY/APPROACH: An integrative review was conducted using the reSEARCH database. Articles met the following criteria: first, a definition of agility; second, descriptions of enablers of becoming an agile organization; and finally, discussions of agile on multiple organizational levels. In total, 60 articles qualified for the final analysis. FINDINGS: Organizational agility rests on the assumption that the environment is uncertain, ranging from frequently changing to highly unpredictable. Proactive, reactive or embracive coping strategies were described as possible ways to handle such uncertain environments. Five organizational capacities were derived as necessary for hospitals to use the strategies optimally: transparent and transient inter organizational links; market sensitivity and customer focus; management by support for self-organizing employees; organic structures that are elastic and responsive; flexible human and resource capacity for timely delivery. Agile is portrayed as either the "new paradigm" following lean, the needed development on top of a lean base, or as complementary to lean in distinct hybrid strategies. PRACTICAL IMPLICATIONS: Environmental uncertainty needs to be matched with coping strategies and organizational capacities to design processes responsive to real needs of health care. This implies that lean and agile can be combined to optimize the design of hospitals, to meet different variations in demand and create good patient management. ORIGINALITY/VALUE: While considerable value has been paid to strategies to improve the internal efficiency within hospitals, this review raise the attention to the value of strategies of external effectiveness. PMID- 26020430 TI - Exploring the effect of complex patients on care delivery tasks. AB - PURPOSE: The needs of complex patients with chronic conditions can be unpredictable and can strain resources. Exploring how tasks vary for different patients, particularly those with complex needs, can yield insights about designing better processes in healthcare. The purpose of this paper is to explore the tasks required to manage complex patients in an anticoagulation therapy context. DESIGN/METHODOLOGY/APPROACH: The authors analyzed interviews with 55 staff in six anticoagulation clinics using the Systems Engineering Initiative for Patient Safety (SEIPS) work system framework. The authors qualitatively described complex patients and their effects on care delivery. FINDINGS: Data analysis highlighted how identifying complex patients and their effect on tasks and organization, and the interactions between them was important. Managing complex patients required similar tasks as non-complex patients, but with greater frequency or more intensity and several additional tasks. After complex patients and associated patient interaction and care tasks were identified, a work system perspective was applied to explore how such tasks are integrated within clinics and the resulting implications for resource allocation. PRACTICAL IMPLICATIONS: The authors present a complex patient management framework to guide workflow design in specialty clinics, to better support high quality, effective, efficient and safe healthcare. ORIGINALITY/VALUE: The complex patient framework presented here, based on the SEIPS framework, suggests a more formal and integrated analysis be completed to provide better support for appropriate resource allocation and care coordination. PMID- 26020431 TI - Investigating emergency room service quality using lean manufacturing. AB - PURPOSE: The purpose of this paper is to investigate a lean manufacturing metric called Takt time as a benchmark evaluation measure to evaluate a public hospital's service quality. Lean manufacturing is an established managerial philosophy with a proven track record in industry. A lean metric called Takt time is applied as a measure to compare the relative efficiency between two emergency departments (EDs) belonging to the same public hospital. Outcomes guide managers to improve patient services and increase hospital performances. DESIGN/METHODOLOGY/APPROACH: The patient treatment lead time within the hospital's two EDs (one department serves male and the other female patients) are the study's focus. A lean metric called Takt time is used to find the service's relative efficiency. FINDINGS: Findings show that the lean manufacturing metric called Takt time can be used as an effective way to measure service efficiency by analyzing relative efficiency and identifies bottlenecks in different departments providing the same services. ORIGINALITY/VALUE: The paper presents a new procedure to compare relative efficiency between two EDs. It can be applied to any healthcare facility. PMID- 26020432 TI - Service quality in contracted facilities. AB - PURPOSE: The purpose of this paper is to explore the readiness of contracted and non-contracted first-level healthcare facilities in Pakistan to deliver quality maternal and neonatal health (MNH) care. A balanced scorecard (BSC) was used as the assessment framework. DESIGN/METHODOLOGY/APPROACH: Using a cross-sectional study design, two rural health centers (RHCs) contracted out to Aga Khan Health Service, Pakistan were compared with four government managed RHCs. A BSC was designed to assess RHC readiness to deliver good quality MNH care. In total 20 indicators were developed, representing five BSC domains: health facility functionality, service provision, staff capacity, staff and patient satisfaction. Validated data collection tools were used to collect information. Pearson chi2, Fisher's Exact and the Mann-Whitney tests were applied as appropriate to detect significant service quality differences among the two facilities. FINDINGS: Contracted facilities were generally found to be better than non-contracted facilities in all five BSC domains. Patients' inclination for facility-based delivery at contracted facilities was, however, significantly higher than non contracted facilities (80 percent contracted vs 43 percent non-contracted, p=0.006). PRACTICAL IMPLICATIONS: The study shows that contracting out initiatives have the potential to improve MNH care. ORIGINALITY/VALUE: This is the first study to compare MNH service delivery quality across contracted and non contracted facilities using BSC as the assessment framework. PMID- 26020433 TI - Care quality instruments. AB - PURPOSE: The purpose of this paper is to describe instruments used for quality assessment in acute care. Quality care assessment is essential for improving care delivery. Quality instruments can be used to evaluate nurse and patient perspectives in multi-professional care. Therefore, valid and reliable measurement instruments are vital. DESIGN/METHODOLOGY/APPROACH: A literature search identified several instruments that measure quality from a nurse and patient perspectives. The questionnaires were appraised in several steps with specific criteria: psychometric properties, underlying construct or test theory, study context, sample characteristics and target population. FINDINGS: Overall, 14 instruments were evaluated, but only eight questionnaires represented nurse and patient views regarding quality. Instruments showed several disparities in their theoretical foundations and their psychometric properties. Two instruments did not provide validity data and one questionnaire did not report reliability data. PRACTICAL IMPLICATIONS: To inform healthcare managers about acute care quality, the authors demonstrated the need for more valid and reliable measurements by using the Guidelines for Critiquing Instrument Development and Validation Reports to evaluate quality care instruments' psychometric properties. ORIGINALITY/VALUE: There is a long tradition in quality care evaluations using questionnaires. Only a few instruments can be recommended for practical use. PMID- 26020434 TI - In Vivo Quantitative MR Imaging of Bound and Pore Water in Cortical Bone. AB - PURPOSE: To translate and evaluate an in vivo magnetic resonance (MR) imaging protocol for quantitative mapping of collagen-bound and pore water concentrations in cortical bone that involves relaxation-selective ultrashort echo time (UTE) methods. MATERIALS AND METHODS: All HIPAA-compliant studies were performed with institutional review board approval and written informed consent. UTE imaging sequences were implemented on a clinical 3.0-T MR imaging unit and were used for in vivo imaging of bound and pore water in cortical bone. Images of the lower leg and wrist were acquired in five volunteers each (lower leg: two men and three women aged 24, 24, 49, 30, and 26 years; wrist: two men and three women aged 31, 23, 25, 24, and 26 years) to generate bound and pore water concentration maps of the tibia and radius. Each volunteer was imaged three times, and the standard error of the measurements at the region-of-interest (ROI) level was computed as the standard deviation across studies, pooled across volunteers and ROIs. RESULTS: Quantitative bound and pore water maps in the tibia and radius, acquired in 8-14 minutes, had per-voxel signal-to-noise ratios of 18 (bound water) and 14 (pore water) and inter-study standard errors of approximately 2 mol (1)H per liter of bone at the ROI level. CONCLUSION: The results of this study demonstrate the feasibility of quantitatively mapping bound and pore water in vivo in human cortical bone with practical human MR imaging constraints. PMID- 26020435 TI - Assessment of Hepatic Vascular Network Connectivity with Automated Graph Analysis of Dynamic Contrast-enhanced US to Evaluate Portal Hypertension in Patients with Cirrhosis: A Pilot Study. AB - PURPOSE: To test whether graph analysis of vascular images obtained with hepatic dynamic contrast material-enhanced (DCE) ultrasonography (US) allows calculation of the degree of organization of the liver circulation and whether graph properties are correlated to the severity of portal hypertension. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Fifteen patients with liver cirrhosis (nine men; mean age +/- standard deviation, 55 years +/- 8) who underwent DCE US and hepatic venous pressure gradient (HVPG) measurement and four healthy subjects (two men and two women; mean age, 34 years +/- 4) were included between January 2007 and December 2008. Individual graph models ("vascular connectomes") were computed on the basis of time series analysis of video sequences of DCE US examinations (conducted with the disruption-reperfusion technique). Graph analysis was performed, and the clustering coefficient C was calculated. Correlations between clustering coefficient and HVPG were assessed. RESULTS: Healthy subjects had a high clustering coefficient of vascular connectome (C = 0.4447; interquartile range [IQR], 0.3864-0.4679), suggesting a highly organized hepatic vascular network. Conversely, patients with cirrhosis showed a low clustering coefficient, indicating disruption of normal anatomy (C = 0.0288; IQR, 0.0157-0.0861; P = .001 vs healthy subjects). The clustering coefficient decreased as HVPG increased, with a clustering coefficient of 0.0237 (IQR, 0.0066-0.0378) in patients with HVPG of at least 10 mm Hg versus 0.1180 (IQR, 0.0987-0.1414) in those with HVPG of less than 10 mm Hg (P = .006). The correlation between the best model derived from the distribution of the clustering coefficient (10 bins) of vascular connectome and HVPG had a Pearson correlation of 0.977 (root mean squared error, 1.57 mm Hg; P < .0001). CONCLUSION: This pilot study demonstrates that graph modeling of vascular connectivity based on video processing of liver DCE US examinations and subsequent graph analysis enable calculation of personalized parameters that reflect the degree of organization of the hepatic microvascular network and are correlated to the severity of portal hypertension in cirrhosis. PMID- 26020437 TI - Adrenal Vein Sampling in Primary Aldosteronism: Sensitivity and Specificity of Basal Adrenal Vein to Peripheral Vein Cortisol and Aldosterone Ratios to Confirm Catheterization of the Adrenal Vein. AB - PURPOSE: To assess the sensitivity and specificity for ratios of adrenal vein cortisol level (Ca) to peripheral vein cortisol level (Cp), adrenal vein aldosterone level (Aa) to peripheral vein aldosterone level (Ap), and combined cortisol and aldosterone levels ("combined ratio") for the detection of successful adrenal vein catheterization ("selectivity") in adrenal vein sampling (AVS) without adrenocorticotropic hormone (ACTH) injection at different cutoff values. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. AVS was performed in 160 consecutive patients (49 women and 111 men; mean age, 53.6 years) between December 1989 and January 2014. Cortisol and aldosterone levels were measured in samples from the adrenal veins and left iliac vein every 5 minutes, two times before (basal) and three times after intravenous cosyntropin (ACTH 1-24) injection. Selectivity was defined by Ca/Cp or Aa/Ap ratio of at least 5 in at least one sampling after ACTH administration. Sensitivity and specificity for the detection of selective adrenal vein catheterization were calculated for basal Ca/Cp ratio, Aa/Ap ratio, and combined ratios for three cutoff values reported in the literature. The McNemar test was used to assess differences in sensitivity and specificity to detect selective adrenal vein catheterization. RESULTS: The sensitivity and specificity for the cutoff values of at least 3, at least 2, and at least 1.1 for the detection of AVS selectivity were respectively 50.4% and 100%, 70.8% and 100%, and 98.5% and 76.9% for Ca/Cp ratio; 61.3% and 100%, 70.8% and 100%, and 94.2% and 53.8% for Aa/Ap ratio; and 75.2% and 100%, 88.3% and 100%, and 99.3% and 46.2% for combined ratios (sensitivity at the >=2 cutoff value: P < .0001 for combined ratio vs Ca/Cp ratio and for combined ratio vs Aa/Ap ratio). CONCLUSION: Basal combined ratio has the best sensitivity for the detection of AVS selectivity at all cutoff values, and for all ratios, the cutoff value of at least 2 has the best sensitivity for 100% specificity. PMID- 26020436 TI - Observer Performance in the Detection and Classification of Malignant Hepatic Nodules and Masses with CT Image-Space Denoising and Iterative Reconstruction. AB - PURPOSE: To determine if lower-dose computed tomographic (CT) scans obtained with adaptive image-based noise reduction (adaptive nonlocal means [ANLM]) or iterative reconstruction (sinogram-affirmed iterative reconstruction [SAFIRE]) result in reduced observer performance in the detection of malignant hepatic nodules and masses compared with routine-dose scans obtained with filtered back projection (FBP). MATERIALS AND METHODS: This study was approved by the institutional review board and was compliant with HIPAA. Informed consent was obtained from patients for the retrospective use of medical records for research purposes. CT projection data from 33 abdominal and 27 liver or pancreas CT examinations were collected (median volume CT dose index, 13.8 and 24.0 mGy, respectively). Hepatic malignancy was defined by progression or regression or with histopathologic findings. Lower-dose data were created by using a validated noise insertion method (10.4 mGy for abdominal CT and 14.6 mGy for liver or pancreas CT) and images reconstructed with FBP, ANLM, and SAFIRE. Four readers evaluated routine-dose FBP images and all lower-dose images, circumscribing liver lesions and selecting diagnosis. The jackknife free-response receiver operating characteristic figure of merit (FOM) was calculated on a per-malignant nodule or per-mass basis. Noninferiority was defined by the lower limit of the 95% confidence interval (CI) of the difference between lower-dose and routine-dose FOMs being less than -0.10. RESULTS: Twenty-nine patients had 62 malignant hepatic nodules and masses. Estimated FOM differences between lower-dose FBP and lower-dose ANLM versus routine-dose FBP were noninferior (difference: -0.041 [95% CI: -0.090, 0.009] and -0.003 [95% CI: -0.052, 0.047], respectively). In patients with dedicated liver scans, lower-dose ANLM images were noninferior (difference: +0.015 [95% CI: -0.077, 0.106]), whereas lower-dose FBP images were not (difference -0.049 [95% CI: -0.140, 0.043]). In 37 patients with SAFIRE reconstructions, the three lower-dose alternatives were found to be noninferior to the routine-dose FBP. CONCLUSION: At moderate levels of dose reduction, lower dose FBP images without ANLM or SAFIRE were noninferior to routine-dose images for abdominal CT but not for liver or pancreas CT. PMID- 26020438 TI - Observer Variability for Classification of Pulmonary Nodules on Low-Dose CT Images and Its Effect on Nodule Management. AB - PURPOSE: To examine the factors that affect inter- and intraobserver agreement for pulmonary nodule type classification on low-radiation-dose computed tomographic (CT) images, and their potential effect on patient management. MATERIALS AND METHODS: Nodules (n = 160) were randomly selected from the Dutch Belgian Lung Cancer Screening Trial cohort, with equal numbers of nodule types and similar sizes. Nodules were scored by eight radiologists by using morphologic categories proposed by the Fleischner Society guidelines for management of pulmonary nodules as solid, part solid with a solid component smaller than 5 mm, part solid with a solid component 5 mm or larger, or pure ground glass. Inter- and intraobserver agreement was analyzed by using Cohen kappa statistics. Multivariate analysis of variance was performed to assess the effect of nodule characteristics and image quality on observer disagreement. Effect on nodule management was estimated by differentiating CT follow-up for ground-glass nodules, solid nodules 8 mm or smaller, and part-solid nodules smaller than 5 mm from immediate diagnostic work-up for solid nodules larger than 8 mm and part solid nodules 5 mm or greater. RESULTS: Pair-wise inter- and intraobserver agreement was moderate (mean kappa, 0.51 [95% confidence interval, 0.30, 0.68] and 0.57 [95% confidence interval, 0.47, 0.71]). Categorization as part-solid nodules and location in the upper lobe significantly reduced observer agreement (P = .012 and P < .001, respectively). By considering all possible reading pairs (28 possible combinations of observer pairs * 160 nodules = 4480 possible agreements or disagreements), a discordant nodule classification was found in 36.4% (1630 of 4480), related to presence or size of a solid component in 88.7% (1446 of 1630). Two-thirds of these discrepant readings (1061 of 1630) would have potentially resulted in different nodule management. CONCLUSION: There is moderate inter- and intraobserver agreement for nodule classification by using current recommendations for low-radiation-dose CT examinations of the chest. Discrepancies in nodule categorization were mainly caused by disagreement on the size and presence of a solid component, which may lead to different management in the majority of cases with such discrepancies. ((c)) RSNA, 2015. PMID- 26020439 TI - Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model. AB - PURPOSE: To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice. MATERIALS AND METHODS: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis. RESULTS: Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P <= .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images. CONCLUSION: Three dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy. PMID- 26020440 TI - Focal Nodular Hyperplasia and Hepatocellular Adenoma: Accuracy of Gadoxetic Acid enhanced MR Imaging--A Systematic Review. AB - PURPOSE: To perform a systematic review to evaluate the diagnostic accuracy of hepatobiliary (HPB) phase gadoxetic acid-enhanced MR imaging of the liver in the diagnosis of focal nodular hyperplasia (FNH) versus hepatocellular adenoma (HCA) and to identify the rate of (a) reported HCAs that are iso- or hyperintense to liver and (b) reported FNHs that are hypointense to liver on HPB phase MR images. MATERIALS AND METHODS: The institutional review board granted a waiver for this study type, and multiple databases were searched for studies in which researchers distinguished between FNH and HCA with gadoxetic acid-enhanced MR imaging. Studies to evaluate diagnostic accuracy were included; case reports and series were included to analyze the rate of iso- or hyperintense HCAs on HPB phase MR images. Risk of bias was assessed by using the Quality Assessment Tool for Diagnostic Accuracy Studies-2. Sensitivity and specificity were plotted with a forest plot; pooling was not performed because a small number of heterogeneous studies were included. Rate of iso- or hyperintense HCA on HPB phase gadoxetic acid-enhanced MR images was evaluated. RESULTS: Six studies (309 patients; 164 with HCA, 233 with FNH) were included for diagnostic accuracy assessment. Twelve case series (129 patients; 81 with HCA, 70 with FNH) were included (studies with insufficient 2 * 2 table data for diagnostic accuracy assessment). Sensitivity was high (range, 0.91-1.00; lower margin of the 95% confidence interval: 0.77). Specificity was high (range, 0.87-1.00; lower margin of the 95% confidence interval: 0.54). Specificity was lowest among studies in which molecular subtyping of HCA was performed. Rate of iso-or hyperintensity of HCA on HPB phase MR images was variable (range, 0%-67%) and occurred more frequently in the inflammatory subtype. High risk of bias was identified in the domains of patient selection and reference standard. CONCLUSION: The reported diagnostic accuracy of HPB phase gadoxetic acid-enhanced MR imaging in the diagnosis of HCA versus FNH is high; however, studies are few, heterogeneous, and at high risk for bias, indicating that diagnostic accuracy may be overestimated. PMID- 26020441 TI - Reconstructing breakage fusion bridge architectures using noisy copy numbers. AB - The Breakage Fusion Bridge (BFB) process is a key marker for genomic instability, producing highly rearranged genomes in relatively small numbers of cell cycles. While the process itself was observed during the late 1930s, little is known about the extent of BFB in tumor genome evolution. Moreover, BFB can dramatically increase copy numbers of chromosomal segments, which in turn hardens the tasks of both reference-assisted and ab initio genome assembly. Based on available data such as Next Generation Sequencing (NGS) and Array Comparative Genomic Hybridization (aCGH) data, we show here how BFB evidence may be identified, and how to enumerate all possible evolutions of the process with respect to observed data. Specifically, we describe practical algorithms that, given a chromosomal arm segmentation and noisy segment copy number estimates, produce all segment count vectors supported by the data that can be produced by BFB, and all corresponding BFB architectures. This extends the scope of analyses described in our previous work, which produced a single count vector and architecture per instance. We apply these analyses to a comprehensive human cancer dataset, demonstrate the effectiveness and efficiency of the computation, and suggest methods for further assertions of candidate BFB samples. Source code of our tool can be found online. PMID- 26020442 TI - Prognostic value of novel biomarkers compared with detailed biochemical evaluation in patients with heart failure. AB - INTRODUCTION: The assessment of prognosis is crucial for the clinical management of patients with heart failure (HF). OBJECTIVES: The aim of the study was to evaluate the usefulness of novel biomarkers for the assessment of prognosis in patients with HF, compared with a detailed assessment based on routine laboratory tests. PATIENTS AND METHODS: The study included 179 patients with HF. In all patients, routine laboratory tests were performed and selected biomarkers were measured (N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, growth hormone, myeloperoxidase, metaloproteinase 9, procollagen type III, soluble toll like receptor 2, insulin growth factor, and neutrophil gelatinase-associated lipocain). The primary endpoint was death or urgent heart transplantation, while the secondary endpoints encompassed primary endpoints plus cardioverter intervention or hospitalization for HF. RESULTS: The mean age of the study group was 52.5 years (91% were men). Most patients had advanced HF. During a 6-month follow-up, 21 primary endpoints and 63 secondary endpoints were recorded. A multiple regression analysis showed that of all laboratory variables and biomarkers, only uric acid and sodium were independent predictors of primary endpoints, and only estimated glomerular filtration rate had a predictive value for secondary endpoints. None of the biomarkers were a significant prognostic factor in the study population. CONCLUSIONS: Biomarkers do not outweigh the value of standard laboratory tests. Routine laboratory workup allows to assess multiorgan damage and provides the most significant prognostic data. Biochemical tests should remain the gold standard for the assessment of prognosis in patients with HF. PMID- 26020443 TI - Probing DNA interactions with proteins using a single-molecule toolbox: inside the cell, in a test tube and in a computer. AB - DNA-interacting proteins have roles in multiple processes, many operating as molecular machines which undergo dynamic meta-stable transitions to bring about their biological function. To fully understand this molecular heterogeneity, DNA and the proteins that bind to it must ideally be interrogated at a single molecule level in their native in vivo environments, in a time-resolved manner, fast enough to sample the molecular transitions across the free-energy landscape. Progress has been made over the past decade in utilizing cutting-edge tools of the physical sciences to address challenging biological questions concerning the function and modes of action of several different proteins which bind to DNA. These physiologically relevant assays are technically challenging but can be complemented by powerful and often more tractable in vitro experiments which confer advantages of the chemical environment with enhanced detection signal-to noise of molecular signatures and transition events. In the present paper, we discuss a range of techniques we have developed to monitor DNA-protein interactions in vivo, in vitro and in silico. These include bespoke single molecule fluorescence microscopy techniques to elucidate the architecture and dynamics of the bacterial replisome and the structural maintenance of bacterial chromosomes, as well as new computational tools to extract single-molecule molecular signatures from live cells to monitor stoichiometry, spatial localization and mobility in living cells. We also discuss recent developments from our laboratory made in vitro, complementing these in vivo studies, which combine optical and magnetic tweezers to manipulate and image single molecules of DNA, with and without bound protein, in a new super-resolution fluorescence microscope. PMID- 26020444 TI - Real-time 3D visualization of the thoraco-abdominal surface during breathing with body movement and deformation extraction. AB - Real-time 3D visualization of the breathing displacements can be a useful diagnostic tool in order to immediately observe the most active regions on the thoraco-abdominal surface. The developed method is capable of separating non relevant torso movement and deformations from the deformations that are solely related to breathing. This makes it possible to visualize only the breathing displacements. The system is based on the structured laser triangulation principle, with simultaneous spatial and color data acquisition of the thoraco abdominal region. Based on the tracking of the attached passive markers, the torso movement and deformation is compensated using rigid and non-rigid transformation models on the three-dimensional (3D) data. The total time of 3D data processing together with visualization equals 20 ms per cycle.In vitro verification of the rigid movement extraction was performed using the iterative closest point algorithm as a reference. Furthermore, a volumetric evaluation on a live subject was performed to establish the accuracy of the rigid and non-rigid model. The root mean square deviation between the measured and the reference volumes shows an error of +/-0.08 dm(3) for rigid movement extraction. Similarly, the error was calculated to be +/-0.02 dm(3) for torsional deformation extraction and +/-0.11 dm(3) for lateral bending deformation extraction. The results confirm that during the torso movement and deformation, the proposed method is sufficiently accurate to visualize only the displacements related to breathing. The method can be used, for example, during the breathing exercise on an indoor bicycle or a treadmill. PMID- 26020445 TI - Optical Activity and Dehydration-Driven Switching of Magnetic Properties in Enantiopure Cyanido-Bridged Co(II)3W(V)2 Trigonal Bipyramids. AB - The unique enantiopure {[Lambda-Co(II)((R)-mpm)2]3[W(V)(CN)8]2}.9H2O [(R)-1] and {[Delta-Co(II)((S)-mpm)2]3[W(V)(CN)8]2}.9H2O [(S)-1], where mpm = alpha methylpyridinemethanol, magnetic spongelike materials, crystallizing in the chiral P21 space group, are constructed of cyanido-bridged {Co3W2} trigonal bipyramids with three cis-[Co(II)(mpm)2(MU-NC)2] moieties in equatorial sites and two [W(V)(CN)8](3-) units in apical positions. The arrangement of {Co3W2} clusters in the crystal lattice is controlled by interactions with crystallization H2O molecules, resulting in two independent hydrogen-bonding systems: the first weaving along open channels in the a direction (weakly bonded H2O) and the second closed in the cages formed by the surrounding [W(CN)8](3-) and mpm fragments (strongly bonded H2O). The strong optical activity of (R)- and (S)-1 together with continuous chirality measure (CCM) analysis confirms the chirality transfer from enantiopure (R)- and (S)-mpm to [Co(mpm)2(MU-NC)2] units, a cyanido-bridged skeleton, and to the whole crystal lattice. Magnetic properties confronted with ab initio calculations prove the ferromagnetic couplings within Co(II)-NC-W(V) linkages inside {Co3W2} molecules, accompanied by weak antiferromagnetic intermolecular interactions. The reversible removal of weakly bonded H2O above 50 degrees C induces the structural phase transition 1 ? 1deh and strongly affects the magnetic characteristics. The observed changes can be interpreted in terms of the combined effects of the decreasing strength of ferromagnetic Co(II)-W(V) coupling and the increasing role of antiferromagnetic intermolecular correlation, both connected with dehydration-induced structural modifications in the clusters' core and supramolecular network of 1. PMID- 26020446 TI - Two-dimensional Kagome phosphorus and its edge magnetism: a density functional theory study. AB - By means of density functional theory calculations, we predict a new two dimensional phosphorus allotrope with the Kagome-like lattice(Kagome-P). It is an indirect gap semiconductor with a band gap of 1.64 eV. The gap decreases sensitively with the compressive strain. In particular, shrinking the lattice beyond 13% can drive it into metallic state. In addition, both the AA and AB stacked Kagome-P multi-layer structures exhibit a bandgap much smaller than 1.64 eV. Edges in the Kagome-P monolayer probably suffer from the edge reconstruction. An isolated zigzag edge can induce antiferromagnetic (AF) ordering with a magnetic transition temperature of 23 K. More importantly, when applying a stretching strain beyond 4%, such an edge turns to possess a ferromagnetic ground state. A very narrow zigzag-edged Kagome-P ribbon displays the spin moment distribution similar to the zigzag-edged graphene nanoribbon because of the coupling between the opposites edges. But the inter-edge coupling in the Kagome-P ribbon vanishes more rapidly as the ribbon width increases. These properties make it a promising material in spintronics. PMID- 26020447 TI - Chemical Makeup and Hydrophilic Behavior of Graphene Oxide Nanoribbons after Low Temperature Fluorination. AB - Here we investigated the fluorination of graphene oxide nanoribbons (GONRs) using H2 and F2 gases at low temperature, below 200 degrees C, with the purpose of elucidating their structure and predicting a fluorination mechanism. The importance of this study is the understanding of how fluorine functional groups are incorporated in complex structures, such as GONRs, as a function of temperature. The insight provided herein can potentially help engineer application-oriented materials for several research and industrial sectors. Direct (13)C pulse magic angle spinning (MAS) nuclear magnetic resonance (NMR) confirmed the presence of epoxy, hydroxyl, ester and ketone carbonyl, tertiary alkyl fluorides, as well as graphitic sp(2)-hybridized carbon. Moreover, (19)F (13)C cross-polarization MAS NMR with (1)H and (19)F decoupling confirmed the presence of secondary alkyl fluoride (CF2) groups in the fluorinated graphene oxide nanoribbon (FGONR) structures fluorinated above 50 degrees C. First principles density functional theory calculations gained insight into the atomic arrangement of the most dominant chemical groups. The fluorinated GONRs present atomic fluorine percentages in the range of 6-35. Interestingly, the FGONRs synthesized up to 100 degrees C, with 6-19% of atomic fluorine, exhibit colloidal similar stability in aqueous environments when compared to GONRs. This colloidal stability is important because it is not common for materials with up to 19% fluorine to have a high degree of hydrophilicity. PMID- 26020448 TI - Multianalytical Study of Historical Luminescent Lithopone for the Detection of Impurities and Trace Metal Ions. AB - We have explored the performance of an integrated multianalytical approach to the analysis of a series of microsamples of historical lithopone (a coprecipitate of ZnS + BaSO4) produced at the beginning of the 20th century, based on the combination of spectrally- and lifetime-resolved photoluminescence (PL) microscopy imaging and electron paramagnetic resonance (EPR) spectroscopy. Multispectral imaging of the PL emission from microsamples revealed the presence of different luminescence centers emitting in the visible spectrum, which we have hypothesized as trace Cu and Mn impurities unintentionally introduced into the ZnS crystal lattice during synthesis, which act as deep traps for electrons. Time resolved PL imaging analyses highlighted the microsecond decay-kinetic behavior of the emission, confirming the trap state nature of the luminescence centers. EPR confirmed the presence of Cu and Mn, further providing information on the microenvironment of defects in the ZnS crystalline lattice related to specific paramagnetic ions. The multianalytical approach provides important insights into the historical synthesis of lithophone and will be useful for the rapid screening and mapping of impurities in complex semiconductor pigments and other artists' materials. PMID- 26020449 TI - First Base-Free Catalytic Wittig Reaction. AB - The first base-free catalytic Wittig reaction utilizing readily available Bu3P (5 mol %) as an organocatalyst is reported. The initial Michael addition of the phosphine to a suitable acceptor substituted alkene ultimately results in the formation of an ylide which is subsequently converted with an aldehyde. The presented (1)H NMR studies actually reveal evidence for the Michael addition and proposed ylide formation. Under the optimized reaction conditions various maleates and fumarates were converted with aromatic, heteroaromatic, and aliphatic aldehydes to evaluate the scope and limitations of this unprecedented reaction. Notably, maleates and fumarates react in a stereoconvergent fashion. The corresponding products were obtained in up to 95% isolated yield and E/Z selectivities up to 99:1. PMID- 26020450 TI - Effect of Pore Size and Interactions on Paracetamol Aggregation in Porous Polyethylene Glycol Diacrylate Polymers. AB - In this study, we report the results of an all-atom molecular dynamics (MD) based simulation that elucidates the effect of pore size and interactions on the aggregation of paracetamol in polyethylene glycol diacrylate (PEGDA) polymers. Recent experimental studies ( J. Am. Chem. Soc. 2011 , 133 , 3756 - 3759 ) have shown that nucleation rate of paracetamol is highest in one of the PEGDA polymers (PEG200DA) but lack clear understanding of the factors responsible for this anomaly. Our simulation results show that paracetamol aggregation is predominantly governed by the size of PEGDA pores and that the polymer paracetamol interactions play a secondary role. The probability of formation of paracetamol aggregates, especially of size four, is highest for pore sizes in the range of 14-25 A, and the drug-drug angle distributions in all the PEGDA polymers that we have studied here have characteristics of both forms I and II of paracetamol crystals. We also demonstrate that the pores in PEGDA polymers can be further engineered by the use of a suitable solvent concentration to achieve pore sizes optimal for improved paracetamol aggregation. PMID- 26020451 TI - Factors Influencing the Clinical Stratification of Suitability to Drive after Stroke: A Qualitative Study. AB - While a clinical pre-selection screening process for a stroke patient's suitability for driving has been acknowledged, little is known about the factors or processes influencing this screening typically conducted by clinicians practicing at a generalist level. This study explored this clinical stratification process through the use of semi-structured interviews with senior occupational therapists (n = 17) and stroke physicians (n = 7) using qualitative description methodology. The findings revealed a trichotomy stratification of stroke patients for driving in the clinical setting; those who are fit to drive, unfit to drive, and a "maybe" group who need more detailed assessment and observation. Factors that had a major influence on this clinical-based stratification of driving suitability were client's levels of awareness, insight, and impulsivity. A period of prolonged contact with the client was preferential to guide the stratification decision in order for clinicians to build a comprehensive picture of the person. A mix of assessment approaches including standardized assessment but with increased emphasis on naturalistic observation of functional performance underpinned the clinical stratification process. This study uncovers some of the factors and processes influencing the early clinical based stratification of driving suitability after stroke, and highlights the contribution of the generalist practitioner in the assessment of fitness to drive continuum. PMID- 26020452 TI - Performance Assessment in Fingerprinting and Multi Component Quantitative NMR Analyses. AB - An interlaboratory comparison (ILC) was organized with the aim to set up quality control indicators suitable for multicomponent quantitative analysis by nuclear magnetic resonance (NMR) spectroscopy. A total of 36 NMR data sets (corresponding to 1260 NMR spectra) were produced by 30 participants using 34 NMR spectrometers. The calibration line method was chosen for the quantification of a five-component model mixture. Results show that quantitative NMR is a robust quantification tool and that 26 out of 36 data sets resulted in statistically equivalent calibration lines for all considered NMR signals. The performance of each laboratory was assessed by means of a new performance index (named Qp-score) which is related to the difference between the experimental and the consensus values of the slope of the calibration lines. Laboratories endowed with a Qp-score falling within the suitable acceptability range are qualified to produce NMR spectra that can be considered statistically equivalent in terms of relative intensities of the signals. In addition, the specific response of nuclei to the experimental excitation/relaxation conditions was addressed by means of the parameter named NR. NR is related to the difference between the theoretical and the consensus slopes of the calibration lines and is specific for each signal produced by a well-defined set of acquisition parameters. PMID- 26020453 TI - The Association Between Heroin Inhalation and Early Onset Emphysema. AB - BACKGROUND: Inhalation/smoking has become the most common method of recreational opiate consumption in the United Kingdom and other countries. Although some heroin smokers appear to develop COPD, little is known about the association. METHODS: We present data from a cohort of 73 heroin smokers with clinician diagnosed and spirometrically confirmed COPD, seen within our clinical service, where symptoms developed before the age of 40 years. RESULTS: The whole group mean age at diagnosis was 41 years, subjects had smoked heroin for 14 years, and mean FEV1 was 1.08 L (31.5% predicted), with mean FEV1/FVC of 0.4. No subject was found to have severe alpha1-antitrypsin deficiency. Forty-four subjects had either a high-resolution CT (HRCT) scan (32) or measurement of lung diffusion (12). Overall HRCT scan emphysema score averaged across the upper, middle, and lower part of the lung was 2.3 (5%-25% emphysema), with 47% subjects having an upper lobe emphysema score >= 3 (25%-50% emphysema). Median diffusing capacity of the lung for carbon monoxide was 48% of predicted value. CONCLUSIONS: Recreational smoking of heroin appears to lead to early onset COPD with a predominant emphysema phenotype. This message is important to both clinicians and the public, and targeted screening and education of this high-risk population may be justified. PMID- 26020454 TI - Impact of Electrode Density of States on Transport through Pyridine-Linked Single Molecule Junctions. AB - We study the impact of electrode band structure on transport through single molecule junctions by measuring the conductance of pyridine-based molecules using Ag and Au electrodes. Our experiments are carried out using the scanning tunneling microscope based break-junction technique and are supported by density functional theory based calculations. We find from both experiments and calculations that the coupling of the dominant transport orbital to the metal is stronger for Au-based junctions when compared with Ag-based junctions. We attribute this difference to relativistic effects, which result in an enhanced density of d-states at the Fermi energy for Au compared with Ag. We further show that the alignment of the conducting orbital relative to the Fermi level does not follow the work function difference between two metals and is different for conjugated and saturated systems. We thus demonstrate that the details of the molecular level alignment and electronic coupling in metal-organic interfaces do not follow simple rules but are rather the consequence of subtle local interactions. PMID- 26020455 TI - In-Depth Understanding of the Morphology-Performance Relationship in Polymer Solar Cells. AB - It is well-established that thermal annealing optimizes the morphology and improves the efficiency of P3HT-based organic solar cells, but the effects of different cooling rates after annealing are not well understood. In this paper, we use a model system based on poly(3-hexylthiophene) (P3HT) and phenyl-C61 butyric acid methyl ester (PCBM) to examine the relationship between morphology and device performance for annealing before (preannealing) and after (postannealing) the application of the electrode, with different cooling rates and in different device architectures. In the conventional structure, postannealing is confirmed to significantly enhance efficiency. The device prepared with a slow cooling rate (3.6%) shows a higher average power conversion efficiency than that prepared with a fast cooling rate (3.3%). The microstructural changes underlying this 10% increase in device performance and further effects of cooling rate, pre- and postannealing, and device architecture are comprehensively examined with a combination of synchrotron-based techniques, including grazing incidence wide-angle X-ray scattering, near-edge X-ray absorption fine structure spectroscopy, and X-ray photoelectron spectroscopy. The best device in the conventional architecture (postannealed with slow cooling rate) shows a more face-on orientation and narrower orientational distribution of P3HT crystallites. In addition, postannealing leads to PCBM diffusion toward the blend/top electrode interface. The enrichment of PCBM at the blend/top electrode interface plays a positive role in aiding electron collection at the electrode in the conventional structure, but it has a negative effect on the performance of the inverted structure, where hole collection at the top electrode instead is required. For this reason, in an inverted structure, preannealed films with slow cooling exhibit the best photovoltaic performance. PMID- 26020456 TI - Helical Antimicrobial Sulfono-gamma-AApeptides. AB - Host-defense peptides (HDPs) such as magainin 2 have emerged as potential therapeutic agents combating antibiotic resistance. Inspired by their structures and mechanism of action, herein we report the first example of antimicrobial helical sulfono-gamma-AApeptide foldamers. The lead molecule displays broad spectrum and potent antimicrobial activity against multi-drug-resistant Gram positive and Gram-negative bacterial pathogens. Time-kill studies and fluorescence microscopy suggest that sulfono-gamma-AApeptides eradicate bacteria by taking a mode of action analogous to that of HDPs. Clear structure-function relationships exist in the studied sequences. Longer sequences, presumably adopting more-defined helical structures, are more potent than shorter ones. Interestingly, the sequence with less helical propensity in solution could be more selective than the stronger helix-forming sequences. Moreover, this class of antimicrobial agents are resistant to proteolytic degradation. These results may lead to the development of a new class of antimicrobial foldamers combating emerging antibiotic-resistant pathogens. PMID- 26020457 TI - 2D Homologous Perovskites as Light-Absorbing Materials for Solar Cell Applications. AB - We report on the fabrication and properties of the semiconducting 2D (CH3(CH2)3NH3)2(CH3NH3)(n-1)Pb(n)I(3n+1) (n = 1, 2, 3, and 4) perovskite thin films. The band gaps of the series decrease with increasing n values, from 2.24 eV (CH3(CH2)3NH3)2PbI4 (n = 1) to 1.52 eV CH3NH3PbI3 (n = infinity). The compounds exhibit strong light absorption in the visible region, accompanied by strong photoluminescence at room temperature, rendering them promising light absorbers for photovoltaic applications. Moreover, we find that thin films of the semi-2D perovskites display an ultrahigh surface coverage as a result of the unusual film self-assembly that orients the [Pb(n)I(3n+1)](-) layers perpendicular to the substrates. We have successfully implemented this 2D perovskite family in solid-state solar cells, and obtained an initial power conversion efficiency of 4.02%, featuring an open-circuit voltage (V(oc)) of 929 mV and a short-circuit current density (J(sc)) of 9.42 mA/cm(2) from the n = 3 compound. This result is even more encouraging considering that the device retains its performance after long exposure to a high-humidity environment. Overall, the homologous 2D halide perovskites define a promising class of stable and efficient light-absorbing materials for solid-state photovoltaics and other applications. PMID- 26020458 TI - Microfluidic Production of Semipermeable Microcapsules by Polymerization-Induced Phase Separation. AB - Semipermeable microcapsules are appealing for controlled release of drugs, study of cell-to-cell communication, and isolation of enzymes or artificial catalysts. Here, we report a microfluidic strategy for creating monodisperse microcapsules with size-selective permeability using polymerization-induced phase separation. Monodisperse water-in-oil-in-water (W/O/W) double-emulsion drops, whose ultrathin middle layer is composed of photocurable resin and inert oil, are generated in a capillary microfluidic device, and irradiated by UV light. Upon UV illumination, the monomers are photopolymerized, which leads to phase separation between the polymerized resin and the oil within the ultrathin shell. Subsequent dissolution of the oil leaves behind regular pores in the polymerized membrane that interconnect the interior and exterior of the microcapsules, thereby providing size-selective permeability. The degree of phase separation can be further tuned by adjusting the fraction of oil in the shell or the affinity of the oil to the monomers, thereby enabling the control of the cutoff value of permeation. High mechanical stability and chemical resistance of the microcapsules, as well as controllable permeability and high encapsulation efficiency, will provide new opportunity in a wide range of applications. PMID- 26020459 TI - Multilayer Multiconfiguration Time-Dependent Hartree Theory. AB - Multilayer multiconfiguration time-dependent Hartree (ML-MCTDH) theory is a rigorous and powerful method to simulate quantum dynamics in complex many-body systems. This approach extends the original MCTDH theory of Meyer, Manthe, and Cederbaum to include dynamically contracted layers in a recursive way, within which the equations of motion are determined from the Dirac-Frenkel variational principle. This paper presents the general derivation of the theory and analyzes the important features that make the ML-MCTDH method numerically efficient. Furthermore, we discuss the generalization of the theory to treat many-body identical particles (fermions or bosons) as well as calculating energy eigenstates via the improved relaxation method. PMID- 26020460 TI - Slow-Reduction Synthesis of a Thiolate-Protected One-Dimensional Gold Cluster Showing an Intense Near-Infrared Absorption. AB - Slow reduction of Au ions in the presence of 4-(2-mercaptoethyl)benzoic acid (4 MEBA) gave Au76(4-MEBA)44 clusters that exhibited a strong (3 * 10(5) M(-1) cm( 1)) near-infrared absorption band at 1340 nm. Powder X-ray diffraction studies indicated that the Au core has a one-dimensional fcc structure that is elongated along the {100} direction. PMID- 26020461 TI - A New Nomenclature for Psychotropic Drugs. AB - INTRODUCTION: Current classifications of psychotropic drugs, developed in the 1960s, are based on beliefs about clinical effectiveness. This article evaluates the scientific validity of current drug terms and possible alternative classifications. METHODS: A historical, conceptual, and empirical review of the psychopharmacology literature is provided. Consistency of classification is examined by 3 major categories: chemical structure, pharmacodynamic mechanism, and clinical efficacy. RESULTS: Current drug terms based on clinical effectiveness are not valid scientifically, either claiming efficacy which is disproven or ignoring other areas of clinical efficacy. Hence, clinical efficacy is not a consistent and scientifically valid way of classifying psychotropic drugs. Chemical structures are also heterogeneous for drugs with similar clinical efficacy. The most consistent way to define drug classes is pharmacodynamic mechanism. Specific drug groups identified are: monoamine agonists ("antidepressants" and "stimulants"), dopamine blockers ("antipsychotics"), second messenger modifiers ("mood stabilizers), and gabaergic agonists ("anxiolytics" or "hypnotics"). CONCLUSIONS: Consistent with a recent proposal of psychopharmacology organizations, this article proposes a new nomenclature based mainly on biological pharmacodynamic mechanisms. Specific terms that are scientifically valid and clinically practical are suggested. It is hoped that this new language would allow for more meaningful and accurate communication between clinicians and patients. PMID- 26020462 TI - Extreme Duration of Diazepam-Associated Sedation in a Patient With Alcohol Delirium and CYP2C19 Polymorphisms. PMID- 26020463 TI - Using Sulfur Stable Isotopes to Understand Feeding Behavior and Selenium Concentrations in Yellow Perch (Perca flavescens). AB - We measured selenium (Se) concentrations in yellow perch (Perca flavescens) muscle and their prey collected from four Se-contaminated lakes located near metal smelters in the eastern Canadian cities of Sudbury and Rouyn-Noranda. Yellow perch Se concentrations were related to their weight in two of the four lakes. Measurements of sulfur stable isotopes (delta(34)S) in yellow perch muscle and stomach contents showed that larger fish tended to feed less on zooplankton and more on benthic invertebrates than did smaller fish. Because Se concentrations are lower and delta(34)S signatures are higher in zooplankton than in sediment-feeding invertebrates, there was an inverse relationship between animal Se concentrations and delta(34)S signatures in all of our study lakes. delta(34)S signatures were highly effective in characterizing these food web relationships. Selenium concentrations in yellow perch were 1.6 times those of its prey, which indicates that Se is biomagnified by this fish in our study lakes. Estimated Se concentrations in yellow perch gonads suggest that in two of our study lakes one-third of fish are at risk of reproductive toxicity. PMID- 26020464 TI - Low Fouling Electrospun Scaffolds with Clicked Bioactive Peptides for Specific Cell Attachment. AB - While electrospun fibers are of interest as scaffolds for tissue engineering applications, nonspecific surface interactions such as protein adsorption often prevent researchers from controlling the exact interactions between cells and the underlying material. In this study we prepared electrospun fibers from a polystyrene-based macroinitiator, which were then grafted with polymer brushes using surface-initiated atom transfer radical polymerization (SI-ATRP). These brush coatings incorporated a trimethylsilyl-protected PEG-alkyne monomer, allowing azide functional molecules to be covalently attached, while simultaneously reducing nonspecific protein adsorption on the fibers. Cells were able to attach and spread on fibrous substrates functionalized with a pendant RGD containing peptide, while spreading was significantly reduced on nonfunctionalized fibers and those with the equivalent RGE control peptide. This effect was observed both in the presence and absence of serum in the culture media, indicating that protein adsorption on the fibers was minimal and cell adhesion within the fibrous scaffold was mediated almost entirely through the cell-adhesive RGD-containing peptide. PMID- 26020465 TI - Synthesis and Resolution of Substituted [5]Carbohelicenes. AB - Three types of racemic [5]helicenyl acetates (1a, 2, and 3a) were synthesized. The synthesis of 2 was achieved by regioselective oxidation using o-iodoxybenzoic acid. The enzymatic kinetic resolution of 1a-3a was studied. The conversion with the highest rate and ee was obtained using 1a as the substrate and lipase Amano PS-IM as the enzyme. The two enantiomers of 1-[5]helicenol 3b were separated using (1S)-10-camphorsulfonyl chloride as the chiral resolving agent. PMID- 26020466 TI - Hot-electron effect in spin relaxation of electrically injected electrons in intrinsic Germanium. AB - The hot-electron effect in the spin relaxation of electrically injected electrons in intrinsic germanium is investigated by the kinetic spin Bloch equations both analytically and numerically. It is shown that in the weak-electric-field regime with E ? 0.5 kV cm(-1), our calculations have reasonable agreement with the recent transport experiment in the hot-electron spin-injection configuration (2013 Phys. Rev. Lett. 111 257204). We reveal that the spin relaxation is significantly enhanced at low temperature in the presence of weak electric field E ? 50 V cm(-1), which originates from the obvious center-of-mass drift effect due to the weak electron-phonon interaction, whereas the hot-electron effect is demonstrated to be less important. This can explain the discrepancy between the experimental observation and the previous theoretical calculation (2012 Phys. Rev. B 86 085202), which deviates from the experimental results by about two orders of magnitude at low temperature. It is further shown that in the strong electric-field regime with 0.5 ? E ? 2 kV cm(-1), the spin relaxation is enhanced due to the hot-electron effect, whereas the drift effect is demonstrated to be marginal. Finally, we find that when 1.4 ? E ? 2 kV cm(-1) which lies in the strong-electric-field regime, a small fraction of electrons (?5%) can be driven from the L to Gamma valley, and the spin relaxation rates are the same for the Gamma and L valleys in the intrinsic sample without impurity. With the negligible influence of the spin dynamics in the Gamma valley to the whole system, the spin dynamics in the L valley can be measured from the Gamma valley by the standard direct optical transition method. PMID- 26020467 TI - Plastic surgical and nonsurgical procedure statistics 2014. PMID- 26020468 TI - Leadership and emotional intelligence: does it matter? PMID- 26020469 TI - Enemies of ethics equals environmental exodus, part 1. AB - Nursing is known as a respected profession in society. Nursing is also ranked as a leading career fostering unethical behavior amongst one another. Historically, nurses are known to "eat their young," meaning new graduate nurses may undergo a brief period of hazing conducted by the experienced nurse. In the past two decades, research demonstrates an increasing trend, often acceptable within an organization, of bullying, lateral violence and mobbing amongst nurses. This type of intentional repetitive harassment inflicts physical and psychological harm to nursing colleagues. It is important for nurses to be familiar with signs of bullying, feel confident in sharing the observation with leadership, and possess the knowledge to make an ethical decision. This type of aggression within an organization affects all employees, the organization's finances and reputation, and most importantly, the quality of patient care, all negatively. The culture of an organization reflects the leadership. Transformational management style, open communication, behavioral expectations, policies and procedures, along with a zero-tolerance course of action for bullying behaviors, are necessary when developing a healthy workplace environment. Laws and regulations in certain states are in place supporting healthy workplace environments. Public awareness concerning bullying, mobbing, and harassment within the workplace has increased secondary to the media's publicity on the subject. Nurses should reflect on the theoretical frameworks of the nursing profession and strive to role model virtues of integrity, ethics and civility within their personal and professional life. PMID- 26020470 TI - Hair transplant: a basic review. AB - The hairline is an important aspect of beauty. Loss of the hairline can contribute to poor self-esteem. Alopecia, or hair loss, has many different causes and can have devastating outcomes to the patient. The plastic surgery team may play a role in restoring the hairline and thus improving one's image of self. This article identifies the different causes of hair loss and then reviews steps and options for hairline restoration. PMID- 26020471 TI - Update on neurotoxins for facial rejuvenation: what they are, how they work, and how to effectively and safely use them. AB - The formal aesthetic introduction of botulinum toxin (i.e., neurotoxins) more than a decade ago has revolutionized the nonsurgical aesthetic market and transformed society's view of facial rejuvenation. Understanding the similarities and differences between U.S. commercially available neurotoxins, their characteristics and composition, where they are effective, their mechanism of action, and how to safely administer them will enable the aesthetic provider to successfully utilize this powerful tool and ultimately deliver optimal facial rejuvenation outcomes. An update on neurotoxins on the horizon is also provided. Please note that this article discusses neurotoxin use in treatment areas that are considered "off label" by the Food and Drug Administration. PMID- 26020472 TI - Plastic surgery ethics: beyond face value. PMID- 26020473 TI - Pediatric burns of the hand. PMID- 26020474 TI - Management of hypotrichosis of the eyelashes: focus on bimatoprost. AB - Prominent eyelashes are generally recognized as enhancing beauty and are often desired by women. Until recently, the options available to augment the prominence of eyelashes were limited to makeup, over-the-counter products, artificial eyelashes, and eyelash transplantation. Originally approved for the treatment of ocular hypertension, the prostamide, bimatoprost, is now approved for the treatment of hypotrichosis of the eyelashes. Bimatoprost ophthalmic solution 0.03%, applied once daily to the skin of the upper eyelid margin using sterile single-use-per-eye applicators, increases eyelash growth, including length, thickness, and darkness. The effectiveness of bimatoprost for eyelash growth has been demonstrated by clinician ratings, digital image analysis, and patient reported measures of satisfaction. The effects of bimatoprost treatment on eyelash length, thickness, and darkness are believed to result from longer anagen duration, increased hair bulb thickness, and increased melanogenesis, respectively. Dermally applied bimatoprost appears to be associated with a lower incidence of adverse events than administration of the medication as an eyedrop. This more favorable safety and tolerability profile is likely mediated by decreased exposure of ocular tissues to bimatoprost when applied dermally. Taken together, available data suggest that cutaneous application of bimatoprost ophthalmic solution 0.03% safely and effectively enhances upper eyelash growth. PMID- 26020475 TI - Skin and skin substitutes--an overview. PMID- 26020476 TI - Elucidating the reaction pathways in the synthesis of organolead trihalide perovskite for high-performance solar cells. AB - The past two years have witnessed unprecedentedly rapid development of organic inorganic halide perovskite-based solar cells. The solution-processability and high efficiency make this technology extraordinarily attractive. The intensive investigations have accumulated rich experiences in the perovskite fabrication; while the mechanism of the chemical synthesis still remains unresolved. Here, we set up the chemical equation of the synthesis and elucidate the reactions from both thermodynamic and kinetic perspectives. Our study shows that gaseous products thermodynamically favour the reaction, while the activation energy and "collision" probability synergistically determine the reaction rate. These understandings enable us to finely tune the crystal size for high-quality perovskite film, leading to a record fill factor among similar device structures in the literature. This investigation provides a general strategy to explore the mechanism of perovskite synthesis and benefits the fabrication of high-efficiency perovskite photoactive layer. PMID- 26020477 TI - GABAB receptor upregulates fragile X mental retardation protein expression in neurons. AB - Fragile X mental retardation protein (FMRP) is an RNA-binding protein important for the control of translation and synaptic function. The mutation or silencing of FMRP causes Fragile X syndrome (FXS), which leads to intellectual disability and social impairment. gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the mammalian central nervous system, and its metabotropic GABAB receptor has been implicated in various mental disorders. The GABAB receptor agonist baclofen has been shown to improve FXS symptoms in a mouse model and in human patients, but the signaling events linking the GABAB receptor and FMRP are unknown. In this study, we found that GABAB receptor activation upregulated cAMP response element binding protein-dependent Fmrp expression in cultured mouse cerebellar granule neurons via two distinct mechanisms: the transactivation of insulin-like growth factor-1 receptor and activation of protein kinase C. In addition, a positive allosteric modulator of the GABAB receptor, CGP7930, stimulated Fmrp expression in neurons. These results suggest a role for GABAB receptor in Fmrp regulation and a potential interest of GABAB receptor signaling in FXS improvement. PMID- 26020478 TI - High-throughput screening for a moderately halophilic phenol-degrading strain and its salt tolerance response. AB - A high-throughput screening system for moderately halophilic phenol-degrading bacteria from various habitats was developed to replace the conventional strain screening owing to its high efficiency. Bacterial enrichments were cultivated in 48 deep well microplates instead of shake flasks or tubes. Measurement of phenol concentrations was performed in 96-well microplates instead of using the conventional spectrophotometric method or high-performance liquid chromatography (HPLC). The high-throughput screening system was used to cultivate forty-three bacterial enrichments and gained a halophilic bacterial community E3 with the best phenol-degrading capability. Halomonas sp. strain 4-5 was isolated from the E3 community. Strain 4-5 was able to degrade more than 94% of the phenol (500 mg . L(-1) starting concentration) over a range of 3%-10% NaCl. Additionally, the strain accumulated the compatible solute, ectoine, with increasing salt concentrations. PCR detection of the functional genes suggested that the largest subunit of multicomponent phenol hydroxylase (LmPH) and catechol 1,2-dioxygenase (C12O) were active in the phenol degradation process. PMID- 26020479 TI - The effects of body position and muscle activation on patellar tendon reflex properties. AB - Our purpose was to examine the effects of body position and a low-intensity voluntary contraction on patellar tendon tap reflex properties.Surface electromyography, torque, and accelerometry signals were obtained from 30 subjects (25.0 +/- 4.6 years) during patellar tendon taps. These signals were used to quantify reflex magnitude and the subcomponents of reflex latency for each subject in the upright position (i.e. control), supine position, and during alpha-gamma coactivation (i.e. a low-intensity contraction). The Jendrassik maneuver was also performed to examine any potential benefits beyond that of standard reinforcement.Neither experimental condition significantly altered reflex magnitude. However, the supine body position condition resulted in a significant decrease in reflex latency (p = 0.037) which appears largely attributable to a decreased electromechanical delay. Interestingly, the low intensity contraction had no effect on any of the latency components.The assessment of reflex latency can be improved by utilizing a supine body position. This effect may be due to the presence of slack within musculotendinous structures during the traditional upright position. A voluntary contraction, however, does not enhance the reflex response beyond that of standard reinforcement. Limitations regarding the use of a light contraction during tendon taps are discussed for future investigations. PMID- 26020480 TI - Mycobacterium bovis Enterocolitis in an Immunocompromised Host. PMID- 26020481 TI - Pediatric Eosinophilic Esophagitis in Slovenia: Data From a Retrospective 2005 2012 Epidemiological Study. AB - OBJECTIVES: The aim of the present study was to assess the incidence, characteristics, therapeutic approach, and response to therapy of eosinophilic esophagitis (EoE) in a pediatric population from Slovenia. METHODS: A retrospective study was conducted on a cohort of children newly diagnosed as having EoE, ages 0 to 18 years, residing in Slovenia, in the period between 2005 and 2012. For each child presenting symptoms, family and personal history of allergies, blood, skin and patch allergy tests, endoscopic and histological findings, types of therapy, and therapeutic success were recorded. RESULTS: In total, 25 patients of EoE were identified during the study period. The mean annual incidence (per 100,000 children) was 0.8 (95% confidence interval [CI] 0.58-1.16). The incidences of EoE increased from 0.2 (0.01-1.36), 0.3 (0.01 1.38), and 0.3 (0.01-1.40) in the period 2005-2007, respectively, to 1.8 (0.72 3.76), 1.0 (0.28-2.60), and 1.8 (0.72-3.65) in the period 2010-2012, respectively (P = 0.002). In 9 patients, symptomatic and histological remissions were achieved with specific food elimination diet: in 8 with 6-food elimination diet and in 1 with an additional budesonide. In majority of patients, budesonide improved only symptoms, but esophageal eosinophilia persisted. Twenty percent of our children had improvement of histology and symptoms of EoE in spite of gradual reintroduction of all food and stopping all medication. CONCLUSIONS: The annual incidence of childhood EoE in Slovenia is comparable with the reports from the developed European countries, and it increased by 6-folds in the last decade. PMID- 26020482 TI - Symptom Profiles in Patients With Irritable Bowel Syndrome or Functional Abdominal Pain Compared With Healthy Controls. AB - OBJECTIVES: Patient-reported outcome (PRO) measures of gastrointestinal symptoms are recommended to determine treatment effects for irritable bowel syndrome (IBS) and functional abdominal pain (FAP). Study objectives were to compare the symptom profiles of pediatric patients with IBS or FAP with healthy controls and with each other using the PedsQL Gastrointestinal Symptoms and Gastrointestinal Worry Scales, and to establish clinical interpretability of PRO scale scores through identification of minimal important difference (MID) scores. METHODS: Gastrointestinal Symptoms and Worry Scales were completed in a 9-site study by 154 pediatric patients and 161 parents (162 families; IBS n = 46, FAP n = 119). Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were administered along with Gastrointestinal Worry Scales. A matched sample of 447 families with healthy children completed the scales. RESULTS: Gastrointestinal Symptoms and Worry Scales distinguished between patients with IBS or FAP compared with healthy controls (P < 0.001), with larger effect sizes (>1.50) for symptoms indicative of IBS or FAP, demonstrating a broad multidimensional gastrointestinal symptom profile and clinical interpretability with MID scores for individual PRO scales. Patients with IBS manifested more symptoms of constipation, gas and bloating, and diarrhea than patients with FAP. CONCLUSIONS: Patients with IBS or FAP manifested a broad gastrointestinal symptom profile compared with healthy controls with large differences, indicating the critical need for more effective interventions to bring patient functioning within the range of healthy functioning. PMID- 26020483 TI - Assessment of Promoter Hypermethylation and Expression Profile of P14ARF and MDM2 Genes in Patients With Pterygium. AB - BACKGROUND: Pterygium is a fairly general condition in many regions of the world. The cause of this abnormality is still ambiguous. However, recent findings suggest that pterygium is a benign progressive tissue and not a degenerative disorder. The main goal of our study was to investigate the effects of P14 and MDM2 promoter methylation on the risk of pterygium. MATERIALS AND METHODS: In this study, the DNA of 81 primary pterygium and 75 normal conjunctiva tissues was extracted and modified for the assessment of methylation of P14 and MDM2 promoters by methylation-specific polymerase chain reaction (MSP). We also estimated the mRNA expression levels of these genes in 23 pterygium and 18 normal conjunctiva tissue samples using real-time quantitative reverse transcriptase polymerase chain reaction. RESULTS: The frequency of methylation for P14 was 92.6% for cases and 97.3% for controls. MDM2 gene methylation at the promoter site was 39.5% and 72.0% for pterygium and normal conjunctiva tissues, respectively. So statistically, a significant relationship between MDM2 gene promoter methylation and the risk of disease was found (odds ratio=5.3; 95% confidence limit, 2.6-10.8; P<0.0001). In addition, the expression of MDM2 gene has increased in pterygium (1.371548+/-0.6727) in comparison with conjunctiva tissues as control (1.20621+/-1.0) (P<0.05), but it was not significant for P14 gene. CONCLUSION: Our results have indicated that hypomethyaltion and overexpression of MDM2 gene take place in patients with the pterygium. To confirm the presented data, suggesting further studies with a larger sample size in various genetic populations. PMID- 26020484 TI - Slitlamp Photography and Videography With High Magnifications. AB - PURPOSE: To demonstrate the use of the slitlamp photography and videography with extremely high magnifications for visualizing structures of the anterior segment of the eye. METHODS: A Canon 60D digital camera with Movie Crop Function was adapted into a Nikon FS-2 slitlamp to capture still images and video clips of the structures of the anterior segment of the eye. Images obtained using the slitlamp were tested for spatial resolution. The cornea of human eyes was imaged with the slitlamp, and the structures were compared with the pictures captured using the ultra-high-resolution optical coherence tomography (UHR-OCT). The central thickness of the corneal epithelium and total cornea was obtained using the slitlamp, and the results were compared with the thickness obtained using UHR OCT. RESULTS: High-quality ocular images and higher spatial resolutions were obtained using the slitlamp with extremely high magnifications and Movie Crop Function, rather than the traditional slitlamp. The structures and characteristics of the cornea, such as the normal epithelium, abnormal epithelium of corneal intraepithelial neoplasia, laser in situ keratomileusis interface, and contact lenses, were clearly visualized using this device. These features were confirmed by comparing the obtained images with those acquired using UHR-OCT. Moreover, the tear film debris on the ocular surface and the corneal nerve in the anterior corneal stroma were also visualized. The thicknesses of the corneal epithelium and total cornea were similar to that measured using UHR-OCT (P<0.05). CONCLUSIONS: We demonstrated that the slitlamp photography and videography with extremely high magnifications allow better visualization of the anterior segment structures of the eye, especially of the epithelium, when compared with the traditional slitlamp. PMID- 26020485 TI - Clinical Experience With PROSE Fitting: Significance of Diagnosis and Age. AB - OBJECTIVE: To compare ease of adoption of the BostonSight Prosthetic Replacement of the Ocular Surface Ecosystem device, a custom-fit scleral lens, by patients in different age and diagnosis groups. METHODS: In this prospective study, patients were categorized by age as younger than 60 or 60 years and older and by diagnosis as corneal irregularity (CI) or ocular surface disease (OSD). Ease of adoption of the scleral device was assessed by (1) number of devices and visits required to complete the fitting process, (2) time needed for device insertion and removal, (3) adaptation to the device, as assessed by daily wear time and by time needed to achieve full-time wear (defined as 8 hours per day), and (4) patients' subjective rating of ease of device insertion and removal. The length of the fitting process was also assessed. RESULTS: There was no significant difference in the number of devices and visits needed between age group younger than 60 and age group of 60 and older or between CI and OSD groups. Patients in all groups achieved full-time wear in less than 2 weeks. Average wear time per week did not differ significantly between age or diagnosis groups. Similarly, the time needed for daily insertion and removal during the fitting period, as well as patients' subjective rating of ease of device insertion and removal, did not differ between age or diagnosis categories. The length of the fitting process was significantly longer in the OSD group compared with the CI group (P<0.001); however, factors not related to ease of adoption of the scleral device may be responsible for this difference. CONCLUSIONS: Patients in both younger and older patient groups adopted the use of a scleral device with equal ease, as did patients in the CI and OSD diagnosis groups. PMID- 26020486 TI - Topiramate-Induced Changes in Anterior Chamber Angle and Choroidal Thickness. AB - PURPOSE: To investigate the acute effects of topiramate on the anterior chamber angle (ACA) and choroidal thickness in patients with migraine. METHODS: This prospective study included 15 eyes of 15 patients with migraine who have been scheduled to start topiramate therapy. All patients underwent complete ophthalmic examination including measurement of the ACA and choroidal thickness using a spectral domain optical coherence tomography device (Optovue Inc.) and refractive status evaluation with an autorefractokeratometer (KR-8100; Topcon) at the baseline and 1 week after starting therapy. The patients were asked to report any pain or discomfort in their eyes during therapy at the follow-up visit. RESULTS: None of the patients experienced pain or discomfort in their eyes. The mean ACA significantly decreased at the first week of the therapy compared with the baseline levels (40.34+/-7.06 degrees and 36.89+/-6.87 degrees , respectively) (P=0.001). However, the mean choroidal thickness increased from 277.33+/-95.60 MUm at the baseline to 323.40+/-84.50 MUm at the first week (P=0.01). There was a nonsignificant increase in the mean refractive error (from -0.25+/-0.54 diopter [D] at the baseline to -0.38+/-0.49 D after 1 week) (P=0.06). CONCLUSIONS: Topiramate can acutely decrease the ACA and increase the choroidal thickness. Because these effects may be asymptomatic, patients with migraine who start this therapy should be warned to be closely followed up by an ophthalmologist. PMID- 26020487 TI - Contact Lens Use in Patients With Boston Keratoprosthesis Type 1: Fitting, Management, and Complications. AB - The Boston type 1 keratoprosthesis (KPro) is the most commonly used artificial cornea worldwide. Long-term bandage contact lenses are the standard of care for patients with these devices. The goal of bandage contact lenses is to maintain hydration and to protect the corneal tissue that surrounds the anterior plate of the keratoprosthesis which is vulnerable to desiccation, epithelial breakdown, dellen formation, and corneal melt. Contact lenses can also improve comfort, correct refractive errors, and improve the cosmesis of patients with artificial corneas. However, the continuous use of contact lenses places these patients at risk for complications such as lens loss, lens deposits, chronic conjunctivitis, and infection. In addition, obtaining an adequate fit in a patient with a compromised ocular surface and history of multiple surgeries including glaucoma drainage devices can present a challenge. This review discusses the types of contact lenses used, special fitting considerations, and common complications in patients with previous KPro surgery. PMID- 26020488 TI - BRAF mutation screening in melanoma: is sentinel lymph node reliable? AB - As the detection of the BRAF V600E mutation has a direct impact on treatment decision, an accurate screening for BRAF mutations in patients with advanced or metastatic melanoma is mandatory. Nevertheless, BRAF oncogene mutation status between different samples from the same patient has been studied with conflicting results. This study investigated the intrapatient homogeneity of BRAF mutation status using pyrosequencing in primary tumors and different metastatic sites of melanoma patients. Paired samples of lymphatic, visceral, and subcutaneous metastases and primary melanoma from 45 metastatic melanoma patients were tested for BRAF mutations using a pyrosequencing assay and by Sanger sequencing. Overall, sequencing for BRAF mutation status was performed in 114 paired samples from 45 patients. Eighteen patients (40%) carried a BRAF mutation, including BRAF V600E (12/18), BRAF V600K (5/18), and BRAF V600R (1/18) mutations. Multiple BRAF mutations (V600E and V600K) were found in one patient. Among the patients with BRAF mutations, a good agreement in BRAF mutation status was found between the first and second tumor samples genotyped (91%; Cohen's kappa coefficient: 0.81). Discordance in BRAF mutation status was found only in four patients, involving all three patients in whom sentinel lymph node (SLN) metastases were sampled. These SLNs exhibited a wild-type genotype and were discordant with the other BRAF mutated samples found in the same patient. The intrapatient BRAF status was predominantly homogeneous. However, SLN genotyping using pyrosequencing might be inaccurate in determining the actual mutation status of melanoma. Further studies are required to confirm the lack of reliability of SLN. PMID- 26020489 TI - Tocilizumab unmasks a stage-dependent interleukin-6 component in statin-induced apoptosis of metastatic melanoma cells. AB - The interleukin (IL)-6 inhibits the growth of early-stage melanoma cells, but not metastatic cells. Metastatic melanoma cells are susceptible to statin-induced apoptosis, but this is not clear for early-stage melanoma cells. This study aimed to investigate the IL-6 susceptibility of melanoma cells from different stages in the presence of simvastatin to overcome loss of growth arrest. ELISA was used to detect secreted IL-6 in human melanoma cells. The effects of IL-6 were measured by western blots for STAT3 and Bcl-2 family proteins. Apoptosis and proliferation were measured by caspase 3 activity, Annexin V staining, cell cycle analysis, and a wound-healing assay. Human metastatic melanoma cells A375 and 518A2 secrete high amounts of IL-6, in contrast to early-stage WM35 cells. Canonical IL-6 signaling is intact in these cells, documented by transient phosphorylation of STAT3. Although WM35 cells are highly resistant to simvastatin-induced apoptosis, coadministration with IL-6 enhanced the susceptibility to undergo apoptosis. This proapoptotic effect of IL-6 might be explained by a downregulation of Bcl-XL, observed only in WM35 cells. Furthermore, the IL-6 receptor blocking antibody tocilizumab was coadministered and unmasked an IL-6-sensitive proportion in the simvastatin-induced caspase 3 activity of metastatic melanoma cells. These results confirm that simvastatin facilitates apoptosis in combination with IL-6. Although endogenous IL-6 secretion is sufficient in metastatic melanoma cells, exogenously added IL-6 is needed for WM35 cells. This effect may explain the failure of simvastatin to reduce melanoma incidence in clinical trials and meta analyses. PMID- 26020490 TI - Algorithm-enabled exploration of image-quality potential of cone-beam CT in image guided radiation therapy. AB - Kilo-voltage (KV) cone-beam computed tomography (CBCT) unit mounted onto a linear accelerator treatment system, often referred to as on-board imager (OBI), plays an increasingly important role in image-guided radiation therapy. While the FDK algorithm is currently used for reconstructing images from clinical OBI data, optimization-based reconstruction has also been investigated for OBI CBCT. An optimization-based reconstruction involves numerous parameters, which can significantly impact reconstruction properties (or utility). The success of an optimization-based reconstruction for a particular class of practical applications thus relies strongly on appropriate selection of parameter values. In the work, we focus on tailoring the constrained-TV-minimization-based reconstruction, an optimization-based reconstruction previously shown of some potential for CBCT imaging conditions of practical interest, to OBI imaging through appropriate selection of parameter values. In particular, for given real data of phantoms and patient collected with OBI CBCT, we first devise utility metrics specific to OBI-quality-assurance tasks and then apply them to guiding the selection of parameter values in constrained-TV-minimization-based reconstruction. The study results show that the reconstructions are with improvement, relative to clinical FDK reconstruction, in both visualization and quantitative assessments in terms of the devised utility metrics. PMID- 26020491 TI - Examination of metabolic responses to phosphorus limitation via proteomic analyses in the marine diatom Phaeodactylum tricornutum. AB - Phosphorus (P) is an essential macronutrient for the survival of marine phytoplankton. In the present study, phytoplankton response to phosphorus limitation was studied by proteomic profiling in diatom Phaeodactylum tricornutum in both cellular and molecular levels. A total of 42 non-redundant proteins were identified, among which 8 proteins were found to be upregulated and 34 proteins were downregulated. The results also showed that the proteins associated with inorganic phosphate uptake were downregulated, whereas the proteins involved in organic phosphorus uptake such as alkaline phosphatase were upregulated. The proteins involved in metabolic responses such as protein degradation, lipid accumulation and photorespiration were upregulated whereas energy metabolism, photosynthesis, amino acid and nucleic acid metabolism tend to be downregulated. Overall our results showed the changes in protein levels of P. tricornutum during phosphorus stress. This study preludes for understanding the role of phosphorous in marine biogeochemical cycles and phytoplankton response to phosphorous scarcity in ocean. It also provides insight into the succession of phytoplankton community, providing scientific basis for elucidating the mechanism of algal blooms. PMID- 26020492 TI - Thermoelectric Signal Enhancement by Reconciling the Spin Seebeck and Anomalous Nernst Effects in Ferromagnet/Non-magnet Multilayers. AB - The utilization of ferromagnetic (FM) materials in thermoelectric devices allows one to have a simpler structure and/or independent control of electric and thermal conductivities, which may further remove obstacles for this technology to be realized. The thermoelectricity in FM/non-magnet (NM) heterostructures using an optical heating source is studied as a function of NM materials and a number of multilayers. It is observed that the overall thermoelectric signal in those structures which is contributed by spin Seebeck effect and anomalous Nernst effect (ANE) is enhanced by a proper selection of NM materials with a spin Hall angle that matches to the sign of the ANE. Moreover, by an increase of the number of multilayer, the thermoelectric voltage is enlarged further and the device resistance is reduced, simultaneously. The experimental observation of the improvement of thermoelectric properties may pave the way for the realization of magnetic-(or spin-) based thermoelectric devices. PMID- 26020493 TI - Nanodusty plasma chemistry: a mechanistic and variational transition state theory study of the initial steps of silyl anion-silane and silylene anion-silane polymerization reactions. AB - The growth of nanodusty particles, which is critical in plasma chemistry, physics, and engineering. The aim of the present work is to understand the detailed reaction mechanisms of early steps in this growth. The polymerization of neutral silane with the silylene or silyl anion, which eliminates molecular hydrogen with the formation of their higher homologues, governs the silicon hydride clustering in nanodusty plasma chemistry. The detailed mechanisms of these important polymerization reactions in terms of elementary reactions have not been proposed yet. In the present work, we investigated the initial steps of these polymerization reactions, i.e., the SiH4 + Si2H4(-)/Si2H5(-) reactions, and we propose a three-step mechanism, which is also applicable to the following polymerization steps. CM5 charges of all the silicon-containing species were computed in order to analyze the character of the species in the proposed reaction mechanisms. We also calculated thermal rate constant of each step using multi-structural canonical variational transition state theory (MS-CVT) with the small-curvature tunneling (SCT) approximation, based on the minimum energy path computed using M08-HX/MG3S electronic structure method. PMID- 26020495 TI - Disease Progression and Changes in Physical Activity in Patients with Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Little is known about the role of physical activity in the course of chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess changes in physical activity in COPD in relation to severity stages and changes in other disease components, and to evaluate the longitudinal association between sustained physical inactivity and disease progression. METHODS: In this prospective cohort study, we measured physical activity (multisensory armband), airflow obstruction (FEV1), health status (St. George's Respiratory Questionnaire), exercise capacity (6-min-walk distance [6MWD]), muscle mass (fat free mass [FFM]), and systemic inflammation (fibrinogen and high-sensitivity C reactive protein) over a 3-year period in 137 patients with COPD and 26 with chronic bronchitis (normal spirometry). MEASUREMENTS AND MAIN RESULTS: Independent of baseline disease severity, steps per day, total daily energy expenditure, and (daily) physical activity level (PAL) decreased by 393, 76 kcal, and 0.04 per year, respectively. The decline in PAL was significantly associated with a decline in FEV1 and an increase in St. George's Respiratory Questionnaire total score. Changes in 6MWD, FFM, and inflammatory markers were not associated with changes in PAL. Independent of FEV1, sustained physical inactivity (i.e., PAL(T0andT1) < 1.40) was related to a greater decline in 6MWD and FFM compared with that in patients with some level of activity (i.e., PAL(T0and/orT1) >= 1.40; difference, 17 m/yr and 0.87 kg/yr, respectively). CONCLUSIONS: Over time, physical activity substantially decreases across all severity stages of COPD, and this decline is paralleled by a worsening of lung function and health status. Sustained physical inactivity is associated with a progression of exercise intolerance and muscle depletion. PMID- 26020496 TI - Rebuttal From Dr Enright. PMID- 26020497 TI - Off-target mutations are rare in Cas9-modified mice. PMID- 26020498 TI - ClearVolume: open-source live 3D visualization for light-sheet microscopy. PMID- 26020499 TI - BigDataViewer: visualization and processing for large image data sets. PMID- 26020500 TI - MAGI: visualization and collaborative annotation of genomic aberrations. PMID- 26020501 TI - Reproducibility: changing the policies and culture of cell line authentication. PMID- 26020502 TI - Visualizing epigenomic data. PMID- 26020507 TI - Self-Deprecating Humor Versus Other-Deprecating Humor in Health Messages. AB - Humor is sometimes used in health messages. However, little is known about contingencies under which different types of humor may or may not be effective. This experiment crossed humorous versus nonhumorous and self- versus other deprecating messages about binge drinking, and tested how differences in personal investment in alcohol use moderates the effects of such messages on college binge drinkers. Results showed significant 3-way interaction effects on subjective norms and behavioral intentions largely consistent with hypotheses. Assessment of significant differences in the interactions indicated that for binge drinkers who were not high in personal investment in alcohol use, other-deprecating humor tended to reduce their perceived subjective norms about the acceptability of binge drinking behavior and their behavioral intentions. The effect of the experimental manipulation on subjective norms among these binge drinkers was shown to mediate the effect on intentions to binge drink in the future. Theoretical and practical implications are discussed. PMID- 26020503 TI - Correlated light and electron microscopy: ultrastructure lights up! AB - Microscopy has gone hand in hand with the study of living systems since van Leeuwenhoek observed living microorganisms and cells in 1674 using his light microscope. A spectrum of dyes and probes now enable the localization of molecules of interest within living cells by fluorescence microscopy. With electron microscopy (EM), cellular ultrastructure has been revealed. Bridging these two modalities, correlated light microscopy and EM (CLEM) opens new avenues. Studies of protein dynamics with fluorescent proteins (FPs), which leave the investigator 'in the dark' concerning cellular context, can be followed by EM examination. Rare events can be preselected at the light microscopy level before EM analysis. Ongoing development-including of dedicated probes, integrated microscopes, large-scale and three-dimensional EM and super-resolution fluorescence microscopy-now paves the way for broad CLEM implementation in biology. PMID- 26020509 TI - MiRNA Profiles in Lymphoblastoid Cell Lines of Finnish Prostate Cancer Families. AB - BACKGROUND: Heritable factors are evidently involved in prostate cancer (PrCa) carcinogenesis, but currently, genetic markers are not routinely used in screening or diagnostics of the disease. More precise information is needed for making treatment decisions to distinguish aggressive cases from indolent disease, for which heritable factors could be a useful tool. The genetic makeup of PrCa has only recently begun to be unravelled through large-scale genome-wide association studies (GWAS). The thus far identified Single Nucleotide Polymorphisms (SNPs) explain, however, only a fraction of familial clustering. Moreover, the known risk SNPs are not associated with the clinical outcome of the disease, such as aggressive or metastasised disease, and therefore cannot be used to predict the prognosis. Annotating the SNPs with deep clinical data together with miRNA expression profiles can improve the understanding of the underlying mechanisms of different phenotypes of prostate cancer. RESULTS: In this study microRNA (miRNA) profiles were studied as potential biomarkers to predict the disease outcome. The study subjects were from Finnish high risk prostate cancer families. To identify potential biomarkers we combined a novel non-parametrical test with an importance measure provided from a Random Forest classifier. This combination delivered a set of nine miRNAs that was able to separate cases from controls. The detected miRNA expression profiles could predict the development of the disease years before the actual PrCa diagnosis or detect the existence of other cancers in the studied individuals. Furthermore, using an expression Quantitative Trait Loci (eQTL) analysis, regulatory SNPs for miRNA miR-483-3p that were also directly associated with PrCa were found. CONCLUSION: Based on our findings, we suggest that blood-based miRNA expression profiling can be used in the diagnosis and maybe even prognosis of the disease. In the future, miRNA profiling could possibly be used in targeted screening, together with Prostate Specific Antigene (PSA) testing, to identify men with an elevated PrCa risk. PMID- 26020510 TI - Experimental and computational analysis of a large protein network that controls fat storage reveals the design principles of a signaling network. AB - An approach combining genetic, proteomic, computational, and physiological analysis was used to define a protein network that regulates fat storage in budding yeast (Saccharomyces cerevisiae). A computational analysis of this network shows that it is not scale-free, and is best approximated by the Watts Strogatz model, which generates "small-world" networks with high clustering and short path lengths. The network is also modular, containing energy level sensing proteins that connect to four output processes: autophagy, fatty acid synthesis, mRNA processing, and MAP kinase signaling. The importance of each protein to network function is dependent on its Katz centrality score, which is related both to the protein's position within a module and to the module's relationship to the network as a whole. The network is also divisible into subnetworks that span modular boundaries and regulate different aspects of fat metabolism. We used a combination of genetics and pharmacology to simultaneously block output from multiple network nodes. The phenotypic results of this blockage define patterns of communication among distant network nodes, and these patterns are consistent with the Watts-Strogatz model. PMID- 26020511 TI - Anti-cancer activity of withaferin A in B-cell lymphoma. AB - Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF kappaB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90. PMID- 26020512 TI - Metagenomic insights into the bioaerosols in the indoor and outdoor environments of childcare facilities. AB - Airborne microorganisms have significant effects on human health, and children are more vulnerable to pathogens and allergens than adults. However, little is known about the microbial communities in the air of childcare facilities. Here, we analyzed the bacterial and fungal communities in 50 air samples collected from five daycare centers and five elementary schools located in Seoul, Korea using culture-independent high-throughput pyrosequencing. The microbial communities contained a wide variety of taxa not previously identified in child daycare centers and schools. Moreover, the dominant species differed from those reported in previous studies using culture-dependent methods. The well-known fungi detected in previous culture-based studies (Alternaria, Aspergillus, Penicillium, and Cladosporium) represented less than 12% of the total sequence reads. The composition of the fungal and bacterial communities in the indoor air differed greatly with regard to the source of the microorganisms. The bacterial community in the indoor air appeared to contain diverse bacteria associated with both humans and the outside environment. In contrast, the fungal community was largely derived from the surrounding outdoor environment and not from human activity. The profile of the microorganisms in bioaerosols identified in this study provides the fundamental knowledge needed to develop public health policies regarding the monitoring and management of indoor air quality. PMID- 26020513 TI - IRES-Containing VEEV Vaccine Protects Cynomolgus Macaques from IE Venezuelan Equine Encephalitis Virus Aerosol Challenge. AB - Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas that is responsible for severe, sometimes fatal, disease in humans and horses. We previously described an IRES-based VEE vaccine candidate based up the IE serotype that offers complete protection against a lethal subtype IE VEEV challenge in mice. Here we demonstrate the IRES-based vaccine's ability to protect against febrile disease in cynomolgus macaques. Vaccination was well tolerated and elicited robust neutralizing antibody titers noticed as early as day 14. Moreover, complete protection from disease characterized by absence of viremia and characteristic fever following aerosolized IE VEEV challenge was observed in all vaccinees compared to control animals, which developed clinical disease. Together, these results highlight the safety and efficacy of IRES-based VEEV vaccine to protect against an endemic, pathogenic VEEV IE serotype. PMID- 26020514 TI - Helicobacter pylori Infection Increases Insulin Resistance and Metabolic Syndrome in Residents Younger than 50 Years Old: A Community-Based Study. AB - This study aimed to analyze the influence of H. pylori infection on insulin resistance and metabolic syndrome (MS) by multivariate analysis of a community based cohort study. From January 2013 to February 2014,811 subjects were enrolled in a community-based cohort study from the northeastern region of Taiwan. All subjects received a demographic survey and blood tests, including an H. pylori antibody test, liver biochemistry tests, lipid profiles, sugar/insulin levels for Homeostatic model assessment (HOMA-IR index), and measurements of adipokines and inflammatory cytokines. A total of 264 men and 547 women were included in this study. The mean age was 59.2 +/- 12.7 years. Subjects seropositive for H. pylori antibodies exhibited higher rates of hypertension, an increased incidence of a HOMA-IR index > 2.5 and a higher level of tumor necrosis factor-alpha than those without H. pylori antibodies. We found a significant difference in the presence of H. pylori antibodies between subjects with MS and those without MS (76.7% vs. 53.7%, p = 0.007) among subjects < 50 y/o. A HOMA-IR index >2.5, H. pylori antibody presence and leptin were predictors for MS in subjects < 50 y/o. The estimated odds ratio of MS for a subject with H. pylori antibodies was 3.717 (95% CI = 1.086-12.719) times that of a subject without H. pylori antibodies. In addition, no difference in H. pylori antibody status was detected for MS prediction in subjects that were ? 50 y/o (p = 0.861). In conclusion, subjects with H. pylori antibodies had a higher incidence of a HOMA-IR >2.5 than those without H pylori antibodies. For subjects aged < 50 y/o, the H. pylori antibody was a predictor for MS. PMID- 26020515 TI - Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion. AB - The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNgamma-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing. PMID- 26020517 TI - Anodic oxidation of textile wastewaters on boron-doped diamond electrodes. AB - The objective of this study is to investigate the potential application of the anodic oxidation (AO) on two electrolytic cells (monopolar (Cell 1) and bipolar (Cell 2)) containing boron-doped diamond electrodes on the treatment of real textile effluents to study the reuse possibility of treated wastewater in the textile industry process. AO is applied in the flocculation coagulation pretreatment of both upstream (BH) and downstream (BS) effluents. The chemical oxygen demand (COD) results show that the final COD removal obtained for the BH effluent in the case of Cell 1 and Cell 2 is 800 and 150 mg O2L-1 after 5 and 6 h of electrolysis, respectively. The treatments of the BS effluent allow for obtaining a final COD of 76 mg L-1 for Cell 1 and a total mineralization for Cell 2. The obtained results demonstrate that the apparent mineralization kinetics of both effluents when using Cell 2 are about four times faster than the one obtained by Cell 1 and highlight the important contribution of the bipolar cell. Besides, the energy consumption values show that the treatment of the BH effluent by Cell 1 consumes 865 kWh kg COD-1 against 411 kWh kg COD(-1) by Cell 2. Therefore, the use of Cell 2 decreases the energy cost by 2.1-6.65 times when compared to Cell 1 in the case of the BH and BS effluent treatment, respectively. PMID- 26020516 TI - The flavonoid luteolin, but not luteolin-7-O-glucoside, prevents a transthyretin mediated toxic response. AB - Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs. PMID- 26020518 TI - Development of relative risk model for regional groundwater risk assessment: a case study in the lower Liaohe River Plain, China. AB - Increasing pressure on water supply worldwide, especially in arid areas, has resulted in groundwater overexploitation and contamination, and subsequent deterioration of the groundwater quality and threats to public health. Environmental risk assessment of regional groundwater is an important tool for groundwater protection. This study presents a new approach for assessing the environmental risk assessment of regional groundwater. It was carried out with a relative risk model (RRM) coupled with a series of indices, such as a groundwater vulnerability index, which includes receptor analysis, risk source analysis, risk exposure and hazard analysis, risk characterization, and management of groundwater. The risk map is a product of the probability of environmental contamination and impact. The reliability of the RRM was verified using Monte Carlo analysis. This approach was applied to the lower Liaohe River Plain (LLRP), northeastern China, which covers 23604 km2. A spatial analysis tool within GIS which was used to interpolate and manipulate the data to develop environmental risk maps of regional groundwater, divided the level of risk from high to low into five ranks (V, IV, III, II, I). The results indicate that areas of relative risk rank (RRR) V cover 2324 km2, covering 9.8% of the area; RRR IV covers 3986 km2, accounting for 16.9% of the area. It is a new and appropriate method for regional groundwater resource management and land use planning, and is a rapid and effective tool for improving strategic decision making to protect groundwater and reduce environmental risk. PMID- 26020519 TI - Age-Related Disparity in Immediate Prognosis of Patients with Triple-Negative Breast Cancer: A Population-Based Study from SEER Cancer Registries. AB - BACKGROUND: Triple-negative breast cancer (TNBC) has been demonstrated to carry poor prognosis, but whether or not there exists any age-related variation in TNBC outcomes has yet to be elucidated. The current population-based study investigated the early survival pattern of elderly women with TNBC and identified outcome-correlated factors. PATIENTS AND METHODS: We searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled female primary non metastatic TNBC cases. The patients were subdivided into elderly (>=70 years) and young groups (<70 years). The survival status of elderly patients was compared to that of the younger women. The primary and secondary endpoints were cancer specific survival (CSS) and overall survival (OS) respectively. RESULTS: 9908 female TNBC patients diagnosed from 2010 to 2011 were included in the current study (20.4% elderly). Elderly patients with relatively advanced diseases exhibited distinctly worse cancer-specific (log-rank, p<0.001) and overall survival (log-rank, p<0.001) than their young counterparts. Advanced age at diagnosis (>=70 years) was significantly predictive of poor outcome in terms of CSS (hazard ratio (HR), 2.125; 95% confidence interval (CI), 1.664 to 2.713; p<0.001) and OS (HR, 3.042; 95%CI, 2.474 to 3.740; p<0.001). Underuse of curative treatment especially radiotherapy was more prevalent in elderly women with stage II or III diseases than in younger patients. CONCLUSION: Elderly patients with TNBC displayed elevated early mortality within the first two years of diagnosis compared to the younger individuals. The observed lower rate of loco-regional treatment might be associated with worse cancer-specific outcome for these patients. PMID- 26020520 TI - Perivascular adipose tissue-derived adiponectin inhibits collar-induced carotid atherosclerosis by promoting macrophage autophagy. AB - OBJECTIVES: Adiponectin (APN) secreted from perivascular adipose tissue (PVAT) is one of the important anti-inflammatory adipokines to inhibit the development of atherosclerosis, but the underlying mechanism has not been clarified. In this study, we aimed to elucidate how APN regulates plaque formation in atherosclerosis. METHODS AND RESULTS: To assess the role of APN secreted by PVAT in atherosclerosis progression, we performed PVAT transplantation experiments on carotid artery atherosclerosis model: ApoE knockout (ApoE-/-) mice with a perivascular collar placement around the left carotid artery in combination with a high-fat diet feeding. Our results show that the ApoE-/- mice with PVAT derived from APN knockout (APN-/-) mice exhibited accelerated plaque volume formation compared to ApoE-/- mice transplanted with wild-type littermate tissue. Conversely, autophagy in macrophages was significantly attenuated in ApoE-/- mice transplanted with APN-/- mouse-derived PVAT compared to controls. Furthermore, in vitro studies indicate that APN treatment increased autophagy in primary macrophages, as evidenced by increased LC3-I processing and Beclin1 expression, which was accompanied by down-regulation of p62. Moreover, our results demonstrate that APN promotes macrophage autophagy via suppressing the Akt/FOXO3a signaling pathway. CONCLUSIONS: Our results indicate that PVAT-secreted APN suppresses plaque formation by inducing macrophage autophagy. PMID- 26020521 TI - Post-transcriptional Regulation of Keratinocyte Progenitor Cell Expansion, Differentiation and Hair Follicle Regression by miR-22. AB - Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth. PMID- 26020522 TI - Mitochondrial reshaping accompanies neural differentiation in the developing spinal cord. AB - Mitochondria, long known as the cell powerhouses, also regulate redox signaling and arbitrate cell survival. The organelles are now appreciated to exert additional critical roles in cell state transition from a pluripotent to a differentiated state through balancing glycolytic and respiratory metabolism. These metabolic adaptations were recently shown to be concomitant with mitochondrial morphology changes and are thus possibly regulated by contingencies of mitochondrial dynamics. In this context, we examined, for the first time, mitochondrial network plasticity during the transition from proliferating neural progenitors to post-mitotic differentiating neurons. We found that mitochondria underwent morphological reshaping in the developing neural tube of chick and mouse embryos. In the proliferating population, mitochondria in the mitotic cells lying at the apical side were very small and round, while they appeared thick and short in interphase cells. In differentiating neurons, mitochondria were reorganized into a thin, dense network. This reshaping of the mitochondrial network was not specific of a subtype of progenitors or neurons, suggesting that this is a general event accompanying neurogenesis in the spinal cord. Our data shed new light on the various changes occurring in the mitochondrial network during neurogenesis and suggest that mitochondrial dynamics could play a role in the neurogenic process. PMID- 26020523 TI - Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report. AB - Liver metastases in breast cancer are associated with a poor prognosis. We report long-term survival of a patient with breast cancer and liver metastases. After operation the patient declined further standard therapy. Instead, she was treated with local hyperthermia, Newcastle disease virus and dendritic cell vaccination at the Immunological and Oncological Center Cologne (IOZK), Germany. A continuous high quality of life was reported and the patient survived more than 66 months after initial diagnosis. No recurrence or further metastases developed under treatment. Following treatment, a long-lasting tumor-reactive memory T-cell responsiveness could be documented. This possibly explains the favorable course of disease. Since this combination of therapies is not restricted to a particular tumor type, further exploration is warranted. PMID- 26020524 TI - Advances and challenges in computational prediction of effectors from plant pathogenic fungi. PMID- 26020525 TI - Assessing movement factors in upper limb kinematics decoding from EEG signals. AB - The past decades have seen the rapid development of upper limb kinematics decoding techniques by performing intracortical recordings of brain signals. However, the use of non-invasive approaches to perform similar decoding procedures is still in its early stages. Recent studies show that there is a correlation between electroencephalographic (EEG) signals and hand-reaching kinematic parameters. From these studies, it could be concluded that the accuracy of upper limb kinematics decoding depends, at least partially, on the characteristics of the performed movement. In this paper, we have studied upper limb movements with different speeds and trajectories in a controlled environment to analyze the influence of movement variability in the decoding performance. To that end, low frequency components of the EEG signals have been decoded with linear models to obtain the position of the volunteer's hand during performed trajectories grasping the end effector of a planar manipulandum. The results confirm that it is possible to obtain kinematic information from low frequency EEG signals and show that decoding performance is significantly influenced by movement variability and tracking accuracy as continuous and slower movements improve the accuracy of the decoder. This is a key factor that should be taken into account in future experimental designs. PMID- 26020526 TI - Insights into transcriptomes of big and low sagebrush. AB - We report the sequencing and assembly of three transcriptomes from Big (Artemisia tridentata ssp. wyomingensis and A. tridentata ssp. tridentata) and Low (A. arbuscula ssp. arbuscula) sagebrush. The sequence reads are available in the Sequence Read Archive of NCBI. We demonstrate the utilities of these transcriptomes for gene discovery and phylogenomic analysis. An assembly of 61,883 transcripts followed by transcript identification by the program TRAPID revealed 16 transcripts directly related to terpene synthases, proteins critical to the production of multiple secondary metabolites in sagebrush. A putative terpene synthase was identified in two of our sagebrush samples. Using paralogs with synonymous mutations we reconstructed an evolutionary time line of ancient genome duplications. By applying a constant mutation rate to the data we estimate that these three ancient duplications occurred about 18, 34 and 60 million years ago. These transcriptomes offer a foundation for future studies of sagebrush, including inferences in chemical defense and the identification of species and subspecies of sagebrush for restoration and preservation of the threatened sage grouse. PMID- 26020527 TI - Oxidative stress and antioxidant strategies in dermatology. AB - Oxidative stress results from a prooxidant-antioxidant imbalance, leading to cellular damage. It is mediated by free radicals, such as reactive oxygen species or reactive nitrogen species, that are generated during physiological aerobic metabolism and pathological inflammatory processes. Skin serves as a protective organ that plays an important role in defending both external and internal toxic stimuli and maintaining homeostasis. It is becoming increasingly evident that oxidative stress is involved in numerous skin diseases and that antioxidative strategies can serve as effective and easy methods for improving these conditions. Herein, we review dysregulated antioxidant systems and antioxidative therapeutic strategies in dermatology. PMID- 26020528 TI - Variations in Temperature Sensitivity (Q10) of CH4 Emission from a Subtropical Estuarine Marsh in Southeast China. AB - Understanding the functional relationship between greenhouse gas fluxes and environmental variables is crucial for predicting the impacts of wetlands on future climate change in response to various perturbations. We examined the relationships between methane (CH4) emission and temperature in two marsh stands dominated by the Phragmites australis and Cyperus malaccensis, respectively, in a subtropical estuarine wetland in southeast China based on three years of measurement data (2007-2009). We found that the Q10 coefficient of CH4 emission to soil temperature (Qs10) from the two marsh stands varied slightly over the three years (P > 0.05), with a mean value of 3.38 +/- 0.46 and 3.89 +/- 0.41 for the P. australis and C. malaccensis stands, respectively. On the other hand, the three-year mean Qa10 values (Q10 coefficients of CH4 emission to air temperature) were 3.39 +/- 0.59 and 4.68 +/- 1.10 for the P. australis and C. malaccensis stands, respectively, with a significantly higher Qa10 value for the C. malaccensis stand in 2008 (P < 0.05). The seasonal variations of Q10 (Qs10 and Qa10) differed among years, with generally higher values in the cold months than those in the warm months in 2007 and 2009. We found that the Qs10 values of both stands were negatively correlated with soil conductivity, but did not obtain any conclusive results about the difference in Q10 of CH4 emission between the two tidal stages (before flooding and after ebbing). There were no significant differences in both Qs10 and Qa10 values of CH4 emission between the P. australis stand and the C. malaccensis stands (P > 0.05). Our results show that the Q10 values of CH4 emission in this estuarine marsh are highly variable across space and time. Given that the overall CH4 flux is governed by a suite of environmental factors, the Q10 values derived from field measurements should only be considered as a semi-empirical parameter for simulating CH4 emissions. PMID- 26020529 TI - Oviduct-specific expression of human neutrophil defensin 4 in lentivirally generated transgenic chickens. AB - The expression of oviduct-specific recombinant proteins in transgenic chickens is a promising technology for the production of therapeutic biologics in eggs. In this study, we constructed a lentiviral vector encoding an expression cassette for human neutrophil defensin 4 (HNP4), a compound that displays high activity against Escherichia coli, and produced transgenic chickens that expressed the recombinant HNP4 protein in egg whites. After the antimicrobial activity of the recombinant HNP4 protein was tested at the cellular level, a 2.8-kb ovalbumin promoter was used to drive HNP4 expression specifically in oviduct tissues. From 669 injected eggs, 218 chickens were successfully hatched. Ten G0 roosters, with semens identified as positive for the transgene, were mated with wild-type hens to generate G1 chickens. From 1,274 total offspring, fifteen G1 transgenic chickens were positive for the transgene, which was confirmed by PCR and Southern blotting. The results of the Southern blotting and genome walking indicated that a single copy of the HNP4 gene was integrated into chromosomes 1, 2, 3, 4, 6 and 24 of the chickens. As expected, HNP4 expression was restricted to the oviduct tissues, and the levels of both transcriptional and translational HNP4 expression varied greatly in transgenic chickens with different transgene insertion sites. The amount of HNP4 protein expressed in the eggs of G1 and G2 heterozygous transgenic chickens ranged from 1.65 MUg/ml to 10.18 MUg/ml. These results indicated that the production of transgenic chickens that expressed HNP4 protein in egg whites was successful. PMID- 26020530 TI - Optimizing the Protection of Cattle against Escherichia coli O157:H7 Colonization through Immunization with Different Combinations of H7 Flagellin, Tir, Intimin 531 or EspA. AB - Enterohemorrhagic Escherichia coli (EHEC) are important human pathogens, causing hemorrhagic colitis and hemolytic uraemic syndrome in humans. E. coli O157:H7 is the most common serotype associated with EHEC infections worldwide, although other non-O157 serotypes cause life-threatening infections. Cattle are a main reservoir of EHEC and intervention strategies aimed at limiting EHEC excretion from cattle are predicted to lower the risk of human infection. We have previously shown that immunization of calves with recombinant versions of the type III secretion system (T3SS)-associated proteins EspA, intimin and Tir from EHEC O157:H7 significantly reduced shedding of EHEC O157 from experimentally colonized calves, and that protection could be augmented by the addition of H7 flagellin to the vaccine formulation. The main aim of the present study was to optimize our current EHEC O157 subunit vaccine formulations by identifying the key combinations of these antigens required for protection. A secondary aim was to determine if vaccine-induced antibody responses exhibited cross-reactive potential with antigens from other EHEC serotypes. Immunization with EspA, intimin and Tir resulted in a reduction in mean EHEC O157 shedding following challenge, but not the mean proportion of calves colonized. Removal of Tir resulted in more prolonged shedding compared with all other groups, whereas replacement of Tir with H7 flagellin resulted in the highest levels of protection, both in terms of reducing both mean EHEC O157 shedding and the proportion of colonized calves. Immunization of calves with recombinant EHEC O157 EspA, intimin and Tir resulted in the generation of antibodies capable of cross reacting with antigens from non-O157 EHEC serotypes, suggesting that immunization with these antigens may provide a degree of cross-protection against other EHEC serotypes. Further studies are now required to test the efficacy of these vaccines in the field, and to formally test the cross-protective potential of the vaccines against other non-O157 EHEC. PMID- 26020531 TI - A reference-free method for brightness compensation and contrast enhancement of micrographs of serial sections. AB - Three-dimensional (3D) reconstruction of an organ or tissue from a stack of histologic serial sections provides valuable morphological information. The procedure includes section preparation of the organ or tissue, micrographs acquisition, image registration, 3D reconstruction, and visualization. However, the brightness and contrast through the image stack may not be consistent due to imperfections in the staining procedure, which may cause difficulties in micro structure identification using virtual sections, region segmentation, automatic target tracing, etc. In the present study, a reference-free method, Sequential Histogram Fitting Algorithm (SHFA), is therefore developed for adjusting the severe and irregular variance of brightness and contrast within the image stack. To apply the SHFA, the gray value histograms of individual images are first calculated over the entire image stack and a set of landmark gray values are chosen. Then the histograms are transformed so that there are no abrupt changes in progressing through the stack. Finally, the pixel gray values of the original images are transformed into the desired ones based on the relationship between the original and the transformed histograms. The SHFA is tested on an image stacks from mouse kidney sections stained with toluidine blue, and captured by a slide scanner. As results, the images through the entire stack reveal homogenous brightness and consistent contrast. In addition, subtle color differences in the tissue are well preserved so that the morphological details can be recognized, even in virtual sections. In conclusion, compared with the existing histogram based methods, the present study provides a practical method suitable for compensating brightness, and improving contrast of images derived from a large number of serial sections of biological organ. PMID- 26020532 TI - Determining Microeukaryotic Plankton Community around Xiamen Island, Southeast China, Using Illumina MiSeq and PCR-DGGE Techniques. AB - Microeukaryotic plankton are important components of aquatic environments and play key roles in marine microbial food webs; however, little is known about their genetic diversity in subtropical offshore areas. Here we examined the community composition and genetic diversity of the microeukaryotic plankton in Xiamen offshore water by PCR-DGGE (polymerase chain reaction-denaturing gradient gel electrophoresis), clone-based sequencing and Illumina based sequencing. The Illumina MiSeq sequencing revealed a much (approximately two orders of magnitude) higher species richness of the microeukaryotic community than DGGE, but there were no significant difference in species richness and diversity among the northern, eastern, southern or western stations based on both methods. In this study, Copepoda, Ciliophora, Chlorophyta, Dinophyceae, Cryptophyta and Bacillariophyta (diatoms) were the dominant groups even though diatoms were not detected by DGGE. Our Illumina based results indicated that two northern communities (sites N2 and N3) were significantly different from others in having more protozoa and fewer diatoms. Redundancy analysis (RDA) showed that both temperature and salinity were the significant environmental factors influencing dominant species communities, whereas the full microeukaryotic community appeared to be affected by a complex of environmental factors. Our results suggested that extensive sampling combined with more deep sequencing are needed to obtain the complete diversity of the microeukaryotic community, and different diversity patterns for both abundant and rare taxa may be important in evaluating the marine ecosystem health. PMID- 26020533 TI - Plant Translation Elongation Factor 1Bbeta Facilitates Potato Virus X (PVX) Infection and Interacts with PVX Triple Gene Block Protein 1. AB - The eukaryotic translation elongation factor 1 (eEF1) has two components: the G protein eEF1A and the nucleotide exchange factor eEF1B. In plants, eEF1B is itself composed of a structural protein (eEF1Bgamma) and two nucleotide exchange subunits (eEF1Balpha and eEF1Bbeta). To test the effects of elongation factors on virus infection, we isolated eEF1A and eEF1B genes from pepper (Capsicum annuum) and suppressed their homologs in Nicotiana benthamiana using virus-induced gene silencing (VIGS). The accumulation of a green fluorescent protein (GFP)-tagged Potato virus X (PVX) was significantly reduced in the eEF1Bbeta- or eEF1Bgamma silenced plants as well as in eEF1A-silenced plants. Yeast two-hybrid and co immunoprecipitation analyses revealed that eEF1Balpha and eEF1Bbeta interacted with eEF1A and that eEF1A and eEF1Bbeta interacted with triple gene block protein 1 (TGBp1) of PVX. These results suggest that both eEF1A and eEF1Bbeta play essential roles in the multiplication of PVX by physically interacting with TGBp1. Furthermore, using eEF1Bbeta deletion constructs, we found that both N- (1 64 amino acids) and C-terminal (150-195 amino acids) domains of eEF1Bbeta are important for the interaction with PVX TGBp1 and that the C-terminal domain of eEF1Bbeta is involved in the interaction with eEF1A. These results suggest that eEF1Bbeta could be a potential target for engineering virus-resistant plants. PMID- 26020534 TI - Correction: the retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration. AB - [This corrects the article DOI: 10.1371/journal.pbio.1001847.]. PMID- 26020535 TI - Does Maternal Country of Birth Matter for Understanding Offspring's Birthweight? A Multilevel Analysis of Individual Heterogeneity in Sweden. AB - BACKGROUND: Many public health and epidemiological studies have found differences between populations (e.g. maternal countries of birth) in average values of a health indicator (e.g. mean offspring birthweight). However, the approach based solely on population-level averages compromises our understanding of variability in individuals' health around the averages. If this variability is high, the exclusive study of averages may give misleading information. This idea is relevant when investigating country of birth differences in health. METHODS AND RESULTS: To exemplify this concept, we use information from the Swedish Medical Birth Register (2002-2010) and apply multilevel regression analysis of birthweight, with babies (n = 811,329) at the first, mothers (n = 571,876) at the second, and maternal countries of birth (n = 109) at the third level. We disentangle offspring, maternal and maternal country of birth components of the total offspring heterogeneity in birthweight for babies born within the normal timespan (37-42 weeks). We found that of such birthweight variation about 50% was at the baby level, 47% at the maternal level and only 3% at the maternal countries of birth level. CONCLUSION: In spite of seemingly large differences in average birthweight among maternal countries of birth (range 3290-3677 g), knowledge of the maternal country of birth does not provide accurate information for ascertaining individual offspring birthweight because of the high inter offspring heterogeneity around country averages. Our study exemplifies the need for a better understanding of individual health diversity for which group averages may provide insufficient and even misleading information. The analytical approach we outline is therefore relevant to investigations of country of birth (and ethnic) differences in health in general. PMID- 26020537 TI - Re: Pareek A, Chandurkar N, Thomas N, et al. Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone. Curr Med Res Opin 2014;30:1257-66. PMID- 26020536 TI - Exposure to fluoride in drinking water and hip fracture risk: a meta-analysis of observational studies. AB - BACKGROUND: Many observational studies have shown that exposure to fluoride in drinking water is associated with hip fracture risk. However, the findings are varied or even contradictory. In this work, we performed a meta-analysis to assess the relationship between fluoride exposure and hip fracture risk. METHODS: PubMed and EMBASE databases were searched to identify relevant observational studies from the time of inception until March 2014 without restrictions. Data from the included studies were extracted and analyzed by two authors. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were pooled using random- or fixed-effects models as appropriate. Sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Finally, publication bias was assessed. RESULTS: Fourteen observational studies involving thirteen cohort studies and one case-control study were included in the meta-analysis. Exposure to fluoride in drinking water does not significantly increase the incidence of hip fracture (RRs, 1.05; 95% CIs, 0.96-1.15). Sensitivity analyses based on adjustment for covariates, effect measure, country, sex, sample size, quality of Newcastle-Ottawa Scale scores, and follow-up period validated the strength of the results. Meta-regression showed that country, gender, quality of Newcastle-Ottawa Scale scores, adjustment for covariates and sample size were not sources of heterogeneity. Little evidence of publication bias was observed. CONCLUSION: The present meta-analysis suggests that chronic fluoride exposure from drinking water does not significantly increase the risk of hip fracture. Given the potential confounding factors and exposure misclassification, further large-scale, high-quality studies are needed to evaluate the association between exposure to fluoride in drinking water and hip fracture risk. PMID- 26020538 TI - Re: Pareek A, Chandurkar N, Thomas N, et al. Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone. Curr Med Res Opin 2014;30:1257-66. PMID- 26020539 TI - Triglyceride-Increasing Alleles Associated with Protection against Type-2 Diabetes. AB - Elevated plasma triglyceride (TG) levels are an established risk factor for type 2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body- mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p<2 x 10-(10)). However, the TG GRS is negatively associated with T2D (p=0.013), upon adjusting for only race, in the full dataset. Upon additionally adjusting for age, sex, BMI, high-density lipoprotein cholesterol and TG, the TG GRS is significantly and negatively associated with T2D incidence (p=7.0 x 10(-8)), with similar trends among both EA and AA. No single SNP appears to be driving this association. We also find a significant statistical interaction of the TG GRS with TG (pi(nteraction) = 3.3 x 10-(4)), whereby the association of TG with incident T2D is strongest among those with low genetic risk for TG. Further research is needed to understand the likely pleiotropic mechanisms underlying these findings, and to clarify the causal relationship between T2D and TG. PMID- 26020540 TI - Incidence patterns and temporal trends of invasive nonmelanotic vulvar tumors in Germany 1999-2011. A population-based cancer registry analysis. AB - OBJECTIVES: Time trends on the incidence and characteristics of invasive vulvar cancer in Germany have so far been studied in few local population- and hospital based tumor registries. We aimed to provide an overview on recent developments of vulvar cancer in Germany, using population-based cancer registry data. METHODS: We analyzed the data on vulvar cancer of eight population-based German cancer registries for the period 1999-2011. ICD-10 codes and ICD-O-3 morphology codes were used to select site and histologic types. The annual percentage change was calculated on age-adjusted incidence rates with a joinpoint regression model. RESULTS: A total of 12,711 registered cases of invasive carcinoma of the vulva were included in the analyses, hereof were 12,205 of squamous cell origin. Age standardized incidence rates of vulvar cancer annually increased by 6.7% (95% confidence limits: 5.6-7.9) from 1.7 per 100,000 women in 1999 to 3.6 per 100,000 women in 2011. An increase was observed among women of all ages, and especially between 30 and 69 years of age. CONCLUSION: The annual incidence of invasive carcinoma of the vulva nearly doubled in the past decade in Germany, considerably exceeding the rates observed in other Western European countries. A combination of changes in risk factors, and documentation practice might have contributed to the observed substantial increase in vulvar cancer incidence. PMID- 26020541 TI - Radiological findings in young children investigated for tuberculosis in Mozambique. AB - INTRODUCTION: Chest radiography remains a critical tool for diagnosing intrathoracic tuberculosis (TB) in young children who are unable to expectorate. We describe the radiological findings in children under 3 years of age investigated for TB in the district of Manhica, southern Mozambique, an area with a high prevalence of TB and HIV. METHODS: Digital antero-posterior and lateral projections were performed and reviewed by two independent readers, using a standardized template. Readers included a local pediatrician and a pediatric radiologist blinded to all clinical information. International consensus case definitions for intra-thoracic TB in children were applied. RESULTS: A total of 766 children were evaluated of whom 43 (5.6%) had TB. The most frequent lesion found in TB cases was air space consolidation (65.1%), followed by suggestive hilar lymphadenopathy (17.1%) and pleural effusion (7.0%). Air space consolidation was significantly more common in TB cases than in non-TB cases (odds ratio 8.9; 95% CI: 1.6-50.5), as were hilar lymphadenopathy (OR 17.2; 95% CI: 5.7-52.1). The only case with miliary infiltrates and 3 with pleural effusions occurred in HIV-infected children. CONCLUSION: Frequent air space consolidation complicates radiological distinction between TB and bacterial pneumonia in young children, underscoring the need for epidemiological contextualization and consideration of all relevant signs and symptoms. PMID- 26020542 TI - Effects of individualized centrifugation training on orthostatic tolerance in men and women. AB - AIMS: Exposure to artificial gravity (AG) at different G loads and durations on human centrifuges has been shown to improve orthostatic tolerance in men. However, the effects on women and of an individual-specific AG training protocol on tolerance are not known. METHODS: We examined the effects of 90 minutes of AG vs. 90 minutes of supine rest on the orthostatic tolerance limit (OTL), using head up tilt and lower body negative pressure until presyncope of 7 men and 5 women. Subjects were placed in the centrifuge nacelle while instrumented and after one-hour they underwent either: 1) AG exposure (90 minutes) in supine position [protocol 1, artificial gravity exposure], or 2) lay supine on the centrifuge for 90 minutes in supine position without AG exposure [protocol 2, control]. The AG training protocol was individualized, by first determining each subject's maximum tolerable G load, and then exposing them to 45 minutes of ramp training at sub-presyncopal levels. RESULTS: Both sexes had improved OTL (14 minutes vs 11 minutes, p < 0.0019) following AG exposure. When cardiovascular (CV) variables at presyncope in the control test were compared with the CV variables at the same tilt-test time (isotime) during post-centrifuge, higher blood pressure, stroke volume and cardiac output and similar heart rates and peripheral resistance were found post-centrifuge. CONCLUSIONS: These data suggest a better-maintained central circulating blood volume post-centrifugation across gender and provide an integrated insight into mechanisms of blood pressure regulation and the possible implementation of in-flight AG countermeasure profiles during spaceflights. PMID- 26020543 TI - Phase contrast MR imaging measurements of blood flow in healthy human cerebral vessel segments. AB - Phase contrast (PC) magnetic resonance imaging was used to obtain velocity measurements in 30 healthy subjects to provide an assessment of hemodynamic parameters in cerebral vessels. We expect a lower coefficient-of-variation (COV) of the volume flow rate (VFR) compared to peak velocity (vpeak) measurements and the COV to increase in smaller caliber arteries compared to large arteries.PC velocity maps were processed to calculate vpeak and VFR in 26 vessel segments. The mean, standard deviation and COV, of vpeak and VFR in each segment were calculated. A bootstrap-style analysis was used to determine the minimum number of subjects required to accurately represent the population. Significance of vpeak and VFR asymmetry was assessed in 10 vessel pairs.The bootstrap analysis suggested that averaging more than 20 subjects would give consistent results. When averaged over the subjects, vpeak and VFR ranged from 5.2 +/- 7.1 cm s(-1), 0.41 +/- 0.58 ml s(-1) (in the anterior communicating artery; mean +/- standard deviation) to 73 +/- 23 cm s(-1), 7.6 +/- 1.7 ml s(-1) (in the left internal carotid artery), respectively. A tendency for VFR to be higher in the left hemisphere was observed in 88.8% of artery pairs, while the VFR in the right transverse sinus was larger. The VFR COV was larger than vpeak COV in 57.7% of segments, while smaller vessels had higher COV.Significance and potential impact: VFR COV was not generally higher than vpeak COV. COV was higher in smaller vessels as expected. These summarized values provide a base against which vpeak and VFR in various disease states can be compared. PMID- 26020544 TI - An Umpolung Approach to Alkene Carboamination: Palladium Catalyzed 1,2-Amino Acylation, -Carboxylation, -Arylation, -Vinylation, and -Alkynylation. AB - Conventional approaches to Pd-catalyzed alkene 1,2-carboamination rely upon the combination of a nucleophilic nitrogen-based component and an internal C-based or external oxidant. In this study, we outline an umpolung approach, which is triggered by oxidative initiation at an electrophilic N-based component and employs "standard" organometallic nucleophiles to introduce the new carbon-based fragment. Specifically, oxidative addition of a Pd(0)-catalyst into the N-O bond of O-pentafluorobenzoyl oxime esters generates imino-Pd(II) intermediates, which undergo 5-exo cyclization with sterically diverse alkenes. The resultant alkyl Pd(II) intermediates are intercepted by organometallic nucleophiles or alcohols, under carbonylative or noncarbonylative conditions, to provide 1,2-carboamination products. This approach provides, for the first time, a unified strategy for achieving alkene 1,2-amino-acylation, -carboxylation, -arylation, -vinylation, and -alkynylation. For carbonylative processes, orchestrated protodecarboxylation of the pentafluorobenzoate leaving group underpins reaction efficiency. This process is likely a key feature in related Narasaka-Heck cyclizations and accounts for the efficacy of O-pentafluorobenzoyl oxime esters in aza-Heck reactions of this type. PMID- 26020545 TI - Erratum, Vol. 12, May 7 release. Use of culturally focused theoretical frameworks for adapting diabetes prevention programs: a qualitative review. PMID- 26020546 TI - Mammography rates for breast cancer screening: a comparison of First Nations women and all other women living in Manitoba, Canada, 1999-2008. AB - INTRODUCTION: First Nations (FN) women historically have low rates of preventive care, including breast cancer screening. We describe the frequency of breast cancer screening among FN women living in Manitoba and all other Manitoba (AOM) women after the introduction of a provincial, organized breast screening program and explore how age, area of residence, and time period influenced breast cancer screening participation. METHODS: The federal Indian Registry was linked to 2 population-based, provincial data sources. A negative binomial model was used to compare breast cancer screening for FN women with screening for AOM women. RESULTS: From 1999 through 2008, 37% of FN and 59% of AOM women had a mammogram in the previous 2 years. Regardless of area of residence, FN women were less likely to have had a mammogram than AOM women (relative rate [RR] = 0.69 in the north, RR = 0.55 in the rural south, and RR = 0.53 in urban areas). CONCLUSIONS: FN women living in Manitoba had lower mammography rates than AOM women. To ensure equity for all Manitoba women, strategies that encourage FN women to participate in breast cancer screening should be promoted. PMID- 26020547 TI - Factors involved in the collaboration between the national comprehensive cancer control programs and tobacco control programs: a qualitative study of 6 States, United States, 2012. AB - INTRODUCTION: Historically, federal funding streams to address cancer and tobacco use have been provided separately to state health departments. This study aims to document the impact of a recent focus on coordinating chronic disease efforts through collaboration between the 2 programs. METHODS: Through a case-study approach using semistructured interviews, we collected information on the organizational context, infrastructure, and interaction between cancer and tobacco control programs in 6 states from March through July 2012. Data were analyzed with NVivo software, using a grounded-theory approach. RESULTS: We found between-program activities in the state health department and coordinated implementation of interventions in the community. Factors identified as facilitating integrated interventions in the community included collaboration between programs in the strategic planning process, incorporation of one another's priorities into state strategic plans, co-location, and leadership support for collaboration. Coalitions were used to deliver integrated interventions to the community. Five states perceived high staff turnover as a barrier to collaboration, and all 5 states felt that federal funding requirements were a barrier. CONCLUSIONS: Cancer and tobacco programs are beginning to implement integrated interventions to address chronic disease. Findings can inform the development of future efforts to integrate program activities across chronic disease prevention efforts. PMID- 26020548 TI - Changes in density of on-premises alcohol outlets and impact on violent crime, Atlanta, Georgia, 1997-2007. AB - INTRODUCTION: Regulating alcohol outlet density is an evidence-based strategy for reducing excessive drinking. However, the effect of this strategy on violent crime has not been well characterized. A reduction in alcohol outlet density in the Buckhead neighborhood of Atlanta from 2003 through 2007 provided an opportunity to evaluate this effect. METHODS: We conducted a community-based longitudinal study to evaluate the impact of changes in alcohol outlet density on violent crime in Buckhead compared with 2 other cluster areas in Atlanta (Midtown and Downtown) with high densities of alcohol outlets, from 1997 through 2002 (preintervention) to 2003 through 2007 (postintervention). The relationship between exposures to on-premises retail alcohol outlets and violent crime were assessed by using annual spatially defined indices at the census block level. Multilevel regression models were used to evaluate the relationship between changes in exposure to on-premises alcohol outlets and violent crime while controlling for potential census block-level confounders. RESULTS: A 3% relative reduction in alcohol outlet density in Buckhead from 1997-2002 to 2003-2007 was associated with a 2-fold greater reduction in exposure to violent crime than occurred in Midtown or Downtown, where exposure to on-premises retail alcohol outlets increased. The magnitude of the association between exposure to alcohol outlets and violent crime was 2 to 5 times greater in Buckhead than in either Midtown or Downtown during the postintervention period. CONCLUSIONS: A modest reduction in alcohol outlet density can substantially reduce exposure to violent crime in neighborhoods with high density of alcohol outlets. Routine monitoring of community exposure to alcohol outlets could also inform the regulation of alcohol outlet density, consistent with Guide to Community Preventive Services recommendations. PMID- 26020551 TI - Values of T/QRS ratio in pregnancies complicated by intrauterine growth restriction. AB - AIMS: To evaluate values of T/QRS ratio in normal pregnancies and those complicated by intrauterine growth restriction (IUGR) using non-invasive method with transabdominal electrodes. Assessment of fetal well-being in IUGR pregnancies. METHODS: Fetal electrocardiograms were recorded and analyzed by KOMPOREL software from ITAM (Zabrze, Poland) and T/QRS ratios were automatically calculated. Doppler velocimetry of the middle cerebral artery and umbilical artery was carried out. The study group consisted of IUGR pregnancies with normal cerebroplacental ratios (CPRs) (n=110), IUGR pregnancies with decreased CPRs (n=29), and healthy controls (n=549). Analyses were performed between the study groups and by gestational age. T/QRS ratio variables and CPRs were calculated. Analysis of variance and linear regression were performed. RESULTS: Maximum values, maximum minimal value differences, and standard deviations of T/QRS ratio were significantly different between the IUGR group with reduced CPRs and normal CPRs (P=0.0009, P=0.0000, P=0.0034, respectively) as well as between the IUGR group with reduced CPRs and healthy controls (P=0.0000, P=0.0001, P=0.0009, respectively). Mean maximum values in the IUGR group with reduced CPRs exceeded normal values. CONCLUSIONS: T/QRS ratio may be useful in assessing fetal well being in IUGR pregnancies; however, future studies are needed to determine typical ranges of T/QRS ratio in pregnancies complicated by IUGR. PMID- 26020549 TI - Self-reported sitting time in New York City adults, the Physical Activity and Transit Survey, 2010-2011. AB - INTRODUCTION: Recent studies have demonstrated the negative health consequences associated with extended sitting time, including metabolic disturbances and decreased life expectancy. The objectives of this study were to characterize sitting time in an urban adult population and assess the validity of a 2-question method of self-reported sitting time. METHODS: The New York City Health Department conducted the 2010-2011 Physical Activity and Transit Survey (N = 3,597); a subset of participants wore accelerometers for 1 week (n = 667). Self reported sitting time was assessed from 2 questions on time spent sitting (daytime and evening hours). Sedentary time was defined as accelerometer minutes with less than 100 counts on valid days. Descriptive statistics were used to estimate the prevalence of sitting time by demographic characteristics. Validity of sitting time with accelerometer-measured sedentary time was assessed using Spearman's correlation and Bland-Altman techniques. All data were weighted to be representative of the New York City adult population based on the 2006-2008 American Community Survey. RESULTS: Mean daily self-reported sitting time was 423 minutes; mean accelerometer-measured sedentary time was 490 minutes per day (r = 0.32, P < .001). The mean difference was 49 minutes per day (limits of agreement: -441 to 343). Sitting time was higher in respondents at lower poverty and higher education levels and lower in Hispanics and people who were foreign-born. CONCLUSION: Participants of higher socioeconomic status, who are not typically the focus of health disparities-related research, had the highest sitting times; Hispanics had the lowest levels. Sitting time may be accurately assessed by self report with the 2-question method for population surveillance but may be limited in accurately characterizing individual-level behavior. PMID- 26020550 TI - Polymeric Nanovehicle Regulated Spatiotemporal Real-Time Imaging of the Differentiation Dynamics of Transplanted Neural Stem Cells after Traumatic Brain Injury. AB - Recent advances in neural stem cell (NSC) transplantation have led to an inspiring progress in alleviating central nervous system (CNS) damages and restoring brain functions from diseases or injuries. One challenge of NSC transplantation is directed differentiation of transplanted NSCs into desired neuronal subtypes, such as neurons, to compensate the adverse impact of brain injury; another challenge lies in the lack of tools to noninvasively monitor the dynamics of NSC differentiation after transplantation in vivo. In this study, we developed a polymer nanovehicle for morphogen sustained release to overcome the drawbacks of conventional methods to realize the long-term directed NSC differentiation in vivo. Moreover, we constructed a bicistronic vector with a unique neuron specific gene tubb3 promoter to drive reporter gene expression for real-time imaging of NSC differentiation and migration. The developed uniform nanovehicle showed efficient NSC uptake and achieved a controlled release of morphogen in cytosol to consistently stimulate NSC differentiation into neurons at a sustainably effective concentration. The spatiotemporal imaging results showed a multiplexed migration, proliferation, differentiation, and apoptosis orchestra of transplanted NSCs regulated by nanovehicles in TBI mice. The imaging results also uncovered the peak time of NSC differentiation in vivo. Although we observed only a handful of NSCs ultimately migrated to the TBI area and differentiated into neurons, those neurons were functional, ameliorating the detrimental impact of TBI. The imaging findings enabled by the nanovehicle and the neuron specific bicistronic vector provide additional understanding of the in vivo behaviors of transplanted NSCs in neuronal regenerative medicine. PMID- 26020552 TI - Clinical experimental stress studies: methods and assessment. AB - Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Stress induction methods are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these methods are also important for the development of novel pharmacological agents for stress management. The well-described methods to induce stress in humans include the cold pressor test, Trier Social Stress Test, Montreal Imaging Stress Task, Maastricht Acute Stress Test, CO2 challenge test, Stroop test, Paced Auditory Serial Addition Task, noise stress, and Mannheim Multicomponent Stress Test. Stress assessment in humans is done by measuring biochemical markers such as cortisol, cortisol awakening response, dexamethasone suppression test, salivary alpha-amylase, plasma/urinary norepinephrine, norepinephrine spillover rate, and interleukins. Physiological and behavioral changes such as galvanic skin response, heart rate variability, pupil size, and muscle and/or skin sympathetic nerve activity (microneurography) and cardiovascular parameters such as heart rate, blood pressure, and self-reported anxiety are also monitored to assess stress response. This present review describes these commonly employed methods to induce stress in humans along with stress assessment methods. PMID- 26020553 TI - Evaluation of the analgesic, anti-inflammatory, anti-oxidant, phytochemical and toxicological properties of the methanolic leaf extract of commercially processed Moringa oleifera in some laboratory animals. AB - BACKGROUND: Moringa oleifera Lam (Moringaceae) is a highly valued plant, distributed in many countries of the tropics and subtropics. It has an impressive range of medicinal uses with high nutritional value. METHODS: The commercially processed M. oleifera was extracted using methanol as its solvent. Phytochemical analysis as well as the anti-oxidant properties of this supplement were also investigated. Acute toxicity was carried out in fasted mice. Carrageenan and histamine tests were used to assess anti-inflammatory effects in rats, while analgesic activities were assessed using the acetic acid-induced writhing test and formalin-induced paw lick test in mice. In the anti-oxidant tests, 1,1 diphenyl-2-picrylhydrazyl, ferrous reducing activity power, 2,21-azinobis-(3 ethylbenthialozine)-6-sulphonic acid and total polyphenolic (TPP) assays were deployed at concentrations of 10 mg/mL and 20 mg/mL. RESULTS: The phytochemical analysis showed that the extract contained flavonoids, terpenoids, glycosides, tannins and saponins. In the acetic acid-induced writhing test, the extract significantly reduced the number of writhes at 100 and 200 mg/kg but not so much at 50 mg/kg. In the formalin-induced paw lick test, the effect was similar to that of the acetic writhing test. The analgesic effects were comparable to that of indomethacin used at 10 mg/kg. In the anti-inflammatory test, the extract reduced the formation of oedema especially at a dose of 200 mg/kg. In the anti oxidant test, the extract was found to possess a free radical-scavenging property and is concentration related. CONCLUSIONS: The use of this extract for medicinal and nutritional purposes may have thus been justified; however, caution must be exercised in its use to prevent the toxic effect. PMID- 26020554 TI - Jobelyn(r) exhibited anti-inflammatory, antioxidant, and membrane-stabilizing activities in experimental models. AB - BACKGROUND: Jobelyn(r) (JB) is an African sorghum-based food supplement claimed to be efficacious for the treatment of rheumatoid arthritis (RA). Although in vitro studies confirmed its anti-inflammatory property, no study had shown the effect of JB using in vivo animal models of inflammation. Thus, its effects on acute and chronic inflammation in rats were evaluated in this study. Its effect on rat red blood cell (RBC) lysis was also assessed. METHODS: Acute inflammation was induced with intraplanter injection of carrageenan and increase in rat paw volume was measured using plethysmometer. The volume of fluid exudates, number of leukocytes, concentrations of malondialdehyde (MDA), and glutathione (GSH) in the fluid were measured on day 5 after induction of chronic inflammation with carrageenan in the granuloma air pouch model. RBC lysis induced by hypotonic medium as determined by release of hemoglobin was measured spectrophotometerically. RESULTS: JB (50-200 mg/kg) given orally produced a significant inhibition of acute inflammation induced by carrageenan in rats. It reduced the volume and number of leukocytes in inflammatory fluid in the granuloma air pouch model of chronic inflammation. It further decreased the levels of MDA in the fluid suggesting antioxidant property. JB elevated the concentrations of GSH in inflammatory exudates indicating free radical scavenging activity. It also significantly inhibited RBC lysis caused by hypotonic medium, suggesting membrane-stabilizing property. CONCLUSIONS: JB has in vivo anti inflammatory activity, which may be related to its antioxidant and membrane stabilizing properties, supporting its use for the treatment of arthritic disorder. PMID- 26020555 TI - Implications of sodium hydrogen exchangers in various brain diseases. AB - Na+/H+ exchangers (NHEs) are the transporter proteins that play an important role in intracellular pH (pHi) regulation, cell differentiation and cell volume and that mediate transepithelial Na+ and HCO3- absorption on the basis of chemical gradients across the plasma membrane. Its activation causes an increase in intracellular Na+, which further leads to Ca+ overload and cell death. The pharmacological inhibition of these transporter proteins prevents myocardial infarction and other heart diseases like congestive heart failure in experimental animal models as well as in clinical situations. The more recent studies have implicated the role of these exchangers in the pathophysiology of brain diseases. Out of nine NHE isoforms, NHE-1 is the major isoform present in the brain and regulates the trans-cellular ion transport through blood-brain barrier membrane, and alteration in their function leads to severe brain abnormalities. NHEs were shown to be involved in pathophysiologies of many brain diseases like epilepsy, Alzheimer's disease, neuropathic pain and ischemia/reperfusion-induced cerebral injury. Na+/H+-exchanger inhibitors (e.g., amiloride and cariporide) produce protective effects on ischemia/reperfusion-induced brain injury (e.g., stroke), exhibit good antiepileptic potential and attenuate neuropathic pain in various animal models. The present review focuses on the pathophysiological role of these ion exchangers in different brain diseases with possible mechanisms. PMID- 26020556 TI - Characterization of a mineral coating of the plant Dyerophytum indicum. AB - The mineral coating of Dyerophytum indicum Kuntze (Plumbaginaceae) was analyzed by isotope ratio mass spectrometry, X-ray diffraction, thermogravimetric and differential thermal analysis, and scanning electron microscopy/energy-dispersive X-ray spectroscopy methods. Its composition was found to be similar to those of the carbonate mixtures isolated from rotting cacti and speleothems. The coating consisted of three major phases (monohydrocalcite, nesquehonite, and calcite), a minor phase of hydromagnesite, and traces of silica and sylvite. This is the first time that the occurrence of monohydrocalcite, nesquehonite, and hydromagnesite in a living higher plant has been reported. A possible mechanism of the formation of the coating is also discussed. PMID- 26020557 TI - Synthesis and antiproliferative evaluation of novel 5-(4-methylpiperazin-1-yl)-2 phenyl- 1H-benzimidazole derivatives. AB - A series of novel 5-(4-methylpiperazin-1-yl)-2-phenyl-1H-benzimidazoles (5-14) were synthesized and evaluated for their in vitro antiproliferative activities against the human leukemia cell line HL-60. Compounds 5-7 and 10-12 exhibited potent antiproliferative activities against this cell line. The quantitative analysis of apoptosis by flow cytometry demonstrated that the percentages of apoptotic HL-60 cells treated with compounds 5 and 10-12 were significantly higher than in the control. PMID- 26020558 TI - Differential cytotoxic activity of the petroleum ether extract and its furanosesquiterpenoid constituents from Commiphora molmol resin. AB - This study revealed a differential cytotoxic activity of the petroleum ether extract (IC50 =5 MUg/mL) of the resinous exudates of Commiphora molmol against two mouse cell lines KA31T and NIH3T3 (untransformed and transformed mouse fibroblasts, respectively). Four new compounds (1-4) and five known compounds (5 9) were isolated from the petroleum ether extract. The identity of these new compounds was determined as gamma-elemane lactone (1), 5-alphaH,8-betaH-eudesma 1,3,7(11)-trien-8,12-olide (2), 2-hydroxy-11,12-dihydrofuranodiene (3), and 2 hydroxyfuranodiene (4). 1 and 2 displayed the highest cytotoxic activity against NIH3T3 cells. 7 and 9 exhibited moderate cytotoxic activity against KA31T cells. Compounds 3-6 showed weak cytotoxic activities against both cell lines. These results may explain the high efficacy of the petroleum ether fraction in several myrrh-derived pharmaceutical preparations. PMID- 26020559 TI - Bioactive compounds isolated from submerged fermentations of the Chilean fungus Stereum rameale. AB - Liquid fermentations of the fungus Stereum rameale (N degrees 2511) yielded extracts with antibacterial activity. The antibacterial activity reached its peak after 216 h of stirring. Bioassay-guided fractionation methods were employed for the isolation of the bioactive metabolites. Three known compounds were identified: MS-3 (1), vibralactone (2) and vibralactone B (3). The three compounds showed antibacterial activity as a function of their concentration. Minimal bactericidal concentrations (MBC) of compound 1 against Gram-positive bacteria were as follows: Bacillus cereus (50 MUg/mL), Bacillus subtilis (10 MUg/mL) and Staphylococcus aureus (100 MUg/mL). Compounds 2 and 3 were active only against Gram-negative bacteria. The MBC of compound 2 against Escherichia coli was 200 MUg/mL. Compound 3 inhibited significantly the growth of E. coli and Pseudomonas aeruginosa, with MBC values of 50 and 100 MUg/mL, respectively. PMID- 26020560 TI - Defects of corneocyte structural proteins and epidermal barrier in atopic dermatitis. AB - The main function of the epidermis is to establish a vital multifunctional barrier between the body and its external environment. A defective epidermal barrier is one of the key features of atopic dermatitis (AD), a chronic and relapsing inflammatory skin disorder that affects up to 20% of children and 2-3% of adults and often precedes the development of allergic rhinitis and asthma. This review summarizes recent discoveries on the origin of the skin barrier alterations in AD at the structural protein level, including hereditary and acquired components. The consequences of the epidermal barrier alteration on our current understanding of the pathogenesis of AD, and its possible implications on the treatment of patients, are discussed here. PMID- 26020561 TI - Second generation analysis of antinuclear antibody (ANA) by combination of screening and confirmatory testing. AB - BACKGROUND: For the serological diagnosis of systemic autoimmune rheumatic diseases, a two-tier approach starting with sensitive antinuclear antibody (ANA) detection by indirect immunofluorescence (IIF) on HEp-2 cells followed by characterization of positive findings with different immunoassays is recommended. To overcome drawbacks of this approach, we developed a novel technique allowing the combination of screening and simultaneous confirmatory testing. For the first time, this creates the basis for second generation ANA testing. METHODS: ANA and autoantibodies (autoAbs) to double-stranded DNA (dsDNA), CENP-B, SS-A/Ro52, SS A/Ro60, SS-B/La, RNP-Sm, Sm, and Scl-70 were determined by IIF and enzyme-linked immunosorbent assay (ELISA), respectively, and compared to simultaneous analysis thereof by second generation ANA analysis in patients with systemic lupus erythematosus (n=174), systemic sclerosis (n=103), Sjogren's syndrome (n=46), rheumatoid arthritis (n=36), mixed and undetermined connective tissue diseases (n=13), myositis (n=21), infectious disease (n=21), autoimmune liver disease (n=93), inflammatory bowel disease (n=78), paraproteinemia (n=11), and blood donors (n=101). RESULTS: There was very good agreement of second generation ANA testing with classical one by IIF and ELISA regarding testing for ANA and autoAbs to dsDNA, CENP-B, SS-B, RNP-Sm, Scl-70, SS-A/Ro52, and SS-A/Ro60 (Cohen's kappa>0.8). The agreement for anti-Sm autoAb was good (kappa=0.77). The differences of both approaches were not significant for autoAbs to SS-B/La, RNP Sm, Scl-70, SS-A/Ro60, and SS-A/Ro52 (McNemar's test, p>0.05, respectively). CONCLUSIONS: Second generation ANA testing can replace the two-tier analysis by combining IIF screening with multiplex confirmative testing. This addresses shortcomings of classical ANA analysis like false-negative ANA findings and lack of laboratory efficiency and standardization. PMID- 26020562 TI - Reply to: The risk of macrovascular complications in subjects genotyped for common IL-6 gene and TNF-alpha gene variants. PMID- 26020563 TI - Testosterone therapy in men with Crohn's disease improves the clinical course of the disease: data from long-term observational registry study. AB - BACKGROUND: Crohn's disease is an inflammatory chronic bowel disease characterized by an imbalanced production of pro-inflammatory mediators (tumor necrosis factor-alpha) and an increased recruitment of leukocytes to the site of inflammation. Low serum testosterone is associated with an increase in inflammatory factors, while testosterone administration reduces them. There is evidence for an immunomodulatory effect of testosterone on differentiation of regulatory T cells. MATERIALS AND METHODS: The research was carried out in clinics in Germany and Syria. The study was a cumulative, prospective, registry study with an increasing number of men over time receiving testosterone. While men diagnosed with Crohn's disease received appropriate treatment for Crohn's disease, they were tested for testosterone deficiency (cut-off point <=12.1 nmol/L). In total, 92 men received parenteral testosterone undecanoate 1000 mg/12 weeks for up to 7 years. Fourteen men opted not to receive testosterone and served as a comparison group. RESULTS: In men receiving testosterone, the Crohn's Disease Activity Index declined from 239.36+/-36.96 to 71.67+/-3.26 at 84 months (p<0.0001 vs. baseline). C-reactive protein levels decreased from 12.89+/-8.64 to 1.78+/-1.37 mg/L at 84 months (p<0.0001 vs. baseline). Leukocyte count decreased from 11.93+/-2.85 to 6.21+/-1.01*109/L (p<0.0001 at 84 months vs. baseline). No changes were observed in the comparison group. There were no significant side effects of testosterone. CONCLUSIONS: Normalizing serum testosterone in hypogonadal men with Crohn's disease had a positive effect on the clinical course, also evidenced by biochemical parameters. Testosterone administration appeared safe. PMID- 26020565 TI - (1)H and (15)N NMR Characterization of the Amine Groups of Heparan Sulfate Related Glucosamine Monosaccharides in Aqueous Solution. AB - Glucosamine is an important constituent of the heterogeneous glycosaminoglycans heparin and heparan sulfate occurring in N-acetylated and N-sulfated forms, and as the unmodified amine. Though the (1)H and (15)N NMR chemical shifts of N acetyl- and N-sulfoglucosamine residues have been extensively characterized, this study provides the first direct NMR characterization of the amine groups of glucosamine and 3-O-sulfoglucosamine in aqueous solution. The solvent exchange properties of the amine protons are examined, and the possibility of a salt bridge between the sulfate and amine groups of 3-O-sulfoglucosamine is explored through (1)H NMR pKa measurements but is not supported by the experimental results. PMID- 26020564 TI - Conformational Dynamics of Two Natively Unfolded Fragment Peptides: Comparison of the AMBER and CHARMM Force Fields. AB - Physics-based force fields are the backbone of molecular dynamics simulations. In recent years, significant progress has been made in the assessment and improvement of commonly used force fields for describing conformational dynamics of folded proteins. However, the accuracy for the unfolded states remains unclear. The latter is however important for detailed studies of protein folding pathways, conformational transitions involving unfolded states, and dynamics of intrinsically disordered proteins. In this work, we compare the three commonly used force fields, AMBER ff99SB-ILDN, CHARMM22/CMAP, and CHARMM36, for modeling the natively unfolded fragment peptides, NTL9(1-22) and NTL9(6-17), using explicit-solvent replica-exchange molecular dynamics simulations. All three simulations show that NTL9(6-17) is completely unstructured, while NTL9(1-22) transiently samples various beta-hairpin states, reminiscent of the first beta hairpin in the structure of the intact NTL9 protein. The radius of gyration of the two peptides is force field independent but likely underestimated due to the current deficiency of additive force fields. Compared to the CHARMM force fields, ff99SB-ILDN gives slightly higher beta-sheet propensity and more native-like residual structures for NTL9(1-22), which may be attributed to its known beta preference. Surprisingly, only two sequence-local pairs of charged residues make appreciable ionic contacts in the simulations of NTL9(1-22), which are sampled slightly more by the CHARMM force fields. Taken together, these data suggest that the current CHARMM and AMBER force fields are globally in agreement in modeling the unfolded states corresponding to beta-sheet in the folded structure, while differing in details such as the native-likeness of the residual structures and interactions. PMID- 26020567 TI - Roll-to-Roll Encapsulation of Metal Nanowires between Graphene and Plastic Substrate for High-Performance Flexible Transparent Electrodes. AB - Transparent conductive film on plastic substrate is a critical component in low cost, flexible, and lightweight optoelectronics. Industrial-scale manufacturing of high-performance transparent conductive flexible plastic is needed to enable wide-ranging applications. Here, we demonstrate a continuous roll-to-roll (R2R) production of transparent conductive flexible plastic based on a metal nanowire network fully encapsulated between graphene monolayer and plastic substrate. Large-area graphene film grown on Cu foil via a R2R chemical vapor deposition process was hot-laminated onto nanowires precoated EVA/PET film, followed by a R2R electrochemical delamination that preserves the Cu foil for reuse. The encapsulated structure minimized the resistance of both wire-to-wire junctions and graphene grain boundaries and strengthened adhesion of nanowires and graphene to plastic substrate, resulting in superior optoelectronic properties (sheet resistance of ~8 Omega sq(-1) at 94% transmittance), remarkable corrosion resistance, and excellent mechanical flexibility. With these advantages, long cycle life flexible electrochromic devices are demonstrated, showing up to 10000 cycles. PMID- 26020566 TI - Blastomycosis in Indiana: Clinical and Epidemiologic Patterns of Disease Gleaned from a Multicenter Retrospective Study. AB - BACKGROUND: To better understand clinical and epidemiologic patterns of blastomycosis, we report on a large series of blastomycosis in Indiana. METHODS: All microbiologically and histopathologically confirmed cases of blastomycosis from four hospitals serving Central Indiana from 1985 to 2014 were identified. Available data were collected. Data on population estimates, annual precipitation, and construction in Indiana were evaluated for correlations with incidence rates of blastomycosis. RESULTS: A total of 114 patients were identified. The mean age was 44.4 years; 27% had diabetes mellitus, and 16% were immunosuppressed. Most presented with pneumonia (90%); 48% had extrapulmonary disease (CNS involvement in 9%), and 15% developed ARDS. Cultures, cytopathology, and histopathology were positive in 86%, 27%, and 85% of the sample, respectively, and fungal antigen was positive in 76%. Amphotericin B was administered in 49%, and 87% received an azole. Total mortality was 12%. Immunosuppression (OR = 3.0), diabetes mellitus (OR = 2.9), and multilobar pneumonia (OR = 2.9) were associated with increased likelihood of ICU admission. There was a significant increase in incidence over time in Marion County. There was no correlation with amount of precipitation, but the rise in incidence coincided with a 2005 state initiative to expand Indiana's highway infrastructure. CONCLUSIONS: The incidence of blastomycosis in Central Indiana may be on the rise. Physicians in endemic areas should be aware of the potentially fulminant consequences of the disease. PMID- 26020568 TI - Activity Limitations, Participation, and Quality of Life in American Indians with and without Diabetes. AB - The objective of this study was to examine activity limitations, participation, and quality of life (QOL) in American Indians with and without diabetes. It was a cross-sectional study that included 43 participants with diabetes and 31 healthy controls. Participants received evaluations of QOL, activity and participation limitations and factors such as pain, joint motion, hand function, and depression. There were no significant differences between the two groups for past, present, or future global QOL. However, there were significant differences between the two groups for the activity and participation measures and all measures of body structure/function except for left hand strength and depression. Current health and pain, and activity limitation correlated with QOL in both groups. Joint motion and participation correlated with QOL in the group with diabetes. American Indians with diabetes had more impairments in body structure and function and limitations in activities and participation compared to American Indians without diabetes. PMID- 26020569 TI - Preoperative serum chemokine (C-C motif) ligand 2 levels and prognosis in colorectal cancer. AB - INTRODUCTION: Chemokines are cytokines with chemotactic functions in the initiation and maintenance of immune reactions. They have also been shown to regulate other processes such as cancer progression and cancer cell migration. OBJECTIVES: The aim of this study was to determine the prognostic role of serum levels of chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) ligand 5 (CCL5) in patients with colorectal cancer. PATIENTS AND METHODS: The study included a group of 45 patients with colorectal cancer. The serum concentrations of CCL2 and CCL5 were measured preoperatively. Peripheral blood mononuclear cells (PBMC) from patients' blood were isolated and cultured alone or with cancer cells. The concentrations of chemokines in serum and culture supernatants were measured using the cytometric bead array method. The cut-off points for serum chemokine levels were set based on the receiver-operating characteristic curve analysis at a level of 103.6 pg/ml for CCL2 and of 11933.2 pg/ml for CCL5. The survival analysis and multivariate analysis of prognostic factors were performed. RESULTS: The 5-year survival was 57.5% for the group with low CCL2 levels and 23.87% for the group with high CCL2 levels. For the groups with low and high CCL5 levels, the survival was 18.3% and 49.3%, respectively. For CCL2, the survival of the low-level group was significantly better than that of the highlevel group (P = 0.0028). In the Cox proportional hazard model, radicality of resection (P = 0.001) and CCL2 levels (P = 0.029) were independent prognostic factors. CONCLUSIONS: The serum level of CCL2 in patients with colorectal cancer may have prognostic value. One of the possible mechanisms of CCL2 production is the interaction of PBMC with cancer cells. PMID- 26020570 TI - Calcium Plasma Implanted Titanium Surface with Hierarchical Microstructure for Improving the Bone Formation. AB - Introducing hierarchical microstructure and bioactive trace elements simultaneously onto the surface of titanium implant is a very effective way to improve the osseointegration between bone and implant. In this work, hierarchical topography was prepared on Ti surface via acid etching and sandblasting (SLA) to form micropits and microcavities then underwent Ca plasma immersion ion implantation (Ca-PIII) process. The surface wettability and roughness did not change obviously before and after Ca-PIII process. The in vitro evaluations including cell adhesion, activity, alkaline phosphatase (ALP), osteogenic genes (Runx2, OSX, ALP, BSP, Col1a1, OPN, and OC), and protein (BSP, Col1a1, OPN, and OC) expressions revealed that the introduction of Ca ions onto the surface of SLA treated Ti can promote greater osteoblasts adhesion, spread and proliferation, which in return further accelerated the maturation and mineralization of osteoblasts. More importantly, in vivo evaluations including Micro-CT evaluation, histological observations, push-out test, sequential fluorescent labeling and histological observations verified that Ca-SLA-treated Ti implants could efficiently promote new bone formation in early times. These promising results suggest that Ca-SLA-treated Ti has the potential for future application in orthopedic field. PMID- 26020572 TI - Toward Homogenization of Heterogeneous Metal Nanoparticle Catalysts with Enhanced Catalytic Performance: Soluble Porous Organic Cage as a Stabilizer and Homogenizer. AB - Organic molecular cage (CC3-R) with intrinsically porous skeleton is used as a support for immobilizing Rh nanoparticles (NPs) in an ultrasmall size of ~1.1 nm for the first time. The CC3-R with the unique characteristic of high solubility can be utilized to homogenize the heterogeneous catalyst in solution. The obtained homogenized heterogeneous catalyst Rh/CC3-R-homo exhibits significantly enhanced catalytic performance toward various liquid-phase catalytic reactions, as compared with the heterogeneous counterpart Rh/CC3-R-hetero. Moreover, Rh/CC3 R-homo shows excellent durability and recyclability. The advantage of combining homogeneous and heterogeneous catalysts is likely to be beneficial for many applications. PMID- 26020571 TI - Bacteria-Derived Compatible Solutes Ectoine and 5alpha-Hydroxyectoine Act as Intestinal Barrier Stabilizers to Ameliorate Experimental Inflammatory Bowel Disease. AB - Earlier studies showed that the compatible solute ectoine (1) given prophylactically before induction of colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats prevented histological changes induced in the colon and the associated rise in inflammatory mediators. This study was therefore conducted to investigate whether ectoine (1) and its 5alpha-hydroxy derivative (2) would also be effective in treating an already established condition. Two days after inducing colitis in rats by instilling TNBS/alcohol in the colon, animals were treated orally once daily for 1 week with either 1 or 2 (50, 100, 300 mg/kg). Twenty-four hours after the last drug administration rats were sacrificed. Ulcerative lesions and colon mass indices were reduced by 1 and 2 in a bell shaped manner. Best results were obtained with 100 mg/kg ectoine (1) and 50 mg/kg 5alpha-hydroxyectoine (2). The solutes normalized the rise in myeloperoxidase, TNFalpha, and IL-1beta induced by TNBS but did not affect levels of reduced glutathione or ICAM-1, while reducing the level of fecal calprotectin, an established marker for inflammatory bowel disease. The findings indicate that the naturally occurring compatible solutes ectoine (1) and 5alpha-hydroxyectoine (2) possess an optimum concentration that affords maximal intestinal barrier stabilization and could therefore prove useful for better management of human inflammatory bowel disease. PMID- 26020573 TI - Fundamentals of MOF Thin Film Growth via Liquid-Phase Epitaxy: Investigating the Initiation of Deposition and the Influence of Temperature. AB - Thin films can integrate the versatility and great potential found in the emerging field of metal-organic frameworks directly into device architectures. For fabrication of smart interfaces containing surface-anchored metal-organic frameworks, it is important to understand how the foundational layers form to create the interface between the underlying substrate and porous framework. Herein, the formation and morphology of the first ten cycles of film deposition are investigated for the well-studied HKUST-1 system. Effects of processing variables, such as deposition temperature and substrate quality, are studied. Sequences of scanning probe microscopy images collected after cycles of alternating solution-phase deposition reveal the formation of a discontinuous surface with nucleating and growing crystallites consistent with a Volmer-Weber growth mechanism. Quantitative image analysis determines surface roughness and surface coverage as a function of deposition cycles, producing insight regarding growth and structure of foundational film layers. For carboxylic acid terminated self-assembled monolayers on gold, preferred crystal orientation is influenced by deposition temperature with crystal growth along [100] observed at 25 degrees C and [111] favored at 50 degrees C. This difference in crystal orientation results in reduced surface roughness and increased surface coverage at 50 degrees C. To properly fabricate and fully determine the potential of this material for industrial applications, fundamental understanding of film formation is crucial. PMID- 26020574 TI - Effect of Pictograph-Based Discharge Instructions on Older Adults' Comprehension and Recall: A Pilot Study. AB - Many older adults return home with limited comprehension of hospital discharge instructions because current text-based instructions are difficult to understand. To address this issue, the author developed discharge instructions using pictographs (i.e., simple line drawings showing step-by-step discharge actions) for older adults under care of hip replacement surgery. The purpose of the current study was to examine the effect of pictograph-based discharge instructions on comprehension and recall of older adults with low literacy skills. A posttest-only comparison group design was used to compare pictograph based (n = 21) to text-only (n = 21) discharge instructions at 4 weeks after discharge instruction education. Significantly greater improvements in scores on comprehension and recall were demonstrated by the pictograph group than the text only group. A follow-up, full-scale study is suggested to examine the effect of pictograph-based instructions on adherence to instructions and health outcomes. PMID- 26020575 TI - Adapting Telemonitoring Technology Use for Older Adults: A Pilot Study. AB - Telehealth technologies are increasing health care access for patients in the home and in community, rural, and underserved areas. Older adults may be challenged to use new technologies due to aging-related changes, lack of experience, and different attitudes toward their use. The current pilot study evaluated potential issues in one-on-one training/instructions and use of a telemonitoring application. Older adults may benefit from specific adaptations and training to use new health care technologies, and behavioral coding is an effective way to evaluate the user interface for new technologies. Feedback from the current study will be used to adapt the application and training to support dementia caregivers. PMID- 26020576 TI - U.S.A.B.I.L.I.T.Y. Framework for Older Adults. AB - The purpose of the current study was to present a framework to determine potential usability of health websites by older adults. Review of the literature showed paucity of nursing theory related to the use of technology and usability, particularly in older adults. The Roy Adaptation Model, a widely used nursing theory, was chosen to provide framework for the new model. Technology constructs from the Technology Acceptance Model and United Theory of Acceptance and Use of Technology and behavioral control construct from the Theory of Planned Behavior were integrated into the construction of the derived model. The Use of Technology for Adaptation by Older Adults and/or Those With Limited Literacy (U.S.A.B.I.L.I.T.Y.) Model was constructed from the integration of diverse theoretical/conceptual perspectives. The four determinants of usability in the conceptual model include (a) efficiency, (b) learnability, (c) perceived user experience, and (d) perceived control. Because of the lack of well-validated survey questionnaires to measure these determinants, a U.S.A.B.I.L.I.T.Y. Survey was developed. A panel of experts evaluated face and content validity of the new instrument. Internal consistency of the new instrument was 0.96. Usability is key to accepting technology. The derived U.S.A.B.I.L.I.T.Y. framework could serve as a guide for nurses in formative evaluation of technology. PMID- 26020577 TI - Cognitive Interviewing: Revising the Preferences for Everyday Living Inventory for Use In the Nursing Home. AB - A valid tool is needed to assess preferences that are relevant and important to nursing home (NH) residents. Originally developed for older adults receiving home care services, the authors adapted the Preferences for Everyday Living Inventory (PELI) for use with NH residents. Content validity was initially established using a panel of experts in long-term care. PELI items were cognitively interviewed with 31 Veteran and 39 non-Veteran participants (N = 70). Responses from cognitive interviewing guided substantial revisions of the PELI (>25% of items) to include language that NH residents use and understand, reducing potential measurement error and ensuring the preferences assessed are relevant to NH residents. Future work will further adapt the PELI for use with more diverse groups and health care settings, and assess its psychometric properties. Using the PELI will help move clinical teams closer to the goal of providing person centered care informed by individual preferences. PMID- 26020578 TI - Rapid Cognitive Assessment of Nursing Home Residents: A Comparison of the Brief Interview for Mental Status (BIMS) and Brief Cognitive Assessment Tool-Short Form (BCAT-SF). AB - In nursing homes, the ability to identify residents with cognitive impairment is critical; however, many providers fail to address symptoms of dementia due to insufficient time to assess cognition. In the current study, the authors compared two rapidly administered instruments, the Brief Interview for Mental Status (BIMS) and Brief Cognitive Assessment Tool-Short Form (BCAT-SF), in predicting specific cognitive stages. Two hundred twenty-five nursing home residents who were referred for neurocognitive evaluation and met inclusion criteria participated in the study. Both cognitive instruments were found to predict cognitive diagnoses generally, but only the BCAT-SF demonstrated sensitivity in differentiating among all cognitive levels. Receiver operating characteristic analyses did not confirm cutoff scores reported in the original BIMS study. However, sensitivity (0.91) and specificity (0.96) values for the BCAT-SF were robust for differentiating between dementia and non-dementia. The BCAT-SF appears to be a more sensitive instrument for predicting cognitive stages than the BIMS for nursing home residents. PMID- 26020579 TI - Role of Advance Care Planning in Proxy Decision Making Among Individuals With Dementia and Their Family Caregivers. AB - Health care proxies make important end-of-life decisions for individuals with dementia. A cross-sectional survey was conducted to examine the role of advance care planning in proxy decision making for 141 individuals with cognitive impairment, Alzheimer's disease, or other types of dementia. Proxies who did not know the preferences of individuals with dementia for life support treatments reported greater understanding of their values. Proxies of individuals with dementia who did not want life support treatments anticipated receiving less support and were more uncertain in decision making. The greater knowledge proxies had about dementia trajectory, family support, and trust of physicians, the more informed, clearer, and less uncertain they were in decision making. In addition to advance care planning, multiple factors influence proxy decision making, which should be considered in developing interventions and future research to support informed decision making for individuals with dementia and their families. PMID- 26020580 TI - Challenges in Recruiting Aging Women Holocaust Survivors to a Case Control Study of Breast Cancer. AB - Older adults are underrepresented in medical research for many reasons, including recruitment difficulties. Recruitment of older adults for research studies is often a time-consuming process and can be more challenging when the study involves older adults with unique exposures to traumatic events and from minority groups. The current article provides a brief overview of (a) challenges encountered while recruiting aging women Holocaust survivors for a case control study and (b) strategies used for meeting those challenges. The case group comprised women Holocaust survivors who were recently diagnosed with breast cancer and the control group comprised healthy women from a Holocaust-survivor community in Israel. PMID- 26020581 TI - Thermodynamic Interactions between Polystyrene and Long-Chain Poly(n-Alkyl Acrylates) Derived from Plant Oils. AB - Vegetable oils and their fatty acids are promising sources for the derivation of polymers. Long-chain poly(n-alkyl acrylates) and poly(n-alkyl methacrylates) are readily derived from fatty acids through conversion of the carboxylic acid end group to an acrylate or methacrylate group. The resulting polymers contain long alkyl side-chains with around 10-22 carbon atoms. Regardless of the monomer source, the presence of alkyl side-chains in poly(n-alkyl acrylates) and poly(n alkyl methacrylates) provides a convenient mechanism for tuning their physical properties. The development of structured multicomponent materials, including block copolymers and blends, containing poly(n-alkyl acrylates) and poly(n-alkyl methacrylates) requires knowledge of the thermodynamic interactions governing their self-assembly, typically described by the Flory-Huggins interaction parameter chi. We have investigated the chi parameter between polystyrene and long-chain poly(n-alkyl acrylate) homopolymers and copolymers: specifically we have included poly(stearyl acrylate), poly(lauryl acrylate), and their random copolymers. Lauryl and stearyl acrylate were chosen as model alkyl acrylates derived from vegetable oils and have alkyl side-chain lengths of 12 and 18 carbon atoms, respectively. Polystyrene is included in this study as a model petroleum sourced polymer, which has wide applicability in commercially relevant multicomponent polymeric materials. Two independent methods were employed to measure the chi parameter: cloud point measurements on binary blends and characterization of the order-disorder transition of triblock copolymers, which were in relatively good agreement with one another. The chi parameter was found to be independent of the alkyl side-chain length (n) for large values of n (i.e., n > 10). This behavior is in stark contrast to the n-dependence of the chi parameter predicted from solubility parameter theory. Our study complements prior work investigating the interactions between polystyrene and short-chain polyacrylates (n <= 10). To our knowledge, this is the first study to explore the thermodynamic interactions between polystyrene and long-chain poly(n-alkyl acrylates) with n > 10. This work lays the groundwork for the development of multicomponent structured systems (i.e., blends and copolymers) in this class of sustainable materials. PMID- 26020582 TI - Tuning the Direction of Intramolecular Charge Transfer and the Nature of the Fluorescent State in a T-Shaped Molecular Dyad. AB - Controlling photoinduced intramolecular charge transfer at the molecular scale is key to the development of molecular devices for nanooptoelectronics. Here, we describe the design, synthesis, electronic characterization, and photophysical properties of two electron donor-acceptor molecular systems that consist of tolane and BF2-containing curcuminoid chromophoric subunits connected in a T shaped arrangement. The two pi-conjugated segments intersect at the electron acceptor dioxaborine core. From steady-state electronic absorption and fluorescence emission, we find that the photophysics of the dialkylamino substituted analogue is governed by the occurrence of two closely lying excited states. From DFT calculations, we show that excitation in either of these two states results in a distinct shift of the electron density, whether it occurs along the curcuminoid or tolane moiety. Femtosecond transient absorption spectroscopy confirmed these findings. As a consequence, the nature of the emitting state and the photophysical properties are strongly dependent on solvent polarity. Moreover, these characteristics can also be switched by protonation or complexation at the nitrogen atom of the amino group. These features set new approaches toward the construction of a three-terminal molecular system in which the lateral branch would transduce a change of electronic state and ultimately control charge transport in a molecular-scale device. PMID- 26020583 TI - Ammonium Laurate Surfactant for Cleaner Deposition of Carbon Nanotubes. AB - Experiments probing the properties of individual carbon nanotubes (CNTs) and those measuring bulk composites show vastly different results. One major issue limiting the results is that the procedures required to separate and test CNTs introduce contamination that changes the properties of the CNT. These contamination residues often come from the resist used in lithographic processing and the surfactant used to suspend and deposit the CNTs, commonly sodium dodecyl sulfate (SDS). Here we present ammonium laurate (AL), a surfactant that has previously not been used for this application, which differs from SDS only by substitution of ionic constituents but shows vastly cleaner depositions. In addition, we show that compared to SDS, AL-suspended CNTs have greater shelf stability and more selective dispersion. These results are verified using transmission electron microscopy, atomic force microscopy, zeta-potential measurements, and Raman and absorption optical spectroscopy. This surfactant is simple to prepare, and the nanotube solutions require minimal sonication and centrifugation in order to outperform SDS. PMID- 26020584 TI - Generation, Characterization, and Tunable Reactivity of Organometallic Fragments Bound to a Protein Ligand. AB - Organotransition metal complexes catalyze important synthetic transformations, and the development of these systems has rested on the detailed understanding of the structures and elementary reactions of discrete organometallic complexes bound to organic ligands. One strategy for the creation of new organometallic systems is to exploit the intricate and highly structured ligands found in natural metalloproteins. We report the preparation and characterization of discrete rhodium and iridium fragments bound site-specifically in a kappa(2) fashion to the protein carbonic anhydrase as a ligand. The reactions of apo human carbonic anhydrase with [Rh(nbd)2]BF4 or [M(CO)2(acac)] (M=Rh, Ir) form proteins containing Rh or Ir with organometallic ligands. A colorimetric assay was developed to quantify rapidly the metal occupancy at the native metal-binding site, and (15)N-(1)H NMR spectroscopy was used to establish the amino acids to which the metal is bound. IR spectroscopy and EXAFS revealed the presence and number of carbonyl ligands and the number total ligands, while UV-vis spectroscopy provided a signature to readily identify species that had been fully characterized. Exploiting these methods, we observed fundamental stoichiometric reactions of the artificial organometallic site of this protein, including reactions that simultaneously form and cleave metal-carbon bonds. The preparation and reactivity of these artificial organometallic proteins demonstrate the potential to study a new genre of organometallic complexes for which the rates and outcomes of organometallic reactions can be controlled by genetic manipulation of the protein scaffold. PMID- 26020586 TI - Comment on "UV disinfection induces a Vbnc state in Escherichia coli and Pseudomonas aeruginosa". PMID- 26020585 TI - Neurobehavioral Concerns Among Males with Dystrophinopathy Using Population-Based Surveillance Data from the Muscular Dystrophy Surveillance, Tracking, and Research Network. AB - OBJECTIVE: To describe the occurrence of selected neurobehavioral concerns among males with a dystrophinopathy and to explore the associations with corticosteroid or supportive device use. METHODS: Medical record abstraction of neurobehavioral concerns was conducted for 857 affected males from 765 families, born since 1982 and followed through 2011, and enrolled in the population-based Muscular Dystrophy Surveillance, Tracking, and Research Network. Cumulative probabilities for attention-deficit hyperactivity disorder (ADHD), behavior problems, and depressed mood were calculated from Kaplan-Meier estimates for the subsample of oldest affected males (n = 765). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for corticosteroid and supportive device use were estimated from Cox regression models with time-dependent covariates. RESULTS: Of the 857 affected males, 375 (44%) had at least 1 of the 3 selected neurobehavioral concerns; a similar percentage (45%) was found among the 765 oldest affected males. The estimated cumulative probabilities among these oldest affected males were 23% for ADHD, 43% for behavior problems, and 51% for depressed mood. Corticosteroid (HR = 2.35, 95% CI = 1.75-3.16) and mobility device (HR = 1.53, 95% CI = 1.06-2.21) use were associated with behavior problems. Use of a mobility device (HR = 3.53, 95% CI = 2.13-5.85), but not corticosteroids, was associated with depressed mood. ADHD was not significantly associated with corticosteroid or mobility device use. Respiratory assist device use was not examined due to low numbers of users before onset of neurobehavioral concerns. CONCLUSION: Selected neurobehavioral concerns were common among males with a dystrophinopathy. Reported associations highlight the importance of increased monitoring of neurobehavioral concerns as interventions are implemented and disease progresses. PMID- 26020587 TI - Mercury Stable Isotopes in Ornithogenic Deposits As Tracers of Historical Cycling of Mercury in Ross Sea, Antarctica. AB - Production of methylmercury (MeHg) in ocean waters and its bioaccumulation in marine organisms are critical processes controlling the fate and toxicity of mercury (Hg). However, these processes are not well understood in the Antarctic, where high levels of MeHg are observed in the subsurface ocean (100-1000 m). We explored the use of Hg stable isotope compositions in historical and modern biological deposits as a new approach for discerning Hg sources and tracing MeHg cycling in the ocean and bioaccumulation in marine biota. We found similar mass independent isotope fractionation (MIF) of Hg between a sediment profile containing historical penguin and seal feces deposits from coastal Antarctica and modern penguin and seal feces, suggesting that penguin and seal feces were the dominant sources of Hg to the sediments at different time periods. Furthermore, sediments dominated by seal feces displayed a significantly lower MIF slope (Delta(199)Hg/Delta(201)Hg) than those dominated by penguin feces despite similar extents of MIF. Since seals forage at greater depths (>400 m) than penguins (<100 m), the high MIF values and lower Delta(199)Hg/Delta(201)Hg in seal feces suggest that a significant fraction of MeHg accumulated by seals was produced in situ in the subsurface ocean from residual inorganic Hg(II) that sank from the euphotic zone after partial photoreduction. Our results suggest that in situ Hg methylation can be an important source of MeHg for marine biota, and Hg isotope compositions in biological archives can be valuable tracers of MeHg cycling. PMID- 26020589 TI - Multisensory attention training for treatment of tinnitus. AB - Tinnitus is the conscious perception of sound with no physical sound source. Some models of tinnitus pathophysiology suggest that networks associated with attention, memory, distress and multisensory experience are involved in tinnitus perception. The aim of this study was to evaluate whether a multisensory attention training paradigm which used audio, visual, and somatosensory stimulation would reduce tinnitus. Eighteen participants with predominantly unilateral chronic tinnitus were randomized between two groups receiving 20 daily sessions of either integration (attempting to reduce salience to tinnitus by binding with multisensory stimuli) or attention diversion (multisensory stimuli opposite side to tinnitus) training. The training resulted in small but statistically significant reductions in Tinnitus Functional Index and Tinnitus Severity Numeric Scale scores and improved attentional abilities. No statistically significant improvements in tinnitus were found between the training groups. This study demonstrated that a short period of multisensory attention training reduced unilateral tinnitus, but directing attention toward or away from the tinnitus side did not differentiate this effect. PMID- 26020591 TI - Negative tunneling magneto-resistance in quantum wires with strong spin-orbit coupling. AB - We consider a two-dimensional magnetic tunnel junction of the FM/I/QW(FM+SO)/I/N structure, where FM, I and QW(FM+SO) stand for a ferromagnet, an insulator and a quantum wire with both magnetic ordering and Rashba spin-orbit (SOC), respectively. The tunneling magneto-resistance (TMR) exhibits strong anisotropy and switches sign as the polarization direction varies relative to the quantum wire axis, due to interplay among the one-dimensionality, the magnetic ordering, and the strong SOC of the quantum wire. PMID- 26020590 TI - Characterization of the Escherichia coli sigma(S) core regulon by Chromatin Immunoprecipitation-sequencing (ChIP-seq) analysis. AB - In bacteria, selective promoter recognition by RNA polymerase is achieved by its association with sigma factors, accessory subunits able to direct RNA polymerase "core enzyme" (E) to different promoter sequences. Using Chromatin Immunoprecipitation-sequencing (ChIP-seq), we searched for promoters bound by the sigma(S)-associated RNA polymerase form (Esigma(S)) during transition from exponential to stationary phase. We identified 63 binding sites for Esigma(S) overlapping known or putative promoters, often located upstream of genes (encoding either ORFs or non-coding RNAs) showing at least some degree of dependence on the sigma(S)-encoding rpoS gene. Esigma(S) binding did not always correlate with an increase in transcription level, suggesting that, at some sigma(S)-dependent promoters, Esigma(S) might remain poised in a pre-initiation state upon binding. A large fraction of Esigma(S)-binding sites corresponded to promoters recognized by RNA polymerase associated with sigma(70) or other sigma factors, suggesting a considerable overlap in promoter recognition between different forms of RNA polymerase. In particular, Esigma(S) appears to contribute significantly to transcription of genes encoding proteins involved in LPS biosynthesis and in cell surface composition. Finally, our results highlight a direct role of Esigma(S) in the regulation of non coding RNAs, such as OmrA/B, RyeA/B and SibC. PMID- 26020592 TI - Complications Related to Metal-on-Metal Articulation in Trapeziometacarpal Joint Total Joint Arthroplasty. AB - Adverse reactions to metal-on-metal (MoM) prostheses are well known from total hip joint resurfacing arthroplasty with elevated serum chrome or cobalt, pain and pseudo tumor formation. It may, however, also be seen after total joint replacement of the trapeziometacarpal joint using MoM articulation, and we present two cases of failure of MoM prostheses due to elevated metal-serum levels in one case and pseudo tumor formation in another case. Furthermore, we suggest a diagnostic algorithm for joint pain after MoM trapeziometacarpal joint replacement based on published experiences from MoM hip prostheses and adverse reactions to metal. PMID- 26020593 TI - Classification of patients undergoing weaning from mechanical ventilation using the coherence between heart rate variability and respiratory flow signal. AB - Weaning from mechanical ventilation is still one of the most challenging problems in intensive care. Unnecessary delays in discontinuation and weaning trials that are undertaken too early are both undesirable. This study investigated the contribution of spectral signals of heart rate variability (HRV) and respiratory flow, and their coherence to classifying patients on weaning process from mechanical ventilation. A total of 121 candidates for weaning, undergoing spontaneous breathing tests, were analyzed: 73 were successfully weaned (GSucc), 33 failed to maintain spontaneous breathing so were reconnected (GFail), and 15 were extubated after the test but reintubated within 48 h (GRein). The power spectral density and magnitude squared coherence (MSC) of HRV and respiratory flow signals were estimated. Dimensionality reduction was performed using principal component analysis (PCA) and sequential floating feature selection. The patients were classified using a fuzzy K-nearest neighbour method. PCA of the MSC gave the best classification with the highest accuracy of 92% classifying GSucc versus GFail patients, and 86% classifying GSucc versus GRein patients. PCA of the respiratory flow signal gave the best classification between GFail and GRein patients (79% accuracy). These classifiers showed a good balance between sensitivity and specificity. Besides, the spectral coherence between HRV and the respiratory flow signal, in patients on weaning trial process, can contribute to the extubation decision. PMID- 26020594 TI - Standing Programs to Promote Hip Flexibility in Children With Spastic Diplegic Cerebral Palsy. AB - PURPOSE: To investigate the effects of a standing program on the range of motion (ROM) of hip abduction in children with spastic diplegic cerebral palsy. METHODS: The participants were 13 children, Gross Motor Functional Classification System level III, who received physical therapy and a daily standing program using a custom-fabricated stander from 12 to 14 months of age to the age of 5 years. Hip abduction ROM was goniometrically assessed at baseline and at 5 years. RESULTS: Baseline hip abduction was 42 degrees at baseline and 43 degrees at 5 years. CONCLUSIONS: This small difference was not clinically significant, but did demonstrate that it was possible to maintain hip abduction ROM in the spastic adductor muscles of children with cerebral palsy with a daily standing program during the children's first 5 years of development. PMID- 26020595 TI - Commentary on: "Standing Programs to Promote Hip Flexibility in Children With Spastic Diplegic Cerebral Palsy". PMID- 26020596 TI - Reliability of Common Lower Extremity Biomechanical Measures of Children With and Without Obesity. AB - PURPOSE: To determine intrarater and interrater reliability of common measures of lower extremity alignment among children with obesity. METHODS: The Craig test for femoral anteversion, tibiofemoral angle, Foot Posture Index-6, and sit-and reach test were performed on 25 children without obesity and 25 children with obesity. RESULTS: Intrarater reliability of all measures in both groups was high. The Craig test demonstrated greatest variability with slight interrater reliability in children who were nonobese [intraclass correlation coefficient [ICC] (95% confidence interval [CI]), 0.372 (-0.051 to 0.6420)] and moderate reliability in children who were obese [ICC (95% CI), 0.527 (0.242 to 0.717)]. Interrater reliability for the tibiofemoral angle and Foot Posture Index-6 was moderate to substantial and for the sit-and-reach test was substantial (ICC >0.99) and highly correlated. Measurement of lower extremity alignment among children with obesity was more reproducible than among children who were not obese. CONCLUSIONS: Measures of lower extremity alignment and general flexibility in children with obesity are both reproducible and reliable. PMID- 26020597 TI - Commentary on "Reliability of Common Lower Extremity Biomechanical Measures for Children With and Without Obesity". PMID- 26020598 TI - The Manual Ability Classification System: A Scoping Review. AB - PURPOSE: To examine the use of the Manual Ability Classification System (MACS) and to identify gaps in the literature by conducting a thorough search of existing publications from 2006 to March 2013. METHODS: An extensive literature search included 15 databases, using the search terms "Manual Ability Classification System" or "MACS" to retrieve relevant abstracts. RESULTS: A total of 161 articles were identified for final inclusion. The review identified literature that supports the reliability, validity, and stability of the MACS. CONCLUSIONS: The MACS could be considered as a standard classification for children with cerebral palsy on the basis of manual abilities. The MACS can be reliably used for children between 4 and 18 years and adults between 18 and 24 years. The use of the MACS is expected to increase; further work is required to explore the use of the MACS in clinical practice. PMID- 26020599 TI - Commentary on "The Manual Ability Classification System: A Scoping Review". PMID- 26020600 TI - Acceptance, Benefits, and Challenges of Public Health-Oriented Pet Business Regulations in King County, Washington. AB - CONTEXT: New regulations were implemented in King County, Washington, in 2010 requiring pet businesses to obtain a permit from Public Health-Seattle & King County (Public Health) and undergo annual inspections to provide education and ensure compliance with regulatory standards. The regulations were developed as a tool for zoonotic disease control and prevention education for businesses and their customers, as well as for environmental protection. OBJECTIVE: To assess the acceptance, benefits, and challenges of the new regulations and identify ways for Public Health to improve educational efforts and assist businesses with compliance. DESIGN: Cross-sectional survey. SETTING: King County, Washington. PARTICIPANTS: Pet businesses with Public Health permits in 2013. MAIN OUTCOME MEASURE: Self-administered survey responses. RESULTS: The response rate was 40.5%. The majority of respondents provided grooming, pet day care, and kennel/boarding services from small, independent businesses. Sixty-one percent reported Public Health inspections as beneficial, especially concerning disinfection procedures and using an infection control plan. Almost three-fourths of respondents used the Public Health template to develop the infection control plan. Forty-four percent reported using the educational materials provided by Public Health, and 62% used educational materials from other sources. Most respondents reported that they gained benefits from the pet business permit, although fewer agreed that they obtained a good value from the permit and fee. The most common benefits reported were protection of animal and human health and establishing the credibility of the pet business. CONCLUSIONS: Major challenges with the implementation of the pet business regulations were not generally reported by respondents. Most respondents reported a collaborative relationship between Public Health and the pet businesses. Improvements in infection control practices and positive responses to the inspections were reported by pet businesses. Survey results were used to improve infection control plan templates, increase the use of educational materials, and improve the Web site and business portal performance. PMID- 26020601 TI - Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort. AB - BACKGROUND: Data evaluating the chronological order of appearance of extraintestinal manifestations (EIMs) relative to the time of inflammatory bowel disease (IBD) diagnosis is currently lacking. We aimed to assess the type, frequency, and chronological order of appearance of EIMs in patients with IBD. METHODS: Data from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. RESULTS: The data on 1249 patients were analyzed (49.8% female, median age: 40 [interquartile range, 30-51 yr], 735 [58.8%] with Crohn's disease, 483 [38.7%] with ulcerative colitis, and 31 [2.5%] with indeterminate colitis). A total of 366 patients presented with EIMs (29.3%). Of those, 63.4% presented with 1, 26.5% with 2, 4.9% with 3, 2.5% with 4, and 2.7% with 5 EIMs during their lifetime. Patients presented with the following diseases as first EIMs: peripheral arthritis 70.0%, aphthous stomatitis 21.6%, axial arthropathy/ankylosing spondylitis 16.4%, uveitis 13.7%, erythema nodosum 12.6%, primary sclerosing cholangitis 6.6%, pyoderma gangrenosum 4.9%, and psoriasis 2.7%. In 25.8% of cases, patients presented with their first EIM before IBD was diagnosed (median time 5 mo before IBD diagnosis: range, 0-25 mo), and in 74.2% of cases, the first EIM manifested itself after IBD diagnosis (median: 92 mo; range, 29-183 mo). CONCLUSIONS: In one quarter of patients with IBD, EIMs appeared before the time of IBD diagnosis. Occurrence of EIMs should prompt physicians to look for potential underlying IBD. PMID- 26020602 TI - Correlation of the Endoscopic and Magnetic Resonance Scoring Systems in the Deep Small Intestine in Crohn's Disease. AB - BACKGROUND: There are no widely accepted endoscopic or magnetic resonance scoring systems to evaluate deep small intestinal lesions in Crohn's disease (CD). This study aimed to determine whether the simplified endoscopic activity score for Crohn's disease (SES-CD) and the Magnetic Resonance Index of Activity (MaRIA) could be adapted for assessing CD lesions in the deep small intestine. METHODS: Magnetic resonance enterocolonography and single-balloon enteroscopy were prospectively performed in 125 patients with CD. SES-CD and MaRIA were applied to the deep small intestine. The correlation between the SES-CD and MaRIA was evaluated. RESULTS: Endoscopic and magnetic resonance active lesions were detected in the terminal and proximal ileal segments at a similar rate. The total MaRIA scores correlated well with the total SES-CD scores (R = 0.808, P < 0.001). A MaRIA score of >=11 had a high sensitivity, specificity, and diagnostic accuracy for ulcerative lesions that were defined by enteroscopy (sensitivity: 78.3%; specificity: 98.0%). Similarly, an MaRIA score of >=7 had a high sensitivity, specificity, and diagnostic accuracy for all mucosal lesions defined by enteroscopy (sensitivity: 87.0%; specificity: 86.0%). CONCLUSIONS: The MaRIA closely correlates with the SES-CD in the deep small intestine, indicating these scoring systems can be used to assess deep small intestinal lesions. We also showed the validity of MaRIA to evaluate the active lesions in the deep small intestine. PMID- 26020603 TI - Impact of Quality Improvement Educational Interventions on Documented Adherence to Quality Measures for Adults with Crohn's Disease. AB - BACKGROUND: In recent years, leading organizations in inflammatory bowel disease (IBD) have developed quality measures for the care of adults with Crohn's disease or ulcerative colitis. We used chart audits to assess the impact of quality improvement educational activities on documented adherence to Physician Quality Reporting System measures for IBD. METHODS: Twenty community-based gastroenterologists were recruited to participate in baseline chart audits (n = 200), a series of 4 accredited educational activities with feedback, and follow up chart audits (n = 200). Trained abstractors reviewed randomly selected charts of adults with moderate or severe Crohn's disease. The charts were retrospectively abstracted for physicians' documented performance of the 2013 Physician Quality Reporting System IBD quality measures. We compared the physicians' baseline and posteducation rates of documented adherence with 10 of these measures. In a secondary analysis, we compared preeducation with posteducation difference scores of low-performing physicians, those whose baseline documentation rates were in the lowest quartile, and the rest of the cohort. RESULTS: At baseline, documentation of mean provider-level adherence to the 10 quality measures ranged from 3% to 98% (grand mean = 35.8%). In the overall analysis, baseline and posteducation rates of documented adherence did not differ significantly for any of the measures. However, for 4 measures, preeducation to posteducation difference scores were significantly greater among low performers than physicians in the highest 3 quartiles. CONCLUSIONS: The results of this preliminary pragmatic study indicate that quality improvement education affords the potential to improve adherence to Physician Quality Reporting System quality measures for IBD among low-performing gastroenterologists. PMID- 26020604 TI - Systematic Review: Rectal Therapies for the Treatment of Distal Forms of Ulcerative Colitis. AB - BACKGROUND: Many therapeutic options are available for patients with distal forms of ulcerative colitis (UC). Rectal therapies (e.g., suppositories, foams, gels, and enemas) may be recommended either alone or in combination with oral treatment. Compared with oral therapies, rectal therapies are underused in patients with distal forms of UC, although rectal therapies have favorable efficacy and safety profiles. METHODS: This systematic review identified 48 articles for inclusion after a comprehensive PubMed search and the identification of additional relevant articles through other sources. Inclusion criteria were clinical studies examining efficacy and safety of 5-aminosalicylic acid, corticosteroid, and non-5-aminosalicylic acid rectal therapies (suppositories, foams, gels, and enemas) that induce or maintain remission in patients with ulcerative proctitis, ulcerative proctosigmoiditis, or left-sided colitis (i.e., distal forms of UC). The quality of the evidence presented was evaluated using the GRADE system. RESULTS: Overall, a greater percentage of patients with distal forms of UC receiving 5-aminosalicylic acids or corticosteroid rectal formulations derived greater therapeutic benefit after treatment compared with patients receiving placebo. Furthermore, most uncontrolled studies of rectal therapies reported that patients with distal forms of UC had marked improvement from baseline after treatment. The overall safety profile of rectal therapies was favorable. Treatment with second-generation corticosteroids, such as budesonide and beclomethasone dipropionate, did not increase the incidence of steroid related adverse effects. CONCLUSIONS: The current literature supports the use of rectal therapies for both induction and maintenance of remission in patients with distal forms of UC. PMID- 26020605 TI - Surgery for Ulcerative Colitis Is Associated with a High Rate of Readmissions at 30 Days. AB - BACKGROUND: Currently, the predictors of readmission after colectomy specifically for ulcerative colitis (UC) are poorly investigated. We sought to determine the rates and predictors of 30-day readmissions after colectomy for UC. METHODS: Patients undergoing total proctocolectomy and end ileostomy, abdominal colectomy with end ileostomy, proctocolectomy with ileoanal pouch anastomosis (IPAA) formation and diverting ileostomy, one stage IPAA, or abdominal colectomy with ileorectal anastomosis at a tertiary care center between January 2002 and January 2012 for UC were included. Patients were identified using ICD-9 code 556.x. Each record was manually reviewed. The electronic record system was reviewed for demographic information, medical histories, UC history, medications, and data regarding the admission and discharge. Charts were reviewed for readmissions within 30 days of surgery. Univariate and multivariate analyses were performed using Stata v.13. RESULTS: Two hundred nine patients with UC underwent a colectomy. Forty-three percent had a proctocolectomy with IPAA and diverting ileostomy and 32% had abdominal colectomy with end ileostomy. Seventy-six percent of surgeries were due to failure of medical therapy and 68% of patients were electively admitted for surgery. Thirty-two percent (n = 67/209) of the cohort was unexpectedly readmitted within 30 days. In multivariate model, proctocolectomy with IPAA and diverting ileostomy (odds ratio [OR] = 2.11; 95% CI, 1.06-4.19; P = 0.033) was the only significant predictor of readmission. Hospital length of stay >7 days (OR = 1.82; 95% CI, 0.98-3.41; P = 0.060), presence of limited UC (OR = 2.10; 95% CI, 0.93-4.74; P = 0.074), and steroid before admission (OR = 1.69; 95% CI, 0.90-3.2; P = 0.100) trended toward significance. CONCLUSIONS: Surgery for UC is associated with a high rate of readmission. Further prospective studies are necessary to determine the means to reduce these readmissions. PMID- 26020607 TI - Should the nuclear medicine community continue to underestimate the potential of 18F-FDG-PET/CT with present generation scanners for the diagnosis of prosthetic joint infection? PMID- 26020606 TI - Scattered gamma rays: can they be useful for lymphoscintigraphy imaging? PMID- 26020608 TI - News and views--July 2015. PMID- 26020609 TI - Real-time selective visual monitoring of Hg(2+) detection at ppt level: An approach to lighting electrospun nanofibers using gold nanoclusters. AB - In this work, fluorescent gold nanocluster (AuNC) decorated polycaprolactone (PCL) nanofibers (AuNC*PCL-NF) for real time visual monitoring of Hg(2+) detection at ppt level in water is demonstrated. The resultant AuNC*PCL-NF exhibiting remarkable stability more than four months at ambient environment and facilitates increased accessibility to active sites resulting in improved sensing performance with rapid response time. The fluorescence changes of AuNC*PCL-NF and their corresponding time dependent spectra, upon introduction of Hg(2+), led to the visual identification of the sensor performance. It is observed that the effective removal of excess ligand (bovine serum albumin (BSA) greatly enhances the surface exposure of AuNC and therefore their selective sensing performance is achieved over competent metal ions such as Cu(2+), Ni(2+), Mn(2+), Zn(2+), Cd(2+), and Pb(2+) present in the water. An exceptional interaction is observed between AuNC and Hg(2+), wherein the absence of excess interrupting ligand makes AuNC more selective towards Hg(2+). The underlying mechanism is found to be due to the formation of Au-Hg amalgam, which was further investigated with XPS, TEM and elemental mapping studies. In short, our findings may lead to develop very efficient fluorescent-based nanofibrous mercury sensor, keeping in view of its stability, simplicity, reproducibility, and low cost. PMID- 26020610 TI - Sub-100 ps coincidence time resolution for positron emission tomography with LSO:Ce codoped with Ca. AB - The coincidence time resolution (CTR) becomes a key parameter of 511 keV gamma detection in time of flight positron emission tomography (TOF-PET). This is because additional information obtained through timing leads to a better noise suppression and therefore a better signal to noise ratio in the reconstructed image. In this paper we present the results of CTR measurements on two different SiPM technologies from FBK coupled to LSO:Ce codoped 0.4%Ca crystals. We compare the measurements performed at two separate test setups, i.e. at CERN and at FBK, showing that the obtained results agree within a few percent. We achieve a best CTR value of 85 +/- 4 ps FWHM for 2 * 2 * 3 mm(3) LSO:Ce codoped 0.4%Ca crystals, thus breaking the 100 ps barrier with scintillators similar to LSO:Ce or LYSO:Ce. We also demonstrate that a CTR of 140 +/- 5 ps can be achieved for longer 2 * 2 * 20 mm(3) crystals, which can readily be implemented in the current generation PET systems to achieve the desired increase in the signal to noise ratio. PMID- 26020611 TI - Magneto-optical properties of ABC-stacked trilayer graphene. AB - The generalized tight-binding model is developed to investigate the magneto optical absorption spectra of ABC-stacked trilayer graphene. The absorption peaks can be classified into nine categories of inter-Landau-level optical excitations, including three intra-group and six inter-group ones. Most of them belong to the twin-peak structures because of the asymmetric Landau level spectrum. The threshold absorption peak alone comes from a certain excitation channel, and its frequency is associated with a specific interlayer atomic interaction. The Landau level anticrossings cause extra absorption peaks. Moreover, a simple relationship between the absorption frequency and the field strength is absent. The magneto optical properties of ABC-stacked trilayer graphene are totally different from those of AAA- and ABA-stacked ones, such as the number, intensity and frequency of absorption peaks. PMID- 26020613 TI - Critical illness in pregnancy: part I: an approach to a pregnant patient in the ICU and common obstetric disorders. AB - Managing critically ill obstetric patients in the ICU is a challenge because of their altered physiology, different normal ranges for laboratory and clinical parameters in pregnancy, and potentially harmful effects of drugs and interventions on the fetus. About 200 to 700 women per 100,000 deliveries require ICU admission. A systematic five-step approach is recommended to enhance maternal and fetal outcomes: (1) differentiate between medical and obstetric disorders with similar manifestations, (2) identify and treat organ dysfunction, (3) assess maternal and fetal risk from continuing pregnancy and decide if delivery/termination of pregnancy will improve outcome, (4) choose an appropriate mode of delivery if necessary, and (5) optimize organ functions for safe delivery. A multidisciplinary team including the intensivist, obstetrician, maternal-fetal medicine specialist, anesthesiologist, neonatologist, nursing specialist, and transfusion medicine expert is key to optimize outcomes. Severe preeclampsia and its complications, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and amniotic fluid embolism, which cause significant organ failure, are reviewed. Obstetric conditions that were not so common in the past are increasingly seen in the ICU. Thrombotic thrombocytopenic purpura of pregnancy is being diagnosed more frequently. Massive hemorrhage from adherent placenta is increasing because of the large number of pregnant women with scars from previous cesarean section. With more complex fetal surgical interventions being performed for congenital disorders, maternal complications are increasing. Ovarian hyperstimulation syndrome is also becoming common because of treatment of infertility with assisted reproduction techniques. Part II will deal with common medical disorders and their management in critically ill pregnant women. PMID- 26020612 TI - Peroxisome Proliferator-Activated Receptor gamma-Mediated Inhibition on Hypoxia Triggered Store-Operated Calcium Entry. A Caveolin-1-Dependent Mechanism. AB - Our previous publication demonstrated that peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits the pathogenesis of chronic hypoxia (CH) induced pulmonary hypertension by targeting store-operated calcium entry (SOCE) in rat distal pulmonary arterial smooth muscle cells (PASMCs). In this study, we aim to determine the role of a membrane scaffolding protein, caveolin-1, during the suppressive process of PPARgamma on SOCE. Adult (6-8 weeks) male Wistar rats (200-250 g) were exposed to CH (10% O2) for 21 days to establish CH-induced pulmonary hypertension. Primary cultured rat distal PASMCs were applied for the molecular biological experiments. First, hypoxic exposure led to 2.5-fold and 1 fold increases of caveolin-1 protein expression in the distal pulmonary arteries and PASMCs, respectively. Second, effective knockdown of caveolin-1 significantly reduced hypoxia-induced SOCE for 58.2% and 41.5%, measured by Mn(2+) quenching and extracellular Ca(2+) restoration experiments, respectively. These results suggested that caveolin-1 acts as a crucial regulator of SOCE, and hypoxia-up regulated caveolin-1 largely accounts for hypoxia-elevated SOCE in PASMCs. Then, by using a high-potency PPARgamma agonist, GW1929, we detected that PPARgamma activation inhibited SOCE and caveolin-1 protein for 62.5% and 59.8% under hypoxia, respectively, suggesting that caveolin-1 also acts as a key target during the suppressive process of PPARgamma on SOCE in PASMCs. Moreover, by using effective small interfering RNAs against PPARgamma and caveolin-1, and PPARgamma antagonist, T0070907, we observed that PPARgamma plays an inhibitory role on caveolin-1 protein by promoting its lysosomal degradation, without affecting the messenger RNA level. PPARgamma inhibits SOCE, at least partially, by suppressing cellular caveolin-1 protein in PASMCs. PMID- 26020614 TI - Spheroidal carbonaceous particles are a defining stratigraphic marker for the Anthropocene. AB - There has been recent debate over stratigraphic markers used to demarcate the Anthropocene from the Holocene Epoch. However, many of the proposed markers are found only in limited areas of the world or do not reflect human impacts on the environment. Here we show that spheroidal carbonaceous particles (SCPs), a distinct form of black carbon produced from burning fossil fuels in energy production and heavy industry, provide unambiguous stratigraphic markers of the human activities that have rapidly changed planet Earth over the last century. SCPs are found in terrestrial and marine sediments or ice cores in every continent, including remote areas such as the high Arctic and Antarctica. The rapid increase in SCPs mostly occurs in the mid-twentieth century and is contemporaneous with the 'Great Acceleration'. It therefore reflects the intensification of fossil fuel usage and can be traced across the globe. We integrate global records of SCPs and propose that the global rapid increase in SCPs in sedimentary records can be used to inform a Global Standard Stratigraphic Age for the Anthropocene. A high-resolution SCP sequence from a lake or peatland may provide the much-needed 'Golden Spike' (Global Boundary Stratotype Section and Point). PMID- 26020616 TI - Erratum: RGB marking with lentiviral vectors for multicolor clonal cell tracking. PMID- 26020615 TI - Construction of a liposome dialyzer for the preparation of high-value, small volume liposome formulations. AB - The liposome dialyzer is a small-volume equilibrium dialysis device, built from commercially available materials, that is designed for the rapid exchange of small volumes of an extraliposomal reagent pool against a liposome preparation. The dialyzer is prepared by modification of commercially available dialysis cartridges (Slide-A-Lyzer cassettes), and it consists of a reactor with two 300 MUl chambers and a 1.56-cm(2) dialysis surface area. The dialyzer is prepared in three stages: (i) disassembling the dialysis cartridges to obtain the required parts, (ii) assembling the dialyzer and (iii) sealing the dialyzer with epoxy. Preparation of the dialyzer takes ~1.5 h, not including overnight epoxy curing. Each round of dialysis takes 1-24 h, depending on the analyte and membrane used. We previously used the dialyzer for small-volume non-enzymatic RNA synthesis reactions inside fatty acid vesicles. In this protocol, we demonstrate other applications, including removal of unencapsulated calcein from vesicles, remote loading and vesicle microscopy. PMID- 26020617 TI - Corrigendum: RNAi-based biosynthetic pathway screens to identify in vivo functions of non-nucleic acid-based metabolites such as lipids. PMID- 26020620 TI - Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. AB - Idarucizumab, a Fab fragment directed against dabigatran, produced rapid and complete reversal of the anticoagulation effect of dabigatran in animals and in healthy volunteers. The Study of the REVERSal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE ADTM) is a global phase 3 prospective cohort study aimed at investigating idarucizumab in dabigatran-treated patients who present with uncontrollable or life-threatening bleeding, and in those requiring urgent surgery or intervention. We describe the rationale for, and design of the trial (clinicaltrials.gov NCT02104947). PMID- 26020622 TI - Zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. AB - BACKGROUND: Diabetes is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels. The risk of developing type 2 diabetes increases with age, obesity and lack of physical activity. Insulin resistance is a fundamental aspect of the aetiology of type 2 diabetes. Insulin resistance has been shown to be associated with atherosclerosis, dyslipidaemia, glucose intolerance, hyperuricaemia, hypertension and polycystic ovary syndrome. The mineral zinc plays a key role in the synthesis and action of insulin, both physiologically and in diabetes mellitus. Zinc seems to stimulate insulin action and insulin receptor tyrosine kinase activity. OBJECTIVES: To assess the effects of zinc supplementation for the prevention of type 2 diabetes mellitus in adults with insulin resistance. SEARCH METHODS: This review is an update of a previous Cochrane systematic review published in 2007. We searched the Cochrane Library (2015, Issue 3), MEDLINE, EMBASE, LILACS and the ICTRP trial register (from inception to March 2015). There were no language restrictions. We conducted citation searches and screened reference lists of included studies. SELECTION CRITERIA: We included studies if they had a randomised or quasi-randomised design and if they investigated zinc supplementation compared with placebo or no intervention in adults with insulin resistance living in the community. DATA COLLECTION AND ANALYSIS: Two review authors selected relevant trials, assessed risk of bias and extracted data. MAIN RESULTS: We included three trials with a total of 128 participants in this review. The duration of zinc supplementation ranged between four and 12 weeks. Risk of bias was unclear for most studies regarding selection bias (random sequence generation, allocation concealment) and detection bias (blinding of outcome assessment). No study reported on our key outcome measures (incidence of type 2 diabetes mellitus, adverse events, health-related quality of life, all cause mortality, diabetic complications, socioeconomic effects). Evaluation of insulin resistance as measured by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) showed neutral effects when comparing zinc supplementation with control (two trials; 114 participants). There were neutral effects for trials comparing zinc supplementation with placebo for total cholesterol, high density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (2 studies, 70 participants). The one trial comparing zinc supplementation with exercise also showed neutral effects for total cholesterol, HDL and LDL cholesterol, and a mean difference in triglycerides of -30 mg/dL (95% confidence interval (CI) -49 to -10) in favour of zinc supplementation (53 participants). Various surrogate laboratory parameters were also analysed in the included trials. AUTHORS' CONCLUSIONS: There is currently no evidence on which to base the use of zinc supplementation for the prevention of type 2 diabetes mellitus. Future trials should investigate patient-important outcome measures such as incidence of type 2 diabetes mellitus, health-related quality of life, diabetic complications, all-cause mortality and socioeconomic effects. PMID- 26020621 TI - Immunogenicity of a novel enhanced consensus DNA vaccine encoding the leptospiral protein LipL45. AB - Leptospirosis is a bacterial zoonotic disease caused by an infection with a spirochete belonging to the genus Leptospira. In animals, leptospirosis displays a wide range of pathologies, including fever, abortion, icterus, and uveitis. Conversely, infection in humans is associated with multi-organ injury, resulting in an increased rate of fatalities. Pathogenic leptospires are able to translocate through cell monolayers at a rate significantly greater than that of non-pathogenic leptospires. Thus, vaccine approaches have been focused on targeting bacterial motility, lipopolysaccharides (LPSs), lipoproteins, outer membrane proteins (OMPs) and other potential virulence factors. Previous studies have indicated that leptospiral proteins elicit long-lasting immunological memory in infected humans. In the study reported here, the efficacy of a synthetic consensus DNA vaccine developed against the Leptospira membrane lipoprotein LipL45 was tested. After in vivo electroporation (EP) mediated intramuscular immunization with a synthetic LipL45 DNA vaccine (pLipL45) immunized mice developed a significant cellular response along with the development of anti LipL45-specific antibodies. Specifically, the pLipL45 vaccine induced a significant Th1 type immune response, indicated by the higher production of IL-12 and IFN-gamma cytokines. The results presented here are the first demonstration that a LipL45 based DNA immunogen has potential as a anti-Leptospira vaccine. PMID- 26020623 TI - Maternal Diabetes Leads to Adaptation in Embryonic Amino Acid Metabolism during Early Pregnancy. AB - During pregnancy an adequate amino acid supply is essential for embryo development and fetal growth. We have studied amino acid composition and branched chain amino acid (BCAA) metabolism at day 6 p.c. in diabetic rabbits and blastocysts. In the plasma of diabetic rabbits the concentrations of 12 amino acids were altered in comparison to the controls. Notably, the concentrations of the BCAA leucine, isoleucine and valine were approximately three-fold higher in diabetic rabbits than in the control. In the cavity fluid of blastocysts from diabetic rabbits BCAA concentrations were twice as high as those from controls, indicating a close link between maternal diabetes and embryonic BCAA metabolism. The expression of BCAA oxidizing enzymes and BCAA transporter was analysed in maternal tissues and in blastocysts. The RNA amounts of three oxidizing enzymes, i.e. branched chain aminotransferase 2 (Bcat2), branched chain ketoacid dehydrogenase (Bckdha) and dehydrolipoyl dehydrogenase (Dld), were markedly increased in maternal adipose tissue and decreased in liver and skeletal muscle of diabetic rabbits than in those of controls. Blastocysts of diabetic rabbits revealed a higher Bcat2 mRNA and protein abundance in comparison to control blastocysts. The expression of BCAA transporter LAT1 and LAT2 were unaltered in endometrium of diabetic and healthy rabbits, whereas LAT2 transcripts were increased in blastocysts of diabetic rabbits. In correlation to high embryonic BCAA levels the phosphorylation amount of the nutrient sensor mammalian target of rapamycin (mTOR) was enhanced in blastocysts caused by maternal diabetes. These results demonstrate a direct impact of maternal diabetes on BCAA concentrations and degradation in mammalian blastocysts with influence on embryonic mTOR signalling. PMID- 26020625 TI - Publication Trends in Thanatology: An Analysis of Leading Journals. AB - To identify important trends in thanatology as a discipline, the authors analyzed over 1,500 articles that appeared in Death Studies and Omega over a 20-year period, coding the category of articles (e.g., theory, application, empirical research), their content focus (e.g., bereavement, death attitudes, end-of-life), and for empirical studies, their methodology (e.g., quantitative, qualitative). In general, empirical research predominates in both journals, with quantitative methods outnumbering qualitative procedures 2 to 1 across the period studied, despite an uptick in the latter methods in recent years. Purely theoretical articles, in contrast, decline in frequency. Research on grief and bereavement is the most commonly occurring (and increasing) content focus of this work, with a declining but still substantial body of basic research addressing death attitudes. Suicidology is also well represented in the corpus of articles analyzed. In contrast, publications on topics such as death education, medical ethics, and end-of-life issues occur with lower frequency, in the latter instances likely due to the submission of such work to more specialized medical journals. Differences in emphasis of Death Studies and Omega are noted, and the analysis of publication patterns is interpreted with respect to overall trends in the discipline and the culture, yielding a broad depiction of the field and some predictions regarding its possible future. PMID- 26020624 TI - Predicting cortical dark/bright asymmetries from natural image statistics and early visual transforms. AB - The nervous system has evolved in an environment with structure and predictability. One of the ubiquitous principles of sensory systems is the creation of circuits that capitalize on this predictability. Previous work has identified predictable non-uniformities in the distributions of basic visual features in natural images that are relevant to the encoding tasks of the visual system. Here, we report that the well-established statistical distributions of visual features--such as visual contrast, spatial scale, and depth--differ between bright and dark image components. Following this analysis, we go on to trace how these differences in natural images translate into different patterns of cortical input that arise from the separate bright (ON) and dark (OFF) pathways originating in the retina. We use models of these early visual pathways to transform natural images into statistical patterns of cortical input. The models include the receptive fields and non-linear response properties of the magnocellular (M) and parvocellular (P) pathways, with their ON and OFF pathway divisions. The results indicate that there are regularities in visual cortical input beyond those that have previously been appreciated from the direct analysis of natural images. In particular, several dark/bright asymmetries provide a potential account for recently discovered asymmetries in how the brain processes visual features, such as violations of classic energy-type models. On the basis of our analysis, we expect that the dark/bright dichotomy in natural images plays a key role in the generation of both cortical and perceptual asymmetries. PMID- 26020626 TI - Field Metabolic Rate Is Dependent on Time-Activity Budget in Ring-Billed Gulls (Larus delawarensis) Breeding in an Anthropogenic Environment. AB - Environmental and behavioral factors have long been assumed to affect variation in avian field metabolic rate (FMR). However, due to the difficulties in measuring continuous behavior of birds over prolonged periods of time, complete time-activity budgets have rarely been examined in relation to FMR. Our objective was to determine the effect of activity (measured by detailed time-activity budgets) and a series of extrinsic and intrinsic factors on FMR of the omnivorous ring-billed gull (Larus delawarensis). The experiment was conducted during the incubation period when both members of the pair alternate between attending the nest-site and leaving the colony to forage in aquatic and anthropogenic environments (city, agricultural). FMR was determined using the doubly labeled water method. Time-activity budgets were extrapolated from spatio-temporal data (2-5 days) obtained from bird-borne GPS data loggers. Gulls had low FMRs compared to those predicted by allometric equations based on recorded FMRs from several seabird species. Gulls proportioned their time mainly to nest-site attendance (71% of total tracking time), which reduced FMR/g body mass, and was the best variable explaining energy expenditure. The next best variable was the duration of foraging trips, which increased FMR/g; FMR/g was also elevated by the proportion of time spent foraging or flying (17% and 8% of tracking time respectively). Most environmental variables measured did not impact FMR/g, however, the percent of time birds were subjected to temperatures below their lower critical temperature increased FMR. Time-activity budgets varied between the sexes, and with temperature and capture date suggesting that these variables indirectly affected FMR/g. The gulls foraged preferentially in anthropogenic related habitats, which may have contributed to their low FMR/g due to the high availability of protein- and lipid-rich foods. This study demonstrates that activities were the best predictors of FMR/g in ring-billed gulls, thus providing strong support for this long-standing theory in bioenergetics. PMID- 26020627 TI - Predicting unprecedented dengue outbreak using imported cases and climatic factors in Guangzhou, 2014. AB - INTRODUCTION: Dengue is endemic in more than 100 countries, mainly in tropical and subtropical regions, and the incidence has increased 30-fold in the past 50 years. The situation of dengue in China has become more and more severe, with an unprecedented dengue outbreak hitting south China in 2014. Building a dengue early warning system is therefore urgent and necessary for timely and effective response. METHODOLOGY AND PRINCIPAL FINDINGS: In the study we developed a time series Poisson multivariate regression model using imported dengue cases, local minimum temperature and accumulative precipitation to predict the dengue occurrence in four districts of Guangzhou, China. The time series data were decomposed into seasonal, trend and remainder components using a seasonal-trend decomposition procedure based on loess (STL). The time lag of climatic factors included in the model was chosen based on Spearman correlation analysis. Autocorrelation, seasonality and long-term trend were controlled in the model. A best model was selected and validated using Generalized Cross Validation (GCV) score and residual test. The data from March 2006 to December 2012 were used to develop the model while the data from January 2013 to September 2014 were employed to validate the model. Time series Poisson model showed that imported cases in the previous month, minimum temperature in the previous month and accumulative precipitation with three month lags could project the dengue outbreaks occurred in 2013 and 2014 after controlling the autocorrelation, seasonality and long-term trend. CONCLUSIONS: Together with the sole transmission vector Aedes albopictus, imported cases, monthly minimum temperature and monthly accumulative precipitation may be used to develop a low-cost effective early warning system. PMID- 26020628 TI - Social media fingerprints of unemployment. AB - Recent widespread adoption of electronic and pervasive technologies has enabled the study of human behavior at an unprecedented level, uncovering universal patterns underlying human activity, mobility, and interpersonal communication. In the present work, we investigate whether deviations from these universal patterns may reveal information about the socio-economical status of geographical regions. We quantify the extent to which deviations in diurnal rhythm, mobility patterns, and communication styles across regions relate to their unemployment incidence. For this we examine a country-scale publicly articulated social media dataset, where we quantify individual behavioral features from over 19 million geo-located messages distributed among more than 340 different Spanish economic regions, inferred by computing communities of cohesive mobility fluxes. We find that regions exhibiting more diverse mobility fluxes, earlier diurnal rhythms, and more correct grammatical styles display lower unemployment rates. As a result, we provide a simple model able to produce accurate, easily interpretable reconstruction of regional unemployment incidence from their social-media digital fingerprints alone. Our results show that cost-effective economical indicators can be built based on publicly-available social media datasets. PMID- 26020629 TI - Birth Weight Is Associated With the IGF-1 Response to GH in Children: Programming of the Anabolic Action of GH? AB - CONTEXT: Intrauterine programming of the somatotropic axis has been hypothesized in cases of intrauterine growth retardation. OBJECTIVE: The objective of the study was to study the effects of birth weight and body composition on GH sensitivity. DESIGN: This was a cross-sectional study with a single GH administration to assess GH sensitivity. SETTING: The study was conducted at the Department of Pediatric Endocrinology of an academic medical center. PATIENTS: One hundred normal short children aged from 4 to 17 years old (44 girls, 56 boys) separated into four groups: early childhood (aged 4-8 y, n = 14), late childhood (aged 9-12 y, pubertal stage 1, n = 30), early puberty (aged 10-15 y, stage 2, n = 32), and midpuberty (aged 12-17 y, stages 3 and 4, n = 24). INTERVENTION AND MAIN OUTCOME MEASURE: Serum IGF-1 at baseline and 24 hours after a single administration of GH (2 mg/m(2)) were measured. RESULTS: deltaIGF-1 significantly increased across the groups (P < .0001) with no gender difference, whereas the percentage of change in IGF-1 was similar (47% +/- 32%). Independent predictors of deltaIGF-1 were birth weight SD score, fat percentage, fasting insulin (all positive predictors), and free fatty acids (negative predictor), with age, puberty, and baseline IGF-1 as adjusting variables (multiple R = 0.73, P < .0001). Independent predictors of the percentage of change in IGF-1 were birth weight SD score, fat percentage, and baseline IGF-1 (multiple R = 0.43, P < .001). CONCLUSION: This study suggests that in cases of low birth weight, intrauterine programming of GH sensitivity may be an adaptation to an expected poor postnatal nutritional environment, serving to restrict the anabolic action of GH. Conversely, postnatal excess energy stores may promote the anabolic action of GH. PMID- 26020630 TI - Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin. AB - Previously, we demonstrated that Pseudomonas aeruginosa ExoT induces potent apoptosis in host epithelial cells in a manner that primarily depends on its ADP ribosyltransferase domain (ADPRT) activity. However, the mechanism underlying ExoT/ADPRT-induced apoptosis remains undetermined. We now report that ExoT/ADPRT disrupts focal adhesion sites, activates p38beta and JNK, and interferes with integrin-mediated survival signaling; causing atypical anoikis. We show that ExoT/ADPRT-induced anoikis is mediated by the Crk adaptor protein. We found that Crk-/- knockout cells are significantly more resistant to ExoT-induced apoptosis, while Crk-/- cells complemented with Crk are rendered sensitive to ExoT-induced apoptosis. Moreover, a dominant negative (DN) mutant form of Crk phenocopies ExoT induced apoptosis both kinetically and mechanistically. Crk is generally believed to be a component of focal adhesion (FA) and its role in cellular survival remains controversial in that it has been found to be either pro-survival or pro apoptosis. Our data demonstrate that although Crk is recruited to FA sites, its function is likely not required for FA assembly or for survival per se. However, when modified by ExoT or by mutagenesis, it can be transformed into a cytotoxin that induces anoikis by disrupting FA sites and interfering with integrin survival signaling. To our knowledge, this is the first example whereby a bacterial toxin exerts its cytotoxicity by subverting the function of an innocuous host cellular protein and turning it against the host cell. PMID- 26020631 TI - Dual annual spawning races in Atlantic sturgeon. AB - Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus, Acipenseridae) populations in the United States were listed as either endangered or threatened under the Endangered Species Act in 2012. Because of the endangered/threatened status, a better understanding of Atlantic sturgeon life-history behavior and habitat use is important for effective management. It has been widely documented that Atlantic sturgeon reproduction occurs from late winter to early summer, varying clinally with latitude. However, recent data show Atlantic sturgeon also spawn later in the year. The group that spawns later in the year seems to be completely separate from the spring spawning run. Recognition of the later spawning season has drastically modified estimates of the population status of Atlantic sturgeon in Virginia. With the combination of new telemetry data and historical documentation we describe a dual spawning strategy that likely occurs in various degrees along most, if not all, of the Atlantic sturgeon's range. Using new data combined with historical sources, a new spawning strategy emerges which managers and researchers should note when determining the status of Atlantic sturgeon populations and implementing conservation measures. PMID- 26020632 TI - The Proportion of Chromatin Graded between Closed and Open States Determines the Level of Transcripts Derived from Distinct Promoters in the CYP19 Gene. AB - The human CYP19 gene encodes aromatase, which converts androgens to estrogens. CYP19 mRNA variants are transcribed mainly from three promoters. Quantitative RT PCR was used to measure the relative amounts of each of the three transcripts and determine the on/off state of the promoters. While some of the promoters were silent, CYP19 mRNA production differed among the other promoters, whose estimated transcription levels were 0.001% to 0.1% of that of the TUBB control gene. To investigate the structural aspects of chromatin that were responsible for this wide range of activity of the CYP19 promoters, we used a fractionation protocol, designated SEVENS, which sequentially separates densely packed nucleosomes from dispersed nucleosomes. The fractional distribution of each inactive promoter showed a similar pattern to that of the repressed reference loci; the inactive regions were distributed toward lower fractions, in which closed chromatin comprising packed nucleosomes was enriched. In contrast, active CYP19 promoters were raised toward upper fractions, including dispersed nucleosomes in open chromatin. Importantly, these active promoters were moderately enriched in the upper fractions as compared to active reference loci, such as the TUBB promoter; the proportion of open chromatin appeared to be positively correlated to the promoter strength. These results, together with ectopic transcription accompanied by an increase in the proportion of open chromatin in cells treated with an H3K27me inhibitor, indicate that CYP19 mRNA could be transcribed from a promoter in which chromatin is shifted toward an open state in the equilibrium between closed and open chromatin. PMID- 26020633 TI - Esophageal microbiome in eosinophilic esophagitis. AB - OBJECTIVE: The microbiome has been implicated in the pathogenesis of a number of allergic and inflammatory diseases. The mucosa affected by eosinophilic esophagitis (EoE) is composed of a stratified squamous epithelia and contains intraepithelial eosinophils. To date, no studies have identified the esophageal microbiome in patients with EoE or the impact of treatment on these organisms. The aim of this study was to identify the esophageal microbiome in EoE and determine whether treatments change this profile. We hypothesized that clinically relevant alterations in bacterial populations are present in different forms of esophagitis. DESIGN: In this prospective study, secretions from the esophageal mucosa were collected from children and adults with EoE, Gastroesophageal Reflux Disease (GERD) and normal mucosa using the Esophageal String Test (EST). Bacterial load was determined using quantitative PCR. Bacterial communities, determined by 16S rRNA gene amplification and 454 pyrosequencing, were compared between health and disease. RESULTS: Samples from a total of 70 children and adult subjects were examined. Bacterial load was increased in both EoE and GERD relative to normal subjects. In subjects with EoE, load was increased regardless of treatment status or degree of mucosal eosinophilia compared with normal. Haemophilus was significantly increased in untreated EoE subjects as compared with normal subjects. Streptococcus was decreased in GERD subjects on proton pump inhibition as compared with normal subjects. CONCLUSIONS: Diseases associated with mucosal eosinophilia are characterized by a different microbiome from that found in the normal mucosa. Microbiota may contribute to esophageal inflammation in EoE and GERD. PMID- 26020634 TI - Towards Elucidating Carnosic Acid Biosynthesis in Lamiaceae: Functional Characterization of the Three First Steps of the Pathway in Salvia fruticosa and Rosmarinus officinalis. AB - Carnosic acid (CA) is a phenolic diterpene with anti-tumour, anti-diabetic, antibacterial and neuroprotective properties that is produced by a number of species from several genera of the Lamiaceae family, including Salvia fruticosa (Cretan sage) and Rosmarinus officinalis (Rosemary). To elucidate CA biosynthesis, glandular trichome transcriptome data of S. fruticosa were mined for terpene synthase genes. Two putative diterpene synthase genes, namely SfCPS and SfKSL, showing similarities to copalyl diphosphate synthase and kaurene synthase-like genes, respectively, were isolated and functionally characterized. Recombinant expression in Escherichia coli followed by in vitro enzyme activity assays confirmed that SfCPS is a copalyl diphosphate synthase. Coupling of SfCPS with SfKSL, both in vitro and in yeast, resulted in the synthesis miltiradiene, as confirmed by 1D and 2D NMR analyses (1H, 13C, DEPT, COSY H-H, HMQC and HMBC). Coupled transient in vivo assays of SfCPS and SfKSL in Nicotiana benthamiana further confirmed production of miltiradiene in planta. To elucidate the subsequent biosynthetic step, RNA-Seq data of S. fruticosa and R. officinalis were searched for cytochrome P450 (CYP) encoding genes potentially involved in the synthesis of the first phenolic compound in the CA pathway, ferruginol. Three candidate genes were selected, SfFS, RoFS1 and RoFS2. Using yeast and N. benthamiana expression systems, all three where confirmed to be coding for ferruginol synthases, thus revealing the enzymatic activities responsible for the first three steps leading to CA in two Lamiaceae genera. PMID- 26020635 TI - Comparison of Respiratory Disease Prevalence among Voluntary Monitoring Systems for Pig Health and Welfare in the UK. AB - Surveillance of animal diseases provides information essential for the protection of animal health and ultimately public health. The voluntary pig health schemes, implemented in the United Kingdom, are integrated systems which capture information on different macroscopic disease conditions detected in slaughtered pigs. Many of these conditions have been associated with a reduction in performance traits and consequent increases in production costs. The schemes are the Wholesome Pigs Scotland in Scotland, the BPEX Pig Health Scheme in England and Wales and the Pig Regen Ltd. health and welfare checks done in Northern Ireland. This report set out to compare the prevalence of four respiratory conditions (enzootic pneumonia-like lesions, pleurisy, pleuropneumonia lesions and abscesses in the lung) assessed by these three Pig Health Schemes. The seasonal variations and year trends associated with the conditions in each scheme are presented. The paper also highlights the differences in prevalence for each condition across these schemes and areas where further research is needed. A general increase in the prevalence of enzootic pneumonia like lesions was observed in Scotland, England and Wales since 2009, while a general decrease was observed in Northern Ireland over the years of the scheme. Pleurisy prevalence has increased since 2010 in all three schemes, whilst pleuropneumonia has been decreasing. Prevalence of abscesses in the lung has decreased in England, Wales and Northern Ireland but has increased in Scotland. This analysis highlights the value of surveillance schemes based on abattoir pathology monitoring of four respiratory lesions. The outputs at scheme level have significant value as indicators of endemic and emerging disease, and for producers and herd veterinarians in planning and evaluating herd health control programs when comparing individual farm results with national averages. PMID- 26020636 TI - In Vitro Whole Genome DNA Binding Analysis of the Bacterial Replication Initiator and Transcription Factor DnaA. AB - DnaA, the replication initiation protein in bacteria, is an AAA+ ATPase that binds and hydrolyzes ATP and exists in a heterogeneous population of ATP-DnaA and ADP-DnaA. DnaA binds cooperatively to the origin of replication and several other chromosomal regions, and functions as a transcription factor at some of these regions. We determined the binding properties of Bacillus subtilis DnaA to genomic DNA in vitro at single nucleotide resolution using in vitro DNA affinity purification and deep sequencing (IDAP-Seq). We used these data to identify 269 binding regions, refine the consensus sequence of the DnaA binding site, and compare the relative affinity of binding regions for ATP-DnaA and ADP-DnaA. Most sites had a slightly higher affinity for ATP-DnaA than ADP-DnaA, but a few had a strong preference for binding ATP-DnaA. Of the 269 sites, only the eight strongest binding ones have been observed to bind DnaA in vivo, suggesting that other cellular factors or the amount of available DnaA in vivo restricts DnaA binding to these additional sites. Conversely, we found several chromosomal regions that were bound by DnaA in vivo but not in vitro, and that the nucleoid associated protein Rok was required for binding in vivo. Our in vitro characterization of the inherent ability of DnaA to bind the genome at single nucleotide resolution provides a backdrop for interpreting data on in vivo binding and regulation of DnaA, and is an approach that should be adaptable to many other DNA binding proteins. PMID- 26020637 TI - Phospholipase D1 Couples CD4+ T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication. AB - Quiescent CD4+ T cells restrict human immunodeficiency virus type 1 (HIV-1) infection at early steps of virus replication. Low levels of both deoxyribonucleotide triphosphates (dNTPs) and the biosynthetic enzymes required for their de novo synthesis provide one barrier to infection. CD4+ T cell activation induces metabolic reprogramming that reverses this block and facilitates HIV-1 replication. Here, we show that phospholipase D1 (PLD1) links T cell activation signals to increased HIV-1 permissivity by triggering a c-Myc dependent transcriptional program that coordinates glucose uptake and nucleotide biosynthesis. Decreasing PLD1 activity pharmacologically or by RNA interference diminished c-Myc-dependent expression during T cell activation at the RNA and protein levels. PLD1 inhibition of HIV-1 infection was partially rescued by adding exogenous deoxyribonucleosides that bypass the need for de novo dNTP synthesis. Moreover, the data indicate that low dNTP levels that impact HIV-1 restriction involve decreased synthesis, and not only increased catabolism of these nucleotides. These findings uncover a unique mechanism of action for PLD1 inhibitors and support their further development as part of a therapeutic combination for HIV-1 and other viral infections dependent on host nucleotide biosynthesis. PMID- 26020638 TI - Macrophage Migration Inhibitory Factor Mediates PAR-Induced Bladder Pain. AB - INTRODUCTION: Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is constitutively expressed in urothelial cells that also express protease-activated receptors (PAR). Urothelial PAR1 receptors were shown to mediate bladder inflammation. We showed that PAR1 and PAR4 activator, thrombin, also mediates urothelial MIF release. We hypothesized that stimulation of urothelial PAR1 or PAR4 receptors elicits release of urothelial MIF that acts on MIF receptors in the urothelium to mediate bladder inflammation and pain. Thus, we examined the effect of activation of specific bladder PAR receptors on MIF release, bladder pain, micturition and histological changes. METHODS: MIF release was measured in vitro after exposing immortalized human urothelial cells (UROtsa) to PAR1 or PAR4 activating peptides (AP). Female C57BL/6 mice received intravesical PAR1- or PAR4-AP for one hour to determine: 1) bladder MIF release in vivo within one hour; 2) abdominal hypersensitivity (allodynia) to von Frey filament stimulation 24 hours after treatment; 3) micturition parameters 24 hours after treatment; 4) histological changes in the bladder as a result of treatment; 5) changes in expression of bladder MIF and MIF receptors using real-time RT-PCR; 6) changes in urothelial MIF and MIF receptor, CXCR4, protein levels using quantitative immunofluorescence; 7) effect of MIF or CXCR4 antagonism. RESULTS: PAR1- or PAR4-AP triggered MIF release from both human urothelial cells in vitro and mouse urothelium in vivo. Twenty-four hours after intravesical PAR1- or PAR4 AP, we observed abdominal hypersensitivity in mice without changes in micturition or bladder histology. PAR4-AP was more effective and also increased expression of bladder MIF and urothelium MIF receptor, CXCR4. Bladder CXCR4 localized to the urothelium. Antagonizing MIF with ISO-1 eliminated PAR4- and reduced PAR1-induced hypersensitivity, while antagonizing CXCR4 with AMD3100 only partially prevented PAR4-induced hypersensitivity. CONCLUSIONS: Bladder PAR activation elicits urothelial MIF release and urothelial MIF receptor signaling at least partly through CXCR4 to result in abdominal hypersensitivity without overt bladder inflammation. PAR-induced bladder pain may represent an interesting pre-clinical model of Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) where pain occurs without apparent bladder injury or pathology. MIF is potentially a novel therapeutic target for bladder pain in IC/PBS patients. PMID- 26020639 TI - Stimulus-rate sensitivity discerns area 3b of the human primary somatosensory cortex. AB - Previous studies have shown that the hemodynamic response of the primary somatosensory cortex (SI) to electrical median nerve stimulation doubles in strength when the stimulus rate (SR) increases from 1 to 5 Hz. Here we investigated whether such sensitivity to SR is homogenous within the functionally different subareas of the SI cortex, and whether SR sensitivity would help discern area 3b among the other SI subareas. We acquired 3-tesla functional magnetic resonance imaging (fMRI) data from nine healthy adults who received pneumotactile stimuli in 25-s blocks to three right-hand fingers, either at 1, 4, or 10 Hz. The main contrast (all stimulations pooled vs. baseline), applied to the whole brain, first limited the search to the whole SI cortex. The conjunction of SR-sensitive contrasts [4 Hz - 1 Hz] > 0 and [10 Hz - 1 Hz] > 0 ([4 Hz - 1 Hz] + [10 Hz - 1 Hz] > 0), applied to the SI cluster, then revealed an anterior ventral subcluster that reacted more strongly to both 10-Hz and 4-Hz stimuli than to the 1-Hz stimuli. No other SR-sensitive clusters were found at the group-level in the whole-brain analysis. The site of the SR-sensitive SI subcluster corresponds to the canonical position of area 3b; such differentiation was also possible at the individual level in 5 out of 9 subjects. Thus the SR sensitivity of the BOLD response appears to discern area 3b among other subareas of the human SI cortex. PMID- 26020640 TI - The Drosophila insulin receptor independently modulates lifespan and locomotor senescence. AB - The Insulin/IGF-like signalling (IIS) pathway plays an evolutionarily conserved role in ageing. In model organisms reduced IIS extends lifespan and ameliorates some forms of functional senescence. However, little is known about IIS in nervous system ageing and behavioural senescence. To investigate this role in Drosophila melanogaster, we measured the effect of reduced IIS on senescence of two locomotor behaviours, negative geotaxis and exploratory walking. Two long lived fly models with systemic IIS reductions (daGAL4/UAS-InRDN (ubiquitous expression of a dominant negative insulin receptor) and d2GAL/UAS-rpr (ablation of insulin-like peptide producing cells)) showed an amelioration of negative geotaxis senescence similar to that previously reported for the long-lived IIS mutant chico. In contrast, exploratory walking in daGAL4/UAS-InRDN and d2GAL/UAS rpr flies declined with age similarly to controls. To determine the contribution of IIS in the nervous system to these altered senescence patterns and lifespan, the InRDN was targeted to neurons (elavGAL4/UAS-InRDN), which resulted in extension of lifespan in females, normal negative geotaxis senescence in males and females, and detrimental effects on age-specific exploratory walking behaviour in males and females. These data indicate that the Drosophila insulin receptor independently modulates lifespan and age-specific function of different types of locomotor behaviour. The data suggest that ameliorated negative geotaxis senescence of long-lived flies with systemic IIS reductions is due to ageing related effects of reduced IIS outside the nervous system. The lifespan extension and coincident detrimental or neutral effects on locomotor function with a neuron specific reduction (elavGAL4/UAS-InRDN) indicates that reduced IIS is not beneficial to the neural circuitry underlying the behaviours despite increasing lifespan. PMID- 26020641 TI - Statin-Induced Increases in Atrophy Gene Expression Occur Independently of Changes in PGC1alpha Protein and Mitochondrial Content. AB - One serious side effect of statin drugs is skeletal muscle myopathy. Although the mechanism(s) responsible for statin myopathy remains to be fully determined, an increase in muscle atrophy gene expression and changes in mitochondrial content and/or function have been proposed to play a role. In this study, we examined the relationship between statin-induced expression of muscle atrophy genes, regulators of mitochondrial biogenesis, and markers of mitochondrial content in slow- (ST) and fast-twitch (FT) rat skeletal muscles. Male Sprague Dawley rats were treated with simvastatin (60 or 80 mg.kg(-1).day(-1)) or vehicle control via oral gavage for 14 days. In the absence of overt muscle damage, simvastatin treatment induced an increase in atrogin-1, MuRF1 and myostatin mRNA expression; however, these were not associated with changes in peroxisome proliferator gamma co-activator 1 alpha (PGC-1alpha) protein or markers of mitochondrial content. Simvastatin did, however, increase neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS) and AMPK alpha-subunit protein expression, and tended to increase total NOS activity, in FT but not ST muscles. Furthermore, simvastatin induced a decrease in beta-hydroxyacyl CoA dehydrogenase (beta-HAD) activity only in FT muscles. These findings suggest that the statin-induced activation of muscle atrophy genes occurs independent of changes in PGC-1alpha protein and mitochondrial content. Moreover, muscle-specific increases in NOS expression and possibly NO production, and decreases in fatty acid oxidation, could contribute to the previously reported development of overt statin-induced muscle damage in FT muscles. PMID- 26020642 TI - Identification of the Mind Bomb1 Interaction Domain in Zebrafish DeltaD. AB - Ubiquitylation promotes endocytosis of the Notch ligands like Delta and Serrate and is essential for them to effectively activate Notch in a neighboring cell. The RING E3 ligase Mind bomb1 (Mib1) ubiquitylates DeltaD to facilitate Notch signaling in zebrafish. We have identified a domain in the intracellular part of the zebrafish Notch ligand DeltaD that is essential for effective interactions with Mib1. We show that elimination of the Mind bomb1 Interaction Domain (MID) or mutation of specific conserved motifs in this domain prevents effective Mib1 mediated ubiquitylation and internalization of DeltaD. Lateral inhibition mediated by Notch signaling regulates early neurogenesis in zebrafish. In this context, Notch activation suppresses neurogenesis, while loss of Notch-mediated lateral inhibition results in a neurogenic phenotype, where too many cells are allowed to become neurons. While Mib1-mediated endocytosis of DeltaD is essential for effective activation of Notch in a neighboring cell (in trans) it is not required for DeltaD to inhibit function of Notch receptors in the same cell (in cis). As a result, forms of DeltaD that have the MID can activate Notch in trans and suppress early neurogenesis when mRNA encoding it is ectopically expressed in zebrafish embryos. On the other hand, when the MID is eliminated/mutated in DeltaD, its ability to activate Notch in trans fails but ability to inhibit in cis is retained. As a result, ectopic expression of DeltaD lacking an effective MID results in a failure of Notch-mediated lateral inhibition and a neurogenic phenotype. PMID- 26020643 TI - Identification of Suitable Reference Genes for Real Time Quantitative Polymerase Chain Reaction Assays on Pectoralis major Muscle in Chicken (Gallus gallus ). AB - Thirteen reference genes were investigated to determine their stability to be used as a housekeeping in gene expression studies in skeletal muscle of chickens. Five different algorithms were used for ranking of reference genes and results suggested that individual rankings of the genes differed among them. The stability of the expression of reference genes were validated using samples obtained from the Pectoralis major muscle in chicken. Samples were obtained from chickens in different development periods post hatch and under different nutritional diets. For gene expression calculation the DeltaDeltaCt approach was applied to compare relative expression of pairs of genes within each of 52 samples when normalized to mitochondrially encoded cytochrome c oxidase II (MT CO2) target gene. Our findings showed that hydroxymethylbilane synthase (HMBS) and hypoxanthine phosphoribosyl transferase 1 (HPRT1) are the most stable reference genes while transferrin receptor (TFRC) and beta-2-microglobulin (B2M) ranked as the least stable genes in the Pectoralis major muscle of chickens. Moreover, our results revealed that HMBS and HPRT1 gene expression did not change due to dietary variations and thus it is recommended for accurate normalization of RT-qPCR data in chicken Pectoralis major muscle. PMID- 26020644 TI - The CD14 rs2569190 TT Genotype Is Associated with an Improved 30-Day Survival in Patients with Sepsis: A Prospective Observational Cohort Study. AB - According to previous investigations, CD14 is suggested to play a pivotal role in initiating and perpetuating the pro-inflammatory response during sepsis. A functional polymorphism within the CD14 gene, rs2569190, has been shown to impact the pro-inflammatory response upon stimulation with lipopolysaccharide, a central mediator of inflammation in sepsis. In this study, we hypothesized that the strong pro-inflammatory response induced by the TT genotype of CD14 rs2569190 may have a beneficial effect on survival (30-day) in patients with sepsis. A total of 417 adult patients with sepsis (and of western European descent) were enrolled into this observational study. Blood samples were collected for rs2569190 genotyping. Patients were followed over the course of their stay in the ICU, and the 30-day mortality risk was recorded as the primary outcome parameter. Sepsis related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure as a secondary variable. Moreover, organ support-free days were evaluated as a secondary outcome parameter. TT-homozygous patients were compared to C-allele carriers. Kaplan Meier survival analysis revealed a higher 30-day mortality risk among C-allele carriers compared with T homozygotes (p = 0.0261). To exclude the effect of potential confounders (age, gender, BMI and type of infection) and covariates that varied at baseline with a p-value < 0.2 (e.g., comorbidities), we performed multivariate Cox regression analysis to examine the survival time. The CD14 rs2569190 C allele remained a significant covariate for the 30-day mortality risk in the multivariate analysis (hazard ratio, 2.11; 95% CI, 1.08-4.12; p = 0.0282). The 30-day mortality rate among C allele carriers was 23%, whereas the T homozygotes had a mortality rate of 13%. Additionally, an analysis of organ specific SOFA scores revealed a significantly higher SOFA-Central nervous system score among patients carrying the C allele compared with T-homozygous patients (1.9+/-1.1 and 1.6+/-1.0, respectively; p = 0.0311). In conclusion, CD14 rs2569190 may act as a prognostic variable for the short-term outcome (30-day survival) in patients with sepsis. PMID- 26020645 TI - UniqTag: Content-Derived Unique and Stable Identifiers for Gene Annotation. AB - When working on an ongoing genome sequencing and assembly project, it is rather inconvenient when gene identifiers change from one build of the assembly to the next. The gene labelling system described here, UniqTag, addresses this common challenge. UniqTag assigns a unique identifier to each gene that is a representative k-mer, a string of length k, selected from the sequence of that gene. Unlike serial numbers, these identifiers are stable between different assemblies and annotations of the same data without requiring that previous annotations be lifted over by sequence alignment. We assign UniqTag identifiers to ten builds of the Ensembl human genome spanning eight years to demonstrate this stability. The implementation of UniqTag in Ruby and an R package are available at https://github.com/sjackman/uniqtag sjackman/uniqtag. The R package is also available from CRAN: install.packages ("uniqtag"). Supplementary material and code to reproduce it is available at https://github.com/sjackman/uniqtag paper. PMID- 26020647 TI - Quantitative Measurement of GPCR Endocytosis via Pulse-Chase Covalent Labeling. AB - G protein-coupled receptors (GPCRs) play a critical role in many physiological systems and represent one of the largest families of signal-transducing receptors. The number of GPCRs at the cell surface regulates cellular responsiveness to their cognate ligands, and the number of GPCRs, in turn, is dynamically controlled by receptor endocytosis. Recent studies have demonstrated that GPCR endocytosis, in addition to affecting receptor desensitization and resensitization, contributes to acute G protein-mediated signaling. Thus, endocytic GPCR behavior has a significant impact on various aspects of physiology. In this study, we developed a novel GPCR internalization assay to facilitate characterization of endocytic GPCR behavior. We genetically engineered chimeric GPCRs by fusing HaloTag (a catalytically inactive derivative of a bacterial hydrolase) to the N-terminal end of the receptor (HT-GPCR). HaloTag has the ability to form a stable covalent bond with synthetic HaloTag ligands that contain fluorophores or a high-affinity handle (such as biotin) and the HaloTag reactive linker. We selectively labeled HT-GPCRs at the cell surface with a HaloTag PEG ligand, and this pulse-chase covalent labeling allowed us to directly monitor the relative number of internalized GPCRs after agonist stimulation. Because the endocytic activities of GPCR ligands are not necessarily correlated with their agonistic activities, applying this novel methodology to orphan GPCRs, or even to already characterized GPCRs, will increase the likelihood of identifying currently unknown ligands that have been missed by conventional pharmacological assays. PMID- 26020646 TI - Inferring horizontal gene transfer. AB - Horizontal or Lateral Gene Transfer (HGT or LGT) is the transmission of portions of genomic DNA between organisms through a process decoupled from vertical inheritance. In the presence of HGT events, different fragments of the genome are the result of different evolutionary histories. This can therefore complicate the investigations of evolutionary relatedness of lineages and species. Also, as HGT can bring into genomes radically different genotypes from distant lineages, or even new genes bearing new functions, it is a major source of phenotypic innovation and a mechanism of niche adaptation. For example, of particular relevance to human health is the lateral transfer of antibiotic resistance and pathogenicity determinants, leading to the emergence of pathogenic lineages. Computational identification of HGT events relies upon the investigation of sequence composition or evolutionary history of genes. Sequence composition-based ("parametric") methods search for deviations from the genomic average, whereas evolutionary history-based ("phylogenetic") approaches identify genes whose evolutionary history significantly differs from that of the host species. The evaluation and benchmarking of HGT inference methods typically rely upon simulated genomes, for which the true history is known. On real data, different methods tend to infer different HGT events, and as a result it can be difficult to ascertain all but simple and clear-cut HGT events. PMID- 26020648 TI - Stemness of the hybrid Epithelial/Mesenchymal State in Breast Cancer and Its Association with Poor Survival. AB - Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial since--depending on the cell-line studied- either epithelial (E) or mesenchymal (M) markers, alone or together have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell-types, our data support a novel model that links a mixed EM signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients as well as with enrichment for stem-like cells in both E and M breast cell-lines. This link between a mixed EM expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness) compared to the more differentiated E and M cell-types. Second, single cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had a combination of several stem-like traits since they displayed increased plasticity, self-renewal, mammosphere formation, and produced ALDH1+ progenies, while more differentiated M cells showed less plasticity and E cells showed less self-renewal. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed EM signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell-lines but E in basal breast cancer cell-lines. Our results suggest that targeting E/M heterogeneity by eliminating hybrid E/M cells and cooperation between E and M cell-types could improve breast cancer patient survival independent of breast cancer-subtype. PMID- 26020649 TI - A Simple Auxin Transcriptional Response System Regulates Multiple Morphogenetic Processes in the Liverwort Marchantia polymorpha. AB - In land plants comparative genomics has revealed that members of basal lineages share a common set of transcription factors with the derived flowering plants, despite sharing few homologous structures. The plant hormone auxin has been implicated in many facets of development in both basal and derived lineages of land plants. We functionally characterized the auxin transcriptional response machinery in the liverwort Marchantia polymorpha, a member of the basal lineage of extant land plants. All components known from flowering plant systems are present in M. polymorpha, but they exist as single orthologs: a single MpTOPLESS (TPL) corepressor, a single MpTRANSPORT inhibitor response 1 auxin receptor, single orthologs of each class of auxin response factor (ARF; MpARF1, MpARF2, MpARF3), and a single negative regulator auxin/indole-3-acetic acid (MpIAA). Phylogenetic analyses suggest this simple system is the ancestral condition for land plants. We experimentally demonstrate that these genes act in an auxin response pathway--chimeric fusions of the MpTPL corepressor with heterodimerization domains of MpARF1, MpARF2, or their negative regulator, MpIAA, generate auxin insensitive plants that lack the capacity to pattern and transition into mature stages of development. Our results indicate auxin mediated transcriptional regulation acts as a facilitator of branching, differentiation and growth, rather than acting to determine or specify tissues during the haploid stage of the M. polymorpha life cycle. We hypothesize that the ancestral role of auxin is to modulate a balance of differentiated and pluri- or totipotent cell states, whose fates are determined by interactions with combinations of unrelated transcription factors. PMID- 26020650 TI - Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population. AB - Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system, and is mediated by N methyl-D-aspartate (NMDA) receptors. Disturbances in this system have been hypothesized to play a major role in SZ pathogenesis. Several studies have revealed that the NMDA receptor subunit 2B (GRIN2B) potentially associates with SZ and its psychiatric symptoms. In this study, we performed a case-control study to identify polymorphisms of the GRIN2B gene that may confer susceptibility to SZ in the Han Chinese population. Thirty-four single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was observed in allele and genotype between SZ and controls at rs2098469 (chi2 = 8.425 and 4.994; p = 0.025 and 0.014, respectively). Significant associations were found in the allele at rs12319804 (chi2 = 4.436; p = 0.035), as well as in the genotype at rs12820037 and rs7298664 between SZ and controls (chi2 = 11.162 and 38.204; p = 0.003 and 4.27*10(-8), respectively). After applying the Bonferroni correction, rs7298664 still had significant genotype associations with SZ (p = 1.71*10(-7)). In addition, rs2098469 genotype and allele frequencies, and 12820037 allele frequencies were nominally associated with SZ. Three haplotypes, CGA (rs10845849-rs12319804 rs10845851), CC (rs12582848-rs7952915), and AAGAC (rs2041986-rs11055665-rs7314376 rs7297101-rs2098469), had significant differences between SZ and controls (chi2 = 4.324, 4.582, and 4.492; p = 0.037, 0.032, and 0.034, respectively). In addition, three SNPs, rs2098469, rs12820037, and rs7298664, were significantly associated with cognition factors PANSS subscores in SZ (F = 16.799, 7.112, and 13.357; p = 0.000, 0.017, and 0.000, respectively). In conclusion, our study provides novel evidence for an association between GRIN2B polymorphisms and SZ susceptibility and symptoms in the Han Chinese population. PMID- 26020652 TI - Mechanism of Action of Sulforaphane as a Superoxide Radical Anion and Hydrogen Peroxide Scavenger by Double Hydrogen Transfer: A Model for Iron Superoxide Dismutase. AB - The mechanism of action of sulforaphane as a scavenger of superoxide radical anion (O2(*-)) and hydrogen peroxide (H2O2) was investigated using density functional theory (DFT) in both gas phase and aqueous media. Iron superoxide dismutase (Fe-SOD) involved in scavenging superoxide radical anion from biological media was modeled by a complex consisting of the ferric ion (Fe(3+)) attached to three histidine rings. Reactions related to scavenging of superoxide radical anion by sulforaphane were studied using DFT in the presence and absence of Fe-SOD represented by this model in both gas phase and aqueous media. The scavenging action of sulforaphane toward both superoxide radical anion and hydrogen peroxide was found to involve the unusual mechanism of double hydrogen transfer. It was found that sulforaphane alone, without Fe-SOD, cannot scavenge superoxide radical anion in gas phase or aqueous media efficiently as the corresponding reaction barriers are very high. However, in the presence of Fe-SOD represented by the above-mentioned model, the scavenging reactions become barrierless, and so sulforaphane scavenges superoxide radical anion by converting it to hydrogen peroxide efficiently. Further, sulforaphane was found to scavenge hydrogen peroxide also very efficiently by converting it into water. Thus, the mechanism of action of sulforaphane as an excellent antioxidant has been unravelled. PMID- 26020653 TI - Nanotube field electron emission: principles, development, and applications. AB - There is a growing trend to apply field emission (FE) electron sources in vacuum electronic devices due to their fast response, high efficiency and low energy consumption compared to thermionic emission ones. Carbon nanotubes (CNTs) have been regarded as a promising class of electron field emitters since the 1990s and have promoted the development of FE technology greatly because of their high electrical and thermal conductivity, chemical stability, high aspect ratio and small size. Recent studies have shown that FE from CNTs has the potential to replace conventional thermionic emission in many areas and that it exhibits advanced features in practical applications. Consequently, FE from nanotubes and applications thereof have attracted much attention. This paper provides a comprehensive review of both recent advances in CNT field emitters and issues related to applications of CNT based FE. FE theories and principles are introduced, and the early development of field emitters is related. CNT emitter types and their FE performance are discussed. The current situation for applications based on nanotube FE is reviewed. Although challenges remain, the tremendous progress made in CNT FE over the past ten years indicates the field's development potential. PMID- 26020651 TI - Widespread changes in white matter microstructure after a day of waking and sleep deprivation. AB - BACKGROUND: Elucidating the neurobiological effects of sleep and waking remains an important goal of the neurosciences. Recently, animal studies indicated that sleep is important for cell membrane and myelin maintenance in the brain and that these structures are particularly susceptible to insufficient sleep. Here, we tested the hypothesis that a day of waking and sleep deprivation would be associated with changes in diffusion tensor imaging (DTI) indices of white matter microstructure sensitive to axonal membrane and myelin alterations. METHODS: Twenty-one healthy adult males underwent DTI in the morning [7:30AM; time point (TP)1], after 14 hours of waking (TP2), and then after another 9 hours of waking (TP3). Whole brain voxel-wise analysis was performed with tract based spatial statistics. RESULTS: A day of waking was associated with widespread increases in white matter fractional anisotropy, which were mainly driven by radial diffusivity reductions, and sleep deprivation was associated with widespread fractional anisotropy decreases, which were mainly explained by reductions in axial diffusivity. In addition, larger decreases in axial diffusivity after sleep deprivation were associated with greater sleepiness. All DTI changes remained significant after adjusting for hydration measures. CONCLUSIONS: This is the first DTI study of sleep deprivation in humans. Although previous studies have observed localized changes in DTI indices of cerebral microstructure over the course of a few hours, further studies are needed to confirm widespread DTI changes within hours of waking and to clarify whether such changes in white matter microstructure serve as neurobiological substrates of sleepiness. PMID- 26020654 TI - Reverse Non-Equilibrium Molecular Dynamics Demonstrate That Surface Passivation Controls Thermal Transport at Semiconductor-Solvent Interfaces. AB - We examine the role played by surface structure and passivation in thermal transport at semiconductor/organic interfaces. Such interfaces dominate thermal transport in semiconductor nanomaterials owing to material dimensions much smaller than the bulk phonon mean free path. Utilizing reverse nonequilibrium molecular dynamics simulations, we calculate the interfacial thermal conductance (G) between a hexane solvent and chemically passivated wurtzite CdSe surfaces. In particular, we examine the dependence of G on the CdSe slab thickness, the particular exposed crystal facet, and the extent of surface passivation. Our results indicate a nonmonotonic dependence of G on ligand-grafting density, with interfaces generally exhibiting higher thermal conductance for increasing surface coverage up to ~0.08 ligands/A(2) (75-100% of a monolayer, depending on the particular exposed facet) and decreasing for still higher coverages. By analyzing orientational ordering and solvent penetration into the ligand layer, we show that a balance of competing effects is responsible for this nonmonotonic dependence. Although the various unpassivated CdSe surfaces exhibit similar G values, the crystal structure of an exposed facet nevertheless plays an important role in determining the interfacial thermal conductance of passivated surfaces, as the density of binding sites on a surface determines the ligand-grafting densities that may ultimately be achieved. We demonstrate that surface passivation can increase G relative to a bare surface by roughly 1 order of magnitude and that, for a given extent of passivation, thermal conductance can vary by up to a factor of ~2 between different surfaces, suggesting that appropriately tailored nanostructures may direct heat flow in an anisotropic fashion for interface-limited thermal transport. PMID- 26020655 TI - [Early detection of abdominal aortic aneurysm in risk population]. AB - INTRODUCTION: An aneurysm is the increase in diameter of an artery>50%; the abdominal aortic aneurysm (AAA) is the most frequent. Abdominal ultrasound is an accessible study, highly recommended for diagnosis. Screening at risk populations reduces morbidity and mortality of this disease. METHODS: To determine the frequency of AAA by duplex Doppler in patients older than 65 years old with risk factors. A cross sectional study was performed, from June to October 2012, 144 patients were included, both genders, >65 years. The diameter of the infrarenal abdominal aorta was measured by duplex Doppler. AAA was defined as an aorta with diameter>3 cm. RESULTS: Mean age was 72.7+/-6.7, 95.1% were male, 13% continued smoking. 127 of 144 were normal. 10 of 144 had AAA with diameters of 3.2 to 7.11 cm, all of them male. Logistic regression showed that active smoking is a significant predictive factor for AAA. CONCLUSION: There is a significant frequency of AAA in male patients>65 years old. PMID- 26020656 TI - [Prevalence and implicated risk factors associated with the exteriorization of cardiac pacemakers: 5 year follow-up]. AB - BACKGROUND: Infection is the most common complication related to permanent pacemaker implantation. The objetive of this study is to establish the prevalence and determine the frequency of risk factors associated with exteriorization of cardiac pacemakers at the Department of Cardiac Electrophysiology at the UMAE Hospital de Especialidades "Dr. Antonio Fraga Mouret" Centro Medico Nacional La Raza, Instituto Mexicano del Seguro Social. METHODS: A descriptive cross sectional study from September 2005 to September 2010, where, for the analysis of the risk factors we selected cases and controls by age, sex and the diagnosis of Diabetes, or not. Was calculated measures of central tendency (mean, median and mode) and chi-squared, Fisher exact test and exact odds ratio. RESULTS: 3192 cardiac pacemakers were implanted, identifying 83 exteriorization cases, where 46 of them were selected for cases and controls, and the mean age was 71 years. CONCLUSIONS: Our prevalence of exteriorization of cardiac pacemakers is 2.6 %, these results are similar to previously published studies. None of the risk factors described are present as a cause in our population. The surgical technique used may be an important risk factor, so further studies analysing all techniques are needed. PMID- 26020657 TI - [Why Hospital de Especialidades del Centro Medico La Raza was called Dr. Antonio Fraga Mouret?]. PMID- 26020658 TI - [Alterations of the thyroid function in patients with morbid obesity]. AB - INTRODUCTION: The morbid obesity (BMI greater than or equal to 40 kg/m2) is associated with dysfunction of the hypothalamus-pituitary-thyroid axis, showing high levels of thyrotropin (TSH), triiodothyronine (T3) total and free, suspecting a real thyroid condition. Our objetive was to describe the alterations in thyroid function in patients with morbid obesity, determining serum levels of TSH, total T3, free T4 and thyroid peroxidase antibodies (TPO). METHODS: Prospective, descriptive, observational, cross-sectional study, we enrolled 52 patients with morbid obesity, at the obesity clinic, from department of Endocrinology, since January 2009 to July 2011. All patients signed a letter of informed consent. Patients with known thyroid disorders and/or under the use of levothyroxine or other medication that causes alteration in thyroid function were excluded. Statistical analysis was performed using measures of central tendency, simple frequencies, percentages and Spearman's correlation. RESULTS: The prevalence of primary hypothyroidism was 8%, 6% subclinical hypothyroidism and thyroid function alterations secondary to obesity of 23% (elevated TSH and/or free T4 Total T3 with normal and TPO antibody negative). CONCLUSIONS: Most morbidly obese patients haven't autoimmune thyroid dysfunction; the alterations in thyroid function are caused by an effect of homeostasis against obesity and can be corrected by reducing weight. PMID- 26020659 TI - [Maternal and fetal outcome in Mexican women with rheumatoid arthritis]. AB - OBJECTIVE: To report our experience in maternal-fetal outcome in women with RA in a national medical referral center. METHODS: A retrospective analysis of the records of pregnant women with rheumatoid arthritis attending at a Pregnancy and Autoimmune Rheumatic Diseases Clinic was performed. Maternal-fetal outcomes such as disease activity, preclampsia/eclampsia, rate of live births, abortions, stillbirths, preterm birth, weeks of gestation, birth weight, congenital malformations and use of anti-rheumatic drugs were studied. RESULTS: We included 73 pregnancies in 72 patients. Disease activity was documented in 47.2% of patients during pregnancy and/or postpartum and 87.7% of patients received some antirheumatic drug. Preclampsia developed in 8.2% of cases. The live birth rate was 98.6%, with preterm delivery in 15.9% and low weight at term in 17.6% of cases. Cesarean section was performed in 77.1% of cases. The disease activity was not associated with a higher percentage of maternal-fetal complications. CONCLUSIONS: Our study showed that most patients do not experience significant activity of RA during pregnancy, fetal outcome is satisfactory and disease activity did not appear to influence significantly the obstetric outcome. PMID- 26020661 TI - [Overweigth, obesity, metabolic syndrome and waist/height index in health staff]. AB - INTRODUCTION: Health staff self-applied strategies are insufficiently to reduce cardiovascular risk factors. The aim of this article is to investigate the prevalence of overweight, obesity and metabolic syndrome and waist/height index on health staff. METHODS: This is a cross-sectional study from January to April 2014 in 735 workers of the UMAE Specialties La Raza. A diagnosis of overweight and obesity was established according to WHO criteria and metabolic syndrome NCEP ATP-III. In 250 participants lipid profile and blood chemistry were obtained. Descriptive statistics was applied, chi square, Student t test or Kruskal-Wallis to compare groups. RESULTS: We included 496 women and 239 men (physicians, nurses and other workers). 38% were overweight; 22% had obesity. We found fasting hyperglycemia>126 mg/dl in 5.1%, between 100-126 mg/dl in 17.4%, hypertriglyceridemia in 40.4%; HDL cholesterol<40 mg/dl 66% in men and HDL cholesterol<50 mg/dl 51.4% in women. Waist measurement was 93+/-11 cm in men vs. 88+/-13 m in women. The waist/height index in the ideal weight group was 0.048+/ 0.04, for overweight 0.55+/-0.04 and for obesity 0.65+/-0.064 (p<0.01). Metabolic syndrome prevalence was 30.6%, smoking 21.6% and alcohol consumption 35%. CONCLUSIONS: The prevalence of obesity-overweight was 60% and metabolic syndrome 30%, making it necessary to take immediate actions to modify the lifestyle of health staff. PMID- 26020660 TI - [Cutaneous manifestations of leukemia]. AB - INTRODUCTION: To describe the type and frequency of cutaneous manifestations of leukemia. METHODS: Observational, descriptive study. We included patients over 16 years of age, with confirmed diagnosis of leukemia from the Hematology and Dermatology Departments of the outpatient clinic and from in-patients. Patients with bone marrow transplantation were excluded. A complete history and physical examination of the skin and appendages was performed, with biopsy and cultures if required. The cutaneous manifestations were classified as infection or drug related, leukemic infiltration, associated dermatosis to leukemia and non specific lesions. Descriptive statistics was employed. RESULTS: We included 142 patients (62 females, 80 males) with the following diagnoses: acute myeloid leukemia (n=36), acute lymphoblastic leukemia (n=52), chronic myeloid leukemia (n=21), chronic lymphocitic leukemia (n=30) and hairy cells leukemia (n=3). 42% of patients (n=60) presented some dermatoses. There were 36 non-specific dermatoses, 21 drug-related, 20 infectious, 3 infiltrative and none associated. CONCLUSIONS: Cutaneous manifestations directly related to leukemia are frequent, being the non-specific ones, the most commonly observed. However, a thorough dermatologic examination is important in these patients as part of an overall evaluation. PMID- 26020662 TI - [In Process Citation]. PMID- 26020663 TI - [Alterations in cerebral perfusion in patients with systemic sclerosis and cognitive impairment]. AB - INTRODUCTION: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by fibrosis, immunological and vascular abnormalities. Cerebral hypoperfusion can be caused by cerebral ischemia. Cognitive impairment (CI) are a major cause of morbidity in SSc The aim of this study is to estimate the frequency of alterations in cerebral perfusion (CP) in SSc patients with CI. METHODS: We studied 88 patients with SSc. The Montreal Test (MT) was given to all patients to evaluate CI. To 15 patients with CI and without systemic hypertension, diabetes mellitus, cerebrovascular disease, vasculitis, hypothyroidism, depression, and drugs that interfere with the cognitive assessment, the PC was measured by cerebral gammagram (CG). RESULTS: Of the 88 patients with ES, 58 had CI by MT. A decrease in CP was observed in following lobes: frontal in 9 of 15 patients, temporal in 7 of 15, and parietal in 3 of 15. Concordance between MT and CG was 60% for the frontal, 46% for the temporal and parietal 13%. CONCLUSIONS: The CI is common in SSc. A decrease in CP was more frequent in the frontal lobe, predominating in older patients and with longer duration of SSc. PMID- 26020664 TI - [Carotid and brachial intima-media thickness of the allelic variants G894T and T 789C of eNOS in systemic sclerosis patients]. AB - OBJECTIVE: To evaluate comparatively the carotid intima media thickness index (IMT) and brachial index with Doppler ultrasound, and pulmonary artery pressure with echocardiography in allelic variation of G894T and T-789C eNOS (endothelial nitric oxide synthase) in patients with systemic sclerosis. METHODS: This is a cross-sectional study in patients with scleroderma. The inclusion criteria were: age 18-70 years, scleroderma diagnosed patients with a prior informed consent. Polymorphism G894T and T-789C of eNOS was measured in blood, and IMT by carotid and brachial Doppler. We analyzed with descriptive statistics, Student's t test or chi square for association of variables and Spearman to correlate Doppler parameters. RESULTS: We found abnormally high IMT in carotid and brachial arteries. We also observed low correlation between both brachial arteries, good correlation between carotids and no correlation between carotid and brachial arteries. The left IMT>0.65 mm in brachial artery corresponds to pulmonary pressure>30 mmHg by echocardiography. G894T gene polymorphism was associated with increased IMT in right carotid. CONCLUSION: The G894T eNOS polymorphism was associated with increased IMT in right carotid. The one side carotid IMT is consistent with its contralateral. The left brachial IMT above to 0.65 mm, suggests the possibility of pulmonary arterial hypertension. PMID- 26020665 TI - [Isotretinoin and depressive symptoms in patiens with severe and recurrent acne]. AB - BACKGROUND: Since use of isotretinoin for acne management it has been published controversial results about its association with depression. The objective of this study was to know if use of isotretinoin in patients with severe and recurrent acne (SRA) is associated with depression. METHODS: 22 patients with diagnosis of SRA were included from the National Medical Center La Raza's Acne Clinic. They completed the Beck Depression inventory (IDB-II) before, during (2 months) and after treatment with isotretinoin (4 months), calculated at 0.5 mg/kg. RESULTS: The patients reported low depressive symptoms before treatment that reduced at the end (median=6 and 0, respectively, p<0.001). CONCLUSIONS: Treatment with isotretinoin in this sample of patients with severe and recurrent acne produced no increase in depressive symptoms, but improvement, due to the best corporal image self-perception. PMID- 26020666 TI - [Fever of unknown origin, comparing two series with 26 years of difference]. AB - INTRODUCTION: Fever of unknown origin (FUO) remains a syndrome with difficult approach and changing spectrum. Our aim was to compare two series of FUO patients seen at the Department of Internal Medicine, Hospital de Especialidades Centro Medico La Raza, Mexico City. METHODS: Data from FUO series from 1979-87 were compared with those from 2004-14 series. We analyzed demographic data, final diagnoses, and diagnostic tests used. We report median and range for numerical variables and frequencies for nominal data, bivariate analysis was done with chi square or Fisher's test as needed using SPSS version 17.0 for MAC and open-epi version 3.7. RESULTS: One hundred twenty seven patients were included in the 1979 87 series and 118 in the 2004-14 series. There were more non-infectious inflammatory diseases (p=0.0004) and less infectious diseases (p=0.024) in the 2004-14 series. We observed no significant differences in neoplastic diseases and undiagnosed cases between the two series. Laboratory tests and their diagnostic utility were similar in both series, but image studies were less useful in the 2004-14 series. Biopsy and laparotomy remained as frequent and useful tools in both series. CONCLUSIONS: The recent series had more non-infectious inflammatory diseases and less infectious causes of FUO. Invasive studies remain as useful diagnostic aids in a significant number of cases. PMID- 26020667 TI - [Clinical and angiographic manifestations inpatients without previous diagnosis of Takayasu's arteritis]. AB - INTRODUCTION: Takayasu's arteritis is a systemic vasculitis that affects the aorta and its main branches mainly seen in young women and it is characterized by decrease or absence of pulses. The arteriography is necessary to corroborate the diagnosis. The aim of this article is to analyze the clinical manifestations and radiological findings in patients with no previous diagnosis of TA. METHODS: The patients were sent to the Department of Radiodiagnosis and Imaging for the performance of an angiography for cerebrovascular disease (CVD) in young patients, renovascular hypertension (RVH) and arterial insufficiency (IA) of limbs. Clinical manifestations were used to investigate the diagnosis of AT according to the criteria of the American College of Rheumatology 1990. A digital subtraction angiography (DSA) was performed and the type of AT was evaluated according to Numano classification. RESULTS: There were 10 women with an average age of 32.4+/-10 years. The reasons for the study of these patients were stroke in young patients 4, RVH 3 and AI of upper extremities 3 patients. The main types of TA were I: 50%, V: 40%, IV 10%. The main arterial involvement were the supraaortic trunk and both carotids 80%, right subclavian 80%, left subclavian 70%, left vertebral 40%, right vertebral 30%, thoracic aortic 40%, abdominal aortic 40%, right renal 40% and left renal 10%. CONCLUSIONS: The most frequent clinical manifestations were stroke in young patients, RVH and AI. The AT type I was the most common, followed by V and IV respectively, which explains the clinical manifestations. PMID- 26020668 TI - [Modification of health-related quality of life in kidney transplant recipients]. AB - INTRODUCTION: The assessment of health-related quality of life is essential to renal replacement therapies. We conducted a study to evaluate the change in quality of life at 6 and 12 months after renal transplantation and compared with healthy population and general population. METHODS: A prospective study in 278 renal transplant recipients using the SF-36 survey at 0, 6 and 12 months after transplantation. The results were compared with those obtained in healthy population (kidney donors) and general population. Student t test was employed for comparisons of means. A value of p<0.05 was considered statistically significant. RESULTS: The quality of life before transplantation was lower than that observed in healthy population and the general population (p<0.001). At 6 months of transplantation significant improvement over the baseline measurement (p<0.001) in the 8 domains and the two composite scales was obtained, but at 12 months, an additional benefit was not observed. The quality of life of recipients at 12 months of transplant was lower only in the concept of general health (p=0.035) compared with healthy population. However, it was higher than general population in physical and mental composite scales (p=0.013 and p=0.001 respectively). CONCLUSIONS: The health related quality of life improved significantly at 6 and 12 months after renal transplantation, achieving equated healthy population and general population. PMID- 26020669 TI - [Effect of pravastatine plus ezetimibe on carotid intima media thickness in patients with lupus erythematosus]. AB - BACKGROUND: Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis that can be assessed by the carotid intima media thickness (CIMT) measurement. A prompt hypolipidemic treatment should be a part of the integral management. The aim of this study is to determine the effect of therapy with pravastatin plus ezetimibe on the CIMT in SLE patients. METHODS: Longitudinal, prospective, quasi-experimental trial. Out of 60 SLE patients in whom a carotid ultrasound was performed, we chose 22 with a CIMT>0.7 mm who were administered pravastatin plus ezetimibe during 6 months with determination of CIMT at the end of the study. We performed the following tests: total cholesterol (TC), HDL cholesterol, LDL-cholesterol, tryglicerides, C-reactive protein (CRP), liver function, muscle enzimes and glucose, basal and at the end of treatment. STATISTICAL ANALYSIS: descriptive statistics and Wilcoxon test were used. RESULTS: There were 22 women with an age of 42+/-6.3 years, average disease evolution 7.5+/-6.6 years, of whom, 18 concluded the study. Right basal CIMT was 0.829+/-0.1448 vs. final 0.688+/-0.1453, p<0.003; left CIMT was 0.820+/-0.1312 vs. 0.724+/-0.1348, p<0.004. TC 208 mg/dl vs 168 mg/dl, LDL-C 125 mg/dl vs. 72 mg/dl, p=0.0004. CRP 3.12 vs. 2.25 p=0.004. In 2 cases there were gastrointestinal, skin and muscle adverse effects. CONCLUSIONS: Treatment with pravastatin plus ezetimibe decreases the CIMT with improvement in the concentration of total cholesterol, LDL-C and CRP levels with good toleration. PMID- 26020670 TI - [Invasive management of trigeminal neuralgia. 8 years experience]. AB - BACKGROUND: Trigeminal neuralgia (TN) is characterized by stereotyped repetitive, unilateral pain, referred as an electric shock, triggered by the stimulation of the rami of the trigeminy nerve. It presents more frequently in women. The aim is to know the efficacy of surgical treatment of TN against pain by means of microvascular decompressive technics (MDT) and balloon percutaneous microcompression (BPM). METHODS: A retrospective study was performed from January 2005 to January 2013, including 73 patients treated for TN. Sixty patients from group 1 (82 %) were treated with MDT, and 13 from group 2 with BPM. We evaluated the presence of pain in patients during the immediate postoperative period, and at 1, 3 and 5 years. RESULTS: 55 female patients and 18 male patients were included. The mean age of presentation for TN was 55 years. In group 1 there was pain remission in the immediate postoperative period in 95% of the cases, in 92% at one year, 91% at 3 years and 88% at 5 years; in group 2 in 85%, 84%, 84% and 70%, respectively. There were no lethal complications in 6.5% in group 1 and in 28% in group 2. CONCLUSIONS: The two therapeutic procedures reduced pain of TN in a long term in most patients. Our results show high and perdurable resolution of the pain with negligible morbimortality. PMID- 26020671 TI - [Frequency, clinical evolution and prognosis of toxic megacolon]. AB - INTRODUCTION: Toxic megacolon (MT) is a potentially lethal complication of inflammatory, ischemic and infectious colitis. Usually it is related to ulcerative nonspecific colitis or Crohn disease. Recently it has been observed an increased in pseudomembranous colitis as cause of TM. The aim of this study is to describe the frequency, clinical evolution and prognosis of patients with TM. METHODS: Retrospective study, from January 2009 to January 2014 1500 patients were hospitalized in the Department of Coloproctology. We included 13 of 1500 patients with diagnosis of TM according to Jalan criteria and surgically corroborated. To determine the averages descriptive statistics was used. RESULTS: We studied 13 patients with TM (79.9% male and 20.1% female), the average age was 47.69+/-18.3 years. The most frequently associated diseases were: nonspecific ulcerative colitis (30.8%), pseudomembranous colitis (30.8%), neutropenic colitis (23.1%), Crohn Disease (7.7%) and ischemic colitis (7.7%). Subtotal colectomy plus terminal ileostomy was done in 84.6%, extended right hemicolectomy with ileostomy plus mucous fistula in 7.7% and extended right hemicolectomy with ileostomy plus Hartmann pouch in 7.7%. The mortality was 61.5%. The prevalence in the 5 years was 13 of 1500 (0.86%) patients. CONCLUSIONS: The prevalence of TM is low with a high mortality. A prompt diagnosis and treatment can improve the poor prognosis in these patients. PMID- 26020672 TI - [The cord blood bank at the Instituto Mexicano del Seguro Social]. AB - BACKGROUND: Hematopoietic stem cells have been used for over 50 years in the treatment of diverse diseases. Umbilical cord blood (UCB) has proved to be a viable source of hematopoietic stem cells for transplantation purposes. The aim was to report the contribution of the umbilical cord blood bank over the past 9 years, in the treatment of various diseases. METHODS: Since 2005 the number of units of blood from the umbilical cord and their use for transplantation in diverse disease were analyzed. A selection of volunteer pregnant women in labor was performed. Umbilical cord blood was obtained from them, which underwent processing, cryopreservation and validation, as well as compatibility test before using for transplantation. RESULTS: Ten thousand and ninety nine candidates to donation were assessed, from whom 2481 unit of UCB were collected. Of these, 893 unit were processed and cryopreserved for transplantation. In 65% of cases there was histocompatibility between the cord cell and the receptors. Transplantation was done in 87 patients, 67% had hematologic neoplasias, who have received 140 units of UCB in 102 transplants. This Bank of UCB ranks second in the world in productivity according to the rate of utility of units in transplantation (3.3%). CONCLUSIONS: Our bank of UCB has been able to develop a cell line (hematopoietic stem cells) with international quality standards and has been beneficial for patients served by our institution with need of a transplant mainly in hemato oncologic patients. PMID- 26020678 TI - Combining Stable Isotope Labeling and Molecular Networking for Biosynthetic Pathway Characterization. AB - Filamentous fungi are a rich source of bioactive compounds, ranging from statins over immunosuppressants to antibiotics. The coupling of genes to metabolites is of large commercial interest for production of the bioactives of the future. To this end, we have investigated the use of stable isotope labeled amino acids (SILAAs). SILAAs were added to the cultivation media of the filamentous fungus Aspergillus nidulans for the study of the cyclic tetrapeptide nidulanin A. Analysis by UHPLC-TOFMS confirmed that the SILAAs were incorporated into produced nidulanin A, and the change in observed m/z could be used to determine whether a compound (known or unknown) incorporated any of the added amino acids. Samples were then analyzed using MS/MS and the data used to perform molecular networking. The molecular network revealed several known and unknown compounds that were also labeled. Assisted by the isotope labeling, it was possible to determine the sequence of several of the compounds, one of which was the known metabolite fungisporin, not previously described in A. nidulans. Several novel analogues of nidulanin A and fungisporin were detected and tentatively identified, and it was determined that these metabolites were all produced by the same nonribosomal peptide synthase. The combination of stable isotope labeling and molecular network generation was shown to very effective for the automated detection of structurally related nonribosomal peptides, while the labeling was effective for determination of the peptide sequence, which could be used to provide information on biosynthesis of bioactive compounds. PMID- 26020673 TI - Response to fluid boluses in the fluid and catheter treatment trial. AB - BACKGROUND: Recent emphasis has been placed on methods to predict fluid responsiveness, but the usefulness of using fluid boluses to increase cardiac index in critically ill patients with ineffective circulation or oliguria remains unclear. METHODS: This retrospective analysis investigated hemodynamic responses of critically ill patients in the ARDS Network Fluid and Catheter Treatment Trial (FACTT) who were given protocol-based fluid boluses. Fluid responsiveness was defined as >= 15% increase in cardiac index after a 15 mL/kg fluid bolus. RESULTS: A convenience sample of 127 critically ill patients enrolled in FACTT was analyzed for physiologic responses to 569 protocolized crystalloid or albumin boluses given for shock, low urine output (UOP), or low pulmonary artery occlusion pressure (PAOP). There were significant increases in mean central venous pressure (9.9 +/- 4.5 to 11.1 +/- 4.8 mm Hg, P < .0001) and mean PAOP (11.6 +/- 3.6 to 13.3 +/- 4.3 mm Hg, P < .0001) following fluid boluses. However, there were no significant changes in UOP, and there were clinically small changes in heart rate, mean arterial pressure, and cardiac index. Only 23% of fluid boluses led to a >= 15% change in cardiac index. There was no significant difference in the frequency of fluid responsiveness between boluses given for shock or oliguria vs boluses given only for low PAOP (24.0% vs 21.8%, P = .59). There were no significant differences in 90-day survival, need for hemodialysis, or return to unassisted breathing between patients defined as fluid responders and fluid nonresponders. CONCLUSIONS: In this cohort of critically ill patients with ARDS who were previously resuscitated, the rate of fluid responsiveness was low, and fluid boluses only led to small hemodynamic changes. PMID- 26020680 TI - A Highly Stereoselective Metal-Free Hydrogenation of Diimines for the Synthesis of Cis-Vicinal Diamines. AB - A highly stereoselective metal-free hydrogenation of vicinal diimines has been successfully realized for the first time using 5-10 mol % of Piers' borane as a catalyst under mild conditions, and a variety of cis-1,2-diamines were obtained in 92-99% yields. The current work provides a novel and efficient approach for the synthesis of vicinal diamines. PMID- 26020679 TI - Gene Regulation by the LiaSR Two-Component System in Streptococcus mutans. AB - The LiaSR two-component signal transduction system regulates cellular responses to several environmental stresses, including those that induce cell envelope damages. Downstream regulons of the LiaSR system have been implicated in tolerance to acid, antibiotics and detergents. In the dental pathogen Streptococcus mutans, the LiaSR system is necessary for tolerance against acid, antibiotics, and cell wall damaging stresses during growth in the oral cavity. To understand the molecular mechanisms by which LiaSR regulates gene expression, we created a mutant LiaR in which the conserved aspartic acid residue (the phosphorylation site), was changed to alanine residue (D58A). As expected, the LiaR-D58A variant was unable to acquire the phosphate group and bind to target promoters. We also noted that the predicted LiaR-binding motif upstream of the lia operon does not appear to be well conserved. Consistent with this observation, we found that LiaR was unable to bind to the promoter region of lia; however, we showed that LiaR was able to bind to the promoters of SMU.753, SMU.2084 and SMU.1727. Based on sequence analysis and DNA binding studies we proposed a new 25-bp conserved motif essential for LiaR binding. Introducing alterations at fully conserved positions in the 25-bp motif affected LiaR binding, and the binding was dependent on the combination of positions that were altered. By scanning the S. mutans genome for the occurrence of the newly defined LiaR binding motif, we identified the promoter of hrcA (encoding a key regulator of the heat shock response) that contains a LiaR binding motif, and we showed that hrcA is negatively regulated by the LiaSR system. Taken together our results suggest a putative role of the LiaSR system in heat shock responses of S. mutans. PMID- 26020681 TI - Tragedy or tragicomedy: Mixed feelings induced by positive and negative emotional events. AB - Based on the theory of appraisal, we predicted that positive and negative events happening to the same people or things in a specific chronological order (i.e., a negative event following a positive event) would induce different mixed feelings than the same events happening to different people or things. Pairs of emotional pictures with different captions were used to create two event groups. In the "tragic event" group, the positive and negative events happened to the same person or things, and in the "tragicomic event" group, the positive and negative events happened to different people or things. We designed two experiments to explore and compare the generation of mixed feelings in those two groups. In Experiment 1, the negative event was shown first, and in Experiment 2, the negative event was shown second (although the chronological order of the depicted events was the same). The participants were 381 undergraduates: 195 in Experiment 1 and 186 in Experiment 2. In both experiments, we found that tragic events introduced less intense mixed feelings than did tragicomic events due to fewer pleasurable feelings induced by the tragic events. There was no significant difference in the report of negative emotions between the groups. Appraisal theory and negative bias effects may explain these results. PMID- 26020682 TI - Ambient Facile Synthesis of Gram-Scale Copper Selenide Nanostructures from Commercial Copper and Selenium Powder. AB - Grams of copper selenides (Cu(2-x)Se) were prepared from commercial copper and selenium powders in the presence of thiol ligands by a one-pot reaction at room temperature. The resultant copper selenides are a mixture of nanoparticles and their assembled nanosheets, and the thickness of nanosheets assembled is strongly dependent on the ratio of thiol ligand to selenium powder. The resultant Cu(2 x)Se nanostructures were treated with hydrazine solution to remove the surface ligands and then explored as a potential thermoelectric candidate in comparison with commercial copper selenide powders. The research provides a novel ambient approach for preparation of Cu(2-x)Se nanocrystallines on a large scale for various applications. PMID- 26020683 TI - Corticosteroids in the treatment of community-acquired pneumonia: an evidence summary. AB - A strong inflammatory response to community-acquired pneumonia (CAP) is associated with excess morbidity and mortality. There is a growing interest in corticosteroids as an adjunctive treatment for patients hospitalized with CAP. We review recent randomized trials addressing the use of corticosteroids across the full range of CAP patients. Thirteen randomized controlled trials including 2005 patients have addressed the effect of short-term (single dose to 10 days) corticosteroid administration in patients with CAP. The results consistently show a shorter time to clinical stability and a shorter length of hospital stay on the order of 1 day. Some studies have also suggested a possible reduction in mortality. Adverse effects, primarily hyperglycemia and neuropsychiatric symptoms, are uncommon and neither serious nor prolonged. The results indicate a possibility that steroid administration should become a standard of care for patients with CAP. PMID- 26020684 TI - Reactions in Nitroimidazole and Methylnitroimidazole Triggered by Low-Energy (0-8 eV) Electrons. AB - Low-energy electrons (0-8 eV) effectively decompose 4-nitroimidazole (4NI) and the two methylated isomers 1-methyl-5-nitroimidazole and 1-methyl-4 nitroimidazole via dissociative electron attachment (DEA). The involved unimolecular decompositions range from simple bond cleavages (loss of H(*), formation of NO2(-)) to complex reactions possibly leading to a complete degradation of the target molecule (formation of CN(-), etc.). At energies below 2 eV, the entire rich chemistry induced by DEA is completely quenched by methylation, as demonstrated in a previous communication (Tanzer, K.; Feketeova, L.; Puschnigg, B.; Scheier, P.; Illenberger. E.; Denifl, S. Angew. Chem., Int. Ed. 2014, 53, 12240). The observation that in 4NI neutral radicals and radical anions are formed via DEA at high efficiency already at threshold (0 eV) may have significant implications for the development of nitroimidazole-based radiosensitizers in tumor radiation therapy. PMID- 26020685 TI - Noninvasive and Reversible Cell Adhesion and Detachment via Single-Wavelength Near-Infrared Laser Mediated Photoisomerization. AB - Dynamically regulating cell-molecule interactions is fundamental to a variety of biological and biomedical applications. Herein, for the first time, by utilizing spiropyran conjugated multishell upconversion nanoparticles (UCNPs) as a new generation of single-wavelength near-infrared (NIR)-controlled photoswitch, we report a simple yet versatile strategy for controlling cell adhesion/detachment reversibly and noninvasively. Specifically, the two-way isomerization of the photoswitch was merely dependent on the excitation power density of the 980 nm laser. At high power density, the ring-opening was prominent, whereas its reverse ring-closing process occurred upon irradiation by the same laser but with the lower power density. Such transformations made the interactions between spiropyran and cell surface protein fibronectin switchable, thus leading to reversible cell adhesion and detachment. Moreover, efficient adhesion-and detachment of cells could be realized even after 10 cycles. Most importantly, the utilization of NIR not only showed little damage toward cells, but also improved penetration depth. Our work showed promising potential for in vivo dynamically manipulating cell-molecule interactions and biological process. PMID- 26020686 TI - Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors. AB - Cleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities of the active sites and paved the way for the rational design of high-affinity proteasome inhibitors. However, details of cleavage preferences remained enigmatic due to the lack of appropriate structural data. In a unique approach, we here systematically examined substrate specificities of yeast and human proteasomes using irreversibly acting alpha',beta'epoxyketone (ep) inhibitors. Biochemical and structural analyses provide unique insights into the substrate preferences of the distinct active sites and highlight differences between proteasome types that may be considered in future inhibitor design efforts. (1) For steric reasons, epoxyketones with Val or Ile at the P1 position are weak inhibitors of all active sites. (2) Identification of the beta2c selective compound Ac-LAE-ep represents a promising starting point for the development of compounds that discriminate between beta2c and beta2i. (3) The compound Ac-LAA-ep was found to favor subunit beta5c over beta5i by three orders of magnitude. (4) Yeast beta1 and human beta1c subunits preferentially bind Asp and Leu in their S1 pockets, while Glu and large hydrophobic residues are not accepted. (5) Exceptional structural features in the beta1/2 substrate binding channel give rise to the beta1 selectivity of compounds featuring Pro at the P3 site. Altogether, 23 different epoxyketone inhibitors, five proteasome mutants, and 43 crystal structures served to delineate a detailed picture of the substrate and ligand specificities of proteasomes and will further guide drug development efforts toward subunit-specific proteasome inhibitors for applications as diverse as cancer and autoimmune disorders. PMID- 26020687 TI - The Degradation of Mitomycin C Under Various Storage Methods. AB - PURPOSE: To compare the effects of common pharmacy preparation and storage conditions on the stability of mitomycin C (MMC) in solution. METHODS: We used C18 reversed-phase high-performance liquid chromatography to determine the stability of 0.4 mg/mL MMC solutions, and liquid chromatography-electrospray ionization-mass spectrometry to identify degradation products. Conditions compared were: compounding and storage by refrigeration (1 and 2 wk), freezing (23 d), shipment "on-ice" (1 mo frozen followed by 1-wk refrigeration), and immediately compounding dry powder (Mitosol; Mobius Therapeutics LLC). We tested 3 samples for each storage method when samples reached room temperature (time 0), and then 1, 4, and 24 hours later. We used MMC peak area as a percentage of total (MMC plus degradants) area detected with high-performance liquid chromatography as a measure of stability. RESULTS: We assessed MMC stability for 5 preparation and storage methods at 4 timepoints (with n=3 per timepoint). At time 0, we found similar stabilities for MMC (F=0.72, P=0.599) between all 5 storage methods: 1 week refrigerated (97.9+/-0.2%), dry powder (97.5+/-0.3%), 2-week refrigerated (96.9+/-0.2%), 23-day frozen (96.7+/-3.1%), and shipment on-ice (96.0+/-1.2%). However, MMC demonstrated significant degradation over a 24-hour period with 2 week refrigeration (95.7+/-0.3%, beta=-0.1%/h, P<0.001) and shipment on-ice (93.1+/-1.8%, beta=-0.1%/h, P=0.013). We identified small amounts (<3.2%) of 2 degradants, cis-hydroxymitosene and trans-hydroxymitosene, across all samples. CONCLUSIONS: The different preparation and storage methods of MMC showed similar stability when used immediately upon reaching room temperature. However, degradation of MMC occurred with further storage at room temperature. The clinical implication of small amounts of MMC degradants is unclear. PMID- 26020688 TI - Evaluation of Corneal Biomechanical Properties in Patients With Thyroid Eye Disease Using Ocular Response Analyzer. AB - PURPOSE: To assess variations in the corneal biomechanical properties in thyroid eye disease (TED) patients using ocular response analyzer (ORA). PATIENTS AND METHODS: In this observational cross-sectional study, 75 patients with TED and 57 healthy subjects were enrolled. The mean age of the patients and healthy subjects were 47.50+/-1.55 and 43.6+/-1.23 years, respectively (P=0.06). All study participants underwent comprehensive ophthalmologic examination, Goldmann applanation tonometry (GAT), corneal pachymetry, and corneal biomechanical analysis using ORA. Corneal hysteresis (CH), corneal resistance factor (CRF), cornea-compensated IOP value (IOPcc), and Goldmann-corrected IOP value (IOPg) were measured with ORA. RESULTS: Central corneal thickness (CCT) in patients group (536.18+/-36.20 MUm) and control group (539.22+/-28.83 MUm) were not significantly different (P=0.1). In TED group, the IOPcc (20.23+/-0.54 mm Hg) was significantly higher than both IOP-GAT (17.54+/-0.49 mm Hg, P<0.001) and IOPg (18.35+/-0.52, P<0.001). CH in TED patients (9.01+/-0.20) was significantly lower compared with CH in healthy subjects (10.45+/-0.21) (P<0.001). Although CRF was lower in TED patients (10.06+/-0.16) in comparison with normal subjects (10.42+/ 0.29), this difference was not statistically significant (P=0.25). Both CH and CRF were positively correlated with CCT (r=0.52, P<0.001 and r=0.62, P<0.001, respectively) in TED group. CONCLUSIONS: In TED patients, CH seems to be lower than in normal subjects. GAT might underestimate the IOP due to differences in corneal properties of cornea in TED patients. PMID- 26020689 TI - Evaluation of the Retinal Nerve Fiber Layer Thickness, the Mean Deviation, and the Visual Field Index in Progressive Glaucoma. AB - PURPOSE: To determine and compare the retinal nerve fiber layer (RNFL) thickness, the mean deviation, and the visual field index (VFI) in glaucoma cases with progression detected by spectral domain optical coherence tomography, standard automated perimetry (SAP), and optic disc stereophotographs. METHODS: The authors studied 246 eyes of 148 patients prospectively (97 glaucoma cases, 132 suspects, and 17 healthy eyes). SAP fields, optical coherence tomography (OCT) images, and optic disc stereophotographs were obtained every 6 to 12 months. Progression was determined in SAP and in OCT with a Glaucoma Progression Analysis software, and also by masked assessment of the stereophotograph series. The Kruskal-Wallis test was applied to evaluate differences between methods in RNFL thickness, visual field (VF) mean deviation, and VFI. The relationship between the baseline classification and the detection of glaucomatous progression by the different tests was assessed by the chi statistic. RESULTS: Ninety-nine eyes (40.2%) presented glaucomatous progression detected by at least 1 examination method. Progressing eyes detected only by OCT had a higher mean RNFL thickness and mean VFI than progressing eyes detected only by VF or stereophotographs (P<0.003). Most progressive cases detected by OCT (68%) were initially classified at baseline as suspects, whereas most eyes with VF progression (61%) were initially classified as glaucoma. The initial classification was significantly related to the presence of progression by different tests [chi (2)=9.643 for VF event analysis and 7.290 for OCT event analysis (P<0.005)]. CONCLUSIONS: Different tests are more likely to detect the progression in different clinical circumstances or stages of glaucoma; these should be taken into consideration when performing the difficult task of progression detection. PMID- 26020690 TI - Endoscopic Cyclophotocoagulation and Pars Plana Ablation (ECP-plus) to Treat Refractory Glaucoma. AB - PURPOSE: To report clinical outcomes after pars plana endoscopic cyclophotocoagulation of the ciliary processes and pars plana (ECP-plus), a novel treatment for refractory glaucoma. DESIGN: Retrospective, noncomparative interventional case series. MATERIALS AND METHODS: SETTING: multicenter tertiary referral academic and clinical practice. STUDY POPULATION: fifty-three eyes of 53 consecutive subjects undergoing ECP-plus who had uncontrolled intraocular pressure (IOP) despite prior glaucoma surgeries and maximally tolerated medical therapy. OBSERVATION PROCEDURE: retrospective analysis of clinical data after ECP plus and pars plana vitrectomy. MAIN OUTCOME MEASURES: primary outcome was IOP at 6 and 12 months. Secondary outcomes were number of glaucoma medications and postoperative complications. RESULTS: Diagnoses were primary open-angle glaucoma (32%), chronic angle-closure glaucoma (26%), and secondary open-angle glaucoma (OAG, 42%); 50/53 of subjects had 6 months' and 28/53 had 12 months' follow-up data. Preoperative IOP was 27.9+/-7.5 mm Hg (mean+/-SD). Postoperative IOP at 6 mo was 10.2+/-5.6 and at 12 mo was 10.7+/-5.2 lower than preoperative levels (all P<0.0001). Cumulative treatment success was 81% at 6 mo and 78% at 12 mo. Number of medications fell from 3.4+/-1.2 pretreatment to 0.8+/-1.0 at 1 to 6 mo and 0.7+/-1.2 at 12 mo postoperatively (all P<0.0001). Complications in the initial postoperative period (<3 mo) were hypotony (3/53, 6%), fibrinous uveitis (2/53, 4%), and cystoid macular edema without hypotony (CME; 4/53, 6%). Complications beyond 6 mo occurred in 8/50 (16%) subjects as hypotony (4/50, 8%), choroidal detachment (4/50, 3 with IOP<5 and 1 with IOP>=5; 8%), CME without hypotony (3/50, 6%), and failed corneal graft (1/50, 2%). CONCLUSIONS: The mean IOP was lowered by at least 61% after ECP-plus and IOP lowering was sustained over the follow-up period. Fewer glaucoma medications were needed. Complication rates were comparable with or slightly higher than anterior endoscopic cyclophotocoagulation and acceptable given the refractory nature of disease being treated. PMID- 26020691 TI - Rod Packing in Chiral Nematic Cellulose Nanocrystal Dispersions Studied by Small Angle X-ray Scattering and Laser Diffraction. AB - The packing of cellulose nanocrystals (CNC) in the anisotropic chiral nematic phase has been investigated over a wide concentration range by small-angle X-ray scattering (SAXS) and laser diffraction. The average separation distance between the CNCs and the average pitch of the chiral nematic phase have been determined over the entire isotropic-anisotropic biphasic region. The average separation distances range from 51 nm, at the onset of the anisotropic phase formation, to 25 nm above 6 vol % (fully liquid crystalline phase) whereas the average pitch varies from ~15 MUm down to ~2 MUm as phi increases from 2.5 up to 6.5 vol %. Using the cholesteric order, we determine that the twist angle between neighboring CNCs increases from about 1 degrees up to 4 degrees as phi increases from 2.5 up to 6.5 vol %. The dependence of the twisting on the volume fraction was related to the increase in the magnitude of the repulsive interactions between the charged rods as the average separation distance decreases. PMID- 26020692 TI - Unusual Concentration Induced Antithermal Quenching of the Bi(2+) Emission from Sr2P2O7:Bi(2.). AB - The resistance of a luminescent material to thermal quenching is essential for the application in high power LEDs. Usually, thermal luminescence quenching becomes more and more serious as the activator concentration increases. Conversely, we found here that a red phosphor Sr2P2O7:Bi(2+) is one of the exceptions to this as we studied the luminescence properties at low (10-300 K) and high (300-500 K) temperatures. As Bi(2+) ions are incorporated into Sr2P2O7, they exhibit the emissions at ~660 and ~698 nm at room temperature and are encoded, hereafter, as Bi(1) and Bi(2) due to the substitutions for two different crystallographic sites Sr(1) and Sr(2), respectively, in the compound. However, they will not substitute for these sites equally. At lower dopant concentration, they will occupy preferentially Sr(2) sites partially due to size match. As the concentration increases, more Bi(2+) ions start to occupy the Sr(1) sites. This can be verified by the distinct changes of emission intensity ratio of Bi(2) to Bi(1). As environment temperature increases, the thermal quenching happens, but it can be suppressed by the Bi(2+) concentration increase. This becomes even more pronounced in Bi(2+) heavily doped sample as we decompose the broad emission band into separated Bi(1) and Bi(2) Gaussian peaks. For the sample, the Bi(1) emission at ~660 nm even shows antithermal-quenching particularly at higher temperatures. This phenomenon is accompanied by the blue shift of the overall emission band and almost no changes of lifetimes. A mechanism is proposed due to volume expansion of the unit cell, the increase of Bi(1) content, and temperature dependent energy transfer between Bi(2) and Bi(1). This work helps us better understand the complex luminescent behavior of Bi(2+) doped materials, and it will be helpful to design in the future the heavily doped phosphor for WLEDs with even better resistance to thermal quenching. PMID- 26020693 TI - Cellular superresolved imaging of multiple markers using temporally flickering nanoparticles. AB - In this paper we present a technique aimed for simultaneous detection of multiple types of gold nanoparticles (GNPs) within a biological sample, using lock-in detection. We image the sample using a number of modulated laser beams that correspond to the number of GNP species that label a given sample. The final image where the GNPs are spatially separated is obtained computationally. The proposed method enables the simultaneous superresolved imaging of different areas of interest within biological sample and also the spatial separation of GNPs at sub-diffraction distances, making it a useful tool in the study of intracellular trafficking pathways in living cells. PMID- 26020695 TI - Response to Comment on "UV disinfection induces a Vbnc state in Escherichia coli and Pseudomonas aeruginosa". PMID- 26020694 TI - Photouncaged Sequence-specific Interstrand DNA Cross-Linking with Photolabile 4 oxo-enal-modified Oligonucleotides. AB - DNA cross-linking technology is an attractive tool for the detection, regulation, and manipulation of genes. In this study, a series of photolabile 4-oxo-enal modified oligonucleotides functionalized with photosensitive omicron-nitrobenzyl derivatives were rationally designed as a new kind of photocaged cross-linking agents. A comprehensive evaluation of cross-linking reactions for different nucleobases in complementary strands under different conditions suggested that the modified DNA oligonucleotides tended to form interstrand cross-linking to nucleobases with the potential of thymidine > guanosine " cytidine ~ adenosine. Different from previous literature reports that cytidine and adenosine were preferential cross-linked nucleobases with 4-oxo-enal moieties, our study represents the first example of DNA cross-linking for T and G selectivity using 4 oxo-enal moiety. The cross-linked adducts were identified and their cross-linking mechanism was also illustrated. This greatly expands the applications of 4-oxo enal derivatives in the studies of DNA damage and RNA structure. PMID- 26020696 TI - The surface stability of Cr2O3(0 0 0 1). AB - The surface of chromia (Cr2O3) has a surface electronic structure distinct from the bulk and a packing density distinct from the bulk. More than a demarcation between the solid and the vacuum, the surface differs from the bulk of chromia, not just because of a partial occupancy of chromium sites, but also because of an increased number of unoccupied surface oxygen sites (vacancy sites), evident in angle-resolved core level photoemission. In spite of the structural differences that exist at the surface, there is, as yet, no evidence that these complications affect the surface Debye temperature beyond the most simple of assumptions regarding the lower coordination of the surface. Using low-energy electron diffraction (LEED), the effective surface Debye temperature (~490 K) is found to be lower than the bulk (~645 K) Debye temperature of Cr2O3(0 0 0 1). This surface effective Debye temperature, indicative of vibrations along the surface normal, uncorrected for anharmonic effects, has a value reduced from the effective bulk Debye temperature yet close to the value ?2 expected from a simple mean field argument. PMID- 26020697 TI - Which method to use for a fast assessment of body fat percentage? AB - Body position affects body water distribution and in turn the accuracy of bioelectrical impedance analysis (BIA), which may consequently distort conclusions about an individual's body composition.We compared body fat percentage (BFP) obtained with leg-to-leg-BIA (LL) and hand-to-leg-BIA (HL) with the reference values.The BFPs of 97 individuals were determined with an LL- (Tanita TBF 215GS, Japan) and HL- (Akern, STA/BIA, Italy) BIA-analyser and with reference skinfold thickness (SF) measurements. Each subject was measured upright with the LL-analyser, and upright and supine with the HL-analyser, both before and after 20 min of supine rest. The one-way ANOVA for repeated measures (HL BIA), Student's t-test (LL-BIA), intraclass correlation coefficients, and Bland Altman's plots were used for statistical analysis.BFPs determined with HL/LL BIA in upright/supine positions differ significantly. Compared to the SF method, HL BIA mostly overestimates, while LL-BIA mostly underestimates BFP. Agreement between anthropometrically determined BFP and HL/LL-BIA determined BFP is better with HL for both sexes, and generally better in females than males.HL-BIA determined estimates of BFP are more similar to reference values than LL-BIA. However, for both BIA methods, BIA-determined estimates of BFP are significantly affected by body position. Consequently, different BIA methods will classify approximately one fifth of subjects into the erroneous body-fat-content category, which calls for urgent standardization. PMID- 26020698 TI - A Comparison of In-House Real-Time LAMP Assays with a Commercial Assay for the Detection of Pathogenic Bacteria. AB - Molecular detection of bacterial pathogens based on LAMP methods is a faster and simpler approach than conventional culture methods. Although different LAMP-based methods for pathogenic bacterial detection are available, a systematic comparison of these different LAMP assays has not been performed. In this paper, we compared 12 in-house real-time LAMP assays with a commercialized kit (Isothermal Master Mix) for the detection of Listeria monocytogenes, Salmonella spp, Staphylococcus aureus, Escherichia coli O157, E. coli O26, E. coli O45, E. coli O103, E. coli O111, E. coli O121, E. coli O145 and Streptococcus agalactiae. False-positive results were observed in all 12 in-house real-time LAMP assays, while all the negative controls of Isothermal Master Mix remained negative after amplification. The detection limit of Isothermal Master Mix for Listeria monocytogenes, Salmonella spp, Staphylococcus aureus, Escherichia coli O157, E. coli O26, E. coli O45, E. coli O103, E. coli O111, E. coli O121 and Streptococcus agalactiae was 1 pg, whereas the sensitivity of the commercialized kit for E. coli O145 was 100 pg. In conclusion, the 12 in-house real-time LAMP assays were impractical to use, while the commercialized kit Isothermal Master Mix was useful for the detection of most bacterial pathogens. PMID- 26020699 TI - Enhanced supersaturation and oral absorption of sirolimus using an amorphous solid dispersion based on Eudragit(r) e. AB - The present study aimed to investigate the effect of Eudragit(r) E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 MUg/mL within 0.5 h that gradually decreased to 173.4 MUg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications. PMID- 26020700 TI - Reply: Intralesional Cryotherapy for the Treatment of Keloid Scars: A Prospective Study. PMID- 26020701 TI - Intralesional Cryotherapy for the Treatment of Keloid Scars: A Prospective Study. PMID- 26020702 TI - Reply: Pedicled Free-Style Perforator Flaps for Trunk Reconstruction: A Reliable Method. PMID- 26020703 TI - Pedicled Free-Style Perforator Flaps for Trunk Reconstruction: A Reliable Method. PMID- 26020704 TI - Prospective Randomized Comparison of Scar Appearances between Cograft of Acellular Dermal Matrix with Autologous Split-Thickness Skin and Autologous Split Thickness Skin Graft Alone for Full-Thickness Skin Defects of the Extremities. PMID- 26020705 TI - Reply: Risk of Adverse Outcomes When Plastic Surgery Procedures Are Combined. PMID- 26020706 TI - Reply: Prospective Randomized Comparison of Scar Appearances between Cograft of Acellular Dermal Matrix with Autologous Split-Thickness Skin and Autologous Split Thickness Skin Graft Alone for Full-Thickness Skin Defects of the Extremities. PMID- 26020707 TI - Endurance Times of the Thoracolumbar Musculature: Reference Values for Female Recreational Resistance Training Participants. AB - The assessment of thoracolumbar muscle endurance (TLME) is common among strength and conditioning professionals and clinicians desiring to quantify baseline muscle performance and determine injury risk. Reference values for such assessments are documented in the literature; however, their utility may be of limited value due to heterogeneous participant selection and limited demographic reporting. Moreover, active cohorts who engage in resistance training (RT) may reach a ceiling effect on existing reference values when testing routinely trained muscles. Thus, the purpose of this study was to establish reference values for standardized TLME tests among women who participate in recreational RT and to determine whether imbalances or asymmetries exist. Participants included 61 women aged 18-59 years who engaged in RT for at least 1 year. Flexor, extensor, and lateral flexor TLME was isometrically assessed using standardized procedures with documented reproducibility (r >= 0.93). Results identified significant differences (p < 0.001) between mean TLME times of flexors (163 +/- 106 seconds) and extensors (105 +/- 57 seconds). Left (66 +/- 38 seconds) and right side bridges (61 +/- 33 seconds) were comparable (p = 0.06). Flexor to extensor imbalances were more pronounced among RT participants when compared with previously reported general population reference values, suggesting a training effect or bias. Moreover, similar imbalances favoring the flexors are a documented risk factor for low back pain. Thus, training considerations inclusive of the extensors may benefit women who engage in RT as a means of mitigating risk. Individuals evaluating muscle performance should consider reference values that represent the population of interest. PMID- 26020708 TI - Acute Endocrine and Force Responses and Long-Term Adaptations to Same-Session Combined Strength and Endurance Training in Women. AB - This study examined acute hormone and force responses and strength and endurance performance and muscle hypertrophy before and after 24 weeks of same-session combined strength and endurance training in previously untrained women. Subjects were assigned 1 of 2 training orders: endurance preceding strength (E + S, n = 15) or vice versa (S + E, n = 14). Acute force and hormone responses to a combined loading (continuous cycling and a leg press protocol in the assigned order) were measured. Additionally, leg press 1 repetition maximum (1RM), maximal workload during cycling (Wmax), and muscle cross-sectional area (CSA) were assessed. Loading-induced decreases in force were significant (p < 0.01-0.001) before (E + S = 20 +/- 11%, S + E = 18 +/- 5%) and after (E + S = 24 +/- 6%, S + E = 22 +/- 8%) training. Recovery was completed within 24 hours in both groups. The acute growth hormone (GH) response was significantly (p < 0.001) higher after S + E than E + S at both weeks 0 and 24. Testosterone was significantly (p < 0.001) elevated only after the S + E loading at week 24 but was not significantly different from E + S. Both groups significantly (p < 0.001) improved 1RM (E + S = 13 +/- 12%, S + E = 16 +/- 10%), Wmax (E + S = 21 +/- 10%, S + E = 16 +/- 12%), and CSA (E + S = 15 +/- 10%, S + E = 11 +/- 8%). This study showed that the acute GH response to combined endurance and strength loadings was significantly larger in S + E compared with E + S both before and after 24 weeks of same-session combined training. Strength and endurance performance and CSA increased to similar extents in both groups during 24 weeks despite differences in the kinetics of GH. Previously untrained women can improve performance and increase muscle CSA using either exercise order. PMID- 26020709 TI - Effects of an Eight-Week Proprioceptive Neuromuscular Facilitation Stretching Program on Kicking Speed and Range of Motion in Young Male Soccer Players. AB - The aim of this study was to determine the effect of the 8-week proprioceptive neuromuscular facilitation (PNF) exercises that were carried out on lower extremity on kicking speed and range of motion (ROM) performance in young soccer players. Twenty-four soccer players (15.6 +/- 0.4 years) were selected from nonprofessional young soccer team. All players' height, weight, ROM (ankle plantar and dorsal flexions, hip flexions and extensions), and kicking speed tests were evaluated before and after 8 weeks. The participants were divided into PNF (n = 11) and control (n = 11) groups. Both groups continued technical and tactical soccer training together 3 days (120 min.d) a week. The PNF group attended additionally unassisted PNF-contract-relax (CR) stretching through 8 weeks, 2 days per week, 20 minutes' session duration. The control group did not participate in any additional PNF stretching sessions. There were significant differences in kicking speed, right ankle active dorsal flexion, and hip active flexion (right and left) (p <= 0.05) of the PNF group, whereas there were no significant differences between groups in left ankle active dorsal flexion, hip active extension (right and left), and ankle active plantar flexion (right and left) (p > 0.05). We conclude that an 8-week unassisted PNF-CR improved on the ROM of particular lower extremity joints and the kicking speed in the young male soccer players. These results provide strength and conditioning coaches with a practical way to use unassisted PNF-CR in warm-up for positive improvements in the ROM of the hip and ankle and the applications of the kicking speed. PMID- 26020710 TI - Use of Relative Speed Zones Increases the High-Speed Running Performed in Team Sport Match Play. AB - This study investigated the activity profiles of junior rugby league players competing in 3 distinct age groups (Under 13, 14, and 15), and 2 distinct playing standards (division 1 and 4). In addition, we reported global positioning system (GPS) data using predefined absolute speed thresholds and speed thresholds expressed relative to a players' individual peak velocity. Ninety male junior rugby league players, representing 1 of 6 teams competing in the Brisbane junior rugby league competition, underwent measurements of peak velocity (through a 40-m sprint) and GPS analysis during competitive matches. Data were described as both absolute speed zones and relative to the individual player's peak velocity. Absolute measures of moderate-, high-, and very high-speed running distances increased with age with the differences among groups typically small to moderate (effect size = 0.24-0.68) in magnitude. However, when data were expressed relative to a players' capacity, younger players and those from lower playing divisions exhibited higher playing intensities and performed greater amounts of high-intensity activity. Moderate and negative relationships (r = -0.43 to -0.46) were found between peak velocity and the amount of relative high-speed running performed. These findings suggest that individualization of velocity bands increases the high-speed running attributed to slower players and decreases the high-speed running attributed to faster players. From a practical perspective, consideration should be given to both the absolute and relative demands of competition to provide insight into training prescription and the recovery requirements of individual players. PMID- 26020711 TI - Optimum Drop Height for Maximizing Power Output in Drop Jump: The Effect of Maximal Muscle Strength. AB - The main purpose of this study was to explore the cause-and-effect relation of maximal muscle strength (MSmax) on the optimum drop height (DHopt) that maximizes power output in drop jump. In total, 30 physically active male students participated in this study, whereas the 16 subjects were selected according to their resistance strength training background (i.e., level of MSmax) and allocated into 2 equal subgroups: strong (n = 8) and weak (n = 8). The main testing session consisted of drop jumps performed from 8 different drop heights (i.e., from 0.12 to 0.82 m). The individual DHopt was determined based on the maximal value power output across applied ranges of drop heights. The tested relationships between DHopt and MSmax were moderate (r = 0.39-0.50, p <= 0.05). In addition, the stronger individuals, on average, showed maximal values of power output on the higher drop height compared with the weaker individuals (0.62 vs. 0.32 m). Finally, significant differences in the individual DHopt between groups were detected (p < 0.01). The present findings suggest that drop height should be adjusted based on a subject's neuromuscular capacity to produce MSmax. Hence, from the perspective of strength and conditioning practitioners, MSmax should be considered as an important factor that could affect the DHopt, and therefore should be used for its adjustment in terms of optimizing athlete's testing, training, or rehabilitation intervention. PMID- 26020712 TI - Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study. AB - Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Asberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (>=10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Asberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Delta-4.2), the Clinical Global Impression Scale-Severity of Illness (Delta-1.2), and the Sheehan Disability Scale (Delta-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period. PMID- 26020713 TI - Effects of long-term valproic acid treatment on hematological and biochemical parameters in adolescent psychiatric inpatients: a retrospective naturalistic study. AB - The objective of this study was to determine the long-term hematological and biochemical side effects of valproic acid (VPA) in psychiatric adolescent inpatients. A retrospective naturalistic study design was used. Participants were psychiatric inpatients treated with VPA, alone or in combination with other medications. Electronic medical files were reviewed for changes in hematological and biochemical parameters following a course of VPA treatment. One hundred and four adolescents aged 12-18 (mean 15.76+/-1.58) years fulfilled the study criteria. The mean blood level and duration of VPA treatment were 65.81+/-22.18 mcg/ml and 98.57+/-135.94 days, respectively. The mean levels of thyroid stimulating hormones and triglyceride levels increased significantly from the first to the last measurement. Platelet count decreased significantly following VPA treatment. No correlation was observed between these parameters and age, duration of treatment, or VPA levels. No serious adverse events were reported. Long-term VPA treatment in adolescents with psychiatric disorders is associated with significant increases in triglyceride levels. Moreover, VPA-treated adolescent psychiatric inpatients may be at risk of developing pituitary-thyroid axis dysregulation and decreased platelet count. Therefore, baseline measurement of thyroid functions and metabolic and hematological parameters and monitoring throughout the treatment are recommended. PMID- 26020714 TI - Treatment of Blepharospasm in Schwartz-Jampel Syndrome: Botulinum Toxin A Injection or Surgery. AB - Schwartz-Jampel syndrome is an autosomal recessive disease that comprises facial and musculoskeletal deformity. Hereby, the authors report 2 cases of Schwartz Jampel syndrome and surgical method of their management. The first case was a boy who was result of twin delivery whose sibling was completely normal. The second case was a girl who was the first child of her family. Both were born to a consanguineous marriage. Both had developed characteristic facial expressions of Schwartz-Jampel syndrome between 18 and 24 months of age. They had Botulinum toxin A injection (twice in the first and ones in the second case) with no improvement. Both were referred because of being functionally blind due to inability to open the eyelids around age 3.5 years. Orbicularis oculi myectomy, partial corrugator muscle excision, levator tucking, and lateral tarsal strip procedure was performed on both cases. No complication and no recurrence of eyelid contraction were observed after 4 years and 6 months follow up in the first and second case, respectively. PMID- 26020716 TI - Image-Guided Dacryolocalization (IGDL) in Traumatic Secondary Acquired Lacrimal drainage Obstructions (SALDO). AB - PURPOSE: The aim of this study was to illustrate the usefulness of stereotactic or image-guided navigation in the management of traumatic secondary acquired lacrimal drainage obstructions. METHODS: Image-guided dacryolocalization was performed on 3 patients. All the patients were posttraumatic nasolacrimal duct obstruction as a consequence of gross naso-orbito-ethmoid fractures. All the procedures were performed through an endoscopic endonasal approach using the intraoperative electromagnetic image-guided Fusion ENT navigation system. Intraoperative anatomical guidance in localizing the lacrimal drainage system, usefulness at crucial phases of surgery, ease of surgery, and complications were noted. RESULTS: All patients underwent a powered endoscopic dacryocystorhinostomy using standard protocols but with an additional intraoperative navigation use at each of the major steps during the surgery. The dacryolocalization provided useful anatomical clues while operating in the vicinity of orbit and skull base. The set up was quick with no additional technical difficulties. CONCLUSIONS: Image-guided dacryolocalization is a very useful adjunctive tool that facilitates safe and precise surgeries in otherwise challenging surgical situations. PMID- 26020715 TI - Recurrent Kimura Disease of the Inner Canthus With No Lymphadenopathy. AB - The Kimura disease is a benign rare inflammatory condition of the soft tissue, especially of the head and neck region presenting as painless nodule with or without lymphadenopathy. This condition with unknown etiology is seen mainly in Asian males, in their thirties. The authors' present a 39-year-old man with the Kimura disease in the inner canthus of his OS and no lymphadenopathy. The subcutaneous nodule was excised, and on histopathological study it was confirmed as the Kimura disease. He presented with a larger recurrence after 1 year. It was fixed to the underlying bone. Excision biopsy proved it to be the Kimura disease. To the authors' knowledge, this is the first report of the Kimura disease affecting ocular structures. The Kimura disease, although a rare condition, should be considered in the differential diagnosis of the primary and recurrent masses arising from the inner canthus of the eye. PMID- 26020717 TI - A Hyalinized Trichilemmoma of the Eyelid in a Teenager. AB - A 16-year-old African American male, the youngest patient to date, presented with a well-circumscribed upper eyelid lesion. On excision, the dermal nodule was contiguous with the epidermis, displayed trichohyalin-like bodies in an expanded outer root sheath, and was composed chiefly of small cellular clusters separated by a prominent network of periodic acid Schiff -positive hyaline bands of basement membrane material. The tumor cells were positive for high molecular weight cytokeratins (CK) 5/6, CK14, and CK34betaE12 and were negative for CK7, carcinoembryonic antigen and epithelial membrane antigen. Negative S100, glial fibrillary acidic protein, and smooth muscle actin immunoreactions ruled out a myoepithelial lesion. The Ki-67 proliferation index was <10%. The diagnosis was a hyalinized trichilemmoma, contrasting with the more common lobular type. As an isolated lesion, trichilemmoma does not portend Cowden syndrome. PMID- 26020718 TI - Demonstration of a Borst-Jadassohn-Like Phenomenon in Sebaceous Carcinoma of the Eyelid. AB - A 77-year-old male presented with a diffuse, papular erythematous conjunctival mass that demonstrated on pathologic examination lobules of tumor in the conjunctival substantia propria and tarsus. The cells displayed numerous cytoplasmic vacuoles with extreme nuclear pleomorphism, consistent with sebaceous carcinoma. The overlying palpebral conjunctival epithelium exhibited regions of carcinoma in situ containing some vacuolated cells, alternating with a more classical appearance of pagetoid spread among normal surviving keratinocytes. Further analysis disclosed vesicular positivity for adipophilin and positive nuclear staining for androgen receptor. One tumor focus harbored exaggerated collections of intraepithelial tumor cells. These simulated the Borst-Jadassohn phenomenon of large nests of alien appearing cells normally encountered within the epidermis of the skin. This is the first description of this pattern created by an eyelid sebaceous carcinoma growing within the conjunctival epithelium. PMID- 26020719 TI - Scanning Electron Microscopic Features of the External and Internal Surfaces of Normal Adult Lacrimal Drainage System. AB - AIM: The aim of this study was to examine the ultrastructural features of the external and internal surfaces of healthy lacrimal drainage systems. METHODS: A prospective interventional study was performed on the healthy adult lacrimal drainage systems obtained from fresh exenterated specimens. Exenteration was performed for malignancies unrelated to lacrimal system where preoperative lacrimal evaluation was normal. A careful and thorough dissection was carried out to isolate the entire lacrimal drainage system from the punctum to the nasolacrimal duct. The analysis was performed using the standard protocols of scanning electron microscopy. RESULTS: Inner punctal surfaces showed a definite and slightly elevated junction between the luminal surfaces of punctum and beginning of the vertical canaliculus. Similar junction could be identified between the lacrimal sac and nasolacrimal duct. The valves of the canaliculi showed broad rugae-like mucosal surfaces, whereas the external surfaces of the canaliculi demonstrated well-defined orbicularis muscle with collagenous attachments. The walls of the lacrimal sac and nasolacrimal duct showed dense vascular plexus which included wide luminal arteries, throttle veins, and large capacitance vessels. CONCLUSIONS: Ultrastructural features of external and internal surfaces of lacrimal drainage system help in better understanding of its anatomy and physiology. The junctional area between the punctum-vertical canaliculus and lacrimal sac-nasolacrimal duct needs further exploration to understand their roles. PMID- 26020720 TI - Recession and Extirpation of the Lower Eyelid Retractors for Paralytic Lagophthalmos. AB - PURPOSE: To describe a technique to correct lower eyelid malposition and lagophthalmos due to facial nerve palsy. METHODS: Chart review was performed and identified 13 patients with facial nerve palsy, who presented with paralytic eyelid malposition and were treated with recession and extirpation of the lower eyelid retractors between September 2012 and March 2014 by 1 surgeon (HBL). RESULTS: A total of 12 eyelids in 11 patients met inclusion criteria. Mean preoperative MRD2 was 10 mm (range, 9.0-12.0 mm) and the mean postoperative MRD2 was 7 mm (range, 5.0-9.0 mm). The MRD2 improved an average of 3.0 mm in each patient (range, 2.0-4.0 mm). Patients had an average of 6.9 mm (range, 4.0-10.0 mm) of lagophthalmos preoperatively, which improved to 2.1 mm (range, 0.0-4 mm). The amount of lagophthalmos improved an average of 4.8 mm in the patients. There were no complications encountered in the patients. All patients had a subjective improvement in ocular comfort. CONCLUSIONS: The authors' surgical technique is effective in addressing lower eyelid malposition and ocular surface disease in paralytic lagophthalmos. PMID- 26020721 TI - Spontaneous Giant Pseudomeningocele in the Middle Cranial Fossa as a Cause of Pulsatile Proptosis. AB - The authors report a case of a 70-year-old man who presented with a long history of left pulsatile proptosis, irritation, and a pressure sensation behind the eye. Initial computed tomography brain demonstrated the presence of a suspected ethmoid sinus mucocele. Endoscopic sinus surgery was performed to drain the mucocele. On cautious opening of the nasal mucosa, cerebrospinal fluid was encountered requiring subsequent repair with local mucosal flap and fat graft. On further magnetic resonance imaging, the lesion was confirmed to be giant pseudomeningocele arising from the sphenoid sinus, with extensive invasion and erosion of the middle cranial fossa including the left lateral orbital wall. Here, the authors report, to the best of their knowledge, the first case of spontaneous giant pseudomeningocele in the middle cranial fossa causing pulsatile proptosis. In examining this case, the authors will also discuss the pathogenesis, diagnosis, and management of giant pseudomeningoceles, especially in the situation of a misdiagnosis. PMID- 26020722 TI - Lean body mass correction of standardized uptake value in simultaneous whole-body positron emission tomography and magnetic resonance imaging. AB - This study explores the possibility of using simultaneous positron emission tomography--magnetic resonance imaging (PET-MRI) to estimate the lean body mass (LBM) in order to obtain a standardized uptake value (SUV) which is less dependent on the patients' adiposity. This approach is compared to (1) the commonly-used method based on a predictive equation for LBM, and (2) to using an LBM derived from PET-CT data. It is hypothesized that an MRI-based correction of SUV provides a robust method due to the high soft-tissue contrast of MRI. A straightforward approach to calculate an MRI-derived LBM is presented. It is based on the fat and water images computed from the two-point Dixon MRI primarily used for attenuation correction in PET-MRI. From these images, a water fraction was obtained for each voxel. Averaging over the whole body yielded the weight normalized LBM. Performance of the new approach in terms of reducing variations of (18)F-Fludeoxyglucose SUVs in brain and liver across 19 subjects was compared with results using predictive methods and PET-CT data to estimate the LBM. The MRI-based method reduced the coefficient of variation of SUVs in the brain by 41 +/- 10% which is comparable to the reduction by the PET-CT method (35 +/- 10%). The reduction of the predictive LBM method was 29 +/- 8%. In the liver, the reduction was less clear, presumably due to other sources of variation. In conclusion, employing the Dixon data in simultaneous PET-MRI for calculation of lean body mass provides a brain SUV which is less dependent on patient adiposity. The reduced dependency is comparable to that obtained by CT and predictive equations. Therefore, it is more comparable across patients. The technique does not impose an overhead in measurement time and is straightforward to implement. PMID- 26020723 TI - Occupational exposure to airborne contaminants during offshore oil drilling. AB - The aim was to study exposure to airborne contaminants in oil drillers during ordinary work. Personal samples were collected among 65 drill floor workers on four stationary and six moveable rigs in the Norwegian offshore sector. Air concentrations of drilling mud were determined based on measurements of the non volatile mud components Ca and Fe. The median air concentration of mud was 140 MUg m(-3). Median air concentrations of oil mist (180 MUg m(-3)), oil vapour (14 mg m(-3)) and organic carbon (46 MUg m(-3)) were also measured. All contaminants were detected in all work areas (drill floor, shaker area, mud pits, pump room, other areas). The highest air concentrations were measured in the shaker area, but the differences in air concentrations between working areas were moderate. Oil mist and oil vapour concentrations were statistically higher on moveable rigs than on stationary rigs, but after adjusting for differences in mud temperature the differences between rig types were no longer of statistical significance. Statistically significant positive associations were found between mud temperature and the concentrations of oil mist (Spearman's R = 0.46) and oil vapour (0.39), and between viscosity of base oil and oil mist concentrations. Use of pressure washers was associated with higher air concentrations of mud. A series of 18 parallel stationary samples showed a high and statistically significant association between concentrations of organic carbon and oil mist (r = 0.98). This study shows that workers are exposed to airborne non-volatilized mud components. Air concentrations of volatile mud components like oil mist and oil vapour were low, but were present in all the studied working areas. PMID- 26020724 TI - Direct Correlation Between Ligand-Induced alpha-Synuclein Oligomers and Amyloid like Fibril Growth. AB - Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha synuclein fibril elongation. PMID- 26020727 TI - Critical Illness in Pregnancy: Part II: Common Medical Conditions Complicating Pregnancy and Puerperium. AB - The first of this two-part series on critical illness in pregnancy dealt with obstetric disorders. In Part II, medical conditions that commonly affect pregnant women or worsen during pregnancy are discussed. ARDS occurs more frequently in pregnancy. Strategies commonly used in nonpregnant patients, including permissive hypercapnia, limits for plateau pressure, and prone positioning, may not be acceptable, especially in late pregnancy. Genital tract infections unique to pregnancy include chorioamnionitis, group A streptococcal infection causing toxic shock syndrome, and polymicrobial infection with streptococci, staphylococci, and Clostridium perfringens causing necrotizing vulvitis or fasciitis. Pregnancy predisposes to VTE; D-dimer levels have low specificity in pregnancy. A ventilation-perfusion scan is preferred over CT pulmonary angiography in some situations to reduce radiation to the mother's breasts. Low-molecular-weight or unfractionated heparins form the mainstay of treatment; vitamin K antagonists, oral factor Xa inhibitors, and direct thrombin inhibitors are not recommended in pregnancy. The physiologic hyperdynamic circulation in pregnancy worsens many cardiovascular disorders. It increases risk of pulmonary edema or arrhythmias in mitral stenosis, heart failure in pulmonary hypertension or aortic stenosis, aortic dissection in Marfan syndrome, or valve thrombosis in mechanical heart valves. Common neurologic problems in pregnancy include seizures, altered mental status, visual symptoms, and strokes. Other common conditions discussed are aspiration of gastric contents, OSA, thyroid disorders, diabetic ketoacidosis, and cardiopulmonary arrest in pregnancy. Studies confined to pregnant women are available for only a few of these conditions. We have, therefore, reviewed pregnancy-specific adjustments in the management of these disorders. PMID- 26020726 TI - Treatment of Hepatitis C in HIV-Infected Patients: Moving Towards an Era of All Oral Regimens. AB - Hepatitis C (HCV)-related liver disease has become one of the leading causes of death in HIV patients. With the development of new direct-acting antivirals for HCV, treatment regimens have become shorter, more effective, and easier to tolerate without interferon. However, cost may be a significant impediment to the widespread use of these newer agents in both resource-rich and resource-poor settings. In HIV patients, treatment for HCV is not always as straightforward compared with HCV monoinfected patients due to potential drug-drug interactions. In this article, we will examine by genotypes the FDA approved direct-acting antivirals, as well as those in clinical trials that will soon be FDA-approved focusing on data in HCV/HIV co-infection. Preferred agents for HCV treatment and potential drug-drug interactions with antiretroviral therapy (ART) will be highlighted. PMID- 26020725 TI - The Tpl2 Kinase Regulates the COX-2/Prostaglandin E2 Axis in Adipocytes in Inflammatory Conditions. AB - Bioactive lipid mediators such as prostaglandin E2 (PGE2) have emerged as potent regulator of obese adipocyte inflammation and functions. PGE2 is produced by cyclooxygenases (COXs) from arachidonic acid, but inflammatory signaling pathways controlling COX-2 expression and PGE2 production in adipocytes remain ill defined. Here, we demonstrated that the MAP kinase kinase kinase tumor progression locus 2 (Tpl2) controls COX-2 expression and PGE2 secretion in adipocytes in response to different inflammatory mediators. We found that pharmacological- or small interfering RNA-mediated Tpl2 inhibition in 3T3-L1 adipocytes decreased by 50% COX-2 induction in response to IL-1beta, TNF-alpha, or a mix of the 2 cytokines. PGE2 secretion induced by the cytokine mix was also markedly blunted. At the molecular level, nuclear factor kappaB was required for Tpl2-induced COX-2 expression in response to IL-1beta but was inhibitory for the TNF-alpha or cytokine mix response. In a coculture between adipocytes and macrophages, COX-2 was mainly increased in adipocytes and pharmacological inhibition of Tpl2 or its silencing in adipocytes markedly reduced COX-2 expression and PGE2 secretion. Further, Tpl2 inhibition in adipocytes reduces by 60% COX-2 expression induced by a conditioned medium from lipopolysaccharide (LPS)-treated macrophages. Importantly, LPS was less efficient to induce COX-2 mRNA in adipose tissue explants of Tpl2 null mice compared with wild-type and Tpl2 null mice displayed low COX-2 mRNA induction in adipose tissue in response to LPS injection. Collectively, these data established that activation of Tpl2 by inflammatory stimuli in adipocytes and adipose tissue contributes to increase COX 2 expression and production of PGE2 that could participate in the modulation of adipose tissue inflammation during obesity. PMID- 26020728 TI - Optical 'magnetic mirror' metasurfaces using interference between Fabry-Perot cavity resonances in coaxial apertures. AB - Here we propose and computationally demonstrate a quasi-planar metasurface consisting of arrays of pairs of concentric coaxial apertures in a metallic film. The structure relies on destructive interference between Fabry-Perot modes excited in each aperture at resonance producing transmitted fields that interfere destructively leading to suppressed transmission. Conversely, we show that in the case of a perfect conductor, near-perfect, broadband reflection can be achieved with zero phase change in the electric field and a variation of 2pi on passing through the coincident resonances. Extending the concept to shorter wavelengths, we show that mirrors exhibiting close to a 2pi phase excursion, albeit with a reduction in the amplitude reflection coefficient at resonance and a lower Q, can be also achieved. Structures such as these can be used to enhance light-matter interactions at surfaces and act as high impedance ground planes for antenna applications. PMID- 26020732 TI - Subjective Sexual Well-Being in Chilean Adults: Evaluation of a Predictive Model. AB - Research on sexuality has traditionally focused on sexual satisfaction, with studies into subjective sexual well-being being a recent phenomenon. This study sought to evaluate the relationship between sexual behavior, happiness, health, and subjective sexual well-being. The data were collected from 862 people aged between 18 and 50 years in Santiago, Chile, and were analyzed by logistic regression analysis. The results showed that sexual behavioral indicators (sexual frequency, sexual caresses, and touching), happiness, and perception of health taken as a whole predicted 47.4% of subjective sexual well-being (SSWB). Analysis of the four items of subjective sexual well-being separately showed that the dimension of physical satisfaction was associated with three variables of sexual behavior indicators with a prediction percentage of 33.5%, whereas emotional satisfaction was associated with three variables of sexual behavior indicators and happiness, with a percentage of prediction of 43.3%. Satisfaction with sexual function was associated with perception of health and one sexual behavior indicator, with a prediction percentage of 29.2% of this variable. The importance of sex was associated with three sexual behavior variables that predicted 26.2% of this variable. The results confirm that subjective sexual well-being can be predicted and that its four dimensions present a different behavior compared to the study predictors. PMID- 26020733 TI - Epidemiology of herpes zoster among adults aged 50 and above in Guangdong, China. AB - Herpes zoster (HZ) exists widely in China and most cases occur among old people, but no epidemiology information of HZ was available. We aimed to investigate the epidemiology characteristics of HZ among adults aged 50 and over in Guangdong, China. A total of 34 counties/districts were randomly selected in Guangdong, and 7149 residents aged 50 and over were investigated by local CDC professionals using accidental sampling method. There were 247 respondents having had HZ before; the lifetime prevalence of HZ among people aged 50 and above in study area was 3.46%. The prevalence in females was higher than that in males. Pearl River Delta had the highest prevalence (5.29%), while Northern Guangdong had the lowest (1.87%). The annual incidence in the year 2013, 2012 and 2011 was 5.8, 3.4 and 4.1 per 1000 person-years, respectively. Detailed investigation of HZ cases showed that all cases meted the definition of HZ and had at least 1 typical symptom. 40% cases had suffered post-herpetic neuralgia. 75.9% cases had sought aid from hospital and 9.1% of them had been hospitalized. People who sought aid from hospital had more serious level of neuralgia. The epidemiology features of HZ in Guangdong were consistent with the current findings in other countries. The results of this study can provide baseline epidemiology information of HZ for further studies. PMID- 26020734 TI - Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. PMID- 26020735 TI - Interventions for replacing missing teeth: alveolar ridge preservation techniques for dental implant site development. AB - BACKGROUND: Alveolar bone changes following tooth extraction can compromise prosthodontic rehabilitation. Alveolar ridge preservation (ARP) has been proposed to limit these changes and improve prosthodontic and aesthetic outcomes when implants are used. OBJECTIVES: To assess the clinical effects of various materials and techniques for ARP after tooth extraction compared with extraction alone or other methods of ARP, or both, in patients requiring dental implant placement following healing of extraction sockets. SEARCH METHODS: The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 22 July 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2014, Issue 6), MEDLINE via OVID (1946 to 22 July 2014), EMBASE via OVID (1980 to 22 July 2014), LILACS via BIREME (1982 to 22 July 2014), the Meta Register of Current Controlled Trials (to 22 July 2014), ClinicalTrials.gov (to 22 July 2014), the World Health Organization International Clinical Trials Registry Platform (to 22 July 2014), Web of Science Conference Proceedings (1990 to 22 July 2014), Scopus (1966 to 22 July 2014), ProQuest Dissertations and Theses (1861 to 22 July 2014) and OpenGrey (to 22 July 2014). A number of journals were also handsearched. Trial authors were contacted to identify unpublished randomised controlled trials. There were no restrictions regarding language and date of publication in the searches of the electronic databases. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) on the use of alveolar ridge preservation techniques with at least six months of follow-up. Outcome measures were: changes in the bucco-lingual/palatal width of alveolar ridge, changes in the vertical height of the alveolar ridge, complications, the need for additional augmentation prior to implant placement, aesthetic outcomes, implant failure rates, peri-implant marginal bone level changes, changes in probing depths and clinical attachment levels at teeth adjacent to the extraction site, and complications of future prosthodontic rehabilitation. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently and assessed risk of bias for each included trial. Corresponding authors were contacted to obtain missing information. Results were combined using random-effects models with mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (95% CI). We constructed 'Summary of findings' tables to present the main findings. MAIN RESULTS: A total of 50 trials were potentially eligible for inclusion, of which 42 trials were excluded. We included eight RCTs with a total of 233 extraction sites in 184 participants. One trial was judged to be at unclear risk of bias and the remaining trials were at high risk of bias. From two trials comparing xenograft with extraction alone (70 participants, moderate quality evidence), there was some evidence of a reduction in loss of alveolar ridge height (MD -2.60 mm; 95% CI -3.43 to -1.76) and width (MD -1.97 mm; 95% CI -2.48 to -1.46). This was also found in one trial comparing allograft with extraction (24 participants, low quality evidence): ridge height (MD -2.20 mm; 95% CI -0.75 to -3.65) and width (MD - 1.40 mm; 95% CI 0.00 to -2.80) and height. From two RCTs comparing alloplast versus xenograft no evidence was found that either ridge preservation technique caused a smaller reduction in loss of ridge height (MD -0.35 mm; 95% CI -0.86 to 0.16) or width (MD -0.44 mm; 95% CI -0.90 to 0.02; two trials (55 participants); moderate quality evidence). There was insufficient evidence to determine whether there are clinically significant differences between different ARP techniques and extraction based on the need for additional augmentation prior to implant placement, complications, implant failure, or changes in peri-implant marginal bone levels and probing depths of neighbouring teeth. We found no trials which evaluated parameters relating to clinical attachment levels, specific aesthetic or prosthodontic outcomes. AUTHORS' CONCLUSIONS: There is limited evidence that ARP techniques may minimise the overall changes in residual ridge height and width six months after extraction. There is also lack of evidence of any differences in implant failure, aesthetic outcomes or any other clinical parameters due to the lack of information or long-term data. There is no convincing evidence of any clinically significant difference between different grafting materials and barriers used for ARP. Further long term RCTs that follow CONSORT guidelines (www.consort-statement.org) are necessary. PMID- 26020736 TI - Surrogate End-of-Life Care Decision Makers' Postbereavement Grief and Guilt Responses. AB - This article examined differences in familial/friend surrogate decision makers' (N = 93) postbereavement grief and guilt associated with decisions to either prioritize comfort or longevity in determining end-of-life care for decisionally incapacitated adult palliative loved ones. Results demonstrated that participants prioritizing the longevity of loved ones experienced significantly and meaningfully higher levels of grief, complicated grief, and trauma related guilt than those who prioritized comfort. PMID- 26020737 TI - INVITED REVIEW: Evolution of meat animal growth research during the past 50 years: Adipose and muscle stem cells. AB - If one were to compare today's animal growth research to research from a mere 50 yr ago, one would see programs with few similarities. The evolution of this research from whole-animal through cell-based and finally molecular and genomic studies has been enhanced by the identification, isolation, and in vitro evaluation of adipose- and muscle-derived stem cells. This paper will highlight the struggles and the milestones that make this evolving area of research what it is today. The contribution of adipose and muscle stem cell research to development and growth, tissue regeneration, and final carcass composition are reviewed. PMID- 26020738 TI - Comparative gut physiology symposium. PMID- 26020739 TI - COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: Comparative physiology of digestion. AB - The digestive systems of all species have been shaped by environmental pressures over long evolutionary time spans. Nevertheless, all digestive systems must achieve the same end points, the ingestion of biological material and its conversion to molecules that serve as energy substrates and structural components of tissues. A range of strategies to extract nutrients, including for animals reliant primarily on foregut fermentation, hindgut fermentation, and enzymatic degradation, have evolved. Moreover, animals have adapted to different foodstuffs as herbivores (including frugivores, folivores, granivores, etc.), carnivores, and omnivores. We present evidence that humans have diverged from other omnivores because of the long history of consumption of cooked or otherwise prepared food. We consider them to be cucinivores. We present examples to illustrate that the range of foodstuffs that can be efficiently assimilated by each group or species is limited and is different from that of other groups or species. Differences are reflected in alimentary tract morphology. The digestive systems of each group and of species within the groups are adaptable, with constraints determined by individual digestive physiology. Although overall digestive strategies and systems differ, the building blocks for digestion are remarkably similar. All vertebrates have muscular tubular tracts lined with a single layer of epithelial cells for most of the length, use closely related digestive enzymes and transporters, and control the digestive process through similar hormones and similarly organized nerve pathways. Extrapolations among species that are widely separated in their digestive physiologies are possible when the basis for extrapolation is carefully considered. Divergence is greatest at organ or organismal levels, and similarities are greatest at the cell and molecular level. PMID- 26020740 TI - COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: Comparative physiology of glucagon-like peptide-2: Implications and applications for production and health of ruminants. AB - Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proteolytic cleavage of proglucagon by prohormone convertase 1/3 in enteroendocrine L cells. Studies conducted in humans, in rodent models, and in vitro indicate that GLP-2 is secreted in response to the presence of molecules in the intestinal lumen, including fatty acids, carbohydrates, amino acids, and bile acids, which are detected by luminal chemosensors. The physiological actions of GLP-2 are mediated by its G protein-coupled receptor expressed primarily in the intestinal tract on enteric neurons, enteroendocrine cells, and myofibroblasts. The biological activity of GLP-2 is further regulated by dipeptidyl peptidase IV, which rapidly cleaves the N-terminus of GLP-2 that is responsible for GLP-2 receptor activation. Within the gut, GLP-2 increases nutrient absorption, crypt cell proliferation, and mesenteric blood flow and decreases gut permeability and motility, epithelial cell apoptosis, and inflammation. Outside the gut, GLP-2 reduces bone resorption, can suppress appetite, and is cytoprotective in the lung. Thus, GLP-2 has been studied intensively as a therapeutic to improve intestinal function of humans during parenteral nutrition and following small bowel resection and, more recently, as a treatment for osteoporosis and obesity related disorders and to reduce cellular damage associated with inflammation of the gut and lungs. Recent studies demonstrate that many biological actions and properties of GLP-2 in ruminants are similar to those in nonruminants, including the potential to reduce intestinal nitro-oxidative stress in calves caused by parasitic diseases such as coccidiosis. Because of its beneficial impacts on nutrient absorption, gut healing, and normal gut development, GLP-2 therapy offers significant opportunities to improve calf health and production efficiency. However, GLP-2 therapies require an extended time course to achieve desired physiological responses, as well as daily administration because of the hormone's short half-life. Thus, practical means of administration and alternative strategies to enhance basal GLP-2 secretion (e.g., through specific feed additives), which are more likely to achieve consumer acceptance, are needed. Opportunities to address these challenges are discussed. PMID- 26020741 TI - Genetic parameters and genetic correlations among triacylglycerol and phospholipid fractions in Angus cattle. AB - The objective of this study was to estimate genetic parameters for intramuscular fatty acids from triacylglycerol (TAG) and phospholipid (PL) fractions in beef LM tissue. Longissimus muscle samples were obtained from 1,833 Angus cattle to determine the intramuscular fatty acid composition for 31 lipids and lipid classes from TAG and PL fractions and were classified by structure into saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), omega-3 (n-3), and omega-6 (n-6) fatty acids. An atherogenic index (AI) was also determined as a measure of the unsaturated fatty acid to SFA ratio. Restricted maximum likelihood methods combined with pedigree data were used to estimate variance components with the WOMBAT software package. Heritability estimates ranged from 0.00 to 0.63 for the major classes of fatty acids. Heritability estimates differed between the TAG and PL fractions, with higher estimates for TAG up to 0.64 and lower estimates for PL that ranged from 0.00 to 0.14. Phenotypic and genetic correlations among individual fatty acids were determined for the TAG fraction as well as among carcass traits, including rib eye area, numerical marbling score, yield grade, ether fat, and Warner-Bratzler shear force value. Strong negative or positive genetic correlations were observed among individual fatty acids in the TAG fraction, which ranged from -0.99 to 0.97 ( < 0.05). Moderate correlations between carcass traits and fatty acids from the TAG fraction ranged from -0.43 to 0.32 ( < 0.05). These results indicate that fatty acids prominent in beef tissues show significant genetic variation as well as genetic relationships with carcass traits. PMID- 26020742 TI - Genomewide association analysis for average birth interval and stillbirth in swine. AB - Reproductive efficiency has a great impact on the economic success of pork production. Stillborn pigs and average birth interval contribute to the number of pigs born alive in a litter. To better understand the underlying genetics of these traits, a genomewide association study was undertaken. Samples of DNA were collected and tested using the Illumina Porcine SNP60 BeadChip from 798 females farrowing over a 4-yr period (all first parity). Birth intervals and piglet birth status (stillborn or alive) were determined by videotaping each farrowing event. A total of 41,148 SNP were tested using the Bayes C option of GenSel (version 4.61) and 1-Mb windows. These 1-Mb windows explained proportions of 0.017, 0.002, 0.032, 0.029, and 0.030 of the total variation, respectively, for litter average birth interval after deletion of the last piglet born, last birth interval in the litter, number of stillborn piglets ignoring the last piglet born, number of stillborns in the last birth position, and percent stillborn ignoring the last piglet. Significant 1-Mb nonoverlapping SNP windows were identified by using a conservative approach requiring 1-Mb windows to have a genetic variance >=1.0% of genomic variance and these were considered to be QTL. Quantitative trait loci were located for number of stillborn piglets ignoring the last piglet born (1 QTL), number of stillborns in the last birth position (1 QTL), and percent stillborn ignoring the last piglet (3 QTL). In addition, 2, 13, 3, and 6 suggestive 1-Mb nonoverlapping SNP windows were identified for litter average birth interval after deletion of the last piglet born, number of stillborn piglets ignoring the last piglet born, number of stillborns in the last birth position, and percent stillborn ignoring the last piglet, respectively. Possible candidate genes affecting both birth interval and stillbirth included () and (). Possible genes affecting only birth interval included (), and (), and those affecting only stillbirth included (), LOC100518697 (a nostrin-like gene), and (). The QTL and the suggestive 1-Mb nonoverlapping SNP windows may lead to genetic markers for marker assisted selection, marker assisted management, or genomic selection applications in commercial pig populations. PMID- 26020743 TI - Genetic grouping strategies in selection efficiency of composite beef cattle ( * ). AB - The inclusion of genetic groups in sire evaluation has been widely used to represent genetic differences among animals not accounted for by the absence of parentage data. However, the definition of these groups is still arbitrary, and studies assessing the effects of genetic grouping strategies on the selection efficiency are rare. Therefore, the aim in this study was to compare genetic grouping strategies for animals with unknown parentage in prediction of breeding values (EBV). The total of 179,302 records of weaning weight (WW), 29,825 records of scrotal circumference (SC), and 70,302 records of muscling score (MUSC) from Montana Tropical animals, a Brazilian composite beef cattle population, were used. Genetic grouping strategies involving year of birth, sex of the unknown parent, birth farm, breed composition, and their combinations were evaluated. Estimated breeding values were predicted for each approach simulating a loss of genealogy data. Thereafter, these EBV were compared to those obtained in an analysis involving a real relationship matrix to estimate selection efficiency and correlations between EBV and animal rankings. The analysis model included the fixed effects of contemporary groups and class of the dam age at calving, the covariates of additive and nonadditive genetic effects, and age, and the additive genetic effect of animal as random effects. A second model also included the fixed effects of genetic group. The use of genetic groups resulted in means of selection efficiency and correlation of 70.4 to 97.1% and 0.51 to 0.94 for WW, 85.8 to 98.8% and 0.82 to 0.98 for SC, and 85.1 to 98.6% and 0.74 to 0.97 for MUSC, respectively. High selection efficiencies were observed for year of birth and breed composition strategies. The maximum absolute difference in annual genetic gain estimated through the use of complete genealogy and genetic groups were 0.38 kg for WW, 0.02 cm for SC, and 0.01 for MUSC, with lower differences obtained when year of birth was adopted as a genetic group criterion. Grouping strategy must consider selection decisions and the number of genetic groups formed, in the way that genetic groups represent the genetic differences in population and allow an adequate prediction of EBV. PMID- 26020744 TI - Genetic effects on birth weight in reciprocal Brahman-Simmental crossbred calves. AB - Brahman-cross calves exhibit unusual inheritance of birth weight: Brahman-sired crossbreds out of females are heavier with greater difference between sexes than calves of the reciprocal cross. The objectives of this work were to confirm that unusual inheritance and to investigate non-Mendelian genetic effects that may influence differences in Brahman * Simmental crossbred calves. Crossbred calves were produced by embryo transfer ( = 2,862) and natural service or artificial insemination ( = 2,125) from 1983 to 1991 by a private seedstock producer. Brahman-sired F embryos out of Simmental donors weighed 9.4 +/- 1.1 ( < 0.001) kg more at birth than Simmental-sired F embryos out of Brahman donor cows when transferred to comparable recipients. This reciprocal difference was accompanied by sexual dimorphism: within Brahman-sired F calves, males were 5.0 +/- 1.4 kg heavier than females, whereas within Simmental-sired F calves, females were 0.7 +/- 0.5 kg heavier than males. Covariates were constructed from the pedigree to represent genetic effects: proportion Brahman in calves and dams (direct and maternal breed effects), direct and maternal breed heterozygosity, probability of Brahman mitochondrial origin, probability of Brahman Y chromosome, probability of Brahman X chromosome, genomic imprinting (the difference between the probabilities of Brahman in the genetic dam and in the sire), nonrandom X inactivation by breed of origin (the probability of breed heterozygosity of the X chromosomes of a female), and nonrandom X inactivation by parent of origin (the difference between probabilities of a female inheriting a paternal or maternal Brahman X chromosome). The maternal breed heterozygosity, genomic imprinting, probability of Brahman X chromosome, and genomic imprinting * sex effect covariates from the full model were significant with regression coefficients of 1.1 +/- 0.5 ( < 0.05), -8.3 +/- 2.3 ( < 0.01), -3.5 +/- 1.3 ( < 0.01), and -5.3 +/- 2.0 ( < 0.01), respectively. Results suggest that sex-specific genomic imprinting may be contributing to the inheritance of birth weight in crossbred calves, similar to patterns of mouse litter and placental weight in interspecific crosses. PMID- 26020745 TI - Evaluation of a semen extender from a bioenergetic perspective. AB - Four premises for sperm preservation were previously outlined. The present work tested 2 of these. The first premise was that sperm mobility phenotype affects procedural efficacy. Random bred roosters were phenotyped with the sperm mobility assay. A normal frequency distribution was observed with 35% (SD = 16.4) mobile sperm. Test subjects had values >51% (high) or between 19 and 35% (below average). Phenotypes were confirmed by repeated measure analysis. Ejaculates were pooled by phenotype. Sperm were washed by centrifugation through 12% (wt/vol) Accudenz. Washed sperm were suspended in Beltsville Poultry Semen Extender (BPSE) at 2 * 10 sperm/mL. Such sperm were stored at 10 degrees C for 24 h. In the case of highly mobile sperm, an exponential decay was observed with a -intercept of 72% and an asymptote of 53%. In contrast, postwash values for below-average males decreased linearly from a -intercept of 31 to 17% after 24 h. A logistic decay was observed when sperm from high phenotype subpopulation males were extended with BPSE rather than washed before storage. Whereas -intercepts were equivalent between experiments, end points were not, that is, 53 vs. 17% mobile sperm. This difference was attributed to the extent of cytotoxic edema. The second premise tested was that the sperm mobility assay can predict the status of sperm cell mitochondria in response to sperm manipulation. Highly mobile sperm were washed and then suspended in either saline or glucose-free extender. Solution pH and osmolality were equivalent. Extender osmolality was controlled by replacing glucose with mannitol. Sperm were stressed by incubation at 2 * 10/mL at 20 degrees C for 8 h. In each case, loss of sperm mobility approximated a logistic function. Whereas -intercepts were equivalent, the time at which loss of function was half maximal was prolonged with the extender ( < 0.01). This difference was attributed to a diminution of the process whereby energy-deprived sperm were rendered immobile by cellular edema. An a posteriori analysis was limited to pretreatment data from males categorized a priori with the high phenotype. Phenotype was independent of time ( = 0.81) during the 14-wk interval in which experiments were performed. In summary, extender efficacy was affected by sperm mobility phenotype as well as the means by which the extender was used. To date, such effects have not been addressed in attempts to preserve chicken sperm in vitro. PMID- 26020746 TI - Effects of selenium and vitamin E on performance, physiological response, and selenium balance in heat-stressed sheep. AB - Forty-two 7-mo-old Australian Merino wethers were used in a 50-d trial to investigate the effects of Se and vitamin E on the performance and physiological responses of heat-stressed sheep. Sheep were exposed to thermoneutral conditions (maximum = 24 degrees C and minimum = 20 degrees C) for 28 d followed by heat (maximum = 38 degrees C and minimum = 28 degrees C) for 22 d. Hot conditions were imposed between 0700 and 1800 h. Sheep were randomly allocated to diets containing 0.8 mg/kg Se (Sel-Plex), 150 mg/kg vitamin E, or 0.8 mg/kg Se and 150 mg/kg vitamin E for either the duration of the study (50 d) or from d 1 of the hot period until the end of the study. A control group that received no supplemental Se and vitamin E for the duration of the study was included. Feed intake was measured daily and sheep were weighed weekly. Blood samples were collected from all sheep before feeding on d 1, 21, and 49 for measurement of biochemical and enzymatic variables. The concentration of Se was determined in offered and refused feed, feces, urine, water, plasma, liver, and kidneys. Exposure to heat reduced ( < 0.05) DMI by 11.9%, ADG by 198 g, serum concentration of urea nitrogen and Se by 17.8%, and plasma total antioxidant status by 26.4%. During hot conditions, sheep receiving Se and vitamin E supplements for 50 d had reduced ( < 0.05) BW loss and elevated G:F compared to control sheep. Serum Se concentration and the plasma total antioxidant status were greatest in sheep receiving Se and vitamin E supplements for 50 d ( < 0.05). These results indicate that dietary supplementation with Se and vitamin E reduces the adverse effects of a high heat load. Additional studies are warranted to elucidate the mechanisms responsible for these effects. PMID- 26020747 TI - Tumor necrosis factor-like weak inducer of apoptosis regulates the phenotype and cytotoxic activity of goat uterine natural killer cells. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has an important role in the promotion of cell proliferation, migration, and differentiation. However, very little is known about the role of TWEAK in modulating uterine natural killer (uNK) cells' comprehensive functions in ruminants. In the present study, the effects of TWEAK on goat uNK cells were investigated by measuring their cytotoxic function and phenotype as well as cytokine expression in vitro. The results showed that TWEAK protein could be detected in the goat endometrium during estrous cycle and pregnancy. However, a significant increase in ( < 0.05) TWEAK protein levels was observed during very early pregnancy when compared with that during mid pregnancy and later pregnancy as well as during different phases of estrous cycle. Tumor necrosis factor-like weak inducer of apoptosis did not affect proliferation but did decrease ( < 0.05) the cytotoxic activity of uNK cells in vitro. Furthermore, the percentage of CD56/NKp46 uNK cells incubated with TWEAK-containing medium was greater ( < 0.05) compared with those treated with control medium. In addition, uNK cells incubated with TWEAK medium were associated with lesser ( < 0.05) secretion levels and protein expression of interferon-gamma (IFN-gamma) compared to those incubated with control medium. However, no differences ( > 0.05) could be observed for the secretion levels and protein expression of vascular endothelial growth factor (VEGF) in the uNK cells incubated with TWEAK-containing medium compared with those incubated with control medium. The present preliminary observations indicate that TWEAK has a biological effect on phenotype of uNK cells as well as the secretion and expression of IFN gamma by uNK cells in goats. Moreover, TWEAK decreases the cytotoxicity of goat uNK cells in vitro. PMID- 26020749 TI - Phosphorus digestibility response of growing pigs to phytase supplementation of triticale distillers' dried grains with solubles. AB - An experiment was conducted in growing pigs to determine the true total-tract digestibility (TTTD) of P in triticale distillers' dried grains with solubles (DDGS) with or without phytase using the regression method. Six diets were formulated in a 3 * 2 factorial arrangement, including 3 levels of triticale DDGS (300, 400, or 500 g/kg) and phytase (0 or 500 phytase units [FTU]/kg of diet). A total of 48 barrows (initial BW 22.2 +/- 1.3 kg) were assigned to the 6 diets in a randomized complete block design. There was a 5-d adjustment period followed by a 5-d total collection of feces. The results show that P intake, fecal P output, and digested P increased linearly ( < 0.01) with increasing level of DDGS in diets. There was a main effect ( < 0.001) of phytase on apparent total-tract digestibility (ATTD) of P. In diets without added phytase, the ATTD of P in triticale DDGS was 65.0, 67.7, and 63.2% for the diets with 300, 400, and 500 g/kg triticale DDGS, respectively; the corresponding values for diets with added phytase were 77.3, 76.3, and 75.7%. By regressing daily digested P against daily P intake, the TTTD of P was estimated at 75.4% for triticale DDGS or 81.1% with added phytase, respectively. In conclusion, the TTTD of P in triticale DDGS without supplemental phytase was 75.4%, and it was 81.1% in the presence of phytase at 500 FTU/kg of the diet, but the difference was not statistically significant. For triticale DDGS, the supplementation of 500 FTU/kg phytase in diet could increase the ATTD of P ( < 0.001) but not the TTTD of P. PMID- 26020748 TI - Efficacy of activated diatomaceous clay in reducing the toxicity of zearalenone in rats and piglets. AB - Two experiments were conducted to evaluate the efficacy of an activated diatomaceous clay (ADC) in reducing the toxic effects of zearalenone (ZEA) in the diet of rats and piglets. In the rat experiment, 90 Sprague-Dawley female weanling rats with an initial BW of 45 +/- 1.0 g were assigned to 1 of 6 dietary treatments for 28 d in a completely randomized design (CRD) with a 2 * 3 factorial arrangement (0 or 6 mg ZEA/kg feed and 0, 1, and 5 g ADC/kg feed). In the piglet experiment, 64 female piglets ([Large White * Landrace] * Pietrain with an initial BW of 14.9 +/- 1.65 kg) were fed 1 of 8 experimental diets for 26 d in a CRD design with a 2 * 4 factorial arrangement (0 or 0.8 mg ZEA/kg feed and 0, 1, 2, and 5 g ADC/kg feed). The ADFI, ADG, and G:F were determined at the end of each experiment. At the conclusion of studies, serum samples were collected and rats and piglets were euthanized to determine visceral organ weights. The diet contaminated with ZEA did not alter the growth of rats and the relative weight of liver and kidneys. However, ZEA increased ( < 0.05) the relative weight of uterus, ovaries, and spleen and decreased ( < 0.05) the serum activities of alkaline phosphatase and alanine aminotransferase compared to the control group. Supplementation of ADC in the rat diets counteracted ( < 0.05) the observed toxic effects of ZEA on the uterus and ovaries weight. The diet contaminated with ZEA (0.8 mg/kg feed) increased ( < 0.05) the weight of the uterus and ovaries in piglets but did not modify the serum biochemical variables or the relative weight of other visceral organs. The addition of 5 g ADC/kg to the contaminated feed reduced the toxic effects of ZEA on uterus and ovary weights to that of the control group. Zearalenone (10.5 MUg/kg bile) and alpha-zearalenol (5.6 MUg/kg bile) residues were detected in the bile of piglets fed the ZEA treatment. Supplementation of ADC to diets contaminated with ZEA reduced ( = 0.001) ZEA content in bile compared to the ZEA treatments. The results of these experiments indicate that a long-term consumption of ZEA-contaminated diets stimulated growth of the reproductive tract in rats and piglets and the presence of ZEA residue in bile in piglets. These effects may be counteracted by the addition of ADC to the diet. PMID- 26020750 TI - Digestibility of energy and detergent fiber and digestible and metabolizable energy values in canola meal, 00-rapeseed meal, and 00-rapeseed expellers fed to growing pigs. AB - There are limited data on the DE and ME values and the digestibility of fiber in canola meal, rapeseed meal, and rapeseed expellers fed to pigs. This experiment was conducted to measure the apparent total tract digestibility (ATTD) of energy, ADF, and NDF and to calculate DE and ME values in canola meal, 00-rapeseed meal, and 00-rapeseed expellers fed to growing pigs. Twenty-three barrows (initial BW: 27.7 +/- 2.92 kg) were allotted to an 8 * 23 Youden square design with 8 periods and 23 animals. Twenty-three diets were prepared: a corn basal diet and 22 diets based on corn and 1 of 22 test ingredients. The test ingredients were 6 canola meals from solvent-extraction crushing plants in North America, eleven 00 rapeseed meals from solvent-extraction crushing plants in Europe, and five 00 rapeseed expellers from mechanical-press crushing plants in Europe. Pigs were placed in metabolism cages that allowed for the total, but separate, collection of feces and urine. The DE and ME values were calculated for each source of canola meal, 00-rapeseed meal, and 00-rapeseed expellers using the difference procedure. The ATTD of GE and the DE and ME values in canola meal were not different from the values in 00-rapeseed meal, but 00-rapeseed expellers had greater ( < 0.01) ATTD of GE and DE and ME values than 00-rapeseed meal. Average DE and ME values were 3,378 and 3,127 kcal/kg DM in canola meal, 3,461 and 3,168 kcal/kg DM in 00-rapeseed, and 4,005 and 3,691 kcal/kg DM in 00-rapeseed expellers. The ATTD of ADF was 12.3% greater ( < 0.01) in 00-rapeseed meal than in canola meal, but no differences were observed in ATTD of NDF between canola meal and 00-rapeseed meal. No differences were observed in ATTD of ADF and NDF between 00-rapeseed meal and 00-rapeseed expellers. The models for predicting the DE and ME values of canola and rapeseed products were DE = -1,583 + 6.64 * ash + 7.01 * ADF - 33.17 * NDF + 98.66 * ADL + 1.07 * GE ( = 0.94) and ME = -630.8 + 14.13 * ash + 5.02 * crude fiber + 3.45 * ADF + 1.03 * DE ( = 0.98). In conclusion, the digestibility of energy and NDF and the DE and ME values are not different between canola meal and 00-rapeseed meal. However, 00-rapeseed expellers have greater energy digestibility and contain 7.6% more DE and 7.7% more ME than 00-rapeseed meal. PMID- 26020751 TI - Nutritional plane of twin-bearing ewes alters fetal mammary gland biochemical composition and mTOR/MAPK pathway signaling. AB - Identifying the biochemical changes and molecular pathways that regulate fetal mammary development in response to maternal nutrition is important for understanding the link between fetal programming of mammary development and future lactation performance. Although there are published studies regarding biochemical changes in the developing mammary gland, there are currently no data on molecular pathway involvement in regulating ruminant fetal mammary development. This study investigated changes in fetal mammary biochemical indices and mechanistic target of rapamycin (mTOR)/mitogen activated protein kinase (MAPK) signaling at d 100 and 140 of gestation in an ovine model of restricted maternal nutrition. Ewes were randomly allocated to ad libitum (A) or maintenance (M) nutritional regimens, under New Zealand pastoral grazing conditions, from d 21 to 140 of pregnancy. At d 100 and 140 of pregnancy, a subgroup of twin-bearing dams was euthanized, and whole fetal mammary glands (fiber, skin, fat, and ducts) were collected. Mammary glands of fetuses carried by M-fed dams were heavier at d 100 than those of fetuses carried by A-fed dams ( = 0.03), with no difference in the abundance of mTOR/MAPK signaling proteins observed. At d 140, mammary glands of fetuses carried by M-fed dams were lighter ( = 0.07) than fetuses carried by A fed dams because of decreased hyperplasia ( = 0.04) and hypertrophy ( = 0.09) but had increased protein synthetic capacity ( = 0.02). Increased protein synthetic capacity was associated with increased abundance of MAPK pathway signaling proteins eukaryotic intiation factor 4E (eIF4E)/eIF4E and mTOR pathway signaling proteins eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)/4E-BP1 and ribosomal protein S6 (RPS6)/RPS6 ( <= 0.05). Increased abundance of MAPK/mTOR pathway proteins is proposed to mediate increased protein synthetic capacity via ribosome biogenesis and the availability of factors required to initiate protein translation. The primary regulator of 4E-BP1 phosphorylation at Ser65 and RPS6 at Ser235/236 is the activated form of mTOR: mTOR. To study potential tissue specific mTOR, mTOR abundance mammary glands, separated into parenchyma and fat pad, were collected from d 140 fetuses carried by dams fed a lucerne-based pellet diet formulated to meet 100% of the NRC-recommended maintenance requirements. Results showed that the abundance of mTOR was primarily localized to the fat pad, indicating that the fat pad plays a potential role in regulating development of the fetal mammary gland. PMID- 26020752 TI - Evaluating nitrogen utilization efficiency of nonpregnant dry cows offered solely fresh cut grass at maintenance levels. AB - The present study aimed to identify key parameters influencing N utilization and develop prediction equations for manure N output (MN), feces N output (FN), and urine N output (UN). Data were obtained under a series of digestibility trials with nonpregnant dry cows fed fresh grass at maintenance level. Grass was cut from 8 different ryegrass swards measured from early to late maturity in 2007 and 2008 (2 primary growth, 3 first regrowth, and 3 second regrowth) and from 2 primary growth early maturity swards in 2009. Each grass was offered to a group of 4 cows and 2 groups were used in each of the 8 swards in 2007 and 2008 for daily measurements over 6 wk; the first group (first 3 wk) and the second group (last 3 wk) assessed early and late maturity grass, respectively. Average values of continuous 3-d data of N intake (NI) and output for individual cows ( = 464) and grass nutrient contents ( = 116) were used in the statistical analysis. Grass N content was positively related to GE and ME contents but negatively related to grass water-soluble carbohydrates (WSC), NDF, and ADF contents ( < 0.01), indicating that accounting for nutrient interrelations is a crucial aspect of N mitigation. Significantly greater ratios of UN:FN, UN:MN, and UN:NI were found with increased grass WSC contents and ratios of N:WSC, N:digestible OM in total DM (DOMD), and N:ME ( < 0.01). Greater NI, animal BW, and grass N contents and lower grass WSC, NDF, ADF, DOMD, and ME concentrations were significantly associated with greater MN, FN, and UN ( < 0.05). The present study highlighted that using grass lower in N and greater in fermentable energy in animals fed solely fresh grass at maintenance level can improve N utilization, reduce N outputs, and shift part of N excretion toward feces rather than urine. These outcomes are highly desirable in mitigation strategies to reduce nitrous oxide emissions from livestock. Equations predicting N output from BW and grass N content explained a similar amount of variability as using NI and grass chemical composition (excluding DOMD and ME), implying that parameters easily measurable in practice could be used for estimating N outputs. In a research environment, where grass DOMD and ME are likely to be available, their use to predict N outputs is highly recommended because they strongly improved of the equations in the current study. PMID- 26020753 TI - Feeding reduced crude protein diets with crystalline amino acids supplementation reduce air gas emissions from housing. AB - The objective of this study was to test the hypothesis that reducing dietary CP by 1.5% and supplementing crystalline AA (CAA) to meet the standardized ileal digestible (SID) AA requirements for growing and finishing pigs decreases air emissions of ammonia (NH), nitrous oxide (NO), and carbon dioxide (CO) compared with an industry standard diet, without reducing growth performance. Seventy-two pigs were allocated to 12 rooms (6 pigs per room) and 2 diets (6 rooms per diet) formulated according to a 5-phase feeding program across the grow-finish period (107 d total). The diets consisted of a standard diet containing 18.5 to 12.2% CP or a reduced CP diet containing 17.5 to 11.0% CP + CAA over the course of the 5 phase feeding program. Gases (NH, NO, hydrogen sulfide, methane, nonmethane total hydrocarbon, and CO) and ventilation rates were measured continuously from the rooms. Compared with standard diet, ADG and feed conversion of pigs fed reduced CP + CAA diets did not differ (2.7 kg gain/d and 0.37 kg gain/kg feed, respectively). Compared with standard diet, feeding reduced CP + CAA diets decreased ( < 0.01) NH emissions by 46% over the 107-d period (5.4 and 2.9 g . pig . d, respectively). Change in NH emissions for each percentage unit reduction in dietary CP concentration corresponded with 47.9, 53.2, 26.8, 26.5, and 51.6% during Phases 1 through 5, respectively. Emissions of other gases did not differ between diets. Feeding reduced CP diets formulated based on SID AA requirements for grow-finisher swine is effective in reducing NH emissions from housing compared with recent industry formulations and does not impact growth performances. PMID- 26020754 TI - Effects of repeated transport on Holstein calf post-transport behavior and feed intake. AB - Previous studies have determined that stress causes decreases in feed intake and efficiency in livestock, but the effect of repeated transport on these parameters has not been well studied. This study determined how repeated transport affected calf post-transport behavior, feed intake, ADG, and feed conversion. Thirty-six 4 mo-old Holstein steer calves were housed in groups of 6 with each group randomly assigned to either transport or control treatments. Each calf was assigned to an individual Calan gate feeder and feed intake was recorded daily. Transport calves were transported for 6 h in their groups in a 7.3 by 2.4 m gooseneck trailer divided into 3 compartments, at an average density of 0.87 m/calf, every 7 d for 5 consecutive weeks. After return to their home pens, behavior was recorded for transported calves at 5-min intervals for 1 h. Calf ADG and feed conversion were analyzed in a mixed model ANOVA, whereas feed intake was analyzed as a repeated measure in a mixed model ANOVA. Post-transport, calves followed a pattern of drinking, eating, and then lying down. The highest (82 +/- 5% calves) and lowest (0 +/- 5% calves) incidences of eating behavior occurred 10 and 60 min post transport, respectively. Control calves had a higher feed intake than transported calves overall (7.29 +/- 0.22 kg for control and 6.91 +/- 0.21 kg for transport; = 0.01), for the feeding posttreatment (6.78 +/- 0.27 kg for control and 6.01 +/- 0.28 kg for transport; = 0.007), and the day after treatment (7.83 +/- 0.23 kg for control and 7.08 +/- 0.15 kg for transport; = 0.02). Feed intake for the feeding post-transport for transport calves significantly decreased after the second transport but increased with each successive transport ( < 0.0001). Overall, control calves had higher ADG than transported calves (1.34 +/- 0.13 kg/d for control and 1.15 +/- 0.12 kg/d for transport; = 0.006). No significant difference ( = 0.12) between treatments was detected for feed conversion. These results suggest that calves exposed to repeated transport may decrease feed intake compared to nontransported calves as an initial response to transport; however, overall feed conversion was not affected and these Holstein calves may have quickly acclimated to repeated transport. PMID- 26020755 TI - Physiological and metabolic responses of gestating Brahman cows to repeated transportation. AB - This study characterized physiological responses to repeated transportation (TRANS) of gestating cows of differing temperaments. Cows were classified as Calm (C; = 10), Intermediate (I; = 28), or Temperamental (T; = 10). Based on artificial insemination date and pregnancy confirmation, cows were TRANS for 2 h on d 60 (TRANS1), 80 (TRANS2), 100 (TRANS3), 120 (TRANS4), and 140 (TRANS5) +/- 5 d of gestation. Indwelling vaginal temperature (VT) monitoring devices were inserted 24 h before each TRANS with VT recorded from 2 h before TRANS and averaged into 5-min intervals through 30 min after TRANS. Serum samples were collected before loading and on unloading from the trailer to determine concentrations of cortisol, glucose, and nonesterified fatty acids (NEFA). Data were analyzed by repeated measures analysis in SAS. Serum cortisol concentrations were affected by temperament ( < 0.001), with T cows having the greater concentrations of cortisol before each TRANS event. All cows (100%) regardless of temperament exhibited elevations in cortisol following each TRANS event. Peak VT was greater ( < 0.001) at TRANS1 relative to all other TRANS events regardless of cow temperament. During TRANS, the T cows tended ( < 0.09) to have greater peak VT (39.86 +/- 0.15 degrees C) compared to C (39.41 +/- 0.16 degrees C) and I cows (39.55 +/- 0.08 degrees C). Area under the VT curve decreased ( = 0.002) from TRANS1 through TRANS5. Pre-TRANS serum glucose concentration at TRANS1 was greater ( < 0.03) for T (68.13 +/- 4.31mg/dL) compared to I (53.42 +/- 2.78 mg/dL) and C cows (52.76 +/- 4.60 mg/dL). The C and I cows had greater changes in NEFA concentration between pre- and post-transport, and T cows showed the least change ( < 0.001). Cow VT and serum glucose concentration decreased in all temperaments ( < 0.01) with repeated TRANS; however, serum NEFA concentration post-TRANS did not vary ( > 0.10) with repeated TRANS events. Serum glucose concentrations were affected ( < 0.02) by a TRANS event by temperament interaction with T cows taking more TRANS events to decrease their change in glucose concentration compared to C and I cows. These results demonstrate that temperament influences physiological responses to stress in gestating Brahman cows. Although repeated transport in our study is confounded with day of gestation, seasonal changes, and learning from repeated handling and transport, repeated transport is a useful model of repeated stress in studying the effects of temperament. PMID- 26020756 TI - Growth parameters, behavior, and meat and ham quality of heavy pigs subjected to photoperiods of different duration. AB - To attain a good level of animal welfare, pigs require a sufficient environmental illumination. Therefore, minimum levels for light duration and light intensity have been set up by the European legislation (Directive 2008/120). An experimental trial was designed to determine whether an increased duration of the photophase (up to 16 h of light per day) could modify the behavior, productive parameters, and meat and ham quality of Italian heavy pigs. Forty crossbred (Large White * Landrace) castrated males pigs (26 kg initial average BW) intended for Protected Designation of Origin (according to European Union Regulation 1151/2012, ) dry-cured ham production were raised according to Parma ham production rules up to the weight of 160 kg. Pigs were homogeneously allotted to 2 experimental groups, each comprising 20 pigs. The short photoperiod (SP) group received the minimum mandatory number of hours of light per day (corresponding to 8 h/d), whereas the long photoperiod (LP) group was subjected 16 h of light per day during the whole production cycle. Light intensity was maintained at 40 lux (i.e., the minimum mandatory level) for both the experimental groups. Growth and slaughtering parameters, carcass traits, fatty acid composition, meat and dry cured ham quality, and animal behavior were assessed. Pigs in the LP group showed a greater live weight and carcass weight compared to the SP group ( = 0.005 and = 0.007, respectively). Similarly, hams obtained from the LP group were significantly heavier and their weight losses during the dry-curing period were reduced ( < 0.01) when compared to the SP group. No significant differences were detected between the experimental groups as concerns meat and ham quality or fatty acid composition of the subcutaneous fat. Pigs in the LP group spent more time resting and less time pseudo-rooting ( < 0.01). Our results indicate that, given an appropriate dark period for animal rest, an increased duration of the photoperiod, even at the lower mandatory light intensity level, can favorably affect growth parameters of heavy pigs without any negative effect on animal behavior, carcass traits, or meat or long-cured ham quality. Therefore, rearing pigs in semidarkness should be considered as a baseless practice, contrary to animal welfare. PMID- 26020757 TI - Growth responses of broiler chickens to different periods of artificial light. AB - This study aimed to establish response curves between broiler chicken growth parameters and artificial light periods, as opposed to optimizing a lighting regimen for broiler production. Medium-growing broiler chickens were illuminated for periods of 12, 14, 16, 18, 20, 22, or 24 h each day. The BW of the broilers were significantly influenced by light periods ( < 0.05). Moreover, BW responded to light periods in a linear fashion, suggesting that long light periods result in greater BW. In addition, a linear relationship was found between feed intake and light periods. However, the relationship between shank length and light period was quadratic. When the light period was too short (12 h) or too long (24 h), the light stimulus did not enhance shank growth in the broiler chickens ( < 0.05). In addition, a quadratic relationship between the quantity of abdominal adipose tissue and light period suggested that the quantity of abdominal adipose decreases when the period of the light stimulus was too short or too long ( < 0.05). Moreover, a broken-stick analysis suggested that the triiodothyronine (T3) concentration in the blood was minimally affected beyond 18 h ( = 0.267), although a quadratic relationship was found between the period (from 18 to 24 h) and T3 concentrations in the blood. The response curves established in the present study will be valuable for designing future lighting regimes for medium growing broiler strains. PMID- 26020758 TI - Effects of anti-phospholipase A(2) antibody supplementation on dry matter intake feed efficiency, acute phase response, and blood differentials of steers fed forage- and grain-based diets. AB - To determine whether supplementation of anti-phospholipase A antibody (aPLA) would alter voluntary DMI, feed efficiency (FE), acute-phase protein concentration, and blood differentials (BD) due to a change in diet from a forage based to a grain-based diet, individual daily DMI was measured on 80 cross-bred steers during a 141-d period. On d 0, steers were blocked by BW and randomly assigned to receive a growing forage diet containing 1) no additive (CON; = 20), 2) inclusion of 30 mg of monensin and 8.8 mg of tylosin per kg of diet DM (MT; = 20), 3) inclusion of an aPLA supplement at 0.4% of the diet DM (0.4% aPLA; = 20), and 4) inclusion of an aPLA supplement at 0.2% of the diet DM (0.2% aPLA; = 20). On d 60, steers were transitioned into a grain-based diet (90% concentrate) over a 21-d "step-up" period while continuing to receive their supplement treatments and were maintained on the high-grain diet until the end of the trial on d 141. On d 0, 60, 81, and 141, individual shrunk BW was recorded. Blood samples were collected on d 60, 63, 65, 67, 70, 72, 74, 77, 79, 81, and 84 for determination of concentration of plasma ceruloplasmin, haptoglobin, and BD. During the growing forage-diet period, steers from the 0.2% aPLA and 0.4% aPLA treatments had lower ( < 0.05) residual feed intake (RFI; -0.12 +/- 0.13 and -0.22 +/- 0.13 kg/d, respectively) than steers from the CON treatment (0.31 +/- 0.13 kg/d). During the grain-based diet period, the 0.2% aPLA (-0.12 +/- 0.10 kg/d), 0.4% aPLA (0.36 +/- 0.10 kg/d), and MT (0.10 +/- 0.10 kg/d) steers had greater ( = 0.04) RFI than CON steers (-0.37 +/- 0.10 kg/d). During the transition phase, white blood cell counts were greater ( = 0.04) for the 0.2% aPLA treatment (13.61 * 10 +/- 0.42 * 10 cells/MUL) than the 0.4% aPLA and MT treatments (12.16 * 10 +/- 0.42 * 10 and 12.37 * 10 +/- 0.42 * 10 cells/MUL, respectively) and concentrations of lymphocytes also were greater ( = 0.01) for the 0.2% aPLA treatment (7.66 * 10 +/ 0.28 * 10 cells/MUL) than the 0.4% aPLA and MT treatments (6.71 * 10 +/- 0.28 * 10 and 6.70 * 10 +/- 0.28 * 10 cells/MUL, respectively). Concentrations of plasma ceruloplasmin and haptoglobin were reduced ( < 0.05) for CON compared to aPLA steers (22.2 +/- 0.83 vs. 24.4 +/- 0.83 mg/dL and 0.18 +/- 0.05 vs. 0.26 +/- 0.05 mg/mL, respectively). Supplementation of aPLA improved FE of steers fed a forage based growing diet but not when feeding grain-based diets. The 0.4% aPLA and MT treatments had decreased white blood cell counts and concentration of lymphocytes during the transition period compared to the 0.2% aPLA treatment, and CON steers had reduced concentrations of plasma ceruloplasmin and haptoglobin during the diet transition phase. PMID- 26020759 TI - Color stability and sensory characteristics of fresh and enhanced pork loins from immunologically castrated barrows. AB - Our objective was to evaluate color changes during storage of fresh pork chops and enhanced and nonenhanced loin quality from anti-gonadotropin-releasing factor (Improvest) immunologically castrated (IC) barrows. In study 1, treatments evaluated were IC barrows, IC barrows fed ractopamine (IC+RAC), physically castrated (PC) barrows, intact males (IM), and gilts. Fresh loins were evaluated for sensory characteristics and instrumental tenderness including both Warner Bratzler Shear force (WBSF) and star probe force. In study 2, treatments evaluated were IC barrows fed 0.55% and 0.65% standard ileal digestible (SID) lysine and PC barrows fed 0.55% SID lysine. Loin chops were displayed for 7 d, and color was evaluated. The remaining loin was halved, and one half was enhanced with a 3.5% salt and phosphate solution. Enhanced loins were evaluated for sensory characteristics and instrumental tenderness. In both studies, pen served as the experimental unit for all traits measured. Data from individual animals were averaged by pen and analyzed, per study, as a 1-way ANOVA using the MIXED procedure of SAS. In study 1, there were no differences ( 0.05) between treatments for juiciness, tenderness, chewiness, or off-flavor. Intact males had the most intense ( 0.05) boar aroma. Gilts had the most intense ( < 0.05) pork flavor, whereas IM had the least intense pork flavor; all other treatments were intermediate. Tenderness (WBSF) was similar between treatments at 1 d of aging; however, at 7, 14, and 21 d of aging, loins from IC barrows were more tender ( 0.05) than those from gilts, IM, and IC+RAC but were similar ( 0.05) to those from PC. In study 2, discoloration of fresh loin chops during storage was similar ( 0.42) between PC and IC barrows. Chops from enhanced loins were more tender and juicy but had more off-flavor than nonenhanced loins ( 0.01). Star probe and WBSF were also reduced ( 0.01) in enhanced loins compared with nonenhanced loins. Sensory characteristics and tenderness were not different between treatments of IC and PC barrows ( > 0.05), and there were no interactions of enhancement with castration treatments. These data suggest that immunological castration does not negatively impact the color stability, sensory characteristics, or tenderness of enhanced or nonenhanced pork loins. PMID- 26020760 TI - Daytime shelter use of individually kept horses during Swedish summer. AB - In Sweden, no provision for summer shelter to protect horses from heat and insects is required, although access to shelter for horses kept outdoors 24 h during winter is a requirement. This study investigated horses' daytime shelter seeking behavior in relation to weather conditions and insect activity during a 2 wk period in summer. Eight Warmblood riding horses had access to 2 shelters of different design to test which shelter design is preferred by horses. Furthermore, rectal and skin temperatures and insect-defensive behavior were measured to test whether horses would benefit from the provision of shade. The horses were kept alone in paddocks for 4 d. During 2 d, horses had access to 2 shelters: 1) open shelter with roof and uncovered sides and 2) closed shelter with roof, wind nets on 2 sides, and opaque plastic opposite the entrance. Weather conditions (ambient temperature, relative humidity, solar radiation, wind speed) were recorded every 10 min. The number of insects (flies, mosquitos) was counted from insect traps placed in each shelter and outside. Behavior (shelter use, insect-defensive behavior, locomotion, grazing) was recorded at 5-min intervals between 0900 to 1200 h and 1300 to 1600 h and rectal and skin temperatures were measured at 0800 h, 1200 h, and 1600 h. Data were analyzed with PROC MIXED and GLIMMIX procedure for Generalized Linear Mixed Models. Ambient temperature ranged from 16 to 25 degrees C (average temperature humidity index 65.7 +/- 1.4). Five horses preferred the closed shelter and were observed inside up to 2.5 h continuously. Greater wind speed decreased the likelihood of observing horses inside the shelter ( < 0.001), as did lower numbers of flies ( < 0.001). The insect-defensive behaviors, skin shiver and ear flick, were performed less frequently when horses were using the closed shelter ( < 0.001), indicating that they were less disturbed by insects. Thirty-minute shelter use had no effect on rectal and skin temperatures ( > 0.05). Results showed that horses made use of shelters during the summer even when weather conditions were moderate. A shelter with roof and covers on 3 sides was preferred over a shelter with roof only and can reduce insect-defensive behavior. PMID- 26020761 TI - The Association of Vitamin D With Femoral Neck Strength: An Additional Evidence of Vitamin D on Bone Health. AB - CONTEXT: Although bone mineral density (BMD) is a strong predictor of fracture risk, additional parameters, such as bone strength, are needed to predict future fracture risk because of the low sensitivity of BMD for predicting fracture risk. OBJECTIVE: The objective was to study the association of vitamin D with femoral neck (FN) strength. DESIGN AND SETTING: This was a population-based, cross sectional study from Korea National Health and Nutrition Examination Surveys. PARTICIPANTS: A total of 1209 Koreans (586 men and 623 women) aged >=50 years participated. MAIN OUTCOME MEASURES: We calculated composite indices of FN strength, such as the compression strength index, bending strength index (BSI), and impact strength index, by combining BMD, body weight, and height with the femoral axis length and width, which were measured by dual-energy x-ray absorptiometry. RESULTS: Multiple regression analysis demonstrated that serum 25 hydroxyvitamin D [25(OH)D] levels were associated with compression strength index, BSI, and impact strength index in both genders. When women were categorized into four quartiles of 25(OH)D, FN BMD and composite indices (except for BSI) significantly increased from the lowest (Q1) to the highest quartile (Q4) (P for trend = .001-.004). In contrast, there is no significant association of quartiles with composite indices in men. When women were divided into two groups according to their serum 25(OH)D levels, the composite indices as well as the FN BMD were markedly higher in subjects with higher 25(OH)D levels (>=51.5 nmol/L). CONCLUSION: These findings provide the first clinical evidence that high serum 25(OH)D levels exhibit higher composite indices of FN strength in a dose dependent manner, especially in women. PMID- 26020762 TI - Myocardial Fat Accumulation Is Independent of Measures of Insulin Sensitivity. AB - BACKGROUND: Myocardial steatosis, an independent predictor of diastolic dysfunction, is frequently present in type 2 diabetes mellitus. High free fatty acid flux, hyperglycemia, and hyperinsulinemia may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (antilipolytic and glucose disposal actions of insulin) and cardiac steatosis. OBJECTIVE: Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the antilipolytic and glucose disposal actions of insulin. METHODS: Pericardial fat (PF) volume, intramyocardial and hepatic fat (MF and HF) content, visceral fat (VF) and sc fat content were assessed by magnetic resonance imaging in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n = 52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) were determined from an insulin-modified frequently sampled iv glucose tolerance test. The Quantitative Insulin Sensitivity Check Index was used as a surrogate for hepatic insulin sensitivity. RESULTS: Individuals with the MetSyn had significantly higher body mass index, total body fat, and MF, PF, HF, and VF content. HF and VF, but not MF, were negatively correlated with the Quantitative Insulin Sensitivity Check Index, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum triglyceride levels independently predicted MF and PF, respectively. Adipo-SI and serum triglyceride levels independently predict HF. CONCLUSION: Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although it is frequently observed in insulin resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis. PMID- 26020763 TI - Adiponectin, Insulin Sensitivity and Diabetic Retinopathy in Latinos With Type 2 Diabetes. AB - CONTEXT AND OBJECTIVE: Insulin resistance and chronic inflammation are key elements in the pathogenesis of type 2 diabetes. We hypothesized that similar mechanisms could have a role in the development of diabetic retinopathy (DR), an important microvascular complication in Latinos with type 2 diabetes. DESIGN AND SETTING: A cross-sectional, family-based, observational cohort study. PATIENTS: Latino subjects with type 2 diabetes (n = 507), ascertained in families via a proband with known diabetes duration of 10 years or more and/or with DR, were included. MAIN OUTCOME MEASURES: Serum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). DR was assessed by seven-field digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale (range of severity levels, 10-85). RESULTS: Fasting adiponectin concentrations were elevated in patients with DR compared to those without (12.9 +/- 0.5 vs 10.5 +/- 0.5 MUg/mL; P = .0004) and remained significant after adjusting for multiple covariates (age, gender, body mass index, glycosylated hemoglobin, diabetes duration, statin use, blood pressure, and renal function; P = .013 to .018). Adiponectin was also positively correlated with severity of DR in patients with nonproliferative DR (P < .0003), significant also after all covariate adjustments (P = .018). When the proliferative DR group was included, this relationship was attenuated by adjustments, possibly an influence of estimated glomerular filtration rate reduction in the proliferative DR group. HOMA-IR was not different in the DR and non-DR groups. Although elevated, adiponectin retained a typical inverse relationship with HOMA-IR in DR, similar to that seen in the non-DR group. CONCLUSIONS: Serum adiponectin is elevated in DR, is positively correlated with DR severity in Latinos with type 2 diabetes, and maintains a relationship to insulin sensitivity. Adiponectin, whether as a marker or biological mediator, may play an important role in DR, which appears to be independent of its relationship to insulin sensitivity. PMID- 26020764 TI - Dysglycemia and Cognitive Dysfunction and Ill Health in People With High CV Risk: Results From the ONTARGET/TRANSCEND Studies. AB - CONTEXT: Avoidance of death, disability, dementia, and cognitive dysfunction (DDCD) are high priorities for people in aging societies. Evidence is mounting that these conditions are associated with impaired glycemic control. OBJECTIVE: The aim of this study was to assess the strength of relationship between the degree of glucose elevation and the development of the composite elements of DDCD that impede successful/healthy aging in a population at high risk for cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURE: The relationship between baseline fasting plasma glucose values and DDCD was determined among 31 227 participants of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE intolerant Subjects With Cardiovascular Disease studies followed up for a median of 4.7 years. Several statistical models were used for the entire cohort and for those with and without normal fasting plasma glucose (ie, < 5.6 mmol/L) or a history of diabetes mellitus. RESULTS: After adjusting for age and sex, a diagnosis of diabetes mellitus was associated with an approximately 1.6 greater odds of DDCD; every 1 mmol/L higher baseline fasting plasma glucose value was associated with a 1.09 (95% confidence interval 1.07, 1.10) greater odds. These associations persisted in the multivariate models (a 1.08 95% confidence interval 1.07, 1.1 greater odds after adjustment for age, sex, education, and depression). CONCLUSION: In individuals with high cardiovascular risk, a direct relationship exists between levels of dysglycemia and the risk of DDCD. Further research is needed to understand the mechanisms underlying such an association and whether benefits can be derived from preventative strategies. PMID- 26020765 TI - Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans? AB - PURPOSE: In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. METHODS AND RESULTS: Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. CONCLUSIONS: The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ~3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility. PMID- 26020766 TI - MicroRNA-193b Controls Adiponectin Production in Human White Adipose Tissue. AB - CONTEXT: MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression. In white adipose tissue (WAT), recent studies suggest that miRNA levels are altered in various metabolic diseases, including obesity. OBJECTIVE: The objective of the study was to determine whether adipocyte-expressed miRNAs altered by obesity can regulate adiponectin expression/secretion in fat cells. DESIGN: Eleven miRNAs previously shown to be altered in obese human WAT were overexpressed in human in vitro-differentiated adipocytes followed by assessments of adiponectin levels in conditioned media. SETTING: This was cohort study (n = 56) in an academic hospital. PATIENTS: Subcutaneous WAT was obtained from nonobese and obese individuals. INTERVENTIONS: There were no interventions in this study. MAIN OUTCOME MEASURE(S): Protein and mRNA levels of adiponectin were measured. RESULTS: Of the 11 investigated miRNAs, three (miR-193b/-126/-26a) increased adiponectin secretion when overexpressed in human adipocytes. However, in human WAT only miR-193b expression correlated with adiponectin gene expression and homeostasis model assessment of insulin resistance. Moreover, quantitative PCR of miR-193b in both WAT and isolated adipocytes showed a significant association with serum adiponectin levels. Overexpression of miR-193b altered the gene expression of seven known adiponectin regulators. 3'-untranslated region reporter assays confirmed binding to cAMP-responsive element binding protein 5, nuclear receptor interacting protein 1, and nuclear transcription factor Yalpha. The effects of miR-193b on nuclear transcription factor Yalpha expression were confirmed at the protein level. Transfection with individual miRNA target protectors selective for nuclear transcription factor Yalpha and nuclear receptor interacting protein 1 abolished the stimulatory effect of miR-193b on adiponectin secretion. CONCLUSIONS: In human adipocytes, miR-193b controls adiponectin production via pathways involving nuclear transcription factor Yalpha and possibly nuclear receptor interacting protein 1. PMID- 26020767 TI - Production of L-allose and D-talose from L-psicose and D-tagatose by L-ribose isomerase. AB - L-ribose isomerase (L-RI) from Cellulomonas parahominis MB426 can convert L psicose and D-tagatose to L-allose and D-talose, respectively. Partially purified recombinant L-RI from Escherichia coli JM109 was immobilized on DIAION HPA25L resin and then utilized to produce L-allose and D-talose. Conversion reaction was performed with the reaction mixture containing 10% L-psicose or D-tagatose and immobilized L-RI at 40 degrees C. At equilibrium state, the yield of L-allose and D-talose was 35.0% and 13.0%, respectively. Immobilized enzyme could convert L-psicose to L-allose without remarkable decrease in the enzyme activity over 7 times use and D-tagatose to D-talose over 37 times use. After separation and concentration, the mixture solution of L-allose and D-talose was concentrated up to 70% and crystallized by keeping at 4 degrees C. L-Allose and d-talose crystals were collected from the syrup by filtration. The final yield was 23.0% L allose and 7.30% D-talose that were obtained from L-psicose and D-tagatose, respectively. PMID- 26020768 TI - Evolutionary, Comparative and Functional Analyses of the Brassinosteroid Receptor Gene, BRI1, in Wheat and Its Relation to Other Plant Genomes. AB - Brassinosteroids (BRs) are plant hormones, fundamental for the growth and development of plants. A trans-membrane protein receptor kinase, Brassinosteroid Insensitive 1 (BRI1), is known to interact with BRs and be directly involved in plant development. This study investigates the structural organization of BRI1 orthologs in several taxa, with a specific interest in Triticum aestivum. True orthologs of Arabidopsis thaliana BRI1 (AtBRI1) from seven-plant species showed sequence identity ranging from 54% to 95% at the protein level. All gene sequences lacked introns, leading to speculation that post-transcriptional processing in TaBRI1 is similar to AtBRI1. Based on in silico analysis, a single copy of BRI1 was present in each of the three wheat genomes on the long arm of chromosome 3. Domain structure of BRI1 orthologs among different taxa showed multiple leucine rich repeats (LRRs), an island domain (ID), a juxtamembrane/transmembrane domain (JTMD), a catalytic kinase domain (KD), C and N-Terminal domains. The KD showed the highest level of conservation while the LRRs and JTMD were most variable. Phosphorylation of residues in the juxtamembrane domain, known to be involved in the activation of the KD, is conserved in TaBRI1. While TaBRI1 has well-defined differences in the ID and LRR domains, many residues involved in ligand binding are conserved. The activation loop present in the KD showed 100% conservation in all taxa. Despite residue differences, hydrophobicity was conserved in the BR binding pocket across taxa, suggesting that function may not differ as drastically as residue identity may suggest. Predicted 3D structure of AtBRI1 and TaBRI1 showed a conserved super helical assembly, a feature essential in protein-protein interactions. An unrooted phylogram showed TaBRI1 in the monocot clade to be distinct from that of dicots. New insight in the structure and functions of BRI1 may help in targeting BR pathway for crop improvement. PMID- 26020769 TI - Causal Modeling of Cancer-Stromal Communication Identifies PAPPA as a Novel Stroma-Secreted Factor Activating NFkappaB Signaling in Hepatocellular Carcinoma. AB - Inter-cellular communication with stromal cells is vital for cancer cells. Molecules involved in the communication are potential drug targets. To identify them systematically, we applied a systems level analysis that combined reverse network engineering with causal effect estimation. Using only observational transcriptome profiles we searched for paracrine factors sending messages from activated hepatic stellate cells (HSC) to hepatocellular carcinoma (HCC) cells. We condensed these messages to predict ten proteins that, acting in concert, cause the majority of the gene expression changes observed in HCC cells. Among the 10 paracrine factors were both known and unknown cancer promoting stromal factors, the former including Placental Growth Factor (PGF) and Periostin (POSTN), while Pregnancy-Associated Plasma Protein A (PAPPA) was among the latter. Further support for the predicted effect of PAPPA on HCC cells came from both in vitro studies that showed PAPPA to contribute to the activation of NFkappaB signaling, and clinical data, which linked higher expression levels of PAPPA to advanced stage HCC. In summary, this study demonstrates the potential of causal modeling in combination with a condensation step borrowed from gene set analysis [Model-based Gene Set Analysis (MGSA)] in the identification of stromal signaling molecules influencing the cancer phenotype. PMID- 26020770 TI - Epileptogenesis following Kainic Acid-Induced Status Epilepticus in Cyclin D2 Knock-Out Mice with Diminished Adult Neurogenesis. AB - The goal of this study was to determine whether a substantial decrease in adult neurogenesis influences epileptogenesis evoked by the intra-amygdala injection of kainic acid (KA). Cyclin D2 knockout (cD2 KO) mice, which lack adult neurogenesis almost entirely, were used as a model. First, we examined whether status epilepticus (SE) evoked by an intra-amygdala injection of KA induces cell proliferation in cD2 KO mice. On the day after SE, we injected BrdU into mice for 5 days and evaluated the number of DCX- and DCX/BrdU-immunopositive cells 3 days later. In cD2 KO control animals, only a small number of DCX+ cells was observed. The number of DCX+ and DCX/BrdU+ cells/mm of subgranular layer in cD2 KO mice increased significantly following SE (p<0.05). However, the number of newly born cells was very low and was significantly lower than in KA-treated wild type (wt) mice. To evaluate the impact of diminished neurogenesis on epileptogenesis and early epilepsy, we performed video-EEG monitoring of wt and cD2 KO mice for 16 days following SE. The number of animals with seizures did not differ between wt (11 out of 15) and cD2 KO (9 out of 12) mice. The median latency to the first spontaneous seizure was 4 days (range 2-10 days) in wt mice and 8 days (range 2 16 days) in cD2 KO mice and did not differ significantly between groups. Similarly, no differences were observed in median seizure frequency (wt: 1.23, range 0.1-3.4; cD2 KO: 0.57, range 0.1-2.0 seizures/day) or median seizure duration (wt: 51 s, range 23-103; cD2 KO: 51 s, range 23-103). Our results indicate that SE-induced epileptogenesis is not disrupted in mice with markedly reduced adult neurogenesis. However, we cannot exclude the contribution of reduced neurogenesis to the chronic epileptic state. PMID- 26020771 TI - Mammalian Base Excision Repair: Functional Partnership between PARP-1 and APE1 in AP-Site Repair. AB - The apurinic/apyrimidinic- (AP-) site in genomic DNA arises through spontaneous base loss and base removal by DNA glycosylases and is considered an abundant DNA lesion in mammalian cells. The base excision repair (BER) pathway repairs the AP site lesion by excising and replacing the site with a normal nucleotide via template directed gap-filling DNA synthesis. The BER pathway is mediated by a specialized group of proteins, some of which can be found in multiprotein complexes in cultured mouse fibroblasts. Using a DNA polymerase (pol) beta immunoaffinity-capture technique to isolate such a complex, we identified five tightly associated and abundant BER factors in the complex: PARP-1, XRCC1, DNA ligase III, PNKP, and Tdp1. AP endonuclease 1 (APE1), however, was not present. Nevertheless, the complex was capable of BER activity, since repair was initiated by PARP-1's AP lyase strand incision activity. Addition of purified APE1 increased the BER activity of the pol beta complex. Surprisingly, the pol beta complex stimulated the strand incision activity of APE1. Our results suggested that PARP-1 was responsible for this effect, whereas other proteins in the complex had no effect on APE1 strand incision activity. Studies of purified PARP 1 and APE1 revealed that PARP-1 was able to stimulate APE1 strand incision activity. These results illustrate roles of PARP-1 in BER including a functional partnership with APE1. PMID- 26020772 TI - Level of Fatty Acid Binding Protein 5 (FABP5) Is Increased in Sputum of Allergic Asthmatics and Links to Airway Remodeling and Inflammation. AB - BACKGROUND: The inflammatory processes in the upper and lower airways in allergic rhinitis and asthma are similar. Induced sputum and nasal lavage fluid provide a non-invasive way to examine proteins involved in airway inflammation in these conditions. OBJECTIVES: We conducted proteomic analyses of sputum and nasal lavage fluid samples to reveal differences in protein abundances and compositions between the asthma and rhinitis patients and to investigate potential underlying mechanisms. METHODS: Induced sputum and nasal lavage fluid samples were collected from 172 subjects with 1) allergic rhinitis, 2) asthma combined with allergic rhinitis, 3) nonallergic rhinitis and 4) healthy controls. Proteome changes in 21 sputum samples were analysed with two-dimensional difference gel electrophoresis (2D-DIGE), and the found differentially regulated proteins identified with mass spectrometry. Immunological validation of identified proteins in the sputum and nasal lavage fluid samples was performed with Western blot and ELISA. RESULTS: Altogether 31 different proteins were identified in the sputum proteome analysis, most of these were found also in the nasal lavage fluid. Fatty acid binding protein 5 (FABP5) was up-regulated in the sputum of asthmatics. Immunological validation in the whole study population confirmed the higher abundance levels of FABP5 in asthmatic subjects in both the sputum and nasal lavage fluid samples. In addition, the vascular endothelial growth factor (VEGF) level was increased in the nasal lavage fluid of asthmatics and there were positive correlations between FABP5 and VEGF levels (r=0.660, p<0.001) and concentrations of FABP5 and cysteinyl leukotriene (CysLT) (r=0.535, p<0.001) in the nasal lavage fluid. CONCLUSIONS: FABP5 may contribute to the airway remodeling and inflammation in asthma by fine-tuning the levels of CysLTs, which induce VEGF production. PMID- 26020773 TI - Chitosan enriched three-dimensional matrix reduces inflammatory and catabolic mediators production by human chondrocytes. AB - This in vitro study investigated the metabolism of human osteoarthritic (OA) chondrocytes encapsulated in a spherical matrix enriched of chitosan. Human OA chondrocytes were encapsulated and cultured for 28 days either in chitosan alginate beads or in alginate beads. The beads were formed by slowly passing dropwise either the chitosan 0.6%-alginate 1.2% or the alginate 1.2% solution through a syringe into a 102 mM CaCl2 solution. Beads were analyzed histologically after 28 days. Interleukin (IL)-6 and -8, prostaglandin (PG) E2, matrix metalloproteinases (MMPs), hyaluronan and aggrecan were quantified directly in the culture supernatant by specific ELISA and nitric oxide (NO) by using a colorimetric method based on the Griess reaction. Hematoxylin and eosin staining showed that chitosan was homogeneously distributed through the matrix and was in direct contact with chondrocytes. The production of IL-6, IL-8 and MMP 3 by chondrocytes significantly decreased in chitosan-alginate beads compared to alginate beads. PGE2 and NO decreased also significantly but only during the first three days of culture. Hyaluronan and aggrecan production tended to increase in chitosan-alginate beads after 28 days of culture. Chitosan-alginate beads reduced the production of inflammatory and catabolic mediators by OA chondrocytes and tended to stimulate the synthesis of cartilage matrix components. These particular effects indicate that chitosan-alginate beads are an interesting scaffold for chondrocytes encapsulation before transplantation to repair cartilage defects. PMID- 26020774 TI - Geometric Constraints Dominate the Antigenic Evolution of Influenza H3N2 Hemagglutinin. AB - We have carried out a comprehensive analysis of the determinants of human influenza A H3 hemagglutinin evolution. We consider three distinct predictors of evolutionary variation at individual sites: solvent accessibility (as a proxy for protein fold stability and/or conservation), Immune Epitope Database (IEDB) epitope sites (as a proxy for host immune bias), and proximity to the receptor binding region (as a proxy for one of the functions of hemagglutinin-to bind sialic acid). Individually, these quantities explain approximately 15% of the variation in site-wise dN/dS. In combination, solvent accessibility and proximity explain 32% of the variation in dN/dS; incorporating IEDB epitope sites into the model adds only an additional 2 percentage points. Thus, while solvent accessibility and proximity perform largely as independent predictors of evolutionary variation, they each overlap with the epitope-sites predictor. Furthermore, we find that the historical H3 epitope sites, which date back to the 1980s and 1990s, only partially overlap with the experimental sites from the IEDB, and display similar overlap in predictive power when combined with solvent accessibility and proximity. We also find that sites with dN/dS > 1, i.e., the sites most likely driving seasonal immune escape, are not correctly predicted by either historical or IEDB epitope sites, but only by proximity to the receptor binding region. In summary, a simple geometric model of HA evolution outperforms a model based on epitope sites. These results suggest that either the available epitope sites do not accurately represent the true influenza antigenic sites or that host immune bias may be less important for influenza evolution than commonly thought. PMID- 26020775 TI - Heat Resistant Characteristics of Major Royal Jelly Protein 1 (MRJP1) Oligomer. AB - Soluble royal jelly protein is a candidate factor responsible for mammiferous cell proliferation. Major royal jelly protein 1 (MRJP1), which consists of oligomeric and monomeric forms, is an abundant proliferative protein in royal jelly. We previously reported that MRJP1 oligomer has biochemical heat resistance. Therefore, in the present study, we investigated the effects of several heat treatments (56, 65 and 96 degrees C) on the proliferative activity of MRJP1 oligomer. Heat resistance studies showed that the oligomer molecular forms were slightly maintained until 56C, but the molecular forms were converted to macromolecular heat-aggregated MRJP1 oligomer at 65C and 96C. But, the growth activity of MRJP1 oligomer treated with 96 degrees C was slightly attenuated when compared to unheated MRJP1 oligomer. On the other hand, the cell proliferation activity was preserved until 96C by the cell culture analysis of Jurkat cells. In contrast, those of IEC-6 cells were not preserved even at 56 degrees C. The present observations suggest that the bioactive heat-resistance properties were different by the origin of the cells. The cell proliferation analysis showed that MRJP1 oligomer, but not MRJP2 and MRJP3, significantly increased cell numbers, suggesting that MRJP1 oligomer is the predominant proliferation factor for mammiferous cells. PMID- 26020776 TI - Metatranscriptomic Analysis of Pycnopodia helianthoides (Asteroidea) Affected by Sea Star Wasting Disease. AB - Sea star wasting disease (SSWD) describes a suite of symptoms reported in asteroids of the North American Pacific Coast. We performed a metatranscriptomic survey of asymptomatic and symptomatic sunflower star (Pycnopodia helianthoides) body wall tissues to understand holobiont gene expression in tissues affected by SSWD. Metatranscriptomes were highly variable between replicate libraries, and most differentially expressed genes represented either transcripts of associated microorganisms (particularly Pseudomonas and Vibrio relatives) or low-level echinoderm transcripts of unknown function. However, the pattern of annotated host functional genes reflects enhanced apoptotic and tissue degradation processes and decreased energy metabolism, while signalling of death-related proteins was greater in asymptomatic and symptomatic tissues. Our results suggest that the body wall tissues of SSWD-affected asteroids may undergo structural changes during disease progression, and that they are stimulated to undergo autocatalytic cell death processes. PMID- 26020777 TI - Correction: A Causal Relation between Bioluminescence and Oxygen to Quantify the Cell Niche. PMID- 26020778 TI - Design space development for the extraction process of Danhong injection using a Monte Carlo simulation method. AB - A design space approach was applied to optimize the extraction process of Danhong injection. Dry matter yield and the yields of five active ingredients were selected as process critical quality attributes (CQAs). Extraction number, extraction time, and the mass ratio of water and material (W/M ratio) were selected as critical process parameters (CPPs). Quadratic models between CPPs and CQAs were developed with determination coefficients higher than 0.94. Active ingredient yields and dry matter yield increased as the extraction number increased. Monte-Carlo simulation with models established using a stepwise regression method was applied to calculate the probability-based design space. Step length showed little effect on the calculation results. Higher simulation number led to results with lower dispersion. Data generated in a Monte Carlo simulation following a normal distribution led to a design space with a smaller size. An optimized calculation condition was obtained with 10,000 simulation times, 0.01 calculation step length, a significance level value of 0.35 for adding or removing terms in a stepwise regression, and a normal distribution for data generation. The design space with a probability higher than 0.95 to attain the CQA criteria was calculated and verified successfully. Normal operating ranges of 8.2-10 g/g of W/M ratio, 1.25-1.63 h of extraction time, and two extractions were recommended. The optimized calculation conditions can conveniently be used in design space development for other pharmaceutical processes. PMID- 26020779 TI - Dissecting the function and assembly of acentriolar microtubule organizing centers in Drosophila cells in vivo. AB - Acentriolar microtubule organizing centers (aMTOCs) are formed during meiosis and mitosis in several cell types, but their function and assembly mechanism is unclear. Importantly, aMTOCs can be overactive in cancer cells, enhancing multipolar spindle formation, merotelic kinetochore attachment and aneuploidy. Here we show that aMTOCs can form in acentriolar Drosophila somatic cells in vivo via an assembly pathway that depends on Asl, Cnn and, to a lesser extent, Spd-2- the same proteins that appear to drive mitotic centrosome assembly in flies. This finding enabled us to ablate aMTOC formation in acentriolar cells, and so perform a detailed genetic analysis of the contribution of aMTOCs to acentriolar mitotic spindle formation. Here we show that although aMTOCs can nucleate microtubules, they do not detectably increase the efficiency of acentriolar spindle assembly in somatic fly cells. We find that they are required, however, for robust microtubule array assembly in cells without centrioles that also lack microtubule nucleation from around the chromatin. Importantly, aMTOCs are also essential for dynein-dependent acentriolar spindle pole focusing and for robust cell proliferation in the absence of centrioles and HSET/Ncd (a kinesin essential for acentriolar spindle pole focusing in many systems). We propose an updated model for acentriolar spindle pole coalescence by the molecular motors Ncd/HSET and dynein in conjunction with aMTOCs. PMID- 26020780 TI - The FP25K Acts as a Negative Factor for the Infectivity of AcMNPV Budded Virus. AB - Baculoviruses generally produce two progeny phenotypes--the budded virus (BV) and the occlusion-derived virus (ODV)--and the intricate mechanisms that regulate the temporal synthesis of the two phenotypes are critical for the virus replication cycle, which are far from being clearly understood. FP25K was reported to be responsible for the regulation of BV/ODV, and the mutations within result in a decrease of normal ODVs formation and an increase of BVs production. In this study, we demonstrated that the increase of BV titer in an fp25k knockout recombinant (fp25k-negative) was a result of higher infectivity of BVs rather than an increased production of BVs. The constitution of the major structural proteins and genome of parental and fp25k-negative BVs were analyzed. The results showed that the integrity of the majority of DNA packaged into the fp25k-negative BVs was intact; i.e., the genomic DNA of fp25k-negative BV had better transformation and transfection efficiency than that of the parental virus, indicating more intact genomes in the virions. Although the analysis of proteins associated with BVs revealed that more envelope protein GP64 were incorporated into the fp25k-negative BVs, subsequent experiments suggested that overexpression of GP64 did not improve the titer of BVs. Thus, we conclude that the main reason for higher infectivity of BVs is due to better genome integrity, which benefits from the deletion of fp25k resulting in increased stability of the genome and produce a higher proportion of infectious BVs. FP25K acts as a negative factor for the infectivity of BV. PMID- 26020781 TI - Candidatus Frankia Datiscae Dg1, the Actinobacterial Microsymbiont of Datisca glomerata, Expresses the Canonical nod Genes nodABC in Symbiosis with Its Host Plant. AB - Frankia strains are nitrogen-fixing soil actinobacteria that can form root symbioses with actinorhizal plants. Phylogenetically, symbiotic frankiae can be divided into three clusters, and this division also corresponds to host specificity groups. The strains of cluster II which form symbioses with actinorhizal Rosales and Cucurbitales, thus displaying a broad host range, show suprisingly low genetic diversity and to date can not be cultured. The genome of the first representative of this cluster, Candidatus Frankia datiscae Dg1 (Dg1), a microsymbiont of Datisca glomerata, was recently sequenced. A phylogenetic analysis of 50 different housekeeping genes of Dg1 and three published Frankia genomes showed that cluster II is basal among the symbiotic Frankia clusters. Detailed analysis showed that nodules of D. glomerata, independent of the origin of the inoculum, contain several closely related cluster II Frankia operational taxonomic units. Actinorhizal plants and legumes both belong to the nitrogen fixing plant clade, and bacterial signaling in both groups involves the common symbiotic pathway also used by arbuscular mycorrhizal fungi. However, so far, no molecules resembling rhizobial Nod factors could be isolated from Frankia cultures. Alone among Frankia genomes available to date, the genome of Dg1 contains the canonical nod genes nodA, nodB and nodC known from rhizobia, and these genes are arranged in two operons which are expressed in D. glomerata nodules. Furthermore, Frankia Dg1 nodC was able to partially complement a Rhizobium leguminosarum A34 nodC::Tn5 mutant. Phylogenetic analysis showed that Dg1 Nod proteins are positioned at the root of both alpha- and beta-rhizobial NodABC proteins. NodA-like acyl transferases were found across the phylum Actinobacteria, but among Proteobacteria only in nodulators. Taken together, our evidence indicates an Actinobacterial origin of rhizobial Nod factors. PMID- 26020782 TI - Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+ Monocytes into Macrophages. AB - Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C- monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C- monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C- monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C- monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C- monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C- monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C- monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C- or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection. PMID- 26020783 TI - Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study). AB - BACKGROUND: Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles. METHODS: Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2) and docetaxel (75 mg/m2 d1) q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly). The primary endpoint was radiological response according to RECIST. RESULTS: 40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95%) underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months. CONCLUSIONS: Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected. TRIAL REGISTRATION: EU Clinical Trials Register; Eudract-Nr: 2006 004639-31. PMID- 26020784 TI - Network reconstruction based on proteomic data and prior knowledge of protein connectivity using graph theory. AB - Modeling of signal transduction pathways is instrumental for understanding cells' function. People have been tackling modeling of signaling pathways in order to accurately represent the signaling events inside cells' biochemical microenvironment in a way meaningful for scientists in a biological field. In this article, we propose a method to interrogate such pathways in order to produce cell-specific signaling models. We integrate available prior knowledge of protein connectivity, in a form of a Prior Knowledge Network (PKN) with phosphoproteomic data to construct predictive models of the protein connectivity of the interrogated cell type. Several computational methodologies focusing on pathways' logic modeling using optimization formulations or machine learning algorithms have been published on this front over the past few years. Here, we introduce a light and fast approach that uses a breadth-first traversal of the graph to identify the shortest pathways and score proteins in the PKN, fitting the dependencies extracted from the experimental design. The pathways are then combined through a heuristic formulation to produce a final topology handling inconsistencies between the PKN and the experimental scenarios. Our results show that the algorithm we developed is efficient and accurate for the construction of medium and large scale signaling networks. We demonstrate the applicability of the proposed approach by interrogating a manually curated interaction graph model of EGF/TNFA stimulation against made up experimental data. To avoid the possibility of erroneous predictions, we performed a cross-validation analysis. Finally, we validate that the introduced approach generates predictive topologies, comparable to the ILP formulation. Overall, an efficient approach based on graph theory is presented herein to interrogate protein-protein interaction networks and to provide meaningful biological insights. PMID- 26020785 TI - Intravoxel Incoherent Motion Diffusion Weighted MR Imaging for Monitoring the Instantly Therapeutic Efficacy of Radiofrequency Ablation in Rabbit VX2 Tumors without Evident Links between Conventional Perfusion Weighted Images. AB - OBJECTIVE: To investigate the intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) as a potential valuable marker to monitor the therapy responses of VX2 to radiofrequency ablation (RF Ablation). METHODS: The institutional animal care and use committee approved this study. In 10 VX2 tumor bearing rabbits, IVIM-DWI examinations were performed with a 3.0T imaging unit by using 16 b values from 0 to 800 sec/mm2. The true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f) of tumors were compared between before and instantly after RF Ablation treatment. The differences of D, D* and f and conventional perfusion parameters (from perfusion CT and dynamic enhanced magnetic resonance imaging, DCE-MRI) in the coagulation necrosis area, residual unablated area, untreated area, and normal control had been calculated by compared t-test. The correlation between f or D* with perfusion weighted CT including blood flow, BF (milliliter per 100 mL/min), blood volume, BV (milliliter per 100 mL/min), and capillary permeability-surface area, PMB (as a fraction) or from DCE-MRI: transfer constant (Ktrans), extra-vascular extra-cellular volume fraction (Ve) and reflux constant (Kep) values had been analyzed by region-of-interest (ROI) methods to calculate Pearson's correlation coefficients. RESULTS: In the ablated necrosis areas, f and D* significantly decreased and D significantly increased, compared with residual unblazed areas or untreated control groups and normal control groups (P < 0.001). The IVIM-DWI derived f parameters showed significant increases in the residual unablated tumor area. There was no significant correlations between f or D* and conventional perfusion parameters. CONCLUSIONS: The IVIM-DW derived f, D and D* parameters have the potential to indicate therapy response immediately after RF Ablation treatment, while no significant correlations with classical tumor perfusion metrics were derived from DCE-MRI and perfusion-CT measurements. PMID- 26020787 TI - Correction: Association of Anaplasma marginale Strain Superinfection with Infection Prevalence within Tropical Regions. PMID- 26020786 TI - Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models. AB - Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model's structure and in silico "experimental" data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation. PMID- 26020788 TI - First shark from the Late Devonian (Frasnian) Gogo Formation, Western Australia sheds new light on the development of tessellated calcified cartilage. AB - BACKGROUND: Living gnathostomes (jawed vertebrates) comprise two divisions, Chondrichthyes (cartilaginous fishes, including euchondrichthyans with prismatic calcified cartilage, and extinct stem chondrichthyans) and Osteichthyes (bony fishes including tetrapods). Most of the early chondrichthyan ('shark') record is based upon isolated teeth, spines, and scales, with the oldest articulated sharks that exhibit major diagnostic characters of the group--prismatic calcified cartilage and pelvic claspers in males--being from the latest Devonian, c. 360 Mya. This paucity of information about early chondrichthyan anatomy is mainly due to their lack of endoskeletal bone and consequent low preservation potential. METHODOLOGY/PRINCIPAL FINDINGS: Here we present new data from the first well preserved chondrichthyan fossil from the early Late Devonian (ca. 380-384 Mya) Gogo Formation Lagerstatte of Western Australia. The specimen is the first Devonian shark body fossil to be acid-prepared, revealing the endoskeletal elements as three-dimensional undistorted units: Meckel's cartilages, nasal, ceratohyal, basibranchial and possible epibranchial cartilages, plus left and right scapulocoracoids, as well as teeth and scales. This unique specimen is assigned to Gogoselachus lynnbeazleyae n. gen. n. sp. CONCLUSIONS/SIGNIFICANCE: The Meckel's cartilages show a jaw articulation surface dominated by an expansive cotylus, and a small mandibular knob, an unusual condition for chondrichthyans. The scapulocoracoid of the new specimen shows evidence of two pectoral fin basal articulation facets, differing from the standard condition for early gnathostomes which have either one or three articulations. The tooth structure is intermediate between the 'primitive' ctenacanthiform and symmoriiform condition, and more derived forms with a euselachian-type base. Of special interest is the highly distinctive type of calcified cartilage forming the endoskeleton, comprising multiple layers of nonprismatic subpolygonal tesserae separated by a cellular matrix, interpreted as a transitional step toward the tessellated prismatic calcified cartilage that is recognized as the main diagnostic character of the chondrichthyans. PMID- 26020789 TI - beta-Catenin Signaling Biases Multipotent Lingual Epithelial Progenitors to Differentiate and Acquire Specific Taste Cell Fates. AB - Continuous taste bud cell renewal is essential to maintain taste function in adults; however, the molecular mechanisms that regulate taste cell turnover are unknown. Using inducible Cre-lox technology, we show that activation of beta catenin signaling in multipotent lingual epithelial progenitors outside of taste buds diverts daughter cells from a general epithelial to a taste bud fate. Moreover, while taste buds comprise 3 morphological types, beta-catenin activation drives overproduction of primarily glial-like Type I taste cells in both anterior fungiform (FF) and posterior circumvallate (CV) taste buds, with a small increase in Type II receptor cells for sweet, bitter and umami, but does not alter Type III sour detector cells. Beta-catenin activation in post-mitotic taste bud precursors likewise regulates cell differentiation; forced activation of beta-catenin in these Shh+ cells promotes Type I cell fate in both FF and CV taste buds, but likely does so non-cell autonomously. Our data are consistent with a model where beta-catenin signaling levels within lingual epithelial progenitors dictate cell fate prior to or during entry of new cells into taste buds; high signaling induces Type I cells, intermediate levels drive Type II cell differentiation, while low levels may drive differentiation of Type III cells. PMID- 26020790 TI - Thyroid fine-needle aspiration biopsy and thyroid cancer diagnosis: a nationwide population-based study. AB - BACKGROUND: Thyroid cancer is the most common endocrine gland malignancy and fine needle aspiration biopsy is widely used for thyroid nodule evaluation. Repeated aspiration biopsies are needed due to plausible false-negative results. This study aimed to investigate the overall relationship between aspiration biopsy and thyroid cancer diagnosis, and to explore factors related to shorter diagnostic time. METHODS: This nationwide retrospective cohort study retrieved data from the Longitudinal Health Insurance Database in Taiwan. Subjects without known thyroid malignancies and who received the first thyroid aspiration biopsy after 2004 were followed-up from 2004 to 2009 (n = 7700). Chi-square test, Kaplan-Meier survival analysis, and Cox proportional hazards model were used for data analysis. RESULTS: Of 7700 newly-aspirated patients, 276 eventually developed thyroid cancer (malignancy rate 3.6%). Among the 276 patients with thyroid cancer, 61.6% underwent only one aspiration biopsy and 81.2% were found within the first year after the initial aspiration. Cox proportional hazards model revealed that aspiration frequency (HR 1.07, 95% CI 1.06-1.08), ultrasound frequency (HR 1.02, 95% CI 1.01-1.03), older age, male sex, and aspiration biopsies arranged by surgery, endocrinology or otolaryngology subspecialties were all associated with shorter time to thyroid cancer diagnosis. CONCLUSIONS: About 17.4% of thyroid cancer cases received more than two aspiration biopsies and 18.8% were diagnosed one year after the first biopsy. Regular follow-up with repeated aspiration or ultrasound may be required for patients with clinically significant thyroid nodules. PMID- 26020791 TI - Effects of Pharmacotherapy on Combat-Related PTSD, Anxiety, and Depression: A Systematic Review and Meta-Regression Analysis. AB - OBJECTIVES: To estimate the effect of pharmacotherapy on PTSD, anxiety, and depression among combat veterans; to determine whether the effects varied according to patient and intervention characteristics; and to examine differential effects of pharmacotherapy on outcomes. MATERIALS AND METHODS: Google Scholar, PILOTS, PsycINFO, PubMed, and Web of Science databases were searched through November 2014. Searches resulted in eighteen double-blind, placebo controlled trials of 773 combat veterans diagnosed with PTSD and included only validated pre- and post-intervention PTSD and anxiety or depression measures. Authors extracted data on effect sizes, moderators, and study quality. Hedges' d effect sizes were computed and random effects models estimated sampling error and population variance. The Johnson-Neyman procedure identified the critical points in significant interactions to define regions of significance. RESULTS: Pharmacotherapy significantly reduced (Delta, 95%CI) PTSD (0.38, 0.23 0.52), anxiety (0.42, 0.30-0.54), and depressive symptoms (0.52, 0.35-0.70). The effects of SSRIs and tricyclic antidepressants on PTSD were greater than other medications independent of treatment duration. The effect of SSRIs and tricyclic antidepressants were greater than other medications up to 5.2 and 13.6 weeks for anxiety and depression, respectively. The magnitude of the effect of pharmacotherapy on concurrently-measured PTSD, anxiety, and depression did not significantly differ. CONCLUSIONS: Pharmacotherapy reduced PTSD, anxiety, and depressive symptoms in combat veterans. The effects of SSRIs and tricyclic antidepressants were greater for PTSD and occurred quicker for anxiety and depression than other medications. PMID- 26020792 TI - The Effect of Cage Space on Behavior and Reproduction in Crl:CD1(Icr) and C57BL/6NCrl Laboratory Mice. AB - Recommendations for the amount of cage space required for female mice with litters were first made in the 2011 Guide for the Care and Use of Laboratory Animals. We hypothesized that if a difference in mouse behavior and reproduction exists within the limits of commercially available caging, this difference would be detected between the smallest and largest cages. C57BL/6NCrl and Crl:CD1(Icr) breeding mice were randomly assigned to a cage treatment: LP 18790 (226 cm2); A RC1 (305 cm2); A N10 (432 cm2); T 1291 (800 cm2) and a breeding configuration: single (male removed after birth); pair (1 male + 1 female); or trio (1 male + 2 females) in a factorial design for 12 weeks. All cages received 8-10 g of nesting material and nests were scored weekly. Pups were weaned between post-natal day 18 and 26 and were weighed at weaning. Adult behavior and location in the cage were recorded by scan samples every 30 min over 48 hr of video recorded on PND 0-8 and PND 14-21 when pups were in the cage. Press posture and play behavior were recorded by 1/0 sampling method. Cage space did not significantly alter typical reproductive measures. Pups in the smallest cage played less than in the other cages. Adults in the smallest cage displayed more press posture than in the two largest cages. Mice in the largest cage spent more time under the feeder than in other areas of the cage. Nest score was also the highest in the largest cage. Housing breeding groups of mice in a range of commercially available cage sizes does not affect reproduction but behavioral measures suggest that the smallest cage tested, LP 18790, may be stressful for outbred mice when pups are present. PMID- 26020793 TI - Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons. AB - The intrinsic mechanisms that promote the degeneration of retinal ganglion cells (RGCs) following the activation of N-Methyl-D-aspartic acid-type glutamate receptors (NMDARs) are unclear. In this study, we have investigated the role of downstream regulatory element antagonist modulator (DREAM) in NMDA-mediated degeneration of the retina. NMDA, phosphate-buffered saline (PBS), and MK801 were injected into the vitreous humor of C57BL/6 mice. At 12, 24, and 48 hours after injection, expression of DREAM in the retina was determined by immunohistochemistry, western blot analysis, and electrophoretic mobility-shift assay (EMSA). Apoptotic death of cells in the retina was determined by terminal deoxynucleotidyl transferace dUTP nick end labeling (TUNEL) assays. Degeneration of RGCs in cross sections and in whole mount retinas was determined by using antibodies against Tuj1 and Brn3a respectively. Degeneration of amacrine cells and bipolar cells was determined by using antibodies against calretinin and protein kinase C (PKC)-alpha respectively. DREAM was expressed constitutively in RGCs, amacrine cells, bipolar cells, as well as in the inner plexiform layer (IPL). NMDA promoted a progressive decrease in DREAM levels in all three cell types over time, and at 48 h after NMDA-treatment very low DREAM levels were evident in the IPL only. DREAM expression in retinal nuclear proteins was decreased progressively after NMDA-treatment, and correlated with its decreased binding to the c-fos-DRE oligonucleotides. A decrease in DREAM expression correlated significantly with apoptotic death of RGCs, amacrine cells and bipolar cells. Treatment of eyes with NMDA antagonist MK801, restored DREAM expression to almost normal levels in the retina, and significantly decreased NMDA-mediated apoptotic death of RGCs, amacrine cells, and bipolar cells. Results presented in this study show for the first time that down-regulation of DREAM promotes the degeneration of RGCs, amacrine cells, and bipolar cells. PMID- 26020794 TI - Multi-action planning for threat management: a novel approach for the spatial prioritization of conservation actions. AB - Planning for the remediation of multiple threats is crucial to ensure the long term persistence of biodiversity. Limited conservation budgets require prioritizing which management actions to implement and where. Systematic conservation planning traditionally assumes that all the threats in priority sites are abated (fixed prioritization approach). However, abating only the threats affecting the species of conservation concerns may be more cost effective. This requires prioritizing individual actions independently within the same site (independent prioritization approach), which has received limited attention so far. We developed an action prioritization algorithm that prioritizes multiple alternative actions within the same site. We used simulated annealing to find the combination of actions that remediate threats to species at the minimum cost. Our algorithm also accounts for the importance of selecting actions in sites connected through the river network (i.e., connectivity). We applied our algorithm to prioritize actions to address threats to freshwater fish species in the Mitchell River catchment, northern Australia. We compared how the efficiency of the independent and fixed prioritization approach varied as the importance of connectivity increased. Our independent prioritization approach delivered more efficient solutions than the fixed prioritization approach, particularly when the importance of achieving connectivity was high. By spatially prioritizing the specific actions necessary to remediate the threats affecting the target species, our approach can aid cost-effective habitat restoration and land-use planning. It is also particularly suited to solving resource allocation problems, where consideration of spatial design is important, such as prioritizing conservation efforts for highly mobile species, species facing climate change-driven range shifts, or minimizing the risk of threats spreading across different realms. PMID- 26020795 TI - Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys. AB - Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese mice lowered blood glucose to levels observed in GCGR-deficient mice. In diet-induced obese mice, REGN1193 reduced food intake, adipose tissue mass, and body weight. REGN1193 increased circulating levels of glucagon and glucagon-like peptide 1 and was associated with reversible expansion of pancreatic alpha-cell area. Hyperglucagonemia and alpha-cell hyperplasia was observed in fibroblast growth factor 21-deficient mice treated with REGN1193. Single administration of REGN1193 to diabetic cynomolgus monkeys normalized fasting blood glucose and glucose tolerance and increased circulating levels of glucagon and amino acids. Finally, administration of REGN1193 for 8 weeks to normoglycemic cynomolgus monkeys did not cause hypoglycemia or increase pancreatic alpha-cell area. In summary, the GCGR-blocking antibody REGN1193 normalizes blood glucose in diabetic mice and monkeys but does not produce hypoglycemia in normoglycemic monkeys. Thus, REGN1193 provides a potential therapeutic modality for diabetes mellitus and acute hyperglycemic conditions. PMID- 26020796 TI - Neonatal Estrogen Receptor beta Is Important in the Permanent Inhibition of Epithelial Cell Proliferation in the Mouse Uterus. AB - Estrogen receptor alpha (ERalpha) plays a pivotal role in the mouse uterine and vaginal epithelial cell proliferation stimulated by estrogen, whereas ERbeta inhibits cell proliferation. ERbeta mRNA is expressed in neonatal uteri and vaginae; however, its functions in neonatal tissues have not been ascertained. In this study, we investigated the ontogenic mRNA expression and localization of ERbeta, and its roles in cell proliferation in neonatal uteri and vaginae of ERbeta knockout (betaERKO) mice. ERbeta mRNA and protein were abundant in the uterine and vaginal epithelia of 2-day-old mice and decreased with age. In uterine and vaginal epithelia of 2-day-old betaERKO mice, cell proliferation was greater than that in wild-type animals and in uterine epithelia of 90- and 365 day-old betaERKO mice. In addition, p27 protein, known as a cyclin-dependent kinase inhibitor, was decreased in the uteri of 90- and 365-day-old betaERKO mice. Inhibition of neonatal ERs by ICI 182780 (an ER antagonist) treatment stimulated cell proliferation and decreased p27 protein in the uterine luminal epithelium of 90-day-old mice but not in the vaginal epithelium. These results suggest that neonatal ERbeta is important in the persistent inhibition of epithelial cell proliferation with accumulation of p27 protein in the mouse uterus. Thus, suppression of ERbeta function in the uterine epithelium during the neonatal period may be responsible for a risk for proliferative disease in adults. PMID- 26020798 TI - Plasma prolactin concentrations during lactation, pouch young development and the return to behavioural oestrus in captive koalas (Phascolarctos cinereus). AB - Plasma prolactin (PRL) concentrations in captive koalas during lactation were determined by serial blood sampling. PRL concentrations were low (1.3 +/- 0.1 ng mL-1; n = 5) during early lactation until pouch young (PY) began to emerge from the pouch (around Day 130) before significantly (P < 0.05) increasing between Day 161 and Day 175 (5.3 +/- 1.0 ng mL-1). A significant (P < 0.001) peak in PRL (7.7 +/- 0.6 ng mL-1) coincided with maturing young between Day 189 and Day 231. All females failed to exhibit any signs of oestrous behaviour until Day 268.8 +/- 8.5 (n = 4), some 102 +/- 19 days before PY were weaned following achieving target weights of 2.5-2.7 kg. Throughout lactation, plasma LH concentrations were relatively high (range 4.9-8.7 ng mL-1) and LH responses to exogenous gonadotrophin-releasing hormone were observed in all koalas at all times during lactation. PMID- 26020797 TI - Statins and Antimicrobial Effects: Simvastatin as a Potential Drug against Staphylococcus aureus Biofilm. AB - Statins are important lipid-lowering agents with other pleiotropic effects. Several studies have explored a possible protective effect of statins to reduce the morbidity and mortality of many infectious diseases. Staphylococcus aureus is one of the main pathogens implicated in nosocomial infections; its ability to form biofilms makes treatment difficult. The present study observed the MIC of atorvastatin, pravastatin and simvastatin against S. aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus faecalis. Simvastatin was the only agent with activity against clinical isolates and reference strains of methicilin sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Thus, the effects of simvastatin on the growth, viability and biofilm formation of S. aureus were tested. In addition, a possible synergistic effect between simvastatin and vancomycin was evaluated. Simvastatin's MIC was 15.65 ug/mL for S. aureus 29213 and 31.25 ug/mL for the other strains of S. aureus. The effect of simvastatin was bactericidal at 4xMIC and bacteriostatic at the MIC concentration. No synergistic effect was found between simvastatin and vancomycin. However, the results obtained against S. aureus biofilms showed that, in addition to inhibiting adhesion and biofilm formation at concentrations from 1/16xMIC to 4xMIC, simvastatin was also able to act against mature biofilms, reducing cell viability and extra-polysaccharide production. In conclusion, simvastatin showed pronounced antimicrobial activity against S. aureus biofilms, reducing their formation and viability. PMID- 26020799 TI - Enantioselective Synthesis of Functionalized Polycarbocycles via a Three Component Organocascade Quadruple Reaction. AB - An efficient organocascade quadruple reaction was conducted to synthesize a functionalized spiropolycyclic scaffold in high chemical yields (43-80%) and excellent levels of stereoselectivity (up to >19:1 dr and 99% ee). The quadruple reaction proceeded smoothly between 1,3-indanedione and aromatic aldehydes with concomitant desymmetrization of prochiral 4-substituted cyclohexanones through the Knoevenagel/Michael/aldol/aldol reaction sequence catalyzed by a bifunctional thiourea catalyst. Two of the formed products were transformed into spirocyclic epoxides containing four contiguous quaternary centers. PMID- 26020800 TI - POINT: Should Oscillometry Be Used to Screen for Airway Disease? Yes. PMID- 26020801 TI - Monte Carlo Modeling of Spectral Diffusion Employing Multiwell Protein Energy Landscapes: Application to Pigment-Protein Complexes Involved in Photosynthesis. AB - We are reporting development and initial applications of the light-induced and thermally induced spectral diffusion modeling software, covering nonphotochemical spectral hole burning (NPHB), hole recovery, and single-molecule spectroscopy and involving random generation of the multiwell protein energy landscapes. The model includes tunneling and activated barrier-hopping in both ground and excited states of a protein-chromophore system. Evolution of such a system is predicted by solving the system of rate equations. Using the barrier parameters from the range typical for the energy landscapes of the pigment-protein complexes involved in photosynthesis, we (a) show that realistic cooling of the sample must result in proteins quite far from thermodynamic equilibrium, (b) demonstrate hole evolution in the cases of burning, fixed-temperature recovery and thermocycling that mostly agrees with the experiment and modeling based on the NPHB master equation, and (c) explore the effects of different protein energy landscapes on the antihole shape. Introducing the multiwell energy landscapes and starting the hole burning experiments in realistic nonequilibrium conditions are not sufficient to explain all experimental observations even qualitatively. Therefore, for instance, one is required to invoke the modified NPHB mechanism where a complex interplay of several small conformational changes is poising the energy landscape of the pigment-protein system for downhill tunneling. PMID- 26020802 TI - MicroRNA analysis suggests an additional level of feedback regulation in the NF kappaB signaling cascade. AB - It is increasingly clear that the biological functions of a transcription factor cannot be fully understood solely on the basis of protein-coding genes that fall under its control. Many transcription factors regulate expression of miRNAs, which affect the cell by modulating translation and stability of mRNAs. The identities and the roles of NF-kappaB-regulated miRNAs have been attracting research interest for a long time. We revisited this issue in a system with controlled expression of one of the key regulators of NF-kappaB, RIPK1. Several regulated miRNAs were identified, including miR-146a, miR-215 and miR-497. The miRNAs were also inducible by IL-1beta, but not when NF-kappaB activity was repressed by mutant IkappaBalpha. The presence of a miR-497 site was predicted in the 3'-UTR of IKBKB gene, which encodes IKKbeta. Using appropriately engineered reporters, we confirmed that this site can be a target of suppressive action of miR-497. Our findings suggest that NF-kappaB controls expression of a miRNA, which may reduce production of IKKbeta. Considering the role of IKKbeta in the canonical pathway of NF-kappaB activation, our observations may indicate a new mechanism that modulates the magnitude of such activation, as well as the propensity of a cell to engage canonical vs. non-canonical pathways. PMID- 26020803 TI - Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer. AB - The oncogenic K-Ras can transform various mammalian cells and plays a critical role in development of pancreatic cancer. MicroRNAs (miRNA) have been shown to contribute to tumorigenic progression. However, the nature of miRNAs involved in K-Ras transformation remains to be investigated. Here, by using microarray we identified miR-155 as the most upregulated miRNA after both acute and prolonged activation of K-Ras in a doxycyline-inducible system. Pharmacological inhibition of MAPK and NF-kappaB pathway blocked the induction of miR-155 in response to K Ras activation. Overexpression of miR-155 caused inhibition of Foxo3a, leading to decrease of major antioxidants including SOD2 and catalase, and enhanced pancreatic cell proliferation induced by ROS generation. Importantly, correlations of K-Ras, miR-155 and Foxo3a were also validated in human pancreatic cancer tissues. Therefore, we propose that miR-155 plays an important role in oncogenic K-Ras transformation mediated by cellular redox regulation. PMID- 26020804 TI - Honokiol inhibits the growth of head and neck squamous cell carcinoma by targeting epidermal growth factor receptor. AB - Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia plant, on human head and neck squamous cell carcinoma (HNSCC). Treatment of HNSCC cell lines from different sub-sites, SCC-1 (oral cavity), SCC-5 (larynx), OSC-19 (tongue) and FaDu (pharynx) with honokiol inhibited their cell viability, which was associated with the: (i) induction of apoptosis, (ii) correction of dysregulatory cell cycle proteins of G0/G1 phase. Honokiol decreased the expression levels of epidermal growth factor receptor (EGFR), mTOR and their downstream signaling molecules. Treatment of FaDu and SCC-1 cell lines with rapamycin, an inhibitor of mTOR pathway, also reduced cell viability of HNSCC cells. Administration of honokiol by oral gavage (100 mg/kg body weight) significantly (P < 0.01-0.001) inhibited the growth of SCC-1 and FaDu xenografts in athymic nude mice, which was associated with: (i) inhibition of tumor cell proliferation, (ii) induction of apoptosis, (iii) reduced expressions of cyclins and Cdks, and (iv) inhibition of EGFR signaling pathway. Molecular docking analysis of honokiol in EGFR binding site indicated that the chemotherapeutic effect of honokiol against HNSCC is mediated through its firm binding with EGFR, which is better than that of gefitinib, a commonly used drug for HNSCC treatment. PMID- 26020805 TI - The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma. AB - The vacuolar H+ ATPase (V-ATPase) is a proton pump responsible for acidification of cellular microenvironments, an activity exploited by tumors to survive, proliferate and resist to therapy. Despite few observations, the role of V-ATPase in human tumorigenesis remains unclear.We investigated the expression of ATP6V0C, ATP6V0A2, encoding two subunits belonging to the V-ATPase V0 sector and ATP6V1C, ATP6V1G1, ATPT6V1G2, ATP6V1G3, which are part of the V1 sector, in series of adult gliomas and in cancer stem cell-enriched neurospheres isolated from glioblastoma (GBM) patients. ATP6V1G1 expression resulted significantly upregulated in tissues of patients with GBM and correlated with shorter patients' overall survival independent of clinical variables.ATP6V1G1 knockdown in GBM neurospheres hampered sphere-forming ability, induced cell death, and decreased matrix invasion, a phenotype not observed in GBM monolayer cultures. Treating GBM organotypic cultures or neurospheres with the selective V-ATPase inhibitor bafilomycin A1 reproduced the effects of ATP6V1G1 siRNA and strongly suppressed expression of the stem cell markers Nestin, CD133 and transcription factors SALL2 and POU3F2 in neurospheres.These data point to ATP6V1G1 as a novel marker of poor prognosis in GBM patients and identify V-ATPase inhibition as an innovative therapeutic strategy for GBM. PMID- 26020806 TI - Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies. AB - Taxane-gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15-20 mg/m) before (part 1a) or after (part 1b) gemcitabine (700-1000 mg/m) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m cabazitaxel plus 1000 mg/m gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3-4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation. PMID- 26020807 TI - Efficacy of fourth-line chemotherapy in advanced non-small-cell lung cancer: a systematic review and pooled analysis of published studies. AB - There are no agents labelled for use as fourth-line therapy for non-small-cell lung cancer, even though it is currently prescribed in about 5-10% of patients. Here, we provide a pooled analysis of published studies on the efficacy of treatments in patients who have had at least three unsuccessful lines of therapy. The literature search was performed on Pubmed, EMBASE, the Web of Science, SCOPUS, CINAHL, Google Scholar and the Cochrane Library using the terms 'lung cancer' OR NSCLC AND 'fourth line'. The response rates and disease control rates were pooled using a random-effect or a fixed-effect model according to heterogeneity. Median progression-free survival and overall survival data were also collected and aggregated to obtain pooled median values of the included studies. Overall, 14 studies (673 patients), which were almost entirely published by Asian institutions, were eligible for this pooled analysis. Among these were two phase II trials and 12 retrospective cohort series. In general, the pooled overall response rate was 13.6% [95% confidence interval (CI) 10-18.3] and the pooled overall disease control rate was 47.3% (95% CI 38-56.9). The pooled median progression-free survival for these studies was 3.34 months (95% CI 2.42-4.27). The pooled median overall survival for these studies was 10.5 months (95% CI 9.57 11.52). In conclusion, for non-small-cell lung cancer patients who have undergone three or more unsuccessful lines of therapy, fourth-line treatment could be offered in select cases to those with a good performance status. PMID- 26020808 TI - Baseline chronic kidney disease is associated with toxicity and survival in patients treated with targeted therapies for metastatic renal cell carcinoma. AB - To assess the impact of baseline chronic kidney disease on targeted therapy (TT) induced toxicities and survival in patients treated for metastatic renal cell carcinoma (mRCC). Data from patients receiving first-line TT from January 2006 to June 2012 were collected retrospectively. TT side effects, time to treatment failure (TTF), and overall survival (OS) were analyzed according to the baseline glomerular filtration rate (GFR) calculated using the modification diet in renal disease formula. Hundred and two patients treated with sunitinib (N=67), sorafenib (N=24), or temsirolimus (N=11) were included. Forty-two patients (41%) had baseline chronic kidney disease with GFR less than 60 ml/min/1.73 m. Patients with GFR less than 60 were more likely to encounter severe (grade 3-4) TT-induced toxicities (79 vs. 32%, P<0.0001). Moreover, renal function impairment was significantly associated with higher median TTF and OS (respectively, 12 vs. 6 months for TTF, P=0.003; and 33 vs. 13 months for OS, P=0.001). On multivariate analysis, GFR less than 60 was identified as the only factor associated with a higher rate of severe toxicity: odds ratio=4.74 (1.67-13.41), P=0.003. Severe toxicity (P=0.05) was identified as an independent prognostic factor for OS and TTF. Baseline chronic kidney disease was associated with higher TT-induced toxicities, which were identified as a prognostic factor of higher survival in mRCC treatment. These results suggest that GFR measurement could be used to optimize the efficacy of TT in patients treated for an mRCC. PMID- 26020809 TI - Newly Elaborated Multipurpose Polymer Electrolyte Encompassing RTILs for Smart Energy-Efficient Devices. AB - Profoundly ion-conducting, self-standing, and tack-free ethylene oxide-based polymer electrolytes encompassing a room-temperature ionic liquid (RTIL) with specific amounts of lithium salt are successfully prepared via a rapid and easily upscalable process including a UV irradiation step. All prepared materials are thoroughly characterized in terms of their physical, chemical, and morphological properties and eventually galvanostatically cycled in lab-scale lithium batteries (LIBs) exploiting a novel direct polymerization procedure to get intimate electrode/electrolyte interfacial characteristics. The promising multipurpose characteristics of the newly elaborated materials are demonstrated by testing them in dye-sensitized solar cells (DSSCs), where the introduction of the iodine/iodide-based redox mediator in the polymer matrix assured the functioning of a lab-scale test cell with conversion efficiency exceeding 6% at 1 sun. The reported results enlighten the promising prospects of the material to be successfully implemented as stable, durable, and efficient electrolyte in next generation energy conversion and storage devices. PMID- 26020810 TI - Moving in on the Action: An Experimental Comparison of Fluorescence Excitation and Photodissociation Action Spectroscopy. AB - Photodissociation action spectroscopy is often used as a proxy for measuring gas phase absorption spectra of ions in a mass spectrometer. Although the potential discrepancy between linear optical and photodissociation spectra is generally acknowledged, direct experimental comparisons are lacking. In this work, we use a quadrupole ion trap that has been modified to enable both photodissociation and laser-induced fluorescence to assess how closely the visible photodissociation action spectrum of a fluorescent dye reflects its fluorescence excitation spectrum. Our results show the photodissociation action spectrum of gaseous rhodamine 110 is both substantially narrower and slightly red-shifted (~120 cm( 1)) compared to its fluorescence excitation spectrum. Power dependence measurements reveal that the photodissociation of rhodamine 110 requires, on average, the absorption of three photons whereas fluorescence is a single-photon process. These differing power dependences are the key to interpreting the differences in the measured spectra. The experimental results provide much-needed quantification and insight into the differences between action spectra and linear optical spectra, and emphasize the utility of fluorescence excitation spectra to provide a more reliable benchmark for comparison with theory. PMID- 26020811 TI - NPK NMR Sensor: Online Monitoring of Nitrogen, Phosphorus, and Potassium in Animal Slurry. AB - Knowledge of the actual content of nitrogen, phosphorus, and potassium (NPK) in animal slurry is highly important to optimize crop production and avoid environmental pollution when slurry is spread on agricultural fields. Here, we present a mobile, low-field nuclear magnetic resonance (NMR) sensor suitable for online monitoring of the NPK content in animal slurry as an alternative to crude estimates or tedious nonspecific, off-site laboratory analysis. The sensor is based on (14)N, (17)O, (31)P, and (39)K NMR in a digital NMR instrument equipped with a 1.5 T Halbach magnet for direct detection of ammonium N, total P, and K and indirect evaluation of the organic N content, covering all practical components of NPK in animal slurry. In correlation studies, the obtained NMR measurements show good agreement with reference measurements from commercial laboratories. PMID- 26020812 TI - Scaling properties of evolutionary paths in a biophysical model of protein adaptation. AB - The enormous size and complexity of genotypic sequence space frequently requires consideration of coarse-grained sequences in empirical models. We develop scaling relations to quantify the effect of this coarse-graining on properties of fitness landscapes and evolutionary paths. We first consider evolution on a simple Mount Fuji fitness landscape, focusing on how the length and predictability of evolutionary paths scale with the coarse-grained sequence length and alphabet. We obtain simple scaling relations for both the weak- and strong-selection limits, with a non-trivial crossover regime at intermediate selection strengths. We apply these results to evolution on a biophysical fitness landscape that describes how proteins evolve new binding interactions while maintaining their folding stability. We combine the scaling relations with numerical calculations for coarse-grained protein sequences to obtain quantitative properties of the model for realistic binding interfaces and a full amino acid alphabet. PMID- 26020819 TI - Religiosity and Impulsivity in Mental Health: Is There a Relationship? AB - Our aim is to evaluate the relationship between religiosity and impulsivity in patients with mental illness who had attempted suicide and in healthy individuals. This is a cross-sectional study that included 61 healthy individuals and 93 patients. The instruments used were a sociodemographic data questionnaire, the Mini International Neuropsychiatric Interview, the Barratt Impulsiveness Scale, and the Duke University Religion Index. The healthy individuals presented higher scores in the religiosity domains (organizational, p = 0.028; non organizational, p = 0.000; intrinsic, p = 0.000). The patients presented higher scores in the impulsivity dimensions (attentional, p = 0.000; motor, p = 0.000; absence of planning, p = 0.000). In the patient group, intrinsic religiosity had a significant inverse relationship with total impulsivity (p = 0.023), attentional (p = 0.010), and absence of planning (p = 0.007), even after controlling for sociodemographic variables. Healthy individuals were more religious and less impulsive than patients. The relationship between religiosity, impulsiveness, and mental illness could be bidirectional; that is, just as mental illness might impair religious involvement, religiosity could diminish the expression of mental illness and impulsive behaviors. PMID- 26020820 TI - High-Resolution Dynamics of Microbial Communities during Dissimilatory Selenate Reduction in Anoxic Soil. AB - Selenate is one of the most common toxic metal compounds in contaminated soils. Its redox status can be changed by microbial activity, thus affecting its water solubility and soil mobility. However, current knowledge of microbial dynamics has been limited by the low sensitivity of past isolation and identification protocols. Here, high-throughput Illumina sequencing of 16S rRNA genes was applied to monitor the shift of the microorganisms in an anoxic contaminated soil after Se(VI) and acetate amendment. An autoclaved soil with both chemicals and a live soil with acetate alone were used as controls. Preliminary chemical analysis clearly showed the occurrence of biological selenate reduction coupled with acetate oxidation. Principal coordinate analysis and diversity indices of Illumina-derived sequence data showed dynamic succession and diversification of the microbial community in response to selenate reduction. High-resolution phylogenetic analysis revealed that the relative frequency of an operational taxonomic unit (OTU) from the genus Dechloromonas increased remarkably from 0.2% to 36% as a result of Se(VI) addition. Multiple OTUs representing less abundant microorganisms from the Rhodocyclaceae and Comamonadaceae families had significant increases as well. This study demonstrated that these microorganisms are concertedly involved in selenate reduction of the employed contaminated soil under anoxic conditions. PMID- 26020813 TI - Signature Patterns of MHC Diversity in Three Gombe Communities of Wild Chimpanzees Reflect Fitness in Reproduction and Immune Defense against SIVcpz. AB - Major histocompatibility complex (MHC) class I molecules determine immune responses to viral infections. These polymorphic cell-surface glycoproteins bind peptide antigens, forming ligands for cytotoxic T and natural killer cell receptors. Under pressure from rapidly evolving viruses, hominoid MHC class I molecules also evolve rapidly, becoming diverse and species-specific. Little is known of the impact of infectious disease epidemics on MHC class I variant distributions in human populations, a context in which the chimpanzee is the superior animal model. Population dynamics of the chimpanzees inhabiting Gombe National Park, Tanzania have been studied for over 50 years. This population is infected with SIVcpz, the precursor of human HIV-1. Because HLA-B is the most polymorphic human MHC class I molecule and correlates strongly with HIV-1 progression, we determined sequences for its ortholog, Patr-B, in 125 Gombe chimpanzees. Eleven Patr-B variants were defined, as were their frequencies in Gombe's three communities, changes in frequency with time, and effect of SIVcpz infection. The growing populations of the northern and central communities, where SIVcpz is less prevalent, have stable distributions comprising a majority of low frequency Patr-B variants and a few high-frequency variants. Driving the latter to high frequency has been the fecundity of immigrants to the northern community, whereas in the central community, it has been the fecundity of socially dominant individuals. In the declining population of the southern community, where greater SIVcpz prevalence is associated with mortality and emigration, Patr-B variant distributions have been changing. Enriched in this community are Patr-B variants that engage with natural killer cell receptors. Elevated among SIVcpz-infected chimpanzees, the Patr-B*06:03 variant has striking structural and functional similarities to HLA-B*57, the human allotype most strongly associated with delayed HIV-1 progression. Like HLA-B*57, Patr-B*06:03 correlates with reduced viral load, as assessed by detection of SIVcpz RNA in feces. PMID- 26020821 TI - Effect of Rebamipide Ophthalmic Suspension on Intraocular Light Scattering for Dry Eye After Corneal Refractive Surgery. AB - PURPOSE: To assess the changes in intraocular scattering before and after instillation of rebamipide ophthalmic suspension in patients with dry eye after corneal refractive surgery. METHODS: This study enrolled 60 eyes of 30 dry eye patients undergoing corneal refractive surgery. Patients were randomly assigned to start topical administration of rebamipide ophthalmic suspension (rebamipide group) or artificial tears (control group) 4 times daily for 4 weeks. Tear secretion, tear break-up time (TBUT), and the fluorescein score were measured before and after treatment. Intraocular light scattering was also measured as the objective scattering index (OSI) at 0.5-second intervals over 10 seconds. RESULTS: In the rebamipide group, the Schirmer I test, TBUT, and fluorescein score improved significantly, from 11.4 +/- 9.0 mm, 2.2 +/- 0.7 seconds, and 4.3 +/- 1.3 to 14.9 +/- 7.4 mm, 4.5 +/- 1.7 seconds, and 1.9 +/- 1.0, respectively (P = 0.006, P < 0.001, P < 0.001, Wilcoxon signed rank test). We found significant improvements in OSI at 5.0 to 10.0 seconds after blinking (5-8 seconds, P = 0.01; 9 seconds, P = 0.02; 10 seconds, P < 0.001). The mean OSI, the OSI change rate, and the OSI slope of the linear regression line improved significantly, from 2.73 +/- 1.52, 74.7 +/- 69.5%, and 0.10 +/- 0.12 to 2.19 +/- 1.19, 28.6 +/- 48.7%, and 0.04 +/- 0.08, respectively (P = 0.02, 0.003, and 0.03). CONCLUSIONS: Rebamipide ophthalmic suspension was effective for improving both ocular surface parameters and optical quality in patients with dry eye undergoing corneal refractive surgery, suggesting that it may hold promise for the treatment of such patients. PMID- 26020822 TI - Inhibitory Effect of Tranilast on Transforming Growth Factor-Beta-Induced Protein in Granular Corneal Dystrophy Type 2 Corneal Fibroblasts. AB - PURPOSE: To investigate the effects of tranilast, an inhibitor of chemical mediators and fibroblast proliferation, on the expression of transforming growth factor-beta (TGF-beta)-induced protein (TGFBIp) in wild-type (WT) and homozygous (HO) granular corneal dystrophy type 2 corneal fibroblasts. METHODS: Cell proliferation and cytotoxicity were measured by Cell Counting Kit-8 and lactate dehydrogenase assay. Western blotting and real-time polymerase chain reaction were used to determine changes in the expression of TGFBIp and TGFBI mRNA. We determined the effects of tranilast on phosphorylated Smad2 (pSmad2) and pSmad3, wound-healing, and expression of alpha-smooth muscle actin (alpha-SMA), type I collagen, and integrins. RESULTS: High concentrations of tranilast decreased proliferation of corneal fibroblasts but did not cause elevation of lactate dehydrogenase, except at 1.0 mM tranilast. TGF-beta increased the expression of TGFBIp and TGFBI mRNA in WT and HO corneal fibroblasts. Cotreatment of corneal fibroblasts with tranilast and TGF-beta reduced the levels of TGFBIp and TGFBI mRNA. In addition, application of tranilast reduced pSmad2 in WT and HO corneal fibroblasts and pSmad3 in HO corneal fibroblasts, both of which were increased initially by TGF-beta. Tranilast delayed wound healing and reduced the expression of alpha-SMA, type I collagen, and some of integrins in WT and HO corneal fibroblasts. CONCLUSIONS: Application of tranilast in WT and HO corneal fibroblasts inhibited the expression of TGFBIp by blocking TGF-beta signaling. Thus, tranilast may be useful in delaying or preventing the recurrence of corneal opacity in TGFBI-linked corneal dystrophies if clinical studies confirm these findings. PMID- 26020823 TI - Risk Factors Predicting the Need for Graft Exchange After Descemet Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: To identify the risk factors predicting the need for graft exchange after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: This is a retrospective cohort study. The study group included all 117 eyes that underwent or necessitated repeat DSAEK performed between January 2005 and June 2014 at Villa Serena-Villa Igea private hospitals (Forli, Italy). The control group consisted of 1033 eyes that underwent only primary DSAEK during the same period. Demographic details, indications for primary surgery, ocular preoperative status and comorbidities, donor endothelial cell density (ECD), and postoperative complications were compared between the groups using univariate and multivariate analyses. RESULTS: The prevalence of graft failure necessitating graft exchange was 10.2% (117 of 1150 eyes). In univariate analysis, a diagnosis of Fuchs endothelial dystrophy was a protective factor against the risk of repeat DSAEK. Prior trabeculectomy or aqueous shunt implantation, postoperative graft detachment, lower donor ECD, and a rejection episode were all associated with a significantly higher risk of requiring repeat DSAEK. The presence of buphthalmos, anterior chamber intraocular lens, aphakia, or prior penetrating keratoplasty were not risk factors for the failure of DSAEK. Of these variables, multivariate analysis showed that only prior aqueous shunt implantation [odds ratio (OR) = 5.5, 95% confidence interval (CI), 1.4-22.2], lower donor ECD (OR = 0.99, 95% CI, 0.997-0.999), and a documented postoperative rejection episode (OR = 18.2, 95% CI, 7.9-45.0) predicted the need for repeat DSAEK. CONCLUSIONS: DSAEK grafts have similarly good long-term survival regardless of the indication for surgery, lens status, or ocular comorbidities, with the only exception being the presence of an aqueous shunt. PMID- 26020824 TI - Anterior Chamber Stabilization in Combined Penetrating Keratoplasty With Scleral Sutured Posterior Chamber Intraocular Lens Implantation. AB - PURPOSE: To describe a novel technique for a stabilized penetrating keratoplasty procedure with implantation of a scleral-sutured posterior chamber intraocular lens in which the anterior chamber (AC) is maintained and the globe stabilized without using a Flieringa ring. METHODS: In this procedure, a deep anterior corneal lamella separation was created. Four small incisions were made in each quadrant along the outer edge of the trephination groove of the residual stromal bed (RSB). The first incision at the 9-o'clock position was advanced with scissors in both clockwise and counterclockwise directions. This procedure was repeated in the remaining 3 quadrants, creating 4 small bridges between the RSB and corneal rim. A donor corneal button coated with a viscoelastic material was sutured at 3 incision sites leaving 1 quadrant sutureless to allow sufficient incision width for IOL insertion for scleral fixation. Scleral fixation of a 1 piece polymethyl methacrylate (PMMA) IOL was performed. After sequential cutting of the bridges, the RSB was removed from the AC. Ten eyes of 10 patients underwent this procedure without significant complications. RESULTS: There were no complications related to the open-sky procedure. Globe stabilization was achieved in all surgeries. Endothelial cell loss, visual acuities, and graft failure rates were comparable with the reports of AC-protecting penetrating keratoplasty surgeries. CONCLUSIONS: This technique provides a secured AC and stabilized globe without the use of a Flieringa ring and increases the surgical safety without a significant reduction of the graft endothelial cell density. PMID- 26020825 TI - Novel Mutation in the CHRDL1 Gene Detected in Patients With Megalocornea. AB - PURPOSE: The aim of this study was to determine the mutation associated with X linked megalocornea (MGC1) found in 2 patients from the same area in southern Italy. METHODS: Diagnosis of megalocornea was confirmed by detailed ophthalmic examination in 2 probands from independent families and in another 3 affected family members. Genomic DNA of the probands was used to amplify and sequence all the coding regions of CHRDL1. RESULTS: Megalocornea diagnosis was associated with a novel mutation found in the probands and affected kindreds (5 subjects). The mutation is an 11-base pair deletion that leads to a stop codon in the second coding exon of the CHRDL1 gene. Research on the CHRDL1 mutation was also performed on other family members (11 subjects) not affected by MGC1, and the mutation was not detected in unaffected male family members. CONCLUSIONS: The detection of mutations in the CHRDL1 gene is useful for differential diagnosis with different forms of megalocornea. PMID- 26020826 TI - Association Between Corneal Deformation and Ease of Lenticule Separation From Residual Stroma in Small Incision Lenticule Extraction. AB - PURPOSE: To study the association between corneal deformation (CD) and ease of lenticule separation from the stroma in small incision lenticule extraction. METHODS: Thirty-six myopic eyes of 36 patients underwent small incision lenticule extraction. Preoperative refraction, intraocular pressure, central corneal thickness, and CD were evaluated with Scheimpflug imaging and air-puff applanation. Fourier transform of CD waveform was also performed. The surgeon also graded the ease of separation of lenticule surfaces from the residual stroma intraoperatively as grades 1 (low effort), 2 (moderate effort), and 3 (high effort). All the procedures were performed by the same surgeon. CD values were concealed from the surgeon. Differences between the grades were assessed with 1 way analysis of variance and analysis of covariance. RESULTS: Mean preoperative refraction, intraocular pressure, central corneal thickness, lenticule thickness, and incision width were similar among the grades (P > 0.05). A total of 5 of the 10 analyzed CD variables were significantly different among the grades. Among them, deformation amplitude (1.20 vs. 1.13 vs. 1.07 mm in the order of increasing grades, P = 0.001), velocity of the corneal apex at the second applanation point (-0.47 vs. -0.43 vs. -0.40 m/s, P = 0.02), peak distance (5.33 vs. 5.25 vs. 5.07 mm, P = 0.006), area under the deformation amplitude (13.40 vs. 12.84 vs. 12.06, P = 0.04), and root mean square of Fourier coefficients (0.12 vs. 0.12 vs. 0.11 mm, P = 0.005) decreased from grades 1 to 3. CONCLUSIONS: CD was inversely correlated with the ease of lenticule separation from the residual stroma and may assist in customization of the energy parameters of the laser. PMID- 26020827 TI - Loteprednol Etabonate 0.5% Gel Vs. Prednisolone Acetate 1% Solution After Descemet Membrane Endothelial Keratoplasty: Prospective Randomized Trial. AB - PURPOSE: To compare intraocular pressure (IOP) elevation and graft rejection with loteprednol etabonate 0.5% gel and prednisolone acetate 1% solution after Descemet membrane endothelial keratoplasty (DMEK). METHODS: In this prospective, evaluator-masked trial, 167 patients were randomized to loteprednol or prednisolone in a 1:1 ratio 1 month after DMEK; 66 fellow eyes were enrolled and assigned to the opposite treatment. Dosing was 4 times daily for 2 months, thrice daily for 1 month, twice daily for 1 month, and once daily for 7 months. The main outcomes were IOP elevation (defined as IOP >= 24 mm Hg or an increase of >=10 mm Hg over the baseline preoperative level) and immunologic rejection episodes, assessed by Kaplan-Meier survival analysis and proportional hazards modeling. RESULTS: A total of 233 eyes were assigned to treatment. Loteprednol etabonate 0.5% gel and prednisolone acetate 1% solution were equally effective in preventing immunologic rejection episodes; none (0%) occurred with either treatment (P = 1). IOP elevation was twice as likely in the prednisolone-treated eyes (relative risk = 2.3, 95% confidence interval: 1.2-4.5, P = 0.016). The proportion with IOP elevation was 25% in prednisolone-treated eyes versus 11% in loteprednol-treated eyes (P = 0.013). In 66 subjects with fellow eyes assigned to opposite treatments, an IOP increase of >=10 mm Hg was significantly more likely in the prednisolone-treated eye (P = 0.031). CONCLUSIONS: Loteprednol etabonate 0.5% gel was as effective as prednisolone acetate 1% solution in preventing immunologic graft rejection episodes after DMEK and was significantly less likely to cause IOP elevation.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01853696. PMID- 26020828 TI - Identification and Characterization of Two Novel DSF-Controlled Virulence Associated Genes Within the nodB-rhgB Locus of Xanthomonas oryzae pv. oryzicola Rs105. AB - Xanthomonas oryzae pv. oryzicola and X. oryzae pv. oryzae are two pathovars of X. oryzae that cause leaf streak and blight in rice, respectively. These two bacterial pathogens cause different disease symptoms by utilizing different infection sites on rice. Compared with X. oryzae pv. oryzae, the molecular virulence mechanism of X. oryzae pv. oryzicola remains largely unknown. Previously, we identified a unique diffusible signal factor (DSF)-controlled virulence-related gene (hshB) in X. oryzae pv. oryzicola Rs105 located in the nodB-rghB locus, which is absent in X. oryzae pv. oryzae PXO99(A). In the present study, we identified two additional genes within this locus (hshA and hshC) that were unique to X. oryzae pv. oryzicola Rs105 compared with X. oryzae pv. oryzae PXO99(A), and we found that the transcription of these genes was regulated by DSF signaling in X. oryzae pv. oryzicola. The mutation of these genes impaired the virulence of the wild-type Rs105 when using a low inoculation density of X. oryzae pv. oryzicola. In contrast to hshB, the mutation of these genes did not have any visible effect on characterized virulence-related functions, including in vitro growth, extracellular polysaccharide production, extracellular protease activity, and antioxidative ability. However, we found that mutation of hshA or hshC significantly reduced the in planta growth ability and epiphytic survival level of X. oryzae pv. oryzicola cells, which was the probable mechanisms of involvement of these two genes in virulence. Collectively, our studies of X. oryzae pv. oryzicola have identified two novel DSF-controlled virulence associated genes (hshA and hshC), which will add to our understanding of the regulatory mechanisms of conserved DSF virulence signaling in Xanthomonas species. PMID- 26020829 TI - Direct Evidence of Egestion and Salivation of Xylella fastidiosa Suggests Sharpshooters Can Be "Flying Syringes". AB - Xylella fastidiosa is unique among insect-transmitted plant pathogens because it is propagative but noncirculative, adhering to and multiplying on the cuticular lining of the anterior foregut. Any inoculation mechanism for X. fastidiosa must explain how bacterial cells exit the vector's stylets via the food canal and directly enter the plant. A combined egestion-salivation mechanism has been proposed to explain these unique features. Egestion is the putative outward flow of fluid from the foregut via hypothesized bidirectional pumping of the cibarium. The present study traced green fluorescent protein-expressing X. fastidiosa or fluorescent nanoparticles acquired from artificial diets by glassy-winged sharpshooters, Homalodisca vitripennis, as they were egested into simultaneously secreted saliva. X. fastidiosa or nanoparticles were shown to mix with gelling saliva to form fluorescent deposits and salivary sheaths on artificial diets, providing the first direct, conclusive evidence of egestion by any hemipteran insect. Therefore, the present results strongly support an egestion-salivation mechanism of X. fastidiosa inoculation. Results also support that a column of fluid is transiently held in the foregut without being swallowed. Evidence also supports (but does not definitively prove) that bacteria were suspended in the column of fluid during the vector's transit from diet to diet, and were egested with the held fluid. Thus, we hypothesize that sharpshooters could be true "flying syringes," especially when inoculation occurs very soon after uptake of bacteria, suggesting the new paradigm of a nonpersistent X. fastidiosa transmission mechanism. PMID- 26020830 TI - Knock-down of heat-shock protein 90 and isocitrate lyase gene expression reduced root-knot nematode reproduction. AB - Crop losses caused by nematode infections are estimated to be valued at USD 157 billion per year. Meloidogyne incognita, a root-knot nematode (RKN), is considered to be one of the most important plant pathogens due to its worldwide distribution and the austere damage it can cause to a large variety of agronomically important crops. RNA interference (RNAi), a gene silencing process, has proven to be a valuable biotechnology alternative method for RKN control. In this study, the RNAi approach was applied, using fragments of M. incognita genes that encode for two essential molecules, heat-shock protein 90 (HSP90) and isocitrate lyase (ICL). Plant-mediated RNAi of these genes led to a significant level of resistance against M. incognita in the transgenic Nicotiana tabacum plants. Bioassays of plants expressing HSP90 dsRNA demonstrated a delay in gall formation and up to 46% reduction in eggs compared with wild-type plants. A reduction in the level of HSP90 transcripts was observed in recovered eggs from plants expressing dsRNA, indicating that gene silencing persisted and was passed along to first progeny. The ICL knock-down had no clear effect on gall formation but resulted in up to 77% reduction in egg oviposition compared with wild-type plants. Our data suggest that both genes may be involved in RKN development and reproduction. Thus, in this paper, we describe essential candidate genes that could be applied to generate genetically modified crops, using the RNAi strategy to control RKN parasitism. PMID- 26020831 TI - Base Mediated Synthesis of Alkyl-aryl Ethers from the Reaction of Aliphatic Alcohols and Unsymmetric Diaryliodonium Salts. AB - The base mediated coupling of aliphatic alcohol pronucleophiles with unsymmetric diaryliodonium salt electrophiles is described. This metal-free reaction is operationally simple, proceeds at mild temperature, and displays broad substrate scope to generate industrially important alkyl-aryl ethers in moderate to excellent yield. The synthetic utility of these reactions is demonstrated, and aspects of sustainability are highlighted by the use of unsymmetric aryl(mesityl)iodonium arylating reagents. PMID- 26020832 TI - Prognostic value of computed tomography texture features in non-small cell lung cancers treated with definitive concomitant chemoradiotherapy. AB - OBJECTIVES: The aim of this study was to investigate whether the computed tomography (CT) texture features of primary tumors are associated with the overall survival (OS) of non-small cell lung cancer (NSCLC) patients undergoing definitive concomitant chemoradiotherapy (CCRT). MATERIALS AND METHODS: In this retrospective study, 98 patients (83 men and 15 women; mean age, 61.9 +/- 8.0 years) with unresectable NSCLCs (stage IIIA, 45; stage IIIB, 53) underwent definitive CCRT at our institution from January 2006 to December 2011. Patients were followed up for 3 years or until death. The CT texture parameters of primary tumors were extracted from contrast-enhanced CT images taken before CCRT using an in-house software program. Each texture parameter was dichotomized based on their optimal cutoff values obtained from receiver operating characteristics curve analysis. Three-year OS was compared between the dichotomized subgroups using Kaplan-Meier analysis and the log-rank test. Multivariate Cox regression analysis was performed to determine significant prognostic factors. RESULTS: The 3-year cumulative survival rate was 0.51. The mean 3-year OS was 24.0 months (95% confidence interval, 21.5-26.6 months). There were no significant differences in 3-year OS according to tumor stage or histologic subtypes. However, entropy (P = 0.030), skewness (P = 0.021), and mean attenuation (P = 0.030) were shown to be significantly associated with 3-year OS. Multivariate Cox regression analysis revealed that higher entropy (adjusted hazard ratio [HR],2.31; P = 0.040), higher skewness (adjusted HR,1.92; P = 0.046), and higher mean attenuation (adjusted HR,1.93; P = 0.028) were independent predictors of decreased 3-year OS. CONCLUSIONS: Computed tomography texture features have the potential to be used as prognostic biomarkers in unresectable NSCLC patients undergoing definitive CCRT. PMID- 26020833 TI - A Caged Electrophilic Probe for Global Analysis of Cysteine Reactivity in Living Cells. AB - Cysteine residues are subject to diverse modifications, such as oxidation, nitrosation, and lipidation. The resulting loss in cysteine reactivity can be measured using electrophilic chemical probes, which importantly provide the stoichiometry of modification. An iodoacetamide (IA)-based chemical probe has been used to concurrently quantify reactivity changes in hundreds of cysteines within cell lysates. However, the cytotoxicity of the IA group precludes efficient live-cell labeling, which is important for preserving transient cysteine modifications. To overcome this limitation, a caged bromomethyl ketone (BK) electrophile was developed, which shows minimal cytotoxicity and provides spatial and temporal control of electrophile activation through irradiation. The caged-BK probe was utilized to monitor cysteine reactivity changes in A431 cells upon epidermal growth factor (EGF)-stimulated release of cellular reactive oxygen species. Decreased reactivity was observed for cysteines known to form sulfenic acids and redox-active disulfides. Importantly, the caged-BK platform provided the first quantification of intracellular disulfide bond formation upon EGF stimulation. In summary, the caged-BK probe is a powerful tool to identify reactivity changes associated with diverse cysteine modifications, including oxidation, metal chelation, and inhibitor binding, within a physiologically relevant context. PMID- 26020834 TI - Chemical Plausibility of Cu(III) with Biological Ligation in pMMO. AB - The mechanisms of dioxygen activation and methane C-H oxidation in particulate methane monooxygenase (pMMO) are currently unknown. Recent studies support a binuclear copper site as the catalytic center. We report the low-temperature assembly of a high-valent dicopper(III) bis(MU-oxide) complex bearing marked structural fidelity to the proposed active site of pMMO. This unprecedented dioxygen-bonded Cu(III) species with exclusive biological ligation directly informs on the chemical plausibility and thermodynamic stability of the bis(MU oxide) structure in such dicopper sites and foretells unusual optical signatures of an oxygenation product in pMMO. Though the ultimate pMMO active oxidant is still debated, C-H oxidation of exogenous substrates is observed with the reported Cu(III) complexes. The assembly of a high valent species both narrows the search for relevant pMMO intermediates and provides evidence to substantiate the role of Cu(III) in biological redox processes. PMID- 26020835 TI - Effects of Te(IV) Oxo-Anion Incorporation into Thorium Molybdates and Tungstates. AB - The exploration of phase formation in the Th-Mo/W-Te systems has resulted in four mixed oxo-anion compounds from high-temperature solid-state reactions: ThWTe2O9, Th(WO4)(TeO3), ThMoTe2O9, and Th2(MoO4)(TeO3)3. All four compounds contain edge sharing thorium polyhedra linked by MoO4/WO6 and different tellurium oxo-groups to form three-dimensional frameworks. In ThWTe2O9, each helical Th based chain is connected by four tungstotellurite clusters resulting in a building fragment which has a cross-section of four-leafed clovers. The structure of Th(WO4)(TeO3) exhibits a multilayer-sandwich framework composed of thorium tellurite layers with tungsten chains in between. In the case of the molybdate family, ThMoTe2O9 and Th2(MoO4)(TeO3)3 are built from puckered Th-Te sheets which are further interconnected by MoO4 tetrahedral linkers. The DSC-TG technique was performed to gain insight into the thermal behavior of the synthesized compounds. Raman spectra of as-prepared phases were obtained and analyzed for signature peaks. PMID- 26020836 TI - The Contribution of Fortified Ready-to-Eat Cereal to Vitamin and Mineral Intake in the U.S. Population, NHANES 2007-2010. AB - Micronutrients play a pivotal role in achieving and maintaining optimum health across all life stages. Much of the U.S. population fails to meet Estimated Average Requirements (EARs) for key nutrients. This analysis aims to assess the contribution of fortified ready-to-eat cereals (RTEC) to micronutrient intake for U.S. residents aged 2-18, 19-99, and 2-99 years of age according to National Health and Nutrition Examination Survey (NHANES) 2007-2010 data. We used the National Cancer Institute (NCI) method to assess usual intake of 21 micronutrients and the percentage of the population under EARs and above Tolerable Upper Intake Levels (UL). Without fortification of RTECs, the percentage of those aged 2-18 years that were below EARs increased by 155, 163, 113, and 35% for niacin, iron, thiamin, and vitamin A, respectively. For vitamins B6 and zinc, the respective numbers were 118% and 60%. Adults aged 19-99 and 2-99 had lower percentages but similar outcomes. RTECs are associated with improved nutrient adequacy and do not widely affect prevalence above the UL. The data indicate that large proportions of the population fail to achieve micronutrient sufficiency without fortification, and that its use can help Americans reach national nutrient intake goals. PMID- 26020837 TI - Shape-Controlled Synthesis of Colloidal Metal Nanocrystals: Thermodynamic versus Kinetic Products. AB - This Perspective provides a contemporary understanding of the shape evolution of colloidal metal nanocrystals under thermodynamically and kinetically controlled conditions. It has been extremely challenging to investigate this subject in the setting of one-pot synthesis because both the type and number of seeds involved would be changed whenever the experimental conditions are altered, making it essentially impossible to draw conclusions when comparing the outcomes of two syntheses conducted under different conditions. Because of the uncertainty about seeds, most of the mechanistic insights reported in literature for one-pot syntheses of metal nanocrystals with different shapes are either incomplete or ambiguous, and some of them might be misleading or even wrong. Recently, with the use of well-defined seeds for such syntheses, it became possible to separate growth from nucleation and therefore investigate the explicit role(s) played by a specific thermodynamic or kinetic parameter in directing the evolution of colloidal metal nanocrystals into a specific shape. Starting from single-crystal seeds enclosed by a mix of {100}, {111}, and {110} facets, for example, one can obtain colloidal nanocrystals with diversified shapes by adjusting various thermodynamic or kinetic parameters. The mechanistic insights learnt from these studies can also be extended to account for the products of conventional one-pot syntheses that involve self-nucleation only. The knowledge can be further applied to many other types of seeds with twin defects or stacking faults, making it an exciting time to design and synthesize colloidal metal nanocrystals with the shapes sought for a variety of fundamental studies and technologically important applications. PMID- 26020838 TI - A case of severe sepsis presenting marked decrease of neutrophils and interesting findings on dynamic CT. AB - BACKGROUND: In a patient with severe sepsis, we sometimes observe immediate decrease of the counts of white blood cells (WBCs) and neutrophils, which is known as an indicator for poor prognosis. We observed marked decrease of white blood cells and neutrophils on blood examination and interesting findings on dynamic CT. Here, we present the case of a patient with severe postoperative sepsis occurring after major abdominal surgery and we discuss the mechanism of such clinical presentations. CASE REPORT: A 60-year-old man received pancreatoduodenectomy with colectomy for pancreatic cancer. He developed a high fever on postoperative day 3. We observed marked decrease of WBCs and neutrophils on blood examination. We also observed slight swelling of the liver, inhomogeneous enhancement of liver parenchyma in arterial phase, and periportal low density in the Glisson capsule in portal phase, without any findings indicating infectious complications on dynamic CT. WBCs and neutrophils increased above normal range in just 6 hours. Blood culture examination performed while the patient had a high fever was positive for Aeromonas hydrophila. After receiving intensive care, he promptly recovered from severe sepsis. The CT findings disappeared on second dynamic CT examination performed 3 days after the first examination. CONCLUSIONS: We treated a patient with severe sepsis after major abdominal surgery who presented very rapid change of the counts of WBCs and neutrophils and interesting CT findings in the liver. We rescued him from a critical situation by prompt and intensive treatment. Research is needed to accumulate and analyze data from more patients who present a similar clinical course to better understand their pathophysiological conditions. PMID- 26020839 TI - Arginine methylation of hnRNPUL1 regulates interaction with NBS1 and recruitment to sites of DNA damage. AB - Arginine methylation is a post-translational modification required for the maintenance of genomic integrity. Cells deficient in protein arginine methyltransferase 1 (PRMT1) have DNA damage signaling defects, defective checkpoint activation and extensive genomic instability. Herein we identify the DNA damage protein and RNA binding protein, hnRNPUL1, to be a substrate of PRMT1. We identify the dimethylation of R584, R618, R620, R645, and R656, as well as the monomethylation of R661 R685 and R690 within hnRNPUL1 in U2OS cells by mass spectrometry. Moreover, we define the arginines within the RGG/RG motifs as the site of methylation by PRMT1 both in vitro and in vivo. The arginines 612, 618, 620, 639, 645, 656 and 661 within the human hnRNPUL1 RGG/RG motifs were substituted with lysines to generate hnRNPUL1(RK). hnRNPUL1(RK) was hypomethylated and lacked the ability to interact with PRMT1, unlike wild type hnRNPUL1. Co-immunoprecipitation studies showed that hnRNPUL1(RK) had impaired ability to associate with the DNA damage protein NBS1. Moreover, hnRNPUL1(RK) was not recruited to sites of DNA damage, unlike wild type hnRNPUL1, in the presence of transcriptional inhibitors. These findings define a role for arginine methylation during the DNA damage response to regulate protein-protein interactions for the recruitment at sites of damage. PMID- 26020840 TI - Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers. AB - Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation. PMID- 26020842 TI - Degenerative Spondylolisthesis: An Analysis of the Nationwide Inpatient Sample Database. AB - STUDY DESIGN: Analysis of the Nationwide Inpatient Sample database. OBJECTIVE: To investigate national trends, risks, and benefits of surgical interventions for degenerative spondylolisthesis (DS). SUMMARY OF BACKGROUND DATA: The surgical management of DS continues to evolve whereas the most clinically and cost effective treatment is debated. With an aging US population and growing restraints on a financially burdened health care system, a clear understanding of national trends in the surgical management of DS is needed. METHODS: The Nationwide Inpatient Sample database was queried for patients with DS undergoing lumbar fusions from 2001 to 2010, using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis and procedure codes. Analyses compared instrumented posterolateral fusion (PLF), posterolateral fusion with anterior lumbar interbody fusion (ALIF + PLF), PLF with posterior interbody fusion (P/TLIF + PLF), anterior instrumented interbody fusion (ALIF), and posterior interbody fusion with posterior instrumentation (P/TLIF). Clinical data were analyzed representing the initial acute phase care after surgery. RESULTS: There were 48,911 DS surgical procedures identified, representing 237,383 procedures. The percentage of patients undergoing PLF, ALIF + PLF, or ALIF increased whereas the percentage of P/TLIF or P/TLIF + PLF decreased over time. Total charges were less (P < 0.001), average length of hospital stay was shorter (P < 0.01), and average age was older (P < 0.01) for patients who underwent PLF compared with any other procedure. Type of procedure varied on the basis of the geographic region of the hospital, teaching versus nonteaching hospital, and size of hospital (P < 0.01). Patients who had P/TLIF + PLF or ALIF had a higher risk of mortality than patients who had PLF (odds ratios: 5.02, 2.22, respectively). Patients were more likely to develop a complication if they had ALIF + PLF, P/TLIF + PLF, ALIF, and P/TLIF than if they had PLF (odds ratios: 1.45, 1.23, 1.49, 1.12, respectively). CONCLUSION: Variation in the surgical management of DS related to patient demographics, hospital charges, length of hospital stay, insurance type, comorbidities, and complication rates was found within the Nationwide Inpatient Sample database. During the acute phase of care immediately after surgery, PLF procedures were found to reduce length of hospital stay, hospital charges, and postoperative complications. LEVEL OF EVIDENCE: 3. PMID- 26020841 TI - Structural Analysis of Substrate, Reaction Intermediate, and Product Binding in Haemophilus influenzae Biotin Carboxylase. AB - Acetyl-CoA carboxylase catalyzes the first and regulated step in fatty acid synthesis. In most Gram-negative and Gram-positive bacteria, the enzyme is composed of three proteins: biotin carboxylase, a biotin carboxyl carrier protein (BCCP), and carboxyltransferase. The reaction mechanism involves two half reactions with biotin carboxylase catalyzing the ATP-dependent carboxylation of biotin-BCCP in the first reaction. In the second reaction, carboxyltransferase catalyzes the transfer of the carboxyl group from biotin-BCCP to acetyl-CoA to form malonyl-CoA. In this report, high-resolution crystal structures of biotin carboxylase from Haemophilus influenzae were determined with bicarbonate, the ATP analogue AMPPCP; the carboxyphosphate intermediate analogues, phosphonoacetamide and phosphonoformate; the products ADP and phosphate; and the carboxybiotin analogue N1'-methoxycarbonyl biotin methyl ester. The structures have a common theme in that bicarbonate, phosphate, and the methyl ester of the carboxyl group of N1'-methoxycarbonyl biotin methyl ester all bound in the same pocket in the active site of biotin carboxylase and as such utilize the same set of amino acids for binding. This finding suggests a catalytic mechanism for biotin carboxylase in which the binding pocket that binds tetrahedral phosphate also accommodates and stabilizes a tetrahedral dianionic transition state resulting from direct transfer of CO2 from the carboxyphosphate intermediate to biotin. PMID- 26020843 TI - Perioperative Major Non-neurological Complications in 105 Patients Undergoing Posterior Vertebral Column Resection Procedures for Severe Rigid Deformities. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To analyze the perioperative major non-neurological complications (MNNCs) in posterior vertebral column resection (PVCR) procedures for severe rigid deformities and to identify the factors that may increase the risk. SUMMARY OF BACKGROUND DATA: Although surgeons constantly attempted to increase the corrective efficacy and neurological safety after PVCR, there are still significant risks of major and potentially life-threatening complications. METHODS: A total of 105 consecutive patients with severe rigid deformity who underwent 1-stage PVCR at a single center from 2004 to 2013 were reviewed. The demographic data, medical and surgical histories, perioperative and final follow-up radiographical measurements, and prevalence of perioperative MNNCs were reviewed. RESULTS: The mean age of patients at the time of surgery was 18.9 years (range: 10-45 yr). The major curve of scoliosis was 108.9 +/- 25.5 preoperatively and 37.2 +/- 16.8 at the final follow-up, and segmental kyphosis was from 89.8 +/- 31.1 to 30.4 +/- 15.3. There were 31 MNNCs in 24 patients: 16 respiratory complications in 13 patients, 9 cardiovascular adverse events in 7 cases, 1 malignant hyperthermia, and 1 optic deficit. There were 3 patients with wound infection, and 1 of them had to undergo partial removal of the implant for infection control. One patient with neurofibromatosis died 1 day after operation. Factors that showed no relationships with an increased prevalence of MNNCs were age, sex, presence of cardiac disease or neural axis malformation, and both sagittal and coronal correction rate. Patients with T6 and upper resected level, undergoing PVCR at the early period, showed a trend toward more MNNCs encountered. Moreover, nonidiopathic deformity, large scoliotic curve greater than 150 degrees , percent predicated forced vital capacity and forced expiratory volume in 1 second (FEV1.0) less than 40%, and estimated blood loss volume more than 5000 mL were identified as risk factors associated with MNNCs. CONCLUSION: Patients who had undergone PVCR experienced expected higher rate of MNNCs, with an overall prevalence of 22.9%. When considering PVCR, it is important to recognize the significantly higher inherent risks and provide appropriate preoperative counseling on the risks and benefits of surgery. LEVEL OF EVIDENCE: 3. PMID- 26020844 TI - An Approach to Primary Tumors of the Upper Cervical Spine With Spondylectomy Using a Combined Approach: Our Experience With 19 Cases. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To examine the link between major complications, surgical techniques, and perioperative care in the intralesional spondylectomy of the upper cervical spine. SUMMARY OF BACKGROUND DATA: Spondylectomy has been demonstrated to prolong cancer-free survival in many patients with locally aggressive spinal tumors. However, the challenging nature of this surgical procedure and the potential for severe complications often limit its application in the upper cervical spine. METHODS: Nineteen patients with primary upper cervical tumors were treated with spondylectomy from March 2005 to August 2009, using either the anterior-posterior or posterior-anterior approach. Anterior procedures were transmandibular, transoral, or high retropharyngeal. Anterior reconstructions were performed in plates with iliac crest strut grafts, plates with mesh cages, and Harms mesh cages alone. Occipitocervical fixation was performed with Halo-vest application for postoperative immobilization. RESULTS: Vertebral artery injuries occurred unilaterally in 5 cases intraoperatively: 4 occurred in the anterior approach of anterior-posterior procedures. Fusion was achieved in 9 patients with intact internal instrumentation. Fusion with the anterior construct in a tilted position occurred in 3 patients, all of whom underwent anterior-posterior procedures with Halo-vest immobilization for less than 1 month. Nonunion occurred in 3 cases after the posterior-anterior procedure because of anterior bone graft absorption. Prolonged Halo-vest immobilization maintained postoperative stability. Failure of internal instrumentation occurred in 3 cases. Anterior construct dislocation and severe tilting occurred in 2 cases after the anterior-posterior procedure. Five patients had a local recurrence. All recurrent lesions were malignant tumors and occurred in regions where surgical exposure was inadequate with incomplete excision. CONCLUSION: The order of the surgical approach is a critical determinant of complications, fusion rates, choice of surgical technique, and reconstruction methods. The postoperative use of a Halo-vest is recommended. Local recurrence is associated with tumor malignancy and inadequate excision margin. LEVEL OF EVIDENCE: 4. PMID- 26020845 TI - Morbidity and Mortality After Vertebral Fractures: Comparison of Vertebral Augmentation and Nonoperative Management in the Medicare Population. AB - STUDY DESIGN: Vertebral compression fracture (VCF) patients in the 100% US Medicare data set (2005-2009). OBJECTIVE: To compare the mortality and morbidity risks for VCF patients undergoing conservative treatment (nonoperated), balloon kyphoplasty (BKP), and vertebroplasty (VP). SUMMARY OF BACKGROUND DATA: Studies have reported lower mortality risk for BKP or VP cohorts than nonoperated cohorts, but it is uncertain whether there are any differences in morbidity risks. METHODS: Survival and morbidity was estimated by the Kaplan-Meier method, and the differences in outcomes were assessed by Cox regression between BKP, VP, and nonoperated cohorts. A propensity matching analysis was used to account for potential bias. RESULTS: A total of 1,038,956 VCF patients were identified, including 141,343 BKP patients and 75,364 VP patients. The nonoperated cohort was found to have a 55% higher adjusted risk of mortality (P < 0.001) than the BKP cohort and 25% higher adjusted risk of mortality (P < 0.001) than the VP cohort. The BKP cohort was also found to have a 19% lower adjusted risk of mortality (P < 0.001) than the VP cohort. The findings were similar for mortality with pneumonia diagnosed in the 90 days before death and also after propensity matching, as well as for subgroups of osteoporotic VCF patients, including those who survived at least 1 year and those with no cancer diagnosis. With propensity matching, the nonoperated cohort had significantly higher adjusted risks of pneumonia, myocardial infarction/cardiac complications, DVT, and urinary tract infection than the BKP cohort but lower adjusted risks of subsequent augmentation/fusion, subsequent augmentation, and pulmonary/respiratory complications. The BKP cohort also had significantly lower risks of morbidity than the VP cohort, except for deep venous thrombosis (DVT), infection, and myocardial infarction/cardiac complications, which were similar between both cohorts. CONCLUSION: VCF patients in the Medicare population who received vertebral augmentation therapies, specifically BKP and VP, experienced lower mortality and overall morbidity than VCF patients who received conservative management. LEVEL OF EVIDENCE: 3. PMID- 26020846 TI - "Sternum-Into-Abdomen" Deformity With Abdominal Compression Following Osteoporotic Vertebral Compression Fractures Managed By 2-Level Vertebral Column Resection and Reconstruction. AB - STUDY DESIGN: A unique case report. OBJECTIVE: To report a case of severe thoracolumbar kyphosis with abdominal compression causing gastric disturbance after treatment of an osteoporotic vertebral compression fracture and its ultimate management by vertebral column resection (VCR). We propose a new terminology "sternum-into-abdomen deformity" to describe this condition. SUMMARY OF BACKGROUND DATA: Management of osteoporotic vertebral compression fractures mainly aims at pain control and deformity reduction. VCR for decreasing abdominal compression due to the development of severe kyphosis after treatment of osteoporotic compression fractures has never been reported in the literature to our knowledge. METHODS: This is a case report on a single patient. The hospital and office charts were reviewed. Reports of prior treatment of his compression fracture were analyzed. RESULTS: This 73-year-old cachectic patient underwent vertebroplasty for a midthoracic compression fracture with progressive, severe kyphosis. His condition worsened and spinal reconstruction with a 2-level VCR restored more normal sagittal alignment and decreased his gastric compression. His back pain decreased and his ability to tolerate oral intake returned. CONCLUSION: We propose the term "sternum-into-abdomen deformity" to describe this type of severe kyphosis with abdominal compression. Treatment with a VCR and fusion for realignment of focal kyphosis can improve the quality of life for patients with this condition. LEVEL OF EVIDENCE: 5. PMID- 26020847 TI - A global perspective on the outcomes of surgical decompression in patients with cervical spondylotic myelopathy: results from the prospective multicenter AOSpine international study on 479 patients. AB - STUDY DESIGN: Prospective, multicenter international cohort. OBJECTIVE: To evaluate outcomes of surgical decompression for cervical spondylotic myelopathy (CSM) at a global level. SUMMARY OF BACKGROUND DATA: CSM is a degenerative spine disease and the most common cause of spinal cord dysfunction worldwide. Surgery is increasingly recommended as the preferred treatment strategy for CSM to improve neurological and functional status and quality of life. The outcomes of surgical intervention for CSM have never been evaluated at an international level. METHODS: Between October 2007 and January 2011, 479 symptomatic patients with image evidence of CSM were enrolled in the prospective, multicenter AOSpine CSM-International study from 16 global sites. Preoperative and postoperative clinical status, functional impairment, and quality of life were evaluated using the modified Japanese Orthopaedic Assessment Scale, Nurick Scale, Neck Disability Index, and Short-Form-36v2. Preoperative and 12- and 24-month postoperative outcomes were compared using mixed-model analysis of covariance for repeated measurements. RESULTS: The study cohort consisted of 310 males and 169 females, with a mean age of 56.37 +/- 11.91 years. There were significant differences in age, etiology, and surgical approaches between the regions. At 24 months postoperatively, the mean modified Japanese Orthopaedic Assessment Scale score improved from 12.50 (95% confidence interval [CI], 12.24-12.76) to 14.90 (95% CI, 14.64-15.16); the Neck Disability Index improved from 36.38 (95% CI, 34.33-38.43) to 23.20 (95% CI, 21.24-25.15); and the SF36v2 Physical Component Score and Mental Composite Score improved from 34.28 (95% CI, 33.46-35.10) to 40.76 (95% CI, 39.71-41.81) and 39.45 (95% CI, 38.25-40.64) to 46.24 (95% CI, 44.94-47.55), respectively. The rate of neurological complications was 3.13%. CONCLUSION: Surgical decompression for CSM is safe and results in improved functional status and quality of life in patients around the world, irrespective of differences in medical systems and sociocultural determinants of health. LEVEL OF EVIDENCE: 3. PMID- 26020848 TI - Outcomes After Operative Management of Combat-Related Low Lumbar Burst Fractures. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: Report the 2-year operative and clinical outcomes of these service members with low lumbar fractures. SUMMARY OF BACKGROUND DATA: The majority of spinal fractures occur at the thoracolumbar level, with fractures caudal to L2 accounting for only 1% of spine fractures. A previous report from this institution regarding combat-related spine burst fractures documented an increased incidence of low lumbar burst fractures in injured service members. METHODS: Review of inpatient and outpatient medical records in addition to radiographs for all patients treated at our institution with combat-related burst fractures occurring at the L3-L5 levels. RESULTS: Twenty-four patients with a mean age of 28.1+/- 7.2 underwent surgery for low lumbar (L3-L5) burst fractures. The mean number of thoracolumbar levels injured was 2.9 +/- 1.4. Eleven patients had neurological injury, 4 of which were complete. The mean days to surgery were 16.8 +/- 24.5. The mean number of levels fused was 4.3 +/- 2.1, with fixation extending to the pelvis in 4 patients (17%). Fourteen (61%) patients had at least 1 postoperative complication, with 7 (30%) requiring reoperation. Five patients had a postoperative wound infection. Five patients had deep venous thromboses, 3 had pulmonary emboli. Mean clinical follow up was 3.3+/- 2.2 years. At latest follow-up, all were separated from military service, 10 experienced persistent bowel/bladder dysfunction, 15 had lower extremity motor deficits, and 10 had documented persistent low back pain. Nineteen had chronic pain with 18 patients still taking pain medications and/or muscle relaxers. CONCLUSION: Low lumbar burst fractures are a rare injury with an increased incidence in combat casualties engaged in the wars in Iraq and Afghanistan. We found a high rate of acute postoperative complications (61%), as well as a high reoperation rate (30%). At approximately 3 years of follow-up, most of these patients had persistent neurological symptoms and chronic pain. LEVEL OF EVIDENCE: 4. PMID- 26020849 TI - Responsiveness of the Chinese versions of the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire and Neck Disability Index in postoperative patients with cervical spondylotic myelopathy. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To evaluate the postoperative responsiveness of the Chinese versions of the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) and the Neck Disability Index (NDI) in a cohort of patients with cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: We have recently completed the translation and cross-cultural adaptation of a Chinese version of JOACMEQ. However, the postoperative responsiveness of the Chinese JOACMEQ and how it compares with the more commonly used NDI remain undetermined. METHODS: Forty-five patients with cervical spondylotic myelopathy undergoing surgical decompression were recruited. All patients completed the Chinese JOACMEQ and the NDI preoperatively and again at 3 month follow-up together with an 11-point Global Rating of Change scale. Patients were dichotomized either as "Improved" or "Stable" on the basis of Global Rating of Change. Paired t test, standardized effect sizes, and Guyatt responsiveness index were used to determine internal responsiveness. External responsiveness was evaluated by the area under the receiver operating characteristic curve and the minimal clinically important change was determined as the optimal cutoff point for patient discrimination anchor-based on Global Rating of Change classification. RESULTS: Bladder function and quality of life (QOL) domains (P < 0.03) of the JOACMEQ and the NDI (P = 0.004) reached statistically significant difference with the paired t test. After the dichotomization, the standardized effect size was strong for the QOL domain in the improved group (0.85) and the Cervical spine function (0.97) in the stable group, respectively. Based on the Guyatt responsiveness index, strong responsiveness was found for the Bladder function (0.88) and QOL (0.76) domains of the JOACMEQ and moderate responsiveness (0.55) for the NDI. The Bladder function (area = 0.82; minimal clinically important change = 6) and QOL (0.83; minimal clinically important change = 8.5) also produced largest area under the receiver operating characteristic curve. CONCLUSION: Bladder function and QOL domains of the JOACMEQ seem to demonstrate the strongest postoperative responsiveness and thus may be more appropriate than NDI when attempting to determine treatment efficacy in cervical spondylotic myelopathy. LEVEL OF EVIDENCE: 3. PMID- 26020850 TI - Urinary Tract Infection Following Posterior Lumbar Fusion Procedures: An American College of Surgeons National Surgical Quality Improvement Program Study. AB - STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To determine the incidence and risk factors for the development of a urinary tract infection (UTI) after a posterior lumbar fusion procedure. SUMMARY OF BACKGROUND DATA: UTI after surgery is common and has important clinical consequences for both patients and the health care system. Few studies have examined UTI after spinal fusion procedures. METHODS: Patients undergoing posterior lumbar fusion procedures during 2011 to 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Statistical comparisons were made using multivariate regression with adjustment for demographic, comorbidity, and operative characteristics. RESULTS: A total of 10,825 patients met inclusion criteria. The incidence of a UTI was 1.77% (95% confidence interval = 1.52%-2.02%). Independent risk factors for a UTI were greater age (for 50-59 yr, relative risk [RR] = 1.0; 60-69 yr, RR = 2.1; >=70 yr, RR = 3.5; P < 0.001), female sex (RR = 2.2, P < 0.001), dependent functional status (RR = 2.1, P = 0.010), malnutrition (RR = 2.3, P = 0.004), diabetic status (for non-insulin-dependent diabetes, RR = 1.5; for insulin-dependent diabetes, RR = 1.9; P = 0.011), and increased operative duration (for 120-179 min, RR = 1.4; 180-239 min, RR = 2.3; and for >=240 min, RR = 2.7; P < 0.001).Patients who developed a UTI had a greater risk for systemic sepsis than other patients (11.5% vs. 0.63%; adjusted RR = 14.4, P < 0.001). Patients who developed a UTI had a greater risk for readmission than other patients (36.7% vs. 5.0%; adjusted RR = 6.1, P < 0.001). CONCLUSION: UTIs occur in nearly 1 in 50 patients undergoing posterior lumbar fusion procedures. Patients who are older, female, dependent, malnourished, or diabetic are at greater risk and should be counseled and monitored accordingly. In addition, morbidity associated with a UTI in this population is substantial, as demonstrated by a 14-fold increase in the risk for systemic sepsis and a 6-fold increase in the risk for readmission. As such, increased preventative measures should be targeted to the patients identified here to be at greatest risk. LEVEL OF EVIDENCE: 3. PMID- 26020851 TI - Do participants with low back pain who respond to spinal manipulative therapy differ biomechanically from nonresponders, untreated controls or asymptomatic controls? AB - STUDY DESIGN: Nonrandomized controlled study. OBJECTIVE: To determine whether patients with low back pain (LBP) who respond to spinal manipulative therapy (SMT) differ biomechanically from nonresponders, untreated controls or asymptomatic controls. SUMMARY OF BACKGROUND DATA: Some but not all patients with LBP report improvement in function after SMT. When compared with nonresponders, studies suggest that SMT responders demonstrate significant changes in spinal stiffness, muscle contraction, and disc diffusion. Unfortunately, the significance of these observations remains uncertain given methodological differences between studies including a lack of controls. METHODS: Participants with LBP and asymptomatic controls attended 3 sessions for 7 days. On sessions 1 and 2, participants with LBP received SMT (+LBP/+SMT, n = 32) whereas asymptomatic controls did not (-LBP/-SMT, n = 57). In these sessions, spinal stiffness and multifidus thickness ratios were obtained before and after SMT and on day 7. Apparent diffusion coefficients from lumbar discs were obtained from +LBP/+SMT participants before and after SMT on session 1 and from an LBP control group that did not receive SMT (+LBP/-SMT, n = 16). +LBP/+SMT participants were dichotomized as responders/nonresponders on the basis of self-reported disability on day 7. A repeated measures analysis of covariance was used to compare apparent diffusion coefficients among responders, nonresponders, and +LBP/-SMT subjects, as well as spinal stiffness or multifidus thickness ratio among responders, nonresponders, and -LBP/-SMT subjects. RESULTS: After the first SMT, SMT responders displayed statistically significant decreases in spinal stiffness and increases in multifidus thickness ratio sustained for more than 7 days; these findings were not observed in other groups. Similarly, only SMT responders displayed significant post-SMT improvement in apparent diffusion coefficients. CONCLUSION: Those reporting post-SMT improvement in disability demonstrated simultaneous changes between self-reported and objective measures of spinal function. This coherence did not exist for asymptomatic controls or no-treatment controls. These data imply that SMT impacts biomechanical characteristics within SMT responders not present in all patients with LBP. This work provides a foundation to investigate the heterogeneous nature of LBP, mechanisms underlying differential therapeutic response, and the biomechanical and imaging characteristics defining responders at baseline. LEVEL OF EVIDENCE: 3. PMID- 26020854 TI - The business of medicine: an introduction. PMID- 26020855 TI - n-type conversion of SnS by isovalent ion substitution: Geometrical doping as a new doping route. AB - Tin monosulfide (SnS) is a naturally p-type semiconductor with a layered crystal structure, but no reliable n-type SnS has been obtained by conventional aliovalent ion substitution. In this work, carrier polarity conversion to n-type was achieved by isovalent ion substitution for polycrystalline SnS thin films on glass substrates. Substituting Pb(2+) for Sn(2+) converted the majority carrier from hole to electron, and the free electron density ranged from 10(12) to 10(15) cm(-3) with the largest electron mobility of 7.0 cm(2)/(Vs). The n-type conduction was confirmed further by the position of the Fermi level (EF) based on photoemission spectroscopy and electrical characteristics of pn heterojunctions. Density functional theory calculations reveal that the Pb substitution invokes a geometrical size effect that enlarges the interlayer distance and subsequently reduces the formation energies of Sn and Pb interstitials, which results in the electron doping. PMID- 26020856 TI - Development of novel agents for idiopathic pulmonary fibrosis: progress in target selection and clinical trial design. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Until recently, the standard therapy for this disease has been essentially supportive, with the exception of a minority of patients who were eligible for lung transplantation. The development pathway for novel medications for IPF has been complicated. There have been several challenges, including an incomplete understanding of the pathogenesis, unpredictable clinical course, lack of validated biomarkers, the low clinical predictive value of animal models of lung injury, and the need to commit to large clinical trials of long duration to obtain initial evidence of clinical efficacy. Despite these challenges, the combination of recent advances in translational medicine and the unprecedented increase in clinical data accumulated from recent large clinical trials has stimulated an increase in the number of clinical development programs for IPF. Clinical programs are increasingly characterized by rational target selection, preclinical optimization of therapeutic molecules, and an emphasis on efficient clinical trial design. A lower rate of functional decline in patients treated with pirfenidone and nintedanib was demonstrated in large clinical trials. In October 2014, these two drugs became the first agents to be approved by the US Food and Drug Administration for the treatment of IPF. (Pirfenidone had already been approved in several countries outside the United States.) In November 2014, the European Medicines Agency approved the use of nintedanib for IPF. The landscape for management of IPF has markedly changed with the advent of approved therapeutic options for IPF. In this article, we review the strategies that are being used to increase the likelihood of success in clinical development programs of novel disease-modifying agents in IPF. PMID- 26020858 TI - Cardiac Arrest in Children: Long-Term Health Status and Health-Related Quality of Life. AB - OBJECTIVE: To assess long-term health status and health-related quality of life in survivors of cardiac arrest in childhood and their parents. In addition, to identify predictors of health status and health-related quality of life. DESIGN: This medical follow-up study involved consecutive children surviving cardiac arrest between January 2002 and December 2011, who had been admitted to the ICU. Health status was assessed with a medical interview, physical examination, and the Health Utilities Index. Health-related quality of life was assessed with the Child Health Questionnaires and Short-Form 36. SETTING: A tertiary care university children's hospital. PATIENTS: Of the eligible 107 children, 57 (53%) filled out online questionnaires and 47 visited the outpatient clinic (median age, 8.7 yr; median follow-up interval, 5.6 yr). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the participants, 60% had an in-hospital cardiac arrest, 90% a nonshockable rhythm, and 50% a respiratory etiology of arrest. Mortality rate after hospital discharge was 10%. On health status, we found that 13% had long-term neurologic deficits, 34% chronic symptoms (e.g., fatigue, headache), 19% at least one sign suggestive of chronic kidney injury, and 15% needed special education. Health Utilities Index scores were significantly decreased on most utility scores and the overall Health Utilities Index mark 3 score. Compared with Dutch normative data, parent-reported health related quality of life of cardiac arrest survivors was significantly worse on general health perception, physical role functioning, parental impact, and overall physical summary. On patient reports, no significant differences with normative data were found. Parents reported better family cohesion and better health-related quality of life for themselves on most scales. Patients' health status, general health perceptions, and physical summary scores were significantly associated with cardiac arrest-related preexisting condition. CONCLUSIONS: Considering the impact of cardiac arrest, the overall outcome after cardiac arrest in childhood is reasonably good. Prospective long-term outcome research in large homogeneous groups is needed. PMID- 26020857 TI - Redox nanoparticles as a novel treatment approach for inflammation and fibrosis associated with nonalcoholic steatohepatitis. AB - AIM: Oxidative stress (OS) is largely thought to be a central mechanism responsible for liver damage, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Our aim was to investigate whether suppression of OS in the liver via redox nanoparticles (RNPs) reduces liver damage in a mouse model of NASH. MATERIALS & METHODS: RNPs were prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals and were orally administered by daily gavage for 4 weeks. RESULTS: The redox polymer was delivered to the liver after disintegration of nanoparticle in the stomach. RNP treatment in NASH mice via gavage led to a reduction of liver OS, improvement of fibrosis, and significant reduction of inflammation. CONCLUSION: These findings uncover RNP as a novel potential NASH therapy. PMID- 26020860 TI - COMPANION ANIMALS SYMPOSIUM: Companion animals and sustainability: Today's impact on the future. PMID- 26020859 TI - Observing microscopic structures of a relativistic object using a time-stretch strategy. AB - Emission of light by a single electron moving on a curved trajectory (synchrotron radiation) is one of the most well-known fundamental radiation phenomena. However experimental situations are more complex as they involve many electrons, each being exposed to the radiation of its neighbors. This interaction has dramatic consequences, one of the most spectacular being the spontaneous formation of spatial structures inside electrons bunches. This fundamental effect is actively studied as it represents one of the most fundamental limitations in electron accelerators, and at the same time a source of intense terahertz radiation (Coherent Synchrotron Radiation, or CSR). Here we demonstrate the possibility to directly observe the electron bunch microstructures with subpicosecond resolution, in a storage ring accelerator. The principle is to monitor the terahertz pulses emitted by the structures, using a strategy from photonics, time stretch, consisting in slowing-down the phenomena before recording. This opens the way to unpreceeded possibilities for analyzing and mastering new generation high power coherent synchrotron sources. PMID- 26020861 TI - COMPANION ANIMALS SYMPOSIUM: Future aspects and perceptions of companion animal nutrition and sustainability. AB - Companion animals play an important role in our lives and are now considered to be and treated as family members in a majority of households in the United States. Because of the high number of pets that now exist, an increasingly stronger pet-human bond, and the importance placed on health and longevity, the pet food industry has realized steady growth over the last few decades. Despite past successes and opportunities that exist in the future, there are also challenges that must be considered. This review will present a brief overview of the current pet food industry and address some of the key issues moving forward. In regards to companion animal research, recent advances and future needs in the areas of canine and feline metabolism, aging, clinical disease, and the gut microbiome using molecular and high-throughput assays; chemical, in vitro, and in vivo testing of feed ingredients; and innovative pet food processing methods is discussed. Training the future workforce for the pet food industry is also of great importance. Recent trends on student demographics and their species and careers of interest, changing animal science department curricula, and technology's impact on instruction are provided. Finally, the sustainability of the pet food industry is discussed. Focus was primarily placed on the disconnect that exists between opinions and trends of consumers and the nutrient recommendations for dogs and cats, the desire for increasing use of animal-based and human-grade products, the overfeeding of pets and the pet obesity crisis, and the issues that involve the evaluation of primary vs. secondary products in terms of sustainability. Moving forward, the pet food industry will need to anticipate and address challenges that arise, especially those pertaining to consumer expectations, the regulatory environment, and sustainability. Given the already strong and increasingly dynamic market for pet foods and supplies, an academic environment primed to supply a skilled workforce, and continued industry support for basic and applied research initiatives, the future of the pet food industry looks very bright. PMID- 26020862 TI - COMPANION ANIMALS SYMPOSIUM: Rendered ingredients significantly influence sustainability, quality, and safety of pet food. AB - The rendering industry collects and safely processes approximately 25 million t of animal byproducts each year in the United States. Rendering plants process a variety of raw materials from food animal production, principally offal from slaughterhouses, but include whole animals that die on farms or in transit and other materials such as bone, feathers, and blood. By recycling these byproducts into various protein, fat, and mineral products, including meat and bone meal, hydrolyzed feather meal, blood meal, and various types of animal fats and greases, the sustainability of food animal production is greatly enhanced. The rendering industry is conscious of its role in the prevention of disease and microbiological control and providing safe feed ingredients for livestock, poultry, aquaculture, and pets. The processing of otherwise low-value OM from the livestock production and meat processing industries through rendering drastically reduces the amount of waste. If not rendered, biological materials would be deposited in landfills, burned, buried, or inappropriately dumped with large amounts of carbon dioxide, ammonia, and other compounds polluting air and water. The majority of rendered protein products are used as animal feed. Rendered products are especially valuable to the livestock and pet food industries because of their high protein content, digestible AA levels (especially lysine), mineral availability (especially calcium and phosphorous), and relatively low cost in relation to their nutrient value. The use of these reclaimed and recycled materials in pet food is a much more sustainable model than using human food for pets. PMID- 26020864 TI - HORSE SPECIES SYMPOSIUM: Advances in equine stem cell biology. PMID- 26020863 TI - COMPANION ANIMALS SYMPOSIUM: Sustainable Ecosystems: Domestic cats and their effect on wildlife populations. AB - Domestic cats are estimated to kill billions of small mammals and birds each year. In certain areas of the world, it is not uncommon for either feral or free ranging cats to have high population densities, creating concern regarding their level of hunting. Many cats are considered to be subsidized predators, as they receive care and food from humans. Arguments abound regarding the presence of cats in the habitats of native small mammals and birds and whether or not local ecosystems can sustain this predator-prey relationship. The effects of cats on native wildlife can depend on several factors, including cat classification (feral vs. free ranging vs. indoor-outdoor), geographical location (islands vs. mainland), and type of habitat (rural vs. suburban vs. urban). Feral and free ranging cats may have a greater impact on native species on islands because habitat is severely limited. Continued urbanization and development of rural areas also creates fragmented habitats, and native species may struggle to survive with the added pressure of hunting by domestic cats. Additionally, cats in rural areas are frequently fed by humans, which can support high population densities and intensify pressure on native species. Species targeted by cats may also vary based on prey availability in different areas, but small mammals are generally preferred over birds, reptiles, or invertebrates. Domestic cats certainly have the potential to roam and hunt in very large areas inhabited by native species and loss of biodiversity is a major concern. Therefore, it is possible that ecosystems may not be able to sustain hunting by domestic cats. Because this predator-prey relationship is probably not sustainable, it is necessary to responsibly manage outdoor domestic cats. PMID- 26020865 TI - HORSE SPECIES SYMPOSIUM: Use of mesenchymal stem cells in fracture repair in horses. AB - Equine bone fractures are often catastrophic, potentially fatal, and costly to repair. Traditional methods of healing fractures have limited success, long recovery periods, and a high rate of reinjury. Current research in the equine industry has demonstrated that stem cell therapy is a promising novel therapy to improve fracture healing and reduce the incidence of reinjury; however, reports of success in horses have been variable and limited. Stem cells can be derived from embryonic, fetal, and adult tissue. Based on the ease of collection, opportunity for autologous cells, and proven success in other models, adipose- or bone marrow-derived mesenchymal stem cells (MSC) are often used in equine therapies. Methods for isolation, proliferation, and differentiation of MSC are well established in rodent and human models but are not well characterized in horses. There is recent evidence that equine bone marrow MSC are able to proliferate in culture for several passages in the presence of autologous and fetal bovine serum, which is important for expansion of cells. Mesenchymal stem cells have the capacity to differentiate into osteoblasts, the bone forming cells, and this complex process is regulated by a number of transcription factors including runt-related transcription factor 2 (Runx2) and osterix (Osx). However, it has not been well established if equine MSC are regulated in a similar manner. The data presented in this review support the view that equine bone marrow MSC are regulated by the same transcription factors that control the differentiation of rodent and human MSC into osteoblasts. Although stem cell therapy is promising in equine bone repair, additional research is needed to identify optimal methods for reintroduction and potential manipulations to improve their ability to form new bone. PMID- 26020866 TI - Genetic gain and economic values of selection strategies including semen traits in three- and four-way crossbreeding systems for swine production. AB - Four semen traits: volume (VOL), concentration (CON), progressive motility of spermatozoa (MOT), and abnormal spermatozoa (ABN) provide complementary information on boar fertility. Assessment of the impact of selection for semen traits is hindered by limited information on economic parameters. Objectives of this study were to estimate economic values for semen traits and to evaluate the genetic gain when these traits are incorporated into traditional selection strategies in a 3-tier system of swine production. Three-way (maternal nucleus lines A and B and paternal nucleus line C) and 4-way (additional paternal nucleus line D) crossbreeding schemes were compared. A novel population structure that accommodated selection for semen traits was developed. Three selection strategies were simulated. Selection Strategy I (baseline) encompassed selection for maternal traits: number of pigs born alive (NBA), litter birth weight (LBW), adjusted 21-d litter weight (A21), and number of pigs at 21 d (N21); and paternal traits: number of days to 113.5 kg (D113), backfat (BF), ADG, feed efficiency (FE), and carcass lean % (LEAN). Selection Strategy II included Strategy I and the number of usable semen doses per collection (DOSES), a function of the 4 semen traits. Selection Strategy III included Strategy I and the 4 semen traits individually. The estimated economic values of VOL, CON, MOT, ABN, and DOSES for 7 to 1 collections/wk ranged from $0.21 to $1.44/mL, $0.12 to $0.83/10 spermatozoa/mm, $0.61 to $12.66/%, -$0.53 to -$10.88/%, and $2.01 to $41.43/%, respectively. The decrease in the relative economic values of semen traits and DOSES with higher number of collections per wk was sharper between 1 and 2.33 collections/wk than between 2.33 and 7 collections/wk. The higher economic value of MOT and ABN relative to VOL and CON could be linked to the genetic variances and covariances of these traits. Average genetic gains for the maternal traits were comparable across strategies. Genetic gains for paternal traits, excluding semen traits, were greater in selection Strategy I than Strategies III and II. Genetic gains for paternal and maternal traits were greater in the 4- and 3-way schemes, respectively. The selection strategy including the 4 semen traits is recommended because this approach enables genetic gains for these traits without compromising the genetic gains for maternal traits and with minimal losses in genetic gains for paternal traits. PMID- 26020867 TI - Assessing peripheral blood cell profile of Yorkshire pigs divergently selected for residual feed intake. AB - The cost of feed is a serious issue in the pork industry, contributing about 65 to 75% of the total production cost. To prevent economic losses and decreased productivity of the herd, it is important to select for animals that eat less for the same lean gain, or more efficient animals. Residual feed intake (RFI) is the difference between observed feed intake and expected feed intake based on estimated maintenance and production requirements. Selection for decreased RFI, or more efficient animals, is a potential solution to higher feed costs in pig production. However, animals that are highly selected for decreased RFI may have reduced energy input to the immune system and fail to withstand diseases and stressors after infection that negatively impact profitability. The objective of this study was to evaluate differences in circulating blood cell profiles at a young age between 2 lines of Yorkshire pigs that were divergently selected for RFI as well as the heritability of these traits, to investigate effects of selection for RFI on immune system parameters, and to identify potential biomarkers for feed efficiency. Previous work has shown that the 2 lines had diverged for IGF-1 in serum in young pigs and, therefore, this stage was investigated for other potential physiological differences. Blood samples were drawn for a complete blood count (CBC) analysis from 517 gilts and barrows, ages 35 to 42 d, across the 2 lines. In general, the low-RFI line had lower numbers of specific types of white blood cells but higher hemoglobin concentration and red blood cell volume compared to the high-RFI line. No significant correlations were found between CBC traits and RFI across and within the lines (0.05 < < 0.1). Of the 15 CBC traits that were measured, 3 were highly heritable (0.56 < < 0.62), 9 were moderately heritable (0.12 < < 0.47), and 3 were lowly heritable ( < 0.12), suggesting a substantial genetic component for CBC traits and that selection for CBC traits could be effective. Our results also show that selection for RFI has significantly impacted the number of circulating blood cells. In this experiment, we studied only healthy animals that were not under known pathogen challenge; therefore, our results cannot be directly applied to a disease challenge situation. Future work will be to challenge the animals and determine the effect of challenge on CBC levels. PMID- 26020868 TI - Comparison of methods to study uniformity of traits: Application to birth weight in pigs. AB - Increasing uniformity of traits is an important objective in livestock production. This study focused on the BWcomparison of a double hierarchical GLM (DHGLM) with the conventional analysis of uniformity, using within-litter variation in birth weight (BW0) in pigs as a case. In pigs, within-litter variation of BW0 is a trait in which uniformity is important in breeding practice. Traditionally, uniformity has been studied by analysis of SD or variances. In DHGLM, differences between animals are studied by analyzing the residual variance of the trait and estimating its variance components. Here we used data on BW0, recorded in 2 sow lines (Large White and Landrace), to compare the estimation of genetic parameters and breeding values for uniformity from DHGLM and traditional analysis of the variance. Comparison of DHGLM with the conventional analysis using the logarithm-transformed variance of BW0 was possible because both methods were on the same scale and the models contained the same random effects. In addition, the genetic CV at the residual SD level (GCV) was proposed as a measure expressing the potential response to selection. Three fold cross-validation was performed to study predictive ability of both methods. The estimated GCV was highly similar using both methods. Results indicate that the SD of BW0 can be decreased by up to approximately 10% after 1 generation of selection, indicating good prospects for response to selection. The correlation between EBV (0.88 in both sow lines) obtained from both methods indicated high similarity between conventional analysis and DHGLM. Comparison of accuracies of EBV showed that the methods were comparable, with moderate accuracies achieved with approximately 100 piglets per maternal grandsire. Cross-validation also indicated very similar predictive ability in estimating EBV for BW0 variation for both methods. Therefore, it was concluded that conventional analysis and DHGLM produced highly comparable results. Still, the DHGLM potentially has a broader application than conventional analysis to study uniformity of traits, because it also can be used for traits with single observations per animal. PMID- 26020869 TI - Survival in crossbred lambs: Breed and heterosis effects. AB - The objective of this study was to estimate genetic and nongenetic effects affecting survival in crossbred lambs during 3 time periods: through 1 d of age ( = 7,933), 2 to 30 d of age ( = 5,370), and 2 to 60 d of age ( = 5,216) in a population being upgraded to the dairy breeds of East Friesian and Lacaune in which lambs were artificially reared on milk replacer. Survival was analyzed for lambs born in 14 yr from 1998 to 2011 using pedigree information from 14,339 animals born in 23 yr from 1989 to 2011. Date of death, sex, age of the dam, birth type, month and year of birth, and breed composition were recorded, and the proportion of retained heterosis was calculated for each animal. Lambs were crossbreds of 2 or more breeds with 14 breeds represented in the population. Due to low mean genetic contribution of the 12 nondairy breeds, they were placed into 2 groups: meat breeds (Hampshire, Suffolk, and Texel) and maternal breeds (Romanov, Finnsheep, Dorset, Targhee, Rambouillet, Polypay, Katahdin, Arcott Rideau, and Commercial). The proportion of individual retained heterosis was positively associated ( < 0.05) with lamb survival from 2 to 30 and from 2 to 60 d of age. The predicted increase in survival of F lambs compared to purebred lambs was +8.8 and +14.6%, respectively. Predicted survival of meat breed lambs and maternal breed lambs was greater ( <= 0.01) than Lacaune lambs during all 3 periods. Predicted survival of East Friesian lambs was consistently lower ( <= 0.01) than meat breed and maternal breed lambs during all periods. The predicted survival of East Friesian lambs was numerically greater but not significantly different from Lacaune lambs. There was a lower ( < 0.01) survival of females compared to males through 1 d of age (-5.6%), but females had higher ( < 0.01) survival than males in the other 2 periods (2 to 30 d = +3.3% and 2 to 60 d = +6.0%). Through 1 d of age, lambs of triplet and greater birth types had lower ( < 0.01) survival than single lambs (-6.2%), and lambs from 1-yr-old dams had lower ( < 0.01) survival than lambs from 2-yr-old dams (+4.5%). Estimates of heritability of lamb survival were 0.14 (SE = 0.03), 0.03 (SE = 0.04), and 0.06 (SE = 0.03) for the 3 time periods, respectively. An increase in the proportion of individual retained heterosis was the most important genetic factor associated with increased lamb survival in this study. PMID- 26020870 TI - Genotype * environment interaction in individual performance and progeny tests in beef cattle. AB - The study reported here evaluated genotype * environment interaction in individual performance and progeny tests in beef cattle. Genetic parameters for final weight (FW), ADG, and scrotal circumference (SC) of 33,013 Nellore young bulls tested on pasture or in feedlots were analyzed. The posterior means (and highest posterior density interval with 90% of samples [HPD90]) of heritability for traits measured on pasture-raised and feedlot-raised animals were 0.44 (HPD90 = 0.40 to 0.48) and 0.50 (HPD90 = 0.43 to 0.56) for FW, 0.26 (HPD90 = 0.23 to 0.29) and 0.26 (HPD90 = 0.20 to 0.32) for ADG, and 0.53 (HPD90 = 0.48 to 0.59) and 0.65 (HPD90 = 0.55 to 0.74) for SC, respectively. The posterior means (and HPD90) of genetic correlations for FW, ADG, and SC on pasture and in feedlots were 0.75 (HPD90 = 0.66 to 0.87), 0.49 (HPD90 = 0.31 to 0.66), and 0.89 (HPD90 = 0.83 to 0.97), respectively. When the selection intensity was kept the same for both the environments, the greatest direct responses for FW and ADG were exhibited by the animals reared and selected in feedlots. The correlated responses relative to production on pasture and based on selection in feedlots were similar to the direct responses, whereas the correlated responses for production in feedlots and based on selection on pasture were lower than the direct responses. When the selection intensity on pasture was higher than the selection intensity in feedlots, the responses to direct selection were similar for both the environments and correlated responses obtained in feedlots by selection on pasture were similar to the direct responses in feedlots. Analyses of few or poor indicators of genotype * environment interaction result in incorrect interpretations of its existence and implications. The present work demonstrated that traits with lower heritability are more susceptible to genotype * environment interaction and that selection intensity plays an important role in the study of genotype * environment interaction in beef cattle. PMID- 26020871 TI - An intervention study demonstrates effects of MC4R genotype on boar taint and performances of growing-finishing pigs. AB - The Asp298Asn polymorphism of the melanocortin-4 receptor (MC4R) in pigs is known to affect economically important traits such as growth rate and backfat thickness. We have assessed the possible use of this polymorphism as a molecular marker to perform genetic selection toward lower boar taint levels without compromising growth performance and carcass and meat quality in commercial boars and gilts. Homozygous boars and gilts of the AA genotype and GG genotype were compared in an intervention study with a 2 * 2 design to assess main effects and possible interactions between sex and genotype. The concentrations of the 3 boar taint compounds androstenone ( = 0.044), skatole ( = 0.049), and indole ( = 0.006) were significantly higher in fat of AA boars compared to GG boars. However, no effect on the sensory analysis of the fat samples could be observed. Between 20 and 115 kg BW, AA pigs showed higher ADFI than GG pigs ( < 0.001). An interaction between genotype and sex was observed for ADG ( = 0.044): AA boars had a significantly higher ADG than GG boars but there was no significant difference between the gilts. Daily lean meat gain tended to be higher in boars compared to gilts ( = 0.051), independent of genotype. Similarly, boars showed higher G:F compared to gilts ( < 0.001), without effect of genotype. Genotype and sex affected several carcass quality parameters but there was no interaction. Pigs of the AA genotype displayed a lower dressing percentage ( = 0.005), lower ham width ( = 0.024), lower muscle thickness ( = 0.011), and higher fat thickness ( < 0.001), resulting in a lower lean meat percentage ( < 0.001) in comparison with GG pigs. Gilts had a significantly higher dressing percentage ( < 0.001), higher muscle thickness ( < 0.001), higher ham width ( < 0.001), and lower ham angle ( < 0.001) compared to boars. Other than the boar taint compounds, meat quality was not affected by genotype. Pork of gilts was darker ( = 0.014) and less exudative during cooking ( < 0.001) and contained more intramuscular fat ( = 0.013). These results indicate that genetic selection against boar taint is possible using this marker. This will also result in lower feed intake and ADG and, consequently, better carcass quality. PMID- 26020872 TI - Genetic properties of residual feed intakes for maintenance and growth and the implications of error measurement. AB - A procedure for estimating residual feed intake (RFI) based on information used in feeding studies is presented. Koch's classical model consists of using fixed regressions of feed intake on metabolic BW and growth, and RFI is obtained as the deviation between the observed feed intake and the expected intake for an individual with a given weight and growth rate. Estimated RFI following such a procedure intrinsically suffers from the inability to separate true RFI from the sampling error. As the latter is never equal to 0, estimated RFI is always biased, and the magnitude of such bias depends on the ratio between the true RFI variance and the residual variance. Additionally, the classical approach suffers from its inability to dissect RFI into its biological components, being the metabolic efficiency (maintaining BW) and growth efficiency. To remedy these problems we proposed a procedure that directly models the individual animal variation in feed efficiency used for body maintenance and growth. The proposed model is an extension of Koch's procedure by assuming animal-specific regression coefficients rather than population-level parameters. To evaluate the performance of both models, a data simulation was performed using the structure of an existing chicken data set consisting of 2,289 records. Data was simulated using 4 ratios between the true RFI and sampling error variances (1:1, 2:1, 4:1, and 10:1) and 5 correlation values between the 2 animal-specific random regression coefficients (-0.95, -0.5, 0, 0.5, and 0.95). The results clearly showed the superiority of the proposed model compared to Koch's procedure under all 20 simulation scenarios. In fact, when the ratio was 1:1 and the true genetic correlation was equal to -0.95, the correlation between the true and estimated RFI for animals in the top 20% was 0.60 and 0.51 for the proposed and Koch's models, respectively. This is an 18% superiority for the proposed model. For the bottom 20% of animals in the ranking, the superiority was 17%. Even when the ratio of variances was 10:1, the superiority of the proposed model was around 6%. PMID- 26020873 TI - Investigation of the diversity and origins of Chinese dairy goats via the mitochondrial DNA D-loop. AB - To determine the genetic diversity, origins, and the phylogeography of Chinese dairy goats, we analyzed 162 complete mitochondrial DNA (mtDNA) D- loop sequences from 9 dairy goat breeds and compared them with 8 goat sequences that were previously reported in GenBank. The length of the mtDNA D-loop was 1,212 to 1,215 bp, and 97 polymorphic sites were identified. We also defined 62 haplotypes, including 35 unique haplotypes. The haplotype diversity value of all the dairy goats was 0.952, and the nucleotide diversity was 0.011 per site. Phylogenetic analyses revealed that Chinese dairy goats were divided into haplogroups A and B, with haplogroup A serving as the predominant group. Median-joining network and analyses of molecular variance indicated that Chinese dairy goats were more weakly phylogeographically structured than other domestic goats. A mismatch distribution analysis and Fu's test revealed that at least 1 population expansion event occurred in the demographic history of Chinese dairy goats. PMID- 26020874 TI - Genomewide association study of lung lesions in cattle using sample pooling. AB - Bovine respiratory disease complex (BRDC) is the most expensive disease in beef cattle in the United States costing the industry at least US$1 billion annually. Bovine respiratory disease complex causes damage to lung tissue resulting in persistent lung lesions observable at slaughter. Severe lung lesions at harvest have been associated with decreased preharvest ADG and increased clinical BRDC in the feedlot. Our objective was to identify SNP that are associated with severe lung lesions observed at harvest in feedlot cattle. We conducted a genomewide association study (GWAS) using a case-control design for severe lung lesions in fed cattle at slaughter using the Illumina Bovine HD array (approximately 770,000 SNP) and sample pooling. Lung samples were collected from 11,520 young cattle, a portion of which had not been treated with antibiotics (participating in a "natural" marketing program), at a large, commercial beef processing plant in central Nebraska. Lung samples with lesions (cases) and healthy lungs (controls) were collected when both phenotypes were in close proximity on the viscera (offal) table. We constructed 60 case and 60 control pools with 96 animals per pool. Pools were constructed by sampling sequence to ensure that case and control pool pairs were matched by proximity on the processing line. The Bovine HD array (770,000 SNP) was run on all pools. Fourteen SNP on BTA 2, 3, 4, 9, 11, 14, 15, 22, 24, and 25 were significant at the genomewide experiment-wise error rate of 5% ( <= 1.49 * 10). Eighty-five SNP on 28 chromosomes achieved a false discovery rate of 5% ( <= 5.38 * 10). Significant SNP were near (+/-100 kb) genes involved in tissue repair and regeneration, tumor suppression, cell proliferation, apoptosis, control of organ size, and immunity. Based on 85 significantly associated SNP in or near a collection of genes with diverse function on 28 chromosomes, we conclude that the genomic footprint of lung lesions is complex. A complex genomic footprint (genes and regulatory elements that affect the trait) is consistent with what is known about the cause of the disease: complex interactions among multiple viral and bacterial pathogens along with several environmental factors including dust, commingling, transportation, and stress. Characterization of sequence variation near significant SNP will enable accurate and cost effective genome-enhanced genetic evaluations for BRDC resistance in AI bulls and seed stock populations. PMID- 26020875 TI - Genetic modeling of feed intake. AB - With the development of automatic self-feeders and electronic identification, automated, repeated measurements of individual feed intake (FI) and BW are becoming available in more species. Consequently, genetic models for longitudinal data need to be applied to study FI or related traits. To handle this type of data, several flexible mixed-model approaches exist such as character process (CPr), structured antedependence (SAD), or random regression (RR) models. The objective of this study was to compare how these different approaches estimate both the covariance structure between successive measurements of FI and genetic parameters and their ability to predict future performances in 3 species (rabbits, ducks, and pigs). Results were consistent between species. It was found that the SAD and CPr models fit the data better than the RR models. Estimations of genetic and phenotypic correlation matrices were quite consistent between SAD and CPr models, whereas correlations estimated with the RR model were not. Structured antedependence and CPr models provided, as expected and in accordance with previous studies, a decrease of the correlations with the time interval between measurements. The changes in heritability with time showed the same trend for the SAD and RR models but not for the CPr model. Our results show that, in comparison with the CPr model, the SAD and RR models have the advantage of providing stable predictions of future phenotypes 1 wk forward whatever the number of observations used to estimate the parameters. Therefore, to study repeated measurements of FI, the SAD approach seems to be very appropriate in terms of genetic selection and real-time managements of animals. PMID- 26020876 TI - Evaluation of single nucleotide polymorphisms in chromosomal regions impacting pregnancy status in cattle. AB - Reproductive success is an important component of commercial beef cattle production, and identification of DNA markers with predictive merit for reproductive success would facilitate accurate prediction of mean daughter pregnancy rate, enabling effective selection of bulls to improve female fertility. A previous study identified SNP associated with beef cattle reproductive efficiency based on a genomewide association analysis approach using genotyping multiple-animal pools of DNA to increase the number of animals that could be genotyped with available resources. For the current study, we expand on this previous study by individually genotyping cattle from the pooling study for 89 SNP that were associated with female pregnancy rate. The aims of the study were to confirm the results of the pooling study and, more specifically, identify modes of gene action and DNA variations such as haplotypes that would not be possible with pooled genotyping. Eighty-nine SNP selected from the pooling study were evaluated using the Sequenom MassARRAY system to individually genotype animals from populations evaluated in the pooling study, including both and breeds. From this research, regions on chromosomes 5 (26.3-48.1 Mb; UMD3.1 assembly) and 9 (37,436,575 bp; UMD3.1 assembly), first identified in the previous pooling study, were shown through individual genotyping to harbor genetic variation ( < 0.05 genomewide significance) affecting reproductive efficiency in interspecific crosses ( and ) of cattle. Each of these markers exhibited additive (vs. dominant) gene action. Additionally, a haplotype block harboring an allele of origin with negative effects on reproduction was identified on chromosome 5 in interspecific composite breeds of * composites. PMID- 26020877 TI - Intensive rearing of male calves during the first three weeks of life has long term effects on number of islets of Langerhans and insulin stained area in the pancreas. AB - Permanent effects of early postnatal nutrition on the development and function of tissues and organs have been previously demonstrated primarily in humans and rodents. The objective of this study in calves was to analyze the impact of rearing conditions during the first 3 wk of life on morphology of insulin producing pancreatic beta-cells. Forty-two male Holstein calves were raised during the first 3 wk of life either intensively (intensively reared [INT]; ad libitum milk feeding and individual hutches; = 21) or according to an established restrictive rearing protocol (4 L milk/d) during wk 1 in hutches and 720 g/d milk replacer (MR) from d 8 to 21 in group pens (restrictively reared [CON]; = 21). Thereafter, all calves were housed and fed under comparable conditions. Birth weight and weekly BW up to wk 10 were recorded. Plasma glucose, insulin, IGF-1, and GH levels were assessed in wk 1, 2, 3, and 10 of life. Slaughtering took place after 8 mo and pancreatic tissue from the medium body (corpus pancreatic) was removed. The number of islets of Langerhans and the insulin stained area were examined histologically. Total milk intake of INT calves was nearly double the intake in CON calves in the first 3 wk of life ( < 0.01). Daily starter intake during wk 4 to 10 of life did not differ between groups ( = 0.24). During the first 3 wk, the ADG were up to 9 times higher in INT calves compared to CON calves ( < 0.01), yet BW at time of slaughter did not differ ( = 0.18). Intensive rearing led to increased plasma glucose, insulin, and IGF-1 concentrations after 3 wk of life compared with rearing to the established standard protocol (all < 0.05), whereas GH was lower in INT calves during the second week of life. At time of slaughter, the mean number of islets of Langerhans was higher in INT calves compared to CON calves (9.1 +/- 0.3 vs. 7.8 +/- 0.3; < 0.01). Also, the total insulin stained area per photograph was higher in INT calves compared to CON calves (107,180 +/- 4,987 vs. 84,249 +/- 4,962 MUm; < 0.01). Number of islets of Langerhans was negatively associated with birth weight but positively correlated with insulin and in trend with IGF-1 plasma levels during the second week of life. Insulin stained area tended to be linked with IGF-1 concentration during the third week of life. In conclusion, differences in the morphology of pancreatic islets of Langerhans indicate that calves can be programmed metabolically by an altered postnatal rearing intensity. PMID- 26020878 TI - Body composition and plasma lipid and stress hormone levels during 3 weeks of feed restriction and refeeding in low birth weight female pigs. AB - Compensatory growth in response to feed restriction (FR) affects deposition rates of lean and adipose tissues. It is, however, unclear whether pigs with low birth weight differ from their counterparts with normal birth weight with regard to compensatory growth. Female littermate pigs with low (UW; 1.1 kg) and normal (NW; 1.5 kg) birth weight were fed to appetite (control, CON) or feed restricted (RES) at 60% of DMI of the CON group between 78 and 98 d of age and subsequently refed at the level of the CON group until 131 d of age. Subgroups of pigs were slaughtered at 75, 98, 104, and 131 d of age to compare BW and body composition. Blood samples were taken at 98 and 119 d of age to analyze plasma metabolites and hormones. At birth UW pigs were shorter and had lower BW until 131 d of age than NW pigs ( < 0.05). Feed intake per kilogram of BW was greater in UW than in NW pigs ( < 0.01). The UW and NW pigs differed in carcass composition as indicated by greater relative subcutaneous fat at 75 d ( < 0.1), greater shoulder back fat ( < 0.05) at 98 d, and lower carcass weight at 131 d with greater abdominal and subcutaneous neck back fat in UW compared with NW pigs ( < 0.05). During FR, BW gain of RES pigs was lower than in NW pigs. The RES pigs showed greater feed intake after termination of FR until 131 d than CON pigs ( < 0.01). At 98 d RES pigs were leaner than CON pigs ( < 0.05). After 6 d of refeeding (104 d) relative fat depot weights were still smaller ( < 0.03) in RES pigs than in CON pigs. After 5 wk of refeeding, RES pigs had lower abdominal fat weights and greater plasma cortisol levels than CON pigs ( < 0.05). Regarding the plasma metabolite and hormone response, at 98-d fasting levels of plasma NEFA and glycerol were greater in RES than in CON pigs ( < 0.05), and after the drop in their levels after morning feeding ( < 0.001), plasma NEFA and glycerol and also triacylglycerol increased until the next meal in RES vs. CON pigs ( < 0.01). Plasma cortisol was greater in RES pigs after 3-wk FR ( < 0.05), whereas only a trend for increased plasma adrenalin concentrations in RES pigs at the end of the FR period and after 5 wk of refeeding was found ( < 0.1). In conclusion, UW pigs at 75 d of age (20 to 23 kg BW) had greater subcutaneous fat, whereas at 131 d (61 to 68 kg BW) they showed greater abdominal fat than NW pigs, suggesting that subcutaneous fat is deposited earlier than abdominal fat. The FR caused similar changes in body composition, plasma lipids, and stress hormones in UW and NW pigs. PMID- 26020879 TI - Enhanced mitogenesis in stromal vascular cells derived from subcutaneous adipose tissue of Wagyu compared with those of Angus cattle. AB - Japanese Wagyu cattle are well known for their extremely high marbling and lower subcutaneous adipose tissue compared with Angus cattle. However, mechanisms for differences in adipose deposition are unknown. The objective of this paper was to evaluate breed differences in the structure of subcutaneous adipose tissue, adipogenesis, and mitogenesis of stromal vascular (SV) cells between Wagyu and Angus cattle. Subcutaneous biopsy samples were obtained from 5 Wagyu (BW = 302 +/ 9 kg) and 5 Angus (BW = 398 +/- 12 kg) heifers at 12 mo of age, and samples were divided into 3 pieces for histological examination, biochemical analysis, and harvest of SV cells. Adipogenesis of SV cells was assessed by the expression of adipogenic markers and Oil Red-O staining, while mitogenesis was evaluated by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium dromide) test, phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB; AKT). Based on histological analysis, Wagyu had larger adipocytes compared with Angus. At the tissue level, protein expression of peroxisome proliferator-activated receptor gamma (PPARG) in Wagyu was much lower compared with that of Angus. Similarly, a lower mRNA expression of PPARG was found in Wagyu SV cells. No significant difference was observed for the zinc finger protein 423 (ZNF423) expression between Wagyu and Angus. As assessed by Oil Red-O staining, Wagyu SV cells possessed a notable trend of lower adipogenic capability. Interestingly, higher mitogenic ability was discovered in Wagyu SV cells, which was associated with an elevated phosphorylation of ERK1/2. There was no difference in AKT phosphorylation of SV cells between Wagyu and Angus. Moreover, exogenous fibroblast growth factor 2 (FGF2) enhanced mitogenesis and ERK1/2 phosphorylation of SV cells to a greater degree in Angus compared with that in Wagyu. Expression of transforming growth factor beta 3 (TGFB3) and bone morphogenetic protein 2 (BMP2) in Wagyu SV cells was lower than that of Angus, providing potential clues for breed differences on proliferation of SV cells in these two cattle breeds. The results of this study suggest that subcutaneous adipose-derived SV cells of Wagyu possess a lower trend of adipogenesis but higher mitogenesis compared with those of Angus. PMID- 26020880 TI - Predicting the digestible energy of corn determined with growing swine from nutrient composition and cross-species measurements. AB - The DE values of corn grain for pigs will differ among corn sources. More accurate prediction of DE may improve diet formulation and reduce diet cost. Corn grain sources ( = 83) were assayed with growing swine (20 kg) in DE experiments with total collection of feces, with 3-wk-old broiler chick in nitrogen-corrected apparent ME (AME) trials and with cecectomized adult roosters in nitrogen corrected true ME (TME) studies. Additional AME data for the corn grain source set was generated based on an existing near-infrared transmittance prediction model (near-infrared transmittance-predicted AME [NIT-AME]). Corn source nutrient composition was determined by wet chemistry methods. These data were then used to 1) test the accuracy of predicting swine DE of individual corn sources based on available literature equations and nutrient composition and 2) develop models for predicting DE of sources from nutrient composition and the cross-species information gathered above (AME, NIT-AME, and TME). The overall measured DE, AME, NIT-AME, and TME values were 4,105 +/- 11, 4,006 +/- 10, 4,004 +/- 10, and 4,086 +/- 12 kcal/kg DM, respectively. Prediction models were developed using 80% of the corn grain sources; the remaining 20% was reserved for validation of the developed prediction equation. Literature equations based on nutrient composition proved imprecise for predicting corn DE; the root mean square error of prediction ranged from 105 to 331 kcal/kg, an equivalent of 2.6 to 8.8% error. Yet among the corn composition traits, 4-variable models developed in the current study provided adequate prediction of DE (model ranging from 0.76 to 0.79 and root mean square error [RMSE] of 50 kcal/kg). When prediction equations were tested using the validation set, these models had a 1 to 1.2% error of prediction. Simple linear equations from AME, NIT-AME, or TME provided an accurate prediction of DE for individual sources ( ranged from 0.65 to 0.73 and RMSE ranged from 50 to 61 kcal/kg). Percentage error of prediction based on the validation data set was greater (1.4%) for the TME model than for the NIT-AME or AME models (1 and 1.2%, respectively), indicating that swine DE values could be accurately predicted by using AME or NIT-AME. In conclusion, regression equations developed from broiler measurements or from analyzed nutrient composition proved adequate to reliably predict the DE of commercially available corn hybrids for growing pigs. PMID- 26020881 TI - Enzymes enhance degradation of the fiber-starch-protein matrix of distillers dried grains with solubles as revealed by a porcine in vitro fermentation model and microscopy. AB - Effects of treating corn and wheat distillers dried grains with solubles (DDGS) with a multicarbohydrase alone or in combination with a protease on porcine in vitro fermentation characteristics and the matrix structure of the DGGS before and after the fermentation were studied. Three DDGS samples (wheat DDGS sample 1 [wDDGS1], wheat DDGS sample 2 [wDDGS2], and corn DDGS [cDDGS]) were predigested with pepsin and pancreatin. Residues were then subjected to in vitro fermentation using buffered mineral solution inoculated with fresh pig feces without or with a multicarbohydrase alone or in combination with protease in a 3 * 3 factorial arrangement. Accumulated gas production was measured for up to 72 h. Concentration of VFA was measured in fermented solutions. The matrix of native DDGS and their residues after fermentation was analyzed using confocal laser scanning microscopy and scanning electron microscopy to determine internal and external structures, respectively. On a DM basis, wDDGS1, wDDGS2, and cDDGS contained 35.5, 43.4, and 29.0% CP; 2.23, 0.51, and 6.40% starch; 0.82, 0.80, and 0.89% available Lys; and 24.8, 22.5, and 23.0% total nonstarch polysaccharides, respectively. The in vitro digestibility of DM for wDDGS1, wDDGS2, and cDDGS was 67.7, 72.1, and 59.6%, respectively. The cDDGS had greater ( < 0.05) total gas and VFA production than both wheat DDGS. The wDDGS2 had lower ( < 0.05) total gas production than wDDGS1. Multicarbohydrase increased ( < 0.05) total gas production for cDDGS and total VFA production for wDGGS1 but did not increase gas or VFA production for wDDGS2. Addition of protease with multicarbohydrase to DDGS reduced ( < 0.05) total gas and VFA productions and increased ( < 0.05) branched chain VFA regardless of DDGS type. Confocal laser scanning microscopy and scanning electron microscopy revealed that DDGS were mainly aggregates of resistant and nonfermentable starchy and nonstarchy complexes formed during DDGS production. After in vitro fermentation with porcine fecal inoculum, particles of enzyme-treated DDGS were generally smaller than those of the untreated DDGS. In conclusion, cDDGS had a more porous matrix that was more fermentable than the wheat DDGS. The wDDGS2 was less fermentable than wDDGS1. Multicarbohydrase increased fermentability of cDDGS and wDDGS1 but not wDDGS2, indicating that its efficacy in DDGS is dependent on matrix porosity and DDGS source. Protease hindered efficacy of multicarbohydrase. PMID- 26020882 TI - The appropriate standardized ileal digestible tryptophan to lysine ratio improves pig performance and regulates hormones and muscular amino acid transporters in late finishing gilts fed low-protein diets. AB - This study investigated the effects of various standardized ileal digestible (SID) Trp to Lys ratios on the performance and carcass characteristics of late finishing gilts receiving low-CP (9.6%) diets supplemented with crystalline AA. Ninety gilts (89.1 +/- 5.1 kg) were used in a dose-response study conducted for 35 d. Crystalline Trp (0, 0.1, 0.2, 0.4, or 0.6 g/kg) was added to a corn-wheat bran basal diet providing SID Trp to Lys ratios of 0.12, 0.15, 0.18, 0.21, or 0.24. Each diet was fed to 6 pens of pigs with 3 gilts per pen. At the end of the experiment, 30 gilts (1 pig per pen) were slaughtered to evaluate carcass traits and meat quality (BW = 121 kg). Increasing the SID Trp to Lys ratio increased ADG (linear and quadratic effect, < 0.05) and also improved G:F (linear and quadratic effect, < 0.05). Serum urea nitrogen (SUN) decreased as the SID Trp to Lys ratio increased (linear and quadratic effects, < 0.05). A quadratic effect of L* light and marbling in the longissimus dorsi was observed as the dietary SID Trp to Lys ratio increased ( < 0.05). Increasing the SID Trp to Lys ratio increased the level of serum GH (quadratic effect, < 0.05) and also increased the level of serum IGF-1 (linear and quadratic effect, < 0.05). Increasing the SID Trp to Lys ratio increased the protein abundance of the muscular AA transporter of sodium coupled neutral amino acid transporter 2 (SNAT2) in the longissimus dorsi muscle (linear and quadratic effect, < 0.05). The optimum SID Trp to Lys ratios to maximize ADG and G:F as well as to minimize SUN levels were 0.16, 0.17, and 0.16 using a linear-breakpoint model and 0.20, 0.20, and 0.20 using a quadratic model. Tryptophan could influence serum GH and IGF-1 secretion and protein abundance of the muscular AA transporter of SNAT2 in the longissimus dorsi muscle in late finishing gilts fed low-protein diets. PMID- 26020883 TI - A dynamic growth model for prediction of nutrient partitioning and manure production in growing-finishing pigs: Model development and evaluation. AB - Nutrient loading and air emissions from swine operations raise environmental concerns. The objective of the study was to describe and evaluate a mathematical model (Davis Swine Model) of nutrient partitioning and predict manure excretion and composition on a daily basis. State variables of the model were AA, fatty acids, and a central pool of metabolites that supplied substrate for lipid synthesis and oxidation. The model traced the fate of ingested nutrients and water through digestion and intermediary metabolism into body protein, fat, water, and ash, where body protein and fat represented the body constituent pools. It was assumed that fluxes of metabolites follow saturation kinetics, depending on metabolite concentrations. The main inputs to the model were diet nutrient composition, feed intake, water-to-feed ratio, and initial BW. First, the model was challenged with nutrient partitioning data and then with excretion data. The data had 48 different feeding regimes with contrasting energy and lysine intakes at 2 different stages of growth. The overall observed and predicted mean were 109 and 112 g/d for protein deposition and 132 and 136 g/d for lipid deposition respectively, suggesting minor mean bias. Root mean square prediction error (RMSPE) was used in evaluation of the model for its predictive power. The overall RMSPE was 2.2 and 4.1 g/d for protein and lipid deposition, respectively. The excretion database used for evaluation of the model was constructed from 150 digestibility trials using growing-finishing pig diets that had a wide range of nutrient chemical composition. Nutrient and water excretion were quantified using the principle of mass conservation. The average daily observed and predicted manure production was 3.79 and 3.99 kg/d, respectively, with a RMSPE of 0.49 kg/d. There was a good agreement between observed and predicted mean fecal N output (9.9 and 9.8 g/d, respectively). Similarly, the overall observed and predicted mean urine N output was 21.7 and 21.3 g/d, respectively, suggesting minor mean bias. The RMSPE was 1.9 and 4.1 g/d for fecal and urinary N, respectively. Evaluation of the model showed that the model predicts manure excretion and N content well and can be used to assess environmental mitigation options from swine operations. PMID- 26020884 TI - The effects of deoxynivalenol-contaminated corn dried distillers grains with solubles in nursery pig diets and potential for mitigation by commercially available feed additives. AB - Four experiments were conducted to investigate the effects of deoxynivalenol (DON) from naturally contaminated dried distillers grains with solubles (DDGS) and the efficacy of feed additives in nursery pig diets. In Exp. 1, 180 pigs (10.3 +/- 0.2 kg BW) were fed 1 of 5 diets for 21 d. Diets were 1) Positive Control (PC; < 0.5 mg/kg DON), 2) Negative Control (NC; 4 mg/kg DON), 3) NC + 0.10% Biofix (Biomin Inc., Herzogenburg, Austria), 4) NC + 0.15% Cel-can (VAST Inc., Mason City, IA) and 0.50% bentonite clay, and 5) NC + 0.25% Defusion Plus (Cargill Animal Nutrition, Minneapolis, MN). Pigs fed the NC diet had poorer ( < 0.01) ADG than those fed the PC. Pigs fed Defusion Plus had improved ( < 0.03) ADG over those fed NC, whereas pigs fed Biofix or Cel-can with bentonite clay had reduced ADG ( < 0.01) compared with those fed PC. In Exp. 2, 340 pigs (11.7 +/- 0.1 kg BW) were fed 1 of 8 diets for 21 d. Diets were 1) PC (< 0.5 mg/kg DON), 2) Low NC (1.5 mg/kg DON), 3) Low NC + 0.15% Biofix, 4) Low NC + 0.30% Biofix, 5) High NC (3.0 mg/kg DON), 6) High NC + 0.30% Biofix, 7) High NC + 0.45% Biofix, and 8) Diet 7 with 5% added water. Increasing the DON level reduced (linear; < 0.05) ADG, ADFI, and pig BW, and Biofix did not improve performance. In Exp. 3, 1,008 pigs (12.5 +/- 0.3 kg BW) were fed 6 treatments for 24 d. Diets were 1) PC ( < 0.5 mg/kg DON), 2) NC (3 mg/kg DON), 3) NC + 0.25% Defusion, 4) NC + 0.50% Defusion, 5) Diet 3 with supplemental nutrients, and 6) Diet 5, pelleted. Pigs fed the NC had decreased ( < 0.01) ADG and ADFI, but adding Defusion improved (linear; < 0.04) ADG and ADFI over pigs fed NC. Pelleting improved ( < 0.01) both ADG and G:F, resulting in ADG above PC pigs. In Exp. 4, 980 pigs (12.0 +/- 0.3 kg BW) were fed 1 of 7 diets in a 28-d trial in a 2 * 3 + 1 factorial arrangement. The 7 treatments were based on 3 diets fed in meal or pellet form: 1) PC (< 0.5 mg/kg DON), 2) NC (3 mg/kg DON), and 3) NC + 0.25% Defusion. Treatment 7 was Diet 3 with supplemental nutrients in pellet form. No interactions were observed between pelleting and Defusion. Pigs fed the NC had decreased ( < 0.01) ADG and ADFI, and pelleting improved ( < 0.01) ADG to PC levels, driven by improved ( < 0.01) G:F. Adding nutrients or Defusion had no effect. Overall, these studies show that Defusion and pelleting can help overcome some of the negative effects of DON, whereas other feed additives and additional nutrients do not. PMID- 26020885 TI - Effect of low dosage of chito-oligosaccharide supplementation on intestinal morphology, immune response, antioxidant capacity, and barrier function in weaned piglets. AB - This study was conducted to determine the effect of dietary supplementation of a low dose of chito-oligosaccharide (COS) on intestinal morphology, immune response, antioxidant capacity, and barrier function in weaned piglets. A total of 120 weaned pigs (21 d of age; 7.86 +/- 0.22 kg average BW) were randomly assigned (6 pens/diet; 10 pigs/pen) to 2 dietary treatments consisting of a basal diet (negative control) or the basal diet supplemented with COS (30 mg/kg) for a 14-d period. Six randomly selected piglets from each treatment were killed for blood and tissue sampling. No significant differences were observed in ADG, ADFI, and G:F between treatment and the control group. Piglets fed the COS-supplemented diet had greater ( < 0.05) stomach pH than those fed the control diet on d 14 postweaning. Dietary supplementation with COS reduced villus height ( < 0.05) and villus height:crypt depth ( < 0.05) in the ileum. Dietary COS supplementation tended to reduce villus height in the duodenum ( = 0.065) and jejunum ( = 0.058). There was no effect on crypt depth in the intestinal segments of treatment group. Piglets fed the COS-supplemented diet increased ( < 0.05) the number of intraepithelial lymphocytes in duodenum or jejunum and goblet cells of ileum. However, COS decreased ( < 0.05) the number of intraepithelial lymphocytes in ileum of weaned piglets. The concentrations of IL-10 (duodenum, jejunum, and ileum) and secretory immunoglobulin (SIgA; duodenum and ileum) were higher in piglets fed the COS-supplemented diet compared with control ( < 0.05). Dietary COS supplementation reduced ( < 0.05) the concentration of total antioxidant capacity and superoxide dismutase of the jejunum or ileum. The mRNA expression of occludin in the ileum and ZO-1 in jejunum and ileum had a significant change in piglets fed the COS-supplemented diet compared with the control group ( < 0.05). In conclusion, these results indicated that dietary COS supplementation at 30 mg/kg had no effects on promoting growth performance and tended to reduce villus height in the duodenum or jejunum of weaned piglets. The results further showed that supplemental COS at this level may cause an immune and oxidative stress response in small intestine and have compromised the intestinal barrier integrity in weaned piglets. The research will provide guidance on the low dosage of COS supplementation on weaning pigs. PMID- 26020886 TI - Effects of pelleting conditioner retention time on nursery pig growth performance. AB - A total of 180 nursery pigs (PIC 327 * 1050; initially 12.6 kg) were used in an 18-d study to determine the effects of pellet mill conditioning parameters and feed form on pig performance. All diets were similar, and different feed processing parameters were used to create experimental treatments. Factors considered were conditioning time (15, 30, or 60 s) and feed form (mash or pelleted). To remove the confounding factor of feed form, pelleted samples were reground to a similar particle size as the mash diet. Treatments included: 1) mash diet without thermal processing (negative control), 2) pelleted diet conditioned for 30 s (positive control), 3) pelleted diet conditioned for 15 s and reground, 4) pelleted diet conditioned for 30 s and reground, and 5) pelleted diet conditioned for 60 s and reground. Pigs were weaned and fed a common acclimation diet for 21 d before the start of the experiment. Growth and feed disappearance were then measured for 18 d. All diets had similar levels of percentage total starch, but thermally processed diets had a 1.67 to 1.87-fold increase in percentage gelatinized starch compared to the mash diet. Average daily gain and G:F did not differ between treatments overall, but pigs fed the positive control pelleted diet had decreased ADFI ( < 0.05) compared to pigs fed all other diets. Preplanned contrasts revealed that pigs fed mash diets tended to have greater ADG ( < 0.10) compared to those fed pelleted and reground diets. This suggests that processing may have had a negative influence on feed utilization, which is further supported by the finding that pigs fed mash diets tended to have greater ADG ( < 0.10) compared to those fed diets that were thermally processed, regardless of regrinding. Considering these results, it was not surprising that pigs fed mash diets had greater ADG and ADFI ( < 0.05) than those fed pelleted diets. When directly comparing diets conditioned at 60 rpm, fed either as whole pellets or reground to mash consistency, pigs fed pelleted diets had improved G:F ( < 0.05) due to lower ADFI ( < 0.05) but similar ADG. The expected improvement in G:F from pelleting (6.8%) was observed but lost when diets were reground to near original mash particle size. This may indicate that diet form from the actual pelleting process impacts G:F more than conditioner retention time. PMID- 26020887 TI - Carbohydrate composition and in vitro digestibility of dry matter and nonstarch polysaccharides in corn, sorghum, and wheat and coproducts from these grains. AB - The objectives of this work were to determine carbohydrate composition and in vitro digestibility of DM and nonstarch polysaccharides (NSP) in corn, wheat, and sorghum and coproducts from these grains. In the initial part of this work, the carbohydrate composition of 12 feed ingredients was determined. The 12 ingredients included 3 grains (corn, sorghum, and wheat), 3 coproducts from the dry grind industry (corn distillers dried grains with solubles [DDGS] and 2 sources of sorghum DDGS), 4 coproducts from the wet milling industry (corn gluten meal, corn gluten feed, corn germ meal, and corn bran), and 2 coproducts from the flour milling industry (wheat middlings and wheat bran). Results indicated that grains contained more starch and less NSP compared with grain coproducts. The concentration of soluble NSP was low in all ingredients. Cellulose, arabinoxylans, and other hemicelluloses made up approximately 22, 49, and 29% (DM basis), respectively, of the NSP in corn and corn coproducts and approximately 25, 43, and 32% (DM basis), respectively, of the NSP in sorghum and sorghum DDGS. Cellulose, arabinoxylans, and other hemicelluloses made up approximately 16, 64, and 20% (DM basis), respectively, of the NSP in wheat and wheat coproducts. The concentration of lignin in grains was between 0.8 and 1.8% (DM basis), whereas coproducts contained between 2.2 and 11.5% lignin (DM basis). The in vitro ileal digestibility of NSP was close to zero or negative for all feed ingredients, indicating that pepsin and pancreas enzymes have no effect on in vitro degradation of NSP. A strong negative correlation ( = 0.97) between in vitro ileal digestibility of DM and the concentration of NSP in feed ingredients was observed. In vitro total tract digestibility of NSP ranged from 6.5% in corn bran to 57.3% in corn gluten meal. In conclusion, grains and grain coproducts contain mostly insoluble NSP and arabinoxylans make up the majority of the total NSP fraction. The in vitro digestibility of NSP depends on the amount and type of NSP and degree of lignification in the feed ingredient. The NSP composition of grains and grain coproducts plays an important role in determining the extent of fermentation of NSP; therefore, NSP composition influences the energy value of grains and grain coproducts. PMID- 26020888 TI - Metabolic profiles in the response to supplementation with composite antimicrobial peptides in piglets challenged with deoxynivalenol. AB - Deoxynivalenol (DON) causes various toxic effects in human and animals. However, our previous studies have shown that composite antimicrobial peptides (CAP) can have a protective effect in piglets challenged with DON. This study was conducted to evaluate the effect of the CAP GLAM 180# on the metabolism of piglets challenged with DON using a nuclear magnetic resonance (NMR)-based metabolomics approach. A total of 28 individually housed piglets (Duroc * Landrace * Large Yorkshire) weaned at 28 d of age were randomly assigned into 4 treatment groups (7 pigs/treatment) based on a 2 * 2 factorial arrangement that were fed, respectively, a basal diet (NC), basal diet + 0.4% CAP (basal + CAP), basal diet + 4 mg/kg DON (basal + DON), and basal diet + 4 mg/kg DON + 0.4% CAP (DON + CAP). A 7-d adaptation period was followed by 30 d of treatment. Blood samples were then collected for metabolite analysis by proton NMR (H-NMR) spectroscopy and liquid chromatography tandem mass spectrometry (LC-MS/MS). The combined results of H-NMR spectroscopy and LC-MS/MS showed that DON increased ( < 0.05) the serum concentrations of low-density lipoprotein, glycoprotein, urea, trimethylamine-N oxide (TMAO), and lactate as well as those of almost all essential AA and some nonessential AA but decreased the concentrations of high-density lipoprotein (HDL), unsaturated lipids, citrate, choline, and fumarate compared with those in NC treatment ( < 0.05). There was a significant interaction effect ( < 0.05) of supplementation with DON and CAP on some metabolites showed that the serum concentrations of HDL, unsaturated lipids, Pro, citrate, and fumarate were greater ( < 0.05) whereas those of glycoprotein, urea, TMAO, Gly, and lactate were lower in the DON + CAP treatment compared with those in the basal + DON treatment ( < 0.05). These findings indicated that DON causes disturbances in AA, lipid, and energy metabolism and that CAP could partially attenuate the above metabolic disturbances induced by DON. PMID- 26020889 TI - The interaction of fiber, supplied by distillers dried grains with solubles, with an antimicrobial and a nutrient partitioning agent on nitrogen balance, water utilization, and energy digestibility in finishing pigs. AB - The objective of this study was to determine if a higher-fiber diet alters the response of finishing pigs to an antimicrobial (tylosin phosphate [TP]) and a nutrient partitioning agent (ractopamine HCl [RAC]) in terms of N and water utilization and energy digestibility. Seventy-two gilts (initial BW = 107.4 +/- 4.2 kg) were blocked by weight and allotted to 1 of 8 dietary treatments. Treatments were arranged as a 2 * 2 * 2 factorial: distillers dried grains with solubles (DDGS; 0 vs. 30%), RAC (0 mg of RAC/kg and 0.70% standardized ileal digestible [SID] Lys vs. 5 mg of RAC/kg and 0.95% SID Lys) and TP (0 vs. 44 mg of TP/kg). Pig was the experimental unit, with 9 replications per treatment. Pigs were housed in individual metabolism crates and fed treatment diets for 17 d. Feed was provided twice daily, as much as the pigs could consume within 1 h per meal, and water was provided to the pigs between feeding periods, ad libitum. Fecal and urine collection occurred on d 7 and 8 and on d 15 and 16, for sampling periods 1 and 2, respectively. Pigs fed the DDGS diets had reduced ADG ( < 0.001) and ADFI ( < 0.0001). The apparent total tract digestibility (ATTD) of N and GE were lower for the 30% DDGS diets than the 0% DDGS diets ( < 0.0001). Ractopamine improved ADG ( < 0.0001), G:F ( < 0.0001), and N retention ( < 0.001) and tended to increase daily water intake ( < 0.10). Pigs fed RAC had higher N intake and urinary excretion and lower N retention in Period 2 than in Period 1 ( < 0.05), indicating a decline in the response to RAC over time. Tylosin phosphate did not affect ADFI or G:F but did improve ATTD of N ( < 0.05). There was a tendency for a TP * DDGS interaction ( < 0.10) for ADG, where TP tended to increase ADG in pigs fed 0% DDGS diets ( < 0.10) but not in pigs fed 30% DDGS diets ( > 0.10). Pigs fed DDGS diets had higher N intake ( < 0.01) and higher fecal ( < 0.0001) and urinary ( < 0.01) N excretion with no difference in N retention (g/d). Overall, RAC increased N retention by 33% ( < 0.0001) and the response to RAC was similar in both corn-soybean meal-based and corn-soybean meal-DDGS-based diets. Tylosin phosphate tended to improve growth performance in pigs fed corn-soybean meal-based diets but not in diets containing 30% DDGS; however, this response was not explained by changes in N balance or in energy digestibility. PMID- 26020890 TI - Standardized ileal digestibility of amino acids in eight genotypes of soft winter wheat fed to growing pigs. AB - A study with growing pigs was conducted to determine the chemical composition and standardized ileal digestibility (SID) of CP and AA of 8 wheat genotypes that have recently been added to the German Descriptive Variety List. These genotypes included Tabasco, KWS Erasmus, Tobak, Skalmeje, Mulan, Event, Tommi, and Adler. The 8 genotypes were grown under identical environmental conditions on the same site, and they were harvested and processed under the same conditions. Nine barrows with an initial BW of 32 +/- 2 kg were surgically fitted with simple ileal T-cannulas and allotted to a row-column design with 9 pigs and 8 periods of 6 d each. Wheat was the sole dietary source of CP and AA. Among the 8 wheat genotypes, contents of CP ranged from 10.9 to 13.3% (as-fed basis), whereas contents of total nonstarch polysaccharides ranged from 8.0 to 9.4% (as-fed basis). The SID of CP in the 8 genotypes ranged from 83 to 87%, with greatest ( = 0.01) values for Event and lowest ( = 0.01) for all other wheat genotypes. Intermediate SID of CP values were obtained for Adler and KWS Erasmus. For Lys, greater ( < 0.05) SID was observed in Adler (73%) and KWS Erasmus (74%) in comparison to Tommi, Tobak, and Mulan (69%). Adler had greater SID of Met (88%; = 0.01) when compared to Tabasco (86%); Tobak, Skalmeje, and Mulan (85%); and Tommi (84%). Among the 8 wheat genotypes, standardized ileal digestible content (cSID) of CP followed total CP content and ranged from 9.1 to 11.3% (as-fed basis). Standardized ileal digestible content of both CP and AA were greater ( < 0.001) in Adler compared to all other genotypes. For most AA, Tabasco had the lowest ( < 0.001; except for His, Trp, Asp, and Cys) cSID values of all wheat genotypes. The cSID of CP decreased ( < 0.001) as the starch content in the 8 wheat genotypes increased, but cSID of CP increased ( < 0.001) as the CP content in the 8 genotypes increased. Because SID and cSID of CP and most AA increased ( < 0.05) with lower test weight and falling number, these variables may aid to predict SID and cSID in wheat batches, whereas other nutrients such as fiber fractions are not suitable due to low variation among the 8 genotypes. The present study provides a comprehensive database on nutritional composition and SID of CP and AA of 8 wheat genotypes grown under identical conditions. Because the SID values in these genotypes are lower when compared to literature data, digestibility values in actual feed tables for wheat may overestimate their protein values and need to be updated. PMID- 26020891 TI - Technical note: Comparison of two methods to quantify exercise energy expenditure in trotters. AB - This study aimed at quantifying energy expenditure during 4 specific training exercises, that is, promenade, jogging, parcours, and interval exercises, using field measurements of oxygen consumption and heart rate in trotters. Six animals performed 2 preliminary tests to determine their individual maximum velocity and to establish their individual oxygen consumption/heart rate relationship from an incremental test. Then, they undertook each of the 4 specific exercises separated by 1 wk to avoid fatigue. The intensity of the 4 exercises was expressed in percent of individual maximum velocity as well as duration and distance set according to current training practices of French trotter trainers. Throughout the incremental test and the 4 exercises, oxygen consumption and heart rate were continuously recorded using a portable respiratory gas analyzer. Energy expenditure of the 3 different phases (warm-up, exercise, and recovery) of the 4 exercises and the total energy expended during exercises (sum of energy expended during the 3 phases) were calculated from direct oxygen uptake measurements and from estimated oxygen uptake using heart rate and O caloric equivalent. The quantification of total energy expenditure from the 2 methods was not significantly different. However, estimated energy expenditure was significantly lower from estimated oxygen consumption than direct oxygen uptake method concerning the warm-up and exercise phase of parcours. Our results indicate that the estimated oxygen uptake from heart rate measurements could be used to evaluate total energy expenditure of exercises in trotters. Whereas this method requires previous establishment of an individual oxygen consumption/heart rate curve, it is easy to record using commercially available instruments under practical conditions and opens new perspectives to assess energy balance in trotters' nutrition. PMID- 26020892 TI - Evaluating the influence of National Research Council levels of copper, iron, manganese, and zinc using organic (Bioplex) minerals on resulting tissue mineral concentrations, metallothionein, and liver antioxidant enzymes in grower-finisher swine diets. AB - Graded levels of a trace mineral premix containing an organic (Bioplex) source of Cu, Fe, Mn, and Zn was evaluated with additional treatments containing organic Zn or Fe. Grower-finisher pigs were fed from 25 to 115 kg BW. The number of pigs in the experiment, the breeding/genetics of the pigs, the management, and the average age of the pigs were previously reported. The experiment was conducted as a randomized complete block design in 7 replicates. Treatments were 1) basal diet without supplemental Cu, Fe, Mn, and Zn; 2) basal diet + 2.5 mg/kg Cu, 50 mg/kg Fe, 1.5 mg/kg Mn, and 40 mg/kg Zn (50% NRC); 3) basal diet + 5 mg/kg Cu, 100 mg/kg Fe, 3 mg/kg Mn, and 80 mg/kg Zn (100% NRC); 4) basal diet + 25 mg Zn/kg; 5) basal diet + 50 mg Zn/kg; and 6) basal diet + 50 mg Fe/kg. Selenium and I were added to all diets at 0.3 and 0.14 mg/kg, respectively. Diets were composed of corn-soybean meal, dicalcium phosphate, and limestone with phytase added to enhance mineral availability. Three pigs per pen were bled at 55, 80, and 115 kg BW and plasma was analyzed for microminerals. When the average replicate BW was 115 kg, 3 pigs per pen of an equal gender ratio were killed. The liver, kidney, and heart were removed and analyzed for microminerals. Liver, duodenum, and jejunal metallothionein and the antioxidant enzymes in the liver containing these microminerals were determined. The results demonstrated that plasma minerals were unaffected at the 3 BW intervals. Liver and duodenum metallothionein protein were greater ( < 0.05) as dietary micromineral levels increased but jejunum metallothionein did not change as microminerals increased. The activity of Cu/Zn superoxide dismutase (SOD) was not affected as the levels of the micromineral increased, whereas the activity of Mn SOD increased slightly ( < 0.05) to the 50% NRC treatment level. Liver Zn (relative and total) increased ( < 0.05) as dietary micromineral levels increased and also when Zn was added singly to the diet. Liver, kidney, and heart Cu and Mn concentrations were similar at the various micromineral levels. The activities of liver enzymes containing graded levels of Zn were not affected by dietary microminerals at 115 kg BW. These results indicate that the supplemental levels of Cu, Fe, and Mn were not necessary for grower-finisher pigs and that these innate microminerals in a corn-soybean meal diet were adequate, whereas a need for supplemental Zn was demonstrated. PMID- 26020893 TI - Effects of cello-oligosaccharide on intestinal microbiota and epithelial barrier function of weanling pigs. AB - A total of 144 piglets (Duroc * Landrace * Yorkshire; average initial weight of 6.13 kg weaned at 21 +/- 1 d age) were allotted to 4 treatments for 2 wk, each of which had 6 pens with 6 pigs per pen. After the feeding experiment, 6 pigs per treatment were slaughtered to investigate the effects of cello-oligosaccharide (COS) on intestinal microbiota and epithelial barrier function. The COS was added to the basal diet at 0, 1.5, 3.0, and 4.5 g/kg diet at the expense of corn, respectively. Plasma -lactate, diamine oxidase (DAO), and the Ussing chamber technique were used to determine the intestinal barrier function. 16S rRNA-based methods were used for intestinal microbiota analysis. The results showed that incremental levels of COS had no effect ( > 0.05) on growth performance. Incremental levels of COS increased lactobacilli in jejunal and colonic contents ( < 0.05); decreased in jejunal contents ( < 0.05) and and in colonic contents ( < 0.05); reduced plasma DAO (linear, = 0.013, and quadratic, = 0.037); increased jejunal mucosa DAO (linear, = 0.003, and quadratic, = 0.008); decreased fluorescein isothiocyanate dextran 4 kDa flux of jejunum and colon ( < 0.05); and increased transepithelial electrical resistance (TER) in colon ( < 0.05), claudin 1 protein expression in jejunal mucosa (linear, = 0.001, and quadratic, = 0.003), and protein expressions of claudin-1 and zonula occludens-1 (ZO-1) in colonic mucosa linearly ( = 0.001 and = 0.001, respectively) and quadratically ( = 0.001 and = 0.002, respectively). The results indicated that the improved microbial ecosystem in the presence of COS might contribute to improvement in intestinal barrier function and tight junction proteins. Results also showed that the appropriate dietary COS supplementation level was 3.0 g/kg in weaned pig diets under our trial conditions. PMID- 26020895 TI - A meta-analysis to assess the effect of the composition of dietary fat on alpha tocopherol blood and tissue concentration in pigs. AB - A meta-analysis based on the results from 13 selected publications was performed to assess the effect of dietary fat supplementation (quantity and fatty acid composition) on alpha-tocopherol (TOL) concentration in 4 pig tissues (blood, liver, muscle, and adipose tissue). Dietary fat supplementation was defined by the quantity of fat added to the basal diet and its fatty acid profile. After standardization of tissue TOL concentration (as the dependent variable), statistical analyses were performed using multiple nonlinear regression, data partitioning, and partial least squares regression with 7 predictor variables including added vitamin E (VE), added fat, PUFA (% fat), MUFA (% fat), SFA (% fat), omega-3 fatty acids (-3; % fat), and omega-6 fatty acids (-6; % fat). The statistical analyses first showed that the VE level in the diet was the main factor that modulates tissue TOL concentration. The dose-response relationship followed a logarithmic curve, with a saturation of tissue TOL concentration in all the studied tissues. Moreover, the amount of dietary fat, at least up to 20%, was not linearly correlated with tissue TOL concentration, considering that the main fatty acid classes, MUFA and, to a lesser extent, SFA, were positively associated with tissue TOL concentrations. Finally, this study suggests that the inclusion of -3 fatty acids in the diet may decrease tissue and, more precisely, blood TOL concentration. PMID- 26020894 TI - Development of prediction equations to estimate the apparent digestible energy content of lipids when fed to lactating sows. AB - Two studies were conducted 1) to determine the effects of free fatty acid (FFA) concentrations and the degree of saturation of lipids (unsaturated to saturated fatty acids ratio [U:S]) on apparent total tract digestibility (ATTD) and DE content of lipids and 2) to derive prediction equations to estimate the DE content of lipids when added to lactating sow diets. In Exp. 1, 85 lactating sows were assigned randomly to a 4 * 5 factorial arrangement of treatments plus a control diet with no added lipid. Factors included 1) FFA concentrations of 0, 18, 36, and 54% and 2) U:S of 2.0, 2.8, 3.5, 4.2, and 4.9. Diets were corn soybean meal based and lipid was supplemented at 6%. Concentrations of FFA and U:S were obtained by blending 4 lipid sources: choice white grease (CWG; FFA = 0.3% and U:S = 2.0), soybean oil (FFA = 0.1% and U:S = 5.5), CWG acid oil (FFA = 57.8% and U:S = 2.1), and soybean-cottonseed acid oil (FFA = 67.5% and U:S = 3.8). Titanium dioxide was added to diets (0.5%) as a digestibility marker. Treatments started on d 4 of lactation and fecal samples were collected after 6 d of adaptation to diets on a daily basis from d 10 to 13. The ATTD of added lipid and DE content of lipids were negatively affected (linear, < 0.001) with increasing FFA concentrations, but negative effects were less pronounced with increasing U:S (interaction, < 0.05). Coefficients of ATTD for the added lipid and DE content of lipids increased with increasing U:S (quadratic, = 0.001), but these improvements were less pronounced when the FFA concentration was less than 36%. Digestible energy content of added lipid was described by DE (kcal/kg) = [8,381 - (80.6 * FFA) + (0.4 * FFA) + (248.8 * U:S) - (28.1 * U:S) + (12.8 * FFA * U:S)] ( = 0.74). This prediction equation was validated in Exp. 2, in which 24 lactating sows were fed diets supplemented with 6% of either an animal-vegetable blend (A-V; FFA = 14.5% and U:S = 2.3) or CWG (FFA = 3.7% and U:S = 1.5) plus a control diet with no added lipids. Digestible energy content of A-V (8,317 and 8,127 kcal/kg for measured and predicted values, respectively) and CWG (8,452 and 8,468 kcal/kg for measured and predicted values, respectively) were accurately estimated using the proposed equation. The proposed equation involving FFA concentration and U:S resulted in highly accurate estimations of DE content (relative error, +0.2 to -2.3%) of commercial sources of lipids for lactating sows. PMID- 26020896 TI - Optimal dietary energy and amino acids for gilt development: Growth, body composition, feed intake, and carcass composition traits. AB - The objective of this study was to determine if body composition of developing gilts could be altered at the onset of estrus by ad libitum feeding diets differing in standard ileal digestible (SID) lysine and ME using levels that are within those used in practice by pig producers in the United States. Crossbred Large White * Landrace gilts ( = 1,221), housed in groups, were randomly allotted to 6 corn-soybean diets in a 2 * 3 factorial arrangement formulated to provide 2 SID lysine and 3 ME levels. Gilts received grower diets formulated to provide 0.86 (low) or 1.02% (high) SID lysine and 2.94 (low), 3.25 (medium), or 3.57 (high) Mcal of ME/kg from 100 d of age until approximately 90 kg BW. Then, gilts were fed finisher diets containing 0.73 (low) or 0.85% (high) SID lysine and 2.94 (low), 3.26 (medium) or 3.59 (high) Mcal of ME/kg until 260 d of age. The medium SID lysine and medium-ME diets were based on an informal survey from the U.S. commercial swine industry to obtain average levels that are currently being formulated for developing gilts. Gilts were weighed and backfat thickness and loin area were recorded at the beginning of the trial and then every 28 d. Feed intake (FI) was recorded as feed disappearance within the pen at 2-wk intervals. Lysine (g) and ME (Mcal) consumed were calculated based on diet formulations. At approximately 260 d of age, gilts were slaughtered and warm carcass weight and fat thickness were recorded. There were no differences between lysine or ME levels for growth and body composition, except for backfat, which was slightly greater for gilts fed a high-ME diet. Gilts fed high-ME diets had a lower FI but a greater ME intake compared with gilts fed low ME ( < 0.05). Additionally, gilts fed the high-ME diet had lower FI and lysine intake per kilogram of BW gain when compared with gilts fed low- or medium-ME diets ( < 0.05). However, there was no difference in the megacalories consumed per kilogram of BW gain among treatments ( > 0.05). Carcasses from gilts fed the high-ME diet were 3.3 and 2.5 kg heavier than those from gilts fed the low- or medium-ME diets ( < 0.05). Despite significant differences in the lysine:ME ratio in the diets, no changes in growth or body composition occurred, likely due to compensatory changes in FI in response to dietary ME content. Caloric efficiency (Mcal to deposit 1 kg of BW) was similar among treatments. PMID- 26020897 TI - Modeling the metabolic fate of dietary phosphorus and calcium and the dynamics of body ash content in growing pigs. AB - A better understanding of the fate of dietary P use by growing pigs will allow an optimization of P use and enhance sustainable practices. The optimization of P utilization is complicated by the multiple criteria, such as growth performance, bone mineralization, and manure P used for assessment of needs. Mathematical modeling is a useful tool to describe relevant biological mechanisms and predict relationships that describe the whole system behavior. Modeling allows development of robust multicriteria approaches to optimize P utilization, feeding cost, and manure application cost. This paper describes and evaluates a model developed to simulate the fate of dietary P, that is, to simulate its digestive and metabolic utilization through digestion, soft tissue, and ash modules. The digestion module takes into account the varied sources of dietary minerals including responses to microbial and plant phytase and Ca and P interactions and predicts absorption and fecal excretion. The soft tissue module simulates the growth of the protein and is based on InraPorc model principles. The ash module simulates the partitioning of absorbed Ca and P into the bone, protein, and lipid compartments as well as urinary excretion. Model behavior showed that the model was able to accurately represent the impact of Lys deficiency on P retention, of Ca and P imbalances, and of Ca and P depletion and repletion sequences. The model's prediction capabilities in simulating whole-body protein, Ca, P, and ash based on published data showed high accuracy, with a slope and intercept that did not differ from 1 and 0, respectively, and an error due to disturbance (ED; variance not accounted for by regression of observed on predicted values). The model's prediction capabilities in simulating balance trial data showed good accuracy for apparent total tract digestibility (ATTD) of P (observed = -0.77 + 1.06 predicted) and P retention coefficient (observed = -4.5 + 1.15 predicted) with an ED of 89% for both criteria. The model's prediction capabilities in simulating Ca ATTD and Ca retention coefficient are lower (ED of 88 and 28%, respectively). This model simulates body ash independently of body protein and accounts for the impact of past and current dietary Ca and P supply. That ability is essential for the real-time adaptation of mineral supplies to suit individual production objectives, which would contribute to the overall success of pig production. PMID- 26020898 TI - Effect of wheat dried distillers grains with solubles and fibrolytic enzymes on ruminal fermentation, digestibility, growth performance, and feeding behavior of beef cattle. AB - Two experiments were conducted to evaluate the effect of wheat dried distillers grains with solubles (DDGS) and fibrolytic enzymes (FE) on ruminal fermentation, in situ ruminal and in vivo total tract digestibility, growth performance, and feeding behavior of growing beef cattle. In Exp. 1, 6 ruminally cannulated Angus heifers (average BW of 794 +/- 44.2 kg) were used in a 6 * 6 Latin square design with 2 * 3 factorial arrangement of treatments. Treatments were a control diet consisting of 50% barley silage, 10% grass hay, and 40% barley grain-based concentrate (CON) and the CON with 15% DDGS substituted for barley grain (WDG) combined with either 0, 1, or 2 mL FE/kg diet DM, respectively. Inclusion of DDGS increased total tract digestibility of CP ( < 0.01), NDF ( = 0.04), and ADF ( = 0.03). Increasing FE linearly ( = 0.03) increased CP digestibility without affecting the digestibility of other nutrients. There were no effects of DDGS inclusion or FE on ruminal pH or VFA concentration except that propionate was greater ( = 0.04) with the WDG. In situ ruminal DM and NDF disappearance of barley silage was greater ( < 0.04) in heifers fed the WDG than in heifers fed the CON after 24 h of incubation. Increasing FE linearly ( = 0.03) increased in situ NDF disappearance of barley silage after 24 h of incubation. In Exp. 2, 120 weaned steers (initial BW of 289 +/- 11.0 kg) were fed diets similar to those in Exp. 1. The steers fed the WDG had greater ( < 0.01) final BW, ADG, DMI, and G:F compared with steers fed the CON. Increasing FE did not alter ADG or G:F but tended ( < 0.07) to linearly decrease DMI. There were interactions ( < 0.02) between DDGS and FE on eating rate and the time spent at the feed bunk. Supplementing FE decreased ( < 0.01) time at the bunk and increased ( < 0.01) eating rate for steers fed the WDG but not for steers fed the CON. Eating rate ( < 0.01) and meal frequency ( = 0.02) were greater but eating duration was shorter ( < 0.01) for steers fed the WDG than for those fed the CON. These results indicate that inclusion of wheat DDGS in a growing diet increased total tract digestibility of NDF and CP and improved the feed efficiency of steers. Moreover, supplementation of FE in barley silage-based growing diets may also have the potential to increase profits, with the evidence of the trend for a decline on DMI without decreasing ADG when adding FE. PMID- 26020899 TI - Impact of ractopamine hydrochloride on growth performance, carcass and pork quality characteristics, and responses to handling and transport in finishing pigs. AB - The effect of feeding ractopamine hydrochloride (RAC) on growth performance, carcass and pork quality, and blood acid-base and catecholamine responses to handling and transport in finishing pigs was evaluated using a randomized complete block design to compare 2 RAC levels (0 vs. 10 mg/kg). Crossbred pigs ( = 144) were housed in single-sex pens (barrow or gilt) of 3 with 24 pens/RAC level. The study was carried out for a 28-d period from 104.0 +/- 5.99 to 136.7 +/- 6.44 kg BW. At the end of the growth study, pigs were subjected to handling and transport procedures that involved an initial aggressive handling procedure (pigs moved 50 m with 8 shocks from an electric prod) followed by a 30-min transport on a standard livestock trailer at a floor space of 0.46 m/pig followed by a final gentle handling procedure (pigs moved 100 m using sort boards and slap paddles). A blood sample was taken and rectal temperature was measured 2 h before (baseline) and immediately after the final handling procedure (final). Barrows ( = 72) were harvested and carcass and pork quality were measured. Feeding RAC increased ( <= 0.05) ADG (19.6%), ADFI (4.2%), and G:F (14.8%). The increase in plasma epinephrine levels from baseline to final was greater ( <= 0.05) for pigs fed RAC; there was a trend ( <= 0.10) for pigs fed RAC to have greater final blood lactate and to show a greater change from baseline to final in blood bicarbonate, partial pressure of and total carbon dioxide, and oxygen saturation levels. However, there were no differences between treatments for changes from baseline to final in rectal temperature, blood pH and lactate, and plasma norepinephrine levels. The incidence of physical indicators of stress and of nonambulatory, noninjured pigs during the handling and transport procedures was similar for the 0 and 10 mg/kg RAC levels. Final farm BW was 4.1 kg heavier, carcass yield was 1.4 percentage units greater, and LM area was 5.18 cm greater for pigs fed RAC compared to the control ( <= 0.05). Minolta a* and b* values were lower ( <= 0.05) and ultimate pH (0.05 units) and Warner-Bratzler shear force (0.43 kg) were greater ( <= 0.05) for pigs fed 10 compared to 0 mg/kg RAC. These results confirm the substantial improvement from feeding 10 mg/kg RAC in growth performance and carcass yield and suggest relatively limited effects on pork quality and on responses to the handling and transport procedures used in this study. PMID- 26020900 TI - Effect of feeding ractopamine hydrochloride on growth performance and responses to handling and transport in heavy-weight pigs. AB - The impact of feeding ractopamine hydrochloride (RAC) on growth performance and responses to handling and transport in heavy BW pigs was evaluated in a study performed as a split-plot design with a 3 * 3 factorial arrangement of treatments: 1) RAC level (0 vs. 5 vs. 7.5 mg/kg of feed) and 2) handling intensity (HI; gentle vs. moderate vs. aggressive); RAC level was the main plot and HI was the subplot. A total of 288 pigs housed in groups of 8 were used to evaluate growth performance over a 28-d RAC feeding period (98.5 +/- 4.58 to 131.5 +/- 7.45 kg BW). On d 29 of the study, the HI treatment was applied to 216 pigs (6/pen; 2/pen on each HI). This was followed by transportation for 1 h on a livestock trailer at the end of which pigs were subjected to a final handling procedure. Blood samples (to measure acid-base, cortisol, and catecholamine levels) were collected and rectal temperature was measured 2 h before the HI treatment (baseline) and after the final handling procedure (final). Feeding RAC (5 and 7.5 mg/kg) improved ( < 0.01) ADG (9.9 and 9.0% for 5 and 7.5 mg/kg RAC, respectively) and G:F (8.8 and 11.8%, respectively) compared to controls, with no differences ( > 0.05) between the 2 RAC levels. Increasing the intensity of handling decreased ( < 0.001) final blood pH, bicarbonate, and base excess and increased ( < 0.001) final blood lactate and plasma cortisol and norepinephrine levels. Aggressive compared to gentle handling increased ( < 0.05) the incidence of pigs exhibiting open-mouth breathing and skin discoloration after the final handling procedure but had no effect ( > 0.05) on the incidence on nonambulatory, noninjured pigs. There was no effect ( > 0.05) of feeding RAC on final rectal temperature or blood acid-base measurements. Feeding 7.5, but not 5, compared to 0 mg/kg RAC increased ( < 0.05) final plasma epinephrine levels and the incidence of nonambulatory, noninjured pigs. This study confirms the improved growth performance of pigs fed RAC and the negative effects of aggressive handling on physical, metabolic, and physiological responses of pigs. It also suggests that pigs fed 5 compared to 0 mg/kg RAC showed similar responses to transport and handling. However, pigs fed 7.5 mg/kg of RAC had a greater incidence of nonambulatory, noninjured pigs when subjected to the handling/transport model and this warrants further investigation. PMID- 26020901 TI - Physiological and behavioral responses of sheep to simulated sea transport motions. AB - The motion of ships can cause discomfort and stress in humans, but little is known about the impact on sheep welfare, despite many sheep traveling long distances by ship during live export. We tested whether exposing sheep to roll (side to side movement), heave (up and down movement), and pitch (front to back movement) with similar amplitude and period conditions to a commercial livestock transport vessel would affect their behavior and physiology. Specifically, we tested the effects of these motions and a control treatment on behavior, heart rate variability, rumination, body posture, and balance of sheep. Four sheep (37 +/- 0.1 kg) were restrained in pairs in a crate, which was placed on a moveable and programmable platform that generated roll and pitch motions. An electric forklift was used to produce heave motion. The treatments were applied for 30 min each time in a changeover design with 1 repetition over 8 consecutive days. Sheep behavior was recorded continuously from video records, and heart rate monitors were attached to determine heart rate and its variability. Heave reduced the time that sheep spent ruminating, compared with the other 3 treatments ( < 0.001). The 2 sheep spent more time during heave with their heads 1 above the head of the other ( < 0.001) and looking toward their companion ( = 0.02), indicating greater affiliative behavior. Sheep spent more time during heave standing with their back supported on the crate ( = 0.006) and less time lying down ( = 0.01). Roll caused more stepping motions than pitch and control, indicating loss of balance ( < 0.001). Sheep experiencing heave and roll had increased heart rates and reduced interbeat intervals (IBI) compared to the control ( < 0.001). The IBI of sheep in the heave treatment had an increased ratio of low to high frequency duration ( = 0.01), indicating reduced parasympathetic control of stress responses. Therefore, there was both behavioral and physiological evidence that heave and roll caused stress, with sheep experiencing roll apparently coping better by regular posture changes and heave causing the sheep to seek the close presence of their companion. PMID- 26020902 TI - The effects of different flooring types on the behavior, health, and welfare of finishing beef steers. AB - Raising beef cattle on concrete floors can negatively impact their welfare by increasing joint swelling and body lesions, as well as abnormalities in resting behavior and postural changes. We hypothesized that the addition of rubber mats to concrete pens would improve beef cattle welfare by improving performance, health, hygiene, and resting behavior. Forty-eight crossbred Angus steers were housed in pens of 4 and randomly assigned to a single flooring treatment: (1) fully slatted concrete (CON), (2) fully slatted rubber mat (SLAT), or (3) solid rubber mat (SOLID; 60% of pen floor) from 36 to 48 wk of age. Weight, ADG, lesions, gait score, joint swelling, and animal and pen cleanliness were collected every 2 wk. Behavioral time budgets and frequency of postural changes (an indicator of floor traction and comfort) were collected at 0, 6, and 12 wk. No differences in weight gain or ADG were observed. Steers on SOLID flooring (0.80 +/- 0.08) showed increased lesions compared to SLAT (0.38 +/- 0.08) and CON (0.37 +/- 0.08; both, = 0.05); however, there was no difference between SLAT and CON. SLAT steers (1.69 +/- 0.04) showed a reduced gait score compared to SOLID (1.95 +/- 0.04) and CON (1.98 +/- 0.04; both, < 0.05), but SOLID and CON did not differ. Steers on SLAT flooring had less joint swelling (both knees and hocks) compared to SOLID and CON (all comparisons, < 0.05), but SOLID and CON did not differ. Steers on SOLID (3.64 +/- 0.05) flooring were dirtier than those on SLAT (2.27 +/- 0.05) and CON (2.19 +/- 0.05; both, < 0.001), whereas SLAT and CON were similar. Additionally, SOLID and SLAT pens were less clean than CON pens ( < 0.001 and = 0.094, respectively), and SOLID was less clean than SLAT ( < 0.001). Time budget behavior was affected by treatment ( = 0.043), where SOLID differed from CON and SLAT (both, < 0.05). Steers on SOLID flooring preferred to rest on the rubber mat vs. slatted concrete ( = 0.001). Steers on SLAT flooring changed their posture more frequently than those on SOLID and CON flooring (both, < 0.05), but SOLID and CON did not differ. Compared to CON steers, SOLID steers showed an increase in lesions and a reduction in cleanliness, whereas SLAT steers showed a decrease in gait score and joint swelling and an increase in postural changes. Combined, these data suggest that the addition of slatted rubber mats to concrete pens may improve beef cattle welfare. PMID- 26020903 TI - Feed efficiency effects on barrow and gilt behavioral reactivity to novel stimuli tests. AB - Increasing feed efficiency is an important goal for improving sustainable pork production and profitability for producers. To study feed efficiency, genetic selection based on residual feed intake (RFI) was used to create 2 divergent lines. Low-RFI pigs consume less feed for equal weight gain compared to their less efficient, high-RFI counterparts. Therefore, our objective was to assess how a pig's behavioral reactivity toward fear-eliciting stimuli related to RFI selection and improvement of feed efficiency. In this study, behavioral reactivity of pigs divergently selected for RFI was evaluated using human approach (HAT) and novel object (NOT) tests. Forty low-RFI and 40 high-RFI barrows and gilts ( = 20 for each genetic line; 101 +/- 9 d old) from ninth generation Yorkshire RFI selection lines were randomly selected and evaluated once using HAT and once using NOT over a 2-wk period utilizing a crossover experimental design. Each pig was individually tested within a 4.9 * 2.4 m test arena for 10 min; behavior was evaluated using live and video observations. The test arena floor was divided into 4 zones; zone 1 being oral, nasal, and/or facial contact with the human (HAT) or orange traffic cone (NOT) and zone 4 being furthest from the human or cone and included the point where the pig entered the arena. During both HAT and NOT, low-RFI pigs entered zone 1 less frequently compared to high-RFI pigs ( <= 0.03). During NOT, low-RFI pigs changed head orientation more frequently ( = 0.001) but attempted to escape less frequently (low-RFI = 0.97 +/- 0.21 vs. high-RFI = 2.08 +/- 0.38; = 0.0002) and spent 2% less time attempting to escape compared to high-RFI pigs ( = 0.04). Different barrow and gilt responses were observed during HAT and NOT. During HAT, barrows spent 2% more time within zone 1 ( = 0.03), crossed fewer zone lines ( < 0.0001), changed head orientation less frequently ( = 0.002), and froze less frequently compared to gilts ( = 0.02). However, during NOT, barrows froze more frequently ( = 0.0007) and spent 2% longer freezing ( = 0.05). When the behavior and RFI relationship was examined using odds ratios, decreasing RFI by 1 kg/d decreased the odds of freezing by 4 times but increased the odds of attempting to escape by 5.26 times during NOT ( <= 0.04). These results suggest that divergent selection for RFI resulted in subtle behavioral reactivity differences and did not impact swine welfare with respect to responses to fear-eliciting stimuli. PMID- 26020904 TI - Assessment of temperament in Rusa timorensis and its relationship to stress. AB - The delayed domestication of may be associated with their poor temperament and to date there is no published information on the temperament of the farmed Understanding of the temperament and selection program for its evaluation in a breeding herd is important not only for farming but also to other types of animal production. We investigated the temperament of ( = 17) raised in the tropics and determined its relationship with stress. A distance of 13.2 m was fixed for the measurement of flight times. hinds with rapid speed are considered temperamental. Each hind was earmarked for a crush test score between 1 and 5; 1 represents calm and 5 represents highly agitated . Stress was determined by measuring plasma cortisol using a cortisol RIA kit and live weight gain was determined by weighing the animals weekly. The hinds were aged using their date of birth records. We found a strong negative correlation between flight time, crush score, and plasma cortisol concentration ( < 0.05). Animals with very poor temperament have elevated plasma cortisol level and lower weight gain ( < 0.05). It was concluded that flight time, crush score, and plasma cortisol concentration could be used for selecting hinds based on temperament for the breeding herd. This method is quick and easy to implement on a farm; therefore, it remains the test choice for selecting animals based on temperament for the breeding herd. PMID- 26020905 TI - Effects of feeding canola meal from high-protein or conventional varieties of canola seeds on growth performance, carcass characteristics, and cutability of pigs. AB - The objectives of this experiment were to determine growth performance, visceral mass differences, carcass characteristics, fresh meat quality, and carcass cutability of growing-finishing pigs fed diets containing high-protein canola meal (CM-HP) or conventional canola meal (CM-CV). Seven dietary treatments were fed to investigate effects of increasing inclusion rates of CM-HP or CM-CV in a corn-soybean meal diet containing no canola meal (control). Inclusion rates were 33, 66, or 100% replacement of soybean meal with either CM-HP or CM-CV. Pigs (140 barrows and 140 gilts; 2 barrows and 2 gilts per pen) were fed experimental diets in 3 phases with each phase lasting 35, 28, and 28 d, respectively. Within each phase, diets were formulated to be similar in concentrations of standardized ileal digestible indispensable AA and in standardized total tract digestible P, but NE concentrations were not equalized among diets. At the conclusion of the experiment, 1 pig per pen was harvested. Over the 91-d growing-finishing period, no effects of CM-HP on ADG, ADFI, or G:F were observed, but final BW tended ( = 0.06) to be reduced as increasing levels of CM-HP were included in the diets. There was a linear increase ( < 0.05) in ADFI and a linear reduction ( < 0.05) in G:F as CM-CV inclusion level increased. Pigs fed CM-CV also had greater ( < 0.05) ADG and ADFI than pigs fed diets containing CM-HP. There was a linear increase ( < 0.01) in liver weights, as a percentage of live weight, as CM-CV inclusion increased, but that was not the case if CM-HP was included in the diets. There was a linear increase ( < 0.05) in kidney weights, as a percentage of live weight, as CM-HP or CM-CV inclusion increased. There were no differences among treatments for ending live weight, HCW, carcass yield, loin eye area, 10th rib backfat thickness, or estimated carcass lean. Shear force, cook loss, LM moisture, LM extractible lipid, and drip loss were also not different among treatment groups. There were no differences among treatments for any subjective LM quality evaluations (color, marbling, firmness). Pigs fed CM-HP had increased ( < 0.05) boneless lean cutting yields and boneless carcass cutting yields compared with pigs fed CM-CV. In conclusion, CM-HP and CM-CV may fully replace soybean meal as protein supplements in growing-finishing pig diets without substantially impairing pig performance or carcass quality. PMID- 26020906 TI - Effects of the Programmed Nutrition Beef Program on feedlot performance and carcass characteristics. AB - The objective of this study was to examine the effects of alternative finishing strategies on feedlot performance and carcass characteristics. Beef steers (64 pens; 8 steers/pen) were allocated to a randomized complete block design with a 2 * 2 factorial treatment arrangement. Factor 1 consisted of diet, with cattle fed a conventional (CON) diet or a diet consisting of Programmed Nutrition Beef Program (PN) supplements. The PN treatment included Programmed Nutrition Beef Receiver fed from d 1 through 20 of feeding and Programmed Nutrition Beef Finisher fed from d 21 to harvest. Factor 2 evaluated the presence (EGP+) or absence (EGP-) of exogenous growth promotants (ExGP) in the production system. Steers in the EGP+ treatments were initially implanted with Component E-S, reimplanted with Component TE-IS, and fed 400 mg.animal.dof ractopamine hydrochloride for the final 28 d before harvest. Steers were harvested on d 175, and strip loins were removed from 2 carcasses selected at random from each pen for transport to Kansas State University. One 1.27-cm-thick steak was removed from the anterior face for proximate and long-chain fatty acid analysis. There were no diet * ExGP interactions ( > 0.10) for feedlot performance except for DMI ( = 0.02). Steers in the PN/EGP+ treatment consumed more feed than all other treatments ( < 0.05). Both diet and ExGP affected DMI ( < 0.05), with PN and EGP+ steers consuming more feed than their contemporaries. Gain:feed and ADG were unaffected ( > 0.10) by diet, but ExGP improved these measures ( < 0.01). There were no diet * ExGP interactions for carcass characteristics except KPH fat and percentages of yield grade 3 and 4 carcasses ( < 0.05). Diet affected total incidence of liver abscesses because PN steers had a greater ( = 0.05) incidence of liver abscesses than steers in the CON treatment. Diet did not affect the other carcass characteristics ( > 0.10). Use of ExGP increased ( < 0.05) HCW, LM area, and 12th-rib fat but did not affect ( > 0.10) marbling score. Using ExGP reduced the percentage carcasses grading Premium Choice ( < 0.05). No diet * ExGP interactions or diet effects were detected for long-chain fatty acid profiles ( > 0.10). Use of ExGP increased ( < 0.05) the ratio of saturated:unsaturated fatty acids. In summary, the alternative feeding strategy presented in this study produced similar feedlot performance and carcass characteristics compared with a conventional feedlot system. PMID- 26020907 TI - Sow and litter factors influencing colostrum yield and nutritional composition. AB - One of the main characteristics of colostrum intake (CI), colostrum yield (CY), and colostrum composition (CC) in pigs is its variability. The present observational study aimed to investigate factors influencing CY and CC in 10 commercial herds. In total, 100 sows of 5 different breeds and their 1,455 live born piglets were included. Sows' CY was estimated by the CI of their suckling piglets. Colostrum composition was analyzed by LactoScope Fourier transform infrared spectroscopy. Colostrum yield averaged 3,500 +/- 110 g and the percentage of colostral fat (CF), protein, and lactose in colostrum averaged 5.39 +/- 0.12, 16.49 +/- 0.14, and 2.02 +/- 0.05 %, respectively. The effect of sow, litter, and parturition factors on CY and CC were evaluated with a linear mixed regression model with herd included as a random factor. Sows with a gestation length (GL) of 113 d had a higher CY (4,178 +/- 506 g) than sows with a GL of 114 to 115 d (3,342 +/- 107 g; = 0.04). An interaction was found between the litter birth weight of suckling piglets (LW) and GL ( = 0.03). In sows with a GL of 114 to 115 d, CY increased with higher LW ( = 0.009). A shorter interval between birth and first suckling of the litter was related to a higher CY ( < 0.01). The percentage of fat in colostrums was higher in Hypor sows (6.35 +/- 0.51) than in PIC (4.98 +/- 0.27; = 0.001), Topigs 20 (5.05 +/- 0.14; < 0.001), and Danbred (5.34 +/- 0.22; < 0.001) sows. The percentage of CF was negatively associated with parity ( = 0.02) and positively associated with the number of live-born piglets ( = 0.03). The percentages of colostral protein and lactose were not significantly associated with any factor in the multivariable model. In conclusion, this study demonstrated that CY and CF are affected by different sow and litter factors. Pig producers may implement these observations in their management to maximize production or reproduction potential by optimizing CI, CY, and CC. PMID- 26020908 TI - Residual feed intake and blood variables in young Nellore cattle. AB - This study was conducted to evaluate associations of performance traits, feed efficiency, and blood variables with residual feed intake (RFI) in growing Nellore cattle. A total of 118 growing Nellore animals, 62 males and 56 females, were used. A diet containing 2 Mcal/kg was offered ad libitum and individual DMI was measured over a period of 84 d. Animals were classified as low (<=0.128 kg/d; = 40), medium (-0.128 to 0.135 kg/d; = 42), or high RFI (>0.135 kg/d; = 36). Blood samples were collected at the beginning and at the end of the test for determination of plasma concentrations of different blood variables. Data were analyzed using a mixed model that included the random effect of facility the fixed effects of sex, RFI class, and linear effect of the covariate age within sex; and the interaction between RFI class and sex. Least squares means were compared using a -test. Animals of different RFI classes presented similar performance traits and different DMI. Low-RFI animals consumed, on average, 0.670 kg/d less DM than high-RFI animals. Among the blood variables analyzed, significant differences among RFI classes were observed for urea, IGF-1, and insulin. Plasma urea concentrations were lower (5.58 vs. 5.91 mmol/L) and insulin (4.45 vs. 3.70 MUIU/mL) and IGF-1 (433 vs. 399 ng/mL) concentrations were higher in low-RFI animals when compared to high-RFI animals. Plasma concentrations of urea, IGF-1, and insulin can be used as indicators of feed utilization efficiency in Nellore cattle. PMID- 26020909 TI - 50 years of the Wyoming ram test: How sheep have changed. AB - Production characteristics of white-faced rams have been systematically evaluated over a 140-d test in Wyoming since 1961. Individual test records ( = 4,240) from rams on test were analyzed to determine change over the past 52 yr. Although rams on test are not older, weight on and off test has increased ( < 0.001) since 1961. Weight off test increased 22.7 kg and contributed to an increase ( < 0.001) in clean fleece weight. Rate of gain ( < 0.001) almost doubled over this 50-yr period. Growth efficiency improved from 0.23 +/- 0.01 kg/d from 1961 to 1966 to 0.39 +/- 0.01 kg/d from 2008 to 2013. Cubic, rather than linear, effects better explain the change in growth characteristics, suggesting a plateau or tapering of these traits. Wool characteristics remain an important component of the test index, and despite increases in body size and gain, wool diameter was unchanged ( > 0.15). Average daily gain correlated ( > 0.67; < 0.001) with lamb and feeder lamb price, with the strongest correlation at a 2-yr ( > 0.76) time lag. U.S. sheep inventory was negatively correlated ( > -0.72; < 0.001) with sheep price and ADG, with the greatest correlation at no time lag. Wool price 0, 2, or 5 yr prior did not correlate ( < 0.1; >= 0.5) with spinning count. Influences on white faced ram selection appear to have largely impacted growth traits while avoiding negative impacts on wool quality. PMID- 26020910 TI - Supplementing metabolizable protein to ewes during late gestation: II. Effects on ewe lamb performance and reproductive efficiency. AB - The objective of the current study was to determine the effects of maternal MP intake in isocaloric diets during late gestation on female offspring growth from birth to breeding and measure reproductive performance of those offspring in their first breeding season. In yr 1, maternal dietary treatments were applied at d 100 of gestation, were similar in total energy, and contained 60MP1, 60% of MP requirements; 80MP1, 80% of MP requirements; and 100MP1, 100% of the MP requirements on a DM basis during late gestation. In yr 2, maternal dietary treatments were similar in total energy and contained 60MP2, 60% of MP requirements; 100MP2, 100% of the MP requirements; and 140MP2, 140% of MP requirements on a DM basis during late gestation. While there was a quadratic effect ( = 0.003) for ewe lamb birth weight with the ewe lambs from 80MP1 ewes having increased birth weights compared with ewe lambs from 60MP1 and 100MP1 ewes in yr 1, there was no effect ( >= 0.22) of maternal diet on growth of ewe lamb offspring thereafter. A quadratic effect ( = 0.02) was observed for the percentage of ewe lambs bred during the first 17 d of the breeding season, with more ewe lambs born to ewes fed 80MP1 bred compared with ewe lambs born to ewes fed 60MP1 and 100MP1. Ewe lambs giving birth within the first 17 d of lambing season increased ( = 0.001) linearly as MP intake increased in the maternal diet. In yr 2, there was no effect ( >= 0.07) of maternal MP treatment during late gestation on growth of ewe lambs and reproductive performance except ADG from birth to weaning and lamb birth weight. There was a quadratic effect ( = 0.01) for ADG from birth to weaning of ewe lambs from ewes consuming 100MP2 being increased compared with ewe lambs from ewes fed 60MP2 and 140MP2. There was a linear ( = 0.04) reduction in birth weight of lambs born to ewe lambs as the dam's maternal dietary MP intake increased. The data from the current study suggest that feeding 80% or 100% of MP requirements during late gestation may have the greatest positive impacts on female offspring reproductive performance. PMID- 26020911 TI - The effects of technology use in feedlot production systems on feedlot performance and carcass characteristics. AB - The objectives of this study were to examine the effects of feedlot production systems with and without the use of a beta-adrenergic agonist compared to an all natural production program on feedlot performance and carcass characteristics. Crossbred beef steers ( = 336; initial BW = 379 +/- 8 kg) were randomized to 1 of 3 treatments in a randomized complete block design (RCBD; 14 steers/pen; 8 pens/treatment). Treatments consisted of an all-natural treatment (NAT), a conventional treatment (CONV), and a conventional treatment with a beta-agonist (CONV-Z). All treatments were fed the same basal diet with NAT cattle receiving no growth promoting technologies. The CONV and CONV-Z cattle were implanted with 40 mg of estradiol and 200 mg of trenbolone acetate (TBA) on d 0 and were fed 33 and 9 mg/kg of monensin and tylosin daily, respectively. The CONV-Z cattle were fed zilpaterol hydrochloride (ZH) at 6.76 mg/kg (90% DM basis) for the last 20 days on feed (DOF) There was no effect of treatment on DMI ( = 0.83); however, CONV-Z steers gained 3.8% faster (1.64 vs. 1.58 kg/d; < 0.01) and were 5.3% more efficient (0.160 vs. 0.152; < 0.01) than CONV steers, and CONV steers gained 32.8% faster (1.58 vs. 1.19 kg/d; < 0.01) and were 26.7% more efficient (0.152 vs. 0.120; < 0.01) than NAT steers. There was a 35.7% improvement in estimated carcass gain (1.29 vs. 0.95 kg/d; < 0.01) and a 32.6% improvement in carcass efficiency (0.126 vs. 0.095; < 0.01) for CONV-Z steers compared to NAT steers. Hot carcass weight was increased by 8 kg for CONV-Z steers compared to CONV steers (394 vs. 386 kg; = 0.05) and 46 kg compared to NAT steers (394 vs. 348 kg; < 0.01). Longissimus muscle area was increased by 3.6 cm for CONV-Z steers compared to CONV steers (92.29 vs. 88.67 cm; = 0.02) and 12.1 cm for CONV-Z steers compared to NAT steers (92.29 vs. 80.16 cm; < 0.01), resulting in a 9.6% unit increase in USDA yield grade (YG) 1 (15.14 vs. 5.52%; < 0.05) and a 21.6% unit reduction in USDA YG 3 for CONV-Z steers compared to CONV steers (30.70 vs. 52.32%; < 0.05). The CONV-Z steers had a lower marbling score compared to the other treatments (432; 0.01), resulting in an 11.7% unit increase (20.70 vs. 9.03%; < 0.05) in USDA Select carcasses compared to CONV steers. The results of this experiment show that CONV-Z and CONV production results in a significant improvement in feedlot performance and USDA YG compared to NAT. PMID- 26020912 TI - Pasture-derived greenhouse gas emissions in cow-calf production systems. AB - There is a lack of information regarding carbon dioxide (CO), methane (CH), and nitrous oxide (NO) emissions from pasture soils and the effects of grazing. The objective of this study was to quantify greenhouse gas (GHG) fluxes from pasture soils grazed with cow-calf pairs managed with different stocking rates and densities. The central hypothesis was that irrigated low-density stocking systems (SysB) would result in greater GHG emissions from pasture soils than nonirrigated high-density stocking systems (SysA) and grazing-exclusion (GRE) pasture sites. The nonirrigated high-density stocking systems consisted of 120 cow-calf pairs rotating on a total of 120 ha (stocking rate 1 cow/ha, stocking density 112,000 kg BW/ha, rest period of 60 to 90 d). The irrigated low-density stocking systems consisted of 64 cow-calf pairs rotating on a total of 26 ha of pasture (stocking rate 2.5 cows/ha, stocking density 32,700 kg BW/ha, rest period of 18 to 30 d). Both systems consisted of mixed cool-season grass-legume pastures. Static chambers were randomly placed for collection of CO, CH, and NO samples. Soil temperature (ST), ambient temperature (temperature inside the chamber; AT), and soil water content (WC) were monitored and considered explanatory variables for GHG emissions. GHG fluxes were monitored for 3 yr (2011 to 2013) at the beginning (P1) and at the end (P2) of the grazing season, always postgrazing. Paddock was the experimental unit (3 pseudoreplicates per treatment), and chambers (30 chambers per paddock) were considered multiple measurements of each experimental unit. A completely randomized design considered the term year * period as a repeated measure and chamber nested within paddock and treatment as the random term. Generally, SysB had greater CO emissions than SysA and GRE pasture sites across years and periods ( < 0.01). Soil temperature, AT, and WC had effects on CO emissions. Methane and NO emissions were observed from pasture sites of the 3 systems, but the effect of grazing was not constantly significant for CH and NO emissions. In addition, ST, AT, and WC did not conclusively explain CH and NO emissions. No clear trade-offs between GHG were observed; generally, GHG emissions increased from 2011 to 2013, which was likely associated with weather conditions, such as higher daily temperature and precipitation events. The central hypothesis that SysB would result in greater GHG emissions from pasture soils than SysA and GRE was not confirmed. PMID- 26020913 TI - Enteric methane from lactating beef cows managed with high- and low-input grazing systems. AB - The objective of this study was to compare methane (CH) emissions from lactating beef cows grazed with different combinations of stocking rate and density. We hypothesized that a low stocking rate coupled with high-stocking-density grazing management would result in poorer forage quality, thereby increasing enteric CH emissions. System A (SysA) consisted of 120 cow-calf pairs rotating on a total of 120 ha divided into 2-ha pastures (stocking rate 1 cow/ha, stocking density 112,000 kg BW/ha, rest period of 60 to 90 d). System B (SysB) consisted of 16 groups of 4 cow-calf pairs each rotating on a 1.6-ha pasture (stocking rate 2.5 cows/ha, stocking density 32,000 kg BW/ha, rest period of 18 to 30 d). Enteric CH measurements were collected using a sulfur hexafluoride (SF) tracer gas method. Sampling occurred during 2012 and 2013 in 2 periods: the beginning (P1) and end of the grazing season (P2). Cannulated Angus cows were stratified by weight, age, and parity and were assigned to each treatment ( = 6) in a crossover design with a doubly repeated measures design, with period and day as repeated measures (alpha = 0.05). Dry matter intake was determined using chromic oxide (CrO) as a marker. Forage samples were collected ( = 3) for nutrient composition analyses and total forage mass determination. Forage botanical composition was determined using the dry-weight-rank method. Postgrazing herbage mass was greater for SysA during P2 in 2012 ( < 0.01) and 2013 ( = 0.01). Grasses were predominant and represented 67% to 96% of pastures; legumes contributed 3% to 21% of pastures across periods and treatments. The proportion of legumes tended to be higher in SysB pasture sites in P2 than in P1. There were no treatment effects on DMI. There was a period effect on DMI ( < 0.01); DMI of SysA and SysB cows increased from P1 to P2 (4 and 1.1 kg DMI/d increase, respectively). Cows ingested, on average, 2.6% (SysA) and 2.8% (SysB) of their BW. There was no year effect on CH emissions ( = 0.16). Daily enteric CH emissions did not vary with treatment and ranged from 195 to 249 g CH/d across treatment. Enteric CH emissions per unit GE intake varied with treatment during P1 (6.4% and 3.8% for SysA and SysB, respectively; < 0.01). Across treatments and periods, enteric CH emission per unit GE intake was 4.6%, which could be considered low for grazing lactating beef cows. It is likely that cows in the present study were selecting high-quality forage and produced comparatively lower CH emissions. PMID- 26020914 TI - Proteolytic changes of myofibrillar proteins in Podolian meat during aging: focusing on tenderness. AB - The aim of this study was to understand the relationship between changes in postmortem degradation of myofibrillar proteins and tenderness development in 3 different muscles from 10 Podolian young bulls aged 1, 7, 14, and 21 d. Psoas major (PM), longissimus dorsi (LD), and semitendinosus muscle () were removed from each half carcass 24 h postmortem. Meat chemical composition, Warner Bratzler shear force (WBSF), myofibril fragmentation index (MFI), total collagen content, and changes in myofibrillar proteins were estimated in triplicate at each aging time. A significant muscle effect was found on meat chemical composition. Semitendinosus muscle showed the lowest intramuscular fat percentage ( < 0.01) and the highest total collagen content ( < 0.01) with respect to LD and PM. Warner-Bratzler shear force decreased during aging in all muscles ( < 0.001), and semitendinosus was the toughest muscle whereas PM was the most tender ( < 0.001). Myofibril fragmentation index significantly increased ( < 0.001) in LD and PM meat throughout aging time whereas in semitendinosus it increased from 14 d of aging. Proteolysis was investigated by SDS-PAGE, western blotting, and 2 dimensional electrophoresis. Throughout postmortem aging, some structural proteins changed in intensity in all muscles analyzed. The blotting profile highlighted that desmin and troponin-T (TnT) bands were affected by both muscle and aging effects. Desmin degradation was more intense and faster in LD muscle than in semitendinosus and PM muscles. A progressive increase of the degraded isoforms of TnT (33 and 30 kDa polypeptides) was found during aging in LD, while, in PM these bands appeared earlier showing a greater intensity from 1 d. During aging, 2-dimensional gel electrophoresis (2DE) image analyses results showed a significant increase of the total number of spots reaching the highest value in the LD muscle at 21 d of aging ( < 0.01). Proteins separation also revealed differences in the spot number and expression patterns of myosin light chain (MLC) isoforms among muscles. A principal components analysis applied to meat chemical composition, tenderness, and myofibrillar proteins accounted for approximately 96.09% of total variance. Data highlight that aging affects the meat tenderness and proteolysis with different intensities in each muscle. These results provide knowledge about the tenderness mechanism in different muscles from a rustic breed and could be useful for the development of muscle specific strategies for improving the quality and value in different commercial cuts. PMID- 26020915 TI - Predicting fat, lean and the weights of primal cuts for growing pigs of different genotypes and sexes using computed tomography. AB - The aim of the present study was to find single equations to predict the amounts of fat, lean, and the weights of the primal cuts (ham, loin, belly, and shoulder) as well as ham composition of pigs from 30 to 120 kg BW of different genotypes (GEN; Exp. 1) and sexual conditions (SEX; Exp. 2). Two types of regression equations, taking into account different work situations, were developed: 1) research applications, using computed tomography (CT) parameters, and 2) potential on-farm applications, which could be obtained using easily accessible equipment. Two data sets were used: Exp. 1 included 90 gilts from 3 different GEN: 30 Duroc * (Landrace * Large White), 30 Pietrain * (Landrace * Large White), and 30 Landrace * Large White, and Exp. 2 included 92 Pietrain * (Landrace * Duroc) pigs of different SEX: 24 each of females, entire males, castrated males, and 20 immunocastrated males. Pigs were fully CT scanned in vivo at 30, 70, 100, and 120 kg BW. A subsample of pigs of each GEN ( = 5) or SEX ( = 4) were slaughtered at 30, 70, and 100 kg BW, and all remaining pigs were slaughtered after weighing and scanning at 120 kg BW. For all the slaughtered pigs, the 4 main cuts were fully (GEN) or partially dissected (SEX). CT images were analyzed and used to predict the lean and fat contents as well as the weights of the primal cuts and the composition of the ham. Total amounts of fat and lean for both populations were predicted with high levels of accuracy ( = 0.994 and 0.993, respectively) and proportions of random error for GEN and SEX effects (0.998 and 0.946 for the fat and 0.997 and 0.836 for the lean predictions, respectively). Moreover, the composition of ham (fat, lean, and bone) was very well predicted with high proportions (> 80%) of random error for GEN and SEX effect using CT and potential on-farm predictors. PMID- 26020916 TI - A stochastic model to determine the economic value of changing diagnostic test characteristics for identification of cattle for treatment of bovine respiratory disease. AB - Bovine respiratory disease is an economically important syndrome in the beef industry, and diagnostic accuracy is important for optimal disease management. The objective of this study was to determine whether improving diagnostic sensitivity or specificity was of greater economic value at varied levels of respiratory disease prevalence by using Monte Carlo simulation. Existing literature was used to populate model distributions of published sensitivity, specificity, and performance (ADG, carcass weight, yield grade, quality grade, and mortality risk) differences among calves based on clinical respiratory disease status. Data from multiple cattle feeding operations were used to generate true ranges of respiratory disease prevalence and associated mortality. Input variables were combined into a single model that calculated estimated net returns for animals by diagnostic category (true positive, false positive, false negative, and true negative) based on the prevalence, sensitivity, and specificity for each iteration. Net returns for each diagnostic category were multiplied by the proportion of animals in each diagnostic category to determine group profitability. Apparent prevalence was categorized into low (<15%) and high (>=15%) groups. For both apparent prevalence categories, increasing specificity created more rapid, positive change in net returns than increasing sensitivity. Improvement of diagnostic specificity, perhaps through a confirmatory test interpreted in series or pen-level diagnostics, can increase diagnostic value more than improving sensitivity. Mortality risk was the primary driver for net returns. The results from this study are important for determining future research priorities to analyze diagnostic techniques for bovine respiratory disease and provide a novel way for modeling diagnostic tests. PMID- 26020917 TI - Changes of coat cover in primitive horses living on a reserve. AB - Changes in the coat cover are important for mammalian thermoregulation. This is especially true where variable environmental conditions exist throughout the seasons. Coat cover shedding is the replacement of old coat hair with new hair. The process differs in various equids. The aim of the study was to examine the changes in the coat of primitive Polish Konik horses living on a reserve in southeast Poland (50.6319 degrees N). The reserve is located in a temperate climate. The mean temperature is below 0 degrees C in winter (December 8 to March 9) and over 15 degrees C in summer (June 8 to September 8). Five adult mares were included in the study. The study used a specific methodical approach to quantitatively assess coat cover changes. Photos were taken once every 2 wk throughout the whole year to document the state of the mares' coat. MultiScanBase software was used to analyze 260 photos. The percentage of the skin surface covered with short hair in relation to the surface of the body (without the head, neck, and limbs; short hair body [SHB]) was determined. To assess the topography of coat changes, surface parts covered with short hair within 6 regions of the body (shoulder, back, chest, loins, belly, and hindquarters; short hair part [SHP]) were considered separately. The regression coefficient was calculated for the SHB and the air temperature. Correlations in SHP and SHB between the left and right sides of the body were determined. The correlations within the right side of the body concerned particular SHP. As the results show, the coat changes take place at the same time on both sides of the horse's body. In spring, the winter hair is shed, and in the fall, the winter hair grows in longer. High regression (0.901; < 0.0001) proved that air temperature strongly affected the coat changes. The most important increase of SHB occurs in April and the first half of May, whereas the main decrease of SHB takes place in September. Changes between SHP are highly correlated (0.967-0.994; < 0.05). Spring and fall coat changes demonstrate that the shoulders, back, and loins require the winter cover for a longer time than the chest and belly, whereas the hindquarters are the least demanding in this respect. The phenomenon may be associated with, among others, the stronger effect of rain and snow on the upper parts of the body. PMID- 26020918 TI - Errata. PMID- 26020920 TI - Controllability of deterministic networks with the identical degree sequence. AB - Controlling complex network is an essential problem in network science and engineering. Recent advances indicate that the controllability of complex network is dependent on the network's topology. Liu and Barabasi, et.al speculated that the degree distribution was one of the most important factors affecting controllability for arbitrary complex directed network with random link weights. In this paper, we analysed the effect of degree distribution to the controllability for the deterministic networks with unweighted and undirected. We introduce a class of deterministic networks with identical degree sequence, called (x,y)-flower. We analysed controllability of the two deterministic networks ((1, 3)-flower and (2, 2)-flower) by exact controllability theory in detail and give accurate results of the minimum number of driver nodes for the two networks. In simulation, we compare the controllability of (x,y)-flower networks. Our results show that the family of (x,y)-flower networks have the same degree sequence, but their controllability is totally different. So the degree distribution itself is not sufficient to characterize the controllability of deterministic networks with unweighted and undirected. PMID- 26020919 TI - Auxin-Mediated Transcriptional System with a Minimal Set of Components Is Critical for Morphogenesis through the Life Cycle in Marchantia polymorpha. AB - The plant hormone auxin regulates many aspects of plant growth and development. Recent progress in Arabidopsis provided a scheme that auxin receptors, TIR1/AFBs, target transcriptional co-repressors, AUX/IAAs, for degradation, allowing ARFs to regulate transcription of auxin responsive genes. The mechanism of auxin-mediated transcriptional regulation is considered to have evolved around the time plants adapted to land. However, little is known about the role of auxin-mediated transcription in basal land plant lineages. We focused on the liverwort Marchantia polymorpha, which belongs to the earliest diverging lineage of land plants. M. polymorpha has only a single TIR1/AFB (MpTIR1), a single AUX/IAA (MpIAA), and three ARFs (MpARF1, MpARF2, and MpARF3) in the genome. Expression of a dominant allele of MpIAA with mutations in its putative degron sequence conferred an auxin resistant phenotype and repressed auxin-dependent expression of the auxin response reporter proGH3:GUS. We next established a system for DEX inducible auxin-response repression by expressing the putatively stabilized MpIAA protein fused with the glucocorticoid receptor domain (MpIAA(mDII)-GR). Repression of auxin responses in (pro)MpIAA:MpIAA(mDII)-GR plants caused severe defects in various developmental processes, including gemmaling development, dorsiventrality, organogenesis, and tropic responses. Transient transactivation assays showed that the three MpARFs had different transcriptional activities, each corresponding to their phylogenetic classifications. Moreover, MpIAA and MpARF proteins interacted with each other with different affinities. This study provides evidence that pleiotropic auxin responses can be achieved by a minimal set of auxin signaling factors and suggests that the transcriptional regulation mediated by TIR1/AFB, AUX/IAA, and three types of ARFs might have been a key invention to establish body plans of land plants. We propose that M. polymorpha is a good model to investigate the principles and the evolution of auxin-mediated transcriptional regulation and its roles in land plant morphogenesis. PMID- 26020921 TI - Association between Multidrug-Resistant Tuberculosis and Risk Factors in China: Applying Partial Least Squares Path Modeling. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) resulting from various factors has raised serious public health concerns worldwide. Identifying the ecological risk factors associated with MDR-TB is critical to its prevention and control. This study aimed to explore the association between the development of MDR-TB and the risk factors at the group-level (ecological risk factors) in China. METHODS: Data on MDR-TB in 120 counties were obtained from the National Tuberculosis Information Management System, and data on risk-factor variables were extracted from the Health Statistical Yearbook, provincial databases, and the meteorological bureau of each province (municipality). Partial Least Square Path Modeling was used to detect the associations. RESULTS: The median proportion of MDR-TB in new TB cases was 3.96% (range, 0-39.39%). Six latent factors were extracted from the ecological risk factors, which explained 27.60% of the total variance overall in the prevalence of MDR-TB. Based on the results of PLS-PM, TB prevention, health resources, health services, TB treatment, TB detection, geography and climate factors were all associated with the risk of MDR-TB, but socioeconomic factors were not significant. CONCLUSIONS: The development of MDR TB was influenced by TB prevention, health resources, health services, TB treatment, TB detection, geography and climate factors. Such information may help us to establish appropriate public health intervention strategies to prevent and control MDR-TB and yield benefits to the entire public health system in China. PMID- 26020922 TI - Sine-Gordon Equation in (1+2) and (1+3) dimensions: Existence and Classification of Traveling-Wave Solutions. AB - The (1+1)-dimensional Sine-Gordon equation passes integrability tests commonly applied to nonlinear evolution equations. Its kink solutions (one-dimensional fronts) are obtained by a Hirota algorithm. In higher space-dimensions, the equation does not pass these tests. Although it has been derived over the years for quite a few physical systems that have nothing to do with Special Relativity, the Sine-Gordon equation emerges as a non-linear relativistic wave equation. This opens the way for exploiting the tools of the Theory of Special Relativity. Using no more than the relativistic kinematics of tachyonic momentum vectors, from which the solutions are constructed through the Hirota algorithm, the existence and classification of N-moving-front solutions of the (1+2)- and (1+3) dimensional equations for all N >= 1 are presented. In (1+2) dimensions, each multi-front solution propagates rigidly at one velocity. The solutions are divided into two subsets: Solutions whose velocities are lower than a limiting speed, c = 1, or are greater than or equal to c. To connect with concepts of the Theory of Special Relativity, c will be called "the speed of light." In (1+3) dimensions, multi-front solutions are characterized by spatial structure and by velocity composition. The spatial structure is either planar (rotated (1+2) dimensional solutions), or genuinely three-dimensional--branes. Planar solutions, propagate rigidly at one velocity, which is lower than, equal to, or higher than c. Branes must contain clusters of fronts whose speed exceeds c = 1. Some branes are "hybrids": different clusters of fronts propagate at different velocities. Some velocities may be lower than c but some must be equal to, or exceed, c. Finally, the speed of light cannot be approached from within the subset of slower than-light solutions in both (1+2) and (1+3) dimensions. PMID- 26020923 TI - Hydrocarbons in Deep-Sea Sediments following the 2010 Deepwater Horizon Blowout in the Northeast Gulf of Mexico. AB - The Deepwater Horizon (DWH) spill released 4.9 million barrels of oil into the Gulf of Mexico (GoM) over 87 days. Sediment and water sampling efforts were concentrated SW of the DWH and in coastal areas. Here we present geochemistry data from sediment cores collected in the aftermath of the DWH event from 1000 1500 m water depth in the DeSoto Canyon, NE of the DWH wellhead. Cores were analyzed at high-resolution (at 2 mm and 5 mm intervals) in order to evaluate the concentration, composition and input of hydrocarbons to the seafloor. Specifically, we analyzed total organic carbon (TOC), aliphatic, polycyclic aromatic hydrocarbon (PAHs), and biomarker (hopanes, steranes, diasteranes) compounds to elucidate possible sources and transport pathways for deposition of hydrocarbons. Results showed higher hydrocarbon concentrations during 2010-2011 compared to years prior to 2010. Hydrocarbon inputs in 2010-2011 were composed of a mixture of sources including terrestrial, planktonic, and weathered oil. Our results suggest that after the DWH event, both soluble and highly insoluble hydrocarbons were deposited at enhanced rates in the deep-sea. We proposed two distinct transport pathways of hydrocarbon deposition: 1) sinking of oil-particle aggregates (hydrocarbon-contaminated marine snow and/or suspended particulate material), and 2) advective transport and direct contact of the deep plume with the continental slope surface sediments between 1000-1200 m. Our findings underline the complexity of the depositional event observed in the aftermath of the DWH event in terms of multiple sources, variable concentrations, and spatial (depth-related) variability in the DeSoto Canyon, NE of the DWH wellhead. PMID- 26020924 TI - Trichloroethylene Hypersensitivity Syndrome Is Potentially Mediated through Its Metabolite Chloral Hydrate. AB - BACKGROUND: We documented previously the entity of trichloroethylene (TCE) hypersensitivity syndrome (THS) in occupational workers. OBJECTIVES: To identify the culprit causative compound, determine the type of hypersensitivity of THS, and establish a screening test for subjects at risk of THS. METHODS: TCE and its main metabolites chloral hydrate (CH), trichloroethanol (TCOH) and trichloroacetic acid (TCA) were used as allergens at different concentrations in skin patch tests. The study included 19 case subjects diagnosed with occupational THS, 22 control healthy workers exposed to TCE (exposure >12 weeks), and 20 validation new workers exposed to TCE for <12 weeks free of THS. All subjects were followed-up for 12 weeks after the patch test. RESULTS: The highest patch test positive rate in subjects with THS was for CH, followed by TCOH, TCA and TCE. The CH patch test positive rate was 100% irrespective of CH concentrations (15%, 10% and 5%). The TCOH patch test positive rate was concentration-dependent (89.5%, 73.7% and 52.6% for 5%, 0.5% and 0.05%, respectively). Lower patch test positive rates were noted for TCA and TCE. All patch tests (including four allergens) were all negative in each of the 22 control subjects. None of the subjects of the validation group had a positive 15% CH patch test. CONCLUSIONS: Chloral hydrate seems to be the culprit causative compound of THS and type IV seems to be the major type of hypersensitivity of THS. The CH patch test could be potentially useful for screening workers at risk of THS. PMID- 26020926 TI - Correction: First Report of Clostridium difficile NAP1/027 in a Mexican Hospital. PMID- 26020925 TI - Parallel changes in structural and functional measures of optic nerve myelination after optic neuritis. AB - INTRODUCTION: Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON. METHODS: Thirty acute ON patients were studied at 1, 3, 6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further. RESULTS: Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76 ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94 ms of latency delay. CONCLUSION: A strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination. PMID- 26020927 TI - Two-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth. AB - Two-photon fluorescence correlation spectroscopy (2P-FCS) within single dendritic spines of living hippocampal pyramidal neurons was used to resolve various subpopulations of mobile F-actin during activity-dependent structural changes such as potentiation induced spine head growth. Two major classes of mobile F actin were discovered: very dynamic and about a hundred times less dynamic F actin. Spine head enlargement upon application of Tetraethylammonium (TEA), a protocol previously used for the chemical induction of long-term potentiation (cLTP) strictly correlated to changes in the dynamics and filament numbers in the different actin filament fractions. Our observations suggest that spine enlargement is governed by a mechanism in which longer filaments are first cut into smaller filaments that cooperate with the second, increasingly dynamic shorter actin filament population to quickly reorganize and expand the actin cytoskeleton within the spine head. This process would allow a fast and efficient spine head enlargement using a major fraction of the actin filament population that was already present before spine head growth. PMID- 26020928 TI - Ancestral alleles in the human genome based on population sequencing data. AB - Ancestral allele information is useful for genetics studies. Previously, the identification of ancestral alleles was primarily based on sequence alignments between species. Alternative ways to identify ancestral alleles were proposed in this study based on population sequencing data. The methods described here utilized the diversity between haplotypes harboring ancestral and newly emerged alleles. Simulations showed that these methods were reliable for identifying ancestral alleles when the variants had not aged too greatly. Application to the human genome sequencing data suggested the role of indels in maintaining the GC content in the human genome. The deletion-to-insertion ratios and GC proportions were correlated depending on the sizes of insertions and deletions in the direction of increasing GC content. There were GC-biased fixations in single base pair insertions and AT-biased fixations in single base-pair deletions in the results based on the proposed methods. In the current study, GC-biased gene conversions in nucleotide substitutions were very slight or insignificant. In the variants of several quantitative trait loci (QTLs), slight GC-biased gene conversion was observed in nucleotide substitutions. For the QTL indels, insertions were observed more often than deletions, and deletion-biased fixation was observed, providing new insights into the evolution of functional genes. PMID- 26020929 TI - Precipitation and primary health care visits for gastrointestinal illness in Gothenburg, Sweden. AB - BACKGROUND: The river Gota Alv is a source of freshwater for the City of Gothenburg, Sweden, and we recently identified a clear influence of upstream precipitation on concentrations of indicator bacteria in the river water, as well as an association with the daily number of phone calls to the nurse advice line related to acute gastrointestinal illnesses (AGI calls). This study aimed to examine visits to primary health-care centers owing to similar symptoms (AGI visits) in the same area, to explore associations with precipitation, and to compare variability in AGI visits and AGI calls. METHODS: We obtained data covering six years (2007-2012) of daily AGI visits and studied their association with prior precipitation (0-28 days) using a distributed lag nonlinear Poisson regression model, adjusting for seasonal patterns and covariates. In addition, we studied the effects of prolonged wet and dry weather on AGI visits. We analyzed lagged short-term relations between AGI visits and AGI calls, and we studied differences in their seasonal patterns using a binomial regression model. RESULTS: The study period saw a total of 17,030 AGI visits, and the number of daily visits decreased on days when precipitation occurred. However, prolonged wet weather was associated with an elevated number of AGI visits. Differences in seasonality patterns were observed between AGI visits and AGI calls, as visits were relatively less frequent during winter and relatively more frequent in August, and only weak short-term relations were found. CONCLUSION: AGI visits and AGI calls seems to partly reflect different types of AGI illnesses, and the patients' choice of medical contact (in-person visits versus phone calls) appears to depend on current weather conditions. An association between prolonged wet weather and increased AGI visits supports the hypothesis that the drinking water is related to an increased risk of AGI illnesses. PMID- 26020930 TI - Phylum-Level Conservation of Regulatory Information in Nematodes despite Extensive Non-coding Sequence Divergence. AB - Gene regulatory information guides development and shapes the course of evolution. To test conservation of gene regulation within the phylum Nematoda, we compared the functions of putative cis-regulatory sequences of four sets of orthologs (unc-47, unc-25, mec-3 and elt-2) from distantly-related nematode species. These species, Caenorhabditis elegans, its congeneric C. briggsae, and three parasitic species Meloidogyne hapla, Brugia malayi, and Trichinella spiralis, represent four of the five major clades in the phylum Nematoda. Despite the great phylogenetic distances sampled and the extensive sequence divergence of nematode genomes, all but one of the regulatory elements we tested are able to drive at least a subset of the expected gene expression patterns. We show that functionally conserved cis-regulatory elements have no more extended sequence similarity to their C. elegans orthologs than would be expected by chance, but they do harbor motifs that are important for proper expression of the C. elegans genes. These motifs are too short to be distinguished from the background level of sequence similarity, and while identical in sequence they are not conserved in orientation or position. Functional tests reveal that some of these motifs contribute to proper expression. Our results suggest that conserved regulatory circuitry can persist despite considerable turnover within cis elements. PMID- 26020931 TI - Different Astrocytic Activation between Adult Gekko japonicus and Rats during Wound Healing In Vitro. AB - Glial scar formation is a major obstacle to regeneration after spinal cord injury. Moreover, it has been shown that the astrocytic response to injury differs between species. Gekko japonicas is a type of reptile and it shows differential glial activation compared to that of rats. The purpose of the present study was to compare the proliferation and migration of astrocytes in the spinal cords of geckos and rats after injury in vitro. Spinal cord homogenate stimulation and scratch wound models were used to induce astrocytic activation in adult and embryonic rats, as well as in adult geckos. Our results indicated that astrocytes from the adult rat were likely activated by mechanical stimulation, even though they showed lower proliferation abilities than the astrocytes from the gecko under normal conditions. Furthermore, a transcriptome analysis revealed that the differentially expressed genes in astrocytes from adult rats and those from geckos were enriched in pathways involved in proliferation and the response to stimuli. This implies that intrinsic discrepancies in gene expression patterns might contribute to the differential activation of astrocytes between species. PMID- 26020933 TI - The 35S U5 snRNP Is Generated from the Activated Spliceosome during In vitro Splicing. AB - Primary gene transcripts of eukaryotes contain introns, which are removed during processing by splicing machinery. Biochemical studies In vitro have identified a specific pathway in which introns are recognised and spliced out. This occurs by progressive formation of spliceosomal complexes designated as E, A, B, and C. The composition and structure of these spliceosomal conformations have been characterised in many detail. In contrast, transitions between the complexes and the intermediates of these reactions are currently less clear. We have previously isolated a novel 35S U5 snRNP from HeLa nuclear extracts. The protein composition of this particle differed from the canonical 20S U5 snRNPs but was remarkably similar to the activated B* spliceosomes. Based on this observation we have proposed a hypothesis that 35S U5 snRNPs represent a dissociation product of the spliceosome after both transesterification reactions are completed. Here we provide experimental evidence that 35S U5 snRNPs are generated from the activated B* spliceosomes during In vitro splicing. PMID- 26020932 TI - Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. AB - The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-gamma as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune mediated host cell damage. PMID- 26020934 TI - Hepatic proliferation and angiogenesis markers are increased after portal deprivation in rats: a study of molecular, histological and radiological changes. AB - BACKGROUND & AIMS: To determine the pathogenesis of liver nodules, and lesions similar to obliterative portal venopathy, observed after portosystemic shunts or portal vein thrombosis in humans. METHODS: We conducted an experimental study comparing portacaval shunt (PCS), total portal vein ligation (PVL), and sham (S) operated rats. Each group were either sacrificed at 6 weeks (early) or 6 months (late). Arterial liver perfusion was studied in vivo using CT, and histopathological changes were noted. Liver mRNA levels were quantified by RT QPCR for markers of inflammation (Il10, Tnfa), proliferation (Il6st, Mki67, Hgf, Hnf4a), angiogenesis: (Vegfa, Vegfr 1, 2 and 3; Pgf), oxidative stress (Nos2, and 3, Hif1a), and fibrosis (Tgfb). PCS and PVL were compared to the S group. RESULTS: Periportal fibrosis and arterial proliferation was observed in late PCS and PVL groups. CT imaging demonstrated increased arterial liver perfusion in the PCS group. RT-QPCR showed increased inflammatory markers in PCS and PVL early groups. Tnfa and Il10 were increased in PCS and PVL late groups respectively. All proliferative markers increased in the PCS, and Hnf4a in the PVL early groups. Mki67 and Hnf4a were increased in the PCS late group. Nos3 was increased in the early and late PCS groups, and Hif1a was decreased in the PVL groups. Markers of angiogenesis were all increased in the early PCS group, and Vegfr3 and Pgf in the late PCS group. Only Vegfr3 was increased in the PVL groups. Tgf was increased in the PCS groups. CONCLUSIONS: Portal deprivation in rats induces a sustained increase in intrahepatic markers of inflammation, angiogenesis, proliferation, and fibrosis. PMID- 26020935 TI - Improving decision making for massive transfusions in a resource poor setting: a preliminary study in Kenya. AB - BACKGROUND: The reality of finite resources has a real-world impact on a patient's ability to receive life-saving care in resource-poor settings. Blood for transfusion is an example of a scarce resource. Very few studies have looked at predictors of survival in patients requiring massive transfusion. We used data from a rural hospital in Kenya to develop a prediction model of survival among patients receiving massive transfusion. METHODS: Patients who received five or more units of whole blood within 48 hours between 2004 and 2010 were identified from a blood registry in a rural hospital in Kenya. Presenting characteristics and in-hospital survival were collected from charts. Using stepwise selection, a logistic model was developed to predict who would survive with massive transfusion versus those who would die despite transfusion. An ROC curve was created from this model to quantify its predictive power. RESULTS: Ninety-five patients with data available met inclusion criteria, and 74% survived to discharge. The number of units transfused was not a predictor of mortality, and no threshold for futility could be identified. Preliminary results suggest that initial blood pressure, lack of comorbidities, and indication for transfusion are the most important predictors of survival. The ROC curve derived from our model demonstrates an area under the curve (AUC) equal to 0.757, with optimism of 0.023 based on a bootstrap validation. CONCLUSIONS: This study provides a framework for making prioritization decisions for the use of whole blood in the setting of massive bleeding. Our analysis demonstrated an overall survival rate for patients receiving massive transfusion that was higher than clinical perception. Our analysis also produced a preliminary model to predict survival in patients with massive bleeding. Prediction analyses can contribute to more efficient prioritization decisions; these decisions must also include other considerations such as equity, acceptability, affordability and sustainability. PMID- 26020936 TI - Lineage range estimation method reveals fine-scale endemism linked to Pleistocene stability in Australian rainforest herpetofauna. AB - Areas of suitable habitat for species and communities have arisen, shifted, and disappeared with Pleistocene climate cycles, and through this shifting landscape, current biodiversity has found paths to the present. Evolutionary refugia, areas of relative habitat stability in this shifting landscape, support persistence of lineages through time, and are thus crucial to the accumulation and maintenance of biodiversity. Areas of endemism are indicative of refugial areas where diversity has persisted, and endemism of intraspecific lineages in particular is strongly associated with late-Pleistocene habitat stability. However, it remains a challenge to consistently estimate the geographic ranges of intraspecific lineages and thus infer phylogeographic endemism, because spatial sampling for genetic analyses is typically sparse relative to species records. We present a novel technique to model the geographic distribution of intraspecific lineages, which is informed by the ecological niche of a species and known locations of its constituent lineages. Our approach allows for the effects of isolation by unsuitable habitat, and captures uncertainty in the extent of lineage ranges. Applying this method to the arc of rainforest areas spanning 3500 km in eastern Australia, we estimated lineage endemism for 53 species of rainforest dependent herpetofauna with available phylogeographic data. We related endemism to the stability of rainforest habitat over the past 120,000 years and identified distinct concentrations of lineage endemism that can be considered putative refugia. These areas of lineage endemism are strongly related to historical stability of rainforest habitat, after controlling for the effects of current environment. In fact, a dynamic stability model that allows movement to track suitable habitat over time was the most important factor in explaining current patterns of endemism. The techniques presented here provide an objective, practical method for estimating geographic ranges below the species level, and including them in spatial analyses of biodiversity. PMID- 26020937 TI - Correction: FBI-1 Enhances ETS-1 Signaling Activity and Promotes Proliferation of Human Colorectal Carcinoma Cells. PMID- 26020938 TI - Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response. AB - The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage. PMID- 26020941 TI - Effects of Biochar Addition on CO2 and N2O Emissions following Fertilizer Application to a Cultivated Grassland Soil. AB - Carbon (C) sequestration potential of biochar should be considered together with emission of greenhouse gases when applied to soils. In this study, we investigated CO2 and N2O emissions following the application of rice husk biochars to cultivated grassland soils and related gas emissions tos oil C and nitrogen (N) dynamics. Treatments included biochar addition (CHAR, NO CHAR) and amendment (COMPOST, UREA, NO FERT). The biochar application rate was 0.3% by weight. The temporal pattern of CO2 emissions differed according to biochar addition and amendments. CO2 emissions from the COMPOST soils were significantly higher than those from the UREA and NO FERT soils and less CO2 emission was observed when biochar and compost were applied together during the summer. Overall N2O emission was significantly influenced by the interaction between biochar and amendments. In UREA soil, biochar addition increased N2O emission by 49% compared to the control, while in the COMPOST and NO FERT soils, biochar did not have an effect on N2O emission. Two possible mechanisms were proposed to explain the higher N2O emissions upon biochar addition to UREA soil than other soils. Labile C in the biochar may have stimulated microbial N mineralization in the C-limited soil used in our study, resulting in an increase in N2O emission. Biochar may also have provided the soil with the ability to retain mineral N, leading to increased N2O emission. The overall results imply that biochar addition can increase C sequestration when applied together with compost, and might stimulate N2O emission when applied to soil amended with urea. PMID- 26020939 TI - Staphylococcus aureus Bloodstream Infection and Endocarditis--A Prospective Cohort Study. AB - OBJECTIVES: To update the epidemiology of S. aureus bloodstream infection (SAB) in a high-income country and its link with infective endocarditis (IE). METHODS: All consecutive adult patients with incident SAB (n = 2008) were prospectively enrolled between 2009 and 2011 in 8 university hospitals in France. RESULTS: SAB was nosocomial in 54%, non-nosocomial healthcare related in 18% and community acquired in 26%. Methicillin resistance was present in 19% of isolates. SAB Incidence of nosocomial SAB was 0.159/1000 patients-days of hospitalization (95% confidence interval [CI] 0.111-0.219). A deep focus of infection was detected in 37%, the two most frequent were IE (11%) and pneumonia (8%). The higher rates of IE were observed in injecting drug users (IE: 38%) and patients with prosthetic (IE: 33%) or native valve disease (IE: 20%) but 40% of IE occurred in patients without heart disease nor injecting drug use. IE was more frequent in case of community-acquired (IE: 21%, adjusted odds-ratio (aOR) = 2.9, CI = 2.0-4.3) or non-nosocomial healthcare-related SAB (IE: 12%, aOR = 2.3, CI = 1.4-3.5). S. aureus meningitis (IE: 59%), persistent bacteremia at 48 hours (IE: 25%) and C reactive protein > 190 mg/L (IE: 15%) were also independently associated with IE. Criteria for severe sepsis or septic shock were met in 30% of SAB without IE (overall in hospital mortality rate 24%) and in 51% of IE (overall in hospital mortality rate 35%). CONCLUSION: SAB is still a severe disease, mostly related to healthcare in a high-income country. IE is the most frequent complication and occurs frequently in patients without known predisposing conditions. PMID- 26020940 TI - The Nutrient-Responsive Hormone CCHamide-2 Controls Growth by Regulating Insulin like Peptides in the Brain of Drosophila melanogaster. AB - The coordination of growth with nutritional status is essential for proper development and physiology. Nutritional information is mostly perceived by peripheral organs before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and the failure of endocrine regulation in humans can cause diseases including obesity and diabetes. In Drosophila melanogaster, the fat body (adipose tissue) has been suggested to play an important role in coupling growth with nutritional status. Here, we show that the peripheral tissue-derived peptide hormone CCHamide-2 (CCHa2) acts as a nutrient-dependent regulator of Drosophila insulin-like peptides (Dilps). A BAC-based transgenic reporter revealed strong expression of CCHa2 receptor (CCHa2-R) in insulin-producing cells (IPCs) in the brain. Calcium imaging of brain explants and IPC-specific CCHa2-R knockdown demonstrated that peripheral-tissue derived CCHa2 directly activates IPCs. Interestingly, genetic disruption of either CCHa2 or CCHa2-R caused almost identical defects in larval growth and developmental timing. Consistent with these phenotypes, the expression of dilp5, and the release of both Dilp2 and Dilp5, were severely reduced. Furthermore, transcription of CCHa2 is altered in response to nutritional levels, particularly of glucose. These findings demonstrate that CCHa2 and CCHa2-R form a direct link between peripheral tissues and the brain, and that this pathway is essential for the coordination of systemic growth with nutritional availability. A mammalian homologue of CCHa2-R, Bombesin receptor subtype-3 (Brs3), is an orphan receptor that is expressed in the islet beta-cells; however, the role of Brs3 in insulin regulation remains elusive. Our genetic approach in Drosophila melanogaster provides the first evidence, to our knowledge, that bombesin receptor signaling with its endogenous ligand promotes insulin production. PMID- 26020942 TI - The effect of the underlying distribution in Hurst exponent estimation. AB - In this paper, a heavy-tailed distribution approach is considered in order to explore the behavior of actual financial time series. We show that this kind of distribution allows to properly fit the empirical distribution of the stocks from S&P500 index. In addition to that, we explain in detail why the underlying distribution of the random process under study should be taken into account before using its self-similarity exponent as a reliable tool to state whether that financial series displays long-range dependence or not. Finally, we show that, under this model, no stocks from S&P500 index show persistent memory, whereas some of them do present anti-persistent memory and most of them present no memory at all. PMID- 26020943 TI - Whole Transcriptome of the Venom Gland from Urodacus yaschenkoi Scorpion. AB - Australian scorpion venoms have been poorly studied, probably because they do not pose an evident threat to humans. In addition, the continent has other medically important venomous animals capable of causing serious health problems. Urodacus yaschenkoi belongs to the most widely distributed family of Australian scorpions (Urodacidae) and it is found all over the continent, making it a useful model system for studying venom composition and evolution. This communication reports the whole set of mRNA transcripts produced by the venom gland. U. yaschenkoi venom is as complex as its overseas counterparts. These transcripts certainly code for several components similar to known scorpion venom components, such as: alpha-KTxs, beta-KTxs, calcins, protease inhibitors, antimicrobial peptides, sodium-channel toxins, toxin-like peptides, allergens, La1-like, hyaluronidases, ribosomal proteins, proteasome components and proteins related to cellular processes. A comparison with the venom gland transcriptome of Centruroides noxius (Buthidae) showed that these two scorpions have similar components related to biological processes, although important differences occur among the venom toxins. In contrast, a comparison with sequences reported for Urodacus manicatus revealed that these two Urodacidae species possess the same subfamily of scorpion toxins. A comparison with sequences of an U. yaschenkoi cDNA library previously reported by our group showed that both techniques are reliable for the description of the venom components, but the whole transcriptome generated with Next Generation Sequencing platform provides sequences of all transcripts expressed. Several of which were identified in the proteome, but many more transcripts were identified including uncommon transcripts. The information reported here constitutes a reference for non-Buthidae scorpion venoms, providing a comprehensive view of genes that are involved in venom production. Further, this work identifies new putative bioactive compounds that could be used to seed research into new pharmacological compounds and increase our understanding of the function of different ion channels. PMID- 26020944 TI - Acute sirolimus overdose: a multicenter case series. AB - BACKGROUND: There are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013. METHODS: An observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose. RESULTS: Five cases of acute sirolimus overdose were reported--three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range. CONCLUSIONS: Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed. PMID- 26020945 TI - Inheritance and QTL Mapping of Leaf Nutrient Concentration in a Cotton Inter Specific Derived RIL Population. AB - Developing and deploying cotton cultivars with high nutrient uptake, use efficiency and tolerance to nutrient related soil stresses is desirable to assist sustainable soil management. Genetic variation, heritability, selection response and quantitative trait loci (QTLs) were investigated for five macronutrients (P, K, Ca, Mg, S) and five micronutrients (Fe, Mn, B, Zn, and Cu) in a recombinant inbred line (RIL) population from an inter-specific cross between Gossypium hirsutum cv. Guazuncho 2, and G. barbadense accession VH8-4602. Na and K/Na ratio were also studied as the imbalance between Na and other nutrients is detrimental to cotton growth and development. The concentrations of nutrients were measured for different plant parts of the two parents and for leaf samples of the whole population collected at early to peak flowering in field experiments over two years in a sodic Vertosol soil. Parental contrast was large for most nutrient concentrations in leaves when compared with other plant parts. Segregation for leaf nutrient concentration was observed within the population with transgression for P, K, K/Na ratio and all micronutrients. Genotypic difference was the major factor behind within-population variation for most nutrients, while narrow sense heritability was moderate (0.27 for Mn and Cu, and 0.43 for B). At least one significant QTL was identified for each nutrient except K and more than half of those QTLs were clustered on chromosomes 14, 18 and 22. Selection response was predicted to be low for P and all micronutrients except B, high for K, Na and B, and very high for K/Na ratio. Correlations were more common between macronutrients, Na and K/Na ratio where the nature and strength of the relations varied (r=-0.69 to 0.76). We conclude that there is sufficient genetic diversity between these two tetraploid cotton species that could be exploited to improve cotton nutrient status by introgressing species-unique favourable alleles. PMID- 26020946 TI - Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap. AB - Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including "vascular disease," "disorder of artery," and "occlusion of artery," as well as disease-related cellular functions including "cellular movement" and "cellular growth and proliferation." In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE /- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall. PMID- 26020947 TI - Circulating MiRNAs of 'Asian Indian Phenotype' Identified in Subjects with Impaired Glucose Tolerance and Patients with Type 2 Diabetes. AB - Several omics technologies are underway worldwide with an aim to unravel the pathophysiology of a complex phenotype such as type 2 diabetes mellitus (T2DM). While recent studies imply a clinically relevant and potential biomarker role of circulatory miRNAs in the etiology of T2DM, there is lack of data on this aspect in Indians--an ethnic population characterized to represent 'Asian Indian phenotype' known to be more prone to develop T2DM and cardiovascular disease than Europeans. We performed global serum miRNA profiling and the validation of candidate miRNAs by qRT-PCR in a cohort of subjects comprised of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and patients with T2DM. Our study revealed 4 differentially expressed miRNAs (miR-128, miR-130b-3p, miR-374a 5p, miR-423-5p) in subjects with IGT and T2DM patients compared to control subjects. They were positively or negatively correlated to cholesterol levels, HbA1C, HOMA-IR and fasting insulin. Interestingly, circulating level of miR-128 and miR-130b-3p were also altered in serum of diet-induced diabetic mice compared to control animals. Among the altered circulating miRNAs, miR-128 had never been described in previous studies/populations and appeared to be a 'New Lead' in Indians. It was positively correlated with cholesterol both in prediabetic subjects and in diet-induced diabetic mice, suggesting that its increased level might be associated with the development of dyslipedemia associated with T2DM. Our findings imply directionality towards biomarker potential of miRNAs in the prevention/diagnosis/treatment outcomes of diabetes. PMID- 26020948 TI - Epidemiology and clinical features of pulmonary nontuberculous mycobacteriosis in Nagasaki, Japan. AB - BACKGROUND AND OBJECTIVES: Recent reports indicate that the incidence of nontuberculous mycobacterial-lung disease (NTM-LD) is increasing. This study aimed to investigate the epidemiology and clinical features of NTM-LD patients in Nagasaki prefecture, Japan to identify the negative prognostic factors for NTM-LD in Japan. METHODS: The medical records of patients newly diagnosed with NTM-LD in eleven hospitals in Nagasaki prefecture between January 2001 and February 2010 were reviewed. Data regarding the annual population of each region and the incidence of all forms of tuberculosis were collected to assess geographic variations in NTM-LD incidence, isolates, and radiological features. RESULTS: A total 975 patients were diagnosed with NTM-LD. The incidence increased over the study period and reached 11.0 and 10.1 per 100,000 population in 2008 and 2009, respectively. M. intracellulare was the most common pathogen in the southern region, and M. avium most common in other regions. The most common radiographic pattern was the nodular-bronchiectatic pattern. Age >60 years, body mass index <18.5 kg/m2, underlying lung disease, and cavitary pattern were the negative prognostic factors at the 1-year follow-up. CONCLUSIONS: The incidence of NTM-LD has been increasing in Nagasaki prefecture. The isolates and radiographic features of patients vary markedly by region. PMID- 26020951 TI - Correction: Functional Characterization of the Chlamydomonas reinhardtii ERG3 Ortholog, a Gene Involved in the Biosynthesis of Ergosterol. PMID- 26020950 TI - Surgical versus non-surgical treatment for vertebral compression fracture with osteopenia: a systematic review and meta-analysis. AB - BACKGROUND: Surgical and non-surgical interventions are the two categories for treatment of vertebral compression fractures (VCFs). However, there is clinical uncertainty over optimal management. This study aimed to examine the safety and effectiveness of surgical management for treatment of VCFs with osteopenia compared with non-surgical treatment. METHODS: We conducted a systematic search through electronic databases from inception to June 2014, with no limits on study data or language. Randomized controlled trials (RCTs) evaluating surgical versus non-surgical interventions for treatment of patients with VCFs due to osteopenia were considered. Primary outcomes were pain and adverse effects. A random-effects model was used to calculate the pooled mean difference (MD) or risk ratios with 95% confidence interval (CI). RESULTS: Sixteen reports (11 studies) met the inclusion criteria, and provided data for the meta-analysis with a total of 1,401 participants. Compared with conservative treatment, surgical treatment was more effective in reducing pain (short-term: MD -2.05, 95% CI -3.55 to -0.56, P=0.007; mid-term: MD -1.70, 95% CI -2.78 to -0.62, P=0.002; long-term: MD -1.24, 95% CI 2.20 to -0.29, P=0.01) and disability on the Roland-Morris Disability score (short-term: MD -4.97, 95% CI -8.71 to -1.23, P=0.009), as well as improving quality of life on the Short-Form 36 Physical Component Summary score (short term: MD 5.53, 95% CI 1.45 to 9.61, P=0.008) and the Quality of Life Questionnaire of the European Foundation for Osteoporosis score (short-term: MD 5.01, 95% CI -8.11 to -1.91, P=0.002). Indirect comparisons between vertebroplasty and kyphoplasty found no evidence that the treatment effect differed across the two interventions for any outcomes assessed. Compared with the sham procedure, surgical treatment showed no evidence of improvement in pain relief and physical function. Based on these two comparisons, no significant difference between groups was noted in the pooled results for adverse events. CONCLUSION: Compared to conservative treatment, surgical treatment was more effective in decreasing pain in the short,mid and long terms. However, no significant mid- and long-term differences in physical function and quality of life was observed. Little good evidence is available for surgical treatment compared with that for sham procedure. PV and BK are currently used to treat VCFs with osteopenia, with little difference in treatment effects. Evidence of better quality and from a larger sample size is required before a recommendation can be made. SYSTEMATIC REVIEW REGISTRATION: http://www.crd.york.ac.uk/PROSPERO PROSPERO registration number: CRD42013005142. PMID- 26020949 TI - Risk of Severe Non AIDS Events Is Increased among Patients Unable to Increase their CD4+ T-Cell Counts >200+/MUl Despite Effective HAART. AB - BACKGROUND: Immunological non-response (INR) despite virological suppression is associated with AIDS-defining events/death (ADE). Little is known about its association with serious non-AIDS-defining events (nADE). METHODS: Patients highly-active antiretroviral therapy (HAART) with <200 CD4+/MUl and achieving HIV RNA <50 copies/ml within 12 (+/-3) months were categorized as INR if CD4+ T-cell count at year 1 was <200/MUl. Predictors of nADE (malignancies, severe infections, renal failure--ie, estimated glomerular filtration rate <30 ml/min, cardiovascular events and liver decompensation) were assessed using multivariable Cox models. Follow-up was right-censored in case of HAART discontinuation or confirmed HIV-RNA>50. RESULTS: 1221 patients were observed for a median of 3 (IQR: 1.3-6.1) years. Pre-HAART CD4+ were 77/MUl (IQR: 28-142) and 56% of patients had experienced an ADE. After 1 year, CD4+ increased to 286 (IQR: 197 387), but 26.1% of patients were INR. Thereafter, 86 nADE (30.2% malignancies, 27.9% infectious, 17.4% renal, 17.4% cardiovascular, 7% hepatic) were observed, accounting for an incidence of 1.83 events (95%CI: 1.73-2.61) per 100 PYFU. After adjusting for measurable confounders, INR had a significantly greater risk of nADE (HR 1.65; 95%CI: 1.06-2.56). Older age (per year, HR 1.03; 95%CI: 1.01 1.05), hepatitis C co-infection (HR 2.09; 95%CI: 1.19-3.7), a history of previous nADE (HR 2.16; 95%CI: 1.06-4.4) and the occurrence of ADE during the follow-up (HR 2.2; 95%CI: 1.15-4.21) were other independent predictors of newly diagnosed nADE. CONCLUSIONS: Patients failing to restore CD4+ to >200 cells/MUl run a greater risk of serious nADE, which is intertwined or predicted by AIDS progression. Improved management of this fragile population and innovative therapy able to induce immune-reconstitution are urgently needed. Also, our results strengthen the importance of earlier diagnosis and HAART introduction. PMID- 26020952 TI - Accurate prediction of immunogenic T-cell epitopes from epitope sequences using the genetic algorithm-based ensemble learning. AB - BACKGROUND: T-cell epitopes play the important role in T-cell immune response, and they are critical components in the epitope-based vaccine design. Immunogenicity is the ability to trigger an immune response. The accurate prediction of immunogenic T-cell epitopes is significant for designing useful vaccines and understanding the immune system. METHODS: In this paper, we attempt to differentiate immunogenic epitopes from non-immunogenic epitopes based on their primary structures. First of all, we explore a variety of sequence-derived features, and analyze their relationship with epitope immunogenicity. To effectively utilize various features, a genetic algorithm (GA)-based ensemble method is proposed to determine the optimal feature subset and develop the high accuracy ensemble model. In the GA optimization, a chromosome is to represent a feature subset in the search space. For each feature subset, the selected features are utilized to construct the base predictors, and an ensemble model is developed by taking the average of outputs from base predictors. The objective of GA is to search for the optimal feature subset, which leads to the ensemble model with the best cross validation AUC (area under ROC curve) on the training set. RESULTS: Two datasets named 'IMMA2' and 'PAAQD' are adopted as the benchmark datasets. Compared with the state-of-the-art methods POPI, POPISK, PAAQD and our previous method, the GA-based ensemble method produces much better performances, achieving the AUC score of 0.846 on IMMA2 dataset and the AUC score of 0.829 on PAAQD dataset. The statistical analysis demonstrates the performance improvements of GA-based ensemble method are statistically significant. CONCLUSIONS: The proposed method is a promising tool for predicting the immunogenic epitopes. The source codes and datasets are available in S1 File. PMID- 26020953 TI - Hepatitis B Vaccines and HPV Vaccines Have Been Hailed as Major Public Health Achievements in Preventing Cancer--Could a Schistosomiasis Vaccine be the Third? PMID- 26020954 TI - Immunological Basis for Rapid Progression of Diabetes in Older NOD Mouse Recipients Post BM-HSC Transplantation. AB - Type I diabetes (T1D), mediated by autoreactive T cell destruction of insulin producing islet beta cells, has been treated with bone marrow-derived hematopoietic stem cell (BM-HSC) transplantation. Older non-obese diabetic (NOD) mice recipients (3m, at disease-onset stage) receiving syngeneic BM-HSC progressed more rapidly to end-stage diabetes post-transplantation than younger recipients (4-6w, at disease-initiation stage). FACS analyses showed a higher percentage and absolute number of regulatory T cells (Treg) and lower proportion of proliferating T conventional cells (Tcon) in pancreatic lymph nodes from the resistant mice among the younger recipients compared to the rapid progressors among the older recipients. Treg distribution in spleen, mesenteric lymph nodes (MLN), blood and thymus between the two groups was similar. However, the percentage of thymic Tcon and the proliferation of Tcon in MLN and blood were lower in the young resistants. These results suggest recipient age and associated disease stage as a variable to consider in BM-HSC transplantation for treating T1D. PMID- 26020955 TI - Proteomic insight into the molecular function of the vitreous. AB - The human vitreous contains primarily water, but also contains proteins which have yet to be fully characterized. To gain insight into the four vitreous substructures and their potential functions, we isolated and analyzed the vitreous protein profiles of three non-diseased human eyes. The four analyzed substructures were the anterior hyaloid, the vitreous cortex, the vitreous core, and the vitreous base. Proteins were separated by multidimensional liquid chromatography and identified by tandem mass spectrometry. Bioinformatics tools then extracted the expression profiles, signaling pathways, and interactomes unique to each tissue. From each substructure, a mean of 2,062 unique proteins were identified, with many being differentially expressed in a specific substructure: 278 proteins were unique to the anterior hyaloid, 322 to the vitreous cortex, 128 to the vitreous base, and 136 to the vitreous core. When the identified proteins were organized according to relevant functional pathways and networks, key patterns appeared. The blood coagulation pathway and extracellular matrix turnover networks were highly represented. Oxidative stress regulation and energy metabolism proteins were distributed throughout the vitreous. Immune functions were represented by high levels of immunoglobulin, the complement pathway, damage-associated molecular patterns (DAMPs), and evolutionarily conserved antimicrobial proteins. The majority of vitreous proteins detected were intracellular proteins, some of which originate from the retina, including rhodopsin (RHO), phosphodiesterase 6 (PDE6), and glial fibrillary acidic protein (GFAP). This comprehensive analysis uncovers a picture of the vitreous as a biologically active tissue, where proteins localize to distinct substructures to protect the intraocular tissues from infection, oxidative stress, and energy disequilibrium. It also reveals the retina as a potential source of inflammatory mediators. The vitreous proteome catalogues the dynamic interactions between the vitreous and surrounding tissues. It therefore could be an indirect and effective method for surveying vitreoretinal disease for specific biomarkers. PMID- 26020956 TI - The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering. AB - We and others have published on the rapid manufacture of micropellet tissues, typically formed from 100-500 cells each. The micropellet geometry enhances cellular biological properties, and in many cases the micropellets can subsequently be utilized as building blocks to assemble complex macrotissues. Generally, micropellets are formed from cells alone, however when replicating matrix-rich tissues such as cartilage it would be ideal if matrix or biomaterials supplements could be incorporated directly into the micropellet during the manufacturing process. Herein we describe a method to efficiently incorporate donor cartilage matrix into tissue engineered cartilage micropellets. We lyophilized bovine cartilage matrix, and then shattered it into microscopic pieces having average dimensions < 10 MUm diameter; we termed this microscopic donor matrix "cartilage dust (CD)". Using a microwell platform, we show that ~0.83 MUg CD can be rapidly and efficiently incorporated into single multicellular aggregates formed from 180 bone marrow mesenchymal stem/stromal cells (MSC) each. The microwell platform enabled the rapid manufacture of thousands of replica composite micropellets, with each micropellet having a material/CD core and a cellular surface. This micropellet organization enabled the rapid bulking up of the micropellet core matrix content, and left an adhesive cellular outer surface. This morphological organization enabled the ready assembly of the composite micropellets into macroscopic tissues. Generically, this is a versatile method that enables the rapid and uniform integration of biomaterials into multicellular micropellets that can then be used as tissue building blocks. In this study, the addition of CD resulted in an approximate 8 fold volume increase in the micropellets, with the donor matrix functioning to contribute to an increase in total cartilage matrix content. Composite micropellets were readily assembled into macroscopic cartilage tissues; the incorporation of CD enhanced tissue size and matrix content, but did not enhance chondrogenic gene expression. PMID- 26020957 TI - Cyclophilin J is a novel peptidyl-prolyl isomerase and target for repressing the growth of hepatocellular carcinoma. AB - Cyclophilin J (CYPJ) is a new member of the peptidyl-prolyl cis/trans-isomerase (PPIase) identified with upregulated expression in human glioma. However, the biological function of CYPJ remained unclear. We aimed to study the role of CYPJ in hepatocellular carcinoma (HCC) carcinogenesis and its therapeutic potential. We determined the expression of CYPJ in HCC/adjacent normal tissues using Western blot, Northern blot and semi-quantitative RT-PCR, analyzed the biochemical characteristics of CYPJ, and resolved the 3D-structure of CYPJ/Cyclosporin A (CsA) complex. We also studied the roles of CYPJ in cell cycle, cyclin D1 regulation, in vitro and in vivo tumor growth. We found that CYPJ expression was upregulated in over 60% HCC tissues. The PPIase activity of CYPJ could be inhibited by the widely used immunosuppressive drug CsA. CYPJ was found expressed in the whole cell of HCC with preferential location at the cell nucleus. CYPJ promoted the transition of cells from G1 phase to S phase in a PPIase-dependent manner by activating cyclin D1 promoter. CYPJ overexpression accelerated liver cell growth in vitro (cell growth assay, colony formation) and in vivo (xenograft tumor formation). Inhibition of CYPJ by its inhibitor CsA or CYPJ-specific RNAi diminished the growth of liver cancer cells in vitro and in vivo. In conclusion, CYPJ could facilitate HCC growth by promoting cell cycle transition from G1 to S phase through the upregulation of cyclin D1. Suppression of CYPJ could repress the growth of HCC, which makes CYPJ a potential target for the development of new strategies to treat this malignancy. PMID- 26020958 TI - A Systematic Study on Tooth Enamel Microstructures of Lambdopsalis bulla (Multituberculate, Mammalia)--Implications for Multituberculate Biology and Phylogeny. AB - Tooth enamel microstructure is a reliable and widely used indicator of dietary interpretations and data for phylogenetic reconstruction, if all levels of variability are investigated. It is usually difficult to have a thorough examination at all levels of enamel structures for any mammals, especially for the early mammals, which are commonly represented by sparse specimens. Because of the random preservation of specimens, enamel microstructures from different teeth in various species are often compared. There are few examples that convincingly show intraspecific variation of tooth enamel microstructure in full dentition of a species, including multituberculates. Here we present a systematic survey of tooth enamel microstructures of Lambdopsalis bulla, a taeniolabidoid multituberculate from the Late Paleocene Nomogen Formation, Inner Mongolia. We examined enamel structures at all hierarchical levels. The samples are treated differently in section orientations and acid preparation and examined using different imaging methods. The results show that, except for preparation artifacts, the crystallites, enamel types, Schmelzmuster and dentition types of Lambdopsalis are relatively consistent in all permanent teeth, but the prism type, including the prism shape, size and density, may vary in different portions of a single tooth or among different teeth of an individual animal. The most common Schmelzmuster of the permanent teeth in Lambdopsalis is a combination of radial enamel in the inner and middle layers, aprismatic enamel in the outer layer, and irregular decussations in tooth crown area with great curvature. The prism seam is another comparably stable characteristic that may be a useful feature for multituberculate taxonomy. The systematic documentation of enamel structures in Lambdopsalis may be generalized for the enamel microstructure study, and thus for taxonomy and phylogenetic reconstruction, of multituberculates and even informative for the enamel study of other early mammals. PMID- 26020959 TI - Admixture in Humans of Two Divergent Plasmodium knowlesi Populations Associated with Different Macaque Host Species. AB - Human malaria parasite species were originally acquired from other primate hosts and subsequently became endemic, then spread throughout large parts of the world. A major zoonosis is now occurring with Plasmodium knowlesi from macaques in Southeast Asia, with a recent acceleration in numbers of reported cases particularly in Malaysia. To investigate the parasite population genetics, we developed sensitive and species-specific microsatellite genotyping protocols and applied these to analysis of samples from 10 sites covering a range of >1,600 km within which most cases have occurred. Genotypic analyses of 599 P. knowlesi infections (552 in humans and 47 in wild macaques) at 10 highly polymorphic loci provide radical new insights on the emergence. Parasites from sympatric long tailed macaques (Macaca fascicularis) and pig-tailed macaques (M. nemestrina) were very highly differentiated (FST = 0.22, and K-means clustering confirmed two host-associated subpopulations). Approximately two thirds of human P. knowlesi infections were of the long-tailed macaque type (Cluster 1), and one third were of the pig-tailed-macaque type (Cluster 2), with relative proportions varying across the different sites. Among the samples from humans, there was significant indication of genetic isolation by geographical distance overall and within Cluster 1 alone. Across the different sites, the level of multi-locus linkage disequilibrium correlated with the degree of local admixture of the two different clusters. The widespread occurrence of both types of P. knowlesi in humans enhances the potential for parasite adaptation in this zoonotic system. PMID- 26020960 TI - Quantitative Analysis of Torso FDG-PET Scans by Using Anatomical Standardization of Normal Cases from Thorough Physical Examinations. AB - Understanding of standardized uptake value (SUV) of 2-deoxy-2-[18F]fluoro-d glucose positron emission tomography (FDG-PET) depends on the background accumulations of glucose because the SUV often varies the status of patients. The purpose of this study was to develop a new method for quantitative analysis of SUV of FDG-PET scan images. The method included an anatomical standardization and a statistical comparison with normal cases by using Z-score that are often used in SPM or 3D-SSP approach for brain function analysis. Our scheme consisted of two approaches, which included the construction of a normal model and the determination of the SUV scores as Z-score index for measuring the abnormality of an FDG-PET scan image. To construct the normal torso model, all of the normal images were registered into one shape, which indicated the normal range of SUV at all voxels. The image deformation process consisted of a whole body rigid registration of shoulder to bladder region and liver registration and a non linear registration of body surface by using the thin-plate spline technique. In order to validate usefulness of our method, we segment suspicious regions on FDG PET images manually, and obtained the Z-scores of the regions based on the corresponding voxels that stores the mean and the standard deviations from the normal model. We collected 243 (143 males and 100 females) normal cases to construct the normal model. We also extracted 432 abnormal spots from 63 abnormal cases (73 cancer lesions) to validate the Z-scores. The Z-scores of 417 out of 432 abnormal spots were higher than 2.0, which statistically indicated the severity of the spots. In conclusions, the Z-scores obtained by our computerized scheme with anatomical standardization of torso region would be useful for visualization and detection of subtle lesions on FDG-PET scan images even when the SUV may not clearly show an abnormality. PMID- 26020961 TI - Semen characteristics of purebred and crossbred male rabbits. AB - The aim of this investigation was to evaluate the semen quality traits of purebred male rabbits and their crosses under subtropical Egyptian conditions. A full 3 x 3 diallel crossing was performed for producing the first generation progeny of New Zealand White (N), Flander (F) and Rex (R) breeds. The highest ejaculate volume (p< 0.05) and percentage of live sperms (p<0.01) with the lowest percentage of sperm cell morphological abnormalities (p<0.05) had been recorded in the NF bucks. Moreover, they possessed positive estimates of direct heterosis for ejaculate volume, mass motility (Mm), individual motility (Im) and sperm cell concentration (SCC). On the contrary, pH had negative estimates of direct heterosis in all crosses and their reciprocal. Semen pH was negatively correlated with SCC (r = -0.18), Mm (r = -0.13) and Im (r = -0.23). In conclusion, the superiority of crossbreeding was particularly obvious in the New Zealand White x Flander males, which cumulated heterosis and favorable maternal effects of the Flander dams. PMID- 26020964 TI - Correction: Physical Warmth and Perceptual Focus: A Replication of IJzerman and Semin (2009). PMID- 26020962 TI - Dietary Vitamin D3 Restriction Exacerbates Disease Pathophysiology in the Spinal Cord of the G93A Mouse Model of Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Dietary vitamin D3 (D3) restriction reduces paw grip endurance and motor performance in G93A mice, and increases inflammation and apoptosis in the quadriceps of females. ALS, a neuromuscular disease, causes progressive degeneration of motor neurons in the brain and spinal cord. OBJECTIVE: We analyzed the spinal cords of G93A mice following dietary D3 restriction at 2.5% the adequate intake (AI) for oxidative damage (4-HNE, 3-NY), antioxidant enzymes (SOD2, catalase, GPx1), inflammation (TNF-alpha, IL-6, IL-10), apoptosis (bax/bcl 2 ratio, cleaved/pro-caspase 3 ratio), neurotrophic factor (GDNF) and neuron count (ChAT, SMI-36/SMI-32 ratio). METHODS: Beginning at age 25 d, 42 G93A mice were provided food ad libitum with either adequate (AI;1 IU D3/g feed; 12 M, 11 F) or deficient (DEF; 0.025 IU D3/g feed; 10 M, 9 F) D3. At age 113 d, the spinal cords were analyzed for protein content. Differences were considered significant at P <= 0.10, since this was a pilot study. RESULTS: DEF mice had 16% higher 4 HNE (P = 0.056), 12% higher GPx1 (P = 0.057) and 23% higher Bax/Bcl2 ratio (P = 0.076) vs. AI. DEF females had 29% higher GPx1 (P = 0.001) and 22% higher IL-6 (P = 0.077) vs. AI females. DEF males had 23% higher 4-HNE (P = 0.066) and 18% lower SOD2 (P = 0.034) vs. AI males. DEF males had 27% lower SOD2 (P = 0.004), 17% lower GPx1 (P = 0.070), 29% lower IL-6 (P = 0.023) and 22% lower ChAT (P = 0.082) vs. DEF females. CONCLUSION: D3 deficiency exacerbates disease pathophysiology in the spinal cord of G93A mice, the exact mechanisms are sex-specific. This is in accord with our previous results in the quadriceps, as well as functional and disease outcomes. PMID- 26020965 TI - Yield responses of wheat to mulching practices in dryland farming on the Loess Plateau. AB - Improving farming practices of soil and water conservation has profound effects on the yield of wheat (Triticum aestivum L.) in dryland farming regions of the Loess Plateau in China. Mulching has proven to be an effective practice to increase crop yield, and possibly contribute to replenishing groundwater. This evaluation study collected and analyzed the data of 1849 observations published in 38 papers using meta-analysis to investigate effects of the mulching practices on wheat yield in terms of different rainfall and regions in comparison with conventional tillage. The main results of the study follow. The effects of the mulching practices were ranked in the order of RFM (ridge-furrow mulching) > MTMC (mulching with two materials combined) > MOM (mulching with other materials) > WSM (wheat straw mulching) > FM (flat mulching). The effects of the mulching practices at the different levels of rainfall during the wheat growing season were in the order: (< 150 mm) > (> 250 mm) > (150-250 mm). The effects of the mulching practices in the different regions were in the order of Henan > Shanxi > Shaanxi > Gansu. WSM, MTMC and FM performed better in improving wheat yield for rainfall of < 150, 150-250 and > 250 mm during the growing season, respectively. The wheat yield with FM, MTMC, MOM and MOM was higher than those with the other mulching practices in Shaanxi, Gansu, Henan and Shanxi. The wheat yield with RFM was 27.4% higher than that with FM, indicating that RFM was the most effective practice to improve wheat yield among all the practices. These findings have important implications for choosing appropriate crop field management to improve wheat yield. PMID- 26020963 TI - Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle. AB - Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIalpha) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIalpha levels across the sleep wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIalpha during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring. PMID- 26020966 TI - Validity of antibodies in lymphocyte supernatant in diagnosing tuberculosis in severely malnourished children presenting with pneumonia. AB - BACKGROUND: The diagnosis of tuberculosis (TB) in young children can be challenging, especially in severely malnourished children. There is a critical need for improved diagnostics for children. Thus, we sought to evaluate the performance of a technique that measures antibodies in lymphocyte supernatant (ALS) for the diagnosis of TB in severely malnourished children presenting with suspected pneumonia. METHODS: Children less than 5 years with severe acute malnutrition and radiological features of pneumonia admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh, were enrolled consecutively following informed written consent. In addition to clinical and radiological assessment, samples taken for TB diagnosis included gastric lavage fluid and induced sputum for microbiological confirmation. ALS was measured from venous blood, and results were evaluated in children classified as "confirmed", "non-confirmed TB" or "not TB". RESULTS: Among 224 children who had ALS analysis, 12 (5.4%) children had microbiologically "confirmed TB", a further 41 (18%) had clinically diagnosed "non-confirmed TB" and the remaining 168 (75%) were considered not to have TB. ALS was positive in 89 (40%) and negative in 85 (39%) of children, with a large number (47 or 21%) reported as "borderline". These proportions were similar between the three diagnostic groups. The sensitivity and specificity of ALS when comparing "Confirmed TB" to "Not TB" was only 67% (95% CI: 31-91%) and 51% (95% CI: 42-60%), respectively. CONCLUSIONS AND SIGNIFICANCE: Our data suggest that ALS is not sufficiently accurate to improve the diagnosis of TB in children with severe malnutrition. PMID- 26020968 TI - Fossil and genetic evidence for the polyphyletic nature of the planktonic foraminifera "Globigerinoides", and description of the new genus Trilobatus. AB - Planktonic foraminifera are one of the most abundant and diverse protists in the oceans. Their utility as paleo proxies requires rigorous taxonomy and comparison with living and genetically related counterparts. We merge genetic and fossil evidence of "Globigerinoides", characterized by supplementary apertures on spiral side, in a new approach to trace their "total evidence phylogeny" since their first appearance in the latest Paleogene. Combined fossil and molecular genetic data indicate that this genus, as traditionally understood, is polyphyletic. Both datasets indicate the existence of two distinct lineages that evolved independently. One group includes "Globigerinoides" trilobus and its descendants, the extant "Globigerinoides" sacculifer, Orbulina universa and Sphaeroidinella dehiscens. The second group includes the Globigerinoides ruber clade with the extant G. conglobatus and G. elongatus and ancestors. In molecular phylogenies, the trilobus group is not the sister taxon of the ruber group. The ruber group clusters consistently together with the modern Globoturborotalita rubescens as a sister taxon. The re-analysis of the fossil record indicates that the first "Globigerinoides" in the late Oligocene are ancestral to the trilobus group, whereas the ruber group first appeared at the base of the Miocene with representatives distinct from the trilobus group. Therefore, polyphyly of the genus "Globigerinoides" as currently defined can only be avoided either by broadening the genus concept to include G. rubescens and a large number of fossil species without supplementary apertures, or if the trilobus group is assigned to a separate genus. Since the former is not feasible due to the lack of a clear diagnosis for such a broad genus, we erect a new genus Trilobatus for the trilobus group (type species Globigerina triloba Reuss) and amend Globoturborotalita and Globigerinoides to clarify morphology and wall textures of these genera. In the new concept, Trilobatus n. gen. is paraphyletic and gave rise to the Praeorbulina/Orbulina and Sphaeroidinellopsis/Sphaeroidinella lineages. PMID- 26020969 TI - Mapping spatial variability of soil salinity in a coastal paddy field based on electromagnetic sensors. AB - In coastal China, there is an urgent need to increase land area for agricultural production and urban development, where there is a rapid growing population. One solution is land reclamation from coastal tidelands, but soil salinization is problematic. As such, it is very important to characterize and map the within field variability of soil salinity in space and time. Conventional methods are often time-consuming, expensive, labor-intensive, and unpractical. Fortunately, proximal sensing has become an important technology in characterizing within field spatial variability. In this study, we employed the EM38 to study spatial variability of soil salinity in a coastal paddy field. Significant correlation relationship between ECa and EC1:5 (i.e. r >0.9) allowed us to use EM38 data to characterize the spatial variability of soil salinity. Geostatistical methods were used to determine the horizontal spatio-temporal variability of soil salinity over three consecutive years. The study found that the distribution of salinity was heterogeneous and the leaching of salts was more significant in the edges of the study field. By inverting the EM38 data using a Quasi-3D inversion algorithm, the vertical spatio-temporal variability of soil salinity was determined and the leaching of salts over time was easily identified. The methodology of this study can be used as guidance for researchers interested in understanding soil salinity development as well as land managers aiming for effective soil salinity monitoring and management practices. In order to better characterize the variations in soil salinity to a deeper soil profile, the deeper mode of EM38 (i.e., EM38v) as well as other EMI instruments (e.g. DUALEM-421) can be incorporated to conduct Quasi-3D inversions for deeper soil profiles. PMID- 26020967 TI - Survey of Microbial Diversity in Flood Areas during Thailand 2011 Flood Crisis Using High-Throughput Tagged Amplicon Pyrosequencing. AB - The Thailand flood crisis in 2011 was one of the largest recorded floods in modern history, causing enormous damage to the economy and ecological habitats of the country. In this study, bacterial and fungal diversity in sediments and waters collected from ten flood areas in Bangkok and its suburbs, covering residential and agricultural areas, were analyzed using high-throughput 454 pyrosequencing of 16S rRNA gene and internal transcribed spacer sequences. Analysis of microbial community showed differences in taxa distribution in water and sediment with variations in the diversity of saprophytic microbes and sulfate/nitrate reducers among sampling locations, suggesting differences in microbial activity in the habitats. Overall, Proteobacteria represented a major bacterial group in waters, while this group co-existed with Firmicutes, Bacteroidetes, and Actinobacteria in sediments. Anaeromyxobacter, Steroidobacter, and Geobacter were the dominant bacterial genera in sediments, while Sulfuricurvum, Thiovirga, and Hydrogenophaga predominated in waters. For fungi in sediments, Ascomycota, Glomeromycota, and Basidiomycota, particularly in genera Philipsia, Rozella, and Acaulospora, were most frequently detected. Chytridiomycota and Ascomycota were the major fungal phyla, and Rhizophlyctis and Mortierella were the most frequently detected fungal genera in water. Diversity of sulfate-reducing bacteria, related to odor problems, was further investigated using analysis of the dsrB gene which indicated the presence of sulfate-reducing bacteria of families Desulfobacteraceae, Desulfobulbaceae, Syntrobacteraceae, and Desulfoarculaceae in the flood sediments. The work provides an insight into the diversity and function of microbes related to biological processes in flood areas. PMID- 26020970 TI - The whole of a scientific career: an interview with Oliver Smithies. PMID- 26020971 TI - Influences of environmental factors on leaf morphology of Chinese jujubes. AB - Rainfall and temperature are the primary limiting factors for optimum quality and yield of cultivated jujube (Ziziphus jujuba Mill.). Adaptation to arid and cool environments has been and remains an important goal of many jujube improvement programs. This study summarized the survey results of 116 Chinese jujube varieties grown at 33 sites in China. The objective was to identify the environmental factors that influence leaf morphology, and the implications for breeding and introduction of new jujube varieties. Jujube leaf morphological traits were evaluated for their potential relationships with mean annual temperature (MAT) and mean annual precipitation (MAP). The results showed that many leaf morphological traits had a strong linear relationship with local precipitation and temperature. Longer veins per unit area (VLA) and reduced leaf area and leaf perimeter were typical of arid areas. VLA was inversely related to MAT and MAP at the centers of origin of jujube. There was a positive relationship between leaf shape (perimeter2/area) and both MAT and MAP. These results indicated that leaf vein traits of Chinese jujubes might have resulted from their adaptation to environmental factors in the course of long-term evolution. Principal component analysis allocated the 116 jujube varieties to three different groups, differentiated on the basis of morphological and physiological leaf characteristics. Jujube varieties from the Hebei, Shandong, Henan, southern Shanxi and central Shaanxi provinces were closely related, as were varieties from northwest Shanxi and northeast Shaanxi provinces, and varieties from the Gansu and Ningxia provinces. These close relationships were partially attributed to the frequent exchanges of varieties within each group. Leaf venation characteristics might be used as reference indices for jujube variety introduction between different locations. PMID- 26020974 TI - [17th colours of Sepsis, Ostrava]. PMID- 26020973 TI - [How to continue the provision care for serious injuries?]. PMID- 26020972 TI - AICAR Enhances the Phagocytic Ability of Macrophages towards Apoptotic Cells through P38 Mitogen Activated Protein Kinase Activation Independent of AMP Activated Protein Kinase. AB - Recent studies have suggested that 5-aminoimidazole-4-carboxamide-1-beta-D ribofuranoside (AICAR) increases macrophage phagocytosis through adenosine monophosphate-activated protein kinase (AMPK). However, little information is available on the effects of AICAR on the clearance of apoptotic cells by macrophages, known as efferocytosis, which is essential in maintaining tissue homeostasis and resolving inflammation. AICAR increased p38 MAPK activation and the phagocytosis of apoptotic cells by macrophages, which were inhibited by the p38 MAPK inhibitor, SB203580, the TGF-beta-activated kinase 1 (TAK1) inhibitor, (5Z)-7-oxozeaenol, and siRNA-mediated knock-down of p38alpha. AICAR increased phosphorylation of Akt, but the inhibition of PI3K/Akt activity using LY294002 did not affect the AICAR-induced changes in efferocytosis in macrophages. CGS15943, a non-selective adenosine receptor antagonist, did not affect AICAR induced changes in efferocytosis, but dipyridamole, an adenosine transporter inhibitor, diminished the AICAR-mediated increases in efferocytosis. AICAR induced p38 MAPK phosphorylation was not inhibited by the AMPK inhibitor, compound C, or siRNA-mediated knock-down of AMPKalpha1. Inhibition of AMPK using compound C or 5'-iodotubercidin did not completely block AICAR-mediated increases in efferocytosis. Furthermore, AICAR also increased the removal of apoptotic neutrophils or thymocytes in mouse lungs. These results reveal a novel mechanism by which AICAR increases macrophage-mediated phagocytosis of apoptotic cells and suggest that AICAR may be used to treat efferocytosis-related inflammatory conditions. PMID- 26020975 TI - Who will step up and lead community nurse drive? PMID- 26020976 TI - Need for more child epilepsy specialist nurses. PMID- 26020977 TI - [Man, life and death: term definition based on current knowledge of genetics and human embryology]. PMID- 26020978 TI - [Assessment of neurologic prognosis in adult patients]. PMID- 26020980 TI - [Not Available]. PMID- 26020979 TI - Crises and criticisms can only hit morale. PMID- 26020981 TI - [Melanoma and non-melanoma skin cancer]. PMID- 26020982 TI - [BRAF inhibitor and MEK inhibitor]. PMID- 26020983 TI - [An update on molecular pathology of melanocytic nerve and melanoma]. PMID- 26020984 TI - [Nivolumab for metastatic melanoma-basic knowledge and clinical data]. PMID- 26020986 TI - Proceedings and abstracts of an International Symposium, February 13-14, 2015, Okayama, Japan. PMID- 26020985 TI - [Ipilimub for advanced melanoma]. PMID- 26020987 TI - Proceedings of the 2nd International Physical Therapy Conference (IPTC) and the 2nd Physical Therapy Mahidol University Research Symposium (PTMURS), July 30- August 1, 2014. PMID- 26020988 TI - Saving the treatment. Affect intolerance in a boy, his parents, the mental health community, and his analyst. AB - Psychoanalytic thinkers have been writing about children's struggles with affect for many years (E. Furman, 1956; Katan, 1973; Chused, 1999; Gilmore, 2005). They have reported on mothers' inability to provide containment and fathers' use of physical punishment, attesting to their own affect intolerance and only making matters worse (Axelman, 2009; Bierman, Silverstein, Finesinger, 1958; Coen, 1998). So, what is different about this article? I'm certainly not the first to insist that we live in an affect-intolerant society, with many parents seeking psychotropic assistance rather than attempting to understand their children's feelings. Nor am I the only one who wags her finger at mental health professionals who freely prescribe. But there you have it. I am willing to report on my own countertransference--the villains who threatened to undermine my treatment with a boy named Joey. PMID- 26020989 TI - Discussion of Victoria Todd's paper. "Saving the treatment: affect intolerance in a boy, his parents, the mental health community, and his analyst". AB - D.W. Winnicott wrote, "One analyst cannot have enough cases to cover all contingencies..." (1958, p. 123). He was referring to the fact that any one analyst has a relatively small number of cases at any one time or even over a lifetime. He was talking then about termination, but his point applies to any issues. here we are grateful for detailed account of a case that offers to all of us additional experience of the successes and challenges of our work. PMID- 26020990 TI - Commentary on Victoria Todd's paper. Saving the treatment: affect intolerance in a boy, his parents, the mental health community, and his analyst". AB - Ms. Todd's paper illustrates both the value of the analytic frame and the relevance of a flexible approach in response to the external reality. In this case, the impingement of the outside environment became an ongoing threat to the analyst's thinking and to the development of a safe and predictable therapeutic relationship. Ms. Todd's narrative of Joey's three-and-a-half-year analysis emphasizes the impact of external interference on the analyst's capacity to experience difficult affects with and for the patient. In addition, it highlights the importance of recognizing and working through one's countertransference resistance. This commentary focuses on Ms. Todd's work with Joey, so I will only refer to her work with his parents and other providers as it is reflected in her analysis. PMID- 26020991 TI - "I want to be all gone". Psychoanalysis of a three-year-old failure-to-thrive child. AB - A three-year-old child said to me, "I want to be all gone." Because this very young child had the capacity to talk about and demonstrate her internal world, this case offered the opportunity to explore both her life-threatening symptoms and the underlying psychological conditions that informed these symptoms. This clinical paper explores aspects of her treatment. PMID- 26020992 TI - The scent of the other. AB - While there are many exchanges that take place during our early development, some have a more profound impact on our developmental trajectory than others. In the milieu of a disturbed mother-child dyad, what becomes of self and other object representations? How do the derivatives of trauma, neglect, and overstimulation become expressed and used during important life transitions? In this paper, convergent themes in the analysis of an eleven-year-old boy and a forty-year-old man illustrate how the evocative nature of smell was used as a means of holding on to early object ties and fantasies of a blissful union. I am proposing that by conceptualizing encopresis and the use of body odors as an expression of the individual's early trauma and object representations, we can advance our understanding of the tenacity of these symptoms and further develop appropriate and effective technical approaches. A select review of the literature is used to establish the relationship between earlier developmental phases and an internalization of early object relations relevant to this paper. PMID- 26020993 TI - Aggression and impulse control in the analysis of a young boy. AB - The analysis of a young boy with aggressive, impulsive problems is reported with an emphasis on technique. The step-by-step analytic work is reported to highlight the gradual emergence of the underlying function, determinants, and developmental context for such difficulties, which helped guide the analytic work. An important focus is on the analyst as a developmental as well as transference object, the use of nonverbal communication until interpretation could be tolerated, and the ways to facilitate the development of reflective function. Needing to address both conflict and developmental interference, the analyst was always guided by the level of mental organization when making interventions. The important work with the parents is also carefully described. PMID- 26020994 TI - Treating children with affect dysregulation. Discussion of Dr. Wendy Olesker's analysis of Matt. AB - This paper is a discussion of Dr. Wendy Olesker's sensitive analytic treatment of an impulsive, affectively dysregulated, preschool child. Drawing on her knowledge and understanding of developmental interference, trauma, and conflict, Dr. Olesker uses a variety of nonverbal, interpretative, developmental, and play techniques during the analysis to help this boy progress in his development. She also works with the parents collaboratively as part of the therapeutic process. Because Dr. Olesker's description of Matt might easily fit a diagnosis of Attention Deficit Hyperactivity Disorder, it is suggested that child analysts recognize the usefulness of considering child analysis when they are evaluating or treating children with this diagnosis. PMID- 26020995 TI - Iatrogenic trauma masquerading as autistic spectrum disorder. The use of psychodynamic psychotherapy in overcoming a persistent developmental interference in a four-year-old boy. PMID- 26020996 TI - Helping a boy with chronic medical problems get on friendly terms with his body and puberty. AB - "My mom wants me to shave off my facial hair, but I like it. I think it makes me look mature," said sixteen-year-old Alex as he proudly stroked the crop of hairs sprouting from his chin. I was speechless. Why? Because for years I had heard about all the medical things that were wrong with Alex's body. Then, when puberty arrived, his distress about his changing body was intense. So how did psychoanalysis help him get on friendly terms with body changes, even enjoying signs of growing up? We shall see. PMID- 26020997 TI - Childhood mourning. An impossible desire in Lois Lowry's a Summer to Die. AB - In Lois Lowry's A Summer to Die, protagonist Meg Chalmers appears wiser than her thirteen years, able to handle such painful crises as her sister's death to leukemia, moving to a new town in the middle of a school year, and witnessing the birth of her neighbors' son with an ease and grace equal to the remarkably well adjusted adults in her life. She also appears to have better sense than some of the not-so-well-adjusted adults who threaten to disrupt her world, such as Clarice Callaway (the town busybody) and Martin Huntington (the-opportunistic lawyer) and even at times her adult friends and neighbors Will, Ben, and Maria. PMID- 26020998 TI - Mum's the word. Are we becoming silent on masturbation? AB - This paper explores the trend in contemporary child analytic technique away from addressing material related to masturbation. The author invites reconsideration of the value of timely, tactful exploration of a child's impulses, fantasies, and related conflicts. The analyst's resistances to open discussion of these are addressed, along with the limiting effect this may have on the patient feeling fully understood. Clinical examples are provided of analytic work with children from prelatency through preadolescence, whose symptoms range from neurotic conflict to more severe and early disturbances. PMID- 26020999 TI - The use of the computer and the Internet in child psychoanalysis. AB - The revolution in communications has affected society at large and psychoanalysis in particular and, in this article, child analysis as well. A technically advanced nine-year-old Korean girl chose to use the computer and the Internet as her ways of revealing her conflicts, family problems, and developmental issues, that is, her inner world. Her presentation forced her less technologically sophisticated analyst and her supervisor to confront and make technical decisions regarding the use of the computer and the Internet in the child analysis, which neither had faced before. Because of the ubiquitous nature of these constantly evolving communication devices, every analyst can expect to be confronted with similar issues to those encountered in this case. PMID- 26021000 TI - Integrating the therapeutic into the developmental in treating disturbed adolescents. AB - This clinical study is organized around the treatment of a late adolescent who feared suiciding impulsively during an immobilizing depression and who proceeded to develop other severe symptoms. Yet he steadfastly refused to take medication and objected to seeing a therapist as well. His reason was an overriding wish to deal with his difficulties himself, a feature of his normal developmental imperative to emancipate to a young-adult level of psychological autonomy. Thus, the therapeutic task was to simultaneously hold him in treatment while supporting that normal developmental requisite. Elaborating upon this integration of the psychodynamic and the developmental is the major purpose of this study. PMID- 26021001 TI - Why aren't we curious about nannies? AB - This paper is an exploration of a topic whose specific intrapsychic significance has remained relatively unformulated in the psychoanalytic literature. Though nannies (that is, caregivers whose job it is to care for children at home in their parents' absence) have had a ubiquitous presence among professional working women and are frequently involved in the lives of patients seen in private practice, their psychological significance for both employers and charges has rarely been considered. The paper attempts to demonstrate how the nanny's literal position is at risk for engendering ambivalence in parents and children alike, since she is necessarily there when the parents are not. It is postulated that the actual, reality-based power of the nanny as placeholder for parents in their absence may be instrumental in the tendency of our patients to scotomatize this relationship. In the first part of the paper, clinical examples are used to underscore the complexity of the nanny's role, while the second half of the paper draws upon the text of the children's classic Mary Poppins, to further explore the subject. PMID- 26021002 TI - The Hampstead Clinic at work. Discussions in the Diagnostic Profile Research Group. AB - Minutes of the Hampstead Clinic's Diagnostic Profile Research Group during a fifteen-month period (1964-1965) are reviewed and discussed. A wide range of topics were considered and discussed, with a special focus on the affective life, object relations, and ego function of atypical children in comparison to the early ego functions and differentiation of normal and neurotic children. These lively clinical and theoretical discussions and their implications for therapeutic work with a wide range of children, demonstrate the multifaceted leadership and contributions of Anna Freud as teacher, clinician, and thinker, and of the Hampstead Clinic as a major center for psychoanalytic studies. PMID- 26021003 TI - Coroners--reformed or readjusted? Personal reflections of a sitting coroner. PMID- 26021004 TI - Amnesia--not what you see in the movies. PMID- 26021005 TI - Where sleep medicine meets psychiatry: a recent understanding of post-traumatic stress disorder and its treatment. AB - I believe that the results of these sleep studies show that in chronic PTSD, most patients have a significant sleep disorder that is independent of their PTSD, but which provides the vulnerability in which PTSD develops. The utility of these studies lies in the fact that for the most part these sleep disorders can be treated, and the PTSD can then subsequently respond to appropriate treatment, or be resolved as sleep normalizes. There's a lot more that can be done--I'd like to end on some words from the American poet, Robert Frost, whose lines "I have promises to keep, and miles to go before I sleep; and miles to go before I sleep" seem to herald the current situation in which sleep medicine and psychiatry are making a tentative beginning to explore a new realm of study. PMID- 26021006 TI - Will post mortem kill the autopsy? PMID- 26021007 TI - Was it poisoning? AB - The aim of post-mortem toxicology is to help establish the role that drugs or other poisons played in a death, or in events immediately before death. If self poisoning is suspected then the diagnosis may be straightforward and all that may be required is confirmation of the agents involved. If the cause of death is not immediately obvious, however, then suspicion of possible poisoning is of course crucial. Blood sampling (needle aspiration, peripheral vein, e.g. femoral, ideally after proximal ligation) before opening the body, minimises the risk of sample contamination with, for example, gut contents or urine. The site of blood sampling should always be recorded. Other specimens (stomach contents, urine, liver, vitreous humor) may also be valuable and may be needed to corroborate unexpected or unusual findings in the absence of other evidence. The availability of ante-mortem specimens should not preclude post-mortem sampling. Appropriate sample preservation, transport, and storage are mandatory. Interpretation of post mortem toxicology must take into account what is known of the clinical pharmacology, including pharmacokinetics, and toxicology of the agent(s) in question, the circumstances under which death occurred including the possible mechanism(s) of exposure, and other factors such as the sample(s) analysed and the analytical methods used. It was thought that concentrations of poisons measured in blood obtained at autopsy reflected the situation peri-mortem. However, we now know that changes may occur in the composition of body fluids, even peripheral blood, after death. Such changes are likely to be greater with centrally-acting drugs such as clozapine with large volumes of distribution, and may perhaps be minimised by prompt refrigeration of the body and performing the autopsy quickly. Better training in analytical toxicology is needed for pathologists and others who may be called upon to interpret toxicological data for the Courts. Undue reliance on quantitative results is likely to confuse sooner rather than later, especially in the case of centrally-acting drugs such as opioids and clozapine. Remember that the question is normally "was it poisoning?" or "was it an overdose?"--and not--"is it a fatal level"? PMID- 26021008 TI - Diagnosis of skin diseases old and new. PMID- 26021009 TI - Why warriors lay down and die. PMID- 26021010 TI - Ordinary meeting. 25th February 2013. PMID- 26021011 TI - Choosing and training tomorrow's doctors: by guess and by God, or by grand design? PMID- 26021012 TI - Mysteries of small bowel neoplasia. PMID- 26021013 TI - Edward Elgar--a medical enigma? PMID- 26021014 TI - The dangers of precautionary thinking and the concept of safety: looking at supplements. PMID- 26021015 TI - "A&E crisis is a serious warning to politicians". PMID- 26021016 TI - A&E nurses fear for patient safety. PMID- 26021017 TI - Unsocial hours income may be cut to pay for "seven-day NHS". PMID- 26021018 TI - Labour uses NT staffing survey to back NHS dossier. PMID- 26021019 TI - Some practice nurses unaware of consent law. PMID- 26021020 TI - Scottish politicians compete for votes with nursing pledges. PMID- 26021021 TI - Herts nurses to claim for hours worked. PMID- 26021022 TI - Care experience fails to improve student grades or attrition rates. PMID- 26021023 TI - Nurse research unit to focus on patient care. PMID- 26021024 TI - Alert issued on KMnO4 after patient death. PMID- 26021025 TI - Over 20 nurses awarded new year honours. PMID- 26021026 TI - Regional staff shortage sparks first self-funded nursing course. PMID- 26021027 TI - "As leaders, we must show we can work on our own lifestyles". PMID- 26021028 TI - "Become a care radical who rocks the boat and stays in it". PMID- 26021029 TI - A tool to calculate safe nurse staffing levels. AB - A guideline from the National Institute for Health and Care Excellence and a NICE endorsed tool on safer nursing care allow decisions on safe staffing levels to be made at a local level. Decisions must be based on sound evidence and factoring in patients' individual needs as well as numbers of patients. The Safer Nursing Care Tool helps nurses decide on safe nurse staffing for acute wards based on patients' level of sickness and dependency. It also includes quality indicators linked to nursing care to help ensure staffing levels achieve best patient care. The tool is easy to use by frontline nursing staff, but must be applied correctly and consistently for data to be valid, and to allow benchmarking against agreed standards. It should be combined with nurses' professional judgement and account for local factors. PMID- 26021030 TI - Using patient passports to improve A&E asthma care. AB - The asthma patient passport (APP) is a patient-specific asthma plan that details what to do when asthma is out of control. It helps patients who have severe, difficult-to-manage asthma, and health professionals when these patients present at accident and emergency. This article shows that, while the APP acts as a patient's advocate, it also facilitates accessing emergency care by making it more streamlined. Case studies explore why people with asthma have avoided going to A&E, putting their lives at risk, and provide an insight into how difficult it can be for people to navigate the healthcare system when they are at their most vulnerable. PMID- 26021031 TI - Ethical approval in studies raising consent issues. AB - This article offers practical advice on applying for ethical approval for research involving participants who may be unable to give informed consent. It briefly outlines my own experiences and offers tips on using the Integrated Research Application System website, going to a social care research ethics committee meeting and resubmitting an application. PMID- 26021032 TI - Taking oral histories to improve end-of-life care. PMID- 26021033 TI - Training new HCAs to give compassionate care. AB - In October 2013, Newcastle upon Tyne Hospitals Foundation Trust set up an academy for all new healthcare assistants, to enable them to develop with the knowledge and skills to deliver compassionate and safe care. HCAs attend the academy before working in clinical practice. They complete knowledge packs in line with national minimum training standards during their probationary period. Evaluation showed that HCAs felt more confident to deliver clinical care after completing academy training. PMID- 26021034 TI - 60 seconds with Susannah Peters. PMID- 26021035 TI - Listen to the workers. PMID- 26021036 TI - "An expensive mistake to count on free labour". PMID- 26021037 TI - Stress at work makes nurses ill. PMID- 26021038 TI - Nurses' wellbeing still needs more attention. PMID- 26021039 TI - Gaps in ebola training for nurses. PMID- 26021040 TI - NHS finances is biggest worry for workforce. PMID- 26021041 TI - Negative media portrayal growing. PMID- 26021042 TI - NMC rubber-stamps updated code for nurses and midwives. PMID- 26021043 TI - Practice nurses praised for shingles jab uptake. PMID- 26021044 TI - NICE warns of SIDS risk from co-sleeping. PMID- 26021047 TI - Rise in Scottish staff tempered by vacancy rate. PMID- 26021045 TI - Nurse wins new compassionate care award. PMID- 26021046 TI - Data sharing system to flag up at-risk children to frontline staff. PMID- 26021048 TI - "Are we right to concentrate on prospective students' values?". PMID- 26021049 TI - "More Santa, less Scrooge--give us extra funds from a non-NHS pot". PMID- 26021050 TI - "With funding, district nurses can train HCAs to support them". PMID- 26021051 TI - Foot assessment and care for older people. AB - Nursing and healthcare literature about foot care focuses predominantly on people who have diabetes. There is a lack of clarity about which health and social care professionals should provide foot care to patients who can no longer manage to carry out this activity of daily living but do not have diabetes. This article explains why patients may no longer be able to look after their own feet and aims to give health professionals guidance on foot problems, assessment and care, and advise them on when it is appropriate to refer patients for specialist advice. PMID- 26021052 TI - The role of the nurse in pulmonary rehabilitation. AB - Pulmonary rehabilitation can help patients with chronic obstructive pulmonary disease improve their exercise tolerance and quality of life. Care packages can be devised and managed by respiratory nurses. PMID- 26021053 TI - Cummings: More work to do to make the 6Cs universal. PMID- 26021054 TI - Leaders have duty to promote public health as a career choice. PMID- 26021055 TI - Framework will help care homes benchmark on performance. PMID- 26021056 TI - Five Year Forward praised for focus on collaboration. PMID- 26021057 TI - Burn urges nurses to take role in genomic revolution. PMID- 26021058 TI - Paralysed ex-patient says kindness helped recovery. PMID- 26021059 TI - Equal treatment of staff will be reflected in better care. PMID- 26021060 TI - Hunt applauds effort but warns of more challenges. PMID- 26021062 TI - 60 seconds with Lorraine Burgess. PMID- 26021061 TI - How the social model of disability evolved. AB - The way nurses conceptualise disability influences their practice. Many use an individualised model, seeing disability as an individual problem arising from activity restriction and psychological loss. However, many disabled people are critical of this approach and instead promote a social way of thinking about disability. This article presents an overview of the individual and social models of disability so nurses can increase their understanding of these approaches. PMID- 26021063 TI - Give support, not sympathy. PMID- 26021064 TI - Don't second their emotion. PMID- 26021065 TI - [To the 50th anniversary of the discovery of the simian hemorrhagic fever and SHF virus]. AB - The results of the study of SHF and virus SHF for the last period since their discovery are summed up. It was established that the source of this infection fatal for Asian macaques are African monkeys--virus carriers. There is still a danger of the occurrence of epizootics in Primatological Centers at the importation of these monkeys for research. The importance of the obtained experimental SHF in macaques was emphasized. This model is unique, safe and adequate. It is necessary for further study of pathogenesis and evaluation of the means of pathogenetic therapy of HF dangerous to human health. PMID- 26021066 TI - [The impact of conservative and hypervariable immunodominant epitopes in internal proteins of the influenza A virus on cytotoxic T-cell immune responses]. AB - The cytotoxic T-cell immune response plays an important role in the prevention of influenza infection and reducing of the illness severity. The knowledge about mechanisms of the virus-specific CD8+ T-cell induction in humans is necessary for better understanding of influenza epidemiology and vaccine development. Due to application of new immunological and genetic methods in last years, considerable amount of.data became available in the literature about CD8+ T-cell immune responses to different influenza A viruses. This review summarizes these data. The main attention is paid to (i) heterosubtypic CTL responses to conservative immunodominant sites; (ii) mechanisms of viral escape from the virus-specific CTLs by means of evolutional escape-mutations; (iii) influence of the HLA haplotype on CD8+ T-cell immune responses. The importance of these data for immunology and vaccinology is discussed. PMID- 26021067 TI - [The biological characteristic of the collection strains of viruses from the subgroup of Japanese encephalitis]. AB - Perennial (since 1966) study of the biological properties of the viruses from the flavivirus subgroups of the Japanese encephalitis (JE) made it possible to collect and deposit in the State collection of JE virus strains JE virus strains isolated from natural foci in different geographic zones, as well as the JE virus strains selected in the laboratory. The collection of the flaviviruses strains of Japanese encephalitis complex, West Nile fever (West Nile virus and Usutu), which were studied and preserved, are listed. The data are provided on the origin of strains and their pathogenicity for laboratory animals. PMID- 26021068 TI - [Indicators of the human immunodeficiency virus drug resistance to antiretroviral drugs in HIV-infected individuals in the Siberian Federal District in 2010-2012]. AB - The prevalence of the mutations of resistance to the main three classes of antiretroviral agents in patients receiving antiretroviral therapy was tested. Among the main drug resistance mutations for the entire period of observation was a high frequency of the occurrence M184V mutation, K101E, K103N, Y181C, and G190S influencing the development of the HIV resistance to nucleoside and non nucleoside reverse transcriptase inhibitors. The problems of the practical application of the study of HIV drug resistance in the regions of the Siberian Federal District were emphasized. PMID- 26021069 TI - [A panel of the drug-resistance HIV-1 clinical isolates]. AB - A panel of 16 HIV-1 isolates was designed. Those isolates were isolated from patients undergoing HAART and developing resistance to the antiretroviral drugs. It was shown that the isolates were resistant to nucleoside RT inhibitors (retrovir, epivir) and non-nucleoside inhibitors (viramun). Isolates had stable replication activity. Average rate of cells expressing viral Ag was 14-20%. The infectious titer was 2.4 Ig TCID50. The sequencing showed that all isolates were of the subtype A dominating in the major part of Russian Federation. This panel could be used as the biotechnological base for studying antiretroviral drugs of new generation and for the design of experimental vaccines. PMID- 26021070 TI - [Evaluation of the antiviral therapy for chronic hepatitis C in patients unresponsive to previous treatment with regard to the interleukin-28B genotypes]. AB - The identification of the single nucleotide polymorphisms (SNP) at rs8099917 and rs12979860 loci of IL-28B gene is presently necessary for patients with the genotype HCV-1 to predict sustained viral response (SVR) in case of combined antiviral therapy with interferon and ribavirin. In addition to the implementation of the antiviral activity of IFN-alpha, interleukin-1beta (IL 1beta) and interferon-gamma (IFN-gamma) are involved. The goal of this work was to evaluate the efficacy of the HCV therapy with cytokines in patients unresponsive to previous therapy with unfavorable genotypes of IL-28B gene. SVR was achieved in 44.4% of patients with an unfavorable IL-28B genetic background with biochemical response without serious adverse effects or unexpected adverse effects, thereby corroborating the inclusion of proven safety Betaleukin(r) and Ingaron in the schemes of the antiviral therapy in combination with standard interferon-alpha and ribavirin in patients with recurrent HCV-infection. PMID- 26021071 TI - [Production of the polyclonal enterovirus antibodies of chicken (IgY) and its evaluation as alternative to the rabbit enterovirus neutralizing sera]. AB - Experimental data show the usefulness of the Leghorn chicken as a producer of the enterovirus neutralizing antibodies (IgY). The resulting serum is not inferior to the specific activity of the commercial rabbit enterovirus diagnostic sera (EDS) in the neutralization reaction. The IgY have lower backgrounds than mammalian IgG and do not cause toxic effect to cell culture. Compared with the conventional manufacturing method EDS IgY, preparation process is much more effective: the number of serum producers is significantly lower, whereas the yield of the product is higher. Reduction of the volume of the immunogens, immunization cycle, and number of injections is also an advantage of this manufacturing method. PMID- 26021072 TI - [Prevalence and incidence of infections among blood donors in Astana]. AB - The prevalence and incidence of infections among 28,248 blood donors in Astana in 2012 was determined. The estimated residual risk of the transfusion infection was as follows: for HIV--1,2, HCV--137,7, HBV--125,4 per 1 million donations. High risk of transfusion infection with HIV, hepatitis B, and C stimulates the active implementation of the measures for increasing the safety of blood: the selection of donors, increasing the sensitivity of infections screening methods, inactivation of pathogens in blood components and transfusion management appointment at the clinic. PMID- 26021073 TI - [Immune signs of activation of the herpes simplex virus in women with physiological pregnancy]. AB - Reactivation of the herpes simplex virus (HSV) is frequently observed in women during pregnancy. However, the concomitant changes in the immune system are still insufficiently understood. The goal of this work was to present a comparative analysis intended to identify specific antiviral IgM antibodies and IgG to determine their titles, concentration, and avidity in paired sera of 49 HSV positive pregnant women without complicated obstetric-gynecological history. The serology results were compared with the quantitative determination in the serum IFNgamma, as well as with the level of spontaneous and induced cytokine production by blood lymphocytes. For this purpose, 5.0 ml of blood from a vein was collected in pregnant women (9-11 weeks of gestation). The procedure was repeated in 4 weeks. The nonspecific induction of the IFNgamma was performed using phytohemagglutinin (PanEco, Russia). Given the concentration of the immune markers in the samples, such values were evaluated by ELISA using certified commercial kits available from Vector-Best Ltd. (Russia) and Diagnostic System Scientific Manufacturing Association (Russia). IgM antibodies in paired sera had not been detected in any of the 49 women. High-avidity IgG antibodies were detected in all women in the titer 1:50-1:100, but in the second sample of sera from 32 women (study group) antibody titers were found to be as high as 1:600 1:800. The women with no growth of the serum antibodies were included in the control group (n = 17). Comparative analysis of the amount of IFNgamma in sera showed that the content of the cytokine in the first blood sample and the level of the spontaneous production in women of the study group were statistically significantly higher than in the control group (4.2 vs. 2.7, p = 0.05; 7.5 vs. 2.0, p = 0.03, respectively). In the blood samples taken after 4 weeks the serum concentration of IFNgamma (2.6 vs. 4.2, p = 0.049), and its spontaneous product (4.5 vs. 7.5, p = 0.046) were considerably lower than in the first blood samples. These results demonstrate that the reactivation of the HSV infection occurs in women with normal pregnancy and the lack of complicated obstetric and gynecological history. Increasing the concentration of IFNgamma serum levels and spontaneous cytokine production is the earliest sign of acute infection in the women during pregnancy. These changes precede the increase in the IgG antibodies and assume normal values when the level of indirect marker of HSV rises. The lack of the IgM antibodies to the virus is not a strict criterion of inactive infection. PMID- 26021074 TI - [The multiplex method of estimation of humoral immunity to vaccine regulated childhood infections]. AB - The goal of this work was to present the results of the laboratory tests of the multiplex dot immunoassay method using protein microarray for complex estimation of humoral immunity to measles, mumps, and rubella viruses. It was shown that the obtained results were in a good agreement with data of commercial monospecific ELISA kits. The developed method is fast, requires fewer resources, and may be used in the field. PMID- 26021075 TI - [Sensitivity and specificity of the ELISA Kit for the detection of antidobies to Junin virus]. AB - The goal of this work was to describe methodological approaches to determination of sensitivity and specificity of the enzyme-linked immunosorbent assay kit (ELISA Kit) for detection of the specific anti-Junin virus (JV) antibody. Comparison of ELISA to plaque reduction neutralization test (PRNT) showed direct relationship between antibody titers in the samples of serum of immunized animals, determined by either PRNT or ELISA methods. The obtained results provided an opportunity to form the panels of positive and negative serum samples to determine the sensitivity and specificity of the ELISA Kit. Sensitivity of the ELISA Kit was at least 98% when studying the samples of serum of immunized guinea pigs and rabbits (determined as positive in PRNT). The sensitivity of the ELISA Kit was at least 68% when studying the samples determined by PNRT as uncertain positive. The specificity was 98%. The specificity of the ELISA Kit was 98%. PMID- 26021076 TI - [Overview of Ebola virus vaccine]. AB - Ebola virus (EBOV) causes hemorrhagic fever, resulting in mortality rates as high as 90% among infected humans and non-human primates (NHPs). The 2014 Ebola epidemic in West Africa is the severest in history, leading to WHO taking all control measures to stop any possibility of cross-border outbreaks. Because no licensed vaccines or effective therapeutics against EBOV are available, the current outbreak management has been limited to palliative care and barrier methods to prevent transmission. Several promising experimental EBOV vaccines have demonstrated protection in NHPs against lethal EBOV challenge, and some progresses have been made through clinical trials of EBOV vaccine candidates. It is believed there will be some licensed vaccine available in the near future to control EBOV outbreaks. In this review we provide some insights for further development of EBOV vaccines. PMID- 26021077 TI - [Research status and prospect on hot water extract of Chlorella: the high value added bioactive substance from Chlorella]. AB - Chlorella is nutritious and has been used as a functional food much earlier than the other microalgae. C. pyrenoidosa, the potential microalgae which is currently cultured and developed for the new strategic industry of biofuels production and biological CO2 fixation, is a new resource food announced by the Ministry of Health of the People's Republic of China late 2012. Accumulation of high value added substances in C. pyrenoidosa during the cultivation for lipid makes it possible to reduce the costs for C. pyrenoidosa-based biofuels production. Among these potential substances, hot water extract of Chlorella (CE), commercially known as "Chlorella growth factor", is the unique one that makes Chlorella more precious than the other algae, and the market price of CE is high. It is believed that CE is effective in growth promotion and immunoregulation. However, there is no systematic analysis on the research status of CE and its bioactivity. The present report summarized recent research progress of CE and its bioactivity. Generally, besides the main effect on immunoregulation and tumor inhibition, CE was efficient in improving metabolic syndrome, scavenging for free radicals, protecting against ultraviolet damage, chelating heavy metals, and protecting liver and bowel. Several major challenges in CE research as well as its prospects were also analysed in the present report. PMID- 26021078 TI - [Alternative oxidase in industrial fungi]. AB - Filamentous fungi have been used in industrial fermentation extensively. Based on non-phosphorylating electron transport process, alternative respiration pathway (ARP) acts as an energy overflow, which can balance carbon metabolism and electron transport, allow the continuance of tricarboxylic acid cycle without the formation of ATP, and permit the turnover of carbon skeletons. Alternative respiration pathway also plays an important role in the stress response of fungi and the physiological function of conditioned pathogen. Alternative oxidase (AOX) is the terminal oxidase responsible for the activity of alternative respiration pathway, which exists widely in higher plants, parts of fungi and algae. Owing to the property that alternative oxidase (AOX) is sensitive to salicylhydroxamic acid (SHAM) and insensitive to conventional inhibitors of cytochrome respiration, alternative respiration pathway by AOX is also named as cyanide-resistant respiration (CRR). In recent years, the study of the alternative respiration pathway and alternative oxidase has been a hot topic in the area involving cellular respiration metabolism. In this review we summarized the latest research advances about the functions of alternative respiration pathway and alternative oxidase in industrial fungi. PMID- 26021079 TI - [Bt transgenic crops for insect-resistance and modification of Bt protein and utilization of stacking strategy]. AB - Insecticidal protein genes from Bacillus thuringiensis are currently the most widely used insect-resistant genes. They have been transferred to many crops for breeding and production. Among them, cotton, maize, potato and other insect resistant crops are commercialized, creating considerable economic benefit. In this review, we summarized advances in identifying functional genes and transgenic crops for insect resistance, compared different strategies for enhancing vigor of insecticidal protein and utilizing gene stacking as well as listing valuable groups of stacked genes. In addition, the methods for multiple gene transformation was discussed. PMID- 26021080 TI - [Prokaryotic expression of vp3 gene of Muscovy duck parvovirus, and its antiserum preparation for detection of virus multiplication]. AB - New epidemic broke out in recent year which was suspected to be caused by variant Muscovy duck parvovirus (MDPV). For this reason, new MDPV detection methods are needed for the new virus strains. In this study, a pair of primers were designed according to the full-length genome of MDPV strain SAAS-SHNH, which were identified in 2012, and were used to amplify the vp3 gene of MDPV by polymerase chain reaction. After being sequenced, the vp3 gene was subcloned into the prokaryotic expression vector PET28a. The recombinant plasmid was transformed into E. coli BL21 and induced with IPTG. SDS-PAGE and Western blotting analysis showed the MDPV vp3 gene was successfully expressed. After being purified by Ni2+ affinity chromatography system, the recombinant protein was used as antigen to immunize rabbits to obtain antiserum. Western blotting analysis showed that the acquired antiserum could react specifically with VP3 protein of J3D6 strain and MDPV vaccine strain. The antiserum could also be used for detection of cultured MDPV from primary duck embryo fibroblasts by immune fluorescence assay (IFA). It could be concluded that the VP3 protein and its antibody prepared in the research could be used for detection of VP3 antiserum and antigen respectively. PMID- 26021081 TI - [Development of monoclonal antibodies against the gp90 protein of reticuloendotheliosis virus and mapping of their recognition regions]. AB - In order to develop monoclonal antibodies (McAbs) against the gp90 protein of reticuloendotheliosis virus (REV), the His-tagged gp90 protein of REV was used to immunize BALB/c mice. Hybridomas were generated by fusing mouse myeloma cells SP2/0 with the splenocytes from the immunized mice. After screening and 3 rounds of cloning process, 3 hybridomas (3G5-B8, 3G5-A10 and 1G12) that stably secreted McAbs against the REV-gp90 were obtained. The isotypes of the McAbs were determined to be IgG1, IgG1 and IgG2b. The McAbs specifically bound to gp90 in REV-infected DF-1 cells, as demonstrated by Western blotting and indirect immunofluorescence assay. The recognition regions on gp90 that were recognized by 3G5-B8/3G5-A10 and 1G12 were located between amino acids 200 to 245 and 230 to 235, respectively, as demonstrated by Western blotting analysis. These McAbs will be useful in the diagnosis and pathogenesis study of REV. PMID- 26021082 TI - [Rescuing Bombyx mori bidensovirus in BmN cells in vitro]. AB - Bombyx mori bidensovirus (BmBDV) has been identified as causing chronic densonucleosis in Bombyx mori specifically. The replication mechanism of BmBDV remains unknown. Its genome comprises two single stands DNA (VD1 and VD2). In order to rescue infectious virions in vitro, we obtained the total viral DNA extracted from the BmBDV-infected larvae midguts, subsequently cloned the full length sequence of BmBDV genome fragments by PCR and constructed recombinant plasmids pMD18T-VD1 and pUC-VD2. The linear genome fragments were obtained by digesting recombinant plasmids with corresponding restriction enzymes, and then collectively transfected BmN cells by the method of liposome-embedding. We determined the replication of the virus gene by PCR with the template of demethylated total DNA extracted from the post-transfect BmN cells. Meanwhile, we collected the total proteins from the post-transfect BmN cells and the larvae midgut of feeding the post-transfect BmN cells to perform Western blotting analysis, and detected the expression of viral genes. Here we firstly confirm that infectious virions can be rescued in BmN cells by linear co-transfect method. PMID- 26021083 TI - [Construction and characterization of an epitope-mutated Asia 1 type foot-and mouth disease virus]. AB - To generate an epitope-mutated foot-and-mouth disease virus (FMDV) as a marker vaccine, the infectious clone pAsia 1-FMDV containing the complete genomic cDNA of Asia 1 type FMDV was used as backbone, the residues at positions 27 and 31 in the 3D gene were mutated (H27Y and N31R). The resulting plasmid pAsia 1-FMDV-3DM encoding a mutated epitope was transfected into BHK-21 cells and the recombinant virus rAsia 1-3DM was rescued. The recombinant virus showed similar biological characteristics comparable with the parental virus. In serological neutralization test the antisera against recombine virus have a good reactivity with parental virus. The antisera against the mutant virus were shown to be reactive with the mutated epitope but not the wild-type one. The results indicated that the two virus strains could be distinguished by western blotting using synthetic peptides. This epitope-mutated FMDV strain will be evaluated as a potential marker vaccine against FMDV infections. PMID- 26021084 TI - [Metabolic engineering of Escherichia coli for thymidine production]. AB - Thymidine is a commercially useful precursor for production of antiviral compounds such as stavudine and azidothymidine. Biosynthesis of thymidine by Escherichia coli BL21 (DE3) was studied using metabolic engineering methods. The deoA, tdk and udp of the salvage pathway were disrupted from E. coli BL21 to construct BS03 that produced 21.6 mg thymidine per liter. Additional deletion of pgi and pyrL increased the supply of thymidine precursors and the resulting strain BS05 produced 90.5 mg thymidine/L. At last, ushA, thyA, dut, ndk, nrdA and nrdB of thymidine biosynthetic pathway were overexpressed, and the resulting strain BS08 produced 272 mg thymidine/L. In fed-batch fermentation, BS08 accumulated 1248.8 mg thymidine/L. Metabolically engineered strain E. coli has potential applications for thymidine production. PMID- 26021085 TI - [Expression of Arabidopsis thaliana thioesterase gene in Pichia pastoris]. AB - Thioesterase catalyzes the hydrolysis of acyl-ACP and saturated fatty acyl chain. It plays a key role in the accumulation of medium chain fatty acids in vivo. In this study, to construct an engineering strain to produce MCFAs, the Arabidopsis acyl-ACP thioesterase gene AtFatA was amplified by PCR from cDNA of arabidopsis and double digested by EcoR I/Xba I, then linked to the plasmid digested with same enzymes to get the recombinant plasmid pPICZaA-AtFatA. We transformed the gene into Pichia pastoris GS115 by electroporation and screened positive colonies by YPD medium with Zeocin. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results showed that the recombinant enzyme had a molecular of 45 kDa band which was consistent with the predicted molecular mass and we constructed the expression system of gene AtFatA in fungus for the first time. Under shake-flask conditions, Gas Chromatograph-Mass Spectrometer-computer results indicated that recombinant strain produced 51% more extracellular free MCFAs than the wild and its yield reached 28.7% of all extracellular fatty acids. This figure is 10% higher than the control group. The result provides a new way to produce MCFAs. PMID- 26021086 TI - [Inhibition of replication and transcription of WSN influenza A virus by IFIT family genes]. AB - IFIT family genes are a kind of interferon stimulated genes (ISGs), and play important roles in antiviral sector and immunity regulation. To study the regulatory effect of IFIT family genes during influenza A virus (IAV) infection, we used RNA-sequencing analysis (RNA-Seq) technique and found that when 293T cells were infected by A/WSN/33 (WSN), the concentration of IFIT family genes were increased. Further study reveals that overexpression of IFIT2 or IFIT3 could inhibit IAV replication and transcription, and cause the dose-dependent inhibition of polymerase activity of vRNP. In addition, IFIT2 and IFIT3 encoding protein could colocalize with NS1 in 293T cells infected by WSN, indicating that they might interact with each other. The results suggest that IFIT family genes can inhibit the replication and transcription of IAV, which contributes to our understanding of the regulatory effect of host factors during influenza virus infection. PMID- 26021087 TI - [Expression, purification of recombinant human cryptochrome I and its application in preparation of protective agent for radiotherapy]. AB - Radiotherapy is a treatment for cancer with undesired by-effects. In order to develop a new radiation protective agent that could reduce the by-effects, we tried to express and purify human cryptochrome 1 (hCRY1). The coding sequence of hCRY1 was inserted into prokaryotic expression plasmid pET28a(+), and this protein was purified from Escherichia coli BL21(DE3) after IPTG induction, ultrasonication, inclusion body dissolution, gradient dialysis, nickel column purification and ultrafiltration. The yield of hCRY1 in 1 L E. coli culture (LB medium) was about 10-15 mg. The radiation protective efficiency of hCRY1 was monitored by detecting X-ray-induced H2A.X foci in HaCaT cells. The results of immunofluorescence show that hCRY1 significantly reduces X-ray stimulated DNA damage response. The apoptosis of HaCaT cell was also detected, and the repression of H2A.X foci formation was not due to hCRY1's cytotoxity. All these data suggest a potential application of recombinant hCRY1 as a protective agent for radiotherapy. PMID- 26021088 TI - [High cell density culture of an engineered yeast strain for sclareol production]. AB - Cell growth profiles were evaluated in shake-flask culture to improve sclareol production by the engineered yeast strain Saccharomyces cerevisiae S7. Product formation was tightly coupled with cell growth. High cell density cultures were performed with different carbon sources using a dissolved oxygen level feedback control strategy in a 3 L bioreactor. The titers of sclareol were 253 mg/L, 386 mg/L and 408 mg/L, respectively, when glucose, ethanol and glucose/ethanol mixture were used as the carbons sources. The maximal titer was 27-fold higher than that obtained under shake-flask culture conditions. The results suggested that the presence of ethanol was beneficial to sclareol production. These results provided useful information for optimization of yeast cell factory and efficient production of terpenoids. PMID- 26021089 TI - [Functional results of type A botulinum toxin versus oral anti-inflammatory agents in the rehabilitation of painful shoulder syndrome caused by rotator cuff lesion]. AB - Rotator cuff conditions are characterized by unspecific signs, as well as anatomic alterations and symptoms. They have a multifactorial etiology and may include everything from tendinitis to massive, full thickness tears of the rotator cuff tendon that compromise the normal biomechanics of the involved shoulder. They usually occur in people over 40 years of age but lesions resulting from trauma may vary according to the mechanism of injury and are not directly related with the age at onset of symptoms. Vascular factors have been described as related with rotator cuff tendon damage in conditions affecting the microcirculation. However, recent studies have not proven that the tendon under direct observation shows hypovascularity. Type A botulinum toxin acts by blocking the release of acetylcholine in the neuromuscular plate; in the joints it releases capsular tension and reduces proinflammatory factors such as interleukin 1 (IL-1). There are only a few papers on its intraarticular benefit; in muscle and tendon groups it not only has a muscle relaxant effect, but several publications support its utility for pain management. It has been widely used in the rehabilitation of this group of patients at low doses. Material and methods: Prospective, investigational and longitudinal study involving the follow-up of 24 patients with a diagnosis of painful shoulder syndrome proven clinically and with imaging tests, and caused by rotator cuff lesions. The patients either did not meet the criteria for immediate surgical repair or had already undergone such a repair. Type A botulinum toxin was applied to 12 patients in the subacromial space around the rotator cuff conjoint tendon, as well as in the painful spots and in the muscle contracture in the shoulder. The total dose of Type A botulinum toxin was 200 IU. The control group, also composed of 12 patients, was given a COX-2 oral antiinflammatory agent for 6 weeks (Celecoxib, 100 mg BID). Both groups followed a pre-established rehabilitation program for a total of 6 weeks and were supervised every 2 weeks. Subjective and objective assessments were made including pain, performance level and possible mobility, using Constant's functional shoulder assessment and the visual analog scale (VAS). RESULTS: Celecoxib group: Mean initial Constant scale score was 60; after the first dose it remained unchanged. After 2 weeks of treatment with Celecoxib the mean Constant score was 66; by 6 weeks it was 70.33, with p > 0.005. The botulinum toxin group received a maximum dose of 200 IU in the affected shoulder, 50 IU were administered subacromially and 150 in the painful spots. This treatment was combined with rehabilitation exercises supervised at the doc tor's office. The mean initial Constant scale score was 58; immediately after the first dose it went up to 70.83. Two weeks after the injection and the supervision of rehabilitation exercises at the office, the mean Constant scale score was 77.16; at six weeks it was 78.5, with p < 0.005 (p = 0.00045). The VAS in the Celecoxib group decreased at six weeks with p < 0.005. PMID- 26021090 TI - [Cervical arthrodesis by means of interbody fusion with autologous bone and/or interbody spacer for cervical disc disease]. AB - The purpose of this study was to compare the results of cervical arthrodesis performed through interbody fusion with autologous bone and/or interbody spacer for cervical disc disease. MATERIAL AND METHODS: Comparative cross-sectional study that included 49 patients who underwent surgery for anterior arthrodesis between January and December 2011, whose clinical records were reviewed. RESULTS: We included 49 patients: 20 (40.8%) males and 29 (59.2%) females. All of them were diagnosed with disc disease (cervical disc herniation) involving one or two levels. Mean operative time was 69.12, with a minimum of 53 and a maximum of 110 +/- 19.61 minutes for cervical arthrodesis with a graft. Mean operative time was 61.18 with a minimum of 50 and a maximum of 96.00 +/- 11.38 minutes for cer vical arthrodesis with an interbody spacer (p = 0.00, Student t test). Patient sociodemographic and clinical characteristics and complications are shown. Patients in whom both surgical techniques were used had appropriate radiological integration, with p = 0.015, considering p < or = a 0.05 as significant, chi2. CONCLUSIONS: In patients with cervical disc disease bone integration is appropriate with the use of either an interbody cage or an autologous iliac crest graft. PMID- 26021091 TI - [Results of the latest generation dual-mobility cup in Spain (135 THAs followed up for a mean of 32 months)]. AB - INTRODUCTION: This multi-center study (Cabuenes Hospital and Santa Lucia University Hospital) assessed the results of a retrospective and ongoing series of 135 total hip arthroplasties (THA) in which a latest generation dual-mobility cup was implanted. MATERIAL AND METHODS: A total of 135 THAs performed between 2005 and 2008 were analyzed. Mean follow-up was 32 months. The causes of surgery were: coxarthrosis in 31.8% and hip fracture in 68.1%. Mean age was 82.1 years. All patients were seen at regular follow-up visits for clinical and radiological assessments. RESULTS: The follow-up lasted over 24 months in 121 THAs (14 patients died). In the most recent follow-up, in May 2011, 119 cups did not show any loosening. Complications were as follows: 2 postoperative dislocations; 4 DVTs; 3 infections; 5 periprosthetic fractures; 2 loosened cups, and one subsided stem. The mean preoperative Harris Hip Score (HHS) was 45, 83; the mean postoperative HHS was 80.03. Only two of the 135 cups analyzed had radiographic modifications without clinical signs. Isolated cup survival at 12 months was 97.03% (87.3-99.2) with a 95% confidence interval; survival at 5 years was 96.7% (85.4-98.8). DISCUSSION: In our study, the new dual-mobility cup showed good results for the following indications: primary coxarthrosis and femur neck fractures. CONCLUSION: The complication rate in our series was similar to the one reported in other series in the literature, except for dislocation. The latter was considerably less frequent (1.48%) in our series compared to the rates reported by the classical series, especially in patients with neuromuscular or cognitive problems (one third of patients). PMID- 26021092 TI - [Geriatric syndromes in patients with a non-recent hip fracture seen at a primary health care unit]. AB - OBJECTIVE: To identify the frequency of geriatric syndromes in patients with a non- recent hip fracture seen at a primary health care unit in the state of Puebla, Mexico. MATERIAL AND METHODS: Cross-sectional study conducted in 376 patients with a non-recent hip fracture screened for geriatric syndromes. We included demographic variables, urinary incontinence, polypharmacy, sleep disorder, nutritional status, depression and autonomy. The two latter were assessed using the Yesavage geriatric depression scale and the Katz index. We used descriptive statistics. RESULTS: The total number of patients was 376; 219 (58%) were females and 157 (42%) were males; mean age was 72.57 years (65-95 +/- 7.08), and 98.7% had at least one geriatric syndrome. Depression was detected in 303 (80.9%), 282 (75%) were on polypharmacy, 262 (69.7%) had sleep disorders, 63 (16.8%) had experienced falls, 19 (5.1%) had urinary incontinence, 15 (4%) were obese, and 3 (0.8%) had loss of autonomy. CONCLUSION: 98.7% of the patients had at least one geriatric syndrome; females were the most affected sex; depression was the most frequent syndrome, followed by polypharmacy, sleep disorders, falls, urinary incontinence, obesity and loss of autonomy. PMID- 26021093 TI - [Alternatives for the treatment of complex tibial pilon fractures]. AB - Tibial pilon fractures are one of the most severe types of fractures, not only due to the complexity of their treatment, but also due to the important sequelae they may cause. Moreover, an important percentage of them are open fractures or importantly involve the soft tissues, thus making treatment even more difficult. Thirty-seven patients with tibial pilon fractures treated surgically were included in this study. The results of the FREMAP functional assessment scale were analyzed together with Burwell-Charnley's radiographic criteria. Although there is no consensus on which is the best treatment, it is evident that combined treatment including external and internal fixation with a plate provides the best results. PMID- 26021094 TI - [Biological effect of controlled fluid hyperthermia on rabbit healthy bones]. AB - Fluid hyperthermia has been used to treat various types of cancers, but its effects on bone have not been determined. The purpose of this prospective study was to show the structural and metabolic changes of bone exposed to fluid hyperthermia and the effects of the latter on bone healing. Thirty New Zealand rabbits were used, weighting 2.8-3.2 kg; they were divided into 9 groups and 3 subgroups. An osteotomy was performed in the mid third of the right femur and this segment was exposed to hyperthermia at 15, 20 and 25 degrees centigrade for 50, 60 and 70 minutes. A bone scan was performed every 4 weeks and X-rays were taken every week up to week 13. The post-hoc Tukey test was used for the statistical analysis. Differences were found in the concentration of chemicals at temperatures above 60 degrees for 20 minutes with statistical significance; bone healing was delayed and there was evidence of metabolic activity. We conclude that exposure to temperatures above 60 degrees for 20 minutes resulted in morphologic alterations in potassium, magnesium, sulfur and phosphorus, and delayed bone healing. These results are used as parameters for the treatment of bone tumors with fluid hyperthermia. PMID- 26021095 TI - [Paraosteal osteosarcoma of the tibia treated with the OSS prosthesis. Case report]. AB - Parosteal osteosarcoma originates on the surface of long bones and spares the medullary canal. Its peak incidence occurs in the third decade of life and it is more frequent in females than males. The juxtacortical variety of parosteal osteosarcoma is one of the most common ones, accounting for 1-6% of all osteosarcomas. The classical radiographic appearance of osteosarcoma includes high ossification density and a lobed mass, usually in the posterior aspect of the distal femur, sparing the medullary canal. We report herein the case of a 31 year-old male patient with a clinical picture that included left knee pain and who was seen as outpatient. He was started on treatment for enbloc resection of the tumor and implantation of the OSS (Orthopedic Salvage System) prosthesis. Treatment consisted of broad resection of the proximal tibia, of approximately 14 cm, as well as the implantation of a nonconventional modular tibial prosthesis. Both the radiographic and the clinical results were good and appropriate at the three week follow up. PMID- 26021096 TI - [Adjuvant administration of plasma rich in growth factors for bilateral quadriceps tendon tear]. AB - BACKGROUND: Bilateral quadriceps tendon tears are infrequent conditions. Surgical repairs are the most appropriate treatments and they involve several months of recovery. METHODS: We report the case of a patient with bilateral quadriceps tendon tear resulting from low energy trauma. He was treated with surgical transpatellar suturing reinforced with plasma rich in growth factors (PRGF Endoret). RESULTS: Short-term results showed functional and radiological recovery at the two-months follow-up. The use of PRGF together with usual surgery may contribute to early rehabilitation. PMID- 26021097 TI - [Multiple cervical spine fractures. Case report]. AB - INTRODUCTION: Multiple cervical spine fractures are a relatively infrequent entity and thus the available information on them is scarce worldwide. The cases reported are usually managed conservatively, with a combination of skeletal traction and various braces, with variable results. There are only a few reports of multiple fractures treated surgically. Objective: This is a report of a clinical case of a multiple cervical fracture treated surgically in 2 stages at the Mexico City Center for Patients with Spine and Spinal Cord Injury (Centro de Atenci6n a Lesionados Raquimedulares de la Ciudad de Mexico), located at "La Villa" General Hospital, SSDF. MATERIAL AND METHODS: We report the clinical case of a male, 46 year-old patient involved in a motor vehicle accident who sustained spine and spinal cord injuries consisting of ASIA C C2-C6 fractures. It was decided to perform two-stage surgery with posterior and anterior instrumentation. We report the 19-month clinical and radiological follow-up. RESULTS: In the 19 month follow-up visit, the patient was found to be ASIA D according to the neurological assessment, with mild motor deficit of the left thoracic limb. The patient had returned to his usual job and had acceptable cervical spine mobility. CONCLUSIONS: The patient's appropriate course from the neurological perspective and his return to his daily activities leads to recommending the surgical management of multiple fractures, customizing it in each case according to the fractures' characteristics. Favorable results may be expected from this approach. PMID- 26021098 TI - [Modern tribology in total hip arthroplasty: pros and cons]. AB - The wear products and adverse reactions that occur on bearing surfaces represent one of the greatest challenges in prosthetic replacements, as the latter experience increasing demands due to the large number of young and older adult patients that have a long life expectancy and remarkable activity. The purpose of this review is to analyze the pros and cons of the new advances in the bearing components of the articular surfaces of current total hip arthroplasties. We also discuss the strategies used historically, their problems, results and the surgeon's role in prescribing the tribologic couple that best fits each patient's needs. We conclude with practical recommendations for the prescription and management of the latest articular couples for total hip arthroplasty. PMID- 26021099 TI - [Keywords, what are they for?]. PMID- 26021100 TI - [Utility of a structured bone allograft for acetabular defects in the setting of a revision prosthesis]. AB - INTRODUCTION: Coxarthrosis is considered as an increasingly frequent condition that will lead to an important demand for primary total hip arthroplasty in the coming decades and this, in turn, will increase the number of revision hip arthroplasties. The most common indications for revision are component loosening, hip ,instability and infection, with involvement of the acetabular component in more than 50% of revision procedures. Acetabular bone loss is one of the major challenges of revision hip arthroplasty. OBJECTIVES: To determine, by means of imaging studies, allograft osseointegration using the AAOS radiographic scales, the performance grade of the affected hip using the Harris Hip Score (HHS), and patient personal satisfaction, as well as identify and describe complications. MATERIAL AND METHODS: Observational, longitudinal, retrospective, descriptive, basic, clinical trial. The records of patients subjected to revision hip arthroplasty who experienced prosthetic loosening and had an acetabular defect treated with structured bone allograft between January 2007 and April 2012 were selected. Patients were followed-up at 6 and 12 months and compared with controls. RESULTS: The total number of patients was 18, 61% females and 39% males. Age range was 47-79 years. The acetabular defect grade was as follows: 44.4% were IIB; 44.4% were IIC, and 11.2% were III, according to the Paprosky classification. The HHS went from 27 to 72.3 at one year. Osseointegration was 100% in 9 patients, 75% in 6, and 50% in 3 patients. One patient had acute periprosthetic infection. CONCLUSIONS: This method represents a good treatment option for acetabular defects, as it provides significant improvement according to the HHS and proper allograft osseointegration, which helps patients increase their bone stock for future revision procedures. PMID- 26021101 TI - [Arthroscopic repair of anterior relapsing shoulder dislocation. Is there a learning curve?]. AB - OBJECTIVE: We reviewed the first cases that underwent arthroscopic surgery at our center due to relapsing glenohumeral stability of the shoulder. The objective of this paper is to analyze the influence of the learning curve on the results obtained. MATERIAL AND METHODS: We analyzed 137 patients who underwent surgery at Hospital 12 de Octubre in Madrid, Spain between.February 1999 and March 2010. A total of 101 patients met the inclusion criteria, and these patients were divided into two groups using a chronological order, the first 50 patients and the second 50 patients. There were no statistically significant differences in sex, age and laterality between both groups (p = 0.51, p = 0.15 and p = 0.23, respectively), so the groups were comparable. We compared the following between both groups: clinical outcomes, number of dislocations, reoperations and complications, i.e., implant migration, arthrosis and axillary nerve neuropathy. We also compared the functional results, which were measured using the Constant and Rowe scales. RESULTS: Four episodes of redislocation occurred in group 1 and 6 in group 2. Three reoperations were performed in group 1 and 6 in group 2. No statistically significant differences were found in the number of redislocations and reoperations (p = 50 and p = 0.48, respectively). PMID- 26021102 TI - [Functional results for Neer III-IV fractures treated with hemiarthroplasty]. AB - OBJECTIVE: To assess the functional results of patients who sustained Neer III-IV shoulder fractures treated with hemiarthroplasty. MATERIAL AND METHODS: Descriptive, ambispective, cross-sectional study. From January to December 2011 patient records were reviewed, a functional assessment was performed using the Constant scale, and the DASH questionnaire was applied. Data was analyzed with the SPSS software, descriptive statistics and frequency analysis. RESULTS: Sixteen patients were evaluated, mean age was 60.9 years (p = 0.004); females represented 56.3% (p = 0.001). The mechanism of injury was low energy trauma in 93.8%. According to the Constant scale, whose maximum score is 100, the score of our population was 40.75 (+/- 14.42). The highest prevalence rates corresponded to: middle pain, 8 (50%); work with full performance, 7 (43.75%); painful range of motion up to the xyphoid process (37.5%). Ranges of motion were as follows: abduction 30-60 degrees 10 (62.5% p = 0.004), flexion 30-60 degrees 6 (37.5%), external rotation, 14 (87.5%) with the hand behind the head, internal rotation up to the lumbosacral region, 7 (43.75% p = 0.005). Power of up to 3 kilograms, 5 (31.3% p = 0.005). Poor results were seen in 13 (81.3%) patients. The DASH questionnaire results were: disability/symptoms, 12 (75%) and special activities, 7 (43.75%) good results; in the work module, 8 (50%) fair results. Satisfaction with the surgical procedure, 87.5 percent. CONCLUSIONS: In this patient sample the function of the operated shoulder was considered as poor according to the Constant scale; it was good considering the symptoms and special activities, and fair for the work module, according to the DASH questionnaire. PMID- 26021103 TI - [Cell saver use during knee arthroplasty]. AB - BACKGOUND: Gonarthrosis is a degenerative condition that importantly limits an individua's performance. Surgical treatment is used in patients with important functional limitation and severe pain. Knee arthroplasty is one of the surgeries with the best functional results in patients with this condition. However, its limitations include the risk of heavy bleeding and the resulting need for blood transfusion. The objective of this study was to assess the need for blood transfusion in patients undergoing knee arthroplasy in whom the cell saver was used postoperatively and find out the cost differences between the cell saver and standard blood transfusion. METHODS: Retrospective, cross-sectional, retrolective trial including 300 records of patients who underwent knee arthroplasty at Hospital Angeles Queretaro that included the use of the cell saver and allogeneic blood transfusion from October 2001 to June 2013. RESULTS: Only 3 of the 246 operated knees required allogeneic blood transfusion. There were no complications/infections resulting from the use of the cell saver. Mean age of patients was 67.1 +/- 9.78 years; females were predominant, as they were 141 (60.5%), compared to 92 (39.5%) males. The blood collected with the cell saver ranged from 150 to 1,225 ml with a mean of 318 +/- 100.6 ml and was retransfused to each patient. CONCLUSIONS: Cell saver use in patients subjected to knee arthroplasty importantly decreases the need for allogeneic blood transfusion. PMID- 26021104 TI - [Adaptation in Spanish for the Mexican population with lumbar radiculopathy of the Standardized Evaluation of Pain]. AB - INTRODUCTION: The clinical assessment of radicular pain associates the signs and symptoms of the painful phenotype with the underlying mechanism. The Standardized Evaluation of Pain (StEP) distinguishes between axial and radicular lumbar pain by means of a questionnaire (3 questions) and a physical exam (8 tests). OBJECTIVE: To adapt the StEP scale to Spanish. METHODOLOGY: Selection of the scale, translation-back translation, adjustments, items and utility, pilot test, validity and reliability tests. Inclusion criteria: Any sex, over age 18, lumbar pain with or without irradiation, signing of the informed consent. Exclusion criteria: Neuropathies, polyneuropathies, myopathies, neurologic, myofascial, venous, psychiatric, cardiovascular disease, postoperative status. Sample: 21 patients. RESULTS: Patients were assessed twice with a one-week interval with the help of 2 evaluators. There were 21 patients, 9 females (42.9%) and 12 males (57.1%); ages 22-58 years (mean 38). Diagnoses: low back pain, 7 (33.3%); lumbosciatica, 6 (28.6%); disc herniation, 5 (23.8%); spondylolisthesis, 2 (9.5%); radiculopathy, 1 (4.8%). Evaluator 1: axial, 18 (85.7%); radicular, 3 (14.3%). Evaluator 2: axial, 14 (66.7%); radicular, 7 (33.3%). Validity results were appropriate. Internal consistency (Cornbach's alpha), 0.7. Test/ re-test time: 10-15 minutes. Inter-evaluator reliability (Kappa index), 0.5. CONCLUSION: The scale showed variability in identifying radicular pain compared to what its author reported initially. However, it is considered as a useful tool to clinically identify radiculopathy. PMID- 26021105 TI - [Severe hand injury due to a high-energy gunshot projectile treated with arthrodesis of the carpus, synthetic bone graft and external fixators. Case report]. AB - BACKGROUND: The incidence of hand gunshot wounds in civil patients has increased in recent years; it causes long-term or permanent disability and has a personal, social and economic impact. Severe hand injuries include: involvement of the greater palmar arch, fracture of two or more carpal bones, irreducible palmar dislocations, articular fractures of the distal radius, and neurovascular injuries. All of these injuries require multiple surgical procedures for the management of soft and musculoskeletal tissues. METHODS: We report the case of a patient with a Gustilo and Anderson grade IIIB open fracture of the right carpal bones caused by a gunshot projectile. He was treated with arthrodesis of the carpus using a synthetic graft, external fixation and rotation of a fasciocutaneous flap. RESULTS: The patient underwent surgical treatment of the carpal injury that consisted of Gustilo and Anderson grade IIIB open fracture of all carpal bones caused by a gunshot projectile. Surgery included arthrodesis of the carpus with a synthetic graft, stabilization with an external fixator, and a fasciocutaneous graft as skin cover. The clinical course according to the DASH scale had a score of 14.2 and the Michigan Hand score was 70, with a 12-month follow-up. CONCLUSIONS: Treatment with external fixation plus arthrodesis of the carpus with a synthetic graft and skin cover using a flap provided a good functional result in a patient who sustained a gunshot wound. PMID- 26021106 TI - [Intramuscular myxoma. Report of three cases]. AB - Intramuscular myxoma is a rare soft tissue benign tumor, arising from the mesenchyma; it presents as a slow-growing painless mass located usually in the thigh. Histologic diagnosis is necessary before resection and treatment consists of exeresis. There are no cases of malignization and recurrence results from incomplete resection. We report herein three cases of intramuscular myxoma treated at our center from 2004 to 2011. At the same time, we conducted a review of the clinical presentation, diagnosis, treatment and functional results. The same diagnostic and therapeutic protocol was used in all cases. It began with the patient's physical exam, and ultrasound and MRI as complementary tests. An incisional biopsy of the tumor was taken for anatomopathological studies and, finally, complete exeresis was performed. PMID- 26021107 TI - [Spondylodiscitis due to Fusobacterium nucleatum: new diagnostic method]. AB - Fusobacterium spp. are Gram negative anaerobe bacteria. Vertebral osteomyelitis caused by these bacteria is very unusual; in fact, we could only find 11 cases in the literature. We report the case of a male, 46 year-old patient who had had lumbar pain for several weeks that irradiated to the right leg, and did not respond to NSAID treatment. The work-up included MRI, biopsy with draining of the collection and a universal PCR followed by 16S rDNA sequencing. The latter was used to make the microbiologic diagnosis, which identified Fusobacterium nucleatum as the causative agent. Final treatment consisted of clindamycin. In conclusion, spondylodiscitis due to Fusobacterium spp. is a rare and difficult to diagnose entity, due both to its clinical characteristics and to the difficulty in making the right microbiologic diagnosis. Vertebral biopsy and molecular microbiologic techniques such as Universal PCR rDNa, are essential to identifying the organism, making the diagnosis and prescribing appropriate antibiotic therapy. PMID- 26021108 TI - [Treatment algorithm proposed for hallux rigidus]. AB - Hallux rigidus is the most frequent arthrosis of the foot and ankle and the second most important condition involving the first metatarsophalangeal joint after hallux valgus. If left untreated, it may cause important alterations in gait, mobility and activities of daily living. The purpose of this review article is to describe a complete treatment algorithm for all grades of this condition, after a thorough bibliographic review. PMID- 26021109 TI - [Medial unicompartmental knee arthroplasty with a phase 3 Oxford prosthesis. Results with a 2 to 11 year follow-up]. AB - INTRODUCTION: There has been great renewed interest in the past few years in unicompartmental arthroplasty for medial arthrosis of the knee due to the advantages over total knee replacement. METHODS: A retrospective epidemiological study was performed with 25 consecutive patients (30 knees) from January 2002 to September 2013, who underwent unicompartmental knee arthroplasty with a phase 3 Oxford prosthesis using polyethylene inserts with an ultra-congruent design. With an average follow-up of 6.1 years (1.1-11.5 years). The following demographical variables were analyzed: weight, size, body mass index and perioperative variables like hemoglobin, bleeding and surgical time; we evaluated the pre and post-operative function of patients according to clinical and functional scales. We performed a clinical and radiological evaluation of the implant to check for the presence of arthrosis changes in non-intervened compartments. RESULTS: We observed optimal survival of the implant. The clinical Knee Score Society improved from 61 in the pre-op to 84 at the end of the follow-up period, with 90% excellent and good results. At the end of the follow-up the average post-surgical flection was 120 degrees and full extension. Only two patients showed satisfactory results due to progression of the arthrosis in the lateral compartment and only one patient required conversion to total replacement in two surgeries due to a periprosthetic infection. CONCLUSION: Unicompartmental knee arthroplasty is a less invasive surgery with good clinical and functional results. The success of the procedure is based on the proper selection of patients. PMID- 26021110 TI - [Prognosis factors in carpal tunnel syndrome surgery]. AB - INTRODUCTION: Carpal tunnel syndrome is the most frequent peripheral neuropathy and it affects nearly 3% of the general population. Although electromyography tests have become the gold standard for diagnosis, currently there is controversy between the correlation of clinical data and electromyography for diagnosis. The purpose of this work is to study this correlation and determine the possible prognostic factors in this pathology. MATERIAL AND METHODS: 139 patients who underwent surgery were reviewed retrospectively between January 1995 and December 2008. All patients had an electromyography preoperatively to obtain motor conduction rate and latency, sensitive conduction rate and clinical examination, especially the Tinel and Phalen signs in order to correlate them with the final postoperative symptoms. In order to establish if there were statistically significant differences, these were determined through the T-Student and chi2. RESULTS: Preoperatively, there is a clinical correlation (p < 0.05) between the Tinel and Phanel clinical signs with the compression electrophysiological grading. Likewise, there is a correlation between clinical persistence in the postoperative period with motor conduction rate and latency involvement specified in the preoperative electrophysiological tests. CONCLUSION: Electrophysiological tests in the diagnosis of carpal tunnel syndrome have an added prognostic value with regards to the final result after surgery. PMID- 26021111 TI - [Effectiveness of two intraarticular drugs in patients with knee arthrosis. Polymerized collagen versus hylan]. AB - The purpose of osteoarthrosis treatment is to improve patient's pain and quality of life. Non-steroidal anti-inflammatory drugs are the first choice but their effectiveness is questionable due to the risk of secondary gastric disease and renal failure. Intra-articular drugs are a safe and effective alternative to improve symptoms and function; they may delay surgery but we don't know if they are disease modifying. Our objective was to compare knee function and pain in patients with osteoarthrosis until treatment is finished. Our hypothesis is that there is no difference in the results of both groups. MATERIAL AND METHODS: A prospective, simple, randomized non blinded trial where we studied two groups of patients with knee osteoarthrosis. Group 1 was treated with Collagen PVP and Group 2 received hylan GF-20. We gave patients a subjective questionnaire of the International Knee Committee IKDC and pain was measured using the visual analog scale at the beginning of treatment, after one month and after three months. RESULTS: Decrease in pain measured with the visual analog scale is statistically significant in both groups, however, when comparing both groups we did not find differences. The results of the IKDC were the same in both groups, there was no difference except in baseline measurements and in the final result. PMID- 26021112 TI - [Efficacy of thiamine pyrophosphate or carboxylase in the salvage of diabetic foot]. AB - Diabetic foot represents one of the most common complications in patients with a long standing disease. The etiology is neuropathy, infections and ischemia that together contribute to the sequence of tissue necrosis, ulceration and gangrene. Since treatment is very difficult, we must look for several options to solve these problems caused by chronic hyperglycemia. Thiamine pyrophosphate or carboxylase perform multiple metabolic and non-metabolic activities that are considered important in the resolution of diabetic impairments, therefore, this work shows the results when using it in patients with diabetic foot. 29 patients with diabetic foot were treated between January 1998 and July 2012: 19 Wagner type III and 12 Wagner type IV. Management was the administration of antibiotics, partial surgical procedures and thiamine pyrophosphate. The infectious process was controlled, the appearance of granulation tissue and scarring of the lesion in a period of 2 to 6 months depending on the severity of the problem. Given the clinical data and evolution of the patients, we conclude that the administration of thiamine pyrophosphate was able to control metabolic and non-metabolic dysfunctions that lead to complications in diabetic patients, therefore we must consider it a tool in the treatment of diabetic patients in general and for diabetic foot salvage in particular. PMID- 26021113 TI - [Competence perception survey among residents of orthopedics and trauma in a hospital of Yucatan Mexico]. AB - BACKGROUND: The competence model states that what is most important is to have the elements to solve problems since abstract training does not provide enough tools to solve them. Therefore, it uses key and auxiliary competences that are linked to values such as attitudes. This study was performed to explore these competences. MATERIAL AND METHODS: This is a cross sectional, observational and descriptive trial. An anonymous survey with profile data of Orthopedics and Trauma residents was given, it contained 14 questions for residents of different academic levels. RESULTS: 24 residents participated out of the 35 registered in the course. 100% agreed to answer the survey, 54% was in the second year, 29% in the first year and 17% in the fourth year. 75% expressed auxiliary competences, 13% did not respond, 8% developed key competences and 4% don't know. CONCLUSIONS: Three main factors that are a negative influence to improve the knowledge of orthopedics were expressed. The most relevant is that residents describe a bad attitude from attending physicians, lack of willingness to teach and, poor interpersonal relationships. Awareness should be raised among orthopedics specialists so they understand that having the knowledge and skills is not enough to approach health issues in a comprehensive manner for each patient and the development of better competences should be fostered, especially key competences. PMID- 26021114 TI - [Synchronous multicentric osteosarcoma: with multiple primary tumors or metastatic disease. Report of one case and literature review]. AB - Synchronous multicentric osteosarcoma, is a tumor with presentation in two or more sites without the appearance of lung metastasis. The incidence is 1 to 3% of all osteosarcomas and only less than 100 cases have been documented in the literature. In our case, we are presenting a six and a half year old patient with a painful tumor in the left thigh diagnosed with an incisional biopsy that reported a high grade conventional osteosarcoma in the left distal femur, a lesion in the contralateral limb in distal femur and proximal tibia, with no favorable response to chemotherapy. Lung and brain metastases were detected; therefore, we decided to give multidisciplinary palliative care for the disease. Years after its description there is still debate whether this condition really corresponds to a primary variable or to a manifestation of the metastatic disease. PMID- 26021115 TI - [Ectrodactyly of the foot]. AB - BACKGROUND: Ectrodactyly is a congenital malformation characterized by the presence of clefts in the feet accompanied by aplasia and hypoplasia of the phalanges and metatarsals. It is a rare genetic disorder with an incidence of 1:90,000-100,000 live births and it is not linked to sex. Its genetic pattern is autosomal dominant with a variable genetic penetrance. Clinical diagnosis is made at birth, however it can be prenatal through ultrasound during the first trimester. Management of ectrodactyly includes both surgical and non-surgical treatment. METHODS: We reviewed the archive of medical histories from January 2005 to January 2010, we included all patients with an ectrodactyly diagnosis. We found two patients who were treated surgically and were followed-up for three years. RESULTS: The long term evolution was favorable, allowing the patient to wear shoes and walk. There were no recurrences or complications observed. The final results were good according to the Tani et al scale. DISCUSSION: According to our medium and long term results in the management of these two cases of ectrodactyly, we recommend the combination of conservative orthopedic treatment as preparation for surgery and the final resolution with closure of the cleft. The surgical treatment performed and appropriate postoperative management allowed the patient to wear shoes, to improve function and appearance in both cases. PMID- 26021116 TI - [Axial-fracture dislocation of the carpal bone, report of three cases and literature review]. AB - We report three cases of axial-fracture dislocation of the carpal bone treated in our department. The three men were between thirty and forty years old who had a work related crushing fracture. We performed an open reduction and stabilization with pins in all cases; patients were then referred to physical medicine and rehabilitation. We assessed the wrist function at ten months using the Mayo Wrist Score and with X-rays to evaluate postoperative results. In this summary we present three examples of patients who suffered these injuries with "good", "satisfactory" and "poor" outcomes. PMID- 26021117 TI - [Total knee replacement due to grade IV gonarthrosis]. AB - OBJECTIVE: To describe the clinical evolution of patients with total knee replacement surgery due to grade IV gonarthrosis secondary to varus angular deformity. MATERIAL AND METHODS: A descriptive trial where we included patients who underwent total knee arthroplasty due to gonarthrosis secondary to varus angular deformity. We used the following variables, sex, age, affected side, type of approach, type of prosthesis, type of gait post-surgically, infection, vascular status, post-surgical pain, rejection of prosthetic material, varusflection angular deformity pre and post-surgically. RESULTS: We reviewed 13 files, 69.2% men and 30.8% women, the mean age was 72.38, minimum 56, maximum 82, DE 7.11 years. Six (46.2%) left knees and 7 (53.8%) right knees. All patients had a medial parapatellar approach and bone balancing, 23.1% had ligament balancing; 7.6% had a total knee replacement stabilized posteriorly and 93.3% not stabilized posteriorly; 1 (7.6%) patient had infection, none had vascular involvement, 76.9% had to walk with a cane, 15.4% walked on their own and 7.6% had no gait. The average grade of the angular deformity pre-surgery was 15.77 and the average post surgery was less than or equal to 5 degrees, the difference of average grades pre and post-surgery was 36.719 and in flection 0.439, p = 0.00 and p = 0.669 respectively (paired t). CONCLUSION: We can conclude that the clinical evolution of patients with gonarthrosis secondary to varus angular deformity who underwent TKA is good, complications are similar to those in the literature. PMID- 26021118 TI - [Tarsal tunnel syndrome. Review of the topic as a result of one case]. AB - The first description of tarsal tunnel is attributed to Richter in 1897, in 1932 Pollock and Davis described the syndrome for the first time, in 1960 Kopell and Thompson described the clinical features of tarsal tunnel syndrome; and in 1962 Charles Keck described tarsal tunnel syndrome in a detailed manner with clinical cases. We present the case of a 61 year old female patient who presented symptoms in 2010, she had intermittent talalgia that increased gradually, six months later pain is constant and limiting gait, EVA is 6/10, she is diagnosed with plantar fasciitis and is referred to physiotherapy with no improvement after two months of treatment. The plantar fascia ultrasound reports thickening with micro tears in the heel bone attachment, we infiltrated the plantar fascia with platelet rich plasma with no improvement, two months later she has shock wave sessions with no changes observed. We reassess the case and make the diagnosis of tarsal tunnel syndrome clinically and with electromyography and in 2011 we infiltrate a steroid with local anesthesia with temporary improvement. In 2012, we found an EVA of 7/10 and an AOFAS of 54 points, we perform surgery and the intraoperative finding is a varicose vein that decreased the caliber of the tarsal tunnel compressing adjacent structures. The clinical case is presented and we reviewed tarsal tunnel syndrome in the literature. PMID- 26021119 TI - [Embryos and gametes cryopreservation for genetic resources conservation of laboratory animals]. AB - Article reviews the use of embryos and gametes cryopreservation for cryobanking the laboratory animal species. The special emphasis is made on the mechanisms of cryoinjury and cryoprotection during program freezing and vitrification. The species specific cryobanking problems are discussed and the prospects to overcome these problems are outlined. PMID- 26021120 TI - [The role of ethylene in activation division cell quiescent center in the cut maize roots]. AB - In the present work we used two maize cultivars in which root meristem responded differently to root tip excision: in Interkras-375 MW we observed meristem opening due to the activation of cell divisions in the quiescent center (QC), while in Krasnodar-194 MW the meristem remained closed. Excised root tips of Interkras M B-375 were shown to produce much more ethylene than excised root tips of Krasnodar-194 MW The inhibitor of ethylene biosynthesis L-alpha-ethoxyvinyl 2amino-glycine-HCl (AVG) and inhibitors of ethylene action AgNO3 and 1-methyl cyclopropene (MCP) prevented meristem opening in excised root tips of Intekras 375 MW. The obtained results allow us to conclude that ethylene plays an important role in the activation of cell divisions in the QC of excised root tips. PMID- 26021121 TI - [Sex identification of the rainbow trout Oncorhynchus mykiss by polymerase chain reaction]. AB - A polymerase chain reaction-based test for rapid sex identification of the rainbow trout Oncorhynchus mykiss has been elaborated. Using the data deposited with the NCBI genome bank, nucleotide sequences of the specific sex-linked locus of salmonid species have been analyzed and the oligonucleotide primers have been selected. The length of the amplification products is 800 nucleotide pairs. Amplification specificity has been tested by nucleotide analysis of the amplicon sequences. All PCR products match the Y chromosome region housing the corresponding specific locus. A comparative analysis of the nucleotide sequences of the fragments carrying the rainbow trout (and other salmonid species) sex linked marker demonstrates a high degree of identity, amounting to 95-99%. The maximal identity between the sequences (99%) is observed when analyzing representatives of the same genus, for example, Oncorhynchus. Thus, the sex is detectable by a simple PCR test, thereby allowing the male revertants emerging via hormonal sex reversion to be identified. This test is a rapid diagnostic method, since it requires only 1 day for testing and informing the fish farm on its results. Results of abdomen opening of rainbow trout revertants and examination of their hormonal status are also described. PMID- 26021122 TI - [Some molecular and genetic properties of progenitor cells in sarcomas induced with foreign body]. AB - One of the important questions in understanding the mechanisms of carcinogenesis induced with foreign body (or plastic carcinogenesis), is a question about normal progenitor cells in sarcomas (FB sarcomas) appearing in close proximity to the plastic plate implanted under the skin of an experimental animal. There is an assumption in literature that progenitor cells in FB sarcomas originate from vascular endothelium cells feeding a connective tissue capsule that forms around foreign body. In our research, we studied mRNA expression of one of the endothelial cell markers--receptor VEGFR2/FIk1--and growth factor VEGF-A, which interacts with it, in precancerous cells of FB sarcomas in mice. In examined cells, mRNA expression of VEGF-A was found while mRNA expression of VEGFR2/FIk1 was absent. In light of this and formerly established properties of progenitor cells in FB sarcomas, possibilities of the origin of these sarcomas from endothelial cells, pericytes, and pluripotent mesenchymal stem cells are being discussed. PMID- 26021123 TI - [Epigenetic mutagenesis as program of age-related protein dysfunction and aging]. AB - DNA methylation plays an important polyfunctional role in ontogenesis of human and mammals. A steep rise in probability of mutational substitution of CpG dinucleotide on TpG dinucleotide in the genome is one of the consequences of DNA methylation. All spectrum (17) of possible DNA and protein mutations caused by CpG-dinucleotide methylation in DNA were characterized, and the three most dangerous mutations (able to result in protein inactivation) were isolated. The computer program that allows one to predict all most probable mutations in the analyzed gene and encoded protein was created. On the example of genes from humans and various mammals, it was demonstrated that the amount of potentially dangerous sites of epigenetic mutagenesis in exons was drastically decreased as a result of genome evolution. But, at the same time, unforced preservation of such sites and their persistence were established, indicating the occurrence of age related protein dysfunction built into the genome epigenetic program, resulting in apoptosis and aging; this program is based on the set and position of methylated codons in exonic gene regions. It is assumed that the program of epigenetic mutagenesis limits the lifetime of an individual, accelerating the deliverance of the population from long-lived individuals that completed the reproductive period. PMID- 26021124 TI - [Developmental abnormalities in salmonids (Salmonidae) under the conditions of large-scale volcanic pollution of their spawning ground (using dolly varden Salvelinus malma as an example)]. AB - Rivers originating from the areas of active volcanism in Kamchatka serve a spawning ground for anadromous and resident populations of dolly varden (Salvelinus malma). In some cases, watercourses with a long-term continuous spawning of S. malma are subjected to chronic pollution with dissolved toxicants and suspended mineral particles. The revealed development conditions range from background ("clean" rivers) to critical (most "polluted" rivers). Medium pollution leads to the development of hatchlings with abnormalities in the ethmoidal head segment, lower jaw, operculum, lobes of the paired fins, and axial skeleton (up to 40% of all specimens). Delayed ossification of skeletal elements takes place. Abnormalities in the development of spinous processes occur more often (up to 49-55% compared to 25-30% in the background areas). The average number of asymmetries per specimen.(in four bilateral structures) increases from 1.1-1.4 to 1.7- 2.5. Similar developmental abnormalities have been registered in underyearlings, both anadromous and resident, influenced by various pollutant combinations. While fish continue to grow, some of them die because of abnormalities; thus, their frequency in 3-year-old specimens nears the background one. Upon extreme pollution, deviant specimens are sampled at earlier developmental stages and characterized by a lower frequency of morphological abnormalities. PMID- 26021125 TI - [Caspar Friedrich Wolff: the emergence of epigenesis]. AB - The role of C.F. Wolff, an outstanding anatomist and embryologist, in the development of embryology is described to mark the 280th anniversary of his birth. His life and work were fully elucidated in the book of A.E. Gaisinovich, a famous historian of biology. Although the alternation of preformation and epigenesis is accompanied by a succession of ideas, the boundary between these concepts is clearly retained and depends on many social and cultural factors. PMID- 26021126 TI - [Dysregulation of microRNA in thalassemia]. PMID- 26021127 TI - Clinical significance of the laparoscopic bariatric surgeries for morbid obesity: initial 30 cases at a single institution in Japan. AB - BACKGROUND: Bariatric surgical procedures are becoming a standard treatment for morbid obesity in many western countries and in some Asian countries. AIM: The aim of the current study was to evaluate the efficacy and safety of the initial 30 cases of bariatric surgical procedures performed for morbid obesity at a single institution in Japan. MATERIALS AND METHODS: From March 2012 until September 2014, 30 bariatric surgical procedures were performed for morbid obesity at a single medical center (Kyushu University Hospital) in Japan. RESULTS: All of the operations procedures were planned laparoscopic procedures, and none required conversion to laparotomy. There were no perioperative or postoperative mortalities. Postoperative complications occurred in 3 patients: 1 patient developed an intra-abdominal abscess, 1 patient experienced temporary food intolerance, and 1 patient developed small bowel obstruction. The excessive body weight reduction rates after surgery at 1 month, 3 months, 6 months, and 1 year post-surgery were 26.1%, 39.2%, 41.7%, and 51.2%, respectively. The mean body mass index (BMI) at the same time points were 38.3%, 36.4%, 35.5%, and 31.4%, respectively. Eighteen patients had type II diabetes mellitus (T2DM). The mean preoperative fasting blood glucose levels were 169 +/- 37 mg/dL. Following surgery, the blood glucose levels at 3, 6 and 12 months were 113 +/- 12, 115 +/- 22, and 110 +/- 19, mg/dL, respectively. The preoperative HbA1c percentage was 7.9 +/- 0.5. Following surgery, the HbA1c percentages at 3, 6, and 12 months were 6.9 +/- 0.5, 6.2 +/- 0.9, and 5.9 +/- 0.6, respectively. CONCLUSIONS: Bariatric surgical procedures are effective and safe for the treatment of morbid obesity. Our results indicate that the mechanism of improvement of diabetes and related diseases following bariatric surgical procedures is not simply as a result of calorie restriction and weight reduction. PMID- 26021128 TI - [Stent graft for rapidly growing thoracic mycotic aneurysm in a patient with advanced lung cancer]. AB - We report a compromised patient with mycotic aneurysm, who was successfully treated by urgent placement of a stent graft. A man in his seventies was admitted to our hospital with relapsing high fever and back pain during chemotherapy for advanced squamous cell carcinoma of the lung. Contrast CT demonstrated a saccular aneurysm of the thoracic aorta and left pleural effusion. Blood cultures were positive for Escherichia coli producing extended spectrum beta-lactamase (ESBL). Therefore, thoracic mycotic aneurysm was diagnosed. Because of rapid growth on consecutive examinations, absolute bed rest was required. Therefore, we performed antibiotic therapy combined with stent graft placement, which achieved complete exclusion of the aneurysm. He was discharged in an ambulatory state, and his quality of life remained good at home until just before death from terminal state of the cancer. PMID- 26021129 TI - Revisiting professional ethics and the nursing care model in an era of healthcare reform. PMID- 26021130 TI - Patients tell the story: interrelationships among patient satisfaction, communications with providers, and emergency department care. AB - This study examines the relationship between four variables and patient satisfaction in an emergency department setting in a small community hospital in Suffolk County New York. Patients were assessed utilizing four variables: communications with doctors, communications with nurses, communications with ancillary staff, and environment of ED care. The study adds to the literature on which factors have the greatest influence on patient satisfaction in an emergency department setting. The purpose of the present study was to explore how ED patient satisfaction was influenced by their communications with physicians, nurses, and ancillary staff. Pearson correlation coefficients resulted in a statistically significant correlation between all variables and patient satisfaction. Path analysis showed the interrelationship between the four variables and patient satisfaction. Regression analysis predicted the extent to which each variable influenced patient satisfaction. The strongest predictor of patient satisfaction was communications with ancillary staff. PMID- 26021131 TI - Perspectives on academic misconduct: implications for education and practice. AB - From Harvard to high school, concern related to academic misconduct, specifically cheating and its impact on societal issues, has become a great concern for educational communities. While a significant number of studies on ethical behaviors in practice in other professions such as business have been published, little research exists on registered nurses in practice. Even fewer studies have, for registered nurses, addressed if there is an association between perceived academic misconduct as students and perceived unethical behaviors in the workplace. The purpose of this study was to determine the relationship between perceptions of registered professional nurses' (RNs) current workplace behaviors and the RNs' retrospective perceptions of their academic misconduct as students. A convenience sample of 1 66 RNs enrolled in master's degree programs at four university schools of nursing completed questionnaires regarding their beliefs and behaviors. The outcome of this study was significant. Results revealed a strong relationship between unethical behaviors of the RN in practice and their prior academic misconduct when they were students. PMID- 26021132 TI - Psychosocial needs of cancer patients living in the Adirondacks: a needs assessment. AB - As the national conversation on solutions to healthcare factors such as affordability and access is likely to intensify, health inequities continue to persist in rural areas. National studies suggest a growing, aging, rural population impacting the revenues of local healthcare facilities, as well as contributing to complexity of care. This paper examines factors influencing the health of rural citizens in upstate New York and offers the results of an initial needs assessment looking at the psychosocial healthcare needs of cancer patients living in the Adirondack Park region. Patients were surveyed regarding their perceptions of psychosocial needs and experiences as a cancer patient. Psychosocial factors while acknowledged as important influences on recovery and healing remain an underdeveloped intervention toward improving the quality of cancer care. Recommendations are made based on the results to enhance the quality of life for this vulnerable population. PMID- 26021133 TI - The answer is questions: accelerated-nursing students report practice questions are fundamental to first-time NCLEX-RN success. AB - There are a number of anecdotal reports on demographic characteristics and academic success of accelerated-nursing students; yet few empirical studies have examined accelerated-nursing students NCLEX-RN success. Applying Knowles' adult learning theory as a guiding framework, the purpose of this qualitative study was to explore, from the accelerated-nursing students' perspective, the factors reported as contributing to their success on the NCLEX-RN. The research questions aimed to elicit participants' descriptions of their experiences and factors contributing to their success via individual interviews. The most significant finding the participants identified as the factor that contributed to their success was the practicing of NCLEX-RN questions. The findings of this study have several implications for educational policy and practice for universities and schools of nursing as the information gained from this study applies to recruitment and retention as well as curriculum and educational strategies in an accelerated-nursing program. PMID- 26021134 TI - [Warning shot of the WHO]. PMID- 26021135 TI - [Psoriasis: advances and challenges in 2015]. AB - Over the course of the last decade advances in the understanding the pathogenesis of psoriasis have resulted in the development of many novel, safe and effective biologics. However, a significant proportion of patients respond inadequately to biologics--defined by failing to respond initially (lack of efficacy) or secondary failure--with diminishing response over time (loss of efficacy). Over the past years insights into molecular and genetic profiles have allowed to better define psoriasis phenotypes and to explain these therapeutic failures. Here we will illustrate these advances, describe the novel therapeutics on the horizon and review the current view of psoriasis as a systemic disease associated with co-morbidities and its important implications for the management of psoriatic patients. PMID- 26021136 TI - [Recurrent erysipelas and cellulitis: management]. AB - Erysipelas and infectious cellulitis are skin infections that develop following the entry of bacteria through gaps in the skin. The most common complication is recurrence. Control of predisposing factors remains essential to prevent it. Prophylactic antibiotics are sometimes prescribed, but this approach is based on small studies and expert opinion. This article reflects the current state of knowledge and the standard of care. PMID- 26021137 TI - [What's new in pediatric dermatology]. AB - Progress in paediatric dermatology is achieved in both research and therapeutic fields. In infectiology, scabies and bed bugs are a scourge for dermatologists, with an important recent outbreak. This article describes the fundamental clinical signs to look for, when suspecting such diagnosis. Hair dermatoscopy seems to be also very precious as a new tool for the diagnosis of ringworm. Regarding eczemas, atopic dermatitis is supported by S. Aureus's skin colonization, the target of eradication of new products in ongoing studies. We will also explain the role of Hemangiol, recently marketed in Switzerland for the treatment of haemangiomas. Alternative beta blockers have also a large number of ongoing projects in the dermatological vascular diseases field. Other various news is to be discovered.... PMID- 26021138 TI - [Chronic leg ulcers and Pseudomonas aeruginosa infection]. AB - Pseudomonas aeruginosa (PA) is a Gram-negative germ, responsible for severe infections. PA infected chronic wounds are a clinically highly relevant topic. PA has a natural resistance to many antibiotics, and there is no consensus on a first-line antibiotic to be used. In the context of chronic ulcers with an unfavorable evolution, we suggest intravenous antibiotic therapy, ideally on an in-patient basis. Given the sparse evidence from clinical trials, we heavily rely on clinical experience when it comes to managing chronic ulcers infected with PA. PMID- 26021139 TI - [Antisepsis of wounds: when and what?]. AB - Bacterial colonisation of a wound is a normal process and usually not dangerous. The role of micro-organisms in the healing process is not fully elucidated, however it is well known that infection interrupts healing and even worse can severely threaten the organism. We present the different types of antiseptics that are used in treating wounds as well as their interactions. We would like to remind the reader that antiseptics are more effective than antibiotics with much fewer resistances. Finally, we provide a flow chart for a reasonable treatment of chronic wounds. PMID- 26021140 TI - [Dermatological implications of omalizumab, an anti-IgE antibody]. AB - The Omalizumab is a humanized anti-IgE monoclonal for which the extensive experience of its use in allergic asthma confirms its very good tolerance. By frequent association with asthma, atopic dermatitis is the first dermatological field has having tested this biological agent, unfortunately without convincing study at present. Surprisingly, this anti-IgE antibody is also reported as effective in certain non-IgE-mediated diseases including several dermatological indications. Since 2014, the Omalizumab got the indication in Europe for the treatment of chronic spontaneous urticaria after escapement to antihistamines. It also seems promising for prevention of anaphylaxis in mastocytosis and some refractory bullous pemphigoid. PMID- 26021141 TI - [Innovative concept in ultrasonography training targeted for the intensivist using e-learning and simulation]. PMID- 26021142 TI - [Treatment of dyslipidemias with statins in primary and seconary prevention]. PMID- 26021143 TI - [Response by Prof N. Rodondi]. PMID- 26021144 TI - [Response by Prof. F. Mach]. PMID- 26021146 TI - [Thumb]. PMID- 26021145 TI - [At what price could colorectal cancer become a chronic condition?]. PMID- 26021147 TI - [Ebola: accusations of MSF, silence of WHO]. PMID- 26021148 TI - [Influence of nalmefene on psychosocial intervention in alcohol-dependent patients]. PMID- 26021150 TI - [Cardiac surgery: extensive consolidation in Zurich]. PMID- 26021149 TI - [Angelina Jolie Pitt, saint and modern martyr]. PMID- 26021151 TI - [More than 30% of doctors in Switzerland come from abroad]. PMID- 26021152 TI - [The wanderings of the Federal council]. PMID- 26021153 TI - [Molecular-genetic mechanisms of cornea morphogenesis]. AB - In this paper, we analyzed our own results and published data on the expression of regulatory genes encoding transcription factors Pax6/PAX6, Pitx2/PITX2, Fox1/FOXC1, Prox1/PROX1, Oct4/OCT4, Nanog/NANOG, and TGFbeta2 signaling protein during morphogenesis of the cornea in vertebrates. We considered the results obtained for the cornea of model animals, primarily mice, and human fetal cornea. The main possibility of establishing common mechanisms of eye development in vertebrates in health and disease is comparative studies of eye morphogenesis of humans and animal models. PMID- 26021154 TI - [Diversity and viability of prokaryotes in primitive soils of the larsemann oasis (East Antarctica)]. AB - The diversity and viability of prokaryotic communities in the primitive organomineral soils of East Antarctica have been studied; it has been shown that the total number of bacteria is smaller than and the viability of bacteria is similar to that in soils of the temperate zone. The prokaryotic communities are characterized by the occurrence of a major part of cells in filterable forms, which is higher than the analogous parameter for the temperate soils. The method of fluorescence in situ hybridization (FISH) revealed that the distribution of the main taxons is similar to that in the temperate soils: the portion of the domain Archaea is smaller than that of the domain Bacteria; the total content of Gram-negative bacteria (the phyla Proteobacteria, Acidobacteria, and Planctomycetes) is higher than that of Gram-positive bacteria (Actinobacteria). Within the phylum Proteobacteria, a significant variation of three proteobacterial classes has been noted along the profiles of the soils studied. PMID- 26021155 TI - [Influence of abscisic acid and fluridone on the content of phytohormones and polyamines and the level of oxidative stress in plants of Mesembryanthemum crystallinum L. under salinity]. AB - The effect of abscisic acid (ABA) and fluridone on the content of endogenous phytohormones and free polyamines and the intensity of oxidative stress was studied in plants of Mesembryanthemum crystallinum L. under salinity. It was shown that the pretreatment of plant roots with 1 MUM ABA, followed by the action of 300 mM NaCl, caused a protective effect and improved the physiological state of the plants, which was manifested in increased biomass and content of available cytokinins and reduced values of the indicators of oxidative stress. It was noted that the inhibitor fluridone reduced the effect of ABA and acted as a pro oxidant. PMID- 26021156 TI - [The oral sucker muscles of six representatives of the order Paramphistomatida (Plathelminthes, Trematoda)]. AB - The spatial arrangement of muscles in the oral suckers of six trematode species belonging to five families of the order Paramphistomatida is described. The functional load and adaptive significance of different muscle groups in the suckers themselves and the associated structures--preoral lip and muscular cap- are discussed. Complete section series in three projections have been examined; this demonstrates the presence of previously unnoticed structures, namely, semicircular and diagonal muscles, regulating shape of the oral cavity, and short longitudinal muscles, acting as a sphincter, as well as localization of the largest internal muscles on the sucker lateral sides. It has been shown that the presence of internal longitudinal muscles suggests that the organs in question are closer to the oral suckers of other trematodes rather than to their pharynxes. PMID- 26021157 TI - [Cytomorphological and biochemical characteristics of the whitefish, Baikal omul Coregonus migratorius, infected by plerocercoids of Diphyllobothrium dendriticum (Cestoda: Pseudophyllidae)]. AB - The cytomorphological and biochemical composition of the blood has been studied for the deep-dwelling (bottom) morphotype of the Baikal omul infected by plerocercoids of Diphyllobothrium dendriticum, during the fish spawning migration. A decrease in hemoglobin synthesis and an increase in the proliferative activity of erythroid cells have been registered. The changes in the leukocyte population composition, immunoglobulin, and total protein concentrations evidenced a disorder of blood cell proliferation and differentiation and suppression of the immune response in the infected fish. The changes in the humoral and cell factors of homeostasis in Coregonus migratorius infected by D. dendriticum during the spawning period remain within the limits of the adaptive possibilities of the species. PMID- 26021158 TI - [Reduction of plant fibers in the digestive tract of two pika species (Ochotona pallasi and O. dauurica, Lagomorpha, Ochotonidae)]. AB - The distribution of fibers of different sizes in the gastrointestinal tract in two species of pikas--Pallas' pika Ochotonapallasi and daurian pika O. dauurica- was studied. It was established that fibers of small-sized fractions dominated in all organs of the digestive tract of both pika species, the proportion of which in the stomach proved to be even higher than in fine-grinding voles. No distinct changes in the composition of the size fractions of fibers from organ to organ were observed in the studied individuals of both species, which may be due to frequent consumption of finely dispersed cecotrophs by pikas, which enrich the primary chewed food with small fibers. PMID- 26021159 TI - [Allosteric effect of serotonin and mianserin on the kinetics of specific [3H] ligand binding to adrenergic and muscarinic receptors in the rat cerebral cortex membranes]. AB - The effects of serotonin receptor activation (by serotonin) and inhibition (by mianserin) on the properties of the alpha1-, alpha2-adrenoreceptors, and muscarinic cholinergic receptors in subcellular membrane fractions from the rat cerebral cortex were studied. Experimental data on the kinetics of specific antagonists binding to adrenergic and muscarinic receptors were analyzed by graphical and mathematical methods. The results suggest the presence of allosteric (cross-talk) interaction. In the control, alpha1- and alpha2 adrenoreceptors were represented by a single pool, and muscarinic receptors, by two pools. Two pools of adrenoreceptors with different affinity were detected against the background of serotonin. It was found that mianserin induces the formation of two pools of only (alpha2-receptors and muscarinic receptors are represented by two pools differing in the main parameters, such as dissociation constants and adrenoreceptor concentrations, in the control and experimental groups. It was shown that the allosteric effect of serotonin and mianserin is manifested in the inhibition of muscarinic receptors. It was assumed that the adrenergic and cholinergic receptors exist as dimers. The interaction between the adrenergic, cholinergic, and serotonergic systems is likely to be implemented at the cell membrane level. PMID- 26021160 TI - [Electrical activity and circulatory effects of nitrite in the rat cerebrum]. AB - An association between the cerebrum electrical activity (CEA) in rats, blood supply of its cortex microregions (linear blood flow), and general cerebrum blood flow under acute nitrite hypoxia was studied. The phase character of the change in hemodynamic indices and the total capacity of electroencephalography (EEG) spectrum for 75 min after sodium nitrite introduction (30 mg/kg of body weight) was detected. The first phase (30 min) was associated with cerebrum adaptation to hypotension caused by nitrite and was completed by EEG normalization. The second phase was characterized by pathological EEG changes (in spite of restoration of hemodynamics in the cerebrum) caused by the growth of oxygen debt in the nervous tissue as a result of a decrease in the blood oxygen capacity by 60-75 min of the effect of nitrite. PMID- 26021161 TI - [Factors limiting distribution of the rare lichen species Lobaria pulmonaria (in forests of the Kologriv Forest Nature Reserve)]. AB - The distribution patterns and coenotic confines ofthe epiphytic lichen Lobaria pulmonaria have been studied. The factors limiting the habitat of this rare lichen species in the Kologriv Forest Nature Reserve (southern taiga subzone) have been revealed. It has been shown that L. pulmonaria is attracted to forest areas, which are less affected by humans and characterized by better light conditions than other communities. It has been found that L. pulmonaria is able to colonize trees at various ontogenetic states, beginning from virginal ones. PMID- 26021162 TI - [Ethological-physiological effects of hypoxia on the honeybee Apis mellifera L]. AB - Information on the effect of hypoxia on the behavior and physiological state of the honeybee was compiled and systematized. It was shown that, in the course of colonization of temperate and cold climate zones by the honeybee, natural selection favored the acquisition of an effective mechanism of thermoregulation and high tolerance to hypoxia. It was noted that bees can develop under conditions when the CO2 concentration exceeds the content of this gas in the surface layer of the Earth by more than three orders of magnitude; however, this leads to deviations in the morphometric traits from the norm. At the adult stage, anesthesia with carbon dioxide was found to reduce the body weight and the water content in it. It was shown that the effect of anesthesia in adult bees increases with temperature and that hypoxia in adult bees and queens accelerates their senescence and reduces viability. PMID- 26021163 TI - [Forage availability to saigas (Saiga tatarica) and their state on steppe pastures with a different ratio of graminoid plants and forbs]. AB - An interfaced analysis of change of forage vegetation, nutrition of saigas (Saiga tatarica), and their state in tne steppe regions of Russia is performed. It is noted that the percent of graminoids has increased considerably and the proportion of forbs has decreased in the vegetation of current pastures, which has had a negative impact on the nutrition and state of saigas. It is shown that the lower nutritional value of graminoids has caused a decrease in the digestibility of forage used by saigas and does not provide the physiological requirements of the animals. It is established that modern steppe pastures, where gramineous communities prevail, are of little use or absolutely unsuitable for the stable existence of saiga populations. Only separate dwelling places with an abundance of forbs continue to provide adequate nutrition for saigas and well being for their local groupings. PMID- 26021164 TI - [Anniversary of Marina Vladimirovna Kholodova]. PMID- 26021165 TI - [New achievements in the development and study of the mechanisms of action of the low molecular weight agonists of receptors of the thyroid-stimulating and the luteinizing hormones]. AB - Pituitary glycoprotein hormones, luteinizing (LH) and thyroid-stimulating (TSH), exert their regulatory effects on cells through the G protein-coupled receptors, specifically binding to their extracellular domain. There is an alternative way of activation of LH and TSH receptors, when low molecular weight organic molecules bind to an allosteric site of the receptors which is localized within their transmembrane channel. Low molecular weight agonists have many advantages over glycoprotein hormones, among them a high efficiency not only in the case of the parenteral but also in the oral administration, low immunogenicity, chemical stability, and a low cost. Unlike pituitary glycoprotein hormones with the agonistic activity, low molecular weight compounds may be either agonists or inverse agonists and neutral antagonists. Recently it was shown that low molecular weight agonists of LH receptor are able to stimulate its mutant forms by restoring the processing of receptor in a cell, and by increasing its sensitivity to LH, which is important for the treatment of reproductive dysfunctions caused by mutations in the LH receptor. This review summarizes the recent achievements that are linked with the development of low molecular weight regulators of TSH and LH receptors and the study of their mechanisms of action. It also presents the author' data concerning the creation of new low molecular weight agonists of LH receptor based on the thienopyrimidine structure, which are effective both in vitro, and in vivo in different ways of administration. PMID- 26021166 TI - [Knotted proteins]. AB - For a long time the presence of knots in a protein structure was not admitted. However, the existence of proteins with various types of knots has now been proven. The functional significance of knotted topology remains unclear despite numerous assumptions. Studing the structure of knots in proteins and their impact on the acquisition of native structure of proteins is important for the understanding of protein folding as a whole. We review the types of knots in the proteins discovered to date, including trefoil knot, figure-of-eight knot, and more complex knots with 5 and 6 crossings of polypeptide chain. We survey the folding of knotted proteins as well. PMID- 26021167 TI - [The role of mitochondrial dynamics in cell death]. AB - Mitochondria are dynamic organelles whose homeostasis is defined by two opposite processes: fission (or fragmentation), or fusion. Fission of mitochondria results in generation of smaller organelles and fusion is when they produce tubular or net-like structures. Although a number of proteins are already known to control the process of fission/fusion additional regulators controlling these processes are being found. The Bcl-2 family members take part in the regulation of apoptosis and according to the current view are involved in the mitochondrial net like structure maintenance. In this review we will discuss mechanisms of mitochondrial fission/fusion regulation and summarize the available information on the role of Bcl-2 family members in the regulation of mitochondrial fission/fusion dynamics. PMID- 26021168 TI - [DNA methylation level and telomere length as a basis for the biological aging clock model construction]. AB - Aging is a process that depends on a variety of both external and internal factors. The biological age of a person determines body deterioration and the risk of age-related diseases. Currently, as indicators of biological age are considered different characteristics including average length of telomeres in cells and the level DNA methylation. We propose to combine the two approaches to create a model to assess the biological age of the person. Application of qPCR to determina the length of telomeres and MS-HRM for analysis of DNA methylation will help us to determine the parameters of interest quickly when using a minimum set of equipment. PMID- 26021169 TI - [Mesenchymal stem cells influence on leukocytes allergen-specific reactions in case of atopic hypersencitivity]. AB - Buffy coat samples containing lymphocytes, monocytes and granulocytes, were obtained from the peripheral blood of 16 donors who had clinical manifestations of atopic hypersensitivity in their medical background. After ex vivo incubation with donor-specific allergens, the percentage of B- and T-lymphocytes and natural killers (NK) remained unchanged. Buffy coat incubation with allergens induced production of IgE and IL-4 in all studied samples. In 13 out of 16 cases the reaction to contact with an allergen was also evident in the increasing of T activated lymphocytes (CD3+, HLA-DR+) subpopulation. Co-cultivation with MSC from bone marrow, adipose tissue and umbilical cord resulted in blocking of allergen induced IgE and IL4 secretion and HLA-DR+ T-lymphocytes subpopulation increase. There were no significant differences in the effect of MSCs, isolated from three different sources, on allergen-specific responses of leukocytes. Co-culturing of leukocytes with MSCs from all three sources led to an increase in the content of regulatory T-lymphocytes by an average of 30%. Thus, the immunomodulatory activity of MSCs in vitro results in blocking of the effector part of allergic reactions. PMID- 26021170 TI - [Histone deacetylase inhibitors cause the TP53-dependent induction of p21/Waf1 in tumor cells carrying mutations in TP53]. AB - p21/Waf1 protein is one of the main cell cycle arrest regulators and one of the most well-known transcriptional targets of TP53 protein. Here, we demonstrated the activation of expression of the p21/Waf1 gene when the cells were treated to sodium butyrate (NaBu)--one of the natural inhibitors of deacetylase, and investigated whether this phenomenon depends on the presence of functionally active TP53 protein. We compared the effect of the NaBu treatment on the human cell line with different TP53 mutation profile, including: wild-type TP53, single nucleotide substitutions, and the complete absence of TP53 gene. NaBu activated the TP53 protein via hyper acetylation at lysine residue K382, without significant changes in the level of protein expression. Western blotting demonstrated that the addition of NaBu triggers a significant increase in the p21/Waf1 protein level in both the TP53 wild-type cells and in the cells with single nucleotide substitutions in the domain responsible for the binding of TP53 protein to DNA. At the same time, no the p21/Waf1 protein induction was observed in the cells with complete deletion of the TP53 gene. However, NaBu was not able to induce the p2 1/Waf1 production when the expression of TP53 was transiently knocked down by the p53 siRNA. Overall, our results suggest that the NaBu dependent induction of p21/Waf1 does require the presence of TP53 protein but unexpectedly it can occur regardless of mutational changes in the domain responsible for the TP53 binding to DNA. One of the hypothetical explanations is that NaBu increases the level of TP53 acetylation, and the modified protein is able to establish a new network of protein-protein interactions or trigger some conformational changes affecting the TP53-dependent transcriptional machinery even when its DNA binding ability is impaired. PMID- 26021171 TI - [Selection of reference genes for transcription analysis for myocarditis studies]. AB - Myocarditis is defined as myocardial inflammation, followed by cardiomyocyte necrosis. Diagnostics of myocarditis is based on unsafe and complicated method of endomyocardial biopsy (EMB). Development of myocarditis might alter gene expression not only in cardiac but in peripheral blood cells (PBC) as well. So, transcription profiles can be considered as possible biomarkers for the given pathology. At the moment, there are no reference genes defined for expression analysis in myocarditis studies. In this study, we analyzed mRNA content of six housekeeping genes in EMB and PBC samples. An algorithm for processing qPCR results obtained under the limited amount of sample is proposed. Set of GAPDH and HPRT1 genes has been selected for normalization of gene expression profiles in cardiac tissue and blood cells under the studies of myocarditis. PMID- 26021172 TI - [Dynamics of the cell cycle in human endothelial cell culture infected with influenza virus]. AB - Cell cycle in a culture of endothelial cells EAhy 926 infected with influenza virus was investigated. Cytometric analysis of culture, synchronized using contact inhibition, has shown that the exposure to the influenza virus in cells EAhy 926 lengthened S-phase of the cell cycle. This result has been tested and proven on culture EAhy 926 treated with nocodazole. Compared with lung carcinoma cells A549, in which influenza virus provokes the arrest of G0/G1 phase of the cycle, elongation of S-phase of cycle at a similar infection of endothelial culture EAhy 926 indicates that the influenza virus differently affects the dynamics of the cell cycle according to the origin of the infected culture. PMID- 26021173 TI - [The reorganization of actin cytoskeleton and microtubule system of human endothelial vein in the intercellular contacts formation]. AB - Endothelial cells are tightly fitted to each other and lining the interior surface of all vessels of living organism to provide vascular permeability regulation and interchange between the blood circulating in vessels and tissue fluids of those organs in which these vessels are located. In vitro endothelial monolayer conserve it's basic barrier function which is native for vessels endothelium. Based on this fact we used endothelial cells growing in vitro as a model system in experimental studies of cytoskeletal and adhesion cell components interaction. In current paper, cultured human vein endothelial cells monolayer was used to quantify cytoskeleton alterations in the of endothelial cells from spreading and formation of the first cell-cell contacts to confluent monolayer formation. The system of actin filaments formed two different cytoskeletal structures in the cells of venous endothelium: 1) cortical actin network; 2) actin stress fibers (bundles) arranged parallel to the substrate. Two actin isoforms, beta- and gamma-cytoplasmic (non-muscle) actins, are expressed in endothelial cells. The bundles of actin stress fibers were detected by immunofluorescent staining with antibody against beta-actin, whereas antibodies against gamma-actin identified cortical and lamellar networks. For assessment of the actin cytoskeleton organization it's fluorescence intensity on the area of 10 MUM2 located (1) near the free edge, and (2) in the zone of cell-cell contacts were analyzed. Fluorescence intensity of beta-actin structures was higher in the areas of cell-cell contact. The fluorescence of gamma-actin structures was more intensive at the leading edges of the lamellae, and was the lowest on the stable edges of the cells with formed cell-cell contacts. The endothelial monolayer formation was accompanied by microtubule system alteration: the number of microtubules increased at the cell edge, and besides the microtubules quantity in the area of already formed cell-cell contact was always higher than in free lamella region. PMID- 26021174 TI - [Mobilization of Ca2+ from intracellular stores of spermatozoa of Bos taurus depending on their functional status]. AB - On the basis of inhibitory analysis by using a fluorescence probe chlortetracycline, calcium transduction pathway in spermatozoa of Bos taurus has been examined. Additional release of Ca2+ from intracellular stores of sperm was found after combiened action of prolactin and GTP, which took place under influence of protein kinase C inhibitor (compound Ro 31-8220); the combined effect of theophylline and GDP also stimulated additional release of Ca2+ from intracellular stores, which was missing when adding inhibitor of protein kinase A, compound H-89. Using chlortetracycline test (analysis localization of chlortetracycline fluorescence in spermatozoa), we have shown the combined action of prolactin and GTP increases the number of sperm with acrosome reaction, which is reduced after influence of Ro 31-8220; the combined effect of theophylline and GDP increases the percentage of capacitated spermatozoa, which was decreased in the presence of H-89. According with the data obtained, we propose the hypothesis that the transduction of Ca2+ between intracellular stores in bull spermatozoa stimulated by the combined action of prolactin and GTP, or theophylline and GDP, determines the functional status of the spermatozoa. Namely: the transduction of Ca2+ between intracellular stores in bull spermatozoa stimulated by the combined action of prolactin and GTP is involved in the regulation of acrosomal processes, while sperm capacitation is mediated by the transduction of calcium between intracellular stores activated by the combined influence of theophylline and GDP. PMID- 26021175 TI - [Necessary but sometimes complicated coordination of healthcare procedures. The example of chronic renal failure]. AB - Chronic renalfailure (CRF), one of several disorders involving progressive loss of function of a vital organ, is a paradigm for medical/paramedical coordination networks, especially in view of the explosion of the geriatric CRF/dialysis population. An efficient network is crucial in this setting, given the very high incidence of CRF, its cost, its impact on employment, quality of life and quality of care; and the progression from medical treatment to replacement therapy (peritoneal or hemodialysis) and, eventually, organ transplantation from a living or deceased donor. There is a constant flow of patients entering and exiting care pathways between community practices (public or private), hospitals (general or teaching), medical laboratories, pharmacies (commuity and hospital) and a large number of allied health professions (nurses, social workers, dieticians, physiotherapists, secretaries, etc.). In the predialytic stage of CRF the goal of the network is to establish the diagnosis, slow disease progression, prevent or treat the many potentially complications, inform patients and their families, and postpone the need for dialysis and transplantation. When renal replacement therapy becomes necessary, the choice between peritoneal dialysis and hemodialysis follows strict rules and requires a more technical approach, with predominant involvement of the nephrologist. Finally, transplantation is highly hospital-centered, but patient monitoring in the community requires an approach very similar to that of the predialytic stage, with the involvement of specialists in internal medicine/general practitioners, as the potential complications cover a very broad field of disciplines (infectious, cardiovascular, metabolic, cancer). CRF is a major public health problem that requires a network-based approach involving multiple specialties and skills, the most difficult problem being its coordination. A similar approach can probably be extrapolated to other patients with chronically failing major organs (liver, lungs, heart). PMID- 26021176 TI - [From treatment history to patient follow-up: the role of the pharmacist]. AB - Pharmacists and physicians have complementary roles. Indeed, pharmacists have specific knowledge of medications and a particular relationship with patients, especially in the community. Integration of pharmacists within medical teams, based on the North-American model, helps to ensure close collaboration founded on mutual trust and face-to-face contacts. This role of the pharmacist is appreciated by physicians, notably because it helps them to verify their prescriptions. It is essential to determine patients' relationships with their medications, through a knowledge of their treatment history. The French educational model of clinical pharmacy, based on the fifth hospital year, is inspired by this experience. The challenge is now to prove the benefits both for patients, physicians and nurses, of integrating a pharmacist within the medical team. This educational model helps to develop the pharmacist's role within the community and facilitates relationships between the hospital and the community. PMID- 26021177 TI - [Prescription and follow-up of antithrombotic treatment with vitamin K antagonists]. AB - The indications for antithrombotic treatment with vitamin K antagonists are now relatively precise, but management of this treatment is often difficult in clinical practice and be set by problems such as unstable hypocoagulability, an increased bleeding risk, interactions with other therapies and pathologies, and high-level vitamin K intake in the diet. Rigorous and accurate information of the patient and family, along with regular and frequent control of the international normalized ratio (INR), are essential for the safety and efficacy of this treatment. Some physicians cite an excessive bleeding risk as one reason for withholding oral anticoagulation therapy from older patients with atrial fibrillation. Indeed, with the increasing aging of the population, and poor therapeutic observance, there is an increased risk of hemorragic adverse effects. However, vitamin K antagonists are associated with a significant reduction in embolic events, and recent guidelines recommend their prescription for elderly patients with atrial fibrillation. Their impact on the risk of thromboembolic events is well documented, with better results than those obtained with new oral anticoagulants. Education of the patient and family, and close cooperation between the patient, family, physician and entire medical team, are essential for the safety and efficacy of this treatment. PMID- 26021178 TI - [Quality of life after kidney transplantation in adolescence]. AB - After a general reflection on the concept of quality of life in medicine, and an outline of the psychological problems relating to kidney transplantation, we report the main results of a prospective study (8 French CHU) involving 40 young people awaiting a kidney graft. The results for quality of life (before and 6 and 18 months after the transplant) are analyzed in the light of the adolescent process. While this study confirms that young kidney graft patients generally have good quality of life, no quantitative parameter or score can fully reflect this aspect or replace interviews with the teenager and his or her family. Only face-to-face meetings canfully explore the underlying situation. When it come to quality of life, it is the transplant patient and not the doctor who is the true expert. PMID- 26021179 TI - [Quality of life after pediatric heart transplantation]. AB - The first pediatric heart transplant was performed more than 25 years ago. The results, in terms of mortality and morbidity, have gradually improved over the years, and quality of life and development are thus becoming increasingly important issues. Functional capacity is considered excellent by most recipients: 90% have few if any symptoms. Objective exercise capacity is usually subnormal, however, mainly owing to the inability of the heart rate to increase with exercise. Early cardiac rehabilitation should be encouraged in order to optimize the capacity for physical activity. Recipients can be expected to have neurodevelopmental outcomes in the low-to-normal range, with a 10- to 15-point deficit compared with normal children. Global cognitive abilities and school performance can be affected, particularly in mathematics. Moreover, 20% to 30% of these patients have behavioral and psychological disorders, which are relatively stable over time. Neurodevelopmental outcome is poorer in patients grafted because of a congenital heart defect and is consistent with that of other children with complex congenital heart diseases requiring surgical intervention. This suggests that these problems may be related more to the underlying heart disease than to transplantation itself. Neurodevelopmental outcome is better in families with good intellectual and socioeconomic status. A global, multidisciplinary approach is needed to manage these problems, both early after transplantation and later during follow-up, particularly during the transition from childhood and adulthood. PMID- 26021180 TI - [Adult socioprofessional status of childhood kidney transplant recipients]. PMID- 26021181 TI - [Kidney or liver transplantation and pregnancy]. AB - Fertility returns quickly after kidney or liver transplantation in women of reproductive age, and most pregnancies are associated with good fetal and maternal outcomes. These pregnancies are nonetheless at a high risk of preterm delivery, preeclampsia, and low birthweight. Pregnancy has no specific impact on the graft if its function is stable prior to conception. Transplanted patients are at higher risk of death than the general population, and morbidity associated with the graft and related treatments may prevent transplanted women from caring normally for their children. Pregnancies in transplanted women must be managed by multidisciplinary teams. PMID- 26021182 TI - [Quality of life in adult liver transplant recipients]. AB - Liver transplantation is associated with an improvement in overall quality of life. This improvement, however, is smaller than expected. Quality of life improves significantly early after liver transplantation but seems to decline after the first year. Identification of patients with unsatisfactory quality of life is crucial, and therapeutic education is essential after liver transplantation. PMID- 26021183 TI - Emerging drugs for Cushing's disease. AB - INTRODUCTION: Considering the effects of uncontrolled hypercortisolism on morbidity and mortality, there is a clear need for effective medical therapy for patients with Cushing's disease (CD). Therefore, the search for new medical effective tools remains active, and already promising results have been obtained. AREAS COVERED: The importance of the design and conduct of trials to validate old drugs or to test new compounds is discussed. The results of the ongoing clinical trials, targeting the specific properties of drugs, such as ketoconazole, LCI699, mifepristone, etomidate and pasireotide, are also reported. The authors also emphasise the advantages and drawbacks of each particular drug, and the potential combined use of agents with complementary mechanisms of action. EXPERT OPINION: CD is an excellent example of a situation where effective therapy is essential, but where the balance of risk and benefit must be carefully judged. Metyrapone is the drug of choice when rapid control of the hypercortisolaemia is required, ketoconazole represents a good second-line drug, although in the future LCI699 may be a better alternative. Mifepristone can also be used in the rare situation when previous drugs are inappropriate. Etomidate is useful where immediate parenteral action is required. For drugs working directly on the pituitary, cabergoline is occasionally effective and pasireotide can be attempted in patients with mild CD. PMID- 26021184 TI - Empirical characterisation of ranges of mainstream smoke toxicant yields from contemporary cigarette products using quantile regression methodology. AB - Approximately 100 toxicants have been identified in cigarette smoke, to which exposure has been linked to a range of serious diseases in smokers. Smoking machines have been used to quantify toxicant emissions from cigarettes for regulatory reporting. The World Health Organization Study Group on Tobacco Product Regulation has proposed a regulatory scenario to identify median values for toxicants found in commercially available products, which could be used to set mandated limits on smoke emissions. We present an alternative approach, which used quantile regression to estimate reference percentiles to help contextualise the toxicant yields of commercially available products with respect to a reference analyte, such as tar or nicotine. To illustrate this approach we examined four toxicants (acetone, N'-nitrosoanatabine, phenol and pyridine) with respect to tar, and explored International Organization for Standardization (ISO) and Health Canada Intense (HCI) regimes. We compared this approach with other methods for assessing toxicants in cigarette smoke, such as ratios to nicotine or tar, and linear regression. We concluded that the quantile regression approach effectively represented data distributions across toxicants for both ISO and HCI regimes. This method provides robust, transparent and intuitive percentile estimates in relation to any desired reference value within the data space. PMID- 26021185 TI - Impact of a brief patient and provider intervention to improve the quality of communication about medication adherence among HIV patients. AB - INTRODUCTION: Medication adherence is essential in HIV care, yet provider communication about adherence is often suboptimal. We designed this study to improve patient-provider communication about HIV medication adherence. METHODS: We randomized 26 providers at three HIV care sites to receive or not receive a one-hour communication skills training based on motivational interviewing principles applied to medication adherence. Prior to routine office visits, non adherent patients of providers who received the training were coached to discuss adherence with their providers. Patients of providers who did not receive the training providers were not coached. We audio-recorded and coded patient-provider interactions using the roter interaction analysis system (RIAS). RESULTS: There was more dialogue about therapeutic regimen in visits with intervention patients and providers (167 vs 128, respectively, p=.004), with the majority of statements coming from providers. These visits also included more brainstorming solutions to nonadherence (41% vs. 22%, p=0.026). Intervention compared with control visit providers engaged in more positive talk (44 vs. 38 statements, p=0.039), emotional talk (26 vs. 18 statements, p<0.001), and probing of patient opinion (3 vs. 2 statements, p=0.009). CONCLUSION: A brief provider training combined with patient coaching sessions, improved provider communication behaviors and increased dialogue regarding medication adherence. PMID- 26021187 TI - Characteristics of HIV infected individuals traveling abroad. Results from the +REDIVI Collaborative Network. AB - INTRODUCTION: The improvement in the prognosis of HIV infection, coupled with the increase in international travel and migration, has led to a rising number of HIV infected travelers. The objective of this study was to describe the epidemiological and clinical features of returning travelers, according to their HIV status. METHODS: An observational prospective study was conducted including travelers and immigrants who traveled to visit friends and relatives (VFRs) registered in the +REDIVI collaborative network (January-2009; October-2014). +REDIVI is a national network that registers information regarding infections imported by travelers and immigrants at 21 different centers using a standardized protocol. RESULTS: A total of 3464 travellers were identified: 72 were HIV+ (2.1%) and 3.392 HIV- (98%). HIV+ vs. HIV- travelers were often older (40.5y vs. 34.2y P=.001), VFRs (79.1% vs. 44.4%; P<.001), and consulted less for pre-travel advice (27% vs. 37%; P=.078). The main destinations for both groups were sub Saharan Africa and Latin America. The most frequent reasons for consultation after travel were fever, request for a health examination, gastrointestinal complaints, and abnormal laboratory tests (mainly eosinophilia and anemia), which differed between groups. The most frequent diagnoses in HIV+ travelers were malaria (38.8%), newly diagnosed HIV infection (25%), and intestinal parasites (19.4%), while for HIV- travelers the main diagnoses were "healthy" (17.9%), malaria (14%), and intestinal parasites (17.3%). CONCLUSIONS: The typical profile of an HIV+ traveler in +REDIVI was that of a VFR traveler who did not seek pre travel advice and made high-risk trips. This may increase the chance of acquiring travel-related infections which may pose a special risk for HIV-infected travelers. The post-travel visit was a good opportunity for HIV infection screening. PMID- 26021188 TI - The Healing Effects of Belief in Medical Practices and Spirituality. AB - Shamans and other healing practitioners have used placebos from earliest recorded history to treat those who were ill. As modern scientific theories of disease developed, the use of placebos was considered to be an ineffective and deceptive practice. Later, medical researchers used placebos primarily as an inactive treatment standard against which scientifically based ("real") medicines could be evaluated. However, placebos were discovered to have their own self-healing effects. Spirituality including transcendent experiences also promotes healing effects and recently has been shown to involve neural systems (brain networks) comparable (if not identical) to those engaged in placebo responses. Therapists can facilitate both of these self-healing processes in different ways, including finding meaningfulness in physically and mentally painful situations using Viktor Frankl's practice of "logotherapy." PMID- 26021186 TI - Executive summary of the GESIDA/National AIDS Plan Consensus Document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2015). AB - In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The strength and grade of the recommendation vary depending on the CD4+ T-lymphocyte count, the presence of opportunistic infections or comorbid conditions, age, and the efforts to prevent the transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should comprise three drugs, namely, two nucleoside reverse transcriptase inhibitors (NRTI) and one drug from another family. Three of the recommended regimens, all of which have an integrase strand transfer inhibitor (INSTI) as the third drug, are considered a preferred regimen; a further seven regimens, which are based on an INSTI, an non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor boosted with ritonavir (PI/r), are considered alternatives. The reasons and criteria for switching ART are presented both for patients with an undetectable PVL and for patients who experience virological failure, in which case the rescue regimen should include three (or at least two) drugs that are fully active against HIV. The specific criteria for ART in special situations (acute infection, HIV-2 infection, pregnancy) and comorbid conditions (tuberculosis and other opportunistic infections, kidney disease, liver disease, and cancer) are updated. PMID- 26021189 TI - Trends in overweight and obesity prevalence in Tuscan schoolchildren (2002-2012). AB - OBJECTIVE: The aim of the present study was to examine the prevalence and time trends in childhood overweight including obesity and obesity among Tuscan children from 2002 to 2012. DESIGN: Cross-sectional study at five time points (Tuscan Nutritional Surveillance Surveys conducted in the years of 2002, 2006, 2008, 2010 and 2012). Trained personnel directly measured the height and weight of the subjects. BMI was assessed by means of the International Obesity Task Force (IOTF) and WHO cut-offs. SETTING: Representative sample of children in the Tuscany region (Italy). SUBJECTS: Children (n 7183) aged between 7.5 and 9.5 years (3711 boys and 3472 girls). RESULTS: With respect to the estimation of the absolute prevalence level of childhood overweight, a discrepancy was observed between the two criteria. In all surveys, more boys than girls were overweight (including obesity). Trend analysis showed a significant decrease in the prevalence of overweight including obesity and obesity in Tuscan children from 2002 to 2012 (32.0 % v. 25.8 %, P<0.001 on using IOTF criteria and 37.7 % v. 34.3 %, P<0.001 on using WHO criteria for overweight including obesity; and 10.0 % v. 6.7 %, P<0.001 on using IOTF criteria and 12.5 % v. 11.3 %, P=0.035 on using WHO criteria for obesity). CONCLUSIONS: The present study is the first report from an Italian region showing a significant decrease in childhood obesity and overweight in the last 10 years. This reduction is probably a result of regional and local actions that have taken place in many sectors of society. However, efforts should be made to lower the prevalence of childhood obesity and overweight further. PMID- 26021190 TI - Empathy and the responsiveness to social affordances. AB - The direct perception theory of empathy claims that we can immediately experience a person's state of mind. I can see for instance that my neighbour is angry with me in his bodily countenance. I develop a version of the direct perception theory of empathy which takes this perceptual capacity to depend upon recognising in what way the other person is responsive to the affordances the environment provides. By recognising which possibilities for action are relevant to a person, I can thereby understand something about the meaning they give to the world. I come to share something of their perspective on the world, and this allows me to grasp based on my perception of them something about their current state of mind. I argue that shared affect plays a central role in this perceptual capacity. Shared affect allows me to orient my attention to possibilities for action that matter to the other person. I end by briefly discuss the implications of this view of empathy for the disturbances in so-called "cognitive empathy" that are found in people diagnosed with autism spectrum disorder. PMID- 26021192 TI - Molecular pathogenesis of Barrett esophagus: current evidence. AB - This article focuses on recent findings on the molecular mechanisms involved in esophageal columnar metaplasia. Signaling pathways and their downstream targets activate specific transcription factors leading to the expression of columnar and the more specific intestinal-type of genes, which gives rise to Barrett metaplasia. Several animal models have been generated to validate and study these distinct molecular pathways but also to identify the Barrett progenitor cell. Currently, the many aspects involved in the development of esophageal metaplasia that have been elucidated can serve to develop novel molecular therapies to improve treatment or prevent metaplasia. Nevertheless, several key events are still poorly understood and require further investigation. PMID- 26021193 TI - Role of Obesity in the Pathogenesis and Progression of Barrett's Esophagus. AB - Central obesity is involved in the pathogenesis and progression of Barrett's esophagus to esophageal adenocarcinoma. Involved are likely both mechanical and nonmechanical effects. Mechanical effects of increased abdominal fat cause disruption of the gastroesophageal reflux barrier leading to increased reflux events. Nonmechanical effects may be mediated by inflammation, via classically activated macrophages, pro-inflammatory cytokines, and adipokines such as Leptin, all of which likely potentiate reflux-mediated inflammation. Insulin resistance, associated with central obesity, is also associated with both Barrett's pathogenesis and progression to adenocarcinoma. Molecular pathways activated in obesity, inflammation and insulin resistance overlap with those involved in Barrett's pathogenesis and progression. PMID- 26021194 TI - Screening for Barrett's Esophagus. AB - There is substantial interest in identifying patients with premalignant conditions such as Barrett's esophagus (BE), to improve outcomes of subjects with esophageal adenocarcinoma. However, there is limited consensus on the rationale for screening, the appropriate target population, and optimal screening modality. Recent progress in the development and validation of minimally invasive tools for BE screening has reinvigorated interest in BE screening. BE risk scores combining clinical, anthropometric, and laboratory variables are being developed that may allow more precise targeting of screening to high-risk individuals. This article reviews and summarizes data on recent progress and challenges in screening for BE. PMID- 26021191 TI - Epidemiology of Barrett's Esophagus and Esophageal Adenocarcinoma. AB - Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC), a disease with increasing burden in the Western world, especially in white men. Risk factors for BE include obesity, tobacco smoking, and gastroesophageal reflux disease (GERD). EAC is the most common form of esophageal cancer in the United States. Risk factors include GERD, tobacco smoking, and obesity, whereas nonsteroidal antiinflammatory drugs and statins may be protective. Factors predicting progression from nondysplastic BE to EAC include dysplastic changes on esophageal histology and length of the involved BE segment. Biomarkers have shown promise, but none are approved for clinical use. PMID- 26021195 TI - Surveillance in Barrett's Esophagus: Utility and Current Recommendations. AB - Surveillance of Barrett's esophagus for preventing death from esophageal adenocarcinoma is attractive and widely practiced. However, empirical evidence supporting its effectiveness is weak. Longer intervals between surveillance examinations are being recommended, supported by computer simulation analyses. If surveillance is performed, an adequate number of biopsies should be performed or the effect of surveillance would be squandered. PMID- 26021197 TI - Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection for Endoscopic Therapy of Barrett's Esophagus-related Neoplasia. AB - A major paradigm shift has occurred in the management of dysplastic Barrett's esophagus (BE) and early esophageal carcinoma. Endoscopic therapy has now emerged as the standard of care for this disease entity. Endoscopic resection techniques like endoscopic mucosal resection and endoscopic submucosal dissection combined with ablation techniques help achieve long-term curative success comparable with surgical outcomes, in this subgroup of patients. This article is an in-depth review of these endoscopic resection techniques, highlighting their role and value in the overall management of BE-related dysplasia and neoplasia. PMID- 26021198 TI - Ablative Endoscopic Therapies for Barrett's-Esophagus-Related Neoplasia. AB - Barrett's esophagus (BE) is more common in developed countries. Endoscopic therapy is an effective treatment method in management of dysplastic BE. Ablation by thermal energy, freezing, or photochemical injury completely eradicates dysplasia and specialized intestinal metaplasia resulting in neosquamation of esophagus. Among the ablative modalities, radiofrequency ablation (RFA) is the most studied with safe, effective, and durable long-term outcomes. Cryotherapy, argon plasma coagulation, and photodynamic therapy can be offered in select patients when RFA is unavailable, has failed, or is contraindicated. Future research on natural disease progression, biomarkers, advanced imaging, and application of endoscopic techniques will lead to better clinical outcomes for BE associated neoplasia. PMID- 26021199 TI - Challenges with Endoscopic Therapy for Barrett's Esophagus. AB - Barrett's esophagus is the only identifiable premalignant condition for esophageal adenocarcinoma. Endoscopic eradication therapy (EET) has revolutionized the management of Barrett's-related dysplasia and intramucosal cancer. The primary goal of EET is to prevent progression to invasive esophageal adenocarcinoma and ultimately improve survival rates. There are several challenges with EET that can be encountered before, during, or after the procedure that are important to understand to optimize the effectiveness and safety of EET and ultimately improve patient outcomes. This article focuses on the challenges with EET and discusses them under the categories of preprocedural, intraprocedural, and postprocedural challenges. PMID- 26021196 TI - Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett's Esophagus. AB - The prevalence of esophageal adenocarcinoma is increasing dramatically. Barrett's esophagus remains the most well-established risk factor for the development of esophageal adenocarcinoma. There are multiple clinical, endoscopic, and pathologic factors that increase the risk of neoplastic progression to high-grade dysplasia or esophageal adenocarcinoma in Barrett's esophagus. This article reviews both risk and protective factors for neoplastic progression in patients with Barrett's esophagus. PMID- 26021200 TI - Biomarkers in Barrett's Esophagus: Role in Diagnosis, Risk Stratification, and Prediction of Response to Therapy. AB - Esophageal adenocarcinoma (EAC) has increased dramatically in the past 3 decades, making its precursor lesion Barrett's esophagus (BE) an important clinical problem. Effective interventions are available, but overall outcomes remain unchanged. Most of the BE population remains undiagnosed; most EACs are diagnosed late, and most BE patients will never progress to cancer. These epidemiologic factors make upper endoscopy an inefficient and ineffective strategy for BE diagnosis and risk stratification. In the current review, biomarkers for diagnosis, risk stratification, and predictors of response to therapy in BE are discussed. PMID- 26021201 TI - Chemoprevention in Barrett's Esophagus: Current Status. AB - Chemoprevention in Barrett's esophagus is currently applied only in research settings. Identifying pathways that can be targeted by safe, pharmaceutical or natural compounds is key to expanding the scope of chemoprevention. Defining meaningful surrogate markers of cancer progression is critical to test the efficacy of chemopreventive approaches. Combinatorial chemoprevention that targets multiple components of the same pathway or parallel pathways could reduce the risk and improve the efficacy of chemoprevention. Here we discuss the role of chemoprevention as an independent or an adjuvant management option in BE associated esophageal adenocarcinoma. PMID- 26021202 TI - The Effect of Proton Pump Inhibitors on Barrett's Esophagus. AB - Proton pump inhibitors (PPIs) may protect against carcinogenesis in Barrett's esophagus because they eliminate the chronic esophageal inflammation of reflux esophagitis, and because they decrease esophageal exposure to acid, which can cause cancer-promoting DNA damage and increase proliferation in Barrett's metaplasia. Most clinical studies of PPIs and cancer development in Barrett's esophagus have found a cancer-protective effect for these drugs, although there are some contradictory data. Chemoprevention of dysplasia and cancer in Barrett's esophagus with PPIs appears to be cost-effective, and the indirect evidence supporting a cancer-protective role for PPIs is strong enough to warrant PPI treatment of virtually all patients with Barrett's esophagus. PMID- 26021203 TI - Cost-Analyses Studies in Barrett's Esophagus: What Is Their Utility? AB - Approximately 10% to 15% of the chronic gastroesophageal reflux disease population is at risk for the development of Barrett's esophagus, particularly in the setting of other risk factors, including male gender, Caucasian race, age more than 50, and central obesity. The risk of cancer progression for patients with nondysplastic BE has been estimated to be approximately 0.2% to 0.5% per year. Given these low progression rates and the high cost of endoscopic surveillance, cost-effectiveness analyses in this area are useful to determine appropriate resource allocation. PMID- 26021204 TI - Advanced Imaging in Barrett's Esophagus. AB - Barrett's esophagus (BE) is present in up to 5.6% of the US population and is the precursor lesion for esophageal adenocarcinoma. Surveillance endoscopy is the primary management approach for BE. However, standard protocol biopsies have been associated with significant miss rates of dysplastic lesions in patients with BE. Thus, a variety of methods to optimize the imaging of BE have been developed to improve the efficiency and diagnostic yield of surveillance endoscopy in detecting early neoplasia. These techniques use changes that occur at macroscopic, microscopic, and subcellular levels in early neoplasia and are the focus of this article. PMID- 26021205 TI - Surgical Management of Barrett's Esophagus. AB - Patients with gastroesophageal reflux disease and Barrett's esophagus can be a management challenge for the treating physician or surgeon. The goals of therapy include relief of reflux symptoms, induction of histologic regression, and prevention of progression of intestinal metaplasia to dysplasia or invasive carcinoma. Antireflux surgery is effective at achieving these end points, although ongoing follow-up and endoscopic surveillance are essential. In cases of dysplasia or early esophageal neoplasia associated with Barrett's esophagus, endoscopic resection and ablation have supplanted esophagectomy as the standard of care in most cases. Esophageal resection continues to have a role, however, in a minority of appropriately selected candidates. PMID- 26021207 TI - Barrett's Esophagus. PMID- 26021206 TI - Genetic and Epigenetic Alterations in Barrett's Esophagus and Esophageal Adenocarcinoma. AB - Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), wherein normal squamous epithelia is replaced by specialized intestinal metaplasia in response to chronic gastroesophageal acid reflux. BE can progress to low- and high-grade dysplasia, intramucosal, and invasive carcinoma. Both BE and EAC are characterized by loss of heterozygosity, aneuploidy, specific genetic mutations, and clonal diversity. Given the limitations of histopathology, genomic and epigenomic analyses may improve the precision of risk stratification. Assays to detect molecular alterations associated with neoplastic progression could be used to improve the pathologic assessment of BE/EAC and to select high-risk patients for more intensive surveillance. PMID- 26021208 TI - Barrett's Esophagus: New Insights and Progress. PMID- 26021209 TI - Increased ADAM10 expression in preeclamptic placentas is associated with decreased expression of hydrogen sulfide production enzymes. AB - Placental soluble fms-like tyrosine kinase 1 (sFlt1) release is increased in preeclampsia, which might be associated with increased shedding of Flt-1 through a disintegrin and metalloproteinase 10 (ADAM10). Here, we explored whether ADAM10 expression is regulated by hydrogen sulfide (H2S) in placenta. Pro- and active ADAM10 expression were significantly increased in preeclamptic placentas and inversely correlated to H2S production enzymes cystathionine beta-synthase and cystathionine gamma-lyase expression. H2S significantly suppressed pro- and active-ADAM10 expression whilst inhibited sFlt-1 release. Knockdown of ADAM10 caused a decrease in sFlt-1 release. Our data suggest that dysregulation of H2S production may contribute to excessive Flt-1shedding in preeclampsia. PMID- 26021210 TI - A review of the incidence of iatrogenic hernia in both laparoscopic and open colorectal surgery: Using CT as the gold standard of detection, cohort study. AB - PURPOSE: The incidence of incisional hernia varies considerably in the literature. The aim of our study was to calculate the incidence of various types of the occult iatrogenic hernias following colorectal surgery, both laparoscopic and open, using CT scan. METHODS: The study included all patients who underwent colorectal resection procedures in a colorectal surgery department over an 11 year period between 2001 and 2012 who went on to have a CT scan post surgery. The term iatrogenic hernia included all postoperative hernias at laparotomy incision site in the open colorectal subgroup, hernias at the site of specimen extraction or port site hernias in the laparoscopic colorectal subgroup, and parastomal hernias in both subgroups. RESULTS: The total number of diagnosed iatrogenic hernias was 74 (61 detected on CT scan and 13 repaired on clinical grounds). Out of the 74 diagnosed iatrogenic hernias, 23 (31.1%) required surgical repair; 11 in the LCR (6 incisional, 2 parastomal and 2 port site hernias) and 12 in the OCR (9 incisional and 3 parastomal). CONCLUSION: The incidence of iatrogenic hernias is underestimated. The use of CT will increase the number detected. There is no significant difference in the incidence of iatrogenic hernias between laparoscopic and open colorectal procedures. PMID- 26021211 TI - Comparison of electrocautery incision with scalpel incision in midline abdominal surgery - A double blind randomized controlled trial. AB - AIM &OBJECTIVES: To compare the electrocautery incision with scalpel incision in patients undergoing abdominal surgery using a midline incision with respect to incision time, blood loss during incision, postoperative incision site pain and wound infection. METHODS: Patients undergoing midline abdominal surgery were randomized into electrocautery and scalpel groups. The incision dimensions, incision time and blood loss during incision were noted intraoperatively. Postoperative pain and wound infection were recorded on every postoperative day for one week. RESULTS: 41 patients in each of the two groups were analyzed. Gender and age distribution was similar in both the groups. The mean incision time per unit wound area in the electrocautery group and scalpel group was 9.40 +/- 3.37 s/cm(2) and 9.07 +/- 3.40 s/cm(2) (p = 0.87) respectively. The mean blood loss per unit wound area was significantly lower in the electrocautery group at 6.46 +/- 3.94 ml when compared to that of 23.40 +/- 15.28 ml in the scalpel group (p= < 0.0001, CI = 11.97-21.89). There was no significant difference in pain on any of the postoperative days between the two groups and there was no significant difference in the wound infection rates between the electrocautery and scalpel groups (14.63% vs. 12.19%; p = 0.347). CONCLUSION: With a comparable Postoperative incision site pain, wound infection rate and significantly lower blood loss with the equal time taken for the incision, electrocautery can be considered safe and effective in making skin incision in midline laparotomy compared to scalpel incision. PMID- 26021212 TI - Face-ism and kernels of truth in facial inferences. PMID- 26021213 TI - A pilot randomised controlled trial (RCT) investigating the effectiveness of reflexology for managing pregnancy low back and/or pelvic pain. AB - Many pregnant women with low back and/or pelvic pain (LBPP) use pain medications to manage this pain, much of which is self-prescribed and potentially harmful. Therefore, there is a need to find effective nonpharmacological treatments for the condition. Reflexology has previously been shown to help nonspecific low back pain. Therefore; a pilot RCT was conducted investigating reflexology in the management of pregnancy-LBPP. 90 primiparous women were randomised to either usual care, a reflexology or footbath intervention. Primary outcome measures were; the Pain Visual Analogue Scale (VAS). 64 women completed the RCT; retention rates for the reflexology group were 80%, usual care group 83.33% and footbath group 50%. The reflexology group demonstrated a Clinically Important Change (CIC) in pain frequency (1.64 cm). Results indicate it is feasible to conduct an RCT in this area, although a footbath is an unsuitable sham treatment. Reflexology may help manage pregnancy-LBPP; however a fully powered trial is needed to confirm this. PMID- 26021214 TI - Sex matters, as do individual differences.... PMID- 26021215 TI - Laminar specific detection of APP induced neurodegeneration and recovery using MEMRI in an olfactory based Alzheimer's disease mouse model. AB - Manganese enhanced MRI (MEMRI) was used to detect specific laminar changes in the olfactory bulb (OB) to follow the progression of amyloid precursor protein (APP) induced neuronal pathology and its recovery in a reversible olfactory based Alzheimer's disease (AD) mouse model. Olfactory dysfunction is an early symptom of AD, which suggests that olfactory sensory neurons (OSNs) may be more sensitive to AD related factors than neurons in other brain areas. Previously a transgenic mouse model was established that causes degeneration of OSNs by overexpressing humanized APP (hAPP), which results in a disruption of the olfactory circuitry with changes in the glomerular structure. In the present work, OB volume and manganese enhancement of the glomerular layer in the OB were decreased in mutant mice. Turning off APP overexpression with doxycycline produced a significant increase in manganese enhancement of the glomerular layer after only 1week, and further recovery after 3weeks, while treatment with Abeta antibody produced modest improvement with MRI measurements. Thus, MEMRI enables a direct tracking of laminar specific neurodegeneration through a non-invasive in vivo measurement. The use of MRI will enable assessment of the ability of different pharmacological reagents to block olfactory neuronal loss and can serve as a unique in vivo screening tool to both identify potential therapeutics and test their efficacy. PMID- 26021216 TI - Comparison of PCA approaches for very large group ICA. AB - Large data sets are becoming more common in fMRI and, with the advent of faster pulse sequences, memory efficient strategies for data reduction via principal component analysis (PCA) turn out to be extremely useful, especially for widely used approaches like group independent component analysis (ICA). In this commentary, we discuss results and limitations from a recent paper on the topic and attempt to provide a more complete perspective on available approaches as well as discussing various issues to consider related to PCA for very large group ICA. We also provide an analysis of computation time, memory use, and number of dataloads for a variety of approaches under multiple scenarios of small and extremely large data sets. PMID- 26021217 TI - The beneficial effects of sounds on attentional blink performance: An ERP study. AB - Auditory information can affect the processing of visual information. The present study used event-related potentials (ERPs) to characterize the temporal dynamics of this interaction in a rapid serial visual presentation (RSVP) task that created an attentional blink (AB), that is, a profound deficit in detecting or identifying the second of two visual targets embedded in an RSVP stream. When a sound preceded the second target, T2, by 250ms or was played simultaneously with T2, T2 identification accuracy increased to a comparable degree. Sound-related modulations of the visual response to T2 emerged from around 140ms when the sound preceded T2, and from around 100ms when the sound was played simultaneously with T2. Timing and topography of this earliest modulation indicated that it is not related to early sensory areas, but suggest an attentional filter mechanism. Subsequent modulations are compatible with an improvement of early visual processing of T2 and of processes related to target selection both when the sound precedes and when it coincides with T2. For the latter condition our results also indicated processes related to a convergence of stimulus-driven and goal-directed attention. We also observed some overlap between neural correlates of sound related modulations of the visual response and of correct vs. incorrect performance. Thus, external task manipulations and internal factors contributing to performance in the AB may rely on overlapping though not identical mechanisms. PMID- 26021221 TI - Abstracts of the Annual SIO Congress XXIII, February 6-7, 2015, Milan, Italy. PMID- 26021222 TI - Editorial: Based on scientific evidence, the sterilisation of customised implant abutments is required. PMID- 26021218 TI - The (in)stability of functional brain network measures across thresholds. AB - The large-scale organization of the brain has features of complex networks that can be quantified using network measures from graph theory. However, many network measures were designed to be calculated on binary graphs, whereas functional brain organization is typically inferred from a continuous measure of correlations in temporal signal between brain regions. Thresholding is a necessary step to use binary graphs derived from functional connectivity data. However, there is no current consensus on what threshold to use, and network measures and group contrasts may be unstable across thresholds. Nevertheless, whole-brain network analyses are being applied widely with findings typically reported at an arbitrary threshold or range of thresholds. This study sought to evaluate the stability of network measures across thresholds in a large resting state functional connectivity dataset. Network measures were evaluated across absolute (correlation-based) and proportional (sparsity-based) thresholds, and compared between sex and age groups. Overall, network measures were found to be unstable across absolute thresholds. For example, the direction of group differences in a given network measure may change depending on the threshold. Network measures were found to be more stable across proportional thresholds. These results demonstrate that caution should be used when applying thresholds to functional connectivity data and when interpreting results from binary graph models. PMID- 26021223 TI - Immediate, early (3 weeks) and conventional loading (4 months) of single implants: Preliminary data at 1 year after loading from a pragmatic multicenter randomised controlled trial. AB - PURPOSE: To compare the clinical outcome of single implants which underwent immediate nonocclusal loading with implants subjected to early non-occlusal loading at 3 weeks, and implants conventionally loaded at 4 months. MATERIALS AND METHODS: One hundred and five patients in five private practices requiring a single implant-supported crown were randomised to immediate loading (35 patients), early loading (35 patients) and conventional loading (35 patients) groups. To be immediately or early loaded, implants had to be inserted with a torque superior to 45 Ncm. Immediately and early loaded implants received non occluding temporary crows, whereas conventionally loaded implants were directly restored with definitive crowns. Temporary crowns were replaced by definitive ones after 4 months. Outcome measures were crown and implant failures, complications and peri-implant marginal bone level changes recorded by a blinded assessor. RESULTS: Two patients dropped out from the immediate loading group up to 1-year post-loading. Two implants failed, one in the immediately loaded and one in the early loaded group (P=0.601). One immediately loaded implant and two early loaded implants were affected by one complication each (P=0.162). Mean peri implant marginal bone loss after 1 year was -0.120+/-0.230 mm (95% CI -0.35, 0.10) for immediate, -0.390+/-0.840 mm (95% CI -1.23, 0.45) for early and 0.201+/-0.306 mm (95% CI -0.51; 0.11) for conventionally loaded implants. There were no statistically significant differences for any of the outcome measures between the three loading strategies up to 1-year post-loading. CONCLUSIONS: No major clinical differences were observed with regard to implant survival, complications and marginal bone level changes when loading single implants immediately, early or conventionally. PMID- 26021224 TI - Do repeated changes of abutments have any influence on the stability of peri implant tissues? Four-month post-loading preliminary results from a multicentre randomised controlled trial. AB - PURPOSE: To evaluate the influence of at least three abutment changes against the placement of a definitive abutment, which was no longer removed, on hard and soft tissue changes, and to compare the clinical outcomes of immediate non-occlusal loading versus conventional loading. MATERIALS AND METHODS: Eighty patients requiring one single crown or one fixed partial prosthesis supported by a maximum of three implants were randomised, after implants were placed with more than 35 Ncm, according to a parallel group design to receive definitive abutments which were loaded immediately (definitive abutment or immediate loading group) or transmucosal abutments which experienced delayed loading after 3 months and were removed at least three times: 1) during the making of the impression (3 months after implant placement); 2) when checking the zirconium core of titanium abutments at single crowns or the fitting of the metal structure at prostheses supported by multiple implants; 3) at delivery of the definitive prostheses (repeated disconnection or conventional loading group). Patients were treated in four centres and each patient contributed to the study with only one prosthesis followed for 4 months after initial loading. Outcome measures were: prosthesis/implant failures, any complication, peri-implant marginal bone level changes, and patient satisfaction. RESULTS: Forty patients were randomly allocated to each group according to a parallel group design. No patient dropped out and no implants failed. However four provisional prostheses and one definitive prosthesis had to be remade because of misfitting (five single crowns) in the repeated disconnection group; and one provisional prosthesis had to be remade because of frequent debondings in the immediate loading group (difference=10%; 95% CI: -1%, 21%; P=0.109). Five complications (all debondings of the provisional prostheses) were reported in two patients of the immediate loading group, in comparison to three biological complications in three patients of the repeated disconnection group (difference=2%; 95% CI: -8%, 13%; P=1). All patients were very satisfied or satisfied with the function and aesthetics of the prostheses, and would undergo the same procedure again. Mean peri-implant marginal bone loss 4 months after loading was -0.08 (0.16) mm for the definitive abutment group and -0.09 (0.20) mm for the repeated abutment changes group (difference=0.01; 95% CI: -0.07, 0.09; P=0.97). There were no statistically significant differences for any of the outcome measures between the two procedures up to 4 months after initial loading. CONCLUSIONS: Preliminary short term data (4-month post-loading) showed that repeated abutment changes do not alter bone levels significantly. Immediate non-occlusal loading of dental implants are a viable alternative to conventional loading. Therefore clinicians can use the procedure they find more convenient for their specific patient. PMID- 26021225 TI - Single preoperative dose of prophylactic amoxicillin versus a 2-day postoperative course in dental implant surgery: A two-centre randomised controlled trial. AB - PURPOSE: To evaluate the difference between a single preoperative dose versus an additional two-day postoperative course of oral amoxicillin in patients undergoing conventional dental implant placement. MATERIALS AND METHODS: Two dentists in two different private practices conducted this study. One hour prior to surgery, patients had to take a single prophylactic antibiotic dose, consisting of 2 g of amoxicillin orally; after implant placement, patients were randomly allocated to two different groups: protocol A (no other antibiotic administration) and protocol B, (1 g of amoxicillin in the evening of the day of surgery and 1 g twice a day for the 2 days after). Outcome measures were prosthetic and implant failures, adverse events and early postoperative complications. Patients were followed up to 6 months after functional loading. RESULTS: Three hundred and sixty patients were randomised and treated (192 patients in one centre and 168 in the other). Five hundred and sixty-seven implants were placed. Protocol A was applied to 180 patients (278 implants) and protocol B also to 180 patients (289 implants). Data for 17 patients, 14 from protocol A and three from protocol B, were not available. No statistically significant differences were found for the reported outcomes. Two patients of protocol B experienced a prosthetic failure, losing four implants, while no prosthetic failures were reported for protocol A (P=0.4836; difference in proportions=-0.0110; 95% CI: -0.0412 to 0.0119). Five patients (3.0%) of protocol A lost five implants versus 5 patients (2.8%) who lost eight implants in protocol B (P=1.0000; difference in proportions=0.0020; 95% CI: -0.0384 to 0.0438). Three adverse events were observed in the total population, all occurring in protocol B (1.69%), with no statistically significant differences between the two groups (P=0.1199; difference in proportions=-0.0170; 95% CI: -0.0487 to 0.0059). However, one patient experienced a severe allergic reaction requiring therapy discontinuation and hospital admission. Early postoperative complications occurred in six patients of protocol A and in four patients of protocol B, with no statistically significant differences (P=0.5170; difference in proportions=0.0130; 95% CI: -0.0254 to 0.0568). CONCLUSIONS: No statistically significant differences were observed between 2 g of preoperative amoxicillin and an additional 2-day postoperative course, although adverse events were reported only in the additional 2-day postoperative group. Based on these findings, it might be sufficient to routinely administer preoperatively 2 g of amoxicillin to patients undergoing routine dental implant placement procedures rather than administering additional postoperative doses. PMID- 26021226 TI - A controlled, cross-sectional exploratory study on markers for the plasminogen system and inflammation in crevicular fluid samples from healthy, mucositis and peri-implantitis sites. AB - PURPOSE: To investigate expression of gene markers for the plasminogen system, inflammation, and bone resorption/remodelling in peri-implant crevicular fluid samples from healthy subjects, subjects with mucositis and subjects with peri implantitis. A possible inhibitory effect of suppuration on the analysis of gene expression in samples from subjects with peri-implantitis was also analysed. MATERIALS AND METHODS: Peri-implant crevicular fluid (PICF) was sampled from 25 healthy subjects (H), 25 subjects with mucositis (M) and 25 subjects with peri implantitis (P) using paper points and suction tips. The samples were analysed by quantitative polymerase chain reaction (qPCR). The following biomarkers associated with the plasminogen system, inflammation and bone resorption/ remodelling were investigated: interleukin-1 beta (IL-1beta), interleukin 8 (IL 8), tissue plasminogen activator (tPA), plasminogen activator inhibitor 2 (PAI 2), tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CatK). RESULTS: IL-1beta and IL-8 were significantly upregulated in the P group, and tPA and PAI 2 were significantly upregulated in the M group. These four genetic markers were oppositely regulated in samples from the subjects in the mucositis compared with the peri-implantitis group. TRAP and CatK showed no differences between the groups. The presence of suppuration did not have a detectable effect on gene analysis in samples from subjects with peri-implantitis. CONCLUSIONS: Markers for the plasminogen system and inflammation could be used to distinguish between mucositis and peri-implantitis. The results suggested that the plasminogen system was sufficiently upregulated allowing for resolution of inflammation and healing at the inflamed implant site in subjects with mucositis, whereas such upregulation was insufficient resulting in impaired healing and prolonged inflammation in subjects with peri-implantitis. The combination of tissue inflammation and low levels of tPA was a strong predictor of marginal bone loss in this study. It may be an interesting candidate for the unambiguous diagnosis of mucositis and peri-implantitis independent of radiographs and could possibly constitute a powerful future tool for rapid assessment of the periimplant tissue condition and the effect of subject treatment. PMID- 26021227 TI - 5-year outcome of cross-arch prostheses supported by four immediately loaded zygomatic implants: A prospective case series. AB - PURPOSE: To evaluate the clinical outcome of maxillary prostheses supported by four immediately loaded zygomatic implants in the rehabilitation of edentulous patients with severe atrophic maxillae after 5 years of function. MATERIALS AND METHODS: Out of a total of 17 consecutive patients with severe atrophy in the maxillae (Cawood and Howell classification C-VI and D-V or D-VI) and whom were rehabilitated using four immediately loaded zygomatic implants, three were lost during follow-up. Outcome measures were success rates of the prostheses, success rates of the zygomatic implants, complications and oral health-related quality of life (OHIP-14 questionnaire). RESULTS: In 14 patients assessed at 5 years after operation, no prosthesis or zygomatic implants failed, although one implant placed in an unfavourable position was not used. Fifty percent of the patients had complications, which included penetration of the orbital cavity during the drilling procedure (1 patient), infection followed by a fistula at one zygomatic implant (1 patient), sinusitis (2 patients), fracture of the abutment screw (1 patient) and fracture of the prostheses (2 patients). All complications were resolved without clinical consequences. At 5 years the mean score of the OHIP-14 was 3.8, which is similar to that of the general population. CONCLUSION: Results at 5 years indicate that the use of four immediately loaded zygomatic implants is a reliable approach for successful rehabilitation of edentulous patients with severely atrophied maxillae. PMID- 26021228 TI - Herpes zoster ophthalmicus reactivation following maxillary sinus lift operation: A case report. AB - PURPOSE: To present a case of Herpes Zoster Ophtalmicus (HZO), which was reactivated postoperatively after a sinus lift operation. MATERIALS AND METHODS: A 39-year-old male was referred to our clinic for implant-supported dental rehabilitation. He had maxillary missing teeth in positions 13, 14, 15 and 16 and a pneumatised right maxillary sinus with a bone height of 2 mm. Lateral sinus lifting and bone block grafting was performed before implant insertion. Twelve days after the sinus lift, the patient complained of pain and itching at the infraorbital area extending to the forehead. Clinical examination revealed no signs of infection or allergy. The patient received consultation from a dermatologist in order to rule out a possible dermatological disorder. Finally he was diagnosed with HZO. RESULTS: HZO was managed with systemic acyclovir treatment. Vesicular rashes and ptosis was seen 3 days after the medical treatment. After 1 month no postoperative skin or orbital sequela was seen. Three implants were inserted at the right posterior maxilla 5 months after sinus lift. One-year followup was uneventful. CONCLUSIONS: Dermatological diseases should always be kept in mind during the differential diagnosis of orofacial pain. In this case the proximity of the operation site and affected area gave rise to the idea that surgical trauma had a possible role in the reactivation of the virus. However, the process of reactivation is not entirely understood and requires further investigations. Early diagnosis is essential for HZO in order to avoid debilitating complications such as postherpetic neuralgia and blindness. PMID- 26021229 TI - Magnetic resonance imaging induced acute midfacial pain - incidental finding of a dislocated dental bur. AB - PURPOSE: To describe the management of a patient with an initially unnoticed dislocated dental bur in the maxillary sinus that became symptomatic during a magnetic resonance imaging (MRI) scan. MATERIALS AND METHODS: A MRI scan provoked strong midfacial pain in a 31-year-old male patient, who exhibited ambiguous neurologic impairment consistent with multiple sclerosis. Conventional radiography revealed an opaque foreign body in close proximity to the orbital floor that most likely caused the painful symptoms during the MRI. RESULTS: After additional X-ray computed tomography (X-ray CT) scans were performed, a metal dental bur was removed by a combined transconjunctival and transnasal approach under perioperative antibiotic treatment. CONCLUSION: The disappearance of instruments during surgical procedures requires diligent investigation and immediate retrieval. PMID- 26021231 TI - A Breath of Fresh AIRE Surrounds Paneth Cells and Defensins. PMID- 26021232 TI - Fecal Microbiota Transplantation for Ulcerative Colitis: Not Just Yet. PMID- 26021233 TI - Comparison of Liver Transplant-Related Survival Benefit in Patients With Versus Without Hepatocellular Carcinoma in the United States. AB - BACKGROUND & AIMS: Patients with T2 hepatocellular carcinoma (HCC) can obtain an exception that allows them to undergo liver transplantation with much lower actual Model for End-Stage Liver Disease (MELD) scores than patients without HCC. We compared patients who received liver transplants, with and without HCC, with regard to transplantation-related survival benefit. METHODS: We modeled the post transplantation survival of adult, first-time liver transplant recipients with HCC (n = 9135) or without (n = 25,890) from 2002 through 2013 using Cox proportional hazards regression. We modeled waitlist survival of patients listed for transplantation with HCC (n = 15,605) or without (n = 85,229) using competing risks analysis and combined outcomes of death or liver failure (defined as MELD score >=30). We used these survival models to calculate monthly transition probabilities and 5-year life expectancies. Survival benefit was calculated as the difference between post-transplantation and waitlist life expectancy. RESULTS: The 5-year survival benefit increased with actual MELD score for patients with and without HCC, ranging from just a few months in patients with low MELD scores (ie, 6-8) to 4 years in patients with the highest MELD scores (ie, 36-40). The survival benefit of patients with HCC was similar to that of patients without HCC who had the same actual MELD score, irrespective of tumor burden or serum level of alpha-fetoprotein. However, because patients with HCC received liver transplants when they had a lower mean MELD score (13.3 +/- 6.2) than patients without HCC (21.8 +/- 8.0), a much lower mean 5-year survival benefit was achieved by providing liver transplants to patients with HCC (0.12 years/patient) than patients without HCC (1.47 years/patient). CONCLUSIONS: The HCC MELD exception policy has unintentionally resulted in a large reduction in transplantation-related survival benefit. PMID- 26021234 TI - Women in Science: Hints for Success. PMID- 26021235 TI - Biliary Stents for Palliation of Obstructive Jaundice: Choosing the Superior Endoscopic Management Strategy. PMID- 26021236 TI - Direct-Acting Antivirals Cure Innate Immunity in Chronic Hepatitis C. PMID- 26021237 TI - The Enigma of Carcinoids. PMID- 26021238 TI - Methylglyoxal, a reactive glucose metabolite, enhances autophagy flux and suppresses proliferation of human retinal pigment epithelial ARPE-19 cells. AB - Methylglyoxal (MGO), a glycolytic metabolite, induces oxidative injury and apoptotic cell death that play a pathogenetic role in age-related macular degeneration (AMD). This study examined the impact of MGO on cell proliferation and autophagy flux in retinal pigment epithelium (RPE) ARPE-19 cells and elucidated the underlying mechanism. Short-term MGO exposure suppressed cell proliferation without induction of apoptotic cell death, increased production of reactive oxygen species, and potentiated H2O2-exhibited cytotoxicity in ARPE-19 cells. Conversely, pretreatment with N-acetylcysteine, a ROS scavenger, and aminoguanidine, an MGO blocker, prevented MGO-induced growth retardation. MGO significantly enhanced autophagy flux and increased intracellular accumulation of autophagosomes, which was functionally confirmed by addition of autophagy enhancer or inhibitors. Signaling kinetic observation indicated that MGO remarkably triggered phosphorylation of Akt, ERK1/2, p38 MAPK, and JNK1/2. Blockade of kinase activity demonstrated that the hyperphosphorylation of Akt, ERK1/2, JNK, and p38 MAPK were all involved in the MGO-enhanced autophagy and growth-arresting effect in ARPE-19 cells. Moreover, pretreatment with autophagic flux inhibitors including 3-methyladenine, bafilomycin A, and chloroquine effectively ameliorated MGO- but not H2O2-mediated ARPE-19 cytotoxicity. In conclusion, modulation of autophagy flux activity by using autophagic or kinase inhibitors may be an applicable modality to treat AMD. PMID- 26021239 TI - Hybrid coronary revascularization: present and future. PMID- 26021240 TI - Galen's (130-201 AD) Conceptions of the Heart. AB - In the 2nd century AD, the prolific Greek physician Galen contributed significantly to the anatomical and physiological knowledge of the cardiovascular system. However his erroneous theory of blood circulation, based on the inaccurate notion that venous blood passes through tiny pores in the heart's septum, moves from the right ventricle to the left, and is mixed with inhaled air from the lungs, was to block any new ideas in this field for more than 1500 years. PMID- 26021241 TI - Association between coronary flow reserve and exercise capacity. AB - INTRODUCTION: Reduced exercise capacity is of clinical importance. Sometimes no corresponding cardiovascular disease can be found to explain this condition. We hypothesized that coronary microvascular dysfunction may have an effect on exercise capacity in patients without apparent cardiovascular disease. METHODS: Fifty patients (33 female, mean age 46.8 +/- 12.4 years) without coronary artery or other cardiac disease were enrolled. Coronary microvascular function was evaluated by measurement of coronary flow reserve (CFR) during transthoracic pulsed-wave Doppler echocardiography with pharmacological stress. CFR was calculated as the ratio of hyperemic to baseline peak diastolic velocities after dipyridamole infusion. Exercise capacity was determined by treadmill exercise testing. Exercise time, metabolic equivalent (MET), and Duke treadmill score (DTS) were recorded and compared with the CFR data. RESULTS: CFR was correlated with exercise time (r=0.376, p=0.007), MET (r=0.435, p=0.002) and DTS (r=0.458, p=0.001). Exercise time, MET, and DTS were lower in patients with impaired CFR (<2) than in those with normal CFR (2) (5.3 +/- 1.8 min vs. 8.6 +/- 2.7 min, p<0.001; 7.3 +/- 3.1 vs. 11.4 +/- 2.8, p=0.002; -1.75 (-5.9, 5.0) vs. 7.5 (5.2, 9.41), p<0.001; respectively). CFR was lower in patients with MET7 as compared to patients with MET>7 (2.0 +/- 0.5 vs. 2.6 +/- 0.6, p=0.015). CONCLUSIONS: CFR is associated with exercise capacity. Thus coronary microvascular dysfunction may be a reason for reduced exercise capacity in patients who have no apparent cardiovascular disease. PMID- 26021242 TI - Visit-to-Visit Blood Pressure Variability and Arterial Stiffness Independently Predict Cardiovascular Risk Category in a General Population: Results from the SEPHAR II Study. AB - INTRODUCTION: The aim of our study was to evaluate visit-to-visit blood pressure variability (BPV) and the association of this parameter with cardiovascular risk determinants, according to the SEPHAR II survey. METHODS: Following a selection based on the multi-stratified proportional sampling procedure, a total of 1975 subjects who gave informed consent were evaluated by means of a questionnaire, anthropometric, blood pressure (BP) and arterial stiffness measurements (pulse wave velocity and augmentation index), 12-lead ECG recordings, and blood and urine analysis. BPV was quantified in terms of the standard deviation (SD) of the mean systolic blood pressure (SBP) and high BPV was defined as SBP-SD above the 4th quartile. Total cardiovascular risk was assessed by the 2013 ESH/ESC risk stratification chart. RESULTS: Mean BP was 132.37/82.01 mmHg. Mean systolic BPV was 6.16 mmHg, with 24.62% of values above the 75th percentile (8.48 mmHg). Factors found to be associated with high systolic BPV were age, SBP, pulse pressure, total and LDL-cholesterol, triglycerides, visceral obesity, diabetes mellitus, metabolic syndrome and increased aortic stiffness. In addition, in the hypertensive group high BPV was associated with the severity of hypertension and a lack of treatment control. Both visit-to-visit systolic BPV and aortic stiffness proved to be positively and independently correlated with the risk category. Based on these parameters it was possible to predict with 72.6% accuracy the probability of finding subjects in a high and very high cardiovascular risk category. CONCLUSIONS: The results of our study indicate a notable prevalence of high BPV, affecting almost a quarter of the Romanian adult population. Visit-to-visit systolic BPV and arterial stiffness are strongly correlated and together might contribute to the improvement of cardiovascular risk prediction models. PMID- 26021243 TI - Differences in Stress Forces and Geometry between Left and Right Coronary Artery: A Pathophysiological Aspect of Atherosclerosis Heterogeneity. AB - INTRODUCTION: We sought to assess noninvasively the differences in hemorrheologic and geometric parameters between the left and right coronary artery (RCA). Low endothelial shear stress (ESS), high molecular viscosity (MV), and high wall stress (WS) induce atherosclerosis, while curvature and torsion have lately been implicated in the atherosclerotic process. METHODS: We studied 28 coronary arteries from 22 subjects undergoing coronary computed tomography angiography. We performed 3D reconstruction of the left anterior descending (LAD, n=14), left circumflex (LCx, n=5), and RCA (n=9) arteries. ESS, MV, and WS were calculated for 2-mm segments using computational fluid dynamics. Curvature and torsion were calculated for each segment using morphometric algorithms. RESULTS: A total length of 187 cm of coronary arteries was studied. ESS was higher in the LAD compared to the LCx and RCA (13.76 Pa vs. 3.49 Pa vs. 3.76 Pa, p<0.001); MV was higher in the LCx compared to the LAD and RCA (0.00542 Pa.s vs. 0.00173 Pa.s vs. 0.00240 Pa.s, p<0.001); and WS had higher values in the RCA compared to the LAD and LCx (289.98 mmHg vs. 255.93 mmHg vs. 235.18 mmHg, p<0.001). Curvature was greater in the LCx compared to the LAD and RCA (0.1447 mm-1 vs. 0.1229 mm-1 vs. 0.1234 mm-1, p<0.05), while torsion was found not to differ among the coronary arteries. CONCLUSIONS: Hemorrheologic and geometric parameters differ between the left and right coronary arteries. These factors, either alone or in association with local flow patterns and geometry, may affect the topography of atherosclerosis in the coronary arterial tree. PMID- 26021244 TI - Association Between rs2200733 Polymorphism on Chromosome 4q25 and Atrial Fibrillation in a Greek Population. AB - INTRODUCTION: Atrial fibrillation (AF) is a common arrhythmia with evidence of genetic susceptibility. The rs2200733 single-nucleotide polymorphism (SNP) in a non-coding region on chromosome 4q25 has been associated with AF. The purpose of this case-control study was to examine the possible association of the rs2200733 polymorphism with AF in the Greek population. METHODS: A total of 295 individuals, 167 AF patients and 128 controls, were genotyped for the presence of the rs2200733 polymorphism using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPs) method. RESULTS: The T/T genotype and the T allele were detected more frequently in patients with AF compared to controls (13.2% vs. 2.3%, p=0.001, and 29.6% vs. 17.9%, p=0.001), suggesting that the rs2200733 polymorphism increases susceptibility to AF in the Greek population. In a multivariate stepwise analysis that included many conventional precipitating factors for AF, T/T genotype and left atrium (LA) diameter were the only independent predictors of AF (OR 1.74, 95% CI: 1.40-2.98, p=0.005, and OR 2.88, 95% CI: 1.835.62, p<0.001, respectively). A trend of association was observed between the T/T genotype and lone AF (p=0.08). CONCLUSIONS: Our results suggest that SNP rs2200733 confers a significant risk of AF in the Greek population, providing further support to the previously reported association between AF and rs2200733 polymorphism on chromosome 4q25. PMID- 26021246 TI - Effects of ranolazine on left ventricular diastolic and systolic function in patients with chronic coronary disease and stable angina. AB - INTRODUCTION: The present study examined the effect of ranolazine, which acts via the mechanism of selective inhibition of late INa+, on parameters of left ventricular systolic and diastolic function in patients suffering from angiographically confirmed chronic coronary artery disease, presenting with chronic stable angina. METHODS: We studied 40 patients (age 67 +/- 9 years; 30 men, 10 women) with chronic coronary artery disease who reported angina symptoms on optimal medication and who were not suitable for invasive treatment. Patients were randomized to the ranolazine group (group A, 20 patients taking oral ranolazine 500 mg bid for 3 months) and the control group (group B, 20 patients who did not receive the drug). Left ventricular systolic and diastolic function was assessed echocardiographically at baseline and after the end of the three month treatment period. Left ventricular ejection fraction by the modified Simpson's method, E and A left ventricular filling velocities, E/A ratio, deceleration time (DT) of E, isovolumic relaxation time (IVRT), E and A waves, and the E/E ratio were measured using 2-dimensional echocardiography, Doppler and tissue Doppler imaging (TDI). RESULTS: Group A patients demonstrated a clear improvement of their initial angina symptoms. There were no adverse effects from ranolazine requiring withdrawal from the study. There was no statistically significant change in left ventricular systolic function in either group. A statistically significant change was seen in indexes of diastolic function measured using both conventional Doppler and TDI in Group A patients compared with Group B patients after three months' ranolazine treatment period. The changes in left ventricular diastolic function indexes in Group A patients were as follows: E 0.58 +/- 0.11 vs. 0.76 +/- 0.12 m/s, p<0.001; A 0.71 +/- 0.22 vs. 0.83 +/- 0.19 m/s, p<0.001; E/A 0.81 +/- 0.14 vs. 0.97 +/- 0.17, p<0.005; 5.4 +/- 0.7 vs. 6.8 +/- 0.9 cm/s, p<0.005; 7.2 +/- 0.8 vs. 8.3 +/- 1.1 cm/s, p<0.005; E/ 10.7 +/- 1.1 vs. 11.1 +/- 0.8, p=ns; DT 251 +/- 14 vs. 226 +/- 17 ms, p<0.004; IVRT 95 +/- 11 vs. 74 +/- 9 ms, p<0.001. Systolic function did not change: EF 46.3 +/- 3.4 vs. 46.7 +/- 2.7%, p: ns. CONCLUSIONS: The use of ranolazine in patients suffering from chronic coronary artery disease has a favorable impact on diastolic function parameters. Accordingly, a clinical benefit could be observed due to an improvement in patients' symptoms. PMID- 26021245 TI - Inducibility of ventricular arrhythmia and tachyarrhythmia recurrences in patients with implantable defibrillator. AB - INTRODUCTION: We evaluated the potential ability of the electrophysiological (EP) inducibility of ventricular arrhythmias to predict the likelihood of appropriate ICD intervention over the long-term in ischemic and nonischemic patients with current primary prevention indications for ICD implantation. METHODS: Between 2006 and 2008, 206 consecutive heart failure patients who were candidates for ICD implantation for the primary prevention of sudden cardiac death according to standard indications underwent EP testing, usually on ICD implantation. RESULTS: On EP testing, 15 (7%) patients had inducible monomorphic ventricular tachycardia (VT) and 14 (7%) ventricular fibrillation (VF). Over 24 months, 64 (31%) patients received appropriate ICD therapies: 51 (25%) for VT and 16 (8%) for VF. The time to the first appropriate ICD therapy trended to be shorter in the group of patients who were inducible on EP testing (p=0.072). Among patients receiving appropriate therapies, the median number of arrhythmic episodes was 2, and the proportion of patients with 2 treated arrhythmic episodes was higher in the group of inducible patients (34% versus 14%, p=0.005). On multivariate analysis, inducibility proved to be an independent predictor of frequent (2) arrhythmic episodes, as did a history of coronary artery bypass grafting. Moreover, patients with 2 treated arrhythmic episodes showed higher mortality (log-rank test, p=0.042). CONCLUSION: Patients with inducibility of VT or VF are more likely to experience frequent appropriate ICD therapies during follow up. PMID- 26021247 TI - Evaluation of cardiac sequelae in patients with sickle cell anemia. AB - INTRODUCTION: The aim of this study was aim to evaluate cardiac function by means of echocardiography in patients with sickle cell anemia. METHODS: This was a case control study that evaluated a total of 44 patients with sickle cell anemia, who were on regular follow up, and 44 age/sex-matched normal healthy control subjects. M-mode, two-dimensional, Doppler and pulse tissue-Doppler echocardiographic measurements were performed in both groups. RESULTS: The mean age was 14.06 +/- 6.4 years (55% female, 45% male). The mean hemoglobin, hemoglobin F, and serum ferritin levels were 9.4 +/- 1.20 g/dL, 22.7 +/- 12.9 g/dL, and 391 +/- 590 ng/dL respectively. Pulsed Doppler echocardiography showed that the early diastolic trans-tricuspid peak flow velocity was greater in the patients than in the control subjects. Assessment of the lateral mitral and tricuspid annulus peak velocities by pulsed tissue Doppler imaging showed that the patients had significantly greater systolic, and early and late diastolic velocities than the controls. The left ventricular diameter, interventricular septum diameter, and posterior wall diameter were statistically significantly greater in the patients compared with the control group, whereas there was no difference in ejection fraction. CONCLUSION: Sickle cell anemia in children results in a volume-overloaded heart with a significant increase in left ventricular dimensions. However, left ventricular systolic dysfunction and pulmonary hypertension were not frequent findings in our patients. PMID- 26021248 TI - Can We Close the Discussion on PFO-Closure? PMID- 26021249 TI - Patient with hypertrophic cardiomyopathy with apical aneurysm and thrombus presenting with progressive congestive heart failure. PMID- 26021250 TI - Real-Time 3-Dimensional Transesophageal Echocardiography: Its Incremental Value over 2-Dimensional Echocardiography in Assessing Acute Mitral Regurgitation. PMID- 26021251 TI - Percutaneous mitral valvuloplasty refined: use of a novel modified antegrade approach. AB - Mitral stenosis usually occurs many years after an episode of rheumatic fever and it has an indolent course until its later stages, when it acutely worsens. The rates of mitral stenosis keep declining; nonetheless, the need for advanced and sophisticated treatment modalities still remains. Our group has been applying a novel modified antegrade approach for treating mitral valve stenosis and, although we have limited experience, the results thus far are favorable. We present the preliminary data of three patients who suffered from symptomatic mitral valve stenosis and underwent successful percutaneous mitral valvuloplasty with this novel modified antegrade approach. This method increases the safety and the efficacy of the procedure and has the same clinical results as other available percutaneous techniques. PMID- 26021252 TI - Quadricuspid pulmonary valve in an adult patient identified by transthoracic echocardiography and multi-detector computed tomography. AB - Quadricuspid pulmonary valve is a rare congenital heart disease. It is infrequently associated with significant clinical complications and tends to be clinically silent. Because of its benign nature, it has been diagnosed mainly post mortem. Its diagnosis by transthoracic echocardiography is very difficult because of the anatomical features. We describe a case of quadricuspid pulmonary valve diagnosed by transthoracic echocardiography and electrocardiography-gated multi-detector row computed tomography. PMID- 26021253 TI - Recurrent Myocardial Infarction or Epistenocardiac Pericarditis: How Can the Surface ECG Be Useful in Clinical Decision Making? PMID- 26021254 TI - A 100 km Run Does Not Induce Persistent Predominance of Sympathetic Activity During 24-Hour Recovery in Amateur Male Athletes. PMID- 26021255 TI - Acute coronary syndromes. PMID- 26021256 TI - Management of arterial hypertension: from no treatment to renal denervation. PMID- 26021257 TI - Spermatozoon of the freshwater rotifer Brachionus calyciflorus (Rotifera, Monogononta): Advances in morphological and ultrastructural studies. AB - The morphological and ultrastructural features of the spermatozoon in Brachionus calyciflorus are described using light, fluorescence and transmission electron microscopy (TEM). The mature spermatozoon, which appears to be thread-like, is composed of a slightly expanded anterior of cell body region and a flagellum region without acrosome. The cell body region and flagellum region are respectively 16-27MUm and 20-33MUm in length (n=60). The spermatozoon is characterized by a mass of dense tubular materials, which occupy most of the cell. Some mitochondria are distributed around the nuclear region in the anterior of the cell body region, while in the posterior portion of cell body, the chromatin often contains a single lobated nucleus arranged at the center of cell. The flagellum contains the classic axoneme (9*2+2) and possesses lateral undulating membrane. Mature B. calyciflorus males have no germ cell stages earlier than the spermatids in the testis. TEM examination reveals rigid rods as well as predominant typical spermatozoon in the testis. Observations, based on successive photographs and videos, enabled a first-time recording of the unique inverted movement of the spermatozoon, which indicated that the movement of the spermatozoon is driven by the flagellum. Our study also provides further supplementary insights into the phylogenetic systematics of the Rotifera. PMID- 26021258 TI - Examination of the electronic structure of crystalline and liquid Al versus temperature by in situ electron energy-loss spectroscopy (EELS). AB - Electron energy-loss near-edge structure (ELNES) analysis using in situ heating in a transmission electron microscope (TEM) was performed to compare the electronic structure of crystalline and liquid Al versus temperature. It was found that the ELNES features in the L2,3 edges of crystalline and liquid Al are qualitatively similar, but that the edge threshold is modified and certain features in the energy range between 102 and 115eV vanish in the liquid, indicating that partial DOS is quantitatively different. Broadening of the L2,3 edge maximum for Al with temperature indicates a decay in the centrifugal barrier for the 2p electrons with increasing temperature. Comparison between the ELNES edge in supercooled liquid and crystalline Al at the same temperature of 600 degrees C shows that the degree of order, i.e., crystallinity, plays an important role in determining the DOS. The ELNES edge of supercooled liquid Al closely resembles that of superheated liquid Al. PMID- 26021259 TI - Morphology of the European species of the aphid genus Eulachnus (Hemiptera: Aphididae: Lachninae) - A SEM comparative and integrative study. AB - Scanning electron microscopy (SEM) methods were used for the first time to elucidate the external morphology of the European species of the genus Eulachnus (Hemiptera: Aphididae: Lachninae), a representative genus of the conifer-feeding aphids tribe Eulachnini. We examined and compared the external morphology of apterous and alate viviparous females from the parthenogenetic generation as well as oviparous females and alate males belonging to the sexual generation. FE-SEM images based on HMDS and cryo-SEM preparation techniques revealed better image quality than the CPD technique in regard to surface tension and morphological signs of cell deteriorations (i.e., existence of depressions, drying artifacts and membrane blebs). Three morphologically different species groups "agilis", "brevipilosus" and "cembrae" were proposed due to the differences in head, antennae, legs and dorsal chaetotaxy as well as dorsal sclerotization. The most characteristic features and differences of representatives of these groups are presented and discussed. PMID- 26021260 TI - Multidimensional stationary probability distribution for interacting active particles. AB - We derive the stationary probability distribution for a non-equilibrium system composed by an arbitrary number of degrees of freedom that are subject to Gaussian colored noise and a conservative potential. This is based on a multidimensional version of the Unified Colored Noise Approximation. By comparing theory with numerical simulations we demonstrate that the theoretical probability density quantitatively describes the accumulation of active particles around repulsive obstacles. In particular, for two particles with repulsive interactions, the probability of close contact decreases when one of the two particle is pinned. Moreover, in the case of isotropic confining potentials, the radial density profile shows a non trivial scaling with radius. Finally we show that the theory well approximates the "pressure" generated by the active particles allowing to derive an equation of state for a system of non-interacting colored noise-driven particles. PMID- 26021261 TI - The Role of Janus Kinase 3 in the Regulation of Na+/K+ ATPase under Energy Depletion. AB - BACKGROUND/AIMS: Janus kinase-3 (JAK3) is activated during energy depletion. Energy-consuming pumps include the Na(+)/K(+)-ATPase. The present study explored whether JAK3 regulates Na(+)/K(+)-ATPase in dendritic cells (DCs). METHODS: Ouabain (100 uM)-sensitive (Iouabain) and K(+)-induced (Ipump) outward currents were determined by utilizing whole cell patch-clamp, Na(+)/K(+)-ATPase alpha1 subunit mRNA levels by RT-PCR, Na(+)/K(+)-ATPase protein abundance by flow cytometry or immunofluorescence, and cellular ATP by luciferase-assay in DCs from bone marrow of JAK3-knockout (jak3(-/-)) or wild-type mice (jak3(+/+)). Ipump was further determined by voltage clamp in Xenopus oocytes expressing JAK3, active (A568V)JAK3 or inactive (K851A)JAK3. RESULTS: Na(+)/K(+)-ATPase alpha1-subunit mRNA and protein levels, as well as Ipump and Iouabain were significantly higher in jak3(-/-)DCs than in jak3(+/+)DCs. Energy depletion by 4h pre-treatment with 2,4-dinitro-phenol significantly decreased Ipump in jak3(+/+) DCs but not in jak3(-/-)DCs. Cellular ATP was significantly lower in jak3(-/-)DCs than in jak3(+/+)DCs and decreased in both genotypes by 2,4-dinitro-phenol, an effect significantly more pronounced in jak3(-/-)DCs than in jak3(+/+)DCs and strongly blunted by ouabain in both jak3(+/+) and jak3(-/-)DCs. Ipump and Iouabain in oocytes were decreased by expression of JAK3 and of (A568V)JAK3 but not of (K851A)JAK3. JAK3 inhibitor WHI-P154 (4-[(3'-bromo-4'-hydroxyphenyl)amino]-6,7 dimethoxyquinazoline, 22 MUM) enhanced Ipump and Iouabain in JAK3 expressing oocytes. The difference between (A568V)JAK3 and (K851A)JAK3 expressing oocytes was virtually abrogated by actinomycin D (50 nM). CONCLUSIONS: JAK3 down regulates Na(+)/K(+)-ATPase activity, an effect involving gene expression and profoundly curtailing ATP consumption. PMID- 26021262 TI - Glycyrrhetinic Acid protects the heart from ischemia/reperfusion injury by attenuating the susceptibility and incidence of fatal ventricular arrhythmia during the reperfusion period in the rat hearts. AB - BACKGROUND/AIMS: Licorice has been used to treat many diseases, including palpitations, in both Eastern and Western societies for thousands of years. It has been reported that glycyrrhetinic acid (GA), an aglycone saponin extracted from licorice root, exerts protective effects on the cardiovascular system, limits infarct sizes and protects against the development of arrhythmia. However, the mechanisms underlying the effects of glycyrrhetinic acid on the cardiovascular system remain poorly understood. This study aimed to determine the mechanisms underlying the protective effects of GA against lethal cardiac arrhythmias induced via ischemia-reperfusion in rat hearts, and to examine its electropharmacological properties. MATERIALS AND METHODS: Anesthetized rats were divided into control (CTL), GA5, GA10, and GA20 groups. GA was administered intravenously 15 min before the occlusion of the left anterior descending coronary artery, at dosages of 5, 10 and 20 mg/kg, respectively. Single ventricular myocytes were isolated using enzymolysis. The whole-cell patch clamp technique was utilized to record Ica, L, Ito and action potentials (APs). RESULTS: During reperfusion, the incidence of ventricular fibrillation (VF) was decreased in each of the groups compared with the CTL group (p<0.05). The ventricular tachycardia (VT)/VF score was significantly decreased in the GA20 group. Action potential durations (APDs) were prolonged by GA; both L-type calcium current (Ica-L) and transient outward potassium current (Ito) were blocked in a concentration-dependent manner by GA. CONCLUSION: These results suggest that GA attenuates both the susceptibility to and the incidence of fatal ventricular arrhythmia during reperfusion in rat hearts via the prolongation of the APD and the inhibition of both Ica-L and Ito. GA appears to be a promising antiarrhythmic agent in the setting of ischemia/reperfusion. PMID- 26021263 TI - Lipocalin 2 Upregulation Protects Hepatocytes from IL1-beta-Induced Stress. AB - BACKGROUND: Lipocalin 2 (LCN2), a protein primarily produced by hepatocytes, is highly upregulated under various conditions that induce cellular stress, such as intoxication, infection or inflammation. However, the precise biological functions and underlying mechanisms of LCN2 in hepatocytes remains unknown. METHODS: Hepatocyte stress was successfully induced by treating Huh7 cells with interleukin-1beta (IL-1beta). Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-alpha) and LCN2 levels were measured in IL-1beta treated Huh7 cells and supernatant. Additionally, microarray analysis was conducted to identify genes differentially expressed in LCN2-silenced and control Huh7 cells. RESULTS: TNF alpha, IL-6 and LCN2 were significantly elevated in Huh7 cells after IL-1beta) treatment. In LCN2-silenced Huh7 cells, expression of IL-6 and TNF-alpha was significantly increased when compared with the expression levels of control Huh7 cells. Furthermore, differentially expressed genes were observed between the LCN2 silenced and control cells. Microarray analysis indicated that LCN2 acted by influencing genes involved in protein metabolism, stress response, cell cycle and proliferation. CONCLUSIONS: Our results suggest that LCN2 upregulation protects hepatocytes from IL-1beta-induced stress. Additionally, our microarray analysis of LCN2-silenced and control cells provides a better understanding of the mechanisms that may be influenced by LCN2 induction. PMID- 26021264 TI - Nexrutine inhibits cancer cell growth as a consequence of mitochondrial damage and mitophagy. AB - BACKGROUND/AIMS: Nexrutine is an herbal extract of Phellodendron amurense and has been used as nutrient supplement in China as well as America. Potential protection effect of Nexrutine has been reported. METHODS: To investigate the mechanism of Nexrutine, we used the HeLa, U2OS and HCT116 as a model. Based on the acidification of cell culture media, we examined the lactate, mitochondria damage as well as mitophagy status by corresponding assay. RESULTS: Our data suggest that Nexrutine alters the cellular glucose metabolism to promote lactate production. This effect is caused by mitochondrial damage, not an alteration to lactate dehydrogenase activity. As a result of the mitochondrial damage, cell proliferation was inhibited and was associated with an elevation in p21/p27 proteins, which are both important cell cycle inhibitors. As another consequence of the mitochondrial damage, mitophagy was highly activated in Nexrutine-treated cells in a dose-dependent manner. When the autophagy pathway was blocked by siRNAs against BECN1 or ATG7, the growth inhibition caused by Nexrutine was reversed. CONCLUSION: Our study revealed that autophagy plays an important role in the inhibition of cancer cell proliferation by Nexrutine. PMID- 26021265 TI - Enhanced suicidal erythrocyte death contributing to anemia in the elderly. AB - BACKGROUND/AIMS: Anemia, a common condition in the elderly, could result from impaired formation and/or from accelerated loss of circulating erythrocytes. The latter could result from premature suicidal erythrocyte death or eryptosis characterized by phosphatidylserine (PS) exposure at the erythrocyte surface. Triggers of eryptosis include increased cytosolic Ca(2+)-concentration ([Ca(2+)]i), oxidative stress and ceramide. The present study explored whether eryptosis is altered in elderly individuals and, if so, to identify underlying mechanisms. METHODS: Blood was drawn from healthy young (n=11, age 31.3 +/- 1.7 years) and elderly (n=16, age 88.6 +/- 0.9 years) individuals. PS exposure was estimated from annexin V-binding, cell volume from forward scatter, [Ca(2+)]i from Fluo3-fluorescence, reactive oxygen species (ROS) from 2',7'dichlorodihydrofluorescein fluorescence, reduced glutathione (GSH) from mercury orange fluorescence and ceramide from FITC-conjugated antibody binding in flow cytometry. Measurements were made in erythrocytes from freshly drawn blood and in erythrocytes exposed in vitro for 24 h to plasma from young or elderly individuals. RESULTS: Elderly individuals suffered from severe anemia (hemoglobin 10.5 +/- 0.3 g/100 ml) despite enhanced number of reticulocytes (2.3 +/- 0.2%). The percentage of PS-exposing erythrocytes was significantly higher in the elderly (2.5 +/- 0.2%) than in the young volunteers (1.3 +/- 0.1%). The increase in PS exposure was paralleled by significant increase of ROS and significantly decreased levels of reduced GSH. Erythrocyte [Ca(2+)]i, and ceramide abundance tended to be higher in the elderly, differences, however, not reaching statistical significance. CONCLUSIONS: The anemia of elderly individuals is mainly if not exclusively due to enhanced eryptosis, resulting at least in part from GSH deficiency and increased oxidative stress. PMID- 26021266 TI - Identification and characterization of cancer stem cells from head and neck squamous cell carcinoma cell lines. AB - BACKGROUND/AIMS: Head and neck squamous cell carcinoma (HNSCC) ranks sixth worldwide for tumor-related mortality. A subpopulation of tumor cells, termed cancer stem cells (CSCs), has the ability to support cancer growth. Therefore, profiling CSC-enriched populations could be a reliable tool to study cancer biology. METHODS: We performed phenotypic characterization of 7 HNSCC cell lines and evaluated the presence of CSCs. CSCs from Hep-2 cell line and HNSCC primary cultures were enriched through sphere formation and sphere-forming cells have been characterized both in vitro and in vivo. In addition, we investigated the expression levels of Nicotinamide N-methyltransferase (NNMT), an enzyme overexpressed in several malignancies. RESULTS: CSC markers were markedly expressed in Hep-2 cell line, which was found to be highly tumorigenic. CSC enriched populations displayed increased expression of CSC markers and a strong capability to form tumors in vivo. We also found an overexpression of CSC markers in tumor formed by CSC-enriched populations. Interestingly, NNMT levels were significantly higher in CSC-enriched populations compared with parental cells. CONCLUSION: Our study provides an useful procedure for CSC identification and enrichment in HNSCC. Moreover, results obtained seem to suggest that CSCs may represent a promising target for an anticancer therapy. PMID- 26021267 TI - Periostin Mediates TGF-beta-Induced Epithelial Mesenchymal Transition in Prostate Cancer Cells. AB - BACKGROUND: In our previous study, we found that periostin was upregulated in prostate cancer, and its expression could be modulated by TGF-beta. TGF-beta could upregulate periostin expression in some cells, and both TGF-beta and periostin could induce epithelial mesenchymal transition (EMT). We aimed to study the effect of periostin in the process of TGF-beta-induced EMT in prostate cancer cells. METHODS: We constructed a lentivirus vector containing the periostin gene and transduced it into PC3 and DU145 cells. After confirming periostin overexpression by PCR and Western blotting, we used an MTT assay to establish a growth curve to measure cell proliferation. Additionally, we performed transwell and wound healing assays to measure cell invasion and migration, respectively. Lastly, we measured the expression of EMT associated factors using Western blot analysis to test the effect of periostin on EMT in prostate cancer cells. RESULTS: PCR and Western blot analyses confirmed that periostin was upregulated after infection with the periostin lentiviral vector. Periostin overexpression promoted increased cell proliferation, invasion, and migration as measured by MTT, transwell, and wound healing assays, respectively. Western blot analysis illustrated that periostin overexpression increased the expression of EMT associated factors, and periostin overexpression activated Akt and GSK-3beta, which could be inhibited using a PI3K inhibitor. Additionally, TGF-beta increased the levels of STAT3, Twist1 and periostin, while both STAT3 shRNA and Twist1 shRNA inhibited periostin expression. However, STAT3 shRNA also decreased Twist1 expression. Although reduction of STAT3, Twist1 or periostin levels with shRNA inhibited TGF-beta-induced overexpression of EMT associated factors, periostin overexpression could reverse such inhibition by interfering with STAT3 and Twist1. Similarly, periostin overexpression also reversed inhibition of cell invasion induced by interference of STAT3 and Twist1. CONCLUSION: Our findings indicate that periostin is an important mediator of TGF-beta-induced EMT and suggest that periostin is a potential therapeutic target for suppressing the metastatic progression of prostate cancer. PMID- 26021268 TI - Ascorbic Acid-Induced Cardiac Differentiation of Murine Pluripotent Stem Cells: Transcriptional Profiling and Effect of a Small Molecule Synergist of Wnt/beta Catenin Signaling Pathway. AB - BACKGROUND: Reproducible and efficient differentiation of pluripotent stem cells (PSCs) to cardiomyocytes (CMs) is essential for their use in regenerative medicine, drug testing and disease modeling. The aim of this study was to evaluate the effect of some previously reported cardiogenic substances on cardiac differentiation of mouse PSCs. METHODS: Differentiation was performed by embryoid body (EB)-based method using three different murine PSC lines. The differentiation efficiency was monitored by RT-qPCR, immunocytochemistry and flow cytometry, and the effect mechanistically evaluated by transcriptome analysis of treated EBs. RESULTS: Among the five tested compounds (ascorbic acid, dorsomorphin, cyclic adenosine 3',5'-monophosphate, cardiogenol C, cyclosporin A) only ascorbic acid (AA) exerted a strong and reproducible cardiogenic effect in CGR8 cells which was less consistent in other two PSC lines. AA induced only minor changes in transcriptome of CGR8 cells after administration during the initial two days of differentiation. Cardiospecific genes and transcripts involved in angiogenesis, erythropoiesis and hematopoiesis were up-regulated on day 5 but not on days 2 or 3 of differentiation. The cardiac differentiation efficiency was improved when QS11, a small-molecule synergist of Wnt/beta-catenin signaling pathway, was added to cultures after AA-treatment. CONCLUSION: This study demonstrates that only minor transcriptional changes are sufficient for enhancement of cardiogenesis of murine PSCs by AA and that AA and QS11 exhibit synergistic effects and enhance the efficiency of CM differentiation of murine PSCs. PMID- 26021269 TI - Acetabuloplasty with bone grafting in uncemented hip replacement for protrusion. AB - PURPOSE: This retrospective study investigated midterm outcomes of uncemented total hip replacement with acetabuloplasty using impacted bone grafts in acetabular protrusion or primary hip arthritis with an inadequate thickness of the medial acetabular wall. METHODS: The medial acetabular wall was augmented by impaction bone grafting, and an uncemented cup was implanted in all cases. Hip centre of rotation, medial acetabular wall thickness and cup positioning were evaluated radiologically, with the Harris Hip Score determined at each follow-up. RESULTS: A total of 32 patients (39 hips) were followed for a mean of 4.5 years, with significant improvement of the Harris Hip Score at the last follow-up. Hip centre of rotation was restored close to the optimal position. Medial acetabular wall thickness and cup position obtained immediately postoperatively were maintained up to the last follow-up, without statistically significant differences. Bone graft integration was observed in all cases by one or two years postoperatively, with no signs of loosening or cup migration at the last follow up. Heterotopic ossification was identified in 15.4% of cases, without clinical evidence of hip mobility impairment or pain. CONCLUSIONS: Impaction bone grafting for acetabuloplasty, associated with the implantation of an uncemented cup, yields good midterm results in patients with acetabular protrusion and with primary hip arthrosis with a thinned medial acetabular wall. The restored bone stock and medial acetabular wall thickness enable the placement of the hip centre of rotation close to the optimal location, which could offer further long-term benefits. PMID- 26021270 TI - Systematic review and meta-analysis of prevalence studies in transsexualism. AB - BACKGROUND: Over the last 50 years, several studies have provided estimates of the prevalence of transsexualism. The variation in reported prevalence is considerable and may be explained by factors such as the methodology and diagnostic classification used and the year and country in which the studies took place. Taking these into consideration, this study aimed to critically and systematically review the available literature measuring the prevalence of transsexualism as well as performing a meta-analysis using the available data. METHODS: Databases were systematically searched and 1473 possible studies were identified. After initial scrutiny of the article titles and removal of those not relevant, 250 studies were selected for further appraisal. Of these, 211 were excluded after reading the abstracts and a further 18 after reading the full article. This resulted in 21 studies on which to perform a systematic review, with only 12 having sufficient data for meta-analysis. The primary data of the epidemiological studies were extracted as raw numbers. An aggregate effect size, weighted by sample size, was computed to provide an overall effect size across the studies. Risk ratios and 95% confidence intervals (CIs) were calculated. The relative weighted contribution of each study was also assessed. RESULTS: The overall meta-analytical prevalence for transsexualism was 4.6 in 100,000 individuals; 6.8 for trans women and 2.6 for trans men. Time analysis found an increase in reported prevalence over the last 50 years. CONCLUSIONS: The overall prevalence of transsexualism reported in the literature is increasing. However, it is still very low and is mainly based on individuals attending clinical services and so does not provide an overall picture of prevalence in the general population. However, this study should be considered as a starting point and the field would benefit from more rigorous epidemiological studies acknowledging current changes in the classification system and including different locations worldwide. PMID- 26021271 TI - Disability and functional burden of disease because of mental in comparison to somatic disorders in general practice patients. AB - BACKGROUND: Severity of illness is not only depending on the symptom load, but also on the burden in life. Mental disorders are among those illnesses, which in particular cause suffering to the individual and society. METHOD: To study burden of disease for mental in comparison to somatic disorders, 2099 patients from 40 general practitioners filled in (a) the Burvill scale which measures acute and chronic illnesses in ten different body systems and (b) the IMET scale which measures impairment in ten different areas of life. RESULTS: Patients were suffering on average from acute and/or chronic illness in 3.5 (SD: 2.0) body systems and 56.6% of patients complained about acute and/or chronic mental disorders. The most significant negative impact on the IMET total score have acute and chronic mental disorders, followed by chronic neurological and musculoskeletal and acute respiratory and gastrointestinal disorders, while cardiovascular, metabolic, urogenital, haematological and ear/eye disorders have no greater impact. Acute as well as chronic mental disorders cause impairment across all areas of life and most burden of disease (functional burden of disease 1.69), followed by musculoskeletal disorders (1.62). CONCLUSION: Mental disorders are among the most frequent health problems with high negative impact across all areas of life. When combining frequency and impairment mental disorders cause most burden of disease in comparison to other illnesses. This should be reflected in the organization of medical care including family medicine. PMID- 26021272 TI - Celebrating 350 years of academic journals. PMID- 26021273 TI - Surgical treatment and rehabilitation of medial Hoffa fracture fixed by locking plate and additional screws: A retrospective cohort study. AB - PURPOSE: Hoffa fracture fixed by only using a single plate or lag screws might be not strong enough to achieve direct stability. The goal of this study is to determine the functional outcome of the surgical treatment and rehabilitation of medial Hoffa fracture by a locking plate combined with cannulated or lag screws. METHODS: A total of 13 patients suffering isolated medical Hoffa fractures were identified during the study period (2005.February-2013.February) and retrospectively analyzed. All the fractures were treated by open reduction via the medial approach, and internal fixation by a locking plate combined with cannulated or lag screws. Early active rehabilitation including tele rehabilitation for rural patients with restricted weight bearing was instituted after the surgical treatment. The radiological and functional outcome analysis was performed by using Knee Society Score (KSS), the range of movement (ROM), and the stability of fixation of the patients during 24 month follow-up. RESULTS: The bone union of medial Hoffa fractures was achieved in all patients. The articular surface of medial femoral condyle was anatomically reduced. There was no loss of reduction and fixation. All patients achieved satisfactory knee joint function and regained their walking ability with good clinical results through early postsurgical rehabilitation. Ten patients (77%) had 0 degrees -130 degrees range of motion with full extension; two patients (15%) had 0 degrees -115 degrees range of motion; one patient (8%) had 0 degrees -110 degrees range of motion. The KSS of all the patients were more than 80, and the scores of seven patients (54%) were more than 85. CONCLUSION: Fixation with a locking plate and cannulated or lag screws for medial Hoffa fracture seemed to be effective and reliable for achieving anatomical reduction, and gave satisfactory functional results when coupled with aggressive rehabilitation. PMID- 26021274 TI - Long-term outcome for open preperitoneal mesh repair of recurrent inguinal hernia. AB - AIM: Recurrent inguinal hernia represents a major challenge for surgeons with high risks of re-recurrence and complications, especially when an anterior approach is adopted. The aim of this study was to evaluate the long-term results of the open preperitoneal mesh repair for recurrent inguinal hernia. METHODS: We performed a prospective clinical study of 107 consecutive patients having recurrent inguinal hernias between April 2006 and November 2010. All patients were operated on using open preperitoneal mesh repair. The demographics, perioperative variables, complications and recurrences were evaluated with all patients. RESULTS: There were no major intraoperative complications. The average operative time was 42.1 min (range 28-83 min) for unilateral and 62.7 min (range 38-106 min) for bilateral hernias. The mean postoperative hospital stay was 1.6 days (range 1-9 days). The overall complication rate was 8.4%. There were two superficial wound infections, two groin seroma and three urinary retention. The mean follow-up time was 42.3 months (range 28-73 months), three patients developed hernia recurrence. No testicular, chronic pain or mesh-related complications were noted in these series. CONCLUSION: Open posterior preperitoneal mesh repair offers a viable option for recurrent inguinal hernias and achieves equally effective results to laparoscopic approaches with acceptable complication and recurrence rates. It is safer and easier to learn than laparoscopic repair and has become the preferred approach for treatment of the majority of recurrent inguinal hernias at our institution, especially useful for complex multirecurrent hernias and patients with cardiopulmonary insufficiency. PMID- 26021275 TI - Cu(II) and Pd(II) complexes of water soluble O-carboxymethyl chitosan Schiff bases: Synthesis, characterization. AB - This study reports the synthesis of two new water soluble O-carboxymethyl chitosan Schiff bases (OCMCS-5 and OCMCS-6a) and their Cu(II) and Pd(II) complexes. Characterizations of these complexes were carried out with FTIR, elemental analysis, (13)C CPMAS, UV-vis, magnetic moment and molar conductivity techniques. The degrees of substitution (DS) for OCMCS-5a and OCMCS-6a were determined to be 0.48 and 0.44 in elemental analysis. The solubility test revealed that OCMCS-5a and OCMCS-6a dissolved thoroughly in water. The surface morphologies of chitosan (CS), OCMCS-5a, OCMCS-6a and their complexes were studied with SEM-EDAX. Thermal stability of the synthesized compounds was evaluated by TG/DTG and their crystallinity values were investigated with powder X-ray diffraction. Cu(II) and Pd(II) contents of the complexes were estimated with ICP-OES. The characterization studies demonstrated that the thermal stability and crystallinity values of the OCMCS-5a and OCMCS-6a were lower than those of CS. PMID- 26021276 TI - Current attitudes to breast reconstruction surgery for women at risk of post mastectomy radiotherapy: A survey of UK breast surgeons. AB - Decision-making for women requiring reconstruction and post-mastectomy radiotherapy (PMRT) includes oncological safety, cosmesis, patient choice, potential delay/interference with adjuvant treatment and surgeon/oncologist preference. This study aimed to quantitatively assess surgeons' attitudes and perceptions about reconstructive options in this setting, and to ascertain if surgical volume influenced advice given. A questionnaire was sent to surgical members of the UK Association of Breast Surgery (ABS) in March-June 2014. The questionnaire elicited information on surgeon volume, reconstructive practice and drivers influencing decision-making. Response rate was 42% (148/355), representing 71% of UK breast units. Delayed breast reconstruction (DBR) was offered more commonly than immediate implant, delayed-immediate or immediate autologous reconstruction (p < 0.05). Cosmesis was thought to be equivalent between IBR and DBR by 15% of surgeons, and 26% believe IBR and DBR offer similar Health-related Quality of Life (HRQoL). Surgeon volume had no effect on reconstruction choice. Common decision-making drivers included negative effects of radiotherapy upon reconstructive and cosmetic outcome. The majority of surgeons (77%) believe the current evidence base is insufficient to guide decision-making. Despite surgeons believing that cosmesis and quality of life are not equivalent between IBR and DBR, DBR remains the commonest approach to this difficult clinical scenario. Surgeons perceive they are using a variety of newer techniques such as Delayed-Immediate Reconstruction and Acellular Dermal Matrices to try to ameliorate the effects of PMRT. This survey demonstrates that there is wide variation in reported surgical practice in this difficult setting. There is widespread acknowledgement of the lack of evidence to guide decision-making. PMID- 26021277 TI - Elucidation of Genetic Backgrounds Necessary for Chlorophyll a Biosynthesis Toward Artificial Creation of Oxygenic Photosynthesis. AB - We succeeded to create the genetically modified purple photosynthetic bacterium capable of synthesizing chlorophyll a. The results indicate that not only chlorophyll synthase, but also an enzyme for galactolipid synthesis and reaction center proteins are required for accumulating chlorophyll a. PMID- 26021278 TI - Decoding Redox Evolution Before Oxygenic Photosynthesis Based on the Sulfur-Mass Independent Fractionation (S-MIF) Record. AB - The isotopic anomaly of stable sulfur isotope could be a useful new tracer for decoding atmospheric chemistry of early Earth from ancient rock samples. Here, we summarize current status of the experimental works and discuss what the isotopic anomaly tells about early Earth's atmosphere. PMID- 26021279 TI - Heteroepitaxy of Ge on singular and vicinal Si surfaces: elastic field symmetry and nanostructure growth. AB - Starting with the basic definition, a short description of a few relevant physical quantities playing a role in the growth process of heteroepitaxial strained systems, is provided. As such, the paper is not meant to be a comprehensive survey but to present a connection between the Stranski-Krastanov mechanism of nanostructure formation and the basic principles of nucleation and growth. The elastic field is described in the context of continuum elasticity theory, using either analytical models or numerical simulations. The results are compared with selected experimental results obtained on GeSi nanostructures. In particular, by tuning the value of quantities such as vicinality, substrate orientation and symmetry of the diffusion field, we elucidate how anisotropic elastic interactions determine shape, size, lateral distribution and composition of quantum dots. PMID- 26021281 TI - The Hormone Levels in the Differential Diagnosis of Central Precocious Puberty. PMID- 26021282 TI - Detection of nitro-based and peroxide-based explosives by fast polarity switchable ion mobility spectrometer with ion focusing in vicinity of Faraday detector. AB - Ion mobility spectrometer (IMS) has been widely deployed for on-site detection of explosives. The common nitro-based explosives are usually detected by negative IMS while the emerging peroxide-based explosives are better detected by positive IMS. In this study, a fast polarity-switchable IMS was constructed to detect these two explosive species in a single measurement. As the large traditional Faraday detector would cause a trailing reactant ion peak (RIP), a Faraday detector with ion focusing in vicinity was developed by reducing the detector radius to 3.3 mm and increasing the voltage difference between aperture grid and its front guard ring to 591 V, which could remove trailing peaks from RIP without loss of signal intensity. This fast polarity-switchable IMS with ion focusing in vicinity of Faraday detector was employed to detect a mixture of 10 ng 2,4,6 trinitrotoluene (TNT) and 50 ng hexamethylene triperoxide diamine (HMTD) by polarity-switching, and the result suggested that [TNT-H](-) and [HMTD+H](+) could be detected in a single measurement. Furthermore, the removal of trailing peaks from RIP by the Faraday detector with ion focusing in vicinity also promised the accurate identification of KClO4, KNO3 and S in common inorganic explosives, whose product ion peaks were fairly adjacent to RIP. PMID- 26021280 TI - Metformin: An Old Drug for the Treatment of Diabetes but a New Drug for the Protection of the Endothelium. AB - The anti-diabetic and oral hypoglycaemic agent metformin, first used clinically in 1958, is today the first choice or 'gold standard' drug for the treatment of type 2 diabetes and polycystic ovary disease. Of particular importance for the treatment of diabetes, metformin affords protection against diabetes-induced vascular disease. In addition, retrospective analyses suggest that treatment with metformin provides therapeutic benefits to patients with several forms of cancer. Despite almost 60 years of clinical use, the precise cellular mode(s) of action of metformin remains controversial. A direct or indirect role of adenosine monophosphate (AMP)-activated protein kinase (AMPK), the fuel gauge of the cell, has been inferred in many studies, with evidence that activation of AMPK may result from a mild inhibitory effect of metformin on mitochondrial complex 1, which in turn would raise AMP and activate AMPK. Discrepancies, however, between the concentrations of metformin used in in vitro studies versus therapeutic levels suggest that caution should be applied before extending inferences derived from cell-based studies to therapeutic benefits seen in patients. Conceivably, the effects, or some of them, may be at least partially independent of AMPK and/or mitochondrial respiration and reflect a direct effect of either metformin or a minor and, as yet, unidentified putative metabolite of metformin on a target protein(s)/signalling cascade. In this review, we critically evaluate the data from studies that have investigated the pharmacokinetic properties and the cellular and clinical basis for the oral hypoglycaemic, insulin-sensitising and vascular protective effects of metformin. PMID- 26021284 TI - Can Rituximab Improve the Outcome of Patients with Nodular Lymphocyte-Predominant Hodgkin's Lymphoma? AB - BACKGROUND: Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma showing strong CD20 expression. The role of rituximab in treating NLPHL still needs clarification. METHODS: We retrospectively reviewed the outcome of 23 patients with NLPHL treated with rituximab alone or in combination with chemotherapy and/or radiotherapy as part of their first- or second-line treatment. RESULTS: The median follow-up of the whole group was 67 months, and all patients remained alive. Twenty-two patients achieved complete remission after rituximab-based therapy, and one of them relapsed 32 months after treatment. One patient treated with rituximab alone achieved partial remission and progressed 22 months after treatment. CONCLUSION: The prognosis of NLPHL is excellent. Rituximab combined with chemotherapy and/or radiotherapy appears to prevent disease progression/relapse. PMID- 26021283 TI - Hearing Impairment Prevalence and Associated Risk Factors in the Hispanic Community Health Study/Study of Latinos. AB - IMPORTANCE: Hearing impairment is common in adults, but few studies have addressed it in the US Hispanic/Latino population. OBJECTIVE: To determine the prevalence of hearing impairment among US Hispanic/Latino adults of diverse backgrounds and determine associations with potential risk factors. DESIGN, SETTING, AND PARTICIPANTS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a population-based sample of Hispanics/Latinos in four US communities (Bronx, New York; Chicago, Illinois; Miami, Florida; and San Diego, California). Examinations were conducted from 2008 through 2011. The HCHS/SOL examined 16,415 self-identified Hispanic/Latino persons aged 18 to 74 years recruited from randomly selected households using a stratified 2-stage area probability sample design based on census block groups and households within block groups. MAIN OUTCOMES AND MEASURES: Hearing thresholds were measured by pure-tone audiometry. Hearing impairment was defined as a pure-tone average (PTA) of thresholds at 0.5, 1, 2, and 4 kHz greater than 25 dB hearing level. Bilateral hearing impairment required a PTA greater than 25 dB hearing level in both ears. Multivariable analyses included adjustments for sociodemographic and lifestyle variables, body mass index, and medical conditions. RESULTS: The prevalence of hearing impairment was 15.06% (SE, 0.44%) overall, and 8.24% (SE, 0.33%) had bilateral hearing impairment. The prevalence of hearing impairment was higher among people 45 years and older, ranging by Hispanic/Latino background from 29.35% to 41.20% among men and 17.89% to 32.11% among women. The multivariable adjusted odds of hearing impairment was greater for participants of Puerto Rican background compared with Mexican background (odds ratio [OR], 1.57 [95% CI, 1.10 2.25]). The odds of hearing impairment were lower with more education (OR, 0.71 [95% CI, 0.59-0.86] for at least high school) and higher income (OR, 0.58 [95% CI, 0.36-0.92] for >$75,000 vs <=$10,000). Noise exposure (OR, 1.35 [95% CI, 1.07 1.70]), diabetes (OR, 1.57 [95% CI, 1.27-1.94]), and prediabetes (OR, 1.37 [95% CI, 1.12-1.67]) were associated with hearing impairment. CONCLUSIONS AND RELEVANCE: Hearing impairment is a common problem for older Hispanics/Latinos in these communities and is associated with socioeconomic factors, noise exposure, and abnormal glucose metabolism. Longitudinal studies are needed to determine whether these factors are involved in the etiology of hearing impairment and to identify ways to prevent or delay age-related changes in hearing. PMID- 26021285 TI - EGb761 Ameliorates Neuropathic Pain by Scavenging Reactive Oxygen Species. AB - BACKGROUND: Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Until recently, researchers have found that increased generation of reactive oxygen species (ROS) contributes to the development of exaggerated pain hypersensitivity during neuropathic pain. METHODS: In this study, we investigated the antinociceptive efficacy of Ginkgo biloba extract (EGb761) in chronic constriction injury (CCI) model of neuropathic pain of rats. To explore the underlying mechanisms, the effects of EGb761 on the excitability of dorsal root ganglion (DRG) neurons and activation of JNK in DRG were explored. RESULTS: We showed that systemic administration of EGb761 inhibited the behavioral responses of neuropathic pain and found that EGb761 treatment could inhibit the H2O2-induced depolarization in the acutely dissociated DRG neurons. In addition, we found that EGb761 treatment could inhibit the expression of p-JNK in DRG. CONCLUSION: Taken together, our results suggest that administration of EGb761 can ameliorate neuropathic pain, and further indicate that JNK, which is activated by both exogenous and endogenous ROS, might be the mechanism underlying the effects of EGb761 on CCI neuropathic pain. PMID- 26021287 TI - Inducing uniform single-crystal like orientation in natural rubber with constrained uniaxial stretch. AB - The effect of flow on crystallization is commonly attributed to entropic reduction, which is caused by stretch and orientation of polymer chains but overlooks the role of flow on final-state free energy. With the aid of in situ synchrotron radiation wide-angle X-ray diffraction (WAXD) and a homemade constrained uniaxial tensile testing machine, polycrystals possessing single crystal-like orientation rather than uniaxial orientation are found during the constrained stretch of natural rubber, whereas the c-axis and a-axis align in the stretch direction (SD) and constrained direction (CD), respectively. Molecular dynamics simulation shows that aligning the a-axis of crystal nuclei in CD leads to the lowest free energy increase and favors crystal nucleation. This indicates that the nomenclature of strain-induced crystallization may not fully account for the nature of flow-induced crystallization (FIC) as strain mainly emphasizes the entropic reduction of initial melt, whereas stress rather than strain plays the dominant role in crystal deformation. The current work not only contributes to a comprehensive understanding of the mechanism of flow-induced crystallization but also demonstrates the potential application of constrained uniaxial tensile stretch for the creation of functional materials containing polycrystals that possess single-crystal-like orientation. PMID- 26021286 TI - Targeting microRNAs for immunomodulation. AB - microRNAs (miRNA) are small regulatory RNAs exerting pleiotropic functions in virtually any immune cell-type. Dozens of miRNAs with a known function in the immune system constitute interesting drug targets for immunomodulation. Chemical modifications of nucleic acid-based miRNA mimics and inhibitors largely solved instability issues but delivery to immune cells remains a major challenge. However, recent success targeting the acidic tumor microenvironment is very promising for inflammatory diseases. Moreover, small molecules are being explored as an interesting alternative. Although RNA is often considered 'undruggable' by small molecules recent progress modulating miRNA function through small molecules is encouraging. Computational approaches even allow predictions about specific small molecule/RNA interactions. Finally, recent clinical success demonstrates that drugs targeting RNAs work in humans. PMID- 26021288 TI - Intercomparison of oil spill prediction models for accidental blowout scenarios with and without subsea chemical dispersant injection. AB - We compare oil spill model predictions for a prototype subsea blowout with and without subsea injection of chemical dispersants in deep and shallow water, for high and low gas-oil ratio, and in weak to strong crossflows. Model results are compared for initial oil droplet size distribution, the nearfield plume, and the farfield Lagrangian particle tracking stage of hydrocarbon transport. For the conditions tested (a blowout with oil flow rate of 20,000 bbl/d, about 1/3 of the Deepwater Horizon), the models predict the volume median droplet diameter at the source to range from 0.3 to 6mm without dispersant and 0.01 to 0.8 mm with dispersant. This reduced droplet size owing to reduced interfacial tension results in a one to two order of magnitude increase in the downstream displacement of the initial oil surfacing zone and may lead to a significant fraction of the spilled oil not reaching the sea surface. PMID- 26021289 TI - Heavy metals and TPH effects on microbial abundance and diversity in two estuarine areas of the southern-central coast of Sao Paulo State, Brazil. AB - Coastal areas may be impacted by human and industrial activities, including contamination by wastewater, heavy metals and hydrocarbons. This study aimed to evaluate the impact of hydrocarbons (TPH) and metals on the microbiota composition and abundance in two estuarine systems in the coast of Sao Paulo: the Santos (SE) and Itanhaem (IE) estuaries. The SE was found to be chronically contaminated by heavy metals and highly contaminated by hydrocarbons. This finding was correlated with the increased density of cyanobacteria in sediments and suggests the possible use of cyanobacteria for bioremediation. These contaminants influence the density and composition of estuarine microbiota that respond to stress caused by human activity. The results are troubling because quantitative and qualitative changes in the microbiota of estuarine sediments may alter microbiological processes such as decomposition of organic matter. Moreover, this pollution can result in damage to the environment, biota and human health. PMID- 26021290 TI - Alterations in the macrobenthic fauna from Guadarranque River (Southern Spain) associated with sediment-seawater acidification deriving from CO2 leakage. AB - Nowadays, Carbon Storage in Sub-Seabed Geological Structures (CS-SSGS) is having much interest. Nonetheless, these technologies are still under development, especially the leakage of the stored CO2 and the consequent acidification of the environment. Therefore, the goal of this study is to test the impact of CO2 induced acidification on a macrobenthic community due to leakages from CS-SSGS using a mesocosm-based experiment. Results confirmed the significant correlation between the abundance of the species and the pH (positively), and the alkalinity (negatively). Additionally, the BIOENV analysis showed that the majority of the variability in the abundance of the total species was explained for the alkalinity. The correlation analysis showed differential vulnerabilities of different species, especially Cyathura carinata and a non-calcifier species as Hediste diversicolor. Nevertheless, these results showed the importance of taking into account the indirect effect associated with acidification processes, as metal release from sediment. PMID- 26021291 TI - Biological risk, source and pollution history of organochlorine pesticides (OCPs) in the sediment in Nansha mangrove, South China. AB - In the last century, organochlorine pesticides (OCPs) have been extensively used, especially in South China, to promote crop yield. In view of their toxicity, persistence and bioavailability, however, the Chinese government has attempted to regulate their production and use. We aimed to examine the biological risk, source and pollution history of OCPs in the sediment in Nansha mangrove which is located in the industrial region in South China. Results showed that HCHs and DDTs, mainly originating from lindane and technical DDT respectively, were the dominant OCPs, but their concentrations were too low to cause adverse effects on biota. In the last decade, the total concentration of HCHs showed a decreasing trend, whereas DDTs remained stable, despite their limited input. This suggests that management of HCHs was effective, while more management efforts should be put on DDTs, especially the use of dicofol and technical DDT, in future. PMID- 26021292 TI - P2X7 Receptor Expression in Peripheral Blood Monocytes Is Correlated With Plasma C-Reactive Protein and Cytokine Levels in Patients With Type 2 Diabetes Mellitus: a Preliminary Report. AB - Chronic inflammation plays a major role in development of type 2 diabetes mellitus (T2DM). C-reactive protein (CRP) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) are directly involved in the occurrence of insulin resistance. Increased extracellular ATP levels can amplify the inflammatory response in vivo via the P2X7 receptor. The present study aimed to assess the relationship between P2X7 receptor expression in human peripheral blood monocytes and plasma levels of TNF alpha, IL-1beta, and CRP in T2DM patients. The results showed the association of increased P2X7 receptor expression of monocytes with high serum CRP, TNF-alpha, and IL-1beta levels. TNF-alpha and IL-1beta levels were lowest in healthy subjects; in T2DM patients, these inflammatory markers were less abundant in individuals with normal CRP levels compared to those with high CRP contents. In contrast, IL-10 levels in T2DM patients with high CRP levels were dramatically decreased. P2X7 receptor expression in monocytes from T2DM patients with high CRP levels was significantly increased in comparison with healthy individuals and T2DM patients with normal CRP levels. These findings indicated that P2X7 receptor in peripheral blood monocytes may be involved in the pathological changes of T2DM, particularly affecting patients with high CRP levels. PMID- 26021293 TI - Mapping-by-sequencing of Ligon-lintless-1 (Li 1 ) reveals a cluster of neighboring genes with correlated expression in developing fibers of Upland cotton (Gossypium hirsutum L.). AB - KEY MESSAGE: Mapping-by-sequencing and SNP marker analysis were used to fine map the Ligon-lintless-1 ( Li 1 ) short fiber mutation in tetraploid cotton to a 255 kb region that contains 16 annotated proteins. The Ligon-lintless-1 (Li 1 ) mutant of cotton (Gossypium hirsutum L.) has been studied as a model for cotton fiber development since its identification in 1929; however, the causative mutation has not been identified yet. Here we report the fine genetic mapping of the mutation to a 255-kb region that contains only 16 annotated genes in the reference Gossypium raimondii genome. We took advantage of the incompletely dominant dwarf vegetative phenotype to identify 100 mutants (Li 1 /Li 1 ) and 100 wild-type (li 1 /li 1 ) homozygotes from a mapping population of 2567 F2 plants, which we bulked and deep sequenced. Since only homozygotes were sequenced, we were able to use a high stringency in SNP calling to rapidly narrow down the region harboring the Li 1 locus, and designed subgenome-specific SNP markers to test the population. We characterized the expression of all sixteen genes in the region by RNA sequencing of elongating fibers and by RT-qPCR at seven time points spanning fiber development. One of the most highly expressed genes found in this interval in wild-type fiber cells is 40-fold under-expressed at the day of anthesis (DOA) in the mutant fiber cells. This gene is a major facilitator superfamily protein, part of the large family of proteins that includes auxin and sugar transporters. Interestingly, nearly all genes in this region were most highly expressed at DOA and showed a high degree of co-expression. Further characterization is required to determine if transport of hormones or carbohydrates is involved in both the dwarf and lintless phenotypes of Li 1 plants. PMID- 26021294 TI - Genetic shift in local rice populations during rice breeding programs in the northern limit of rice cultivation in the world. AB - The rapid accumulation of pre-existing mutations may play major roles in the establishment and shaping of adaptability for local regions in current rice breeding programs. The cultivated rice, Oryza sativa L., which originated from tropical regions, is now grown worldwide due to the concerted efforts of breeding programs. However, the process of establishing local populations and their origins remain unclear. In the present study, we characterized DNA polymorphisms in the rice variety KITAAKE from Hokkaido, one of the northern limits of rice cultivation in the world. Indel polymorphisms were attributed to transposable element-like insertions, tandem duplications, and non-TE deletions as the original mutation events in the NIPPONBARE and KITAAKE genomes. The allele frequencies of the KITAAKE alleles markedly shifted to the current variety types among the local population from Hokkaido in the last two decades. The KITAAKE alleles widely distributed throughout wild rice and cultivated rice over the world. These have accumulated in the local population from Hokkaido via Japanese landraces as the ancestral population of Hokkaido. These results strongly suggested that combinations of pre-existing mutations played a role in the establishment of adaptability. This approach using the re-sequencing of local varieties in unique environmental conditions will be useful as a genetic resource in plant breeding programs in local regions. PMID- 26021295 TI - Predictors of Outcome in Inpatients with Anorexia Nervosa: A Prospective Multi Center Study. PMID- 26021297 TI - The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis. AB - Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11(+) endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly. PMID- 26021296 TI - Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants. AB - Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ~4 and ~3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease relevant epigenetic and genetic variants for large-scale EWAS. PMID- 26021299 TI - DGPPN guideline on anxiety disorders and cognitive dysfunction in the elderly or patients with multiple sclerosis. PMID- 26021298 TI - The Hippo pathway promotes cell survival in response to chemical stress. AB - Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. PMID- 26021300 TI - Ileal Mesenteric Leiomyosarcoma--Report of a Rare Neoplasm. PMID- 26021301 TI - A mitochondria-targeted colorimetric and ratiometric fluorescent probe for biological SO2 derivatives in living cells. AB - A ratiometric fluorescent probe for SO2 derivatives based on the conjugate of carbazole and indolium was presented, which could selectively respond to HSO3(-) over other thiol compounds. More importantly, CZ-Id is a novel mitochondria targeted ratiometric fluorescent probe to image exogenous SO2 derivatives. PMID- 26021302 TI - Contrast and decay of cathodoluminescence from phosphor particles in a scanning electron microscope. AB - Cathodoluminescence (CL) studies are reported on phosphors in a field emission scanning electron microscope (FESEM). ZnO: Zn and other luminescent powders manifest a bright ring around the periphery of the particles: this ring enhances the contrast. Additionally, particles resting on top of others are substantially brighter than underlying ones. These phenomena are explained in terms of the combined effects of electrons backscattered out of the particles, together with light absorption by the substrate. The contrast is found to be a function of the particle size and the energy of the primary electrons. Some phosphor materials exhibit a pronounced comet-like structure at high scan rates in a CL-image, because the particle continues to emit light after the electron beam has moved to a position without phosphor material. Image analysis has been used to study the loss of brightness along the tail and hence to determine the decay time of the materials. The effect of phosphor saturation on the determination of decay times by CL-microscopy was also investigated. PMID- 26021303 TI - The Impact of Green Tea Consumption on the Prevention of Hemorrhagic Stroke. AB - BACKGROUND: Different types of tea may have varying effects on the risk of hemorrhagic stroke, but previous studies have generated inconsistent results. We performed a nationwide, multi-center, case-control study to evaluate the association between the consumption of tea and the risk of hemorrhagic stroke. METHODS: This study included 940 patients aged 30 to 84 with non-traumatic acute hemorrhagic stroke who did not have a history of stroke or hemorrhage-prone brain lesions, as well as 940 community controls and 940 hospital controls matched to each patient by age and gender. Pre-trained interviewers obtained information on potential confounders. Consumption of tea was assessed by using a food frequency questionnaire. Participants were asked to indicate the number of cups of tea (green, black, and oolong tea) they consumed per day or per week during the preceding year. RESULTS: The adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression. The adjusted ORs of hemorrhagic stroke were 0.71 (95% CI: 0.59-0.87), 0.86 (95% CI: 0.55 1.37), and 1.34 (95% CI: 0.91-1.98) for consumption of green, oolong, and black tea, respectively, compared with no consumption. There was no significant linear trend for green tea consumption. CONCLUSIONS: Consumption of green tea may protect against hemorrhagic stroke, whereas consumption of black tea may have no meaningful effect on risk. PMID- 26021304 TI - Thalamic and Cerebellar Gray Matter Volume Reduction in Synthetic Cannabinoids Users. AB - BACKGROUND: Synthetic cannabinoids are compounds that bind cannabinoid receptors with a high potency and have been used widely in Europe by young people. However, little is known about the pharmacology and morphological effects of this group of substances in the brain. This study is aimed at investigating the morphological differences among synthetic cannabinoids users and healthy controls. METHODS: Voxel-based morphometry was used to investigate the differences in brain tissue composition in 20 patients with synthetic cannabinoids use and 20 healthy controls. All participants were male. RESULTS: Compared to healthy controls, voxel of interest analyses showed that regional grey matter volume in both left and right thalamus and left cerebellum was significantly reduced in synthetic cannabinoids users (p < 0.05). No correlation has been found between the age of first cannabis use, duration of use, frequency of use and grey matter volume. DISCUSSION: These preliminary results suggest an evidence of some structural differences in the brain of synthetic cannabinoids users, and point the need for further investigation of morphological effects of synthetic cannabinoids in the brain. PMID- 26021305 TI - The differential roles of Slit2-exon 15 splicing variants in angiogenesis and HUVEC permeability. AB - Slit2, a secreted glycoprotein, is down-regulated in many cancers. Slit2/Robo signaling pathway plays an important, but controversial, role in angiogenesis. We identified splicing variants of Slit2 at exon 15, Slit2-WT and Slit2-DeltaE15, with differential effects on proliferation and invasive capability of lung cancer cells. The aim of this study was to elucidate the differential roles of these exon 15 splicing variants in angiogenesis. Our results revealed that both Slit2 WT and Slit2-DeltaE15 inhibit motility of human umbilical vein endothelial cells (HUVECs). The conditioned medium (CM) collected from CL1-5/VC or CL1-5/Slit2-WT lung adenocarcinoma cells blocked HUVEC tube formation and angiogenesis on chorioallantoic membrane (CAM) assay when compared with untreated HUVECs and CAM, respectively. However, CM of CL1-5/Slit2-DeltaE15 restored the quality of tubes and the size of vessels. Although both Slit2-WT and Slit2-DeltaE15 inhibited permeability induced by CM of cancer cells, Slit2-DeltaE15 exhibited stronger effect. These results suggested that Slit2-DeltaE15 plays important roles in normalization of blood vessels by enhancing tube quality and tightening endothelial cells, while Slit2-WT only enhances tightening of endothelial cells. It appears that Robo4 is responsible for Slit2 isoform-mediated inhibition of permeability, while neither Robo1 nor Robo4 is required for Slit2-DeltaE15 enhanced tube quality. The results of this study suggest that Slit2-DeltaE15 splicing form is a promising molecule for normalizing blood vessels around a tumor, which, in turn, may increase efficacy of chemotherapy and radiotherapy. PMID- 26021306 TI - An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models. AB - Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow derived cells were performed on peripheral blood mononuclear cells from tumor bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1( )CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1( )CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer. PMID- 26021307 TI - Immune activity of sweet potato (Ipomoea batatas L.) glycoprotein after enzymatic and chemical modifications. AB - This study aimed to investigate the immune activity of sweet potato (Ipomoea batatas L.) glycoprotein (SPG-1) before and after enzymatic and chemical modifications. The protein portion of SPG-1 was modified by pepsin, trypsin, and acetylation treatments. The carbohydrate portion was modified by glucoamylase, NaIO4, and sulfation treatments. The carbohydrate chain of SPG-1 (SPG-1-C) was obtained. Immune activity was analyzed by measuring the serum lysozyme activity and T cell immune response. SPG-1 increased immune activity with a dose-response effect. Immune activity was slightly decreased after pepsin and trypsin hydrolysis, whereas it increased after a moderate degree (DS = 0.68) of acetylation. Immune activity was partly decreased after glucoamylase hydrolysis, remarkably decreased after NaIO4 oxidation, or was lost after a high modification by sulfation. Compared with SPG-1 groups, the SPG-1-C groups increased immune activities had insignificant (P > 0.05) differences. Hence, appropriate modifications of the protein portion could be conducted and it was found that high modifications of the carbohydrate portion should be avoided to improve or maintain the immune function of SPG-1. PMID- 26021308 TI - Acute pancreatitis as an adverse event in patients with the duodenal-jejunal bypass liner. AB - Placement of the duodenal-jejunal bypass liner (DJBL) is a minimally invasive technique for the management of patients with type 2 diabetes mellitus and obesity. Acute pancreatitis was seen in 5 of 167 patients (3 %) in our series. It is suggested that acute pancreatitis in patients with the DJBL results from either direct blockage or edema of the major duodenal papilla, which may be caused by the following: migration of the anchor of the DJBL, accumulation of food debris between the liner and the duodenal wall, or reflux of duodenal contents into the pancreatic duct due to intraluminal hypertension caused by the liner. Early removal of the DJBL resulted in fast and complete recovery, whereas delayed diagnosis and removal led to severe, necrotizing acute pancreatitis. PMID- 26021309 TI - Endoscopic ultrasound-guided biliary drainage using a lumen-apposing self expanding metal stent: a case series. AB - Endoscopic ultrasound-guided biliary drainage (EUS-BD) might be an alternative to percutaneous or transpapillary biliary drainage in unresectable pancreatic or biliary cancer. A lumen-apposing, fully covered, self-expanding metal stent, which creates a sealed transluminal conduit between the biliary and gastrointestinal tract may offer advantages over conventional plastic and metal stents. In this retrospective, observational, open-label case study, five patients underwent EUS-BD for obstructive jaundice in pancreatic cancer (n = 4) or distal cholangiocarcinoma (n = 1). Technical and functional success was achieved in all patients without complications. The development of specialized stent and delivery systems may render EUS-BD an effective and safe alternative to percutaneous or transpapillary approaches. PMID- 26021310 TI - Endoscopic detachable snare ligation: a new treatment method for colonic diverticular hemorrhage. AB - BACKGROUND AND STUDY AIMS: Colonic diverticular hemorrhage is the most common cause of lower intestinal bleeding. We tried to develop a convenient and reliable hemostatic method, endoscopic detachable snare ligation (EDSL), to treat diverticular hemorrhage and retrospectively explored its safety and efficacy. PATIENTS AND METHODS: The definitive bleeding diverticulum was ligated with a detachable snare, instead of a rubber band, in a procedure similar to endoscopic band ligation. Removal of the scope to attach a ligation device and reinsertion for treatment are not needed in this method. RESULTS: From November 2013 to September 2014, EDSL was used to treat 8 patients with colonic diverticular hemorrhage. The mean procedure time required for hemostasis after identification of the bleeding diverticulum was 5 +/- 2 minutes. Sustained hemostasis was achieved in 7 patients (88 %), and early rebleeding occurred in 1 patient, in whom the applied suction seemed inadequate. No complications occurred in any patient. CONCLUSIONS: EDSL may be a safe and effective treatment for colonic diverticular hemorrhage. However, additional studies are warranted to confirm these initial exploratory data. PMID- 26021311 TI - Histological features of advanced colorectal adenomas detected by endoscopy and fecal immunochemical test. AB - BACKGROUND AND STUDY AIMS: The detection of advanced adenomas within organized screening programs using either immunochemical fecal occult blood test (FIT) or endoscopy has been associated with the prevention of colorectal cancer. The histological changes and pathogenetic mechanisms that lead to the detection of such lesions by either of these screening methods have not yet been addressed. PATIENTS AND METHODS: The histological specimens of 50 advanced adenomas detected by FIT were compared with those of 50 advanced adenomas detected by primary endoscopy screening that were matched for size and histology. The following variables were systematically recorded: 1) histopathological changes compatible with luminal bleeding induced by ischemia; 2) hypoxia in the adenomatous tissue, assessed through the expression of carbonic anhydrase IX; and 3) microvessel quantitative analysis, evaluated by CD31 and CD105 immunostains. All specimens were reviewed blindly by an expert gastrointestinal pathologist. RESULTS: Histopathological changes associated with ischemia-related luminal bleeding were significantly more frequent in FIT-positive than in endoscopy-detected advanced adenomas (78 % vs. 14 %; P < 0.001). Carbonic anhydrase IX expression was also significantly higher in FIT-detected advanced adenomas (immunohistochemical score: 12.0 vs. 4.1; P < 0.001). Conversely, no differences were found in microvessel density. CONCLUSIONS: The detection of advanced adenomas by FIT screening appears to be related to ischemia-associated luminal bleeding, which, in turn, may be due to periods of hypoxia. The absence of such changes in endoscopy-detected advanced adenomas would suggest that the two screening methods may be complementary for the detection of advanced neoplasia within organized screening programs. PMID- 26021312 TI - Diagnosis of prosthetic joint infections using UMD-Universal Kit and the automated multiplex-PCR Unyvero i60 ITI((r)) cartridge system: a pilot study. AB - BACKGROUND: Prosthetic joint infections (PJI) are associated with high morbidity and costs. Various efforts have been made to improve the diagnosis of PJI over the past years, but only few studies have assessed the diagnostic utility of nucleic acid amplification test (NAAT) techniques in this context. Here, we report our experience with a commercial 16S rRNA gene PCR and an automated multiplex-PCR cartridge system in identifying pathogens causing PJI. MATERIALS AND METHODS: A prospective single-centre study was performed including 54 patients with either septic or aseptic prosthetic joint replacement or surgical revision between February 2012 and April 2013. Conventional cultures of periprosthetic tissue samples were compared with the results of broad-range 16S rRNA gene real-time PCR (UMD-Universal Pathogen DNA Extraction and PCR Analysis, Molzym GmbH, Germany) and the multiplex-PCR Unyvero ITI((r)) cartridge system (U ITI; Curetis AG, Germany). Conventional culture and broad-range 16S rRNA gene real-time PCR were performed on all samples. U-ITI was used in a subgroup of 28 cases including all culture-positive cases. The agreement of the results from the methods was assessed. RESULTS: Of 54 cases, seven were culture-positive. Broad range 16S rRNA gene real-time PCR gave 6, U-ITI 3 concordant positive results. Of the 47 culture-negative samples, 46 were also negative by broad-range 16S rRNA gene real-time PCR resulting in a 96 % (52/54) agreement between 16S rRNA gene PCR and culture. Of the 21 culture-negative samples analysed with U-ITI, 20 gave negative results, including the single 16S rRNA gene PCR-positive/culture negative specimen. The rate of agreement between U-ITI and culture results was 82 % (23/28). CONCLUSION: This pilot study gave no indication of superiority of the used NAATs over conventional culture methods for the microbiological diagnosis of PJI. Drawbacks are susceptibility to contamination in the case of 16S rRNA gene real-time PCR, labour-intensive DNA extraction and limited pathogen panel in the case of the multiplex cartridge PCR system. More prospective trials are needed to evaluate the diagnostic performance of NAATs and their impact on the clinical management of PJI. PMID- 26021313 TI - Communicating under medical patriarchy: gendered doctor-patient communication between female patients with overactive bladder and male urologists in Hong Kong. AB - BACKGROUND: Gender differences between patients and doctors markedly influence the quality of communication in treatment processes. Previous studies have shown that communication between patients and doctors of the same gender is usually more satisfactory, particularly for female patients. However, in Hong Kong, where urology is a male-dominated specialty, female patients typically require medical care from male doctors for diseases such as overactive bladder (OAB). The literature about gender-related doctor-patient communication predominantly involves people in non-Chinese communities, with few studies conducted with Chinese populations. However, the differences between Western and Chinese cultures are expected to result in different treatment and communication experiences. Furthermore, OAB has received little attention in many Chinese communities; few studies in the literature address the communication quality between OAB patients and their urologists in Chinese communities, particularly regarding female OAB patients' experiences when seeking treatment from male urologists. This study, therefore, investigated the doctor-patient communication between female OAB patients and male urologists in Hong Kong. METHODS: This study adopted a qualitative research approach by conducting semistructured interviews with 30 female OAB patients on an individual basis from April 2012 to July 2012. The participants were purposively sampled from a patient self-help group for OAB patients in Hong Kong. RESULTS: The participants' communication experiences with male urologists were unpleasant. Embarrassment, feelings of not being treated seriously, not being understood, and not being given the autonomy to choose treatment approaches prevailed among the participants. Furthermore, the perceived lack of empathy from their urologists made the participants' communication experiences unpleasant. CONCLUSIONS: The gender and power differential between the participants and their urologists, which was contributed by the social and cultural values of patriarchy and doctors' dominance in Hong Kong, made the participants' communication with the urologists unpleasant and difficult. Poor doctor-patient communication can endanger patients' treatment compliance and thus the treatment outcome. Although altering such social and cultural values would be difficult, providing complementary chronic care services, such as nurse-led clinics as well as support and sharing from patient self-help groups, might be a possible solution. PMID- 26021314 TI - COSMC knockdown mediated aberrant O-glycosylation promotes oncogenic properties in pancreatic cancer. AB - BACKGROUND: Human pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies in the world and despite great efforts in research types of treatment remain limited. A frequently detected alteration in PDACs is a truncated O-linked N-acetylgalactosamine (GalNAc) glycosylation with expression of the Tn antigen. Changes in O-glycosylation affect posttranslationally modified O-GalNAc proteins resulting in profound cellular alterations. Tn antigen is a tumor associated glycan detected in 75-90 % of PDACs and up to 67 % in its precursor lesions. Since the role of Tn antigen expression in PDAC is insufficiently understood we analyzed the impact of COSMC mediated Tn antigen expression in two human PDAC cell lines on cellular oncogenic properties. METHODS: Forced expression of Tn antigen on O-glycosylated proteins in pancreatic cancer cells was induced by lentiviral-mediated knockdown of the COSMC chaperone, which prevented O-glycan elongation beyond the initial GalNAcalpha1- residue on O linked glycoproteins. Altered O-GalNAc glycosylation was analyzed in human pancreatic cancer cell lines Panc-1 and L3.6pl using Western and Far-Western blot as well as immunocytochemical techniques. To assess the biological implications of COSMC function on oncogenic properties, cell viability assays, scratch assays combined with live cell imaging, migration and apoptosis assays were performed. Lectin based glycoprotein enrichment with subsequent mass spectrometric analysis identified new cancer O-GalNAc modified proteins. Expression of Tn antigen bearing Nucleolin in patient derived PDAC tumor specimens was evaluated and correlated with clinicopathological data. RESULTS: Tn antigen expression was induced on various O-GalNAc glycoproteins in COSMC deficient cell lines compared to the control. Proliferation was reduced (p < 0.001) in COSMC knockdown cells, whereas migration was increased (p < 0.001) and apoptosis was decreased (p = 0.03), highlighting the importance of Tn antigen expression on metastatic and anti-apoptotic behavior of PDAC derived cells. Nucleolin was identified as O GalNAc modified protein in COSMC deficient PDAC cell lines. Interestingly, immunohistochemical staining and co-localization studies of patient derived PDACs revealed poor survival for patients with strong co-localization of Tn antigen and Nucleolin (p = 0.037). CONCLUSION: This study substantiates the influence of altered O-glycan (Tn/STn) expression on oncogenic properties in pancreatic cancer and identifies O-GalNAc modified Nucleolin as novel prognostic marker. PMID- 26021316 TI - Parental smoking and child poverty in the UK: an analysis of national survey data. AB - BACKGROUND: In 2011/12 approximately 2.3 million children, 17% of children in the UK, were estimated to be in relative poverty. Cigarette smoking is expensive and places an additional burden on household budgets, and is strongly associated with socioeconomic deprivation. The aim of this study was to provide an illustrative first estimate of the extent to which parental smoking exacerbates child poverty in the UK. METHODS: Findings from the 2012 Households Below Average Income report and the 2012 Opinions and Lifestyle Survey were combined to estimate the number of children living in poor households containing smokers; the expenditure of typical smokers in these households on tobacco; and the numbers of children drawn into poverty if expenditure on smoking is subtracted from household income. RESULTS: 1.1 million children - almost half of all children in poverty - were estimated to be living in poverty with at least one parent who smokes; and a further 400,000 would be classed as being in poverty if parental tobacco expenditure were subtracted from household income. CONCLUSIONS: Smoking exacerbates poverty for a large proportion of children in the UK. Tobacco control interventions which effectively enable low income smokers to quit can play an important role in reducing the financial burden of child poverty. PMID- 26021315 TI - The Aurora A-HP1gamma pathway regulates gene expression and mitosis in cells from the sperm lineage. AB - BACKGROUND: HP1gamma, a well-known regulator of gene expression, has been recently identified to be a target of Aurora A, a mitotic kinase which is important for both gametogenesis and embryogenesis. The purpose of this study was to define whether the Aurora A-HP1gamma pathway supports cell division of gametes and/or early embryos, using western blot, immunofluorescence, immunohistochemistry, electron microscopy, shRNA-based knockdown, site-directed mutagenesis, and Affymetrix-based genome-wide expression profiles. RESULTS: We find that the form of HP1gamma phosphorylated by Aurora A, P-Ser83 HP1gamma, is a passenger protein, which localizes to the spermatozoa centriole and axoneme. In addition, disruption in this pathway causes centrosomal abnormalities and aberrations in cell division. Expression profiling of male germ cell lines demonstrates that HP1gamma phosphorylation is critical for the regulation of mitosis-associated gene expression networks. In female gametes, we observe that P Ser83-HP1gamma is not present in meiotic centrosomes of M2 oocytes, but after syngamy, it becomes detectable during cleavage divisions, coinciding with early embryonic genome activation. CONCLUSIONS: These results support the idea that phosphorylation of HP1gamma by Aurora A plays a role in the regulation of gene expression and mitotic cell division in cells from the sperm lineage and in early embryos. Combined, this data is relevant to better understanding the function of HP1gamma in reproductive biology. PMID- 26021317 TI - Antigen-specific assessment of the immunological status of various groups in a leprosy endemic region. AB - BACKGROUND: Serological tests can be important tools to assist in the diagnosis of leprosy and can contribute to an earlier diagnosis. The aim of this study was to evaluate the antibody responses against phenolic glycolipid-1 (PGL-1), natural disaccharide linked to human serum albumin via an octyl (NDO-HSA), Leprosy IDRI Diagnostic-1 (LID-1) and natural disaccharide octyl--Leprosy IDRI Diagnostic-1 (NDO-LID) in leprosy patients, household contacts of patients and the general population. METHODS: Enzyme-linked immunosorbent assays were used to analyze the antigen-specific antibody responses of 94 leprosy cases, 104 household contacts of cases and 2.494 individuals from the general population. RESULTS: A positive correlation was observed for the antibody responses to all antigens studied. A higher proportion of seropositivity for all antigens, along with stronger magnitude of response, was observed in multibacillary (MB) leprosy patients and household contacts of MB leprosy patients compared with the levels observed in paucibacillary (PB) leprosy patients and household contacts of PB leprosy patients. A substantial and significant positive correlation was found between seropositivity and the bacterial index for the leprosy patients. Anti-PGL-1 tests were more frequently positive than anti-NDO-HSA tests among patients with all clinical forms of leprosy and among the group of household contacts. The LID-1 and NDO-LID antigens showed a greater capacity to identify household contacts and individuals from the general population infected with M. leprae. CONCLUSIONS: Tests that measure the antibody responses against LID-1, NDO-LID, NDO-HSA and PGL 1 were effective tools for the detection of patients with MB leprosy. Our data indicate that the anti-LID-1 and anti-NDO-LID responses were more effective than an anti-NDO-HSA response for the identification of individuals with subclinical infection. PMID- 26021318 TI - Retrotransposons shape species-specific embryonic stem cell gene expression. AB - Over half of our genome is composed of retrotransposons, which are mobile elements that can readily amplify their copy number by replicating through an RNA intermediate. Most of these elements are no longer mobile but still contain regulatory sequences that can serve as promoters, enhancers or repressors for cellular genes. Despite dominating our genetic content, little is known about the precise functions of retrotransposons, which include both endogenous retroviruses (ERVs) and non-LTR elements like long interspersed nuclear element 1 (LINE-1). However, a few recent cutting-edge publications have illustrated how retrotransposons shape species-specific stem cell gene expression by two opposing mechanisms, involving their recruitment of stem cell-enriched transcription factors (TFs): firstly, they can activate expression of genes linked to naive pluripotency, and secondly, they can induce repression of proximal genes. The paradox that different retrotransposons are active or silent in embryonic stem cells (ESCs) can be explained by differences between retrotransposon families, between individual copies within the same family, and between subpopulations of ESCs. Since they have coevolved with their host genomes, some of them have been co-opted to perform species-specific beneficial functions, while others have been implicated in genetic disease. In this review, we will discuss retrotransposon functions in ESCs, focusing on recent mechanistic advances of how HERV-H has been adopted to preserve human naive pluripotency and how particular LINE-1, SVA and ERV family members recruit species-specific transcriptional repressors. This review highlights the fine balance between activation and repression of retrotransposons that exists to harness their ability to drive evolution, while minimizing the risk they pose to genome integrity. PMID- 26021320 TI - Reliability and validity of a new physical activity questionnaire for India. AB - BACKGROUND: Measurement of physical activity in epidemiological studies requires tools which are reliable, valid and culturally relevant. We attempted to develop a physical activity questionnaire (PAQ) that would measure physical activity in various domains over a year and which would be valid for use in adults of different age groups with varying levels of activity in urban and rural settings in low and middle income countries like India. The present paper aims to assess the reliability and validity of this new PAQ- termed the Madras Diabetes Research Foundation- Physical Activity Questionnaire (MPAQ). METHODS: The MPAQ was administered by trained interviewers to 543 individuals of either gender aged 20 years and above from urban and rural areas in 10 states of India from May to August 2011, followed by a repeat administration within a month for assessing reliability. Relative validity was performed against the Global Physical Activity Questionnaire (GPAQ). Construct validity was tested by plotting time spent in sitting and moderate and vigorous physical activity (MVPA) against body-mass index (BMI) and waist circumference. Criterion validity was assessed using the triaxial accelerometer, in a separate subset of 103 individuals. Bland and Altman plots were used to assess the agreement between MPAQ and accelerometer. RESULTS: The interclass correlation coefficients (ICC) for total energy expenditure and physical activity levels were 0.82 and 0.73 respectively, between baseline and 1st month. The ICC between GPAQ and the MPAQ was 0.40 overall. The construct validity of the MPAQ showed linear association between sitting and MVPA, and BMI and waist circumference independent of age and gender. The Spearman's correlation coefficients for sedentary activity, MVPA and overall PA for MPAQ against the accelerometer were 0.48 (95%CI-0.32-0.62), 0.44 (0.27-0.59) and 0.46 (0.29-0.60) respectively. Bland and Altman plots showed good agreement between MPAQ and accelerometer for sedentary behavior and fair agreement for MVPA. CONCLUSION: The MPAQ is an acceptable, reproducible and valid instrument, which captures data from multiple activity domains over the period of a year from adults of both genders and varying ages in various walks of life residing in urban and rural India. PMID- 26021319 TI - High prevalence of hypertension and of risk factors for non-communicable diseases (NCDs): a population based cross-sectional survey of NCDS and HIV infection in Northwestern Tanzania and Southern Uganda. AB - BACKGROUND: The burden of non-communicable diseases (NCDs) is increasing in sub Saharan Africa, but data available for intervention planning are inadequate. We determined the prevalence of selected NCDs and HIV infection, and NCD risk factors in northwestern Tanzania and southern Uganda. METHODS: A population-based cross-sectional survey was conducted, enrolling households using multistage sampling with five strata per country (one municipality, two towns, two rural areas). Consenting adults (>=18 years) were interviewed using the WHO STEPS survey instrument, examined, and tested for HIV and diabetes mellitus (DM). Adjusting for survey design, we estimated population prevalences of hypertension, DM, obstructive pulmonary disease, cardiac failure, epilepsy and HIV, and investigated factors associated with hypertension using logistic regression. RESULTS: Across strata, hypertension prevalence ranged from 16 % (95 % confidence interval (CI): 12 % to 22 %) to 17 % (CI: 14 % to 22 %) in Tanzania, and from 19 % (CI: 14 % to 26 %) to 26 % (CI: 23 % to 30 %) in Uganda. It was high in both urban and rural areas, affecting many young participants. The prevalence of DM (1 % to 4 %) and other NCDs was generally low. HIV prevalence ranged from 6 % to 10 % in Tanzania, and 6 % to 12 % in Uganda. Current smoking was reported by 12 % to 23 % of men in different strata, and 1 % to 3 % of women. Problem drinking (defined by Alcohol Use Disorder Identification Test criteria) affected 6 % to 15 % men and 1 % to 6 % women. Up to 46 % of participants were overweight, affecting women more than men and urban more than rural areas. Most patients with hypertension and other NCDs were unaware of their condition, and hypertension in treated patients was mostly uncontrolled. Hypertension was associated with older age, male sex, being divorced/widowed, lower education, higher BMI and, inversely, with smoking. CONCLUSIONS: The high prevalence of NCD risk factors and unrecognized and untreated hypertension represent major problems. The low prevalence of DM and other preventable NCDs provides an opportunity for prevention. HIV prevalence was in line with national data. In Tanzania, Uganda and probably elsewhere in Africa, major efforts are needed to strengthen health services for the PREVENTION, early detection and treatment of chronic diseases. PMID- 26021321 TI - The inflammatory response in cardiac surgery: an overview of the pathophysiology and clinical implications. AB - During cardiac surgery different factors, such as the aortic clamp, the extracorporeal circulation and the surgical injury itself, produce complex inflammatory responses which can lead to varying degrees of ischemia-reperfusion injury and/or systemic inflammatory response. This may have clinical implications due to hemodynamic changes related with an enlarged vasodilatory response. Thus, maintaining adequate levels of blood pressure during and after cardiac surgery represents a challenge for physicians when inflammatory response appears. The use of noradrenaline to raise arterial pressure is the most current pharmacological approach in the operating room and ICU. However, it is not always effective and other drugs, such as methylene blue, have to be used among others in specific cases as rescue therapy. The aim of our research is to review briefly the pathophysiology and clinical implications in the treatment of the inflammatory response in cardiac surgery, together with the mechanisms involved in those treatments. PMID- 26021322 TI - Mechanistic overview of immune modulatory effects of environmental toxicants. AB - The immune system is an integrated organization, comprising of specific organs, cells and molecules playing a crucial role in the maintenance of health. The purpose of this paper is to give a mechanistic overview of toxic effects of various chemicals and pharmacological agents, and their interaction with the various components of the immune system that leads to modulation of the immune responses. Studies suggest that many chemical agents present in the environment like; heavy metals, agrochemicals, and various types of hydrocarbons possess immune toxicity and cause either structural, functional or compositional changes in various components of the immune system that alters immune response. There is present a complex bidirectional relationship between central nervous system (CNS) and the immune system. And receptors for neuropeptides, neurotransmitters, and hormones are located on lymphoid organs. Therefore, we are of the opinion that Endocrine Disrupting Chemicals (EDCs) present in our environment may be indirectly involved in causing immune toxicity via neuroendocrine channels, and vice versa many neurological disorders may be associated with environmental pollutants utilizing immuno-neuroendocrine pathways. PMID- 26021323 TI - A systematic review of drugs in late-stage development for the treatment of multiple sclerosis: a focus on oral synthetic drugs. AB - Multiple sclerosis (MS) is a heterogeneous, chronic, debilitating immune-mediated disease of the central nervous system (CNS). There are four types of MS according to their relapsing or progressive pattern that include relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS). There is no definite cure for MS, thus medications typically focus on slowing the progression of the disease, managing symptoms and improving the quality of life. There is no specific medication for the management of PPMS and thus these patients are often neglected. New medicines in this phase of the disease are needed. On the other hand injectable immunomodulatory medicines, which dominated the MS market for over the past two decades, raise the issues of adherence and tolerance while oral therapies do offer a step forward in convenience. This systematic review article discusses the emerging synthetic small molecule that administered orally for MS treatment. We searched PubMed, Web of Science and Google Scholar to summaries the present knowledge on mechanism of action, and completed and current clinical trial of laquinimod, masitinib and siponimod. Data were collected from 1985 to January 2015. The development of effective medicines for MS is critically dependent upon understanding the biological basis of this complex multifactorial disease. The current pharmacotherapeuetic options for its treatment are mainly immunomodulators which were developed on the basis that MS is an autoimmune disease. The new synthetic small molecule agents such as laquinimod, masitinib and siponimod with different mechanism of actions can be administered orally rather than by injection. PMID- 26021324 TI - Suramin attenuated inflammation and reversed skin tissue damage in experimentally induced atopic dermatitis in mice. AB - Atopic dermatitis (AD) is a skin disease that is characterized by inflammation. Skin barrier dysfunction is commonly seen in AD leading to commonly seen infectious lesions in the skin of AD. Most people develop the skin inflammation condition first, before any skin lesions become visible. Suramin is potent competitive inhibitor of reverse transcriptase and blocks the infectivity and cytopathic effects. Therefore, the following study was performed to illustrate if suramin could produce protection against AD in-vivo. AD like symptoms were introduced in mice by epicutaneous application of DNCB on shaved dorsal skin and ears. 20 mg/kg suramin was taken by intra-peritoneal injection twice weekly for 3 weeks to assess their anti-pruritic effects. Serum levels of inflammatory cytokine, interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alphawere assessed by using ELISA kits. We found that suramin alleviated DNCB-induced AD like symptoms as quantified by skin lesion, dermatitis score, ear thickness and scratching behavior. Levels of reactive oxygen species in the suramin group were significantly inhibited as compared with that in the DNCB group. In parallel, suramin blocked DNCB-induced elevation in serum TNF-alpha, IL-1beta, IL-6 and IgE. The collective results indicate that suramin suppresses DNCB-induced AD in mice via reduction of inflammatory mediators. PMID- 26021326 TI - India's medical council reintroduces ID system to tackle "ghost faculty" problem in medical colleges. PMID- 26021325 TI - The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles. AB - CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 Genomes project (http://browser.1000genomes.org/index.html) indicated rs12769205 is in linkage disequilibrium with rs4244285 on CYP2C19*2, but found alone on CYP2C19*35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this single nucleotide polymorphism (SNP) alone leads to exon 2B and decreases CYP2C19 canonical mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19*2/*2 and *1/*35 liver microsomes with an exon 2 probe. However, an exon 4 probe, downstream from rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205, demonstrating rs12769205 alone can lead to complete loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205 and rs4244285 (CYP2C19*2/*2), but with little effect on mephenytoin disposition of CYP2C19*1/*2, CYP2C19*1/*3, or CYP2C19*1/*35 heterozygous alleles. Extended haplotype homozygosity tests of the HapMap Yorubans (YRI) showed both haplotypes carrying rs12769205 (CYP2C19*35 and CYP2C19*2) are under significant natural selection, with CYP2C19*35 having a higher relative extended haplotype homozygosity score. The phylogenetic tree of the YRI CYP2C19 haplotypes revealed rs12769205 arose first on CYP2C19*35 and that rs4244285 was added later, creating CYP2C19*2. In conclusion, rs12769205 is the ancestral polymorphism leading to aberrant splicing of CYP2C19*35 and CYP2C19*2 alleles in liver. PMID- 26021327 TI - Applicability of ISNT and IST rules to the retinal nerve fibre layer using spectral domain optical coherence tomography in early glaucoma. AB - BACKGROUND: To report the applicability of ISNT (inferior>superior>nasal>temporal) and IST (inferior>superior>temporal) rules on the retinal nerve fibre layer (RNFL) using spectral domain optical coherence tomography (SD-OCT) for detecting early glaucoma. METHODS: A prospective, cross sectional study which included 80 eyes of 80 normal subjects and 76 eyes of 76 patients with early glaucoma by Hodapp-Anderson-Parrish classification. All subjects were of age more than 18 years, best corrected visual acuity 20/40 or better and a refractive error within +/-5 dioptres (D) sphere and +/-3 D cylinder. Control subjects had a normal ocular examination, intraocular pressure <22 mm Hg, no past history of high intraocular pressure, no family history of glaucoma, normal optic disc morphology and visual field. All eyes underwent SD OCT examination for RNFL analysis. The sensitivity, specificity and likelihood ratio for violation of ISNT and IST rules was calculated for early glaucoma diagnosis. RESULTS: The ISNT rule was followed by 44 (55%) normal and 28 (36.84%) early glaucoma eyes. The IST rule was followed by 48 (60%) normal and 40 (52.63%) early glaucoma eyes. The sensitivity/specificity for violation of ISNT and IST rules for early glaucoma diagnosis was 63.2%/55% and 47.4%/60% respectively. The positive/negative likelihood ratio for ISNT and IST rules was 1.4/0.67 and 1.2/0.88, respectively, for diagnosing early glaucoma. CONCLUSIONS: Even though useful during ophthalmoscopy, ISNT and IST rules by themselves don't clearly distinguish normal eyes from those with glaucoma when applied to the quadrant values on RNFL on SD-OCT examination. PMID- 26021328 TI - Analysis of behaviour transitions in tumour growth using a cellular automaton simulation. AB - The authors used computational biology as an approach for analysing the emergent dynamics of tumour growth at cellular level. They applied cellular automata for modelling the behaviour of cells when the main cancer cell hallmarks are present. Their model is oriented to mimic the development of multicellular spheroids of tumour cells. In their modelling, cells have a genome associated with the different cancer hallmarks, indicating if those are acquired as a consequence of mutations. The presence of the cancer hallmarks defines cell states and cell mitotic behaviours. These hallmarks are associated with a series of parameters, and depending on their values and the activation of the hallmarks in each of the cells, the system can evolve to different dynamics. With the simulation tool the authors performed an analysis of the first phases of cancer growth, using different and alternative strategies: firstly, studying the evolution of cancer cells and hallmarks in different representative situations regarding initial conditions and parameters, analysing the relative importance of the hallmarks for tumour progression; secondly, being the focus of this work, inspecting the behaviour transitions when the cancer cells are killed with a given probability during the cellular system progression. PMID- 26021329 TI - Synthesising gene clock with toggle switch and oscillator. AB - The usefulness of a genetic clock lies in its role to stimulate a sequence of logic reactions for sequential biological circuits. A clock signal is a periodic square wave, its amplitude alternates at a steady frequency between fixed minimal and maximal levels. Transition between the minimum and the maximum is instantaneous for an ideal square wave; however, the function is unrealisable in physical bio-systems. This research develops a new genetic clock generator based on a genetic oscillator, in which, a sine wave generator is adopted as a signal oscillator. It is shown that combination of a genetic oscillator with a toggle switch is able to generate clock signals forming an efficient way to generate a near square wave. In silico study confirms the proposed idea. PMID- 26021330 TI - Global stability of infection-free state and endemic infection state of a modified human immunodeficiency virus infection model. AB - This study proposes a modified human immunodeficiency virus (HIV) infection differential equation model with a saturated infection rate. This model has an infection-free equilibrium point and an endemic infection equilibrium point. Using Lyapunov functions and LaSalle's invariance principle shows that if the model's basic reproductive number R0 < 1, the infection-free equilibrium point is globally asymptotically stable, otherwise the endemic infection equilibrium point is globally asymptotically stable. It is shown that a forward bifurcation will occur when R0 = 1. The basic reproductive number R0 of the modified model is independent of plasma total CD4+ T cell counts and thus the modified model is more reasonable than the original model proposed by Buonomo and Vargas-De-Leon. Based on the clinical data from HIV drug resistance database of Stanford University, using the proposed model simulates the dynamics of two group patients' anti-HIV infection treatments. The simulation results have shown that the first 4 weeks' treatments made the two group patients' R'0 < 1, respectively. After the period, drug resistance made the two group patients' R'0 > 1. The results explain why the two group patients' mean CD4+ T cell counts raised and mean HIV RNA levels declined in the first period, but contrary in the following weeks. PMID- 26021332 TI - Discovering the dementia evidence base: Tools to support knowledge to action in dementia care (innovative practice). AB - Dementia requires expert care and decision making, based on sound evidence. Reliable evidence is difficult for busy dementia care professionals to find quickly. This study developed an experimentally tested search filter as an innovative tool to retrieve literature on dementia. It has a known retrieval performance and can be provided as an open access web link directly to current literature. The Dementia Search Filter was developed using validated methodology. An Expert Advisory Group of dementia care practitioners and researchers ratified a representative set of relevant studies and undertook post hoc relevance assessment, to ensure the usefulness of the search filter. The Dementia Search Filter is published on two websites and combined with expert searches to link to evidence on dementia, at end of life in aged care settings and more generally. Evidence accessed by the Dementia Search Filter will help overcome barriers to finding current relevant research in the field, for practitioners, researchers and decision makers. PMID- 26021331 TI - Assessment of tumour viability in human lung cancer xenografts with texture-based image analysis. AB - AIMS: To build and evaluate an automated method for assessing tumour viability in histological tissue samples using texture features and supervised learning. METHODS: H&E-stained sections (n=56) of human non-small cell lung adenocarcinoma xenografts were digitised with a whole-slide scanner. A novel image analysis method based on local binary patterns and a support vector machine classifier was trained with a set of sample regions (n=177) extracted from the whole-slide images and tested with another set of images (n=494). The extracted regions, or single-tissue entity images, were chosen to represent as pure as possible examples of three morphological tissue entities: viable tumour tissue, non-viable tumour tissue and mouse host tissue. RESULTS: An agreement of 94.5% (area under the curve=0.995, kappa=0.90) was achieved to classify the single-tissue entity images in the test set (n=494) into the viable tumour and non-viable tumour tissue categories. The algorithm assigned 250 of the 252 non-viable and 219 of the 242 of viable sample regions to the correct categories, respectively. This corresponds to a sensitivity of 90.5% and specificity of 99.2%. CONCLUSIONS: The proposed image analysis-based tumour viability assessment resulted in a high agreement with expert annotations. By providing extraction of detailed information of the tumour microenvironment, the automated method can be used in preclinical research settings. The method could also have implications in cancer diagnostics, cancer outcome prognostics and prediction. PMID- 26021334 TI - Use of an Anastomotic Coupling Device for the Creation of Spliced Autogenous Grafts in Lower Extremity Revascularization. AB - INTRODUCTION: Despite a recent rise in popularity of endovascular techniques, open bypass surgery is still required for treating many lower extremity vascular lesions. Greater saphenous vein (GSV) of adequate length and caliber for successful infrainguinal lower extremity bypass is unavailable in 15% to 45% of patients. To overcome limitations imposed by absent vein due to prior use, short vessel length, or sclerotic segments, both alternate (ie, basilic and cephalic) and GSV conduits may be "spliced" together in series via venovenostomy. Although vascular surgeons typically perform a hand-sewn venovenostomy, device-based venous coupling has been performed by plastic surgeons for many years. We therefore sought to review our experience with venous coupling for segmental lower extremity bypass graft assembly. METHODS: A retrospective review was performed in all patients who underwent lower extremity revascularization using autogenous vein grafts spliced together with the Synovis (Birmingham, Alabama) anastomotic coupler at a single institution over a 5-year period. RESULTS: The anastomotic coupler device was used on 5 patients for 7 venovenostomies. The mean age of patients was 66 years, and the mean follow-up period was 751 days. Two patients were lost to follow-up, while 2 other patients died of causes unrelated to their lower extremity bypass. The average time to perform venovenostomy was 3 minutes. Three patients developed stenosis of their composite graft at a site other than the venovenostomy, who were successfully treated with either angioplasty or bypass revision. One-year primary and primary-assisted patency rates were 50% and 75%, respectively. CONCLUSIONS: Given the known benefits of the anastomotic coupling device when used for venous anastomoses in microsurgical reconstruction, transition of this device to the vascular surgery realm represents a logical progression. Although small, our series demonstrates that the anastomotic coupler can successfully be used for the formation of spliced autogenous grafts for lower extremity revascularization in the absence of adequate GSV. PMID- 26021333 TI - Outcomes Following Limb Crossing in Endovascular Aneurysm Repairs. AB - BACKGROUND: Crossing the limbs of the stent during endovascular aneurysm repair (EVAR) is often used to aid cannulation of the contralateral limb. This study assessed outcomes following the use of this technique. METHODS: Retrospective review of crossed (n = 43) and uncrossed (n = 269) EVARs was performed at a tertiary vascular center over 5 years. Primary end points were graft limb occlusion (GLO), endoleak, and sac expansion rates. Indications for limb crossing were also assessed. RESULTS: Two-year GLO (P = .34) and type 1 endoleak (P = .413) rates were similar between groups. Patients undergoing crossed EVAR experienced more type 2 endoleaks (P = .002) at 24 months but no increase in sac expansion rates was observed (P = .275). Thirty-day (P = .57) and late (P = .268) mortalities were similar between groups. The main indication for limb crossing was distal aortic angulation (48.8%). CONCLUSIONS: Crossed EVAR does not increase the risk of GLOs or clinically significant endoleaks. Further studies are needed to determine the effect on type 2 endoleak rates. PMID- 26021335 TI - The Bone-Inflammation-Cartilage (BIC) Stain: A Novel Staining Method Combining Safranin O and Van Gieson's Stains. PMID- 26021336 TI - The era of transcatheter valve therapy. Where are we? PMID- 26021337 TI - Medtronic CoreValve: Achieving Optimal Outcomes. PMID- 26021338 TI - The SAPIEN-XT and SAPIEN-3 Valves: How to Implant and Obtain the Best Outcomes. PMID- 26021339 TI - PorticoTM Transcatheter Heart Valve. PMID- 26021340 TI - Managing complications in transcatheter aortic valve implantation. PMID- 26021341 TI - The Abbott Vascular MitraClip: Patient Selection and How to Obtain the Best Outcomes. AB - The MitraClip procedure is an important procedure for the treatment of high-risk patients with severe MR, offering an effective and clinically meaningful reduction in the degree of MR, with low perioperative morbidity and mortality. Careful screening of prospective patients and evaluation by the multidisciplinary Heart Team are essential. A dedicated interventional team combining technical skills and advanced imaging is critical for success. PMID- 26021342 TI - Emerging kinase inhibitors of the treatment of gastric cancer. AB - INTRODUCTION: Gastric cancer (GC) is the fifth most common malignancy in the world. In the last years, for the first time in literature, the addition of a targeted therapy to standard chemotherapy has proved to prolong median overall survival. In this scenario, kinase inhibitors (KIs), smaller intracellular agents, could be an interesting and novel type of targeted treatment of metastatic GC both in first and further lines of therapy. AREAS COVERED: Several KI have been evaluated in the preclinical setting. This review will underline the most relevant targeted pathways involved in GC tumorigenesis and disease progression including EGFR, VEGFR, c-MET, mTOR, fibroblast growth factor receptor, Src and Aurora kinases. EXPERT OPINION: Despite the good results of TOGA, RAINBOW and REGARD trials about the addition of monoclonal antibodies to standard of care in GC, the addition of KI seems not to achieve comparable interesting results in management of GC. However, an improved patient selection before and during treatment according to molecular characteristics, as well as combination studies evaluating the synergistic effect of combination schedules of different KIs and standard chemotherapy, or KI plus KI or KI plus antibodies based therapy may reveal interesting results and lead to understand mechanisms of multi-drug resistance. PMID- 26021343 TI - Characterization of Darai Limestone Composition and Porosity Using Data Constrained Modeling and Comparison with Xenon K-Edge Subtraction Imaging. AB - Data-constrained modeling is a method that enables three-dimensional distribution of mineral phases and porosity in a sample to be modeled based on micro-computed tomography scans acquired at different X-ray energies. Here we describe an alternative method for measuring porosity, synchrotron K-edge subtraction using xenon gas as a contrast agent. Results from both methods applied to the same Darai limestone sample are compared. Reasonable agreement between the two methods and with other porosity measurements is obtained. The possibility of a combination of data-constrained modeling and K-edge subtraction methods for more accurate sample characterization is discussed. PMID- 26021344 TI - Follow-up study of the treatment outcomes at a psychiatric trauma clinic for refugees. AB - PURPOSE: To describe change in mental health after treatment with antidepressants and trauma-focused cognitive behavioral therapy. METHODS: Patients receiving treatment at the Psychiatric Trauma Clinic for Refugees in Copenhagen completed self-ratings of level of functioning, quality of life, and symptoms of PTSD, depression and anxiety before and after treatment. Changes in mental state and predictors of change were evaluated in a sample that all received well-described and comparable treatment. RESULTS: 85 patients with PTSD or depression were included in the analysis. Significant improvement and effect size were observed on all rating scales (p-value <0.01 and Cohen's d 45-0.68). Correlation analysis showed no association between severity of symptoms at baseline and the observed change. CONCLUSION: Despite methodological limitations, the finding of a significant improvement on all rating scales is important considering that previous follow-up studies of comparable patient populations have not found significant change in the patients'condition after treatment. PMID- 26021345 TI - Cognitive behavioral psychotherapeutic treatment at a psychiatric trauma clinic for refugees: description and evaluation. AB - INTRODUCTION: Cognitive behavioural therapy (CBT) with trauma focus is the most evidence supported psychotherapeutic treatment of PTSD, but few CBT treatments for traumatized refugees have been described in detail. PURPOSE: To describe and evaluate a manualized cognitive behavioral therapy for traumatized refugees incorporating exposure therapy, mindfulness and acceptance and commitment therapy. MATERIAL AND METHODS: 85 patients received six months' treatment at a Copenhagen Trauma Clinic for Refugees and completed self-ratings before and after treatment. The treatment administered to each patient was monitored in detail. The changes in mental state and the treatment components associated with change in state were analyzed statistically. RESULTS: Despite the low level of functioning and high co-morbidity of patients, 42% received highly structured CBT, which was positively associated with all treatment outcomes. The more methods used and the more time each method was used, the better the outcome. The majority of patients were able to make homework assignments and this was associated with better treatment outcome. Correlation analysis showed no association between severity of symptoms at baseline and the observed change. CONCLUSION: The study suggests that CBT treatment incorporating mindfulness and acceptance and commitment therapy is promising for traumatized refugees and punctures the myth that this group of patients are unable to participate fully in structured CBT. However, treatment methods must be adapted to the special needs of refugees and trauma exposure should be further investigated. PMID- 26021346 TI - "After all the traumas my body has been through, I feel good that it is still working."--Basic Body Awareness Therapy for traumatised refugees. AB - Basic Body Awareness Therapy (BBAT) is a form of physiotherapy that is often used for psychiatric patients in Scandinavian countries. To our knowledge there has not been any studies investigating BBAT as a treatment for traumatised refugees until now. OBJECTIVE: To explore the compliance, acceptability and treatment satisfaction using group BBAT in traumatised refugees. To study changes in psychiatric and somatic symptoms as well as quality of life, level of functioning and quality of movement during treatment with BBAT. METHOD: All Arabic speaking patients that previously had received treatment at the Competence Centre for Transcultural Psychiatry in Copenhagen from April 2008 to June 2009 were invited to participate (N=29). Nine persons were included in a male (N=4) and female (N=5) group. All participants were traumatised refugees. The BBAT treatment consisted of 14 sessions over a period of 14 weeks. Before and after treatment the participants were interviewed using a semi-structured interview guide. The interviews were transcribed and analysed with a thematic approach. The participants also filled out self-administrated questionnaires and two physiotherapists tested the participants' movement harmony using the Body Awareness Rating Scale-Movement Harmony (BARS-MH) test. At the end of the study, the participants filled out anonymous questionnaires about treatment satisfaction. RESULTS: The results showed that the participants had a high compliance, acceptability and treatment satisfaction with BBAT. The majority of participants showed improvements in symptoms from baseline to post-intervention on the self-administrated questionnaires and in the BARS-MH test. CONCLUSIONS: Further research is needed to expand the scientific knowledge regarding the use of BBAT in traumatised refugees. If future research can confirm our positive findings it will have a considerable impact on future treatment designs and for the individual patient. PMID- 26021347 TI - The DSM 5 and the Istanbul Protocol: Diagnosis of psychological sequels of torture. AB - The Manual on Effective Investigation and Documentation of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment, commonly known as the Istanbul Protocol, is an interdisciplinary standard supported by, among others, the United Nations and the World Medical Association. It aims at aiding the fight against torture by giving clear guidelines to ensure better and more effective assessment of physical and psychological sequels. Mental health is a key aspect of diagnostical assessment and documentation due to the severe and frequently long-lasting impact of torture that often lasts longer than physical sequels. The inclusion of psychological aspects and a psychiatric diagnosis is to be treated as an important obligatory. Care must be taken to avoid common pitfalls. The new and substantial revisions in the frequently used but also criticised Diagnostical and Statistical Manual (DSM) reflect challenges and opportunities in a comprehensive approach to the documentation of torture. PMID- 26021348 TI - Statement on virginity testing. PMID- 26021349 TI - WNT/beta-catenin signaling inhibits CBP-mediated RelA acetylation and expression of proinflammatory NF-kappaB target genes. AB - The discovery of functional crosstalk between WNT and nuclear factor kappaB (NF kappaB) signaling has established a more complex role for these two pathways in inflammation and cancer. However, the molecular mechanisms of the crosstalk and its biological consequences are largely unknown. Here, we show that WNT/beta catenin signaling selectively inhibits the expression of a proinflammatory subset of IL-1beta-induced NF-kappaB target genes. WNT/beta-catenin signaling does not affect nuclear translocation of the RelA subunit of NF-kappaB or its association with CBP (also known as CREBBP), but reduces CBP-mediated acetylation and chromatin recruitment of RelA. Thus, beta-catenin selectively regulates NF-kappaB gene expression through its negative effects on RelA acetylation. This anti inflammatory effect may be relevant for cancer treatment. PMID- 26021351 TI - The contractome--a systems view of actomyosin contractility in non-muscle cells. AB - Actomyosin contractility is a highly regulated process that affects many fundamental biological processes in each and every cell in our body. In this Cell Science at a Glance article and the accompanying poster, we mined the literature and databases to map the contractome of non-muscle cells. Actomyosin contractility is involved in at least 49 distinct cellular functions that range from providing cell architecture to signal transduction and nuclear activity. Containing over 100 scaffolding and regulatory proteins, the contractome forms a highly complex network with more than 230 direct interactions between its components, 86 of them involving phosphorylation. Mapping these interactions, we identify the key regulatory pathways involved in the assembly of actomyosin structures and in activating myosin to produce contractile forces within non muscle cells at the exact time and place necessary for cellular function. PMID- 26021352 TI - Tobacco-free generation legislation. PMID- 26021350 TI - Genome-wide RNAi screen for nuclear actin reveals a network of cofilin regulators. AB - Nuclear actin plays an important role in many processes that regulate gene expression. Cytoplasmic actin dynamics are tightly controlled by numerous actin binding proteins, but regulation of nuclear actin has remained unclear. Here, we performed a genome-wide RNA interference (RNAi) screen in Drosophila cells to identify proteins that influence either nuclear polymerization or import of actin. We validate 19 factors as specific hits, and show that Chinmo (known as Bach2 in mammals), SNF4Agamma (Prkag1 in mammals) and Rab18 play a role in nuclear localization of actin in both fly and mammalian cells. We identify several new regulators of cofilin activity, and characterize modulators of both cofilin kinases and phosphatase. For example, Chinmo/Bach2, which regulates nuclear actin levels also in vivo, maintains active cofilin by repressing the expression of the kinase Cdi (Tesk in mammals). Finally, we show that Nup98 and lamin are candidates for regulating nuclear actin polymerization. Our screen therefore reveals new aspects of actin regulation and links nuclear actin to many cellular processes. PMID- 26021354 TI - Time to implement national mental health reform. PMID- 26021355 TI - The scourge of managerialism and the Royal Australasian College of Physicians. PMID- 26021356 TI - Response - The Royal Australasian College of Physicians: a 21st century college. PMID- 26021357 TI - Rapid response systems. PMID- 26021358 TI - Rapid response systems. PMID- 26021359 TI - Strongyloidiasis: a case for notification in Australia? PMID- 26021360 TI - Inappropriate pathology ordering and pathology stewardship. PMID- 26021361 TI - General practitioner management of notifiable diseases is central to communicable disease control. PMID- 26021362 TI - The gap remains: NHMRC research funding for suicide and self-harm, 2000-2014. PMID- 26021363 TI - General practitioner-referred magnetic resonance imaging for musculoskeletal conditions: not a substitute for plain x-ray. PMID- 26021364 TI - Potential public health benefits of HIV testing occurring at home in Australia. AB - In many countries, including Australia, policies have recently changed to support HIV self-testing. The decision has created much debate about the public health benefits of the strategy versus the risks. Self-testing for HIV was approved in the US on the basis that it would facilitate greater HIV testing uptake, despite having a lower sensitivity than laboratory HIV immunoassays. We calculated the frequency of self-testing that would be required among Australian gay and bisexual men at high-risk for there to be a public health benefit (detection of HIV infections that would have otherwise remained undiagnosed). At a population level, if access to HIV self-testing led to men supplementing their usual sexual health check-ups (involving a laboratory HIV immunoassay) with one or more self tests at home, or self-tests led to untested gay and bisexual men having an HIV test for the first time, there would be a public health benefit. If men replaced their average of one laboratory HIV immunoassay per year with self-testing at home, then three self-tests would be needed to counteract the lower sensitivity of the self-test (so zero infections would be missed). If four self-tests were undertaken then additional infections would be detected (ie, there would be a public health benefit). Additional public health benefits include a reduction in the period of undiagnosed infection, which is known to be a period of relatively high infectiousness. PMID- 26021365 TI - The services provided to young people through the headspace centres across Australia. AB - OBJECTIVES: To describe the services provided to young people aged 12-25 years who attend headspace centres across Australia, and how these services are being delivered. DESIGN: A census of headspace clients commencing an episode of care between 1 April 2013 and 31 March 2014. PARTICIPANTS: All young people first attending one of the 55 fully established headspace centres during the data collection period (33,038 young people). MAIN OUTCOME MEASURES: Main reason for presentation, wait time, service type, service provider type, funding stream. RESULTS: Most young people presented for mental health problems and situational problems (such as bullying or relationship problems); most of those who presented for other problems also received mental health care services as needed. Wait time for the first appointment was 2 weeks or less for 80.1% of clients; only 5.3% waited for more than 4 weeks. The main services provided were a mixture of intake and assessment and mental health care, provided mainly by psychologists, intake workers and allied mental health workers. These were generally funded by the headspace grant and the Medicare Benefits Schedule. CONCLUSIONS: headspace centres are providing direct and indirect access to mental health care for young people. PMID- 26021366 TI - Changes in psychological distress and psychosocial functioning in young people visiting headspace centres for mental health problems. AB - OBJECTIVES: To examine changes in psychological distress and psychosocial functioning in young people presenting to headspace centres across Australia for mental health problems. DESIGN: Analysis of routine data collected from headspace clients who had commenced an episode of care between 1 April 2013 and 31 March 2014, and at 90-day follow-up. PARTICIPANTS: A total of 24 034 people aged 12-25 years who had first presented to one of the 55 fully established headspace centres for mental health problems during the data collection period. MAIN OUTCOME MEASURES: Main reason for presentation, types of therapeutic services provided, Kessler Psychological Distress Scale (K10) scores, and Social and Occupational Functioning Assessment Scale (SOFAS) scores. RESULTS: Most headspace mental health clients presented with symptoms of depression and anxiety and were likely to receive cognitive behaviour therapy (CBT). Younger males were more likely than other age- and sex-defined groups to present for anger and behavioural problems, while younger females were more likely to present for deliberate self-harm. From presentation to last assessment, over one-third of clients had significant improvements in psychological distress (K10) and a similar proportion in psychosocial functioning (SOFAS). Sixty per cent of clients showed significant improvement on one or both measures. CONCLUSIONS: Data regarding outcomes for young people using mental health care services similar to headspace centres are scarce, but the current results compare favourably with those reported overseas, and show positive outcomes for young people using headspace centres. PMID- 26021367 TI - A bolt out of the blue: the night of the blue pills. PMID- 26021368 TI - A maple leaf among the gum trees. PMID- 26021370 TI - [Internet-based Report Cards for Hospital Choice Making in Germany: A Clinical Area-focused Perspective]. AB - Objectives: Aims of this study are to provide (i) a presentation of quality of care information about German hospitals on internet report cards, and (ii) derive a guidance tool for using certain report cards. Methods: We undertook (i) a systematic internet search to identify hospital report cards, (ii) whereby several inclusion and exclusion criteria were applied, (iii) We developed a scheme to describe the presented quality information, (iv) We also analysed the report cards and (v) evaluated the results and derived further usage guidance. Results: 18 report cards were included. 8 report cards present nationwide quality information while ten report cards focus on regional areas. The AOK Krankenhaus navigator provides the most information about 5 clinical areas of the external quality assurance (S 137 SGB V). Regarding the remaining 26 clinical areas, the TK Klinikfuhrer, the Barmer Krankenhausnavi, and the Weisse Liste provide the largest amount of quality information. Qualitatskliniken.de reports on 9, the Klinikfuhrer Rheinland on 8, the Bremer Krankenhausspiegel on 4, and the Hamburger Krankenhausspiegel on 2 additional clinical areas. Conclusions: This study shows that a differentiated view for each clinical area is necessary when searching for information about the quality of hospitals. Further studies should assess the quality of the report cards as well as the information that they display. PMID- 26021371 TI - [Brachytherapy for Prostate Cancer: Potentials and Limitations of Social Health Insurance Data for Benefit Assessment]. AB - BACKGROUND: Due to the insufficient data base the Federal Joint Committee (G-BA) had in 2009 after 7 years of deliberation decided to initiate consultation regarding ambulatory brachytherapy for localised prostate cancer for 10 years from social health insurance (SHI) benefits. The aim is to gain more findings by means of comparative studies. PROBLEM: Based on the non-availability of clinical primary data of a methodologically acceptable level, it was analysed to what extent secondary data of the SHI may be used in order to arrive at valid conclusions for benefit aspects. METHODS: As base approx. 8 million insured of TK with their data of cost reimbursement between 2006 and 2011 were considered. In SHI secondary data no clinical information regarding tumour stage and other prognostic factors are available. Therefore, a novel method with therapy-specific multisectoral inclusion and exclusion criteria, respectively, was developed in order to differentiate between localised and advanced tumours of the prostate. Overall survival, relapse-free survival, event-free survival and side-effects associated to prostate cancer were analysed. RESULTS: Out of 87 822 insured persons with the diagnosis prostate cancer, 795 with PBT, 10 936 with RP and 1 925 with EBRT were investigated in detail. The 4-year event-free survival rate was 73% for RP, 77% for PBT and 71% for EBRT. Many prostate cancer-specific side effects appeared already before intervention. Side effects of the intestinal tract (23.8%) and sexual impairments (26.5%) were more frequent for EBRT than for RP (17.1%/14.8%) and PBT (16.4%/13.2%). CONCLUSION: By means of SHI secondary data and adequate operationalisation important findings regarding relevant aspects of prostate cancer in healthcare research can be generated. However, these hold methodological limitations and are not suited to draw valid conclusions for benefit assessment. Based solely on SHI routine data valid statements regarding comparative benefit assessment are limited. Limitations could be reduced by applying a record linkage with clinical data. Such primary data should include information on tumour stages as well as therapy assignment and observation of survival time. PMID- 26021372 TI - [Dentists' Knowledge of Ethical Questions Regarding Dental Medicine - A Survey of Dentists from Saxony, Saxony-Anhalt and Thuringia (Germany)]. AB - Background: Subjects regarding ethical questions in dental medicine are only slightly touched in the study of dental medicine or in the working regulations of the dentists' association. However, dentists are confronted with these matters in everyday working life. The empirical study at hand collects current data regarding the ethical knowledge about dental medicine in the practical experience of dentists in Saxony, Saxony-Anhalt, and Thuringia. Methods: The tool used in the survey was a structured questionnaire. Out of 600 randomly chosen and contacted dentists from Saxony, Saxony-Anhalt, and Thuringia, 290 replied (response rate: 48.3%). The anonymised assessment took place between June and November 2013. Results: Dentists frequently encounter ethical questions regarding dental matters. The dentists interviewed in the study are in favour of a participative relationship between patient and dentist. Simultaneously, the patient's health is predominantly seen as the good of higher value than his or her self-determination. The dentists show competent knowledge of ethical dental subjects, although increased uncertainties could be observed in more complex situations, e. g. considering contact with patients who are HIV-positive. Conclusions: Questions dealing with dental ethical questions do play a major role in the daily professional life of dentists. In order to further support and strengthen dentists in their individual dental ethical competence, we see a need for advanced training and further education regarding questions and problems in the area of ethics in dental medicine. Also, these topics should become a component in the curriculum of the study of dental medicine. PMID- 26021374 TI - Survey of Italian pediatricians' perspectives and knowledge about neonatal screening. AB - BACKGROUND: The goal of newborn screening is early identification of babies with a high risk for disorders that may not be clinically evident at birth, but have severe consequences if untreated. New insight into inherited diseases and the ability to test for numerous diseases using new technique such as tandem mass spectrometry have made it practical to greatly expand the number of conditions tested. The expanded neonatal screening is now available and relatively simple, but this represents only a part of the picture. Positive results require follow up confirmation. Most disorders screened require confirmatory biochemical or genetic tests and specialist visits. An efficient system is needed for managing the care of affected newborns. Expanded newborn screening is not yet available in all Regions of Italy, but discussions aimed at organizing universal access are underway. If these are successful, the role of the pediatrician as the primary contact with the parents is expected to become even more important. METHODS: We have conducted a survey of Italian pediatricians to assess their familiarity and opinions on newborn screening in general and on expanded newborn screening. All members of the Italian Association of Pediatricians (n = 9000) were invited to compile a 10-item questionnaire online. RESULTS: The response rate was 10 %, corresponding to 605 of 6000 active members. Respondents were from all Regions of Italy, with the highest number of responses coming from Lombardy (138, 22.8 %), Campania and Puglia (n = 61; 10.1 %). Interestingly, expanded neonatal screening was not available in any of these Regions at the time of the survey. Regarding their understanding of neonatal screening in general, most respondents (n = 552; 91.1 %) considered that they had at least a sufficient level of knowledge; however, only 59.6 % thought they had sufficient knowledge of expanded newborn screening. CONCLUSIONS: Successful implementation of a universal expanded NBS program will require efficient procedures for follow-up, diagnosis and treatment to prevent morbidity and mortality of infants and to reduce the period of uncertainty for unaffected families. Pediatricians may need additional training to allow them to fulfill their tasks of coordinating this process while keeping families informed and reassured. PMID- 26021373 TI - Baicalein reduces the occurrence of cirrhotic endotoxemia by reducing intestinal mucosal apoptosis. AB - BACKGROUND: The dried roots of Scutellaria baicalensis Georgi, is known in traditional Chinese medicine as Huang Qin (H. qin), and it has been officially and traditionally used in treatment of various diseases such as hepatitis in China. Baicalein (BA), a flavonoid originally isolated from H. qin, has shown a wide range of biological activities. This study was to evaluate whether baicalein, can reduce the intestinal mucosal cell apoptosis caused by cirrhotic endotoxemia and its possible mechanisms. METHODS: For this purpose, compound factors modeling was used to establish endotoxemic cirrhotic rat model. Firstly, we evaluated endotoxin, ALT, AST and TBIL levels after the baicalein treatment (20 mg/kg, i.v.). To investigate the mechanism of baicalein effect on apoptosis, TUNEL assay was used to detect intestinal mucosal apoptosis. RT-PCR was used to detect the expression levels of gene Bcl-2 mRNA and Bax mRNA in intestinal mucosal tissues. Caspase-3 activity of intestinal tissue was detected with colorimetric method in our experiments. RESULTS: After treatment with BA, the serum endotoxin concentration, the intestinal mucosal apoptosis rate and the activity of caspase-3 of the baicalein group were significantly lower than that of the model and the glutamine group. The serum ALT, AST and TBIL concentration of the BA group were significantly lower than that of the model group. The body weight of the baicalein group was significantly lower than that of the normal group, but it was higher than that of the model group. Among the treatment groups, the mRNA level of anti-apoptotic gene Bcl-2 was the lowest in the model group and the highest in the baicalein group while the mRNA level of pro apoptotic gene Bax was the lowest in the baicalein group and the highest in the model group. CONCLUSION: The present results demonstrated that baicalein could reduce the occurrence of cirrhotic endotoxemia partly by reducing intestinal mucosal apoptosis. PMID- 26021375 TI - Chronic kidney disease is common in sickle cell disease: a cross-sectional study in the Tema Metropolis, Ghana. AB - BACKGROUND: Renal involvement in sickle cell disease (SCD) contributes significantly to morbidity and mortality. The aim of this study was to determine the prevalence of chronic kidney disease (CKD) amongst SCD patients, and how basic clinical variables differ across haemoglobin genotypes. METHODS: A hospital based cross-sectional study conducted from December 2013 to May 2014 at the Sickle cell clinic of the Tema General Hospital. One hundred and ninety-four (194) participants with SCD, receiving medical care at the outpatient sickle cell clinic were enrolled onto the study. A structured questionnaire was administered to obtain information on demography, clinical history, blood pressure and anthropometry. Blood and urine samples were taken for serum creatinine and proteinuria determination respectively. The estimated GFR (eGFR) was calculated using the CKD-EPI and Schwartz equations. CKD was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Analysis was performed using GraphPad prism and P <0.05 was considered statistically significant. RESULTS: CKD was present in 39.2% of participants. Using KDIGO guidelines, 40.8% of the HbSS participants had stage 1 CKD and none had stage 2 CKD. In addition, 30.8% of the HbSC participants had stage 1 CKD and 3.8% had stage 2 CKD. There was a trend of increasing age across CKD stages and stage 2 CKD participants were oldest (P < 0.001). CONCLUSION: Results from the current study suggest that CKD is common amongst SCD patients and prevalence and intensity increases with age. Proteinuria and CKD was more common in HbSS genotype than in HbSC genotype. PMID- 26021376 TI - Severe malaria in children leads to a significant impairment of transitory otoacoustic emissions--a prospective multicenter cohort study. AB - BACKGROUND: Severe malaria may influence inner ear function, although this possibility has not been examined prospectively. In a retrospective analysis, hearing impairment was found in 9 of 23 patients with cerebral malaria. An objective method to quickly evaluate the function of the inner ear are the otoacoustic emissions. Negative transient otoacoustic emissions are associated with a threshold shift of 20 dB and above. METHODS: This prospective multicenter study analyses otoacoustic emissions in patients with severe malaria up to the age of 10 years. In three study sites (Ghana, Gabon, Kenya) 144 patients with severe malaria and 108 control children were included. All malaria patients were treated with parental artesunate. RESULTS: In the control group, 92.6 % (n = 108, 95 % confidence interval 86.19-6.2 %) passed otoacoustic emission screening. In malaria patients, 58.5 % (n = 94, malaria vs controls p < 0.001, 95 % confidence interval 48.4-67.9 %) passed otoacoustic emission screening at the baseline measurement. The value increased to 65.2 % (n = 66, p < 0.001, 95 % confidence interval 53.1-75.5 %) at follow up 14-28 days after diagnosis of malaria. The study population was divided into severe non-cerebral malaria and severe malaria with neurological symptoms (cerebral malaria). Whereas otoacoustic emissions in severe malaria improved to a passing percentage of 72.9 % (n = 48, 95 % confidence interval 59-83.4 %) at follow-up, the patients with cerebral malaria showed a drop in the passing percentage to 33 % (n = 18) 3-7 days after diagnosis. This shows a significant impairment in the cerebral malaria group (p = 0.012 at days 3-7, 95 % confidence interval 16.3-56.3 %; p = 0.031 at day 14-28, 95 % confidence interval 24.5-66.3 %). CONCLUSION: The presented data show that 40 % of children have involvement of the inner ear early in severe malaria. In children, audiological screening after severe malaria infection is not currently recommended, but is worth investigating in larger studies. PMID- 26021378 TI - Transarterial catheter embolisation for an unusual cause of upper gastrointestinal haemorrhage. AB - A 72-year-old man with a history of gallstones, and complex cardiac and endocrinological comorbidities, presented with severe abdominal pain and melaena. CT mesenteric angiogram showed a cystic artery pseudoaneurysm and gallbladder distended by haematoma. Subsequent mesenteric angiography confirmed a cystic artery pseudoaneurysm, which was successfully embolised with microcoils. The patient made a rapid recovery and was discharged after 3 days. PMID- 26021377 TI - CXCL14 and MCP1 are potent trophic factors associated with cell migration and angiogenesis leading to higher regenerative potential of dental pulp side population cells. AB - INTRODUCTION: The release of trophic factors from mesenchymal stem cells (MSCs) is critical for tissue regeneration. A systematic investigation of the regenerative potential of trophic factors from different MSCs, however, has not been performed. Thus, in the present study, the regenerative potential of conditioned medium (CM) from dental pulp, bone marrow, and adipose tissue-derived CD31(-) side population (SP) cells from an individual source was compared in an ectopic tooth transplantation model. METHODS: The tooth root transplantation in an ectopic site model was used for investigation of the regenerative potential and trophic effects in vivo. Either pulp CD31(-) SP cell populations (1*10(6) cells) at the third to fourth passage or 5 MUg/ml of CM from dental pulp, bone marrow, and adipose stem cells from four different individuals were injected into the root with collagen TE. Each root was transplanted subcutaneously in 5-week old severe combined immunodeficiency mice. Each root with surrounding tissue was harvested for histology on days 7, 21, and 28 and for Western blot analysis and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis on day 28. Furthermore, the trophic factors responsible for the regenerative potential were identified as the upregulated genes present in pulp CD31(-) SP cells when compared with the genes in both bone marrow and adipose CD31(-) SP cells by using microarray analysis, real-time RT-PCR, and Western blot analysis. RESULTS: Transplantation of pulp CM yielded increased volume of pulp regeneration, more bromodeoxyuridine (BrdU)-positive migrated cells, and fewer caspase 3-positive cells in the regenerated pulp compared with the others. Pulp CM also demonstrated significantly increased cell migration, anti-apoptosis, and angiogenesis in C2C12 cells. Higher expression of CXCL14 and MCP1 in pulp SP cells suggested candidate trophic factors. The stimulatory effects on both migration and angiogenesis of CXCL14 and MCP1 were demonstrated in vitro. In the regenerated tissue, BrdU-positive migrated cells expressed CXCR4 and CCR2, receptors for CXCL14 and MCP1, respectively. CONCLUSIONS: The higher regenerative potential of pulp SP cells may be due to potent trophic factors, including CXCL14 and MCP1, which promote migration and angiogenesis. PMID- 26021379 TI - Two cases with HSS/DRESS syndrome developing after prosthetic joint surgery: does vancomycin-laden bone cement play a role in this syndrome? AB - We report two cases of hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (HSS/DRESS) syndrome following systemic and local (via antibiotic laden bone cement (ALBC)) exposures to vancomycin. Both cases developed symptoms 2-4 weeks after the initiation of treatment. They responded to systemic corticosteroid treatment and were cured completely. Various drug groups may cause HSS/DRESS syndrome, and vancomycin-related cases do not exceed 2-5% of the reported cases. Almost all of these cases developed the syndrome following systemic exposure to vancomycin. ALBC seems to be the safer antibiotic administration method, as systemic antibiotic levels did not reach a toxic threshold level. However, local administration may not always be sufficient for bone-related/joint-related infections; these infections may require systemic antibiotics as well. As HSS/DRESS syndrome can mimic infectious diseases, it must be considered during differential diagnosis before suspecting failure of treatment and initiation of a different antibiotic course. PMID- 26021380 TI - Proliferative diabetic retinopathy in typical retinitis pigmentosa. AB - A 39-year-old woman with typical retinitis pigmentosa (RP) for 9 years and a positive family history of night blindness was diagnosed with diabetes mellitus (DM). She developed proliferative diabetic retinopathy (PDR) during the course of disease. She was promptly managed with pan retinal photocoagulation (PRP). PDR developing in a case of typical RP is extremely rare and has not been reported in the literature to date. Recognition of this rare, vision threatening complication, points out a definite need to further look deep into the pathogenesis of diabetic retinopathy. PMID- 26021381 TI - Hypertrophic pachymeningitis with sarcoidosis: a rare cause of craniocervical compression. AB - We describe a case of a 58-year-old woman with a suspected dural tumour. She presented with progressive pyramidal weakness. MRI confirmed compression of the medulla oblongata and spinal cord at the level of C1-3. The localised dural mass lesion homogenously enhanced on T1 MRI and was considered most likely to be a meningioma. Incidentally, CT scan of the chest revealed peribronchial soft tissue thickening, suggestive of pulmonary sarcoidosis. Owing to the progressive nature of her weakness, she had a posterior occipitocervical decompression with a C1-3 laminectomy and resection of the thickened dura. Histology showed densely collagenous tissue with scanty psammoma bodies and multinucleate giant cells, consistent with hypertrophic pachymeningitis (HP)-a rare, chronic inflammatory condition, characterised by thickening and fibrosis of the dura. This case demonstrates that masses in the craniocervical junction can be varied in pathology and when there is evidence of systemic inflammation, HP should be considered. PMID- 26021382 TI - ECG artefacts mimicking atrial flutter in posterior fossa surgery. AB - ECG artefacts are defined as abnormalities in the monitored ECG, which result from measurement of cardiac potentials on the body surface and are not related to the electrical activity of the heart. In the operation theatre, the use of various types of electrical equipment may interfere with ECG interpretation. We describe our experience with artefacts resembling atrial fibrillation when a nerve integrity monitoring device was used on a patient undergoing posterior fossa surgery for epidermoid tumour. These artefacts resemble serious arrhythmias and may result in unwanted interventions. To enable better identification of such artefacts, a 12-lead ECG should be considered as it will display rhythm in all the leads; while artefacts will present in only a few leads, true arrhythmia will be present in all the 12 leads. Our case report aims to increase awareness regarding ECG artefacts and to explain how to distinguish them from actual arrhythmias. PMID- 26021383 TI - Severe hyponatraemia with absence of hyperkalaemia in rapidly progressive Addison's disease. AB - We present a case of rapidly progressing Addison's disease in adrenal crisis with severe hyponatraemia and absence of hyperkalaemia in a 10-year-old girl. She presented with 2 weeks of vomiting, fatigue and weight loss. Her serum electrolytes obtained 1 week prior to presentation were normal, except for mild hyponatraemia at 131 mmol/L, which dropped to 112 mmol/L on admission. She had normal serum potassium, low-serum osmolality, with elevated urine sodium and osmolality, indistinguishable from syndrome of inappropriate antidiuretic hormone (SIADH). Subsequently, Addison's disease was diagnosed on the basis of gingival hyperpigmentation and undetectable cortisol on adrenocorticotropic hormone stimulation test. She rapidly responded to stress dose hydrocortisone, followed by hydrocortisone and fludrocortisone replacement therapy. The absence of hyperkalaemia in the presence of severe hyponatraemia cannot rule out Addison's disease in children. The mechanism of hypo-osmolar hyponatraemia in primary adrenal insufficiency and clinical clues to differentiate it from SIADH are discussed. PMID- 26021384 TI - Rowell's syndrome induced by terbinafine. AB - Terbinafine, a systemic antifungal commonly prescribed for onychomycosis (fungal infection involving the nails) has been reported to cause various cutaneous adverse effects. We describe an overlap syndrome between cutaneous lupus and erythaema multiforme induced by this medication with a review of other reported cases. PMID- 26021385 TI - Effect of Mg2+ and Al2+ Ions on Thermodynamic and Physiochemical Properties of Aspergillus niger Invertases. AB - In the present study, we reported for the first time the effect of various concentrations (0.5- 3.0 mM) of Mg(2+) and Al(3+) ions on the kinetics and thermodynamics of Aspergillus niger invertases for sucrose hydrolysis. We found that both metal ions enhanced the affinity of invertase for sucrose by decreasing the Km. In the presence of 0.5 mM Al(3+) ions invertase have maximum affinity for sucrose (Km = 0.00914 M sucrose). Invertase was activated by Mg(2+) ions at low concentrations (0.5-2.0 mM) and 341% increase in turnover (Kcat) and maximum decrease in DeltaG* was observed in the presence of 0.5 mM Mg(2+) ions. The entropy change for activation of substrate hydrolysis (DeltaS*) was increased by all concentrations of Mg(2+) ions and was highest (-94 J mol(-1) K(-1)) for invertases bound with 1.5 mM Mg(2+) ions. PMID- 26021386 TI - Characterization and cloning of an 11S globulin with hemagglutination activity from Murraya paniculata. AB - A ~56 kDa protein having hemagglutination activity was purified and characterized from the Murraya paniculata seeds. The gel electrophoresis studies demonstrated that protein is primarily of two different subunits, molecular weight ~ 35 and 21 kDa held together by disulfide-linkages and predominantly by secondary forces. The cloning and sequence analysis revealed that the protein exhibited a substantial sequence identity to seed storage 11S globulin family proteins. The sequence analysis of Murraya paniculata globulin (MPG) demonstrated higher and lower molecular weight polypeptides to be acidic (alpha) and basic (beta) respectively. The sequence analysis further showed that it possesses a characteristic bi-cupin motif and a putative metal binding pocket. CD analysis revealed that the MPG was a beta/alpha protein with a slightly higher content of the former. Conformational changes in protein have been studied by fluorescence spectrometry by using various chemical treatments. The results demonstrated that MPG belongs to 11S globulin family and exhibit's hemagglutination activity, which implicates it to be possessing lectin-like property. PMID- 26021387 TI - Current approaches to the diagnosis and treatment of white sponge nevus. AB - White sponge nevus (WSN) in the oral mucosa is a rare autosomal dominant genetic disease. The involved mucosa is white or greyish, thickened, folded and spongy. The genes associated with WSN include mutant cytokeratin keratin 4 (KRT4) and keratin 13 (KRT13). In recent years, new cases of WSN and associated mutations have been reported. Here, we summarise the recent progress in our understanding of WSN, including clinical reports, genetics, animal models, treatment, pathogenic mechanisms and future directions. Gene-based diagnosis and gene therapy for WSN may become available in the near future and could provide a reference and instruction for treating other KRT-associated diseases. PMID- 26021388 TI - Computed tomography in the preoperative study of portal hypertension. PMID- 26021389 TI - Repeat resection leads to long-term survival: analysis of 10-year follow-up of patients with colorectal liver metastases. AB - BACKGROUND: Some reports have shown that a significant number of patients experience recurrence, even after 5 or more years after surgery for colorectal liver metastases (CLMs). This study aimed to determine the actual cure rate and identify clinical characteristics among long-term survivors. METHODS: A prospectively maintained database was used to retrospectively review patients who underwent liver resection for CLM between 1994 and 2001. RESULTS: A total of 130 patients underwent liver resection for CLM with a complete 10-year follow-up. The 10-year disease-specific survival rate was 31.1%, and the survival curve reached a plateau after 10 years from the time of hepatic resection. There were 35 actual 10-year survivors. Multivariate analysis revealed that female patients and those with negative surgical margins were independent prognostic factors for disease specific survival. CONCLUSION: A 10-year survival following initial hepatectomy should be defined as cure. PMID- 26021390 TI - Bilateral Renal Autotransplantation May Be an Effective and Definitive Treatment in Case of Loin Pain Haematuria Syndrome. AB - Loin pain haematuria (LPHS) is a rare and difficult-to-diagnose syndrome. Different therapeutic approaches have been used historically with little or no success. We report a case of LPHS in which bilateral renal autotransplantation led to pain relief, cessation of all medication and no recurrence beyond two years of follow-up. PMID- 26021392 TI - Management of disasters and complex emergencies in Africa: The challenges and constraints. AB - Natural and man-made catastrophes have caused significant destruction and loss of lives throughout human history. Disasters accompany a wide variety of events with multiple causes and consequences often leading to a cascade of related events. African continent has not been spared of these events. A new phenomenon in the continent is terrorism that is fuelled by globalization of arms trade and has contributed significantly to escalation of conflicts in sub-Saharan Africa (SSA) resulting in complex emergencies and destruction of socioeconomic structures. The aim of this paper is to review relevant papers on management of disasters and complex emergencies in Africa and the challenges and constraints against the background of a weakened health system. Systematic search of published literature was conducted between 1990 and 2013. Grey literature (technical reports, government documents), published peer review journals, abstracts, relevant books and internet articles were reviewed. The review revealed that the frequency of both natural and man-made disasters in Africa is escalating. Complex emergencies are also on the increase since the Rwandan crisis in 1994. The impact of these events has overstretched and overwhelmed the health care system that is least prepared to handle and cope with the surge capacity and also render normal services. In conclusion, there is an urgent need for national emergency agencies/departments across Africa to develop a robust emergency preparedness and response plan. Every hospital most have a disaster management committee with flexible disaster management plan to respond to these catastrophes. There is a need for curriculum review in tertiary institutions across SSA to introduce and or expand training in disaster management. PMID- 26021393 TI - Relationship between ultrasound estimated fetal gestational age and cerebellar appearance in healthy pregnant Nigerian women. AB - BACKGROUND: Fetal biometry by ultrasound provides reliable and important information about fetal growth and wellbeing. Evaluation of the fetal posterior fossa is useful in the assessment of neural tube-defects. Studies on normal ultrasound fetal cerebellar appearance and diameter across gestational age (GA) are scanty in the Nigerian medical literature. This study was carried out to study normal fetal cerebellar appearance and diameter at various GAs among healthy pregnant Nigerian Africans. MATERIALS AND METHODS: This was a prospective study of 450 healthy singleton pregnant women between 13 and 42 weeks gestation. A curvilinear probe with a 3.5 MHz transducer of a SonoAce X6 (Medison Inc., Korea 2010) scanner was used to assess fetal transcerebellar diameter (TCD) and appearance. GA was also determined using fetal biometric parameters such as the biparietal diameter, femur length, and abdominal circumference. Fetal cerebellar appearance was correlated against GA. RESULTS: The cerebellar appearance was graded into: Grade I: 164 fetuses (36.4%), Grade II; 102 fetuses (22.7%) and Grade III: 184 fetuses (40.9%). Mean GA and TCD was 21 weeks and 21.2 mm for Grade I; 28 weeks and 32.6 mm for Grade II; and 35 weeks and 47.1 mm for Grade III. There was significance difference among the cerebellar grades at the GA groups and transverse cerebellar diameter (P < 0.000). CONCLUSION: There is a gradual and steady change in ultrasonographic appearance of the fetal cerebellar and diameter appearance with advancing gestation. The changes ranged from anechoic, "pair of eye glass" appearance at second trimester to relatively echogenic, "dumb-bell" appearance at early third trimester, and solid, "fan shape" in late third trimester. PMID- 26021394 TI - Screening for risk factors of chronic kidney disease in a community in Niger Delta Nigeria. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with many traditional and nontraditional risk factors. Screening for these risk factors has been associated with appropriate interventions and preventive measures in the management of CKD. The aims and objective of this study are to screen for risk factors of CKD in a Niger Delta community in Nigeria. SUBJECTS AND METHODS: This was a cross sectional study. The study location was Ido, a Niger Delta community in Rivers State. All subjects aged 18 years and above who gave consent were recruited for the study. Their bio data, relevant medical history, clinical and laboratory parameters were documented. The obtained data were analyzed with SPSS versions 17.0. RESULTS: A total of 105 persons participated in the study. The age range was 18-86 years, 50.5% were above 50 years. Females were 75.0%, 66.7% had either primary or no education, 14.6% were retiree and 40.4% were traders. 14.1% were known hypertensive, and 39.4% had elevated blood pressure. 6.1% were known diabetic and 6.1% had random blood sugar of 200 mg/dl and above. 27.2% of subjects were obese. About 10.5% and 27.8% had a history of significant intake of tobacco and alcohol respectively. Total serum cholesterol was higher than 200 mg/dl in 51.5%. None of the participants had past or family history of kidney disease. CONCLUSION: The prevalence of risk factors for CKD in the Niger Delta community is high. PMID- 26021395 TI - Combined spinal-epidural analgesia for laboring parturients in a Nigerian Hospital. AB - BACKGROUND: Awareness and demand for neuraxial pain relief for labor are on the increase, but epidural technique appears to be the preferred option among anesthetists in Nigeria. We describe our experience with combined spinal-epidural (CSE) analgesia to fill the gap in knowledge in order to boost its utilization. MATERIALS AND METHODS: In this retrospective observational study, data were collected from the obstetric analgesia proforma completed for all CSE analgesia performed for labor pain relief between January 1, 2011 and June 30, 2014. RESULTS: Thirty parturients (21 nulliparous: 9 parous) with a singleton gestation in labor with a mean age of 31.0 +/- 4.1 years were studied. In all, 56.7% of parturients requested for analgesia following oxytocin augmentation. The overall mean onset of analgesia and cervical os dilatation at initiation of analgesia were 2.23 +/- 0.43 min and 3.4 +/- 1.3 cm respectively, with no significant difference between groups. Overall analgesia was adequate in 90% of cases, and 76.7% had spontaneous vaginal delivery; although only nulliparous parturients (23.3%) had cesarean delivery, it was not significant (P = 0.07). There was a significant difference in Apgar score at 1-min between nulliparous and parous groups (7.7 vs. 8.9; P = 0.03), but no difference at 5-min. The side effects observed were vomiting and shivering. CONCLUSION: CSE technique can be safely used in every laboring parturient irrespective of parity either in early or late labor situations. PMID- 26021391 TI - Rodent models and mechanisms of voluntary binge-like ethanol consumption: Examples, opportunities, and strategies for preclinical research. AB - Binge ethanol consumption has widespread negative consequences for global public health. Rodent models offer exceptional power to explore the neurobiology underlying and affected by binge-like drinking as well as target potential prevention, intervention, and treatment strategies. An important characteristic of these models is their ability to consistently produce pharmacologically relevant blood ethanol concentration. This review examines the current available rodent models of voluntary, pre-dependent binge-like ethanol consumption and their utility in various research strategies. Studies have demonstrated that a diverse array of neurotransmitters regulate binge-like drinking, resembling some findings from other drinking models. Furthermore, repeated binge-like drinking recruits neuroadaptive mechanisms in mesolimbocortical reward circuitry. New opportunities that these models offer in the current context of mechanistic research are also discussed. PMID- 26021396 TI - Management of salivary gland tumors in a Nigerian tertiary institution. AB - BACKGROUND: The salivary glands consist of three major paired glands (the parotid, submandibular and sublingual) as well as numerous minor salivary glands, situated mostly in the oral cavity but also found in the pharynx, larynx, trachea, and sinuses. Tumours of salivary glands show a wide variety of pathologic types varying from benign to malignant. More salivary gland tumours are benign than malignant. PATIENTS AND METHODS: Data for this study were obtained from retrospective survey of case notes of all patients with Salivary gland tumours seen at the Maxillofacial Unit, Ahmadu Bello University Teaching Hospital, Shika, Zaria between January 2003 and August 2013. RESULTS: There were 135 patients 73 (54.1%) females and 62 (45.9%) males within the age range of 2.5 to 80 years (41.85 years). Thirty nine (28.9%) were benign while 96 (71.1%) were malignant. Major salivary glands were involved in 60.7% of tumours; the rest 39.3% involved minor salivary glands. Pleomorphic adenoma (86.7%) formed the bulk of benign tumours while adenoid cystic carcinoma (47.5%) was the predominant malignant tumour of salivary glands. Of 135 patients (n=,57.1% had surgery in our institution and were followed up. Those with malignancy also benefited from radiotherapy, chemotherapy or palliative oncology treatment. CONCLUSION: Management of salivary glands tumours in our environment is a challenge due to late presentation and the size of the tumour. PMID- 26021397 TI - Combined microsurgical extra-axial and transcortical transventricular endoscopic excision of parasellar tumors with ventricular extension. AB - Sella/parasellar tumors with intraventricular extension present unique neurosurgical challenges in achieving gross total resection with minimal morbidity and mortality. Firm attachment of large tumors, especially craniopharyngiomas, in this location to critical structures, makes the goal of complete microsurgical resection more difficult to attain. Several traditional surgical approaches are available. We report two patients who had novel combination of the traditional extra-axial microsurgical and transcortical transventricular endoscopic approaches to resect sellar/suprasellar tumors with intraventricular extension as either staged or simultaneous procedures. PMID- 26021398 TI - Barriers to HIV treatment adherence: Perspectives from the nonadherent at a treatment center in South-South, Nigeria. PMID- 26021399 TI - Condom use among people living with HIV/AIDS. PMID- 26021400 TI - Thiopentone sodium and propofol for facilitation of laryngeal mask airway insertion. PMID- 26021401 TI - Advances in emerging drugs for osteosarcoma. AB - INTRODUCTION: Osteosarcoma (OS), the most common primary malignant bone tumor, is currently treated with pre- and postoperative chemotherapy in association with the surgical removal of the tumor. Conventional treatments allow to cure about 60 - 65% of patients with primary tumors and only 20 - 25% of patients with recurrent disease. New treatment approaches and drugs are therefore highly warranted to improve prognosis. AREAS COVERED: This review focuses on the therapeutic approaches that are under development or clinical evaluation in OS. Information was obtained from different and continuously updated data bases, as well as from literature searches, in which particular relevance was given to reports and reviews on new targeted therapies under clinical investigation in high-grade OS. EXPERT OPINION: OS is a heterogeneous tumor, with a great variability in treatment response between patients. It is therefore unlikely that a single therapeutic tool will be uniformly successful for all OS patients. This claims for the validation of new treatment approaches together with biologic/(pharmaco)genetic markers, which may select the most appropriate subgroup of patients for each treatment approach. Since some promising novel agents and treatment strategies are currently tested in Phase I/II/III clinical trials, we may hope that new therapies with superior efficacy and safety profiles will be identified in the next few years. PMID- 26021402 TI - [Maximizing return on investment for public health with open-source medical hardware]. PMID- 26021403 TI - Peptide-Conjugated Fluorescent Silicon Nanoparticles Enabling Simultaneous Tracking and Specific Destruction of Cancer Cells. AB - We herein introduce a kind of fluorescent silicon nanoparticles (SiNPs) bioprobes, that is, peptides-conjugated SiNPs, which simultaneously feature small sizes (<10 nm), biological functionality, and stable and strong fluorescence (photoluminescent quantum yield (PLQY): ~28%), as well as favorable biocompatibility. Taking advantage of these merits, we further demonstrate such resultant SiNPs bioprobes are superbly suitable for real-time immunofluorescence imaging of cancer cells. Meanwhile, malignant tumor cells could be specifically destroyed by the peptides-conjugated SiNPs, suggesting potential promise of simultaneous detection and treatment of cancer cells. PMID- 26021404 TI - Exploring Diversification as A Management Strategy in Substance Use Disorder Treatment Organizations. AB - Implementation of the Affordable Care Act (ACA) creates both environmental uncertainties and opportunities for substance use disorder (SUD) treatment providers. One managerial response to uncertainties and emergent opportunities is strategic diversification of various dimensions of organizational activity. This paper explored organizational outcomes related to diversification of funding sources, services offered, and referral sources in a national sample of 590 SUD treatment organizations. Funding diversification was related to higher average levels of census, organization size, and recent expansion of operations. Service diversification was related to higher average levels of use of medication assisted treatment (MAT), organization size, and expansion. Referral source diversification was related only to greater average use of MAT. Overall, strategic diversification in the three areas explored was related to positive organizational outcomes. Considering alternative strategies of diversification may help position SUD treatment centers to deliver more innovative treatments such as MAT as well as enhance capacity to satisfy current unmet treatment needs of individuals with behavioral health coverage provided under the ACA. PMID- 26021405 TI - Adolescent Substance Treatment Engagement Questionnaire for Incarcerated Teens. AB - BACKGROUND: Treatment engagement is often measured in terms of treatment retention and drop out, resource utilization, and missed appointments. Since persons may regularly attend treatment sessions but not pay close attention, actively participate, or comply with the program, attendance may not reflect the level of effort put into treatment. Teens in correctional settings may feel coerced to attend treatment, making it necessary to develop measures of treatment involvement beyond attendance. This study describes the development and validation of the Adolescent Substance Treatment Engagement Questionnaire (ASTEQ), Teen and Counselor versions. METHODS: The psychometric properties of the ASTEQ were examined in a sample of incarcerated teens (N = 205) and their counselors. Principal component analysis was conducted on teen and counselor versions of the questionnaire. RESULTS: Scales of positive and negative treatment engagement were found, reflecting both overt behaviors (joking around, talking to others) and attitudes (interest in change). Significant correlations with constructs related to treatment attitudes and behaviors, and misbehaviors (including substance use) demonstrate good concurrent and predictive validity. Teen and counselor ratings of engagement produced validity correlations in the medium effect size range. CONCLUSIONS: These measures comprise a valid and reliable method for measuring treatment engagement for incarcerated teens. PMID- 26021406 TI - A framework for developing rural academic general practices: a qualitative case study in rural Victoria. AB - INTRODUCTION: There is increasing pressure for Australian rural general practices to engage in educational delivery as a means of addressing workforce issues and accommodating substantial increases in learners. For practices that have now developed a strong focus on education, there is the challenge to complement this by engaging in research activity. This study develops a rural academic general practice framework to assist rural practices in developing both comprehensive educational activity and a strong research focus thus moving towards functioning as mature academic units. METHODS: A case study research design was used with the unit of analysis at the level of the rural general practice. Purposively sampled practices were recruited and individual interviews conducted with staff (supervisors, practice managers, nurses), learners (medical students, interns and registrars) and patients. Three practices hosted 'multi-level learners', two practices hosted one learner group and one had no learners. Forty-four individual interviews were conducted with staff, learners and patients. Audio recordings were transcribed for thematic analysis. After initial inductive coding, deductive analysis was undertaken with reference to recent literature and the expertise of the research team resulting in the rural academic general practice framework. RESULTS: Three key themes emerged with embedded subthemes. For the first theme, organisational considerations, subthemes were values/vision/culture, patient population and clinical services, staffing, physical infrastructure/equipment, funding streams and governance. For the second theme, educational considerations, subthemes were processes, clinical supervision, educational networks and learner presence. Third, for research considerations, there were the subthemes of attitude to research and research activity. The framework maps the development of a rural academic practice across these themes in four progressive stages: beginning, emerging, consolidating and established. CONCLUSIONS: The data enabled a framework to be constructed to map rural general practice activity with respect to activity characteristic of an academic general practice. The framework offers guidance to practices seeking to transition towards becoming a mature academic practice. The framework also offers guidance to educational institutions and funding bodies to support the development of academic activity in rural general practices. The strengths and limitations of the study design are outlined. PMID- 26021407 TI - Glomerular structure in diabetes - can it predict the future? PMID- 26021408 TI - Percutaneous endovascular treatment of peripheral arterial disease in Germany. AB - PURPOSE: The general distribution of balloon angioplasty, stenting and other endovascular interventions in treating peripheral arterial disease (PAD) is unclear. METHODS AND RESULTS: We used national statistics (DRG statistics) published by the Federal Statistical Office including data from almost all hospitals in Germany to calculate the rates and types of lower extremity endovascular procedures in 2012. In 2012 150,503 peripheral endovascular procedures were documented in Germany. The predominant procedures were percutaneous transluminal angioplasty (PTA) with 86.0% followed by thrombolysis with 7.2% and thrombectomy with 2.9%. In 50,092 (33.3%) of all peripheral endovascular procedures performed in the lower limb arteries a stent was placed: 66.7% in iliac, 34.3% in femoro-popliteal and 9.7% in cruro-pedal procedures. From these 50,092 procedures DES were coded in 3063 (6.1%) and covered stents in 1841 (3.7%). The highest rate of covered stents was placed in the aorta (8.6%) but the highest rate of DES was in the cruro-pedal arteries (23.1%). CONCLUSION: Pure PTA is still the most frequently performed procedure in peripheral arteries and in only one third of all procedures was a stent placed in Germany in 2012. PMID- 26021411 TI - Spatially coupled catalytic ignition of CO oxidation on Pt: mesoscopic versus nano-scale. AB - Spatial coupling during catalytic ignition of CO oxidation on MUm-sized Pt(hkl) domains of a polycrystalline Pt foil has been studied in situ by PEEM (photoemission electron microscopy) in the 10(-5) mbar pressure range. The same reaction has been examined under similar conditions by FIM (field ion microscopy) on nm-sized Pt(hkl) facets of a Pt nanotip. Proper orthogonal decomposition (POD) of the digitized FIM images has been employed to analyze spatiotemporal dynamics of catalytic ignition. The results show the essential role of the sample size and of the morphology of the domain (facet) boundary in the spatial coupling in CO oxidation. PMID- 26021410 TI - In vivo Monitoring of Cerebral Hemodynamics in the Immature Rat: Effects of Hypoxia-Ischemia and Hypothermia. AB - BACKGROUND: Neonatal hypoxic-ischemic (HI) encephalopathy occurs in 1-4 per 1,000 live term births and can cause devastating neurodevelopmental disabilities. Currently, therapeutic hypothermia (TH) is the only treatment with proven efficacy. Since TH is associated with decreased cerebral metabolism and cerebral blood flow (CBF), it is important to assess CBF at the bedside. Diffuse correlation spectroscopy (DCS) has emerged as a promising optical modality to noninvasively assess an index of CBF (CBFi) in both humans and animals. In this initial descriptive study, we employ DCS to monitor the evolution of CBFi following HI with or without TH in immature rats. We investigate potential relationships between CBF and subsequent cerebral damage. METHODS: HI was induced on postnatal day 10 or 11 rat pups by right common carotid artery ligation followed by 60-70 min hypoxia (8% oxygen). After HI, the pups recovered for 4 h under hypothermia (HI-TH group, n = 23) or normothermia (HI-N group, n = 23). Bilateral measurements of hemispheric CBFi were made with DCS in unanesthetized animals at baseline, before HI, and 0, 1, 2, 3, 4, 5, and 24 h after HI. The animals were sacrificed at either 1 or 4 weeks, and brain injury was scored on an ordinal scale of 0-5 (0 = no injury). RESULTS: Carotid ligation caused moderate bilateral decreases in CBFi. Following HI, an initial hyperemia was observed that was more prominent in the contralateral hemisphere. After initiation of TH, CBFi dropped significantly below baseline levels and remained reduced for the duration of TH. In contrast, CBFi in the HI-N group was not significantly decreased from baseline levels. Reductions in CBFi after 4 h of TH were not associated with reduced damage at 1 or 4 weeks. However, elevated ipsilateral CBFi and ipsilateral-to-contralateral CBFi ratios at 24 h were associated with worse outcome at 1 week after HI. CONCLUSIONS: Both HI and TH alter CBFi, with significant differences in CBFi between hypothermic and normothermic groups after HI. CBFi may be a useful biomarker of subsequent cerebral damage. PMID- 26021412 TI - About the Therapy of Laryngotracheitis (Croup): Significance of Rectal Dosage Forms. AB - Glucocorticoids are drugs of choice for treatment of laryngotracheitis (croup). They may be administered orally as tablets or juice, locally as inhalation or rectally as suppository or capsule. If doctors decide to use a rectal administration for practical reasons, it is obvious from a pharmacokinetic and pharmacodynamic point of view that prednisolone capsules have an earlier and stronger anti-inflammatory effect than a prednisone suppository. PMID- 26021413 TI - Analytical and clinical evaluation of a new immunoassay for therapeutic drug monitoring of etanercept. PMID- 26021415 TI - The WHO Surgical Safety Checklist : an Innovative or an Irrelevant Tool ? PMID- 26021414 TI - Surgical safety checklists : an update. AB - Surgical safety checklists aim to improve patient safety by prompting the attention of the surgical team towards critical steps during the operation. The checklist's items are aimed to improve compliance with proven interventions, and to facilitate multidisciplinary communication and teamwork. Based on the current literature, corroborated by systematic reviews and meta-analysis, surgical safety checklists have a positive impact on communication and reduce postoperative complications including mortality. However, despite their effectiveness, the implementation of these checklists is not straightforward. Several determinants leading to behaviour were checklists are checked but not properly executed have been highlighted. As surgical safety checklists are in essence complex sociological interventions, they must be implemented accordingly. Key factors for the implementation of these checklists have been suggested in the literature, although, the most profound way of implementation remains unclear. PMID- 26021416 TI - Fighting human error : what surgeons can learn from aviators. AB - BACKGROUND: The rigorous implementation of safety policies have made air travel one of the safest modes of transport. Health institutions and hospital managing bodies increasingly adopt cues from aviation safety protocols and policies in an attempt to reduce medical errors and patient harm. Among hospital staff, surgeons are most likely to be confronted with these aviation-derived safety concepts. METHODS: This article aims to familiarize surgeons with the concepts and methodology of safety policies in modern aviation safety, many of which have been applied in the setting of surgery, or have potential to do so. We review the use of checklists, crew resource management, the sterile cockpit, blame free reporting and human fatigue. We discuss how these concepts can be translated to the operating room and illustrate their relevance through a comparative description of historical air accidents and surgical incidents from our own clinical experience. We also indicate relevant differences and similarities between flight crews and surgical teams and their respective infrastructures, as these may impede or facilitate the adoption of aviation safety policies. Finally, we offer some recommendations to effectively implement aviation safety policies in the operating room. PMID- 26021417 TI - A belgian multicenter prospective observational cohort study shows safe and efficient use of a composite mesh with incorporated oxidized regenerated cellulose in laparoscopic ventral hernia repair. AB - BACKGROUND: A variety of anti-adhesive composite mesh products have become available to use inside the peritoneal cavity. However, reimbursement of these meshes by the Belgian Governemental Health Agency (RIZIV/INAMI) can only be obtained after conducting a prospective study with at least one year of clinical follow-up. This -Belgian multicentric cohort study evaluated the experience with the use of Proceed(r)-mesh in laparoscopic ventral hernia repair. METHODS: During a 25 month period 210 adult patients underwent a laparoscopic primary or incisional hernia repair using an intra-abdominal placement of Proceed(r)-mesh. According to RIZIV/INAMI criteria recurrence rate after 1 year was the primary objective, while postoperative morbidity, including seroma formation, wound and mesh infections, quality of life and recurrences after 2 years were evaluated as secondary endpoints (NCT00572962). RESULTS: In total 97 primary ventral and 103 incisional hernias were repaired, of which 28 (13%) were recurrent. There were no conversions to open repair, no enterotomies, no mesh infections and no mortality. One year cumulative follow-up showed 10 recurrences (n = 192, 5.2%) and chronic discomfort or pain in 4.7% of the patients. Quality of life could not be analyzed due to incomplete data set. CONCLUSIONS: More than 5 years after introduction of this mesh to the market, this prospective multicentric study documents a favorable experience with the Proceed mesh in laparoscopic ventral hernia repair. However, it remains to be discussed whether reimbursement of these meshes in Belgium should be limited to the current strict criteria and therefore can only be obtained after at least 3-4 years of clinical data gathering and necessary follow-up. PMID- 26021418 TI - The quality of life in long-term breast cancer survivors with breast cancer related lymphedema. AB - AIM: To compare the health related quality of life (HRQOL) of long-term breast cancer survivors with and without breast cancer related lymphedema (BCRL) treated in the sentinel lymph node biopsy (SLNB) era. METHODS: HRQOL was assessed as subject of a secondary analysis of data gathered for a study evaluating the prevalence of BCRL in long-term breast cancer survivors. The 145 women in this study cohort had undergone SLNB and or axillary lymph node dissection (ALND) according to Dutch Breast cancer treatment guidelines. HRQOL was assessed using two questionnaires : the European Organization for Research and Treatment of Cancer Quality (QLQ-C30) and the Breast Cancer-specific Quality of life questionnaire (QLQ-BR23). RESULTS: Twenty-six women, of whom 5 only underwent SLNB, were identified with objectively measured lymphedema and/or self-perceived arm swelling. Patients with BCRL scored significantly lower on the social (p = 0.000) functioning scale after adjustment for BMI and age compared to women without BCRL. Compared to normative data, women with BCRL scored significantly lower on social- (p < 0.001) and role (p = 0.001) functioning scales. CONCLUSIONS: HRQOL in long-term breast cancer survivors with BCRL is structurally lower than of those without BCRL, even in this small cohort of cancer survivors treated in the SLNB-era. PMID- 26021419 TI - Malignant Pleural Mesothelioma : Rationale for a New TNM Classification. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with a poor prognosis. In this regard, a well-defined staging system is of utmost importance in order to correctly diagnose and assign an appropriate treatment to the patient. METHODS: The current TNM-staging system (7th edition) enables to either clinically or pathologically stage the severity of the disease according to extension of the tumor (T), number of nodes (N) and presence of metastases (M). Patients with stage I-III are considered for surgery, while palliative treatment is indicated for stage IV patients according to the current classification. RESULTS: Despite its widespread use, the validity of this staging system is questioned due to the low prevalence, histological variety and retrospective nature of the previous study design. In addition, the role of specific treatment modalities including surgery, has yet to be determined, especially for treatment of early-stage disease. In this regard, the International Association for the Study of Lung Cancer (IASLC) initiated the multi-centre, prospective "Mesothelioma Staging Project" in order to address limitations of the 7th edition and to optimize the staging system in accordance to current needs. CONCLUSIONS: An improved staging system will contribute to the design of prospective multi-institutional clinical trials investigating novel treatment strategies for mesothelioma. In this way comparison of outcome between different medical centres also becomes feasible. PMID- 26021420 TI - A new score to predict post operative complications after endovascular treatment of thoraco abdominal aortic aneurysms. AB - BACKGROUND: The endovascular treatment of thoraco abdominal aortic aneurysms (TAAA) is a minimally invasive solution. However, patient selection remains a major problem. We have analysed our experience to identify the risk factors for post-operative morbidity and mortality and to construct a scoring system to identify those patients likely to benefit from this treatment. METHODS: We have analysed a consecutive cohort of patients treated electively for TAAA using endovascular techniques between 2006 and October 2012. All data were collected prospectively. The risk factors associated with spinal cord ischemia (SCI), the need for post-operative dialysis and 30 day mortality were determined using multivariate statistical techniques and a logistic regression model including all variables that were significant on univariate analysis (p < 0.05). A predictive score was calculated using a Received Operating Characteristic (ROC) curve, defining best specificity and sensibility. RESULTS: We analysed the data from 123 patients (median age 70 years). The 30 day mortality rate was 8% (10 patients). The SCI rate was 6% (7 patients). One patient (1%) required long-term dialysis after the aortic procedure. The cumulative early mortality, SCI and permanent dialysis rate was 14% (17 patients). In multivariate analysis, adverse outcome was associated with advanced age (OR = 1.110 ; p = 0.022), and Crawford type I or II or III (OR = 9.292 ; p = 0.002) as compared with Crawford type IV. Pre operative beta blocker (BB) treatment was a protective factor (OR = 0.099 ; p = 0.005). A predictive score was then constructed : Score = -10.060 + 0.104x(A) +2.229x(B) -2.315x(C) (A = patient age ; B = 1 if TAAA Crawford type 1, 2 or 3, 0 if TAAA type 4 ; C = 1 if on-going BB treatment (30 days pre-surgery minimum), 0 if none). Its sensitivity and specificity were 88% and 89% respectively. CONCLUSIONS: We propose a simple predictive scoring system. This tool is useful in predicting the most feared complications after endovascular TAAA repair and has potential use in the identification and counselling of vulnerable patients being considered for surgery. More data are needed to refine the prediction of individual operative risks. PMID- 26021421 TI - Endovenous Laser Ablation of the Great Saphenous Vein with a 1470 nm Wavelength Laser : Results of a Prospective, Single Centre Cohort Study. AB - BACKGROUND: Endovenous laser ablation (EVLA) is a widely accepted treatment for venous insufficiency. Our aim was to report the standardised technique used in our centre and to evaluate the anatomic and clinical success rates. METHODS: All details of patients treated with EVLA were prospectively collected in a database. A standardized examination and surgical protocol was used, and every detail in the technique was registered. A follow-up visit was organised after 1 week and after 4-6 weeks with a duplex. RESULTS: A total of 441 limbs were treated in 366 patients using a 1470 nm wavelength laser with bare tip fiber -(Biolitec((r))). At 6 weeks postoperative a total obliteration of the vein was established in 98.62% of the cases with 78.67% of the patients free from complaints. No major complications were reported. Minor complaints were low (10.74% induration, 3.9% paresthesia). 93.11% reported no pain, 5.2% mentioned moderate pain. Mean duration of absence was equal or less than 1 week (65,28%). Satisfaction level was high (92.84%, level 10). CONCLUSIONS: EVLA of the GSV and the Anterior Accessory Vein (AAV) with a 1470 nm wavelength laser with bare tip fiber is a minimally invasive, safe and effective technique. We are convinced that every detail is important : tumescence technique, Trendelenburg position, no external compression, and the position of the vein in the fascial sheath. Further reduction of linear endovenous energy density (LEED) used for EVLA can improve the therapy. This is possible by using a new fiber tip design (radial optical fiber) and needs further investigation. PMID- 26021422 TI - Injection of a sclerosing agent as first line treatment in anal fissure. AB - BACKGROUND: In our institution, the first line treatment in acute anal fissures (AAF) or chronic anal fissures (CAF) is the injection of a sclerosing agent consisting of phenol, menthol and peanut oil (Phenomen(r), Sterop laboratory, Belgium) under the fissure after a local anaesthesia. This retrospective study presents the technique of injection, evaluates its efficacy and demonstrates the minimal occurrence of complications, continence problems and recurrences. METHODS: 129 patients with an anal fissure were treated between January 2010 and June 2011. 124 patients were reviewed retrospectively. 109 patients benefited from a sclerosis in our outpatient clinic. RESULTS: Of the 109 patients treated by a sclerosis, 58 had an AAF and 51 had a CAF. 53/58 AAF (91.4%) healed and 40/51 CAF (78.4%). Duration of pain after injection was 2 days or less in 55 cases (50.4%), 1 week or less in 35 cases (32.2%) and more than 1 week in 19 cases (17.4%). The complication rate was low (2.7%) : 2 necrosis of the skin and 1 abscess at the site of injection. The rate of troubles of continence was 2.7% : 2 cases of soiling and 1 case of incon-tinence for gas all resolving within a month. At the end of the study, a fissure had recurred in 17 patients (15.6%). CONCLUSIONS: The injection of a sclerosing agent under the fissure is performed in the practitioner's office. Healing rates are high, complications and recurrences are low. This therapeutic option may be a good alternative to classical treatments in case of anal fissures. PMID- 26021423 TI - Whole natal cleft excision and flap : an alternative surgical method in extensive sacrococcygeal pilonidal sinus disease. AB - BACKGROUND: Pilonidal sinus disease (PSD) is a benign disease caused by hair follicles in sacrococcygeal -region. Despite the use of different methods in treatment, there is no consensus reached for treatment modalities. In this study, we used a whole natal cleft excision and flap (WNCEF) method to remove the natal cleft in cases of extensive sacrococcygeal PSD. METHODS: 243 patients with PSD were evaluated retrospectively. 47 patients with extensive sacrococcygeal PSD were included in the study. In these patients, the natal cleft was excised by using a whole natal cleft excision and flap -(WNCEF) method which was performed by an incision to include all the natal cleft (Kite incision) and the remaining defect was closed with a single fasciocutaneous flap by sliding along the midline intergluteal sulcus. RESULTS: The mean age of patients was 25.7 years (17-43). The average hospital stay of patients was 2.7 days (2-4), mean operative time was 59 min (35-80), mean duration of drain removal was 2.7 days (2-4), mean postoperative follow-up was 16.4 months (3-24) and mean BMI was 26.9 (22-30). Flap edema occured in one patient (2.1%), seroma in three patients (6.3%) and surgical site infection requiring re-use of antibiotics were observed in two patients (4.2%). Flap -necrosis and failure did not occur in our patients. No recurrence was observed in any patient during an average follow-up of 16 months. CONCLUSIONS: In sacrococcygeal PSD treatment, removal of the natal cleft with Kite incision by WNCEF method and shifting of the midline completely are thought to be an effective method that can reduce recurrence. PMID- 26021424 TI - Late diagnosis of intestinal malrotation treated with gastrojejunal bypass : a case report. AB - We report the case of a male African patient who presented at day 8 of life with recurrent episodes of proximal small intestine occlusion, which was treated conservatively, because of misdiagnosis. Physical and cognitive development was normal throughout with, however, some episodes of stagnation. At the age of 15 years the recurrence of symptoms, not responding to the current conservative treatment, resulted in severe weight loss with BMI at 11 kg/m(2). The oesogastroduodenal barium study disclosed an extrinsic duodenal compression compatible with a congenital duodenal band. Because of the major concerns related to the patient and to the medical environment, jejunostomy for feeding was first performed to improve his weight. A year later the intestinal malrotation was cured by gastrojejunal bypass. The postoperative clinical course was favorable. The patient resumed a normal life and schooling. His BMI is currently 21.5 kg/m(2). PMID- 26021425 TI - Sigmoid Resection with Primary Anastomosis for Uncomplicated Giant Colonic Diverticulum : a Report of two Cases. AB - Giant colonic diverticulum (GCD) is a rare complication of colonic diverticulosis. A small number of cases has been reported in the literature. Patients with GCD have often few non-specific symptoms. Unfortunately, severe complications exist and may lead to surgical acute abdomen. Therefore, this complication of the diverticular disease must be known and properly treated. There is no gold standard diagnostic test, but an air-fluid or air-filled, rounded, pseudocystic image in relation with the colonic wall in a patient with colonic diverticula should suggest this diagnosis to the clinician. We report two cases of a 70-year-old male patient and a 44-year-old female patient having a giant sigmoid diverticulum. The treatment of choice of an uncomplicated GCD is an elective colonic resection, including the giant -diverticulum, with primary anastomosis ; while in case of complicated GCD (peritonitis, abscess or complex fistula), a two-stage resection should be considered. PMID- 26021426 TI - Recurrent invasive thymoma with pleural dissemination : disease management and treatment possibilities. AB - Thymoma is the most common benign neoplasm of the anterior mediastinum presenting often an agressive behaviour typical for the malignants tumors. The rate of invasive thymoma recurrency is relatively high. We present the case of a 55-year old man with a recurrent invasive thymoma with a pleural dissemination, detected on CT-imaging 2 years following his primary surgery. Since the first pre operative imaging studies showed no invasion of the adjacent organs and a thymoma was suspected, a surgical resection was decided as a first line treatment. Per operatively a number of adjacent structures were invaded and despite a macroscopical RO resection, the margins were microscopically positive. An invasive thymoma, WHO classification B3, Masaoka stage IVb was diagnosed and the patient received adjuvant radiotherapy. We highlight the role of multimodality treatement and disscus the potential of surgical, radiotherapeutical and systemic therapy in stage IV thymoma as well as in recurrent disease. PMID- 26021427 TI - Femoral vein injury managed by in situ saphenous vein bypass : a case report. AB - Injured veins of the lower limbs may cause massive haemorrhage requiring early control. Operative management of injured veins remains a controversial topic and reconstruction or ligation depends on venous and adjacent tissue damage. Nevertheless, venous reconstruction seems to reduce the complications of venous ligation. The case of a 33 year old women with a venous wound to the right groin is presented. Surgical management consisted of controlling the bleeding and venous revascularisation with an in situ saphenous vein bypass to substitute the injured femoral vein. The patient had an uneventful postoperative period without any complications. The case demonstrates this method of vascular venous repair is the preferable one. PMID- 26021428 TI - Surgery during world war I : a great breakthrough of techniques. PMID- 26021429 TI - Single-port Laparoscopic Total Hysterectomy and Bilateral Salpingo-oopherectomy Combined with Burch Colposuspension. AB - Recently, scarless surgery has become a widely used surgical technique and many laparoscopic surgeons have attempted to reduce incisional morbidity and improve cosmetic outcomes by using fewer and smaller ports. Laparoscopic combined procedures permit simultaneous treatments for multiple pathologies. In single time anaesthesia, these combined minimally invasive procedures gives the advantages of less pain and morbidity, faster recovery and shorter hospital stay. Moreover, these combined procedures can be performed with a single incision and can have additional benefits for the patients and the hospital. Here we describe a single port laparoscopic total hysterectomy and bilateral salpingo-oopherectomy combined with Burch colposuspension. The operation was completed laparoscopically with single port, without intra-operative or postoperative complications, in a single session. The patient was discharged the following morning. With a single incision multidisciplinary laparoscopic approaches can offer suitable, effective and safe treatments. PMID- 26021430 TI - Revisiting Clinical Utility of Chest Radiography and Electrocardiogram to Determine Ischemic Stroke Subtypes: Special Reference on Vascular Pedicle Width and Maximal P-Wave Duration. AB - BACKGROUNDS: It is often difficult to diagnose stroke subtypes at admission, particularly in sinus rhythm cases. Vascular pedicle width (VPW) on chest X-ray (CXR) and maximal P-wave duration (P-max) on electrocardiogram (ECG) are again realized as useful parameters reflecting intravascular volume and atrial conduction status, respectively. We investigated the utility of VPW and P-max as a tool for differentiating ischemic stroke subtypes. METHODS: We studied 343 acute stroke patients showing sinus rhythm on admission. Dividing the patients into cardioembolic (CE) stroke (n = 57) and non-CE (n = 286) groups, we compared clinical backgrounds including VPW on CXR, and P-max in lead II and premature atrial contraction (PAC) on 12-leads ECG. Then, we investigated the independent factors for CE. RESULTS: Independent factors associated with CE were VPW (>=59.3 mm) (p < 0.001; odds ratio (OR), 10.12; 95% confidence interval (CI), 4.13-24.8), P-max in lead II (>=120 ms) (p < 0.001; OR, 8.61; 95% CI, 3.96-18.7), PAC (p = 0.002; OR, 7.35; 95% CI, 2.14-25.3) and D-dimer level (>=1.11 ug/ml) (p = 0.016; OR, 2.57; 95% CI, 1.20-5.51). CONCLUSIONS: VPW, P-max, PAC and D-dimer are useful parameters for diagnosing CE stroke in patients with sinus rhythm at admission. PMID- 26021431 TI - Adsorption characteristics of amino acids on to calcium oxalate. AB - Adsorption of amino acids on to calcium oxalate found in urinary calculus has been studied and the adsorption characteristics were analyzed. Pseudo-first order, pseudo-second-order and intraparticle diffusion models were used to fit the kinetics data. The pseudo-second-order model best described the dynamic behavior of the adsorption process. The uptake of glutamic acid and aspartic acid were found to decrease as solution pH increasing from 4 to 8. The experimental data obtained at different pH conditions were analyzed and fitted by Langmuir, Freundlich, Redlich-Peterson, Temkin and Sips isotherm models using linear and nonlinear regression analysis. Error analysis (correlation coefficient, residual root mean square error and chi-square test) showed that the Langmuir I isotherm model and the non-linear form of Sips isotherm model should be primarily adopted for fitting the equilibrium data. The maximum adsorption capacity of glutamic acid and aspartic acid onto calcium oxalate monohydrate crystals are 0.059 and 0.066MUmol/g at pH 4, respectively. These studies have the vital significance for research aimed at exploring the role of urinary amino acids effect the formation process of calcium oxalate crystals found in urinary calculus and for potential application in the design of synthetic peptides used for urinary calculi therapy. PMID- 26021432 TI - The coupling of surface charge and boundary slip at the solid-liquid interface and their combined effect on fluid drag: A review. AB - Fluid drag of micro/nano fluidic systems has inspired wide scientific interest. Surface charge and boundary slip at the solid-liquid interface are believed to affect fluid drag. This review summarizes the recent studies on the coupling of surface charge and slip, and their combined effect on fluid drag at micro/nano scale. The effect of pH on surface charge of borosilicate glass and silica surfaces in deionized (DI) water and saline solution is discussed using a method based on colloidal probe atomic force microscopy (AFM). The boundary slip of various oil-solid interfaces are discussed for samples with different degrees of oleophobicity prepared by nanoparticle-binder system. By changing the pH of solution or applying an electric field, effect of surface charge on slip of a smooth hydrophobic octadecyltrichlorosilane (OTS) in DI water and saline solution is studied. A theoretical model incorporating the coupling relationship between surface charge and slip is used to discuss the combined effect of surface charge induced electric double layer (EDL) and slip on fluid drag of pressure-driven flow in a one-dimensional parallel-plates microchannel. A theoretical method is used to reduce the fluid drag. The studies show that the increasing magnitude of surface charge density leads to a decrease in slip length. The surface charge results in a larger fluid drag, and the coupling of surface charge and slip can further increase the fluid drag. Surface charge-induced EDLs with asymmetric zeta potentials can effectively reduce the fluid drag. PMID- 26021433 TI - Adsorption and oxidation of oxalic acid on anatase TiO2 (001) surface: A density functional theory study. AB - Anatase TiO2 (001) surfaces have attracted great interest for photo-degradation of organic species recently due to their high reactivity. In this work, adsorption properties and oxidation mechanisms of oxalic acid on the anatase TiO2 (001) surface have been theoretically investigated using the first-principles density functional theory. Various possible adsorption configurations are considered by diversifying the connectivity of carboxylic groups with the surface. It is found that the adsorption of oxalic acid on the anatase (001) surface prefer the dissociative states. A novel double-bidentate configuration has been found due to the structural match between oxalic acid and the (001) surface. More charge is transferred from the adsorbed oxalic acid to the surface with the double-bidentate configuration when comparing with other adsorption structures. Thus, there is a positive correlation relationship between the transferred charge amount and the interfacial bond numbers when oxalic acid adsorbs on the anatase TiO2 (001) surface. The adsorption energies with dispersion corrections have demonstrated that the van der Waals interactions play an important role in the adsorption, especially when adsorbates are close to the surface. PMID- 26021434 TI - Increasing aclarubicin dose in low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) is efficacious as salvage chemotherapy for relapsed/refractory mixed-phenotype acute leukemia. AB - We treated 60 relapsed/refractory mixed-phenotype acute leukemia patients (MPAL 1) with increasing the aclarubicin dose in CAG regimen (HD-CAG, cytarabine (10 mg/m(2)/12 h, days 1-14), aclarubicin (5-7 mg/m(2)/day, days 1-14), granulocyte colony-stimulating factor (200 MUg/m(2)/day, days 1-14). This was compared to 64 relapsed/refractory MPAL patients (MPAL-2) treated with DOAP regimen (daunorubicin, vincristine/vindesine, cytarabine and prednisone), 113 relapsed/refractory acute myeloid leukemia (AML) patients and 78 acute lymphocytic leukemia (ALL) patients treated with HD-CAG regimen. After one course, complete remission (CR) and overall response [OR, CR+partial remission (PR)] rates for MPAL-1 exceeded MPAL-2 (CR, 61.02% vs. 28.13%, P=0.000; OR, 72.88% vs. 34.38%, P=0.000), but these data were similar to AML and ALL (P>0.05). In MPAL-1 group, CR and OR rates of T-lymphoid+myeloid immunophenotype were higher than B-lymphoid+myeloid immunophenotype (CR, 81.82% vs. 44.12%, P=0.005; OR, 90.91% vs. 58.82%, P=0.009). The overall survival at 3 years in MPAL-1, MPAL 2, AML and ALL groups were 14.2%+/-6.8%, 14.1%+/-6.4%, 17.3%+/-5.0% and 15.0%+/ 5.3% (P>0.05). Side effects were similar between HD-CAG and DOAP (P>0.05). HD-CAG regimen is efficacious for relapsed/refractory MPAL, especially for T+My patients. PMID- 26021435 TI - Fighting cancer drug resistance: Opportunities and challenges for mutation specific EGFR inhibitors. AB - Multiple mutations in the EGFR gene are a major cause for the failure of Erlotinib and Gefitinib in the treatment of patients harboring non-small-cell lung cancer (NSCLC) who initially responded to this therapy. The development of these tyrosine kinase inhibitors (TKIs) is going back to the early 90s, where cancer was widely considered and fully treated as a disease of an organ. Fundamental gain of knowledge in cell biology in general and cancer genetics in particular led us to where we currently stand: cancer is a disease that originates in the genome. Fast and affordable gene sequencing paved the way and opened our eyes for the genetic instability of many cancers, particularly EGFR driven NSCLC. This might allow highly rational and personal therapies by aiming at a very particular wild type and mutant kinase pattern. However, the paradigm "one disease - one target - one drug" is currently challenged. Both activating and deactivating EGFR mutations are known to render the development of novel targeted drugs difficult. Among all lung adenocarcinomas, only 20% are driven by EGFR and only a subpopulation has an activating mutation (e.g. L858R), making them sensitive to first generation EGFR inhibitors. Unfortunately, most of them acquire second deactivating mutations (e.g. T790M) during treatment, leading to a complete loss of response. Are specific inhibitors of the double EGFR mutant L858R/T790M the magic bullet? Much scientific evidence but also high expectations justify this approach. Structural biology of EGFR mutants constitutes the basis for highly rational approaches. Second generation pan EGFR inhibitors inhibiting wild type (WT) and mutant EGFR like Afatinib suffer from dose-limiting adverse effects. Inhibition of WT EGFR is considered to be the culprit. Third generation EGFR inhibitors follow two strategies. Mutant selectivity and improved target residential time. These inhibitors display high mutant selectivity and irreversible binding patterns while sparing WT EGFR activity, hence enhancing tumor selectivity while minimizing adverse effects. Third generation EGFR inhibitors are still undergoing preclinical and clinical evaluation. The most advanced are Rociletinib and AZD9291 which displayed encouraging preliminary clinical phase II data regarding response and adverse effects. In the current review we show both a medicinal chemists' approach toward the design of third generation EGFR inhibitors as well as a detailed overview of the development of EGFR inhibitors over the last decade. High interdisciplinary approaches, such as structural biology and time-resolved tumor genetics pave the way toward the development of drugs that target EGFR mutants. This might lead to highly effective targeted and personalized therapies with enhanced response rates for a minor cohort of patients which have to undergo continuous gene sequencing, hence enabling therapies with tailor-made TKIs. PMID- 26021437 TI - The value of information: Current challenges in surveillance implementation. AB - Animal health surveillance is a complex activity that involves multiple stakeholders and provides decision support across sectors. Despite progress in the design of surveillance systems, some technical challenges remain, specifically for emerging hazards. Surveillance can also be impacted by political interests and costly consequences of case reporting, particularly in relation to international trade. Constraints on surveillance can therefore be of technical, economic and political nature. From an economic perspective, both surveillance and intervention are resource-using activities that are part of a mitigation strategy. Surveillance provides information for intervention decisions and thereby helps to offset negative effects of animal disease and to reduce the decision uncertainty associated with choices on disease control. It thus creates monetary and non-monetary benefits, both of which may be challenging to quantify. The technical relationships between surveillance, intervention and loss avoidance have not been established for most hazards despite being important consideration for investment decisions. Therefore, surveillance cannot just be maximised to minimise intervention costs. Economic appraisals of surveillance need to be done on a case by case basis for any hazard considering both surveillance and intervention performance, the losses avoided and the values attached to them. This can be achieved by using an evaluation approach which provides a systematic investigation of the worth or merit of surveillance activities. Evaluation is driven by a specific evaluation question which for surveillance systems commonly considers effectiveness, efficiency, implementation and/or compliance issues. More work is needed to provide guidance on the appropriate selection of evaluation attributes and general good practice in surveillance evaluation. Due to technical challenges, economic constraints and variable levels of capacity, the implementation of surveillance systems remains variable. Political and legal issues are also influential. A particular challenge exists during outbreaks when surveillance needs to be conducted under emergency conditions. Decision support systems can help make epidemiologically and economically sound choices amongst surveillance options. However, contingency planning is advisable so that pre defined options allow for rapid decision making. PMID- 26021436 TI - Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta analysis of 22 prospective studies. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA) inhibits the production of nitric oxide, a key regulator of the vascular tone, and may be important in the development of cardiovascular disease (CVD). Our aim was to reliably quantify the association of ADMA and its isomer symmetric dimethylarginine (SDMA) with the risk of CVD outcomes in long-term cohort studies. METHODS AND RESULTS: Data were collated from 22 prospective studies involving a total of 19 842 participants, which have recorded 2339 CVD, 997 coronary heart disease, and 467 stroke outcomes during a mean follow-up of 7.1 years. In a comparison of individuals in the top with those in the bottom third of baseline ADMA values, the combined risk ratios were 1.42 (95% confidence interval: 1.29 to 1.56) for CVD, 1.39 for coronary heart disease (1.19 to 1.62), and 1.60 for stroke (1.33 to 1.91). Broadly similar results were observed according to participants' baseline disease status (risk ratios for CVD: 1.35 [1.18 to 1.54] in general populations; 1.47 [1.16 to 1.87] in individuals with pre-existing CVD; and 1.52 [1.26 to 1.84] in individuals with pre-existing kidney disease) and by different study characteristics, including geographical location, sample type, assay method, number of incident outcomes, and level of statistical adjustment (all P values>0.05). In contrast, in 8 prospective studies involving 9070 participants and 848 outcomes, the corresponding estimate for SDMA concentration was 1.32 (0.92 to 1.90) for CVD. CONCLUSIONS: Available prospective studies suggest associations between circulating ADMA concentration and CVD outcomes under a broad range of circumstances. Further research is needed to better clarify these associations, particularly in large general population studies. PMID- 26021438 TI - Regulation of the survival and differentiation of hepatic stem/progenitor cells by acyclic retinoid. AB - During embryonic liver development, hepatic stem/progenitor cells (HpSCs) have a high proliferative ability and bipotency to differentiate into hepatocytes and cholangiocytes. Retinoic acid is a derivative of vitamin A and is involved in the proliferation and differentiation of stem/progenitor cells in several tissues. However, whether retinoic acid regulates the characteristics of HpSCs in the normal liver is still unknown. A recent study has shown that acyclic retinoid regulates the survival and proliferation of HpSCs derived from mouse foetal liver. Acyclic retinoid suppressed the expansion of CD29(+)CD49f(+) HpSCs through the induction of hepatocytic differentiation and progression of apoptosis. PMID- 26021439 TI - Phylogenetic analysis of the Australian rosella parrots (Platycercus) reveals discordance among molecules and plumage. AB - Relationships and species limits among the colourful Australian parrots known as rosellas (Platycercus) are contentious because of poorly understood patterns of parapatry, sympatry and hybridization as well as complex patterns of geographical replacement of phenotypic forms. Two subgenera are, however, conventionally recognised: Platycercus comprises the blue-cheeked crimson rosella complex (Crimson Rosella P. elegans and Green Rosella P. caledonicus), and Violania contains the remaining four currently recognised species (Pale-headed Rosella P. adscitus, Eastern Rosella P. eximius, Northern Rosella P. venustus, and Western Rosella P. icterotis). We used phylogenetic analysis of ten loci (one mitochondrial, eight autosomal and one z-linked) and several individuals per nominal species primarily to examine relationships within the subgenera, especially the relationships and species limits within Violania. Of these, P. adscitus and P. eximius have long been considered sister species or conspecific due to a morphology-based hybrid zone and an early phylogenetic analysis of mitochondrial DNA restriction fragment length polymorphisms. The multilocus phylogenetic analysis presented here supports an alternative hypothesis aligning P. adscitus and P. venustus as sister species. Using divergence rates published in other avian studies, we estimated the divergence between P. venustus and P. adscitus at 0.0148-0.6124MYA and that between the P. adscitus/P. venustus ancestor and P. eximius earlier at 0.1617-1.0816MYA, both within the Pleistocene. Discordant topologies among gene and species trees are discussed and proposed to be the result of historical gene flow and/or incomplete lineage sorting (ILS). In particular, we suggest that discordance between mitochondrial and nuclear data may be the result of asymmetrical mitochondrial introgression from P. adscitus into P. eximius. The biogeographical implications of our findings are discussed relative to similarly distributed groups of birds. PMID- 26021440 TI - Comparative molecular species delimitation in the charismatic Nawab butterflies (Nymphalidae, Charaxinae, Polyura). AB - The charismatic tropical Polyura Nawab butterflies are distributed across twelve biodiversity hotspots in the Indomalayan/Australasian archipelago. In this study, we tested an array of species delimitation methods and compared the results to existing morphology-based taxonomy. We sequenced two mitochondrial and two nuclear gene fragments to reconstruct phylogenetic relationships within Polyura using both Bayesian inference and maximum likelihood. Based on this phylogenetic framework, we used the recently introduced bGMYC, BPP and PTP methods to investigate species boundaries. Based on our results, we describe two new species Polyura paulettae Toussaint sp. n. and Polyura smilesi Toussaint sp. n., propose one synonym, and five populations are raised to species status. Most of the newly recognized species are single-island endemics likely resulting from the recent highly complex geological history of the Indomalayan-Australasian archipelago. Surprisingly, we also find two newly recognized species in the Indomalayan region where additional biotic or abiotic factors have fostered speciation. Species delimitation methods were largely congruent and succeeded to cross-validate most extant morphological species. PTP and BPP seem to yield more consistent and robust estimations of species boundaries with respect to morphological characters while bGMYC delivered contrasting results depending on the different gene trees considered. Our findings demonstrate the efficiency of comparative approaches using molecular species delimitation methods on empirical data. They also pave the way for the investigation of less well-known groups to unveil patterns of species richness and catalogue Earth's concealed, therefore unappreciated diversity. PMID- 26021442 TI - Replacing the term "binge eating" with "loss of control over eating" affects eating disorder screening in clinical care. PMID- 26021441 TI - Antinociceptive, muscle relaxant and sedative activities of gold nanoparticles generated by methanolic extract of Euphorbia milii. AB - BACKGROUND: Nanotechnology has potential future for enhancing therapeutic efficacy and reducing the unwanted effects of herbal drugs. The biological research on Euphorbia species has been supported by the use of some plants in traditional medicines. Many species of Euphorbia have been reported as having strong sedative and analgesic effects. In the present research work gold nanoparticles of Euphorbia milii methanolic extract (Au-EM) were synthesized, characterized and tested for antinociceptive, muscle relaxant and sedative activities. METHODS: Au-EM was prepared by stirring 1 mM warm trihydrated tetrachloroaurate solution with E. milii methanolic extract without using any external reducing agents. The gold nanoparticles were characterized by UV-Visible spectroscopy, infrared spectrophotometery, atomic force microscopy and scanning electron microscopy while their stability was evaluated against varying pH and different volumes of sodium chloride (NaCl). The metal sensing capacity of Au-EM was tested towards cobalt, copper, lead, mercury and nickel. Au-EM was evaluated in BALB/c mice at a dose of 10 and 20 mg/kg for antinociceptive, muscle relaxant and sedative activities in comparison with the crude E. milii methanolic extract. RESULTS: Au-EM showed remarkable stability in different NaCl and pH solutions. Au EM produced significant (P < 0.01) antinociceptive effect at doses of 10 and 20 mg/kg as compared to the crude E. milii methanolic extract. In the rotarod test, Au-EM showed significant muscle relaxant effect at 10 mg/kg (P < 0.05) and 20 mg/kg (P < 0.01) after 30, 60 and 90 min. In an open field test significant sedative effect (P < 0.05) of Au-EM was observed at 10 and 20 mg/kg. Moreover significant detection sensitivity was demonstrated towards all the tested heavy metals. CONCLUSIONS: These results concluded that the gold nanoparticles improved the potency of E. milii methanolic extract and exhibited significant analgesic, muscle relaxant and sedative properties. The significant metals sensing ability and enhanced stability in different NaCl and pH solutions may enable us to explore different formulations of E. milii gold nanoparticles for potentially effective and safe nano-herbal therapy. PMID- 26021443 TI - Maternal body composition in the first trimester as a predictor of neonatal body composition after birth. PMID- 26021444 TI - Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response. AB - INTRODUCTION: The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL. METHODS: Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 - T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software. RESULTS: When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 - T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS - T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS. CONCLUSIONS: Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002. PMID- 26021446 TI - Genome-wide histone acetylation correlates with active transcription in maize. AB - Gene expression is regulated at many different levels during the life cycle of all plant species. Recent investigations have taken advantage of next-generation sequencing to study the relevance of DNA methylation and sRNAs in controlling tissue-specific gene expression in maize at the genome-wide level. Here, we profiled H3K27ac in maize, which has one of the largest sequenced plant genomes due to the amplification of retrotransposons. Because transcribed genes represent only a small proportion of its genome, gene-specific epigenetic modifications are concentrated in a relatively small percentage of the genome. Indeed, H3K27ac marks are mostly in gene-rich, in contrast to gene-poor regions. A large proportion of those marks are located in transcribed regions of genes, including 111 out of 458 known genetic loci. Moreover, increased transcription correlates with the presence of H3K27ac modification in gene bodies. Using maize as an example, we suggest that H3K27ac marks actively transcribed genes in plants. PMID- 26021445 TI - Rosiglitazone infusion therapy following minimally invasive surgery for intracerebral hemorrhage evacuation decreases matrix metalloproteinase-9 and blood-brain barrier disruption in rabbits. AB - BACKGROUND: The objective of this study was to investigate the effects of Rosiglitazone (RSG) infusion therapy following minimally invasive surgery (MIS) for intracerebral hemorrhage(ICH) evacuation on perihematomal secondary brain damage as assessed by MMP-9 levels, blood-brain barrier (BBB) permeability and neurological function. METHODS: A total of 40 male rabbits (2.8-3.4 kg) was randomly assigned to a normal control group (NC group; 10 rabbits), a model control group (MC group; 10 rabbits), a minimally invasive treatment group (MIS group; 10 rabbits) or a combined MIS and RSG group (MIS + RSG group; 10 rabbits). ICH was induced in all the animals, except for the NC group. MIS was performed to evacuate ICH 6 hours after the successful preparation of the ICH model in the MIS and MIS + RSG groups. The animals in the MC group underwent the same procedures for ICH evacuation but without hematoma aspiration, and the NC group was subjected to sham surgical procedures. The neurological deficit scores (Purdy score) and ICH volumes were determined on days 1, 3 and 7. All of the animals were sacrificed on day 7, and the perihematomal brain tissue was removed to determine the levels of PPARgamma, MMP-9, BBB permeability and brain water content (BWC). RESULTS: The Purdy score, perihematomal PPARgamma levels, BBB permeability, and BWC were all significantly increased in the MC group compared to the NC group. After performing the MIS for evacuating the ICH, the Purdy score and the ICH volume were decreased on days 1, 3 and 7 compared to the MC group. A remarkable decrease in perihematomal levels of PPARgamma, MMP-9, BBB permeability and BWC were observed. The MIS + RSG group displayed a remarkable increase in PPARgamma as well as significant decrease in MMP-9, BBB permeability and BWC compared with the MIS group. CONCLUSIONS: RSG infusion therapy following MIS for ICH treatment might be more efficacious for reducing the levels of MMP-9 and secondary brain damage than MIS therapy alone. PMID- 26021447 TI - Rapid and efficient purification of ficolin-2 using a disposable CELLine bioreactor. AB - The human opsonin ficolin-2 (L-ficolin) is an innate pattern-recognizing molecule that binds to acetylated moieties. Upon binding, ficolin-2 activates complement through the lectin pathway, opsonizing the target to promote phagocytic clearance. Ficolin-2 has been found to interact with a growing number of pathogenic bacteria, fungi, and viruses. Ficolin-2 also has proposed roles in host homeostasis, including the clearance of apoptotic cells. Consequently, there is an increased interest in studying ficolin-2, and access to purified ficolin-2 is necessary for these studies. Ficolin-2 purified from serum, plasma, or cell culture supernatants has been a useful tool in the characterization of ficolin-2 function; however, available protocols are laborious and inefficient, requiring additional processing of starting materials (e.g., polyethylene glycol precipitation or dialysis) and multiple steps of purification. Here, we investigated a simple solution to the problem: use of a simple, disposable bioreactor requiring only standard tissue culture equipment. Using this system, we generated cell culture supernatants containing high concentrations of recombinant ficolin-2, which permitted rapid purification of high-purity recombinant ficolin-2 without processing the supernatants. Purified recombinant ficolin-2 retained its binding capacity and supported complement activation in vitro. Bioreactor cultivation will likely be generally useful in the production of other recombinant proteins in the study of the complement system. PMID- 26021448 TI - Immunogenicity of infectious pathogens and vaccine antigens. AB - The concept of the immunogenicity of an antigen is frequently encountered in the context of vaccine development, an area of intense interest currently due to the emergence or re-emergence of infectious pathogens with the potential for worldwide spread. However, the theoretical notion of immunogenicity as discussed in older textbooks of immunology needs reconsideration due to advances in our understanding of immunologic responses. Immunogenicity is a property that can either be a desirable attribute, for example in the generation of an effective protective immunity against infectious pathogens or an undesirable trait, for example when it relates to novel therapeutic compounds and drugs, where an immune response needs to be prevented or inhibited. In this Forum Article, we aimed to revisit the issue of immunogenicity to discuss a series of simple questions relevant to the concept that are frequently rephrased but incompletely resolved in the immunologic literature. PMID- 26021450 TI - Pediatric Tympanostomy Tube Removal Technique and Effect on Rate of Persistent Tympanic Membrane Perforation. AB - IMPORTANCE: Tympanostomy tube removal is a commonly performed pediatric procedure. Few studies have evaluated whether removal technique influences the likelihood of the tympanic membrane (TM) to heal. OBJECTIVE: To determine whether the technique used for tympanostomy tube removal affects the likelihood of persistent TM perforation healing in children. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series with medical chart review in a tertiary care pediatric health system of 247 children undergoing tympanostomy tube removal (341 ears) between 2010 and 2013 by 1 of 4 different techniques: (1) tube removal only; (2) freshening TM perforation edges; (3) performing patch myringoplasty; or (4) both freshening edges and performing patch myringoplasty. MAIN OUTCOMES AND MEASURES: Rate of persistent TM perforation after tympanostomy tube removal using the different removal techniques. Secondary outcomes included associations between persistent TM perforation and patient and tympanostomy tube characteristics. RESULTS: The overall persistent TM perforation rate was 10% (34 of 341 ears). Tube removal technique did not significantly influence likelihood for the TM to heal: perforations persisted in 11 of 97 ears (11%) with tube removal only, 6 of 68 ears (9%) with freshened TM perforation edges, 7 of 57 (12%) with patch myringoplasty, and 10 of 119 (8%) with both edges freshened and patch myringoplasty (P = .81). The mean (SD) age of patients with a persistent perforation at the time of tympanostomy tube removal was 8.5 (3.9) years vs 6.5 (3.2) years for those without a persistent perforation (P = .01). In patients with trisomy 21, there was a significantly higher rate of persistent TM perforation (OR, 8.65; 95% CI, 2.13-34.74; P = .002). Short-acting tubes were found to have a significantly lower rate of persistent TM perforation (13 of 194; 7%) than longer-acting tubes (9 of 41; 22%) (OR, 0.26; 95% CI, 0.09-0.71; P = .002). CONCLUSIONS AND RELEVANCE: No reduction in persistent TM perforation rate was found following tympanostomy tube removal if TM edges were freshened and/or a patch myringoplasty was performed. Increased pediatric age, longer-acting tympanostomy tubes, and history of trisomy 21 may negatively influence likelihood of closure. PMID- 26021449 TI - Energy expenditure during common sitting and standing tasks: examining the 1.5 MET definition of sedentary behaviour. AB - BACKGROUND: Sedentary behavior is defined as any waking behavior characterized by an energy expenditure of 1.5 METS or less while in a sitting or reclining posture. This study examines this definition by assessing the energy cost (METs) of common sitting, standing and walking tasks. METHODS: Fifty one adults spent 10 min during each activity in a variety of sitting tasks (watching TV, Playing on the Wii, Playing on the PlayStation Portable (PSP) and typing) and non-sedentary tasks (standing still, walking at 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, and 1.6 mph). Activities were completed on the same day in a random order following an assessment of resting metabolic rate (RMR). A portable gas analyzer was used to measure oxygen uptake, and data were converted to units of energy expenditure (METs). RESULTS: Average of standardized MET values for screen-based sitting tasks were: 1.33 (SD: 0.24) METS (TV), 1.41 (SD: 0.28) (PSP), and 1.45 (SD: 0.32) (Typing). The more active, yet still seated, games on the Wii yielded an average of 2.06 (SD: 0.5) METS. Standing still yielded an average of 1.59 (SD: 0.37) METs. Walking MET values increased incrementally with speed from 2.17 to 2.99 (SD: 0.5 - 0.69) METs. CONCLUSIONS: The suggested 1.5 MET threshold for sedentary behaviors seems reasonable however some sitting based activities may be classified as non-sedentary. The effect of this on the definition of sedentary behavior and associations with metabolic health needs further investigation. PMID- 26021451 TI - [Dermo-hypodermitis caused by group B Streptococcus in infants under 3 months of age: A retrospective study in two hospitals]. AB - BACKGROUND: Very few studies describe group B streptococcal dermo-hypodermitis in newborns. OBJECTIVES: To describe the incidence, clinical characteristics, and course of group B streptococcal dermo-hypodermitis in infants less than 3 months old. PATIENTS AND METHODS: Infants under 3 months of age, hospitalized for group B streptococcal dermo-hypodermitis at Robert Debre University Hospital, Paris, France, and at Orsay Hospital, Orsay, France, between January 2002 and August 2013, were included in a retrospective study. RESULTS: Five infants were included in this study. All the infections occurred late. Dermo-hypodermitis accounted for 7% of the overall late-onset group B streptococcal infections during the same period. Four patients were male and had a risk factor of maternal-fetal infection (prematurity/hypotrophy). Four patients had specific clinical signs of dermo hypodermitis with septic shock features on admission. One patient had meningitis and associated parotitis. Group B Streptococcus was isolated from blood culture of all patients. Serotype III Streptococcus was identified in four cases. The duration of intravenous antibiotic therapy varied from 7 to 23 days and the total duration of antibiotic therapy was between 14 and 44 days. The progression was favorable for all the infants, with no recurrence. CONCLUSION: Dermo-hypodermitis in infants under 3 months of age is rare but could be an early indicator of group B streptococcal bacteremia and/or sepsis. Early diagnosis of this severe complication and appropriate antibiotic therapy are critical. PMID- 26021452 TI - [Challenges of personalized medicine for cystic fibrosis]. AB - Personalized medicine, or P4 medicine for "Personalized", "Predictive", "Preventive" and "Participatory", is currently booming for cystic fibrosis, with the development of therapies targeting specific CFTR mutations. The various challenges of personalized medicine applied to cystic fibrosis issues are discussed in this paper. PMID- 26021453 TI - Comparisons of financial and short-term outcomes between laparoscopic and open hepatectomy: benefits for patients and hospitals. AB - PURPOSES: This retrospective analysis compared the cost outcomes for both patients and hospitals, as well as the short-term outcomes, for laparoscopic hepatectomy (LH) and open hepatectomy (OH). METHODS: The subjects comprised 70 patients who underwent LH or OH. The total hospital charge was calculated using the Japanese lump-sum payment system according to the diagnosis procedure combination. RESULTS: Of the 70 patients, 10 in the LH group and 16 in the OH group underwent primary single limited/anatomic resection or left lateral sectoriectomy. The operation time, blood loss, and postoperative complications did not differ significantly between the two groups. The median [range] time of inflow occlusion was significantly longer [120 (50-194) vs. 57 (17-151) min, P = 0.03] and the postoperative hospital stay was significantly shorter [5 (4-6) vs. 9 (5-12) days, P < 0.01] in the LH group than in the OH group, respectively. The mean +/- standard deviation surgical costs (1307 +/- 596 vs. 1054 +/- 365 US$, P = 0.43) and total hospital charges (12046 +/- 1174 vs. 11858 +/- 2096 US$, P > 0.99) were similar in the LH and OH groups, respectively, although the charges per day were significantly higher in the LH group than in the OH group (1388 +/- 217 vs. 1016 +/- 134 US$, P < 0.01). CONCLUSIONS: The costs to patients for LH are similar to those for OH. However, LH provides a financial advantage to hospitals due to a reduced hospital stay and comparable surgical costs. PMID- 26021454 TI - Granulomatosis with Polyangiitis (Wegener's Granulomatosis) Complicated with Ruptured Posteromedial Papillary Muscle in the Absence of Coronary Angiographic Findings. AB - Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis, associated with antineutrophil cytoplasmic autoantibody-associated systemic vasculitis, and it can affect many organ systems via the inflammation of small-to medium-sized vessels. Cardiac involvements in GPA are relatively rare. We report a 75-year-old woman who was diagnosed with GPA and rapid progressive glomerulonephritis that resulted in a partial posteromedial papillary muscle rupture, but with no coronary angiographic findings. The surgical and pathological findings with regard to the ruptured papillary muscle revealed necrotic muscle and acute ischemic change. The mechanism of papillary muscle rupture in GPA is coronary vasculitis leading to myocardial infarction. The ischemic change is not always detected on coronary angiography, so assessment using an echocardiogram is important. PMID- 26021455 TI - Functional characterization of IgM+ B cells and adaptive immunity in lumpfish (Cyclopterus lumpus L.). AB - The innate immune responses in lumpfish (Cyclopterus lumpus L.) have been shown to be functional, but little is currently known about the B cells, immunoglobulins or adaptive immune responses in this species. We have used anti IgM antiserum to isolate B cells and compared them morphologically and functionally with other cell types. The fraction of IgM(+) cells among isolated peripheral blood leukocytes (PBL), head kidney leukocytes (HKL) and spleen leukocytes (SL) was in the range of 40%, 12% and 34%, respectively. The IgM(+) B cells had high phagocytic ability and were the predominant phagocytes in blood with higher capacity than IgM(+) B cells in HKL. Interestingly, among PBL, the most potent phagocytes were, in addition to monocytes, some small agranular uncharacterized IgM(-) cells. The IgM(+) B cells were positive for acid phosphatases (AcP), but negative for myeloperoxidase (MPO). Neutrophils were positive for MPO, while monocytes/macrophages and dendritic-like cells stained negatively. Monocytes/macrophages and the small, agranular IgM(-) cells stained most strongly positive for AcP corresponding to their high phagocytic capacity. Further, the ability to produce specific antibodies upon immunization verified adaptive immunity in the species. The high proportion of phagocytic IgM(+) B cells and their phagocytic ability indicate a significant role of phagocytic B cells in lumpfish innate immunity. The present analyses also give strong indications that vaccination and immunostimulation of farmed lumpfish can be used to prevent disease and mortality caused by pathogenic organisms. PMID- 26021456 TI - Spatially directed vesicle capture in the ordered pores of breath-figure polymer films. AB - This work describes a new method to selectively capture liposomes and other vesicle entities in the patterned pores of breath-figure polymer films. The process involves the deposition of a hydrophobe containing biopolymer in the pores of the breath figure, and the tethering of vesicles to the biopolymer through hydrophobic interactions. The process is versatile, can be scaled up and extended to the deposition of other functional materials in the pores of breath figures. PMID- 26021457 TI - Recent development of biotin conjugation in biological imaging, sensing, and target delivery. AB - Despite encouraging results from preliminary studies of anticancer therapies, the lack of tumor specificity remains an important issue in the modern pharmaceutical industry. New findings indicate that biotin or biotin-conjugates could be favorably assimilated by tumor cells that over-express biotin-selective transporters. Furthermore, biotin can form stable complexes with avidin and its bacterial counterpart streptavidin. The strong bridging between avidin and biotin moieties on other molecules is a proven adaptable tool with broad biological applications. Under these circumstances, a biotin moiety is certainly an attractive choice for live-cell imaging, biosensing, and target delivery. PMID- 26021458 TI - MCT8 is Downregulated by Short Time Iodine Overload in the Thyroid Gland of Rats. AB - Wolff-Chaikoff effect is characterized by the blockade of thyroid hormone synthesis and secretion due to iodine overload. However, the regulation of monocarboxylate transporter 8 during Wolff-Chaikoff effect and its possible role in the rapid reduction of T4 secretion by the thyroid gland remains unclear. Patients with monocarboxylate transporter 8 gene loss-of-function mutations and monocarboxylate transporter 8 knockout mice were shown to have decreased serum T4 levels, indicating that monocarboxylate transporter 8 could be involved in the secretion of thyroid hormones from the thyroid gland. Herein, we aimed to evaluate the regulation of monocarboxylate transporter 8 during the Wolff Chaikoff effect and the escape from iodine overload, besides the importance of iodine organification for this regulation. Monocarboxylate transporter 8 mRNA and protein levels significantly decreased after 1 day of NaI administration to rats, together with decreased serum T4; while no alteration was observed in LAT2 expression. Moreover, both monocarboxylate transporter 8 expression and serum T4 was restored after 6 days of NaI. The inhibition of thyroperoxidase activity by methimazole prevented the inhibitory effect of NaI on thyroid monocarboxylate transporter 8 expression, suggesting that an active thyroperoxidase is necessary for MCT8 downregulation by iodine overload, similarly to other thyroid markers, such as sodium iodide symporter. Therefore, we conclude that thyroid monocarboxylate transporter 8 expression is downregulated during iodine overload and that the normalization of its expression parallels the escape phenomenon. These data suggest a possible role for monocarboxylate transporter 8 in the changes of thyroid hormones secretion during the Wolff-Chaikoff effect and escape. PMID- 26021459 TI - Serum Apolipoprotein-A1 and Cholesterol Levels in Nigerian Children with Plasmodium falciparum Infection. AB - OBJECTIVE: This study was carried out to determine whether or not Plasmodium falciparum malaria infection significantly affected apolipoprotein-A1 and cholesterol levels and if apolipoprotein-A1 correlated with the malaria severity in children younger than 5 years old. SUBJECTS AND METHODS: Two hundred and fifty five children, 170 of whom had microscopically confirmed P. falciparum infection, i.e. 85 cases of uncomplicated malaria (UM) and 85 of complicated malaria (CM), and 85 healthy controls were enrolled in this study. Serum levels of apolipoprotein-A1, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides were determined. These levels were compared among the malaria and control groups, using ANOVA and post hoc analyses at p = 0.05. RESULTS: There were significant differences in the mean serum levels of apolipoprotein-A1 (UM: 104.5 +/- 38.1 mg/dl, CM: 90.9 +/- 33.3 mg/dl and controls: 129.7 +/- 48.3 mg/dl; p < 0.001), total cholesterol (UM: 138.8 +/- 62.9 mg/dl, CM: 121.2 +/- 55.2 mg/dl and controls: 155.1 +/- 69.8 mg/dl; p = 0.002) and LDL (UM: 98.2 +/- 55.5 mg/dl, CM: 84.3 +/- 47.4 mg/dl and controls: 122.7 +/- 69.4 mg/dl; p < 0.001). Post hoc analyses revealed that children with UM and CM had significantly lower levels of apolipoprotein-A1, cholesterol, HDL and LDL than controls but that there was no difference between the 2 malaria groups. Reductions in levels of lipids and apolipoprotein-A1 were worse in CM than in UM. CONCLUSION: Altered levels of serum lipids with CM were associated with a reduction in apolipoprotein-A1. These findings have potential diagnostic utility for the management of malaria. PMID- 26021460 TI - Quantifying coordination and coordination variability in backward versus forward running: Implications for control of motion. AB - The aims of this study were to compare coordination and coordination variability in backward and forward running and to investigate the effects of speed on coordination variability in both backward and forward running. Fifteen healthy male participants took part in this study to run forwards and backwards on a treadmill at 80%, 100% and 120% of their preferred running speeds. The coordinate data of passive reflective markers attached to body segments were recorded using motion capture systems. Coordination of shank-foot and thigh-shank couplings in sagittal plane was quantified using the continuous relative phase method. Coordination variability was calculated as the standard deviation of a coordination pattern over 50 strides. Cross-correlation coefficients and associated phase shifts were determined to quantify similarity in coordination patterns between forward and backward running. Our results demonstrated that the coordination pattern in a gait cycle of backward running was in reverse to that of forward running at all speeds implying that the same neural circuitry is responsible for regulating both forward and backward running gaits. In addition, results demonstrated that there was an average of approximately 11% phase shift between the coordination patterns of backward and forward running which indicates that a single underlying mechanism might be responsible for generating motor patterns in both forward and backward running. Finally, backward running had significantly higher magnitude of coordination variability compared to forward running, signifying that more degrees of freedom were involved in backward running. Speed however, did not affect coordination variability in either task. PMID- 26021461 TI - Primary-care-based social prescribing for mental health: an analysis of financial and environmental sustainability. AB - Aim To assess the effects of a social prescribing service development on healthcare use and the subsequent economic and environmental costs. BACKGROUND: Social prescribing services for mental healthcare create links with support in the community for people using primary care. Social prescribing services may reduce future healthcare use, and therefore reduce the financial and environmental costs of healthcare, by providing structured psychosocial support. The National Health Service (NHS) is required to reduce its carbon footprint by 80% by 2050 according to the Climate Change Act (2008). This study is the first of its kind to analyse both the financial and environmental impacts associated with healthcare use following social prescribing. The value of this observational study lies in its novel methodology of analysing the carbon footprint of a service at the primary-care level. METHOD: An observational study was carried out to assess the impact of the service on the financial and environmental impacts of healthcare use. GP appointments, psychotropic medications and secondary-care referrals were measured. Findings Results demonstrate no statistical difference in the financial and carbon costs of healthcare use between groups. Social prescribing showed a trend towards reduced healthcare use, mainly due to a reduction in secondary-care referrals compared with controls. The associations found did not achieve significance due to the small sample size leading to a large degree of uncertainty regarding differences. This study demonstrates that these services are potentially able to pay for themselves through reducing future healthcare costs and are effective, low-carbon interventions, when compared with cognitive behavioral therapy or antidepressants. This is an important finding in light of Government targets for the NHS to reduce its carbon footprint by 80% by 2050. Larger studies are required to investigate the potentials of social prescribing services further. PMID- 26021462 TI - The Genetic Overlap of Attention-Deficit/Hyperactivity Disorder and Autistic-like Traits: an Investigation of Individual Symptom Scales and Cognitive markers. AB - Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) frequently co-occur. However, due to previous exclusionary diagnostic criteria, little is known about the underlying causes of this covariation. Twin studies assessing ADHD symptoms and autistic-like traits (ALTs) suggest substantial genetic overlap, but have largely failed to take into account the genetic heterogeneity of symptom subscales. This study aimed to clarify the phenotypic and genetic relations between ADHD and ASD by distinguishing between symptom subscales that characterise the two disorders. Moreover, we aimed to investigate whether ADHD-related cognitive impairments show a relationship with ALT symptom subscales; and whether potential shared cognitive impairments underlie the genetic risk shared between the ADHD and ALT symptoms. Multivariate structural equation modelling was conducted on a population-based sample of 1312 twins aged 7-10. Social-communication ALTs correlated moderately with both ADHD symptom domains (phenotypic correlations around 0.30) and showed substantial genetic overlap with both inattention and hyperactivity-impulsivity (genetic correlation = 0.52 and 0.44, respectively). In addition to previously reported associations with ADHD traits, reaction time variability (RTV) showed significant phenotypic (0.18) and genetic (0.32) association with social-communication ALTs. RTV captured a significant proportion (24 %) of the genetic influences shared between inattention and social-communication ALTs. Our findings suggest that social-communication ALTs underlie the previously observed phenotypic and genetic covariation between ALTs and ADHD symptoms. RTV is not specific to ADHD symptoms, but is also associated with social-communication ALTs and can, in part, contribute to an explanation of the co-occurrence of ASD and ADHD. PMID- 26021463 TI - Assessment of both serum S-100B protein and neuropeptide-Y levels in childhood breath-holding spells. AB - OBJECTIVE: Breath-holding spells are common paroxysmal events in children. Although the spells have a benign prognosis in the long term, they may be complicated by loss of consciousness, tonic-clonic movements, and occasionally seizures. Hence, this study aimed to measure the levels of serum S-100B proteins and neuropeptide-Y in the blood of children who experience breath-holding spells. METHODS: The study groups consisted of 45 patients (13 females, 32 males) with breath-holding spells and a control group of 32 healthy individuals (12 females, 20 males). The serum S-100B levels were measured using commercially available ELISA kits. The neuropeptide-Y levels in the serum were measured with RayBio(r) Human/Mouse/Rat Neuropeptide Y ELISA kits. RESULTS: The mean serum S-100B protein level of the breath-holding spells group was 56.38 +/- 13.26 pg/mL, and of the control group, 48.53 +/- 16.77 pg/mL. The mean neuropeptide-Y level was 62.29 +/- 13.89 pg/mL in the breath-holding spells group and 58.24 +/- 12.30 pg/mL in the control group. There were significant differences between the groups with respect to serum S-100B protein levels (p = 0.025), while there was no statistically significant difference in neuropeptide-Y levels between the breath-holding spells group and the control group (p = 0.192). CONCLUSIONS: The findings of this study suggest that frequent and lengthy breath-holding may lead to the development of neuronal metabolic dysfunction or neuronal damage which is most likely related to hypoxia. In light of these findings, future studies should be conducted using biochemical and radiological imaging techniques to support these results. PMID- 26021464 TI - Seizure precipitants in Dravet syndrome: What events and activities are specifically provocative compared with other epilepsies? AB - OBJECTIVES: This study aimed to describe seizure precipitants in Dravet syndrome (DS) compared with other epilepsies. METHODS: Seizure precipitants as reported in a Dutch cohort of patients with DS with pathogenic SCN1A mutations (n=71) were compared with those of a cohort with childhood epilepsy (n=149) and of a community-based cohort with epilepsy (n=248); for all three Dutch cohorts, the same type of questionnaire was used. Seizure precipitants were categorized as 'fever', 'visual stimuli', 'sleep deprivation', 'stress, including physical exercise', 'auditory stimuli', and 'other'. RESULTS: For 70 (99%) of 71 patients with DS, at least one seizure precipitant was recalled by parents. Seizure precipitants that were reported in more than half of the cohort with DS were as follows: having a fever (97%), having a cold (68%), taking a bath (61%), having acute moments of stress (58%), and engaging in physical exercise (56%). Seizure precipitants freely recalled by parents were often related to ambient warmth or cold-warmth shifts (41%) and to various visual stimuli (18%). Patients with DS had more positive seizure precipitant categories (median 4) compared with the cohort with childhood epilepsy (median 2) and the community-based cohort with epilepsy (median 0) (p<0.001) and showed the highest percentage in each category (all p<0.001). Within the category 'stress, including physical exercise', physical exercise was more often reported to provoke seizures in stress-sensitive patients in the cohort with DS than in the cohort with childhood epilepsy (78% vs. 35%, p<0.001). In the cohort with childhood epilepsy, physical exercise was more often reported in fever-sensitive children than in other children (25% vs. 12%, p=0.042). CONCLUSIONS: Our study shows a high prevalence of a range of seizure precipitants in DS. Our results underscore elevated body temperature as an important seizure precipitant, whether caused by fever, warm bath, ambient warmth, or physical exercise. Knowledge of these seizure precipitants may improve preventive strategies in the otherwise difficult treatment of DS. PMID- 26021466 TI - Outpatient Thyroid Surgery in a Low-Surgical Volume Hospital. AB - BACKGROUND: To determine the safety and outcome of outpatient thyroid surgery in a small low-surgical volume hospital. To evaluate clinical and social factors that may prohibit outpatient thyroid surgery. METHODS: Retrospective analysis of all thyroid surgery performed at a low-surgical volume hospital from August 2006 to July 2014. One-hundred and sixty patients underwent thyroid surgery during the study period. Electronic medical records were reviewed for all patients. Data collection included demographic information, extent of thyroid surgery, length of hospital stay, laboratory/pathology results, co-morbidities, and complications. RESULTS: Of the 160 patients who underwent thyroid surgery, 109 (68.1%) were discharged on the day of surgery. Forty-three patients (26.9%) were admitted for 23-h observation and eight patients (5%) required full admission (longer than 24 h). Sixty-one patients (38.1%) underwent a total thyroidectomy, while 99 patients (61.9%) underwent a hemithyroidectomy. Complications included four temporary recurrent laryngeal nerve (RLN) injuries (2.5% patients/1.8% of total RLN at risk), one permanent RLN injury (0.63% patients/0.45% of total RLN as risk), one temporary bilateral RLN injury (0.63%), two delayed hematomas (1.3%), and eight cases of transient hypocalcemia (5%). CONCLUSION: Outpatient thyroid surgery can be performed safely in a low-surgical volume center. Reasons for a longer stay include clinical as well as social factors. PMID- 26021465 TI - RLIP76 Targeted Therapy for Kidney Cancer. AB - Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer. PMID- 26021467 TI - Invariants reveal multiple forms of robustness in bifunctional enzyme systems. AB - Experimental and theoretical studies have suggested that bifunctional enzymes catalyzing opposing modification and demodification reactions can confer steady state concentration robustness to their substrates. However, the types of robustness and the biochemical basis for them have remained elusive. Here we report a systematic study of the most general biochemical reaction network for a bifunctional enzyme acting on a substrate with one modification site, along with eleven sub-networks with more specialized biochemical assumptions. We exploit ideas from computational algebraic geometry, introduced in previous work, to find a polynomial expression (an invariant) between the steady state concentrations of the modified and unmodified substrate for each network. We use these invariants to identify five classes of robust behavior: robust upper bounds on concentration, robust two-sided bounds on concentration ratio, hybrid robustness, absolute concentration robustness (ACR), and robust concentration ratio. This analysis demonstrates that robustness can take a variety of forms and that the type of robustness is sensitive to many biochemical details, with small changes in biochemistry leading to very different steady-state behaviors. In particular, we find that the widely-studied ACR requires highly specialized assumptions in addition to bifunctionality. An unexpected result is that the robust bounds derived from invariants are strictly tighter than those derived by ad hoc manipulation of the underlying differential equations, confirming the value of invariants as a tool to gain insight into biochemical reaction networks. Furthermore, invariants yield multiple experimentally testable predictions and illuminate new strategies for inferring enzymatic mechanisms from steady-state measurements. PMID- 26021468 TI - Erratum to: Study on the mesothelin-specific cytotoxicity against epithelial ovarian cancer with full-length mesothelin cDNA-transduced dendritic cells. PMID- 26021469 TI - Erratum to: Effect of circulating tumor cells combined with negative enrichment and CD45-FISH identification in diagnosis, therapy monitoring and prognosis of primary lung cancer. PMID- 26021470 TI - Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by inhibition of proliferation. Pretreatment of U-2932 or U-2940 cell lines with PPP at biologically active concentrations did not prevent ligand-induced phosphorylation of IGF-1R at Tyr1131/1136 or its downstream targets AKT and ERK1/2. In contrast, the IGF-1R inhibitor NVP-AEW541 clearly inhibited phosphorylation of IGF-1R and AKT, while ERK1/2 phosphorylation was less affected. Taken together, the inhibitory effects of PPP in DLBCL cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease. However, we suggest that the primary target of PPP in these cells is not related to inhibition of IGF-1R phosphorylation. PMID- 26021471 TI - Reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for chronic lymphocytic leukemia. PMID- 26021472 TI - The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer. AB - The transcription factor c-Myc plays critical roles in cancer development and progression through regulating expression of targeted genes. Lactate dehydrogenase A (LDHA), which catalyzes the conversion of L-lactate to pyruvate in the final step of anaerobic glycolysis, is frequently upregulated in pancreatic cancer. However, little is known about the effects of c-Myc-LDHA axis in the progression of pancreatic cancer. In this study, we found that c-Myc and LDHA are concomitantly overexpressed in pancreatic cancer cell lines and clinical specimens. c-Myc overexpression and LDHA overexpression were correlated with TNM stage and tumor size and indicated poor prognosis in patients with pancreatic cancer. Knockdown of c-Myc reduced the protein expression of LDHA, lactate production and glucose consumption, and silencing of LDHA mimicked this effect. Meanwhile, reduced c-Myc-LDHA signaling resulted in decreased tumor growth and metastasis in pancreatic cancer. Treatment with 2-Deoxy-D-glucose, an inhibitor of anaerobic glycolysis, completely blocked the oncogenic roles of c-Myc-LDHA signaling. Taken together, dysregulated c-Myc-LDHA signaling plays important roles in aerobic glycolysis and facilitates tumor progression of pancreatic cancer. PMID- 26021473 TI - Induced abortion in villages of Ballabgarh HDSS: rates, trends, causes and determinants. AB - BACKGROUND: Induced abortion has been legal in India on a broad range of medical and social grounds since 1980s. Often, induced abortion is resorted to as a means for contraception, and has a potential to be misused for sex selective feticide. We assessed the rates, trends, causes and determinants of induced abortions from 2008-12 in a rural community of northern India. METHODS: Present study is a secondary data analysis of pregnancy outcomes at Ballabgarh Health and Demographic Surveillance System from 2008-12. The data was retrieved from the Health and Management Information System maintained at Ballabgarh. Cause of abortion was self-reported by the women who underwent abortion. RESULTS: Of the 11,102 pregnancies, 1,226 (11%) culminated as abortions of which 425 (3.8%) were induced abortions. Spontaneous abortion rate (7.2%) was twice that of induced abortion rate (3.8%). Both abortion rates had an increasing trend during the course of the study period. Self-reported reasons for opting for induced abortions were bleeding per vaginum (23%), unwanted pregnancy (16%), and unviable fetus diagnosed by ultrasonography (11%). Eight percent of the induced abortions were due to the female sex of the fetus. About 11% of the abortions were performed beyond 20 weeks of gestation which was the upper legal permissible gestational age for performing induced abortions in India. About 10% of the abortions were performed by unqualified practitioners. Caste, wealth index, birth order and size of the village population were the factors that were significantly associated with induced abortion. CONCLUSIONS: Though the abortion rate was low, the proportionate contribution of induced abortion was more than what could be expected. Unsafe and sex selective abortion, though illegal, was prevalent. Upper caste and higher socio-economic status families were more likely to opt for induced abortion. PMID- 26021474 TI - Population data for 15 autosomal STR loci from Latvia. AB - Population data of 15 short tandem repeat (STR) loci were determined from 500 unrelated Latvian individuals. The samples were amplified using the AmpFlSTR(r) NGMTM PCR Amplification Kit and the PowerPlex(r) ESX 16 System. No significant deviation from the Hardy-Weinberg equilibrium was detected, except for locus D3S1358. Calculated forensically relevant population statistics show that the investigated loci are very discriminating in the Latvian population, with a combined discrimination power of 0.9999999999999999998. A comparison with previously published allele frequency data from other populations is presented. PMID- 26021475 TI - Innovations in multidisciplinary education in healthcare and technology. AB - The growing importance of technology in health care calls for interdisciplinary study programmes in which students with various backgrounds work together in exploring and designing new solutions for real-life problems. The Centre of Healthcare and Technology of Fontys University of Applied Sciences (Fontys EGT), the Netherlands, is presented as an example of how new initiatives in the field of education at the crossroads of health care and technology can be shaped and implemented in practice. A case study illustrating one of the student projects is provided as an example of the approach to educational innovation and interdisciplinary collaboration. PMID- 26021476 TI - Identification of the proteins associated with low potassium tolerance in cultivated and Tibetan wild barley. AB - In previous studies, we found Tibetan wild barley accessions with high tolerance to low K. In this study, ionomics and proteomics analyses were done on two wild genotypes (XZ153, tolerant and XZ141, sensitive), and a cultivar (B1031, tolerance to low K) to understand the mechanism of low-K tolerance. XZ153 was much less affected by low K stress than the other two genotypes in plant biomass and shoot K content. A total of 288 differentially accumulated proteins were identified between low-K and normal K treated plants. Among them, 129 proteins related to low-K tolerance were mainly involved in defense, transcription, signal transduction, energy, and protein synthesis. The analysis of tandem mass tag (TMT) detected 51 proteins which were increased in relative abundance under low K in XZ153, but unaltered or decreased in XZ141. The proteomics results showed that XZ153 is highly capable of rearranging ion homeostasis and developing an antioxidant defense system under low-K stress. Moreover, ethylene response and phenylpropanoid pathways could determine the genotypic difference in low-K tolerance. The current results confirmed the possibility of Tibetan wild barley providing low-K tolerant germplasm and identified some candidate proteins for use in developing the cultivars with low-K tolerance. PMID- 26021477 TI - Profiling of urinary proteins in Karan Fries cows reveals more than 1550 proteins. AB - Urine is a non-invasive source of biological fluid, which reflects the physiological status of the mammals. We have profiled the cow urinary proteome and analyzed its functional significance. The urine collected from three healthy cows was concentrated by diafiltration (DF) followed by protein extraction using three methods, namely methanol, acetone, and ammonium sulphate (AS) precipitation and Proteo Spin urine concentration kit (PS). The quality of the protein was assessed by two-dimensional gel electrophoresis (2DE). In-gel digestion method revealed more proteins (1191) in comparison to in-solution digestion method (541). Collectively, 938, 606 and 444 proteins were identified in LC-MS/MS after in-gel and in-solution tryptic digestion of proteins prepared by AS, PS and DF methods, respectively resulting in identification of a total of 1564 proteins. Gene ontology (GO) using Panther7.0 grouped the majority of the proteins into cytoplasmic (location), catalytic activity (function), and metabolism (biological processes), while Cytoscape grouped proteins into complement and coagulation cascades; protease inhibitor activity and wound healing. Functional significance of few selected proteins seems to play important role in their physiology. Comparative analysis with human urine revealed 315 overlapping proteins. This study reports for the first time evidence of more than 1550 proteins in urine of healthy cow donors. This article is part of a Special Issue entitled: Proteomics in India. PMID- 26021478 TI - Cadmium toxicity in diazotrophic Anabaena spp. adjudged by hasty up-accumulation of transporter and signaling and severe down-accumulation of nitrogen metabolism proteins. AB - Present study demonstrates interspecies variation in proteome and survival strategy of three Anabaena species i.e., Anabaena L31, Anabaena sp. PCC 7120 and Anabaena doliolum subjected to respective LC50 doses of Cd at 0, 1, 3, 5 and 7day intervals. The proteome coverage with 452 differentially accumulated proteins unveiled species and time specific expression and interaction network of proteins involved in important cellular functions. Statistical analysis of protein abundance across Cd-treated proteomes clustered their co-expression pattern into four groups viz., (i) early (days 1 and 3) accumulated proteins, (ii) proteins up accumulated for longer duration, (iii) late (days 5 and 7) accumulated proteins, and (iv) mostly down-accumulated proteins. Appreciable growth of Cd treated A L31 over other two species may be ascribed to proteins contained in the first and second groups (belonging to energy and carbohydrate metabolism (TK, G6-PI, PGD, FBA, PPA, ATP synthase)), sulfur metabolism (GR, GST, PGDH, PAPS reductase, GDC P, and SAM synthetase), fatty acid metabolism (AspD, PspA, SQD-1), phosphorous metabolism (PhoD, PstB and SQD1), molecular chaperones (Gro-EL, FKBP-type peptidylprolyl isomerase), and antioxidative defense enzymes (SOD-A, catalase). Anabaena sp. PCC 7120 harboring proteins largely from the third group qualified as a late accumulator and A. doliolum housing majority of proteins from the fourth group emerged as the most sensitive species. Thus early up-accumulation of transporter and signaling category proteins and drastic reduction of nitrogen assimilation proteins could be taken as a vital indicator of cadmium toxicity in Anabaena spp. This article is part of a Special Issue entitled: Proteomics in India. PMID- 26021479 TI - Application of inverse probability weights in survival analysis. PMID- 26021480 TI - The lipopeptides pseudofactin II and surfactin effectively decrease Candida albicans adhesion and hydrophobicity. AB - A serious problem for humans is the propensity of Candida albicans to adhere to various surfaces and its ability to form biofilms. Surfactants or biosurfactants can affect the cell surfaces of microorganisms and block their adhesion to different substrates. This study investigated adhesion of C. albicans strains differing in cell surface hydrophobicity (CSH) to polystyrene microplates in order to compare the ability of lipopeptide biosurfactants pseudofactin (PF II) and surfactin (SU) to prevent fungal adhesion to polystyrene. The biosurfactants decreased adhesion of tested strains by 35-90 % when microplates were conditioned before the addition of cells. A 80-90 % reduction of adhesion was observed when cells were incubated together with lipopeptides in microplates. When microplates were pre-coated with biosurfactants, PF II was less active than SU, but when cells were incubated together with biosurfactants, the activity of both compounds was similar, independent of the CSH of strains. When cells were preincubated with lipopeptides and then the compounds were washed out, the adhesion of hydrophobic strains increased two times in comparison to control samples. This suggests irreversible changes in the cell wall after the treatment with biosurfactants. CSH of hydrophobic strains decreased only by 20-60 % after incubation with biosurfactants while adhesion decreased by 80-90 %; the changes in cell adhesion can be thus only partially explained through the modification of CSH. Preincubation of C. albicans with biosurfactants caused extraction of cell wall proteins with molecular mass in the range of 10-40 kDa, which is one possible mechanism of action of the tested lipopeptides. PMID- 26021481 TI - Vibrio mexicanus sp. nov., isolated from a cultured oyster Crassostrea corteziensis. AB - A bacterial strain was taxonomically characterised by means of a genomic approach comprising 16S rRNA gene sequence analysis, multilocus sequence analysis (MLSA), the DNA G+C content, whole genome analyses (ANI and GGDC) and phenotypic characterisation. The strain CAIM 1540(T) was isolated from a cultured oyster Crassostrea corteziensis in La Cruz, Sinaloa state, Mexico. The isolate was found to be catalase and oxidase positive, cells were observed to be motile, O/129 sensitive and facultatively anaerobic. The almost-complete 16S rRNA gene sequence placed this strain within the genus Vibrio; the closest related species were found to be Vibrio aestivus, Vibrio marisflavi, Vibrio maritimus and Vibrio variabilis with similarity values of 99.02, 97.05, 96.70, and 96.59 % respectively. MLSA of four housekeeping genes (ftsZ, gapA, recA, and topA) was performed with the closely related species. A draft genome sequence of strain CAIM 1540(T) was obtained. The DNA G+C content of this strain was determined to be 43.7 mol%.The ANI values with V. aestivus were 89.6 % (ANIb), 90.6 % (ANIm) and a GGDC value of 39.5 +/- 2.5 % was obtained; with V. marisflavi the genomic similarities were 71.5 % (ANIb), 85.5 % (ANIm) and 20.2 +/- 2.3 % (GGDC); with V. maritimus 72.6 % (ANIb), 85.7 % (ANIm) and 22.0 +/- 2.0 % (GGDC); and with V. variabilis 72.6 % (ANIb), 85.8 % (ANIm) and 21.6 +/- 1.6 % (GGDC). These ANI and GGDC values are below the threshold for the delimitation of prokaryotic species, i.e. 95-96 and 70 %, respectively. Phenotypic characters also showed differences with the closest related species analysed. The results presented here support the description of a novel species, for which the name Vibrio mexicanus sp. nov. is proposed, with strain CAIM 1540(T) (= CECT 8828(T), = DSM 100338(T)) as the type strain. In addition, we found that the recently described species Vibrio thalassae and Vibrio madracius might be a single species because the values of ANIb 95.8 %, ANIm 96.6 % and GGDC 70.2 +/- 2.9 % are above the accepted species thresholds. PMID- 26021482 TI - Diosmetin inhibits the expression of alpha-hemolysin in Staphylococcus aureus. AB - Staphylococcus aureus is a significant human pathogen that causes a wide range of diseases. Alpha-hemolysin (Hla), a pore-forming cytotoxin that is produced by most S. aureus strains, can cause tissue injury and plays a critical role in the virulence of this pathogen. In the present study, we discovered that diosmetin, a natural flavonoid that occurs primarily in citrus fruits and exhibits little anti S. aureus activity, could diminish the production of Hla in culture supernatants in a concentration-dependent manner. The analysis of cytotoxicity in the co culture system of S. aureus and A549 epithelial cells showed that such inhibition confers significant protection against S. aureus-mediated injury. Our results suggested that diosmetin has the potential to be a new anti-virulence drug for S. aureus infection, particularly for the targeting of Hla. PMID- 26021483 TI - Transmission of Tomato Yellow Leaf Curl Virus by Bemisia tabaci as Affected by Whitefly Sex and Biotype. AB - Bemisia tabaci is a serious pest of vegetables and other crops worldwide. The most damaging and predominant B. tabaci biotypes are B and Q, and both are vectors of tomato yellow leaf curl virus (TYLCV). Previous research has shown that Q outperforms B in many respects but comparative research is lacking on the ability of B and Q to transmit viruses. In the present study, we tested the hypothesis that B and Q differ in their ability to transmit TYLCV and that this difference helps explain TYLCV outbreaks. We compared the acquisition, retention, and transmission of TYLCV by B and Q females and males. We found that Q females are more efficient than Q males, B females, and B males at TYLCV acquisition and transmission. Although TYLCV acquisition and transmission tended to be greater for B females than B males, the differences were not statistically significant. Based on electrical penetration graphs determination of phloem sap ingestion parameters, females fed better than males, and Q females fed better than Q males, B females, or B males. These results are consistent with the occurrences of TYLCV outbreaks in China, which have been associated with the spread of Q rather than B. PMID- 26021484 TI - Molecularly Targeted Therapy of Human Hepatocellular Carcinoma Xenografts with Radio-iodinated Anti-VEGFR2 Murine-Human Chimeric Fab. AB - Vascular endothelial growth factor receptor 2 (VEGFR2) is traditionally regarded as an important therapeutic target in a wide variety of malignancies, such as hepatocellular carcinoma (HCC). We previously generated a murine-human anti VEGFR2 chimeric Fab (cFab), named FA8H1, which has the potential to treat VEGFR2 overexpressing solid tumors. Here, we investigated whether FA8H1 can be used as a carrier in molecularly targeted therapy in HCC xenograft models. FA8H1 was labeled with (131)I, and two HCC xenograft models were generated using BEL-7402 (high VEGFR2-expressing) and SMMC-7721 (low VEGFR2-expressing) cells, which were selected from five HCC cell lines. The biodistribution of (131)I-FA8H1 was determined in both models by Single-Photon Emission Computed Tomography and therapeutic effects were monitored in nude mice bearing BEL-7402 xenografts. Finally, we determined the involvement of necrosis and apoptotic pathways in treated mice using immunohistochemistry. (131)I-FA8H1 levels were dramatically reduced in blood and other viscera. The therapeutic effect of (131)I-labeled FA8H1 in the BEL-7402 model was significantly better than that by (131)I and FA8H1 alone. We observed extensive necrosis in the treated tumors, and both FasL and caspase 3 were up-regulated. Thus, (131)I-anti-VEGFR2 cFab has the potential to be used for molecularly targeted treatment of HCC overexpressing VEGFR2. PMID- 26021485 TI - Self-assembled three-dimensional and compressible interdigitated thin-film supercapacitors and batteries. AB - Traditional thin-film energy-storage devices consist of stacked layers of active films on two-dimensional substrates and do not exploit the third dimension. Fully three-dimensional thin-film devices would allow energy storage in bulk materials with arbitrary form factors and with mechanical properties unique to bulk materials such as compressibility. Here we show three-dimensional energy-storage devices based on layer-by-layer self-assembly of interdigitated thin films on the surface of an open-cell aerogel substrate. We demonstrate a reversibly compressible three-dimensional supercapacitor with carbon nanotube electrodes and a three-dimensional hybrid battery with a copper hexacyanoferrate ion intercalating cathode and a carbon nanotube anode. The three-dimensional supercapacitor shows stable operation over 400 cycles with a capacitance of 25 F g(-1) and is fully functional even at compressions up to 75%. Our results demonstrate that layer-by-layer self-assembly inside aerogels is a rapid, precise and scalable route for building high-surface-area 3D thin-film devices. PMID- 26021486 TI - Clinically applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem gliomas. AB - Pediatric brainstem glioma is an incurable malignancy because of its inoperability. As a result of their extensive tropism toward cancer and the possibility of autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to brainstem gliomas. In this study, in a good manufacturing practice (GMP) facility, we established clinically applicable hAT-MSCs expressing therapeutic genes and investigated their therapeutic efficacy against brainstem glioma in mice. For feasible clinical applications, (1) primary hAT-MSCs were cultured from human subcutaneous fat to make autologous transplantation possible, (2) hAT-MSCs were genetically engineered to express carboxyl esterase (CE) and (3) a secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) expression vector for synergistic effects was delivered by a gene transfer technology that did not result in genomic integration of the vector. (4) Human CE and sTRAIL sequences were utilized to avoid immunological side effects. The hAT MSCs expressing CE+/-sTRAIL showed significant therapeutic effects against brainstem gliomas in vitro and in vivo. However, the simultaneous expression of CE and sTRAIL had no synergistic effects in vivo. The results indicate that non viral transient single sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for brainstem gliomas in terms of therapeutic effects and safety. PMID- 26021487 TI - Dietary fibre and incidence of type 2 diabetes in eight European countries: the EPIC-InterAct Study and a meta-analysis of prospective studies. AB - AIMS/HYPOTHESIS: Intake of dietary fibre has been associated with a reduced risk of type 2 diabetes, but few European studies have been published on this. We evaluated the association between intake of dietary fibre and type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study and in a meta-analysis of prospective studies. METHODS: During 10.8 years of follow-up, 11,559 participants with type 2 diabetes were identified and a subcohort of 15,258 participants was selected for the case-cohort study. Country specific HRs were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Eighteen other cohort studies were identified for the meta-analysis. RESULTS: In the EPIC InterAct Study, dietary fibre intake was associated with a lower risk of diabetes (HRQ4 vs Q1 0.82; 95% CI 0.69, 0.97) after adjustment for lifestyle and dietary factors. Similar inverse associations were observed for the intake of cereal fibre and vegetable fibre, but not fruit fibre. The associations were attenuated and no longer statistically significant after adjustment for BMI. In the meta analysis (19 cohorts), the summary RRs per 10 g/day increase in intake were 0.91 (95% CI 0.87, 0.96) for total fibre, 0.75 (95% CI 0.65, 0.86) for cereal fibre, 0.95 (95% CI 0.87, 1.03) for fruit fibre and 0.93 (95% CI 0.82, 1.05) for vegetable fibre. CONCLUSIONS/INTERPRETATION: The overall evidence indicates that the intake of total and cereal fibre is inversely related to the risk of type 2 diabetes. The results of the EPIC-InterAct Study suggest that the association may be partially explained by body weight. PMID- 26021488 TI - Impact of high dose n-3 polyunsaturated fatty acid treatment on measures of microvascular function and vibration perception in non-alcoholic fatty liver disease: results from the randomised WELCOME trial. AB - AIMS/HYPOTHESIS: The effect of n-3 fatty acid treatment on vibration perception thresholds (VPTs) and cutaneous microvascular reactivity is not known. We tested whether: (1) a 15-18 month treatment with high dose (4 g/day) docosahexaenoic (DHA) plus eicosapentaenoic (EPA) acid improved VPT and microvascular reactivity in patients with non-alcoholic fatty liver disease; and (2) there are associations between VPT, microvascular reactivity and metabolic variables. METHODS: In the completed single centre, randomised, parallel group, placebo controlled Wessex Evaluation of fatty Liver and Cardiovascular markers in non alcoholic fatty liver disease with OMacor thErapy (WELCOME) trial, we tested the effect of DHA+EPA on VPT at 125 Hz (big toe) and the cutaneous hyperaemic response (forearm) to arterial occlusion (ratio of maximum to resting blood flux [MF/RF]). Allocation and dispensing was carried out by an independent research pharmacist; all participants and research team members were blinded to group assignment. RESULTS: In all, 51 and 49 patients were randomised to placebo and DHA+EPA, respectively (mean age 51.4 years). Of these, 32 had type 2 diabetes. Forty-six (placebo) and 47 (DHA+EPA) patients completed the study; there were no important adverse (or unexpected) effects or side effects. In multivariable adjusted regression models (intention-to-treat analyses), DHA+EPA treatment was associated with an increase in VPT (beta coefficient 1.49 [95% CI 0.04, 2.94], p = 0.04). For VPT, the adjusted mean differences (95% CIs) in the placebo and DHA+EPA treatment groups were -0.725 (-1.71, 0.25) and 0.767 (-0.21, 1.75) m/s(2), respectively. With DHA+EPA treatment, there was no change in MF/RF (beta coefficient 0.07 [95% CI -0.56, 0.70], p = 0.84), the adjusted mean differences (95% CIs) in the placebo and DHA+EPA treatment groups were -0.549 (-1.03, -0.07) and -0.295 (-0.77, 0.18) respectively. VPT was independently associated with age (beta coefficient 0.019 [95% CI 0.010, 0.029], p < 0.0001) and MF/RF (beta coefficient -0.074 [95% CI -0.132, -0.016], p = 0.013), but not with diabetes (p = 0.38). CONCLUSIONS/INTERPRETATION: High dose n-3 fatty acid treatment did not improve measures of microvascular function or vibration perception. Ageing and microvascular reactivity are associated with a measure of peripheral nerve function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00760513. FUNDING: The study was funded by the National Institute for Health Research UK and Diabetes UK. PMID- 26021489 TI - The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. AB - AIMS/HYPOTHESIS: Several forkhead box (FOX) transcription factor family members have important roles in controlling pancreatic cell fates and maintaining beta cell mass and function, including FOXA1, FOXA2 and FOXM1. In this study we have examined the importance of FOXP1, FOXP2 and FOXP4 of the FOXP subfamily in islet cell development and function. METHODS: Mice harbouring floxed alleles for Foxp1, Foxp2 and Foxp4 were crossed with pan-endocrine Pax6-Cre transgenic mice to generate single and compound Foxp mutant mice. Mice were monitored for changes in glucose tolerance by IPGTT, serum insulin and glucagon levels by radioimmunoassay, and endocrine cell development and proliferation by immunohistochemistry. Gene expression and glucose-stimulated hormone secretion experiments were performed with isolated islets. RESULTS: Only the triple compound Foxp1/2/4 conditional knockout (cKO) mutant had an overt islet phenotype, manifested physiologically by hypoglycaemia and hypoglucagonaemia. This resulted from the reduction in glucagon-secreting alpha cell mass and function. The proliferation of alpha cells was profoundly reduced in Foxp1/2/4 cKO islets through the effects on mediators of replication (i.e. decreased Ccna2, Ccnb1 and Ccnd2 activators, and increased Cdkn1a inhibitor). Adult islet Foxp1/2/4 cKO beta cells secrete insulin normally while the remaining alpha cells have impaired glucagon secretion. CONCLUSIONS/INTERPRETATION: Collectively, these findings reveal an important role for the FOXP1, 2, and 4 proteins in governing postnatal alpha cell expansion and function. PMID- 26021490 TI - Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis. AB - Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease associated with a germline mutation in the RUNX1 gene and is characterized by thrombocytopenia and an increased risk of developing myeloid malignancies. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a patient with FPD/AML possessing a nonsense mutation R174X in the RUNX1 gene. Consistent with the clinical characteristics of the disease, FPD iPSC-derived hematopoietic progenitor cells were significantly impaired in undergoing megakaryocytic differentiation and subsequent maturation, as determined by colony-forming cell assay and surface marker analysis. Notably, when we corrected the RUNX1 mutation using transcription activator-like effector nucleases in conjunction with a donor plasmid containing normal RUNX1 cDNA sequences, megakaryopoiesis and subsequent maturation were restored in FPD iPSC derived hematopoietic cells. These findings clearly indicate that the RUNX1 mutation is robustly associated with thrombocytopenia in patients with FPD/AML, and transcription activator-like effector nuclease-mediated gene correction in iPSCs generated from patient-derived cells could provide a promising clinical application for treatment of the disease. PMID- 26021491 TI - Opinion Paper: NANOMACHINES AND "NANOSOLUTIONS": THEY ARE CHANGING THE PERSPECTIVE OF MEDICAL TREATMENTS. PMID- 26021492 TI - Anti-IL-4/-13 based therapy in asthma. AB - It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of IL 4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were for the most part disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review is an update of the evidence demonstrating the effectiveness or otherwise of the targeting of the TH2 cytokines IL-4 and IL-13 with biologics in patients with asthma. PMID- 26021493 TI - [Diagnosis of infectious lymphadenitis]. AB - Adenitis is a common disorder requesting numerous medical specialties. Etiologies are dominated by viral and bacterial infections, and more rarely parasitic, or by neoplastic and inflammatory diseases. Nevertheless, etiology remains often unknown and invasive tests may be required. On nodal tissue sample, histological examination, culture and polymerase chain reaction (PCR) are realized. PCR has revolutionized the diagnostic approach and consequently, knowledge of infectious lymphadenopathy. Previously, staphylococcus, streptococcus and mycobacterium were the main infectious agents identified in lymph nodes. Since its use, new emergent microorganisms responsible of lymphadenitis have been identified. Bartonella henselae, responsible of cat scratch disease, is to date the infectious agent most often encountered in adenitis. Mycobacterium avium subsp. hominisuis has been recently described as responsible of children lymphadenitis. PCR has become an essential tool in the diagnostic process of infectious lymphadenitis. Here, we propose a literature review on infectious adenitis and we emphasize the diagnostic strategy of adenitis. PMID- 26021494 TI - Positive End-expiratory Pressure Titration after Alveolar Recruitment Directed by Electrical Impedance Tomography. AB - BACKGROUND: Electrical impedance tomography (EIT) is a real-time bedside monitoring tool, which can reflect dynamic regional lung ventilation. The aim of the present study was to monitor regional gas distribution in patients with acute respiratory distress syndrome (ARDS) during positive-end-expiratory pressure (PEEP) titration using EIT. METHODS: Eighteen ARDS patients under mechanical ventilation in Department of Critical Care Medicine of Peking Union Medical College Hospital from January to April in 2014 were included in this prospective observational study. After recruitment maneuvers (RMs), decremental PEEP titration was performed from 20 cmH 2 O to 5 cmH 2 O in steps of 3 cmH 2 O every 5-10 min. Regional over-distension and recruitment were monitored with EIT. RESULTS: After RMs, patient with arterial blood oxygen partial pressure (PaO 2) + carbon dioxide partial pressure (PaCO 2 ) >400 mmHg with 100% of fractional inspired oxygen concentration were defined as RM responders. Thirteen ARDS patients was diagnosed as responders whose PaO 2 + PaCO 2 were higher than nonresponders (419 +/- 44 mmHg vs. 170 +/- 73 mmHg, P < 0.0001). In responders, PEEP mainly increased recruited pixels in dependent regions and over-distended pixels in nondependent regions. PEEP alleviated global inhomogeneity of tidal volume and end-expiratory lung volume. PEEP levels without significant alveolar derecruitment and over-distension were identified individually. CONCLUSIONS: After RMs, PEEP titration significantly affected regional gas distribution in lung, which could be monitored with EIT. EIT has the potential to optimize PEEP titration. PMID- 26021495 TI - Fracture union in closed interlocking nail in humeral shaft fractures. AB - BACKGROUND: Fracture shaft humerus is a major cause of morbidity in patients with upper extremity injuries. The aim of this study was to evaluate the outcome of interlocking nail in humeral shaft fractures. METHODS: This study was conducted in the Department of Orthopedic Surgery in SMS and R Sharda University from January 2010 to November 2013. Seventy-eight patients were recruited from emergency and out-patient department having a close fracture of humerus shaft. All patients were operated under general anesthesia and closed reamed interlocking nailing was done. All patients were followed for 9 months. RESULTS: Out of 78 patients, 69 patients underwent union in 90-150 days with a mean of 110.68 days. Complications found in four patients who had nonunion, and five patients had delayed union, which was treated with bone grafting. All the patients were assessed clinically and radiologically for fracture healing, joint movements and implant failure. The results were excellent in 88.46% and good in 6.41% patients. Complete subjective, functional, and clinical recovery had occurred in almost 100% of the patients. CONCLUSIONS: The results of the present study indicates that in the presence of proper indications, reamed antegrade intramedullary interlocked nailing appears to be a method of choice for internal fixation of osteoporotic and pathologic fractures. PMID- 26021496 TI - Plaques of Nonstenotic Basilar Arteries with Isolated Pontine Infarction on Three dimensional High Isotropic Resolution Magnetic Resonance Imaging. AB - BACKGROUND: There are few studies for evaluating plaque characteristics of nonstenotic basilar arteries (BA). Our aim was to determine entire BA plaques with a three-dimensional volumetric isotropic turbo spin-echo acquisition (VISTA) and investigate the differences between the patients with and without isolated pontine infarction (IPI). METHODS: Twenty-four consecutive symptomatic patients with nonstenotic BA on time of flight magnetic resonance angiography (TOF MRA) were enrolled from China-Japan Friendship Hospital between January 2014 and December 2014. BA was classified as "normal" or "irregular" based on TOF MRA, and "normal wall", "slight wall-thickening", and "plaque" based on three-dimensional VISTA images. Outcomes from MRA and VISTA were compared. Patients were categorized as IPI and non-IPI groups based on the diffusion-weighted imaging. Clinical and plaque characteristics were compared between the two groups. RESULTS: A total of 1024 image slices including 311 (30.37%) plaque slices, 427 (41.70%) slight wall-thickening slices, and 286 (27.93%) normal wall slices for the entire BA from 23 patients were finally included for analysis. VISTA images detected plaques in all the 9 (100%) irregular MRA patients and 7 of 14 (50%) normal MRA patients. IPI was found in 11 (47.83%) patients. Compared to non-IPI group, the IPI group had a higher percentage of plaque slices (P = 0.001) and lower percentage of normal wall slices (P = 0.014) than non-IPI group. CONCLUSIONS: Three-dimensional VISTA images enable detection of BA plaques not visualized by MRA. BA plaques could be found in both the IPI and non-IPI group. However, IPI group showed plaques more extensively in BA than the non-IPI group. PMID- 26021497 TI - Factors Related to Complicated Grief among Bereaved Individuals after the Wenchuan Earthquake in China. AB - BACKGROUND: The Wenchuan earthquake in China caused shock and grief worldwide. Sudden bereavement caused by the earthquake led to physical disorders as well as psychological disturbances in the bereaved individuals. The bereaved had a high risk for complicated grief (CG), which may have led to significant distress and impairment in their health. However, there was few available studies on CG among disaster-bereaved individuals in China after the disaster. The aim of this study was to identify factors (demographic characteristics and disaster-related variables) associated with symptoms of CG among the bereaved 18 months after the Wenchuan earthquake. METHODS: This study was conducted with a cross-sectional design and a convenience sample of 271 bereaved individuals from three of the hardest hit areas. Data were collected by questionnaires and the instruments used in the study were: General questionnaire and Inventory of CG (ICG). Multivariate linear regression analysis was used to identify factors associated with symptoms of CG. RESULTS: The mean score on ICG was 52.77 (standard deviation: 10.00). Being female and loss of a child were related to higher level of CG while having another child after the disaster and receiving psychological counseling experience were associated with lower level of CG. Forty-nine percent of the variance of CG was explained by these identified factors. CONCLUSIONS: Eighteen months after the Wenchuan earthquake, the symptoms of CG among the bereaved were higher than the previous studies with bereaved individuals. This study uncovers a vulnerable population of the bereaved at high risk for CG. Early assessments, targeted interventions, and policy support tailored for the disaster-bereaved individuals are necessary to identify and alleviate symptoms of CG and to improve their well-being. PMID- 26021498 TI - Diagnostic Utility of Diffusion-weighted Magnetic Resonance Imaging in Differentiating Small Solid Renal Tumors (<= 4 cm) at 3.0T Magnetic Resonance Imaging. AB - BACKGROUND: The aim of this study was to assess the performance of apparent diffusion coefficient (ADC) measurement obtained with diffusion-weighted magnetic resonance imaging (DW-MRI) to distinguish renal cell carcinomas (RCCs) from small benign solid renal tumors (<= 4 cm). METHODS: In this cross-sectional study, 49 consecutive patients with histopathologically confirmed small solid renal tumors, and seven healthy volunteers were imaged using nonenhanced MRI and DW-MRI. The ADC map was calculated using the b values of 0, 50, 400, and 600 s/mm 2 and values compared via the Kruskal-Wallis and Mann-Whitney tests. The utility of ADC for differentiating RCCs and benign lesions was assessed using a receiver operating characteristic curve. Multiple nonenhanced MRI features were analyzed by Logistic regression. RESULTS: The tumors consisted of 33 cases of clear-cell RCCs (ccRCCs) and 16 cases of benign tumors, including 14 cases of minimal fat angiomyolipomas and 2 cases of oncocytomas. The ADCs showed significant differences among benign tumors ([0.90 +/- 0.52] * 10-3 mm 2 /s), ccRCCs ([1.53 +/- 0.31] * 10-3 mm 2 /s) and the normal renal parenchyma ([2.22 +/- 0.12] * 10-3 mm 2 /s) (P < 0.001). Moreover, there was statistically significant difference between high and low-grade ccRCCs (P = 0.004). Using a cut-off ADC of 1.36 * 10-3 mm 2 /s, DW-MRI resulted in an area under the curve (AUC), sensitivity, and specificity equal to 0.839, 75.8%, and 87.5%, respectively. Nonenhanced MRI alone and the combination of imaging methods led to an AUC, sensitivity and specificity equal to 0.919, 93.9%, and 81.2%, 0.998, 97%, and 100%, respectively. The Logistic regression showed that the location of the center of the tumor (inside the contour of the kidney) and appearance of stiff blood vessel were significantly helpful for diagnosing ccRCCs. CONCLUSIONS: DW-MRI has potential in distinguishing ccRCCs from benign lesions in human small solid renal tumors (<= 4 cm), and in increasing the accuracy for diagnosing ccRCCs when combined with nonenhanced MRI. PMID- 26021499 TI - Relationships of High-sensitive C-reactive Protein and P-wave Dispersion in Lone Atrial Fibrillation. AB - BACKGROUND: Current evidence links atrial fibrillation (AF) to the inflammation. Inflammatory indexes such as high-sensitive C-reactive protein (hs-CRP) have been related to the development and persistence of AF. However, the role of inflammation in the atrial electrophysiological remodeling indexed by P-wave dispersion (P d ) remains unclear. METHODS: The study consisted of 71 patients with lone paroxysmal AF (AF group) and 71 age- and gender-matched controls of paroxysmal supraventricular tachycardia without history of AF (control group). Electrocardiography, P d , hs-CRP, and other clinical characteristics were compared between the two groups. RESULTS: There was no significant difference between the two groups regarding age, gender, hyperlipidemia, etc. Compared to controls, left atrial diameter (44 +/- 7 vs 39 +/- 7 mm), P d (49 +/- 13 vs 26 +/ 8 ms), and hs-CRP (2.17 [1.46-2.89] vs 1.12 [0.74-1.41] mg/L) were increased (P < 0.05), respectively. Linear regression identified hs-CRP as an independent correlation of P d level both in the total population and the AF group (r = 0.464 and 0.313; P < 0.001, respectively). Multiple logistic regression revealed hs-CRP as an independent determinant of AF (odds ratio [OR] =15.430, 95% confidence interval: 6.031-39.476: P <0.001). Further adjusted for P d , both P d and hs-CRP were independent predictors for AF, but the OR for hs-CRP in predicting AF has been attenuated from 15.430 to 6.246. CONCLUSIONS: In lone AF, P d and plasma hs CRP concentration are inter-associated and related to AF. The interaction between hs-CRP and AF may be mediated by P d , suggesting an important role of inflammation in the atrial electrophysiological remodeling predisposing to AF. PMID- 26021500 TI - Clinical Control Study of Endoscopic Full-thickness Resection and Laparoscopic Surgery in the Treatment of Gastric Tumors Arising from the Muscularis Propria. AB - BACKGROUND: Gastric stromal tumors arising from the muscularis propria are located in deeper layers. Endoscopic resection may be contraindicated due to the possibility of perforation. These tumors are therefore usually removed by surgical or laparoscopic procedures. This study evaluated the curative effects, safety and feasibility of endoscopic full-thickness resection (EFR) of gastric stromal tumors originating from the muscularis propria. METHODS: This study enrolled 92 patients with gastric stromal tumors >2.5 cm originating from the muscularis propria. Fifty patients underwent EFR, and 42 underwent laparoscopic intragastric surgery. Operation time, complete resection rate, length of hospital stay, incidence of complications, and recurrence rates were compared in these two groups. RESULTS: EFR resulted in complete resection of all 50 gastric stromal tumors, with a mean procedure time of 85 +/- 20 min, a mean hospitalization time of 7.0 +/- 1.5 days and no complications. Laparoscopic intragastric surgery also resulted in a 100% complete resection rate, with a mean operation time of 88 +/- 12 min and a mean hospitalization period of 7.5 +/- 1.6 days. The two groups did not differ significantly in operation time, complete resection rates, hospital stay or incidence of complications (P > 0.05). No patient in either group experienced tumor recurrence. CONCLUSIONS: EFR technique is effective and safe for the resection of gastric stromal tumors arising from the muscularis propria. PMID- 26021501 TI - Early results of coronary endarterectomy combined with coronary artery bypass grafting in patients with diffused coronary artery disease. AB - BACKGROUND: It is still a challenge for the cardiac surgeons to achieve adequate revascularization for diffused coronary artery disease (CAD). Coronary endarterectomy (CE) offers an alternative choice of coronary artery reconstruction and revascularization. In this study, short-term result of CE combined with coronary artery bypass graft (CABG) was discussed in the treatment for the diffused CAD. METHODS: From January 2012 to April 2014, 221 cases of CABG were performed by the same surgeon in our unit. Among these cases, 38 cases of CE + CABG were performed, which was about 17.2% (38/221) of the cohort. All these patients were divided into two groups: CE + CABG group (Group A) and CABG alone group (Group B). All clinical data were compared between the two groups, and postoperative complications and in-hospital mortality were analyzed. The categorical and continuous variables were analyzed by Chi-square test and Student's t-test respectively. RESULTS: Diabetes mellitus, hypertension, hyperlipidemia, and peripheral vascular disease were more common in group A. In this cohort, a total of 50 vessels were endarterectomized. Among them, CE was performed on left anterior descending artery in 11 cases, on right coronary artery in 29 cases, on diagonal artery in 3 cases, on intermediate artery in 2 cases, on obtuse marginal artery in 5 cases. There was no hospital mortality in both groups. The intro-aortic balloon pump was required in 3 cases in Group A (3/38), which was more often than that in Group B (3/183). At the time of follow up, coronary computed tomography angiogram showed all the grafts with CE were patent (50/50). There is no cardio-related mortality in both groups. All these patients were free from coronary re-intervention. CONCLUSIONS: Coronary endarterectomy + CABG can offer satisfactory result for patients with diffused CAD in a short-term after the operation. PMID- 26021502 TI - Correlation of Lower Concentrations of Hydrogen Sulfide with Activation of Protein Kinase CbetaII in Uremic Accelerated Atherosclerosis Patients. AB - BACKGROUND: Hydrogen sulfide (H 2 S) plays a protective role in chronic hemodialysis (CHD) patients. In this study, we further investigate the relationship between H 2 S and conventional protein kinase CbetaII (cPKCbetaII) in CHD patients with uremic accelerated atherosclerosis (UAAS). METHODS: A total of 30 healthy people, 30 CHD patients without AS and 30 CHD patients with AS (CHD + AS) were studied. Plasma H 2 S was measured with a sulfide sensitive electrode, and cPKCbetaII membrane translocation was detected by Western blotting. RESULTS: Plasma H 2 S in CHD + AS group was significantly lower than that in CHD patients. cPKCbetaII membrane translocation in CHD + AS group increased significantly compared with CHD group. Plasma H 2 S concentration was negatively correlated with cPKCbetaII membrane translocation in CHD + AS patients. CONCLUSIONS: These findings suggest a possible linkage between H 2 S metabolism and cPKCbetaII activation, which may contribute to the development of UAAS in CHD patients. PMID- 26021503 TI - Clinical and angiographic predictors of major side branch occlusion after main vessel stenting in coronary bifurcation lesions. AB - BACKGROUND: Major side branch (SB) occlusion is one of the most serious complications during percutaneous coronary intervention (PCI) for bifurcation lesions. We aimed to characterize the incidence and predictors of major SB occlusion during coronary bifurcation intervention. METHODS: We selected consecutive patients undergoing PCI (using one stent or provisional two stent strategy) for bifurcation lesions with major SB. All clinical characteristics, coronary angiography findings, PCI procedural factors and quantitative coronary angiographic analysis data were collected. Multivariate logistic regression analysis was performed to identify independent predictors of SB occlusion. SB occlusion after main vessel (MV) stenting was defined as no blood flow or any thrombolysis in myocardial infarction (TIMI) flow grade decrease in SB after MV stenting. RESULTS: Among all 652 bifurcation lesions, 32 (4.91%) SBs occluded. No blood flow occurred in 18 lesions and TIMI flow grade decreasing occurred in 14 lesions. In multivariate analysis, diameter ratio between MV/SB (odds ratio [OR]: 7.71, 95% confidence interval [CI]: 1.53-38.85, P = 0.01), bifurcation angle (OR: 1.03, 95% CI: 1.02-1.05, P < 0.01), diameter stenosis of SB before MV stenting (OR: 1.05, 95% CI: 1.03-1.07, P < 0.01), TIMI flow grade of SB before MV stenting (OR: 3.59, 95% CI: 1.48-8.72, P < 0.01) and left ventricular eject fraction (LVEF) (OR: 1.06, 95% CI: 1.02-1.11, P < 0.01) were independent predictors of SB occlusion. CONCLUSIONS: Among clinical and angiographic findings, diameter ratio between MV/SB, bifurcation angle, diameter stenosis of SB before MV stenting, TIMI flow grade of SB before MV stenting and LVEF were predictive of major SB occlusion after MV stenting. PMID- 26021504 TI - Application of percutaneous balloon mitral valvuloplasty in patients of rheumatic heart disease mitral stenosis combined with tricuspid regurgitation. AB - BACKGROUND: Tricuspid regurgitation (TR) is frequently associated with severe mitral stenosis (MS), the importance of significant TR was often neglected. However, TR influences the outcome of patients. The aim of this study was to investigate the efficacy and safety of percutaneous balloon mitral valvuloplasty (PBMV) procedure in rheumatic heart disease patients with mitral valve (MV) stenosis and tricuspid valve regurgitation. METHODS: Two hundred and twenty patients were enrolled in this study due to rheumatic heart disease with MS combined with TR. Mitral balloon catheter made in China was used to expand MV. The following parameters were measured before and after PBMV: MV area (MVA), TR area (TRA), atrial pressure and diameter, and pulmonary artery pressure (PAP). The patients were followed for 6 months to 9 years. RESULTS: After PBMV, the MVAs increased significantly (1.7 +/- 0.3 cm 2 vs. 0.9 +/- 0.3 cm 2 , P < 0.01); TRA significantly decreased (6.3 +/- 1.7 cm 2 vs. 14.2 +/- 6.5 cm 2 , P < 0.01), right atrial area (RAA) decreased significantly (21.5 +/- 4.5 cm 2 vs. 25.4 +/- 4.3 cm 2 , P < 0.05), TRA/RAA (%) decreased significantly (29.3 +/- 3.2% vs. 44.2 +/- 3.6%, P < 0.01). TR velocity (TRV) and TR continue time (TRT) as well as TRV * TRT decreased significantly (183.4 +/- 9.4 cm/s vs. 254.5 +/- 10.7 cm/s, P < 0.01; 185.7 +/- 13.6 ms vs. 238.6 +/- 11.3 ms, P < 0.01; 34.2 +/- 5.6 cm vs. 60.7 +/- 8.5 cm, P < 0.01, respectively). The postoperative left atrial diameter (LAD) significantly reduced (41.3 +/- 6.2 mm vs. 49.8 +/- 6.8 mm, P < 0.01) and the postoperative right atrial diameter (RAD) significantly reduced (28.7 +/- 5.6 mm vs. 46.5 +/- 6.3 mm, P < 0.01); the postoperative left atrium pressure significantly reduced (15.6 +/- 6.1 mmHg vs. 26.5 +/- 6.6 mmHg, P < 0.01), the postoperative right atrial pressure decreased significantly (13.2 +/- 2.4 mmHg vs. 18.5 +/- 4.3 mmHg, P < 0.01). The pulmonary arterial pressure decreased significantly after PBMV (48.2 +/- 10.3 mmHg vs. 60.6 +/- 15.5 mmHg, P < 0.01). The symptom of chest tightness and short of breath obviously alleviated. All cases followed-up for 6 months to 9 years (average 75 +/- 32 months), 2 patients with severe regurgitation died (1 case of massive cerebral infarction, and 1 case of heart failure after 6 years and 8 years, respectively), 2 cases lost access. At the end of follow-up, MVA has been reduced compared with the postoperative (1.4 +/- 0.4 cm 2 vs. 1.7 +/- 0.3 cm 2 , P < 0.05); LAD slightly increased compared with the postoperative (45.2 +/- 5.7 mm vs. 41.4 +/- 6.3 mm, P < 0.05), RAD slightly also increased compared with the postoperative (36.1 +/- 6.3 mm vs. 28.6 +/- 5.5 mm, P < 0.05), but did not recover to the preoperative level. TRA slightly increased compared with the postoperative, but the difference was not statistically significant (P > 0.05). The PAP and left ventricular ejection fraction appeared no statistical difference compared with the postoperative (P > 0.05), the remaining patients without serious complications. CONCLUSIONS: PBMV is a safe and effective procedure for MS combined with TR in patients of rheumatic heart disease. It can alleviate the symptoms and reduce the size of TR. It can also improve the quality-of-life and prognosis. Its recent and mid-term efficacy is certain. While its long-term efficacy remains to be observed. PMID- 26021505 TI - Clinical Characteristics and Prognosis of End-stage Hypertrophic Cardiomyopathy. AB - BACKGROUND: End-stage hypertrophic cardiomyopathy (HCM) is complicated by substantial adverse events. However, few studies have focused on electrocardiographic features and their prognostic values in HCM. This study aimed to evaluate the clinical manifestations and prognostic value of electrocardiography in patients with end-stage HCM. METHODS: End-stage HCM patients were enrolled from a total of 1844 consecutive HCM patients from April 2002 to November 2013 at Fuwai Hospital. Clinical data, including medical history, electrocardiography, and echocardiography, were analyzed. Cox hazards regression analysis was used to assess the risk factors for cardiovascular mortality. RESULTS: End-stage HCM was identified in 99 (5.4%) patients, averaged at 52 +/- 16 years old at entry. Atrial fibrillation was observed in 53 patients and mural thrombus in 19 patients. During 3.9 +/- 3.0 years of follow-up, embolic stroke, refractory heart failure, and death or transplantation were observed in 20, 39, and 51 patients, respectively. The incidence of annual mortality was 13.2%. Multivariate Cox hazards regression analysis identified New York Heart Association Class (NYHA) III/IV at entry (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.05-3.80; P = 0.036), left bundle branch block (LBBB) (HR: 2.80; 95% CI: 1.47-5.31; P = 0.002), and an abnormal Q wave (HR: 2.21; 95% CI: 1.16 4.23; P = 0.016) as independent predictors of cardiovascular death, in accordance with all-cause death and heart failure-related death. CONCLUSIONS: LBBB and an abnormal Q wave are risk factors of cardiovascular mortality in end-stage HCM and provide new evidence for early intervention. Susceptibility of end-stage HCM patients to mural thrombus and embolic events warrants further attention. PMID- 26021506 TI - Transmastoid approach for resurfacing the superior semicircular canal dehiscence with a dumpling structure. AB - BACKGROUND: Superior semicircular canal dehiscence (SSCD) is gradually recognized by otologists in recent years. The patients with SSCD have a syndrome comprising a series of vestibular symptoms and hearing function disorders which can be cured by the operation. In this study, we evaluated the characteristics of patients with SSCD and determined the effectiveness of treating this syndrome by resurfacing the canal via the transmastoid approach using a dumpling structure. METHODS: Patients with SSCD, confirmed by high-resolution computed tomography and hospitalized at Beijing Tongren Hospital between November 2009 and October 2012, were included in the study. All of the patients underwent the unilateral transmastoid approach for resurfacing the canal, and received regular follow-up after surgery. Data from preoperative medical records and postoperative follow-up were comparatively analyzed to evaluate the effect of surgery. RESULTS: In total, 10 patients and 13 ears (three left ears, four right ears, three bilateral ears) were evaluated in the study, which included 7 men and 3 women. Different symptoms and distinctive manifestations of vestibular evoked myogenic potential were found in these patients. After surgery, 4 patients had complete resolution, 5 had partial resolution, and 1 patient, with bilateral SSCD, had aggravation. None of the patients suffered from serious complications such as sensorineural hearing loss, facial paralysis, cerebrospinal fluid leakage, or intracranial hypertension. CONCLUSIONS: In patients with unilateral SSCD, resurfacing the canal via the transmastoid approach using a dumpling structure is an effective and safe technique. However, more consideration is needed for patients with bilateral SSCD. PMID- 26021507 TI - Clinical and Magnetic Resonance Imaging Results of Arthroscopic Repair of Intratendinous Partial-thickness Rotator Cuff Tears. AB - BACKGROUND: Partial-thickness rotator cuff tears (PTRCTs) are being diagnosed more often because of high-resolution magnetic resonance imaging (MRI). Compared with articular and bursal side tears, there have been few studies about evaluating the clinical and structural outcomes after intratendinous tear repair. METHODS: From 2008 to 2012, 33 consecutive patients with intratendinous PTRCTs underwent arthroscopic repair. All of them were retrospectively evaluated. The University of California at Los Angeles (UCLA) and constant scores were evaluated before operation and at the final follow-up. Postoperative cuff integrity was determined using MRI according to Sugaya's classification. RESULTS: At the 2-year follow-up, the average UCLA score increased from 16.7 +/- 1.9 to 32.5 +/- 3.5, and the constant score increased from 66.2 +/- 10.5 to 92.4 +/- 6.9 (P < 0.001). Twenty seven patients received follow-up MRI examinations at an average of 15.2 months after surgery. Of these 27 patients, 22 (81.5%) had a healed tendon, and five patients had partial tears. There was no association between functional and anatomic results. CONCLUSIONS: For intratendinous PTRCT, clinical outcomes and tendon healing showed good results at a minimum 2-year after arthroscopic repair. PMID- 26021508 TI - Postoperative Regulatory T-Cells and Natural Killer Cells in Stage I Nonsmall Cell Lung Cancer Underwent Video-assisted Thoracoscopic Lobectomy or Thoracotomy. AB - BACKGROUND: Regulatory T-cells (Treg) play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer (NSCLC). Video-assisted thoracoscopic (VATS) lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient's immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer (NK) cell levels in NSCLC patients who underwent major lobectomy by VATS or thoracotomy. METHODS: Totally, 98 consecutive patients with stage I NSCLC were recruited and assigned into VATS or thoracotomy groups. Peripheral blood samples were taken on 1-day prior to operation, postoperative days (PODs) 1, 3, 7, 30, and 90. Circulating Treg and NK cell counts were assayed by flow cytometry, defined as CD4 + CD25 + CD127 low cells in CD4 + lymphocytes and CD56 + 16 + CD3- cells within CD45 + leukocytes respectively. With SPSS software version 21.0 (SPSS Inc., USA), differences between VATS and thoracotomy groups were determined by one-way analysis of variance (ANOVA), and differences between preoperative baseline and PODs in each group were evaluated by one-way ANOVA Dunnett t-test. RESULTS: In both groups, postoperative Treg percentages were lower than preoperative status. No statistical difference was found between VATS and thoracotomy groups on PODs 1, 3, 7, and 30. On POD 90, Treg percentage in VATS group was significantly lower than in thoracotomy group (5.26 +/- 2.75 vs. 6.99 +/- 3.60, P = 0.012). However, a higher level of NK was found on all PODs except on POD 90 in VATS group, comparing to thoracotomy group. CONCLUSIONS: Lower Treg level on POD 90 and higher NK levels on PODs 1, 3, 7, 30 in VATS group might imply better preserved cell-mediated immune function in NSCLC patients, than those in thoracotomy group. PMID- 26021509 TI - Changes in Rat Brain MicroRNA Expression Profiles Following Sevoflurane and Propofol Anesthesia. AB - BACKGROUND: Sevoflurane and propofol are widely used anesthetics for surgery. Studies on the mechanisms of general anesthesia have focused on changes in protein expression properties and membrane lipid. MicroRNAs (miRNAs) regulate neural function by altering protein expression. We hypothesize that sevoflurane and propofol affect miRNA expression profiles in the brain, expect to understand the mechanism of anesthetic agents. METHODS: Rats were randomly assigned to a 2% sevoflurane group, 600 MUg.kg - 1.min - 1 propofol group, and a control group without anesthesia (n = 4, respectively). Treatment group was under anesthesia for 6 h, and all rats breathed spontaneously with continuous monitoring of respiration and blood gases. Changes in rat cortex miRNA expression profiles were analyzed by miRNA microarrays and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Differential expression of miRNA using qRT-PCR among the control, sevoflurane, and propofol groups were compared using one-way analysis of variance (ANOVA). RESULTS: Of 677 preloaded rat miRNAs, the microarray detected the expression of 277 miRNAs in rat cortex (40.9%), of which 9 were regulated by propofol and (or) sevoflurane. Expression levels of three miRNAs (rno-miR-339-3p, rno-miR-448, rno-miR-466b-1FNx01) were significantly increased following sevoflurane and six (rno-miR-339-3p, rno-miR-347, rno-miR 378FNx01, rno-miR-412FNx01, rno-miR-702-3p, and rno-miR-7a-2FNx01) following propofol. Three miRNAs (rno-miR-466b-1FNx01, rno-miR-3584-5p and rno-miR-702-3p) were differentially expressed by the two anesthetic treatment groups. CONCLUSIONS: Sevoflurane and propofol anesthesia induced distinct changes in brain miRNA expression patterns, suggesting differential regulation of protein expression. Determining the targets of these differentially expressed miRNAs may help reveal both the common and agent-specific actions of anesthetics on neurological and physiological function. PMID- 26021510 TI - Correlation of in vivo and in vitro methods in measuring choroidal vascularization volumes using a subretinal injection induced choroidal neovascularization model. AB - BACKGROUND: In vivo quantification of choroidal neovascularization (CNV) based on noninvasive optical coherence tomography (OCT) examination and in vitro choroidal flatmount immunohistochemistry stained of CNV currently were used to evaluate the process and severity of age-related macular degeneration (AMD) both in human and animal studies. This study aimed to investigate the correlation between these two methods in murine CNV models induced by subretinal injection. METHODS: CNV was developed in 20 C57BL6/j mice by subretinal injection of adeno-associated viral delivery of a short hairpin RNA targeting sFLT-1 (AAV.shRNA.sFLT-1), as reported previously. After 4 weeks, CNV was imaged by OCT and fluorescence angiography. The scaling factors for each dimension, x, y, and z (MUm/pixel) were recorded, and the corneal curvature standard was adjusted from human (7.7) to mice (1.4). The volume of each OCT image stack was calculated and then normalized by multiplying the number of voxels by the scaling factors for each dimension in Seg3D software (University of Utah Scientific Computing and Imaging Institute, available at http://www.sci.utah.edu/cibc-software/seg3d.html). Eighteen mice were prepared for choroidal flatmounts and stained by CD31. The CNV volumes were calculated using scanning laser confocal microscopy after immunohistochemistry staining. Two mice were stained by Hematoxylin and Eosin for observing the CNV morphology. RESULTS: The CNV volume calculated using OCT was, on average, 2.6 times larger than the volume calculated using the laser confocal microscopy. The correlation statistical analysis showed OCT measuring of CNV correlated significantly with the in vitro method (R 2 =0.448, P = 0.001, n = 18). The correlation coefficient for CNV quantification using OCT and confocal microscopy was 0.693 (n = 18, P = 0.001). CONCLUSIONS: There is a fair linear correlation on CNV volumes between in vivo and in vitro methods in CNV models induced by subretinal injection. The result might provide a useful evaluation of CNV both for the studies using CNV models induced by subretinal injection and human AMD studies. PMID- 26021511 TI - Protective effects of salubrinal on liver injury in rat models of brain death. AB - BACKGROUND: Previous studies have indicated that endoplasmic reticulum stress participates in and mediates liver injury and apoptosis in brain-dead (BD) rats. In this study, we observed the effect of salubrinal (Sal, Sigma, USA) on liver cells in BD rats and explored its relevant mechanisms. METHODS: Thirty Sprague Dawley rats were equally randomized into three groups: BD group, Sal group, and DMSO group. The BD models were established by increasing intracranial pressure in a modified, slow, and intermittent way. In the drug groups, Sal was administered 1 h before the induction of BD. After modeling was completed, the blood and liver samples were harvested. CHOP and Caspase-12 mRNA expression was detected using quantitative polymerase chain reaction. PKR-like ER kinase (PERK), P-eukaryotic translation initiation factor 2alpha (eIF2alpha), eIF2alpha, CHOP and caspase-12 expression was detected using western blotting (WB). CHOP and caspase-12 distribution and expression in liver tissues were determined using immunohistochemistry (IHC). Alanine aminotransferase and aspartate aminotransferase level were detected using an automatic biochemical analyzer. Hepatic cell apoptosis was detected using TUNEL. The results were analyzed using Quantity-one v4.62 software (Bio-Rad, USA). RESULTS: CHOP and caspase-12 expression and PERK, eIF2alpha, and P-eIF2alpha protein expression showed no significant difference between BD group and DMSO group. Compared with BD group, Sal group had a significantly higher P-eIF2C level and a lower P-PERK level 2 h and 6 h after BD (P < 0.05). However, eIF2alpha expression showed no significant difference (P > 0.05). After the Sal treatment, CHOP and caspase-12 mRNA expression significantly decreased 4 h after BD (P < 0.05). WB and IHC indicated that CHOP and caspase-12 expression also significantly decreased after Sal treatment. Sal was associated with improved liver function and decreased hepatic cell apoptosis. CONCLUSIONS: Sal can significantly reduce apoptosis in hepatic cells of BD rats. This protective effect may be achieved via the PERK-eIF2alpha signaling pathway. PMID- 26021512 TI - Thymosin Beta-4 Recombinant Adeno-associated Virus Enhances Human Nucleus Pulposus Cell Proliferation and Reduces Cell Apoptosis and Senescence. AB - BACKGROUND: Thymosin beta-4 (TB-4) is considered key roles in tissue development, maintenance and pathological processes. The study aimed to prove TB-4 positive biological function on nucleus pulposus (NP) cell apoptosis and slowing the process of cell aging while increasing the cell proliferation. METHODS: TB-4 recombinant adeno-associated virus (AAV) was constructed and induced to human NP cells. Cell of same group were cultured without gene modification as controlled group. Proliferation capacity and cell apoptosis were observed during 6 passages of the cells. Morphology and expression of the TB-4 gene were documented as parameter of cell activity during cell passage. RESULTS: NP cells with TB-4 transfection has normal TB-4 expression and exocytosis. NP cells with TB-4 transfection performed significantly higher cell activity than that at the control group in each generation. TB-4 recombinant AAV-transfected human NP cells also show slower cell aging, lower cell apoptosis and higher cell proliferation than control group. CONCLUSIONS: TB-4 can prevent NP cell apoptosis, slow NP cell aging and promote NP cell proliferation. AAV transfection technique was able to highly and stably express TB-4 in human NP cells, which may provide a new pathway for innovation in the treatment of intervertebral disc degenerative diseases. PMID- 26021513 TI - Efficacy of mild hypothermia for the treatment of patients with cardiac arrest. AB - BACKGROUND: Therapeutic hypothermia has been recommended for the treatment of cardiac arrest patients who remain comatose after the return of spontaneous circulation. The aim of this study was to evaluate the effectiveness and safety of mild hypothermia on patients with cardiac arrest by conducting a meta analysis. METHODS: The relevant trials were searched in Cochrane Library, PubMed, Web of Science, Embase, CNKI and Wan Fang Data from the date of their establishment to October 2014. Thereafter, the studies retrieved were screened based on predefined inclusion and exclusion criteria. Data were extracted, and the quality of the included studies was evaluated. A meta-analysis was conducted using the Cochrane Collaboration Review Manager 5.2 software. RESULTS: Six randomized controlled trials involving 531 cases were included, among which 273 cases were assigned to the treatment group and the other 258 cases to the control group. The meta-analysis indicated that mild hypothermia therapy after cardiac arrest produced significant differences in survival rate (relative risk [RR] =1.23, 95% confidence interval [CI]: 1.02-1.48, P = 0.03) and neurological function (RR = 1.33, 95% CI: 1.08-1.65, P = 0.007) after 6 months compared with normothermia therapy. However, no significant differences were observed in the survival to the hospital discharge (RR = 1.35, 95% CI: 0.87-2.10, P = 0.18), favorable neurological outcome at hospital discharge (RR = 1.53, 95% CI: 0.95 2.45, P = 0.08) and adverse events. CONCLUSIONS: The meta-analysis demonstrated that mild hypothermia can improve the survival rate and neurological function of patients with cardiac arrest after 6 months. On the other hand, regarding the survival to hospital discharge, favorable neurological outcome at hospital discharge, and adverse events, our meta-analysis produced nonsignificant results. PMID- 26021515 TI - Suspected Pulmonary Thromboembolism and Deep Venous Thrombosis: A Comprehensive 64-slice Multidetector Computed Tomography Diagnosis in Gynecologic Patients. PMID- 26021514 TI - Evidence for DNA damage as a biological link between diabetes and cancer. AB - OBJECTIVE: This review examines the evidence that: Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage; DNA damage can cause mutations; and DNA mutation is linked to carcinogenesis. DATA SOURCES: We retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis. STUDY SELECTION: We included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes. RESULTS: There are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification (i.e., oxidation). Emerging experimental data suggest that signal pathways (i.e., Akt/tuberin) link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk. CONCLUSIONS: This review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer. PMID- 26021516 TI - Brain Abscess Caused by Bacillus megaterium in an Adult Patient. PMID- 26021517 TI - The ethics of prescription of placebos to patients with major depressive disorder. PMID- 26021518 TI - Four-branch Prosthetic Graft Used for Stanford Type A Aortic Dissection with Aberrant Right Subclavian Artery. PMID- 26021519 TI - Healing effects of omalizumab in a patient with cholinergic urticaria associated severe dyspeptic complaints. PMID- 26021520 TI - Cerebral Hemorrhage Complicating Heparin-induced Thrombocytopenia after Percutaneous Coronary Intervention: A Clinical Dilemma of Medical Treatment. PMID- 26021521 TI - Diseases of the Equine Urinary System. AB - Uncommon diseases of the equine urinary system span a variety of etiologies and frequently have nonspecific clinical presentations. Because of the infrequency of equine urinary disease and inconsistencies in clinical symptoms, diagnosis and subsequent treatment of urinary disease in this species may be challenging. This article reviews various diseases of the equine urinary system, morphologies, and potential discriminating clinical and clinicopathologic presentations to aid the clinician in determining a definitive diagnosis in practice. PMID- 26021522 TI - Field Necropsy of the Horse. AB - Being able to conduct an equine field necropsy in a safe and proficient manner is a helpful skill for the equine practitioner. Use of a systematic process enables the practitioner to develop a familiarity with normal anatomic positioning and tissue appearance such that abnormalities are quickly identified. This article outlines a systematic necropsy protocol that can be used to investigate mortality events and clinical questions. PMID- 26021524 TI - Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review. AB - BACKGROUND/AIMS: To systematically assess contemporary knowledge regarding the effectiveness and safety of bisphosphonates (BPs) in children with osteogenesis imperfecta (OI). METHODS: PubMed/MEDLINE, Embase, and Cochrane were searched for eligible articles up to June 2014. Studies eligible for inclusion were (randomized) controlled trials assessing the effects of BPs in children with OI. Methodological quality was assessed independently by 4 reviewers using the Cochrane Collaboration's tool for risk of bias. RESULTS: Ten studies (519 children) were included. Four studies (40%) showed a low risk of bias. All studies investigating lumbar spine areal bone mineral density indicated a significant increase as a result of BP treatment. Most studies observed a significant decrease in fracture incidence. The most frequently reported adverse events were gastrointestinal complaints, fever, and muscle soreness. A significant decrease in (bone) pain due to BP treatment was observed in more than half of the studies. Most studies measuring urinary markers of bone resorption reported a significant decrease. The majority of studies with intravenous treatment showed a significant increase in lumbar projection area, whereas studies with oral treatment did not. CONCLUSIONS: Treatment with oral or intravenous BPs in children with OI results in an increase in bone mineral density and seems to be safe and well tolerated. PMID- 26021523 TI - Podocyte structural parameters do not predict progression to diabetic nephropathy in normoalbuminuric type 1 diabetic patients. AB - BACKGROUND: Podocyte injury has been implicated in diabetic nephropathy (DN) ranging from normoalbuminuria to proteinuria in both type 1 and type 2 diabetes. METHODS: To determine whether podocyte structural parameters predict DN risk in initially normoalbuminuric long-standing type 1 diabetic patients, we performed a nested case-control study in sex and diabetes duration-matched progressors (progression to proteinuria or ESRD, n = 10), non-progressors (normoalbuminuric at follow-up, n = 10), and non-diabetic controls (n = 10). RESULTS: HbA1c and diastolic blood pressure were higher in progressors versus non-progressors. Podocyte number per glomerulus, numerical density of podocyte per glomerulus, and foot process width were not different among groups. The glomerular basement membrane width was greater in progressors versus non-progressors or controls, and in non-progressors versus controls. As expected, the mesangial fractional volume was greater in progressors and non-progressors versus controls, with no differences between progressors and non-progressors. CONCLUSION: This study does not indicate that podocyte structural changes are preconditions for later DN progression in initially normoalbuminuric type 1 diabetic patients. However, this does not preclude an important role for podocyte injury at a later stage of DN. PMID- 26021525 TI - Downregulation of BDNF Expression by PKC and by TNF-alpha in Human Endothelial Cells. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin best characterized for its survival and differentiative effects on neurons. Recent studies demonstrated that BDNF and its receptors are also expressed in the peripheral vasculature, where it stimulates angiogenesis and promotes the survival of endothelial cells. This study was designed to investigate the angiogenic effects of BDNF and its expressional regulation by tumor necrosis factor (TNF-alpha) and protein kinase C (PKC) in endothelial cells. In the Matrigel angiogenesis assay, BDNF-stimulated vascular tube formation of human umbilical vein endothelial cells (HUVEC) was completely blocked by an inhibition of the TrkB receptor, but only partially inhibited by the inhibition of the p75(NTR) signaling. Treatment of HUVEC and HUVEC-derived EA.hy 926 cells with TNF-alpha resulted in a downregulation of BDNF expression, which could be prevented by the TNFR1 antagonist WP9QY. BDNF downregulation by TNF-alpha was associated with decreased angiogenic activity of HUVEC. The effect of TNF-alpha on BDNF expression could not be abolished by the inhibition of PKC. Treatment of HUVEC and EA.hy 926 cells with PKC-activating phorbol esters (phorbol-12-myristate-13-acetate, PMA or phorbol-12,13-dibutyrate) resulted in a downregulation of BDNF expression, whereas the inactive 4alpha phorbol-12,13-didecanoate was without effect. PMA had no significant effect on BDNF mRNA stability and the downregulation of BDNF mRNA expression by PKC activation was likely a transcriptional event. BDNF downregulation by PMA could be prevented by PKC inhibitors Go 6983 and rottlerin, but not by Go 6976. Thus, a Go 6983/rottlerin-sensitive PKC isoform is likely to be responsible for PMA induced BDNF downregulation. PMID- 26021526 TI - Spread of Leishmania infantum in Europe with dog travelling. AB - Leishmania infantum is the etiological agent of canine leishmaniosis (CanL) in Europe, where it is endemic in the Mediterranean region, with dogs being considered the major reservoir of the parasite for humans and other mammalian hosts. The main transmission mode of Leishmania is by the bite of infected phlebotomine sand fly insects (genus Phlebotomus), which are the only proven vectors of this zoonotic protozoan. Less common, non-vectorial transmission between dogs include infection through transfused blood products from infected donors, transplacental and venereal transmission. CanL has exhibited an expansion to new locations in Europe, mainly northwards, either by territorial contiguity, often in association with global warming that favours vectorial transmission, or by the long-distance importation of infected dogs. The increasing incidence of CanL in countries where the disease is not endemic is challenging owners, veterinarians and government authorities. Most infected dogs in these new areas have been relocated from or travelled with their owners to endemic regions, but in some cases transmission might have also been autochthonous. In the absence of prophylactic measures, the introduction of infected dogs in areas previously free of endemic CanL but which have competent sand fly vectors can result in a potential persistence of L. infantum. The spread of L. infantum in Europe is reviewed with a focus on transmission, epidemiology and geographic distribution of endemic and non-endemic CanL, infection and disease in humans and animal hosts other than dogs, together with prevention and additional control strategies. PMID- 26021527 TI - Orientation behaviour of Culicoides obsoletus (Diptera: Ceratopogonidae), a relevant virus vector in northern Europe, toward host-associated odorant cues. AB - Some Culicoides biting midge species (Diptera: Ceratopogonidae) are biological virus vectors worldwide and have recently been associated with outbreaks of important epizootic diseases such as bluetongue and Schmallenberg in northern Europe. These diseases, which affect domestic and wild ruminants, have caused considerable economic losses. Knowledge of host preferences of these biting midges - especially of the relevant vectors of arboviruses near farms, such as Culicoides obsoletus in northern Europe - is essential to understand pathogen transmission cycles and the epidemiology of associated diseases. This study aimed to determine host preferences of C. obsoletus using an in-field flight tunnel containing pairs of calf, sheep, chicken, and human hosts (and controls) and a laboratory two-choice bioassay containing volatile extracts of host skin (and controls). Behavioural responses of nulliparous C. obsoletus females in the in field flight tunnel showed a preference for human (but also calf and sheep) hosts, probably due to their exhalation of greater quantities of carbon dioxide. The laboratory experiment revealed that volatile organic compounds released from the skin of chicken and sheep seemed to attract this species. Culicoides obsoletus, thus, seems to have a wide host range and to be particularly attracted by humans under field conditions. A better understanding of vector-host interaction could enable the development of control strategies against adult biting midges, by exploiting insect-repelling or -attractive semiochemicals. Volatile extracts of chicken and/or sheep skin could be used to identify volatile compounds attractive to C. obsoletus, which in turn could be used in baited traps. PMID- 26021528 TI - Renal Outcomes Following Fenestrated and Branched Endografting. AB - OBJECTIVE: The purpose of this study was to analyze immediate and long-term renal outcomes (renal function and renal events) after fenestrated (FEVAR) and branched endovascular aortic aneurysm repair (BEVAR). METHODS: All FEVAR and BEVAR performed between October 2004 and October 2012 were included in this study. Post operative acute renal failure (ARF) was defined according to the RIFLE criteria. Renal volume (calculated with a 3D workstation) and estimated glomerular filtration rate (GFR) (estimated with the Modification of Diet in Renal Disease [MDRD] formula) were evaluated before the procedure, before discharge, 12 months after, and yearly thereafter. Renal stent occlusion, dissection, fracture, stenosis, kink, renal stent related endoleak, and renal stent secondary intervention were all considered "renal composite events" and analyzed. A time to event analysis was performed for renal events and secondary renal interventions. RESULTS: 225 patients were treated with FEVAR and BEVAR. Renal target vessels (n = 427) were perfused by fenestrations (n = 374), or branches (n = 53). Median follow up was 3.1 years (2.9-3.3 years). Technical success was achieved in 95.5% of patients. Post-operative ARF was seen in 64 patients (29%). Mean total renal volume and eGFR at 1 year, 2 year, and 3 year follow up were significantly lower when compared with pre-operative levels (after BEVAR and FEVAR); the decrease at 3 years was 14.8% (6.7%; 22.2%) (p = .0006) for total renal volume and 14.3% (3.1%; 24.3%) (p = .02) for eGFR. The 30 day and 5 year freedom from renal composite event was 98.6% (95.8-99.6%) and 84.5% (76.5-89.9%) after FEVAR and BEVAR (NS). The 30 day and 5 year freedom from renal occlusion was 99.5% (96.7 99.9%) and 94.4% (89.3-97.1%) after FEVAR and BEVAR (NS). CONCLUSION: FEVAR and BEVAR are durable options for the treatment of complex aortic aneurysms and are associated with low renal morbidity, without differences between devices types. The clinical impact of decreasing renal volume over time in these patients is yet to be fully understood. PMID- 26021529 TI - Technical and Clinical Success and Long-Term Durability of Endovascular Treatment for Atherosclerotic Aortic Arch Branch Origin Obstruction: Evaluation of 144 Procedures. AB - OBJECTIVES: Endovascular treatment of atherosclerotic obstruction of aortic arch branch origins (AABO) has largely replaced open surgery, but long-term outcome data are lacking. This study evaluated mid-term and long-term results of these procedures. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: Patients underwent endovascular treatment for symptomatic atherosclerotic stenosis of AABO between 1995 and 2012. Technical success was defined as uncomplicated revascularization and residual stenosis <=30%. The primary end point was freedom from restenosis >=50% on Duplex ultrasonography or magnetic resonance angiography. Secondary end points were freedom from target lesion revascularization or recurrent symptoms. RESULTS: 144 lesions were treated in 114 patients (75 female; mean age 66.3 years), by percutaneous transluminal angioplasty (PTA) in 20 patients and PTA and stent in 117 patients (brachiocephalic artery [BCA] 9/54; left common carotid artery [LCCA] 0/7; left subclavian artery [LSA] 11/56). The lesion could not be passed in four patients, and in three patients the intervention was terminated before angioplasty. The 30 day technical success was 94.4%, without deaths or strokes. Mean follow-up was 52.0 months (range 2-163 months). Restenosis-free survival was 95.6%, 92.9%, 87.6%, and 83.2% at 12, 24, 48, and 60 months, respectively. Log-rank test showed no significant difference between PTA only and PTA with additional stent placement at any point (p = .375), nor between BCA (n = 51), LCCA (n = 6), or LSA (n = 57). During follow-up, 27 patients (23.7%) became symptomatic (15 BCA, 1 LCCA, and 11 LSA); 19 patients with a restenosis of the target lesion (mean 56.7 months). Symptom-free survival was 94.7%, 92.0%, 82.3%, and 77.9% at 12, 24, 48, and 60 months, respectively. CONCLUSION: Endovascular treatment of aortic arch branch origin obstruction is safe and efficacious in experienced hands and can be considered as the preferred treatment, with good mid-term durability. Recurrent symptomatic lesions can be treated safely by renewed endovascular means. PMID- 26021530 TI - How should I treat a patient with a tandem carotid artery atherosclerotic stenosis involving the internal carotid artery and the innominate/proximal common carotid artery? PMID- 26021535 TI - Interleukin-10 Levels and Clinical Outcome : Comparison of Retroperitoneal versus Transperitoneal Approaches in Infra-Renal Abdominal Aorta Reconstruction. AB - BACKGROUND: To compare retroperitoneal (RP) vs. transperitoneal (TP) approaches in abdominal aorta reconstruction in terms of operative characteristics, plasma interleukin-10 levels and postoperative complications. METHODS: A total of 100 patients scheduled for elective abdominal aortic surgery for occlusive disease under general anesthesia from May 2005 to January 2010 were included in this prospective study with allocation of patients randomly to TP approach (n = 50 ; mean (SD) age : 64.3 (4.0) years ; 76.0% were males) or RP approach (n = 50 ; mean (SD) age : 63.8 (5.6) years ; 75.0% were males) for aortic surgery. Demographic data, risk factors, perioperative and postoperative data and IL-10 levels were analyzed in two groups. RESULTS: TP approach was associated with higher levels for IL-10 measured at the time of T1 (before unclamping of aorta) [(8.4 (5.1) vs. 6.5 (4.9) pg/mL, p < 0.05)] and T2 (sixty minutes after declamping) [(11.7 (6.0) vs. 8.3 (6.2) pg/mL, p < 0.01)] compared with RP approach. Postoperative evaluation revealed a higher percentage of patients with postoperative ileus (10.0 vs. 0.0%, p < 0.001) and pulmonary complications (18.0 vs. 4.0%, p < 0.001) in the TP rather than RP groups. The TP and RP groups were similar in terms of mortality rates whereas TP approach was associated with longer mean (SD) length of hospital stay (6.2 (1.0) vs. 3.8 (1.0) days, p < 0.001) compared with the RP approach. CONCLUSIONS: Our findings revealed that the RP approach has significant advantages over the TP approach in aortic reconstruction surgery leading better pulmonary function and low ileus rate in the postoperative period as well as shorter length of hospital stay. While an increase in IL-10 levels was reported in both approaches, probably in relation to higher degree of tissue trauma, the increase was more profound in the TP approach. PMID- 26021536 TI - Outcomes of endoscopically harvested saphenous vein for lower extremity bypass. AB - OJECTIVES: The purpose of this study was to evaluate the outcomes of endoscopically harvested saphenous vein (EHSV) for lower extremity bypass (LEB) surgery. METHODS: Data from 91 consecutive patients who underwent LEB using EHSV between February 2003 and November 2012 were analyzed. Outcomes of interest were wound infection, patency, re-intervention and limb loss. RESULTS: Fifty-eight (64%) and 33 (36%) patients underwent femoropopliteal (FP) and femorotibial (FT) bypass using EHSV. Three (3%) patients had superficial and 1 (1%) deep wound infection. Primary and primary assisted patency at 5 years was 68% and 71% in the FP group and 56% and 65% in the FT group. Six (6%) patients underwent major amputation. No predicting factors for wound infection or graft patency were found. CONCLUSIONS: EHSV carries a low incidence of perioperative wound complication and has a reasonable mid-to-long-term patency regardless of the length of vein harvested. PMID- 26021537 TI - Effect of clinical examination and anatomical location on native arteriovenous fistula maturation rate in high risk patients. AB - BACKGROUND: Maximal use of native arteriovenous fistulas (AVFs) for patients on hemodialysis therapy remains a clinical challenge. Primary failure rates remain high with risk factors such as female gender, diabetes mellitus, lower arm AVF and higher age. We wondered if a strategy of careful clinical examination prior to AVF creation and a preference towards an upper arm AVF in case of doubt about the quality of the vein in patients with any of the above mentioned risk factors, would lead to better maturation rates. METHODS: The records of all patients who received an AVF between January 2005 and December 2009 at our University Hospitals Leuven were studied retrospectively. Demographic data, comorbidity, fistula characteristics, fistula maturation and fistula complications were recorded and analyzed. RESULTS: Of 344 patients enrolled, 156 (45.3%) received a lower arm AVF and 188 (54.7%) an upper arm AVF. Two hundred and seventy-six (80.2%) fistulas had a normal maturation. Lower arm AVF was a significant risk factor for non-maturation in this series (73.1% versus 86.2% ; p = 0,0024). Female gender, diabetes and high age were not, but female gender showed a significant difference in distribution in upper arm versus lower arm fistulas (62.40% versus 37.6% ; p = 0,0218). CONCLUSIONS: Careful clinical examination prior to upper or lower arm AVF creation together with the integration of risk assessment in the planning of AVF is worthwhile. A preference towards upper arm fistulas if major risk factors are -present can improve overall maturation rates and lead to the same maturation rates as in the overall dialysis population. Therefore, the presence of risk factors for non-maturation should not lead to the underuse of native AVFs. PMID- 26021538 TI - Gastrointestinal complications after cardiac surgery : eight years experience in a single center. AB - BACKGROUND: The aim of this study was to evaluate the frequency of gastrointestinal complications (GICs) and associated risk factors in patients after cardiac surgery, and to stratify them according to the risk of developing GICs in order to improve our diagnostic protocols. METHODS: A total of 5959 patients who underwent cardiac surgery within a period of 97 months were retrospectively evaluated. Surgical procedures included coronary artery bypass grafting, heart valve surgery, aortic surgery, surgical correction of adult congenital heart defects, or combined procedures. RESULTS: The frequency of GICs was 1.3% (75 patients). Intestinal ischemia and upper or lower gastrointestinal bleeding were the most common GICs. From 27 patients affected by intestinal ischemia, 21 patients were previously treated with intra-aortic balloon pump (p < 0.001). Low cardiac output, renal failure or dysfunction, renal risk, peripheral arterial disease, history of myocardial infarction, male gender, intra-aortic balloon pump, cardiopulmonary bypass time, aortic cross-clamp time, duration of intubation, SIRS, and MODS were associated with significantly increased risk of GICs. CONCLUSIONS: To decrease the occurrence of intestinal ischemia, we suggest that placement of intra-aortic balloon pump should be preceded by examination of the descending aorta to rule out severe atherosclerotic changes, in which case alternative cardiac support should be attempted. PMID- 26021539 TI - Long-term Evaluation of a Modified Double Staple Technique for Low Anterior Resection. AB - BACKGROUND: When performing low anterior resection for rectal cancer with the double staple technique, -closing the rectum with a linear stapler in the abdomen can be challenging, especially when dealing with a narrow pelvis. For such instances we proposed to modify this technique by pulling the rectal stump through the anus, doing an extra-anal resection of the tumor and linear suture of the rectal stump, before performing a standard, stapled colorectal anastomosis. The purpose of this study was to assess the adequacy of this modification of the double staple technique. METHODS: Retrospective review of 108 patients undergoing a stapled, low colorectal or coloanal anastomosis, after -eversion, extra-anal resection of the tumor and linear closure of the rectal stump for colorectal cancer, from January 1990 to December 2012. RESULTS: Operative mortality was 0.9%. Fourteen patients (13%) presented early, surgery-related complications consisting of 7 anastomotic leaks, 5 wound infections, 1 ureteral lesion, and 1 peristomal abscess. Late complications related to surgery included 5 incisional hernias (4.6%), 4 anastomotic strictures (3.7%), 4 neurogenic bladders (3.7%) and 2 fecal incontinences (1.8%). The incidence of local disease recurrence was 10%. CONCLUSIONS: Surgical and oncological results validate the proposed modification of the double staple technique, when facing difficulties in suturing the rectum from the abdomen. PMID- 26021540 TI - Perirectal sepsis after rubber band ligation of haemorrhoids : a case report. AB - Rubber band ligation (Barron ligation, RBL) is a widely used method for the treatment of symptomatic -haemorrhoids. In general, it is considered as a safe, effective and easily performed way of treating second and third -degree haemorrhoids. Perineal and pelvic sepsis was already known to be a rare, but possible complication after stapled haemorrhoidopexy. However, there have been some reports of severe sepsis after rubber band ligation as well. We -present a patient who was treated twice for haemorrhoids with rubber band ligation and attended the emergency department 10 days later. He was diagnosed with perirectal sepsis and aggressive antibiotic treatment was the first attempt of treatment. Because of further deterioration under medical therapy, our patient required extensive surgery. PMID- 26021541 TI - Pulmonary Artery Aneurysm : A Case Report and Management of this Uncommon Pathology. AB - Pulmonary artery aneurysm is a rare pathology and the optimal treatment approach remains unclear in the absence of clear guidelines. We report a case of pulmonary aneurysm and discuss the treatment options. PMID- 26021542 TI - The Chilaiditi Syndrome : Another Greek Tragedy ? Case report and short review of literature. AB - The Chilaiditi syndrome is a rare disorder, characterized by a broad spectrum of (gastro-intestinal) symptoms due to an interposition of a segment of bowel between the liver and the diaphragm. This anatomical variation is diagnosed through abdominal x-ray and is known as the Chilaiditi sign. Since the syndrome can lead to severe complications, such as perforation, intestinal obstruction or bowel ischemia, awareness of this syndrome is essential for every general surgeon. Knowledge of predisposing factors is necessary to treat possible complications accordingly. Conservative -management often is sufficient. Surgical intervention is reserved for those who do not respond to conservative line of management or those with severe complications. PMID- 26021543 TI - Extramammary Paget's Disease : Case Report of a Penoscrotal Presentation. AB - We report the case of a 72 year old male with penoscrotal extramammary Paget's disease (EMPD). The patient presented with an eczematous lesion on the scrotum extending on to the base of the penis. Given the persistent and progressive nature of the lesion a biopsy was taken which revealed a malignant lesion suggestive of extramammary Paget's disease. After performing a CAT-scan of the lower abdomen and inguinal region, which was negative, a primary surgical approach with curative intentions was taken. One year after surgery the patient is doing well and shows no sign of local recurrence. PMID- 26021544 TI - Ectopic Pleural Thymoma : Report of a case. AB - Thymomas are uncommon neoplasms that account for 50% of all masses in the anterior mediastinum. Medial sternotomy is the typical approach for resection. We report a case of an ectopic thymoma within the right pleural cavity in a 76-year old Caucasian women. This patient was diagnosed on preoperative assessment with a large nodal lesion, measuring 12.5 * 9 * 11 cm. Extensive imaging and histology hinted the diagnosis of an ectopic thymoma type B1 according to the World Health Organisation (WHO) classification. Due to the rare location of this tumor, we decided to use a right lateral thoracotomy instead of the more commonly used medial sternotomy. Complete resection of the tumor was performed with relative ease and histopathology verified the diagnosis of a thymoma type B1. No continuity towards the superior anterior mediastinum was documented and the thymoma was considered 'ectopic'. To our knowledge ectopic thymomas are very rare, and few reports have been made about removing thymic tumors by means of a lateral thoracotomy. PMID- 26021545 TI - Cortical Microvascularization and Leptomeningeal Collaterals in Moyamoya Disease. PMID- 26021546 TI - Acute fever and seizure in a patient with recent atrial fibrillation ablation. AB - Patients undergoing radiofrequency ablation for treatment of atrial fibrillation may present critically ill with complications of atrial esophageal fistula, commonly manifesting as neurologic deficits and septicemia difficult to distinguish from other acute etiologies without a high index of suspicion. The temporal variability in fistula formation and symptom presentation, along with their nonspecific features, makes diagnosis often a late finding with historically high morbidity and mortality. We present a patient admitted to a medical intensive care unit with status epilepticus and recurrent positive blood cultures for organisms commonly associated with the gastrointestinal (GI) tract. Chest computed tomography (CT) without contrast, transthoracic echocardiography, and initial neurologic imaging were unhelpful. A diagnosis was ultimately made by upper endoscopy of the esophagus after hematemesis with suspicion for GI bleed, at which point surgical intervention was attempted but without success. This case reviews the clinical features of atrial esophageal fistula formation and its initial diagnosis and management. PMID- 26021547 TI - Persistent Legionnaire's disease in an adult with hairy cell leukemia successfully treated with prolonged levofloxacin therapy. AB - Legionnaire's disease (LD) manifests most commonly as an atypical community acquired pneumonia (CAP) with systemic extrapulmonary manifestations. Disorders associated with impaired cell mediated immunity (CMI) are particularly predisposed to LD. Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative leukemia associated with decreased CMI. LD has only rarely been reported in HCL. We present a most interesting case of persistent LD in a elderly male with HCL who required prolonged antibiotic therapy. PMID- 26021548 TI - Biological and biochemical characteristics of a Mediterranean population with Gestational Diabetes Mellitus. AB - The interplay of various nutrients provided to the developing foetus determines the growth potential of the conceptus. This study assessed the inter-relationship between these nutrients in a Mediterranean population including 1062 pregnant, previously non-diabetic women. These underwent an oral glucose tolerance test (oGTT) and were accordingly classified into gestational hyperglycaemic and normoglycaemic groups. Fasting insulin, HbA1c, and lipid profiles were further assessed, and the anthropomorphic characteristics of the mother and child at birth were measured. Lipid profiles were compared between the two groups and related to the biological characteristics of the mother and child at birth. Gestational hyperglycaemia was significantly associated with elevated triglycerides (P<0.0001) and decreased low density lipoprotein cholesterol (LDL C) (P=0.02). There were no significant changes in total cholesterol and high density lipoprotein cholesterol (HDL-C) levels. Maternal BMI correlated positively with the various glycaemic indices (P<0.0001) and triglycerides (P<0.0001), but inversely with cholesterol (P<0.0001), HDL-C (P<0.0001) and LDL-C (P<0.0001). The infant birth weight correlated positively with maternal body weight (P<0.0001), LDL-C (P<0.0001) and the glycaemic indices (P<0.0001), but negatively with cholesterol (P<0.0001), triglycerides (P<0.0001), HDL-C (P<0.0001) and FBG (P<0.0001). This study confirms that the maternal body mass index (BMI), insulin resistance, and LDL-C levels positively contribute towards foetal growth, whereas a negative correlation was noted with cholesterol, triglycerides, and HDL-C. PMID- 26021549 TI - Draft genome sequence of Strain ATCC 17802(T), the type strain of Vibrio parahaemolyticus. AB - We report the draft genome of Vibrio parahaemolyticus ATCC 17802(T), containing 5067729 bp. The G+C content of the genome is 45.24 %. This strain possesses genes encoding a Type III secretion system 1, a Type III secretion system 2 and a Tdh related hemolysin (TRH). Its taxonomically important phenotypes were also experimentally characterized. PMID- 26021550 TI - Yield of MRI, high-density electric source imaging (HD-ESI), SPECT and PET in epilepsy surgery candidates. AB - OBJECTIVE: Preoperative workup aims at localizing the epileptogenic focus to achieve postoperative seizure-freedom. We studied the predictive value of non invasive techniques, i.e. structural magnetic resonance imaging [MRI], high density electric source imaging [HD-ESI] and metabolic imaging (positron emission tomography [PET]; single-photon emission computed tomography [SPECT]), in surgically treated patients. METHODS: A prospective study of 190 epileptic operated patients, with >12 months follow-up and analyzed with state-of-the-art algorithms. 58 patients underwent all techniques. We computed sensitivity, specificity, predictive value and diagnostic odds ratio (OR) in relation to postoperative outcome. RESULTS: Of 190 patients, 148 (77.9%) were seizure-free at follow-up. Resection of the epileptogenic focus was associated with favorable postsurgical outcome (p<0.05). Among 58 patients who underwent all tests, only MRI and HD-ESI were favorable outcome predictors (MRI: OR 10.9, p=0.004; HD-ESI: OR 13.1, p=0.004). Patients with concordant structural MRI and HD-ESI results had 92.3% (24/26) probability of favorable outcome. When both results were negative, probability was 0% (0/5); and when they disagreed, it was 63.0% (17/27). CONCLUSIONS: Combination of MRI and HD-ESI offered the highest predictive value for postoperative seizure-freedom. SIGNIFICANCE: This finding highlights the added value of HD-ESI in the presurgical workup, in particular in combination with an informative MRI. PMID- 26021552 TI - Circulating 25-hydroxyvitamin D3 and survival after diagnosis with kidney cancer. AB - Prospective cohort studies have provided some evidence that circulating vitamin D is associated with risk of, and survival from, renal cell carcinoma (RCC), but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis. We conducted a case-cohort study of 630 RCC cases, including 203 deaths, from a multicenter case-control study in Eastern Europe. Vitamin D was assessed as 25-hydroxyvitamin D3 [25(OH)D3], and we used weighted Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) by categories of season-adjusted 25(OH)D3. Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage, age, sex, and country (HR highest vs. lowest category 0.57; 95% CI, 0.34-0.97). The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease. In summary, 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates, but not specifically with RCC outcome. PMID- 26021554 TI - Impact of neoadjuvant therapy on cancer-associated fibroblasts in rectal cancer. AB - BACKGROUND AND PURPOSE: Cancer-associated fibroblasts (CAFs) are increasingly recognised as promoters of tumour progression. It is poorly investigated whether cancer management protocols, such as neoadjuvant radio(chemo)therapy, have an impact on CAFs and, by consequence, on tumour progression. This prompted us to study the impact of neoadjuvant radio(chemo)therapy on the alpha-SMA/epithelial area ratio in rectal cancer, and the impact of this ratio on recurrence-free survival. MATERIAL AND METHODS: Immunohistochemistry for the CAF marker alpha-SMA and the proliferation marker Ki67 was performed on sections from 98 rectal cancers of which 62 had undergone neoadjuvant radio(chemo)therapy. RESULTS: Computer-assisted quantitative analysis showed that the alpha-SMA/neoplastic epithelial area ratio was higher after neoadjuvant therapy, and that rectal cancers with high alpha-SMA/epithelial area ratio had low proliferation rates. Interestingly, the alpha-SMA/epithelial area ratio was an adverse prognostic factor with regard to recurrence-free survival in univariate analysis. In addition, multivariate analysis showed that an alpha-SMA/epithelial area ratio above 1 provides an independent prognostic value associated with a poor recurrence-free survival. CONCLUSION: These results suggest that neoadjuvant treatment has an impact on CAFs in rectal cancer. The correlation of CAFs with decreased recurrence-free survival and abundant experimental data in the literature suggest that under certain circumstances, not yet very well understood, CAFs may favour tumour progression. PMID- 26021553 TI - Animal Models of Bone Metastasis. AB - Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID- 26021556 TI - GP cancer referral delays may explain UK's low cancer survival rates. PMID- 26021557 TI - Long-lasting spatial learning and memory impairments caused by chronic cerebral hypoperfusion associate with a dynamic change of HCN1/HCN2 expression in hippocampal CA1 region. AB - Chronic cerebral hypoperfusion (CCH) causes learning and memory impairments and increases the risk of Alzheimer disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the mechanisms underlying the disease process remained unclear particularly in a temporal manner. We performed permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) to induce CCH. To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are altered at different stages of cognitive impairment caused by CCH, adult male SD rats were randomly distributed into sham-operated 4, 8 and 12weeks group, 2VO 4, 8 and 12weeks group. Learning and memory performance were evaluated with Morris water maze (MWM) and long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Expression of NeuN, HCN1 and HCN2 in hippocampal CA1, DG and CA3 areas was quantified by immunohistochemistry and western blotting. Our data showed that CCH induced a remarkable spatial learning and memory deficits in rats of 2VO 4, 8, and 12weeks group although neuronal loss only occurred after 4weeks of 2VO surgery in CA1. In addition, a significant reduction of HCN1 surface expression in CA1 was observed in the group that suffered 4weeks ischemia but neither 8 nor 12weeks. However, HCN2 surface expression in CA1 increased throughout the ischemia time-scales (4, 8 and 12w). Our findings indicate spatial learning and memory deficits in the CCH model are associated with disturbed HCN1 and HCN2 surface expression in hippocampal CA1. The altered patterns of both HCN1 and HCN2 surface expression may be implicated in the early stage (4w) of spatial learning and memory impairments; and the stable and long-lasting impairments of spatial learning and memory may partially attribute to the up-regulated HCN2 surface expression. PMID- 26021555 TI - Macronutrients and caloric intake in health and longevity. AB - Both lifespan and healthspan are influenced by nutrition, with nutritional interventions proving to be robust across a wide range of species. However, the relationship between nutrition, health and aging is still not fully understood. Caloric restriction is the most studied dietary intervention known to extend life in many organisms, but recently the balance of macronutrients has been shown to play a critical role. In this review, we discuss the current understanding regarding the impact of calories and macronutrient balance in mammalian health and longevity, and highlight the key nutrient-sensing pathways that mediate the effects of nutrition on health and ageing. PMID- 26021558 TI - Timing for intracoronary administration of bone marrow mononuclear cells after acute ST-elevation myocardial infarction: a pilot study. AB - INTRODUCTION: Most studies on intracoronary bone marrow mononuclear cell transplantation for acute myocardial infarction involve treatment 3-7 days after primary percutaneous coronary intervention (PCI); however, the optimal timing is unknown. The present study assessed the therapeutic effect at different times after ST-elevation myocardial infarction. METHODS: The present trial was not blinded. A total of 104 patients with a first ST-elevation myocardial infarction and a left ventricular ejection fraction below 50 %, who had PCI of the infarct related artery, were randomly assigned to receive intracoronary infusion of bone marrow mononuclear cells within 24 hours (group A, n = 27), 3 to 7 days after PCI (group B, n = 26), or 7 to 30 days after PCI (group C, n = 26), or to the control group (n = 25), which received saline infusion performed immediately after emergency PCI. All patients in groups A, B and C received an injection of 15 ml cell suspension containing approximately 4.9 * 10(8) bone marrow mononuclear cells into the infarct-related artery after successful PCI. RESULTS: Compared to control and group C patients, group A and B patients had a significantly higher absolute increase in left ventricular ejection fraction from baseline to 12 months (change: 3.4 +/- 5.7 % in control, 7.9 +/- 4.9 % in group A, 6.9 +/- 3.9 % in group B, 4.7 +/- 3.7 % in group C), a greater decrease in left ventricular end systolic volumes (change: -6.4 +/- 15.9 ml in control, -20.5 +/- 13.3 ml in group A, -19.6 +/- 11.1 ml in group B, -9.4 +/- 16.3 ml in group C), and significantly greater myocardial perfusion (change from baseline: -4.7 +/- 5.7 % in control, 7.8 +/- 4.5 % in group A, -7.5 +/- 2.9 % in group B, -5.0 +/- 4.0 % in group C). Group A and B patients had similar beneficial effects on cardiac function (p = 0.163) and left ventricular geometry (left ventricular end-distolic volume: p = 0.685; left ventricular end-systolic volume: p = 0.622) assessed by echocardiography, whereas group C showed similar results to those of the control group. Group B showed more expensive care (p < 0.001) and longer hospital stays during the first month after emergency PCI (p < 0.001) than group A, with a similar improvement after repeat cardiac catheterization following emergency PCI. CONCLUSION: Cell therapy in acute myocardial infarction patients that is given within 24 hours is similar to 3-7 days after the primary PCI. TRIAL REGISTRATION: NCT02425358 , registered 30 April 2015. PMID- 26021559 TI - Postnatal TLR2 activation impairs learning and memory in adulthood. AB - Neuroinflammation in the central nervous system is detrimental for learning and memory, as evident form epidemiological studies linking developmental defects and maternal exposure to harmful pathogens. Postnatal infections can also induce neuroinflammatory responses with long-term consequences. These inflammatory responses can lead to motor deficits and/or behavioral disabilities. Toll like receptors (TLRs) are a family of innate immune receptors best known as sensors of microbial-associated molecular patterns, and are the first responders to infection. TLR2 forms heterodimers with either TLR1 or TLR6, is activated in response to gram-positive bacterial infections, and is expressed in the brain during embryonic development. We hypothesized that early postnatal TLR2-mediated neuroinflammation would adversely affect cognitive behavior in the adult. Our data indicate that postnatal TLR2 activation affects learning and memory in adult mice in a heterodimer-dependent manner. TLR2/6 activation improved motor function and fear learning, while TLR2/1 activation impaired spatial learning and enhanced fear learning. Moreover, developmental TLR2 deficiency significantly impairs spatial learning and enhances fear learning, stressing the involvement of the TLR2 pathway in learning and memory. Analysis of the transcriptional effects of TLR2 activation reveals both common and unique transcriptional programs following heterodimer-specific TLR2 activation. These results imply that adult cognitive behavior could be influenced in part, by activation or alterations in the TLR2 pathway at birth. PMID- 26021560 TI - Inflammatory molecules in Frontotemporal Dementia: cerebrospinal fluid signature of progranulin mutation carriers. AB - Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean+/-SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27+/-151.5 versus 159.7+/-49pg/ml; P?0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-gamma-inducible protein-10 (IP-10) levels were increased (809.17+/-240.0 versus 436.61+/-202.5pg/ml; P=0.012). In the same group, TNFalpha and Interleukin (IL)-15 levels were decreased (3.18+/ 1.41 versus 35.68+/-30.5pg/ml; P=0.013 and 9.34+/-5.54 versus 19.15+/-10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63+/-3.30 and 2.58+/-20 versus 87.57+/-70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (rho=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group. PMID- 26021561 TI - Sugar concentration and timing of feeding affect feeding characteristics and survival of a parasitic wasp. AB - The availability of food sources is important for parasitoid survival, especially for those that inhabit ecosystems where nectar and honeydew are spatially or temporally scarce. Therefore, the value of even a single meal can be crucial for survival. Psyttalia lounsburyi is a parasitoid, and biological control agent, of the olive fruit fly, Bactrocera oleae. In order to improve our understanding of the basic nutritional ecology of P. lounsburyi and its role in survival we evaluated the effect of a single sucrose meal on the longevity of female and male wasps. We measured the duration of feeding, volume ingested, sucrose consumption, energy content, and longevity of wasps provided with different concentrations of sucrose (0.5, 1, and 2M) at different times after emergence (0, 1, 2 or 3 days after emergence). Our results showed that longevity was significantly influenced by sucrose concentration and timing of feeding. For females, feeding on sucrose increased the likelihood of survival to varying degrees, ranging from 32.3% to 95.4%, compared to water-only controls. The longest duration of feeding was observed for the highest sucrose concentrations and oldest wasps. The amount of sugar ingested and energy uptake increased, up to a point, as sugar concentration increased. Our results suggest that P. lounsburyi derived greatest benefit from the intermediate concentration (1M) of sucrose provided 2 or 3 days after emergence. Our study emphasizes the importance of finding balance between increasing longevity and limiting the duration of feeding, and concomitant uptake of nutrients, that is fundamental for survival of the wasp in nature. PMID- 26021562 TI - Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months. AB - BACKGROUND: Chronic continuous glucose monitoring options for animal research have been very limited due to various technical and biological challenges. We provide an evaluation of a novel telemetry device for continuous monitoring of temperature, activity, and plasma glucose levels in the arterial blood of rats for up to 2 months. METHODS: In vivo testing in rats including oral glucose tolerance tests (OGTTs) and intraperitoneal glucose tolerance tests (IPGTTs) and ex vivo waterbath testing were performed to evaluate acute and chronic sensor performance. Animal studies were in accordance with the guidelines for the care and use of laboratory animals and approved by the corresponding animal care and use committees (Data Sciences International, Eli Lilly). RESULTS: Results demonstrated the ability to record continuous measurements for 75 days or longer. Bench testing demonstrated a high degree of linearity over a range of 20-850 mg/dL with R(2) = .998 for linear fit and .999 for second order fit (n = 8 sensors). Evaluation of 6 rats over 28 days with 52 daily and OGTT test strip measurements each resulted in mean error of 3.8% and mean absolute relative difference of 16.6%. CONCLUSIONS: This device provides significant advantages in the quality and quantity of data that can be obtained relative to existing alternatives such as intermittent blood sampling. These devices provide the opportunity to expand the understanding of both glucose metabolism and homeostasis and to work toward improved therapies and cures for diabetes. PMID- 26021563 TI - Intraoperative brief electrical stimulation (BES) for prevention of shoulder dysfunction after oncologic neck dissection: study protocol for a randomized controlled trial. AB - BACKGROUND: Shoulder pain and dysfunction are common after oncologic neck dissection for head and neck cancer (HNC), due to traction, compression, and devascularization injuries to the spinal accessory nerve (SAN). Shoulder pain and dysfunction can hinder postoperative rehabilitation and hygiene, activities of daily living (ADLs), and return to work after treatment for HNC. Due to the rising incidence of human papillomavirus (HPV)-associated oropharyngeal cancer, patients are often diagnosed in the third or fourth decade of life, leaving many potential working years lost if shoulder dysfunction occurs. Brief electrical stimulation (BES) is a novel technique that has been shown to enhance and accelerate neuronal regeneration after injury through a brain-derived neurotrophic growth factor (BDNF)-driven molecular pathway in multiple peripheral nerves in both humans and animals. METHODS/DESIGN: This is a randomized controlled trial testing the effect of intraoperative BES on postoperative shoulder pain and dysfunction. All adult participants with a new diagnosis of HNC undergoing surgery with neck dissection, including Level IIb and postoperative radiotherapy, will be enrolled. Participants will undergo intraoperative BES after completion of neck dissection for 60 min continuously at 20 Hz, 3 to 5 V, in 100-msec pulses. Postoperatively, participants will be evaluated using the Constant-Murley Shoulder Score, a scale that assesses shoulder pain, ADLs, strength, and range of motion. Secondary outcomes measured will include nerve conduction studies (NCS) and electromyographic (EMG) studies, as well as scores on the Oxford Shoulder Score (OSS), the Neck Dissection Impairment Index (NDII), and the University of Washington Quality of Life (UW-QOL) score. Primary and secondary outcomes will be assessed at 6 weeks, 3 months, 6 months, and 12 months. DISCUSSION: The objective of this study is to evaluate the effect of BES on postoperative clinical and objective shoulder functional outcomes and pain after oncologic neck dissection. BES has been shown to be successful in accelerating peripheral nerve regeneration in both animal and human participants in multiple different peripheral nerves. If successful, this technique may provide an adjunctive prevention option for shoulder pain and dysfunction in HNC patients. TRIAL REGISTRATION: NCT02268344: 17 October 2014. PMID- 26021564 TI - "You cannot know if it's a baby or not a baby": uptake, provision and perceptions of antenatal care and routine antenatal ultrasound scanning in rural Kenya. AB - BACKGROUND: Antenatal care early in pregnancy enables service providers to identify and manage risks to mother and fetus. In the global north, ultrasound scans are routinely offered in pregnancy to provide an accurate estimate of gestational age and identify potential problems. In sub-Saharan Africa, such services are rarely available and women often delay initiating antenatal care. This study describes the uptake and provision of antenatal care in a rural Kenyan hospital and explores how pregnant women and healthcare providers perceived the provision of ultrasound scanning, following its introduction in an international foetal growth study. METHODS: A descriptive study, using qualitative and quantitative methods, was conducted in Kilifi District Hospital, Kenya, between June 2011 and April 2012. In-depth interviews were conducted with 10 nurses working in the antenatal clinic (ANC) and 59 pregnant women attending ANC. Structured observations of 357 ANC consultations and 30 ultrasound scans were made. RESULTS: Women sought antenatal care for information about the health of their baby and the protection provided by the ANC services. Uncertainty about pregnancy status contributed to delay in ANC attendance; more than 78 % of women were over 20 weeks' gestation at their first visit. Healthcare workers found it difficult to detect pregnancies below 16 weeks gestation and, accurate assessment of gestational age below 20 weeks' gestation could be problematic. Provision of services depended on the pregnancy being detected and gestational age assessed. The "seeing", made possible through ultrasound scanning was perceived by pregnant women and healthcare workers to be beneficial: confirming the pregnancy, and providing reassurance about the fetus' condition. Few participants raised concerns about ultrasound scanning. CONCLUSIONS: Uncertainty about pregnancy status and gestational age for women and healthcare providers is a key factor influencing timing of ANC attendance, contributing to delays and restricting early provision of ANC services. Ultrasound scanning was perceived to enhance antenatal care through confirmation of pregnancy status and enabling more accurate estimation of gestational age and the health status of the fetus. There is a need to make available more affordable means of pregnancy testing as a strategy towards encouraging early attendance, and delivery of antenatal care. PMID- 26021565 TI - Posterior indirect reduction and pedicle screw fixation without laminectomy for Denis type B thoracolumbar burst fractures with incomplete neurologic deficit. AB - PURPOSE: The aim of this study is to evaluate the efficacy of posterior indirect reduction and pedicle screw fixation without laminectomy for the treatment of Denis type B thoracolumbar burst fractures with incomplete neurologic deficit. METHODS: From March 2008 to May 2012, 36 consecutive patients of Denis type B thoracolumbar burst with incomplete neurologic deficit were enrolled. All of the patients accepted the treatments of posterior indirect reduction and pedicle screw fixation without laminectomy. Clinical and radiologic outcomes were assessed preoperatively and postoperatively. RESULTS: Operations were performed in a relatively short time without massive hemorrhage. Their neurologic functions were improved by at least one Frankel grade. The average score of American Spinal Injury Association (ASIA) motor increased from 25.4 +/- 10.8 to 42.1 +/- 10.5, and the recovery rate of the ASIA score was also increased. The pain level was relieved for all the patients. The local kyphosis angle was reduced from 25.9 degrees +/- 3.4 degrees to 6.9 degrees +/- 2.2 degrees (P <0.05) and remained 7.9 degrees +/- 2.0 degrees (P > 0.05) at the latest follow-up. After the operation, the mean vertebral canal diameter increased from 5.5 +/- 1.3 to 11.1 +/- 2.2 mm (P < 0.05) and the mean canal stenosis index increased from 32.9 +/- 7.8 to 84.8 +/- 7.3% (P < 0.05). There were no serious complications and fixation failures during follow-up. CONCLUSION: Denis type B thoracolumbar burst fractures with incomplete neurologic deficit can be effectively treated by posterior indirect reduction and pedicle screw fixation without laminectomy. PMID- 26021566 TI - Inhibition of RORgammat activity and Th17 differentiation by a set of novel compounds. AB - BACKGROUND: Retinoic acid receptor-related orphan receptor gamma t (RORgammat) is the master regulator of Th17 cell differentiation, which plays a critical role in the pathology of several autoimmune diseases. By directing Th17 cells function, RORgammat could be a potential target for drug development for Th17 related autoimmune disease. METHODS: A Jurkat cell-based reporter assay system was used for screening RORgammat inhibitors from a drug-like chemical library, following with mouse Th17 cells differentiation study to identify the effect of targeted compounds in primary T cells. 293T cell-based reporter assay was conducted to determine the cell specificity, and MTT assay was performed to determine the cell toxicity of those compounds. RESULTS: In this study, we identified four lead compounds that suppressed RORgammat activity, Th17 differentiation and IL-17A secretion. These candidates displayed inhibition ability on RORgammat activity in T cell derived Jurkat cell, but not in 293 T cell, which indicated the restricted effects of these compounds to other cells or tissues. Futhermore, our results demonstrated that these candidates exhibited more robust inhibitory on IL-17 F transcription expression than IL-17A, which is different from one reported compound, SR1001, that mainly suppressed IL-17A, rather than IL-17 F production. CONCLUSIONS: Our study discovered four novel compounds that inhibited RORgammat activity and Th17 function, which indicates their potential in therapeutic application of Th17 related autoimmune disorders. PMID- 26021568 TI - Paying for Prevention: A Novel Test of Medicare Value-Based Payment for Cardiovascular Risk Reduction. PMID- 26021567 TI - Impact of tea drinking upon tuberculosis: a neglected issue. AB - BACKGROUND: Tuberculosis (TB) is a global public health issue posing serious harm to the human health. Many studies have suggested that smoking and excessive alcohol consumption are risk factors for TB. Laboratory evidence suggests that EGCG in tea leaves can arrest the growth of tubercle bacillus. Can drinking tea lead to decreased susceptibility of TB in humans? METHODS: A total of 574 TB patients and 582 healthy controls were recruited to participate in this case control study. Self-designed questionnaire was used to collect data. Unconditioned logistic regression analysis was conducted to identify the associations between tea drinking and TB. RESULTS: Tea drinking has a negative association with TB, with OR = 0.583(0.423, 0.804) and P < 0.05. Drinking black tea, oolong and green tea are all negative association with TB, with OR being 0.683(0.517, 0.902), 0.674(0.508, 0.894) and 0.534(0.349, 0.817) respectively and P < 0.05. Trend chi (2) test indicated a decreasing risk for TB with increased tea consumption, with P < 0.05. CONCLUSION: There is a significance negative association between tea drinking and TB. Promoting the consumption of tea as the daily drink among populations, particularly those with high TB risk, may reduce the incidence of TB in the populations. PMID- 26021569 TI - An inducible expression system for high-level expression of recombinant proteins in slow growing mycobacteria. AB - A novel protein expression vector utilising the inducible hspX promoter of Mycobacterium tuberculosis was constructed and evaluated in this study. High level induction of three mycobacterial antigens, comprising up to 9% of bacterial sonicate, was demonstrated in recombinant Mycobacterium bovis BCG when grown under low-oxygen tension, which serves to enhance hspX promoter activity. Recombinant proteins were efficiently purified from bacterial lysates in a soluble form by virtue of a C-terminal 6-histidine tag. Purification of the immunodominant M. tuberculosis Ag85B antigen using this system resulted in a recombinant protein that stimulated significant IFN-gamma release from Ag85B reactive T cells generated after vaccination of mice with an Ag85B-expressing vaccine. Further, the M. tuberculosis L-alanine dehydrogenase (Ald) protein purified from recombinant BCG displayed strong enzymatic activity in recombinant form. This study demonstrated that high levels of native-like recombinant mycobacterial proteins can be produced in mycobacterial hosts, and this may aid the analysis of mycobacterial protein function and the development of new treatments. PMID- 26021570 TI - A series of medium and high copy number arabinose-inducible Escherichia coli expression vectors compatible with pBR322 and pACYC184. AB - The original pBAD24 plasmid and the derived lower copy number (the pBAD322 series) expression vectors have been widely used in Escherichia coli, Salmonella enterica, and related bacteria. However, a flexible pBAD expression system has been available only in pMB1 (ColE1) vectors. We report a series of pBAD vectors that replicate using the origin of plasmid RSF1030 that are compatible with pMB1 (ColE1) and p15A (pACYC) vectors. Both high (>=pBAD24) and medium (~pBAD322) copy number plasmids encoding resistance to ampicillin, chloramphenicol, kanamycin, tetracycline, spectinomycin/streptomycin, gentamycin, or trimethoprim are available. PMID- 26021571 TI - [Importance of the dense fine speckled pattern and anti-DFS70 antibodies for the diagnosis of systemic autoimmune rheumatic diseases]. PMID- 26021572 TI - [Atypical presentation and delayed diagnosis in a case of primary bile acid synthesis disorder]. PMID- 26021573 TI - [Partial 3beta-hydroxysteroid dehydrogenase type 2 deficiency: Diagnosis of a novel mutation after positive newborn screening for 21-hydroxylase deficiency]. PMID- 26021575 TI - [Security of the medicinal therapy: Cartography of risks a priori within service of orthopaedic surgery]. AB - INTRODUCTION: Security and quality of the Medicinal Therapy are one of the most important objectives of the April 6th, 2011 order. The objective is to realize this study of the risks incurred by patients related to management and security of medicinal therapy in order to establish a plan to reduce the risks of drug's dispensation. MATERIALS AND METHOD: The method of the Preliminary Risk Analysis (PRA) has been implemented by a multidisciplinary group in a hospital service of orthopaedic surgery. The study focused on the dispensation phase of medicinal circuit. RESULTS: This analysis revealed 148 scenarii, 35 were criticality unacceptable. Fifty-four initial risk control actions were proposed and their stress levels to put them in place were evaluated. DISCUSSION: The main measures of risk management are: training, information, communication, computerization, automation, dual control, updating the documentation system, drug reconciliation and respect for Best Practices Hospitallers (BPH). CONCLUSIONS: Risk management requires a significant human and financial investment as well as, material resources and multidisciplinary expertise in order to offer the best solutions. PMID- 26021574 TI - Bacterial spread from cell to cell: beyond actin-based motility. AB - Several intracellular pathogens display the ability to propagate within host tissues by displaying actin-based motility in the cytosol of infected cells. As motile bacteria reach cell-cell contacts they form plasma membrane protrusions that project into adjacent cells and resolve into vacuoles from which the pathogen escapes, thereby achieving spread from cell to cell. Seminal studies have defined the bacterial and cellular factors that support actin-based motility. By contrast, the mechanisms supporting the formation of protrusions and their resolution into vacuoles have remained elusive. Here, we review recent advances in the field showing that Listeria monocytogenes and Shigella flexneri have evolved pathogen-specific mechanisms of bacterial spread from cell to cell. PMID- 26021576 TI - Roxithromycin potency quantification in pharmaceutical preparation by applying a validated bioassay method and comparison with HPLC analysis. AB - Roxithromycin (RXM) is used to treat bacterial infections. An alternative bioassay for the assessment of the potency of this drug in pharmaceutical formulations has not been reported earlier. This study reports the development and validation of cost-effective, simple, sensitive, precise, accurate and reproducible one-level agar diffusion (5+1) bioassay for estimation of potency and bioactivity of RXM in tablet. Among six tested microbial strains, Streptococcus pneumoniae (MTCC-1935) was used as the most susceptible strain against RXM. Bioassay was optimized by investigating buffer pH, inoculums and reference standard concentration. The results of proposed bioassay displayed high linearity, precision, accuracy, robustness and specificity. All potency results were statistically analyzed and found to be linear (R(2)=0.9957) in between 2.0 and 6.0MUg/mL, precise with relative standard deviation (RSD) of repeatability intra-assay below 1.5%, and intermediate precision between day RSD 0.39% and accurate (100.68%). The bioassay and previously validated HPLC methods were compared, which indicated that there was no significant difference between these two methods. The results demonstrated the validity of the proposed microbial assay, which allows reliable quantitation of RXM in pharmaceutical samples and therefore can be used as a substitute alternative methodology for the routine quality control of this medicine, in situation when HPLC is not affordable in the laboratory. PMID- 26021577 TI - Observations on Golf and the Cardiac Patient: The Unsolved Mystery of the Intention Tremor. PMID- 26021578 TI - Cortical bone trajectory and traditional trajectory--a radiological evaluation of screw-bone contact. AB - BACKGROUND: Cortical bone trajectory (CBT), a relatively new technique for pedicle screw insertion in the lumbar spine, is believed to have equivalent pullout and toggle characteristics compared with the traditional trajectory (TT). It has been hypothesized that the new trajectory offers higher cortical bone contact with the pedicle screws and therefore has an improved anchoring property over the traditional trajectory where the screws are inserted into the vertebral body trabecular space. The aim of this study is to evaluate the pedicle screw cortical bone contact between the two trajectories from a radiological standpoint. METHODS: Two hundred twenty-two patients with degenerative lumbar spine disease underwent computed tomography scanning. For each patient, axial slices of the L4 and L5 vertebra were cut in two planes, one horizontal to the pedicle representing the plane at which pedicle screws are inserted using the TT and another in a more caudo-cranial plane representing the plane at which pedicle screws are inserted using CBT. For each trajectory, a region of interest (ROI) was selected within the area in which the screws are inserted. A CT number (Hounsfield scale) was then calculated within each ROI to compare the bone density. RESULTS: The CT numbers within the ROI for CBT were constantly almost over four times higher than that for the TT, and there was a significant difference between the values (p < 0.0001). CONCLUSIONS: This study has demonstrated that, with the cortical bone trajectory, the pedicle screws penetrate a region that is richer in cortical bone compared to when using the traditional trajectory. This is in keeping with previous hypotheses that the new trajectory offers higher cortical bone contact. PMID- 26021579 TI - What is the best timing for fluorescein injection during surgical removal of high grade gliomas? PMID- 26021581 TI - The shoulder: back to basics. PMID- 26021580 TI - Linked Records of Children with Traumatic Brain Injury. Probabilistic Linkage without Use of Protected Health Information. AB - OBJECTIVE: Record linkage may create powerful datasets with which investigators can conduct comparative effectiveness studies evaluating the impact of tests or interventions on health. All linkages of health care data files to date have used protected health information (PHI) in their linkage variables. A technique to link datasets without using PHI would be advantageous both to preserve privacy and to increase the number of potential linkages. METHODS: We applied probabilistic linkage to records of injured children in the National Trauma Data Bank (NTDB, N = 156,357) and the Pediatric Health Information Systems (PHIS, N = 104,049) databases from 2007 to 2010. 49 match variables without PHI were used, many of them administrative variables and indicators for procedures recorded as International Classification of Diseases, 9th revision, Clinical Modification codes. We validated the accuracy of the linkage using identified data from a single center that submits to both databases. RESULTS: We accurately linked the PHIS and NTDB records for 69% of children with any injury, and 88% of those with severe traumatic brain injury eligible for a study of intervention effectiveness (positive predictive value of 98%, specificity of 99.99%). Accurate linkage was associated with longer lengths of stay, more severe injuries, and multiple injuries. CONCLUSION: In populations with substantial illness or injury severity, accurate record linkage may be possible in the absence of PHI. This methodology may enable linkages and, in turn, comparative effectiveness studies that would be unlikely or impossible otherwise. PMID- 26021582 TI - Normal shoulder ultrasound: anatomy and technique. AB - Shoulder ultrasound (US) is one of the most common applications of musculoskeletal US due to the high incidence of rotator cuff disorders. It can be used effectively for the diagnosis of rotator cuff diseases, and several studies have shown very high sensitivity and specificity for rotator cuff tears comparable with that of MRI. Shoulder US has several advantages over MRI such as lower cost, comparatively easier availability, short examination duration, dynamic capability, and ability to perform guided injection at the same appointment. However, it depends on the skill of the operator and therefore requires a standardized detailed protocol to avoid errors in diagnosis. A symptomatic area-only focused examination should not be performed because it is not uncommon to have symptoms away from the actual site of pathology. Detailed understanding of what anatomy can be evaluated is required, and this article discusses the relevant anatomy covering the rotator cuff, subacromial bursa, and acromioclavicular joint. The equipment requirements and technique of examination of different anatomical structures with transducer positions and normal sonographic appearances are described. Pitfalls and artifacts associated with shoulder US are covered; understanding them is crucial to avoid misinterpretation of findings. PMID- 26021583 TI - Normal Shoulder MRI and MR Arthrography: Anatomy and Technique. AB - The use of MR for the diagnosis of shoulder lesions is well established, as well as MR arthrography for the diagnosis for shoulder instability and microinstability. For an accurate evaluation is essential to know the normal anatomy and variants to avoid the misdiagnosis of a pitfall as pathological condition. In addition we will discuss which variants might be clinically relevant. We will review the classical frequent variants such as intraarticular structures, especially glenohumeral ligaments and labrum but also bone, cartilage and rotator cuff variants and pitfalls. Both static and dynamic structures play an important role providing stability at different positions and with different range of motion. PMID- 26021584 TI - Rotator cuff and subacromial pathology. AB - Both MRI and ultrasound (US) demonstrate equivalent accuracy in the evaluation of the rotator cuff. Both modalities have their advantages, disadvantages, and pitfalls. Radiography is an important complementary modality in that it can demonstrate occult sources of shoulder pain. MRI is recommended for the evaluation of shoulder pain in patients < 40 years of age because labral pathology is frequently identified. However, in patients > 40 years, US should be the first-line modality because the incidence of rotator cuff pathology increases with age. US is useful to guide procedures such as subacromial injection and calcific tendinosis lavage. Radiologists should be knowledgeable of both MRI and US of the shoulder to tailor these examinations to the specific needs of their patients. PMID- 26021585 TI - Rotator interval. AB - The rotator interval is an anatomically complex region of the shoulder joint that is difficult to evaluate on clinical examination and by imaging. Abnormalities of its components may contribute to instability, shoulder stiffness, and pain and are challenging to diagnose and treat. This article gives an overview of the anatomy, MR anatomy, and normal variants of the rotator interval, together with basic technical aspects of MR imaging of this area. Pathologic conditions of the rotator interval capsule, the long head of biceps tendon, and the pulley system are reviewed and illustrated with several clinical examples. PMID- 26021586 TI - Imaging of shoulder instability. AB - The glenohumeral joint is an inherently unstable articulation and consequently the most frequently subluxed and frankly dislocated joint in the body. Shoulder instability can be uni- or multidirectional related to acute or repetitive stress and is occasionally secondary to congenital or developmental abnormalities such as a lax joint capsule or glenoid dysplasia. The clinical diagnosis of instability can be difficult, and knowledge of the imaging findings of anterior, posterior, multidirectional, and microinstability is essential to guide the correct treatment of these patients. This requires the appropriate use of many different imaging modalities as well as specific positioning and directed protocols. This review article explains the clinical scenarios associated with shoulder instability and how they relate to the choice of imaging techniques. The imaging findings of the most common soft tissue and osseous pathology are reviewed and explained with specific attention to anterior and posterior instability. PMID- 26021587 TI - Superior labrum anterior to posterior lesions and the superior labrum. AB - The fibrocartilaginous glenoid labrum contributes to shoulder stability and provides attachment for the long head of biceps tendon and the glenohumeral ligaments. The superior site of attachment of the long head of biceps (biceps anchor) represents a site of injury to the superior labrum where tearing may extend into the biceps tendon as well as anterior and/or posterior to the biceps anchor. Such tears are known as superior labrum anterior and posterior (SLAP) tears and are a cause of both shoulder instability and pain. SLAP tears are frequently seen in those undertaking repetitive frequent overarm activity such as throwing athletes and swimmers. This article reviews the mechanisms and types of SLAP tears and their imaging appearances. It also discusses associated injuries and pitfalls in diagnosing these injuries. PMID- 26021588 TI - Microinstability and internal impingement of the shoulder. AB - Internal impingement refers to entrapment of the rotator cuff and capsulolabral structures between the glenoid and humeral head in certain positions of the shoulder. This may be a normal physiologic phenomenon. However, it may occur as a pathologic process, especially in sports with repetitive overhead activity. The two types of internal impingement are posterosuperior and anterosuperior, with established radiologic manifestations. These conditions were initially thought to be due to repetitive mechanical entrapment. Subsequent observational studies have led to the concepts of microinstability and glenohumeral internal rotatory deficit. Controversy remains regarding the exact pathophysiology, reflected in the variable outcomes in the treatment of these syndromes. The reporting radiologist must be aware of the constellation of image findings to alert the referring physician to the possibility of microinstability and internal impingement. PMID- 26021589 TI - Soft Tissue Tumors about the Shoulder. AB - Soft tissue tumors (STTs) are not infrequent about the shoulder girdle. This article provides a short overview of useful parameters in grading and characterization of those lesions. The most frequent histologic types of STT about the shoulder girdle are also discussed. Benign STTs and mimickers of STTs are emphasized because precise imaging characterization of aggressive STTs is much more difficult than of their benign counterparts. Besides evaluation of the lesion's extent, a major role for imaging is to select those lesions that should undergo biopsy. MRI is the preferred imaging technique. PMID- 26021590 TI - Acromioclavicular joint disease. AB - The acromioclavicular joint is an important component of the shoulder girdle experiencing significant loading during normal activities of daily living. The joint is frequently subjected to trauma and as a synovial articulation can become involved in rheumatoid arthritis and the seronegative arthropathies. PMID- 26021591 TI - Arthritis at the shoulder joint. AB - The shoulder is a complex joint with numerous structures contributing to mobility and stability. Shoulder pain is a common clinical complaint that may be due to a wide spectrum of disorders including rotator cuff disease, instability, and arthropathy. Primary osteoarthritis of the shoulder joint is uncommon because it is a non-weight-bearing joint. Significant osteoarthritis of the glenohumeral joint is unusual in the absence of trauma, and the detection of advanced degenerative changes in patients without a known history of trauma should alert the clinician to search for other disorders. This article reviews the pathogenesis, clinical manifestations, and key imaging findings of the common categories of the arthritis affecting the glenohumeral joint. PMID- 26021592 TI - Acute and Late Bowel Toxicity in Radiotherapy Patients with Inflammatory Bowel Disease: A Systematic Review. AB - AIMS: Inflammatory bowel disease has traditionally been considered a relative contraindication for radiotherapy due to a perceived increased risk of disease exacerbation and bowel toxicity. The aim of this review was to evaluate the current literature regarding rates of radiotherapy-induced acute and late bowel toxicity in patients with inflammatory bowel disease and to compare these data with those of patients without the disease. MATERIALS AND METHODS: An Ovid Medline search was conducted to identify original articles pertaining to the review question. Using the PRISMA convention a total of 442 articles screened, resulting 8 articles which were suitable for inclusion in the review. RESULTS: In general, the grading of toxicity was scored using either the Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. It was found that acute bowel toxicity of >= grade 3 occurred in 20% of patients receiving external beam radiotherapy (EBRT) and in 7% of patients receiving brachytherapy. Late bowel toxicity >= grade 3 occurred in 15% of EBRT patients and in 5% of patients receiving brachytherapy. Brachytherapy was shown to have similar rates of toxicity and EBRT produced a moderate increase in both acute and late toxicity when compared with individuals without inflammatory bowel disease. CONCLUSION: In view of these results, we suggest that brachytherapy should be considered as a suitable treatment option for treating pelvic malignancy in patients with inflammatory bowel disease, whereas EBRT should be used with caution. PMID- 26021593 TI - Is there a relationship between apolipoprotein E genetic variants and obstructive sleep apnea syndrome? Consideration needed from evidence-based medicine. PMID- 26021594 TI - Estimation of the in situ degradation of the washout fraction of starch by using a modified in situ protocol and in vitro measurements. AB - The in situ degradation of the washout fraction of starch in six feed ingredients (i.e. barley, faba beans, maize, oats, peas and wheat) was studied by using a modified in situ protocol and in vitro measurements. In comparison with the washing machine method, the modified protocol comprises a milder rinsing method to reduce particulate loss during rinsing. The modified method markedly reduced the average washout fraction of starch in these products from 0.333 to 0.042 g/g. Applying the modified rinsing method, the fractional degradation rate (k d ) of starch in barley, oats and wheat decreased from on average 0.327 to 0.144 h-1 whereas for faba beans, peas and maize no differences in k d were observed compared with the traditional washing machine rinsing. For barley, maize and wheat, the difference in non-fermented starch in the residue between both rinsing methods during the first 4 h of incubation increased, which indicates secondary particle loss. The average effective degradation of starch decreased from 0.761 to 0.572 g/g when using the new rinsing method and to 0.494 g/g when applying a correction for particulate matter loss during incubation. The in vitro k d of starch in the non-washout fraction did not differ from that in the total product. The calculated ratio between the k d of starch in the washout and non-washout fraction was on average 1.59 and varied between 0.96 for oats and 2.39 for maize. The fractional rate of gas production was significantly different between the total product and the non-washout fraction. For all products, except oats, this rate of gas production was larger for the total product compared with the non washout fraction whereas for oats the opposite was observed. The rate of increase in gas production was, especially for grains, strongly correlated with the in vitro k d of starch. The results of the present study do not support the assumption used in several feed evaluation systems that the degradation of the washout fraction of starch in the rumen is much faster than that of the non washout fraction. PMID- 26021595 TI - ADAPT-NMR 3.0: utilization of BEST-type triple-resonance NMR experiments to accelerate the process of data collection and assignment. AB - ADAPT-NMR (Assignment-directed Data collection Algorithm utilizing a Probabilistic Toolkit in NMR) is a software package whose Bayesian core uses on the-fly chemical shift assignments to guide data acquisition by non-uniform sampling from a panel of through-bond NMR experiments. The new version of ADAPT NMR (ADAPT-NMR v3.0) has the option of utilizing 2D tilted-plane versions of 3D fast spectral acquisition with BEST-type pulse sequences, while also retaining the capability of acquiring and processing data from tilted-plane versions of conventional sensitivity-enhanced experiments. The use of BEST experiments significantly reduces data collection times and leads to enhanced performance by ADAPT-NMR. PMID- 26021596 TI - Massive Bleeding from Guidewire Perforation of an External Iliac Artery: Treatment with Hand-made Stent-Graft Placement. AB - We report life-threatening bleeding from an external iliac artery perforation following guidewire manipulation in a patient with atherosclerotic iliac artery disease. This complication was successfully managed by indigenous hand-made stent graft made from two peripheral stents in the catheterization laboratory. PMID- 26021597 TI - Arterial Embolization of Hemorrhoids: Reply. PMID- 26021598 TI - Predicting pork quality using Vis/NIR spectroscopy. AB - Visible and near-infrared reflectance spectroscopy (Vis/NIRS) was used to predict the ultimate pH (pHu), color, intramuscular fat (IMF) and shear force (WBSF) of pork samples and to build classifiers capable of categorizing the samples by tenderness (tender or tough) and juiciness (juicy and dry). Spectra were collected from 400 to 1495nm, and 200 data points were generated for every sample (n=134). Sixty-seven percent of the sample set was used for calibration, and 33% was used for validation. Partial least squares (PLS) calibration models were developed for each characteristic measured. A coefficient of determination (R(2)) and residual prediction deviation (RPD) were used to evaluate the accuracy of the calibration models. The pHu and color prediction models developed in this study fit this classification, indicating that these predictive models can be used to predict quality traits of intact pork samples. The Vis/NIRS offered great potential for correctly classifying pork Longissimus into two tenderness and two juiciness classes. PMID- 26021599 TI - Cp*Rh(III) and Cp*Ir(III)-catalysed redox-neutral C-H arylation with quinone diazides: quick and facile synthesis of arylated phenols. AB - Cp*Rh(III)- and Cp*Ir(III)-catalysed direct C-H arylation with quinone diazides as efficient coupling partners is disclosed. This redox-neutral protocol offers a facile, operationally simple and environmentally benign access to arylated phenols. The reaction represents the first example of Cp*Ir(III)-catalysed C-H direct arylation reaction. PMID- 26021600 TI - Quantifying cell-induced matrix deformation in three dimensions based on imaging matrix fibers. AB - During processes such as development and cancer metastasis, cells migrate into three-dimensional fibrous matrices. Previous studies have speculated on the mechanical forces required for migration by observing matrix fiber alignment, densification, and degradation, but these forces remain difficult to quantify. Here we present a new experimental technique to simultaneously measure full-field 3D displacements and structural remodeling of a fibrous matrix, both of which result from cellular forces. We apply this "2-in-1" experimental technique to follow single cells as they invade a physiologically relevant fibrin matrix. We find that cells generate tube-like structures in the matrix by plastically deforming their surroundings, and they re-use these tubes to extend protrusions. Cells generate these tubular structures by applying both pulling and pushing forces. PMID- 26021601 TI - Temporal lobe epilepsy is a predisposing factor for sleep apnea: A questionnaire study in video-EEG monitoring unit. AB - OBJECTIVE: The interaction between epilepsy and sleep is known. It has been shown that patients with epilepsy have more sleep problems than the general population. However, there is no recent study that compares the frequency of sleep disorders in groups with medically refractory temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE). The main purpose of this study was to investigate the occurrence of sleep disorders in two subtypes of epilepsy by using sleep questionnaire forms. METHODS: One hundred and eighty-nine patients, out of 215 who were monitored for refractory epilepsy and were followed by the video-EEG monitoring unit, were divided into a group with TLE and a group with ETLE. The medical outcome study-sleep scale (MOS-SS), Epworth sleepiness scale (ESS), and sleep apnea scale of the sleep disorders questionnaire (SD-SDQ) were completed after admission to the video-EEG monitoring unit. The total scores in the group with TLE and group with ETLE were compared. RESULTS: Of the patients, TLE was diagnosed in 101 (53.4%) (45 females), and ETLE was diagnosed in 88 (46.6%) (44 females). Comparison of MOS-SS and Epworth sleepiness scale scores in the two subgroups did not reveal significant differences. In the group with TLE, SD-SDQ scores were significantly higher compared to that in the group with ETLE. CONCLUSION: Patients with temporal lobe epilepsy have higher risk of obstructive sleep apnea (OSA) according to their reported symptoms. Detection of OSA in patients with epilepsy by using questionnaire forms may decrease the risk of ictal or postictal respiratory-related 'Sudden Unexpected Death in Epilepsy'. PMID- 26021603 TI - Potent Intracellular Knock-Down of Influenza A Virus M2 Gene Transcript by DNAzymes Considerably Reduces Viral Replication in Host Cells. AB - Influenza A virus has been known to be an important respiratory pathogen and cause of several epidemics and devastating pandemics leading to loss of life and resources across the globe. The M2 ion channel protein is highly conserved and essentially required during the trafficking, assembly, and budding processes of virus, thus an attractive target for designing antiviral drugs. We designed several 10-23 DNAzymes (Dz) targeting different regions of the M2 gene and analyzed their ability to specifically cleave the target RNA in both cell-free system as well as in cell culture using transient transfections. Dz114, among several others, directed against the predicted single-stranded bulge regions showed 70% inhibition of M2 gene expression validated by PCR and Western blot analysis. The activity was dependent on Mg(2+) (10-50 mM) in a dose-dependent manner. The mutant-Dz against M2 gene showed no down-regulation thereby illustrating high level of specificity of designed Dz114 towards the target RNA. Our findings suggest that Dz may be used as potential inhibitor of viral RNA replication and can be explored further for development of an effective therapeutic agent against influenza infection. These catalytic nucleic acid molecules may further be investigated as an alternative to the traditional influenza vaccines that require annual formulation. PMID- 26021604 TI - Trial-to-trial latency variability of somatosensory evoked potentials as a prognostic indicator for surgical management of cervical spondylotic myelopathy. AB - BACKGROUND: Early detection of neural conductivity changes at the compressed spinal cord is important for predicting the surgical outcomes of patients with cervical spondylotic myelopathy (CSM). The prognostic value of median nerve somatosensory evoked potential (SEP) has been proposed previously. The present prospective study evaluates the use of trial-to-trial variability in SEP as a valuable predictor of neurological recovery after surgery of CSM. METHODS: A total of 35 CSM patients who underwent surgery with up to 6-month follow-up were recruited in this study. SEP signals were recorded preoperatively. The single trial SEP was extracted by a newly developed second-order blind identification method. The postoperative recovery was assessed using the modified Japanese Orthopaedic Association. The correlation between the latency variability of trial to-trial SEP and post-operative recovery ratio was analyzed. The prognostic value of trial-to-trial SEP for CSM was evaluated using a receiver operator characteristic curve which can accurately reflect the relationship between sensitivity and specificity of a diagnostic method and represent the accuracy of prognosis. RESULTS: The correlation coefficient of trial-to-trial latency variability and the 6-month recovery ratio was statistically significant (r = 0.82, P < 0.01). The trial-to-trial SEP had a higher prognostic accuracy (AUC = 0.928, P < 0.001) with an optimal prognostic value of 9.25 % compared with averaged SEP when the threshold of recovery ratio was 40 %, and was more sensitive (93.80 %) than the averaged SEP (43.80 %). CONCLUSIONS: These findings indicate that the latency variability of trial-to-trial SEP reflect the recovery ratio of CSM patients after surgery. It is suggested that the latency variability of trial-to-trial SEP is useful for predicting the surgical outcomes for patients with CSM, which would be a potential indication of surgical treatment for CSM to help decision making of surgical planning for CSM patients. PMID- 26021605 TI - Gastrointestinal delivery of propofol from fospropofol: its bioavailability and activity in rodents and human volunteers. AB - BACKGROUND: Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1-8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. METHODS: Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. RESULTS: In rats, bioavailability of propofol from fospropofol delivered orally was found to be appreciable, in the order of around 20-70%, depending on dose. Availability was especially marked following fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. CONCLUSIONS: These data suggest potential utility of oral administration of fospropofol for various therapeutic indications previously considered for propofol. PMID- 26021602 TI - Suspension arrays based on nanoparticle-encoded microspheres for high-throughput multiplexed detection. AB - Spectrometrically or optically encoded microsphere based suspension array technology (SAT) is applicable to the high-throughput, simultaneous detection of multiple analytes within a small, single sample volume. Thanks to the rapid development of nanotechnology, tremendous progress has been made in the multiplexed detecting capability, sensitivity, and photostability of suspension arrays. In this review, we first focus on the current stock of nanoparticle-based barcodes as well as the manufacturing technologies required for their production. We then move on to discuss all existing barcode-based bioanalysis patterns, including the various labels used in suspension arrays, label-free platforms, signal amplification methods, and fluorescence resonance energy transfer (FRET) based platforms. We then introduce automatic platforms for suspension arrays that use superparamagnetic nanoparticle-based microspheres. Finally, we summarize the current challenges and their proposed solutions, which are centered on improving encoding capacities, alternative probe possibilities, nonspecificity suppression, directional immobilization, and "point of care" platforms. Throughout this review, we aim to provide a comprehensive guide for the design of suspension arrays, with the goal of improving their performance in areas such as multiplexing capacity, throughput, sensitivity, and cost effectiveness. We hope that our summary on the state-of-the-art development of these arrays, our commentary on future challenges, and some proposed avenues for further advances will help drive the development of suspension array technology and its related fields. PMID- 26021606 TI - Small RNA and degradome sequencing reveals microRNAs and their targets involved in tomato pedicel abscission. AB - MAIN CONCLUSION: We constructed small RNA and degradome sequencing libraries to identify miRNAs and targets involved in tomato pedicel abscission, and confirmed their roles via quantitative real-time PCR. MicroRNAs (miRNAs) are endogenous small RNAs which play crucial negatively regulatory roles at both the transcriptional and post-transcriptional levels in plants; however, limited knowledge is available on the expression profiles of miRNAs and their target genes during tomato pedicel abscission. Taking advantage of small RNA (sRNA) and degradome sequencing technology, a total of 56 known and 11 novel candidate miRNAs targeting 223 mRNA genes were confirmed during pedicel abscission. Gene ontology annotation and KEGG pathway analysis showed that these target genes were significantly enriched in intracellular, membrane-bounded organelle-related biological processes as well as in metabolic, plant-pathogen interaction and hormone signaling pathways. We screened 17 miRNA/target pairs for further analysis and performed quantitative real-time PCR to identify the roles. Cluster analysis of selected miRNAs revealed that the expression profiles of miRNAs varied in different stages of abscission and could be impacted by ethylene treatment. In the present study, the correlations between miRNAs and targets suggested a complex regulatory network of miRNA-mediated target interaction during pedicel abscission. Additionally, the expression profiles of miRNAs and their targets changed by ethylene might be a considerable reason why ethylene promotes pedicel abscission. Our study provides new insights into the expression and regulatory profiles of miRNAs during tomato pedicel abscission. PMID- 26021607 TI - Heat shock transcription factors involved in seed desiccation tolerance and longevity retard vegetative senescence in transgenic tobacco. AB - MAIN CONCLUSION: Transcription factors normally expressed in sunflower seeds delayed vegetative senescence induced by severe stress in transgenic tobacco. This revealed a novel connection between seed heat shock factors, desiccation tolerance and vegetative longevity. HaHSFA9 and HaHSFA4a coactivate a genetic program that, in sunflower (Helianthus annuus L.), contributes to seed longevity and desiccation tolerance. We have shown that overexpression of HaHSFA9 in transgenic tobacco seedlings resulted in tolerance to drastic dehydration and oxidative stress. Overexpression of HaHSFA9 alone was linked to a remarkable protection of the photosynthetic apparatus. In addition, the combined overexpression of HaHSFA9 and HaHSFA4a enhanced all these stress-resistance phenotypes. Here, we find that HaHSFA9 confers protection against damage induced by different stress conditions that accelerate vegetative senescence during different stages of development. Seedlings and plants that overexpress HaHSFA9 survived lethal treatments of dark-induced senescence. HaHSFA9 overexpression induced resistance to effects of culture under darkness for several weeks. Only some homoiochlorophyllous resurrection plants are able to withstand this experimental severe stress condition. The combined overexpression of HaHSFA9 and HaHSFA4a did not result in further slowing of dark-induced seedling senescence. However, combined expression of the two transcription factors caused improved recovery of the photosynthetic organs of seedlings after lethal dark treatments. At later stages of vegetative development, HaHSFA9 delayed the appearance of senescence symptoms in leaves of plants grown under normal illumination. This delay was observed under either control or stress treatments. Thus, HaHSFA9 delayed both natural and stress-induced leaf senesce. These novel observations connect transcription factors involved in desiccation tolerance with leaf longevity. PMID- 26021608 TI - Architectural RNAs (arcRNAs): A class of long noncoding RNAs that function as the scaffold of nuclear bodies. AB - Mammalian transcriptome analyses elucidated the presence of thousands of unannotated long noncoding RNAs (lncRNAs) with distinct transcriptional units. Molecular characterization and functional classification of these lncRNAs are important challenges in the next decade. A subset of these lncRNAs is the core of nuclear bodies, which are the sites of the biogenesis, maturation, storage, and sequestration of specific RNAs, proteins, and ribonucleoprotein complexes. Here, we define a class of lncRNAs termed architectural RNAs (arcRNAs) that function as the essential scaffold or platform of nuclear bodies. Presently, five lncRNAs from mammals, insects, and yeast are classified as arcRNAs. These arcRNAs are temporarily upregulated upon specific cellular stresses, in developmental stages, or in various disease conditions, and sequestrate specific regulatory proteins, thereby changing gene expression patterns. In this review, we introduce common aspects of these arcRNAs and discuss why RNA is used as the architectural component of nuclear bodies. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26021609 TI - Infestation dynamics of Brevipalpus phoenicis (Geijskes) (Acari: Tenuipalpidae) in citrus orchards as affected by edaphic and climatic variables. AB - Brevipalpus phoenicis (Geijskes) is a cosmopolitan and polyphagous mite that transmits important phytoviruses, such as coffee ringspot virus, passion fruit green spot virus and Citrus leprosis virus C. To characterise the dynamics of the probability and the rate of B. phoenicis infestation in response to edaphic and climatic factors, monthly inspections were performed in nine orchards in a citrus region of the State of Bahia, Brazil, for 35 months. Three fruits per plant were examined using a magnifying glass (10*) on 21 plants distributed along a "W" shaped path in each orchard. Meteorological data were collected from a conventional station. To determine the correlations among the climatic variables, the data were analysed using Spearman correlations. Variables were selected by principal component analysis, and those that contributed the most to differentiate the groups were evaluated via a Mann-Whitney test. Using the quantile-quantile method, the limit values for the following climatic variables were determined: temperature (24.5 degrees C), photoperiod (12 h), relative humidity (83%), evapotranspiration (71 mm) and rainy days (14 days). The combination of longer days, higher temperatures, lower relative humidity levels and lower evapotranspiration increased the probability of B. phoenicis infestation, whereas successive rain events decreased that risk. Infestation rates were negatively affected by relative humidity levels above 83% and were positively affected by a decreasing available soil-water fraction and increasing insolation and photoperiod. PMID- 26021611 TI - Follower ants in a tandem pair are not always naive. AB - In addition to foraging individually several species of ants guide nestmates to a goal by tandem running. We found that the Australian ant, Camponotus consobrinus, forages both individually and by tandem running to head to the same goal, nest specific native Australian trees on which they forage. While paths of solitary foragers and initial paths of tandem followers showed no differences in heading directions or straightness, tandem followers moved at about half the speed of solitary runs. When leaders were experimentally removed, follower ants initially engaged in a systematic search around the point of interruption, following which they either (a) headed directly towards and successfully reached the foraging trees, or (b) continued searching or (c) returned to the nest. The high incidence of followers that successfully navigated towards the foraging trees on their own provides strong evidence that many tandem followers are in fact experienced foragers. Detailed analysis of the searching behaviour revealed that even seemingly lost followers displayed a directional bias towards the foraging trees in their search path. Our results show that in a foraging context follower ants in a tandem pair are not always naive. PMID- 26021610 TI - The GHSG Approach to Treating Hodgkin's Lymphoma. AB - Hodgkin's lymphoma (HL) is a relatively rare disease accounting for 15 % of all lymphoma. This disease has developed from an incurable disease to the adult malignancy with the most favorable prognosis. With current therapeutic approaches consisting of polychemo- and small-field radiotherapy, up to 80 % of all patients can be cured long term. In refractory or relapsed HL, intensified treatment including high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is associated with progression-free survival (PFS) of 50 %. Evaluation of novel drugs in multiple relapsed or refractory cases, better treatment options for elderly patients and reducing treatment-related side effects are the main focus of current research. Recent clinical developments and future approaches in the treatment of HL will be discussed in this review. PMID- 26021612 TI - Irrelevant tactile stimulation biases visual exploration in external coordinates. AB - We evaluated the effect of irrelevant tactile stimulation on humans' free-viewing behavior during the exploration of complex static scenes. Specifically, we address the questions of (1) whether task-irrelevant tactile stimulation presented to subjects' hands can guide visual selection during free viewing; (2) whether tactile stimulation can modulate visual exploratory biases that are independent of image content and task goals; and (3) in which reference frame these effects occur. Tactile stimulation to uncrossed and crossed hands during the viewing of static images resulted in long-lasting modulation of visual orienting responses. Subjects showed a well-known leftward bias during the early exploration of images, and this bias was modulated by tactile stimulation presented at image onset. Tactile stimulation, both at image onset and later during the trials, biased visual orienting toward the space ipsilateral to the stimulated hand, both in uncrossed and crossed hand postures. The long-lasting temporal and global spatial profile of the modulation of free viewing exploration by touch indicates that cross-modal cues produce orienting responses, which are coded exclusively in an external reference frame. PMID- 26021614 TI - Dengue Awareness in Latin American Populations: A Questionnaire Study. AB - INTRODUCTION: Dengue is an escalating public health concern in Latin American Countries with a dramatic increase of cases reported during the past decade. The objectives of this study were to identify and provide insights into current management and attitudes toward dengue and to understand attitudes to vaccination and current behaviors to prevent dengue in Mexico and Colombia. METHODS: This was a community-based, cross-sectional, descriptive study conducted in urban and rural areas in endemic and non-endemic regions. The interviews were conducted face-to-face using a structured questionnaire containing 58 questions. A quota sampling approach was used to obtain a nationally representative sample of the adult population. All data were weighted to correct for differences between the samples surveyed in each country relative to their general population. RESULTS: A total of 1978 participants completed the survey. Two percent and 10% of participants in Mexico and Colombia, respectively, had experienced dengue fever, with just under one-third of adults and almost two-thirds of their children hospitalized as a result of the illness. Awareness of dengue was similar in Colombia (76%) and Mexico (68%), with awareness higher in endemic regions than in non-endemic regions. Colombia had a higher proportion of participants (84%) who considered dengue to be a common disease in their country, compared with Mexico (56%). In Mexico and Colombia, 55% and 54% in endemic areas, and 28% and 46% in non-endemic areas believed that everyone was at risk of contracting dengue. In both countries, the most common action undertaken by participants to prevent dengue infection was removal of standing water. At least 70% of participants believe their government could do more to prevent dengue in their country. CONCLUSIONS: Dengue was identified as a severe and common disease in Mexico and Colombia. Most participants recognized the need to reduce the risk of dengue infection by removal of standing water. Awareness was similar in Colombia and Mexico. PMID- 26021613 TI - Multisensory training reverses midbrain lesion-induced changes and ameliorates haemianopia. AB - Failure to attend to visual cues is a common consequence of visual cortex injury. Here, we report on a behavioural strategy whereby cross-modal (auditory-visual) training reinstates visuomotor competencies in animals rendered haemianopic by complete unilateral visual cortex ablation. The re-emergence of visual behaviours is correlated with the reinstatement of visual responsiveness in deep layer neurons of the ipsilesional superior colliculus (SC). This functional recovery is produced by training-induced alterations in descending influences from association cortex that allowed these midbrain neurons to once again transform visual cues into appropriate orientation behaviours. The findings underscore the inherent plasticity and functional breadth of phylogenetically older visuomotor circuits that can express visual capabilities thought to have been subsumed by more recently evolved brain regions. These observations suggest the need for reevaluating current concepts of functional segregation in the visual system and have important implications for strategies aimed at ameliorating trauma-induced visual deficits in humans. PMID- 26021616 TI - Removal of Polycyclic Aromatic Hydrocarbons from Precipitation in an Urban Forest of Guangzhou, South China. AB - Polycyclic aromatic hydrocarbon (PAH) concentrations and fluxes were measured monthly in situ from rain events in an urban forest in the megapolitan city Guangzhou, China, to investigate impacts of forest canopy and soils on PAHs. Mean Sigma9-PAH concentrations were 107.5, 101.6, 106.3, 107.1 and 42.4 ng L(-1) in precipitation, throughfall, seepage water at the 30 and 60 cm soil depth, and runoff, respectively, indicating a great decrease in the form of runoff. Meanwhile, annual fluxes of total PAHs decreased from precipitation (205.9 ug m( 2) year(-1)), to throughfall (156.3 ug m(-2) year(-1)), and to seepage water (65.3 ug m(-2) year(-1) at 30-cm soil depth and 7.5 ug m(-2) year(-1) at 60-cm soil depth), but increased in runoff (34.1 ug m(-2) year(-1)). When compared to precipitation, PAH fluxes decreased by 83.4% in runoff, with 29% contributed by forest canopy and 71% by soils. Soil biodegradation explained 18.2% of PAH reduction by the surface soil layer and 34.6% by the middle soil layer. PMID- 26021615 TI - Park7 interacts with p47(phox) to direct NADPH oxidase-dependent ROS production and protect against sepsis. AB - Inappropriate inflammation responses contribute to mortality during sepsis. Through Toll-like receptors (TLRs), reactive oxygen species (ROS) produced by NADPH oxidase could modulate the inflammation responses. Parkinson disease (autosomal recessive, early onset) 7 (Park7) has a cytoprotective role by eliminating ROS. However, whether Park7 could modulate inflammation responses and mortality in sepsis is unclear. Here, we show that, compared with wild-type mice, Park7(-/-) mice had significantly increased mortality and bacterial burdens in sepsis model along with markedly decreased systemic and local inflammation, and drastically impaired macrophage phagocytosis and bacterial killing abilities. Surprisingly, LPS and phorbol-12-myristate-13-acetate stimulation failed to induce ROS and proinflammatory cytokine production in Park7(-/-) macrophages and Park7-deficient RAW264.7 cells. Through its C-terminus, Park7 binds to p47(phox), a subunit of the NADPH oxidase, to promote NADPH oxidase-dependent production of ROS. Restoration of Park7 expression rescues ROS production and improves survival in LPS-induced sepsis. Together, our study shows that Park7 has a protective role against sepsis by controlling macrophage activation, NADPH oxidase activation and inflammation responses. PMID- 26021617 TI - Data quality issues impede comparability of hospital treatment delay performance indicators. AB - AIM: To assess the comparability of five performance indicator scores for treatment delay among patients diagnosed with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention in relation to the quality of the underlying data. METHODS: Secondary analyses were performed on data from 1017 patients in seven Dutch hospitals. Data were collected using standardised forms for patients discharged in 2012. Comparability was assessed as the number of occasions the indicator threshold was reached for each hospital. RESULTS: Hospitals recorded different time points based on different interpretations of the definitions. This led to substantial differences in indicator scores, ranging from 57 to 100 % of the indictor threshold being reached. Some hospitals recorded all the required data elements for calculating the performance indicators but none of the data elements could be retrieved in a fully automated way. Moreover, recording accessibility and completeness of time points varied widely within and between hospitals. CONCLUSION: Hospitals use different definitions for treatment delay and vary greatly in the extent to which the necessary data are available, accessible and complete, impeding comparability between hospitals. Indicator developers, users and hospitals providing data should be aware of these issues and aim to improve data quality in order to facilitate comparability of performance indicators. PMID- 26021618 TI - Prognostic significance of incident atrial fibrillation following STEMI depends on the timing of atrial fibrillation. AB - Atrial fibrillation (AF) is associated with short-term mortality after ST elevation myocardial infarction (STEMI), but there is limited data on the temporal association between AF and mortality after STEMI. A total of 830 patients were included (age: 62 +/- 12 years, 76 % male). Patients with new-onset AF < 30 days after STEMI were divided among three subgroups: AF on the day of admission, AF 24-72 h and AF > 72 h after admission. Thirty-day mortality was assessed by telephone and via the municipal population registry. Twenty patients died < 30 days after admission. In 41 patients, AF was detected on the day of admission, in 14 patients 24-72 h after admission and in 18 patients > 72 h after admission. Mortality was higher in patients with AF on the day of admission (7.3 vs 2.2 %, p = 0.036) and 24-72 h after admission (14.3 vs 1.4 %, p < 0.001), but not in patients with AF > 72 h after admission (0 vs 1.1 %, p > 0.999). Age (odds ratio (OR) 1.123, p < 0.001), Killip class (adjusted OR 8.341, p < 0.001), AF on the day of admission (OR 3.585, p = 0.049) and 24-72 h after admission (OR 11.515, p = 0.003) were, amongst other variables, associated with an increased 30 day mortality. In conclusion, only new-onset incident AF during the first 72 h after admission was associated with 30-day mortality in STEMI patients. PMID- 26021619 TI - Peripheral arterial tonometry cannot detect patients at low risk of coronary artery disease. AB - BACKGROUND: Endothelial dysfunction precedes coronary artery disease (CAD) and can be measured by peripheral arterial tonometry (PAT). We examined the applicability of PAT to detect a low risk of CAD in a chest pain clinic. METHODS: In 93 patients, PAT was performed resulting in reactive hyperaemia (RHI) and augmentation (AIx) indices. Patients were risk classified according to HeartScore, Diamond and Forrester pretest probability (DF), exercise testing (X ECG), and computed tomography calcium scoring (CCS) and angiography (CTA). Correlations, risk group differences and prediction of revascularisation within 1 year were calculated. RESULTS: RHI correlated with HeartScore (r = - 0.21, p = 0.05), AIx with DF (r = 0.26, p = 0.01). However, both were not significantly different between normal and ischaemic X-ECG groups. In addition RHI and AIx were similar between low risk as compared with intermediate-to-high risk, based on risk algorithms (RHI: 1.98 (0.67) vs 1.94 (0.78); AIx: 0.0 (21) vs 5.0 (25); p = NS), or CCS and CTA (RHI: 1.99 (0.58) vs 1.89 (0.82); AIx: - 2.0 (24) vs 4.0 (25); p = NS). Finally, RHI and AIx failed to predict revascularisation (RHI: OR 1.42, CI 0.65-3.1; AIx: OR 1.02, CI 0.98-1.05). CONCLUSIONS: PAT cannot detect a low risk of CAD, possibly because RHI and AIx versus X-ECG, CCS and CTA represent independent processes. PMID- 26021620 TI - Increased Prevalence of Developmental Venous Anomalies in Children with Intracranial Neoplasms. AB - BACKGROUND AND PURPOSE: Developmental venous anomalies are considered variants of venous development that, in and of themselves, are of little clinical import. A possible association between intrinsic brain tumors and developmental venous anomalies has been suggested, but a rigorous investigation has not been performed. The aim of this study was to assess any association between developmental venous anomalies and intrinsic brain neoplasms. MATERIALS AND METHODS: A radiology report text search of terms used to describe developmental venous anomalies was performed on a study population of 580 patients with primary intracranial neoplasms and on a control population of 580 patients without neoplasms from the same time period. All positive results were reviewed to confirm that the report was describing a developmental venous anomaly, and the imaging examination was reviewed to confirm the diagnosis. RESULTS: Fifty-nine of the 580 subjects with brain tumors (10.17%) had a developmental venous anomaly identified by report and confirmed on review of the imaging. Thirty-one of the 580 controls (5.34%) had a developmental venous anomaly identified by report and confirmed on review of the imaging (P = .003). No statistically significant difference was noted in the prevalence of developmental venous anomalies among tumor types. No developmental venous anomaly drained the vascular territory of the tumor, and there was no correlation between the location of the developmental venous anomaly and the location of the neoplasm. CONCLUSIONS: The prevalence of developmental venous anomalies in this pediatric population with intracranial primary neoplasms is significantly greater than in those without neoplasms, suggesting an association that may be related to shared causative factors or susceptibilities to the development of these 2 separate entities. PMID- 26021621 TI - Choroid Plexus Neoplasms: Toward a Distinction between Carcinoma and Papilloma Using Arterial Spin-Labeling. AB - Pediatric choroid plexus papillomas and carcinomas are highly vascularized neoplasms, which are difficult to distinguish with conventional imaging. We aimed to analyze the diagnostic accuracy of PWI, by using both pseudocontinuous arterial spin-labeling and DSC-PWI. We reviewed the PWI of 13 children with choroid plexus neoplasms (7 papillomas and 6 carcinomas). We quantified CBF, relative CBF, and relative CBV in each lesion and compared papillomas and carcinomas. Relative CBF values by using arterial spin-labeling were significantly higher for carcinomas (P = .028). The median value of relative CBF was 1.7 (range, 1.4-1.9) for carcinomas and 0.4 (range, 0.3-0.6) for papillomas. The CBF median value was 115 mL/min/100 g (range, 90-140 mL/min/100 g) for carcinomas and 41 mL/min/100 g (range, 10-73 mL/min/100 g) for papillomas (P = .056). Measures with DSC-PWI were more variable and not significantly different (P = .393). Arterial spin-labeling is a promising technique to differentiate choroid plexus carcinomas and papillomas. PMID- 26021622 TI - Influence of Resting-State Network on Lateralization of Functional Connectivity in Mesial Temporal Lobe Epilepsy. AB - BACKGROUND AND PURPOSE: Although most studies on epilepsy have focused on the epileptogenic zone, epilepsy is a system-level disease characterized by aberrant neuronal synchronization among groups of neurons. Increasingly, studies have indicated that mesial temporal lobe epilepsy may be a network-level disease; however, few investigations have examined resting-state functional connectivity of the entire brain, particularly in patients with mesial temporal lobe epilepsy and hippocampal sclerosis. This study primarily investigated whole-brain resting state functional connectivity abnormality in patients with mesial temporal lobe epilepsy and right hippocampal sclerosis during the interictal period. MATERIALS AND METHODS: We investigated resting-state functional connectivity of 21 patients with mesial temporal lobe epilepsy with right hippocampal sclerosis and 21 neurologically healthy controls. A multivariate pattern analysis was used to identify the functional connections that most clearly differentiated patients with mesial temporal lobe epilepsy with right hippocampal sclerosis from controls. RESULTS: Discriminative analysis of functional connections indicated that the patients with mesial temporal lobe epilepsy with right hippocampal sclerosis exhibited decreased resting-state functional connectivity within the right hemisphere and increased resting-state functional connectivity within the left hemisphere. Resting-state network analysis suggested that the internetwork connections typically obey the hemispheric lateralization trend and most of the functional connections that disturb the lateralization trend are the intranetwork ones. CONCLUSIONS: The current findings suggest that weakening of the resting state functional connectivity associated with the right hemisphere appears to strengthen resting-state functional connectivity on the contralateral side, which may be related to the seizure-induced damage and underlying compensatory mechanisms. Resting-state network-based analysis indicated that the compensatory mechanism among different resting-state networks may disturb the hemispheric lateralization. PMID- 26021623 TI - Optimal Virtual Monochromatic Images for Evaluation of Normal Tissues and Head and Neck Cancer Using Dual-Energy CT. AB - BACKGROUND AND PURPOSE: Dual-energy CT is not used routinely for evaluation of the head and neck, and there is no consensus on the optimal virtual monochromatic image energies for evaluating normal tissues or head and neck cancer. We performed a quantitative evaluation to determine the optimal virtual monochromatic images for visualization of normal tissues, head and neck squamous cell carcinoma, and lymphadenopathy. MATERIALS AND METHODS: Dual-energy CT scans from 10 healthy patients and 30 patients with squamous cell carcinoma were evaluated at different virtual monochromatic energy levels ranging from 40 to 140 keV. The signal-to-noise ratios of muscles at 6 different levels, glands (parotid, sublingual, submandibular, and thyroid), 30 tumors, and 17 metastatic lymph nodes were determined as measures of optimal image quality. Lesion attenuation and contrast-to-noise ratios (compared with those of muscle) were evaluated to assess lesion conspicuity. RESULTS: The optimal signal-to-noise ratio for all the tissues was at 65 keV (P < .0001). However, tumor attenuation (P < .0001), attenuation difference between tumor and muscles (P = .03), and lesion contrast-to-noise ratios (P < .0001) were highest at 40 keV. CONCLUSIONS: The optimal image signal-to-noise ratio is at 65 keV, but tumor conspicuity compared with that of muscle is greatest at 40 keV. Optimal evaluation of the neck may be best achieved by a multiparametric approach, with 65-keV virtual monochromatic images providing the best overall image quality and targeted use of 40-keV virtual monochromatic images for tumor evaluation. PMID- 26021624 TI - Stent-Assisted Coiling of Wide-Neck Intracranial Aneurysms Using Low-Profile LEO Baby Stents: Initial and Midterm Results. AB - BACKGROUND AND PURPOSE: Low-profile self-expandable stents were recently introduced for the treatment of wide-neck intracranial aneurysms. This study investigated the initial and midterm clinical and angiographic results of LEO Baby stent-assisted coiling in the treatment of wide-neck intracranial aneurysms. MATERIALS AND METHODS: A retrospective review was performed to identify patients who were treated with LEO Baby stent-assisted coiling. Eighty patients with 80 wide-neck intracranial aneurysms were included in the study. Eleven patients (13.8%) presented with subarachnoid hemorrhage. All patients were treated with LEO Baby stent-assisted coiling. Technical success and immediate postprocedural clinical and angiographic outcomes were evaluated. Seventy-three patients attended angiographic and clinical follow-up for a mean duration of 7.2 +/- 3.8 months. Periprocedural and delayed complications were reviewed. Preprocedural and follow-up clinical statuses were assessed by using the modified Rankin Scale. RESULTS: The technical success rate of the procedure was 97.5%. The immediate postprocedural angiography revealed a complete occlusion of the aneurysm in 75% of the 80 patients. The last follow-up angiograms showed complete occlusion in 85.7% of the 77 patients with an angiographic follow-up. Of the 77 patients with a follow-up angiography, 6.5% showed an increase in the filling status of the aneurysm and 5.2% required retreatment. The overall procedure-related complication rate, including asymptomatic complications, was 11.3%. The permanent morbidity rate was 3.8%. There was no mortality in this study. CONCLUSIONS: This case series demonstrates the relative safety, efficacy, and midterm durability of the LEO Baby stent-assisted coiling procedure for the treatment of wide-neck intracranial aneurysms. PMID- 26021625 TI - Blood pressure target goals from guidelines of 2002-2014. PMID- 26021626 TI - The left atrial neural network: more complicated than we thought? PMID- 26021627 TI - Benefits of an integrated heart failure service at critical periods in the heart failure disease trajectory. PMID- 26021628 TI - An apple a day: changing medicine through technology and engagement. PMID- 26021629 TI - Highlights from the British Society for Heart Failure 17th annual autumn meeting: "yesterday's problems, today's solutions". AB - The 17th Annual Autumn meeting of the British Society of Heart Failure entitled "Yesterday's problems, today's solutions" took place on the 27-28 November 2014 at the Queen Elizabeth II Conference Centre in London. Over 700 delegates joined together from across the UK, Europe and as far away as Australia to attend this year's meeting. Professionals from a range of backgrounds including physicians, surgeons, nurses, psychologists, pharmacists and trainees highlighted the multidisciplinary nature of heart failure care. The symposium, which is accredited by the Royal College of Physicians and the Royal College of Nursing, delivered the key message this year of the importance of a holistic approach to patients with heart failure. PMID- 26021630 TI - Advances in interventional neuroradiology: novel use of mechanical thrombectomy in acute ischemic stroke. AB - Dr Sanjeev Nayak speaks to Sean Fitzpatrick, Commissioning Editor: Dr Sanjeev Nayak is a Consultant Neuroradiologist with special interest in Interventional Neuroradiology at the University Hospital of North Midlands, Stoke on Trent. He was responsible for the development of Interventional Stroke Service which he did immediately following his appointment in 2009 and was the lead neuroradiologist from 2010 to 2013. Dr Nayak and his team have pioneered in the field of mechanical thrombectomy and stenting in acute ischemic stroke and treated the largest number of such cases in the UK. His team has produced one of the best clinical outcomes for such patients with the lowest mortality rates in the UK. This work has been nominated for numerous national awards in various categories of BMJ, Patient Safety and Care integration awards. Dr Nayak was the finalist at the HSJ awards under the category of 'Clinical Leader of the Year 2012' and NHS Leadership awards 'NHS Inspirational Leader of the Year 2013. Dr Nayak is also involved in patents and designs involving new stroke interventional devices and is actively involved in stroke research which has led to numerous publications in peer reviewed journals. Dr Nayak has organized national conferences and lectured at various national and international conferences in his field of interest. PMID- 26021631 TI - Electronic cigarettes and cardiovascular risk: hype or up in smoke? PMID- 26021632 TI - Evolving cardiovascular care for women: a decade of progress. PMID- 26021633 TI - Pharmacogenomics in cardiology--genetics and drug response: 10 years of progress. PMID- 26021634 TI - Gating pore current is a novel biophysical defect of Nav1.5 mutations associated with unusual cardiac arrhythmias and dilation. PMID- 26021635 TI - Combined subpectoral implantation of a cardioverter defibrillator and breast augmentation surgery in a patient with Emery-Dreifuss muscular dystrophy. AB - We present the case of a 28-year-old female with Emery-Dreifuss muscular dystrophy and breast hypoplasia, who underwent implantation of a subpectoral defibrillator and bilateral breast augmentation during a single elective procedure at our institution. PMID- 26021636 TI - Gene expression of cytokines, growth factors and apoptosis regulators in a neonatal model of pulmonary stenosis. AB - BACKGROUND: Right ventricular remodeling due to pulmonary stenosis increases morbidity in children. Its pathophysiology needs to be clarified. METHODS: Six newborn lambs underwent pulmonary arterial banding, seven sham operation. mRNA encoding for cytokines, growth factors and regulators of apoptosis was sequentially measured in myocardium and blood before and up to 12 weeks postoperatively. RESULTS: Experimental animals showed hypertrophy and fibrosis of the right ventricular myocardium, myocardial over-expression of CT-1-mRNA and higher blood concentrations of mRNA encoding for VEGF, TGF-beta, Bak and BcL-xL than controls, respectively. CONCLUSION: Neonatal pulmonary stenosis leads to myocardial hypertrophy that is associated with CT-1 gene expression and with activation of growth- and apoptosis pathways in blood cells. PMID- 26021637 TI - Cardiomyocytes, endothelial cells and cardiac fibroblasts: S100A1's triple action in cardiovascular pathophysiology. AB - Over the past decade, basic and translational research delivered comprehensive evidence for the relevance of the Ca(2+)-binding protein S100A1 in cardiovascular diseases. Aberrant expression levels of S100A1 surfaced as molecular key defects, driving the pathogenesis of chronic heart failure, arterial and pulmonary hypertension, peripheral artery disease and disturbed myocardial infarction healing. Loss of intracellular S100A1 renders entire Ca(2+)-controlled networks dysfunctional, thereby leading to cardiomyocyte failure and endothelial dysfunction. Lack of S100A1 release in ischemic myocardium compromises cardiac fibroblast function, entailing impaired damage healing. This review focuses on molecular pathways and signaling cascades regulated by S100A1 in cardiomyocytes, endothelial cells and cardiac fibroblasts in order to provide an overview of our current mechanistic understanding of S100A1's action in cardiovascular pathophysiology. PMID- 26021639 TI - An update on insertable cardiac monitors: examining the latest clinical evidence and technology for arrhythmia management. AB - Continuous cardiac rhythm monitoring has undergone compelling progress over the past decades. Cardiac monitoring has emerged from 12-lead electrocardiograms being performed at the discretion of the treating physician to in-hospital telemetry, Holter monitoring, prolonged external event monitoring and most recently toward insertable device monitoring for several years. Significant advantages and disadvantages pertaining to these monitoring options will be addressed in this review. Insertable cardiac monitors have several advantages over external monitoring techniques and may signify a clinical turning point in the field of arrhythmia management. However, their role in the detection of paroxysmal atrial fibrillation after cryptogenic strokes has yet to evolve. This will be the main focus of this review. Issues surrounding patient selection, clinical relevance and determination of cost-effectiveness for prolonged cardiac monitoring require further studies. Furthermore, insertable cardiac monitoring has not only the potential to augment diagnostic capabilities but also to improve the management of paroxysmal atrial fibrillation. PMID- 26021638 TI - Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. AB - Atrial fibrillation (AF) has long been associated with a heightened risk of ischemic stroke and systemic thromboembolism, but recent data require a re evaluation of our understanding of the nature of this relationship. New findings about the temporal connection between AF and stroke, alongside evidence linking markers of left atrial abnormalities with stroke in the absence of apparent AF, suggest that left atrial thromboembolism may occur even without AF. These observations undermine the hypothesis that the dysrhythmia that defines AF is necessary and sufficient to cause thromboembolism. In this commentary, we instead suggest that the substrate for thromboembolism may often be the anatomic and physiological atrial derangements associated with AF. Therefore, our understanding of cardioembolic stroke may be more complete if we shift our representation of its origin from AF to the concept of atrial cardiopathy. PMID- 26021640 TI - Alternative stents in ST-segment elevation myocardial infarction: improving the efficacy of primary percutaneous coronary intervention. AB - Despite the efficacy of primary percutaneous coronary intervention in achieving epicardial reperfusion in ST-segment elevation myocardial infarction, it is often limited by impaired microvascular perfusion attributable to distal embolization of plaque and thrombus, and stent malappostion due to vessel constriction and thrombus apposition, attenuating the full benefits of myocardial reperfusion and resulting in unfavorable clinical outcomes. In the long run implantation of permanent metallic implants have negative effect the biological behavior of the target vessel with a continuous low device failure over the years. Recently, however, efforts have been realized to tackle these shortcomings and optimize mechanical reperfusion by improvements to stent design, as substantiated by the self-expanding stent, the mesh-covered stent and the bioresorbable vascular scaffold. In this article, we provide an overview of the role of these novel, innovatively designed, alternative devices in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. PMID- 26021641 TI - Environmental enrichment attenuates the age-related decline in the mRNA expression of steroidogenic enzymes and reduces the methylation state of the steroid 5alpha-reductase type 1 gene in the rat hippocampus. AB - We analyzed the effects of aging and environmental enrichment on the mRNA expression and DNA methylation state of steroidogenic enzymes in the hippocampus. The effects of aging were evaluated by comparing young adult (90-day-old) and middle-aged (450-day-old) female Wistar rats. To elucidate the effects of environmental enrichment, a subgroup of middle-aged rats exposed to sensory and social stimulation for 105 days was compared to rats housed under standard laboratory conditions. Aging decreased the transcription of neurosteroidogenic related genes and increased the promoter methylation state of cytochrome P450 side chain cleavage, 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) and 5alpha reductase-1. Exposure of middle-aged rats to environmental enrichment increased mRNA levels of 5alpha-reductase-1, 3alpha-HSD and cytochrome P450 17alpha hydroxylase/c17,20-lyase and decreased the methylation state of the 5alpha reductase-1 gene. Thus, sensory and social stimulation attenuate the age-related decline in the mRNA expression of hippocampal steroidogenic enzymes. Epigenetic mechanisms associated with differential promoter methylation could be involved. PMID- 26021643 TI - Food safety: A public health priority. PMID- 26021642 TI - Fluphenazine.HCl and Epigallocatechin Gallate Modulate the Rate of Formation and Structural Properties of Apolipoprotein C-II Amyloid Fibrils. AB - Protein misfolding and aggregation, leading to amyloid fibril formation, are characteristic of many devastating and debilitating amyloid diseases. Accordingly, there is significant interest in the mechanisms underlying amyloid fibril formation and identification of possible intervention tools. Small molecule drug compounds approved for human use or for use in phase I-III clinical trials were investigated for their effects on amyloid formation by human apolipoprotein (apo) C-II. Several of these compounds modulated the rate of amyloid formation by apoC-II. Epigallocatechin gallate (EGCG), a green tea catechin, was an effective inhibitor of apoC-II fibril formation, and the antipsychotic drug, fluphenazine.HCl, was a potent activator. Both EGCG and fluphenazine.HCl exerted concentration-dependent effects on the rate of fibril formation, bound to apoC-II fibrils with high affinity, and competitively reduced thioflavin T binding. EGCG significantly altered the size distribution of fibrils, most likely by promoting the lateral association of fibrils and subsequent formation of large aggregates. Fluphenazine.HCl did not significantly alter the size distribution of fibrils, but it may induce the formation of a small population of rod-like fibrils that differ from the characteristic ribbon like fibrils normally observed for apoC-II. The findings of this study emphasize the effects of small molecule drugs on the kinetics of amyloid fibril formation and their roles in determining fibril structure and aggregate size. PMID- 26021644 TI - Non-medical use of prescription drugs in Bangalore, India. AB - BACKGROUND: Non-medical prescription drug use is an ongoing problem in India; however, there is paucity of literature in the Indian population. OBJECTIVE: The objective of the present study is to explore the non-medical use of prescription medicines in urban Bangalore, South India (N = 717). MATERIALS AND METHODS: Participants were recruited using a mall-intercept approach, wherein they were intercepted in 5 randomly selected shopping malls, and interviewed on their use of prescription medicines. RESULTS: The mean age of the participants was 28 years (S.D. 5). The non-medical use of different prescription medicine classes over the past 12 months was as follows: anti-inflammatories and analgesics (26%), opioids (17%), antibiotics (13%), and sedatives (12%). The majority reported "use without prescription," while "use in ways other than as prescribed" was also reported. In all cases, chemist shops were the main source of obtaining the drugs non medically. In multivariate logistic regression analyses, non-medical use was found to be significantly associated with participants' baseline characteristics like gender, education, current employment status, and marital status. Sixty-five percent stated that although "doctor's prescription is not required for common complaints, we can decide ourselves," while 60% stated, "it's okay to deviate from a prescription as needed." One hundred percent said that "using prescription medicines is more socially acceptable, and safer, compared to alcohol or illicit drugs." CONCLUSION: These findings underscore the need for considering various contextual factors in tailoring preventive interventions for reducing non-medical use of prescription drugs. PMID- 26021645 TI - Stress, anxiety, and depression among call handlers employed in international call centers in the national capital region of Delhi. AB - BACKGROUND: Call handlers employed in call centers repeatedly undergo stress in their day-to-day lives and this can have deleterious effects on their health. OBJECTIVES: The objectives were to study the levels of stress, anxiety, and depression, and their predictors among call handlers employed in international call centers in the National Capital Region (NCR) of Delhi. MATERIALS AND METHODS: A cross-sectional questionnaire-based survey was conducted among 375 call handlers aged 18-39 years. Depression Anxiety Stress Scale- 42 (DASS-42) was used to measure stress, anxiety, and depression along with a pretested sociodemographic questionnaire. Univariate analysis was done to find out the association of stress, anxiety, and depression with various factors. Variables with P < 0.25 were included in multiple logistic regression and three models were developed each for stress, anxiety, and depression. RESULTS: The prevalence of stress, anxiety, and depression among call handlers was 46.7%, 57.1%, and 62.9% respectively. Abnormal sleep quality, prolonged travel time, and lack of relaxation facilities at the office were predictors of stress and depression. The presence of physical ailments, the absence of hobbies, temporary/part-time employment, and traveling long-distance to office were significant predictors of anxiety among call handlers. CONCLUSION: Call handlers face a high burden of stress, anxiety, and depression. Public health specialists need to pay adequate attention to their health problems. PMID- 26021646 TI - Sodium intake prediction with health promotion model constructs in rural hypertensive patients. AB - BACKGROUND: Hypertension is the most common cause of cardiovascular disease, and the growing epidemic is a serious warning to pay more attention to this disease. The aims of this study were to examine the relationships between the health promotion model (HPM) constructs and sodium intake, and to determine the predictive power of the HPM constructs as the possible mediators of sodium intake in rural Iranian hypertensive patients. MATERIALS AND METHODS: This cross sectional study was conducted on 671 hypertensive patients in Ardabil, Iran in 2013. The data were obtained during a 25-40 min face-to-face conversation by validated and reliable instruments. The nutritional data were assessed with Nutritionist version 4 (N4) software. Descriptive statistics, Spearman's correlations were calculated using SPSS Statistics version 18.0. Structural equation modeling was conducted using AMOS version 18. RESULTS: Sodium intake was negatively correlated with perceived benefits (r = -0.707; P < 0.01), perceived self-efficacy (r = -0.719; P < 0.01), situational influences (r = -0.590; P < 0.01), interpersonal influences (r = -0.637; P < 0.01), commitment to action (r = -0.605; P < 0.01), affects related behavior (r = -0.499; P < 0.01), and positively associated with the perceived barriers score (r = 0.563; P < 0.01). The structural equation modeling showed that the model explained 63.0% of the variation in sodium intake. CONCLUSIONS: HPM constructs were significantly associated with sodium intake and dietary perceptions based on HPM constructs can predict acceptable rate of the variation of sodium intake. Therefore, we suggest using this model constructs to improve the effectiveness of nutritional interventions. PMID- 26021647 TI - Mass chemoprophylaxis in control of pneumococcal pneumonia outbreak in a military training centre. AB - BACKGROUND: Outbreaks of streptococcal pneumonia among young recruits in military training centers are well-documented. A significant outbreak of pneumonia occurred between November 19, 2011 and February 4, 2012 among the young recruits of a large training center located in Southern India. OBJECTIVES: The objective of this investigation was to identify the cause of the outbreak, to control the outbreak at the earliest, and to provide future strategies for containing such an outbreak. MATERIALS AND METHODS: The outbreak was investigated using standard epidemiological methods so as to describe its epidemiology, to identify the causative organism, to guide the outbreak control efforts, and to provide future strategies for containing such an outbreak. RESULTS: Over 2 months, 58 cases of pneumonia occurred among the recruits of the center, giving an attack rate of 4.81 cases per 1,000 person-months. Radiological positivity was found in 72.4% of the cases. Streptococcus pneumoniae (S. pneumoniae) was grown in all the three bronchoalveolar lavage (BAL) samples. The outbreak rapidly ended following prophylaxis with oral azithromycin. CONCLUSIONS: This outbreak of pneumococcal disease occurred in the setting of intense military training and a crowded environment. Oral azithromycin was found to be the suitable strategy for control of the outbreak. PMID- 26021648 TI - Internet addiction: Prevalence and risk factors: A cross-sectional study among college students in Bengaluru, the Silicon Valley of India. AB - BACKGROUND: The Internet is a widely used tool known to foster addictive behavior, and Internet addiction threatens to develop into a major public health issue in the near future in a rapidly developing country like India. OBJECTIVE: This cross-sectional study intends to estimate prevalence, understand patterns, and evaluate risk factors for Internet addiction among college students in the city of Bengaluru, India. MATERIALS AND METHODS: Out of a total of 554 data samples from eight colleges selected through multistage cluster sampling, 515 samples were analyzed. Young's 20-item Internet Addiction Test (IAT), an inventory including demographic factors and patterns of internet use, was administered. RESULTS: This study of college students aged 16-26 years (mean +/- SD 19.2 +/- 2.4 years), with marginally high female representation (56%), identified 34% [95% confidence interval (CI) 29.91-38.09%] and 8% (95%, CI 5.97 10.63%) as students with mild and moderate Internet addiction respectively. Binary logistic regression found Internet addiction to be associated with male gender [adjusted odds ratio (AOR) 1.69, 95% CI, 1.081- 2.65, P = 0.021], continuous availability online (AOR 1.724, 95% CI, 1.018-2.923, P = 0.042), using the Internet less for coursework/assignments (AOR 0.415, 95% CI, 0.263-0.655, P < 0.001), making new friendships online (AOR 1.721, 95% CI, 1.785-2.849, P = 0.034), getting into relationships online (AOR 2.283, 95% CI, 1.424-3.663, P = 0.001). CONCLUSION: The results highlight the vulnerability of college students to Internet addiction. The findings provide explanations on the addictive behavior of the internet users, support the inclusion of "Internet Addiction" in the DSM-VI, and open up new paths for further research. PMID- 26021649 TI - Reporting guidelines in health research: A review. AB - Contemporary health research has come under close scrutiny, exposing alarming flaws in the reporting of research. The reporting guidelines can aid in identification of poorly reported studies and can bring transparency to health research. The guidelines also help journal editors, peer reviewers, funding agencies, and readers to better discern health research. Reporting guidelines encourage accurate and thorough reporting of fundamental aspects of health research so that the results of studies can be replicated by others. Reporting guidelines are potent tools to improve the practice of research and in reducing reporting bias. For the present review, both electronic and manual literature search was carried out. Electronic databases like PubMed, MEDLINE, EBSCO host, and Science Direct were searched for extracting relevant articles. Various key words and their combinations were used for literature search like reporting guidelines, checklist, research, publishing standards, study design, medicine, and dentistry. The search results were scrutinized for relevance to the topic and only full text articles in English were incorporated. Various reporting guidelines were identified and grouped under headings based on study design. This review article attempts to highlight the various reporting guidelines in literature relating to health research, its potential applications, and its limitations. PMID- 26021650 TI - Results-based management - Developing one's key results areas (KRAs). AB - In spite of aspiring to be a good manager, we public health experts fail to evaluate ourselves against our personal and professional goals. The Key Result Areas (KRAs) or key performance indicators (KPIs) help us in setting our operational (day-to-day) and/or strategic (long-term) goals followed by grading ourselves at different times of our careers. These shall help in assessing our strengths and weaknesses. The weakest KRA should set the maximum extent to which one should use his/her skills and abilities to have the greatest impact on his/her career. PMID- 26021651 TI - Evidence-based public health: Barriers and facilitators to the transfer of knowledge into practice. AB - This paper underscores some of the barriers and facilitators in the practice of evidence-based public health (EBPH). A large body of evidence-based interventions (EBIs) exists, which has been generated through highly robust systematic reviews. These EBIs have been widely disseminated and promoted by public health researchers and the World Health Organization (WHO) as effective public health interventions against various preventable/treatable diseases. The inability of many low- and middle-income countries to contextually adapt and effectively implement evidence-informed interventions (EBIs) has been identified as a major obstacle to progress in achieving Millennium Development Goals (MDGs). Hence, it is imperative to identify and understand the factors that are detrimental to the successful transfer of evidence into policy as well as practice. This paper discusses how factors such as political, contextual, and organizational factors; nature of evidence; and community participation influence the practice of EBPH. PMID- 26021652 TI - Self-reported physical activity and its correlates among adult women in the expanded part of Thiruvananthapuram City, India. AB - Data on correlates of physical activity (PA) are limited in India. This study estimated the prevalence and correlates of PA among women. A cross-sectional survey was conducted among 1303 women (mean age 45 years) selected by multistage cluster sampling. Information was collected using a pretested interview schedule. Multivariate logistic regression analysis was used to determine the correlates of PA. Self-reported moderate or high level PA prevalence was 73.4% [95% confidence interval (CI); 71.1-75.9]. Women who perceived themselves as being underweight [odds ratio (OR) 3.68: 1.97-6.74]; had an exercising member in the household (OR 3.41: 2.52-4.66); had access to exercise facilities (OR 2.17: 1.63-2.95); were married (OR 2.14: 1.40-3.25), were in the age group of 35-54 years (OR 1.91: 1.32 2.63); reported having knowledge about the benefits of PA (OR 1.62: 1.13-2.25); and who reported having the support of friends and neighbors (OR 1.42: 1.05-2.01) were more likely to report PA than their counterparts. PMID- 26021653 TI - Clinical profile of hand, foot, and mouth disease and its associated complications among children in Shimoga City, southern Karnataka: A hospital based study. AB - Hand, foot, and mouth disease (HFMD) is one of the important public health problems. It has become a common childhood illness in our part of the country. In most instances, this is a mild self-limiting illness. The affected children are often given outpatient care. However, over the last decade, HFMD has emerged as a growing health problem in Asian countries following frequent outbreaks of deaths associated with HFMD caused by a more virulent member of human enterovirus (HEV), namely, HEV71. A hospital-based descriptive study about the clinical presentations and complications of HFMD at the hospitals of Shimoga city between March 2013 and August 2013 is documented and presented here. HFMD was more common in the 1-3-year old age group, with aseptic meningitis being the most common complication. Surveillance of HFMD must be maintained as there is no effective chemoprophylaxis or vaccine available. PMID- 26021654 TI - Newborn screening for G6PD deficiency: A 2-year data from North India. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common erythrocyte enzymopathy, being present in more than 400 million people worldwide that may lead to neonatal jaundice or hemolytic crisis due to drugs or infections. In our study, we aimed to study the frequency of G6PD deficiency in neonates and the proportion of deficient neonates, who developed neonatal hyperbilirubinemia in the study population. The study was an observational one, conducted at the Division of Genetics of Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, over a 2-year period from January 2011 to December 2012. A total of 6,000 newborns delivered during that period underwent newborn screening on 24-72 h of birth. Neonatal hyperbilirubinemia was presented in 13.3% of the study population. Of female neonates, 16% demonstrated G6PD deficiency. This is worth noting for an X-linked recessive trait. Thus, in view of a high gene frequency for a disorder that is manageable with just elimination of few drugs and foodstuff, we stress the need for a newborn screening program for G6PD deficiency. PMID- 26021655 TI - Experiences from Garbha-Swasthya helpline. AB - Garbha-Swasthya helpline is a telephone helpline run by a tertiary care private hospital to address issues related to pregnancy and its complications. A review of the helpline data from September 2010 to December 2012 was conducted to study caller characteristics, number of calls and related information, and the reasons to call. Out of the total 696 voice calls, 421 were new callers and 275 were repeat callers and they comprised mainly pregnant women (73.3%), their relatives (24.8%), and medical professionals (1.9%). Most calls were related to first pregnancy and were mainly from Pune and other cities of Maharashtra. All calls by the medical professionals were regarding drug safety in pregnancy. The commonest category of questions (27.4%) was about exposures (drugs, alcohol, eclipse, radiation, etc.) and preexisting medical illness followed by pregnancy complications (18.5%), common medical issues such as nausea/vomiting during pregnancy, and delivery and postpartum period (14% each). Although the total number of calls received has steadily increased, efforts to create public and professional awareness to increase the usage of this helpline are warranted. PMID- 26021656 TI - Application of water quality index for the assessment of suitability of natural sources of water for drinking in rural areas of east Sikkim, India. AB - In Sikkim, especially in the rural areas where there is no supply of treated water for drinking and other domestic uses, natural surface water is the only source. The objective was to assess the water quality of natural sources of water in the rural areas of East Sikkim using a water quality index (WQI) for different seasons. A total of 225 samples, that is, 75 in winter, 75 in summer, and 75 in monsoon were collected from different sources for physicochemical analysis, and a WQI was calculated. The water quality values ranged 32.01-96.71. The results showed that most of the water samples were in poor condition (85.3%) and very few of them were in good condition (2.6%). The water quality of the natural sources indicated that the water is poor-quality and not totally safe for human consumption, and that it needs treatment before consumption. PMID- 26021657 TI - Updating income ranges for Kuppuswamy's socio-economic status scale for the year 2014. PMID- 26021658 TI - Race for publications: Isn't it killing the real purpose of research? PMID- 26021659 TI - Emplementation of national iron plus initiative for child health: Challanges ahead: Erratum. PMID- 26021660 TI - The analysis of functional and radiographic outcomes of conservative treatment in patients with low lumbar burst fractures. AB - INTRODUCTION: Burst fractures of the low lumbar spine constitute approximately one percent of all lumbar fractures. There is still no consensus on the optimal treatment of low lumbar burst factures. We aimed to evaluate the functional and radiographic outcomes of conservative treatment in patients with low lumbar burst fracture. METHODS: 15 patients (11 males, 4 females; mean age 32+/-8) who had low lumbar spine burst fracture treated with a custom-moulded thoracolumbosacral orthosis (TLSO) with a thigh extension were enrolled. The mean follow-up period was 22+/-6 months. 14 patients were neurologically intact and one had isolated nerve root injury. There were 24% type A fractures and 76% type B fractures according to the Denis classification system. Functional outcomes were evaluated by using Oswestry Disability Index (ODI), Short-Form 36 (SF-36) and Visual Analogue Scale (VAS). Radiographic outcome was analyzed by measuring anterior vertebral height loss, kyphosis angle, amount of canal retropulsion. Functional and radiographic outcomes were reviewed initially and at 1, 3, 6, 12 months, and at the latest follow-up. Functional and radiographic improvements were analyzed statistically. RESULTS: The mean bracing period was 11.9+/-1.7 weeks. The mean initial ODI, SF-36, and VAS score of the patients was 78.3+/-9.6, 23.7+/-8.9, and 8.7+/-0.7, respectively. The mean ODI, SF-36, and VAS score of the patients at the final follow-up was 26.4+/-6.5, 68.1+/-11.2, and 2.8+/-1.7, respectively. The improvement in functional outcomes was measured to be significant (p<0.05 for ODI, SF-36 and VAS). The mean initial anterior vertebral height loss, kyphosis angle, amount of canal retropulsion was found to be 27.2%+/-9.6%, -6.8 degrees +/ 3.2 degrees , 37.4%+/-10.2%, respectively. The mean anterior vertebral height loss, kyphosis angle, and amount of canal retropulsion at the final follow-up was 23.1%+/-.6.7%, -4.2 degrees +/-2.4 degrees , 19.6%+/-7.7%, respectively. Among the radiographic outcomes, only the amount of canal retropulsion improved statistically (p=0.042). CONCLUSION: Conservative treatment using a custom moulded thoracolumbosacral orthosis with a thigh extension is a safe and effective method in patients with low lumbar spine burst fractures and can improve functional and radiographic outcomes. PMID- 26021661 TI - Scaphoid nonunion treated with vascularised bone graft from dorsal radius. AB - INTRODUCTION: The main aim of this retrospective study was to present our experience on scaphoid nonunion treated with vascularised bone graft. METHODS: Between 2006 and 2012, 58 patients presenting with symptomatic scaphoid nonunion were eligible to participate in this study. Topography of the nonunion included 29 proximal, 25 waist and 4 distal scaphoid nonunions. Vascularised bone graft from distal dorsal radius was used in all cases which were stabilised with the headless cannulated compression screws. Scapholunate angles, Natrass carpal height ratio were evaluated pre and postoperatively. Range of motion of the affected side was compared to that of the contralateral side after the surgery. RESULTS: Radiographic union was achieved in 50, out of 58 cases with an average time of 9.9 weeks (range, 6-18 weeks). Out of all the non-united cases, four of them were in proximal, three in the waist and one was in distal scaphoid. In nine proximal nonunions treated by 4+5 ECA graft all but one were united. The mean follow up was 21.7 months (12-62 months). The flexion was 91.6%, the extension was 91.5%, the radial deviation was 81.2%, and the ulnar deviation was 89.5% compared to the other side. The grip strength was 93%. Preoperative DASH score was 61.5 diminishing to 28.7 postoperatively. There was no significant change in Natrass carpal height ratio but a slight improvement occurred in scapholunate angles both pre and postoperatively. CONCLUSION: Vascularised bone graft is a good solution for scaphoid nonunion to enhance the healing rate especially in the presence of avascular necrosis. Proximal pole nonunions, humpback deformity and smoking are important negative factors for scaphoid nonunion despite the use of a vascularised bone graft. A trapezoidal wedge graft is necessary for the volar type nonunions with humpback deformity. 1,2 ICSRA offer an advantage with its proximity to scaphoid in all nonunion locations. Nonetheless, 4+5 ECA graft is also a good solution for proximal nonunions. PMID- 26021662 TI - Should full threaded compression screws be used in adult femoral neck fractures? AB - INTRODUCTION: Operative treatment consisting of fracture reduction and fixation, or arthroplasty to permit early patient mobilization, continues to be the treatment of choice for most femoral neck fractures. Options for internal fixation have included a variety of implants; however most recent reports and textbooks cite parallel multiple cancellous screws as the surgical technique of choice. METHODS: The study was prospective, randomized and IRB approved. Inclusion criteria included skeletal maturity, closed femoral neck fracture without concomitant fractures or injuries with complete charts and adequate radiographs obtained from the initial injury till the last follow-up. Forty-four patients were enrolled in this study during one-year period at two university centers. 22 were randomized to be treated with full threaded, cannulated compression screws (Acutrak 6/7, ACUMED) (Group 1) and the other 22 with 16mm partial threaded, 6.5mm or 7.3mm cannulated screws (SYNTHES) (Group 2). Three or four screws were used in both groups according to fracture type and surgeon's preference. Data evaluated included surgical time, fluoroscopy time, fracture type, radiological outcome, complications and functional status using the Harris Hip Score. RESULTS: Both groups were comparable in terms of age and gender. There was not a significant difference in terms of surgical time, follow-up period, fracture type, or fluoroscopy time. There were eight complications in Group 1 and two in Group 2 (P=0.049) Time to union was significantly longer in Group 1 (P=0.001). However, Hip Scores were not significantly different in both groups (P=0.20). CONCLUSION: When compared with full threaded compression screws, partial-threaded cannulated screws provides a shorter union time and less complication rate while providing equivalent functional results in adult femoral neck fractures. PMID- 26021663 TI - Factors affecting pain in acute ankle fractures: A prospective evaluation. AB - Pain has been identified as the dominant factor in patient outcomes. The purpose of this study was to evaluate the degree of pain reported in a large series of acute ankle fractures and to determine what factors are associated with higher pain scores. We prospectively evaluated 457 consecutive patients with acute Weber B supination external rotation ankle fractures upon presentation for pain in 9 areas of the ankle. There were 231 females and 226 males, average age 46.2 (18 96) with 133 bi/tri-malleolar and 324 lateral malleolar fractures. There were 101 SE2, 73 stress (+) SE4, and 150 ligamentous SE4 injuries. The highest pain score (VAS 0-10) for the medial and lateral regions was chosen for analysis. Other factors included in the multivariate analysis were: age, ethnicity, DM, alcohol presence, and days from injury to presentation on the level of pain reported using a linear regression model and set statistical significance at 0.05. In univariate analysis, the type of injury (medial malleolus or deltoid ligament) nor instability differed with respect to medial pain. However, patients presenting with instability had more lateral pain (5.6+/-3) than those with stable injuries (2.6+/-3) (p<001). Additionally, those with bony medial injury had more lateral pain (7+/-2.7) than those with isolated lateral malleolar fractures (4.0+/-3.4) (p<0.001). Most importantly, in the multivariate analysis, the only factor that was significant for both medial and lateral pain (separate regressions) was ethnicity, with blacks having more pain given the same injury than whites (p<0.001). Latinos trended towards having more lateral pain than whites (p=0.15), but not more medial pain (p=0.3). For lateral pain, in addition to ethnicity, presence of a displaced mortise (p<0.0001), having a medial bony injury (p<0.0001), and the days from injury (p=0.008) were significant. Pain decreased with time from injury. In this evaluation of over 450 patients with Weber B, SE pattern ankle fractures we confirmed previous work in the upper extremity indicating an important difference in the reported pain by ethnicity. In particular, black patients have more pain than white or latino patients given the same injury. PMID- 26021664 TI - The regeneration and augmentation of bone with injectable osteogenic cell sheet in a rat critical fracture healing model. AB - Limitations in the current treatment strategies make cases with compromised bone healing challenging clinical problems. Osteogenic cell sheets (OCSs), fabricated from rat bone marrow stromal cells (BMSCs), contain enriched osteoblasts and extracellular matrix. Here, we evaluated whether the minimally invasive percutaneous injection of OCSs without a scaffold could be used as a treatment to increase bone regeneration in a critical fracture healing model. Critical fracture healing model was created in the femora of 60 male Fischer 344 inbred rats using marrow ablation and periosteal removal. The rats were then randomly divided into two groups. Six hours after fracture, one group received an injection of OCSs (OCS group), while the second group was injected with phosphate buffered saline (PBS) (control group). Fracture healing was evaluated using radiological, histological, micro-computed tomography (CT) and biomechanical analyses. The radiological and histological evaluations demonstrated enhanced bone regeneration in the OCS group compared with that in the control group. By 12 weeks, the hard callus had been remodelled via recorticalization in the OCS group. By contrast, no fracture union was found in the rats in the control group. Biomechanical testing revealed a significantly higher maximum bending load in the OCS group compared with that in the control group. The results of the present study demonstrate that the injection of entire OCSs can enhance bone regeneration and lead to bony union in a critical fracture healing model. Therefore, this procedure offers a minimally invasive technique to promote hard tissue reconstruction and, in particular, bone repair strategies for cases with compromised bone healing. PMID- 26021665 TI - Unstable intertrochanteric femur fractures in geriatric patients treated with the DLT trochanteric nail. AB - OBJECTIVE: To evaluate clinical-functional and radiological results of geriatric patients with unstable intertrochanteric femur fracture treated with intramedullary nail. MATERIALS AND METHODS: Thirty-two patients treated with intramedullary nail (DLT trochanteric nail) due to unstable intertrochanteric femur fractures were reviewed retrospectively. Fractures 31-A2 and 31-A3 (AO classification) were evaluated. Operation time, blood loss, and blood transfusion requirements, hospitalization period, time to fracture union were evaluated and perioperative and postoperative complications were recorded. According to the modified Baumgaertner criteria fracture reduction was analyzed radiologically, and nail tip-apex distance was measured. Femoral neck-shaft angle was also evaluated. Harris Hip Score for clinical evaluation and Kyo criteria for walking capacity were used. RESULTS: The mean age was 72 years (65-81), mean follow up time was 18.3 months (12-26). Nineteen patients had type 31-A2 and 13 had type 31 A3 fractures. Mean operation time was 36.3min (25-45), blood loss 185.9ml (100 250). Blood transfusion was required in 7 patients. The average hospitalization duration was 6 days (4-14) while the time to surgery from admission was 2.9 days (2-6). Radiologically, in 21 of the cases fracture reduction was well (65.6%), acceptable in 9 (28.1%), and poor in 2 (6.3%). In early postoperative period, the mean collo-diaphyseal angle was 129.1 degrees (120-140 degrees ), mean tip-apex distance was 15.5mm (10-27). The mean Harris Hip Score was 63.4 (38-90). Two patients (6.3%) had excellent, 21 patients (65.6%) had good, 7 patients (21.8%) had moderate, and 2 patients (6.3%) had poor results. Walking capacity in the last follow-up in 20 of the cases (62.5%) was pre-fracture level. While complications were observed in seventeen patients (53.1%) (5 superficial wound infections, 5 fractures of the greater trochanter, 3 cases of secondary varus angulation and 4 cases of heterotopic ossification) none of them required additional surgery, no implant failures or cut-outs were observed. CONCLUSION: Functional and radiological results are satisfactory in using intramedullary nailing in the treatment of geriatric patients with unstable intertrochanteric fractures. Optimum surgical technique can minimize the risk of implant-related complications. PMID- 26021666 TI - Dual locked plating of unstable bicondylar tibial plateau fractures. AB - The operative treatment of displaced bicondylar tibial plateau fractures is challenging. The displaced condyles must be reduced, depressed plateaus must be elevated and adequately supported and early rehabilitation must be encouraged in order to obtain good clinical results. This retrospective study was designed to evaluate the clinical outcomes of patients with bicondylar tibial plateau fractures treated with dual locked plates using raft screws with MIPO technique and autologous bone grafting. We hypothesized that in this group of patients dual locked plating reduces the complication rates by avoiding loss of reduction due to the accomplished rigid fixation. Twenty-two consecutive patients with bicondylar tibial plateau fractures (AO Type C) were included in this study. The mean follow up was 26 months. Bone healing was achieved in all patients with 3 cases of superficial and 1 case of deep infection. Secondary loss of reduction, secondary loss of alignment, early post-traumatic arthritis were not observed in this study. The Lysholm knee score showed an average of 80.5 points (range: 61.5 90) at the final follow up assessment. Optimal fixation of the fracture with dual locked plating which allows immediate motion and partial weight bearing may be an alternative concept to prevent secondary loss of reduction to obtain a good clinical outcome. PMID- 26021667 TI - Examining user satisfaction with single sign-on and computer application roaming within emergency departments. AB - In an age where mandatory computer usage within clinical care settings is a non negotiable term of employment, the amount of applications a provider must access to document care is rapidly increasing. Each application contains an associated username and password. The increasing frequency with which clinicians have to log in and out of different applications is a source of frustration for many healthcare professionals. Healthcare executives see lost productivity. Single sign-on with added computer application roaming capabilities on shared workstations is a viable solution for both the clinician and the organization. The aim of this study is to assess the effect of implementation of single sign-on technology with application roaming on shared workstations. This study focuses on the perception of satisfaction with the implementation of single sign-on technologies within a midsized integrated delivery health network's five emergency departments. We contribute to theory with the following: (1) the development of a construct called facilitated technology interruptions, (2) validation of the construct facilitated technology interruptions, and (3) application of a quantitative method to test the relationship between facilitated technology interruptions and user satisfaction. We surveyed five emergency departments and proposed five hypotheses. We found the positive relationship between facilitated technology interruptions and user satisfaction; the positive relationships between effort expectancy and satisfaction, and effort expectancy and willingness to recommend; and the positive relationship between satisfaction and willingness to recommend. We did not confirm the positive relationship between facilitated technology interruptions and willingness to recommend. We conclude that single sign-on technology increases user satisfaction. Other organizations may use the findings from this study and perform pre-single sign-on versus post-single sign-on evaluations. In practice, single sign-on improved productivity and ensured compliance with the Health Insurance Portability and Accountability Act, minimization of errors, and disruption for critical work. PMID- 26021668 TI - Dissemination of a theory-based online bone health program: Two intervention approaches. AB - With the increasing nationwide emphasis on eHealth, there has been a rapid growth in the use of the Internet to deliver health promotion interventions. Although there has been a great deal of research in this field, little information is available regarding the methodologies to develop and implement effective online interventions. This article describes two social cognitive theory-based online health behavior interventions used in a large-scale dissemination study (N = 866), their implementation processes, and the lessons learned during the implementation processes. The two interventions were a short-term (8-week) intensive online Bone Power program and a longer term (12-month) Bone Power Plus program, including the Bone Power program followed by a 10-month online booster intervention (biweekly eHealth newsletters). This study used a small-group approach (32 intervention groups), and to effectively manage those groups, an eLearning management program was used as an upper layer of the Web intervention. Both interventions were implemented successfully with high retention rates (80.7% at 18 months). The theory-based approaches and the online infrastructure used in this study showed a promising potential as an effective platform for online behavior studies. Further replication studies with different samples and settings are needed to validate the utility of this intervention structure. PMID- 26021669 TI - Applying artificial intelligence technology to support decision-making in nursing: A case study in Taiwan. AB - This study applied artificial intelligence to help nurses address problems and receive instructions through information technology. Nurses make diagnoses according to professional knowledge, clinical experience, and even instinct. Without comprehensive knowledge and thinking, diagnostic accuracy can be compromised and decisions may be delayed. We used a back-propagation neural network and other tools for data mining and statistical analysis. We further compared the prediction accuracy of the previous methods with an adaptive-network based fuzzy inference system and the back-propagation neural network, identifying differences in the questions and in nurse satisfaction levels before and after using the nursing information system. This study investigated the use of artificial intelligence to generate nursing diagnoses. The percentage of agreement between diagnoses suggested by the information system and those made by nurses was as much as 87 percent. When patients are hospitalized, we can calculate the probability of various nursing diagnoses based on certain characteristics. PMID- 26021670 TI - Update on the treatment of ANCA associated vasculitis. AB - The introduction of glucocorticoids and cyclophosphamide has transformed ANCA associated vasculitis (AAV) from a fatal to a largely treatable condition. Over the past 40 years, considerable progress has been made in refining immunosuppressive regimens with a focus on minimising toxicity. As knowledge of the pathogenesis of AAV grows, it is mirrored by the availability of biological agents. Lymphocyte and cytokine targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. Rituximab has transformed management of AAV in the past decade. However, there remains unmet need in the treatment of AAV; the majority of patients will relapse within five years of diagnosis despite maintenance immunosuppression; a small number of patients remain refractory to current therapies and treatment toxicity continues to contribute to mortality and chronic disability. As in rare diseases, treatment advances in vasculitis depend on international collaborative research networks to both establish an evidence base for newer agents and develop recommendations for optimal patient management. PMID- 26021672 TI - Influence of Hormonal Profile on Resting Metabolic Rate in Normal, Overweight and Obese Individuals. AB - AIMS: To investigate whether blood thyroid stimulating hormone (TSH), cortisol, insulin and glucose concentrations (plus glucose:insulin ratio; GIR) could improve the accuracy of resting metabolic rate (RMR) prediction in normal, overweight and obese persons. METHODS: Predictive equations were developed and compared against indirect calorimetry measures for RMR in 217 weight-control clinic participants (n = 128 males and n = 89 females: ~24% normal weight, ~39% overweight and ~37% obese). RESULTS: Using the common accuracy criteria of the proportion of predicted RMR within +/-10% of measured RMR, our equations (using age, height, weight and gender, plus the blood factors, both independently and in combination) were accurate ~36-44% of the time, for the whole sample, and when separated by gender and weight class. Specifically, the addition of the blood hormone and glucose concentrations improved the accuracy of predicted RMR by only 1-8% (NS). CONCLUSIONS: Including blood TSH, cortisol, insulin, glucose and GIR into RMR prediction equations did not significantly improve estimation accuracy, which in any case only met a criterion of +/-10% of the measured RMR ~40% of the time. Further work to refine the prediction of RMR is still needed, and at present, direct measurements should be made wherever possible. PMID- 26021673 TI - Vivid Mental Imagery of Biomechanically Impossible Movements Elicited by Cortical Electrostimulation of the Central Region in an Awake Patient. AB - BACKGROUND: The perception we have of our own body, called 'body image,' is crucial for self-awareness. Here, we evoked reproducible mental imagery of a postural illusion by intrasurgical electrostimulation of the central cortex. CASE REPORT: A 24-year-old patient experienced seizures involving vivid mental imagery of biomechanically impossible movements of the upper limb. A right precentral low grade glioma was diagnosed. Awake surgery with intraoperative electrostimulation sensorimotor mapping was performed. Remarkably, the same mental representations of biomechanically impossible movements of the left upper limb were repeatedly elicited during stimulation of the central cortex. These eloquent areas were preserved, even though the precentral part of the knob of the hand was removed. After a transient monoplegia, the patient recovered and resumed a normal life which included playing the guitar. CONCLUSION: These mental experiences of a postural illusion generated by intraoperative stimulation could be related to neuroplasticity mechanisms induced by the slow growth of low-grade glioma within the knob of the hand. Such a functional reorganization may explain why this area was removed without permanent deficits. This perception of biomechanically impossible movements during surgery might be due to a transient disruption by stimulating the frontoparietal network involved in the coding of the body image. PMID- 26021674 TI - Intracranial aneurysm in a patient with glucocorticoid-remediable aldosteronism. AB - Glucocorticoid-remediable aldosteronism (GRA) is an autosomal dominant disorder in which the increase in aldosterone secretion produced by Adrenocorticotropic hormone (ACTH) is no longer transient. Here we present a case of a 32-year-old man with GRA who was found to have an intracranial aneurysm following screening. His blood pressure had been well controlled and closely monitored since diagnosis and the institution of treatment at age 13 years. This is a rarely reported example of this manifestation in GRA, and both the treatment and rationale for therapy are discussed below. PMID- 26021671 TI - Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites. AB - Cytosine methylation at CpG dinucleotides is a central component of epigenetic regulation in vertebrates, and the base excision repair (BER) pathway is important for maintaining both the genetic stability and the methylation status of CpG sites. This perspective focuses on two enzymes that are of particular importance for the genetic and epigenetic integrity of CpG sites, methyl binding domain 4 (MBD4) and thymine DNA glycosylase (TDG). We discuss their capacity for countering C to T mutations at CpG sites, by initiating base excision repair of G . T mismatches generated by deamination of 5-methylcytosine (5mC). We also consider their role in active DNA demethylation, including pathways that are initiated by oxidation and/or deamination of 5mC. PMID- 26021675 TI - Endoscopic Third Ventriculostomy in Children with Myelomeningocele: A Case Series. AB - Hydrocephalus develops in up to 80-90% of children with myelomeningocele (MM) after closure of the defect. Traditionally, ventriculoperitoneal shunts have been used to manage hydrocephalus in these patients. A role for endoscopic third ventriculostomy (ETV) in MM has provoked much debate, principally due to anatomical variants described, which may complicate the procedure. We present 7 cases of children with MM and hydrocephalus undergoing a total of 10 ETV procedures. All patients demonstrated clinical improvement (in acute/subacute cases) or stabilization (in chronic cases). Three patients requiring a second ETV have shown clinical stability and renewed radiological evidence of functioning ventriculostomies in follow-up since reintervention. ETV can be used, albeit cautiously, in selected cases of hydrocephalus associated with MM. However, the frequency with which anatomical variation is encountered and the difficulty of the assessment of success make the procedure more challenging than usual. PMID- 26021676 TI - The Phonetic Realization of Devoiced Vowels in the Southern Ute Language. AB - In this article, we analyze the phonetic realizations of devoiced vowels from 8 fluent speakers of Southern Ute, a severely endangered Southern Numic Uto-Aztecan language spoken in Southwestern Colorado. Devoiced vowels are considered to be an important aspect of the phonology of Southern Ute, yet very little is known about the pronunciation of such segments. Our findings indicate that devoiced vowels are realized phonetically in three ways: (i) fully voiceless, (ii) partially devoiced, and (iii) fully reduced with concurrent lengthening, lower intensity and greater voicelessness of the preceding consonant. Such variable and noncategorical devoicing is seen for both high and nonhigh vowels and all consonants regardless of their manner of articulation. PMID- 26021678 TI - Hyaluronan and its function as an unspecific regulator of cell-bound receptors. AB - In a former study on primary mesangial cells a regulatory function of hyaluronan (HA) was shown. HA is the backbone of a cell-bound jelly-barrier. The thickness of that cell-bound jelly-barrier regulates the access of ligands to their cellular receptors in an unspecific way. The thickness of that barrier is reduced by degradation of HA. The hypothesis was that this regulatory mechanism is not restricted to mesangial cells, but applies for other cell types as well. A selective and topic oriented review of the literature was performed to collect references, which support the impression, that this unspecific mechanism of receptor-regulation by HA is not restricted to primary mesangial cells. On the basis of the data from the review of the literature it was concluded that the regulatory mechanism of HA also applies for other than mesangial cells. On the basis of the said mechanism it was concluded that a tissue-specific regulation of HA on the cell surface might be relevant in therapy, especially in chronic diseases. PMID- 26021677 TI - Airway Hyperreactivity Is Delayed after Mild Neonatal Hyperoxic Exposure. AB - BACKGROUND: Wheezing disorders are prominent in former preterm infants beyond the neonatal period. OBJECTIVES: We used a neonatal mouse model to investigate the time course of airway hyperreactivity in response to mild (40% oxygen) or severe (70% oxygen) neonatal hyperoxia. METHODS: After hyperoxic exposure during the first week of postnatal life, we measured changes in airway reactivity using the in vitro living lung slice preparation at the end of exposure [postnatal day 8 (P8)] and 2 weeks later (P21). This was accompanied by measures of smooth muscle actin, myosin light chain (MLC) and alveolar morphology. RESULTS: Neither mild nor severe hyperoxia exposure affected airway reactivity to methacholine at P8 compared to normoxic controls. In contrast, airway reactivity was enhanced at P21 in mice exposed to mild (but not severe) hyperoxia, 2 weeks after exposure ended. This was associated with increased airway alpha-smooth muscle actin expression at P21 after 40% oxygen exposure without a significant increase in MLC. Alveolar morphology via radial alveolar counts was comparably diminished by both 40 and 70% oxygen at both P8 and P21. CONCLUSIONS: These data demonstrate that early mild hyperoxia exposure causes a delayed augmentation of airway reactivity, suggesting a long-term alteration in the trajectory of airway smooth muscle development and consistent with resultant symptomatology. PMID- 26021679 TI - Endoscopic versus radiology-based location of rectal cancer. AB - BACKGROUND: Rigid proctosigmoidoscopy is recommended for measuring the height of rectal neoplasms but appears to be performed in only a minority of patients. Our aim was to compare endoscopic and radiological measurement of rectal tumour location with a focus on differentiation between mid and high rectal cancer. METHODS: Medical records of 66 rectal cancer patients were reviewed. Tumour location defined at colonoscopy (66 patients), rigid proctosigmoidoscopy (20 patients) and endorectal ultrasound (35 patients) was recorded. Rectilinear and curvilinear methods were used to estimate the distance between the lower tumour level and the anal verge on sagittal CT or MR images (66 patients). Agreement, intra- and inter-observer variation of radiology-based measurements were assessed using intra-class correlation (ICC) and within-subject coefficient of variation (WSCV). RESULTS: Tumour location was performed at rigid proctosigmoidoscopy in 30% of patients. Intra- and inter-observer agreement for radiology-based measurements were high. Tumour location using the rectilinear method or proctosigmoidoscopy was similar on average, for a difference of only 0.34 cm (SD 2.0 cm, p = 0.330), although agreement was -moderate (ICC = 0.54, WSCV = 16.7%). Measurements based on colonoscopy and the curvilinear radiological method were -characterized by a systematic overestimation of the location, increasing with tumour height. CONCLUSIONS: Radiology-based measurement of the lower tumour level is a reproducible alternative for tumour location at rigid or flexible endoscopy. Its validity should be further assessed. PMID- 26021680 TI - Clinical Value of (18)F-FDG- PET-CT in the Preoperative Staging of Peritoneal Carcinomatosis from Colorectal Origin. AB - BACKGROUND: dequate staging is essential in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) who are candidates for cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Metabolic imaging using (18)F-FDG-PET-CT is commonly used to exclude distant metastasis in these patients. Here, we aimed to assess the performance of (18)F-FDG-PET-CT in locoregional staging of the extent of PC. METHODS: Patients with PC from CRC underwent staging including 18F-FDG-PET-CT. In the absence of systemic -dissemination, CRS and oxaliplatin based HIPEC were performed. The extent of PC was quantified during surgery using the modified 7 region count (7RC). The correlation between imaging based estimation of PC extent and surgical 7RC was analyzed using Pearson correlation using both patient based and region based analyses. RESULTS: Fifty-five patients were included between February 2005 and October 2018. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 57%, 98%, 95%, 78% and 82% respectively for non-mucinous tumors and 32%, 100%, 100%, 55% and 63% respectively. (18)F-FDG-PET CT detected the presence of colorectal PC in 96% of patients suffering from PC with nonmucinous histology and in 60% of patients suffering from PC with mucinous histology. Correlation between imaging 7RC and surgical 7RC was better for PC with nonmucinous histology (r = 0.623) than for PC with mucinous histology (r = 0.180). CONCLUSIONS: Despite of underestimating the exact extent of disease involvement, (18)F-FDG-PET-CT shows good performance in detecting colorectal PC with nonmucinous histology. For colorectal PC with mucinous histology, (18)F-FDG PET-CT, however, shows poor performance. Since (18)F-FDG-PET-CT did not detect the presence of colorectal PC in all patients in whom long-term survival could be achieved, (18)F-FDG-PET-CT should be implemented into a broad pre-operative assessment strategy. PMID- 26021681 TI - Can a flap help the plug ? Or vice versa ? Proposing a combined sphincter-sparing anal fistula repair. AB - BACKGROUND: To evaluate the results of a combination of fistulectomy with a rectal advancement flap and an anal fistula plug in the treatment of transsphincteric anal fistulas. METHODS: All patients with a transsphincteric fistula and a limited number of anterior intersphincteric fistulas in female patients were registered from July 1(st), 2010 until November 30(th), 2012. All operations were performed by one surgeon (CdG). Patient data and results (healing, continence) were collected in a prospective database. RESULTS: 28 patients were treated with a healing rate of 75% after one procedure. Four out of seven patients who failed to heal underwent a redo anal fistula plug and rectal advancement flap. Three of them were cured. Cumulative healing rate was 86% after two procedures. There were four minor complications. Mean postoperative Wexner score was 0.62. CONCLUSIONS: Combination of anal fistula plug and rectal advancement flap in treating transsphincteric anal fistulas can result in good healing rates with minimal incontinence. PMID- 26021682 TI - Morbidity of redo surgery for thyroid disease. AB - OBJECTIVE: Redo thyroid surgery is generally associated with more complications than firsthand surgery. The actual study reports a single center experience of redo thyroid surgery compared to primary bilateral thyroidectomy. STUDY DESIGN: Mono institutional retrospective study. METHODS: Institutional review of redo thyroid surgery patients (Group 2 : completion thyroidectomy and Group 3 : thyroidectomy for recurrent thyroid diseases) compared to Group 1 : primary bilateral thyroidectomy operated on during the same time interval. RESULTS: Demographic characteristics were not different between groups. Substernal extension and hyperthyroidism were more frequent in group 1. Weight of the resected thyroid gland was lower in groups 2 and 3. Incidence of transient hypocalcemia, permanent hypoparathyroidism, transient and permanent recurrent laryngeal palsy was not different between the groups. Hematoma occurred in 5% of cases in the 3 groups and postoperative length of stay was 1 day in 92% of cases of the 3 groups. CONCLUSIONS: Redo thyroid surgery can be performed with no excess morbidity provided strict selection criteria, having reoperation in mind while performing firsthand intervention. PMID- 26021683 TI - Differentiated thyroid carcinoma in early adulthood patients. AB - BACKGROUND: This paper reviews the clinico-pathologic features and outcomes of differentiated thyroid -carcinoma in early adulthood patients. STUDY DESIGN: Retrospective study. MATERIAL: From january 2000 to december 2012, 71 patients aged between 20 and 44 years who underwent thyroidectomy for differentiated thyroid carcinoma were included. The following parameters were recorded : age, gender, pre-operative symptoms and diagnosis, thyroid hormonal status, substernal extension, operative details, preoperative and postoperative calcium and phosphorous values, perioperative complications, length of hospital stay, final histology, survival and disease progression. RESULTS: There were 59 females (83%) and 12 males with a median age of 29 years (20-44 years). None had a previous neck irradiation. Total thyroidectomy was performed on 65 patients (92%). There were 66 papillary (93%) and 5 follicular carcinomas. Extrathyroidal invasion and lymph node involvement were present in 44% and 37% of cases respectively. Transient hypocalcemia and dysphonia occurred in 15% and 4 % of cases respectively. Permanent hypocalcemia and vocal cord paralysis occurred in 1% and 0% of cases respectively. Adjuvant radioactive I(131) therapy was given to 50 patients. There were 7 cases (10%) of lymph node recurrences but no disease related deaths. The only statistical differences between this group and all ages group were the extracapsular invasion (44% vs 20% p = 0,0014) and lymph node metastasis (37% vs 18% p = 0,0091). CONCLUSIONS: Differentiated thyroid carcinoma has a good prognosis in early adulthood patients. Although death from this condition is rare, recurrence is frequent and long term follow up is mandatory. PMID- 26021684 TI - Results of surgical treatment of anterior abdominal wall desmoid tumours : 13 cases reviewed with literature. AB - BACKGROUND: We retrospectively evaluated the results of surgical treatment for anterior abdominal wall -desmoid tumours. METHODS: Records for 13 patients operated on for desmoid tumours from 1997-2013 were searched for age, gender, abdominal/pelvic surgical history, pregnancy, Gardner's syndrome, pre-operative radiological examinations, tumour size, multifocality, surgical procedure, tumour presence at surgical margins, recurrence, morbidity, and mortality. Local recurrence-free survival probabilities were estimated by the Kaplan-Meier method and stratified by various clinicopathological variables. RESULTS: There were 11 female (84,6%) and 2 male (15,4%) patients with a median age of 36 years. Seven (53,8%) -patients had previous abdominal/pelvic surgery, five (38,5%) had a history of pregnancy, and one (7,6%) had Gardner's Syndrome. Two (15,3%) patients had multifocality on their pre-operative radiological examinations. Mean tumour diameter was 4,6 cm (SD 3,2 cm ; range 2-12 cm). After the excision of the masses in five (38,5%) patients, synthetic materials were used to close the abdominal wall defects. Two (15,3%) patients with positive surgical margins after -surgery were re-operated. Three (23%) patients required a second surgical intervention after the mass excisions were performed. Mean follow-up time was 56,7 months. Recurrence was observed in three patients during follow-up. Increased tumour size, history of previous abdominal/pelvic surgery, and the presence of multifocality had a negative effect on local recurrence-free survival. There was no mortality during follow-up. CONCLUSIONS: Desmoid tumours are characterized by high recurrence, even after proper surgical excisions. Preoperative differential diagnoses of these tumours should be done and a post-operative follow-up protocol should be followed. PMID- 26021685 TI - The effectiveness and impact of 10 gram glucose and 10 units insulin in treating hyperkalemia during living donor liver transplantation. AB - BACKGROUND: The aim of this retrospective observational study is to evaluate the effectiveness and impact on glycemia of the administration of 10 gram glucose and 10 units insulin in treating hyperkalemia during living donor liver transplantation (LDLT). METHODS: In LDLT, patients whose serum potassium exceeded 5.4 mEq/L and were treated with 10 gram glucose and 10 U regular insulin were included in this study. The descriptive statistics summarize the demographic data, baseline laboratory values, and intra-operative parameters of the treated patients. The changes of the serum potassium and serum glucose levels after treatment were analyzed by the paired Student's t-test. All the data were given as means +/- SD. A P value < 0.05 was regarded as statistically significant. RESULTS: After administration of 10 gram glucose and 10 units regular insulin bolus intravenously, a drastic and significant decreased of serum potassium from 5.73 +/- 0.44 to 4.48 +/- 0.06 mEq/L was noted. The serum glucose level was slightly higher after the treatment (166.6 +/- 32.1 and 196.8 +/- 44.3 mg/dl respectively, p = 0.05). CONCLUSIONS: An intravenous bolus of 10 units regular insulin with 10 gram glucose was able to decrease the serum -potassium level effectively and additionally increase serum glucose in LDLT patients. PMID- 26021686 TI - Protective Effects of Carvacrol Against Methotrexate-induced Liver Toxicity in Rats. AB - BACKGROUND: To investigate whether carvacrol (CAR) pretreatment reduces the severity of methotrexate (MTX)-induced hepatotoxicity in rats. METHODS: A total of 24 rats were equally divided into three groups : group I, control ; group II, MTX-treated ; and group III, CAR+MTX-treated. On Day 1 group III received a one time intraperitoneal dose of CAR (73 mg/kg), and on Day 2 both groups II and III received a single dose of intraperitoneal MTX (20 mg/kg). The rats were then sacrificed so to harvest blood and liver tissue samples to determine malondialdehyde (MDA), total antioxidant capacity (TAS), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels. Histological specimens were examined via light microscopy. RESULTS: Levels of MDA, ALT, AST and ALP in rat liver tissue samples were significantly higher in the MTX-treated group relative to the control group. However, TAS was significantly reduced in the MTX-treated group when compared to controls. Pretreating rats with CAR counteracted the effect of MTX exposure as MDA was significantly decreased and TAS was elevated in liver tissues when contrasted with the MTX-treated group. Furthermore, histological examination demonstrated significant liver injury in the MTX-treated group versus the CAR+MTX group. CONCLUSIONS: Pretreatment with CAR markedly diminished liver damage induced by MTX. Therefore, CAR administration preceding MTX treatment might be a promising therapeutic modality to prevent and/or lessen the extent of MTX-induced hepatotoxicity. PMID- 26021687 TI - Perianal mucinous adenocarcinoma arising from a chronic fistula-in-ano. AB - Mucinous adenocarcinoma arising in a long-standing anorectal fistula is rare in clinical practice. Evidenced-based guidelines for treatment are lacking due to the rarity of this tumour. We present the clinical case of an advanced perianal mucinous adenocarcinoma associated with a longstanding perianal fistula, successfully treated by extended -abdomino-perineal resection, reconstructed by bilateral myocutaneous gluteus flaps, without any adjuvant therapy. PMID- 26021688 TI - Biker's Nodule : A Case Report and Review of the Literature. AB - We describe a 17-year-old cyclist who presented with a biker's nodule which is a painful perineal mass resulting from chronic perineal compression and friction during extensive cycling. The treatment of choice is surgical excision. A review of the literature was made concerning this condition. Health care workers who are involved with sportsmen, especially in countries like Belgium where professional and recreational cycling is increasingly popular, should be aware of the diagnostic and therapeutic features of this condition. PMID- 26021689 TI - Madelung disease : report of a case and review of the literature. AB - Madelung disease is a rare disorder characterized by the presence of multiple, symmetric, nonencapsulated fatty accumulations diffusely involving the cheeks, the neck, the upper trunk, the shoulder girdle area, and the upper extremities. The cause of this syndrome is unknown, but it has been associated with alcoholism in 60% to 90% of -patients. The long-term lipomatous deposits are often large and cosmetically deforming, and the upper aerodigestive tract and great veins may be compressed. We report the case of a man with MD, involving the cervical and upper dorsal -regions, who underwent surgical treatment at our Department. PMID- 26021690 TI - Mycotic Aneurysm of the Popliteal Artery Secondary to Enterococcus Endo-carditis : a Case Report. AB - A mycotic popliteal aneurysm (MAAP) is a very rare condition [1]. We describe a 87-year-old Caucasian male who presented with a MAAP of the right leg due to an enterococcus mitral valve endocarditis. The aneurysm was excised and a reversed vein graft was interposed between the normal popliteal artery and the posterior tibial artery. A second vein graft was interposed between the first graft and the anterior tibial artery. PMID- 26021691 TI - Gastric diffuse hamartomatous polyposis as unique manifestation of peutz-jeghers syndrome. AB - INTRODUCTION: Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine, but can also occur in the stomach and large bowel. Gastric polyps usually coexist with hamartomatous polyps in other locations of the gastro intestinal tract. We present the second case reported in literature of diffuse gastric polyposis without affecting the rest of the gastrointestinal tract. CASE REPORT: A 41-years-old woman complained of repeated, self-limited episodes of hematemesis. She presented with anaemia. An upper gastrointestinal endoscopy revealed multiple polyps in all the gastric surface, whose biopsy diagnosed of hamartomatous polyps. No other polyps were detecting the gastrointestinal tract. The patient underwent a total gastrectomy with Roux-en-Y reconstruction. Pathology revealed a gastric diffuse hamartomatous polyposis. A mis-sense mutation encoding the serine/threonine kinase STK11 gene was been identified, compatible with Peutz Jeghers polyposis. PMID- 26021692 TI - Diffusion-Perfusion Mismatch in Single Subcortical Infarction: A Predictor of Early Neurological Deterioration and Poor Functional Outcome. AB - BACKGROUND/AIMS: Early neurological deterioration (END) is frequently observed and related to poor functional outcome in patients with single subcortical infarction (SSI). We evaluated the role of diffusion-perfusion mismatch (DPM) as a predictor of END and functional outcome in patients with SSI. METHODS: We retrospectively analyzed data for 274 patients with acute SSI. DPM was positive in the presence of a lesion on the perfusion map that was larger than that on the corresponding slice on diffusion-weighted imaging. END was defined as an increase of <1 points in the motor portion of the National Institute of Health Stroke Scale (NIHSS) within 72 h from MRI acquisition. Patients with a modified Rankin Scale (mRS) score of 3 or more at day 30 were considered having a poor functional outcome. RESULTS: DPM was more frequently observed in the END (+) than in the END (-) group (21/35 (60.0%) vs. 50/239 (20.9%); p < 0.001). After adjusting for covariates, the presence of DPM and NIHSS score on admission were independently associated with END (DPM, OR 5.03, p < 0.001; NIHSS, OR 1.14, p = 0.033) and poor functional outcome (DPM, OR 2.44, p = 0.018; NIHSS, OR 1.48, p < 0.001). CONCLUSIONS: The DPM concept is applicable to prediction of END and functional disability in patients with SSI. PMID- 26021693 TI - Dissecting the membrane cholesterol requirement for mycobacterial entry into host cells. AB - Mycobacteria are intracellular pathogens that can invade and survive within host macrophages, and are a major cause of mortality and morbidity worldwide. The molecular mechanism involved in the internalization of mycobacteria is poorly understood. In this work, we have explored the role of host membrane cholesterol in the entry of the avirulent surrogate mycobacterial strain Mycobacterium smegmatis into THP-1 macrophages. Our results show that depletion of host membrane cholesterol using methyl-beta-cyclodextrin results in a significant reduction in the entry of M. smegmatis into host cells. More importantly, we show that the inhibition in the ability of M. smegmatis to enter host macrophages could be reversed upon replenishment of membrane cholesterol. To the best of our knowledge, these results constitute the first report showing that membrane cholesterol replenishment can reverse the inhibition in the entry of mycobacteria into host cells. In addition, we demonstrate that cholesterol complexation using amphotericin B (without physical depletion) is sufficient to inhibit mycobacterial entry. Importantly, we observed a significant reduction in mycobacterial entry upon enrichment of host membrane cholesterol. Taken together, our results demonstrate, for the first time, that an optimum host plasma membrane cholesterol is necessary for the entry of mycobacteria. These results assume relevance in the context of developing novel therapeutic strategies targeting cholesterol-mediated mycobacterial host cell entry. PMID- 26021694 TI - [Acne and folliculitis in infants due to misuse of "liniment oleo-calcaire"]. PMID- 26021695 TI - Are effects of common ragwort in the Ames test caused by pyrrolizidine alkaloids? AB - It has previously been demonstrated by others that acetone extracts of Senecio jacobaea (syn. Jacobaea vulgaris, common or tansy ragwort) test positive in the Salmonella/microsome mutagenicity test (Ames test). Pyrrolizidine alkaloids (PAs) are thought to be responsible for these mutagenic effects. However, it was also observed that the major PA present in common ragwort, jacobine, produced a negative response (with and without the addition of rat liver S9) in Salmonella test strains TA98, TA100, TA1535 and TA1537. To investigate which compounds in the plant extracts were responsible for the positive outcome, the present study investigated the contents and mutagenic effects of methanol and acetone extracts prepared from dried ground S. jacobaea and Senecio inaequidens (narrow-leafed ragwort). Subsequently, a fractionation approach was set up in combination with LC-MS/MS analysis of the fractions. It was shown that the positive Ames test outcomes of S. jacobaea extracts are unlikely to be caused by PAs, but rather by the flavonoid quercetin. This study also demonstrates the importance of identifying compounds responsible for positive test results in bioassays. PMID- 26021696 TI - Oxidovanadium(IV) sulfate-induced glucose uptake in HepG2 cells through IR/Akt pathway and hydroxyl radicals. AB - The insulin-mimetic and anti-diabetic properties of vanadium and related compounds have been well documented both in vitro and in vivo. However, the molecular basis of the link between vanadium and the insulin signaling pathway in diabetes mellitus is not fully described. We investigated the effects of reactive oxygen species (ROS) induced by oxidovanadium(IV) sulfate (VOSO4) on glucose uptake and the insulin signaling pathway in human hepatoma cell line HepG2. Exposure of cells to VOSO4 (5-50 MUM) resulted in an increase in glucose uptake, insulin receptor (IR) and protein kinase B (Akt) phosphorylation and intracellular ROS generation. Using Western blot, we found that catalase and sodium formate, but not superoxide dismutase, prevented the increase of hydroxyl radical (.OH) generation and significantly decreased VOSO4-induced IR and Akt phosphorylation. These results suggest that VOSO4-induced .OH radical, which is a signaling species, promotes glucose uptake via the IR/Akt signaling pathway. PMID- 26021697 TI - Reduced accumulation of platinum drugs is not observed in drug-resistant ovarian cancer cell lines derived from cisplatin-treated patients. AB - The resistance of ovarian cancer towards front-line chemotherapy, usually cisplatin or carboplatin in combination with paclitaxel or docetaxel, remains a major clinical challenge. Resistance to these agents has been largely studied using cell lines selected for resistance to agents in vitro. We examined a series of paired cell lines derived from patients with ovarian cancer prior to chemotherapy (PEO1, PEO4, PEO14 and PEA1), and following the acquisition of resistance to a platinum-based chemotherapy regimen (PEO6, PEO23 and PEA2, respectively). All resistant patient lines showed resistance to cisplatin (2-5 fold), but this did not correspond with lowered accumulation. No general cross resistance was observed for oxaliplatin, paclitaxel or docetaxel, and paclitaxel accumulation was not affected. PEO1 cells carrying BRCA2 mutations were hypersensitive to the PARP inhibitors olaparib and velaparib, but all other cell lines expressing functional forms of BRCA2 were less sensitive. While reduced drug accumulation was not observed, we believe these pairs of lines are of use to researchers studying Pt drug resistance and experimental therapeutics against drug-resistant ovarian cancer. PMID- 26021698 TI - Reactivity of dinuclear copper(II) complexes towards melanoma cells: Correlation with its stability, tyrosinase mimicking and nuclease activity. AB - In this work, the influence of two new dinuclear copper(II) complexes in the viability of melanoma cells (B16F10 and TM1MNG3) was investigated, with the aim of verifying possible correlations between their cytotoxicity and their structure. One of the complexes had a polydentate dinucleating amine-imine ligand (complex 2), and the other a tridentate imine and a diamine-bridging ligand (complex 4). The analogous mononuclear copper(II) species (complexes 1 and 3, respectively) were also prepared for comparative studies. Crystal structure determination of complex 2 indicated a square-based pyramidal geometry around each copper, coordinated to three N atoms from the ligand and the remaining sites being occupied by either solvent molecules or counter-ions. Complex 4 has a tetragonal geometry. Interactions of these complexes with human albumin protein (HSA) allowed an estimation of their relative stabilities. Complementary studies of their reactivity towards DNA indicated that all of them are able of causing significant oxidative damage, with single and double strand cleavages, in the presence of hydrogen peroxide. However, nuclease activity of the dinuclear species was very similar and much higher than that of the corresponding mononuclear compounds. Although complex 2, with a more flexible structure, exhibits a much higher tyrosinase activity than complex 4, having a more rigid environment around the metal ion, both complexes showed comparable cytotoxicity towards melanoma cells. Corresponding mononuclear complexes showed to be remarkably less reactive as tyrosinase mimics as well as cytotoxic agents. Moreover, the dinuclear complexes showed higher cytotoxicity towards more melanogenic cells. The obtained results indicated that the structure of these species is decisive for its activity towards the malignant tumor cells tested. PMID- 26021699 TI - Our diversity and the Italian Constitution: do we really need human races? PMID- 26021701 TI - Response to "Characterization of the painful restless legs syndrome". PMID- 26021703 TI - The impact of a cold pressor test on brachial artery handgrip exercise-induced flow-mediated dilation. AB - It is unknown how endothelial-dependent flow-mediated dilation (FMD) stimulated by a sustained, exercise-induced increase in shear stress (EX-FMD) is affected by a simultaneous sympathoexcitatory painful stimulus. The purpose of this study was to examine the impact of a cold pressor test (CPT) on brachial artery EX-FMD elicited by a handgrip exercise-induced increase in shear stress. Participants were healthy males (age 21+/-2 years) (n=28; 16 Experimental group, 12 Control). Brachial artery diameter and blood velocity were measured using echo and Doppler ultrasound, respectively. Shear stress was estimated by shear rate (shear rate = blood velocity / diameter) and targeted to reach 75 s(-1) in each of two EX-FMD trials in all subjects. In the Experimental group, the second EX-FMD trial was accompanied by simultaneous foot immersion in ice water (simultaneous CPT). The shear rate stimulus did not differ between groups (p=0.823) or trials (p=0.726) (group * trial interaction: p=0.646) (average exercise shear rate (mean +/- SD): 67.6+/-6.2 s(-1)). The CPT (experienced during EX-FMD trial 2 in the Experimental group) increased mean arterial pressure (p<0.001) and heart rate (p=0.002) relative to the Control group. %EX-FMD was not different between groups (p=0.508) or trials (p=0.592) (group * trial interaction: p=0.879) (EX-FMD: Experimental group trial 1: 5.4+/-3.4%, trial 2: 5.6+/-2.6%; Control group trial 1: 6.0+/ 3.7%, trial 2: 6.4+/-2.2%). In conclusion, the CPT did not impact concurrent EX FMD, and this indicates that an acute painful stimulus does not interfere with conduit artery FMD responses during exercise in young healthy men. PMID- 26021702 TI - Serotonin Attenuates Feedback Excitation onto O-LM Interneurons. AB - The serotonergic system is a subcortical neuromodulatory center that controls cortical information processing in a state-dependent manner. In the hippocampus, serotonin (5-HT) is released by ascending serotonergic fibers from the midbrain raphe nuclei, thereby mediating numerous modulatory functions on various neuronal subtypes. Here, we focus on the neuromodulatory effects of 5-HT on GABAergic inhibitory oriens lacunosum-moleculare (O-LM) cells in the hippocampal area CA1 of the rat. These interneurons are thought to receive primarily local excitatory input and are, via their axonal projections to stratum lacunosum-moleculare, ideally suited to control entorhinal cortex input. We show that 5-HT reduces excitatory glutamatergic transmission onto O-LM interneurons. By means of paired recordings from synaptically connected CA1 pyramidal cells and O-LM interneurons we reveal that this synapse is modulated by 5-HT. Furthermore, we demonstrate that the reduction of glutamatergic transmission by serotonin is likely to be mediated via a decrease of calcium influx into presynaptic terminals of CA1 pyramidal cells. This modulation of excitatory synaptic transmission onto O-LM interneurons by 5-HT might be a mechanism to vary the activation of O-LM interneurons during ongoing network activity and serve as a brain state-dependent switch gating the efficiency of entorhinal cortex input to CA1 pyramidal neurons. PMID- 26021704 TI - Minos as a novel Tc1/mariner-type transposable element for functional genomic analysis in Aspergillus nidulans. AB - Transposons constitute powerful genetic tools for gene inactivation, exon or promoter trapping and genome analyses. The Minos element from Drosophila hydei, a Tc1/mariner-like transposon, has proved as a very efficient tool for heterologous transposition in several metazoa. In filamentous fungi, only a handful of fungal specific transposable elements have been exploited as genetic tools, with the impala Tc1/mariner element from Fusarium oxysporum being the most successful. Here, we developed a two-component transposition system to manipulate Minos transposition in Aspergillus nidulans (AnMinos). Our system allows direct selection of transposition events based on re-activation of niaD, a gene necessary for growth on nitrate as a nitrogen source. On average, among 10(8) conidiospores, we obtain up to ~0.8*10(2) transposition events leading to the expected revertant phenotype (niaD(+)), while ~16% of excision events lead to AnMinos loss. Characterized excision footprints consisted of the four terminal bases of the transposon flanked by the TA target duplication and led to no major DNA rearrangements. AnMinos transposition depends on the presence of its homologous transposase. Its frequency was not significantly affected by temperature, UV irradiation or the transcription status of the original integration locus (niaD). Importantly, transposition is dependent on nkuA, encoding an enzyme essential for non-homologous end joining of DNA in double strand break repair. AnMinos proved to be an efficient tool for functional analysis as it seems to transpose in different genomic loci positions in all chromosomes, including a high proportion of integration events within or close to genes. We have used Minos to obtain morphological and toxic analogue resistant mutants. Interestingly, among morphological mutants some seem to be due to Minos elicited over-expression of specific genes, rather than gene inactivation. PMID- 26021706 TI - Editorial. The Cognitive Neuroscience of Aging and Memory. PMID- 26021705 TI - Sugar transporters in the black truffle Tuber melanosporum: from gene prediction to functional characterization. AB - In a natural forest ecosystem, ectomycorrhiza formation is a way for soil fungi to obtain carbohydrates from their host plants. However, our knowledge of sugar transporters in ectomycorrhizal ascomycetous fungi is limited. To bridge this gap we used data obtained from the sequenced genome of the ectomycorrhizal fungus Tuber melanosporum Vittad. to search for sugar transporters. Twenty-three potential hexose transporters were found, and three of them (Tmelhxt1, Tmel2281 and Tmel131), differentially expressed during the fungus life cycle, were investigated. The heterologous expression of Tmelhxt1 and Tmel2281 in an hxt-null Saccharomyces cerevisiae strain restores the growth in glucose and fructose. The functional characterization and expression profiles of Tmelhxt1 and Tmel2281 in the symbiotic phase suggest that they are high affinity hexose transporters at the plant-fungus interface. On the contrary, Tmel131 is preferentially expressed in the fruiting body and its inability to restore the S. cerevisiae mutant strain growth led us to hypothesize that it could be involved in the transport of alternative carbon sources important for a hypothetical saprophytic strategy for the complete maturation of the carpophore. PMID- 26021707 TI - Synthesis, characterization and antiamoebic activity of chalcones bearing N substituted ethanamine tail. AB - A series of chalcones (4-21) possessing N-substituted ethanamine were synthesized by the aldol condensation reaction of 1-(4-(2-substituted ethoxy)phenyl)ethanones with different aldehydes preceded by the reaction of 2-chloro N-substituted ethanamine hydrochloride and 4-hydroxy acetophenone. The structure of all the synthesized compounds was elucidated by various spectral and X-ray diffraction studies. The compounds were screened against HM1: IMSS strain of Entamoeba histolytica and cytotoxicity was performed on A549 (non-small cell lung cancer cell line) cells by MTT assay. Out of eighteen compounds twelve showed better activity then the standard drug metronidazole. The compound 9, 14 and 19 showed good cell viability, hence were least toxic. PMID- 26021708 TI - Design and synthesis of pH-sensitive polyamino-ester magneto-dendrimers: Surface functional groups effect on viability of human prostate carcinoma cell lines DU145. AB - Novel pH-sensitive, biocompatible and biodegradable magneto-dendrimers with OH and/or NH2 functional groups based on poly amino-ester were synthesized for delivery of anti-cancer drugs. Magnetite nanoparticles (MNPs) were synthesized by the co-precipitation method and their surfaces were modified by 3-aminopropyl triethoxysilane. The first and second generations of the magneto-dendrimer with hydroxyl end groups were produced by sequential acrylation and Michael addition reactions using the required amounts of acryloyl chloride and diethanolamine, respectively. The dendrimer containing amino functional surface groups up to second generation was synthesized by the same method using the necessary amounts of acryloyl chloride and ethylenediamine. These dendrimers were fully characterized by the Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), dynamic light scattering (DLS) and zeta potential analysis, vibrating-sample magnetometer (VSM), scanning electron microscope (SEM), transmission electron microscopy (TEM) and selected area electron diffraction (SAED). In-vitro release profiles of the drug-loaded magnetic nanoparticles and their cytotoxicity assay were investigated at two pHs (7.4 and 5.8). The hydrolytic degradation behavior of magneto-dendrimers was evaluated in PBS buffer. Our research suggests that magneto-dendrimers having amine or hydroxyl functional groups could be considered as the suitable nanocarriers for therapy applications. PMID- 26021709 TI - Four tobacco companies plan action against UK government over standard packaging. PMID- 26021710 TI - Beyond single modification: Reanalysis of the acetylproteome of human sperm reveals widespread multiple modifications. AB - Sperm is an ideal model for studying post-translational modifications since its transcriptional and translational activities are nearly silent. Thus, sperm functions are mainly regulated at the protein level, especially by means of post translational modifications. Published proteomic datasets may contain valuable undiscovered information. In this study, we reanalyzed the raw data from previous acetylproteome study on human capacitated sperm to include two additional modifications: phosphorylation and ubiquitination. We successfully identified approximately 500 proteins with multiple types of modifications. Compared with recently developed serial enrichment strategy for multiple modifications, reanalysis of single modification enriched data provides a direct and efficient alternative approach. These results greatly expand our knowledge of protein modifications in human sperm. PMID- 26021711 TI - Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy. AB - The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LCs) produce the pro angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reactions for caspase-3, 17beta-HSD6, CD163 (ED2 macrophage), PK-1 and androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17beta-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1-immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LCs damage. PMID- 26021712 TI - Prenatal factors associated with autism spectrum disorder (ASD). AB - Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known associated prenatal factors affecting the fetus throughout pregnancy; whenever relevant, also summarize some animal data. Among the maternal diseases in pregnancy associated with ASD are pregestational and/or gestational diabetes mellitus (PGDM, GDM), maternal infections (i.e. rubella, cytomegalovirus (CMV)), prolonged fever and maternal inflammation, which cause changes in a variety of inflammatory cytokines. Among the drugs are valproic acid, thalidomide, and possibly misoprostol and serotonin reuptake inhibitors (SSRIs). Associations were described with ethanol, and possibly cocaine, heavy metals heavy smoking and Folic acid deficiency. Heavy exposure to pesticides and air pollution during pregnancy was recently associated with ASD. We need more epidemiologic data to establish many of these associations; if proven, they might be promising avenues for prevention. PMID- 26021714 TI - The use of -omic tools in the study of disease processes in marine bivalve mollusks. AB - Our understanding of disease processes and host-pathogen interactions in model species has benefited greatly from the application of medium and high-throughput genomic, metagenomic, epigenomic, transcriptomic, and proteomic analyses. The rate at which new, low-cost, high-throughput -omic technologies are being developed has also led to an expansion in the number of studies aimed at gaining a better understanding of disease processes in bivalves. This review provides a catalogue of the genetic and -omic tools available for bivalve species and examples of how -omics has contributed to the advancement of marine bivalve disease research, with a special focus in the areas of immunity, bivalve-pathogen interactions, mechanisms of disease resistance and pathogen virulence, and disease diagnosis. The analysis of bivalve genomes and transcriptomes has revealed that many immune and stress-related gene families are expanded in the bivalve taxa examined thus far. In addition, the analysis of proteomes confirms that responses to infection are influenced by epigenetic, post-transcriptional, and post-translational modifications. The few studies performed in bivalves show that epigenetic modifications are non-random, suggesting a role for epigenetics in regulating the interactions between bivalves and their environments. Despite the progress -omic tools have enabled in the field of marine bivalve disease processes, there is much more work to be done. To date, only three bivalve genomes have been sequenced completely, with assembly status at different levels of completion. Transcriptome datasets are relatively easy and inexpensive to generate, but their interpretation will benefit greatly from high quality genome assemblies and improved data analysis pipelines. Finally, metagenomic, epigenomic, proteomic, and metabolomic studies focused on bivalve disease processes are currently limited but their expansion should be facilitated as more transcriptome datasets and complete genome sequences become available for marine bivalve species. PMID- 26021713 TI - Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study. AB - INTRODUCTION: Stem cell therapy with bone marrow-derived mononuclear cells (BMMCs) is an option for improving joint function in osteonecrosis of the femoral head (ONFH). Bone marrow-derived mesenchymal stromal cell (MSC) numbers and their osteogenic differentiation are decreased in patients with ONFH. However, whether this decrease also extends to the early stages of ONFH in sickle cell disease (SCD) is still unclear. METHODS: We conducted a phase I/II, non-controlled study to determine efficacy and safety of BMMC implantation using a minimally invasive technique in SCD patients with ONFH. Eighty-nine patients were recruited and followed up for 60 months after surgery. Clinical and radiographic findings were assessed, and data were completed by in vitro analysis. RESULTS: At the final follow-up (60 months) there was a significant improvement in clinical joint symptoms and pain relief as measured by the Harris Hip Score (P = 0.0005). In addition, after the BMMC implantation procedure, radiographic assessment showed disease stabilization and only 3.7 % of the treated patients did not achieve a satisfactory clinical result. The amount of fibroblast colony-forming units was 28.2 +/- 13.9 per 1 million BMMCs after concentration. Flow cytometry analysis showed a significantly higher number of hematopoietic stem/endothelial progenitor cell markers in concentrated BMMCs when compared with bone marrow aspirate, indicating an enrichment of these cell types. Isolated MSCs from SCD patients with pre-collapse ONFH maintained the replicative capacity without significant loss of their specific biomolecular characteristics, multi-differentiation potential, and osteogenic differentiation activities. Cytokines and growth factors (interleukin-8, transforming growth factor-beta, stromal cell-derived factor-1alpha and vascular endothelial growth factor) that mediate endogenous bone regeneration were also produced by expanded MSCs from SCD patients. CONCLUSION: The autologous BMMC implantation with a minimally invasive technique resulted in significant pain relief and halted the progression of early stages of ONFH in SCD patients. MSCs from SCD patients display biological properties that may add to the efficiency of surgical treatment in ONFH. In summary, our results indicate that infusion of BMMCs enriched with stem/progenitor cells is a safe and effective treatment for the early stages of ONFH in SCD patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02448121; registered 15 May 2015. PMID- 26021715 TI - Role of 5-aminolevulinic acid-conjugated gold nanoparticles for photodynamic therapy of cancer. AB - There are three possible mechanisms for 5-aminolevulinic acid (5-ALA) conjugated gold nanoparticles (GNPs) through electrostatic bonding for photodynamic therapy (PDT) of cancer: GNPs delivery function,singlet oxygen generation (SOG) by GNPs irradiated by light, and surface resonance enhancement (SRE) of SOG. Figuring out the exact mechanism is important for further clinical treatment. 5-ALA-GNPs and human chronic myeloid leukemia K562 cells were used to study delivery function and SOG by GNPs. The SRE of SOG enabled by GNPs was explored by protoporphyrin IX (PpIX)-GNPs conjugate through electrostatic bonding.Cell experiments show that the GNPs can improve the efficiency of PDT, which is due to the vehicle effect of GNPs. PpIX-GNPs conjugate experiments demonstrated that SOG can be improved about 2.5 times over PpIX alone. The experiments and theoretical results show that the local field enhancement (LFE) via localized surface plasmon resonance (LSPR) of GNPs is the major role; the LFE was dependent on the irradiation wavelength and the GNP's size. The LFE increased with an increase of the GNP size (2R <= 50 nm). However, the LSPR function of the GNPs was not found in cell experiments. Our study shows that in 5-ALA-conjugated GNPs PDT, the delivery function of GNPs is the major role. PMID- 26021716 TI - Dynamic measurement of the corneal tear film with a Twyman-Green interferometer. AB - An interferometer for measuring dynamic properties of the in vivo tear film on the human cornea has been developed. The system is a near-infrared instantaneous phase-shifting Twyman-Green interferometer. The laser source is a 785 nm solid state laser, and the system has been carefully designed and calibrated to ensure that the system operates at eye-safe levels. Measurements are made over a 6 mm diameter on the cornea.Successive frames of interferometric height measurements are combined to produce movies showing both the quantitative and qualitative changes in the topography of the tear film surface and structure. To date, measurement periods of up to 120 s at 28.6 frames per second have been obtained. Several human subjects have been examined using this system, demonstrating a surface height resolution of 25 nm and spatial resolution of 6 MUm. Examples of features that have been observed in these preliminary studies of the tear film include postblink disruption, evolution, and stabilization of the tear film; tear film artifacts generated by blinking; tear film evaporation and breakup; and the propagation of foreign objects in the tear film. This paper discusses the interferometer design and presents results from in vivo measurements. PMID- 26021717 TI - Ex vivo characterization of normal and adenocarcinoma colon samples by Mueller matrix polarimetry. AB - Mueller matrix polarimetry along with polar decomposition algorithm was employed for the characterization of ex vivo normal and adenocarcinoma human colon tissues by polarized light in the visible spectral range (425-725 nm). Six derived polarization metrics [total diattenuation (DT ), retardance (RT ), depolarization(DeltaT ), linear diattenuation (DL), retardance (delta), and depolarization (DeltaL)] were compared for normal and adenocarcinoma colon tissue samples. The results show that all six polarimetric properties for adenocarcinoma samples were significantly higher as compared to the normal samples for all wavelengths. The Wilcoxon rank sum test illustrated that total retardance is a good candidate for the discrimination of normal and adenocarcinoma colon samples. Support vector machine classification for normal and adenocarcinoma based on the four polarization properties spectra (DeltaT , DeltaL, RT ,and delta) yielded 100% accuracy, sensitivity, and specificity, while both DTa nd DL showed 66.6%, 33.3%, and 83.3% accuracy, sensitivity, and specificity, respectively. The combination of polarization analysis and given classification methods provides a framework to distinguish the normal and cancerous tissues. PMID- 26021718 TI - Label-free imaging and quantitative chemical analysis of Alzheimer's disease brain samples with multimodal multiphoton nonlinear optical microspectroscopy. AB - We developed multimodal multiphoton microspectroscopy using a small-diameter probe with gradient-index lenses and applied it to unstained Alzheimer's disease (AD) brain samples. Our system maintained the image quality and spatial resolution of images obtained using an objective lens of similar numerical aperture. Multicolor images of AD brain samples were obtained simultaneously by integrating two-photon excited fluorescence and second-harmonic generation on a coherent anti-Stokes Raman scattering (CARS) microendoscope platform. Measurements of two hippocampal regions, the cornus ammonis-1 and dentate gyrus, revealed more lipids, amyloid fibers, and collagen in the AD samples than in the normal samples. Normal and AD brains were clearly distinguished by a large spectral difference and quantitative analysis of the CH mode using CARS microendoscope spectroscopy. We expect this system to be an important diagnosis tool in AD research PMID- 26021719 TI - Pulse transit time differential measurement by fiber Bragg grating pulse recorder. AB - The present study reports a noninvasive technique for the measurement of the pulse transit time differential (PTTD) from the pulse pressure waveforms obtained at the carotid artery and radial artery using fiber Bragg grating pulse recorders (FBGPR). PTTD is defined as the time difference between the arrivals of a pulse pressure waveform at the carotid and radial arterial sites. The PTTD is investigated as an indicator of variation in the systolic blood pressure. The results are validated against blood pressure variation obtained from a Mindray Patient Monitor. Furthermore, the pulse wave velocity computed from the obtained PTTD is compared with the pulse wave velocity obtained from the color Doppler ultrasound system and is found to be in good agreement. The major advantage of the PTTD measurement via FBGPRs is that the data acquisition system employed can simultaneously acquire pulse pressure waveforms from both FBGPRs placed at carotid and radial arterial sites with a single time scale, which eliminates time synchronization complexity. PMID- 26021720 TI - Ammonia and ethylene biomarkers in the respiration of the people with schizophrenia using photoacoustic spectroscopy. AB - Oxidative stress has become an exciting area of schizophrenia (SCZ) research, and provides ample opportunities and hope for a better understanding of its pathophysiology, which may lead to new treatment strategies. The first objective of the present study was to analyze the oxidative stress markers in breath samples of patients with SCZ before and after the treatment with Levomepromazine. The second objective was to analyze the deficiency of amino acids marker in breath samples of patients with SCZ before and after the treatment. Exhaled breath was collected from 15 SCZ patients and 19 healthy controls; subsequently, CO2 laser photoacoustic spectroscopy was used to assess the exhaled breath compounds of the study subjects. One of the main breath biomarkers of the oxidative stress is ethylene, while one of the main breath biomarkers of the amino acids deficiency is ammonia. The breath biomarkers in the exhalation of SCZ patients exhibited significant differences from the breath biomarkers in the exhalation of healthy controls. Analysis of breath ethylene and breath ammonia provides a related model of SCZ exhalation that could represent an effective and convenient screening method for this intellectual disability. PMID- 26021721 TI - Strikingly rapid neural basis of motion-induced position shifts revealed by high temporal-resolution EEG pattern classification. AB - Several visual illusions demonstrate that the neural processing of visual position can be affected by visual motion. Well-known examples are the flash-lag, flash-drag, and flash-jump effect. However, where and when in the visual processing hierarchy such interactions take place is unclear. Here, we used a variant of the flash-grab illusion (Vision Research 91 (2013), pp. 8-20) to shift the perceived positions of flashed stimuli, and applied multivariate pattern classification to individual 64-channel EEG trials to dissociate neural signals corresponding to veridical versus perceived position with high temporal resolution. We show illusory effects of motion on perceived position in three separate analyses: (1) A classifier can distinguish different perceived positions of a flashed object, even when the veridical positions are identical. (2) When the perceived positions of two objects presented in different locations become more similar, the classifier performs less well than when they become more different, even if the veridical positions remain unchanged. (3) Finally, a classifier can discriminate the perceived position of an object even when trained on objects presented in physically different positions. These effects are evident as early as 81ms post-stimulus, concurrent with the very first EEG signals indicating that any stimulus is present at all. This finding shows that the illusion must begin at an early level, probably as part of a predominantly feed forward mechanism, leaving the influence of any recurrent processes to later stages in the development of the effect. PMID- 26021722 TI - Low-dose capecitabine adjuvant chemotherapy in elderly stage II/III colorectal cancer patients (LC-ACEC): study protocol for a randomized controlled trial. AB - BACKGROUND: Over half of the patients were diagnosed with colorectal cancer after 70 years of age. The choice of the most suitable chemotherapy strategy is the major challenge for elderly patients. Previous trials indicated that elderly patients with stage II/III colorectal cancer obtained no significant benefits from oxaliplatin-based adjuvant chemotherapy. Therefore, single-agent oral capecitabine is regarded as an effective alternative with retained efficacy and improved flexibility. However, the optimal dose of capecitabine for elderly patients remains controversial. Recent studies have adopted a low-dose strategy (1,000 mg/m(2)) for elderly patients, but the long-term efficacy of this strategy has not been identified so far. Thus, we designed this trial to investigate non inferiority of the lower-dose strategy of capecitabine compared with the approved dose strategy for adjuvant chemotherapy of elderly patients with stage II/III colorectal cancer. METHODS: LC-ACEC (Low-dose Capecitabine Adjuvant Chemotherapy for Elderly Patients With Stage II/III Colorectal Cancer) is a prospective, randomized, open-label, non-inferiority phase III clinical trial including 926 eligible patients. Patients will be randomly assigned to receive a capecitabine adjuvant chemotherapy strategy of lower dose (1,000 mg/m(2) twice daily on days 1 to 14 of every 21 days) or approved dose (1,250 mg/m(2) twice daily on days 1 to 14 of every 21 days). The primary outcome is 3-year disease-free survival. Secondary outcomes include 3-year overall survival, toxic and side effects during treatment, completion rate, and quality of life. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a low-dose strategy of capecitabine in adjuvant chemotherapy of elderly patients with stage II/III colorectal cancer, and the results are believed to provide new evidence on the treatment of elderly patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02316535 (Dec. 12, 2014). PMID- 26021723 TI - Objectives, design and enrollment results from the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure Study (INSPIRE). AB - BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) during infancy has been consistently associated with an increased risk of childhood asthma. In addition, evidence supports that this relationship is causal. However, the mechanisms through which RSV contributes to asthma development are not understood. The INSPIRE (Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure) study objectives are to: 1) characterize the host phenotypic response to RSV infection in infancy and the risk of recurrent wheeze and asthma, 2) identify the immune response and lung injury patterns of RSV infection that are associated with the development of early childhood wheezing illness and asthma, and 3) determine the contribution of specific RSV strains to early childhood wheezing and asthma development. This article describes the INSPIRE study, including study aims, design, recruitment results, and enrolled population characteristics. METHODS/DESIGN: The cohort is a population based longitudinal birth cohort of term healthy infants enrolled during the first months of life over a two year period. Respiratory infection surveillance was conducted from November to March of the first year of life, through surveys administered every two weeks. In-person illness visits were conducted if infants met pre-specified criteria for a respiratory illness visit. Infants will be followed annually to ages 3-4 years for assessment of the primary endpoint: wheezing illness. Nasal, urine, stool and blood samples were collected at various time points throughout the study for measurements of host and viral factors that predict wheezing illness. Nested case-control studies will additionally be used to address other primary and secondary hypotheses. DISCUSSION: In the INSPIRE study, 1952 infants (48% female) were enrolled during the two enrollment years and follow-up will continue through 2016. The mean age of enrollment was 60 days. During winter viral season, more than 14,000 surveillance surveys were carried out resulting in 2,103 respiratory illness visits on 1189 infants. First year follow-up has been completed on over 95% percent of participants from the first year of enrollment. With ongoing follow-up for wheezing and childhood asthma outcomes, the INSPIRE study will advance our understanding of the complex causal relationship between RSV infection and early childhood wheezing and asthma. PMID- 26021724 TI - Children with positive attitudes towards mind-wandering provide invalid subjective reports of mind-wandering during an experimental task. AB - This study investigated mind-wandering (MW) in children during a laboratory task, and explored the influence of children's attitudes towards MW on the accuracy of their subjective reports. Children's MW experiences were probed during the adapted Sustained-Attention-to-Response-Task (SART), and their attitudes was measured by a questionnaire, according to which children were divided into positive or negative group. Results showed that (1) MW in children was basically identical to MW in adults which was associated with poor performance, increased behavioural variability, and a prospective bias; (2) reliable correlations between behavioural correlates and MW frequency were observed in negative group, but not in positive group; and (3) positive group reported more MW than negative group, while no behavioural correlate was significantly different between the two groups. We concluded that (1) overall, children could accurately introspect their MW experiences during SART; and (2) children with positive attitudes provided invalid subjective reports of MW. PMID- 26021725 TI - Rotavirus VP6 preparations as a non-replicating vaccine candidates. AB - Rotavirus (RV) structural proteins VP4 and VP7, located on the surface of viral particles, elicit neutralizing antibodies (Abs) and are therefore considered to be important components of RV vaccines. However, despite inducing neutralizing Abs, limits of cross-neutralizing activity and lack of full correlation with protection limit the usefulness of these proteins as protective agents against RV disease. VP6 protein, which forms the middle layer of RV particles, is discussed as an alternative vaccine candidate since it can induce cross-protective immune responses against different RV strains although the Ab raised is not neutralizing. This report reviews different functions of VP6 that can lead to considering it as an alternative vaccine against RV disease. PMID- 26021726 TI - Effect of obstructive sleep apnea diagnosis on health related quality of life. AB - BACKGROUND: Perceived Health Related Quality of Life (HRQoL) is impaired in obstructive sleep apnea (OSA). To our knowledge, no study has analyzed the effect of OSA diagnosis communication on HRQoL. We evaluated self-perceived HRQoL in patients afferent to our sleep center, in order to examine the effect of the diagnosis disclosure on their HRQoL. METHODS: Two hundred ninety-seven consecutive outpatients (227 M) (mean age 54.1 +/- 11.6 yrs, range 23-80 yrs) were evaluated, before first clinical visit and nocturnal diagnostic examination (Time A), and after diagnosis disclosure (Time B), with two self-reported questionnaires for HRQoL assessment: Psychological General Well-Being Index (PGWBI), consisting of anxiety, depressed mood, positive well-being, self control, general health, vitality subscales, and 12-Item Short-Form Health Survey (SF-12), comprising Physical (PCS) and Mental Component Summaries (MCS). RESULTS: Comparison of mean HRQoL scores at Time A with reference values, showed worse scores. Mean PGWBI Total and subscales scores improved at Time B. Similar improvement was observed for SF-12 MCS (p = 0.0148), but nor for SF-12 PCS. At Time B, Anxiety, Depression and Well-being PGWBI subscales became similar to reference values, while the scores in the other PGWBI subscales and SF-12 remained worse. Comparison between males and females showed higher HRQoL values for males at both times. Score changes were independent from age, gender, BMI, AHI, TSat90 and excessive daytime sleepiness. CONCLUSIONS: Diagnosis communication improves patients' HRQoL, regardless of the severity. Changes in HRQoL after diagnosis disclosure may be due to patients' motivation for medical check and diagnostic expectations. PMID- 26021727 TI - Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders. AB - Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits. PMID- 26021729 TI - Autophagy and Apoptosis in the Response of Human Vascular Endothelial Cells to Oxidized Low-Density Lipoprotein. AB - OBJECTIVES: Oxidized low-density lipoprotein (ox-LDL) may induce autophagy, apoptosis, necrosis or proliferation of cultured endothelial cells depending on the concentration and exposure time. Our previous studies found that ox-LDL exposure for 6 h increases the autophagic level of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. The present study investigates the relationship between autophagy and apoptosis in HUVECs exposed to ox-LDL. METHODS: Flow cytometry and Western blot were used to study the apoptotic and autophagic phenomena. The contribution of autophagic and apoptotic mechanisms to ox-LDL-induced upregulation of MAP1-LC3, beclin1 and p53 protein levels were assessed by pretreatment with the autophagic inhibitors 3-MA and Atg5 small interfering (si)RNA, as well as z-vad-fmk, an apoptosis inhibitor. RESULTS: ox-LDL induced the apoptosis of HUVECs in a concentration-dependent way. The increased expression of the autophagic proteins, LC3-II and beclin1, can be reversed by 3-MA and z-vad-fmk pretreatment. 3-MA and Atg5 siRNA increased the ox LDL-induced increases of the p53 protein level and the annexin V-positive staining, which was decreased by z-vad-fmk. CONCLUSION: These results suggest that overstimulation of ox-LDL can induce autophagy and apoptosis in HUVECs. Inhibition of apoptosis leads to an inhibition of autophagy induced by ox-LDL. However, inhibition of autophagy leads to an increase in the ox-LDL-induced apoptosis. PMID- 26021728 TI - Regulation of the pstSCAB operon in Corynebacterium glutamicum by the regulator of acetate metabolism RamB. AB - BACKGROUND: The pstSCAB operon of Corynebacterium glutamicum, which encodes an ABC transport system for uptake of phosphate (Pi), is induced during the Pi starvation response. The two-component regulatory system PhoRS is involved in this response, but partial Pi starvation induction of pstSCAB in a DeltaphoRS mutant indicated the involvement of additional regulator(s). Regulation of pstSCAB also involves the global transcriptional regulator GlxR. RESULTS: DNA affinity chromatography identified the regulator of acetate metabolism RamB as a protein binding to pstS promoter DNA in vitro. Gel mobility shift assays and mutational analysis of the pstS promoter region revealed that RamB binds to two sites localized at positions -74 to -88 and -9 to +2 with respect to the transcriptional start site of pstSCAB. Reporter gene studies supported the in vivo relevance of both binding sites for activation of pstSCAB by RamB. DNA microarray analysis revealed that expression of many Pi starvation genes reached higher levels during the Pi starvation response on minimal medium with glucose as sole carbon source than in Pi starved acetate-grown C. glutamicum cells. CONCLUSIONS: In C. glutamicum, RamB is involved in expression control of pstSCAB operon. Thus, transcriptional regulation of pstSCAB is complex involving activation by the phosphate-responsive two-component regulatory system PhoSR and the regulators of carbon metabolism GlxR and RamB. PMID- 26021730 TI - Clinical features and impact of myasthenia gravis disease in Australian patients. AB - We performed a community-based survey of 165 Australian patients with a physician confirmed diagnosis of myasthenia gravis (MG). MG is an autoimmune disease of the neuromuscular junction causing fatiguable muscle weakness. Patients with early onset MG (<40 years of age) were more frequently female (22 males, 60 females) whereas patients with late onset MG (>40 years of age) were more frequently male (50 males, 28 females; p < 0.001). Triggering and exacerbating factors included physical and emotional stress, infections, surgery or trauma, seasonal changes and medications. The co-occurrence of other immune-related diseases was reported by 54% of patients. The median MG quality of life (QOL) score was 92 (range: 24 186). The factor most strongly associated with poor QOL was depression. Only 40.6% of patients were working at the time of the survey and of these, almost half had required sick leave due to MG in the past 12 months. A further 39.4% had stopped work due to MG and 19.4% having to change occupation. Full-time or part time care was required by 29% of patients and government financial support was received by 52.7%. PMID- 26021731 TI - Lumboatrial shunt in a patient with Crouzon syndrome complicated by pseudotumor cerebri. AB - A 25-year-old man with Crouzon syndrome complicated by pseudotumor cerebri and multiple shunt failures presented with progressive back and neck pain, intermittent headaches, and associated vomiting secondary to shunt infection. Due to his previous history of repeated failure of both ventriculoperitoneal and lumboperitoneal (LP) shunting procedures, the decision was made to place a lumboatrial (LA) shunt via an approach through the internal jugular vein. The procedure was uncomplicated and the man's symptoms were relieved. Despite significant improvement, the LA shunt limited his exercise tolerance, and as an avid runner and weight lifter, he requested reconversion back to an LP shunt. At a follow-up of 20months, he continued to do well both clinically and radiographically. This case report summarizes the successful placement and use of an LA shunt for the treatment of intracranial hypertension in the setting of Crouzon syndrome. PMID- 26021732 TI - Interaction model of steviol glycosides from Stevia rebaudiana (Bertoni) with sweet taste receptors: A computational approach. AB - Docking studies were performed on natural sweeteners from Stevia rebaudiana by constructing homology models of T1R2 and T1R3 subunits of human sweet taste receptors. Ramachandran plot, PROCHECK results and ERRAT overall quality factor were used to validate the quality of models. Furthermore, docking results of steviol glycosides (SG's) were correlated significantly with data available in the literature which enabled to predict the exact sweetness rank order of SG's. The binding pattern indicated that Asn 44, Ans 52, Ala 345, Pro 343, Ile 352, Gly 346, Gly 47, Ala 354, Ser 336, Thr 326 and Ser 329 are the main interacting amino acid residues in case of T1R2 and Arg 56, Glu 105, Asp 215, Asp 216, Glu 148, Asp 258, Lys 255, Ser 104, Glu 217, Leu 51, Arg 52 for T1R3, respectively. Amino acids interact with SG's mainly by forming hydrogen bonds with the hydroxyl group of glucose moieties. Significant variation in docked poses of all the SG's were found. In this study, we have proposed the mechanism of the sweetness of the SG's in the form of multiple point stimulation model by considering the diverse binding patterns of various SG's, as well as their structural features. It will give further insight in understanding the differences in the quality of taste and will be used to improve the taste of SG's using semi-synthetic approaches. PMID- 26021733 TI - Changes in lipid substances in rice during grain development. AB - Lipid substances, such as fatty acids, gamma-oryzanol, policosanols, and tocol (tocopherol+tocotrienol), were investigated in two rice cultivars, Ilpum and Dasan, during rice development. In both cultivars, the lipid extract level decreased steadily after it reached its maximum level. Additionally, there were differences in the fatty acid composition, depending on the rice developmental stage, between the two cultivars. The gamma-oryzanol level increased during rice development, and there were differences in the composition of gamma-oryzanol between the two cultivars. The levels of policosanols drastically decreased during the early stage of rice development in the two cultivars. The total tocol level showed a downward trend during rice development. The predominant tocol isomer in Ilpum was alpha-tocopherol during rice development. In Dasan, the predominant tocol isomer was alpha-tocopherol at the early stage, but gamma tocotrienol at the later stage. This study provided information on the levels and composition of lipid substances, such as fatty acids, gamma-oryzanol, policosanols, and tocol during rice development. PMID- 26021734 TI - Diterpenoid alkaloids from Aconitum vilmorinianum. AB - Diterpenoid alkaloids, named vilmorines A-D, in addition to fifteen known alkaloids, were isolated from roots of Aconitum vilmorinianum. Their structures were established on the basis of extensive spectroscopic analyses. Antibacterial and antioxidant studies on isolated compounds were also carried out. PMID- 26021735 TI - Assessment of the degree of asymmetry of pathological features in neurodegenerative diseases. What is the significance for brain banks? AB - Brain banks allow researchers access to tissue from well-characterised neurodegenerative disease cases. Fixed tissue employed for diagnosis is often not appropriate for research and frozen tissue is therefore made available. Many brain banks use a protocol where half the brain is fixed and half frozen. Recently a study has shown that there can be asymmetry in protein deposition between the hemispheres especially with tau and TDP-43. We aimed to test this hypothesis by prospectively taking bilateral cortical blocks from 30 brains on arrival, and immunostaining to assess the degree of asymmetry. In 6 out 14 cases of AD (Alzheimer's Disease) (Modified Braak Stage V-VI), there was some asymmetrical staining for tau. In 2 cases, there was moderate discrepancy for tau staining between left and right calcarine cortices. However, careful analysis in both these cases revealed discrepancies in tau staining in adjacent regions even on the same side. The alpha-synuclein staining showed asymmetry in one case only, the Abeta showed only mild asymmetry in 3 cases of AD. The TDP-43 pathology appeared symmetrical in the 2 cases of frontotemporal lobar degeneration with motor neurone disease, but there was asymmetry noted when seen in conjunction with AD. In conclusion, there is the potential for asymmetrical pathology in neurodegenerative diseases and caution should be maintained when freezing half and fixing half of the brain in neurodegenerative diseases. Nevertheless, marked variability in staining can also be identified in adjacent cortical areas so there is no guarantee that an alternative strategy would be superior. PMID- 26021736 TI - Thoughtful Methods to Increase Evidence Levels and Analyze Nonparametric Data. PMID- 26021737 TI - Fatigue Is Associated with Increased Risk of Mortality in Patients on Chronic Hemodialysis. AB - BACKGROUND: Little is known about the correlation between fatigue and survival in patients on chronic hemodialysis and whether fatigue is an independent predictor of outcome above and beyond the effects of depression. The aim of the present study was to determine if fatigue is a predictor of mortality in patients on chronic hemodialysis (CHP) and if this occurs independently of the symptoms of depression. METHODS: CHP referring to the Hemodialysis Service of the Universita Cattolica of Rome, Italy between November 2007 and January 2015 were studied. Demographic, clinical, and laboratory data were recorded for each patient at the moment of the inclusion in the study. Fatigue levels were assessed in patients using the Vitality Scale of SF-36 (SF-36 VS), functional ability by the activities of daily living (ADL) and instrumental activities of daily living (IADL), depressive symptoms through the Geriatric Depression Scale (GDS), cognitive function using the Mini Mental State Examination (MMSE), and comorbidity through the Charlson Comorbidity Index (CCI). Patients were grouped into four groups (quartiles): Quartile 1 (Q1), >65; Q2, >=50 to <65; Q3, >=35 to <50; Q4, <35. RESULTS: We studied 126 patients: 11 were transplanted and 53 died. Patients who later died were older and had a worse cognitive performance, higher CCI and GDS scores, lower ADL, IADL and SF-36 VS scores, lower serum creatinine and albumin levels. Kaplan-Meier survival was significantly lower in Q4 than in Q1 (p = 0.0001). According to Cox regression analysis, higher fatigue (Q4) was associated with a higher risk of mortality (HR, 95% CI: 5.29, 2.2-12.73). CONCLUSION: Fatigue is associated with an increased risk of mortality in CHP, with the relationship independent of symptoms of depression. Fatigue should be assessed routinely and may be a potential target of interventions that aim to reduce mortality in CHP. PMID- 26021738 TI - Putting meaning into medicine: why context matters in psychiatry. AB - Mainstream psychiatry emphasises controlling symptoms by taking medications. This approach ignores the role of context in shaping illness experiences and how people engage with mental health professionals. The focus on symptom control and medication management also narrows the function of the psychiatrist. This editorial argues that knowledge of patients' lives is important for providing empathic care that is oriented to the outcomes that matter to patients. In addition, care that attends to the person-in-context motivates and sustains mental health providers by putting meaning back into medicine. Truly patient centred care demands pushing back against the reductionism of contemporary psychiatry to thoughtfully engage with the complexities of patients' lives. PMID- 26021739 TI - Patients' reasons for accepting a free community pharmacy asthma service. AB - BACKGROUND: Challenges in recruiting patients at the pharmacy counter for cognitive services have been observed, hampering development in this area. To overcome this barrier, insight into the patient perspective is crucial to understanding their lack of appreciation of the services. However, very few studies have been conducted so far to explore why patients accept or decline offers of cognitive services at the pharmacy counter. OBJECTIVE: To explore patients' reasons for accepting a particular cognitive service (the Inhaler Technique Assessment Service) a service intended to detect inhalation technique errors. The service is reimbursed by the Danish state and takes approximately 10 min. Setting Ten community pharmacies located in different regions of Denmark, including the center and suburbs of Copenhagen. METHOD: Two types of interviews were conducted: long and short semi-structured interviews with 24 patients suffering mainly from asthma and COPD. Researchers from Copenhagen University conducted 11 long interviews and pharmacy internship students from Copenhagen University carried out 13 short interviews. The interviews were analyzed using descriptive analysis. MAIN OUTCOME MEASURE: Patients' perceived needs of an inhalation counseling service as well as their motivation for accepting the service, including their accounts of how the service was orally offered by staff. RESULTS: The majority of participants were used to using inhaler devices. The participants felt, for several reasons, little need of an inhaler service and seldom noticed the precise way the service was offered. Patients did not seem to accept the service expecting personal benefits. First timers appeared to accept the service to learn how to use the device correctly, whereas experienced users appeared to accept the ITAS to be helpful to staff or to learn more about health issues in general or were convinced by individual employees who showed a special interest in the participant receiving the service. Privacy problems were felt by several participants. CONCLUSION: The patients felt little need for the inhaler counseling service. Patients however accepted the service for various reasons of which the feeling how staff showing an interest in helping them seemed especially convincing. PMID- 26021740 TI - Cutaneous microcirculation in preterm neonates: comparison between sidestream dark field (SDF) and incident dark field (IDF) imaging. AB - Incident dark field imaging (IDF) is a new generation handheld microscope for bedside visualization and quantification of microcirculatory alterations. IDF is the technical successor of sidestream dark field imaging (SDF), currently the most used device for microcirculatory measurements. In (pre)term neonates the reduced thickness of the skin allows non-invasive transcutaneous measurements. The goal of this study was to compare the existing device (SDF) and its technical successor (IDF) in preterm neonates. We hypothesized that IDF imaging produces higher quality images resulting in a higher vessel density. After written informed consent was given by the parents, skin microcirculation was consecutively measured on the inner upper arm with de SDF and IDF device. Images were exported and analyzed offline using existing software (AVA 3.0). Vessel density and perfusion were calculated using the total vessel density (TVD) proportion of perfused vessels (PPV) and perfused vessel density. The microcirculation images quality score was used to evaluate the quality of the video images. In a heterogeneous group of twenty preterm neonates (median GA 27.6 weeks, range 24-33.4) IDF imaging visualized 19.9% more vessels resulting in a significantly higher vessel density (TVD 16.9 vs. 14.1/mm, p value < 0.001). The perfusion of vessels could be determined more accurately in the IDF images, resulting in a significant lower PPV (88.7 vs. 93.9%, p value 0.002). The IDF video images scored optimal in a higher percentage compared to the SDF video images. IDF imaging of the cutaneous microcirculation in preterm neonates resulted in a higher vessel density and lower perfusion compared to the existing SDF device. PMID- 26021742 TI - Peptoid nanosheets as soluble, two-dimensional templates for calcium carbonate mineralization. AB - Nacre-mimetic materials are of great interest, but difficult to synthesize, because they require the ordering of organic and inorganic materials on several length scales. Here we introduce peptoid nanosheets as a versatile two dimensional platform to develop nacre mimetic materials. Free-floating zwitterionic nanosheets were mineralized with thin films of amorphous calcium carbonate (of 2-20 nm thickness) on their surface to produce planar nacre synthons. These can serve as tunable building blocks to produce layered brick and mortar nanoarchitectures. PMID- 26021741 TI - Pharmacodynamic study of axitinib in patients with advanced malignancies assessed with (18)F-3'deoxy-3'fluoro-L-thymidine positron emission tomography/computed tomography. AB - PURPOSE: Rapid disease progression associated with increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy. We characterize the dynamics of withdrawal flare for axitinib. METHODS: Thirty patients with metastatic solid malignancies received axitinib for 2 weeks, followed by a 1-week drug holiday. Twenty patients suitable for PET imaging received scans with (18)F 3'deoxy-3'fluoro-L-thymidine (FLT), a marker of proliferation. Plasma VEGF and axitinib pharmacokinetic levels were also assessed at specified time points. RESULTS: During axitinib withdrawal, significant increases in both SUVmax (+22 %; p = 0.006) and SUVmean (+20 %; p = 0.001) were observed. Significant increases relative to peak axitinib concentration were observed at day 2 withdrawal for SUVmax and SUVmean, with no further significant increase from day 2 to day 7 of withdrawal. No significant change in SUVmax or SUVmean was observed during the treatment period, relative to baseline. VEGF concentration significantly increased when on drug (p < 0.001) and decreased back to a level indistinguishable from baseline by day 7 of drug washout (p = 0.448). No correlation between change in VEGF and change in imaging metrics was observed. CONCLUSIONS: A significant increase in tumor proliferation was observed during withdrawal of axitinib therapy, and this flare occurred within 2 days of axitinib withdrawal. An exploratory analysis indicated that this flare may be associated with poor clinical outcome. PMID- 26021744 TI - Enhanced DNA binding affinity of RecA protein from Deinococcus radiodurans. AB - Deinococcus radiodurans (Dr) has a significantly more robust DNA repair response than Escherichia coli (Ec), which helps it survive extremely high doses of ionizing radiation and prolonged periods of desiccation. DrRecA protein plays an essential part in this DNA repair capability. In this study we directly compare the binding of DrRecA and EcRecA to the same set of short, defined single (ss) and double stranded (ds) DNA oligomers. In the absence of cofactors (ATPgammaS or ADP), DrRecA binds to dsDNA oligomers more than 20 fold tighter than EcRecA, and binds ssDNA up to 9 fold tighter. Binding to dsDNA oligomers in the absence of cofactor presumably predominantly monitors DNA end binding, and thus suggests a significantly higher affinity of DrRecA for ds breaks. Upon addition of ATPgammaS, this species-specific affinity difference is nearly abolished, as ATPgammaS significantly decreases the affinity of DrRecA for DNA. Other findings include that: (1) both proteins exhibit a dependence of binding affinity on the length of the ssDNA oligomer, but not the dsDNA oligomer; (2) the salt dependence of binding is modest for both species of RecA, and (3) in the absence of DNA, DrRecA produces significantly shorter and/or fewer free-filaments in solution than does EcRecA. The results suggest intrinsic biothermodynamic properties of DrRecA contribute directly to the more robust DNA repair capabilities of D. radiodurans. PMID- 26021743 TI - Association of the Rad9-Rad1-Hus1 checkpoint clamp with MYH DNA glycosylase and DNA. AB - Cell cycle checkpoints provide surveillance mechanisms to activate the DNA damage response, thus preserving genomic integrity. The heterotrimeric Rad9-Rad1-Hus1 (9 1-1) clamp is a DNA damage response sensor and can be loaded onto DNA. 9-1-1 is involved in base excision repair (BER) by interacting with nearly every enzyme in BER. Here, we show that individual 9-1-1 components play distinct roles in BER directed by MYH DNA glycosylase. Analyses of Hus1 deletion mutants revealed that the interdomain connecting loop (residues 134-155) is a key determinant of MYH binding. Both the N-(residues 1-146) and C-terminal (residues 147-280) halves of Hus1, which share structural similarity, can interact with and stimulate MYH. The Hus1(K136A) mutant retains physical interaction with MYH but cannot stimulate MYH glycosylase activity. The N-terminal domain, but not the C-terminal half of Hus1 can also bind DNA with moderate affinity. Intact Rad9 expressed in bacteria binds to and stimulates MYH weakly. However, Rad9(1-266) (C-terminal truncated Rad9) can stimulate MYH activity and bind DNA with high affinity, close to that displayed by heterotrimeric 9(1-266)-1-1 complexes. Conversely, Rad1 has minimal roles in stimulating MYH activity or binding to DNA. Finally, we show that preferential recruitment of 9(1-266)-1-1 to 5'-recessed DNA substrates is an intrinsic property of this complex and is dependent on complex formation. Together, our findings provide a mechanistic rationale for unique contributions by individual 9-1-1 subunits to MYH-directed BER based on subunit asymmetry in protein-protein interactions and DNA binding events. PMID- 26021745 TI - Improving the activity of Lycium barbarum polysaccharide on sub-health mice. AB - Sub-health has been described as a chronic condition of unexplained deteriorated physiological function, which falls between health and illness and includes fatigue as one of its principal manifestations. Mitochondrial dysfunctions have been discovered in fatigue-type sub-health such as impaired oxidative phosphorylation and mitochondrial damage. In the present study, we evaluated the effects of Lycium barbarum polysaccharide (LBP-4a), a polysaccharide fraction purified from Lycium barbarum, on anti-fatigue in sub-health mice, and the relevant mechanisms were studied. Forty mice were divided into control, model, LBP-4a(L) and LBP-4a(H) groups. Model mice were prepared through compound factors, including forced swim tests, sleep deprivation and wrapping restraint stress tests. After LBP-4a treatment for 4 weeks, the gastrocnemius muscles were obtained for morphological observation and the activities of SOD, GSH-Px and MDA content were detected. Furthermore, mitochondrial membrane potential and Ca(2+) content were measured in isolated skeletal muscle mitochondria. The results showed that LBP-4a could reduce skeletal muscle damage and MDA levels and enhance of SOD and GSH-Px activities compared with the model group. The levels of mitochondrial membrane potential and Ca(2+) were increased in LBP-4a-treated skeletal muscle mitochondria; moreover, the high-dosage group was better than that of the low dosage. In conclusion, LBP-4a exhibited anti-fatigue activity on sub-health mice, and the mechanism was closely correlated with a reduction in lipid peroxidation levels and an increase in antioxidant enzyme activities in skeletal muscle tissue, improving the intracellular calcium homeostasis imbalance and increasing mitochondrial membrane potential. These observations provided the background for the further development of LBP-4a as a type of anti-fatigue therapy used in sub-health treatment. PMID- 26021746 TI - Overexpression of Fibulin-5 Attenuates Ischemia/Reperfusion Injury After Middle Cerebral Artery Occlusion in Rats. AB - Ischemia/reperfusion (I/R) injury after middle cerebral artery occlusion (MCAO) induces detrimental processes such as oxidative stress, inflammation, and apoptosis. All parts of the neurovascular unit are involved in these pathological processes. Fibulin-5 is a 66-kD glycoprotein secreted by various vascular cells, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. As an extracellular matrix protein involved in cell adhesion, fibulin-5 has been widely studied in tumor growth and invasion. However, the effects of fibulin-5 on brain injury following ischemia/reperfusion have not been reported. In this study, we examined the effect of overexpressed fibulin-5 on reactive oxygen species (ROS) production. Fibulin-5 overexpression attenuated ROS expression, which in turn decreased apoptosis and blood-brain barrier (BBB) permeability following MCAO and reperfusion. Fibulin-5 also improved neurological deficits but had no effect on infarction volume. T2-weighted MRI and electron microscopy further confirmed brain edema reduction and decreased BBB disruption in fibulin-5 overexpression recombinant adenovirus (Ad-FBLN) treated rats. In addition, tight junction protein occludin was significantly degraded and matrix metalloproteinase 9 (MMP-9) immunoreactivity was significantly increased. Fibulin 5-mediated ROS decrease was not due to increased total superoxide dismutase levels but was instead correlated with the activation of Rac-1 pathway. The findings highlight the importance of antioxidant mechanism underlying cerebral ischemia/reperfusion. PMID- 26021747 TI - Endogenous Docosahexaenoic Acid (DHA) Prevents Abeta1-42 Oligomer-Induced Neuronal Injury. AB - The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) or n-3 fatty acid has been associated with reduced risk of Alzheimer's disease (AD) in epidemiological reports. However, the underlying mechanism remains to be elucidated. Here, we report that exogenous DHA administration could protect neurons against Abeta oligomer-induced injury both in vitro and in vivo, partly through reducing the endoplasmic reticulum (ER) stress, and preventing cell apoptosis. In transgenic fat-1 mice with enriched omega-3 fatty acids, Abeta oligomers induced fewer neuronal losses, when compared to wild-type (WT) mice. We conclude that endogenous DHA are neuroprotective in pathogenesis processes of AD. PMID- 26021748 TI - An action-incongruent secondary task modulates prediction accuracy in experienced performers: evidence for motor simulation. AB - We provide behavioral evidence that the human motor system is involved in the perceptual decision processes of skilled performers, directly linking prediction accuracy to the (in)ability of the motor system to activate in a response specific way. Experienced and non-experienced dart players were asked to predict, from temporally occluded video sequences, the landing position of a dart thrown previously by themselves (self) or another (other). This prediction task was performed while additionally performing (a) an action-incongruent secondary motor task (right arm force production), (b) a congruent secondary motor task (mimicking) or (c) an attention-matched task (tone-monitoring). Non-experienced dart players were not affected by any of the secondary task manipulations, relative to control conditions, yet prediction accuracy decreased for the experienced players when additionally performing the force-production, motor task. This interference effect was present for 'self' as well as 'other' decisions, reducing the accuracy of experienced participants to a novice level. The mimicking (congruent) secondary task condition did not interfere with (or facilitate) prediction accuracy for either group. We conclude that visual-motor experience moderates the process of decision making, such that a seemingly visual cognitive prediction task relies on activation of the motor system for experienced performers. This fits with a motor simulation account of action prediction in sports and other tasks, and alerts to the specificity of these simulative processes. PMID- 26021749 TI - Working memory capacity, controlled attention and aiming performance under pressure. AB - This study explored the possibility that individual differences in working memory capacity (WMC) could predict those individuals who would experience attentional disruptions and performance decrements under pressure. Two WMC groups performed a Stroop handgun task under counterbalanced conditions of threat whilst wearing eye tracking equipment that measured visual search activity and quiet eye (QE) aiming duration. Performance was measured in terms of shooting accuracy. Low-WMC individuals experienced impaired visual search time to locate the target and reduced QE durations when shooting at incongruent target words. Furthermore, the low-WMC group experienced significant reductions in shooting accuracy when anxious. Conversely, high-WMC individuals experienced no significant differences in attentional control or performance across congruency or threat conditions. Results support the suggestion that WMC is not only a good predictor of an individual's ability to control their attention but can also predict those likely to fail under pressure. PMID- 26021750 TI - Non-linear optical flow cytometry using a scanned, Bessel beam light-sheet. AB - Modern flow cytometry instruments have become vital tools for high-throughput analysis of single cells. However, as issues with the cellular labeling techniques often used in flow cytometry have become more of a concern, the development of label-free modalities for cellular analysis is increasingly desired. Non-linear optical phenomena (NLO) are of growing interest for label free analysis because of the ability to measure the intrinsic optical response of biomolecules found in cells. We demonstrate that a light-sheet consisting of a scanned Bessel beam is an optimal excitation geometry for efficiently generating NLO signals in a microfluidic environment. The balance of photon density and cross-sectional area provided by the light-sheet allowed significantly larger two photon fluorescence intensities to be measured in a model polystyrene microparticle system compared to measurements made using other excitation focal geometries, including a relaxed Gaussian excitation beam often used in conventional flow cytometers. PMID- 26021751 TI - The effects of H3N2 swine influenza virus infection on TLRs and RLRs signaling pathways in porcine alveolar macrophages. AB - BACKGROUND: Swine influenza is an economically important respiratory disease of swine resulting from infection with influenza A virus. Swine influenza virus (SIV) becomes the focus as pigs have been hypothesized to serve as an intermediate host for the adaptation of avian influenza viruses to humans or as mixing vessels for the generation of genetically reassortant viruses. The ability of the innate immune system to detect and respond to pathogens is important for survival. Therefore, there is a critical need to evaluate the immediate response to viral infection, especially the role of the toll-like receptors (TLRs) and RNA helicase RIG-I-like receptors (RLRs) innate immunity signaling pathways in H3N2 swine influenza virus infection. METHOD: In this study, porcine alveolar macrophages (PAMs) were obtained from porcine lungs and were infected with SIV at a multiplicity of infection (MOI) of 5 in vitro. The changes of the related receptors, signaling proteins and effector molecules of TLRs and RLRs signaling pathways post H3N2 virus infection of PAMs were quantified by Real-time quantitative RT-PCR and western blotting. RESULTS: The results showed that H3N2 SIV infection significantly increased mRNA expression of TLR-3, TLR-7, RIG- I and MDA5 after 4 hpi (P < 0.05). Western blotting showed that the protein levels of TLR-3, TLR-7 and RIG-I also had a significantly increase after PAM exposed to virus. A significant change of MyD88, MAVS, IRF-3 and IRF-7 mRNA expression were present at 8 hpi. More than a 4-fold increase was induced for TNF-alpha and IL 1beta mRNA expression. And the concentration of TNF-alpha and IL-1beta peaked at 12 and 24 hpi, respectively. IFN-alpha, IFN-beta mRNA and protein levels increased after SIV infection and significant differences was observed at 8, 12 and 24 hpi. CONCLUSION: These results indicate that H3N2 swine influenza virus infection significantly influences the expression of the receptors, adapter proteins and downstream effector molecules of RLRs and TLRs signaling pathways. This study enhances our understanding of innate immunity signaling pathways in PAM anti-infection of H3N2 SIV. PMID- 26021753 TI - Managing intrathecal drug delivery (ITDD) in cancer patients. AB - Pain is a commonly reported symptom in cancer patients. Patients with cancer pain often fail conservative medical management or have significant side effects to systemic medications. The implantation of an intrathecal drug delivery (ITDD) system may be the most effective treatment option for these patients and can improve their quality of life. This article aims to discuss the choice of intrathecal medications for patients suffering from intractable cancer pain, the management of ITDD throughout a patient's disease course, and the management of complications related to the ITDD system and intrathecal medications. PMID- 26021752 TI - Evaluation of the prognostic significance of HER family mRNA expression in high risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) validation study. AB - BACKGROUND: The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as a validation analysis of another previously published HeCOG study. METHODS: RNA was extracted from 663 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples of high-risk early breast cancer patients enrolled in the randomized HE10/00 trial. Relative mRNA expression of all four HER family members was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: In compliance with our previous study, the overall agreement between qRT-PCR and IHC/FISH for HER2 status determination was good (69%). Likewise, the overall concordance between qRT-PCR and IHC for EGFR status was high (81%). In line with our previously reported data, we demonstrated a positive association between HER2 and HER3 mRNA expression. Similarly, mRNA expression of HER3 and HER4 was positively associated with each other and negatively associated with EGFR. Regarding relationships with clinico-pathological parameters, our findings are also in agreement with our previous results. Generally, increased EGFR and HER2 mRNA expression was related to unfavorable, whereas high HER3 and HER4 mRNA expression was associated with favorable clinico-pathological parameters. In univariate analysis, no significant association between EGFR, HER2 and HER3 mRNA expression and overall survival (OS) or disease-free survival (DFS) was demonstrated. However, high EGFR protein expression was associated with significantly shorter OS (log-rank, p = 0.015). In compliance with our previously published data, increased HER4 mRNA expression had a significantly favorable prognostic value in terms of OS (p = 0.044) and DFS (p = 0.047). In multivariate analysis, among all HER receptors, only EGFR protein expression was found to affect OS (Wald's p = 0.028) and DFS (p = 0.015) independently. Concerning the combined expression of all four HER family receptors, the combination of high EGFR, high HER2, low HER3 and low HER4 mRNA expression was associated with a trend for shorter OS (log-rank, p = 0.065) and significantly worse DFS (p = 0.033), compared with all other co-expression profiles. CONCLUSIONS: These data indicate that qRT-PCR may represent a valid alternative method for evaluating the expression of HER family members in FFPE breast carcinoma tissue samples. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609001036202. PMID- 26021754 TI - From ophthalmoplegic migraine to cranial neuropathy. AB - Ophthalmoplegic migraine (OM)/recurrent painful ophthalmoplegic neuropathy (RPON) is a rare disease consisting of recurrent unilateral headache accompanied or followed by ipsilateral ophthalmoplegia. Because MRI findings suggest neuropathy and the relationship to typical migraine remains unclear, the disease has been renamed from "ophthalmoplegic migraine" to "recurrent painful oculomotor neuropathy" in the third edition of the International Classification of Headache Disorders (ICHD). However, it remains a fact that most cases of OM/RPON described in the literature have a history of migraine and that the headache during OM/RPON often has migrainous features. A more detailed clinical description of the headache during OM/RPON and additional results from imaging and possibly histology will be needed to better understand the pathophysiology of the disease and its relationship to typical migraine. PMID- 26021755 TI - Do trigeminal autonomic cephalalgias represent primary diagnoses or points on a continuum? AB - The question of whether the trigeminal autonomic cephalalgias (TACs) represent primary diagnoses or points on a continuum has been debatable for a number of years. Patients with TACs may present with similar clinical characteristics, and occasionally, TACS respond to similar treatments. Prima facie, these disorders may seem to be intimately related. However, due to the current evidence, it would be challenging to accurately conclude whether they represent different primary headache diagnoses or the same primary headache disorder represented by different points on the same continuum. Ultimately, the TACs may utilize similar pathways and activate nociceptive responses that result in similar clinical phenotypes but "original and initiating" etiology may differ, and these disorders may not be points on the same continuum. This paper seeks to provide a brief comparison of TACs via diagnostic criteria, secondary causes, brief overview of pathophysiology, and the use of some key treatments and their mechanism of actions to illustrate the TAC similarities and differences. PMID- 26021756 TI - Visual snow--persistent positive visual phenomenon distinct from migraine aura. AB - Patients with visual snow complain of uncountable flickering tiny dots in the entire visual field similar to the view of a badly tuned analogue TV channel (TV snow). The symptoms are often continuous and can persist over years. This condition is grouped among the persistent visual phenomena in migraine, although it clinically presents a unique entity distinct from persistent migraine aura or migraine aura status. Here, we review the recent literature leading to the identification of the visual snow syndrome. The additional visual and non-visual symptoms are described in detail, and criteria are presented for future studies. Using these criteria, the relationship to migraine and typical migraine aura was recently evaluated. Further, patients with visual snow differ from controls in respect of hypermetabolism in the supplementary visual cortex (lingual gyrus). This provides evidence that visual snow, despite being purely subjective in the individual patient, has a clear biological basis. The area of hypermetabolism overlaps with the functional correlates of photophobia in migraine supporting the close relationship of migraine and visual snow. PMID- 26021758 TI - A lead-halide perovskite molecular ferroelectric semiconductor. AB - Inorganic semiconductor ferroelectrics such as BiFeO3 have shown great potential in photovoltaic and other applications. Currently, semiconducting properties and the corresponding application in optoelectronic devices of hybrid organo-plumbate or stannate are a hot topic of academic research; more and more of such hybrids have been synthesized. Structurally, these hybrids are suitable for exploration of ferroelectricity. Therefore, the design of molecular ferroelectric semiconductors based on these hybrids provides a possibility to obtain new or high-performance semiconductor ferroelectrics. Here we investigated Pb-layered perovskites, and found the layer perovskite (benzylammonium)2PbCl4 is ferroelectric with semiconducting behaviours. It has a larger ferroelectric spontaneous polarization Ps=13 MUC cm(-2) and a higher Curie temperature Tc=438 K with a band gap of 3.65 eV. This finding throws light on the new properties of the hybrid organo-plumbate or stannate compounds and provides a new way to develop new semiconductor ferroelectrics. PMID- 26021757 TI - The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels. AB - Voltage-gated CLC-1 chloride channels play a critical role in controlling the membrane excitability of skeletal muscles. Mutations in human CLC-1 channels have been linked to the hereditary muscle disorder myotonia congenita. We have previously demonstrated that disease-associated CLC-1 A531V mutant protein may fail to pass the endoplasmic reticulum quality control system and display enhanced protein degradation as well as defective membrane trafficking. Currently the molecular basis of protein degradation for CLC-1 channels is virtually unknown. Here we aim to identify the E3 ubiquitin ligase of CLC-1 channels. The protein abundance of CLC-1 was notably enhanced in the presence of MLN4924, a specific inhibitor of cullin-RING E3 ligases. Subsequent investigation with dominant-negative constructs against specific subtypes of cullin-RING E3 ligases suggested that CLC-1 seemed to serve as the substrate for cullin 4A (CUL4A) and 4B (CUL4B). Biochemical examinations further indicated that CUL4A/B, damage specific DNA binding protein 1 (DDB1), and cereblon (CRBN) appeared to co-exist in the same protein complex with CLC-1. Moreover, suppression of CUL4A/B E3 ligase activity significantly enhanced the functional expression of the A531V mutant. Our data are consistent with the idea that the CUL4A/B-DDB1-CRBN complex catalyses the polyubiquitination and thus controls the degradation of CLC-1 channels. PMID- 26021760 TI - Erratum: Ventriculo-atrial defect after bioprosthetic aortic valve replacement. PMID- 26021759 TI - An important role for peroxiredoxin II in survival of A549 lung cancer cells resistant to gefitinib. AB - Redox adaptation is an important concept that explains the mechanisms by which cancer cells survive under persistent endogenous oxidative stress and become resistant to certain anticancer agents. To investigate this concept, we determined the expression levels of peroxiredoxins (Prxs), antioxidant enzymes in drug-resistant non-small cell lung carcinoma cells. Prx II was remarkably increased only in A549/GR (gefitinib-resistant) cells compared with A549 cells, consistent with methylation/demethylation. Prx II was highly methylated in the A549 cells but was demethylated in the A549/GR cells. The elevated expression of Prx II resulted in the downregulation of reactive oxygen species (ROS) and cell death and upregulation of cell cycle progression in the A549/GR cells. When Prx II mRNA in the A549/GR cells was knocked down, the levels of ROS and apoptosis were significantly recovered to the levels of the controls. In addition, signaling molecules involved in apoptosis were increased in the A549/GR-shPrx II cells. There was no difference in the expression of MAPK/ERK between the A549/GR cells and A549/GR-shPrx II cells, but the phosphorylation of JNK was increased in the A549/GR cells and was markedly decreased in the A549/GR-shPrx II cells. Colony number and tumor growth were significantly decreased in the A549/GR-shPrx II cells compared with the A549/GR cells. Our findings suggest that Prx II has an important role in cancer cell survival via the modulation of signaling molecules involved in apoptosis and the phosphorylation of JNK by the downregulation of ROS levels in A549/GR cells. PMID- 26021762 TI - Radiographic Characteristics of Adrenal Masses Preceding the Diagnosis of Adrenocortical Cancer. AB - Incidentally discovered adrenal masses are common and the clinical evaluation and surveillance aims to diagnose hormone excess and malignancy. Adrenocortical cancer (ACC) is a very rare malignancy. This study aims to define the imaging characteristics of adrenal tumors preceding the diagnosis of ACC. Patients with prior (>5 months) adrenal tumors (<6 cm) subsequently diagnosed with ACC were identified in a large registry at a tertiary referral center. Retrospective chart and image review for patient characteristics and initial, interval, and diagnostic imaging characteristics (size, homogeneity, borders, density, growth rate, etc.) was conducted. Twenty patients with a diagnosis of ACC and a prior adrenal tumor were identified among 422 patients with ACC. Of these, 17 patients were initially imaged with CT and 3 with MR. Only 2 of the 20 patients had initial imaging characteristics suggestive of a benign lesion. Of initial tumors, 25% were <2 cm in size. Surveillance led to the diagnosis of ACC within 24 months in 50% of patients. The growth pattern was variable with some lesions showing long-term stability (up to 8 years) in size. In conclusion, antecedent lesions in patients with a diagnosis of ACC are often indeterminate by imaging criteria and can be small. Surveillance over 2 years detected only 50% of ACCs. Current practice and guidelines are insufficient in diagnosing ACCs. Given the rarity of ACC, the increased risk and health care costs of additional evaluation may not be warranted. PMID- 26021763 TI - Parathyroid Hormone is Related to Dysplasia and a Higher Rate of Distal Colorectal Adenoma in Women but Not Men. AB - Molecular and clinical observations provide evidence for a potential role of parathyroid hormone (PTH) in colorectal cancer development. We therefore aimed to assess the association of PTH with regard to colorectal cancer precursor lesions. A cohort of 1432 participants, 777 men, 58.4 +/- 9.6 years and 701 women, 59.1 +/ 10.6 years, undergoing screening colonoscopy were allocated to PTH serum concentrations either above or below 55 ng/L. The number, localization, size, and histology of the polypoid lesions detected during screening colonoscopy were recorded according to PTH serum concentrations. Serum PTH concentrations were not different between men and women. Women with PTH serum concentrations above the cut-off had significantly more adenomas (13/40; 32.5%) of the distal colon compared to women below the cut-off (91/659; 13.8%; P = 0.001). Additionally, the rate of dysplasia in adenomas of the distal colon was higher in women with high compared to low PTH concentrations (P = 0.001). These findings remained robust after adjustments for serum vitamin D, age, plasma creatinine, BMI, diabetes, and liver steatosis. No associations were observed between serum PTH concentrations and colorectal lesions in men. These data suggest that elevated PTH serum concentrations might have a role in colorectal cancer development as indicated by higher rates of adenomas, specifically with dysplasia, in women. The role of PTH in colon carcinogenesis and its sex specificity deserve further study. PMID- 26021761 TI - Vertebral Scheuermann's disease in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over. AB - In 27 centres across Europe, the prevalence of deforming spinal Scheuermann's disease in age-stratified population-based samples of over 10,000 men and women aged 50+ averaged 8% in each sex, but was highly variable between centres. Low DXA BMD was un-associated with Scheuermann's, helping the differential diagnosis from osteoporosis. INTRODUCTION: This study aims to assess the prevalence of Scheuermann's disease of the spine across Europe in men and women over 50 years of age, to quantitate its association with bone mineral density (BMD) and to assess its role as a confounder for the radiographic diagnosis of osteoporotic fracture. METHODS: In 27 centres participating in the population-based European Vertebral Osteoporosis Study (EVOS), standardised lateral radiographs of the lumbar and of the thoracic spine from T4 to L4 were assessed in all those of adequate quality. The presence of Scheuermann's disease, a confounder for prevalent fracture in later life, was defined by the presence of at least one Schmorl's node or irregular endplate together with kyphosis (sagittal Cobb angle >40 degrees between T4 and T12) or a wedged-shaped vertebral body. Alternatively, the (rare) Edgren-Vaino sign was taken as diagnostic. The 6-point per-vertebral-body (13 vertebrae) method was used to assess osteoporotic vertebral shape and fracture caseness. DXA BMD of the L2-L4 and femoral neck regions was measured in subsets. We also assessed the presence of Scheuermann's by alternative published algorithms when these used the radiographic signs we assessed. RESULTS: Vertebral radiographic images from 4486 men and 5655 women passed all quality checks. Prevalence of Scheuermann's varied considerably between centres, and based on random effect modelling, the overall European prevalence using our method was 8% with no significant difference between sexes. The highest prevalences were seen in Germany, Sweden, the UK and France and low prevalences were seen in Hungary, Poland and Slovakia. Centre-level prevalences in men and women were highly correlated. Scheuermann's was not associated with BMD of the spine or hip. CONCLUSIONS: Since most of the variation in population impact of Scheuermann's was unaccounted for by the radiological and anthropometric data, the search for new genetic and environmental determinants of this disease is encouraged. PMID- 26021764 TI - Spatio-temporal changes in glutathione and thioredoxin redox couples during ionizing radiation-induced oxidative stress regulate tumor radio-resistance. AB - Ionizing radiation (IR)-induced oxidative stress in tumor cells is effectively managed by constitutive and inducible antioxidant defense systems. This study was initiated to understand the relative contribution of different redox regulatory systems in determining the tumor radio-resistance. In this study, human T-cell lymphoma (Jurkat) cells were exposed to IR (4 Gy) and monitored for the spatio temporal changes in cellular redox regulatory parameters. We monitored the changes in the levels of reactive oxygen species (ROS) (total, mitochondrial, primary, and secondary), thiols (total, surface, and intracellular), GSH/GSSG ratio, antioxidant enzyme activity viz. thioredoxin (Trx), Trx reductase (TrxR), glutathione peroxidase, and glutathione reductase with respect to time. We have also measured protein glutathionylation. We observed that tumor cells mount a biphasic response after IR exposure which can be divided into early (0-6 h) and late (16-48 h) responses in terms of changes in cellular redox parameters. During early response, constitutively active GSH and Trx systems respond to restore cellular redox balance to pre-exposure levels and help in activation of redox sensitive transcription factor Nrf-2. During late response, increase in the levels of antioxidants GSH and Trx rescue cells against IR-mediated damage. We observed that disruption of either glutathione or thioredoxin metabolism led to partial impairment of ability of cells to survive against IR-induced damage. But simultaneous disruption of both the pathways significantly increased radio sensitivity of Jurkat cells. This highlighted the importance of these two antioxidant pathways in regulating redox homeostasis under conditions of IR induced oxidative stress. PMID- 26021765 TI - Near infrared photoimmunotherapy for lung metastases. AB - Lung metastases are a leading cause of cancer related deaths; nonetheless current treatments are limited. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR-light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases. Experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye700DX, was synthesized. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. With 3D culture, repeated NIR-PIT could eradicate entire spheroids. In vivo anti tumor effects of NIR-PIT included significant reductions in both tumor volume (p = 0.0141 vs. APC) and bioluminescence image (BLI) (p = 0.0086 vs. APC) in the flank model, and prolonged survival (p < 0.0001). BLI demonstrated a significant reduction in lung metastases volume (p = 0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastasis model (p < 0.0001). These results suggested that NIR-PIT is a potential new therapy for the local control of lung metastases. PMID- 26021766 TI - Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5 fluorouracil in colorectal cancer cells. AB - Cancer cells rely mostly on glycolysis to meet their energetic demands, producing large amounts of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). The role of MCTs in the survival of colorectal cancer (CRC) cells is scarce and poorly understood. In this study, we aimed to better understand this issue and exploit these transporters as novel therapeutic targets alone or in combination with the CRC classical chemotherapeutic drug 5-Fluorouracil. For that purpose, we characterized the effects of MCT activity inhibition in normal and CRC derived cell lines and assessed the effect of MCT inhibition in combination with 5-FU. Here, we demonstrated that MCT inhibition using CHC (alpha-cyano-4-hydroxycinnamic acid), DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and quercetin decreased cell viability, disrupted the glycolytic phenotype, inhibited proliferation and enhanced cell death in CRC cells. These results were confirmed by specific inhibition of MCT1/4 by RNA interference. Notably, we showed that 5 FU cytotoxicity was potentiated by lactate transport inhibition in CRC cells, either by activity inhibition or expression silencing. These findings provide novel evidence for the pivotal role of MCTs in CRC maintenance and survival, as well as for the use of these transporters as potential new therapeutic targets in combination with CRC conventional therapy. PMID- 26021767 TI - Temporal changes in radiocesium deposition in various forest stands following the Fukushima Dai-ichi Nuclear Power Plant accident. AB - In this study, we investigated the transfer of canopy-intercepted radiocesium to the forest floor following the Fukushima Dai-ichi Nuclear Power Plant accident. The 137Cs content of throughfall, stemflow, and litterfall were monitored in two coniferous stands (plantations of Japanese cedar) and a deciduous mixed broad leaved forest stand (oak with red pine) from July 2011 to December 2012. The forest floor of cedar stands had received higher levels of additional 137Cs deposition compared with the mixed broad-leaved stand during the sampling period. The cumulative 137Cs deposition during the study period was 119 kBq m-2 for the mature cedar stand, 105 kBq m-2 for the young cedar stand, and 41.5 kBq m-2 for the broad-leaved stand. The deposition of 137Cs to the forest floor occurred mainly in throughfall during the first rainy season, from July to September 2011 (<200 d after the initial fallout); thereafter, the transfer of 137Cs from the canopy to forest floor occurred mainly through litterfall. A double exponential field-loss model, which was used to simulate the removal of 137Cs from canopies, was the best fit for the temporal changes in the canopy 137Cs inventory. PMID- 26021768 TI - Gaseous O2, NO, and CO in signal transduction: structure and function relationships of heme-based gas sensors and heme-redox sensors. PMID- 26021769 TI - Outcomes after cesarean myomectomy versus cesarean alone among pregnant women with uterine leiomyomas. AB - OBJECTIVE: To determine whether myomectomy during cesarean delivery is safe and feasible among pregnant women with leiomyomas. METHODS: In a retrospective study, data were reviewed from pregnant women with uterine leiomyomas who delivered by cesarean at a center in Turkey between May 1, 2007, and April 30, 2014. Women were divided into two groups: cesarean myomectomy (CM) or cesarean only (CO). Data were analyzed for characteristics of the uterine leiomyomas, hematologic changes occurring between the preoperative and postoperative periods, duration of the operation, and length of hospital stay. RESULTS: Overall, 76 women formed the CM group and 60 formed the CO group. The mean diameter of the leiomyomas did not differ between CM and CO groups (4.6+/-2.5cm vs 5.2+/-2.2cm; P=0.175). More patients in the CM group than in the CO group had subserous (24 [31.6%] vs 7 [11.7%]; P=0.006) and uterine corpus (57 [75.0%] vs 30 [50.0%]; P=0.003) leiomyomas. Fewer patients in the CM group had intramural (44 [57.9%] vs 49 [81.7%]; P=0.003) and fundal (15 [19.7%] vs 25 [41.7%]; P=0.005) leiomyomas. CONCLUSION: Surgeons were more likely to remove corporal and subserous leiomyomas than other types; size did not seem to affect decision making. CM can be a safe operation for some patients. PMID- 26021770 TI - Colorectal cancer: A review of the genome-wide association studies in the kingdom of Saudi Arabia. AB - Genome-wise association studies (GWAS) identify risk variants and modifiers that can influence the pathophysiological processes involved in colorectal cancer (CRC) and thus are important to detect associations between disease phenotypes. Our literature review, performed as per PRISMA statement indicates a significant lack of GWAS functional studies in Saudi Arabia. Therefore, studies on sequencing and mapping are needed to identify gene variants that play a role in the pathophysiology of CRC in this specific population. Because it is not apt to generalize disease associations found in other racial and/or ethnic groups to the Arabic or Middle Eastern population, it is very important to conduct GWAS taking into account multiple ethnicities in this region. In addition, linkage studies and case-control studies that include the various confounding and epigenetic factors are needed for appropriate diagnosis of CRC. We recommend that studies in this region be conducted to understand the role of gene-environment interactions across the various ethnic groups, stages of cancer, tumor type, clinical variables, and the population risk to CRC. PMID- 26021771 TI - Extrahepatic portal vein obstruction and portal vein thrombosis in special situations: Need for a new classification. AB - Extrahepatic portal vein obstruction is a vascular disorder of liver, which results in obstruction and cavernomatous transformation of portal vein with or without the involvement of intrahepatic portal vein, splenic vein, or superior mesenteric vein. Portal vein obstruction due to chronic liver disease, neoplasm, or postsurgery is a separate entity and is not the same as extrahepatic portal vein obstruction. Patients with extrahepatic portal vein obstruction are generally young and belong mostly to Asian countries. It is therefore very important to define portal vein thrombosis as acute or chronic from management point of view. Portal vein thrombosis in certain situations such as liver transplant and postsurgical/liver transplant period is an evolving area and needs extensive research. There is a need for a new classification, which includes all areas of the entity. In the current review, the most recent literature of extrahepatic portal vein obstruction is reviewed and summarized. PMID- 26021772 TI - The relationship of circulating fetuin-a with liver histology and biomarkers of systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease. AB - BACKGROUND/AIMS: Fetuin-A, a glycoprotein with anti-inflammatory properties, plays an important role in counter-regulating inflammatory responses. It has also been associated with insulin resistance and metabolic syndrome. We aimed to investigate circulating concentrations of fetuin-A and its possible association with hepatic and systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: We included 105 nondiabetic male subjects with NAFLD [nonalcoholic steatohepatitis (NASH, n = 86) and simple steatosis (SS, n = 19)]. Plasma levels of fetuin-A and markers of inflammation [high-sensitive C reactive protein (hsCRP), tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), and adiponectin] were measured by enzyme-linked immunosorbent assay method. Insulin sensitivity was determined by homeostasis model assessment of insulin resistance (HOMA-IR) index. RESULTS: Fetuin-A was negatively correlated with age (r = -0.27, P = 0.006), however there was no association between fetuin-A and body mass index, waist circumference (WC), glucose, insulin, HOMA-IR, lipid parameters, and inflammatory markers. In addition, no significant association was observed between fetuin-A and histological findings including liver fibrosis. CONCLUSION: This study demonstrated that plasma fetuin-A levels are not correlated with the hepatic histology and systemic markers of inflammation in nondiabetic subjects with NAFLD. Our data also suggested that age is significantly associated with fetuin-A in this clinically relevant condition. PMID- 26021774 TI - Clinical, endoscopic, and radiologic features of three subtypes of achalasia, classified using high-resolution manometry. AB - BACKGROUND/AIMS: High-resolution manometry (HRM) has improved the accuracy of manometry in detecting achalasia and determining its subtypes. However, the correlation of achalasia subtypes with clinical, endoscopic, and radiologic findings has not been assessed. We aimed to evaluate and compare the clinical, endoscopic, and fluoroscopy findings associated with three subtypes of achalasia using HRM. PATIENTS AND METHODS: The retrospective clinical data, HRM, endoscopy, and radiologic findings were obtained from the medical records of untreated achalasia patients. RESULTS: From 2011 to 2013, 374 patients underwent HRM. Fifty two patients (14%) were diagnosed with achalasia, but only 32 (8.5%) of these patients had not received treatment and were therefore included in this study. The endoscopy results were normal in 28% of the patients, and a barium swallow was inconclusive in 31% of the achalasia patients. Ten patients (31%) were classified as having type I achalasia, 17 (53%) were classified as type II, and 5 (16%) were classified as type III. Among the three subtypes, type I patients were on average the youngest and had the longest history of dysphagia, mildest chest pain, most significant weight loss, and most dilated esophagus with residual food. Chest pain was most common in type III patients, and frequently had normal fluoroscopic and endoscopic results. CONCLUSION: The clinical, radiologic, and endoscopic findings were not significantly different between patients with type I and type II untreated achalasia. Type III patients had the most severe symptoms and were the most difficult to diagnose based on varied clinical, radiologic, and endoscopic findings. PMID- 26021773 TI - Virologic response and safety of tenofovir versus entecavir in treatment-naive chronic Hepatitis B patients. AB - BACKGROUND/AIMS: This study aimed to evaluate the antiviral response and safety of tenofovir (TDF) versus entecavir (ETV) in treatment-naive CHB patients. PATIENTS AND METHODS: We performed a retrospective cohort study of treatment naive CHB patients who were treated with TDF or ETV. We analyzed virologic, biochemical, and serologic responses at 3, 6, and 12 months. RESULTS: A total of 107 patients (TDF group = 49, ETV group = 58) were included. Baseline characteristics were similar between the two groups. The estimated proportion of complete virologic response (CVR) in the TDF or ETV group was 44.9% versus 39.7% at 6 months and 89.6% versus 83.2% at 12 months, respectively (P = 0.991). Viral breakthrough was not observed in both groups. One patient in the TDF group and two patients in the ETV group experienced HBeAg loss, respectively (P = 0.657). High HBV DNA level at baseline was a significant negative predictor of virologic response by Cox regression analysis (P = 0.007). The safety profile was similar between the two groups. There was no case with serious adverse event. CONCLUSIONS: Both TDF and ETV were effective in achieving CVR and had a favorable safety profile in treatment-naive CHB patients. High viral load at baseline was a negative predictive factor of CVR. PMID- 26021775 TI - gamma-glutamyl transpeptidase in men and alanine aminotransferase in women are the most suitable parameters among liver function tests for the prediction of metabolic syndrome in nonviral hepatitis and nonfatty liver in the elderly. AB - BACKGROUND/AIMS: Nonalchoholic fatty liver disease (NAFLD) has been reported as a hepatic manifestation of metabolic syndrome (MetS); it is common and accounts for 80% of the cases with abnormal liver function tests (LFTs). In addition, several studies have proved that there is a correlation between abnormal LFTs and MetS. Therefore, LFTs may represent the abnormal metabolic status of livers in the patients with MetS. To identify the early state of metabolic dysfunction, we investigate the value of LFTs for the future MetS development in the relatively healthy (non-NAFLD) elderly. PATIENTS AND METHODS: A total of 16,912 subjects met the criteria for analysis. In the first stage of this study, subjects were enrolled in the cross-sectional study in order to find out the optimal cutoff value in different LFTs with higher chances to have MetS. In the second stage of the present study, subjects with MetS at baseline were excluded from the same study group, and a median 5.6-year longitudinal study was conducted on the rest of the group. RESULTS: Among all LFTs, only aspartate aminotransferase in both genders and the alpha-fetal protein in women failed to show the significance in distinguishing subjects with MetS by the receiver operating characteristic curve. In the Kaplan-Meier plot, only gamma-glutamyl transpeptidase (gamma-GT) in men and the alanine aminotransferase (ALT) in women could be used to successfully separate subjects with higher risk of developing the MetS from those with lower risk. Finally, in the multivariant Cox regression model, similar results were identified. Still, the hazard ratio (HR) to have future MetS, gamma-GT in men, and ALT in women showed significance (HR = 1.511 in men and 1.504 in women). CONCLUSION: Among all the different LFTs, gamma-GT (>16 U/L) in male and ALT (>21 U/L) in female were the best predictors for the development of MetS in healthy elderly. These two liver markers could be an ancillary test in predicting future MetS development/diagnosis. Elevation of the LFTs without underlying liver diseases should be treated as a warning sign of the possible MetS development in the elderly. PMID- 26021776 TI - Role of D-dimer in the Development of Portal Vein Thrombosis in Liver Cirrhosis: A Meta-analysis. AB - BACKGROUND AND AIMS: A meta-analysis was performed to explore the role of the D dimer in the development of portal vein thrombosis (PVT) in liver cirrhosis. METHODS: All papers were searched via PubMed, EMBASE, China National Knowledge Infrastructure, Wan Fang, and VIP databases. A standardized mean difference (SMD) with 95% confidence interval (CI) was pooled. RESULTS: Overall, 284 studies were initially identified, of which 21 were included. Cirrhotic patients with PVT had a significantly higher D-dimer concentration than those without PVT (pooled SMD = 1.249, 95%CI = 0.740-1.758). After the portal hypertension-related surgery, cirrhotic patients with PVT had a similar preoperative D-dimer concentration to those without PVT (pooled SMD = 0.820, 95%CI = -0.122-0.286), but a higher postoperative value of D-dimer concentration than those without PVT (pooled SMD = 2.505, 95%CI = 0.975-4.036). Notably, the D-dimer concentration at the 1 st postoperative day was similar between cirrhotic patients with and without PVT (pooled SMD = 0.137, 95%CI = -0.827-1.101), but that at the 7 th post-operative day was higher in cirrhotic patients with PVT than in those without PVT (pooled SMD = 1.224, 95%CI = 0.277-2.171). CONCLUSION: D-dimer might be regarded as a diagnostic marker for PVT in liver cirrhosis. In addition, postoperative D-dimer testing is worthwhile for the diagnosis of PVT after portal hypertension-related surgery. PMID- 26021777 TI - Doxorubicin-loaded drug-eluting beads versus conventional transarterial chemoembolization for nonresectable hepatocellular carcinoma. AB - BACKGROUND/AIMS: To compare the efficacy and safety profile of doxorubicin-loaded drug-eluting beads (DEB) to the conventional TACE (C-TACE) in the management of nonresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: All patients with nonresectable HCC who underwent either c-TACE or DEB-TACE during the period 2006-2014 and fulfilled the inclusion criteria were included in this retrospective study. Primary endpoints were tumor response rate at first imaging follow up, treatment-related liver toxicity, and treatment emergent adverse events (TEAE). RESULTS: Thirty-five patients (51 procedures) in the DEB-TACE group and 19 patients (25 procedures) in the c-TACE group were included in the analysis. The median follow up time was 61 days (range 24-538 days) in the DEB TACE group and 86 days (range 3-152 days) for the c-TACE group patients. Complete response (CR), objective response (OR), disease control (DC), and progressive disease (PD) rates were 11%, 24%, 17%, and 47%, respectively, in the DEB = TACE group compared with 4%, 32%, 28%, and 36%, respectively, in the c-TACE group. Mean ALT change from baseline was minimal in the DEB-TACE patients compared with c-TACE group (7.2 vs 79.4 units, P = 0.001). Hospital stay was significantly shorter in the DEB-TACE group (7.8 days vs 11.4 days; P = 0.038). The 2-year survival rate was 60% for the c-TACE patients and 58% for the DEB-TACE (P = 0.4). CONCLUSIONS: DEB-TACE compared with c-TACE is associated with lesser liver toxicity benefit, better tolerance, and shorter hospital stay. The two modalities however had similar survival and efficacy benefits. PMID- 26021778 TI - Child and Adolescent Sleep Patterns and Early School Start Times: Recognizing the Role of the Pediatric Nurse. PMID- 26021779 TI - Contralateral routing of signal hearing aid versus transcutaneous bone conduction in single-sided deafness. AB - The aim of this study was to compare a contralateral routing of signal (CROS) hearing aid to a transcutaneous bone-anchored device in the same conditions. This prospective crossover study included 18 adult patients with a single-sided deafness (SSD). After a trial period of 60 days with CROS and 7 days with a transcutaneous bone-anchored device (Alpha 1(r), Sophono, Boulder, Colo., USA) on a headband, 13 (72%) patients opted for Alpha 1, 2 patients for CROS, and 3 rejected both rehabilitation methods. Clinical tolerance, satisfaction, hearing performances (pure-tone audiometry, speech test in quiet and in noise, stereo audiometry, sound localization, and Hearing in Noise Test), and quality of life (Glasgow Benefit Inventory, Abbreviated Profile of Hearing Aid Benefit and Glasgow Hearing Aid Benefit questionnaires) were measured at 3 and 12 months after the implantation. Both devices improved equally the hearing in noise and the quality of life. Transcutaneous devices represent an effective option in SSD. PMID- 26021780 TI - Remission Time after Rituximab Treatment for Autoimmune Bullous Disease: A Proposed Update Definition. AB - A therapeutic endpoint is a very important tool to evaluate response in clinical trials. In 2005, a consensus statement identified two late endpoints of disease activity in pemphigus: complete remission off therapy and complete remission on therapy, both definitions applying to patients without lesions for at least 2 months. The same period of time was considered for partial remission off/on therapy. These definitions were later applied to bullous pemphigoid and are considered in most studies on autoimmune bullous disease. These endpoints were established for different adjuvant agents, but at that moment, rituximab was not considered. Rituximab is known for the long duration of its effect, and in most studies relapses have been reported later than 6 months after treatment. In our opinion, time to remission after rituximab treatment should be redefined. PMID- 26021781 TI - Kinect-Based Five-Times-Sit-to-Stand Test for Clinical and In-Home Assessment of Fall Risk in Older People. AB - BACKGROUND: Accidental falls remain an important problem in older people. The five-times-sit-to-stand (5STS) test is commonly used as a functional test to assess fall risk. Recent advances in sensor technologies hold great promise for more objective and accurate assessments. OBJECTIVE: The aims of this study were: (1) to examine the feasibility of a low-cost and portable Kinect-based 5STS test to discriminate between fallers and nonfallers and (2) to investigate whether this test can be used for supervised clinical, supervised and unsupervised in home fall risk assessments. METHODS: A total of 94 community-dwelling older adults were assessed by the Kinect-based 5STS test in the laboratory and 20 participants were tested in their own homes. An algorithm was developed to automatically calculate timing- and speed-related measurements from the Kinect based sensor data to discriminate between fallers and nonfallers. The associations of these measurements with standard clinical fall risk tests and the results of supervised and unsupervised in-home assessments were examined. RESULTS: Fallers were significantly slower than nonfallers on Kinect-based measures. The mean velocity of the sit-to-stand transitions discriminated well between the fallers and nonfallers based on 12-month retrospective fall data. The Kinect-based measures collected in the laboratory correlated strongly with those collected in the supervised (r = 0.704-0.832) and unsupervised (r = 0.775-0.931) in-home assessments. CONCLUSION: In summary, we found that the Kinect-based 5STS test discriminated well between the fallers and nonfallers and was feasible to administer in clinical and supervised in-home settings. This test may be useful in clinical settings for identifying high-risk fallers for further intervention or for regular in-home assessments in the future. PMID- 26021782 TI - Marek's disease virus associated ocular lymphoma in Roulroul partridges (Rollulus rouloul). AB - Two 1-year old Roulroul partridges (Rollulus rouloul), one male and one female, were presented because of eye problems and anorexia. Twenty of the 30 Roulroul partridges in the owner's collection had already died. The affected birds stopped eating, became thinner, and eventually died. Antibiotic treatment, which started because of the suspicion of a septicaemic process, was unsuccessful. At clinical examination of the two partridges it was found that in both birds, one eye ball was filled with a whitish yellow amorphous material and the other eye ball of the female showed a distinct corneal opacity. Both presented birds were euthanized. Necropsy revealed no significant abnormalities in addition to the eye lesions. Histology and immunohistochemistry of the female's eye revealed an infiltrate of T-lymphocytes corresponding to ocular lymphoma. Herpesvirus genus-specific PCR, followed by Sanger sequencing confirmed the presumptive diagnosis of Marek's disease in both birds. To our knowledge, this is the first confirmed case of infection with Gallid Herpesvirus 2 (Marek's disease virus) in partridges and the first case in this specific species. PMID- 26021783 TI - The muscle protein synthetic response to food ingestion. AB - Preservation of skeletal muscle mass is of great importance for maintaining both metabolic health and functional capacity. Muscle mass maintenance is regulated by the balance between muscle protein breakdown and synthesis rates. Both muscle protein breakdown and synthesis rates have been shown to be highly responsive to physical activity and food intake. Food intake, and protein ingestion in particular, directly stimulates muscle protein synthesis rates. The postprandial muscle protein synthetic response to feeding is regulated on a number of levels, including dietary protein digestion and amino acid absorption, splanchnic amino acid retention, postprandial insulin release, skeletal muscle tissue perfusion, amino acid uptake by muscle, and intramyocellular signaling. The postprandial muscle protein synthetic response to feeding is blunted in many conditions characterized by skeletal muscle loss, such as aging and muscle disuse. Therefore, it is important to define food characteristics that modulate postprandial muscle protein synthesis. Previous work has shown that the muscle protein synthetic response to feeding can be modulated by changing the amount of protein ingested, the source of dietary protein, as well as the timing of protein consumption. Most of this work has studied the postprandial response to the ingestion of isolated protein sources. Only few studies have investigated the postprandial muscle protein synthetic response to the ingestion of protein dense foods, such as dairy and meat. The current review will focus on the capacity of proteins and protein dense food products to stimulate postprandial muscle protein synthesis and identifies food characteristics that may modulate the anabolic properties. PMID- 26021784 TI - Indocyanine green near-infrared fluorescence in pure laparoscopic living donor hepatectomy: a reliable road map for intra-hepatic ducts? AB - Indocyanine green (ICG) near-infrared (NIR) fluorescence cholangiography (FC) has shown its usefulness to visualize the biliary ducts in open living donor hepatectomy (LDH) to check the intraoperative biliary anatomy. The fully laparoscopic LDH approach has been recently described. However, this procedure is very demanding for a possible misperception of right parenchymal transection line and the cut point of the lobar biliary ducts (BD). To explore the potential of ICG-NIR-FC method we report our experience in 11 fully laparoscopic left LDH using 5 different protocols. Protocol-A, consisted on intravenous (i.v.) ICG injection of 2.5 mg with immediate cut of the BD; -B, same dose and late cut; -C, 1 mg i.v. and late cut; -D, intra-cystic duct injection of 2.5 mg and immediate cut; -E, intra-cystic injection of 5 mg and immediate cut. Protocol-A showed fast fluorescence in the lobar artery and portal vein followed by the BD sheet ; -B showed intraductal excretion with a high parenchymal signal; -C showed a very week signal; -D failed to visualize the ducts; -E showed a good signal without parenchymal fluorescence. ICG-NIR-FC is an additional method to visualize the lobar ducts in fully laparoscopy LDH, but still insufficient for the segmental ducts. PMID- 26021785 TI - Effect of neoadjuvant radiation dose on surgical and oncological outcome in locally advanced esophageal cancer. AB - INTRODUCTION: Neoadjuvant chemoradiation (CRT) confers a survival benefit in locally advanced esophageal cancer. The optimal dose of radiotherapy remains undefined. METHODS: From a prospective database, we identified patients who received CRT followed by Ivor Lewis esophagectomy. Surgical complications, pathological response, and oncological outcome were compared between patients who received a radiotherapy (RT) dose of 36 Gy (group 1) versus a dose of > 40 Gy (group 2). RESULTS: 147 patients were evaluated : 109 received 36 Gy, while 38 received 41-50 Gy. Mean age was 61 +/- 9 years (84% male). Median hospital stay was 16 days. Anastomotic leakage occurred in 4.0%. Pulmonary complications occurred in 41.8%, neither being influenced by RT dose. Complete resection (R0) was achieved in 95% (group 1) and 100% (group 2), P = 0.3. Pathological complete response (pCR) was observed in 19% (group 1) and 37% (group 2), P = 0.04. Local recurrence developed in 9% in group 1, and 3% in group 2 (P = 0.3), but regional recurrence developed significantly higher in the low dose group (28% vs 3%, P < 0.001). Metastatic recurrence occurred in 48% in group 1 and 13% in group 2 (P < 0.001). CONCLUSIONS: In patients with locally advanced esophageal cancer a higher RT dose does not affect surgical outcome, enhances pCR rate, and reduces the locoregional and metastatic recurrence risk. PMID- 26021786 TI - Prevention of Parastomal Hernia Using Pre-peritoneal Mesh - Long Term Outcome of a Prospective Study. AB - BACKGROUND: Parastomal hernia is a frequent complication after stoma formation. The objective of this prospective study was to find long-term outcome of prophylactic mesh placement in the pre-peritoneal space in order to prevent parastomal hernia. METHODS: Patients undergoing elective formation of permanent stoma were included in the study. A polypropylene mesh was placed in the pre peritoneal space without any anchoring stitches and bowel was taken out through a central circular hole made in the mesh. These patients were followed up for 5 years-by clinical examination and CT scan when needed. RESULTS: A total of 42 patients were included in the study. These patients were followed up for a median period of 60 months (range 32-100 months). Twelve patients died before the 5-year follow up due to causes unrelated to stoma. As two patients were unable to be contacted, 28 patients remained in the long-term follow up. Three cases of parastomal hernia were detected after 5 years. None of these patients required repairing of the parastomal hernia. However, a previous study conducted 3 years ago found 4 cases of parastomal hernia that was treated by resiting the stomas. Therefore the total number of parastomal hernia detected in our series is 7 (incidence 25%). CONCLUSIONS: Putting a pre-peritoneal polypropylene mesh is an easy, quick and inexpensive method, and easy to learn. The outcome is better than creating stomas without mesh, but further studies are needed to explore potential benefits of different types of mesh and their methods of positioning and anchoring. PMID- 26021787 TI - The CR-POSSUM Risk Calculator Predicts Failure of Enhanced Recovery after Colorectal Surgery. AB - AIMS: To determine predictors of failed enhanced recovery after surgery (ERAS) in patients after elective colorectal surgery. METHODS: A cohort of 55 patients undergoing elective colorectal surgery was monitored prospectively. Perioperative care was based on a previously established protocol for ERAS. Pre-, intra-, and postoperative parameters were analyzed to elicit predictors of ERAS failure. ERAS failure was defined as prolonged hospital stay (> 7 days). The risk calculator CR POSSUM was evaluated for its clinical utility. RESULTS: Body mass index (BMI) or the American Society of Anesthesiologists score (ASA) was not associated with ERAS failure on univariate analysis, but patients that failed ERAS were significantly older (64 y vs 54 y ; p = 0.023). Prolonged length of stay (> 7 days) was also associated with an open approach (p = 0.009), intraoperative nasogastric tube placement (p = 0.005), blood loss > 500 ml (p = 0.008), stoma formation (p = 0.006) and insertion of more than one intraabdominal drain during surgery (p = 0.005). Postoperative continuation of intravenous fluids (p = 0.027), reinsertion of urinary catheter (p = 0.045) and postoperative ileus (p = 0.020) were also strongly associated with delayed discharge on univariate analysis. After multivariate analysis the preoperative parameters CR-POSSUM score (p = 0.022), increasing BMI (p = 0.014) and preoperative albumin level (p = 0.031) were all independently associated with failure of ERAS. CONCLUSIONS: A variety of perioperative factors contribute to failure of ERAS in routine practice. CR-POSSUM can help to identify patients at risk for possible failure of ERAS. This may help to optimize avoidable factors, or accommodate those patients likely to require a longer post-operative stay. PMID- 26021788 TI - Comparison of predictive factors for the diagnosis and clinical course of phyllodes tumours of the breast. AB - BACKGROUND: To compare predicting factors for the diagnosis and clinical course of benign and malign/ borderline phyllodes tumours (PT) of the breast, and to discuss treatment modalities. METHODS: Clinical and demographic characteristics of the patients with histopathological diagnosis of phyllodes tumour were examined. Patients were divided into group 1 (benign PT) and group 2 (borderline/malignant PT). Groups were compared in terms of demographic and clinical characteristics. RESULTS: Of the patients studied, 37 (68.5%) had benign, 7 (12.9%) had borderline and 10 (18.5) had malignant histopathology. A statistically significant relationship was detected between the incidence of malignancy and mass diameter (p = 0.001) and age (p = 0.030) when the two groups were compared. Wide surgical excision was performed on 46 (82.5%) patients, simple mastectomy on 7 (13%) patients and modified radical mastectomy on one (1.9%) patient. Ten (18.5%) patients were re-operated for surgical margin positivity. Local recurrence was determined only in one (1.9%) patient. Distant metastasis due to malignant PT developed in two (3.7%) patients. CONCLUSIONS: Among the patients who were considered to have PT, malignancy was likely to be present, especially if the patient's age was over 40 and the diameter of the mass was above 33.5 mm. Therefore, in patients with similar characteristics, surgical margins should be kept slightly wider or wider excisions should be preferred with or without simultaneous reconstructive surgery in appropriate cases. PMID- 26021789 TI - Oncological and surgical outcome after oncoplastic breast surgery. AB - BACKGROUND: Oncoplastic surgery combines breast-conserving treatment and plastic surgery techniques. The aim of the study was to identify breast and tumor-related characteristics that contribute to the rate of complications and recurrence. METHODS: This retrospective study included 72 patients with a median follow-up of 32 months. For each patient, a comprehensive set of data was collected, including epidemiology, tumor characteristics, preoperative information, detailed pathology reports, radiotherapy treatment and type of surgical technique. The rate of complications, recurrence and survival were studied. RESULTS: Complete tumor removal was performed with clear margins in all patients but in 25 of them margins were less than 2 mm. One patient had local recurrence and another developed distant metastases. The study showed that the size of the margin was not predictive of recurrence as long as not positive; the greater the resection volume, the larger the excision margin. The resection size was the only factor influencing complications and no specific tumor-related factor significantly increased the complication rate. Surgical complications did not delay the initiation of chemotherapy and radiotherapy. CONCLUSIONS: This is the first oncoplastic study where both tumor and breast characteristics were analyzed using the most recent criteria of the literature. Oncoplastic surgery can be considered as oncologically safe. The resection size was the sole significant risk factor for postoperative complications. Complications after oncoplastic breast surgery did not differ neoadjuvant therapy. Long-term event-free survival was excellent (96% at 7 years). PMID- 26021790 TI - Impact of Anxiety in Ambulatory Superficial Venous Surgery : A Prospective Study Using the HADS-A Scale. AB - BACKGROUND: The aim of the present prospective clinical study is to evaluate the impact of the level of anxiety in patients undergoing ambulatory superficial venous surgery (SVS) and to select a specific group of patients who need more of our attention to reduce the postoperative adverse events. METHODS: Preoperative anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS), especially the HADS-A (Anxiety subscale) in 340 consecutive patients undergoing elective SVS. Venous disease was assessed in all patients according to the established CEAP classification, the Venous Clinical Severity and the Venous Disability scores. RESULTS: According to the HADS-A scores, we could distinguish two groups of patients, with (group A with score >= 8; 61 patients) and without potential anxious state (group B with score <= 7; 279 patients). Demographic data, varicose veins risk factors and preoperative symptoms were comparable in both groups. The median HADS-A score was 9 (8-17; IQR: 2) in group A and 3 (0-7; IQR: 3) in group B. The rate of complications or adverse events in the recovery room, the mean postoperative pain scores, the apprehension before discharge hospital and the incidence of unexpected hospitalisation rate were significantly higher in group A when compared with group B. CONCLUSIONS: We observed that the presence of preoperative anxiety, even although infrequent, was associated with high incidence of complications or adverse events in the recovery room and a greater postoperative pain level. In this context, this group of patients needs more of our attention, particularly to limit potential anxiety and improve their satisfaction score. PMID- 26021791 TI - Small bowel intussusception caused by multiple intestinal metastases from a giant cell carcinoma of the lung: a case report. AB - Small bowel obstruction (SBO) due to intussusception in adults is a rare condition. Diagnosis at the time of admission is usually challenging. More often than not, a bowel intussusception in adults is secondary to an organic condition, frequently malignancies. Therefore, a surgical approach is indicated most of the times. We report the case of a forty-nine years old lady presenting with a SBO secondary to small bowel metastases with two ileo-ileal intussusceptions, one of which was missed at initial surgical exploration. A giant cell carcinoma of the lung (GCCL) with small bowel metastases was diagnosed subsequently. The case is presented as well as a brief review of literature. PMID- 26021792 TI - Single-centre 20-year experience with surgical treatment of thymic tumours. AB - BACKGROUND: Large single-centre institutional series on thymic tumours are rare. Complete resection remains the mainstay of successful treatment. Characteristics and survival were reviewed in all patients treated between 1993-2013. METHODS: Hospital databases revealed 134 patients with pathologically-proven thymic tumour. Follow-up (median 63 months) was through patient notes and telephone contact with general practitioner. RESULTS: Patients were classified in Masaoka Koga stages: I: 50 (37%); IIa: 14 (10%); IIb: 14 (10%); III: 27 (20%); IVa: 19 (14%); IVb: 4 (3%); unknown: 6 (5%). According to WHO classification, pathological subtypes were A: 19 (14%); AB: 25 (19%); B1: 21 (16%); B2: 31 (23%); B3: 15 (11%); thymic carcinoma: 23 (17%). Parathymic syndromes were diagnosed in 45 patients : myasthenia gravis (84%); pure red-cell aplasia (4%); hypogammaglobulinemia (2%); and others. 124 patients (93%) underwent surgery with complete resection in 104 (84%). Surgical approach was: sternotomy: 79; thoracotomy: 35; cervicotomy: 2; other/unknown: 8. In 73 patients (59%) no biopsy was taken prior to surgical resection, 25 were treated with induction chemotherapy, 36 received adjuvant radiotherapy. Hospital mortality was 0.81%. 35 patients died during follow-up (13 of tumour or treatment-related causes). Overall and recurrence-free survival at 5, 10, and 15 years were 86%; 64%; 47% and 67%; 49%; and 31%, respectively and were significantly (p < 0.01) different according to Masaoka-Koga stage. There was a significant association between WHO classification and Masaoka-Koga stages I-IIa-IIb versus III-IVa-IVb (p < 0.01). CONCLUSIONS: Operability and complete resectability of thymic tumours in our experience is high resulting in prolonged overall and recurrence-free survival. Masaoka-Koga stage is an important predictor for survival and shows a significant association with WHO classification. PMID- 26021793 TI - Survival and prognostic factors of anaplastic thyroid carcinoma. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC) is relatively rare and represents one of the most aggressive tumours with poor prognosis, despite therapy. The aim of the study was to analyse demographic and clinical characteristics of ATC patients, and to identify survival rates and prognostic factors. METHODS: In a retrospective study (1995-2005) ATC was found in 150 patients treated at our institution. Survival was calculated by Kaplan-Meier curve and log-rank test. Potential prognostic factors affecting survival were compared by Cox univariate and multivariate analyses. RESULTS: Mean survival time was 56 weeks; median survival time was 16 weeks and 1 and 5-year survival were 17% and 8%. More than 10% died during the first month and 50% died up to the fourth month. Multivariate analysis showed that age, goitre and surgery were independent prognostic factors of survival in all ATC patients. Among operated patients, the extent of tumour resection, distant metastasis and multicentricity were independent prognostic risk factors of survival. Postoperative radiotherapy was a protective factor. CONCLUSIONS: There is still no successful treatment of ATC that can guarantee long term survival. Younger patients with pre-existing goitre, who undergo complete resection of unilocular early stage ATC without distant metastasis and with postoperative external radiotherapy, stand a better chance of long-term survival. PMID- 26021794 TI - The Development of an Electronic Portfolio for Postgraduate Surgical Training in Flanders. AB - BACKGROUND: Contemporary surgical postgraduate training is characterized by clear outcomes for the profession and an assessment program that shows that trainees master these outcomes. The tool used to collect assessment and feedback instruments is the portfolio, nowadays used in many countries worldwide. METHODS: The four Flemish surgical coordinators, together with experts from different universities, devised an electronic portfolio. This portfolio holds both the logbook, as imposed by the evaluation committee and assessment instruments used for the Master in Specialized Medicine. RESULTS: The e-portfolio is now used by a number of surgical trainees and has been approved by the evaluation committee. In 2015, all Flemish surgical trainees will be using one and the same e-portfolio. CONCLUSIONS: Although the e-portfolio for surgical training has now been devised and accepted by all major parties involved, a lot of work has to be done to implement the instrument. As resident duty hours show no improvement on education in surgery (but rather a perception of worsened education) surgery training is fazing huge challenges. PMID- 26021795 TI - Hydronephrosis in acute uncomplicated appendicitis. AB - BACKGROUND: Right-sided hydronephrosis as a sign of appendicitis occurs rarely in the literature. To our knowledge, this is the first published account of the occurrence of right-sided hydronephrosis as a result of uncomplicated appendicitis. CASE DESCRIPTION: We describe a 15 year old patient referred to the emergency department with suspected appendicitis. Additional ultrasound examination showed a right-sided hydronephrosis. This finding was discussed with the urologist who noted the hydronephrosis as a chance finding. Because of persistent clinical suspicion of appendicitis, a diagnostic laparoscopy was performed. A retrocaecal appendicitis with secondary hydronephrosis was found. CONCLUSIONS: Right-sided hydronephrosis may be a sign of acute uncomplicated (retrocaecal) appendicitis. It is important to keep sight of these findings, especially in view of the emphasis on imaging techniques in the current Dutch guideline on appendicitis. PMID- 26021796 TI - Conservative treatment of spontaneous dissection of the subclavian artery. AB - Dissection of the subclavian artery usually occurs as a result of trauma, endovascular interventions or connective tissue disorders. Only rarely has it been described occurring spontaneously. The treatment can be endovascular, open surgery, conservative or a combination of the above. There are no guidelines. The best approach is the one tailored to the lesion itself. This case presents a 73 year-old man with a tiresome and heavy feeling in the right arm. He was diagnosed having a spontaneous dissection of the right subclavian artery, accompanied by a complete occlusion more distally. Because of the relatively minor symptoms he was treated conservatively using anticoagulants. After 6 months of treatment there was complete revascularisation with good pulsations at the right wrist. PMID- 26021797 TI - Gastric bypass for morbid obesity in a patient with situs inversus totalis. AB - The aim of this case report is to outline the challenge and the feasibility of laparoscopic gastric bypass in a patient with situs inversus totalis. Situs inversus totalis does not seem to be a contraindication for laparoscopic surgery. PMID- 26021798 TI - Possible familial presentation in two siblings with carotid fibromuscular dysplasia. AB - Fibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflammatory vascular disease which can affect the cervical, renal and visceral arteries. Here we report on two sisters diagnosed with carotid FMD at the same age, presenting with similar symptoms of pulsating tinnitus. The familial presentation of this rare disorder attracted our attention and was suggestive of a genetic etiology. Conservative treatment with aspirin was initiated. Carotid FMD is a rare disorder of which the exact pathophysiology is not known. A review of the literature on the clinical presentation, diagnosis and management is presented. In addition possible etiological factors and the genetic nature of the disease are discussed. PMID- 26021799 TI - Postradiation dermatofibrosarcoma protuberans : case report and literature review. AB - Radiotherapy has long been known to induce soft tissue sarcomas. However, there are only six cases of postradiation dermatofibrosarcoma protuberans (DFSP) reported in the literature, and no case in Asians has been reported so far. Herein, we report a case of DFSP, confirmed by immunohistochemistry, which developed on the old scar at the irradiated right chest wall of an Asian woman. We performed a radical surgical excision of the lesion and covered the defect with latissimus dorsi island myocutaneous flap followed the surgical treatment. 12 months postoperatively, the patient leads a good result without signs of recurrence. PMID- 26021800 TI - Vesalius' experience with aortic aneurysms. PMID- 26021801 TI - Leiomyosarcoma of the Inferior Vena Cava Level II Including Both Renal Veins : Surgical Approach. AB - A 66 years old male developping an acute lower right limb oedema due to an extended venous thrombosis of the common femoral and iliac veins was diagnosed to have a leiomyosarcoma of the inferior vena cava (IVC) involving both renal veins. The characteristics and management of this level II IVC leiomyosarcoma are discussed with particular attention to the renal vein reconstruction and neo adjuvant therapy. PMID- 26021802 TI - Statins for Treating Alzheimer's Disease: Truly Ineffective? AB - BACKGROUND: Animal studies suggest that statins may have a protective effect on Alzheimer's disease (AD), but some clinical trials have reported negative results. OBJECTIVE: To evaluate the efficacy and safety of statins in the treatment of AD. METHODS: We searched the PubMed, Cochrane Library, EMBASE, OVID SP, and ProQuest databases to select double-blind, randomized controlled trials pertaining to statins given to patients diagnosed with AD. The meta-analysis used main outcomes such as scores on the Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale (ADAS-Cog) and secondary outcomes such as scores on the Dependence Scale, Activities of Daily Living Scale (ADCS-ADL), Neuropsychiatric Inventory (NPI), Clinical Global Impression of Change (CGIC), and Alzheimer's Disease Functional Assessment and Change Scale (ADFACS). Safety measures included the standard reporting of any adverse events or laboratory abnormalities. RESULTS: Four studies (1,127 participants) involving patients with a diagnosis of probable or possible AD were included. There were no significant differences between the statins and placebo groups regarding the main outcomes, secondary outcomes, or adverse events. Most of the studies ignored or downplayed risk factors for cerebral vascular disease. CONCLUSION: Statins are well tolerated without unexpected adverse events. However, more research is needed to determine whether statins are effective for AD with vascular risk factors. PMID- 26021803 TI - Evidence for TLR4 and FcRgamma-CARD9 activation by cholera toxin B subunit and its direct bindings to TREM2 and LMIR5 receptors. AB - Cholera toxin (CTX) is a virulent factor of Vibrio cholerae that causes life threatening diarrheal disease. Its non-toxic subunit CTB has been extensively studied for vaccine delivery. In immune cells, CTB induces a number of signaling molecules related to cellular activation and cytokine production. The mechanisms by which CTB exerts its immunological effects are not understood. We report here the immunological targets of CTB. The unexpected finding that GM1 ganglioside inhibited NF-kappaB activation in human monocytes stimulated with CTX and agonists of Toll-like receptors (TLR) suggests the possibility of CTX-TLR interaction. Indeed, CTX-induced IL-6 production was substantially reduced in MyD88(-/-) or TLR4(-/-) macrophages. Ectopic expression of TLR4 was required for CTX-induced NF-kappaB activation in HEK 293 cells. Furthermore, the inflammatory capacity of CTB was lost in the absence of TLR4, adaptor protein FcRgamma, or its downstream signaling molecule CARD9. Attempts have been made to identify CTB binding targets from various C-type lectin and immunoglobulin-like receptors. CTB targeted not only GM1 and TLR4 but also TREM2 and LMIR5/CD300b. CTB-TREM2 interaction initiated signal transduction through adaptor protein DAP12. The binding of CTB inhibited LMIR5 activation induced by its endogenous ligand 3-O sulfo-beta-d-galactosylceramide C24:1. In summary, CTB targets TLR4, FcRgamma CARD9, TREM2, and LMIR5. These findings provide new insights into the immunobiology of cholera toxin. PMID- 26021804 TI - IFN-gamma differentially regulates subsets of Gr-1(+)CD11b(+) myeloid cells in chronic inflammation. AB - During chronic inflammation, prolonged over-reactive immune response may lead to tissue destruction, while immune suppression hinders tissue repair and pathogen elimination. Therefore, precise regulation of the immune response is needed to avoid immuno-pathology. Interferon-gamma (IFN-gamma) is widely used in clinical treatment of inflammatory diseases. However, the underlying mechanism remains unclear. Here, we evaluated the role of IFN-gamma on CD11b(+)Gr-1(+) myeloid cell differentiation and function, using a heat-killed Mycobacterium bovis BCG-induced chronic inflammation model. After challenge with heat-killed BCG, two subpopulations of CD11b(+)Gr-1(+) myeloid cells were generated in the mouse spleen. Phenotypical, morphological and functional analysis indicated that the CD11b(+)Gr-1(high) Ly6G(high) Ly6C(low) subset was neutrophil-like myeloid derived inducer cells (N-MDICs), which promoted T cell activation, while the other subset was CD11b(+)Gr-1(low) Ly6G(neg) Ly6C(high) monocyte-like myeloid derived suppressor cells (M-MDSCs) that displayed extensive suppressor function. IFN-gamma treatment dampened N-MDICs-mediated T cell activation through up regulating T cell suppressive mediators, reactive oxygen species (ROS) and arginase I. While for M-MDSCs, IFN-gamma reduced their suppressing activity by decreasing the arginase activity. Our study provides evidence that IFN-gamma balances the over-reactive vs compromised immune response through different regulation of distinct myeloid subsets, and therefore displays significant therapeutic potential for effective immuno-therapy of chronic inflammatory diseases. PMID- 26021805 TI - Dyadic co-regulation, affective intensity and infant's development at 12 months: A comparison among extremely preterm and full-term dyads. AB - Extremely low gestational age children (ELGA, born below 28 weeks of GA) represent the most at-risk preterm group in terms of survival, developmental sequelae and rates of impairment and cognitive delays. However, the impact of an extremely preterm birth on mother-infant co-regulation and affective intensity which may affect early infant's development has not been investigated. Based on a relational dynamic system approach, our study aimed to investigate the quality of co-regulation and affective intensity during spontaneous play interaction in 20 mother-infant ELGA dyads compared to 20 full-term (FT) dyads at 12 months (corrected age for ELGA infants). Relationships between the quality of dyadic co regulation and the infant's level of cognitive, motor and language development were also investigated. The quality of dyadic co-regulation was assessed using the Revised Relational Coding System (R-RCS) by Fogel et al. (2003), the mothers' and infants' affective intensity was coded using a coding system by Lunkenheimer, Olson, Hollenstein, Sameroff, and Winter (2011). Infants' development was assessed using the Bayley Scales (BSID-III, 2006). With respect to FT dyads, ELGA dyads were characterised by less frequent symmetric and more frequent unilateral co-regulation patterns and by less positive and more neutral affective intensity of both infants and mothers. Cognitive, motor and language scores were lower in ELGA infants than in FT infants. Symmetrical co-regulation was related to motor scores in ELGA infants, and to cognitive scores in FT infants. Our findings contribute to the literature by demonstrating the difficulties of ELGA mother infant dyads at 12 months in sharing the symmetric co-regulation and positive affective intensity and how symmetric co-regulation is strictly related to motor development in ELGA infants. Based on these findings, intervention programmes to foster joint attention, active involvement and positive affective intensity in ELGA dyads and infants' development in the first year of life should be designed. PMID- 26021806 TI - A cross-cultural comparison of tonal synchrony and pitch imitation in the vocal dialogs of Belgian Flemish-speaking and Mexican Spanish-speaking mother-infant dyads. AB - This study reports a cross-cultural comparison of the vocal pitch patterns of 15 Mexican Spanish-speaking and 15 Belgian Flemish-speaking dyads, recorded during 5min of free-play in a laboratory setting. Both cultures have a tradition of dyadic face-to-face interaction but differ in language origins (i.e., Romanic versus Germanic). In total, 374 Mexican and 558 Flemish vocal exchanges were identified, analyzed and compared for their incidence of tonal synchrony (harmonic/pentatonic series), non-tonal synchrony (with/without imitations) and pitch and/or interval imitations. The main findings revealed that dyads in both cultures rely on tonal synchrony using similar pitch ratios and timing patterns. However, there were significant differences in the infants' vocal pitch imitation behavior. Additional video-analyzes on the contingency patterns involved in pitch imitation showed a cross-cultural difference in the maternal selective reinforcement of pitch imitation. The results are interpreted with regard to linguistic, developmental and cultural aspects and the 'musilanguage' model. PMID- 26021808 TI - TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis. AB - Quiescent phases of inflammatory bowel disease (IBD) are often accompanied by chronic abdominal pain. Although the transient receptor potential vanilloid 1 (TRPV1) ion channel has been postulated as an important mediator of visceral hypersensitivity, its functional role in postinflammatory pain remains elusive. This study aimed at establishing the role of TRPV1 in the peripheral sensitization underlying chronic visceral pain in the context of colitis. Wild type and TRPV1-deficient mice were separated into three groups (control, acute colitis, and recovery), and experimental colitis was induced by oral administration of dextran sulfate sodium (DSS). Recovery mice showed increased chemically and mechanically evoked visceral hypersensitivity 5 wk post-DSS discontinuation, at which point inflammation had completely resolved. Significant changes in nonevoked pain-related behaviors could also be observed in these animals, indicative of persistent discomfort. These behavioral changes correlated with elevated colonic levels of substance P (SP) and TRPV1 in recovery mice, thus leading to the hypothesis that SP could sensitize TRPV1 function. In vitro experiments revealed that prolonged exposure to SP could indeed sensitize capsaicin-evoked currents in both cultured neurons and TRPV1-transfected human embryonic kidney (HEK) cells, a mechanism that involved TRPV1 ubiquitination and subsequent accumulation at the plasma membrane. Importantly, although TRPV1 deficient animals experienced similar disease severity and pain as wild-type mice in the acute phase of colitis, TRPV1 deletion prevented the development of postinflammatory visceral hypersensitivity and pain-associated behaviors. Collectively, our results suggest that chronic exposure of colon-innervating primary afferents to SP could sensitize TRPV1 and thus participate in the establishment of persistent abdominal pain following acute inflammation. PMID- 26021809 TI - Sporotrichoid lesions: an age-old conundrum. PMID- 26021807 TI - Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention. AB - Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective preventive strategies aimed at inhibiting the development and progression of CRC is critical for reducing the incidence and mortality of this malignancy. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase 2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action. This review will discuss the molecular mechanisms being studied for the CRC chemopreventive activity of NSAIDs (i.e., aspirin, sulindac, and ibuprofen), COX-2 inhibitors (i.e., celecoxib), natural products (i.e., curcumin, resveratrol, EGCG, genistein, and baicalein), and metformin. A deeper understanding of how these anti-inflammatory agents inhibit CRC will provide insight into the development of potentially safer and more effective chemopreventive drugs. PMID- 26021810 TI - Pulmonary Langerhans cell histiocytosis with systemic features. PMID- 26021811 TI - Not Necessarily a Myocardial Infarction: New Left Bundle Branch Block. PMID- 26021812 TI - Resistant hypertension. PMID- 26021813 TI - From polyuria to renal mass: an unexpected link. PMID- 26021814 TI - Repealed and replaced: SGR gives way to value-based Medicare payment reform. PMID- 26021815 TI - Fool me once, fool me twice: hypertrophic cardiomyopathy with aortic stenosis. PMID- 26021817 TI - The effect of a patellar strap on knee joint proprioception in healthy participants and athletes with patellar tendinopathy. AB - OBJECTIVES: The primary aim of this study is to investigate the effect of the use of a patellar strap on knee joint proprioception in both healthy participants and in patients with patellar tendinopathy (PT). Secondary aims are to examine whether there is a difference in effectiveness of the use of a patellar strap between participants with low and high proprioceptive acuity and if possible predictors of effectiveness can be determined. DESIGN: Case-control. METHODS: The threshold to detect passive motion with and without a patellar strap was assessed in 22 healthy participants and 21 unilateral PT patients. RESULTS: The results from the mixed model analysis show that in both groups of participants a small but statistically significant improvement in proprioception was found, primarily in those who had low proprioceptive acuity. A notable finding was that in the symptomatic leg of the PT group no improvement in proprioception by wearing a strap could be determined. Male gender and having fewer symptoms were possible predictors of effectiveness in PT patients. CONCLUSIONS: As proprioception plays a role in optimising movements and reducing load to joint-related structures like tendons and ligaments, it is considered an important protection mechanism. Although the improvements in proprioception as a result of wearing the strap are small, it might be that the use of a patellar strap can potentially play a role in injury prevention since poor proprioception can be a risk factor for (re) injury. PMID- 26021816 TI - Histone modifications change with age, dietary restriction and rapamycin treatment in mouse brain. AB - The risk of developing neurodegenerative disorders such as Alzheimer's disease (AD) increases dramatically with age. Understanding the underlying mechanisms of brain aging is crucial for developing preventative and/or therapeutic approaches for age-associated neurological diseases. Recently, it has been suggested that epigenetic factors, such as histone modifications, maybe be involved in brain aging and age-related neurodegenerations. In this study, we investigated 14 histone modifications in brains of a cohort of young (3 months), old (22 months), and old age-matched dietary restricted (DR) and rapamycin treated BALB/c mice. Results showed that 7 out of all measured histone markers were changed drastically with age. Intriguingly, histone methylations in brain tissues, including H3K27me3, H3R2me2, H3K79me3 and H4K20me2 tend to disappear with age but can be partially restored by both DR and rapamycin treatment. However, both DR and rapamycin treatment also have a significant impact on several other histone modifications such as H3K27ac, H4K16ac, H4R3me2, and H3K56ac, which do not change as animal ages. This study provides the first evidence that a broad spectrum of histone modifications may be involved in brain aging. Besides, this study suggests that both DR and rapamycin may slow aging process in mouse brain via these underlying epigenetic mechanisms. PMID- 26021818 TI - In vitro effect of ursolic acid on the inhibition of Mycobacterium tuberculosis and its cell wall mycolic acid. AB - Mycobacterium tuberculosis is a dangerous intracellular pathogen. In order to protect against mycobacterium infection, novel agents with anti-mycobacterial activity should be given emergency priority for evaluation. Ursolic acid (UA), a plant triterpenoid, shows promising bioactivities, including anti-mycobacterial potency. In this study, the action of UA against Mycobacterium tuberculosis H37Ra was evaluated, and the inhibitory concentration was found to range between 10 and 20 MUg/ml in a resazurin assay and MGIT 960 instrument. The total mycolic acid in UA-treated H37Ra was detected and compared with INH-treated and non-treated bacterium by LC-MS/MS. Quantitative LC-MS/MS data confirmed that both UA and INH decreased mycolic acid biosynthesis in a dose-dependent manner. Thin-layer chromatogram (TLC) analysis showed that all mycolic acid subtypes were affected by UA treatment in the wild type but not in strains resistant to UA. Electron microscopy images also confirmed that UA treatment affected both H37Ra cell and intracellular content of H37Ra. Altogether, these data confirmed the promise of the inhibitory action of UA in mycolic acid, which might further delineate the mechanistic pathway of mycobacterial inhibition by UA. PMID- 26021819 TI - Non-labile silver species in biosolids remain stable throughout 50 years of weathering and ageing. AB - Increasing commercial use of nanosilver has focussed attention on the fate of silver (Ag) in the wastewater release pathway. This paper reports the speciation and lability of Ag in archived, stockpiled, and contemporary biosolids from the UK, USA and Australia, and indicates that biosolids Ag concentrations have decreased significantly over recent decades. XANES revealed the importance of reduced-sulfur binding environments for Ag speciation in materials ranging from freshly produced sludge to biosolids weathered under ambient environmental conditions for more than 50 years. Isotopic dilution with (110 m)Ag showed that Ag was predominantly non-labile in both fresh and aged biosolids (13.7% mean lability), with E-values ranging from 0.3 to 60 mg/kg and 5 mM CaNO3 extractable Ag from 1.2 to 609 MUg/kg (0.002-3.4% of the total Ag). This study indicates that at the time of soil application, biosolids Ag will be predominantly Ag-sulfides and characterised by low isotopic lability. PMID- 26021820 TI - Dermato-protective properties of ergothioneine through induction of Nrf2/ARE mediated antioxidant genes in UVA-irradiated Human keratinocytes. AB - UVA irradiation-induced skin damage and redox imbalance have been shown to be ameliorated by ergothioneine (EGT), a naturally occurring sulfur-containing amino acid. However, the responsible molecular mechanism with nanomolar concentrations of EGT remains unclear. We investigated the dermato protective efficacies of EGT (125-500nM) against UVA irradiation (15J/cm(2)), and elucidated the underlying molecular mechanism in human keratinocyte-derived HaCaT cells. We found that EGT treatment prior to UVA exposure significantly increased the cell viability and prevented lactate dehydrogenase release into the medium. UVA-induced ROS and comet-like DNA formation were remarkably suppressed by EGT with a parallel inhibition of apoptosis, as evidenced by reduced DNA fragmentation (TUNEL), caspase-9/-3 activation, and Bcl-2/Bax dysregulation. Furthermore, EGT alleviated UVA-induced mitochondrial dysfunction. Dose-dependent increases of antioxidant genes, HO-1, NQO-1, and gamma-GCLC and glutathione by EGT were associated with upregulated Nrf2 and downregulated Keap-1 expressions. This was confirmed by increased nuclear accumulation of Nrf2 and inhibition of Nrf2 degradation. Notably, augmented luciferase activity of ARE may explain Nrf2/ARE-mediated signaling pathways behind EGT dermato-protective properties. We further demonstrated that Nrf2 translocation was mediated by PI3K/AKT, PKC, or ROS signaling cascades. This phenomenon was confirmed with suppressed nuclear Nrf2 activation, and consequently diminished antioxidant genes in cells treated with respective pharmacological inhibitors (LY294002, GF109203X, and N acetylcysteine). Besides, increased basal ROS by EGT appears to be crucial for triggering the Nrf2/ARE signaling pathways. Silencing of Nrf2 or OCTN1 (EGT carrier protein) signaling with siRNA showed no such protective effects of EGT against UVA-induced cell death, ROS, and apoptosis, which is evidence of the vitality of Nrf2 translocation and protective efficacy of EGT in keratinocytes. Our findings conclude that EGT at nanomolar concentrations effectively ameliorated UVA-induced skin damage, and may be considered as a desirable food supplement for skin protection and/or preparation of skin care products. PMID- 26021821 TI - Glucagon induces airway smooth muscle relaxation by nitric oxide and prostaglandin E2. AB - Glucagon is a hyperglycemic pancreatic hormone that has been shown to provide a beneficial effect against asthmatic bronchospasm. We investigated the role of this hormone on airway smooth muscle contraction and lung inflammation using both in vitro and in vivo approaches. The action of glucagon on mouse cholinergic tracheal contraction was studied in a conventional organ bath system, and its effect on airway obstruction was also investigated using the whole-body pletysmographic technique in mice. We also tested the effect of glucagon on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and inflammation. The expression of glucagon receptor (GcgR), CREB, phospho-CREB, nitric oxide synthase (NOS)-3, pNOS-3 and cyclooxygenase (COX)-1 was evaluated by western blot, while prostaglandin E2 (PGE2) and tumour necrosis factor-alpha were quantified by enzyme-linked immunoassay and ELISA respectively. Glucagon partially inhibited carbachol-induced tracheal contraction in a mechanism clearly sensitive to des-His1-[Glu9]-glucagon amide, a GcgR antagonist. Remarkably, GcgR was more expressed in the lung and trachea with intact epithelium than in the epithelium-denuded trachea. In addition, the glucagon-mediated impairment of carbachol-induced contraction was prevented by either removing epithelial cells or blocking NOS (L-NAME), COX (indomethacin) or COX-1 (SC-560). In contrast, inhibitors of either heme oxygenase or COX-2 were inactive. Intranasal instillation of glucagon inhibited methacholine-induced airway obstruction by a mechanism sensitive to pretreatment with L-NAME, indomethacin and SC-560. Glucagon induced CREB and NOS-3 phosphorylation and increased PGE2 levels in the lung tissue without altering COX-1 expression. Glucagon also inhibited LPS induced AHR and bronchoalveolar inflammation. These findings suggest that glucagon possesses airway-relaxing properties that are mediated by epithelium-NOS 3-NO- and COX-1-PGE2-dependent mechanisms. PMID- 26021822 TI - US guideline may have led to drop in PSA testing among primary care physicians, studies find. PMID- 26021823 TI - Nanotechnology in respiratory medicine. AB - Like two sides of the same coin, nanotechnology can be both boon and bane for respiratory medicine. Nanomaterials open new ways in diagnostics and treatment of lung diseases. Nanoparticle based drug delivery systems can help against diseases such as lung cancer, tuberculosis, and pulmonary fibrosis. Moreover, nanoparticles can be loaded with DNA and act as vectors for gene therapy in diseases like cystic fibrosis. Even lung diagnostics with computer tomography (CT) or magnetic resonance imaging (MRI) profits from new nanoparticle based contrast agents. However, the risks of nanotechnology also have to be taken into consideration as engineered nanomaterials resemble natural fine dusts and fibers, which are known to be harmful for the respiratory system in many cases. Recent studies have shown that nanoparticles in the respiratory tract can influence the immune system, can create oxidative stress and even cause genotoxicity. Another important aspect to assess the safety of nanotechnology based products is the absorption of nanoparticles. It was demonstrated that the amount of pulmonary nanoparticle uptake not only depends on physical and chemical nanoparticle characteristics but also on the health status of the organism. The huge diversity in nanotechnology could revolutionize medicine but makes safety assessment a challenging task. PMID- 26021824 TI - Postoperative Pain Management after Radical Cystectomy: Comparing Traditional versus Enhanced Recovery Protocol Pathway. AB - PURPOSE: Opioids have traditionally been the mainstay of pain management after radical cystectomy for bladder cancer but they have many side effects. The efficacy of opioid sparing analgesics after cystectomy as part of a protocol of enhanced recovery after surgery has yet to be proved. We compared opioid use, pain score and postoperative ileus in consecutive patients on a protocol of enhanced recovery after surgery and those on a traditional protocol after radical cystectomy. MATERIALS AND METHODS: Using our institutional review board approved bladder cancer database we retrospectively reviewed the records of patients who underwent open radical cystectomy using a traditional protocol or a protocol of enhanced recovery after surgery for pain management. A total of 205 patients were ultimately enrolled in study, including 81 on a traditional protocol and 124 on the enhanced protocol. Opioid use and pain scores were analyzed and compared up to postoperative day 4. All routes of opioid use were recorded and converted to the morphine equivalent dose for comparison. Postoperative pain was recorded using a visual analog scale. Postoperative records were reviewed for the incidence of ileus. RESULTS: Patients on the enhanced recovery after surgery protocol and those on a traditional protocol were similar demographically. When analyzing data up to the median hospital stay on the case group, patients on enhanced recovery used significantly less opioids per day (4.9 mg vs 20.67 mg morphine equivalents, p <0.001) and reported more pain (visual analog scale 3.1 vs 1.14, p <0.001). They also experienced a significantly lesser incidence of postoperative ileus (7.3% vs 22.2%, p = 0.003) and had a significantly shorter median length of hospital stay (4 vs 8 days, p <0.001). CONCLUSIONS: Patients on the protocol of enhanced recovery after surgery used significantly less opioid analgesics, possibly contributing to decreased postoperative ileus and shorter length of hospital stay. PMID- 26021825 TI - TLR1 expression in mouse brain was increased in a KA-induced seizure model. AB - OBJECTIVE: Toll-like receptors (TLRs) that mediate inflammatory responses play an important role in epilepsy; however, whether TLR1 is also involved in epileptogenesis remains unclear. Thus, in this study, we investigated the extent and pattern of TLR1 expression in epileptic tissues. METHODS: One-hundred and thirty-two mice were intra-cerebroventricularly injected with PBS or kainic acid (KA) and were examined at 1, 3, 8 and 24 h. The expression pattern and distribution of TLR1 were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry staining. RESULTS: The mRNA and protein levels of TLR1 were significantly upregulated in the hippocampus and temporal cortex of epileptic mice compared with those of controls. TLR1 expression was increased as early as 1 h following KA treatment and peaked at 8 and 24 h. Immunohistochemistry staining demonstrated that TLR1 was distributed in the CA1-3, dentate gyrus and hilus regions of the hippocampus and different cortical regions. Immunofluorescent staining further revealed that TLR1 was primarily expressed in the neurons, microglia, and astrocytes of epileptogenic tissue. SIGNIFICANCE: These results demonstrate that cortical and hippocampal sub-regional expression of TLR1 is altered during epileptogenesis in a time- and location-specific manner, suggesting a close association with the process of epilepsy. PMID- 26021826 TI - Frontal recess anatomy in Japanese subjects and its effect on the development of frontal sinusitis: computed tomography analysis. AB - BACKGROUND: Comprehensive understanding of frontal recess anatomy is essential for the successful treatment of patients with frontal sinus disease. This study was designed to determine the prevalence of specific frontal recess cells in Japanese subjects and the association of these cells with the development of frontal sinusitis. METHODS: Frontal recess anatomy was analyzed using high resolution spiral computed tomography images of paranasal sinuses from December 2008 through September 2011. The distribution of various frontal recess cells in patients with and without frontal sinusitis was compared by logistic regression analysis. RESULTS: A total of 150 patients met the criteria, and 300 sides were analyzed. Agger nasi cells were present in 88.0 % of sides; frontal cell types 1 (FC1), 2 (FC2), 3 (FC3), and 4 (FC4) were present in 37.0 %, 6.3 %, 4.3 %, and 1.3 %, respectively; supraorbital ethmoid cells in 6.0 %, suprabullar cells in 37.0 %, frontal bullar cells (FBC) in 7.0 %, and interfrontal sinus septal cells in 8.6 %. Multiple logistic regression analysis showed that the presence of FBCs was significantly associated with the development of frontal sinusitis (p = 0.043). CONCLUSIONS: The frequencies of frontal recess cells in Japanese adult patients were similar to those reported for other East Asian adult populations, including Chinese, Korean, and Taiwanese. Anatomically, FBCs may show a greater association with the development of frontal sinusitis than other frontal recess cells. PMID- 26021827 TI - Endotoxin-minimized HIV-1 p24 fused to murine hsp70 activates dendritic cells, facilitates endocytosis and p24-specific Th1 response in mice. AB - Heat shock proteins hsp70 and gp96 have been confirmed as adjuvants enabling induction of cell- and antibody-mediated immunity specific to associated protein or peptide antigens due to the activation of naive dendritic cells and supporting cross-presentation of associated antigen. An efficacious vaccine preventing HIV-1 infection should induce (1) antibodies neutralizing HIV-1 Env protein, preventing virus spreading and (2) CD4(+) Th1 and CD8(+) T cells specific to viral proteins, especially gag p24, important for elimination of HIV-1 infected cells. As p24 is relatively poorly recognized by dendritic cells, its targeting to DC is important for enhancement of vaccine efficacy. In this study, a p24 protein fused to the C- or N-terminus of murine hsp70 was produced as a recombinant protein and administered without any adjuvant to experimental BALB/c mice. Consequently, p24 specific cellular and humoral immune responses were measured. To minimize the effect of bacterial endotoxin, each protein was subjected to a repeated endotoxin phase extraction until each preparation contained less than 2.5 endotoxin unit (EU) per mg of antigen. In addition, endocytosis of p24 fused to hsp70 by dendritic cells and their activation were characterized. The fusion to hsp70 protein enhanced endocytosis of p24 as well as activation of dendritic cells in vitro. After immunization of mice, hsp70-p24 fusion protein induced the strongest p24-specific CD4(+) and CD8(+) T cells (IFN-gamma production) and humoral (IgG2b) responses corresponding to Th1 type dominance, whereas p24-hsp70 or p24 itself induced weaker responses. PMID- 26021828 TI - "Planning eye health services in Varamin district, Iran: a cross-sectional study". AB - BACKGROUND: A recent survey of avoidable blindness in Varamin District, Iran, identified moderately high levels of visual impairment (10%) and blindness (1.5%) in people >50 years. This study aimed to define current provision, identify gaps and suggest practical solutions for improving eye health services in this area. METHODS: The World Health Organization (WHO) framework for analyzing health systems has several key components: service delivery, health workforce, information system, medical products and technologies, financing, and governance. We used this structure to investigate the strengths and weaknesses of the eye health system in Varamin. All public and private eye care facilities and a random selection of primary health care (PHC) units were assessed using semi-structured researcher-administered questionnaires. RESULTS: Varamin has 16 ophthalmic clinics, including two secondary hospitals that provide cataract surgery. There were ten ophthalmologists (1:68,000 population), two ophthalmic nurses and five optometrists working in Varamin district. There were no eye care social or community workers, ophthalmic counsellors, low vision rehabilitation staff. Although the Vision 2020 target for ophthalmologists has been met, numbers of other eye care staff were insufficient. The majority of patients travel to Tehran for surgery. The recent survey identified cataract as the leading cause of blindness, despite the availability of surgical services in the district and high health insurance coverage. Poor awareness is a major barrier. No units had a written blindness prevention plan, formal referral pathways or sufficient eye health promotion activities. Only one of the PHC units referred people with diabetes for retinal examination. There is partial integration between eye care services and the general health system particularly for prevention of childhood blindness: chemo-prophylaxis for ophthalmia neonatorum, school vision tests, measles immunization and Vitamin A supplementation. CONCLUSIONS: This analysis demonstrated the need for better integration between eye care services and the general health system, local planning for prevention of blindness, an information system, a better staff mix and health education to increase community awareness and service uptake. There is the capacity to deliver far more surgery locally. All aspects of a health system need to be developed to deliver comprehensive and efficient eye care. PMID- 26021830 TI - Does Diabetes Have an Influence on Regional Deformation Parameters in Patients with Normal Systolic Function during Off-Pump Coronary Artery Bypass Grafting? AB - OBJECTIVES: The aim of this study was to assess the recovery of regional myocardial function of the left-ventricular septal wall and the septal site of the mitral valve (MV) annulus by tissue Doppler imaging (TDI). METHODS: In 63 (32 diabetic and 31 control) patients having off-pump coronary artery bypass grafting (OPCABG), including the left internal mammary artery (LIMA) and the left anterior descending coronary artery (LAD), TDI measurements were performed before operation (baseline), 5 min after LIMA-LAD revascularization (early reperfusion) and after completion of all anastomoses (after revascularization). RESULTS: Compared to the patients with diabetes, the controls had higher peak systolic velocities of the mid septal segments in the early reperfusion measurement (p = 0.002). After revascularization, values of peak systolic strain at the basal ( 10.13 vs. -13.36%, p = 0.044) and mid septal segments (-8.25 vs. -12.69%, p = 0.009) were decreased in the diabetic patients compared to the controls. There was no difference between the groups with respect to the velocities acquired at the septal site of the MV annulus. CONCLUSIONS: This study demonstrates an insufficient recovery of regional myocardial function in patients with type II diabetes undergoing OPCABG. PMID- 26021829 TI - Effects of a DPP4 inhibitor on cisplatin-induced acute kidney injury: study protocol for a randomized controlled trial. AB - BACKGROUND: Cisplatin is a potent chemotherapeutic agent, but its nephrotoxicity, which results in acute kidney injury (AKI), often limits its clinical application. Although many studies have attempted to target the mechanism responsible for its nephrotoxicity, no such method has been demonstrated to be effective in clinical trials. Recently, a dipeptidyl peptidase-4 (DPP4) inhibitor has been reported to have a renoprotective effect in a mouse model of cisplatin induced AKI. Therefore, we will evaluate whether a DPP4 inhibitor protects the kidney from cisplatin-induced injury in humans. METHODS/DESIGN: This is a single center, prospective, randomized, double-blind, placebo-controlled trial. A total of 182 participants who are scheduled for cisplatin treatment will be enrolled and randomly assigned to receive either a DPP4 inhibitor (gemigliptin) or a placebo. Participants will take the study drugs for 8 days starting 1 day before cisplatin treatment. The primary outcome of interest is the incidence of AKI at 7 days after finishing treatment with cisplatin. The secondary outcomes include changes in serum creatinine levels and estimated glomerular filtration rates from baseline to 7 days after cisplatin treatment. DISCUSSION: This is the first clinical trial to investigate the effect of a DPP4 inhibitor on cisplatin-induced AKI. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02250872, December 26, 2014. PMID- 26021832 TI - Results of anatomic gracilis MPFL reconstruction with precise tensioning. AB - BACKGROUND: The medial patellofemoral ligament (MPFL) is the most commonly injured structure in patients with objective patellar instability. The objective of this study was to prospectively evaluate the clinical and radiographic results of MPFL reconstruction in 50 patients with chronic patellar instability. METHODS: Fifty patients with chronic patellar instability, aged 15-39 years, were included. The MPFL was reconstructed using a free gracilis autograft tendon. Two anchors were used for patellar fixation, and femoral fixation was achieved with an interference screw placed into a tunnel between the adductor tubercle and medial epicondyle. The graft was tensioned to 10 N with the knee in 30 degrees flexion. IKDC and Kujala scores were assessed pre- and post-operatively. Patellar tilt was measured from CT scans with the quadriceps relaxed and contracted, both pre- and post-operatively. RESULTS: The follow-up period was 7 to 44 months (mean: 25 months, SD 10.3). The mean raw IKDC score increased from 51.5 preoperatively to 71.7 at last follow-up, the mean overall IKDC score increased from 38.5 to 61.7 and the Kujala score increased from 48.3 to 82.4. On CT scans, the mean patellar tilt went from 24 degrees to 16.2 degrees with the quadriceps relaxed and 27.7 degrees to 18.1 degrees in contraction. No recurrent dislocation was observed. CONCLUSION: This technique of MPFL reconstruction provided significant improvements in IKDC and Kujala scores and significant reduction in patellar tilt. No recurrent dislocations were observed during the study period. PMID- 26021831 TI - Multiple gene aberrations and breast cancer: lessons from super-responders. AB - BACKGROUND: The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes. CASE PRESENTATIONS: We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2 negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response. CONCLUSIONS: Patients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted. PMID- 26021833 TI - Complex relation among Health Belief Model components in TB prevention and care. AB - OBJECTIVES: This study aims to explore the relationships among components of the Health Belief Model, tuberculosis (TB) preventive behavior, and intention of seeking TB care. STUDY DESIGN: Cross section study. METHODS: Using convenience sampling, 1154 rural-to-urban migrant workers were selected between the ages of 18-50 years in six urban areas of three provinces in China. The survey was conducted by individual, face-to-face interviews with a standardized questionnaire. Lisrel 8.7 was used to conduct path analysis. RESULTS: The knowledge and benefits components of the Health Belief Model predicted preventive behaviors: cover nose/mouth when coughing or sneezing (beta = 0.24, 0.33 respectively), evade others' coughs (beta = 0.13, 0.25) and also predicted seeking TB care (beta = 0.27, 0.19). Susceptibility and severity also predicted seeking TB care (beta = 0.12, 0.16). There were also important relationships among model components. Knowledge of TB predicted both susceptibility (beta = 0.32-0.60) and severity (beta = 0.41-0.45). Further, each of susceptibility (beta = 0.30) and severity (beta = 0.41) predicted perceived benefits of preventive care. CONCLUSION: Thus, a path from knowledge, through severity and susceptibility, and then through benefits predicted prevention and TB care seeking behaviors. PMID- 26021834 TI - Relationship between health-related quality of life, comorbidities and acute health care utilisation, in adults with chronic conditions. AB - BACKGROUND: There is increased interest in developing multidisciplinary ambulatory care models of service delivery to manage patients with complex chronic diseases. These programs are expensive and given limited resources it is important that care is targeted effectively. One potential screening strategy is to identify individuals who report the greatest decrement in health related quality of life (HRQoL) and thus greater need. The aim of this study was to explore the relationship between HRQoL, comorbid conditions and acute health care utilisation. METHODS: A prospective, longitudinal cohort design was used to evaluate the impact of HRQoL on acute care utilisation rates over three-years of follow-up. Participants were enrolled in chronic disease management programs run by a metropolitan health service in Australia. Baseline data was collected from 2007-2009 and follow-up data until 2012. Administrative data was used to classify patients' primary reasons for enrolment, number of comorbidities (Charlson Score) and presentations to acute care. At enrolment, HRQoL was measured using the Assessment of Quality of Life (AQoL) instrument, for analysis AQoL scores were dichotomised at two standard deviations below the population norm. RESULTS: There were 1999 participants (54 % male) with a mean age of 63 years (range 18-101), enrolled in the study. Participants' primary health conditions at enrolment were: diabetes 915 (46 %), chronic respiratory disease 463 (23 %), cardiac disease 260 (13 %), peripheral vascular disease, and 181 (9 %) and aged care 180 (9 %). At 1 year multivariate logistic regression models demonstrated that AQOL utility score was not predictive of acute care presentations after adjusting for comorbidities. Over 3-years an AQoL utility score in the lowest quartile was predictive of both ED presentation (OR 1.58, 95 % CI, 1.16-2.13, p = 0.003) and admissions (OR 1.67, 95 % CI.1.21 to 2.30, p = 0.002) after adjusting for differences in age and comorbidities. CONCLUSION: This study found that both HRQoL and comorbidities were predictive of subsequent acute care attendance over 3-years of follow-up. At 1-year, comorbidities was a better predictor of acute care representation than HRQoL. To maximise benefits, programs should initially focus on medical disease management, but subsequently switch to strategies that enhance health independence and raise HRQoL. PMID- 26021836 TI - Molecular detection of kobuviruses in European roe deer (Capreolus capreolus) in Italy. AB - Kobuvirus RNA was found in 6.6 % (13/198) of stool specimens from roe deer (Capreolus capreolus) captured during the regular hunting season. Upon sequence analysis of a fragment of the 3D gene, nine strains displayed the highest nucleotide sequence identity (91.2-97.4 %) to bovine kobuviruses previously detected in either diarrhoeic or asymptomatic calves. Interestingly, four strains were genetically related to the newly discovered caprine kobuviruses (84.2-87.6 % nucleotide identity) identified in black goats in Korea. PMID- 26021835 TI - Detection of pepper mild mottle virus in pepper sauce in China. AB - Pepper mild mottle virus (PMMoV) was detected by RT-PCR in all 42 pepper sauce samples from the 10 main manufacturing provinces in China at concentrations ranging from 3.8 to 8.8 (Log10 copies/mL). Their coat protein nucleotide sequences had 97.4 to 100 % identity to each other and 92.4 to 100 % to other published isolates. The samples remained infectious to N. benthamiana, indicating that commercial trade in sauce could contribute to the natural spread of PMMoV. PMID- 26021837 TI - Skin Grafts vs Local Flaps for Reconstruction of Nasal Defects: A Retrospective Cohort Study. AB - IMPORTANCE: Nasal defects commonly are a result of removal of skin lesions, and reconstruction presents a cosmetic challenge to surgeons. Conventional thought and study results have held that cosmetic outcomes of local flap reconstructions may be superior to those of skin grafts. However, local flap reconstructions require more adjunctive procedures. We propose that in select cases, skin grafts can provide aesthetic outcomes equal to those of local flaps with fewer adjunctive procedures. OBJECTIVE: To evaluate the cosmetic outcomes of skin grafts vs local flaps in the reconstruction of nasal defects. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective review of medical records for 103 patients who underwent nasal reconstruction with either skin graft (n=39) or local flap (n=64) between 2005 and 2013. All patients were treated by a single surgeon at an academic medical institution. Patients who had defects larger than 30 * 35 mm or a history of adjacent reconstruction that would detract from the cosmetic outcome of the procedure under analysis were excluded. MAIN OUTCOMES AND MEASURES: Cosmetic outcome was graded using a visual analog scale (VAS) score based on an ordinal 5-point Likert scale (1, excellent; 5, poor) by 4 independent raters blinded to reconstruction technique. Information was collected regarding patient demographics, defect size, pathology, type of reconstruction, and any postoperative procedures performed. RESULTS: The mean VAS score for the skin graft group was 2.18, while the mean score for the flap group was 2.12 (P = .43). The 39 patients with graft reconstruction had a total of 11 triamcinolone acetonide injections and 8 dermabrasion sessions postoperatively. The 64 patients with local flap reconstruction had a total of 259 triamcinolone acetonide injections and 13 dermabrasion sessions postoperatively plus 39 additional staged surgical procedures. CONCLUSIONS AND RELEVANCE: Skin grafts are a valuable reconstructive option that provide aesthetic outcomes comparable to those of local flap procedures and with less need for additional postoperative interventions in properly selected nasal defects. LEVEL OF EVIDENCE: 3. PMID- 26021838 TI - Risk of psychiatric disorders following gastroesophageal reflux disease: a nationwide population-based cohort study. AB - BACKGROUND: Recent studies have shown that the peripheral inflammation may cause the up-regulation of central nervous system inflammation and therefore possibly plays a vital role in the pathophysiology of subsequent psychiatric disorders. OBJECTIVE: We explored the relationship between gastroesophageal reflux disease (GERD) and the subsequent development of psychiatric disorders including schizophrenia as well as bipolar, depressive, anxiety, and sleep disorders. METHODS: We investigated patients who were diagnosed with GERD according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort comprised patients without GERD who were matched according to age and sex. The incidence rate and the hazard ratios (HRs) of subsequent new-onset psychiatric disorders were calculated for both cohorts, based on the diagnoses of psychiatrists. RESULTS: The GERD cohort consisted of 3813 patients, and the comparison cohort comprised 15,252 matched control patients without GERD. The risks of depressive disorder (HR=3.37, 95% confidence interval [CI]=2.49-4.57), anxiety disorder (HR=2.99, 95% CI=2.12-4.22), and sleep disorder (HR=2.69, 95% CI=1.83-3.94), were higher in the GERD cohort than in the comparison cohort. In addition, the incidence of newly diagnosed depressive, anxiety, and sleep disorders remained significantly increased in all of the stratified follow-up durations (0-1, >=1year). CONCLUSIONS: GERD may increase the risks of subsequent depressive, anxiety, and sleep disorders. These psychiatric disorders have a negative effect on people's quality of life. Clinicians should pay a particular attention to psychiatric comorbidities in GERD patients. PMID- 26021839 TI - Short and long term survival following hospitalization with a primary versus non primary diagnosis of acute heart failure. AB - OBJECTIVE: To compare the short-term and long-term outcomes of patients hospitalized with a primary diagnosis of acute heart failure (AHF) versus AHF associated with an alternative principal diagnosis. METHODS: The Israel nationwide Heart Failure (HF) survey examined prospectively 4102 consecutive HF patients admitted to all 25 public hospitals in the country. This study focused on 2302 patients hospitalized with a diagnosis of AHF. In 1594 patients, AHF was the principal diagnosis of hospitalization. In 708 patients, AHF was a secondary diagnosis with an alternative principal diagnosis of hospitalization. RESULTS: Patients with secondary diagnosis of AHF were younger with an overall less comorbidities except for concomitant ischemic heart disease. Despite that, hospital duration was longer (median days (Q1-Q3), 4 (3-7), and 6(4-9), respectively, P<0.001) and in-hospital mortality was higher (7.2% vs. 4.9%, p value=0.03) among patients with a secondary diagnosis of AHF. Consistently, the age and sex adjusted OR of secondary diagnosis of AHF for in-hospital mortality was 1.76 (C.I. 1.2-2.54; p-val=0.003). However, long-term follow-up showed a risk reversal wherein the adjusted risk for 10-year mortality was significantly lower among those hospitalized with a secondary vs. primary diagnosis of AHF (HR=0.88, C.I. 0.79-0.99; p-val=0.04). CONCLUSIONS: While hospitalization with secondary diagnosis of AHF is associated with a higher risk for in-hospital mortality in comparison to hospitalization with principal diagnosis of AHF, it is independently associated with a lower risk for 10-year mortality. These findings may have implications for short and long term risk stratification after AHF hospitalization. PMID- 26021840 TI - Association Study of the TREM2 Gene and Identification of a Novel Variant in Exon 2 in Iranian Patients with Late-Onset Alzheimer's Disease. AB - OBJECTIVE: To analyze the association between TREM2 exon 2 variants and late onset (sporadic) Alzheimer's disease (AD) in an elderly Iranian population. MATERIALS AND METHODS: Exon 2 of TREM2 in a total of 131 AD patients and 157 controls was genotyped using polymerase chain reaction and Sanger sequencing. Fisher's exact test was used to compare the allele and genotype frequency between the 2 study groups. RESULTS: One homozygous and 2 heterozygous carriers of rs75932628-T in the AD patients and 1 heterozygous carrier in the control group were identified. One novel damaging variant, G55R, was also detected in the AD patient group. The frequency of rs75932628-T as well as the amount of rare variants were higher in the AD patients than in the controls, but this did not reach a statistically significant association with AD (odds ratio: 4.8; 95% confidence interval: 0.54 to 43.6; p = 0.270). CONCLUSION: The rs75932628-T allele frequency in the elderly Iranian population (0.86%) was high. PMID- 26021841 TI - Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. AB - BACKGROUND: Oral squamous cell carcinoma is the most common form of malignancy of the lip and oral cavity, often being proceeded by potentially malignant disorders (PMD). Early detection can reduce the malignant transformation of PMD and can improve the survival rate for oral cancer. The current standard of scalpel biopsy with histology is painful for patients and involves a delay whilst histology is completed; other tests are available that are unobtrusive and provide immediate results. OBJECTIVES: PRIMARY OBJECTIVE: To estimate the diagnostic accuracy of index tests for the detection of oral cancer and PMD of the lip and oral cavity, in people presenting with clinically evident lesions. SECONDARY OBJECTIVE: To estimate the relative accuracy of the different index tests. SEARCH METHODS: The electronic databases were searched on 30 April 2013. We searched MEDLINE (OVID) (1946 to April 2013) and four other electronic databases (the Cochrane Diagnostic Test Accuracy Studies Register, the Cochrane Oral Health Group's Trials Register, EMBASE (OVID) and MEDION (Ovid)). There were no restrictions on language in the searches of the electronic databases. We conducted citation searches and screened reference lists of included studies for additional references. SELECTION CRITERIA: We selected studies that reported the diagnostic test accuracy of the following index tests when used as an adjunct to conventional oral examination in detecting PMD or oral squamous cell carcinoma of the lip or oral cavity: vital staining, oral cytology, light-based detection and oral spectroscopy, blood or saliva analysis (which test for the presence of biomarkers in blood or saliva). DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance. Eligibility, data extraction and quality assessment were carried out by at least two authors, independently and in duplicate. Studies were assessed for methodological quality using QUADAS-2. Meta-analysis was used to combine the results of studies for each index test using the bivariate approach to estimate the expected values of sensitivity and specificity. MAIN RESULTS: We included 41 studies, recruiting 4002 participants, in this review. These studies evaluated the diagnostic accuracy of conventional oral examination with: vital staining (14 studies), oral cytology (13 studies), light-based detection or oral spectroscopy (13 studies). Six studies assessed two combined index tests. There were no eligible diagnostic accuracy studies evaluating blood or salivary sample analysis.The summary estimates for vital staining obtained from the meta-analysis were sensitivity of 0.84 (95% CI 0.74 to 0.90) with specificity of 0.70 (0.59 to 0.79), with 14 studies were included in the meta analysis. For cytology, sensitivity was 0.91 (0.81 to 0.96) and specificity was 0.91 (0.81 to 0.95) with 12 studies included in the meta-analysis. For light based detection, sensitivity was 0.91 (0.77 to 0.97) and specificity was 0.58 (0.22 to 0.87) with 11 studies included in the meta-analysis. The relative test accuracy was assessed by adding covariates to the bivariate analysis, no difference in model fit was observed. AUTHORS' CONCLUSIONS: The overall quality of the included studies was poor. None of the adjunctive tests can be recommended as a replacement for the currently used standard of a scalpel biopsy and histological assessment. Given the relatively high values of the summary estimates of sensitivity and specificity for cytology, this would appear to offer the most potential. Combined adjunctive tests involving cytology warrant further investigation. PMID- 26021842 TI - Prevalence of AIP mutations in a series of Turkish acromegalic patients: are synonymous AIP mutations relevant? AB - CONTEXT: In sporadic acromegaly, overall AIP(mut) prevalence is reported as 3, 4.1 and 16 % in studies carried out across Europe. However, it is not known whether the prevalence shows any changes across different ethnicities. The aim of the study was to identify prevalence of AIP(mut) in a series of Turkish acromegalic patients. PATIENTS AND METHODS: Direct sequencing of AIP gene was performed in 92 sporadic acromegalic patients. RESULTS: One patient was found to have a new mutation in exon 6: g67.258,286 (G/A) heterozygote; (GGC/GAC; gly/asp). Apart from this new mutation, previously defined synonymous mutations in AIP gene were detected in seven patients (Exon 4; rs2276020; (GAC/GAT; asp/asp) and six patients were found to have five different intronic mutations in AIP gene which were not previously defined. The patient with pathogenic AIP(mut) presented at a young age and had an aggressive and treatment resistant tumour. The prevalence of AIP(mut) in Turkish patients was found to be 1 % in sporadic acromegaly in the present study. In addition, one synonymous mutation which was previously defined and six new intronic mutations have been described in Turkish acromegalic patients. All acromegalic patients with synonymous AIP(mut) presented with macroadenoma and majority of them had invasive tumour. CONCLUSION: The prevalence of AIP(mut) in Turkish patients was found to be 1 % in sporadic acromegaly in the present study. This ratio increases when younger age groups are taken into account 6 % among patients <30 years of age at the time of diagnosis of acromegaly. The clinical features of acromegaly, such as having large and invasive tumours, may be affected by the presence of synonymous AIP(mut). PMID- 26021843 TI - The Paracrine Effect of Skeletal Myoblasts Is Cardioprotective Against Oxidative Stress and Involves EGFR-ErbB4 Signaling, Cystathionase, and the Unfolded Protein Response. AB - Therapeutic effects of skeletal myoblast transplantation into the myocardium are mediated via paracrine factors. We investigated the ability of myoblast-derived soluble mediators to protect cardiomyocytes from oxidative stress. Fetal rat cardiac cells were treated with conditioned medium from cultures of myoblasts or cardiac fibroblasts, and oxidative stress was induced with H2O2. Myoblast-derived factors effectively prevented oxidative stress-induced cardiac cell death and loss of mitochondrial membrane potential. This protective effect was mediated via epidermal growth factor (EGF) receptor and c-Met signaling, and mimicked by neuregulin 1 but not EGF. Microarray analysis of cardiac cells treated with myoblast versus cardiac fibroblast-derived mediators revealed differential regulation of genes associated with antioxidative effects: cystathionine-gamma lyase (cst), xanthine oxidase, and thioredoxin-interacting protein as well as tribbles homolog 3 (trib3). Cardiac cell pretreatment with tunicamycin, an inducer of trib3, also protected them against H2O2-induced cell death. Epicardial transplantation of myoblast sheets in a rat model of acute myocardial infarction was used to evaluate the expression of CST and trib3 as markers of myoblasts' paracrine effect in vivo. Myoblast sheets induced expression of the CST as well as trib3 in infarcted myocardium. CST localized around blood vessels, suggesting smooth muscle cell localization. Our results provide a deeper molecular insight into the therapeutic mechanisms of myoblast-derived paracrine signaling in cardiac cells and suggest that myoblast transplantation therapy may prevent oxidative stress-induced cardiac deterioration and progression of heart failure. PMID- 26021844 TI - Regulatory role of BOTRYTIS INDUCED KINASE1 in ETHYLENE INSENSITIVE3-dependent gene expression in Arabidopsis. AB - KEY MESSAGE: Arabidopsis BIK1 negatively regulates EIN3-depedent gene expression as an immediate cellular response. BIK1 localizes to the plasma membrane and its autophosphorylation and kinase activity involves in EIN3 repression. BOTRYTIS INDUCED KINASE1 (BIK1) is a multifunctional receptor-like kinase that involves in ethylene-mediated plant defense signaling. The loss of function BIK1 becomes insensitive to ethylene, but it still accumulates a higher level of ETHYLENE INSENSITIVE3 (EIN3) that serves as the key transcription activator in ethylene signaling. To unequivocally elucidate BIK1 function on EIN3 regulation in ethylene signaling, we took a combined approach of transient expression assay and stable expression analysis of BIK1. In our cell-based functional assay BIK1 destabilized EIN3 and down-regulated EIN3-dependent transcription. Membrane localization and autophosphorylation of BIK1 were required for full repression of EIN3 function, but its kinase activity potential compromised such regulatory action. Consistently, the analysis of transgenic plants verified BIK1 function on EIN3 repression. Our findings have clarified that autophosphorylated BIK1 in the plasma membrane negatively regulates EIN3-dependent gene expression. Thus, ethylene insensitivity in bik1 appears to be an indirect or a feedback long-term response. PMID- 26021845 TI - Silicon improves salt tolerance by increasing root water uptake in Cucumis sativus L. AB - KEY MESSAGE: Silicon enhances root water uptake in salt-stressed cucumber plants through up-regulating aquaporin gene expression. Osmotic adjustment is a genotype dependent mechanism for silicon-enhanced water uptake in plants. Silicon can alleviate salt stress in plants. However, the mechanism is still not fully understood, and the possible role of silicon in alleviating salt-induced osmotic stress and the underlying mechanism still remain to be investigated. In this study, the effects of silicon (0.3 mM) on Na accumulation, water uptake, and transport were investigated in two cucumber (Cucumis sativus L.) cultivars ('JinYou 1' and 'JinChun 5') under salt stress (75 mM NaCl). Salt stress inhibited the plant growth and photosynthesis and decreased leaf transpiration and water content, while added silicon ameliorated these negative effects. Silicon addition only slightly decreased the shoot Na levels per dry weight in 'JinYou 1' but not in 'JinChun 5' after 10 days of stress. Silicon addition reduced stress-induced decreases in root hydraulic conductivity and/or leaf specific conductivity. Expressions of main plasma membrane aquaporin genes in roots were increased by added silicon, and the involvement of aquaporins in water uptake was supported by application of aquaporin inhibitor and restorative. Besides, silicon application decreased the root xylem osmotic potential and increased root soluble sugar levels in 'JinYou 1.' Our results suggest that silicon can improve salt tolerance of cucumber plants through enhancing root water uptake, and silicon-mediated up-regulation of aquaporin gene expression may in part contribute to the increase in water uptake. In addition, osmotic adjustment may be a genotype-dependent mechanism for silicon-enhanced water uptake in plants. PMID- 26021846 TI - Microemulsion liquid chromatographic method for simultaneous separation and determination of six flavonoids of Apocynum venetum leaf extract. AB - A simple, cost-effective, and efficient method was developed for the rapid simultaneous separation and determination of six flavonoids (rutin, hyperoside, quercetin-3-O-sophoroside, isoquercitrin, astragalin and quercetin) of Apocynum venetum leaf extract by reversed phase high performance liquid chromatography using a microemulsion system mixture as the mobile phase. Separations were performed on the Zorbax Extend-C18 column with UV detection at 360nm. The flow rate was 0.8mLmin(-1). The optimized microemulsion mobile phase consisted of 2.5% (v/v) n-butanol, 1.2% (v/v) of Genapol X-080, 0.5% (v/v) ethyl acetate and 95.8% (w/v) of aqueous 20mM phosphoric acid, pH adjusted to 6.0 with 0.3% triethylamine. Under the optimized conditions, the calibration curve for six flavonoids was linear in the range of 5-1000MUgmL(-1) with the correlation coefficients greater than 0.9994. The intra-day and inter-day precision (RSD) were below 8.11% and the limits of detection (LOD) for the six flavonoids were 1.7-6.0MUgmL(-1) (S/N=3). The microemulsion liquid chromatography (MELC) method was successfully applied to separate and determine the six flavonoids of A. venetum leaf extract. PMID- 26021847 TI - Simultaneous determination of amino acid and monoamine neurotransmitters in PC12 cells and rats models of Parkinson's disease using a sensitizing derivatization reagent by UHPLC-MS/MS. AB - Multi-analytes simultaneous monitoring of amino acid and monoamine neurotransmitters (NTs) has important scientific significance for their related pathology, physiology and drug screening. In this work, in virtue of a mass spectrometry sensitizing reagent 10-ethyl-acridone-3-sulfonyl chloride (EASC) as derivatization reagent, an Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous determination of six amino acid NTs, two monoamine ones and its one metabolite. The simple and rapid derivatization reaction was innovatively combined with plasma preparation by using EASC acetonitrile solution as protein precipitant. This interesting combination brought the advantages of speediness, simpleness and high-throughput in a cost-effective way. Under the optimized conditions, LODs (0.004-3.80nM) and LOQs (0.014-13.3nM) of EASC derivatized-NTs were calculated and found to be significantly lower than those of direct UHPLC MS/MS detection about 11.5-275.0 and 14.4-371.4 times, respectively. Moreover, EASC derivatization significantly improved chromatographic resolution and matrix effect when compared with direct UPLC-MS/MS detection method without derivatization. Meanwhile, it also brought acceptable precision (3.0-13.0%, peak area CVs%), accuracy (86.4-112.9%), recovery (88.3-107.8%) and stability (3.8 8.5%, peak area CVs%) results. This method was successfully applied for the antiparkinsonian effect evaluation of levodopa and Ginsenoside Rg1 using PC12 cells and rats models by measuring multiple NTs. This provided a new method for the NTs related studies in the future. PMID- 26021848 TI - Simultaneous determination of acetylpuerarin and puerarin in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study following intravenous and oral administration. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the simultaneous determination of acetylpuerarin (AP) and its major metabolite puerarin (PUE) in rat plasma using genistein as the internal standard (IS). Plasma samples were pretreated by protein precipitation with a mixture of methanol and acetonitrile. Chromatographic separation was performed on a CAPCELL PAK C18 MGSH column with a mixture of 0.1% formic acid in water and methanol (35:65, v/v) as the mobile phase. The analytes were detected using a tandem mass spectrometer in the positive ionization and multiple-reaction monitoring mode. The ion transition of m/z 669.4->627.3, 417.5->297.6 and 271.3->153.0 was utilized to quantify AP, PUE and the IS, respectively. The calibration curves showed good linearity over the plasma concentration range of 1-2000ng/mL for AP and 2.5-5000ng/mL for PUE. The intra- and inter-day precisions (RSD %) for each analyte were less than 6.91%, and the accuracies ranged from -2.17% to 2.93%. The validated LC-MS/MS method was further successfully applied to a pharmacokinetic study of AP and PUE in rats following intravenous and oral administration. PMID- 26021849 TI - Optimization of derivatization procedure and gas chromatography-mass spectrometry method for determination of bensulfuron-methyl herbicide residues in water. AB - A simple and efficient technique based on liquid phase extraction with CH2Cl2 solvent followed by derivatization with (C2H5)2O.BF3 solution and confirmation analysis with GC-MS analytical method was developed for detecting the bensulfuron methyl (BSM) residues in water. Box-Behnken response surface methodology was employed for optimization of the derivatization efficiency. According to the optimization model, the derivatization time of 45min, derivatization temperature at 55 degrees C and 0.2mL (C2H5)2O.BF3 solvent were selected as the optimal derivatization condition for obtaining the maximum desirability of response. Method validation was performed at 6 working standard levels (0.05, 0.1, 0.2, 0.5, 1.0, 5.0MUg/mL) and the linearity of the calibration curve was linear well over the 6 fortification levels with the squared correlation coefficient of determination r(2)=0.998 and the LOD was found to be 0.1MUg/L for BSM herbicide. The mean value of BSM was detected from 0.0414 to 4.7542MUg/mL at levels from 0.05 to 5MUg/mL with the recoveries remained at the acceptable level (42.8-95.0%) with the RSD values from 3.5% to 6.2%, which is more accptable and desirable than the results obtained by LC methods. Moreover, the method allowed the determination of BSM residue in real paddy field water samples at concentrations between 0.0902 and 3.4605MUg/L. Average recovery rates of the BSM spiked at levels 0.1, 0.2, 0.5, 1.0MUg/mL into thirty water samples ranged from 74.1% and 94.1% with the relative standard derivation (RSD) values from 1.9% to 6.7%. PMID- 26021850 TI - Three-phase molecularly imprinted sol-gel based hollow fiber liquid-phase microextraction combined with liquid chromatography-tandem mass spectrometry for enrichment and selective determination of a tentative lung cancer biomarker. AB - In the present study, the modification of a polysulfone hollow fiber membrane with in situ molecularly imprinted sol-gel process (as a novel and one-step method) was prepared and investigated. 3-(propylmethacrylate)trimethoxysilane (3PMTMOS) as an inorganic precursor was used for preparation of molecularly imprinted sol-gel. The modified molecularly imprinted sol-gel hollow fiber membrane (MSHM) was used for the liquid-phase microextraction (LPME) of hippuric acid (HA) in human plasma and urine samples. MSHM as a selective, robust, and durable tool was used for at least 50 extractions without significant decrease in the extraction efficiency. The non-molecularly imprinted sol-gel hollow fiber membrane (NSHM) as blank hollow fiber membrane was prepared by the same process, only without HA. To achieve the best condition, influential parameters on the extraction efficiency were thoroughly investigated. The capability of this robust, green, and simple method for extraction of HA was successfully accomplished with LC/MS/MS. The limits of detection (LOD) and quantification (LOQ) in human plasma and urine samples were 0.3 and 1.0nmolL(-1), respectively. The standard calibration curves were obtained within the concentration range 1 2000nmolL(-1) for HA in human plasma and urine. The coefficients of determination (r(2)) were >=0.998. The obtained data exhibited recoveries were higher than 89% for the extraction of HA in human plasma and urine samples. PMID- 26021851 TI - Development and validation of an UFLC-MS/MS assay for the absolute quantitation of nine notoginsenosides in rat plasma: Application to the pharmacokinetic study of Panax Notoginseng Extract. AB - Notoginsenosides, the main active gradients of Chinese traditional medicine Panax notoginseng, possesses a variety of biological activities including antioxidant property, anti-hyperglycemic, anti-obese, etc. However, pharmacokinetic evaluation for notoginsenosides is still a formidable task due to their low concentrations and complex components in vivo. The summation of this work generated a rapid and sensitive method for quantitative analysis of multi notoginsenoside in rat plasma based on ultra fast liquid chromatographic-tandem mass spectrometric. After liquid-liquid extraction by n-butanol, notoginsenoside R1, Rg3, Rd, Rg2, Rb2, Rf, Rg1, Rb1 and Re were simultaneously monitored in negative ionization mode after separating on a Thermo ODS C18 column (5mm 50mm*2.1mm) by a binary gradient elution, and all compounds were analyzed within 9min. Multiple reaction monitoring (MRM) was performed as follows: R1 (m/z 967.7 >637.4), Rg3 (m/z 819.6->621.4), Rd (m/z 981.6->783.5), Rg2 (m/z 819.6->475.4), Rb2 (m/z 1113.4->783.4), Rf (m/z 835.6->475.4), Rg1 (m/z 835.6->637.6), Rb1 (m/z 1143.7->945.6), Re (m/z 981.6->637.4), internal standard (digoxin, m/z 815.5 >779.4). Validation parameters (linearity, sensitivity, intra-and inter-assay precision and accuracy, recovery and matrix effect) were within acceptable ranges and biological extracts were stable during the entire storing and preparing process. This UFLC-MS/MS approach was further validated by being applied to the pharmacokinetic study for P. Notoginseng extract in rats, and the pharmacokinetic parameters were calculated by Winolin software. Thus, the presently developed methodology was simple, robust, accurate, precise, and would be useful for the pharmacokinetic studies for all kinds of notoginsenosides and other herbal saponins. PMID- 26021853 TI - Selective electrochemical reduction of CO2 to CO with a cobalt chlorin complex adsorbed on multi-walled carbon nanotubes in water. AB - Electrocatalytic reduction of CO2 occurred efficiently using a glassy carbon electrode modified with a cobalt(II) chlorin complex adsorbed on multi-walled carbon nanotubes at an applied potential of -1.1 V vs. NHE to yield CO with a Faradaic efficiency of 89% with hydrogen production accounting for the remaining 11% at pH 4.6. PMID- 26021852 TI - Well plate-based perfusion culture device for tissue and tumor microenvironment replication. AB - There are significant challenges in developing in vitro human tissue and tumor models that can be used to support new drug development and evaluate personalized therapeutics. The challenges include: (1) working with primary cells which are often difficult to maintain ex vivo, (2) mimicking native microenvironments from which primary cells are harvested, and (3) the lack of culture devices that can support these microenvironments to evaluate drug responses in a high-throughput manner. Here we report a versatile well plate-based perfusion culture device that was designed, fabricated and used to: (1) ascertain the role of perfusion in facilitating the expansion of human multiple myeloma cells and evaluate drug response of the cells, (2) preserve the physiological phenotype of primary murine osteocytes by reconstructing the 3D cellular network of osteocytes, and (3) circulate primary murine T cells through a layer of primary murine intestine epithelial cells to recapitulate the interaction of the immune cells with the epithelial cells. Through these diverse case studies, we demonstrate the device's design features to support: (1) the convenient and spatiotemporal placement of cells and biomaterials into the culture wells of the device; (2) the replication of tissues and tumor microenvironments using perfusion, stromal cells, and/or biomaterials; (3) the circulation of non-adherent cells through the culture chambers; and (4) conventional tissue and cell characterization by plate reading, histology, and flow cytometry. Future challenges are identified and discussed from the perspective of manufacturing the device and making its operation for routine and wide use. PMID- 26021857 TI - Disclosure of Spousal Violence: Viewpoints From the Jordanian Society. AB - The objectives of this study were to identify reasons behind not disclosing spousal violence and examine relationships between these reasons and women's demographic profile including the experience of spousal violence. Jordanian women ( N = 709) aged 16 to 66 years ( M = 32.6, SD = 8.7) attending health care centers were recruited. Results indicated that women's intentions to maintain the family unit and use of patience with abuser represented the top two reasons for not disclosing violence. Non-significant relationships were, generally, identified between not disclosing spousal violence and women's demographic profile. Women's justification of spousal violence and witnessing parental violence were the proposed reasons for women's lack of disclosure of violence. Implications for this study include health professionals' use of evidence-based knowledge and skills to deal with victims of violence. Researchers' roles include creating physical and emotional environment that urges disclosure of violence. Furthermore, they can contribute with health professionals in the implementation of health education programs directing victims and perpetrators in the places where they can be located. Proper collaboration between health professionals, researchers, and policy makers may significantly limit suffering of victims of violence. PMID- 26021856 TI - Signal detection analysis of blindsight in monkeys. AB - Macaque monkeys with a unilateral lesion in V1 have been used as an animal model of blindsight. While objective proof of blindsight requires that the two aspects of blindsight (residual forced-choice localization and attenuated yes-no detection) should be tested under identical stimulus conditions using bias-free measures of sensitivity, these have not been attained in studies of nonhuman primates. Here we tested two macaque monkeys with a unilateral V1 lesion with two saccade tasks using identical stimuli: a forced-choice (FC) task and a yes-no (YN) task. An analysis based on signal detection theory revealed that sensitivity in the FC task was significantly higher than that in the YN task. Such dissociation of sensitivity between the two tasks was not observed when near threshold visual stimuli were presented in the normal, unaffected hemifield. These results suggest that the V1-lesioned monkeys resemble the well-studied blindsight patient G.Y., whose visual experience per se was completely abolished. PMID- 26021855 TI - Treatment of infantile haemangiomas: recommendations of a European expert group. AB - With a prevalence of 2.6-4.5 %, infantile haemangiomas (IH) represent the most common tumour of infancy. While the majority of IH does not require therapy and regresses spontaneously, about 10 % of IH exhibit complications such as obstruction, ulceration or disfigurement. With the advent of oral propranolol, many conventional treatment options have become obsolete. This paper summarizes current recommendations for management of complicated IH. These recommendations have been written by an expert group after a consensus process including bibliographic review, several drafts of synthesis, meetings with quantitative voting system and redaction of an approved final manuscript. CONCLUSION: Oral propranolol is the first-line agent for the treatment of complicated IH. WHAT IS KNOWN: * Infantile haemangiomas (IH) are the most common tumours of infancy. Within a very short period after its discovery and long before the publication of randomized controlled trials, propranolol has become the number one agent for the treatment of complicated IH. What is New: * We report IH treatment recommendations of an international, interdisciplinary team of experts, based on an up-to-date review of the literature. PMID- 26021858 TI - Relationship Satisfaction Mediates the Link Between Partner Aggression and Relationship Dissolution: The Importance of Considering Severity. AB - Physically and psychologically aggressive behaviors between members of a couple often lead to relationship dissatisfaction and dissolution. The current study utilized data from 346 clinical couples to investigate associations between psychological and moderate physical aggression and relationship dissolution, and whether relationship satisfaction acts as a mediator of these associations. Results from two series of Actor-Partner Interdependence Models (APIMs) were considered in which cases of severe aggression were initially removed from the analytic sample and then were included for secondary analyses. The first series of models showed that dyadic physical aggression was a weak predictor of the male partner's steps taken to leave the relationship and was not associated with the female's steps. Dyadic psychological aggression, however, was related to steps taken toward leaving by both partners, accounting for approximately 14% of the variance. Relationship satisfaction mediated associations between physical and psychological partner aggression and steps taken to leave. Findings from the second series of models, including cases of severe aggression, showed a significant association between dyadic physical aggression and the female's steps toward leaving. Moreover, relationship satisfaction no longer fully mediated associations between psychological or physical aggression and relationship dissolution risk. The importance of considering severity of physical partner aggression in research and clinical practice is discussed. PMID- 26021859 TI - Prevalence and Risk Factors of Domestic Violence Against Women Attending a Primary Care Center in Riyadh, Saudi Arabia. AB - Domestic violence (DV) against women can negatively affect the physical, mental, sexual, and reproductive health of the women as well as the well-being of their children. The objective was to estimate among Saudi women the prevalence of different types of DV, to identify its associated risk factors, and to determine the immediate victims' reactions to such violence. A cross-sectional study was carried between March and July, 2011. Self-administrated questionnaire was administered to ever-married Saudi women attending Al-Wazarat primary health care center, in Riyadh, Saudi Arabia. Out of the 720 women studied, 144 (20%) reported exposure to DV over the last year. The most common DV types were emotional (69%), social (34%), economic (26%), physical (20%), and sexual violence (10%). In multivariate logistic regression analysis, the following characteristics were independently associated with DV: younger women age, longer duration of marriage, higher women education, lower husband education, working husbands, military occupation, fewer children, husbands with multiple wives, smoking husbands, aggressive husbands, presence of chronic disease in women or husbands, and non sufficient family income. The most common impacts of DV on women were medical or behavioral problems (72%) and psychiatric problems (58%). The most common reactions to DV were seeking separation (56%) and doing nothing (41%). More than 90% of children of abused women suffered psychological or behavioral problems. In conclusion, DV against Saudi women is considerable and the response is generally passive. Promoting a culture non-tolerant to DV and providing accessible, effective, and trustful social services to abused women are critically needed. PMID- 26021860 TI - Exploring the Effects of Court Dispositions on Future Domestic Violence Offending: An Analysis of Two Specialized Domestic Violence Courts. AB - This study seeks to explore the relationship between court dispositions and reoffending within and across two specialized domestic violence (DV) courts located in the United States. The samples for this study are comprised of defendants whose cases were disposed of within the two courts between 2004 and 2006. This study assessed the effects of prosecution, conviction, and sentencing decisions on the prevalence, incidence, and time-to-rearrest for a new DV offense in the 3 years post-disposition both within and across courts. Findings indicate a limited crime-control effect of court dispositions on future offending. Furthermore, despite differences in the community context, policies, and court dispositions across the two courts, the magnitude of the disposition-recidivism relationship is similar across courts. It is important to understand the findings within the context of the specific courts; a discussion of the results is provided. PMID- 26021861 TI - The Effects of Intimate Partner Violence Exposure on the Maternal Bond and PTSD Symptoms of Children. AB - The quality of the maternal bond can be disrupted in women exposed to intimate partner violence (IPV), causing them to be less available to their children. The aim of this study was to examine difficulties in emotional regulation in women exposed to IPV and the impact of IPV on both the maternal bond and posttraumatic symptoms among children. A cross-sectional study was carried out with two groups: IPV dyads ( n = 36) comprising mothers who had been exposed to IPV and their children, and control dyads ( n = 27) comprising non-abused mothers and their children. Information was obtained via structured interviews including scales regarding IPV, posttraumatic stress disorder (PTSD) symptoms, maternal bond, and difficulties in emotional regulation. Correlation analyses showed a positive association between the severity of IPV, PTSD symptom severity in children, and difficulties of emotional regulation in mothers. They also showed a negative association between IPV and the quality of the maternal bond. Regression models demonstrated that exposure to sexual IPV, maternal difficulties in emotion regulation, and younger age of the mother are important predictors of lower quality of the maternal bond. Difficulties in emotional regulation and sexual IPV disrupted the quality of the maternal bond among women and their children. In addition, lower quality of maternal bond was associated with higher PSTD symptoms among children. PMID- 26021862 TI - A public health approach to address the mental health burden of youth in situations of political violence and humanitarian emergencies. AB - This paper describes how socio-ecological theory and a syndemic health systems and public health approach may help address the plight of youth in situations of political violence and humanitarian emergencies. We describe the treatment gap caused by discrepancies in epidemiological prevalence rates, individual and family needs, and available human and material resources. We propose four strategies to develop a participatory public health approach for these youth, based on principles of equity, feasibility, and a balance between prevention and treatment. The first strategy uses ecological and transgenerational resilience as a theoretical framework to facilitate a systems approach to the plight of youth and families. This theoretical base helps to engage health care professionals in a multisectoral analysis and a collaborative public health strategy. The second strategy is to translate pre-program assessment into mental health and psychosocial support (MHPSS) priorities. Defining priorities helps to develop programs and policies that align with preventive and curative interventions in multiple tiers of the public health system. The third is a realistic budgetary framework as a condition for the development of sustainable institutional capacity including a monitoring system. The fourth strategy is to direct research to address the knowledge gap about effective practices for youth mental health in humanitarian settings. PMID- 26021863 TI - Decreased expression of CHIP leads to increased angiogenesis via VEGF-VEGFR2 pathway and poor prognosis in human renal cell carcinoma. AB - CHIP (c-terminal Hsp70-interacting protein) is an E3 ligase which may play different roles in different cancers. The elucidation of the VHL-HIF-1alpha (hypoxia inducible factor-1alpha)-VEGF (vascular endothelial growth factor) pathway has led to the development of targeted therapy in renal cell carcinoma (RCC). However, little is known about the role of CHIP and the relationship between CHIP and VEGF-VEGFR2 (VEGF receptor 2) pathway in RCC. In this study, we found that the expression of CHIP was downregulated and significantly correlated with pT status (P = 0.022) and TNM stage (P = 0.022) in 304 RCC and 35 normal renal tissues using tissue microarray. Moreover, low expression of CHIP is a strong and independent negative prognostic value for RCC. In vitro, CHIP negatively regulated RCC cell migration, invasion and angiogenesis. In addition, ELISA tests showed that restoration of CHIP inhibited, while knockdown promoted, the secreted level of VEGF. Furthermore, western blot indicated that the VEGFR2 protein level was reduced after CHIP overexpression. Our findings demonstrate for the first time that CHIP may be involved in RCC angiogenesis through regulating VEGF secretion and expression of VEGFR2. CHIP may serve as promising prognostic biomarker of angiogenesis and may constitute a potential therapeutic target in RCC. PMID- 26021864 TI - PAX6 does not regulate Nfia and Nfib expression during neocortical development. AB - The Nuclear factor I (NFI) family of transcription factors regulates proliferation and differentiation throughout the developing central nervous system. In the developing telencephalon of humans and mice, reduced Nfi expression is associated with agenesis of the corpus callosum and other neurodevelopmental defects. Currently, little is known about how Nfi expression is regulated during early telencephalic development. PAX6, a transcription factor important for telencephalic development, has been proposed as an upstream regulator of Nfi expression in the neocortex. Here we demonstrate that, in the developing neocortex of mice, NFIA and NFIB are endogenously expressed in gradients with high caudo-medial to low rostro-lateral expression and are most highly expressed in the cortical plate. We found that this expression pattern deviates from that of PAX6, suggesting that PAX6 does not drive Nfi expression. This is supported by in vitro reporter assays showing that PAX6 over-expression does not regulate Nfi promoter activity. Similarly, we also found that in the Pax6 Small Eye mutant, no changes in Nfi mRNA or protein expression are observed in the neocortical ventricular zone where PAX6 and the NFIs are expressed. Together these data demonstrate that in mice, PAX6 is not a transcriptional activator of Nfi expression during neocortical development. PMID- 26021865 TI - Hybrid procedure for orbital venous malformation in the endovascular operation room. AB - PURPOSE: To describe a hybrid procedure for orbital venous malformation in the endovascular operating room (EVOR). METHODS: Five consecutive patients with venous malformation in the periocular and orbital region were included. All patients received a one-stage direct puncture venogram, image-guided glue injection, and surgical resection in the EVOR equipped with a biplane digital subtraction angiography system (BDSAS). RESULTS: The mean age at the time of operation was 37.4 years (range, 22-69 years). The mean operative time was 193 min (range, 138-324 min). No intraoperative complications were noted. The mean follow-up duration was 18.8 months (range, 10-24 months). Three patients had complete removal of the vascular lesions. At the latest follow-up, no recurrence of symptoms related to the lesions was noted. All patients had an uneventful recovery and satisfactory outcome. CONCLUSIONS: The hybrid procedure of orbital venous malformation in the EVOR is a novel application in ophthalmology. It is a safe and well-controlled procedure with real-time high-quality BDSAS surveillance to facilitate surgical resection. Its success requires collaboration between the interventional radiologist, the surgeon, and the ophthalmologist. PMID- 26021866 TI - Cotton-wool spots and migraine: a case series of three patients. PMID- 26021867 TI - Structural changes of the choroid in sarcoid- and tuberculosis-related granulomatous uveitis. AB - AIM: The aim of this study is to characterise the choroidal features of patients diagnosed with sarcoid- and tuberculosis (TB)-associated granulomatous uveitis using spectral domain optical coherence tomography (OCT). METHODS: Twenty-seven patients (27 eyes) diagnosed with sarcoid- (13 eyes) and TB (14 eyes)-related uveitis were included in this retrospective, cross-sectional study. Over a six month period, patients diagnosed with sarcoid and TB granulomatous uveitis were scanned using enhanced depth imaging OCT. Clinical and demographical characteristics were recorded, including the method of diagnosis, disease activity, site of inflammation (anterior or posterior), treatments, and visual acuity (VA). Manual segmentation of the choroidal layers was performed using custom image analysis software. RESULTS: The main outcome measure was OCT-derived thickness measurements of the choroid and choroidal sublayers (Haller's large vessel and Sattler's medium vessel layers) at the macula region. The ratio of Haller's large vessel to Sattler's medium vessel layer was significantly different at the total macula circle in eyes diagnosed with TB uveitis (1.47 (=140.71/95.72 MUm)) compared with sarcoid uveitis (1.07 (=137.70/128.69 MUm)) (P=0.001). A thinner choroid was observed in eyes with a VA >=0.3 LogMAR (Snellen 6/12; 198.1 MUm (interquartile range (IQR)=147.0-253.4 MUm) compared with those with VA <0.3 LogMAR (292.4 MUm (IQR=240.1-347.6 MUm)) at the total macula circle (P=0.004). At the foveal central subfield, the median choroidal thickness was 336.8 MUm (IQR=272.3-375.4 MUm) in active compared with 239.3 MUm (IQR=195.3 330.9 MUm) in quiescent disease (P=0.04). CONCLUSION: A disproportionately enlarged Sattler's layer may indicate a diagnosis of sarcoid-related uveitis, and choroidal thickening may be a feature of active granulomatous uveitis. PMID- 26021868 TI - Ganglion cell complex thickness in nonexudative age-related macular degeneration. AB - PURPOSE: TO evaluate ganglion cell complex (GCC) thickness with spectral domain optical coherence tomography (SD-OCT) in eyes with nonexudative age-related macular degeneration (NEAMD). METHODS: Forty-seven eyes of 28 patients with nonexudative age-related macular degeneration (NEAMD) and 54 eyes of 28 age matched healthy subjects were enrolled. Each subject underwent a complete ophthalmic examination before SD-OCT were obtained. Macular scans were taken with software version 6.0 of the ganglion cell analysis (GCA) algorithm. GCC thickness was evaluated automatically as the average, minimum, temporal superior, superior, nasal superior, nasal inferior, inferior, and temporal-inferior segments by SD OCT and parameters were compared between groups. RESULTS: The mean age was 68.7+/ 8.73 years in patient group, and 61.51+/-5.66 years in control group. There were no significant differences in mean age, gender distribution, intraocular pressure, and sferic equivalent at imaging between the groups (P>0.05). The mean (+/-SD) GCC thicknesses were as follows; average 71.53+/-16.53 MUm, minumum 62.36+/-21.51 MUm, temporal superior 72.23+/-14.60 MUm, superior 72.76+/-20.40 MUm, nasal superior 72.31+/-20.13 MUm, nasal inferior 69.74+/-20.51 MUm, inferior 69.38+/-19.03 MUm, and temporal-inferior 73.12+/-15.44 MUm in patient group. Corresponding values in control group were 81.46+/-4.90 MUm, 78.66+/-6.00 MUm, 81.51+/-4.66 MUm, 82.94+/-5.14 MUm, 81.79+/-5.86 MUm, 80.94+/-6.18 MUm, 80.14+/ 6.30 MUm, and 81.75+/-5.26 MUm, respectively. There were significant differences between two groups in each segments (Mann-Whitney U-test, P<0.05). CONCLUSION: The average GCC thickness values (in all segments) of NEAMD patients were lower than control group. NEAMD, which is considered as a disease of outer layers of retina, may be accompanied with a decrease of ganglion cell thickness, so inner layers of retina may be affected. PMID- 26021869 TI - Intravitreal aflibercept for choroidal neovascularisation in angioid streaks. PMID- 26021870 TI - Transitioning to intravitreal aflibercept following a previous treat-and-extend dosing regimen in neovascular age-related macular degeneration: 24-month results. AB - PURPOSE: To evaluate frequency of injections, visual and anatomical outcomes of neovascular age-related macular degeneration (nAMD) patients transitioned to intravitreal aflibercept after failure to extend treatment interval beyond 8 weeks with prior intravitreal bevacizumab or ranibizumab. METHODS: Retrospective review of patients with nAMD switched to aflibercept following >= 6 prior intravitreal ranibizumab or bevacizumab injections at 4-8-week intervals. Three monthly aflibercept injections were given followed by a treat-and-extend dosing regimen. RESULTS: Twenty-one eyes of 18 patients who had received a mean of 23.8 +/- 18.8 (mean +/- SD; range 6-62) prior ranibizumab or bevacizumab injections were included. Over a mean follow-up of 24 months after the transition, 9.2 +/- 2.9 (range 4-21) aflibercept injections were required. Interval between aflibercept injections increased to 57.3 days (range 35-133 days), as compared with 37 +/- 6.1 days (range 29-54 days) with the prior agents (P = 0.01). Mean best-corrected visual acuity was preserved (0.42 +/- 0.31 vs 0.42 +/- 0.23 logMAR; P = 0.2). Mean OCT central subfoveal thickness (292.1 +/- 83.2 MUm to 283.6 +/- 78.6 MUm; P = 0.4) and mean macular volume (7.9 +/- 0.95 mm(3) to 7.67 +/- 0.94 mm(3); P = 0.16) remained stable. CONCLUSION: Patients requiring treatment more frequently than every 8 weeks with ranibizumab and bevacizumab were transitioned to > 8-week treatment interval with aflibercept while maintaining the anatomic and visual gains. PMID- 26021871 TI - Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population. AB - BACKGROUND: The current increase of obesity and metabolic syndrome (MS) focuses attention on bisphenol-A (BPA), "obesogen" endocrine disruptor, main plastic component. Aim was to verify the role of BPA in metabolic alterations, insulin resistance, low grade inflammation and visceral obesity. METHODS: A cross sectional study was performed in 76 out of 139 environmentally exposed adult males, unselected Caucasian subjects, enrolled by routine health survey at the "Federico II" University of Naples outpatient facilities. BPA plasma levels (ELISA), metabolic risk factors, homeostasis model assessment of insulin resistance index, plasma monocyte chemoattractant protein 1, interleukin-6 (IL-6) and tumor necrosis factor-alpha were performed. Clinical and biochemical parameters have been compared with BPA and pro-inflammatory cytokines levels. RESULTS: In total 24 subjects out of 76 (32%) presented with waist circumference (WC) >102 cm, 36 (47%) had impaired fasting glucose and 24 (32%) subjects had insulin resistance [11 out 52 (21%) with WC <=102 cm and 13 out of 24 with WC >102 cm (54%), chi(2) 6.825, p = 0.009]. BPA and pro-inflammatory cytokine levels were significantly higher in subjects with visceral adiposity (WC > 102 cm). BPA correlated with WC, triglycerides, glucose homeostasis and inflammatory markers. At the multivariate analysis WC and IL-6 remained the main predictors of BPA. CONCLUSIONS: Detectable BPA plasma levels have been found also in our population. The strictly association between BPA and WC, components of MS, and inflammatory markers, further supports the BPA role in visceral obesity-related low grade chronic inflammation. PMID- 26021872 TI - Flow cytometric analysis with a fluorescently labeled formyl peptide receptor ligand as a new method to study the pharmacological profile of the histamine H2 receptor. AB - The histamine H2 receptor (H2R) is a Gs protein-coupled receptor. Its activation leads to increases in the second messenger adenosine-3',5'-cyclic monophosphate (cAMP). Presently, several systems are established to characterize the pharmacological profile of the H2R, mostly requiring radioactive material, animal models, or human blood cells. This prompted us to establish a flow cytometric analysis with a fluorescently labeled formyl peptide receptor (FPR) ligand in order to investigate the H2R functionally and pharmacologically. First, we stimulated U937 promonocytes, which mature in a cAMP-dependent fashion upon H2R activation, with histamine (HA) or selective H2R agonists and measured increases in cAMP concentrations by mass spectrometry. Next, indicative for the maturation of U937 promonocytes, we assessed the FPR expression upon incubation with HA or H2R agonists. FPR expression was measured either indirectly by formyl peptide induced changes in intracellular calcium concentrations ([Ca(2+)]i) or directly with the fluorescein-labeled FPR ligand fNleLFNleYK-Fl. HA and H2R agonists concentration-dependently induced FPR expression, and potencies and efficacies of fMLP-induced increases in [Ca(2+)]i and FPR density correlated linearly. Accordingly, flow cytometric analysis of FPR expression constitutes a simple, inexpensive, sensitive, and reliable method to characterize the H2R pharmacologically. Furthermore, we evaluated FPR expression at the mRNA level. Generally, quantitative real-time polymerase chain reaction confirmed functional data. Additionally, our study supports the concept of functional selectivity of the H2R, since we observed dissociations in the efficacies of HA and H2R agonists in cAMP accumulation and FPR expression. PMID- 26021874 TI - Ethics, genetics and public policies in Uruguay: newborn and infant screening as a paradigm. AB - Uruguay is a middle-income country and the smallest in South America. Its population is under 3.3 million. The demographic and epidemiological characteristics are similar to those of developed countries, with a high burden associated with congenital anomalies. Infant mortality rate (IMR) decreased from 37/1000 live births, in 1980, to 8.8/1000, in 2013. This is largely explained by medical and social policies. IMR related to congenital anomalies, however, remained unchanged for the last 30 years. Therefore, programmes for prevention of congenital disorders were developed, such as the National Newborn Screening Programme. Mandatory, universal, free infant screening was implemented two decades ago. The Ministry of Public Health created the Comprehensive Plan on Birth Defects and Rare Diseases (PIDCER), to develop a strategic public policy tool enabling comprehensive, universal, quality care during their entire lifetime. Recent national legislation created provisions for newborn and infant screening, including for congenital hypothyroidism, phenylketonuria, congenital adrenal hyperplasia, cystic fibrosis and medium-chain acyl-CoA dehydrogenase, via blood spot test, otoacoustic emissions, systematic physical examination and hip ultrasound. We discuss how this programme was implemented, the current situation of rare diseases, the institution managing disability in Uruguay and the development of new laws based on the MPH's PIDCER. It illustrates how Uruguay is developing public policies in the genomic era, based both on science and bioethics. PMID- 26021873 TI - microRNA-26a suppresses recruitment of macrophages by down-regulating macrophage colony-stimulating factor expression through the PI3K/Akt pathway in hepatocellular carcinoma. AB - BACKGROUND: microRNAs (miRNAs) have been reported to modulate macrophage colony stimulating factor (M-CSF) and macrophages. The aim of this study was to find whether miR-26a can suppress M-CSF expression and the recruitment of macrophages. METHODS: Hepatocellular carcinoma (HCC) cell lines with decreased or increased expression of miR-26a were established in a previous study. M-CSF expression by tumor cells was measured by enzyme-linked immunosorbent assay, and cell migration assays were used to explore the effect of HCC cell lines on macrophage recruitment in vitro. Real-time PCR measured a panel of mRNAs expressed by macrophages. Xenograft models were used to observe tumor growth. Immunohistochemistry was conducted to study the relation between miR-26a expression and M-CSF expression and macrophage recruitment in patients with HCC. RESULTS: Ectopic expression of miR-26a reduced expression of M-CSF. The conditioned medium (CM) from HepG2 cells that overexpressed miR-26a reduced the migration ability of THP-1 cells stimulated by phorbol myristate acetate (PMA) increased expression of interleukin (IL)-12b or IL-23 mRNA and decreased expression of chemokine (C-C motif) ligand (CCL)22, CCL17, and IL-10 mRNA, in comparison to the medium from the parental HepG2 cells. These effects could be interrupted by the PI3K/Akt pathway inhibitor LY294002. Ectopic expression of miR 26a in HCC cells suppressed tumor growth, M-CSF expression, and infiltration of macrophages in tumors. Similar results were also found when using HCCLM3 cells. Furthermore, the expression of miR-26a was inversely correlated with M-CSF expression and macrophage infiltration in tumor tissues from patients with HCC. CONCLUSIONS: miR-26a expression reduced M-CSF expression and recruitment of macrophages in HCC. PMID- 26021875 TI - Impaired adult hippocampal neurogenesis and cognitive ability in a mouse model of intrastriatal hemorrhage. AB - Thrombin released by hematoma is an important mediator of the secondary injury of intracerebral hemorrhage (ICH), however, the effect of thrombin on adult neurogenesis and cognitive ability remains elusive. In this study, intrastriatal injection of 0.05 U thrombin didn't affect the neurogenesis at the subgranular zone (SGZ), which was distal to the injection site. 0.1 U thrombin increased the 5-bromo-2-deoxyuridine(+) (BrdU(+), S-phase proliferating cells)/doublecortin(+) (DCX(+), immature neurons) double labelled neurons, but decreased BrdU(+)/NeuN(+) double labelled mature neurons. Higher doses of thrombin (1 U, 2 U, and 5 U) significantly decreased the BrdU(+)/DCX(+) and BrdU(+)/NeuN(+) double labelled cells. After 1 U thrombin injection, cell apoptosis was found at the dentate gyrus of hippocampus at 3-24 h, but not 5 d post-injury. Thrombin infusion (1 U) induced spatial memory deficits in Morris water maze test; whereas, hirudin, the thrombin antagonist, significantly reversed both neurogenesis loss and spatial learning and memory impairment. In conclusion, at least at short term (5 days) after striatum ICH, the effect of high dose of thrombin on neurogenesis of SGZ, and the spatial learning and memory ability, is detrimental. PMID- 26021876 TI - Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury. AB - Autophagy is a process of cellular self-cannibalization, and provides an adaptive mechanism to protect cells against diverse pathological settings. Following peripheral nerve injury, autophagic process was changed in Schwann cells and spinal neurons and glial cells, implicating a vital role of autophagy in chronic pain. However, little is known about the role of autophagy in dorsal root ganglion (DRG) in neuropathic pain. In the present study, we investigated the autophagic process in DRG and its effect on neuropathic pain induced by L5 spinal nerve ligation (SNL). The level of microtubule associated protein 1 light chain 3 (LC3)-II, a general marker for autophagy, was increased in L5 DRG after SNL. Immunofluorescence staining showed that LC3-II puncta were observed in DRG neurons after SNL. Injection of autophagy inducer rapamycin into L5 DRG before or after SNL dose-dependently attenuated neuropathic pain. The expression of LC3 was enhanced in L5 DRG by rapamycin. These data suggest that the autophagy in L5 DRG neurons is a defensive reaction to L5 spinal nerve injury, and pharmacological enhancement of autophagy may be a potential treatment to prevent the onset and chronification of neuropathic pain. PMID- 26021877 TI - Experience-dependent regulation of tissue-type plasminogen activator in the mouse barrel cortex. AB - It has been suggested that tissue-type plasminogen activator (tPA), a serine protease, plays a key role in regulating the extracellular matrix core proteins, thereby impacting the structural plasticity in the cerebral cortex. Much is known about its role in regulating plasticity in the visual cortex. However, its permissive role has not been demonstrated to generalize to other cerebral cortical areas. By utilizing a combination of immunofluorescent histochemistry and confocal microscopy, we demonstrate that endogenous tPA is indeed present in the somatosensory cortex, and its expression is experience-dependent. Chronic sensory deprivation induced by whisker trimming from birth for one month leads to increased tPA immunoreactivity in all layers of the barrel cortex. Furthermore, tPA immunoreactivity remains high even after sensation has been restored to the mystacial pad (by allowing whiskers to grow back to full length for one month). Our results suggest that tPA levels in the cerebral cortex are regulated by sensory experience, and play a key role in regulating structural remodeling in the cerebral cortex. PMID- 26021878 TI - Posterior tibial slope and femoral sizing affect posterior cruciate ligament tension in posterior cruciate-retaining total knee arthroplasty. AB - BACKGROUND: During cruciate-retaining total knee arthroplasty, surgeons sometimes encounter increased tension of the posterior cruciate ligament. This study investigated the effects of femoral size, posterior tibial slope, and rotational alignment of the femoral and tibial components on forces at the posterior cruciate ligament in cruciate-retaining total knee arthroplasty using a musculoskeletal computer simulation. METHODS: Forces at the posterior cruciate ligament were assessed with the standard femoral component, as well as with 2-mm upsizing and 2-mm downsizing in the anterior-posterior dimension. These forces were also determined with posterior tibial slope angles of 5 degrees , 7 degrees , and 9 degrees , and lastly, were measured in 5 degrees increments when the femoral (tibial) components were positioned from 5 degrees (15 degrees ) of internal rotation to 5 degrees (15 degrees ) of external rotation. FINDINGS: Forces at the posterior cruciate ligament increased by up to 718N with the standard procedure during squatting. The 2-mm downsizing of the femoral component decreased the force at the posterior cruciate ligament by up to 47%. The 2 degrees increment in posterior tibial slope decreased the force at the posterior cruciate ligament by up to 41%. In addition, posterior cruciate ligament tension increased by 11% during internal rotation of the femoral component, and increased by 18% during external rotation of the tibial component. INTERPRETATION: These findings suggest that accurate sizing and bone preparation are very important to maintain posterior cruciate ligament forces in cruciate-retaining total knee arthroplasty. Care should also be taken regarding malrotation of the femoral and tibial components because this increases posterior cruciate ligament tension. PMID- 26021880 TI - A kinematic and kinetic analysis of spinal region in subjects with and without recurrent low back pain during one leg standing. AB - BACKGROUND: The purpose of this study was to evaluate the relationship between normalized kinematic and kinetic stability indices for spinal regions with eyes open and eyes-closed conditions during non-dominant leg standing between subjects with recurrent low back pain and control subjects. METHODS: The kinematic stability index for the spinal regions (core spine model, lumbar spine, lower and upper thorax) and the kinetic stability index from force plate were measured. All participants were asked to maintain non-dominant leg standing with the dominant hip and knee flexed approximately 90 degrees for 25 seconds. Forty-two participants enrolled in the study, including 22 subjects with low back pain (12 male, 10 female) and 20 control subjects (12 male, 8 female). FINDINGS: For the kinematic index for stability, the visual condition (F=30.06, p=0.0001) and spinal region (F=10.82, p=0.002) were statistically significant. The post hoc test results indicated a significant difference in the lumbar spine compared with the upper and lower thorax and the core spine model. The kinetic stability (average [standard deviation]) during the eyes-closed condition significantly decreased in the low back pain group (t=-3.24, p=0.002). INTERPRETATION: The subjects with recurrent low back pain demonstrated higher lumbar spine stability in eyes-open condition. This higher stability of the lumbar spine might be due to a possible pain avoiding strategy from the standing limb. The low back pain group also significantly decreased kinetic stability during the eyes-closed condition. Clinicians need to consider both kinetic and kinematic indices while considering visual condition for lumbar spine stability in subjects with recurrent low back pain. PMID- 26021879 TI - The effects of movement speed on kinematic variability and dynamic stability of the trunk in healthy individuals and low back pain patients. AB - BACKGROUND: Comparison of the kinematic variability and dynamic stability of the trunk between healthy and low back pain patient groups can contribute to gaining valuable information about the movement patterns and neuromotor strategies involved in various movement tasks. METHODS: Fourteen chronic low back pain patients with mild symptoms and twelve healthy male volunteers performed repeated trunk flexion-extension movements in the sagittal plane at three different speeds: 20 cycles/min, self-selected, and 40 cycles/min. Mean standard deviations, coefficient of variation and variance ratio as variability measures; maximum finite-time Lyapunov exponents and maximum Floquet multipliers as stability measures were computed from trunk kinematics. FINDINGS: Higher speed significantly reduced the kinematic variability, while it increased short-term Lyapunov exponents. Long-term Lyapunov exponents were higher at self-selected speed and lower in low back pain patients as compared to control volunteers. Floquet multipliers were larger at self-selected speed and during higher pace trunk movements. INTERPRETATION: Our findings suggest that slower pace flexion extension trunk movements are associated with more motor variation as well as local and orbital stability, implying less potential risk of injury for the trunk. Individuals with and without low back pain consistently recruited a closed loop control strategy towards achieving trunk stability. Chronic low back pain patients exhibited more stable trunk movements over long-term periods, indicating probable temporary pain relief functional adaption strategies. These results may be used towards the development of more effective personalized rehabilitation strategies and quantitative spinal analysis tools for low back pain detection, diagnosis and treatment, as well as improvement of workspace and occupational settings. PMID- 26021881 TI - Two new triterpenoid saponins from the aerial parts of Anemone taipaiensis. AB - Phytochemical study on the aerial parts of Anemone taipaiensis for the first time led to the isolation of two new oleanane-type triterpenoid saponins 1 and 2, together with four known saponins (3-6). Their structures were elucidated by extensive spectroscopic analysis and chemical evidences. Saponins 2-4 exhibited cytotoxicity against human glioblastoma U251MG cell line with IC50 values ranging from 1.56 to 80.62 MUM. PMID- 26021882 TI - Rational Design of Multilayer Collagen Nanosheets with Compositional and Structural Control. AB - Two collagen-mimetic peptides, CP(+) and CP(-), are reported in which the sequences comprise a multiblock architecture having positively charged N-terminal (Pro-Arg-Gly)3 and negatively charged C-terminal (Glu-Hyp-Gly)3 triad extensions, respectively. CP(+) rapidly self-associates into positively charged nanosheets based on a monolayer structure. In contrast, CP(-) self-assembles to form negatively charged monolayer nanosheets at a much slower rate, which can be accelerated in the presence of calcium(II) ion. A 2:1 mixture of unassociated CP( ) peptide with preformed CP(+) nanosheets generates structurally defined triple layer nanosheets in which two CP(-) monolayers have formed on the identical surfaces of the CP(+) nanosheet template. Experimental data from electrostatic force microscopy (EFM) image analysis, zeta potential measurements, and charged nanoparticle binding assays support a negative surface charge state for the triple-layer nanosheets, which is the reverse of the positive surface charge state observed for the CP(+) monolayer nanosheets. The electrostatic complementarity between the CP(+) and CP(-) triple helical cohesive ends at the layer interfaces promotes a (CP(-)/CP(+)/CP(-)) compositional gradient along the z-direction of the nanosheet. This structurally informed approach represents an attractive strategy for the fabrication of two-dimensional nanostructures with compositional control. PMID- 26021883 TI - Neurofeedback, Self-Regulation, and Brain Imaging: Clinical Science and Fad in the Service of Mental Disorders. AB - Neurofeedback draws on multiple techniques that propel both healthy and patient populations to self-regulate neural activity. Since the 1970s, numerous accounts have promoted electroencephalography-neurofeedback as a viable treatment for a host of mental disorders. Today, while the number of health care providers referring patients to neurofeedback practitioners increases steadily, substantial methodological and conceptual caveats continue to pervade empirical reports. And yet, nascent imaging technologies (e.g., real-time functional magnetic resonance imaging) and increasingly rigorous protocols are paving the road towards more effective applications and a better scientific understanding of the underlying mechanisms. Here, we outline common neurofeedback methods, illuminate the tenuous state of the evidence, and sketch out future directions to further unravel the potential merits of this contentious therapeutic prospect. PMID- 26021884 TI - Verbal cognition in deaf children using cochlear implants: effect of unilateral and bilateral stimulation. AB - The aim of this study is to assess the role of bilateral/bimodal device use in auditory speech perception in complex listening situations and long-term verbal cognition in deaf children using cochlear implants (CIs). Two groups of children are compared (unilateral and bilateral device users) concerning vocabulary, speech perception at conversational level and in complex listening situations, and verbal cognition. In this retrospective study, we collected data of 37 deaf children with normal learning potential of whom 16 were unilateral CI users and 21 were bilateral device users (9 with a bimodal fitting and 12 with bilateral CIs). We came to the conclusion that deaf children who use bilateral devices have the opportunity to develop good speech perception skills in complex listening conditions. These abilities enable at least some of the children to develop age equivalent verbal cognition skills. PMID- 26021885 TI - Gender differences in experiences with and adjustments to infertility: A literature review. AB - BACKGROUND: It has been widely recognized that infertility and its treatment affects a couple as a dyad. Given biomedical differences and differences in socialization processes and gender-role expectations, it is reasonable to suspect that females and males may experience and respond to infertility in different ways. OBJECTIVE: To explore gender differences among infertile couples with regard to experiences with and adjustments to infertility. DESIGN: A literature review. DATA SOURCES: A literature search was performed using the following databases: PubMed, CINAHL, PsycInfo, Web of Science, Scopus, and the China Academic Journal Full-text Database. REVIEW METHODS: The studies that were included were those published in English or Chinese from the years 2000 to 2014. The references of all of the studies selected for this review were also searched. An author search was also performed to retrieve relevant articles. Experiences with and adjustments to infertility were explored from the perspective of gender. RESULTS: A total of 33 studies were included in this review. The experiences with infertility can be grouped under the five domains of the biopsychosocial theory, namely: existential stressors, physical stressors, emotional stressors, interpersonal stressors, and the moderators of stress. In general, females had more negative experiences with infertility than men in most of the domains, including lower levels of identity, self-esteem, and physical health; and higher levels of depression, stress, anxiety, stigma, and shame. Infertile couples experienced stress in their married life, although there were no gender differences in the areas of marital adjustment, marital satisfaction, and sexual satisfaction. Females were likely to perceive themselves as being less confident than their partners in coping with infertility. For both men and women, partner support was found to be negatively related to stress due to infertility. CONCLUSIONS: This review revealed that while there were gender differences in the experience with infertility in many realms, both men and women were subject to a stressful married life. Partner support was an important element of coping with infertility. Therefore, a supportive intervention, focusing on enhancing a sense of partnership among infertile couples is a way of helping them to cope. PMID- 26021886 TI - Comparing Bleeding Complications of Double and Single Access Totally Tubeless PCNL: Is It Safe to Obtain More Accesses? AB - PURPOSE: To assess bleeding complications in totally tubeless double-access percutaneous nephrolithotomy (PCNL) and compare it with the single-access method. METHODS: One hundred and seven patients with large or scattered renal stones were enrolled in this cohort study. Totally tubeless PCNL with one access (group A, 70 cases) or two accesses (group B, 37 cases) was done and bleeding was assessed by measuring the hemoglobin drop of the patients, blood transfusion rate and need for performing angioembolization. RESULTS: The mean (SD) hemoglobin drops in groups A and B were 1.97 (1.24) and 2.31 (1.24), respectively; p = 0.176. Blood transfusion rates in two groups were 7.1 and 10.8% (p = 0.716), respectively. None of our patients required angioembolization. The average hemoglobin drop and blood transfusion rate with double tracts were approximately near to those in single tract group and in acceptable ranges. The average hospital stay in groups A and B were 3.1 and 3.2 days (p = 0.074), respectively. There was no leakage from puncture site/s and stone free rates in the two groups were 85.7 and 97.3% (p = 0.093). CONCLUSION: Totally tubeless double-access PCNL is feasible and bleeding complications are comparable to single access totally tubeless PCNL making it an effective strategy to achieve more stone free rates. PMID- 26021887 TI - Lipoteichoic acid isolated from Lactobacillus plantarum inhibits melanogenesis in B16F10 mouse melanoma cells. AB - Lipoteichoic acid (LTA) is a major component of the cell wall of Gram-positive bacteria. Its effects on living organisms are different from those of lipopolysaccharide (LPS) found in Gram-negative bacteria. LTA contributes to immune regulatory effects including anti-aging. In this study, we showed that LTA isolated from Lactobacillus plantarum (pLTA) inhibited melanogenesis in B16F10 mouse melanoma cells. pLTA reduced the cellular activity of tyrosinase and the expression of tyrosinase family members in a dose-dependent manner. The expression of microphthalmia-associated transcription factor (MITF), a key factor in the synthesis of melanin, was also decreased by pLTA. Further, we showed that pLTA activated melanogenesis signaling, such as extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinse (PI3K)/AKT. In addition, the expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and HuR, which are important RNA-binding proteins (RBPs), was reduced. pLTA likely degrades MITF via regulation of melanogenic signaling and RNA stability of melanogenic proteins, resulting in the reduction of melanin. Thus, our data suggest that pLTA has therapeutic potential for treating hyperpigmentation disorders and can also be used as a cosmetic whitening agent. PMID- 26021888 TI - Characterization of single nucleotide polymorphisms in the promoter region of the bovine paraoxonase 1 (PON1) gene affecting serum enzyme activity in dairy cows. AB - The aim of the present study was to characterize single nucleotide polymorphisms (SNPs) in the promoter region of the bovine paraoxonase 1 (PON1) gene and determine their relationship with PON1 serum activity. Blood samples were collected from 47 Holstein cows during the periparturient period. Serum PON1 was measured and DNA extracted for PCR and sequencing of the promoter region of the PON1 gene. Seven novel SNPs were identified and of these, five SNPs, at positions -105, -221, -392, -611 and -674, upstream of the start of the published mRNA sequence (NM_001046269.2), were found to be associated with variability in serum PON1 activity (P < 0.05). The SNPs at positions -221 and -611 were located in regions predicted to bind to transcription factors linked to the acute phase response. PMID- 26021889 TI - Magnetic resonance compositional imaging of articular cartilage: What can we expect in veterinary medicine? AB - Since cartilage has limited ability to repair itself, it is useful to determine its biochemical composition early in clinical cases. It is also important to assess cartilage content in research animals in longitudinal studies in vivo. In recent years, compositional imaging techniques using magnetic resonance imaging (MRI) have been developed to assess the biochemical composition of cartilage. This article describes MR compositional imaging techniques, and discusses their use and interpretation. Technical concerns still limit the use of some techniques for research and clinical use, especially in veterinary medicine. Glycosaminoglycan chemical-exchange saturation transfer and sodium imaging are better used with high field magnets, which have limited availability. Long acquisition times are sometimes required, for instance in T1rho (rho) and diffusion-weighted imaging, and necessitate general anaesthesia. Even in human medicine, some techniques such as ultra-short echo T2 are not fully validated, and nearly all techniques require validation for veterinary research and clinical practice. Delayed gadolinium-enhanced MRI of cartilage and T2 mapping appear to be the most applicable methods for compositional imaging of animal cartilage. Combining T2 mapping and T1rho allows for the assessment of proteoglycans and the collagen network, respectively. PMID- 26021890 TI - Targeted drug delivery in oncology: where drug discovery meets physics. PMID- 26021891 TI - C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic. AB - Cutaneous mast cell tumours (MCTs) are some of the most common canine neoplasms and their variable and often aggressive biological behaviour makes them particularly challenging for the veterinary practitioner. Over the years, scientists have accumulated a wealth of knowledge on these tumours and developed better prognostic markers and targeted therapies, mostly focused on inhibiting c kit, a protein that plays a major role in the biopathology of MCTs. Masitinib and toceranib, targeted inhibitors of c-kit and other receptor tyrosine-kinases (RTKs), offer the promise of improving the outcome of patients with aggressive MCTs. Much of the available knowledge on MCTs is dispersed, making it difficult for practitioners to benefit when consulting a pathologist or making therapeutic decisions. This article seeks to bring together current knowledge on the biopathology of MCTs, reviewing prognostic markers and their applications, and the development of c-kit inhibitors in the context of the basic cellular, molecular and pathological features of MCTs. Future perspectives following recent biopathological data and experimental therapeutic approaches are also addressed. PMID- 26021892 TI - IgG4-related disease: a primer on diagnosis and management. PMID- 26021893 TI - Tailoring interventions: identifying predictors of poor asthma control. AB - BACKGROUND: Determining the factors that will predict long-term asthma control is essential for improving health outcomes and decreasing the burden on the health care system. Patient-reported outcomes (PROs) on health behaviors can provide valuable information about future asthma control but have rarely been considered in previous analyses. OBJECTIVE: To develop statistical models for evaluating the predictors of long-term asthma control using PROs such as scores of the Asthma Control Test and the Asthma Self-Efficacy Scale. METHODS: Of 1,437 individuals contacted, 566 (39%) at baseline and 486 (34%) at follow-up completed the questionnaires, including 4 PROs (Asthma Control Test, Asthma Self-Efficacy Scale, Mini-Asthma Quality of Life Questionnaire, and Beliefs about Medication Questionnaire). Long-term asthma control was evaluated by assessing overuse of rescue medication and emergency department visits. A multivariate logistic generalized estimating equation model was fitted to evaluate the possible effect of the studied factors on asthma control. RESULTS: The complete case generalized estimating equation analysis included 286 participants who had complete PROs at the 2 evaluation times. After adjusting for socioeconomic status and smoking status, the Mini-Asthma Quality of Life Questionnaire was a significant predictor of asthma exacerbation. For each 1-point increase on the Mini-Asthma Quality of Life Questionnaire, there was a 0.25 decrease in the odds of a patient's asthma getting out of control. CONCLUSION: These findings suggest opportunities to decrease the burden on health care by tailoring interventions that combine PROs with other clinical and sociodemographic variables. PMID- 26021894 TI - Omalizumab adherence in an observational study of patients with moderate to severe allergic asthma. AB - BACKGROUND: Adherence to omalizumab is not well characterized and its association with asthma control has not been well established. OBJECTIVE: To evaluate adherence in patients initiating omalizumab in the Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate to Severe Asthma (EXCELS) observational study. METHODS: Adherence was assessed over 5 years using the proportion of patients who missed any dose, rates of doses missed, and proportions of patients with good (<10% doses missed) or poor (>=30% doses missed) adherence. Multivariable analyses identified independent predictors of good adherence. Associations between adherence and asthma control were assessed using the minimum important difference for the Asthma Control Test at various time points. RESULTS: A total of 289 patients newly initiated on omalizumab completed 5 years of EXCELS. Of these, 83.0% on the 2-week dosing regimen (n = 152) and 65.0% on the 4-week dosing regimen (n = 137) missed at least 1 dose. More frequent dosing was associated with a larger number of missed doses. Older age (odds ratio per year 1.02, 95% confidence interval 1.01-1.03) and lower prebronchodilator percentage of predicted forced expiratory volume in 1 second (<76; odds ratio 1.88, 95% confidence interval 1.09-3.24) were independent predictors of good adherence. CONCLUSION: Adherence to omalizumab is characterized by distinct factors. Patients receiving the 4-week dosing regimen achieved better adherence than those treated every 2 weeks. Improved adherence could be associated with better asthma control. Age and lung function could interact with dosing frequency to affect patient adherence, thus warranting prospective planning at the time of prescribing to support long-term adherence. PMID- 26021895 TI - Acceptability of an interactive asthma management mobile health application for children and adolescents. PMID- 26021896 TI - Utility of delayed reading of intradermal test in carboplatin-induced drug hypersensitivity. PMID- 26021897 TI - Health care professionals' understanding of the use of a metered-dose inhaler. PMID- 26021898 TI - Response to "mold allergy revisited". PMID- 26021899 TI - Authors' response. PMID- 26021900 TI - Author's response. PMID- 26021901 TI - Allergen of the month--annual ryegrass. PMID- 26021902 TI - Highly Cross-Linked Versus Conventional Polyethylene in Posterior-Stabilized Total Knee Arthroplasty at a Mean 5-Year Follow-up. AB - Concerns of highly cross-linked polyethylene (XLPE) in total knee arthroplasty (TKA) exist regarding fatigue resistance and oxidation, particularly in posterior stabilized (PS) designs. A prospective cohort study of 114 consecutive PS TKAs utilized conventional polyethylene in 50 knees and second-generation annealed XLPE in 64 TKAs. Clinical (Short-Form 36, Knee Society Scores, and LEAS) and radiographic outcomes were evaluated at a mean of 5 years in 103 TKAs. Mean KSS scores were 12 points higher (P=0.01) and SF-36 physical function subset 14 points higher (P=0.005) in the XLPE group. There was no radiographic osteolysis or mechanical failure related to the tibial polyethylene in either group. At 5 year follow-up, no deleterious effects related to highly cross-linked posterior stabilized tibial polyethylene inserts were observed. PMID- 26021903 TI - The Effect of Porous Tantalum Cones on Mechanical Alignment and Canal-Fill Ratio in Revision Total Knee Arthroplasty Performed with Uncemented Stems. AB - In revision total knee arthroplasty (TKA), the internal diameter of metal cones may limit the ability of the stem to properly fill the medullary canal. We prospectively studied 115 patients who underwent revision TKA with uncemented stems to evaluate the effect of metal cones on mechanical alignment and stem positioning. Correction on the mechanical alignment was well achieved in all patients, regardless of whether a metal cone was used. The proportion of patients achieving restoration of neutral mechanical alignment was similar between groups, as were the mean canal fill ratio (CFR) and the proportion of patients achieving CFR >= 85%. The use of porous tantalum cones in revision TKA with uncemented stems is not an obstacle in achieving optimal mechanical alignment and stem positioning. PMID- 26021905 TI - Wear Patterns in Knee Articular Surfaces in Varus Deformity. AB - This study was performed to study the relationship between the degree of varus deformity of osteoarthritic knees and the anatomic distribution of cartilage pathology. Bone wafers resected from the distal femur and proximal tibia were obtained from 107 patients (195 knees) with primary varus osteoarthritis. Severity and distribution of joint damage was scored for each articular surface and related to potential prognostic factors, including varus deformity, the ligamentous status of the knee, age, gender and BMI. There was highly significant association between varus angulation of the knee and the total damage score for the tibia (P=0.001), but not the femur (P=0.2947). The degree of deformity, and not the status of the ACL alone, determines wear pattern and provides insight for preoperative planning of TKA. PMID- 26021904 TI - Variability in Distal Femoral Anatomy in Patients Undergoing Total Knee Arthroplasty: Measurements on 13,546 Computed Tomography Scans. AB - Proper mechanical and rotational alignment plays an important role in achieving the success of the total knee arthroplasty (TKA). The purpose of the present study was to retrospectively determine with computed tomography (CT) the distal femoral valgus angle (DFVA) and femoral rotation angle (FRA). Our cohort included 13,546 CT scans of patients undergoing TKA. The average DFVA was 5.7 +/- 2.3 degrees (range from 1 to -16 degrees ) with 13.8% of patients identified as outliers. The distal FRA angle average was 3.3 +/- 1.5 degrees (range from -3 to 11 degrees ) with 2.8% of patients identified as outliers. These data can be useful in making orthopedic surgeons aware of the variability of femoral anatomy. Using the same cutting angle may lead to malposition of the femoral component. PMID- 26021906 TI - Early Postoperative Outcomes of Primary Total Knee Arthroplasty After Solid Organ Transplantation in the United States, 1998-2011. AB - This review of the Nationwide Inpatient Sample (1998-2011) examined trends in solid organ transplant patients who received a total knee arthroplasty (TKA) to determine whether length of stay (LOS), cost, and perioperative complications differed from non-transplant peers. Primary TKA patients (n=5,870,421) were categorized as: (1) those with a history of solid organ transplant (n=6104) and (2) those without (n=5,864,317). Propensity matching was used to estimate adjusted effects of solid organ transplant history on perioperative outcomes. The percentage of TKA patients with a transplant history grew during the study period from 0.069% to 0.103%. Adjusted outcomes showed patients with a transplant had a 0.44 day longer LOS, $962 higher cost of admission, and were 1.43 times more likely to suffer any complication (P=0.0002). PMID- 26021907 TI - Postoperative Deep Infection After Cemented Versus Cementless Total Hip Arthroplasty: A Meta-Analysis. AB - Periprosthetic joint infection (PJI) is a serious complication of total hip arthroplasty (THA). The objective of this meta-analysis was to compare the PJI rate between cemented and cementless THAs. Eight clinical studies (2 randomized controlled trials and 6 observational studies) were available for the analysis. Meta-analysis (with a fixed-effects model) and subgroup analysis were performed by research design and meta-regression was performed by continuous moderator. The overall incidence of PJI was 0.4% (357/84,200). The incidence was 0.5% (310/67,531) in cemented group, and 0.3% (47/16,669) in cementless group (P=0.008). The meta-analysis revealed that the use of cement in THA was associated with an increased risk of PJI (odds ratio 1.53; 95% confidence interval 1.120 to 2.100; P=0.008). PMID- 26021908 TI - Template-Directed Instrumentation Reduces Cost and Improves Efficiency for Total Knee Arthroplasty: An Economic Decision Analysis and Pilot Study. AB - Template-directed instrumentation (TDI) for total knee arthroplasty (TKA) may streamline operating room (OR) workflow and reduce costs by preselecting implants and minimizing instrument tray burden. A decision model simulated the economics of TDI. Sensitivity analyses determined thresholds for model variables to ensure TDI success. A clinical pilot was reviewed. The accuracy of preoperative templates was validated, and 20 consecutive primary TKAs were performed using TDI. The model determined that preoperative component size estimation should be accurate to +/-1 implant size for 50% of TKAs to implement TDI. The pilot showed that preoperative template accuracy exceeded 97%. There were statistically significant improvements in OR turnover time and in-room time for TDI compared to an historical cohort of TKAs. TDI reduces costs and improves OR efficiency. PMID- 26021909 TI - Genome Sequence of an Alphabaculovirus Isolated from the Oak Looper, Lambdina fiscellaria, Contains a Putative 2-Kilobase-Pair Transposable Element Encoding a Transposase and a FLYWCH Domain-Containing Protein. AB - The genome sequence of an alphabaculovirus isolated from Lambdina fiscellaria indicated that it is a novel member of a group II lineage. A putative transposable element was identified that contained two genes, including a transposase ortholog. These genes were most closely related to genes of the pea aphid, Acyrthosiphon pisum. PMID- 26021910 TI - Draft Genome Sequences of Three Capnocytophaga canimorsus Strains Isolated from Septic Patients. AB - Capnocytophaga canimorsus is a bacterium from the normal oral flora of dogs and cats that causes rare generalized infections in humans. In an attempt to determine whether infections could be caused by a subset of strains and to identify pathogenicity factors, we sequenced the genomes of three strains isolated from human infections. PMID- 26021911 TI - Novel HIV-1 Recombinant Identified in a Foreign Heterosexual Resident in Japan: Relatedness to Recently Reported CRF69_01B, Detected Primarily among Japanese Men Who Have Sex with Men. AB - We report here an HIV-1 recombinant composed of CRF01_AE and subtype B, with a total of eight recombination breakpoints in the gag-pol and vpr-tat regions. This recombinant was identified from a Myanmarese heterosexual male in Japan and showed the chimera structure identical to recently reported CRF69_01B, detected primarily among men who have sex with men in Japan. PMID- 26021912 TI - Draft Genome Sequences of Three Capnocytophaga canimorsus Strains Isolated from Healthy Canine Oral Cavities. AB - Here, we present the draft genome sequences of three strains of Capnocytophaga canimorsus, each isolated from a different dog's mouth. Genome analysis provided evidence that these organisms may belong to a different nonpathogenic subtype of C. canimorsus. PMID- 26021913 TI - Draft Genome Sequences of Three Capnocytophaga cynodegmi Strains Isolated from the Oral Cavity of Healthy Dogs. AB - Here, we present the draft genome sequences of three strains of Capnocytophaga cynodegmi. In contrast to the very close relationship among them, C. cynodegmi and Capnocytophaga canimorsus differ dramatically in terms of virulence in humans. Comparative genomics provided some understanding on how Capnocytophaga species may switch from being dog commensals to human pathogens. PMID- 26021914 TI - Draft Genome Sequence of the Archiascomycetous Yeast Saitoella complicata. AB - The draft genome sequence of the archiasomycetous yeast Saitoella complicata was determined. The assembly of newly and previously sequenced data sets resulted in 104 contigs (total of 14.1 Mbp; N 50, 239 kbp). On the newly assembled genome, a total of 6,933 protein-coding sequences (7,119 transcripts, including alternative splicing forms) were identified. PMID- 26021915 TI - Draft Genome Sequence of 24570, the Type Strain of Shigella flexneri. AB - Shigella flexneri is a diarrheal pathogen that causes a large disease burden worldwide. We sequenced the genome of the publicly available type strain (S. flexneri 2a strain 24570) of this bacterial species to increase its utility as a reference. We present genome assembly results and comparisons with other reference strains. PMID- 26021916 TI - Draft Genome Sequence of Bacillus sp. Strain CMAA 1185, a Cellullolytic Bacterium Isolated from Stain House Lake, Antarctic Peninsula. AB - The aim of this study was to report the genome sequence of the cellulolytic Bacillus sp. strain CMAA 1185, isolated from Stain House Lake, Antarctica. PMID- 26021917 TI - Whole-Genome Sequence of a Novel Hantavirus Isolated from the European Mole (Talpa europaea). AB - The complete genome sequence of Nova virus, a novel hantavirus isolated from a European mole (Talpa europaea) captured in central Poland, was determined. The availability of this sequence will facilitate the search for other mole-borne hantaviruses and will accelerate the acquisition of new knowledge about their phylogeography and evolutionary origin. PMID- 26021918 TI - Draft Genome Sequence of Vibrio sp. Strain Vb278, an Antagonistic Bacterium Isolated from the Marine Sponge Sarcotragus spinosulus. AB - We report here the draft genome sequence of Vibrio sp. Vb278, a biofilm-producing strain isolated from the marine sponge Sarcotragus spinosulus, showing in vitro antibacterial activity. The annotated genome displays a range of symbiotic factors and the potential for the biosynthesis of several biologically active natural products. PMID- 26021919 TI - Draft Genome Sequence of Enterohemorrhagic Escherichia coli O157 NCCP15739, Isolated in the Republic of Korea. AB - Enterohemorrhagic Escherichia coli (EHEC) is the main cause of the recent outbreaks of diarrhea, hemolytic-uremic syndrome (HUS), and hemorrhagic colitis worldwide. Herein, we present the draft genome sequence of the NCCP15739 isolate from a patient in the Republic of Korea. PMID- 26021920 TI - Draft genome sequences of 24 microbial strains assembled from direct sequencing from 4 stool samples. AB - The ability to assemble genomes from metagenomic sequencing avoids the need for culture and any associated culture biases. We assembled 24 essentially complete draft genomes from metagenomic pair-end and size-selected mate pair sequencing from 4 stool samples, 2 from subjects diagnosed with colorectal cancer and 2 from healthy controls. PMID- 26021921 TI - Draft Genome Sequence of Aneurinibacillus tyrosinisolvens LL-002T, Which Possesses Some Pseudouridine Synthases. AB - We report the 5.7-Mb draft genome sequence of Aneurinibacillus tyrosinisolvens strain LL-002(T), isolated from organic- and methane-rich sea sediments. The draft genome sequence of strain LL-002(T) consists of 5,693,818 bp in 136 contigs, with a G+C content of 44.5%, 5,946 potential coding sequences (CDS), 2 rRNAs, and 39 tRNAs. PMID- 26021922 TI - Whole-Genome Sequence of Serratia liquefaciens HUMV-21, a Cytotoxic, Quorum Sensing, and Biofilm-Producing Clinical Isolate. AB - A clinical isolate of Serratia liquefaciens (strain HUMV-21) was obtained from a skin ulcer of an adult patient. We report here its complete genome assembly using PacBio single-molecule real-time (SMRT) sequencing, which resulted in a single circular chromosome with 5.3 Mb. About 5,844 protein-coding genes are predicted from this assembly. PMID- 26021923 TI - Draft Genome Sequence of Mycobacterium chelonae Type Strain ATCC 35752. AB - Mycobacterium chelonae is a rapidly growing opportunistic nontuberculous mycobacterial (NTM) species that causes infections in humans and other hosts. Here, we report the draft genome sequence of Mycobacterium chelonae type strain ATCC 35752, consisting of 4.89 Mbp, 63.96% G+C content, 4,489 protein-coding genes, 48 tRNAs, and 3 rRNA genes. PMID- 26021925 TI - Genome Sequence of Banana Streak MY Virus from the Pacific Ocean Island of Tonga. AB - Banana streak disease is caused by a variety of banana-infecting badnaviruses. A genome of the episomal form of a banana streak MY virus was recovered from an infected banana plant sampled on Vava'u Island, Tonga, and shares >98% pairwise identity with the six other genomes available in public databases. PMID- 26021924 TI - Genome Anatomy of Streptococcus parasanguinis Strain C1A, Isolated from a Patient with Acute Exacerbation of Chronic Obstructive Pulmonary Disease, Reveals Unusual Genomic Features. AB - Streptococcus parasanguinis causes invasive diseases. However, the mechanism by which it causes disease remains unclear. Here, we describe the complete genome sequence of S. parasanguinis C1A, isolated from a patient diagnosed with an acute exacerbation of chronic obstructive pulmonary disease. Several genes that might be associated with pathogenesis are also described. PMID- 26021926 TI - Draft Genome Sequence of Mycoparasite Clonostachys rosea Strain 67-1. AB - Clonostachys rosea is a promising mycoparasite. In this study, we sequenced the draft genome of the highly effective strain 67-1 using the Illumina HiSeq 2500 sequencing platform. The genome is 55.4 Mb with a G+C content of 49.2% and provides a powerful resource for future studies on the molecular mechanisms underlying Clonostachys rosea's antagonism on fungal pathogens. PMID- 26021927 TI - Complete Genome Sequence of Sulfolobus solfataricus Strain 98/2 and Evolved Derivatives. AB - Sulfolobus solfataricus is a thermoacidophilic crenarcheote with a 3.0-Mb genome. Here, we report the genome sequence of S. solfataricus strain 98/2, along with several evolved derivatives generated through experimental microbial evolution for enhanced thermoacidophily. PMID- 26021928 TI - Complete Genome Sequence of Microcystis aeruginosa NIES-2549, a Bloom-Forming Cyanobacterium from Lake Kasumigaura, Japan. AB - Microcystis aeruginosa NIES-2549 is a freshwater bloom-forming cyanobacterium isolated from Lake Kasumigaura, Japan. We report the complete 4.29-Mbp genome sequence of NIES-2549 and its annotation and discuss the genetic diversity of M. aeruginosa strains. This is the third genome sequence of M. aeruginosa isolated from Lake Kasumigaura. PMID- 26021929 TI - Genome Sequence of Lactobacillus curieae CCTCC M 2011381T, a Novel Producer of Gamma-aminobutyric Acid. AB - Lactobacillus curieae CCTCC M 2011381(T) is a novel species of the genus Lactobacillus and a gamma-aminobutyric acid producer that was isolated from stinky tofu brine. Here, we present a 2.19-Mb assembly of its genome, which may provide further insights into the molecular mechanisms underlying its beneficial properties. PMID- 26021930 TI - Complete Genome Sequence of Listeria monocytogenes N2306, a Strain Associated with the 2013-2014 Listeriosis Outbreak in Switzerland. AB - We present the complete genome sequence of Listeria monocytogenes N2306, a serotype 4b clinical strain isolated during the 2013-2014 nationwide listeriosis outbreak in Switzerland. PMID- 26021931 TI - Complete Genome Sequence of an Evolved Thermotoga maritima Isolate. AB - Thermotoga maritima is a hyperthermophilic bacterium with a small genome (1.86 Mbp). Genome resequencing of Tma200, a derivative produced by experimental microbial evolution, revealed the occurrence of deletions and substitution mutations. Their identification contributes to a better understanding of genome instability in this organism. PMID- 26021932 TI - Complete Genome Sequence of Uropathogenic Escherichia coli Strain CI5. AB - Escherichia coli represents the primary etiological agent responsible for urinary tract infections, one of the most common infections in humans. We report here the complete genome sequence of uropathogenic Escherichia coli strain CI5, a clinical pyelonephritis isolate used for studying pathogenesis. PMID- 26021933 TI - Complete genome sequence of a novel circovirus from zebra finch. AB - A novel circovirus was identified in zebra finches (Taeniopygia guttata). The genome of the circovirus strain, designated 8454V25-1, comprised 1,982 nucleotides with two major open reading frames encoding a replication-associated protein and a viral capsid protein. PMID- 26021934 TI - Complete Genome Sequence of Mycoplasma synoviae Strain WVU 1853T. AB - A hybrid sequence assembly of the complete Mycoplasma synoviae type strain WVU 1853(T) genome was compared to that of strain MS53. The findings support prior conclusions about M. synoviae, based on the genome of that otherwise uncharacterized field strain, and provide the first evidence of epigenetic modifications in M. synoviae. PMID- 26021935 TI - Pandoraea sp. Strain E26: Discovery of Its Quorum-Sensing Properties via Whole Genome Sequence Analysis. AB - We report the draft genome sequence of Pandoraea sp. strain E26 isolated from a former landfill site, sequenced by the Illumina MiSeq platform. This genome sequence will be useful to further understand the quorum-sensing system of this isolate. PMID- 26021936 TI - Draft Genome Sequence of Isoproturon-Mineralizing Sphingomonas sp. SRS2, Isolated from an Agricultural Field in the United Kingdom. AB - Sphingomonas sp. SRS2 was the first described pure strain that is capable of mineralizing the phenylurea herbicide isoproturon and some of its related compounds. This strain has been studied thoroughly and shows potential for bioremediation purposes. We present the draft genome sequence of this bacterium, which will aid future studies. PMID- 26021937 TI - Complete Genome Sequence of Corynebacterium kutscheri DSM 20755, a Corynebacterial Type Strain with Remarkably Low G+C Content of Chromosomal DNA. AB - The complete genome sequence of the type strain Corynebacterium kutscheri DSM 20755 comprises 2,354,065 bp and 2,047 protein-coding genes. The mean G+C content of the chromosomal DNA is 46.46%, which is the lowest value detected so far in a member of the genus Corynebacterium. PMID- 26021938 TI - Complete Genome Sequence of Corynebacterium camporealensis DSM 44610, Isolated from the Milk of a Manchega Sheep with Subclinical Mastitis. AB - Corynebacterium camporealensis has been isolated in pure culture from milk samples of dairy sheep affected by subclinical mastitis. The complete genome sequence of the type strain DSM 44610, recovered from milk of a Manchega sheep, comprises 2,451,810 bp with a mean G+C content of 59.41% and 2,249 protein-coding genes. PMID- 26021939 TI - Descriptive analysis of endoscopic findings in patients with a family history of colorectal cancer. AB - BACKGROUND: The presence of a family history implies an increased risk for developing colorectal cancer (CRC), and may require a different screening strategy. The aim of this study was to evaluate lesions found during colonoscopies of patients that had a family history of CRC. MATERIAL AND METHODS: A retrospective study was conducted that included consecutive colonoscopies performed on patients with a family history of CRC at a referral center within the period from April 2000 to January 2012. The colonoscopic findings were analyzed in relation to sex, age, and the presence or absence of symptoms. RESULTS: Data from 3,792 colonoscopies were collected. The mean age of the patients was 53.14 years (SD 12.22), and 57.4% were women. Colonoscopy was normal in 71.7% of the cases, with hyperplastic polyps being detected in 7.1%, and adenomatous polyps in 19.8% (39.4% of them were high risk). There was a 1.5% presence of adenocarcinomas in the subjects. Polyps and CRC were predominant in men (P=.001 and P=.027, respectively) and there was a linear increase with age. Symptomatic patients had a higher CRC detection rate (P<.001), but no differences were observed in relation to polyp diagnosis. CONCLUSIONS: Age and male sex increased the risk for presenting with CRC or adenomas in the group of patients with a family history of CRC, and the presence of symptoms was associated with a greater risk for presenting with CRC. PMID- 26021940 TI - Informed consent in colonoscopy: A comparative analysis of 2 methods. AB - BACKGROUND: The manner in which informed consent is obtained varies. The aim of this study is to evaluate the level of knowledge about colonoscopy and comparing 2 methods of obtaining informed consent. MATERIALS AND METHODS: A comparative, cross-sectional, observational study was conducted on patients that underwent colonoscopy in a public hospital (Group A) and in a private hospital (Group B). Group A received information verbally from a physician, as well as in the form of printed material, and Group B only received printed material. A telephone survey was carried out one or 2 weeks later. RESULTS: The study included a total of 176 subjects (group A [n=55] and group B [n=121]). As regards education level, 69.88% (n=123) of the patients had completed university education, 23.29% (n= 41) secondary level, 5.68% (n=10) primary level, and the remaining subjects (n=2) had not completed any level of education. All (100%) of the subjects knew the characteristics of the procedure, and 99.43% were aware of its benefits. A total of 97.7% received information about complications, 93.7% named some of them, and 25% (n=44) remembered major complications. All the subjects received, read, and signed the informed consent statement before the study. There were no differences between the groups with respect to knowledge of the characteristics and benefits of the procedure, or the receipt and reading of the consent form. Group B responded better in relation to complications (P=.0027) and group A had a better recollection of the major complications (P<.0001). Group A had a higher number of affirmative answers (P<.0001). CONCLUSIONS: The combination of verbal and written information provides the patient with a more comprehensive level of knowledge about the procedure. PMID- 26021941 TI - Facial transplantation: history and update. AB - BACKGROUND: Composite tissue allografting (CTA) represents the essence of reconstructive surgery, combining principles of solid organ transplantation (SOT) and modern plastic surgery techniques. The purpose of this article is to give a review of the history of facial CTA and an update of the cases that have been operated so far worldwide. METHODS: A systematic review of the medical literature was performed. Ten relevant publications were selected and analyzed for clinical data of the patients, surgical aspects of transplantation, complications and outcome. RESULTS: The past 9 years, 31 face transplants have been performed worldwide. The main indication was posttraumatic deformity. In all cases standard triple drug immunosuppression as used in SOT was successfully used and at least 1 period of acute rejection was seen in all patients, controllable with conventional immunosuppressive regimens. Overall functional outcomes are good and satisfaction rate is high, surpassing initial expectations. The main complications are opportunistic infections; 4 deaths occurred. CONCLUSIONS: Facial CTA is a life changing procedure and has led to new treatment options for patients with complex, devastating and otherwise unreconstructable facial deformities to restore appearance and overall wellbeing in a single operation. The key to success lies in the selection of the appropriate patient, who is stable, well-motivated and therapy compliant. Thorough screening and follow-up by a multidisciplinary team, well prepared surgical approach and intensive, early rehabilitation are all crucial factors for minimizing complications and a safe and rapid recovery. PMID- 26021942 TI - Advances in tissue engineering; a novel technology making use of an in vivo vascularized chamber. AB - INTRODUCTION: Regenerative therapies aim to repair or replace damaged tissues. Clinical applications may vary from organ replacement, to breast reconstruction or limb regeneration. In growing 3-dimensional tissue constructs, access to a nourishing vascular network is essential. METHODS: In rats, an arteriovenous loop was surgically established from the femoral vessels and positioned inside a perforated chamber in the groin. Chambers were filled with 2 ml Adipogel, a novel acellular tissue engineering gel -containing growth factors and polymers. Constructs were harvested at 6 and 12 weeks (n=6) and assessed for volume and histological content. RESULTS: The chambers filled with tissue to about half of their content. Histological assessment showed growth of different tissue types within the chamber; not only had a vascular network grown throughout the construct by 12 weeks, adipose, muscular and connective tissue was abundantly present as well. The grown tissue-types seemed to resemble surrounding groin tissue. CONCLUSIONS: This in vivo study makes use of a novel technology for tissue generation. In a surgically established vascularized chamber, spontaneous tissue growth within an acellular gel was achieved. Most likely, stem cells residing in adjacent tissues were driven to the chamber to form new tissue. With this technology, hope rises for a variety of novel patient-tailored therapies, such as organ regeneration or soft tissue repair. In all of these strategies, the surgeon is playing an essential role. PMID- 26021943 TI - Preliminary results after Single-Incision Laparoscopic Colorectal Surgery. AB - OBJECTIVE: Single-incision laparoscopic surgery (SILS) represents the recent advance in laparoscopic surgery claiming to be less invasive than conventional laparoscopic surgery. This study investigates the feasibility and safety of the procedure in colorectal surgery and reports the experiences in our center. METHODS: We retrospectively evaluated 41 consecutive patients surgically treated in our institution (February 2011-April 2013). The patient characteristics were evaluated for: gender, age, body mass index and ASA-score. Data included: indication, procedure, intraoperative complications, operation time, number of lymph nodes, postoperative complications, length of stay (LOS), morbidity and cosmesis. RESULTS: SILS was performed in 41 patients including 9 patients with colorectal cancer resection. We performed 3 ileocaecal resections, 11 right hemicolectomies, 7 sigmoidectomies and 20 rectosigmoidectomies. The operation time ranged from 45-210 min (median 123 min). Number of lymph nodes identified, ranged from 1-37 (median n=8). Six post-operative complications (14%) occurred: 1 gastroparesis, 1 subobstruction, 1 anastomotic leak and 3 patients needed a blood transfusion postoperatively. Median LOS was 6 days (range 4-21 days). One delayed complication (2,4%) occurred (eventration). None of the patients died. All patients had satisfactory cosmetic results. CONCLUSIONS: With the proviso that the study population was limited in size, SILS is feasible and is a save procedure in colorectal surgery and the procedure has an obvious cosmetic benefit. The results are comparable to other international reports. Still the procedure should be restricted to selected patients and performed by experienced surgeons. Additional prospective studies are essential to define the further benefit. PMID- 26021944 TI - Single-port laparoscopic appendectomy in children: single center experience in 50 patients. AB - BACKGROUND: Recent years evolution of minimal invasive laparoscopic procedures led to new techniques, like single-port laparoscopy (SPL), resulting in nearly scarless procedures. The purpose of this study is to evaluate that SPL appendectomy is a safe and feasible procedure using a commercially available trocar (LESS: Laparo Endoscopic Single Site trocar; Olympus TriPort+) in pediatric patients. METHODS: From July 2011 to March 2014 all patients undergoing SPL appendectomy under 18 years were included in this retrospective study. Per- en postoperative data were collected in a prospective database. RESULTS: A total of 50 children (mean age 12 years) diagnosed as acute appendicitis underwent SPL appendectomy. SPL appendectomy was feasible and safe in all cases, both in non perforated and perforated appendicitis. In one procedure (2%) an extra trocar was placed. Seven patients (14%) were readmitted to the hospital after initial uncomplicated postoperative course. One patient (2%) needed reoperation due to a wound abscess. Three patients (6%) were readmitted due to intra-abdominal abscesses for which antibiotics were given. CONCLUSIONS: SPL appendectomy is a safe and feasible procedure in children with acute appendicitis. PMID- 26021945 TI - Mortality after gastrectomy: a 10 year single institution experience. AB - BACKGROUND: Although the general postoperative mortality rate after gastrectomy is decreasing worldwide, it still varies in individual centers and regions of the world. The objective of our work was to analyze the postoperative mortality rate at the Institute of Oncology, Vilnius University over a period of 10 years. METHODS: All patients who underwent total and subtotal gastrectomy for gastric cancer between 2003-2012 were retrospectively analyzed. Comprehensive evaluation of postoperative mortality was done according to the age, sex, comorbidities, BMI, tumor stage, extent or resection and lymphadenectomy, splenectomy, neoadjuvant chemotherapy and stage of disease. The causes of death were also analyzed. RESULTS: The analysis of postoperative mortality for patients treated for gastric cancer in the period of 2003-2012 revealed that 1676 surgeries were performed with 54 lethal outcomes (3.22%). Complication rate was 20.58%. 1011 subtotal gastrectomies were performed with 24 lethal cases (2.37%). 30 patients died after 665 total gastrectomies (4.51%). The vast majority of deceased patients were older than 60 years (92.6%) and had advanced gastric cancer--stage III and IV (70.4%). 33 of 54 patients died from non-surgical complications (61.1%). Surgical complications accounted for 35.2% of dead patients, which totals 19 of 54 patients. Progression of cancer and cachexia caused the deaths of 3.7% of patients. CONCLUSIONS: Elderly age, comorbidities, advanced stage of tumor and disease, and more radical surgery are related with higher postoperative mortality. The most common cause of death was pulmonary arterial thromboembolism. Therefore, risk assessment of venous thrombosis and thromboembolism prophylaxis should be an important component of gastric cancer surgical treatment. PMID- 26021946 TI - Outcomes following major emergency gastric surgery: the importance of specialist surgeons. AB - BACKGROUND: The increasing subspecialisation of general surgeons in their elective work may result in problems for the provision of expert care for emergency cases. There is very little evidence of the impact of subspecialism on outcomes following emergency major upper gastrointestinal surgery. This prospective study investigated whether elective subspecialism of general surgeon is associated with a difference in outcome following major emergency gastric surgery. METHODS: Between February 1994 and June 2010, the data from all emergency major gastric procedures (defined as patients who underwent laparotomy within 12 hours of referral to the surgical service for bleeding gastroduodenal ulcer and/or undergoing major gastric resection) was prospectively recorded. The sub-specialty interest of operating surgeon was noted and related to post operative outcomes. RESULTS: Over the study period, a total of 63 major gastric procedures were performed of which 23 (37%) were performed by specialist upper gastrointestinal (UGI) consultants. Surgery performed by a specialist UGI surgeon was associated with a significantly lower surgical complication (4% vs. 28% of cases; p=0.04) and in-patient mortality rate (22% vs. 50%; p=0.03). CONCLUSIONS: Major emergency gastric surgery has significantly better clinical outcomes when performed by a specialist UGI surgeon. These results have important implications for provision of an emergency general surgical service. PMID- 26021947 TI - Long term outcome after lichtenstein hernia repair using general, locoregional or local anaesthesia. AB - BACKGROUND: Chronic pain or discomfort after hernia surgery is nowadays a more challenging concern than recurrence. This study aimed to evaluate the long-term impact of local anaesthetic repair (LA) on pain, discomfort, paraesthesia and functional outcome after Lichtenstein hernia repair as compared to locoregional (LRA) and general anaesthesia (GA). METHODS: patients with primary or recurrent inguinal hernia underwent Lichtenstein repair with a polypropylene mesh. All patients with a follow-up of at least three years were sent a detailed questionnaire and offered an outpatient visit. Kaplan-Meier estimates and Cox proportional hazard regressions were used to analyse the relationship between time to event variables and explanatory variables including anaesthesia type. RESULTS: Between 1994 and 2006, in two cohorts, 330 patients answered the questionnaire: 100 under GA, 35 under LRA, and 195 under LA. This represented a response rate of 95, 94, and 98% respectively. Compared to GA and LRA, LA resulted in less long term pain, discomfort and paraesthesia. Moreover, resumption of social and professional activities was faster after LA. Recurrence rates were 1, 0, and 0.5% respectively. CONCLUSIONS: After Lichtenstein inguinal hernia repair, LA results in beneficial effects beyond the immediate postoperative period. PMID- 26021948 TI - The Telematics Surgical Training Logbook in Belgium: dream or reality? AB - BACKGROUND: The French Chamber of the Recognition Commission for General Surgery decided to launch the Telematics Surgical Logbook for the academic period 2012 2013 which replaced the previous excel version logbook of surgery. The aim of this article is to describe the process of development, the possibilities and the configuration of this program. METHODS: In this telematics logbook, statistical feedback is interactive and allows surgeons candidates, supervisors and members of the Commission to follow training in real time. Utilities were developed to make the correlation with the previous logbook allowing all levels trainees to be recruited. Quotas of operations, fixed as 38% of the standard deviation, less than average values, are computed for the different surgical common trunks (after 2, 4 and 6 years). The trainee's autonomy can be estimated by a "corrected fraction" of activity taking into account the heaviness of operations. RESULTS: Until October 2014, 218 surgeons in specialization and 32 supervisors were registered. We counted around 118.000 surgical procedures of which 52.600 were included in comparative statistics. At the end of October 2014 the first 29 annual logbooks, including 4 agreements, were analyzed and closed by the Commission. CONCLUSIONS: This telematics tool, able to work on computers, tablets and Smartphones, facilitates the mission of the surgical Commission and gives the cartography of the traineeship organization. PMID- 26021949 TI - The World Health Organisation's Surgical Safety Checklist in Belgian Operating Theatres: a Content-Driven Evaluation. AB - OBJECTIVE: It is unclear which items of the WHO surgical safety checklist are most -crucial for producing its associated benefits. Thoughtless modification, especially removing items, can therefore potentially lead to reduced effectiveness of the instrument. This study describes the modifications made by Belgian hospitals. METHODS: An online survey was used to find out which checklists are used. An expert panel conducted a content-driven evaluation of the retrieved checklists by verifying the presence of the WHO items and evaluating any modifications made. RESULTS: All hospitals participating in the survey (n=36) reported the use of a surgical safety checklist. Based on self-report, 69.4% (n=25) of hospitals reported to use all WHO items. The expert panel determined that 17.1% (n=6) of checklists included all WHO items. Inclusion ranged from 7 to 22 items (mean=16.6, Std. Dev.=4.48). Detailing on the functional parts of the checklist, 48.6% (n=17) of checklists contained all sign-in items, 25.7% (n=9) contained all time-out items and 37.1% (n=13) enclosed all sign-out items. Sixty percent (n=21) of checklists added items not -mentioned in the original WHO checklist. CONCLUSIONS: The modifications made to the WHO checklist vary between hospitals. Only a small number of hospitals included all 22 WHO items. It is unknown whether these modified checklists will be equally effective in decreasing the number of postoperative complications, including mortality. More detailed recommendations and guidance regarding the modification of the WHO surgical checklist is required. PMID- 26021950 TI - Primary presacral adenocarcinoma: a case report and review of the literature. AB - Primary presacral adenocarcinoma is a rare presacral lesion. We report a 36-year old male patient with -primary presacral adenocarcinoma. The patient presented with a six-month history of sacrococcygeal pain. MRI demonstrated a 4*3 cm2, well defined presacral mass. He underwent a parasacrococcygeal procedure with complete resection of the -tumor, which subsequent histology showed adenocarcinoma. At 15 months follow-up, he remains disease free. PMID- 26021951 TI - Gallstone Ileus Post-cholecystectomy. AB - Gallstone ileus is a rather rare condition and in most cases it involves a cholecysto-enteric fistula, through which a gallstone passes into the bowel. If the gallstone is large enough it may obstruct the bowel and a gallstone ileus emerges. In the presented case, the patient was subjected to a cholecystectomy over 40 years ago, but despite this, he developed a gallstone ileus. A gallstone that obstructed the small bowel was suspected with computed tomography and confirmed with exploratory laparotomy. Although a few cases of gallstone ileus after cholecystectomy are described in the literature, our case describes a unique pathogenic mechanism. PMID- 26021952 TI - Stent Graft Dislocation after EVAR Treated with an Endostapling Fixation System. AB - Stent-graft migration and type I endoleak are major complications after endovascular aneurysm repair (EVAR). We present a case of an 88-year-old female patient with a 56-mm-diameter progredient infrarenal AAA, with severely angulated proximal aneurysm neck and iliac arteries. EVAR was performed using a Gore Excluder stent-graft. -Computed tomography angiography (CTA) at one week postoperatively demonstrated a dislocation of the stent-graft and a proximal Type I endoleak. Placement of a proximal cuff with the use of 6 endostaples resulted in proximal neck seal and exclusion of the endoleak. CTA 2 years postoperatively showed no signs of a proximal type I endoleak. Use of an endostapling fixation system is a viable treatment option in cases of stent-graft dislocation resulting from angulation of the proximal neck. PMID- 26021953 TI - Transanal endoscopic microsurgery following treatment with imatinib : a case report of a patient with a rectal gastrointestinal stromal tumor. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) of the rectum are a challenge for the colorectal surgeon. In case of a locally advanced rectal GIST, an extended or multivisceral resection with significant morbidity and -mortality is often necessary. Literature is lacking on the combined modality of transanal endoscopisc microsurgery (TEM) following imatinib for these patients. METHODS: We describe a combined approach for a locally advanced GIST of the rectum with preoperative imatinib -treatment and subsequent local excision using the TEM procedure. RESULTS: After six months of treatment with imatinib the TEM procedure was successfully performed with a radical -resection of the remnant tumor. Twenty four months after surgery this patient has no evidence of disease. CONCLUSIONS: A TEM procedure following treatment with imatinib may safely be performed in selected patients with a locally advanced GIST. PMID- 26021954 TI - I. Juvara (1913-1996), a surgeon for all seasons. AB - Ion Juvara is a creator of a genuine Romanian school of surgery. If I. Juvara had lived and worked in a country that had been the proud owner of a Pantheon, undoubtedly he would have rested there to the end of time, among the eternal ones i.e. those who triumphed against time and who had never been defeated. If the first generation of Romanian surgeons represented mainly by Thoma Ionesco (1860 1926) was educated mainly abroad, the next generation was trained professionally at the Romanian school of surgery. Despite of the hostile period he lived in, I. Juvara kept intact his freedom of thinking and opposed with all his powers abuses of any kind, always preserving his integrity, avoiding with elegance the traps of the totalitarian regime. But even so nobody can state that the professor, who came from -Moldavia, as his master, N. Hortolomei, could not say at the end of his life that he hadn't had a fulfilled professional life, as he is considered even today the greatest surgeon of Romania in the latter half of the 20th century. He was, after all, a surgeon for all seasons. PMID- 26021955 TI - Long head of biceps femoris flap in anal fistula treatment: anatomical study and case report. AB - In case of complex anal fistulae, the treatment can include muscular flaps. The gracilis transposition flap is the gold-standard in perineal reconstructive surgery, with wide use during the past decades. However, in some cases, this flap is too short to reach difficult locations such as the posterior perineum. The long head of the biceps femoris, which has already been studied in the electrically stimulated neosphincter formation, could be more appropriate in such clinical situations. Furthermore, its potential advantages, amongst which an excellent functional outcome, would be to allow persistent prone position, during both treatment and reconstruction, as well as a more favorable intramuscular vascularisation. We report the case of a 39-year-old man with a complex recurrent transphincteric posterior anal fistula with an external orifice in the right buttock and complicated with a severe cellulitis, treated with an endo-anal flap combined with a long head of biceps femoris pediculised flap. PMID- 26021956 TI - Lung salvage by pulmonary arterioplasty after vascular injury during video assisted thoracoscopic surgical right upper lobectomy. AB - Video Assisted Thoracoscopic Surgical (VATS) lobectomy is now considered feasible and safe. Nevertheless, thoracic surgeons need to be aware of dramatic complications that may occur during this procedure and how best to manage them. We report the case of a severe tear of the right pulmonary artery (PA) during elective VATS upper lobectomy, leading to emergency conversion to control the bleeding. Initial arterial repair was performed by end-to-end anastomosis. Early CT angiography showed thrombosis of the right PA due to anastomotic stenosis. We performed emergency pulmonary arterioplasty with a prosthetic patch to save the right lung. A CT scan days after surgical lung salvage confirmed the permeability of the PA and normal vascularization of the two remaining right lobes. We discuss herein this dramatic complication of VATS lobectomy, the viability of the lung after pulmonary arterial thrombosis, and advocate for early postoperative imaging after pulmonary arterioplasty. PMID- 26021957 TI - [Acupuncture in Germany today - from euphoria to disillusion]. PMID- 26021958 TI - Autonomic Function in Seasonal Allergic Rhinitis and Acupuncture - an Experimental Pilot Study within a Randomized Trial. AB - BACKGROUND: Acupuncture was shown to reduce symptoms of seasonal allergic rhinitis (SAR). The present study investigated (a) whether autonomic function would differ in SAR patients and healthy controls, and (b) whether acupuncture treatment would evoke changes in autonomic function compared to sham acupuncture. PATIENTS AND METHODS: SAR patients (n = 30) were recruited from a larger randomized controlled trial investigating the efficacy of acupuncture in SAR. 21 patients received acupuncture, and 9 patients received sham acupuncture. Among other we measured resting heart rate variability and cardiovascular reactivity to a cold pressure test prior to and after 12 sessions of acupuncture or sham acupuncture. In addition, 30 age- and sex-matched healthy controls were tested once. RESULTS: SAR patients showed higher resting heart rate and lower heart rate variability as well as blunted cardiovascular responses compared to controls. After treatment, resting heart rate had decreased, and systolic blood pressure response to the cold pressure test had increased in SAR patients. We found no significant differences in autonomic function changes between patients receiving acupuncture or sham acupuncture. CONCLUSION: SAR patients showed alterations in autonomic function, which had partially normalized after treatment. However, in this sample we found no specific effect of acupuncture compared to sham acupuncture. PMID- 26021959 TI - Which subtype of functional dyspepsia patients responses better to acupuncture? A retrospective analysis of a randomized controlled trial. AB - BACKGROUND: Whether subgroups of functional dyspepsia (FD) should be treated with different approaches is controversially discussed in research. As our previous study has demonstrated the effect of acupuncture in FD treatment, we now further analyze the therapeutic effect of acupuncture in the treatment of postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). METHODS: A retrospective analysis was conducted in 465 eligible PDS patients and 241 EPS patients. 4 acupuncture groups (group A: specific acupoints along the stomach meridian; group B: non-specific acupoints along the stomach meridian; group C: alarm and transport acupoints; group D: specific acupoints along the gallbladder meridian) were compared with a non-acupoint sham acupuncture group and an itopride group. The patients were treated in 5 consecutive sessions per week for 4 weeks and were followed-up for 12 weeks afterwards. Primary outcome of the study was defined as response rate and symptom improvement as measured by the Symptom Index of Dyspepsia, while secondary outcome was designated as improvement in quality of life (QoL) as determined by the Nepean Dyspepsia Index. RESULTS: Symptoms of dyspepsia and QoL were improved from baseline in all groups. In EPS patients, no statistically significant differences could be observed in response rate (p = 0.239) and symptoms improvement (p = 0.344 for epigastric pain; p = 0.465 for epigastric burning). In contrast, PDS patients of the acupuncture group A showed higher response rate (53.2% vs. 19.7%, p<0.001; 53.2% vs. 35.1%, p = 0.025) and score change in postprandial fullness (1.01 vs. 0.27, p<0.001; 1.01 vs. 0.57, p<0.001), early satiation (0.81 vs. 0.21, p<0.001; 0.81 vs. 0.39, p=0.001), and QoL (14.5 vs. 4.33, p<0.001; 14.5 vs. 8.5, p<0.001) compared to the sham acupuncture and itopride group. CONCLUSIONS: FD patients with PDS responded better to the acupuncture therapies, especially at the specific acupoints along the stomach meridian. The positive therapeutic effect of acupuncture on PDS was correlated with the improvement in postprandial fullness. TRIAL REGISTRATION: ClinicalTrial.gov NCT00599677. PMID- 26021960 TI - Acupuncture therapies for psoriasis vulgaris: a systematic review of randomized controlled trials. AB - The purpose of this review was to evaluate the efficacy and safety of acupuncture therapies in the treatment of psoriasis vulgaris. Embase, CENTRAL, PubMed, AMED, CINAHL, CNKI, CQVIP, CBM, and Wanfang databases were searched from inceptions to May 2013 for prospective randomized controlled trials evaluating acupuncture therapies for psoriasis vulgaris. No language limitations were applied. Studies were assessed using the Cochrane risk of bias tool. The primary outcome was Psoriasis Area Severity Index (PASI) score. Six studies (involving 522 participants) met the eligibility criteria for this review, and 5 were included in quantitative analysis. Due to the diversity of interventions, comparators and reported outcomes, meta-analysis was not possible. Results from single studies produced conflicting results for the outcomes PASI reduction, lesion reduction (non-PASI), PASI score, and relapse rate. There is some evidence of benefit of acupuncture therapies for the treatment of psoriasis vulgaris. However, the conclusions are limited by the small number of included trials and conflicting results from single studies. More research is needed to clarify the effect of acupuncture therapies for psoriasis vulgaris. PMID- 26021961 TI - Potential benefits of acupuncture for enhanced recovery in gynaecological surgery. AB - We aimed to evaluate if acupuncture can improve clinical benefits and patient satisfaction after gynaecological surgery supported by enhanced recovery after surgery (ERAS) programmes. Therefore, we evaluated patient as well as clinical outcome in patient recovery after surgery. We searched MEDLINE, PubMed and EMBASE for articles dealing with post-operative acupuncture and extracted 9 suitable studies. We expected acupuncture to alleviate surgical stress, reduce emetic symptom and accelerate recovery from complications in pre-, intra-, and post operative phases. Gastrointestinal motility and coldness achieved the full improvement rate of 50%. With regard to post-operative nausea and vomiting, 3 studies showed more than 30% and 1 showed 16% improvement. Sore throat and urinary retention achieved a mild improvement rate of 16% and 12%, respectively. In this study, we demonstrated that acupuncture can enhance recovery in gynaecological surgery without adverse effects and thus should be considered in ERAS. PMID- 26021962 TI - [Reimbursement for Acupuncture Treatments in the German Statutory Health Insurance System]. AB - Since 2007, acupuncture in Germany is reimbursed by the statutory health insurance. However, this policy is limited to the diagnoses 'chronic pain in lumbar spine' and 'chronic pain in knee joint through gonarthrosis' and connected to semi-standardized specifications for acupuncture treatment that partly do not correspond with standards in professional acupuncture training. Predominantly, acupuncture is applied in orthopedic practice. High demands in qualification and quality assurance as well as the difficulty to establish an economically attractive framework in acupuncture treatment are issues that curtail the appeal of acupuncture as treatment option to be offered by statutory health insurance. PMID- 26021963 TI - The future of complementary and integrative medicine research - international perspectives. PMID- 26021964 TI - Mixed copper-platinum complex formation could explain synergistic antiproliferative effect exhibited by binary mixtures of cisplatin and copper 1,10-phenanthroline compounds: An ESI-MS study. AB - Cisplatin, cis-diammineplatinum(II) dichloride, is a metal complex used in clinical practice for the treatment of cancer. Despite its great efficacy, it causes adverse reactions and most patients develop a resistance to cisplatin. To overcome these issues, a multi-drug therapy was introduced as a modern approach to exploit the drug synergy. A synergistic effect had been previously found when testing binary combinations of cisplatin and three copper complexes in vitro, namely, Cu(phen)(OH2)2(OClO3)2, [Cu(phen)2(OH2)](ClO4)2 and [Cu(phen)2(H2dit)](ClO4)2,(phen=1,10-phenanthroline, H2dit=imidazolidine-2 thione), against the human acute T-lymphoblastic leukaemia cell line (CCRF-CEM). In this work [Cu(phen)2(OH2)](ClO4)2 was also tested in combination with cisplatin against cisplatin-resistant sublines of CCRF-CEM (CCRF-CEM-res) and ovarian (A2780-res) cancer cell lines. The tested combinations show a synergistic effect against both the types of resistant cells. The possibility that this effect was caused by the formation of new adducts was considered and mass spectra of solutions containing cisplatin and one of the three copper complexes at a time were measured using electrospray ionisation at atmospheric-pressure mass spectrometry (ESI-MS). A mixed complex was detected and its stoichiometry was assessed on the basis of the isotopic pattern and the results of tandem mass spectrometry experiments. The formed complex was found to be [Cu(phen)(OH)MU (Cl)2Pt(NH3)(H2O)](+). PMID- 26021965 TI - The relation of depression to in-hospital outcomes among adults hospitalized for firearm-related injury. AB - INTRODUCTION: Firearm injuries are a major health problem contributing to significant morbidity and mortality. Depression is associated with increased risk of adverse health outcomes in trauma patients and those hospitalized for serious disorders. We examined the relation between preexisting depression and adverse hospital outcomes and related injury severity among adult (>16-years) firearm hospitalizations (FH). METHODS: Using nationally representative Nationwide Inpatient Sample (2005 to 2011) and survey weighted multinomial logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (95%CI) to determine the risk of care facility discharge and in-hospital mortality by pre existing depression. RESULTS: Pre-existing depression was associated with a 3 fold risk of discharge to care facility (OR=2.91, 95%CI=2.57-3.30) and a 2-fold risk of in-hospital mortality (OR=2.05, 95%CI=1.69-2.47). ORs for risk of care facility discharge compared to routine discharge associated with depression among assault/legal-FH, unintentional-FH, suicide-FH and undetermined-FH was 2.73 (95%CI=2.23-3.33), 1.90 (95%CI=1.50-2.41), 1.52 (95%CI=1.26-1.83) and 2.42 (95%CI=1.60-3.67), while risk of inhospital mortality was 0.17 (95%CI=0.05-0.54), 0.60 (95%CI=0.28-1.29), 0.79 (95%CI=0.63-0.98) and 0.74 (95%CI=0.36-1.52). LIMITATIONS: Lack of information regarding re-hospitalization due to the cross sectional data. CONCLUSION: Persons with depression who were hospitalized due to firearm-related injury were less likely to survive than those without depression, and those discharged alive were at higher risk of discharge to a facility. Depression was associated with greater risk of discharge to facility among all intents, and lower risk of in-hospital mortality among assault- and suicide-FH. These findings are important considering the increasing numbers of non-fatal firearm hospitalizations and the associated increase in healthcare expenditure. PMID- 26021966 TI - Does Mood Disorder Questionnaire identify sub-threshold bipolarity? Evidence studying worsening of quality of life. AB - OBJECTIVE: It is debated whether the Mood Disorder Questionnaire (MDQ) can generate false positives by screening other disorders as bipolar, or identify sub threshold bipolarity. The aim is to verify if Quality of Life (QoL) impairment in MQD positives in the community is due to MDQ positivity itself, or to psychiatric diagnosis associated with MDQ positivity (supporting the former hypothesis). METHOD: Community survey. Sample randomized after stratification of the adult population in the records of seven Italian regions. TOOLS: MDQ; Short Form Health Survey (SF-12); semi-structured clinical interview carried out by clinicians. RESULTS: Positives at MDQ show worsening QoL with an attributable burden of 2.8 +/- 1.8 lower than in MDD (5.6 +/- 3.6, p < 0.001) or Eating Disorders (4.4 +/- 6.6, p < 0.03) and similar to Panic Disorder (2.9 +/- 0.9, p = 0.44). The burden is lower in the middle-aged (25-59 years) than in the young (18-24) (4.65 +/- 4.5 vs 2.58 +/- 2.0, p=0.007) or in the elderly (>=60) (4.12 +/- 3.2; p = 0.024). In the elderly the burden is independent from comorbid psychiatric disorders. LIMITATIONS: This is a preliminary study based on one survey not designed to test this specific hypothesis, thus its results have a heuristic value only. CONCLUSIONS: The worsening of QoL due to positivity at MDQ is largely independent from comorbid conditions, supporting the hypothesis that MDQ positivity identifies a specific area of suffering that is "subthreshold" to the psychiatric diagnosis, and relevant for public health. PMID- 26021967 TI - MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. METHODS: A total of 613 MDD patients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. RESULTS: The A1298C CC homozygotes were more frequent in MDD patients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. LIMITATION: We did not measure folate and homocisteine levels. CONCLUSION: This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene*gene and gene*environment interactions of MDD etiopathogenesis. PMID- 26021968 TI - Harm avoidance involved in mediating the association between nerve growth factor (NGF) gene polymorphisms and antidepressant efficacy in patients with major depressive disorder. AB - BACKGROUND: Antidepressants have variable efficacies in subjects with major depressive disorder (MDD). Nerve growth factor (NGF) has been suggested to play an important role in the pathogenesis of depressive symptoms and the response to antidepressant therapy. The aim of this study was to examine whether NGF gene polymorphisms are associated with the antidepressant therapeutic efficacy in subjects with MDD. METHODS: A naturalistic follow-up study was carried out on 557 subjects with MDD. Of the enrolled patients, 304 completed the 8-week open-label antidepressant treatment. Seven single-nucleotide polymorphisms (SNPs) of the NGF gene were genotyped. The 21-item Hamilton Depression Rating Scale was used to assess depressive severity from baseline to endpoint. Tridimensional Personality Questionnaire was used to assess baseline personality traits. Single marker and haplotype analyses were conducted. Binary logistic regression was used to calculate odds ratios of remission. Structural equation modeling was used to analyze the predicted mediation effect. RESULTS: A significant difference in genotype frequencies between remitters and non-remitters was observed in three NGF SNPs (rs12760036, rs7523654, and rs17033692). The haplotype analysis revealed that the CCC haplotype (rs2254527-rs6678788-rs12760036) was associated with a higher remission rate, while the CCA haplotype was associated with a lower remission rate. The harm avoidance psychological factor partially mediated the effect of NGF variants on antidepressant efficacy. LIMITATIONS: The selected SNPs may not cover whole NGF gene. CONCLUSIONS: NGF variants are associated with remission rates after 8-week antidepressant treatment, and harm avoidance partially mediated the effect of NGF variants on treatment outcomes. PMID- 26021969 TI - Validation of the "rule of three", the "red sign" and temperament as behavioral markers of bipolar spectrum disorders in a large sample. AB - BACKGROUND: Akiskal proposed the "rule of three" for behavioral indicators with high specificity for bipolarity in patients with major depression episodes. We evaluated these distinctive behaviors in controls and subjects with major depression or bipolar disorder. METHODS: data was collected in the BRAINSTEP project with questions on general behaviors, style and talents. Univariate analysis was first conducted in 36,742 subjects and confirmatory multivariate analysis in further 34,505 subjects (22% with a mood disorder). Odds ratios were calculated adjusting for age. RESULTS: Univariate analysis showed that 29 behavioral markers differentiated bipolar subjects from those with unipolar depression. The most robust differences in those with bipolarity (ORs >4) were >=3 religion changes, >=3 marriages, cheating the partner regularly, having >=60 lifetime sexual partners, pathological love, heavy cursing, speaking >=3 foreign languages, having >=2 apparent tattoos, circadian dysregulation and high debts. Most behaviors were expressed in a minority of patients (usually around 5-30%) and usually the "rule of three" was the best numerical marker to distinguish those with bipolarity. However, multivariate analysis confirmed 11 of these markers for differentiating bipolar disorder from unipolar depression (reversed circadian rhythm and high debts for both genders, >=3 provoked car accidents and talent for poetry in men, and frequent book reading, >=3 religion changes, >=60 sexual partners, pathological love >=2 times, heavy cursing and extravagant dressing style in women). LIMITATIONS: Self-report data collection only. CONCLUSIONS: These behavioral markers should alert the clinician to perform a thorough investigation of bipolarity in patients presenting with a depressive episode. PMID- 26021970 TI - Foreign body aspiration. PMID- 26021971 TI - Appropriate Centralised Care - the Next Surgical Challenge. PMID- 26021972 TI - Giant Hernia of Morgagni with Acute Coronary Syndrome: A Rare Case Report and Review of Literature. AB - Hernia of Morgagni is a congenital defect of the sternal part of the diaphragm and frequently presents on the right side of the midline. The hernial sac is usually small and can be dealt with through either an abdominal approach or through a lateral thoracotomy incision. Median sternotomy as an approach to repair these defects has very rarely been described in the literature when concomitant cardiac surgical procedures were required. We report the case of a 42 year-old male with Morgagni hernia that was approached through median sternotomy because of concomitant requirement for open heart surgery. The patient presented with acute coronary syndrome necessitating urgent coronary artery bypass surgery and was found to have a giant hernia of Morgagni due to bilateral defects. This entity is very rarely described and may pose difficulty in repair due to excessive adhesions to the surrounding thoracic or mediastinal tissues. Median sternotomy seems to be the ideal approach to deal with these giant lesions. Clinical presentation of Morgagni hernia and different options for surgical repair of the defect are discussed with reference to relevant literature. PMID- 26021974 TI - Biomarkers and subtypes of cancer. PMID- 26021973 TI - Rat optic nerve head anatomy within 3D histomorphometric reconstructions of normal control eyes. AB - The purpose of this study is to three-dimensionally (3D) characterize the principal macroscopic and microscopic relationships within the rat optic nerve head (ONH) and quantify them in normal control eyes. Perfusion-fixed, trephinated ONH from 8 normal control eyes of 8 Brown Norway Rats were 3D histomorphometrically reconstructed, visualized, delineated and parameterized. The rat ONH consists of 2 scleral openings, (a superior neurovascular and inferior arterial) separated by a thin connective tissue strip we have termed the "scleral sling". Within the superior opening, the nerve abuts a prominent extension of Bruch's Membrane (BM) superiorly and is surrounded by a vascular plexus, as it passes through the sclera, that is a continuous from the choroid into and through the dural sheath and contains the central retinal vein (CRV), (inferiorly). The inferior scleral opening contains the central retinal artery and three long posterior ciliary arteries which obliquely pass through the sclera to obtain the choroid. Bruch's Membrane Opening (BMO) is irregular and vertically elongated, enclosing the nerve (superiorly) and CRV and CRA (inferiorly). Overall mean BMO Depth, BMO Area, Choroidal Thickness and peripapillary Scleral Thickness were 29 MUm, 56.5 * 10(3) MUm(2), 57 MUm and 104 MUm respectively. Mean anterior scleral canal opening (ASCO) and posterior scleral canal opening (PSCO) radii were 201 +/- 15 MUm and 204 +/- 16 MUm, respectively. Mean optic nerve area at the ASCO and PSCO were 46.3 * 10(3)+/-4.4 * 10(3) MUm(2) and 44.1 * 10(3)+/-4.5 * 10(3) MUm(2) respectively. In conclusion, the 3D complexity of the rat ONH and the extent to which it differs from the primate have been under-appreciated within previous 2D studies. Properly understood, these anatomic differences may provide new insights into the relative susceptibilities of the rat and primate ONH to elevated intraocular pressure. PMID- 26021975 TI - Letter to the Editor Regarding 'A Comparison Between Serum Carbohydrate-Deficient Transferrin and Hair Ethyl Glucuronide in Detecting Chronic Alcohol Consumption in Routine'. PMID- 26021976 TI - Organization of wound healing services: The impact on lowering the diabetes foot amputation rate in a ten-year review and the importance of early debridement. AB - Diabetes foot ulceration (DFU) has a negative impact on the quality of life and leads to disabling morbidity, such as lower extremity amputation (LEA). This study aimed to evaluate the LEA trend before and after the establishment of the diabetes foot team, an on-time debridement, on-site screening, and multidisciplinary integration with standardizing care, in Chang Gung Memorial Hospital, Chia Yi, Taiwan, starting in 2010. The study retrospectively investigated the non-traumatic LEA rate in diabetes foot (identified by using ICD 9-Clinical Modification (CM) codes, 250.70-250.83) and whole patients with diabetes (ICD-9 250.XX) yearly from 2004 to 2013. Patients were enrolled from hospitalization, emergency room (ER), or outpatient departments, respectively. Despite the overall incidence of diabetes foot in patients with diabetes remaining constant, from 3.47% in 2004 to 3.58% in 2013, the incidence of hospitalized diabetes foot from diabetes reduced, from 2.83% in 2004 to 1.51% in 2013. Introduction of integrated wound care also led to a reduction of the average LEA rate in hospitalized patients, from 15.27% (2004-2009) to 6.08% (2010 2013) (P<0.001). A similar decline of the LEA rate was observed for patients from hospitalization, ER and outpatient departments together with an average LEA rate from 7.99% (2004-2009) down to 3.02% (2010-2013) (P<0.001). In trend analysis, the curve estimation revealed a quadratic trend in the relationship between LEA rate and time (R-square=0.869, P=0.001) for hospitalized patients as well as a linear (R-square=0.819, P<0.001) and quadratic (R-square=0.845, P=0.001) trend in the relationship between LEA rate and time for hospitalization, ER, and outpatient departments together. The LEA rate for DM patients declined from 372.72/100,000 in 2004 to 61.74/100,000 in 2013. With establishment of an organizing, standardized wound care protocol and integrated multidisciplinary team, we demonstrated a significant decline in the LEA rate both in diabetes foot patients and all patients with diabetes. These improvements can be attributed to introducing an efficient pathway with on-time debridement and early intervention of diabetes foot ulcers. PMID- 26021977 TI - Urinary albumin excretion within the normal range predicts the development of diabetes in Korean men. AB - AIMS: Urine albumin creatinine ratio (UACR) is a reliable index of urinary albumin excretion. Elevated UACR is known to be associated with increased risk for diabetes complications. However there is only limited information about the predictability of UACR within normal range for diabetes. Therefore, this study was designed to investigate the association between UACR within the normal range and the development of diabetes. METHODS: The 1410 non-diabetic Korean men with UACR within the normal range were identified in 2005 and followed-up until 2010. All subjects were classified into four categories according to their baseline level of UACR, from the lowest to the highest quartile. Cox proportional hazards analysis was used to evaluate the independent hazard ratios (HRs) for diabetes according to the UACR levels of their quartile group. RESULTS: During follow-up, diabetes developed in 114 out of 1410 subjects (8.1%), and incidence of diabetes increased in proportion to the level of UACR (quartile 1; 4.5%, quartile 2; 7.9%, quartile 3: 8.8%, quartile 4: 11.1%, p = 0.002). The subjects with incident diabetes had a higher UACR than those without incident diabetes (6.6 +/- 5.5 MUg/mg v 5.3 +/- 4.2 MUg/mg, p=0.013). When quartile 1 was considered as the reference, HRs (95% confidential interval) for diabetes was higher in quartile 2 (1.04; 0.45-2.38), quartile 3 (1.09; 0.47-2.52) and quartile 4 (2.16; 1.02-4.57), even after adjusting for other potential confounders. CONCLUSIONS: Elevated UACR, even within the normal range, could predict the future development of diabetes. PMID- 26021978 TI - Effects of obesity and gestational diabetes mellitus on placental phospholipids. AB - Gestational diabetes mellitus (GDM) is associated with adverse effects in the offspring. The composition of placental glycerophospholipids (GPL) is known to be altered in GDM and might reflect an aberrant fatty acid transfer across the placenta and thus affect the foetal body composition. The aim of this study was to investigate possible effects of obesity and GDM, respectively, on placental GPL species composition. We investigated molecular species of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS) in term placentas from controls (lean non-diabetic, body-mass-index [BMI] 18-24.9k g/m(2), n=31), obese non-diabetics (BMI >=30 kg/m(2), n=17) and lean diabetics (n=15), using liquid chromatography - triple quadrupole mass spectrometry. PE(16:0/22:6) and PE(18:0/20:4) were increased in GDM and decreased species were PC(18:0/20:3), PC(18:1/20:3) and PS(18:0/18:2). A consistent difference between BMI related changes and changes caused by GDM was not observed. Arachidonic acid percentages of cord blood correlated with placental PC(16:0/20:4), whereas foetal docosahexaenoic acid correlated to placental PE species. Furthermore, a positive correlation of placental weight was found to levels of PE containing arachidonic acid. We demonstrated that obesity and GDM are associated with decreased dihomo gamma-linolenic acid and increased arachidonic acid and docosahexaenoic acid contents of placental GPL, with unknown consequences for the foetus. PC(16:0/20:4) was identified as the major component for the supply of arachidonic acid to the foetal circulation, whereas PE containing arachidonic acid was found to be associated to the placental and infant growth. PMID- 26021979 TI - High glucose and/or high insulin affects HIF-1 signaling by regulating AIP1 in human umbilical vein endothelial cells. AB - OBJECTIVE: The objective of this study was to explore the effects of high glucose/high insulin on AIP1 expression in HUVECs and the possible regulation of HIF-1alpha signaling by AIP1. METHODS: We investigated the expression of AIP1 and HIF-1alpha signaling in HUVECs at the levels of mRNA and protein following exposure to 30 mmol/L glucose (high glucose), 1 nmol/L insulin (high insulin), and the combination of the two (high glucose/high insulin). We detected changes in HIF-1alpha and VEGF expression with AIP1 siRNA interference by real-time PCR and western blotting. The CCK8 cell proliferation assay, the scratch/wound healing assay, and flow cytometry were used to assess cell proliferation, migration and apoptosis, respectively. Matrigel was used to perform a tubule formation assay. RESULTS: Compared with 5.5 mmol/L glucose alone (control), high glucose, high insulin, and the combination of high glucose+high insulin increased AIP1 expression at 24 h at the mRNA and protein levels. High glucose, high insulin, and high glucose+high insulin decreased HIF-1alpha expression at the mRNA and protein levels. AIP1 knockdown significantly increased HIF-1alpha and VEGF expression at both the mRNA and protein levels in HUVECs under high glucose conditions. In the presence of high insulin, the effect of high glucose on target gene expression was altered. The downregulation of AIP1 promoted cell proliferation, migration, and tubule formation, and it decreased apoptosis. CONCLUSIONS: High glucose increases AIP1 expression and decreases the expression of HIF-1alpha and downstream molecules. Decreased HIF-1alpha signaling may be regulated by increased AIP1 under high glucose. PMID- 26021980 TI - The digestive morphophysiology of wild, free-living, giraffes. AB - We have measured rumen-complex (rumen, reticulum, omasum, abomasum) and intestine (small and large combined) mass in 32 wild giraffes of both sexes with body masses ranging from 289 to 1441 kg, and parotid gland mass, tongue length and mass, masseter and mandible mass in 9 other giraffes ranging in body mass from 181 to 1396 kg. We have estimated metabolic and energy production rates, feed intake and home range size. Interspecific analysis of mature ruminants show that components of the digestive system increase linearly (Mb(1)) or positively allometric (Mb(>1)) with body mass while variables associated with feed intake scale with metabolic rate (Mb(.75)). Conversely, in giraffes ontogenetic increases in rumen-complex mass were negatively allometric (Mb(<1)), and increases in intestine mass, parotid gland mass, masseter mass, and mandible mass were isometric (Mb(1)). The relative masseter muscle mass (0.14% of Mb) and the relative parotid mass (0.03% of Mb) are smaller than in other ruminants. Increases in tongue length scale with head length(0.72) and Mb(.32) and tongue mass with Mb(.69). Absolute mass of the gastrointestinal tract increased throughout growth but its relative mass declined from 20% to 15% of Mb. Rumen complex fermentation provides ca 43% of daily energy needs, large intestine fermentation 24% and 33% by digestion of soluble carbohydrates, proteins, and lipids. Dry matter intake (kg) was 2.4% of body mass in juveniles and 1.6% in adults. Energy requirements increased from 35 Mj/day to 190 Mj/day. Browse production rate sustains a core home range of 2.2-11.8 km(2). PMID- 26021981 TI - In vivo and in vitro effects of high-K(+) stress on branchial expression of ROMKa in seawater-acclimated Mozambique tilapia. AB - Recently, a teleost ortholog of renal outer medullary K(+) channel (ROMK) expressed in gill ionocytes (ROMKa) has emerged as a primary K(+)-excreting pathway in fish. However, the mechanisms by which ROMKa expression is regulated in response to perturbations of plasma K(+) levels are unknown. In this study, we aimed to identify potential links between the endocrine system and K(+) regulation in a euryhaline fish. We assessed time-course changes in multiple endocrine parameters, including plasma cortisol and gene expression of branchial glucocorticoid and mineralocorticoid receptors (GR1, GR2, and MR) and pituitary hormones, in seawater (SW)-acclimated Mozambique tilapia (Oreochromis mossambicus) exposed to high-K(+) (H-K) SW. Exposure to H-K SW elicited little effects on plasma cortisol or mRNA levels of GRs and pituitary hormones. Since plasma K(+) and branchial ROMKa expression was increased within 6h after H-K treatment in vivo, the effect of high K(+) was subsequently tested in a gill filament incubation experiment using media with differing K(+) concentrations. ROMKa mRNA levels were induced following incubation of filaments in H-K medium for 6h. The present study is the first to demonstrate that the expression of ROMKa in teleost ionocytes can respond to high K(+) conditions independent from systemic signaling. PMID- 26021982 TI - Erratum: PPARgamma activation but not PPARgamma haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors. PMID- 26021983 TI - Indian minister denies plan for nurse practitioners to fill doctor gap. PMID- 26021984 TI - Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival. AB - BACKGROUND: The chemokine CXCL16 and its receptor CXCR6 are expressed by a variety of immune cells and have been shown to influence angiogenesis. The expression of CXCR6 and CXCL16 has been examined in numerous human cancers; however no studies have yet investigated their influence on prognosis in non small cell lung cancer (NSCLC). We aimed to explore their prognostic significance in NSCLC, in addition to examining associations with previously investigated markers. METHODS: Resected tumor tissue from 335 consecutive unselected stage I IIIA NSCLC patients (1990-2005) were collected. Immunohistochemistry was used to evaluate the expression of CXCR6 and CXCL16 on tissue microarrays. In vitro, NSCLC cells (NCI-H460, A549 cells) were transfected with CXCL16 siRNA to examine effects on proliferation. RESULTS: In univariate analysis, ? stromal cell CXCL16 expression was a significant positive prognostic factor (P = 0.016). CXCR6 was expressed in cancer cells, but did not show any prognostic impact. In the multivariate analysis, combined ?cancer, and ?stromal cell CXCL16 expression was an independent positive prognostic factor when compared to ?stromal and ?cancer cell expression (HR: 0.42; 95 % CI: 0.20-0.88; P = 0.022). Knockdown of CXCL16 by siRNA resulted in accelerated proliferation of NSCLC cell lines. CONCLUSION: We have shown that combined ?cancer and ?stromal cell CXCL16 expression is an independent positive prognostic factor in NSCLC. Further studies are warranted to elucidate the biological mechanism underlying this finding. PMID- 26021985 TI - Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis. AB - BACKGROUND: To measure circulating anti-citrullinated peptide antibodies (ACPA) and cytokines pre- and 6 months post-therapy as a strategy to predict and optimize responses to traditional disease-modifying antirheumatic drugs (DMARDs) in early RA, which is an unmet need in developing countries. PATIENTS AND METHODS: A cohort of 140 predominantly (88.5 %) black female South African patients with early RA was treated with synthetic DMARDs, mostly methotrexate (MTX) alone, or in combination with low-dose oral corticosteroids (CS). Circulating ACPA and a panel of circulating cytokines/chemokines/growth factors were measured at baseline and after 6 months of therapy in relation to disease activity and Shared Epitope (SE). RESULTS: Following 6 months of therapy, the median simplified disease activity index (SDAI) declined from a baseline of 41.4 to 16.0 (p = 0.0001) for the entire cohort, which was paralleled by significant falls in median serum ACPA levels (516.6 vs. 255.7 units/ml, p = <0.0001) and several of the circulating cytokines (IL-4, IL-7, IL-8, G-CSF, VEGF; p < 0.0010 - p < 0.0001) which were most evident in the subgroup of patients treated with a combination of MTX and CS. Although biomarker concentrations decreased most notably in the low-disease activity group post-therapy, no significant correlations between these biomarkers and disease activity were observed, Baseline ACPA levels, but not SDAI or cytokines, were significantly higher in the subgroup of risk allele-positive patients (561.1 vs. 331.9 units/ml, p < 0.05), while no associations with ACPA and a smoking history were evident. CONCLUSIONS: The use of DMARDs in RA is associated with significant decreases in ACPA and cytokines which did not correlate with changes in SDAI, precluding the utility of serial measurement of these biomarkers to monitor early responses to therapy, but may have prognostic value. PMID- 26021986 TI - Expression of active trypsin-like serine peptidases in the midgut of sugar feeding female Anopheles aquasalis. AB - BACKGROUND: Anopheles aquasalis is a dipteran of the family Culicidae that is widely distributed in the coastal regions of South and Central America. This species acts as a vector of Plasmodium vivax, an important etiological agent of malaria, which represents a serious public health problem. In mosquitoes, trypsin like serine proteases are important in blood meal digestion, immune responses and reproductive functions. The study of peptidases expressed in the mosquito midgut is essential to understanding the mechanisms of parasite-host interaction and the physiological process of nutrient digestion. METHODS: Our study aimed to identify and characterize the proteolytic activities in the midgut of sugar-fed An. aquasalis females using zymographic analyses (substrate-SDS-PAGE), in-solution assays and mass spectrometry. RESULTS: Here, we used a zymographic analysis to further biochemically characterize the proteolytic profile of the midgut of sugar feeding An. aquasalis females. The trypsin peptidases migrated between ~17 and ~76 kDa and displayed higher proteolytic activities between pH 7.5 and 10 and at temperatures between 37 degrees C and 50 degrees C. Four putative trypsin-like serine peptidases were identified using mass spectrometry and data mining. The molecular masses of these peptidases were similar to those observed using zymography, which suggested that these peptidases could be responsible for some of the observed proteolytic bands. CONCLUSIONS: Taken together, our results contribute to the gene annotation of the unknown genome of this species, to the tissue location of these peptidases, and to the functional prediction of these crucial enzymes, which all impact further studies of this species. PMID- 26021987 TI - Influence of frailty on health-related quality of life in pre-dialysis patients with chronic kidney disease in Korea: a cross-sectional study. AB - BACKGROUND: Chronic kidney disease (CKD) is a progressive and lifelong condition with multiple medical comorbidities. Patients with CKD experience frailty more frequently and have lower health-related quality of life than do those with other chronic diseases. The purpose of this study was to examine the prevalence of frailty and investigate the contribution of frailty to quality of life in pre dialysis CKD patients in Korea. METHODS: Using a cross-sectional survey design, data were collected at an outpatient CKD clinic in a general hospital in Korea. The frailty criterion was modified from previous studies. The Short Form-36 Health Survey version 2 was used to measure physical and mental component summary scores. Data were analyzed using chi-square, t-tests, and hierarchical linear regression. RESULTS: Of the 168 CKD patients, 63 (37.5 %) were frail. Frail patients were significantly older and had lower physical and mental quality of life than those who were non-frail. In hierarchical regression evaluating the influence of frailty on physical and mental quality of life, the initial model was significantly improved when frailty was included. Frail patients had lower physical and mental quality of life. CONCLUSIONS: Frailty affected both physical and mental quality of life in pre-dialysis patients with CKD. More attention should be paid to the potential role of early detection and prevention of frailty to improve patients' quality of life. PMID- 26021988 TI - Deaths Reported to the Vaccine Adverse Event Reporting System, United States, 1997-2013. AB - BACKGROUND: Vaccines are among the safest medical products in use today. Hundreds of millions of vaccinations are administered in the United States each year. Serious adverse reactions are uncommon. However, temporally associated deaths can occur following vaccination. Our aim was to characterize main causes of death among reports submitted to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous vaccine safety surveillance system. METHODS: We searched VAERS for US reports of death after any vaccination from 1 July 1997 through 31 December 2013. Available medical records, autopsy reports, and death certificates were reviewed to identify cause of death. RESULTS: VAERS received 2149 death reports, most (n = 1469 [68.4%]) in children. Median age was 0.5 years (range, 0-100 years); males accounted for 1226 (57%) reports. The total annual number of death reports generally decreased during the latter part of the study period. Most common causes of death among 1244 child reports with available death certificates/autopsy reports included sudden infant death syndrome (n = 544 [44%]), asphyxia (n = 74 [6.0%]), septicemia (n = 61 [4.9%]), and pneumonia (n = 57 [4.6%]). Among 526 adult reports, most common causes of death included diseases of the circulatory (n = 247 [46.9%]) and respiratory systems (n = 77 [14.6%]), certain infections and parasitic diseases (n = 62 [11.8%]), and malignant neoplasms (n = 20 [3.8%]). For child death reports, 79.4% received >1 vaccine on the same day. Inactivated influenza vaccine given alone was most commonly associated with death reports in adults (51.4%). CONCLUSIONS: No concerning pattern was noted among death reports submitted to VAERS during 1997 2013. The main causes of death were consistent with the most common causes of death in the US population. PMID- 26021989 TI - Deep Sequencing of HIV-1 in Cerebrospinal Fluid. AB - Using deep sequencing, human immunodeficiency virus (HIV) resistance-associated mutations were detected as minority species in the cerebrospinal fluid (CSF) of 4 patients with higher HIV type 1 RNA load in CSF than in plasma, but not in 2 patients with higher plasma viral load. Deep sequencing could help our understanding of viral escape in the central nervous system. PMID- 26021991 TI - Ceftolozane/Tazobactam Therapy of Respiratory Infections due to Multidrug Resistant Pseudomonas aeruginosa. PMID- 26021992 TI - Liver Fibrosis by Transient Elastography and Virologic Outcomes After Introduction of Tenofovir in Lamivudine-Experienced Adults With HIV and Hepatitis B Virus Coinfection in Ghana. AB - BACKGROUND: Antiretroviral treatment (ART) programs in sub-Saharan Africa have for many years included lamivudine as the sole hepatitis B virus (HBV) inhibitor. Long-term outcomes and the effects of introducing tenofovir as part of ART in these populations have not been characterized. METHODS: The study comprised a cross-sectional analysis of 106 human immunodeficiency virus (HIV)/HBV-coinfected subjects maintained on lamivudine, as well as a prospective analysis of 76 lamivudine-experienced subjects who introduced tenofovir. Patients underwent assessment of liver fibrosis by transient elastography (TE) and testing to characterize HIV type 1 (HIV-1) and HBV replication. RESULTS: After a median of 45 months of lamivudine treatment, HIV-1 RNA and HBV DNA were detectable in 35 of 106 (33.0%) and 54 of 106 (50.9%) subjects, respectively, with corresponding drug resistance rates of 17 of 106 (16.0%) and 31 of 106 (29.2%), respectively. Median TE values were 5.7 kPa (interquartile range, 4.7-7.2 kPa) and independently associated with HBV DNA load, aspartate aminotransferase levels, and platelet counts; 13 of 106 (12.3%) subjects had TE measurements >9.4 kPa. Twelve months after the first assessment, and a median of 7.8 months after introducing tenofovir, HBV DNA levels declined by a mean of 1.5 log10 IU/mL (P < .001). TE values changed by a mean of -0.2 kPa (P = .097), and declined significantly in subjects who had pretenofovir HBV DNA levels >2000 IU/mL (mean, -0.8 kPa; P = .048) or TE values >7.6 kPa (mean, -1.2 kPa; P = .021). HIV-1 RNA detection rates remained unchanged. CONCLUSIONS: A proportion of HIV/HBV-coinfected patients on long-term lamivudine-containing ART had poor HIV and HBV suppression, drug resistance, and TE values indicative of advanced liver fibrosis. Tenofovir improved HBV control and reduced liver stiffness in subjects with high HBV DNA load and TE values. PMID- 26021993 TI - Supportive Care of the First 2 Ebola Virus Disease Patients at the Monrovia Medical Unit. AB - We describe the first 2 patients admitted to the Monrovia Medical Unit, a facility established to treat Liberian and international response workers with suspected or known Ebola virus disease (EVD). Their recoveries illustrate the value of local point-of-care diagnostics, parenteral therapies, and electrolyte replacement in EVD supportive care. PMID- 26021994 TI - Pneumonia Prevention to Decrease Mortality in Intensive Care Units. PMID- 26021995 TI - Reply to Kuriyama and Urushidani. PMID- 26021996 TI - Ribavirin Reduces Absolute Lymphocyte Counts in Hepatitis C Virus-Infected Patients Treated With Interferon-Free, Direct-Acting Antiviral Regimens. AB - In clinical trials of interferon-free, direct-acting antiviral treatment of chronic hepatitis C, subjects who received ribavirin had reduced lymphocyte levels (median decline of approximately 0.4-0.5 * 10(9) cells/L). A modest decline in CD4(+) T cells was observed in subjects with human immunodeficiency virus type 1 coinfection without documented opportunistic infections. PMID- 26021997 TI - Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study. AB - The human endometrium is a fertility-determining tissue and a target of steroid hormones' action. Endocrine disruptors (EDs) can exert adverse effects on the physiological function of the decidua at the maternal-fetal interface. We examined the potential effects of an ED, bisphenol A (BPA), on endometrial maturation/decidualization, receptivity, and secretion of decidual factors (biomarkers). In vitro decidualized, endometrial stromal cells from six hysterectomy specimens were treated with 1 pM-1 MUM of BPA, for 24 h and assessed for cell viability and proliferation. Three non-toxic concentrations of BPA (1 MUM, 1 nM, and 1 pM) were selected to study its influence on secretion of cell decidualization biomarkers (IGF-binding protein and decidual prolactin (dPRL)), macrophage migration inhibitory factor (MIF) secretion, and hormone receptors' expression (estrogen receptors (ERalpha and ERbeta); progesterone receptors (PRA and PRB); and human chorionic gonadotropin (hCG)/LH receptor (LH R)). The results showed a decrease in cell viability (P<0.001) in response to BPA at the level of 1 mM. At the non-toxic concentrations used, BPA perturbed the expression of ERalpha, ERbeta, PRA, PRB, and hCG/LH-R (P<0.05). Furthermore, 1 MUM of BPA reduced the mRNA transcription of dPRL (P<0.05). Secretion of MIF was stimulated by all BPA treatments, the lowest concentration (1 pM) being the most effective (P<0.001). The multi-targeted disruption of BPA on decidual cells, at concentrations commonly detected in the human population, raises great concern about the possible consequences of exposure to BPA on the function of decidua and thus its potential deleterious effect on pregnancy. PMID- 26021998 TI - New insights into the function of Cullin 3 in trophoblast invasion and migration. AB - Cullin 3 (CUL3), a scaffold protein, assembles a large number of ubiquitin ligase complexes, similar to Skp1-Cullin 1-F-box protein complex. Several genetic models have shown that CUL3 is crucial for early embryonic development. Nevertheless, the role of CUL3 in human trophoblast function remains unclear. In this study, immunostaining revealed that CUL3 was strongly expressed in the villous cytotrophoblasts, the trophoblast column, and the invasive extravillous trophoblasts. Silencing CUL3 significantly inhibited the outgrowth of villous explant ex vivo and decreased invasion and migration of trophoblast HTR8/SVneo cells. Furthermore, CUL3 siRNA decreased pro-MMP9 activity and increased the levels of TIMP1 and 2. We also found that the level of CUL3 in the placental villi from pre-eclamptic patients was significantly lower as compared to that from their gestational age-matched controls. Moreover, in the lentiviral-mediated placenta-specific CUL3 knockdown mice, lack of CUL3 resulted in less invasive trophoblast cells in the maternal decidua. Taken together, these results suggest an essential role for CUL3 in the invasion and migration of trophoblast cells, and dysregulation of its expression may be associated with the onset of pre eclampsia. PMID- 26021999 TI - Counteracting negative venous line pressures to avoid arterial air bubbles: an experimental study comparing two different types of miniaturized extracorporeal perfusion systems. AB - BACKGROUND: Because of its low rate of clinical complications, miniaturized extracorporeal perfusion systems (MEPS) are frequently used in heart centers worldwide. However, many recent studies refer to the higher probability of gaseous microemboli formation by MEPS, caused by subzero pressure values. This is the main reason why various de-airing devices were developed for today's perfusion systems. In the present study, we investigated the potential benefits of a simple one-way-valve connected to a volume replacement reservoir (OVR) for volume and pressure compensation. METHODS: In an experimental study on 26 pigs, we compared MEPS (n = 13) with MEPS plus OVR (n = 13). Except OVR, perfusion equipment was identical in both groups. Primary endpoints were pressure values in the venous line and the right atrium as well as the number and volume of air bubbles. Secondary endpoints were biochemical parameters of systemic inflammatory response, ischemia, hemodilution and hemolysis. RESULTS: One animal was lost in the MEPS + OVR group. In the MEPS + OVR group no pressure values below -150 mmHg in the venous line and no values under -100 mmHg in right atrium were noticed. On the contrary, nearly 20% of venous pressure values in the MEPS group were below 150 and approximately 10% of right atrial pressure values were below -100 mmHg. Compared with the MEPS group, the bubble counter device showed lower numbers of arterial air bubbles in the MEPS + OVR group (mean +/- SD: 13444 +/- 5709 vs. 1 +/- 2, respectively; p < 0.001). In addition, bubble volume was significantly lower in the MEPS + OVR group than in the MEPS group (mean +/- SD: 1522 +/- 654 MUl vs. 4 +/- 6 MUl, respectively; p < 0.001). The proinflammatory cytokine interleukin-6 and biochemical indices of cardiac ischemia (creatine kinase, and troponin I) were comparable between both groups. CONCLUSIONS: The use of a miniaturized perfusion system with a volume replacement reservoir is able to counteract excessive negative venous line pressures and to reduce the number and volume of arterial air bubbles. This approach may lead to a lower rate of neurological complications. PMID- 26022000 TI - Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood. AB - Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is used in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased anxiety-like behavior in adulthood. PMID- 26022001 TI - A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs. AB - Polychlorinated Biphenyls (PCBs) are very stable environmental contaminants whose exposure induces a number of health and cognitive concerns. Currently, it is well known that PCB exposure leads to poor performance on inhibitory control tasks. It is also well known that dopamine (DA) depletion within medial prefrontal cortex (mPFC) leads to poor performance on inhibitory control tasks. However, what is not well established is whether or not the inhibitory control problems found following PCB exposure are mediated by DA depletion in mPFC. This study was an investigation into the link between perinatal exposure to PCBs, the effect of this exposure on DA neurotransmission in the mPFC, and inhibitory-control problems during adulthood using a rodent model. The current study served to determine if microinjections of different DA agonists (the presynaptic DA transporter inhibitor and vesicular monoamine transporter agonist bupropion, the postsynaptic DA receptor 2 (DAD2) agonist quinpirole, and the postsynaptic DA receptor 1 (DAD1) agonist SKF81297) directly into the mPFC would differentially improve performance on an inhibitory control task in rats perinatally exposed to an environmentally relevant PCB mixture. Findings suggest several significant sex based differences on differential reinforcement of low rates (DRL) 15 performance as well as some evidence of differential effectiveness of the DA agonists based on PCB exposure group. PMID- 26022002 TI - Bioengineering Novel Chimeric microRNA-34a for Prodrug Cancer Therapy: High-Yield Expression and Purification, and Structural and Functional Characterization. AB - Development of anticancer treatments based on microRNA (miRNA/miR) such as miR 34a replacement therapy is limited to the use of synthetic RNAs with artificial modifications. Herein, we present a new approach to a high-yield and large-scale biosynthesis, in Escherichia coli using transfer RNA (tRNA) scaffold, of chimeric miR-34a agent, which may act as a prodrug for anticancer therapy. The recombinant tRNA fusion pre-miR-34a (tRNA/mir-34a) was quickly purified to a high degree of homogeneity (>98%) using anion-exchange fast protein liquid chromatography, whose primary sequence and post-transcriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-34a showed a favorable cellular stability while it was degradable by several ribonucleases. Deep sequencing and quantitative real-time polymerase chain reaction studies revealed that tRNA-carried pre-miR-34a was precisely processed to mature miR-34a within human carcinoma cells, and the same tRNA fragments were produced from tRNA/mir-34a and the control tRNA scaffold (tRNA/MSA). Consequently, tRNA/mir-34a inhibited the proliferation of various types of human carcinoma cells in a dose dependent manner and to a much greater degree than the control tRNA/MSA, which was mechanistically attributable to the reduction of miR-34a target genes. Furthermore, tRNA/mir-34a significantly suppressed the growth of human non-small cell lung cancer A549 and hepatocarcinoma HepG2 xenograft tumors in mice, compared with the same dose of tRNA/MSA. In addition, recombinant tRNA/mir-34a had no or minimal effect on blood chemistry and interleukin-6 level in mouse models, suggesting that recombinant RNAs were well tolerated. These findings provoke a conversation on producing biologic miRNAs to perform miRNA actions, and point toward a new direction in developing miRNA-based therapies. PMID- 26022004 TI - Shortness of breath and cardiac conduction abnormality caused by infiltrative cardiomyopathy. PMID- 26022003 TI - Activation of Sirtuin-1 Promotes Renal Fibroblast Activation and Aggravates Renal Fibrogenesis. AB - Although activation of sirtuin-1 (SIRT1) has been shown to protect the kidney from acute injury, its role in renal fibrosis remains controversial since both inhibition and activation of SIRT1 have been reported to attenuate renal fibrosis. To resolve this conflict, we further examined the effect of SIRT1 activators on the activation of renal interstitial fibroblasts and development of renal fibrosis in vivo and in vitro. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, administration of SRT1720 (N-[2-[3-(piperazin 1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide), a potent activator of SIRT1, accelerated deposition of collagen fibrils and increased expression of fibroblast activation markers (alpha-smooth muscle actin [alpha-SMA], collagen I, and fibronectin) in the obstructive kidney of mice. In cultured rat renal interstitial fibroblasts (NRK-49F), exposure of cells to SRT1720 or YK-3-237 (B-[2-methoxy-5-[(1E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1 propen-1-yl]phenyl]-boronic acid), another SIRT1 activator, also resulted in enhanced expression of alpha-SMA and fibronectin. Mechanistic studies showed that augmentation of renal fibrogenesis by SRT1720 is associated with elevated phosphorylation of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRbeta). SRT1720 treatment also increased the phosphorylation of signal transducer and activator of transcription 3 and protein kinase B in the fibrotic kidney and NRK-49F cells. However, SRT1720 treatment did not affect expression of proliferating cell nuclear protein, a proliferation marker and activation of extracellular signal regulated kinase 1/2 in vitro and in vivo. These results indicate that SIRT1-activating compounds can provoke renal fibrogenesis through a mechanism involved in the activation of EGFR and PDGFR signaling pathways and suggest that long-term use of SIRT1 activators risks the development and progression of chronic kidney disease. PMID- 26022005 TI - Atrial fibrillation ablation: less is more? PMID- 26022007 TI - Stroke: a rare but devastating procedural complication of PCI. PMID- 26022006 TI - Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. AB - AIMS: The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death. METHODS AND RESULTS: PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II-IV symptoms, and left ventricular ejection fraction <=40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72-0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64-0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non cardiovascular deaths. CONCLUSIONS: LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, NCT01035255. PMID- 26022008 TI - Effort syncope and pencil-point left main coronary artery: cause or unsual finding? PMID- 26022009 TI - Changing of the guard? PMID- 26022010 TI - Cardiovascular magnetic resonance imaging for the detection and follow-up of isolated partial anomalous pulmonary venous connection. PMID- 26022011 TI - Light chain nephropathy. AB - Light chain deposition disease (LCDD) is characterized by the tissue deposition of monotypic immunoglobulin light chains of either kappa or lambda isotype. It is the archetypal systemic disease that is most frequently diagnosed on a kidney biopsy, although the deposits may involve several other organs. This brief review focuses on the clinicopathological features of LCDD-associated nephropathy with an emphasis on the diagnostic and therapeutic difficulties related to this elusive condition. PMID- 26022012 TI - Frequency of occurrence of urinary tract infection in double j stented versus non stented renal transplant recipients. AB - Prophylactic ureteric stenting in renal transplant recipients prevents major surgical complications such as ureteric leak and obstruction on the one hand while, on the other hand, it is associated with complications like urinary tract infections (UTI), hematuria, stent migration, stent encrustation and forgotten stents. UTI is documented to be most common complication associated with double J (DJ) stent. In this retrospective observational study involving 157 patients, we compared the frequency of occurrence of UTI in DJ-stented versus non-stented renal transplant recipients. The study patients had undergone renal transplantation, with or without DJ-stenting, between January 2007 and June 2012. The mean age of the study subjects was 34.01 +/- 14.63 years. The patients were followed-up for one year post-transplantation with regular evaluation, including detailed assessment, complete blood picture, renal function tests, routine urine examination and cultures. Data were collected through chart and electronic record review. Of a total of 157 patients, 61 (38.85%) developed UTI, including 30 of 74 stented patients (40.54%) and 31 of 83 non-stented renal transplant recipients (37.34%). Relative risk was calculated to be 1.08. The mean serum creatinine at the end of one year was 1.47 mg/dL in DJ-stented patients and 1.36 mg/dL in nonstented patients. Our study suggests that there is no significant difference in the frequency of UTI between DJ-stented and non-stented renal transplant recipients. PMID- 26022013 TI - Comparison of safety and efficacy of general and spinal anesthesia in kidney transplantation: Evaluation of the peri-operative outcome. AB - General anesthesia is a routine anesthetic technique for kidney transplantation. This study evaluated and compared the peri-operative hemodynamic, cardiopulmonary and general condition status in patients in whom spinal anesthesia (SA) or general anesthesia (GA) was used for kidney transplantation. A prospective study was carried out on 49 consecutive patients who underwent kidney transplantation with either GA (19 patients, mean age 37.53 +/- 11.78 years) or SA (30 patients, mean age 42.17 +/- 14.89 years), without any selection bias. One obese patient with a body mass index of 32.52 kg/m 2 died 22 days after transplantation in the GA group. One other patient, who developed severe nausea and vomiting, was changed from SA to GA. There were no statistical differences in gender, mean age, body mass index and hemodynamic and cardiopulmonary status between the two groups. Time to post-operative diet tolerance, defecation, ambulation and adequate urination were significantly better in the SA group. The mean operation time was 264.32 +/- 18.91 and 233 +/- 15.12 min in the GA and SA groups, respectively. Brisk diuresis was seen in all patients except one in the SA group. Our study suggests that kidney transplantation under SA is feasible and safe, particularly for patients who cannot receive GA. PMID- 26022014 TI - Comparison between valganciclovir and aciclovir/valaciclovir for CMV prophylaxis in pediatric renal transplantation. AB - Prophylaxis has dramatically decreased the occurrence of cytomegalovirus (CMV) infection after renal transplantation. Optimal regimens of treatment remain controversial, especially in pediatric recipients. The aim of this study was to evaluate the effectiveness of valganciclovir (VGC) versus aciclovir/valaciclovir (ACV) in a pediatric renal transplant population. Data from 101 renal transplantations were retrospectively analyzed. Except those with R-/Dstatus, all patients received prophylaxis either with ACV, n = 39 or VGC, n = 38. Incidences of positive CMV antigenemia and disease, as well as the delay in relation to the prophylaxis, were collected during at least 12 months after the end of treatment. Positive CMV antigenemia was reported in 34 patients (ACV: 16, VGC: 16, no prophylaxis: 2). CMV disease occurred in 15 patients (ACV: 5; VGC: 8) (ns). For the majority of patients under VGC, positive CMV antigenemia occurred within the year following the withdrawal of prophylaxis (VGC: 14; ACV: 5, P <0.05), whereas it occurred during prophylaxis in 11 patients under ACV versus two under VGC (P <0.05). The over-all incidence of positive CMV antigenemia was similar between ACV and VGC prophylaxis. However, VGC was more efficient to prevent early CMV infection while patients treated with ACV had less CMV infection or disease after the end of the prophylaxis. PMID- 26022015 TI - Tumor necrosis factor gene expression in regular hemodialysis patients. AB - This study evaluates tumor necrosis factor (TNF)-alfa gene expression in patients with end-stage renal disease (ESRD) on regular hemodialysis as an expression of cardiovascular disease (CVD) risk even on a sub-clinical level and its relation to some of the parameters incriminated in the pathogenesis and the establishment of uremic arteriopathy. A total of 51 patients with ESRD on regular hemodialysis and 20 healthy subjects matching in age and gender as a control group were recruited. All selected cases were subjected to serum lipid profile, Creactive protein (CRP), TNF-alfa gene expression and Doppler study of carotid arteries to estimate carotid intimal media thickness (cIMT). Serum triglycerides (TGS) level (P <0.001), CRP positivity (P = 0.002), relative quantification (RQ) of TNF-alfa gene expression (P = 0.007) and cIMT (P = 0.02) were significantly higher while high-density lipoprotein (HDL) level (P <0.001) was significantly lower among cases compared with controls. RQ showed a significant positive correlation with CRP titer (rho = 0.583, P = 0.011). Results also showed a significant strong negative correlation between with CRP titer and cIMT (rho = -0.590, P = 0.010). CRP titer showed only a significant strong negative correlation with age (rho = 0.589, P = 0.01) and positive correlation with HDL (rho = 0.51, P = 0.031). Patients with ESRD have increased gene expression of TNF-alfa and CRP titer together with increased atherosclerosis as expressed by increased cIMT. PMID- 26022016 TI - Effect of vitamin C supplementation on marital satisfaction in patients undergoing hemodialysis: A randomized, double-blind and placebo-controlled trial. AB - One of the common problems in patients on hemodialysis (HD) is marital dissatisfaction. Because anemia and fatigue are two important factors for marital dissatisfaction, and vitamin C can ameliorate both of them, we carried out this study to evaluate the effect of vitamin C on marital satisfaction among HD patients. This randomized, placebo-controlled, double-blind and parallel-group trial was conducted on 62 HD patients. The MFI-20 and ENRICH questionnaires were completed at the start and end of study. Required laboratory parameters including serum levels of hemoglobin (Hb), hematocrit (Hct) and ferritin were also measured at the start and at the end of the study. In the intervention group, 250 mg of vitamin C was injected intravenously immediately at the end of each HD session three times a week for eight consequent weeks. In the control group, placebo saline was injected. There was a significant change in the level of fatigue (P = 0.01) and the serum levels of Hb (P = 0.006) and Hct (P = 0.02). The mean of the marital satisfaction score increased significantly in the intervention group (P = 0.001): Baseline score of 35.7 +/- 5.10 versus a final score of 38.0 +/- 5.30. However, the mean of marital satisfaction score decreased in the control group: Baseline 37.1 +/- 7.10 versus a final score of 34.7 +/- 7.40. Our findings suggest that vitamin C supplementation can modify the marital satisfaction. Further studies are recommended. PMID- 26022017 TI - The effectiveness of systemic antibiotic therapy with and without ethanol-locked solution in the treatment of hemodialysis-related catheter infection. AB - Bacterial overgrowth in the inner layer of the catheter as a biofilm is highly encountered in routine medical care, and it may occur in a few days after inserting a catheter as an access in hemodialysis (HD) patients. Catheter-induced bacteremia is often due to the development of biofilms. Locking catheters with antimicrobial agents is an effective way of reducing the risk of catheter-related infection. In a controlled, randomized clinical trial, 64 chronic HD patients (32 men and 32 women with a mean age of 57.5 +/- 15.6 years) were divided into case and control groups, with 32 patients in each group. The case group received systemic antibiotic and a lock of catheters with 60% ethanol and the control group received only systemic antibiotic. The results were evaluated after three weeks of treatment. The success rate of clearing infection in group A (29 patients) and group B (18 patients) was 90.6% and 56.2%, respectively (P = 0.002). We conclude that the significant difference in the success rate of clearing catheter infection in HD patients is due to the use of 60% ethanol-lock along with antibiotic therapy, and suggest this for routine use. PMID- 26022018 TI - Renal failure in patients with multiple myeloma. AB - Renal dysfunction is encountered in 20-25% of patients with multiple myeloma (MM) at the time of diagnosis. There is often a precipitating event. Several biochemical and clinical correlations with renal failure in MM have been reported. Renal failure in MM is associated with worse outcome of the disease. We retrospectively analyzed the medical records of 64 patients with MM admitted to our institution during the period January 1992 to December 2012. Abnormal renal function was observed in 24 (37.5%) patients and 17 (26.6%) of them had renal failure; 14 of the 17 (82.4%) of patients with renal failure had Stage III MM. Urine Bence- Jones protein was positive in ten (58.8%) patients with renal failure versus ten (21.3%) patients without renal failure (P = 0.004). Potential precipitating factors of renal failure were determined in nine patients. Renal function normalized in 11 patients with simple measures, while six patients required hemodialysis; one remained dialysis dependent till time of death. Early mortality occurred in five (29.4%) patients with renal failure as compared with two (4.3%) patients in the group without renal failure (P = 0.005). In conclusion, renal failure is associated with a higher tumor burden and Bence Jones proteinuria in patients with MM. It is reversible in the majority of patients; however, early mortality tends to be higher in patients with persistent renal failure. PMID- 26022019 TI - Cardiac surgery-associated acute kidney injury in a developing country: Prevalence, risk factors and outcome. AB - Little is known about cardiac surgery-associated acute kidney injury (CS-AKI) in children in developing regions of the world. The study aimed to determine the prevalence of CSAKI, associated factors and its impact on mortality and utilization of hospital services. The hospital records of children aged 0-17 years who underwent CS at an Indian hospital were reviewed. CS-AKI was defined as a rise in serum creatinine of >=0.3 mg/dL in any 48 h and or by urine output <0.5 mL/kg/h for an 8-h period in the first five days after CS. The study included 323 children with a median age of one year (0.04-17), of whom 22 (6.8%) were neonates and 18.3% had a single ventricle. About 60% of the children had Risk Adjusted Congenital Heart Surgery-I category 1 or 2 interventions. CS-AKI occurred in 39 children (12.1%). Factors associated with CS-AKI were sepsis and intraand post operative hypotension. In-hospital mortality was six-fold higher in children who developed CS-AKI. CS-AKI was associated with two to three days more of mechanical ventilation and Intensive care unit stay. CS-AKI occurs in children in developing countries, but at a lower frequency mainly due to the predominance of post neonatal children undergoing less-complex CSs. CS-AKI was associated with higher in-hospital mortality and increased utilization of hospital services. Factors associated with CS-AKI included intraand post-operative hypotension and sepsis. PMID- 26022020 TI - Serum cystatin C, urinary neutrophil gelatinase-associated lipocalin and N-acetyl beta-D-glucosaminidase in juvenile and adult patients with systemic lupus erythematosus: Correlation with clinical manifestations, disease activity and damage. AB - Lupus nephritis (LN) is a potentially devastating outcome of systemic lupus erythematosus (SLE). It is important to identify reliable, non-invasive methods to assess the kidneys in patients with SLE. The aim of the study was to measure the level of novel markers of renal involvement in these patients and assess their correlation with disease activity and damage. Sixtyone patients with SLE (33 adults and 28 juvenile) were included in the study. Fifty-two ageand sex matched healthy individuals served as controls. Full history taking, thorough clinical examination and laboratory investigations were performed and disease activity and damage were assessed for all patients. Renal bio-markers including serum cystatin C, urinary neutrophil gelatinase-associated lipocalin (UNGAL) and N-acetyl-beta-D-glucosaminidase (UNAG) were assessed in patients and controls. There was a significant increase in serum cystatin C, UNGAL and UNAG levels in the adult SLE patients compared with controls (P = 0.000, P = 0.013 and P = 0.018, respectively); serum cystatin C and UNGAL levels were higher in the juvenile patients compared with controls (P = 0.038 and P = 0.000, respectively). Serum cystatin C significantly correlated with the damage index, renal biopsy class and negatively with the serum albumin; UNGAL correlated with albuminuria and the level of nephritis and UNAG negatively correlated with serum albumin level. Our study suggests that serum cystatin C, UNGAL and UNAG are important markers of LN and both cystatin C and UNAG would help in predicting the renal biopsy class. PMID- 26022021 TI - Urinary monocyte chemoattractant protein-1 as a biomarker of lupus nephritis activity in children. AB - Systemic lupus erythematosus (SLE) is a life-long, life-limiting and multi systemic autoimmune disease. Glomerulonephritis is one of the most serious manifestations of SLE. Younger children have an increased incidence, severity and morbidity of lupus nephritis (LN) compared with adult-onset disease. Monocyte chemoattractant protein-1 (MCP-1) enhances leukocyte adhesiveness and endothelial permeability in the kidneys of murine and human LN models. Our study aimed to assess the role of urinary MCP-1 in the early diagnosis of LN activity. Sixty children, of whom 45 children aged from six to 12 years old and of both sexes (15 SLE patients without nephritis, 15 active LN and 15 inactive LN) fulfilling the American College of Rheumatology Classification Criteria for SLE were studied in comparison with 15 healthy subjects. We investigated the serum and urinary MCP-1 in all groups using the enzyme-linked immunosorbent assay test. Urinary MCP-1 was significantly higher in active LN in comparison with inactive LN and controls, and also significantly higher in inactive LN in comparison with SLE without nephritis and controls. There was also a significant difference between SLE without nephritis and controls. Serum MCP-1 was significantly higher in the group with active LN in comparison with the inactive group and SLE without nephritis and controls, but there was no significant difference between SLE and controls. The urinary MCP-1 level correlated well with SLE disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Urinary MCP-1 correlates positively with proteinuria, blood urea nitrogen level and creatinine and negatively with hemoglobin and creatinine clearance. We concluded that measurement of MCP-1 in urine may be useful for monitoring the severity of renal involvement in SLE. We recommend measuring urinary MCP-1 in pediatric SLE for the early diagnosis of LN and for the evaluation of the severity of renal involvement. PMID- 26022022 TI - Treatment of IgA nephropathy based on the severity of clinical and histological features. AB - Immunoglobulin A (IgA) nephropathy (IgAN) represents a common glomerular disease treated by various therapeutic regimens. We studied 50 IgAN patients to determine the effect of different regimens selected according to severity of the disease on the clinical outcome of patients over a follow-up period of five years. Patients with normal renal function and proteinuria <1 g/24-h received no treatment (Group A, n = 6). Thomicronse with normal renal function, proteinuria >1 g/24-h and mild to moderate histological lesions received angiotensin-converting enzyme inhibitors (ACEi) and corticosteroids (Group B, n = 23). Patients with baseline serum creatinine (Scr) <2.5 mg/dL, proteinuria >3.5 g/24-h and severe histological lesions received ACEi, corticosteroids and other immunosuppressive drugs (Group C, n = 18). Finally, patients with Scr >2.5 mg/dL, glomerulosclerosis and tubulointerstitial fibrosis received ACEi and fish oil (Group D, n = 3). Doubling of baseline Scr was observed in nine (18%) patients; two (8.7%) patients from Group B, five (27.7%) patients from Group C and two (66.7%) patients from Group D. Of the seven (14%) patients who reached end-stage renal disease, one (4.3%) patient was from Group B, four (21.0%) patients were from Group C and two (66.7%) patients were from Group D. Reduction of proteinuria was observed in all (100%) patients from Group B and in 15 (83.3%) patients from Group C. Adverse reactions occurred in three of 18 (16%) patients treated with immunosuppressive drugs. The choice of therapeutic regimen used in the treatment of patients with IgAN could be based on the severity of clinical and histological involvement in order to achieve the maximum effect with the least of adverse reactions. PMID- 26022023 TI - Cardiovascular risk in lupus nephritis: Do renal disease-related and other traditional risk factors play a role? AB - This study was performed to evaluate the prevalence of thickened carotid intima media thickness (CIMT) in a Sri Lankan cohort of lupus nephritis (LN) patients and to identify associations between traditional cardiovascular disease (CVD) and LN-related risk factors with increased CIMT. Consecutive patients with biopsy proven LN were evaluated for conventional CVD risk factors, renal parameters and extent of organ involvement in this cross-sectional study. Current disease activity and damage were assessed by the British Isles Lupus Activity Group (BILAG) score and the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index, respectively. CIMT was assessed by B Mode grey scale ultrasonography. Increased CIMT was defined as CIMT more than the 75th percentile based on cutoffs from the "Carotid Atherosclerosis Progression Study." Forty patients (98% female), with a mean age of 38 years (age range of 20-50) and of South Asian descent, were evaluated. The mean duration of disease of 6.15 years (SD = 4.66). The overall prevalence of cardiovascular events was low and included previous acute coronary syndromes in 7.5%, stable angina in 5%, cerebrovascular accidents in 7.5% and transient ischemic attacks in 2.5% of the patients; 72.5% had hypertension (HTN) [mean blood pressure (BP) 140/80 mm Hg]; 32.5% had dyslipidemias (mean serum cholesterol 5.9; SD = 5.6) and 25% had diabetes (mean blood sugar 103.7; SD = 15.6). Forty percent were obese and 20% were overweight (Asian cutoffs). Increased CIMT (57.5%) and atherosclerotic plaques (15.36%) indicated a high CVD risk in this cohort. Diabetes (P = 0.016), HTN (P = 0.002), dyslipidemia (P = 0.002) and obesity (P = 0.048) were associated with thickened CIMT. The only LN-related risk factor associated with thickened CIMT (P <0.05) was the SLICC/ACR damage index. The independent predictors of thickened CIMT determined by logistic regression analysis were HTN and dyslipidemia. PMID- 26022024 TI - Short-term effects of renal transplantation on coronary artery calcification: A prospective study. AB - Cardiovascular disease is a leading cause of mortality in renal transplant recipients. Coronary artery calcification (CAC) has been found to have good correlation with atherosclerosis and cardiovascular morbidity. The objective of our study was to assess the prevalence of CAC and the long-term effects of renal transplantation on CAC and carotid intima-medial thickness (CIMT) in Indian renal transplant recipients. Twenty-eight renal transplant recipients were included in this prospective study. Dual-source computed tomography and calcium scoring using Agatston's method and CIMT measurement were performed at the time of transplant and then repeated at six and 12 months after transplantation. The prevalence of CAC in our study patients was low (32%), probably because they were young, had been on dialysis for a short duration and had undergone live-related renal transplant. An overall improvement in biochemical parameters was observed after transplantation. Patients with zero baseline calcium score did not show progression. Patients with baseline calcium score more than zero showed initial progression at 6 months and no further progression afterwards. There was good correlation between CIMT and CAC score. Our study suggests that renal transplantation does not reverse the calcification but appears to decrease the rate of progression in the long term. PMID- 26022025 TI - Level of dietary awareness among Saudi dialysis patients and the influence of various factors. AB - Our objective was to investigate the degree of dietary awareness of Saudi patients on chronic hemodialysis and influencing factors on this awareness. This is an interviewadministered survey-based cross-sectional study carried out on adult dialysis patients at the King Abdulaziz Medical City, Riyadh. The first part of the survey consisted of the collection of demographic data and the second part consisted of questions in the areas of awareness on the dietary influence of sodium, potassium, fluid intake and calcium/phosphorous and lipids. The questions are simply answered as "yes" or "no." The overall awareness score was 79%. The awareness scores were highest in the area of lipids (86.5%) and lowest in the fluid intake area (71.3%). The scores for sodium, phosphorous/calcium and potassium were 80%, 79.6% and 73%, respectively. The degree of awareness was influenced by the number of visits by the dietitian (P = 0.008) and the educational level of the patients (P = 0.02), but not by age, duration on dialysis or gender. In conclusion, our findings suggest that there is a need for better of awareness among our dialysis patients. The highest score for awareness was seen in the cholesterol-related questions and the lowest score was seen in the fluid intake questions area. This is influenced by the number of visits by the dietitian and the educational level of the patients, but not by age, duration on dialysis or gender. PMID- 26022026 TI - Incidence and risk factors of acute kidney injury among the critically ill neonates. AB - Acute kidney injury (AKI) is a complex disorder with clinical manifestations ranging from mild dysfunction to complete kidney failure. The published literature on the incidence and outcome of AKI in the critically ill neonatal population is scarce. The aim of this study was to evaluate the types, the associated risk factors and short-term outcome of AKI in the critically ill neonates. A cohort study was conducted including 100 critically ill neonates successively admitted to the Neonatal Intensive Care Unit. The inclusion criteria were a gestational age >=28 weeks and body weight >=1 kg. Exclusion criteria included those with multiple congenital anomalies or on drugs altering glomerular filtration rate or AKI developing postoperatively. Neonates were evaluated for the development of AKI [creatinine >1.5 mg/dL and/or blood urea nitrogen (BUN) >20 mg/dL] and were assigned as group A (who developed AKI) and group B (who did not develop AKI). Forty-one patients developed AKI (group A) among whom nine (22%) showed oliguric AKI. The most common risk factors among group A patients were sepsis (75.6%) and nephrotoxic drug administration (75.6%), followed by shock (39%). There were no statistically significant differences between both groups except for male sex predominance and necrotizing enterocolitis (NEC), which were significantly higher among group A (P <0.05). Use of continuous positive airway pressure (CPAP) ventilation was significantly higher in neonates without AKI (13.6% vs 0.0%, P = 0.02). The mortality rate among group A reached 51.2%. Various risk factors including gender, gestational age, birth weight, shock, NEC, sepsis, nephrotoxic drugs, oliguria and mechanical ventilation were studied as regards outcome of group A, and all factors except gender and oliguria proved to be significantly higher in deceased neonates. Male sex and NEC were important risk factors for developing AKI that was predominantly non-oliguric. CPAP ventilation may have a protective effect against AKI. The mortality rate was more than three times higher in the AKI group. PMID- 26022027 TI - Orthotropic liver transplantation for intractable neurological manifestations of Wilson's disease. AB - Wilson's disease (WD) is an inherited autosomal recessive disorder characterized by copper accumulation and toxicity, affecting mainly the liver and brain. Orthotopic liver transplantation (OLT) is the definitive therapy for patients with WD. Acute fulminant hepatic failure and decompensated cirrhosis are well established indications for OLT. Patients with severe neurologic impairment can also be benefited by OLT. Here, we present a patient who underwent OLT for isolated neurological WD. PMID- 26022028 TI - The stuck dialysis catheter: A nasty astonishment. AB - Removal of a tunneled cuffed central venous catheter can be challenging and risky. In some cases, the catheter firmly adheres to the surrounding tissues, becoming an integrated part of the vessel wall. We present the case of an adult female hemodialysis (HD) patient with a dysfunctioning HD tunneled cuffed catheter. The catheter removal procedure proved mazy. After several attempts, the catheter was removed together with the peri-catheter fibrin sheath. However, the post-procedure period was uneventful. PMID- 26022029 TI - Multiple cephalic vein aneurysms with calcification in a patient undergoing hemodialysis: An unusual entity. AB - Peripheral venous aneurysms are a known complication following autogenous arteriovenous fistula (AVF) for hemodialysis. We present a case of aneurysms involving the cephalic vein associated with calcification, a condition that, to the best of our knowledge, has not been reported earlier in the literature. PMID- 26022030 TI - Sphingomonas paucimobilis peritonitis: A case report and review of the literature. AB - Sphingomonas paucimobilis, a yellow-pigmented, aerobic, glucose non-fermenting, Gram-negative bacillus, is a rare cause of human infection normally associated with immunocompromised hosts. It has been associated with a few cases of continuous ambulatory peritoneal dialysis (PD) and is notorious for its resistance to the commonly used antibiotics. In half of the cases reported so far, the peritonitis was refractory to treatment, necessitating PD catheter removal. We report a case of Sphingomonas paucimobilis peritonitis in a 50-year old patient who had been on PD for two years. The patient was successfully treated with intraperitoneal and intravenous antibiotics and the PD catheter was salvaged. PMID- 26022031 TI - Herb-induced acute bone marrow intoxication and interstitial nephritis superimposing glomerular C1q deposition in a patient with paroxysmal nocturnal hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria is a rare disease of the red blood cell membrane that renders it lyzable by the complement system, leading to chronic intravascular hemolysis. Renal hemosiderosis is a well-known complication of intravascular hemolytic anemia and can lead to acute kidney injury and renal failure. The use of herbal medicine is common worldwide. The nephrotoxicity of herbal remedies can take several forms, which include acute kidney injury and acute and chronic interstitial nephritis. In addition, the use of herbal remedies can result in bone marrow toxicity and suppression. C1q nephropathy is an uncommon form of glomerular disease characterized by dominant or co-dominant glomerular immunofluorescence positivity for C1q in the absence of clinical and serological evidence of systemic lupus erythematosus, and has various clinical presentations and outcome. Here, we report a patient of undiagnosed paroxysmal nocturnal hemoglobinuria who consumed herbal medicine of unknown constituents and clinically presented with anemia and acute kidney injury. The pathological findings of bone marrow and renal biopsies that include bone marrow intoxication, severe renal hemosiderosis and acute interstitial nephritis and kidney injury, as well as co-dominant glomerular deposition of C1q, are discussed. In addition, we discuss and hypothesize the possible pathogenesis of glomerular C1q deposition in the setting of paroxysmal nocturnal hemoglobulinuria. PMID- 26022032 TI - Hypothermia and hypokalemia in a patient with diabetic ketoacidosis. AB - We present the case of a 36-year-old man with type-1 diabetes who was hospitalized with diabetic ketoacidosis (DKA). On admission, he had hypothermia, hypokalemia and combined metabolic and respiratory alkalosis, in addition to hyperglycemia. Hypothermia, hypokalemia and metabolic alkalosis, with a concurrent respiratory alkalosis, are not commonly seen in DKA. After admission, intravenous infusion of 0.45% saline was administered, which resulted in the development of pure metabolic acidosis. After starting insulin infusion, hypokalemia and hypophosphatemia became evident and finally resulted in massive rhabdomyolysis. Hyperkalemia accompanying oliguric acute kidney injury (AKI) warranted initiation of hemodialysis (HD) on Day-five. On the 45th hospital day, his urine output started to increase and a total of 22 HD sessions were required. We believe that in this case severe dehydration, hypothermia and hypokalemia might have contributed to the initial symptoms of DKA as well as the prolongation of AKI. PMID- 26022033 TI - Coexistence of sickle cell nephropathy and lupus nephritis in a Sudanese child. AB - In spite of the wide distribution of sickle cell disease (SCD) in Africa, an association with systemic lupus erythromatosis (SLE) is seldom reported. This may be due to the poor association between the two diseases or the high prevalence of missed cases. Progressive renal injury is prominent in both SCD and SLE. In this communication, we are presenting a case of an 11-year-old male who presented with sickle cell nephropathy that manifested as nephrotic syndrome with no response to conservative therapy, alongside unexplained massive hemolysis. His renal biopsy proved SLE superimposed on sickle cell nephropathy. We are stressing the importance of considering alternate disease processes in patients with SCD when symptoms change or when there is an atypical clinical course. PMID- 26022034 TI - Anesthetic management of renal transplantation in glucose-6-phosphate dehydrogenase-deficient patient. PMID- 26022035 TI - Social trends in living kidney donors in a single center. PMID- 26022036 TI - Mycotic aneurysm of a native brachiocephalic fistula. PMID- 26022037 TI - Irreversible fatal renal failure resulting from isolated renal mucormycosis. PMID- 26022038 TI - The effect of induced urinary tract infection during gestation in mother rats on infection in the neonates. PMID- 26022039 TI - Pseudotumor cerebri associated with uremia and NSAIDs. PMID- 26022040 TI - Renal vascular lesions in lupus nephritis: A need for further characterization of vasculopathy. PMID- 26022041 TI - Bilateral partial duplex collecting system in horseshoe kidney with stone in the left upper and lower moiety: An unusual association. PMID- 26022042 TI - Clinical use of the metal chelators calcium disodium edetate, DMPS, and DMSA. PMID- 26022043 TI - Profile of renal diseases in Iraqi children: A single-center report. AB - Renal disease in hospitalized children can be difficult to diagnose early as it may exhibit few symptoms, unlike in adults. This study reports the epidemiological data, percentages and types of renal disorders in children seen at the pediatric nephrology center of the AlKadhymia Teaching Hospital, Baghdad, Iraq. A retrospective review of the charts of all patients, aged between one month and 14 years, who were admitted and followed-up for a period of three years from January 2009 till January 2012 were studied. The presence of renal disease based on their clinical records, laboratory tests and final diagnosis were noted. A total of 4785 children were admitted during the study period, of whom 326 renal disorders were observed in 281 children (5.8%). The affected children included 158 males (56.2%) and 123 females (43.7%). Majority of the cases were above two years of age (n = 181; 64.4%). Among them, urinary tract infection, seen in 60 patients (18.4%), was the most common renal disease, followed by nephrotic syndrome (n = 52; 15.9%), renal stone disease (n = 49; 15%), congenital malformations (n = 46; 14.1%), acute renal failure (n = 37; 11.3%), chronic renal failure (n = 22; 6.7%), glomerulonephritis (n = 16; 4.9%), isolated hematuria (n = 14; 4.2%), hypertension (n = 8; 2.4%), tubular disorders [renal tubular acidosis (n = 8; 2.4%), isolated hypercalciuria (n = 7; 2.1%), Bartter syndrome (n = 1; 0.3%)] and Wilm's tumor in six (1.8%) patients. The spectrum of renal disorders in Iraq is wide, and is similar to those reported from other developing countries with a predominance of infectious diseases. PMID- 26022044 TI - Outcome assessment of pregnancy-related acute kidney injury in Morocco: A national prospective study. AB - Acute kidney injury (AKI) is a rare but life-threatening complication of pregnancy. The aim of this paper is to study the characteristics of acute AKI in pregnancy and to emphasize on its management modalities in Moroccan hospitals. This is a national prospective study performed over six months from July 1 to December 31 2010 on AKI developing in pregnant patients, both preand post-partum period. Patients with pre-existing kidney disease were excluded from the study. Outcome was considered unfavorable when complete recovery of renal function was not achieved and/or maternal death occurred. Forty-four patients were included in this study. They were 29.6 +/- 6 years old and mostly illiterate (70.6%). Most AKI occurred in the post-partum period, with 66% of the cases occurring in those who did not receive antenatal care. The main etiologies were pre-eclampsia (28 cases), hemorrhagic shock (six cases) and septic events (five cases). We noted three cases of acute fatty liver, one case of obstructive kidney injury and one case of lupus nephritis. Hemodialysis was necessary in 17 (38.6%) cases. The outcome was favorable in 29 patients. The maternal mortality rate was 11.4%. Two poor prognostic factors were identified: Age over 38 years and sepsis. AKI is a severe complication of pregnancy in developing countries. Its prevention necessitates the improvement of the sanitary infrastructure and the establishment of the obligatory antenatal care. PMID- 26022045 TI - Restless leg syndrome in hemodialysis patients: A disorder that should be noticed. AB - Restless leg syndrome (RLS) is a distressing sleep disorder that is commonly experienced by patients undergoing maintenance hemodialysis. The aim of this study was to assess the prevalence of RLS and its related factors among hemodialysis patients. This was an analytical cross-sectional study that was performed on hemodialysis patients of the Bu"Ali Hospital of Qazvin during 2009 and 2010. One hundred and twelve patients were selected by the census sampling method as the study sample. Data collection was performed using the Insomnia Severity Index (ISI), Pittsburg Sleep Quality Index (PSQI), Berlin, Epworth Sleepiness Scale (ESS) and International Restless Leg Syndrome Study Group criteria (IRRLS) questionnaires. Student's ttest and chi-square test were applied to analyze the collected data. RLS complaints were very common among patients on long-term dialysis therapy and were reported in about 42.9% of the patients. Patients with RLS had higher daytime sleepiness, insomnia complaints and poorer sleep quality. Percentage of patients in the high-risk group was higher in the RLS group. RLS symptoms appear to be correlated with age (P = 0.012) and use of sedative drugs (P = 0.035). RLS is common in dialysis patients and is associated with a higher prevalence of other sleep disturbances. Therefore, the effective assessment and management of this sleep disturbance has the potential to significantly enhance patient outcomes. PMID- 26022046 TI - Quality of life in patients on continuous ambulatory peritoneal dialysis in an African setting. AB - To determine the quality of life (QOL) of patients on continuous ambulatory peritoneal dialysis (CAPD), we studied all the CAPD patients attending their monthly follow-up care clinics at three tertiary hospitals in Johannesburg by administering the World Health Organization QOL-Bref questionnaire. The patients were grouped according to age, duration of peritoneal dialysis and gender. Data were analyzed to determine the significant differences in the QOL scores among the subgroups. There were 114 patients [64 males (56.1%), with a mean age of 42.4 +/- 11.3 years) and 38 healthy control subjects (22 males (57.9%), with a mean age of 42.1 +/- 12.4 years]. Twenty-one patients (18.4%) had hemoglobin <10 g/dL, while 16 patients (14%) had serum albumin <3 g/dL. The mean QOL scores in the physical, psychological, social relationships and environment domains of the CAPD patients were 55.7 +/- 15.0, 56.6 +/- 16.4, 55.3 +/- 24.7 and 56.3 +/- 16.6, respectively. The CAPD patients had significantly lower QOL scores compared with controls, and those aged <30 years had better scores in the physical and psychological domains, gender and hemoglobin concentration. Serum albumin levels did not have a significant impact on the QOL of the CAPD patients. PMID- 26022047 TI - Nephrectomy in adults: Experience at the Korle Bu Teaching Hospital, Accra, Ghana. AB - The objective of this study was to analyze nephrectomies performed in adults over a 12-year period at the Korle Bu Teaching Hospital, Accra and to compare our findings with reports from other institutions. In this retrospective study, medical records of 97 consecutive adult patients who underwent nephrectomy from January 2000 to December 2011 were reviewed. The parameters extracted included the patients' age, gender, indication for nephrectomy and the side of nephrectomy. Also considered were the histology of the nephrectomy specimen and the peri-operative mortality. The data were analyzed using the Statistical Package for Social Sciences for Windows (Version 19.0). Of the 97 nephrectomies performed, 62 were performed for suspected malignant renal tumors and 35 were performed for clinically benign renal conditions. Malignancy was confirmed in 85.5% (53/62) of the suspected cases. The mean age of this group was 52.2 +/- 15.5 years and the male to female ratio was 1:0.9. Thirty-two tumors (60.4%) were in the right kidney and 21 (39.6%) tumors were in the left kidney; the mean tumor size was 16.8 +/- 4.0 cm. The predominant presenting complaints included flank pain (67.9%), flank mass (50.9%) and hematuria (24.5%). In one case (1.9%), the renal mass was found incidentally. Among patients who had benign disease, non functioning kidney due to renal cystic disease was the most common lesion (11/44; 25.0%). A peri-operative mortality rate of 3.1% was recorded. Our study suggests that malignant renal tumors constitute the main indication for nephrectomy in our institution. Non-functioning kidney due to renal cystic disease was the most common benign renal indication for nephrectomy. PMID- 26022048 TI - microRNA represses macromolecule. AB - In this issue of Blood, Xiang et al identify a novel mechanism, involving activation of the polyol pathway and repression of microRNA-24 (miR-24), through which hyperglycemia augments von Willebrand factor (VWF) expression and secretion. PMID- 26022049 TI - Fitness deficits in long-term ALL survivors. AB - In this issue of Blood, Ness et al report that, despite the omission of prophylactic cranial radiotherapy (CRT) in the treatment of acute lymphoblastic leukemia (ALL), adult survivors of childhood ALL remain at risk for impaired fitness, body composition, and energy balance. PMID- 26022050 TI - Chronic lymphocytic leukemia and the Warburg effect. AB - In this issue of Blood, Jitschin et al demonstrate a microenvironmental glycolytic shift in chronic lymphocytic leukemia (CLL) cells mediated by Notch-c Myc signaling. Interfering in the Notch-c-Myc pathway and reprogramming glycolytic metabolism could contribute to overcoming drug resistance in CLL. PMID- 26022051 TI - ATRA and ATO team up against NPM1. AB - In this issue of Blood, Martelli et al and El Hajj et al independently report that nucleophosmin-1 (NPM1)-mutant leukemia is particularly vulnerable to a novel strategy combining all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). The era of targeted therapy has seen some of its greatest successes in the hematologic arena (eg, breakpoint cluster region [BCR]/Abelson [ABL] kinase inhibitors in chronic myeloblastic leukemia and ATRA in acute promyelocytic leukemia [APL]). Moreover, addition of ATO, an agent that induces oxidative stress and interferes with protein translation, to ATRA sharply increases APL cell killing to the extent that cures in this disease are no longer unrealistic. A theoretical (and practical) basis for translating ATRA/ATO-based strategies to non-APL acute myelocytic leukemia (AML) is currently lacking. PMID- 26022052 TI - Lupus anticoagulant, thrombosis, and death. AB - In this issue of Blood, Gebhart et al report a prospective observational cohort study evaluating 151 patients with persistently positive lupus anticoagulant (LA) for a median period of 8.2 years. They observed increased mortality in LA positive patients, mainly due to new thrombotic events. PMID- 26022053 TI - The first specific antiplatelet antidote. AB - In this issue of Blood, Buchanan and coauthors present the development of a specific antidote for ticagrelor. In fact, this is the first specific antidote against any antiplatelet agent. PMID- 26022054 TI - A party of three: iNKT cells in GVHD prevention. AB - In this issue of Blood, Schneidawind et al demonstrate that the adoptive transfer of CD4+ invariant natural killer T (iNKT) cells from third-party mice protects from lethal graft-versus-host disease (GVHD) through expansion of donor regulatory T cells (Tregs) in a murine model of allogeneic hematopoietic cell transplantation (HCT). PMID- 26022055 TI - An autopsy case of myocardial infarction due to idiopathic thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by systemic platelet-von Willebrand factor aggregation, organ ischemia and profound thrombocytopenia. In this report, we describe an autopsy case of a 77-year-old Japanese man diagnosed with idiopathic TTP. He had no history of cardiovascular disease symptoms, such as chest pain, ST segment elevation, and elevation of cardiac enzyme levels, except arrhythmia. The patient suddenly died despite receiving many treatments. On autopsy, macroscopically and microscopically, acute and chronic myocardial infarction manifested as petechiae and fibrotic foci and covered a wide area in the myocardium, including the area near the atrioventricular node. The microthrombi in the small arterioles and capillaries were platelet thrombi, which showed positive results for periodic acid-Schiff stain and factor VIII on immunohistochemical staining. The cause of the sudden death was suspected to be myocardial infarction, including a cardiac conduction system disorder due to multiple platelet microthrombi. Asymptomatic myocardial infarction is an important cause of death in TTP. Therefore, the heart tissue, including the sinus-atrial node and the atrioventricular node, should be microscopically examined more closely in autopsy cases of patients with TTP who experienced sudden death of TTP. This report is a critical teaching case considering that its cause of sudden death may be arrhythmia due to a myocardial infarction including cardiac conduction system disorder by platelet microthrombi. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2113354005156739. PMID- 26022056 TI - A synopsis of original research projects published in scientific database in the Russian Federation. AB - The article describes the current state of scientific publications in the field of psychiatry in the Russian Federation. Issues of academic dissertations, lack of access to recent Russian language research in foreign databases, and recent reforms in the Ministry of Education and Science for overcoming these limitations are discussed in detail. Four exemplary dissertation studies published in Russian language are summarized. The first research examines the contribution of patient's verbal behavior to the reliable diagnosis of mild depression, identifying objective signs for distinguishing it from normal sadness; the mood component influenced the whole mental status and was represented in both structure and semantics of patients' speech. The second paper describes the course of panic disorder with agoraphobia, with the notable results that debut of panic disorder with full-blown panic attacks, often declines to a second accompanied with agoraphobia, which after several years gives way to limited symptom attacks and decreased agoraphobic avoidance. The third study describes the high prevalence of affective and anxiety disorders in patients with diabetes mellitus type 1 and 2, and the role of personality traits in adherence to treatment in patients with poor glucose control. The fourth project uses functional MRI for probing the features of neuronal resting-state networks in patients with temporal lobe epilepsy; the association with affective symptoms provides a model for investigating the pathophysiology of mood disorder. PMID- 26022057 TI - The impact of pornography on gender-based violence, sexual health and well-being: what do we know? PMID- 26022058 TI - Comparing the impact of personal and parental risk factors, and parental lifespan on all-cause mortality and cardiovascular disease: findings from the Midspan Family cohort study. AB - BACKGROUND: We aimed to identify which personal and parental factors best explained all-cause mortality and cardiovascular disease (CVD). METHODS: In 1996, data were collected on 2338 adult offspring of the participants in the 1972-1976 Renfrew and Paisley prospective cohort study. Recorded risk factors were assigned to 5 groups: mid-life biological and behavioural (BB), mid-life socioeconomic, parental BB, early-life socioeconomic and parental lifespan. Participants were followed up for mortality and hospital admissions to the end of 2011. Cox proportional hazards models were used to analyse how well each group explained all-cause mortality or CVD. Akaike's Information Criterion (AIC), a measure of goodness-of-fit, identified the most important groups. RESULTS: For all-cause mortality (1997 participants with complete data, 111 deaths), decreases in AIC from the null model (adjusting for age and sex) to models including mid-life BB, mid-life socioeconomic, parental BB, early-life socioeconomic and parental lifespan were 55.8, 21.6, 10.3, 7.3 and 5.9, respectively. For the CVD models (1736 participants, 276 with CVD), decreases were 37.8, 3.7, 6.7, 17.3 and 0.4. Mid-life BB factors were the most important for both all-cause mortality and CVD; mid-life socioeconomic factors were important for all-cause mortality, and early life socioeconomic factors were important for CVD. Parental lifespan was the weakest factor. CONCLUSIONS: As mid-life BB risk factors best explained all-cause mortality and CVD, continued action to reduce these is warranted. Targeting adverse socioeconomic factors in mid-life and early life may contribute to reducing all-cause mortality and CVD risk, respectively. PMID- 26022059 TI - Hemispheric lateralization of semantic feature distinctiveness. AB - Recent models of semantic memory propose that the semantic representation of concepts is based, in part, on a network of features. In this view, a feature that is distinctive for an object (a zebra has stripes) is processed differently from a feature that is shared across many objects (a zebra has four legs). The goal of this paper is to determine whether there are hemispheric differences in such processing. In a feature verification task, participants responded 'yes' or 'no' following concepts which were presented to a single visual field (left or right) paired with a shared or distinctive feature. Both hemispheres showed faster reaction times to shared features than to distinctive features, although right hemisphere responses were significantly slower overall and particularly in the processing of distinctive features. These findings support models of semantic processing in which the dominant left hemisphere more efficiently performs highly discriminating 'fine' encoding, in contrast to the right hemisphere which performs less discriminating 'coarse' encoding. PMID- 26022060 TI - Cognitive-behavioral therapy induces sensorimotor and specific electrocortical changes in chronic tic and Tourette's disorder. AB - BACKGROUND: Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. METHODS: To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. RESULTS: Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy. CONCLUSIONS: Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given that LRPs are partially generated within the sensorimotor and supplementary motor area, the reported reduction in tic frequency and improvements of LRPs components suggest that CBT induced a physiological change in patients' motor area. PMID- 26022061 TI - Erratum: Relationship between MRI derived right ventricular mass and left ventricular involvement in patients with Anderson-Fabry disease. PMID- 26022063 TI - The Path Toward Universal Health Coverage. AB - Lebanon is a middle-income country with a market-maximized healthcare system that provides limited social protection for its citizens. Estimates reveal that half of the population lacks sufficient health coverage and resorts to out-of-pocket payments. This study triangulated data from a comprehensive review of health packages of countries similar to Lebanon, the Ministry of Public Health statistics, and services suggested by the World Health Organization for inclusion in a health benefits package (HBP). To determine the acceptability and viability of implementing the HBP, a stakeholder analysis was conducted to identify the knowledge, positions, and available resources for the package. The results revealed that the private health sector, having the most resources, is least in favor of implementing the package, whereas the political and civil society sectors support implementation. The main divergence in opinions among stakeholders was on the abolishment of out-of-pocket payments, mainly attributed to the potential abuse of the HBP's services by users. The study's findings encourage health decision makers to capitalize on the current political readiness by proposing the HBP for implementation in the path toward universal health coverage. This requires a consultative process, involving all stakeholders, in devising the strategy and implementation framework of a HBP. PMID- 26022066 TI - 3D-QSAR Based Pharmacophore Modeling and Virtual Screening for Identification of Novel G Protein-Coupled Receptor40 Agonists. AB - Pharmacophore models of G protein-coupled receptor40 (GPR40) agonists were developed using Discovery Studio V2.1. One hydrogen bond acceptor and three hydrophobic features, Hypo 1 which was the best hypothesis, had a correlation co efficient of 0.971, cost difference of 73.041, and RMSD 0.680. This model was validated by test set, Fischer randomization test and decoy set. Subsequently, Hypo 1 was employed as a 3D query to identify potent molecules from chembridge database. 21 compounds were identified with estimated EC50 less than 500 nM. Seven top-scored hit compounds were chosen for further evaluation in FLIPR assay and two compounds were discovered as potent GPR40 agonists. PMID- 26022067 TI - Development of Global Consensus of Dengue Virus Envelope Glycoprotein for Epitopes Based Vaccine Design. AB - Dengue virus (DENV) is the member of Flaviviridae and causative agent of Dengue Haemorrhagic Fever and Dengue Shock Syndrome. Every year, around 70% of the world population is at risk, due to epidemic episodes orchestrated by one or more of its serotypes. So, a tetravalent DENV vaccine is needed which may induce the immune response against all four DENV serotypes. In this study, B-cell and T-cell epitopes have been predicted from the DENV envelope glycoprotein (Eg) using a consensus based approach in complement with the physico-chemical property (PCP) conservancy analysis. Through DENV-Eg analysis, a total of 7 PCP conserved, water soluble, in vitro and in vivo stable epitopes were predicted which may induce the B-cell and T-cell mediated anti-viral immune response. PMID- 26022068 TI - Emission Computed Tomography for the Diagnosis of Mandibular Invasion by Head and Neck Cancers: A Systematic Review and Meta-Analysis. AB - PURPOSE: To detect the diagnostic efficacy of emission computed tomography (ECT) in detecting mandibular invasion caused by head and neck cancers. MATERIALS AND METHODS: Thirteen databases were searched electronically to retrieve studies for inclusion and a manual search also was conducted. Study inclusion, data extraction, and quality assessment were completed by 2 reviewers independently. Meta-DiSc 1.4 and STATA 11.0 were used to conduct the meta-analysis. RESULTS: Seventeen studies involving 668 participants were included. One study had a low risk of bias, 2 had a high risk, and the rest had unclear risk. Meta-analysis showed that for the diagnosis of mandibular invasion single-photon ECT (SPECT) had a mean sensitivity (SEN) of 0.96, a mean specificity (SPE) of 0.66, an area under the curve (AUC) of 0.8989, and a Q* (point on the summary reviewer operator characteristic curve when SEN equaled SPE) of 0.8300. Positron emission tomography combined with computed tomography (PET/CT) had a mean SEN of 0.83, a mean SPE of 0.90, an AUC of 0.9290, and a Q* of 0.8640. The comparison between the diagnostic efficacy of SPECT and PET/CT showed that SPECT was superior for SEN (P = .0014) and PET/CT had a significantly better SPE (P = .001). The summary diagnostic efficacy between these modalities did not differ significantly (P > .05). CONCLUSIONS: The present clinical evidence showed that SPECT is an excellent tool to exclude patients with no mandibular invasion, but is not as good as PET/CT to confirm the diagnosis. PMID- 26022064 TI - Biogenesis of endosome-derived transport carriers. AB - Sorting of macromolecules within the endosomal system is vital for physiological control of nutrient homeostasis, cell motility, and proteostasis. Trafficking routes that export macromolecules from the endosome via vesicle and tubule transport carriers constitute plasma membrane recycling and retrograde endosome to-Golgi pathways. Proteins of the sorting nexin family have been discovered to function at nearly every step of endosomal transport carrier biogenesis and it is becoming increasingly clear that they form the core machineries of cargo-specific transport pathways that are closely integrated with cellular physiology. Here, we summarize recent progress in elucidating the pathways that mediate the biogenesis of endosome-derived transport carriers. PMID- 26022069 TI - Genetic characterization of peste des petits ruminants virus, Turkey, 2009-2013. AB - Peste des petits ruminants is an endemic disease of small ruminants in Turkey and vaccination has been the method of control but sporadic outbreaks have been reported. This study was carried out to characterize the local peste des petits ruminants virus (PPRV) by sequencing fusion (F) protein and nucleoprotein (N) gene segments and phylogenetic analysis, so as to focus on genetic variation in the field viruses. Samples were collected from sheep and goats clinically suspected of having PPRV infection in Central and Mediterranean regions of Turkey during 2009-2013. Phylogenetic analysis based on the F gene sequences showed that the field isolates in the present study belong to lineage 4 with other Middle East isolates. While N gene sequences revealed a different pattern, the field isolates in the present study clustered with previous Turkish isolates, which probably represents the true picture of molecular epidemiology for PPRV. PMID- 26022070 TI - Evolution of porcine reproductive and respiratory syndrome virus GP5 and GP3 genes under swIFN-beta immune pressure and interferon regulatory factor-3 activation suppressed by GP5. AB - In this study, a highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) strain, PRRSV GD07 was continuously propagated in MARC-145 cell cultures primed with swIFN-beta for 50 passages to develop the PRRSV GDbetafn strains. And a control strain PRRSV GDfn was passaged without swIFN-beta. The sequencing analysis indicated that under swIFN-beta immune pressure, molecular variation of PRRSV GP5 was accelerated in gene (NS/S>2.50), and the acceleration of GP3 was not significant (NS/S<2.50). swIFN-beta mRNA level induced by Poly(I:C) is lower in cells primed with PRRSV GDbetafn than in cells without PRRSV GDfn, although both of them are much less than the control group. Effect of GP5 on IRF3 was analyzed by SDS-PAGE and western-blot. Our results indicated that GP5 protein prevents IRF3 phosphorylation. Therefore, we conclude that swIFN can promote viral mutation in GP5, and, in turn GP5 inhibits IRF3 activation to escape from swIFN-beta. PMID- 26022071 TI - Effects of heme-PrP complex on cell-free conversion and peroxidase-linked immunodetection of prions in blood-based assays. AB - Prion protein (PrP) binding to natural and synthetic porphyrins has been previously demonstrated but the effects of endogenous heme interactions with PrP remain uncertain. This study investigated implications of this interaction in blood-based peroxidase-linked prion immunodetection and seeded conversion of cellular prion (PrP(C)) into disease associated form (PrP(Sc)). Heme binding to recombinant PrP(C) enhanced intrinsic peroxidase activity (POD) by 2.5-fold and POD inherent to denatured blood accounted for over 84% of luminol-based substrate oxidation in a prion immunodetection assay. An immuno-capture assay showed that 75-98% of blood POD was attributable to binding of PrP(C) with endogenous heme. Additionally, 10 MUM heme inhibited (P<0.05) the seeded conversion of PrP(C) to PrP(Sc) through the protein misfolding cycling amplification assay. We conclude that the observed effects can interfere with cell-free conversion and peroxidase linked immunodetection of prions in blood-based assays. These results indicate that heme-PrP interactions could modulate intrinsic POD and protect PrP(C) from conversion into PrP(Sc). PMID- 26022073 TI - Expression of Toll-like receptor signaling-related genes in pigs co-infected with porcine reproductive and respiratory syndrome virus and porcine circovirus type 2. AB - Pigs co-infected with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) have been shown to develop more severe diseases than pigs infected with PRRSV or PCV2 only. The underlying interaction mechanisms between the two viruses in developing the disease are unclear. The present study investigates the mRNA expression of Toll-like receptor (TLR) signaling-related molecules in peripheral blood mononuclear cells from pigs infected with PRRSV or PCV2 or both. The mRNA expression levels were determined by quantitative real-time RT-PCR. Co-infection of pigs with PRRSV and PCV2 resulted in a negatively synergistic effect on the mRNA expression of the negative regulators of TLR, including A20, Bcl-3, IRAK-M, MKP-1, SARM1 and SIGIRR, as well as the TLR downstream transcription factors IRF-1 and IRF-3. A positively synergistic effect of a combined infection of PRRSV and PCV2 on the CD14 mRNA expression was also observed. PMID- 26022072 TI - The effect of manganese-induced toxicity on the cytokine mRNA expression of chicken spleen lymphocytes in vitro. AB - Manganese (Mn) is essential for life, but excess Mn exposure is harmful. This study investigated the effect of excess Mn on the cytokines of spleen lymphocytes in chicken. Lymphocytes were incubated with or without MnCl2 (2, 4, 6, and 8*10( 4) mmol/L) for 12, 24, 36, and 48 h, respectively. The mRNA expression of interleukin (IL) -2, IL-4, IL-6, IL-12beta, and IL-17 and interferon (INF) -gamma was examined using RT-PCR. Excess Mn inhibited IL-2, IL-4, IL-6, IL-12beta, and IL-17 mRNA expression in chicken spleen lymphocytes in a dose-dependent manner. IFN-gamma was inhibited by 8*10(-4) mmol/L Mn for 48 h. This study demonstrates that excess Mn affects cytokine mRNA expression and causes immunosuppression in chicken spleen lymphocytes. The relationships between IL-6 and IL-17 and between IL-2 and IL-12beta were strong under immunosuppression caused by excess Mn in lymphocytes. PMID- 26022074 TI - N-3 polyunsaturated fatty acids and 17beta-estradiol injection induce antidepressant-like effects through regulation of serotonergic neurotransmission in ovariectomized rats. AB - Previous studies have suggested that estrogen and n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antidepressant-like effects. The purpose of the present study was to determine the interaction between n-3 PUFAs and estrogen, and their neurotrophic mechanism in rats after the forced swimming test (FST). Rats were fed a modified American Institute of Nutrition 93G diet with 0%, 1% or 2% EPA+DHA relative to the total energy intake during 12 weeks. At 8 weeks, rats were ovariectomized and injected with either 17beta-estradiol-3-benzoate (E2) or corn oil during the last 3 weeks. Both n-3 PUFA supplementation and E2 injection increased climbing and decreased immobility during the FST. Serum serotonin concentration was also increased by both n-3 PUFA and E2. N-3 PUFA and E2 decreased hippocampal expressions of interleukin (IL)-6 and tumor necrosis factor-alpha, and increased cAMP response element binding protein (CREB), phosphorylated CREB and brain-derived neurotrophic factor (BDNF). N-3 PUFA supplementation decreased hippocampal expression of IL-1beta only in rats injected with E2. Both n-3 PUFA supplementation and E2 injection increased estrogen receptor (ER)-alpha in the hippocampus, but ER-beta was increased only by E2 injection. Additionally, there was a significant interaction between n-3 PUFA supplementation and E2 injection on the hippocampal expression of pCREB, suggesting membrane-mediated interaction of n-3 PUFAs and E2. In conclusion, both n-3 PUFA and E2 had antidepressant-like effects by regulating serotonergic neurotransmission through BDNF and inflammatory cytokines. PMID- 26022065 TI - The short and long of noncoding sequences in the control of vascular cell phenotypes. AB - The two principal cell types of importance for normal vessel wall physiology are smooth muscle cells and endothelial cells. Much progress has been made over the past 20 years in the discovery and function of transcription factors that coordinate proper differentiation of these cells and the maintenance of vascular homeostasis. More recently, the converging fields of bioinformatics, genomics, and next generation sequencing have accelerated discoveries in a number of classes of noncoding sequences, including transcription factor binding sites (TFBS), microRNA genes, and long noncoding RNA genes, each of which mediates vascular cell differentiation through a variety of mechanisms. Alterations in the nucleotide sequence of key TFBS or deviations in transcription of noncoding RNA genes likely have adverse effects on normal vascular cell phenotype and function. Here, the subject of noncoding sequences that influence smooth muscle cell or endothelial cell phenotype will be summarized as will future directions to further advance our understanding of the increasingly complex molecular circuitry governing normal vascular cell differentiation and how such information might be harnessed to combat vascular diseases. PMID- 26022075 TI - Putative Microcircuit-Level Substrates for Attention Are Disrupted in Mouse Models of Autism. AB - BACKGROUND: Deep layer excitatory circuits in the prefrontal cortex represent the strongest locus for genetic convergence in autism, but specific abnormalities within these circuits that mediate key features of autism, such as cognitive or attentional deficits, remain unknown. Attention normally increases the sensitivity of neural populations to incoming signals by decorrelating ongoing cortical circuit activity. Here, we investigated whether mechanisms underlying this phenomenon might be disrupted within deep layer prefrontal circuits in mouse models of autism. METHODS: We isolated deep layer prefrontal circuits in brain slices then used single-photon GCaMP imaging to record activity from many (50 to 100) neurons simultaneously to study patterns of spontaneous activity generated by these circuits under normal conditions and in two etiologically distinct models of autism: mice exposed to valproic acid in utero and Fmr1 knockout mice. RESULTS: We found that modest doses of the cholinergic agonist carbachol normally decorrelate spontaneous activity generated by deep layer prefrontal networks. This effect was disrupted in both valproic acid-exposed and Fmr1 knockout mice but intact following other manipulations that did not model autism. CONCLUSIONS: Our results suggest that cholinergic modulation may contribute to attention by acting on local cortical microcircuits to decorrelate spontaneous activity. Furthermore, defects in this mechanism represent a microcircuit-level endophenotype that could link diverse genetic and developmental disruptions to attentional deficits in autism. Future studies could elucidate pathways leading from various etiologies to this circuit-level abnormality or use this abnormality itself as a target and identify novel therapeutic strategies that restore normal circuit function. PMID- 26022076 TI - DD Genotype of ACE I/D Polymorphism Might Confer Protection against Dental Caries in Polish Children. AB - The aim of the study was to examine the frequencies of the genotypes and alleles of ACE insertion/deletion (I/D) polymorphism and their association with dental caries in a sample of Polish children. The study subjects were 120 children with dental caries experience (cases) and 41 caries-free individuals (controls). The genotyping was performed using polymerase chain reaction. The genotype distributions of ACE I/D polymorphism were not statistically different between carious and control children. However, we found a borderline overrepresentation of the II + ID genotypes versus the DD genotype in the carious compared to the control group (69.2% and 51.2%, respectively, p = 0.057). Logistic regression analysis adjusted for age and sex revealed that I allele carriage was a significant predictor of dental caries susceptibility (OR = 2.14, 95% CI = 1.02 4.49, p = 0.041). In conclusion, the DD genotype of ACE I/D polymorphism might be protective against dental caries in Polish children. PMID- 26022079 TI - Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR ABL kinase inhibitors. AB - 4-(Pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives have been proposed as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. In the present study, a series of 4-(pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were synthesized and their activities against BCR-ABL1 kinase in vitro were evaluated by using Kinase-Glo assay. All new compounds showed from moderate to potent activities against wild-type (wt) BCR-ABL1 kinase with an IC50 range from 14.2 to 326.0nM. Among them, seven compounds exhibited BCR-ABL1 kinase inhibitory activities with IC50 values less than 50nM. Compound 7a displayed the most potent inhibitory activity to BCR-ABL kinase (IC50: 14.2nM). Docking simulation was performed for compounds 7a and 7i into the BCR-ABL kinase structure active site to determine the probable binding model. The preliminary structure-activity relationship was discussed. The interesting activities of these compounds may make them promising candidates as therapeutic agents for chronic myelogenous leukemia. PMID- 26022078 TI - Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates. AB - Collagen is the most abundant protein in animals. A variety of indications are associated with the overproduction of collagen, including fibrotic diseases and cancer metastasis. The stability of collagen relies on the posttranslational modification of proline residues to form (2S,4R)-4-hydroxyproline. This modification is catalyzed by collagen prolyl 4-hydroxylases (CP4Hs), which are Fe(II)- and alpha-ketoglutarate (AKG)-dependent dioxygenases located in the lumen of the endoplasmic reticulum. Human CP4Hs are validated targets for treatment of both fibrotic diseases and metastatic breast cancer. Herein, we report on 2,2' bipyridinedicarboxylates as inhibitors of a human CP4H. Although most 2,2' bipyridinedicarboxylates are capable of inhibition via iron sequestration, the 4,5'- and 5,5'-dicarboxylates were found to be potent competitive inhibitors of CP4H, and the 5,5'-dicarboxylate was selective in its inhibitory activity. Our findings clarify a strategy for developing CP4H inhibitors of clinical utility. PMID- 26022080 TI - Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study of 2-phenyl- or hydroxylated 2-phenyl-4 aryl-5H-indeno[1,2-b]pyridines. AB - A series of novel twenty-eight rigid 2-phenyl- or hydroxylated 2-phenyl-4-aryl-5H indeno[1,2-b]pyridines were synthesized and evaluated for their topoisomerase inhibitory activity as well as their cytotoxicity against several human cancer cell lines. Generally, hydroxylated compounds (16-18, 22-25, and 29-31) containing furyl or thienyl moiety at 4-position of central pyridine exhibited strong topoisomerase I and II inhibitory activity compared to positive control, camptothecin and etoposide, respectively, in low micromolar range. Structure activity relationship study revealed that indenopyridine compounds with hydroxyl group at 2-phenyl ring in combination with furyl or thienyl moiety at 4-position are important for topoisomerase inhibition. Compounds (22-25) which contain hydroxyl group at meta position of the 2-phenyl ring at 2-position and furanyl or thienyl substitution at 4-position of indenopyridine, showed concrete correlations between topo I and II inhibitory activity, and cytotoxicity against evaluated human cancer cell lines. PMID- 26022081 TI - Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis. AB - Cancer cell resistance to chemotherapy is still a heavy burden that impairs the response of many cancer patients to conventional chemotherapy. Using drug combinations is one therapeutic approach to overcome the developing resistance to any one drug. Oxidative stress is now a generally regarded hallmark of cancer that can be one approach to selectively target cancer cells while sparing normal cells. With the aim of increasing oxidative stress in cancer cells to a lethal set point, we have generated and combined several series of redox active compounds that act at different points of the cellular oxidative cascade. The premise of such combinations is to deplete of endogenous antioxidant defence proteins (e.g., Glutathione) while concomitantly increasing the generation of ROS via metal redox recycling and Fenton chemistry which eventually leads to the disruption of cellular redox homeostasis and induction of cell death. Through this approach, we have identified highly synergistic combinations of two distinctive classes of compounds (Azines and Copper(II) complexes of 2-pyridyl ketone thiosemicarbazones) which are capable of eliminating cancer cells without concomitant increase in toxicity toward normal cells. In one of our most potent combinations, a combination index (CI) value of 0.056 was observed, representing a 17 fold enhancement in activity beyond additive effects. Such new combination regimen of redox active compounds can be one step closer to potentially safer low dose chemotherapy. PMID- 26022082 TI - Glycosyl hydroperoxides: a new class of potential antimalarial agents. AB - Motivated by the antimalarial properties observed in organic peroxides, an extensive series of glycosyl hydroperoxides was prepared with the aim of identifying new bioactive molecules. Selected compounds were tested against a Plasmodium falciparum culture (chloroquine-susceptible strain D10 and chloroquine resistant strain W2). Screening results indicated that the factors critical for antimalarial activity were the presence of a hydroperoxide moiety and solubility in water at pH 5.0. Moreover, the ability to inhibit beta-hematin formation in vitro has been evaluated (BHIA Assay). PMID- 26022083 TI - Evaluation of BBLTM Sensi-DiscsTM and FTA(r) cards as sampling devices for detection of rotavirus in stool samples. AB - Rotavirus is the most important cause of severe childhood gastroenteritis worldwide. Rotavirus vaccines are available and rotavirus surveillance is carried out to assess vaccination impact. In surveillance studies, stool samples are stored typically at 4 degrees C or frozen to maintain sample quality. Uninterrupted cold storage is a problem in developing countries because of power interruptions. Cold-chain transportation of samples from collection sites to testing laboratories is costly. In this study, we evaluated the use of BBLTM Sensi-DiscsTM and FTA((r)) cards for storage and transportation of samples for virus isolation, EIA, and RT-PCR testing. Infectious rotavirus was recovered after 30 days of storage on Sensi-DiscsTM at room temperature. We were able to genotype 98-99% of samples stored on Sensi-DiscsTM and FTA((r)) cards at temperatures ranging from -80 degrees C to 37 degrees C up to 180 days. A field sampling test using samples prepared and shipped from Cameroon, showed that both matrices yielded 100% genotyping success compared with whole stool and Sensi DiscsTM demonstrated 95% concordance with whole stool in EIA testing. The utilization of BBLTM Sensi-DiscsTM and FTA((r)) cards for stool sample storage and shipment has the potential to have great impact on global public health by facilitating surveillance and epidemiological investigations of rotavirus strains worldwide at a reduced cost. PMID- 26022084 TI - Magnetic Resonance Imaging in Epidemic Adenoviral Keratoconjunctivitis. PMID- 26022085 TI - Small-scale evaluation of the efficacy and residual activity of alpha cypermethrin WG (250 g AI/kg) for indoor spraying in comparison with alpha cypermethrin WP (50 g AI/kg) in India. AB - BACKGROUND: Indoor residual spraying (IRS) with different formulations of insecticides is being used for the control of mosquito vectors in many countries. In the present study, residual efficacy and duration of effectiveness of IRS with alpha-cypermethrin WG-SB (250 g AI/m2) formulation was compared with WP formulation (50 g AI/kg) in a small scale (Phase II) field trial. METHODS: Two dosages, i.e. 20 and 30 mg AI/m2, were used and the efficacy and duration of effectiveness was assessed on alpha-cypermethrin susceptible population of Anopheles stephensi. Four types of surfaces were selected, namely cement wall with distemper coating, cement wall with lime coating, mud wall with lime coating, and brick wall unpainted. Spraying was carried out with Hudson sprayer fitted with control flow valve. Bioassays were carried out at weekly and then fortnightly intervals. Chemical analysis of filter paper samples collected from the sprayed surfaces was done at Walloon Agricultural Research Institute, Gembloux, Belgium. RESULTS: Alpha-cypermethrin WG-SB showed residual efficacy (>80% mortality) for 13-15 weeks for the 20 mg/m2 dosage and 13-16 weeks for the 30 mg/m2 dosage, whereas alpha-cypermethrin WP showed residual efficacy for 11-15 weeks for the 20 mg/m2 dosage and 11-14 weeks for the 30 mg/m2 dosage on the surfaces tested. The average of the applied to target dose ratio ranged from 0.89 to 1.17 for alpha-cypermethrin WG-SB at 20 mg AI/m2, 0.83-1.80 for the WG-SB at 30 mg AI/m2, 0.87-1.66 for alpha-cypermethrin WP at 20 mg AI/m2, and 0.68-1.06 for WP at 30 mg AI/m2. No adverse events were reported, either by the spray men or the household inhabitants, during and after the spray operations. CONCLUSIONS: The results suggest that the dose of WG 30 mg/m2 gave slightly longer effective residual action against malaria vector (16 weeks) on most common indoor surfaces and could be used for effective control of Anopheles mosquitoes. The WG formulation was found to be easy to handle, no smell was reported during the spraying and was found to be operationally acceptable for indoor residual spraying. PMID- 26022086 TI - Drosophila Rif1 is an essential gene and controls late developmental events by direct interaction with PP1-87B. AB - Rif1, identified as a regulator of telomerase in yeast, is an evolutionarily conserved protein and functions in diverse processes including telomere length regulation, epigenetic gene regulation, anti-checkpoint activity, DNA repair and establishing timing of firing at replication origins. Previously we had identified that all Rif1 homologues have PP1 interacting SILK-RVxF motif. In the present study, we show that Drosophila Rif1 is essential for normal fly development and loss of dRif1 impairs temporal regulation of initiation of DNA replication. In multiple tissues dRif1 colocalizes with HP1, a protein known to orchestrate timing of replication in fly. dRif1 associates with chromosomes in a mitotic stage-dependent manner coinciding with dephosphorylation of histones. Ectopic expression of dRif1 causes enlarged larval imaginal discs and early pupal lethality which is completely reversed by co-expression of PP1 87B, the major protein phosphatase in Drosophila, indicating genetic and functional interaction. These findings suggest that dRif1 is an adaptor for PP1 and functions by recruiting PP1 to multiple sites on the chromosome. PMID- 26022089 TI - The Supramolecular Organization of a Peptide-Based Nanocarrier at High Molecular Detail. AB - Nanovesicles self-assembled from amphiphilic peptides are promising candidates for applications in drug delivery. However, complete high-resolution data on the local and supramolecular organization of such materials has been elusive thus far, which is a substantial obstacle to their rational design. In the absence of precise information, nanovesicles built of amphiphilic "lipid-like" peptides are generally assumed to resemble liposomes that are organized from bilayers of peptides with a tail-to-tail ordering. Using the nanocarrier formed by the amphiphilic self-assembling peptide 2 (SA2 peptide) as an example, we derive the local and global organization of a multimega-Dalton peptide-based nanocarrier at high molecular detail and at close-to physiological conditions. By integrating a multitude of experimental techniques (solid-state NMR, AFM, SLS, DLS, FT-IR, CD) with large- and multiscale MD simulations, we show that SA2 nanocarriers are built of interdigitated antiparallel beta-sheets, which bear little resemblance to phospholipid liposomes. Our atomic level study allows analyzing the vesicle surface structure and dynamics as well as the intermolecular forces between peptides, providing a number of potential leads to improve and tune the biophysical properties of the nanocarrier. The herein presented approach may be of general utility to investigate peptide-based nanomaterials at high-resolution and at physiological conditions. PMID- 26022087 TI - Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin. AB - Peripheral neurotoxicity is one of the serious dose-limiting side effects of oxaliplatin (Oxa) when used in the treatment of malignant conditions. It is documented that it elicits major side effects specifically neurotoxicity due to oxidative stress forcing the patients to limit its clinical use in long-term treatment. Oxidative stress has been proven to be involved in Oxa-induced toxicity including neurotoxicity. The mitochondria have recently emerged as targets for anticancer drugs in various kinds of toxicity including neurotoxicity that can lead to neoplastic disease. However, there is paucity of literature involving the role of the mitochondria in mediating Oxa-induced neurotoxicity and its underlying mechanism is still debatable. The purpose of this study was to investigate the dose-dependent damage caused by Oxa on isolated brain mitochondria under in vitro conditions. The study was also designed to investigate the neuroprotective effects of nutraceuticals, curcumin (CMN), and quercetin (QR) on Oxa-induced mitochondrial oxidative stress and respiratory chain complexes in the brain of rats. Oxidative stress biomarkers, levels of nonenzymatic antioxidants, activities of enzymatic antioxidants, and mitochondrial complexes were evaluated against the neurotoxicity induced by Oxa. Pretreatment with CMN and QR significantly replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. CMN and QR ameliorated altered nonenzymatic and enzymatic antioxidants and complex enzymes of mitochondria. We conclude that CMN and QR, by attenuating oxidative stress as evident by mitochondrial dysfunction, hold promise as agents that can potentially reduce Oxa-induced adverse effects in the brain. PMID- 26022088 TI - The solute specificity profiles of nucleobase cation symporter 1 (NCS1) from Zea mays and Setaria viridis illustrate functional flexibility. AB - The solute specificity profiles (transport and binding) for the nucleobase cation symporter 1 (NCS1) proteins, from the closely related C4 grasses Zea mays and Setaria viridis, differ from that of Arabidopsis thaliana and Chlamydomonas reinhardtii NCS1. Solute specificity profiles for NCS1 from Z. mays (ZmNCS1) and S. viridis (SvNCS1) were determined through heterologous complementation studies in NCS1-deficient Saccharomyces cerevisiae strains. The four Viridiplantae NCS1 proteins transport the purines adenine and guanine, but unlike the dicot and algal NCS1, grass NCS1 proteins fail to transport the pyrimidine uracil. Despite the high level of amino acid sequence similarity, ZmNCS1 and SvNCS1 display distinct solute transport and recognition profiles. SvNCS1 transports adenine, guanine, hypoxanthine, cytosine, and allantoin and competitively binds xanthine and uric acid. ZmNCS1 transports adenine, guanine, and cytosine and competitively binds, 5-fluorocytosine, hypoxanthine, xanthine, and uric acid. The differences in grass NCS1 profiles are due to a limited number of amino acid alterations. These amino acid residues do not correspond to amino acids essential for overall solute and cation binding or solute transport, as previously identified in bacterial and fungal NCS1, but rather may represent residues involved in subtle solute discrimination. The data presented here reveal that within Viridiplantae, NCS1 proteins transport a broad range of nucleobase compounds and that the solute specificity profile varies with species. PMID- 26022090 TI - Highly sensitive turn-on biosensors by regulating fluorescent dye assembly on liposome surfaces. AB - We developed a new self-signaling sensory system built on phospholipid liposomes having H-aggregated R6G dyes on their surface. Selective molecular recognition of a target by the phospholipid displaces R6G from the liposome surface to turn on fluorescence signal. Selective and sensitive detection of neomycin down to 2.3 nM is demonstrated. PMID- 26022091 TI - Is ayurveda the key to universal healthcare in India? PMID- 26022092 TI - Tests of conspecificity for allopatric vectors: Simulium nodosum and Simulium shirakii (Diptera: Simuliidae) in Asia. AB - BACKGROUND: Allopatric populations present challenges for biologists working with vectors. We suggest that conspecificity can be concluded in these cases when data from four character sets-chromosomal, ecological, molecular, and morphological express variation no greater between the allopatric populations than between corresponding sympatric populations. We use this approach to test the conspecificity of Simulium nodosum Puri on the mainland of Southeast Asia and Simulium shirakii Kono & Takahasi in Taiwan. The validity of these two putative species has long been disputed given that they are morphologically indistinguishable. FINDINGS: The mitochondria-encoded cytochrome c oxidase subunit I (COI), 12S rRNA, and 16S rRNA genes and the nuclear-encoded 28S rRNA gene support the conspecific status of S. nodosum from Myanmar, Thailand, and Vietnam and S. shirakii from Taiwan; 0 to 0.19 % genetic differences between the two taxa suggest intraspecific polymorphism. The banding patterns of the polytene chromosomes of the insular Taiwanese population of S. shirakii and mainland populations of S. nodosum are congruent. The overlapping ranges of habitat characteristics and hosts of S. nodosum and S. shirakii corroborate the chromosomal, molecular, and morphological data. CONCLUSIONS: Four independent sources of evidence (chromosomes, DNA, ecology, and morphology) support the conspecificity of S. nodosum and S. shirakii. We, therefore, synonymize S. shirakii with S. nodosum. This study provides a guide for applying the procedure of testing conspecificity to other sets of allopatric vectors. PMID- 26022093 TI - Profiling and relative quantification of multiply nitrated and oxidized fatty acids. AB - The levels of nitro fatty acids (NO2-FA), such as nitroarachidonic, nitrolinoleic, nitrooleic, and dinitrooleic acids, are elevated under various inflammatory conditions, and this results in different anti-inflammatory effects. However, other multiply nitrated and nitro-oxidized FAs have not been studied so far. Owing to the low concentrations in vivo, NO2-FA analytics usually relies on targeted gas chromatography-tandem mass spectrometry (MS/MS) or liquid chromatography-MS/MS, and thus require standard compounds for method development. To overcome this limitation and increase the number and diversity of analytes, we performed in-depth mass spectrometry (MS) profiling of nitration products formed in vitro by incubating fatty acids with NO2BF4, and ONOO(-). The modified fatty acids were used to develop a highly specific and sensitive multiple reaction monitoring LC-MS method for relative quantification of 42 different nitrated and oxidized species representing three different groups: singly nitrated, multiply nitrated, and nitro-oxidized fatty acids. The method was validated in in vitro nitration kinetic studies and in a cellular model of nitrosative stress. NO2-FA were quantified in lipid extracts from 3-morpholinosydnonimine-treated rat primary cardiomyocytes after 15, 30, and 70 min from stress onset. The relatively high levels of dinitrooleic, nitroarachidonic, hydroxynitrodocosapenataenoic, nitrodocosahexaenoic, hydroxynitrodocosahexaenoic, and dinitrodocosahexaenoic acids confirm the presence of multiply nitrated and nitro-oxidized fatty acids in biological systems for the first time. Thus, in vitro nitration was successfully used to establish a targeted LC-MS/MS method that was applied to complex biological samples for quantifying diverse NO2-FA. Graphical Abstract Schematic representation of study design which combined in vitro nitration of different fatty acids, MS/MS characterization and optimization of MRM method for relative quantification, which was applied to follow dynamic of fatty acid nitration in cellular model of SIN-1 treated cardiomyoctes. PMID- 26022094 TI - ddpcRquant: threshold determination for single channel droplet digital PCR experiments. AB - Digital PCR is rapidly gaining interest in the field of molecular biology for absolute quantification of nucleic acids. However, the first generation of platforms still needs careful validation and requires a specific methodology for data analysis to distinguish negative from positive signals by defining a threshold value. The currently described methods to assess droplet digital PCR (ddPCR) are based on an underlying assumption that the fluorescent signal of droplets is normally distributed. We show that this normality assumption does not likely hold true for most ddPCR runs, resulting in an erroneous threshold. We suggest a methodology that does not make any assumptions about the distribution of the fluorescence readouts. A threshold is estimated by modelling the extreme values in the negative droplet population using extreme value theory. Furthermore, the method takes shifts in baseline fluorescence between samples into account. An R implementation of our method is available, allowing automated threshold determination for absolute ddPCR quantification using a single fluorescent reporter. PMID- 26022095 TI - Silica-based 2-(N,N-dimethylamino)-1,3-propanediol hydrophilic interaction liquid chromatography stationary phase for separating cephalosporins and carbapenems. AB - A silica-based stationary phase bearing both hydrophilic hydroxyl and amino groups was developed by covalently bonding a small molecular N,N-dimethylamino 1,3-propanediol moiety onto silica beads via copper(I)-catalyzed Huisgen azide alkyne 1,3-dipolar cycloaddition (CuAAC). This new stationary phase showed good HILIC characteristics and high column efficiency (the theoretical plate number is up to 37000 plates m(-1) in the case of inosine) in the separation of polar compounds, such as nucleosides and bases, organic acids, cephalosporins, and carbapenems. PMID- 26022096 TI - Metabolic fingerprinting of Lactobacillus paracasei: a multi-criteria evaluation of methods for extraction of intracellular metabolites. AB - An untargeted multi-criteria approach was used to select the best extraction method among freeze-thawing in methanol (FTM), boiling ethanol (BE) and chloroform-methanol (CM) for gas chromatography mass spectrometry (GC-MS) metabolic fingerprinting of Lactobacillus paracasei subsp. paracasei (CRL 431(r)). The following results were obtained: (i) coverage and efficiency, measured by the number of features extracted and the sum of feature intensities, showed that FTM extraction resulted in the largest compound coverage with a total number of features 8.9 * 10(3) +/- 0.5 * 10(3), while merely 6.6 * 10(3) +/- 0.9 * 10(3) and 7.9 * 10(3) +/- 0.8 * 10(3) were detected in BE or CM, respectively; (ii) the similarity of extraction methods, measured by common features, demonstrated that FTM yielded the most complementary information to BE and CM; i.e. 17 and 33 % of the features of FTM extracted were unique compared to CM and BE, respectively; and (iii) a clear-cut separation according to extraction method was demonstrated by assessment of the metabolic fingerprints by pixel-based data analysis. Indications of metabolite degradation were observed under the elevated temperature for BE extraction. A superior coverage of FTM together with a high repeatability over nearly the whole range of GC-amenable compounds makes this the extraction method of choice for metabolic fingerprinting of L. paracasei. PMID- 26022097 TI - Erratum to: Magnetic-nanobead-based competitive enzyme-linked aptamer assay for the analysis of oxytetracycline in food. PMID- 26022098 TI - Tunicamycin promotes apoptosis in leukemia cells through ROS generation and downregulation of survivin expression. AB - Tunicamycin (TN), one of the endoplasmic reticulum stress inducers, has been reported to inhibit tumor cell growth and exhibit anticarcinogenic activity. However, the mechanism by which TN initiates apoptosis remains poorly understood. In the present study, we investigated the effect of TN on the apoptotic pathway in U937 cells. We show that TN induces apoptosis in association with caspase-3 activation, generation of reactive oxygen species (ROS), and downregulation of survivin expression. P38 MAPK (mitogen-activated protein kinase) and the generation of ROS signaling pathway play crucial roles in TN-induced apoptosis in U937 cells. We hypothesized that TN-induced activation of p38 MAPK signaling pathway is responsible for cell death. To test this hypothesis, we selectively inhibited MAPK during treatment with TN. Our data demonstrated that inhibitor of p38 (SB), but not ERK (PD) or JNK (SP), partially maintained apoptosis during treatment with TN. Pre-treatment with NAC and GSH markedly prevented cell death, suggesting a role for ROS in this process. Ectopic expression of survivin in U937 cells attenuated TN-induced apoptosis by suppression of caspase-3 cleavage, mitochondrial membrane potential, and cytochrome c release in U937 cells. Taken together, our results show that TN modulates multiple components of the apoptotic response of human leukemia cells and raise the possibility of a novel therapeutic strategy for hematological malignancies. PMID- 26022100 TI - A discussion of the ethical implications of random drug testing in the workplace. AB - This article discusses the scientific and ethical implications of random drug testing in the workplace. Random drug testing, particularly in safety-sensitive sectors, is a common practice, yet it has received little critical analysis. My conclusion is that there are important ethical challenges with these programs. Employers must ensure that every aspect of their policies are rooted in scientific evidence, linked rationally to the goal of workplace safety, and are ethically justifiable. PMID- 26022099 TI - 17beta-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells. AB - BACKGROUND: To sustain cell growth, cancer cells exhibit an altered metabolism characterized by increased lipogenesis. Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the production of monounsaturated fatty acids that are essential for membrane biogenesis, and is required for cell proliferation in many cancer cell types. Although estrogen is required for the proliferation of many estrogen sensitive breast carcinoma cells, it is also a repressor of SCD-1 expression in liver and adipose. The current study addresses this apparent paradox by investigating the impact of estrogen on SCD-1 expression in estrogen receptor alpha-positive breast carcinoma cell lines. METHODS: MCF-7 and T47D mammary carcinomas cells and immortalized MCF-10A mammary epithelial cells were hormone starved then treated or not with 17beta-estradiol. SCD-1 activity was assessed by measuring cellular monounsaturated/saturated fatty acid (MUFA/SFA) ratios, and SCD-1 expression was measured by qPCR, immunoblot, and immunofluorescence analyses. The role of SCD-1 in cell proliferation was measured following treatment with the SCD-1 inhibitor A959372 and following SCD-1 silencing using siRNA. The involvement of IGF-1R on SCD-1 expression was measured using the IGF 1R antagonist AG1024. The expression of SREBP-1c, a transcription factor that regulates SCD-1, was measured by qPCR, and by immunoblot analyses. RESULTS: 17beta-estradiol significantly induced cell proliferation and SCD-1 activity in MCF-7 and T47D cells but not MCF-10A cells. Accordingly, 17beta-estradiol significantly increased SCD-1 mRNA and protein expression in MCF-7 and T47D cells compared to untreated cells. Treatment of MCF-7 cells with 4-OH tamoxifen or siRNA silencing of estrogen receptor-alpha largely prevented 17beta-estradiol induced SCD-1 expression. 17beta-estradiol increased SREBP-1c expression and induced the mature active 60 kDa form of SREBP-1. The selective SCD-1 inhibitor or siRNA silencing of SCD-1 blocked the 17beta-estradiol-induced cell proliferation and increase in cellular MUFA/SFA ratios. IGF-1 also induced SCD-1 expression, but to a lesser extent than 17beta-estradiol. The IGF-1R antagonist partially blocked 17beta-estradiol-induced cell proliferation and SCD-1 expression, suggesting the impact of 17beta-estradiol on SCD-1 expression is partially mediated though IGF-1R signaling. CONCLUSIONS: This study illustrates for the first time that, in contrast to hepatic and adipose tissue, estrogen induces SCD-1 expression and activity in breast carcinoma cells. These results support SCD-1 as a therapeutic target in estrogen-sensitive breast cancer. PMID- 26022101 TI - High-density lipoprotein-based drug discovery for treatment of atherosclerosis. AB - INTRODUCTION: Although there has been great progress achieved by the use of intensive statin therapy, the burden of atherosclerotic cardiovascular disease (CVD) remains high. This has initiated the search for novel high-density lipoprotein (HDL)-based therapeutics. Recent years have witnessed a shift from traditional raising HDL-C levels to enhancing HDL functionality, in which the process of reverse cholesterol transport (RCT) has acquired much attention. AREAS COVERED: In this review, the authors describe the key factors involved in RCT process for potential drug targets to reduce the CVD risk. Furthermore, the review provides a summary of the effective screening methods that have been developed to target RCT and their applications. This review also introduces some new strategies currently being clinically developed, which have the potential to improve HDL function in the RCT process. EXPERT OPINION: It is rational that the functionality of HDL is more important than the plasma HDL-C level in the evaluation of pharmacological treatment in atherosclerosis. HDL-based strategies designed to promote macrophage RCT are a major area of current drug discovery and development for atherosclerotic diseases. A better understanding of the functionality of HDL and its relationship with atherosclerosis will expand our knowledge of the role of HDL in lipid metabolism, holding promise for a future successful HDL-based therapy. PMID- 26022102 TI - The effect of changing movement and posture using motion-sensor biofeedback, versus guidelines-based care, on the clinical outcomes of people with sub-acute or chronic low back pain-a multicentre, cluster-randomised, placebo-controlled, pilot trial. AB - BACKGROUND: The aims of this pilot trial were to (i) test the hypothesis that modifying patterns of painful lumbo-pelvic movement using motion-sensor biofeedback in people with low back pain would lead to reduced pain and activity limitation compared with guidelines-based care, and (ii) facilitate sample size calculations for a fully powered trial. METHODS: A multicentre (8 clinics), cluster-randomised, placebo-controlled pilot trial compared two groups of patients seeking medical or physiotherapy primary care for sub-acute and chronic back pain. It was powered for longitudinal analysis, but not for adjusted single time point comparisons. The intervention group (n = 58) received modification of movement patterns augmented by motion-sensor movement biofeedback (ViMove, dorsaVi.com) plus guidelines-based medical or physiotherapy care. The control group (n = 54) received a placebo (wearing the motion-sensors without biofeedback) plus guidelines-based medical or physiotherapy care. Primary outcomes were self-reported pain intensity (VAS) and activity limitation (Roland Morris Disability Questionnaire (RMDQ), Patient Specific Functional Scale (PSFS)), all on 0-100 scales. Both groups received 6-8 treatment sessions. Outcomes were measured seven times during 10-weeks of treatment and at 12, 26 and 52 week follow-up, with 17.0 % dropout. Patients were not informed of group allocation or the study hypothesis. RESULTS: Across one-year, there were significant between-group differences favouring the intervention group [generalized linear model coefficient (95 % CI): group effect RMDQ -7.1 (95 % CI 12.6;-1.6), PSFS -10.3 (-16.6; -3.9), QVAS -7.7 (-13.0; -2.4); and group by time effect differences (per 100 days) RMDQ -3.5 (-5.2; -2.2), PSFS -4.7 (-7.0; -2.5), QVAS -4.8 (-6.1; -3.5)], all p < 0.001. Risk ratios between groups of probability of improving by >30 % at 12-months = RMDQ 2.4 (95 % CI 1.5; 4.1), PSFS 2.5 (1.5; 4.0), QVAS 3.3 (1.8; 5.9). The only device-related side-effects involved transient skin irritation from tape used to mount motion sensors. CONCLUSIONS: Individualised movement retraining using motion-sensor biofeedback resulted in significant and sustained improvements in pain and activity limitation that persisted after treatment finished. This pilot trial also refined the procedures and sample size requirements for a fully powered RCT. This trial (Australian New Zealand Clinical Trials Registry NCT01572779) was equally funded by dorsaVi P/L and the Victorian State Government. PMID- 26022104 TI - Response to letter in regard to Lorente et al, "Serum melatonin levels are associated with mortality in severe septic patients". PMID- 26022103 TI - Cognitive-behavioural therapy in medication-treated adults with attention deficit/hyperactivity disorder and co-morbid psychopathology: a randomized controlled trial using multi-level analysis. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by high rates of co-morbid psychopathology. Randomized controlled trials of multimodal interventions, combining pharmacological and psychological treatments, have shown a robust treatment effect for ADHD symptoms but outcomes for co-morbid symptoms have been mixed. This may be accounted for by the type of intervention selected and/or by methodological problems including lack of follow-up and low power. The current study addressed these limitations in a parallel-group randomized controlled trial conducted in Iceland. METHOD: A total of 95 adult ADHD patients who were already being treated with medication (MED) were randomly assigned to receive treatment as usual (TAU/MED) or 15 sessions of cognitive-behavioural therapy (CBT/MED) using the R&R2ADHD intervention which employs both group and individual modalities. Primary measures of ADHD symptoms and severity of illness, and secondary measures of anxiety, depression and quality of life were given at baseline, end of treatment and 3-month follow-up. Primary outcomes were rated by clinicians blind to treatment condition assignment. RESULTS: CBT/MED showed overall (combined outcome at end of treatment and 3-month follow-up) significantly greater reduction in primary outcomes for clinician-rated and self rated ADHD symptoms. Treatment effect of primary outcomes was maintained at follow-up, which suggests robust and lasting findings. In contrast to the primary outcomes, the secondary outcomes showed significant improvement over time. CONCLUSIONS: The study provides evidence for the effectiveness of R&R2ADHD and demonstrates that there are differential effects over time for ADHD symptoms versus co-morbid problems, the latter taking longer to show positive effects. PMID- 26022105 TI - Oocyte quality is decreased in women with minimal or mild endometriosis. AB - Endometriosis, a pathological condition in which the endometrium grows outside the uterus, is one of the most common causes of female infertility; it is diagnosed in 25-40% of infertile women. The mechanism by which endometriosis affects the fertility of females remains largely unknown. We examined the ultrastructure of oocytes from patients with minimal or mild endometriosis and control females undergoing in vitro fertilization (IVF) treatment by transmission electron microscopy (TEM) to investigate the physiological significance of oocyte quality for patients with minimal or mild endometriosis. The TEM results revealed that the oocytes from women with minimal or mild endometriosis exhibited abnormal mitochondrial structure and decreased mitochondria mass. Quantitative real time PCR analysis revealed that the mitochondrial DNA copy number was significantly reduced in the oocytes from women with minimal or mild endometriosis compared with those of the control subjects. Our results suggest that decreased oocyte quality because of impaired mitochondrial structure and functions probably an important factor affecting the fertility of endometriosis patients. PMID- 26022106 TI - Implementation of photobiological H2 production: the O 2 sensitivity of hydrogenases. AB - The search for the ultimate carbon-free fuel has intensified in recent years, with a major focus on photoproduction of H2. Biological sources of H2 include oxygenic photosynthetic green algae and cyanobacteria, both of which contain hydrogenase enzymes. Although algal and cyanobacterial hydrogenases perform the same enzymatic reaction through metallo-clusters, their hydrogenases have evolved separately, are expressed differently (transcription of algal hydrogenases is anaerobically induced, while bacterial hydrogenases are constitutively expressed), and display different sensitivity to O2 inactivation. Among various physiological factors, the sensitivity of hydrogenases to O2 has been one of the major factors preventing implementation of biological systems for commercial production of renewable H2. This review addresses recent strategies aimed at engineering increased O2 tolerance into hydrogenases (as of now mainly unsuccessful), as well as towards the development of methods to bypass the O2 sensitivity of hydrogenases (successful but still yielding low solar conversion efficiencies). The author concludes with a description of current approaches from various laboratories to incorporate multiple genetic traits into either algae or cyanobacteria to jointly address limiting factors other than the hydrogenase O2 sensitivity and achieve more sustained H2 photoproduction activity. PMID- 26022107 TI - Metastatic liver disease from non-colorectal, non-neuroendocrine, non-sarcoma cancers: a systematic review. AB - BACKGROUND: Hepatic resection of liver metastases of non-colorectal, non neuroendocrine, and non-sarcoma (NCNNNS) primary malignancies seems to improve survival in selected patients. The aims of the current review were to describe long-term results of surgery and to evaluate prognostic factors for survival in patients who underwent resection of NCNNNS liver metastases. METHODS: We identified 30 full texts (25 single-center and 5 multicenter studies) published after year 1995 and published in English with a total of 3849 patients. For NCNNNS liver metastases, 83.4 % of these subjects were resected. RESULTS: No prior systematic reviews or meta-analyses on this topic were identified. All studies were case series without matching control groups. The most common primary sites were breast (23.8 %), genito-urinary (21.8 %), and gastrointestinal tract (19.8 %). The median 5- and 10-year overall survival were 32.3 % (range 19-42 %) and 24 % (indicated only in two studies, range 23-25 %), respectively, with 71 % of R0 resections. CONCLUSIONS: There is evidence suggesting that surgery of NCNNNS metastases is safe, feasible, and effective if treatment is part of a multidisciplinary approach and if indication is based on the prognostic factors underlined in literature analysis. PMID- 26022110 TI - Repeats are one of the main characteristics of RNA-binding proteins with prion like domains. AB - It is not surprising that a large number of diseases related to amyloid fibril depositions are formed in various organs. Therefore, it is necessary to understand the transformation of native proteins into amyloid fibrils in order to clarify which key elements of this process determine the pathway of protein misfolding. Significant attention has been directed recently to investigating the mechanism of formation of cross-beta structures that have the properties of liquids but can also exist in gel-like forms, thus facilitating the retention of both RNAs and RNA-binding proteins. Proteins that form stress granules are believed to do this rapidly, and they are expected to contain a prion-like domain that can facilitate this process. By analyzing the known yeast prion proteins and 29 RNA-binding proteins with prion-like domains, we demonstrate here that the existence of repeats is one of the general characteristics of prion-like domains. The presence of repeats should help to determine the border of prion domains as in the case of Rnq1: five found repeats shift the border of the prion domain from the 153-rd to at least the 133-th residue. One can suggest that such repeats assist in the rapid initiation of the process of assembly and formation of cross beta structures and such domains most likely should be disordered. These repeats should contain aromatic amino acid residues for the formation of a hydrogel because its amino acid context modulates the strength of interaction. The key factors determined here can be used to control the process of aggregation to prevent the development of pathologies and diseases caused by prion-like domains. PMID- 26022108 TI - Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. AB - Cell migration and invasion are highly regulated processes involved in both physiological and pathological conditions. Here we show that autophagy modulation regulates the migration and invasion capabilities of glioblastoma (GBM) cells. We observed that during autophagy occurrence, obtained by nutrient deprivation or by pharmacological inhibition of the mTOR complexes, GBM migration and chemokine mediated invasion were both impaired. We also observed that SNAIL and SLUG, two master regulators of the epithelial-mesenchymal transition (EMT process), were down-regulated upon autophagy stimulation and, as a consequence, we found a transcriptional and translational up-regulation of N- and R-cadherins. Conversely, in BECLIN 1-silenced GBM cells, an increased migration capability and an up-regulation of SNAIL and SLUG was observed, with a resulting decrease in N- and R-cadherin mRNAs. ATG5 and ATG7 down-regulation also resulted in an increased migration and invasion of GBM cells combined to an up-regulation of the two EMT regulators. Finally, experiments performed in primary GBM cells from patients largely confirmed the results obtained in established cell cultures. Overall, our results indicate that autophagy modulation triggers a molecular switch from a mesenchymal phenotype to an epithelial-like one in GBM cellular models. Since the aggressiveness and lethality of GBM is defined by local invasion and resistance to chemotherapy, we believe that our evidence provides a further rationale for including autophagy/mTOR-based targets in the current therapeutical regimen of GBM patients. PMID- 26022109 TI - BRCA1 regulates transforming growth factor-beta (TGF-beta1) signaling through Gadd45a by enhancing the protein stability of Smad4. AB - BRCA1 is a well established tumor suppressor gene, which is involved in many cellular processes, including DNA damage repair, cell cycle control, apoptosis, as well as transcriptional control. In this work, we have found that BRCA1 is involved in regulating TGF-beta1/Smad pathway. The loss of endogenous BRCA1 greatly attenuated TGF-beta1-induced growth inhibition and cell cycle G1 arrest. BRCA1 greatly maintains stability of Smad4 protein, and the loss of BRCA1 results in Smad4 down-regulation, which is likely related to its downstream gene Gadd45a. Gadd45a is able to interact with beta-Trcp1, a-F-box protein of SCF E3 ligase, and consequently suppresses the ubiquitin-degradation of Smad4 by SCF(beta trcp1), as reflected by the observations that the induction of Gadd45a substantially stabilizes Smad4 protein. In addition, exogenous expression of Gadd45a can largely rescue the protein level of Smad4 in BRCA1 deficient cells. These results further demonstrate that BRCA1 may act as an important negative regulator in cell cycle progression and tumorigenesis through regulating the stability of Smad4, and define a novel link that connects BRCA1 to TGF-beta1/Smad pathway. PMID- 26022111 TI - Fixator-assisted Technique Enables Less Invasive Plate Osteosynthesis in Medial Opening-wedge High Tibial Osteotomy: A Novel Technique. AB - BACKGROUND: Opening-wedge high tibial osteotomy is a well-established procedure in the management of medial osteoarthritis of the knee and correction of proximal tibia vara. Recently, surgical approaches using less invasive plate osteosynthesis have been used with the goal of minimizing complications from more extensive soft tissue exposures. However, to our knowledge, less invasive fixator assisted plate osteosynthesis has not been tested in the setting of opening-wedge high tibial osteotomy. QUESTIONS/PURPOSES: The purposes of this study were (1) to assess the complications associated with use of a fixator-assisted less invasive plate osteosynthesis technique to stabilize an opening-wedge high tibial osteotomy in the treatment of proximal tibial vara; and (2) to evaluate the ability of this technique to achieve correction of the proximal tibial deformity and achieve osseous union. METHODS: From June 2011 to June 2013, a total of 157 limbs in 83 patients who underwent fixator-assisted high tibial osteotomy for (1) idiopathic genu vara; or (2) osteoarthritis of the knee with proximal tibia vara were initially enrolled. Of these, eight limbs (5%) were excluded on the way; thus, 149 limbs in 77 patients were evaluated. During the period in question, no other techniques were used for proximal tibial osteotomy. The surgical procedures included less preparation of soft tissue, proximal tibial osteotomy, application of a temporary external fixator, correction of alignment, and final fixation with the help of an external fixator. Complications were assessed by chart review and the alignment in both coronal and sagittal planes was compared pre- and postoperatively. Radiographic review to confirm osseous union and alignment was performed by two of the authors not involved in clinical care of the patient. Delayed union was described as union occurring later than 4 months. RESULTS: Thirty limbs out of 149 tibiae (20%) showed complications, all of which were resolved without leaving any sequela. Twenty-seven limbs out of 149 limbs (18%) showed lateral cortical hinge fracture and three limbs out of 149 limbs (2%) showed soft tissue complications (two superficial infections, one wound hematoma). The overall completeness of reaching the target correction was excellent. In the coronal plane, the difference between the amount of real correction and the amount of target correction was 0.3 degrees +/- 0.7 degrees (p < 0.001). In the sagittal plane, the difference between pre- and postoperative posterior proximal tibial angle was -0.1 degrees +/- 0.2 degrees (p < 0.001). All osteotomies healed before 4 months. CONCLUSIONS: Fixator-assisted high tibial osteotomy is a valid option for medial opening-wedge high tibial osteotomy, which enables less invasive surgery with excellent coronal/sagittal/rotational alignment control. However, future studies should compare this approach with other approaches for proximal tibial osteotomy to ascertain whether indeed this procedure is less invasive or more reliable. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26022112 TI - Does Open Reduction and Internal Fixation versus Primary Arthrodesis Improve Patient Outcomes for Lisfranc Trauma? A Systematic Review and Meta-analysis. AB - BACKGROUND: Although Lisfranc injuries are uncommon, representing approximately 0.2% of all fractures, they are complex and can result in persistent pain, degenerative arthritis, and loss of function. Both open reduction and internal fixation (ORIF) and primary fusion have been proposed as treatment options for these injuries, but debate remains as to which approach is better. QUESTIONS/PURPOSES: We asked whether ORIF or primary fusion led to (1) fewer reoperations for hardware removal; (2) less frequent revision surgery; (3) higher patient outcome scores; and (4) more frequent anatomic reduction. METHODS: A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Three trials met the criteria for inclusion within the meta-analysis. Qualifying articles for the meta analysis had data extracted independently by two authors (NS, AF). The quality of each study was assessed using the Center for Evidence Based Medicine's evaluation strategy; data were extracted from articles rated as good and fair: two and one article, respectively. RESULTS: The risk ratio for hardware removal was 0.23 (95% confidence interval [CI], 0.11-0.45; p < 0.001) indicating more hardware removal for ORIF than fusion. For other revision surgery, the risk ratio for ORIF was 0.36 (95% CI, 0.08-1.59; p = 0.18) favoring neither. Similarly, neither was favored using patient-reported outcomes; the standard mean difference was calculated to be 0.50 (95% CI, -2.13 to 3.12; p = 0.71). When considering the risk of nonanatomic alignment, neither was favored (risk ratio, 1.48; 95% CI, 0.34-6.38; p = 0.60). CONCLUSIONS: The surgeon should consider the increased risk of hardware removal along with its associated morbidity and discuss this with the patient preoperatively when considering ORIF of Lisfranc injuries. Because no new trials have been performed since 2012, further randomized controlled trials will be needed improve our understanding of these interventions. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 26022113 TI - In Brief: Kanavel's Signs and Pyogenic Flexor Tenosynovitis. PMID- 26022114 TI - Does CT-based Rigidity Analysis Influence Clinical Decision-making in Simulations of Metastatic Bone Disease? AB - BACKGROUND: There is a need to improve the prediction of fracture risk for patients with metastatic bone disease. CT-based rigidity analysis (CTRA) is a sensitive and specific method, yet its influence on clinical decision-making has never been quantified. QUESTIONS/PURPOSES: What is the influence of CTRA on providers' perceived risk of fracture? (2) What is the influence of CTRA on providers' treatment recommendations in simulated clinical scenarios of metastatic bone disease of the femur? (3) Does CTRA improve interobserver agreement regarding treatment recommendations? METHODS: We conducted a survey among 80 academic physicians (orthopaedic oncologists, musculoskeletal radiologists, and radiation oncologists) using simulated vignettes of femoral lesions presented as three separate scenarios: (1) no CTRA input (baseline); (2) CTRA input suggesting increased risk of fracture (CTRA+); and (3) CTRA input suggesting decreased risk of fracture (CTRA-). Participants were asked to rate the patient's risk of fracture on a scale of 0% to 100% and to provide a treatment recommendation. Overall response rate was 62.5% (50 of 80). RESULTS: When CTRA suggested an increased risk of fracture, physicians perceived the fracture risk to be slightly greater (37% +/- 3% versus 42% +/- 3%, p < 0.001; mean difference [95% confidence interval {CI}] = 5% [4.7%-5.2%]) and were more prone to recommend surgical stabilization (46% +/- 9% versus 54% +/- 9%, p < 0.001; mean difference [95% CI] = 9% [7.9-10.1]). When CTRA suggested a decreased risk of fracture, physicians perceived the risk to be slightly decreased (37% +/- 25% versus 35% +/- 25%, p = 0.04; mean difference [95% CI] = 2% [2.74%-2.26%]) and were less prone to recommend surgical stabilization (46% +/- 9% versus 42% +/ 9%, p < 0.03; mean difference [95% CI] = 4% [3.9-5.1]). The effect size of the influence of CTRA on physicians' perception of fracture risk and treatment planning varied with lesion severity and specialty of the responders. CTRA did not increase interobserver agreement regarding treatment recommendations when compared with the baseline scenario (kappa = 0.41 versus kappa = 0.43, respectively). CONCLUSIONS: Based on this survey study, CTRA had a small influence on perceived fracture risk and treatment recommendations and did not increase interobserver agreement. Further work is required to properly introduce this technique to physicians involved in the care of patients with metastatic lesions. Given the number of preclinical and clinical studies outlining the efficacy of this technique, better education through presentations at seminars/webinars and symposia will be the first step. This should be followed by clinical trials to establish CTRA-based clinical guidelines based on evidence based medicine. Increased exposure of clinicians to CTRA, including its underlying methodology to study bone structural characteristics, may establish CTRA as a uniform guideline to assess fracture risk. LEVEL OF EVIDENCE: Level III, economic and decision analyses. PMID- 26022115 TI - Erratum to: Sex Differences in Cartilage Topography and Orientation of the Developing Acetabulum: Implications for Hip Preservation Surgery. PMID- 26022116 TI - Cyclohexenones and isocoumarins from an endophytic fungus of Sarcosomataceae sp. AB - Three new cyclohexenones (1-3, named sarcosones A-C) and two new isocoumarins (4 and 5), together with five known isocoumarins (6-10), were isolated from the solid cultures of an endophytic fungus Sarcosomataceae sp. NO.49-14-2-1. Their chemical structures were elucidated by analyses of HR-ESI-TOF-MS, (1)H, (13)C NMR, (1)H-(1)H COSY, HSQC, and HMBC spectra. Their absolute configurations were determined via modified Mosher's method and circular dichroism spectra method. PMID- 26022117 TI - Duloxetine Hydrochloride-Induced Oral Lichenoid Reaction: A Case Report. AB - OBJECTIVE: To report the first case of duloxetine hydrochloride (DH)-induced oral lichenoid drug reaction (OLDR). CLINICAL PRESENTATION AND INTERVENTION: A 57-year old male patient presented with painful ulcerative lesions on the bilateral buccal mucosa of 2-year duration. The patient was on multiple drug therapy for his systemic ailments. After thorough evaluation for possible medical ailments and with the physician's consent, withdrawal of DH was done. The oral lesions were resolved after 2 weeks. CONCLUSION: In this case, DH induced OLDR. PMID- 26022118 TI - In situ neutralisation of the antibacterial effect of 0.2% Chlorhexidine on salivary microbiota: Quantification of substantivity. AB - OBJECTIVE: To quantify the substantivity of a single 0.2% Chlorhexidine mouthwash in saliva after its neutralisation with tooth-brushing and 1% acetic acid, in order to identify the effect of Chlorhexidine substantivity in regard to the re growing period of the salivary bacteria. METHODS: Unstimulated saliva samples were collected from a group of 15 healthy individuals at baseline (BS), and then 30s and 1, 3, 5 and 7h after the following protocols were performed: a single sterile water mouthwash (M-WATER) (negative control), a single 0.2% Chlorhexidine mouthwash (M-0.2% CHX) (positive control) and a single 0.2% Chlorhexidine mouthwash followed by a complete and detailed tooth-brushing, and a single 1% acetic acid mouthwash (M-0.2% CHX+NP). The samples were analysed using an epifluorescence microscope in combination with LIVE/DEAD((r)) BacLightTM fluorescence solution. RESULTS: After the M-0.2% CHX treatment, the bacterial vitality was significantly lower than BS until 7h (87.6 +/- 6.5% vs. 73.6 +/- 8.8%; p<0.001). However, after M-0.2% CHX+NP, the bacterial vitality remained significantly lower until 3h with regard to BS (81.4 +/- 3.8% vs. 68.1 +/- 10.6%; p=0.001), increasing at 5 and 7h (no differences from BS). CONCLUSION: The immediate antibacterial effect of a single 0.2% Chlorhexidine mouthwash is so potent that the bacterial population needs more than 3h to return to baseline bacterial vitality levels. The substantivity of a 0.2% Chlorhexidine mouthwash is a property that significantly increases its antibacterial activity from the first hour and contributes to extend the duration of its effect by at least double. PMID- 26022120 TI - DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line. AB - We investigated mechanisms of cytotoxicity induced by doxycycline (doxy) and minocycline (mino) in the chronic myeloid leukemia K562 cell line. Doxy and mino induced cell death in exposure-dependent manner. While annexin V/propidium iodide staining was consistent with apoptosis, the morphological changes in Giemsa staining were more equivocal. A pancaspase inhibitor Z-VAD-FMK partially reverted cell death morphology, but concurrently completely prevented PARP cleavage. Mitochondrial involvement was detected as dissipation of mitochondrial membrane potential and cytochrome C release. DNA double strand breaks detected with gammaH2AX antibody and caspase-2 activation were found early after the treatment start, but caspase-3 activation was a late event. Decrement of Bcl-xL protein levels and electrophoretic shift of Bcl-xL molecule were induced by both drugs. Phosphorylation of Bcl-xL at serine 62 was ruled out. Similarly, Bcr/Abl tyrosine kinase levels were decreased. Lysosomal inhibitor chloroquine restored Bcl-xL and Bcr/Abl protein levels and inhibited caspase-3 activation. Thus, the cytotoxicity of doxy and mino in K562 cells is mediated by DNA damage, Bcl-xL deamidation and lysosomal degradation with activation of mitochondrial pathway of apoptosis. PMID- 26022121 TI - Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity. AB - Nanoparticles are becoming promising carriers for gene delivery because of their high capacity in gene loading and low cell cytotoxicity. In this study, a chitosan-based nanoparticle encapsulated within a recombinant pcDNA3.1-dsNKG2D-IL 15 plasmid was generated. The fused dsNKG2D-IL-15 gene fragment consisted of double extracellular domains of NKG2D with IL-15 gene at downstream. The average diameter of the gene nanoparticles ranged from 200 nm to 400 nm, with mean zeta potential value of 53.8 +/- 6.56 mV. The nanoparticles which were loaded with the dsNKG2D-IL-15 gene were uptaken by tumor cells with low cytotoxicity. Tumor cells pre-transfected by gene nanopartilces stimulated NK and T cells in vitro. Intramuscular injection of gene nanoparticles suppressed tumor growth and prolonged survival of tumor-bearing mice through activation of NK and CD8(+) T cells. Thus, chitosan-based nanoparticle delivery of dsNKG2D-IL-15 gene vaccine can be potentially used for tumor therapy. PMID- 26022122 TI - Crystal structure of the karyopherin Kap121p bound to the extreme C-terminus of the protein phosphatase Cdc14p. AB - In Saccharomyces cerevisiae, the protein phosphatase Cdc14p is an antagonist of mitotic cyclin-dependent kinases and is a key regulator of late mitotic events such as chromosome segregation, spindle disassembly and cytokinesis. The activity of Cdc14p is controlled by cell-cycle dependent changes in its association with its competitive inhibitor Net1p (also known as Cfi1p) in the nucleolus. For most of the cell cycle up to metaphase, Cdc14p is sequestered in the nucleolus in an inactive state. During anaphase, Cdc14p is released from Net1p, spreads into the nucleus and cytoplasm, and dephosphorylates key mitotic targets. Although regulated nucleocytoplasmic shuttling of Cdc14p has been suggested to be important for exit from mitosis, the mechanism underlying Cdc14p nuclear trafficking remains poorly understood. Here we show that the C-terminal region (residues 517-551) of Cdc14p can function as a nuclear localization signal (NLS) in vivo and also binds to Kap121p (also known as Pse1p), an essential nuclear import carrier in yeast, in a Gsp1p-GTP-dependent manner in vitro. Moreover we report a crystal structure, at 2.4 A resolution, of Kap121p bound to the C terminal region of Cdc14p. The structure and structure-based mutational analyses suggest that either the last five residues at the extreme C-terminus of Cdc14p (residues 547-551; Gly-Ser-Ile-Lys-Lys) or adjacent residues with similar sequence (residues 540-544; Gly-Gly-Ile-Arg-Lys) can bind to the NLS-binding site of Kap121p, with two residues (Ile in the middle and Lys at the end of the five residues) of Cdc14p making key contributions to the binding specificity. Based on comparison with other structures of Kap121p-ligand complexes, we propose "IK-NLS" as an appropriate term to refer to the Kap121p-specific NLS. PMID- 26022123 TI - miR-139-5p inhibits epithelial-mesenchymal transition, migration and invasion of hepatocellular carcinoma cells by targeting ZEB1 and ZEB2. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide. miRNAs have been suggested to have important roles in HCC development. The purpose of this study was to determine the role of miR-139-5p in regulation of epithelial-mesenchymal transition (EMT) and metastasis of HCC cells. Expression levels of miR-139-5p in 49 HCC specimens with adjacent tissues and five HCC cell lines were assessed by quantitative RT-PCR. We found that miR-139 5p was down-regulated in 89.7% of the HCC tissue samples and all of the HCC cell lines. In addition, luciferase reporter assays validated direct binding of miR 139-5p to the 3' untranslated region of zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. Ectopic expression of miR-139-5p suppressed and miR-139-in promoted EMT, migration, and invasion in Hep3B and SMMC7721 cells. Furthermore, over-expression of ZEB1 and ZEB2 ablated the inhibitory effects of miR-139-5p on migration and invasion in HCC cells. Our study indicates that miR-139-5p functions as a suppressor of HCC EMT and metastasis by targeting ZEB1 and ZEB2, and it may be a therapeutic target for metastatic HCC. PMID- 26022124 TI - ER stress-associated CTRC mutants decrease stimulated pancreatic zymogen secretion through SIRT2-mediated microtubule dysregulation. AB - Pancreatitis has been suspected for a long time to have an autodigestive genesis. The main events occurring in the pancreatic acinar cell that initiate acute pancreatitis include inhibition of zymogen secretion and intracellular activation of proteases. Chymotrypsin C (CTRC) is a protective protease that limits trypsin and trypsinogen proteolytic activity. Hereditary pancreatitis-associated CTRC mutants such as p.A73T and p.G61R precipitate within the endoplasmic reticulum (ER) causing ER stress. We found that expression of these mutants reduces amylase secretion from carbachol-stimulated rat pancreatic acinar cells AR42J and isolated mice pancreatic acini. Furthermore, this expression also reduces the levels of acetylated tubulin by increasing both the levels and phosphorylation of the deacetylase SIRT2. Remarkably, inhibition of SIRT2 not only greatly recovers tubulin acetylation, but also amylase secretion in pancreatic acinar cells and isolated acini. However, SIRT2 inhibition does not rescue secretion of the CTRC mutants. These results strongly suggest that CTRC variants associated to ER stress inhibit secretagogue-stimulated pancreatic zymogen secretion by altering microtubule stability. Of note, the extent of this inhibition correlates with the degree of ER stress exhibited by the particular CTRC variant. PMID- 26022125 TI - SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt. AB - SG2NA in association with striatin and zinedin forms a striatin family of WD-40 repeat proteins. This family of proteins functions as scaffold in different signal transduction pathways. They also act as a regulatory subunit of protein phosphatase 2A. We have shown that SG2NA which evolved first in the metazoan evolution among the striatin family members expresses different isoforms generated out of alternative splicing. We have also shown that SG2NA protects cells from oxidative stress by recruiting DJ-1 and Akt to mitochondria and membrane in the post-mitotic neuronal cells. DJ-1 is both cancer and Parkinson's disease related protein. In the present study we have shown that SG2NA protects DJ-1 from proteasomal degradation in cancer cells. Hence, downregulation of SG2NA reduces DJ-1/Akt colocalization in cancer cells resulting in the reduction of anchorage dependent and independent growth. Thus SG2NA enhances cancer cell survival. Reactive oxygen species enhances SG2NA, DJ-1 and Akt trimerization. Removal of the reactive oxygen species by N-acetyl-cysteine thus reduces cancer cell growth. PMID- 26022126 TI - Acetyl-CoA carboxylase 2 suppression rescues human proximal tubular cells from palmitic acid induced lipotoxicity via autophagy. AB - Autophagy is a catabolic process that degrades damaged proteins and organelles in mammalian cells. Although acetyl-CoA carboxylase 2 (ACC2) plays a crucial role in the fatty acid metabolism, it keeps unknown whether ACC2 is associated with autophagic activity. The present work was designed to investigate the effects of ACC2 on palmitic acid (PA) induced lipotoxicity in human proximal tubular cells and the putative role of autophagy in this process. Here we show that autophagy was induced by PA in HK-2 cells. Moreover, the PA induced autophagy was regulated both by ACC2 suppression and CPTI inhibitor treatment, which represent an altered fatty acid beta-oxidation. And the knockdown of ACC2 reduced PA-induced autophagy and thus protects the cells from PA-induced lipotoxicity with attenuated lipid accumulation and rescued cell viability. Collectively, the present study proposed a novel autophagy-involved mechanism of PA-induced renal lipotoxicity and provided potential therapeutic strategy by modulating lipid beta-oxidation for diabetic nephropathy. PMID- 26022127 TI - Transcription factor genes essential for cell proliferation and replicative lifespan in budding yeast. AB - Many of the lifespan-related genes have been identified in eukaryotes ranging from the yeast to human. However, there is limited information available on the longevity genes that are essential for cell proliferation. Here, we investigated whether the essential genes encoding DNA-binding transcription factors modulated the replicative lifespan of Saccharomyces cerevisiae. Heterozygous diploid knockout strains for FHL1, RAP1, REB1, and MCM1 genes showed significantly short lifespan. (1)H-nuclear magnetic resonance analysis indicated a characteristic metabolic profile in the Deltafhl1/FHL1 mutant. These results strongly suggest that FHL1 regulates the transcription of lifespan related metabolic genes. Thus, heterozygous knockout strains could be the potential materials for discovering further novel lifespan genes. PMID- 26022128 TI - Compound 13, an alpha1-selective small molecule activator of AMPK, inhibits Helicobacter pylori-induced oxidative stresses and gastric epithelial cell apoptosis. AB - Half of the world's population experiences Helicobacter pylori (H. pylori) infection, which is a main cause of gastritis, duodenal and gastric ulcer, and gastric cancers. In the current study, we investigated the potential role of compound 13 (C13), a novel alpha1-selective small molecule activator of AMP activated protein kinase (AMPK), against H. pylori-induced cytotoxicity in cultured gastric epithelial cells (GECs). We found that C13 induced significant AMPK activation, evidenced by phosphorylation of AMPKalpha1 and ACC (acetyl-CoA carboxylase), in both primary and transformed GECs. Treatment of C13 inhibited H. pylori-induced GEC apoptosis. AMPK activation was required for C13-mediated GEC protection. Inhibition of AMPK kinase activity by the AMPK inhibitor Compound C, or silencing AMPKalpha1 expression by targeted-shRNAs, alleviated C13-induced GEC protective activities against H. pylori. Significantly, C13 inhibited H. pylori induced reactive oxygen species (ROS) production in GECs. C13 induced AMPK dependent expression of anti-oxidant gene heme oxygenase (HO-1) in GECs. Zinc protoporphyrin (ZnPP) and tin protoporphyrin (SnPP), two HO-1 inhibitors, not only suppressed C13-mediated ROS scavenging activity, but also alleviated its activity in GECs against H. pylori. Together, these results indicate that C13 inhibits H. pylori-induced ROS production and GEC apoptosis through activating AMPK-HO-1 signaling. PMID- 26022129 TI - Effect of hyperglycemia on hepatocellular carcinoma development in diabetes. AB - Compared with other cancers, diabetes mellitus is more closely associated with hepatocellular carcinoma (HCC). However, whether hyperglycemia is associated with hepatic carcinogenesis remains uncertain. In this study, we investigate the effect of hyperglycemia on HCC development. Mice pretreated with 7,12 dimethylbenz (a) anthracene were divided into three feeding groups: normal diet (Control), high-starch diet (Starch), and high-fat diet (HFD) groups. In addition, an STZ group containing mice that were fed a normal diet and injected with streptozotosin to induce hyperglycemia was included. The STZ group demonstrated severe hyperglycemia, whereas the Starch group demonstrated mild hyperglycemia and insulin resistance. The HFD group demonstrated mild hyperglycemia and severe insulin resistance. Multiple HCC were macroscopically and histologically observed only in the HFD group. Hepatic steatosis was observed in the Starch and HFD groups, but levels of inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor-alpha, and IL-1beta, were elevated only in the HFD group. The composition of gut microbiota was similar between the Control and STZ groups. A significantly higher number of Clostridium cluster XI was detected in the feces of the HFD group than that of all other groups; it was not detectable in the Starch group. These data suggested that hyperglycemia had no effect on hepatic carcinogenesis. Different incidences of HCC between the Starch and HFD groups may be attributable to degree of insulin resistance, but diet-induced changes in gut microbiota including Clostridium cluster XI may have influenced hepatic carcinogenesis. In conclusion, in addition to the normalization of blood glucose levels, diabetics may need to control insulin resistance and diet contents to prevent HCC development. PMID- 26022130 TI - Lung metastases in oligometastatic patients: outcome with stereotactic body radiation therapy (SBRT). AB - PURPOSE: To assess the clinical results in terms of local control, toxicity, failure pattern and toxicity of SBRT in oligometastatic patients with inoperable lung metastases. METHODS: Forty-four patients were treated (53 metastases). Dose regimen: 5 * 12 Gy (66 %), 8 * 7.5 Gy (20.8 %) and 10 * 5 Gy (13.2 %). Response was assessed using PET/CT at 6 months after SBRT. RESULTS: Local control at 1 and 2 years was 86.7 %. Seventy-five percent of local failures had received a BED <105 Gy. After a median follow-up of 13.3 months, 25 % experienced distant progression. Overall survival at 1 and 2 years was 86.7 and 60.4 %, and cancer specific survival was 95.3 and 75.2 %, respectively. Grade 2 toxicity was 6.8 %. There was no grade 3-4 toxicity. CONCLUSION: SBRT is effective and safe. The main failure pattern is distant progression. The selection of patients with a high probability of remaining oligometastatic is crucial for the efficiency of SBRT, both clinically and in terms of resources. PMID- 26022131 TI - Selection of a novel DNA thioaptamer against HER2 structure. AB - PURPOSE: Human epithelial growth factor receptor 2 (HER2) is over-expressed in several malignancies and represents an important therapeutic target. Aptamers are oligonucleotides that may potentially serve as tumor-homing ligand with excellent affinity and specificity for targeted cancer therapy. However, aptamers need to have nuclease resistance in order to function in vivo. The aim of this study was to generate a novel HER2 thioaptamer with enhanced nuclease resistance. METHODS: The HER2 thioaptamer is selected in an evolutionary process called systematic evolution of ligands by exponential enrichment. RESULTS: The thioaptamer could bind to the extracellular domain of HER2 with a K d of 172 nM and had minimal cross reactivity to trypsin or IgG. Moreover, the thioaptamer was found capable of binding with the HER2-positive breast cancer cells SK-BR-3 and MDA-MB-453, but not the HER2-negative cells MDA-MB-231. Notably, the thioaptamer HY6 largely maintained its structural integrity facing the nucleases in serum, while regular DNA aptamers were mostly digested. Additionally, the thioaptamer retained the capability of binding with the HER2-positive cells in the presence of serum, whereas non-thionated HER2 aptamer lost the binding function. CONCLUSION: The results indicated that the selected thioaptamer was more resistant to nuclease than regular DNA aptamers and might potentially function as a HER2-targeting ligand in complicated environment. PMID- 26022132 TI - Association of ERCC1 polymorphisms (rs3212986 and rs11615) with the risk of head and neck carcinomas based on case-control studies. AB - PURPOSE: Current data regarding association between ERCC1 polymorphisms and the risk of head and neck squamous cell carcinomas (HNSCC) have shown controversial results. The current study aims to achieve a more accurate estimation of the association between two well-characterized ERCC1 polymorphisms (rs3212986 and rs11615) and HNSCC risk by a meta-analysis of all eligible studies. METHODS: The meta-analysis was performed by reviewing seven studies on the ERCC1 C8092A (rs3212986) polymorphism including 2055 cases and 2635 controls and four studies on the T19007C (rs11615) polymorphism including 910 cases and 1337 controls. RESULTS: For ERCC1 rs3212986 polymorphism, no significant association with HNSCC was found in overall analysis, but subgroup analysis revealed that a significant association of the rs3212986 polymorphism was found among Asians (A vs. C: OR 0.83; 95% CI 0.70-0.99) but not Caucasians. For ERCC1 rs11615 polymorphism, a significant association with HNSCC (TC + CC vs. TT: OR 1.23; 95% CI 1.03-1.47) was found in overall analysis. Consistently, subgroup analysis revealed that significant associations of the rs3212986 polymorphism were found among Asians (C vs. T: OR 1.32; 95% CI 1.04-1.69) and in laryngeal carcinoma (CC vs. TC + TT: OR 1.32; 95% CI 1.02-1.72). CONCLUSION: The findings of the meta-analysis indicated that a decreased risk for the ERCC1 rs3212986 polymorphism was found among Asians, and an increased risk for the ERCC1 rs11615 polymorphism was found in overall HNSCC, especially in Asian subgroup and laryngeal site, suggesting that ERCC1 rs3212986 polymorphism in Asians may act as a protective factor and rs11615 polymorphism may be a risk factor for HNSCC. PMID- 26022133 TI - Clinicopathological significance of orphan nuclear receptor Nurr1 expression in gastric cancer. AB - BACKGROUND: Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related deaths worldwide. Gastric cancer is characterized by high levels of invasion and metastasis. Increasing attention is being focused on discovering molecular markers for the diagnosis of gastric cancer and for predicting its prognosis. The objective of the present study was to evaluate Nurr1 expression in gastric cancer and to assess its correlation with clinicopathological parameters and prognosis in gastric cancer patients. METHODS: Tissue samples were obtained from 120 gastric cancer patients. We investigated Nurr1 expression in human normal and gastric cancer tissues using real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. We determined the association between Nurr1 and recurrence, prognosis and patient clinicopathological parameters. Univariate and multivariate survival analyses with a Cox's proportional hazards regression model were used to identify independent factors related to recurrence and prognosis. RESULTS: The immunohistochemical, qRT-PCR and western blot analyses revealed that Nurr1 expression was increased in gastric cancer tissues compared with normal gastric tissue (P < 0.05). Nurr1 expression was significantly correlated with the tumor size, depth of tumor invasion, lymph node metastasis, recurrence, and distant metastasis of gastric cancer (P < 0.05). Moreover, Nurr1-high patients also exhibited poorer overall survival (OS) and disease-free survival compared with Nurr1-low patients (P < 0.01). The univariate and multivariate survival analyses suggested that Nurr1 expression (P = 0.011), histology (P = 0.018), depth of tumor invasion (P = 0.037), and presence of lymph node metastasis (P = 0.031) were independent prognostic factors for recurrence. In addition, Nurr1 expression (P = 0.007), depth of tumor invasion (P = 0.014), lymph node metastasis (P = 0.044), distant metastasis (P = 0.023), and recurrence (P = 0.011) were independent prognostic factors of OS in gastric cancer patients. CONCLUSIONS: The Nurr1 protein may be useful as a marker of recurrence, metastasis, and poor prognosis following curative resection in patients with gastric cancer. PMID- 26022134 TI - Multidisciplinary Proactive Psychiatric Consultation Service: Impact on Length of Stay for Medical Inpatients. AB - BACKGROUND: Mental illness correlates with an increased length of stay (LOS) for patients hospitalized for medical conditions. While psychiatric consultations help manage mental illness among those hospitalized for medical conditions, consultations initiated by nonpsychiatric mental disease may lack maximum effectiveness. METHODS: In a before-and-after design, in 2 contiguous years LOS for internist-initiated, conventional consultation (CC) as usual treatment was compared to LOS of a proactive, mental health professional-initiated, multidisciplinary intervention delivered by the behavioral intervention team (BIT) on the same units. The patient populations included general medical patients with a variety of illnesses. Patients were treated in 3 different inpatient settings with a total capacity of 92 beds serving 15,858 patient visits over 3 comparison years. BIT comprised a psychiatrist, a nurse, and a social worker, each of whom performed the specific tasks of their professional discipline, while collaborating among themselves and their health-care colleagues. BIT provided timely, appropriate, and effective patient care alongside consultative advice and education to their corresponding professional peers. BIT was compared to CC on the outcome of LOS. RESULTS: There was a statistically significant reduction of LOS favoring BIT over CC for patients with an LOS of <31 days which persisted while controlling for multiple co-morbid factors. Also, a statistically significant spillover effect was suggested by the overall improvement of LOS on units implementing BIT. CONCLUSION: BIT is a promising means of lowering LOS on general medical units while providing a high level of care and staff support. PMID- 26022135 TI - Successful empirical antifungal therapy of intravenous itraconazole with pharmacokinetic evidence in pediatric cancer patients undergoing hematopoietic stem cell transplantation. AB - BACKGROUND AND OBJECTIVES: Empirical antifungal therapy prevents invasive fungal infections in patients with cancer. This study assessed the empirical efficacy of intravenous itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation, and investigated the pharmacokinetics and clinical implications. METHODS: Oral itraconazole syrup was started (2.5 mg/kg twice daily) for prophylaxis, and patients with persistent neutropenic fever for more than 2 days were switched to intravenous itraconazole (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance) as empirical treatment. Empirical antifungal efficacy was assessed retrospectively in 159 transplantations, and a full pharmacokinetic study was prospectively conducted in six of these patients. Successful antifungal efficacy was defined as the fulfillment of all components of a five-part composite end point. RESULTS: The overall empirical antifungal success rate fulfilling all criteria was 42.1 %. No death or drug-related serious adverse events occurred during the study. Mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1659.7 MUg/L, respectively. Mean area under the concentration-time curve of itraconazole and its metabolite at steady state were 42,837 +/- 24,746 MUg.h/L and 63,094 +/- 19,255 MUg.h/L. CONCLUSIONS: Intravenous itraconazole was effective and safe as an empirical antifungal agent in pediatric patients; this was due to the fast and satisfactory increase in drug concentration by switching from oral to intravenous therapy. PMID- 26022137 TI - Assessing Polycyclic Aromatic Hydrocarbons (PAHs) using passive air sampling in the atmosphere of one of the most wood-smoke-polluted cities in Chile: The case study of Temuco. AB - This study addresses human health concerns in the city of Temuco that are attributed to wood smoke and related pollutants associated with wood burning activities that are prevalent in Temuco. Polycyclic Aromatic Hydrocarbons (PAHs) were measured in air across urban and rural sites over three seasons in Temuco using polyurethane foam (PUF) disk passive air samplers (PUF-PAS). Concentrations of SigmaPAHs (15 congeners) in air ranged from BDL to ~70 ng m(-3) and were highest during the winter season, which is attributed to emissions from residential heating by wood combustion. The results for all three seasons showed that the PAH plume was widespread across all sites including rural sites on the outskirts of Temuco. Some interesting variations were observed between seasons in the composition of PAHs, which were attributed to differences in seasonal point sources. A comparison of the PAH composition in the passive samples with active samples (gas+particle phase) from the same site revealed similar congener profiles. Overall, the study demonstrated that the PUF disk passive air sampler provides a simple approach for measuring PAHs in air and for tracking effectiveness of pollution control measures in urban areas in order to improve public health. PMID- 26022136 TI - Impact of soluble epoxide hydrolase inhibition on early kidney damage in hyperglycemic overweight mice. AB - This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFkappaB inhibitor Ikappa= and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal inflammation in overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of diabetic nephropathy. PMID- 26022138 TI - Molecular marker characterization and source appointment of particulate matter and its organic aerosols. AB - This study was carried out to identify possible sources and to estimate their contribution to total suspended particle (TSP) organic aerosol (OA) contents. A total of 120 TSP and PM2.5 samples were collected simultaneously every third day over a one-year period in urban area of Incheon, Korea. High concentration in particulate matters (PM) and its components (NO3(-), water soluble organic compounds (WSOCs), and n-alkanoic acids) were observed during the winter season. Among the organics, n-alkanes, n-alkanoic acids, levoglucosan, and phthalates were major components. Positive matrix factorization (PMF) analysis identified seven sources of organic aerosols including combustion 1 (low molecular weight (LMW)-polycyclic aromatic hydrocarbons (PAHs)), combustion 2 (high molecular weight (HMW)-PAHs), biomass burning, vegetative detritus (n-alkane), secondary organic aerosol 1 (SOA1), secondary organic aerosol 2 (SOA2), and motor vehicles. Vegetative detritus increased during the summer season through an increase in biogenic/photochemical activity, while most of the organic sources were prominent in the winter season due to the increases in air pollutant emissions and atmospheric stability. The correlation factors were high among the main components of the organic carbon (OC) in the TSP and PM2.5. The results showed that TSP OAs had very similar characteristics to the PM2.5 OAs. SOA, combustion (PAHs), and motor vehicle were found to be important sources of carbonaceous PM in this region. Our results imply that molecular markers (MMs)-PMF model can provide useful information on the source and characteristics of PM. PMID- 26022139 TI - High-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after percutaneous coronary intervention: a report from the CREDO-Kyoto registry cohort-2. AB - OBJECTIVE: To determine whether low HDL-C is a risk factor for adverse cardiovascular events in patients with known CAD. METHODS: We evaluated 10,391 patients who underwent PCI from January 2005 to December 2007. In total, 3838 (36.9%) patients had low HDL-C (HDL-C <40 mg/dL in males and <50 mg/dL in females) and 6553 (63.1%) patients had normal HDL-C based on measurements on admission. RESULTS: The unadjusted 5-year incidence of major adverse cardiac events (MACE: composite of cardiovascular death, myocardial infarction or stroke) was significantly higher in the low HDL-C group than in the normal HDL-C group (17.6% vs. 14.0%, P < 0.0001). However, after adjusting for confounders, low HDL C was not associated with a higher risk of MACE (adjusted hazard ratio [HR] 1.07, 95% confidence interval (CI) 0.97-1.19; P = 0.19). There was no significant interaction between the effect of low HDL-C on MACE and several subgroup factors including age, sex, clinical presentation of CAD, statins use, serum low-density lipoprotein cholesterol level, and serum triglycerides level. CONCLUSION: Low HDL C, as compared with normal HDL-C, was not associated with higher 5-year risk of MACE in patients who underwent PCI. PMID- 26022140 TI - Grape powder treatment prevents anxiety-like behavior in a rat model of aging. AB - Earlier, we have reported that grape powder (GP) treatment prevented pharmacologic and psychological stress-induced anxiety-like behavior and memory impairment in rats. Protective effects of GP were attributed to its antioxidant effects. In this study, we tested the hypothesis that age-associated behavioral and cognitive deficits such as anxiety and memory impairment will be ameliorated with GP treatment. Using a National Institute of Aging recommended rodent model of aging, we examined a potentially protective role of antioxidant-rich GP in age associated anxiety-like behavior and memory impairment. Male Fischer 344 rats were randomly assigned into 4 groups: young rats (3 months old) provided with tap water or with 15 g/L GP dissolved in tap water for 3 weeks, aged rats (21 months old) provided with tap water or with GP-treated tap water for 3 weeks (AG-GP). Anxiety-like behavior was significantly greater in aged rats compared with young rats, GP-treated young rats, or aged control rats (P < .05). Also, GP treatment prevented age-induced anxiety-like behavior in AG-GP rats (P < .05). Neither short-term nor long-term age-associated memory deficits improved with GP treatment in AG-GP rats. Furthermore, aged rats showed increased level of physiological stress (corticosterone) and increased oxidative stress in the plasma (8-isoprostane) as well as in selected brain areas (protein carbonylation). Grape powder treatment prevented age-induced increase in corticosterone levels and plasma 8-isoprostane levels in aged rats (P < .05), whereas protein carbonylation was recovered in the amygdala region only (P < .05). Grape powder by regulating oxidative stress ameliorates age-induced anxiety like behavior in rats, whereas age-associated memory deficits seem unaffected with GP treatment. PMID- 26022142 TI - Axis-dependent magnetic behavior of C60 and C60(10+). consequences of spherical aromatic character. AB - The magnetic response of C60 has been studied and compared to its spherical aromatic counterpart C60(10+), focusing on the overall and local shielding tensors. A high axis dependence behavior at the outside region of the structure is characterized, unravelling a characteristic pattern of the local chemical shift anisotropy as a consequence of the spherical aromatic behavior. PMID- 26022141 TI - Targeted mutagenesis in soybean using the CRISPR-Cas9 system. AB - Genome editing is a valuable technique for gene function analysis and crop improvement. Over the past two years, the CRISPR-Cas9 system has emerged as a powerful tool for precisely targeted gene editing. In this study, we predicted 11 U6 genes in soybean (Glycine max L.). We then constructed two vectors (pCas9-GmU6 sgRNA and pCas9-AtU6-sgRNA) using the soybean U6-10 and Arabidopsis U6-26 promoters, respectively, to produce synthetic guide RNAs (sgRNAs) for targeted gene mutagenesis. Three genes, Glyma06g14180, Glyma08g02290 and Glyma12g37050, were selected as targets. Mutations of these three genes were detected in soybean protoplasts. The vectors were then transformed into soybean hairy roots by Agrobacterium rhizogenes infection, resulting in efficient target gene editing. Mutation efficiencies ranged from 3.2-9.7% using the pCas9-AtU6-sgRNA vector and 14.7-20.2% with the pCas9-GmU6-sgRNA vector. Biallelic mutations in Glyma06g14180 and Glyma08g02290 were detected in transgenic hairy roots. Off-target activities associated with Glyma06g14180 and Glyma12g37050 were also detected. Off-target activity would improve mutation efficiency for the construction of a saturated gene mutation library in soybean. Targeted mutagenesis using the CRISPR-Cas9 system should advance soybean functional genomic research, especially that of genes involved in the roots and nodules. PMID- 26022143 TI - Evaluation of larval density Cochliomyia macellaria F. (Diptera: Calliphoridae) for therapeutic use in the recovery of tegumentar injuries. AB - Larval therapy (LT) is the application of carrion flies (Diptera) sterile larvae on chronic or infected wounds to promote or accelerate the healing process. High cost and the development of resistance by certain groups of pathogenic bacteria to these drugs encouraged the resurgence of LT, currently used in approximately 20 countries and more recently in Brazil. This study evaluated the behavior and larval density of Cochliomyia macellaria F. (Calliphoridae), one of the most appropriate species for debridement of injuries with necrotic tissue. Tegumentar lesions were induced in Wistar rats by subcutaneously application of 0.2 ml of a 1:4 hydrochloric acid and sterile distilled water in the dorsal region. Five experimental groups were set up: (LT 5) treatment with 5 larvae/cm(2); (LT 15) 15 larvae/cm(2); (LT 25) 25 larvae/cm(2); (DEB) mechanical debridement, and (NUL) animals that did not receive any treatment. In the LT groups, larvae used were sterilized with sodium hypochlorite (NaClO) and maintained for 12 h in the lesions. The healing process was assessed qualitatively (macroscopically and microscopically) and quantitatively (time interval to complete healing). It was observed that the immature fed only on necrotic tissue, thus C. macellaria is an excellent candidate for use in LT. There was no significant difference in healing time between experimental groups. However, it was observed that in LT 25, there was greater vascularization in tissues when compared to the other treatments. The mechanisms involved in this process are unknown, but it is evident that the larvae have an important role in modulating the host immune response. It is essential that future applications of larval therapy consider using a higher density of larvae (minimum of 25 larvae/cm(2)) than is currently recommended. PMID- 26022144 TI - Parasite introduction with an invasive goby in Belgium: double trouble? AB - Non-indigenous species may have negative impacts on the native fauna in their competition for food and habitat, but they can also introduce non-indigenous parasite species, with sometimes devastating consequences. Co-introduction of parasites should therefore be carefully monitored, but this aspect is mostly overlooked. The round goby Neogobius melanostomus (Pallas, 1814) and the tubenose goby Proterorhinus semilunaris (Heckel, 1937), both known for their invasiveness, have recently been discovered in Belgium. Here, we morphologically and genetically document the co-introduction of the Ponto-Caspian Gyrodactylus proterorhini Ergens, 1967, originally described on tubenose goby in southern Slovakia. Because of their direct life cycle and extraordinary reproductive capacities, gyrodactylid monogenean parasites can readily invade new areas together with the host. Moreover, G. proterorhini has a wide host range and might therefore represent a threat to other gobiid fishes. The Gyrodactylus parasite found on the Belgian round goby population is probably acquired through secondary infection from local fish, as suggested by molecular phylogenetic analysis. PMID- 26022145 TI - Association of Fragmented QRS with Subclinical Left Ventricular Dysfunction in Patients with Obstructive Sleep Apnea. AB - OBJECTIVE: We aimed to investigate whether fragmented QRS (fQRS) is associated with subclinical left ventricular (LV) dysfunction in patients with obstructive sleep apnea (OSA). SUBJECTS AND METHODS: A total of 141 patients with OSA who had normal LV ejection fraction (LVEF) were included in the study. The fQRS was defined as the presence of an additional R wave, notching of R or S wave or the presence of fragmentation in 2 contiguous electrocardiography (ECG) leads. Subclinical LV dysfunction was defined as the presence of a tissue Doppler derived Tei index of >= 0.5 in the absence of impaired LVEF (<50%) as assessed by transthoracic echocardiography. RESULTS: Of the 141 patients, 71 (50.4%) had subclinical LV dysfunction. Overall, the prevalence of the fQRS was 61% (86/141). Patients with fQRS had significantly higher Tei indices than those without fQRS [median 0.66, interquartile range (IQR) 0.39 vs. median 0.40, IQR 0.15, p < 0.001]. The presence of fQRS on ECG predicted subclinical LV dysfunction in univariate logistic regression analysis [odds ratio (OR) 6.69, 95% confidence interval (CI) 3.10-14.43]. The association remained significant after adjusting for all potential confounders (OR 4.59, 95% CI 1.94-10.87). CONCLUSION: fQRS on ECG was an independent predictor of subclinical LV dysfunction in patients with OSA. This simple tool might help to identify OSA patients who could be at risk for developing overt cardiac dysfunction. PMID- 26022146 TI - Aggression Among Male Migrant Farmworkers Living in Camps in Eastern North Carolina. AB - The living and working arrangements of migrant farmworkers in North Carolina are shaped by grower provided housing, codified by the US Department of Labor's H-2A temporary worker program. Growers typically dictate all facets about residences, living conditions, and even food acquirements. Farmworker camps likely contribute to aggression because of the forced relationships among a small group of people that live, work and recreate together for extended time periods. Participants in the study consisted of 371 farmworkers living in 183 camps. The Revised Conflict Tactics Scale was used to assess aggression among migrant farmworkers. Results indicated that aggressive acts were prevalent among the farmworkers, but the frequency of aggressive acts was low. The most common aggressive act was minor psychological aggression. Results also indicated that alcohol misuse was a common characteristic for both victims and perpetrators and the majority of aggressive acts occurred later in the agricultural season. PMID- 26022147 TI - Economic Hardship and Depression Among Women in Latino Farmworker Families. AB - Farmworker family members risk poor mental health due to stressors including poverty, relocation, and documentation status. This paper explores the relationship between farm-work related stressors and depressive symptoms in women of Latino farmworker families. 248 mothers of young children completed fixed response interviews in Spanish. Measures included the Center for Epidemiologic Studies-Depression Scale, Migrant Farmworker Stress Inventory, and USDA Household Food Security Survey Module. Bivariate analyses indicated greater depressive symptoms with more economic hardship, more farm work-related stressors, greater age, and being unmarried. In multivariable logistic regression, economic hardship remained the only factor associated with depressive symptoms. Greater economic hardship, but not general farm work-related stress, is a main factor associated with depression in women of Latino farmworker families. Maternal depression can have consequences for both mothers and families. Mental health services for women in farmworker families should be targeted to those with the greatest economic challenges. PMID- 26022149 TI - Interventions for improving employment outcomes for workers with HIV. AB - BACKGROUND: The vast majority of people infected with human immunodeficiency virus (HIV) are adults of working age. Therefore unemployment and job loss resulting from HIV infection are major public health and economic concerns. Return to work (RTW) after diagnosis of HIV is a long and complex process, particularly if the individual has been absent from work for long periods. There have been various efforts to improve the RTW of persons living with HIV (HIV+), and many of these have been assessed formally in intervention studies. OBJECTIVES: To evaluate the effect of interventions aimed at sustaining and improving employment in HIV+ persons. SEARCH METHODS: We conducted a comprehensive search from 1981 until December 2014 in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, OSH UPDATE databases (CISDOC, HSELINE, NIOSHTIC, NIOSHTIC-2, RILOSH), and PsycINFO. SELECTION CRITERIA: We considered for inclusion all randomized controlled trials (RCTs) or controlled before-after (CBA) studies assessing the effectiveness of pharmacological, vocational and psychological interventions with HIV+ working-aged (16 years or older) participants that had used RTW or other indices of employment as outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all potential references for inclusion. We determined final selection of studies by consensus. We performed data extraction and management, as well as Risk of bias assessment, in duplicate. We measured the treatment effect using odds ratio (OR) for binary outcomes and mean difference (MD) for continuous outcomes. We applied the GRADE approach to appraise the quality of the evidence. MAIN RESULTS: We found one RCT with 174 participants and five CBAs with 48,058 participants assessing the effectiveness of vocational training (n = 1) and antiretroviral therapy (ART) (n = 5). We found no studies assessing psychological interventions. The one RCT was conducted in the United States; the five CBA studies were conducted in South Africa, India, Kenya, and Uganda. We graded all six studies as having a high risk of bias.The effectiveness of vocational intervention was assessed in only one study but we could not infer the intervention effect due to a lack of data.For pharmacological interventions, we found very low-quality evidence for a beneficial effect of ART on employment outcomes in five studies. Due to differences in outcome measurement we could only combine the results of two studies in a meta-analysis.Two studies compared employment outcomes of HIV+ persons on ART therapy to healthy controls. One study found a MD of -1.22 days worked per month (95% confidence interval (CI) -1.74 to 1.07) at 24-months follow-up. The other study found that the likelihood of being employed steadily increased for HIV+ persons compared to healthy individuals from ART initiation (OR 0.35, 95% CI 0.26 to 0.47) to three- to five-years follow-up (OR 0.73, 95% CI 0.42 to 1.28).Three other studies compared HIV+ persons on ART to HIV+ persons not yet on ART. Two studies indicated an increase in the likelihood of employment over time due to the impact of ART for HIV+ persons compared to HIV+ persons pre-ART (OR 1.75, 95% CI 1.44 to 2.12). One study found that the group on ART worked 12.1 hours more (95% CI 6.99 to 17.21) per week at 24-months follow-up than the average of the cohort of ART and pre-ART HIV+ persons which was 20.1 hours.We rated the evidence as very low quality for all comparisons due to a high risk of bias. AUTHORS' CONCLUSIONS: We found very low quality evidence showing that ART interventions may improve employment outcomes for HIV+ persons. For vocational interventions, the one included study produced no evidence of an intervention effect. We found no studies that assessed psychological interventions. We need more high-quality, preferably randomized studies to assess the effectiveness of RTW interventions for HIV+ persons. PMID- 26022148 TI - betaA3/A1-crystallin and persistent fetal vasculature (PFV) disease of the eye. AB - BACKGROUND: Persistent fetal vasculature (PFV) is a human disease in which the fetal vasculature of the eye fails to regress normally. The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently regressing after formation of the retinal vessels. PFV causes serious congenital pathologies and is responsible for as much as 5% of blindness in the United States. SCOPE OF REVIEW: The causes of PFV are poorly understood, however there are a number of animal models in which aspects of the disease are present. One such model results from mutation or elimination of the gene (Cryba1) encoding betaA3/A1-crystallin. In this review we focus on the possible mechanisms whereby loss of functional betaA3/A1-crystallin might lead to PFV. MAJOR CONCLUSIONS: Cryba1 is abundantly expressed in the lens, but is also expressed in certain other ocular cells, including astrocytes. In animal models lacking betaA3/A1 crystallin, astrocyte numbers are increased and they migrate abnormally from the retina to ensheath the persistent hyaloid artery. Evidence is presented that the absence of functional betaA3/A1-crystallin causes failure of the normal acidification of endolysosomal compartments in the astrocytes, leading to impairment of certain critical signaling pathways, including mTOR and Notch/STAT3. GENERAL SIGNIFICANCE: The findings suggest that impaired endolysosomal signaling in ocular astrocytes can cause PFV disease, by adversely affecting the vascular remodeling processes essential to ocular development, including regression of the fetal vasculature. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID- 26022150 TI - Fungal sterol C22-desaturase is not an antimycotic target as shown by selective inhibitors and testing on clinical isolates. AB - Inhibition of concise enzymes in ergosterol biosynthesis is one of the most prominent strategies for antifungal chemotherapy. Nevertheless, the enzymes sterol C5-desaturase and sterol C22-desaturase, which introduce double bonds into the sterol core and side chain, have not been fully investigated yet for their potential as antifungal drug targets. Lathosterol side chain amides bearing N alkyl groups of proper length are known as potent inhibitors of the enzymes sterol C5-desaturase and sterol Delta(24)-reductase in mammalian cholesterol biosynthesis. Here we present the results of our evaluation of these amides for their ability to inhibit enzymes in fungal ergosterol biosynthesis. In the presence of inhibitor(s) an accumulation of sterols lacking a double bond at C22/23 (mainly ergosta-5,7-dien-3beta-ol) was observed in Candida glabrata, Saccharomyces cerevisiae, and Yarrowia lipolytica. Hence, the lathosterol side chain amides were identified as selective inhibitors of the fungal sterol C22 desaturase, which was discussed as a specific target for novel antifungals. One representative inhibitor, (3S,20S)-20-N-butylcarbamoylpregn-7-en-3beta-ol was subjected to antifungal susceptibility testing on patient isolates according to modified EUCAST guidelines. But, the test organisms showed no significant reduction of cell growth and/or viability up to an inhibitor concentration of 100MUg/mL. This leads to the conclusion that sterol C22-desaturase is not an attractive target for the development of antifungals. PMID- 26022151 TI - Prognostic value of lymph node ratio in survival of patients with locally advanced rectal cancer. AB - BACKGROUND: The lymph node ratio (LNR) has been shown to be an important prognostic factor in patients with gastric, breast, pancreatic and colorectal cancer. We investigated the prognostic impact of the LNR in addition to TNM classification in patients with locally advanced rectal cancer. METHODS: We retrospectively analyzed patients who underwent curative resection for locally advanced rectal cancer between July 2005 and December 2010. We determined the LNR cutoff value using a receiver operating characteristic curve. The Kaplan-Meier method was used to estimate survival curves, while Cox regression analyses were used to evaluate the relationship between LNR and survival. RESULTS: We included 180 patients aged 28-83 years with median follow-up of 41.8 months. The median number of lymph nodes examined and lymph nodes involved were 11.5 and 4, respectively, and the median LNR was 0.366. An LNR of 0.19 (19%) was the cutoff point to separate patients with regard to median overall survival. Median overall survival was 64.2 months for patients with an LNR of 0, 59.1 for an LNR of 0.19 or less and 37.6 for an LNR greater than 0.19 (p = 0.004). The median disease free survival was 32.9 months for patients with an LNR of 0, 30.4 for an LNR of 0.19 or less and 17.8 for an LNR greater than 0.19 (p = 0.002). CONCLUSION: Our results suggest that LNR should be considered an additional prognostic factor in patients with locally advanced rectal cancer. PMID- 26022152 TI - Penetrating nontorso trauma: the extremities. AB - Similar to penetrating torso trauma, nontorso injuries have undergone a fascinating oscillation between invasive and noninvasive approaches. This article discusses an organized approach to the evaluation and initial treatment of penetrating extremity injuries based on regional anatomy and clinical examination. The approach is reliable, efficient and minimizes both delays in diagnosis and missed injuries. Outpatient follow- up is particularly important for patients with extremity injuries who are discharged home from the emergency department. PMID- 26022153 TI - Traffic in the operating room during joint replacement is a multidisciplinary problem. AB - BACKGROUND: Door openings disrupt the laminar air flow and increase the bacterial count in the operating room (OR). We aimed to define the incidence of door openings in the OR during primary total joint arthroplasty (TJA) surgeries and determine whether measures were needed and/or possible to reduce OR staff traffic. METHODS: We recorded the number of door openings during 100 primary elective TJA surgeries; the OR personnel were unaware of the observer's intention. Operating time was divided into the preincision period, defined as the time from the opening of surgical trays to skin incision, and the postincision period, defined as time from incision to dressing application. RESULTS: The mean number of door openings during primary TJA was 71.1 (range 35-176) with a mean operative time of 111.9 (range 53-220) minutes, for an average of 0.64 (range 0.36-1.05) door openings/min. Nursing staff were responsible for 52.2% of total door openings, followed by anesthesia staff at 23.9% and orthopedic staff at 12.7%. In the preincision period, we observed an average of 0.84 door openings/ min, with nursing and orthopedic personnel responsible for most of the door openings. The postincision period yielded an average of 0.54 door openings/min, with nursing and anesthesia personnel being responsible for most of the door openings. CONCLUSION: There is a high incidence of door openings during TJA. Because we observed a range in the number of door openings per surgery, we believe it is possible to reduce this number during TJA. PMID- 26022154 TI - Penetrating nontorso trauma: the head and the neck. AB - Acute penetrating injuries to the head and neck cause considerable anxiety for most clinicians owing to concern for airway control and neurologic injury and to limited clinician experience in most centres. This article discusses an organized approach to the evaluation and initial treatment of penetrating injuries to the head and neck based on regional anatomy and clinical examination. The approach is particularly helpful in the context of ongoing hemorrhage and/or airway compromise. PMID- 26022155 TI - Colonoscopy after CT-diagnosed acute diverticulitis: Is it really necessary? AB - BACKGROUND: Computed tomography (CT) scans are commonly used to diagnose acute diverticulitis, but there are overlapping features between diverticulitis and colorectal cancer (CRC) on imaging studies. Hence, colonoscopy is typically recommended after an episode of acute diverticulitis to rule out underlying malignancy. Currently, 64-slice multidetector CT scanners are capable of providing higher-resolution images and may be able to distinguish malignancy from diverticular inflammation. We aimed to determine the prevalence of CRC among patients with CT-diagnosed acute diverticulitis. METHODS: We performed a retrospective study of patients with acute diverticulitis diagnosed on CT scan between December 2005 and December 2010 at St. Paul's Hospital, Vancouver, BC. Nonresidents were excluded. We reviewed CT scan reports that included the term "diverticulitis," reports of follow-up colonic evaluation within 1 year of diagnosis and pathology results. We queried the provincial cancer registry to ensure no cases of CRC were missed. RESULTS: A total of 293 patients had acute diverticulitis diagnosed on CT scan, but 8 were nonresidents and were excluded. Of the 285 included in the analysis, the mean age was 59.4 +/- 15.1 years, and 167 (58.6%) were men. Among the 114 patients who underwent follow-up evaluation, malignancy was diagnosed in 4 (3.5%). The overall prevalence of malignancy among patients with CT-diagnosed diverticulitis was 1.4%. CONCLUSION: Routine endoscopic evaluation after an episode of diverticulitis diagnosed with high resolution CT scan does not appear to be necessary. Selective approach in patients with protracted clinical course or those with mass lesion/obstruction on CT scan may be of benefit. PMID- 26022156 TI - Patient and observer scar assessment scores favour the late appearance of a transverse cervical incision over a vertical incision in patients undergoing carotid endarterectomy for stroke risk reduction. AB - BACKGROUND: Carotid endarterectomy (CEA) is a very common operation, but there is no agreement on the appropriate orientation of the surgical incision. METHODS: We retrospectively reviewed the charts of patients who had undergone CEA between Jul. 1, 2010, and Dec. 31, 2013. We contacted patients identified in the review to solicit participation in a clinical follow-up examination, during which the esthetic outcome of the scar was evaluated using the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: During the study period 237 CEAs were performed. Nine patients refused the use of their personal health information in this study. There were no significant differences in the neurologic outcomes of patients based on the incision orientation (perioperative stroke and death 1.4% with transverse incision v. 0% with a vertical incision, p = 0.44). Fifty-two patients presented for follow-up examination. Thirty-three had a transverse incision and 19 had a vertical incision. Results of the POSAS significantly favoured the transverse incision (p = 0.03). Vertical incisions were more often associated with persistent, mild marginal mandibular nerve dysfunction (p = 0.04). CONCLUSION: Carotid endarterectomy performed through a transverse skin incision compared with a vertically oriented skin incision is associated with improved esthetic outcome, as measured by the POSAS, without an observed statistically significant difference in the risk of perioperative stroke or death between the 2 techniques. PMID- 26022157 TI - Zebrafish in oncology. PMID- 26022158 TI - MST-312 induces G2/M cell cycle arrest and apoptosis in APL cells through inhibition of telomerase activity and suppression of NF-kappaB pathway. AB - Telomerase-targeted therapy for cancer has received great attention because telomerase is expressed in almost all cancer cells but is inactive in most normal somatic cells. This study was aimed to investigate the effects of telomerase inhibitor MST-312, a chemically modified derivative of epigallocatechin gallate (EGCG), on acute promyelocytic leukemia (APL) cells. Our results showed that MST 312 exerted a dose-dependent short-term cytotoxic effect on APL cells, with G2/M cell cycle arrest. Moreover, MST-312 induced apoptosis of APL cells in caspase mediated manner. Telomeric repeat amplification protocol (TRAP) assay revealed significant reduction in telomerase activity of APL cells following short-term exposure to MST-312. Interestingly, MST-312-induced telomerase inhibition was coupled with suppression of NF-kappaB activity as evidenced by inhibition of IkappaBalpha phosphorylation and its degradation and decreased NF-kappaB DNA binding activity. In addition, gene expression analysis showed downregulation of genes regulated by NF-kappaB, such as antiapoptotic (survivin, Bcl-2, Mcl-1), proliferative (c-Myc), and telomerase-related (hTERT) genes. Importantly, MST-312 did not show any apoptotic effect in normal human peripheral blood mononuclear cells (PBMCs). In conclusion, our data suggest that dual inhibition of telomerase activity and NF-kappaB pathway by MST-312 represents a novel treatment strategy for APL. PMID- 26022159 TI - Robo1 promotes angiogenesis in hepatocellular carcinoma through the Rho family of guanosine triphosphatases' signaling pathway. AB - Robo1 is a member of the Robo immunoglobulin superfamily of proteins, and it plays an important role in angiogenesis and cancer. In this study, we investigate the role of roundabout 1 (Robo1) in tumor angiogenesis in hepatocellular carcinoma (HCC). Firstly, the relationship between Robo1 expression on tumors and patient's survival and endothelial cells in tumor blood vessels and patient's survival was studied. Secondly, Robo1 was overexpressed or knocked down in human umbilical vein endothelial cells (HUVECs). Cell proliferation, motility, and tube formation were compared in HUVEC with different Robo1 expression. Also, HUVECs with different Robo1 expression were mixed with HCCLM3 and HepG2 hepatoma cells and then implanted in a nude mouse model to examine the effects of Robo1 in endothelial cells on tumor growth and angiogenesis. Cell motility-related molecules were studied to investigate the potential mechanism how Robo1 promoted tumor angiogenesis in HCC. The disease-free survival of the patients with high Robo1 expression in tumoral endothelial cells was significantly shorter than that of those with low expression (P = 0.021). Overexpression of Robo1 in HUVECs resulted in increased proliferation, motility, and tube formation in vitro. In the implanted mixture of tumor cells and HUVECs with an increased Robo1 expression, tumor growth and microvessel density were enhanced compared with controls. Robo1 promoted cell division cycle 42 (Cdc42) expression in HUVECs, and a distorted actin cytoskeleton in HUVECs was observed when Robo1 expression was suppressed. In conclusion, Robo1 promoted angiogenesis in HCC mediated by Cdc42. PMID- 26022160 TI - Gene polymorphisms in the folate metabolism and their association with MTX related adverse events in the treatment of ALL. AB - The antifolate drug methotrexate (MTX) is widely used in the treatment of various neoplastic diseases, including acute lymphoblastic leukemia (ALL). MTX significantly increases cure rates and improves patients' prognosis. Despite that it achieved remarkable clinical success, a large number of patients still suffer from treatment toxicities or side effects. Even to this date, chemotherapeutic regiments have not been personalized because of interindividual differences that affect MTX response, especially polymorphisms in key genes. The pharmacological pathway of MTX in cells is useful to identify gene polymorphisms that influence the process of treatment. The aim of this review was to discuss the gene polymorphisms of drug-metabolizing enzymes in the MTX pathway and their toxicities on ALL treatment. PMID- 26022161 TI - Loss of 5-hydroxymethylcytosine and intratumoral heterogeneity as an epigenomic hallmark of glioblastoma. AB - Glioblastoma (GBM) is the most malignant neoplasm with predominant astrocytic differentiation and the most frequent primary brain tumor of the adult. Here, we investigated 170 human GBM specimens deriving from 162 patients, as well as 66 healthy control tissue specimens deriving from 27 patients, and analyzed the amount of 5-hydroxymethylcytosine (5hmC) in GBMs compared to normal brain and tumor infiltration zones. Additionally, we correlated the amount of 5hmC with two different proliferation markers, Ki67 and H3S10p. Genetic characterization of GBMs enabled us to analyze the effect of isocitrate dehydrogenase 1 (IDH1) mutations, O6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation, and loss of heterozygosity of chromosome 1p and 19q (LOH1p/19q) on 5hmC amount. We found that GBMs show a tremendous loss of 5hmC, and we observed that even the infiltration zones show reduced amounts of 5hmC. Interestingly, the amount of 5hmC was inversely proportional to the two investigated proliferation markers, Ki67 and H3S10p. Correlation of 5hmC amount and molecular genetic markers of GBMs showed that there are no correlations of 5hmC amount and IDH1 mutations, MGMT promoter methylation, and LOH1p/19q. Furthermore, we evaluated the intratumoral distribution of 5hmC in compact and infiltrating areas and found that the quantification of the 5hmC amount is a useful tool in evaluation of tumor infiltration. In summary, our data emphasize that GBMs show a disturbed hydroxymethylome that is disrupted by IDH1 independent pathways, and that loss of 5hmC shows astonishing intratumoral heterogeneity. PMID- 26022162 TI - Prognostic significance of Nemo-like kinase expression in patients with hepatocellular carcinoma. AB - Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine protein kinase and belongs to the extracellular signal-regulated kinases/microtubule associated protein kinase families (Erks/MAPKs). Previous studies have indicated that abnormal expressions of NLK played critical roles in various types of human cancers. Recent studies suggested that NLK expression was significantly upregulated in the hepatocellular carcinoma (HCC) specimens. However, the clinical significance of NLK expression in HCC remains largely unknown. In this study, we focused on the clinical significance of NLK in HCC and found that high expression of NLK was significantly associated with Edmondson-Steiner grade (P = 0.002), tumor size (P = 0.022), and no. of tumor nodules (P < 0.001), and NLK was positively correlated with proliferation marker Ki-67 (P < 0.01). Univariate analysis suggested that NLK expression was associated with poor prognosis (P < 0.001). Multivariate analysis indicated that NLK expression was an independent prognostic indicator for HCC (P = 0.0370). In conclusion, NLK overexpression is associated with poor overall survival in patients with HCC, it might be an independent poor prognostic marker for HCC. PMID- 26022163 TI - Genomic variants and variations in malformations of cortical development. AB - Malformations of cortical development (MCDs) are a common cause of neurodevelopmental delay and epilepsy and are caused by disruptions in the normal development of the cerebral cortex. Several causative genes have been identified in patients with MCD. There is increasing evidence of role of de novo mutations, including those occurring post fertilization, in MCD. These somatic mutations may not be detectable by traditional methods of genetic testing performed on blood DNA. Identification of the genetic cause can help in guiding families in future pregnancies. Research has highlighted how elucidation of key molecular pathways can also allow for targeted therapeutic interventions. PMID- 26022164 TI - Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes. AB - Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15q11-q13 locus: Prader-Willi syndrome, Angelman syndrome, and 15q11-q13 duplication syndrome. Each of these disorders results from the loss of function or overexpression of at least 1 imprinted gene. This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders. PMID- 26022166 TI - Comparative analysis of self-injury in people with psychopathology or neurodevelopmental disorders. AB - Self-injury is a complex and poorly understood behavior observed in people with psychopathology or neurodevelopmental disorders (NDD). Despite the differences in etiology and progression of these distinct disease domains, it is possible that overlapping molecular pathways underlie the expression of self-injurious behaviors (SIBs). This review outlines the similarities and differences at the behavioural and molecular level, where SIBs in both conditions may involve opioid, nucleoside, and dopamine signalling. These points of convergence have important implications for treatment and research of SIB in both populations. PMID- 26022165 TI - Diagnosis and management of autism spectrum disorder in the era of genomics: rare disorders can pave the way for targeted treatments. AB - Although the diagnosis of autism spectrum disorder (ASD) is based on behavioral signs and symptoms, the evaluation of a child with ASD has become increasingly focused on the identification of the genetic etiology of the disorder. In this review, we begin with a clinical overview of ASD, highlighting the heterogeneity of the disorder. We then discuss the genetics of ASD and present updated guidelines on genetic testing. We then consider the insights gained from the identification of both single gene disorders and rare variants, with regard to clinical phenomenology and potential treatment targets. PMID- 26022167 TI - Tuberous sclerosis complex. AB - Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The genetic cause is mutations in the TSC1 gene, found on chromosome 9q34, and TSC2 gene, found on chromosome 16p13. The clinical phenotypes resulting from mutations in either of the 2 genes are variable in each individual. Herein, advances in the understanding of molecular mechanisms in tuberous sclerosis complex are reviewed, and current guidelines for diagnosis, treatment, follow-up, and management are summarized. PMID- 26022169 TI - Autoimmune encephalopathies. AB - Antibody-mediated diseases of the central nervous system are a relatively new and challenging field in autoimmune neurologic disease and of major clinical importance in children and adults. The antibodies bind to cell-surface epitopes on neuronal or glial proteins, and the patients demonstrate either focal or more generalized clinical signs depending on the extent of brain regions targeted by the antibodies. The presence of seizures, movement disorders, autonomic dysfunction and sleep disorders, alongside neuroimaging and electrophysiological features may indicate a specific antibody-mediated disorder. However, phenotypic variation may be observed in children with the same antibody. Regardless, many patients benefit from immunotherapy with substantial improvement. PMID- 26022170 TI - Advances in Tourette syndrome: diagnoses and treatment. AB - Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and often one or more comorbid psychiatric disorders. Premonitory sensory urges before tic execution and desire for "just-right" perception are central features. The pathophysiology involves cortico-striato-thalamo-cortical circuits and possibly dopaminergic system. TS is considered a genetic disorder but the genetics is complex and likely involves rare mutations, common variants, and environmental and epigenetic factors. Treatment is multimodal and includes education and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions. PMID- 26022168 TI - Emerging treatments for pediatric leukodystrophies. AB - The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Improved diagnostic methods have allowed identification of the underlying cause of these diseases, facilitating identification of their pathologic mechanisms. Clinicians are now able to prioritize treatment strategies and advance research in therapies for specific disorders. Although only a few of these disorders have well-established treatments or therapies, a number are on the verge of clinical trials. As investigators are able to shift care from symptomatic management of disorders to targeted therapeutics, the unmet therapeutic needs could be reduced for these patients. PMID- 26022171 TI - Genetics of pediatric epilepsy. AB - As the genetic etiologies of an expanding number of epilepsy syndromes are revealed, the complexity of the phenotype genotype correlation increases. As our review will show, multiple gene mutations cause different epilepsy syndromes, making identification of the specific mutation increasingly more important for prognostication and often more directed treatment. Examples of that include the need to avoid specific drugs in Dravet syndrome and the ongoing investigations of the potential use of new directed therapies such as retigabine in KCNQ2-related epilepsies, quinidine in KCNT1-related epilepsies, and memantine in GRIN2A related epilepsies. PMID- 26022172 TI - Genetics and emerging treatments for Duchenne and Becker muscular dystrophy. AB - Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades. PMID- 26022173 TI - Spinal muscular atrophies. AB - Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is caused by decreased levels of the survival of motor neuron (SMN) protein and is the most common genetic cause of infant mortality. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. Unlike other autosomal recessive diseases, the SMN gene has a unique structure (an inverted duplication) that presents potential therapeutic targets. Although there is currently no effective treatment of SMA, the field of translational research in this disorder is active and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with SMA also offer hope for improved life expectancy and quality of life. PMID- 26022174 TI - Pediatric Charcot-Marie-Tooth disease. AB - Heritable diseases of the peripheral nerves (Charcot-Marie-Tooth disease [CMT]) affect the motor units and sensory nerves, and they are among the most prevalent genetic conditions in the pediatric patient population. The typical clinical presentation includes distal muscle weakness and atrophy, but the severity and progression are largely variable. Improvements in supportive treatment have led to better preservation of patients' motor functions. More than 80 genes have been associated with CMT. These genetic discoveries, along with the developments of cellular and transgenic disease models, have allowed clinicians to better understand the disease mechanisms, which should lead to more specific treatments. PMID- 26022175 TI - Ethical and policy issues in newborn screening of children for neurologic and developmental disorders. AB - Genetic testing for neurologic and developmental disorders spans the spectrum from universal newborn screening for conditions like phenylketonuria to diagnostic testing for suspected genetic conditions, to predictive genetic testing for childhood-onset conditions. Given that virtually all children in the United States undergo genetic screening in the newborn period, this article focuses on 3 actual case studies of neurologic and developmental disorders that have been included or proposed for inclusion in newborn screening programs: Duchenne muscular dystrophy (a neuromuscular disorder), Krabbe disease (a neurodegenerative disorder), and fragile X syndrome (a neurodevelopmental disorder). PMID- 26022176 TI - Transformative technologies and understanding. PMID- 26022177 TI - Pediatric neurology in the era of genomics. PMID- 26022178 TI - NK cell function triggered by multiple activating receptors is negatively regulated by glycogen synthase kinase-3beta. AB - Activation of NK cells is triggered by combined signals from multiple activating receptors that belong to different families. Several NK cell activating receptors have been identified, but their role in the regulation of effector functions is primarily understood in the context of their individual engagement. Therefore, little is known about the signaling pathways broadly implicated by the multiple NK cell activation cues. Here we provide evidence pointing to glycogen synthase kinase (GSK)-3beta as a negative regulator of multiple NK cell activating signals. Using an activation model that combines NKG2D and 2B4 and tests different signaling molecules, we found that GSK-3 undergoes inhibitory phosphorylation at regulatory serine residues by the engagement of NKG2D and 2B4, either individually or in combination. The extent of such phosphorylation was closely correlated with the degree of NK cell activation. NK cell functions, such as cytokine production and cytotoxicity, were consistently enhanced by the knockdown of GSK-3beta or its inhibition with different pharmacological inhibitors, whereas inhibition of the GSK-3alpha isoform had no effect. In addition, NK cell function was augmented by the overexpression of a catalytically inactive form of GSK-3beta. Importantly, the regulation of NK cell function by GSK-3beta was common to diverse activating receptors that signal through both ITAM and non-ITAM pathways. Thus, our results suggest that GSK-3beta negatively regulates NK cell activation and that modulation of GSK-3beta function could be used to enhance NK cell activation. PMID- 26022179 TI - The BARD1 BRCT domain contributes to p53 binding, cytoplasmic and mitochondrial localization, and apoptotic function. AB - BARD1 is a breast cancer tumor suppressor with multiple domains and functions. BARD1 comprises a tandem BRCT domain at the C-terminus, and this sequence has been reported to target BARD1 to distinct subcellular locations such as nuclear DNA breakage sites and the centrosome through binding to regulatory proteins such as HP1 and OLA1, respectively. We now identify the BRCT domain as a binding site for p53. We first confirmed previous reports that endogenous BARD1 binds to p53 by immunoprecipitation assay, and further show that BARD1/p53 complexes locate at mitochondria suggesting a cellular location for p53 regulation of BARD1 apoptotic activity. We used a proximity ligation assay to map three distinct p53 binding sequences in human BARD1, ranging from weak (425-525) and modest (525-567) to strong (551-777 comprising BRCT domains). Deletion of the BRCT sequence caused major defects in the ability of BARD1 to (1) bind p53, (2) localize to the cytoplasm and mitochondria, and (3) induce Bax oligomerization and apoptosis. Our data suggest that BARD1 can move to mitochondria independent of p53, but subsequently associates with p53 to induce Bax clustering in part by decreasing mitochondrial Bcl-2 levels. We therefore identify a role for the BRCT domain in stimulating BARD1 nuclear export and mitochondrial localization, and in assembling mitochondrial BARD1/p53 complexes to regulate specific activities such as apoptotic function. PMID- 26022180 TI - Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling. AB - The ubiquitously expressed phosphoinositide 3-kinase (PI3K) family of lipid kinases control diverse cellular functions including cell survival, proliferation, metabolism and migration. Class I PI3Ks generate two distinct 3 phosphoinositide lipid messengers, PI(3,4,5)P3 (PIP3) and PI(3,4)P2, that recruit signaling effectors such as pleckstrin homology (PH) domain-containing proteins. Historically, the function of PI3K signaling has often been attributed to PIP3, with PI(3,4)P2 considered an inconsequential byproduct of PIP3 hydrolysis by SHIP phosphatases. However, accumulating evidence has demonstrated that PI(3,4)P2 directs a distinct branch of the PI3K pathway that regulates a variety of cellular processes with relevance to health and disease, such as B cell activation and autoantibody production, insulin sensitivity, neuronal dynamics, endocytosis and cell migration. Signaling through PI(3,4)P2 can be negatively regulated by inositol polyphosphate 4-phosphatases (INPP4A and INPP4B), which selectively degrade PI(3,4)P2. A number of signaling proteins that specifically bind to PI(3,4)P2 have been characterized, including the tandem PH domain containing proteins (TAPP1 and TAPP2) and lamellipodin/RAPH1. A number of PIP3 binding proteins also bind to PI(3,4)P2, such as the protein kinase Akt/PKB, the most studied effector of PI3K signaling. Here, we review the current progress in understanding the functions and mechanisms of action of the PI(3,4)P2-specific phosphatases and binding proteins. A summary of available data addressing the relative contribution of PI(3,4)P2 versus PIP3 in regulation of Akt is provided to highlight the potential independent role of PI(3,4)P2 in regulating some PIP3 binding proteins. In summary, PI(3,4)P2-specific phosphatases and binding proteins are now firmly established players in cell biology, and this "neglected" phosphoinositide needs to take its place as one of the central components of the PI3K signaling pathway. PMID- 26022181 TI - NEU3 sialidase as a marker of insulin sensitivity: Regulation by fatty acids. AB - The plasma membrane-associated enzyme NEU3 sialidase functions to cleave sialic acid residues from the ganglioside GM3 thereby promoting its degradation, and has been implicated in the modulation of insulin action. Herein, we report for the first time that impaired insulin sensitivity in skeletal muscle and liver of obese Zucker fatty rats and aged C57BL/6 mice coincides with reduced NEU3 protein abundance. In addition, high fat feeding was found to significantly reduce NEU3 protein in white adipose tissue of rats. Notably, we also demonstrate the ability of the fatty acids palmitate and oleate to repress and induce NEU3 protein in L6 myotubes, concomitant with their insulin desensitising and enhancing effects, respectively. Moreover, we show that the palmitate-driven loss in NEU3 protein is mediated, at least in part, by intracellular ceramide synthesis but does not involve the proteasomal pathway. Strikingly, we further reveal that protein kinase B (PKB/Akt) acts as a key positive modulator of NEU3 protein abundance. Together, our findings implicate NEU3 as a potential biomarker of insulin sensitivity, and provide novel mechanistic insight into the regulation of NEU3 expression. PMID- 26022182 TI - ERK and RSK are necessary for TRH-induced inhibition of r-ERG potassium currents in rat pituitary GH3 cells. AB - The transduction pathway mediating the inhibitory effect that TRH exerts on r-ERG channels has been thoroughly studied in GH3 rat pituitary cells but some elements have yet to be discovered, including those involved in a phosphorylation event(s). Using a quantitative phosphoproteomic approach we studied the changes in phosphorylation caused by treatment with 1MUM TRH for 5min in GH3 cells. The activating residues of Erk2 and Erk1 undergo phosphorylation increases of 5.26 and 4.87 fold, respectively, in agreement with previous reports of ERK activation by TRH in GH3 cells. Thus, we studied the possible involvement of ERK pathway in the signal transduction from TRH receptor to r-ERG channels. The MEK inhibitor U0126 at 0.5MUM caused no major blockade of the basal r-ERG current, but impaired the TRH inhibitory effect on r-ERG. Indeed, the TRH effect on r-ERG was also reduced when GH3 cells were transfected with siRNAs against either Erk1 or Erk2. Using antibodies, we found that TRH treatment also causes activating phosphorylation of Rsk. The TRH effect on r-ERG current was also impaired when cells were transfected with any of two different siRNAs mixtures against Rsk1. However, treatment of GH3 cells with 20nM EGF for 5min, which causes ERK and RSK activation, had no effect on the r-ERG currents. Therefore, we conclude that in the native GH3 cell system, ERK and RSK are involved in the pathway linking TRH receptor to r-ERG channel inhibition, but additional components must participate to cause such inhibition. PMID- 26022183 TI - Downregulation of beta-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein: Proteomics-Based Identification in Early-Stage Prion Disease. AB - Prion diseases are known as neurodegenerative diseases of the central nervous system with a long incubation period. Alzheimer's disease (AD) and prion diseases share the hallmark of severe neuronal loss, although their pathogenic mechanisms are similarly incomplete. It appears that these two neurodegenerative diseases share a complex deterioration of function involved in the onset of neuronal loss. To investigate presymptomatic biochemical changes indicative of the initial stage of prion diseases and decipher the pathophysiological mechanisms of these two neurodegenerative diseases, we performed a differential proteomic analysis on brain tissues of 263K-infected hamsters during the presymptomatic period and transgenic APPSWE, PSEN1dE9 mice (a mouse model of AD). We identified 7 differentially expressed proteins including the beta-soluble N-ethylmaleimide sensitive factor attachment protein (beta-SNAP) by 2-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The beta-SNAP expression patterns in the brains of cases and controls were further quantified by Western blotting. beta-SNAP showed an early decrease followed by a progressive depletion. The expression of beta-SNAP was also significantly downregulated in the mouse model of AD. beta-SNAP is brain specific and known to bind to the SNAP receptors and is therefore involved in the control of neurotransmitter release as well as in constitutive vesicular transport. Our results suggest that presynaptic failure and abnormalities in neurotransmission may be early events in the development of neuronal dysfunction. PMID- 26022184 TI - Malignant neuroendocrine tumour of the appendix in childhood with loco-regional lymph node invasion. AB - VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1006600359152743. PMID- 26022185 TI - Intracellular calcium attenuates late current conducted by mutant human cardiac sodium channels. AB - BACKGROUND: Mutations of the cardiac voltage-gated sodium channel (SCN5A gene encoding voltage-gated sodium channel [NaV1.5]) cause congenital long-QT syndrome type 3 (LQT3). Most NaV1.5 mutations associated with LQT3 promote a mode of sodium channel gating in which some channels fail to inactivate, contributing to increased late sodium current (INaL), which is directly responsible for delayed repolarization and prolongation of the QT interval. LQT3 patients have highest risk of arrhythmia during sleep or during periods of slow heart rate. During exercise (high heart rate), there is elevated steady-state intracellular free calcium (Ca(2+)) concentration. We hypothesized that higher levels of intracellular Ca(2+) may lower arrhythmia risk in LQT3 subjects through effects on INaL. METHODS AND RESULTS: We tested this idea by examining the effects of varying intracellular Ca(2+) concentrations on the level of INaL in cells expressing a typical LQT3 mutation, delKPQ, and another SCN5A mutation, R225P. We found that elevated intracellular Ca(2+) concentration significantly reduced INaL conducted by mutant channels but not wild-type channels. This attenuation of INaL in delKPQ expressing cells by Ca(2+) was not affected by the CaM kinase II inhibitor KN-93 but was partially attenuated by truncating the C-terminus of the channel. CONCLUSIONS: We conclude that intracellular Ca(2+) contributes to the regulation of INaL conducted by NaV1.5 mutants and propose that, during excitation-contraction coupling, elevated intracellular Ca(2+) suppresses mutant channel INaL and protects cells from delayed repolarization. These findings offer a plausible explanation for the lower arrhythmia risk in LQT3 subjects during fast heart rates. PMID- 26022186 TI - Electroanatomical voltage and morphology characteristics in postinfarction patients undergoing ventricular tachycardia ablation: pragmatic approach favoring late potentials abolition. AB - BACKGROUND: Catheter ablation is an important therapeutic option in postmyocardial infarction patients with ventricular tachycardia (VT). We analyzed the endo-epicardial electroanatomical mapping (EAM) voltage and morphology characteristics, their association with clinical data and their prognostic value in a large cohort of postmyocardial infarction patients. METHODS AND RESULTS: We performed total and segmental analysis of voltage (bipolar dense scar [DS] and low voltage areas, unipolar low voltage and penumbra areas) and morphology characteristics (presence of abnormal late potentials [LPs] and early potentials [EPs]) in 100 postmyocardial infarction patients undergoing electroanatomical mapping-based VT ablation (26 endo-epicardial procedures) from 2010-2012. All patients had unipolar low voltage areas, whereas 18% had no identifiable endocardial bipolar DS areas. Endocardial bipolar DS area >22.5 cm(2) best predicted scar transmurality. Endo-epicardial LPs were recorded in 2/3 patients, more frequently in nonseptal myocardial segments and were abolished in 51%. Endocardial bipolar DS area >7 cm(2) and endocardial bipolar scar density >0.35 predicted epicardial LPs. Isolated LPs are located mainly epicardially and EPs endocardially. As a primary strategy, LPs and VT-mapping ablation occurred in 48%, only VT-mapping ablation in 27%, only LPs ablation in 17%, and EPs ablation in 6%. Endocardial LP abolition was associated with reduced VT recurrence and increased unipolar penumbra area predicted cardiac death. CONCLUSIONS: Endocardial scar extension and density predict scar transmurality and endo epicardial presence of LPs, although DS is not always identified in postmyocardial infarction patients. LPs, most frequently located in nonseptal myocardial segments, were abolished in 51% resulting in improved outcome. PMID- 26022187 TI - Playing doctor: Simulation in medical school as affective practice. AB - Simulated patient encounters, in which a trained layperson role-plays a patient, have become increasingly important in medical education. One such type is the gynecological teaching associate (GTA), who teaches medical students how to perform the pelvic examination using her own body. This paper considers the role that simulation like the GTA session plays in medical students' professional socialization. Drawn from interviews and archival sources gathered from medical students, medical faculty, and GTAs, this paper explores the tensions between artificiality and authenticity in order to understand how, through pedagogical practice, medical students come to embody medical culture through simulation. This paper uses the theoretical framework of the medical habitus to understand the role of emotion in medical student socialization. It argues that simulation is an example of affective practice: any rehearsal of techniques or styles of expressing, experiencing, or managing emotion that reshape the body's capacity to feel. PMID- 26022188 TI - Ultrasound-guided synovial biopsy: a systematic review according to the OMERACT filter and recommendations for minimal reporting standards in clinical studies. AB - OBJECTIVES: To describe existing techniques of US-guided synovial biopsy (USG-SB) and critically appraise the literature on this technology through the OMERACT filter. METHODS: USG-SB techniques are described and compared. A systematic literature search of PubMed and Embase was performed for original research reports including US and SB. The subjects, procedure protocols and reported results were analysed. A future research agenda is proposed. RESULTS: USG-SB can be performed using a portal-and-forceps or a dedicated semi-automatic guillotine type biopsy needle approach. Of 50 reports identified, 7 were included in the review. Large, intermediate and small joints were all amenable to USG-SB. We found great heterogeneity with regard to indications for and definition of a successful procedure and of synovitis. Adverse events were assessed in most papers with an overall major complication rate of 0.4%. However, there was a lack of construct validity using a histological comparator. Relatively few papers reported details on the technique used, tissue processing, synovitis scoring and blinding for tissue analysis. CONCLUSION: USG-SB can be regarded as a valuable tool for large-scale synovial tissue sampling. Standardization of the techniques of USG-SB and tissue processing is needed. Future research should focus on the reliability, responsiveness and feasibility of this procedure in prospective studies. PMID- 26022189 TI - Projectile haemorrhage of a brachial artery in a patient with clinically amyopathic dermatomyositis. PMID- 26022190 TI - Clinical massively parallel sequencing for the diagnosis of myopathies. AB - Massively parallel sequencing, otherwise known as high-throughput or next generation sequencing, is rapidly gaining wide use in clinical practice due to possibility of simultaneous exploration of multiple genomic regions. More than 300 genes have been implicated in neuromuscular disorders, meaning that many genes need to be considered in a differential diagnosis for a patient affected with myopathy. By providing sequencing information for numerous genes at the same time, massively parallel sequencing greatly accelerates the diagnostic processes of myopathies compared to the classical "gene-after-gene" approach by Sanger sequencing. In this review, we describe multiple advantages of this powerful sequencing method for applications in myopathy diagnosis. We also outline recent studies that used this approach to discover new myopathy-causing genes and to diagnose cohorts of patients with muscular disorders. Finally, we highlight the key aspects and limitations of massively parallel sequencing that a neurologist considering this test needs to know in order to interpret the results of the test and to deal with other issues concerning the test. PMID- 26022191 TI - Mortality among US-born and immigrant Hispanics in the US: effects of nativity, duration of residence, and age at immigration. AB - OBJECTIVES: We examined the effects of duration of residence and age at immigration on mortality among US-born and foreign-born Hispanics aged 25 and older. METHODS: We analyzed the National Health Interview Survey-National Death Index linked files from 1997-2009 with mortality follow-up through 2011. We used Cox proportional hazard models to examine the effects of duration of US residence and age at immigration on mortality for US-born and foreign-born Hispanics, controlling for various demographic, socioeconomic and health factors. Age at immigration included 4 age groups: <18, 18-24, 25-34, and 35+ years. Duration of residence was 0-15 and >15 years. RESULTS: We observed a mortality advantage among Hispanic immigrants compared to US-born Hispanics only for those who had come to the US after age 24 regardless of how long they had lived in the US. Hispanics who immigrated as youths (<18) did not differ from US-born Hispanics on mortality despite duration of residence. CONCLUSIONS: Findings suggest that age at immigration, rather than duration of residence, drives differences in mortality between Hispanic immigrants and the US-born Hispanic population. PMID- 26022192 TI - Deprivation and suicide mortality across 424 neighborhoods in Seoul, South Korea: a Bayesian spatial analysis. AB - OBJECTIVES: A neighborhood-level analysis of mortality from suicide would be informative in developing targeted approaches to reducing suicide. This study aims to examine the association of community characteristics with suicide in the 424 neighborhoods of Seoul, South Korea. METHODS: Neighborhood-level mortality and population data (2005-2011) were obtained to calculate age-standardized suicide rates. Eight community characteristics and their associated deprivation index were employed as determinants of suicide rates. The Bayesian hierarchical model with mixed effects for neighborhoods was used to fit age-standardized suicide rates and other covariates with consideration of spatial correlations. RESULTS: Suicide rates for 424 neighborhoods were between 7.32 and 71.09 per 100,000. Ninety-nine percent of 424 neighborhoods recorded greater suicide rates than the Organization for Economic Cooperation and Development member countries' average. A stepwise relationship between area deprivation and suicide was found. Neighborhood-level indicators for lack of social support (residents living alone and the divorced or separated) and socioeconomic disadvantages (low educational attainment) were positively associated with suicide mortality after controlling for other covariates. CONCLUSIONS: Finding from this study could be used to identify priority areas and to develop community-based programs for preventing suicide in Seoul, South Korea. PMID- 26022193 TI - Comparability of Icare Pro Rebound Tonometer with Goldmann Applanation and Noncontact Tonometer in a Wide Range of Intraocular Pressure and Central Corneal Thickness. AB - PURPOSE: To evaluate the agreement between the reading values of the Goldmann applanation tonometer (GAT), Icare Pro rebound tonometer (IRT) and noncontact tonometer (NCT) in glaucoma patients. METHODS: This cross-sectional study comprised 292 eyes of 292 patients selected from a glaucoma outpatient clinic. The intraocular pressure (IOP) was measured sequentially, at a 10-min interval each, in the following order: NCT, IRT and GAT. The central corneal thickness (CCT) was measured using Pentacam HR before the IOP measurements. RESULTS: The mean IOPs measured by the GAT, NCT and IRT were 20.17 +/- 6.73 mm Hg (range: 4 48), 19.77 +/- 6.88 mm Hg (range: 3-46) and 19.30 +/- 5.15 mm Hg (range: 7.30 44.5), respectively. The correlation coefficients of the GAT and IRT, NCT and IRT, and GAT and NCT measurements were r(2) = 0.673, r(2) = 0.663 and r(2) = 0.938 (all p < 0.001), respectively. The IRT tends to overestimate in the low GAT measured IOPs, whereas it underestimates in high GAT-measured IOPs. The measurements of all 3 devices were also correlated with the CCT at a statistically significant level (GAT: r(2) = 0.063, NCT: r(2) = 0.063, IRT: r(2) = 0.058). CONCLUSION: The agreement between the IRT and GAT measurements is higher in the IOP range of 9-22 mm Hg, whereas significant discrepancies occur as the IOP deviates from normal values. The variability of the IRT and GAT measurements over a wide range of CCT is minimal. PMID- 26022194 TI - Transnational cocaine and heroin flow networks in western Europe: A comparison. AB - BACKGROUND: A comparison of the properties of drug flow networks for cocaine and heroin in a group of 17 western European countries is provided with the aim of understanding the implications of their similarities and differences for drug policy. METHODS: Drug flow data for the cocaine and heroin networks were analyzed using the UCINET software package. Country-level characteristics including hub and authority scores, core and periphery membership, and centrality, and network level characteristics including network density, the results of a triad census, and the final fitness of the core-periphery structure of the network, were computed and compared between the two networks. RESULTS: The cocaine network contains fewer path redundancies and a smaller, more tightly knit core than the heroin network. Authorities, hubs and countries central to the cocaine network tend to have higher hub, authority, and centrality scores than those in the heroin network. The core-periphery and hub-authority structures of the cocaine and heroin networks reflect the west-to-east and east-to-west patterns of flow of cocaine and heroin respectively across Europe. The key nodes in the cocaine and heroin networks are generally distinct from one another. CONCLUSION: The analysis of drug flow networks can reveal important structural features of trafficking networks that can be useful for the allocation of scarce drug control resources. The identification of authorities, hubs, network cores, and network-central nodes can suggest foci for the allocation of these resources. In the case of Europe, while some countries are important to both cocaine and heroin networks, different sets of countries occupy positions of prominence in the two networks. The distinct nature of the cocaine and heroin networks also suggests that a one-size fits-all supply- and interdiction-focused policy may not work as well as an approach that takes into account the particular characteristics of each network. PMID- 26022195 TI - Randomized Controlled Trial Comparing the Effects of Vessel Sealing Device and Milligan Morgan Technique on Postoperative Pain Perception after Hemorrhoidectomy. AB - BACKGROUND: The aim of this study was to compare postoperative pain perception after Milligan Morgan and LigasureTM techniques in hemorrhoidectomy. METHODS: Fifty-four patients diagnosed with Grade 3-4 hemorrhoids requiring surgery between May 2013 and September 2013 were enrolled in the study. Patients were randomized into either the LigasureTM hemorrhoidectomy group (Group 1, n = 26) or the Milligan Morgan hemorrhoidectomy group (Group 2, n = 28). RESULTS: The difference between visual analogue scale scores on postoperative day 1 was not statistically significant but on the third postoperative day, the LigasureTM group had higher visual analogue scale scores (4 +/- 2.61) when compared to the Milligan Morgan hemorrhoidectomy group (2.43 +/- 1.20). This difference on the third postoperative day visual analogue scale scores was statistically significant (p < 0.025). CONCLUSIONS: LigasureTM does not seem to have an advantage in postoperative pain when compared to Milligan Morgan hemorrhoidectomy. PMID- 26022197 TI - Mouse lung slices: An ex vivo model for the evaluation of antiviral and anti inflammatory agents against influenza viruses. AB - The influenza A virus is notoriously known for its ability to cause recurrent epidemics and global pandemics. Antiviral therapy is effective when treatment is initiated within 48h of symptom onset, and delaying treatment beyond this time frame is associated with decreased efficacy. Research on anti-inflammatory therapy to ameliorate influenza-induced inflammation is currently underway and seems important to the impact on the clinical outcome. Both antiviral and anti inflammatory drugs with novel mechanisms of action are urgently needed. Current methods for evaluating the efficacy of anti-influenza drugs rely mostly on transformed cells and animals. Transformed cell models are distantly related to physiological and pathological conditions. Although animals are the best choices for preclinical drug testing, they are not time- or cost-efficient. In this study, we established an ex vivo model using mouse lung slices to evaluate both antiviral and anti-inflammatory agents against influenza virus infection. Both influenza virus PR8 (H1N1) and A/Human/Hubei/3/2005 (H3N2) can replicate efficiently in mouse lung slices and trigger significant cytokine and chemokine responses. The induction of selected cytokines and chemokines were found to have a positive correlation between ex vivo and in vivo experiments, suggesting that the ex vivo cultured lung slices may closely resemble the lung functionally in an in vivo configuration when challenged by influenza virus. Furthermore, a set of agents with known antiviral and/or anti-inflammatory activities were tested to validate the ex vivo model. Our results suggested that mouse lung slices provide a robust, convenient and cost-efficient model for the assessment of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. This ex vivo model may predict the efficacy of drug candidates' antiviral and anti-inflammatory activities in vivo. PMID- 26022196 TI - Vitamin D-update for the pediatric rheumatologists. AB - Vitamin D, upon its discovery one century ago, was classified as a vitamin. This classification still greatly affects our perception about its biological role. 1,25(OH)2D (now known as the D hormone) is a pleiotropic steroid hormone that has multiple biologic effects. It is integral to the regulation of calcium homeostasis and bone turnover as well as having anti-proliferative, pro differentiation, anti-bacterial, immunomodulatory and anti-inflammatory properties within the body in various cells and tissues. Vitamin D (cholecalciferol) should be considered a nutritional substrate that must be ingested or synthesized in sufficient amounts for the further synthesis of the very important regulatory steroid hormone (D hormone), especially in patients with pediatric rheumatic diseases (PRD). Vitamin D insufficiency or deficiency was shown to be pandemic and associated with numerous chronic inflammatory and malignant diseases and even with increased risk of mortality. Several studies have demonstrated that a high percentage of children with pediatric rheumatic diseases (PRD-e.g., JIA, jSLE) have a vitamin D deficiency or insufficiency which might correlate with disease outcome and flares. Glucocorticoids used to treat disease may have a regulatory effect on vitamin D metabolism which can additionally aggravate bone turnover in PRD. An effort to define the optimal serum 25(OH)D concentrations for healthy children and adults was launched in 2010 but as of now there are no guidelines about supplementation in PRD. In this review we have tried to summarize the strong evidence now suggesting that as the knowledge of the optimal approach to diagnosis and treatment PRD has evolved, there is also an emerging need for vitamin D supplementation as an adjunct to regular disease treatment. So in accordance with new vitamin D recommendations, we recommend that a child with rheumatic disease, especially if treated with steroids, needs at least 2-3 time higher doses of vitamin D than the dose recommended for age (approximately 2000 UI/day). Vitamin D supplementation has become an appealing and important adjunct treatment option in PRD. PMID- 26022198 TI - Meeting report: First International Conference on Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is the most widespread tick-borne disease of humans, occurring from western China to the Balkans in Eurasia and south throughout the length of Africa. Its incidence has increased over the past decade, particularly in Turkey and Iran, and the disease has also emerged in India. Research has been hindered by limited laboratory capacity in many regions where the disease is prevalent, indicating the need for collaboration between investigators in endemic countries and those with greater scientific resources. In an effort to increase such collaboration, the First International Conference on Crimean-Congo hemorrhagic fever was held in Thessaloniki, Greece, from February 13 to 14, 2015. This meeting followed the conclusion of an EU-supported Collaborative Project under the Health Cooperation Work Programme of the 7th Framework Programme (Grant agreement No. 260427). It is expected to be the first in a series of meetings that will bring together researchers from around the world to exchange knowledge and experience on various aspects of CCHF. This report summarizes major presentations by the invited speakers at the First International Conference on CCHF. PMID- 26022199 TI - Evaluation of a dry powder delivery system for laninamivir in a ferret model of influenza infection. AB - Laninamivir is a long-acting antiviral requiring only a single dose for the treatment of influenza infection, making it an attractive alternative to existing neuraminidase inhibitors that require multiple doses over many days. Like zanamivir, laninamivir is administered to patients by inhalation of dry powder. To date, studies investigating the effectiveness of laninamivir or zanamivir in a ferret model of influenza infection have administered the drug in a solubilised form. To better mimic the delivery action of laninamivir in humans, we assessed the applicability of a Dry Powder InsufflatorTM (DPI) as a delivery method for laninamivir octanoate (LO) in ferrets to determine the effectiveness of this drug in reducing influenza A and B virus infections. In vitro characterisation of the DPI showed that both the small particle sized LO (0.7-6.0MUm diameter) and the large particle sized lactose carrier (20-100MUm diameter) were effectively discharged. However, LO delivered to ferrets via the DPI prior to infection with either A(H1N1)pdm09 or B viruses had a limited effect on nasal inflammation, clinical symptoms and viral shedding compared to placebo. Our preliminary findings indicate the feasibility of administering powder drugs into ferrets, but a better understanding of the pharmacokinetics and pharmacodynamics of LO in ferrets following delivery by the DPI is warranted prior to further studies. PMID- 26022200 TI - Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells. AB - Antiviral medication is used for the treatment of severe influenza infections, of which the neuraminidase inhibitors (NAIs) are the most effective drugs, approved so far. Here, we investigated the antiviral efficacy of the peptidomimetic furin inhibitor MI-701 in combination with oseltamivir carboxylate and ribavirin against the infection of highly pathogenic avian influenza viruses (HPAIV) that are activated by the host protease furin. Cell cultures infected with the strains A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Rostock/1934 (H7N1) were treated with each agent alone, or in double and triple combinations. MI-701 alone achieved a concentration-dependent reduction of virus propagation. Double treatment of MI 701 with oseltamivir carboxylate and triple combination with ribavirin showed synergistic inhibition and a pronounced delay of virus propagation. MI-701 resistant mutants were not observed. Emergence of NA mutation H275Y conferring high oseltamivir resistance was significantly delayed in the presence of MI-701. Our data indicate that combination with a potent furin inhibitor significantly enhances the therapeutic efficacy of conventional antivirals drugs against HPAIV infection. PMID- 26022201 TI - Nano-mechanical behaviour of lithium metasilicate glass-ceramic. AB - This paper reports the first study on the mechanical behavior of lithium metasilicate glass-ceramic using nanoindentation and in situ scanning probe imaging techniques. Indentation contact hardness, Hc, and Young's modulus, E, were measured at 10 mN peak load and 0.1-2 mN/s loading rates to understand the loading rate effect on its properties. Indentation imprints were analysed with the in situ scanning probe imaging to understand indentation mechanisms. The average contact hardness increased by 112% with the loading rate (ANOVA, p<0.05) while the Young's modulus showed the loading rate independence (ANOVA, p>0.05). A strain rate sensitivity model was applied to determine the intrinsic contact hardness. Extensive discontinuities and largest maximum, contact and final depths were also observed at the lowest loading rate. These phenomena corresponded to inhomogeneous shear-band flow and densification leading to the material strain softening. The in situ scanning probe images of indentation imprints showed plastic deformation at all loading rates and shear band-induced pileups at the lowest loading rate. With the increase in loading rate, the induced pile-ups decreased. The continuum model predicted the largest densified shear zone at the lowest loading rate. Finally, these results provide scientific insights into the abrasive machining responses of lithium metasilicate glass-ceramic during dental CAD/CAM processes using sharp diamond abrasives. PMID- 26022202 TI - Evaluation of trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid accumulation in low-grade glioma in chemically induced rat models: PET and autoradiography compared with morphological images and histopathological findings. AB - INTRODUCTION: Magnetic resonance imaging (MRI) can have a problem to delineate diffuse gliomas with an intact blood-brain barrier (BBB) especially when a marked peritumoral edema is present. We evaluated the potential of trans-1-amino-3-(18)F fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) positron emission tomography (PET) to delineate the extent of diffuse gliomas by comparing PET findings with autoradiography, in vivo and ex vivo MRI, and histopathology findings. METHODS: Dynamic PET was performed in rats with N-ethyl-N-nitrosourea-induced glioma for 60 min after anti-(18)F-FACBC injection. Contrast-enhanced MRI was performed before or after PET. The PET images were fused with in vivo and ex vivo MR images, and histopathological images for direct comparisons. Autoradiograms were compared with the results of Evans Blue (EB) extravasation (to assess BBB integrity) and hematoxylin-eosin staining. RESULTS: Histopathological examination, including EB extravasation assessment, and enhanced T1-weighted MRI identified several diffuse gliomas with slight BBB disruption, similar to low grade human gliomas. Anti-(18)F-FACBC uptake was specific and high in the gliomas, irrespective of BBB integrity. Higher anti-(18)F-FACBC uptake corresponded to areas of T2 hyperintensity, independent of gadolinium enhancement. Ex vivo autoradiography also showed high anti-(18)F-FACBC accumulation in tumors lacking EB extravasation and a correlation between anti (18)F-FACBC accumulation and tumor cell density, but not EB extravasation. CONCLUSIONS: Anti-(18)F-FACBC-PET allowed visualization of gliomas irrespective of BBB integrity. The tumor-to-normal uptake ratio of anti-(18)F-FACBC generally correlated with the relative cell density. Anti-(18)F-FACBC PET combined with MRI shows promise for preoperative glioma delineation. ADVANCES IN KNOWLEDGE: Radiopharmaceuticals that cross the BBB, such as anti-(18)F-FACBC, are taken up by low-grade gliomas with equivocal MRI findings due to an intact BBB. IMPLICATIONS FOR PATIENT CARE: Surgery is the first-line therapy for low-grade gliomas; therefore, delineation of their extent in the presence of an intact BBB is essential to planning surgery that removes the entire neoplasm, which will positively affect long-term survival. PMID- 26022203 TI - Asymptotic accuracy of Bayesian estimation for a single latent variable. AB - In data science and machine learning, hierarchical parametric models, such as mixture models, are often used. They contain two kinds of variables: observable variables, which represent the parts of the data that can be directly measured, and latent variables, which represent the underlying processes that generate the data. Although there has been an increase in research on the estimation accuracy for observable variables, the theoretical analysis of estimating latent variables has not been thoroughly investigated. In a previous study, we determined the accuracy of a Bayes estimation for the joint probability of the latent variables in a dataset, and we proved that the Bayes method is asymptotically more accurate than the maximum-likelihood method. However, the accuracy of the Bayes estimation for a single latent variable remains unknown. In the present paper, we derive the asymptotic expansions of the error functions, which are defined by the Kullback Leibler divergence, for two types of single-variable estimations when the statistical regularity is satisfied. Our results indicate that the accuracies of the Bayes and maximum-likelihood methods are asymptotically equivalent and clarify that the Bayes method is only advantageous for multivariable estimations. PMID- 26022205 TI - Need for Antibiotic Prophylaxis for Pseudophakic Endophthalmitis. PMID- 26022204 TI - HER2/neu-directed therapy for biliary tract cancer. AB - BACKGROUND: Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown. PATIENTS AND METHODS: We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed. RESULTS: Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3 TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy. CONCLUSIONS: HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study. PMID- 26022206 TI - Knowingly repeating an incorrect and inefficient analysis is flawed logic. PMID- 26022207 TI - Reply to Collins and Le Manach. PMID- 26022208 TI - Effect of Ambient Temperature Variations on Positivity of Manual Fecal Immunochemical Tests. AB - INTRODUCTION: In the United States, many fecal occult blood tests are mailed by patients to a laboratory for analysis. Hemoglobin is not stable in feces and can be affected by the heat. Effects of season and ambient temperature on fecal immunochemical tests (FITs) have demonstrated a decrease in positivity rates during the hottest season. OBJECTIVE: To investigate the potential effect of the average of 4-day ambient maximum temperature variations on the positivity of a single sample, one-time Clinical Laboratory Improvement Amendments (CLIA)-waived FIT. SETTING: Midwestern tertiary care hospital. METHODS: Individuals scheduled for a colonoscopy were invited to complete a qualitative FIT prior to their colonoscopy in 2010 and 2011. FITs were read as positive or negative. RESULTS: Valid FITs were received from 1026 individuals over 25 months. The positivity rate was 10.9%. The mean 4-day average of daily maximum ambient temperatures was calculated including the day of receipt for each sample. Fahrenheit temperatures ranged from 16.0 to 96.8. Based on the odds ratio of 1.04 with a confidence interval of 0.94 to 1.14 for a 10 degrees F increase in temperature, there was no statistically significant evidence of an effect of the preceding maximum average 4-day ambient temperature on FIT positivity. CONCLUSION: No evidence was found that ambient temperature had an effect on positivity rate over a 25-month period using 4 different qualitative FIT products. Further analysis on effect of ambient temperatures is warranted for the automated FITs and CLIA-waived FITs, including liquid-vial and dry-slide FITs. Primary care providers need to be aware of potential adverse effects of FITs. PMID- 26022209 TI - Ventricular and vascular stiffening in aging and hypertension. AB - The assessment of arterial stiffness, a common feature of aging, exacerbated by pathological conditions like hypertension, has become an attractive tool for identifying structural and functional changes of the arteries even in an early stage of the atherosclerotic disease. Arterial stiffness has been recognized as an important physio-pathological determinant for the age-related rise in systolic blood pressure, demonstrating also an independent predictive value for cardiovascular events. In the recent decades, many techniques and indices to evaluate vascular stiffness have been developed and extensive data concerning their prognostic value have been collected. Moreover, it has become clear that vessel and heart must be considered as a unique system, in which combined stiffness of vessel and heart interacts to limit cardiovascular performance. In this review, main methods and indices used to estimate arterial and ventricular stiffness are presented, focusing on their alteration in physiological aging and arterial hypertension. Furthermore, the concept of ventricular-arterial coupling is explained in order to give an insight to the interplay between arterial and ventricular stiffness in aging and hypertension. PMID- 26022210 TI - Oxidative stress and antioxidants in hypertension-a current review. AB - Free radicals or reactive oxygen species (ROS) are generated by oxygen metabolism which is balanced by the rate of oxidant formation and the rate of oxidant elimination. Oxidative stress is a result of imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defence systems. Hypertension is one of the major risk factors for cardiovascular diseases and is considered as a leading cause of mortality and morbidity. These diseases affect more than 600 million people and it has been estimated that 29% of the world population will be suffering from hypertension by 2025. It has been indicated by experimental evidence that reactive oxygen species (ROS) play an important role in the pathophysiology of hypertension. The vasculature is a rich source of NADPH oxidase which produces most of the reactive oxygen species and plays an important role in renal dysfunction and vascular damage. Recent studies indicate that increased oxidative stress is the important mediator of endothelial injury in the pathology of hypertension associated to increased production of pro oxidants such as superoxideanion hydrogen peroxide, reduced nitric oxide synthesis and decreased bioavailability of antioxidants. Oxidative stress is found to be associated with endothelial dysfunction, inflammation, hypertrophy, apoptosis, cell migration, fibrosis, and angiogenesis in relation to vascular remodelling of hypertension. Results in humans are still less conclusive inspite of data available that involve oxidative stress as a causative factor of essential hypertension. The aim of this review is to present a novel focus on the role of oxidative stress in the pathophysiology of hypertension and recent biomarkers which are found to be associated with reactive oxygen species and the role of antioxidants as therapy of hypertension. PMID- 26022212 TI - Abstracts of the 16th International Congress of ESCAP European Society for Child and Adolescent Psychiatry. PMID- 26022211 TI - The involvement of uric acid in the pathogenesis of preeclampsia. AB - Preeclampsia is a common disorder of human pregnancy and a major cause of worldwide pregnancy-related maternal and neonatal morbidity and mortality. Oxidative stress, angiogenic imbalance, placental ischemia and an inflammatory response have been proposed to play role in the pathogenesis of the disease. Hyperuricemia is a key biochemical feature in preeclampsia with elevated levels of uric acid being diagnosed as early as the 10(th) week of gestation. Traditionally, elevated uric acid levels were considered a result of renal dysfunction known to exist in preeclampsia. The contribution of uric acid in the pathogenesis of preeclampsia is being recently further investigated. We, hereby, review the possible mechanisms by which uric acid contributes to the development of the disease and its complications both on mother and fetus. PMID- 26022213 TI - A New Interleukin-13 Amino-Coated Gadolinium Metallofullerene Nanoparticle for Targeted MRI Detection of Glioblastoma Tumor Cells. AB - The development of new nanoparticles as next-generation diagnostic and therapeutic ("theranostic") drug platforms is an active area of both chemistry and cancer research. Although numerous gadolinium (Gd) containing metallofullerenes as diagnostic magnetic resonance imaging (MRI) contrast agents have been reported, the metallofullerene cage surface, in most cases, consists of negatively charged carboxyl or hydroxyl groups that limit attractive forces with the cellular surface. It has been reported that nanoparticles with a positive charge will bind more efficiently to negatively charged phospholipid bilayer cellular surfaces, and will more readily undergo endocytosis. In this paper, we report the preparation of a new functionalized trimetallic nitride template endohedral metallofullerene (TNT EMF), Gd3N@C80(OH)x(NH2)y, with a cage surface bearing positively charged amino groups (-NH3(+)) and directly compare it with a similar carboxyl and hydroxyl functionalized derivative. This new nanoparticle was characterized by X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), and infrared spectroscopy. It exhibits excellent (1)H MR relaxivity. Previous studies have clearly demonstrated that the cytokine interleukin-13 (IL-13) effectively targets glioblastoma multiforme (GBM) cells, which are known to overexpress IL-13Ralpha2. We also report that this amino coated Gd-nanoplatform, when subsequently conjugated with interleukin-13 peptide IL-13-Gd3N@C80(OH)x(NH2)y, exhibits enhanced targeting of U-251 GBM cell lines and can be effectively delivered intravenously in an orthotopic GBM mouse model. PMID- 26022215 TI - A nanoliter self-priming compartmentalization chip for point-of-care digital PCR analysis. AB - A nanoliter self-priming compartmentalization (SPC) microfluidic chip suited for the digital polymerase chain reaction (dPCR) analysis in point-of-care testing (POCT) has been developed. This dPCR chip is fabricated of polydimethylsiloxane (PDMS). After the dPCR chip is evacuated, there will be a negative pressure environment in the chip because of the gas solubility of PDMS. The negative pressure environment can provide a self-priming power so that the sample solutions can be sucked into each reaction chamber sequentially. The whole sampling process requires no external power and is valve-free. Channels that contain water are designed around each sample panel to prevent the solvent (water) from evaporating during dPCR process. A glass coverslip is also used as a waterproof layer, which is more convenient and more efficient than other waterproof methods seen in literature. This dPCR chip allows three samples to be amplified at the same time. Each sample is distributed into 1040 reaction chambers, and each chamber is only 2.08 nL. Human beta-actin DNA solutions of known concentrations are used as the templates for the dPCR analyses to verify the sensitivity and accuracy of the method. Template DNA solutions diluted to concentrations of 300, 100 and 10 copies/MUL are tested and shown that this simple, portable and self-priming dPCR chip can be used at any clinic as a real POCT technique. PMID- 26022214 TI - Improvement of antioxidant status after Brazil nut intake in hypertensive and dyslipidemic subjects. AB - OBJECTIVES: To investigate the effect of partially defatted Granulated Brazil nut (GBN) on biomarkers of oxidative stress and antioxidant status of hypertensive and dyslipidemic patients on nutrition and drug approaches. METHODS: Ninety one hypertensive and dyslipidemic subjects of both genders (51.6 % men), mean age 62.1 +/- 9.3 years, performed a randomized crossover trial, double-blind, placebo controlled. Subjects received a diet and partially defatted GBN 13 g per day (~227.5 MUg/day of selenium) or placebo for twelve weeks with four-week washout interval. Anthropometric, laboratory and clinic characteristics were investigated at baseline. Plasma selenium (Se), plasma glutathione peroxidase (GPx3) activity, total antioxidant capacity (TAC), 8-epi PGF2alpha and oxidized LDL were evaluated at the beginning and in the end of each intervention. RESULTS: GBN intake significantly increased plasma Se from 87.0 +/- 16.8 to 180.6 +/- 67.1 MUg/L, increased GPx3 activity in 24,8% (from 112.66 +/- 40.09 to 128.32 +/- 38.31 nmol/min/mL, p < 0,05), and reduced 3.25% of oxidized-LDL levels (from 66.31 +/- 23.59 to 60.68 +/- 20.88 U/L, p < 0.05). An inverse association between GPx3 and oxidized LDL levels was observed after supplementation with GBN by simple model (beta -0.232, p = 0.032) and after adjustment for gender, age, diabetes and BMI (beta -0.298, p = 0.008). There wasn't association between GPx3 and 8-epi PGF2alpha (beta -0.209, p = 0.052) by simple model. CONCLUSION: The partially defatted GBN intake has a potential benefit to increase plasma selenium, increase enzymatic antioxidant activity of GPx3 and to reduction oxidation in LDL in hypertensive and dyslipidemic patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01990391; November 20, 2013. PMID- 26022218 TI - Membership spotlight. PMID- 26022216 TI - The proteome of Hypobaric Induced Hypoxic Lung: Insights from Temporal Proteomic Profiling for Biomarker Discovery. AB - Exposure to high altitude induces physiological responses due to hypoxia. Lungs being at the first level to face the alterations in oxygen levels are critical to counter and balance these changes. Studies have been done analysing pulmonary proteome alterations in response to exposure to hypobaric hypoxia. However, such studies have reported the alterations at specific time points and do not reflect the gradual proteomic changes. These studies also identify the various biochemical pathways and responses induced after immediate exposure and the resolution of these effects in challenge to hypobaric hypoxia. In the present study, using 2-DE/MS approach, we attempt to resolve these shortcomings by analysing the proteome alterations in lungs in response to different durations of exposure to hypobaric hypoxia. Our study thus highlights the gradual and dynamic changes in pulmonary proteome following hypobaric hypoxia. For the first time, we also report the possible consideration of SULT1A1, as a biomarker for the diagnosis of high altitude pulmonary edema (HAPE). Higher SULT1A1 levels were observed in rats as well as in humans exposed to high altitude, when compared to sea-level controls. This study can thus form the basis for identifying biomarkers for diagnostic and prognostic purposes in responses to hypobaric hypoxia. PMID- 26022217 TI - Linear synthesis and immunological properties of a fully synthetic vaccine candidate containing a sialylated MUC1 glycopeptide. AB - A strategy for the linear synthesis of a sialylated glycolipopeptide cancer vaccine candidate has been developed using a strategically designed sialyl-Tn building block and microwave-assisted solid-phase peptide synthesis. The glycolipopeptide elicited potent humoral and cellular immune responses. T-cells primed by such a vaccine candidate could be restimulated by tumor-associated MUC1. PMID- 26022219 TI - Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review. AB - BACKGROUND: Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects. METHODS: MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol. RESULTS: There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg). CONCLUSIONS: Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise. PMID- 26022220 TI - Adverse symptoms with anti-TNF-alpha therapy in inflammatory bowel disease: systematic review and duration-response meta-analysis. AB - BACKGROUND: Anti-tumor necrosis factor-alpha (TNF-alpha) agents have considerable advances in treating inflammatory bowel disease (IBD). These drugs carry possible risk of adverse symptoms, and no meta-analysis has examined this issue and the potential duration-response relationship. PURPOSE: The purpose of this study was to assess duration-response relationship between anti-TNF-alpha agents and risk of adverse symptoms from all available randomized control trials (RCTs) with placebo arms in IBD. METHODS: PubMed, OVID, and Cochrane Library were searched to January 2015. The RCTs comparing anti-TNF-alpha therapy with placebo in adults with IBD were eligible. We estimated pooled relative risks (RRs) of adverse symptoms for anti-TNF-alpha therapy and examined both non-linear and linear duration-response relations between therapy duration and significant related adverse symptoms. RESULTS: Twenty-three RCTs with 7325 patients were included. Adverse symptoms of headache, nausea/vomit, abdominal pain, fever, and arthralgia showed no significant relationship with anti-TNF-alpha therapy, respectively. Fatigue was significantly associated with anti-TNF-alpha therapy (RR 1.35, 95% confidence interval (CI) 1.01-1.81), and subgroup analysis indicated that long therapy duration (>30 weeks) and combination without azathioprine (AZA) were two risk factors for the occurrence of fatigue (RR 1.74, 95% CI 1.03-2.93; RR 1.65, 95% CI 1.13-2.40). In the trials without AZA combination, there was a linear duration-response relationship between therapy duration and risk of fatigue (P = 0.0217), and duration of 35 weeks increased the risk of fatigue by 50%. CONCLUSION: This meta-analysis suggested a promotive effect of anti-TNF-alpha therapy to the occurrence of fatigue, and for the anti-TNF-alpha therapy without AZA combination, a linear duration-response relationship existed between therapy duration and risk of fatigue. PMID- 26022222 TI - Diagnosis and treatment of cancer using genomics. AB - The field of cancer diagnostics is in constant flux as a result of the rapid discovery of new genes associated with cancer, improvements in laboratory techniques for identifying disease causing events, and novel analytic methods that enable the integration of many different types of data. These advances have helped in the identification of novel, informative biomarkers. As more whole genome sequence data are generated and analyzed, emerging information on the baseline variability of the human genome has shown the importance of the ancestral genomic background in patients with a potential disease causing variant. The recent discovery of many novel DNA sequence variants, advances in sequencing and genomic technology, and improved analytic methods enable the impact of germline and somatic genome variation on tumorigenesis and metastasis to be determined. New molecular targets and companion diagnostics are changing the way geneticists and oncologists think about the causes, diagnosis, and treatment of cancer. PMID- 26022221 TI - Phlebotomus papatasi SP15: mRNA expression variability and amino acid sequence polymorphisms of field populations. AB - BACKGROUND: The Phlebotomus papatasi salivary protein PpSP15 was shown to protect mice against Leishmania major, suggesting that incorporation of salivary molecules in multi-component vaccines may be a viable strategy for anti Leishmania vaccines. METHODS: Here, we investigated PpSP15 predicted amino acid sequence variability and mRNA profile of P. papatasi field populations from the Middle East. In addition, predicted MHC class II T-cell epitopes were obtained and compared to areas of amino acid sequence variability within the secreted protein. RESULTS: The analysis of PpSP15 expression from field populations revealed significant intra- and interpopulation variation.. In spite of the variability detected for P. papatasi populations, common epitopes for MHC class II binding are still present and may potentially be used to boost the response against Le. major infections. CONCLUSIONS: Conserved epitopes of PpSP15 could potentially be used in the development of a salivary gland antigen-based vaccine. PMID- 26022224 TI - Necking and notch strengthening in metallic glass with symmetric sharp-and-deep notches. AB - Notched metallic glasses (MGs) have received much attention recently due to their intriguing mechanical properties compared to their unnotched counterparts, but so far no fundamental understanding of the correlation between failure behavior and notch depth/sharpness exists. Using molecular dynamics simulations, we report necking and large notch strengthening in MGs with symmetric sharp-and-deep notches. Our work reveals that the failure mode and strength of notched MGs are strongly dependent on the notch depth and notch sharpness. By increasing the notch depth and the notch sharpness, we observe a failure mode transition from shear banding to necking, and also a large notch strengthening. This necking is found to be caused by the combined effects of large stress gradient at the notch roots and the impingement and subsequent arrest of shear bands emanating from the notch roots. The present study not only shows the failure mode transition and the large notch strengthening in notched MGs, but also provides significant insights into the deformation and failure mechanisms of notched MGs that may offer new strategies for the design and engineering of MGs. PMID- 26022223 TI - Early Palliative Care-Health services research and implementation of sustainable changes: the study protocol of the EVI project. AB - BACKGROUND: International medical organizations such as the American Society of Medical Oncology recommend early palliative care as the "gold standard" for palliative care in patients with advanced cancer. Nevertheless, even in Comprehensive Cancer Centers, early palliative care is not yet routine practice. The main goal of the EVI project is to evaluate whether early palliative care can be implemented-in the sense of "putting evidence into practice"-into the everyday clinical practice of Comprehensive Cancer Centers. In addition, we are interested in (1) describing the type of support that patients would like from palliative care, (2) gaining information about the effect of palliative care on patients' quality of life, and (3) understanding the economic burden of palliative care on patients and their families. METHODS/DESIGN: The EVI project is a multi-center, prospective cohort study with a sequential control group design. The study is a project of the Palliative Care Center of Excellence (KOMPACT) in Baden Wurttemberg, Germany, which was recently established to combine the expertise of five academic, specialist palliative care departments. The study is divided into two phases: preliminary phase (months 1-9) and main study phase (months 10-18). In each of all five participating academic Comprehensive Cancer Centers, an experienced palliative care physician will be hired for 18 months. During the preliminary phase, the physician will be allowed time to establish the necessary structures for early palliative care within the Comprehensive Cancer Center. In the main study phase, patients with metastatic cancer will be offered a consultation with the palliative care physician within eight weeks of diagnosis. After the initial consultation, follow-up consultations will be offered as needed. The study is built upon a convergent parallel design. In the quantitative arm, patients will be surveyed in both the preliminary and main study phase at three points in time (baseline, 12 weeks, 24 weeks). Standardized questionnaires will be used to measure patients' quality of life, symptom burden and mood. Using interviews with palliative care physicians, oncologists, department heads, patients and their caregivers, the qualitative arm will explore (1) what factors encourage and hinder the early integration of palliative care into standard oncology care, (2) what support patients and their caregivers would like from palliative care, and (3) what effect palliative care has on the economic disease burden of patients and their families. DISCUSSION: The study proposed is meant to serve as a catalyzer. Local palliative care teams should be put in position to routinely cooperate with the primary treating department at their respective cancer center. The long-term goal of this project is to create sustainable improvements in the care of patients with incurable cancer. TRIAL REGISTRATION: DRKS00006162 ; date of registration: 19/05/2014. PMID- 26022225 TI - Primary idiopathic chylopericardium: a retrospective case series. AB - BACKGROUND: Primary idiopathic chylopericardium is a rare clinical entity characterized by the accumulation of chyle within the pericardial cavity without a definitive cause. The aim of this study was to assess the clinical presentation, etiology, diagnosis, treatment and follow-up of primary idiopathic chylopericardium. METHODS: We retrospectively reviewed 9 cases of patients who suffered from primary idiopathic chylopericardium at our hospital from January 1993 to November 2013. RESULTS: There were two males and seven females among our patients. Their ages ranged from 13 to 55 years. The most common clinical presentation was dyspnea. The etiology was idiopathic. All patients were diagnosed by pericardiocentesis, computed tomography of the chest and lymphoscintigraphy. Non-surgical therapy was adopted in all nine patients and failed in six, who underwent subsequent successful surgery. Thoracic duct ligation with the creation of a pericardial window was the most common surgical procedure. All patients were followed up from 3 months to 9 years, and no recurrence occurred. CONCLUSIONS: In assessing patients with an enlarged cardiac silhouette, one should be aware of primary idiopathic chylopericardium. The most effective treatment is ligation of the thoracic duct and the creation of a pericardial window. PMID- 26022226 TI - Current Challenges and Opportunities in Psychiatric Administration and Leadership. PMID- 26022228 TI - Natural Language Processing for Real-Time Catheter-Associated Urinary Tract Infection Surveillance: Results of a Pilot Implementation Trial. AB - BACKGROUND: Incidence of catheter-associated urinary tract infection (CAUTI) is a quality benchmark. To streamline conventional detection methods, an electronic surveillance system augmented with natural language processing (NLP), which gathers data recorded in clinical notes without manual review, was implemented for real-time surveillance. OBJECTIVE: To assess the utility of this algorithm for identifying indwelling urinary catheter days and CAUTI. SETTING: Large, urban tertiary care Veterans Affairs hospital. METHODS: All patients admitted to the acute care units and the intensive care unit from March 1, 2013, through November 30, 2013, were included. Standard surveillance, which includes electronic and manual data extraction, was compared with the NLP-augmented algorithm. RESULTS: The NLP-augmented algorithm identified 27% more indwelling urinary catheter days in the acute care units and 28% fewer indwelling urinary catheter days in the intensive care unit. The algorithm flagged 24 CAUTI versus 20 CAUTI by standard surveillance methods; the CAUTI identified were overlapping but not the same. The overall positive predictive value was 54.2%, and overall sensitivity was 65% (90.9% in the acute care units but 33% in the intensive care unit). Dissimilarities in the operating characteristics of the algorithm between types of unit were due to differences in documentation practice. Development and implementation of the algorithm required substantial upfront effort of clinicians and programmers to determine current language patterns. CONCLUSIONS: The NLP algorithm was most useful for identifying simple clinical variables. Algorithm operating characteristics were specific to local documentation practices. The algorithm did not perform as well as standard surveillance methods. PMID- 26022227 TI - Emergency department and inpatient health care utilization among patients who require interpreter services. AB - BACKGROUND: Limited English proficiency is associated with health disparities and suboptimal health outcomes. Although Limited English proficiency is a barrier to effective health care, its association with inpatient health care utilization is unclear. The aim of this study was to examine the association between patients with limited English proficiency, and emergency department visits and hospital admissions. METHODS: We compared emergency department visits and hospitalizations in 2012 between patients requiring interpreter services and age-matched English proficient patients (who did not require interpreters), in a retrospective cohort study of adult patients actively empanelled to a large primary health care network in a medium-sized United States city (n = 3,784). RESULTS: Patients who required interpreter services had significantly more Emergency Department visits (841 vs 620; P <= .001) and hospitalizations (408 vs 343; P <= .001) than patients who did not require interpreter services. On regression analysis the risk of a first Emergency Department visit was 60% higher for patients requiring interpreter services than those who did not (unadjusted hazard ratio [HR], 1.6; 95% confidence interval (CI), 1.4-1.9; P < .05), while that of a first hospitalization was 50% higher (unadjusted HR, 1.5; 95% CI, 1.2-1.8; P < .05). These findings remained significant after adjusting for age, sex, medical complexity, residency and outpatient health care utilization. CONCLUSIONS: Patients who required interpreter services had higher rates of inpatient health care utilization compared with patients who did not require an interpreter. Further research is required to understand factors associated with this utilization and to develop sociolinguistically tailored interventions to facilitate appropriate health care provision for this population. PMID- 26022229 TI - Bispectral index monitoring for diagnosis and assessment of severity of hepatic encephalopathy in cirrhotic patients. AB - BACKGROUND: Recent evidence suggests that bispectral index may aid in the diagnosis of hepatic encephalopathy. We evaluated its utility to diagnose, grade and monitor clinical course of hepatic encephalopathy in patients with cirrhosis. METHODS: 200 patients (70.5% males, mean age 39.5+/-9.1 years) with cirrhosis and 20 healthy controls were enrolled prospectively. Cirrhotic patients were divided into groups based on encephalopathy grades I-IV assessed by West Haven criteria; minimal encephalopathy was assessed by psychometric tests. Bispectral index was measured at baseline and after one week of lactulose therapy in patients with overt encephalopathy, and after 3 months in patients with minimal encephalopathy. RESULTS: Bispectral index scores were significantly different in patients with different grades of encephalopathy; 79.5+/-4.2, 67.5+/-4.3, 56.4+/-3.5, 44.8+/ 3.9 and 85.0+/-4.3 respectively for grade I, II, III, IV overt and minimal hepatic encephalopathy, but similar (92.6+/-3.7 vs 93.75+/-2.8) in cirrhotics without encephalopathy and healthy controls. Bispectral scores' cut off values for minimal and overt encephalopathy grade I, II, III, IV were 90.5 and 77.5, 70.5, 60.5, 50.5, respectively. Changes in bispectral index after treatment corresponded to cut-off scores for grades of overt and minimal hepatic encephalopathy. CONCLUSIONS: Bispectral index was found to be useful in diagnosis, grading and monitoring of treatment response in cirrhotic patients with hepatic encephalopathy. PMID- 26022230 TI - Subclinical Myocardial Impairment Occurred in Septal and Anterior LV Wall Segments After Anthracycline-Embedded Chemotherapy and did not Worsen During Adjuvant Trastuzumab Treatment in Breast Cancer Patients. AB - In a previous study of breast cancer patients, we found changes in cardiac function and size during the early stages of adjuvant trastuzumab (Herceptin((r))) therapy. Here we present a subgroup analysis of this patient cohort. This subgroup received a anthracycline-embedded chemotherapy followed by at least 3 months up to 6 months of adjuvant Herceptin((r)) therapy. Twenty-seven female breast cancer patients with Her-2/-neu overexpression were studied using conventional echocardiography and 2D speckle tracking. These methods were done before anthracycline-embedded chemotherapy, before adjuvant trastuzumab therapy, and both 3 and 6 months after the start of the therapy (T3, T6). The LV-EF (Simpson biplane) decreased significantly from before the chemotherapy to after the chemotherapy and further decreased after 3 months of trastuzumab therapy (66.2 +/- 1.5 vs. 58.7 +/- 1.2 vs. 55.6 +/- 1.3 vs. 55.9 +/- 1.5 %; p < 0.05). The stroke volume index remained constant after chemotherapy (22.0 +/- 0.8 vs. 22.6 +/- 1.3 ml/m(2); p = 0.9), but increased significantly during trastuzumab therapy (26.7 +/- 1.1 and 27.3 +/- 1.0 ml/m(2); p < 0.01). Global longitudinal strain exclusively decreased during chemotherapy (-21.0 +/- 0.5 vs. -18.9 +/- 0.5 %, p < 0.001). Regional longitudinal strain decreased significantly after chemotherapy in septal, anteroseptal, anterolateral, and apex segments. Mitral valve regurgitation increased during the whole treatment, but especially during trastuzumab. Right ventricular function decreased exclusively during chemotherapy. Anthracycline-embedded chemotherapy in patients with breast cancer led to a decrease in LV function, especially of the septal and anterior segments, and did not worsen during adjuvant trastuzumab treatment. PMID- 26022231 TI - Effects of preovulatory estradiol on embryo survival and pregnancy establishment in beef cows. AB - The role of preovulatory estradiol on post-fertilization embryo survival and pregnancy establishment has not been well characterized in beef cows. We hypothesized that preovulatory estradiol is important for embryo survival and pregnancy establishment in beef cows. Twenty-four ovariectomized multiparous cows were used in a replicated 3*3 Latin Square design. Cows received estradiol cypionate (ECP) 36h, estradiol benzoate (EB) 12h, or no estradiol (CON) before a gonadotropin-releasing hormone (d 0) induced LH surge. Luteal phase progesterone was mimicked with twice daily progesterone injections from d 3 to 6. On d 7 cows received one embryo and progesterone was supplemented with progesterone-releasing devices (CIDR). Expression of interferon stimulated genes, ISG15, MX2, and OAS1, in leukocytes was determined on d 17, 19, 21, and 28 to determine capability of embryonic signaling. Pregnancy specific protein B concentrations were measured in serum samples from d 17 through 29 to determine embryonic attachment. Transrectal ultrasonography was performed on d 29 and 32 to determine pregnancy viability (heartbeat). Serum estradiol profiles during simulated proestrus/estrus were different (P<0.001) between treatments. Mean serum progesterone concentrations from d 17 to 24 were decreased (P=0.05) in EB and ECP cows compared to CON. Transrectal ultrasonography indicated that fewer CON (4%) cows had a viable embryo present compared to estradiol treated cows (25%). Embryonic loss in cows that did not receive estradiol during the simulated preovulatory period occurred following maternal recognition of pregnancy, indicating that its impact was likely on uterine receptivity and embryonic attachment. PMID- 26022232 TI - Development of an injection molded ethylene-vinyl acetate copolymer (EVA) intravaginal insert for the delivery of progesterone to cattle. AB - The purpose of this study was to develop a new injection-molded intravaginal insert manufactured from ethylene-vinyl acetate containing progesterone for a 7 day insertion period in cattle. The manufacturing process resulted in a reduction in the residual drug compared to the silicone insert available while still maintaining biological performance. PMID- 26022233 TI - Three new cyathane diterpenoids from the medicinal fungus Cyathus africanus. AB - Three new cyathane diterpenoids, cyathin W (1), cyathin V (2), and cyathin T (3), were isolated from the solid culture of Cyathus africanus. The structures and configurations of these new compounds were elucidated on the basis of comprehensive spectroscopic analysis including 1D NMR, 2D NMR (HSQC, HMBC, NOESY), and HR-ESI-MS experiments. Compounds 1 and 3 showed moderate inhibition against nitric oxide production in lipopolysaccaride-activated macrophages with IC50 value of 80.07 and 88.87 MUM, respectively. In cytotoxicity assay, compound 1 showed weak cytotoxicity against K562 cell line with IC50 value of 12.1 MUM. PMID- 26022234 TI - Induction of apoptosis in human cancer cells by targeting mitochondria with gold nanoparticles. AB - A major challenge in designing cancer therapies is the induction of cancer cell apoptosis, although activation of intrinsic apoptotic pathways by targeting gold nanoparticles to mitochondria is promising. We report an in vitro procedure targeting mitochondria with conjugated gold nanoparticles and investigating effects on apoptosis induction in the human breast cancer cell line Jimt-1. Gold nanoparticles were conjugated to a variant of turbo green fluorescent protein (mitoTGFP) harbouring an amino-terminal mitochondrial localization signal. Au nanoparticle conjugates were further complexed with cationic maltotriose-modified poly(propylene imine) third generation dendrimers. Fluorescence and transmission electron microscopy revealed that Au nanoparticle conjugates were directed to mitochondria upon transfection, causing partial rupture of the outer mitochondrial membrane, triggering cell death. The ability to target Au nanoparticles into mitochondria of breast cancer cells and induce apoptosis reveals an alternative application of Au nanoparticles in photothermal therapy of cancer. PMID- 26022235 TI - Single-Incision Laparoscopic Cholecystectomy after Endoscopic Nasogallbladder Drainage: A Case Report. AB - OBJECTIVE: To report a single-incision laparoscopic cholecystectomy (SILC) for a patient with cholecystitis that required endoscopic nasogallbladder drainage (ENGBD). CLINICAL PRESENTATION AND INTERVENTION: A 75-year-old man was diagnosed with moderate acute cholecystitis and underwent antiplatelet therapy for a history of brain infarction. An ENGBD was performed as an initial treatment for his cholecystitis. After recovery from the cholecystitis, a SILC was performed using a SILS Port with an additional forceps. Because neither Rouviere's sulcus nor Calot's triangle could be identified with a favorable laparoscopic view, the fundus-first procedure was selected. The patient's postoperative course was uneventful, and he was discharged from the hospital on day 3 after surgery. CONCLUSION: In this case of a patient who had cholecystitis that required ENGBD, a SILC was successful performed using a combination of SILS Port with additional forceps and fundus-first procedure. PMID- 26022236 TI - [Neoadjuvant chemotherapy in muscular invasive bladder cancer: Complications and consequences with cystectomy]. AB - INTRODUCTION: The fear of the deterioration of the patient's condition related to the toxicity of neoadjuvant chemotherapy is a barrier to its development. This multicenter retrospective study aims to present the secondary effects of neoadjuvant chemotherapy and its impact on the achievement of cystectomy. MATERIALS AND METHODS: Patients with urothelial carcinoma classified cT2 to cT4a N0M0 were included. Chemotherapy with 6 cycles of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) followed by a cysto-prostatectomy or anterior pelvectomy was scheduled. RESULTS: A total 32 patients were included. Six cycles of neoadjuvant chemotherapy were performed in all 11 patients. Shutdown causes were toxicity in 85% of cases. Cystectomy was performed in 86.6% of patients. Surgery was not performed in 6 patients. The reasons were the alteration of the general condition in 2 cases, 2 patients had advanced cancers diagnosed intraoperatively, and 2 refused surgery. Complications of grades 3 and 4 according to the classification of Clavien and Dindo had occurred respectively in 15.3% and 11.5%. DISCUSSION: This study reports results close to what is found in the literature on the effects of neoadjuvant chemotherapy on achieving cystectomy, but it has some limitations: the retrospective analysis of data on surgery and the lack of control group. In addition, the short follow-up does not yet allow to know the long-term oncological results. CONCLUSION: This study supports the fact that the toxicity of neoadjuvant chemotherapy does not seem to cause a significant risk of non-completion of cystectomy. LEVEL OF EVIDENCE: 4. PMID- 26022237 TI - [Tibial nerve transcutaneous stimulation for refractory idiopathic overactive bladder in children and adolescents]. AB - INTRODUCTION: The purpose of this study was to evaluate safety and tolerability of transcutaneous tibial nerve stimulation (TENS) in patients under 15years of age with refractory overactive bladder. MATERIALS AND METHODS: A retrospective analysis was conducted on outcomes of TENS (1daily 20-minute session, 10Hz) in patients with refractory overactive bladder, excluding patients with neurogenic bladder. Treatment efficacy was evaluated on symptomatic improvement and voiding schedule. Healing was defined as following: no recurrence of urinary tract infection, normal urodynamic voiding parameters, no nighttime continence disorder, normal uroflowmetry. RESULTS: Nineteen consecutive patients with refractory overactive bladder were treated from November 2010 to March 2012 (11girls, 8boys, age 12.1+/-2.7 years). Three patients reported only daytime voiding disorders, the others reported daytime and nighttime voiding disorders. Ten patients reported febrile urinary tract infection (1 boy, 9 girls). The average length of treatment was 6 months. Two patients were lost to follow-up. Thirteen patients had only tibial TENS; 3 patients had tibial TENS and trospium chloride or desmopressin. At 1-month assessment, 16 patients out of 17 (94%) reported symptomatic improvement. At the end of treatment, 12 patients out of 17 (70%) met healing criteria (5 boys, 7girls), without relapse within 9 months. Three boys (18%) had partial improvement (no daytime wetting, but increased daytime frequency). No patient reported side effects. CONCLUSION: Tibial TENS is a safe, non invasive and effective treatment in refractory overactive bladder in children. The success rate is 70%, with no side effect and no relapse at the end of the treatment in our study. PMID- 26022238 TI - Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells. AB - Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34(+) cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. PMID- 26022239 TI - High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. AB - We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients treated first line with immunochemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age, 56 years) was analyzed by multiplex ligation-dependent probe amplification and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments. As expected, MYC (18%) was the more frequently gained, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%), and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A, TP53, and CDKN1B were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (hazard ratio, 2.3; P = .007, MIPI adjusted) and TP53 deletions (hazard ratio, 2.4; P = .007), reflected in a dismal outcome with simultaneous deletions (median OS, 1.8 years) compared with single deletions (median OS, 4.3 and 5.1 years) or without these deletions (median OS, 7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A and TP53 deletions were independent of the Ki-67 index. Despite immunochemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. This trial was registered at www.clinicaltrials.gov as #NCT00209222. PMID- 26022240 TI - Visualizing Molecular Functions and Cross-Species Activity of Sex-Peptide in Drosophila. AB - The Drosophila melanogaster sex-peptide (melSP) is a seminal fluid component that induces postmating responses (PMR) of females via the sex-peptide receptor (SPR) . Although SP orthologs are found in many Drosophila species, their functions remain poorly characterized. It is unknown whether SP functions are conserved across species or rather specific to each species. Here, we developed a GFP tagged melSP (G-SP) and used it to visualize cross-species binding activity to the female reproductive system of various species. First we demonstrated that ectopically expressed G-SP induced PMR in D. melanogaster females and bound to the female reproductive system, most notably to the common oviduct. No binding occurred in the females lacking SPR, indicating that G-SP binding was dependent on SPR. Next we tested whether G-SP binds to the common oviducts from 11 Drosophila species using dissected reproductive tracts. The binding was observed in six species belonging to the D. melanogaster species group, but not to those outside the group. Injection of melSP reduced the receptivity of females belonging to the D. melanogaster species group, but not of those outside the group, being consistent with the ability to bind G-SP. Thus the SP-mediated PMR appears to be limited to this species group. SPR was expressed in the oviducts at high levels in this group; therefore, we speculate that an enhanced expression of SPR in the oviduct was critical to establish the SP-mediated PMR during evolution. PMID- 26022241 TI - Lineage-Specific Evolution of the Complex Nup160 Hybrid Incompatibility Between Drosophila melanogaster and Its Sister Species. AB - Two genes encoding protein components of the nuclear pore complex Nup160 and Nup96 cause lethality in F2-like hybrid genotypes between Drosophila simulans and Drosophila melanogaster. In particular, D. simulans Nup160 and Nup96 each cause inviability when hemizygous or homozygous in species hybrids that are also hemizygous (or homozygous) for the D. melanogaster X chromosome. The hybrid lethality of Nup160, however, is genetically complex, depending on one or more unknown additional factors in the autosomal background. Here we study the genetics and evolution of Nup160-mediated hybrid lethality in three ways. First, we test for variability in Nup160-mediated hybrid lethality within and among the three species of the D. simulans clade- D. simulans, D. sechellia, and D. mauritiana. We show that the hybrid lethality of Nup160 is fixed in D. simulans and D. sechellia but absent in D. mauritiana. Second, we explore how the hybrid lethality of Nup160 depends on other loci in the autosomal background. We find that D. simulans Nup160-mediated hybrid lethality does not depend on the presence of D. melanogaster Nup96, and we find that D. simulans and D. mauritiana are functionally differentiated at Nup160 as well as at other autosomal factor(s). Finally, we use population genetics data to show that Nup160 has experienced histories of recurrent positive selection both before and after the split of the three D. simulans clade species ~240,000 years ago. Our genetic results suggest that a hybrid lethal Nup160 allele evolved before the split of the three D. simulans clade species, whereas the other autosomal factor(s) evolved more recently. PMID- 26022242 TI - Dual Color Neural Activation and Behavior Control with Chrimson and CoChR in Caenorhabditis elegans. AB - By enabling a tight control of cell excitation, optogenetics is a powerful approach to study the function of neurons and neural circuits. With its transparent body, a fully mapped nervous system, easily quantifiable behaviors and many available genetic tools, Caenorhabditis elegans is an extremely well suited model to decipher the functioning logic of the nervous system with optogenetics. Our goal was to establish an efficient dual color optogenetic system for the independent excitation of different neurons in C. elegans. We combined two recently discovered channelrhodopsins: the red-light sensitive Chrimson from Chlamydomonas noctigama and the blue-light sensitive CoChR from Chloromonas oogama. Codon-optimized versions of Chrimson and CoChR were designed for C. elegans and expressed in different mechanosensory neurons. Freely moving animals produced robust behavioral responses to light stimuli of specific wavelengths. Since CoChR was five times more sensitive to blue light than the commonly used ChR2, we were able to use low blue light intensities producing no cross-activation of Chrimson. Thanks to these optogenetics tools, we revealed asymmetric cross-habituation effects between the gentle and harsh touch sensory motor pathways. Collectively, our results establish the Chrimson/CoChR pair as a potent tool for bimodal neural excitation in C. elegans and equip this genetic model organism for the next generation of in vivo optogenetic analyses. PMID- 26022243 TI - Synthetic trehalose esters of cis-alkene and diene alpha'-mycolic acids of Mycobacteria. AB - The synthesis of an alpha'-mycolic acid of Mycobacterium smegmatis and other mycobacteria, containing a cis,cis-diene, and of the trehalose mono- and di mycolates of this, and of a related alpha'-mycolic acid containing one cis alkene, is reported. PMID- 26022244 TI - Outcomes of endovascular treatment for patients with TASC II D femoropopliteal occlusive disease: a single center study. AB - BACKGROUND: Advances in endovascular technology led to an alternative treatment option for TASC II D (TransAtlantic Inter-Society Consensus II class D) lesions. This study was aimed to evaluate the outcomes of endovascular treatment for TASC II D femoropopliteal lesions. METHODS: Endovascular intervention with bare nitinol stent implantation was performed on 58 limbs (53 patients) with TASC II D femoropopliteal lesions from January 2011 to March 2013. Kaplan-Meier curves of primary patency, assisted patency and second patency were performed. Predictive factors of re-stenosis/occlusion were evaluated by univariate methods. RESULTS: Total 53 patients with mean age of 74.2 +/- 8.2 (range, 58.0-91.0 years) and mean lesion length of 314.8 +/- 64.3 mm (188.2-400.4 mm) were enrolled. The mean follow-up time was 12.2 +/- 6.1 months (5-38 months). Revascularization was successfully on 95% lesions by bare nitinol stent implantation. Primary patency rates at 1, 2 and 3 years were 63%, 12% and 12%, respectively. Assisted primary patency rates at 1, 2 and 3 years were 77%, 31% and 31%, respectively. Secondary patency rates at 1, 2 and 3 years were 96%, 63% and 63%. During one-year follow up, no major amputation was occurred. Univariate analysis revealed that number of run-off vessels was a potential predictor of re-stenosis/occlusion. CONCLUSION: Endovascular treatment of TASC II D femoropopliteal artery occlusion has a high technical success rate with acceptable one-year patency rate. The long-term outcomes are poor, but endovascular intervention could be a good alternative for patients unsuitable for surgical bypass. PMID- 26022245 TI - Functional Polymorphism rs13306560 of the MTHFR Gene Is Associated With Essential Hypertension in a Mexican-Mestizo Population. AB - BACKGROUND: Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been associated with diastolic blood pressure, hypertension, and other cardiovascular diseases; however, results of these studies are still controversial. In this study, we sought to determine whether 2 functional variants (rs1801133 and rs13306560) within the MTHFR are associated with hypertension in Mexican-Mestizos. METHODS AND RESULTS: We performed a case control study with 1214 subjects including adults and children to test for the association of both single nucleotide polymorphisms with essential hypertension. The adult group included 764 participants (372 patients and 391 controls) and the group of children included 418 participants (209 patients and 209 controls). rs13306560 was associated with essential hypertension in adults (odds ratio, 4.281; 95% confidence interval, 1.841-9.955; P=0.0003) with a statistical power >0.8. In children, none of the polymorphisms was associated with essential hypertension. In addition, we assessed the effect of the rs13306560 polymorphism on the MTHFR promoter region by means of luciferase reporter gene assays using human umbilical vein endothelial cells. Cells transfected with the pMTHFRaLUC construct showed an ~25% reduction in luciferase activity (P=0.003). Furthermore, the promoter activity was reduced considerably by in vitro methylation of CpG sequences. CONCLUSIONS: Our data suggest that the rs13306560 polymorphism of the MTHFR may be part of the observed hypertension process in Mexican-Mestizo populations, but further studies are warranted. In addition, the allele A of the rs13306560 polymorphism as well as the in vitro methylation of CpGs reduced the promoter activity of the MTHFR regulatory region. PMID- 26022247 TI - Allelic imbalance at the HER2/TOP2A locus in breast cancer. AB - BACKGROUND: Breast cancer is a heterogeneous disease with various histological features and molecular markers. These are utilized for the prediction of clinical outcome and therapeutic decision making. In addition to well established markers such as HER2 overexpression and estrogen and progesterone receptor (ER and PR) status, chromosomal instability is evolving as an important hallmark of cancers. The HER2/TOP2A locus is of great importance in breast cancer. The copy number variability at this locus has been proposed to be a marker for the degree of chromosomal instability. We therefore developed a Single Nucleotide Polymorphism (SNP) assay to evaluate allelic imbalance at the HER2/TOP2A locus in three different entities of primary breast tumors. METHODS: Eleven SNPs were carefully selected and detected by real time PCR using DNA extracted from paired (histologically normal and tumor) paraffin-embedded tissues. Primary breast tumors of 44 patients were included, 15 tumors with HER2 overexpression, 16 triple negative tumors, defined by the absence of HER2 overexpression and a negative ER and PR status and 13 ER and PR positive tumors without HER2 overexpression. As controls, histologically normal breast tissues from 10 patients with no breast tumor were included. RESULTS: Allelic imbalance was observed in 13/15 (87 %) HER2 positive tumors, the remaining 2 being inconclusive. Of the 16 triple negative tumors, 12 (75 %) displayed instability, 3 (19 %) displayed no instability, and 1 was inconclusive. Of the 13 hormone receptor positive tumors, 5 (38 %) displayed allelic imbalance, while 8 did not. CONCLUSIONS: We conclude that the SNP assay is suitable for rapid testing of allelic (im)balance at the HER2/TOP2A locus using paraffin-embedded tissues. Based on allelic imbalance at this locus, both triple negative and ER and PR positive breast tumors can be subcategorized. The clinical relevance of the allelic (im)balance status at the HER2/TOP2A locus in breast cancer is subject of future study. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2086062232155220. PMID- 26022248 TI - Thermodynamic examination of 1- to 5-nt purine bulge loops in RNA and DNA constructs. AB - Bulge loops are common features of RNA structures that are involved in the formation of RNA tertiary structures and are often sites for interactions with proteins and ions. Minimal thermodynamic data currently exist on the bulge size and sequence effects. Using thermal denaturation methods, thermodynamic properties of 1- to 5-nt adenine and guanine bulge loop constructs were examined in 10 mM MgCl(2) or 1 M KCl. The [Formula: see text] loop parameters for 1- to 5 nt purine bulge loops in RNA constructs were between 3.07 and 5.31 kcal/mol in 1 M KCl buffer. In 10 mM magnesium ions, the DeltaDeltaG degrees values relative to 1 M KCl were 0.47-2.06 kcal/mol more favorable for the RNA bulge loops. The [Formula: see text] loop parameters for 1- to 5-nt purine bulge loops in DNA constructs were between 4.54 and 5.89 kcal/mol. Only 4- and 5-nt guanine constructs showed significant change in stability for the DNA constructs in magnesium ions. A linear correlation is seen between the size of the bulge loop and its stability. New prediction models are proposed for 1- to 5-nt purine bulge loops in RNA and DNA in 1 M KCl. We show that a significant stabilization is seen for small bulge loops in RNA in the presence of magnesium ions. A prediction model is also proposed for 1- to 5-nt purine bulge loop RNA constructs in 10 mM magnesium chloride. PMID- 26022249 TI - Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging. AB - Recent findings have led to a renewed interest and support for an active role of inflammation in neurodegenerative dementias and related neurologic disorders. Detection of neuroinflammation in vivo throughout the course of neurodegenerative diseases is of great clinical interest. Studies have shown that microglia activation (an indicator of neuroinflammation) may present at early stages of frontotemporal dementia (FTD), but the role of neuroinflammation in the pathogenesis of FTD is largely unknown. The first-generation translocator protein (TSPO) ligand ([(11)C]-PK11195) has been used to detect microglia activation in FTD, and the second-generation TSPO ligands have imaged neuroinflammation in vivo with improved pharmacokinetic properties. This paper reviews related literature and technical issues on mapping neuroinflammation in FTD with positron-emission tomography (PET) imaging. Early detection of neuroinflammation in FTD may identify new tools for diagnosis, novel treatment targets, and means to monitor therapeutic efficacy. More studies are needed to image and track neuroinflammation in FTD. It is anticipated that the advances of TSPO PET imaging will overcome technical difficulties, and molecular imaging of neuroinflammation will aid in the characterization of neuroinflammation in FTD. Such knowledge has the potential to shed light on the poorly understood pathogenesis of FTD and related dementias, and provide imaging markers to guide the development and assessment of new therapies. PMID- 26022251 TI - Functional morphology of the respiratory organs in the cellar spider Pholcus phalangioides (Arachnida, Araneae, Pholcidae). AB - Morphometric evaluation of the lungs of male and female cellar spiders (Pholcus phalangioideus) was carried out in 2 test groups with different body masses (mean value 10.8, males, and 26.6 mg, females). Males have significant higher lung volume to body mass ratios (2.49 vs. 2.13 * 10(-3) cm(3) g(-1)), which might result from the differences in body mass between sexes. Moreover, males have slightly more respiratory surface area per body mass (8.2 vs. 7.7 cm(2) g(-1)) and a little bit larger morphological diffusing capacities for oxygen (9.3 vs. 8.2 nmol s(-1) g(-1) kPa(-1)) than females, but both values were not significant. Metabolic rates were measured using flow through respirometry under video tracking: the CO2 release of male and female spiders was measured. Resting rates were 1.7 (males) and 1.5 nmol s(-1) g(-1) (females). Gluing of one spiracle did not influence the resting metabolic rate. Factorial scopes during stimulation to maximum metabolic rates were about 12 in intact animals, while elimination of one spiracle reduced the factorial scope to 5.2. Comparison with other araneomorph spiders strengthens the hypothesis that tracheae in spiders increase the metabolic rates of the tracheated species and do not only replace reduced lung capacity. PMID- 26022250 TI - Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments. AB - BACKGROUND: The mouse is an organism that is widely used as a mammalian model for studying human physiology or disease, and the development of immunodeficient mice has provided a valuable tool for basic and applied human disease research. Following the development of large-scale mouse knockout programs and genome editing tools, it has become increasingly efficient to generate genetically modified mouse strains with immunodeficiency. However, due to the lack of a standardized system for evaluating the immuno-capacity that prevents tumor progression in mice, an objective choice of the appropriate immunodeficient mouse strains to be used for tumor engrafting experiments is difficult. METHODS: In this study, we developed a tumor engraftment index (TEI) to quantify the immunodeficiency response to hematologic malignant cells and solid tumor cells of six immunodeficient mouse strains and C57BL/6 wild-type mouse (WT). RESULTS: Mice with a more severely impaired immune system attained a higher TEI score. We then validated that the NOD-scid-IL2Rg-/- (NSI) mice, which had the highest TEI score, were more suitable for xenograft and allograft experiments using multiple functional assays. CONCLUSIONS: The TEI score was effectively able to reflect the immunodeficiency of a mouse strain. PMID- 26022252 TI - CYCD3 D-type cyclins regulate cambial cell proliferation and secondary growth in Arabidopsis. AB - A major proportion of plant biomass is derived from the activity of the cambium, a lateral meristem responsible for vascular tissue formation and radial organ enlargement in a process termed secondary growth. In contrast to our relatively good understanding of the regulation of primary meristems, remarkably little is known concerning the mechanisms controlling secondary growth, particularly how cambial cell divisions are regulated and integrated with vascular differentiation. A genetic loss-of-function approach was used here to reveal a rate-limiting role for the Arabidopsis CYCLIN D3 (CYCD3) subgroup of cell-cycle genes in the control of cambial cell proliferation and secondary growth, providing conclusive evidence of a direct link between the cell cycle and vascular development. It is shown that all three CYCD3 genes are specifically expressed in the cambium throughout vascular development. Analysis of a triple loss-of-function CYCD3 mutant revealed a requirement for CYCD3 in promoting the cambial cell cycle since mutant stems and hypocotyls showed a marked reduction in diameter linked to reduced mitotic activity in the cambium. Conversely, loss of CYCD3 provoked an increase in xylem cell size and the expression of differentiation markers, showing that CYCD3 is required to restrain the differentiation of xylem precursor cells. Together, our data show that tight control of cambial cell division through developmental- and cell type-specific regulation of CYCD3 is required for normal vascular development, constituting part of a novel mechanism controlling organ growth in higher plants. PMID- 26022253 TI - Quantitative trait locus mapping of deep rooting by linkage and association analysis in rice. AB - Deep rooting is a very important trait for plants' drought avoidance, and it is usually represented by the ratio of deep rooting (RDR). Three sets of rice populations were used to determine the genetic base for RDR. A linkage mapping population with 180 recombinant inbred lines and an association mapping population containing 237 rice varieties were used to identify genes linked to RDR. Six quantitative trait loci (QTLs) of RDR were identified as being located on chromosomes 1, 2, 4, 7, and 10. Using 1 019 883 single-nucleotide polymorphisms (SNPs), a genome-wide association study of the RDR was performed. Forty-eight significant SNPs of the RDR were identified and formed a clear peak on the short arm of chromosome 1 in a Manhattan plot. Compared with the shallow rooting group and the whole collection, the deep-rooting group had selective sweep regions on chromosomes 1 and 2, especially in the major QTL region on chromosome 2. Seven of the nine candidate SNPs identified by association mapping were verified in two RDR extreme groups. The findings from this study will be beneficial to rice drought-resistance research and breeding. PMID- 26022254 TI - The paralogous R3 MYB proteins CAPRICE, TRIPTYCHON and ENHANCER OF TRY AND CPC1 play pleiotropic and partly non-redundant roles in the phosphate starvation response of Arabidopsis roots. AB - Phosphate (Pi) deficiency alters root hair length and frequency as a means of increasing the absorptive surface area of roots. Three partly redundant single R3 MYB proteins, CAPRICE (CPC), ENHANCER OF TRY AND CPC1 (ETC1) and TRIPTYCHON (TRY), positively regulate the root hair cell fate by participating in a lateral inhibition mechanism. To identify putative targets and processes that are controlled by these three transcription factors (TFs), we conducted transcriptional profiling of roots from Arabidopsis thaliana wild-type plants, and cpc, etc1 and try mutants grown under Pi-replete and Pi-deficient conditions using RNA-seq. The data show that in an intricate interplay between the three MYBs regulate several developmental, physiological and metabolic processes that are putatively located in different tissues. When grown on media with a low Pi concentration, all three TFs acquire additional functions that are related to the Pi starvation response, including transition metal transport, membrane lipid remodelling, and the acquisition, uptake and storage of Pi. Control of gene activity is partly mediated through the regulation of potential antisense transcripts. The current dataset extends the known functions of R3 MYB proteins, provides a suite of novel candidates with critical function in root hair development under both control and Pi-deficient conditions, and challenges the definition of genetic redundancy by demonstrating that environmental perturbations may confer specific functions to orthologous proteins that could have similar roles under control conditions. PMID- 26022255 TI - Phenotypic and genetic dissection of component traits for early vigour in rice using plant growth modelling, sugar content analyses and association mapping. AB - Early vigour of rice, defined as seedling capacity to accumulate shoot dry weight (SDW) rapidly, is a complex trait. It depends on a genotype propensity to assimilate, store, and/or use non-structural carbohydrates (NSC) for producing large and/or numerous leaves, involving physiological trade-offs in the expression of component traits and, possibly, physiological and genetic linkages. This study explores a plant-model-assisted phenotyping approach to dissect the genetic architecture of rice early vigour, applying the Genome Wide Association Study (GWAS) to morphological and NSC measurements, as well as fitted parameters for the functional-structural plant model, Ecomeristem. Leaf size, number, SDW, and source-leaf NSC concentration were measured on a panel of 123 japonica accessions. The data were used to estimate Ecomeristem genotypic parameters driving organ appearance rate, size, and carbon dynamics. GWAS was performed based on 12 221 single-nucleotide polymorphisms (SNP). Twenty-three associations were detected at P <1*10(-4) and 64 at P <5*10(-4). Associations for NSC and model parameters revealed new regions related to early vigour that had greater significance than morphological traits, providing additional information on the genetic control of early vigour. Plant model parameters were used to characterize physiological and genetic trade-offs among component traits. Twelve associations were related to loci for cloned genes, with nine related to organogenesis, plant height, cell size or cell number. The potential use of these associations as markers for breeding is discussed. PMID- 26022256 TI - Identification of regulatory network hubs that control lipid metabolism in Chlamydomonas reinhardtii. AB - Microalgae-based biofuels are promising sources of alternative energy, but improvements throughout the production process are required to establish them as economically feasible. One of the most influential improvements would be a significant increase in lipid yields, which could be achieved by altering the regulation of lipid biosynthesis and accumulation. Chlamydomonas reinhardtii accumulates oil (triacylglycerols, TAG) in response to nitrogen (N) deprivation. Although a few important regulatory genes have been identified that are involved in controlling this process, a global understanding of the larger regulatory network has not been developed. In order to uncover this network in this species, a combined omics (transcriptomic, proteomic and metabolomic) analysis was applied to cells grown in a time course experiment after a shift from N-replete to N depleted conditions. Changes in transcript and protein levels of 414 predicted transcription factors (TFs) and transcriptional regulators (TRs) were monitored relative to other genes. The TF and TR genes were thus classified by two separate measures: up-regulated versus down-regulated and early response versus late response relative to two phases of polar lipid synthesis (before and after TAG biosynthesis initiation). Lipidomic and primary metabolite profiling generated compound accumulation levels that were integrated with the transcript dataset and TF profiling to produce a transcriptional regulatory network. Evaluation of this proposed regulatory network led to the identification of several regulatory hubs that control many aspects of cellular metabolism, from N assimilation and metabolism, to central metabolism, photosynthesis and lipid metabolism. PMID- 26022257 TI - Illuminating light, cytokinin, and ethylene signalling crosstalk in plant development. AB - Integrating important environmental signals with intrinsic developmental programmes is a crucial adaptive requirement for plant growth, survival, and reproduction. Key environmental cues include changes in several light variables, while important intrinsic (and highly interactive) regulators of many developmental processes include the phytohormones cytokinins (CKs) and ethylene. Here, we discuss the latest discoveries regarding the molecular mechanisms mediating CK/ethylene crosstalk at diverse levels of biosynthetic and metabolic pathways and their complex interactions with light. Furthermore, we summarize evidence indicating that multiple hormonal and light signals are integrated in the multistep phosphorelay (MSP) pathway, a backbone signalling pathway in plants. Inter alia, there are strong overlaps in subcellular localizations and functional similarities in components of these pathways, including receptors and various downstream agents. We highlight recent research demonstrating the importance of CK/ethylene/light crosstalk in selected aspects of plant development, particularly seed germination and early seedling development. The findings clearly demonstrate the crucial integration of plant responses to phytohormones and adaptive responses to environmental cues. Finally, we tentatively identify key future challenges to refine our understanding of the molecular mechanisms mediating crosstalk between light and hormonal signals, and their integration during plant life cycles. PMID- 26022258 TI - Characterization, localization, and seasonal changes of the sucrose transporter FeSUT1 in the phloem of Fraxinus excelsior. AB - Trees are generally assumed to be symplastic phloem loaders. A typical feature for most wooden species is an open minor vein structure with symplastic connections between mesophyll cells and phloem cells, which allow sucrose to move cell-to-cell through the plasmodesmata into the phloem. Fraxinus excelsior (Oleaceae) also translocates raffinose family oligosaccharides in addition to sucrose. Sucrose concentration was recently shown to be higher in the phloem sap than in the mesophyll cells. This suggests the involvement of apoplastic steps and the activity of sucrose transporters in addition to symplastic phloem-loading processes. In this study, the sucrose transporter FeSUT1 from F. excelsior was analysed. Heterologous expression in baker's yeast showed that FeSUT1 mediates the uptake of sucrose. Immunohistochemical analyses revealed that FeSUT1 was exclusively located in phloem cells of minor veins and in the transport phloem of F. excelsior. Further characterization identified these cells as sieve elements and possibly ordinary companion cells but not as intermediary cells. The localization and expression pattern point towards functions of FeSUT1 in phloem loading of sucrose as well as in sucrose retrieval. FeSUT1 is most likely responsible for the observed sucrose gradient between mesophyll and phloem. The elevated expression level of FeSUT1 indicated an increased apoplastic carbon export activity from the leaves during spring and late autumn. It is hypothesized that the importance of apoplastic loading is high under low-sucrose conditions and that the availability of two different phloem-loading mechanisms confers advantages for temperate woody species like F. excelsior. PMID- 26022260 TI - Poly(ADP)-Ribose Polymerase-1 Inhibitors as a Potential Treatment for Cocaine Addiction. AB - As of 2008, according to the National Survey on Drug Use and Health, nearly 1.4 million Americans met the Diagnostic and Statistical Manual of Mental Disorders criteria for dependence or abuse of cocaine (in any form) in the past 12 months. However, there are no treatments for cocaine use disorders approved by the Federal Drug Administration (FDA). Alterations in gene regulation contribute significantly to the changes that occur in the brain, both structurally and functionally, and the resultant addictive phenotype that occurs with chronic exposure to drugs of abuse. The Emerging Targets of Cocaine Use Disorders meeting sought to explore novel targets for the treatment of stimulant use disorder. The evidence for a role of one novel target, Poly(ADP)-ribose polymerase-1 (PARP-1), was presented at the meeting and will be summarized in this review. PMID- 26022259 TI - Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine. AB - Psychotropic actions of cocaine are generally thought to involve its blockade of monoamine transporters leading to increased synaptic levels of monoamines, especially dopamine. Subsequent intracellular events have been less well characterized. We describe a signaling system wherein lower behavioral stimulant doses of cocaine, as well as higher neurotoxic doses, activate a cascade wherein nitric oxide nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to generate a complex with the ubiquitin-E3-ligase Siah1 which translocates to the nucleus. With lower cocaine doses, nuclear GAPDH augments CREB signaling, while at higher doses p53 signaling is enhanced. The drug CGP3466B very potently blocks GAPDH nitrosylation, hindering both signaling cascades and inhibits both behavioral activating and neurotoxic effects of cocaine. This system affords potentially novel approaches to the therapy of cocaine abuse. PMID- 26022261 TI - Neurokinin-1 (NK1) receptor antagonists as possible therapeutics for psychostimulant use disorders. AB - Abuse of and addiction to psychostimulants such as cocaine or amphetamines remain a significant societal burden, and attempts at successfully developing effective treatments for substance use disorders involving psychostimulants have been disappointingly unsuccessful to date. In addition, most pharmacologically based approaches to treating psychostimulant use disorders have largely focused on targeting monoaminergic or amino acid neurotransmission, with little emphasis being placed on neuropeptide systems. One such neuropeptide system that has received little attention is the tachykinin family of peptides and their corresponding neurokinin (NK) receptor subtypes designated NK1, NK2, and NK3. Tachykinins and their receptors are widely expressed in numerous cell types in the periphery and central nervous system, and in the latter, regulate fundamental processes such as nociception, reward, motivation, affect, and stress responses. In recent years, various small molecule brain penetrant NK1 antagonists have been developed which appear to be beneficial and well tolerated in patients undergoing treatment for chemotherapy-induced and post-operative nausea and vomiting. The purpose of this review is to summarize the small body of preclinical and clinical studies that suggest NK1 antagonists may be of potential use in the treatment of substance use disorders involving psychostimulants. Additional topics of discussion will be the importance of full receptor occupancy and known species differences in NK1 receptor ligand binding, which represent significant obstacles to utilizing standard rodent models of psychostimulant addiction for future screening of potentially efficacious NK1 antagonists. PMID- 26022262 TI - The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use. AB - A high rate of relapse is a defining characteristic of substance use disorder for which few treatments are available. Exposure to environmental cues associated with previous drug use can elicit relapse by causing the involuntary retrieval of deeply engrained associative memories that trigger a strong motivation to seek out drugs. Our lab is focused on identifying and disrupting mechanisms that support these powerful consolidated memories, with the goal of developing therapeutics. A particularly promising mechanism is regulation of synaptic dynamics by actin polymerization within dendritic spines. Emerging evidence indicates that memory is supported by structural and functional plasticity dendritic spines, for which actin polymerization is critical, and that prior drug use increases both spine and actin dynamics. Indeed we have found that inhibiting amygdala (AMY) actin polymerization immediately or twenty-four hours prior to testing disrupted methamphetamine (METH)-associated memories, but not food reward or fear memories. Furthermore, METH training increased AMY spine density which was reversed by actin depolymerization treatment. Actin dynamics were also shifted to a more dynamic state by METH training. While promising, actin polymerization inhibitors are not a viable therapeutic, as a multitude of peripheral process (e.g. cardiac function) rely on dynamic actin. For this reason, we have shifted our focus upstream of actin polymerization to nonmuscle myosin II. We and others have demonstrated that myosin IIb imparts a mechanical force that triggers spine actin polymerization in response to synaptic stimulation. Similar to an actin depolymerizing compound, pre-test inhibition of myosin II ATPase activity in the AMY produced a rapid and lasting disruption of drug-seeking behavior. While many questions remain, these findings indicate that myosin II represents a potential therapeutic avenue to target the actin cytoskeleton and disrupt the powerful, extinction-resistant memories capable of triggering relapse. PMID- 26022264 TI - Histone Deacetylases as Potential Targets for Cocaine Addiction. AB - Drug-induced changes in gene expression likely contribute to long-lasting structural and functional alterations in the brain's reward circuitry and the persistence of addiction. Modulation of chromatin structure through covalent histone modifications has emerged as an important regulator of gene transcription in brain and increasing evidence suggests that misregulation of histone acetylation contributes to the establishment and maintenance of aberrant neuronal gene programs and behaviors associated with cocaine or amphetamine exposure. In this review, we summarize evidence supporting a role for histone acetylation in psychostimulant-induced plasticity and discuss findings from preclinical studies investigating histone deacetylase (HDAC) action and the use of small-molecule HDAC inhibitors (HDACis) to correct drug-mediated transcriptional dysregulation. PMID- 26022263 TI - Metabotropic Glutamate Receptor 7 (mGluR7) as a Target for the Treatment of Psychostimulant Dependence. AB - Although few medications have been approved by the U.S. Food and Drug Administration (FDA) to assist people to quit tobacco smoking, there are no FDA approved medications to treat dependence on other psychostimulant drugs, such as cocaine. The motivation to maintain psychostimulant drug seeking and self administration involves alterations in glutamatergic neurotransmission. Thus, medications that modulate glutamate transmission may be effective treatments for psychostimulant dependence. One presynaptic inhibitory glutamate receptor that critically regulates glutamate transmission is the metabotropic glutamate 7 receptor (mGluR7). This review summarizes nonhuman experimental animal data that indicate a critical role for mGluR7 in drug-taking and drug-seeking behaviors for the psychostimulants cocaine and nicotine. AMN082, the only commercially available allosteric receptor agonist, has been used to investigate the role of mGluR7 in psychostimulant dependence. Systemic administration or microinjection of AMN082 into brain sites within the mesocorticolimbic system decreased self administration and reinstatement of both cocaine and nicotine seeking. In vivo microdialysis results indicated that a nucleus accumbens-ventral pallidum gamma aminobutyric acid-ergic mechanism may underlie AMN082-induced antagonism of the reinforcing effects of cocaine, whereas a glutamate mGlu2/3 receptor mechanism underlies the AMN082-induced blockade of cocaine seeking. These findings indicate an important role for mGluR7 in mesolimbic areas in modulating the reinforcing effects of psychostimulant drugs, such as nicotine and cocaine, and the conditioned behaviors associated with drugs of abuse. Thus, selective mGluR7 agonists or positive allosteric modulators may have the potential to treat psychostimulant dependence. PMID- 26022266 TI - From Ancient Chinese Medicine to a Novel Approach to Treat Cocaine Addiction. AB - Pharmacologic agents for CNS disorders are often inhibitors that occupy receptors, with frequent unavoidable side effects likely due to continuous binding. This review summarizes development of a novel aldehyde dehydrogenase 2 (ALDH2) inhibitor that specifically targets unique drug related episodic surges in dopamine (DA), a pathophysiologic mechanism that appears to underlie much of drug-seeking behavior. We have synthesized highly selective novel ALDH2 inhibitors (ALDH2i) that block alcohol- and cocaine cue-induced surges in nucleus accumbens (NAc) DA and prevent reinstatement of alcohol heavy drinking, cocaine self-administration and reinstatement of cocaine relapse-like behavior. The mechanism of action of ALDH2i depends on inhibiting dopamine aldehyde (DOPAL) clearance by ALDH2, enabling unmetabolized DOPAL to condense with DA to generate tetrahydropapaveroline (THP). THP selectively inhibits the activated (phosphorylated) tyrosine hydroxylase (TH) to suppress DA synthesis. Selective inhibition of ALDH2 appears to have therapeutic potential for treating cue induced drug relapse, a major unmet need for treating addicted subjects. PMID- 26022267 TI - Dopamine D4 Receptor Antagonists for the Treatment of Cocaine Use Disorders. AB - The identification of effective medications for the management of cocaine use disorders remains an unmet public health challenge. In view of the prominent role of dopaminergic mechanisms in cocaine's abuse-related effects, research has focused on the development of subtype-selective dopamine D1-4 receptor antagonists. Here, we briefly recap the current status of this research effort, with a focus on several aspects of D4 research that may be pertinent to the consideration of D4 ligands in the development of candidate medications. Additionally, we present data from self administration studies in nonhuman primates showing that intravenous cocaine-maintained behavior is moderately, though non-significantly, decreased by doses of the D4-selective partial agonist Ro10-5824 and dramatically reduced by the D4- selective receptor antagonist NGD 94-1. The effects of these D4 ligands on cocaine self-administration were consistent among subjects and occurred in the absence of comparable effects on food-maintained responding. These data suggest that available D4 receptor antagonists should be investigated further as candidate medications for the management of cocaine use disorders. PMID- 26022265 TI - Glutamate Transporter GLT-1 as a Therapeutic Target for Substance Use Disorders. AB - The development of new treatments for substance use disorders requires identification of targetable molecular mechanisms. Pathology in glutamatergic neurotransmission system in brain reward circuitry has been implicated in relapse to multiple classes of drugs. Glutamate transporter 1 (GLT-1) crucially regulates glutamatergic signaling by removing excess glutamate from the extrasynaptic space. The purpose of this review is to highlight the effects of addictive drug use on GLT-1 and glutamate uptake, and using GLT-1 as a target in addiction pharmacotherapy. Cocaine, opioids, ethanol, nicotine, amphetamines, and cannabinoids each affect GLT-1 expression and glutamate uptake, and restoring GLT 1 expression with N-acetylcysteine or ceftriaxone shows promise in correcting pre clinical and clinical manifestations of drug addiction. PMID- 26022268 TI - Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4. AB - There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse. PMID- 26022270 TI - Does It Matter Who Provides Psychological Interventions for Medically Unexplained Symptoms? A Meta-Analysis. AB - BACKGROUND: Patients with medically unexplained symptoms (MUS) are difficult to treat and cause high health-care costs. Psychological interventions might be a beneficial option for treating patients with MUS, but evidence is inconsistent. This meta-analysis compares the effectiveness of psychological interventions for MUS - delivered either by psychotherapists (PTs) or by general practitioners (GPs) - with that of usual care. METHOD: We conducted a systematic review and meta-analysis on randomised controlled trials of psychological interventions for MUS. Physical symptoms were the primary outcome, and physical functioning and psychological symptoms were the secondary outcomes. We pooled between-group effect sizes (ESs) after the treatment and at the follow-up in random-effects meta-regressions and stratified meta-analyses. We repeated these analyses with the intervention provider, intervention dose, MUS severity and methodological quality as predictors of relative intervention effects. RESULTS: A total of 3,225 patients in 20 studies were analysed. After the treatment, small and significant ESs were found for all 3 outcome domains (ES range: 0.13-0.19, all p < 0.05). Psychological interventions were more beneficial for physical symptoms when delivered by PTs than by GPs (p = 0.02). There was no difference between PTs and GPs in terms of physical functioning and psychological symptoms. CONCLUSION: Psychological interventions are effective for patients with MUS, but the effects are small and most likely of short duration. Interventions that are delivered by PTs appear to have larger effects on unexplained physical symptoms than those delivered by GPs. Whether this superiority is due to a larger number of sessions of PT interventions remains unclear from our findings. PMID- 26022269 TI - Diagnosis and treatment of chlamydia and gonorrhoea in general practice in England 2000-2011: a population-based study using data from the UK Clinical Practice Research Datalink. AB - OBJECTIVES: To determine the relative contribution of general practices (GPs) to the diagnosis of chlamydia and gonorrhoea in England and whether treatment complied with national guidelines. DESIGN: Analysis of longitudinal electronic health records in the Clinical Practice Research Datalink (CPRD) and national sexually transmitted infection (STI) surveillance databases, England, 2000-2011. SETTING: GPs, and community and specialist STI services. PARTICIPANTS: Patients diagnosed with chlamydia (n=1,386,169) and gonorrhoea (n=232,720) at CPRD GPs, and community and specialist STI Services from 2000-2011. MAIN OUTCOME MEASURES: Numbers and rates of chlamydia and gonorrhoea diagnoses; percentages of patients diagnosed by GPs relative to other services; percentage of GP patients treated and antimicrobials used; percentage of GP patients referred. RESULTS: The diagnosis rate (95% CI) per 100,000 population of chlamydia in GP increased from 22.8 (22.4-23.2) in 2000 to 29.3 (28.8-29.7) in 2011 (p<0.001), while the proportion treated increased from 59.5% to 78.4% (p=0.001). Over 90% were prescribed a recommended antimicrobial. Over the same period, the diagnosis rate (95% CI) per 100,000 population of gonorrhoea in GP ranged between 3.2 (3-3.3) and 2.4 (2.2-2.5; p=0.607), and the proportion treated ranged between 32.7% and 53.6% (p=0.262). Despite being discontinued as a recommended therapy for gonorrhoea in 2005, ciprofloxacin accounted for 42% of prescriptions in 2007 and 20% in 2011. Over the study period, GPs diagnosed between 9% and 16% of chlamydia cases and between 6% and 9% of gonorrhoea cases in England. CONCLUSIONS: GP makes an important contribution to the diagnosis and treatment of bacterial STIs in England. While most patients diagnosed with chlamydia were managed appropriately, many of those treated for gonorrhoea received antimicrobials no longer recommended for use. Given the global threat of antimicrobial resistance, GPs should remain abreast of national treatment guidelines and alert to treatment failure in their patients. PMID- 26022271 TI - Lung cancer at the intensive care unit: The era of targeted therapy. AB - Lung cancer is the most common solid tumor that requires admission to an intensive care unit (ICU). The overall perception about the value of ICU admission for lung cancer patients remains negative, given the poor overall prognosis of patients with advanced lung cancer. Recently developed highly effective targeted therapies for lung cancers with an oncogene driver have an expected rapid onset of action and a decreased risk of toxicity. Therefore, ICU care for lung cancer patients has to be reconsidered. We present an illustrative case of a young woman with stage IV ALK-translocated pulmonary adenocarcinoma. Her disease dramatically worsened while waiting for central confirmation of the ALK-translocation to start treatment in a clinical trial with ceritinib, a 2nd generation ALK tyrosine kinase inhibitor. She needed mechanical ventilation and veno-venous extracorporal membranous oxygenation, to have sufficient time to recover from overwhelming bilateral lung adenocarcinoma, while on treatment. She is now doing fine 1 year later. PMID- 26022272 TI - Improved amplification efficiency on stool samples by addition of spermidine and its use for non-invasive detection of colorectal cancer. AB - BACKGROUND: Using quantitative methylation-specific PCR (QM-MSP) is a promising method for colorectal cancer (CRC) diagnosis from stool samples. Difficulty in eliminating PCR inhibitors of this body fluid has been extensively reported. Here, spermidine is presented as PCR facilitator for the detection of stool DNA methylation biomarkers using QM-MSP. We examined its effectiveness with NPY, PENK and WIF1, three biomarkers which we have previously shown to be of relevance to CRC. RESULTS: We determined an optimal window for the amplification of the albumin (Alb) gene (100 ng of bisulfite-treated stool DNA added of 1 mM spermidine) at which we report that spermidine acts as a PCR facilitator (AE = 1680%) for SG RT-PCR. We show that the amplification of methylated PENK, NPY and WIF1 is considerably facilitated by QM-MSP as measured by an increase of CMI (Cumulative Methylation Index, i.e. the sum of the three methylation values) by a factor of 1.5 to 23 fold in individual samples, and of 10 fold in a pool of five samples. CONCLUSIONS: We contend that spermidine greatly reduces the problems of PCR inhibition in stool samples. This observed feature, after validation on a larger sampling, could be used in the development of stool-based CRC diagnosis tests. PMID- 26022273 TI - Animal-inflicted ocular and adnexal injuries in children: A systematic review. AB - Eye injury remains the leading cause of monocular blindness in children despite 90% of injuries being potentially preventable. Children interact with animals in a variety of situations, and the associated dangers may be underestimated. Animals are capable of causing ocular and adnexal injuries that are cosmetically and visually devastating. We examine the current literature regarding the nature and severity of animal-inflicted ocular and adnexal injuries in children. PMID- 26022274 TI - Primary Synovial Sarcoma of the Pharynx: A Series of Five Cases and Literature Review. AB - Synovial sarcoma comprises approximately 10 % of all soft tissue sarcomas. Although synovial sarcoma has been reported in practically every organ, the extremities are the commonest site of occurrence followed by the head and neck. Primary synovial sarcoma of the pharynx is rare and only case reports have been published. We report a series of five cases of primary synovial sarcoma involving the pharynx. PMID- 26022275 TI - Cost and feasibility: an exploratory case study comparing use of a literature review method with questionnaires, interviews and focus groups to identify barriers for a behaviour-change intervention. AB - BACKGROUND: It is often recommended that behaviour-change interventions be tailored to barriers. There is a scarcity of research into the best method of barrier identification, although combining methods has been suggested to be beneficial. This paper compares the feasibility and costs of three different methods of barrier identification used in three implementation projects conducted in primary care. METHODS: Underpinned by a theory-base, project one used a questionnaire and interviews; project two used a single focus group and questionnaire, and project three used a literature review of published barriers. The feasibility of each project, as experienced by the research team, and labour costs are summarised. RESULTS: The literature review of published barriers was the least costly and most feasible method, being quick to conduct and avoiding the challenges of recruitment experienced when using interviews or a questionnaire. The feasibility of using questionnaires was further reduced by the time taken to develop the instruments. Conducting a single focus group was also found to be a more feasible method, taking less time than interviews to collect and analyse the barriers. CONCLUSIONS: Considering the ease of recruitment, time required and cost of the different methods to collect barriers is crucial at the start of implementation studies. The literature review method is the least costly and most feasible method. Use of a single focus group was found to be more feasible than conducting individual interviews or administering a questionnaire, with less recruitment challenges experienced, and quicker data collection. Future research would benefit from comparing the robustness of the methods in terms of the comprehensiveness of barriers identified. PMID- 26022276 TI - The novel secretory protein CGREF1 inhibits the activation of AP-1 transcriptional activity and cell proliferation. AB - The transcription factor AP-1 plays an important role in inflammation and cell survival. Using a dual-luciferase reporter assay system and a library of 940 candidate human secretory protein cDNA clones, we identified that CGREF1 can inhibit the transcriptional activity of AP-1. We demonstrated that CGREF1 is secreted via the classical secretory pathway through the ER-to-Golgi apparatus. Functional investigations revealed that overexpression of CGREF1 can significantly inhibit the phosphorylation of ERK and p38 MAPK, and suppress the proliferation of HEK293T and HCT116 cells. Conversely, specific siRNAs against CGREF1 can increase the transcriptional activity of AP-1. These results clearly indicated that CGREF1 is a novel secretory protein, and plays an important role in regulation of AP-1 transcriptional activity and cell proliferation. PMID- 26022277 TI - Coronaridine congeners inhibit human alpha3beta4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. AB - To characterize the interaction of coronaridine congeners with human (h) alpha3beta4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca(2+) influx results established that coronaridine congeners noncompetitively inhibit halpha3beta4 AChRs with the following potency (IC50's in MUM) sequence: (-)-ibogamine (0.62+/-0.23)~(+)-catharanthine (0.68+/ 0.10)>(-)-ibogaine (0.95+/-0.10)>(+/-)-18-methoxycoronaridine [(+/-)-18-MC] (1.47+/-0.21)>(-)-voacangine (2.28+/-0.33)>(+/-)-18-methylaminocoronaridine (2.62+/-0.57 MUM)~(+/-)-18-hydroxycoronaridine (2.81+/-0.54)>(-)-noribogaine (6.82+/-0.78). A good linear correlation (r(2)=0.771) between the calculated IC50 values and their polar surface area was found, suggesting that this is an important structural feature for its activity. The radioligand competition results indicate that (+/-)-18-MC and (-)-ibogaine partially inhibit [(3)H]imipramine binding by an allosteric mechanism. Molecular docking, molecular dynamics, and in silico mutation results suggest that protonated (-)-18-MC binds to luminal [i.e., beta4-Phe255 (phenylalanine/valine ring; position 13'), and alpha3-Leu250 and beta4-Leu251 (leucine ring; position 9')], non-luminal, and intersubunit sites. The pharmacophore model suggests that nitrogens from the ibogamine core as well as methylamino, hydroxyl, and methoxyl moieties at position 18 form hydrogen bonds. Collectively our data indicate that coronaridine congeners inhibit halpha3beta4 AChRs by blocking the ion channel's lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites. PMID- 26022278 TI - KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis. AB - INTRODUCTION: Our previous proteomic study on fibroblast-like synoviocytes (FLSs) derived from the synovial tissues found that the expression of KIAA1199 was higher in rheumatoid arthritis (RA) patients than in healthy controls. The aim of this study was to examine the biological function of KIAA1199 and evaluate its clinical diagnosis value in RA. METHODS: The over-expression of KIAA1199 was verified by quantitative real-time polymerase chain reaction (qPCR), Immunohistochemistry, Immunofluorescence and enzyme linked immunosorbent assay (ELISA) in inactive and active RA patients and healthy controls. The effect of KIAA1199 expression on FLSs proliferation, angiogenesis and related pathway were analyzed by MTT, cell migration, tube formation, chorioallantoic membrane (CAM) assay, qPCR and western-blotting after KIAA1199 knockdown and over-expression. RESULTS: The verification results show the up-regulation of KIAA1199 in RA patients at mRNA and protein level as compared to that in healthy controls. ELISA and receiver operator characteristic (ROC) analysis shows that KIAA1199 concentration in serum, synovial fluid and synovial tissues could be used as dependable biomarkers for the diagnosis of active RA, provided an area under roc curve (AUC) of 0.83, 0.92 and 0.92. Sensitivity and specificity, which were determined by cut-off points, reached 72% 84% and 80% in sensitivity and 80%, 93.3%, 93.3% in specificity, respectively. Moreover, KIAA1199 also enhance the proliferation and angiogenesis of synovial membrane, and KIAA1199/ PLXNB3/ SEMA5A/CTGF axis may be a newly found pathway enhancing cell proliferation and angiogenesis. CONCLUSION: KIAA1199 may be a potential diagnostic biomarker of RA related to angiogenesis. PMID- 26022279 TI - "Half-sandwich" Yb(III) single-ion magnets with metallacrowns. AB - The first "half-sandwich" Yb(III) single-ion magnets (SIMs) based on [12-MCZn(ii) 4] are reported, in which the central ytterbium ion is coordinated by YbO8 geometry in D4d symmetry. The anisotropic barrier is extracted from the analysis of static, dynamic magnetism and emission spectrum offering an insight into the magneto-optical correlation. PMID- 26022281 TI - Sebum Secretion of the Trunk and the Development of Truncal Acne in Women: Do Truncal Acne and Sebum Affect Each Other? AB - BACKGROUND: There are few published data on truncal acne because most studies have focused on facial acne. AIMS: The objective of this study was to investigate truncal sebum secretion levels in patients with acne vulgaris and to evaluate the relationship between sebum secretion and the development of acne lesions. METHODS: The sebum casual levels at five different facial sites and ten truncal sites were measured in 35 Korean females with acne using a Sebumeter(r). We performed an analysis of the correlation between sebum excretion and acne lesion number. RESULTS: We found that all of the truncal sites analyzed had lower sebum secretion levels than the facial sites. There was no significant correlation between sebum secretion and acne lesions on the trunk. CONCLUSION: Pathogenic factors other than sebum may have a predominant role in the development of truncal acne. PMID- 26022280 TI - Characterisation of recycled acrylonitrile-butadiene-styrene and high-impact polystyrene from waste computer equipment in Brazil. AB - Polymeric materials constitute a considerable fraction of waste computer equipment and polymers acrylonitrile-butadiene-styrene and high-impact polystyrene are the main thermoplastic polymeric components found in waste computer equipment. Identification, separation and characterisation of additives present in acrylonitrile-butadiene-styrene and high-impact polystyrene are fundamental procedures to mechanical recycling of these polymers. The aim of this study was to evaluate the methods for identification of acrylonitrile-butadiene styrene and high-impact polystyrene from waste computer equipment in Brazil, as well as their potential for mechanical recycling. The imprecise utilisation of symbols for identification of the polymers and the presence of additives containing toxic elements in determinate computer devices are some of the difficulties found for recycling of acrylonitrile-butadiene-styrene and high impact polystyrene from waste computer equipment. However, the considerable performance of mechanical properties of the recycled acrylonitrile-butadiene styrene and high-impact polystyrene when compared with the virgin materials confirms the potential for mechanical recycling of these polymers. PMID- 26022282 TI - Woman with gene for Huntington's disease fails in attempt to sue her father's doctors for failing to alert her. PMID- 26022283 TI - Alginate fouling reduction of functionalized carbon nanotube blended cellulose acetate membrane in forward osmosis. AB - Functionalized multi-walled carbon nanotube blended cellulose acetate (fCNT-CA) membranes were synthesized for forward osmosis (FO) through phase inversion. The membranes were characterized through SEM, FTIR, and water contact angle measurement. AFM was utilized to investigate alginate fouling mechanism on the membrane. It reveals that the fCNT contributes to advance alginate fouling resistance in FO (57% less normalized water flux decline for 1% fCNT-CA membrane was observed than that for bare CA membrane), due to enhanced electrostatic repulsion between the membrane and the alginate foulant. Furthermore, it was found that the fCNT-CA membranes became more hydrophilic due to carboxylic groups in functionalized carbon nanotube, resulting in approximately 50% higher water permeated flux than bare CA membrane. This study presents not only the fabrication of fCNT-CA membrane and its application to FO, but also the quantification of the beneficial role of fCNT with respect to alginate fouling in FO. PMID- 26022284 TI - Interactions of carbon nanotubes with aqueous/aquatic media containing organic/inorganic contaminants and selected organisms of aquatic ecosystems--A review. AB - Due to their unique molecular architecture translating into numerous every-day applications, carbon nanotubes (CNTs) will be ultimately an increasingly significant environmental contaminant. This work reviews qualitative/quantitative analyses of interactions of various types of CNTs and their chemically modified analogues with aqueous/aquatic media containing organic and inorganic contaminants and selected organisms of aquatic ecosystems. A special emphasis was placed on physicochemical interactions between CNTs as adsorbents of heavy metal cations and aromatic compounds (dyes) with its environmental consequences. The studies revealed CNTs as more powerful adsorbents of aromatic compounds (an order of magnitude higher adsorption capacity) than metal cations. Depending on the presence of natural organic matter (NOM) and/or co-contaminants, CNTs may act as Trojan horse while passing through biological membranes (in the absence of NOM coordinating metal ions). Nanotubes, depending on flow conditions and their morphology/surface chemistry, may travel with natural waters or sediment with immobilized PAHs or metals and/or increase cyto- and ecotoxicity of PAHs/metal ions by their release via competitive complexation, or cause synergic ecotoxicity while adsorbing nutrients. Additionally, toxicity of CNTs against exemplary aquatic microorganisms was reviewed. It was found for Daphnia magna that longer exposures to CNTs led to higher ecotoxicity with a prolonged CNTs excretion. SWCNTs were more toxic than MWCNTs, while hydrophilization of CNTs via oxidation or anchoring thereto polar/positively charged polymer chains enhanced stability of nanotubes dispersion in aqueous media. On the other hand, bioavailability of functionalized CNTs was improved leading to more complex both mechanisms of uptake and cytotoxic effects. PMID- 26022285 TI - [Efficacy, safety and cost of eribulin in patients with metastatic breast cancer]. AB - Eribulin gained its approval in March 2011 for the treatment of patients with locally advanced or metastatic breast cancer (MBC) whose disease has progressed despite anthracycline and taxane-containing regimens. This study retrospectively assessed the efficacy, safety and cost of this treatment for all patients with MBC treated by eribulin in Franche-Comte. Ninety-four patients received eribulin between July 2006 and October 2013. The median age was 62 years (35-83). Median overall survival was 10.3 months [95% CI: 7.6 to 17.9]. Median progression-free survival was 3.8 months [95% CI: 2.9 to 5.0]. Clinical benefit was obtained in 55% evaluable patients [95% CI: 43.1 to 66.9] by RECIST criteria. Most common grade 3-4 adverse events (AEs) were neutropenia (38%), asthenia (10%) and peripheral neuropathy (7%). Median cost of the treatment was 9767 ? per patient (6344-17,517). This analysis found similar results to the EMBRACE study despite less selected population. A medico-economic evaluation cost-utility type would assess the effectiveness of this strategy compared to standard treatments. PMID- 26022286 TI - [New therapies in metastatic castration resistant prostate cancer]. AB - Therapeutic arsenal in prostate cancer widens for several years. New hormonal therapies such as acetate abiraterone or enzalutamide were the first molecules to revolutionize the treatment of metastatic castration resistant prostate cancer. Several other treatments are on trial targeting different pathways: androgene pathway (TAK-007, ARN-509, ODM-201, TOK-001), immune system (sipuleucel, ipilimumab, PROSTVAC-V/F, tasquinimod), but also tumor cell (PARP inhibitor, cabozantinib). The treatment sequencing will therefore soon be problematic, raising the necessity to identify predictive markers of response to the new therapies. PMID- 26022287 TI - [Thoraco-abdomino-pelvic surgery for tumors in children: Postoperative sequelae]. AB - Thoracic surgery for pediatric tumors may induce a large variety of sequelae that mainly concern skin, muscles and bones (ribs), thoracic nerve and spinal cord and respiratory system. Muscle-sparing thoracotomy, intrathoracic expanders inserted after right pneumonectomy, early orthopedic evaluation and follow-up are useful preventive proceedings able to decrease postoperative sequelae. Surgery for abdominal tumors in children is part of a sequence where each therapeutic treatment can induce its own sequelae possibly potentiated by other therapies. Scars and occlusions represent classic effects, others like diarrhea, intestinal ischemia may require specific and sometimes partially effective long-term treatment. The pelvic cavity is characterized by an anatomy dedicated to urinary and digestive continence and reproductive functions. The oncologic resection of tumors developed in this region exposed to significant risk of sequelae that may strongly affect the quality of life. The development of conservative approaches for local treatment and of fertility preservation techniques has significantly reduced this morbidity and must be known by the surgeon to optimize the therapeutic strategy. PMID- 26022288 TI - [Mucosal melanomas of the head and neck: State of the art and current controversies]. AB - Mucosal melanomas of the head and neck (sinonasal and oral cavity) account for 1% of neoplasms, 4% of all melanomas and over 50% of all mucosal melanomas. They have a high metastatic potential. Five-year overall survival does not exceed 30%. Diagnosis may be difficult and includes adequate immunohistochemical staining. Risk factors, presentation and molecular biology are different from those of cutaneous melanomas. The mainstay of treatment is surgery and postoperative radiotherapy. Endoscopic surgery should be evaluated prospectively. Neck dissection is recommended for N0 oral cavity melanomas, while it can generally be omitted for sinonasal melanomas. Inoperable tumors can be treated with exclusive radiotherapy. Molecular guidance for metastatic cases is a relevant option despite low level of evidence, based on the rarity of disease and low response rates to chemotherapy. c-KIT inhibitors and immunotherapy appear promising. PMID- 26022289 TI - Predictive value of the time interval between embryo loading and transfer for IVF/ICSI success: a prospective cohort study. AB - BACKGROUND: The influence of embryo loading time (ELT) and the time interval between embryo loading and embryo transfer (TIEL-ET) on the success of IVF/ICSI is unknown. METHODS: In a prospective cohort study, we aimed to ascertain the influence of ELT and TIEL-ET on ongoing pregnancy rate (OPR) and life birth rate (LBR). Data from 603 consecutive embryo transfers between January 2008 and December 2013 were collected. A complete data set including the outcomes of interest OPR and LBR was available for 410 women. The primary outcome was IVF/ICSI success, defined as OPR and LBR. RESULTS: We used univariate and multivariate logistic regression for analysis. In a multivariate analysis, age (odds ratio [OR] 0.94; 95% confidence interval [CI] 0.89-0.99), catheter type (OR 0.45; 95% CI 0.24-0.84), and uterine length (OR 1.03; 95% CI 1.01-1.06), but not ELT and TIELT-ET were independently associated with OPR. Regarding LBR, age (OR 0.93; 95% CI 0.88-0.98), catheter type (OR 0.41; 95% CI 0.22-0.79), and uterine length (OR 1.03; 95% CI 1.01-1.06), but not ELT and TIELT-ET were independent predictors. CONCLUSION: We conclude that speed of embryo transfer is not critical for the success of IVF/ICSI. However, care should be taken to choose catheter types proven to be associated with a high success rate. PMID- 26022290 TI - Psycholinguistic Evidence for Inverse Scope in Korean. AB - We use experimental data to shed light on the ongoing question of whether Korean allows inverse scope interpretation in sentences containing an indefinite subject and a universally quantified direct object (e.g., 'Someone bought each loaf of bread at the bakery'). The results of an off-line acceptability judgment task (n = 38) and an online self-paced reading task (n [Formula: see text] 22) indicate that inverse scope interpretations are in fact permitted in Korean as a secondary option, as is also the case in English. We argue that the dispreference for the inverse scope reading reflects processing considerations related to burden on working memory. PMID- 26022291 TI - Clever space saving-how the cerebral cortex folds. PMID- 26022292 TI - Departure gate of acidic Ca2+ confirmed. PMID- 26022294 TI - [In a scientific paper: who should be the first author?]. PMID- 26022293 TI - SDN-1/Syndecan Acts in Parallel to the Transmembrane Molecule MIG-13 to Promote Anterior Neuroblast Migration. AB - The Q neuroblasts in Caenorhabditis elegans display left-right asymmetry in their migration, with QR and descendants on the right migrating anteriorly, and QL and descendants on the left migrating posteriorly. Initial QR and QL migration is controlled by the transmembrane receptors UNC-40/DCC, PTP-3/LAR, and the Fat-like cadherin CDH-4. After initial migration, QL responds to an EGL-20/Wnt signal that drives continued posterior migration by activating MAB-5/Hox activity in QL but not QR. QR expresses the transmembrane protein MIG-13, which is repressed by MAB 5 in QL and which drives anterior migration of QR descendants. A screen for new Q descendant AQR and PQR migration mutations identified mig-13 as well as hse-5, the gene encoding the glucuronyl C5-epimerase enzyme, which catalyzes epimerization of glucuronic acid to iduronic acid in the heparan sulfate side chains of heparan sulfate proteoglycans (HSPGs). Of five C. elegans HSPGs, we found that only SDN-1/Syndecan affected Q migrations. sdn-1 mutants showed QR descendant AQR anterior migration defects, and weaker QL descendant PQR migration defects. hse-5 affected initial Q migration, whereas sdn-1 did not. sdn-1 and hse 5 acted redundantly in AQR and PQR migration, but not initial Q migration, suggesting the involvement of other HSPGs in Q migration. Cell-specific expression studies indicated that SDN-1 can act in QR to promote anterior migration. Genetic interactions between sdn-1, mig-13, and mab-5 suggest that MIG 13 and SDN-1 act in parallel to promote anterior AQR migration and that SDN-1 also controls posterior migration. Together, our results indicate previously unappreciated complexity in the role of multiple signaling pathways and inherent left-right asymmetry in the control of Q neuroblast descendant migration. PMID- 26022295 TI - Ring-tailed lemurs: a species re-imagined. AB - For over 50 years, ring-tailed lemurs have been studied continuously in the wild. As one of the most long-studied primate species, the length and breadth of their study is comparable to research on Japanese macaques, baboons and chimpanzees. They are also one of the most broadly observed of all primates, with comprehensive research conducted on their behaviour, biology, ecology, genetics, palaeobiology and life history. However, over the last decade, a new generation of lemur scholars, working in conjunction with researchers who have spent decades studying this species, have greatly enhanced our knowledge of ring-tailed lemurs. In addition, research on this species has expanded beyond traditional gallery forest habitats to now include high altitude, spiny thicket, rocky outcrop and anthropogenically disturbed coastal forest populations. The focus of this special volume is to 're-imagine' the 'flagship species of Madagascar', bringing together three generations of lemur scholars. PMID- 26022296 TI - Dr. Alison Jolly. PMID- 26022297 TI - Reproductive Female Feeding Strategies in Spiny Forest-Dwelling Lemur catta in Southern and Southwestern Madagascar: How Do Females Meet the Challenges of Reproduction in this Harsh Habitat? AB - The spiny forest ecoregion of southern and southwestern Madagascar is characterized by low annual rainfall, high temperatures, short-stature xeric vegetation and lack of canopy. Lemur catta is often the only diurnal primate persisting in this habitat. For reproductive females living in spiny forests, gestation and early-to-mid lactation periods occur during the dry season when food resources are limited. We conducted a between-site comparison of variables important to the feeding ecology of reproductive female L. catta inhabiting spiny forest at 3 sites: Berenty spiny forest (BSF), Cap Sainte-Marie (CSM) and Tsimanampesotse National Park (TNP). We hypothesize that the ability for pregnant and lactating females to adequately obtain plant foods high in protein, low in fiber and with a high water content is crucial to their survival and successful reproduction in spiny habitat. We found favorable or relatively equal protein-to fiber ratios in plant foods most frequently consumed by reproductive females, and preferred foods contained high water content. Some overlap in preferred plant species at the 3 sites suggests important plant foods for reproductive females inhabiting spiny forests. We suggest that choosing foods high in protein, relatively low in fiber and with high water content are behavioral adaptations allowing female L. catta to reproduce and survive in this habitat. PMID- 26022298 TI - Seasonal feeding ecology of ring-tailed lemurs: a comparison of spiny and gallery forest habitats. AB - Although Lemur catta persists in many habitat types in southern Madagascar, its ecology has been primarily studied within gallery forests. We compare plant food selection and properties for ring-tailed lemurs in the spiny and gallery forests over the synchronized lactation period (September to March) that includes both the dry and wet seasons. We found no significant habitat-specific differences in the type of plant part consumed per month (i.e. flower, fruit, leaf) or between the intake of soluble carbohydrates. However, the presence and use of Tamarindus indica plants appear to elevate protein and fiber intake in the gallery forest lemurs' diets. Protein is especially important for reproductive females who incur the added metabolic costs associated with lactation; however, fiber can disrupt protein digestion. Future work should continue to investigate how variations of protein and fiber affect ring-tailed lemur dietary choice and nutrient acquisition. PMID- 26022299 TI - Beyond the Gallery Forest: Contrasting Habitat and Diet in Lemur catta Troops at Beza Mahafaly Special Reserve. AB - Ring-tailed lemurs have been studied intensively in the Parcel 1 gallery forest of Beza Mahafaly Special Reserve. Here, we report on lemur groups in a mixture of deciduous dry forest and spiny forest just 5 km to the west. Compared to Parcel 1, Parcel 2 (P2) has a lower density of Tamarindus indica, a major dietary plant species for gallery forest lemurs. Recent studies in drier habitats have called into question the association of lemur density and tamarind presence. In order to address this question, we measured forest structure and composition of plant plots between parcels and conducted lemur feeding observations. The trees and shrubs within the parcels did not differ in height or diameter at breast height, but the frequencies of plant species that were common between parcels were significantly different. Numbers of feeding observations on foods common to both parcels did not differ, but their relative rankings within parcels did. Frequencies of food plants corresponded to earlier reports of lemur population densities. However, we found that the ring-tailed lemur diet is a mixture of plants that are eaten in abundance regardless of frequency and those that are locally available. In terms of their reliance on Tamarindus, P2 animals appear intermediate between those in gallery forests and nontamarind sites. PMID- 26022300 TI - Examining visual measures of coat and body condition in wild ring-tailed lemurs at the Beza Mahafaly Special Reserve, Madagascar. AB - Coat and body mass status provide a potential noninvasive way to assess primate health status as well as the effects of seasonality, resource use and reproductive state. Coat and body condition were scored visually for 36 wild Lemur catta at the Beza Mahafaly Special Reserve, Madagascar, from July 2012 to March 2013. Coat quality generally increased during the wet season when resource availability increased, in contrast to that observed during the resource-depleted dry season. Alopecia frequency increased from June to December and declined between January and March. Sex differences for coat condition were only observed in January, when males had superior coat scores. Body condition did not vary by month or sex except in February, when males were larger than females. Females that birthed infants were of lower body size than individuals who did not for November and from January to March. Our results indicate visual methods effectively detect variability in coat and body condition related to seasonality and reproductive status. Such methods present a noninvasive means for assessing the impact of seasonal resource availability, stresses of infant care and reproductive state on ring-tailed lemurs, and may be useful for assessing the impacts of these factors on general health status. PMID- 26022301 TI - Ring-Tailed Lemur (Lemur catta) Health Parameters across Two Habitats with Varied Levels of Human Disturbance at the Beza Mahafaly Special Reserve, Madagascar. AB - The health of 36 wild, free-ranging ring-tailed lemurs (Lemur catta) at the Beza Mahafaly Special Reserve was assessed across 2 habitats of varied human impact: a reserve riverine gallery forest, and a degraded mixed dry deciduous and Alluaudia dominated spiny forest. While there were no statistically significant differences in leukocyte count or differential between habitats, female lemurs in the reserve gallery forest had significantly higher percentages of monocytes and eosinophils than male lemurs in the gallery forest. Lemurs from the degraded spiny habitat had significantly higher mean packed cell volume, hematocrit, hemoglobin, total protein, blood urea nitrogen, chloride, ionized calcium and urine specific gravity than lemurs from the reserve gallery forest. These findings may reflect lower hydration levels in lemurs living in degraded habitat, providing evidence that environmental degradation has identifiable impacts on the physiology and health of wild, free-ranging ring-tailed lemurs living in nearby habitats. Given the greater evidence of human impact in the mixed dry deciduous/spiny forest habitat, a pattern seen throughout southern Madagascar, biomedical markers suggestive of decreased hydration can provide empirical data to inform new conservation policies facilitating the long-term survival of this lemur community. PMID- 26022302 TI - Genetic Evidence for Male and Female Dispersal in Wild Lemur catta. AB - Lemur catta has traditionally been considered a species with male-biased dispersal; however, occasional female dispersal occurs. Using molecular data, we evaluated dispersal patterns in 2 L. catta populations in southwestern Madagascar: Tsimanampesotse National Park (TNP) and Beza Mahafaly Special Reserve (BMSR). We also investigated the genetic differentiation between the populations and dispersal partner relatedness. Results showed minor genetic differentiation between the populations (Theta(ST) = 0.039), which may indicate gene flow historically occurring in this region, made possible by the presence of L. catta groups between the sites. Different patterns of sex-biased dispersal were found between the sites using corrected assignment indices: male-biased dispersal in TNP, and a lack of sex-biased dispersal in BMSR. Observational evidence of female dispersal in BMSR supports these results and may imply intense female resource competition in and around BMSR, because small groups of 2-3 females have been observed dispersing within BMSR and entering the reserve from outside. These dispersing groups largely consisted of mothers transferring with daughters, although we have an aunt-niece pair transferring together. Genetic data suggest that males also transfer with relatives. Our data demonstrate that dispersal partners consist of same-sexed kin for L. catta males and females, highlighting the importance of kin selection. PMID- 26022303 TI - Genetic Diversity of the Ring-Tailed Lemur (Lemur catta) in South-Central Madagascar. AB - Madagascar's lemurs, now deemed the most endangered group of mammals, represent the highest primate conservation priority in the world. Due to anthropogenic disturbances, an estimated 10% of Malagasy forest cover remains. The endangered Lemur catta is endemic to the southern regions of Madagascar and now occupies primarily fragmented forest habitats. We examined the influence of habitat fragmentation and isolation on the genetic diversity of L. catta across 3 different forest fragments in south-central Madagascar. Our analysis revealed moderate levels of genetic diversity. Genetic differentiation among the sites ranged from 0.05 to 0.11. These data suggest that the L. catta populations within south-central Madagascar have not yet lost significant genetic variation. However, due to ongoing anthropogenic threats faced by ring-tailed lemurs, continued conservation and research initiatives are imperative for long-term viability of the species. PMID- 26022304 TI - The Gut Microbiome of Wild Lemurs: A Comparison of Sympatric Lemur catta and Propithecus verreauxi. AB - Mammalian gut microbes are invaluable to the host's metabolism, but few researchers have examined gut microbial dynamics under natural conditions in wild mammals. This study aims to help fill this knowledge gap with a survey of the natural variation of the gut microbiome in 2 wild lemur species, Lemur catta and Propithecus verreauxi. The wild L. catta were also compared to a captive population to discern the effect of habitat within a species. Gut microbial DNA was extracted from fecal samples collected in Madagascar and the Vienna Zoo and sequenced. The wild and captive L. catta had distinct microbial communities, likely due to differences in diet and development between their populations. The wild L. catta and P. verreauxi also had distinct gut microbiomes, due to a change in microbial abundance, not composition. Within each lemur species, there was abundant variation between individuals and from the dry to the wet season. The intraspecific and temporal microbial variation requires more investigation, with changes in diet a likely contributor. PMID- 26022305 TI - Ecological risk aversion and juvenile ring-tailed lemur feeding and foraging. AB - The extended primate juvenile period has been linked to interactions between feeding ecology and sociality. However, accumulating field data on juvenile primates suggest variation in the linkages between foraging efficiency, group foraging and social behaviour. In many non-human primates, juvenile ability (strength, coordination and motor skills) does not limit foraging success. If predicted limitations in feeding are not found in juvenile monkeys, it is possible that the gregarious strepsirrhines may show foraging patterns similar to those implicated in the evolution of a life history where long juvenile periods are advantageous. To test these behavioural predictions, I present a mixed longitudinal sample of observations on feeding and foraging behaviour from ring tailed lemurs (Lemur catta) at the Beza Mahafaly Special Reserve, Madagascar. Like several platyrrhine species, close proximity during foraging, low feeding efficiency and low dietary diversity are not typical of ring-tailed lemurs. The lack of ecological trade-offs in these species may indicate stronger common roles of sociality and social complexity in structuring the elongation of the primate juvenile period. PMID- 26022306 TI - Cognition in ring-tailed lemurs. AB - In order to better understand the evolution of cognitive abilities in primates, information on cognitive traits of the most basal living primates can provide important comparative baseline data. Compared to haplorhine primates, lemurs have relatively smaller brains and reduced abilities to solve problems in the technical and social domain. However, recent studies have suggested that some cognitive abilities of lemurs are qualitatively equal to those of haplorhines. Here, we review studies investigating cognitive abilities in the technical and social domain of ring-tailed lemur cognition. In the physical domain, ring-tailed lemurs exhibit similar qualitative cognitive skills as other lemurs but also haplorhine primates. In the social domain, ring-tailed lemurs appear to be more skilled in visual perspective taking than other lemurs. Compared to other lemurs, they also have highly elaborated communicative skills. Moreover, within-group coalitions have been observed in female ring-tailed lemurs during rare events of female evictions but not in other lemur species. However, in several other aspects of social cognition, such as reconciliation and social learning, ring tailed lemurs' cognitive abilities are equal to those of other lemurs. Thus, additional systematic comparative studies in physical and social cognition are required for a more comprehensive understanding of the processes of cognitive evolution among primates. PMID- 26022307 TI - Anchoring the Clade: Primate-Wide Comparative Analysis Supports the Relationship between Juvenile Interest in Infants and Adult Patterns of Infant Care. AB - Female-biased juvenile interest in infants is common in primates. Proposed hypotheses to explain juvenile infant interest are that it helps immature individuals learn to parent, is a by-product of selection on adult infant care behavior, is kin-selected cooperative rearing, or is a form of harassment. If juvenile infant interest is associated with adult infant care, either functionally or as a by-product, sex-biased patterns of juvenile infant interest and adult infant care should show correlated evolution; if juvenile infant interest functions as cooperative rearing or harassment, they should not. Comparisons of nested bayesian Markov chain Monte Carlo models of independent and dependent evolution of juvenile infant interest and adult infant care indicate strong support for coevolution of juvenile infant interest and adult infant care. Expanding comparative analysis to include available data from lemurs strengthens this support, suggesting that the function of juvenile infant interest does not differ between strepsirrhines and haplorhines. As such, strepsirrhine taxa currently maintained in captivity will be particularly useful in future work aiming to test between the learning to parent and by-product hypotheses for juvenile infant interest. PMID- 26022308 TI - Antipredator Vocalization Usage in the Male Ring-Tailed Lemur (Lemur catta). AB - The ring-tailed lemur (Lemur catta) is a group-living strepsirrhine primate endemic to Madagascar that faces considerable predation pressure from aerial and terrestrial predators. This species engages in mobbing and vigilance behavior in response to predators, and has referential alarm vocalizations. Because L. catta is female dominant, less is known about the alarm calls of males. We tested 3 hypotheses for male antipredator vocalization behavior on L. catta at the Beza Mahafaly Special Reserve in Madagascar: the predator confusion, group maintenance, and predation risk allocation hypotheses. We found support for 2 hypotheses. When a male L. catta made an antipredator call, other group members vocalized in response. Dominant males did not make alarm calls at higher rates than subordinate males. Predators were more abundant on the western side of Parcel 1, but an even greater number of antipredator vocalizations occurred in this area than predator abundance warranted. We show that male L. catta consistently participated in group-level antipredator vocalization usage in high risk locations. Although female L. catta are known to hold the primary role in group defense, male L. catta are also key participants in group-wide behaviors that may confuse or drive away predators. PMID- 26022309 TI - Lifespan and Reproductive Senescence in a Free-Ranging Ring-Tailed Lemur (Lemur catta) Population at Berenty, Madagascar. AB - The lifespan and age-specific fecundity of female ring-tailed lemurs (Lemur catta) were estimated from a 24-year longitudinal dataset based on individual identification at Berenty Reserve, Madagascar. The mean lifespan of females in 10 year (1989-1998) birth cohorts was 4.9 +/- 4.9 years (n = 77), and the longest recorded lifespan in the population was 20 years. The mortality rate of adult females increased to >=20% at 10-11 years old and reached 33-50% at 12-15 years old. Although the birth rate of old females (12-17 years old) was 72.0%, slightly lower than that of prime adult females (4-11 years old), i.e. 80.2%, no significant difference was found between them. Half of the females who reached the age of 12 years gave birth in the last year of their life. The oldest mother to give birth was 17 years old. These results suggest that most females can maintain reproductive performance in their later life and that there is no evidence for a postreproductive lifespan in this species. PMID- 26022310 TI - Patterns of Dental Macrowear in Subfossil Lemur catta from Ankilitelo Cave, Madagascar: Indications of Ecology and Habitat Use over Time. AB - The Ankilitelo cave site, Madagascar, contains a large collection of extant and recently extinct subfossil lemurs including the extant taxa Lemur catta and Eulemur rufifrons, which today are rarely found in sympatry. Dates for this assemblage range from 300 to 13,000 BP, though known dates for extinct primate specimens range between ~500 and ~600 BP. Data from Ankilitelo L. catta and E. rufifrons were compared to assess tooth wear in sympatric, related forms. Wear was scored using an ordinal scale from 0 to 5. For P4, M1 and M2, E. rufifrons displays significantly more wear than L. catta. Ankilitelo represents one of the most southerly samples of E. rufifrons, and wear data suggest that in the recent (i.e. Holocene) past, their diet near the edges of their geographic range included mechanically challenging foods. In contrast, sympatric L. catta was using foods in this transitional humid-dry forest with succulent woodlands that were not significantly impacted by recent human actions, and for which they were dentally adapted. Results also suggest that this non-gallery forest habitat may be the 'adaptive home' of L. catta, given the lack of notable tooth wear when compared to populations currently living in tamarind-dominated riverine gallery forests. PMID- 26022311 TI - A new polymeric ionic liquid-based magnetic adsorbent for the extraction of inorganic anions in water samples. AB - In this work, a novel type of polymeric ionic liquid (PIL)-based magnetic adsorbent was successfully synthesized and applied for the extraction and determination of seven inorganic anions in water samples by coupling with ion chromatography. The new adsorbent was synthesized by simple free radical copolymerization of 1-ally-3-vinylimidazolium chloride, ethylene glycol dimethacrylate and silica-coated magnetite. The adsorbent exhibited well-defined core-shell structure and good magnetic response ability. Furthermore, due to the presence of abundant anion-exchange groups in the PIL, the adsorbent displayed expected extraction performance for anions including F(-), Cl(-), Br(-), NO2(-), NO3(-), PO4(3-) and SO4(2-). Various experimental parameters that could affect the extraction performance, such as the amount of adsorbent, desorption solvent, extraction and desorption time, the pH value of sample solution were investigated in detail. Under the optimized conditions, low limits of detection (S/N=3) and quantification limits (S/N=10) of the proposed method for the target anions were achieved within the range of 0.061-0.73MUg/L and 0.19-2.41MUg/L, respectively. The repeatability was investigated by evaluating the intra-day, inter-day precisions and batch-to-batch reproducibility with relative standard deviations (RSDs) lower than 11%. At the same time, the method also showed high extraction speed, simplicity, practicality and low cost for the extraction inorganic anions. Finally, the proposed method was used to detect anions in different water samples successfully. The recoveries were in the range of 71.0-111%, and the RSDs were below 12% in the all cases. PMID- 26022312 TI - Simultaneous quantitation of five Panax notoginseng saponins by multi heart cutting two-dimensional liquid chromatography: Method development and application to the quality control of eight Notoginseng containing Chinese patent medicines. AB - Current China Pharmacopoeia (ChP) standards employ diversified and case-dependent assay methods to evaluate the quality of different Chinese patent medicines (CPMs) that contain Panax notoginseng as the monarch drug. These conventional, HPLC-based approaches, utilizing a complex sample preparation procedure, can easily result in low analytical efficiency and possible component loss. Here, a "monomethod-heterotrait matrix" (MHM) strategy is proposed, that is, developing a universal multi heart-cutting two-dimensional liquid chromatography (MHC-2D-LC) approach that facilitates the simultaneous quantitation of five P. notoginseng saponins (noto-R1, Re, Rg1, Rb1, and Rd) in eight different CPMs. The MHC-2D-LC system was constructed on a dual-gradient liquid chromatography instrument equipped with a Poroshell SB C18 column and a Zorbax SB-Aq column for respective (1)D and (2)D separation. Method validation was performed in terms of specificity, linearity (r(2) and F-test), intra-/inter-day precision (0.4-7.9%), stability (1.2-3.9%), and recovery (90.2-108.7%), and the LODs and LOQs (loaded masses) of the five analytes varied between 4.0-11.0ng and 6.0-33.0ng, respectively. The validated MHC-2D-LC approach was subsequently applied to quantify the five saponins in thirty batches of different CPMs. The method demonstrated superiority over the current ChP assay methods in respect of specificity (avoiding co-elution), resolution (Rs>1.5), sample preparation (easy to-implement ultrasonic extraction without repeated re-extraction), and transfer rate (minimum component loss). This is the first application of an MHC-2D-LC method for the quantitative assessment of the constituents of CPMs. The MHM approach represents a new, strategically significant methodology for the quality control of CPMs that involve complex chemical matrix. PMID- 26022313 TI - Polymethacrylate monolithic columns for hydrophilic interaction liquid chromatography prepared using a secondary surface polymerization. AB - Zwitterionic methacrylate based polymeric monolithic columns were prepared in two step polymerizations, with reduced polymerization times. Characteristic properties such as hydrodynamic permeability, porosity, retention factors, and pore size distribution charts were used for column evaluation. A scaffold column was fabricated by polymerization of poly(lauryl methacrylate-co tetraethyleneglycol dimethacrylate) and was used without further modification as a support for a poly(N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine-co-bisphenol A glycerolate dimethacrylate) second monolith layer with zwitterionic functionality, for HILIC separations. An additional internal structure was formed by the second monolithic layer. The fabrication procedure was reproducible with RSD<5%. Field emission scanning electron microscopy has also been used to investigate column pore morphology, using a novel technique where the polymeric material is imaged directly, without coverage with a conducting film or particles. The new polar monolithic columns were used for HILIC separations of phenolic acids, flavones, nucleosides, and bases of nucleic acids, with similar efficiencies but different selectivities for zwitterionic methacrylate monolithic columns recently prepared by single step polymerization. PMID- 26022315 TI - Plasmodium falciparum complicated malaria: Modulation and connectivity between exportome and variant surface antigen gene families. AB - In temperate and sub-tropical regions of Asia and Latin America, complicated malaria manifested as hepatic dysfunction or renal dysfunction is seen in all age groups. There has been a concerted focus on understanding the patho-physiological and molecular basis of complicated malaria in children, much less is known about it in adults. We report here, the analysis of data from a custom, cross strain microarray (Agilent Platform) using material from adult patient samples, showing hepatic dysfunction or renal failure. These are the most common manifestations seen in adults along with cerebral malaria. The data has been analyzed with reference to variant surface antigens, encoded by the var, rifin and stevor gene families. The differential regulation profiles of key genes (comparison between Plasmodium falciparum complicated and uncomplicated isolates) have been observed. The exportome has been analyzed using similar parameters. Gene ontology term based functional enrichment of differentially regulated genes identified, up regulated genes statistically enriched (P<0.05) to critical biological processes like generation of precursor metabolite and energy, chromosome organization and electron transport chain. Systems network based functional enrichment of overall differentially regulated genes yielded a similar result. We are reporting here, up-regulation of var group B and C genes whose proteins are predicted to interact with CD36 receptor in the host, the up-regulation of domain cassette 13 (DC13) containing var group A, as also the up-regulation of group A rifins and many of the stevors. This is contrary to most other reports from pediatric patients, with cerebral malaria where the up-regulation of mostly var A group genes have been seen. A protein-protein interaction based network has been created and analysis performed. This co-expression and text mining based network has shown overall connectivity between the variant surface antigens (VSA) and the exportome. The up regulation of var group B and C genes encoding PfEMP1 with different domain architecture would be important for deciding strategies for disease prevention. PMID- 26022314 TI - Serum biomarkers of treatment response within a randomized clinical trial for pulmonary tuberculosis. AB - RATIONALE: Biomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda. METHODS: We consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age. RESULTS: All but one analyte decreased from baseline to week 8 (all p < 0.01). Individual biomarkers were not associated with 8 week culture status. Logistic models including increasing age, higher baseline soluble tumor necrosis factor receptor alpha 1 (sTNF-R1), and higher week 8 C-reactive protein (CRP) concentration classified subjects by culture status with up to 85% accuracy and acceptable discrimination (cross-validated C-statistic 0.76) and calibration (Hosmer-Lemeshow P > 0.2). CONCLUSION: Exploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy. PMID- 26022316 TI - Baltic Sea ecosystem-based management under climate change: Integrating social and ecological perspectives. PMID- 26022317 TI - Baltic Sea management: Successes and failures. AB - Severe environmental problems documented in the Baltic Sea in the 1960s led to the 1974 creation of the Helsinki Convention for the Protection of the Marine Environment of the Baltic Sea Area. We introduce this special issue by briefly summarizing successes and failures of Baltic environmental management in the following 40 years. The loads of many polluting substances have been greatly reduced, but legacy pollution slows recovery. Top predator populations have recovered, and human exposure to potential toxins has been reduced. The cod stock has partially recovered. Nutrient loads are decreasing, but deep-water anoxia and cyanobacterial blooms remain extensive, and climate change threatens the advances made. Ecosystem-based management is the agreed principle, but in practice the various environmental problems are still handled separately, since we still lack both basic ecological knowledge and appropriate governance structures for managing them together, in a true ecosystem approach. PMID- 26022318 TI - Projected future climate change and Baltic Sea ecosystem management. AB - Climate change is likely to have large effects on the Baltic Sea ecosystem. Simulations indicate 2-4 degrees C warming and 50-80 % decrease in ice cover by 2100. Precipitation may increase ~30 % in the north, causing increased land runoff of allochthonous organic matter (AOM) and organic pollutants and decreased salinity. Coupled physical-biogeochemical models indicate that, in the south, bottom-water anoxia may spread, reducing cod recruitment and increasing sediment phosphorus release, thus promoting cyanobacterial blooms. In the north, heterotrophic bacteria will be favored by AOM, while phytoplankton production may be reduced. Extra trophic levels in the food web may increase energy losses and consequently reduce fish production. Future management of the Baltic Sea must consider the effects of climate change on the ecosystem dynamics and functions, as well as the effects of anthropogenic nutrient and pollutant load. Monitoring should have a holistic approach, encompassing both autotrophic (phytoplankton) and heterotrophic (e.g., bacterial) processes. PMID- 26022319 TI - Developing an analytical framework for assessing progress toward ecosystem-based management. AB - Ecosystem-based management (EBM) has become a key instrument of contemporary environmental policy and practice. Given the increasingly important role of EBM, there is an urgent need for improved analytical approaches to assess if and to what extent EBM has been accomplished in any given case. Drawing on the vast literature on EBM, we identify five key ecosystem aspects for assessment. By linking these aspects to four phases of management, we develop an interdisciplinary, analytical framework that enables a high-resolution and systematic assessment of the degree of specificity and integration of ecosystem aspects in an EBM. We then apply the framework to evaluate five coastal EBM initiatives in Sweden, four on the Baltic coast and one on the west coast. Our results demonstrate our framework's usefulness for in-depth and continuous assessments of processes aiming for EBM, and also provide an empirical basis for inferences about the key challenges for successful EBM. PMID- 26022320 TI - Legal prerequisites for ecosystem-based management in the Baltic Sea area: The example of eutrophication. AB - The purpose of this paper is to discuss the role of law in the management of the Baltic Sea, with focus on eutrophication. It aims to identify legal instruments or structures realizing an ecosystem approach. This also includes a discussion of the prerequisites of law as contributor to ecosystem-based management (EBM), as well as evaluation of current legal instruments. While ecosystem approach to environmental management is central to contemporary environmental management policy, it is still unclear what such an approach entails in concrete legal terms. The scope of the analysis stretches from international and EU legal regimes, to implementation and regulation within the national legal systems. A conclusion is that the management structures need further development to properly realize EBM, for example, through concretization of management measures, and clarification of duties and responsibilities for their realization. PMID- 26022321 TI - Variability in climate change simulations affects needed long-term riverine nutrient reductions for the Baltic Sea. AB - Changes to runoff due to climate change may influence management of nutrient loading to the sea. Assuming unchanged river nutrient concentrations, we evaluate the effects of changing runoff on commitments to nutrient reductions under the Baltic Sea Action Plan. For several countries, climate projections point to large variability in load changes in relation to reduction targets. These changes either increase loads, making the target more difficult to reach, or decrease them, leading instead to a full achievement of the target. The impact of variability in climate projections varies with the size of the reduction target and is larger for countries with more limited commitments. In the end, a number of focused actions are needed to manage the effects of climate change on nutrient loads: reducing uncertainty in climate projections, deciding on frameworks to identify best performing models with respect to land surface hydrology, and increasing efforts at sustained monitoring of water flow changes. PMID- 26022322 TI - Relationships between colored dissolved organic matter and dissolved organic carbon in different coastal gradients of the Baltic Sea. AB - Due to high terrestrial runoff, the Baltic Sea is rich in dissolved organic carbon (DOC), the light-absorbing fraction of which is referred to as colored dissolved organic matter (CDOM). Inputs of DOC and CDOM are predicted to increase with climate change, affecting coastal ecosystems. We found that the relationships between DOC, CDOM, salinity, and Secchi depth all differed between the two coastal areas studied; the W Gulf of Bothnia with high terrestrial input and the NW Baltic Proper with relatively little terrestrial input. The CDOM:DOC ratio was higher in the Gulf of Bothnia, where CDOM had a greater influence on the Secchi depth, which is used as an indicator of eutrophication and hence important for Baltic Sea management. Based on the results of this study, we recommend regular CDOM measurements in monitoring programmes, to increase the value of concurrent Secchi depth measurements. PMID- 26022323 TI - Consequences of increased terrestrial dissolved organic matter and temperature on bacterioplankton community composition during a Baltic Sea mesocosm experiment. AB - Predicted increases in runoff of terrestrial dissolved organic matter (DOM) and sea surface temperatures implicate substantial changes in energy fluxes of coastal marine ecosystems. Despite marine bacteria being critical drivers of marine carbon cycling, knowledge of compositional responses within bacterioplankton communities to such disturbances is strongly limited. Using 16S rRNA gene pyrosequencing, we examined bacterioplankton population dynamics in Baltic Sea mesocosms with treatments combining terrestrial DOM enrichment and increased temperature. Among the 200 most abundant taxa, 62 % either increased or decreased in relative abundance under changed environmental conditions. For example, SAR11 and SAR86 populations proliferated in combined increased terrestrial DOM/temperature mesocosms, while the hgcI and CL500-29 clades (Actinobacteria) decreased in the same mesocosms. Bacteroidetes increased in both control mesocosms and in the combined increased terrestrial DOM/temperature mesocosms. These results indicate considerable and differential responses among distinct bacterial populations to combined climate change effects, emphasizing the potential of such effects to induce shifts in ecosystem function and carbon cycling in the future Baltic Sea. PMID- 26022324 TI - Nitrogen fixation by cyanobacteria stimulates production in Baltic food webs. AB - Filamentous, nitrogen-fixing cyanobacteria form extensive summer blooms in the Baltic Sea. Their ability to fix dissolved N2 allows cyanobacteria to circumvent the general summer nitrogen limitation, while also generating a supply of novel bioavailable nitrogen for the food web. However, the fate of the nitrogen fixed by cyanobacteria remains unresolved, as does its importance for secondary production in the Baltic Sea. Here, we synthesize recent experimental and field studies providing strong empirical evidence that cyanobacterial nitrogen is efficiently assimilated and transferred in Baltic food webs via two major pathways: directly by grazing on fresh or decaying cyanobacteria and indirectly through the uptake by other phytoplankton and microbes of bioavailable nitrogen exuded from cyanobacterial cells. This information is an essential step toward guiding nutrient management to minimize noxious blooms without overly reducing secondary production, and ultimately most probably fish production in the Baltic Sea. PMID- 26022325 TI - Interannual variability of phyto-bacterioplankton biomass and production in coastal and offshore waters of the Baltic Sea. AB - The microbial part of the pelagic food web is seldom characterized in models despite its major contribution to biogeochemical cycles. In the Baltic Sea, spatial and temporal high frequency sampling over three years revealed changes in heterotrophic bacteria and phytoplankton coupling (biomass and production) related to hydrographic properties of the ecosystem. Phyto- and bacterioplankton were bottom-up driven in both coastal and offshore areas. Cold winter temperature was essential for phytoplankton to conform to the successional sequence in temperate waters. In terms of annual carbon production, the loss of the spring bloom (diatoms and dinoflagellates) after mild winters tended not to be compensated for by other taxa, not even summer cyanobacteria. These results improve our ability to project Baltic Sea ecosystem response to short- and long term environmental changes. PMID- 26022326 TI - Microbial metagenomics in the Baltic Sea: Recent advancements and prospects for environmental monitoring. AB - Metagenomics refers to the analysis of DNA from a whole community. Metagenomic sequencing of environmental DNA has greatly improved our knowledge of the identity and function of microorganisms in aquatic, terrestrial, and human biomes. Although open oceans have been the primary focus of studies on aquatic microbes, coastal and brackish ecosystems are now being surveyed. Here, we review so far published studies on microbes in the Baltic Sea, one of the world's largest brackish water bodies, using high throughput sequencing of environmental DNA and RNA. Collectively the data illustrate that Baltic Sea microbes are unique and highly diverse, and well adapted to this brackish-water ecosystem, findings that represent a novel base-line knowledge necessary for monitoring purposes and a sustainable management. More specifically, the data relate to environmental drivers for microbial community composition and function, assessments of the microbial biodiversity, adaptations and role of microbes in the nitrogen cycle, and microbial genome assembly from metagenomic sequences. With these discoveries as background, prospects of using metagenomics for Baltic Sea environmental monitoring are discussed. PMID- 26022327 TI - Ecology, evolution, and management strategies of northern pike populations in the Baltic Sea. AB - Baltic Sea populations of the northern pike (Esox lucius) have declined since the 1990s, and they face additional challenges due to ongoing climate change. Pike in the Baltic Sea spawn either in coastal bays or in freshwater streams and wetlands. Pike recruited in freshwater have been found to make up about 50 % of coastal pike stocks and to show natal homing, thus limiting gene flow among closely located spawning sites. Due to natal homing, sub-populations appear to be locally adapted to their freshwater recruitment environments. Management actions should therefore not involve mixing of individuals originating from different sub populations. We offer two suggestions complying with this advice: (i) productivity of extant freshwater spawning populations can be boosted by modifying wetlands such that they promote spawning and recruitment; and (ii) new sub-populations that spawn in brackish water can potentially be created by transferring fry and imprinting them on seemingly suitable spawning environments. PMID- 26022328 TI - Declining coastal piscivore populations in the Baltic Sea: Where and when do sticklebacks matter? AB - Intraguild predation interactions make fish communities prone to exhibit alternative stable states with either piscivore or prey fish dominance. In the Baltic Sea, local declines of coastal piscivores like perch (Perca fluviatilis) have been observed to coincide with high densities of sticklebacks (Gasterosteus aculeatus). Mechanisms behind this shift between piscivore and stickleback dominance were studied both experimentally and in field. Results showed that predation by sticklebacks has a strong negative effect on perch larvae survival, but this effect rapidly decreases with increasing perch size, likely due to gape limitations and digestion constraints in sticklebacks. Large spatial and temporal variations in patterns of stickleback migration into perch spawning sites were observed. Whether or not high density of sticklebacks will cause declines in coastal piscivore populations is suggested to depend on the availability of spawning sites in which sticklebacks do not migrate into or arrive late in the reproduction season of coastal piscivores. PMID- 26022329 TI - Atmospheric pathways of chlorinated pesticides and natural bromoanisoles in the northern Baltic Sea and its catchment. AB - Long-range atmospheric transport is a major pathway for delivering persistent organic pollutants to the oceans. Atmospheric deposition and volatilization of chlorinated pesticides and algae-produced bromoanisoles (BAs) were estimated for Bothnian Bay, northern Baltic Sea, based on air and water concentrations measured in 2011-2012. Pesticide fluxes were estimated using monthly air and water temperatures and assuming 4 months ice cover when no exchange occurs. Fluxes were predicted to increase by about 50 % under a 2069-2099 prediction scenario of higher temperatures and no ice. Total atmospheric loadings to Bothnian Bay and its catchment were derived from air-sea gas exchange and "bulk" (precipitation + dry particle) deposition, resulting in net gains of 53 and 46 kg year(-1) for endosulfans and hexachlorocyclohexanes, respectively, and net loss of 10 kg year( 1) for chlordanes. Volatilization of BAs releases bromine to the atmosphere and may limit their residence time in Bothnian Bay. This initial study provides baseline information for future investigations of climate change on biogeochemical cycles in the northern Baltic Sea and its catchment. PMID- 26022330 TI - Temporal and spatial trends of PCBs, DDTs, HCHs, and HCB in Swedish marine biota 1969-2012. AB - In the 1960s, the Baltic Sea was severely polluted by organic contaminants such as PCBs, HCHs, HCB, and DDTs. Elevated concentrations caused severe adverse effects in Baltic biota. Since then, these substances have been monitored temporally and spatially in Baltic biota, primarily in herring (Clupea harengus) and in guillemot (Uria aalge) egg, but also in cod (Gadus morhua), perch (Perca fluviatilis), eelpout (Zoarces viviparous), and blue mussel (Mytilus edulis). These chemicals were banned in Sweden in the late 1970s/early 1980s. Since the start of monitoring, overall significant decreases of about 70-90 % have been observed. However, concentrations are still higher in the Baltic Sea than in, for example, the North Sea. CB-118 and DDE exceed the suggested target concentrations (24 ug kg(-1) lipid weight and 5 ug kg(-1) wet weight, respectively) at certain sites in some of the monitored species, showing that concentrations may still be too high to protect the most sensitive organisms. PMID- 26022331 TI - Application of a novel modeling tool with multistressor functionality to support management of organic contaminants in the Baltic Sea. AB - Organic contaminants constitute one of many stressors that deteriorate the ecological status of the Baltic Sea. When managing environmental problems in this marine environment, it may be necessary to consider the interactions between various stressors to ensure that averting one problem does not exacerbate another. A novel modeling tool, BALTSEM-POP, is presented here that simulates interactions between climate forcing, hydrodynamic conditions, and water exchange, biogeochemical cycling, and organic contaminant transport and fate in the Baltic Sea. We discuss opportunities to use the model to support different aspects of chemicals management. We exemplify these opportunities with a case study where two emission-reduction strategies for a chemical used in personal care products (decamethylcyclopentasiloxane) are evaluated, and where the confounding influence of future climate change and eutrophication on the impact of the emission-reduction strategies are assessed. PMID- 26022332 TI - Baltic Sea ecosystem-based management under climate change: Synthesis and future challenges. AB - Ecosystem-based management (EBM) has emerged as the generally agreed strategy for managing ecosystems, with humans as integral parts of the managed system. Human activities have substantial effects on marine ecosystems, through overfishing, eutrophication, toxic pollution, habitat destruction, and climate change. It is important to advance the scientific knowledge of the cumulative, integrative, and interacting effects of these diverse activities, to support effective implementation of EBM. Based on contributions to this special issue of AMBIO, we synthesize the scientific findings into four components: pollution and legal frameworks, ecosystem processes, scale-dependent effects, and innovative tools and methods. We conclude with challenges for the future, and identify the next steps needed for successful implementation of EBM in general and specifically for the Baltic Sea. PMID- 26022334 TI - Inhibitory role of reactive oxygen species in the differentiation of multipotent vascular stem cells into vascular smooth muscle cells in rats: a novel aspect of traditional culture of rat aortic smooth muscle cells. AB - Proliferative or synthetic vascular smooth muscle cells (VSMCs) are widely accepted to be mainly derived from the dedifferentiation or phenotypic modulation of mature contractile VSMCs, i.e., a phenotype switch from a normally quiescent and contractile type into a proliferative or synthetic form. However, this theory has been challenged by recent evidence that synthetic VSMCs predominantly originate instead from media-derived multipotent vascular stem cells (MVSCs). To test these hypotheses further, we re-examine whether the conventional rat aortic SMC (RASMC) culture involves the VSMC differentiation of MVSCs or the dedifferentiation of mature VSMCs and the potential mechanism for controlling the synthetic phenotype of RASMCs. We enzymatically isolated RASMCs and cultured the cells in both a regular growth medium (RGM) and a stem cell growth medium (SCGM). Regardless of culture conditions, only a small portion of freshly isolated RASMCs attaches, survives and grows slowly during the first 7 days of primary culture, while expressing both SMC- and MVSC-specific markers. RGM-cultured cells undergo a process of synthetic SMC differentiation, whereas SCGM-cultured cells can be differentiated into not only synthetic SMCs but also other somatic cells. Notably, compared with the RGM-cultured differentiated RASMCs, the SCGM-cultured undifferentiated cells exhibit the phenotype of MVSCs and generate greater amounts of reactive oxygen species (ROS) that act as a negative regulator of differentiation into synthetic VSMCs. Knockdown of phospholipase A2, group 7 (Pla2g7) suppresses ROS formation in the MVSCs while enhancing SMC differentiation of MVSCs. These results suggest that cultured synthetic VSMCs can be derived from the SMC differentiation of MVSCs with ROS as a negative regulator. PMID- 26022335 TI - Comparative analysis of neural differentiation potential in human mesenchymal stem cells derived from chorion and adult bone marrow. AB - The finding of a reliable and abundant source of stem cells for the replacement of missing neurons in nervous system diseases requires extensive characterization of neural-differentiation-associated markers in stem cells from various sources. Chorion-derived stem cells from the human placenta have recently been described as an abundant, ethically acceptable, and easily accessible source of cells that are not limited in the same way as bone marrow (BM) mesenchymal stem cells (MSCs). We have isolated and cultured chorion MSCs (C-MSCs) and compared their proliferative capacity, multipotency, and neural differentiation ability with BM MSCs. C-MSCs showed a higher proliferative capacity compared with BM-MSCs. The expression and histone modification of Nestin, as a marker for neural stem/progenitor cells, was evaluated quantitatively between the two groups. The Nestin expression level in C-MSCs was significantly higher than that in BM-MSCs. Notably, modifications of lys9, lys4, and lys27 of histone H3 agreed with the remarkable higher expression of Nestin in C-MSCs than in BM-MSCs. Furthermore, after neural differentiation of MSCs upon retinoic acid induction, both immunocytochemical and flow cytometry analyses demonstrated that the expression of neural marker genes was significantly higher in neural-induced C-MSCs compared with BM-MSCs. Mature neuron marker genes were also expressed at a significantly higher level in C-MSCs than in BM-MSCs. Thus, C-MSCs have a greater potential than BM-MSCs for differentiation to neural cell lineages and can be regarded as a promising source of stem cells for the cell therapy of neurological disorders. PMID- 26022333 TI - Assessment of a panel of tumor markers for the differential diagnosis of benign and malignant effusions by well-based reverse phase protein array. AB - BACKGROUND: The differential diagnosis of benign and malignant effusion is often hampered by low cell content or insufficiently preserved tumor cells. In this study, we evaluated the combined diagnostic value of six tumor markers measured by well-based reverse-phase protein array (RPPA) for diagnosis of malignant effusion. METHODS: A total of 114 patients (46 with malignant effusions, 32 with probable malignant effusions, and 36 with benign effusions) were enrolled. Expressional levels of MUC1, EMA, Pan-CK, HSP90, TGF-beta and CA125 were determined by well-based RPPA. RESULTS: Median relative expression of MUC1, Pan CK and EMA were significantly higher in malignant effusion than those in probable malignant or benign (p < 0.001, p = 0.003, p < 0.001, respectively), whereas the level of TGF-beta in malignant effusions were significantly lower than that in the other groups (p = 0.005). For predicting malignancy, EMA presented the best areas under the curve of 0.728 followed by MUC1 of 0.701. The sensitivity of 52.0% for MUC1 and 48.0% for EMA were not better than cytology. However, sensitivity, negative predictive value, and accuracy of the tumor marker panel were better than cytology by 14.7%, 7.5%, and 6.1%, respectively. CONCLUSIONS: Tumor marker panel measured by well-based RPPA showed values in the differential diagnosis between benign and malignant effusions. Further large scale studies need to be performed to evaluate the utility of this panel of markers. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1433424467160224. PMID- 26022336 TI - Induction of forkhead box M1 (FoxM1) by EGF through ERK signaling pathway promotes trophoblast cell invasion. AB - Successful placentation depends on the proper invasion of extravillous trophoblast (EVT) cells into maternal tissues. Previous reports have demonstrated that FoxM1 is oncogenic and plays important roles in angiogenesis, invasion, and metastasis. However, little is known about the roles of FoxM1 in the invasion of EVT cells. EGF, as a growth factor (epidermal growth factor), has been studied extensively in reproduction. JAR cells are a reliable model for studying early invasive trophoblast regulation. We have observed the relationship between EGF and FoxM1 in JAR cells by using specific inhibitors for the intervention in and study of potential signal pathways. We have also tested the ability of JAR cells to be influenced by the expression of FoxM1. Our data indicate that EGF promotes FoxM1 expression through the ERK signal pathway. Over-FoxM1 expression upregulates the ability of JAR cells to migrate and invade and vice versa. Our investigation of FoxM1 should provide new insights into the molecular mechanisms of EVT invasion. PMID- 26022337 TI - The roles of endoplasmic reticulum stress response in female mammalian reproduction. AB - Endoplasmic reticulum stress (ERS) activates a protective pathway, called the unfold protein response, for maintaining cellular homeostasis, but cellular apoptosis is triggered by excessive or persistent ERS. Several recent studies imply that the ERS response might have broader physiological roles in the various reproductive processes of female mammals, including embryo implantation, decidualization, preimplantation embryonic development, follicle atresia, and the development of the placenta. This review summarizes the existing data concerning the molecular and biological roles of the ERS response. The study of the functions of the ERS response in mammalian reproduction might provide novel insights into and an understanding of reproductive cell survival and apoptosis under physiological and pathological conditions. The ERS response is a novel signaling pathway for reproductive cell survival and apoptosis. Infertility might be a result of disturbing the ERS response during the process of female reproduction. PMID- 26022338 TI - Fast copper extraction from printed circuit boards using supercritical carbon dioxide. AB - Technological development and intensive marketing support the growth in demand for electrical and electronic equipment (EEE), for which printed circuit boards (PCBs) are vital components. As these devices become obsolete after short periods, waste PCBs present a problem and require recycling. PCBs are composed of ceramics, polymers, and metals, particularly Cu, which is present in highest percentages. The aim of this study was to develop an innovative method to recover Cu from the PCBs of old mobile phones, obtaining faster reaction kinetics by means of leaching with supercritical CO2 and co-solvents. The PCBs from waste mobile phones were characterized, and evaluation was made of the reaction kinetics during leaching at atmospheric pressure and using supercritical CO2 with H2O2 and H2SO4 as co-solvents. The results showed that the PCBs contained 34.83 wt% of Cu. It was found that the supercritical extraction was 9 times faster, compared to atmospheric pressure extraction. After 20 min of supercritical leaching, approximately 90% of the Cu contained in the PCB was extracted using a 1:20 solid:liquid ratio and 20% of H2O2 and H2SO4 (2.5 M). These results demonstrate the efficiency of the process. Therefore the supercritical CO2 employment in the PCBs recycling is a promising alternative and the CO2 is environmentally acceptable and reusable. PMID- 26022339 TI - Removal of lead from cathode ray tube funnel glass by combined thermal treatment and leaching processes. AB - The reduction melting process is useful to recover toxic lead from cathode ray tube funnel glass; however, this process generates SiO2-containing residues that are disposed in landfill sites. To reduce the volume of landfill waste, it is desirable to recycle the SiO2-containing residues. In this study, SiO2 powder was recovered from the residue generated by reduction melting. The funnel glass was treated by a process combining reduction melting at 1000 degrees C and annealing at 700 degrees C to recover a large quantity of lead from the glass. The oxide phase generated by the thermal treatment was subjected to water leaching and acid leaching with 1M hydrochloric acid to wash out unwanted non-SiO2 elements for SiO2 purification. In the water washing, the oxide phase was microparticulated, and porous structures formed on the oxide surfaces. This increased the surface area of the oxide phase, and the unwanted elements were effectively washed out during the subsequent acid leaching. By controlling the acid leaching time and the amount of added acid, porous and amorphous SiO2 (purity >95 wt%) was recovered. In the obtained SiO2-concentrated product, unrecovered lead remained at concentrations of 0.25-0.79 wt%. When the Na2CO3 dosage in the thermal treatment was increased, the lead removal by acid leaching was enhanced, and the lead concentration in the obtained product decreased to 0.016 wt%. PMID- 26022340 TI - Pyrrolidinyl PNA with alpha/beta-Dipeptide Backbone: From Development to Applications. AB - The specific pairing between two complementary nucleobases (A.T, C.G) according to the Watson-Crick rules is by no means unique to natural nucleic acids. During the past few decades a number of nucleic acid analogues or mimics have been developed, and peptide nucleic acid (PNA) is one of the most intriguing examples. In addition to forming hybrids with natural DNA/RNA as well as itself with high affinity and specificity, the uncharged peptide-like backbone of PNA confers several unique properties not observed in other classes of nucleic acid analogues. PNA is therefore suited to applications currently performed by conventional oligonucleotides/analogues and others potentially beyond this. In addition, PNA is also interesting in its own right as a new class of oligonucleotide mimics. Unlimited opportunities exist to modify the PNA structure, stimulating the search for new systems with improved properties or additional functionality not present in the original PNA, driving future research and applications of these in nanotechnology and beyond. Although many structural variations of PNA exist, significant improvements to date have been limited to a few constrained derivatives of the privileged N-2-aminoethylglycine PNA scaffold. In this Account, we summarize our contributions in this field: the development of a new family of conformationally constrained pyrrolidinyl PNA having a nonchimeric alpha/beta-dipeptide backbone derived from nucleobase-modified proline and cyclic beta-amino acids. The conformational constraints dictated by the pyrrolidine ring and the beta-amino acid are essential requirements determining the binding efficiency, as the structure and stereochemistry of the PNA backbone significantly affect its ability to interact with DNA, RNA, and in self-pairing. The modular nature of the dipeptide backbone simplifies the synthesis and allows for rapid structural optimization. Pyrrolidinyl PNA having a (2'R,4'R)-proline/(1S,2S)-2-aminocyclopentanecarboxylic backbone (acpcPNA) binds to DNA with outstanding affinity and sequence specificity. It also binds to RNA in a highly sequence-specific fashion, albeit with lower affinity than to DNA. Additional characteristics include exclusive antiparallel/parallel selectivity and a low tendency for self-hybridization. Modification of the nucleobase or backbone allowing site-specific incorporation of labels and other functions to acpcPNA via click and other conjugation chemistries is possible, generating functional PNAs that are suitable for various applications. DNA sensing and biological applications of acpcPNA have been demonstrated, but these are still in their infancy and the full potential of pyrrolidinyl PNA is yet to be realized. With properties competitive with, and in some aspects superior to, the best PNA technology available to date, pyrrolidinyl PNA offers great promise as a platform system for future elaboration for the fabrication of new functional materials, nanodevices, and next-generation analytical tools. PMID- 26022341 TI - A cause of severe sacral injury, sledding with a plastic bag: Case report. AB - INTRODUCTION: Various injuries are associated with winter sports, of which the most frequently encountered are traumas to the extremities. Sledding on hills using plastic-based materials appears to be one of the major forms of entertainment for children living in cities during winter. However, this can lead to injury because such areas are inappropriate for winter sports. PRESENTATION OF CASE: We herein document a case of a 32-year-old male who presented to the emergency department following severe injury to the sacral region, caused by contact with a metal object while sledding with plastic bags. Patient had sacral defect including coccyx and sacral vertebrae and soft tissue. Primary closure, vacuum assisted closure and reconstruction with de-epithelized skin flap techniques were performed in 35 days period after injury. DISCUSSION: Winter sports are associated with a wide variety of injuries, but tissue defects are rare. Seroma formation due to dead spaces can occur in traumas causing bony and soft tissue loss in sacral region as seen in our case. In order overcome this problem primary closure can be delayed or defect can be filled with a bulky flaps. CONCLUSION: This case represents the first report of this particular combination of injury and treatment. PMID- 26022342 TI - Diagnostic Frequency Ratios Are Insufficient to Measure Laboratory Precision with The Bethesda System for Reporting Thyroid Cytopathology. AB - OBJECTIVE: Diagnostic frequency ratios such as the atypia of undetermined significance (AUS):malignant ratio are touted to be useful for laboratory precision benchmarking. We therefore sought to examine their reproducibility and usefulness at a tertiary hospital. METHODS: We reviewed thyroid fine-needle aspirates (FNA) submitted to our institution from outside laboratories and evaluated the ability of diagnostic frequency ratios to capture the complexity of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Specifically, we evaluated the ability of the AUS:malignant ratio to describe the frequencies of the other TBSRTC diagnoses. RESULTS: A total of 2,784 cases from 19 laboratories were included. The use of the AUS category varied the most. There was insufficient reflection of the non-AUS nonmalignant TBSRTC diagnostic frequencies in our analysis, and these results do not appear to arise from observer variability in the outside laboratories. CONCLUSION: Diagnostic frequency ratios are not reproducible in our experience and fail to describe the other TBSRTC categories. As such, they are unlikely to prove sufficient for benchmarking laboratory precision with TBSRTC. PMID- 26022343 TI - IRRIVIANS Are Forever. PMID- 26022344 TI - Radiological Position and Clinical Outcome of Preoperative Self-Expanding Metal Stents for Obstructing Colonic Cancer: A Single-Centre Cohort Study. AB - BACKGROUND: Preoperative placement of self-expanding metal stents is used in patients with obstructing colon carcinoma to prevent an emergency operation. The perceived benefits remain the subject of discussion. The data-evaluating function and complications of stents in relation to radiological position are limited. METHODS: Patients receiving a preoperative stent between 2003 and 2013 were retrospectively analysed in this single-centre study. We analysed radiological deployment, eccentricity and angulation of the stent directly after placement. Endpoints were clinical success (resolution of ileus), complications needing non elective surgery (blow-out, perforation, persistent ileus, dislocation) and other complications (bleeding, infiltrate). Associations were corrected for other potential influences. RESULTS: Eighty-two patients were included. In 22 patients (26.8%), the stent was placed proximal to the splenic flexure. Clinical success was present in 85.4%. Twenty-two patients (26.8%) had a complication of which 16 (19.5%) underwent urgent surgery for insufficient functioning of the stent; there were two blow-outs (2.4%). A more symmetrically placed stent was associated with clinical success (p = 0.042), with large overlap between groups. However, no association was found with non-elective surgery or complications. Also, angulation and deployment were unassociated with these outcomes. CONCLUSIONS: We could not establish an association between symmetry, angulation or deployment of self-expandable colonic stents with clinical success and complications. PMID- 26022345 TI - MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies. AB - Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol(r)) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings. PMID- 26022346 TI - Host species vary in infection probability, sub-lethal effects, and costs of immune response when exposed to an amphibian parasite. AB - The amphibian parasite Batrachochytrium dendrobatidis (Bd) is regarded as an extreme generalist, infecting over 500 species, but amongst these hosts there exists a great deal of variation in the susceptibility to and the costs of parasite exposure. We use two infection experiments to determine whether inter specific variation in the sublethal and lethal effects of parasite exposure exist in two host species. We then tested the relative roles of host density and diversity on infection probability of a focal susceptible host. Our results show significant heterogeneity in host species response to parasite exposure, and that both lethal and sub-lethal costs exist in individuals that are able to resist infection, indicating that successful immune response to infection comes at a cost. Further, we show that increasing host density significantly increased the likelihood of susceptible individuals becoming infected with Bd irrespective of host diversity and variation in host susceptibility. These results suggest that populations of resistant species are likely to suffer ill-effects of exposure to Bd regardless of their infection status, and that at the stage of initial infection there was no support for the dilution of transmission events, in contrast to other studies that focus on subsequent transmission of infection. PMID- 26022347 TI - Aspirin and prostate cancer prevention. PMID- 26022348 TI - HBOC multi-gene panel testing: comparison of two sequencing centers. AB - Multi-gene panels are used to identify genetic causes of hereditary breast and ovarian cancer (HBOC) in large patient cohorts. This study compares the diagnostic workflow in two centers and gives valuable insights into different next-generation sequencing (NGS) strategies. Moreover, we present data from 620 patients sequenced at both centers. Both sequencing centers are part of the German consortium for hereditary breast and ovarian cancer (GC-HBOC). All 620 patients included in this study were selected following standard BRCA1/2 testing guidelines. A set of 10 sequenced genes was analyzed per patient. Twelve samples were exchanged and sequenced at both centers. NGS results were highly concordant in 12 exchanged samples (205/206 variants = 99.51 %). One non-pathogenic variant was missed at center B due to a sequencing gap (no technical coverage). The custom enrichment at center B was optimized during this study; for example, the average number of missing bases was reduced by a factor of four (vers. 1: 1939.41, vers. 4: 506.01 bp). There were no sequencing gaps at center A, but four CCDS exons were not included in the enrichment. Pathogenic mutations were found in 12.10 % (75/620) of all patients: 4.84 % (30/620) in BRCA1, 4.35 % in BRCA2 (27/620), 0.97 % in CHEK2 (6/620), 0.65 % in ATM (4/620), 0.48 % in CDH1 (3/620), 0.32 % in PALB2 (2/620), 0.32 % in NBN (2/620), and 0.16 % in TP53 (1/620). NGS diagnostics for HBOC-related genes is robust, cost effective, and the method of choice for genetic testing in large cohorts. Adding 8 genes to standard BRCA1- and BRCA2-testing increased the mutation detection rate by one-third. PMID- 26022349 TI - Racial differences in outcomes for patients with metastatic breast cancer by disease subtype. AB - Treatment advances have differed by breast cancer subtype. We examined the impact of race on survival of women with metastatic breast cancer by disease subgroup. Using surveillance, epidemiology, and end results -Medicare data, we included white and black patients aged >=66 with de novo metastatic breast cancer diagnosed between 1998 and 2009. Using trastuzumab as a proxy for human epidermal growth factor receptor 2 (HER2)-positive status, we defined three disease subgroups: (1) HER2-positive (received trastuzumab), (2) HER2-negative/unknown (never received trastuzumab)/hormone receptor (HR)-positive, and (3) HER2 negative/unknown/HR-negative. Multivariate Cox proportional models assessed the impact of race on overall survival (OS) and breast cancer-specific survival by subgroup. We also examined trastuzumab treatment patterns. Among 4364 women (86 % white, 14 % black), 9 % had HER2-positive, 72 % had HER2-negative/unknown/HR positive, and 18 % had HER2-negative/unknown/HR-negative tumors. Patients with HER2-positive disease experienced longer median OS compared with others: 2.4 versus 1.8 years for women with HER2-negative/unknown/HR-positive and 0.5 years for women with HER2-negative/unknown/HR-negative disease (P < 0.001). Racial differences in OS were only observed among patients with HER2-positive tumors: median OS: 1.4 versus 2.7 years for black and white women, adjusted hazard ratio 1.45; 95 % Confidence interval 1.01-2.08. Results for breast cancer-specific survival were similar. We also observed racial differences in trastuzumab utilization, with longer median time to trastuzumab initiation and lower likelihood of continuation over time for black (vs. white) patients. Among women with de novo metastatic breast cancer, racial differences in survival were only apparent for those with inferred HER2-positive tumors. Further study of how treatment patterns affect outcomes is warranted. PMID- 26022351 TI - Inhibition of breast cancer cell migration by activation of cAMP signaling. AB - Almost all deaths from breast cancer arise from metastasis of the transformed cells to other sites in the body. Hence, uncovering a means of inhibiting breast cancer cell migration would provide a significant advance in the treatment of this disease. Stimulation of the cAMP signaling pathway has been shown to inhibit migration and motility of a number of cell types. A very effective way of selectively stimulating cAMP signaling is through inhibition of cyclic nucleotide phosphodiesterases (PDEs). Therefore, we examined full expression profiles of all known PDE genes at the mRNA and protein levels in four human breast cancer cell lines and eight patients' breast cancer tissues. By these analyses, expression of almost all PDE genes was seen in both cell lines and tissues. In the cell lines, appreciable expression was seen for PDEs 1C, 2A, 3B, 4A, 4B, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 9A, 10A, and 11A. In patients' tissues, appreciable expression was seen for PDEs 1A, 3B, 4A, 4B, 4C, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 8B, and 9A. PDE8A mRNA in particular is prominently expressed in all cell lines and patients' tissue samples examined. We show here that stimulation of cAMP signaling with cAMP analogs, forskolin, and PDE inhibitors, including selective inhibitors of PDE3, PDE4, PDE7, and PDE8, inhibit aggressive triple negative MDA-MB-231 breast cancer cell migration. Under the same conditions, these agents had little effect on breast cancer cell proliferation. This study demonstrates that PDE inhibitors inhibit breast cancer cell migration, and thus may be valuable therapeutic targets for inhibition of breast cancer metastasis. Since PDE8A is expressed in all breast cancer samples, and since dipyridamole, which inhibits PDE8, and PF 04957325, a selective PDE8 inhibitor, both inhibit migration, it suggests that PDE8A may be a valuable novel target for treatment of this disease. PMID- 26022350 TI - Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer. AB - Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer. PMID- 26022352 TI - [Shock in infants and children]. AB - The clinical signs and symptoms of shock in newborns and children are often more subtle compared to adults. Recurring, avoidable factors for optimal outcome include failure of health care workers to recognize shock at the time of presentation. Children are able to compensate a shock state for longer periods than adults resulting in a sudden, sometimes irreversible, cardiopulmonary collapse. Different forms of shock, their therapy, and frequent errors are depicted and illustrated with practical examples. Early recognition of shock in children is crucial for optimal outcome but is not always obvious. Clinical experience, gut feeling, and careful and repeated interpretation of the vital parameters are essential to recognize and effectively treat the various forms of shock. PMID- 26022353 TI - C-arm flat detector computed tomography parenchymal blood volume imaging: the nature of parenchymal blood volume parameter and the feasibility of parenchymal blood volume imaging in aneurysmal subarachnoid haemorrhage patients. AB - INTRODUCTION: C-arm flat detector computed tomography (FDCT) parenchymal blood volume (PBV) measurements allow assessment of cerebral haemodynamics in the neurointerventional suite. This paper explores the feasibility of C-arm computed tomography (CT) PBV imaging and the relationship between the C-arm CT PBV and the MR-PWI-derived cerebral blood volume (CBV) and cerebral blood flow (CBF) parameters in aneurysmal subarachnoid haemorrhage (SAH) patients developing delayed cerebral ischemia (DCI). METHODS: Twenty-six patients with DCI following aneurysmal SAH underwent a research C-arm CT PBV scan using a biplane angiography system and contemporaneous MR-PWI scan as part of a prospective study. Quantitative whole-brain atlas-based volume-of-interest analysis in conjunction with Pearson correlation and Bland-Altman tests was performed to explore the agreement between C-arm CT PBV and MR-derived CBV and CBF measurements. RESULTS: All patients received medical management, while eight patients (31%) underwent selective intra-arterial chemical angioplasty. Colour-coded C-arm CT PBV maps were 91% sensitive and 100% specific in detecting the perfusion abnormalities. C arm CT rPBV demonstrated good agreement and strong correlation with both MR-rCBV and MR-rCBF measurements; the agreement and correlation were stronger for MR-rCBF relative to MR-rCBV and improved for C-arm CT PBV versus the geometric mean of MR rCBV and MR-rCBF. Analysis of weighted means showed that the C-arm CT PBV has a preferential blood flow weighting (~ 60% blood flow and ~ 40% blood volume weighting). CONCLUSIONS: C-arm CT PBV imaging is feasible in DCI following aneurysmal SAH. PBV is a composite perfusion parameter incorporating both blood flow and blood volume weightings. That PBV has preferential (~ 60%) blood flow weighting is an important finding, which is of clinical significance when interpreting the C-arm CT PBV maps, particularly in the setting of acute brain ischemia. PMID- 26022354 TI - Quantitative multiparametric MRI in uveal melanoma: increased tumor permeability may predict monosomy 3. AB - INTRODUCTION: Uveal melanoma is a rare intraocular tumor with heterogeneous biological behavior, and additional noninvasive markers that may predict outcome are needed. Diffusion- and perfusion-weighted imaging may prove useful but have previously been limited in their ability to evaluate ocular tumors. Our purpose was to show the feasibility and potential value of a multiparametric (mp-) MRI protocol employing state of the art diffusion- and perfusion-weighted imaging techniques. METHODS: Sixteen patients with uveal melanoma were imaged with mp MRI. Multishot readout-segmented echoplanar diffusion-weighted imaging, quantitative dynamic contrast-enhanced (DCE) MR perfusion imaging, and anatomic sequences were obtained. Regions of interest (ROIs) were drawn around tumors for calculation of apparent diffusion coefficient (ADC) and perfusion metrics (K (trans) , v e , k ep , and v p ). A generalized linear fit model was used to compare various MRI values with the American Joint Commission on Cancer (AJCC) tumor group and monosomy 3 status with significance set at P < 0.05. RESULTS: mp MRI was performed successfully in all cases. MRI tumor height (mean [standard deviation]) was 6.5 mm (3.0). ROI volume was 278 mm(3) (222). ADC was 1.07 (0.27) * 10-3 mm(2)/s. DCE metrics were K (trans) 0.085/min (0.063), v e 0.060 (0.052), k ep 1.20/min (0.32), and v p 1.48 % (0.82). Patients with >33 % monosomy 3 had higher K (trans) and higher v e values than those with disomy 3 or <=33 % monosomy (P < 0.01). There were no significant differences between ADC (P = 0.07), k ep (P = 0.37), and v p with respect to monosomy 3. CONCLUSION: mp-MRI for ocular tumor imaging using multishot EPI DWI and quantitative DCE perfusion is technically feasible. mp-MRI may help predict monosomy 3 in uveal melanoma. PMID- 26022355 TI - Evaluation of electrode position in deep brain stimulation by image fusion (MRI and CT). AB - INTRODUCTION: Imaging has an essential role in the evaluation of correct positioning of electrodes implanted for deep brain stimulation (DBS). Although MRI offers superior anatomic visualization of target sites, there are safety concerns in patients with implanted material; imaging guidelines are inconsistent and vary. The fusion of postoperative CT with preoperative MRI images can be an alternative for the assessment of electrode positioning. The purpose of this study was to assess the accuracy of measurements realized on fused images (acquired without a stereotactic frame) using a manufacturer-provided software. METHODS: Data from 23 Parkinson's disease patients who underwent bilateral electrode placement for subthalamic nucleus (STN) DBS were acquired. Preoperative high-resolution T2-weighted sequences at 3 T, and postoperative CT series were fused using a commercially available software. Electrode tip position was measured on the obtained images in three directions (in relation to the midline, the AC-PC line and an AC-PC line orthogonal, respectively) and assessed in relation to measures realized on postoperative 3D T1 images acquired at 1.5 T. RESULTS: Mean differences between measures carried out on fused images and on postoperative MRI lay between 0.17 and 0.97 mm. CONCLUSION: Fusion of CT and MRI images provides a safe and fast technique for postoperative assessment of electrode position in DBS. PMID- 26022356 TI - High-performance sodium batteries with the 9,10-anthraquinone/CMK-3 cathode and an ether-based electrolyte. AB - We here report a much improved electrochemical performance of sodium batteries with the 9,10-anthraquinone (AQ) cathode encapsulated in CMK-3, an ether-based electrolyte of high-concentration CF3SO3Na (NaTFS) as a sodium salt in triethylene glycol dimethyl ether (TEGDME) solvent, and the Na anode. PMID- 26022357 TI - Triggering mitophagy with far-red fluorescent photosensitizers. AB - Cells identify defective mitochondria and eliminate them through mitophagy: this allows cells to rid themselves of unwanted stress to maintain health and avoid the activation of cell death. One approach to experimentally investigate mitophagy is through the use of mitochondrial photosensitizers, which when coupled with light allows one to precisely control mitochondrial damage with spatial and temporal precision. Here we report three far-red fluorophores that can be used as robust mitochondrial photosensitizers to initiate mitophagy. The dyes offer maximal compatibility with multi-color live-cell imaging, as they do not spectrally overlap with commonly used fluorescent proteins. Through the use of these far-red fluorescent photosensitizers we found that mitophagic engulfment and mitophagosome maturation rates are highly correlated with the cellular Parkin labeled mitochondria levels. This may represent a protective cellular mechanism to avoid membrane and lysosome depletion during mitophagy. PMID- 26022358 TI - Sensitivity of spiral ganglion neurons to damage caused by mobile phone electromagnetic radiation will increase in lipopolysaccharide-induced inflammation in vitro model. AB - BACKGROUND: With the increasing popularity of mobile phones, the potential hazards of radiofrequency electromagnetic radiation (RF-EMR) on the auditory system remain unclear. Apart from RF-EMR, humans are also exposed to various physical and chemical factors. We established a lipopolysaccharide (LPS)-induced inflammation in vitro model to investigate whether the possible sensitivity of spiral ganglion neurons to damage caused by mobile phone electromagnetic radiation (at specific absorption rates: 2, 4 W/kg) will increase. METHODS: Spiral ganglion neurons (SGN) were obtained from neonatal (1- to 3-day-old) Sprague Dawley(r) (SD) rats. After the SGN were treated with different concentrations (0, 20, 40, 50, 100, 200, and 400 MUg/ml) of LPS, the Cell Counting Kit-8 (CCK-8) and alkaline comet assay were used to quantify cellular activity and DNA damage, respectively. The SGN were treated with the moderate LPS concentrations before RF-EMR exposure. After 24 h intermittent exposure at an absorption rate of 2 and 4 W/kg, DNA damage was examined by alkaline comet assay, ultrastructure changes were detected by transmission electron microscopy, and expression of the autophagy markers LC3-II and Beclin1 were examined by immunofluorescence and confocal laser scanning microscopy. Reactive oxygen species (ROS) production was quantified by the dichlorofluorescin-diacetate assay. RESULTS: LPS (100 MUg/ml) induced DNA damage and suppressed cellular activity (P < 0.05). LPS (40 MUg/ml) did not exhibit cellular activity changes or DNA damage (P > 0.05); therefore, 40 MUg/ml was used to pretreat the concentration before exposure to RF-EMR. RF-EMR could not directly induce DNA damage. However, the 4 W/kg combined with LPS (40 MUg/ml) group showed mitochondria vacuoles, karyopyknosis, presence of lysosomes and autophagosome, and increasing expression of LC3-II and Beclin1. The ROS values significantly increased in the 4 W/kg exposure, 4 W/kg combined with LPS (40 MUg/ml) exposure, and H2O2 groups (P < 0.05, 0.01). CONCLUSIONS: Short-term exposure to radiofrequency electromagnetic radiation could not directly induce DNA damage in normal spiral ganglion neurons, but it could cause the changes of cellular ultrastructure at special SAR 4.0 W/kg when cells are in fragile or micro-damaged condition. It seems that the sensitivity of SGN to damage caused by mobile phone electromagnetic radiation will increase in a lipopolysaccharide-induced inflammation in vitro model. PMID- 26022359 TI - Stimulation of endothelin B receptors by IRL-1620 decreases the progression of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment that ultimately leads to death. Endothelin (ET) and its receptors have been considered as therapeutic targets for AD. Recent studies in our lab have shown that stimulation of ETB receptors provide significant neuroprotection following Abeta1-40 administration. It is possible that IRL-1620 may be neuroprotective due to angiogenesis. However, the effect of IRL-1620 on neurovascular remodeling following Abeta1-40 administration has not been established. The purpose of this study was to determine the effect of stimulation of ETB receptors by IRL-1620 on vascular and neuronal growth factors after Abeta1-40 administration. Rats were treated with Abeta1-40 (day 1, 7 and 14) in the lateral cerebral ventricles using stereotaxically implanted cannula and received three intravenous injections of IRL-1620 (an ETB agonist), and/or BQ788 (an ETB antagonist) at 2-h interval on day 8; experiments were performed on day 15. Rats were sacrificed for estimation of brain ETB receptors, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression using immunofluorescence and Western blot. In the Morris swim task, amyloid-beta (Abeta)-treated rats showed a significant (p<0.0001) impairment in spatial memory. Rats treated with IRL-1620 significantly (p<0.001) reduced the cognitive impairment induced by Abeta. BQ788 treatment completely blocked IRL 1620-induced improvement in cognitive impairment. IRL-1620 treatment enhanced the number of blood vessels labeled with VEGF compared to vehicle treatment. Additionally, cells showed increased (p<0.001) positive staining for NGF in IRL 1620-treated animals. ETB, VEGF and NGF protein expression significantly (p<0.001) increased in the brain of IRL-1620-treated rats as compared to vehicle. Pretreatment with BQ788 blocked the effects of IRL-1620, thus confirming the role of ETB receptors in the neurovascular remodeling actions of IRL-1620. Results of the present study demonstrate that IRL-1620 improves both acquisition (learning) and retention (memory) on the water maze task and enhances angiogenic and neurogenic remodeling. These findings indicate that the ETB receptor may be a novel therapeutic target for AD and other neurovascular degenerative disorders. PMID- 26022360 TI - Comparison between single and combined post-treatment with S-Methyl-N,N diethylthiolcarbamate sulfoxide and taurine following transient focal cerebral ischemia in rat brain. AB - We have recently reported on the efficacy of an N-methyl-d-aspartate (NMDA) receptor partial antagonist, S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC MeSO), in improving outcome following stroke, including reduced infarct size and calcium influx, suppressing the endoplasmic reticulum (ER) stress-induced apoptosis as well as improving behavioral outcome. DETC-MeSO was shown to suppress the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, one of the major ER stress pathways. Several studies including ours have provided evidence that taurine also has neuroprotective effects through reducing apoptosis and inhibiting activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE-1) pathways. We hypothesized that a combined treatment with DETC MeSO and taurine would ameliorate ischemia-induced brain injury by inhibiting all three ER stress pathways. Twenty four hours following reperfusion of a 2-h ischemic stroke, rats received either 0.56-mg/kg DETC-MeSO or 40-mg/kg of taurine, either alone or in combination, subcutaneously for 4days. Our study showed that combined DETC-MeSO and taurine, but not DETC-MeSO alone at the dose used, greatly reduced the infarct size, improved performance on the neuro-score test and attenuated proteolysis of alphaII-spectrin. Meanwhile, the level of the pro-apoptotic protein, Bax, declined and the anti-apoptotic protein, B-cell lymphoma 2 (BCL-2), expression was markedly increased. Combination therapy decreased both caspase-12 and caspase-3 activation by preventing the release of Cytochrome-c from mitochondria, indicating attenuation of apoptosis in ischemic infarct. Glucose-regulated protein (GRP)78 as a marker of the unfolded protein response decreased and levels of the key ER stress protein markers p-PERK-ATF4, p eIF2alpha and cleaved-ATF-6 were found to significantly decline. NeuN expression levels indicated that more neurons were protected in the presence of DETC-MeSO and taurine. We also showed that combined treatment can prevent gliosis and increase p-AKT a pro-survival marker in the penumbra. Therefore, we conclude that combined treatment with both DETC-MeSO and taurine synergistically inhibits all three ER stress pathways and apoptosis and therefore can be a novel and effective treatment after ischemic stroke. PMID- 26022361 TI - Orexins/hypocretins modulate the activity of NPY-positive and -negative neurons in the rat intergeniculate leaflet via OX1 and OX2 receptors. AB - Orexins/hypocretins (OXA and OXB) are two hypothalamic peptides involved in the regulation of many physiological processes including the sleep-wake cycle, food intake and arousal. The orexinergic system of the lateral hypothalamus is considered a non-specific peptidergic system, and its nerve fibers innervate numerous brain areas. Among many targets of orexinergic neurons is the intergeniculate leaflet (IGL) of the thalamus - a small but important structure of the mammalian biological clock. In rats, the IGL consists of GABAergic cells which also synthesize different neuropeptides. One group of neurons produces neuropeptide Y (NPY) and sends its axons to the master biological clock known as the suprachiasmatic nuclei. Another neuronal group produces enkephalin and is known to connect contralateral IGLs. This study evaluated the effects of orexins on identified IGL neurons revealing that 58% of the recorded neurons were sensitive to OXA (200nM) and OXB (200nM) administration. Both NPY-positive and negative neurons were depolarized by these neuropeptides. Experiments using selective orexin receptor antagonists (SB-334867, 10MUM and TCS-OX2-29, 10MUM) suggested that both orexin receptors participate in the recorded OXA effects. In addition, IGL neurons were either directly depolarized by OXA or their activity was altered by changes in presynaptic inputs. We observed an increase of GABA release onto the investigated IGL neuron after OXA application, consistent with a presynaptic localization of the orexin receptors. An increase in miniature excitatory postsynaptic current frequency was not observed within the IGL. Our findings reinforce the connection between circadian clock physiology and the orexinergic system. PMID- 26022364 TI - Organic reactions for the electrochemical and photochemical production of chemical fuels from CO2--The reduction chemistry of carboxylic acids and derivatives as bent CO2 surrogates. AB - The present review covers organic transformations involved in the reduction of CO2 to chemical fuels. In particular, we focus on reactions of CO2 with organic molecules to yield carboxylic acid derivatives as a first step in CO2 reduction reaction sequences. These biomimetic initial steps create opportunities for tandem electrochemical/chemical reductions. We draw parallels between long standing knowledge of CO2 reactivity from organic chemistry, organocatalysis, surface science and electrocatalysis. We point out some possible non-faradaic chemical reactions that may contribute to product distributions in the production of solar fuels from CO2. These reactions may be accelerated by thermal effects such as resistive heating and illumination. PMID- 26022362 TI - The inhibition of high-voltage-activated calcium current by activation of MrgC11 involves phospholipase C-dependent mechanisms. AB - High-voltage-activated (HVA) calcium channels play an important role in synaptic transmission. Activation of Mas-related G-protein-coupled receptor subtype C (MrgC; mouse MrgC11, rat homolog rMrgC) inhibits HVA calcium current (ICa) in small-diameter dorsal root ganglion (DRG) neurons, but the intracellular signaling cascade underlying MrgC agonist-induced inhibition of HVA ICa in native DRG neurons remains unclear. To address this question, we conducted patch-clamp recordings in MrgA3-eGFP-wild-type mice, in which most MrgA3-eGFP(+) DRG neurons co-express MrgC11 and can be identified for recording. We found that the inhibition of HVA ICa by JHU58 (0.001-100nM, a dipeptide, MrgC-selective agonist) was significantly reduced by pretreatment with a phospholipase C (PLC) inhibitor (U73122, 1MUM), but not by its inactive analog (U73343) or vehicle. Further, in rats that had undergone spinal nerve injury, pretreatment with intrathecal U73122 nearly abolished the inhibition of mechanical hypersensitivity by intrathecal JHU58. The inhibition of HVA ICa in MrgA3-eGFP(+) neurons by JHU58 (100nM) was partially reduced by pretreatment with a Gbetagamma blocker (gallein, 100MUM). However, applying a depolarizing prepulse and blocking the Galphai and Galphas pathways with pertussis toxin (PTX) (0.5MUg/mL) and cholera toxin (CTX) (0.5MUg/mL), respectively, had no effect. These findings suggest that activation of MrgC11 may inhibit HVA ICa in mouse DRG neurons through a voltage-independent mechanism that involves activation of the PLC, but not Galphai or Galphas, pathway. PMID- 26022363 TI - Current Management of Pediatric Vitiligo. AB - Vitiligo is a common inflammatory disorder with worldwide prevalence of 0.4-2 % of the population, with half of cases beginning in childhood. The management of childhood vitiligo should be tailored to avoid negative effects on the overall growth and psychological development of the patient. Therapy of vitiligo in childhood is chosen based on the location of the lesions, lesion age, and extent of lesions in the context of the child's age and the developmental status of the child. There are four age categories in childhood vitiligo: [1] infantile and toddler (rare) (ages 0-3 years), [2] ages 4-8 years, [3] ages 9-12 years, and [4] 13+ years of age, based on developmental stage, psychological maturation, and ability to comply or participate in therapy. These categories are also differentiated psychologically by susceptibility to bullying, self-image development, and personal concern with lesion appearance, which increases with time. Intervention is advisable in cases with facial and leg involvement due to prominence of lesions and cosmetic defect. Medical interventions are largely the usage of topical therapies including corticosteroids and calcineurin inhibitors, some vitamin therapy (oral and topical vitamin D), and judicious introduction of phototherapy sources based on age and severity. Screening and appropriate subspecialist referral for co-morbidities (e.g., thyroid disease, celiac disease, psychological distress, and vitamin D deficiency) may enhance overall health. Cosmesis and camouflage are generally safe in childhood and have been noted to improve overall quality of life in this grouping. Genetic transmission of vitiligo is minimal at 5-6 % in first-degree relatives. This article reviews the therapeutics of pediatric vitiligo from the perspective of developmental stages and response to therapy. PMID- 26022365 TI - Evaluation of the Quality of Reprocessing of Gastrointestinal Endoscopes. AB - OBJECTIVES: To evaluate the quality of gastrointestinal endoscope reprocessing and discuss the advantages of microbiological surveillance testing of these endoscopes. METHODS: Retrospective analysis of the results of endoscope sampling performed from October 1, 2006, through December 31, 2014, in a gastrointestinal endoscopy unit of a teaching hospital equipped with 89 endoscopes and 3 automated endoscope reprocessors, with an endoscopy quality assurance program in place. The compliance rate was defined as the proportion of the results classified at target or alert levels according to the French guidelines. A multivariate analysis (logistic regression) was used to identify the parameters influencing compliance. RESULTS: A total of 846 samples were taken. The overall compliance rate was 86% and differed significantly depending on the sampling context (scheduled or not scheduled), the type of endoscope, and the season. No other parameter was associated with compliance. A total of 118 samples carried indicator microorganisms such as Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Enterobacteriaceae, and Candida sp. CONCLUSION: The systematic use of an automated endoscope reprocessor does not provide totally satisfactory compliance. Microbiological surveillance is indispensable to monitor reprocessing, reinforce good practices (endoscopes, reprocessing units), and detect endoscopes requiring early technical maintenance. PMID- 26022366 TI - Factors associated with postrhinoplasty mucous cyst in cleft lip patients. AB - PURPOSE: The purpose of this study was to identify risk factors associated with postrhinoplasty mucous cyst (PMC) among adult cleft patients undergoing rhinoplasty. PMC has been reported sporadically in the literature. Its aetiology is uncertain. The purpose of this study was to determine whether three factors, (1) patient age, (2) surgical trauma, and/or (3) use of a nasal septal cartilage graft (NSCG), were risk factors for PMC. METHODS: We organized a retrospective, single-center study and enrolled cleft rhinoplasty patients treated between January 2003 and December 2008. The predictor variables included age at surgery, use of a NSCG, and length of surgery. The primary outcome was presence of PMC. Other study variables included demographic, surgical, and postoperative data. Appropriate descriptive and univariate statistics were calculated, and P < 0.05 was regarded as indicative of statistical significance. RESULTS: The sample comprised 314 cleft rhinoplasty patients (118 females; 37.6 %) with a mean age of 14.9 +/- 10.7 years (range 0-65). Three patients had a PMC after secondary cleft rhinoplasty. Average time to disease was 26 +/- 19.3 months after surgery (range 12-48). There was no significant association between the presence of the PMC and the three predictor variables-patient's age, NSCG transplantation, and protracted surgery (P > 0.05). CONCLUSIONS: These study findings suggest that young age, use of a NSCG, and protracted surgery are not risk factors for PMC. The prevalence of PMC is greater for cleft patients after rhinosurgery than for noncleft patients. PMID- 26022367 TI - Directly observed therapy for treating tuberculosis. AB - BACKGROUND: Tuberculosis (TB) requires at least six months of treatment. If treatment is incomplete, patients may not be cured and drug resistance may develop. Directly Observed Therapy (DOT) is a specific strategy, endorsed by the World Health Organization, to improve adherence by requiring health workers, community volunteers or family members to observe and record patients taking each dose. OBJECTIVES: To evaluate DOT compared to self-administered therapy in people on treatment for active TB or on prophylaxis to prevent active disease. We also compared the effects of different forms of DOT. SEARCH METHODS: We searched the following databases up to 13 January 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; EMBASE; LILACS and mRCT. We also checked article reference lists and contacted relevant researchers and organizations. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi RCTs comparing DOT with routine self-administration of treatment or prophylaxis at home. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias of each included trial and extracted data. We compared interventions using risk ratios (RR) with 95% confidence intervals (CI). We used a random effects model if meta-analysis was appropriate but heterogeneity present (I(2) statistic > 50%). We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Eleven trials including 5662 participants met the inclusion criteria. DOT was performed by a range of people (nurses, community health workers, family members or former TB patients) in a variety of settings (clinic, the patient's home or the home of a community volunteer). DOT versus self-administered Six trials from South Africa, Thailand, Taiwan, Pakistan and Australia compared DOT with self-administered therapy for treatment. Trials included DOT at home by family members, community health workers (who were usually supervised); DOT at home by health staff; and DOT at health facilities. TB cure was low with self-administration across all studies (range 41% to 67%), and direct observation did not substantially improve this (RR 1.08, 95% CI 0.91 to 1.27; five trials, 1645 participants, moderate quality evidence). In a subgroup analysis stratified by the frequency of contact between health services in the self-treatment arm, daily DOT may improve TB cure when compared to self administered treatment where patients in the self-administered group only visited the clinic every month (RR 1.15, 95% CI 1.06 to 1.25; two trials, 900 participants); but with contact in the control becoming more frequent, this small effect was not apparent (every two weeks: RR 0.96, 95% CI 0.83 to 1.12; one trial, 497 participants; every week: RR 0.90, 95% CI 0.68 to 1.21; two trials, 248 participants).Treatment completion showed a similar pattern, ranging from 59% to 78% in the self-treatment groups, and direct observation did not improve this (RR 1.07, 95% CI 0.96 to 1.19; six trials, 1839 participants, moderate quality evidence). DOT at home versus DOT at health facility In four trials that compared DOT at home by family members, or community health workers, with DOT by health workers at a health facility there was little or no difference in cure or treatment completion (cure: RR 1.02, 95% CI 0.88 to 1.18, four trials, 1556 participants, moderate quality evidence; treatment completion: RR 1.04, 95% CI 0.91 to 1.17, three trials, 1029 participants, moderate quality evidence). DOT by family member versus DOT by community health workerTwo trials compared DOT at home by family members with DOT at home by community health workers. There was also little or no difference in cure or treatment completion (cure: RR 1.02, 95% CI 0.86 to 1.21; two trials, 1493 participants, moderate quality evidence; completion: RR 1.05, 95% CI 0.90 to 1.22; two trials, 1493 participants, low quality evidence). Specific patient categoriesA trial of 300 intravenous drug users in the USA evaluated direct observation with no observation in TB prophylaxis to prevent active disease and showed little difference in treatment completion (RR 1.00, 95% CI 0.88 to 1.13; one trial, 300 participants, low quality evidence). AUTHORS' CONCLUSIONS: From the existing trials, DOT did not provide a solution to poor adherence in TB treatment. Given the large resource and cost implications of DOT, policy makers might want to reconsider strategies that depend on direct observation. Other options might take into account financial and logistical barriers to care; approaches that motivate patients and staff; and defaulter follow-up. PMID- 26022369 TI - Critical examination of knowledge to action models and implications for promoting health equity. AB - INTRODUCTION: Knowledge and effective interventions exist to address many current global health inequities. However, there is limited awareness, uptake, and use of knowledge to inform action to improve the health of disadvantaged populations. The gap between knowledge and action to improve health equity is of concern to health researchers and practitioners. This study identifies and critically examines the usefulness of existing knowledge to action models or frameworks for promoting health equity. METHODS: We conducted a scoping review of existing literature to identify knowledge to action (KTA) models or frameworks and critiqued the models using a health equity support rubric. RESULTS: We identified forty-eight knowledge to action models or frameworks. Six models scored between eight and ten of a maximum 12 points on the health equity support rubric. These high scoring models or frameworks all mentioned equity-related concepts. Attention to multisectoral approaches was the factor most often lacking in the low scoring models. The concepts of knowledge brokering, integrative processes, such as those in some indigenous health research, and Ecohealth applied to KTA all emerged as promising areas. CONCLUSIONS: Existing knowledge to action models or frameworks can help guide knowledge translation to support action on the social determinants of health and health equity. There is a need to further test existing models or frameworks. This process should be informed by participatory and integrative research. There is room to develop more robust equity supporting models. PMID- 26022368 TI - Targeting neoplastic B cells and harnessing microenvironment: the "double face" of ibrutinib and idelalisib. AB - Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110delta isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements. PMID- 26022370 TI - Apparent Usher Syndrome Caused by the Combination of BBS1-Associated Retinitis Pigmentosa and SLC26A4-Associated Deafness. PMID- 26022371 TI - Synergistic effects of beta-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells. AB - A large body of evidence support major roles of mitochondrial dysfunction and insulin action in the Alzheimer's disease (AD) brain. However, interaction between cellular expression of beta-amyloid (Abeta) and insulin resistance on mitochondrial metabolism has not been explored in neuronal cells. We investigated the additive and synergistic effects of intracellular Abeta42 and ceramide induced insulin resistance on mitochondrial metabolism in SH-SY5Y and Neuro-2a cells. In our model, mitochondria take-up Abeta42 expressed through viral mediated transfection and exposure of the same cells to ceramide produces resistance to insulin signaling. Ceramide alone increased phosphorylated MAP kinases while decreasing phospho-Akt (Ser473). The combination of Abeta42 and ceramide synergistically decreased phospho-Thr308 on Akt. Abeta42 and ceramide synergistically also decreased mitochondrial complex III activity and ATP generation whereas Abeta alone was largely responsible for complex IV inhibition and increases in mitochondrial reactive oxygen species production (ROS). Proteomic analysis showed that a number of mitochondrial respiratory chain and tricarboxylic acid cycle enzymes were additively or synergistically decreased by ceramide in combination with Abeta42 expression. Mitochondrial fusion and fission proteins were notably dysregulated by Abeta42 (Mfn1) or Abeta42 plus ceramide (OPA1, Drp1). Antioxidant vitamins blocked the Abeta42 alone-induced ROS production, but did not reverse Abeta42-induced ATP reduction or complex IV inhibition. Abeta expression combined with ceramide exposure had additive effects to decrease cell viability. Taken together, our data demonstrate that Abeta42 expression and ceramide-induced insulin resistance synergistically interact to exacerbate mitochondrial damage and that therapeutic efforts to reduce insulin resistance could lessen failures of energy production and mitochondrial dynamics. PMID- 26022373 TI - Influence of Regio- and Chemoselectivity on the Properties of Fluoro-Substituted Thienothiophene and Benzodithiophene Copolymers. AB - By studying the regio- and chemoselectivity of fluoro-substituted thienothiophene and benzodithiophene copolymers, we found polymers made from conventional one-pot polycondensation reaction consist of two distinctly different segments with a ratio of 0.36/0.64. Through further comparative studies of neat regioregular polymers based on each individual segment, we have identified the specific segment that contributes to the superior absorption, packing order, and charge mobility in the corresponding polymers. The unique structure-property relationships are the result of cooperative molecular arrangements of the key segment and noncovalent interaction between the fluoro group and the aromatic proton on the thiophene side-chain of the polymers. PMID- 26022372 TI - Ink4/Arf locus restores glucose tolerance and insulin sensitivity by reducing hepatic steatosis and inflammation in mice with impaired IRS2-dependent signalling. AB - Single nucleotide polymorphisms near the Ink4/Arf locus have been associated with type-2 diabetes mellitus. Previous studies indicate a protective role of the locus in the carbohydrate metabolism derangement associated with ageing in wild type mice. The present study demonstrates that the increased Ink4/Arf locus expression in 1-year-old mice, partially-deficient for the insulin receptor substrate (IRS)2 (Irs2+/-SuperInk4/Arf mice) ameliorates hepatic steatosis, inflammation and insulin resistance. Irs2+/-SuperInk4/Arf mice displayed improved glucose tolerance and insulin sensitivity compared with Irs2+/- mice which were glucose intolerant and insulin resistant compared with age-matched wild-type mice. These changes in Irs2+/- mice were accompanied by enhanced hepatic steatosis, proinflammatory macrophage phenotype, increased Ly6C(hi)-monocyte percentage, T-lymphocyte activation and MCP1 and TNF-alpha cytokine levels. In Irs2+/-SuperInk4/Arf mice, steatosis and inflammatory parameters were markedly reduced and similar to those of wild-type counterparts. In vivo insulin signalling also revealed reduced activation of the IRS/AKT-dependent signalling in Irs2+/- mice. This was restored upon increased locus expression in Irs2+/ SuperInk4/Arf mice which display similar activation levels as those for wild-type mice. In vivo treatment of Irs2+/-SuperInk4/Arf mice with TNF-alpha diminished insulin canonical IRS/AKT-signalling and enhanced the stress SAPK/JNK phosphoSer307IRS1-pathway suggesting that cytokine levels might potentially affect glucose homeostasis through changes in these insulin-signalling pathways. Altogether, these results indicate that enhanced Ink4/Arf locus expression restores glucose homeostasis and that this is associated with diminished hepatic steatosis and inflammation in mice with insulin resistance. Therefore, pharmacological interventions targeted to modulate the Ink4/Arf locus expression could be a tentative therapeutic approach to alleviate the inflammation associated with insulin resistance. PMID- 26022374 TI - The Limitations of Routine Magnetic Resonance Imaging for Long-Term Post Treatment Locoregional Surveillance of Salivary Carcinoma. AB - BACKGROUND/AIMS: To determine the utility of head and neck magnetic resonance imaging (HN-MRI) for the routine surveillance of patients without concurrent symptoms or signs of recurrence more than 6 months after treatment for salivary gland carcinoma (SGC). METHODS: This is a retrospective single-institution review of SGC patients from 2000 to 2011 who underwent one or more HN-MRI scans without concurrent suspicious symptoms or signs of recurrence more than 6 months after the completion of treatment, with at least 6 months of follow-up after each scan. RESULTS: Out of an original 283 SGC patients treated surgically, 41 patients, who were disease free 6 months after treatment, had undergone 96 routine HN-MRIs without concurrent suspicious symptoms or signs. Ten out of the 41 patients (24%) experienced a false-positive finding with routine HN-MRI. None of the 96 HN-MRIs demonstrated a true-positive or false-negative finding. CONCLUSION: More than 6 months after treatment, routine HN-MRI for the detection of locoregional recurrence of SGC has a low utility in patients without concurrent suspicious symptoms or signs. While these data support the judicious use of routine HN-MRIs, the managing physician should ultimately decide on the best course of surveillance for an individual patient based on the unique risk factors and circumstances present. PMID- 26022375 TI - Secondly ECG recordings in the emergency room revealed Garenoxacin-induced abnormal QT interval prolongation in a patient with multiple syncopal attacks. AB - A 73-year-old woman first visited our emergency room with multiple syncopal attacks. Before admission, she had received an antibiotic (Garenoxacin) for 3 days from a local clinic. First electrocardiogram (ECG) showed no ST-segment deviation but mild QT interval prolongation with a positive U wave. Second ECG recording 3 h later showed slightly slower heart rate and revealed marked QTU interval prolongation suggesting the cause of her syncopal attacks. After cessation of Garenoxacin, the QTU interval prolongation shortened. However, both epinephrine infusion and treadmill exercise test reproduced similar QTU interval prolongation and T wave deformities. Later, genetic analysis demonstrated that this patient had a mutation in KCNH2 gene, and she was diagnosed as a type-2 long QT syndrome which was accentuated by use of garenoxacin. At the emergency out patient clinic, repetitive ECG recordings can be useful and should be considered in order to identify the cause of syncopal attacks in patients who were prescribed antibiotics and had mild QT interval abnormalities. PMID- 26022377 TI - Down-Regulation of miR-101 Contributes to Rheumatic Heart Disease Through Up Regulating TLR2. AB - BACKGROUND: RHD is an autoimmune disease that arises following infection by S. pyogenes and imposes a heavy burden on public health. MATERIAL AND METHODS: We detected 11 selected miRNAs expressed in the cardiac tissues of 11 RHD patients and 11 controls. By employing dual-luciferase assay and Western blot, we identified the relationship between TLR2 and miR-101 and miR-101. We used ELISA to test the concentration of TNF-alpha, IL-1beta, and IL-6. RESULTS: In cardiac tissue of RHD patients, miR-101 was significantly down-regulated (p=0.011). Ectopically expressed miR-101 repressed the luciferase activity by 27% through targeting TLR2 3'UTR. Combined with the results of Western blot, we confirmed that TLR2 is a direct target gene of miR-101. miR-101 knock-down is related to over-stimulated immune response in PGN-activated THP-1 cells. We detected a significantly higher concentration of TNF-alpha (p=0.0017), IL-1beta (p=0.015), and IL-6 (p=0.014) in serum samples. TLR2 had a higher expression in patients in the protein level rather than the mRNA level, indicating that post transcriptional regulation factors play a crucial role in regulating TLR2 expression. CONCLUSIONS: The present study confirmed that miR-101 targets TLR2 3'UTR and represses TLR2 expression. This work also found an association between down-regulated miR-101 and rheumatic heart disease. PMID- 26022376 TI - Prescription patterns of oral anticoagulants for patients with non-valvular atrial fibrillation: experience at a Japanese single institution. AB - New oral anticoagulants (NOACs) are now clinically available. However, few studies have demonstrated which patients with non-valvular atrial fibrillation (NVAF) actually receive NOACs in a clinical setting. We analyzed 182 NVAF patients who received oral anticoagulants. Clinical backgrounds and the risk of stroke, systemic embolism, and bleeding associated with oral anticoagulants were investigated. Seventy-three (40 %) patients were treated with NOACs and 109 (60 %) patients were treated with warfarin. A significantly lower mean number of bleeding risk factors was observed among the patients treated with NOACs than among those treated with warfarin (P = 0.010). Of the bleeding risk factors, NOACs were significantly less frequently prescribed in patients with a bleeding history and elderly subjects (>65 years) than in those who received warfarin (P < 0.001 and P = 0.029). A multivariate logistic regression analysis revealed that CHF and bleeding history were independently and significantly associated with the administration of NOACs (P = 0.047 and P = 0.003). The rate of a history of intracranial hemorrhage was comparable between the patients treated with NOACs and those treated with warfarin (P = 1.000). Significantly lower rates of a history of gastrointestinal and other minor bleeding were observed in the patients who received NOACs versus those who received warfarin (P = 0.001 and P = 0.026). NOACs were less frequently prescribed in patients with a history of bleeding, especially those with a history of gastrointestinal bleeding in a clinical setting. PMID- 26022378 TI - Are Growing Pains Related to Vitamin D Deficiency? Efficacy of Vitamin D Therapy for Resolution of Symptoms. AB - OBJECTIVES: The aim of this study was to investigate the 25-hydroxyvitamin D [25(OH)D] status of children with growing pains and to evaluate the efficacy of vitamin D treatment on the resolution of pain symptoms. SUBJECTS AND METHODS: One hundred and twenty children with growing pains were included in a prospective cohort study. Serum 25(OH)D and bone mineral levels were measured in all subjects at the time of enrollment. The pain intensity of those with vitamin D deficiency was measured using a pain visual analog scale (VAS). After a single oral dose of vitamin D, the pain intensity was remeasured by means of the VAS at 3 months. The 25(OH)D levels and VAS scores before and after oral vitamin D administration were compared by means of a paired Student's t test. RESULTS: In the 120 children with growing pains, vitamin D insufficiency was noted in 104 (86.6%). Following vitamin D supplementation, the mean 25(OH)D levels increased from 13.4 +/- 7.2 to 44.5 +/- 16.4 ng/ml, the mean pain VAS score decreased from 6.8 +/- 1.9 to 2.9 +/ 2.5 cm (a mean reduction of -3.8 +/- 2.1, p < 0.001) and the difference was statistically significant. CONCLUSION: Supplementation with oral vitamin D resulted in a significant reduction in pain intensity among these children with growing pains who had hypovitaminosis D. PMID- 26022379 TI - Cooked oatmeal consumption is associated with better diet quality, better nutrient intakes, and reduced risk for central adiposity and obesity in children 2-18 years: NHANES 2001-2010. AB - BACKGROUND: None of the studies of whole grains that have looked either at diet or weight/adiposity measures have focused exclusively on oatmeal. OBJECTIVE: The objective of this study was to assess the association between oatmeal consumption and nutrient intake, diet quality, and weight/adiposity of children aged 2-18. DESIGN: A nationally representative sample of children aged 2-18 (N=14,690) participating in National Health and Nutrition Examination Survey 2001-2010 was used. Intake was determined from a single 24-h dietary recall. Diet quality was measured using the Healthy Eating Index-2010 (HEI-2010). Covariate-adjusted regression analyses, using appropriate sample weights, were used to determine differences between oatmeal consumers and non-consumers for demographics, nutrient intakes, diet quality, and weight/adiposity measures (p<0.01). Logistic regression was performed to calculate odds ratios for weight measures and obesity (p<0.05). RESULTS: Compared to non-consumers, oatmeal consumers were more likely to be younger and less likely to be smokers. Consumers had higher intakes of dietary fiber, vitamin A, thiamin, riboflavin, calcium, phosphorus, magnesium, iron, copper, and potassium, and significantly lower intakes of total, monounsaturated and saturated fatty acids, cholesterol, and sodium. Oatmeal consumers had higher dietary quality scores attributable to higher intakes of whole grains and lower intakes of refined grains and empty calories. Children consuming oatmeal were at lower risk for having central adiposity and being obese. CONCLUSIONS: Consumption of oatmeal by children was associated with better nutrient intake, diet quality, and reduced risk for central adiposity and obesity and should be encouraged as part of an overall healthful diet. PMID- 26022380 TI - Protective Role of Diabetes Mellitus on Abdominal Aortic Aneurysm Pathogenesis: Myth or Reality? AB - An inverse association between diabetes mellitus (DM) and abdominal aortic aneurysm (AAA) risk have been reported. Apart from a lower AAA prevalence among patients with vs without DM, there are data showing that DM may exert a protective role on aneurysmal growth in patients with small AAAs, thus decreasing the risk of rupture. As atherosclerosis has almost the same risk factors as aneurysms, the decreased AAA prevalence in patients with DM may indicate that atherosclerosis is an associated feature and not a cause of the aneurysms. Alternatively, DM may be associated with factors that influence AAA formation. In this narrative review, we discuss the inverse association between DM and AAA. We also comment on underlying cellular and genetic pathophysiological mechanisms of DM, AAA and atherosclerosis. The effects of drugs, commonly prescribed in DM patients, on AAA development and growth are also considered. PMID- 26022381 TI - Atrial fibrillation pathophysiology and prognosis: insights from cardiovascular imaging. PMID- 26022382 TI - Unusual case of congestive heart failure: cardiac magnetic resonance imaging and histopathologic findings in cobalt cardiomyopathy. PMID- 26022383 TI - Systematic review and meta-analysis of the impact of depression on subsequent smoking cessation in patients with chronic respiratory conditions. AB - OBJECTIVE: To systematically review the impact of depression on subsequent smoking cessation in prospective studies of chronic respiratory patients. METHOD: A systematic search of electronic databases (MEDLINE, PsycINFO, CINAHL) was conducted to identify prospective studies of chronic respiratory patients that measured depression at baseline and smoking status at follow-up, dating from 1st January 1990 to 21st February 2014. The standardized mean difference (SMD) and 95% confidence interval (CI) for the association between baseline depressive symptoms and subsequent smoking cessation was estimated from available data using random effects meta-analysis. RESULTS: A total of 1314 citations were retrieved and 197 articles were further evaluated by two reviewers. Seven articles provided sufficient data to estimate the association between depressive symptoms and subsequent smoking cessation. Those with elevated depressive symptoms were significantly less likely to quit smoking at follow-up than those not reporting elevated depressive symptoms (SMD=-.31, 95% CI -.43 to -.19; I(2)=0%, P=.506). CONCLUSIONS: The association between depression and subsequent smoking was poorly reported or omitted in most studies. However, the available evidence suggests that depression decreases the likelihood that patients with chronic respiratory conditions will quit smoking. Future research is needed to determine how best to manage depression and smoking cessation in this population. PMID- 26022384 TI - Neurosyphilis in psychiatric practice: a case-based discussion of clinical evaluation and diagnosis. AB - OBJECTIVE: Neurosyphilis can present with a wide range of neuropsychiatric symptoms. Hence, psychiatrists need to be familiar with tests for syphilis screening and how to interpret syphilis serologic tests. METHODS: We present four cases of patients with positive syphilis tests encountered in a psychiatric hospital. RESULTS: Two cases were treated for neurosyphilis, while the other two cases did not have active syphilis infection despite positive results. CONCLUSION: We thus highlight the challenges encountered by psychiatrists in screening for and diagnosing cases of neurosyphilis. PMID- 26022385 TI - Vasomotor symptoms in women and cardiovascular risk markers: Systematic review and meta-analysis. AB - We performed a systematic review and meta-analysis of the observational or interventional studies assessing the association of vasomotor symptoms (hot flushes and night sweats) with various cardiovascular risk markers (systolic (SBP) and diastolic blood pressure (DBP), hypertension, total cholesterol, body mass index (BMI), and measures of subclinical atherosclerosis), in peri menopausal, menopausal, or postmenopausal women. Eleven unique studies were identified with data available on 19,667 non-overlapping participants. Pooled analysis showed that women with hot flushes, compared to those without, tended to have significant higher levels of SBP (mean difference (MD): 1.95 mmHg (95%CI, 0.27 to 33.63)), and DBP (MD 1.17 mmHg (95%CI, -0.21 to 2.54)) and higher odds of having hypertension (OR: 1.18, 95%CI: 0.93 to 1.51), albeit non-significant. Similarly, women who reported night sweats compared to those who did not, had significant higher levels of SBP, (MD: 1.33 mmHg (95%CI, 0.63 to 2.03)), DBP (MD: 0.55 mmHg (95%CI, 0.19 to 0.91)), total cholesterol (MD: 0.17 mmHg (95%CI, 0.03 to 0.31)) and BMI (MD: 0.64 mmHg (95%CI, 0.47 to 0.80)). Vasomotor symptoms in women were not associated with measures of subclinical atherosclerosis. Women with vasomotor symptoms may have an unfavorable cardiovascular risk profile compared to women without vasomotor complaints. PMID- 26022386 TI - Determinants of changes in muscle mass after bariatric surgery. AB - AIM: The constituents of weight loss following bariatric surgery are poorly known. There is an expectation of a limited loss of lean body mass (LBM), and a significant loss of fat mass (FM) as well as muscle mass (MM), which could lead to functional loss and metabolic impairment. This prospective study analysed the determinants of MM changes after Roux-en-Y gastric bypass and sleeve gastrectomy. METHODS: The study cohort comprised 114 consecutive candidates for bariatric surgery referred to a bariatric surgery centre. Using DEXA, the subjects' body composition was assessed before, and three and 12 months (n=92) after, the surgery, along with their biological status. The main study outcome was changes in MM. RESULTS: At three months, patients had lost 20.3 kg, made up of 41% LBM and 59% FM. The contribution of MM to weight loss was 16.4%. Cluster analysis showed that 52 patients lost<15% of their weight as MM, while 62 patients lost>15% as MM. At 12 months, patients had lost 37 kg, made up of 70% FM and 30% LBM. At this time, only 27 patients lost>15% of their weight as MM. The determinants that were negatively and independently associated with MM changes at three months were FM loss and changes in glycaemia and thyroid-stimulating hormone ([TSH]; thyrotropin) before surgery, whereas change in glycaemia was the only 12-month determinant associated with MM changes. CONCLUSION: Two phenotypes one with muscle wasting and the other with acceptable muscle loss - with a threshold of 15% and very few predictive factors were identified by this study. PMID- 26022387 TI - Fast Activity Evoked by Intracranial 50 Hz Electrical Stimulation as a Marker of the Epileptogenic Zone. AB - Epilepsy is a disease characterized by aberrant connections between brain areas. The altered activity patterns generated by epileptic networks can be analyzed with intracerebral electrodes during pre-surgical stereo-electroencephalographic (EEG) monitoring in patients candidate to epilepsy surgery. The responses to high frequency stimulation (HFS) at 50 Hz performed for diagnostic purposes during SEEG were analyzed with a new algorithm, to evaluate signal parameters that are masked to visual inspection and to define the boundaries of the epileptogenic network. The analysis was focused on 60-80 Hz activity that represented the largest frequency component evoked by HFS. The distribution of HFS-evoked fast activity across all (up to 162) recording contacts allowed to define different clusters of contacts that retrospectively correlated to the epileptogenic zone identified by the clinicians on the basis of traditional visual analysis. The study demonstrates that computer-assisted analysis of HFS-evoked activities may contribute to the definition of the epileptogenic network on intracranial recordings performed in a pre-surgical setting. PMID- 26022388 TI - Early Seizure Detection Algorithm Based on Intracranial EEG and Random Forest Classification. AB - The goal of this study is to provide a seizure detection algorithm that is relatively simple to implement on a microcontroller, so it can be used for an implantable closed loop stimulation device. We propose a set of 11 simple time domain and power bands features, computed from one intracranial EEG contact located in the seizure onset zone. The classification of the features is performed using a random forest classifier. Depending on the training datasets and the optimization preferences, the performance of the algorithm were: 93.84% mean sensitivity (100% median sensitivity), 3.03 s mean (1.75 s median) detection delays and 0.33/h mean (0.07/h median) false detections per hour. PMID- 26022389 TI - Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (omega3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines and eicosanoids involved in RA pathogenesis. The aim of this study was to determine the therapeutic potential of omega3 monoglyceride (MAG-omega3) compounds in an in vivo rat model of RA induced by Complete Freund's Adjuvant (CFA). METHOD: CFA rats were untreated or treated per os with three specific compounds, namely, MAG docosahexaenoic acid (MAG-DHA), MAG-eicosapentaenoic acid (MAG-EPA) and MAG docosapentaenoic acid (MAG-DPA). Morphological and histological analyses, as well as pro-inflammatory marker levels were determined following MAG-omega3 treatments. RESULTS: Morphological and histological analyses revealed that MAG EPA and MAG-DPA exhibited strong activity in reducing the progression and severity of arthritic disease in CFA rats. Following MAG-EPA and MAG-DPA treatments, plasma levels of the pro-inflammatory cytokines; interleukin 17A (IL 17A), IL-1beta, IL-6 and tumor necrosis factor alpha (TNFalpha) were markedly lower when compared to CFA-untreated rats. Results also revealed a decreased activation of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor kappa B (NFkappaB) pathways correlated with a reduced expression of TNFalpha, cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2) and MMP-9 in paw homogenates derived from MAG-EPA and MAG-DPA-treated rats. Of interest, the combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in CFA rats. CONCLUSION: Altogether, the present data suggest that MAG-EPA, without vitamin E, represents a new potential therapeutic strategy for resolving inflammation in arthritis. PMID- 26022390 TI - Rapid high-yield expression of a candidate influenza vaccine based on the ectodomain of M2 protein linked to flagellin in plants using viral vectors. AB - BACKGROUND: The extracellular domain of matrix protein 2 (M2e) of influenza A virus is a promising target for the development of a universal vaccine against influenza because M2e sequences are highly conserved among human influenza A strains. However, native M2e is poorly immunogenic, but its immunogenicity can be increased by delivery in combination with adjuvants or carrier particles. It was previously shown that fusion of M2e to bacterial flagellin, the ligand for Toll like receptor (TLR) 5 and powerful mucosal adjuvant, significantly increases the immunogenicity and protective capacity of M2e. RESULTS: In this study, we report for the first time the transient expression in plants of a recombinant protein Flg-4M comprising flagellin of Salmonella typhimurium fused to four tandem copies of the M2e peptide. The chimeric construct was expressed in Nicotiana benthamiana plants using either the self-replicating potato virus X (PVX) based vector, pA7248AMV-GFP, or the cowpea mosaic virus (CPMV)-derived expression vector, pEAQ HT. The highest expression level up to 30% of total soluble protein (about 1 mg/g of fresh leaf tissue) was achieved with the PVX-based expression system. Intranasal immunization of mice with purified Flg-4M protein induced high levels of M2e-specific serum antibodies and provided protection against lethal challenge with influenza virus. CONCLUSIONS: This study confirms the usefulness of flagellin as a carrier of M2e and its relevance for the production of M2e-based candidate influenza vaccines in plants. PMID- 26022391 TI - Accessing doctors at times of need-measuring the distance tolerance of rural residents for health-related travel. AB - BACKGROUND: Poor access to doctors at times of need remains a significant impediment to achieving good health for many rural residents. The two-step floating catchment area (2SFCA) method has emerged as a key tool for measuring healthcare access in rural areas. However, the choice of catchment size, a key component of the 2SFCA method, is problematic because little is known about the distance tolerance of rural residents for health-related travel. Our study sought new evidence to test the hypothesis that residents of sparsely settled rural areas are prepared to travel further than residents of closely settled rural areas when accessing primary health care at times of need. METHODS: A questionnaire survey of residents in five small rural communities of Victoria and New South Wales in Australia was used. The two outcome measures were current travel time to visit their usual doctor and maximum time prepared to travel to visit a doctor, both for non-emergency care. Kaplan-Meier charts were used to compare the association between increased distance and decreased travel propensity for closely-settled and sparsely-settled areas, and ordinal multivariate regression models tested significance after controlling for health related travel moderating factors and town clustering. RESULTS: A total of 1079 questionnaires were completed with 363 from residents in closely-settled locations and 716 from residents in sparsely-settled areas. Residents of sparsely settled communities travel, on average, 10 min further than residents of closely settled communities (26.3 vs 16.9 min, p < 0.001), though this difference was not significant after controlling for town clustering. Differences were more apparent in terms of maximum time prepared to travel (54.1 vs 31.9 min, p < 0.001). Differences of maximum time remained significant after controlling for demographic and other constraints to access, such as transport availability or difficulties getting doctor appointments, as well as after controlling for town clustering and current travel times. CONCLUSIONS: Improved geographical access remains a key issue underpinning health policies designed to improve the provision of rural primary health care services. This study provides empirical evidence that travel behaviour should not be implicitly assumed constant amongst rural populations when modelling access through methods like the 2SFCA. PMID- 26022392 TI - The role of the effector caspases drICE and dcp-1 for cell death and corpse clearance in the developing optic lobe in Drosophila. AB - In the developing Drosophila optic lobe, cell death occurs via apoptosis and in a distinctive spatio-temporal pattern of dying cell clusters. We analyzed the role of effector caspases drICE and dcp-1 in optic lobe cell death and subsequent corpse clearance using mutants. Neurons in many clusters required either drICE or dcp-1 and each one is sufficient. This suggests that drICE and dcp-1 function in cell death redundantly. However, dying neurons in a few clusters strictly required drICE but not dcp-1, but required drICE and dcp-1 when drICE activity was reduced via hypomorphic mutation. In addition, analysis of the mutants suggests an important role of effecter caspases in corpse clearance. In both null and hypomorphic drICE mutants, greater number of TUNEL-positive cells were observed than in wild type, and many TUNEL-positive cells remained until later stages. Lysotracker staining showed that there was a defect in corpse clearance in these mutants. All the results suggested that drICE plays an important role in activating corpse clearance in dying cells, and that an additional function of effector caspases is required for the activation of corpse clearance as well as that for carrying out cell death. PMID- 26022393 TI - An improved shielded RF transmit coil for low-frequency NMR and MRI. AB - We describe an actively shielded cylindrical RF transmit coil producing a highly uniform internal field (+/-0.5%) over an extended volume and a strongly suppressed (/20) external field. Direct field mapping and experimental checks using in-situ NMR and MRI of polarised (3)He at low temperature demonstrate performance consistent with numerical field computations. PMID- 26022394 TI - Electron spin resonance microscopic imaging of oxygen concentration in cancer spheroids. AB - Oxygen (O2) plays a central role in most living organisms. The concentration of O2 is important in physiology and pathology. Despite the importance of accurate knowledge of the O2 levels, there is very limited capability to measure with high spatial resolution its distribution in millimeter-scale live biological samples. Many of the current oximetric methods, such as oxygen microelectrodes and fluorescence lifetime imaging, are compromised by O2 consumption, sample destruction, invasiveness, and difficulty to calibrate. Here, we present a new method, based on the use of the pulsed electron spin resonance (ESR) microimaging technique to obtain a 3D mapping of oxygen concentration in millimeter-scale biological samples. ESR imaging requires the incorporation of a suitable stable and inert paramagnetic spin probe into the desirable object. In this work, we use microcrystals of a paramagnetic spin probe in a new crystallographic packing form (denoted tg-LiNc-BuO). These paramagnetic species interact with paramagnetic oxygen molecules, causing a spectral line broadening that is linearly proportional to the oxygen concentration. Typical ESR results include 4D spatial spectral images that give an indication about the oxygen concentration in different regions of the sample. This new oximetry microimaging method addresses all the problems mentioned above. It is noninvasive, sensitive to physiological oxygen levels, and easy to calibrate. Furthermore, in principle, it can be used for repetitive measurements without causing cell damage. The tissue model used in this research is spheroids of Human Colorectal carcinoma cell line (HCT-116) with a typical diameter of ~600MUm. Most studies of the microenvironmental O2 conditions inside such viable spheroids carried out in the past used microelectrodes, which require an invasive puncturing of the spheroid and are also not applicable to 3D O2 imaging. High resolution 3D oxygen maps could make it possible to evaluate the relationship between morphological and physiological alterations in the spheroids, which would help understand the oxygen metabolism in solid tumors and its correlation with the susceptibility of tumors to various oncologic treatments. PMID- 26022395 TI - Assessment of the service performance of drainage system and transformation of pipeline network based on urban combined sewer system model. AB - In recent years, due to global climate change and rapid urbanization, extreme weather events occur to the city at an increasing frequency. Waterlogging is common because of heavy rains. In this case, the urban drainage system can no longer meet the original design requirements, resulting in traffic jams and even paralysis and post a threat to urban safety. Therefore, it provides a necessary foundation for urban drainage planning and design to accurately assess the capacity of the drainage system and correctly simulate the transport effect of drainage network and the carrying capacity of drainage facilities. This study adopts InfoWorks Integrated Catchment Management (ICM) to present the two combined sewer drainage systems in Yangpu District, Shanghai (China). The model can assist the design of the drainage system. Model calibration is performed based on the historical rainfall events. The calibrated model is used for the assessment of the outlet drainage and pipe loads for the storm scenario currently existing or possibly occurring in the future. The study found that the simulation and analysis results of the drainage system model were reliable. They could fully reflect the service performance of the drainage system in the study area and provide decision-making support for regional flood control and transformation of pipeline network. PMID- 26022396 TI - Effect-based assessment of persistent organic pollutant and pesticide dumpsite using mammalian CALUX reporter cell lines. AB - A combined chemical and biological analysis of samples from a major obsolete pesticide and persistent organic pollutant (POP) dumpsite in Northern Tajikistan was carried out. The chemical analytical screening focused on a range of prioritized compounds and compounds known to be present locally. Since chemical analytics does not allow measurements of hazards in complex mixtures, we tested the use of a novel effect-based approach using a panel of quantitative high throughput CALUX reporter assays measuring distinct biological effects relevant in hazard assessment. Assays were included for assessing effects related to estrogen, androgen, and progestin signaling, aryl hydrocarbon receptor-mediated signaling, AP1 signaling, genotoxicity, oxidative stress, chemical hypoxia, and ER stress. With this panel of assays, we first quantified the biological activities of the individual chemicals measured in chemical analytics. Next, we calculated the expected sum activity by these chemicals in the samples of the pesticide dump site and compared the results with the measured CALUX bioactivity of the total extracts of these samples. The results showed that particularly endocrine disruption-related effects were common among the samples. This was consistent with the toxicological profiles of the individual chemicals that dominated these samples. However, large discrepancies between chemical and biological analysis were found in a sample from a burn place present in this site, with biological activities that could not be explained by chemical analysis. This is likely to be caused by toxic combustion products or by spills of compounds that were not targeted in the chemical analysis. PMID- 26022397 TI - Indoor air quality in a restaurant kitchen using margarine for deep-frying. AB - Indoor air quality has a great impact on human health. Cooking, in particular frying, is one of the most important sources of indoor air pollution. Indoor air CO, CO2, particulate matter (PM), and volatile organic compound (VOC) concentrations, including aldehydes, were measured in the kitchen of a small establishment where a special deep-frying margarine was used. The objective was to assess occupational exposure concentrations for cooks of such restaurants. While individual VOC and PM2.5 concentrations were measured before, during, and after frying events using active sampling, TVOC, PM10, CO, CO2, temperature, and relative humidity were continuously monitored through the whole period. VOC and aldehyde concentrations did not increase to considerable levels with deep-frying compared to the background and public indoor environment levels, whereas PM10 increased significantly (1.85 to 6.6 folds). The average PM2.5 concentration of the whole period ranged between 76 and 249 MUg/m(3). Hence, considerable PM exposures could occur during deep-frying with the special margarine, which might be sufficiently high to cause health effects on cooks considering their chronic occupational exposures. PMID- 26022398 TI - Benserazide, the first allosteric inhibitor of Coxsackievirus B3 3C protease. AB - Coxsackievirus B3 is the main cause of human viral myocarditis and cardiomyopathy. Virally encoded Coxsackievirus 3C protease (3C(pro)) plays an essential role in viral proliferation. Here, benserazide was discovered as a novel inhibitor from a drug library screen targeting Coxsackievirus 3C(pro) using a FRET-based enzyme assay. Benserazide, whose chemical structure has no electrophilic functional groups, was characterized as a non-competitive inhibitor by enzyme kinetic studies. A molecular docking study with benserazide and its analogs indicated that a novel putative allosteric binding site was involved. Specifically, a 2,3,4-trihydroxybenzyl moiety was determined to be a key pharmacophore for the enzyme's inhibitory activity. We suggest that the putative allosteric binding site may be a novel target for future therapeutic strategies. PMID- 26022399 TI - Efficient delivery of antigen to DCs using yeast-derived microparticles. AB - Some pathogens can be naturally recognized and internalized by antigen presentation cells (APCs) in vivo, providing a platform for efficient vaccine delivery. However, the biosafety concerns discourage the clinical applications of live pathogens. Here, yeast-derived microparticles were prepared for cancer vaccine delivery. By chemical treatment of bread yeast, capsular yeast shell (YS) microparticles were obtained. Ovalbumin (OVA), as a model antigen, was conjugated to the surface of YS. Results indicated that these YS microparticles with a uniform size of ~3.4 MUm can be recognized and internalized by dendritic cells (DCs). The YS-mediated antigen delivery can enhance the cellular uptake of antigen by DCs, promote the maturation of DCs, and trigger DCs to release immune co-stimulatory molecules. Immunization with YS-mediated antigen can induce an effective immune response against tumor cells in vivo, with contributions from both humoral and cellular immunity. This work suggests that yeast shell microparticles as efficient vaccine delivery system has promising applications in cancer immunotherapy. PMID- 26022400 TI - Surface decorations of poly(amidoamine) dendrimer by various pendant moieties for improved delivery of nucleic acid materials. AB - In recent years, the discovery of novel nucleic acid-based drug candidates (e.g., siRNA and miRNA) and the groundbreaking studies for somatic cell reprogramming into a state of pluripotency have led to reconsideration for the use of human gene therapy as a new paradigm with great therapeutic potential. However, the success of gene therapy is dependent on overcoming intra- and extracellular barriers hampering the efficient delivery of nucleic acid therapeutics into the target cells or tissues. Despite relatively low transfection efficiency, great attention has been directed to cationic polymers and dendrimers due to their ability to condense DNA and RNA molecules into nano-sized particles which is a necessary prerequisite for efficient transfer of nucleic acids into cells. These gene carriers show remarkable adaptability and significant capacity to transfer larger sizes of nucleic acid materials. Polyamidoamine (PAMAM) dendrimer has been employed as non-viral gene carrier due to its globular shape and well-defined structure containing abundant amino surface groups which provide possibility for surface decoration of the dendrimer via the conjugation of various moieties. In this review, we have brought out the various functionalization strategies of the PAMAM surface amines using different pendant moieties such as amino acids, proteins, cyclodextrins, and hydrophobic units in order to overcome intra- and extracellular barriers. These surface-decorated dendrimers possessing favorable properties provide substantial information and insight for redesigning existing dendrimers and polymers. By understanding the role played by the conjugated moieties, more efficient and novel designs of gene vehicles may be possible. PMID- 26022401 TI - Paracetamol induced liver failure varies widely across Europe, study finds. PMID- 26022402 TI - Integrated risk assessment of suicidal ideation and behavior in drug development. AB - Treatment-related suicidal ideation and behavior (SIB) adverse events are under increasing public, legal and regulatory scrutiny. Prospective assessment of SIB is emerging as a challenging safety requirement by health authorities for the development of drugs but the underlying risk factors remain ill defined. To help with the understanding of risk factors that trigger a prospective assessment of SIB in clinical trials, we present an industry consensus framework for risk assessment and decision making of SIB during drug development. Application of this strategy is based on chemical and pharmacological similarities of compounds with clinical evidence of suicidal intent, target or indication classes associated with high incidence of SIB, in vitro neuropharmacological activity profile, in vivo ADME properties, patient population of the underlying indication and regulatory precedents. PMID- 26022404 TI - Assessing traffic and industrial contributions to ambient nitrogen dioxide and volatile organic compounds in a low pollution urban environment. AB - Land use regression (LUR) modeling is an effective method for estimating fine scale distributions of ambient air pollutants. The objectives of this study are to advance the methodology for use in urban environments with relatively low levels of industrial activity and provide exposure assessments for research on health effects of air pollution. Intraurban distributions of nitrogen dioxide (NO2) and the volatile organic compounds (VOCs) benzene, toluene and m- and p xylene were characterized based on spatial monitoring and LUR modeling in Ottawa, Ontario, Canada. Passive samplers were deployed at 50 locations throughout Ottawa for two consecutive weeks in October 2008 and May 2009. Land use variables representing point, area and line sources were tested as predictors of pooled pollutant distributions. LUR models explained 96% of the spatial variability in NO2 and 75-79% of the variability in the VOC species. Proximity to highways, green space, industrial and residential land uses were significant in the final models. More notably, proximity to industrial point sources and road network intersections were significant predictors for all pollutants. The strong contribution of industrial point sources to VOC distributions in Ottawa suggests that facility emission data should be considered whenever possible. The study also suggests that proximity to road network intersections may be an effective proxy in areas where reliable traffic data are not available. PMID- 26022403 TI - Do we need tailored smoking cessation interventions for smokers with COPD? A comparative study of smokers with and without COPD regarding factors associated with tobacco smoking. AB - BACKGROUND: The prevalence of tobacco smoking in patients with chronic obstructive pulmonary disease (COPD) is high. It is assumed that this group of smokers has more difficulties quitting than smokers without COPD. In order to increase the effectiveness of smoking cessation treatments in smokers with COPD it is important to identify any smoking-related factors which are specific to this group of smokers. OBJECTIVE: To compare smokers with COPD with smokers without COPD regarding factors associated with tobacco smoking and quitting. METHODS: We conducted a questionnaire survey in all smoking patients with a recorded diagnosis of COPD from a large Dutch primary health care network. We compared this group with twice as many age-, sex- and health care centre-matched smokers without COPD. RESULTS: Respondents were 107 smokers with COPD and 86 smokers without COPD. The number of attempts to quit was similar in both groups but more smokers with COPD had ever used pharmacological, behavioural and alternative smoking cessation treatments. Furthermore, smokers with COPD more often received triggers to quit from their environment and from their general practitioner, and they were more concerned about, and aware of, the health risks of smoking. Importantly, smokers with COPD reported higher levels of depression and cigarette dependence and a lower self-efficacy to refrain from smoking than smokers without COPD. CONCLUSION: Smokers with COPD differ from smokers without COPD on several factors which are associated with tobacco smoking and quitting. Taking into account these differences may help to increase the effectiveness of smoking cessation treatments for the specific group of smokers with COPD. PMID- 26022405 TI - Life cycle assessment of post-consumer plastics production from waste electrical and electronic equipment (WEEE) treatment residues in a Central European plastics recycling plant. AB - Plastics play an increasingly important role in reaching the recovery and recycling rates defined in the European WEEE Directive. In a recent study we have determined the life cycle environmental impacts of post-consumer plastics production from mixed, plastics-rich WEEE treatment residues in the Central European plant of a market-leading plastics recycler, both from the perspective of the customers delivering the residues and the customers buying the obtained post-consumer recycled plastics. The results of our life cycle assessments, which were extensively tested with sensitivity analyses, show that from both perspectives plastics recycling is clearly superior to the alternatives considered in this study (i.e. municipal solid waste incineration (MSWI) and virgin plastics production). For the three ReCiPe endpoint damage categories, incineration in an MSWI plant results in an impact exceeding that of the examined plastics recycling facility each by about a factor of 4, and the production of virgin plastics has an impact exceeding that of the post-consumer recycled (PCR) plastics production each by a factor of 6-10. On a midpoint indicator level the picture is more differentiated, showing that the environmental impacts of the recycling options are lower by 50% and more for almost all impact factors. While this provides the necessary evidence for the environmental benefits of plastics recycling compared to existing alternatives, it can, however, not be taken as conclusive evidence. To be conclusive, future research will have to address the fate of hazardous substances in the outputs of such recycling systems in more detail. PMID- 26022406 TI - Targeting allergenic fungi in agricultural environments aids the identification of major sources and potential risks for human health. AB - Fungi are, after pollen, the second most important producers of outdoor airborne allergens. To identify sources of airborne fungal allergens, a workflow for qPCR quantification from environmental samples was developed, thoroughly tested, and finally applied. We concentrated on determining the levels of allergenic fungi belonging to Alternaria, Cladosporium, Fusarium, and Trichoderma in plant and soil samples from agricultural fields in which cereals were grown. Our aims were to identify the major sources of allergenic fungi and factors potentially influencing their occurrence. Plant materials were the main source of the tested fungi at and after harvest. Amounts of A. alternata and C. cladosporioides varied significantly in fields under different management conditions, but absolute levels were very high in all cases. This finding suggests that high numbers of allergenic fungi may be an inevitable side effect of farming in several crops. Applied in large-scale studies, the concept described here may help to explain the high number of sensitization to airborne fungal allergens. PMID- 26022407 TI - Trends of persistent organic pollutants in American eel (Anguilla rostrata) from eastern Lake Ontario, Canada, and their potential effects on recruitment. AB - This study reports the history of contamination of American eels (Anguilla rostrata) from eastern Lake Ontario (LO) by persistent organic pollutants (POPs). Three groups of 10 large female eels captured in eastern LO in each of 1988, 1998, and 2008 were analysed for polychlorinated dibenzo-p-dioxins and furans, polychlorinated biphenyls, several organochlorine pesticides, and polybrominated diphenyl ethers. Mean concentrations were up to 3-fold lower in 2008 compared to previous years. When combined with the results of previous studies, these data show that concentrations of POPs in American eels have declined exponentially since the early 1980s by an average of 9.1+/-1.9% per year. Toxic equivalent (TEQ) concentrations of dioxin-like compounds (DLCs) were calculated from fish toxic equivalency factors. Assuming an efficient transfer of DLCs to their eggs, egg TEQs prior to 2000 exceeded the threshold for chronic toxicity to embryos of European eels (Anguilla anguilla) and lake trout (Salvelinus namaycush) (4-5 pg/g ww of TEQ). These results suggest that embryotoxicity of maternally-derived DLCs from LO eels, historically a major contributor to the spawning stock of American eels, could have impaired the reproductive and recruitment success of the species. PMID- 26022408 TI - Gender-specific differences of interaction between obesity and air pollution on stroke and cardiovascular diseases in Chinese adults from a high pollution range area: A large population based cross sectional study. AB - BACKGROUND: Little information exists regarding the interaction effects of obesity with long-term air pollution exposure on cardiovascular diseases (CVDs) and stroke in areas of high pollution. The aim of the present study is to examine whether obesity modifies CVD-related associations among people living in an industrial province of northeast China. METHODS: We studied 24,845 Chinese adults, aged 18 to 74 years old, from three Northeastern Chinese cities in 2009 utilizing a cross-sectional study design. Body weight and height were measured by trained observers. Overweight and obesity were defined as a body mass index (BMI) between 25-29.9 and >=30 kg/m(2), respectively. Prevalence rate and related risk factors of cardiovascular and cerebrovascular diseases were investigated by a questionnaire. Three-year (2006-2008) average concentrations of particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxides (NO2), and ozone (O3) were measured by fixed monitoring stations. All the participants lived within 1 km of air monitoring sites. Two-level logistic regression (personal level and district specific pollutant level) was used to examine these effects, controlling for covariates. RESULTS: We observed significant interactions between exposure and obesity on CVDs and stroke. The associations between annual pollutant concentrations and CVDs and stroke were strongest in obese subjects (OR 1.15-1.47 for stroke, 1.33-1.59 for CVDs), less strong in overweight subjects (OR 1.22-1.35 for stroke, 1.07-1.13 for CVDs), and weakest in normal weight subjects (OR ranged from 0.98-1.01 for stroke, 0.93-1.15 for CVDs). When stratified by gender, these interactions were significant only in women. CONCLUSIONS: Study findings indicate that being overweight and obese may enhance the effects of air pollution on the prevalence of CVDs and stroke in Northeastern metropolitan China. Further studies will be needed to investigate the temporality of BMI relative to exposure and onset of disease. PMID- 26022409 TI - Predicting the preservation of cultural artefacts and buried materials in soil. AB - This study identifies factors affecting the fate of buried objects in soil and develops a method for assessing where preservation of different materials and stratigraphic evidence is more or less likely in the landscape. The results inform the extent of the cultural service that soil supports by preserving artefacts from and information about past societies. They are also relevant to predicting the state of existing and planned buried infrastructure and the persistence of materials spread on land. Soils are variable and preserve different materials and stratigraphic evidence differently. This study identifies the material and soil properties that affect preservation and relates these to soil types; it assesses their preservation capacities for bones, teeth and shells, organic materials, metals (Au, Ag, Cu, Fe, Pb and bronze), ceramics, glass and stratigraphic evidence. Preservation of Au, Pb and ceramics, glass and phytoliths is good in most soils but degradation rates of other materials (e.g. Fe and organic materials) is strongly influenced by soil type. A method is proposed for using data on the distribution of soil types to map the variable preservation capacities of soil for different materials. This is applied at a continental scale across the EU for bones, teeth and shells, organic materials, metals (Cu, bronze and Fe) and stratigraphic evidence. The maps produced demonstrate how soil provides an extensive but variable preservation of buried objects. PMID- 26022410 TI - Cognitive Behavioral Analysis System of Psychotherapy versus Escitalopram in Chronic Major Depression. AB - BACKGROUND: A specific psychotherapy for chronic depression, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), was compared to escitalopram (ESC). METHODS: Sixty patients with chronic major depression were randomized to 'CBASP' (22 sessions) or 'ESC plus clinical management' (ESC/CM) at two treatment sites. The primary outcome measure was the score on the Montgomery-Asberg Depression Rating Scale (MADRS) after 8 weeks of acute treatment assessed by blinded raters. In the case of nonimprovement (<20% reduction in the MADRS score), the other condition was augmented for the following 20 weeks of extended treatment. Secondary end points were, among others, depressive symptoms, remission (MADRS score of <=9) and response rates (reduction of MADRS score of >=50%) 28 weeks after randomization. RESULTS: An intent-to-treat analysis revealed that clinician-rated depression scores decreased significantly after 8 and 28 weeks with no significant differences between the groups. The response rates after 28 weeks of treatment were high (CBASP: 68.4%, ESC/CM: 60.0%), and the remission rates were moderate (CBASP: 36.8%, ESC/CM: 50.0%) with neither group being superior. Nonimprovers to the initial treatment caught up with the initial improvers in terms of depression scores and response and remission rates by the end of the treatment after being augmented with the respective other condition. CONCLUSIONS: CBASP and ESC/CM appear to be equally effective treatment options for chronically depressed outpatients. For nonimprovers to the initial treatment, it is efficacious to augment with medication in the case of nonresponse to CBASP and vice versa. PMID- 26022411 TI - Potential use of Bacillus thuringiensis bacteriocins to control antibiotic resistant bacteria associated with mastitis in dairy goats. AB - Mastitis caused by microbial infections in dairy goats reduces milk yield, modifies milk composition, and potentially contributes to morbidity in herds and consumers of dairy products. Microorganisms associated with mastitis in dairy goats are commonly controlled with antibiotics, but it is known that continued use of these chemical agents promotes antibiotic resistance among bacterial populations. Recently, it has been shown that bacteriocins of Bacillus thuringiensis inhibit growth of food-borne pathogens and also bacteria associated with bovine mastitis. However, there is no report on their ability to inhibit microorganisms linked to mastitis in dairy goats. In this study, using 16S rDNA and ITS regions of rDNA, we identified nine bacterial isolates and an encapsulated yeast associated with mastitis in dairy goats. Enterococcus durans, Brevibacillus sp., and Staphylococcus epidermidis 2 were resistant to, respectively, 75, ~67, ~42, and ~42 % of the antibiotics screened. In addition, 60 % of the bacterial isolates were resistant to penicillin, ampicillin, vancomycin, and dicloxacillin. Importantly, 60 % of the isolates were inhibited by the bacteriocins, but S. epidermidis 1, Enterobacter sp., Escherichia vulneris, and Cryptococcus neoformans were not susceptible to these antimicrobial peptides. Using Brevibacillus sp. and Staphylococcus chromogenes as indicator bacteria, we show that peptides of ~10 kDa that correspond to the molecular mass of bacteriocins used in this study are responsible for the inhibitory activity. Our results demonstrate that multiple antibiotic-resistant bacteria associated with subclinical mastitis in dairy goats from Guanajuato, Mexico, are susceptible to bacteriocins produced by B. thuringiensis. PMID- 26022413 TI - Accuracy of limited four-slice CT-scan in diagnosis of chronic rhinosinusitis. AB - OBJECTIVE: Chronic rhinosinusitis (CRS) is a common chronic health condition worldwide. Standard CT-scan is the method of choice for diagnosis of CRS but its high price and considerable radiation exposure have limited its application. The main goal of this study was to evaluate the accuracy of limited four-slice coronal CT-scan in the diagnosis of CRS. MATERIAL AND METHOD: This cross sectional study was conducted on 46 patients with CRS, for one year, based on American Society of Head and Neck Surgery criteria. All patients received the preoperative standard and four-slice CT-scans, after which endoscopic sinus surgery was performed. Findings of four-slice CT-scans were compared with those of conventional CT-scan and the sensitivity and specificity of four-slice CT-scan and its agreement with conventional CT-scan was calculated. RESULT: In this study, 46 patients including 32 males (69.6%) and 14 females (30.46%) with a mean age of 33 and standard deviation of 9 years, were evaluated. Sensitivity and specificity of four-slice CT-scan were 97.5% and 100%, respectively. Also, positive predictive value (PPV) and negative predictive value (NPV) of four-slice CT was 100% and 85.71%, respectively. There was a strong agreement between four slice CT and conventional CT findings. CONCLUSION: Considering the high sensitivity and specificity of four-slice CT-scan and strong agreement with conventional CT-scan in the diagnosis of CRS and the lower radiation exposure and cost, application of this method is suggested for both diagnosis and treatment follow-up in CRS. PMID- 26022414 TI - Stability and Change in Adjustment Profiles Among Chinese American Adolescents: The Role of Parenting. AB - Asian American adolescents are often depicted as academically successful but psychologically distressed, a pattern known as the achievement/adjustment paradox. In a sample of 444 Chinese American adolescents (54 % females), we identified three distinct patterns of adjustment in early adolescence, middle adolescence, and emerging adulthood: the well-adjusted group, which was the largest, exhibited high achievement and low psychological distress; the poorly adjusted group exhibited poor achievement and moderate distress; and the paradox group exhibited relatively high achievement and high distress. More than half of the adolescents remained in the same profile over time. Adolescents with supportive parents were more likely to stay well-adjusted, and those with "tiger" parents were more likely to stay in the paradox group over time. The present study focused on the critical role of parenting in early adolescence, highlighting variations in Chinese American adolescents' adjustment in multiple domains over time. PMID- 26022412 TI - CD8(+) T activation attenuates CD4(+) T proliferation through dendritic cells modification. AB - Emerging evidence has suggested that CD8(+) T had modulatory function on CD4(+) T mediated autoimmune and inflammatory diseases. However, the underlying mechanisms remain unclear. In this study, we found that CD8(+) T activation inhibited OVA(323-339) antigen specific CD4(+) T cells proliferation in vitro and in vivo. Further investigation demonstrated that this immunosuppression largely depended on the soluble factor from activated CD8(+) T to modify the phenotype and functions of DCs. Moreover, not only the inhibitors for IDO or iNOS, but also IFN gamma neutralization markedly reversed this immunosuppression on OVA(323-339) antigen specific CD4(+) T cells proliferation. Interestingly, CD8(+) T cells absence aggravated the pathological damage in lung in OVA-induced asthma model, but alleviated by CD8(+) T transfer and activation. Thus, these findings suggested that activated CD8(+) T population exerted feedback regulation in DCs modification, and then attenuated CD4(+) T mediated immune response. PMID- 26022415 TI - COMETARY NUCLEI. The shape and structure of cometary nuclei as a result of low velocity accretion. AB - Cometary nuclei imaged from flyby and rendezvous spacecraft show common evidence of layered structures and bilobed shapes. But how and when these features formed is much debated, with distinct implications for solar system formation, dynamics, and geology. We show that these features could be a direct result of accretionary collisions, based on three-dimensional impact simulations using realistic constitutive properties. We identify two regimes of interest: layer-forming splats and mergers resulting in bilobed shapes. For bodies with low tensile strength, our results can explain key morphologies of cometary nuclei, as well as their low bulk densities. This advances the hypothesis that nuclei formed by collisional coagulation-either out of cometesimals accreting in the early solar system or, alternatively, out of comparable-sized debris clumps paired in the aftermath of major collisions. PMID- 26022417 TI - Retraction. When contact changes minds: an experiment on transmission of support for gay equality. PMID- 26022416 TI - GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. AB - Forward genetic screens in Drosophila melanogaster for modifiers of position effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A nonlethal forward genetic screen in near haploid KBM7 cells identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing. PMID- 26022418 TI - Deficiencies in reporting results of lesbians and gays after donor intrauterine insemination and assisted reproductive technology treatments: a review of the first emerging studies. AB - At a time when increasing numbers of lesbians and gays consider parenthood using reproductive assistance in infertility centers, the present review aims to summarize the results obtained so far by lesbians after intrauterine insemination (IUI) and in-vitro fertilization (IVF) using donor spermatozoa (D-IUI and D-IVF, respectively) and gays entering into gestational-surrogacy programs. Data show that gays display normal semen parameters and lesbians exhibit no specific causes of female infertility except perhaps for polycystic ovary syndrome (PCOS) and some PCOS-related factors. Pair-bonded lesbians entering into D-IUI programs, tend to have higher pregnancy and delivery percentages following spontaneous or induced ovulation than single or pair-bound heterosexual women. The only single study reporting success percentages of lesbians after D-IVF provides, however, puzzling results. In particular, pair-bonded lesbians have lower pregnancy and live-birth percentages than pair-bonded heterosexual women in fresh D-IVF cycles but percentages are similar in frozen/thawed D-IVF cycles. Like in lesbians after D-IUI, surrogate women recruited by pair-bonded gays/single men tend to have higher pregnancy percentages and lower miscarriage percentages than surrogate women recruited by heterosexual couples. Notably, all the reports reviewed in the present study are methodologically flawed because of sampling bias, small sample sizes and inadequate use of statistical methods to control for the effects of influential covariates including age, smoking habits, previous gynecological problems, hormonal stimulation type and protocol, and number of prior treatment types and pregnancies/deliveries. Clinicians, reproductive biologists and editors of fertility/infertility journals should make efforts to prevent these deficiencies in future data reporting. PMID- 26022419 TI - Doubtful Role of IL28B Polymorphism in Occult Hepatitis B Infection. AB - AIMS: To investigate the influence of IL28B polymorphism in occult hepatitis B infection (OBI) and whether IL28B genetic variants are associated with hepatitis B virus (HBV)-specific T-cell responses. PATIENTS AND METHODS: The rs12979860 IL28B genotype was determined in 34 OBI blood donors, 22 spontaneous HBV resolvers, 36 inactive HBV carriers and 25 seronegative donors. T-cell responses to HBV recombinant proteins were assessed by interferon-gamma enzyme-linked immunospot assay. RESULTS: The frequency of the IL28B CC genotype among OBI patients was similar to that of inactive carriers [41 vs. 39%, respectively, p = 0.961; odds ratio (OR) = 1.10; 95% confidence interval (CI) = 0.42-2.86; p = 0.845]. The IL28B CC genotype was found more frequently in spontaneous resolvers, although the differences were not significant (45 vs. 39%, spontaneous resolvers and inactive carriers, respectively; p = 0.828; OR = 1.31; 95% CI = 0.45-3.83; p = 0.622). HBV-specific T-cell responses were detected in OBIs, and significantly stronger T-cell responses towards hepatitis B envelope antigen were observed in those with the IL28B CC genotype. In spontaneous resolvers and inactive carriers, IL28B CC did not correlate with the magnitude of T-cell responses. CONCLUSIONS: In OBI donors, IL28B CC correlates with the intensity of HBV-specific T-cell responses. In this study, IL28B CC is not statistically associated with OBI or with HBV clearance, but a larger number of cases is needed before completely ruling out its role in HBV infection. PMID- 26022420 TI - [Scuba diving in children: Physiology, risks and recommendations]. AB - INTRODUCTION: The increase in recreational scuba diving in recent years, including children, involves risks and the possibility of accidents. While legislation, conditions and risks of scuba diving are well documented in adults, scientific evidence in scuba diving by children and adolescents is sparse and isolated. Furthermore, existing guidelines and recommendations for adults cannot be transferred directly to children. METHODS: These circumstances have led to the Group on Techniques of the Spanish Society of Pediatric Pulmonology (SENP) to perform a literature search to review and update the knowledge about scuba diving in children. RESULTS: Physiological adaptations of the body are examined during the dive, as well as the anatomical and physiological characteristics of children that should be taken into account in scuba diving. The most common types of accidents and its causes, as well as the risks of scuba diving practice in children with previous diseases are discussed, along with details of the medical and psychological requirements for scuba diving to be considered in the assessment of child and adolescent. CONCLUSIONS: A list of recommendations for scuba diving with compressed air in children is presented by a group of experts. PMID- 26022421 TI - Enzymatic production of l-citrulline by hydrolysis of the guanidinium group of l arginine with recombinant arginine deiminase. AB - In this study, a simple, efficient enzymatic production process for the environmentally friendly synthesis of l-citrulline from l-arginine was developed using arginine deiminase (ADI) from Lactococcus lactis. Following overexpression of L. lactis ADI in Escherichia. coli BL21 (DE3) and experimental evolution using error-prone PCR, mutant FMME106 was obtained with a Km for l-arginine of 3.5mM and a specific activity of 195.7U/mg. This mutant exhibited a maximal conversion of 92.6% and achieved a final l-citrulline concentration of 176.9g/L under optimal conditions (190g/L l-arginine, 15g/L whole-cell biocatalyst treated with 2% isopropanol for 30min, 50 degrees C, pH 7.2, 8h). The average l-citrulline synthesis rate of 22.1g/L/h is considerably higher than that reported for other similar biocatalytic approaches, therefore the process developed in the present work has great potential for large-scale production of l-citrulline. PMID- 26022422 TI - Pichia pastoris production of a prolyl 4-hydroxylase derived from Chondrosia reniformis sponge: A new biotechnological tool for the recombinant production of marine collagen. AB - Prolyl 4-hydroxylase (P4H) is a alpha2beta2 tetramer catalyzing the post translational hydroxylation of prolines in collagen. Its recombinant production is mainly pursued to realize biotechnological tools able to generate animal contaminant-free hydroxylated collagen. One promising candidate for biomedical applications is the collagen extracted from the marine sponge Chondrosia reniformis, because of its biocompatibility and because is devoid of the health risks associated with bovine and porcine collagens. Here we report on the production and selection, by enzymatic and biomolecular analyses, of a triple transformed Pichia pastoris strain expressing a stable P4H tetramer derived from C. reniformis sponge and a hydroxylated non fibrillar procollagen polypeptide from the same animal. The percentage of recombinant procollagen hydroxylated prolines inside the transformed yeast was of 36.3% analyzed by mass spectrometry indicating that the recombinant enzyme is active on its natural substrate inside the yeast cell host. Furthermore, the recombinant sponge P4H has the ability to hydroxylate its natural substrate in both X and Y positions in the Xaa-Yaa-Gly collagenous triplets. In conclusion this Pichia system seems ideal for high-level production of hydroxylated sponge- or marine-derived collagen polypeptides as well as of conotoxins or other marine proteins of high pharmacological interest needing this particular post-translational modification. PMID- 26022423 TI - Full genome sequence of Brevibacillus laterosporus strain B9, a biological control strain isolated from Zhejiang, China. AB - Brevibacillus laterosporus was newly classified from Bacillus laterosporus, which has ability to be used as a biological control agent in crop field. B. laterosporus strain B9 is an aerobic, motile, Gram-positive, spore-forming rod that was isolated from a field of Oryza sativa in Zhejiang, China in 2011. This bacterium has been confirmed to be a strong antagonist against bacterial brown strip of rice caused by Acidovorex avenae subsp. avenae. Here we describe the features of B. laterosporus strain B9, together with the complete genome sequence and its annotation. The 5,272,435bp genome contains 4804 protein-coding genes and 227 RNA-only encoding genes with 2 plasmids. PMID- 26022424 TI - Isolation of Chlamydomonas reinhardtii mutants with altered mitochondrial respiration by chlorophyll fluorescence measurement. AB - The unicellular green alga Chlamydomonas reinhardtii is a model organism for studying energetic metabolism. Most mitochondrial respiratory-deficient mutants characterized to date have been isolated on the basis of their reduced ability to grow in heterotrophic conditions. Mitochondrial deficiencies are usually partly compensated by adjustment of photosynthetic activity and more particularly by transition to state 2. In this work, we explored the opportunity to select mutants impaired in respiration and/or altered in dark metabolism by measuring maximum photosynthetic efficiency by chlorophyll fluorescence analyses (FV/FM). Out of about 2900 hygromycin-resistant insertional mutants generated from wild type or from a mutant strain deficient in state transitions (stt7 strain), 22 were found to grow slowly in heterotrophic conditions and 8 of them also showed a lower FV/FM value. Several disrupted coding sequences were identified, including genes coding for three different subunits of respiratory-chain complex I (NUO9, NUOA9, NUOP4) or for isocitrate lyase (ICL1). Overall, the comparison of respiratory mutants obtained in wild-type or stt7 genetic backgrounds indicated that the FV/FM value can be used to isolate mutants severely impaired in dark metabolism. PMID- 26022425 TI - A novel one-stage cultivation/fermentation strategy for improved biogas production with microalgal biomass. AB - The use of alga biomass for biogas generation has been studied for over fifty years but until today, several distinct features, like inefficient degradation and low C/N ratios, limit the applicability of algal biomass for biogas production in larger scale. In this work we investigated a novel, one-stage combined cultivation/fermentation strategy including inherently progressing nitrogen starvation conditions to generate improved microalgal biomass substrates. For this strategy, comparable low amounts of nitrogen fertilizers were applied during cultivation and no additional enzymatic, chemical or physical pretreatments had to be performed. The results of this study demonstrate that progressing nitrogen limitation leads to continuously increasing C/N ratios of the biomass up to levels of 24-26 for all three tested alga strains (Chlamydomonas reinhardtii, Parachlorella kessleri and Scenedesmus obliquus). Importantly, the degradation efficiency of the algal cells increased with progressing starvation, leading to strain-specific cell disintegration efficiencies of 35%-100% during the fermentation process. Nitrogen limitation treatment resulted in a 65% increase of biogas yields for C. reinhardtii biomass (max. 698+/-23mL biogas g(-1) VS) when compared to replete conditions. For P. kessleri and S. obliquus, yields increased by 94% and 106% (max. 706+/-39mL and 586+/-36mL biogas g(-1) VS, respectively). From these results we conclude that this novel one-stage cultivation strategy with inherent nitrogen limitation can be used as a pretreatment for microalgal biomass generation, in order to produce accessible substrates with optimized C/N ratios for the subsequent anaerobic fermentation process, thus increasing methane production and avoiding the risk of ammonia inhibition effects within the fermenter. PMID- 26022426 TI - The mechanism of the resolution of chronic right bundle branch block during acute myocardial infarction. PMID- 26022427 TI - Inferior vena cava duplication. PMID- 26022428 TI - [Erratum to: Opioids in chronic low back pain. A systematic review and meta analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration]. AB - In Infobox 1 (Excluded with reason), p. 9, two reference numbers are missing. Item 2 (Gordon et al.): [34] Item 4 (Yarlas et al.): All data published by [39] PMID- 26022429 TI - [Erratum to: Opioids for chronic non-tumor-related pain--are not opioid analgesics superior? Systematic Review and Meta-analysis of Efficacy, tolerability and safety in randomized direct comparison of opioids and non-opioid analgesia for at least 4 weeks]. AB - Fig. 1 is slightly flawed as shown (the last line is missing). We enter the picture again correctly. PMID- 26022430 TI - [Erratum to: Long-term therapy with opioids for chronic non-tumor-related pain. Systematic Review and Meta-analysis of the efficacy, tolerability and security in open connection studies over at least 26 weeks]. AB - On p. 7, right column, the sentence "The mean average reductions in pain and disability were maintained from the end of the double-blind to the end of the open-label period up to 3 years later" is not correct. It should read "2 years" instead of "3 years". PMID- 26022431 TI - [Erratum to: Methodology of the development of the updated LONTS guidelines for long-term administration of opioids in noncancer pain]. AB - In the sentence "For dichotomous variables, the threshold for 'appreciable benefit' or 'appreciable harm' was set at a relative risk reduction (RRR) or relative risk increase (RRI) >= 10 % [5]" the relative risk increase (RRI) is not >=10 %, but >= 25 %. PMID- 26022432 TI - Follow-up strategies for patients with gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery. AB - BACKGROUND: Patients with gastrointestinal stromal tumour (GIST) are often followed up after surgery with longitudinally repeated imaging examinations to detect recurrence early. Studies on follow-up of GIST patients are few, the optimal follow-up methods are unknown and the recommendations for follow-up vary in guidelines. METHODS: We reviewed the current evidence for follow-up of patients treated with surgery alone and of patients who were treated with adjuvant or neoadjuvant imatinib. RESULTS: Imaging of the abdomen and the pelvis with computerised tomography (CT) or magnetic resonance imaging (MRI) usually suffices, since metastases are uncommon at other sites. The frequency of imaging may be adjusted with the risk of recurrence with time. Very low risk GISTs are very frequently cured with surgery and usually require no regular follow-up after complete surgery, and annual CT of the abdomen and the pelvis for 5 years suffices for most patients with a low to intermediate risk for recurrence. Most high-risk patients are treated with imatinib for at least 3 years after surgery. CT or MRI may be carried out 6-monthly during adjuvant imatinib, 3 to 4-monthly during the 2 years that follow discontinuation of imatinib when the risk of recurrence is high, and then at 6-12 month intervals to complete 10 years of follow-up. Recurrence after the first 10 years of follow-up is infrequent. CONCLUSIONS: The follow-up schedules are best tailored with the risk of recurrence. The risk of recurrence should be estimated with the prognostic tools that consider the most relevant prognostic factors. PMID- 26022433 TI - Embryonic Origin of the Islet1 and Pax6 Neurons of the Chicken Central Extended Amygdala Using Cell Migration Assays and Relation to Different Neuropeptide Containing Cells. AB - In a recent study, we tentatively identified different subdivisions of the central extended amygdala (EAce) in chicken based on the expression of region specific transcription factors (including Pax6 and Islet1) and several phenotypic markers during embryonic development. Such a proposal was partially based on the suggestion that, similarly to the subdivisions of the EAce of mammals, the Pax6 and Islet1 neurons of the comparable chicken subdivisions derive from the dorsal (Std) or ventral striatal embryonic domains (Stv), respectively. To investigate whether this is true, in the present study, we carried out cell migration assays from chicken Std or Stv combined with immunofluorescence for Pax6 or Islet1. Our results showed that the cells of the proposed chicken EAce truly originate in either Std (expressing Pax6) or Stv (expressing Islet1). This includes lateral subdivisions previously compared to the intercalated amygdalar cells and the central amygdala of mammals, also rich in Std-derived Pax6 cells and/or Stv derived Islet1 cells. In the medial region of the chicken EAce, the dorsal part of the lateral bed nucleus of the stria terminalis (BSTL) contains numerous cells expressing Nkx2.1 (mostly derived from the pallidal domain), but our migration assays showed that it also contains neuron subpopulations from the Stv (expressing Islet1) and Std (expressing Pax6), resembling the mouse BSTL. These findings, together with those previously published in different species of mammals, birds and reptiles, support the homology of the chicken EAce to that of other vertebrates, and reinforce the existence of several cell subcorridors inside the EAce. In addition, together with previously published data on neuropeptidergic cells, these results led us to propose the existence of at least seventeen neuron subtypes in the EAce in rodents and/or some birds (chicken and pigeon). The functional significance and the evolutionary origin of each subtype needs to be analyzed separately, and such studies are mandatory in order to understand the multifaceted modulation by the EAce of fear responses, ingestion, motivation and pain in different vertebrates. PMID- 26022434 TI - Randomized Controlled Trial to Evaluate Regional Citrate Anticoagulation Plus Low Dose of Dalteparin in Continuous Veno-Venous Hemofiltration. AB - BACKGROUND/AIMS: To evaluate the efficacy and safety of regional citrate anticoagulation (RCA) plus low-dose dalteparin in patients receiving continuous veno-venous hemofiltration (CVVH). METHODS: Patients requiring pre-dilution CVVH at 4 l/h were randomly assigned to group A (RCA only), group B (normal-dose dalteparin anticoagulation only) or group C (RCA plus low-dose dalteparin). The primary endpoint was filter runtime and the secondary endpoints were premature clotting of the filter and anticoagulation-related side effects. RESULTS: Fifty three patients completed the study. The mean filter runtime was significantly longer in group C (40.4 +/- 30.9 h) than those in group A (21.2 +/- 13.5 h, p = 0.006) and group B (25.1 +/- 24.0 h, p = 0.040). The rate of premature clotting, new onset of bleeding, hypocalcemia and metabolic acidosis did not differ significantly in three groups. CONCLUSIONS: RCA plus low-dose dalteparin prolonged filter runtime compared with RCA only or normal-dose dalteparin only without increasing the incidence of anticoagulation-related complications. PMID- 26022435 TI - Malignant perivascular epithelioid cell tumor (PEComa) of the femur: a case report and literature review. AB - BACKGROUND: We describe a case of malignant perivascular epithelial cell tumor (PEComa) arising primarily in the distal left femur of a 47-year-old male. CASE PRESENTATION: The patient presented with pain accompanied by progressive swelling of his left thigh. Computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed an osteolytic lesion. Curettage of the lesion was reported as a clear cell tumor with recommendation for exclusion of a metastatic clear cell carcinoma. However, thorough examinations did not find any primary site elsewhere, apart from the presence of bilateral pulmonary metastases. Evaluation of the submitted H & E slides identified a malignant PEComa which was further confirmed by subsequent immunohistochemical study. CONCLUSIONS: The occurrence of PEComa as a primary bone lesion is extremely rare. We present here a malignant PEComa of the distal left femur, and summarize the clinicopathological characteristics of this rare entity with literature review. VIRTUAL SLIDES: The virtual slide (s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5729035221600545 . PMID- 26022436 TI - Brain-Derived Neurotrophic Factor and Delayed Verbal Recall in Crack/Cocaine Dependents. AB - BACKGROUND/AIMS: Considering the role of brain-derived neurotrophic factor (BDNF) in memory processes and its peripheral response during the detoxification of cocaine, the aim of this study was to investigate whether plasma BDNF levels could be related to memory performance in women with crack/cocaine dependence. METHODS: Twenty-five abstinent female crack/cocaine users (CCD) and 25 unmedicated healthy women (HW), carefully matched for age and years of formal education, were assessed regarding memory performance. Logical Memory was used to assess the immediate verbal recall (IVR), delayed verbal recall (DVR) and memory retention. Plasma BDNF levels were measured by Elisa immunoassay. Beck Depression Inventory was used to assess the severity of depressive symptoms, and the Cocaine Selective Severity Assessment the severity of cocaine abstinence symptoms. RESULTS: The CCD group had lower DVR scores and higher plasma BDNF levels when compared to HW group. In addition, a linear regression model showed that BDNF levels predicted DVR scores within CCD group independently of depressive symptoms (R = 0.51; R(2) = 0.26; t(22) = 4.025, p = 0.03). CONCLUSION: Despite higher plasma BDNF levels, crack users exhibited memory impairments when compared to healthy women. Specifically, peripheral BDNF levels predicted better cognitive performance only within individuals who already had cognitive impairment. PMID- 26022437 TI - Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis. AB - Marine actinomycete-derived natural products continue to inspire chemical and biological investigations. Nocardioazines A and B (3 and 4), from Nocardiopsis sp. CMB-M0232, are structurally unique alkaloids featuring a 2,5-diketopiperazine (DKP) core functionalized with indole C3-prenyl as well as indole C3- and N methyl groups. The logic of their assembly remains cryptic. Bioinformatics analyses of the Nocardiopsis sp. CMB-M0232 draft genome afforded the noz cluster, split across two regions of the genome, and encoding putative open reading frames with roles in nocardioazine biosynthesis, including cyclodipeptide synthase (CDPS), prenyltransferase, methyltransferase, and cytochrome P450 homologs. Heterologous expression of a twelve gene contig from the noz cluster in Streptomyces coelicolor resulted in accumulation of cyclo-l-Trp-l-Trp DKP (5). This experimentally connected the noz cluster to indole alkaloid natural product biosynthesis. Results from bioinformatics analyses of the noz pathway along with challenges in actinomycete genetics prompted us to use asymmetric synthesis and mass spectrometry to determine biosynthetic intermediates in the noz pathway. The structures of hypothesized biosynthetic intermediates 5 and 12-17 were firmly established through chemical synthesis. LC-MS and MS-MS comparison of these synthetic compounds with metabolites present in chemical extracts from Nocardiopsis sp. CMB-M0232 revealed which of these hypothesized intermediates were relevant in the nocardioazine biosynthetic pathway. This established the early and mid-stages of the biosynthetic pathway, demonstrating that Nocardiopsis performs indole C3-methylation prior to indole C3-normal prenylation and indole N1'-methylation in nocardioazine B assembly. These results highlight the utility of merging bioinformatics analyses, asymmetric synthetic approaches, and mass spectrometric metabolite profiling in probing natural product biosynthesis. PMID- 26022438 TI - Reactive resistance to anti-angiogenic drugs. PMID- 26022439 TI - High-definition computed tomography for coronary artery stents: image quality and radiation doses for low voltage (100 kVp) and standard voltage (120 kVp) ECG triggered scanning. AB - The noninvasive assessment of coronary stents by coronary CT angiography (CCTA) is an attractive method. However, the radiation dose associated with CCTA remains a concern for patients. The purpose of this study is to compare the radiation doses and image qualities of CCTA performed using tube voltages of 100 or 120 kVp for the evaluation of coronary stents. After receiving institutional review board approval, 53 consecutive patients with previously implanted stents (101 stents) underwent 64-slice CCTA. Patients were divided into three different protocol groups, namely, prospective ECG triggering at 100 kVp, prospective ECG triggering at 120 kVp, or retrospective gating at 100 kVp. Two reviewers qualitatively scored the quality of the resulting images for coronary stents and determined levels of artificial lumen narrowing (ALN), stent lumen attenuation increase ratio (SAIR), image noise, and radiation dose parameters. No significant differences were found between the three protocol groups concerning qualitative image quality or SAIR. Coronary lumen attenuation and in-stent attenuation of 100 kVp prospective CCTA (P-CCTA) were higher than in the 120 kVp P-CCTA protocol (all Ps < 0.001). Mean ALN was significantly lower for 100 kVp P-CCTA than for 100 kVp retrospective CCTA (R-CCTA, P = 0.007). The mean effective radiation dose was significantly lower (P < 0.001) for 100 kVp P-CCTA (3.3 +/- 0.4 mSv) than for the other two protocols (100 kVp R-CCTA 6.7 +/- 1.0 mSv, 120 kVp P-CCTA 4.6 +/- 1.2 mSv). We conclude that the use of 100 kVp P-CCTA can reduce radiation doses for patients while maintaining the imaging quality of 100 kVp R-CCTA and 120 kVp P-CCTA for the evaluation of coronary stents. PMID- 26022440 TI - Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines. AB - Stat1(-/-) mice lack a response to interferon alpha, beta, and gamma, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors. PMID- 26022441 TI - Characterization of a Bivalent Vaccine Capable of Inducing Protection Against Both Ebola and Cross-clade H5N1 Influenza in Mice. AB - BACKGROUND: Ebola virus (EBOV) is a lethal pathogen that causes up to 90% mortality in humans, whereas H5N1 avian influenza has a 60% fatality rate. Both viruses are considered pandemic threats. The objective was to evaluate the protective efficacy of a bivalent, recombinant vesicular stomatitis virus vaccine expressing both the A/Hanoi/30408/2005 H5N1 hemagglutinin and the EBOV glycoprotein (VSVDeltaG-HA-ZGP) in a lethal mouse model of infection. METHODS: Mice were vaccinated 28 days before or 30 minutes after a lethal challenge with mouse-adapted EBOV or selected H5N1 influenza viruses from clades 0, 1, and 2. Animals were monitored for weight loss and survival, in addition to humoral and cell-mediated responses after immunization. RESULTS: A single VSVDeltaG-HA-ZGP injection was efficacious when administered 28 days before a homologous H5N1 and/or mouse-adapted EBOV challenge, as well as a heterologous H5N1 challenge. Postexposure protection was only observed in vaccinated animals challenged with homologous H5N1 and/or mouse-adapted EBOV. Analysis of the adaptive immune response postvaccination revealed robust specific T- and B-cell responses, including a potent hemagglutinin inhibition antibody response against all H5N1 strains tested. CONCLUSIONS: The results highlight the ability of vesicular stomatitis virus-vectored vaccines to rapidly confer protection against 2 unrelated pathogens and stimulate cross-protection against H5N1 influenza viruses. PMID- 26022442 TI - Inhibition of p-IkappaBalpha Ubiquitylation by Autophagy-Related Gene 7 to Regulate Inflammatory Responses to Bacterial Infection. AB - BACKGROUND: Klebsiella pneumoniae causes serious infections and healthcare burdens in humans. We have previously reported that the deficiency of autophagy related gene (Atg) 7 in macrophages (murine alveolar macrophage cell line [MH-S]) induced irregular host immunity against K. pneumoniae and worsened pathologic effects in the lung. In the current study, we investigated the molecular mechanism by which Atg7 influenced K. pneumoniae-induced inflammatory responses. METHODS: Expression levels of Atg7, ubiquitin (Ub), and tumor necrosis factor (TNF) alpha and phosphorylation of IkappaBalpha (p-IkappaBalpha) were determined with immunoblotting. Ubiquitylation of p-IkappaBalpha was determined with immunoprecipitation. RESULTS: We noted an interaction between Atg7 and p IkappaBalpha, which was decreased in MH-S after K. pneumoniae infection, whereas the interaction between Ub and p-IkappaBalpha was increased. Knock-down of Atg7 with small interfering RNA increased p-IkappaBalpha ubiquitylation, promoted nuclear factor kappaB translocation into the nucleus, and increased the production of TNF-alpha. Moreover, knock-down of Ub with lentivirus-short hairpin RNA Ub particles decreased binding of p-IkappaBalpha to Ub and inhibited TNF alpha expression in the primary alveolar macrophages and lung tissue of atg7 knockout mice on K. pneumoniae infection. CONCLUSIONS: Loss of Atg7 switched binding of p-IkappaBalpha from Atg7 to Ub, resulting in increased ubiquitylation of p-IkappaBalpha and intensified inflammatory responses against K. pneumoniae. Our findings not only reveal a regulatory role of Atg7 in ubiquitylation of p IkappaBalpha but also indicate potential therapeutic targets for K. pneumoniae control. PMID- 26022444 TI - Design of enzyme-interfaced DNA logic operations (AND, OR and INHIBIT) with an assaying application for single-base mismatch. AB - We devised AND, OR and INHIBIT logic gates. They were based on the enzyme-induced DNA base flipping mechanism, which caused significant local conformation changes in DNA. This can be monitored via photonic signals as outputs. We also provided a prototype of a built-in biosensor capable of distinguishing single-base mismatches in a DNA duplex. PMID- 26022443 TI - Association of TGFBR2 rs6785358 Polymorphism with Increased Risk of Congenital Ventricular Septal Defect in a Chinese Population. AB - Transforming growth factor beta receptor 2 (TGFBR2) plays a central role in normal heart development, and we investigated whether TGFBR2 polymorphism confers the risk of congenital ventricular septal defect (CVSD). The case-control study included 115 CVSD children and 188 healthy children in a Chinese population. TGFBR2 rs6785358 polymorphism was genotyped with polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Enzyme-linked immunoassay (ELISA) was used to detect serum TGFBR2 levels. The genotype and allele frequency of TGFBR2 rs6785358 were significantly higher in the CVSD group than in the controls (all P < 0.05). The G allele carriers were associated with increased CVSD risk compared with the A allele carriers in CVSD group (OR 3.503, 95 % CI 2.670-4.596). Stratified analysis by gender revealed that the TGFBR2 rs6785358 genotype and allele frequency were significantly different between the CVSD case and controls, in both the male subgroup and the female subgroup (all P < 0.001). The G allele carriers were more susceptible to CVSD risk than the A allele carriers in both the male subgroup (OR 9.096, 95 % CI 5.398-15.33) and the female subgroup (OR 3.148, 95 % CI 1.764-5.618). Logistic regression analysis revealed that age, gender and genotype were associated with the risk of CVSD (all P < 0.05). The study findings revealed that TGFBR2 rs6785358 polymorphism contributes to CVSD susceptibility, and the G allele may increase the risk of CVSD. PMID- 26022446 TI - Bufadienolides with cytotoxic activity from the skins of Bufo bufo gargarizans. AB - Twelve new bufadienolides (1-12), along with fourteen known analogues (13-26) were isolated from the skins of Bufo bufo gargarizans Cantor. Their chemical structures were elucidated on the basis of NMR, HRESIMS and X-ray diffraction analysis. Compound 1 was an unusual bufadienolide with 3,19-epoxy moiety and A/B trans ring junction. Compounds 2-4 were rare bufadienolides possessing 10-H or 10 carboxyl units. All the isolated compounds were tested for their cytotoxic effects on HepG2, A549 and HeLa cells. Six new compounds (2, 3, 5, 6, 10 and 12) displayed significant anti-proliferative activities with IC50 values ranging from 0.049 to 1.856 MUM. Arenobufagin (24) exhibited the most potent cytotoxic activity with IC50 value 0.011 MUM. In addition, the present data provided more insight into the structure-activity relationships of bufadienolides. PMID- 26022445 TI - Shedding dynamics of Morogoro virus, an African arenavirus closely related to Lassa virus, in its natural reservoir host Mastomys natalensis. AB - Arenaviruses can cause mild to severe hemorrhagic fevers. Humans mainly get infected through contact with infected rodents or their excretions, yet little is known about transmission dynamics within rodent populations. Morogoro virus (MORV) is an Old World arenavirus closely related to Lassa virus with which it shares the same host species Mastomys natalensis. We injected MORV in its host, and sampled blood and excretions at frequent intervals. Infection in adults was acute; viral RNA disappeared from blood after 18 days post infection (dpi) and from excretions after 39 dpi. Antibodies were present from 7 dpi and never disappeared. Neonatally infected animals acquired a chronic infection with RNA and antibodies in blood for at least 3 months. The quantified excretion and antibody patterns can be used to inform mathematical transmission models, and are essential for understanding and controlling transmission in the natural rodent host populations. PMID- 26022447 TI - Rapid eye movement sleep behavior disorder in patients with probable Alzheimer's disease. AB - BACKGROUND AND AIMS: Rapid eye movement (REM) sleep behavior disorder (RBD) is commonly associated with neurodegenerative disorders characterized by alpha synuclein deposition, including Parkinson's disease, multiple system atrophy, and Lewy body dementia. However, this tendency in tauopathy-mediated diseases is rare and only sporadically reported. We systematically illustrate the occurrence of RBD and sleep features among a cohort of patients with Alzheimer's disease (AD), a non-synucleinopathy. METHODS: We recruited 105 clinically probable AD patients. Fifteen clinically probable AD patients with suspected RBD underwent a video polysomnography (vPSG) examination. RESULTS: Five patients with probable AD exhibited RBD. One of the patients performed repeated touching of the head and the face with his hands and flailed his arms. Three patients exhibited hand twisting, exploring, prominent limb kicking, and jerking. The fifth patient exhibited all of the characteristics of RBD (he recalled a dream about fighting animals), and his wife was awakened by his screaming. Of these five patients, one patient took the acetylcholinesterase inhibitor drug donepezil. The patients with AD + RBD demonstrated increases in both tonic and phasic electromyography activity during REM sleep, but sleep architecture did not differ between the AD + RBD and AD-alone groups. CONCLUSION: RBD can occur in patients with AD. The occurrence of RBD does not change the sleep architecture of AD patients. PMID- 26022448 TI - Patterns of sedentary behavior and physical function in older adults. AB - BACKGROUND/AIMS: The purposes of this study were to examine the relationship between various objectively measured sedentary behavior (SB) variables and physical function in older adults, examine the measurement properties of an SB questionnaire, and describe the domains of SB in our sample. METHODS: Forty-four older adults (70 +/- 8 years, 64 % female) had their SB measured via activPAL activity monitor and SB questionnaire for 1 week followed by performance-based tests of physical function. RESULTS: The pattern of SB was more important than total SB time. Where a gender by SB interaction was found, increasing time in SB and fewer breaks were associated with worse function in the males only. The SB questionnaire had acceptable test-retest reliability but poor validity compared to activPAL-measured SB. The majority of SB time was spent watching television, using the computer and reading. DISCUSSION/CONCLUSIONS: This study provides further evidence for the association between SB and physical function and describes where older adults are spending their sedentary time. This information can be used in the design of future intervention to reduce sedentary time and improve function in older adults. PMID- 26022449 TI - Emerging concepts on drug resistance in bladder cancer: Implications for future strategies. AB - The combination chemotherapies with methotrexate plus vinblastine, doxorubicin and cisplatin (MVAC or CMV regimens) or gemcitabine plus cisplatin represent the standard as first-line therapy for patients with metastatic urothelial cancer. In Europe, vinflunine is an option for second-line therapy for patients progressed during first-line or perioperative platinum-containing regimen. Alternative regimens containing taxanes and/or gemcitabine may be valuated case by case. Furthermore, carboplatin should be considered in patients unfit for cisplatin both in the first and second-line setting. Based on these findings, a better comprehension of the mechanisms underlying the development of drug resistance in patients with bladder cancer will represent a major step forward in optimizing patients' outcome. This article reviews the current knowledge of the mechanisms and emerging strategies to overcome resistance in patients with advanced urothelial cancer. PMID- 26022450 TI - Anxiety and styles of coping with occupational stress resulting from work with 'dangerous' prisoners in prison service officers. AB - OBJECTIVE: Prisoners categorised as 'dangerous' are a category of prisoners that require and/or force into using special measures of caution, protection and security. The aim of the study was to examine the intensity of anxiety (as a state and as a trait) experienced by officers working with 'dangerous' prisoners and styles of coping with stress they adopt. METHODS: A total of 40 officers working with 'dangerous' prisoners (the study group, SG) and 60 officers of the security department not working with 'dangerous' prisoners (the reference group, RG) were studied. The intensity of anxiety was assessed applying the Polish version of 'State-Trait Anxiety Inventory' (STAI); styles of coping with stress were explored employing the Polish version of 'Coping Inventory for Stressful Situations' (CISS) and the author's own questionnaire. Data were analysed using the mean, standard deviation, difference testing (the Mann-Whitney U test), correlation-regression procedure (Kendall's tau, tau correlation coefficient and forward stepwise multiple regression). RESULTS: Officers in the SG faced verbal and physical aggression; nevertheless, scores of officers in both the groups were within the interval of mean scores for all the studied STAI and CISS variables. Officers in the SG achieved significantly higher scores on the state-anxiety scale and the Emotion-Oriented Style (EOS), and lower scores on the Task-Oriented Style (TOS) and Social Diversion (SD). The correlation-regression procedure indicated that there were relationships between anxiety and styles of coping with stress but they differed slightly between the groups. CONCLUSIONS: Officers in the SG feel state anxiety stronger and display a stronger preference for the EOS than officers in the RG. Officers in the RG more strongly prefer the TOS and SD. State anxiety is a variable negatively explaining the TOS in the SG, whereas anxiety as a trait is a variable explaining the EOS in both the groups. The coping styles of warders dealing with dangerous prisoners are different and may need specific psychological counselling and training programmes. PMID- 26022451 TI - Aberrant intermediate filament and synaptophysin expression is a frequent event in malignant melanoma: an immunohistochemical study of 73 cases. AB - Malignant melanomas are known to express vimentin, among other intermediate filaments. Though anomalous keratin expression by malignant melanoma has been reported, its frequency is not well-established and this phenomenon is not well known. We have seen in consultation a number of malignant melanomas with anomalous expression of keratin, other intermediate filaments, or synaptophysin, and therefore studied a large group of primary and metastatic melanomas to determine the frequency of these events. About 73 cases of malignant melanoma (22 primaries and 51 metastases) from 71 patients (51 male, 20 female; mean 59 years, range 17-87 years) were retrieved from our archives. Prior diagnoses were confirmed by re-review of hematoxylin and eosin sections and relevant (e.g., S100 protein, HMB45, Melan-A, and tyrosinase) immunohistochemical studies. Available sections were immunostained for keratin (OSCAR and AE1/AE3 antibodies), desmin, neurofilament protein, glial fibrillary acidic protein, synaptophysin, and chromogranin A. Not all cases could be tested for all markers. Cases were predominantly epithelioid (48/73, 66%) or spindle cell/desmoplastic (25/73, 34%). S100 protein, Melan-A, HMB45, and tyrosinase were positive in 60/65 (92%), 34/64 (53%), 30/60 (50%), 25/48 (52%) of cases, respectively. All five S100-protein negative cases expressed at least one of the other melanocytic markers: Melan-A (two of four, 50%), HMB45 (two of three, 67%), and tyrosinase (one of two, 50%). All cases expressed at least one melanocytic marker. Cases were positive for keratin (OSCAR, 17/61, 28%; AE1/AE3, 16/40, 40%), desmin (11/47, 24%), neurofilament protein (5/31, 16%), glial fibrillary acidic protein (3/32, 9%), and synaptophysin (10/34, 29%), typically only in a minority of cells. Chromogranin was negative (0/32, 0%). Altogether 9/73 cases (12%) showed expression of >1 intermediate filament. All S100-protein-negative melanomas showed anomalous intermediate filament expression (keratin--one case, desmin- three cases, neurofilament protein--one case). Anomalous intermediate filament or synaptophysin expression was more common in epithelioid (intermediate filament, 27/48, 56%; synaptophysin, 7/22, 32%) as compared with spindle cell/desmoplastic (intermediate filament, 8/25, 32%; synaptophysin, 3/12, 25%) melanomas. Overall, 48% (35/73) of cases showed anomalous expression of at least one intermediate filament. Anomalous expression of all intermediate filaments and synaptophysin was found in significant subsets of malignant melanoma, representing potentially serious diagnostic pitfalls. While the inclusion of consultation cases may inflate the frequency of these findings in this series, similar findings were also seen in institutional cases. Malignant melanoma showing anomalous intermediate filament and synaptophysin expression may easily be mistaken for carcinomas, rhabdomyosarcomas, and neuroendocrine tumors. Awareness of this phenomenon, careful histopathological evaluation, and an appropriate melanocytic immunohistochemical panel should facilitate the diagnosis of malignant melanoma with unusual immunophenotypes. PMID- 26022452 TI - Alternative lengthening of telomeres and loss of ATRX are frequent events in pleomorphic and dedifferentiated liposarcomas. AB - Telomerase activation and alternative lengthening of telomeres are two major mechanisms of telomere length maintenance. Soft tissue sarcomas appear to use the alternative lengthening of telomeres more frequently. Loss of alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death domain associated protein 6 (DAXX) expression has been implicated in the pathogenesis of alternative telomere lengthening in pancreatic endocrine neoplasm and glioma. The mechanism leading to the alternative lengthening of telomeres in liposarcoma remains unknown. Whereas alternative telomere lengthening was determined to be an indicator of poor prognosis in liposarcomas as a whole, its prognostic power has not been verified in any subtype of liposarcoma. In this study, we characterized the status of alternative telomere lengthening and expression of ATRX and DAXX in 111 liposarcomas (28 well-differentiated, 52 dedifferentiated, 20 myxoid or round cell, and 11 pleomorphic liposarcomas) by telomere fluorescence in situ hybridization and immunohistochemistry, respectively. Alternative lengthening of telomere was observed in 0% (0/16) of well-differentiated, 30% (14/46) of dedifferentiated, 5% (1/19) of myxoid or round cell, and 80% (8/10) of pleomorphic liposarcomas. Eighteen (16%) and one (1%) tumors were negative for ATRX and DAXX immunostaining, respectively. Remarkably, all cases with loss of either ATRX or DAXX expression had alternative lengthening of telomeres, and 83% (19/23) of tumors that had alternative lengthening of telomeres showed loss of either protein. The correlation between loss of either ATRX or DAXX and alternative telomere lengthening was 100% in dedifferentiated liposarcoma. The presence of alternative telomere lengthening in dedifferentiated liposarcoma suggested poor overall survival (hazard ratio=1.954, P=0.077) and was the most significant indicator of short progression-free survival (hazard ratio=3.119, P=0.003). In conclusion, we found that ATRX loss was the most likely mechanism of alternative telomere lengthening in liposarcoma and alternative telomere lengthening was a prognostic factor of poor outcome in dedifferentiated liposarcoma. PMID- 26022453 TI - Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma. AB - Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven 'pure' Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52-89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression. PMID- 26022454 TI - Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation. AB - Solitary fibrous tumors, which are characterized by their broad morphological spectrum and unpredictable behavior, are rare mesenchymal neoplasias that are currently divided into three main variants that have the NAB2-STAT6 gene fusion as their unifying molecular lesion: usual, malignant and dedifferentiated solitary fibrous tumors. The aims of this study were to validate molecular and immunohistochemical/biochemical approaches to diagnose the range of solitary fibrous tumors by focusing on the dedifferentiated variant, and to reveal the genetic events associated with dedifferentiation by integrating the findings of array comparative genomic hybridization. We studied 29 usual, malignant and dedifferentiated solitary fibrous tumors from 24 patients (including paired samples from five patients whose tumors progressed to the dedifferentiated form) by means of STAT6 immunohistochemistry and (when frozen material was available) reverse-transcriptase polymerase chain reaction and biochemistry. In addition, the array comparative genomic hybridization findings were used to profile 12 tumors from nine patients. The NAB2/STAT6 fusion was detected in all of the tumors, but immunohistochemistry and western blotting indicated that chimeric protein expression was atypical or absent in 9 out of 11 dedifferentiated tumors. The comparative genomic hybridization results revealed that the usual and malignant solitary fibrous tumors had a simple profile, whereas the genome of the dedifferentiated tumors was complex and unstable, and suggested that 13q and 17p deletions and TP53 mutations may be present in malignant lesions before the full expression of a dedifferentiated phenotype. Solitary fibrous tumor dedifferentiation is associated with the loss of chimeric oncoprotein expression, genomic instability, and cell decommitment and reprogramming. The assessment of dedifferentiated solitary fibrous tumors is based on the presence of the fusion transcripts and, in principle, negative STAT6 immunohistochemistry should not rule out a diagnosis of solitary fibrous tumor. PMID- 26022456 TI - Accuracy of the IASLC/ATS/ERS histological subtyping of stage I lung adenocarcinoma on intraoperative frozen sections. AB - Histological subtyping of surgically resected lung adenocarcinoma has been shown to be of prognostic significance, and limited surgical resection has been proposed as a treatment of choice for early-stage lung adenocarcinoma. The accuracy of histological subtyping has been recently assessed in the surgical resection and small biopsy specimens; however, the accuracy of intraoperative subtyping on frozen sections remains relatively unknown. The aim of this study was to determine diagnostic accuracy and interobserver variability in histological subtyping of lung adenocarcinoma on intraoperative frozen sections. Overall, 112 consecutive cases of surgically resected stage I lung adenocarcinoma were reviewed independently by three pathologists. Histological patterns (acinar, lepidic, papillary, micropapillary, and solid) and mucinous variant were recorded in 5% increments for each intraoperative frozen and permanent sections. Primary and secondary histological patterns were assigned in each case. Kappa scores were calculated to evaluate agreement between pathologists in the assessment of histological subtype on intraoperative frozen sections versus permanent sections. Overall agreement between intraoperative frozen and permanent sections was moderate for primary pattern (69.7% of cases), with kappa scores ranging from 0.43 to 0.58, with more consistent agreement for stage IA tumors. Kappa scores for the secondary pattern ranged from 0.16 to 0.32. Acinar and solid patterns were most likely to be correctly identified as primary growth patterns. Micropapillary pattern was recognized in only 11-55% of cases. The main reasons for discrepancies between intraoperative frozen and permanent sections were inadequate sampling and poor quality of frozen sections. Our study suggests that it is difficult to predict the primary adenocarcinoma pattern on a single representative frozen section. This observation suggests a potential impact on the extent of frozen section sampling by pathologists at the time of intraoperative consultation, if surgical management of stage I lung adenocarcinoma will be guided by its histological subtype. PMID- 26022455 TI - BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. AB - The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1 positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection. PMID- 26022457 TI - Extraparenchymal (Racemose) Neurocysticercosis and Its Multitude Manifestations: A Comprehensive Review. AB - Neurocysticercosis is an infection of the central nervous system caused by the larval form of the pork tapeworm Taenia solium. In the brain it occurs in two forms: parenchymal and extraparenchymal or racemose cysts. The clinical presentation of racemose cysts is pleomorphic, and is quite different from parenchymal cysticercosis. The clinical diagnosis of racemose cysts is quite challenging, with neuroimaging being the mainstay. However, the advent of newer brain imaging modalities has made a more accurate diagnosis possible. The primary focus of this article is racemose neurocysticercosis and its multitude manifestations, and includes a discussion of the newer diagnostic modalities and treatment options. PMID- 26022459 TI - Clinical and Genetic Characterization of Female Dystrophinopathy. AB - BACKGROUND AND PURPOSE: Duchenne and Becker muscular dystrophies are the most common X-linked recessive muscular dystrophies. Dystrophin gene mutations usually affect men, but reportedly 2.5-7.8% of women are affected and are classified as symptomatic carriers. The aim of this study was to clinically and genetically characterize symptomatic female dystrophinopathy carriers. METHODS: The clinical and genetic data of 11 female dystrophinopathy carriers among 285 patients who underwent multiplex ligation-dependent probe amplification (MLPA) analysis for the dystrophin gene were reviewed. Women with muscle weakness and/or dilated cardiomyopathy were classified as symptomatic carriers, while subjects with high serum creatine kinase (CK) levels and/or minor myopathic signs such as muscle cramps and myalgia were classified as asymptomatic. RESULTS: Twelve female carriers were identified, but 1 symptomatic carrier who also had Turner syndrome was excluded from the study. Of the 11 included female carriers, 4 were symptomatic and 7 were asymptomatic. The age at symptom onset in the symptomatic female carriers ranged from 15 to 31 years (mean, 30.6 years), and the age at diagnosis for asymptomatic carriers ranged from 4 to 38 years (mean, 24.5 years). Serum CK levels were markedly elevated (mean, 1,301 IU/mL) in three of the four (75%) symptomatic female carriers, and mildly elevated in three of the seven (42%) asymptomatic female carriers. Symptomatic female carriers typically presented with asymmetric bilateral leg weakness as the initial symptom, with aggravated symptoms after labor. CONCLUSIONS: Female dystrophinopathy is not uncommon, and it is an important factor with respect to males with dystrophinopathy who may be born to such patients. Screening with MLPA is useful because it can aid in early diagnosis and appropriate management. PMID- 26022458 TI - Prevalence and Incidence of Epilepsy in an Elderly and Low-Income Population in the United States. AB - BACKGROUND AND PURPOSE: The purpose of this study was to estimate the incidence and prevalence of epilepsy among an elderly and poor population in the United States. METHODS: Arizona Medicaid claims data from January 1, 2008 to December 31, 2010 were used for this analysis. Subjects who were aged >=65 years and were continuously enrolled in any Arizona Medicaid health plans (eligible to patients with low income) for >=12 months between January 1, 2008 and December 31, 2009 were considered eligible for inclusion in the study cohort. In addition to meeting the aforementioned criteria, incident and prevalent cases must have had epilepsy-related healthcare claims. Furthermore, incident cases were required to have a 1-year "clean" period immediately preceding the index date. Negative binomial and logistic regression models were used to assess the factors associated with epilepsy incidence and prevalence. RESULTS: The estimated epilepsy incidence and prevalence for this population in 2009 were 7.9 and 19.3 per 1,000 person-years, respectively. The incidence and prevalence rates were significantly higher for patients with comorbid conditions that were potential risk factors for epilepsy and were of younger age than for their non-comorbid and older counterparts (p<0.05). The prevalence rates were significantly higher for non-Hispanic Blacks and male beneficiaries than for non-Hispanic Whites and female beneficiaries, respectively (p<0.05). CONCLUSIONS: This patient population had higher epilepsy incidence and prevalence compared with the general US population. These differences may be at least in part attributable to their low socioeconomic status. PMID- 26022460 TI - Benign Multiple Sclerosis is Associated with Reduced Thinning of the Retinal Nerve Fiber and Ganglion Cell Layers in Non-Optic-Neuritis Eyes. AB - BACKGROUND AND PURPOSE: It is exceedingly difficult to differentiate benign multiple sclerosis (BMS) from relapsing-remitting multiple sclerosis (RRMS) based on clinical characteristics, neuroimaging, and cerebrospinal fluid tests. Optical coherence tomography (OCT) allows quantification of retinal structures, such as the retinal nerve fiber layer (RNFL) thickness, at the optic disc and the ganglion cell layer (GCL) at the macula, on a micrometer scale. It can also be used to trace minor alterations and the progression of neurodegeneration, help predict BMS, and influence the choice of therapy. To utilize OCT to detect the extent of changes of the optic disk and macular microstructure in patients with BMS and RRMS compared to healthy controls (HCs), with special focus on changes related to the presence/absence of optic neuritis (ON). METHODS: Spectral-domain OCT was applied to examine eyes from 36 patients with multiple sclerosis (MS), comprising 11 with BMS and 25 with RRMS, and 34 HCs. RESULTS: The RNFL and GCL were significantly thinner in eyes previously affected by ON, irrespective of the type of MS (i.e., BMS or RRMS), than in HCs. Significant thinning of the GCL was also observed in non-ON RRMS (and not non-ON BMS) compared to HCs. Correspondingly, a significant association between disease duration and thinning rates of the RNFL and GCL was observed only in non-ON RRMS (-0.54+/-0.24 and 0.43+/-0.21 MUm/year, mean+/-SE; p<0.05 for both), and not in non-ON BMS (-0.11+/ 0.27 and -0.24+/-0.24 MUm/year). CONCLUSIONS: The RNFL and GCL were thinner in both ON- and non-ON MS, but the change was more pronounced in ON MS, irrespective of the MS subtype studied herein. GCL thinning and the thinning rate of both the GCL and RNFL were less pronounced in non-ON BMS than in non-ON RRMS. These findings may help to predict the course of BMS. PMID- 26022462 TI - Uncommon Posterior Reversible Encephalopathy Syndrome in a Sickle-Cell Patient. PMID- 26022461 TI - Diagnosis and Treatment of Anterior-Canal Benign Paroxysmal Positional Vertigo: A Systematic Review. AB - BACKGROUND AND PURPOSE: In contrast to the posterior- and horizontal-canal variants, data on the frequency and therapeutic management of anterior-canal benign paroxysmal positional vertigo (AC-BPPV) are sparse. To synthesize the existing body of evidence into a systematic review regarding the incidence and treatment of AC-BPPV. METHODS: Systematic search of medical databases employing predefined criteria, using the term "anterior canal benign paroxysmal positional vertigo." RESULTS: The electronic search retrieved 178 unique citations, 31 of which were considered eligible for further analysis. Analysis of the collected data revealed an estimated occurrence of AC-BPPV among benign paroxysmal positional vertigo patients of 3% (range 1-17.1%). No controlled therapeutic trials could be identified, and so the analysis was focused on uncontrolled case series. Treatment was categorized into three groups: Epley maneuver, Yacovino maneuver, and specific, nonstandard maneuvers described in individual articles. All three categories demonstrated success rates of over 75%, and the overall sample-size-weighted mean was 85.6%. CONCLUSIONS: The present analysis demonstrated that AC-BPPV comprises about 3% of all BPPV cases. It can be treated safely using the Epley, Yacovino, and other maneuvers with rates of symptom resolution lying in the range of that reported for the other, more frequent canal variants. Multicenter controlled trials are needed in order to develop evidence based guidelines for the treatment of AC-BPPV. PMID- 26022463 TI - Beta-Propeller-Protein-Associated Neurodegeneration: A Case of Mutation in WDR45. PMID- 26022464 TI - Mirinho: An efficient and general plant and animal pre-miRNA predictor for genomic and deep sequencing data. AB - BACKGROUND: Several methods exist for the prediction of precursor miRNAs (pre miRNAs) in genomic or sRNA-seq (small RNA sequences) data produced by NGS (Next Generation Sequencing). One key information used for this task is the characteristic hairpin structure adopted by pre-miRNAs, that in general are identified using RNA folders whose complexity is cubic in the size of the input. The vast majority of pre-miRNA predictors then rely on further information learned from previously validated miRNAs from the same or a closely related genome for the final prediction of new miRNAs. With this paper, we wished to address three main issues. The first was methodological and aimed at obtaining a more time-efficient predictor, however without losing in accuracy which represented a second issue. We indeed aimed at better predicting miRNAs at a genome scale, but also from sRNAseq data where in some cases, notably of plants, the current folding methods often infer the wrong structure. The third issue is related to the fact that it is important to rely as little as possible on previously recorded examples of miRNAs. We therefore also sought a method that is less dependent on previous miRNA records. RESULTS: As concerns the first and second issues, we present a novel alternative to a classical folder based on a thermodynamic Nearest-Neighbour (NN) model for computing the free energy and predicting the classical hairpin structure of a pre-miRNA. We show that the free energies thus computed correlate well with those of RNAFOLD. This novel method, called MIRINHO, has quadratic instead of cubic complexity and is much more efficient also in practice. When applied to sRNAseq data of plants, it gives in general better results than classical folders. On the third issue, we show that MIRINHO, which uses as only knowledge the length of the loops and stem-arms and the free energy of the pre-miRNA hairpin, compares well with algorithms that require more information. The results, obtained with different datasets, are indeed similar to those of other approaches with which such a comparison was possible. These needed to be publicly available softwares that could be used on a large input. In some cases, MIRINHO is even better in terms of sensitivity or precision. CONCLUSION: We provide a simpler and much faster method with very reasonable sensitivity and precision, which can be applied without special adaptation to the prediction of both animal and plant pre-miRNAs, using as input either genomic sequences or sRNA-seq data. PMID- 26022465 TI - First rank symptoms of schizophrenia: their nature and origin. AB - Kurt Schneider's insight nearly 80 years ago that schizophrenia could be demarcated from other psychoses by a small set of particular delusions and hallucinations powerfully influenced diagnostic practice. The theoretical status of such 'first rank symptoms' as a whole, however, has rarely been addressed. But if they are sensitive and specific to the condition, it is about time that their essential nature and potential origin be considered. This is the purpose of the present paper. I argue that these psychopathological phenomena are indeed relatively sensitive and specific to the condition, that their nature can be formulated within a Schelerian model of what constitutes a human being, and that their origin fits anthropological and neuropsychological notions of the make-up of contemporary human beings. PMID- 26022466 TI - 'At variance with the most elementary principles': the state of British colonial lunatic asylums in 1863. AB - In 1863 the Colonial Office reviewed colonial hospitals and lunatic asylums in those parts of the British Empire it administered - probably the first and widest international comparative study up to that date. This article outlines the background, process and scope of the review of asylums, and considers its significance. The resulting 'digest' is an important source to explain how, why, when and by whom metropolitan ideas acquired official endorsement and spread throughout the British world. Using the review's general findings and suggestions, a tool is provided for comparing inter-colonial achievements. With New Zealand as a case study, the article concludes that, relative to other influences, the digest played a limited and largely indirect part in shaping New Zealand's mental health policy before 1876. PMID- 26022467 TI - World citizenship and the emergence of the social psychiatry project of the World Health Organization, 1948-c.1965. AB - This paper examines the relationship between 'world citizenship' and the new psychiatric research paradigm established by the World Health Organization in the early post-World War II period. Endorsing the humanitarian ideological concept of 'world citizenship', health professionals called for global rehabilitation initiatives to address the devastation after the war. The charm of world citizenship had not only provided theoretical grounds of international collaborative research into the psychopathology of psychiatric diseases, but also gave birth to the international psychiatric epidemiologic studies conducted by the World Health Organization. Themes explored in this paper include the global awareness of mental rehabilitation, the application of public health methods in psychiatry to improve mental health globally, the attempt by the WHO to conduct large-scale, cross-cultural studies relevant to mental health and the initial problems it faced. PMID- 26022468 TI - Psychiatrists, mental health provision and 'senile dementia' in England, 1940s 1979. AB - Until around 1979, 'confused' or mentally unwell people over 65 years of age tended to be labelled as having 'senile dementia'. Senile dementia was usually regarded as a single, inevitably hopeless condition, despite gradually accumulating clinical and pathological evidence to the contrary. Specific psychiatric services for mental illness in older people began to emerge in the 1950s, but by 1969 there were fewer than 10 dedicated services nationally. During the 1970s, 'old age psychiatrists' established local services and campaigned nationally for them. By 1979, about 100 old age psychiatrists were leading multi disciplinary teams in half the health districts in England. This paper explores the tortuous development of these new services, focusing on provision for people with dementia. PMID- 26022469 TI - Herculano Sa de Figueiredo (1911-74): a sculptor in the Conde de Ferreira Hospital, Portugal. AB - Herculano Sa de Figueiredo's sculptures remained anonymous inside the Conde de Ferreira Hospital of Oporto (Portugal) for over 30 years. The accidental discovery of the patient's clinical file enabled the authors of this paper to establish the link between the man, his work and his psychiatric pathology. The artwork kept in the hospital was not previously known in academic and artistic circles. Studying and recovering Figueiredo's work is important because a considerable part of his oeuvre was produced from 1955 to 1973, when he was a patient in the Conde de Ferreira Hospital. The models represented in his sculptures were technicians and patients at the institution. PMID- 26022470 TI - 'The meaning of the symptom in psychiatry. An overview', by Hans W. Gruhle (1913): Introduction by Johan Schioldann and German Berrios: Translation by Johan Schioldann. AB - At the beginning of the 20th century there took place in German Psychiatry an important debate on the nature and relative importance of mental symptoms and diseases. Young psychiatrists such as Storring, Ziehen, Gaupp, Hoche, Jaspers and Gruhle challenged, from various perspectives, the nosology of established figures such as Kraepelin and Wernicke. The Classic Text is a commented translation of Gruhle's 1913 lecture on the meaning of mental symptoms. After concluding that mental symptoms should be used as the epistemological unit of analysis in psychiatry, Gruhle rued the fact that little was yet known about their inner structure. He believed that any account of the latter should include an account of the 'meaning' of mental symptoms, that is, of their role in the patient's total disease. Gruhle found Freud's account of meaning wanting, but was himself unable to offer a viable alternative. Be that as it may, his concern remains unanswered and is as relevant today as it was in 1913. PMID- 26022478 TI - Phylogeny in the service of ecological restoration. PMID- 26022479 TI - Comparison of the effects of temperature and water potential on seed germination of Fabaceae species from desert and subalpine grassland. AB - PREMISE OF THE STUDY: Temperature and water potential for germination based on the thermal and hydrotime models have been successfully applied in predicting germination requirements of physiologically dormant seeds as well as nondormant seeds. However, comparative studies of the germination requirements of physically dormant seeds from different ecosystems have not been done. METHODS: Germination of scarified seeds of four legume species collected from the Qing-Tibetan Plateau and of four collected in the Alax Desert in China was compared over a range of temperatures and water potentials based on thermal time and hydrotime models. KEY RESULTS: Seeds of species from the Qing-Tibetan Plateau had a lower base temperature (T b) and optimal temperature (T o) for germination than those from the Alax Desert. Seeds of the four species from the Qing-Tibetan Plateau germinated to high percentages at 5 degrees C, whereas none of the four desert species did so. Seeds of species from the Alax Desert germinated to a high percentage at 35 degrees C or 40 degrees C, while no seeds of species from the Qing-Tibetan Plateau germinated at 35 degrees C or 40 degrees C. The base median water potential [Psi b(50)] differed among species but not between the two habitats. CONCLUSIONS: The thermal time and hydrotime models accurately predicted the germination time course of scarified seeds of most of the eight species in response to temperature and water potential; thus, they can be useful tools in comparative studies on germination of seeds with physical dormancy. Habitat temperatures but not rainfall is closely related to germination requirements of these species. PMID- 26022480 TI - Indirect effects of herbivory on plant-pollinator interactions in invasive Lythrum salicaria. AB - PREMISE OF THE STUDY: Herbivory can affect a plant's fitness in a variety of ways, including modifying the biotic interactions of the plant. In particular, when herbivory influences floral display, we hypothesize that pollinator visitation will be altered accordingly. Here we studied the indirect effects of feeding by two beetles, Neogalerucella calmariensis and N. pusilla, released as a biological control, on plant-pollinator interactions and fitness in the invasive plant, purple loosestrife (Lythrum salicaria). METHODS: Two herbivory treatments (ambient and simulated) were applied to plants in a naturally occurring population of purple loosestrife. During flowering, traits of plants in the treatment and control groups were recorded. Data on pollinator visitation behavior was then collected after intense larval herbivory had ended. KEY RESULTS: Plants exposed to herbivory treatments produced more flowers and inflorescences but flowered significantly later than those in the control group. Moreover, we found a significant, positive association of herbivory with the number of flowers probed by bumblebees and with the number of times a foraging pollinator moved among inflorescences on a single plant. No differences in female fitness (fruit or seed production) were detected. CONCLUSIONS: We conclude that herbivore-mediated differences in floral display traits impacted pollinator visitation behavior. However, as we discuss, differences in pollinator visitation did not translate into detectable differences in female reproductive success. We postulate that herbivory could influence other unmeasured aspects of fitness, such as seed quality or the number of seeds sired. PMID- 26022481 TI - Flowering and biomass allocation in U.S. Atlantic coast Spartina alterniflora. AB - PREMISE OF THE STUDY: Salt marshes are highly productive and valuable ecosystems, providing many services on which people depend. Spartina alterniflora Loisel (Poaceae) is a foundation species that builds and maintains salt marshes. Despite this species' importance, much of its basic reproductive biology is not well understood, including flowering phenology, seed production, and the effects of flowering on growth and biomass allocation. We sought to better understand these life history traits and use that knowledge to consider how this species may be affected by climate change. METHODS: We examined temporal and spatial patterns in flowering and seed production in S. alterniflora at a latitudinal scale (along the U.S. Atlantic coast), regional scale (within New England), and local scale (among subhabitats within marshes) and determined the impact of flowering on growth allocation using field and greenhouse studies. KEY RESULTS: Flowering stem density did not vary along a latitudinal gradient, while at the local scale plants in the less submerged panne subhabitats produced fewer flowers and seeds than those in more frequently submerged subhabitats. We also found that a shift in biomass allocation from above to belowground was temporally related to flowering phenology. CONCLUSIONS: We expect that environmental change will affect seed production and that the phenological relationship with flowering will result in limitations to belowground production and thus affect marsh elevation gain. Salt marshes provide an excellent model system for exploring the interactions between plant ecology and ecosystem functioning, enabling better predictions of climate change impacts. PMID- 26022482 TI - Coordination of stomatal physiological behavior and morphology with carbon dioxide determines stomatal control. AB - PREMISE OF THE STUDY: Stomatal control is determined by the ability to alter stomatal aperture and/or the number of stomata on the surface of new leaves in response to growth conditions. The development of stomatal control mechanisms to the concentration of CO2within the atmosphere ([CO2]) is fundamental to our understanding of plant evolutionary history and the prediction of gas exchange responses to future [CO2]. METHODS: In a controlled environment, fern and angiosperm species were grown in atmospheres of ambient (400 ppm) and elevated (2000 ppm) [CO2]. Physiological stomatal behavior was compared with the stomatal morphological response to [CO2]. KEY RESULTS: An increase in [CO2] or darkness induced physiological stomatal responses ranging from reductions (active) to no change (passive) in stomatal conductance. Those species with passive stomatal behavior exhibited pronounced reductions of stomatal density in new foliage when grown in elevated [CO2], whereas species with active stomata showed little morphological response to [CO2]. Analysis of the physiological and morphological stomatal responses of a wider range of species suggests that patterns of stomatal control to [CO2] do not follow a phylogenetic pattern associated with plant evolution. CONCLUSIONS: Selective pressures may have driven the development of divergent stomatal control strategies to increased [CO2]. Those species that are able to actively regulate guard cell turgor are more likely to respond to [CO2] through a change in stomatal aperture than stomatal number. We propose a model of stomatal control strategies in response to [CO2] characterized by a trade-off between short-term physiological behavior and longer-term morphological response. PMID- 26022483 TI - Effective prey attraction in the rare Drosophyllum lusitanicum, a flypaper-trap carnivorous plant. AB - PREMISE OF THE STUDY: Carnivorous plants have unusually modified leaves to trap insects as an adaptation to low-nutrient environments. Disparate mechanisms have been suggested as luring traits to attract prey insects into their deadly leaves, ranging from very elaborate to none at all. Drosophyllum lusitanicum is a rare carnivorous plant with a common flypaper-trap mechanism. Here we tested whether Drosophyllum plants lure prey insects into their leaves or they act just as passive traps. METHODS: We compared prey capture between live, potted plants and Drosophyllum-shaped artificial mimics coated with odorless glue. Since this species is insect-pollinated, we also explored the possible existence of a pollinator-prey conflict by quantifying the similarity between the pollination and prey guilds in a natural population. All experiments were done in southern Spain. KEY RESULTS: The sticky leaves of Drosophyllum captured significantly more prey than mimics, particularly small dipterans. Prey attraction, likely exerted by scent or visual cues, seems to be unrelated to pollinator attraction by flowers, as inferred from the low similarity between pollinator and prey insect faunas found in this species. CONCLUSIONS: Our results illustrate the effectiveness of this carnivorous species at attracting insects to their flypaper trap leaves. PMID- 26022485 TI - Evolution of zygomycetous spindle pole bodies: Evidence from Coemansia reversa mitosis. AB - PREMISE OF THE STUDY: The earliest eukaryotes were likely flagellates with a centriole that nucleates the centrosome, the microtubule-organizing center (MTOC) for nuclear division. The MTOC in higher fungi, which lack flagella, is the spindle pole body (SPB). Can we detect stages in centrosome evolution leading to the diversity of SPB forms observed in terrestrial fungi? Zygomycetous fungi, which consist of saprobes, symbionts, and parasites of animals and plants, are critical in answering the question, but nuclear division has been studied in only two of six clades. METHODS: Ultrastructure of mitosis was studied in Coemansia reversa (Kickxellomycotina) germlings using cryofixation or chemical fixation. Character evolution was assessed by parsimony analysis, using a phylogenetic tree assembled from multigene analyses. KEY RESULTS: At interphase the SPB consisted of two components: a cytoplasmic, electron-dense sphere containing a cylindrical structure with microtubules oriented nearly perpendicular to the nucleus and an intranuclear component appressed to the nuclear envelope. Markham's rotation was used to reinforce the image of the cylindrical structure and determine the probable number of microtubules as nine. The SPB duplicated early in mitosis and separated on the intact nuclear envelope. Nuclear division appears to be intranuclear with spindle and kinetochore microtubules interspersed with condensed chromatin. CONCLUSIONS: This is the sixth type of zygomycetous SPB, and the third type that suggests a modified centriolar component. Coemansia reversa retains SPB character states from an ancestral centriole intermediate between those of fungi with motile cells and other zygomycetous fungi and Dikarya. PMID- 26022486 TI - Genetic analysis of rhizomatousness and its relationship with vegetative branching of recombinant inbred lines of Sorghum bicolor * S. propinquum. AB - PREMISE OF THE STUDY: Rhizomes, subterranean stems that grow horizontally, are a storage organ that is highly associated with overwintering and regrowth. This quantitative study aimed to discover genetic determinants of rhizomatousness, an important trait related to perenniality and invasiveness. METHODS: A population of 161 individuals of a recombinant inbred line (RIL) derived from morphologically distinct parents, Sorghum bicolor and Sorghum propinquum, which segregates for rhizomatousness, was phenotyped and genetically mapped. KEY RESULTS: Seven genomic regions influenced rhizomatousness in this population; four were "consensus" regions that correspond with previously detected quantitative trait loci (QTLs) in an F2 population of the same pedigree and with different levels of vegetative branching. Because rhizomatousness is a plastic trait that is greatly influenced by environment, overlap between regions discovered in the RIL and F2 populations validates the position and effect of QTLs. Correspondence with regions influencing vegetative branching indicates that some genes and biochemical pathways may influence both vegetative branching and rhizomatousness, while genes influencing only one trait may confer divergent aspects of development of these organs. CONCLUSIONS: Identifying genes conferring rhizomatousness and understanding their functions may provide opportunities to regulate plant growth for diverse applications. Increasing rhizomatousness may promote the productivity and perenniality of many grasses, especially biomass dedicated crops, while decreasing rhizomatousness may improve monocarpic grain production and offer means to control many noxious weeds. PMID- 26022487 TI - Icacinaceae from the eocene of Western North America. AB - PREMISE OF THE STUDY: The Icacinaceae are a pantropical family of trees, shrubs, and climbers with an extensive Paleogene fossil record. Our improved understanding of phylogenetic relationships within the family provides an excellent context for investigating new fossil fruit and leaf material from the Eocene of western North America. METHODS: We examined fossils from early and middle Eocene sediments of western Wyoming, northeastern Utah, northwestern Colorado, and Oregon and compared them with extant species of Iodes and other icacinaceous genera as well as previously described fossils of the family. KEY RESULTS: Three new fossil species are described, including two based on endocarps (Iodes occidentalis sp. nov. and Icacinicaryites lottii sp. nov.) and one based on leaves (Goweria bluerimensis sp. nov.). The co-occurrence of I. occidentalis and G. bluerimensis suggests these might represent detached organs of a single species. A new genus, Biceratocarpum, is also established for morphologically distinct fossil fruits of Icacinaceae previously placed in Carpolithus. Biceratocarpum brownii gen. et comb. nov. resembles the London Clay species "Iodes" corniculata in possessing a pair of subapical protrusions. CONCLUSIONS: These fossils increase our knowledge of Icacinaceae in the Paleogene of North America and highlight the importance of the Northern Hemisphere in the early diversification of the family. They also document interchange with the Eocene flora of Europe and biogeographic connections with modern floras of Africa and Asia, where Icacinaceae are diverse today. The present-day restriction of this family to tropical regions offers ecological implications for the Eocene floras in which they occur. PMID- 26022484 TI - The Miocene to Pleistocene colonization of the Philippine archipelago by Begonia sect. Baryandra (Begoniaceae). AB - PREMISE OF THE STUDY: One third of the species-rich Philippine flora is endemic, and most of the islands in the archipelago have never been connected to a continental region. We currently lack any well-sampled angiosperm phylogenies that span the archipelago, prohibiting the formation of informed hypotheses as to the evolution of this rich and highly endemic flora. METHODS: We produced time calibrated phylogenetic trees from both nuclear (ITS) and chloroplast (ndhA intron, ndhF-rpl32 spacer, rpl32-trnL spacer, trnC-trnD spacer) regions of 41 species of Begonia sect. Baryandra, all except one endemic to the Philippines. Historical biogeography was reconstructed across the chloroplast phylogeny using a Bayesian binary method of character optimization. Comparison of phylogenies from the two genomes permitted insight into the prevalence of hybridization in the group. KEY RESULTS: The Philippine archipelago was colonized by Begonia sect. Baryandra in the late Miocene, via long-distance dispersal from western Malesia and a point of entry likely to be in the northwestern region of the archipelago. Palawan, Luzon, and Panay all bear early-branching lineages from this initial colonization. There have been Plio-Pleistocene dispersals from these islands into Borneo and Mindanao. Hybridization was common between species as evidenced by haplotype sharing and phylogenetic incongruence. CONCLUSIONS: The phylogenies show a high degree of geographic structure, which millions of years of exposure to typhoons have not blurred, showing long-term species and population stability. The recent dispersals to Mindanao are congruent with the geologically recent arrival of the island at its current latitude in the southern Philippines. PMID- 26022488 TI - Geographic variation in floral allometry suggests repeated transitions between selfing and outcrossing in a mixed mating plant. AB - PREMISE OF THE STUDY: Isometric and allometric scaling of a conserved floral plan could provide a parsimonious mechanism for rapid and reversible transitions between breeding systems. This scaling may occur during transitions between predominant autogamy and xenogamy, contributing to the maintenance of a stable mixed mating system. METHODS: We compared nine disjunct populations of the polytypic, mixed mating species Oenothera flava (Onagraceae) to two parapatric relatives, the obligately xenogamous species O. acutissima and the mixed mating species O. triloba. We compared floral morphology of all taxa using principal component analysis (PCA) and developmental trajectories of floral organs using ANCOVA homogeneity of slopes. KEY RESULTS: The PCA revealed both isometric and allometric scaling of a conserved floral plan. Three principal components (PCs) explained 92.5% of the variation in the three species. PC1 predominantly loaded on measures of floral size and accounts for 36% of the variation. PC2 accounted for 35% of the variation, predominantly in traits that influence pollinator handling. PC3 accounted for 22% of the variation, primarily in anther-stigma distance (herkogamy). During O. flava subsp. taraxacoides development, style elongation was accelerated relative to anthers, resulting in positive herkogamy. During O. flava subsp. flava development, style elongation was decelerated, resulting in zero or negative herkogamy. Of the two populations with intermediate morphology, style elongation was accelerated in one population and decelerated in the other. CONCLUSIONS: Isometric and allometric scaling of floral organs in North American Oenothera section Lavauxia drive variation in breeding system. Multiple developmental paths to intermediate phenotypes support the likelihood of multiple mating system transitions. PMID- 26022489 TI - Mating system variation and assortative mating of sympatric bromeliads (Pitcairnia spp.) endemic to neotropical inselbergs. AB - PREMISE OF THE STUDY: The mating system is an important component of the complex set of reproductive isolation barriers causing plant speciation. However, empirical evidence showing that the mating system may promote reproductive isolation in co-occurring species is limited. The mechanisms by which the mating system can act as a reproductive isolation barrier are also largely unknown. METHODS: Here we studied progeny arrays genotyped with microsatellites and patterns of stigma-anther separation (herkogamy) to understand the role of mating system shifts in promoting reproductive isolation between two hybridizing taxa with porous genomes, Pitcairnia albiflos and P. staminea (Bromeliaceae). KEY RESULTS: In P. staminea, we detected increased selfing and reduced herkogamy in one sympatric relative to two allopatric populations, consistent with mating system shifts in sympatry acting to maintain the species integrity of P. staminea when in contact with P. albiflos. CONCLUSIONS: Mating system variation is a result of several factors acting simultaneously in these populations. We report mating system shifts as one possible reproductive barrier between these species, acting in addition to numerous other prezygotic (i.e., flower phenology and pollination syndromes) and postzygotic barriers (Bateson-Dobzhansky-Muller genetic incompatibilities). PMID- 26022491 TI - Biogeographic analysis of the woody plants of the Southern Appalachians: Implications for the origins of a regional flora. AB - PREMISE OF THE STUDY: We investigated the origins of 252 Southern Appalachian woody species representing 158 clades to analyze larger patterns of biogeographic connectivity around the northern hemisphere. We tested biogeographic hypotheses regarding the timing of species disjunctions to eastern Asia and among areas of North America. METHODS: We delimited species into biogeographically informative clades, compiled sister-area data, and generated graphic representations of area connections across clades. We calculated taxon diversity within clades and plotted divergence times. KEY RESULTS: Of the total taxon diversity, 45% were distributed among 25 North American endemic clades. Sister taxa within eastern North America and eastern Asia were proportionally equal in frequency, accounting for over 50% of the sister-area connections. At increasing phylogenetic depth, connections to the Old World dominated. Divergence times for 65 clades with intercontinental disjunctions were continuous, whereas 11 intracontinental disjunctions to western North America and nine to eastern Mexico were temporally congruent. CONCLUSIONS: Over one third of the clades have likely undergone speciation within the region of eastern North America. The biogeographic pattern for the region is asymmetric, consisting of mostly mixed-aged, low-diversity clades connecting to the Old World, and a minority of New World clades. Divergence time data suggest that climate change in the Late Miocene to Early Pliocene generated disjunct patterns within North America. Continuous splitting times during the last 45 million years support the hypothesis that widespread distributions formed repeatedly during favorable periods, with serial cooling trends producing pseudocongruent area disjunctions between eastern North America and eastern Asia. PMID- 26022490 TI - Phylogenetic relationships in Asarum: Effect of data partitioning and a revised classification. AB - PREMISE OF THE STUDY: Generic boundaries and infrageneric relationships among the charismatic temperate magnoliid Asarum sensu lato (Aristolochiaceae) have long been uncertain. Previous molecular phylogenetic analyses used either plastid or nuclear loci alone and varied greatly in their taxonomic implications for the genus. We analyzed additional molecular markers from the nuclear and plastid genomes, reevaluated the possibility of a derived loss of autonomous self pollination, and investigated the topological effects of matrix-partitioning scheme choice. METHODS: We sequenced seven plastid regions and the nuclear ITS1 ITS2 region of 58 individuals representing all previously recognized Asarum s.l. segregate genera and the monotypic genus Saruma. Matrices were partitioned using common a priori partitioning schemes and PartitionFinder. KEY RESULTS: Topologies that were recovered using a priori partitioning of matrices differed from those recovered using a PartitionFinder-selected scheme, and by analysis method. We recovered six monophyletic groups that we circumscribed into three subgenera and six sections. Putative fungal mimic characters served as synapomorphies only for subgenus Heterotropa. Subgenus Geotaenium, a new subgenus, was recovered as sister to the remainder of Asarum by ML analyses of highly partitioned datasets. Section Longistylis, also newly named, is sister to section Hexastylis. CONCLUSIONS: Our analyses do not unambiguously support a single origin for all fungal-mimicry characters. Topologies recovered through the analysis of PartitionFinder-optimized matrices can differ drastically from those inferred from a priori partitioned matrices, and by analytical method. We recommend that investigators evaluate the topological effects of matrix partitioning using multiple methods of phylogenetic reconstruction. PMID- 26022492 TI - Evidence for natural hybridization between native and introduced lineages of Phragmites australis in the Chesapeake Bay watershed. AB - PREMISE OF THE STUDY: The introduction of nonnative taxa into areas occupied by conspecifics can lead to local extinction of native taxa via habitat modification and competitive dominance, and be exacerbated by outbreeding depression or the formation of invasive hybrid lineages following intraspecific gene flow. The expansion of Eurasian Phragmites australis into tidal wetlands of North America has been accompanied by a dramatic decline of native P. australis, with few relic populations remaining along the Atlantic coastline of the United States, particularly in the Virginia portion of the Chesapeake Bay. METHODS: We sampled populations from the York River and its two major tributaries to determine the pattern of Phragmites invasion and identify remnant native populations that warrant conservation. We used chloroplast DNA haplotypes and nuclear DNA microsatellite profiles to classify individuals as belonging to the native or introduced lineage. KEY RESULTS: Although native Phragmites stands were identified in the brackish upstream reaches of the two York River tributaries, the majority of Phragmites stands surveyed contained the introduced lineage. We also identified a single putative hybrid plant, based on its microsatellite profile. This plant possessed the native cpDNA haplotype and was located in an otherwise native Phragmites stand that is adjacent to an isolated patch of introduced Phragmites. CONCLUSIONS: Although evidence of field hybridization between native and introduced lineages of Phragmites in North America is still relatively rare, the continued encroachment of the introduced lineage into native wetlands may increase the likelihood of future hybrid formation. Careful genetic monitoring to identify remnant native and potential hybrid Phragmites is essential for prioritizing ongoing management efforts. PMID- 26022494 TI - Need for Antibiotic Prophylaxis for Pseudophakic Endophthalmitis-Reply. PMID- 26022493 TI - Functional differences between microglia and monocytes after ischemic stroke. AB - BACKGROUND: The brain's initial innate response to stroke is primarily mediated by microglia, the resident macrophage of the CNS. However, as early as 4 h after stroke, the blood-brain barrier is compromised and monocyte infiltration occurs. The lack of discriminating markers between these two myeloid populations has led many studies to generate conclusions based on the grouping of these two populations. A growing body of evidence now supports the distinct roles played by microglia and monocytes in many disease models. METHODS: Using a flow cytometry approach, combined with ex-vivo functional assays, we were able to distinguish microglia from monocytes using the relative expression of CD45 and assess the function of each cell type following stroke over the course of 7 days. RESULTS: We found that at 72 h after a 90-min middle cerebral artery occlusion (MCAO), microglia populations decrease whereas monocytes significantly increase in the stroke brain compared to sham. After stroke, BRDU incorporation into monocytes in the bone marrow increased. After recruitment to the ischemic brain, these monocytes accounted for nearly all BRDU-positive macrophages. Inflammatory activity peaked at 72 h. Microglia produced relatively higher reactive oxygen species and TNF, whereas monocytes were the predominant IL-1beta producer. Although microglia showed enhanced phagocytic activity after stroke, monocytes had significantly higher phagocytic capacity at 72 h. Interestingly, we found a positive correlation between TNF expression levels and phagocytic activity of microglia after stroke. CONCLUSIONS: In summary, the resident microglia population is vulnerable to the effects of severe ischemia, show compromised cell cycle progression, and adopt a largely pro-inflammatory phenotype after stroke. Infiltrating monocytes are primarily involved with early debris clearance of dying cells. These findings suggest that the early wave of infiltrating monocytes may be beneficial to stroke repair and future therapies aimed at mitigating microglia cell death may prove more effective than attempting to elicit targeted anti-inflammatory responses from damaged cells. PMID- 26022496 TI - Goal attributions and instrumental helping at 14 and 24 months of age. AB - Infants reason about goals and helping as early as 3 months of age, but toddlers fail to help others appropriately until well into the second year. Five experiments explored the reasons for this discrepancy. First, we verified that 14 month-old toddlers encode the goal of an actor's reaching action, in a situation in which a social agent selectively reaches for one of two objects. Then, four further experiments presented toddlers with a social agent who manifested her goal in this manner when the two objects were accessible, and then requested help in obtaining her goal object when the two objects were out of reach. In all the experiments, toddlers responded to the actor's request for help by handing her an out-of-reach object, showing that they understood that a prosocial action was called for and were motivated to perform it. When the two objects had moved out of the social agent's sight so that she could not indicate the goal object directly, 24-month-old children used her prior goal-directed action to select the appropriate goal object, but 14-month-old toddlers did not. The 14-month-olds toddlers helped appropriately only when no attribution of enduring goals was necessary, because the social agent could see the out-of-reach object and both looked at and reached toward it while making her request. These findings suggest striking limits to 14-month-old toddlers' understanding of helping. PMID- 26022495 TI - Id2a is required for hepatic outgrowth during liver development in zebrafish. AB - During development, inhibitor of DNA binding (Id) proteins, a subclass of the helix-loop-helix family of proteins, regulate cellular proliferation, differentiation, and apoptosis in various organs. However, a functional role of Id2a in liver development has not yet been reported. Here, using zebrafish as a model organism, we provide in vivo evidence that Id2a regulates hepatoblast proliferation and cell death during liver development. Initially, in the liver, id2a is expressed in hepatoblasts and after their differentiation, id2a expression is restricted to biliary epithelial cells. id2a knockdown in zebrafish embryos had no effect on hepatoblast specification or hepatocyte differentiation. However, liver size was greatly reduced in id2a morpholino-injected embryos, indicative of a hepatic outgrowth defect attributable to the significant decrease in proliferating hepatoblasts concomitant with the significant increase in hepatoblast cell death. Altogether, these data support the role of Id2a as an important regulator of hepatic outgrowth via modulation of hepatoblast proliferation and survival during liver development in zebrafish. PMID- 26022497 TI - The role of cognitive abilities in decisions from experience: Age differences emerge as a function of choice set size. AB - People seldom enjoy access to summarized information about risky options before making a decision. Instead, they may search for information and learn about environmental contingencies-thus making decisions from experience. Aging is associated with notable deficits in learning and memory-but do these translate into poorer decisions from experience? We report three studies that used a sampling paradigm to investigate younger (M=24 years) and older (M=71 years) adults' decisions from experience. In Study 1 (N=121) participants made 12 decisions between pairs of payoff distributions in the lab. Study 2 (N=70) implemented the same paradigm using portable devices, collecting 84 decisions per individual over a week. Study 3 (N=84) extended the sampling paradigm by asking participants to make 12 decisions between two, four, and eight payoff distributions (in the lab). Overall, the behavioral results suggest that younger and older adults are relatively similar in how they search and what they choose when facing two payoff distributions (Studies 1 and 2). With an increasing number of payoff distributions, however, age differences emerged (Study 3). A modeling analysis on the level of individual participants showed that a simple delta learning rule model best described the learning processes of most participants. To the extent that ongoing updating processes unfold relatively automatically and effortlessly, older adults may be liberated from the detrimental consequences of cognitive aging in the case of decisions from experience with few decision options. We discuss implications for research on decisions from experience and choice performance over the lifespan. PMID- 26022498 TI - Absorption and Bioavailability of Nano-Size Reduced Calcium Citrate Fortified Milk Powder in Ovariectomized and Ovariectomized-Osteoporosis Rats. AB - The aim of this study was to evaluate the effects of fortification and nano-size reduction on calcium absorption and bioavailability of milk powder formula in sham, ovariectomized, and ovariectomized-osteoporosis rats as a menopause and menopause-osteoporosis model. Skim milk powder and skim milk powder fortified with calcium citrate and the suitable doses of inulin, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamins D3, K1, and B6 were formulated based on the North American and Western European recommended dietary allowances. Optimization on cycle and pressure of high-pressure homogenizer was done to produce nano-fortified milk powder. In vivo study demonstrated that fortification and calcium citrate nano-fortified milk powder increased absorption and bioavailability of calcium, as well as bone stiffness and bone strength in sham, ovariectomized, and ovariectomized-osteoporosis rats. This study successfully developed an effective fortified milk powder for food application. PMID- 26022499 TI - A Cell Culture Model of Latent and Lytic Herpes Simplex Virus Type 1 Infection in Spiral Ganglion. AB - PURPOSE OF THE STUDY: Reactivation of latent herpes simplex virus type 1 (HSV-1) in spiral ganglion neurons (SGNs) is supposed to be one of the causes of idiopathic sudden sensorineural hearing loss. This study aims to establish a cell culture model of latent and lytic HSV-1 infection in spiral ganglia. PROCEDURES: In the presence of acyclovir, primary cultures of SGNs were latently infected with HSV-1 expressing green fluorescent protein. Four days later, these cells were treated with trichostatin A (TSA), a known chemical reactivator of HSV-1. TCID50 was used to measure the titers of virus in cultures on Vero cells. RNA from cultures was detected for the presence of transcripts of ICP27 and latency associated transcript (LAT) using reverse transcription polymerase chain reaction. RESULTS: There is no detectable infectious HSV-1 in latently infected cultures, whereas they could be observed in both lytically infected and latently infected/TSA-treated cultures. LAT was the only detectable transcript during latent infection, whereas lytic ICP27 transcript was detected in lytically infected and latently infected/TSA-treated cultures. CONCLUSION: Cultured SGNs can be both latently and lytically infected with HSV-1. Furthermore, latently infected SGNs can be reactivated using TSA, yielding infectious virus. PMID- 26022500 TI - Surgery for infants with catastrophic epilepsy: an analysis of complications and efficacy. AB - PURPOSE: Infants with epilepsy often have a catastrophic course. There is a reluctance to operate in the very young, due to the perception of an unacceptable risk of morbidity with early operations. The purpose of this investigation was to better characterize the efficacy and safety of epilepsy surgery in infants. METHODS: Epilepsy operations performed on children under 1 year old, between 2002 and 2013, were reviewed for demographic information, epilepsy characteristics, surgical approach, outcomes, and surgical complications. RESULTS: Twenty-five patients, ages 11 days to 11.5 months (mean 4.7) at operation, were identified. All had daily seizures. Twenty-two (88%) had an abnormal magnetic resonance imaging (MRI). Sixteen (64%) patients underwent hemispherotomy at initial operation. Seven (28%) infants had grid placement followed by focal resection. Focal cortical dysplasia was the most common pathology (40%) followed by hemimegalencephaly (32%). Complications occurred in 36% of patients. These included hydrocephalus in five patients (20%). Two patients had significant intra operative complications which required unplanned staging of their operations. Both recovered without permanent injury. Mean follow-up was 62.4 months. Twenty patients (80%) are seizure-free, and 10 (40%) are off anticonvulsant medication. Two patients are Engel class 2, and the remaining three patients were Engel class 4, one of whom died with status epilepticus from the contralateral hemisphere. CONCLUSION: Infants with localization-related catastrophic epilepsy can have excellent outcomes from early epilepsy surgery. Complications are common in this patient group and proper diagnosis can be challenging. Young age should not exclude infants with catastrophic epilepsy from consideration for early surgical intervention. PMID- 26022501 TI - A unique CD4+ large granular lymphocytosis occurring in patients treated with tumor necrosis factor alpha inhibitors: report of 2 cases. AB - We report 2 cases of CD4(+) large granular lymphocyte (LGL) lymphocytosis occurring in patients being treated with a monoclonal antibody against tumor necrosis factor alpha for underlying autoimmune disorders. CD4(+) LGL lymphocytosis is a rare subset of LGL disease that has previously only been described in patients without underlying autoimmune disorders, and most demonstrate uniform coexpression of CD56 on the atypical T cells. The clinical features, with both cases occurring in patients with autoimmune disease, and immunophenotypic features, with both cases showing dim CD8 coexpression without CD56 in the CD4(+) LGLs, suggest that the reported cases are distinct from those previously described and may represent a novel T-cell LGL lymphocytosis emerging from iatrogenic immune modulation of patients with underlying autoimmune disorders. PMID- 26022502 TI - Aerosol transfer of bladder urothelial and smooth muscle cells onto demucosalized colonic segments for bladder augmentation: in vivo, long term, and functional pilot study. AB - BACKGROUND: Bladder augmentation technique has changed over the years and the current practice has significant adverse health effects and long-term sequelae. Previously, we reported a novel cell transfer technology for covering demucosalized colonic segments with bladder urothelium and smooth muscle cells through an aerosol spraying of these cells and a fibrin glue mixture. OBJECTIVE: To determine the long-term durability and functional characteristics of demucosalized segments of colon repopulated with urothelial cells in the bladder of swine for use in augmentation cystoplasty. STUDY DESIGN: Nine swine were divided into three groups. The first group (control) underwent standard colocystoplasty; the second group underwent colocystoplasty with colonic demucosalization and aerosol application of fibrin glue and urothelial cell mixture; in the third group detrusor cells were added to the mixture described in group two. The animals were kept for 6 months. Absorptive and secretory function was assessed. Bladders were harvested for histological and immunohistochemical evaluation. RESULTS: All animals but one in the experimental groups showed confluent urothelial coverage of the colonic segment in the bladder without any evidence of fibrosis, inflammation, or regrowth of colonic epithelial cells. Ten percent of the instilled water in the bladder was absorbed within an hour in the control group, but none in experimental groups(p = 0.02). The total urine sediment and protein contents were higher in the control group compared with experimental groups (p < 0.05). DISCUSSION: Both study groups developed a uniform urothelial lining. Histologically, the group with smooth muscle had an added layer of submucosal smooth muscle. Six months after bladder augmentation the new lining was durable. We were also able to demonstrate that the reconstituted augmented segments secrete and absorb significantly less than the control colocystoplasty group. We used a non-validated simple method to evaluate permeability of the new urothelial lining to water. To determine if the aerosol transfer of bladder cells would have behaved differently in the neurogenic bladder population, this experiment should have been performed in animals with neuropathic bladders. CONCLUSION: Aerosol spraying of single cell suspension of urothelial and muscular cells with fibrin glue resulted in coverage of the demucosalized intestinal segment with a uniform urothelial layer. This new lining segment was durable without regrowth of colonic mucosa after 6 months. The new reconstituted segment absorbs and secretes significantly less than control colocystoplasty. PMID- 26022503 TI - Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. AB - BACKGROUND: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously. METHODS: We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis were also broadly characterized with respect to MTX resistance. This included measurement of concentrations of MTX polyglutamates in leukemic cells, mRNA expression of enzymes involved in MTX metabolism (FPGS, FPGH, RFC, DHFR, and TS), MTX sensitivity as determined by the TS inhibition assay, and FPGS activity. RESULTS: Herein we demonstrate that higher accumulation of long-chain polyglutamates of MTX is strongly associated with better overall (10-year OS: 90.6 vs 64.1%, P = 0.008) and event-free survival (10-year EFS: 81.2 vs 57.6%, P = 0.029) of ALL patients. In addition, we assessed both the association of several MTX resistance related parameters determined in vitro with treatment outcome as well as clinical characteristics of pediatric ALL patients treated with MTX-containing combination chemotherapy. High MTX sensitivity was associated with DNA hyperdiploid ALL (P < 0.001), which was linked with increased MTX accumulation (P = 0.03) and elevated reduced folate carrier (RFC) expression (P = 0.049) in this subset of ALL patients. TEL-AML1 fusion was associated with increased MTX resistance (P = 0.023). Moreover, a low accumulation of MTX polyglutamates was observed in MLL rearranged and TEL-AML1 rearranged ALL (P < 0.05). CONCLUSIONS: These findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients. PMID- 26022504 TI - Induced Pluripotent Stem Cells as a new Strategy for Osteogenesis and Bone Regeneration. AB - Induced pluripotent stem (iPS) cells, possess high proliferation and differentiation ability, are now considered an attractive option for osteogenic differentiation and bone regeneration. In fact, recent discoveries have demonstrated that iPS cells can be differentiated into osteoblasts, suggesting that iPS cells have the potential to advance future bone regenerative therapies. Herein, we provide an overview of the recent findings on osteogenic characteristics and differentiation potential of iPS cells. In addition, we discuss current methods for inducing their specification towards osteogenic phenotype as well as in vivo evidence supporting the therapeutic benefit of iPS derived osteoblasts. Finally, we describe recent findings regarding the use of iPS-derived cells for osteogenic differentiation and bone regeneration, which have indicated that these pluripotent cells represent an ideal tool for regenerative cell therapies and might contribute to the development of future bone tissue engineering. PMID- 26022505 TI - Focus on People and the Science Will Follow: Motivating Forces for Professional Movement in Stem Cell Research. AB - The migration of researchers across geographic borders, or "brain drain" as it is commonly called, remains an important issue for governments around the world as loss or gain of highly qualified personnel in research can have substantial social, economic and political consequences. In the present study we seek to examine the forces that drive international professional migration of stem cell (SC) researchers, for which variation of SC policy in different jurisdictions has previously been implicated as a driving force. Structured interviews were carried out with a purposive sample of SC researchers in the professoriate who had made international moves after postdoctoral work between the years 2001-2014, or were actively anticipating a future move. Participants were asked to rank motivators of international movement on a 5-point Likert scale and prompted to elaborate on their answers. The results suggest that career considerations, availability of research funding, and personal considerations are of high importance to the participants when considering an international move, while the permissiveness or restrictiveness SC research policy is of comparably lower importance. Participants also expressed that international movements are beneficial to scientific careers overall. The findings have important implications for policy and strategies to attract and retain members of the SC research community. PMID- 26022506 TI - Wnt/beta-Catenin and MEK-ERK Signaling are Required for Fibroblast-Derived Extracellular Matrix-Mediated Endoderm Differentiation of Embryonic Stem Cells. AB - Human embryonic stem cells (hESCs) have the potential to differentiate into all cells of the three germ layers, thus making them an attractive source of cells for use in regenerative medicine. The greatest challenge lies in regulating the differentiation of hESCs into specific cell lineages by both intrinsic and extrinsic factors. In this study we determined the effect of a fibroblast-derived extracellular matrix (fd-ECM) on hESCs differentiation. We demonstrate that growth of hESCs on fd-ECM results in hESCs losing their stemness and proliferation potential. As the stem cells differentiate they attain gene expression profiles similar to the primitive streak of the in vivo embryo. The activation of both the MEK-ERK and Wnt/beta-catenin signaling pathways is required for the fd-ECM-mediated differentiation of hESCs towards the endoderm and involves integrins alpha1, alpha2, alpha3 and beta1. This study illustrates the importance of the cellular microenvironment in directing stem cell fate and that the nature and composition of the extracellular matrix is a crucial determining factor. PMID- 26022507 TI - p16ink4a Expression Is Increased through 12-Lipoxygenase in High Glucose Stimulated Glomerular Mesangial Cells and Type 2 Diabetic Glomeruli. AB - BACKGROUND/AIMS: Arachidonic acid-metabolizing enzyme, 12-lipoxygenase (12-LO), is involved in the glomerular hypertrophy of diabetic nephropathy (DN), in which cyclin-dependent kinase inhibitors (CKIs) play important roles. However, it is unclear whether 12-LO regulates the expression of the CKI p16(ink4a) in DN. METHODS: Primary glomerular mesangial cells (MCs) and glomeruli isolated from rats were used in this study. The rats were fed a high-fat diet and given low dose streptozotocin to induce type 2 diabetes. The 12-LO product, 12(S) hydroxyeicosatetraenoic acid (12(S)-HETE), was infused through an osmotic minipump. Enzyme-linked immunosorbent assay, Western blot, and morphometric analyses were performed. RESULTS: High glucose (HG) increased the p16(ink4a) protein expression in MCs, but this increase was prevented by the 12-LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cynanocinnamate (CDC). The levels of p p38MAPK and p16(ink4a) in MCs were significantly elevated after the 12(S)-HETE treatment, whereas the p38MAPK inhibitor SB203580 prevented these increases. Compared with levels in control MCs, marked increases in p38MAPK activation and p16(ink4a) expression were observed in MCs plated on collagen IV, while the CDC treatment prevented these changes. Subcutaneous injection of CDC did not affect glucose levels, but completely attenuated the diabetes-related increases in the 12(S)-HETE content, p16(ink4a) expression, p-p38MAPK levels, glomerular volume, and the kidney/body weight ratio. Compared with levels in controls, p16(ink4a) and p-p38MAPK in the glomeruli derived from 12(S)-HETE-treated rats were significantly higher. CONCLUSIONS: 12-LO-p38MAPK mediates the upregulation of p16(ink4a) in HG-stimulated MCs and type 2-diabetic glomeruli, and new therapies aimed at 12-LO inhibition may prove beneficial in ameliorating diabetes-induced glomerular hypertrophy. PMID- 26022508 TI - Comparison of Adrenal Suppression between Etomidate and Dexmedetomidine in Children with Congenital Heart Disease. AB - BACKGROUND: The aim of this study was to compare plasma cortisol concentration during anesthesia of children with congenital heart disease who received dexmedetomidine (DEX) with those who received etomidate (ETO). MATERIAL AND METHODS: We recruited 99 ASA physical status II-III pediatric patients scheduled for congenital heart disease (CHD) corrective surgery and divided into them into 3 groups. Group DEX received an infusion of DEX intravenously with a bolus dose of 0.5 ug.kg-1 within 10 min during anesthesia induction, followed by a maintenance dose of DEX 0.5 ug.kg-1.h-1. Group ETO received ETO intravenously with a bolus dose of 0.3 mg.kg-1 without a maintenance dose. Group CON received routine anesthetics as controls. The preset timepoints were: before anesthesia induction (T0), at the end of induction (T1), 30 min after anesthesia induction (T2), at the time of aortic and inferior vena catheterization (T3), and at 180 min (T4) and 24 h (T5) after anesthesia induction. RESULTS: The cortisol concentration decreased gradually after anesthesia induction in all groups, and returned to baseline values after 24 h. The cortisol concentration was significantly lower in Group ETO children than in Group DEX or group CON at T4. CONCLUSIONS: The plasma concentrations of cortisol decreased in CHD children after the operation, but returned to baseline after 24 h of anesthesia induction. The adrenal cortex function inhibition induced by ETO in CHD children is longer and more serious than that induced by DEX (if any) during the preoperative period. PMID- 26022509 TI - Using a split luciferase assay (SLA) to measure the kinetics of cell-cell fusion mediated by herpes simplex virus glycoproteins. AB - Herpes simplex virus (HSV) entry and cell-cell fusion require the envelope proteins gD, gH/gL and gB. We propose that receptor-activated conformational changes to gD activate gH/gL, which then triggers gB (the fusogen) into an active form. To study this dynamic process, we have adapted a dual split protein assay originally developed to study the kinetics of human immunodeficiency virus (HIV) mediated fusion. This assay uses a chimera of split forms of renilla luciferase (RL) and green fluorescent protein (GFP). Effector cells are co-transfected with the glycoproteins and one of the split reporters. Receptor-bearing target cells are transfected with the second reporter. Co-culture results in fusion and restoration of RL, which can convert a membrane permeable substrate into a luminescent product, thereby enabling one to monitor initiation and extent of fusion in live cells in real time. Restoration of GFP can also be studied by fluorescence microscopy. Two sets of split reporters have been developed: the original one allows one to measure fusion kinetics over hours whereas the more recent version was designed to enhance the sensitivity of RL activity allowing one to monitor both initiation and rates of fusion in minutes. Here, we provide a detailed, step-by-step protocol for the optimization of the assay (which we call the SLA for split luciferase assay) using the HSV system. We also show several examples of the power of this assay to examine both the initiation and kinetics of cell-cell fusion by wild type forms of gD, gB, gH/gL of both serotypes of HSV as well as the effect of mutations and antibodies that alter the kinetics of fusion. The SLA can be applied to other viral systems that carry out membrane fusion. PMID- 26022511 TI - Autologous blood injection for the treatment of recurrent mandibular dislocation. AB - The purpose of the present study was to evaluate the effectiveness of autologous blood injection in the treatment of recurrent temporomandibular joint dislocation. Eleven patients diagnosed with recurrent dislocation of the joint that could not be self-reduced, received bilateral injections of autologous blood in the superior joint compartment and pericapsular region. During a follow-up period ranging from 24 to 35 months (average 29.6 months), eight patients (72.7%) did not show new episodes of dislocation. The most advocated treatment for recurrent dislocation is eminectomy, which involves a skin incision, with the risk of damaging the facial nerve, requires general anaesthesia, and presents an average success rate of 85% according to the literature. Autologous blood injection is a simple, rapid, minimally invasive, and cost-effective technique, with a low possibility of complications, and is a feasible alternative treatment before surgical intervention. PMID- 26022510 TI - Serum-free culture alters the quantity and protein composition of neuroblastoma derived extracellular vesicles. AB - Extracellular vesicles (EVs) play a significant role in cell-cell communication in numerous physiological processes and pathological conditions, and offer promise as novel biomarkers and therapeutic agents for genetic diseases. Many recent studies have described different molecular mechanisms that contribute to EV biogenesis and release from cells. However, little is known about how external stimuli such as cell culture conditions can affect the quantity and content of EVs. While N2a neuroblastoma cells cultured in serum-free (OptiMEM) conditions did not result in EVs with significant biophysical or size differences compared with cells cultured in serum-containing (pre-spun) conditions, the quantity of isolated EVs was greatly increased. Moreover, the expression levels of certain vesicular proteins (e.g. small GTPases, G-protein complexes, mRNA processing proteins and splicing factors), some of which were previously reported to be involved in EV biogenesis, were found to be differentially expressed in EVs under different culture conditions. These data, therefore, contribute to the understanding of how extracellular factors and intracellular molecular pathways affect the composition and release of EVs. PMID- 26022512 TI - External Nasal Valve Efficacy Index: a simple test to evaluate the external nasal valve. AB - Many methods and techniques have been proposed for the assessment of the nasal valve, most requiring special equipment. Furthermore the main focus has been on the internal valve, while the role of the external nasal valve (ENV) has usually been underestimated. An index to assess ENV is presented herein. Two photographs of the basal view of the nose are taken, one in the resting position and the other after deep inspiration. These two life-size views are used to calculate the External Nasal Valve Efficacy Index (ENVE Index). Using simple software, the surface area of the nostril in the resting view (A) and breathing view (B) is measured. The ENVE Index is calculated by dividing the deep inspiration surface area by the resting surface area (B/A). The clinical indications for the use of the ENVE Index include rhinoplasty treatment planning, postoperative evaluation to assess the effects of surgery with regard to improvement or deterioration of the airway, and orthognathic surgery and the planning of appropriate postoperative care (such as elastic or intermaxillary fixation) according to the airway patency. The ENVE Index is a relatively simple, reproducible, and documentable test. This index can help the surgeon to make better decisions during treatment planning and postoperative care. PMID- 26022513 TI - Isolated orbital floor fractures in the paediatric patient: case series and review of management. AB - Orbital injuries warranting surgical intervention are infrequent in the paediatric population, but 'blowout, trap door' fractures are unique in children and may constitute a relative surgical emergency. A retrospective review of isolated orbital floor fractures at the Royal Children's Hospital of Melbourne over a 10-year period was undertaken to evaluate the outcome of those patients who required surgical exploration. Twenty-two patients with documented isolated orbital floor injuries were studied. Preoperative signs and symptoms including diplopia, ocular motility, paresthesia, enophthalmos, hypoglobus, and the presence of nausea and vomiting were recorded. Thirteen patients underwent non surgical management and nine patients underwent surgical exploration of the orbital floor via a trans-subconjunctival approach to reduce any entrapped soft tissue. Postoperative follow-up of these patients varied between 1 month and 18 months and none had any visual disturbance or diplopia in central gaze; however, two patients experienced diplopia in upward gaze at follow-up, although this did not impair the quality of life. Due to the risk of permanent soft tissue damage from the entrapment of the periorbita with or without extraocular muscle tissue, it is recommended that exploration be undertaken as soon as possible to minimize the risk of persistent diplopia due to impaired ocular motility. PMID- 26022514 TI - Immune responses and protection induced by Brucella suis S2 bacterial ghosts in mice. AB - With the purpose of generating Brucella suis bacterial ghosts and investigating the immunogenicity of bacterial ghosts as a vaccine candidate, the lysis gene E and temperature-sensitive regulator cassette were cloned into a shuttle plasmid, pBBR1MCS-2, for construction of a recombinant temperature-sensitive shuttle lysis plasmid, pBBR1MCS-E. pBBR1MCS-E was then introduced into attenuated B. suis live vaccine S2 bacteria, and the resultant transformants were used for production of B. suis ghosts (BSGs) by inducing lysis gene E expression. The BSGs were characterized by observing their morphology by transmission electron microscopy. The safety and immunogenicity of BSGs were further evaluated using a murine model, the result suggested that BSG was as safe as formalin-killed B. suis. In mice, BSG demonstrated a similar capacity of inducing pathogen-specific serum IgG antibody response, spleen CD3(+) and CD4(+) T cell responses, induce secretion of gamma interferon and interleukin-4, and protection levels against Brucella melitensis 16M challenge, as the attenuated B. suis live vaccine. These data suggesting that BSG could confer protection against Brucella infection in a mouse model of disease and may be developed as a new vaccine candidate against Brucella infection. PMID- 26022515 TI - Crystal structure of a symbiosis-related lectin from octocoral. AB - D-Galactose-binding lectin from the octocoral, Sinularia lochmodes (SLL-2), distributes densely on the cell surface of microalgae, Symbiodinium sp., an endosymbiotic dinoflagellate of the coral, and is also shown to be a chemical cue that transforms dinoflagellate into a non-motile (coccoid) symbiotic state. SLL-2 binds with high affinity to the Forssman antigen (N acetylgalactosamine(GalNAc)alpha1-3GalNAcbeta1-3Galalpha1-4Galbeta1-4Glc ceramide), and the presence of Forssman antigen-like sugar on the surface of Symbiodinium CS-156 cells was previously confirmed. Here we report the crystal structures of SLL-2 and its GalNAc complex as the first crystal structures of a lectin involved in the symbiosis between coral and dinoflagellate. N-Linked sugar chains and a galactose derivative binding site common to H-type lectins were observed in each monomer of the hexameric SLL-2 crystal structure. In addition, unique sugar-binding site-like regions were identified at the top and bottom of the hexameric SLL-2 structure. These structural features suggest a possible binding mode between SLL-2 and Forssman antigen-like pentasaccharide. PMID- 26022516 TI - Human sialic acid acetyl esterase: Towards a better understanding of a puzzling enzyme. AB - Sialic acid acetyl esterase (SIAE) removes acetyl moieties from the hydroxyl groups in position 9 and 4 of sialic acid. Recently, a dispute has been opened on its association to autoimmunity. In order to get new insights on human SIAE biology and to clarify its seemingly contradictory molecular properties, we combined in silico characterization, phylogenetic analysis and homology modeling with cellular studies in COS7 cells. Genomic and phylogenetic analysis revealed that in most tissues only the "long" isoform, originally referred to lysosomal sialic acid esterase, is detected. Using the homology modeling approach, we predicted a model of SIAE 3D structure, which fulfills the topological features of SGNH-hydrolase family. In addition, the model and site-directed mutagenesis experiments allowed the definition of the residues involved in catalysis. SIAE transient expression revealed that the protein is glycosylated and is active in vitro as an esterase with a pH optimum corresponding to 8.4-8.5. Moreover, glycosylation influences the biological activity of the enzyme and is essential for release of SIAE into the culture medium. According to these findings, co localization experiments demonstrated the presence of SIAE in membranous structures corresponding to endoplasmic reticulum and Golgi complex. Thus, at least in COS7 cells, SIAE behaves as a typical secreted enzyme, subjected to glycosylation and located along the classical secretory route or in the extracellular space. In these environments, the enzyme could act on 9-O acetylated sialic acid residues, contributing to the fine-tuning of the various functions played by this acidic sugar. PMID- 26022517 TI - Quantum coherence effects in natural light-induced processes: cis-trans photoisomerization of model retinal under incoherent excitation. AB - We present a theoretical study of quantum coherence effects in the primary cis trans photoisomerization of retinal in rhodopsin induced by incoherent solar light. Using the partial secular Bloch-Redfield quantum master equation approach based on a two-state two-mode linear vibronic coupling model of the retinal chromophore [S. Hahn and G. Stock, J. Phys. Chem. B, 2000, 104, 1146-1149], we show that a sudden turn-on of incoherent pumping can generate substantial Fano coherences among the excited states of retinal. These coherences are the most pronounced in the regime where the matrix elements of the transition dipole moment between the ground and excited eigenstates are parallel to one another. We show that even when the transition dipole moments are perpendicular (implying the absence of light-induced Fano coherence) a small amount of excited-state coherence is still generated due to the coupling to intramolecular vibrational modes and the protein environment, causing depopulation of the excited eigenstates. The overall effect of the coherences on the steady-state population and on the photoproduct quantum yield is shown to be small; however we observe a significant transient effect on the formation of the trans photoproduct, enhancing the photoreaction quantum yield by ~11% at 200 fs. These calculations suggest that coupling to intramolecular vibrational modes and the protein environment play an important role in photoreaction dynamics, suppressing oscillations in the quantum yield associated with Fano interference. PMID- 26022518 TI - Intrahepatic and hilar mass-forming cholangiocarcinoma: Qualitative and quantitative evaluation with diffusion-weighted MR imaging. AB - OBJECTIVE: To qualitatively and quantitatively analyze the presentation of intrahepatic and hilar mass-forming cholangiocarcinoma with diffusion-weighted magnetic resonance imaging (DW-MRI). MATERIALS AND METHODS: Twenty-eight patients with histopathologically proven mass-forming cholangiocarcinoma (hilar, n=17; intrahepatic, n=11) underwent hepatic DW-MRI at 1.5-T using free-breathing acquisition and three b-values (0,400,800s/mm(2)). Cholangiocarcinomas were evaluated qualitatively using visual analysis of DW-MR images and quantitatively with conventional ADC and normalized ADC measurements using liver and spleen as reference organs. RESULTS: All cholangiocarcinomas (28/28; 100%) were visible on DW-MR images. DW-MRI yielded best conspicuity of cholangiocarcinomas than the other MRI sequences (P<0.001). Seven cholangiocarcinomas (7/11; 64%) showed hypointense central area on DW-MR images. Conventional ADC value of cholangiocarcinomas (1.042*10(-3)mm(2)/s+/-0.221*10(-3)mm(2)/s; range: 0.616*10( 3)mm(2)/s to 2.050*10(-3)mm(2)/s) was significantly lower than that of apparently normal hepatic parenchyma (1.362*10(-3)mm(2)/s+/-0.187*10(-3)mm(2)/s) (P<0.0001), although substantial overlap was found. No significant differences in ADC and normalized ADC values were found between intrahepatic and hilar cholangiocarcinomas. The use of normalized ADC using the liver as reference organ resulted in the most restricted distribution of ADC values of cholangiocarcinomas (variation coefficient=16.6%). CONCLUSION: There is a trend towards a common appearance of intrahepatic and hilar mass-forming cholangiocarcinomas on DW-MRI but variations may be observed. Familiarity with these variations may improve the diagnosis of mass-forming cholangiocarcinoma. PMID- 26022519 TI - Diagnostic value of quantitative stenosis predictors with coronary CT angiography compared to invasive fractional flow reserve. AB - OBJECTIVE: To evaluate the diagnostic performance of CCTA-derived stenosis predictors including CT-FFR for the detection of ischemia-inducing stenosis compared to invasive FFR. MATERIALS AND METHODS: Stenosis parameters were assessed using dual-source CT (DSCT). All patients underwent both CCTA and invasive FFR within 3 months and were retrospectively analyzed. Observers visually assessed all CCTA studies and performed multiple lesion measurements. Lesion length/minimal luminal diameter(4) (LL/MLD(4)), transluminal attenuation gradient (TAG), corrected coronary attenuation (CCO) and CT-FFR were calculated. RESULTS: The cohort included 32 patients (58+/-12 years, 66%male). Among 32 coronary lesions, 8 (25%) were considered hemodynamically significant with an FFR <0.80. Compared to invasive FFR, the per-vessel sensitivity and specificity of CCTA, CT-FFR, LL/MLD(4), CCO and TAG for detecting hemodynamically significant lesions were 100% and 54%, 100% and 91%, 85% and 92%, 66% and 88%, 37% and 58%, respectively. Receiver operating characteristics analysis resulted in an area under the curve of 0.91 for CT-FFR (p=0.0005), 0.88 for LL/MLD(4) (p<0.0001), 0.85 for CCO (p<0.0001). TAG with an AUC of 0.67 (p=0.152) was unable to discriminate between vessels with or without hemodynamically significant lesions. CONCLUSION: CT-FFR, LL/MLD(4) and CCO provide enhanced diagnostic performance over CCTA analysis alone for discrimination of hemodynamically significant coronary stenosis. PMID- 26022520 TI - Pancreatic neuroendocrine tumors: Correlation between the contrast-enhanced computed tomography features and the pathological tumor grade. AB - OBJECTIVE: To determine whether CT features can predict the pathological tumor grades of pancreatic neuroendocrine tumors (PanNETs) according to the recent WHO classification. MATERIALS AND METHODS: In all, 28 patients with histologically confirmed PanNETs underwent preoperative contrast CT examinations. Thirteen tumors were classified as G1 and 15 as G2. Two radiologists independently evaluated the CT features (tumor delineation, peripancreatic vascular involvement, upstream pancreatic duct dilatation, N (regional lymph node metastasis) and M (distant metastasis) grades, tumor homogeneity, cystic or necrotic change, and tumor conspicuity). The tumor sizes and Hounsfield unit values of all PanNETs during each phase on CT were measured by one radiologist. We compared the CT features between pathological tumor grades using Fisher's exact test for nominal scales and Mann-Whitney U test for ordinal scales or continuous variables. Additionally, we evaluated the performances of the CT findings and their combinations to diagnose G2 tumors. RESULTS: G2 tumors showed significantly larger in tumor size than G1 tumors (p=0.029). All 4 tumors with hepatic metastases were G2. Non-hyperattenuation compared with pancreatic parenchyma during portal venous phase (PVP) was significantly associated with G2 (p=0.016). The accuracy for G2 diagnosis of tumor size (>=20mm), M grade (M1), and tumor conspicuity (non-hyperattenuation during PVP) were 71%, 61%, and 71%, respectively, while the accuracy of their combination was 82%. CONCLUSION: Contrast-enhanced CT features (tumor size, M grade, and tumor conspicuity during PVP) can predict the pathological tumor grades of PanNETs. PMID- 26022521 TI - Microvascular obstruction on delayed enhancement cardiac magnetic resonance imaging after acute myocardial infarction, compared with myocardial (201)Tl and (123)I-BMIPP dual SPECT findings. AB - BACKGROUND: The hypo-enhanced regions within the hyper-enhanced infarct areas detected by cardiac magnetic resonance (CMR) imaging reflect microvascular obstruction (MO) after acute myocardial infarction (AMI). The combined myocardial thallium-201 ((201)Tl)/iodine-123-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid ((123)I-BMIPP) dual single-photon emission computed tomography (SPECT) is a useful tool for detecting myocardial reversibility after AMI. We evaluated whether MO could be an early predictor of irreversible myocardial damage in comparison with (201)Tl and (123)I-BMIPP dual SPECT findings in AMI patients. METHODS: Sixty-two patients with initial AMI who successfully underwent coronary revascularization were enrolled. MO was defined by CMR imaging. Patients were divided into 2 groups as follows: MO group (n=32) and non-MO group (n=30). Scintigraphic defect scores were calculated using a 17-segment model with a 5 point scoring system. The mismatch score (MMS) was calculated as follows: the total sum of (Sigma) (123)I-BMIPP defect score minus Sigma(201)Tl defect score. The percentage mismatch score (%MMS) was calculated as follows: MMS/(Sigma(123)I BMIPP score)*100 (%). RESULTS: The percentage infarct size (%IS) was significantly greater in the MO group than in the non-MO group (32.2+/-13.8% vs. 18.3+/-12.1%, p<0.001). The %MMS significantly correlated with the %IS and the percentage MO (r=-0.26, p=0.03; r=-0.45, p<0.001, respectively). The %MMS was significantly greater in the non-MO group than in the MO group (45.4+/-42.4% vs. 13.3+/-28.0%, p=0.001), and was an independent predictor for MO (OR 0.97, 95%CI 0.94-0.99, p=0.02). CONCLUSIONS: Our results reconfirm that, in comparison with myocardial dual scintigraphy, MO is an important structural abnormality. CMR imaging is useful for the early detection of irreversible myocardial damage after AMI. PMID- 26022522 TI - Carpal tunnel syndrome: Analysis of online patient information with the EQIP tool. AB - Patients suffering from carpal tunnel syndrome (CTS) actively search for medical information on the Internet. The World Wide Web represents the main source of patient information. The aim of this study was to systematically assess the quality of patient information about CTS in the Internet. A qualitative and quantitative assessment of websites was performed with the modified Ensuring Quality Information for Patients (EQIP) tool that contains 36 standardized items. Five hundred websites with information on CTS treatment options were identified through Google, Bing, Yahoo, Ask.com and AOL. Duplicates and irrelevant websites were excluded. One hundred and ten websites were included. Only five websites addressed more than 20 items; quality scores were not significantly different between the various providing groups. A median of 15 EQIP items was found, with the top website addressing 26 out of 36 items. Major complications such as median nerve injury were reported in 27% of the websites and their treatment in only 3%. This analysis revealed several critical shortcomings in the quality of the information provided to patients suffering from CTS. There is a collective need to provide interactive, informative and educational websites for standard procedures in hand surgery. These websites should be compatible with international quality standards for hand surgery procedures. PMID- 26022523 TI - Lack of clinical benefit of zoledronic acid in myelofibrosis: results of a prospective multi-center phase II trial. PMID- 26022524 TI - A lower dosage of imatinib is sufficient to maintain undetectable disease in patients with chronic myeloid leukemia with long-term low-grade toxicity of the treatment. AB - The information about chronic myeloid leukemia (CML) patients with a deep molecular response of >= 4.5 log reduction (MR4.5) in whom the dose of imatinib (IM) had to be reduced to relieve toxicity is insufficient. In 205 CML patients the dose of IM was reduced in 19 (31.2%) out of 61 patients with MR4.5. The patients (12 pretreated with interferon-alpha) achieved MR4.5 after an average of 27.7 months. The duration of MR4.5 before the reduction of the dose was 16-123 (mean = 56.7) months. After the IM reduction (200 mg daily to 400 mg twice weekly for 15-90 (mean = 48) months) MR4.5 or major molecular response (MMR) was maintained in 14 (73.7%) and 2 (10.5%) patients, respectively. Three patients who lost MMR (15.8%) after the discontinuation of IM regained MR4.5 after the reintroduction of a lower dose. A lower dosage of IM should be tested for the management of side effects in patients with MR4.5 in prospective studies. PMID- 26022525 TI - Wound Care. AB - Wound care requires an understanding of normal wound healing, causes of delays of wound healing, and the management of wounds. Every wound must be treated as an individual with regard to cause, chronicity, location, and level of microbial contamination, as well as patient factors that affect wound healing. Knowledge of wound care products available and when negative pressure wound therapy and drain placement is appropriate can improve outcomes with wound healing. Inappropriate product use can cause delays in healing. As a wound healing progresses, management of a wound and the bandage material used must evolve. PMID- 26022526 TI - Analgesia in the Perioperative Period. AB - Untreated or undermanaged perioperative pain has systemic effects that may negatively impact a patient's welfare and return to function. A consistent analgesic plan that assesses a patient's pain and comfort at regular intervals during the perioperative period should be incorporated into practice. Validated pain assessment tools are available for use in dogs and cats. Multimodal analgesic plans should be created for individual patients and modified according to pain assessments. These plans, based on a thorough history, physical examination, and knowledge of the expected pain, should be combinations of an opioid, a nonsteroidal anti-inflammatory drug, a local anesthetic, and nonpharmacologic analgesic techniques. PMID- 26022527 TI - Update on sentinel lymph node biopsy for early-stage vulvar cancer. AB - Two prospective, multicenter clinical trials have demonstrated the feasibility and reproducibility of sentinel lymph node (SLN) biopsy as part of the standard management of early-stage vulvar carcinoma. On the basis of the results of these trials, many gynecologic oncologists have incorporated SLN biopsy for vulvar cancer into their practice. Studies have further shown that SLN biopsy is associated with better quality of life than full lymphadenectomy, is more cost effective than full lymphadenectomy, and improved pathologic evaluation. A large observational study is currently evaluating the outcomes of patients with early stage vulvar cancer according to the results of their SLN biopsy and the approach to their care; this study may confirm that full inguinofemoral lymphadenectomy is no longer necessary in most patients with this disease. Here, we review the published data supporting SLN biopsy as part of the standard of care for women with early-stage vulvar cancer and discuss future considerations for the management of this disease. PMID- 26022528 TI - Cervical cancer prevention practices through screening and vaccination: A cross sectional study among Hong Kong Chinese women. AB - OBJECTIVE: No published data are available that currently evaluate Chinese adult women's cervical cancer prevention practices through screening and vaccination using population-based samples. This study describes patterns and correlates of these behaviors among Hong Kong Chinese women aged 30-59 years. METHODS: From February to November 2014 a random sample of 1482 Hong Kong Chinese women having at least one 12-17 year-old daughter, who had heard of HPV vaccine before but had not sought HPV vaccination for daughter(s) completed structured telephone interviews. Multiple logistic regression analyses were conducted to examine factors associated with participants' cervical screening attendance, HPV vaccination uptake and intention to uptake. RESULTS: Overall, 80.8% of the participants reported attending asymptomatic cervical screening and 73% had regular screening. Family income and attitudes to cervical smear testing were associated with asymptomatic cervical screening attendance. Only 3.0% (45/1482) of all participants had received HPV vaccination. Among those who had not received HPV vaccination, 12.3% (183/1437) indicated positive intentions. Age below 50, household income and encouragement from family/friends were significantly associated with women's intended and actual uptake of HPV vaccination. Trusting formal and informal HPV vaccination information was positively associated with vaccination intention, while lack of concrete recommendation from doctors was negatively associated with vaccination uptake. CONCLUSIONS: Information trust was associated with vaccination intention but not actual uptake whereas encouragement from family/friends facilitates women's HPV vaccination. Continued efforts are needed to ensure Chinese women adopting cervical cancer preventive behaviors, and must consider different specific needs of population subgroups. PMID- 26022529 TI - In vitro pharmacological characterization of vorapaxar, a novel platelet thrombin receptor antagonist. AB - Vorapaxar is a novel protease-activated receptor-1 (PAR1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. The present study provides a comprehensive in vitro pharmacological characterization of vorapaxar interaction with the PAR1 receptor on human platelets. Similar studies were performed with a metabolite of vorapaxar (M20). Vorapaxar and M20 were competitive PAR1 antagonists that demonstrated concentration-dependent, saturable, specific, and slowly reversible binding to the receptor present on intact human platelets. The affinities of vorapaxar and M20 for the PAR1 receptor were in the low nanomolar range, as determined by saturation-, kinetic- and competitive binding studies. The calculated Kd and Ki values for vorapaxar increased in the presence of plasma, indicating a decrease in the free fraction available for binding to the PAR1 receptor on human platelets. Vorapaxar was also evaluated in functional assays using thrombin or a PAR1 agonist peptide (SFLLRN). Vorapaxar and M20 completely blocked thrombin-stimulated PAR1/beta-arrestin association in recombinant cells and abolished thrombin-stimulated calcium influx in washed human platelets and vascular smooth muscle cells. Moreover, vorapaxar and M20 inhibited PAR1 agonist peptide-mediated platelet aggregation in human platelet rich plasma with a steep concentration response relationship. Vorapaxar exhibited high selectivity for inhibition of PAR1 over other platelet GPCRs. In conclusion, vorapaxar is a potent PAR1 antagonist exhibiting saturable, reversible, selective binding with slow off-rate kinetics and effectively inhibits thrombin's PAR1-mediated actions on human platelets. PMID- 26022531 TI - Do existing mechanisms contribute to improvements in care coordination across levels of care in health services networks? Opinions of the health personnel in Colombia and Brazil. AB - BACKGROUND: The fragmentation of healthcare provision has given rise to a wide range of interventions within organizations to improve coordination across levels of care, primarily in high income countries but also in some middle and low income countries. The aim is to analyze the use of coordination mechanisms in healthcare networks and its implications for the delivery of health care. This is studied from the perspective of health personnel in two countries with different health systems, Colombia and Brazil. METHODS: A qualitative, exploratory and descriptive-interpretative study was conducted, based on a case study of healthcare networks in two municipalities in each country. Individual semi structured interviews were conducted with a three stage theoretical sample of a) health (112) and administrative (66) professionals of different care levels, and b) managers of providers (42) and insurers (14). A thematic content analysis was conducted, segmented by cases, informant groups and themes. RESULTS: The results show that care coordination mechanisms are poorly implemented in general. However, the results are marginally better in certain segments of the Colombian networks analyzed (ambulatory centres with primary and secondary care co-location owned by or tied to the contributory scheme insurers, and public providers of the subsidized scheme); and in the network of the state capital in Brazil. Professionals point to numerous problems in the use of existing mechanisms, such as the insufficient recording of information in referral forms, low frequency and level of participation in shared clinical sessions, low adherence to the few available clinical guidelines and the lack of or inadequate referral of patients by the patient referral centres, particularly in the Brazilian networks. The absence or limited use of care coordination mechanisms leads, according to informants, to the inadequate follow-up of patients, interruptions in care and duplication of tests. Professionals use informal strategies to try to overcome these limitations. CONCLUSIONS: The results indicate not only the limited implementation of mechanisms for coordination across care levels, but also a limited use of existing mechanisms in the healthcare networks analyzed. This has a negative impact on coordination, efficiency and quality of care. Organizational changes are required in the networks and healthcare systems to address these problems. PMID- 26022532 TI - A global perspective on decadal challenges and priorities in biodiversity informatics. AB - Biodiversity informatics is a field that is growing rapidly in data infrastructure, tools, and participation by researchers worldwide from diverse disciplines and with diverse, innovative approaches. A recent 'decadal view' of the field laid out a vision that was nonetheless restricted and constrained by its European focus. Our alternative decadal view is global, i.e., it sees the worldwide scope and importance of biodiversity informatics as addressing five major, global goals: (1) mobilize existing knowledge; (2) share this knowledge and the experience of its myriad deployments globally; (3) avoid 'siloing' and reinventing the tools of knowledge deployment; (4) tackle biodiversity informatics challenges at appropriate scales; and (5) seek solutions to difficult challenges that are strategic. PMID- 26022530 TI - N-3 polyunsaturated fatty acids modulate B cell activity in pre-clinical models: Implications for the immune response to infections. AB - B cell antigen presentation, cytokine production, and antibody production are targets of pharmacological intervention in inflammatory and infectious diseases. Here we review recent pre-clinical evidence demonstrating that pharmacologically relevant levels of n-3 polyunsaturated fatty acids (PUFA) derived from marine fish oils influence key aspects of B cell function through multiple mechanisms. N 3 PUFAs modestly diminish B cell mediated stimulation of classically defined naive CD4(+) Th1 cells through the major histocompatibility complex (MHC) class II pathway. This is consistent with existing data showing that n-3 PUFAs suppress the activation of Th1/Th17 cells through direct effects on helper T cells and indirect effects on antigen presenting cells. Mechanistically, n-3 PUFAs lower antigen presentation and T cell signaling by disrupting the formation of lipid microdomains within the immunological synapse. We then review data to show that n 3 PUFAs boost B cell activation and antibody production in the absence and presence of antigen stimulation. This has potential benefits for several clinical populations such as the aged and obese that have poor humoral immunity. The mode of action by which n-3 PUFA boost B cell activation and antibody production remains unclear, but may involve Th2 cytokines, enhanced production of specialized proresolving lipid mediators, and targeting of protein lateral organization in lipid microdomains. Finally, we highlight evidence to show that different n-3 PUFAs are not biologically equivalent, which has implications for the development of future interventions to target B cell activity. PMID- 26022533 TI - Salivary gland ultrasonography: a highly specific tool for the early diagnosis of primary Sjogren's syndrome. AB - INTRODUCTION: Recently, a great interest has arisen for salivary gland ultrasonography (SGUS) as a valuable tool for the assessment of major salivary gland involvement in primary Sjogren's syndrome (pSS. The aims of this study were to test the accuracy of SGUS for the early detection of pSSand to compare the diagnostic performance of SGUS with minor salivary gland biopsy (MSGB) and unstimulated salivary flow (USFR) in this context. METHOD: Patients with suspected pSS and symptoms duration of <=5 years were consecutively enrolled in this study. The diagnosis of pSS was made according to the AECG criteria. SGUS was performed by two radiologists blinded to the diagnosis and a previously reported ultrasound scoring system (De Vita et al. 1992, cut-off >= 1) was used to grade the echostructure alterations of the salivary glands. Statistical analysis was performed using SPSS v16. RESULTS: This study included 50 pSS patients and 57 controls with no-SS sicca symptoms. The mean(SD) age of the pSS group was lower than non-SS group (47(13) vs 53(12)yrs, p = 0.006). No further differences between the two groups were observed. Patients with pSS showed a significantly higher SGUS score in comparison with controls (mean(SD) = 2.1(1.8) vs 0.0(0.4), p = 0.000). The SGUS cut-off >= 1 showed a sensitivity (SE) of 66 %, a specificity (SP) of 98 %, a positive predictive value (PPV) of 97 % and a negative predictive value (NPV) of 73 % for pSS diagnosis. The SGUS score correlated also with patients' MSGB/FS and USFR. CONCLUSIONS: This study confirmed the good performance of SGUS for the early non-invasive diagnosis of pSS. Further research in larger international cohort of patients is mandatory in order to assess the role of SGUS in the diagnostic algorithm of pSS. PMID- 26022534 TI - A rise in peak performance age in female athletes. AB - It was reported in 1980s that ages at which peak performance was observed had remained remarkably stable in the past century, although absolute levels of athletic performance increased dramatically for the same time span. The emergence of older (masters) athletes in the past few decades has changed the demographics and age-spectrum of Olympic athletes. The primary aim of the present study was to determine whether the ages at which peak performance was observed had increased in the recent decades. The data spanning 114 years from the first Olympics (1898) to the most recent Olympics (2014) were collected using the publically available data. In the present study, ages at which Olympic medals (gold, silver, and bronze) were won were used as the indicators of peak performance age. Track and field, swimming, rowing, and ice skating events were analyzed. In men, peak performance age did not change significantly in most of the sporting events (except in 100 m sprint running). In contrast, peak performance ages in women have increased significantly since 1980s and consistently in all the athletic events examined. Interestingly, as women's peak performance age increased, they became similar to men's peak ages in many events. In the last 20-30 years, ages at which peak athletic performance is observed have increased in women but not in men. PMID- 26022535 TI - Thrombogenicity and early vascular healing response in metallic biodegradable polymer-based and fully bioabsorbable drug-eluting stents. AB - BACKGROUND: Acute thrombogenicity and re-endothelialization represent clinically relevant end points pertaining to the safety of coronary stents, which have not been compared among biodegradable polymer-based drug-eluting metallic stents and fully bioabsorbable scaffolds to date. METHODS AND RESULTS: We investigated comparative outcomes with respect to acute thrombogenicity and re endothelialization among thin-strut biodegradable polymer metallic everolimus eluting stents (EES), thick-strut fully bioabsorbable EES, thick-strut biodegradable polymer metallic biolimus-eluting stents and control bare metal stents. An ex-vivo porcine arterio-venous shunt model was used to assess platelet aggregation, whereas a healthy rabbit model of iliofemoral stent implantation was used to assess re-endothelialization and inflammation. Confocal microscopy was used to detect fluorescently labeled antibody staining directed against CD61/CD42b for the identification of aggregated thrombocytes, CD14/PM-1, and RAM 11 for identification of neutrophils and monocytes/macrophages. Endothelial recovery was assessed by scanning electron microscopy, whereas CD31/PECAM-1 was used to confirm endothelial maturity. EES demonstrated significantly less acute thrombogenicity compared with bioabsorbable EES and biolimus-eluting stents. EES showed greater re-endothelialization at 28 days and reduced inflammatory cell adhesion of monocytes/macrophages at 14 days compared with bioabsorbable EES. Only bare metal stents showed complete re-endothelialization at 28 days. CONCLUSIONS: These outcomes indicate differential trends in thrombogenicity and vascular healing among contemporary stents used in clinical practice and suggest a need for long-term adjunct antithrombotic pharmacotherapy for bioabsorbable EES. PMID- 26022537 TI - Vortioxetine : a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder. AB - INTRODUCTION: Vortioxetine is a pharmacodynamically novel antidepressant that exerts effects on various neurotransmitters including serotonin, noradrenaline, dopamine, glutamate, histamine and acetylcholine. Its efficacy in the symptomatic management of major depressive disorder (MDD) has been established in several short- and long-term trials. Vortioxetine has also demonstrated independent pro cognitive effects in adults with MDD. AREAS COVERED: This report provides a concise review of the pharmacology, efficacy and safety of vortioxetine as they pertain to cognition. EXPERT OPINION: The significant impact of cognitive dysfunction in MDD has achieved increased consideration among researchers over the past decade. Vortioxetine is the first antidepressant agent to demonstrate meaningful clinical efficacy in the improvement of cognition in adults with MDD, independent of improvement in affective symptomatology. These results provide the impetus for further study into the potential pro-cognitive effects of vortioxetine in other conditions wherein cognitive dysfunction is prominent. PMID- 26022536 TI - Fully percutaneous transthoracic left atrial entry and closure as a potential access route for transcatheter mitral valve interventions. AB - BACKGROUND: Percutaneous access for mitral interventions is currently limited to transapical and transseptal routes, both of which have shortcomings. We hypothesized that the left atrium could be accessed directly through the posterior chest wall under imaging guidance. METHODS AND RESULTS: We tested percutaneous transthoracic left atrial access in 12 animals (10 pigs and 2 sheep) under real-time magnetic resonance imaging or x-ray fluoroscopy plus C-arm computed tomographic guidance. The pleural space was insufflated with CO2 to displace the lung, an 18F sheath was delivered to the left atrium, and the left atrial port was closed using an off-the-shelf nitinol cardiac occluder. Animals were survived for a minimum of 7 days. The left atrial was accessed, and the port was closed successfully in 12/12 animals. There was no procedural mortality and only 1 hemodynamically insignificant pericardial effusion was observed at follow up. We also successfully performed the procedure on 3 human cadavers. A simulated trajectory to the left atrium was present in all of 10 human cardiac computed tomographic angiograms analyzed. CONCLUSIONS: Percutaneous transthoracic left atrial access is feasible without instrumenting the left ventricular myocardium. In our experience, magnetic resonance imaging offers superb visualization of anatomic structures with the ability to monitor and address complications in real time, although x-ray guidance seems feasible. Clinical translation seems realistic based on human cardiac computed tomographic analysis and cadaver testing. This technique could provide a direct nonsurgical access route for future transcatheter mitral implantation. PMID- 26022538 TI - Scottish parliament rejects "right to die" for terminally ill people. PMID- 26022539 TI - Placebo analgesia enhances descending pain-related effective connectivity: a dynamic causal modeling study of endogenous pain modulation. AB - The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia remains incomplete. This study used functional magnetic resonance imaging data from 30 healthy individuals and dynamic causal modeling to investigate changes in effective connectivity associated with the placebo analgesic response. Before scanning, participants were conditioned to expect less thermal pain at 2 of 4 sites on their feet. Visual analog scale pain ratings revealed a significant but small difference between the baseline and placebo sites (mean difference = 6.63, t(29) = 3.91, P <= .001, d = .97), confirming an analgesic effect. However, no significant differences in the magnitude of brain activation between conditions were observed via traditional random effects general linear modeling. Dynamic causal modeling was then used to investigate changes in effective connectivity during placebo analgesia. The results indicate that during placebo analgesia but not baseline condition, couplings between brain regions, including those involved in cognitive processes (eg, attention, expectation, evaluation), were significantly enhanced. Specifically, a significantly consistent decrease in the dorsolateral prefrontal cortex -> periaqueductal gray coupling was found. These findings highlight the differences between pain processing and modulation at the network level. Moreover, our results suggest that small placebo effects may be better characterized via changes in the temporal dynamics among pain modulatory regions than only via changes in the magnitude of blood oxygenation level dependent activation. Further application of nuanced analytical approaches that are sensitive to temporal dynamics of pain-related processes such as dynamic causal modeling are necessary to better understand the neural mechanisms underlying pain processing in patient populations. PERSPECTIVE: Changes in effective connectivity among pain-related brain regions may be more sensitive detectors of the neural representation of small placebo effects than are changes in the magnitude of brain activation. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation. PMID- 26022540 TI - New breast cancer prognostic factors identified by computer-aided image analysis of HE stained histopathology images. AB - Computer-aided image analysis (CAI) can help objectively quantify morphologic features of hematoxylin-eosin (HE) histopathology images and provide potentially useful prognostic information on breast cancer. We performed a CAI workflow on 1,150 HE images from 230 patients with invasive ductal carcinoma (IDC) of the breast. We used a pixel-wise support vector machine classifier for tumor nests (TNs)-stroma segmentation, and a marker-controlled watershed algorithm for nuclei segmentation. 730 morphologic parameters were extracted after segmentation, and 12 parameters identified by Kaplan-Meier analysis were significantly associated with 8-year disease free survival (P < 0.05 for all). Moreover, four image features including TNs feature (HR 1.327, 95%CI [1.001-1.759], P = 0.049), TNs cell nuclei feature (HR 0.729, 95%CI [0.537-0.989], P = 0.042), TNs cell density (HR 1.625, 95%CI [1.177-2.244], P = 0.003), and stromal cell structure feature (HR 1.596, 95%CI [1.142-2.229], P = 0.006) were identified by multivariate Cox proportional hazards model to be new independent prognostic factors. The results indicated that CAI can assist the pathologist in extracting prognostic information from HE histopathology images for IDC. The TNs feature, TNs cell nuclei feature, TNs cell density, and stromal cell structure feature could be new prognostic factors. PMID- 26022541 TI - Assessment of the HNF1B Score as a Tool to Select Patients for HNF1B Genetic Testing. AB - BACKGROUND/AIMS: Diagnosing hepatocyte nuclear factor 1beta (HNF1B)-related disease is a challenging task due to the phenotypic variability and frequent absence of a family history. An HNF1B score has recently been developed to help select appropriate patients for genetic testing with a negative predictive value (NPV) of 99%. We aimed at testing the clinical utility of this score in a large number of referrals for HNF1B genetic testing to the UK diagnostic testing service for the HNF1B gene. METHODS: An HNF1B score was assigned for 686 UK referrals for HNF1B genetic testing using clinical information available at referral. The performance of the score was evaluated by receiver-operating characteristic curve analysis. The relative discriminatory ability of different clinical features for making a genetic diagnosis of HNF1B-related disease were estimated in the UK dataset alone and pooled with French data. RESULTS: The HNF1B score discriminated between patients with and without a mutation reasonably well with an area under the curve of 0.72. Applying the suggested cut-off score of >=8 gave a NPV of 85%. In a pooled analysis, antenatal renal abnormalities, renal hyperechogenicity and cysts were discriminatory in children, whereas renal hypoplasia and cysts were discriminatory in adults. Pancreatic abnormalities were discriminatory in both, whereas other extra-renal characteristics had a large effect size only in adults. CONCLUSION: The HNF1B score was discriminatory for HNF1B mutations in a large cohort of individuals tested in a single UK centre. The lower NPV (85 vs. 99%) reduces its clinical utility in selecting patients for HNF1B genetic testing, although validation in a prospective cohort is required. PMID- 26022542 TI - Strategies for alveolar ridge reconstruction and preservation for implant therapy. AB - PURPOSE: In dental implant treatment, ridge preservation and immediate or early implant placement are recommended to minimize bone resorption after tooth extraction and achieve esthetic outcomes. However, there is no consensus concerning the efficacy of this surgical method. There is also no consensus on the efficacy of bone and soft tissue grafts and surgical methods for alveolar ridge reconstruction. STUDY SELECTION: This paper reports ridge alteration in the anterior maxilla after tooth extraction, and summarizes the efficacy of various ridge preservation methods and immediate or early implant placement as alveolar ridge preservation methods to minimize bone resorption after tooth extraction. The advantages and complications of alveolar ridge reconstruction methods, and the efficacy and surgical method of soft tissue graft are reviewed. RESULTS: The anterior maxilla is in the esthetic zone, and the thickness of the bone on the labial side around the natural tooth is less than 1mm in many cases. Therefore, it is impossible to prevent bone resorption completely, even if ridge preservation and immediate or early implant placement are performed after tooth extraction. It is necessary to obtain stable and long-term esthetics by combining connective tissue and free gingival grafts, in addition to hard tissue augmentation. CONCLUSIONS: It is important to consider the burden and level of satisfaction of patients, such as in terms of donor site morbidity in hard and soft tissue grafting, and to pay attention to appropriate indications to avoid overtreatment. PMID- 26022543 TI - Are Group Psychotherapeutic Treatments Effective for Patients with Schizophrenia? A Systematic Review and Meta-Analysis. AB - BACKGROUND: Different psychotherapeutic treatments for schizophrenia are delivered in groups. However, little is known about the effectiveness of these group therapies for people with schizophrenia across different treatments with varying therapeutic orientations. This review aimed to (1) estimate the effect of different group psychotherapeutic treatments for schizophrenia and (2) explore whether any overall 'group effect' is moderated by treatment intensity, diagnostic homogeneity and therapeutic orientation. METHODS: A systematic search of randomised controlled trials exploring the effectiveness of group psychotherapeutic treatments for people with schizophrenia was conducted. Random effect meta-analyses on endpoint symptom scores compared group psychotherapeutic treatments with treatment as usual and active sham groups. Findings on social functioning were described narratively, and meta-regression analyses on group characteristics were carried out. RESULTS: Thirty-four eligible trials were included. A weak-to-moderate significant between-group difference in favour of group psychotherapeutic treatments was found for negative symptom scores (standard mean difference = -0.37, 95% confidence interval -0.60, -0.14; p < 0.01, I(2) = 59.8%) only when compared to treatment as usual and not to active sham groups. Improved social functioning was reported as a treatment outcome in the majority of studies compared to treatment as usual. The 'group effect' on negative symptoms was positively related to 'treatment intensity' (beta = 0.32, standard error = 0.121; p < 0.05). CONCLUSION: Group psychotherapeutic treatments can improve negative symptoms and social functioning deficits in the treatment of schizophrenia. The effect occurs across different treatments and appears to be non-specific. Future research should identify the underlying mechanisms for the positive effect of participating in groups and explore how they can be maximised to increase the therapeutic benefit. PMID- 26022544 TI - Social network as predictor for onset of alcohol use disorder: A prospective cohort study. AB - OBJECTIVE: Social network has been linked to alcohol use disorder in several studies. However, since the majority of such findings are cross-sectional, causal interpretation is difficult. The aim of the present study was to test if social network characteristics predict alcohol use disorder in a prospective design. METHODS: Information on social network and covariates was obtained from 9589 men and women aged 21-99 years in the Copenhagen City Heart Study, followed for registration of alcohol use disorder in the Danish National Patient Registry and the WINALCO database. RESULTS: Men who lived alone, were separated or divorced or widowers had a higher risk of developing alcohol use disorder: HR among men living alone vs. men not living alone was 2.28 (95% CI: 1.59-3.27), and HR among separated/divorced men vs. married men was 2.55 (95% CI: 1.33-4.89). No such associations were found among women. Frequency of contact with friends was associated with risk of developing alcohol use disorder among both sexes. For example, the HRs were 1.72 (CI 95%: 0.99-3.01) and 2.59 (95% CI: 1.42-4.71) among women who had contact with friends a couple of times per week and daily, respectively, compared with more rarely. Frequency of contact with family was not associated with risk of developing alcohol use disorder among either sex. CONCLUSION: Living alone and not being married or cohabiting with a partner were predictors of developing alcohol use disorder among men. Further, frequent contact with friends was associated with higher risk of alcohol use disorder among both sexes. PMID- 26022545 TI - Effect of Porosity on Strength Distribution of Microcrystalline Cellulose. AB - Fracture strength of pharmaceutical compacts varies even for nominally identical samples, which directly affects compaction, comminution, and tablet dosage forms. However, the relationships between porosity and mechanical behavior of compacts are not clear. Here, the effects of porosity on fracture strength and fracture statistics of microcrystalline cellulose compacts were investigated through diametral compression tests. Weibull modulus, a key parameter in Weibull statistics, was observed to decrease with increasing porosity from 17 to 56 vol.%, based on eight sets of compacts at different porosity levels, each set containing ~ 50 samples, a total of 407 tests. Normal distribution fits better to fracture data for porosity less than 20 vol.%, whereas Weibull distribution is a better fit in the limit of highest porosity. Weibull moduli from 840 unique finite element simulations of isotropic porous materials were compared to experimental Weibull moduli from this research and results on various pharmaceutical materials. Deviations from Weibull statistics are observed. The effect of porosity on fracture strength can be described by a recently proposed micromechanics-based formula. PMID- 26022546 TI - Electrospinning of Cross-Linked Magnetic Chitosan Nanofibers for Protein Release. AB - A poly(vinylalcohol) (PVA) electrospun/magnetic/chitosan nanocomposite fibrous cross-linked network was fabricated using in situ cross-linking electrospinning technique and used for bovine serum albumin (BSA) loading and release applications. Sodium tripolyphosphate (TPP) and glutaraldehyde (GA) were used as cross-linkers which modified magnetic-Fe3O4 chitosan as Fe3O4/CS/TPP and Fe3O4/CS/GA, respectively. BSA was used as a model protein drugs which was encapsulated to form Fe3O4/CS/TPP/BSA and Fe3O4/CS/GA/BSA nanoparticles. The composites were electrospun with PVA to form nanofibers. Nanofibers were characterized by field emission scanning electron microscopy (FESEM) and Fourier transform infrared spectroscopy (FTIR). The characterization results suggest that Fe3O4 nanoparticles with average size of 45 nm were successfully bound on the surface of chitosan. The cross-linked nanofibers were found to contain uniformly dispersed Fe3O4 nanoparticles. The size and morphology of the nanofibers network was controlled by varying the cross-linker type. FTIR data show that these two polymers have intermolecular interactions. The sample with TPP cross-linker showed an enhancement of the controlled release properties of BSA during 30-h experimental investigation. Graphical Abstract ?. PMID- 26022547 TI - New Method for Monitoring the Process of Freeze Drying of Biological Materials. AB - A capacitive sensor was proposed and tested for the monitoring and control of a freeze drying process of a vaccine against the Newcastle disease of birds. The residual moisture of the vaccine was measured by the thermogravimetric method. The vaccine activity was determined by titration in chicken embryos. It was shown that, at the stages of freezing and primary drying, a capacitive sensor measured the fraction of unfrozen liquid phase in a material and allowed one to control the sublimation stage of drying in an optimal way. This prevented the foaming of the material and shortened the total drying time approximately twice. The control range at the sublimation stage of drying expanded up to -70 degrees C. It was found at the final stage of drying that the signal of a capacitive sensor passed through a maximum value. We supposed that this maximum corresponds to the minimum of intramolecular mobility of biological macromolecules and hence to the optimal residual moisture of the material, which ensures long-term preservation of its activity. We also suppose that using the capacitive sensor at the final stage of drying allows one to more precisely detect the time when the residual moisture of dried material reaches the optimal value. PMID- 26022548 TI - The curious case of women in hospital medicine. PMID- 26022549 TI - Curiosity. Are you curious enough to read on? PMID- 26022550 TI - Lower limb amputation: indication is the key. PMID- 26022551 TI - A brief history of the cluster randomised trial design. PMID- 26022555 TI - Involvement of oxidative stress and cytoskeletal disruption in microcystin induced apoptosis in CIK cells. AB - The outbreak of cyanobacterial blooms induces the production and release of microcystins (MCs) into water, representing a health hazard to aquatic organisms and even humans. Some recent studies have suggested that kidney is another important target organ of MCs except liver, however, the potential toxicity mechanisms are still unclear. In this study, we first investigated the collaborative effect of oxidative stress and cytoskeletal disruption in microcystin-induced apoptosis in CIK (Ctenopharyngodon idellus kidney) cells in vitro. CIK cells were treated with 0, 1, 10, and 100MUg/L microcystin-LR (MC-LR) for 24 and 48h. Cell viability was increased by MC-LR in 1MUg/L group, while decreased in 100MUg/L group at 48h. Cell cycle assay showed that 1 and 10MUg/L MC LR induced cell cycle through G1 into S and G2/M phases, while 100MUg/L MC-LR reduced G2/M phase population. MC-LR markedly induced apoptosis in 10 and 100MUg/L groups. Elevated reactive oxygen species (ROS) production, increased malondialdehyde (MDA) contents, decreased glutathione (GSH) levels, and modulated antioxidant enzymes including catalase (CAT) and superoxide dismutase (SOD) were observed in CIK cells exposed to MC-LR. These alterations were more pronounced at higher doses (10 and 100MUg/L), indicating that oxidative stress was induced by MC-LR. Laser scanning confocal microscope observation showed aggregation and collapse of microfilaments (MFs) and microtubules (MTs) in CIK cells, and even loss of some cytoskeleton structure. Moreover, transcriptional changes of cytoskeletal genes (beta-actin, lc3a, and keratin) were also determined, which have a high probability with cytoskeleton structure damage. Our data suggest that oxidative stress and cytoskeletal disruption may interact with each other and jointly lead to apoptosis and renal toxicity induced by MCs. PMID- 26022556 TI - Alterations in mitochondrial electron transport system activity in response to warm acclimation, hypoxia-reoxygenation and copper in rainbow trout, Oncorhynchus mykiss. AB - Fish expend significant amounts of energy to handle the numerous potentially stressful biotic and abiotic factors that they commonly encounter in aquatic environments. This universal requirement for energy singularizes mitochondria, the primary cellular energy transformers, as fundamental drivers of responses to environmental change. Our study probed the interacting effects of thermal stress, hypoxia-reoxygenation (HRO) and copper (Cu) exposure in rainbow trout to test the prediction that they act jointly to impair mitochondrial function. Rainbow trout were acclimated to 11 (controls) or 20 degrees C for 2 months. Liver mitochondria were then isolated and their responses in vitro to Cu (0-20MUM) without and with HRO were assessed. Sequential inhibition and activation of mitochondrial electron transport system (ETS) enzyme complexes permitted the measurement of respiratory activities supported by complex I-IV (CI-IV) in one run. The results showed that warm acclimation reduced fish and liver weights but increased mitochondrial protein indicating impairment of energy metabolism, increased synthesis of defense proteins and/or reduced liver water content. Whereas acute rise (11->20 degrees C) in temperature increased mitochondrial oxidation rates supported by CI IV, warm acclimation reduced the maximal (state 3) and increased the basal (state 4) respiration leading to global uncoupling of oxidative phosphorylation (OXPHOS). HRO profoundly inhibited both maximal and basal respiration rates supported by CI-IV, reduced RCR for all except CII and lowered CI:CII respiration ratio, an indication of decreased OXPHOS efficiency. The effects of Cu were less pronounced but more variable and included inhibition of CII-IV maximal respiration rates and stimulation of both CI and CIII basal respiration rates. Surprisingly, only CII and CIII indices exhibited significant 3-way interactions whereas 2-way interactions of acclimation either with Cu or HRO were portrayed mostly by CIV, and those of HRO and Cu were most common in CI and II respiratory indices. Our study suggests that warm acclimation blunts sensitivity of the ETS to temperature rise and that HRO and warm acclimation impose mitochondrial changes that sensitize the ETS to Cu. Overall, our study highlights the significance of the ETS in mitochondrial bioenergetic dysfunction caused by thermal stress, HRO and Cu exposure. PMID- 26022557 TI - Chlamydomonas reinhardtii cells adjust the metabolism to maintain viability in response to atrazine stress. AB - Chlamydomonas reinhardtii cells were exposed to a sublethal concentration of the widespread herbicide atrazine for 3 and 24h. Physiological parameters related to cellular energy status, such as cellular activity and mitochondrial and cytoplasmic membrane potentials, monitored by flow cytometry, were altered in microalgal cells exposed to 0.25MUM of atrazine. Transcriptomic analyses, carried out by RNA-Seq technique, displayed 12 differentially expressed genes between control cultures and atrazine-exposed cultures at both tested times. Many cellular processes were affected, but the most significant changes were observed in genes implicated in amino acid catabolism and respiratory cellular process. Obtained results suggest that photosynthesis inhibition by atrazine leads cells to get energy through a heterotrophic metabolism to maintain their viability. PMID- 26022558 TI - Estimating the concordance probability in a survival analysis with a discrete number of risk groups. AB - A clinical risk classification system is an important component of a treatment decision algorithm. A measure used to assess the strength of a risk classification system is discrimination, and when the outcome is survival time, the most commonly applied global measure of discrimination is the concordance probability. The concordance probability represents the pairwise probability of lower patient risk given longer survival time. The c-index and the concordance probability estimate have been used to estimate the concordance probability when patient-specific risk scores are continuous. In the current paper, the concordance probability estimate and an inverse probability censoring weighted c index are modified to account for discrete risk scores. Simulations are generated to assess the finite sample properties of the concordance probability estimate and the weighted c-index. An application of these measures of discriminatory power to a metastatic prostate cancer risk classification system is examined. PMID- 26022559 TI - MST-312 Alters Telomere Dynamics, Gene Expression Profiles and Growth in Human Breast Cancer Cells. AB - BACKGROUND: Targeting telomerase is a potential cancer management strategy given that it allows unlimited cellular replication in the majority of cancers. Dysfunctional telomeres are recognized as double-strand breaks. However, the status of DNA repair response pathways following telomerase inhibition is not well understood in human breast cancer cells. Here, we evaluated the effects of MST-312, a chemically modified derivative from tea catechin, epigallocatechin gallate, on telomere dynamics and DNA damage gene expression in breast cancer cells. METHODOLOGY: Breast cancer cells MCF-7 and MDA-MB-231 were treated with MST-312, and telomere-telomerase homeostasis, induced DNA damage and gene expression profiling were analyzed. RESULTS: MST-312 decreased telomerase activity and induced telomere dysfunction and growth arrest in breast cancer cells with more profound effects in MDA-MB-231 than in MCF-7 cells. Consistent with these data, the telomere-protective protein TRF2 was downregulated in MDA-MB 231 cells. MST-312 induced DNA damage at telomeres accompanied by reduced expression of DNA damage-related genes ATM and RAD50. Co-treatment with MST-312 and the poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor PJ-34 further enhanced growth reduction as compared to single treatment with MST-312 or PJ-34. CONCLUSIONS: Our work demonstrates potential importance for the establishment of antitelomerase cancer therapy using MST-312 along with PARP-1 inhibition in breast cancer therapy. PMID- 26022560 TI - Introduction to the supplement. AB - In July of 2014, a symposium entitled "Enhancing Vaccine Immunity and Value" was held in Siena, Italy. The focus of the symposium was on how to best meet the challenge of developing and implementing vaccines for future disease targets. Vaccination has been responsible for averting estimated 3 billion cases of disease and more than 500 million lives to date through the prevention of infectious diseases. This has largely been responsible for dramatic increases in life span in developed countries. However, with the demographics of the world's population are changing, with many adults now surviving into their 80s, we now face the challenge of protecting the aging and other underserved populations not only against infectious diseases but also against cancer and other chronic conditions that occur in older adults. To face this challenge, we must harness new technologies derived from recent advances in the fields of immunology, structural biology, synthetic biology and genomics that promise a revolution in the vaccine field. Specifically, vaccine adjuvants have the potential to harness the immune system to provide protection against new types of diseases, improve protection in young children and expand this protection to adults and the elderly. However, in order to succeed, we need to overcome the non-technical challenges that could limit the implementation of innovative vaccines, including controversies regarding the safety of adjuvants, increasing regulatory complexity, the inadequate methods used to assess the value of novel vaccines, and the resulting industry alienation from future investment. In this supplement, we have assembled manuscripts from lectures and discussions of the symposium last July that addressed two related questions: how to improve vaccine efficacy using breakthrough technologies and how to capture the full potential of novel vaccines. PMID- 26022561 TI - New generation adjuvants--from empiricism to rational design. AB - Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. PMID- 26022563 TI - Valuing vaccines: deficiencies and remedies. AB - Current evaluation models for the value of vaccines typically account for a small subset of the full social and economic benefits of vaccination. Health investments yield positive economic benefits via several channels at the household, community, and national levels. Underestimating, or worse, not considering these benefits can lead to ill-founded recommendations regarding the introduction of vaccines into immunization programs. The clear and strong links between health and wealth suggest the need to redesign valuation frameworks for vaccination so that the full costs may be properly weighed against the full benefits of vaccines. PMID- 26022564 TI - Safety and effectiveness of MF-59 adjuvanted influenza vaccines in children and adults. AB - The squalene oil-in-water emulsion MF-59 adjuvant was developed initially to enhance the immunogenicity of influenza vaccines in populations such as children and adults with known suboptimal response. Developed in the 1990s, it was initially licensed in Europe for use in seasonal influenza vaccine in the elderly. Since that time, both Avian and p2009H1N1 vaccines have also been developed. Overall, more than 30,000 individuals have participated in clinical trials of MF-59 adjuvanted vaccine and more than 160 million doses of licensed vaccine have been administered. Safety and effectiveness data from clinical trials and observation studies attest to the safety of MF-59 and to its ability to enhance the effectiveness of influenza vaccines in children and the elderly. PMID- 26022565 TI - Bridging the gap: need for a data repository to support vaccine prioritization efforts. AB - As the mechanisms for discovery, development, and delivery of new vaccines become increasingly complex, strategic planning and priority setting have become ever more crucial. Traditional single value metrics such as disease burden or cost effectiveness no longer suffice to rank vaccine candidates for development. The Institute of Medicine-in collaboration with the National Academy of Engineering has developed a novel software system to support vaccine prioritization efforts. The Strategic Multi-Attribute Ranking Tool for Vaccines-SMART Vaccines-allows decision makers to specify their own value structure, selecting from among 28 pre defined and up to 7 user-defined attributes relevant to the ranking of vaccine candidates. Widespread use of SMART Vaccines will require compilation of a comprehensive data repository for numerous relevant populations-including their demographics, disease burdens and associated treatment costs, as well as characterizing performance features of potential or existing vaccines that might be created, improved, or deployed. While the software contains preloaded data for a modest number of populations, a large gap exists between the existing data and a comprehensive data repository necessary to make full use of SMART Vaccines. While some of these data exist in disparate sources and forms, constructing a data repository will require much new coordination and focus. Finding strategies to bridge the gap to a comprehensive data repository remains the most important task in bringing SMART Vaccines to full fruition, and to support strategic vaccine prioritization efforts in general. PMID- 26022562 TI - Beyond adjuvants: immunomodulation strategies to enhance T cell immunity. AB - Engagement of CD8T cells is a crucial aspect of immune responses to pathogens and in tumor surveillance. Nonetheless most vaccination strategies with common adjuvants fail to elicit long-term memory CD8T cells. Increased knowledge on the cellular and molecular requirements for CD8T cell activation has unveiled new opportunities to directly modulate CD8T cells to generate optimal responses. During chronic infections and cancer, immunomodulation strategies to enhance T cell responses may be particularly necessary to overcome the immunosuppressive microenvironment. In this review we will discuss blockade of inhibitory receptors; interleukin-2 administration; regulatory T cell modulation; and targeting of mTOR, as means to enhance CD8T cell immunity. PMID- 26022566 TI - Gaps in knowledge and prospects for research of adjuvanted vaccines. AB - A panel of researchers working in different areas of adjuvanted vaccines deliberated over the topic, "Gaps in knowledge and prospects for research of adjuvanted vaccines" at, "Enhancing Vaccine Immunity and Value" conference held in July 2014. Several vaccine challenges and applications for new adjuvant technologies were discussed. PMID- 26022567 TI - Communicating the role and value of vaccine adjuvants. AB - Despite the inclusion of adjuvants in many routinely used vaccines to improve the immune response, their presence and role are neither clear in product details such as the packaging or in the Summaries of Product Characteristics, nor understood by health professionals or the public. For many vaccines the adjuvant may simply be described as 'Adsorbed' without clarification that the adsorbing onto a material such as aluminium hydroxide adjuvants the antigens. As many future vaccines are likely to be adjuvanted, the presence of adjuvants, either those used in existing vaccines or novel formulations, may raise public and professional concerns unless communication materials are prepared in advance to allay anxieties such as those that have arisen over some present vaccine ingredients such as thiomersal. This raises a dilemma about how active such communications should be: over-promotion of the presence of a new adjuvant may cause unneeded anxieties; under-promotion may raise concerns over concealment of information. Research is needed and appropriate communication materials should be prepared. PMID- 26022568 TI - Challenges in early clinical development of adjuvanted vaccines. AB - A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. PMID- 26022569 TI - Vaccines: from valuation to resource allocation. AB - This review focuses on selected challenges and opportunities concerning broader valuation of vaccines and immunization. The challenges involve conceptualizing and measuring the value of vaccines, while the opportunities relate to the strategic and systematic use of that information in health policy decisions that range from the adoption of particular vaccines in national immunization plans to the allocation of resources to vaccine research, development, and delivery. Clarifying the demonstrable individual, family, and community-level benefits of vaccines will allow the public health community to make better-informed and more meaningful comparisons of the costs of vaccines in relation to their full benefits. Taking advantage of this opportunity will require enhanced data collection and the development of strategic planning tools for transparently assessing trade-offs among the myriad attributes of different vaccines in various social and economic contexts. PMID- 26022570 TI - Beyond adjuvants: Antagonizing inflammation to enhance vaccine immunity. AB - Since the development of the first vaccine over 200 years ago, vaccines have saved millions of lives and have become the most cost-effective modern medical intervention. However, over 70 years ago, Freund recognized that the effectiveness of the vaccine-induced immune responses could be vastly improved via the co-delivery of inflammation-induced agents, giving birth to the adjuvant field. Since the first description of adjuvants, revolutionary discoveries, including the discovery of dendritic cells and pattern recognition receptors, that drive remarkably different biological profiles, have opened the landscape of opportunities for the development of novel adjuvants able to trigger a remarkably diverse inflammatory profiles, thereby qualitatively and quantitatively skewing adaptive immunity in a tailored manner against target pathogens. However, mounting data point to a critical role for pre-existing inflammation as a predictor of vaccine responsiveness. Thus, in this review we will discuss novel opportunities by which pre-existing inflammation may be modulated, skewed, or tuned via next-generation vaccine approaches to enhanced vaccine-induced immunity in the elderly, immunocompromised, or subjects with chronic diseases. PMID- 26022571 TI - The narcolepsy-pandemic influenza story: can the truth ever be unraveled? AB - A safety signal around Pandemrix, an AS03 adjuvanted influenza A(H1N1) pdm09 vaccine potentially causing narcolepsy in children and adolescents became public in August 2010, long after cessation of the influenza A(H1N1) pdm09 campaigns in Europe. The signal originated from Finland and Sweden, two countries with school based pandemic vaccination campaigns, with high vaccine coverage, and vaccinations being provided at the peak of the circulating wild virus. Since the announcement awareness grew in Europe, with extensive public media dissemination and regulatory actions. This resulted in a steep increase in the spontaneous reports of exposed cases, a decrease in diagnostic lag times of this rare, underdiagnosed disease and finally victim compensation. The signaling countries conducted rapid risk assessment studies to quantify the signal to the best of their abilities, in the midst of the public awareness, most of which could not distinguish between a vaccine and an awareness effect. Due to the strong but variable associations from the epidemiological studies, the search for biological mechanisms started. Currently it is not yet understood how Pandemrix might cause narcolepsy, and whether it would be specific to Pandemrix. The paper describes the current evidence and puts forward the questions that remain to be answered, which are relevant for future pandemic preparedness when adjuvants may be used for dose sparing. PMID- 26022572 TI - The path forward. AB - For many decades the only adjuvants accepted in human licensed vaccines have been particulate substances such as alum and emulsions. These compounds have been identified empirically, based on their ability to enhance immune responses to vaccination in animals, without understanding their mechanism of action. Thanks to the increased knowledge of the innate immune system, many new adjuvants, designed around known Pattern Recognition Receptors (PRRs) including Toll-like receptors (TLRs) have been identified. A TLR4 agonist is part of a licensed vaccine and TLR9 ligands are in late stage clinical testing. Adjuvants targeting alternative PRRs have been validated in preclinical models. In the future we have to expect more sophisticated adjuvant formulations, including multiple PPR ligands combined with novel antigen delivery systems. In addition to traditional adjuvants, other innovative strategies improving vaccine immunity are emerging. Among them combinations of vaccines with cytokines, inhibitors of metabolic pathways, modulators of baseline inflammation levels, monoclonal antibodies targeting checkpoint inhibitors and compounds depleting of regulatory cells. The introduction of novel technologies has the potential to support the development of vaccines with increased efficacy targeting infections as well as non communicable diseases. However, the full potential of any novel vaccine strategy can be only captured if vaccination programs are implemented with sufficient coverage. New methods to fully capture the benefits of vaccination and appropriate communication strategies to increase vaccine acceptance by the public are two key elements that all stakeholders involved in the whole vaccine development cycle, including scientists, must consider very carefully. PMID- 26022574 TI - Oral involvement in patients with primary Sjogren's syndrome. Multidisciplinary care by dentists and rheumatologists. AB - Primary Sjogren's syndrome is a chronic systemic autoimmune disease that causes destruction of lacrimal and salivary glands. The most common and earliest symptoms are oral and ocular dryness. Dry mouth makes talking difficult, tasting and chewing properly, impairing quality of life of these patients. The most common oral signs and symptoms are hyposialia with or without xerostomia, tooth decay, fungal infections, traumatic oral lesions, dysphagia, dysgeusia, and inflammation of salivary glands. There are different therapeutic strategies, depending on the severity of each case, and the increase in the amount of saliva, to reduce the number of cavities and oral infections. It is particularly important to establish a close relationship between the dentist and the rheumatologist in order to make an early and correct diagnosis, promoting appropriate dietary and hygiene measures, as well as to treat and prevent potential oral complications. PMID- 26022575 TI - Unilateral lymphedema as first presentation of sarcoidosis. PMID- 26022573 TI - Single-cycle replicable Rift Valley fever virus mutants as safe vaccine candidates. AB - Rift Valley fever virus (RVFV) is an arbovirus circulating between ruminants and mosquitoes to maintain its enzootic cycle. Humans are infected with RVFV through mosquito bites or direct contact with materials of infected animals. The virus causes Rift Valley fever (RVF), which was first recognized in the Great Rift Valley of Kenya in 1931. RVF is characterized by a febrile illness resulting in a high rate of abortions in ruminants and an acute febrile illness, followed by fatal hemorrhagic fever and encephalitis in humans. Initially, the virus was restricted to the eastern region of Africa, but the disease has now spread to southern and western Africa, as well as outside of the African continent, e.g., Madagascar, Saudi Arabia and Yemen. There is a serious concern that the virus may spread to other areas, such as North America and Europe. As vaccination is an effective tool to control RVFV epidemics, formalin-inactivated vaccines and live attenuated RVFV vaccines have been used in endemic areas. The formalin inactivated vaccines require boosters for effective protection, whereas the live attenuated vaccines enable the induction of protective immunity by a single vaccination. However, the use of live-attenuated RVFV vaccines for large human populations having a varied health status is of concern, because of these vaccines' residual neuro-invasiveness and neurovirulence. Recently, novel vaccine candidates have been developed using replication-defective RVFV that can undergo only a single round of replication in infected cells. The single-cycle replicable RVFV does not cause systemic infection in immunized hosts, but enables the conferring of protective immunity. This review summarizes the properties of various RVFV vaccines and recent progress on the development of the single-cycle replicable RVFV vaccines. PMID- 26022576 TI - ZIRK-Technique: Zero Ischemia Resection in the Kidney for High-Risk Renal Masses: Perioperative Outcome. AB - OBJECTIVES: This study evaluates the feasibility and safety of open-partial nephrectomies in the ZIRK-technique (Zero Ischemia Resection in the Kidney) for renal masses with high-risk anatomical features--objectified by the PADUA score. METHODS: We identified 40 consecutive cases of partial nephrectomies performed without clamping of the renal artery in our department of urology. Retrospective analysis of the preoperative CT or MRI scans showed 27 cases with a PADUA score >=8, of which 15 cases had a score >=10. Cases were in particular assessed regarding operation time (ORT), estimated blood loss (EBL), surgical margins and postoperative complications using the Clavien classification. RESULTS: The mean age of the study population was 67.6 years with an average BMI of 26.8 kg/m2. The mean ORT was 1:46 with an average EBL of 521 ml. Clavien grade II complications were observed seven times, while 3 patients had a grade IIIa complication. Despite complex and adverse location of the tumors, nephron-sparing surgery without ischemia could be performed with negative surgical margins for all cases. EBL, transfusion rate and complication were considerably more frequent in high risk tumors. CONCLUSION: Highly complex renal tumors, PADUA >=10, can be resected in ZIRK-technique with good operative outcome and a low complication rate. PMID- 26022577 TI - Validation of a locked nucleic acid based wild-type blocking PCR for the detection of EGFR exon 18/19 mutations. AB - BACKGROUND: Treatment decisions in advanced non-small cell lung cancer rely on accurate analysis of the EGFR mutation status in small tissue samples. Sanger sequencing of PCR products is unbiased and cheap, but its detection threshold requiring 20 % infiltration by malignant cells is not optimal. Commercial kits, based on quantitative real-time PCR have better detection limits and can detect a wide spectrum of mutations but are considerably more expensive. METHODS: We developed a wild-type blocking PCR for EGFR G719A/S/C (exon 18), exon 19 deletions, and exon 20 insertions using locked nucleic acid (LNA) probes. The amplification products of positive reactions were analyzed by Sanger sequencing. We retrospectively validated this assay by comparison of the EGFR mutation status as obtained with Fragment Length Analysis and the Therascreen EGFR RGQ PCR kit. RESULTS: The EGFR mutation status for exon 18 and 19 as obtained with the LNA PCR/sequencing assay correlated adequately with the results obtained by the other independent methods. Due to the lack of structural consistency among the insertions in exon 20, the latter are less amenable for a LNA-PCR design. CONCLUSIONS: The LNA-PCR/sequencing assay presented here is specific, sensitive, and has a low detection threshold. In combination with allele-specific PCR reactions for T790M (exon 20) and L858R (exon 21), a wider scope of EGFR mutations can be assessed at a lower cost. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1272520418142748. PMID- 26022579 TI - BATF2 in human colorectal cancer. PMID- 26022578 TI - Microneedle characterisation: the need for universal acceptance criteria and GMP specifications when moving towards commercialisation. AB - With interest in microneedles as a novel drug transdermal delivery system increasing rapidly since the late 1990s (Margetts and Sawyer Contin Educ Anaesthesia Crit Care Pain. 7(5):171-76, 2007), a diverse range of microneedle systems have been fabricated with varying designs and dimensions. However, there are still very few commercially available microneedle products. One major issue regarding microneedle manufacture on an industrial scale is the lack of specific quality standards for this novel dosage form in the context of Good Manufacturing Practice (GMP). A range of mechanical characterisation tests and microneedle insertion analysis techniques are used by researchers working on microneedle systems to assess the safety and performance profiles of their various designs. The lack of standardised tests and equipment used to demonstrate microneedle mechanical properties and insertion capability makes it difficult to directly compare the in use performance of candidate systems. This review highlights the mechanical tests and insertion analytical techniques used by various groups to characterise microneedles. This in turn exposes the urgent need for consistency across the range of microneedle systems in order to promote innovation and the successful commercialisation of microneedle products. PMID- 26022580 TI - Prevalence and molecular characterization of rotaviruses as causes of nosocomial diarrhea in children. AB - Rotaviruses have been confirmed as causative agents of nosocomial gastroenteritis in children, but limited data exist concerning the epidemiology of nosocomial rotavirus gastroenteroentritis in Iran. The aim of this study was to determine the prevalence and molecular characteristics of rotavirus in children less than five years old with nosocomial diarrhea in Shahrekord (southwest of Iran).This cross-sectional study was conducted between December 2010 and October 2011. The study population consisted of children aged 6 to 60 months who were hospitalized in the pediatric ward of Hajar Hospital in Shahrekord, Iran, due to diseases other than diarrhea. Nosocomial diarrhea was defined as that occurring more than 48 hours after admission to the hospital for non-diarrheal causes. Rotavirus and G genotypes were determined by seminested reverse transcriptase polymerase chain reaction in 100 stool samples. In these 100 samples, the prevalence of rotavirus infection was 30%; the most common genotyes were G1 (20%) and G9 (20%). According to the findings of the study, genotyping of rotavirus is necessary to monitor changes in strain prevalence. Identifying strains over time could affect future vaccine strategies and detect any regional differences of genotype prevalence. PMID- 26022581 TI - Effects of seasonal variation and maternal clothing style on vitamin D levels of mothers and their infants. AB - In Turkey, vitamin D deficiency has been seen in children as well as in their mothers. We assessed the vitamin D status of 83 infants and their mothers, categorized into four groups according to season and mothers' clothing style. We measured serum levels of 25-hydroxy vitamin D, calcium, inorganic phosphorus and alkaline phosphatase in each mother-infant pair. In the summer, the rate of vitamin D deficiency was higher in mothers who wore clothing that covered nearly all of the body (55%) than in mothers whose clothing covered less of the body (13.6%) (p=0.016). In the winter, nearly half of both groups of mothers had vitamin D deficiency or insufficiency, and there were no significant differences based on their clothing style (p>0.05). In all groups of infants, vitamin D deficiency and insufficiency rates were found to be very low. It seems that 400 IU/daily vitamin D intake is adequate for infants in Turkey; for mothers, we propose vitamin D supplementation during the pregnancy and lactation period. PMID- 26022582 TI - Disease-modifying therapies in Chinese children with multiple sclerosis. AB - Limited data are available about the use of disease-modifying therapies (DMTs) in children with multiple sclerosis (MS). This study aimed to present our experience using DMTs in Chinese children with MS and provide additional evidence to consider treating these patients with cyclophosphamide. A retrospective chart review was conducted and data were obtained from 25 children with MS. Only three (12%) of these patients received and responded well to first-line interferon beta 1b therapy, while 10 (40%) chose cyclophosphamide and 12 (48%) refused to use DMTs. For the 10 patients being treated with cyclophosphamide, the median annualized relapse rate decreased from 3.0 to 1.0, and the median score on the Expanded Disability Status Scale decreased from 3.5 to 2.0. After 12 months of treatment, no gadolinium-enhancing lesions were reported in seven of the 10 patients. The use of DMTs plays an important role in the treatment of children with MS. If first-line therapies fail, cyclophosphamide may be a good option. PMID- 26022583 TI - Frequency of red cell allo- and autoimmunization in patients with transfusion dependent beta thalassemia and affecting factors. AB - In this study, we aimed to determine the frequency of red cell allo- and autoimmunization and analyze the factors responsible for the development of antibodies in patients with transfusion-dependent thalassemia. This crosssectional study was conducted on 139 patients with thalassemia major and intermedia who received leukodepleted RBC transfusions on a regular basis. Patients with a positive antibody screen were further tested for antibody identification by a gel method. Red cell alloantibodies were found in 9 (6.4%) patients, and autoantibodies were found in 17 (12.2%) patients. The most common alloantibodies detected were those against Rh and Kell antigen systems. The alloantibody development rate was higher in thalassemia intermedia patients, in Rh(-) patients, in patients with an initial transfusion age >2 years and in patients with a transfusion interval >3 weeks (p<0.05). The autoantibody development rate was found to be higher in adult and splenectomized patients (p<0.05). Data from this study demonstrate that the RBC antibody development rate is high in our region. RBC antigen phenotyping and crossmatching with Kell and Rh subgroups may reduce alloimmunization in chronically transfused beta-thalassemia patients. PMID- 26022584 TI - Prevalence of asthma among children in an industrial town. AB - Studies of the prevalence of asthma should be supported by objective markers. We aimed to measure the prevalence of childhood asthma in a particular area and age group using a questionnaire, and to compare the results with the rates of asthma diagnosed by objective measures. All students aged 13-14 (n=1511) in Kemalpasa, Izmir, were included in the study. Children whose responses on the ISAAC Phase-I Questionnaire revealed current wheezing were invited to the district health center. The prevalence of clinically proven asthma (current wheezing supported by objective markers) was investigated. The questionnaire was answered by 1373 (90.87%) students. Current wheezing was indicated in 428 children (31.0%), significantly more in girls than in boys (p<0.05). However, the prevalence of clinically proven asthma decreased by 42.5% when using objective markers. This study provided important epidemiologic information about the prevalence of asthma as indicated by questionnaires as opposed to that indicated by objective measures, especially in countries where the language lacks a word for "wheezing." PMID- 26022585 TI - Composition of parenteral nutrition solution affects the time of occurrence but not the incidence of cholestasis in surgical infants. AB - Parenteral nutrition-associated cholestasis (PNAC) is one of the most important complications of parenteral nutrition (PN). This study was conducted to define the incidence, characteristics and precipitating factors of PNAC in infants treated with two different PN regimens in the pediatric surgery department. The records of infants who received two different PN regimens during January 2000-May 2008 (Group 1) and June 2008-May 2012 (Group 2) were reviewed retrospectively. Patients with and without PNAC comprised the study (Groups 1a-2a) and control groups (Groups 1b-2b), respectively. With Group 1 (n=109) and Group 2 (n=46) constituted as indicated, Group 1a (n=13), Group 1b (n=32), Group 2a (n=6) and Group 2b (n=8) were evaluated. The incidence of PNAC was 14.1% (n=22), and the type of PN regimen did not affect the incidence (14.6% vs. 13.0%, p=0.39). The duration of PN was longer in Group 1a than in Group 1b (34 +/- 3 7 vs. 13 +/- 10 days, p=0.01), and longer in Group 2a than in Group 1a or Group 2b (146 +/- 148 vs. 34 +/- 37 days, p=0.02, and 14.0 +/- 5.9 days, p=0.002). PNAC developed later in Group 2a than in Group 1a (42.0 +/- 24.6 vs. 9.0 +/- 8.3 day, p=0.02). The lipid dosage was higher in Group 1a than in Group 1b (3.5 +/- 0.7 vs. 3.45 +/- 0.54 g/ kg/day, p=0.001) or Group 2a (2.2 +/- 0.4 g/kg/day, p=0.01). The lipid dosage was also higher in Group 2a than in Group 2b (p=0.001). Two different regimens resulted in similar PNAC rates. The composition of nutrients in PN solution affects the time of occurrence but not the duration of PNAC. PNAC should be detected as early as possible and treated promptly. PMID- 26022586 TI - Outcome of children with acute disseminated encephalomyelitis in a tertiary care center in India. AB - Acute disseminated encephalomyelitis (ADEM) is an immune-mediated disease of the brain that follows viral infection or vaccination, or even appears spontaneously. The objective of the study was to evaluate the clinical, neuroimaging and laboratory profiles of children with ADEM. Seventeen children admitted to the Pediatric Department of Dayanand Medical College and Hospital, Ludhiana, whose cases were consistent with the diagnosis of ADEM, were included. Their clinical and neuroimaging profiles and outcomes were studied. The most common presenting features were fever (71%), altered sensorium (59%) and headache and convulsions (41%). Brain MRI identified lesions in subcortical white matter (75%) and periventricular white matter (38%). Most patients were treated with corticosteroids. A favorable outcome was seen in 88% of patients. Although 59% of patients had neurologic sequelae at discharge, only one patient had a major neurological deficit at follow-up. Prognosis for survival and outcome was good in the majority of patients. Neurological sequelae at discharge do not predict poor outcome. PMID- 26022587 TI - Myeloperoxidase 463 G>A and superoxide dismutase Ala16Val gene polymorphisms in obese children. AB - The aim of the study was to determine the role of MnSOD Ala16Val and MPO G-463A gene polymorphisms in the pathogenesis of metabolic syndrome in obese children. A total of 97 obese children with insulin resistance and, as a control group, 96 healthy children were enrolled in the study. In the obese group, AA, AV and VV genotype frequencies of the MnSOD gene and GG, GA and AA genotype frequencies of the MPO gene were not significantly different from the frequencies found in the control group (p=0.555 and 0.530, respectively). In the obese group, children who carry both VV (for MnSOD) and GG (for MPO) alleles (n= 26) had higher HOMA-IR levels (6.51 +/- 3.91 vs 5.03 +/- 2.12) than those of all other genotype combinations (n=71) (p=0.013). Children who have the maximum risk of developing oxidative stress with the combination of the VV (for MnSOD) and GG (for MPO) genotypes had higher HOMA-IR levels, suggesting these polymorphisms may lead to insulin resistance. PMID- 26022589 TI - Comparison of familial and psychological factors in groups of encopresis patients with constipation and without constipation. AB - The study aimed to evaluate the differences between groups of encopresis patients with constipation and without constipation. The Symptom Checklist- 90-Revised, the COPE Questionnaire, the Relationship Scales Questionnaire, the McMaster Family Assessment Device and the Parenting Style Scale were used to evaluate, respectively, maternal psychiatric symptoms, coping abilities, attachment style, family functioning and children's perceptions of parenting behaviors. Psychiatric diagnoses were evaluated using the K-SADS. A higher level of maternal psychiatric symptoms, impaired role and affective involvement functioning of the family and less psychological autonomy were observed in the group of encopresis patients with constipation than in the group of encopresis patients without constipation. No significant differences were found between the groups in psychiatric comorbidities, maternal coping abilities and attachment style. The two groups had a similar pattern of comorbid psychiatric disorders and maternal psychological factors, although some familial factors-related mainly to parental authority-were differentiated in the encopresis with constipation group. PMID- 26022588 TI - Myopia, visual acuity and strabismus in the long term following treatment of retinopathy of prematurity. AB - The purpose of this retrospective study is to evaluate the long-term ophthalmological outcome in children with retinopathy of prematurity (ROP) who were treated for threshold disease with indirect laser photocoagulation. 107 eyes of 56 patients with threshold ROP treated with indirect laser photocoagulation and 202 eyes of 101 control patients with spontaneously regressed ROP were included. Fixation pattern, ocular motility findings, visual acuity, anterior segment examination, cycloplegic refraction and indirect ophthalmoscopic dilated fundus examination findings of all the included subjects were recorded. The incidence of unfavorable visual outcome defined as Snellen acuity of < 0.2, esotropia, strabismus surgery, nystagmus, myopia (>= -0.50 D) and astigmatism (>= 1.50 D) was significantly higher in the treated group than in the control group. These results indicate that premature babies with threshold ROP treated with indirect laser photocoagulation require frequent and long-term follow-up in order to determine refractive status and the presence of ocular motility disorders over time. PMID- 26022590 TI - Papaverine intoxication in a newborn: an unusual case report. AB - Herbal agents are increasingly used for medicinal purposes, but there is a lack of knowledge about the content of these agents. Indiscriminate use of herbal agents may cause severe side effects and also death. We report a newborn who developed convulsions and respiratory arrest after oral intake of an opium poppy preparation containing papaverine for its antitussive effect. The infant experienced a good outcome with supportive treatment. To the best of our knowledge, this is the first time a newborn with papaverine intoxication has been described. Parents should avoid self-medication of their children, and the possibility of exposure to foreign products should be kept in mind in any seizure of a newborn with unexplained origin. PMID- 26022591 TI - Neuroleptic malignant syndrome associated with metoclopramide in a child. AB - Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of treatment with antipsychotic medication. NMS has also been associated with non neuroleptic agents that block central dopamine pathways, such as metoclopramide, amoxapine and lithium. Metoclopromide has antidopaminergic properties and is a rare but well-recognized perpetrator in the development of NMS. NMS has a constellation of signs and symptoms, including hyperthermia, muscle rigidity, autonomic instability, tachycardia, tachypnea, diaphoresis, hypertension and altered mental status. We present a 2-year-old girl who developed neuroleptic malignant syndrome after metoclopromide therapy. High-dose metoclopromide was given to our patient, and it is very likely that she was dehydrated while using metoclopromide, as she developed NMS two hours after treatment. The patient was discharged on the sixth day after admission to our hospital, having been cured. In summary, NMS developed in this patient very soon after metoclopromide treatment. NMS is a life-threatening emergency; if not recognized, or left untreated, it may be fatal. Therefore, early recognition of the developing signs and symptoms, along with a thorough medical history, is of great importance. PMID- 26022592 TI - A preterm infant with intractable metabolic acidosis: a devastating presentation of Chryseobacterium meningosepticum meningitis. AB - Sepsis-related mortality and morbidity are the leading issues that neonatal intensive care units struggle with worldwide. We report a preterm infant with septic shock and intractable metabolic acidosis whose postmortem microbiologic examination revealed Chryseobacterium meningosepticum meningitis. We would like to alert clinicians about this uncommon sepsis agent, and to call into question the treatment modalities for metabolic acidosis. PMID- 26022593 TI - Jervell and Lange-Nielsen syndrome with homozygous missense mutation of the KCNQ1 gene. AB - Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive cardioauditory ion channel disorder characterized by congenital bilateral sensorineural deafness and long QT interval. JLNS is a ventricular repolarization abnormality and is caused by mutations in the KCNQ1 or KCNE1 gene. It has a high mortality rate in childhood due to ventricular tachyarrhythmias, episodes of torsade de pointes which may cause syncope or sudden cardiac death. Here, we present a 4.5-year-old female patient who had a history of syncope and congenital sensorineural deafness. She had a cochlear implant operation at 15 months of age and received an implantable cardioverter defibrillator (ICD) at 3 years of age because of recurrent syncope attacks. Five months after cochlear implant placement, she could say her first words and is now able to speak. With beta blocker therapy and ICD, she has remained syncope-free for a year. On the current admission, the family visited the genetics department to learn about the possibility of prenatal diagnosis of sensorineural deafness, as the mother was 9 weeks pregnant. A diagnosis of JLNS was established for the first time, and a homozygous missense mutation in the KCNQ1 gene (c.128 G>A, p.R243H) was detected. Heterozygous mutations of KCNQ1 were identified in both parents, thereby allowing future prenatal diagnoses. The family obtained prenatal diagnosis for the current pregnancy, and fetal KCNQ1 analysis revealed the same homozygous mutation. The pregnancy was terminated at the 12th week of gestation. The case presented here is the third molecularly confirmed Turkish JLNS case; it emphasizes the importance of timely genetic diagnosis, which allows appropriate genetic counseling and prenatal diagnosis, as well as proper management of the condition. PMID- 26022594 TI - Bilateral congenital cataracts in an infant with Klinefelter syndrome. AB - Congenital cataract is one of the most treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of approximately 2.5:10,000 infants under the age of 1 year. Congenital cataract can be observed with certain chromosomal abnormalities, such as trisomies, deletions, translocations and Turner syndrome. In Klinefelter syndrome, however, ocular complications and cataract are not commonly encountered, so reports in the literature are very rare. In this manuscript, we present a 3-month-old male infant who had congenital cataracts. Chromosomal analysis revealed that his karyotype was 47,XXY. He did not show any of the main clinical signs of Klinefelter syndrome because of his very young age. To the best of our knowledge, our patient is only the second-ever case reported in the literature in which congenital cataracts have been found in an infant with a nonmosaic 47,XXY karyotype. The aim of the present report is to both describe the ocular abnormalities that can sometimes be found in Klinefelter syndrome and to emphasize the importance of performing a karyotype analysis in order to rule out chromosome abnormalities in patients with congenital cataracts. PMID- 26022595 TI - Internal herniation through the falciform ligament: an unusual cause of intestinal obstruction. AB - The most common cause of intestinal obstruction in children is postsurgical adhesions. Internal herniation through the falciform ligament is very rare, but frequently causes small bowel obstruction when it occurs. To the best of our knowledge, this is the first case report regarding large bowel obstruction associated with midgut malrotation through the falciform ligament in a child. PMID- 26022596 TI - A case of anorexia nervosa with multiple medical complications. AB - Anorexia nervosa (AN) is a potentially life-threatening eating disorder characterized by an intense fear of gaining weight and a distorted body image. Although AN is a psychiatric illness, it is also very important from a pediatric perspective, as it can cause major medical complications in every organ system in the growing and developing body. The medical complications of anorexia nervosa may endanger the patient in several ways, and the severity of medical complications may be underestimated. Pediatricians should be aware of the possibility of medical complications in adolescent patients who have an eating disorder and understand that, if not managed correctly, such complications may be fatal. This case report describes the vast number of medical complications that can be observed in an adolescent due to an eating disorder. PMID- 26022597 TI - Traumatic multiple lower cranial nerve palsy: a case report and review of the literature. AB - Lower cranial nerve palsy, also known as Collet-Sicard syndrome, is a fairly rare pathology characterized by unilateral palsy of the IX-X-XI-XII cranial nerves. We report a multiple cranial nerve palsy developing after a head trauma that might have been considered negligible. A 16-year-old boy was admitted with swallowing and articulation problems and difficulty lifting one shoulder after a head trauma suffered during a football match. No pathology was revealed in the subsequent imaging. Cranial nerve palsies due to head trauma are very rare. Awareness of the possibility of such a condition, leading to early recognition and treatment, may result in significant functional recovery. PMID- 26022598 TI - Fibrodysplasia ossificans progressiva: a case report. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling, autosomal dominant disease characterized by recurrent painful episodes of soft tissue swelling and the development of heterotopic ossification. The main target is the axial musculature, but eventually ectopic bone formation occurs in the ligaments, the fascia, the tendons and the joint capsules. Small soft tissue traumas and intramuscular injections exacerbate this extraskeletal bone formation. We present a 16-year-old male patient who has osseous lesions beginning from the left ramus mandible and extending along the sternocleidomastoid muscle, vertebral region and deltoid, with visible restriction in temporomandibuler joint movement. Surgery was not performed due to parental concerns. Unfortunately, no effective medical therapy for FOP is known. These patients may require extra care during some oral surgery and anesthetic procedures. In this report, the importance of the decision to perform surgery has been stressed. PMID- 26022599 TI - Mycosis fungoides mimicking nevoid hyperkeratosis of the nipple and areola in an adolescent. AB - Mycosis fungoides is one of the great imitators in dermatology; it can mimic many dermatoses. Nevoid hyperkeratosis of the nipple and areola is a rare idiopathic disease with typical clinical features of verrucous thickening and brownish discoloration of the nipple, areola or both. Here, a 16-year-old male patient with mycosis fungoides mimicking nevoid hyperkeratosis of the nipple and areola has been reported. To our knowledge, this is the first atypical MF patient to have presented with a NHNA-like lesion. Although the clinical appearance of nevoid hyperkeratosis of the nipple and areola is highly characteristic for diagnosis, histopathological examination is recommended, especially in cases with atypical features such as unexpected age, male gender and unilateral location. PMID- 26022600 TI - The influence of IgM-enriched immunoglobulin therapy on neonatal mortality and hematological variables in newborn infants with blood culture-proven sepsis. PMID- 26022601 TI - Reply: To PMID 25341598. PMID- 26022603 TI - Spring frost vulnerability of sweet cherries under controlled conditions. AB - Spring frost is a significant production hazard in nearly all temperate fruit growing regions. Sweet cherries are among the first fruit varieties starting their development in spring and therefore highly susceptible to late frost. Temperatures at which injuries are likely to occur are widely published, but their origin and determination methods are not well documented. In this study, a standardized method was used to investigate critical frost temperatures for the sweet cherry cultivar 'Summit' under controlled conditions. Twigs were sampled at four development stages ("side green," "green tip," "open cluster," "full bloom") and subjected to three frost temperatures (-2.5, -5.0, -10.0 degrees C). The main advantage of this method, compared to other approaches, was that the exposition period and the time interval required to reach the target temperature were always constant (2 h). Furthermore, then, the twigs were placed in a climate chamber until full bloom, before the examination of the flowers and not further developed buds started. For the first two sampling stages (side green, green tip), the number of buds found in open cluster, "first white," and full bloom at the evaluation date decreased with the strength of the frost treatment. The flower organs showed different levels of cold hardiness and became more vulnerable in more advanced development stages. In this paper, we developed four empirical functions which allow calculating possible frost damages on sweet cherry buds or flowers at the investigated development stages. These equations can help farmers to estimate possible frost damages on cherry buds due to frost events. However, it is necessary to validate the critical temperatures obtained in laboratory with some field observations. PMID- 26022602 TI - Characterization of Apoptosis Signaling Cascades During the Differentiation Process of Human Neural ReNcell VM Progenitor Cells In Vitro. AB - Apoptosis is an essential physiological process accompanying the development of the central nervous system and human neurogenesis. However, the time scale and the underlying molecular mechanisms are yet poorly understood. Due to this fact, we investigated the functionality and general inducibility of apoptosis in the human neural ReNcell VM progenitor cell line during differentiation and also after exposure to staurosporine (STS) and ultraviolet B (UVB) irradiation. Transmission light microscopy, flow cytometry, and Western-/Immunoblot analysis were performed to compare proliferating and differentiating, in addition to STS- and UVB-treated cells. In particular, from 24 to 72 h post-initiation of differentiation, G0/G1 cell cycle arrest, increased loss of apoptotic cells, activation of pro-apoptotic BAX, Caspase-3, and cleavage of its substrate PARP were observed during cell differentiation and, to a higher extent, after treatment with STS and UVB. We conclude that redundant or defective cells are eliminated by apoptosis, while otherwise fully differentiated cells were less responsive to apoptosis induction by STS than proliferating cells, likely as a result of reduced APAF-1 expression, and increased levels of BCL-2. These data provide the evidence that apoptotic mechanisms in the neural ReNcell VM progenitor cell line are not only functional, but also inducible by external stimuli like growth factor withdrawal or treatment with STS and UVB, which marks this cell line as a suitable model to investigate apoptosis signaling pathways in respect to the differentiation processes of human neural progenitor cells in vitro. PMID- 26022604 TI - [Noninvasive diagnostic imaging in dermatology]. PMID- 26022605 TI - Is Drinking with Parents Associated with High-Risk Drinking among Adolescents? AB - BACKGROUND/AIMS: What are the implications of drinking with parents (DWP) on adolescents' drinking behavior? We expanded the meagre body of research on this controversial issue by assessing the association between the frequency of DWP and adolescent high-risk drinking, taking a number of parental factors into account. METHOD: Data stemmed from a subsample of 14-17-year-old current drinkers (n = 7,616) who participated in a cross-sectional Norwegian school survey (response rate: 84%). RESULTS: One in four reported DWP during the past year. The higher the frequency of DWP, the higher was the prevalence of high-risk drinking. Parental drunkenness, permissive alcohol-related parenting, and indicators of suboptimal parenting more generally also correlated with DWP. After controlling for these confounders, only frequent DWP remained significantly associated with high-risk drinking. CONCLUSIONS: DWP was related to adolescent high-risk drinking, yet the association was in part attributable to parents' drinking and parenting style. The risk of involvement in high-risk drinking was about the same for adolescents reporting no DWP and infrequent DWP, while it was significantly elevated among those reporting frequent DWP. This study thus demonstrated that the frequency of DWP matters and that parents who drink with their adolescent children differ from other parents in important ways. PMID- 26022606 TI - TGFbeta Induces a Pro-Bone Metastasis Program in Prostate Cancer. AB - PMEPA1 is induced by TGFbeta and inhibits TGFbeta signaling to suppress prostate cancer bone metastasis. PMID- 26022607 TI - FCgammaRIIIA and FCgammaRIIA Engagement Mediates Antitumor Cellular Immunity. AB - FcgammaRIIIA on macrophages and FcgammaRIIA on dendritic cells mediate ADCC and vaccinal effects, respectively. PMID- 26022608 TI - Domain-Focused CRISPR Screening Identifies Potential Drug Targets. AB - Targeting protein domain-encoding exons in CRISPR-Cas9 screens can reveal genetic dependencies. PMID- 26022609 TI - Marrow-Infiltrating Lymphocytes Are Effective in Multiple Myeloma. AB - Adoptive transfer of activated marrow-infiltrating lymphocytes (MIL) induces anti myeloma immunity. PMID- 26022610 TI - MET Promotes Antitumor Neutrophil Recruitment and Cytotoxicity. AB - MET is critical for antitumor neutrophil infiltration to HGF-secreting tumors and inflammatory sites. PMID- 26022611 TI - Similar performance of Brasfield and Wisconsin scoring systems in young children with cystic fibrosis. AB - BACKGROUND: To assess the severity of lung disease in cystic fibrosis (CF), scoring systems based on chest radiographs (CXRs), CT and MRI have been used extensively, although primarily in research settings rather than for clinical purposes. It has recently been shown that those based on CXRs (primarily the Brasfield and Wisconsin systems) are as sensitive and valid as those based on CT. The reproducibility and correlation of both systems to pulmonary function tests (PFTs) were recently investigated and were found to be statistically identical. However, the relative performance of these systems has not been specifically assessed in children younger than 5 years old with mild lung disease, a critical age range in which PFTs is rarely performed. OBJECTIVE: To investigate and compare the performance of the Brasfield and Wisconsin systems in children 0-5 years old with predominantly mild lung disease. MATERIALS AND METHODS: Fifty-five patients 0-5 years old with 105 CXRs were included in the study. Given that the goal was to compare system performance in mild disease, only the first two CXRs from each patient were included (all but five patients had two images). When only one image was available in the target age range, it only was included. Agreement between the Brasfield and Wisconsin systems was assessed using a 2X2 contingency table assuming binary classification of CF lung disease using CXR scoring systems (mild vs. non-mild). In the absence of PFTs or another external gold standard for comparison, the Wisconsin system was used as an arbitrary gold standard against which the Brasfield was compared. Correlation between the two systems was assessed via a concordance correlation coefficient (CCC) for repeated measures. RESULTS: Scores were rated as mild or non-mild based on published numerical cutoffs for each system. The systems agreed on 89/105 (85%) and disagreed on 16/105 (15%) of the CXRs. Agreement between the two systems was statistically significant (P < 0.001). Relative sensitivity and specificity of the Brasfield system (which since using the Wisconsin as the gold standard reflects relative agreement rather than absolute performance of the Brasfield) was also fairly high (85% and 84%, respectively). Relatively high correlation between the two systems was also estimated (r = 0.72). CONCLUSION: The current study, powered to find at least a mild correlation between the two systems, confirms the Brasfield and Wisconsin systems are in agreement when assessing CF lung disease even in patients younger than 5 years of age with predominantly mild disease. PMID- 26022612 TI - Incidence of Adverse Events during Continuous Renal Replacement Therapy. AB - BACKGROUND/AIMS: The incidence of adverse events (AEs) in adults who receive continuous renal replacement therapy (CRRT) is unknown. We report the incidence of mechanical, metabolic, and hemodynamic CRRT AEs. METHODS: This is a retrospective study of all consecutive adult patients (>=18 years) who underwent CRRT from January 1, 2007 to December 31, 2009. RESULTS: Out of 595 patients who underwent CRRT, 366 (62%) were male and 500 (84%) were Caucasian. Regional citrate anticoagulation was used in 98.6% of all patients. The most common clinically significant electrolyte derangements were ionized hypocalcemia (22%), ionized hypercalcemia (23%), and hyperphosphatemia (44%). Almost all (97%) patients had at least one additional AE including new onset hypotension (within the first hour after CRRT initiation) (43%), hypothermia (44%), new onset arrhythmias (29%), new onset anemia (31%) and thrombocytopenia (40%). CONCLUSIONS: ICU patients who require CRRT have a high incidence of AEs. Although the extent to which these complications are attributable to CRRT is not known, clinicians need to be cautious and aware of their high prevalence in this patient population. PMID- 26022613 TI - Exceptionally long 5' UTR short tandem repeats specifically linked to primates. AB - We have previously reported genome-scale short tandem repeats (STRs) in the core promoter interval (i.e. -120 to +1 to the transcription start site) of protein coding genes that have evolved identically in primates vs. non-primates. Those STRs may function as evolutionary switch codes for primate speciation. In the current study, we used the Ensembl database to analyze the 5' untranslated region (5' UTR) between +1 and +60 of the transcription start site of the entire human protein-coding genes annotated in the GeneCards database, in order to identify "exceptionally long" STRs (>=5-repeats), which may be of selective/adaptive advantage. The importance of this critical interval is its function as core promoter, and its effect on transcription and translation. In order to minimize ascertainment bias, we analyzed the evolutionary status of the human 5' UTR STRs of >=5-repeats in several species encompassing six major orders and superorders across mammals, including primates, rodents, Scandentia, Laurasiatheria, Afrotheria, and Xenarthra. We introduce primate-specific STRs, and STRs which have expanded from mouse to primates. Identical co-occurrence of the identified STRs of rare average frequency between 0.006 and 0.0001 in primates supports a role for those motifs in processes that diverged primates from other mammals, such as neuronal differentiation (e.g. APOD and FGF4), and craniofacial development (e.g. FILIP1L). A number of the identified STRs of >=5-repeats may be human-specific (e.g. ZMYM3 and DAZAP1). Future work is warranted to examine the importance of the listed genes in primate/human evolution, development, and disease. PMID- 26022614 TI - Kinetics of intramolecular chemical exchange by initial growth rates of spin saturation transfer difference experiments (SSTD NMR). AB - We report here the Initial Growth Rates SSTD NMR method, as a new powerful tool to obtain the kinetic parameters of intramolecular chemical exchange in challenging small organic and organometallic molecules. PMID- 26022615 TI - A micro-patterned silicon chip as sample holder for macromolecular crystallography experiments with minimal background scattering. AB - At low emittance synchrotron sources it has become possible to perform structure determinations from the measurement of multiple microcrystals which were previously considered too small for diffraction experiments. Conventional mounting techniques do not fulfill the requirements of these new experiments. They significantly contribute to background scattering and it is difficult to locate the crystals, making them incompatible with automated serial crystallography. We have developed a micro-fabricated sample holder from single crystalline silicon with micropores, which carries up to thousands of crystals and significantly reduces the background scattering level. For loading, the suspended microcrystals are pipetted onto the chip and excess mother liquor is subsequently soaked off through the micropores. Crystals larger than the pore size are retained and arrange themselves according to the micropore pattern. Using our chip we were able to collect 1.5 A high resolution diffraction data from protein microcrystals with sizes of 4 micrometers and smaller. PMID- 26022616 TI - Moire Nanosphere Lithography. AB - We have developed moire nanosphere lithography (M-NSL), which incorporates in plane rotation between neighboring monolayers, to extend the patterning capability of conventional nanosphere lithography (NSL). NSL, which uses self assembled layers of monodisperse micro/nanospheres as masks, is a low-cost, scalable nanofabrication technique and has been widely employed to fabricate various nanoparticle arrays. Combination with dry etching and/or angled deposition has greatly enriched the family of nanoparticles NSL can yield. In this work, we introduce a variant of this technique, which uses sequential stacking of polystyrene nanosphere monolayers to form a bilayer crystal instead of conventional spontaneous self-assembly. Sequential stacking leads to the formation of moire patterns other than the usually observed thermodynamically stable configurations. Subsequent O2 plasma etching results in a variety of complex nanostructures. Using the etched moire patterns as masks, we have fabricated complementary gold nanostructures and studied their optical properties. We believe this facile technique provides a strategy to fabricate complex nanostructures or metasurfaces. PMID- 26022617 TI - A Shortage of Medical Residency Positions: Parallels with Psychology. AB - Physician shortages in the US are expected to intensify with the implementation of the Patient Protection and Affordable Care Act. These shortages may negatively impact access to care, quality of care, and confidence in the system's ability to adequately provide for health needs in the US. Concerns regarding physician demand underscore how critical Graduate Medical Education funding is to preparing the physician workforce. In 2014 5.6 % of US medical school seniors did not match into residency. Psychology has faced longstanding training imbalance issues with a misalignment between the number of internship positions and the number of applicants. The authors summon attention to the damaging effects a training imbalance poses to a health care profession, its trainees, and ultimately the public it serves. PMID- 26022618 TI - The origin of the anomeric effect: probing the impacts of stereoelectronic interactions. AB - To gain further insight on the origin of the anomeric effect [stabilization energies associated with electron delocalization (SE), electrostatic models associated with the dipole-dipole interactions (EM) and Pauli exchange-type repulsions (PETR)], the correlations between SE, EM, PETR, bond-orders, donor and acceptor orbital energies and occupancies, structural parameters and configurational behavior of 2,3-difluoro-1,4-oxathiane (1), 2,3-dichloro-1,4 oxathiane (2), and 2,3-dibromo-1,4-oxathiane (3) as well as 2,5-difluoro-1,4 oxathiane (4), 2,5-dichloro-1,4-oxathiane (5), and 2,5-dibromo-1,4-oxathiane (6) were investigated by means of the complete basis set (CBS-4), hybrid density functional theory method (B3LYP/6-311+G**) and natural bond orbital (NBO) interpretations. The differences in the total energies among four possible configurations of compounds 1-6 do not correlate with the differences in their corresponding SE, EM or PETR values but can be controlled by their cooperative or uncooperative impacts. The results obtained showed that the SE has a determining impact on the structural properties of compounds 1-6 but fails to account solely for the variations of the energy differences between the configurations in compounds 1-6. The SE and PETR components are in favor of the (ax,ax) forms (the most stable configuration) going from compound 1 to compound 3 but the EM has the opposite impact; therefore, these factors have counterintuitive impacts on the configurational properties of compounds 1-3. Because there are no significant dipole moment values for the (ax,ax) and (eq,eq) forms of compounds 4-6, the energy differences between these forms can result from the conflict between the SE and PETR components. Therefore, the conclusions published previously in the literature about the origin of the anomeric effect should be reexamined. PMID- 26022619 TI - A study of the effects of prenatal alcohol exposure on white matter microstructural integrity at birth. AB - BACKGROUND: Neuroimaging studies have indicated that prenatal alcohol exposure is associated with alterations in the structure of specific brain regions in children. However, the temporal and regional specificity of such changes and their behavioural consequences are less known. Here we explore the integrity of regional white matter microstructure in infants with in utero exposure to alcohol, shortly after birth. METHODS: Twenty-eight alcohol-exposed and 28 healthy unexposed infants were imaged using diffusion tensor imaging sequences to evaluate white matter integrity using validated tract-based spatial statistics analysis methods. Second, diffusion values were extracted for group comparisons by regions of interest. Differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity were compared between groups and associations with measures from the Dubowitz neonatal neurobehavioural assessment were examined. RESULTS: Lower AD values (p<0.05) were observed in alcohol-exposed infants in the right superior longitudinal fasciculus compared with non-exposed infants. Altered FA and MD values in alcohol-exposed neonates in the right inferior cerebellar were associated with abnormal neonatal neurobehaviour. CONCLUSION: These exploratory data suggest that prenatal alcohol exposure is associated with reduced white matter microstructural integrity even early in the neonatal period. The association with clinical measures reinforces the likely clinical significance of this finding. The location of the findings is remarkably consistent with previously reported studies of white matter structural deficits in older children with a diagnosis of foetal alcohol spectrum disorders. PMID- 26022621 TI - Does it mean anything to diagnose fibromyalgia (FM) in somebody with chronic widespread pain? PMID- 26022620 TI - A cross-sectional study of autoantibody profiles in the Waikato systemic sclerosis cohort, New Zealand. AB - The autoantibody profiles in New Zealand systemic sclerosis patients have not previously been reported. The aim of this study was to evaluate the autoantibody profiles of patients in the Waikato Hospital Systemic Sclerosis Clinic cohort. The EUROLINE (IgG) Systemic Sclerosis panel test kit (which tests for Scl-70, CENP-A, CENP-B, RP11, RP155, Fib, NOR90, Th/To, PM100, PM75, Ku, PDGFR and Ro-52) was selected for the purpose of this study. All patients attending the Waikato Hospital Systemic Sclerosis clinic were invited to participate. These patients were categorised by systemic sclerosis subtypes [1]. Results were compared with previously published data, including the EUSTAR database. Sixty patients (56 female) were recruited, with a median age of 61 years (range 29-81 years). Forty one had limited cutaneous systemic sclerosis (lcSSc). Of these lcSSc patients, 31 (75.6%) were positive for CENP-A and CENP-B (anti-centromere) antibodies, 12 (29.3%) for Ro-52 antibodies, 5 (12.2%) for RP11 and RP155, 4 (9.8%) for Scl-70 and 1 (2.4%) each for anti-Fib and Th/To antibodies. Fifteen patients had diffuse cutaneous systemic sclerosis (dcSSc), of which 7 patients (47.6%) were positive for RP11 and RP155, 4 (26.7%) for Scl-70. Three dcSSc patients did not have either of these two major antibodies, but of these 15 dcSSc patients, 4 patients (26.7%) were positive also for Ro-52, 2 (13.3%) for anti-Ku, and 1 (6.7%) each for anti-Fib and NOR90. Four patients had overlap syndrome (OLS), 1 had CENP-A and CENP-B antibodies, 1 had Ro-52 autoantibodies 1 had anti-Ku antibodies. Three patients had no autoantibodies. This is the first study to look at the autoantibody profile of SSc patients in New Zealand. A higher prevalence of antibodies against centromere and RNA polymerase III was demonstrated in our group compared with the EUSTAR database suggesting that antibody prevalence may vary geographically. PMID- 26022622 TI - The road to mitochondrial gene transfer: follow the middle lane. PMID- 26022625 TI - Genome editing of the germline: broadening the discussion. AB - Genome editing that results in humans with precisely modified germ cells may never become practical. Nonetheless, the implications are great enough that we strongly support the idea of starting the conversation now, providing time for a broad consensus to be developed. We are confident that if diverse voices are heard, a consensus can be reached on a strategy in which societal mores are respected, the desires of parents are integrated, and the health of future generations is maximized. PMID- 26022626 TI - Arresting the colonial destiny of metastatic seeds with DNA aptamers. PMID- 26022627 TI - RNA mimics as therapeutics for cardiac regeneration: a paradigm shift. PMID- 26022628 TI - Landing Preference and Reproduction of Rhopalosiphum padi (Hemiptera: Aphididae) in the Laboratory on Three Maize, Potato, and Wheat Cultivars. AB - The bird cherry-oat aphid Rhopalosiphum padi (L.) transmits the nonpersistent Potato virus Y (PVY) to seed potatoes. Planting a nonvirus host plant around the main crop can reduce PVY incidence, because aphids tend to land in high numbers at the edge of a field and the crop border acts as a virus sink. This study determined R. padi landing and settling preferences and reproductive rates on three cultivars each of maize and wheat compared with potato in the laboratory as a basis for identifying an attractive crop border plant. Aphids were reared on maize and wheat to control for bias due to previous experience. Irrespective of origin, alates preferred to land almost exclusively on maize and wheat rather than on potato cultivars in choice experiments. Aphid settling on the maize and wheat cultivars depended on aphid origin. In no-choice experiments, R. padi produced the highest number of offspring on the wheat cultivars, irrespective of origin. Plant nitrogen content and trichome density did not influence R. padi reproduction. The study demonstrates that host plant preference of aphids may vary between plant cultivars and can therefore influence the effectiveness of a crop border. The high landing rate but low reproduction suggest that maize cultivars '6Q-121' and '78-15B' could be suitable crop border plants in regions where R. padi is abundant. Before testing potential crop border plants in the field, cultivars should be screened using aphid landing, settling and reproduction as selection criteria. PMID- 26022629 TI - Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor AIP induced antinociception in rats with mononeuropathy. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine- dependent protein kinase, which has been implicated in pain modulation at different levels of the central nervous system. The present study was performed in rats with mononeuropathy induced by left common sciatic nerve ligation. Unilateral sciatic nerve loose ligation produced decreases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation. Intra nucleus accumbens (NAc) injection of 3 MUg, 6 MUg and 12 MUg of myristoylated autocamtide-2-inhibitory peptide (AIP), the CaMKII inhibitor, dose-dependently increased the HWL to noxious thermal and mechanical stimulation in rats with mononeuropathy. Furthermore, intra-NAc administration of morphine, the HWL to noxious thermal and mechanical stimulation increased markedly, and there were no significant differences between morphine group and AIP group. Taken together, the results showed that intra-NAc injection of AIP induced significant antinociceptive effects in rats with mononeuropathy, indicating that CaMKII may play an important role in the transmission and/or modulation of nociceptive information in the NAc in rats with mononeuropathy. PMID- 26022630 TI - Blockade of D1-like dopamine receptors within the ventral tegmental area and nucleus accumbens attenuates antinociceptive responses induced by chemical stimulation of the lateral hypothalamus. AB - It was established that stimulation of the lateral hypothalamus (LH) can induce antinociception. Previous studies showed a role for the ventral tegmental area (VTA) and nucleus accumbens (NAc) in antinociception induced by LH stimulation through the orexinergic system. In this study, we tried to assess the involvement of dopamine D1-like receptors within the VTA and NAc in the LH stimulation induced antinociception. Male Wistar rats were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA or intra accumbal infusion of SCH-23390, as a D1-like dopamine receptor antagonist (0.125, 0.25, 1 and 4 MUg/rat), 2 min before intra-LH administration of carbachol (125 nM/rat). The antinociceptive effects of SCH-23390 were measured by using a tail flick analgesiometer and represented as maximal possible effect (%MPE). Results showed that intra-VTA and/or accumbal administration of SCH-23390 could prevent carbachol-induced antinociception. These findings revealed that D1-like dopamine receptors within the VTA and NAc play an important role in antinociceptive effect induced by chemical stimulation of the LH. PMID- 26022631 TI - Inter- and Intra-Rater Reliability of the Visual Vertical in Subacute Stroke. AB - BACKGROUND AND PURPOSE: Visual vertical (VV) has been used increasingly as a routine clinical assessment to identify alteration of verticality perception as a possible cause of postural disorders after stroke. This study aims to determine whether the reliability of VV is sufficient to support a wide clinical use in neurorehabilitation for monitoring of patients with stroke. METHODS: Twenty patients with subacute stroke in neurorehabilitation unit were tested after a first and unique hemispheric stroke. To evaluate the inter-rater reliability, VV was assessed the same day by 2 examiners whose degrees of expertise differed. The second examiner repeated the test the next day to investigate intrarater reliability. VV orientation (mean, primary criterion) and uncertainty (SD, secondary criterion) were calculated for 10 trials. Their reliability was quantified by the intraclass correlation coefficient, Bland-Altman plots, and the minimal detectable change. The concordance between 2 examiners was quantified by Cohen's kappa coefficients (kappa). RESULTS: About VV orientation, inter- and intrarater reliability were excellent (intraclass correlation coefficient, 0.979 and 0.982). The Bland-Altman plots and the minimal detectable change revealed a difference inferior to 2 degrees between 2 tests. The concordance between 2 assessments for the diagnosis of abnormal VV orientation was absolute for the same examiner (kappa=1; P<0.05) and excellent between 2 examiners (kappa=0.92; P<0.05). As for VV uncertainty the intrarater reliability was satisfactory (intraclass correlation coefficient, 0.836) but the inter-rater reliability was poor (intraclass correlation coefficient, 0.211). CONCLUSIONS: The orientation of the VV is a highly reliable criterion, which may be used both in research and in routine clinical practice. PMID- 26022632 TI - Serum Soluble Corin is Decreased in Stroke. AB - BACKGROUND AND PURPOSE: Soluble corin was decreased in coronary heart disease. Given the connections between cardiac dysfunction and stroke, circulating corin might be a candidate marker of stroke risk. However, the association between circulating corin and stroke has not yet been studied in humans. Here, we aimed to examine the association in patients wtith stroke and community-based healthy controls. METHODS: Four hundred eighty-one patients with ischemic stroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls were studied. Serum soluble corin and some conventional risk factors of stroke were examined. Because circulating corin was reported to be varied between men and women, the association between serum soluble corin and stroke was evaluated in men and women, respectively. RESULTS: Patients with ischemic and hemorrhagic stroke had a significantly lower level of serum soluble corin than healthy controls in men and women (all P values, <0.05). In multivariate analysis, men in the lowest quartile of serum soluble corin were more likely to have ischemic (odds ratio [OR], 4.90; 95% confidence interval, 2.99-8.03) and hemorrhagic (OR, 17.57; 95% confidence interval, 4.85-63.71) stroke than men in the highest quartile. Women in the lowest quartile of serum soluble corin were also more likely to have ischemic (OR, 3.10; 95% confidence interval, 1.76-5.44) and hemorrhagic (OR, 8.54; 95% confidence interval, 2.35-31.02) stroke than women in the highest quartile. ORs of ischemic and hemorrhagic stroke were significantly increased with the decreasing levels of serum soluble corin in men and women (all P values for trend, <0.001). CONCLUSIONS: Serum soluble corin was decreased in patients with stroke compared with healthy controls. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke. PMID- 26022633 TI - Response to Letter Regarding Article, "Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke". PMID- 26022635 TI - Heart of the Matter. PMID- 26022634 TI - Different Imaging Strategies in Patients With Possible Basilar Artery Occlusion: Cost-Effectiveness Analysis. AB - BACKGROUND AND PURPOSE: This study evaluated the cost-effectiveness of different noninvasive imaging strategies in patients with possible basilar artery occlusion. METHODS: A Markov decision analytic model was used to evaluate long term outcomes resulting from strategies using computed tomographic angiography (CTA), magnetic resonance imaging, nonenhanced CT, or duplex ultrasound with intravenous (IV) thrombolysis being administered after positive findings. The analysis was performed from the societal perspective based on US recommendations. Input parameters were derived from the literature. Costs were obtained from United States costing sources and published literature. Outcomes were lifetime costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and net monetary benefits, with a willingness-to-pay threshold of $80,000 per QALY. The strategy with the highest net monetary benefit was considered the most cost-effective. Extensive deterministic and probabilistic sensitivity analyses were performed to explore the effect of varying parameter values. RESULTS: In the reference case analysis, CTA dominated all other imaging strategies. CTA yielded 0.02 QALYs more than magnetic resonance imaging and 0.04 QALYs more than duplex ultrasound followed by CTA. At a willingness-to-pay threshold of $80,000 per QALY, CTA yielded the highest net monetary benefits. The probability that CTA is cost-effective was 96% at a willingness-to-pay threshold of $80,000/QALY. Sensitivity analyses showed that duplex ultrasound was cost effective only for a prior probability of <=0.02 and that these results were only minimally influenced by duplex ultrasound sensitivity and specificity. Nonenhanced CT and magnetic resonance imaging never became the most cost effective strategy. CONCLUSIONS: Our results suggest that CTA in patients with possible basilar artery occlusion is cost-effective. PMID- 26022636 TI - Effect of Blood Pressure Lowering in Early Ischemic Stroke: Meta-Analysis. AB - BACKGROUND AND PURPOSE: Elevated blood pressure is common in acute stage of ischemic stroke and the strategy to manage this situation is not well established. We therefore conducted a meta-analysis of randomized controlled trials comparing active blood pressure lowering and control groups in early ischemic stroke. METHODS: Pubmed, EMBASE, and Clinicaltrials.gov from January 1966 to March 2015 were searched to identify relevant studies. We included randomized controlled trials with blood pressure lowering started versus control within 3 days of ischemic stroke onset. The primary outcome was unfavorable outcome at 3 months or at trial end point, defined as dependency or death, and the key secondary outcome was recurrent vascular events. Pooled relative risks and 95% confidence intervals were calculated using random-effects model. RESULTS: The systematic search identified 13 randomized controlled trials with 12 703 participants comparing early blood pressure lowering and control. Pooling the results with the random-effects model showed that blood pressure lowering in early ischemic stroke did not affect the risk of death or dependency at 3 months or at trial end point (relative risk, 1.04; 95% confidence interval, 0.96-1.13; P=0.35). Also, blood pressure lowering also had neutral effect on recurrent vascular events, as well as on disability or death, all-cause mortality, recurrent stroke, and serious adverse events. CONCLUSIONS: This meta-analysis suggested blood pressure lowering in early ischemic stroke had a neutral effect on the prevention of death or dependency. PMID- 26022637 TI - Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. AB - PURPOSE: The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of spontaneous intracerebral hemorrhage. METHODS: A formal literature search of PubMed was performed through the end of August 2013. The writing committee met by teleconference to discuss narrative text and recommendations. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Oversight Committee and Stroke Council Leadership Committee. RESULTS: Evidence-based guidelines are presented for the care of patients with acute intracerebral hemorrhage. Topics focused on diagnosis, management of coagulopathy and blood pressure, prevention and control of secondary brain injury and intracranial pressure, the role of surgery, outcome prediction, rehabilitation, secondary prevention, and future considerations. Results of new phase 3 trials were incorporated. CONCLUSIONS: Intracerebral hemorrhage remains a serious condition for which early aggressive care is warranted. These guidelines provide a framework for goal-directed treatment of the patient with intracerebral hemorrhage. PMID- 26022638 TI - Letter by Macrez et al. Regarding Article, "Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke". PMID- 26022639 TI - Effect Size Estimates for the ESCAPE Trial: Proportional Odds Regression Versus Other Statistical Methods. AB - BACKGROUND AND PURPOSE: Ordinal outcomes, such as modified Rankin Scale (mRS), are the standard primary end points in acute stroke trials. Regression models for assessing treatment efficacy after adjusting for baseline covariates have been developed for continuous, binary, or ordinal end points. There has been no consensus on the best choice of method for analyzing these data. METHODS: We compared several regression models for assessing treatment efficacy in acute stroke trials using existing data sets from the Interventional Management of Stroke-III and Prolyse in Acute Cerebral Thromboembolism II (PROACT-2) trials. Patients with baseline non-contrast computed tomographic Alberta Stroke Program Early CT Score (ASPECTS) > 5, baseline computed tomographic angiography, or conventional angiogram showing an intracranial internal carotid artery or middle cerebral artery trunk (M-1) occlusion, adequate collateral circulation shown on computed tomographic angiography, and treatment times of non-contrast computed tomographic to groin puncture of <=90 minutes, were included. Monte Carlo techniques were used to compare the statistical power of these regression models under a variety of simulated data analytic scenarios. RESULTS: Binary logistic regression showed greater power when the treatment is predicted to show evidence of benefit on one end of the mRS with no other gains across other levels of the scale. Proportional odds regression showed greater power when the treatment is predicted to show evidence of improvement on both ends of the mRS. CONCLUSIONS: The mRS distribution for both treatment and control groups influences the power of the investigated statistical models to assess treatment efficacy. A careful evaluation of the expected outcome distribution across the mRS scale is required to determine the best choice of primary analysis. PMID- 26022640 TI - Population-Based Study of Cerebral Microbleeds in Stroke-Free Older Adults Living in Rural Ecuador: The Atahualpa Project. AB - BACKGROUND AND PURPOSE: Prevalence of cerebral microbleeds (CMB) in white and Asian populations range from 4% to 15%. However, there is no information from indigenous Latin American people. We aimed to assess prevalence and cerebrovascular correlates of CMB in stroke-free older adults living in rural Ecuador. METHODS: Of 311 Atahualpa residents aged >=60 years identified during a door-to-door survey, 258 (83%) underwent brain magnetic resonance imaging. Twenty one were further excluded for a diagnosis of overt stroke. Using multivariate logistic regression models, adjusted for demographics and cardiovascular risk factors, we evaluated whether CMB were independently associated with silent strokes, white matter hyperintensities, and global cortical atrophy. RESULTS: Twenty-six (11%) of 237 participants had CMB, which were single in 54% of cases. CMB were deep in 11 patients, cortical in 9, and located both deep and cortical in 6. In univariate analyses, CMB were associated with age, systolic blood pressure, moderate-to-severe white matter hyperintensities, silent lacunar infarcts, and cortical atrophy. Mean (+/-SD) values for systolic blood pressure were 155+/-27 mm Hg in patients who had CMB versus 142+/-26 mm Hg in those who did not (P=0.017). In the adjusted models, moderate-to-severe white matter hyperintensities (P=0.009), silent lacunar infarcts (P=0.003), and global cortical atrophy (P=0.04) were independently associated with CMB. CONCLUSIONS: Prevalence of CMB in stroke-free older adults living in Atahualpa is comparable with those reported from other ethnic groups. There is a strong relationship between CMB and increased age, high systolic blood pressure, silent markers of cerebral small vessel disease, and cortical atrophy. PMID- 26022641 TI - Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus. AB - IMPORTANCE: Caloric restriction mimetic drugs have geroprotective effects that delay or reduce risks for a variety of age-associated systemic diseases, suggesting that such drugs might also have the potential to reduce risks of blinding ophthalmologic conditions for which age is a major risk factor. OBJECTIVE: To determine whether the caloric restriction mimetic drug metformin hydrochloride is associated with reduced risk of open-angle glaucoma (OAG) in persons with diabetes mellitus. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of patients aged 40 years or older with diabetes mellitus and no preexisting record of OAG in a large US managed care network from January 1, 2001, through December 31, 2010. EXPOSURES: Quantity of metformin and other prescribed diabetes medications as captured from outpatient pharmacy records. MAIN OUTCOMES AND MEASURES: Risk of developing OAG. RESULTS: Of 150 016 patients with diabetes mellitus, 5893 (3.9%) developed OAG. After adjusting for confounding factors, those prescribed the highest quartile of metformin hydrochloride (>1110 g in 2 years) had a 25% reduced OAG risk relative to those who took no metformin (hazard ratio = 0.75; 95% CI, 0.59-0.95; P = .02). Every 1 g increase in metformin hydrochloride use was associated with a 0.16% reduction in OAG risk (adjusted hazard ratio = 0.99984; 95% CI, 0.99969-0.99999; P = .04), which predicts that taking a standard dose of 2 g of metformin hydrochloride per day for 2 years would result in a 20.8% reduction in risk of OAG. After accounting for potential confounders, including metformin and diabetic medications, the risk of developing OAG was increased by 8% (hazard ratio = 1.08; 95% CI, 1.03-1.13; P = .003) for each unit of increase in glycated hemoglobin level. CONCLUSIONS AND RELEVANCE: Metformin use is associated with reduction in risk of developing OAG, and risk is reduced even when accounting for glycemic control in the form of glycated hemoglobin level. Other diabetes medications did not confer a similar OAG risk reduction. This study suggests that metformin may be affecting OAG risk on multiple levels, some involving improved glycemic control and some involving mechanisms outside glycemic control such as neurogenesis, inflammatory systems, or longevity pathways targeted by caloric restriction mimetic drugs. If confirmed by prospective clinical trials, these findings could lead to novel treatments for this sight-threatening disease. PMID- 26022643 TI - A strategy for in-silico prediction of skin absorption in man. AB - For some time, in-silico models to address substance transport into and through the skin are gaining more and more importance in different fields of science and industry. In particular, the mathematical prediction of in-vivo skin absorption is of great interest to overcome ethical and economical issues. The presented work outlines a strategy to address this problem and in particular, investigates in-vitro and in-vivo skin penetration experiments of the model compound flufenamic acid solved in an ointment by means of a mathematical model. Experimental stratum corneum concentration-depth profiles (SC-CDP) for various time intervals using two different in-vitro systems (Franz diffusion cell, Saarbruecken penetration model) were examined and simulated with the help of a highly optimized three compartment numerical diffusion model and compared to the findings of SC-CDPs of the in-vivo scenario. Fitted model input parameters (diffusion coefficient and partition coefficient with respect to the stratum corneum) for the in-vitro infinite dose case could be used to predict the in-use conditions in-vitro. Despite apparent differences in calculated partition coefficients between in-vivo and in-vitro studies, prediction of in-vivo scenarios from input parameters calculated from the in-vitro case yielded reasonable results. PMID- 26022642 TI - Nanoengineering of therapeutics for retinal vascular disease. AB - Retinal vascular diseases, including diabetic retinopathy, neovascular age related macular degeneration, and retinal vein occlusion, are leading causes of blindness in the Western world. These diseases share several common disease mechanisms, including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation, which provide opportunities for common therapeutic strategies. Treatment of these diseases using laser therapy, anti-VEGF injections, and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying root causes of pathology, and may have deleterious side effects. Furthermore, many patients continue to progress toward legal blindness despite receiving regular therapy. Nanomedicine, the engineering of therapeutics at the 1-100 nm scale, is a promising approach for improving clinical management of retinal vascular diseases. Nanomedicine based technologies have the potential to revolutionize the treatment of ophthalmology, through enabling sustained release of drugs over several months, reducing side effects due to specific targeting of dysfunctional cells, and interfacing with currently "undruggable" targets. We will discuss emerging nanomedicine-based applications for the treatment of complications associated with retinal vascular diseases, including angiogenesis and inflammation. PMID- 26022644 TI - Insights into the Packing Switching of the EphA2 Transmembrane Domain by Molecular Dynamic Simulations. AB - Receptor tyrosine kinases play an important role in mediating cell migration and adhesion associated with various biology processes. With a single-span transmembrane domain (TMD), the activities of the receptors are regulated by the definite packing configurations of the TMDs. For the EphA2 receptor, increasing studies have been conducted to investigate the packing domains that induce its switching TMD dimerization. However, the inherent transformation mechanisms including the interrelations among the involved packing domains remain unclear. Herein, we applied multiple simulation methods to explore the underlying packing mechanisms within the EphA2 TMD dimer. Our results demonstrated that the G(540)xxxG(544) contributed to the formation of the right-handed configuration while the heptad repeat L(535)xxxG(539)xxA(542)xxxV(546)xxL(549)xxxG(553) motif together with the FFxH(559) region mediated the parallel mode. Furthermore, the FF(557) residues packing mutually as rigid riveting structures were found comparable to the heptad repeat motif in maintaining the parallel configuration. In addition, the H(559) residue associated definitely with the lower bilayer leaflet, which was proved to stabilize the parallel mode significantly. The simulations provide a full range of insights into the essential packing motifs or residues involved in the switching TMD dimer configurations, which can enrich our comprehension toward the EphA2 receptor. PMID- 26022645 TI - Effects of high molecular weight hyaluronic acid on induced arthritis of the temporomandibular joint in rats. AB - High molecular weight hyaluronic acid (HMWHA) has been used to treat temporomandibular joint (TMJ) disorders, but controversial results have been described. This study aimed to characterize the morphological and biochemical actions of HMWHA on induced arthritis of the TMJ. Twenty-four male Wistar rats were used, and arthritis of the TMJ was induced through an intra-articular injection of Complete Freund's Adjuvant (CFA) (50 MUl). One week after arthritis induction, the animals were treated with HMWHA (once per week for three weeks). Histological analyses were performed using sections stained with hematoxylin eosin, toluidine blue and Picrosirius. Were also performed histomorphometric analysis and birefringence of collagenous fibers (polarization microscopy). Biochemical analyses of TMJ tissues were carried out through measurements of sulfated glycosaminoglycans and zymography for evaluation of metalloproteinase-2 and -9 (MMP-2 and -9). Data were analyzed using paired t-test and unpaired t test, with a 5% significance level. HMWHA reduced histologic changes and thickness of the articular disc, led to a greater arrangement of collagenous fibers, lower concentration of sulfated glycosaminoglycans and lower activity in all isoforms of MMP-2 and -9 in TMJs with induced arthritis. These findings suggest that HMWHA may exert a protective effect on the TMJ. PMID- 26022646 TI - The Co-Expression of Kallikrein 5 and Kallikrein 7 Associates with Poor Survival in Non-HPV Oral Squamous-Cell Carcinoma. AB - OBJECTIVE: Oral squamous-cell carcinoma (OSCC) still has a poor prognosis. Lymph node metastasis (LNM) is a major determinant of treatment decisions and prognosis. Serine protease inhibitor Kazal-type 5 (SPINK5) is the inhibitor of kallikrein 5 (KLK5) and KLK7. SPINK5, KLK5 and KLK7 are three of the genes of a recently validated LNM-predicting gene expression profile in OSCC. This study evaluates their clinicopathological role and value as biomarkers in OSCC. METHODS: Eighty-three patients with primary OSCC, treated surgically between 1996 and 2000, were included. Gene expression data were acquired from a previously reported study. Human papillomavirus (HPV) status was determined by an algorithm for HPV-16. Protein expression for KLK5, KLK7 and SPINK5 was semi-quantitatively determined in all 83 tumours by immunohistochemistry. All expression data were correlated with clinicopathological parameters. RESULTS: Concurrent loss of KLK5 and KLK7 correlates with worse disease-specific and overall survival (DSS and OS). Multivariate analysis proved that co-expression is an independent prognostic factor for DSS (p = 0.029) and OS (p = 0.001). CONCLUSION: This report demonstrates that concurrent loss of KLK5 and KLK7 associates with a poor clinical outcome in OSCC and could therefore serve as prognostic marker in this disease. PMID- 26022647 TI - Large bowel mucosal neoplasia in the original specimen may increase the risk of ileal pouch neoplasia in patients following restorative proctocolectomy for ulcerative colitis. AB - PURPOSE: Restorative proctocolectomy is a current gold standard procedure for patients who require a colectomy for ulcerative colitis. The incidence of ileal pouch neoplasia is low. The aims of this study were to assess the prevalence of neoplasia in ileal pouch and investigate the risk factors for ileal pouch neoplasia. METHODS: A total of 276 patients who underwent restorative proctocolectomy for ulcerative colitis between 1984 and 2009 were analyzed. Results of histological examinations of both original specimen and biopsies from the J-pouch taken during routine pouch endoscopy were evaluated. Patients' records were analyzed for ulcerative colitis duration, the time from pouch creation to pouch neoplasia, presence of pouchitis, as well as the concurrent primary sclerosing cholangitis. RESULTS: Analyzing the original specimen of large bowel, fifty-six lesions of low-grade dysplasia, twenty-five high-grade dysplasia, and five adenocarcinoma were revealed. All patients with dysplasia (n = 8) or adenocarcinoma (n = 1) of the J-pouch were positive for dysplasia in the original specimen. Duration of ulcerative colitis before surgery and duration time following restorative proctocolectomy were found as risk factors for J-pouch neoplasia with a significant difference (p = 0.01 and p = 0.0003, respectively). Patients with pouch neoplasia developed significantly more severe pouchitis (p = 0.00001). CONCLUSIONS: Neoplasia of the J-pouch is rare. Patients with neoplasia in the original specimen are more susceptible to develop neoplasia in the J pouch. Precise follow-up in patients with neoplasia lesions in the original specimen should be recommended. Moreover, in patients with risk factors, the exact surveillance pouch endoscopy should be recommended. PMID- 26022648 TI - Immunoglobulins stimulate cultured Schwann cell maturation and promote their potential to induce axonal outgrowth. AB - BACKGROUND: Schwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies. Intravenous immunoglobulins (IVIG) are widely used to treat autoimmune and inflammatory diseases including immune-mediated neuropathies. Nevertheless, promotion of peripheral nerve regeneration is currently an unmet therapeutical goal. We therefore examined whether immunoglobulins affect glial cell homeostasis, differentiation, and Schwann cell dependent nerve regenerative processes. METHODS: The responses of different primary Schwann cell culture models to IVIG were investigated: immature or differentiation competent Schwann cells, myelinating neuron/glial cocultures, and dorsal root ganglion explants. Immature or differentiating Schwann cells were used to study cellular proliferation, morphology, and gene/protein expression. Myelination rates were determined using myelinating neuron/glia cocultures, whereas axonal outgrowth was assessed using non-myelinating dorsal root ganglion explants. RESULTS: We found that IVIG specifically bind to Schwann cells and detected CD64 Fc receptor expression on their surface. In response to IVIG binding, Schwann cells reduced proliferation rates and accelerated growth of cellular protrusions. Furthermore, we observed that IVIG treatment transiently boosts myelin gene expression and myelination related signaling pathways of immature cells, whereas in differentiating Schwann cells, myelin expression is enhanced on a long-term scale. Importantly, myelin gene upregulation was not detected upon application of IgG1 control antibodies. In addition, we demonstrate for the first time that Schwann cells secrete interleukin-18 upon IVIG stimulation and that this cytokine instructs these cells to promote axonal growth. CONCLUSIONS: We conclude that IVIG can positively influence the Schwann cell differentiation process and that it enhances their regenerative potential. PMID- 26022649 TI - Intranasal therapies for acute seizures. AB - Most seizure emergencies occur outside of the hospital, and there is a need for treatment interventions that can be administered quickly and safely by nonclinical caregivers. Intranasal benzodiazepine administration does not require intravenous access and offers rapid seizure cessation. Intranasal midazolam is faster at aborting seizure activity than rectal diazepam and quicker to administer than intravenous diazepam. Although time to seizure cessation varies from study to study, intranasal midazolam is efficacious when administered not only by emergency department personnel but also by paramedics and caregivers in out-of-hospital and home settings. Absorption of midazolam intranasal formulations appears to be relatively rapid compared to diazepam formulations. Its shorter elimination half-life may also be beneficial in that patients may more quickly return to normal function because of rapid offset of effect. On the other hand, the faster rate of elimination of midazolam may expose patients to a higher rate of seizure recurrence compared with diazepam. Two diazepam formulations and one midazolam formulation are being currently developed for intranasal use. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26022650 TI - Two Cases of Successful Autologous Hematopoietic Stem Cell Harvest after Treatment with Brentuximab Vedotin. PMID- 26022651 TI - Comparison of blood culture and multiplex real-time PCR for the diagnosis of nosocomial sepsis. AB - BACKGROUND: In many cases of suspected sepsis, causative microorganisms cannot be isolated. Multiplex real-time PCR generates results more rapidly than conventional blood culture systems. METHODS: In this study, we evaluated the diagnostic performance of multiplex real-time PCR (LightCycler(r) SeptiFast, Roche, Mannheim, Germany), and compared with blood cultures and cultures from focus of infection in nosocomial sepsis. RESULTS: Seventy-eight nosocomial sepsis episodes in 67 adult patients were included in this study. The rates of microorganism detection by blood culture and PCR were 34.2% and 47.9%, respectively. Sixty-five microorganisms were detected by both methods from 78 sepsis episodes. Nineteen of these microorganisms were detected by both blood culture and PCR analysis from the same sepsis episode. There was statistically moderate concordance between the two methods (kappa=0.445, P<0.001). There was no significant agreement between the blood culture and PCR analysis in terms of microorganism detected (kappa=0.160, P=0.07). Comparison of the results of PCR and cultures from focus of infection revealed no significant agreement (kappa=0.110, P=0.176). However, comparison of the results of PCR and blood cultures plus cultures from focus of infection (positive blood culture and/or positive culture from focus of infection) showed poor agreement (kappa=0.17, P=0.026). When the blood culture was used as the gold standard, the sensitivity, specificity, positive and negative predictive value of PCR in patients with bacteremia was 80%, 69%, 57% and 87%, respectively. CONCLUSIONS: SeptiFast may be useful when added to blood culture in the diagnosis and management of sepsis. PMID- 26022652 TI - Estimation of risk for diabetes according to the metabolically healthy status stratified by degree of obesity in Korean men. AB - Although obesity is clearly identified as a risk factor for diabetes, the relationship between diabetes and metabolically healthy status of obesity is less clear. This study was aimed to evaluate the incidental risk of diabetes according to metabolically healthy status of obesity. 31,834 Korean men without diabetes categorized into six groups according to their metabolically healthy status stratified by degree of obesity were followed up for 5 years: metabolically healthy normal weight (MH-NW), metabolically healthy overweight (MH-OW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MU-NW), metabolically unhealthy overweight (MU-OW), and metabolically unhealthy obese (MUO). Cox proportional hazards analysis was used to measure the risk for diabetes according to their categories. While overall incidence was 9.0 %, incidence of diabetes was in proportion to the degree of obesity and metabolically healthy status (MH-NW: 6.3 %, MH-OW: 7.5 %, MHO: 9.2 %, MU-NW: 11.8 %, MU-OW: 14.9 %, MUO: 20.1 %). When MH-NW was set as reference, the adjusted HRs (95 % CI) for diabetes of the MH-OW, MHO, MU-NW, MU-OW, MUO compared to MH-NW were 1.18 (1.06-1.32), 1.58 (1.03-2.41), 1.81 (1.61-2.04), 2.36 (2.11-2.63), and 3.47 (2.84-4.24), respectively. In conclusion, risk for diabetes was in proportion to the degree of obesity in both metabolically healthy and unhealthy group. Metabolically healthy status was more significant determinant for incident diabetes than obesity itself. PMID- 26022653 TI - Maternal exposure to sexually transmitted infections and schizophrenia among offspring. AB - Animal models and epidemiologic studies suggest that prenatal maternal infection, and sexually transmitted infection (STI) in particular, is associated with an increased risk of schizophrenia in the offspring. However, findings from prior research studies on common infections, including herpes simplex virus type 2 (HSV 2) and Chlamydia trachomatis (C. trachomatis) have been inconsistent. To investigate these associations, we conducted a case-control study nested in the population-based Finnish Prenatal Study of Schizophrenia. Using linked national registries, 963 cases with schizophrenia (ICD-10 F20) or schizoaffective disorder (ICD-10 F25), and 963 matched controls were identified from among all persons born between 1983 and 1998 in Finland. HSV-2 IgG antibody levels were quantified in archived maternal serum samples drawn during pregnancy. Mothers of 16.4% of cases versus 12.6% of controls were HSV-2 seropositive. Mean levels of maternal HSV-2 IgG were marginally higher among cases than controls (index values of 0.98 versus 0.86; p=0.06). The unadjusted odds ratio (OR) of maternal HSV-2 IgG seropositivity was 1.33 (95% confidence interval (CI)=1.03-1.72, p=0.03). Following adjustment for covariates, the relationship was attenuated (OR=1.22, CI=0.93-1.60; p=0.14). In an exploratory analysis of another STI, C. trachomatis antibodies were measured in a subsample of 207 case-control pairs drawn from the cohort. The proportions of subjects that were seropositive and the mean levels of C. trachomatis antibodies were similar for cases and controls. This study does not support a strong association of HSV-2 or C. trachomatis IgG antibodies in maternal serum during early to mid-gestation with the development of schizophrenia in the offspring. PMID- 26022655 TI - Construction of polyoxometalates from dynamic lacunary polyoxotungstate building blocks and lanthanide linkers. AB - A series of polynuclear metal-oxo clusters have been constructed from the dynamic polyoxometalate (POM) building block {B-alpha-Sb(III)W9O33} and lanthanide (Ln) linkers via a stepwise synthetic strategy with the molecular formulas of [Ln2(H2O)4{WO2(pic)}2(SbW8O30)2](10-) (Na4Li6[La-1].28H2O, Na3Li7[Pr-2].30H2O) and [{Ln(H2O)}{Ln(pic)}(Sb3O4)(SbW8O31)(SbW10O35)]2(24-) (K2Na6Li16[Tb-3].63H2O, Na9Li15[Dy-4].61H2O, Na7Li17[Ho-5].53H2O) (Hpic = picolinic acid). The five compounds have been characterized by FT-IR, elemental analysis, TG, powder X-ray diffraction (PXRD) and single crystal X-ray diffraction. In compounds 1-5, various POM moieties, such as {B-beta-SbW8O30}, {B-alpha-SbW8O31} and {B-alpha SbW10O35}, were formed through a series of disassembling and re-assembling processes of the dynamic {B-alpha-SbW9O33} precursor with specific pH, reaction temperature and time. Furthermore, the use of oxytropic Ln(3+) ions as linkers, together with auxiliary organic pic ligands and/or inorganic Sb(3+) ions, led to diverse connection modes between the POM building blocks and Ln linkers and the assembly of new polynuclear metal-oxo clusters. The polyoxoanions of La-1 and Pr 2 possess the same structural feature, which can be viewed as a sandwich-type cluster composed of two {B-beta-SbW8O30} units connected by two {WO2(pic)} fragments and two hydrated Ln ions. These sandwich-type polyoxoanions are further linked by the hydrated Ln ions to form a 1-D helical chain. The polyoxoanions of Tb-3, Dy-4 and Ho-5 display the same structural features, although they contain different counter-cations and lattice water molecules. In the polyoxoanions of 3 5, one {B-alpha-SbW8O31} POM moiety and one {B-alpha-SbW10O35} POM unit are connected by one {Sb3O4} fragment and one {Ln(pic)} linker, forming an asymmetric sandwich-type metal-oxo cluster. Two of these sandwich-type clusters are further fused together by extra two hydrated Ln ions, leading to an isolated polynuclear metal-oxo cluster with a size of 16.4 * 28.5 A. The photoluminescence properties of Tb-3 and Dy-4 were investigated. Both compounds exhibit characteristic Tb(3+) and Dy(3+) luminescence. The relationship between the luminescence properties and the crystal structure of the polyoxoanion was discussed. PMID- 26022654 TI - Implementation of community-based adherence clubs for stable antiretroviral therapy patients in Cape Town, South Africa. AB - INTRODUCTION: Community-based models of antiretroviral therapy (ART) delivery have been recommended to support ART expansion and retention in resource-limited settings. However, the evidence base for community-based models of care is limited. We describe the implementation of community-based adherence clubs (CACs) at a large, public-sector facility in peri-urban Cape Town, South Africa. METHODS: Starting in May 2012, stable ART patients were down-referred from the primary care community health centre (CHC) to CACs. Eligibility was based on self reported adherence, >12 months on ART and viral suppression. CACs were facilitated by four community health workers and met every eight weeks for group counselling, a brief symptom screen and distribution of pre-packed ART. The CACs met in community venues for all visits including annual blood collection and clinical consultations. CAC patients could send a patient-nominated treatment supporter ("buddy") to collect their ART at alternate CAC visits. Patient outcomes [mortality, loss to follow-up and viral rebound (>1000 copies/ml)] during the first 18 months of the programme are described using Kaplan-Meier methods. RESULTS AND DISCUSSION: From June 2012 to December 2013, 74 CACs were established, each with 25-30 patients, providing ART to 2133 patients. CAC patients were predominantly female (71%) and lived within 3 km of the facility (70%). During the analysis period, 9 patients in a CAC died (<0.1%), 53 were up referred for clinical complications (0.3%) and 573 CAC patients sent a buddy to at least one CAC visit (27%). After 12 months in a CAC, 6% of patients were lost to follow-up and fewer than 2% of patients retained experienced viral rebound. CONCLUSIONS: Over a period of 18 months, a community-based model of care was rapidly implemented decentralizing more than 2000 patients in a high-prevalence, resource-limited setting. The fundamental challenge for this out of facility model was ensuring that patients receiving ART within a CAC were viewed as an extension of the facility and part of the responsibility of CHC staff. Further research is needed to support down-referral sooner after ART initiation and to describe patient experiences of community-based ART delivery. PMID- 26022656 TI - Polycarbonate filtration technique is noninferior to mCCDA for isolation of Campylobacter species from stool samples. AB - A total of 5963 diarrheic stool samples were cultivated for Campylobacter spp. with use of modified charcoal cefoperazone deoxycholate agar (mCCDA) plates as well as a polycarbonate (PC) filter technique on blood agar plates. A total of 376 Campylobacter jejuni/coli were isolated from both PC and mCCDA. Six and three were isolated from PC and mCCDA only, respectively (P = ns). The PC technique is noninferior to mCCDA for isolation of C. jejuni/coli. PMID- 26022657 TI - Functional characterization of 20 allelic variants of CYP1A2. AB - Genetic variations in cytochrome P450 1A2 (CYP1A2) are associated with interindividual variability in the metabolism and efficacy of many medications. Twenty CYP1A2 variants harboring amino acid substitutions were analyzed for functional changes in enzymatic activity. Recombinant CYP1A2 variant proteins were heterologously expressed in COS-7 cells. Enzyme kinetic analyses were performed with two representative CYP1A2 substrates, phenacetin and 7 ethoxyresorufin. Among the 20 CYP1A2 allelic variants, CYP1A2*4, CYP1A2*6, CYP1A2*8, CYP1A2*15, CYP1A2*16, and CYP1A2*21 were inactive toward both substrates. CYP1A2*11 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A2*14 and CYP1A2*20 exhibited increased activity compared to the wild-type enzyme, CYP1A2*1. This comprehensive in vitro assessment provided insight into the specific metabolic activities of CYP1A2 proteins encoded by variant alleles, which may to be valuable when interpreting the results of in vivo studies. PMID- 26022658 TI - Effectiveness of facemasks for pediatric populations against submicron-sized aerosols. AB - BACKGROUND: In the event of a public-health threat involving bioaerosols, such as a terrorist attack or pandemic, options for devices to protect the pediatric population are limited. One strategy involves deployment of facemasks meant for the pediatric population, although protection against bioaerosols was not an intended use of such masks and little is known about their effectiveness. METHODS: We chose 3 brands of facemasks for pediatric use for characterizing penetration. To validate our experimental technique, 2 N95 respirator brands were also tested. All barriers were subjected to neutralized polydispersed sodium chloride aerosols, and their intrinsic penetration was evaluated in the submicron size range at different flow rates. RESULTS: As expected, the N95 brands had low penetration (5% or less) at the highest flow rates. However, for the facemasks for pediatric use, penetration varied significantly amongst brands at the highest flow rates (~15%->50%). Studies with isopropanol-dipped respirators and facemasks demonstrated that not all brands of facemasks for pediatric use have electret layers. CONCLUSIONS: Our bench tests suggest that the intrinsic penetration through facemasks for pediatric use can be high in the submicron size range. These data can be used in risk-assessment models to determine the extent to which facemasks for pediatric use reduce the likelihood of infection in emergency situations. PMID- 26022659 TI - Importance of asymptomatic shedding of Clostridium difficile in environmental contamination of a neonatal intensive care unit. AB - A survey of C. difficle in a neonatal intensive care unit (NICU) was conducted. Approximately 25% of infants in the NICU were colonized with Clostridium difficle. Environmental surface cultures were obtained from the NICU and compared with cultures taken from infant, adolescent, and hematology/oncology units. From 150 surface cultures, C difficle was recovered exclusively from the NICU. Of the 16 different types of surfaces cultured, diaper scales and the surrounding area were contaminated most often at 50%. PMID- 26022661 TI - The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists. AB - Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists. PMID- 26022660 TI - The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. AB - Infection with Human papillomaviruses (HPVs) leads to the development of a wide range of cancers, accounting for 5% of all human cancers. A prominent example is cervical cancer, one of the leading causes of cancer death in women worldwide. It has been well established that tumor development and progression induced by HPV infection is driven by the sustained expression of two oncogenes E6 and E7. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways that may be equally important for transformation. Among these pathways, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling cascade plays a very important role in HPV-induced carcinogenesis by acting through multiple cellular and molecular events. In this review, we summarize the frequent amplification of PI3K/Akt/mTOR signals in HPV-induced cancers and discuss how HPV oncogenes E6/E7/E5 activate the PI3K/Akt/mTOR signalling pathway to modulate tumor initiation and progression and affect patient outcome. Improvement of our understanding of the mechanism by which the PI3K/Akt/mTOR signalling pathway contributes to the immortalization and carcinogenesis of HPV-transduced cells will assist in devising novel strategies for preventing and treating HPV-induced cancers. PMID- 26022662 TI - Dynamics of Pertussis Transmission in the United States. AB - Past patterns of infectious disease transmission set the stage on which modern epidemiologic dynamics are played out. Here, we present a comprehensive account of pertussis (whooping cough) transmission in the United States during the early vaccine era. We analyzed recently digitized weekly incidence records from Morbidity and Mortality Weekly Reports from 1938 to 1955, when the whole-cell pertussis vaccine was rolled out, and related them to contemporary patterns of transmission and resurgence documented in monthly incidence data from the National Notifiable Diseases Surveillance System. We found that, during the early vaccine era, pertussis epidemics in US states could be categorized as 1) annual, 2) initially annual and later multiennial, or 3) multiennial. States with predominantly annual cycles tended to have higher per capita birth rates, more household crowding, more children per family, and lower rates of school attendance than the states with multiennial cycles. Additionally, states that exhibited annual epidemics during 1938-1955 have had the highest recent (2001 2010) incidence, while those states that transitioned from annual cycles to multiennial cycles have had relatively low recent incidence. Our study provides an extensive picture of pertussis epidemiology in the United States dating back to the onset of vaccination, a back-story that could aid epidemiologists in understanding contemporary transmission patterns. PMID- 26022663 TI - Analysis of Preventive Interventions for Malaria: Exploring Partial and Complete Protection and Total and Primary Intervention Effects. AB - Event dependence, the phenomenon in which future risk depends on past disease history, is not commonly accounted for in the statistical models used by malaria researchers. However, recently developed methods for the analysis of repeated events allow this to be done, while also accounting for heterogeneity in risk and nonsusceptible subgroups. Accounting for event dependence allows separation of the primary effect of an intervention from its total effect, which is composed of its primary effect on risk of disease and its secondary effect mediated by event dependence. To illustrate these methods and show the insights they can provide, we have reanalyzed 2 trials of seasonal malaria chemoprevention (SMC) in Bousse, Burkina Faso, and Kati, Mali, in 2008-2009, as well as a trial of intermittent preventive treatment of malaria in infants in Navrongo, Ghana, in 2000-2004. SMC completely protects a large fraction of recipients, while intermittent preventive treatment in infants provides modest partial protection, consistent with the rationale of these 2 different chemopreventive approaches. SMC has a primary effect that is substantially greater than the total effect previously estimated by trials, with the lower total effect mediated by negative event dependence. These methods contribute to an understanding of the mechanisms of protection from these interventions and could improve understanding of other tools to control malaria, including vaccines. PMID- 26022664 TI - Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages. AB - Macrophages can be polarised to adopt the M1 or M2 phenotype and functional outcomes of activation include altered secretion of immune molecules such as insulin-like growth factor (IGF)-1 as well as upregulation of cell surface molecules specifically associated with each state. Interleukin (IL)-4 mediates its effects through two receptors, the type I and II receptors and activation of these receptors results in phosphorylation of signal transducers and activators of transcription (STAT)6. JAK3 is activated as a consequence of ligation of the type I IL-4R, which participates in Akt activation. We set out to investigate the impact of perturbation of IGF-1 tone on IL-4- and interferon (IFN)gamma-induced activation, the mechanisms by which this may occur and the contribution of type I IL-4R activation to adoption of the M2 state. The data presented here indicate that IL-4-induced activation of Akt is JAK3-dependent, enhanced by release of IGF 1 and necessary for full adoption of the M2 phenotype, since blocking IGF-1 activity blunts the ability of IL-4 to induce activation of Akt and to upregulate expression of some M2-associated molecules. In addition, differential control of the expression of mannose receptor (MRC1), arginase-1 (Arg-1), chitinase-3 like 3 (Chi3l3) and found in inflammatory zone 1 (FIZZ1) was observed. The IFNgamma induced decrease in IGF-1 was exacerbated by inhibition of phosphatidylinositol-3 (PI3) kinase, indicating that Akt may regulate its own activation via IGF-1. Overall, a deficit in IGF-1/Akt signalling is associated with decreased capacity to induce the M2 state and an increased responsiveness to IFNgamma. PMID- 26022665 TI - Co-culture of 3D tumor spheroids with fibroblasts as a model for epithelial mesenchymal transition in vitro. AB - Epithelial-mesenchymal transition (EMT) acts as a facilitator of metastatic dissemination in the invasive margin of malignant tumors where active tumor stromal crosstalks take place. Co-cultures of cancer cells with cancer-associated fibroblasts (CAFs) are often used as in vitro models of EMT. We established a tumor-fibroblast proximity co-culture using HT-29 tumor spheroids (TSs) with CCD 18 co fibroblasts. When co-cultured with TSs, CCD-18 co appeared activated, and proliferative activity as well as cell migration increased. Expression of fibronectin increased whereas laminin and type I collagen decreased in TSs co cultured with fibroblasts compared to TSs alone, closely resembling the margin of in vivo xenograft tissue. Active TGFbeta1 in culture media significantly increased in TS co-cultures but not in 2D co-cultures of cancer cells fibroblasts, indicating that 3D context-associated factors from TSs may be crucial to crosstalks between cancer cells and fibroblasts. We also observed in TSs co-cultured with fibroblasts increased expression of alpha-SMA, EGFR and CTGF; reduced expression of membranous beta-catenin and E-cadherin, together suggesting an EMT-like changes similar to a marginal region of xenograft tissue in vivo. Overall, our in vitro TS-fibroblast proximity co-culture mimics the EMT state of the invasive margin of in vivo tumors in early metastasis. PMID- 26022667 TI - Fast Dissolving/Disintegrating Dosage Forms: Growth from Immediate Release to Sustained Release and Traditional Medicines. PMID- 26022666 TI - Transitions to Care in the Community for Prison Releasees with HIV: a Qualitative Study of Facilitators and Challenges in Two States. AB - One in seven people living with HIV in the USA passes through a prison or jail each year, and almost all will return to the community. Discharge planning and transitional programs are critical but challenging elements in ensuring continuity of care, maintaining treatment outcomes achieved in prison, and preventing further viral transmission. This paper describes facilitators and challenges of in-prison care, transitional interventions, and access to and continuity of care in the community in Rhode Island and North Carolina based on qualitative data gathered as part of the mixed-methods Link Into Care Study of prisoners and releasees with HIV. We conducted 65 interviews with correctional and community-based providers and administrators and analyzed the transcripts using NVivo 10 to identify major themes. Facilitators of effective transitional systems in both states included the following: health providers affiliated with academic institutions or other entities independent of the corrections department; organizational philosophy emphasizing a patient-centered, personal, and holistic approach; strong leadership with effective "champions"; a team approach with coordination, collaboration and integration throughout the system, mutual respect and learning between corrections and health providers, staff dedicated to transitional services, and effective communication and information sharing among providers; comprehensive transitional activities and services including HIV, mental health and substance use services in prisons, timely and comprehensive discharge planning with specific linkages/appointments, supplies of medications on release, access to benefits and entitlements, case management and proactive follow-up on missed appointments; and releasees' commitment to transitional plans. These elements were generally present in both study states but their absence, which also sometimes occurred, represent ongoing challenges to success. The qualitative findings on the facilitators and challenges of the transitional systems were similar in the two states despite differences in context, demographics of target population, and system organization. Recommendations for improved transitional systems follow from the analysis of the facilitators and challenges. PMID- 26022668 TI - Anti-Cancer Products from Marine Sponges: Progress and Promise. PMID- 26022669 TI - Radium-223 dichloride for the treatment of bone metastatic castration-resistant prostate cancer: an evaluation of its safety. AB - INTRODUCTION: Approximately 10 - 20% of prostate cancer cases ultimately progress to castration-resistant prostate cancer (CRPC), for which there is a poor prognosis and a therapeutic need. Radium-223 dichloride (radium-223 [Xofigo]) is a first-in-class alpha-emitting radiopharmaceutical shown to significantly prolong overall survival in patients with CRPC with symptomatic bone metastases and no visceral metastases. Current treatment guidelines recommended it in both pre- and post-docetaxel settings. AREAS COVERED: Radium-223 mechanism of action, pharmacokinetics and key efficacy and safety data are reviewed. The evaluation of adverse events reported in the Phase III ALSYMPCA trial is summarized for the overall population and patient subpopulations (prior docetaxel, concomitant external beam radiation therapy and baseline opioid use). An evaluation of how radium-223 is being incorporated into the CRPC treatment paradigm and the implications of its safety profile for future use are provided. EXPERT OPINION: The pronounced efficacy and safety profile of radium-223 positions it as a valuable new therapeutic tool in the CRPC armamentarium. Its novel mechanism of action underlies low rates of hematologic adverse events. Radium-223 treatment will become common in the majority of pre-docetaxel symptomatic CRPC cases, as it has proved to be highly efficient with few safety concerns earlier in the course of disease. PMID- 26022670 TI - Seroma observed 6 months after anterior lumbar interbody fusion that included use of recombinant bone morphogenetic protein 2. PMID- 26022671 TI - Lumbar osteochondroma presented with low back pain. PMID- 26022672 TI - Malignant mesenchymal tumor of the sacrum. PMID- 26022673 TI - Minimally invasive combined direct lateral and posterior transpedicular approach for 360 degrees resection of a lumbar aneurysmal bone cyst with spinal stabilization. PMID- 26022674 TI - Congenital lordoscoliosis and stenosis of the external ostium of the foraminal canal induced by a nonsegmented transversal bony bar associated to rachischisis and meningocele. PMID- 26022675 TI - Utilizing associational resistance for biocontrol: impacted by temperature, supported by indirect defence. AB - BACKGROUND: Associational herbivore resistance is potentiated by neighbouring heterogenic plant species that impact a focal plant's attraction to herbivores or the damage that they cause. One mechanism to confer associational resistance is believed to be exposure to neighbour-emitted volatiles, the receivers of which range from intra- and interspecific neighbour plants to higher-trophic-level insects. In previous studies the passive adsorption of neighbour-emitted semivolatiles has been reported, but little is known regarding the mechanisms and ecological consequences on the receiver plant and its associated biota. To utilize volatile-based associational resistance for agricultural applications, it is imperative to know its effectiveness under varying diurnal temperatures and whether herbivore natural enemies, providing biological control, are impacted. Mimicking varying diurnal temperatures in a laboratory set-up, we assessed how the tritrophic model system Brassica oleracea var. italica (broccoli)-Plutella xylostella (crucifer specialist herbivore)-Cotesia vestalis (endoparasitoid of P. xylostella) is influenced by exposure to the natural semivolatile emitter plant Rhododendron tomentosum Harmaja. RESULTS: Rhododendron tomentosum-exposed B. oleracea was less susceptible to P. xylostella oviposition at both night-time (12 degrees C) and day-time (22 degrees C) temperatures and less favoured and damaged by P. xylostella larvae at 12 degrees C. Exposure did not interfere with indirect defence, i.e. attraction of the natural enemy C. vestalis on host-damaged, R. tomentosum-exposed B. oleracea under 22 degrees C, while there was a reduction in attraction (marginal preference towards host-damaged B. oleracea) under 12 degrees C. CONCLUSIONS: The ability of R. tomentosum exposure to render associational resistance against an agriculturally important Brassica herbivore P. xylostella without severely compromising the specialist parasitoid C. vestalis host location encourages further studies on the potential of using this naturally abundant plant for biocontrol. The generality of our finding on temperature as a potential regulating mechanism for the efficacy of semivolatile emitter-based associational resistance towards specialist pest larval damage should be further studied in natural and agricultural associations. Our study emphasizes the need to develop techniques to compare volatiles at the leaf versus air interface and associate their appearance and ecological role with times of activity and level of specialisation of herbivores and their natural enemies. PMID- 26022676 TI - Recycling endosomes. AB - The endosomal membrane recycling system represents a dynamic conduit for sorting and re-exporting internalized membrane constituents. The recycling system is composed of multiple tubulovesicular recycling pathways that likely confer distinct trafficking pathways for individual cargoes. In addition, elements of the recycling system are responsible for assembly and maintenance of apical membrane specializations including primary cilia and apical microvilli. The existence of multiple intersecting and diverging recycling tracks likely accounts for specificity in plasma membrane recycling trafficking. PMID- 26022677 TI - Left Ventricular T-Cell Recruitment Contributes to the Pathogenesis of Heart Failure. AB - BACKGROUND: Despite the emerging association between heart failure (HF) and inflammation, the role of T cells, major players in chronic inflammation, has only recently begun to be explored. Whether T-cell recruitment to the left ventricle (LV) participates in the development of HF requires further investigation to identify novel mechanisms that may serve for the design of alternative therapeutic interventions. METHODS AND RESULTS: Real-time videomicroscopy of T cells from nonischemic HF patients or from mice with HF induced by transverse aortic constriction revealed enhanced adhesion to activated vascular endothelial cells under flow conditions in vitro compared with T cells from healthy subjects or sham mice. T cells in the mediastinal lymph nodes and the intramyocardial endothelium were both activated in response to transverse aortic constriction and the kinetics of LV T-cell infiltration was directly associated with the development of systolic dysfunction. In response to transverse aortic constriction, T cell-deficient mice (T-cell receptor, TCRalpha( /-)) had preserved LV systolic and diastolic function, reduced LV fibrosis, hypertrophy and inflammation, and improved survival compared with wild-type mice. Furthermore, T-cell depletion in wild-type mice after transverse aortic constriction prevented HF. CONCLUSIONS: T cells are major contributors to nonischemic HF. Their activation combined with the activation of the LV endothelium results in LV T-cell infiltration negatively contributing to HF progression through mechanisms involving cytokine release and induction of cardiac fibrosis and hypertrophy. Reduction of T-cell infiltration is thus identified as a novel translational target in HF. PMID- 26022679 TI - Xenopus Cytogenetics and Chromosomal Evolution. AB - The genus Xenopus represents important model organisms in the field of developmental biology and chromosomal evolution. Developmental processes are tightly coupled with the analysis of gene function via genetic linkage and mapping. Cytogenetic techniques such as chromosome banding or FISH are essential tools for the determination of gene position and subsequently for the construction of linkage and physical maps. Here, we present a summary of key achievements in X. tropicalis and X. laevis cytogenetics with emphasis on the gene localization to chromosomes. The second part of this review is focused on the chromosomal evolution regarding both above-mentioned species. With respect to methodology, hybridization techniques such as FISH and chromosome-specific painting FISH are highlighted. PMID- 26022678 TI - SUMO1 Affects Synaptic Function, Spine Density and Memory. AB - Small ubiquitin-like modifier-1 (SUMO1) plays a number of roles in cellular events and recent evidence has given momentum for its contributions to neuronal development and function. Here, we have generated a SUMO1 transgenic mouse model with exclusive overexpression in neurons in an effort to identify in vivo conjugation targets and the functional consequences of their SUMOylation. A high expressing line was examined which displayed elevated levels of mono-SUMO1 and increased high molecular weight conjugates in all brain regions. Immunoprecipitation of SUMOylated proteins from total brain extract and proteomic analysis revealed ~95 candidate proteins from a variety of functional classes, including a number of synaptic and cytoskeletal proteins. SUMO1 modification of synaptotagmin-1 was found to be elevated as compared to non-transgenic mice. This observation was associated with an age-dependent reduction in basal synaptic transmission and impaired presynaptic function as shown by altered paired pulse facilitation, as well as a decrease in spine density. The changes in neuronal function and morphology were also associated with a specific impairment in learning and memory while other behavioral features remained unchanged. These findings point to a significant contribution of SUMO1 modification on neuronal function which may have implications for mechanisms involved in mental retardation and neurodegeneration. PMID- 26022680 TI - Short-term Heparin Re-exposure During Heart Transplantation in Patients With Ventricular Assist Devices and Acute Heparin-induced Thrombocytopenia. PMID- 26022681 TI - Comment on 'A Meta-Analysis of the Efficacy of Acceptance and Commitment Therapy for Clinically Relevant Mental and Physical Health Problems'. PMID- 26022683 TI - Erratum to: Maternal dietary intake of folate, vitamin B12 and MTHFR 677C>T genotype: their impact on newborn's anthropometric parameters. PMID- 26022682 TI - Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice. AB - Dietary flavonoid intake is associated with reduced risk of cardiovascular diseases, possibly by affecting metabolic health. The relative potency of different flavonoids in causing beneficial effects on energy and lipid metabolism has not been investigated. Effects of quercetin, hesperetin, epicatechin, apigenin and anthocyanins in mice fed a high-fat diet (HF) for 12 weeks were compared, relative to normal-fat diet. HF-induced body weight gain was significantly lowered by all flavonoids (17-29 %), but most by quercetin. Quercetin significantly lowered HF-induced hepatic lipid accumulation (71 %). Mesenteric adipose tissue weight and serum leptin levels were significantly lowered by quercetin, hesperetin and anthocyanins. Adipocyte cell size and adipose tissue inflammation were not affected. The effect on body weight and composition could not be explained by individual significant effects on energy intake, energy expenditure or activity. Lipid metabolism was not changed as measured by indirect calorimetry or expression of known lipid metabolic genes in liver and white adipose tissue. Hepatic expression of Cyp2b9 was strongly downregulated by all flavonoids. In conclusion, all flavonoids lowered parameters of HF-induced adiposity, with quercetin being most effective. PMID- 26022685 TI - Racial and ethnic differences in Takotsubo cardiomyopathy presentation and outcomes. PMID- 26022684 TI - Low testosterone in men predicts impaired arterial elasticity and microvascular function. AB - BACKGROUND: A low testosterone level in men is associated with increased adiposity, insulin resistance, and dyslipidemia. Whether low testosterone level is associated with arterial stiffness and endothelial and microvascular dysfunction remains unknown and was investigated in this study. METHODS: Serum testosterone was measured in 237 healthy men aged 50 years (SD 12). Endothelial and microvascular function were assessed as brachial artery flow-mediated dilation (FMD) and digital reactive hyperemia index (RHI), respectively. Arterial stiffness was evaluated by tonometry-derived pulse wave velocity (PWV) and central augmentation index (AIX). RESULTS: Mean total testosterone level was 16.3 nmol/L (SD 6.11) and 25% of subjects had low levels (<12.0 nmol/L). Testosterone level correlated positively with RHI (r=0.24, p<0.001) and inversely with AIX (r= 0.14, p=0.033) but not with FMD or PWV, indicating impaired microvascular hyperemia and arterial elasticity with lower testosterone levels. After multivariate adjustment for the Framingham Risk Score and weight, testosterone level remained an independent predictor of RHI and AIX (beta=0.23, -0.13; p=0.001, 0.04, respectively). CONCLUSION: In men with few co-morbidities, lower serum testosterone level is associated with microvascular dysfunction and increased pulse wave reflections, mechanisms by which lower testosterone levels may confer increased cardiovascular risk. Whether normalization of low testosterone level improves vascular function needs further investigation. PMID- 26022686 TI - Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds. AB - The discovery of novel scaffolds against a specific target has long been one of the most significant but challengeable goals in discovering lead compounds. A scaffold that binds in important regions of the active pocket is more favorable as a starting point because scaffolds generally possess greater optimization possibilities. However, due to the lack of sufficient chemical space diversity of the databases and the ineffectiveness of the screening methods, it still remains a great challenge to discover novel active scaffolds. Since the strengths and weaknesses of both fragment-based drug design and traditional virtual screening (VS), we proposed a fragment VS concept based on Bayesian categorization for the discovery of novel scaffolds. This work investigated the proposal through an application on VEGFR-2 target. Firstly, scaffold and structural diversity of chemical space for 10 compound databases were explicitly evaluated. Simultaneously, a robust Bayesian classification model was constructed for screening not only compound databases but also their corresponding fragment databases. Although analysis of the scaffold diversity demonstrated a very unevenly distribution of scaffolds over molecules, results showed that our Bayesian model behaved better in screening fragments than molecules. Through a literature retrospective research, several generated fragments with relatively high Bayesian scores indeed exhibit VEGFR-2 biological activity, which strongly proved the effectiveness of fragment VS based on Bayesian categorization models. This investigation of Bayesian-based fragment VS can further emphasize the necessity for enrichment of compound databases employed in lead discovery by amplifying the diversity of databases with novel structures. PMID- 26022687 TI - Role of Red Meat and Resistant Starch in Promutagenic Adduct Formation, MGMT Repair, Thymic Lymphoma and Intestinal Tumourigenesis in Msh2 -Deficient Mice. AB - Red meat may increase promutagenic lesions in the colon. Resistant starch (RS) can reduce these lesions and chemically induced colon tumours in rodents. Msh2 is a mismatch repair (MMR) protein, recognising unrepaired promutagenic adducts for removal. We determined if red meat and/or RS modulated DNA adducts or oncogenesis in Msh2-deficient mice. A total of 100 Msh2-/- and 60 wild-type mice consumed 1 of 4 diets for 6 months: control, RS, red meat and red meat+RS. Survival time, aberrant crypt foci (ACF), colon and small intestinal tumours, lymphoma, colonic O6-methyl-2-deoxyguanosine (O6MeG) adducts, methylguanine methyltransferase (MGMT) and cell proliferation were examined. In Msh2-/- mice, red meat enhanced survival compared to control (p<0.01) and lowered total tumour burden compared to RS (p<0.167). Msh2-/- mice had more ACF than wild-type mice (p<0.014), but no colon tumours developed. Msh2-/- increased cell proliferation (p<0.001), lowered DNA O6MeG adducts (p<0.143) and enhanced MGMT protein levels (p<0.001) compared to wild-type mice, with RS supplementation also protecting against DNA adducts (p<0.01). No link between red meat-induced promutagenic adducts and risk for colorectal cancer was observed after 6 months' feeding. Colonic epithelial changes after red meat and RS consumption with MMR deficiency will differ from normal epithelial cells. PMID- 26022688 TI - Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. AB - BACKGROUND & AIMS: The differentiation of stem cells to hepatocyte-like cells (HLC) offers the perspective of unlimited supply of human hepatocytes. However, the degree of differentiation of HLC remains controversial. To obtain an unbiased characterization, we performed a transcriptomic study with HLC derived from human embryonic and induced stem cells (ESC, hiPSC) from three different laboratories. METHODS: Genome-wide gene expression profiles of ESC and HLC were compared to freshly isolated and up to 14days cultivated primary human hepatocytes. Gene networks representing successful and failed hepatocyte differentiation, and the transcription factors involved in their regulation were identified. RESULTS: Gene regulatory network analysis demonstrated that HLC represent a mixed cell type with features of liver, intestine, fibroblast and stem cells. The "unwanted" intestinal features were associated with KLF5 and CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions (n=1057) and downregulated proliferation associated genes (n=1562) that approach levels of primary hepatocytes. However, three further clusters containing 447, 101, and 505 genes failed to reach levels of hepatocytes. Key TF of two of these clusters include SOX11, FOXQ1, and YBX3. The third unsuccessful cluster, controlled by HNF1, CAR, FXR, and PXR, strongly overlaps with genes repressed in cultivated hepatocytes compared to freshly isolated hepatocytes, suggesting that current in vitro conditions lack stimuli required to maintain gene expression in hepatocytes, which consequently also explains a corresponding deficiency of HLC. CONCLUSIONS: The present gene regulatory network approach identifies key transcription factors which require modulation to improve HLC differentiation. PMID- 26022690 TI - Interleukin-1alpha deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice. AB - BACKGROUND & AIMS: ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1alpha is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1alpha is involved in ER stress-induced apoptosis and steatohepatitis. METHODS: We employed WT and IL-1alpha-deficient mice to study the role of IL-1alpha in ER stress induced steatohepatitis. RESULTS: Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1alpha deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1alpha deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1beta, IL-6, TNFalpha, and CHOP, with no effect on the degree of fatty liver formation. IL-1alpha was upregulated in ER stressed-macrophages and the protein was localized to the nucleus. IL-1beta mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL 1alpha deficient compared to WT mice. ER stress induced the expression of IL 1alpha and IL-1beta also in mouse primary hepatocytes. Recombinant IL-1alpha treatment in hepatocytes did not affect CHOP expression but upregulated both IL 1alpha and IL-1beta mRNA levels. CONCLUSION: We show that IL-1alpha is upregulated in response to ER stress and IL-1alpha deficiency reduces ER stress induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1alpha may contribute to the induction of CHOP intracellularly, while IL-1alpha released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells. PMID- 26022689 TI - Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. AB - BACKGROUND & AIMS: Regeneration of the hepatic mass is crucial to liver repair. Proliferation of hepatic parenchyma is intimately dependent on angiogenesis and resident macrophage-derived cytokines. However the role of circulating monocyte interactions in vascular and hepatic regeneration is not well-defined. We investigated the role of these interactions in regeneration in the presence and absence of intact monocyte adhesion. METHODS: Partial hepatectomy was performed in wild-type mice and those lacking the monocyte adhesion molecule CD11b. Vascular architecture, angiogenesis and macrophage location were analyzed in the whole livers using simultaneous angiography and macrophage staining with fluorescent multiphoton microscopy. Monocyte adhesion molecule expression and sprouting-related pathways were evaluated. RESULTS: Resident macrophages (Kupffer cells) did not migrate to interact with vessels whereas infiltrating monocytes were found adjacent to sprouting points. Infiltrated monocytes colocalized with Wnt5a, angiopoietin 1 and Notch-1 in contact points and commensurate with phosphorylation and disruption of VE-cadherin. Mice deficient in CD11b showed a severe reduction in angiogenesis, liver mass regeneration and survival following partial hepatectomy, and developed unstable and leaky vessels that eventually produced an aberrant hepatic vascular network and Kupffer cell distribution. CONCLUSIONS: Direct vascular interactions of infiltrating monocytes are required for an ordered vascular growth and liver regeneration. These outcomes provide insight into hepatic repair and new strategies for hepatic regeneration. PMID- 26022692 TI - Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit? PMID- 26022691 TI - Splenectomy attenuates murine liver fibrosis with hypersplenism stimulating hepatic accumulation of Ly-6C(lo) macrophages. AB - BACKGROUND & AIMS: Splenectomy in cirrhotic patients has been reported to improve liver function; however the underlying mechanism remains obscure. In the present study, we investigated the mechanism using a murine model, which represents well the compensated liver cirrhosis. METHODS: C57BL/6 male mice were allowed to drink water including thioacetamide (TAA: 300 mg/L) ad libitum for 32 weeks. After splenectomy at 32 weeks, mice were sacrificed on days one, seven, and 28, respectively, while TAA-administration was continued. Perioperative changes in peripheral blood and liver tissues were analyzed. RESULTS: TAA treatment of mice for 32 weeks reproducibly achieved advanced liver fibrosis with splenomegaly, thrombocytopenia, and leukocytopenia. After splenectomy, liver fibrosis was attenuated, and macrophages/monocytes were significantly increased in peripheral blood, as well as in the liver. Progenitor-like cells expressing CK-19, EpCAM, or CD-133 appeared in the liver after TAA treatment, and gradually disappeared after splenectomy. Macrophages/monocytes accumulated in the liver, most of which were negative for Ly-6C, were adjacent to the hepatic progenitor-like cells, and quantitative RT-PCR indicated increased canonical Wnt and decreased Notch signals. As a result, a significant amount of beta-catenin accumulated in the progenitor-like cells. Moreover, relatively small Ki67-positive hepatic cells were significantly increased. Protein expression of MMP-9, to which Ly-6G positive neutrophils contributed, was also increased in the liver after splenectomy. CONCLUSIONS: The hepatic accumulation of macrophages/monocytes, most of which are Ly-6C(lo), the reduction of fibrosis, and the gradual disappearance of hepatic progenitor-like cells possibly play significant roles in the tissue remodeling process in cirrhotic livers after splenectomy. PMID- 26022694 TI - Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4. AB - BACKGROUND & AIMS: Regulation of bile acid homeostasis in mammals is a complex process regulated via extensive cross-talk between liver, intestine and intestinal microbiota. Here we studied the effects of gut microbiota on bile acid homeostasis in mice. METHODS: Bile acid homeostasis was assessed in four mouse models. Germfree mice, conventionally-raised mice, Asbt-KO mice and intestinal specific Gata4-iKO mice were treated with antibiotics (bacitracin, neomycin and vancomycin; 100 mg/kg) for five days and subsequently compared with untreated mice. RESULTS: Attenuation of the bacterial flora by antibiotics strongly reduced fecal excretion and synthesis of bile acids, but increased the expression of the bile acid synthesis enzyme CYP7A1. Similar effects were seen in germfree mice. Intestinal bile acid absorption was increased and accompanied by increases in plasma bile acid levels, biliary bile acid secretion and enterohepatic cycling of bile acids. In the absence of microbiota, the expression of the intestinal bile salt transporter Asbt was strongly increased in the ileum and was also expressed in more proximal parts of the small intestine. Most of the effects of antibiotic treatment on bile acid homeostasis could be prevented by genetic inactivation of either Asbt or the transcription factor Gata4. CONCLUSIONS: Attenuation of gut microbiota alters Gata4-controlled expression of Asbt, increasing absorption and decreasing synthesis of bile acids. Our data support the concept that under physiological conditions microbiota stimulate Gata4, which suppresses Asbt expression, limiting the expression of this transporter to the terminal ileum. Our studies expand current knowledge on the bacterial control of bile acid homeostasis. PMID- 26022693 TI - 3D molecular MR imaging of liver fibrosis and response to rapamycin therapy in a bile duct ligation rat model. AB - BACKGROUND & AIMS: Liver biopsy, the gold standard for assessing liver fibrosis, suffers from limitations due to sampling error and invasiveness. There is therefore a critical need for methods to non-invasively quantify fibrosis throughout the entire liver. The goal of this study was to use molecular Magnetic Resonance Imaging (MRI) of Type I collagen to non-invasively image liver fibrosis and assess response to rapamycin therapy. METHODS: Liver fibrosis was induced in rats by bile duct ligation (BDL). MRI was performed 4, 10, or 18 days following BDL. Some BDL rats were treated daily with rapamycin starting on day 4 and imaged on day 18. A three-dimensional (3D) inversion recovery MRI sequence was used to quantify the change in liver longitudinal relaxation rate (DeltaR1) induced by the collagen-targeted probe EP-3533. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for Sirius Red staining and hydroxyproline content. RESULTS: DeltaR1 increased significantly with time following BDL compared to controls in agreement with ex vivo measures of increasing fibrosis. Receiver operating characteristic curve analysis demonstrated the ability of DeltaR1 to detect liver fibrosis and distinguish intermediate and late stages of fibrosis. EP-3533 MRI correctly characterized the response to rapamycin in 11 out of 12 treated rats compared to the standard of collagen proportional area (CPA). 3D MRI enabled characterization of disease heterogeneity throughout the whole liver. CONCLUSIONS: EP-3533 allowed for staging of liver fibrosis, assessment of response to rapamycin therapy, and demonstrated the ability to detect heterogeneity in liver fibrosis. PMID- 26022695 TI - Differentiation of blood T cells: Reprogramming human induced pluripotent stem cells into neuronal cells. AB - BACKGROUND: Human induced pluripotent stem cells (iPSCs) morphologically and functionally resemble human embryonic stem cells, which presents the opportunity to use patient-specific somatic cells for disease modeling and drug screening. In order to take one step closer to clinical applications, it is important to generate iPSCs through a less invasive approach and from any accessible tissue, including peripheral blood. Meanwhile, how to differentiate blood cell-derived iPSCs into neuron-like cells is still unclear. METHODS: We utilized Epstein-Barr nuclear antigen-1-based episomal vectors, a nonviral system that can reprogram somatic cells into iPSCs in both feeder-dependent and feeder-free conditions, to generate iPSCs from T cells via electroporation and then induce them into neuronal cells. RESULTS: We successfully isolated sufficient T cells from 20 mL peripheral blood of the donors and reprogrammed these T cells into iPSCs within 4 weeks. These iPSCs could be stably passaged to at least 50 passages, and exhibited the abilities of pluripotency and multiple-lineage differentiation. Notably, under the medium induction for 21 days, these T-cell-derived iPSCs could be differentiated into Nestin (neural progenitor marker)-, GFAP (glial cell marker)-, and MAP2 (neuron cell marker)-positive cells detected by immunofluorescence methods. CONCLUSION: We have developed a safer method to generate integration-free and nonviral human iPSCs from adult somatic cells. This induction method will be useful for the derivation of human integration-free iPSCs and will also be applicable to the generation of iPSCs-derived neuronal cells for drug screening or therapeutics in the near future. PMID- 26022698 TI - Foreperiod and range effects on time interval categorization. AB - One factor influencing the perceived duration of a brief interval is the length of the period preceding it, namely the foreperiod (FP). When multiple FPs are varied randomly within a testing session, longer FPs result in longer perceived duration. The purpose of this study was to identify what characteristics modulate this effect. In a task where participants were asked to categorize the duration of target intervals with respect to a 100-ms standard, the FPs were distributed over a 150-, 300-, or 900-ms range with the midpoint (1000 ms) of these distributions being kept constant. The results indicate that the effect of the length of variable FPs on perceived duration was much stronger in the 900-ms range condition. More specifically, this effect is due to the differences between the shortest FPs. The results also reveal that, overall, there are more short responses in the 300-ms condition than in the other range conditions. Moreover, the data reveal that the narrower the distribution, the better the discrimination. One interpretation of the main result (range effect) is that a wider distribution leads to an increased prior uncertainty towards the foreperiod length. PMID- 26022696 TI - Elaboration and Innervation of the Vibrissal System in the Rock Hyrax (Procavia capensis). AB - Mammalian tactile hairs are commonly found on specific, restricted regions of the body, but Florida manatees represent a unique exception, exhibiting follicle sinus complexes (FSCs, also known as vibrissae or tactile hairs) on their entire body. The orders Sirenia (including manatees and dugongs) and Hyracoidea (hyraxes) are thought to have diverged approximately 60 million years ago, yet hyraxes are among the closest relatives to sirenians. We investigated the possibility that hyraxes, like manatees, are tactile specialists with vibrissae that cover the entire postfacial body. Previous studies suggested that rock hyraxes possess postfacial vibrissae in addition to pelage hair, but this observation was not verified through histological examination. Using a detailed immunohistochemical analysis, we characterized the gross morphology, innervation and mechanoreceptors present in FSCs sampled from facial and postfacial vibrissae body regions to determine that the long postfacial hairs on the hyrax body are in fact true vibrissae. The types and relative densities of mechanoreceptors associated with each FSC also appeared to be relatively consistent between facial and postfacial FSCs. The presence of vibrissae covering the hyrax body presumably facilitates navigation in the dark caves and rocky crevices of the hyrax's environment where visual cues are limited, and may alert the animal to predatory or conspecific threats approaching the body. Furthermore, the presence of vibrissae on the postfacial body in both manatees and hyraxes indicates that this distribution may represent the ancestral condition for the supraorder Paenungulata. PMID- 26022697 TI - Clinical, serologic, and immunogenetic characterization (HLA-DRB1) of late-onset lupus erythematosus in a Colombian population. AB - INTRODUCTION: Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup that is defined as onset after 50 years of age. Late-onset lupus may have a different clinical course and serological findings, which may delay diagnosis and timely treatment. OBJECTIVES: The objective of this paper is to determine the clinical, serologic, and immunogenetic differences among Colombian patients with late-onset SLE versus conventional SLE patients. METHODOLOGY: This was a cross-sectional study in a Colombian population. Patients and their medical records were analyzed from the services of Rheumatology in Bogota and met the criteria for SLE, according to the American College of Rheumatology (ACR) revised criteria for the classification of SLE.In a reference group of late-onset SLE patients (98 participants, with an onset after 50 years of age) and a group of conventional SLE patients (72 participants, with an onset of age of 49 years or less), multiple clinical variables (age, clinical criteria for lupus, alopecia, weight loss, fever, Raynaud's phenomenon) and multiple serological variables (blood count, blood chemistry profile, autoantibodies) were analyzed. Additionally, the HLA class II (DRB1) of all the patients was genotyped, including an additional group of patients without the autoimmune disease. Statistical analysis was performed using the STATA 10.0 package. RESULTS: In the group of late-onset lupus, there was a higher frequency of pleurisy (p = 0.002), pericarditis (p = 0.026), dry symptoms (p = 0.029), lymphopenia (p = 0.007), and higher titers of rheumatoid factor (p = 0.001) compared with the group of conventional SLE. Late-onset SLE patients had a lower seizure frequency (p = 0.019), weight loss (p = 0.009), alopecia (p < 0.001), and Raynaud's phenomenon (p = 0.013) compared to the conventional SLE group. In late-onset SLE, HLA DR17 (DR3) was found more frequently compared with individuals without autoimmune disease (OR 3.81, 95% CI 1.47 to 10.59) (p = 0.0016). CONCLUSION: In the Colombian SLE population analyzed, there may be a probable association of several clinical and serologic variants, which would allow the differentiation of variables in the presentation of the disease among patients with late-onset SLE vs. conventional SLE. PMID- 26022699 TI - The role of policy actors and contextual factors in policy agenda setting and formulation: maternal fee exemption policies in Ghana over four and a half decades. AB - BACKGROUND: Development of health policy is a complex process that does not necessarily follow a particular format and a predictable trajectory. Therefore, agenda setting and selecting of alternatives are critical processes of policy development and can give insights into how and why policies are made. Understanding why some policy issues remain and are maintained whiles others drop off the agenda is an important enquiry. This paper aims to advance understanding of health policy agenda setting and formulation in Ghana, a lower middle-income country, by exploring how and why the maternal (antenatal, delivery and postnatal) fee exemption policy agenda in the health sector has been maintained over the four and half decades since a 'free antenatal care in government facilities' policy was first introduced in October 1963. METHODS: A mix of historical and contemporary qualitative case studies of nine policy agenda setting and formulation processes was used. Data collection methods involved reviews of archival materials, contemporary records, media content, in-depth interviews, and participant observation. Data was analysed drawing on a combination of policy analysis theories and frameworks. RESULTS: Contextual factors, acting in an interrelating manner, shaped how policy actors acted in a timely manner and closely linked policy content to the intended agenda. Contextual factors that served as bases for the policymaking process were: political ideology, economic crisis, data about health outcomes, historical events, social unrest, change in government, election year, austerity measures, and international agendas. Nkrumah's socialist ideology first set the agenda for free antenatal service in 1963. This policy trajectory taken in 1963 was not reversed by subsequent policy actors because contextual factors and policy actors created a network of influence to maintain this issue on the agenda. Politicians over the years participated in the process to direct and approve the agenda. Donors increasingly gained agenda access within the Ghanaian health sector as they used financial support as leverage. CONCLUSION: Influencers of policy agenda setting must recognise that the process is complex and intertwined with a mix of political, evidence-based, finance-based, path-dependent, and donor-driven processes. Therefore, influencers need to pay attention to context and policy actors in any strategy. PMID- 26022700 TI - The Influence of Social Disadvantage on Children's Emotional and Behavioral Difficulties at Age 4-7 Years. AB - OBJECTIVE: To examine associations between indicators of social disadvantage and emotional and behavioral difficulties in children aged 4-7 years. STUDY DESIGN: This cross-sectional study was based on data collected in a questionnaire completed by parents of children enrolled in their first year of school in Victoria, Australia, in 2010. Just over 57000 children participated (86% of children enrolled), of whom complete data were available for 38955 (68% of the dataset); these children formed the analysis sample. The outcome measure was emotional and behavioral difficulties, assessed by the Strengths and Difficulties Questionnaire Total Difficulties score. Logistic regression analyses were undertaken. RESULTS: Having a concession card (a government-issued card enabling access to subsidized goods and services, particularly in relation to medical care, primarily for economically vulnerable households) was the strongest predictor of emotional and behavioral difficulties (OR, 2.71; 95% CI, 2.39-3.07), followed by living with 1 parent and the parent's partner or not living with either parent (OR, 1.93; 95% CI, 1.58-2.37) and having a mother who did not complete high school (OR, 1.27; 95% CI, 1.11-1.45). CONCLUSION: These findings may assist schools and early childhood practitioners in identifying young children who are at increased risk of emotional and behavioral difficulties, to provide these children, together with their parents and families, with support from appropriate preventive interventions. PMID- 26022701 TI - Elemental sulfur formation and nitrogen removal from wastewaters by autotrophic denitrifiers and anammox bacteria. AB - Elemental sulfur (S(0)) formation from and nitrogen removal on sulfide, nitrate and ammonium-laden wastewaters were achieved by denitrifying ammonium oxidation (DEAMOX) reactor with autotrophic denitrifiers and anaerobic ammonium oxidation (anammox) bacteria. The sulfide to nitrate ratio is a key process parameter for excess accumulation of S(0) and a ratio of 1.31:1 is a proposed optimum. The Alishewanella, Thauera and Candidatus Anammoximicrobium present respectively the autotrophic denitrifiers and anammox bacteria for the reactor. DEAMOX is demonstrated promising biological process for treating organics-deficient (S+N) wastewaters with excess S(0) production. PMID- 26022702 TI - Personalized virotherapy in cancer. PMID- 26022704 TI - Endoscopic Gallbladder Drainage in Medically Inoperable Patients with Symptomatic Cholelithiasis: A Tube to Avoid "Going Down the Tubes"? PMID- 26022703 TI - Imported Lassa fever: a report of 2 cases in Ghana. AB - BACKGROUND: Lassa fever is a potentially fatal acute viral illness caused by Lassa virus which is carried by rodents and is endemic in some West African countries. Importation of emerging infections such as Lassa fever, Ebola Virus Disease and other viral hemorrhagic fevers into non endemic regions is a growing threat particularly as international travel and commitments in resolving conflicts in endemic countries in the West Africa sub-region continue. CASE PRESENTATION: We report the first two recorded imported cases of Lassa fever among Ghanaian Peace keepers in rural Liberia, who became ill while on Peace keeping mission. They were subsequently evacuated to the UN level IV hospital in Accra, where their illnesses were laboratory confirmed. One of the patients recovered with ribavirin treatment and supportive therapy. No secondary clinical cases occurred in Ghana. CONCLUSIONS: Healthcare providers at all levels of care should thus have a high index of suspicion for these infectious diseases and adopt standard infection control measures when treating patients in endemic regions or returning travelers from an endemic region with a febrile illness even of a known etiology. PMID- 26022705 TI - A 59-Year-Old Woman with Upper Gastrointestinal Hemorrhage: Understanding the Gist of GISTs. PMID- 26022707 TI - Erratum to: Comparison of the acceptability and benefits of two mindfulness-based interventions in women with breast or gynecologic cancer: a pilot study. PMID- 26022706 TI - Factors influencing work functioning after cancer diagnosis: a focus group study with cancer survivors and occupational health professionals. AB - PURPOSE: Cancer survivors (CSs) frequently return to work, but little is known about work functioning after return to work (RTW). We aimed to identify barriers and facilitators of work functioning among CSs. METHODS: Three focus groups were conducted with CSs (n = 6, n = 8 and n = 8) and one focus group with occupational health professionals (n = 7). Concepts were identified by thematic analysis, using the Cancer and Work model as theoretical framework to structure the results. RESULTS: Long-lasting symptoms (e.g. fatigue), poor adaptation, high work ethics, negative attitude to work, ambiguous communication, lack of support and changes in the work environment were mentioned as barriers of work functioning. In contrast, staying at work during treatment, open dialogue, high social support, appropriate work accommodations and high work autonomy facilitated work functioning. CONCLUSIONS: Not only cancer-related symptoms affect work functioning of CSs after RTW but also psychosocial and work-related factors. The barriers and facilitators of work functioning should be further investigated in studies with a longitudinal design to examine work functioning over time. PMID- 26022708 TI - GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies. PMID- 26022709 TI - Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. AB - Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18 70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972. PMID- 26022710 TI - Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120). AB - Multiple myeloma is preceded by an asymptomatic phase, comprising monoclonal gammopathy of uncertain significance and smoldering myeloma. Compared to the former, smoldering myeloma has a higher and non-uniform rate of progression to clinical myeloma, reflecting a subset of patients with higher risk. We evaluated the gene expression profile of smoldering myeloma plasma cells among 105 patients enrolled in a prospective observational trial at our institution, with a view to identifying a high-risk signature. Baseline clinical, bone marrow, cytogenetic and radiologic data were evaluated for their potential to predict time to therapy for symptomatic myeloma. A gene signature derived from four genes, at an optimal binary cut-point of 9.28, identified 14 patients (13%) with a 2-year therapy risk of 85.7%. Conversely, a low four-gene score (< 9.28) combined with baseline monoclonal protein < 3 g/dL and albumin >= 3.5 g/dL identified 61 patients with low-risk smoldering myeloma with a 5.0% chance of progression at 2 years. The top 40 probe sets showed concordance with indices of chromosome instability. These data demonstrate high discriminatory power of a gene-based assay and suggest a role for dysregulation of mitotic checkpoints in the context of genomic instability as a hallmark of high-risk smoldering myeloma. PMID- 26022712 TI - Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. PMID- 26022713 TI - Lethality of Opioid Overdose in a Community Cohort of Young Heroin Users. AB - BACKGROUND: The aim of the study was to estimate the lethality of opioid overdose among young heroin users. METHODS: A prospective community cohort study was conducted in Barcelona and Madrid, Spain. Participants included 791 heroin users aged 18-30 years who were followed up between 2001 and 2006. Fatal overdoses were identified by record linkage of the cohort with the general mortality register, while non-fatal overdoses were self-reported at baseline and follow-up interviews. The person-years (py) at risk were computed for each participant. Fatal and non-fatal overdose rates were estimated by city. Transition towards injection shortly before the overdose could not be measured. Overdose lethality (rate of fatal overdose in proportion to total overdose) and its 95% CI was estimated using Bayesian models. RESULTS: The adjusted rates of fatal and non fatal opioid overdose were 0.7/100 py (95% CI: 0.4-1.1) and 15.8/100 py (95% CI: 14.3-17.6), respectively. The adjusted lethality was 4.2% (95% CI: 2.5-6.5). CONCLUSIONS: Four out of 100 opioid overdoses are fatal. These are preventable deaths that could be avoided before or after the overdose takes place. Resources are urgently needed to prevent fatal opioid overdose. PMID- 26022711 TI - The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. AB - Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/MUL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells. PMID- 26022714 TI - Is Planktonic Diversity Well Recorded in Sedimentary DNA? Toward the Reconstruction of Past Protistan Diversity. AB - Studies based on the coupling of a paleolimnological approach and molecular tools (e.g., sequencing of sedimentary DNA) present a promising opportunity to obtain long-term data on past lacustrine biodiversity. However, certain validations are still required, such as the evaluation of DNA preservation in sediments for various planktonic taxa that do not leave any morphological diagnostic features. In this study, we focused on the diversity of planktonic unicellular eukaryotes and verified the presence of their DNA in sediment archives. We compared the molecular inventories (high-throughput sequencing of 18S ribosomal DNA) obtained from monitoring the water column with those obtained for DNA archived in the first 30 cm of sediment. Seventy-one percent of taxonomic units found in the water samples were detected in sediment samples, including pigmented taxa, such as Chlorophyta, Dinophyceae, and Chrysophyceae, phagotrophic taxa, such as Ciliophora, parasitic taxa, such as Apicomplexa and Chytridiomycota, and saprotrophs, such as Cryptomycota. Parallel analysis of 18S ribosomal RNA (rRNA) transcripts revealed the presence of living eukaryotic taxa only in the top 2 cm of sediment; although some limits exist in using RNA/DNA ratio as indicator of microbial activity, these results suggested that the sedimentary DNA mostly represented DNA from past and inactive communities. Only the diversity of a few groups, such as Cryptophyta and Haptophyta, seemed to be poorly preserved in sediments. Our overall results showed that the application of sequencing techniques to sedimentary DNA could be used to reconstruct past diversity for numerous planktonic eukaryotic groups. PMID- 26022715 TI - A Perspective on the Global Pandemic of Waterborne Disease. AB - Waterborne diseases continue to take a heavy toll on the global community, with developing nations, and particularly young children carrying most of the burden of morbidity and mortality. Starting with the historical context, this article explores some of the reasons why this burden continues today, despite our advances in public health over the past century or so. While molecular biology has revolutionized our abilities to define the ecosystems and etiologies of waterborne pathogens, control remains elusive. Lack of basic hygiene and sanitation, and failing infrastructure, remain two of the greatest challenges in the global fight against waterborne disease. Emerging risks continue to be the specter of multiple drug resistance and the ease with which determinants of virulence appear to be transmitted between strains of pathogens, both within and outside the human host. PMID- 26022716 TI - Outcome Predictors of Acute Stroke Patients in Need of Intensive Care Treatment. AB - BACKGROUND: The prognosis of stroke patients admitted to intensive care units (ICU) is commonly regarded to be poor. However, only limited data regarding outcome predictors are available. PATIENTS AND METHODS: Out of 4,958 consecutive patients admitted to our stroke unit with the diagnosis of acute stroke, after analysis we identified 347 patients (164 male) in need of ICU management. In hospital and post-rehabilitation mortality as well as functional outcome at discharge and after rehabilitation were analyzed. RESULTS: Ischemic stroke was diagnosed in 252 patients (72.6%) and intracerebral hemorrhage occurred in 95 patients (27.4%). The mean age in our cohort was considerably high (70.8 years). One hundred patients were comatose at admission. The median NIHSS score at admission in the remaining patients was 12. Apart from stroke-related disturbances of consciousness (47.1%), the most common reasons for ICU treatment were cardiac (23.4%) and respiratory (12.1%) complications or interventional procedures requiring mechanical ventilation (11%). In all, 231/347 patients (66.6%) were mechanically ventilated (mean 84 h). In-hospital mortality (143/347; 41.2%) was associated with old age, poor NIHSS score at admission, intracerebral hemorrhage and mechanical ventilation (p < 0.001 in all). Further, admission to ICU because of stroke-related impairment of consciousness increased in-hospital mortality (p < 0.001). Similarly, poor outcome after rehabilitation was associated with old age (p = 0.029) and mechanical ventilation (p < 0.001). In patients >=80 years with either intracerebral hemorrhage or need of mechanical ventilation, outcome was unfavorable in nearly any case. However, the overall post-rehabilitation outcome did not differ between patients with intracerebral hemorrhage and ischemic stroke (p = 0.275). CONCLUSION: The stroke population in our study was associated with an increased early mortality; however, given the same conditions, it was old with a high percentage of patients requiring mechanical ventilation. This did not result in increased in-hospital mortality rates compared to younger and less severely affected cohorts. Thus, ICU management is a life-saving initiative even among the elderly. However, the functional outcome was poor in older patients, thus limiting the benefits of ICU care in these patients. PMID- 26022717 TI - Study of gaseous benzene effects upon A549 lung epithelial cells using a novel exposure system. AB - Volatile organic compounds (VOCs) are ubiquitous pollutants known to be present in both indoor and outdoor air arising from various sources. Indoor exposure has increasingly become a major cause of concern due to the effects that such pollutants can have on health. Benzene, along with toluene, is one of the main components of the VOC mixture and is a known carcinogen due to its genotoxic effects. The aim of this study was to test the feasibility of an in vitro model to study the short-term effects of exposure of lung cells to airborne benzene. We studied the effects of exposure on DNA and the production of reactive oxygen species (ROS) in A549 cells, exposed to various concentrations of benzene (0.03; 0.1; 0.3 ppm) in gaseous form using a custom designed cell exposure chamber. Results showed a concentration-dependent increase of DNA breaks and an increase of ROS production, confirming the feasibility of the experimental procedure and validating the model for further in vitro studies of exposure to other VOCs. PMID- 26022718 TI - Glutathione metabolism in the HaCaT cell line as a model for the detoxification of the model sensitisers 2,4-dinitrohalobenzenes in human skin. AB - Glutathione (GSH) is the most prominent antioxidant in cells and the co-factor of an important set of enzymes involved in the skin metabolic clearance system, glutathione S-transferases (GST). Here, we describe an LC-MS (liquid chromatography-mass spectroscopy) method to measure GSH and its disulfide form (GSSG) in HaCaT cells and a 3D Reconstructed Human Epidermis (RHE) model. In our assay, the basal level of GSH in both systems was in the low nmol/mg soluble protein range, while the level of GSSG was systematically below our limit of quantification (0.1 MUM). We found that 2,4-dinitrohalobenzenes deplete the GSH present in HaCaT cells within the first hour of exposure, in a dose dependent manner. The level of GSH in HaCaT cells treated with a single non-toxic dose of 10 MUM of dinitrohalobenzene was also shown to increase after two hours. While cells treated with 1-chloro-2,4-dinitrobenzene (DNCB) and 1-fluoro-2,4 dinitrobenzene (DNFB) repleted GSH to levels similar to untreated control cells within 24h, 1-bromo-2,4-dinitrobenzene (DNBB) seemed to prevent such a repletion and appeared to be the most toxic compound in all assays. A mathematical modelling of experimental results was performed to further rationalise the differences observed between test chemicals. For this purpose the biological phenomena observed were simplified into two sequential events: the initial depletion of the GSH stock after chemical treatment followed by the repletion of the GSH once the chemical was cleared. Activation of the nuclear factor E2 related factor 2 (Nrf2) pathway was observed with all compounds within two hours, and at concentrations less than 10 MUM. These data show that GSH depletion and repletion occur rapidly in skin cells and emphasize the importance of conducting kinetic studies when performing in vitro experiments exploring skin sensitization. PMID- 26022719 TI - Photo-induced sol-gel processing for low-temperature fabrication of high performance silsesquioxane membranes for use in molecular separation. AB - Silsesquioxane (SQ) membranes derived from 3-methacryloxypropyltrimethoxysilane and bis(trimethoxysilyl)ethane were successfully fabricated at low temperature via photo-induced sol-gel processing. Radical and cationic polymerization of SQ membranes showed high degrees of separation factor and permeance for water/isopropanol separation in pervaporation. PMID- 26022720 TI - Relationship between social support during pregnancy and postpartum depressive state: a prospective cohort study. AB - Although the association between social support and postpartum depression has been previously investigated, its causal relationship remains unclear. Therefore, we examined prospectively whether social support during pregnancy affected postpartum depression. Social support and depressive symptoms were assessed by Japanese version of Social Support Questionnaire (J-SSQ) and Edinburgh Postnatal Depression Scale (EPDS), among 877 pregnant women in early pregnancy and at one month postpartum. First, J-SSQ was standardized among peripartum women. The J-SSQ was found to have a two-factor structure, with Number and Satisfaction subscales, by exploratory and confirmatory factor analyses. Analysis of covariance was performed to examine how EPDS and J-SSQ scores during pregnancy affected the EPDS score at postpartum. Significant associations were found between postpartum EPDS score and both EPDS and total scores on the Number subscales during pregnancy (beta = 0.488 and -0.054, ps < 0.001). Specifically, this negative correlation was stronger in depressive than non-depressive groups. Meanwhile, total score on Satisfaction subscales was not significantly associated with postpartum EPDS score. These results suggest that having a larger number of supportive persons during pregnancy helps protect against postpartum depression, and that this effect is greater in depressive than non-depressive pregnant women. This finding is expected to be vitally important in preventive interventions. PMID- 26022721 TI - Hemodiafiltration improves free light chain removal and normalizes kappa/lambda ratio in hemodialysis patients. AB - BACKGROUND/AIMS: Serum free light chain (FLC) levels are correlated with chronic kidney disease (CKD) stages and are highest in patients on hemodialysis (HD). Aim of this study was to assess the FLC removal efficiency of ElisioTM-210H dialyzer using either high-flux HD or on line high efficiency hemodiafiltration (HDF) modalities in CKD-5D patients. METHODS: In this prospective and comparative study, 20 CKD-5D patients free from multiple myeloma were randomized in two groups: HD versus on line HDF. All patients were dialyzed with ElisioTM-210H dialyzer. Serum samples were collected before and after the midweek dialysis session, before randomization and at the end of the study to measure kappa and lambda FLC concentrations. Reduction ratios were corrected for net ultrafiltration. RESULTS: For both HD and HDF mode, kappa and lambda FLC concentrations were significantly lower after dialysis than before but median reductions in kappa and lambda FLC levels were significantly higher in HDF versus HD groups (kappa 73.5 vs. 65.5 %, p = 0.04 and lambda 51.0 vs. 36.6 %, p = 0.07). After dialysis, all kappa/lambda ratio values were between 0.26 and 1.65 which is the reference range described in subjects with normal kidney function, for both HD and HDF groups (median kappa/lambda ratios were 0.80 [0.47-1.22] and 0.67 [0.50-0.79] respectively). CONCLUSION: This study shows the superiority of on line HDF compared with HD to remove both kappa and lambda FLC. Moreover, all post dialysis kappa/lambda ratios reached normal reference range. PMID- 26022722 TI - Treatment effect, adherence, and safety of high fluid intake for the prevention of incident and recurrent kidney stones: a systematic review and meta-analysis. AB - BACKGROUND: The objective of this systematic review and meta-analysis were to evaluate the effectiveness of high fluid intake for the prevention of incident and recurrent kidney stones, as well as its adherence and safety. METHODS: A literature search was performed encompassing 1980 through July 2014. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of kidney stone events in patients with high vs inadequate fluid intake were included. Pooled risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. RESULTS: Nine studies [2 randomized controlled trials (RCTs) with 269 patients; 7 observational studies with 273,685 individuals] were included in the meta-analysis. Pooled RRs of kidney stones in individuals with high-fluid intake were 0.40 (95 % CI 0.20 0.79) and 0.49 (0.34-0.71) in RCTs and observational studies, respectively. High fluid intake was significantly associated with reduced risk of recurrent kidney stones: RRs 0.40 (95 % CI 0.20-0.79) and 0.20 (0.09-0.44) in RCTs and observational studies, respectively. Adherence and safety data on high fluid intake treatment were limited; 1 RCT reported no withdrawals due to adverse events. CONCLUSION: This analysis demonstrated a significantly reduced risk of incident kidney stones among individuals with high fluid consumption. High fluid consumption also reduced the risk of recurrent kidney stones. Furthermore, the magnitude of risk reduction was high. Although increased water intake appears to be safe, future studies on its safety in patients with high risk of volume overload or hyponatremia may be indicated. PMID- 26022724 TI - Near-Infrared Squaraine Dye Encapsulated Micelles for in Vivo Fluorescence and Photoacoustic Bimodal Imaging. AB - Combined near-infrared (NIR) fluorescence and photoacoustic imaging techniques present promising capabilities for noninvasive visualization of biological structures. Development of bimodal noninvasive optical imaging approaches by combining NIR fluorescence and photoacoustic tomography demands suitable NIR active exogenous contrast agents. If the aggregation and photobleaching are prevented, squaraine dyes are ideal candidates for fluorescence and photoacoustic imaging. Herein, we report rational selection, preparation, and micelle encapsulation of an NIR-absorbing squaraine dye (D1) for in vivo fluorescence and photoacoustic bimodal imaging. D1 was encapsulated inside micelles constructed from a biocompatible nonionic surfactant (Pluoronic F-127) to obtain D1 encapsulated micelles (D1(micelle)) in aqueous conditions. The micelle encapsulation retains both the photophysical features and chemical stability of D1. D1(micelle) exhibits high photostability and low cytotoxicity in biological conditions. Unique properties of D1(micelle) in the NIR window of 800-900 nm enable the development of a squaraine-based exogenous contrast agent for fluorescence and photoacoustic bimodal imaging above 820 nm. In vivo imaging using D1(micelle), as demonstrated by fluorescence and photoacoustic tomography experiments in live mice, shows contrast-enhanced deep tissue imaging capability. The usage of D1(micelle) proven by preclinical experiments in rodents reveals its excellent applicability for NIR fluorescence and photoacoustic bimodal imaging. PMID- 26022723 TI - Severe acute kidney injury following cardiac surgery: short-term outcomes in patients undergoing continuous renal replacement therapy (CRRT). AB - BACKGROUND: Acute kidney injury (AKI) represents a major complication of cardiac surgery. Our aim was to evaluate, in patients undergoing continuous renal replacement therapy (CRRT) for cardiac surgery-associated AKI (CS-AKI), prognostic factors related to in-hospital survival and renal function recovery to independence from RRT. METHODS: We conducted a retrospective analysis in patients with severe CS-AKI who underwent CRRT for at least 48 h. The sequential organ failure assessment (SOFA) score was calculated on a daily basis to evaluate illness severity throughout the intensive care unit (ICU) stay. RESULTS: In 264 patients (age 66.4 +/- 11.7 years, 192 males), 30-day survival was 57.6 % while survival to discharge from the hospital was 40.5 %. Renal function recovery occurred in 96.3 % of survivors and in 13.4 % of non-survivors (p < 0.001). Multivariate analysis selected advancing age, oliguria, sepsis and the highest level of SOFA score within the first week of CRRT (SOFA-max) as independent prognostic factors for failure to recover renal function. Female gender was associated with a higher probability of survival, while higher serum creatinine at the start of CRRT, oliguria, sepsis and SOFA-max were independently associated with mortality. The subgroup of patients with a day-1 SOFA score above the median (>=10) showed a lower probability of survival and a lower cumulative incidence of renal function recovery. CONCLUSIONS: In a selected population of patients with severe CS-AKI requiring RRT, short-term outcomes appear strongly associated with the worst grade of illness severity during the first week of CRRT, thus reflecting the sequential occurrence of additional major complications during ICU stay. Renal function recovery and in-hospital survival appear mutually linked, sharing oliguria, sepsis and SOFA score as the main determinants of both outcomes. PMID- 26022725 TI - Detection of boronic acid derivatives in cells using a fluorescent sensor. AB - The detection of boron-containing compounds requires very expensive facilities and/or tedious sample pretreatments. In an effort to develop a convenient detection method for boronic acid derivatives, boron chelating-ligands were synthesized for use as fluorescent sensors. In this paper, the synthesis and properties of fluorescent sensors for boronic acid derivatives are reported. PMID- 26022726 TI - Con: Ambulatory blood pressure measurement in patients receiving haemodialysis: a sore arm and a waste of time? AB - Ambulatory blood pressure monitoring (ABPM) has become popular in the investigation and management of patients with essential hypertension. In patients receiving haemodialysis, ABPM identifies patients who may fare worse in the long term. However, the available studies are small, and when conventional risk factors are included, there is no added value to ABPM over conventional BP measurements. In haemodialysis, ABPM remains an experimental investigation, and in the absence of specific, evidence-based targets for blood pressure in this population, it would be better to invest in large-scale trials to provide specific blood pressure targets and strategies, rather than concentrating on an alternative technique for blood pressure measurement. PMID- 26022727 TI - Moderator's view: Ambulatory blood pressure monitoring and home blood pressure for the prognosis, diagnosis and treatment of hypertension in dialysis patients. AB - Major health agencies now recommend the systematic application of ambulatory blood pressure monitoring (ABPM) for the diagnosis of hypertension. Given the exceedingly high prevalence of nocturnal hypertension, masked and white coat hypertension and the overt inadequacy of peridialysis (pre-, intra- and post dialysis) BP measurements, more extensive application of ABPM for the diagnosis of hypertension in dialysis patients would appear logical. In a recent survey performed in NDT Educational, organizational problems and/or cognitive resistance emerged as important factors hindering more extensive application of ABPM and home BP by nephrologists. External validation of observations made in landmark studies in a single institution about hypertension subcategorization by ABPM is urgently needed. Furthermore, apparent cognitive resistance by nephrologists may be justified by the fact that these techniques have been insufficiently tested in the dialysis population for applicability in everyday clinical practice, tolerability, organizational impact and cost-effectiveness. We should be more resolute in abandoning peridialysis measurements for diagnosing and treating hypertension in haemodialysis patients. Home BP is a formidable educational instrument for patient empowerment and self-care, and evidence exists that this technique is superior to peridialysis values to better hypertension control as defined on the basis of ABPM. We should strive to promote more extensive application of home BP monitoring to diagnose and manage hypertension in haemodialysis patients. ABPM with novel, user friendly and better tolerated techniques is to be awaited in the near future. PMID- 26022728 TI - Pro: Ambulatory blood pressure should be used in all patients on hemodialysis. AB - In the adult population in general and among people with chronic kidney disease in particular, it is now well established that hypertension is a major driver of renal disease progression and cardiovascular morbidity and mortality. Although the contribution of hypertension to cardiovascular morbidity and mortality among patients on long-term dialysis continues to be debated, a major barrier to detect hypertension as a risk factor for cardiovascular events in these patients has been the inability to diagnose hypertension. Largely to blame has been the easy availability of pre-dialysis and post-dialysis blood pressure recordings in stark contrast to ambulatory blood pressure measurements in dialysis patients to accurately diagnose the presence or control of hypertension. It is increasingly becoming clear that out-of-office blood pressure recordings are superior to clinic recordings in making a diagnosis, assessing target organ damage, evaluating prognosis and managing patients with hypertension. In this debate, I have been asked to defend the position that ambulatory blood pressure recordings should be systematically applied to all patients on hemodialysis. PMID- 26022729 TI - Discussions around goals of care: An ethical imperative. PMID- 26022730 TI - Aortic dilatation in patients with Turner's syndrome without structural cardiac anomaly. AB - INTRODUCTION: Dilatation of the ascending aorta is described in Turner's syndrome with variable prevalence (6.8-32%). Reported series typically include patients with associated cardiac anomalies. OBJECTIVE: To characterise the prevalence, age of onset, and the progress of dilatation of the ascending aorta in Turner's syndrome patients free of structural cardiac anomalies. Potential risk factors such as karyotype and growth hormone therapy were analysed for correlation with aortic dilatation. METHODS: We carried out a retrospective study with data collected from medical records and echocardiography studies. Patients with Tuner's syndrome followed-up between 1992 and 2010 with at least two echocardiography studies were eligible. Patients with previous cardiac surgery or under anti-hypertensive medication were excluded. Ascending aorta diameter measurements were adjusted for body surface area, and dilatation was defined as Z score>2. RESULTS: The study population consisted of 44 patients, aged 11.9+/-7.4 years at the first echocardiogram and 17.9+/-7.3 years at the last follow-up, with a follow-up duration of 6.0+/-3.7 years. A total of 13 (29.5%) patients exhibited aortic dilatation during follow-up, suggesting an actuarial estimate of the freedom from aortic dilatation dropping from 86 to 70% and then to 37% at 10, 20, and 30 years of age, respectively. There was no statistically significant impact of karyotype or growth hormone therapy on aortic Z-score progression. CONCLUSION: The prevalence of dilatation of the ascending aorta in Turner's syndrome patients free of structural aortic anomalies is comparable with published data with associated lesions. Growth hormone therapy and karyotype had no significant impact; however, longitudinal follow-up is warranted. PMID- 26022731 TI - Effect of different irrigant activation protocols on push-out bond strength. AB - The study aimed to evaluate the effect of various final irrigant activation protocols on push-out bond strength of fiber post. Thirty-two single-rooted human maxillar central teeth were sectioned below the cementoenamel junction, instrumented and obturated. Post-space preparation was performed, and roots were randomly divided into eight groups (n = 4) according to the final irrigant activation protocols; distilled water was used as an irrigant in group 1. The other groups were treated with 2.5% NaOCl and 17% EDTA. Conventional syringe irrigation (CSI, no activation) was used in group 2. Irrigation solutions were activated using passive ultrasonic irrigation (PUI, group 3), EndoVac apical negative pressure (ANP, group 4), diode laser (group 5), neodymium:yttrium aluminum-garnet (Nd:YAG) laser (group 6), erbium:yttrium-aluminum-garnet (Er:YAG) laser (group 7), and Er:YAG laser using with photon-induced photoacoustic streaming (PIPSTM) technique (group 8). In all groups, fiber posts (White Post DC, FGM) were luted using Panavia F 2.0 (Kuraray, Osaka, Japan). The specimens were transversally sectioned, and all slices from coronal and apical regions were subjected to push-out tests. The data were calculated as megapascals and analyzed by using two-way analysis of variance followed by post hoc Tukey honestly significant difference (HSD) tests. Removing the smear layer increased the bond strength to dentine when compared with the control group (p < 0.05). The highest bond strength was obtained in the PIPS laser-activated irrigation group (p < 0.05). Coronal root region presented significantly higher bond strength than the apical region (p < 0.05). PIPS laser-activated irrigation showed higher efficiency as a final irrigant activation protocol on push-out bond strength of fiber post. PMID- 26022732 TI - Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates. AB - The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme alpha-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy. PMID- 26022734 TI - bmj.com at 20 years. PMID- 26022735 TI - Index to Estimate the Efficiency of an Ophthalmic Practice. AB - IMPORTANCE: A metric of efficiency, a function of the ratio of quality to cost per patient, will allow the health care system to better measure the impact of specific reforms and compare the effectiveness of each. OBJECTIVE: To develop and evaluate an efficiency index that estimates the performance of an ophthalmologist's practice as a function of cost, number of patients receiving care, and quality of care. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 36 ophthalmology subspecialty practices from October 2011 to September 2012 at a university-based eye institute. EXPOSURES: The efficiency index (E) was defined as a function of adjusted number of patients (N(a)), total practice adjusted costs (C(a)), and a preliminary measure of quality (Q). Constant b limits E between 0 and 1. Constant y modifies the influence of Q on E. Relative value units and geographic cost indices determined by the Centers for Medicare and Medicaid for 2012 were used to calculate adjusted costs. The efficiency index is expressed as the following: E = b(N(a)/C(a))Q(y). Independent, masked auditors reviewed 20 random patient medical records for each practice and filled out 3 questionnaires to obtain a process-based quality measure. MAIN OUTCOMES AND MEASURES: The adjusted number of patients, adjusted costs, quality, and efficiency index were calculated for 36 ophthalmology subspecialties. RESULTS: The median adjusted number of patients was 5516 (interquartile range, 3450 11,863), the median adjusted cost was 1.34 (interquartile range, 0.99-1.96), the median quality was 0.89 (interquartile range, 0.79-0.91), and the median value of the efficiency index was 0.26 (interquartile range, 0.08-0.42). CONCLUSIONS AND RELEVANCE: The described efficiency index is a metric that provides a broad overview of performance for a variety of ophthalmology specialties as estimated by resources used and a preliminary measure of quality of care provided. The results of the efficiency index could be used in future investigations to determine its sensitivity to detect the impact of interventions on a practice such as training modules or practice restructuring. PMID- 26022733 TI - An Inducible Caspase-9 Suicide Gene to Improve the Safety of Therapy Using Human Induced Pluripotent Stem Cells. AB - Human induced pluripotent stem cells (hiPSC) hold promise for regenerative therapies, though there are several safety concerns including the risk of oncogenic transformation or unwanted adverse effects associated with hiPSC or their differentiated progeny. Introduction of the inducible caspase-9 (iC9) suicide gene, which is activated by a specific chemical inducer of dimerization (CID), is one of the most appealing safety strategies for cell therapies and is currently being tested in multicenter clinical trials. Here, we show that the iC9 suicide gene with a human EF1alpha promoter can be introduced into hiPSC by lentiviral transduction. The transduced hiPSC maintain their pluripotency, including their capacity for unlimited self-renewal and the potential to differentiate into three germ layer tissues. Transduced hiPSC are eliminated within 24 hours of exposure to pharmacological levels of CID in vitro, with induction of apoptosis in 94-99% of the cells. Importantly, the iC9 suicide gene can eradicate tumors derived from hiPSC in vivo. In conclusion, we have developed a direct and efficient hiPSC killing system that provides a necessary safety mechanism for therapies using hiPSC. We believe that our iC9 suicide gene will be of value in clinical applications of hiPSC-based therapy. PMID- 26022736 TI - Thymoquinone prevents RANKL-induced osteoclastogenesis activation and osteolysis in an in vivo model of inflammation by suppressing NF-KB and MAPK Signalling. AB - Osteoclasts are multinuclear giant cells responsible for bone resorption in inflammatory bone diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Because of deleterious side effects with currently available drugs the search continues for novel effective and safe therapies. Thymoquinone (TQ), the major bioactive component of Nigella sativa has been investigated for its anti-inflammatory, antioxidant and anticancer activities. However, its effects in osteoclastogenesis have not been reported. In the present study we show for the first time that TQ inhibits nuclear factor-KB ligand (RANKL) induced osteoclastogenesis in RAW 264.7 and primary bone marrow derived macrophages (BMMs) cells. RANKL induced osteoclastogenesis is associated with increased expression of multiple transcription factors via activation of NF-KB, MAPKs signalling and reactive oxygen species (ROS). Mechanistically TQ blocked the RANKL induced NF-KB activation by attenuating the phosphorylation of IkB kinase (IKKalpha/beta). Interestingly, in RAW 264.7 cells TQ inhibited the RANKL induced phosphorylation of MAPKs and mRNA expression of osteoclastic specific genes such as TRAP, DC-STAMP, NFATc1 and c-Fos. In addition, TQ also decreased the RANKL stimulated ROS generation in macropahges (RAW 264.7) and H2O2 induced ROS generation in osteoblasts (MC-3T3-E1). Consistent with in vitro results, TQ inhibited lipopolysaccharide (LPS) induced bone resorption by suppressing the osteoclastogenesis. Indeed, micro-CT analysis showed that bone mineral density (BMD) and bone architecture parameters were positively modulated by TQ. Taken together our data demonstrate that TQ has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-KB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors. PMID- 26022737 TI - Characterization of the Glycosylation Site of Human PSA Prompted by Missense Mutation using LC-MS/MS. AB - Prostate specific antigen (PSA) is currently used as a diagnostic biomarker for prostate cancer. It is a glycoprotein possessing a single glycosylation site at N69. During our previous study of PSA N69 glycosylation, additional glycopeptides were observed in the PSA sample that were not previously reported and did not match glycopeptides of impure glycoproteins existing in the sample. This extra glycosylation site of PSA is associated with a mutation in KLK3 genes. Among single nucleotide polymorphisms (SNPs) of KLKs families, the rs61752561 in KLK3 genes is an unusual missense mutation resulting in the conversion of D102 to N in PSA amino acid sequence. Accordingly, a new N-linked glycosylation site is created with an N102MS motif. Here we report the first qualitative and quantitative glycoproteomic study of PSA N102 glycosylation site by LC-MS/MS. We successfully applied tandem MS to verify the amino acid sequence possessing N102 glycosylation site and associated glycoforms of PSA samples acquired from different suppliers. Among the three PSA samples, HexNAc2Hex5 was the predominant glycoform at N102, while HexNAc4Hex5Fuc1NeuAc1 or HexNAc4Hex5Fuc1NeuAc2 was the primary glycoforms at N69. D102 is the first amino acid of "kallikrein loop", which is close to a zinc-binding site and catalytic triad. The different glycosylation of N102 relative to N69 might be influenced by the close vicinity of N102 to these functional sites and steric hindrance. PMID- 26022738 TI - The Effects of Sub-Chronic Treatment with Aripiprazole on Pentylenetetrazole- and Electroshock-Induced Seizures in Mice: The Role of Nitric Oxide. AB - Almost all antipsychotics have been associated with a risk of epileptic seizure provocation. Aripiprazole is a novel atypical antipsychotic. The risk of seizures with aripiprazole is reported to be the lowest among atypical agents. In this study, we investigated the effect of aripiprazole on seizure of mice in sub chronic treatments. We also examined the interaction of nitric oxide (NO) with aripiprazole in seizure experiments. Mice received aripiprazole for 6 days and then on the 7th day aripiprazole was injected 60 min before intraperitoneal pentylenetetrazole or electroshock. L-NAME (non-selective NO synthase (NOS) inhibitor), 7-nitroindazole (neuronal NOS selective inhibitor), aminoguanidine (inducible NOS selective inhibitors) or L-arginine (NO donor), all were injected 5 min before aripiprazole in separate groups. The results of both seizure models demonstrated anti-epileptic properties of aripiprazole in sub-chronic administrations. Co-administration of aripiprazole and selective and non selective NOS inhibitors prevented the anticonvulsant effect of aripiprazole. While L-arginine and aripiprazole co-administration increased the clonic seizure threshold and protection against tonic seizure and death, these effects were not significant. The current results indicated that aripiprazole has anticonvulsant effects probably through the release of NO. PMID- 26022739 TI - Influence of non-cardiac comorbidities on outcome after percutaneous mitral valve repair: results from the German transcatheter mitral valve interventions (TRAMI) registry. AB - AIMS: To investigate the influence of non-cardiac comorbidities on outcomes of patients enrolled in the German transcatheter mitral valve interventions (TRAMI) registry. METHODS AND RESULTS: Intrahospital and 30-day MACCE rates (death of all causes, stroke and myocardial infarction) of 828 patients from the TRAMI registry were stratified by the number of non-cardiac comorbidities. The following non cardiac comorbidities were prospectively recorded in the registry: diabetes, renal insufficiency, extracardiac arteriopathy, chronic lung disease, neurological disease or malignancy on palliative care. The 375 (45.3 %) patients with multiple (>=2) non-cardiac comorbidities presented with higher NYHA classes, higher logistic Euroscores, higher levels of NT-proBNP and a shorter 6-min walk distance. Rates of intraprocedural death (0.3 vs. 0.0 %, p = 0.41) and intrahospital MACCE (3.6 vs. 1.9 %, p = 0.16) were not significantly higher in patients with multiple non-cardiac comorbidities, but 30-day MACCE rate was significantly enhanced (6.4 vs. 3.6 %, p = 0.049). However, both patient groups showed a similar clinical improvement after 30 days. Renal insufficiency was the only non-cardiac comorbidity which was independently associated with the 30-day MACCE rate. CONCLUSIONS: MitraClip device placement is feasible and safe in patients with multiple non-cardiac comorbidities resulting in a significant clinical improvement and acceptable intrahospital and 30-day event rates. Renal failure is an independent predictor of outcome. PMID- 26022740 TI - Discrimination of cell cycle phases in PCNA-immunolabeled cells. AB - BACKGROUND: Protein function in eukaryotic cells is often controlled in a cell cycle-dependent manner. Therefore, the correct assignment of cellular phenotypes to cell cycle phases is a crucial task in cell biology research. Nuclear proteins whose localization varies during the cell cycle are valuable and frequently used markers of cell cycle progression. Proliferating cell nuclear antigen (PCNA) is a protein which is involved in DNA replication and has cell cycle dependent properties. In this work, we present a tool to identify cell cycle phases and in particular, sub-stages of the DNA replication phase (S-phase) based on the characteristic patterns of PCNA distribution. Single time point images of PCNA immunolabeled cells are acquired using confocal and widefield fluorescence microscopy. In order to discriminate different cell cycle phases, an optimized processing pipeline is proposed. For this purpose, we provide an in-depth analysis and selection of appropriate features for classification, an in-depth evaluation of different classification algorithms, as well as a comparative analysis of classification performance achieved with confocal versus widefield microscopy images. RESULTS: We show that the proposed processing chain is capable of automatically classifying cell cycle phases in PCNA-immunolabeled cells from single time point images, independently of the technique of image acquisition. Comparison of confocal and widefield images showed that for the proposed approach, the overall classification accuracy is slightly higher for confocal microscopy images. CONCLUSION: Overall, automated identification of cell cycle phases and in particular, sub-stages of the DNA replication phase (S-phase) based on the characteristic patterns of PCNA distribution, is feasible for both confocal and widefield images. PMID- 26022741 TI - Assessment of the European Union's illicit trade agreements with the four major Transnational Tobacco Companies. AB - To address the illicit cigarette trade, the European Union (EU) has signed agreements with the four major Transnational Tobacco Companies (TTCs) that involve establishing extensive systems of cooperation. All agreements foresee two types of payments: annual payments (totalling US$ 1.9 billion over 20 years) and supplementary seizure payments, equivalent to 100% of the evaded taxes in the event of seizures of their products. While limited by the fundamental lack of transparency in this area, our analysis suggests that these agreements have served largely to secure the TTCs' interests and are threatening progress in tobacco control. The seizure payments are paltry and a wholly inadequate deterrent to TTC involvement in illicit trade. Despite the agreements, growing evidence indicates the TTCs remain involved in the illicit trade or are at best failing to secure their supply chains as required by the agreements. The intention of the seizure-based payments to deter the tobacco industry from further involvement in the illicit cigarette trade has failed because the agreements contain too many loopholes that provide TTCs with both the incentive and opportunity to classify seized cigarettes as counterfeit. In addition, the shifting nature of cigarette smuggling from larger to smaller consignments often results in seizures that are too small to qualify for the payments. Consequently, the seizure payments represent a tiny fraction of the revenue lost from cigarette smuggling, between 2004 and 2012, 0.08% of the estimated losses due to illicit cigarette trade in the EU. Our evidence suggests the EU should end these agreements. PMID- 26022742 TI - Thalassemia Major: Who Is Afraid of Serum Ferritin below 500 MUg/l? PMID- 26022744 TI - Perfectionism and burnout in women professional golfers. AB - BACKGROUND: Perfectionism and burnout have been thought to affect performance in sports. The aim of current study was to analyze differences between members of the Korean Ladies Professional Association (KLPGA) and non-KLPGA golfers as they relate to perfectionism, burnout and commitment as well as analyze the relationship between the same psychological factors and golf score during a 3-day professional golf tournament. METHODS: Participants were 245 LPGA athletes and 233 non-LPGA athletes, all of whom were members of the Korean Golf Association. Participants were assessed using Multidimensional Perfectionism Scale, Athletes Burnout Questionnaires, Expansion of Sports Commitment Model and State-Trait Anxiety Inventory-Y. RESULTS: Perfectionism (t=48.47, P<0.001) and burnout (t=3.5, P=0.01) scores in the KLPGA group were lower than those observed in the non-KLPGA group (Mann-Whitney U Test). Sport devaluation of burnout (t=3.84, P<0.001) was also lower in the KLPGA group than the non-KLPGA group (Mann-Whitney U Test). Perfectionism, burnout, and psychological factors were also found to be associated with golf scores during a 3-day professional golf tournament. There were significant differences in score change patterns from the first 9-holes of round 1 (R1) to the last 9-holes of R1 (F=10.92, P=0.003), as well as from the first 9-holes of R3 to the last 9-holes of R3 (F=4.47, P=0.04) between the LPGA top 10 group and LPGA non-top 10 group (repeated measures ANOVA). First 9-hole scores of R1 were positively correlated with total perfectionism (r=0.58, P=0.001), total burnout (r=0.50, P=0.008), and state anxiety (r=0.50, P=0.0049) (spearman correlation). CONCLUSIONS: Findings suggest that golfers seeking to attain high levels of performance must consider the importance of the mental aspect of the game of golf, and find ways to minimize stress and perfectionist strivings. PMID- 26022743 TI - Cell cycle progression is regulated by intertwined redox oscillators. AB - The different phases of the eukaryotic cell cycle are exceptionally well preserved phenomena. DNA decompaction, RNA and protein synthesis (in late G1 phase) followed by DNA replication (in S phase) and lipid synthesis (in G2 phase) occur after resting cells (in G0) are committed to proliferate. The G1 phase of the cell cycle is characterized by an increase in the glycolytic metabolism, sustained by high NAD+/NADH ratio. A transient cytosolic acidification occurs, probably due to lactic acid synthesis or ATP hydrolysis, followed by cytosolic alkalinization. A hyperpolarized transmembrane potential is also observed, as result of sodium/potassium pump (NaK-ATPase) activity. During progression of the cell cycle, the Pentose Phosphate Pathway (PPP) is activated by increased NADP+/NADPH ratio, converting glucose 6-phosphate to nucleotide precursors. Then, nucleic acid synthesis and DNA replication occur in S phase. Along with S phase, unpublished results show a cytosolic acidification, probably the result of glutaminolysis occurring during this phase. In G2 phase there is a decrease in NADPH concentration (used for membrane lipid synthesis) and a cytoplasmic alkalinization occurs. Mitochondria hyperfusion matches the cytosolic acidification at late G1/S transition and then triggers ATP synthesis by oxidative phosphorylation. We hypothesize here that the cytosolic pH may coordinate mitochondrial activity and thus the different redox cycles, which in turn control the cell metabolism. PMID- 26022745 TI - Effects of rhythmical and extra-rhythmical qualities of music on heart rate during stationary bike activities. AB - BACKGORUND: The aim of this study was to evaluate the effects of rhythmical and extra-rhythmical qualities of music on the heart rate (HR) and rates of perceived exertion (RPE), during sub-maximal stationary bike activity. METHODS: HR of 28 female adult participants was monitored during 3 session of physical activity, performed under 3 different conditions: Hi-BPM (music with 150-170 BPM), RHYTHM (rhythmical qualities only of Hi-BPM condition) and control condition without music (CONTROL). Four parameters were analyzed: the highest HR value (High-HR), High-HR minus starting HR (?HR), time to reach the 75% of Maximal HR (MHR) (TimeTo75%) and time over 75% MHR (TimeOver75%). HR trend analysis was performed to evaluate differences among the three conditions. OMNI-Cycle Scale was administered to evaluate RPE. RESULTS: MANOVA showed significant differences between the three conditions in TimeTo75%, ?HR (P<0.01) and TimeOver75% (P<0.05). In RHYTHM and CONTROL conditions after reaching 75% MHR, the HR increase were significantly lower than Hi-BPM (P<0.01). No significant differences were found in OMNI-Cycle Scale scores of Hi-BPM and RHYTHM whereas RPE was significantly higher in CONTROL condition (P<0.05). CONCLUSIONS: Hi-BPM and RHYTHM music allowed a faster reaching of the aerobic training zone compared to CONTROL conditions. Nevertheless, after 75% MHR, extra-rhythmical qualities are necessary to maintain or to increase the working HR levels. PMID- 26022746 TI - Exercise-induced muscle damage following dance and sprint-specific exercise in females. AB - BACKGROUND: There is a paucity of studies investigating exercise-induced muscle damage (EIMD) in females and only one in response to dance-type exercise. This study sought to firstly elucidate the physiological profile of EIMD following a dance-specific protocol, and second to compare the magnitude of damage to that experienced following a sport-specific protocol in physically active females. METHODS: Twenty-nine female recreational dancers (19+/-1 years) were recruited. Participants completed either a dance-specific protocol (DPFT; N.=15) or sport specific repeated sprint protocol (SSRS; N.=14). Muscle soreness, limb girths, creatine kinase (CK), countermovement jump height (CMJ), reactive strength index (RSI), maximal voluntary contraction (MVC) and 30 m sprint time were recorded pre, 0-, 24-, 48-, and 72 h post exercise. RESULTS: The DPFT induced muscle damage, with significant time effects for all variables except RSI. However the response was acute, and muscle function returned to near-baseline levels by 48 h. Although no group differences existed, there were significant interaction effects; notably in CMJ (P=0.038) where the decline at 0 h (-6.9%) was smaller and recovery was greater at 72 h (which exceeded pre-exercise levels by 3.7%) post DPFT compared to post SSRS. CONCLUSIONS: The results offer new information showing that dance-specific activity results in EIMD in females. In addition, the magnitude of damage was similar to repeated sprint exercise and demonstrated that, in this population, recovery from these strenuous activities takes several days. These data have important implications for understanding the consequences of dance activity and other strenuous exercise in females. PMID- 26022747 TI - Differences in physical performance between U-20 and senior top-level Brazilian futsal players. AB - BACKGROUND: The aim of this study was to compare performance in the Yo-Yo IR1, 20 meter sprint, COD test, loaded and unloaded lower-limb muscle power tests (squat jump [SJ], countermovement jump [CMJ] and jump squat [JS] tests), as well as resting and exercise heart rate variability parameters in high-level senior professional and under-20 (U-20) futsal players. METHODS: All the players (18 senior and 15 U-20 male players) performed the Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1), 20-m sprint, COD test, loaded and unloaded lower-limb power tests (SJ, CMJ and JS tests), as well as resting and post-exercise log transformed root-mean-square difference of successive normal RR intervals (lnRMSSD) recording. The t-test for independent samples and magnitude-based inference were used to compare the groups. RESULTS: Seniors were likely to very likely superior than U-20 in the Yo-Yo IR1 (1506.7+/-287.1 and 1264.0+/-397.9 m, P<0.05), and resting (3.43+/-0.32 and 3.21+/-0.37 ms) and post-exercise lnRMSSD (2.95+/-0.39 and 2.48+/-0.59 ms, P<0.05). Conversely, U-20 players performed very likely to almost certainly better than seniors in the relative mean propulsive power (10.39+/-1.60 and 9.05+/-1.57 W/kg, P<0.05), 20-m sprint time (2.92+/-0.10 and 3.05+/-0.10 s, P<0.05) and COD (5.50+/-0.15 and 5.71+/-0.22 s, P<0.05). CONCLUSIONS: Findings from this cross-sectional study indicate that long-term exposure to futsal may lead to improvement in the aerobic fitness and cardiac autonomic regulation, while impairing the muscle power and speed performance of players. Future longitudinal studies are necessary to confirm the occurrence of such concurrent training adaptations. PMID- 26022748 TI - Automated methods for hippocampus segmentation: the evolution and a review of the state of the art. AB - The segmentation of the hippocampus in Magnetic Resonance Imaging (MRI) has been an important procedure to diagnose and monitor several clinical situations. The precise delineation of the borders of this brain structure makes it possible to obtain a measure of the volume and estimate its shape, which can be used to diagnose some diseases, such as Alzheimer's disease, schizophrenia and epilepsy. As the manual segmentation procedure in three-dimensional images is highly time consuming and the reproducibility is low, automated methods introduce substantial gains. On the other hand, the implementation of those methods is a challenge because of the low contrast of this structure in relation to the neighboring areas of the brain. Within this context, this research presents a review of the evolution of automatized methods for the segmentation of the hippocampus in MRI. Many proposed methods for segmentation of the hippocampus have been published in leading journals in the medical image processing area. This paper describes these methods presenting the techniques used and quantitatively comparing the methods based on Dice Similarity Coefficient. Finally, we present an evaluation of those methods considering the degree of user intervention, computational cost, segmentation accuracy and feasibility of application in a clinical routine. PMID- 26022750 TI - The effect of Hypericum perforatum L. (St. John's Wort) on prevention of myringosclerosis after myringotomy in a rat model. AB - OBJECTIVES: The purpose of this study was to identify the possible effects of Hypericum Perforatum (HP) on the prevention of experimentally induced myringosclerosis (MS). METHODS: Twenty eight Wistar Albino rats were used and they were divided into four groups. Tympanic membranes of all animals were perforated and then group I had no treatment as a control group, group II had treated with olive oil only, group III had treated with HP orally and group IV had treated with HP topically. RESULTS: Groups I and II showed extensive myringosclerosis in contrast to those of Groups III and IV which had significantly less changes (p<0.05). The inflammation and fibrosis in the lamina propria of the tympanic membranes of Groups I and II were found to be significantly more pronounced (p<0.05). The tympanic membranes were found to be significantly thinner in Groups III and IV when compared with Groups I and II (p<0.05). CONCLUSIONS: The results of the present study suggested that oral or topical administration of HP extract after myringotomy suppressed the inflammation and fibroblastic activity in the lamina propria of the myringotomized TMs of the rats. Further clinical studies with larger population using HP and other antioxidants will be essential to provide further evidence for use of antioxidant therapy in patients with myringotomy and ventilation tube insertion for otitis media with effusion. PMID- 26022749 TI - Subperiosteal abscesses in acute mastoiditis in 115 Swedish children. AB - OBJECTIVES: To study the outcome of different surgical methods of treating subperiosteal abscesses resulting from acute mastoiditis. METHODS: Medical records for all children from a Swedish retrospective multicentre study, conducted between 1993 and 2007, with acute mastoiditis and subperiosteal abscess, but without predisposing diseases or other complications, were studied. A total of 115 children aged 0-16 years were identified. All patients had received intravenous antibiotics and most had undergone myringotomy. RESULTS: Thirty-three children had been treated with only minor interventions such as retroauricular needle aspiration and/or incision, while 67 had undergone mastoidectomy. Fifteen had undergone both needle aspiration and mastoidectomy. The group treated with needle aspiration/incision was compared with those treated with mastoidectomy. One of the few significant differences found between the groups was a longer hospital stay in the group that had undergone mastoidectomy. CONCLUSIONS: Retroauricular needle aspiration and/or incision combined with intravenous antibiotics and myringotomy was an effective first-line treatment for subperiosteal abscesses resulting from acute mastoiditis. In this retrospective study, no greater risk of further complications was seen in this group compared to the group in which mastoidectomy was performed. PMID- 26022751 TI - Toxicity of lanthanum oxide (La2O3) nanoparticles in aquatic environments. AB - This study demonstrates the acute toxicity of lanthanum oxide nanoparticles (La2O3 NP) on two sentinel aquatic species, fresh-water microalgae Chlorella sp. and the crustacean Daphnia magna. The morphology, size and charge of the nanoparticles were systematically studied. The algal growth inhibition assay confirmed absence of toxic effects of La2O3 NP on Chlorella sp., even at higher concentration (1000 mg L(-1)) after 72 h exposure. Similarly, no significant toxic effects were observed on D. magna at concentrations of 250 mg L(-1) or less, and considerable toxic effects were noted in higher concentrations (effective concentration [EC50] 500 mg L(-1); lethal dose [LD50] 1000 mg L(-1)). In addition, attachment of La2O3 NP on aquatic species was demonstrated using microscopy analysis. This study proved to be beneficial in understanding acute toxicity in order to provide environmental protection as part of risk assessment strategies. PMID- 26022752 TI - When practice and policy conflict: blood cultures in community-acquired pneumonia. AB - Optimal evidence-based management of patients with uncomplicated community acquired pneumonia in the emergency department (ED) setting remains a topic of discussion. This discussion was recently revitalized by a 2014 study published in JAMA Internal Medicine by Makam et al showing an increase in the use of blood cultures for patients with community-acquired pneumonia during ED visits from 29.4% of patients in 2002 to 51.1% in 2010. As the authors acknowledge, one of the most likely explanations could be the former pneumonia core measures required by the Centers for Medicaid & Medicare Services and the Joint Commission, potentially encouraging both ED and inpatient providers to reflexively order cultures. As these measures were the subject of fierce debate in the emergency medicine literature almost a decade ago, with recent policy changes affecting practicing clinicians, we aimed to briefly revisit the developments and concerning guidelines and discuss some important potentials for research in this setting. PMID- 26022753 TI - Visits by the elderly to United States EDs for alcohol-related disorders. AB - OBJECTIVES: The objectives are to estimate the number of elderly patients presenting to emergency departments (EDs) in the United States from 2006 to 2011 for alcohol-related disorders and examine their demographic and clinical features. METHODS: This study used 2006 to 2011 data from the Nationwide ED Sample, a stratified, multistage sample designed to give national estimates of US ED visits each year. Clinical Classifications Software 660 code ("alcohol-related disorders") was used. The clinical and demographic features that were examined were as follows: number of admissions, disposition, sex, age, expected payer, income, geographic region, charges, and primary diagnoses and procedures performed. RESULTS: From 2006 to 2011, there were 1620345 ED visits for alcohol related disorders in elderly patients. Roughly one-third were discharged from the ED, whereas 66% (1078677) were admitted to the hospital. Approximately 73% were male, and the mean age was 73 years. Most patients used Medicare (84%), resided in neighborhoods with the lowest median income national quartile (29%), and lived in the South (36.4%). The average charge for discharged patients was $4274.95 (4050.30-4499.61) and $37857.20 (36813.00-38901.40) for admitted patients. The total charges for all patients treated and released from the ED were $2166082965.40 and admitted was $40835690924.40. CONCLUSIONS: This study provided insight not only into the sociodemographic characteristics of this patient population but also the health care costs related to alcohol-related ED visits. These results may contribute to the development of future interventions targeted toward this population. PMID- 26022754 TI - Validation of cerebrospinal fluid findings in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Recently proposed cutoff criteria for cerebrospinal fluid (CSF) analyses might safely exclude a diagnosis of aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: The objective of this study was to examine the sensitivity of a CSF red blood cell (RBC) count greater than 2000 * 10(6)/L (ie, 2000 RBCs per microliter) or the presence of visible CSF xanthochromia in identifying patients with aSAH. METHODS: We identified a retrospective case series of patients diagnosed with aSAH after lumbar puncture (LP) in an integrated health delivery system between January 2000 and June 2013 by chart review. All identified patients had at least 1 cerebral aneurysm that was treated with a neurosurgical or endovascular intervention during the index hospitalization. The lowest CSF RBC count was used for validation analysis. Cerebrospinal fluid color was determined by visual inspection. Xanthochromia was defined as pink, orange, or yellow pigmentation of CSF supernatant. RESULTS: Sixty-four patients met study inclusion criteria. Of these, 17 (33%) of 52 underwent LP within 12 hours of headache onset, and 49 (84%) of 58 exhibited CSF xanthochromia. The median CSF RBC count was 63250 * 10(6)/L. The sensitivity of a CSF RBC count of greater than 2000 * 10(6)/L in identifying aSAH was 96.9% (95% confidence interval, 89.3%-99.1%). Additional consideration of CSF xanthochromia resulted in a sensitivity of 100% (95% confidence interval, 94.3%-100%). CONCLUSIONS: All patients in this case series of patients with aSAH had either a CSF RBC count greater than 2000 * 10(6)/L or visible CSF xanthochromia, increasing the likelihood that this proposed cutoff strategy may safely identify patients who warrant further investigation for an aneurysmal cause of subarachnoid hemorrhage. PMID- 26022755 TI - Neuronavigation-guided transcranial magnetic stimulation of the dentate nucleus improves cerebellar ataxia: A sham-controlled, double-blind n = 1 study. PMID- 26022756 TI - IAPRD annual report - 2014. PMID- 26022757 TI - Controlled mechanotransduction in therapeutic MSCs: can remotely controlled magnetic nanoparticles regenerate bones? PMID- 26022758 TI - Toward an 'off the shelf' technology for burn victims: healing wounds with mesenchymal stem cells. PMID- 26022760 TI - World Stem Cell Summit 2014. 3-5 December 2014, San Antonio, TX, USA. AB - Among the many international conferences in the field of stem cells and regenerative medicine, WSCS is distinct in focusing its efforts to serve as the meeting point by multisector communities of research, clinics, industry, regulation, policy making and ethics. All are aiming at advancing stem cell innovation and new therapies, under the banner of 'connect, collaborate and cure'. As same as past years, presenters and attendees included not only researchers but also clinicians, funding agencies, government officials, industries and patients. Thus, many sessions focused on the clinical translation from basic research. Another important agenda were industrial and social aspects, and problems to be solved before realization of practical and sustainable stem cell-based therapies. PMID- 26022761 TI - US clinics marketing unproven and unlicensed adipose-derived autologous stem cell interventions. PMID- 26022762 TI - Increases in plasma Tbeta4 after intracardiac cell therapy in chronic ischemic heart failure is associated with symptomatic improvement. AB - AIM: Tbeta4 is an integral factor in repair of myocardium in animal models. To investigate whether Tbeta4 is important in human cardiac disease and has a role in mediating the beneficial cardiac effects of bone-marrow-derived stem cell (BMSC) therapy, we measured serial plasma Tbeta4 levels in patients enrolled on the REGENERATE-IHD cell therapy trial. PATIENTS & METHODS: Plasma Tbeta4 concentrations were measured in 13 patients who received BMSCs and 14 controls. RESULTS: There was a significant increase in plasma Tbeta4 in the BMSC group 24 h after intracardiac injection. Increases in Tbeta4 levels were associated with improvement in New York Heart Association symptom class. CONCLUSION: This exploratory study highlights the need for further study of Tbeta4 in human cardiovascular disease. PMID- 26022763 TI - Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. AB - BACKGROUND: Mesenchymal stem cells (MSC) are easily harvested, and possess anti inflammatory and trophic properties. Furthermore, MSC promote neuroprotection and neurogenesis, which could greatly benefit neurodegenerative disorders, such as Parkinson's disease. METHODS: MSC were transplanted one week after 6 hydroxydopamine lesioning and effects were evaluated after 6 months. RESULTS: MSC localized around the substantia nigra and the arachnoid mater, expressing pericyte and endothelial markers. MSC protected dopamine levels and upregulated peripheral anti-inflammatory cytokines. Furthermore, adipose-derived MSC increased neurogenesis in hippocampal and subventricular regions, and boosted memory functioning. CONCLUSION: Considering that hyposmia and loss of memory function are two major nonmotor symptoms in Parkinson's disease, transplants with modulatory effects on the hippocampus and subventricular zone could provide a disease-modifying therapy. PMID- 26022765 TI - Comparison of human dental follicle cells and human periodontal ligament cells for dentin tissue regeneration. AB - AIM: To compare the odontogenic potential of human dental follicle cells (DFCs) and periodontal ligament cells (PDLCs). MATERIALS & METHODS: In vitro and in vivo characterization studies of DFCs and PDLCs were performed comparatively. DFCs and PDLCs were subcutaneously implanted into the dorsum of mice for 8 weeks after combined with treated dentin matrix scaffolds respectively. RESULTS: Proteomic analysis identified 32 differentially expressed proteins in DFCs and PDLCs. Examination of the harvested grafts showed PDLCs could form the dentin-like tissues as DFCs did. However, the structure of dentin tissues generated by DFCs was more complete. CONCLUSION: PDLCs could contribute to regenerate dentin-like tissues in the inductive microenvironment of treated dentin matrix. DFCs presented more remarkable dentinogenic capability than PDLCs did. PMID- 26022766 TI - Stem cell-based therapy of corneal epithelial and endothelial diseases. AB - Corneal dysfunction is the second leading cause of blindness. Approximately 10 million patients worldwide are affected by some form of corneal disease. More than 50,000 cornea transplants are performed every year, but this procedure is limited by cornea donation availability. Recently, new cell replacement procedures have been developed to treat a variety of corneal diseases. This review will focus on the recent advances in the use of limbal epithelial stem cells (LESCs) to treat corneal epithelial cell deficiency and improvements in replacing dysfunctional corneal endothelial cells (CECs) with exogenous CECs. Several protocols have been developed to differentiate pluripotent stem cells into LESC- or CEC-like cells, potentially yielding an unlimited source for the cell replacement therapy of corneal diseases. PMID- 26022764 TI - Increased yield of endothelial cells from peripheral blood for cell therapies and tissue engineering. AB - AIM: Peripheral blood-derived endothelial cells (pBD-ECs) are an attractive tool for cell therapies and tissue engineering, but have been limited by their low isolation yield. We increase pBD-EC yield via administration of the chemokine receptor type 4 antagonist AMD3100, as well as via a diluted whole blood incubation (DWBI). MATERIALS & METHODS: Porcine pBD-ECs were isolated using AMD3100 and DWBI and tested for EC markers, acetylated LDL uptake, growth kinetics, metabolic activity, flow-mediated nitric oxide production and seeded onto titanium tubes implanted into vessels of pigs. RESULTS: DWBI increased the yield of porcine pBD-ECs 6.6-fold, and AMD3100 increased the yield 4.5-fold. AMD3100-mobilized ECs were phenotypically indistinguishable from nonmobilized ECs. In porcine implants, the cells expressed endothelial nitric oxide synthase, reduced thrombin-antithrombin complex systemically and prevented thrombosis. CONCLUSION: Administration of AMD3100 and the DWBI method both increase pBD-EC yield. PMID- 26022767 TI - Cells and stimuli in small-caliber blood vessel tissue engineering. AB - The absence of successful solutions in treatments of small-caliber vessel diseases led to the Vascular Tissue Engineering approach to develop functional nonimmunogenic tissue engineered blood vessels. In this context, the choice of cells to be seeded and the microenvironment conditioning are pivotal. Biochemical and biomechanical stimuli seem to activate physiological regulatory pathways that induce the production of molecules and proteins stimulating stem cell differentiation toward vascular lineage and reproducing natural cross-talks among vascular cells to improve the maturation of tissue engineered blood vessels. Thus, this review focuses on (1) available cell sources, and (2) biochemical and biomechanical stimuli, with the final aim to obtain the long-term stability of the endothelium and mechanical properties suitable for withstanding physiological load. PMID- 26022768 TI - EIF4G1 mutations do not cause Parkinson's disease. AB - EIF4G1 mutations were previously reported as a cause of Parkinson's disease (PD). As a result of this finding, considerable work has been performed to test this idea and to examine the functional role of eukaryotic translation initiation factor 4-gamma in the pathogenic process underlying PD. Here, we show that the originally described mutation is likely a rare benign variant. We tested this variant in a very large series of subjects and show that it is more frequent in controls than cases. We argue here that this infers that EIF4G1 mutations are not related to PD. PMID- 26022769 TI - JNK-interacting protein 1 mediates Alzheimer's-like pathological features in AICD transgenic mice. AB - Amyloid precursor protein, which generates amyloid beta peptides, is intimately associated with Alzheimer's disease (AD) pathogenesis. We previously showed that transgenic mice overexpressing amyloid precursor protein intracellular domain (AICD), a peptide generated simultaneously with amyloid beta, develop AD-like pathologies, including hyperphosphorylated tau, loss of synapses, and memory impairments. AICD is known to bind c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1), a scaffold protein that associates with and activates JNK. The aim of this study was to examine the role of JIP1 in AICD-induced AD-like pathologies in vivo, since the JNK pathway is aberrantly activated in AD brains and contributes to AD pathologies. We generated AICD-Tg mice lacking the JIP1 gene (AICD; JIP1(-/-)) and found that although AICD; JIP1(-/-) mice exhibit increased AICD, the absence of JIP1 results in decreased levels of hyperphosphorylated tau and activated JNK. AICD; JIP1(-/-) mice are also protected from synaptic loss and show improved performance in behavioral tests. These results suggest that JIP1 mediates AD-like pathologies in AICD-Tg mice and that JNK signaling may contribute to amyloid-independent mechanisms of AD pathogenesis. PMID- 26022771 TI - Influence of socioeconomic status on the association between body mass index and cause-specific mortality among older Japanese adults: The AGES Cohort Study. AB - OBJECTIVE: Many studies have suggested a U-shaped curve for the association between body size and mortality risks, i.e., mortality risks increase in those who are both overweight and underweight. The strength of the associations may vary according to socioeconomic statuses (SES), as they determine levels of access to healthcare and psychosocial stresses. We investigated the modifying effects of SES on the relationship between body mass index (BMI) and mortality. METHOD: We used prospective cohort data of participants in the Aichi Gerontological Evaluation Study in 2003 (n=14,931), who were 65years or older and physically and cognitively independent at baseline, and residing in eight municipalities in Japan. Data on all-causes mortality and mortality from cancer, cardiovascular disease, and respiratory disease was obtained from municipal government registries. RESULTS: Proportional hazard regression analyses showed that, among men, the associations between overweight (BMI>=25kg/m(2)) and higher mortality risks by any cause were stronger among lower income groups. Even adjusting for multiple confounding factors, hazard ratios (95% confidence intervals) for mortality by all causes among low income group (household income<1.5 million yen) were 1.96 (1.02-3.73) for overweight compared with BMIs between 23.0 and 24.9, whereas they were 0.94 (0.57-1.38) among men in high income group (income>3 million yen). The modifying effects of income were not marked among women. CONCLUSION: Household income, which may directly reflect accessibility to healthcare and psychosocial stress among older Japanese men, may be an important modifying factor in the health risks attributable to overweight. PMID- 26022770 TI - Effects of noninvasive brain stimulation on cognitive function in healthy aging and Alzheimer's disease: a systematic review and meta-analysis. AB - The study aimed to evaluate the effects of noninvasive brain stimulation on cognitive function in healthy older adults and patients with Alzheimer's disease. A comprehensive literature search was performed on noninvasive stimulation studies published from January 1990 to November 2014 in Pubmed and Web of Science. Fourteen articles with a total of 331 participants were identified as studies with healthy older adults, and the mean effect size and 95% confidence interval were estimated. A significant effect size of 0.42 was found for the cognitive outcome. Further subgroup analyses demonstrated more prominent effects for studies delivering the stimulation before the execution of the task and studies applying multiple sessions of stimulation. To assess the effects of stimulation on Alzheimer's disease patients, 11 studies with a total of 200 patients were included in the analysis. A significant effect size of 1.35 was found for the cognitive outcomes. Subgroup analyses indicated more pronounced effects for studies applying the stimulation during the execution of the task compared with studies delivering the stimulation before the execution of the task. Noninvasive brain stimulation has a positive effect on cognitive function in physiological and pathological aging. PMID- 26022772 TI - Do psychosocial factors moderate the association between objective neighborhood walkability and older adults' physical activity? AB - This study investigated moderating effects of psychosocial factors on the association between walkability and physical activity (PA) in 433 Belgian older adults. Furthermore, main effects of psychosocial factors on PA were determined. No moderating effects were observed for the associations between walkability and transport walking, or moderate-to-vigorous PA (MVPA). Walkability was positively associated with recreational walking in those with high self-efficacy. Regarding main effects, benefits and social norm were positively associated with recreational walking. Benefits were positively and barriers were negatively associated with MVPA. There were no significant main effects for transport walking. The overall lack of moderation suggests that environmental interventions might enhance all older adults' transport walking and MVPA. Recreational walking might be enhanced by simultaneously targeting self-efficacy and neighborhood environmental factors. PMID- 26022773 TI - Does conurbation affect the risk of poor mental health? A population based record linkage study. AB - To determine if urban residence is associated with an increased risk of anxiety/depression independent of psychosocial stressors, concentrated disadvantage or selective migration between urban and rural areas, this population wide record-linkage study utilised data on receipt of prescription medication linked to area level indicators of conurbation and disadvantage. An urban/rural gradient in anxiolytic and antidepressant use was evident that was independent of variation in population composition. This gradient was most pronounced amongst disadvantaged areas. Migration into increasingly urban areas increased the likelihood of medication. These results suggest increasing conurbation is deleterious to mental health, especially amongst residents of deprived areas. PMID- 26022774 TI - The Outdoor MEDIA DOT: The development and inter-rater reliability of a tool designed to measure food and beverage outlets and outdoor advertising. AB - Few studies of the food environment have collected primary data, and even fewer have reported reliability of the tool used. This study focused on the development of an innovative electronic data collection tool used to document outdoor food and beverage (FB) advertising and establishments near 43 middle and high schools in the Outdoor MEDIA Study. Tool development used GIS based mapping, an electronic data collection form on handheld devices, and an easily adaptable interface to efficiently collect primary data within the food environment. For the reliability study, two teams of data collectors documented all FB advertising and establishments within one half-mile of six middle schools. Inter-rater reliability was calculated overall and by advertisement or establishment category using percent agreement. A total of 824 advertisements (n=233), establishment advertisements (n=499), and establishments (n=92) were documented (range=8-229 per school). Overall inter-rater reliability of the developed tool ranged from 69 89% for advertisements and establishments. Results suggest that the developed tool is highly reliable and effective for documenting the outdoor FB environment. PMID- 26022775 TI - Properties and Clinical Relevance of Speckle-Type POZ Protein in Human Colorectal Cancer. AB - BACKGROUND: The aims of this study are to evaluate the effect of Speckle-type POZ protein (SPOP) in colorectal cancer (CRC) patients and explore its significance in the prognosis. METHODS: We used immunohistochemistry to detect the expression of SPOP in CRC. Moreover, this result was further confirmed at the protein and messenger RNA (mRNA) level in paired CRC specimens and matched adjacent noncancerous colon tissues by Western blotting and real-time quantitative PCR (qRT-PCR), respectively. Furthermore, we evaluate the effects of SPOP on CRC cell proliferation and migration in vitro. The Kaplan-Meier method and log-rank test were employed to compare the overall survival between SPOP low expression group and SPOP high expression group. Correlation of survival with clinicopathologic parameters, including SPOP level, was investigated with multivariate analyses. RESULTS: We confirmed frequent SPOP downregulation in both mRNA (P = 0.0286) and protein (P = 0.004) levels in CRC tissues as compared to matched adjacent nontumorous tissues. Besides, the downregulated SPOP expression in CRC tissues was significantly correlated to poor differentiation (P = 0.013), distant metastasis (P = 0.003), gross type (P < 0.001), and high TNM stage (P = 0.002). Kaplan-Meier survival analysis showed that low SPOP expression exhibited a significant correlation with poor prognosis for CRC patients. Overexpression of SPOP in CRC cell lines significantly suppressed cell proliferation, migration, and clone formation. In contrast, SPOP knockdown dramatically promoted cell proliferation, migration, and clone formation in vitro. In addition, overexpression of SPOP increased E-cadherin and suppressed vimentin in HCT116 cells and silencing of SPOP reversed all these biomarkers. Furthermore, SPOP significantly downregulated MMP2 and MMP7 protein levels in HCT116 cell lines. CONCLUSION: Our results suggest that SPOP plays a pivotal role in colorectal cancer (CRC) through mesenchymal-epithelial transition and MMPs, and it may be a potential therapeutic target in colorectal cancer. PMID- 26022777 TI - Idalopirdine as a treatment for Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for mild-to-moderate AD and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly counteracting the progression of the disease. Idalopirdine is an antagonist of the serotonin 6 (5-HT6) receptor, which is expressed in areas of the CNS involved with memory. Given that there is evidence suggesting that the blockade of 5-HT6 receptors induces acetylcholine release, it became reasonable to consider that 5 HT6 antagonism could also be a promising approach for restoring acetylcholine levels in a deteriorated cholinergic system. AREAS COVERED: This review discusses the history leading to the discovery of idalopirdine, its pharmacokinetics and pharmacodynamics profile and safety issues, together with an overview of clinical trials carried out so far. A literature search was performed with PubMed using the keywords idalopirdine, AD and 5-HT6 antagonists. The article is also based on information derived from the ClinicalTrials.gov site for clinical trials with idalopirdine. EXPERT OPINION: Idalopirdine is safe and well tolerated. It could be used as add-on therapy to potentiate the effect of available AChEIs in AD. Nevertheless, results from ongoing Phase III trials are needed to verify whether this drug has a significant clinical effect on cognition in association with AChEIs. PMID- 26022776 TI - Perioperative Management of Hilar Cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma is the most common primary tumor of the biliary tract although it accounts for only 2 % of all human malignancies. We herein review hilar cholangiocarcinoma including its risk factors, the main classification systems for tumors, current surgical management of the disease, and the role chemotherapy and liver transplantation may play in selected patients. METHODS: We performed a comprehensive literature search using PubMed, Medline, and the Cochrane library for the period 1980-2015 using the following MeSH terms: "hilar cholangiocarcinoma", "biliary cancer", and "cholangiocarcinoma". Only recent studies that were published in English and in peer reviewed journals were included. FINDINGS: Hilar cholangiocarcinoma is a disease of advanced age with an unclear etiology, most frequently found in Southeast Asia and relatively rare in Western countries. The best chance of long term survival and potential cure is surgical resection with negative surgical margins, but many patients are unresectable due to locally advanced or metastatic disease at diagnosis. As a result of recent efforts, new methods of management have been identified for these patients, including preoperative portal vein embolism and biliary drainage, neoadjuvant chemotherapy with subsequent transplantation, and chemoradiation therapy. CONCLUSION: Current management of hilar cholangiocarcinoma depends on extent of the tumor at presentation and includes surgical resection, liver transplantation, portal vein embolization, and chemoradiation therapy. Our understanding of hilar cholangiocarcinoma has improved in recent years and further research offers hope to improve the outcome in patients with these rare tumors. PMID- 26022778 TI - Febrile seizures: a population-based study. AB - OBJECTIVES: To determine the prevalence of benign febrile seizures of childhood and describe the clinical and epidemiological profile of this population. METHODS: This was a population-based, cross-sectional study, carried out in the city of Barra do Bugres, MT, Brazil, from August 2012 to August 2013. Data were collected in two phases. In the first phase, a questionnaire that was previously validated in another Brazilian study was used to identify suspected cases of seizures. In the second phase, a neurological evaluation was performed to confirm diagnosis. RESULTS: The prevalence was 6.4/1000 inhabitants (95% CI: 3.8-10.1). There was no difference between genders. Simple febrile seizures were found in 88.8% of cases. A family history of febrile seizures in first-degree relatives and history of epilepsy was present in 33.3% and 11.1% of patients, respectively. CONCLUSIONS: The prevalence of febrile seizures in Midwestern Brazil was lower than that found in other Brazilian regions, probably due to the inclusion only of febrile seizures with motor manifestations and differences in socioeconomic factors among the evaluated areas. PMID- 26022779 TI - Transcription and processing of mitochondrial RNA in the human pathogen Acanthamoeba castellanii. AB - The size, structure, gene content and organisation of mitochondrial genomes can be highly diverse especially amongst the protists. We investigated the transcription and processing of the mitochondrial genome of the opportunistic pathogen Acanthamoeba castellanii and here we present a detailed transcription map of the 41.6 kb genome that encodes 33 proteins, 16 tRNAs and 2 rRNAs. Northern hybridisation studies identified six major polycistronic transcripts, most of which are co-transcriptionally processed into smaller mono-, di- and tricistronic RNAs. The maturation of the polycistronic transcripts is likely to involve endonucleolytic cleavage where tRNAs serve as processing signals. Reverse transcription polymerase chain reactions across the intervening regions between the six major polycistronic transcripts suggest that these transcripts were once part of an even larger transcript. Our findings indicate that the mitochondrial genome of A. castellanii is transcribed from only one or two promoters, very similar to the mode of transcription in the mitochondria of its close relative Dictyostelium discoideum, where transcription is known to occur from only a single transcription initiation site. Transcription initiation from a minimal number of promoters despite a large genome size may be an emerging trend in the mitochondria of protists. PMID- 26022781 TI - Quantum-dot biosensor for hybridization and detection of R3500Q mutation of apolipoprotein B-100 gene. AB - A quantum-dot electrode system was developed as a transducer surface for covalent immobilization of a designed synthetic ApoB-100 specific probe, DNA hybridization and monitoring of DNA synthesis for the sensitive detection of R3500Q mutation of apolipoprotein B-100 (ApoB-100) gene. CdS-QDs cause an improvement in the fundamental characteristics of the electrode interface, such as its electroactive surface area, diffusion coefficient and electron transfer kinetics. The sensing characteristics of this biosensor offer a suitable potential for detection of target oligonucleotide with a detection limit of 3.4 * 10(-17)M. Also, the electrochemical responses of single-stranded DNA (ssDNA), DNA hybridization and DNA synthesis were investigated using electrochemical impedance spectroscopy (EIS). The extracted genomic DNA was detected based on changes in the charge transfer resistance (RCT) with [Fe(CN)6](3-/4-) as a redox probe. The proposed biosensor can distinguish between the normal sequence and the mutant sequence of ApoB-100 gene, promising a possibility to apply the QD-based biosensor for clinical investigations. PMID- 26022780 TI - Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic "functional" symptomatology including pain, fatigue and gastrointestinal dysmotility. AB - Functional disorders are common conditions with a substantial impact on a patients' wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction. In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility. Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients. Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P = 0.0001) and with two other interacting variants (OR 18, P = 0.0005). Considering a 1-2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology. PMID- 26022782 TI - U-shaped fiber-optic ATR sensor enhanced by silver nanoparticles for continuous glucose monitoring. AB - An implantable U-shaped fiber ATR sensor enhanced by silver nanoparticles on cylindrical surface was presented for continuous glucose monitoring to overcome the drawbacks of traditional glucose sensing technique based on enzyme electrodes. A U-shaped structure was addressed to increase effective optical length at limited implantable space to enhance the sensitivity of fiber ATR sensor. A novel method to fabricate silver nanoparticles on cylindrical surface of U-shaped fiber ATR sensor based on chemical reduction of its silver halide material directly without any preliminary nanoparticles synthesis and following covalent bond or self-assembly was proposed. Five glucose absorption wavelengths in the mid-infrared band were employed for specific glucose monitoring. The experimental results indicate that the sensitivity and resolution of the silver nanoparticle-enhanced U-shaped fiber-optic ATR sensor are approximately three times those of a conventional one. The high sensitivity and low-noise performance makes it promising for in vivo glucose monitoring in the future clinical applications. PMID- 26022783 TI - Double-helix micro-channels on microfluidic chips for enhanced continuous on-chip derivatization followed by electrophoretic separation. AB - Micro-channels that contain a special inner structure are critical for efficient mixing and chemical reactions. In this paper, we described the facile fabrication of an integrated microchip with double-helix type micro-channels to improve mixing efficiency and to facilitate multi-step derivatization reactions prior to electrophoretic separation. With a prepared microchip, reagents, samples and reaction products could be driven through micro-channels by siphon, and no other pumping device was necessary. To test its performance, reductive amination of aldehydes with 8-aminonaphthalene-1,3,6-trisulfonate acid disodium (ANTS) was attempted via microchip electrophoresis with laser induced fluorescence (LIF). The effect of the geometry of the reaction micro-channel on the reaction's efficiency was evaluated. Under the selected conditions, successful derivatization of five aldehydes was realized for highly reproducible analysis. The relative standard deviations of the peak areas for 30 consecutive injections were in the range of 0.28-1.61%. The method was applied for the determination of aldehydes in real samples with standard addition recoveries of 87.8-102.8%. Good tolerance of organic solvents was achieved, and the proposed method can potentially be employed for rapid screening of excessively added aldehyde food flavoring. PMID- 26022784 TI - Ultra-high frequency piezoelectric aptasensor for the label-free detection of cocaine. AB - This paper describes a label-free and real-time piezoelectric aptasensor for the detection of cocaine. The acoustic wave sensing platform is a quartz substrate functionalized with an adlayer of S-(11-trichlorosilyl-undecanyl) benzenethiosulfonate (BTS) cross-linker onto which the anti-cocaine MN4 DNA aptamer is next immobilized. Preparation of the sensor surface was monitored using X-ray photoelectron spectroscopy (XPS), while the binding of cocaine to surface-attached MN4 was evaluated using the electromagnetic piezoelectric acoustic sensor (EMPAS). The MN4 aptamer, unlike other cocaine aptamer variants, has its secondary structure preformed in the unbound state with only tertiary structure changes occurring during target binding. It is postulated that the highly sensitive EMPAS detected the binding of cocaine through target mass loading coupled to aptamer tertiary structure folding. The sensor achieved an apparent Kd of 45 +/- 12 uM, and a limit of detection of 0.9 uM. Repeated regenerability of the sensor platform was also demonstrated. This work constitutes the first application of EMPAS technology in the field of aptasensors. Furthermore, it is so far one of the very few examples of a bulk acoustic wave aptasensor that is able to directly detect the binding interaction between an aptamer and a small molecule in a facile one-step protocol without the use of a complex assay or signal amplification step. PMID- 26022786 TI - Policy brief. PMID- 26022785 TI - Meta-analysis of the association of MTHFR polymorphisms with multiple myeloma risk. AB - The association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with multiple myeloma (MM) risk has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensively estimate. The case-control studies about MTHFR C677T and A1298C polymorphisms with MM risk were collected by searching PubMed, Elsevier, China National Knowledge Infrastructure and Wanfang Databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the strength of association. Overall, no significant association was found between MTHFR A1298C polymorphism and MM risk under all four genetic models (AC vs. AA, OR = 0.99, 95%CI = 0.82 1.20; CC vs. AA, OR = 1.14, 95%CI = 0.77-1.68; recessive model, OR = 1.10, 95%CI = 0.76-1.59; dominant model, OR = 1.01, 95%CI = 0.84-1.22). The risk was also not significantly altered for C677T polymorphism and MM in overall comparisons (CT vs. CC, OR = 1.04, 95%CI = 0.93-1.17; TT vs. CC, OR = 1.16, 95%CI = 0.98-1.37; recessive model, OR = 1.13, 95%CI = 0.98-1.32; dominant model, OR = 1.07, 95%CI = 0.96-1.20). In subgroup analyses by ethnicity, no significant association was observed in both Caucasians and Asians. This meta-analysis suggested that MTHFR polymorphisms were not associated with MM risk. PMID- 26022787 TI - The Sequencing of a College Degree during the Transition to Adulthood: Implications for Obesity. AB - In this study we consider the health implications of the sequencing of a college degree vis-a-vis familial roles during the transition to adulthood. We hypothesize that people who earned a college degree before assuming familial roles will have better health than people who earned a college degree afterwards. To test this hypothesis, we focus on obesity and use data from the National Longitudinal Study of Adolescent Health. Results show that marriage before completion of college was associated with a 50% higher probability of becoming obese when compared with marriage after completion of college. Parenthood before college completion was associated with a greater than twofold increase in the probability of becoming obese when compared to parenthood afterwards for black men. These findings suggest that the well-established association of education with health depends on its place in a sequence of roles. PMID- 26022789 TI - Reducing Biases in Meta-Analyses: Reply to Hertenstein and Nissen. PMID- 26022790 TI - Gender and health: Studying the differences to improve the outcomes. PMID- 26022788 TI - Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats. AB - Cognitive impairments appear early in the progression of schizophrenia, often preceding the symptoms of psychosis. Thus, the systems subserving these functions may be more vulnerable to, and mechanistically linked with, the initial pathology. Understanding the trajectory of behavioral and anatomical abnormalities relevant to the schizophrenia prodrome and their sensitivity to interventions in relevant models will be critical to identifying early therapeutic strategies. Isolation rearing of rats is an environmental perturbation that deprives rodents of social contact from weaning through adulthood and produces behavioral and neuronal abnormalities that mirror some pathophysiology associated with schizophrenia, e.g. frontal cortex abnormalities and prepulse inhibition (PPI) of startle deficits. Previously, we showed that PPI deficits in isolation-reared rats emerge in mid-adolescence (4 weeks after weaning; approx. postnatal day 52) but are not present when tested at 2 weeks after weaning (approx. postnatal day 38). Because cognitive deficits are reported during early adolescence, are relevant to the prodrome, and are linked to functional outcome, we examined the putative time course of reversal learning deficits in isolation-reared rats. Separate groups of male Sprague Dawley rats were tested in a two-choice discrimination task at 2 and 8 weeks after weaning, on postnatal day 38 and 80, respectively. The isolation-reared rats displayed impaired reversal learning at both time points. Isolation rearing was also associated with deficits in PPI at 4 and 10 weeks after weaning. The reversal learning deficits in the isolated rats were accompanied by reductions in parvalbumin immunoreactivity, a marker for specific subpopulations of GABAergic neurons, in the hippocampus. Hence, isolation rearing of rats may offer a unique model to examine the ontogeny of behavioral and neurobiological alterations that may be relevant to preclinical models of prodromal psychosis. (c) 2015 S. Karger AG, Basel. PMID- 26022792 TI - Contrast-enhanced ultrasound with perflubutane in the assessment of anti angiogenic effects: early prediction of the anticancer activity of bevacizumab in a mouse xenografted model. AB - To investigate the feasibility of contrast-enhanced ultrasound (CEUS) with perflubutane for evaluating anti-angiogenic effects, we assessed the contrast enhancement of mice xenograft treated with bevacizumab. SJSA-1 implanted mice were imaged before and 2, 6, 9 and 13 d after initiation of bevacizumab or saline treatment. Intra-tumoral perfusion areas were quantified by binarizing the ultrasound images and the micro-vessel density was observed by CD31 immunohistochemistry. As a result, the perfusion area and its ratio in the tumor were smaller in the bevacizumab group than the control group at 9 and 13 d, although tumor size was not significantly different. CD31-positive areas were smaller in the bevacizumab group than the control group and correlated well with the ratio of intra-tumoral perfusion areas. CEUS with perflubutane was found to have potential for early prediction of the anti-cancer activity of bevacizumab, and the perfusion area measured by binarized ultrasound images could be used as an indicator. PMID- 26022791 TI - Poly(lactide-co-glycolide) microspheres for MRI-monitored delivery of sorafenib in a rabbit VX2 model. AB - Transcatheter arterial embolization and chemoembolization are standard locoregional therapies for hepatocellular carcinoma (HCC). However, these can result in tumor hypoxia, thus promoting tumor angiogenesis. The anti-angiogenic agent sorafenib is hypothesized to improve outcomes; however, oral administration limits patient tolerance. Therefore, the purpose of this study was to fabricate poly(lactide-co-glycolide) microspheres for local sorafenib delivery to tumors during liver-directed embolotherapies. Iron oxide nanoparticles (IONP) were co encapsulated for magnetic resonance imaging (MRI) of microsphere delivery. Microspheres were fabricated using a double emulsion/solvent evaporation method and characterized for size, sorafenib and IONP content, and MRI properties. MRI was performed before and after intra-arterial microsphere infusions in a rabbit VX2 liver tumor model. The microspheres were 13 microns in diameter with 8.8% and 0.89% (w/w) sorafenib and IONP, respectively. 21% and 28% of the loaded sorafenib and IONP, respectively, released within 72 h. Rabbit VX2 studies demonstrated that sorafenib microspheres normalized VEGFR 2 activity and decreased microvessel density. Quantitative MRI enabled in vivo visualization of intra-hepatic microsphere distributions. These methods should avoid systemic toxicities, with MRI permitting follow-up confirmation of microsphere delivery to the targeted liver tumors. PMID- 26022793 TI - Applicability of shear wave elastography of the major salivary glands: values in healthy patients and effects of gender, smoking and pre-compression. AB - Our aim in this study was to determine normal shear wave elastography (SWE) values for the parenchyma of the major salivary glands and to evaluate the influences of gender, smoking, side and type of gland and varying amounts of ultrasound probe pressure on SWE values. Twenty-five consecutive healthy patients were examined with ultrasound. SWE velocities were measured with acoustic radiation force imaging in the hilum and central region of both glands with "normal" and very low pressure. Mean SWE velocities were 1.854 m/s for the parotid gland and 1.932 m/s for the submandibular gland. No statistically significant differences were detected between males and females, smokers and non smokers, parotid and submandibular gland and left and right sides. Greater pre compression with the ultrasound probe resulted in a statistically significant increase in the SWE values of both salivary glands (p < 0.000). The degree of pre compression by the ultrasound transducer should be standardized, so that the reliability and reproducibility of this innovative method can be improved. PMID- 26022795 TI - Microcirculatory disorder hypothesis in Takotsubo cardiomyopathy. PMID- 26022794 TI - Pulmonary Gangrene Due to Rhizopus spp., Staphylococcus aureus, Klebsiella pneumoniae and Probable Sarcina Organisms. AB - Pulmonary gangrene is a life-threatening condition, which represents the fulminant end of the infectious lung diseases usually caused by polymicrobial infection. Aerobic and anaerobic bacteria act synergistically to produce massive tissue necrosis which might be augmented by the angioinvasive nature of fungi like Mucor. We report a successfully treated case of pulmonary gangrene in a poorly controlled diabetic patient, which was associated with polymicrobial infection. It was caused by Rhizopus spp., Staphylococcus aureus, Klebsiella pneumoniae and unusual anaerobic organism Sarcina. This is the first report describing the presence of Sarcina organisms in a case of pulmonary gangrene. Adequate glycemic control, treatment of coexisting polymicrobial infection and prompt antifungal therapy along with surgical intervention were useful in the index patient. This case also highlights the effectiveness of combined medical and surgical intervention in a case of pulmonary gangrene. PMID- 26022796 TI - Chest distress in a young adult due to simultaneous occurrence of single left coronary artery anomaly and coronary-left ventricular fistula. PMID- 26022797 TI - Association between orthostatic hypotension, mortality, and cardiovascular disease in Asians. AB - BACKGROUND: Orthostatic hypotension (OH) is a common condition encountered in the elderly. The present study aimed to examine the relationship between OH and adverse events in Asians. METHODS: We used the "National Health Insurance Research Database" in Taiwan. A total of 1226 patients with OH and without previous history of ischemic stroke and myocardial infarction were identified as the study group. For each study patient, ten age-, sex- and comorbidity-matched subjects without OH were selected to constitute the control group (n = 12,260). The clinical endpoints were ischemic stroke, myocardial infarction and all-cause mortality. RESULTS: The mean age of the study population was 54.8 +/- 19.0 years and males accounted for 47% of the patients. During the follow-up of 4.5 +/- 2.9 years, 704 (5.2%) patients developed ischemic stroke, 190 (1.4%) patients developed myocardial infarction, and 733 (5.4%) patients died. In the multivariable Cox regression analyses which were adjusted for age, gender and differences in medication usages, OH was significantly associated with an increased risk of ischemic stroke (hazard ratio [HR] = 1.40, 95% confidence interval (CI) = 1.09-1.81, p = 0.009), all-cause mortality (HR = 1.35; 95% CI = 1.05-1.73, p = 0.018) and adverse events (ischemic stroke, myocardial infarction or mortality) (HR = 1.41; 95% CI = 1.18-1.68, p < 0.001). CONCLUSION: OH is an independent factor associated with ischemic stroke and mortality in Asians. Whether aggressive managements for stroke prevention could improve the outcome for OH patients deserves further study. PMID- 26022798 TI - Spontaneous and Isoprenaline-evoked response of isolated heart preparations from rats submitted to leptin treatment during lactation. PMID- 26022799 TI - Response to the Letter of Dr. Tomoyuki Kawada, "Acute Myocardial Infarction and Sleep Apnea". PMID- 26022800 TI - Clinical and prognostic role of ammonia in advanced decompensated heart failure. The cardio-abdominal syndrome? AB - BACKGROUND: Advanced heart failure is associated with end-organ damage. Recent literature suggested an intriguing crosstalk between failing heart, abdomen and kidneys. Venous ammonia, as a by-product of the gut, could be a marker of abdominal injury in heart failure patients. The aim of the study was to investigate the clinical and prognostic role of ammonia in patients with advanced decompensated heart failure (ADHF). METHODS & RESULTS: 90 patients admitted with ADHF were prospectively studied. The prognostic role of ammonia at admission was evaluated. Primary end-points were: a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 3 months and need for renal replacement therapies (RRT). In the study cohort (age 59.0 +/- 12.0 years, FE 21.6 +/- 9.0%, INTERMACS profile 3.7 +/- 0.9, creatinine 1.71 +/- 0.95 mg/dl) 27 patients (30%) underwent the cardiac composite endpoint, while 9 patients (10%) needed RRT. At ROC curve analysis ammonia >= 130 MUg/dl (abdominal damage) showed the best diagnostic accuracy. At multivariate analysis abdominal damage predicted the cardiac composite endpoint. Abdominal damage further increased risk among patient with cold profile at admission (HR 2.7, 95% CI 1.1-7.0, p = 0.046). At multivariate analysis abdominal damage also predicted need for RRT (OR 10.8, 95% CI 1.5-75.8, p = 0.017). The combined use of estimated right atrial pressure and ammonia showed the highest diagnostic accuracy and a very high specificity in prediction of need for RRT. CONCLUSION: In a selected population admitted for ADHF ammonia, as a marker of abdominal derangement, predicted adverse cardiac events and need for RRT. PMID- 26022801 TI - DNA Methylation Changes Induced by a High-Fat Diet and Fish Oil Supplementation in the Skeletal Muscle of Mice. AB - BACKGROUND/AIMS: To investigate the global changes in DNA methylation and methylation of the promoter region of the peroxisome proliferator-activated receptor gamma transcript variant 2 (Pparg2) gene resulting from a high-fat diet (HFD) and/or fish oil supplementation. METHODS: Fish oil, rich in omega-3 polyunsaturated fatty acids, or water was orally administered to male mice for 12 weeks. After the first 4 weeks, the animals were fed a control diet or an HFD until the end of the experimental protocol, when the epididymal fat, gastrocnemius muscle and liver were excised. RESULTS: Pparg2 mRNA expression was upregulated by obesity and downregulated by fish oil supplementation in the liver. In the gastrocnemius muscle, diet-induced obesity increased global DNA methylation. Fish oil prevented the decrease in Pparg2 promoter methylation induced by obesity in the gastrocnemius muscle. Regardless of the diet given, fish oil supplementation increased Pparg2 promoter methylation at CpG-263 in muscle and adipose tissue. CONCLUSION: HFD and fish oil modified global and Pparg2 promoter DNA methylation in a tissue-specific manner. Fish oil supplementation attenuated body weight gain, abolished the increase in Pparg2 expression in the liver and prevented the decrease in Pparg2 promoter methylation in the muscle induced by the HFD. PMID- 26022802 TI - Stress, cues, and eating behavior. Using drug addiction paradigms to understand motivation for food. AB - Eating patterns that lead to overconsumption of high fat, high sugar (HFHS) foods share similar features with addictive behaviors. Application of addiction paradigms, such as stress inductions, cue reactivity and behavioral economic assessments, to the study of motivation for HFHS food consumption may be a promising means of understanding food consumption. To date, few studies have investigated the interaction of stress and environmental cues on craving, and no study leveraged the state relative reinforcing value of foods (RRVfood) under varying conditions of affective states, the foci of the current study. This study used a mixed factorial design (Mood Induction: Neutral, Stress; Cues: Neutral, Food) with repeated measures on time (Baseline, Post-Mood Induction, Post-Cue Exposure). Participants (N = 133) were community adults who endorsed liking of HFHS snacks but denied eating pathology. The primary DVs were subjective craving and RRVfood. Negative and positive affect (NA, PA), the amount of food consumed, and latency to first bite were also examined. Participants in the Stress condition reported no change in craving or RRVfood. Exposure to food cues significantly increased participants' craving and RRVfood, but an interaction of stress and cues was not present. Participants did not differ on how many calories they consumed based on exposure to stress or food cues, but participants in the food cues condition had a shorter latency to the first bite of food. This study highlights the importance of environmental cues in food motivation. It also demonstrates the utility of using RRVfood to further characterize food motivation. PMID- 26022803 TI - Thermal transitions in serum amyloid A in solution and on the lipid: implications for structure and stability of acute-phase HDL. AB - Serum amyloid A (SAA) is an acute-phase protein that circulates mainly on plasma HDL. SAA interactions with its functional ligands and its pathogenic deposition in reactive amyloidosis depend, in part, on the structural disorder of this protein and its propensity to oligomerize. In vivo, SAA can displace a substantial fraction of the major HDL protein, apoA-I, and thereby influence the structural remodeling and functions of acute-phase HDL in ways that are incompletely understood. We use murine SAA1.1 to report the first structural stability study of human plasma HDL that has been enriched with SAA. Calorimetric and spectroscopic analyses of these and other SAA-lipid systems reveal two surprising findings. First, progressive displacement of the exchangeable fraction of apoA-I by SAA has little effect on the structural stability of HDL and its fusion and release of core lipids. Consequently, the major determinant for HDL stability is the nonexchangeable apoA-I. A structural model explaining this observation is proposed, which is consistent with functional studies in acute phase HDL. Second, we report an alpha-helix folding/unfolding transition in SAA in the presence of lipid at near-physiological temperatures. This new transition may have potentially important implications for normal functions of SAA and its pathogenic misfolding. PMID- 26022804 TI - Phenotyping drug polypharmacology via eicosanoid profiling of blood. AB - It is widely accepted that small-molecule drugs, despite their selectivity at primary targets, exert pharmacological effects (and safety liabilities) through a multiplicity of pathways. As such, it has proved extremely difficult to experimentally assess polypharmacology in an agnostic fashion. Profiling of metabolites produced as part of physiological responses to pharmacological stimuli provides a unique opportunity to explore drug pharmacology. A total of 122 eicosanoid lipids in human whole blood were monitored from 10 different donors upon stimulation with several inducers of immunological responses and treatment with modulators of prostaglandin (PG) and leukotriene biosynthesis, including clinical and investigational molecules. Such analysis revealed differentiation between drugs nominally targeting different eicosanoid biosynthetic enzymes, or even those designed to target the same enzyme. Profiled agents, some of them marketed products, affect eicosanoid biosynthesis in ways that cannot be predicted from information on their intended targets. As an example, we used this platform to discriminate drugs based on their ability to silence PG biosynthesis in response to bacterial lipopolysaccharide, resulting in differential pharmacological activity in an in vivo model of endotoxemia. Some of the observed effects are subject to variability among individuals, indicating a potential application of this methodology to the patient stratification, based on their responses to benchmark drugs and experimental compounds read on the eicosanome via a simple blood test. PMID- 26022805 TI - Establishment of LC-MS methods for the analysis of palmitoylated surfactant proteins. AB - The surfactant proteins (SPs), SP-B and SP-C, are important components of pulmonary surfactant involved in the reduction of alveolar surface tension. Quantification of SP-B and SP-C in surfactant drugs is informative for their quality control and the evaluation of their biological activity. Western blot analysis enabled the quantification of SP-B, but not SP-C, in surfactant drugs. Here, we report a new procedure involving chemical treatments and LC-MS to analyze SP-C peptides. The procedure enabled qualitative analysis of SP-C from different species with discrimination of the palmitoylation status and the artificial modifications that occur during handling and/or storage. In addition, the method can be used to estimate the total amount of SP-C in pulmonary surfactant drugs. The strategy described here might serve as a prototype to establish analytical methods for peptides that are extremely hydrophobic and behave like lipids. The new method provides an easy measurement of SP-C from various biological samples, which will help the characterization of various experimental animal models and the quality control of surfactant drugs, as well as diagnostics of human samples. PMID- 26022807 TI - Seeing is not necessarily believing. PMID- 26022806 TI - Ethanol-induced hepatic steatosis is modulated by glycogen level in the liver. AB - Alcoholic liver disease (ALD) is a major health problem worldwide and hepatic steatosis is an early response to alcohol consumption. Fat and glycogen are two major forms of energy storage in the liver; however, whether glycogen metabolism in the liver impacts alcohol-induced steatosis has been elusive. In this study, we used a mouse model with overexpression of PPP1R3G in the liver to dissect the potential role of glycogen on alcohol-induced fatty liver formation. PPP1R3G is a regulatory subunit of protein phosphatase 1 and stimulates glycogenesis in the liver. Chronic and binge ethanol (EtOH) feeding reduced glycogen level in the mouse liver and such inhibitory effect of EtOH was reversed by PPP1R3G overexpression. In addition, PPP1R3G overexpression abrogated EtOH-induced elevation of serum levels of alanine aminotransferase and aspartate aminotransferase, increase in liver triglyceride concentration, and lipid deposition in the liver. EtOH-stimulated sterol regulatory element-binding protein (SREBP)-1c, a master regulator of lipogenesis, was also reduced by PPP1R3G overexpression in vivo. In AML-12 mouse hepatocytes, PPP1R3G overexpression could relieve EtOH-induced lipid accumulation and SREBP-1c stimulation. In conclusion, our data indicate that glycogen metabolism is closely linked to EtOH-induced liver injury and fatty liver formation. PMID- 26022808 TI - NHS Health Check: an innovative component of local adult health improvement and well-being programmes in England. PMID- 26022809 TI - Response to Waterall et al. PMID- 26022810 TI - NHS Health Checks--a naked emperor? PMID- 26022811 TI - Response to Capewell et al. PMID- 26022812 TI - Knowledge Translation for researchers: developing training to support public health researchers KTE efforts. PMID- 26022813 TI - Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. AB - BACKGROUND: Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES: This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS: Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS: Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p<0.001). The hazard ratio in the highest/lowest quintile (>175/<=80 mg/dl) was 1.61 (95% confidence interval: 1.34 to 1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short term risk increased across tertiles of baseline triglycerides (p=0.03), with a hazard ratio of 1.50 [corrected] (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/<=135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies. CONCLUSIONS: Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515). PMID- 26022814 TI - The remnants of residual risk. PMID- 26022816 TI - Personalizing your airspace and your health. PMID- 26022815 TI - Cardiopulmonary benefits of reducing indoor particles of outdoor origin: a randomized, double-blind crossover trial of air purifiers. AB - BACKGROUND: Indoor exposure to fine particulate matter (PM2.5) from outdoor sources is a major health concern, especially in highly polluted developing countries such as China. Few studies have evaluated the effectiveness of indoor air purification on the improvement of cardiopulmonary health in these areas. OBJECTIVES: This study sought to evaluate whether a short-term indoor air purifier intervention improves cardiopulmonary health. METHODS: We conducted a randomized, double-blind crossover trial among 35 healthy college students in Shanghai, China, in 2014. These students lived in dormitories that were randomized into 2 groups and alternated the use of true or sham air purifiers for 48 h with a 2-week washout interval. We measured 14 circulating biomarkers of inflammation, coagulation, and vasoconstriction; lung function; blood pressure (BP); and fractional exhaled nitric. We applied linear mixed-effect models to evaluate the effect of the intervention on health outcome variables. RESULTS: On average, air purification resulted in a 57% reduction in PM2.5 concentration, from 96.2 to 41.3 MUg/m3, within hours of operation. Air purification was significantly associated with decreases in geometric means of several circulating inflammatory and thrombogenic biomarkers, including 17.5% in monocyte chemoattractant protein-1, 68.1% in interleukin-1beta, 32.8% in myeloperoxidase, and 64.9% in soluble CD40 ligand. Furthermore, systolic BP, diastolic BP, and fractional exhaled nitrous oxide were significantly decreased by 2.7%, 4.8%, and 17.0% in geometric mean, respectively. The impacts on lung function and vasoconstriction biomarkers were beneficial but not statistically significant. CONCLUSIONS: This intervention study demonstrated clear cardiopulmonary benefits of indoor air purification among young, healthy adults in a Chinese city with severe ambient particulate air pollution. (Intervention Study on the Health Impact of Air Filters in Chinese Adults; NCT02239744). PMID- 26022817 TI - Intestinal cholesterol absorption, treatment with atorvastatin, and cardiovascular risk in hemodialysis patients. AB - BACKGROUND: Hemodialysis patients are high absorbers of intestinal cholesterol; they benefit less than other patient groups from statin therapy, which inhibits cholesterol synthesis. OBJECTIVES: This study sought to investigate whether the individual cholesterol absorption rate affects atorvastatin's effectiveness to reduce cardiovascular risk in hemodialysis patients. METHODS: This post-hoc analysis included 1,030 participants in the German Diabetes and Dialysis Study (4D) who were randomized to either 20 mg of atorvastatin (n=519) or placebo (n=511). The primary endpoint was a composite of major cardiovascular events. Secondary endpoints included all-cause mortality and all cardiac events. Tertiles of the cholestanol-to-cholesterol ratio, which is an established biomarker of cholesterol absorption, were used to identify high and low cholesterol absorbers. RESULTS: A total of 454 primary endpoints occurred. On multivariate time-to-event analyses, the interaction term between tertiles and treatment with atorvastatin was significantly associated with the risk of reaching the primary endpoint. Stratified analysis by cholestanol-to-cholesterol ratio tertiles confirmed this effect modification: atorvastatin reduced the risk of reaching the primary endpoint in the first tertile (hazard ratio [HR]: 0.72; p=0.049), but not the second (HR: 0.79; p=0.225) or third tertiles (HR: 1.21; p=0.287). Atorvastatin consistently significantly reduced all-cause mortality and the risk of all cardiac events in only the first tertile. CONCLUSIONS: Intestinal cholesterol absorption, as reflected by cholestanol-to-cholesterol ratios, predicts the effectiveness of atorvastatin to reduce cardiovascular risk in hemodialysis patients. Those with low cholesterol absorption appear to benefit from treatment with atorvastatin, whereas those with high absorption do not benefit. PMID- 26022818 TI - Cholesterol metabolism and statin effectiveness in hemodialysis patients. PMID- 26022819 TI - Sudden death in childhood cardiomyopathy: results from a long-term national population-based study. AB - BACKGROUND: Children with cardiomyopathy (CM) are at risk of sudden cardiac death (SCD), but the incidence and risk factors for this outcome are not clear. OBJECTIVES: This study sought to determine the incidence and risk factors for SCD in children with varying CM phenotypes from a long-term population-based study of childhood CM. METHODS: The NACCS (National Australian Childhood Cardiomyopathy Study) is an ongoing longitudinal cohort study including all children in Australia with primary CM who were diagnosed between January 1, 1987, and December 31, 1996, and were <10 years of age. The cumulative incidence and risk factors for SCD within individual CM phenotypes were explored using survival analysis. RESULTS: Of 289 eligible patients, 16 (5.5%) experienced SCD over a median follow-up of 11.9 years (interquartile range: 1.7 to 15.4). The risk of SCD varied according to CM phenotype (p=0.007). The cumulative incidence of SCD at 15 years was 5% for dilated cardiomyopathy (DCM), 6% for hypertrophic cardiomyopathy (HCM), 12% for restrictive cardiomyopathy, and 23% for left ventricular (LV) noncompaction. Older age at diagnosis, positive family history of CM, and severity of LV dysfunction were related to increased risk of SCD in patients with DCM, and a higher posterior wall thickness Z-score was the sole risk factor identified for patients with HCM. CONCLUSIONS: Predictors of SCD include CM phenotype, family history of CM (DCM), severity of systolic dysfunction (DCM), and extent of LV hypertrophy (HCM). Continuing follow-up of this cohort into adulthood is likely to reveal an ongoing risk of SCD. PMID- 26022820 TI - Sudden cardiac death in pediatric cardiomyopathy: the importance of well-designed population-based studies. PMID- 26022822 TI - Implementation of miRNAs to Reduce In-Stent Restenosis in the Future. PMID- 26022821 TI - Reducing In-Stent Restenosis: Therapeutic Manipulation of miRNA in Vascular Remodeling and Inflammation. AB - BACKGROUND: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro-ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury. OBJECTIVES: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents. METHODS: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis. RESULTS: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR 21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation. CONCLUSIONS: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting. PMID- 26022823 TI - Functional tricuspid regurgitation: a need to revise our understanding. AB - The assessment of the etiology and severity of functional tricuspid regurgitation (FTR) has many limitations, especially when tricuspid regurgitation (TR) is more than severe. Instead of relying solely on TR severity, a new approach not only takes into account the severity of TR, but also pays strict attention to tricuspid annular dilation (size), the mode of tricuspid leaflet coaptation, and tricuspid leaflet tethering-factors often influenced by right ventricular enlargement and dysfunction. To simplify things, we propose a new staging system for functional tricuspid valve pathology using 3 parameters that may more accurately reflect the severity of the disease: TR severity, annular dilation, and mode of leaflet coaptation (extent of tethering). We believe that by utilizing these parameters, cardiologists and cardiac surgeons will be offered a better system for appraisal and decision-making in FTR. PMID- 26022824 TI - Strategies to incorporate left atrial appendage occlusion into clinical practice. AB - The left atrial appendage (LAA) has been identified as a predominant source of thrombus formation leading to significant thromboembolic events in patients with nonvalvular atrial fibrillation. Medical therapy to eliminate thrombus formation in the LAA has been the standard of care for several decades, but mechanical approaches designed to exclude the LAA from the circulation have recently been developed. The largest body of randomized and nonrandomized data to date has been for the Watchman device (Boston Scientific, Natick, Massachusetts), which was recently approved by the Food and Drug Administration for selected patients in the United States. There are no current guidelines or guidance for institutions and operators looking to become involved in this therapy. This perspective is aimed at exploring these issues and providing necessary information and guidance to these programs and operators to help ensure a successful launch of a LAA occlusion program and optimize patient selection, procedural performance, and outcome. PMID- 26022825 TI - A call for collaboration: the evolving heart failure apprenticeship network. PMID- 26022826 TI - Transcatheter mitral valve replacement for the treatment of mitral regurgitation: in-hospital outcomes of an apically tethered device. PMID- 26022827 TI - Cardiovascular screening in college athletes. PMID- 26022828 TI - Myocardial edema should be stratified according to the state of cardiomyocytes within the ischemic region. PMID- 26022829 TI - Reply: myocardial edema should be stratified according to the state of cardiomyocytes within the ischemic region. PMID- 26022830 TI - Myocardial Salvage, Area at Risk by T2w CMR: The Resolution of the Retrospective Radio Wave Paradigm? PMID- 26022831 TI - Reply: Myocardial Salvage, Area at Risk by T2w CMR: The Resolution of the Retrospective Radio Wave Paradigm? PMID- 26022832 TI - Noninferiority of 6 versus 12 months of dual antiplatelet therapy. PMID- 26022833 TI - SECURITY Did Not Establish Noninferiority. PMID- 26022834 TI - Reply: Noninferiority of 6 Versus 12 Months of Dual Antiplatelet Therapy: SECURITY Did Not Establish Noninferiority. PMID- 26022835 TI - Early Social Experience Affects Neural Activity to Affiliative Facial Gestures in Newborn Nonhuman Primates. AB - A fundamental issue in cognitive neuroscience is how the brain encodes the actions and intentions of others. The discovery of an action-production perception mechanism underpinning such a capacity advanced our knowledge of how these processes occur; however, no study has examined how the early postnatal environment may shape action-production-perception. Here, we examined the effects of social experience on action-production-perception in 3-day-old rhesus macaques that were raised either with or without their biological mothers. We measured the neonatal imitation skills and brain electrical activity responses, while infants produced and observed facial gestures. We hypothesized that early social experiences may shape brain activity, as assessed via electroencephalogram suppression in the alpha band (5-7 Hz in infants, known as the mu rhythm) during action observation, and lead to more proficient imitation skills. Consistent with this hypothesis, the infants reared by their mothers were more likely to imitate lipsmacking (LS) - a natural, affiliative gesture - and exhibited greater mu rhythm desynchronization while viewing LS gestures than the nursery-reared infants. These effects were not found in response to tongue protrusion, a meaningless gesture, or a nonsocial control. These data suggest that socially enriched early experiences in the first days after birth increase brain sensitivity to socially relevant actions. (c) 2015 S. Karger AG, Basel. PMID- 26022836 TI - Absolutely relative or relatively absolute: violations of value invariance in human decision making. AB - Making decisions based on relative rather than absolute information processing is tied to choice optimality via the accumulation of evidence differences and to canonical neural processing via accumulation of evidence ratios. These theoretical frameworks predict invariance of decision latencies to absolute intensities that maintain differences and ratios, respectively. While information about the absolute values of the choice alternatives is not necessary for choosing the best alternative, it may nevertheless hold valuable information about the context of the decision. To test the sensitivity of human decision making to absolute values, we manipulated the intensities of brightness stimuli pairs while preserving either their differences or their ratios. Although asked to choose the brighter alternative relative to the other, participants responded faster to higher absolute values. Thus, our results provide empirical evidence for human sensitivity to task irrelevant absolute values indicating a hard-wired mechanism that precedes executive control. Computational investigations of several modelling architectures reveal two alternative accounts for this phenomenon, which combine absolute and relative processing. One account involves accumulation of differences with activation dependent processing noise and the other emerges from accumulation of absolute values subject to the temporal dynamics of lateral inhibition. The potential adaptive role of such choice mechanisms is discussed. PMID- 26022837 TI - Imperfect pitch: Gabor's uncertainty principle and the pitch of extremely brief sounds. AB - How brief must a sound be before its pitch is no longer perceived? The uncertainty tradeoff between temporal and spectral resolution (Gabor's principle) limits the minimum duration required for accurate pitch identification or discrimination. Prior studies have reported that pitch can be extracted from sinusoidal pulses as brief as half a cycle. This finding has been used in a number of classic papers to develop models of pitch encoding. We have found that phase randomization, which eliminates timbre confounds, degrades this ability to chance, raising serious concerns over the foundation on which classic pitch models have been built. The current study investigated whether subthreshold pitch cues may still exist in partial-cycle pulses revealed through statistical integration in a time series containing multiple pulses. To this end, we measured frequency-discrimination thresholds in a two-interval forced-choice task for trains of partial-cycle random-phase tone pulses. We found that residual pitch cues exist in these pulses but discriminating them requires an order of magnitude (ten times) larger frequency difference than that reported previously, necessitating a re-evaluation of pitch models built on earlier findings. We also found that as pulse duration is decreased to less than two cycles its pitch becomes biased toward higher frequencies, consistent with predictions of an auto correlation model of pitch extraction. PMID- 26022838 TI - Quality of life and risk of psychiatric disorders among regular users of alcohol, nicotine, and cannabis: An analysis of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). AB - Research is limited on the effects of regular substance use on mental health related outcomes. We used a large nationally representative survey to examine current and future quality of life and risk of psychiatric disorders among past year regular (weekly) users of alcohol, nicotine, and cannabis. Data on psychiatric disorders and quality of life from two waves (Wave 1 N = 43,093, Wave 2 N = 34,653) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) were used to test study aims. In cross-sectional analyses, regular nicotine and cannabis use were associated with higher rates of psychiatric disorder, though regular alcohol use was associated with lower rates of disorders. Prospective analyses found that regular nicotine use predicted onset of anxiety, depressive, and bipolar disorders. Regular alcohol use predicted lower risk of these disorders. Regular cannabis use uniquely predicted the development of bipolar disorder, panic disorder with agoraphobia, and social phobia. Lastly, regular alcohol use predicted improvements in physical and mental health-related quality of life, whereas nicotine predicted deterioration in these outcomes. Regular cannabis use predicted declines in mental, but not physical health. These data add to the literature on the relations between substance use and mental and physical health and suggest increased risk of mental health problems among regular nicotine and cannabis users and better mental and physical health among regular alcohol users. Examination of mechanisms underlying these relationships is needed. PMID- 26022839 TI - Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup. AB - Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate. PMID- 26022840 TI - Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents. AB - Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 MUM. Interestingly, trans-3,4- and trans 3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212. PMID- 26022841 TI - High throughput screening identifies ATP-competitive inhibitors of the NLRP1 inflammasome. AB - Nod-like receptors (NLRs) are cytoplasmic pattern recognition receptors that are promising targets for the development of anti-inflammatory therapeutics. Drug discovery efforts targeting NLRs have been hampered by their inherent tendency to form aggregates making protein generation and the development of screening assays very challenging. Herein we report the results of an HTS screen of NLR family member NLRP1 (NLR family, pyrin domain-containing 1) which was achieved through the large scale generation of recombinant GST-His-Thrombin-NLRP1 protein. The screen led to the identification of a diverse set of ATP competitive inhibitors with micromolar potencies. Activity of these hits was confirmed in a FP binding assay, and two homology models were employed to predict the possible binding mode of the leading series and facilitate further lead-optimization. These results highlight a promising strategy for the identification of inhibitors of NLR family members which are rapidly emerging as key drivers of inflammation in human disease. PMID- 26022842 TI - Synthesis and Biological evaluation of novel 4beta-[(5-substituted)-1,2,3,4 tetrazolyl] podophyllotoxins as anticancer compounds. AB - A series of novel 4beta-[(5-substituted)-1,2,3,4-tetrazolyl] podophyllotoxin derivatives were synthesized by employing azide-nitrile click chemistry approach. All the derivatives were evaluated for their cytotoxicity against a panel of four human cancer cell lines and their IC50 values were found to be in the range of 2.4-29.06 MUM. The cytotoxicity exhibited by the majority of test compounds were found to comparable and often more effective than doxorubicin and all compounds exhibited higher cytotoxicity on A-549 cell lines. Cell cycle analysis showed that the novel 4beta-[(5-substituted)-1,2,3,4-tetrazolyl] podophyllotoxins resulted in cell cycle arrest at G2/M phase and were also found to be the potent inhibitors of tubulin polymerization in vitro. PMID- 26022843 TI - Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design. AB - Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low MUM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1). PMID- 26022844 TI - Discovery of xanthine oxidase inhibitors and/or alpha-glucosidase inhibitors by carboxyalkyl derivatization based on the flavonoid of apigenin. AB - Three series of apigenin derivatives have been prepared by coupling the carboxyl alkyl group to 4'-, 5- or 7-hydroxyl groups of apigenin respectively. Preliminary biological evaluation in vitro revealed that xanthine oxidase inhibitory activity was improved by modifications at 4'-position and decreased by similar modifications at 5-, 7-positions while alpha-glucosidase inhibitory activity was maintained by modifications at 5-, 7-positions but lost by modifications at 4' position. Administration (ip) of 7e markedly lowered serum uric acid levels in potassium oxonate induced hyperuricemic mouse model and administration (p.o.) of 11d or 11e effectively suppressed the elevation of serum glucose in the oral sucrose tolerance test in mice, while apigenin were not significantly effective in both tests. PMID- 26022845 TI - Prostate tumor specific peptide-peptoid hybrid prodrugs. AB - Inspired by naturally occurring host defense peptides, cationic amphipathic peptoids provide a promising scaffold for anti-cancer therapeutics. Herein, we report a library of peptide-peptoid hybrid prodrugs that can be selectively activated by prostate cancer cells. We have identified several compounds demonstrating potent anti-cancer activity with good to moderate selectivity. We believe that these prodrugs can provide a useful design principle for next generation peptide-peptoid hybrid prodrugs. PMID- 26022846 TI - The cancer experience map: an approach to including the patient voice in supportive care solutions. AB - The perspective of the patient, also called the "patient voice", is an essential element in materials created for cancer supportive care. Identifying that voice, however, can be a challenge for researchers and developers. A multidisciplinary team at a health information company tasked with addressing this issue created a representational model they call the "cancer experience map". This map, designed as a tool for content developers, offers a window into the complex perspectives inside the cancer experience. Informed by actual patient quotes, the map shows common overall themes for cancer patients, concerns at key treatment points, strategies for patient engagement, and targeted behavioral goals. In this article, the team members share the process by which they created the map as well as its first use as a resource for cancer support videos. The article also addresses the broader policy implications of including the patient voice in supportive cancer content, particularly with regard to mHealth apps. PMID- 26022847 TI - Background levels of some major, trace, and rare earth elements in indigenous plant species growing in Norway and the influence of soil acidification, soil parent material, and seasonal variation on these levels. AB - Baseline levels of 43 elements, including major, trace, and rare earth elements (REEs) in several native plant species growing in boreal and alpine areas, are presented. Focus is placed on species metal levels at different soil conditions, temporal variations in plant tissue metal concentrations, and interspecies variation in metal concentrations. Vegetation samples were collected at Sogndal, a pristine site in western Norway, and at Risdalsheia, an acidified site in southernmost Norway. Metal concentrations in the different species sampled in western Norway are compared with relevant literature data from Norway, Finland, and northwest Russia, assumed to represent natural conditions. Except for aluminium (Al) and macronutrients, the levels of metals were generally lower in western Norway than in southern Norway and may be considered close to natural background levels. In southern Norway, the levels of cadmium (Cd) and lead (Pb) in particular appear to be affected by air pollution, either by direct atmospheric supply or through soil acidification. Levels of some elements show considerable variability between as well as within plant species. Calcium (Ca), magnesium (Mg), and potassium (K) are higher in most species at Sogndal compared to Risdalsheia, despite increased extractable concentrations in surface soil in the south, probably attributed to different buffer mechanisms in surface soil. Antagonism on plant uptake is suggested between Ca, Mg, and K on one hand and Al on the other. Tolerance among calcifuges to acid conditions and a particular ability to detoxify or avoid uptake of Al ions are noticeable for Vaccinium vitis idaea. PMID- 26022848 TI - Phytoremediation assessment of Gomphrena globosa and Zinnia elegans grown in arsenic-contaminated hydroponic conditions as a safe and feasible alternative to be applied in arsenic-contaminated soils of the Bengal Delta. AB - Several agricultural fields show high contents of arsenic because of irrigation with arsenic-contaminated groundwater. Vegetables accumulate arsenic in their edible parts when grown in contaminated soils. Polluted vegetables are one of the main sources of arsenic in the food chain, especially for people living in rural arsenic endemic villages of India and Bangladesh. The aim of this study was to assess the feasibility of floriculture in the crop rotation system of arsenic endemic areas of the Bengal Delta. The effects of different arsenic concentrations (0, 0.5, 1.0, and 2.0 mg As L(-1)) and types of flowering plant (Gomphrena globosa and Zinnia elegans) on plant growth and arsenic accumulation were studied under hydroponic conditions. Total arsenic was quantified using atomic absorption spectrometer with hydride generation (HG-AAS). Arsenic was mainly accumulated in the roots (72 %), followed by leaves (12 %), stems (10 %), and flowers (<1 %). The flowering plants studied did not show as high phytoremediation capacities as other wild species, such as ferns. However, they behaved as arsenic tolerant plants and grew and bloomed well, without showing any phytotoxic signs. This study proves that floriculture could be included within the crop rotation system in arsenic-contaminated agricultural soils, in order to improve food safety and also food security by increasing farmer's revenue. PMID- 26022849 TI - Survey on nutrient content of different organic fertilisers. AB - The knowledge of nutrient aspects of organic fertilisers is of much relevance in assessing their availability and long-term effect to the soil and crop and in formulating sound fertiliser recommendation. Around 619 organic fertiliser samples under different categories, which were received by the analytical laboratory of UPASI Tea Research Institute, Valparai, were examined for their nutrient status. The trend in the number of samples received every year for the past 5 years showed that there is a gradual, steady and linear increase in the number of samples received by the laboratory which, in turn, authenticates the increase in the production and utilisation of organic fertilisers in agricultural sector. This also reveals the awareness of organic farming among farmers in recent times. The organic fertilisers received by the laboratory were categorised into different groups based on their nomenclature. The number of samples received each year under different categories varies to a larger extent. The nutritional status was unpredictable based on the nomenclature of the sample received. In addition to this frequency distribution, the nutritional values analysed are discussed in this paper. Correlation matrix was worked out between all the parameters estimated. It is evident that if maintenance of proper carbon-to nitrogen ratio and moisture content is ascertained in the finished product, one can guarantee the quality of the organic fertiliser in terms of nutrient content. PMID- 26022850 TI - A piece of the 'chemobrain' puzzle: pNF-H. PMID- 26022851 TI - PES mixed matrix nanofiltration membrane embedded with polymer wrapped MWCNT: Fabrication and performance optimization in dye removal by RSM. AB - MWCNTs were wrapped by poly(sodium 4-styrenesulfonate) (PSS), and different amounts of raw and polymer wrapped MWCNTs were implemented to fabricate PES mixed matrix membranes by phase inversion method. Success of wrapping was probed by FTIR spectroscopy, and prepared membranes were characterized by SEM, AFM, porosity, and water contact angle measurements. Response surface methodology (RSM) was employed to optimize the permeate flux and dye removal efficiency of membranes with three variables of concentration, pH of dye solution, and membrane composition. A response surface (RS) with a D-optimal design was defined to build the mathematical model, minimize the number of experiments, and investigate the effect of parameters on the response. Adequacy of the obtained model was confirmed by means of variance analysis and additional experiments. Based on observed and predicted results, wrapping CNTs by PSS improved permeation flux and dye removal efficiency of MMMs. Validity of model was verified according to the good agreement between predicted and experimental results. Membrane mixed with 0.1 wt.% polymer wrapped MWCNTs offered the highest permeation flux as well as dye removal efficiency. According to the model response, in order to achieve a higher dye removal, an acidic pH and a moderate dye solution concentration are recommended. Additionally, basic solution pH (9.0) and a dilute dye solution are suggested to reach a higher permeation flux. PMID- 26022852 TI - Decreased blood hepatitis B surface antibody levels linked to e-waste lead exposure in preschool children. AB - Lead (Pb) is a widespread environmental contaminant that can profoundly affect the immune system in vaccinated children. To explore the association between blood Pb and HBsAb levels in children chronically exposed to Pb, we measured hepatitis B surface antibody (HBsAb) titers, to reflect the immune response in the children of Guiyu, an electronic and electrical waste (e-waste) recycling area well known for environmental Pb contamination. We performed secondary exploratory analyses of blood Pb levels and plasma HBsAb titers in samples, taken in two phases between 2011 and 2012, from 590 children from Guiyu (exposed group) and Haojiang (reference group). Children living in the exposed area had higher blood Pb levels and lower HBsAb titers compared with children from the reference area. At each phase, generalized linear mixed models (GLMMs) showed that HBsAb titers were significantly negatively associated with child blood Pb levels. This work shows that a decreased immune response to hepatitis B vaccine and immune system might have potential harm to children with chronic Pb exposure. Importantly, nearly 50% of chronically exposed children failed to develop sufficient immunity to hepatitis in response to vaccination. Thus different vaccination strategies are needed for children living under conditions of chronic Pb exposure. PMID- 26022853 TI - Heavy metal-immobilizing organoclay facilitates polycyclic aromatic hydrocarbon biodegradation in mixed-contaminated soil. AB - Soils contaminated with a mixture of heavy metals and polycyclic aromatic hydrocarbons (PAHs) pose toxic metal stress to native PAH-degrading microorganisms. Adsorbents such as clay and modified clay minerals can bind the metal and reduce its toxicity to microorganisms. However, in a mixed-contaminated soil, an adsorption process more specific to the metals without affecting the bioavailability of PAHs is desired for effective degradation. Furthermore, the adsorbent should enhance the viability of PAH-degrading microorganisms. A metal immobilizing organoclay (Arquad((r)) 2HT-75-bentonite treated with palmitic acid) (MIOC) able to reduce metal (cadmium (Cd)) toxicity and enhance PAH (phenanthrene) biodegradation was developed and characterized in this study. The MIOC differed considerably from the parent clay in terms of its ability to reduce metal toxicity (MIOC>unmodified bentonite>Arquad-bentonite). The MIOC variably increased the microbial count (10-43%) as well as activities (respiration 3-44%; enzymatic activities up to 68%), and simultaneously maintained phenanthrene in bioavailable form in a Cd-phenanthrene mixed-contaminated soil over a 21-day incubation period. This study may lead to a new MIOC-assisted bioremediation technique for PAHs in mixed-contaminated soils. PMID- 26022854 TI - [Psychosocial trauma]. PMID- 26022855 TI - [Personalized therapy for gliomas]. AB - Current therapies for patients with malignant gliomas are starting to integrate molecular factors and age. Nonetheless, these therapies are still not sufficiently individualized. Some positive examples of transfer from basic science to clinical application are currently integrated into the standard treatment and guidelines. These are mainly genetic and other molecular factors that improve diagnosis and classification of gliomas and markers supporting prognostication. Examples for predictive biomarkers are methylation of the O-6 methylguanine-DNA methyltransferase (MGMT) promoter and the codeletion of chromosome arms 1p and 19q (1p/19q codel). The autoactive, truncated form of epidermal growth factor receptor (EGFRvIII) and the R132H mutation of isocitrate dehydrogenase 1 (IDH-1) are used as targets in currently running immunotherapeutic, targeted trials. Integration of functional imaging parameters into the monitoring and development of uniform assessment criteria improve the ability to evaluate therapy response and implement imaging biomarkers to guide therapies. As a result of the current efforts there are better classified prognostic groups and improved survival times with maintained functional and quality of life parameters in some glioma subgroups. Given the current dynamics, an improved, better differentiated classification of brain tumors including molecular parameters as well as more rational precise guiding of therapies with early, uniform response assessment is expected in the near future. PMID- 26022856 TI - [Posttraumatic disorders in patients with schizophrenia spectrum disorders]. AB - BACKGROUND: The findings of international studies suggest high rates of interpersonal violence and posttraumatic stress disorder (PTSD) among patients with schizophrenia spectrum disorders. Only few studies, however, have so far been conducted in the German-speaking countries. OBJECTIVES: The aim of our study was to determine the prevalence of lifetime experiences of interpersonal violence and comorbid PTSD among inpatients in a German university hospital. METHOD: In N = 145 consecutively admitted patients with schizophrenia spectrum disorders (67 % male) the structured trauma interview (STI) was used to assess experiences of interpersonal violence and the structured clinical interview for DSM-IV (SCID) to assess comorbid PTSD. RESULTS: Sexual violence under the age of 16 years was reported by 17 % of the patients (women 27 %, men 12 %). Approximately one third (32 %) reported physical violence by parental figures (women 38 %, men 29 %). At least one form of early violence (sexual or physical) was reported by half of the women (48 %) and one third of the men (34 %). Negative sexual experiences later in life were reported by 17 %, physical violence by 38 % and at least one of these forms by 48 % of the patients. In total two thirds of all patients (66 %) reported experiences of violence during their lifetime. The prevalence of acute PTSD was 12 %. Another 9 % of patients had a subsyndromal PTSD. CONCLUSION: The present study confirmed the high rates of experiences of interpersonal violence and comorbid PTSD in a German sample of patients with schizophrenia spectrum disorders. Violence and it's consequences should therefore be routinely assessed and the full spectrum of trauma-specific therapies should be integrated into the treatment of this group of patients. PMID- 26022857 TI - Altered Neural Activity in the Anterior and Posterior Insula in Individuals with Problematic Internet Use. AB - BACKGROUND: Individuals with problematic Internet use (PIU) are known to experience increased craving for immediate monetary reward despite long-term negative consequences. What remains unclear is whether their sensitivity to monetary loss is altered. We investigated neural alterations in brain regions involved in the anticipation of a monetary reward and loss avoidance in order to advance our understanding of the characteristics of PIU. METHODS: A total of 11 adults with PIU and 22 age-matched controls participated in this functional magnetic resonance imaging study. Inside the scanner, participants performed a monetary incentive learning task during which they chose one of two fractal stimuli associated with monetary gain (reward trials) or avoidance of monetary loss (avoidance trials). RESULTS: We found that, relative to controls, activity in the posterior insula during reward anticipation was greater in participants with PIU, whereas its activity during avoidance anticipation was reduced. No group differences in activation were found during reception phases. CONCLUSIONS: Given the roles of the posterior insula in the cortical representation of somatosensory arousal, our results suggest that individuals with PIU may experience more elaborate somatosensory arousal during the anticipation of monetary reward and yet experience less elaborate somatosensory arousal during the anticipation of loss avoidance compared with typical controls. PMID- 26022858 TI - Characterization of a novel beta-cypermethrin-degrading Aspergillus niger YAT strain and the biochemical degradation pathway of beta-cypermethrin. AB - Aspergillus niger YAT strain was obtained from Chinese brick tea (Collection number: CGMCC 10,568) and identified on the basis of morphological characteristics and internal transcribed spacer (ITS) sequence. The strain could degrade 54.83 % of beta-cypermethrin (beta-CY; 50 mg L(-1)) in 7 days and 100 % of 3-phenoxybenzoic acid (3-PBA; 100 mg L(-1)) in 22 h. The half-lives of beta-CY and 3-PBA range from 3.573 to 11.748 days and from 5.635 to 12.160 h, respectively. The degradation of beta-CY and 3-PBA was further described using first-order kinetic models. The pathway and mechanism of beta-CY degraded by YAT were investigated by analyzing the degraded metabolites through high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). Relevant enzymatic activities and substrate utilization were also investigated. beta-CY degradation products were analyzed. Results indicated that YAT strain transformed beta-CY into 3-PBA. 3-PBA was then gradually transformed into permethric acid, protocatechuic acid, 3-hydroxy-5-phenoxy benzoic acid, gallic acid, and phenol gradually. The YAT strain can also effectively degrade these metabolites. The results indicated that YAT strain has potential applications in bioremediation of pyrethroid insecticide (PI)-contaminated environments and fermented food. PMID- 26022859 TI - Historical background, definitions and differential diagnosis. AB - Although awareness that food can cause adverse symptoms and even death in some individuals has been present since the times of Hippocrates, it was not until the seminal experiment of Prausnitz that the investigation of food allergy had a more scientific basis. In the first half of the 20th century, there were periodic reports in the medical literature describing various food allergic reactions. Until the studies of Charles May and colleagues in the mid- to late '70s, there was a great deal of skepticism in the medical world about the relevance of food allergy and how to diagnose it, since standard skin testing was known to correlate poorly with clinical symptoms. With the introduction of the double blind, placebo-controlled oral food challenge by May, the study of food allergy has become evidence based, and tremendous strides have been made in the study of basic immunopathogenic mechanisms and natural history as well as in the diagnosis and management of food allergies. Today, various IgE- and non-IgE-mediated food allergic disorders have been well characterized, and efforts to reverse these allergies using various immunotherapeutic strategies are well under way. PMID- 26022860 TI - Immunological basis of food allergy (IgE-mediated, non-IgE-mediated, and tolerance). AB - Food allergy includes a number of diseases that present with adverse immunological reactions to foods and can be IgE-mediated, non-IgE-mediated, or a combination of both mechanisms. IgE-mediated food allergy involves immediate hypersensitivity through the action of mast cells, whereas non-IgE-mediated food allergy is most commonly cell-mediated. These food allergies are thought to occur as a result of a breakdown in oral tolerance and, more specifically, from an aberrant regulatory T-cell response. Ongoing studies of experimental treatments for food allergy strive to induce oral tolerance and to teach us more about the pathogenesis of food allergy. PMID- 26022861 TI - Food allergens: molecular and immunological aspects, allergen databases and cross reactivity. AB - The currently known food allergens are assigned to a relatively small number of protein families. Food allergens grouped into protein families share common functional and structural features that can be attributed to the allergenic potency and potential cross-reactivity of certain proteins. Molecular data, in terms of structural information, biochemical characteristics and clinical relevance for each known allergen, including isoforms and variants, are mainly compiled into four open-access databases. Allergens are designated according to defined criteria by the World Health Organization and the International Union of Immunological Societies Allergen Nomenclature Sub-committee. Food allergies are caused by primary sensitisation to the disease-eliciting food allergens (class I food allergen), or they can be elicited as a consequence of a primary sensitisation to inhalant allergens and subsequent IgE cross-reaction to homologous proteins in food (class II food allergens). Class I and class II allergens display different clinical significance in children and adults and are characterised by different molecular features. In line with this, high stability when exposed to gastrointestinal digestion and heat treatment is attributed to many class I food allergens that frequently induce severe reactions. The stability of a food allergen is determined by its molecular characteristics and can be influenced by structural (chemical) modifications due to thermal processing. Moreover, the immunogenicity and allergenicity of food allergens further depends on specific T cell and B cell epitopes. Although the T cell epitope pattern can be highly diverse for individual patients, several immuno prominent T cell epitopes have been identified. Such conserved T cell epitopes and IgE cross-reactive B cell epitopes contribute to cross-reactivity between food allergens of the same family and to clinical cross-reactivity, similar to the birch pollen-food syndrome. PMID- 26022862 TI - Epidemiology: international point of view, from childhood to adults, food allergens. AB - Recent studies have suggested that the prevalence of food allergy is increasing in many parts of the world. However, many epidemiology studies have been based only on questionnaires without objective testing. The data from these studies do show that the pattern of food allergies is different across the world. In general, studies using objective testing reported a lower prevalence than those without objective testing. The most common food allergens are cow's milk, hen's egg, wheat, fish, shellfish, peanuts, and tree nuts. Recent evidence also suggested that some of these allergies might not persist longer than the childhood years. However, unlike milk and egg allergies, seafood allergy is more likely to persist into adulthood. Peanuts and tree nuts are some of the most common causes of anaphylaxis in developed countries, but these are rather rare in developing countries. Given the early evidence of an increasing prevalence of food allergies, continual monitoring of the changing prevalence and patterns in different countries should help us understand the true causes of food allergy. PMID- 26022863 TI - Food allergy in childhood (infancy to school age). AB - Food allergy is a potentially life-threatening condition affecting almost 10% of children, with an increasing incidence in the last few decades. It is defined as an immune reaction to food, and its pathogenesis may be IgE mediated, mixed IgE and non-IgE mediated, or non-IgE mediated. Potentially all foods can cause food allergy, but a minority of foods are responsible for the vast majority of reactions reported. A good clinical history is crucial for an accurate diagnosis. Allergy tests, including the skin prick test and measurement of specific IgE antibodies, are useful tools in the case of IgE-mediated or mixed allergy but have not been shown to be of any help in delayed allergic reactions to foods. PMID- 26022864 TI - Food allergy in adolescence and adulthood. AB - In young children, food allergy is usually acquired via the gastrointestinal tract and directed toward egg and milk. Adolescent and adult patients, however, mainly acquire food allergy via primary sensitization to inhalant allergens on the basis of cross-reactivity between proteins in inhalant sources and in food. This type of food allergy is frequently mediated by sensitization to broadly represented allergens, or so-called panallergens. Food allergic reactions in adult patients - similar to those in children - range in severity from very mild and local symptoms, as in contact urticaria of the oral mucosa, to systemic symptoms involving distal organs, to a fatal outcome. Plant foods, such as fruits, nuts, and vegetables, are the most prevalent allergenic foods in this age group. PMID- 26022865 TI - Hints for diagnosis. AB - The diagnosis of food allergy requires responses to two important questions: Does the patient have a food allergy? If so, which foods will elicit allergic symptoms? The first question will most often have to be answered following a physical examination and an interview with the patient and/or caretakers. Based on this, a provisional decision to pursue a food allergy diagnosis may be made after carefully considering other possible reasons for an adverse reaction to a food: aversion, infection, intoxication, or an underlying metabolic disease. To respond to the next question, the anamnesis is highly important in selecting which tests and, ultimately, oral food challenges the patient should undergo to reach the final diagnosis. For the diagnosing doctor, it is important to know and consider the regional pattern of inhalation and food allergies, the food consumption patterns in the local community, and the selection of patients--in terms of both age groups and symptoms--visiting the center. PMID- 26022866 TI - IgE-related examination in food allergy with focus on allergen components. AB - Molecular allergology is a breakthrough science that enables the quantification of IgE antibodies against individual allergen protein components at the molecular level. The diagnosis of IgE-mediated allergic disorders is based on the clinical history and on sensitization demonstrated through an allergy test. Identifying whether the sensitization is primary (species specific) or due to cross reactivity with proteins with similar protein structures helps the clinician to judge the risk of allergic reaction. This is possible today because allergen component tests for food allergy are now available for clinicians to use in everyday practice. PMID- 26022867 TI - Non-IgE-related diagnostic methods (LST, patch test). AB - Although most food allergy patients have immediate-type reactions, some have delayed-type reactions. Unlike for the detection of food-specific IgE antibody in immediate-type (IgE-mediated) food allergies, only a few tests are currently available to aid in the diagnosis of delayed-type (non-IgE-mediated) food allergies. This chapter summarizes our current understanding of one in vitro test and one in vivo test for non-IgE-mediated food allergies: the lymphocyte stimulation test (LST) and the atopy patch test (APT). Although the LST is not yet standardized, a food protein-specific LST might be a useful tool for diagnosing delayed-type food allergies, and especially those manifesting with gastrointestinal symptoms but not skin symptoms. Various remaining issues - including basophil contamination of the peripheral blood mononuclear cell fraction and lipopolysaccharide contamination of food antigen preparations - are also discussed. The APT uses an epicutaneous patch technique to occlusively apply food antigens to the skin to induce inflammatory reactions at the patch application site. Because the APT shows modest sensitivity and specificity, the clinical benefit of the APT in the diagnosis of food allergies in patients with atopic dermatitis is limited. A position paper on the APT issued by the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network in 2006 is briefly summarized, and several recent APT-related topics, including APT use for the diagnosis of food protein-induced enterocolitis syndrome, are discussed. PMID- 26022868 TI - Diagnostic elimination diets and oral food provocation. AB - Accurately diagnosing patients with suspected food allergy is obviously critically important. The patient's health may be compromised if problem foods are left in the diet, while nutrition and quality of life may be negatively affected if foods are unnecessarily removed from the diet. In some patients, the diagnosis is very straightforward, such as with anaphylaxis with the first known exposure to peanut, but in many cases, the diagnosis will not be clear based on the history, skin tests, and serologic tests, especially because these tests often yield falsely positive results. In these instances, further testing will be needed, typically including diagnostic elimination diets and/or oral food challenges, which are the gold standard for the diagnosis of food allergy. PMID- 26022869 TI - Pharmacological management of acute food-allergic reactions. AB - There is currently no well-established disease-modifying treatment for food allergy, so management relies upon strict avoidance of food allergen(s), implementation of risk minimisation strategies to avoid inadvertent exposure and allergic reactions, and prompt management of acute allergic reactions, should they occur. The pharmacological management of acute food-induced allergic reactions is dependent on the underlying pathophysiology of the allergic reaction and the severity of clinical symptoms and signs. Mild to moderate symptoms of an immunoglobulin E-mediated acute allergic reaction may be treated effectively with an oral anti-histamine. In patients exhibiting the clinical features of anaphylaxis, adrenaline is the only first-line therapy recommended by expert consensus. Adjunctive therapies, including anti-histamines, beta-agonists and glucocorticoids, may be used in the subsequent management of immunoglobulin E mediated anaphylaxis. Here, we present the current recommendations for the pharmacological management of acute food-induced allergic reactions, together with a summary of the evidence supporting these recommendations. PMID- 26022870 TI - Oral immunotherapy and potential treatment. AB - The standardized therapeutic approach for food allergy is based on avoidance of allergens in foods. Oral immunotherapy (OIT) is a significant focus of food allergy research and appears to be effective in inducing desensitization. However, most patients receiving OIT have mild to moderate symptoms during the therapy, and it has not been clearly established whether OIT is effective in inducing permanent tolerance. Recently, novel therapeutic approaches for food allergy, or sublingual immunotherapy and epicutaneous immunotherapy using an anti IgE monoclonal antibody (omalizumab), have been examined in some studies. These studies showed that the frequency of adverse reactions is lower than with OIT and that patients can increase their food tolerance. Other novel approaches, including the use of omalizumab in combination with OIT, may be useful in food allergy treatment. There is some evidence that a combination of OIT with omalizumab increases threshold doses of food without causing symptoms. OIT offers a new approach for treating food allergy, although further study is needed to demonstrate long-term safety and benefits in larger numbers of patients. PMID- 26022872 TI - Hen's Egg Allergy. AB - Egg allergy is one of the most frequent food allergies in infants and young children. The prevalence of egg allergy is estimated to be between 1.8 and 2% in children younger than 5 years of age. The reactions are mainly mediated by IgE and partially by non-IgE or are a mix of both types. Egg white contains more than 20 different proteins and glycoproteins. Ovomucoid (Gal d 1), ovalbumin (Gal d 2), conalbumin (ovotransferrin) (Gal d 3) and lysozyme (Gal d 4) have been identified as major allergens in hen's egg. Alpha-livetin (Gal d 5) is thought to be a main egg yolk allergen responsible for bird-egg syndrome. The diagnosis of egg allergy is based on history taking, antigen-specific IgE measurements, such as the skin prick test, in vitro antigen-specific blood IgE tests and histamine release tests, and oral food challenges. The measurements of specific IgE to ovomucoid and its linear epitopes are more useful in the diagnosis of heated egg allergy and in the prediction of prognosis. Currently, the management of egg allergy is essentially minimal elimination based on the correct identification of the causative allergen. Although oral immunotherapy is promising as a tolerance induction protocol, several questions and concerns still remain, predominantly regarding safety. PMID- 26022871 TI - Cow's milk allergy in children and adults. AB - Cow's milk allergy is among the more frequent food allergies in infants and children. Because its suspicion stems from a plethora of symptoms, it is frequently reported. However, the development of a rigorous diagnostic pathway will reduce the diagnosed children to less than 50% of those reported. Cow's milk allergy is the only specific food allergy for which an EBM guideline exists. According to the guidelines (Diagnosis and Rationale for Action against Cow's Milk Allergy), a diagnostic process based on the pre-test probability of this condition is available. Treatments include avoidance, the substitution of cow's milk with an appropriate formula, and in some cases, oral immunotherapy. Treatment choice is also guided by these guidelines. PMID- 26022873 TI - Peanut and tree nut allergy. AB - Allergy to peanut and tree nuts is a major worldwide health concern. The prevalence of these allergies may be increasing, but the reasons for these increases remain unclear. This group of foods accounts for a large proportion of severe and fatal food-allergic reactions. These allergies present most often during childhood but can occur at any age. Resolution is possible but uncommon, and frequent lifetime reactions caused by accidental ingestion are a serious problem. The major allergens of peanut and most tree nuts have been identified, allowing for insights into patient diagnoses, clinical outcomes, and potential future immunotherapies. PMID- 26022874 TI - Grain and legume allergy. AB - Among grains and legumes, wheat and soybean are the most frequent and well characterized allergenic foods. Wheat proteins are divided into water/salt soluble and water/salt-insoluble (gluten) fractions. The most dominant allergen in the former is alpha-amylase/trypsin inhibitor, which acts as an inhaled allergen causing baker's asthma. Gluten allergens, including omega-5 gliadin and high- and low-molecular-weight glutenins, contribute to wheat-dependent exercise induced anaphylaxis in adults and immediate-type wheat allergies, including anaphylaxis, in children. Recently, wheat allergies exclusively caused by hydrolyzed wheat proteins or deamidated glutens have been reported, and the presence of unique IgE-binding epitopes has been suggested. Soybean allergens contributing to immediate-type allergic reactions in children are present in seed storage proteins, namely Gly m 5, Gly m 6 and Gly m 8. However, pollen-related soybean allergy in adults is caused by the Bet v 1 homolog of soybeans, Gly m 4. Taken together, the varying clinical manifestations of wheat and soybean allergies are predominantly caused by their different allergen components. PMID- 26022875 TI - Fish and shellfish allergy. AB - Fish and shellfish consumption has increased worldwide, and there are increasing reports of adverse reactions to fish and shellfish, with an approximate prevalence of 0.5-5%. Fish allergy often develops early in life, whilst shellfish allergy tends to develop later, from adolescence onwards. Little is known about the natural history of these allergies, but both are thought to be persistent. The clinical manifestations of shellfish allergy, in particular, may vary from local to life-threatening 'anaphylactic' reactions within an individual and between individuals. Parvalbumin and tropomyosin are the two major allergens, but several other allergens have been cloned and described. These allergens are highly heat and biochemically stable, and this may in part explain the persistence of these allergies. Diagnosis requires a thorough history, skin prick and in-vitro-specific IgE tests, and oral challenges may be needed for diagnostic confirmation. Strict avoidance of these allergens is the current standard of clinical care for allergic patients, and when indicated, an anaphylactic plan with an adrenaline auto-injector is prescribed. There are no published clinical trials evaluating specific oral immunotherapy for fish or shellfish allergy. PMID- 26022876 TI - Fruit and vegetable allergy. AB - Fruit and vegetable allergies are the most prevalent food allergies in adolescents and adults. The identification of the allergens involved and the elucidation of their intrinsic properties and cross-reactivity patterns has helped in the understanding of the mechanisms of sensitisation and how the allergen profiles determine the different phenotypes. The most frequent yet contrasting fruit and vegetable allergies are pollen-food syndrome (PFS) and lipid transfer protein (LTP) syndrome. In PFS, fruit and vegetable allergies result from a primary sensitisation to labile pollen allergens, such as Bet v 1 or profilin, and the resulting phenotype is mainly mild, consisting of local oropharyngeal reactions. In contrast, LTP syndrome results from a primary sensitisation to LTPs, which are stable plant food allergens, inducing frequent systemic reactions and even anaphylaxis. Although much less prevalent, severe fruit allergies may be associated with latex (latex-fruit syndrome). Molecular diagnosis is essential in guiding the management and risk assessment of these patients. Current management strategies comprise avoidance and rescue medication, including adrenaline, for severe LTP allergies. Specific immunotherapy with pollen is not indicated to treat pollen-food syndrome, but sublingual immunotherapy with LTPs seems to be a promising therapy for LTP syndrome. PMID- 26022877 TI - Gastrointestinal food allergies. AB - Gastrointestinal food allergies present during early childhood with a diverse range of symptoms. Cow's milk, soy and wheat are the three most common gastrointestinal food allergens. Several clinical syndromes have been described, including food protein-induced enteropathy, proctocolitis and enterocolitis. In contrast with immediate, IgE-mediated food allergies, the onset of gastrointestinal symptoms is delayed for at least 1-2 hours after ingestion in non-IgE-mediated allergic disorders. The pathophysiology of these non-IgE mediated allergic disorders is poorly understood, and useful in vitro markers are lacking. The results of the skin prick test or measurement of the food-specific serum IgE level is generally negative, although low-positive results may occur. Diagnosis therefore relies on the recognition of a particular clinical phenotype as well as the demonstration of clear clinical improvement after food allergen elimination and the re-emergence of symptoms upon challenge. There is a significant clinical overlap between non-IgE-mediated food allergy and several common paediatric gastroenterological conditions, which may lead to diagnostic confusion. The treatment of gastrointestinal food allergies requires the strict elimination of offending food allergens until tolerance has developed. In breast fed infants, a maternal elimination diet is often sufficient to control symptoms. In formula-fed infants, treatment usually involves the use an extensively hydrolysed or amino acid-based formula. Apart from the use of hypoallergenic formulae, the solid diets of these children also need to be kept free of specific food allergens, as clinically indicated. The nutritional progress of infants and young children should be carefully monitored, and they should undergo ongoing, regular food protein elimination reassessments by cautious food challenges to monitor for possible tolerance development. PMID- 26022878 TI - Atopic eczema and food allergy. AB - Approximately one-third of children with severe atopic eczema suffer from a food allergy, whereas in adult patients, food allergies are rare. In child patients, three different clinical reaction patterns can be differentiated as follows: (1) immediate-type reactions, (2) isolated late eczematous reactions, and (3) combined immediate-type and late eczematous reactions. In childhood food allergies, food allergens, such as cow's milk or hen's egg, are primarily responsible for allergic reactions, while in adolescents and adults, food allergies often develop consecutively after primary sensitization to pollen allergens. Dysfunctions in the epidermal barrier seem to be vitally important in the development of food allergies in patients with atopic eczema by facilitating sensitization after epicutaneous allergen exposure. Further investigation is required to determine the role of intestinal epithelial barrier defects in the pathogenesis of these allergies as well as the genetic characteristics associated with an increased risk of food allergy. The diagnosis of eczematous reactions to food requires a careful diagnostic procedure, taking into account a patient's history and sensitization patterns. The clinical relevance of sensitization often has to be proven by an oral food challenge, with the rating of the skin condition by validated scores after 24 h and the later evaluation of the eczematous reaction. PMID- 26022879 TI - Anaphylaxis in food allergy. AB - Food allergy is a known trigger of anaphylaxis. Although the awareness of food allergies has improved, food-related allergic reactions and anaphylaxis still commonly occur. The recognition of anaphylaxis, its prompt treatment, and patient education are important for the prevention of future food reactions. Patients and health care providers should also recognize the importance of epinephrine as the primary treatment of anaphylaxis. When food-related anaphylaxis occurs, patients should receive education regarding their food allergies, an epinephrine auto injector, and follow-up with a food allergy specialist to reduce the risk of future food-related reactions. PMID- 26022880 TI - Eosinophilic oesophagitis. AB - Eosinophilic oesophagitis (EoE) is an antigen-driven pan-oesophagitis that is defined by the presence of at least 15 eosinophils per high power field on oesophageal histology in conjunction with upper gastrointestinal symptoms. EoE is closely associated with atopic disorders, in particular with food allergy, and as for other atopic diseases in childhood, there is a strong preponderance of male patients who have this disorder. The mechanisms leading to EoE have been characterised at the molecular level. Eotaxin-3, interleukin-5 and interleukin-13 are the key effector molecules in EoE pathogenesis. EoE presents with a diverse range of gastrointestinal symptoms, including regurgitation, vomiting, feeding difficulties or feeding refusal in infancy, as well as heartburn, dysphagia and food bolus impaction in older children and adults. The diagnosis may also be ascertained as an incidental finding in patients undergoing gastroscopy for other suspected conditions, including coeliac disease. EoE is different from gastro oesophageal reflux disease and does not improve in response to proton pump inhibitors. Therefore, EoE needs to be distinguished from so-called PPI responsive oesophageal eosinophilia. The long-term prognosis of EoE remains poorly defined, and complications mainly relate to subepithelial remodelling and fibrosis that may result in dysmotility, dysphagia and oesophageal strictures. The treatment of EoE involves elimination diets and topical swallowed aerosolised corticosteroids, while biological therapies targeting molecular mechanisms have so far been unsuccessful. In children, elemental diets have proved highly effective, but multiple food elimination diets are more sustainable in the long term. Further randomised, controlled trials on dietary or pharmacological interventions are needed to inform the optimal long-term management of EoE. PMID- 26022881 TI - Nutritional aspects and diets in food allergy. AB - Dietary intervention is a crucial component of food allergy management but can negatively impact nutrient intake. A comprehensive nutrition assessment with appropriate intervention is warranted in all children with food allergies to meet nutrient needs and optimize growth. Nutrition assessment may also be indicated in adults with food allergy. Frequently, an elimination diet is absolutely necessary to prevent potentially life-threatening anaphylaxis. Allergen elimination can also improve chronic symptoms, such as atopic dermatitis, when a food is proven to trigger symptoms. Allergen elimination goals are to prevent acute and chronic food-allergic reactions in the safest and least restrictive environment to supply a balanced diet that promotes health in children and adults. PMID- 26022882 TI - Food allergy: psychosocial impact and public policy implications. AB - Given its increasing prevalence and potential severity, food allergy not only negatively impacts the health and quality of life of affected individuals but also carries a significant economic burden. To address these problems, a community approach including efforts to increase awareness of food allergy among the general public and the implementation of appropriate public policies to keep affected individuals safe is required. This chapter reviews the general public's knowledge and perceptions of food allergy, the disease's psychosocial impact on affected individuals, and the current state and future directions of food allergy public policy. PMID- 26022883 TI - Worldwide food allergy labeling and detection of allergens in processed foods. AB - The labeling of allergenic foods is an important public health measure to assist food-allergic consumers in avoiding foods that can cause allergic reactions. The regulatory framework for such labeling depends upon the selection of priority allergenic foods, which vary among countries. Most countries include milk, eggs, fish, crustacean shellfish, peanuts, tree nuts, soybeans, and cereal sources of gluten on the priority allergenic foods list, as recommended by the Codex Alimentarius Commission. However, a variety of other foods appear on the priority lists of some countries but not on others. Sesame seeds, molluscan shellfish, buckwheat, and mustard are identified in two or more countries. In most countries, all ingredients derived from these priority allergen sources must also be declared on labels by source. However, exemptions exist for some ingredients in some countries but not in others. Detection methods are critical for the enforcement of allergen labeling regulations and for the investigation of allergic reactions in the community by public health officials. The development of detection methods has advanced considerably over the past several decades and will be briefly reviewed in this chapter. Because of the emphasis on labeling and the development of detection methods, the ingredient statement on packaged food labels now contains more information than ever before to assist food-allergic consumers. PMID- 26022884 TI - The effects of food allergy on quality of life. AB - The majority of research on food allergy has been bio-medical in orientation, focusing on issues such as the molecular structure of allergens, or aimed at methods of diagnosis. In the last decade, there has been a growing interest in the development of questionnaires that measure the impact of food allergy on health-related quality of life (HRQL). These studies have provided insight into the everyday burden of living with food allergy and have suggested ways that HRQL can be improved. The EuroPrevall project (europrevall@bbsrc.ac.uk) has given great impetus to research in the area of HRQL. In addition to clinical research on the prevalence, mechanisms and causes of food allergy, research output in the area of psycho-social impact has included HRQL measures for all age groups and examination of the socio-economic impact of food allergy. In this chapter, we review the literature on the impact of food allergy on children, teens and their parents; the majority of this data was generated over the life of the EuroPrevall project. We then examine both quantitative and qualitative research findings to provide an in-depth picture of the impact of food allergy on the concerns and everyday lives of children, teens, adults and parents. Research on factors that are related to and impact HRQL is also discussed. There is a strong emphasis throughout the chapter on developmental considerations of food allergy, spanning from infants to adults. We conclude by discussing methodological issues in relation to the measurement of HRQL in relation to food allergy. We offer some recommendations for future research and practice on HRQL so that HRQL measures can reach their full potential in research, practice and policy, with the help of the findings in this review. Overall, the findings suggest that food allergy has a strong impact on HRQL in terms of social, dietary, and psychological factors. 'Rules' and restrictions ostensibly apply to food, but because food is such an integral part of everyday life, these restrictions extend far beyond 'mealtimes'. Therefore, social events are experienced differently and have a different meaning for those living with food allergy, giving rise to feelings of exclusion and difference when compared to those without allergy. Children, teens, and parents need to cope with normal developmental changes as well as with the food allergy, placing them under increased psycho-social stress and leading to adverse effects on HRQL and coping. To address and attempt to alleviate such stressors, both quantitative and qualitative research suggests that targeting uncertainty should be a major goal for health professionals working with children, teens and families with a food allergy. Remarkable similarities in response to food allergy across countries suggest that policies and programmes that address quality of life issues may be relevant to many different populations. An in-depth understanding of the relationship between a diagnosis of food allergy and HRQL, as well as the factors that impact it, will ultimately lead to the promotion of earlier, more effective preventive strategies and interventions that are focused on maximising optimal health development and quality of life. PMID- 26022885 TI - Prevention of food allergy. AB - Despite a trend towards delayed weaning, food allergies (FAs) have increased in the past few decades and are now considered a public health concern, resulting in significant morbidity as well as occasional mortality. Whilst genetic factors are clearly important in the development of FA, a rise in FAs has occurred over a short period of time and is therefore unlikely to be due to germ-line genetic changes alone. Thus, it seems plausible that one or more environmental exposures may, via epigenetic changes, result in the interruption of the 'default immunologic state' of tolerance to foods. Strategies are therefore required for the prevention of FA: primary prevention seeks to prevent the onset of IgE sensitisation; secondary prevention seeks to interrupt the development of FA in IgE-sensitised children; and tertiary prevention seeks to reduce the expression of 'end-organ' allergic disease in children with established FA. This chapter will outline the major findings in this field, with the aim of equipping the clinician with an evidence-based approach to a burgeoning yet poorly understood clinical problem. We also highlight the methodological challenges hindering the interpretation of existing FA studies. Fortunately, there are now robust studies underway, the results of which are expected to guide public health recommendations with respect to how and when to introduce major allergenic foods to children, regardless of allergic risk. PMID- 26022886 TI - Educational programmes in food allergy. AB - About 17% of German children and adolescents suffer from at least one of the following atopic illnesses: allergic rhinoconjunctivitis, atopic eczema or asthma. Consistent professional therapy is necessary to limit the health-related risks and improve these medical conditions. The consequences of a diagnosis often mean an additional task for the parents of diseased children, where they have to act simultaneously as an educator and therapist for their children. Structured educational programmes were developed for a few diseases such as asthma and atopic eczema in order to prepare parents and affected children to accept this important responsibility. Moreover, a structured programme for anaphylaxis is being developed. These proposals aim not only to transfer knowledge about the disease but also to effectively support self-reliant treatment and emotional coping with the disease as well as its collateral strain. PMID- 26022888 TI - Investigation of microemulsion microstructure and its impact on skin delivery of flufenamic acid. AB - Microemulsions are well known penetration enhancing delivery systems. Several properties are described that influence the transdermal delivery of active components. Therefore, this study aimed to characterize fluorosurfactant-based microemulsions and to assess the impact of formulation variables on the transdermal delivery of incorporated flufenamic acid. The microemulsion systems prepared in this study consisted of bistilled water, oleic acid, isopropanol as co-solvent, flufenamic acid as active ingredient and either Hexafor(TM)670 (Hex) or Chemguard S-550-100 (Sin) as fluorosurfactant. Characterization was performed by a combination of techniques including electrical conductivity measurements, small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) self diffusion experiments. In vitro skin permeation experiments were performed with each prepared microemulsion using Franz type diffusion cells to correlate their present microstructure with their drug delivery to skin. Electrical conductivity increased with added water content. Consequently, the absence of a conductivity maximum as well as the NMR and SAXS data rather suggest O/W type microemulsions with spherical or rod-like microstructures. Skin permeation data revealed enhanced diffusion for Hex- and Sin-microemulsions if the shape of the structures was rather elongated than spherical implying that the shape of droplets had an essential impact on the skin permeation of flufenamic acid. PMID- 26022890 TI - Porous clay heterostructures: A new inorganic host for 5-fluorouracil encapsulation. AB - This study proposed a new inorganic host for drug encapsulation. Porous clay heterostructure (PCH), synthesized using modified montmorillonite with hexadecyltrimethylammonium bromide, was used as host material and 5-fluorouracil (5-FU) as guest drug. Drug encapsulation within PCH in different conditions (soaking time, temperature and pH value) was investigated. Possible interactions of 5-FU with PCH were pointed out using different characterization methods like spectroscopic techniques (FT-IR, UV-vis, XPS), thermogravimetrical and BET analysis. The obtained results suggested that PCH host exhibits a high drug encapsulation efficiency which was influenced by factors like soaking time and pH value. PCH zeta potential value was strongly influenced by pH value. The PCH zeta potential significantly varies at acid pH, while a pH value higher than 7 provides a less variation. UV-vis analysis showed that after 30 min PCH host registered a maximum encapsulation efficiency value (44%) at room temperature using an incubation solution with a pH of 11. The soaking temperature does not substantially affect the loading of drug in PCH host. Thermogravimetrical analysis highlighted that drug encapsulation efficiency of PCH was mainly influenced by pH values. BET results confirmed the PCH synthesis and drug loading capacity. PMID- 26022891 TI - CO2-promoted oxidative cross-coupling reaction for C-S bond formation via masked strategy in an odourless way. AB - Cu-catalyzed direct oxidative cross-coupling between boronic acids and masked sulfides delivering thioethers was described, in which the SO3(-), as a mask, has shown a distinctive effect on the oxidative cross-coupling condition. Disulfide could be suppressed efficiently via masked strategy under CO2 atmosphere. A broad scope of aromatics and scalable processes indicates its practicality, which could be further applied to drug late-stage modification and unsymmetrical dibenzothiophenes (DBTs) synthesis. PMID- 26022889 TI - Developing dissolution testing methodologies for extended-release oral dosage forms with supersaturating properties. Case example: Solid dispersion matrix of indomethacin. AB - The objective of this study was to develop an in vitro dissolution test method with discrimination ability for an extended-release solid dispersion matrix of a lipophilic drug using the United States Pharmacopeia (USP) Apparatus 4, flow through cell apparatus. In the open-loop configuration, the sink condition was maintained by manipulating the flow rate of the dissolution medium. To evaluate the testing conditions, the drug release mechanism from an extended-release solid dispersion matrix containing hydrophobic and hydrophilic polymers was investigated. As the hydroxypropyl methylcellulose (HPMC) maintained concentrations of indomethacin higher than the solubility in a dissolution medium, the release of HPMC into the dissolution medium was also quantified using size-exclusion chromatography. We concluded that the USP Apparatus 4 is suitable for application to an in vitro dissolution method for orally administered extended-release solid dispersion matrix formulations containing poorly water soluble drugs. PMID- 26022892 TI - Notch strengthening or weakening governed by transition of shear failure to normal mode fracture. AB - It is generally observed that the existence of geometrical discontinuity like notches in materials will lead to strength weakening, as a resultant of local stress concentration. By comparing the influence of notches to the strength of three typical materials, aluminum alloys with intermediate tensile ductility, metallic glasses with no tensile ductility, and brittle ceramics, we observed strengthening in aluminum alloys and metallic glasses: Tensile strength of the net section in circumferentially notched cylinders increases with the constraint quantified by the ratio of notch depth over notch root radius; in contrast, the ceramic exhibit notch weakening. The strengthening in the former two is due to resultant deformation transition: Shear failure occurs in intact samples while samples with deep notches break in normal mode fracture. No such deformation transition was observed in the ceramic, and stress concentration leads to its notch weakening. The experimental results are confirmed by theoretical analyses and numerical simulation. The results reported here suggest that the conventional criterion to use brittleness and/or ductility to differentiate notch strengthening or weakening is not physically sound. Notch strengthening or weakening relies on the existence of failure mode transition and materials exhibiting shear failure while subjected to tension will notch strengthen. PMID- 26022893 TI - Crosstalk Between Co-cultured A549 Cells and THP1 Cells Exposed to Cigarette Smoke. AB - Cigarette smoke (CS) is considered as a major etiological factor in the pathogenesis of chronic obstructive pulmonary disease. In this study we used A549 cells and THP-1 cells grown for 24 h in monoculture or in co-culture in CS conditioned media and changes in their proliferation, viability, acetylated histone H3 levels and expression of extracellular antigens CD14, HLA-DR, CD11a, and CD11b were assessed. CS was highly toxic to A549 cells but not to THP1 cells. In A549 cells, oxidative stress reached the highest values after 1 h of CS exposure and then decreased. In THP1 cells oxidative stress was lower and increased progressively with time. CS decreased proliferation of A549 and THP1 cells by about 80% and 21%, respectively. CS did not alter acetylated histone H3 levels in A549 cells, while in THP1 cells the levels were reduced by about 35%. CS significantly increased expression of CD14, HLA-DR, CD11a, and CD11b in THP1 cells. In co-culture, naive or CS-pretreated THP1 cells significantly protected A549 cells against CS toxicity but had higher death rates. These results show that epithelial cells are more fragile to CS than monocytes and that CS-activated monocytes may protect epithelial cells against CS-induced cytotoxicity. PMID- 26022895 TI - Specific Inhalation Challenge in Persulfate Asthma. AB - Specific inhalation challenge (SIC) may be considered the 'gold standard' for the diagnosis of occupational asthma due to persulfate salts. The aim of the study was to develop a safe SIC protocol. Between 2003 and 2014, eight patients with suspected occupational asthma due to persulfate salts were examined (7 females, all hair-dressers). SIC was done with a dosimeter and a nebulizer using ammonium persulfate dissolved in phosphate buffer. Until 2009, a four-step-protocol (doses: 0.0004, 0.0045, 0.045, 0.45 mg; cumulative: 0.5 mg) was used, afterwards a six-step-protocol (doses: 0.0004, 0.0018, 0.007, 0.028, 0.113, 0.45 mg; cumulative: 0.6 mg). With each SIC protocol, four subjects were tested. Skin prick tests with ammonium persulfate (20 mg/mL) were performed in all and patch tests in four subjects. In total, four subjects showed a positive SIC, two with each protocol. All subjects showed an isolated late reaction. The greatest decrease of volume in 1 s was 35 % about 3.5 h after the last inhalation (four step-protocol). Skin prick test with ammonium persulfate was positive in one SIC positive (2 mm wheal) and in two SIC negative patients (3 and 4 mm wheal). All four subjects tested with patch tests showed a positive reaction; three of them were SICpos. We recommend to include patch-testing in the diagnosis of suspected occupational asthma due to persulfate salts. Isolated late asthmatic reactions may occur after SIC. The proposed six-step SIC protocol was safe in this limited number of subjects. PMID- 26022896 TI - Factors Influencing Utilization of Primary Health Care Services in Patients with Chronic Respiratory Diseases. AB - The purpose of our study was to determine the factors affecting the level of services provided in primary health care among patients with chronic respiratory diseases. The study group consisted of 299 adults (median age: 65, min-max: 18-92 years) with mixed chronic respiratory diseases, recruited from patients of 135 general practitioners. In the analysis, in addition to the assessment of the provided medical services, the following were used: Patient Satisfaction Questionnaire, Camberwell Assessment of Needs Short Appraisal Schedule, Acceptance of Illness Scale, and WHO Quality of Life Instrument Short Form. Variables that determined the level of services were the following: age, place of residence, marital status, number of chronic diseases, and level of disease acceptance, quality of life, and health behaviors. The level of provided services correlated with variables such as gender, severity of somatic symptoms, level of satisfied needs, and satisfaction with health care. We concluded that in patients with mixed chronic respiratory diseases a higher level of health care utilization should be expected in younger patients, those living in the countryside, those having a partner, with multimorbidity, a low level of disease acceptance, those satisfied with their current quality of life, with positive mental attitudes, and maintaining health practices. PMID- 26022894 TI - Comparative Expression of Apoptotic Markers in Lung Adenocarcinoma and Squamous Cell Carcinoma. AB - Lung cancer is still an oncology challenge. A 5-year survival reaches less than 20 % of patients. Apoptosis disturbances are a key step in cancer development. The evaluation of apoptosis markers has a great potential in lung cancer. The goal of our study was a comparative evaluation of apoptosis regulators: p53, Bcl 2, Bax, COX-2, and survivin in lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). We also evaluated the relationship between apoptosis markers and clinicopathological parameters. Fifty six patients with non-small cell lung cancer (NSCLC) were included into the study (20 women and 36 men). AC was diagnosed in 30 and SCC in 26 cases. The evaluation of markers was performed using an immunohistochemical method on paraffin embedded tissue specimens. We used monoclonal antibodies for p53, bcl-2, and COX2-proteins (clone DO7, bcl 2/100/D5, and 4H12, respectively), Bax (B-9 clone) and survivin (clone 12C4). The results of immunostaining were viewed by light microscopy. We revealed significantly more frequent expression of Bax and survivin in lung AC than SCC (p < 0.01 and p < 0.019). Bcl-2 immunoreactivity was seen more often in AC without lymph node metastases than with metastases (p = 0.046). There was no correlation between the apoptosis markers and gender or the presence of vessel emboli. A greater variability in markers expression was seen in lung AC than SCC. There were significant differences in the Bax and survivin expression in the two major pathological types of NSCLC. We did not revealed any correlation between the markers and TNM characteristics, accept for Bcl-2 presence along with the lymph node involvement in the AC group. PMID- 26022897 TI - Interleukin-33 as a New Marker of Pulmonary Sarcoidosis. AB - The mechanisms of sarcoidosis (Besniera-Boeck-Schaumann disease, BBS) remain incompletely understood, although recent observations suggested an important contribution of interleukin-33 (IL-33). So far, there are no data about bronchoalveolar lavage fluid (BALF) concentration of IL-33 in patients with BBS. In the present study we attempted to relate the concentration of IL-33 to IL-18, a well-known marker of BBS activity, in BALF of BBS patients. We examined 24 BBS patients (stage II). The age-matched control group consisted of 24 healthy subjects. The levels of IL-33 and IL-18 in BALF were higher in BBS patients than in the control group [IL-33: 4.8 (0.1-12.5) vs. 3.4 (0.6-56.9) pg/ml, p=0.024; IL 18: 33.2 (5.7-122.0) vs. 10.8 (1.9-45.8) pg/ml, p=0.002]. In the BBS group, the correlations between IL-33 and IL-18 (r=0.606, p=0.002), and between IL-33 and diffusion lung capacity for carbon monoxide (DLCO) (r=-0.500, p=0.035) were found. The receiver-operating characteristic curves were applied to find the cut off serum levels of IL-33 and IL-18 in BALF (BBS vs. healthy: IL-33 2.7 pg/ml and IL-18 16.4 pg/ml). We conclude that IL-33 appears an important factor of pulmonary BBS activity. PMID- 26022898 TI - Ondine's Curse - Genetic and Iatrogenic Central Hypoventilation as Diagnostic Options in Forensic Medicine. AB - In the Nordic mythology a man lost his ability to breathe without remembering it after he was cursed by water nymph - referred to as 'Ondine's curse' - and then he died as soon as he fell asleep. Family medicine specialists are familiar with many sleeping disorders that their patients commonly call by the term Ondine's Curse. In medical sciences this term is historically related to the group of conditions that have as the common denominator seemingly spontaneous onset of life-threatening hypoventilation. The physiology and genetics specialists focus mainly on congenital central hypoventilation syndrome (CCHS), which was proven to be linked to several genetic mutations. Anesthesiologists tend to be more interested in similarly manifesting iatrogenic condition. Typically, patients that were previously subjected to general anesthesia, after temporarily waking up and regaining the spontaneous respiratory drive, later fall back into unconsciousness and develop hypoventilation. Anesthesiologists also call it Ondine's curse because of the sudden and unexpected sleep onset. The iatrogenic Ondine's curse is proven to be precipitated by delayed anesthetics release from patients' fat tissue - where it was deposited at the time general anesthesia was administered - back into bloodstream. Forensic medicine has to consider the latter form of Ondine's curse called scenario more often, as they investigate sudden deaths related to surgery and general anesthesia in the post-operational care period. These cases may also fall into the category of medical malpractice related deaths. PMID- 26022899 TI - Expression of HIF-1A/VEGF/ING-4 Axis in Pulmonary Sarcoidosis. AB - Angiogenesis/angiostasis regulated by hypoxia inducible factor-1A (HIF 1A)/vascular endothelial growth factor (VEGF)/inhibitor of growth protein 4 (ING 4) axis may be crucial for the course and outcome of sarcoidosis. Overexpression of angiogenic factors (activation of VEGF through HIF-1A) may predispose to chronic course and lung fibrosis, whereas immunoangiostasis (related to an overexpression of inhibitory ING-4) may be involved in granuloma formation in early sarcoid inflammation, or sustained or recurrent formation of granulomas. In this work we investigated gene expression of HIF-1A, VEGF and ING-4 in bronchoalveolar fluid (BALF) cells and in peripheral blood (PB) lymphocytes of sarcoidosis patients (n=94), to better understand mechanisms of the disease and to search for its biomarkers. The relative gene expression level (RQ value) was analyzed by qPCR. The results were evaluated according to the presence of lung parenchymal involvement (radiological stage I vs. II-IV), acute vs. insidious onset, lung function tests, calcium metabolism parameters, percentage of lymphocytes (BALL%) and BAL CD4+/CD8+ in BALF, age, and gender. In BALF cells, the ING-4 and VEGF RQ values were increased, while HIF-1A expression was decreased. In PB lymphocytes all studied genes were overexpressed. Higher expression of HIF-1A in PB lymphocytes of patients with abnormal spirometry, and in BALF cells of patients with lung volume restriction was found. VEGF gene expression in BALF cells was also higher in patients with abnormal spirometry. These findings were in line with previous data on the role of HIF-1A/VEGF/ING-4 axis in the pathogenesis of sarcoidosis. Up-regulated HIF-1A and VEGF genes are linked to acknowledged negative prognostics. PMID- 26022900 TI - Inflammatory Activity in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder in early childhood characterized by impairment in communication and behavior. Recent research is focused on the immune dysregulation as a potential pathomechanism leading to ASD. Thus, we addressed the hypothesis that inflammatory activity might be enhanced in children suffering from ASD. We examined 15 children with ASD (13 boys/2 girls, mean age of 9.3 +/- 0.7 years) and 20 age/gender-matched healthy subjects as a control group. All children were medication free and in good health. Hematological parameters in venous blood and plasma levels of pro inflammatory cytokines - tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), and interleukin 8 (IL-8) - were assessed in each subject using human ultra-sensitive ELISA kits. In addition, TBARS as a marker of oxidative stress was evaluated. We found that the level of IL-8 was significantly increased in the ASD children, whereas the other markers remained unappreciably changed compared to controls (p = 0.003). In conclusion, the study demonstrates a discrete immune dysfunction in ASD of pro-inflammatory character. PMID- 26022901 TI - Comparison of Small Bore Catheter Aspiration and Chest Tube Drainage in the Management of Spontaneous Pneumothorax. AB - Beside standard chest tube drainage other less invasive techniques have been used in the management of patients with an acute episode of spontaneous pneumothorax. The aim of the study was to evaluate the short term effect of spontaneous pneumothorax treatment with small-bore pleural catheter and manual aspiration as compared to large-bore chest tube drainage. Patients with an episode of pneumothorax who required pleural intervention were enrolled in the study and randomly assigned to one of the treatment arms: (1) small-bore pleural catheter (8 Fr) with manual aspiration; (2) standard chest tube drainage (20-24 Fr). Success rate of the first line treatment, duration of catheter or chest tube drainage, and the need for surgical intervention were the outcome measures. The study group included 49 patients (mean age 46.9+/-21.3 years); with 22 and 27 allocated to small bore manual aspiration and chest tube drainage groups, respectively. There were no significant differences in the baseline characteristics of patients in both therapeutic arms. First line treatment success rates were 64% and 82% in the manual aspiration and chest tube drainage groups, respectively; the difference was insignificant. Median time of treatment with small bore catheter was significantly shorter than conventional chest tube drainage (2.0 vs. 6.0 days; p<0.05). Our results show that treatment of spontaneous pneumothorax with small-bore pleural catheter and manual aspiration might be similarly effective as is chest tube drainage in terms of immediate lung re-expansion. PMID- 26022902 TI - Regulatory T Cells in Obesity. AB - The current concept of the pathogenesis of obesity relates to the inflammation caused by excess of adipose tissue. Regulatory T cells accumulated in visceral adipose tissue (VAT-resident Tregs) are also involved in this pathogenesis. In the present paper the mechanisms responsible for alterations in the number and function of VAT-resident Tregs T in obesity are described. The role of Tregs in inflammation, insulin resistance, atherogenesis, and also the influence on VAT resident Tregs of adipocytokines and insulin are reviewed. PMID- 26022903 TI - Influence of Iron Overload on Immunosuppressive Therapy in Children with Severe Aplastic Anemia. AB - Children with severe aplastic anemia (AA) require multiple transfusions of the red blood cells during the immunosuppressive therapy. This leads to iron overload and manifests as elevated levels of ferritin in blood. The aim of this study was a retrospective analysis of the influence of the elevated serum ferritin on the overall survival, event-free survival, the risk of relapse, and response to treatment in children with AA during immunosuppressive therapy. We analyzed 38 children with AA (19 girls, 19 boys, aged 2-17 years) treated according to the obligatory protocol for AA in Poland. The response rate was assessed on days 84, 112, and 360. Patients were divided into three groups: group I consisted of children with ferritin below 285 ng/mL (6 children), group II with ferritin between 286 and 1,000 ng/mL (13 children), and group III ferritin>1,000 ng/mL (19 children). Kaplan-Meier plot was used to estimate the overall survival and event free survival. We found the overall survival did not differ between the three groups. Event-free survival was significantly shorter (p=0.03) in patients with ferritin levels>1,000 ng/mL compared with the groups with ferritin bellow 1,000 ng/mL. The time to relapse was significantly shorter in group III than in the other two groups (p=0.02). We also found the differences in the treatment response at day 84 (p=0.03) and day 112 (p<0.0001) of immunosuppressive therapy. These findings confirm a negative influence of iron overload in children with AA on the effect of treatment and the risk of relapse. PMID- 26022904 TI - Brown Adipose Tissue and Browning Agents: Irisin and FGF21 in the Development of Obesity in Children and Adolescents. AB - In the pediatric population, especially in early infancy, the activity of brown adipose tissue (BAT) is the highest. Further in life BAT is more active in individuals with a lower body mass index and one can expect that BAT is protective against childhood obesity. The development of BAT throughout the whole life can be regulated by genetic, endocrine, and environmental factors. Three distinct adipose depots have been identified: white, brown, and beige adipocytes. The process by which BAT can become beige is still unclear and is an area of intensive research. The "browning agents" increase energy expenditure through the production of heat. Numerous factors known as "browning agents" have currently been described. In humans, recent studies justify a notion of a role of novel myokines: irisin and fibroblast growth factor 21 (FGF21) in the metabolism and development of obesity. This review describes a possible role of irisin and FGF21 in the pathogenesis of obesity in children. PMID- 26022905 TI - Finite Elements Modeling in Diagnostics of Small Closed Pneumothorax. AB - Posttraumatic pneumothorax still remains to be a serious clinical problem and requires a comprehensive diagnostic and monitoring during treatment. The aim of this paper is to present a computer method of modeling of small closed pneumothorax. Radiological images of 34 patients of both sexes with small closed pneumothorax were taken into consideration. The control group consisted of X-rays of 22 patients treated because of tension pneumothorax. In every single case the model was correlated with the clinical manifestations. The procedure of computational rapid analysis (CRA) for in silico analysis of surgical intervention was introduced. It included implementation of computerize tomography images and their automatic conversion into 3D finite elements model (FEM). In order to segmentize the 3D model, an intelligent procedure of domain recognition was used. In the final step, a computer simulation project of fluid-structure interaction was built, using the ANSYS?Workbench environment of multi-physics analysis. The FEM model and computer simulation project were employed in the analysis in order to optimize surgical intervention. The model worked out well and was compatible with the clinical manifestations of pneumothorax. We conclude that the created FEM model is a promising tool for facilitation of diagnostic procedures and prognosis of treatment in the case of small closed pneumothorax. PMID- 26022906 TI - Sleep-Related Breathing Disorders and Bruxism. AB - Obstructive sleep apnea (OSA) syndrome is a sleep-related breathing disorder, due mainly to peripheral causes, characterized by repeated episodes of obstruction of the upper airways, associated with snoring and arousals. The sleep process fragmentation and oxygen desaturation events lead to the major health problems with numerous pathophysiological consequences. Micro-arousals occurring during sleep are considered to be the main causal factor for night jaw-closing muscles activation called bruxism. Bruxism is characterized by clenching and grinding of the teeth or by bracing or thrusting of the mandible. The causes of bruxism are multifactorial and are mostly of central origin. Among central factors there are secretion disorders of central nervous system neurotransmitters and basal ganglia disorders. Recently, sleep bruxism has started to be regarded as a physiological phenomenon occurring in some parts of the population. In this article we present an evaluation of the relationship between OSA and sleep bruxism. It has been reported that the frequency of apneic episodes and that of teeth clenching positively correlates in OSA. However, clinical findings suggest that further studies are needed to clarify sleep bruxism pathophysiology and to develop new approaches to tailor therapy for individual patients with concomitant sleep bruxism and OSA. PMID- 26022907 TI - Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes. AB - Since the first report of the enhanced permeability and retention (EPR) effect, the research in nanocarrier based antitumor drugs has been intense. The field has been devoted to treatment of cancer by exploiting EPR-based accumulation of nanocarriers in solid tumors, which for many years was considered to be a ubiquitous phenomenon. However, the understanding of differences in the EPR effect between tumor types, heterogeneities within each patient group, and dependency on tumor development stage in humans is sparse. It is therefore important to enhance our understanding of the EPR-effect in large animals and humans with spontaneously developed cancer. In the present paper, we describe a novel loading method of copper-64 into PEGylated liposomes and use these liposomes to evaluate the EPR-effect in 11 canine cancer patients with spontaneous solid tumors by PET/CT imaging. We thereby provide the first high resolution analysis of EPR-based tumor accumulation in large animals. We find that the EPR-effect is strong in some tumor types but cannot be considered a general feature of solid malignant tumors since we observed a high degree of accumulation heterogeneity between tumors. Six of seven included carcinomas displayed high uptake levels of liposomes, whereas one of four sarcomas displayed signs of liposome retention. We conclude that nanocarrier-radiotracers could be important in identifying cancer patients that will benefit from nanocarrier-based therapeutics in clinical practice. PMID- 26022908 TI - An update on new methods to synthesize cyclotetrapeptides. AB - Cyclotetrapeptides are important bioactive lead drug molecules that display a wide spectrum of pharmacological activities. However, the synthesis of cyclotetrapeptides from their linear precursors is challenging due to the highly constrained conformation required for cyclisation, thus hampering their progress to a clinical setting. This review provides an account of the reported methods used for the synthesis of cyclotetrapeptides. PMID- 26022909 TI - Use of Appropriate Use Criteria Is Increasing, but What Are Their Effects on Medical Care? PMID- 26022910 TI - Temporal Trends in Percutaneous Coronary Intervention Appropriateness: Insights From the Clinical Outcomes Assessment Program. AB - BACKGROUND: It is unknown whether the appropriate use of percutaneous coronary intervention (PCI) has improved over time and whether trends in PCI appropriateness have been accompanied by changes in the use of PCI. METHODS AND RESULTS: We applied appropriate use criteria to determine the appropriateness of all 51 872 PCI performed in Washington State from 2010 through 2013. We evaluated the number of PCIs performed from 2006 through 2013 to provide a comparator period that preceded statewide appropriateness assessment beginning in 2010. Between 2010 and 2013, the overall number of PCI decreased by 6.8% (13 267 PCIs in 2010 to 12 193 in 2013) with a 43% decline in the number of PCIs for elective indications (3818 PCIs in 2010 to 2193 PCIs in 2013). The decline in the use of elective PCI was significantly larger after the onset of statewide PCI appropriateness assessment in 2010 (P=0.03). The proportion of elective PCIs classified as appropriate increased from 26% in 2010 to 38% in 2013, whereas the proportion of inappropriate PCIs decreased from 16% to 13% (P<0.001 for trends). Significant improvements in the proportion of inappropriate PCI were limited to the tertile of hospitals with the largest decline in PCIs classified as inappropriate (25% in 2010 to 12% in 2013; P=0.03). CONCLUSIONS: In Washington State, the use of PCI for elective indications has decreased over time with concurrent improvements in PCI appropriateness. However, improvements in PCI appropriateness were limited to a minority of hospitals. Understanding processes at these high-performing hospitals may inform efforts to improve PCI appropriateness. PMID- 26022912 TI - Target-Controlled Infusion of Remifentanil Without Muscle Relaxants Allows Acceptable Surgical Conditions During Thoracotomy Performed Under Sevoflurane Anesthesia. AB - OBJECTIVES: To test the hypothesis that the use of a nonmuscle relaxant anesthetic technique (NMRT) during thoracotomy would be associated with comparable surgical conditions with the standard use of neuromuscular blocking drugs. DESIGN: A prospective, randomized, single-blind, controlled study. SETTING: A single university hospital. PARTICIPANTS: Sixty-six patients scheduled for open thoracotomy under sevoflurane anesthesia with a target-controlled infusion (TCI) of remifentanil. INTERVENTIONS: After ethical approval, patients were randomly assigned to receive cisatracurium or saline (n = 33 for each group) during the entire study period. MEASUREMENTS AND MAIN RESULTS: The four-point ordinal surgical rating scale, the intubating conditions, the use of anesthetics and vasopressors, the incidence of light anesthesia (defined as an episode with state entropy values that exceeded 50 and/or mean arterial blood pressure and heart rate values that exceeded the baseline by 20% and lasted for more than 3 consecutive minutes), and the times to clinical recovery and postanesthesia care unit (PACU) discharge, hospital stays, and postoperative residual curarization (PORC) were recorded. Compared with the use of cisatracurium, the use of NMRT resulted in comparable good-to-excellent surgical rating scales (90.9% v 94.0%, respectively; p = 0.642), good-to-excellent laryngoscopy and endobronchial intubating conditions (93.9% v 100%, respectively; p>0.09), use of anesthetic and vasopressor medications, and hospital stays, together with shorter clinical recovery, extubation times (7.6 [95% CI 6.82 to 8.39] v 19.0 [95% CI 15.76 to 22.23] minutes, respectively; p<0.001), and PACU stays (37.4 [95% CI 35.09 to 39.79] v 70.9 [95% CI 56.90 to 84.91] minutes, respectively; p<0.001). The use of cisatracurium resulted in a nonstatistical number of light anesthesia episodes upon positioning, skin incision, and rib separation (p>0.624, with Fisher's exact test). There were no failed intubations in the 2 groups. No patient received cisatracurium in the NMRT group. Two patients (6.1%) in the cisatracurium group experienced PORC that required tracheal intubation in the PACU. CONCLUSION: The use of TCI of remifentanil with NMRT offers acceptable laryngoscopy, intubating, and surgical conditions during sevoflurane anesthesia for open thoracotomy, especially when. the anesthesiologists have more than 10 years' experience. PMID- 26022911 TI - Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death. AB - BACKGROUND: Hemoglobin A1c (HbA1c) is the standard measure to monitor glucose control in diabetes mellitus and is a marker of future cardiovascular risk. Fructosamine and glycated albumin are markers of short-term glycemic control, but their associations with cardiovascular outcomes are uncharacterized. METHODS AND RESULTS: We measured glycated albumin and fructosamine in 11 104 participants with and without diabetes in the community-based Atherosclerosis Risk in Communities (ARIC) Study in 1990 to 1992 (baseline). We evaluated associations of fructosamine and glycated albumin with risk of coronary heart disease, ischemic stroke, heart failure, and mortality. We compared associations with those observed for HbA1c. During two decades of follow-up there were 1096 new cases of coronary heart disease, 605 of ischemic stroke, 1432 of heart failure, and 2860 deaths. Elevated baseline concentrations of fructosamine and glycated albumin were significantly associated with each of the outcomes even after adjustment for traditional cardiovascular risk factors, with especially strong associations in persons with diabetes mellitus. Associations were of similar magnitude to those observed for HbA1c and-as has been previously observed for HbA1c-the associations tended to be J-shaped, with an elevation of risk at the lowest levels of each biomarker. CONCLUSIONS: The acceptance of new measures of hyperglycemia is partly dependent on establishing their association with long-term outcomes. We found that fructosamine and glycated albumin were associated with vascular outcomes and mortality and that these associations were similar to those observed for HbA1c. PMID- 26022913 TI - Use of Blood Products and Diseased Ascending Aorta Are Determinants of Stroke After Off-Pump Coronary Artery Bypass Grafting. AB - OBJECTIVE: To examine the effect of blood products on the occurrence of stroke after coronary artery surgery. DESIGN: Institutional retrospective analysis. SETTING: University hospital. PARTICIPANTS: One thousand three hundred fourteen patients undergoing coronary artery surgery. INTERVENTIONS: Off-pump coronary artery bypass grafting (OPCAB). Epiaortic ultrasound was performed in all patients. MEASUREMENTS AND MAIN RESULTS: Complete pre-, intra- and postoperative data including the number of transfused blood products as well as the timing, type, and course of stroke were available in all patients. Postoperative stroke occurred in 23 patients (1.8%). Logistic regression identified transfusion of platelets (3.6% v 1.1%, p = 0.003, OR 3.34, 95%CI 1.46-7.67) and diseased ascending aorta (3.0% v 1.2%, p = 0.022, OR 2.64, 95% CI 1.15-6.06) as independent predictors of stroke. When these variables were adjusted for CHA2DS2VASc (p = 0.005, OR 1.44, 95% CI 1.12-1.86), only transfusion of platelets (p = 0.012, OR 2.91, 95% CI 1.26-6.70) was associated with stroke. Neither nadir hematocrit on the day of surgery nor nadir hematocrit during the perioperative period was an independent predictor of stroke. Chi-squared automatic interaction detection analysis identified solvent/detergent-treated plasma (Octaplas; Octapharma AG, Lachen, Switzerland) units >2 and platelet units >4 along with diseased ascending aorta as independent predictors of stroke. The stroke rate was 8.9% in patients receiving >2 units of Octaplas and having a diseased ascending aorta. In patients receiving <=2 units of Octaplas, the stroke rate was as high as 3.8% in patients receiving >4 units of platelets. CONCLUSIONS: The results of this study indicated that atherosclerosis of the ascending aorta as well as transfusion of platelets and/or Octaplas were independent predictors of stroke after OPCAB. PMID- 26022914 TI - Iron+folic acid distribution and consumption through antenatal care: identifying barriers across countries. AB - OBJECTIVE: The prevalence of maternal anaemia remains unacceptably high in developing countries. At the same time, the percentage of women who consume one or more Fe+folic acid (IFA) tablets during pregnancy remains persistently low. The objective of the present study was to identify where, within antenatal care (ANC) programmes, pregnant women falter in obtaining and consuming an ideal minimum of 180 IFA tablets. DESIGN: Data from Demographic and Health Surveys were used to develop a schematic which identifies four sequential 'falter points' to consuming 180 IFA tablets: ANC attendance, IFA receipt or purchase, IFA consumption and the number of tablets consumed. SETTING: Twenty-two countries with high burdens of undernutrition. SUBJECTS: A sample of 162 958 women, 15 to 49 years of age, with a live birth in the past 5 years. RESULTS: Across all countries, 83 % of all pregnant women had at least one ANC visit, 81 % of whom received IFA tablets. Of those receiving IFA tablets, 95 % consumed at least one. Overall adherence to the ideal supplementation regimen, however, was extremely low: only 8 % consumed 180 or more IFA tablets. There were only two countries in which the percentage of pregnant women consuming 180 or more tablets exceeded 30 %. CONCLUSIONS: While most women receive and take some IFA tablets, few receive or take enough. The analysis identifies where ANC-based distribution of IFA falters in each country. It enables policy makers to design and prioritize follow up activities to more precisely identify barriers, an essential next step to improving IFA distribution through ANC. PMID- 26022915 TI - Valuing productivity costs in a changing macroeconomic environment: the estimation of colorectal cancer productivity costs using the friction cost approach. AB - BACKGROUND: The friction cost approach (FCA) has been proposed as an alternative to the human capital approach for productivity cost valuation. However, FCA estimates are context dependent and influenced by extant macroeconomic conditions. We applied the FCA to estimate colorectal cancer labor productivity costs and assessed the impact of a changing macroeconomic environment on these estimates. METHODS: Data from colorectal cancer survivors (n = 159) derived from a postal survey undertaken in Ireland March 2010 to January 2011 were combined with national wage data, population-level survival data, and occupation-specific friction periods to calculate temporary and permanent disability, and premature mortality costs using the FCA. The effects of changing labor market conditions between 2006 and 2013 on the friction period were modeled in scenario analyses. Costs were valued in 2008 euros. RESULTS: In the base-case, the total FCA per person productivity cost for incident colorectal cancer patients of working age at diagnosis was ?8543. In scenario 1 (a 2.2 % increase in unemployment), the fall in the friction period caused total productivity costs to decrease by up to 18 % compared to base-case estimates. In scenario 2 (a 9.2 % increase in unemployment), the largest decrease in productivity cost was up to 65 %. Adjusting for the vacancy rate reduced the effect of unemployment on the cost results. CONCLUSIONS: The friction period used in calculating labor productivity costs greatly affects the derived estimates; this friction period requires reassessment following changes in labor market conditions. The influence of changes in macroeconomic conditions on FCA-derived cost estimates may be substantial. PMID- 26022916 TI - Gut healing: haemocytes aid via Sax and Tkv jazzes it down. AB - Control of stem cell activity is essential for accurate regeneration. Pathogen- or chemical-induced intestinal damage is now shown to recruit haemocytes expressing bone morphogenetic protein signals that stimulate proliferation of intestinal stem cells and subsequently induce their quiescence, in conjunction with muscle-derived bone morphogenetic proteins. A temporal switch in expression of Type I receptors enables this two-phase response. PMID- 26022917 TI - A niche role for cancer exosomes in metastasis. AB - Cancer cells are known to secrete exosomes with pro-metastatic effects. Pancreatic-cancer-derived exosomes are now shown to promote liver metastasis by eliciting pre-metastatic niche formation through a multi-step process. This involves uptake of exosome-derived factors by liver Kupffer cells and hepatic stellate cell activation to generate a fibrotic microenvironment with immune cell infiltrates that favours metastasis. PMID- 26022918 TI - Clarifying the role of condensin in shaping chromosomes. AB - A major controversy in the field of chromosome research has been whether condensin is required for achieving the highly compacted state of chromatin fibres in mitosis and meiosis. Through genetic experiments in mouse oocytes, condensin is now found to be indispensable for meiotic chromosome assembly by mediating chromosome compaction and disentanglement of sister chromatids and by conferring rigidity to chromosomes. PMID- 26022919 TI - Corrigendum: Nuclear actin and myosins: Life without filaments. PMID- 26022921 TI - Development and Validation of a Smartphone-Based Visual Acuity Test (Peek Acuity) for Clinical Practice and Community-Based Fieldwork. AB - IMPORTANCE: Visual acuity is the most frequently performed measure of visual function in clinical practice and most people worldwide living with visual impairment are living in low- and middle-income countries. OBJECTIVE: To design and validate a smartphone-based visual acuity test that is not dependent on familiarity with symbols or letters commonly used in the English language. DESIGN, SETTING, AND PARTICIPANTS: Validation study conducted from December 11, 2013, to March 4, 2014, comparing results from smartphone-based Peek Acuity to Snellen acuity (clinical normal) charts and the Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart (reference standard). This study was nested within the 6-year follow-up of the Nakuru Eye Disease Cohort in central Kenya and included 300 adults aged 55 years and older recruited consecutively. MAIN OUTCOMES AND MEASURES: Outcome measures were monocular logMAR visual acuity scores for each test: ETDRS chart logMAR, Snellen acuity, and Peek Acuity. Peek Acuity was compared, in terms of test-retest variability and measurement time, with the Snellen acuity and ETDRS logMAR charts in participants' homes and temporary clinic settings in rural Kenya in 2013 and 2014. RESULTS: The 95% CI limits for test-retest variability of smartphone acuity data were +/-0.033 logMAR. The mean differences between the smartphone-based test and the ETDRS chart and the smartphone-based test and Snellen acuity data were 0.07 (95% CI, 0.05-0.09) and 0.08 (95% CI, 0.06-0.10) logMAR, respectively, indicating that smartphone-based test acuities agreed well with those of the ETDRS and Snellen charts. The agreement of Peek Acuity and the ETDRS chart was greater than the Snellen chart with the ETDRS chart (95% CI, 0.05-0.10; P = .08). The local Kenyan community health care workers readily accepted the Peek Acuity smartphone test; it required minimal training and took no longer than the Snellen test (77 seconds vs 82 seconds; 95% CI, 71-84 seconds vs 73-91 seconds, respectively; P = .13). CONCLUSIONS AND RELEVANCE: The study demonstrated that the Peek Acuity smartphone test is capable of accurate and repeatable acuity measurements consistent with published data on the test-retest variability of acuities measured using 5-letter per-line retroilluminated logMAR charts. PMID- 26022922 TI - Characterizing and prototyping genetic networks with cell-free transcription translation reactions. AB - A central goal of synthetic biology is to engineer cellular behavior by engineering synthetic gene networks for a variety of biotechnology and medical applications. The process of engineering gene networks often involves an iterative 'design-build-test' cycle, whereby the parts and connections that make up the network are built, characterized and varied until the desired network function is reached. Many advances have been made in the design and build portions of this cycle. However, the slow process of in vivo characterization of network function often limits the timescale of the testing step. Cell-free transcription-translation (TX-TL) systems offer a simple and fast alternative to performing these characterizations in cells. Here we provide an overview of a cell-free TX-TL system that utilizes the native Escherichia coli TX-TL machinery, thereby allowing a large repertoire of parts and networks to be characterized. As a way to demonstrate the utility of cell-free TX-TL, we illustrate the characterization of two genetic networks: an RNA transcriptional cascade and a protein regulated incoherent feed-forward loop. We also provide guidelines for designing TX-TL experiments to characterize new genetic networks. We end with a discussion of current and emerging applications of cell free systems. PMID- 26022923 TI - Is Klotho F352V Polymorphism the Missing Piece of the Bone Loss Puzzle in Renal Transplant Recipients? AB - BACKGROUND: Bone disorders are next to cardiovascular problems in frequency in renal transplant (RT) recipients. Reduction in 1,25-dihydroxycholecalciferol (1,25D) levels is among the reasons causing bone loss in these patients. Klotho (KL) serves as a co-receptor for fibroblast growth factor 23 (FGF23), and functions in vitamin D metabolism. KL polymorphisms have been identified in several studies, and phenylalanine to valine substitution at amino acid position 352 seemed to be important to KL function. We investigated KL F352V polymorphism and its relation with 1,25D levels in RT recipients. METHODS: The study included 25 RT recipients (8 female, 17 male) and 26 (14 female, 12 male) healthy control subjects who were wild (FF) phenotypes in terms of KL F352V polymorphism. RT recipients with (FV, n = 11) and without (FF, n = 14) a heterozygote polymorphism were determined with high resolution DNA melting analysis of KL F352V polymorphism. Serum 1,25D levels were measured using the RIA method. RESULTS: RT recipients with FV phenotype had significantly lower 1,25D levels (17.58 +/- 18.38 pg/ml) compared to recipients with FF phenotype (44.91 +/- 24.68 pg/ml) and control subjects (28.24 +/- 12.13 pg/ml). 1,25D levels in RT recipients with FF phenotype were significantly higher than control subjects. CONCLUSIONS: KL F352V polymorphism may increase the expression of FGF23 co-receptor, KL protein and thus may decrease renal expression of 1alpha-hydroxylase, and/or stimulate 24 hydroxylase in RT recipients. The resultant decrease 1,25D levels may participate in bone loss in these patients. PMID- 26022925 TI - The influence of PRNP polymorphisms on human prion disease susceptibility: an update. AB - Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Straussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility. PMID- 26022927 TI - What Is the Role of Rituximab in Nodular Lymphocyte-Predominant Hodgkin Lymphoma? PMID- 26022924 TI - Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration. AB - We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p = 0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient's age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p = 0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion. PMID- 26022928 TI - High leukocyte mitochondrial DNA content contributes to poor prognosis in glioma patients through its immunosuppressive effect. AB - BACKGROUND: Epidemiological studies have indicated significant associations of leukocyte mitochondrial DNA (mtDNA) copy number with risk of several malignancies, including glioma. However, whether mtDNA content can predict the clinical outcome of glioma patients has not been investigated. METHODS: The mtDNA content of peripheral blood leukocytes from 336 glioma patients was examined using a real-time PCR-based method. Kaplan-Meier curves and Cox proportional hazards regression model were used to examine the association of mtDNA content with overall survival (OS) and progression-free survival (PFS) of patients. To explore the potential mechanism, the immune phenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines from another 20 glioma patients were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: Patients with high mtDNA content showed both poorer OS and PFS than those with low mtDNA content. Multivariate Cox regression analysis demonstrated that mtDNA content was an independent prognostic factor for both OS and PFS. Stratified analyses showed that high mtDNA content was significantly associated with poor prognosis of patients with younger age, high-grade glioma or adjuvant radiochemotherapy. Immunological analysis indicated that patients with high mtDNA content had significantly lower frequency of natural killer cells in PBMCs and higher plasma concentrations of interleukin-2 and tumour necrosis factor-alpha, suggesting an immunosuppression-related mechanism involved in mtDNA-mediated prognosis. CONCLUSIONS: Our study for the first time demonstrated that leukocyte mtDNA content could serve as an independent prognostic marker and an indicator of immune functions in glioma patients. PMID- 26022929 TI - Utility of pre-treatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors in breast cancer. AB - BACKGROUND: Peripheral blood-derived inflammation-based scores such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have recently been proposed as prognostic markers in solid tumours. Although evidence to support these markers as unfavourable prognostic factors is more compelling in gastrointestinal cancers, very little is known of their impact on breast cancer. We investigated the association between the NLR and PLR, and overall survival after breast cancer. METHODS: Data from the University of Malaya Medical Centre Breast Cancer Registry was used. Of 2059 consecutive patients diagnosed from 2000 to 2008, we included 1435 patients with an available pre-treatment differential blood count (~70%). Patients were stratified into quintiles of the NLR/PLR. Multivariable Cox regression was used to determine the independent prognostic significances of the NLR/PLR. RESULTS: Compared with the first quintile of the NLR, women in quintile 5 were younger, had bigger tumours, nodal involvement, distant metastases and higher tumour grades. Higher NLR quintiles were significantly associated with poorer survival with a 5-year relative survival ratio (RSR) of 76.4% (95% CI: 69.6-82.1%) in quintile 1, 79.4% (95% CI: 74.4 83.7%) in quintile 2, 72.1% (95% CI: 66.3-77.3%) in quintile 3, 65.6% (95% CI: 59.8-70.8%) in quintile 4 and 51.1% (95% CI: 43.3-58.5%) in quintile 5. Following adjustment for demography, tumour characteristics, treatment and the PLR, the adjusted hazard ratio (HR) for quintile 5 vs quintile 1 was 1.50 (95% CI: 1.08 1.63); Ptrend=0.004. Results were unchanged when the NLR was analysed as a dichotomous variable using different cutoff points. Although patients in PLR quintile 5 had lower survival than in quintile 1 (5-year RSR: 53.2% (95% CI: 46.9 59.2%) vs 77.0% (95% CI: 70.9-82.2%)), this association was not significant after multivariable adjustment. However, a PLR >185 was significantly associated with poorer survival; adjusted HR: 1.25 (95% CI: 1.04-1.52). CONCLUSIONS: Both the NLR and PLR are independently associated with an increased risk of mortality in breast cancer. Their added value in the prognostication of breast cancer in clinical practice warrants investigation. PMID- 26022931 TI - New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans. AB - Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been explored as anticancer and antimicrobial agents. In this study, a library of analogues based on a DHFR inhibitor, trimetrexate (TMQ), an FDA-approved drug, was screened and three new analogues that selectively inhibited S. mutans were identified. The most potent inhibitor had a 50% inhibitory concentration (IC50) of 454.0+/-10.2nM for the biofilm and 8.7+/-1.9nM for DHFR of S. mutans. In contrast, the IC50 of this compound for human DHFR was ca. 1000nM, a >100-fold decrease in its potency, demonstrating the high selectivity of the analogue. An analogue that exhibited the least potency for the S. mutans biofilm also had the lowest activity towards inhibiting S. mutans DHFR, further indicating that inhibition of biofilms is related to reduced DHFR activity. These data, along with docking of the most potent analogue to the modelled DHFR structure, suggested that the TMQ analogues indeed selectively inhibited S. mutans through targeting DHFR. These potent and selective small molecules are thus promising lead compounds to develop new effective therapeutics to prevent and treat dental caries. PMID- 26022932 TI - Sudden death due to acute adrenal crisis. PMID- 26022930 TI - Molecular identification of aminoglycoside-modifying enzymes in clinical isolates of Escherichia coli resistant to amoxicillin/clavulanic acid isolated in Spain. AB - The activity of eight aminoglycosides (amikacin, apramycin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin and tobramycin) against a collection of 257 amoxicillin/clavulanic acid (AMC)-resistant Escherichia coli isolates was determined by microdilution. Aminoglycoside resistance rates, the prevalence of aminoglycoside-modifying enzyme (AME) genes, the relationship between AME gene detection and resistance phenotype to aminoglycosides, and the association of AME genes with mechanisms of AMC resistance in E. coli isolates in Spain were investigated. Aminoglycoside-resistant isolates were screened for the presence of genes encoding common AMEs [aac(3)-Ia, aac(3)-IIa, aac(3)-IVa, aac(6')-Ib, ant(2")-Ia, ant(4')-IIa and aph(3')-Ia] or 16S rRNA methylases (armA, rmtB, rmtC and npmA). In total, 105 isolates (40.9%) were resistant to at least one of the aminoglycosides tested. Amikacin, apramycin and arbekacin showed better activity, with MIC90 values of 2mg/L (arbekacin) and 8mg/L (amikacin and apramycin). Kanamycin presented the highest MIC90 (128mg/L). The most common AME gene was aac(6')-Ib (36 strains; 34.3%), followed by aph(3')-Ia (31 strains; 29.5%), ant(2")-Ia (29 strains; 27.6%) and aac(3)-IIa (23 strains; 21.9%). aac(3)-Ia, aac(3)-IVa, ant(4')-IIa and the four methylases were not detected. The ant(2")-Ia gene was usually associated with OXA-1 [21/30; 70%], whilst 23/25 (92%) strains producing CTX-M-15 had the aac(6')-Ib gene. The most prevalent AME gene was aac(6')-Ib (18/41; 44%) in nosocomial isolates, whilst ant(2")-Ia and aph(3')-Ia genes (20/64; 31%) were more frequent in strains of community origin. In 64.6% isolates the phenotypic profile correlated with the presence of commonly encountered AMEs. PMID- 26022933 TI - Suction pump injuries mimicking child abuse. PMID- 26022934 TI - Adipokines in health and disease. AB - Obesity increases the risk for metabolic, cardiovascular, chronic inflammatory, and several malignant diseases and, therefore, may contribute to shortened lifespan. Adipokines are peptides that signal the functional status of adipose tissue to targets in the brain, liver, pancreas, immune system, vasculature, muscle, and other tissues. Secretion of adipokines, including leptin, adiponectin, fibroblast growth factor 21 (FGF21), retinol-binding protein 4 (RBP4), dipeptidyl peptidase 4 (DPP-4), bone morphogenetic protein (BMP)-4, BMP 7, vaspin, apelin, and progranulin, is altered in adipose tissue dysfunction and may contribute to a spectrum of obesity-associated diseases. Adipokines are promising candidates both for novel pharmacological treatment strategies and as diagnostic tools, provided that we can develop a better understanding of the function and molecular targets of the more recently discovered adipokines. PMID- 26022935 TI - Falls and Implementation of NEXUS in the Elderly (The FINE Study). AB - BACKGROUND: The incidence of cervical spine injuries (CSI) in people over 65 years of age from low-energy mechanisms is far greater than in younger populations. Algorithms and decision rules exist for selection of trauma patients requiring cervical spine imaging. OBJECTIVES: To determine the validity of the NEXUS criteria in the elderly population with low-mechanism injuries. METHODS: We prospectively conducted computed tomography (CT) imaging in patients > 65 years of age presenting with fall from standing height or less to rule out predefined clinically significant CSI. Eligible patients were prospectively categorized into NEXUS positive or negative. RESULTS: There were 169 patients included in the final analyses. One hundred twenty (71%) patients in the cohort were classified as "NEXUS positive." Eleven patients (6.5% of the cohort) had CSI detected on CT imaging of the cervical spine. Nine patients had clinically significant CSI. The NEXUS decision instrument demonstrated 88.9% sensitivity (50.7-99.4%) and 98% negative predictive value (NPV) (87.8-99.9%) in detecting clinically significant CSI. The NEXUS decision instrument demonstrated 81.8% sensitivity (47.8-96.8%) and 95.9% NPV (84.9-99.3%) in detecting any CSI. CONCLUSION: In our study, the NEXUS decision instrument was not a valid tool to rule out imaging for patients > 65 years of age presenting after a fall from standing height or less. We advocate the liberal use of CT imaging of the cervical spine in this cohort of patients to rule out cervical spine injury. PMID- 26022936 TI - The Assessment of Acute Pain in Pre-Hospital Care Using Verbal Numerical Rating and Visual Analogue Scales. AB - BACKGROUND: Prehospital care (PHC) pain evaluation is an essential patient assessment to be performed by paramedics. Pain intensity is frequently assessed using Verbal Numerical Rating Scale (VNRS) or Visual Analog Scale (VAS). OBJECTIVE: Our aim was to evaluate the agreement between VNRS and VAS in measuring acute pain in prehospital setting and to identify the preference among paramedics and patients. METHODS: This was a 3-month cross-sectional study. Convenience sampling was used to enroll patients with acute pain responded to by the ambulance team. Data from consented patients were analyzed using Bland-Altman method, Spearman's correlation test, and Cohen's kappa test. RESULTS: One hundred and thirty-three patients participated in this study (median age 32 years; 72.2% male). The median for pain score at the scene was 7.50 (interquartile range [IQR]: 5.00) for VAS and 7.00 (IQR: 5.00) for VNRS. The median for pain score on arrival at the hospital was 7.00 (IQR: 3.10) for VAS and 7.00 (IQR: 4.00) for VNRS. There was a strong correlation between VNRS and VAS at the scene (r = 0.865; p < 0.001), as well as on arrival at the hospital (r = 0.933; p < 0.001). Kappa coefficient values and Bland-Altman analysis indicates good agreement between both scales for measuring acute pain. VNRS was the preferred method to measure acute pain by patients and paramedics. CONCLUSIONS: VAS performs as well as VNRS in assessing acute pain in PHC. VAS and VNRS must not be used interchangeably to assess acute pain; either method should be used consistently. PMID- 26022937 TI - Altered Mental Status and Fever. PMID- 26022938 TI - Crystal nucleation from solutions--transition states, rate determining steps and complexity. AB - This introductory paper offers a contemporary view of crystal nucleation. We begin with a molecular interpretation of the transition state and then revisit the use of classical nucleation theory as a means of obtaining molecular scale information from kinetic data. Traditional physical organic chemistry has always utilised the combination of kinetics and thermodynamics in order to gain insight over reaction pathways. Here we demonstrate for the cases of sucrose and p aminobenzoic acid how solution chemistry, crystallography and kinetics come together to provide self-consistent pictures of the molecular scale processes occurring during nucleation. In this and a number of other systems desolvation of specific functional groups is highlighted as the rate determining step. Finally we move on to discuss the question of complexity, both from a phase and molecular perspective. PMID- 26022940 TI - Predictive scoring systems in multiorgan failure: A cohort study. AB - OBJECTIVE: An evaluation is made of the hospital mortality predicting capacity of the main predictive scoring systems. DESIGN: A 2-year retrospective cohort study was carried out. SETTING: A third level ICU with surgical and medical patients. PATIENTS: All patients with multiorgan failure during the first day in the ICU. MAIN VARIABLES: APACHE II and IV, SAPS II and III, MPM II and hospital mortality. RESULTS: A total of 568 patients were included. Mortality rate: 39.8% (226 patients). Discrimination (area under the ROC curve; 95% CI): APACHE IV (0.805; 0.751-0.858), SAPS II (0.755; 0.697-0.814), MPM II (0.748; 0.688-0.809), SAPS III (0.737; 0.675-0.799) and APACHE II (0.699; 0.633-0.765). MPM II showed the best calibration, followed by SAPS III. APACHE II, SAPS II and APACHE IV showed very poor calibration. Standard mortality ratio (95% CI): APACHE IV 1.9 (1.78-2.02); APACHE II 1.1 (1.07-1.13); SAPS III 1.1 (1.06-1.14); SAPS II 1.03 (1.01-1.05); MPM 0.9 (0.86-0.94). CONCLUSIONS: APACHE IV showed the best discrimination, with poor calibration. MPM II showed good discrimination and the best calibration. SAPS II, in turn, showed the second best discrimination, with poor calibration. The APACHE II calibration and discrimination values currently disadvise its use. SAPS III showed good calibration with modest discrimination. Future studies at regional or national level and in certain critically ill populations are needed. PMID- 26022942 TI - Targeting EGFR in lung cancer: Lessons learned and future perspectives. AB - The development of individualized therapies has become the focus of current oncology research. Precision medicine has demonstrated great potential for bringing safe and effective drugs to those patients stricken with cancer, and is becoming a reality as more oncogenic drivers of malignancy are discovered. The discovery of Epidermal Growth Factor Receptor (EGFR) mutations as a driving mutation in non-small cell lung cancer (NSCLC) and the subsequent success of the tyrosine kinase inhibitors (TKI) have led the way for NSCLC to be at the forefront of biomarker-based drug development. However, this direction was not always so clear, and this article describes the lessons learned in targeted therapy development from EGFR in NSCLC. PMID- 26022943 TI - Novel uses of fluorescent proteins. AB - The field of genetically encoded fluorescent probes is developing rapidly. New chromophore structures were characterized in proteins of green fluorescent protein (GFP) family. A number of red fluorescent sensors, for example, for pH, Ca(2+) and H2O2, were engineered for multiparameter imaging. Progress in development of microscopy hardware and software together with specially designed FPs pushed superresolution fluorescence microscopy towards fast live-cell imaging. Deeper understanding of FPs structure and photophysics led to further development of imaging techniques. In addition to commonly used GFP-like proteins, unrelated types of FPs on the base of flavin-binding domains, bilirubin binding domains or biliverdin-binding domains were designed. Their distinct biochemical and photophysical properties opened previously unexplored niches of FP uses such as labeling under anaerobic conditions, deep tissue imaging and even patients' blood analysis. PMID- 26022941 TI - RNA biomarkers to facilitate the identification of aggressive prostate cancer. AB - A large number of men are diagnosed with prostate cancer each year, but many will not experience morbidity or mortality as a result of their cancers. Therefore, biomarkers for prostate cancer are necessary to carefully select patients for initial diagnostic biopsy or to facilitate care decisions for men who have already been diagnosed with prostate cancer. RNA-based approaches to biomarker discovery allow the investigation of non-coding RNAs, gene fusion transcripts, splice variants, and multi-gene expression panels in tissue, urine, or blood as opportunities to improve care decisions. This review focuses on RNA biomarkers that are available as commercial assays, and therefore already available for potential clinical use, as well as providing an overview of newer RNA biomarkers that are in earlier stages of clinical development. PMID- 26022944 TI - Comparisons of the clinicopathological features and survival outcomes between lung cancer patients with adenocarcinoma and squamous cell carcinoma. AB - OBJECTIVE: Patients with lung cancer should be treated according to histological subtype because of the disparities in tumor aggressiveness and treatment responses. It is important to re-evaluate the clinicopathological features of the two major subtypes of lung cancer, adenocarcinoma (AD) and squamous cell carcinoma (SQ). METHODS: We retrospectively analyzed data on the clinicopathological features and outcomes of 2059 patients with pulmonary AD and pulmonary SQ who had undergone complete resection at Nagoya University Hospital and Aichi Cancer Center between 1995 and 2012. RESULTS: The cohort consisted of 1587 patients with AD (77 %) and 472 with SQ (23 %). Female gender, no history of smoking, and small tumor size were distinct characteristics of AD patients, and a higher age was a characteristic of SQ patients (p < 0.0001). A significant difference was observed in overall survival, with 5-year survival rates of 78 % in AD patients and 63 % in SQ patients. Patients with stage IA and IB SQ had significantly worse outcomes than patients with AD at the same stage (p < 0.0001). Because no survival difference was observed between SQ patients with stage IA, IB, and IIA tumors (p = 0.75), these patients were considered to have proposed stage IIA disease. Then, comparable survival curves were obtained between stages II and IIIA SQ and AD. CONCLUSIONS: Patients with stage I SQ had significantly worse outcomes than patients with stage I AD. A newly defined stage grouping for SQ patients provided outcomes comparable to those of AD patients. PMID- 26022945 TI - Obstructive sleep apnoea in the elderly: role of continuous positive airway pressure treatment. AB - Almost all the information about the effect of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnoea (OSA) comes from clinical trials involving only middle-aged patients. The objective of this study was to assess the effect of CPAP treatment in elderly patients with severe OSA on clinical, quality-of-life and neurocognitive spheres. We performed an open-label, randomised, multicentre clinical trial in a consecutive clinical cohort of 224 elderly (>=70 years old) patients with confirmed severe OSA (apnoea-hypopnea index >=30) randomised to receive CPAP (n=115) or no CPAP (n=109) for 3 months. A sleep study was performed by either full polysomnography or respiratory polygraphy. CPAP titration was performed by an autoCPAP device. The primary endpoint was quality of life (Quebec Sleep Questionnaire) and secondary endpoints included sleep-related symptoms, presence of anxiety/depression, office-based blood pressure and some neurocognitive tests. The mean+/-sd age was 75.5+/-3.9 years. The CPAP group achieved a greater improvement in all quality-of-life domains (p<0.001; effect size: 0.41-0.98), sleep-related symptoms (p<0.001; effect size 0.31-0.91) as well as anxiety (p=0.016; effect size 0.51) and depression (p<0.001; effect size: 0.28) indexes and some neurocognitive tests (digit symbol test (p=0.047; effect size: 0.20) and Trail Making Test A (p=0.029; effect size: 0.44)) in an intention-to-treat analysis. In conclusion, CPAP treatment resulted in an improvement in quality of life, sleep-related symptoms, anxiety and depression indexes and some neurocognitive aspects in elderly people with severe OSA. PMID- 26022947 TI - Efficacy of an inhaled corticosteroid/long-acting beta2-agonist combination in symptomatic COPD patients in GOLD groups B and D. PMID- 26022946 TI - Pseudomonas aeruginosa quorum sensing molecules correlate with clinical status in cystic fibrosis. AB - Pseudomonas aeruginosa produces quorum sensing signal molecules that are potential biomarkers for infection.A prospective study of 60 cystic fibrosis patients with chronic P. aeruginosa, who required intravenous antibiotics for pulmonary exacerbations, was undertaken. Clinical measurements and biological samples were obtained at the start and end of the treatment period. Additional data were available for 29 of these patients when they were clinically stable.Cross-sectionally, quorum sensing signal molecules were detectable in the sputum, plasma and urine of 86%, 75% and 83% patients, respectively. They were positively correlated between the three biofluids. Positive correlations were observed for most quorum sensing signal molecules in sputum, plasma and urine, with quantitative measures of pulmonary P. aeruginosa load at the start of a pulmonary exacerbation. Plasma concentrations of 2-nonyl-4-hydroxy-quinoline (NHQ) were significantly higher at the start of a pulmonary exacerbation compared to clinical stability (p<0.01). Following the administration of systemic antibiotics, plasma 2-heptyl-4-hydroxyquinoline (p=0.02) and NHQ concentrations (p<0.01) decreased significantly.In conclusion, quorum sensing signal molecules are detectable in cystic fibrosis patients with pulmonary P. aeruginosa infection and are positively correlated with quantitative measures of P. aeruginosa. NHQ correlates with clinical status and has potential as a novel biomarker for P. aeruginosa infection. PMID- 26022948 TI - Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection. AB - Pleural infection is increasing in incidence. Despite optimal medical management, up to 30% of patients will die or require surgery. Case reports suggest that irrigation of the pleural space with saline may be beneficial.A randomised controlled pilot study in which saline pleural irrigation (three times per day for 3 days) plus best-practice management was compared with best-practice management alone was performed in patients with pleural infection requiring chest tube drainage. The primary outcome was percentage change in computed tomography pleural fluid volume from day 0 to day 3. Secondary outcomes included surgical referral rate, hospital stay and adverse events.35 patients were randomised. Patients receiving saline irrigation had a significantly greater reduction in pleural collection volume on computed tomography compared to those receiving standard care (median (interquartile range) 32.3% (19.6-43.7%) reduction versus 15.3% (-5.5-28%) reduction) (p<0.04). Significantly fewer patients in the irrigation group were referred for surgery (OR 7.1, 95% CI 1.23-41.0; p=0.03). There was no difference in length of hospital stay, fall in C-reactive protein, white cell count or procalcitonin or adverse events between the treatment groups, and no serious complications were documented.Saline irrigation improves pleural fluid drainage and reduces referrals for surgery in pleural infection. A large multicentre randomised controlled trial is now warranted to evaluate its effects further. PMID- 26022949 TI - Haemoptysis in adults: a 5-year study using the French nationwide hospital administrative database. AB - Haemoptysis is a serious symptom with various aetiologies. Our aim was to define the aetiologies, outcomes and associations with lung cancer in the entire population of a high-income country.This retrospective multicentre study was based on the French nationwide hospital medical information database collected over 5 years (2008-2012). We analysed haemoptysis incidence, aetiologies, geographical and seasonal distribution and mortality. We studied recurrence, association with lung cancer and mortality in a 3-year follow-up analysis.Each year, ~15 000 adult patients (mean age 62 years, male/female ratio 2/1) were admitted for haemoptysis or had haemoptysis as a complication of their hospital stay, representing 0.2% of all hospitalised patients. Haemoptysis was cryptogenic in 50% of cases. The main aetiologies were respiratory infections (22%), lung cancer (17.4%), bronchiectasis (6.8%), pulmonary oedema (4.2%), anticoagulants (3.5%), tuberculosis (2.7%), pulmonary embolism (2.6%) and aspergillosis (1.1%). Among incident cases, the 3-year recurrence rate was 16.3%. Of the initial cryptogenic haemoptysis patients, 4% were diagnosed with lung cancer within 3 years. Mortality rates during the first stay and at 1 and 3 years were 9.2%, 21.6% and 27%, respectively.This is the first epidemiological study analysing haemoptysis and its outcomes in an entire population. Haemoptysis is a life threatening symptom unveiling potentially life-threatening underlying conditions. PMID- 26022950 TI - Serum 25-hydroxyvitamin D level, smoking and lung function in adults: the HUNT Study. AB - The association between serum 25-hydroxyvitamin D (25(OH)D) level and lung function changes in the general population remains unclear.We conducted cross sectional (n=1220) and follow-up (n=869) studies to investigate the interrelationship of serum 25(OH)D, smoking and lung function changes in a random sample of adults from the Nord-Trondelag Health (HUNT) Study, Norway.Lung function was measured using spirometry and included forced expiratory volume in 1 s (FEV1) % predicted, forced vital capacity (FVC) % pred and FEV1/FVC ratio. Multiple linear and logistic regression models estimated the adjusted difference in lung function measures or lung function decline, adjusted odds ratios for impaired lung function or development of impaired lung function and 95% confidence intervals.40% of adults had serum 25(OH)D levels <50 nmol.L(-1). Overall, those with a serum 25(OH)D level <50 nmol.L(-1) showed worse lung function and increased odds of impaired lung function compared to the >=50 nmol.L(-1) group. These associations tended to be stronger among ever-smokers, including greater decline in FEV1/FVC ratio and greater odds of the development of impaired lung function (FEV1/FVC <70% OR 2.4, 95% CI 1.2-4.9). Associations among never-smokers were null. Results from cross-sectional and follow-up studies were consistent. There were no associations between serum 25(OH)D levels and lung function or lung function changes in never-smokers, whereas significant associations were observed in ever-smokers. PMID- 26022951 TI - Smoke-free legislation and childhood hospitalisations for respiratory tract infections. AB - Second-hand smoke exposure is a major risk factor for respiratory tract infections (RTIs). Although evidence suggests important early-life health benefits of smoke-free public environments, the impact on childhood RTIs is unclear. We investigated the association between England's smoke-free legislation and childhood RTI hospitalisations.We used the Hospital Episode Statistics database to obtain nationwide data on hospital admissions for acute RTIs among children (<15 years of age) from 2001 to 2012. Hospitalisation counts were disaggregated by month, age group, sex and small-area level, and linked to urbanisation, region, deprivation index and corresponding population estimates. Negative binomial regression analyses were adjusted for confounders, seasonal variation, temporal autocorrelation, population-size changes and underlying incidence trends. Models allowed for sudden and gradual changes following the smoke-free legislation. We performed sensitivity and subgroup analyses, and estimated number of events prevented.We analysed 1 651 675 hospital admissions. Introduction of smoke-free legislation was followed by an immediate reduction in RTI admissions (-3.5%, 95% CI -4.7- -2.3%), this mainly being attributable to a decrease in lower RTI admissions (-13.8%, 95% CI -15.6- -12.0%). The reductions in admissions for upper RTI were more incremental.The introduction of national smoke-free legislation in England was associated with ~11 000 fewer hospital admissions per year for RTIs in children. PMID- 26022952 TI - Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: real-world insights. AB - Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option.This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting.Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3-4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003).The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting. PMID- 26022953 TI - Antipyretic effect of dexamethasone in community-acquired pneumonia. PMID- 26022954 TI - Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth. AB - The hypoxic environment of cystic fibrosis airways allows the persistence of facultative anaerobic bacteria, which can produce short-chain fatty acids (SCFAs) through fermentation. However, the relevance of SCFAs in cystic fibrosis lung disease is unknown. We show that SCFAs are present in sputum samples from cystic fibrosis patients in millimolar concentrations (mean+/-sem 1.99+/-0.36 mM).SCFAs positively correlated with sputum neutrophil count and higher SCFAs were predictive for impaired nitric oxide production. We studied the effects of the SCFAs acetate, propionate and butyrate on airway inflammatory responses using epithelial cell lines and primary cell cultures. SCFAs in concentrations present in cystic fibrosis airways (0.5-2.5 mM) affected the release of granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin (IL)-6. SCFAs also resulted in higher IL-8 release from stimulated cystic fibrosis transmembrane conductance regulator (CFTR) F508del-mutant compared to wild-type CFTR-corrected bronchial epithelial cells. At 25 mM propionate reduced IL-8 release in control but not primary cystic fibrosis epithelial cells. Low (0.5-2.5 mM) SCFA concentrations increased, while high (25 50 mM) concentrations decreased inducible nitric oxide synthase expression. In addition, SCFAs affected the growth of Pseudomonas aeruginosa in a concentration- and pH-dependent manner.Thus, our data suggest that SCFAs contribute to cystic fibrosis-specific alterations of responses to airway infection and inflammation. PMID- 26022955 TI - Criteria for diagnosis of exercise pulmonary hypertension. AB - The previous definition of exercise pulmonary hypertension (PH) with a mean pulmonary artery pressure (mPAP) >30 mmHg was abandoned because healthy individuals can exceed this threshold at high cardiac output (CO). We hypothesised that incorporating assessment of the pressure-flow relationship using the mPAP/CO ratio, i.e. total pulmonary resistance (TPR), might enhance the accuracy of diagnosing an abnormal exercise haemodynamic response.Exercise haemodynamics were evaluated in 169 consecutive subjects with normal resting mPAP <=20 mmHg. Subjects were classified into controls without heart or lung disease (n=68) versus patients with pulmonary vascular disease (PVD) (n=49) and left heart disease (LHD) (n=52).TPR and mPAP at maximal exercise produced diagnostic accuracy with area under the receiver operating curve of 0.99 and 0.95, respectively, for discriminating controls versus patients with PVD and LHD. The old criterion of mPAP >30 mmHg had sensitivity of 0.98 but specificity of 0.77. Combining maximal mPAP >30 mmHg and TPR >3 mmHg.min.L(-1) retained sensitivity at 0.93 but improved specificity to 1.0. The accuracy of the combined criteria was high across different age groups, sex, body mass index and diagnosis (PVD or LHD).Combining mPAP >30 mmHg and TPR >3 mmHg.min.L(-1) is superior to mPAP >30 mmHg alone for defining a pathological haemodynamic response of the pulmonary circulation during exercise. PMID- 26022956 TI - Is Europe ready to reach tuberculosis elimination? An outbreak report from Southern Italy. PMID- 26022957 TI - The problem of early mortality in pneumococcal pneumonia: a study of risk factors. PMID- 26022958 TI - Bronchial thermoplasty in asthma: 2-year follow-up using optical coherence tomography. PMID- 26022959 TI - Outcomes of beta-blocker use in pulmonary arterial hypertension: a propensity matched analysis. AB - The utility and safety of beta-blockers in pulmonary hypertension is controversial. Anecdotal reports suggest that beta-blockers may be harmful in these patients. The aim of our study was to evaluate outcomes of beta-blocker use in pulmonary hypertension.We reviewed patients from our pulmonary hypertension registry between 2000 and 2011. Patients who continued to use beta-blockers were compared to those who never used beta-blockers for all-cause mortality, time to clinical worsening events, defined as death, lung transplantation and hospitalisation due to pulmonary hypertension. We also evaluated the effect of beta-blockers on 6-min walking distance and New York Heart Association (NYHA) functional class.133 patients used beta-blockers and 375 patients never used beta blockers. Mean+/-sd age was 57+/-16 years and the median follow-up period was 78 months. Propensity-matched analysis showed that the adjusted odds ratio (95% CI) for mortality with beta-blocker use was 1.13 (0.69-1.82) and for clinical worsening events was 0.96 (0.55-1.68). No significant difference was noted in probability of survival and time to clinical worsening events. Patients on beta blockers walked a shorter distance on follow-up 6 min walk test; follow-up NYHA class was similar between groups.Pulmonary hypertension patients receiving beta blockers had a similar survival and time to clinical worsening events compared to patients not receiving them. Functional outcomes were similar, although beta blocker use was associated with a tendency towards shorter walking distance. PMID- 26022960 TI - Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis. AB - Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen. PMID- 26022961 TI - Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials. AB - There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress.59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events.h(-1)) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. "Treatment" effects (sham CPAP versus CPAP) were calculated via linear regression.Sham CPAP provoked moderate-to severe OSA (mean ODI 46 events.h(-1)), but blood markers of oxidative stress did not change significantly (MDA "treatment" effect (95% CI) -0.02 (-0.23 to +0.19) MUmol.L(-1)). Urinary F2-isoprostane fell significantly by ~30% (-0.26 (-0.42 to 0.10) ng.mL(-1)) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng.mL(-1)).We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress. PMID- 26022962 TI - Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. AB - Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. PMID- 26022963 TI - Palliative care needs in COPD patients with or without cancer: an epidemiological study. AB - Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide. However, many patients with severe COPD do not receive adequate palliative care. The main goals of our study were to identify the percentage of hospital patients with palliative care needs, particularly those who suffer from COPD.Data were collected prospectively from inpatients at the University Medical Centre Freiburg (Freiburg, Germany). Based on the World Health Organization definition of palliative care, the treating physician reported for each patient discharged whether the patient had palliative care needs or not. Data from 39 849 patients could be analysed, of which 1455 were suffering from COPD.Of all COPD patients, 9.1% had palliative care needs. In COPD patients with palliative care needs, hospital stay was significantly longer (13.7 versus 10.3 days) than in the group without palliative care needs, and significantly more patients died during their hospital stay (8.3% versus 3.7%). The presence of metastases was the highest risk factor for developing palliative care needs (OR 4.18). Furthermore, a main diagnosis of COPD implied an increased probability of palliative care needs (OR 1.87).Our results show that COPD patients have a high risk of developing palliative care needs. Further efforts are required to provide palliative care to COPD patients. PMID- 26022964 TI - Real-life long-term omalizumab therapy in children with severe allergic asthma. PMID- 26022967 TI - Bioactive bilayered dressing for compromised epidermal tissue regeneration with sequential activity of complementary agents. AB - The article deals with the design, preparation, and evaluation of a new bilayered dressing for application in the healing of compromised wounds. The system is based on the sequential release of two complementary bioactive components to enhance the activation of the regeneration of dermal tissue. The internal layer is a highly hydrophilic and biodegradable film of gelatin and hyaluronic acid (HG), crosslinked with the natural compound genipin, which reacts with the amine groups of gelatin. This film is loaded with the proangiogenic, anti-inflammatory, and antibacterial peptide, proadrenomedullin N-terminal 20 peptide (PAMP), that is released slowly in the wound site. The external layer, more stable and less hydrophilic, is constituted by a biodegradable polyurethane derived from poly(caprolactone) and pluronic L61. This layer is loaded with resorbable nanoparticles of bemiparin (a fractionated low molecular weight heparin), which promotes the activation of growth factors, FGF and VEGF, and provides a good biomechanical stability and controlled permeability of the bilayered dressing. Experiments carried out in mice demonstrate the excellent angiogenic effect of the HG film in the dermal tissue. Application of the bilayered dressing in the wound healing rabbit ear model shows an improved cicatrization of the wound in both ischemic and non-ischemic defects, favoring epithelialization and reducing noticeably the contraction and the inflammation. PMID- 26022966 TI - Shear lag sutures: Improved suture repair through the use of adhesives. AB - Suture materials and surgical knot tying techniques have improved dramatically since their first use over five millennia ago. However, the approach remains limited by the ability of the suture to transfer load to tissue at suture anchor points. Here, we predict that adhesive-coated sutures can improve mechanical load transfer beyond the range of performance of existing suture methods, thereby strengthening repairs and decreasing the risk of failure. The mechanical properties of suitable adhesives were identified using a shear lag model. Examination of the design space for an optimal adhesive demonstrated requirements for strong adhesion and low stiffness to maximize the strength of the adhesive coated suture repair construct. To experimentally assess the model, we evaluated single strands of sutures coated with highly flexible cyanoacrylates (Loctite 4903 and 4902), cyanoacrylate (Loctite QuickTite Instant Adhesive Gel), rubber cement, rubber/gasket adhesive (1300 Scotch-Weld Neoprene High Performance Rubber & Gasket Adhesive), an albumin-glutaraldehyde adhesive (BioGlue), or poly(dopamine). As a clinically relevant proof-of-concept, cyanoacrylate-coated sutures were then used to perform a clinically relevant flexor digitorum tendon repair in cadaver tissue. The repair performed with adhesive-coated suture had significantly higher strength compared to the standard repair without adhesive. Notably, cyanoacrylate provides strong adhesion with high stiffness and brittle behavior, and is therefore not an ideal adhesive for enhancing suture repair. Nevertheless, the improvement in repair properties in a clinically relevant setting, even using a non-ideal adhesive, demonstrates the potential for the proposed approach to improve outcomes for treatments requiring suture fixation. Further study is necessary to develop a strongly adherent, compliant adhesive within the optimal design space described by the model. PMID- 26022968 TI - A novel injectable thermoresponsive and cytocompatible gel of poly(N isopropylacrylamide) with layered double hydroxides facilitates siRNA delivery into chondrocytes in 3D culture. AB - Hybrid hydrogels composed of poly(N-isopropylacrylamide) (pNIPAAM) and layered double hydroxides (LDHs) are presented in this study as novel injectable and thermoresponsive materials for siRNA delivery, which could specifically target several negative regulators of tissue homeostasis in cartilaginous tissues. Effectiveness of siRNA transfection using pNIPAAM formulated with either MgAl-LDH or MgFe-LDH platelets was investigated using osteoarthritic chondrocytes. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an endogenous model gene to evaluate the extent of silencing. No significant adverse effects of pNIPAAM/LDH hydrogels on cell viability were noticed. Cellular uptake of fluorescently labeled siRNA was greatly enhanced (>75%) in pNIPAAM/LDH hydrogel constructs compared to alginate, hyaluronan and fibrin gels, and was absent in pNIPAAM hydrogel without LDH platelets. When using siRNA against GAPDH, 82-98% reduction of gene expression was found in both types of pNIPAAM/LDH hydrogel constructs after 6 days of culturing. In the pNIPAAM/MgAl-LDH hybrid hydrogel, 80 95% of GAPDH enzyme activity was reduced in parallel with gene. Our findings show that the combination of a cytocompatible hydrogel and therapeutic RNA oligonucleotides is feasible. Thus it might hold promise in treating degeneration of cartilaginous tissues by providing supporting scaffolds for cells and interference with locally produced degenerative factors. PMID- 26022969 TI - Properties of biomass-derived biochars: Combined effects of operating conditions and biomass types. AB - Combined effects of operating conditions including heating temperature (200-700 degrees C), time (1-8h) and rate, and atmosphere (air-flow, air-limited and N2) on the physicochemical properties of biochars with pine sawdust, maize straw and sugarcane bagasse as feedstocks were investigated. The results demonstrated that production temperature and atmosphere acted as the predominant factors that determined the properties of biochars. The X-ray diffraction data confirmed the occurrence of phase transition in the biomass structures at around 400 degrees C. Heating time and rate showed little effect on the functional group compositions of the biochars within 8h, particularly under N2 atmosphere. In addition, the molecular weights of the biochar-derived dissolved organic carbon tended to increase with increasing temperature. Feedstock type also affected the biochar properties by the compositional differences in mineral salts and cellulose/lignin in the three biomass materials. This work provides important information for optimizing procedures for biochar production with desired properties and high yield. PMID- 26022965 TI - The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease. AB - No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.Physical activity was assessed in a 6-week, randomised, two-way cross over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled "amount" and "difficulty". After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's alpha>0.8), test-retest reliability (intraclass correlation coefficient >=0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.Daily and clinical visit "PROactive physical activity in COPD" instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients. PMID- 26022970 TI - Engineering of yeast pyruvate decarboxylase for enhanced selectivity towards carboligation. AB - The aim of the study was to increase production of (R)-PAC by altering carboligation activity of Pdc in Saccharomyces cerevisiae. Pdc1 activity was modified by over-expression as well as changing the rate of decarboxylation and carboligation by site specific mutation in Pdc1. Over-expression of mutant Pdc1 resulted in 50 +/- 2.5% increase in levels of (R)-PAC in wild-type and further 30 40% in pdc null background. The combination of mutant Pdc1 in pdc null background was successfully evaluated for production of (R)-PAC at industrial scale. This is the first report of enhancing (R)-PAC product in yeast by recombinant technology with capability of commercial production. PMID- 26022971 TI - Sustainable production of toxin free marine microalgae biomass as fish feed in large scale open system in the Qatari desert. AB - Mass cultivation of microalgae biomass for feed should be cost effective and toxin free. Evaporation loss in Qatar can be as high as 2 cm/d. Hence, production of marine microalgae biomass in Qatar would also require mitigating water loss as there was only very limited groundwater reserve. To address these issues, a combination of four growth conditions were applied to a 25,000 L raceway pond: locally isolated microalgae strain was selected which could grow in elevated salinity; strain that did not require silica and vitamins; volume of the culture would increase over time keeping denser inoculum in the beginning, and evaporation water loss would be balanced by adding seawater only. A local saline tolerant Nannochloropsis sp. was selected which did not require silica and vitamins. When the above conditions were combined in the pond, average areal biomass productivities reached 20.37 g/m(2)/d, and the culture was not contaminated by any toxic microalgae. PMID- 26022972 TI - A comprehensive study into fouling properties of extracellular polymeric substance (EPS) extracted from bulk sludge and cake sludge in a mesophilic anaerobic membrane bioreactor. AB - This study focused on the fouling behaviors of extracellular polymeric substances (EPS) in a mesophilic anaerobic membrane bioreactor (AnMBR) to obtain the relations of EPS specific constituents with membrane fouling. It was found that for the EPS extracted from bulk sludge, the LB-EPS induced the largest flux decline; however, for EPS extracted from cake sludge, the S-EPS caused the highest flux decline. The preferential rejection fraction by membrane further confirmed that the greater flux decline was exhibited with the higher percent rejection of EPS fractions. The adhesion and cohesion interactions of EPS fractions and membranes could explain the different rejection rates of the EPS components. The structural characteristics analysis indicated that the fouling layers of different EPS fractions with the greater loss of filterability had the smaller porosity. Further investigations demonstrated that these changes could be attributed to the different content of HPO-N in EPS fractions. PMID- 26022973 TI - A Late Devonian fertile organ with seed plant affinities from China. AB - Seed plants underwent first major evolutionary radiation in the Late Devonian (Famennian), as evidenced by the numerous ovules described to date. However, the early pollen organs are underrepresented, so that their structure and evolution remain poorly known. Here we report a new taxon of pollen organ Placotheca minuta from the Late Devonian. The synangium consists of many basally and more or less laterally fused microsporangia borne on the margin of a pad. The prepollen is spherical and trilete. The appearance of Famennian synangia especially in Placotheca does not support the current understanding that the earliest pollen organs closely resembled the fructifications of the ancestral progymnosperms. Placotheca indicates earlier diversification of pollen organs than previously expected and is highly derived among the early pollen organs with trilete prepollen. It is suggested that, immediately after the origination of seed plants, pollen organs had evolved at a rapid rate, whereas their prepollen remained primitively spore-like. PMID- 26022974 TI - A conceptual framework for dynamic extension of the red clearance interval as a countermeasure for red-light-running. AB - This manuscript describes the development and evaluation of a conceptual framework for real-time operation of dynamic on-demand extension of the red clearance interval as a countermeasure for red-light-running. The framework includes a decision process for determining, based on the real-time status of vehicles arriving at the intersection, when extension of the red clearance interval should occur and the duration of each extension. A zonal classification scheme was devised to assess whether an approaching vehicle requires additional time to safely clear the intersection based on the remaining phase time, type of vehicle, current speed, and current distance from the intersection. Expected performance of the conceptual framework was evaluated through modeling of replicated field operations using vehicular event data collected as part of this research. The results showed highly accurate classification of red-light-running vehicles needing additional clearance time and relatively few false extension calls from stopping vehicles, thereby minimizing the expected impacts to signal and traffic operations. Based on the recommended parameters, extension calls were predicted to occur once every 26.5cycles. Assuming a 90scycle, 1.5 extensions per hour were expected per approach, with an estimated extension time of 2.30s/h. Although field implementation was not performed, it is anticipated that long-term reductions in targeted red-light-running conflicts and crashes will likely occur if red clearance interval extension systems are implemented at locations where start-up delay on the conflicting approach is generally minimal, such as intersections with lag left-turn phasing. PMID- 26022975 TI - Database and Informatic Challenges in Representing Both Diploid and Tetraploid Xenopus Species in Xenbase. AB - At the heart of databases is a data model referred to as a schema. Relational databases store information in tables, and the schema defines the tables and provides a map of relationships that show how the different table/data types relate to one another. In Xenbase, we were tasked to represent genomic, molecular, and biological data of both a diploid and tetraploid Xenopus species. When the database model was built over a decade ago, we had very little information on the nature of the X.laevis tetraploidization, but a Chado-based data model was proposed that could deal with the various forms of data in both species. Once the X.laevis genome was sequenced and annotated, it became clear that the data schema is very like the evolutionary schema that resulted in the X.laevis genome. PMID- 26022976 TI - Association between Media Use, Acute Stress Disorder and Psychological Distress. PMID- 26022977 TI - Tamoxifen and risk of contralateral breast cancer among women with inherited mutations in BRCA1 and BRCA2: a meta-analysis. AB - Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutation in BRCA1 or BRCA2, the present meta analysis was addressed to determine whether adjuvant tamoxifen treatment for breast cancer is associated with reduced CBC risk for these patients. We searched the database of PubMed for eligible studies about the effectiveness of tamoxifen on CBC risk among BRCA1/2 mutation carriers, and we calculated the pooled relative risks (RRs) for CBC risk along with 95 % confidence intervals (CIs). Fixed- or random-effects model was conducted according to study heterogeneity. Four non-overlapping studies met the inclusion criteria for the meta-analysis. Tamoxifen was found to be significantly associated with reduced risk of CBC among BRCA1/2 mutation carriers (summary RR = 0.56, 95 % CI = 0.41-0.76). Similar findings were observed in BRCA1 mutation carriers (summary RR = 0.47, 95 % CI = 0.37-0.60) and BRCA2 mutation carriers (summary RR = 0.39, 95 % CI = 0.28-0.54), respectively. In conclusion, tamoxifen significantly reduces the incidence of CBC among BRCA1/2 mutation carriers with primary unilateral breast cancer. It can reasonably be offered to breast cancer patients with BRCA1 or BRCA2 mutation for the prevention of CBC. Further studies are required to get a more precise estimation of the benefits and harms of tamoxifen in these patients. PMID- 26022978 TI - Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH triggered chemotherapy. AB - Dihydroartemisinin (DHA) is a unique anti-malarial drug isolated from the plant Artemisia annua. Recently, it has been studied as an alternative modality for cancer therapy, utilizing its reactive oxygen species (ROS) yielding mechanism from interacting with Ferrous ion (Fe (II)). In this work, a novel nanodrug (DHA GO-Tf) is constructed based on nanoscale Graphene oxide (GO) dual-dressed with DHA and Transferrin (Tf). Tf dually functions as a pilot for the nanoparticle to target tumor cell with over expressed Transferrin receptor (TfR) and a ferric ion carrier. Upon tumor cellular endocytosis, Ferric ion (Fe(III)) is released from the Tf, triggered by the low pH in the lysosomes of the tumor cell. The intracellular Fe (III) is reduced to Fe (II) and interacts with DHA to increase its cytotoxicity. The potential of this alternative anti-tumor modality is demonstrated both in vitro and in vivo. Comparing with DHA alone, the nanodrug DHA-GO-Tf resulted in a significantly enhanced tumor delivery specificity and cytotoxicity, and achieved a complete tumor cure in mice with minimal side effects. PMID- 26022979 TI - Is the autophagy a friend or foe in the silver nanoparticles associated radiotherapy for glioma? AB - Malignant glioma is the most common intracranial tumor with a dismal prognosis. The radiosensitizing effect of silver nanoparticles (AgNPs) on glioma both in vitro and in vivo had been demonstrated in the previous studies of our group. However, the underlying mechanism is still unclear. Consistent with previous studies, a size and dose dependent antitumor effect and significant radiosensitivity enhancing effect of AgNPs were observed in our experiment system. We also found that cell protective autophagy could be induced by AgNPs and/or radiation, which was verified by the use of 3-MA. The mechanism through which had autophagy and the enhancement of radiosensitivity taken place was further investigated with inhibitors of ERK and JNK pathways. We demonstrated that ERK and JNK played pivotal roles in the radiosensitivity enhancement. Inhibiting ERK and JNK with U0126 and SP600125 respectively, we found that the autophagy level of the cells treated with AgNPs and radiation were attenuated. Moreover, SP600125 down-regulated the apoptosis rate of the co-treated cells significantly. Taken together, the present study would have important impact on biomedical applications of AgNPs and clinical treatment for glioma. PMID- 26022980 TI - Low-aspect ratio nanopatterns on bioinert alumina influence the response and morphology of osteoblast-like cells. AB - Topographical features on the nanometer scale are known to influence cellular behavior. The response of specific cell types to various types of surface structures is currently still being investigated. Alumina ceramics play an important role as biomaterials, e.g., in medical and dental applications. In this study, we investigated the influence of nanoscale surface features with low aspect ratio (< 0.1) on the response of osteoblast-like MG-63 cells. To this end, low-energy ion irradiation was employed to produce shallow nanoscale ripple patterns on Al2O3(0001) surfaces with lateral periodicities of 24 nm and 179 nm and heights of only 0.7 and 11.5 nm, respectively. The nanopatterning was found to increase the proliferation of MG-63 cells and may lead to pseudopodia alignment along the ripples. Furthermore, focal adhesion behavior and cell morphology were analyzed. We found that MG-63 cells are able to recognize surface nanopatterns with extremely low vertical variations of less than 1 nm. In conclusion, it is shown that surface topography in the sub-nm range significantly influences the response of osteoblast-like cells. PMID- 26022981 TI - Radiofrequency ablation and vertebral augmentation for palliation of painful spinal metastases. AB - Radiofrequency ablation (RFA) and vertebral augmentation is an emerging combination therapy for painful osseous metastases that cannot be or are incompletely palliated with radiation therapy. Herein, we report our experience performing RFA and vertebral augmentation of spinal metastases for pain palliation. Institutional review board approval was obtained to retrospectively review our tumor ablation database for all patients who underwent RFA of osseous metastases between April 2012 and July 2014. Patient demographics, lesion characteristics, concurrent palliative therapies, and complications were recorded. Pre- and post-procedure mean worst pain scores 1 and 4 weeks after treatment were measured using the Numeric Rating Scale (10-point scale) and compared. During the study period, 72 RFA treatments of 110 spinal metastases were performed. Eighty one percent (89/110) of metastases involved the posterior vertebral body and 45 % (49/110) involved the pedicles. Vertebral augmentation was performed after 95 % (105/110) of ablations. Mean and median pre-procedure pain scores were 8.0 +/- 1.9 and 8.0, respectively. Patients reported clinically significant decreased pain scores at both 1-week (mean, 3.9 +/- 3.0; median, 3.25; P < 0.0001) and 4-week (mean, 2.9 +/- 3.0; median, 2.75; P < 0.0001) follow up. No major complications occurred related to RFA and there were no instances of symptomatic cement extravasation. Combination RFA and vertebral augmentation is a safe and effective therapy for palliation of painful spinal metastases, including tumor involving the posterior vertebral body and/or pedicles. PMID- 26022984 TI - Postnatal weight gain induced by overfeeding pups and maternal high-fat diet during the lactation period modulates glucose metabolism and the production of pancreatic and gastrointestinal peptides. AB - The impact of rapid weight gain on glucose metabolism during the early postnatal period remains unclear. We investigated the influence of rapid weight gain under different nutritional conditions on glucose metabolism, focusing on the production of pancreatic and gastric peptides. On postnatal day (PND) 2, C57BL/6N pups were divided into three groups: control (C) pups whose dams were fed a control diet (10%kcal fat) and nursed 10 pups each; maternal high-fat diet (HFD) pups whose dams were fed an HFD (45%kcal fat) and nursed 10 pups each; and overfeeding (OF) pups whose dams were fed the control diet and nursed 4 pups each. Data were collected on PND 7, 14 and 21. The body weight gains of the HFD and OF pups were 1.2 times higher than that of the C pups. On PND 14, the HFD pups had higher blood glucose levels, but there were no significant differences in serum insulin levels between the HFD and C pups. The OF pups had higher blood glucose and serum insulin levels than that of the C pups. Insulin resistance was found in the HFD and OF pups. On PND 14, the content of incretins in the jejunum was increased in the OF pups, and acyl ghrelin in the stomach was upregulated in the HFD and OF pups. These results suggest that neonatal weight gain induced by overfeeding pups and maternal high-fat diet during the early postnatal period modulates the insulin sensitivity and the production of pancreatic and gastrointestinal peptides. PMID- 26022982 TI - Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2. AB - Vestibular schwannoma (VS) growth in neurofibromatosis type 2 (NF2) can be responsible for brainstem compression and hearing loss. Surgical removal remains the standard therapy despite potential morbidity. Previous studies suggested that the inhibition of the VEGF-pathway with bevacizumab could result in hearing improvement, reduction of the tumor volume or both in adults. We retrospectively describe the French experience of bevacizumab treatment delivered for progressive VS in pediatric NF2 patients. Patients received Bevacizumab 5 or 10 mg/kg every 2 weeks according to the physician's choice. Follow-up included clinical assessment, audiometry and volumetric MRI every 3-6 months. Seven patients harboring 11 VS were included. The median age at inclusion was 15 years (11.4 18.8), and the median treatment duration was 11.3 months (3.2-55.6). At baseline, the median tumor volume was 1.2 cm(3) (0.52-13.5) and the median word recognition score was 90 % (0-100). We observed one major response, two minor responses and a decrease in the rate of tumor growth for the 4 other patients. The median annual growth rate before treatment was significantly higher than after 1 year of treatment (138 vs. 36 %, n = 5, p = 0.043). We noted one hearing improvement over the course of 1 year under treatment (hearing response rate was 14 %). Overall, the treatment was well tolerated. Our study supports that bevacizumab is an attractive therapeutic option for pediatric NF2 patients with growing VS. Thorough multidisciplinary evaluation is necessary to identify the best candidates prior to treatment. It is likely that a better functional outcome would be expected if targeted therapies were discussed early in the management of the disease. PMID- 26022983 TI - Toxigenic Clostridium difficile PCR ribotypes in edible marine bivalve molluscs in Italy. AB - Even though food of animal sources and different foodstuffs are well known to be potentially carrier of Clostridium difficile, few data are available on the occurrence of C. difficile in seafood. This work investigated the occurrence of C. difficile in edible bivalve molluscs in southern Italy. Out of the 925 investigated samples, 3.9% contained C. difficile. Eighteen strains harboured both genes for toxins A and B whereas 1 only had toxin B gene. Binary toxin genes were found in 22.2% of the isolates. The most frequently ribotypes found were 078/126 (22.2%), 010 (19.4%), and 001 (8.3%). All isolates were susceptible to metronidazole, vancomycin, fidaxomicin, and to the new semisynthetic thiopeptide antibiotic LFF571, whereas 19.4% of them were resistant to moxifloxacin, 30.5% to clindamycin, 38.8% to erythromycin, and 100% to ciprofloxacin. This study points out that edible molluscs could be a potential source of toxigenic C. difficile ribotypes and a potential risk for human health. PMID- 26022985 TI - Diameter of parathyroid glands measured by computed tomography as a predictive indicator for response to cinacalcet in dialysis patients with secondary hyperparathyroidism. AB - BACKGROUND/AIMS: Cinacalcet is one of the important treatments of secondary hyperparathyroidism (SHPT). We evaluated the role of computed tomography (CT) for parathyroid glands (PTGs) to determine the response to cinacalcet therapy in dialysis patients. METHODS: In study 1, we compared the predictive cutoff values of the largest volume or diameter of PTGs on ultrasonography or CT for achievement of target intact parathyroid hormone (iPTH) level according to K/DOQI guideline after cinacalcet treatment in a single dialysis center. In study 2, the role of the cutoff diameter of PTGs on CT in predicting responsive to cinacalcet therapy was reevaluated in dialysis patients with SHPT in multiple centers. RESULTS: In study 1, among the total population of 26 patients, the number of patients with baseline iPTH over 600 pg/mL was 16 (61%). In study 2, it was 45 (54%), among 82 patients. In study 1, the number of PTGs equal to or larger than the cutoff value (>= 11.2 mm) on CT, not ultrasonography, was significantly higher in non-responders than in responders (p=0.038). In study 2, the proportion of patients with PTGs >= 11.2 mm on CT was significantly higher in non-responders than responders (p=0.003). Multivariate analysis showed that pretreatment iPTH (odds ratio [OR] 1.498, p=0.003) and the existence of enlarged PTGs on CT (OR 8.940, p=0.015) were significant clinical factors affecting the response to cinacalcet. CONCLUSIONS: The diameter of PTGs on CT could predict the response to cinacalcet in dialysis patients with SHPT. PMID- 26022986 TI - You have been reclassified! Challenges in creating and applying noninvasive risk models for coronary artery disease. PMID- 26022988 TI - Growth hormone deficiency in adults impacts left ventricular mechanics: a two dimensional speckle-tracking study. AB - BACKGROUND: Growth hormone deficiency (GHD) in adults is associated with increased cardiovascular events, but detailed assessment of cardiac and vascular function is lacking. Thus we assessed cardiac, arterial, and endothelial functions, using conventional and speckle-tracking echocardiography, in adults with GHD compared with controls with similar cardiovascular risk. METHODS: Fifty two patients with GHD (47 +/- 16 years; 34 men) and no cardiovascular disease or diabetes were enrolled prospectively and compared with 50 age- and sex-matched controls. Comprehensive echocardiography was performed in all participants. Regional left ventricular (LV) function was assessed from global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS), whereas LV torsion (LVtor) was calculated from basal (RotB) and apical (RotA) rotations. Arterial function was assessed from intima-media thickening, local wave speed, and beta index of stiffness, whereas endothelial function was assessed from flow-mediated dilation. Levels of pro-brain natriuretic peptide (proBNP) were measured. RESULTS: GLS and GCS were decreased more in patients with GHD than in controls (-17.2% +/- 2.7% vs. -19.3% +/- 3.3% and -15.9% +/- 5.4% vs. -18.8% +/- 3.5%; both P < 0.01), whereas GRS was similar. RotB and LVtor were also decreased in patients with GHD (-4.8 degrees +/- 2.6 degrees vs. -6.2 degrees +/- 2.1 degrees /cm and 1.8 degrees +/- 0.6 degrees vs. 2.3 degrees +/- 1.1 degrees /cm; both P < 0.05). ProBNP was increased in patients with GHD (61.0 +/- 74 pg/dL vs. 24.7 +/- 21 pg/dL; P = 0.002). Arterial and endothelial functions were similar between groups. CONCLUSIONS: In conclusion, adults with GHD had LV longitudinal dysfunction and increased proBNP levels compared with controls, suggesting intrinsic myocardial disease. Further studies are needed to assess if this cardiac impairment in adults with GHD is reversible after GH replacement. PMID- 26022987 TI - A New Integrated Clinical-Biohumoral Model to Predict Functionally Significant Coronary Artery Disease in Patients With Chronic Chest Pain. AB - BACKGROUND: In patients with chronic angina-like chest pain, the probability of coronary artery disease (CAD) is estimated by symptoms, age, and sex according to the Genders clinical model. We investigated the incremental value of circulating biomarkers over the Genders model to predict functionally significant CAD in patients with chronic chest pain. METHODS: In 527 patients (60.4 years, standard deviation, 8.9 years; 61.3% male participants) enrolled in the European Evaluation of Integrated Cardiac Imaging (EVINCI) study, clinical and biohumoral data were collected. RESULTS: Functionally significant CAD-ie, obstructive coronary disease seen at invasive angiography causing myocardial ischemia at stress imaging or associated with reduced fractional flow reserve (FFR < 0.8), or both-was present in 15.2% of patients. High-density lipoprotein (HDL) cholesterol, aspartate aminotransferase (AST) levels, and high-sensitivity C reactive protein (hs-CRP) were the only independent predictors of disease among 31 biomarkers analyzed. The model integrating these biohumoral markers with clinical variables outperformed the Genders model by receiver operating characteristic curve (ROC) (area under the curve [AUC], 0.70 [standard error (SE), 0.03] vs 0.58 [SE, 0.03], respectively, P < 0.001) and reclassification analysis (net reclassification improvement, 0.15 [SE, 0.07]; P = 0.04). Cross validation of the ROC analysis confirmed the discrimination ability of the new model (AUC, 0.66). As many as 56% of patients who were assigned to a higher pretest probability by the Genders model were correctly reassigned to a low probability class (< 15%) by the new integrated model. CONCLUSIONS: The Genders model has a low accuracy for predicting functionally significant CAD. A new model integrating HDL cholesterol, AST, and hs-CRP levels with common clinical variables has a higher predictive accuracy for functionally significant CAD and allows the reclassification of patients from an intermediate/high to a low pretest likelihood of CAD. PMID- 26022989 TI - Low-level baroreceptor stimulation suppresses atrial fibrillation by inhibiting ganglionated plexus activity. AB - BACKGROUND: The autonomic nervous system (ANS) plays an important role in the initiation and maintenance of atrial fibrillation (AF), and modulation of the ANS function may contribute to AF control. METHODS: Anesthetized dogs received either sham treatment (SHAM group, n = 8) or low-level carotid baroreceptor stimulation (LL-CBS) treatment (LL-CBS group, n = 8). The stimulation voltage was set at 80% below the threshold. To simulate focal AF, high-frequency stimulation (HFS) was applied to local nerves during the atrial refractory period. Multielectrode catheters were attached to the atria and all the pulmonary veins to determine the changes in the AF threshold (AF-TH), the atrial effective refractory period (AERP), and the window of vulnerability (WOV) during HFS in both groups. Microelectrodes were inserted into the anterior right ganglionated plexus (ARGP) to record neural firing. RESULTS: HFS induced sinus rate (SR) slowing in the superior left ganglionated plexus (SLGP). LL-CBS induced a progressive increase in AF-TH and AERP at all sites and a significant decrease in the sum of WOV at 2 hours (all P < 0.05). LL-CBS inhibited the ability of SLGP stimulation to slow the SR and the mean values of frequency and amplitude of ARGP neural activity compared with the SHAM group (all P < 0.05). CONCLUSIONS: LL-CBS suppressed AF inducibility by inhibiting the neural activity of ganglionated plexuses. LL-CBS may serve as a novel therapeutic modality to treat AF. PMID- 26022990 TI - Baseline Functional Class and Therapeutic Efficacy of Common Heart Failure Interventions: A Systematic Review and Meta-analysis. AB - BACKGROUND: New York Heart Association (NYHA) functional class provides important prognostic information and is often used to select patients for cardiovascular therapies, yet, the effect of NYHA class on therapeutic efficacy has not been systematically studied. METHODS: In this systematic review and meta-analysis we compared the relative and absolute mortality benefit of 5 common heart failure interventions (angiotensin-converting enzyme [ACE] inhibitors, beta-blockers, mineralocorticoid receptor antagonists [MRAs], implantable cardioverter defibrillator [ICD], and cardiac resynchronization therapy [CRT]) across NYHA class. We included 26 randomized clinical trials of these interventions that reported all-cause mortality stratified according to baseline NYHA class in 36,406 patients. RESULTS: Pooled relative risk for NYHA I/II vs. III/IV strata were similar for ACE inhibitors (0.90 vs. 0.88), beta-blockers (0.72 vs. 0.79), MRA (0.79 vs. 0.75), and CRT (0.80 vs. 0.80), with all heterogeneity P > 0.8. Conversely, ICD efficacy was greater for class I/II (relative risk, 0.65 vs 0.86, heterogeneity P = 0.02). The pooled absolute risk difference was smaller for NYHA I/II vs III/IV with ACE inhibitors (-0.02 vs. -0.06, P = 0.12), beta-blockers ( 0.02 vs. -0.05, P = 0.047), MRA (-0.03 vs. -0.11, P = 0.001), and CRT (-0.01 vs. 0.04, P = 0.036), but was similar across NYHA class for the ICD (-0.07 vs. -0.05; P = 0.27). CONCLUSIONS: Relative mortality reductions with most interventions were independent of baseline NYHA class. However, ICD efficacy was greater with NYHA I/II vs. III/IV limitation, and absolute benefit was greater with higher NYHA class. For interventions other than the ICD, there is little evidence supporting use of NYHA class as a rigid criterion for selecting heart failure therapies. PMID- 26022991 TI - Pericardial effusions: do they all require pericardiocentesis? AB - Pericardial effusions are associated with multiple disorders, the causes of which are dependent on local epidemiologic and patient-specific factors. Pericardial effusions exhibit a broad spectrum of clinical presentations and may or may not be symptomatic. Echocardiographically guided pericardiocentesis should be reserved for patients with hemodynamic compromise, an intrathoracic mass effect, or an uncertain cause. Not all patients with pericardial effusions require pericardiocentesis, and an algorithmic approach to the decision to perform pericardiocentesis is recommended. PMID- 26022992 TI - Transcatheter intervention in cor triatriatum sinister. AB - Cor triatriatum sinister is a rare condition caused by a membrane in the left atrium, resulting in left ventricular inflow obstruction. This developmental anomaly is usually diagnosed in childhood. However, a rare presentation during adulthood is observed when the membrane is incomplete. Surgical excision of the membrane is the first line of treatment. We present a 51-year-old woman who underwent successful transcatheter balloon dilation with complete loss of the membrane waist and hemodynamic and symptomatic improvement. PMID- 26022993 TI - Pregnancy increases heart rates during paroxysmal supraventricular tachycardia. PMID- 26022994 TI - Perceptions on the Psychological Impact of Facial Erythema Associated with Rosacea: Results of International Survey. AB - INTRODUCTION: Rosacea (including facial erythema) has a negative impact on psychological and emotional health. This survey aimed to assess the impact of facial erythema on subconscious perceptions and the initial reactions of others and how this affects attitudes in different settings. The survey also measured the impact of facial erythema on a person's emotional and psychological wellbeing. METHODS: A total of 6831 participants from eight countries completed online computer-assisted web interviewing psychological assessments based on the implicit association test. Traditional questionnaires provided data on the impact of facial erythema and perceptions of people with rosacea from other participants. RESULTS: Facial erythema was strongly associated with poor health and negative personality traits with participants reporting negative impacts of rosacea emotionally, socially and in the workplace. Nearly 80% reported difficulty in controlling facial erythema but those with physician-diagnosed rosacea had significantly improved control versus those with undiagnosed rosacea (39% vs 20%, p < 0.05). CONCLUSIONS: People with facial erythema have to manage their own psychological barriers to cope with the disease and deal with the prejudice and negative first impressions of others. Formal diagnosis, advice and treatment from a healthcare professional improve rosacea control. FUNDING: Galderma. PMID- 26022995 TI - FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. PMID- 26022997 TI - Postoperative neutrophil-to-lymphocyte ratio plus platelet-to-lymphocyte ratio predicts the outcomes of hepatocellular carcinoma. AB - BACKGROUND: There is limited information regarding NLR-PLR (the combination of the neutrophil-to-lymphocyte ratio [NLR] and platelet-to-lymphocyte ratio [PLR]) in hepatocellular carcinoma (HCC). This study aimed to assess the predictive ability of NLR-PLR in patients with resectable hepatitis B virus-related HCC within Milan criteria after hepatectomy. METHODS: Two hundred thirty-six consecutive HCC patients were included in the study. The postoperative NLR-PLR was calculated based on the data obtained on the first postoperative month after liver resection as follows: patients with both an elevated PLR and an elevated NLR, which were detected by receiver operating characteristic curve analysis, were allocated a score of 2, and patients showing one or neither of these elevations were allocated a score of 1 or 0, respectively. RESULTS: During the follow-up period, 113 patients experienced recurrence and 41 patients died. Multivariate analyses suggested that tumor-node-metastasis stage, preoperative alpha-fetal protein, and postoperative NLR-PLR were independently associated with recurrence, whereas microvascular invasion and postoperative NLR-PLR adversely impacted the overall survival. The 5-y recurrence-free and overall survival rates of the patients with a postoperative NLR-PLR of 0, 1, or 2 were 43.6%, 35.6%, or 8.3% (P < 0.001) and 82.1%, 73.0%, or 10.5% (P < 0.001), respectively. CONCLUSIONS: The postoperative NLR-PLR predicted outcomes of hepatitis B virus related HCC patients within Milan criteria after liver resection. PMID- 26022996 TI - Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants. AB - We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms. PMID- 26022998 TI - Multidisciplinary team approach to end-stage dialysis access patients. AB - BACKGROUND: The hemodialysis reliable outflow (HeRO) access device is a permanent dialysis graft used in patients with central venous obstruction. Given the complexity of care related to end-stage dialysis access (ESDA) patients, a multidisciplinary approach has been used to achieve operative success of HeRO graft placement. METHODS: The single-center retrospective review included adult patients that were seen in ESDA clinic who underwent a HeRO graft placement from September 2010-September 2014 under the care of a team consisting of a nephrologist, an interventional radiologist, and a surgeon. The effectiveness of the multidisciplinary approach was evaluated using outcome variables including successful HeRO graft placement, operative complications, the rate of obtaining central venous access, and advanced endovascular maneuvers performed by interventional radiology to obtain central venous access. RESULTS: A multidisciplinary approach has been used in 33 ESDA patients. Access to the right atrium was achieved in 100% of cases. Fifty-eight percent of patients required advanced endovascular maneuvers in the interventional radiology suite to obtain central venous access. Successful HeRO graft placement was achieved in 94% (31 of 33) of the study population. No intraoperative complications were encountered. Median primary and secondary patency rates were 83 d (interquartile range: 45 170) and 345 d (interquartile range: 146-579) per HeRO graft placement, respectively. Primary and secondary patency rates at 60 d were 70% (23 of 33) and 79% (26 of 33), respectively. CONCLUSIONS: In this difficult patient population, a multidisciplinary team can provide a unique and collaborative approach to HeRO graft placement in patients with complex central venous outflow obstruction. PMID- 26022999 TI - Disease course and therapeutic approach in dermatomyositis: A four-center retrospective study of 100 patients. AB - Dermatomyositis is a life-altering inflammatory disorder of skin and muscle. Details regarding the natural course of this disorder, the effects of specific therapies on its progression, and the optimal therapeutic dosage and duration of prednisone are limited. We performed a retrospective medical record review of dermatomyositis patients at four medical centers. All patients were over the age of 21 and had a clinical diagnosis of dermatomyositis with pathological confirmation. We reviewed average muscle strength, corticosteroid use, creatine kinase levels, and supplemental immunosuppressant use during the 36-month period following each patient's initial assessment. One hundred patients participated with an average age of 50.1 years. Average muscle strength improved and prednisone requirements lessened six months after initial assessment. There was no difference in the mean change in muscle strength or cumulative corticosteroid use over 36 months among those initially treated with methotrexate, mycophenolate mofetil, pulse IVIG, or azathioprine. There was a 5% mortality rate in dermatomyositis patients due to infections. Treated dermatomyositis patients demonstrate the most significant improvement in strength during the first six-to twelve months following their initial clinical assessment. Additional prospective studies are needed to determine the relative benefit of select immunosuppressant agents in preserving strength and reducing corticosteroid use in dermatomyositis. PMID- 26023000 TI - Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy. AB - Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P = 0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R(2) = 0.503; P = 0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1 +/- 1.9 vs. 3.2 +/- 1.2; P <0.0001) and body mass index (26.9 +/- 6.0 vs. 22.9 +/- 4.0 kg/m(2); P = 0.003) and a smaller number of D4Z4 allele repeats (4.8 +/- 1.6 vs. 5.7 +/- 1.8; P = 0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index. PMID- 26023001 TI - Adoption and Usage of mHealth Technology on Quality and Experience of Care Provided by Frontline Workers: Observations From Rural India. AB - BACKGROUND: mHealth apps are deployed with the aim of improving access, quality, and experience of health care. It is possible that any mHealth intervention can yield differential impacts for different types of users. Mediating and determining factors, including personal and socioeconomic factors, affect technology adoption, the way health workers leverage and use the technology, and subsequently the quality and experience of care they provide. OBJECTIVE: To develop a framework to assess whether mHealth platforms affect the quality and experience of care provided by frontline workers, and whether these effects on quality and experience are different depending on the level of technology adoption and individual characteristics of the health worker. Literacy, education, age, and previous mobile experience are identified as individual factors that affect technology adoption and use, as well as factors that affect the quality and experience of care directly and via the technology. METHODS: Formative research was conducted with 15 community health workers (CHWs) using CommCare, an mHealth app for maternal and newborn care, in Bihar, India. CHWs were first classified on the level of CommCare adoption using data from CommCareHQ and were then shadowed on home visits to evaluate their levels of technology proficiency, and the quality and experience of care provided. Regression techniques were employed to test the relationships. Out of all the CHWs, 2 of them refused to participate in the home visits, however, we did have information on their levels of technology adoption and background characteristics, which were included in the analysis as relevant. RESULTS: Level of technology adoption was important for both quality and experience of care. The quality score for high users of CommCare was higher by 33.4% (P=.04), on average, compared to low users of CommCare. Those who scored higher on CommCare proficiency also provided significantly higher quality and experience of care, where an additional point in CommCare proficiency score increased the quality score by around half a point (0.541, P=.07), and experience score by around a third of a point (0.308, P=.03). Age affected CommCare user type negatively, with an increase in age increasing the likelihood of belonging to a lower category of CommCare adoption (-0.105, P=.08). Other individual characteristics did not affect adoption or the predicted values estimating the relationship between adoption and quality and experience of care, although illiteracy was able to affect the relationship negatively. CONCLUSIONS: mHealth technology adoption by frontline workers can positively impact the quality and experience of care they provide. Individual characteristics, especially literacy and age, can be important elements affecting technology adoption and the way users leverage the technology for their work. Our formative study provides informed hypotheses and methods for further research. PMID- 26023002 TI - Development of seahorse (Hippocampus reidi, Ginsburg 1933): histological and histochemical study. AB - Biological aspects and global demand for aquarium promote seahorses as new species with high potential for commercial purposes; however, the low newborn survival rate represents the main bottleneck of seahorses farming. In this study, the organogenesis of the Hippocampus reidi was analysed from release until the 30th day after birth, using histological and histochemical approaches. To study the stages of their early life, 360 individuals were killed, sectioned, and stained with haematoxylin and eosin, periodic acid-Schiff, and Sudan Black B techniques. At birth, mouth and anus were open, the swim bladder inflated, and the visual system highly developed. Among the results, it was emphasized the presence of the yolk sac until the 2nd day after birth, the loops of the intestine to accommodate its elongation, and the ability of the larvae to absorb lipids in the anterior and posterior tract of the intestine. A short time (7/8 days) between reabsorption of yolk sac and formation of gonads was registered, with primordial follicles visible from the 10th day after birth. For the first time, organogenesis in H. reidi was described in detail; seahorses underwent a marked metamorphosis, and the indirect development observed in this species lead up to reconsider the term "juvenile" used for H. reidi during this period. PMID- 26023003 TI - Scleroderma renal crisis or thrombotic thrombocytopenic purpura: seeing through the masquerade. AB - SCLERODERMA: renal crisis (SRC), a somewhat rare but serious complication of systemic scleroderma, is one of only a few known rheumatologic emergencies; it presents in as many as 10% of patients with scleroderma. Before the use of angiotensin converting enzyme (ACE) inhibitors to treat SRC, the mortality rate for SRC was extremely high-as much as 90% after 1 year. However, the mortality rate has significantly improved with the early and aggressive use of ACE inhibitors. SRC typically includes acute renal failure and accelerated hypertension. Patients may report headache, changes in vision, fever, dyspnea, and encephalopathy. Laboratory study results can show elevated creatinine levels, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA) with schistocytes on blood smear. Given this clinical and laboratory presentation, SRC can easily be mistaken for TTP in clinical practice, as we demonstrate in 2 presentations of similar cases of SRC, the first in a 36-year-old Caucasian woman and the second in a 54-year-old Caucasian woman. In both cases, SRC masqueraded as TTP, and both patients were almost mistakenly treated for TTP until the clinical picture changed and certain laboratory test and kidney biopsy results confirmed otherwise. PMID- 26023004 TI - Long-term effects of childhood chest infections. PMID- 26023007 TI - Imaging of the postoperative liver: review of normal appearances and common complications. AB - Several benign and malignant liver diseases may require surgical treatment for cure, including anatomical resections based on the segmental anatomy of the liver, non-anatomical (wedge) resections, and surgical management of biliary cysts. The type of surgery depends not only on the location and the nature of the disease, but also on the expertise of the surgeon. Whereas ultrasonography is often the first-line imaging examination in case of suspected postoperative complication, multidetector computed tomography (MDCT) is of greater value for identifying normal findings after surgery, early postoperative pathologic fluid collections and vascular thromboses, and tumor recurrence in patients who have undergone hepatic surgery. Magnetic resonance cholangiopancreatography (MRCP) is the imaging modality of choice for depicting early postoperative bile duct injuries and ischemic cholangitis that may occur in the late postoperative phase. Both MDCT and MRCP can accurately depict tumor recurrence. Radiologists should become familiar with these surgical procedures to better understand postoperative changes, and with the normal imaging appearances of various postoperative complications to better differentiate between complications and normal findings. PMID- 26023008 TI - MR imaging of spleen in beta-thalassemia major. AB - PURPOSE: Splenomegaly and splenic siderosis are well-known findings in beta thalassemia major. We explored the relation between splenic size, splenic and hepatic siderosis in transfusion-dependent beta-thalassemic patients, assessed by MR imaging. MATERIALS AND METHODS: Abdominal MR imaging studies of 47 consecutive thalassemic patients and 10 healthy subjects, used as controls, were retrospectively reviewed. The signal intensity ratios of spleen and liver to the right paraspinous muscle (S/M, L/M, respectively) were calculated on T1, intermediate, and T2*-weighted gradient-echo sequences, splenic volume was estimated on axial images and serum ferritin levels were recorded. RESULTS: Decreased S/M on all MR sequences was displayed in 36 patients. Six patients presented with normal S/M on all MR sequences and 5 patients displayed splenic hypointensity only on T2* sequence. No correlation between S/M and L/M was found whereas both L/M and S/M correlated with serum ferritin (P < 0.03). Splenic volume correlated to L/M (P < 0.05) but not to S/M values. CONCLUSION: In transfusion-dependent patients with beta-thalassemia, iron deposition in spleen cannot be predicted by the degree of hepatic siderosis, whereas splenomegaly relates to liver, but not splenic, iron overload. MR imaging can be a valuable tool in elucidating iron kinetics. PMID- 26023006 TI - [Lung diseases in children]. AB - BACKGROUND: Lung diseases belong to the most common acute and chronic childhood diseases. With specific diagnostics and therapy the outcome of many congenital and acquired pulmonary diseases in children and adults can be substantially improved. OBJECTIVE: The aim of this review is the presentation and evaluation of important lung diseases in children taking recent developments into consideration. MATERIAL AND METHODS: This article presents a review of the literature on selected acute and chronic lung diseases in children and adolescents. RESULTS: Acute pneumonia remains one of the most frequent causes of mortality in children worldwide. Antibiotic treatment has reduced the morbidity and mortality in Western industrialized countries; however, the treatment of complications, such as pleural empyema and lung abscesses remains challenging. With a prevalence of 10 %, asthma has evolved into the most common chronic disease in children and adolescents in Germany. Using anti-inflammatory inhalation therapy, effective control of asthma symptoms can be achieved in most patients. Cystic fibrosis (CF) remains the most common fatal inherited disease among Caucasians. More than 90 % of the mortality and morbidity of CF are caused by an early onset and progressive chronic obstructive lung disease. Approval of the first causal mutation-specific pharmacotherapy for a subgroup of patients with CF represents a milestone in individualized therapy of lung diseases. The pathogenesis of other rare chronic lung diseases including interstitial lung diseases (ILD) is still mostly unknown. CONCLUSION: Continuous improvement in the diagnostics and therapy is crucial to further improve the management and outcome of acute and chronic lung diseases in children. Pediatric pulmonology, as an interdisciplinary subspecialty at the interface of pediatrics, pulmonology and infectious diseases, plays a key role in the translation of scientific progress into clinical practice. PMID- 26023005 TI - Arbuscular mycorrhizal fungal communities and Rhizophagus irregularis populations shift in response to short-term ploughing and fertilisation in a buffer strip. AB - Short-term effects of soil physical disturbance by ploughing and nitrogen and phosphate fertilisation on arbuscular mycorrhizal fungal (AMF) communities and on intraspecific populations of Rhizophagus irregularis in a buffer strip surrounded by arable fields were studied. Pre-grown Plantago lanceolata plantlets were transplanted into fertilised and/or ploughed experimental plots. After 3 months, the glomeromycotan communities in the roots of these trap plants were analysed using 454 pyrosequencing of a fragment of the RNA polymerase II gene (RPB1). Intraspecific populations of R. irregularis were studied by restriction fragment length polymorphism (RFLP) analysis of the mitochondrial large ribosomal subunit (mtLSU) gene. Soil disturbance significantly increased the diversity of species level molecular taxa (MTs) and altered community structure, whilst fertilisation alone had no significant effect, unless coupled with ploughing. At the population level, the expected shift from genotypes of R. irregularis typically found in grasslands to those usually found in arable sites was only partially observed. In conclusion, in the short-term, physical soil disturbance, as well as nitrogen fertilisation when coupled with physical soil disturbance, affected AMF community and to a smaller extent population composition. PMID- 26023009 TI - Clinical effect of pre-dilution hemodiafiltration based on the permeation of the hemodiafilter. AB - The removal characteristics of on-line pre-dilution hemodiafiltration (HDF) were compared with those of hemodialysis using so-called 'super high-flux' or 'class V' dialyzers. A strong correlation between the reduction rate (RR) of alpha1 microglobulin (MG) and relief of clinical symptoms was found. The treatment conditions, including flow rates as well as selection of diafilter performance, were determined in consideration of the target symptoms to be removed and the target RR of alpha1-MG or, alternately, the albumin loss. An RR of beta2-MG >80% corresponded to that of alpha1-MG being >35% in both modalities, and these numbers were more easily achieved by employing on-line pre-dilution HDF, rather than hemodialysis with super high-flux dialyzers. In some situations, however, albumin loss of 6 g or more may be admissible when a patient shows severe clinical symptoms, such as restless legs syndrome. HDF with a large amount of fluid exchange and a large amount of albumin loss is worth trying, as long as the albumin loss is controlled in a measured manner. PMID- 26023010 TI - The past, present and future of the dialyzer. AB - Several types of dialysis membranes have been developed in the history of hemodialysis therapy. Regenerated cellulose had been widely used for a long time, since the beginning of dialysis therapy. Regenerated cellulose is strongly hydrophilic, which enables lower membrane thickness and miniaturization of the dialyzer. The cellulose triacetate membrane has greater performance because of the lower thickness of the membrane and its lack of swelling due to high hydrophobicity. Many types of synthetic membranes, such as polysulfone, polyethersulfone and polyester polymer alloy membranes, have asymmetrical structures. Dialyzers with these membranes show higher capacities for water and solute transport because the actual membrane thickness, which is related to the water and solute transfer resistance, is quite small compared to that in membranes with homogeneous structures. The development of highly biocompatible membranes will be required in the future so as to prevent the development of adverse reactions and related complications. The performance of a dialyzer depends not only on the membrane permeability but also on the flow conditions of the blood and dialysate. Many types of dialyzers with high-performance membranes have been developed as a result of advances in membrane and device technologies. Recently, many types of high-flux dialyzers with high-performance membranes with a high internal filtration (IF)/backfiltration (BF) flow rate have been introduced. IF-enhanced hemodialysis using an enhanced IF dialyzer seems to be more convenient than hemodiafiltration therapy because it requires no additional equipment, such as a roller pump. In the near future, dialyzers should be developed with high capacities for the removal of low-molecular-weight proteins (LMWPs) related to complications and with low capacities for the loss of albumin and amino acid. Dialyzers with a sharp cut-off membrane between LMWPs and albumin and dialyzers with a special function, i.e., an adsorptive property for some LMWPs, are required. In addition, dialyzers with biocompatible membranes are necessary to prevent severe adverse reactions, although the causal relationship between these reactions and some complications are yet to be clarified. PMID- 26023011 TI - Importance of abnormal bone metabolism in the acceleration of atherosclerosis in hemodialysis patients. AB - Increases in serum calcium and phosphate are known as main risk factors for cardiovascular mortality in hemodialysis patients. However, increased phosphate, a definite mortality risk in the general population, should be more remarkable in hemodialysis patients, as their renal capacity to excrete phosphate into urine is negligible. Phosphate acts directly and indirectly to cause vascular injury by stimulating the apoptosis of vascular endothelial cells and the vascular calcification of vascular smooth muscle cells. Bone releases not only phosphate but also calcium during bone resorption. An increased calcium load reduces bone turnover by suppressing parathyroid function, resulting in the formation of adynamic bone disease. Adynamic bone disease is a major risk factor for ectopic calcification in areas including the vascular wall by diminishing the capacity of bone to absorb surplus calcium and phosphate in the circulation. Therefore, it is recognized that the maintenance of bone turnover within a normal range might be the most important strategy to protect against the development of vascular calcification and to attenuate the load of phosphate and calcium, particularly in hemodialysis patients. PMID- 26023012 TI - Dysregulated iron metabolism in patients on hemodialysis. AB - The two main causes of death in patients on maintenance hemodialysis (MHD) are cardiovascular disease and infection. In the current report, we discuss the association of the iron-catalyzed Fenton reaction and iron sequestration with complications in MHD patients. In particular, we have studied the deregulation of several iron transport systems of polymorphonuclear leukocytes (PMNLs) and the effects of TNF-alpha on human umbilical vein endothelial cells or PMNLs obtained from MHD patients and controls, and the following results were obtained. (1) Iron was sequestered in MHD-PMNLs, in which the protein governing iron transport was dysregulated. (2) TNF-alpha accelerated iron accumulation and oxidative stress in human umbilical vein endothelial cells in a manner similar to that in MHD-PMNLs. (3) An endosomal iron transport protein, or natural resistance-associated macrophage protein 1, was decreased in PMNLs from MHD patients, and TNF-alpha caused a decline in this protein's expression in control PMNLs. (4) The mitochondrial iron chaperone protein frataxin was decreased in MHD-PMNLs, which was linked to the acceleration of oxidative stress and hypercytokinemia. (5) The index of arterial stiffness was aggravated in MHD patients and was associated with serum hepcidin and TNF-alpha levels, which could inhibit iron exit from cells. With regard to bacterial infections, iron availability to these intracellular pathogens is critical for their growth. In particular, iron accumulation in cells and endosomes may accelerate the spread of infection. Cardiovascular disease has been shown to be linked to oxidative stress caused by iron sequestration in vascular cells and macrophages as well as by the alteration of iron metabolism in mitochondria, and the observed increase in hepcidin and TNF alpha may accelerate these crucial steps of oxidative stress in vascular disease. Thus, because surplus iron in the body may escalate the dysregulation of iron metabolism, as observed in MHD patients, iron supplementation for renal anemia treatment should be prudent. PMID- 26023013 TI - The present status of and perspectives on home hemodialysis therapy in Japan. AB - Home hemodialysis (HHD) is one of the best choices for improving the quality of life and survival rate of dialysis patients because it can lead to longer and more frequent dialysis programs to aid in achieving adequate dialysis. There were 461 dialysis patients treated with HHD as of the end of 2013 in Japan, comprising only 0.1% of all dialysis patients in this country. Although this is a very small expansion rate, the number of HHD patients has been rapidly increasing in recent years. The Japanese Society for Home Hemodialysis was established in 1998 and formed the following 3 working groups to survey various problems underlying current HHD: Patient Registry, Supply and Waste, and Self-pay Burden. In order to achieve a successful HHD program in Japan, there are several issues to be resolved, including the development of standard recruitment and education programs, optimization of the composition of dialysis fluid, sufficient reimbursement for HHD, and the establishment of a business model for HHD similar to that for peritoneal dialysis. PMID- 26023014 TI - Safety and efficacy evaluation of lanthanum carbonate for hyperphosphatemia in end-stage renal disease patients. AB - In end-stage renal disease patients, various abnormalities of bone mineral metabolism adversely affect mortality. Hyperphosphatemia is known to adversely affect mortality and quality of life in chronic kidney disease patients and has been shown to be involved not only in the onset and progression of secondary hyperparathyroidism but also in vascular calcification. Thus, hyperphosphatemia is the main treatment target indicated in several guidelines for chronic kidney disease-mineral and bone disorder treatment. Phosphate binders are typically required for the management of hyperphosphatemia because dietary phosphorus restriction and phosphorus removal by hemodialysis alone are insufficient. We are able to prescribe five phosphate binders (calcium carbonate, sevelamer HCl, lanthanum carbonate (LaC), bixalomer, and ferric citrate) to Japanese hemodialysis patients. LaC is the most powerful noncalcium-containing phosphate binder for the treatment of hyperphosphatemia. In this chapter, we discuss the efficacy and safety of LaC, the safety of which has been under debate. In particular, we consider its toxic effects on the skeletal system. LaC is effective for hyperphosphatemia treatment in end-stage renal failure patients. It has been shown to be able to decrease serum fibroblast growth factor-23 levels. This result suggests that it may have beneficial effects on the cardiovascular system in patients undergoing renal replacement therapy. However, the effects of LaC remain obscure. Further investigations are required. No negative effects of LaC on bone metabolism or bone morphometry have been reported, but long-term clinical data are needed. PMID- 26023015 TI - Klotho/FGF23 Axis in CKD. AB - The sequential bone disorders, serum parameter abnormalities and vascular calcification that are associated with chronic kidney disease (CKD) have come to be generally known as CKD-mineral bone disorder (MBD). Klotho, a causative protein of aging, and fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic factor, have been reported to be involved in CKD-MBD, and their relationship to the pathophysiology of this disease is gradually being elucidated. Klotho functions as a cofactor of FGF receptors and has been reported to cause FGF23 action and specificity in the kidney. In addition, the presence of secreted Klotho in membrane protein fractions has been determined, and its specific actions are now garnering attention. FGF23, in cooperation with Klotho, inhibits phosphate reabsorption and vitamin D production at the kidney. Blood Klotho and FGF23 levels have been reported to increase beginning at the early stages of CKD, and these factors are receiving attention as new surrogate markers that are reported to be related to life expectancy. In this chapter, we summarize and outline the pathophysiology of Klotho and FGF23 in CKD-MBD as well as important points that are starting to influence clinical practice. PMID- 26023016 TI - Cell sheet-based tissue engineering for mesothelial cell injury. AB - Mesothelial cells are an integral part of the peritoneum and play an important role in maintaining its structure and functions. A number of studies have been performed to evaluate the ability of mesothelial cells to regenerate and transdifferentiate. Mesothelial cells are also involved in repairing the damage to the peritoneum as a result of surgery or peritonitis. Previous cell sheet engineering research has made it possible to transplant cells that retain their function, and stacking different types of cells in cell sheet layers has also become possible. Mesothelial cell transplantation as a means of achieving peritoneal regeneration needs to be performed under conditions in which the surface area of the visceral peritoneum is large and the area of mesothelial cell damage is small. In this chapter, we explain cell sheet engineering as a technology for transplanting cells in which a variety of intercellular adhesion and cell membrane molecules remain intact and the application of this technology to peritoneal regeneration. PMID- 26023017 TI - Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients. AB - Approximately 5-10% of patients with end-stage renal disease (ESRD) exhibit hyporesponsiveness to erythropoiesis-stimulating agents (ESAs), defined as a continued need for higher than 300 IU/kg/week doses of epoetin or a 1.5 mg/kg/week dose of darbepoetin. ESA hyporesponsiveness contributes to the morbidity, mortality and health-care economic burden of ESRD patients. The most common causes of ESA resistance are absolute or functional iron deficiency and inflammation. Maintaining adequate iron stores is clearly accepted as the most important strategy for reducing the ESA requirement and for enhancing ESA efficacy. Recent clinical studies have shown that iron administration to ESRD patients is associated with an increased risk of infection and atherosclerosis. ESA hyporesponsiveness due to chronic inflammation in ESRD patients has been reported to be improved by a number of interventions, including the use of biocompatible hemodialysis membranes, ultrapure dialysate, ascorbic acid therapy, vitamin E supplementation, and statin therapy. Other causes of ESA hyporesponsiveness include inadequate dialysis, hyperparathyroidism, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, primary bone marrow disorders, myelosuppressive agents, hemoglobinopathies, hemolysis, and hypersplenism. This article summarizes the common causes of ESA hyporesponsiveness and the proposed therapeutic interventions. PMID- 26023018 TI - Past and present perspectives on encapsulating peritoneal sclerosis. AB - Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis. The mortality rate for EPS has been high, primarily due to complications related to bowel obstruction. However, recent advances in clinical research have established the pathogenesis, the disease course, and a treatment strategy. Currently, there is consensus on therapy; however, treatment with corticosteroids and tamoxifen should be administered in a timely manner. The final therapeutic option for EPS is surgical enterolysis (adhesiolysis). Moreover, a biocompatible peritoneal dialysis solution has become available for patients worldwide, which may further reduce peritoneal deterioration and EPS risk. These activities have promoted a better understanding of and have prompted countermeasures against EPS. EPS is no longer considered a fatal complication. PMID- 26023019 TI - DPP-4 Inhibitors in Diabetic Patients with Chronic Kidney Disease and End-Stage Kidney Disease on Dialysis in Clinical Practice. AB - Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. The therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because the patients' reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Although recommended oral antidiabetic agents for patients with CKD differ between countries, all of the currently available dipeptidyl peptidase-4 (DPP-4) inhibitors can be used in not only patients with CKD but also patients with end-stage kidney disease on dialysis, and these inhibitors' use is increasing. Numerous clinical trials have shown that DPP-4 inhibitors provide effective and consistent glycemic control with a good tolerability profile and without severe hypoglycemia or weight gain. The glucose-lowering effect of DPP-4 inhibitors in diabetic patients with CKD is similar to the changes seen when DPP 4 inhibitors are prescribed to patients without CKD. Therefore, kidney function is unaffected by treatment with DPP-4 inhibitors. Moreover, DPP-4 inhibitors reduce the levels of glycated albumin, which is a better indicator of glycemic control than glycated hemoglobin is, without hypoglycemia in patients with end stage kidney disease undergoing dialysis. Furthermore, it has been suggested that DPP-4 inhibitors might have a kidney-protective effect since they can potentially reduce the incidence of albuminuria. Although these results suggest that DPP-4 inhibitors can protect against diabetic nephropathy, insufficient evidence is available to conclude that this class of agent directly prevents or decreases nephropathy in humans independently from improved glucose control. Further long term studies are needed to address whether DPP-4 inhibitors reduce the development and progression of diabetic nephropathy and improve cardiovascular outcomes in diabetic patients with CKD. Here, we describe the clinical efficacy and safety of DPP-4 inhibitors for patients with CKD, including those receiving dialysis. PMID- 26023020 TI - Present status and future of peritoneal dialysis in Japan. AB - The results of a nationwide statistical survey of peritoneal dialysis (PD) in Japan (PD registry) were reported at the end of 2012. There were 9,514 PD patients at the end of 2012 (3.1%), indicating 128 fewer than in the 2011 survey (9,642 patients). There were 347 non-PD+catheter patients, and 175 patients were started on PD in 2012 but were switched to another therapy in the same year. The sum of these 522 patients and the total number of PD patients (i.e. the total number of PD-therapy-related patients) was 10,036 (522 + 9,514). The PD-only patients numbered 7,323 (80.4%), and the PD+hemodialysis (HD) patients numbered 1,788 (19.6%). Of these 9,111 PD patients, 1,428 patients (15.7%) underwent HD once per week; 219 patients (2.4%), twice per week; and 55 patients (0.6%), three times per week. The PD+HD patients (1,788) accounted for 19.6% of all PD patients. In addition, 39.8% of PD patients were using the poly-glucose dialysis solution icodextrin (Extraneal). Around 40% of PD patients were using icodextrin, a much higher percentage than in other countries. What is the likelihood that the number of PD patients in Japan will gradually decrease (or increase) in the future? Regarding the dialysis trend in Japan, it is unlikely that the number of PD patients will increase. I think that if the government greatly increases the medical insurance coverage of PD treatment, the number of PD patients in Japan will increase as much as it recently has in the United States. If not, it is extremely unlikely that there will be a large increase in the number of PD patients in Japan. PMID- 26023021 TI - Cost-effectiveness of hemodialysis in Japan. AB - Evaluation of the socioeconomic value of medical intervention and establishment of the resources necessary for clinical practice are important for continued development of the medical system. The purpose of this study was to investigate the cost-effectiveness of maintenance hemodialysis (MHD) for end-stage kidney disease in Japan. There were two aims: a socioeconomic evaluation of online hemodiafiltration (HDF) in the medical system and an analysis of MHD with respect to the primary diseases of chronic kidney disease. We performed a cost effectiveness analysis based on quality-adjusted life years (QALY) and the incremental cost-effectiveness ratio (ICER). QALY were estimated using the EuroQOL-5 dimension. Reimbursement for medical fees in the national health insurance system was used as an indicator of costs. In a comparative analysis of hemodialysis and online HDF, a total of 288 dialysis interventions were observed for 4 weeks in 3 clinics. Among the subjects, nine patients were assigned to the HDF group. Consequently, the incremental cost-effectiveness ratio of HDF to hemodialysis was 20,589 DeltaUSD/DeltaQALY. In a comparative analysis of diabetic nephropathy and glomerulonephritis, seventeen patients (with a total of 243 dialysis sessions and a mean age of 63.2 +/- 11.7 years) who underwent MHD for end-stage kidney disease (primary diseases: chronic glomerulonephritis [64.7%], diabetic nephropathy [35.3%]) were enrolled. After stratification for primary disease, the cost-effectiveness values for diabetic nephropathy were 88,774 +/- 27,801 USD/QALY for 1 month and 97,416 +/- 36,156 USD/QALY for 36 months. These results suggest that HDF is a cost-effective therapy. Additionally, the cost effectiveness after 36 months of observation increased mainly among diabetic nephropathy patients. PMID- 26023022 TI - Vascular access for long-term hemodialysis/hemodiafiltration patients in Japan. AB - BACKGROUND: Many patients are receiving long-term hemodialysis (HD) or hemodiafiltration (HDF) treatment in Japan. Vascular access is a lifeline for patients on HD or HDF, and proper maintenance of vascular access is one of the key factors that make long-term HD and HDF possible. We investigated the conditions of vascular access in patients undergoing chronic HD or HDF in our hospital group in Japan to assess the relationship between the type of vascular access and long-term treatment. PATIENTS AND METHODS: We studied the conditions of vascular access in 899 patients who were on chronic HD or HDF, including patients who had been on dialysis for over 20 years as of December 2014. RESULTS: There were 125 patients who had been on dialysis treatment for over 20 years, with the longest dialysis vintage being 37 years, and they accounted for 13.9% of the total number of subjects. The primary disease was diabetes in two cases and chronic glomerulonephritis in the rest. There were 105 patients with an arteriovenous fistula and only 20 with an arteriovenous graft (AVG) (16.0%), whereas 91 had an AVG (11.7%) among the 774 patients who had been on dialysis treatment for less than 20 years, which indicated that the percentage of patients with an AVG increased with dialysis vintage. CONCLUSIONS: An arteriovenous fistula was the main type of vascular access used in patients who had been on dialysis treatment for over 20 years, which is very rare, even on the global scale. However, switching to an AVG is unavoidable in cases of vein deterioration due to long-term use. Access via an AVG is expected to increase further in long term patients in the future. PMID- 26023023 TI - New aspects of cerebrovascular diseases in dialysis patients. AB - Growing evidence suggests that chronic kidney disease is a significant risk factor for stroke, subclinical cerebrovascular abnormalities, and cognitive impairment, independent of known cardiovascular risk factors. Cerebrovascular disease is also a major cause of death in dialysis patients, who have a much higher incidence of stroke compared to the normal population. Strokes in dialysis patients are also characterized by a higher incidence of hypertensive intracerebral hemorrhage compared with those in the general population. Recent studies on dialysis cohorts have shown that asymptomatic cerebrovascular diseases, including silent cerebral infarction (SCI), white matter hyperintensities (WMHs), and cerebral microbleeds (CMBs), are related to future onset of stroke, cognitive impairment, and dementia. Magnetic resonance imaging studies have revealed a higher prevalence of SCI in hemodialysis patients compared with that in controls, and a subsequent longitudinal study found that SCI is a risk factor for stroke and cardiovascular events as a whole. Other studies have shown that the prevalence of WMHs is significantly higher in dialysis patients than in healthy subjects and that WMHs are a risk factor for cardiovascular events. There is also a high prevalence of CMBs in hemodialysis patients, but the clinical significance of CMBs in these patients has not been examined in a longitudinal study. The incidence of cognitive impairment and dementia in dialysis patients is also twice as high as that in age-matched healthy subjects, and dialysis patients tend to have vascular-type dementia rather than Alzheimer-type dementia. More studies in dialysis patients are required to examine the prevention of stroke, cognitive impairment, and dementia in these patients. PMID- 26023024 TI - Current topics of purification and constitutions of dialysis fluid. AB - Dialysis fluid is a fundamental component of hemodialysis treatment, and its roles include the correction of electrolyte levels, pH, and osmolality, as well as the removal of uremic solutes from the blood of patients with renal failure. In recent years, purification of dialysis fluid has become essential due to the use of high-flux membrane dialyzers. Therefore, rigorous standards have been established for the purification of dialysis fluid, which is becoming widely practiced in Japan. The effects of dialysis fluid purification include the prevention of micro-inflammation, preservation of residual renal function, improvement of nutritional status, and resolution of resistance to erythropoiesis stimulating agents. When purifying the dialysis fluid used in the central dialysis fluid delivery system, validation of the system is also important. Dialysis fluid that does not contain acetate has become available, and there have been reports of decreased micro-inflammation, etc., with this innovation. In addition, dialysis fluid containing a higher concentration of bicarbonate than is conventionally employed has become available. Although correction of acidosis remains important, excess alkalosis may reportedly worsen the survival prognosis of hemodialysis patients. Sufficient attention should be paid to these issues. PMID- 26023025 TI - Vascular calcification in end-stage renal disease patients. AB - Vascular calcification is very common in patients with end-stage renal disease (ESRD) and has been found to be associated with mineral and bone disorders. There are two types of vascular calcification: intimal and medial calcification. The transformation of vascular smooth muscle cells into osteoblast-like cells seems to be a key element in the pathogenesis of medial calcification in the presence of calcium and phosphate deposition. Vascular calcification causes increased arterial stiffness by medial calcification, which leads to left ventricular hypertrophy and decreased coronary artery perfusion and causes myocardial ischemia by intimal calcification. Thus, vascular calcification is thought to be associated with increased cardiovascular morbidity and mortality. Although current treatment strategies focus on correcting abnormal calcium, phosphate, parathyroid hormone, or vitamin D levels in ESRD patients, a better understanding of the mechanisms of vascular calcification may lead to the development of new therapeutic strategies that are capable of reducing vascular calcification and improving the cardiovascular outcome of ESRD patients. This review summarizes the pathophysiology, diagnostic procedure and therapeutic implication of vascular calcification in ESRD patients. PMID- 26023027 TI - Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding. AB - Protein-protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at high resolution. Here we exploited ubiquitin's noncovalent dimerization equilibrium to assess the potential of atomistic simulations to reproduce reversible protein-protein binding, by running submicrosecond simulations of systems with multiple copies of the protein at millimolar concentrations. The simulations essentially fail because they lead to aggregates, yet they reproduce some specificity in the binding interfaces as observed in known covalent and noncovalent ubiquitin dimers. Following similar observations in literature we hint at electrostatics and water descriptions as the main liable force field elements, and propose that their optimization should consider observables relevant to multi-protein systems and unfolded proteins. Within limitations, analysis of binding events suggests salient features of protein-protein recognition and binding, to be retested with improved force fields. Among them, that specific configurations of relative direction and orientation seem to trigger fast binding of two molecules, even over 50 A distances; that conformational selection can take place within surface-to-surface distances of 10 to 40 A i.e. well before actual intermolecular contact; and that establishment of contacts between molecules further locks their conformations and relative orientations. PMID- 26023028 TI - Anti-diabetic potential of selected ethno-medicinal plants of north east India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Through one-to-one interaction with the traditional healers, the present study has identified 15 medicinal plant species traditionally used as remedies to control diabetes. MATERIALS AND METHODS: The methanolic extracts were screened for their alpha-glucosidase inhibitory activity. Hypoglycemic activity was assessed following glucose, sucrose and starch tolerance test on normal and STZ induced diabetic rats. RESULTS: Ficus cunia extract had the highest alpha-glucosidase inhibitory potency with IC50 1.39+/-0.74 ug mL(-1) followed by Schima wallichi (IC50 1.43+/-0.20 ug mL(-1)) and Wendlandia glabrata (IC50 1.67+/-0.33 ug mL(-1)). In STZ induced diabetic rat model, F. cunia and W glabrata extracts reduced blood glucose concentration to near normal up to 14 days when administered 48 h after STZ. CONCLUSION: The present study supports the traditional use of some of these medicinal plants in anti-diabetic remedies. The present study contributes to evidence for use of traditional medicine. PMID- 26023029 TI - Antacid activity of Laportea aestuans (L.) Chew. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Laportea aestuans (L.) Chew (Urticaceae) was historically ingested together with chalk by pregnant women in Ghana when suffering from heartburn. The aim of this study was to evaluate the antacid activity of the aerial parts of L. aestuans. MATERIALS AND METHODS: Aerial parts of L. aestuans were collected in the Accra region of Ghana. The antacid activity was measured according to Fordtran's titration model. 90 mL tap water and test material in a 500 mL beaker were warmed to 37 degrees C on a magnetic stirrer and was continuously stirred at approximately 30 rpm in order to mimic the movements of the stomach. A titration was carried out with an artificial gastric acid to the end point of pH 3. The acid secretion rate was approximately 3 mL and pH was monitored with a pH meter. Concentrations of 666 and 1332 mg dried plant material were tested, both with and without addition of calcium carbonate (CaCO3). RESULTS: Both CaCO3 and L. aestuans had a significant better ability than water to neutralise an artificial stomach acid. 666 mg plant material together with CaCO3 compared to CaCO3 alone showed approximately the same neutralisation time. When mixing 1332 mg plant material with CaCO3 the neutralisation time was significantly higher than for CaCO3 alone and exhibited an antacid profile that was able to maintain the neutralising activity one pH-unit higher for an extended period of time. CONCLUSION: The results indicate that L. aestuans showed an antacid activity when combined with CaCO3. With further investigations of the active compound, mechanism of action and possible toxicity, the plant could form the basis of a novel antacid. PMID- 26023030 TI - Ethnomedicinal plants of Kathua district, J&K, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Natural products, especially those derived from plants, continue to provide new and important leads in the drug discovery process. The first step in drug discovery is to document material traditionally used to treat an ailment. Documentation of such knowledge will lead to its conservation and facilitate future research on medicinal plant safety and efficacy to validate traditional use. The present study was undertaken with an aim to document the ethnomedicinal plants of Kathua district. MATERIAL AND METHODS: The data were quantitatively analysed using indices like use-value (UV), informant consensus factor (ICF) and fidelity level (Fl). RESULTS: A total of 112 informants (78 males and 34 females) were interviewed. They were using a total of 197 plants from 87 families and 174 genera for the ethnomedicinal purposes. The most dominant families were Fabaceae, Asteraceae and Lamiaceae. The most important plants of the study site on the basis of use-value were Mentha longifolia, Curcuma domestica, Zingiber officinale, Ocimum tenuiflorum, Adiantum capillus-veneris, Viola odorata, Mentha arvensis and Acorus calamus. The diabetes treatment had the maximum consensus (0.96 ICF) among the informants. Other important categories with high ICF values were gastrointestinal disorders and respiratory disorders. Total 23 species recorded 100% Fl. Medicinal plants with high Fl were Brassica rapa, Plumbago zeylanica, Punica granatum, Catharanthus rosea, Tinospora cordifolia, Acacia catechu, Aegle marmelos, Abrus precatorius, Oxalis corniculata, Nicotiana plumbaginifolia, Achillea millefolium, Tamarindus indica, Taxus baccata and Butea monosperma. CONCLUSION: The plants with high UV and Fl like M. longifolia, C. domestica, Z. officinale, O. tenuiflorum, A. capillus-veneris, A. calamus, B. rapa, P. zeylanica, C. rosea, T. cordifolia, A. catechu, O. corniculata, N. plumbaginifolia, A. millefolium, T. indica, T. baccata and B. monosperma should be analysed for pharmacological components and discovery of new drugs. PMID- 26023031 TI - Effect of Centaurium erythraea Rafn, Artemisia herba-alba Asso and Trigonella foenum-graecum L. on liver fat accumulation in C57BL/6J mice with high-fat diet induced type 2 diabetes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Centaurium erythraea Rafn (CE), Artemisia herba alba Asso (AHA) and Trigonella foenum-graecum L. (TFG) are traditionally used to treat type 2 diabetes in Algeria, previous studies have found that extracts of these plants were effective to treat or prevent experimental diabetes induced by high-fat diet (HFD). AIM OF THE STUDY: Describe the additional effects of these extracts on lipid tissue deposition in HFD. MATERIALS AND METHODS: Male C57BL/6J mice were fed with HFD to induce type 2 Diabetes. Groups of mice were given plant extracts orally at 2g/kg/bodyweight daily for 20 weeks during establishment of diabetes, or for 18 weeks after confirmation of diabetes at the 17th week. Liver and other tissue samples were stained with Oil Red O. RESULTS: Liver steatosis was confirmed with HFD. CE, AHA and TFG extracts improved liver steatosis by the end of the preventive (20 weeks) and curative periods (35 weeks). This was most marked for CE extract (p<0.05), less so with TFG and AHA. No steatosis was found in other tissues. CONCLUSION: CE extract had a clear hepatoprotective effect in this mouse model of diet-induced type 2 diabetes. AHA and TFG had a minimal or no significant effect on steatosis. Beyond its effect as an antidiabetic agent, CE may also be promising to prevent or treat non-alcoholic liver steatosis. PMID- 26023032 TI - An ethnobotanical survey of medicinal plants used by traditional health practitioners to manage HIV and its related opportunistic infections in Mpoza, Eastern Cape Province, South Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of the study was to identify and document plants traditionally used to manage HIV and treat its opportunistic infections (OIs) in Mpoza, a rural village located in the Mount Frere Alfred Nzo District, Eastern Cape Province, South Africa. MATERIALS AND METHODS: Semi-structured interviews and focus group discussions (FGDs) were conducted with 18 traditional health practitioners from January 2012 to August 2012 to obtain information about medicinal plants used in the management of HIV and treatment of OIs. RESULTS: Seventeen plant species belonging to 12 families were identified for the management of HIV and treatment of OIs in Mpoza. The identified plant species belonged mostly to the families Asparagaceae (12%), Araliaceae (12%), Apiaceae (12%), Xanthorrhoeaceae (12%) and Lamiaceae (12%). The remaining 40% of identified plant species was evenly split over seven families - Urticaceae, Hypoxidaceae, Leguminosae, Verbenaceae, Rosaceae, Compositae and Rutaceae. The most frequently used medicinal plants were Hypoxis hemerocallidea (85%), Asparagus densiflorus (68%) and Lessertia frutescens (68%). The leaves (43.5%) and roots (21.7%) were the most frequently used plant parts, usually prepared as infusions and decoctions for oral administration. CONCLUSION: This study provides documentation of medicinal plants used in the management of HIV and treatment of commonly associated OIs, which might provide a potential lead that will significantly contribute in reducing the burden of HIV infections in South Africa. We envisage that this paper will provide some background for further studies in developing new, effective, safe and affordable plant-derived medicines. PMID- 26023033 TI - meso-Tetraphenylporphyrin with a pi-system extended by fusion with anthraquinone. AB - Fusion with a 9,10-anthraquinone moiety was achieved to extend porphyrin's pi system. A bridged dihydroisoindole derivative was used to prepare the corresponding meso-tetraphenyltetraanthraquinonoporphyrin (Ph4TAQP) via a thermal retro-Diels-Alder reaction. The basic optical properties of the prepared new anthraquinonoporphyrin and its complexes with Zn and Pd were studied. PMID- 26023034 TI - Bridge to transplantation with long-term mechanical assist device in adults after the Mustard procedure. AB - BACKGROUND: There is limited clinical experience with bridging to transplant with a left ventricular assist device (VAD) in patients with previously palliated transposition of great arteries. METHODS: Five adult patients presenting with systemic right ventricular failure 30 years after a Mustard operation were implanted with a HeartMate II VAD. The implant was completed using standard procedures with only minor modifications to accommodate right ventricular cannulation. RESULTS: All 5 patients were men, with a mean age of 31.5 +/- 1.8 years and a median time since Mustard operation of 30 (range 28 to 32) years. All patients had sternal closure on Post-operative Day (POD) 1, and 2 patients required additional re-operation for bleeding. One patient required temporary support of the non-systemic ventricle. The mean duration of VAD support was 284 +/- 177 days; 3 patients underwent heart transplant and 2 died on PODs 502 and 34, respectively. Both deaths were due to progressive heart failure and pump thrombosis. Comorbidities, anatomy and mediastinal scarring did not preclude implantation and heart failure symptoms improved in all patients. CONCLUSIONS: With the increased prevalence of late post-Mustard heart failure, bridge to transplant with a VAD may be a suitable treatment option for patients who are severely ill. PMID- 26023035 TI - Survival in pediatric lung transplantation: The effect of center volume and expertise. AB - BACKGROUND: Institutional operative volume has been shown to impact outcomes of various procedures including lung transplantation (LTx). We sought to determine whether this holds true with pediatric LTx by comparing outcomes of adult centers (with larger overall volume) to those of pediatric centers (with smaller volume but more pediatric-specific experience). METHODS: A retrospective analysis of the Organ Procurement and Transplant Network data was performed. Centers were categorized as either adult (LTx volume predominantly in adult patients), high volume pediatric (HVP, >=4 LTxs/year), or low-volume pediatric (LVP, <4 LTxs/year). Outcomes were compared in "younger children" (<12 years) and "older children and adolescents" (12 to 17 years). RESULTS: In total, 1,046 pediatric LTxs were performed between 1987 and 2012 at 62 centers (adult 51 [82%], HVP 3 [5%], LVP 8 [13%]). Although adult centers had larger overall LTx volume, their pediatric experiences were severely limited (median 1/year). In younger children, HVP centers were significantly better than LVP centers for patient survival (half life: 7.3 vs 2.9 years, p = 0.002). Similarly, in older children and adolescents, HVP centers were significantly better than adult centers for patient survival (half-life: 4.6 vs 2.5 years, p = 0.001). Of note, even LVP centers tended to have longer patient survival than adult centers (p = 0.064). Multivariable analysis identified adult centers as an independent risk factor for graft failure (hazard ratio: 1.5, p < 0.001) as with LVP (hazard ratio: 1.3, p = 0.0078). CONCLUSIONS: Despite larger overall clinical volume, outcomes among pediatric LTx recipients in adult centers are not superior to those of pediatric centers. Not only center volume but pediatric-specific experience has an impact on outcomes in pediatric LTx. PMID- 26023036 TI - Oncologic Long-Term Results of Robot-Assisted Minimally Invasive Thoraco Laparoscopic Esophagectomy with Two-Field Lymphadenectomy for Esophageal Cancer. AB - BACKGROUND: Open transthoracic esophagectomy is the worldwide gold standard in the treatment of resectable esophageal cancer. Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) for esophageal cancer may be associated with reduced blood loss, shorter intensive care unit (ICU) stay, and less cardiopulmonary morbidity; however, long-term oncologic results have not been reported to date. METHODS: Between June 2007 and September 2011, a total of 108 patients with potentially resectable esophageal cancer underwent RAMIE at the University Medical Centre Utrecht, with curative intent. All data were recorded prospectively. RESULTS: Median duration of the surgical procedure was 381 min (range 264-636). Pulmonary complications were most common and were observed in 36 patients (33 %). Median ICU stay was 1 day, and median overall postoperative hospital stay was 16 days. In-hospital mortality was 5 %. The majority of patients (78 %) presented with T3 and T4 disease, and 68 % of patients had nodal positive disease (cN1-3). In 65 % of patients, neoadjuvant treatment (chemotherapy 57 %, chemoradiotherapy 7 %, radiotherapy 1 %) was administered, and in 103 (95 %) patients, a radical resection (R0) was achieved. The median number of lymph nodes was 26, median follow-up was 58 months, 5-year overall survival was 42 %, median disease-free survival was 21 months, and median overall survival was 29 months. Tumor recurrence occurred in 51 patients and was locoregional only in 6 (6 %) patients, systemic only in 31 (30 %) patients, and combined in 14 (14 %) patients. CONCLUSION: RAMIE was shown to be oncologically effective, with a high percentage of R0 radical resections and adequate lymphadenectomy. RAMIE provided good local control with a low percentage of local recurrence at long-term follow up. PMID- 26023037 TI - Value of Peritoneal Drain Placement After Total Gastrectomy for Gastric Adenocarcinoma: A Multi-institutional Analysis from the US Gastric Cancer Collaborative. AB - BACKGROUND: The effect of routine drainage after abdominal surgery with enteric anastomoses is controversial. In particular, the role of peritoneal drain (PD) placement after total gastrectomy for adenocarcinoma is not well established. METHODS: Patients who underwent total gastrectomy for gastric adenocarcinoma (GAC) at seven institutions from the US Gastric Cancer Collaborative, from 2000 to 2012, were identified. The association of PD placement with postoperative outcomes was analyzed. RESULTS: Overall, 344 patients were identified and 253 (74 %) patients received a PD. The anastomotic leak rate was 9 %. Those with PD placement had similar American Society of Anesthesiologists score, tumor size, TNM stage, and the need for additional organ resection when compared with their counterparts. No difference was observed in the rate of any complication (54 vs. 48 %; p = 0.45), major complication (25 vs. 24 %; p = 0.90), or 30-day mortality (7 vs. 4 %; p = 0.51) between the two groups. In addition, no difference in anastomotic leak (9 vs. 10 %; p = 0.90), the need for secondary drainage (10 vs. 9 %; p = 0.92), or reoperation (13 vs. 8 %; p = 0.28) was identified. On multivariate analysis, PD placement was not associated with decreased postoperative complications. Subset analysis, stratified by patients who did not undergo concomitant pancreatectomy (n = 319) or those who experienced anastomotic leak (n = 31), similarly demonstrated no association of PD placement with reduced complications or mortality. CONCLUSIONS: PD placement after total gastrectomy for GAC is associated with neither a decrease in the frequency and severity of adverse postoperative outcomes, including anastomotic leak and mortality, nor a decrease in the need for secondary drainage procedures or reoperation. Routine use of PDs is not warranted. PMID- 26023038 TI - A Three-Step Method for Laparoscopic Mobilization of the Splenic Flexure. AB - BACKGROUND: Splenic flexure mobilization (SFM) is sometimes required for secure and tension-free anastomosis during laparoscopic colorectal surgery. Although several approaches have been used for laparoscopic SFM,1 it is still considered complicated and troublesome because of the lack of a standardized technique. We propose a three-step method for laparoscopic SFM, aimed at providing a simplified and standardized method, which is presented in the video. METHOD: First, the mesocolon of the transverse and descending colon is dissected from the retroperitoneal tissue using a medial approach. The appropriate plane for dissection can be recognized just beneath the inferior mesenteric vein, and the gauze should be placed in the dissected space. Second, the transverse colon and transverse mesocolon are detached from the pancreas and spleen by means of an anterior approach. The lesser sac is opened, and the attachment to the pancreas or spleen is cut using the inserted gauze as a landmark. Third, the lateral attachment of the descending colon to the left abdominal wall is dissected cranially or caudally. RESULTS: Using this method, we performed laparoscopic SFM for 13 patients with colorectal cancer with no conversion to another approach or to open surgery. No intraoperative complications were reported, including bleeding from the spleen and injury of the pancreas. The mean time for SFM was 55 min. CONCLUSIONS: We consider this three-step method as being useful, and it might help the standardization of laparoscopic SFM. PMID- 26023039 TI - Erratum to: Bis Expression in Patients with Surgically Resected Lung Cancer and its Clinical Significance. PMID- 26023040 TI - Tumor Involvement of the Nipple in Total Skin-Sparing Mastectomy: Strategies for Management. AB - BACKGROUND: Despite a growing body of literature on oncologic and reconstructive outcomes after total skin-sparing mastectomy (TSSM), some questions related to this approach remain unanswered, including strategies for managing tumor involvement of the nipple while maintaining the aesthetic benefits of TSSM. METHODS: A prospectively maintained database of patients undergoing TSSM and immediate breast reconstruction from 2005 to 2013 was reviewed. Outcomes included tumor involvement of resected nipple tissue and subsequent management, recurrences after nipple involvement, and trends in management of involved nipple tissue. RESULTS: The study included 1176 breasts in 751 patients treated with TSSM. The follow-up period was 31.3 months. The nipple-areolar complex (NAC) of 32 breasts (2.7 %) had a positive margin or involvement of nipple tissue. Of these breasts, 56 % contained invasive cancer, and 44 % had in situ disease. Management included repeat excision (11 cases, 34 % of cases), radiation of the NAC (as part of the postmastectomy breast field) without further excision (5 cases, 16 %), complete NAC removal (8 cases, 25 %), and no further treatment (8 cases, 25 %). Management by complete NAC skin excision significantly decreased during the study period (p = 0.003). The overall local recurrence rate was 6.2 %. No patients had recurrence in the preserved NAC skin. CONCLUSIONS: Despite expanding indications for TSSM, it can be performed safely with low rates of nipple involvement. Over time, tumor involvement of the nipple has been treated with re-excision or other alternative approaches to NAC removal that preserve the aesthetic benefits of total skin-sparing approaches without an early adverse impact on local recurrence. PMID- 26023041 TI - The dynamics of methylammonium ions in hybrid organic-inorganic perovskite solar cells. AB - Methylammonium lead iodide perovskite can make high-efficiency solar cells, which also show an unexplained photocurrent hysteresis dependent on the device-poling history. Here we report quasielastic neutron scattering measurements showing that dipolar CH3NH3(+) ions reorientate between the faces, corners or edges of the pseudo-cubic lattice cages in CH3NH3PbI3 crystals with a room temperature residence time of ~14 ps. Free rotation, pi-flips and ionic diffusion are ruled out within a 1-200-ps time window. Monte Carlo simulations of interacting CH3NH3(+) dipoles realigning within a 3D lattice suggest that the scattering measurements may be explained by the stabilization of CH3NH3(+) in either antiferroelectric or ferroelectric domains. Collective realignment of CH3NH3(+) to screen a device's built-in potential could reduce photovoltaic performance. However, we estimate the timescale for a domain wall to traverse a typical device to be ~0.1-1 ms, faster than most observed hysteresis. PMID- 26023042 TI - Postradiation Tumor in the Floor of Mouth. PMID- 26023044 TI - Effects of Silodosin, an alpha1A-Adrenoceptor Antagonist, and Distigmine, an Acetylcholinesterase Inhibitor, and Their Combined Effects on Impaired Voiding Function in Zucker Diabetic Fatty Rats. AB - BACKGROUND/AIMS: To evaluate the effects of silodosin (alpha1A-adrenoceptor antagonist) and distigmine (acetylcholinesterase inhibitor), alone or in combination, on voiding dysfunction in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model, by pressure flow study. METHODS: Male ZDF rats were anesthetized with urethane and a catheter was implanted into the bladder through the dome. Saline was continuously infused into the bladder at 6 ml/h to induce the micturition reflex. Intravesical pressure and micturition volume were recorded continuously and various urodynamic parameters were calculated using a waveform analysis system. RESULTS: Increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate, considered to be detrusor underactivity-like symptoms, were observed in ZDF rats. Although both silodosin and distigmine improved impaired voiding function, administration of both drugs in combination was more effective than either drug alone. CONCLUSIONS: ZDF rats showed symptoms suggestive of detrusor underactivity, and silodosin tended to ameliorate these symptoms in ZDF rats. These results suggested that an alpha1A-adrenoceptor antagonists may be effective against the voiding disorder accompanying not only bladder outlet obstruction but also deficiency of bladder function. Moreover, combined administration of an alpha1A-adrenoceptor antagonist with an acetylcholinesterase inhibitor may have additive efficacy in clinical use. PMID- 26023043 TI - Osteocyte lacunar properties in rat cortical bone: Differences between lamellar and central bone. AB - Recently, the roles of osteocytes in bone maintenance have gained increasing attention. Osteocytes reside in lacunae that are interconnected by canaliculi resulting in a vast cellular network within the mineralized bone matrix. As the structure of the lacuno-canalicular network is highly connected to osteocyte function, osteocyte lacunar properties such as volume, shape, orientation, and density are now frequently reported in studies investigating osteocyte activity. Despite this increasing interest in lacunar morphometrics, many studies show a large spread in such values, suggesting a large inter-species but also inter-site variation in lacunar properties. Here, osteocyte lacunae in rat cortical bone have been studied using synchrotron radiation micro computed tomography (SR MUCT) and backscattered electron (BE) microscopy. Quantitative lacunar geometric characteristics are reported based on the synchrotron radiation data, differentiating between circumferential lamellar bone and a central, more disordered bone type. From these studies, no significant differences were found in lacunar volumes between lamellar and central bone, whereas significant differences in lacunar orientation, shape and density values were observed. The 3D nature of the SR MUCT data sets furthermore revealed that lacunae in central bone, which appear to be poorly aligned in transverse 2D cross sections, are in fact highly aligned along the bone long axis. These results demonstrate the importance of using 3D methods to investigate anisotropic biological materials such as bone and that the appropriate choice of subregions for high resolution imaging is not trivial. PMID- 26023045 TI - Validation of the Menopause Rating Scale in Serbian language. AB - PURPOSE: The study aim was to translate the Menopause Rating Scale (MRS) to Serbian language and assess its validity and reliability in the population of Serbian menopausal women. METHODS: The study included 200 peri- and postmenopausal women from two Community Health Centers (city center and outskirts) in the Serbian capital-Belgrade. Women filled out general questionnaire (socio-demographics, habits, medical history), the MRS, Short Form 36 questionnaire (SF-36) and Beck's Depression Inventory (BDI). The MRS was translated according to recommended methodology and its psychometric properties (internal consistency, factor analysis, discriminant, construct and criterion validity) were assessed. RESULTS: The Cronbach's alpha coefficient for the whole scale was 0.884 (psychological alpha = 0.902, somato-vegetative alpha = 0.761, urogenital alpha = 0.734). Values of the CI-TC coefficient for Serbian MRS were adequate for 10 items, proving their suitability in the scale. On factor analysis, we obtained the same 3 factors as in the original scale (73.1 % of variance). Communalities of all items were appropriate (>0.4). There was no common method bias. The MRS total score was correlated positively with BDI score (p = 0.001) and negatively with all SF-36 domains (p = 0.001) except General Health. Based on ROC analysis, MRS scores were more consistent for post- than perimenopausal Serbian women. Similar results of two raters (p > 0.05) implied on adequate translation and reliability of MRS. CONCLUSION: Serbian version of MRS demonstrated excellent reliability and validity. The MRS in Serbian language can be used in daily clinical work with menopausal women for assessing their symptoms and quality of life. PMID- 26023047 TI - An open-source genetic algorithm for determining optimal seed distributions for low-dose-rate prostate brachytherapy. AB - PURPOSE: An open source optimizer that generates seed distributions for low-dose rate prostate brachytherapy was designed, tested, and validated. METHODS: The optimizer was a simple genetic algorithm (SGA) that, given a set of prostate and urethra contours, determines the optimal seed distribution in terms of coverage of the prostate with the prescribed dose while avoiding hotspots within the urethra. The algorithm was validated in a retrospective study on 45 previously contoured low-dose-rate prostate brachytherapy patients. Dosimetric indices were evaluated to ensure solutions adhered to clinical standards. The SGA performance was further benchmarked by comparing solutions obtained from a commercial optimizer (inverse planning simulated annealing [IPSA]) with the same cohort of 45 patients. RESULTS: Clinically acceptable target coverage by the prescribed dose (V100) was obtained for both SGA and IPSA, with a mean +/- standard deviation of 98 +/- 2% and 99.5 +/- 0.5%, respectively. For the prostate D90, SGA and IPSA yielded 177 +/- 8 Gy and 186 +/- 7 Gy, respectively, which were both clinically acceptable. Both algorithms yielded reasonable dose to the rectum, with V100 < 0.3 cc. A reduction in dose to the urethra was seen using SGA. SGA solutions showed a slight prostate volume dependence, with smaller prostates (<25 cc) yielding less desirable, although still clinically viable, dosimetric outcomes. SGA plans used, on average, fewer needles than IPSA (21 vs. 24, respectively), which may lead to a reduction in urinary toxicity and edema that alters post-implant dosimetry. CONCLUSIONS: An open source SGA was validated that provides a research tool for the brachytherapy community. PMID- 26023048 TI - A repertoire of high-affinity monoclonal antibodies specific to S. typhi: as potential candidate for improved typhoid diagnostic. AB - Typhoid fever is a significant global health problem with highest burden on the developing world. The severity of typhoid is often underestimated, and currently available serological diagnostic assays are inadequate due to lack in requisite sensitivity and specificity. This underlines an absolute need to develop a reliable and accurate diagnostics that would benefit long-term disease control and treatment and to understand the real disease burden. Here, we have utilized flagellin protein of S. typhi that is surface accessible, abundantly expressed, and highly immunogenic, for developing immunodiagnostic tests. Flagellin monomers are composed of conserved amino-terminal and carboxy-terminal, and serovar specific middle region. We have generated a panel of murine monoclonal antibodies (mAbs) against the middle region of flagellin, purified from large culture of S. typhi to ensure its native conformation. These mAbs showed unique specificity and very high affinity toward S. typhi flagellin without showing any cross-reactivity with other serovars. Genetic analysis of mAbs also revealed high frequency of somatic mutation due to antigenic selection process across variable region to achieve high binding affinity. These antibodies also displayed stable binding in stringent reaction conditions for antigen-antibody interactions, like DMSO, urea, KSCN, guanidinium HCl, and extremes of pH. One of the mAbs potentially reversed the TLR5-mediated immune response, in vitro by inhibiting TLR5-flagellin interaction. In our study, binding of these mAbs to flagellin, with high affinity, present on bacterial surface, as well as in soluble form, validates their potential use in developing improved diagnostics with significantly higher sensitivity and specificity. PMID- 26023049 TI - UK law on consent finally embraces the prudent patient standard. PMID- 26023051 TI - Subchronic Oral Toxicity of Sodium Tungstate in Sprague-Dawley Rats. AB - The subchronic toxicity of sodium tungstate dihydrate aqueous solution in male and female Sprague-Dawley rats was evaluated by daily oral gavage of 0, 10, 75, 125, or 200 mg/kg/d for 90 days. Measured parameters included food consumption, body weight measurements, hematology, clinical chemistry, and histopathological changes. There was a significant decrease in food consumption and body weight gain in males at 200 mg/kg/d from days 77 to 90; however, there was no effect in food consumption and body weights in females. There were no changes in the hematological and clinical parameters studied. Histopathological changes were seen in kidney of male and female and epididymis of male rats. Histopathological changes were observed in the kidneys of male and female rats dosed at 125 or 200 mg/k/d consisting of mild to severe cortical tubule basophilia in 2 high-dose groups. Histological changes in epididymides included intraluminal hypospermia with cell debris in the 200 mg/kg/d dosed male rats. Histopathological changes were observed in the glandular stomach including inflammation and metaplasia in the high-dose groups (125 or 200 mg/kg/d) of both sexes of rats. Based on histopathology effects seen in the kidneys, the lowest observable adverse effect level was 125 mg/kg/d and the no observable adverse effect level was 75 mg/kg/d in both sexes of rats for oral subchronic toxicity. PMID- 26023052 TI - Long-Term Chronic Toxicity and Mesothelial Cell Reactions Induced by Potassium Octatitanate Fibers (TISMO) in the Left Thoracic Cavity in A/J Female Mice. AB - The present study was conducted to examine the chronic effects of potassium octatitanate fibers (trade name TISMO; chemical formula K2O.6TiO2) on the mouse lung and thoracic cavity. This method of infusion was employed to examine the direct effects of the fibers to the pleura. In the present study, 52- and 65-week experiments were employed to examine the long-term chronic effects after infusion of fiber-shaped TISMO into the thoracic cavities of A/J mice. Following this infusion, TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura. The additional histopathological detection of TISMO fibers in the liver, spleen, kidneys, ovary, heart, bone marrow, and brain of TISMO-infused mice indicated migration of the fibers out from the thoracic cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. This study demonstrated that intrathoracic infusion of TISMO fiber did not cause malignant mesothelioma but did cause severe chronic inflammation and proliferation of pleural mesothelial cells. PMID- 26023054 TI - Synthesis of pyrazolylbisindoles over mesoporous Lewis acidic ZrTUD-1: Potential application in selective Cu(2+) colorimetric detection. AB - A series of pyrazolylbisindole (PBI) derivatives were prepared by simple condensation of indole and pyrazole aldehyde utilizing amorphous mesoporous ZrTUD 1 having predominant Lewis acid sites. The applicability of pyrazolylbisindolyl derivate as a colorimetric chemosensor with high selectivity toward Cu(2+) over other cations were tested. Among heavy and transition metal (HTM) ions in CH3CN solution, the probe only sensed Cu(2+) detectable by naked eye. The sensor exhibited a new absorption band at 488 nm (a red shift of 206 nm from 282 nm) with a large colorimetric response and affinity to Cu(2+) over other cations tested (Al(3+), Pb(2+), Cd(2+), Mg(2+), Mn(2+), Zn(2+), K(+), Fe(2+), Ca(2+), Cu(2+) and Hg(2+)). PMID- 26023053 TI - Determination of the isoflavone composition and estrogenic activity of commercial dietary supplements based on soy or red clover. AB - Dietary supplements high in isolated isoflavones are commercially available for human consumption primarily to alleviate menopausal symptoms in women. The isoflavone composition, quantity and importantly their estrogenic potency are poorly standardised and can vary considerably between different products. The aim of this study was to analyse the isoflavone composition of 11 dietary supplements based on soy or red clover using the HPLC/MS/MS technique. Furthermore, we investigated the transactivational potential of the supplements on the estrogen receptors (ER), ERalpha and ERbeta, performing luciferase reporter gene assays. As expected, we found that the isoflavone composition varies between different products. The measured total isoflavone contents in various supplements were mostly comparable to those claimed by the manufacturers in their product information. However expressing the isoflavone content as isoflavone aglycone equivalents, soy-based supplements had a clearly lower quantity compared to the manufacturer information. All supplements transactivated more or less ERalpha and ERbeta with a preference for ERbeta. The transactivational efficiency exceeded partly the maximal 17beta-estradiol induced ER activation. While the different soy-based supplements revealed similar transactivation potential to both ERs, red clover-based supplements differed considerably. We conclude that different commercial dietary supplements based on soy or red clover vary in their isoflavone composition and quantity. They are estrogenically active, although especially the red clover-based supplements show considerable differences in their estrogenic potential to ERalpha and ERbeta. Thus, different isoflavone-rich products cannot be necessarily compared regarding possible biological effects. PMID- 26023055 TI - Bivalent transition metal complexes of (E)-3-(2-benzylidenehydrazinyl)-3-oxo-N-(p tolyl)propanamide: Spectroscopic, computational, biological activity studies. AB - Schiff base complexes of Co(II), Ni(II) and Cu(II) with (E)-3-(2 benzylidenehydrazinyl)-3-oxo-N-(p-tolyl)propanamide (H2BHAH) containing N and O donor sites were synthesized. Both ligand and its metal complexes were characterized by elemental analysis, thermal analysis (TG and DTG), spectroscopy ((1)H NMR, IR, UV-visible, MS spectra), and physical measurements (magnetic susceptibility and molar conductance). The kinetic and thermodynamic parameters of the different decomposition steps of some complexes were calculated using the Coats-Redfern and Horowitz-Metzger methods. Also, the DFT studying was evaluated to confirm the geometry of the investigated compounds. Moreover, the association and formation constants of Ni(II) and Cu(II) ions in mixed solvent at 290.15K were calculated by using electrical conductance. The antimicrobial activities of the ligand and its complexes were studied against gram positive bacteria Staphylococcus aureus, gram negative bacteria; Escherichia coli and pathogenic fungi; Candida albicans by using minimum inhibition concentrations method. The antioxidant (ABTS-derived free radical method) and cytotoxic (in vitro Ehrlich Ascites) activities of the isolated compounds were estimated. PMID- 26023056 TI - Raman analysis of complex pigment mixtures in 20th century metal knight shields of the Order of the Elephant. AB - The pigment composition of six painted metal knight shields of the Order of the Elephant dating from the second half of the 20th century belonging to the Danish royal collection were studied using Raman microscopy. By focusing a 785 nm laser with a 50* objective on particles in paint cross sections, it was possible to identify the following 20 compounds: hematite, goethite, chrome red/orange, chrome yellow, zinc chrome yellow, carbon black, toluidine red PR3, chlorinated para red PR4, dinitroaniline orange PO5, phthalocyanine blue PB15, indanthrone blue PB60, ultramarine, Prussian blue, lead white, anatase, rutile, calcium carbonate, barium sulphate, gypsum and dolomite. The components were frequently present in complex pigment mixtures. Additional information was obtained by elemental analysis with scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) to identify cobalt blue, zinc white and cadmium red, as well as to indicate the presence of zinc white in some pigment mixtures. The study allowed a comparison between the industrially applied preparation layers and the artistic paint layers applied by the heraldic painter. Differences in the choice of paint and pigment types were observed on the earliest knight shields, demonstrating a general delay of industrial materials into artist paints. PMID- 26023057 TI - Determination of dexamethasone by flow-injection chemiluminescence method using capped CdS quantum dots. AB - L-Cysteine capped CdS quantum dots (QDs) were synthesized through a facile hydrothermal method and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), photoluminescence (PL) and UV-Vis spectroscopy. The light emitted from KMnO4-L-cysteine capped CdS QDs reaction in acidic medium was applied as a simple and sensitive chemiluminescence (CL) system for determination of dexamethasone. The CL intensity of KMnO4-L-cysteine capped CdS QDs CL system was remarkably enhanced in the presence of dexamethasone. Under optimum experimental conditions, the enhanced CL intensity was related to dexamethasone concentration in the range of 0.004-25.0 mg L(-1), with the detection limit (3sigma) of 0.0013 mg L(-1). The analytical applicability of the proposed CL system was assessed by determining dexamethasone in spiked environmental water samples and pharmaceutical formulation. The analytical performances of proposed flow-injection CL method for the determination of dexamethasone were compared with those obtained by corona discharge ionization ion mobility spectrometry (CD IMS) method. The proposed CL system exhibits a higher sensitivity and precision than the CD-IMS method for the determination of dexamethasone. PMID- 26023058 TI - The usefulness of left atrial volume index and left ventricular mass index in determining subclinical cardiac involvement in patients with early-stage sarcoidosis. AB - BACKGROUND AND AIM: Sarcoidosis is a multi-systemic granulomatous disease of unknown etiology. The present study has been designed to evaluate the importance of diastolic dysfunction with left atrial volume index (LAVi) and left ventricular mass index (LVMi) in determining subclinical cardiac involvement in subjects with stage I-II pulmonary sarcoidosis. METHODS: A total of 54 patients under follow-up for sarcoidosis without cardiac involvement and 56 healthy subjects were included in the study. The echocardiographic assessment of the patients revealed no significant difference between the two groups regarding left ventricular end-systolic and end-diastolic diameters, ejection fraction (LVEF) and annular velocity determined by tissue Doppler evaluation. RESULTS: The LVEF calculated was 61.8 +/- 7.8 % in the sarcoidosis group versus 64.1 +/- 2.7 % in the control group (p = 0.04). Left ventricular interventricular septum thickness, posterior wall thickness, and relative wall thickness were significantly higher in the sarcoidosis group compared to the control group (p < 0.001). The sarcoidosis group had higher LVM and LVMi values compared to the control group (145 +/- 18.1 and 79 +/- 14 g/m(2), 135 +/- 27.7 and 74 +/- 14.2 g/m(2); p = 0.020 and p = 0.021, respectively). Left atrial end-systolic volume and LAVi were higher in the sarcoidosis group (28.7 +/- 18.5; 15.6 +/- 10.2) compared to the control group (16.6 +/- 10.9; 8.9 +/- 5.5) with a statistically significant difference (p < 0.001). CONCLUSION: The present study indicates diastolic dysfunction and increased LVMi despite normal systolic function in patients with early-stage sarcoidosis without cardiac involvement. Also, the diastolic parameters were normal without showing any significant difference compared to the control group while there was a statistically significant increase in LAVi. This finding suggests that LAVi may be the earliest marker of diastolic dysfunction in patients with early-stage sarcoidosis without cardiac involvement. PMID- 26023059 TI - Co-ordination among leaf water relations and xylem vulnerability to embolism of Eucalyptus trees growing along a depth-to-groundwater gradient. AB - The importance of groundwater resources in arid and semi-arid areas for plant survival is well documented. However, there have been few studies examining the importance and impacts of groundwater availability in mesic environments. The aim of this study was to determine how depth-to-groundwater (DGW) impacts on leaf water relations, leaf structure and branch xylem vulnerability to embolism in a mesic environment. We hypothesize that increasing DGW results in increased resistance to drought stress and that this will be manifested across leaf and branch attributes pertaining to water relations. We further investigate whether there is co-ordination across leaf and branch-scale level responses to increased DGW. Four species were used in this study: Eucalyptus globoidea Blakely, E. piperita Sm., E. sclerophylla (Blakely) L.A.S.Johnson & Blaxell and E. sieberi L.A.S.Johnson. Six sites were chosen along an 11 km transect to span a range of average DGW: 2.4, 4.3, 9.8, 13, 16.3 and 37.5 m. Leaf water relations of trees showed less sensitivity to drought stress as DGW increased. This was reflected in significantly lower leaf turgor loss point and maximum osmotic potential, increased maximum turgor and a reduced leaf relative water content as DGW increased. At shallow DGW sites, minimum diurnal leaf water potentials were generally more negative than leaf water potential at zero turgor, but the reverse was observed at deep sites, indicating a larger growth potential safety margin at deep sites compared with shallow sites. Leaf cell wall elasticity varied independently of DGW. Xylem vulnerability to embolism was quantified as the water potential associated with 50% loss of conductance (P 50). In both summer and winter P 50 was significantly and negatively correlated with DGW. Co-ordination between leaf- and branch-level responses to increase in DGW was apparent, which strongly supports the conclusion that groundwater supply influenced woodland structure and functional behaviour. PMID- 26023061 TI - Electromagnetically induced absorption in a three-resonator metasurface system. AB - Mimicking the quantum phenomena in metamaterials through coupled classical resonators has attracted enormous interest. Metamaterial analogs of electromagnetically induced transparency (EIT) enable promising applications in telecommunications, light storage, slow light and sensing. Although the EIT effect has been studied extensively in coupled metamaterial systems, excitation of electromagnetically induced absorption (EIA) through near-field coupling in these systems has only been sparsely explored. Here we present the observation of the EIA analog due to constructive interference in a vertically coupled three resonator metamaterial system that consists of two bright and one dark resonator. The absorption resonance is one of the collective modes of the tripartite unit cell. Theoretical analysis shows that the absorption arises from a magnetic resonance induced by the near-field coupling of the three resonators within the unit cell. A classical analog of EIA opens up opportunities for designing novel photonic devices for narrow-band filtering, absorptive switching, optical modulation, and absorber applications. PMID- 26023060 TI - AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. AB - AIMS: AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK beta1/beta2 subunits (AMPKbeta1beta2-deficient mice, beta1beta2M-KO) have been generated and possess <10% of normal AMPK activity in muscle. However, how/if dramatic AMPK deficiency alters cardiac metabolism, function, or morphology has not been investigated. Therefore, the aim of this study was to determine whether a significant loss of AMPK activity alters cardiac function, metabolism, and hypertrophy, and whether this may play a role in the pathogenesis of heart failure. METHODS AND RESULTS: beta1beta2M-KO mice exhibit an approximate 25% reduction in systolic and diastolic function compared with wild-type (WT) littermates. Despite the well-documented role of AMPK in controlling myocardial energy metabolism, there was no difference in basal glucose and fatty acid oxidation rates between beta1beta2M-KO and WT mice. However, there was reduced AMPK-mediated phosphorylation of troponin I in beta1beta2M-KO and reduced ventricular cell shortening in the presence of low Ca(2+), which may explain the impaired cardiac function in these mice. Interestingly, beta1beta2M-KO mice did not display any signs of compensatory cardiac hypertrophy, which could be attributed to impaired activation of p38 MAPK. CONCLUSIONS: beta1beta2M-KO mice display evidence of dilated cardiomyopathy. This is the first mouse model of AMPK deficiency that demonstrates cardiac dysfunction in the absence of pathological stress and provides insights into the role of AMPK in regulating myocardial function, metabolism, hypertrophy, and the progression to heart failure. PMID- 26023062 TI - Periappendicitis during adalimumab treatment for ileocecal Crohn's disease in a 29-year-old male. AB - A 29-year-old male was diagnosed with ileocolic Crohn's disease (CD) approximately 2 years ago. Adalimumab was prescribed as CD remission induction therapy. Three months after beginning adalimumab, watery diarrhea and lower abdominal pain developed. He was admitted under a diagnosis of CD exacerbation. Despite fasting and antibiotic treatment, symptoms of acute panperitonitis appeared. He was diagnosed as acute appendicitis and we performed emergency surgery for peritoneal drainage and ileocecal resection on the fifth hospital day. We diagnosed periappendicitis based on the operative findings. This is the first report of periappendicitis with CD during adalimumab treatment. PMID- 26023050 TI - Calcium-independent phospholipases A2 and their roles in biological processes and diseases. AB - Among the family of phospholipases A2 (PLA2s) are the Ca(2+)-independent PLA2s (iPLA2s) and they are designated group VI iPLA2s. In relation to secretory and cytosolic PLA2s, the iPLA2s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA2s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca(2+) for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membrane-associated iPLA2gamma) and PNPLA9 (cytosol-associated iPLA2beta) are the most widely studied and understood. The iPLA2s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA2s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA2s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA2s and discussion of the potential mechanisms of action of the iPLA2s and related involved lipid mediators. PMID- 26023063 TI - Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats. AB - Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (beta-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI. PMID- 26023065 TI - Metronidazole CNS toxicity. PMID- 26023064 TI - Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency. AB - Methamphetamine (METH) is a highly addictive psychostimulant, and cessation of use is associated with reduced monoamine signalling, and increased anxiety/depressive states. Neurons expressing the neuropeptide, relaxin-3 (RLN3), and its cognate receptor, RXFP3, constitute a putative 'ascending arousal system', which shares neuroanatomical and functional similarities with serotonin (5-HT)/dorsal raphe and noradrenaline (NA)/locus coeruleus monoamine systems. In light of possible synergistic roles of RLN3 and 5-HT/NA, endogenous RLN3/RXFP3 signalling may compensate for the temporary reduction in monoamine signalling associated with chronic METH withdrawal, which could alter the profile of 'behavioural despair', bodyweight reductions, and increases in anhedonia and anxiety-like behaviours observed following chronic METH administration. In studies to test this theory, Rln3 and Rxfp3 knockout (KO) mice and their wildtype (WT) littermates were injected once daily with saline or escalating doses of METH (2 mg/kg, i.p. on day 1, 4 mg/kg, i.p. on day 2 and 6 mg/kg, i.p. on day 3-10). WT and Rln3 and Rxfp3 KO mice displayed an equivalent sensitivity to behavioural despair (Porsolt swim) during the 2-day METH withdrawal and similar bodyweight reductions on day 3 of METH treatment. Furthermore, during a 3-week period after the cessation of chronic METH exposure, Rln3 KO, Rxfp3 KO and corresponding WT mice displayed similar behavioural responses in paradigms that measured anxiety (light/dark box, elevated plus maze), anhedonia (saccharin preference), and social interaction. These findings indicate that a whole-of-life deficiency in endogenous RLN3/RXFP3 signalling does not markedly alter behavioural sensitivity to chronic METH treatment or withdrawal, but leave open the possibility of a more significant interaction with global or localised manipulations of this peptide system in the adult brain. PMID- 26023066 TI - Spinopelvic parameters evaluation in a Brazilian population sample. AB - INTRODUCTION: The morphology of the spine is variable within a population, and its maintenance in appropriate values implies a decrease in the energy expended. We need to know their normal values in population. This study aims to carry out a literature review and evaluate published papers on spinopelvic parameters in a Brazilian population sample. METHODS AND POPULATION: Eleven potentially eligible papers were initially identified for inclusion in this review: three papers from PubMed and eight from Medicine. Out of these, only five papers contained methodology and relevant significance level, and therefore, they were included in the final analytical run. DISCUSSION: According to a Brazilian study, Pratali mentions no significant difference in the average values of spinopelvic balance in the Brazilian population and those found in the literature; there was also no significant difference comparing Brazilian and Korean population; however, a difference was found in comparison with European population regarding PI parameters and SS, but the latter with higher values. According to Kulcheski (Column/Columna 12:224-227, 2013), the values of pelvic tilt in the Brazilian population evaluated in his research were 19 degrees (10 degrees -35 degrees ) and the sacral inclination was 38 degrees (30 degrees -55 degrees ), presenting similar values concerning the European population. In another Brazilian paper, Oliveira (Rev Bras Ort 49:189-193, 2014) reports that the research population had PI average of 45 degrees (41.9 degrees -48.1 degrees ). CONCLUSION: The values obtained are relatively minor when compared to the European population. However, all of these are within the normal margin considered in the worldwide literature. PMID- 26023067 TI - Development of Diagnostic Fragment Ion Library for Glycated Peptides of Human Serum Albumin: Targeted Quantification in Prediabetic, Diabetic, and Microalbuminuria Plasma by Parallel Reaction Monitoring, SWATH, and MSE. AB - Human serum albumin is one of the most abundant plasma proteins that readily undergoes glycation, thus glycated albumin has been suggested as an additional marker for monitoring glycemic status. Hitherto, only Amadori-modified peptides of albumin were quantified. In this study, we report the construction of fragment ion library for Amadori-modified lysine (AML), N(epsilon)-(carboxymethyl)lysine (CML)-, and N(epsilon)-(carboxyethyl)lysine (CEL)-modified peptides of the corresponding synthetically modified albumin using high resolution accurate mass spectrometry (HR/AM). The glycated peptides were manually inspected and validated for their modification. Further, the fragment ion library was used for quantification of glycated peptides of albumin in the context of diabetes. Targeted Sequential Window Acquisition of all THeoretical Mass Spectra (SWATH) analysis in pooled plasma samples of control, prediabetes, diabetes, and microalbuminuria, has led to identification and quantification of 13 glycated peptides comprised of four AML, seven CML, and two CEL modifications, representing nine lysine sites of albumin. Five lysine sites namely K549, K438, K490, K88, and K375, were observed to be highly sensitive for glycation modification as their respective m/z showed maximum fold change and had both AML and CML modifications. Thus, peptides involving these lysine sites could be potential novel markers to assess the degree of glycation in diabetes. PMID- 26023068 TI - RiboTALE: A modular, inducible system for accurate gene expression control. AB - A limiting factor in synthetic gene circuit design is the number of independent control elements that can be combined together in a single system. Here, we present RiboTALEs, a new class of inducible repressors that combine the specificity of TALEs with the ability of riboswitches to recognize exogenous signals and differentially control protein abundance. We demonstrate the capacity of RiboTALEs, constructed through different combinations of TALE proteins and riboswitches, to rapidly and reproducibly control the expression of downstream targets with a dynamic range of 243.7 +/- 17.6-fold, which is adequate for many biotechnological applications. PMID- 26023069 TI - Supraventricular tachycardia with cycle length variation and apparent VA dissociation: what is the mechanism? PMID- 26023070 TI - Catheter ablation of ventricular tachycardia originating from a coronary arterial right ventricle fistula. PMID- 26023071 TI - Catheter ablation of idiopathic ventricular ectopy in the vicinity of the His bundle under the septal leaflet of the tricuspid valve. PMID- 26023072 TI - Refugees: time for moral leadership from the Western democracies. PMID- 26023073 TI - Quantitative lipopolysaccharide analysis using HPLC/MS/MS and its combination with the limulus amebocyte lysate assay. AB - Quantitation of plasma lipopolysaccharides (LPSs) might be used to document Gram negative bacterial infection. In the present work, LPS-derived 3-hydroxymyristate was extracted from plasma samples with an organic solvent, separated by reversed phase HPLC, and quantitated by MS/MS. This mass assay was combined with the limulus amebocyte lysate (LAL) bioassay to monitor neutralization of LPS activity in biological samples. The described HPLC/MS/MS method is a reliable, practical, accurate, and sensitive tool to quantitate LPS. The combination of the LAL and HPLC/MS/MS analyses provided new evidence for the intrinsic capacity of plasma lipoproteins and phospholipid transfer protein to neutralize the activity of LPS. In a subset of patients with systemic inflammatory response syndrome, with documented infection but with a negative plasma LAL test, significant amounts of LPS were measured by the HPLC/MS/MS method. Patients with the highest plasma LPS concentration were more severely ill. HPLC/MS/MS is a relevant method to quantitate endotoxin in a sample, to assess the efficacy of LPS neutralization, and to evaluate the proinflammatory potential of LPS in vivo. PMID- 26023075 TI - A survey of overuse problems in patients with acquired or congenital upper limb deficiency. AB - BACKGROUND: Little is known about secondary impairments and overuse problems in patient with acquired or congenital upper limb deficiency. OBJECTIVES: Our aim was to estimate the frequency of overuse problems in persons after unilateral upper limb deficiency and identify the factors relevant for development of these problems. STUDY DESIGN: Cross-sectional study conducted at the University Rehabilitation Institute in Ljubljana. METHODS: In total, 65 persons after unilateral upper limb deficiency who had visited our subspecialist outpatient clinic during the 2011-2013 period (excluding those with other possible medical causes of overuse-type problems) were interviewed about the frequency, duration and severity of neck, elbow and shoulder pain and the presence of carpal tunnel syndrome and filled in the Orthotics and Prosthetics User Survey-Upper Extremity Functional Status questionnaire. RESULTS: The most frequent problem was carpal tunnel syndrome, followed by shoulder pain, neck pain and elbow pain. No statistically significant association of deficiency level, cause of deficiency, time since deficiency, extent of daily prosthesis use or type of prosthesis with frequency or severity of pain or number of problems was found. The presence of carpal tunnel syndrome decreased from wearing no prosthesis through aesthetic and body-powered to myoelectric prosthesis (p = 0.014). CONCLUSION: Factors contributing to overuse problems after upper limb deficiency are not straightforward, so a large multicentric study is warranted. CLINICAL RELEVANCE: Persons with acquired or congenital upper limb deficiency are under a heightened risk of developing overuse problems but the contributing factors are not clear, so regular individual follow-up is required. PMID- 26023074 TI - Aneurysmal vasculopathy in human-acquired immunodeficiency virus-infected adults: Imaging case series and review of the literature. AB - BACKGROUND: Intracranial vasculopathy in adult patients with human-acquired immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a rare but increasingly recognized disease entity. OBJECTIVE: We aimed to contribute to and summarize the adult literature describing patients with HIV/AIDS who have intracranial vasculopathy. METHODS: A retrospective review of adult patients with HIV/AIDS undergoing diagnostic cerebral angiography at our institution from 2007 2013 was performed. A literature review of relevant existing studies was performed. RESULTS: Five adult patients with HIV-related aneurysmal and occlusive vasculopathy were diagnosed and/or treated at our institution. A comprehensive review of the literature yielded data from 17 series describing 28 adult patients with HIV/AIDS and intracranial vasculopathy. Our review suggests that low CD4 count, motor weakness, and meningismus may be associated with the sequelae of intracranial vasculopathy/vasculitis in patients with HIV/AIDS. CONCLUSION: Patients with HIV/AIDS who have aneurysmal and stenotic vascular disease may benefit from earlier surveillance with the onset of neurological symptoms. The roles of medical, open surgical, and endovascular therapy in this unique entity will be further defined as the pathological basis of the disease is better understood. PMID- 26023076 TI - R.I.P. SIDAWAY: PATIENT-ORIENTED DISCLOSURE-A STANDARD WORTH WAITING FOR? Montgomery v Lanarkshire Health Board[2015] UKSC 11. PMID- 26023077 TI - Daily Affective and Behavioral Forecasts in Romantic Relationships: Seeing Tomorrow Through the Lens of Today. AB - The current research examined accuracy and bias in daily forecasts within romantic relationships. Results of an extensive daily report study involving 200 romantic dyads and 4,822 daily observations suggested that predictions regarding affect and partner behavior that will occur tomorrow are somewhat accurate, predicted by actual experiences tomorrow, but are largely biased by current experiences. Participants appeared to project the current state of their relationship into the future, a temporal projection bias. This bias predicted forecasters' pro-relationship motivation and behavior. Forecasters were less likely to exhibit the temporal projection bias when they were high in relationship commitment, and they were more likely to exhibit the bias when they were high in need for cognitive closure, suggesting that motivation can constrain or amplify tendencies to project the present into the future. Implications for interpersonal relationships are discussed. PMID- 26023078 TI - Deregulation of Retinaldehyde Dehydrogenase 2 Leads to Defective Angiogenic Function of Endothelial Colony-Forming Cells in Pediatric Moyamoya Disease. AB - OBJECTIVE--: Moyamoya disease (MMD) is a common cause of childhood stroke, in which the abnormal function of the endothelial colony-forming cell (ECFC) plays a key role in the pathogenesis of the disease. This study was designed to identify genes involved in MMD pathogenesis using gene expression profiling and to understand the defective function of MMD ECFCs. APPROACH AND RESULTS--: We compared gene expression profiles of ECFCs isolated from patients with MMD and normal controls. Among the differentially expressed genes, we selected a gene with the most downregulated expression, retinaldehyde dehydrogenase 2 (RALDH2). The activity of RALDH2 in MMD ECFCs was assessed by in vitro tube formation assay and in vivo Matrigel plug assay in the presence of all-trans retinoic acid. The transcriptional control of RALDH2 was tested using ChIP assays on acetyl-histone H3. In the results, MMD ECFCs inefficiently formed capillary tubes in vitro and capillaries in vivo, a defect restored by all-trans retinoic acid treatment. Knockdown of RALDH2 mRNA in normal ECFCs also induced decreased activity of capillary formation in vitro. The decreased level of RALDH2 mRNA in MMD ECFCs was attributed to defective acetyl-histone H3 binding to the promoter region. CONCLUSIONS--: From these results, we conclude that the expression of RALDH2 was epigenetically suppressed in ECFCs from patients with MMD, which may play a key role in their functional impairment. PMID- 26023079 TI - Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction. AB - OBJECTIVE: Calcific aortic valve disease (CAVD) is a significant cardiovascular disorder, and controversy exists as to whether it is primarily a dystrophic or osteogenic process in vivo. In this study, we sought to clarify the mechanism of CAVD by assessing a genetic mutation, Notch1 heterozygosity, which leads to CAVD with 100% penetrance in humans. APPROACH AND RESULTS: Murine immortalized Notch1(+/-) aortic valve interstitial cells (AVICs) were isolated and expanded in vitro. Molecular signaling of wild-type and Notch1(+/-) AVICs were compared to identify changes in pathways that have been linked to CAVD-transforming growth factor-beta1/bone morphogenetic protein, mitogen-activated protein kinase, and phosphoinositide 3-kinase/protein kinase B-and assessed for calcification potential. Additionally, AVIC mechanobiology was studied in a physiologically relevant, dynamic mechanical environment (10% cyclic strain) to investigate differences in responses between the cell types. We found that Notch1(+/-) AVICs resembled a myofibroblast-like phenotype expressing higher amounts of cadherin 11, a known mediator of dystrophic calcification, and decreased Runx2, a known osteogenic marker. We determined that cadherin-11 expression is regulated by Akt activity, and inhibition of Akt phosphorylation significantly reduced cadherin-11 expression. Moreover, in the presence of cyclic strain, Notch1(+/-) AVICs exhibited significantly upregulated phosphorylation of Akt at Ser473 and smooth muscle alpha-actin expression, indicative of a fully activated myofibroblast. Finally, these Notch1-mediated alterations led to enhanced dystrophic calcific nodule formation. CONCLUSIONS: This study presents novel insights in our understanding of Notch1-mediated CAVD by demonstrating that the mutation leads to AVICs that are fully activated myofibroblasts, resulting in dystrophic, but not osteogenic, calcification. PMID- 26023080 TI - Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9. AB - OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low-density lipoprotein receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk. Although much work is currently focused on developing therapies for inhibiting PCSK9, the endogenous regulation of PCSK9, particularly by insulin, remains unclear. The objective of these studies was to determine the effects of insulin on PCSK9 in vitro and in vivo. APPROACH AND RESULTS: Using rat hepatoma cells and primary rat hepatocytes, we found that insulin increased PCSK9 expression and increased low-density lipoprotein receptor degradation in a PCSK9 dependent manner. In parallel, hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55% to 75% in mice with liver-specific knockout of the insulin receptor; 75% to 88% in mice made insulin-deficient with streptozotocin; and 65% in ob/ob mice treated with antisense oligonucleotides against the insulin receptor. However, antisense oligonucleotide-mediated knockdown of insulin receptor in lean, wild-type mice had little effect. In addition, we found that fasting was able to reduce PCSK9 expression by 80% even in mice that lack hepatic insulin signaling. CONCLUSIONS: Taken together, these data indicate that although insulin induces PCSK9 expression, it is not the sole or even dominant regulator of PCSK9 under all conditions. PMID- 26023081 TI - Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5. AB - OBJECTIVE: Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. APPROACH AND RESULTS: To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. CONCLUSIONS: JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylase-dependent manner. PMID- 26023082 TI - beta-Cryptoxanthin Synergistically Enhances the Antitumoral Activity of Oxaliplatin through DeltaNP73 Negative Regulation in Colon Cancer. AB - BACKGROUND: The acquired resistance to chemotherapy represents the major limitation in the treatment of cancer. New strategies to solve this failure and improve patients' outcomes are necessary. The cancer preventive effect of beta cryptoxanthin has been widely described in population studies. Few reports support its putative use as an antitumoral compound. Here we focus on the therapeutic potential of beta-cryptoxanthin individually or in combination with oxaliplatin in colon cancer and try to decipher the molecular basis underlying its effect. METHODS: Apoptosis, viability and proliferation assays, mouse models, and an intervention study in 20 healthy subjects were performed. A PCR array was carried out to unravel the molecular putative basis of the beta-cryptoxanthin effect, and further signaling experiments were conducted. Comet Assay was completed to evaluate the genotoxicity of the treatments. RESULTS: beta Cryptoxanthin differentially regulates the expression of the P73 variants in vitro, in vivo, and in a human intervention study. This carotenoid decreases the proliferation of cancer cells and cooperates with oxaliplatin to induce apoptosis through the negative regulation of DeltaNP73. The antitumoral concentrations of oxaliplatin decrease in the presence of beta-cryptoxanthin to achieve same percentage of growth inhibition. The genotoxicity in peripheral blood mononuclear cells of mice decreased in the combined treatment. CONCLUSIONS: We propose a putative novel therapeutic strategy for the treatment of colon cancer based on the combination of beta-cryptoxanthin and oxaliplatin. The combined regimen produced more benefit than either individual modality without increasing side effects. In addition, the concentration-limiting toxicity of oxaliplatin is reduced in the presence of the carotenoid. PMID- 26023083 TI - miR-663 Suppresses Oncogenic Function of CXCR4 in Glioblastoma. AB - PURPOSE: To identify the miRNA regulators of C-X-C motif chemokine receptor 4 (CXCR4) and the underlying mechanism as well as the therapeutic and prognostic values in human glioblastoma (GBM). EXPERIMENTAL DESIGN: miRNA profile analyses and bioinformatics predictions were used to identify the mediators of CXCR4, which were confirmed by luciferase reporter assay, Western blot assay and immunohistochemistry. The effects of miR-663 on CXCR4-mediated GBM malignancy were investigated by gain-of-function experiments. Orthotopic xenografts derived from constitutive or induced miR-663-expressing GBM cells were used to determine the antitumor effects of miR-663 and CXCR4-specific antagonist AMD3100. Bivariate correlation analyses were used to examine the correlation of miR-663 and CXCR4 levels in glioma. The prognostic values of miR-663 and CXCR4 were examined in 281 cases of astrocytic glioma from our hospital and 476 cases of GBM from The Cancer Genome Atlas database using the multivariate Cox regression analysis and Kaplan Meier analysis. RESULTS: miR-663 negatively regulated CXCR4 expression by targeting its coding sequence in GBM and compromised the proliferative and invasive capacities of GBM cells induced by CXCR4 overexpression. Constitutive or induced miR-663 overexpression combined with CXCR4 antagonist AMD3100 suppressed orthotopic GBM growth and prolonged tumor-bearing mice survival. Clinically, miR 663 and CXCR4 were inversely correlated in GBM and composed a valuable biomarker set in predicting the outcomes of GBM patients. CONCLUSIONS: miR-663 negatively regulated CXCR4 to inhibit its oncogenic effect. Combination of miR-663 and CXCR4 can serve as a valuable prognostic biomarker set as well as molecular targets for therapeutic intervention of GBM. PMID- 26023084 TI - New DNA Methylation Markers for Pancreatic Cancer: Discovery, Tissue Validation, and Pilot Testing in Pancreatic Juice. AB - PURPOSE: Discriminant markers for pancreatic cancer detection are needed. We sought to identify and validate methylated DNA markers for pancreatic cancer using next-generation sequencing unbiased by known targets. EXPERIMENTAL DESIGN: At a referral center, we conducted four sequential case-control studies: discovery, technical validation, biologic validation, and clinical piloting. Candidate markers were identified using variance-inflated logistic regression on reduced-representation bisulfite DNA sequencing results from matched pancreatic cancers, benign pancreas, and normal colon tissues. Markers were validated technically on replicate discovery study DNA and biologically on independent, matched, blinded tissues by methylation-specific PCR. Clinical testing of six methylation candidates and mutant KRAS was performed on secretin-stimulated pancreatic juice samples from 61 patients with pancreatic cancer, 22 with chronic pancreatitis, and 19 with normal pancreas on endoscopic ultrasound. Areas under receiver-operating characteristics curves (AUC) for markers were calculated. RESULTS: Sequencing identified >500 differentially hyper-methylated regions. On independent tissues, AUC on 19 selected markers ranged between 0.73 and 0.97. Pancreatic juice AUC values for CD1D, KCNK12, CLEC11A, NDRG4, IKZF1, PKRCB, and KRAS were 0.92*, 0.88, 0.85, 0.85, 0.84, 0.83, and 0.75, respectively, for pancreatic cancer compared with normal pancreas and 0.92*, 0.73, 0.76, 0.85*, 0.73, 0.77, and 0.62 for pancreatic cancer compared with chronic pancreatitis (*, P = 0.001 vs. KRAS). CONCLUSIONS: We identified and validated novel DNA methylation markers strongly associated with pancreatic cancer. On pilot testing in pancreatic juice, best markers (especially CD1D) highly discriminated pancreatic cases from controls. PMID- 26023086 TI - Individualized identification of disease-associated pathways with disrupted coordination of gene expression. AB - Current pathway analysis approaches are primarily dedicated to capturing deregulated pathways at the population level and cannot provide patient-specific pathway deregulation information. In this article, the authors present a simple approach, called individPath, to detect pathways with significantly disrupted intra-pathway relative expression orderings for each disease sample compared with the stable, normal intra-pathway relative expression orderings pre-determined in previously accumulated normal samples. Through the analysis of multiple microarray data sets for lung and breast cancer, the authors demonstrate individPath's effectiveness for detecting cancer-associated pathways with disrupted relative expression orderings at the individual level and dissecting the heterogeneity of pathway deregulation among different patients. The portable use of this simple approach in clinical contexts is exemplified by the identification of prognostic intra-pathway gene pair signatures to predict overall survival of resected early-stage lung adenocarcinoma patients and signatures to predict relapse-free survival of estrogen receptor-positive breast cancer patients after tamoxifen treatment. PMID- 26023087 TI - Reform of medical regulation is left off the Queen's speech for a second time. PMID- 26023085 TI - Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents. AB - PURPOSE: We showed previously that in HT29 colon cancer cells, modulation of hypoxia-induced stress signaling affects oxaliplatin cytotoxicity. To further study the significance of hypoxia-induced signaling through JNK, we set out to investigate how modulation of kinase activities influences cellular responses of hypoxic colon cancer cells to cytotoxic drugs. EXPERIMENTAL DESIGN: In a panel of cell lines, we investigated effects of pharmacologic and molecular inhibition of JNK on sensitivity to oxaliplatin, SN-38, and 5-FU. Combination studies for the drugs and JNK inhibitor CC-401 were carried out in vitro and in vivo. RESULTS: Hypoxia-induced JNK activation was associated with resistance to oxaliplatin. CC 401 in combination with chemotherapy demonstrates synergism in colon cancer cell lines, although synergy is not always hypoxia specific. A more detailed analysis focused on HT29 and SW620 (responsive), and HCT116 (nonresponsive) lines. In HT29 and SW620 cells, CC-401 treatment results in greater DNA damage in the sensitive cells. In vivo, potentiation of bevacizumab, oxaliplatin, and the combination by JNK inhibition was confirmed in HT29-derived mouse xenografts, in which tumor growth delay was greater in the presence of CC-401. Finally, stable introduction of a dominant negative JNK1, but not JNK2, construct into HT29 cells rendered them more sensitive to oxaliplatin under hypoxia, suggesting differing input of JNK isoforms in cellular responses to chemotherapy. CONCLUSIONS: These findings demonstrate that signaling through JNK is a determinant of response to therapy in colon cancer models, and support the testing of JNK inhibition to sensitize colon tumors in the clinic. PMID- 26023088 TI - Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles. AB - Axonal transport is critical for maintaining synaptic transmission. Of interest, anterograde and retrograde axonal transport appear to be interdependent, as perturbing one directional motor often impairs movement in the opposite direction. Here live imaging of Drosophila and hippocampal neuron dense-core vesicles (DCVs) containing a neuropeptide or brain-derived neurotrophic factor shows that the F-actin depolymerizing macrolide toxin mycalolide B (MB) rapidly and selectively abolishes retrograde, but not anterograde, transport in the axon and the nerve terminal. Latrunculin A does not mimic MB, demonstrating that F actin depolymerization is not responsible for unidirectional transport inhibition. Given that dynactin initiates retrograde transport and that amino acid sequences implicated in macrolide toxin binding are found in the dynactin component actin-related protein 1, we examined dynactin integrity. Remarkably, cell extract and purified protein experiments show that MB induces disassembly of the dynactin complex. Thus imaging selective retrograde transport inhibition led to the discovery of a small-molecule dynactin disruptor. The rapid unidirectional inhibition by MB suggests that dynactin is absolutely required for retrograde DCV transport but does not directly facilitate ongoing anterograde DCV transport in the axon or nerve terminal. More generally, MB's effects bolster the conclusion that anterograde and retrograde axonal transport are not necessarily interdependent. PMID- 26023089 TI - Cellular context-mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis. AB - The formation of new blood vessels by sprouting angiogenesis is tightly regulated by contextual cues that affect angiogeneic growth factor signaling. Both constitutive activation and loss of Akt kinase activity in endothelial cells impair angiogenesis, suggesting that Akt dynamics mediates contextual microenvironmental regulation. We explored the temporal regulation of Akt in endothelial cells during formation of capillary-like networks induced by cell cell contact with vascular smooth muscle cells (vSMCs) and vSMC-associated VEGF. Expression of constitutively active Akt1 strongly inhibited network formation, whereas hemiphosphorylated Akt1 epi-alleles with reduced kinase activity had an intermediate inhibitory effect. Conversely, inhibition of Akt signaling did not affect endothelial cell migration or morphogenesis in vSMC cocultures that generate capillary-like structures. We found that endothelial Akt activity is transiently blocked by proteasomal degradation in the presence of SMCs during the initial phase of capillary-like structure formation. Suppressed Akt activity corresponded to the increased endothelial MAP kinase signaling that was required for angiogenic endothelial morphogenesis. These results reveal a regulatory principle by which cellular context regulates Akt protein dynamics, which determines MAP kinase signaling thresholds necessary drive a morphogenetic program during angiogenesis. PMID- 26023091 TI - Genomically guided cancer treatments: from "promising" to "clinically useful". PMID- 26023090 TI - Control of the spindle checkpoint by lateral kinetochore attachment and limited Mad1 recruitment. AB - We observed the dynamic recruitment of spindle checkpoint proteins Mad1 and Bub1 to detached kinetochores in budding yeast using real-time live-cell imaging and quantified recruitment in fixed cells. After induced de novo kinetochore assembly at one pair of sister centromeres, Mad1 appeared after the kinetochore protein Mtw1. Detached kinetochores were not associated with the nuclear envelope, so Mad1 does not anchor them to nuclear pore complexes (NPCs). Disrupting Mad1's NPC localization increased Mad1 recruitment to detached sister kinetochores. Conversely, increasing the number of detached kinetochores reduced the amount of Mad1 per detached kinetochore. Bub1 also relocalized completely from the spindle to detached sister centromeres after kinetochore assembly. After their capture by microtubules, Mad1 and Bub1 progressively disappeared from kinetochores. Sister chromatids that arrested with a lateral attachment to one microtubule exhibited half the Mad1 of fully detached sisters. We propose that detached kinetochores compete with alternate binding sites in the nucleus to recruit Mad1 and Bub1 from available pools that are small enough to be fully depleted by just one pair of detached kinetochores and that lateral attachment licenses Mad1 removal from kinetochores after a kinetic delay. PMID- 26023092 TI - Mycobacterium avium complex-associated cholecystitis in AIDS patient: a case description and review of literature. AB - AIDS-related cholangiopathy was common in patients with AIDS prior to the advent of highly active antiretroviral therapy. Mycobacterium avium complex (MAC) is the most common opportunistic bacterial infection seen in AIDS patients and one of many opportunistic pathogens implicated in AIDS cholangiopathy. We describe a case of acute cholecystitis secondary to MAC in a patient with likely AIDS cholangiopathy. The patient, a 37-year-old Hispanic woman with CD4+ cell count of 10 cells/mm3 who was previously diagnosed with disseminated MAC, presented with a eight days of diffuse abdominal pain and anorexia. Radiologic imaging suggested acute cholecystitis, so the patient underwent open cholecystectomy. Pathology staining of the gall bladder wall revealed acid-fast bacilli consistent with MAC. The patient had been receiving appropriate therapy as an outpatient for MAC with presumed reliable adherence, but we suggest her burden of disease was high due to her severe immunosuppressive state. A thorough review of the literature showed that there are many infectious and non-infectious aetiologies for AIDS-associated cholangiopathy. Acute cholecystitis can develop in the setting of AIDS cholangiopathy, potentially secondary to the opportunistic infection that initially caused the cholangiopathy. MAC-related gallbladder disease needs to be considered in patients with advanced AIDS who present with evidence of acute cholecystitis. PMID- 26023093 TI - WHO condemns attacks on healthcare workers in Yemen. PMID- 26023096 TI - Management of the unstable shoulder. PMID- 26023094 TI - The real world effectiveness of hematopoietic transplant among elderly individuals with multiple myeloma. AB - BACKGROUND: Hematopoietic stem cell transplant (HSCT) is the preferred treatment for young patients with multiple myeloma (MM), but for older adults there is limited evidence on its effectiveness from clinical trials. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify individuals age 66 years and older with multiple myeloma (MM) who were diagnosed between 2000 and 2007. We used traditional multivariable analysis, propensity score-based analysis, coarsened exact matching, and an instrumental variable analysis to compare survival for individuals who did or did not receive an hematopoietic stem cell transplant. Survival was measured by Cox proportional hazard models. All statistical tests were two-sided. RESULTS: Patients with MM receiving an HSCT were more likely to be white, married, younger, and have fewer comorbidities. Results from all analytic techniques consistently showed that HSCT statistically significantly improved survival, with hazard ratios (HRs) ranging from 0.531 to 0.608 (traditional multivariable analysis: HR = 0.582, 95% confidence interval [CI] = 0.49 to 0.69; propensity score analysis: HR = 0.572, 95% CI = 0.46 to 0.72; coarsened exact matching: HR = 0.608, 95% CI = 0.49 to 0.76; instrumental variable analysis: HR = 0.531, 95% CI = 0.36 to 0.78, all P values <= .001). CONCLUSIONS: Overall survival has increased among patients with MM receiving HSCT. This finding was consistent across statistical methods, indicating robustness of our findings. PMID- 26023095 TI - The feasibility, acceptability, and preliminary effectiveness of a Promotora-Led Diabetes Prevention Program (PL-DPP) in Latinas: a pilot study. AB - PURPOSE: The purpose of this pilot study is to test the feasibility, acceptability, and preliminary effectiveness of a Promotora-Led Diabetes Prevention Program (PL-DPP) in Hispanic women (Latinas). METHODS: Twenty Latina adults with prediabetes were enrolled in this single-arm pilot trial of PL-DPP. Participants underwent a year-long lifestyle intervention consisting of 24 sessions divided into 14 weekly core sessions and 10 post-core sessions offered either biweekly or monthly. Each session was led by a promotora in Spanish. The primary outcome was weight change over the 12-month study period. RESULTS: The study participants were socioeconomically challenged, middle-aged Latinas with limited access to health care. Eighteen participants (90%) completed at least 12 sessions, and 1 was lost to follow-up. Overall, participants reported high levels of satisfaction with PL-DPP. At 12 months, the participants achieved a mean weight loss of 10.8 pounds, which corresponded to 5.6% of initial body weight. Significant pre-post reductions in waist circumference, diastolic blood pressure, LDL cholesterol, and insulin levels were also observed. Modest reductions in A1C and fasting plasma glucose were not significant. CONCLUSIONS: The PL-DPP demonstrated feasibility, acceptability, and preliminary effectiveness in a high risk population of Latinas. Future research examining this intervention in a randomized clinical trial should explore factors impacting its effects using both qualitative and quantitative methods. PMID- 26023098 TI - Interspecific in vitro assay for the chimera-forming ability of human pluripotent stem cells. AB - Functional assay limitations are an emerging issue in characterizing human pluripotent stem cells (PSCs). With rodent PSCs, chimera formation using pre implantation embryos is the gold-standard assay of pluripotency (competence of progeny to differentiate into all three germ layers). In human PSCs (hPSCs), however, this can only be monitored via teratoma formation or in vitro differentiation, as ethical concerns preclude generation of human-human or human animal chimeras. To circumvent this issue, we developed a functional assay utilizing interspecific blastocyst injection and in vitro culture (interspecies in vitro chimera assay) that enables the development and observation of embryos up to headfold stage. The assay uses mouse pre-implantation embryos and rat, monkey and human PSCs to create interspecies chimeras cultured in vitro to the early egg-cylinder stage. Intra- and interspecific chimera assays with rodent PSC lines were performed to confirm the consistency of results in vitro and in vivo. The behavior of chimeras developed in vitro appeared to recapitulate that of chimeras developed in vivo; that is, PSC-derived cells survived and were integrated into the epiblast of egg-cylinder-stage embryos. This indicates that the interspecific in vitro chimera assay is useful in evaluating the chimera forming ability of rodent PSCs. However, when human induced PSCs (both conventional and naive-like types) were injected into mouse embryos and cultured, some human cells survived but were segregated; unlike epiblast-stage rodent PSCs, they never integrated into the epiblast of egg-cylinder-stage embryos. These data suggest that the mouse-human interspecies in vitro chimera assay does not accurately reflect the early developmental potential/process of hPSCs. The use of evolutionarily more closely related species as host embryos might be necessary to evaluate the developmental potency of hPSCs. PMID- 26023097 TI - Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis. AB - Hair follicle morphogenesis requires precisely controlled reciprocal communications, including hedgehog (Hh) signaling. Activation of the Hh signaling pathway relies on the primary cilium. Disrupting ciliogenesis results in hair follicle morphogenesis defects due to attenuated Hh signaling; however, the loss of cilia makes it impossible to determine whether hair follicle phenotypes in these cilia mutants are caused by the loss of cilia, disruption of Hh signaling, or a combination of these events. In this study, we characterized the function of Ift27, which encodes a subunit of intraflagellar transport (IFT) complex B. Hair follicle morphogenesis of Ift27-null mice was severely impaired, reminiscent of phenotypes observed in cilia and Hh mutants. Furthermore, the Hh signaling pathway was attenuated in Ift27 mutants, which was in association with abnormal ciliary trafficking of SMO and GLI2, and impaired processing of Gli transcription factors; however, formation of the ciliary axoneme was unaffected. The ciliary localization of IFT25 (HSPB11), the binding partner of IFT27, was disrupted in Ift27 mutant cells, and Ift25-null mice displayed hair follicle phenotypes similar to those of Ift27 mutants. These data suggest that Ift27 and Ift25 operate in a genetically and functionally dependent manner during hair follicle morphogenesis. This study suggests that the molecular trafficking machineries underlying ciliogenesis and Hh signaling can be segregated, thereby providing important insights into new avenues of inhibiting Hh signaling, which might be adopted in the development of targeted therapies for Hh-dependent cancers, such as basal cell carcinoma. PMID- 26023101 TI - Extent of surgical resection of high-grade glioma among the elderly. PMID- 26023102 TI - Corrigendum. PMID- 26023099 TI - Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium. AB - The DNA methyltransferase Dnmt1 maintains DNA methylation patterns and genomic stability in several in vitro cell systems. Ablation of Dnmt1 in mouse embryos causes death at the post-gastrulation stage; however, the functions of Dnmt1 and DNA methylation in organogenesis remain unclear. Here, we report that Dnmt1 is crucial during perinatal intestinal development. Loss of Dnmt1 in intervillus progenitor cells causes global hypomethylation, DNA damage, premature differentiation, apoptosis and, consequently, loss of nascent villi. We further confirm the crucial role of Dnmt1 during crypt development using the in vitro organoid culture system, and illustrate a clear differential requirement for Dnmt1 in immature versus mature organoids. These results demonstrate an essential role for Dnmt1 in maintaining genomic stability during intestinal development and the establishment of intestinal crypts. PMID- 26023104 TI - xHeinz: an algorithm for mining cross-species network modules under a flexible conservation model. AB - MOTIVATION: Integrative network analysis methods provide robust interpretations of differential high-throughput molecular profile measurements. They are often used in a biomedical context-to generate novel hypotheses about the underlying cellular processes or to derive biomarkers for classification and subtyping. The underlying molecular profiles are frequently measured and validated on animal or cellular models. Therefore the results are not immediately transferable to human. In particular, this is also the case in a study of the recently discovered interleukin-17 producing helper T cells (Th17), which are fundamental for anti microbial immunity but also known to contribute to autoimmune diseases. RESULTS: We propose a mathematical model for finding active subnetwork modules that are conserved between two species. These are sets of genes, one for each species, which (i) induce a connected subnetwork in a species-specific interaction network, (ii) show overall differential behavior and (iii) contain a large number of orthologous genes. We propose a flexible notion of conservation, which turns out to be crucial for the quality of the resulting modules in terms of biological interpretability. We propose an algorithm that finds provably optimal or near optimal conserved active modules in our model. We apply our algorithm to understand the mechanisms underlying Th17 T cell differentiation in both mouse and human. As a main biological result, we find that the key regulation of Th17 differentiation is conserved between human and mouse. AVAILABILITY AND IMPLEMENTATION: xHeinz, an implementation of our algorithm, as well as all input data and results, are available at http://software.cwi.nl/xheinz and as a Galaxy service at http://services.cbib.u-bordeaux2.fr/galaxy in CBiB Tools. CONTACT: gunnar.klau@cwi.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26023105 TI - antaRNA: ant colony-based RNA sequence design. AB - MOTIVATION: RNA sequence design is studied at least as long as the classical folding problem. Although for the latter the functional fold of an RNA molecule is to be found ,: inverse folding tries to identify RNA sequences that fold into a function-specific target structure. In combination with RNA-based biotechnology and synthetic biology ,: reliable RNA sequence design becomes a crucial step to generate novel biochemical components. RESULTS: In this article ,: the computational tool antaRNA is presented. It is capable of compiling RNA sequences for a given structure that comply in addition with an adjustable full range objective GC-content distribution ,: specific sequence constraints and additional fuzzy structure constraints. antaRNA applies ant colony optimization meta heuristics and its superior performance is shown on a biological datasets. AVAILABILITY AND IMPLEMENTATION: http://www.bioinf.uni freiburg.de/Software/antaRNA CONTACT: backofen@informatik.uni-freiburg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26023107 TI - Employees are ambivalent about health checks in the occupational setting. AB - BACKGROUND: Employees are increasingly provided with preventive health checks. However, participation rates are low and several ethical issues arise, such as a potential perceived threat to autonomy and privacy. AIMS: To assess what employees think about preventive health checks in the occupational setting. METHODS: Samples of construction workers and the general working population in the Netherlands completed a survey about preventive health checks in the occupational setting. We asked half of each sample about potential benefits and drawbacks of health checks, and the other half about how they should be offered. We employed explorative factor analysis to identify constructs related to perceived benefits and drawbacks, and the way health checks should be provided. We then conducted descriptive analyses and t-tests to compare subgroups of respondents. RESULTS: A total of 482 (27%) of construction workers and 738 (65%) employees from the general population responded. The overall survey response rate was 42% with 41% completing the first questionnaire and 42% the second. We identified three constructs related to perceived benefits and drawbacks: self control over health, disturbance and negative emotion and lack of autonomy. Participants rated 'self-control over health' as the highest potential benefit (mean = 3.40; SD = 0.69), and 'your employer interfering in your personal life' as the most important potential drawback (mean = 3.27; SD = 1.00). Participants indicated that they would like to receive help from their occupational physician when an increased health risk is identified (mean = 4.02; SD = 0.69). CONCLUSIONS: Employees are ambivalent and hesitant concerning preventive health checks in the occupational setting. PMID- 26023106 TI - GPR43 Potentiates beta-Cell Function in Obesity. AB - The intestinal microbiome can regulate host energy homeostasis and the development of metabolic disease. Here we identify GPR43, a receptor for bacterially produced short-chain fatty acids (SCFAs), as a modulator of microbiota-host interaction. beta-Cell expression of GPR43 and serum levels of acetate, an endogenous SCFA, are increased with a high-fat diet (HFD). HFD-fed GPR43 knockout (KO) mice develop glucose intolerance due to a defect in insulin secretion. In vitro treatment of isolated murine islets, human islets, and Min6 cells with (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide (PA), a specific agonist of GPR43, increased intracellular inositol triphosphate and Ca(2+) levels, and potentiated insulin secretion in a GPR43-, Galphaq-, and phospholipase C-dependent manner. In addition, KO mice fed an HFD displayed reduced beta-cell mass and expression of differentiation genes, and the treatment of Min6 cells with PA increased beta-cell proliferation and gene expression. Together these findings identify GPR43 as a potential target for therapeutic intervention. PMID- 26023109 TI - Watchdogs of the European system. PMID- 26023108 TI - Cucumis sativus L. WAX2 Plays a Pivotal Role in Wax Biosynthesis, Influencing Pollen Fertility and Plant Biotic and Abiotic Stress Responses. AB - Cuticular waxes play an important part in protecting plant aerial organs from biotic and abiotic stresses. In previous studies, the biosynthetic pathway of cuticular waxes and relative functional genes has been researched and understood; however, little is known in cucumber (Cucumis sativus L.). In this study, we cloned and characterized an AtWAX2 homolog, CsWAX2, in cucumber and found that it is highly expressed in the epidermis, where waxes are synthesized, while subcellular localization showed that CsWAX2 protein is localized to the endoplasmic reticulum (ER). The transcriptional expression of CsWAX2 was found to be induced by low temperature, drought, salt stress and ABA, while the ectopic expression of CsWAX2 in an Arabidopsis wax2 mutant could partially complement the glossy stem phenotype. Abnormal expression of CsWAX2 in transgenic cucumbers specifically affected both very long chain (VLC) alkanes and cutin biosynthesis. Furthermore, transgenic cucumber plants of CsWAX2 showed significant changes in pollen viability and fruit resistance to water loss and pathogens compared with the wild type. Collectively, these results indicated that CsWAX2 plays a pivotal role in wax biosynthesis, influencing pollen fertility and the plant's response to biotic and abiotic stresses. PMID- 26023111 TI - Natural resources. Brazil cuts red tape stifling biodiversity studies. PMID- 26023112 TI - Agricultural research. Reading the tea leaves for effects of climate change. PMID- 26023113 TI - The endangered palates list. PMID- 26023114 TI - Regenerative medicine. Report finds misconduct by surgeon. PMID- 26023115 TI - Science policy. Debate sharpens over proposed criteria for NSF grants. PMID- 26023116 TI - Is measles next? PMID- 26023117 TI - In Vietnam, an anatomy of a measles outbreak. PMID- 26023118 TI - Science and regulation. Congress's attacks on science-based rules. PMID- 26023119 TI - Cell biology. Blocking stress response for better memory? PMID- 26023120 TI - Shape-memory alloys. Taming the temperamental metal transformation. PMID- 26023121 TI - Structural biology. A close view of photosystem I. PMID- 26023122 TI - Neuroscience. Exploiting sleep to modify bad attitudes. PMID- 26023123 TI - Applied physics. Obtaining optical properties on demand. PMID- 26023124 TI - Infectious diseases. Overcoming neglect of kinetoplastid diseases. PMID- 26023125 TI - Immunology. Expanding the role of metabolism in T cells. PMID- 26023126 TI - Microbiology. Flexible gene pools. PMID- 26023127 TI - Time for a data revolution in China. PMID- 26023128 TI - Qualifying pollinator decline evidence. PMID- 26023129 TI - Qualifying pollinator decline evidence-response. PMID- 26023130 TI - Comment on "Evidence for mesothermy in dinosaurs". AB - Grady et al. (Reports, 13 June 2014, p. 1268) suggested that nonavian dinosaur metabolism was neither endothermic nor ectothermic but an intermediate physiology termed "mesothermic." However, rates were improperly scaled and phylogenetic, physiological, and temporal categories of animals were conflated during analyses. Accounting for these issues suggests that nonavian dinosaurs were on average as endothermic as extant placental mammals. PMID- 26023131 TI - Comment on "Evidence for mesothermy in dinosaurs". AB - Grady et al. (Reports, 13 June 2014, p. 1268) studied dinosaur metabolism by comparison of maximum somatic growth rate allometry with groups of known metabolism. They concluded that dinosaurs exhibited mesothermy, a metabolic rate intermediate between endothermy and ectothermy. Multiple statistical and methodological issues call into question the evidence for dinosaur mesothermy. PMID- 26023132 TI - Response to Comments on "Evidence for mesothermy in dinosaurs". AB - D'Emic and Myhrvold raise a number of statistical and methodological issues with our recent analysis of dinosaur growth and energetics. However, their critiques and suggested improvements lack biological and statistical justification. PMID- 26023133 TI - Photosynthesis. Structural basis for energy transfer pathways in the plant PSI LHCI supercomplex. AB - Photosynthesis converts solar energy to chemical energy by means of two large pigment-protein complexes: photosystem I (PSI) and photosystem II (PSII). In higher plants, the PSI core is surrounded by a large light-harvesting complex I (LHCI) that captures sunlight and transfers the excitation energy to the core with extremely high efficiency. We report the structure of PSI-LHCI, a 600 kilodalton membrane protein supercomplex, from Pisum sativum (pea) at a resolution of 2.8 angstroms. The structure reveals the detailed arrangement of pigments and other cofactors-especially within LHCI-as well as numerous specific interactions between the PSI core and LHCI. These results provide a firm structural basis for our understanding on the energy transfer and photoprotection mechanisms within the PSI-LHCI supercomplex. PMID- 26023134 TI - Inorganic chemistry. Synthesis and characterization of P2N3-: an aromatic ion composed of phosphorus and nitrogen. AB - Aromaticity is predominantly associated with carbon-rich compounds but can also occur in all-inorganic ones. We report the synthesis of the diphosphatriazolate anion, a rare example of a planar aromatic inorganic species. Treatment of azide (N3(-)) in tetrahydrofuran solution with P2A2 (A = C14H10), a source of P2, produced P2N3(-), which we isolated as its [Na-kryptofix-221](+) salt in 22% yield and characterized by single-crystal x-ray diffraction. Salts [Na-kryptofix 221] [P2N3] and [Na-kryptofix-221] [P2(15)NN2] were analyzed by infrared and Raman spectroscopy, (15)N and (31)P nuclear magnetic resonance spectroscopy, and mass spectrometry. The formation of the P2N3(-) anion was investigated using density functional theory, and its aromatic character was confirmed by NICS (nucleus-independent chemical shift) and QTAIM (quantum theory of atoms in molecules) methods. PMID- 26023135 TI - Shape memory alloys. Ultralow-fatigue shape memory alloy films. AB - Functional shape memory alloys need to operate reversibly and repeatedly. Quantitative measures of reversibility include the relative volume change of the participating phases and compatibility matrices for twinning. But no similar argument is known for repeatability. This is especially crucial for many future applications, such as artificial heart valves or elastocaloric cooling, in which more than 10 million transformation cycles will be required. We report on the discovery of an ultralow-fatigue shape memory alloy film system based on TiNiCu that allows at least 10 million transformation cycles. We found that these films contain Ti2Cu precipitates embedded in the base alloy that serve as sentinels to ensure complete and reproducible transformation in the course of each memory cycle. PMID- 26023136 TI - Memory. Engram cells retain memory under retrograde amnesia. AB - Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor-induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process. PMID- 26023138 TI - Paleoclimate. Enhanced tropical methane production in response to iceberg discharge in the North Atlantic. AB - The causal mechanisms responsible for the abrupt climate changes of the Last Glacial Period remain unclear. One major difficulty is dating ice-rafted debris deposits associated with Heinrich events: Extensive iceberg influxes into the North Atlantic Ocean linked to global impacts on climate and biogeochemistry. In a new ice core record of atmospheric methane with ultrahigh temporal resolution, we find abrupt methane increases within Heinrich stadials 1, 2, 4, and 5 that, uniquely, have no counterparts in Greenland temperature proxies. Using a heuristic model of tropical rainfall distribution, we propose that Hudson Strait Heinrich events caused rainfall intensification over Southern Hemisphere land areas, thereby producing excess methane in tropical wetlands. Our findings suggest that the climatic impacts of Heinrich events persisted for 740 to 1520 years. PMID- 26023137 TI - Cognitive neuroscience. Unlearning implicit social biases during sleep. AB - Although people may endorse egalitarianism and tolerance, social biases can remain operative and drive harmful actions in an unconscious manner. Here, we investigated training to reduce implicit racial and gender bias. Forty participants processed counterstereotype information paired with one sound for each type of bias. Biases were reduced immediately after training. During subsequent slow-wave sleep, one sound was unobtrusively presented to each participant, repeatedly, to reactivate one type of training. Corresponding bias reductions were fortified in comparison with the social bias not externally reactivated during sleep. This advantage remained 1 week later, the magnitude of which was associated with time in slow-wave and rapid-eye-movement sleep after training. We conclude that memory reactivation during sleep enhances counterstereotype training and that maintaining a bias reduction is sleep dependent. PMID- 26023139 TI - Microbial diversity. Fine-scale diversity and extensive recombination in a quasisexual bacterial population occupying a broad niche. AB - Extensive fine-scale genetic diversity is found in many microbial species across varied environments, but for most, the evolutionary scenarios that generate the observed variation remain unclear. Deep sequencing of a thermophilic cyanobacterial population and analysis of the statistics of synonymous single nucleotide polymorphisms revealed a high rate of homologous recombination and departures from neutral drift consistent with the effects of genetic hitchhiking. A sequenced isolate genome resembled an unlinked random mixture of the allelic diversity at the sampled loci. These observations suggested a quasisexual microbial population that occupies a broad ecological niche, with selection driving frequencies of alleles rather than whole genomes. PMID- 26023141 TI - All in the family. PMID- 26023140 TI - Cell adhesion. Mechanical strain induces E-cadherin-dependent Yap1 and beta catenin activation to drive cell cycle entry. AB - Mechanical strain regulates the development, organization, and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. Here, we showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then beta-catenin. Inhibition of Yap1- and beta catenin-mediated transcription blocked cell cycle reentry and progression through G1 into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion, and beta-catenin transcriptional responses to mechanical strain required E cadherin extracellular engagement. Thus, activation of Yap1 and beta-catenin may represent a master regulator of mechanical strain-induced cell proliferation, and cadherins provide signaling centers required for cellular responses to externally applied force. PMID- 26023142 TI - Porous materials. Function-led design of new porous materials. AB - Porous solids are important as membranes, adsorbents, catalysts, and in other chemical applications. But for these materials to find greater use at an industrial scale, it is necessary to optimize multiple functions in addition to pore structure and surface area, such as stability, sorption kinetics, processability, mechanical properties, and thermal properties. Several different classes of porous solids exist, and there is no one-size-fits-all solution; it can therefore be challenging to choose the right type of porous material for a given job. Computational prediction of structure and properties has growing potential to complement experiment to identify the best porous materials for specific applications. PMID- 26023143 TI - Microbial Flora and Antibiotic Resistance in Peritonsillar Abscesses in Upstate New York. AB - OBJECTIVES: To identify the common bacteria in recent peritonsillar abscesses and the prevalence of antibiotic resistance and compare both between adults and children. METHODS: This is a retrospective chart review at a single academic institution of patients who underwent either incision and drainage or tonsillectomy for a peritonsillar abscess between 2002 and 2012 (n=69). Medical records were reviewed for cultures, comorbidities, and drainage procedures. RESULTS: Cultures obtained from 62.32% of peritonsillar abscesses were polymicrobial, and 34.78% were monomicrobial. The most common pathogens were beta hemolytic Streptococcus (31.88%), alpha-hemolytic Streptococcus (21.74%), Neisseria (14.49%), and Streptococcus milleri (13.04%). Group A beta-hemolytic streptococcus was more common in children and Streptococcus milleri was more common in adults. Alpha-hemolytic streptococcus was resistant to clindamycin (6.67%) and erythromycin (6.67%). Streptococcus milleri was resistant to clindamycin (11.11%) and erythromycin (11.11%). Staphylococcus was resistant to penicillin (37.5%), oxacillin (25%), erythromycin (25%), and clindamycin (12.5%). CONCLUSIONS: beta- and alpha-hemolytic Streptococci, Neisseria, and Streptococcus milleri are the most common pathogens. Streptococcus milleri is more common in adults, and beta-hemolytic streptococcus is more common in children. Resistance to clindamycin and erythromycin is common in Streptococci and Staphylococci, and penicillin resistance is common in Staphylococci. PMID- 26023145 TI - Novel delivery systems for improving the clinical use of peptides. AB - Peptides have long been recognized as a promising group of therapeutic substances to treat various diseases. Delivery systems for peptides have been under development since the discovery of insulin for the treatment of diabetes. The challenge of using peptides as drugs arises from their poor bioavailability resulting from the low permeability of biological membranes and their instability. Currently, subcutaneous injection is clinically the most common administration route for peptides. This route is cost-effective and suitable for self-administration, and the development of appropriate dosing equipment has made performing the repeated injections relatively easy; however, only few clinical subcutaneous peptide delivery systems provide sustained peptide release. As a result, frequent injections are needed, which may cause discomfort and additional risks resulting from a poor administration technique. Controlled peptide delivery systems, able to provide required therapeutic plasma concentrations over an extended period, are needed to increase peptide safety and patient compliancy. In this review, we summarize the current peptidergic drugs, future developments, and parenteral peptide delivery systems. Special emphasis is given to porous silicon, a novel material in peptide delivery. Biodegradable and biocompatible porous silicon possesses some unique properties, such as the ability to carry exceptional high peptide payloads and to modify peptide release extensively. We have successfully developed porous silicon as a carrier material for improved parenteral peptide delivery. Nanotechnology, with its different delivery systems, will enable better use of peptides in several therapeutic applications in the near future. PMID- 26023146 TI - Acute haemorrhagic diarrhoea syndrome in dogs: 108 cases. AB - No prospective studies including large numbers of dogs with acute haemorrhagic diarrhoea syndrome (AHDS) are published so far. The aim of this case-control study was to describe signalment, history, clinical signs, laboratory values and course of disease in dogs with AHDS. Dogs (108) with idiopathic acute haemorrhagic diarrhoea (<3 days) were prospectively enrolled. Clinical assessment was performed by calculation of the 'AHDS index' (0-18). The hospital population and 21 healthy dogs served as control groups. Dogs with AHDS had a significantly lower body weight (median 9.8 kg) and age (median five years) than other dogs of the hospital population (20 kg; 10 years) (P<0.001). Predisposed breeds were Yorkshire terrier, miniature pinscher, miniature schnauzer and Maltese. The syndrome was more likely to occur during winter. Vomiting preceded the onset of bloody diarrhoea in 80 per cent of dogs and haematemesis was observed in half of those cases. Median AHDS index at presentation was 12 (range 3-17). Haematocrit was generally high (median 57.1 per cent; range 33-76 per cent), but exceeded 60 per cent only in 31.4 per cent of dogs. Haematocrit of 48.1 per cent of dogs was above reference range, as was monocyte (50.0 per cent), segmented (59.6 per cent) and band neutrophil count (45.2 per cent). A rapid clinical improvement occurred during the first 48 hours. PMID- 26023147 TI - On Jeffrey Lieberman's Shrinks. PMID- 26023148 TI - Leon Hoffman on Lieberman's Shrinks. PMID- 26023149 TI - Viroporins: structure, function and potential as antiviral targets. AB - The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health. PMID- 26023150 TI - Genome sequence and comparative virulence of raccoonpox virus: the first North American poxvirus sequence. AB - We report here the complete genome sequence of raccoonpox virus (RCNV), a naturally occurring North American poxvirus. This is the first such North American sequence to the best of our knowledge, and the data showed that RCNV forms a new phylogenetic branch between orthopoxviruses and Yoka poxvirus. RCNV shared overall similarity in genome organization with orthopoxviruses, and the proteins in the central conserved region shared approximately 90 % amino acid identity with orthopoxviruses. RCNV proteins shared approximately 81 % amino acid identity with Yokapox virus proteins. RCNV is missing 10 genes normally conserved in orthopoxviruses, most of which are implicated in virulence. These gene deletions may explain the attenuated phenotype of RCNV in mammals. RCNV contained one unique genome region containing approximately 1 kb of DNA sequence that is not present in any reported poxvirus. It contained a unique ORF predicted to encode a protein with a transmembrane domain. RCNV replicates well in mammalian cells, is naturally attenuated and has been shown to be effective as a vaccine vector platform, so we further tested its safety. We showed here that RCNV is substantially more attenuated than even the highly attenuated VACV-A35Del mutant virus in pregnant, nude and severe combined immunodeficient (SCID) mouse models. RCNV was much safer in pregnant mice and was cleared rapidly from tissues, even in immunocompromised animals, whereas the VACV-A35Del mutant retains virulence and persists in tissues. Thus, RCNV is expected to be a superior vaccine vector for infectious diseases and cancer due to its excellent safety profile, reported vaccine efficacy and ability to replicate in mammalian cells. PMID- 26023151 TI - How Can We Identify the Elimination of Infectious Diseases? Experience From an Active Measles Laboratory Surveillance System in the Republic of Korea. AB - Global efforts have markedly decreased the disease burden of vaccine-preventable diseases. Many countries have made considerable progress toward the elimination of measles. As elimination is approached, the very low incidence achieved by high vaccination coverage has underscored the need for a sensitive and timely surveillance system. In the Republic of Korea, an active laboratory surveillance system (ALSS) was implemented to supplement the existing passive surveillance system in 2006. The ALSS connects 5 major commercial laboratories and the national measles reference laboratory, where referred samples with positive or equivocal results are retested. Annually, from 2009 to 2013, 3714 suspected cases were detected through the ALSS, an expansion of 8- to 57-fold, compared with only the passive surveillance system. The ALSS, with its sensitivity and timeliness, is a reasonable strategy to supplement the existing measles surveillance system and to help identify the elimination of measles. PMID- 26023152 TI - Accuracy and Use of WHO Hemoglobin Color Scale for Diagnosis of Anemia Among Pregnant Women by Health Care Providers in Periurban Settings in Karachi, Pakistan. AB - The study assessed the diagnostic accuracy of the Hemoglobin Color Scale (HCS), comparing clinical signs assessment technique (CSAT) of health care providers against the gold standard of laboratory hemoglobinometry. A cross-sectional validation study was conducted among 194 pregnant women located in 2 towns of periurban settings in Karachi, from June 2012 to February 2013. Anemia was assessed by HCS and CSAT by health care providers and compared with laboratory hemoglobinometry. The sensitivity and specificity of HCS were 70.9% (95% CI = 62.7-78.3) and 49.1% (95% CI = 35.1-63.2); for CSAT they were 95.7% (95% CI = 91.0-98.4) and 5.7% (95% CI = 1.2-15.7), respectively. The area under the curve for HCS for diagnosis of anemia was 0.60 (95% CI = 0.52-0.66), compared with 0.50 (95% CI = 0.43-0.57) for CSAT (P = .01). The accuracy of HCS is better than CSAT for assessing anemia by health care providers among pregnant women. PMID- 26023153 TI - Effect of machined profile, zinc oxide and titanium dioxide particles on checking southern pine deck boards during weathering. AB - The aim of this research was to test the hypothesis that the combination of profiling, treatment and a surface coating with nanoparticles will be effective at reducing checking in deck boards exposed to the weather. In this study southern pine (Pinus sp.) deck boards were machined to flat (control) and ribbed surface profiles. The specimens were treated with aqueous copper amine azole (CA C) using a vacuum/pressure method and coated with nano-ZnO and micronised TiO2. Boards were exposed to accelerated weathering for 576 h. The number, length and width of checks that developed in the boards were quantified and the average amounts of cupping, twist and bowing occurring in the weathered wood were examined. The results of the statistical analysis showed that all of the coated ribbed decking samples had lower average check numbers, lengths and widths compared to the end-matched flat untreated specimens. Checks were also shorter and narrower in the profiled southern pine deck board than in the unprofiled specimens. Furthermore, the lowest amount of cupping, twist and bowing were observed for specimens profiled and coated with the TiO2. Therefore, the authors conclude that the coated ribbed decks looked significantly better than the flat decking. PMID- 26023154 TI - Comparative analysis of biosynthesised and chemosynthesised silver nanoparticles with special reference to their antibacterial activity against pathogens. AB - The present study reports the synthesis of silver nanoparticles (AgNPs) using both biological and chemical routes to find out the best method for control of their size and activity. The fungal agent (Fusarium oxysporum) and the plant (Azadirachta indica) were found to be the best source for AgNPs synthesis. Both biosynthesis and chemosynthesis were achieved by challenging filtrate with AgNO3 (1 mM) solution. The synthesised nanoparticles were characterised by ultraviolet visible spectroscopy, Fourier transform infrared spectroscopy, nanoparticle tracking analysis (LM20), zeta potential measurement and transmission electron microscopy. The biologically synthesised nanoparticles were spherical, polydispersed and in the range of 10-40 nm, while chemically synthesised nanoparticles were highly monodispersed with a size of 5 nm. The antimicrobial assay against Escherichia coli and Staphylococcus aureus proved biogenic AgNPs to be more potent antibacterial agents than chemically synthesised AgNPs. The possible antibacterial mechanism of AgNPs has also been discussed. Biogenic AgNPs have shown more activity because of the protein capping and their mode of entry into the bacterial cell. These findings may encourage the use of biosynthesis over the chemosynthesis method. PMID- 26023144 TI - International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators. AB - Estrogens are critical mediators of multiple and diverse physiologic effects throughout the body in both sexes, including the reproductive, cardiovascular, endocrine, nervous, and immune systems. As such, alterations in estrogen function play important roles in many diseases and pathophysiological conditions (including cancer), exemplified by the lower prevalence of many diseases in premenopausal women. Estrogens mediate their effects through multiple cellular receptors, including the nuclear receptor family (ERalpha and ERbeta) and the G protein-coupled receptor (GPCR) family (GPR30/G protein-coupled estrogen receptor [GPER]). Although both receptor families can initiate rapid cell signaling and transcriptional regulation, the nuclear receptors are traditionally associated with regulating gene expression, whereas GPCRs are recognized as mediating rapid cellular signaling. Estrogen-activated pathways are not only the target of multiple therapeutic agents (e.g., tamoxifen, fulvestrant, raloxifene, and aromatase inhibitors) but are also affected by a plethora of phyto- and xeno estrogens (e.g., genistein, coumestrol, bisphenol A, dichlorodiphenyltrichloroethane). Because of the existence of multiple estrogen receptors with overlapping ligand specificities, expression patterns, and signaling pathways, the roles of the individual receptors with respect to the diverse array of endogenous and exogenous ligands have been challenging to ascertain. The identification of GPER-selective ligands however has led to a much greater understanding of the roles of this receptor in normal physiology and disease as well as its interactions with the classic estrogen receptors ERalpha and ERbeta and their signaling pathways. In this review, we describe the history and characterization of GPER over the past 15 years focusing on the pharmacology of steroidal and nonsteroidal compounds that have been employed to unravel the biology of this most recently recognized estrogen receptor. PMID- 26023155 TI - Component analyses of urinary nanocrystallites of uric acid stone formers by combination of high-resolution transmission electron microscopy, fast Fourier transformation, energy dispersive X-ray spectroscopy, X-ray diffraction and Fourier transform infrared spectroscopy. AB - This study aimed to analyse the components of nanocrystallites in urines of patients with uric acid (UA) stones. X-ray diffraction (XRD), Fourier transform infrared spectroscopy, high-resolution transmission electron microscopy (HRTEM), fast Fourier transformation (FFT) of HRTEM, and energy dispersive X-ray spectroscopy (EDS) were performed to analyse the components of these nanocrystallites. XRD and FFT showed that the main component of urinary nanocrystallites was UA, which contains a small amount of calcium oxalate monohydrate and phosphates. EDS showed the characteristic absorption peaks of C, O, Ca and P. The formation of UA stones was closely related to a large number of UA nanocrystallites in urine. A combination of HRTEM, FFT, EDS and XRD analyses could be performed accurately to analyse the components of urinary nanocrystallites. PMID- 26023156 TI - Self-assembly: a review of scope and applications. AB - Self-assembly (SA) is the preferred growth mechanism in the natural world, on scales ranging from the molecular to the macro-scale. It involves the assembling of components, which governed by a set of local interaction rules, lead to the formation of a global minimum energy structure. In this survey, the authors explore the extensive research conducted to exploit SA in three domains; first, as a bottom-up approach to fabricate semiconductor heterostructures and nano scale devices composed of carbon nanotubes and nanowires; second, for meso-scale assembly to build systems such as three-dimensional electrical networks and microelectromechanical systems by utilising capillary force, external magnetic field and so on as the binding force; and third, as an emerging means to achieve computing via tiling, biomolecular automata and logic gates. DNA, in particular, has been a molecule of choice because of its easy availability, biological importance and high programmability as a result of its highly specific component bases. PMID- 26023157 TI - Uptake and clearance analysis of Technetium99m labelled iron oxide nanoparticles in a rabbit brain. AB - Nanoparticles as solid colloidal particles are extensively studied and used as anticancer drug delivery agents because of their physical properties. This current research aims to prepare water base suspension of uncoated iron oxide nanoparticles and their biodistribution study to different organs, especially the brain, by using a single photon emission computed tomography gamma camera. The water-based suspension of iron oxide nanoparticles was synthesised by a reformed version of the co-precipitation method and labelled with Tc99m for intravenous injection. The nanoparticles were injected without surface modification. X-ray diffraction (XRD), energy dispersive spectrometry (EDS) and transmission electron microscope (TEM) techniques were used for characterisation. Peaks of XRD and EDS indicate that the particles are magnetite and exist in aqueous suspension. The average diameter of iron oxide nanoparticles without any surface coating determined by TEM is 10 nm. These particles are capable of evading the reticuloendothelial system and can cross the blood-brain barrier in the rabbit. The labelling efficiency of iron oxide nanoparticles labelled with Tc99m is 85%, which is good for the biodistribution study. The sufficient amount of iron oxide nanoparticles concentration in the brain as compared with the surrounding soft tissues and their long blood retention time indicates that the water-based suspension of iron oxide nanoparticles may be an option for drug delivery into the brain. PMID- 26023158 TI - Silver nanoparticles synthesised using plant extracts show strong antibacterial activity. AB - In this study, three plants Populus alba, Hibiscus arboreus and Lantana camara were explored for the synthesis of silver nanoparticles (SNPs). The effect of reaction temperature and leaf extract (LE) concentration of P. alba, H. arboreus and L. camara was evaluated on the synthesis and size of SNPs. The SNPs were characterised by ultra-violet-visible spectroscopy, scanning electron microscopy and atomic force microscopy. The synthesis rate of SNPs was highest with LE of L. camara followed by H. arboreus and P. alba under similar conditions. L. camara LE showed maximum potential of smaller size SNPs synthesis, whereas bigger particles were formed by H. arboreous LE. The size and shape of L. camara LE synthesised SNPs were analysed by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX). TEM analysis revealed the formation of SNPs of average size 17+/-9.5 nm with 5% LE of L. camara. The SNPs synthesised by LE of L. camara showed strong antibacterial activity against Escherichia coli. The results document that desired size SNPs can be synthesised using these plant LEs at a particular temperature for applications in the biomedical field. PMID- 26023159 TI - AC electrical characterisation and insight to charge transfer mechanisms in DNA molecular wires through temperature and UV effects. AB - In this study, AC characterisation of DNA molecular wires, effects of frequency, temperature and UV irradiation on their conductivity is presented. lambda-DNA molecular wires suspended between high aspect-ratio electrodes exhibit highly frequency-dependent conductivity that approaches metal-like behaviour at high frequencies (~MHz). Detailed temperature dependence experiments were performed that traced the impedance response of lambda-DNA until its denaturation. UV irradiation experiments where conductivity was lost at higher and longer UV exposures helped to establish that it is indeed lambda-DNA molecular wires that generate conductivity. The subsequent renaturation of lambda-DNA resulted in the recovery of current conduction, providing yet another proof of the conducting DNA molecular wire bridge. The temperature results also revealed hysteretic and bi modal impedance responses that could make DNA a candidate for nanoelectronics components like thermal transistors and switches. Further, these experiments shed light on the charge transfer mechanism in DNA. At higher temperatures, the expected increase in thermal-induced charge hopping may account for the decrease in impedance supporting the 'charge hopping mechanism' theory. UV light, on the other hand, causes damage to GC base-pairs and phosphate groups reducing the path available both for hopping and short-range tunneling mechanisms, and hence increasing impedance--this again supporting both the 'charge hopping' and 'tunneling' mechanism theories. PMID- 26023160 TI - A Dedicated Type II NADPH Dehydrogenase Performs the Penultimate Step in the Biosynthesis of Vitamin K1 in Synechocystis and Arabidopsis. AB - Mutation of Arabidopsis thaliana NAD(P)H DEHYDROGENASE C1 (NDC1; At5g08740) results in the accumulation of demethylphylloquinone, a late biosynthetic intermediate of vitamin K1. Gene coexpression and phylogenomics analyses showed that conserved functional associations occur between vitamin K biosynthesis and NDC1 homologs throughout the prokaryotic and eukaryotic lineages. Deletion of Synechocystis ndbB, which encodes for one such homolog, resulted in the same defects as those observed in the cyanobacterial demethylnaphthoquinone methyltransferase knockout. Chemical modeling and assay of purified demethylnaphthoquinone methyltransferase demonstrated that, by virtue of the strong electrophilic nature of S-adenosyl-l-methionine, the transmethylation of the demethylated precursor of vitamin K is strictly dependent on the reduced form of its naphthoquinone ring. NDC1 was shown to catalyze such a prerequisite reduction by using NADPH and demethylphylloquinone as substrates and flavine adenine dinucleotide as a cofactor. NDC1 displayed Michaelis-Menten kinetics and was markedly inhibited by dicumarol, a competitive inhibitor of naphthoquinone oxidoreductases. These data demonstrate that the reduction of the demethylnaphthoquinone ring represents an authentic step in the biosynthetic pathway of vitamin K, that this reaction is enzymatically driven, and that a selection pressure is operating to retain type II NAD(P)H dehydrogenases in this process. PMID- 26023161 TI - Functional and Genetic Analysis Identify a Role for Arabidopsis ARGONAUTE5 in Antiviral RNA Silencing. AB - RNA silencing functions as an antiviral defense through the action of DICER-like (DCL) and ARGONAUTE (AGO) proteins. In turn, plant viruses have evolved strategies to counteract this defense mechanism, including the expression of suppressors of RNA silencing. Potato virus X (PVX) does not systemically infect Arabidopsis thaliana Columbia-0, but is able to do so effectively in mutants lacking at least two of the four Arabidopsis DCL proteins. PVX can also infect Arabidopsis ago2 mutants, albeit less effectively than double DCL mutants, suggesting that additional AGO proteins may mediate anti-viral defenses. Here we show, using functional assays, that all Arabidopsis AGO proteins have the potential to target PVX lacking its viral suppressor of RNA silencing (VSR), P25, but that only AGO2 and AGO5 are able to target wild-type PVX. However, P25 directly affects only a small subset of AGO proteins, and we present evidence indicating that its protective effect is mediated by precluding AGO proteins from accessing viral RNA, as well as by directly inhibiting the RNA silencing machinery. In agreement with functional assays, we show that Potexvirus infection induces AGO5 expression and that both AGO2 and AGO5 are required for full restriction of PVX infection in systemic tissues of Arabidopsis. PMID- 26023162 TI - Repair of DNA Damage Induced by the Cytidine Analog Zebularine Requires ATR and ATM in Arabidopsis. AB - DNA damage repair is an essential cellular mechanism that maintains genome stability. Here, we show that the nonmethylable cytidine analog zebularine induces a DNA damage response in Arabidopsis thaliana, independent of changes in DNA methylation. In contrast to genotoxic agents that induce damage in a cell cycle stage-independent manner, zebularine induces damage specifically during strand synthesis in DNA replication. The signaling of this damage is mediated by additive activity of ATAXIA TELANGIECTASIA MUTATED AND RAD3-RELATED and ATAXIA TELANGIECTASIA MUTATED kinases, which cause postreplicative cell cycle arrest and increased endoreplication. The repair requires a functional STRUCTURAL MAINTENANCE OF CHROMOSOMES5 (SMC5)-SMC6 complex and is accomplished predominantly by synthesis-dependent strand-annealing homologous recombination. Here, we provide insight into the response mechanism for coping with the genotoxic effects of zebularine and identify several components of the zebularine-induced DNA damage repair pathway. PMID- 26023165 TI - Generalized anxiety disorder: psychopharmacotherapy update on a common and commonly overlooked condition. AB - OBJECTIVE: This article provides a brief review of the practical implications of the current diagnostic conceptualisation of generalised anxiety disorder (GAD) and an update on its pharmacotherapy. CONCLUSIONS: The diagnostic criteria for GAD need to be refined, to better reflect its clinical features and to make GAD more clinically useful. Various pharmacological agents are effective for GAD and to some extent, allow a tailored treatment approach. In addition to effectiveness, the choice of medication is influenced by the speed of therapeutic action, tolerability and habit-forming properties. PMID- 26023163 TI - Mutant Allele-Specific Uncoupling of PENETRATION3 Functions Reveals Engagement of the ATP-Binding Cassette Transporter in Distinct Tryptophan Metabolic Pathways. AB - Arabidopsis (Arabidopsis thaliana) penetration (PEN) genes quantitatively contribute to the execution of different forms of plant immunity upon challenge with diverse leaf pathogens. PEN3 encodes a plasma membrane-resident pleiotropic drug resistance-type ATP-binding cassette transporter and is thought to act in a pathogen-inducible and PEN2 myrosinase-dependent metabolic pathway in extracellular defense. This metabolic pathway directs the intracellular biosynthesis and activation of tryptophan-derived indole glucosinolates for subsequent PEN3-mediated efflux across the plasma membrane at pathogen contact sites. However, PEN3 also functions in abiotic stress responses to cadmium and indole-3-butyric acid (IBA)-mediated auxin homeostasis in roots, raising the possibility that PEN3 exports multiple functionally unrelated substrates. Here, we describe the isolation of a pen3 allele, designated pen3-5, that encodes a dysfunctional protein that accumulates in planta like wild-type PEN3. The specific mutation in pen3-5 uncouples PEN3 functions in IBA-stimulated root growth modulation, callose deposition induced with a conserved peptide epitope of bacterial flagellin (flg22), and pathogen-inducible salicylic acid accumulation from PEN3 activity in extracellular defense, indicating the engagement of multiple PEN3 substrates in different PEN3-dependent biological processes. We identified 4-O-beta-D-glucosyl-indol-3-yl formamide (4OGlcI3F) as a pathogen inducible, tryptophan-derived compound that overaccumulates in pen3 leaf tissue and has biosynthesis that is dependent on an intact PEN2 metabolic pathway. We propose that a precursor of 4OGlcI3F is the PEN3 substrate in extracellular pathogen defense. These precursors, the shared indole core present in IBA and 4OGlcI3F, and allele-specific uncoupling of a subset of PEN3 functions suggest that PEN3 transports distinct indole-type metabolites in distinct biological processes. PMID- 26023164 TI - PKCepsilon Is an Essential Mediator of Prostate Cancer Bone Metastasis. AB - The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCepsilon), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCepsilon expression was silenced using shRNA. Interestingly, while PKCepsilon depletion had only marginal effects on the proliferative, adhesive, and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculation, it caused a significant reduction in cell invasiveness. Notably, PKCepsilon was required for transendothelial cell migration (TEM) as well as for the growth of PC3-ML cells in a bone biomimetic environment. At a mechanistic level, PKCepsilon depletion abrogates the expression of IL1beta, a cytokine implicated in skeletal metastasis. Taken together, PKCepsilon is a key factor for driving the formation of bone metastasis by prostate cancer cells and is a potential therapeutic target for advanced stages of the disease. IMPLICATIONS: This study uncovers an important new function of PKCepsilon in the dissemination of cancer cells to the bone; thus, highlighting the promising potential of this oncogenic kinase as a therapeutic target for skeletal metastasis. PMID- 26023166 TI - Accumulating too much stuff: what is hoarding and what is not? AB - OBJECTIVE: This paper considers the meaning of the terms hoarding, collecting and accumulation, with a focus on what is abnormal and what is not. CONCLUSIONS: Hoarding is an adaptive behaviour. When hoarding is excessive and interferes with people's lives, it is a disorder. A central feature of hoarding disorder is accumulation of items due to unwillingness to discard them. This must be distinguished from abnormal accumulation of material caused by poor motivation or unawareness concerning the need to discard. PMID- 26023167 TI - Anti-N-methyl-D-aspartate encephalitis - a case study of symptomatic progression. AB - OBJECTIVE: To present the diagnosis course and sequelae of a case of anti-N methyl-D-aspartate (NMDA) receptor encephalitis, drawing attention to early psychiatric symptoms. METHOD: The literature on anti-NMDA encephalitis is reviewed and possible psychopathological mechanisms discussed. RESULT: New onset psychoses, presenting with the combination of hallucinations, dyskinesias and seizures and progressing to catatonia should be referred to neurology for consideration of anti-NMDA receptor encephalitis. CONCLUSION: Early diagnosis is important for a favourable prognosis. PMID- 26023168 TI - Predicament suicide: an update. AB - OBJECTIVE: We aim to outline the notion of predicament suicide and progress in the field. CONCLUSION: The term predicament suicide was initially applied when the individual without mental disorder completed suicide to escape intolerable circumstances. Subsequently, painful untreated or unresponsive mental disorder was conceptualized as an internal predicament and the term was applied to all suicide. It continues to be used in both the restricted and broad forms. Our group has substantiated the restricted form by describing suicide in the setting of financial loss, forced marriage and other predicaments. The broad form gave rise to the Operationalized Predicaments of Suicide tool for use in quantitative research. Some literature from other workers supports the general thrust of the notion. PMID- 26023169 TI - Correction: A Combinatory Strategy for Detection of Live CTCs Using Microfiltration and a New Telomerase-Selective Adenovirus. PMID- 26023170 TI - Characterization of the antithrombotic fingerprint of the branded and copies of the low-molecular-weight enoxaparin using thrombin generation assay. AB - BACKGROUND: The patent protection of low-molecular-weight heparins (LMWHs) expired, so the definition of criteria for the biological similarity between LMWH copies and the original product is a real need. AIM: The present in vitro study compared copies and branded enoxaparin using the specific anti-Xa activity and the calibrated automated thrombogram assay. METHODS: Samples of platelet-poor plasma (PPP) and platelet-rich plasma (PRP) from 15 healthy volunteers were spiked with branded enoxaparin (Lovenox) or its copies (Cutenox, Dilutol, Enoxa, Fibrinox, Loparin, Lupenox, Novex, Noxprin, and Versa). The specific anti-Xa activity was measured in PPP, and thrombin generation was assessed in PPP and PRP in the presence of tissue factor or pancreatic cancer cells BXPC3. RESULTS: The anti-Xa activity of enoxaparin copies ranged from 0.072 to 0.088 IU/MUg, being lower as compared to the branded enoxaparin (0.095 anti-Xa IU/MUg). The potency of each copy to inhibit thrombin generation varied in the 3 experimental systems. The presence of platelets or pancreatic cancer cells BXPC3 in human plasma induced significant modifications in the inhibitory efficiency of enoxaparin copies on thrombin generation, which distinguished them from the branded product. CONCLUSION: Enoxaparin copies showed significant variability regarding their inhibitory potency on thrombin generation. Platelets and cancer cells significantly increased the variability of the antithrombotic efficiency of the copies as compared to the branded enoxaparin. The present study underlines the need for the elaboration of additional functional criteria to evaluate the global antithrombotic capacity of enoxaparin copies in order to evaluate their potential sameness with the branded drug. PMID- 26023171 TI - Effect of Persistent Thrombocytopenia on Mortality in Surgical Critical Care Patients: A Retrospective Study. AB - Thrombocytopenia is common among surgical critically ill patients. The relationship between the duration of thrombocytopenia and mortality is not well studied. This retrospective 12-month cohort study was designed to evaluate the association between persistent thrombocytopenia and mortality among surgical critically ill patients to determine the risk factors for persistent thrombocytopenia. The study included adult patients consecutively admitted to the surgical intensive care unit (SICU) at our institution. Patients with a diagnosis of thrombocytopenia were identified from a prospective critical care database. We defined patients with persistent thrombocytopenia as those with thrombocytopenia lasting more than 7 consecutive days. The primary outcome of this study was 28 day mortality and the secondary outcomes were lengths of SICU stay and hospital stay. Fifty-one patients experienced persistent thrombocytopenia and 71 experienced nonpersistent thrombocytopenia. Among patients with persistent thrombocytopenia, mortality was significantly higher, and SICU and hospital stays were longer than those with nonpersistent thrombocytopenia. Risk factor analysis failed to predict which patients with thrombocytopenia would develop into persistent thrombocytopenia. Persistent thrombocytopenia is a clinically significant disorder and is associated with poorer outcomes. Future studies are needed to further define this process. PMID- 26023172 TI - Erratum. AB - In issue 21.1 three of the DOIs were printed incorrectly, please see below for the correct information. Andrea Giorgianni, et al. Flow-diverter stenting of post traumatic bilateral anterior cerebral artery pseudoaneurysm: A case report. Doi: 10.15274/INR-2014-10059 Correct: Doi: 10.1177/1591019915575441 Lee-Anne Slater, et al. Effect of flow diversion with silk on aneurysm size: A single center experience. Doi: 10.15274/INR-2014-10062 Correct DOI: 10.1177/1591019915576433 Robert J McDonald, et al. Periprocedural safety of Pipeline therapy for unruptured cerebral aneurysms: Analysis of 279 Patients in a multihospital database. Doi: 10.15274/INR-2014-10074 Correct DOI: 10.1177/1591019915576289. PMID- 26023173 TI - Risk of ADHD After Multiple Exposures to General Anesthesia: A Nationwide Retrospective Cohort Study. AB - OBJECTIVE: To study the association between general anesthesia exposure before age 3 years and having a later ADHD diagnosis. METHOD: In a birth cohort, data were collected from a nationwide population database for children born between 1997 and 1999 who were exposed to general anesthesia before their third birthday. Age- and gender-matched enrollees without general anesthesia exposure were taken as the comparison. Groups were compared to identify the incidence of ADHD after age 4 and anesthesia-related predictive factors. RESULTS: Among the 1,146 exposed children, 74 ADHD cases were identified, and 158 ADHD cases were identified in 3,438 matched controls. After adjusting for comorbid conditions and possible confounding factors, if exposure on more than one occasion or >=3 hr, an increased likelihood of having a later ADHD diagnosis was found (HR, 1.71 and 2.43, respectively). CONCLUSION: Children with multiple or >=3 hr general anesthesia exposures before age 3 years have an increased likelihood of a later ADHD diagnosis. PMID- 26023174 TI - A case of ridge-related re-entrant atrial tachycardia utilizing the vein of Marshall to span a conduction gap at the mitral isthmus scar. PMID- 26023175 TI - The development of AF over time in patients with permanent pacemakers: objective assessment with pacemaker diagnostics demonstrates distinct patterns of AF. AB - AIMS: To describe the long-term patterns of atrial fibrillation (AF) in patients with permanent pacemakers. METHODS AND RESULTS: A total of 2092 pacemaker Holter downloads were analysed in 323 patients with dual chamber permanent pacemakers, describing a cumulative 1031 patient-years of beat-to-beat monitoring. Four subtypes of AF were applied: (i) non-progressive low-burden PAF (NPLB-PAF, n = 120): such patients never have >1% AF burden throughout follow-up; (ii) chronic progressive PAF (CP-PAF, n = 55): AF burden increases but is never 100%; (iii) relapsing-remitting PAF (RR-PAF, n = 78): AF burden has reduced at least once by more than 2% and is never 100%; (iv) persistent AF (PersAF, n = 70): 100% AF burden for at least 28 days. Overall, mean AF burden rose 0.34% per year (P < 0.0001). After accounting for age, heart failure (HF) had a significant interaction with AF burden (P = 0.0022), but HATCH score and CVA/TIA did not. There were no differences in the frequency or duration of monitoring between the four AF subtypes. Atrial fibrillation episode frequency discriminated between subtypes (P = 0.0004). Eighteen of 70 (26%) patients with PersAF had pacemaker documented episodes of sinus rhythm (i.e. reversion to 'paroxysmal AF') after the onset of PersAF. CONCLUSION: In this cohort, the development of AF over time appears more complex than current definitions suggest. Atrial fibrillation can remain low burden without progression, remit-relapse, or progress as is described in currently accepted definitions. More frequent episodes of AF indicated a favourable subtype. Persistent AF is not inevitable, and can revert to paroxysmal AF. CLINICAL TRIAL REGISTRATION: NCT02016950, http://clinicaltrials.gov/show/NCT02016950. PMID- 26023176 TI - Headache during cryoballoon ablation for atrial fibrillation. AB - AIMS: Headache has been reported to occur during cryoballoon ablation for atrial fibrillation (AF). No study has systematically analysed this phenomenon. METHODS AND RESULTS: Twenty consecutive patients with symptomatic AF underwent cryoballoon ablation without sedation. Headache was evaluated before, during, and after the first cryoapplication in every pulmonary vein (PV) using a visual representation of a head for location of the headache, a numerical rating scale (NRS) for measuring pain intensity and the short-form McGill pain questionnaire (MPQ) for qualitative analysis of pain. The order in which the PVs were ablated was randomized. Sixteen (80%) patients perceived mainly frontal headache during cryoablation. The overall NRS scores were significantly higher during (5.1 +/- 1.7), compared with before (2.7 +/- 1.4), and after (3.5 +/- 2.2) a cryoapplication (P < 0.05). The NRS score was significantly higher during ablation of the first PV. The intensity of the perceived headache was not related to the temperature reached 150 s after initiation of a cryoapplication (P = 0.81). Of the MPQ, three sensory adjectives and one affective adjective averaged between scores 1 and 2, representing mild-to-moderate severity of pain. CONCLUSION: The majority of patients treated by balloon cryoablation experienced headache during a cryoapplication. There was no correlation between the temperature reached during a cryoballoon freeze and the intensity of the headache. Cryoballoon ablation of the first PV was significantly more painful than the remaining PVs. PMID- 26023177 TI - Oral anticoagulant therapy for stroke prevention in patients with atrial fibrillation undergoing ablation: results from the First European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA). AB - The European Snapshot Survey on Procedural Routines in Atrial Fibrillation Ablation (ESS-PRAFA) is a prospective, multicentre snapshot survey of patients undergoing atrial fibrillation (AF) ablation, conducted to collect patient-based data on current clinical practices in AF ablation in context of the latest AF Guidelines and contemporary oral anticoagulant therapies. The EP Research Network Centres were asked to prospectively enrol consecutive patients during a 6-week period (September/October 2014). Data were collected via the web-based case report form. We present the results pertinent to the use of antithrombotic therapies. Thirteen countries prospectively enrolled 455 eligible consecutive patients [mean age 59 +/- 10.8 years, 131 (28.8%) females]. The mean CHA2DS2-VASc score was 1.12 +/- 1.06 [137 patients (30.1%) had a score of >=2]. Before ablation, 443 patients (97.4%) were on anticoagulant therapy [143 (31.4%) on non vitamin K antagonist oral anticoagulants (NOACs) and 264 (58.0%) on vitamin K antagonists (VKAs)]. Of the latter, 79.7% underwent ablation without VKA interruption, whilst a variety of strategies were used in patients taking NOAC. After ablation, most patients (89.3%) continued the same anticoagulant as before, and 2 (0.4%) were not prescribed any anticoagulation. At discharge, 280 patients (62.2%) were advised oral anticoagulation for a limited period of mean 3.8 +/- 2.2 months. On multivariate analysis, CHA2DS2-VASc, AF duration, prior VKA use, and estimated AF ablation success were significantly associated with the decision on short-term anticoagulation. Our results show the increasing use of NOAC in patients undergoing AF ablation and emphasize the need for more information to guide the periprocedural use of both NOACs and VKAs in real-world setting. PMID- 26023178 TI - How are European patients at risk of malignant arrhythmias or sudden cardiac death identified and informed about their risk profile: results of the European Heart Rhythm Association survey. AB - The purpose of this EP wire is to examine clinical practice in the field of screening of patients of risk of ventricular arrhythmias and/or sudden cardiac death (SCD) in European countries. A systematic screening programme existed in the majority of centres and was organized by a multidisciplinary dedicated team or by an activity programme of implantable cardioverter-defibrillator (ICD) or heart failure clinics. In particular, high-risk subgroups of patients with ischaemic and non-ischaemic cardiomyopathy ICD implantation are considered strongly indicated within 90 days of myocardial revascularization or initial diagnosis. Cardiac magnetic resonance imaging appears as an important tool to better characterize the left ventricular arrhythmogenic substrate in patients at risk of SCD. PMID- 26023180 TI - Retinoblastoma. AB - Retinoblastoma is the most common primary intraocular malignancy of childhood. It typically presents with leukocoria or strabismus. In later stages of the disease, the child may exhibit proptosis, buphthalmos, or hypopyon. The pathognomonic molecular aberration is a loss of function mutation in the RB1 gene on chromosome 13q. The degree of tumor involvement within the eye is defined by its group. Grouping was historically done with Reese-Ellsworth System. Recent therapeutic advances have led to the development of a new grouping system, the International Classification of Retinoblastoma (ICRB). In cases of extraocular extension and metastatic disease, the degree of tumor involvement outside of the eye is defined by its stage. Retinoblastoma is staged using the International Retinoblastoma Staging System (IRSS). Children with intraocular retinoblastoma have an excellent overall and ocular survival. In order to avoid the morbidity of enucleation and external beam radiation, treatments for isolated intraocular retinoblastoma have progressively moved toward targeted local modalities. Patients with extraocular involvement, such as those with trilateral retinoblastoma, have a poorer prognosis. The majority of these higher stage patients are now able to be cured with combination chemotherapy. PMID- 26023179 TI - Strontium- and calcium-containing, titanium-stabilised phosphate-based glasses with prolonged degradation for orthopaedic tissue engineering. AB - Strontium- and calcium-releasing, titanium-stabilised phosphate-based glasses with a controlled degradation rate are currently under development for orthopaedic tissue engineering applications. Ca and/or Sr were incorporated at varying concentrations in quaternary phosphate-based glasses, in order to promote osteoinduction. Ti was incorporated at a fixed concentration in order to prolong degradation. Glasses of the general formula (P2O5)-(Na2O)-(TiO2)-(CaO)-(SrO) were prepared via the melt-quench technique. The materials were characterised by energy-dispersive X-ray spectroscopy, X-ray diffraction, (31)P magic angle spinning nuclear magnetic resonance, Fourier transform infrared spectroscopy, differential thermal analysis and density determination. The dissolution rate in distilled water was determined by measuring mass loss, ion release and pH change over a two-week period. In addition, the cytocompatibility and alkaline phosphatase activity of an osteoblast-like cell line cultured on the surface of glass discs was assessed. The glasses were shown to be amorphous and contained Q(1), Q(2) and Q(3) species. Fourier transform infrared spectroscopy revealed small changes in the glass structure as Ca was substituted with Sr and differential thermal analysis confirmed a decrease in crystallisation temperature with increasing Sr content. Degradation and ion release studies also showed that mass loss was positively correlated with Sr content. These results were attributed to the lower electronegativity of Sr in comparison to Ca favouring the formation of phosphate-based mineral phases. All compositions supported cell proliferation and survival and induced at least 2.3-fold alkaline phosphatase activity relative to the control. Glass containing 17.5 mol% Sr had 3.6-fold greater alkaline phosphatase activity than the control. The gradual release of Ca and Sr supported osteoinduction, indicating their potential suitability in orthopaedic tissue engineering applications. PMID- 26023181 TI - Normalization panels for the reliable quantification of circulating microRNAs by RT-qPCR. AB - Circulating microRNAs (miRNAs) have been reported as biomarkers for disease diagnosis. RT-qPCR is most commonly used to detect miRNAs; however, no consensus on the most appropriate method for data normalization exists. Via a standardized selection method, we aimed to determine separate miRNA normalization panels for RT-qPCR measurements on whole blood, platelets, and serum. Candidate miRNAs were selected from studies describing circulating miRNA microarray data in the Gene Expression Omnibus or ArrayExpress. miRNA expression data of healthy controls were retrieved from each study. For each sample type, we selected those miRNAs that were least variable and sufficiently highly expressed in multiple microarray experiments, performed on at least 2 different platforms. Stability of the candidate miRNAs was assessed using NormFinder and geNorm algorithms in a RT-qPCR cohort of 10 patients with coronary artery disease and 10 healthy controls. We selected miRNA normalization panels for RT-qPCR measurements on whole blood, platelets, and serum. As a validation, we assessed the precision of all 3 panels in 3 independent RT-qPCR cohorts and compared this with normalization for miR-16 or RNU6B. The proposed normalization panels for whole blood, platelets, and serum show better precision than normalization for miR-16 or RNU6B. PMID- 26023182 TI - Annexin A4 is a novel direct regulator of adenylyl cyclase type 5. AB - Annexin A4 (AnxA4), a Ca(2+)- and phospholipid-binding protein, is up-regulated in the human failing heart. In this study, we examined the impact of AnxA4 on beta-adrenoceptor (beta-AR)/cAMP-dependent signal transduction. Expression of murine AnxA4 in human embryonic kidney (HEK)293 cells dose-dependently inhibited cAMP levels after direct stimulation of adenylyl cyclases (ACs) with forskolin (FSK), as determined with an exchange protein activated by cAMP-Forster resonance energy transfer (EPAC-FRET) sensor and an ELISA (control vs. +AnxA4: 1956 +/- 162 vs. 1304 +/- 185 fmol/ug protein; n = 8). Disruption of the anxA4 gene led to a consistent increase in intracellular cAMP levels in isolated adult mouse cardiomyocytes, with heart-directed expression of the EPAC-FRET sensor, stimulated with FSK, and as determined by ELISA, also in mouse cardiomyocytes stimulated with the beta-AR agonist isoproterenol (ISO) (anxA4a(+/+) vs. anxA4a( /-): 5.1 +/- 0.3 vs. 6.7 +/- 0.6 fmol/ug protein) or FSK (anxA4a(+/+) vs. anxA4a( /-): 1891 +/- 238 vs. 2796 +/- 343 fmol/ug protein; n = 9-10). Coimmunoprecipitation experiments in HEK293 cells revealed a direct interaction of murine AnxA4 with human membrane-bound AC type 5 (AC5). As a functional consequence of AnxA4-mediated AC inhibition, AnxA4 inhibited the FSK-induced transcriptional activation mediated by the cAMP response element (CRE) in reporter gene studies (10-fold vs. control; n = 4 transfections) and reduced the FSK-induced phosphorylation of the CRE-binding protein (CREB) measured on Western blots (control vs. +AnxA4: 150 +/- 17% vs. 105 +/- 10%; n = 6) and by the use of the indicator of CREB activation caused by phosphorylation (ICAP)-FRET sensor, indicating CREB phosphorylation. Inactivation of AnxA4 in anxA4a(-/-) mice was associated with an increased cardiac response to beta-AR stimulation. Together, these results suggest that AnxA4 is a novel direct negative regulator of AC5, adding a new facet to the functions of annexins. PMID- 26023183 TI - Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity. AB - Retinal bipolar (BP) cells mediate the earliest steps in image processing in the visual system, but the genetic pathways that regulate their development and function are incompletely known. We identified PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) as a highly conserved transcription factor that is abundantly expressed in mouse retina. During development and in maturity, PRDM8 is expressed strongly in BP cells and a fraction of amacrine and ganglion cells. To determine whether Prdm8 is essential to BP cell development or physiology, we targeted the gene in mice. Prdm8(EGFP/EGFP) mice showed nonprogressive b-wave deficits on electroretinograms, consistent with compromised BP cell function or circuitry resembling the incomplete form of human congenital stationary night blindness (CSNB). BP cell specification was normal in Prdm8(EGFP/EGFP) retina as determined by VSX2(+) cell numbers and retinal morphology at postnatal day 6. BP subtype differentiation was impaired, however, as indicated by absent or diminished expression of BP subtype-specific markers, including the putative PRDM8 regulatory target PKCalpha (Prkca) and its protein. By adulthood, rod bipolar (RB) and type 2 OFF-cone bipolar (CB) cells were nearly absent from Prdm8 null mice. Although no change was detected in total amacrine cell (AC) numbers, increased PRKCA(+) and cholinergic ACs and decreased GABAergic ACs were seen, suggesting an alteration in amacrine subtype identity. These findings establish that PRDM8 is required for RB and type 2 OFF-CB cell survival and amacrine subtype identity, and they present PRDM8 as a candidate gene for human CSNB. PMID- 26023185 TI - Correction for Bardy et al., Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. PMID- 26023186 TI - Correction for Katsnelson, News Feature: Microplastics present pollution puzzle. PMID- 26023184 TI - Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum. AB - The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) alpha and beta are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRalpha/beta in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes. PMID- 26023187 TI - Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. AB - Rnf43 (RING finger protein 43) and Znrf3 (zinc/RING finger protein 3) (RZ) are two closely related transmembrane E3 ligases, encoded by Wnt target genes, that remove surface Wnt (wingless-int) receptors. The two genes are mutated in various human cancers. Such tumors are predicted to be hypersensitive to, yet still depend on, secreted Wnts. We previously showed that mutation of RZ in the intestine yields rapidly growing adenomas containing LGR5(+) (leucine-rich repeat containing G-protein coupled receptor 5) stem cells and Wnt3-producing Paneth cells. We now show that removal of Paneth cells by Math1 mutation inhibits RZ(-/ ) tumor formation. Similarly, deletion of Wnt3 inhibits tumorigenesis. Treatment of mice carrying RZ(-/-) intestinal neoplasia with a small molecule Wnt secretion inhibitor (porcupine inhibitor C59) strongly inhibited growth, whereas adjacent normal crypts remained intact. These results establish that paracrine Wnt secretion is an essential driver of RZ(-/-) tumor growth and imply that a therapeutic window exists for the use of porcupine inhibitors for RZ-mutant cancers. PMID- 26023189 TI - Correction for Migliore et al., Sensing of molecules using quantum dynamics. PMID- 26023188 TI - Direct observation of DNA overwinding by reverse gyrase. AB - Reverse gyrase, found in hyperthermophiles, is the only enzyme known to overwind (introduce positive supercoils into) DNA. The ATP-dependent activity, detected at >70 degrees C, has so far been studied solely by gel electrophoresis; thus, the reaction dynamics remain obscure. Here, we image the overwinding reaction at 71 degrees C under a microscope, using DNA containing consecutive 30 mismatched base pairs that serve as a well-defined substrate site. A single reverse gyrase molecule processively winds the DNA for >100 turns. Bound enzyme shows moderate temperature dependence, retaining significant activity down to 50 degrees C. The unloaded reaction rate at 71 degrees C exceeds five turns per second, which is >10(2)-fold higher than hitherto indicated but lower than the measured ATPase rate of 20 s(-1), indicating loose coupling. The overwinding reaction sharply slows down as the torsional stress accumulates in DNA and ceases at stress of mere ~ 5 pN ? nm, where one more turn would cost only sixfold the thermal energy. The enzyme would thus keep DNA in a slightly overwound state to protect, but not overprotect, the genome of hyperthermophiles against thermal melting. Overwinding activity is also highly sensitive to DNA tension, with an effective interaction length exceeding the size of reverse gyrase, implying requirement for slack DNA. All results point to the mechanism where strand passage relying on thermal motions, as in topoisomerase IA, is actively but loosely biased toward overwinding. PMID- 26023190 TI - Meteorite-catalyzed synthesis of nucleosides and other prebiotic compounds. PMID- 26023191 TI - Abrupt global shifts in ecosystem states. PMID- 26023193 TI - eComment. The underestimated role of frailty in cardiac surgery. PMID- 26023192 TI - Increased erythrocytic osmotic fragility in anemic domestic shorthair and purebred cats. AB - OBJECTIVES: Increased erythrocytic osmotic fragility and splenomegaly have been reported in anemic Abyssinian and Somali cats. Here we report on this condition in anemic domestic shorthair cats and two other breeds, and describe common features of the clinicopathological profiles, management and outcomes. METHODS: Anemic cats, other than Abyssinians and Somalis, were included. The erythrocytic osmotic fragility test was performed, known causes of anemia were excluded, the illness was followed and medical records were reviewed. RESULTS: Twelve neutered cats were first found to be anemic between 0.5 and 9.0 years of age. Pallor, lethargy, inappetence, pica, weight loss and splenomegaly were commonly observed. A moderate-to-severe macrocytic and hypochromic anemia with variable regeneration was noted. Infectious disease screening, direct Coombs' and pyruvate kinase DNA mutation test results were negative. Freshly drawn blood did not appear hemolysed but became progressively lysed during storage at 4 degrees C. The sigmoid osmotic fragility curves were moderately to severely right shifted, indicating erythrocytic fragility at 20 degrees C. Cross-correction studies indicated an intrinsic red cell effect rather than plasma effect. Most cats were treated with immunosuppressive doses of prednisolone and doxycycline, with variable responses. Five cats with recurrent or persistent anemia responded well to splenectomy. However, two had occasional recurrence of severe anemia: one was found to be Bartonella vinsonii-positive during one episode and responded to azithromycin and prednisolone, while the other cat had two episodes of severe anemia of unknown cause. Finally, six cats were euthanized within 1 month and 7 years after initial presentation. Histopathology of six spleens revealed mainly congestion and extramedullary hematopoiesis. CONCLUSIONS AND RELEVANCE: Similarly to Abyssinian and Somali cats, domestic shorthair and cats of other breeds can also develop severe erythrocytic osmotic fragility with anemia and splenomegaly, which should be considered as a differential diagnosis in anemic cats. PMID- 26023194 TI - eReply. The underestimated role of frailty in cardiac surgery. PMID- 26023195 TI - eComment. Perfusion strategies in type A acute aortic dissection. PMID- 26023196 TI - eComment. Radical vs selective lymphadenectomy for non-small-cell lung cancer: which is the optimal procedure? PMID- 26023197 TI - eComment. Integrating three-dimensional vision in thoracoscopic surgery: Is there a learning curve? PMID- 26023198 TI - Treatment solution by Botta et al. PMID- 26023199 TI - Treatment solution by reader: Endovascular treatment of aortic isthmus pseudoaneurysm involving a right aberrant subclavian artery long after multiple coarctation repairs following cervical debranching. PMID- 26023201 TI - Mechanosensitive ion channel MscL controls ionic fluxes during cold and heat stress in Synechocystis. AB - Calcium plays an essential role in a variety of stress responses of eukaryotic cells; however, its function in prokaryotes is obscure. Bacterial ion channels that transport Ca(2+) are barely known. We investigated temperature-induced changes in intracellular concentration of Ca(2+), Na(+) and K(+) in the cyanobacterium Synechocystis sp. strain PCC 6803 and its mutant that is defective in mechanosensitive ion channel MscL. Concentration of cations rapidly and transiently increased in wild-type cells in response to cold and heat treatments. These changes in ionic concentrations correlated with the changes in cytoplasmic volume that transiently decreased in response to temperature treatments. However, no increase in ionic concentrations was observed in the MscL-mutant cells. It implies that MscL functions as a non-specific ion channel, and it participates in regulation of cell volume under temperature-stress conditions. PMID- 26023200 TI - Characterization of outer membrane vesicles from a neonatal meningitic strain of Cronobacter sakazakii. AB - Cronobacter sakazakii is associated with severe and often fatal cases of infant meningitis and necrotizing enterocolitis. The form of meningitis differs from that due to Neisseria meningitidis and Streptococcus spp., in that it is highly invasive and destructive towards human brain cells. However, there is relatively little understanding of the cytopathogenic interaction of C. sakazakii with host cells which results in stimulation of an inflammatory immune response. The production of Cronobacter outer membrane vesicles (OMV) and their potential pathogenic functions have not yet been elucidated. This study is the first to show that C. sakazakii produce OMV, which may play a role in the activation of cytopathogenic and host cell responses on human intestinal epithelial cells. Cronobacter sakazakii strain 767 was used which had been isolated from a fatal outbreak of neonatal meningitis and necrotizing enterocolitis. Cronobacter sakazakii OMV were internalized by Caco-2 cells, increased cell proliferation and stimulated the host's innate proinflammatory response without inducing overt toxicity. A total of 18 OMV-associated proteins were identified by mass spectrometry and their potential pathogenicity roles were evaluated. Collectively, these data indicate that C. sakazakii OMV could play a role in pathogenesis by delivering bacterial toxins into host epithelial cells, driving proliferative and proinflammatory responses. PMID- 26023202 TI - Adult-onset Alexander's disease mimicking degenerative disease. AB - Adult-onset Alexander's disease is a rare leukodystrophy that can present later in life in a variety of ways, often mimicking more common neurodegenerative conditions. We present two cases with novel mutations, diagnosed from their characteristic MR scan findings. Even in much older people, clinicians should have a high clinical suspicion if there are typical imaging findings. PMID- 26023204 TI - Musician's dystonia. AB - Musician's dystonia is a task-specific dystonia that usually affects the embouchure or the most active digits of the most active hand, and therefore differs between instruments. Since it is usually painless and intermittent, the diagnosis is often delayed and it is commonly misdiagnosed as being an overuse disorder or tendon pathology. It arises from pathological brain plasticity: physiological studies suggest that it is an exaggeration of brain changes that are required to achieve advanced musical skills. Its treatment often has limited success; however, musical retraining, botulinum toxin or rehabilitation based on modifying the aberrant plasticity may help. PMID- 26023203 TI - Spatial neglect. AB - The syndrome of visuospatial neglect is a common consequence of unilateral brain injury. It is most often associated with stroke and is more severe and persistent following right hemisphere damage, with reported frequencies in the acute stage of up to 80%. Neglect is primarily a disorder of attention whereby patients characteristically fail to orientate, to report or to respond to stimuli located on the contralesional side. Neglect is usually caused by large strokes in the middle cerebral artery territory and is heterogeneous, such that most patients do not manifest every feature of the syndrome. A number of treatments may improve neglect, but there is no widely accepted universal approach to therapy. Although most patients recover spontaneously, the evidence suggests that they continue to have significant cognitive impairments, particularly relating to attention. PMID- 26023205 TI - Paenibacillus xanthinilyticus sp. nov., isolated from agricultural soil. AB - A bacterial strain designated 11N27(T) was isolated from an agricultural soil sample. Cells of this strain were Gram-reaction-variable, facultatively anaerobic, endospore-forming, white-pigmented, peritrichously flagellated and hydrolysed xanthine. The major fatty acids of strain 11N27(T) were anteiso-C15 : 0, iso-C16 : 0 and C16 : 0. The polar lipid profile contained phosphatidylethanolamine, two unknown phospholipids, two unknown aminolipids, one unknown aminophospholipid and two unknown polar lipids. The G+C content of the genomic DNA of strain 11N27(T) was 50.3 mol%. MK-7 was the predominant respiratory quinone. meso-Diaminopimelic acid was the diagnostic diamino acid in the peptidoglycan. 16S rRNA gene sequence analysis showed that strain 11N27(T) was phylogenetically related to Paenibacillus mendelii C/2(T) (96.2% sequence similarity) and Paenibacillus sepulcri CMM 7311(T) (96.0%). The genotypic and phenotypic data showed that strain 11N27(T) could be distinguished from phylogenetically related species and that this strain represents a novel species of the genus Paenibacillus. The name Paenibacillus xanthinilyticus sp. nov. is proposed with the type strain 11N27(T)( = KACC 17935(T) = NBRC 109108(T)). PMID- 26023206 TI - Oceanobacillus arenosus sp. nov., a moderately halophilic bacterium isolated from marine sand. AB - A Gram-stain-positive, spore-forming, rod-shaped, motile, strictly aerobic bacterium, designated CAU 1183(T), was isolated from marine sand and its taxonomic position was investigated by using a polyphasic approach. The bacterium grew optimally at 30 degrees C, at pH 8.5 and in the presence of 2% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CAU 1183(T) formed a distinct lineage within the genus Oceanobacillus and exhibited the highest similarity to Oceanobacillus chungangensis CAU 1051(T) (97.6%). The strain contained MK-7 as the predominant isoprenoid quinone and anteiso-C15 : 0 was the major cellular fatty acid. The cell-wall peptidoglycan contained meso diaminopimelic acid. The polar lipid pattern of strain CAU 1183(T) consisted of diphosphatidylglycerol, phosphatidylglycerol and unidentified lipids, including two phospholipids, two glycolipids, a phosphoglycolipid and two lipids. The G+C content of the genomic DNA was 37.5 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain CAU 1183(T) should be assigned to a novel species in the genus Oceanobacillus, for which the name Oceanobacillus arenosus sp. nov. is proposed. The type strain is CAU 1183(T) ( = KCTC 33037(T) = CECT 8560(T)). PMID- 26023207 TI - Sphingobacterium mucilaginosum sp. nov., isolated from rhizosphere soil of a rose. AB - A Gram-stain-negative, strictly aerobic, motile, short-rod-shaped bacterium, designated strain THG-SQA8(T), was isolated from rhizosphere soil of rose in PR China. Strain THG-SQA8(T) was closely related to members of the genus Sphingobacterium, showed the highest sequence similarities with Sphingobacterium multivorum KACC 14105(T) (98.0%) and Sphingobacterium ginsenosidimutans KACC 14526(T) (97.4%). DNA-DNA hybridization showed values of 35.2 +/- 0.9% and 8.8 +/ 0.3% DNA reassociation with S. multivorum KACC 14105(T) and S. ginsenosidimutans KACC 14526(T), respectively. Chemotaxonomic data revealed that strain THG-SQA8(T) possesses menaquinone-7 as the only respiratory quinone, and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C1 : 0 and C16 : 0 as the major fatty acids. The major polar lipid was phosphatidylethanolamine. The DNA G+C content was 40.7 mol%. These data corroborated the affiliation of strain THG-SQA8(T) to the genus Sphingobacterium. Thus, the isolate represents a novel species, for which the name Sphingobacterium mucilaginosum sp. nov. is proposed, with THG SQA8(T) as the type strain ( = CCTCC AB 2014317(T) = KCTC 42503(T)). PMID- 26023208 TI - 'If you see something, say something': Reducing the incidence of deterioration in children. PMID- 26023209 TI - Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two 'old' antibiotics-polymyxin B and chloramphenicol. AB - OBJECTIVES: Combination therapy is an important option in the fight against Gram negative 'superbugs'. This study systematically investigated bacterial killing and the emergence of polymyxin resistance with polymyxin B and chloramphenicol combinations used against New Delhi metallo-beta-lactamase (NDM)-producing MDR Klebsiella pneumoniae. METHODS: Four NDM-producing K. pneumoniae strains were employed. The presence of genes conferring resistance to chloramphenicol was examined by PCR. Time-kill studies (inocula ~10(6) cfu/mL) were conducted using various clinically achievable concentrations of each antibiotic (range: polymyxin B, 0.5-2 mg/L; chloramphenicol, 4-32 mg/L), with real-time population analysis profiles documented at baseline and 24 h. The microbiological response was examined using the log change method and pharmacodynamic modelling in conjunction with scanning electron microscopy (SEM). RESULTS: Multiple genes coding for efflux pumps involved in chloramphenicol resistance were present in all strains. Polymyxin B monotherapy at all concentrations produced rapid bacterial killing followed by rapid regrowth with the emergence of polymyxin resistance; chloramphenicol monotherapy was largely ineffective. Combination therapy significantly delayed regrowth, with synergy observed in 25 out of 28 cases at both 6 and 24 h; at 24 h, no viable bacterial cells were detected in 15 out of 28 cases with various combinations across all strains. No polymyxin-resistant bacteria were detected with combination therapy. These results were supported by pharmacodynamic modelling. SEM revealed significant morphological changes following treatment with polymyxin B both alone and in combination. CONCLUSIONS: The combination of polymyxin B and chloramphenicol used against NDM-producing MDR K. pneumoniae substantially enhanced bacterial killing and suppressed the emergence of polymyxin resistance. PMID- 26023210 TI - Is reduced vancomycin susceptibility a factor associated with poor prognosis in MSSA bacteraemia? AB - OBJECTIVES: The known data about the influence of vancomycin MIC on Staphylococcus aureus bacteraemia are contradictory. Our objective was to study the possible impact of vancomycin MIC >=1.5 mg/L on short- and medium-term mortality. METHODS: A prospective cohort study was carried out from March 2008 to January 2011 on adult patients with MSSA bacteraemia admitted to a tertiary hospital located in Seville (Spain). We studied the relationship between vancomycin MIC, accessory gene regulator (agr) type and absence of delta haemolysin and poor prognosis. All isolates were genotyped by PFGE. Multivariate analysis, including a propensity score for having a vancomycin MIC of >=1.5 mg/L, was performed by Cox regression. RESULTS: One hundred and thirty-five episodes of bacteraemia due to MSSA were included in the analysis. Twenty-nine (21.5%) isolates had a vancomycin MIC of >=1.5 mg/L by Etest. There were no differences in agr distribution or absence of delta-haemolysin between isolates with reduced vancomycin susceptibility (RVS) and those without. RVS was not more frequent in specific clones; RVS was not associated with higher 14 or 30 day crude mortality (relative risk = 0.44, 95% CI = 0.14-1.35; and relative risk = 1.01, 95% CI = 0.52-1.96) rates, and it did not show higher rates of complicated bacteraemia (14.2% versus 13.8%, P = 0.61). Cox regression analysis did not significantly modify the results for 14 day mortality (HR = 0.39, 95% CI = 0.11-1.34) or 30 day mortality (HR = 0.89, 95% CI = 0.39-2.04). CONCLUSIONS: Contrary to previously published data, we did not find a relationship between RVS and higher mortality in patients with MSSA bacteraemia and we did not find a link with higher complicated bacteraemia rates. PMID- 26023211 TI - Genomic resistance island AGI1 carrying a complex class 1 integron in a multiply antibiotic-resistant ST25 Acinetobacter baumannii isolate. AB - OBJECTIVES: The objective of this study was to locate the antibiotic resistance determinants in the multiply antibiotic-resistant Acinetobacter baumannii isolate D4. METHODS: The genome was sequenced using Illumina HiSeq and assembled de novo using Velvet. PCR was used to link the relevant contigs and fill the gaps. Sequences were compared with ones in GenBank and annotated. RESULTS: A sporadic A. baumannii isolate D4, recovered in Sydney in 2006 from a wound, was multiply antibiotic resistant. D4 is ST25 (Institut Pasteur scheme) and exhibited resistance to third-generation cephalosporins and reduced susceptibility to ciprofloxacin, as well as resistance to aminoglycosides (gentamicin, kanamycin, neomycin and tobramycin) and further older antibiotics, nalidixic acid, sulfamethoxazole, streptomycin, spectinomycin and trimethoprim. The gyrA gene has a mutation consistent with nalidixic acid resistance. The bla PER conferring cephalosporin resistance, together with the aadB, aadA13/2, aadA2, strAB and sul1 resistance genes, are located within a 29 173 bp complex class 1 integron that includes three copies of intI1, three cassette arrays and two copies of the 3' conserved segment. This integron is adjacent to the resG gene of an integrative genomic resistance island, AGI1 (Acinetobacter genomic island 1), with a backbone related to that of islands in the SGI1, SGI2 and PGI1 families. AGI1 is located at the 3'-end of the chromosomal trmE (formerly thdF) gene. CONCLUSIONS: AGI1 represents a new lineage of genomic resistance islands that belongs in the same broad group as members of the SGI1, SGI2 and PGI1 families. Genes conferring resistance to cephalosporins, aminoglycosides and sulphonamides are located in a complex class 1 integron within AGI1. PMID- 26023212 TI - Residual HIV-1 replication may impact immune recovery in patients on first-line lopinavir/ritonavir monotherapy. AB - BACKGROUND: Antiretroviral combination therapy raises issues of long-term adherence and toxicity. Initial treatment simplification based on single-drug therapy was investigated in the MONARK trial, which compared first-line lopinavir/ritonavir monotherapy (arm A) with first-line lopinavir/ritonavir + zidovudine/lamivudine tritherapy (arm B). The MONARK trial is registered as a randomized trial at clinical trials.gov under identifier NCT 00234923. PATIENTS AND METHODS: Immune recovery was compared in patients with undetectable plasma virus (<50 copies/mL) after 60 weeks of treatment (arm A, n = 21; arm B, n = 13). RESULTS: The week 60 CD4 T cell count and CD4 T cell subset distribution did not differ significantly between the treatment arms. Memory CD4 T cell responses to HIV and recall antigens were better with triple therapy than with monotherapy. The frequencies of activated CD8 T cells and anti-HIV CD8 T cell effector responses were similar in the two arms. However, the repertoire of CD8 T cell effector responses was broader and persistent residual viraemia more frequent (by ultrasensitive PCR) in the monotherapy arm. CONCLUSIONS: While viral control can be achieved with first-line lopinavir/ritonavir monotherapy, the quality of immune recovery is inferior to that obtained with triple therapy, possibly owing to a higher level of residual viral replication. Thus, the benefits of first-line lopinavir/ritonavir monotherapy in terms of toxicity and adherence might be offset by an increased risk of residual viral replication, which may also fuel latent viral reservoirs. PMID- 26023214 TI - Predictive Value of General Movement Assessment for Cerebral Palsy in Routine Clinical Practice. AB - BACKGROUND: Early identification of children at high risk of future neurodevelopmental disability is important for the initiation of appropriate therapy. In research settings, the assessment of fidgety movements (FMs) at 3 months supports a general movement assessment (GMA) as a strong predictor for subsequent motor development, but there are few studies from routine clinical settings. OBJECTIVE: The study objective was to examine the relationship between FMs and neurodevelopmental outcome by the age of 2 years in high-risk infants in a routine hospital clinical setting. DESIGN: This was a prospective study. METHODS: A GMA was performed in 87 high-risk infants at 3 months after term age. The infants were clinically assessed for cerebral palsy (CP) at 2 years. Sensitivity, specificity, likelihood ratios, and positive and negative predictive values were computed. The relative risk of motor problems by the age of 2 years, according to the GMA, was estimated. RESULTS: Of the infants with normal FMs, 93% (50/54) had normal development and none was diagnosed with CP, whereas 75% (12/16) with abnormal or sporadic FMs had normal development. In contrast, 53% (9/17) of those without FMs had CP. When the GMA was considered to be a test for CP and absent FMs were considered to be a positive test result, the sensitivity was 90% and the specificity was 90%. The likelihood ratios for positive and negative test results were 8.7 and 0.1, respectively. The negative predictive value was 99%, and the positive predictive value was 53%. The risk of motor problems by the age of 2 years increased linearly with the extent of pathological results on the GMA and was 10 times higher when FMs were absent at 3 months than when FMs were normal. LIMITATIONS: The relatively small study sample was a study limitation. CONCLUSIONS: When applied in a routine clinical setting, the GMA strongly predicted neurodevelopmental impairments at 2 years in high-risk infants. PMID- 26023213 TI - Effects of Adding an Internet-Based Pain Coping Skills Training Protocol to a Standardized Education and Exercise Program for People With Persistent Hip Pain (HOPE Trial): Randomized Controlled Trial Protocol. AB - BACKGROUND: Persistent hip pain in older people is usually due to hip osteoarthritis (OA), a major cause of pain, disability, and psychological dysfunction. OBJECTIVE: The purpose of this study is to evaluate whether adding an Internet-based pain coping skills training (PCST) protocol to a standardized intervention of education followed by physical therapist-instructed home exercise leads to greater reductions in pain and improvements in function. DESIGN: An assessor-, therapist-, and participant-blinded randomized controlled trial will be conducted. SETTING: The study will be conducted in a community setting. PARTICIPANTS: The participants will be 142 people over 50 years of age with self reported hip pain consistent with hip OA. INTERVENTION: Participants will be randomly allocated to: (1) a control group receiving a 24-week standardized intervention comprising an 8-week Internet-based education package followed by 5 individual physical therapy exercise sessions plus home exercises (3 times weekly) or (2) a PCST group receiving an 8-week Internet-based PCST protocol in addition to the control intervention. MEASUREMENTS: Outcomes will be measured at baseline and 8, 24, and 52 weeks, with the primary time point at 24 weeks. Primary outcomes are hip pain on walking and self-reported physical function. Secondary outcomes include health-related quality-of-life, participant-perceived treatment response, self-efficacy for pain management and function, pain coping attempts, pain catastrophizing, and physical activity. Measurements of adherence, adverse events, use of health services, and process measures will be collected at 24 and 52 weeks. Cost-effectiveness will be assessed at 52 weeks. LIMITATIONS: A self-reported diagnosis of persistent hip pain will be used. CONCLUSIONS: The findings will help determine whether adding an Internet-based PCST protocol to standardized education and physical therapist-instructed home exercise is more effective than education and exercise alone for persistent hip pain. This study has the potential to guide clinical practice toward innovative modes of psychosocial health care provision. PMID- 26023215 TI - Self-Reported Disability: Association With Lower Extremity Performance and Other Determinants in Older Adults Attending Primary Care. AB - BACKGROUND: Measurement of function usually involves the use of both performance based and self-report instruments. However, the relationship between both types of measures is not yet completely understood, in particular for older adults attending primary care. OBJECTIVE: The main objective of the study was to investigate the association between the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) and the Short Physical Performance Battery (SPPB) for older adults at primary care. A secondary objective was to determine the influence of sociodemographic and health-related variables on this relationship. DESIGN: This was a cross-sectional study. METHODS: A total of 504 participants aged 60 years and older from 18 different primary care centers underwent a one-session assessment including: sociodemographic variables, comorbidities, performance, self-reported disability, pain, depressive symptoms, and physical activity. Performance was assessed using the SPPB, and self-reported disability was assessed using the WHODAS 2.0. RESULTS: The correlation between WHODAS 2.0 and SPPB scores was strong (r=.65). Regression analysis showed that the SPPB total score explained 41.7% of the variance in WHODAS 2.0 scores (adjusted R(2)=41.6%). A second model including the SPPB subtests (balance, gait, and sit-to-stand), depressive symptoms, number of pain sites, pain intensity, and level of physical activity explained 61.7% of the variance in WHODAS 2.0 scores (adjusted R(2)=60.4%). No model improvement was found when considering the 6 WHODAS 2.0 individual domains. LIMITATIONS: The cross-sectional nature of the study does not allow inferences on causal relationships. CONCLUSIONS: This study's findings confirm that self-report and performance-based measures relate to different aspects of functioning. Further study is needed to determine if primary care interventions targeting lower extremity performance and depressive symptoms improve self-reported disability. PMID- 26023216 TI - Comparison of Patterns of Physical Activity and Sedentary Behavior Between Children With Cerebral Palsy and Children With Typical Development. AB - BACKGROUND: Reduced participation in physical activity and increased time spent in sedentary behavior are associated with overweight, chronic disease, and disability. In order to optimize recommendations and interventions to increase physical activity and reduce sedentary behavior in children with cerebral palsy (CP), knowledge of their physical activity and sedentary behavior is needed. OBJECTIVES: The aim of this study was to describe light, moderate, and vigorous physical activity and sedentary behavior in preadolescent children with and without CP and compare physical activity and sedentary behavior between the 2 groups. DESIGN: This was a cross-sectional study of 33 children, aged 6 to 10 years, with CP (Gross Motor Function Classification System [GMFCS] levels I-III) and 33 age- and sex-matched children with typical development. METHODS: Physical activity was measured using the RT3 accelerometer over 7 days. RESULTS: Children with CP spent more time in sedentary behavior and accumulated less total activity, moderate activity, vigorous activity, and sustained bouts of moderate to-vigorous activity (MVPA). They also accumulated a fewer number of bouts of MVPA and vigorous activity, despite spending a similar amount of time in each bout. LIMITATIONS: The small number of children in GMFCS levels II and III did not allow for adjustment for GMFCS level when comparing physical activity between children with and without CP. CONCLUSIONS: Preadolescent children with CP spent less time in moderate and vigorous activity and more time in sedentary behavior than children with typical development. Children with CP also accumulated less continuous MVPA and vigorous activity as a result of achieving fewer sustained bouts of MVPA and vigorous activity throughout the day. PMID- 26023217 TI - Effectiveness of Soft Tissue Massage for Nonspecific Shoulder Pain: Randomized Controlled Trial. AB - BACKGROUND: Soft tissue massage and exercise are commonly used to treat episodes of shoulder pain. OBJECTIVE: The study objective was to compare the effects of soft tissue massage and exercise with those of exercise alone on pain, disability, and range of motion in people with nonspecific shoulder pain. DESIGN: This was a randomized controlled trial. SETTING: The study was conducted in public hospital physical therapy clinics in Sydney, New South Wales, Australia. PARTICIPANTS: The study participants were 80 people with an average age of 62.6 years (SD=12.2) who were referred to physical therapists for treatment of nonspecific shoulder pain. INTERVENTION: Participants were randomly assigned to either a group that received soft tissue massage around the shoulder and exercises (n=40) or a group that received exercise only (n=40) for 4 weeks. MEASUREMENTS: The primary outcome was improvement in pain, as measured on a 100 mm visual analog scale, 1 week after the cessation of treatment. Secondary outcomes were disability and active flexion, abduction, and hand-behind-back range of motion. Measurements were obtained at baseline, 1 week after the cessation of treatment, and 12 weeks after the cessation of treatment. RESULTS: The between-group difference in pain scores from the baseline to 12 weeks after the cessation of treatment demonstrated a small significant difference in favor of the group receiving exercise only (mean difference=14.7 mm). There were no significant differences between groups in any other variable. LIMITATIONS: It was not possible to mask therapists or participants to group allocation. Diagnostic tests were not used on participants to determine specific shoulder pathology. CONCLUSIONS: The addition of soft tissue massage to an exercise program for the shoulder conferred no additional benefit for improving pain, disability, or range of motion in people with nonspecific shoulder pain. PMID- 26023218 TI - Clinical Ratings of Pain Sensitivity Correlate With Quantitative Measures in People With Chronic Neck Pain and Healthy Controls: Cross-Sectional Study. AB - BACKGROUND: Correlations between clinical and quantitative measures of pain sensitivity are poor, making it difficult for clinicians to detect people with pain sensitivity. Clinical detection of pain sensitivity is important because these people have a different prognosis and may require different treatment. OBJECTIVE: The purpose of this study was to investigate the relationship between clinical and quantitative measures of pain sensitivity across individuals with and without neck pain. METHODS: This cross-sectional study included 40 participants with chronic neck pain and 40 age- and sex-matched controls. Participants underwent quantitative sensory testing of cold pain thresholds (CPTs) and pressure pain thresholds (PPTs). Clinical tests for pain sensitivity were the ice pain test and the pressure pain test. All tests were undertaken at standardized local (neck and upper trapezius muscles) and remote (wrist and tibialis anterior muscles) sites. Median and interquartile range (IQR) were calculated for neck pain and control groups, and parametric and nonparametric tests were used to compare groups. Correlation coefficients were calculated between quantitative and clinical measures. RESULTS: There were significant differences for clinical and quantitative measures of cold and pressure sensitivity between the neck pain and control groups (eg, CPT neck pain group: median=22.31 degrees C, IQR=18.58 degrees C; control group: median=5.0 degrees C, IQR=0.74 degrees C). Moderate-to-good correlations were found between the clinical ice pain test and CPT at all sites (.46 to .68) except at the wrist (.29 to .40). Fair correlations were found for the clinical pressure pain test and PPT (-.26 to -.45). Psychological variables contributing to quantitative measures of pain sensitivity included catastrophization, sleep quality, and female sex. LIMITATIONS: Clinical pressure pain tests were not quantitatively standardized in this study. CONCLUSIONS: The ice pain test may be useful as a clinical correlate of CPT at all sites except the wrist, whereas the pressure pain test is less convincing as a clinical correlate of PPT. PMID- 26023219 TI - Effects of Vibration Intensity, Exercise, and Motor Impairment on Leg Muscle Activity Induced by Whole-Body Vibration in People With Stroke. AB - BACKGROUND: Whole-body vibration (WBV) has increasingly been used as an adjunct treatment in neurological rehabilitation. However, how muscle activation level changes during exposure to different WBV protocols in individuals after stroke remains understudied. OBJECTIVE: The purpose of this study was to examine the influence of WBV intensity on the magnitude of biceps femoris (BF) and tibialis anterior (TA) muscle activity and its interaction with exercise and with severity of motor impairment and spasticity among individuals with chronic stroke. METHODS: Each of the 36 individuals with chronic stroke (mean age=57.3 years, SD=10.7) performed 8 different static exercises under 3 WBV conditions: (1) no WBV, (2) low-intensity WBV (frequency=20 Hz, amplitude=0.60 mm, peak acceleration=0.96g), and (3) high-intensity WBV (30 Hz, 0.44 mm, 1.61g). The levels of bilateral TA and BF muscle activity were recorded using surface electromyography (EMG). RESULTS: The main effect of intensity was significant. Exposure to the low-intensity and high-intensity protocols led to a significantly greater increase in normalized BF and TA muscle electromyographic magnitude in both legs compared with no WBV. The intensity * exercise interaction also was significant, suggesting that the WBV-induced increase in EMG activity was exercise dependent. The EMG responses to WBV were similar between the paretic and nonparetic legs and were not associated with level of lower extremity motor impairment and spasticity. LIMITATIONS: Leg muscle activity was measured during static exercises only. CONCLUSIONS: Adding WBV during exercise significantly increased EMG activity in the TA and BF muscles. The EMG responses to WBV in the paretic and nonparetic legs were similar and were not related to degree of motor impairment and spasticity. The findings are useful for guiding the design of WBV training protocols for people with stroke. PMID- 26023220 TI - Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) and Alberta Infant Motor Scale (AIMS): Validity and Responsiveness. AB - BACKGROUND: Although preliminary studies have established a good psychometric foundation for the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) for a broad population of youth with disabilities, additional validation is warranted for young children. OBJECTIVE: The study objective was to (1) examine concurrent validity, (2) evaluate the ability to identify motor delay, and (3) assess responsiveness of the PEDI-CAT Mobility domain and the Alberta Infant Motor Scale (AIMS). METHODS: Fifty-three infants and young children (<18 months of age) admitted to a pediatric postacute care hospital and referred for a physical therapist examination were included. The PEDI-CAT Mobility domain and the AIMS were completed during the initial physical therapist examination, at 3-month intervals, and at discharge. A Spearman rank correlation coefficient was used to examine concurrent validity. A chi-square analysis of age percentile scores was used to examine the identification of motor delay. Mean score differences from initial assessment to final assessment were analyzed to evaluate responsiveness. RESULTS: A statistically significant, fair association (rs=.313) was found for the 2 assessments. There was no significant difference in motor delay identification between tests; however, the AIMS had a higher percentage of infants with scores at or below the fifth percentile. Participants showed significant changes from initial testing to final testing on the PEDI-CAT Mobility domain and the AIMS. LIMITATIONS: This study included only young patients (<18 months of age) in a pediatric postacute hospital; therefore, the generalizability is limited to this population. CONCLUSIONS: The PEDI-CAT Mobility domain is a valid measure for young children admitted to postacute care and is responsive to changes in motor skills. However, further item and standardization development is needed before the PEDI-CAT is used confidently to identify motor delay in children <18 months of age. PMID- 26023221 TI - Oxidative capacity and glycogen content increase more in arm than leg muscle in sedentary women after intense training. AB - The hypothesis that the adaptive capacity is higher in human upper- than lower body skeletal muscle was tested. Furthermore, the hypothesis that more pronounced adaptations in upper-body musculature can be achieved by "low-volume high intensity" compared with "high-volume low-intensity" exercise training was evaluated. A group of sedentary premenopausal women aged 45 +/- 6 yr (+/- SD) with expected high adaptive potential in both upper- and lower-extremity muscle groups participated. After random allocation to high-intensity swimming (HIS, n = 21), moderate-intensity swimming (MOS, n = 21), soccer (SOC, n = 21) or a nontraining control group (CON, n = 20), the training groups completed three workouts per week for 15 wk. Resting muscle biopsies were obtained from the vastus lateralis muscle and deltoideus muscle before and after the intervention. After the training intervention, a larger (P < 0.05) increase existed in deltoideus muscle of the HIS group compared with vastus lateralis muscle of the SOC group for citrate synthase maximal activity (95 +/- 89 vs. 27 +/- 34%), citrate synthase protein expression (100 +/- 29 vs. 31 +/- 44%), 3-hydroxyacyl CoA dehydrogenase maximal activity (35 +/- 43 vs. 3 +/- 25%), muscle glycogen content (63 +/- 76 vs. 20 +/- 51%), and expression of mitochondrial complex II, III, and IV. Additionally, HIS caused higher (P < 0.05) increases than MOS in deltoideus muscle citrate synthase maximal activity, citrate synthase protein expression, and muscle glycogen content. In conclusion, the deltoideus muscle has a higher adaptive potential than the vastus lateralis muscle in sedentary women, and "high-intensity low-volume" training is a more efficient regime than "low intensity high-volume" training for increasing the aerobic capacity of the deltoideus muscle. PMID- 26023222 TI - An estimation of mechanical stress on alveolar walls during repetitive alveolar reopening and closure. AB - Alveolar overdistension and mechanical stresses generated by repetitive opening and closing of small airways and alveoli have been widely recognized as two primary mechanistic factors that may contribute to the development of ventilator induced lung injury. A long-duration exposure of alveolar epithelial cells to even small, shear stresses could lead to the changes in cytoskeleton and the production of inflammatory mediators. In this paper, we have made an attempt to estimate in situ the magnitudes of mechanical stresses exerted on the alveolar walls during repetitive alveolar reopening by using a tape-peeling model of McEwan and Taylor (35). To this end, we first speculate the possible ranges of capillary number (Ca) = MUU/gamma (a dimensionless combination of surface tension gamma, fluid viscosity MU, and alveolar opening velocity U) during in vivo alveolar opening. Subsequent calculations show that increasing respiratory rate or inflation rate serves to increase the values of mechanical stresses. For a normal lung, the predicted maximum shear stresses are <15 dyn/cm(2) at all respiratory rates, whereas for a lung with elevated surface tension or viscosity, the maximum shear stress will notably increase, even at a slow respiratory rate. Similarly, the increased pressure gradients in the case of elevated surface or viscosity may lead to a pressure drop >300 dyn/cm(2) across a cell, possibly inducing epithelial hydraulic cracks. In addition, we have conceived of a geometrical model of alveolar opening to make a prediction of the positive end expiratory pressure (PEEP) required to splint open a collapsed alveolus, which as shown by our results, covers a wide range of pressures, from several centimeters to dozens of centimeters of water, strongly depending on the underlying pulmonary conditions. The establishment of adequate regional ventilation-to-perfusion ratios may prevent recruited alveoli from reabsorption atelectasis and accordingly, reduce the required levels of PEEP. The present study and several recent animal experiments likewise suggest that a lung-protective ventilation strategy should not only include small tidal volume and plateau pressure limitations but also consider such cofactors as ventilation frequency and inflation rate. PMID- 26023223 TI - Depth-dependent variations in Achilles tendon deformations with age are associated with reduced plantarflexor performance during walking. AB - The anatomical arrangement of the Achilles tendon (AT), with distinct fascicle bundles arising from the gastrocnemius and soleus muscles, may facilitate relatively independent behavior of the triceps surae muscles. A reduced capacity for sliding between adjacent tendon fascicles with age may couple gastrocnemius and soleus muscle behavior, thereby potentially contributing to diminished plantarflexor performance commonly observed in old adults. Nine healthy young (mean age, 23.9 yr) and eight healthy old (69.9 yr) adults walked at three speeds (0.75, 1.00, and 1.25 m/s) on a force-sensing treadmill. We coupled dynamic ultrasound imaging of the free AT with motion capture and inverse dynamic analyses to compute, in part: 1) depth-dependent variations in AT tissue displacements and elongations and 2) net ankle joint kinetics during push-off. The difference in displacements between superficial and deep AT regions, and in their corresponding elongations, did not differ between old and young adults at the slower two walking speeds (P > 0.61). However, old adults walked with 41% smaller depth-dependent variations in free AT displacements and elongations at 1.25 m/s (P = 0.02). These more uniform tendon deformations in old adults most strongly correlated with reduced peak ankle moment (R(2) = 0.40), but also significantly correlated with reduced peak power generation (R(2) = 0.15) and positive ankle work during push-off (R(2) = 0.19) (P > 0.01). Our findings: 1) demonstrate a potential role for nonuniform AT deformations in governing gastrocnemius and soleus muscle-tendon function and 2) allude to altered tendon behavior that may contribute to the age-related reduction in plantarflexor performance during walking. PMID- 26023224 TI - Combined unilateral blockade of cholinergic, peptidergic, and serotonergic receptors in the ventral respiratory column does not affect breathing in awake or sleeping goats. AB - Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5 HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5 HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing (P >= 0.05) in goats that were awake or in non rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P (P < 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neuromodulator systems collaborate to stabilize breathing when a deficit in one or multiple excitatory neuromodulators exists. PMID- 26023225 TI - Pneumothorax effects on pulmonary acoustic transmission. AB - Pneumothorax (PTX) is an abnormal accumulation of air between the lung and the chest wall. It is a relatively common and potentially life-threatening condition encountered in patients who are critically ill or have experienced trauma. Auscultatory signs of PTX include decreased breath sounds during the physical examination. The objective of this exploratory study was to investigate the changes in sound transmission in the thorax due to PTX in humans. Nineteen human subjects who underwent video-assisted thoracic surgery, during which lung collapse is a normal part of the surgery, participated in the study. After subjects were intubated and mechanically ventilated, sounds were introduced into their airways via an endotracheal tube. Sounds were then measured over the chest surface before and after lung collapse. PTX caused small changes in acoustic transmission for frequencies below 400 Hz. A larger decrease in sound transmission was observed from 400 to 600 Hz, possibly due to the stronger acoustic transmission blocking of the pleural air. At frequencies above 1 kHz, the sound waves became weaker and so did their changes with PTX. The study elucidated some of the possible mechanisms of sound propagation changes with PTX. Sound transmission measurement was able to distinguish between baseline and PTX states in this small patient group. Future studies are needed to evaluate this technique in a wider population. PMID- 26023226 TI - The perturbation paradigm modulates error-based learning in a highly automated task: outcomes in swallowing kinematics. AB - Traditional motor learning studies focus on highly goal-oriented, volitional tasks that often do not readily generalize to real-world movements. The goal of this study was to investigate how different perturbation paradigms alter error based learning outcomes in a highly automated task. Swallowing was perturbed with neck surface electrical stimulation that opposes hyo-laryngeal elevation in 25 healthy adults (30 swallows: 10 preperturbation, 10 perturbation, and 10 postperturbation). The four study conditions were gradual-masked, gradual unmasked, abrupt-masked, and abrupt-unmasked. Gradual perturbations increasingly intensified overtime, while abrupt perturbations were sustained at the same high intensity. The masked conditions reduced cues about the presence/absence of the perturbation (pre- and postperturbation periods had low stimulation), but unmasked conditions did not (pre- and postperturbation periods had no stimulation). Only hyo-laryngeal range of motion measures had significant outcomes; no timing measure demonstrated learning. Systematic-error reduction occurred only during the abrupt-masked and abrupt-unmasked perturbations. Only the abrupt-masked perturbation caused aftereffects. In this highly automated task, gradual perturbations did not induce learning similarly to findings of some volitional, goal-oriented adaptation task studies. Furthermore, our subtle and brief adjustment of the stimulation paradigm (masked vs. unmasked) determined whether aftereffects were present. This suggests that, in the unmasked group, sensory predictions of a motor plan were quickly and efficiently modified to disengage error-based learning behaviors. PMID- 26023227 TI - l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. AB - The purpose of this study was to compare the effects of l-citrulline (Cit) and l arginine (Arg) supplementation on nitric oxide (NO) biomarkers, pulmonary O2 uptake (Vo2) kinetics, and exercise performance. In a randomized, placebo (Pla) controlled, crossover study, 10 healthy adult men completed moderate- and severe intensity cycling exercise on days 6 and 7 of a 7-day supplementation period with Pla, Arg (6 g/day), and Cit (6 g/day). Compared with Pla, plasma Arg concentration was increased by a similar magnitude with Arg and Cit supplementation, but plasma Cit concentration was only increased (P < 0.001) with Cit supplementation. Plasma nitrite (NO2 (-)) concentration was increased with Arg supplementation (P < 0.05) and tended to increase with Cit supplementation (P = 0.08) compared with Pla (83 +/- 25, 106 +/- 41, and 100 +/- 38 nM with Pla, Arg, and Cit, respectively); however, mean arterial blood pressure was only lower (P < 0.05) after Cit supplementation. The steady-state Vo2 amplitude during moderate-intensity cycle exercise was not significantly different between supplements, but Cit lowered the Vo2 mean response time (59 +/- 8 and 53 +/- 5 s with Pla and Cit, respectively, P < 0.05) during severe-intensity exercise, improved tolerance to severe-intensity exercise (589 +/- 101 and 661 +/- 107 s with Pla and Cit, respectively), and increased the total amount of work completed in the exercise performance test (123 +/- 18 and 125 +/- 19 kJ with Pla and Cit, respectively, P < 0.05). These variables were not altered by Arg supplementation (P > 0.05). In conclusion, these results suggest that short-term Cit, but not Arg, supplementation can improve blood pressure, Vo2 kinetics, and exercise performance in healthy adults. PMID- 26023229 TI - Apoptotic lymphocytes induce progenitor cell mobilization after exercise. AB - There is evidence that apoptotic cells and their components have immunmodulatory properties and signaling function. The present study investigated first whether exercise-induced apoptosis and exercise-induced mobilization of progenitor cells are similarly affected by subjects' training status and, second, whether the appearance of dying cells in the circulation might mobilize progenitor cells. CD1 SWISS mice were subjected to a 10-wk endurance training using free wheel running or served as untrained controls. Mice of both groups performed an intensive exercise test after the training period at a velocity corresponding to 80% maximal oxygen uptake for 30 min. Cells from blood and bone marrow were analyzed, and apoptosis and number of progenitor cells determined via flow cytometry. In a second experiment, apoptotic cells were transferred into recipient mice, and mobilization of progenitor cells was analyzed while vital cells served as controls. In untrained animals, the exhaustive exercise was followed by an enhanced rate of annexin V positive CD3(+) cells in blood and bone marrow (P < 0.05), whereas no increase was found in trained mice. Similarly, exercise mobilized Sca-1(+)/c-kit(+) and Sca-1(+)/Flk(+) cells in untrained (P < 0.05) but not trained mice. Furthermore, application of apoptotic cells and their supernatant mobilized Sca-1(+)/c-kit(+) cells into the blood (P < 0.05), whereas Sca-1(+)/Flk(+) cells were not affected. The present study demonstrated that both lymphocyte apoptosis, as well as mobilization of progenitor cells are similarly related to training status. Furthermore, apoptotic cells seem to induce signals that effectively mobilize hematopoietic progenitor cells. The relevance of this effect for the adaptation to exercise stimuli remains to be shown. PMID- 26023228 TI - Skeletal muscle vasodilation during systemic hypoxia in humans. AB - In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite significant reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that 1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; 2) PGs do not normally contribute to vascular tone during hypoxia, however, they do affect vascular tone when NO is inhibited; 3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and 4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, skeletal muscle blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts augmented vasodilation and hyperemia compared with control (normoxic) conditions by ~50%; however, in contrast to hypoxia alone, the response is not abolished, suggesting that other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release, or nitrite reduction to NO, or both likely play a role in regulating this response. PMID- 26023231 TI - The effect of prenatal maternal infection on respiratory function in mouse offspring: evidence for enhanced chemosensitivity. AB - Systemic maternal inflammation is implicated in preterm birth and bronchopulmonary dysplasia (BPD) and may induce morbidities including reduced pulmonary function, sleep-disordered breathing, and cardiovascular disorders. Here we test the hypothesis that antenatal maternal inflammation per se causes altered alveolar development and increased chemoreflex sensitivity that persists beyond infancy. Pregnant C57BL/6 mice were administered lipopolysaccharide (LPS) (150 MUg/kg ip) to induce maternal inflammation or saline (SHAM) at embryonic day 16 (randomized). Pups were weighed daily. On days 7, 28, and 60 (D07, D28, and D60), unrestrained wholebody plethysmography quantified ventilation and chemoreflex responses to hypoxia (10%), hypercapnia (7%), and asphyxia (hypoxic hypercapnia). Lungs were harvested to quantify alveolar number, size, and septal thickness. LPS pups had reduced baseline ventilation per unit bodyweight (~40%, P < 0.001) vs. SHAM. LPS increased ventilatory responses to hypoxia (D07: 66% vs. 28% increase in ventilation; P < 0.001) hypercapnia (170% vs. 88%; P < 0.001), and asphyxia (249% vs. 154%; P < 0.001); hypersensitive hypoxic responsiveness persisted until D60 (P < 0.001). LPS also increased apnea frequency (P < 0.01). LPS caused thicker alveolar septae (D07, P < 0.001), diminished alveolar number (D28, P < 0.001) vs. SHAM, but effects were minimal by D60. Pups delivered from mothers exposed to antenatal inflammation exhibit deficits in lung structure and hypersensitive responses to respiratory stimuli that persist beyond the newborn period. Antenatal inflammation may contribute to impaired gas exchange and unstable breathing in newborn infants and adversely affect long-term health. PMID- 26023230 TI - Aging is associated with altered vasodilator kinetics in dynamically contracting muscle: role of nitric oxide. AB - We tested the hypothesis that aging would be associated with slowed vasodilator kinetics in contracting muscle in part due to a reduced nitric oxide (NO) bioavailability. Young (n = 10; 24 +/- 2 yr) and older (n = 10; 67 +/- 2 yr) adults performed rhythmic forearm exercise (4 min each) at 10, 20, and 30% of max during saline infusion (control) and NO synthase (NOS) inhibition. Brachial artery diameter and velocities were measured using Doppler ultrasound. Forearm vascular conductance (FVC) was calculated for each duty cycle (1 s contraction/2 s relaxation) from forearm blood flow (FBF; ml/min) and blood pressure (mmHg) and fit with a monoexponential model. The main parameters derived from the model were the amplitude of the FBF and FVC response and the number of duty cycles for FBF and FVC to change 63% of the steady-state amplitude (tauFBF and tauFVC). Under control conditions 1) the amplitude of the FVC response at 30% maximal voluntary contraction (MVC) was lower in older compared with young adults (319 +/- 33 vs. 462 +/- 52 ml.min(-1).100 mmHg(-1); P < 0.05) and 2) tauFVC was slower in older (10 +/- 1, 13 +/- 1, and 15 +/- 1 duty cycles) compared with young (6 +/- 1, 9 +/ 1, and 11 +/- 1 duty cycles) adults at all intensities (P < 0.05). In young adults, NOS inhibition blunted the amplitude of the FVC response at 30% MVC and prolonged the tauFVC at all intensities (10 +/- 2, 12 +/- 1, and 16 +/- 2 duty cycles; P < 0.05), whereas it did not change in older adults. Our data indicate that the blood flow and vasodilator kinetics in exercising muscle are altered with aging possibly due to blunted NO signaling. PMID- 26023232 TI - Role of the Cytosolic Loop C2 and the C Terminus of YidC in Ribosome Binding and Insertion Activity. AB - Members of the YidC/Oxa1/Alb3 protein family mediate membrane protein insertion, and this process is initiated by the assembly of YidC.ribosome nascent chain complexes at the inner leaflet of the lipid bilayer. The positively charged C terminus of Escherichia coli YidC plays a significant role in ribosome binding but is not the sole determinant because deletion does not completely abrogate ribosome binding. The positively charged cytosolic loops C1 and C2 of YidC may provide additional docking sites. We performed systematic sequential deletions within these cytosolic domains and studied their effect on the YidC insertase activity and interaction with translation-stalled (programmed) ribosome. Deletions within loop C1 strongly affected the activity of YidC in vivo but did not influence ribosome binding or substrate insertion, whereas loop C2 appeared to be involved in ribosome binding. Combining the latter deletion with the removal of the C terminus of YidC abolished YidC-mediated insertion. We propose that these two regions play an crucial role in the formation and stabilization of an active YidC.ribosome nascent chain complex, allowing for co-translational membrane insertion, whereas loop C1 may be involved in the downstream chaperone activity of YidC or in other protein-protein interactions. PMID- 26023233 TI - Generation of Dopamine Neurons from Rodent Fibroblasts through the Expandable Neural Precursor Cell Stage. AB - Recent groundbreaking work has demonstrated that combined expression of the transcription factors Brn2, Ascl1, and Myt1L (BAM; also known as Wernig factors) convert mouse fibroblasts into postmitotic neuronal cells. However, questions remain regarding whether trans-conversion is achieved directly or involves an intermediary precursor stage. Trans-conversion toward expandable neural precursor cells (NPCs) is more useful than direct one-step neuron formation with respect to yielding a sufficient number of cells and the feasibility of manipulating NPC differentiation toward certain neuron subtypes. Here, we show that co-expression of Wernig factors and Bcl-xL induces fibroblast conversion into NPCs (induced NPCs (iNPCs)) that are highly expandable for >100 passages. Gene expression analyses showed that the iNPCs exhibited high expression of common NPC genes but not genes specific to defined embryonic brain regions. This finding indicated that a regional identity of iNPCs was not established. Upon induction, iNPCs predominantly differentiated into astrocytes. However, the differentiation potential was not fixed and could be efficiently manipulated into general or specific subtypes of neurons by expression of additional genes. Specifically, overexpression of Nurr1 and Foxa2, transcription factors specific for midbrain dopamine neuron development, drove iNPCs to yield mature midbrain dopamine neurons equipped with presynaptic DA neuronal functions. We further assessed the therapeutic potential of iNPCs in Parkinson disease model rats. PMID- 26023234 TI - STAP-2 Protein Expression in B16F10 Melanoma Cells Positively Regulates Protein Levels of Tyrosinase, Which Determines Organs to Infiltrate in the Body. AB - Melanoma is the most serious type of skin cancer, with a highly metastatic phenotype. In this report, we show that signal transducing adaptor protein 2 (STAP-2) is involved in cell migration, proliferation, and melanogenesis as well as chemokine receptor expression and tumorigenesis in B16F10 melanoma cells. This was evident in mice injected with STAP-2 shRNA (shSTAP-2)-expressing B16F10 cells, which infiltrated organs in a completely different pattern from the original cells, showing massive colonization in the liver, kidney, and neck but not in the lung. The most important finding was that STAP-2 expression determined tyrosinase protein content. STAP-2 colocalized with tyrosinase in lysosomes and protected tyrosinase from protein degradation. It is noteworthy that B16F10 cells with knocked down tyrosinase showed similar cell characteristics as shSTAP-2 cells. These results indicated that tyrosinase contributed to some cellular events beyond melanogenesis. Taken together, one possibility is that STAP-2 positively regulates the protein levels of tyrosinase, which determines tumor invasion via controlling chemokine receptor expression. PMID- 26023235 TI - Structural Basis of a Key Factor Regulating the Affinity between the Zonula Occludens First PDZ Domain and Claudins. AB - The molecular seal between epithelial cells, called the tight junction (TJ), is built by several membrane proteins, with claudins playing the most prominent role. The scaffold proteins of the zonula occludens family are required for the correct localization of claudins and hence formation of the TJ. The intracellular C terminus of claudins binds to the N-terminal PDZ domain of zonula occludens proteins (PDZ1). Of the 23 identified human claudin proteins, nine possess a tyrosine at the -6 position. Here we show that the claudin affinity for PDZ1 is dependent on the presence or absence of this tyrosine and that the affinity is reduced if the tyrosine is modified by phosphorylation. The PDZ1 beta2-beta3 loop undergoes a significant conformational change to accommodate this tyrosine. Cell culture experiments support a regulatory role for this tyrosine. Plasticity has been recognized as a critical property of TJs that allow cell remodeling and migration. Our work provides a molecular framework for how TJ plasticity may be regulated. PMID- 26023236 TI - Oviductosome-Sperm Membrane Interaction in Cargo Delivery: DETECTION OF FUSION AND UNDERLYING MOLECULAR PLAYERS USING THREE-DIMENSIONAL SUPER-RESOLUTION STRUCTURED ILLUMINATION MICROSCOPY (SR-SIM). AB - Oviductosomes ((OVS), exosomes/microvesicles), which deliver the Ca(2+) efflux pump, plasma membrane Ca(2+)ATPase 4 (PMCA4), to sperm are likely to play an important role in sperm fertilizing ability (Al-Dossary, A. A., Strehler, E. E., and Martin-DeLeon, P. A. (2013) PloS one 8, e80181). It is unknown how exosomes/microvesicles deliver transmembrane proteins such as PMCA4 to sperm. Here we define a novel experimental approach for the assessment of the interaction of OVS with sperm at a nanoscale level, using a lipophilic dye (FM4 64FX) and three-dimensional SR/SIM, which has an 8-fold increase in volumetric resolution, compared with conventional confocal microscopy. Coincubation assays detected fusion of prelabeled OVS with sperm, primarily over the head and midpiece. Immunofluorescence revealed oviductosomal delivery of PMCA4a to WT and Pmca4 KO sperm, and also endogenous PMCA4a on the inner acrosomal membrane. Fusion was confirmed by transmission immunoelectron microscopy, showing immunogold particles in OVS, and fusion stalks on sperm membrane. Immunofluorescence colocalized OVS with the alphav integrin subunit which, along with CD9, resides primarily on the sperm head and midpiece. In capacitated and acrosome reacted sperm, fusion was significantly (p < 0.001) inhibited by blocking integrin/ligand interactions via antibodies, exogenous ligands (vitronectin and fibronectin), and their RGD recognition motif. Our results provide evidence that receptor/ligand interactions, involving alphavbeta3 and alpha5beta1integrins on sperm and OVS, facilitate fusion of OVS in the delivery of transmembrane proteins to sperm. The mechanism uncovered is likely to be also involved in cargo delivery of prostasomes, epididymosomes, and uterosomes. PMID- 26023237 TI - Increased Serine-Arginine (SR) Protein Phosphorylation Changes Pre-mRNA Splicing in Hypoxia. AB - The removal of introns from mRNA precursors (pre-mRNAs) is an essential step in eukaryotic gene expression. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to altered cellular conditions. Inhibitory PAS domain protein (IPAS), a dominant negative regulator of hypoxia-inducible gene expression, is generated from hypoxia inducible transcription factor-3alpha (HIF-3alpha) pre-mRNA by an alternative splicing mechanism. Inactivation of the IPAS transcript in mice leads to the neo vascularization of the cornea, suggesting that IPAS is an important regulator of anti-angiogenesis in this tissue. For the first time we demonstrate that serine arginine (SR) proteins are involved in oxygen tension-dependent changes in pre mRNA splicing. SR proteins isolated from hypoxic cells differentially interact with RNA (compared with proteins isolated from cells cultured under normoxic conditions). They possess the differential ability to activate hypoxia-dependent splice sites, and they are more phosphorylated than those isolated from normoxic HeLa cells. We also show that expression of SR protein kinases (CLK1, SRPK1, SRPK2) in hypoxic cells is elevated at mRNA and protein levels. Increased expression of CLK1 kinase is regulated by HIFs. Reduction of CLK1 cellular expression levels reduces hypoxia-dependent full-length carbonic anhydrase IX (CAIX) mRNA and CAIX protein formation and changes hypoxia-dependent cysteine rich angiogenic inducer 61 (Cyr61) mRNA isoform formation profiles. PMID- 26023238 TI - Pancreatic alpha-Amylase Controls Glucose Assimilation by Duodenal Retrieval through N-Glycan-specific Binding, Endocytosis, and Degradation. AB - alpha-Amylase, a major pancreatic protein and starch hydrolase, is essential for energy acquisition. Mammalian pancreatic alpha-amylase binds specifically to glycoprotein N-glycans in the brush-border membrane to activate starch digestion, whereas it significantly inhibits glucose uptake by Na(+)/glucose cotransporter 1 (SGLT1) at high concentrations (Asanuma-Date, K., Hirano, Y., Le, N., Sano, K., Kawasaki, N., Hashii, N., Hiruta, Y., Nakayama, K., Umemura, M., Ishikawa, K., Sakagami, H., and Ogawa, H. (2012) Functional regulation of sugar assimilation by N-glycan-specific interaction of pancreatic alpha-amylase with glycoproteins of duodenal brush border membrane. J. Biol. Chem. 287, 23104-23118). However, how the inhibition is stopped was unknown. Here, we show a new mechanism for the regulation of intestinal glucose absorption. Immunohistochemistry revealed that alpha-amylase in the duodena of non-fasted, but not fasted, pigs was internalized from the pancreatic fluid and immunostained. We demonstrated that after N-glycan binding, pancreatic alpha-amylase underwent internalization into lysosomes in a process that was inhibited by alpha-mannoside. The internalized alpha-amylase was degraded, showing low enzymatic activity and molecular weight at the basolateral membrane. In a human intestinal Caco-2 cell line, Alexa Fluor 488-labeled pancreatic alpha-amylase bound to the cytomembrane was transported to lysosomes through the endocytic pathway and then disappeared, suggesting degradation. Our findings indicate that N-glycan recognition by alpha-amylase protects enterocytes against a sudden increase in glucose concentration and restores glucose uptake by gradual internalization, which homeostatically controls the postprandial blood glucose level. The internalization of alpha-amylase may also enhance the supply of amino acids required for the high turnover of small intestine epithelial cells. This study provides novel and significant insights into the control of blood sugar during the absorption stage in the intestine. PMID- 26023240 TI - Direct estimation of differential networks. AB - It is often of interest to understand how the structure of a genetic network differs between two conditions. In this paper, each condition-specific network is modeled using the precision matrix of a multivariate normal random vector, and a method is proposed to directly estimate the difference of the precision matrices. In contrast to other approaches, such as separate or joint estimation of the individual matrices, direct estimation does not require those matrices to be sparse, and thus can allow the individual networks to contain hub nodes. Under the assumption that the true differential network is sparse, the direct estimator is shown to be consistent in support recovery and estimation. It is also shown to outperform existing methods in simulations, and its properties are illustrated on gene expression data from late-stage ovarian cancer patients. PMID- 26023241 TI - Demographic Patterns of Cumulative Arrest Prevalence By Ages 18 and 23. AB - In this study, we examine race, sex, and self-reported arrest histories (excluding arrests for minor traffic violations) from the 1997 National Longitudinal Survey of Youth (NLSY; N = 7,335) for the period 1997 through 2008 covering cumulative arrest histories through ages 18 and 23. The analysis produces three key findings: (1) males have higher cumulative prevalence of arrest than females; and (2) there are important race differences in the probability of arrest for males but not for females. Assuming the missing cases are missing at random, about 30% of black males have experienced at least one arrest by age 18 (vs. about 22% for white males); by age 23 about 49% of black males have been arrested (vs. about 38% for white males). Earlier research using the NLSY showed that the risk of arrest by age 23 was 30%, with nonresponse bounds [25.3%, 41.4%]. This study indicates that the risk of arrest is not evenly distributed across the population. Future research should focus on the identification and management of collateral risks that often accompany arrest experiences. PMID- 26023239 TI - Signaling through the Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Axis Is Responsible for Aerobic Glycolysis mediated by Glucose Transporter in Epidermal Growth Factor Receptor (EGFR)-mutated Lung Adenocarcinoma. AB - Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6 phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells. PMID- 26023243 TI - The Innuendo Effect: Hearing the Positive but Inferring the Negative. AB - Speakers can convey mixed impressions by providing only positive information. As a series of studies shows, when communicators omit information on a salient, relevant dimension of social perception, listeners make negative inferences about the target on that omitted dimension, despite directly receiving only positive information on another dimension (Studies 1 and 2a). These negative inferences mediated the effect of the innuendo manipulation on judgments about the target person's suitability for inclusion in one's group. Simulating communication, Study 2b participants read Study 2a's descriptions and showed this innuendo effect is stronger for descriptions of female as opposed to male targets in an academic domain. We discuss implications of innuendo for the communication and perpetuation of mixed impressions and their prevalence in descriptions of subordinate group members. PMID- 26023242 TI - Variation of Magnetic Particle Imaging Tracer Performance With Amplitude and Frequency of the Applied Magnetic Field. AB - The magnetic response of magnetic particle imaging (MPI) tracers varies with the slew rate of the applied magnetic field, as well as with the tracer's average magnetic core size. Currently, 25 kHz and 20 mT/MU0 drive fields are common in MPI, but lower field amplitudes may be necessary for patient safety in future designs. We studied how several different sizes of monodisperse MPI tracers behaved under different drive field amplitude and frequency, using magnetic particle spectrometry and ac hysteresis for drive field conditions at 16, 26, and 40 kHz, with field amplitudes from 5 to 40 mT/MU0. We observed that both field amplitude and frequency can influence the tracer behavior, but that the magnetic behavior is consistent when the slew rate (the product of field amplitude and frequency) is consistent. However, smaller amplitudes provide a correspondingly smaller field of view, sometimes resulting in excitation of a minor hysteresis loop. PMID- 26023244 TI - Exiting and Returning to the Parental Home for Boomerang Kids. AB - Young adults commonly exit from and return to the parental home, yet few studies have examined the motivation behind these exits and returns using a life course framework. Using data from the National Longitudinal Survey of Youth 1997, the authors examined associations between mental health problems and economic characteristics and exits from (n = 8,162), and returns to (n = 6,530), the parental home during the transition to adulthood. The average age of the respondents was 24 years. The authors found evidence that mental health and economic characteristics were related to home leaving and returning. Emotional distress was associated with earlier exits from, and returns to, the parental home; alcohol problems were associated with earlier returns to the parental home. The findings regarding economic resources were unexpectedly mixed. Greater economic resources were linked to delayed exits from, and earlier returns to, the parental home. The implications of these findings for young adults are discussed. PMID- 26023245 TI - Derivation of a new parametric impulse response matrix utilized for nodal wind load identification by response measurement. AB - This paper provides new formulations to derive the impulse response matrix, which is then used in the problem of load identification with application to wind induced vibration. The applied loads are inversely identified based on the measured structural responses by solving the associated discrete ill-posed problem. To this end - based on an existing parametric structural model - the impulse response functions of acceleration, velocity and displacement have been computed. Time discretization of convolution integral has been implemented according to an existing and a newly proposed procedure, which differ in the numerical integration methods. The former was evaluated based on a constant rectangular approximation of the sampled data and impulse response function in a number of steps corresponding to the sampling rate, while the latter interpolates the sampled data in an arbitrary number of sub-steps and then integrates over the sub-steps and steps. The identification procedure was implemented for a simulation example as well as an experimental laboratory case. The ill conditioning of the impulse response matrix made it necessary to use Tikhonov regularization to recover the applied force from noise polluted measured response. The optimal regularization parameter has been obtained by L-curve and GCV method. The results of simulation represent good agreement between identified and measured force. In the experiments the identification results based on the measured displacement as well as acceleration are provided. Further it is shown that the accuracy of experimentally identified load depends on the sensitivity of measurement instruments over the different frequency ranges. PMID- 26023246 TI - Recession and Divorce in the United States, 2008-2011. AB - Recession may increase divorce through a stress mechanism, or reduce divorce by exacerbating cost barriers or strengthening family bonds. After establishing an individual-level model predicting U.S. women's divorce, the paper tests period effects, and whether unemployment and foreclosures are associated with the odds of divorce using the 2008-2011 American Community Survey. Results show a downward spike in the divorce rate after 2008, almost recovering to the expected level by 2011, which suggests a negative recession effect. On the other hand, state foreclosure rates are positively associated with the odds of divorce with individual controls, although this effect is not significant when state fixed effects are introduced. State unemployment rates show no effect on odds of divorce. Future research will have to determine why national divorce odds fell during the recession while state-level economic indicators were not strongly associated with divorce. Exploratory analysis which shows unemployment decreasing divorce odds for those with college degrees, while foreclosures have the opposite effect, provides one possible avenue for such research. PMID- 26023247 TI - Bucking the Trend: Is Ethnoracial Diversity Declining in American Communities? AB - Although increasing diversity at the national scale is a well-documented trend, substantial variation in patterns of ethnoracial change occurs across American communities. Our research considers one theoretically implied path: that some communities are 'bucking the trend', becoming more homogeneous over time. Using 1980 through 2010 decennial census data, we calculate panethnic (five-group) entropy index scores to measure the magnitude of diversity for nearly 11,000 census-defined places. Our results indicate that while certain places reach their diversity peak in 1980 or 1990, they are few in number. Moreover, they experience a variety of post-peak trajectories other than monotonic diversity decline. Decreasing diversity is concentrated in the South and West, among places with higher levels of diversity and larger proportions of Hispanic or black residents at the beginning of the study period. These places exhibit complex shifts in racial-ethnic structure, but Hispanic succession predominates. PMID- 26023248 TI - Longitudinal graph-based segmentation of macular OCT using fundus alignment. AB - Segmentation of retinal layers in optical coherence tomography (OCT) has become an important diagnostic tool for a variety of ocular and neurological diseases. Currently all OCT segmentation algorithms analyze data independently, ignoring previous scans, which can lead to spurious measurements due to algorithm variability and failure to identify subtle changes in retinal layers. In this paper, we present a graph-based segmentation framework to provide consistent longitudinal segmentation results. Regularization over time is accomplished by adding weighted edges between corresponding voxels at each visit. We align the scans to a common subject space before connecting the graphs by registering the data using both the retinal vasculature and retinal thickness generated from a low resolution segmentation. This initial segmentation also allows the higher dimensional temporal problem to be solved more efficiently by reducing the graph size. Validation is performed on longitudinal data from 24 subjects, where we explore the variability between our longitudinal graph method and a cross sectional graph approach. Our results demonstrate that the longitudinal component improves segmentation consistency, particularly in areas where the boundaries are difficult to visualize due to poor scan quality. PMID- 26023249 TI - Segmentation of microcystic macular edema in Cirrus OCT scans with an exploratory longitudinal study. AB - Microcystic macular edema (MME) is a term used to describe pseudocystic spaces in the inner nuclear layer (INL) of the human retina. It has been noted in multiple sclerosis (MS) as well as a variety of other diseases. The processes that lead to MME formation and their change over time have yet to be explained sufficiently. The low rate at which MME occurs within such diverse patient groups makes the identification and consistent quantification of this pathology important for developing patient-specific prognoses. MME is observed in optical coherence tomography (OCT) scans of the retina as changes in light reflectivity in a pattern suggestive of fluid accumulations called pseudocysts. Pseudocysts can be readily identified in higher signal-to-noise ratio (SNR) images, however pseudocysts can be indistinguishable from noise in lower SNR scans. In this work, we expand upon our earlier MME identification methods on Spectralis OCT scans to handle lower quality Cirrus OCT scans. Our approach uses a random forest classifier, trained on manual segmentation of ten subjects, to automatically detect MME. The algorithm has a true positive rate for MME identification of 0.95 and a Dice score of 0.79. We include a preliminary longitudinal study of three patients over four to five years to explore the longitudinal changes of MME. The patients with relapsing-remitting MS and neuromyelitis optica appear to have dynamic pseudocyst volumes, while the MME volume appears stable in the one patient with primary progressive MS. PMID- 26023250 TI - Ontogeny of worker body size distribution in bumble bee (Bombus impatiens) colonies. AB - Bumble bees exhibit worker size polymorphisms; highly related workers within a colony may vary up to 10-fold in body mass. As size variation is an important life history feature in bumble bees, the distribution of body sizes within the colony and how it fluctuates over the colony cycle were analysed.Ten commercially purchased colonies of Bombus impatiens (Cresson) were reared in ad libitum conditions. The size of all workers present and newly emerging workers (callows) was recorded each week.The average size of bumble bee workers did not change with colony age, but variation in body size tended to decrease over time. The average size of callows did not change with population size, but did tend to decrease with colony age. In all measures, there was considerable variation among colonies.Colonies of B. impatiens usually produced workers with normally distributed body sizes throughout the colony life cycle. Unlike most polymorphic ants, there was no increase in worker body size with colony age or colony size. This provides the first, quantitative data on the ontogeny of bumble bee worker size distribution. The potential adaptive significance of this size variation is discussed. PMID- 26023251 TI - Moving Block Bootstrap for Analyzing Longitudinal Data. AB - In a longitudinal study subjects are followed over time. I focus on a case where the number of replications over time is large relative to the number of subjects in the study. I investigate the use of moving block bootstrap methods for analyzing such data. Asymptotic properties of the bootstrap methods in this setting are derived. The effectiveness of these resampling methods is also demonstrated through a simulation study. PMID- 26023253 TI - Significance tests for functional data with complex dependence structure. AB - We propose an L2-norm based global testing procedure for the null hypothesis that multiple group mean functions are equal, for functional data with complex dependence structure. Specifically, we consider the setting of functional data with a multilevel structure of the form groups-clusters or subjects-units, where the unit-level profiles are spatially correlated within the cluster, and the cluster-level data are independent. Orthogonal series expansions are used to approximate the group mean functions and the test statistic is estimated using the basis coefficients. The asymptotic null distribution of the test statistic is developed, under mild regularity conditions. To our knowledge this is the first work that studies hypothesis testing, when data have such complex multilevel functional and spatial structure. Two small-sample alternatives, including a novel block bootstrap for functional data, are proposed, and their performance is examined in simulation studies. The paper concludes with an illustration of a motivating experiment. PMID- 26023252 TI - Therapeutic prospects for spinocerebellar ataxia type 2 and 3. AB - Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are autosomal-dominant neurodegenerative disorders. SCA2 primarily affects cerebellar Purkinje neurons. SCA3 primarily affects dentate and pontine nuclei and substantia nigra. Both disorders belong to a class of polyglutamine (polyQ) expansion disorders. SCA2 is caused by a polyQ expansion in the amino-terminal region of a cytosolic protein ataxin-2 (Atxn2). SCA3 is caused by a polyQ expansion in the carboxy-terminal portion of a cytosolic protein ataxin-3 (Atxn3). Both disorders are found worldwide, but SCA2 is common among people of Cuban decent and SCA3 is common among people of Portuguese decent. No effective treatment exist for SCA2, SCA3 or any other polyQ-expansion disorder. Based on anecdotal evidence, a number of small scale clinical trials have been attempted previously for SCA2 and SCA3. These trials were underpowered and did not yield any promising results so far. A number of pathogenic mechanisms have been proposed to explain neuronal dysfunction and degeneration in SCA2 and SCA3. Knockdown of mutant Atxn2 and Atxn3 protein by RNAi or similar approach is most promising avenue of therapeutic development in the long term, but translation of this approach to clinic faces very serious technical challenges. Recent preclinical studies in SCA2 and SCA3 genetic mouse model suggested that abnormal neuronal calcium (Ca2+) signaling may play an important role in SCA2 and SCA3 pathology. These studies also suggested that dantrolene and other Ca2+ signaling inhibitors and stabilizers may have a therapeutic value for treatment of SCA2 and SCA3. Controlled clinical evaluation of dantrolene, memantine, riluzole, dihydropyridines, CoQ10, creatine or other Ca2+ blockers and stabilizers in SCA2 and SCA3 patients is necessary to test clinical importance of these ideas. The EUROSCA consortium provides a potential framework for such clinical evaluation. PMID- 26023254 TI - A Study of Long-Term fMRI Reproducibility Using Data-Driven Analysis Methods. AB - The reproducibility of functional magnetic resonance imaging (fMRI) is important for fMRI-based neuroscience research and clinical applications. Previous studies show considerable variation in amplitude and spatial extent of fMRI activation across repeated sessions on individual subjects even using identical experimental paradigms and imaging conditions. Most existing fMRI reproducibility studies were typically limited by time duration and data analysis techniques. Particularly, the assessment of reproducibility is complicated by a fact that fMRI results may depend on data analysis techniques used in reproducibility studies. In this work, the long-term fMRI reproducibility was investigated with a focus on the data analysis methods. Two spatial smoothing techniques, including a wavelet-domain Bayesian method and the Gaussian smoothing, were evaluated in terms of their effects on the long-term reproducibility. A multivariate support vector machine (SVM)-based method was used to identify active voxels, and compared to a widely used general linear model (GLM)-based method at the group level. The reproducibility study was performed using multisession fMRI data acquired from eight healthy adults over 1.5 years' period of time. Three regions-of-interest (ROI) related to a motor task were defined based upon which the long-term reproducibility were examined. Experimental results indicate that different spatial smoothing techniques may lead to different reproducibility measures, and the wavelet-based spatial smoothing and SVM-based activation detection is a good combination for reproducibility studies. On the basis of the ROIs and multiple numerical criteria, we observed a moderate to substantial within-subject long term reproducibility. A reasonable long-term reproducibility was also observed from the inter-subject study. It was found that the short-term reproducibility is usually higher than the long-term reproducibility. Furthermore, the results indicate that brain regions with high contrast-to-noise ratio do not necessarily exhibit high reproducibility. These findings may provide supportive information for optimal design/implementation of fMRI studies and data interpretation. PMID- 26023255 TI - Histological dermal changes caused by preparation and application procedures in percutaneous dose toxicity studies in dogs, rabbits and rats. AB - We reevaluated histological slides of dorsal skin in control animals from past percutaneous dose toxicity studies using dogs, rabbits and rats to provide background data concerning histological changes related to preparation and application procedures and vehicles or embrocations of every variety. Acanthosis, dermal or perifollicular inflammatory cell infiltration in dogs; hyperkeratosis, acanthosis, dermal inflammatory cell infiltration or hemorrhage in rabbits; and acanthosis, dermal inflammatory cell infiltration, crust or foreign body granuloma in rats were present as procedure-related underlying histological changes in the control animals. Four mechanical acts, (1) rubbing with gauze to remove an administered substance for reapplication, (2) use of a taut bandage to avoid slipping from the application site, (3) peeling a patch off as a preparation procedure for reapplication, and (4) clipping or shaving, were considered to cause injury to the skin. The degree of influence of the various application procedures was found to be as follows: sham, lotion < cream < ointment and tape in dogs; untreated control, sham < lotion < tape and poultice in rabbits; and sham, sodium carboxymethylcellulose < olive oil and lotion < ointment and tape in rats. The degree of ointment influence on rabbits is equivocal. PMID- 26023256 TI - Mead acid supplementation does not rescue rats from cataract and retinal degeneration induced by N-methyl-N-nitrosourea. AB - Fatty acids and their derivatives play a role in the response to ocular disease. Our current study investigated the effects of dietary mead acid (MA, 5,8,11 eicosatrienoic acid) supplementation on N-methyl-N-nitrosourea (MNU)-induced cataract and retinal degeneration in Sprague-Dawley rats. Experiment 1 was designed to inhibit cataract formation, with the dams fed a 2.4% MA or basal (<0.01% MA) diet during lactational periods. On postnatal day 7, male pups received a single intraperitoneal (ip) injection of 50 mg/kg MNU or vehicle. Lens opacity and morphology were examined 7 and 14 days after the MNU injection. Experiment 2 was designed to inhibit retinal degeneration and was performed with female postweaning rats. In this experiment, dams were fed the 2.4% MA or basal diet during the lactational periods. Thereafter, the female pups were continuously fed the same diets during their postweaning periods. On postnatal day 21 (at weaning), pups received a single ip injection of 50 mg/kg MNU. Retinal morphology was examined 7 days after the MNU injection. In experiment 3, six-week old female rats were fed the 2.4% MA or basal diet starting at one week before the MNU injection and were then continuously fed the same diets until sacrifice. Rats at 7 weeks of age were given a single ip injection of 40 mg/kg MNU, and the retina was then examined morphologically one week after the MNU injection. In experiment 1, mature cataract was found in all of the MNU-treated groups, with or without MA supplementation. In experiments 2 and 3, atrophy of both the peripheral and central outer retina occurred in all rats exposed to MNU, with or without MA supplementation, respectively. The severities of the cataracts and retinal atrophy in the rats were similar regardless of MA supplementation. Dietary mead acid, which is used as a substitute in essential fatty acid deficiency in the body, does not modify MNU-induced cataract and retinal degeneration in rat models. PMID- 26023257 TI - Establishment of a syngeneic orthotopic model of prostate cancer in immunocompetent rats. AB - We previously established 3 cell lines (PLS10, PLS20 and PLS30) from a chemically induced prostate carcinoma in F344 rats, and demonstrated high potential for metastasis in nude mice. In the present study, we investigated the feasibility of establishing an orthotopic model using the 3 rat prostate cancer cell lines in immunocompetent rats with the aim of resolving species-mismatch problems and defects of immune systems. The PLS10, PLS20 and PLS30 cell lines were injected into the ventral prostates of 6-week-old rats, which were then sacrificed at experimental weeks 4 and 8. Tumor mass formation was found in rats with PLS10, but not in those with PLS20 or PLS30. Additionally, metastatic carcinomas could be detected in lymph nodes and lungs of PLS10-inoculated rats. Genetic analysis demonstrated K-ras gene mutations in PLS10 and PLS20, but not in PLS30 cells. There were no mutations in p53 and KLF6. In conclusion, we established a syngeneic orthotopic model for prostate cancer in immunocompetent rats simulating human castration-resistant prostate cancer (CRPC), which should prove useful for development and validation of therapeutic agents, especially with immunotherapy. PMID- 26023258 TI - Induction of cell proliferation in the rat liver by the short-term administration of ethyl tertiary-butyl ether. AB - In the present study, in continuation of our previous experiment in order to investigate the mode of action (MOA) of ethyl tertiary-butyl ether (ETBE) hepatotumorigenicity in rats, we aimed to examine alterations in cell proliferation, that are induced by short-term administration of ETBE. F344 rats were administered ETBE at doses of 0, and 1,000 mg/kg body weight twice a day by gavage for 3, 10, 17 and 28 days. It was found that the previously observed significant increase of P450 total content and hydroxyl radical levels after 7 days of ETBE administration, and 8-OHdG formation at day 14, accompanied by accumulation of CYP2B1/2B2, CYP3A1/3A2, CYP2C6, CYP2E1 and CYP1A1 and downregulation of DNA oxoguanine glycosylase 1, was preceded by induction of cell proliferation at day 3. Furthermore, we observed an increase in regenerative cell proliferation as a result of ETBE treatment at day 28, followed by induction of cell cycle arrest and apoptosis by day 14. These results indicated that short term administration of ETBE led to a significant early increase in cell proliferation activity associated with induction of oxidative stress, and to a regenerative cell proliferation as an adaptive response, which could contribute to the hepatotumorigenicity of ETBE in rats. PMID- 26023259 TI - Autopsy report for a caffeine intoxication case and review of the current literature. AB - Caffeine (1,3,7-trimethylxanthine) is a popular mild central nervous system stimulant found in the leaves, seeds and fruits of various plants and in foodstuffs such as coffee, tea, and chocolate, among others. Caffeine is widely used and is not associated with severe side effects when consumed at relatively low doses. Although rarely observed, overdoses can occur. However, only a few fatal caffeine intoxication cases have been reported in the literature. Herein, we report the pathological examination results and information on caffeine concentrations in the blood, urine and main organs in a fatal caffeine intoxication case. Even though high caffeine concentrations were found in the systemic organs, no caffeine-related pathological changes were detected. PMID- 26023260 TI - Lipopolysaccharide induces expression of collagen VI in the rat lung. AB - The involvement of the lung during the septic systemic inflammatory response elicited by administration of lipopolysaccharide (LPS) was investigated. Eight week-old male Sprague-Dawley rats were injected i.p. with 15 mg/kg LPS. After 24 h, the lungs were excised to evaluate the cellular responses to LPS. Matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) analysis revealed that type VI collagen (ColVI) was extremely upregulated during sepsis in the rat lung within the first 24 h of LPS administration. Upregulation of ColVI protein and its mRNA was demonstrated by Western blot analysis, real time PCR, and immunohistochemistry. To the best of our knowledge, this is the first report demonstrating the activation of ColVI in the rat lung at the early stage of systemic inflammation. Activation of ColVI might be involved in sepsis mediated lung fibrosis at an early stage. PMID- 26023261 TI - The PFA-AMeX method achieves a good balance between the morphology of tissues and the quality of RNA content in DNA microarray analysis with laser-capture microdissection samples. AB - Recently, large-scale gene expression profiling is often performed using RNA extracted from unfixed frozen or formalin-fixed paraffin embedded (FFPE) samples. However, both types of samples have drawbacks in terms of the morphological preservation and RNA quality. In the present study, we investigated 30 human prostate tissues using the PFA-AMeX method (fixation using paraformaldehyde (PFA) followed by embedding in paraffin by AMeX) with a DNA microarray combined with laser-capture microdissection. Morphologically, in contrast to the case of atypical adenomatous hyperplasia, loss of basal cells in prostate adenocarcinomas was as obvious in PFA-AMeX samples as in FFPE samples. As for quality, the loss of rRNA peaks 18S and 28S on the capillary electropherograms from both FFPE and PFA-AMeX samples showed that the RNA was degraded equally during processing. However, qRT-PCR with 3' and 5' primer sets designed against human beta-actin revealed that, although RNA degradation occurred in both methods, it occurred more mildly in the PFA-AMeX samples. In conclusion, the PFA-AMeX method is good with respect to morphology and RNA quality, which makes it a promising tool for DNA microarrays combined with laser-capture microdissection, and if the appropriate RNA quality criteria are used, the capture of credible GeneChip data is well over 80% efficient, at least in human prostate specimens. PMID- 26023262 TI - International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) progress to date and future plans. AB - The INHAND Proposal (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) has been operational since 2005. A Global Editorial Steering Committee (GESC) manages the overall objectives of the project and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups (OWG), drawing upon experts from North America, Europe and Japan.Great progress has been made with 9 systems published to date - Respiratory, Hepatobiliary, Urinary, Central/Peripheral Nervous Systems, Male Reproductive and Mammary, Zymbals, Clitoral and Preputial Glands in Toxicologic Pathology and the Integument and Soft Tissue and Female Reproductive System in the Journal of Toxicologic Pathology as supplements and on a web site - www.goreni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photo-micrographs of morphologic changes, information regarding pathogenesis, and key references. During 2012, INHAND GESC representatives attended meetings with representatives of the FDA Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to begin incorporation of INHAND terminology as preferred terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of this nomenclature. The purpose of this publication is to provide an update on the progress of INHAND. PMID- 26023263 TI - Seasonal migration - A developmental challenge? PMID- 26023264 TI - Mental health effects of climate change. AB - We all know that 2014 has been declared as the hottest year globally by the Meteorological department of United States of America. Climate change is a global challenge which is likely to affect the mankind in substantial ways. Not only climate change is expected to affect physical health, it is also likely to affect mental health. Increasing ambient temperatures is likely to increase rates of aggression and violent suicides, while prolonged droughts due to climate change can lead to more number of farmer suicides. Droughts otherwise can lead to impaired mental health and stress. Increased frequency of disasters with climate change can lead to posttraumatic stress disorder, adjustment disorder, and depression. Changes in climate and global warming may require population to migrate, which can lead to acculturation stress. It can also lead to increased rates of physical illnesses, which secondarily would be associated with psychological distress. The possible effects of mitigation measures on mental health are also discussed. The paper concludes with a discussion of what can and should be done to tackle the expected mental health issues consequent to climate change. PMID- 26023266 TI - Hearing loss in shipyard employees. AB - BACKGROUND: Noise-induced hearing loss (NIHL) is one of the most prevalent occupational illnesses, with a higher incidence in the heavy industry. OBJECTIVES OF THE STUDY: The aim of this study is to investigate the prevalence of NIHL in Greece and explore its correlations with other job and individual-related factors. MATERIALS AND METHODS: Questionnaires were administered, and audiograms were conducted to 757 employees of a shipyard company in Greece, both white- and blue-collar, during the period 2006-2009. A modification of the 1979' equation of the American Academy of Otolaryngology was used to calculate hearing loss. Statistical analysis was conducted by means of the SPSS v. 17. RESULTS: A 27.1% of the employees were hearing handicap. Hearing loss was correlated with age, past medical history of ear disease (Meniere's disease, acoustic neuroma, otosclerosis) or injury, hyperlipidemia, job title and level of education. A few questions on subjective hearing ability and symptoms showed strong discriminatory power of hearing pathology. CONCLUSIONS: The results of this study emphasize the burden of disease in the shipyard industry, and the need for continuous monitoring, implementation of preventive measures and hearing conservation programs. PMID- 26023267 TI - Feasibility of integrating mental health and noncommunicable disease risk factor screening in periodical medical examination of employees in industries: An exploratory initiative. AB - BACKGROUND: Noncommunicable disease (NCDs), psychological, substance use disorders, and stress-related issues have been less understood in Indian industrial settings. Systems for screening and early identification of the above have not been integrated in workplaces, nor there is a strong regulatory backing for the same. AIM: To explore the feasibility of integrating mental health and select NCD risk factor screening with the periodical medical examination of employees. To identify proportion of employees with select NCD risk factors and symptoms suggestive of mental health problems. SETTINGS AND DESIGN: Around 10% of employees from a leading motor industry in Bangalore, (706) participated in this cross-sectional voluntary screening program. MATERIALS AND METHODS: This screening was conducted as a part of their annual medical examination. A mixed method of self-report and interview administered technique was adopted for the same. STATISTICAL ANALYSIS: Descriptive statistical methods (proportions, median, mean, and standard deviation (SD)) and Chi-square test of significance. RESULTS AND CONCLUSIONS: Screening revealed the following; tobacco use (18%), alcohol use (57%), perceived work stress (10%), and obesity (3%). Nearly 23% screened positive for psychological distress. Time consumed for this assessment was 1-5 min. Initial attempts point out that it is feasible to integrate screening for mental health, substance use, and NCD risk factors in periodic medical examination using a combination of self-report and interview-administered method, though further detailed assessments for confirmation is necessary. PMID- 26023265 TI - Application environmental epidemiology to vehicular air pollution and health effects research. AB - Vehicular pollution is one of the major contributors to the air pollution in urban areas and perhaps and accounts for the major share of anthropogenic green house gases such as carbon dioxide, carbon monoxide, nitrogen oxides. Knowledge of human health risks related to environmental exposure to vehicular pollution is a current concern. Analyze the range health effects are attributed varied constituents of vehicular air pollution examine evidence for a causal association to specific health effect. In many instances scenario involves exposure to very low doses of putative agents for extended periods, sometimes the period could mean over a lifetime of an individual and yet may result in small increase in health risk that may be imperceptible. Secondary data analysis and literature review. In environmental exposures, traditional epidemiological approaches evaluating mortality and morbidity indicators display many limiting factors such as nonspecificity of biological effects latency time between exposure and magnitude of the effect. Long latency period between exposure and resultant disease, principally for carcinogenic effects and limitation of epidemiological studies for detecting small risk increments. The present paper discusses the methodological challenges in studying vehicular epidemiology and highlights issues that affect the validity of epidemiological studies in vehicular pollution. PMID- 26023268 TI - Development and implementation of healthy workplace model in a selected industry of Puducherry, South India. AB - BACKGROUND: The workplace is increasingly being used as a setting for health promotion and preventive health activities; not only to prevent occupational injury, but to assess and improve people's overall health. OBJECTIVE: This study aims at developing and implementing a healthy workplace model in a software industry of Puducherry. METHODS: Operations research was carried out in a purposively selected industry in Puducherry. The study was planned in four phases baseline assessment and risk profiling, intervention, final evaluation and dissemination of results. Baseline evaluation of employees (n = 907) was done by a self-administered questionnaire to collect sociodemographic variables and risk factor profile using noncommunicable diseases (NCDs) LITE Proforma. RESULTS: Healthy workplace committee comprising of several stakeholders was formed, and a formal launch of the health awareness campaign was organized. Broad themes for health education sessions and support activities were identified. Risk profiling of employees showed high levels of risk factors and morbidity-more than 15% were found to be hypertensive and around 55% were obese. Stress and back ache were reported by almost half of the respondents. Modifications in the workplace targeting physical and psychosocial work environment were suggested to the committee, as part of the initiative. This study has demonstrated the feasibility of developing and implementing a healthy workplace model in South India. This model can be replicated or adapted in other industries for health promotion and prevention of NCDs. CONCLUSION: Dedicated and concerted efforts of the management consistent with the requirements of safety, health and environment at work place with appropriate support from the health system can improve the quality of work and working life. PMID- 26023269 TI - Vision-related problems among the workers engaged in jewellery manufacturing. AB - BACKGROUND: American Optometric Association defines Computer Vision Syndrome (CVS) as "complex of eye and vision problems related to near work which are experienced during or related to computer use." This happens when visual demand of the tasks exceeds the visual ability of the users. Even though problems were initially attributed to computer-related activities subsequently similar problems are also reported while carrying any near point task. Jewellery manufacturing activities involves precision designs, setting the tiny metals and stones which requires high visual attention and mental concentration and are often near point task. It is therefore expected that the workers engaged in jewellery manufacturing may also experience symptoms like CVS. AIM: Keeping the above in mind, this study was taken up (1) To identify the prevalence of symptoms like CVS among the workers of the jewellery manufacturing and compare the same with the workers working at computer workstation and (2) To ascertain whether such symptoms have any permanent vision-related problems. SETTING AND DESIGN: Case control study. MATERIALS AND METHODS: The study was carried out in Zaveri Bazaar region and at an IT-enabled organization in Mumbai. The study involved the identification of symptoms of CVS using a questionnaire of Eye Strain Journal, opthalmological check-ups and measurement of Spontaneous Eye Blink rate. The data obtained from the jewellery manufacturing was compared with the data of the subjects engaged in computer work and with the data available in the literature. STATISTICAL ANALYSIS: A comparative inferential statistics was used. RESULTS AND CONCLUSION: Results showed that visual demands of the task carried out in jewellery manufacturing were much higher than that of carried out in computer related work. PMID- 26023270 TI - Injuries in marginal workers and social trauma in female: Important cause of the paradigm shift in eye injury over a decade. AB - BACKGROUND: Changing profile of work force can give rise different types of injuries. PURPOSE: To analyse causative factors (Host-Agent-Event) in ocular trauma over last 15 years. METHODS: Hospital based prospective study during 1997 2012. Detailed information on nature of trauma; agent and setting were recorded. RESULTS: Cohort included 12365 eye injuries, 1241 serious cases. Prevalence - 0.45 /10000 Mean age 45.8 with bi- modal pattern of incidence, 3:1 male-female ratio. 80% closed globe, 48% workplace injury (90% in marginal labourers with an exponential annual increase). 10% cases from garage mechanics.60% of eye injuries in female were related to "social violence". Multivariate analysis has detected new causative agents. CONCLUSION: Significant change in parameters of trauma (Host-Agent-Event) is resulting in paradigm shift in eye injury. Unorganised unaccustomed labour in workplace injury and "social trauma" in females has become an important cause of eye injury. PMID- 26023272 TI - Sources of occupational stress in the police personnel of North India: An exploratory study. AB - BACKGROUND: Police personnel in India are subjected to several distinct occupational stressors which impact their mental health and their work performance negatively. AIM: The study aimed to explore various sources of stress among police personnel. METHOD: In this study, 100 constables, 100 inspectors and 100 police officers of Uttar Pradesh, were evaluated using the occupational stress questionnaire. This was subjected to the quantitative as well as the qualitative analysis. RESULT: Occupational stress was commonly perceived among all police personnel, but the major attributes of stress in various groups were diverse. PMID- 26023271 TI - Prevalence of musculoskeletal discomfort among the workers engaged in jewelry manufacturing. AB - BACKGROUND: The workers engaged in jewellery manufacturing exposed to various occupational risk factors that lead to development of musculoskeletal disorders. But there is scarcity of reporting the prevalence of the musculoskeletal disorders among them. AIMS: To evaluate the prevalence of musculoskeletal discomfort among the workers engaged in jewellery manufacturing in India. SETTING AND DESIGN: Case Control Study. MATERIALS AND METHODS: This study was divided into two phases. First phase: prevalence rate were calculated using Modified Nordic musculoskeletal questionnaire and compared with the control group. Second phase: strength, flexibility and tightness of the muscle groups (neck, lower back and knee) were evaluated through physical examination for the subjects who reported positive prevalence. STATISTICAL ANALYSIS: A comparative inferential statistics was used. RESULTS: This study was divided into two phases. First phase: prevalence rate were calculated using Modified Nordic musculoskeletal questionnaire and compared with the control group. Second phase:strength, flexibility and tightness of the muscle groups (neck, lower back and knee) were evaluated through physical examination for the subjects who reported positive prevalence. CONCLUSIONS: The musculoskeletal disorders among the workers engaged in jewellery manufacturing were found to be specific to the occupation. PMID- 26023273 TI - Occupational health hazards related to informal recycling of E-waste in India: An overview. AB - The innovation in science and technology coupled with the change in lifestyle of an individual has made an incredible change in the electronic industry show casing an assorted range of new products every day to the world. India too has been impacted by this digital revolution where consumption of electronics goods grows at a rapid rate producing a large amount of waste electrical and electronic equipment. This substantial generation of electronic waste referred to as e-waste accompanied with the lack of stringent environmental laws and regulations for handling the hazardous e-waste has resulted in the cropping of number of informal sectors. Over 95% of the e-waste is treated and processed in the majority of urban slums of the country, where untrained workers carry out the dangerous procedures without personal protective equipment, which are detrimental not only to their health but also to the environment. This paper focuses on the occupational health hazards due to the informal recycling of e-waste and then proceeds to show the safe disposal methods for handling the large quantities of e waste generated in this electronic era and thus finds a sustainable solution for the formal processing of e-waste. PMID- 26023274 TI - Swachh Bharat: A scheme or dream. PMID- 26023275 TI - Conducting systematic sampling. PMID- 26023276 TI - Mate choice and genetic monogamy in a biparental, colonial fish. AB - In socially monogamous species, in which both sexes provide essential parental care, males as well as females are expected to be choosy. Whereas hundreds of studies have examined monogamy in biparental birds, only several such studies exist in fish. We examined mate choice in the biparental, colonial cichlid fish Neolamprologus caudopunctatus in Lake Tanganyika, Zambia. We genotyped more than 350 individuals at 11 microsatellite loci to investigate their mating system. We found no extrapair paternity, identifying this biparental fish as genetically monogamous. Breeders paired randomly according to their genetic similarity, suggesting a lack of selection against inbreeding avoidance. We further found that breeders paired assortatively by body size, a criterion of quality in fish, suggesting mutual mate choice. In a subsequent mate preference test in an aquarium setup, females showed a strong preference for male size by laying eggs near the larger of 2 males in 13 of 14 trials. PMID- 26023277 TI - Cicadas impact bird communication in a noisy tropical rainforest. AB - Many animals communicate through acoustic signaling, and "acoustic space" may be viewed as a limited resource that organisms compete for. If acoustic signals overlap, the information in them is masked, so there should be selection toward strategies that reduce signal overlap. The extent to which animals are able to partition acoustic space in acoustically diverse habitats such as tropical forests is poorly known. Here, we demonstrate that a single cicada species plays a major role in the frequency and timing of acoustic communication in a neotropical wet forest bird community. Using an automated acoustic monitor, we found that cicadas vary the timing of their signals throughout the day and that the frequency range and timing of bird vocalizations closely track these signals. Birds significantly avoid temporal overlap with cicadas by reducing and often shutting down vocalizations at the onset of cicada signals that utilize the same frequency range. When birds do vocalize at the same time as cicadas, the vocalizations primarily occur at nonoverlapping frequencies with cicada signals. Our results greatly improve our understanding of the community dynamics of acoustic signaling and reveal how patterns in biotic noise shape the frequency and timing of bird vocalizations in tropical forests. PMID- 26023278 TI - When a Date Changes From Fun to Dangerous: Factors Affecting Women's Ability to Distinguish. AB - Women's ability to perceive risk of acquaintance sexual assault is key to decreasing its likelihood. This study examined the relationship between women's recognition of known situational risk factors and global perceived risk, prior victimization, and drinking habits. Women consistently distinguished between clear and ambiguous situational risk factors although these were not related to perceived global risk. They also manifested positivity bias, the tendency to underestimate their own risk of being assaulted relative to other women. Both prior victimization and drinking habits were related to risk judgments. This study raises important issues concerning developing effective defensive strategies for combating sexual assault. PMID- 26023279 TI - Assessing Assay Variability of Pesticide Metabolites in the Presence of Heavy Left-Censoring. AB - Assessing assay variability for field samples in environmental research is challenging, since a quantitative assay is typically constrained by a lower limit of detection. The purpose of this paper is to compare three parametric models for assessing assay variability using duplicate data subject to heavy left-censoring. Efron information criterion (EIC) and Bayesian information criterion (BIC) are used to aid in model selections. Distributional parameter estimates are obtained using maximum likelihood estimation for bivariate lognormal, bivariate zero inflated lognormal, and bivariate 3-component mixture models. We illustrate a practical application using duplicate pesticide data from the Community Participatory Approach to Measuring Farmworker Pesticide Exposure (PACE3) study. Furthermore, a simulation study is conducted to empirically evaluate the performance of the three models. The results from PACE3 indicate that the bivariate zero-inflated lognormal model is fairly competitive based on EIC or BIC. Further, total variability for the lognormal component can be decomposed into between-subject and within-subject variance based on this model. Assay variability estimates such as within-subject coefficient variation, minimum detectable change, and probability of k-fold difference can be easily derived under the bivariate zero-inflated lognormal model. Additionally, the assay variability is rather large for the PACE3 data. Therefore, apparent longitudinal change in pesticide exposure should be examined cautiously in the context of substantial assay variability. PMID- 26023280 TI - A hypothesis-directed approach to the targeted development of a multiplexed proteomic biomarker assay for cancer. AB - In recent years, hundreds of candidate protein biomarkers have been identified using discovery-based proteomics. Despite the large number of candidate biomarkers, few proteins advance to clinical validation. We propose a hypothesis driven approach to identify candidate biomarkers, previously characterized in the literature, with the highest probability of clinical applicability. A ranking method, called the "hypothesis-directed biomarker ranking" (HDBR) system, was developed to score candidate biomarkers based on seven criteria deemed important in the selection of clinically useful biomarkers. To demonstrate its application, we applied the HDBR system to identify candidate biomarkers for the development of a diagnostic test for the early detection of colorectal cancer. One-hundred and fifty-one candidate biomarkers were identified from the literature and ranked based on the specified criteria. The top-ranked candidates represent a group of biomarkers whose further study and validation would be justified in order to expedite the development of biomarkers that could be used in a clinical setting. PMID- 26023281 TI - Zinc Supplementation in a Randomized Controlled Trial Decreased ZIP4 and ZIP8 mRNA Abundance in Peripheral Blood Mononuclear Cells of Adult Women. AB - Zinc plays an integral role in numerous cellular processes including regulation of gene expression. This randomized placebo-controlled trial in adult women evaluated the effects of 20 mg Zn for 23 days. The mRNA abundance of zinc transporters (ZnT1/ZIP3/ZIP4/ZIP8) and metallothionein (MT1) from peripheral blood mononuclear cells was determined by real-time quantitative polymerase chain reaction. In paired samples (n = 6-9), the ZIP4 (P = 0.036) and ZIP8 (P = 0.038) mRNA abundance decreased following zinc supplementation. ZnT1, ZIP3, and MT1 mRNA abundance did not change significantly. The mean +/- standard deviation plasma zinc concentration (by inductively coupled plasma mass spectrometry) at baseline was 680 +/- 110 MUg/L for the zinc group (n = 24) and 741 +/- 92 MUg/L for the placebo group (n = 23). At endpoint, plasma zinc in the zinc group increased to 735 +/- 80 MUg/L (P < 0.01) while in the placebo group (717 +/- 100 MUg/L) it did not change significantly from baseline. The change in mRNA abundance highlights the importance of further investigating ZIP4 and ZIP8 mRNA abundance as potential zinc status biomarkers. PMID- 26023282 TI - The role of 64/128-slice multidetector computed tomography to assess the progression of coronary atherosclerosis. AB - OBJECTIVES: We studied the progression of coronary atherosclerosis over time as detected by multidetector computed tomography (MDCT) in relation to risk factors and plaque composition. BACKGROUND: Studies using MDCT are limited to the assessment of the degree of stenosis without taking into consideration the plaque composition that is seen by MDCT. METHODS: This study included 200 patients, complaining of chest pain and referred to do 64/128-contrast-enhanced MDCT for the second time, and both studies were retrieved and evaluated for the presence of plaque, plaque type, vessel wall remodeling, percent area, and diameter stenosis and compared in both studies. Plaque progression over time and its association with risk factors were determined. RESULTS: We included 200 patients, and 348 plaques were detected by 64/128 MDCT. The duration between follow-up and baseline studies was 25.9 +/- 19.2 month. In all, 200 plaques showed progression (57.47%), 122 were stable (35.06%), and 26 regressed (7.47%). In longitudinal regression analysis, the presence of history of diabetes mellitus and dyslipidemia and the absence of intraplaque calcium deposits were independently associated with plaque progression over time (P < 0.0001). CONCLUSION: Coronary plaque burden of patients with chest pain and no history of acute coronary syndrome significantly increased over time. Progression is dependent on plaque composition and cardiovascular risk factors. Larger studies and longer follow-up period are needed to confirm the determinant factors for plaque progression. PMID- 26023283 TI - A Comprehensive Profile of ChIP-Seq-Based Olig2 Target Genes in Motor Neuron Progenitor Cells Suggests the Possible Involvement of Olig2 in the Pathogenesis of Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that primarily affects motor neurons in the cerebral cortex and the spinal cord. Recent evidence indicates that dysfunction of oligodendrocytes is implicated in the pathogenesis of ALS. The basic helix-loop helix (bHLH) transcription factor Olig2 plays a pivotal role in the development of both motor neurons and oligodendrocytes in the progenitor of motor neuron (pMN) domain of the spinal cord, supporting evidence for the shared motor neuron/oligodendrocyte lineage. However, a comprehensive profile of Olig2 target genes in pMNs and oligodendrocyte progenitor cells (OPCs) with relevance to the pathogenesis of ALS remains to be characterized. METHODS: By analyzing the ChIP Seq datasets numbered SRP007566 and SRP015333 with the Strand NGS program, we identified genome-wide Olig2 target genes in pMNs and OPCs, followed by molecular network analysis using three distinct bioinformatics tools. RESULTS: We identified 5966 Olig2 target genes in pMNs, including Nkx2.2, Pax6, Irx3, Ngn2, Zep2 (Cip1), Trp3, Mnx1 (Hb9), and Cdkn1a, and 1553 genes in OPCs. The genes closely related to the keyword "alternative splicing" were enriched in the set of 740 targets overlapping between pMNs and OPCs. Furthermore, approximately one third of downregulated genes in purified motor neurons of presymptomatic mutant SOD1 transgenic mice and in lumbar spinal cord tissues of ALS patients corresponded to Olig2 target genes in pMNs. Molecular networks of Olig2 target genes indicate that Olig2 regulates a wide range of genes essential for diverse neuronal and glial functions. CONCLUSIONS: These observations lead to a hypothesis that aberrant regulation of Olig2 function, by affecting biology of both motor neurons and oligodendrocytes, might be involved in the pathogenesis of ALS. PMID- 26023284 TI - Collecting and preserving marine and freshwater isopoda (crustacea: peracarida). AB - BACKGROUND: Isopoda are the most diverse Crustacea. In order to encourage the study of isopod crustaceans and their use in biodiversity studies, systematics, ecology, physiology and more, one needs to know who the isopods are and where to find them. NEW INFORMATION: This is a short "how to" guide focusing on the free living marine and freshwater isopods: where they live and how to collect and preserve them. The tools and techniques described here are simple, but invaluable in accessing the natural history of these remarkable creatures. PMID- 26023285 TI - New data on recently described rodent species Paulina's Limestone Rat Saxatilomys paulinae Musser, Smith, Robinson & Lunde, 2005 (Mammalia: Rodentia). AB - BACKGROUND: Paulina's Limestone Rat Saxatilomys paulinae Musser et al., 2005 was first discovered by Musser et al. (2005) based on specimens from the Khammouane Limestone National Biodiversity Conservation Area (NBCA) in Khammouane Province in central Lao People's Democratic Republic (PDR). This tower karst landscape is part of the Central Indochina Limestone massif, which extends eastward into north central Vietnam in Quang Binh and Quang Tri Provinces. NEW INFORMATION: In April 2014, we conducted a rodent survey and collected four (4) whole specimens of Saxatilomys paulinae in Quang Binh province. This is the first record of Saxatilomys paulinae in Vietnam. External and craniodental characteristics of all specimens clearly exhibit the characters of Saxatilomys paulinae as described in Musser et al. (2005). The rats are of medium size (HB: 160.3 +/- 2.03 mm, T: 192.3 +/- 6.69 mm) with some specific morpological characteristics. The external and craniodental measurement of the specimens from Vietnam tend to be larger than those of specimens from Lao. However, this needs to be verified by more studies in future. The habitat of Saxatilomys paulinae in Vietnam is characterized by complicated terrain comprising low karst towers (around 400 m) with steep slopes covered under limestone humid evergreen forest. The forest has been affected by selected timber logging in the past, but still has a complex 4-layer structure. The population of Saxatilomys paulinae in Vietnam is threatened by rodent trapping/snaring and habitat disturbance. More status surveys should be conducted to assess the species distributional range and its population status for undertaking relevant conservation measures. PMID- 26023286 TI - Integrating and visualizing primary data from prospective and legacy taxonomic literature. AB - Specimen data in taxonomic literature are among the highest quality primary biodiversity data. Innovative cybertaxonomic journals are using workflows that maintain data structure and disseminate electronic content to aggregators and other users; such structure is lost in traditional taxonomic publishing. Legacy taxonomic literature is a vast repository of knowledge about biodiversity. Currently, access to that resource is cumbersome, especially for non-specialist data consumers. Markup is a mechanism that makes this content more accessible, and is especially suited to machine analysis. Fine-grained XML (Extensible Markup Language) markup was applied to all (37) open-access articles published in the journal Zootaxa containing treatments on spiders (Order: Araneae). The markup approach was optimized to extract primary specimen data from legacy publications. These data were combined with data from articles containing treatments on spiders published in Biodiversity Data Journal where XML structure is part of the routine publication process. A series of charts was developed to visualize the content of specimen data in XML-tagged taxonomic treatments, either singly or in aggregate. The data can be filtered by several fields (including journal, taxon, institutional collection, collecting country, collector, author, article and treatment) to query particular aspects of the data. We demonstrate here that XML markup using GoldenGATE can address the challenge presented by unstructured legacy data, can extract structured primary biodiversity data which can be aggregated with and jointly queried with data from other Darwin Core-compatible sources, and show how visualization of these data can communicate key information contained in biodiversity literature. We complement recent studies on aspects of biodiversity knowledge using XML structured data to explore 1) the time lag between species discovry and description, and 2) the prevelence of rarity in species descriptions. PMID- 26023287 TI - DNA Barcoding of the parasitoid wasp subfamily Doryctinae (Hymenoptera: Braconidae) from Chamela, Mexico. AB - Background and aims. The Doryctinae is a considerably diverse, poorly studied group of parasitoid wasps and one of the most diverse subfamilies within Braconidae. Taxonomic knowledge of this group remains highly incomplete, specially in the tropics. In Mexico, it has been reported as the subfamily with the highest number of recorded genera. A preliminary Barcoding study carried out in the Chamela region, located near the Mexican pacific coast in Jalisco, identified 185 barcoding species of Dorytinae assigned to 19 identified doryctine genera. This work updates the later study, representing a three years effort to assess the species richness of this subfamily for the Chamela region. Materials and methods. Ten collecting field trips of 5 to 10 days each were carried out from June 2009 to May 2011. A 2% divergence criterion using the BIN system implemented in BOLD was followed in order to establish species boundaries among the specimens that were collected. Results and conclusions. A total of 961 specimens were collected, from which 883 COI sequences were obtained. The sequences generated corresponded to 289 barcoding species and 30 identified genera. The most speciose genera were Heterospilus Haliday (170 spp.), Ecphylus Forster (19 spp.), Allorhogas Gahan (15 spp.) and Callihormius Ashmead (14 spp.). Addition of previously collected material increased the diversity of the subfamily in the region to 34 genera and 290 species. Paraphyly of Heterospilus with respect to Neoheterospilus and Heterospathius was again recovered. Twenty new species and two new genera (Sabinita Belokobylskij, Zaldivar-Riveron et Martinez, Ficobolus Martinez, Belokobylskij et Zaldivar-Riveron) have been described so far from the material collected in this work. PMID- 26023288 TI - Intrinsic Size Parameters for Palmitoylated and Carboxyamidomethylated Peptides. AB - Cross sections for 61 palmitoylated peptides and 73 cysteine-unmodified peptides are determined and used together with a previously obtained tryptic peptide library to derive a set of intrinsic size parameters (ISPs) for the palmitoyl (Pal) group (1.26 +/- 0.04), carboxyamidomethyl (Am) group (0.92 +/- 0.04), and the 20 amino acid residues to assess the influence of Pal- and Am-modification on cysteine and other amino acid residues. These values highlight the influence of the intrinsic hydrophobic and hydrophilic nature of these modifications on the overall cross sections. As a part of this analysis, we find that ISPs derived from a database of a modifier on one amino acid residue (CysPal) can be applied on the same modification group on different amino acid residues (SerPal and TyrPal). Using these ISP values, we are able to calculate peptide cross sections to within +/- 2% of experimental values for 83% of Pal-modified peptide ions and 63% of Am-modified peptide ions. We propose that modification groups should be treated as individual contribution factors, instead of treating the combination of the particular group and the amino acid residue they are on as a whole when considering their effects on the peptide ion mobility features. PMID- 26023289 TI - The record-setting flood of 2014 in kelantan: challenges and recommendations from an emergency medicine perspective and why the medical campus stood dry. AB - Floods are considered an annual natural disaster in Kelantan. However, the record setting flood of 2014 was a 'tsunami-like disaster'. Hospital Universiti Sains Malaysia was the only fully functioning hospital in the state and had to receive and manage cases from the hospitals and clinics throughout Kelantan. The experiences, challenges, and recommendations resulting from this disaster are highlighted from an emergency medicine perspective so that future disaster preparedness is truly a preparation. The history of how the health campus was constructed with the collaboration of Perunding Alam Bina and Perkins and Willis of Chicago is elaborated. PMID- 26023291 TI - Electrophoretic Techniques for the Detection of Human Microsatellite D19S884. AB - BACKGROUND: The detection and analysis of microsatellites is very important for the mapping of genetic diseases because they are commonly used as genetic markers. Microsatellite marker D19S884 has been associated with polycystic ovary syndrome (PCOS), the most common reproductive endocrine disease of women in their childbearing years. It is responsible for an estimated 70% of cases of anovulatory infertility. In this work, we detected microsatellites in DNA extracted from the blood of PCOS patients. METHODS: DNA microsatellites were amplified by polymerase chain reaction (PCR) using a pair of specific primers tagged with fluorescence to yield products of 160-200 base pairs in length. Alleles were separated on 4% low-melting agarose gels; stained with a safe gel staining, GelRedTM, which is an alternative to ethidium bromide; and visualised by ultraviolet illumination. RESULTS: Bands were observed, but their base-pairs differences were difficult to distinguish. To identify each allele clearly, the PCR products were also analysed using capillary gel electrophoresis for fragment analysis where it was possible to discriminate even in case of difference between two pairs of bases between the alleles. CONCLUSION: In this article, we present a protocol that combines the use of gel electrophoresis and fragment analysis in the identification of genetic biomarkers for PCOS. PMID- 26023292 TI - Effects of Hydro-alcoholic Extract from Arctium lappa L. (Burdock) Root on Gonadotropins, Testosterone, and Sperm Count and Viability in Male Mice with Nicotinamide/ Streptozotocin-Induced Type 2 Diabetes. AB - BACKGROUND: Reproductive dysfunction is a complication of diabetes. Arctium lappa (burdock) root has hypoglycemic and antioxidative properties, which are traditionally used for treatment of impotence and sterility. Therefore, the aim of this study is to investigate the effects of its hydro alcoholic extract on gonadotropin, testosterone, and sperm parameters in nicotinamide/ streptozotocin induced diabetic mice. METHODS: In this experimental study, 56 adult male Naval Medical Research Institute (NMRI) mice (30-35 g) were randomly divided into seven groups: control, diabetes, diabetes + glibenclamide (0.25 mg/kg), diabetes + extract (200 or 300 mg/kg), and extract (200 or 300 mg/kg). Diabetes was induced with intraperitoneal injection of nicotinamide (NA) and streptozotocin (STZ). Twenty-four hours after the last extract and drug administration, serum samples, testes, and cauda epididymis were removed immediately for experimental assessment. RESULTS: Body weight, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone levels, and sperm count (P < 0.05) and viability (P < 0.01) decreased in diabetic mice. Administration of glibenclamide significantly improved these reductions in diabetic animals (P < 0.05). However, the hydro alcoholic extract (300 mg/kg) enhanced sperm viability only in diabetic mice (P < 0.01). In addition, this dose of extract increased sperm count, LH, FSH, and testosterone in nondiabetic animals compared with the control group (P < 0.05). CONCLUSION: The results indicate that applied burdock root extract has anti-infertility effects in nondiabetic mice. Hence, this part of the A. lappa plant has an effect on the health of the reproductive system in order to improve diabetic conditions. PMID- 26023290 TI - Role of endothelium-dependent hyperpolarisation and prostacyclin in diabetes. AB - The endothelium plays a crucial role in maintaining vascular homeostasis by producing several vasodilating factors, including nitric oxide (NO), prostacyclin (PGI2), and endothelium-dependent hyperpolarisation (EDH); however, the balance between endothelial relaxing and contracting factors is disrupted in disease states such as diabetes mellitus and hypertension. Most reported studies of endothelial dysfunction in diabetes focused on the actions of NO; however, there is accumulating evidence demonstrating that in addition to NO, PGI2 and EDH are likely to contribute to the vasodilatation of blood vessels. EDH plays an important role as a regulator of vascular tone and reactivity in resistance and conduit arteries of animal models and humans. PGI2 only plays a minimal role in endothelium-dependent vasodilatation but may serve as an important compensatory mechanism in conditions in which NO and EDH activities are decreased. Further studies are needed to determine the exact roles of EDH and PGI2 in the development of endothelial dysfunction and clinical vasculopathy in humans with type 1 and type 2 diabetes. PMID- 26023293 TI - Effects of Temporary Inactivation and Electrical Stimulation of the Dorsal Raphe Nucleus on Morphine-induced Conditioned Place Preference. AB - BACKGROUND: The dorsal raphe nucleus (DRN) influences a wide range of behavioral and reward function. In this study, we evaluated electrical stimulation and inactivation of DRN on morphine conditioned place preference (CPP). METHODS: The rats were anesthetised (n = 7 for each group) and the electrode and cannula were implanted into the DRN by stereotaxic instrument. Electrical stimulation (100MUA) and reversible inactivation by lidocaine were induced into DRN and then morphine induced CPP was investigated. RESULTS: The stimulation of DRN in combination with effective dose of morphine showed a significant decrease only on expression phases 20s (SD 33.7) when compared with morphine group 119.85s (SD 23.7) (One way ANOVA, Tukey's; P = 0.036). Also, this stimulation in combination with ineffective dose of morphine showed a significant increase only on acquisition phases 67.5s (SD 41.2) of CPP compared with morphine group -46s (SD 18.51) (P = 0.034). Also, there were not significant differences in inactivation of DRN by lidocaine on different phase of CPP (P = 0.091) CONCLUSION: It is possible that electrical stimulation of the DRN with changes in concentration of serotonin or involving other transmitters such as glutamate and gamma amino butyric acid (GABA) would be involved to these changes of CPP. PMID- 26023294 TI - Clinical Factors affecting Minor Amputation in Diabetic Foot Disease at Tengku Ampuan Afzan Hospital, Kuantan. AB - BACKGROUND: Diabetic foot disease poses a substantial problem in Malaysian diabetic population. We evaluate the clinical factors affecting minor amputation in diabetic foot disease. METHODS: A cross-sectional study enrolling patients admitted to orthopaedic wards of a single tertiary hospital for diabetic foot disease was conducted. Patients who had undergone major amputation or with medical condition above the ankle joint were not included. Clinical data were collected by measurement of ankle brachial systolic index and Semmes-Weinstein 5.07 gauge monofilament test with foot clinical evaluation using King's classification respectively. RESULTS: The total number of patients included was 138, with mean age of 59.7 years (range 29 to 94 years old). Fifty patients (36.2%) had minor amputations. Poor compliance to diabetic treatment, King's classification stage 5, low measures of ankle brachial systolic index, sensory neuropathy, high serum C-Reactive protein and high serum creatinine are significant predictive factors for minor amputation (P < 0.05). CONCLUSION: Identifying these risk factors may help in prevention of minor amputation and subsequently reduce limb loss in diabetic foot. PMID- 26023295 TI - Walking devices used by the elderly living in rural areas of Thailand. AB - BACKGROUND: The use of all types of external devices was previously investigated for elderly with and without orthopaedic problems of a developed country. This study describes the proportion, types and the reasons of using a walking device in elderly who live in many rural areas of Thailand. METHODS: Participants (n = 390) were interviewed using a questionnaire to ascertain their demographics, health status and types of walking device required for daily activities. RESULTS: Forty-one participants (11%) used a walking device, particularly when walking long distances due to a fear of falling, musculoskeletal pain, and impaired walking ability. The proportion of walking devices used dramatically increased in participants aged 75 years and over (six times of those aged 60-74 years). Most of the participants used a modified walking stick by their own determination (81%), while only 7% used one according to medical prescription. A significant increase in the need of a walking device was seen in participants aged 75 years and over (OR = 13.9; 95% CI 5.9-32.7; P < 0.001), with a medical problem (OR = 45.9; 95% CI 6.7-73.4; P < 0.001) and who required regular medication (OR = 12.7; 95% CI 5.0-33.6; P = 0.001). CONCLUSION: The findings emphasise the importance of a community health service to promote health status, particularly before 75 years of age. PMID- 26023296 TI - Common dental anomalies in cleft lip and palate patients. AB - BACKGROUND: Cleft lip and palate (CLP) is the most common orofacial congenital malformation in live births. CLP can occur individually or in combination with other congenital deformities. Affected patients experience a number of dental, aesthetic, speech, hearing, and psychological complications and have a higher incidence of severe dental conditions. The purpose of this study is to characterise the different types of dental anomalies that are frequently associated with CLP patients based on a literature survey. METHODS: By literature survey, this study characterises the different types of dental anomalies that are frequently associated with cleft lip and palate patients. RESULTS: Common dental anomalies associated with CLP are supernumerary tooth, congenitally missing tooth, delayed tooth development, morphological anomalies in both deciduous and permanent dentition, delayed eruption of permanent maxillary incisors, microdontia, and abnormal tooth number. CONCLUSION: The incidence of certain dental anomalies is strongly correlated with Cleft lip and palate, a finding that is consistent with previous studies. PMID- 26023297 TI - Case of pseudoaneurysm mimicking a soft tissue sarcoma: a diagnostic pitfall. AB - Pseudoaneurysms represent a pulsating encapsulated hematoma in communication with the lumen of a ruptured vessel. We present a 33-year-old male with a pseudoaneurysm of the profunda femoris artery. At presentation and on further evaluation, he was diagnosed with a possible soft tissue sarcoma of the distal thigh. Catastrophic haemorrhage occurred at the time of a planned, elective open biopsy. This case report emphasises the importance of considering pseudoaneurysm as a crucial differential diagnosis in atypical swellings and scrutinising all suspected soft tissue tumours with a contrast study or a Doppler ultrasound. PMID- 26023298 TI - Isolated intramuscular cysticercosis: a case report. AB - Human cysticercosis is caused by Cysticercus cellulosae, larvae of a tapeworm, Taenia solium. Cysticercosis can involve any tissue in the body; the most common affected sites are central nervous system, subcutaneous tissue, eyes, and muscles. A few cases of isolated intramuscular cysticercosis without any other tissue involvement have been reported in pediatric population. Here, we report a case of intramuscular cysticercosis diagnosed by ultrasonography in a 5.5 year old boy who presented with the swellings over the calf and the scapular region, without any associated neurological or ocular involvement. The patient responded well to the course of steroids and Albendazole with complete resolution of both the swellings. PMID- 26023299 TI - Kimura's Disease: A Rare Cause of Chronic Lymphadenopathy in a Child. AB - Kimura's disease is an uncommon entity that affects adults, with a predilection for the Asian population. This may rarely be encountered in children, and the knowledge of this fact is essential to rule out the remote possibility of Kimura's disease in children with a slow-growing painless mass in the head and neck region. In this case report, we document this disease in an 8-year-old boy with a slow-growing swelling in the right posterior auricular region. PMID- 26023300 TI - Ectopic lingual thyroid presenting with nasal twang and hemoptysis. AB - Ectopic lingual thyroid is a rare developmental anomaly. It is caused by aberrant embryogenesis during the thyroid descent to the neck. It may remain asymptomatic or present with dysphagia, hemoptysis, dyspnoea or dysphonia. Clinically, it presents as a mass lesion on the base of the tongue. The most important diagnostic tool for an ectopic lingual thyroid is the 99mTc radionuclide scan, but imaging modalities such as computed tomography scan and magnetic resonance imaging may also help to assess its location and extent and to rule out the presence of normal thyroid tissue in the thyroid bed. The management of an ectopic thyroid remains controversial. No treatment is required for asymptomatic patients in the euthyroid state. Patients with hypothyroidism should be treated with thyroid hormone substitution therapy. Malignant transformation is an indication for complete surgical resection. Ablative radioiodine therapy can be considered for older patients and those who are unfit for surgery. In complicated cases, surgical resection is recommended through the transoral, transhyoid or lateral pharyngectomy approach. We report a case of ectopic lingual thyroid in a 35-year-old man who presented with nasal twang and hemoptysis. PMID- 26023301 TI - Inositol 1,4,5-triphosphate-associated cGMP kinase substrate: Basis Sequence: Mouse. AB - Inositol 1, 4, 5-trisphosphate (IP3) receptor associated cyclic GMP (cGMP) kinase substrate (IRAG, also known as Mrv1) is a type-2 integral membrane endoplasmic reticulum (ER) protein, which interacts with IP3 Receptor type 1 (IP3R1), cGMP kinase I-beta (cGKI beta) and other associated proteins. It plays a key role in NO, cGMP, and cGKI beta mediated inhibition of IP3R1 activity and thus relaxes smooth muscle tone and inhibits platelet aggregation. As a scaffolding protein Mrv1 maintains the conformation of a heteroprotein complex containing cGKI beta, IP3R1 and other proteins and enables efficient activity of cGKI beta within the complex. Increased expression of Mrv1 or IRAG in the absence of tumor related transcription factor in pancreatic cancer cells suggest that it might be involved in tumorigenesis. Downregulation of Mrv1 during megakaryocyte maturation indicates that it is involved in cell growth and differentiation. PMID- 26023302 TI - Associations Between Psychiatric Impairment and Sexual Risk Behavior Among Teens in Mental Health Treatment. AB - AIMS: To assess the associations of sexual risk behavior with psychiatric impairment and individual, peer, and partner attitudes among adolescents receiving mental health treatment. METHODS: Adolescents (N=893, 56% female, 67% African American) completed assessments of psychiatric impairment, rejection sensitivity, peer norms, HIV knowledge, perceived vulnerability, self-efficacy and condom use intentions. Two structural equation models were used to test the study hypotheses; one for sexually active youth and one for non-active youth. RESULTS: For non-active youth, psychiatric impairment influenced self-efficacy and condom use intentions via peer norms, rejection sensitivity, and perceived vulnerability. Among the sexually active youth, sexual risk was related to impairment and previous condom use. DISCUSSION: These results suggest that individual, peer, and partner factors are related to impairment and to sexual risk attitudes, but depend on previous sexual experience. PMID- 26023303 TI - Simultaneous Estimation of Elasticity for Multiple Deformable Bodies. AB - Material property has great importance in deformable body simulation and medical robotics. The elasticity parameters, such as Young's modulus of the deformable bodies, are important to make realistic animations. Further in medical applications the (recovered) elasticity parameters can assist surgeons to perform better pre-op surgical planning and enable medical robots to carry out personalized surgical procedures. Previous elasticity parameters estimation methods are limited to recover one elasticity parameter of one deformable body at a time. In this paper, we propose a novel elasticity parameter estimation algorithm that can recover the elasticity parameters of multiple deformable bodies or multiple regions of one deformable body simultaneously from (at least two sets of) images. We validate our algorithm with both synthetic test cases and real patient CT images. PMID- 26023304 TI - High sodium intake: review of recent issues on its association with cardiovascular events and measurement methods. AB - There has been a long-known association between high dietary sodium intake and hypertension, as well as the increased risk of cardiovascular disease. Reduction of sodium intake is a major challenge for public health. Recently, there have been several controversial large population-based studies regarding the current recommendation for dietary sodium intake. Although these studies were performed in a large population, they aroused controversies because they had a flaw in the study design and methods. In addition, knowledge of the advantages and disadvantages of the methods is essential in order to obtain an accurate estimation of sodium intake. I have reviewed the current literatures on the association between sodium intake and cardiovascular events, as well as the methods for the estimation of sodium intake. PMID- 26023306 TI - Mortality trends of cardiovascular disease in Korea; big challenges in ischemic heart disease. PMID- 26023305 TI - Function and dysfunction of human sinoatrial node. AB - Sinoatrial node (SAN) automaticity is jointly regulated by a voltage (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release). Using optical mapping in Langendorff-perfused canine right atrium, we previously demonstrated that the beta-adrenergic stimulation pushes the leading pacemaker to the superior SAN, which has the fastest activation rate and the most robust late diastolic intracellular calcium (Cai) elevation. Dysfunction of the superior SAN is commonly observed in animal models of heart failure and atrial fibrillation (AF), which are known to be associated with abnormal SAN automaticity. Using the 3D electroanatomic mapping techniques, we demonstrated that superior SAN served as the earliest atrial activation site (EAS) during sympathetic stimulation in healthy humans. In contrast, unresponsiveness of superior SAN to sympathetic stimulation was a characteristic finding in patients with AF and SAN dysfunction, and the 3D electroanatomic mapping technique had better diagnostic sensitivity than corrected SAN recovery time testing. However, both tests have significant limitations in detecting patients with symptomatic sick sinus syndrome. Recently, we reported that the location of the EAS can be predicted by the amplitudes of P wave in the inferior leads. The inferior P-wave amplitudes can also be used to assess the superior SAN responsiveness to sympathetic stimulation. Inverted or isoelectric P-waves at baseline that fail to normalize during isoproterenol infusion suggest SAN dysfunction. P-wave morphology analyses may be helpful in determining the SAN function in patients at risk of symptomatic sick sinus syndrome. PMID- 26023307 TI - Usefulness of Hyperemic Microvascular Resistance Index as a Predictor of Clinical Outcomes in Patients with ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND AND OBJECTIVES: Microvascular function is a useful predictor of left ventricular functional changes in patients with ST-segment elevation myocardial infarction (STEMI). We evaluated the usefulness of the hyperemic microvascular resistance index (hMVRI) for predicting long-term major adverse cardiovascular events (MACEs) in patients with STEMI assessed immediately after primary percutaneous coronary intervention (PCI). SUBJECTS AND METHODS: hMVRI were evaluated in 145 patients with first acute STEMI treated with primary PCI using an intracoronary Doppler wire. hMVRI was defined as the ratio of mean aortic pressure over hyperemic averaged peak velocity of infarct-related artery. Major adverse cardiovascular events (MACEs) included cardiac death and re hospitalization for congestive heart failure. RESULTS: During the mean follow-up of 85+/-43 months, MACEs occurred in 17.2% of patients. Using a receiver operating characteristics analysis, hMVRI >2.82 mm Hg.cm-1.sec (sensitivity: 87%; specificity: 69%; and area under curve: 0.818) was the best cut-off values for predicting future cardiac events. The Cox proportional hazard analysis showed that hMVRI was an independent predictor for long-term MACEs (hazard ratio 1.741, 95% confidence interval 1.348-2.264, p<0.001). The Kaplan-Meier survival analysis showed a higher incidence of MACEs in patients with hMVRI >2.82 mm Hg.cm-1.sec (p<0.001). CONCLUSION: hMVRI was a strong predictor of long-term MACEs in patients with STEMI treated with primary PCI. PMID- 26023308 TI - Thirty-year trends in mortality from cardiovascular diseases in Korea. AB - BACKGROUND AND OBJECTIVES: An understanding of cardiovascular diseases (CVD) mortality is important for the development of strategies aimed at reducing the burden of CVD. Thus, we examined the changing pattern of CVD mortality in Korea over 30 years (1983-2012) by analyzing the Cause of Death Statistics. MATERIALS AND METHODS: Deaths from diseases of the circulatory system and those of five CVD categories were analyzed: total heart diseases, acute rheumatic fever/chronic rheumatic heart disease, hypertensive heart disease, ischemic heart disease (IHD) and atherosclerosis. To assess the effects of population ageing on CVD mortality, crude and age-adjusted mortality rates were calculated. Age-adjusted mortality rates were calculated by using the direct standardization method. RESULTS: Over the 30-year period analyzed in this study, circulatory system disease mortality markedly declined. The age-adjusted mortality rate decreased by 78.5% in men and by 76.3% in women. Consistent decreasing trends were observed for mortalities from rheumatic heart disease, hypertensive heart disease, and atherosclerosis. However, IHD mortality rapidly increased during the 30 years. Crude IHD mortality showed a steady increase until 2007, after which there were fluctuations. But the penalized regression splines showed that crude IHD mortality continued to increase. Age-adjusted IHD mortality peaked in the early 2000s, and started to decrease during the last few years. CONCLUSION: In summary, total CVD mortality rate has significantly decreased over the 30-year period analyzed in this study but the IHD mortality rate has continuously increased until recently. The prevention and management of cardiovascular diseases amongst the Korean population, especially IHD, still represents a great challenge. PMID- 26023309 TI - The Association between Subclinical Hypothyroidism and Epicardial Adipose Tissue Thickness. AB - BACKGROUND AND OBJECTIVES: Subclinical hypothyroidism (SH) is considered to be a potential risk factor for cardiovascular disease. Epicardial adipose tissue (EAT) thickness is also closely related to cardiovascular disorders. The aim of this study was to evaluate whether SH is associated with higher EAT thickness. SUBJECTS AND METHODS: Fifty-one consecutive patients with SH and 51 healthy control subjects were prospectively enrolled into this trial. Thyroid hormone levels, lipid parameters, body mass index, waist and neck circumference, and EAT thickness measured by echocardiography were recorded in all subjects. RESULTS: Mean EAT thickness was increased in the SH group compared to the control group (6.7+/-1.4 mm vs. 4.7+/-1.2 mm, p<0.001). EAT thickness was shown to be correlated with thyroid stimulating hormone level (r=0.303, p=0.002). Multivariate logistic regression analysis revealed that EAT thickness was independently associated with SH {odds ratio (OR): 3.87, 95% confidence interval (CI): 1.92-7.78, p<0.001; OR: 3.80, 95% CI: 2.18-6.62, p<0.001}. CONCLUSION: Epicardial adipose tissue thickness is increased in patients with SH compared to control subjects, and this increase in EAT thickness may be associated with the potential cardiovascular adverse effects of SH. PMID- 26023310 TI - Small left atrial size complicating percutaneous transcatheter device closure of secundum atrial septal defect with conventional approach. AB - BACKGROUND AND OBJECTIVES: Transcatheter device closure becomes the first option for treating secundum atrial septal defect (ASD), but the conventional method is sometimes unsuccessful even when the defect size indicates the closure to be feasible. To increase the success rate, modified methods have been introduced and used. This study aimed to find predictors for using the modified methods in the device closure of secundum ASDs. SUBJECTS AND METHODS: Between October 2010 and December 2012, 92 patients with ASDs underwent the transcatheter device closure. We analyzed the sizes of the defect, the surrounding rims, and the ratios of the left atrium (LA) dimensions to the device size in the patients who underwent the procedure either using the conventional or modified methods. RESULTS: Among the 88 successful cases (95.7%), 22 patients (25%) required modified methods (12 using pulmonary vein and 10 using balloon). The modified method group had the larger size of ASDs and smaller posterosuperior rim. The mean ratios of the LA anteroposterior diameter, width, and length to the device size were all significantly smaller in the modified methods group than in the conventional group (1.20 vs. 1.56, 1.32 vs. 1.71, and 1.61 vs. 2.07, respectively). We found that the risk factors for the modified methods were smaller retroaortic rim, larger ASD, and smaller LA dimension/device size. CONCLUSION: In addition to larger defects and smaller retroaortic rim, the smaller ratios of the LA dimensions to the device size influenced the need for the application of modified methods in the transcatheter device closure of ASDs. PMID- 26023312 TI - Glucose-insulin-potassium solution protects ventricular myocytes of neonatal rat in an in vitro coverslip ischemia/reperfusion model. AB - BACKGROUND AND OBJECTIVES: The benefit of high glucose-insulin-potassium (GIK) solution in clinical applications is controversial. We established a neonatal rat ventricular myocyte (NRVM) in vitro coverslip ischemia/reperfusion (I/R) model and investigated the effects of GIK solution on suppressing reactive oxygen species (ROS) and upregulating O-GlcNacylation, which protects cells from ischemic injury. MATERIALS AND METHODS: NRVMs were isolated from postnatal day 3 4 Sprague-Dawley rat pups and grown in Dulbecco's modified Eagle's medium containing high glucose (4.5 g/L), fetal bovine serum, and penicillin/streptomycin. The effects of the GIK solution on ROS production, apoptosis, and expression of O-GlcNAc and O-GlcNAc transferase (OGT) were investigated in the coverslip I/R model. RESULTS: Covering the 24-well culture plates for 3 hr with 12 mm diameter coverslips resulted in the appropriate ischemic shock. Glucose and insulin synergistically reduced ROS production, protected NRVM dose-dependently from apoptosis, and altered O-GlcNAc and OGT expression. CONCLUSION: The high GIK solution protected NRVM from I/R injury in vitro by reducing ROS and altering O-GlcNacylation. PMID- 26023311 TI - Additive beneficial effects of valsartan combined with rosuvastatin in the treatment of hypercholesterolemic hypertensive patients. AB - BACKGROUND AND OBJECTIVES: We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients. SUBJECTS AND METHODS: Patients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed. RESULTS: A total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study. CONCLUSION: Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy. PMID- 26023313 TI - The Relationship between Spontaneous Multi-Vessel Coronary Artery Dissection and Celiac Disease. AB - Celiac disease (CD) is an immune-mediated enteropathy involving the small intestines. Genetic and environmental risk factors as well as autoimmunity have been linked to its etiology. Studies have shown that coronary artery disease, autoimmune myocarditis, arrhythmias and premature atherosclerosis are more prevalent in individuals with CD compared to individuals without the disease. In this case report a young male patient with CD presented with acute myocardial infarction with spontaneous coronary artery dissections of two vessels. To the best of our knowledge, this is the first case report of spontaneous multi-vessel coronary artery dissection in a patient with CD. PMID- 26023314 TI - Coronary artery fistula with giant aneurysm and coronary stenosis treated by transcatheter embolization and stent. AB - Coronary artery fistula (CAF) with giant aneurysm and accompanied by coronary artery stenosis is a very rare disease. Herein, we report a case of a 76-year-old woman having a complex coronary-to-pulmonary artery fistula associated with a giant aneurysm and accompanied by coronary artery stenosis. The patient was successfully treated using transcatheter coil embolization and coronary stent implantation. Eight years later, we performed a follow-up coronary angiogram, which revealed the CAF and the aneurysm were completely occluded and previous stent patency. PMID- 26023315 TI - Mechanical extraction of a massive intracoronary thrombus from the super-dominant right coronary artery in thrombogenic lung cancer patient. AB - The congenital absence of the left circumflex artery and a compensatory super dominant right coronary artery (RCA) is a very rare benign coronary anomaly in the clinic. The presence of a massive thrombus in the super-dominant RCA can lead to fatal results in cases of acute myocardial infarction, unless the thrombus is mechanically removed. Aspiration of the thrombus using a 6 Fr right Judkins guide catheter is useful to extract a massive thrombus and is both safe and effective. We report a case of complete revascularization of the super-dominant RCA after thrombus aspiration using a 6 Fr Judkins right catheter in a patient with acute inferior and inferolateral wall myocardial infarction. PMID- 26023316 TI - Swallowing-induced atrial tachyarrhythmias successfully ablated at the left posterior interatrial septum in patient with wolff-Parkinson-white syndrome. AB - We reported a case of a 55-year-old patient who presented with palpitation after swallowing. Initial surface electrocardiogram revealed ventricular preexcitation utilizing a left lateral bypass tract. The orthodromic atrioventricular reentrant tachycardia (AVRT) was induced during electrophysiologic studies. After successful ablation of the AVRT utilizing a left lateral free wall bypass tract, 2 different atrial tachycardias (ATs) were induced under isoproterenol infusion. When the patient swallowed saliva or drank water, 2 consecutive beats of atrial premature complexes (APCs) preceded another non-sustained AT repeatedly, which was coincident with the patient's symptom. The preceding APC couplet had the same activation sequence with one induced AT, and the subsequent non-sustained AT had the same activation sequence with the other induced AT, respectively. We first targeted the preceding 2 consecutive APCs at the left posterior interatrial septum. The following non-sustained AT was also eliminated following ablation of the APCs. After ablation, the patient remained free from the swallowing-induced atrial tachyarrhythmias during the one year follow-up. PMID- 26023317 TI - Factors affecting morbidity and mortality in traumatic colorectal injuries and reliability and validity of trauma scoring systems. AB - BACKGROUND AND AIM: This study aims to determine the factors that affect morbidity and mortality in colon and rectum injuries related with trauma, the use of trauma scoring systems in predicting mortality and morbidity. PATIENTS AND METHODS: Besides patient demographic characteristics, the mechanism of injury, the time between injury and surgery, accompanying body injuries, admittance Glasgow coma scale (GCS), findings at surgery and treatment methods were also recorded. With the obtained data, the abbreviated injury scale (AIS), injury severity score (ISS), revised trauma score (RTS) and trauma-ISS (TRISS) scores of each patient were calculated by using the 2008 revised AIS. RESULTS: Of the patients, 172 (88.7 %) were male, 22 (11.3 %) were female and the mean age was 29.15 +/- 12.392 (15-89) years. The morbidity of our patients were 32 % and mortality were 12.4 %. ISS (p < 0.001), RTS (p < 0.001), and the TRISS (p < 0.001) on mortality were found to be significant. TRISS (p = 0.008), the ISS (p < 0.001), the RTS (p = 0.03), the trauma surgery interval (TSI, p < 0.001) were observed to have significant effects on morbidity. Regression analysis showed that the ISS (OR 1.1; CI 95 % 1.01-1.2; p = 0.02), the RTS (OR 0.37; CI 95 % 0.21 0.67; p = 0.001) had significant effects on mortality. While the effects of TSI (OR 5.3; CI 95 % 1.5-18.8; p = 0.01) on morbidity were found to be significant. CONCLUSION: Predicting mortality by using scoring systems and close postoperative follow up of patients in the risk group may ensure decreases in the rates of morbidity and mortality. PMID- 26023318 TI - A facile, stereoselective, one-pot synthesis of resveratrol derivatives. AB - BACKGROUND: Compounds based on trans-1,2-diphenylethene are the subject of intense interest both for their optical properties and as potential leads for drug discovery, as a consequence of their anticancer, anti-inflammatory and antioxidant properties. Perhaps the best known of these is trans-3,5,4' trihydroxystilbene (resveratrol), that has been identified as a promising lead in the search for anti-ageing therapeutics. RESULTS: We report here a new, convenient, one-pot stereo-selective synthesis of resveratrol and other trans stilbene derivatives. A wide range of known and novel "Resveralogues" were synthesised by using this simple protocol, including examples with electron donating and electron withdrawing substituents, in uniformly high yield. The structures of all compounds were confirmed by standard methods including (1)H and (13)C NMR, IR and High Resolution Mass spectroscopy. CONCLUSIONS: We have established a simple and convenient protocol for resveralogue synthesis. It is readily scalable, and sufficiently robust and simple for ready use in automated synthesis or for library development of resveralogues. This supersedes previously reported synthetic methods that required inert conditions, extensive purification and/or costly reagents. Graphical abstractOne-pot preparation of diverse Resveralogues - high yields of product with minimal purification. PMID- 26023319 TI - Slow release anti-fungal skin formulations based on citric acid intercalated layered double hydroxides nanohybrids. AB - BACKGROUND: During the past few decades, the occurrence of superficial fungal infections has rapidly increased. As the fungal infections take longer time to get cured, concepts such as designing drugs with extended persistence and controlled release have gained attention. In this context, nanotechnology has been identified as the latest technological revolution which has opened up new pathways for designing new therapeutic materials. Out of the many available nano structures layered double hydroxides have gained increased scientific attention in applications as slow and controlled release drug formulations. This study focuses on the encapsulation of citric acid which has anti-fungal properties into a Mg-Al- layered double hydroxide (LDH) in order to be used as slow release topical skin formulations. RESULTS: Citrate ions were encapsulated into Mg-Al LDH using one step co-precipitation reaction. The successful intercalation of citrate ions into the layered structure has been proved referring to the expansion in the interlayer spacing as observed by the shift in the basal peak of the powder X-ray diffraction pattern. Fourier transform infra-red spectroscopy data suggests the change in the electron density around the carboxylate groups of the citrate ion thus providing evidences for formation of encapsulated hybrid composite. The resulting nanohybrid has been then, introduced into a general body cream formulation containing cocoa-butter. Both citrate LDH and the resulting body cream formulations demonstrated prolonged slow release characteristics up to 8 h in aqueous medium under different pH values (3, 4, and 5) compared to quick and fast release of pure citric acid. It was observed that the slow reelase was most efficient at low pH values. The encapsulation between the nano-layers and citrate ions are the key to the slow release characteristics. The body cream has been tested for the anti-fungal activity against three common Candida species (C. albicans, C. glabrata, C. tropicalis). The novel nanohybrid has shown an improved activity and slow release characteristics up to 48 h against the C. albicans and C. glabrata but not for C. tropicalis. CONCLUSION: The study confirms that the citrate ion intercalated LDHs have the potential for use in future slow release antifungal drug formulation. Graphical AbstractSlow release nanohybrids based on citrate intercalated layered double hydroxides. PMID- 26023320 TI - Microarray-based genomic profiling and in situ hybridization on fibrotic bone marrow biopsies for the identification of numerical chromosomal abnormalities in myelodysplastic syndrome. AB - BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological malignancies. In MDS patients with a fibrotic bone marrow the aspiration of cells often fails (dry-tap), which hampers standard karyotyping. Obtaining genetic data from these fibrotic marrows is therefore challenging, and up till now in situ hybridization applied to bone marrow biopsies is the only option. The microarray-based genomic profiling technology has already proven its value for bone marrow aspirates and peripheral blood samples, but has never been applied to the technically challenging bone marrow biopsies. We describe an approach for microarray-based genomic profiling on bone marrow biopsies and demonstrate its ability to obtain clinically relevant cytogenetic aberrations. In addition the data were compared with those obtained by in situ hybridization and karyotyping. RESULTS: We have evaluated the success rate of microarray-based genomic profiling by studying twenty-one bone marrow biopsies (7 fibrotic MDS, 12 non-fibrotic MDS and 2 reactive), by microarray-based genomic profiling and in situ hybridization (12 of 21 cases). The data obtained with these techniques were compared with conventional karyotyping data on corresponding bone marrow aspirates. Of the 15 copy number aberrations that were detected by in situ hybridization, 13 were concordant with microarray-based genomic profiling and karyotyping, whereas two hybridizations were misinterpreted. In 20 of 21 patients, the data obtained by microarray-based genomic profiling and karyotyping were identical or differences could be explained by the presence of marker chromosomes, complex karyotypes, clonal heterogeneity or disease progression. CONCLUSIONS: We demonstrate that genome wide microarray-based genomic profiling performed on bone marrow biopsies has a similar success rate compared to in situ hybridization, and prevents misinterpretation of chromosomal losses as observed by FISH. In addition, equal to even higher resolutions were obtained with genomic profiling compared to conventional karyotyping. Our findings indicate that microarray-based profiling, even on bone marrow biopsies, is a valid approach for the identification of genetic abnormalities. This is a valuable substitution in cases of fibrotic MDS lacking cytogenetic results. PMID- 26023321 TI - Insulin stimulates SGLT2-mediated tubular glucose absorption via oxidative stress generation. AB - BACKGROUND: Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on the apical membrane of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is enhanced under diabetic conditions, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. However, it remains unclear which diabetes-associated factors are involved in overexpression of SGLT2. METHODS: Therefore, in this study, we examined whether insulin, high glucose, advanced glycation end products (AGEs), or H2O2 stimulated SGLT2 expression in human cultured proximal tubular cells, and then investigated the underlying molecular mechanisms. RESULTS: High glucose or AGEs did not affect SGLT2 expression in tubular cells. Insulin significantly increased tubular SGLT2 level in a dose-dependent manner, whereas bell-shaped dose-response curves were observed for H2O2-treated cells. An anti-oxidant, N acetylcysteine completely blocked insulin-induced up-regulation of SGLT2 as well as increase in glucose absorption by tubular cells. Furthermore, insulin dose dependently increased reactive oxygen species generation in tubular cells. CONCLUSIONS: Our present study demonstrated that insulin could stimulate SGLT-2 mediated glucose entry into cultured proximal tubular cells via oxidative stress generation. Suppression of the insulin-induced overexpression of SGLT2 in tubular cells might be a novel therapeutic strategy for the treatment of diabetic nephropathy. PMID- 26023322 TI - Severity of allergic rhinitis and asthma development in children. AB - Allergic rhinitis (AR) is a relevant risk factor for the development of asthma in children. We recruited a cohort of 104 children with AR and re-evaluated them after 5 years. We considered the ARIA classification. All patients, who had moderate to severe persistent AR at baseline, developed asthma symptoms. These results strongly indicate that the severity of AR may be an important factor that increases the risk of asthma development in children. PMID- 26023324 TI - How an online survey on the treatment of allergic rhinitis and its impact on asthma (ARIA) detected specialty-specific knowledge-gaps. AB - BACKGROUND: To enhance the dissemination of the ARIA document (Allergic rhinitis (AR) and its impact on asthma) in Mexico, a Working Group composed of 35 specialists of 8 professional medical societies developed a transculturized ARIA Mexico 2014 guideline. The ARIA guidelines use the GRADE system, which builds recommendations and suggestions around clinical questions (CQ). METHODS: As part of the dissemination strategy and to detect the physicians' view and knowledge gaps concerning the treatment of AR an online survey was sent out to members of participating societies containing the CQ of ARIA Mexico. Replies were analyzed per specialty against the ARIA Mexico 2014 experts' recommendations/suggestions; differences between specialties were analyzed with Pearson's Chi-squares. RESULTS: 807 surveys were returned, 657 completed (81%). We analyze replies from 158 alergists, 188 ENTs, 64 pulmonologists, 220 pediatricians and 177 GPs/family doctors. More than half of the surveyed physicians of all specialties would give an allergen reduced diet to pregnant/lactating women and avoid pets at home, which is against ARIA experts' suggestions. ARIA experts suggest intranasal antihistamines can be part of the AR treatment: 46-63% of the ENTs, pulmonologists and pediatricians disagree; and experts prefer oral H1 antihistamines over leukotriene receptor antagonists (LTRA) for the treatment of AR: 52-36% of the pulmonologists, pediatricians and GPs prefer LTRAs. Concerning glucocorticosteroids (GCS): GPs are more reluctant to use intranasal GCS (p < 0.001) and 47% prefers oral H1-antihistamines. As for the treatment of recalcitrant AR ARIA experts suggest the use of oral, but not intramuscular, GCS: a quarter of pulmonologists, pediatricians and GPs considers they should not be used. Contrarily, 40% of ENTs favors intramuscular GCS. In patients with AR and comorbid asthma several physicians of all specialties -except pulmonologists- erroneously considers antihistamines, intranasal GCS and LTRAs useful for the treatment of asthma, while first-line recommended asthma treatment is inhaled GCS. CONCLUSION: On certain issues in the treatment of AR the physicians' opinion diverges from the recommendations/suggestions of ARIA experts. Moreover, physicians' opinions depend on their specialty. As such, an online survey can help to detect knowledge-gaps and guide the development of more focused and specialty-specific postgraduate learning tools. PMID- 26023325 TI - Probing Prejudice with Startle Eyeblink Modification: A Marker of Attention, Emotion, or Both? AB - In social neuroscience research, startle eyeblink modification can serve as a marker of emotion, but it is less clear whether it can also serve as a marker of prejudice. In Experiment 1, 30 White students viewed photographs of White and Black targets while the startle eyeblink reflex and facial EMG from the brow and cheek regions were recorded. Prejudice was related to facial EMG activity, but not to startle modification, which instead appeared to index attention to race. To test further whether racial categorizations are associated with differential attention, a dual-task paradigm was used in Experiment 2. Fifty-four White and fifty-five Black participants responded more slowly to a tone presented when viewing a racial outgroup member or a negative stimulus, indicating that both draw more attention than ingroup members or positive stimuli. We conclude that startle modification is useful to index differential attention to groups when intergroup threat is low. PMID- 26023323 TI - Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. AB - Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation and chronic infections has led to a variety of targeted therapeutic approaches. Allergen-specific immunotherapy (AIT) has been used for 100 years as a desensitizing therapy for allergic diseases and represents the potentially curative and specific way of treatment. The mechanisms by which allergen-AIT has its mechanisms of action include the very early desensitization effects, modulation of T- and B-cell responses and related antibody isotypes as well as inhibition of migration of eosinophils, basophils and mast cells to tissues and release of their mediators. Regulatory T cells (Treg) have been identified as key regulators of immunological processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in AIT. Naturally occurring FoxP3(+) CD4(+)CD25(+) Treg cells and inducible type 1 Treg (Tr1) cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector Th1, Th2 and Th17 cells; suppression of allergen-specific IgE, and induction of IgG4; suppression of mast cells, basophils and eosinophils and suppression of effector T cell migration to tissues. New strategies for immune intervention will likely include targeting of the molecular mechanisms of allergen tolerance and reciprocal regulation of effector and regulatory T cell subsets. PMID- 26023327 TI - Ruthenium-Caged Antisense Morpholinos for Regulating Gene Expression in Zebrafish Embryos. AB - Photochemical approaches afford high spatiotemporal control over molecular structure and function, for broad applications in materials and biological science. Here, we present the first example of a visible light responsive ruthenium-based photolinker, Ru(bipyridine)2(3-ethynylpyridine)2 (RuBEP), which was reacted stoichiometrically with a 25mer DNA or morpholino (MO) oligonucleotide functionalized with 3' and 5' terminal azides, via Cu(I)-mediated [3+2] Huisgen cycloaddition reactions. RuBEP-caged circular morpholinos (Ru-MOs) targeting two early developmental zebrafish genes, chordin and notail, were synthesized and tested in vivo. One-cell-stage zebrafish embryos microinjected with Ru-MO and incubated in the dark for 24 h developed normally, consistent with caging, whereas irradiation at 450 nm dissociated one 3-ethynylpyridine ligand (phi = 0.33) and uncaged the MO to achieve gene knockdown. As demonstrated, Ru photolinkers provide a versatile method for controlling structure and function of biopolymers. PMID- 26023326 TI - Alterations of local spontaneous brain activity and connectivity in adults with high-functioning autism spectrum disorder. AB - BACKGROUND: Previous autism research has hypothesized that abnormalities of functional connectivity in autism spectrum disorder (ASD) may vary with the spatial distance between two brain regions. Although several resting-state functional magnetic resonance imaging (rsfMRI) studies have extensively examined long-range (or distant) connectivity in the adult ASD brain, short-range (or local) connectivity has been investigated in less depth. Furthermore, the possible relationship between functional connectivity and brain activity level during the resting state remains unclear. METHODS: We acquired rsfMRI data from 50 adults with high-functioning ASD and 50 matched controls to examine the properties of spontaneous brain activity using measures of local and distant connectivity together with a measure of the amplitude of brain activity, known as fractional amplitude of low-frequency fluctuation (fALFF). The two connectivity measures were calculated using a common graph-theoretic framework. We also examined the spatial overlaps between these measures and possible relationships of these disrupted functional measures with autistic traits assessed by the Autism-Spectrum Quotient (AQ). RESULTS: Compared to the controls, participants with ASD exhibited local over-connectivity in the right superior frontal gyrus and middle frontal gyrus, accompanied by local under-connectivity in the bilateral fusiform gyri (FG) and right middle temporal gyrus (MTG). On the other hand, we did not find any significant alterations in distant connectivity. Participants with ASD also exhibited reduced fALFF in the right middle occipital gyrus, lingual gyrus, and FG. Further conjunction and spatial overlap analyses confirmed that the spatial pattern of reduced fALFF substantially overlapped with that of local under-connectivity, demonstrating the co-occurrence of disrupted connectivity and spontaneous activity level in the right inferior occipital gyrus, posterior MTG (pMTG), and FG. Finally, within the ASD group, disrupted local connectivity in the right pMTG significantly correlated with the "social interaction" subscale score of the AQ. CONCLUSIONS: These findings revealed local functional disruptions in the occipital and temporal regions, especially the right FG and pMTG, in the form of co-occurrence of spontaneous brain activity level and local connectivity, which may underline social and communicative dysfunctions in adult ASD. PMID- 26023328 TI - The biophysical nature of cells: potential cell behaviours revealed by analytical and computational studies of cell surface mechanics. AB - BACKGROUND: The biophysical characteristics of cells determine their shape in isolation and when packed within tissues. Cells can form regular or irregular epithelial structures, round up and form clusters, or deform and attach to substrates. The acquired shape of cells and tissues is a consequence of (i) internal cytoskeletal processes, such as actin polymerisation and cortical myosin contraction, (ii) adhesion molecules within the cell membrane that interact with substrates and neighbouring cells, and (iii) processes that regulate cell volume. Although these processes seem relatively simple, when combined they unleash a rich variety of cellular behaviour that is not readily understandable outside a theoretical framework. METHODS: We perform a mathematical analysis of a commonly used class of model formalisms that describe cell surface mechanics using an energy-based approach. Predictions are then confirmed through comparison with the computational outcomes of a Vertex model and 2D and 3D simulations of the Cellular Potts model. RESULTS: The analytical study reveals the complete possible spectrum of single cell behaviour and tissue packing in both 2D and 3D, by taking the typical core elements of cell surface mechanics into account: adhesion, cortical tension and volume conservation. We show that from an energy-based description, forces and tensions can be derived, as well as the prediction of cell behaviour and tissue packing, providing an intuitive and biologically relevant mapping between modelling parameters and experiments. CONCLUSIONS: The quantitative cellular behaviours and biological insights agree between the analytical study and the diverse computational model formalisms, including the Cellular Potts model. This illustrates the generality of energy-based approaches for cell surface mechanics and highlights how meaningful and quantitative comparisons between models can be established. Moreover, the mathematical analysis reveals direct links between known biophysical properties and specific parameter settings within the Cellular Potts model. PMID- 26023329 TI - Comparative analysis between endometrial proteomes of pregnant and non-pregnant ewes during the peri-implantation period. AB - BACKGROUND: Early pregnancy failure has a profound impact on both human reproductive health and animal production. 2/3 pregnancy failures occur during the peri-implantation period; however, the underlying mechanism(s) remains unclear. Well-organized modification of the endometrium to a receptive state is critical to establish pregnancy. Aberrant endometrial modification during implantation is thought to be largely responsible for early pregnancy loss. RESULT: In this study, using well-managed recipient ewes that received embryo transfer as model, we compared the endometrial proteome between pregnant and non pregnant ewes during implantation period. After embryo transfer, recipients were assigned as pregnant or non-pregnant ewes according to the presence or absence of an elongated conceptus at Day 17 of pregnancy. By comparing the endometrial proteomic profiles between pregnant and non-pregnant ewes, we identified 94 and 257 differentially expressed proteins (DEPs) in the endometrial caruncular and intercaruncular areas, respectively. Functional analysis showed that the DEPs were mainly associated with immune response, nutrient transport and utilization, as well as proteasome-mediated proteolysis. CONCLUSION: These analysis imply that dysfunction of these biological processes or pathways of DEP in the endometrium is highly associated with early pregnancy loss. In addition, many proteins that are essential for the establishment of pregnancy showed dysregulation in the endometrium of non-pregnant ewes. These proteins, as potential candidates, may contribute to early pregnancy loss. PMID- 26023330 TI - Quantification of folate metabolism using transient metabolic flux analysis. AB - BACKGROUND: Systematic quantitative methodologies are needed to understand the heterogeneity of cell metabolism across cell types in normal physiology, disease, and treatment. Metabolic flux analysis (MFA) can be used to infer steady state fluxes, but it does not apply for transient dynamics. Kinetic flux profiling (KFP) can be used in the context of transient dynamics, and it is the current gold standard. However, KFP requires measurements at several time points, limiting its use in high-throughput applications. RESULTS: Here we propose transient MFA (tMFA) as a cost-effective methodology to quantify metabolic fluxes using metabolomics and isotope tracing. tMFA exploits the time scale separation between the dynamics of different metabolites to obtain mathematical equations relating metabolic fluxes to metabolite concentrations and isotope fractions. We show that the isotope fractions of serine and glycine are at steady state 8 h after addition of a tracer, while those of purines and glutathione are following a transient dynamics with an approximately constant turnover rate per unit of metabolite, supporting the application of tMFA to the analysis of folate metabolism. Using tMFA, we investigate the heterogeneity of folate metabolism and the response to the antifolate methotrexate in breast cancer cells. Our analysis indicates that methotrexate not only inhibits purine synthesis but also induces an increase in the AMP/ATP ratio, activation of AMP kinase (AMPK), and the inhibition of protein and glutathione synthesis. We also find that in some cancer cells, the generation of one-carbon units from serine exceeds the biosynthetic demand. CONCLUSIONS: This work validates tMFA as a cost-effective methodology to investigate cell metabolism. Using tMFA, we have shown that the effects of treatment with the antifolate methotrexate extend beyond inhibition of purine synthesis and propagate to other pathways in central metabolism. PMID- 26023331 TI - Identification of clinical and serological factors during induction treatment of lupus nephritis that are associated with renal outcome. AB - OBJECTIVE: To identify factors associated with clinical outcome in patients with lupus nephritis. METHODS: Data from the Aspreva Lupus Management Study (ALMS) were analysed. Using multivariate analysis, we assessed the prognostic value of demographic, clinical, laboratory and histopathological features on the frequency of either complete remission (CR) or treatment failure (TF) during the maintenance phase. RESULTS: Among the 370 subjects who entered the trial (complete population), non-Hispanic ethnicity was associated with a higher likelihood of CR (OR=2.0). Several factors were independently associated with a greater likelihood of TF, including: (1) anti-double-stranded DNA (anti-dsDNA) at trial entry (OR=12.7), (2) failure to reduce anti-dsDNA within 8 weeks (OR=2.9) and (3) failure to reduce urine protein:creatinine ratio (UP/C) by >=25% within 8 weeks (OR=2.6). Among the 227 subjects who entered the maintenance phase (maintenance population), baseline estimated glomerular filtration rate (eGFR) >=90 mL/min/1.73 m(2) was associated with a greater likelihood of CR (OR=2.0), and UP/C >1 at the end of induction was associated with a lower likelihood of CR (OR=0.3). Induction treatment with intravenous cyclophosphamide (IVC) was associated with a lower likelihood of TF (OR=0.5), while lack of treatment with antimalarials (OR=2.4), failure to reduce anti-dsDNA during the first 8 weeks of induction (OR=3.5), failure to reduce UP/C during the first 8 weeks of induction (OR=2.1) and anti-dsDNA positivity at the end of induction (OR=8.3) were independently associated with a greater likelihood of TF. CONCLUSIONS: This analysis demonstrates that levels of anti-dsDNA and UP/C during induction treatment are independently associated with renal outcome over the ensuing 3 years in both the complete and maintenance populations. Ethnicity is associated with renal outcome in just the complete population, and eGFR, induction treatment and treatment with antimalarials are associated with renal outcome in just the maintenance population. PMID- 26023332 TI - Evaluation of In Vivo Transfection Efficiency of Eudragit Coated Nanoparticles of Chitosan-DNA: A pH-sensitive System Prepared for Oral DNA Delivery. AB - BACKGROUND: Success of any gene therapy protocol relies mostly on using an efficient carrier to direct nucleic acid to the place of action. The system should also have transfection ability at release site. Different routes are available for delivering genetic materials to the target organs, amongst them; oral delivery is particularly attractive for certain reasons. However, serious obstacles, like acidic environment of stomach and presence of protease and nuclease enzymes in gastrointestinal (GI) tract, make oral route a highly challenging option. OBJECTIVES: The present study suggests preparation of gene nanoparticles (NPs) of chitosan within a layer of Eudragit L100 for oral delivery of nucleic acid. The nanoparticles have some features both in size and polymer properties that can be penetrating enough to transfect epithelial layer cells of intestine and protect the entrapped materials against stomach harsh condition. MATERIALS AND METHODS: In this experimental study, conducted in Iran, particles were prepared by coacervation technique followed by encapsulation of nanoparticle within a coat of Eudragit L100 using solvent evaporation technique. Formulation behavior was monitored both in vitro and in vivo. Stability of particle construction and release profile of DNA were examined at pH of +/- 0.8 environ pKa of Eudragit. Size and zeta potential of particles were measured. To demonstrate transfection efficiency of the constructed carrier, reverse transcription polymerase chain reaction (RT-PCR) was carried out using human insulin specific primers on total RNA extracted from upper part of small intestine of 48-hour post-transfected rats (sampled by simple random selection, n = 3). RESULTS: The mean size and zeta potential of particles were 300 +/- 4 nm and 14 +/- 0.5 mV, respectively. Encapsulation of this system was 89.6 +/- 1.2%. DNA release from batches was less than 12% at pH = 5.2 and more than 60% at pH = 6.8 with significant difference of P < 0.05. RT-PCR product confirmed the presence of insulin transcript of 437 bp in upper intestinal extracts of the transfected rats. No band of DNA was seen after RT-PCR of placebo form of nanoparticles received group. CONCLUSIONS: Eudragit coated nanoparticle of chitosan is an efficient choice for oral delivery of DNA to upper part of GI tract. PMID- 26023333 TI - Comparison of visual status of Iranian military and commercial drivers. AB - BACKGROUND: There is no legal requirement for Iranian military truck drivers to undergo regular visual checkups as compared to commercial truck drivers. OBJECTIVES: This study aimed to evaluate the impact of drivers' visual checkups by comparing the visual function of Iranian military and commercial truck drivers. PATIENTS AND METHODS: In this comparative cross-sectional study, two hundred military and 200 commercial truck drivers were recruited and their Visual Acuity (VA), Visual Field (VF), color vision and Contrast Sensitivity (CS) were assessed and compared using the Snellen chart, confrontation screening method, D15 test and Pelli-Robson letter chart, respectively. A questionnaire regarding driving exposure and history of motor-vehicle crashes (MVCs) was also filled by drivers. Results were analyzed using an independent samples t-test, one-way ANOVA (assessing difference in number of MVCs across different age groups), chi-square test and Pearson correlation at statistical significance level of P < 0.05. RESULTS: Mean age was 41.6 +/- 9.2 for the military truck drivers and 43.4 +/- 10.9 for commercial truck drivers (P > 0.05). No significant difference between military and commercial drivers was found in terms of driving experience, number of MVCs, binocular VA, frequency of color vision defects and CS scores. In contrast, the last ocular examination was significantly earlier in military drivers than commercial drivers (P < 0.001). In addition, 4% of military drivers did not meet the national standards to drive as opposed to 2% of commercial drivers. There was a significant but weak correlation between binocular VA and age (r = 0.175, P < 0.001). However, CS showed a significantly moderate correlation with age (r = -0.488, P < 0.001). CONCLUSIONS: The absence of legal requirement for regular eye examination in military drivers caused the incompetent drivers to be missed in contrast to commercial drivers. The need for scientific revision of VA standard for Iranian drivers is also discussed. The CS measurement in visual checkups of older drivers deserves to be investigated more thoroughly. PMID- 26023334 TI - Patients' Experience of Tuberculosis Treatment Using Directly Observed Treatment, Short-Course (DOTS): A Qualitative Study. AB - BACKGROUND: Despite effective diagnosis and treatment, prevalence of tuberculosis (TB) is still growing. The directly observed treatment, short-course (DOTS) strategy to treat TB was introduced by the World Health Organization more than a decade ago. Little is known about patients' experience of TB treatment, according to DOTS, in Iran. OBJECTIVES: This study aimed to understand the patients' experience of tuberculosis treatment according to DOTS in Iran. PATIENTS AND METHODS: This study is a qualitative study, using content analysis to examine patients' experience of TB treatment and to understand their compliance during DOTS. In this study, a semi-structured interview with open questions was answered by 40 patients, who had a diagnosis of pulmonary and extrapulmonary tuberculosis, and improved during the course of their treatment. The method of sampling was purposive sample and the interview process lasted until data saturation. RESULTS: Data analysis resulted in the extraction of six themes, which reflect the experiences of the study participants. The themes are: 1) individual factors; 2) change of the attitudes and beliefs of patients on TB treatment; 3) support terms of patients with tuberculosis; 4) the role of health care professionals; 5) social factors and 6) the financial burden. CONCLUSIONS: Successful completion of TB treatment requires an effective partnership between the patient and health care professionals, and a harmony between the cultural context, attitude of the patient, family support and health literacy. Future health policies should address these issues to improve patients' adherence to DOTS. PMID- 26023335 TI - An experimental study: does the neuroprotective effect increase when hypothermia deepens after traumatic brain injury? AB - BACKGROUND: Experimental approaches have been promising with the use of therapeutic hypothermia after Traumatic Brain Injury (TBI) whereas clinical data have not supported its efficacy. OBJECTIVES: This study aimed to investigate whether using selective deeper brain cooling correlates with a more neuroprotective effect on Intracranial Pressure (ICP) increments following TBI in rats. MATERIALS AND METHODS: Adult male Sprague-Dawley rats (mean weight = 300 g; n = 25) were subjected to brain injury using a modified Marmarou method. Immediately after the onset of TBI, rats were randomized into three groups. Selective brain cooling was applied around the head using ice packages. Intracranial Temperature (ICT) and ICP were continuously measured at 0, 30, 60, 120, and 180 minutes and recorded for all groups. Group 1 (n = 5) was normothermia and was assigned as the control group. Group 2 (n = 10) received moderate hypothermia with a target ICT of between 32 degrees C - 33 degrees C and Group 3 (n = 10) was given a deeper hypothermia with a target ICT of below 32 degrees C. RESULTS: All subjects reached the target ICT by the 30th minute of hypothermia induction. The ICT was significantly different in Group 2 compared to Group 1 only at the 120th minute (P = 0.017), while ICP was significantly lower starting from the 30th minute (P = 0.015). The ICT was significantly lower in Group 3 compared to Groups 1 and 2 starting from the 30th minute (P = 0.001 and P = 0.003, respectively). The ICP was significantly lower in Group 3 compared to Group 1 starting from 30th minute (P = 0.001); however, a significant difference in ICP between Group 3 and Group 2 was observed only at the 180th minute (P = 0.047). CONCLUSIONS: Results of this study indicate that selective brain cooling is an effective method of decreasing ICP in rats; however, the deeper hypothermia caused a greater decrease in ICP three hours after hypothermia induction. PMID- 26023336 TI - Post cholecystectomy gossypiboma mimicking a liver hydatid cyst: comprehensive literature review. AB - BACKGROUND: Gossypiboma is the term for forgotten textile products such as a surgical sponge and compress in the body cavity after a surgical procedure. OBJECTIVES: The aim of this study was to evaluate previously published articles related to post cholecystectomy gossypiboma. MATERIALS AND METHODS: We conducted a systematic search using PubMed, Medline, Google and Google Scholar on post cholecystectomy gossypiboma. The keywords used were: gossypiboma and cholecystectomy, textiloma and cholecystectomy and post cholecystectomy gossypiboma. Furthermore, we also present a new case of post cholecystectomy gossypiboma. RESULTS: A total of 32 articles concerning 38 patients with post cholecystectomy gossypiboma that met the aforementioned criteria were included. Detailed intraoperative findings and surgical management were provided. The patients were aged from 26 to 79 years (Mean +/- SD: 47 +/- 13.6 years); 32 were female and six were male. The time from the causative operation to presentation with a retained surgical sponge ranged from one to 480 months (Mean +/- SD: 56.5 +/- 93.5 months). CONCLUSIONS: Gossypiboma may not be symptomatic for many years or could be symptomatic for a short duration of time. Besides being a rare surgical complication, gossypiboma can lead to serious morbidity and mortality that may cause medico-legal problems. Diagnosis with imaging methods is difficult. PMID- 26023337 TI - The effect of estrogen usage on eccentric exercise-induced damage in rat testes. AB - BACKGROUND: Recent years, lots of scientific studies are focused on the possible mechanism of inflammatory response and oxidative stress which are the mechanism related with tissue damage and exercise fatigue. It is well-known that free oxygen radicals may be induced under invitro conditions as well as oxidative stress by exhaustive physical exercise. OBJECTIVES: The aim of this study was to investigate the effects of anabolic steroids in conjunction with exercise in the process of spermatogenesis in the testes, using histological and stereological methods. MATERIALS AND METHODS: Thirty-six male Sprague Dawley rats were divided to six groups, including the control group, the eccentric exercise administered group, the estrogen applied group, the estrogen applied and dissected one hour after eccentric exercise group, the no estrogen applied and dissected 48 hours after eccentric exercise group and the estrogen applied and dissected 48 hours after eccentric exercise group. Eccentric exercise was performed on a motorized rodent treadmill and the estrogen applied groups received daily physiological doses by subcutaneous injections. Testicular tissues were examined using specific histopathological, immunohistochemical and stereological methods. Sections of the testes tissue were stained using the TUNEL method to identify apoptotic cells. Apoptosis was calculated as the percentage of positive cells, using stereological analysis. A statistical analysis of the data was carried out with one-way analysis of variance (ANOVA) for the data obtained from stereological analysis. RESULTS: Conventional light microscopic results revealed that testes tissues of the eccentric exercise administered group and the estrogen supplemented group exhibited slight impairment. In groups that were both eccentrically exercised and estrogen supplemented, more deterioration was detected in testes tissues. Likewise, immunohistochemistry findings were also more prominent in the eccentrically exercised and estrogen supplemented groups. CONCLUSIONS: The findings suggest that estrogen supplementation increases damage in testicular tissue due to eccentric exercise. PMID- 26023338 TI - Nurse-physician collaboration: the attitudes of baccalaureate nursing students at tehran university of medical sciences. AB - BACKGROUND: Establishing professional communication between physicians and nurses regarding their supplemental roles in health care for patients is unavoidable. Existing studies have reported on related problems concerning ineffective professional collaboration among health care providers. OBJECTIVES: The aim of this study was to determine Iranian bachelor of nursing students' attitudes regarding collaboration between physicians and nurses at Tehran University of Medical Sciences. PATIENTS AND METHODS: This study was an inferential cross sectional study. The study population consisted of all first and fourth academic year Iranian bachelor of nursing students at Tehran University of Medical Sciences (277 individuals), who were selected by convenience sampling. The participation rate was 97.47% (270 individuals). A questionnaire including demographic information and professional experience was used to gather information (included 12 questions). Additionally, the Jefferson Scale of Attitudes toward Physician-Nurse Collaboration (JSAPNC) was also used (included 15 questions). Data were analyzed using the SPSS software. The applied statistical tests included: chi(2), t student and ANOVA test. RESULTS: The obtained mean attitude score for the first academic year (51.28 +/- 4.98) was higher than the mean attitude score of the fourth academic year nursing students (50.56 +/- 4.05). However, the results of the independent statistical t-test showed no significant difference between the two groups of students (P = 0.322). In the four dimensions of JSAPNC, concerning only the dimension of physician authority, there were significant differences between the two groups of students (P < 0.05). The obtained means for the first and fourth academic year of bachelor nursing students reflected their positive attitudes about collaboration between physicians and nurses. CONCLUSIONS: The positive attitude of most nursing students found in this study showed the need for appropriate and effective collaboration between medical staff; this collaboration will give patients and prospective patients the best possible care. PMID- 26023339 TI - Comparison of the Effects of pH-Dependent Peppermint Oil and Synbiotic Lactol (Bacillus coagulans + Fructooligosaccharides) on Childhood Functional Abdominal Pain: A Randomized Placebo-Controlled Study. AB - BACKGROUND: Still there is no consensus on the best treatment for abdominal pain related functional Gastrointestinal Disorders (FGIDs). OBJECTIVES: The purpose of this study was to compare the effects of a synbiotic Lactol (Bacillus coagulans + fructooligosaccharide (FOS)), peppermint oil (Colpermin) and placebo (folic acid) on abdominal pain-related FGIDs except for abdominal migraine. PATIENTS AND METHODS: This placebo-controlled study was conducted on 120 children aged 4 - 13 years to compare the efficacy of pH-dependent peppermint oil (Colpermin) versus synbiotic Lactol (Bacillus coagulans + fructooligosaccharids (FOS)) in decreasing duration, severity and frequency of functional abdominal pain. The patients were randomly allocated into three equal groups (n = 40 in each group) and each group received Colpermin or Lactol or placebo. RESULTS: Eighty-eight out of 120 enrolled patients completed a one-month protocol and analyses were performed on 88 patients' data. Analyses showed that improvement in pain duration, frequency and severity in the Colpermin group was better than the placebo group (P = 0.0001, P = 0.0001 and P = 0.001, respectively). Moreover, pain duration and frequency were decreased in the Lactol group more than the placebo (P = 0.012 and P = 0.0001, respectively), but changes in pain severity were not significant (P = 0.373). Colpermin was superior to Lactol in decreasing pain duration and severity (P = 0.040 and P = 0.013, respectively). No known side effects or intolerance were seen with Colpermin or Lactol. CONCLUSIONS: The pH-dependent peppermint oil capsule and Lactol tablet (Bacillus coagulans+ FOS) as synbiotics seem to be superior to placebo in decreasing the severity, duration and frequency of pain in abdominal pain-related functional GI disorders. PMID- 26023340 TI - Diagnosing tuberculosis with a novel support vector machine-based artificial immune recognition system. AB - BACKGROUND: Tuberculosis (TB) is a major global health problem, which has been ranked as the second leading cause of death from an infectious disease worldwide. Diagnosis based on cultured specimens is the reference standard, however results take weeks to process. Scientists are looking for early detection strategies, which remain the cornerstone of tuberculosis control. Consequently there is a need to develop an expert system that helps medical professionals to accurately and quickly diagnose the disease. Artificial Immune Recognition System (AIRS) has been used successfully for diagnosing various diseases. However, little effort has been undertaken to improve its classification accuracy. OBJECTIVES: In order to increase the classification accuracy of AIRS, this study introduces a new hybrid system that incorporates a support vector machine into AIRS for diagnosing tuberculosis. PATIENTS AND METHODS: Patient epacris reports obtained from the Pasteur laboratory of Iran were used as the benchmark data set, with the sample size of 175 (114 positive samples for TB and 60 samples in the negative group). The strategy of this study was to ensure representativeness, thus it was important to have an adequate number of instances for both TB and non-TB cases. The classification performance was measured through 10-fold cross-validation, Root Mean Squared Error (RMSE), sensitivity and specificity, Youden's Index, and Area Under the Curve (AUC). Statistical analysis was done using the Waikato Environment for Knowledge Analysis (WEKA), a machine learning program for windows. RESULTS: With an accuracy of 100%, sensitivity of 100%, specificity of 100%, Youden's Index of 1, Area Under the Curve of 1, and RMSE of 0, the proposed method was able to successfully classify tuberculosis patients. CONCLUSIONS: There have been many researches that aimed at diagnosing tuberculosis faster and more accurately. Our results described a model for diagnosing tuberculosis with 100% sensitivity and 100% specificity. This model can be used as an additional tool for experts in medicine to diagnose TBC more accurately and quickly. PMID- 26023341 TI - Serum Ferritin Levels Correlation With Heart and Liver MRI and LIC in Patients With Transfusion-Dependent Thalassemia. AB - BACKGROUND: Iron-loaded cardiac complication is the essential cause of mortality in patients with thalassemia. Early detection and treatment of cardiac over-load can reduce mortality. OBJECTIVES: The current study aimed to evaluate the relationship between serum ferritin levels and T2* magnetic resonance imaging (MRI) of heart and liver and liver iron concentration (LIC) to diagnose iron over load in countries with limited access. PATIENTS AND METHODS: In the current cross sectional study, 85 Iranian patients with thalassemia with the mean age of 22.7 +/- 7 years were randomly selected. All patients were on regular blood transfusion. Echocardiography of heart and liver T2* MRI, determination of serum ferritin levels, and LIC were performed in all subjects at the same time. The correlation of serum ferritin levels with T2*MRI of heart and liver, and LIC was assessed. P value < 0.05 was considered statistically significant. RESULTS: Abnormal myocardial iron load (T2* MRI < 20 ms) was detected in 58% of the patients and among whom, 36% had severe myocardial iron load (T2* MRI < 10 ms). Median and interquartile range of serum ferritin levels were 1434 and 2702 respectively in patients with thalassemia. Serum ferritin levels showed a statistically significant positive correlation with LIC (rs = 0.718, P < 0.001) and significant negative correlation with T2* Heart (rs = -0.329, P = 0.002), and T2* Liver (rs = -0.698, P < 0.001). However, Ejection fraction was not significantly correlated with serum ferritin levels in the patients (P = 0.399). CONCLUSIONS: Serum ferritin levels can be used to diagnose iron over-load in patients with thalassemiaas an alternative method in areas where T2* MRI is not available. PMID- 26023342 TI - Evaluation of the protective effect of silibinin against diazinon induced hepatotoxicity and free-radical damage in rat liver. AB - BACKGROUND: Diazinon (0,0-Diethyl 0-(1-6-methyl-2-isoprophyl 4 pyrimidinyl) phosphorothioate) (DI) is a very effective organophosphate pesticide, used widely in agriculture. Consequently, data on poisoning cases secondary to DI exposure are important. The DI may affect a variety of tissues, including liver. Silibinin is a pharmacologically active constitute of Silybum marianum, with documented antioxidant activity. OBJECTIVES: The aim of our study was to evaluate both histopathologically and biochemically whether silibinin is protective in DI induced liver damage. MATERIALS AND METHODS: Thirty two Wistar albino rats were divided into four groups, as follows: 1) control group - oral corn oil was given; 2) DI group - rats were administered orally 335 mg/kg in the corn oil solution; 3) Silibinin group - 100 mg/kg/day silibinin was given alone orally, every 24 hours for 7 days; 4) Silibinin + DI group - DI plus silibinin was given. All rats were sacrificed at the end of experiment. Superoxide dismutases (SOD), glutathione peroxidase (GPX), nitric oxide (NO) and myeloperoxidase (MPO) were investigated in serum and liver tissue. In addition, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activities were evaluated. The liver tissue was evaluated histopathologically with Hematoxilin & Eosin dye. RESULTS: Biochemically, ALT, AST, NO, MPO in serum and NO, MPO in liver tissue were found to be significantly higher in DI group, compared to control group (P < 0.001). In Group Silibinin + DI, serum AST, ALT, NO, MPO levels were significantly lower (P < 0.01), and both serum and tissue SOD activities were significantly higher, compared to DI group (P < 0.001). Diazinon induced histopathological changes in liver tissue were: severe sinusoidal dilatation, moderate disruption of the radial alignment of hepatocytes around the central vein, severe vacuolization in the hepatocyte cytoplasm, inflammation around central vein and portal region. In rats receiving both DI and silibinin, the DI induced changes accounted for less sinusoidal dilatation, vacuolization in the hepatocyte cytoplasm and the inflammation around central vein and portal region (P < 0.05). CONCLUSIONS: The DI was found to induce liver damage by oxidative stress mechanisms. Silibinin reduced the oxidative stress by inducing antioxidant mechanisms, thereby showing protective effect against DI induced liver damage. Further studies with silibinin should be performed regarding DI toxicity. PMID- 26023343 TI - Lavender fragrance essential oil and the quality of sleep in postpartum women. AB - BACKGROUND: Labor and delivery is a stressful stage for mothers. During these periods, sleep-related disorders have been reported. The problems of inadequate sleep include decrease in concentration, judgment, difficulty in performing daily activities, and an increase in irritability. Even the effects of moderate sleep loss on life and health quality can be similar to sleep deprivation. some research aggravated by aromatherapy on sleep quality in different periods of life so might be useful for the improve of sleep quality in postpartum women. OBJECTIVES: This study aimed to determine the effect of aromatherapy on the quality of sleep in postpartum women. The sample was recruited from medical health centers of Zanjan University of Medical Sciences. PATIENTS AND METHODS: This study was a randomized clinical trial with the control group. A total of 158 mothers in postpartum period (with certain inclusion criteria) were enrolled in the study and assigned randomly to two groups of control and intervention. Lavender fragrance (made by Barij Essence Pharmaceutical Co.) was used by participants in the intervention group nightly before sleeping. The fragrance was dropped on cotton balls, which were placed on a cylindrical container at mothers' disposal. Keeping the container at a projected distance of 20 cm, the participants inhaled 10 deep breaths and then the container was placed beside their pillow until morning. This procedure was done 4 times a week for 8 weeks. For the control group, the same intervention was done with the placebo. The instrument for collecting data was Pittsburgh sleep quality index, which was completed at the baseline, fourth, and eighth weeks after the intervention. Data were analyzed using independent t test and repeated measures analysis of variance calculated by SPSS16. RESULTS: Before the intervention, there were no significant differences between mothers in two groups (P > 0.05). After 8 weeks follow up, a significant improvement appeared in mothers' sleep quality in the intervention group. Aromatherapy increased sleep quality mean score (+/-SD) from 8.2911 (+/- 2.1192) to 6.7975 (+/- 2.3663) (P < 0.05), but in the control group sleep quality mean score (+/-SD) changes from 8.4557 (+/- 2.3027) to 7.5696 (+/- 1.1464) (P > 0.05). Comparing sleep quality between control and intervention groups after 8 weeks from the beginning of the intervention indicated that aromatherapy was effective in the improvement of mothers' sleep quality (P < 0.05). CONCLUSIONS: Considering the effects of aromatherapy on the improvement of mother's sleep quality during postpartum period, aromatherapy has been suggested as a non pharmacological method for the improvement of the maternal health. PMID- 26023344 TI - Analgesic effects of oligonol, acupuncture and quantum light therapy on chronic nonbacterial prostatitis. AB - BACKGROUND: Chronic Nonbacterial Prostatitis (CNBP) is a condition that frequently causes long-term pain and a significant decrease in the quality of life. OBJECTIVES: The present study aimed to examine the analgesic effects of oligonol, acupuncture, quantum light therapy and their combinations on estrogen induced CNBP in rats. MATERIALS AND METHODS: This experimental study was conducted in Edirne, Turkey, using a simple randomized allocation. A total of 90 adult male Wistar rats were randomized into 9 groups of 10 rats each: Group I, control; Group II, CNBP, Group III, oligonol only, Group IV, acupuncture only; Group V, quantum only; Group VI, oligonol + quantum; Group VII, acupuncture + oligonol; Group VIII, quantum + acupuncture; Group IX, acupuncture + quantum + oligonol. Oligonol treatment was given at a dose of 60 mg/day for 6 weeks. Conceptual vessels (CV) 3 and 4, and bilaterally urinary bladder (Bl) 32 and 34 points were targeted with 1-hour acupuncture stimulation. The quantum light therapy was applied in 5-minute sessions for 6 weeks (3-times/a week). For pain measurements, mechanical pressure was applied to a point 2 cm distal to the root of the tail to elicit pain and consequent parameters (peak force, latency time of response and total length of measurement) were assessed. RESULTS: Analgesic effects were observed with all treatment regimens; however, the most prominent median analgesic effect was shown in the quantum light therapy in combination with acupuncture for estrogen-induced CNBP (PF1 = 663.9, PF2 = 403.4) (P = 0.012). Furthermore, we observed that monotherapy with quantum light showed a better analgesic efficacy as compared to oligonol and acupuncture monotherapies (PF1 = 1044.6, PF2 = 661.2) (P = 0.018, P = 0.008, P = 0.018; respectively). CONCLUSIONS: All treatment modalities showed a significant analgesic effect on CNBP in rats, being most prominent with the quantum light therapy. PMID- 26023345 TI - Aerial firing and stray bullet injuries: a rising tide. AB - BACKGROUND: Aerial firing is shooting, using fire arm, into the air usually during a celebration. OBJECTIVES: This observational study aimed to quantify magnitude and impact of stray bullet injuries by aerial firing at surgical emergencies of the Liaquat University Hospital (a university hospital), Hyderabad, Sindh, Pakistan from January 2009 to December 2010 (2 years). PATIENTS AND METHODS: During the study period, 144 firearm injuries due to stray bullet reported to the A and E departments of the university hospital. All patients referred to surgical unit providing emergency cover on that day irrespective of the severity of the injury for medico-legal reasons. For this study, the cases were divided into those having trivial injury and do not require any active surgical intervention and those having serious injury mandating surgical intervention. One hundred and two cases of stray bullet injury sustained trivial injury and followed as outpatients after an overnight period of indoor hospitalization; however, 42 patients with stray bullet injuries requiring surgical intervention were hospitalized. RESULTS: The most common events leading to aerial firing and stray bullet injuries were marriage ceremonies, followed by a political rallies and New Year celebrations. Stray bullet injury also reported after aerial firing on cricket/hockey team victories, Pakistan Independence Day (14th August), cultural day in Sindh and Basant (Kite) festival in Punjab. The most frequent sites with serious stray bullet injury were chest (15), head and neck (10), abdomen (9) and limbs (8), respectively. Surgical interventions performed included chest intubation, exploration of wound tract to retrieve bullet if lodged superficially and was palpable, laparotomy to managed intra abdominal injury, reduction of fracture site followed by reconstruction, flap reconstruction and graft for nonhealing wound. The mean duration of hospital stay was 19 days. No mortality was observed in this series of patients. CONCLUSIONS: We conclude that the prevalence of aerial firing resulting in stray bullet injuries is alarmingly on rise in our country. Above all, those doing aerial firing do not considered it as crime, instead taken it as they are privileged to do anything when celebrating. Awareness of the consequences must be propagated by every means to condemn this social crime. PMID- 26023346 TI - The effect of regular aerobic exercise on reverse cholesterol transport A1 and apo lipoprotein a-I gene expression in inactive women. AB - BACKGROUND: Atherosclerotic cardiovascular disease is currently a cause of mortality in some parts of the world. The ATP-Binding Cassette Transporter (ABCA1) gene prepares instructions to produce the ATP-binding cassette transporter protein whose operation is for export of phospholipids and cholesterol, outside cells where they are limited to Apolipoprotein A1 (apoA1). Increased ABCA1 activity could inhibit atherosclerosis. OBJECTIVES: In the present study, the effect of aerobic exercise was investigated on gene expression and biochemical parameters. PATIENTS AND METHODS: The participants included 36 inactive women, which were randomly assigned to control (CON) and experimental (EX) groups. The EX group performed 12 weeks of aerobic exercise and the CON group remained inactive. Fasting blood samples were collected 24 hours before the first session and 48 hours after completion of the course. The ABCA1 and APOA1 gene expressions were measured using semi-quantitative-RT-PCR. Data were analyzed by the SPSS software (version 18). RESULTS: A significant increase in blood ABCA1 (EX group P < 0.002, t = - 9.876) and Apo A-I (EX group P < 0.05, t = 2.76) gene expression was shown following the 12 weeks of training. Plasma high-density lipoprotein-cholesterol (HDL-C) concentration increased (P < 0.001, t = 4.90 respectively) while plasma low-density lipoprotein-cholesterol (LDL-C) concentration decreased (P < 0.001, t = 4.27) in the EX group compared with the CON group. CONCLUSIONS: Aerobic exercises can increase ABCA1 and APO-A1 gene expression. Induction of these genes can effectively prevent cardiovascular disease. PMID- 26023347 TI - Married Women's Sexual Satisfaction Questionnaire; A Developmental and Psychometric Evaluation. AB - BACKGROUND: Despite the significant contribution of cultural factors to sexual satisfaction, most of the current sexual satisfaction scales pay little attention, if any, to cultural factors and marital status. OBJECTIVES: The current study aimed to develop and validate the Married Women's Sexual Satisfaction Scale. PATIENTS AND METHODS: The current methodological study went through three consecutive phases. In the first phase, the concept of sexual satisfaction was defined and analyzed by the hybrid model approach. In the second phase, an item pool was generated by the findings of the first phase. Finally, the psychometric properties of the scale were evaluated in the third phase. All data analyses were performed by the SPSS version 19.0. RESULTS: A 78-item pool was generated based on the findings of the concept analysis phase. After assessing and confirming its face and content validity, 27 items remained in the final version of the scale. The exploratory factor analysis revealed a four factor structure for the scale. The results of the known-groups comparison showed that females with lower educational status had significantly lower sexual satisfaction. Moreover, there was a significant correlation between the scores of the finalized scale and those of the ENRICH Marital Satisfaction Scale (r = 0.706, P = 0.01). The interclass correlation between the test and the retest measurements was also statistically significant (ICC = 0.939, P value = 0.001). CONCLUSIONS: The 27-item Iranian Married Women's Sexual Satisfaction Scale is a simple, valid, and reliable tool to assess married women's sexual satisfaction. PMID- 26023348 TI - Prevalence of hepatitis B and knowledge about hepatitis B among migrant workers in shandong province, china: a cross-sectional study. AB - BACKGROUND: China is a country with a high prevalence of hepatitis B. As a special population, migrant workers are more vulnerable to hepatitis B. OBJECTIVES: The present study was conducted to gain insight into the prevalence of hepatitis B and knowledge about hepatitis B among migrant workers in Shandong Province, China, as well as to explore a series of strategies for preventing and controlling the spread and prevalence of hepatitis B. PATIENTS AND METHODS: A cross-sectional study was conducted without age restriction, in Shandong Province in China. The sample-size was determined scientifically. The study population was selected using the random multistage cluster sampling. Personal information, including sex, age, ethnicity, marital status, education level, years of duration of stay in Jinan and health insurance were obtained from 2065 migrant workers. Moreover, blood samples were collected for hepatitis B infection screening. Knowledge about hepatitis B was assessed using a self-administered questionnaire. Correct response rates were calculated. RESULTS: Of 2065 migrant workers tested for Hepatitis B Surface Antigen (HBsAg), 167 (126 men and 41 women) tested positive for HBsAg; the overall prevalence was 8.1%. The prevalence rates in men and women were 9.6% and 5.4%, respectively. The prevalence rates in subjects 18 - 30 years old and 30 years older were 3.5% and 9.3%, respectively. There were statistically significant differences between those groups (P < 0.05). Correct response rates for the transmission of hepatitis B questions were low, especially for a question regarding whether hepatitis B can be transferred by sexual contact (36.8%) and whether it can be transferred from mothers to infants (33.9%). A total of 80.9% of migrant workers correctly responded that vaccination is effective for hepatitis B. However, 68% of migrants also had the misconception that it is necessary to receive a booster vaccination. CONCLUSIONS: The hepatitis B virus infection rate in migrant workers is higher than average infection rates in China, and these workers' knowledge regarding hepatitis B is poor. It is urgent that an appropriate program be undertaken for the prevention and control of hepatitis B among migrant workers. PMID- 26023349 TI - Air pollution and quality of sperm: a meta-analysis. AB - CONTEXT: Air pollution is common in all countries and affects reproductive functions in men and women. It particularly impacts sperm parameters in men. This meta-analysis aimed to examine the impact of air pollution on the quality of sperm. EVIDENCE ACQUISITION: The scientific databases of Medline, PubMed, Scopus, Google scholar, Cochrane Library, and Elsevier were searched to identify relevant articles published between 1978 to 2013. In the first step, 76 articles were selected. These studies were ecological correlation, cohort, retrospective, cross sectional, and case control ones that were found through electronic and hand search of references about air pollution and male infertility. The outcome measurement was the change in sperm parameters. A total of 11 articles were ultimately included in a meta-analysis to examine the impact of air pollution on sperm parameters. The authors applied meta-analysis sheets from Cochrane library, then data extraction, including mean and standard deviation of sperm parameters were calculated and finally their confidence interval (CI) were compared to CI of standard parameters. RESULTS: The CI for pooled means were as follows: 2.68 +/- 0.32 for ejaculation volume (mL), 62.1 +/- 15.88 for sperm concentration (million per milliliter), 39.4 +/- 5.52 for sperm motility (%), 23.91 +/- 13.43 for sperm morphology (%) and 49.53 +/- 11.08 for sperm count. CONCLUSIONS: The results of this meta-analysis showed that air pollution reduces sperm motility, but has no impact on the other sperm parameters of spermogram. PMID- 26023350 TI - The effect of cinnamon on menstrual bleeding and systemic symptoms with primary dysmenorrhea. AB - BACKGROUND: Primary dysmenorrhea with interferes in daily activities can have adverse effects on quality of life of women. OBJECTIVES: Regarding the use of herbal medicine, the aim of this study was to assess the effect of cinnamon on primary dysmenorrhea in a sample of Iranian female college students from Ilam University of Medical Sciences (west of Iran) during 2013-2014. PATIENTS AND METHODS: In a randomized double-blind trial, 76 female student received placebo (n = 38, capsules containing starch, three times a day (TDS)) or cinnamon (n = 38, capsules containing 420 mg cinnamon, TDS) in 24 hours. Visual analogue scale (VAS) was used to determine the severity of pain and nausea. Vomiting and menstrual bleeding were assessed by counting the number of saturated pads. The parameters were recorded in the group during the first 72 hours of the cycle. RESULTS: The mean amount of menstrual bleeding in the cinnamon group was significantly lower than the placebo group (P < 0.05 and P < 0.001, respectively). The mean pain severity score in the cinnamon group was less than the placebo group at various intervals (4.1 +/- 0.5 vs. 6.1 +/- 0.4 at 24 hours, 3.2 +/- 0.6 vs. 6.1 +/- 0.4 at 48 hours, and 1.8 +/- 0.4 vs. 4.0 +/- 0.3 at 72 hours, respectively) (P < 0.001). The mean severity of nausea and the frequencies of vomiting significantly decreased in the cinnamon group compared with the placebo group at various intervals (P < 0.001, P < 0.05). CONCLUSIONS: Regarding the significant effect of cinnamon on reduction of pain, menstrual bleeding, nausea and vomiting with primary dysmenorrhea without side effects, it can be regarded as a safe and effective treatment for dysmenorrhea in young women. PMID- 26023351 TI - Urinary metabonomics for diagnosis of depression in hepatitis B virus-infected patients. AB - BACKGROUND: Depression is concomitantly presented in Hepatitis B Virus (HBV) infected patients and decreases these patients' quality of life. However, there are no laboratory-based methods to objectively diagnose this disorder. OBJECTIVES: The aim of this study was to investigate the alteration of urinary metabolites in depressed HBV-infected patients. PATIENTS AND METHODS: In this study, 81 depressed HBV-infected patients, 68 non-depressed HBV-infected patients and 64 Healthy Controls (HC) were recruited. A nuclear magnetic resonance (NMR) based urinary metabonomic method was used to characterize the urinary metabolic profiling of depressed and non-depressed subjects. RESULTS: Seventeen differential urinary metabolites responsible for discriminating depressed HBV infected patients from non-depressed HBV-infected patients and HC were identified. Among these metabolites, pyruvate, isobutyrate, N-methylnicotinamide, alpha-hydroxybutyrate, acetoacetate and malonate were identified as potential biomarkers for diagnosing depression in HBV-infected patients. A combined panel of these potential biomarkers could effectively discriminate depressed HBV infected patients from non-depressed HBV-infected patients and HC, with an average accuracy of 89.6% in the training set and a predictive accuracy of 86.4% in the test set. CONCLUSIONS: These findings suggest that NMR-based urinary metabonomics approach might be a useful tool for the clinical diagnosis of depression in HBV-infected patients and the six potential biomarkers could be helpful for developing an objective diagnostic method. Limited by the number of recruited subjects, future studies are required to validate our conclusions. PMID- 26023352 TI - Breastfeeding practices during the first month postpartum and associated factors: impact on breastfeeding survival. AB - BACKGROUND: The introduction of fluids to infants during the first days postpartum, which may be harmful to infant health, is a common practice in Iran. OBJECTIVES: This study aimed to find the prevalence of breastfeeding practices using monthly dietary recall and factors associated with introduction of fluids during the first month of life and determine the effects of these supplementations on breastfeeding survival. PATIENTS AND METHODS: This longitudinal study carried out in Shahroud, Iran from May 2011 to October 2013. Using convenient sampling strategy, 358 mothers in their third trimester of pregnancy were enrolled in the study and completed the questionnaires. Then the data regarding the introduction of fluids during first month postpartum was collected. We followed women monthly up to breastfeeding cessation. Kaplan-Meier and time-to-event methods were used to assess breastfeeding survival. A multinomial logistic regression analysis was used to identify the variables that determined breastfeeding practices at the first month postpartum. The Cox regression analysis was used to estimate the effect of variables on breastfeeding survival. RESULTS: The prevalence of exclusive, predominant, and partial breastfeeding during the first month postpartum were 33.1%, 58.2%, and 8.6%, respectively. Predominant breastfeeding was associated with the lack of breastfeeding experience (OR = 1.93; 95% CI [1.02 - 3.66]). Partial breastfeeding was associated with the maternal age >= 30 y (OR = 5.96; CI [1.66 - 21.37]), family income higher than the mean (OR = 3.39; 95% CI [1.17 - 9.81]), and breastfeeding difficulties score higher than mean (OR = 3.09; 95% CI [1.10 - 8.71]). The Cox regression analysis revealed that breastfeeding practices at the first month was associated with an increased risk for breastfeeding discontinuation. The hazard ratio of breastfeeding discontinuation for predominant and partial breastfeeding groups were 1.11 (95% CI: 0.82, 1.51; P = 0.49) and 2.23 (95% CI: 1.39, 3.58; P = 0.001), respectively compared to the exclusive group. CONCLUSIONS: The prevalence of predominant breastfeeding during the first month postpartum is high in Shahroud. Interventions to strengthen adherence to WHO guidelines for breastfeeding should be considered. Breastfeeding education providers at the hospitals should emphasize the effects of formula on breastfeeding continuation at early postpartum. PMID- 26023353 TI - Prediction of the grade of acute cholecystitis by plasma level of C-reactive protein. AB - BACKGROUND: Acute cholecystitis is the most common complication of gallbladder stones. Today, Tokyo guidelines criteria are recommended for diagnosis, grading, and management of acute cholecystitis. OBJECTIVES: We aimed to evaluate the levels of C-reactive protein (CRP) at different cut-off values to predict the severity of the disease and its possible role in grading the disease with regard to the guideline. PATIENTS AND METHODS: This is a retrospective study, analyzing 682 cases out of consecutive 892 patients with acute cholecystitis admitted to two different general surgery clinics in Istanbul, Turkey. Records of patients diagnosed with acute cholecystitis were screened retrospectively from the hospital computer database between January 2011 and July 2014. A total of 210 patients with concomitant diseases causing high CRP levels were excluded from the study. The criteria of Tokyo guidelines were used in grading the severity of acute cholecystitis, and patients were divided into 3 groups. CRP values at the time of admission were analyzed and compared among the groups. RESULTS: Mean CRP levels of groups were found to be significantly different, 18.96 mg/L in Group I, 133.51 mg/L in Group II, and 237.23 mg/L in Group III (P < 0.001). Having examined CRP values among the groups, they were found to be highly and significantly correlated with the disease grade (P < 0.0001). After evaluating CRP levels according to the grade of the disease, group 2 was distinguished from group 1 with a cut-off CRP level of 70.65 mg/L, and from group 3 with a value of 198.95 mg/L. Those results were found to be statistically significant (P < 0.001). CONCLUSIONS: CRP, a well-known acute phase reactant that increases rapidly in various inflammatory processes, can be accepted as a strong predictor in classifying different grades of the disease, and treatment can be reliably planned according to this classification. PMID- 26023354 TI - Immune Dysregulation in Patients Persistently Infected with Human Papillomaviruses 6 and 11. AB - Human Papillomaviruses (HPVs) 6 and 11 are part of a large family of small DNA viruses, some of which are commensal. Although much of the population can contain or clear infection with these viruses, there is a subset of individuals who develop persistent infection that can cause significant morbidity and on occasion mortality. Depending on the site of infection, patients chronically infected with these viruses develop either recurrent, and on occasion, severe genital warts or recurrent respiratory papillomas that can obstruct the upper airway. The HPV induced diseases described are likely the result of a complex and localized immune suppressive milieu that is characteristic of patients with persistent HPV infection. We review data that documents impaired Langerhans cell responses and maturation, describes the polarized adaptive T-cell immune responses made to these viruses, and the expression of class select II MHC and KIR genes that associate with severe HPV6 and 11 induced disease. Finally, we review evidence that documents the polarization of functional TH2 and T-regulatory T-cells in tissues persistently infected with HPV6 and 11, and we review evidence that there is suppression of natural killer cell function. Together, these altered innate and adaptive immune responses contribute to the cellular and humoral microenvironment that supports HPV 6 and 11-induced disease. PMID- 26023355 TI - The Experience of Screening for HIV/AIDS Medical Studies among African American/Black and Latino/Hispanic Persons Living with HIV/AIDS: A Mixed-Methods Exploration. AB - OBJECTIVE: African-American/Black and Latino/Hispanic persons living with HIV/AIDS (i.e., "PLHA of color") are under-represented in HIV/AIDS medical studies (HAMS). A crucial entry point into HAMS is screening, but PLHA of color face serious barriers to screening compared to Whites. Recently we evaluated a social/behavioral intervention that substantially increased rates of HAMS screening among PLHA of color. Yet very little is known about the actual screening experience for these under-represented subgroups. Thus, the objectives of the present study were to explore participants' motivations for and experiences of HAMS screening. METHODS: A total of 186 participants in the larger study's intervention arm were screened for HAMS, 35 of whom also participated in qualitative interviews. Participants engaged in a structured interview about the screening experience at 4- and 12- months post-baseline (14 items, Cronbach's alpha=0.72). Further, from a qualitative data set we purposively selected a set of three case studies to contextualize and enrich quantitative findings on screening experiences. RESULTS: The screening experience was overwhelmingly positive. Almost all participants reported being treated with dignity and respect, did not feel they were being treated like a "guinea pig," and experienced a high level of trust in the setting and the screener, with no gender or racial/ethnic differences, and no differences based on whether participants were found eligible for HAMS during screening. A number of areas where screening could be improved were also identified. CONCLUSIONS: Despite the complex barriers PLHA of color experience to screening for HAMS, the experience of screening was positive. Moreover, HAMS screening experiences were positive regardless of gender, race/ethnicity, or HAMS eligibility. HAMS screening can therefore be a productive learning experience that may reduce patient concerns about participating in HAMS. As such, fostering screening among PLHA of color can be an important component of reducing racial/ethnic disparities in HAMS. PMID- 26023356 TI - HIV-1 Treated Patients with Undetectable Viral Loads have Lower Levels of Innate Immune Responses via Cytosolic DNA Sensing Systems Compared with Healthy Uninfected Controls. AB - OBJECTIVES: After DNA or RNA virus infection, cytosolic foreign DNA or RNA derived from the infecting viruses is recognized by intracellular pathogen recognition receptors (PRRs) and induces activation of the innate immune system. Transfection of DNA has been used as an experimental model for DNA virus-mediated innate responses. We have previously reported that DNA transfection preferentially induces Type-III IFN (IFN-lambda1) rather than Type-I IFN (IFN beta). In this study, we compared the DNA-mediated immune response between healthy controls and HIV-1 infected patients with undetectable viral loads and assessed potential innate immune responses in these patients. METHODS: The study consisted of 50 HIV-1 negative healthy donors, 46 patients on combination antiretroviral therapy with HIV-1 viral loads <50 copies/ml and 7 long term non progressors (LTNPs). PBMCs were isolated from whole blood using Ficoll-Paque. DNA transfection was performed using Lipofectamine 2000. After 22 hours incubation, total cellular RNA was extracted and real time RT-PCR was performed to determine gene expression level of IFN-lambda1, IFN-beta and RANTES. Gene induction was compared by fold change. RESULTS: Baseline levels of endogenous gene expression of IFN-lambda1, IFN-beta and RANTES in HIV-1 patients were higher than in controls. Following DNA transfection, both HIV infected patients and healthy controls induced gene induction, however, the induction in HIV-1 patients was at a significantly lower level compared to uninfected controls. CONCLUSION: HIV-1 treated patients with undetectable viral loads have lower levels of innate immune responses via cytosolic DNA sensing systems. This may be caused by persistent immune activation. PMID- 26023358 TI - Global spine congress 2015: disclosure index. PMID- 26023357 TI - Secondary Structure Predictions for Long RNA Sequences Based on Inversion Excursions and MapReduce. AB - Secondary structures of ribonucleic acid (RNA) molecules play important roles in many biological processes including gene expression and regulation. Experimental observations and computing limitations suggest that we can approach the secondary structure prediction problem for long RNA sequences by segmenting them into shorter chunks, predicting the secondary structures of each chunk individually using existing prediction programs, and then assembling the results to give the structure of the original sequence. The selection of cutting points is a crucial component of the segmenting step. Noting that stem-loops and pseudoknots always contain an inversion, i.e., a stretch of nucleotides followed closely by its inverse complementary sequence, we developed two cutting methods for segmenting long RNA sequences based on inversion excursions: the centered and optimized method. Each step of searching for inversions, chunking, and predictions can be performed in parallel. In this paper we use a MapReduce framework, i.e., Hadoop, to extensively explore meaningful inversion stem lengths and gap sizes for the segmentation and identify correlations between chunking methods and prediction accuracy. We show that for a set of long RNA sequences in the RFAM database, whose secondary structures are known to contain pseudoknots, our approach predicts secondary structures more accurately than methods that do not segment the sequence, when the latter predictions are possible computationally. We also show that, as sequences exceed certain lengths, some programs cannot computationally predict pseudoknots while our chunking methods can. Overall, our predicted structures still retain the accuracy level of the original prediction programs when compared with known experimental secondary structure. PMID- 26023360 TI - Prognosis of surgical neonates. PMID- 26023361 TI - On the birth of journal of neonatal surgery. PMID- 26023359 TI - FLIM-FRET for Cancer Applications. AB - Optical imaging assays, especially fluorescence molecular assays, are minimally invasive if not completely noninvasive, and thus an ideal technique to be applied to live specimens. These fluorescence imaging assays are a powerful tool in biomedical sciences as they allow the study of a wide range of molecular and physiological events occurring in biological systems. Furthermore, optical imaging assays bridge the gap between the in vitro cell-based analysis of subcellular processes and in vivo study of disease mechanisms in small animal models. In particular, the application of Forster resonance energy transfer (FRET) and fluorescence lifetime imaging (FLIM), well-known techniques widely used in microscopy, to the optical imaging assay toolbox, will have a significant impact in the molecular study of protein-protein interactions during cancer progression. This review article describes the application of FLIM-FRET to the field of optical imaging and addresses their various applications, both current and potential, to anti-cancer drug delivery and cancer research. PMID- 26023362 TI - Prognostic factors determining mortality in surgical neonates. AB - BACKGROUND: To assess the prognosis of surgical neonates at admission and the factors responsible for mortality in neonates. MATERIAL AND METHODS: A prospective study was conducted in a tertiary level hospital over 15 months and various clinical and biochemical parameters were collected and analyzed using STATA((r)) and SPSS((r)). RESULTS: On multivariate analysis of 165 neonates, early gestational age, respiratory distress and shock at presentation were the factors of poor prognosis in neonates. The factors could be related to poor antenatal care and sepsis acquired before transfer of the baby to the nursery. CONCLUSION: The improvement in antenatal care and asepsis during transfer and handling the babies is of utmost importance to improve the prognosis of surgical neonates. PMID- 26023363 TI - Colonic atresia and stenosis: our experience. AB - BACKGROUND: Colonic atresia and stenosis are rare entities. On average 1 case per year of colonic atresia is being seen in most of pediatric surgical centers and to date less than 10 cases of colonic stenosis have been reported. MATERIAL AND METHODS: The medical record of patients of colonic atresia and stenosis managed during March 2006 to March 2010 was reviewed. RESULTS: A total of 15 patients of colonic atresia (11) and stenosis (4) were the study population. Four were ascending colon atresia, 2 at hepatic flexure and transverse colon each, and 1 at sigmoid colon. Two patients had multiple colonic atresias. One patient of ascending colon atresia also had pyloric atresia. In colonic stenosis population (two congenital and two secondary to necrotizing enterocolitis), two were transverse colon stenosis and two were sigmoid colon stenosis. The preoperative diagnosis was distal small bowel atresia in 11 patients. Colonic atresias were managed by colocolic anastomosis with covering ileostomy in 8 patients. The remaining 3 patients were managed by exteriorizing both ends of atresia. Colonic stenosis cases were managed by primary colocolic anastomosis in 1 patient and colocolic anastomosis under covering ileostomy in 3 patients. Three patients of colonic atresia succumbed postoperatively. CONCLUSION: Colonic atresia and stenosis are rare entities. Associated alimentary tract malformations may result poor prognosis. Colonic atresia can safely be managed by colocolic anastomosis with covering ileostomy. PMID- 26023364 TI - An audit of malignant solid tumors in infants and neonates. AB - BACKGROUND: To audit the demographics, outcome and factors affecting long-term survival in infants and neonates with solid tumors. MATERIAL AND METHODS: Retrospective case series was performed for 13 years. Demographics, surgical notes, treatment protocols and outcome details were reviewed. RESULTS: Of total 372 tumors over 13 years, there were 59 infants (15.86%) of which 8 were neonates, with M:F 1.2:1, and mean age of presentation was 5.18months. Fifty three of the infants had tumors which were > 5 cm in size. Thirty two (54%) had a rapid progression of the lesion during investigations. Tumors markers and pre operative biopsy were diagnostic in 61.5% and 30% respectively. Neuroblastoma was the commonest tumor (22%), followed by hepatoblastoma (20.3%), malignant germ cell tumor (20.3%), soft tissue sarcomas (11.9%), and others (8.5%). Staging distribution for 39 (66%) infants showed Stage 1-n=9, Stage 2-n=15, Stage 3-n=7, Stage 4-n= 5 and Stage IVs-n=3. Nineteen (32.2%) babies received chemotherapy. Almost half (50.8%) of the children underwent surgical removal of the tumor; with gross total resection in 76.6%. The overall mortality was 35.6%. About 30.5% are alive, well and tumor free on 2-12 years follow-up. CONCLUSION: A much higher incidence (15.8%) of infantile tumors in our region as compared to literature (2%) is alarming. Treatment failures from deaths or non-compliance amounted to be 69.5%. These are the two major issues which need to be addressed in the future management of infantile tumors. Reduction in deaths due to chemotherapy toxicity, rapid surgical intervention and R0 resection and risk stratification needs to be incorporated, to improve long-term tumor free survival in infants. PMID- 26023365 TI - Pyloric atresia in association with multiple colonic atresias in a neonate: an unreported association. AB - Pyloric atresia is rare cause of gastrointestinal obstruction in neonates and usually occurs as an isolated anomaly. They have been associated with multiple small bowel and colonic atresias but not reported in association with isolated multiple colonic atresias. A case of pyloric atresia occurring in association with multiple colonic atresias is being reported here. PMID- 26023366 TI - Sirenomelia: a rare presentation. AB - We are presenting two cases of Sirenomelia (Mermaid Syndrome), which is an extreme example of the caudal regression syndrome. It invariably presents with lower limb fusion, sacral and pelvic bony anomalies, absent external genitalia, imperforate anus, and renal agenesis or dysgenesis. There are approximately 300 cases reported in the literature, 15% of which are associated with twinning, most often monozygotic. The syndrome of caudal regression is thought to be the result of injury to the caudal mesoderm early in gestation. One of our cases survived for 12 days after birth. This new born had an unusually high anorectal anomaly in which the colon was ending at the level of mid transverse colon, fused lower limbs and genital anomalies. Ultrasound of the abdomen revealed horseshoe kidney. Colostomy was performed on day 2 of life. The second case encountered was a stillborn baby on whom an autopsy was performed. PMID- 26023367 TI - Aplasia cutis congenita scalp presenting with life threatening hemorrhage: a case report. AB - Aplasia cutis congenita is a rare congenital anomaly characterized by the absence of a patch of skin since birth. It may lead to life threatening complications at times. A 5-day-old neonate with Aplasia cutis congenita was received in a state of shock due to tremendous blood loss from the superior sagittal sinus. The neonate was resuscitated immediately followed by closure of the superior sagittal sinus and flap coverage to the defect as a life saving procedure. PMID- 26023368 TI - Sirenomelia: adding something new. AB - A case of sirenomelia is being reported who was born in a twin pregnancy and showed different anatomy of lower torso. PMID- 26023369 TI - Neonatal perforated appendicitis. PMID- 26023370 TI - Spontaneous Perforation of Meckel's Diverticulum in a Neonate. PMID- 26023371 TI - Prevention of hypothermia in surgical neonates in operation theatre: recommendations of neonatal surgery research group. PMID- 26023372 TI - Electronic journals: a new dimension to research. PMID- 26023373 TI - Physiological and anaesthetic considerations for the preterm neonate undergoing surgery. PMID- 26023374 TI - Release of tongue-tie in neonates. PMID- 26023375 TI - Esophageal atresia with/without tracheoesophageal fistula. PMID- 26023376 TI - Sequestered bowel in a atresia. PMID- 26023377 TI - Current trends in neonatal surgery in India. PMID- 26023378 TI - Scope of journal of neonatal surgery. PMID- 26023379 TI - Duodenal webs: an experience with 18 patients. AB - AIM: To describe the management and outcome of patients with duodenal webs, managed over a period of 12 1/2 years in our unit. METHODS: It is a retrospective case series of 18 patients with congenital duodenal webs, managed in our unit, between 1999 and 2011. The medical record of these patients was retrieved and analyzed for demographic details, clinical presentation, associated anomalies, and outcome. RESULTS: The median age of presentation was 8 days (range 1 day to 1.5 years). Antenatal diagnosis was made in only 2 (11.1%) patients. The commonest presentation was bilious vomiting. Associated anomalies were present in 8/18 patients, common being malrotation of gut. Down's syndrome was seen in 2 patients and congenital heart disease in 1 patient. One patient had double duodenal webs. There was a delay in presentation of more than 5 days of life in 11/18 (61%) patients. Three patients who presented beyond neonatal age group had fenestrated duodenal membranes causing partial obstruction. In addition, the diagnosis was missed in patients operated for malrotation elsewhere (n=2), imperforate anus (n=2) and esophageal atresia with tracheo-esophageal fistula (n=1). A lateral duodenotomy with excision of the obstructive membrane was done in all patients. A trans-anastomotic tube (TAT) for enteral feeding was used in 8 patients The mortality rate was 4/18 (22%); the main causes being sepsis, prematurity, very low birth weight and associated congenital anomalies. The mean hospital stay for the 14 survivors was 18 days. Total parental nutrition (TPN) was not given to any patient. CONCLUSIONS: Congenital duodenal webs are different as the diagnosis is often missed especially in case of perforated webs. Outcome depends upon the time of presentation and associated anomalies. The use of TAT feeding for nutritional support is an easy alternative to TPN. PMID- 26023380 TI - Neural tube defect repair and ventriculoperitoneal shunting: indications and outcome. AB - Neural tube defect with its global involvement of nervous system has lot of implications. There is cotroversy in terms of timing of repair, simultaneous or metachronous ventriculoperitoneal shunt and criteria for shunt surgery in neonatal age. We are reporting our approach and results of management of this disease in neonatal period. PMID- 26023381 TI - Giant hepatic cysts: prenatal findings and uncommon postnatal outcome. AB - With modern prenatal imaging, liver cysts are being diagnosed more often. Although large cysts are usually asymptomatic, they may present as an abdominal emergency requiring surgery in the first weeks of life. We report a series of 3 patients with prenatal diagnosis of isolated cystic liver lesions diagnosed at 22, 31 and 33 weeks of gestational age. The hepatic origin of the cysts was confirmed prenatally by a MRI in 2 cases, with visualization of a normal gallbladder. The prenatal course was uneventful. Postnatal ultrasound confirmed the diagnosis of liver cyst, showed normality of the biliary tract and in one case, rupture of the cyst during delivery. Because of an uncommon rapid increase in size, the 3 children underwent surgical excision of the cysts within the first weeks of life. These were non-bile-containing intrahepatic cysts arising from segment IV. Long-term follow up was uneventful. PMID- 26023382 TI - Multiple associated anomalies in patients of duodenal atresia: a case series. AB - Duodenal atresia has been reported in association with various malformations and syndromes common being Down syndrome, malrotation, and annular pancreas. Its association with multiple anomalies is rare and scarcely reported in literature. Herein 3 cases of duodenal atresia associated with multiple congenital anomalies are being reported. PMID- 26023383 TI - Where Should the Surgical Neonates be Nursed? PMID- 26023384 TI - Athena's Pages. PMID- 26023385 TI - Megacystis-microcolon-intestinal hypoperistalsis syndrome associated with prune belly syndrome: a case report. AB - Megacystis Microcolon Intestinal Hypoperistalsis Syndrome is a quite rare congenital anomaly that presents with a functional obstruction of the gastrointestinal tract which is usually fatal. It is three to four times more prevalent in females. We present a case of a rare association of a male neonate with Megacystis Microcolon Intestinal Hypoperistalsis Syndrome who in addition had the classical triad of Prune Belly Syndrome and thus suggest a possibility of different spectrums with a common pathogenesis. PMID- 26023386 TI - Ileal atresia with duplication cyst of terminal ileum: a rare association. AB - A case of ileal atresia in association with duplication of terminal ileum is being reported here. PMID- 26023387 TI - Gastric teratoma: a rare neoplasm. AB - A 3-day-old male child was brought to the hospital with complaints of abdominal distension and a mass in the upper abdomen causing respiratory difficulty. Child underwent exploratory laparotomy and a large multicystic mass arising from postero-inferior wall of the stomach along its greater curvature was excised and stomach repaired. On histopathology it came out mature gastric teratoma. PMID- 26023388 TI - Eventration of diaphragm with hiatal hernia: a case report. AB - A 25-day-old female baby having eventration of diaphragm associated with a big hiatal hernia is being reported here. This is the second report describing the rare association. PMID- 26023389 TI - Prenatal torsion of testis: a rare emergency. PMID- 26023390 TI - Congenital epulis: a rare benign jaw tumor of newborn. PMID- 26023391 TI - Missed congenital pyloric atresia with gastric perforation in a neonate. PMID- 26023392 TI - Concomitant jejunoileal and colonic atresias. PMID- 26023393 TI - Neonatal necrotizing enterocolitis. PMID- 26023394 TI - Unusually aggressive myofibromatosis in a neonate. PMID- 26023395 TI - Trans-Fistula Anorectoplasty (TFARP): Our Experience in the Management of Anorectovestibular Fistula in Neonates. AB - AIM: The purpose of the study was to observe the outcome of trans-fistula anorectoplasty (TFARP) in treating female neonates with anorectovestibular fistula (ARVF). METHODS: A prospective study was carried out on female neonates with vestibular fistula, admitted into the surgical department of a tertiary level children hospital during the period from January 2009 to June 2011. TFARP without a covering colostomy was performed for definitive correction in the neonatal period in all. Data regarding demographics, clinical presentation, associated anomalies, preoperative findings, preoperative preparations, operative technique, difficulties faced during surgery, duration of surgery, postoperative course including complications, hospital stay, bowel habits and continence was prospectively compiled and analyzed. Anorectal function was measured by the modified Wingspread scoring as, "excellent", "good", "fair" and "poor". RESULTS: Thirty-nine neonates with vestibular fistula underwent single stage TFARP. Mean operation time was 81 minutes and mean hospital stay was 6 days. Three (7.7%) patients suffered vaginal tear during separation from the rectal wall. Two patients (5.1%) developed wound infection at neoanal site that resulted in anal stenosis. Eight (20.51%) children in the series are more than 3 years of age and are continent; all have attained "excellent" fecal continence score. None had constipation or soiling. Other 31 (79.5%) children less than 3 years of age have satisfactory anocutaneous reflex and anal grip on per rectal digital examination, though occasional soiling was observed in 4 patients. CONCLUSION: Primary repair of ARVF in female neonates by TFARP without dividing the perineum is a feasible procedure with good cosmetic appearance and good anal continence. Separation of the rectum from the posterior wall of vagina is the most delicate step of the operation, takes place under direct vision. It is very important to keep the perineal body intact. With meticulous preoperative bowel preparation and post operative wound care and bowel management, single stage reconstruction is possible in neonates with satisfactory results. PMID- 26023396 TI - Outcome of jejuno-ileal atresia associated with intraoperative finding of volvulus of small bowel. AB - AIM: To compare the outcome of patients with jeuno-ileal atresia (JIA) associated with the intraoperative finding of volvulus of small bowel (group A) with that of JIA without volvulus (group B). MATERIALS AND METHODS: It is a retrospective observational study conducted at one of the two units of Pediatric Surgery, in a tertiary care public hospital of India, from January 2001 to December 2010. Hospital records were retrieved and analyzed. During this time period, 65 patients with JIA were operated of which 40 (61.5%) had ileal atresia (IA) and 25 (38.5%) had jejunal atresia (JA). Eleven (16.9%) patients had associated intraoperative finding of volvulus of small bowel (Group A) and were studied and compared with group B- not associated with intraoperative findings of volvulus of small bowel (n=54). The demography, clinical features, operative findings, associated anomalies, anastomotic leakage, and outcome were compared. RESULTS: Group A comprising of 6 boys and 5 girls, had 8 IA and 3 JA; one case each of Type 3b and Type 4 JIA was seen. Associated anomalies included meconium ileus (n=2), Down's syndrome (n=1) and malrotation (n=1). Anastomotic leak rate was 75% for IA and 66.7% for JA. The mortality was 91% in Group A, 100% for IA and 67% for JA. Group B comprising of 37 boys and 17 girls, had 32 IA and 22 JA; 2 cases of Type 4 and 1 case of Type 3b JIA was seen. Associated anomalies were malrotation (n=2), meconium ileus (n=1), exomphalos (n=1), gastroschisis (n=1) and ileal duplication cyst (n=1). The anastomotic leak rate for JA was 8/21 (38.1%) and IA was 3/28 (10.7%); persistent obstruction was seen in 3/21(14.3%) JA and 1/28 (3.6%) IA patients. In group B, overall mortality rate was 8/22 (36.4%) for JA and 9/32 (28%) for IA. The morbidity and mortality was significantly higher in group A when compared to group B. CONCLUSIONS: JIA associated with volvulus (without malrotation) is a sinister entity with a dismal outcome in our experience. PMID- 26023398 TI - Genital prolapse causing urinary obstruction and hydronephrosis in a neonate: a case and review of the literature. AB - Neonatal genital prolapse is a rare condition seen early in life, often in conjunction with spinal cord anomalies. We present a case of a 38-week gestational age female in whom urinary obstruction and bilateral hydronephrosis resulted from genital prolapse. We suggest that although a serious urologic outcome can potentially result from this condition, cure for both can be achieved swiftly and without major complications. PMID- 26023397 TI - Congenital pouch colon: a preliminary report from pakistan. AB - BACKGROUND: Congenital pouch colon (CPC) is a rare entity in patients of anorectal malformations (ARM) requiring special consideration as to the management. This study is aimed at evaluating the presentation, management, and the outcome of initial surgery in patients with CPC. MATERIALS AND METHODS: This retrospective study was conducted in the department of Pediatric Surgery of our institute during May 2007- May 2010. The Information about the demography, clinical features, investigations, management, and the outcome of initial surgery was retrieved and analyzed. RESULTS: There were 21 patients of CPC managed during the study period. Sixteen (76%) were males and five (24%) females (M:F 3.2:1). Mean age of presentation was 4.8 days with a range of 12 hours to 45 days. In 18 (85.7%) patients, CPC was found with high ARMs, whereas, in 3 (14.3%) patients it was associated with low ARMs. Imperforate anus with moderate to massive abdominal distension was the presentation in 16 (76%) patients. Abdominal radiographs helped in preoperative diagnosis in 8 patients. Two patients had pneumoperitoneum on abdominal radiographs. At operation, type I CPC was found in 9 (42.8%) patients, type II in 5 (23.8%), type III in 2 (9.5%) patients, and type IV CPC in 5 (23.8%) patients. In 11 (52.4%) patients, pouch was emptied and retained with proximal enterostomy. In 7 (33.3%) patients, end enterostomy with pouch excision was done. In two patients, a window colostomy was formed. In one patient, pouch was disconnected from the normal bowel and Hartmann's pouch with end ileostomy was formed. There were 2 (9.5%) deaths in our series. CONCLUSION: CPC is a rare malformation. Massive abdominal distension with imperforate anus is the common presentation. Optimum management can reduce the morbidity and mortality. PMID- 26023399 TI - Multiple congenital segmental dilatations of colon: a case report. AB - Congenital segmental dilatation of colon (CSDC) is a rare malformation in neonates. A single segmental dilatation of colon is mentioned in the available case reports. Not a single case of multiple CSDC is reported hitherto. We report a case of multiple CSDC associated with cleft lip and palate, and rectal atresia. PMID- 26023400 TI - Prenatally diagnosed retroperitoneal fetus-in-fetu with ipsilateral testicular atrophy: a case report. AB - We report a case of prenatally diagnosed Fetus-in-fetu (FIF) residing in the left retro-peritoneum in a 2-week-old neonate which was also associated with ipsilateral testicular atrophy. A comparison of features differentiating FIF from a retroperitoneal teratoma, and various theories of origin of FIF are described. The causal relationship of ipsilateral atrophic testis with FIF in this case is also discussed. PMID- 26023401 TI - Gastric duplication cyst causing gastric outlet obstruction. AB - This is a case report of a newborn baby with gastric duplication cyst presented with non-bilious vomiting and upper abdominal distension. The diagnosis was suspected clinically and established by ultrasonography and computed tomography. The cyst was completely excised with uneventful recovery. PMID- 26023402 TI - Spina bifida defying folic Acid supplementation. PMID- 26023403 TI - Complete resolution of cystic hygroma with single session of intralesional bleomycin. PMID- 26023404 TI - Polysplenia Syndrome Associated With Heterotaxy of Abdominal Viscera and Type IV Intestinal Atresias. PMID- 26023405 TI - A Neglected Case of Massive Urinary Ascites Secondary to Posterior Urethral Valve: A Developing World's Scenario. PMID- 26023406 TI - Limb threatening constriction ring syndrome of right leg. PMID- 26023407 TI - Bilateral choanal atresia with tessier type 3 facial cleft: a rare association. PMID- 26023408 TI - Congenital pouch colon. PMID- 26023409 TI - Esophageal anastomosis medial to preserved azygos vein in esophageal atresia with tracheoesophageal fistula: restoration of normal mediastinal anatomy. AB - OBJECTIVE: We intended to prospectively study the technical feasibility and advantages of esophageal anastomosis medial to the preserved azygos vein in neonates diagnosed with esophageal atresia with tracheoesophageal fistula (EA/TEF). The results were compared to the cases where azygos vein was either not preserved, or the anastomosis was done lateral to the arch of preserved azygos vein. MATERIAL AND METHODS: A total of 134 patients with EA/TEF were admitted between January 2007 and July 2008 of which 116 underwent primary repair. Eleven patients with long gap esophageal atresia with or without tracheoesophageal fistula and 7 patients who expired before surgery were excluded. Patients were randomly divided in three groups comparable with respect to the gestational age, age at presentation, sex, birth weight, associated anomalies and the gap between the pouches after mobilization: Group A (azygos vein ligated and divided), Group B (azygos vein preserved with esophageal anastomosis lateral to the vein), and Group C azygos vein preserved with esophageal anastomosis medial to the vein). All the patients were operated by extra-pleural approach. The three groups were compared with respect to operative time and early postoperative complications like pneumonitis, anastomotic leaks and mortality. Odds ratio and Chi square test were used for the statistical analysis. RESULTS: Group A, B and C had 35, 43 and 38 patients respectively. No significant difference was observed in average operative time in the 3 groups. Though incidence of postoperative pneumonitis was higher in group A (28%) as compared to group B (13.95%) and group C (11.62%), it was not statistically significant (p > 0.005). Anastomotic leak occurred in 7 patients in group A (20%), 6 patients in group B (13.95%) and 4 patients (10.52%) in group C (p > 0.005). Group A had 3 major and 4 minor anastomotic leaks; group B had 2 major and 4 minor leaks and group C had 1 major and 3 minor leaks. There were10 deaths in the series- 5 in group A, 3 in group B and 2 in group C (p > 0.005). Patients with major anastomotic leaks in all 3 groups expired after re exploration. The minor leaks were managed conservatively and all of them healed spontaneously. Severe pneumonitis and septicemia in patients having major associated anomalies also contributed to the mortality. CONCLUSIONS: Although esophageal anastomosis medial to the preserved azygos vein restores the normal mediastinal anatomy without technical difficulty or increased operative time, the study could not prove a statistically significant advantage in terms of mortality and postoperative complications. PMID- 26023410 TI - Initial conservative management of exomphalos major with gentian violet. AB - AIM: The purpose of the study was to assess the results of topical use of gentian violet (GV), among the babies with exomphalos major in our institute. METHODS: The study was carried out retrospectively in a tertiary care hospital during the period from 2005 to 2010 inclusive. Exomphalos patients were classified as major if diameter was >5 cm and/or had liver in the sac as content. These patients were initially preferentially treated conservatively with topical 1% GV over the sac resultig a ventral hernia to be repaired later. RESULTS: A total of 84 exomphalos patients were admitted during the study period. Among them, 37 neonates (26 males and 11 females) had exomphalos major (EM). Ten of them were prenatally diagnosed. The mean gestational age at delivery was 35 weeks, and mean birth weight was 2.1 Kg. Mean age at presentation was 3.7 days. Thirty (81%) had other associated anomalies, mostly cardiac (66.6%) and pulmonary (46.6%). Ten patients with EM needed early operation because of ruptured sac, and other anomalies. There were 2 pre-operative and 8 postoperative deaths in this subgroup. Twenty seven patients were treated conservatively, among these 4 died of overwhelming sepsis. Remaining 23 patients left the hospital with a ventral hernia planned to be repaired at 1 year of age. Overall mortality in our series was 37.83%. CONCLUSION: Initial conservative treatment of the sac with GV results in satisfactory outcome for infants with EM who cannot undergo immediate closure. PMID- 26023411 TI - Feasibility of peritoneal dialysis in extremely low birth weight infants. AB - Acute renal injury is common in extremely low birth weight (ELBW) infants with a frequency ranging from 8% to 24%. Peritoneal dialysis (PD) has been used only occasionally in ELBW. We report our experience and share the solutions used to tackle the difficulties rising from the small size of this type of patients. PD was successfully performed in three ELBW infants with acute renal failure. A neonatal, single-cuff, straight Tenckhoff catheter was placed in 2 patients, while a Broviac single cuff vascular catheter was used in another. PD was feasible and effective in all children. Leakage was observed with Tenckhoff catheters, but this did not impair the PD efficacy. The technical difficulties were related to the size and shape of the peritoneal catheters, not easily fitting with the very thin abdominal wall of the preterm infants. We conclude that PD is feasible and effective, can be considered as the rescue therapy in preterm ELBW infants with acute renal failure. PMID- 26023412 TI - Etiology of gastroschisis. PMID- 26023413 TI - Auto-amputated Ovarian Cyst with Compression Sequelae: A Case Report. AB - Ovarian cysts contribute a major share of cystic lesions in fetal life. Quite often, these cysts are benign and resolve spontaneously. Occasionally, these cysts can twist, resulting in ovarian loss. We report a case of auto-amputated ovarian cyst presetting with intestinal obstruction. PMID- 26023414 TI - Diagnostic difficulties in a case of persistent cloaca with hydrocolpos. AB - Pelvic midline cystic mass associated with renal malformation represents typical imaging features of a cloacal anomaly. We report a case of persistent cloaca that was diagnosed antenatally with fetal ultrasonography and MRI. PMID- 26023415 TI - A peculiar cause for metabolic acidosis in the newborn. AB - Metabolic acidosis is often encountered in a sick neonate and intestinal duplication with heterotopic gastric mucosa is a well-established condition. We present a previously unreported relationship between neonatal metabolic acidosis, resulting from transperitoneal absorption of hydrochloric acid, and a ruptured non- communicating ileal duplication cyst with gastric mucosal heterotopia. The neonate recovered rapidly after resection of the ileal duplication. We present this case to highlight a rare but surgically correctable cause of neonatal metabolic acidosis. PMID- 26023416 TI - Large gastric perforation in carmi syndrome: a morbid complication in a rare association. AB - The association between epidermolysis bullosa (EB) and congenital pyloric atresia (CPA) named Carmi Syndrome is rare. We report unusual and morbid complication of gastric perforation resulting in peritonitis in a preterm neonate born with Carmi Syndrome. PMID- 26023417 TI - Bedside repair of omphalocele. PMID- 26023418 TI - Anorectal malformation associated with small and large bowel atresias: a rare association. PMID- 26023419 TI - Gastroschisis. PMID- 26023420 TI - Rectal stenosis: a rare anorectal malformation. PMID- 26023421 TI - On reducing mortality and morbidity of neonatal surgical care. PMID- 26023422 TI - Looking back on the first anniversary. PMID- 26023423 TI - Single-stage surgical correction of anorectal malformation associated with rectourinary fistula in male neonates. AB - INTRODUCTION: The treatment of children affected by anorectal malformations (ARM) is characterized by some unsolved problems. The three-stage surgical correction has been known to be most effective in preventing complications, but recently new approaches have been proposed. We describe our experience with the newer approaches. METHODS: Twenty three male newborns, affected by ARM and recto urinary fistula, were treated in 2 different centers in 8 years. Nineteen neonates (birth weight 2.4 - 3.5 kg) received a primary posterior sagittal anorectoplasty (PSARP) at the Department of Pediatric Surgery of the Chittagong Medical College Hospital (group 1). Four term neonates (birth weight 2.9 - 3.4 kg) received a primary pull-through with combined abdomino-perineal approach at the Pediatric Surgery Department of Fondazione Ca Granda of Milan (group 2). RESULTS: Among patients of Group 1, 11 patients had a recto-bulbar fistula and 8 a recto-prostatic fistula. Among the Group 2, 2 had a recto-bulbar fistula and 2 a recto-prostatic fistula. The site of fistula was decided at the time of surgery. In Group 1, 5 post-surgical complications were recorded (26%); 1 child died of sepsis, 3 had dehiscence and 1 stenosis, which resolved with dilatation. In Group 2, the only post-operative complication of small rectal prolapse resolved spontaneously after a few months on follow-up. Group 2 patients were followed-up in a dedicated multidisciplinary colorectal center. CONCLUSIONS: Primary repair of ARMs with recto-urinary fistula is a feasible, safe and effective technique in the neonatal period. A combined abdominal and perineal approach seems to guarantee better results. A dedicated team is mandatory, both for the surgical correction and for a long-term follow-up. PMID- 26023424 TI - Neonatal sacrococcygeal teratoma: our experience with 10 cases. AB - AIM: To analyse the outcome of neonatal sacrococcygeal teratomas (SCT) in our setup. MATERIALS AND METHODS: Hospital records of 10 neonates, who were operated for SCT during 14 years time period, were retrieved and analysed. Letters were sent to 6 parents/ caretakers of children who were lost to follow up; none of them responded. RESULTS: Seven girls and 3 boys with a mean age of 9 days (range 1-30 days) underwent excision of SCT in the neonatal period. Antenatal pickup rates were poor (2/10). Two patients presented with tumor rupture. Though all had an obvious mass at birth, only half of them presented on day 1 of life. The remaining 5 patients came late at a mean age of 11 days. Half of the SCTs were 10 cm or larger in size. One patient was misdiagnosed as meningomyelocoele. All underwent complete excision with coccygectomy by posterior approach in prone position. There were only 2 patients who could be classified as Altman Type II, the rest were all Altman Type I. Histopathology (HPE) revealed mature cystic teratoma (n=8), grade 1 immature teratoma (n=1) and grade 3 immature teratoma (n=1). There was no mortality; and complications were seen in 3/10 patients (1 neurogenic bladder, 1 major wound infection with ventriculitis and 1 minor wound infection). The mean follow up was 25 months (range 1 month to 6 years) in 4 patients with no recurrence. CONCLUSIONS: Neonatal SCTs are usually benign with a good outcome after complete surgical excision with a low complication rate. Although long term follow up has been advocated, the follow up was poor in this series. PMID- 26023425 TI - Spectrum of etiologies causing hydrometrocolpos. AB - BACKGROUND: Hydrometrocolpos (HMC) develops as a result of vaginal outflow obstruction and the accumulation of secretions. It might be secondary to persistent cloaca, urogenital sinus, some syndromes, presence of the vaginal septum, vaginal atresia, and imperforate hymen. Each of them has different treatment options and follow-up protocols. This study was performed to identify the etiology and the related management of patients with HMC. MATERIALS AND METHODS: A descriptive series of patients with HMC managed in our hospital between 2004 and 2011 is being presented. The medical record of these patients was analyzed for etiology, management, and outcome. RESULTS: Eight patients with HMC were managed during 7 years at our department. Underlying etiologies included urogenital sinus (n=3), and 1 each of imperforate hymen, transverse vaginal septum, Herlyn-Werner-Wunderlich syndrome, persistent cloaca, and a variant of the cloaca. Four patients were prenatally diagnosed. The patient with imperforate hymen was managed successfully with incision and drainage. Abdominal vaginostomy was done in three patients with urogenital sinus as initial procedure. In patient with persistent cloaca, a colostomy and abdominal vaginostomy were performed. Patient with cloaca variant died due to persistent acidosis and salt wasting. CONCLUSION: HMC may have different etiological factors which may dictate different surgical management. Etiology of HMC can be as simple as imperforate hymen to the most severe cloacal malformations. PMID- 26023426 TI - Primary segmental volvulus mimicking ileal atresia. AB - Neonatal intestinal volvulus in the absence of malrotation is a rare occurrence and rarer still is the intestinal volvulus in absence of any other predisposing factors. Primary segmental volvulus in neonates is very rare entity, which can have catastrophic outcome if not intervened at appropriate time. We report two such cases, which were preoperatively diagnosed as ileal atresia and intraoperatively revealed to be primary segmental volvulus of the ileum. PMID- 26023427 TI - Mckusick-kaufman syndrome presenting as acute intestinal obstruction. AB - Hydrometrocolpos and polydactyly have been associated with many syndromes and can present at any age. Rarely does hydrometrocolpos present as neonatal intestinal obstruction. We report two cases of McKusick-Kaufman syndrome presenting with intestinal obstruction. In both cases, intestinal obstruction got relieved after a cutaneous vaginostomy. PMID- 26023428 TI - Centennial of pyloromyotomy. PMID- 26023429 TI - Type IV Sacrococcygeal Teratoma Associated with Urogenital Sinus: Difficulties in the Prenatal Differential Diagnosis. AB - Sacrococcygeal teratoma (SCT) is being more often detected due to availability of prenatal ultrasonography. Type IV SCT could be misdiagnosed as cloacal abnormalities due to the pelvic midline cystic mass associated with renal malformations and obstructive uropathy during the pregnancy. We discuss difficulties in the prenatal differential diagnosis of SCT and urogenital sinus in a 26-year-old pregnant woman, admitted to our prenatal diagnosis centre for a detailed US for a pre-sacral mass. PMID- 26023430 TI - Extracorporeal Testicular Ectopia through Inguinal Canal: A Case Report. AB - A preterm (36 week) neonate, presented with his left testicle hanging outside through the inguinal canal. The testicle was pexed in a sub-dartos pouch. PMID- 26023431 TI - Extra hepatic biliary atresia associated with choledochal cyst: a diagnostic dilemma in neonatal obstructive jaundice. AB - The presentation of extra hepatic biliary-atresia (EHBA) as well as choledochal cyst (CDC) in the neonate may be similar. Since the surgical management and prognosis are entirely different, it is important to differentiate between the two entities. We present a case with co-existing EHBA and CDC which led to a diagnostic dilemma. PMID- 26023432 TI - Abdominal cocoon secondary to meconium peritonitis in a neonate: a case report. AB - Abdominal cocoon is a complete or partial encasement of intestines and rarely viscera by a fibrocollagenous sac which is usually formed by a nonspecific chronic inflammatory reaction. We report a case of abdominal cocoon in a 2-day old neonate presenting with intestinal obstruction. PMID- 26023433 TI - Preampullary duodenal web simulating gastric outlet obstruction. PMID- 26023434 TI - Imperforate anus associated with eventration of diaphragm. PMID- 26023435 TI - Cutaneous stigmata of occult spinal dysraphism. PMID- 26023436 TI - Pyloric atresia. PMID- 26023437 TI - Management of Congenital Talipes Equino Varus (CTEV) by Ponseti Casting Technique in Neonates: Our Experience. AB - OBJECTIVE: The purpose of this study is to evaluate the results of Ponseti technique in the management of congenital Talipes Equino Varus (CTEV) in neonatal age group. METHODS: It is a prospective observational study, conducted during the period of July 2010 to December 2011 at the Department of Pediatric Surgery in a tertiary hospital. All the neonates with CTEV were treated with Ponseti casting technique. Neonates with other congenital deformities, arthrogryposis and myelomeningocele were excluded. RESULTS: Total 58 CTEV feet of 38 neonates were treated. Twenty six were males and 12 were females. Thirty seven (63.8%) feet were of rigid variety and 21(36.2 %) feet were of non-rigid variety. Twenty patients had bilateral and 18 had unilateral involvement. Mean pre-treatment Pirani score of study group was 5.57. Mean number of plaster casts required per CTEV was 3.75 (range: 2-6). Thirty five rigid and 15 non-rigid (total 86.2%) feet required percutaneous tenotomy. Out of 58 feet 56 (96.6%) were managed successfully. Three (5.2%) patients developed complications like skin excoriation and blister formation. Mean post-treatment Pirani score of the study group was: 0.36 +/- 0.43. CONCLUSION: The Ponseti technique is an excellent, simple, effective, minimally invasive, and inexpensive procedure for the treatment CTEV deformity. Ideally it can be performed as a day case procedure without general anesthesia even in neonatal period. PMID- 26023438 TI - Sacrococcygeal teratoma. PMID- 26023439 TI - Pain relief in neonates. PMID- 26023440 TI - Bedside neonatal intensive care unit surgery- myth or reality! AB - Neonatal transport is associated with complications, more so in sick and unstable neonates who need immediate emergency surgery. To circumvent these problems, surgery in Neonatal intensive care unit (NICU) is proposed for these neonates. This article reviews the literature regarding feasibility of this novel concept and based on the generated evidence, suggest the NICU planners to always include infrastructure for this. Also neonatal surgical team can be developed that could be transported. PMID- 26023441 TI - Esophageal atresia and tracheoesophageal fistula with unilateral pulmonary agenesis - hypoplasia. AB - Association of unilateral severe pulmonary hypoplasia or agenesis and esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is an exceedingly rare and highly lethal combination. We report a case of full term male baby who had EA with TEF and right lung hypoplasia, managed at our centre. He is alive and doing well at 10 years of age. PMID- 26023442 TI - Intra-peritoneal rectal perforation in a neonate leading to acquired rectal atresia. AB - A neonate sustaining iatrogenic rectal injury that led to acquired rectal atresia is reported. It was successfully treated by transanal, end-to-end, rectorectal anastomosis. PMID- 26023443 TI - Liver abscess: increasing occurrence in premature newborns. AB - Neonatal liver abscess is a very rare condition associated with high morbidity and mortality rates. There seems to be an increasing trend of this rare condition amongst the newborns admitted to neonatal intensive care units. We report a case of liver abscess in a premature newborn and briefly review the literature and discuss its management. PMID- 26023444 TI - Perforated appendicitis in a neonate presenting with intestinal obstruction. AB - We report a case of neonatal perforated appendicitis presenting with an early picture of intestinal obstruction secondary to entrapment of small bowel under inflamed appendix vermiformis. PMID- 26023445 TI - Hirschsprung's Disease Presenting as Neonatal Appendicitis. PMID- 26023446 TI - Surgical management of congenital hyperinsulinism in a resource-limited setting. PMID- 26023447 TI - Unilateral huge hydronephrosis necessitating fetal interventions. PMID- 26023448 TI - Sacrococcygeal teratoma. PMID- 26023449 TI - Necrotizing enterocolitis in full term neonates: is there always an underlying cause? AB - OBJECTIVE: To review our experience with full-term neonates with necrotizing enterocolitis (NEC) and to compare its characteristics to those published in the literature. DESIGN: Retrospective review of all neonates born after 35 weeks of gestation managed in Reunion Island for NEC from 2000 to 2012. RESULTS: Among the 217 diagnosed NEC, 27 patients (12.4%) were full term neonates, who were born at a mean gestational age of 36.8 +/-1.7 weeks. The mean onset of the disease was 12.1+/-11.2 days after birth. Twenty patients had underlying causes (15 organic pathologies of the child, 3 isolated maternal disease, and 2 infections); 7 had idiopathic NEC. Surgery was required in 12 patients (37.5%) at 23.2+/-20 days after birth. NEC affected most of the time the colon (n=6) and the rectum (n=3). Overall survival rate was 88.8% (24/27). Two patients required partial non enteral nutrition for1.3 and 2.1 years. CONCLUSIONS: NEC in full term neonates is a rare pathology. The onset of the disease in our experience was slightly later than described in the literature, but remains earlier than in the premature population. In some cases, no obvious cause can be found, suggesting a different pathogenesis. Further investigations are required in order to better understand this pathology. The goal will be to find measures to reduce global mortality. PMID- 26023450 TI - Gastrointestinal perforation in neonates: aetiology and risk factors. AB - BACKGROUND: Gastrointestinal perforation (GIP) in neonates presents important challenges and mortality can be high. This is a report of recent experience with GIP in neonates in a developing country. PATIENTS AND METHODS: A retrospective review of 16 neonates treated for GIP in a 3 year period. RESULTS: There were 9 males and 7 females, aged 0-28 days (median age =7days). Their weights at presentation ranged from 0.9 - 4.7kg (median =2.6). Five infants were premature. Twelve infants presented more than 72 hours after onset of symptoms. Plain abdominal radiographs showed peumoperitoneum in 9 infants. The cause of perforation was necrotising enterocolitis 6, intestinal obstruction 6, iatrogenic 3 and spontaneous 1. The site of perforation was ileum in 12 infants, stomach in 4 and colon in 4; 4 patients had involvement of more than one site. All the neonates underwent exploratory laparotomy with primary closure ( n=5) , resection and anastomosis( n=6), colostomy (n=3), Ileostomy ( n=2), partial gastrectomy (n=2) ,or gastrojejunostomy ( n=1). Two neonates had multiple procedures. Two very sick preterm babies had an initial peritoneal lavage. Surgical site infection is the commonest postoperative complication occurring in 9 infants. Anaesthesia sepsis and malnutrition is responsible for the seven deaths recorded. CONCLUSIONS: Neonatal GIP has multiple aetiologies; NEC is the most common cause. Major mortality risk factors include NEC, multiple perforations, delayed presentation and prematurity. PMID- 26023451 TI - Neonatal mastauxe (breast enlargement of the newborn). PMID- 26023452 TI - Management of Duodenal Atresia in the setting of Congenital Leukemia with Massive Hepatomegaly. AB - Down's syndrome (DS) is associated with duodenal atresia (DA) in about 8-10% of cases. Transient Myeloproliferative Disorder (TMD)/Acute Myeloid Leukemia (AML) is also associated with the trisomy 21 mutation. The occurrence of the two conditions together complicates the diagnosis and surgical management of the DA. We discuss the technical aspects of management of the DA in this clinical setting. PMID- 26023453 TI - Congenital immature teratoma of the retroperitoneum. AB - Congenital teratomas occur in extragonadal locations, the commonest site being the sacrococcygeal region. This report describes a rare case of antenatally detected, large, immature retroperitoneal teratoma. The diagnostic and therapeutic challenges of dealing with such a case have been discussed and the relevant literature reviewed. The recurrence of the tumor after gross surgical removal indicates a definitive role of administering chemotherapy in such a case. PMID- 26023454 TI - Congenital strangulated transmesenteric hernia: a rare cause of acute bowel obstruction. AB - A case of congenital transmesenteric hernia leading to intestinal obstruction is being reported here. PMID- 26023455 TI - Umbilical arteriovenous malformation in a healthy neonate with umbilical hernia. AB - We describe the case of a neonate with an umbilical hernia and persistent wet umbilicus. Examination revealed a pulsatile umbilical cord with palpable thrill. Doppler ultrasound suspected umbilical arteriovenous malformation and contrast enhanced computed tomography was performed leading to a definitive diagnosis. Surgery was successfully performed on day 27. PMID- 26023456 TI - Pyloric Atresia Type II. AB - Successful management of a neonate with type II pyloric atresia is reported and the relevant literature has been briefly reviewed. PMID- 26023457 TI - Posterior urethral valves in neonate. PMID- 26023458 TI - Agenesis of azygos vein in a case of esophageal atresia and tracheoesophageal fistula. PMID- 26023459 TI - Single Stage Transanal Pull-Through for Hirschsprung's Disease in Neonates: Our Early Experience. AB - OBJECTIVE: Hirschsprung's disease is one of the common causes of intestinal obstruction in neonates. Transanal endorectal pull-through represents the latest development in the concept of the minimally invasive surgery for Hirschsprung's disease. In this study, we present our early experience with single stage transanal pull through in neonates. DESIGN: Retrospective study of neonates with single stage transanal pull-through done for Hirschsprung's disease in our institute from January 2011 to January 2013. MATERIAL AND METHOD: Five newborn boys who presented with Hirschsprung's disease were studied. The selection criteria included radiological transition zone at rectosigmoid or mid-sigmoid region, weight more than 2 kg, no evidence of enterocolitis or sepsis and no associated major anomaly. Single stage transanal endorectal pull-through was done in these patients. The follow-up period ranged from 6 months to 2 years. RESULTS: Five patients with a mean age of 26.4 days (range 15-45 days) and a mean weight of 2.6 Kg (range 2.2 to 3.7 Kg) underwent transanal endorectal pull through. The mean operating time was 68 min (range 60 to 120 min). The average intra-operative blood loss was 20 ml (range - 10 to 30 ml) and the average length of bowel resected was 12.8 cm (range - 10 to 18 cm). Post-operatively patients passed first stool between 2nd and 3rd day. Oral feeding was resumed on 5th to 6th post operative day. The average post-operative duration of stay in hospital was 10 days. None of the patients had post-operative bleeding, urethral injury, anastomotic leak or retraction of anastomotic site. Three patients developed perianal excoriation and one patient had post-operative enterocolitis. No mortality occurred in the series. CONCLUSION: Advancement in pediatric anaesthesia, availability of pediatric surgical expertise, improvement in pre operative and post-operative management and nursing care has made single stage transanal pull-through in neonates a feasible option. The early results are comparable to single stage or multistage surgery in older children. PMID- 26023460 TI - Congenital pyloric atresia and associated anomalies: a case series. AB - Congenital pyloric atresia (CPA) is a very rare surgical condition. Eleven patients with the diagnosis of CPA treated at our hospital were retrospectively studied for the age at diagnosis, sex, presenting symptoms, associated anomalies, operative findings, treatment and outcome. Male: Female is 8:3. The age at diagnosis ranged from one day to three years. Associated anomalies were seen in four (36.6%). These included epidermolysis bullosa (EB) in two, oesophageal atresia with distal trachea-oesophageal fistula in one, colonic atresia in one, sensorineural deafness and dysplastic kidney in one patient. All three types of CPA were observed; six (54.5%) had type 1, four (36.3%) had type 2 and one (9%) had type 3 [(core)]. Different procedures performed were Heineke-Mickulicz pyloroplasty, Finney's pyloroplasty and gastro-duodenostomy. Post-operatively, nine out of eleven did well while other two died giving an overall survival of 81.8%. Sepsis was the cause of death in both of them. PMID- 26023461 TI - Gastrointestinal mucormycosis mimicking necrotizing enterocolitis of newborn. PMID- 26023462 TI - Pseudo double bubble: jejunal duplication mimicking duodenal atresia on prenatal ultrasound. AB - Prenatal ultrasound showing a double bubble is considered to be pathognomonic of duodenal atresia. We recently encountered an infant with prenatal findings suggestive of duodenal atresia with a normal karyotype who actually had a jejunal duplication cyst on exploration. A finding of an antenatal double bubble should lead to a thorough evaluation of the gastrointestinal tract and appropriate prenatal/neonatal testing and management as many cystic lesions within the abdomen can present with this prenatal finding. PMID- 26023463 TI - Asymptomatic meconium peritonitis presenting as inguinal hernia in a female neonate. AB - Inguinal hernias in girls are often irreducible when they contain ovaries. Rarely the hernial sacs may have unusual contents like vermiform appendix, uterus and urinary bladder. We report a case of a female infant who presented with bilateral irreducible inguinal hernias presumed to be due to ovaries. However at exploration, the hernial sacs contained bilaterally an omental mass with calcifications. Presence of mucin with meconium- laden macrophages in the mass on histology suggested an antenatal intestinal perforation. To the best of our knowledge no such case has been reported in a female neonate. We present this rare case and discuss the unusual findings and the outcome. PMID- 26023464 TI - Extra-hepatic biliary atresia in association with polysplenia and intestinal malrotation. AB - The syndromic form of biliary atresia accounts for 10-25% and is associated with a poor prognosis due to associated anomalies. We report a case of extrahepatic biliary atresia and polysplenia syndrome with jaundice since 19th day of life and who had undergone surgical correction of malrotation in the neonatal period. Inspite of successful Kasai's portoenterostomy at 52nd day of life, the child succumbed to post-operative sepsis. PMID- 26023465 TI - Broken umbilical vein catheter as an embolus in a neonate- an unusual preventable complication. AB - Umbilical vein catheter (UVC) is used in managing critically sick neonates all over the world. It is generally considered to be safe although various complications can arise and are well known. Herein we describe a successful retrieval of a broken and migrated UVC across the heart in a neonate. Pertinent literature regarding rarity of its occurrence and mechanism of occurrence has been touched upon to prevent such untoward complications. PMID- 26023466 TI - Gallbladder duplication associated with duodenal atresia. AB - Gallbladder duplication is an extremely rare anomaly. Association of gall bladder agenesis with duodenal atresia and biliary atresia has been described. However, association of gall bladder duplication with duodenal atresia hasn't been described so far; we report a case in view of its rarity. PMID- 26023467 TI - Unusual cause of esophageal obstruction in a neonate presenting as esophageal atresia. AB - Esophageal atresia is the commonest cause of obstruction to esophageal lumen in neonates. Foreign bodies in newborns are extremely rare. We report a rare case of esophageal obstruction closely mimicking atresia due to foreign bodies inserted in a female neonate with homicidal intension. PMID- 26023468 TI - Congenital Pouch Colon with Double Meckel's Diverticulae. PMID- 26023469 TI - Prepenile scrotum- an extreme form of penoscrotal transposition. PMID- 26023470 TI - Pre-axial fibrolipoma. PMID- 26023471 TI - Hirschsprung's Disease in Newborns. PMID- 26023472 TI - Journal of neonatal surgery celebrates second anniversary. PMID- 26023473 TI - Neonatal mastitis: a clinico-microbiological study. AB - OBJECTIVE: Neonatal breast hypertrophy is a common phenomenon in term infants, superadded infection can lead to mastitis and that can progress to breast abscess with short and long term detrimental effects. Our effort is to study the prevalence, risk factors, the current microbial profile and sensitivity pattern in these infections in order to suggest an optimal treatment plan for these patients. DESIGN: Case series. SETTING: Hospital based study conducted in Kashmir on the native population. DURATION: 2011 to 2013. MATERIALS AND METHODS: 32 neonates with features of mastitis or abscess were included in the study. Demographic and clinical data, laboratory work-up were recorded for all these patients in a patient form. Gram stain of the purulent nipple discharge or pus obtained on drainage was done and the specimens were culture plated. Antibiotic sensitivity was determined by disk diffusion and categorized by current Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: Most babies were full term, the age range was 6-48 days. Peak incidence for mastitis was in the 2nd week and for abscess in the 4th week. The ratio of male: female was 1:2 in the entire group, there was greater preponderance of female involvement with increasing age. Massage for expression of secretions a common practice in the study population had been done in 15 patients, especially in male babies. The babies were generally well and associated skin pustulosis was common. Laboratory workup showed polymorphonuclear leucocytosis and CRP positivity. Gram staining showed gram positive cocci in 13 patients and gram negative rods in 1 patient. Culture revealed Staphylococcus aureus in 18, E.col in 2, klebsiella in 1 patient and was sterile in 2 patients. Most strains of Staphylococcus aureus were resistant to macrolides and penicillins. Fifteen were methicillin sensitive and 3 were resistant but were sensitive to amikacin, ofloxacin and vancomycin. Gram negative rods were sensitive to, aminoglycosides, chloramphenicol, quinolones, piperacillin-tazobactum and cefoperazone-sulbactum, but were resistant to cephalosporins including third generation cephalosporins. Treatment with oral antibiotic was not successful. Patients responded well to open drainage via a stab incision away from the breast mound; 4 patients were managed by repeated needle aspirations. IV antibiotics were prescribed in all patients for 2-5 days, followed by oral continuation therapy of 7-14 days. CONCLUSION: From our study, we can conclude that parental counseling to avoid massage, and early treatment for pustulosis is important to prevent mastitis. Intravenous antibiotics should be used for this condition guided by gram stain or culture sensitivity once available. Empirically a drug with good anti-staph cover may be instituted till appropriate reports are available. Incision drainage gives uniformly good results, though; multiple sittings of needle drainage may obviate the need for incision drainage. Therapy can be shifted to oral drugs once clinical improvement is seen. PMID- 26023474 TI - Omphalocele with intra abdominal anomalies. AB - Abdominal wall defects are associated with other intra-abdominal anomalies. We report two neonates with omphalocele associated with intra-abdominal anomalies. One neonate had multicystic kidney. Other neonate had duplication cyst of ileum which was missed during initial closure in neonatal life. PMID- 26023475 TI - Neonatal ilio-psoas abscess: report of two cases. AB - Ilio-psoas abscess (IPA) is rare in children and exceptional in the neonate. However, we recently managed two consecutive male neonates with right-sided IPA. The first baby was born two days after rupture of the membranes and had thick meconium-stained amniotic fluid. There was no such high risk factor in the second child. Diagnosis was made by ultrasonography in both the patients. Extraperitoneal surgical drainage was done and systemic antibiotics were given. Delay in presentation and uncontrolled sepsis, led to mortality in the first case. On the contrary, relatively early presentation, prompt drainage of the abscess and good response to higher antibiotics, lead to successful salvage of the second baby. PMID- 26023476 TI - Carbimazole embryopathy and choanal atresia. PMID- 26023477 TI - Idiopathic neonatal colonic perforation. AB - Though the perforation of the colon in neonates is rare, it is associated with more than 50% mortality in high-risk patients. We report a case of idiopathic neonatal perforation of the sigmoid colon in an 8-day-old, healthy, male neonate without any demonstrable cause. PMID- 26023478 TI - Congenital hairy polyp of posterior tonsillar pillar. AB - Congenital hairy polyps are exceedingly rare congenital anomalies. We report a case of congenital hairy polyp arising from posterior tonsillar pillar which was excised with bipolar cautry. PMID- 26023479 TI - Antenatally diagnosed wilms' tumour. AB - Wilms' tumour (WT) is seldom seen in a neonate and prenatal diagnosis is rare. We present a case of antenatally diagnosed left sided WT with features of hydrops foetalis in a girl baby. Emergency LSCS was done at 34 weeks of gestation for foetal distress. Patient required mechanical ventilation for birth asphyxia and congestive cardiac failure. After stabilization, gross total resection of the tumour was done on day 4 of life. Histopathology HPE confirmed classical WT (stage I). Unfortunately, the patient died on the second postoperative day despite all supportive measures. PMID- 26023480 TI - Biliary atresia associated with polysplenia syndrome, dextrocardia, situs inversus totalis and malrotation of intestines. AB - Biliary atresia (BA) is a rare disease and the end result of a destructive, inflammatory cholangiopathy, leading to fibrosis and biliary cirrhosis. It is classified into syndromic variety with various congenital anomalies and non syndromic (isolated anomaly). We present here a 1-month-old female child with the syndromic variety of BA associated with polysplenia syndrome, dextrocardia, situs inversus totalis and malrotation of intestines. She developed jaundice in the first week of life. Kasai operation was performed but she developed cholangitis and septicemia 2.5 months after surgery and succumbed later. PMID- 26023481 TI - Congenital arhinia: a rare case. PMID- 26023482 TI - Neonatal duodenal duplication cyst. PMID- 26023483 TI - Double pouch colon revisited. PMID- 26023484 TI - Mckusick-kaufman syndrome: diagnosis and management. PMID- 26023485 TI - Duodenal atresia. PMID- 26023486 TI - Urogenital sinus developmental anomaly with phallus and accessory phallic urethra presented as disorder of sex differentiation in female. PMID- 26023487 TI - Role of laparoscopy in the management of neonatal ovarian cysts. AB - AIM: Ovarian cysts in the newborn period are simple cysts which resolve on their own. Complications like torsion leading to loss of ovarian units are well documented. Surgical treatment should always be performed in a way to protect the ovaries and to ensure future fertility. The aim of this study was to study the safety and efficacy of laparoscopic management of neonatal ovarian cysts. MATERIALS AND METHODS: Neonates with ovarian cysts over last 6 years were retrospectively studied. Thirty seven ovarian cysts were detected antenatally and 32 of them persisted postnatally. All babies were asymptomatic. Nine babies with cyst size more than 5cms underwent laparoscopic deroofing, fenestration or cystectomy; the rest 23 babies were managed conservatively. Sonographic monitoring was done at monthly interval for change in contents, echogenicity of walls and features of torsion. Follow up was done with USG at 3 and 6 months and MRI after 1 year. RESULTS: No procedure related complications were seen in the laparoscopy group and no loss of ovarian units were seen in 1 year follow-up. In the observation group, cysts resolved in 3- 12 months period. Three babies developed complications and 4(17%) ovarian units were lost. CONCLUSION: Ovarian cysts are the most frequent among intra-abdominal cysts in newborns. Neonatal ovarian cysts are known to resolve spontaneously. Laparoscopic management of these cysts is safe and efficacious even in neonatal age and should be the treatment of choice when indicated. PMID- 26023488 TI - Energy sources in neonatal surgery: principles and practice. PMID- 26023489 TI - Endotracheal intubation in a neonate with esophageal atresia and trachea esophageal fistula: pitfalls and techniques. PMID- 26023490 TI - Long-Term Survival of Biliary Atresia without any Surgery: Lessons Learnt from Lamprey. PMID- 26023491 TI - Extra Hepatic Biliary Atresia associated with Choledochal Cyst: A Challenging Neonatal Obstructive Jaundice. AB - Biliary atresia and choledochal cyst have the similar clinical presentation in infants. Herein, we report a case that presented with prolonged hyperbilirubinemia and abdominal distension and diagnosed as choledochal cyst. At surgery, in addition to a large choledochal cyst, biliary atresia was also encountered. PMID- 26023492 TI - Colonic Atresia due to Internal Herniation through the Falciform Ligament Defect: A Case Report. AB - Colonic atresia is the rarest outcome of all gastrointestinal type of internal hernia. We report a case of neonate with atresia of the transverse colon caused by herniation of the transverse colon through a defect in falciform-ligament. PMID- 26023493 TI - Persistent Cloaca associated with Unilateral Lung Agenesis- A Rare Presentation. AB - We report a case of full term female child having persistent cloaca who was diagnosed to have right lung agenesis on investigations. PMID- 26023494 TI - An epigastric heteropagus twin with ruptured giant omphalocele. AB - We present a case of heteropagus twins attached to the epigastric region. The neonate also had ruptured giant omphalocoele with most of gut and liver lying outside the abdominal cavity. Patient had uneventful surgery for separation of twins and repair of ruptured omphalocoele. PMID- 26023495 TI - An approach to presacral mass in neonates. PMID- 26023496 TI - Autosomal recessive polycystic kidney disease. PMID- 26023497 TI - Hernia of umbilical cord with congenital short gut. PMID- 26023498 TI - Characteristic Radiological findings in Preterm Infants with Missed Intestinal Perforation. AB - BACKGROUND: Pneumoperitoneum on radiological imaging is typical in intestinal perforation in necrotizing enterocolitis [NEC]. However, it is not seen in all cases and intestinal perforation is missed on occasions. We present a series of preterm infants with characteristic x-ray findings that on exploration revealed missed intestinal perforation. METHODS: Retrospective review of neonates with intra-operative diagnosis of intestinal perforation which was missed on x-ray abdomen over a period of 6 months is being presented here. RESULTS: Three neonates born at 24 (24-30) weeks of gestation were identified. PDA was noted in all 3 patients and they required ventilator and inotropic support. Feeds were commenced at 5 (2-7) days of life. All three patients were treated for NEC. Surgical opinion was sought in view of localized gas shadow in a fixed position seen on repeated x-rays in all three patients. All three patients had laparotomy and small bowel resection with ileostomy formation at a mean age of 26 (24-46) days. Intra-operatively, small bowel perforation and adjacent pseudocysts filled with air and intestinal contents were noted in all 3 patients. Post-operatively full feeds were established in all patients. CONCLUSION: In premature infants with NEC, intestinal perforation can be missed on occasions. Our patients interestingly, developed characteristic abdominal x-ray findings that in our experience should prompt for surgical intervention. PMID- 26023499 TI - Perils of total colonic aganglionosis presenting in neonatal age. AB - BACKGROUND: The purpose of this study is to review the cases of total colonic aganglionosis seen in the span of ten years at a pediatric surgery unit of a tertiary care public hospital in New Delhi. METHODS: Medical records of twelve patients with total colonic aganglionosis were retrieved. RESULTS: Ten out of the twelve patients were males; seven were of the Muslim community. Average recorded birth weight was 2.2 kg. Ten patients presented with features of intestinal obstruction, while two presented with perforation peritonitis. Among the cases of obstruction, Hirschsprung's disease was suspected in eight cases (one was associated with Shah-Waardenburg syndrome), one case each was preoperatively diagnosed as ileal atresia and meconium ileus. Abdominal X-rays at presentation of all the neonates except in one with Shah-Waardenburg syndrome showed multiple air fluid levels. Contrast enema was done in five patients. It showed micro-colon in two patients, and typical question mark sign, dilated small bowel with transition zone in hepatic flexure and normal caliber colon in one each. All the patients underwent exploratory laparotomy. Intra-operatively, the transition zone was seen at distal ileum in ten cases and at hepatic flexure and transverse colon in one each. Biopsies of all the twelve patients eventually showed absence of ganglion cells in entire colon. Ileostomy was done in nine cases, colostomy in two and primary Kimura's procedure in one (this patient was discharged and lost to follow up). Left colonic patch with Swenson's pull through with ileostomy was done for one patient on colostomy. His stoma was closed; he was eventually discharged and lost to follow up. In the other patient with colostomy, the stoma was closed and an ileostomy was created. Of all the patients on ileostomy, three expired in the immediate postoperative period. Four were lost to follow up. Two underwent Kimura's procedure; and expired few months later. One patient on ileostomy is awaiting further treatment. CONCLUSION: The outcomes for total colonic aganglionosis in those presenting in neonatal age tend to be unsatisfactory in the developing countries. PMID- 26023500 TI - Trans-mesenteric hernia in infants: report of two cases. AB - Internal hernias are rare causes of intestinal obstruction in children. Trans mesenteric hernia remains the most common form. We report transmesenteric hernia in a neonate and infant presented with intestinal obstruction. PMID- 26023501 TI - Hypertrophic pyloric stenosis following repair of esophageal atresia and tracheo esophageal fistula. AB - Two cases of hypertrophic pyloric stenosis (HPS) developed after a few weeks of repair of an esophageal atresia and tracheo-esophageal fistula (EA and TEF). Both cases were dealt successfully with laparoscopic pyloromyotomy. PMID- 26023502 TI - Controversies regarding neonatal inguinal hernia. PMID- 26023503 TI - Pneumoperitoneum in the newborn: is surgical intervention always indicated? AB - Pneumoperitoneum in the neonate generally is an acute surgical emergency, which has grave implications, and immediate surgical intervention is needed to ensure survival. The most common cause is a perforated hollow viscus. However, there are causes that cannot be attributed to this etiology, constituting what has been called non-surgical, asymptomatic, benign, misleading, spontaneous or idiopathic pneumoperitoneum. Knowledge of this entity and its likely aetiological factors should improve awareness and possibly reduce the imperative to perform an unnecessary emergency laparotomy on an otherwise normal neonate with an unexplained pneumoperitoneum. PMID- 26023504 TI - Traumatic diaphragmatic hernia or something else? AB - Subcutaneous emphysema (SCE) mimicking diaphragmatic hernia on X-ray is hitherto unreported and this case has been presented with the aim to alert the clinician about this unusual presentation of SCE to avert undue panic and initiate appropriate evaluation and management. This case also reemphasizes the importance of a thorough clinical examination, which probably could have revealed the subcutaneous emphysema earlier. PMID- 26023505 TI - Fourth branchial anomaly presenting with a lateral neck mass in a neonate. AB - Branchial cleft anomalies are an important differential diagnosis in congenital neck masses in infants. The third and fourth branchial anomalies are rare branchial cleft anomalies, which are hard to differentiate. We report here an uncommon case of the fourth branchial anomaly that was presented as an asymptomatic neck mass in a neonate. PMID- 26023506 TI - Clear cell sarcoma of kidney in a neonate. AB - A neonate presented with abdominal mass in left flank was investigated and operated upon. Histopathology confirmed the diagnosis of clear cell sarcoma of the kidney. Post-operatively, chemotherapy was given according to the NWTS-5 protocol. During follow-up, the patient has shown good recovery after 7 months of surgery. PMID- 26023507 TI - H-type Tracheoesophageal Fistula in a Newborn: Determining the Exact Position of Fistula by Intra-operative Guidewire Placement. AB - H-type tracheoesophageal fistula is a rare congenital anomaly that is seldom diagnosed in the neonatal age. Documenting it and then locating it at surgery are both difficult. A case is presented to highlight the diagnostic and therapeutic utility of trans-fistula guidewire placement. PMID- 26023508 TI - Congenital Pyloric Atresia with Distal Duodenal Atresia- Role of CT Scan. AB - The mainstay of diagnosis of congenital pyloric atresia is by plain X-ray of the abdomen showing a large gas bubble with no gas distally. But very rarely it can be associated with distal duodenal atresia when the baby may present as lump abdomen. In such a situation apart from the X-ray, another radiological investigation is needed to delineate the exact nature of the lump. Since the role of ultrasonography is limited in intestinal pathologies and contrast studies are not informative in atresias, the CT scan is the ideal choice. We had managed a case of pyloric atresia with similar presentation with preoperative CT scan. PMID- 26023509 TI - Complicated Amyand's Hernia in a Neonate. AB - Amyand's hernia is a rare clinical entity in which the vermiform appendix is present within the inguinal hernia sac. Here, we report a 5-day-old neonate with dysmorphic features referred to us with a tender irreducible right inguino scrotal swelling. Surgical exploration showed gangrenous appendix with a peri appendicular abscess in the inguinal hernia sac. Appendectomy and right herniotomy was performed. PMID- 26023510 TI - Hereditary Multiple Gastrointestinal Atresia associated with Choledochal Cyst: A Rare Entity with Management Dilemma. AB - Multiple intestinal atresias are rare and its treatment is challenging. Here, we present a case of multiple gastro-intestinal atresia associated with choledochal cyst posing us a surgical challenge. PMID- 26023511 TI - Anal Injury in a Neonate due to Artificial Rupture of Membrane. PMID- 26023512 TI - Exomphalos major associated with thoracic teratoma and hamartoma of left leg: a rare association. PMID- 26023513 TI - Congenital trigger finger. PMID- 26023514 TI - Neonatal resuscitation. PMID- 26023515 TI - Intestinal strictures post-necrotising enterocolitis: clinical profile and risk factors. AB - BACKGROUND: Intestinal stricture is an important complication of necrotising enterocolitis (NEC). We aimed to describe clinical profile and identify the risk factors for post-NEC intestinal strictures. METHOD: A retrospective study of infants with NEC over 10 year period. RESULTS: Of the 61 infants with NEC, 18 (29.5%) developed intestinal strictures. Leucocytosis and longer length of bowel resection during acute stage of NEC was associated with a later diagnosis of intestinal stricture. Infants with NEC who did not develop stricture had non specific intestinal dilatation on abdominal x-ray during acute NEC. Intestinal strictures were diagnosed at a median interval of 34 days after NEC. Majority of strictures (67%) occurred in the colon. A significant proportion (77%) of infants with intestinal stricture had associated co-morbidities. No mortality occurred in infants with intestinal strictures. CONCLUSION: The incidence of post-NEC intestinal stricture is high but development of stricture is difficult to predict. Leucocytosis during NEC and length of bowel resected at surgery may be associated with development of post-NEC intestinal stricture. A substantial number of infants with post-NEC intestinal stricture fail to thrive, have co morbidities and need prolonged hospitalisation. PMID- 26023516 TI - NEC in Twin Pregnancies: Incidence and Outcomes. AB - BACKGROUND: Necrotizing Enterocolitis (NEC) is the most common gastrointestinal emergency in neonates. Previously established risk factors for the development of NEC include prematurity and low birth weight. However, it is not clear to date as to whether the etiology of NEC is due to host, environmental, or yet other unknown factors. We analyzed the differences in incidence of NEC in twin pregnancies to further clarify its etio-pathogenesis. METHODS: After IRB approval, a retrospective search of the medical records of the Department of Pediatric Surgery was done to identify all the neonates treated for surgical NEC from 2006-2013. Patients that had been treated for NEC elsewhere and subsequently transferred in to our facility were excluded. The medical records of the resulting 45 patients were then analyzed for demographics, antenatal screening, risk factors, treatment (medical and surgical), and outcomes. The resulting data was then analyzed using relative risk calculations and standard statistical tests. RESULTS: Of the 45 patients who developed surgical NEC, 9 neonates (20%) were born of a twin pregnancy. There were no cases in which both twin A and twin B developed NEC. NEC in twin pregnancy neonates showed a female preponderance (p less than 0.0001) and developed universally in the first born of the twins. Birth weight, time of onset of NEC, hospital stay and mortality were similar between twin and non-twin NEC. There was an average lead-time of three weeks to development of NEC in both singletons and twin pregnancies. CONCLUSION: There is a remarkable higher incidence of NEC amongst twins. Abnormal colonization of the gastrointestinal tract appears to be an immediate postpartum event. NEC in twin pregnancy does not appear to have a deleterious outcome compared to NEC in singleton pregnancy. PMID- 26023517 TI - Pseudocyst and a collar stud abscess: new face of necrotizing enterocolitis. AB - Meconium pseudocyst formation secondary to antenatal perforation is well described. We present a preterm infant who had intra-abdominal pseudocyst formation following postnatal intestinal perforation secondary to necrotizing enterocolitis (NEC) and secondarily leading to extra-abdominal collar stud abscess. This is new face of NEC and this presentation has not been reported earlier. PMID- 26023518 TI - Reverse Tissue Expansion in Gastroschisis: What to do if the Defect is too large to close after Silo Removal? AB - A female baby with an antenatal diagnosis of gastroschisis was transferred to our institution. The defect was large but the bowel was in good condition and a silo was placed. After successful reduction of the bowel the abdominal wall defect was too large to allow fascial or even skin closure. We utilised a Gore-tex patch with two prolene purse string sutures placed concentrically to enable the diameter of the patch to be sequentially reduced. This enabled gradual stretching of the tissues with a progressive reduction in the size of the defect. The patch was removed after 8 days and a delayed fascial closure was achieved. PMID- 26023519 TI - Metabolic Alkalosis resulting from a Congenital Duodenal Diaphragm. AB - Duodenal diaphragm is an unusual cause of upper intestinal obstruction. We present here a neonate with duodenal diaphragm who presented with features of metabolic alkalosis. Further, an algorithm of management of metabolic alkalosis in a newborn is suggested. PMID- 26023520 TI - Congenital tuberculosis in a neonate: a diagnostic dilemma. AB - Though tuberculosis (TB) among pregnant women is not unusual in our country, documented cases of congenital tuberculosis are rare. Diagnosis is often difficult as signs and symptoms in a neonate are non- specific. Maternal history of tuberculosis is often missed, as many of them are asymptomatic. Here we present a neonate who was operated in view of intestinal obstruction which intra operatively showed disseminated abdominal tuberculosis with infected ascites. PMID- 26023521 TI - Mesoplasty with Pedanculated Seromuscular Flap in Type IIIb Jejuno-ileal Atresia. PMID- 26023522 TI - Pneumoperitoneum without Gastrointestinal Perforation in a Neonate with Esophageal Atresia. PMID- 26023523 TI - Herniation of a Meckel's diverticulum in the Umbilical Cord. PMID- 26023524 TI - Bilateral maxillo-mandibular syngnathia in a newborn. PMID- 26023525 TI - Journal of neonatal surgery turns three. PMID- 26023526 TI - The impact of surgery on the developmental status of late preterm infants - a cohort study. AB - AIMS: Despite increasing evidence in the literature regarding the impact of late prematurity on subsequent developmental impairment, the developmental outcome of late preterm infants who undergo major surgery remains unclear. The aim of this study therefore was to determine the developmental outcome for a cohort of late preterm surgical population. METHODS: Late preterm infants with a gestational age from 34-36 weeks inclusive who were enrolled in the state-wide prospective Development After Infant Surgery (DAISy) study and who had undergone non-cardiac major surgery within the first ninety days of life were eligible for inclusion. Infants were assessed at one and three years of ages. RESULTS: Forty-six infants were enrolled in the study, of which 38 infants had a complete developmental assessment at one year of age. Of these infants, late preterm infants scored significantly lower than the standardized norms of the assessment on the expressive language and gross motor subscales. At three years of age 26 infants were reassessed: late preterm infants who underwent major surgery only scored significantly lower than the standardized norms on the cognitive subscale (p less than 0.001). CONCLUSIONS: These data provide the evidence that late preterm infants who undergo major non-cardiac surgery are at risk of developmental impairment and consideration should be given to enrolling this cohort in multi disciplinary developmental follow-up clinics. PMID- 26023527 TI - Tongue-tie assessment and division: a time-critical intervention to optimise breastfeeding. AB - OBJECTIVES: Recent reports have highlighted the benefits of surgical division of tongue-tie (frenulotomy) in infants with breastfeeding difficulties. There is no clear consensus defining the appropriate age for this procedure to be undertaken in selected infants. We aimed to evaluate the impact of delays in time between referral and frenulotomy in relation to maternal abandonment of breastfeeding. MATERIALS AND METHODS: This was a prospective cohort study done in out-patient Neonatal Surgery Department, Birmingham Heartlands Hospital, Birmingham, UK, between April 2013 and July 2013. All infants, referred to our tongue-tie clinic between April and July 2013, were studied prospectively. Referral time lags were calculated using computer records; details regarding breastfeeding were collected by an independent interviewer completing a questionnaire. RESULTS: Seventy patients were included. The median infant age at clinic was 28.5 days [range 1 126]. Fifty eight [82%] of mothers had breastfeeding difficulty and their infants were confirmed to have a prominent tongue-tie. By the time of their clinic attendance, breastfeeding had either not been established or abandoned in 21%. Despite difficulty, 61% of mothers persisted breastfeeding and all these mothers consented for frenulotomy. At time of clinic, median age of infants whose mothers had abandoned breastfeeding was 37 days [range 1-80] compared to 27 days [range 1 126] in infants whose mothers had persisted. CONCLUSIONS: We demonstrated a time critical dimension for frenulotomy: delay beyond 4-weeks from referral to assessment of neonatal tongue-tie is more likely to be associated with abandonment of breastfeeding. Timely assessment and division of tongue-tie in selected infants can therefore play an important role in a birthing unit's breastfeeding strategy. PMID- 26023528 TI - Neonatal Appendicitis (Part 1): A Review of 52 cases with Abdominal Manifestation. PMID- 26023529 TI - Primary neonatal diaphragmatic abscess. AB - Neonatal diaphragmatic abscesses are extremely rare and they usually develop by direct extension from a liver abscess. The first case of primary diaphragmatic abscess in a neonate is reported and the difficulties of diagnosing this rare entity are discussed. PMID- 26023530 TI - Displacement of Small bowel into the Lesser Sac in a Case of Complete Congenital Pouch Colon. AB - Postoperative neonatal intestinal obstruction has a myriad of etiology. An operated case of imperforate anus developed intestinal obstruction early postoperatively. At re-operation, missed complete congenital pouch colon with a small perforation and displacement of small bowel into the lesser sac were found. The patient was managed by adhesionolysis, excision of pouch colon, and end ileostomy. The patient did well postoperatively. PMID- 26023531 TI - Anorectal malformations (part 1). PMID- 26023532 TI - An improvisation in fixation of stamm gastrostomy in neonates. PMID- 26023533 TI - Congenital transmesenteric hernia in a neonate. PMID- 26023534 TI - Congenital Pouch Colon with Double Meckel's Diverticulum in a Patient with Persistent Cloaca. PMID- 26023535 TI - Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS): A Rarity. PMID- 26023536 TI - Erratum: Two Cases of Acute Lymphoblastic Leukemia with an e1a3 BCR-ABL1 Fusion Transcript. PMID- 26023537 TI - Reader's Forum. PMID- 26023538 TI - Accuracy and precision of integumental linear dimensions in a three-dimensional facial imaging system. AB - OBJECTIVE: A recently developed facial scanning method uses three-dimensional (3D) surface imaging with a light-emitting diode. Such scanning enables surface data to be captured in high-resolution color and at relatively fast speeds. The purpose of this study was to evaluate the accuracy and precision of 3D images obtained using the Morpheus 3D(r) scanner (Morpheus Co., Seoul, Korea). METHODS: The sample comprised 30 subjects aged 24-34 years (mean 29.0 +/- 2.5 years). To test the correlation between direct and 3D image measurements, 21 landmarks were labeled on the face of each subject. Sixteen direct measurements were obtained twice using digital calipers; the same measurements were then made on two sets of 3D facial images. The mean values of measurements obtained from both methods were compared. To investigate the precision, a comparison was made between two sets of measurements taken with each method. RESULTS: When comparing the variables from both methods, five of the 16 possible anthropometric variables were found to be significantly different. However, in 12 of the 16 cases, the mean difference was under 1 mm. The average value of the differences for all variables was 0.75 mm. Precision was high in both methods, with error magnitudes under 0.5 mm. CONCLUSIONS: 3D scanning images have high levels of precision and fairly good congruence with traditional anthropometry methods, with mean differences of less than 1 mm. 3D surface imaging using the Morpheus 3D(r) scanner is therefore a clinically acceptable method of recording facial integumental data. PMID- 26023539 TI - Comparison of occlusal contact areas of class I and class II molar relationships at finishing using three-dimensional digital models. AB - OBJECTIVE: This study compared occlusal contact areas of ideally planned set-up and accomplished final models against the initial in class I and II molar relationships at finishing. METHODS: Evaluations were performed for 41 post orthodontic treatment cases, of which 22 were clinically diagnosed as class I and the remainder were diagnosed as full cusp class II. Class I cases had four first premolars extracted, while class II cases had maxillary first premolars extracted. Occlusal contact areas were measured using a three-dimensional scanner and RapidForm 2004. Independent t-tests were used to validate comparison values between class I and II finishings. Repeated measures analysis of variance was used to compare initial, set up, and final models. RESULTS: Molars from cases in the class I finishing for the set-up model showed significantly greater contact areas than those from class II finishing (p < 0.05). The final model class I finishing showed significantly larger contact areas for the second molars (p < 0.05). The first molars of the class I finishing for the final model showed a tendency to have larger contact areas than those of class II finishing, although the difference was not statistically significant (p = 0.078). CONCLUSIONS: In set up models, posterior occlusal contact was better in class I than in class II finishing. In final models, class I finishing tended to have larger occlusal contact areas than class II finishing. PMID- 26023540 TI - Three-dimensional assessment of the temporomandibular joint and mandibular dimensions after early correction of the maxillary arch form in patients with Class II division 1 or division 2 malocclusion. AB - OBJECTIVE: This study aimed to assess three-dimensional changes in the temporomandibular joint positions and mandibular dimensions after correction of dental factors restricting mandibular growth in patients with Class II division 1 or division 2 malocclusion in the pubertal growth period. METHODS: This prospective clinical study included 14 patients each with Class II division 1 (group I) and Class II division 2 (group II) malocclusions. The quad-helix was used for maxillary expansion, while utility arches were used for intrusion (group I) or protrusion and intrusion (group II) of the maxillary incisors. After approximately 2 months of treatment, an adequate maxillary arch width and acceptable maxillary incisor inclination were obtained. The patients were followed for an average of 6 months. Intraoral and extraoral photographs, plaster models, and cone-beam computed tomography (CBCT) images were obtained before and after treatment. Lateral cephalometric and temporomandibular joint measurements were made from the CBCT images. RESULTS: The mandibular dimensions increased in both groups, although mandibular positional changes were also found in group II. There were no differences in the condylar position within the mandibular fossa or the condylar dimensions. The mandibular fossa depth and condylar positions were symmetrical at treatment initiation and completion. CONCLUSIONS: Class II malocclusion can be partially corrected by achieving an ideal maxillary arch form, particularly in patients with Class II division 2 malocclusion. Restrictions of the mandible in the transverse or sagittal plane do not affect the temporomandibular joint positions in these patients because of the high adaptability of this joint. PMID- 26023541 TI - Color stability of laboratory glass-fiber-reinforced plastics for esthetic orthodontic wires. AB - OBJECTIVE: In our previous study, glass-fiber-reinforced plastics (GFRPs) made from polycarbonate and glass fibers were prepared for esthetic orthodontic wires using pultrusion. These laboratory GFRP wires are more transparent than the commercially available nickel-titanium wire; however, an investigation of the color stability of GFRP during orthodontic treatment is needed. Accordingly, in the present study, the color stability of GFRP was assessed using colorimetry. METHODS: Preparation of GFRP esthetic round wires (diameter: 0.45 mm [0.018 inch]) using pultrusion was described previously. Here, to investigate how the diameter of fiber reinforcement affects color stability, GFRPs were prepared by incorporating either 13-um (GFRP-13) or 7-um glass (GFRP-7) fibers. The color changes of GFRPs after 24 h, and following 1, 2, and 4 weeks of coffee immersion at 37C, were measured by colorimetry. We evaluated the color stability of GFRPs by two evaluating units: the color difference (DeltaE(*)) and National Bureau of Standards (NBS). RESULTS: After immersion, both GFRPs showed almost no visible color change. According to the colorimetry measurements, the DeltaE(*) values of GFRP-13 and GFRP-7 were 0.73-1.16, and 0.62-1.10, respectively. In accordance with NBS units, both GFRPs showed "slight" color changes. As a result, there were no significant differences in the DeltaE(*) values or NBS units for GFRP-13 or GFRP-7. Moreover, for both GFRPs, no significant differences were observed in any of the immersion periods. CONCLUSIONS: Our findings suggest that the GFRPs will maintain high color stability during orthodontic treatment, and are an attractive prospect as esthetic orthodontic wires. PMID- 26023542 TI - Management of open bite that developed during treatment for internal derangement and osteoarthritis of the temporomandibular joint. AB - This case report describes the orthodontic treatment performed for open bite caused by internal derangement (ID) and osteoarthritis (OA) of the temporomandibular joint (TMJ). A Japanese woman, aged 31 years and 11 months, referred to our department by an oral surgeon had an open bite with clockwise rotation of the mandible and degeneration of the condyle. The overbite was corrected through intrusion of the maxillary and mandibular molars using mini screw implants to induce counterclockwise rotation of the mandible. Then, the mandibular second premolars were extracted and comprehensive orthodontic treatment was performed to establish a Class I molar relationship with distalization of the maxillary arch and to eliminate anterior crowding. Following treatment, her facial profile improved and a functional and stable occlusion was achieved without recurrence of the TMJ symptoms. These results suggest that orthodontic intrusion of the molars is one of the safer and less stressful alternatives for the management of open bite due to degeneration of the condyles caused by ID and OA of TMJ. PMID- 26023543 TI - Scar formation and revision after the removal of orthodontic miniscrews. AB - Many clinicians expect complete healing after the removal of temporary anchorage devices, but clinical examination may reveal scar-like tissue. This report presents the typical features of scarring detected after the removal of miniscrews, and the clinical outcome of scar revision along with its pathologic features. PMID- 26023544 TI - Variation in fatty acid composition of the bigeye snapper Lutjanus lutjanus collected in coral reef habitats of the Malaysian South China Sea. AB - BACKGROUND: In order to understand trophic ecology, habitat use and migration of coral reef fish, fatty acid composition and levels were examined in the bigeye snapper Lutjanus lutjanus collected in the Malaysian South China Sea. RESULTS: Proportions of saturated fatty acids (SAFA) ranged from 55.0% to 66.5%, with the highest proportions in fatty acids, the second highest was monounsaturated fatty acids (MUFA) ranged from 30.7% to 40.2% while the proportion of polyunsaturated fatty acids (PUFA) was the lowest ranged from 2.8% to 4.8%. Palmitic acid (16:0) was the most common in SAFA, oleic acid (C18:1omega9c) was the dominant in MUFA and linolenic acid (C18:3n3) showed the highest value in PUFA. Fatty acid concentrations, especially in SAFA and MUFA, increased with fish growth, suggesting diet and habitat shifts during the fish life history. Most of the fish had more than 1 of EPA: DHA ratio, which suggested that diets of L. lutjanus tended to be higher trophic organisms such as zooplankton and crustacean in coral ecosystem. CONCLUSIONS: The diet shift revealed by the composition and levels of the fatty acid profile revealed potential pattern in the habitat use and migration scale in coral reef environment of L. lutjanus. PMID- 26023545 TI - Aberrant innervation of the sternocleidomastoid muscle by the transverse cervical nerve: a case report. AB - Two aberrant rami originating from the right transverse cervical nerve and innervated the midportion of the sternocleidomastoid muscle (SM) were detected during routine cadaver dissection. Although SM is commonly innervated by the accessory nerve, as well as by cervical nerves, it is likely to be innervated additionally by other nerves such as hypoglossal nerve, ansa cervicalis, facial or external laryngeal nerve. Some considerations as regards the possible composition of the aberrant rami of the transverse cervical nerve detected in the current study, as well as the relevant literature is discussed. PMID- 26023546 TI - Evaluation of serum magnesium, lipid profile and various biochemical parameters as risk factors of cardiovascular diseases in patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is chronic inflammatory disease, associated with increased risk of cardiovascular diseases (CVD) than the general population. Chronic inflammatory conditions are likely to alter magnesium level and various biochemical parameters. OBJECTIVES: To study the probable changes in serum magnesium, lipid profile and various biochemical parameters and to assess risk factors of CVD in newly diagnosed RA patients compared to controls. MATERIALS AND METHODS: We studied 50 newly diagnosed RA adult patients and 50 healthy individuals as controls. Serum magnesium, calcium, lipid profile, uric acid and other biochemical parameters were measured in study subjects. Results were expressed as Mean +/- SD and compared between RA subjects and controls by Independent sample t-test and Pearson correlation. RESULTS: We found decreased serum magnesium and calcium in RA subjects compared to the controls (p < 0.001). RA subjects had atherogenic lipid profile characterized by elevated total cholesterol (p = 0.054), LDL cholesterol (p = 0.008) and decreased HDL cholesterol (p <0.001). Serum uric acid was higher in RA cases compared to controls (p = 0.025). Serum magnesium was negatively correlated with total cholesterol, LDL cholesterol and positively correlated with HDL cholesterol in RA cases. CONCLUSION: Decreased magnesium level, dyslipidemia and increased uric acid observed in our study together may be more potent risk factors for CVD in newly diagnosed RA subjects. We recommend that serum magnesium should be investigated as a part of cardiovascular risk management in RA. We suggest that decreased serum magnesium and increased serum uric acid may be considered as nontraditional risk factors of CVD in RA. Further prospective studies are needed to confirm the impact of inflammation on various biochemical parameters and cardiovascular outcomes in patients with RA. PMID- 26023547 TI - The significance of evalution of haematocrit in plateletpheresis donors. AB - BACKGROUND: The collection of platelets by apheresis is considered as a very great progress in transfusion medicine. In present era, many automated cell separation are available each model has tried to improve productivity, quality of plateletpheresis. Further various studies have been done to correlate the quality of platelet concentrates. Also, various biochemical studies have been done on plateletpheresis donors. However, safety issue with regards to post procedure levels of biochemical parameters decreased in donors undergoing plateletpheresis have been only minimally explored. OBJECTIVES: Investigating Haematological and Biochemical parameters (Hematocrit value and Serum Calcium levels) pre and post in plateletpheresis donors. MATERIALS AND METHODS: Sixty two healthy first time voluntary plateletpheresis donors at Apheresis unit in blood bank Bharati Vidyapeeth Deemed University Medical College & Hospital, Sangli, Maharashtra, India. Hematocrit value of plateletpheresis donors were analysed and based on mean value 43.2% considering this as standard in the present study. We categorized plateletpheresis donors in two groups (A) these having value less than 43.2% (n = 36) and Group (B) having haematocrit more than 43.3% (n = 26). Volume of ACD required for donors from both group were noted. RESULT: We observed mean of ACD infused in group A plateletpheresis donors was 347.7 ml +/- 35.75 SD while group 'B' donors required mean volume ACD to be infused was 379.6 ml +/- 46.24 S.D. was statistically significant (p <0.005). CONCLUSION: Plateletpheresis induces marked metabolic effects, with sustained changes in serum calcium and haematocrit after ACD infusion, the results show, before procedure (Plateletpheresis) one must consider the haematocrit value along with serum calcium levels in Plateletpheresis donor to avoid severe symptoms of hypocalcaemia. PMID- 26023548 TI - Bronze diabetes. AB - Thalassemia is a group of disorders characterized by deficient production of the beta-globin sub unit of hemoglobin. The mandatory blood transfusions in patients with thalassemia to maintain adequate erythrocyte levels, leads to iron overload. The prevalence of diabetes in patients with thalassemia varies from 6 to 14%. We here by present a known case of thalassemia major in an 18 year old boy. He was diagnosed with thalassemia before the age of one year and is on regular blood transfusion every two weeks since then. The repeated blood transfusion is one of the common causes for haemochromatosis. Iron overload initially leads to glucose abnormalities such as insulin resistance and hyperinsulinemia, which is followed by impaired secretion of insulin. Diagnosed as a case of bronze diabetes, this patient is on insulin therapy for the last two years. Currently the patient is on iron chelation therapy at Kasturba Medical College Hospital, Mangalore, Karnataka, India. PMID- 26023549 TI - Effect of diallyl disulphide on diabetes induced dyslipidemia in male albino rats. AB - BACKGROUND: Diabetes Mellitus is a chronic metabolic disorder which may lead to various complications, the important being dyslipidemia leading to Coronary Heart Disorders (CHD), the major cause for morbidity and mortality in diabetic patients. Diabetes Mellitus could be treated by nutritional therapy/drug therapy and others. But the drug therapy would have its own limitations and side effects. To overcome from this an herbal extract is recommended, such as Diallyl Disulphide (DADS) a principle compound of Garlic oil. AIM: To assess the hypolipidemic effect of Diallyl Disulphide (DADS) in alloxan induced diabetic rats. MATERIALS AND METHODS: Healthy adult wistar strain male albino rats weighing around 100-150 grams were randomly selected from the animal house at BLDE University's Shri B.M.Patil Medical College, Hospital and Research Centre, Bijapur, India. Diabetes was induced using alloxan and was treated with DADS. After a stipulated time the rats were anesthetised and sacrificed to collect the blood and liver tissue. Various Lipid parameters, HMG CoA Reductase, Fecal bile acids were estimated in the blood, feces and homogenised liver tissue using standard procedures. STATISCAL ANALYSIS: One-way ANOVA followed by post-hoc t test is done. RESULT: There was significant decrease in the blood and liver tissue lipid parameters of DADS treated alloxan induced diabetic rats when compared to the alloxan induced diabetic rats. CONCLUSION: From this study it can be concluded that the DADS a principle compound of garlic, definitely has the hypolipidemic effect in diabetic rats, which is reducing the morbidity in diabetic cases due to dyslipidemia without the adverse effects. PMID- 26023550 TI - Effect of yoga on blood glucose levels in patients with type 2 diabetes mellitus. AB - INTRODUCTION: In view of people embracing sedentary life style, and the effectiveness of treatment becoming less, the role of regular exercise especially 'yoga' seems to be a beneficial and economical adjuvant in the management of the Type 2 diabetes mellitus (T2DM). OBJECTIVES: To assess the beneficial effects of yoga on blood glucose levels in normal and T2DM volunteers. MATERIALS AND METHODS: A prospective case-control study was conducted in the Department of Physiology and Diabetic clinic of a tertiary care teaching hospital over period of two years. The study subjects consisted of 30 male diabetic patients attending diabetic clinic and 30 non-diabetic male volunteers constituted control group. The patients in the age group of 36 to 55 years with T2DM of at least one year duration and those on diabetic diet and oral hypoglycemic agents were included in the study group. The age matched healthy male volunteers who had come to join yoga training at yoga centre were included in the control group. All the participants were trained by yoga experts and subjected to regular practice under supervision for six months. In all the participants fasting (FBS) and post prandial blood sugar (PPBS) was estimated before, during (at three months) and after (six months) yoga training. Paired Student t-test was used to estimate difference in means calculated before and after yoga training in a same group. A p-value of <0.05 was considered as statistically significant. RESULTS: The distribution of age, mean height and mean weight among both the groups were comparable. The reduction in mean values of FBS and PPBS at the end of six months was highly significant (p <0.001) in both the groups when compared with the mean values before and during (three months) yoga practice. The reduction in these values at three months during yoga was highly significant in T2DM group when compared with mean values before yoga (p <0.001), but it was insignificant (p<0.05) in control group. CONCLUSION: The results of the present study demonstrated that the yoga is effective in reducing the blood glucose levels in patients with T2DM. PMID- 26023551 TI - Impact of music therapy on breast milk secretion in mothers of premature newborns. AB - INTRODUCTION: The promotion of breastfeeding is a simple and efficient strategy in reducing morbidity and mortality in neonates worldwide. Milk from the mother of a Preterm New Born (PTNB) infant contains a higher concentration of nutrients and energy than that produced by mothers of a full-term infant. Studies have shown that music therapy can reduce maternal anxiety, helping mothers cope with the hospitalization of their newborns in Neonatal Intensive Care Unit (NICU). OBJECTIVE: To evaluate the impact of music therapy on amount of breast milk secretion among mothers of premature newborns by reducing maternal stress. MATERIALS AND METHODS: Mothers of premature babies who were admitted to NICU at a tertiary health care centre were included as subjects. Mothers of premature infants were enrolled in the study once they came to NICU to express breast milk from Dec 2012 to May 2013. Each subject was assessed for 4 sessions on MT (Music Therapy) and 4 sessions on NMT (No Music Therapy) over 4 days. Breast milk was expressed using breast milk pump and quantity was measured for two sessions each day once at 11.00am and other at 4.00pm. Raga malkauns and yaman by flute was used for music therapy. MT was administered for 4 sessions in a randomized manner during the study period of 30mins (15mins prior to and 15mins during Breast milk amount). To assess the psychological stress, PSS questionnaire was administered on day 1 and day 4 of MT. Mother's saliva was collected to estimate salivary cortisol level on the last day of study during the sessions with MT and NMT. RESULTS: Music therapy was associated with a significant reduction in stress level as shown by improved PSS score and reduced salivary cortisol. Subjects who received music therapy had significant increase (p-value- 0.033) in breast milk expression when compared to mothers who didn't. CONCLUSION: Music therapy can be easily used in the breast milk expression room as a method to increase breast milk secretion in mothers who are stressed because of their neonates being admitted in NICU. PMID- 26023552 TI - Effect of Short Term CPAP Therapy in Obstructive Sleep Apnea Patients with Metabolic Syndrome. AB - BACKGROUND: Patients of obstructive sleep apnea (OSA) with metabolic syndrome (MetS) are at increased risk of cardiovascular morbidity and mortality. The role of oxidative stress in pathogenesis of OSA and MetS has been widely reported. Continuous positive airway pressure (CPAP) therapy remains the first-line of treatment in OSA. The beneficial effect of long term CPAP therapy in OSA is well known. However, the effect of short term CPAP on the components of MetS and oxidative stress-antioxidant levels is still unclear. AIM: The present study explored the effects of one night of CPAP therapy on the oxidant-antioxidant status and components of MetS in patients of OSA with MetS. MATERIALS AND METHODS: Twenty adult males and postmenopausal females with MetS and symptoms suggestive of OSA were enrolled in the study. None of the subjects were smoker or alcoholic. They did not consume any drugs that would alter their antioxidant levels. Overnight polysomnography was done to confirm diagnosis and assess CPAP pressure. Following which they spent one night in the sleep lab for CPAP therapy. Blood pressure data and blood samples were collected at baseline and after CPAP. Collected samples were transferred immediately to the laboratory for analysis of serum thiol, lipid peroxidation, insulin resistance (HOMA-IR) and lipid profile. RESULTS: Paired t-test with two-tail significance was used to compare the changes in study parameters in the same patient before and after treatment. The antioxidant level increased and oxidative stress decreased as evidenced by serum thiol concentration (204.2+/-65.7 vs 254.9+/-72 MUmol/L, p<0.001) and lipid peroxidation levels (13.1+/-6.2 vs 8.4+/-3.1 MUmol/L, p<0.01).There was a significant decrease in both systolic (132.1+/-16.1 vs 127.2+/-14.3 mmHg, p<0.01) and diastolic blood pressure (86.4+/-9.4 vs 81.2+/-9.8 mmHg, p<0.01) after one night of CPAP. However, there was no change in lipid parameters and the reduction seen in insulin resistance was not statistically significant. CONCLUSION: One night of CPAP therapy seems to be helpful in reducing oxidative stress, improving antioxidant levels and decreasing the severity of various components of MetS. PMID- 26023553 TI - Keratomycosis Caused By Graphium eumorphum (Graphium State of Scedosporium apiospermum). AB - Graphium eumorphum is rarely associated with mycotic keratitis. We report the case of a 30-year-old female presented with complaints of redness and defective vision in the left eye for one month. Gram staining and 10% KOH wet mount of corneal smears revealed fungal filaments. On potato dextrose agar, fast growing greyish white colonies turning grayish black on maturity was obtained. Lactophenol cotton blue (LPCB) staining confirmed the isolate as Graphium eumorphum. The infection was resolved with the combination of natamycin, econazole and itraconazole. PMID- 26023554 TI - Comparative Changes Noted in Renal Biopsies on Light Microscopy of ANCA Positive Vs ANCA Negative Serology. AB - OBJECTIVES: Pauci-immune glomerulonephritis is the commonest cause of rapidly progressive glomerulonephritis (RPGN) which is associated with increased mortality and morbidity. More than 90% of these patients have serological presence of either antineutrophil cytoplasmic antibodies (ANCA), of cytoplamic (C) or perinuclear (P) type. "Immunofluoresence studies" exhibiting minimal or no fluorescence is diagnostic in all such cases. The present study aims to study the differences between renal biopsies of serologically ANCA negative versus ANCA positive individuals. MATERIALS AND METHODS: One hundred and twenty renal biopsies (of clinically suspected cases of systemic vasculitis) were sub-divided sub-divided under the heading of serologically ANCA positive and serologically ANCA negative; and scoring them by means of a semi-quantitative scoring system devised at the beginning of the study to identify statistically significant, specific light microscopic features in the sub-components of renal biopsy. RESULTS: Fifteen parameters were found to be statistically significantly (p-value <0.05) in ANCA positive serological cases. These were glomerular capillary loop infiltration by neutrophils, cellular crescents, fibro-cellular crescents, glomerular fibrinoid necrosis, glomerular sclerosis, peri-glomerular infiltration, interstitial oedema, interstitial eosinophils, tubular atrophy, tubular necrosis, tubulitis, arterial hyalinization, arterial necrosis, arterial vessel wall polymorpho nuclear infiltrate and myointimal hypertrophy. CONCLUSION: The presence of above parameters in a renal biopsy report of a patient (in absence of facilities of autoimmune serology and immunofluoresence) can alert both nephrologist and nephropathologist to keep a possibility of renal symptoms arising out of systemic vasculitis. PMID- 26023555 TI - Paratesticular rhabdomyosarcoma in young adult- a case report. AB - Para testicular rhabdomyosarcoma is a rare malignant tumour, which usually presents as a painless mass in the scrotum or groin. A case of para testicular rhabdomyosarcoma in a 17-year-old male is being reported here who presented with chronic scrotal pain. Paratesticular rhabdomyosarcoma is a rare non germ cell tumour of scrotal sac in children and young adult/teens which can invade testis at presentation. Embryonal variant is the most common type. 40% cases can have metastasis to retroperitoneal lymph node. Diagnosis can be done on high degree of clinical suspicion coupled with biopsy and immunohistochemistry. Multimodality approach of treatment is often beneficial for patients. PMID- 26023556 TI - Neurofibroma at unusual locations: report of two cases in teenage girls. AB - Solitary neurofibromas are rare occurrence in salivary gland region as well as mons pubis of females. We present two cases of teenage girls with swelling in parotid region and mons pubis. Fine needle aspiration cytology was inconclusive in both cases. They were both managed surgically and a diagnosis of neurofibroma was ascertained histopathologically and also confirmed with S-100 immunohistochemistry. The patients were followed up for a period of six months, however, no recurrence was noted. Though, one patient had a previous history of recurrence. We report these cases in view of their rarity of site and age as well as no correlation with neurofibromatosis and clitoromegaly. PMID- 26023557 TI - Invasive lobular carcinoma of the breast with extracellular mucin- a new rare variant. AB - Historically, extracellular mucin secretion is by default a feature of ductal carcinoma. Lobular carcinoma is known to be associated with only intracytoplasmic mucin production and signet ring cells. As ductal carcinoma and lobular carcinoma have different therapeutic and prognostic implications, it is important to classify them into respective groups. Here, we present a case of invasive lobular carcinoma with abundant extracellular and intracellular mucin in a 38-year-old female patient. Invasive lobular carcinoma with extracellular mucin is an extremely rare and new variant. Only 3 cases are reported in the literature so far. PMID- 26023558 TI - Nerve sheath myxoma: report of a rare case. AB - Nerve sheath myxoma defined by Harkin and Reed is an uncommon benign neoplasm with nerve sheath like features. It has several cytological and histological differential diagnoses. One such lesion is neurothekeoma, which can be differentiated using immunohistochemistry. In most of the previous reports nerve sheath myxoma and neurothekeoma were considered synonymous and were often confused for one another. This case report separates the two using immunohistochemistry. Also, the cytological features of nerve sheath myxoma are not well documented in the past. This case report attempts to display the cyto morphology of nerve sheath myxoma. We report a rare case of nerve sheath myxoma diagnosed on cytological features confirmed by histopathology and immunohistochemistry in a 32-year-old lady who presented with an asymptomatic nodule over the left cervical area and discuss its cyto-histological mimics. PMID- 26023559 TI - Post electric shock reactive thrombocytosis. AB - Thrombocytosis is defined as a platelet count greater than 400*10(9)/L. Electric shock may lead to tissue injury and marked thrombocytosis. We herein report a case of 45-year-old woman, who was hospitalized with progressively increasing weakness, tingling sensation, and numbness of the bilateral lower limbs. She had a history of receiving electric shock during household work, 15 days prior to her admission. Her laboratory investigations revealed a markedly increased platelet count (1,570*10(9)/L) along with increased level of serum uric acid (12 mg/dL), and mild increase in serum potassium (6.7 mmol/L), and serum alanine transaminase (50 U/L). She was treated with intravenous fluids, calcium, and multivitamins. Following hospitalization and treatment, condition of the patient improved, her symptoms resolved, and her platelet counts declined. We report this case because of rare presentation of marked thrombocytosis secondary to electric shock with a brief discussion on pathophysiology of this condition. PMID- 26023560 TI - Synchronous diffuse large B-cell lymphoma and malignant clonal plasma cells in bone marrow as primary presentation: a diagnostic and therapeutic challenge. AB - Coexistence of Diffuse Large B-Cell Lymphoma (DLBCL) with other morphologically and phenotypically distinct lymphoid neoplasm although unusual, has been reported in literature. The most common lymphoid neoplasms associated with DLBCL are Hodgkin's lymphoma, mantle cell lymphoma and marginal zone lymphoma. However, they have been reported predominantly in the sites other than the bone marrow. Rarely, DLBCL associated with paraproteinemia of IgM type, result of monoclonal plasma cell proliferation, has also been reported in literature. There is either an associated increase in the free light chain levels or disruption in the normal kappa: lambda ratio. However, co-existence of DLBCL with malignant non secretory clonal plasma cells, diagnosed primarily in the bone marrow has not been reported in the literature. PMID- 26023561 TI - Malignant melanoma arising in an ovarian mature cystic teratoma - a rare entity. AB - Mature cystic teratomas, also known as dermoid cysts, are composed of a mixture of tissues derived from all three germ layers and constitute about 20% of all ovarian neoplasms. However, malignant transformation in a mature cystic teratoma is an uncommon event occurring only in about 1.8% cases. A variety of tumours can arise within a mature cystic teratoma (most common being squamous cell carcinoma), with malignant melanoma being extremely rare among such tumors. While most authors believe that primary ovarian melanoma almost always arises within a mature cystic teratoma, the primary nature of an ovarian malignant melanoma can be ascertained only once metastasis from a cutaneous melanoma is ruled out. The first case of malignant melanoma arising in an ovarian mature cystic teratoma was reported in 1901 and only about 45 additional cases have been reported till date. We present another case of a primary malignant melanoma arising within a mature cystic teratoma. PMID- 26023562 TI - Pancreatic extra-gastrointestinal stromal tumour with documentation of C-kit mutation: a case report. AB - Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms located in the alimentary tract. Stromal tumours that arise outside the gastrointestinal tract as primary tumour are designated as extra-gastrointestinal stromal tumours (EGIST). The EGIST are located in mesentry, omentum, retroperitoneum and rarely in pancreas. Only 19 cases of pancreatic EGIST (pEGIST) have been reported in the literature. Of these, there were only two cases of pEGIST with documentation of molecular alteration in C-Kit gene. We here report a third case of primary pEGIST with documentation of C-kit mutation. PMID- 26023563 TI - Laboratory Diagnosis of Extra-pulmonary Tuberculosis (EPTB) in Resource constrained Setting: State of the Art, Challenges and the Need. AB - During the last decade, remarkable progress has been made in the diagnostics of pulmonary tuberculosis; however, diagnostic challenges in extra-pulmonary tuberculosis (EPTB) remain to be addressed. Diagnosis of EPTB is difficult due to the pauci-bacillary nature of disease, the variable clinical presentation, and need for invasive procedures to secure appropriate sample, and lack of laboratory facilities in the resource-limited settings. A more accurate test to diagnose various forms of EPTB, which can easily be incorporated in the routine TB control programme, would contribute significantly towards improving EPTB case-detection and thus reducing the morbidity and mortality. In this overview, we describe the status of current conventional and newer methods available for laboratory diagnosis of EPTB and discuss the challenges in their implementation in the resource-limited settings, and suggestion for better EPTB diagnostic algorithms, which can be incorporated in the routine TB control programmes. PMID- 26023564 TI - Wrong sample dispensing may cause false positive malaria test. AB - Both false positive (FP) and false negative are known limitations of any diagnostic test. Malaria parasite (MP) rapid diagnostic tests (RDTs) may give FP results due to interference by substance in blood sample. We detected a FP in a MP RDT for first time in 36-year-old female whole blood donor due to incorrect sample dispensing technique. As per manufacturer's instructions, while allowing all kit components and blood specimen to come to room temperature before testing, blood samples usually separate into lower layer of red blood cells (RBC) and upper layer of plasma. Technician performing the test took the sample from the bottom of the vacutainer thus taking RBC instead of whole blood (WB-recommended by manufacturer). This test showed reactive result and as per our standard protocol was re-tested to confirm the result. This second test was performed after re-mixing the same sample, which now tested as non-reactive sample, buffer and other kit component mix-up were ruled out. Repeated test on another sample of same donor produced same results. Thick and thin peripheral blood smear examination for malaria was found negative. This case highlights wrong MP RDT result due to wrong sample dispensing. PMID- 26023565 TI - Auditing Analgesic Use in Post-operative Setting in a Teaching Hospital. AB - INTRODUCTION: Managing postoperative pain efficiently is one important therapeutic challenge in the hospitals. Combination use of analgesics is in vogue, where in drugs from the opioid and non-opioid group are given synergistically. The aim of this study is to audit the use of different analgesics on the first postoperative day. Effort has been made to look into the drug or drug combinations used and other factors associated with their use. MATERIALS AND METHODS: Retrospective, cross sectional observational study was conducted over a period of 11 months in a tertiary care teaching hospital at Hyderabad with approval from institutional ethics committee. Medical records of 649 patients on the first postoperative day were analysed for analgesics by various indicators. RESULTS: Average number of drugs per encounter was 4.23. Percentage of patients prescribed drugs from national essential drug list/WHO was 81.94%. Most common analgesic (monotherapy) prescribed was tramadol followed by diclofenac and the most common combination drugs prescribed were tramadol+Paracetamol. The most common route of administration was intravenous. All the drugs except piroxicam, were in the lower limit of the recommended daily dose. CONCLUSION: The present study gives an idea of the overall pattern of analgesic drug use in postoperative patients. The drug combinations used, the most common single use drug can be made out. The health professionals can be encouraged to prescribe by generic name and from the National List of Essential Medicines NLEMs. PMID- 26023566 TI - To study the efficacy and safety of doxophylline and theophylline in bronchial asthma. AB - BACKGROUND: Asthma is a non communicable chronic disease prevalent all over the world. Two commonly used methylxanthines, theophylline and doxofylline were compared in the study in stable asthmatic patients at recommended doses by various spirometric lung function tests with forced expiratory volume at second one (FEVI) between 50 to 80% of predicted FEVI. MATERIALS AND METHODS: A total of 100 patients were divided in two groups. Group I was administered 300 mg theophylline twice a day and Group II was administered doxofylline 400 mg twice a day orally for six weeks. Spirometric variables symptom score, and adverse effects were recorded at the baseline level and after six weeks of therapy. Data was compared and analysed statistically. RESULTS: The spirometric values of forced expiratory volume in 1 second (FEVI), forced vital capacity (FVC), and FEV1/FVC showed a statistically significant improvement over base line with the use of both theophylline as well as doxophylline, but were not statistically different from each other. There was a statistically significant improvement in peak expiratory flow rate (PEFR) after six weeks of treatment with doxophylline compared to theophylline. It was found that the doxophylline has a better safety profile as compared to theophylline. Adverse events occurred in a greater proportion of patients in the theophylline group. CONCLUSION: In the study it was concluded that both theophylline and doxofylline improved the lung function tests and symptoms in patients of mild Bronchial Asthma, but doxofylline has a better profile in terms of safety. PMID- 26023567 TI - Efficacy and tolerability of levosulipride, domperidone and metoclopramide in patients with non-ulcer functional dyspepsia: a comparative analysis. AB - OBJECTIVE: This is a prospective, randomized study designed to demonstrate the efficacy of three study drugs (Levosulpiride, Domperidone and Metoclopramide) in Functional Dyspepsia. Subject recruitment was done from medicine outpatient department of the teaching hospital from June 2013 to November 2013. MATERIALS AND METHODS: The data collection was performed by the Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) question instrument for assessing the dyspeptic symptoms of functional dyspepsia in patients enrolled in the study were assessed at base line (Prior to initiation of therapy) and at the next 4 weeks on a 5-point scale. RESULT: Among 120 patients 113 patients completed this study in three groups (G-1 Levosulpiride 40 patients, G-2 Domperidone 35 patients and G-3 Metoclopramide 38 patients) were followed up. Female gender was dominated (75), occupation wise most of patients belong to laborer (49) class. Highly significant improvement in symptoms scale was noticed in G-1 Levosulpiride 40 patients' group. CONCLUSION: Functional Gastrointestinal disorders are not serious ailments but have a key impact on quality of life. overall dyspeptic symptom relief rates were significantly high in the Levosulpiride group (p<0.004) as compare to Domperidone and Metoclopramide groups. A proper understanding of disease process by health care personnel and by sufferer is obligatory to enhance the quality of life and daunting the self/over the counter medication in this condition. PMID- 26023568 TI - Preventive role of Indian black pepper in animal models of Alzheimer's disease. AB - INTRODUCTION: Dementia is the clinical symptom of alzheimer's disease. Brain cholinesterase levels and behavioural changes are the markers for Alzheimer's disease and aluminium chloride is one causative agent for polymerization of tau protein and amyloid plaque formation in Alzheimer's disease. Effect of piper nigrum and its role in prevention of alzhimer's disease and symptoms are well linked in this study. AIM: To study the effect of piper nigrum for the prevention of alzheimer's associated histopathological, biochemical and behaviour changes in rat model. MATERIALS AND METHODS: Twenty four rats were taken in this study. Their baseline behavioural parameters were noted and group was separated randomly in four. Rats were pretreated with piper nigrum and Alzheimer's disease was induced. Biochemical and histopathological changes were noted at the end of experiment. RESULTS: There was marked decrease in cholinesterase level, amyloidal plaque formation in rats brain who were pretreated with piper nigrum. At the same time there was decrease in escape latency time (ELT) and increase in memory in piper treated rats. CONCLUSION: Piper nigrum prove to be effective for prevention of Alzheimer's disease. This finding has to be confirmed with studies including larger population. Further research on cholinesterase inhibitors, role of flavonoids on prevention of neurodegeneration in Alzheimer's disease can be encouraged. PMID- 26023569 TI - Association of Angiotensin converting enzyme gene insertion / deletion polymorphism with risk of ischemic heart disease in a population of smokers in southern India. AB - BACKGROUND: Ischemic heart disease (IHD) remains a major public health problem nationally and internationally. Smoking is a major risk factor for IHD.The deletion (D) allele of the angiotensin converting enzyme (ACE) gene polymorphism has been associated with hypertension, ischemic stroke and myocardial infarction. The present study was carried out to determine the association of the ACE gene insertion/deletion (I/D) polymorphism in IHD patients with and without smoking. MATERIALS AND METHODS: One hundred seven male IHD patients admitted consecutively in the Cardiology unit of a Government Hospital and 100 age and sex matched healthy controls were enrolled in this study.The patients were further divided into smokers and nonsmokers. All the subjects were checked for I/D polymorphism of ACE gene, which is mapped to 17q23.3 with OMIM no 106180, by polymerase chain reaction (PCR). The subjects were also investigated for lipid profile and ejection fraction (EF). RESULTS: We found significant difference in the distribution of D allele between patients and controls (p=0.009, OR 1.69, 95% CI 1.139 to 2.517).The significantly lower EF (p<0.001) was suggestive of greater cardiovascular compromise in smokers. The frequency of ID genotype was significantly associated with cases compared to controls (p=0.012, OR 2.054, 95% CI 1.1694-3.624) but was not significantly associated with smokers as compared to nonsmokers. CONCLUSION: We infer significant association of D allele with IHD. The smokers with ID genotype should be put on prophylactic ACE inhibitor therapy to prevent the morbidity and mortality associated with IHD. PMID- 26023570 TI - Chromosomal Study is Must for Prepubertal Girl with Inguinal Hernia: Opportunity to Diagnose Complete Androgen Insensitivity Syndrome. AB - The sufferers of complete androgen insensitivity syndrome (CAIS) are phenotypic females despite of having functional testes and normal male karyotype. They usually present late with primary amenorrhea but delayed diagnosis increases chance of gonadal malignancy. Alertness for this entity is crucial as with early diagnosis such disorder can be managed more appropriately for a better future. We hereby describe a case of CAIS in an 8-year-old girl presented with bilateral inguinal swellings. Endocrinological analysis, radiological investigations and cytogenetic studies were done. Investigations revealed absence of female internal genitalia. Karyotyping and molecular study confirmed the presence of Y chromosome. Parents were counseled regarding timely gonadectomy, fertility and other long term social issues. PMID- 26023571 TI - Study of morbidity pattern among salt workers in marakkanam, Tamil Nadu, India. AB - BACKGROUND: Salt workers are exposed to occupational hazards like contact with salt crystals and brine, physical stress, sunlight and glare due to sunlight reflected by salt crystals. Very few studies have documented the morbidity among the salt workers. AIM: To assess the morbidity pattern among salt workers in Marakkanam, Tamil Nadu, India. MATERIALS AND METHODS: A community based cross sectional study was undertaken in 4 randomly selected salt worker villages. Three hundred thirty one salt workers were reached by a house-to-house survey during April 2010 to March 2011. Demographic data was collected; clinical examination was conducted using a predesigned and pretested questionnaire. A pilot study was conducted to estimate the prevalence of morbidity before initiating the study. The data was analyzed using SPSS Version 11.5. Chi-square test and odds ratios (OR) with 95% confidence intervals (CI) were calculated to determine the association of morbidity levels with various factors. RESULTS: Of the 331 salt workers in the study, 58% were females, mean age was 41.9 +/- 10.8 y. Eighty seven percent salt workers had some or other morbidity. The observed morbidities include clinical pallor (44.4%), ocular morbidities including cataract, pterygium, conjunctivitis, pingecula and corneal ulcer (42%), caries teeth (41.7%), hypertension (23.3%), underweight (19.3%), goiter (19%), obesity (14.8%) and dermal conditions including dermatitis, thickening of palm and sole, tinea unguum, follicultitis (9.1%). The presence of morbidity did not show any significant association with increase in age, gender, duration of employment or the type of salt work involved with. However, the lower the education level, the higher is the morbidity level among salt workers (OR = 5.23, 95% CI= 2.07 to 13.21). CONCLUSION: Morbidity among salt workers is high. Intervention programs are needed to alleviate the health problems in the salt workers. PMID- 26023572 TI - Married Men's Involvement in Family Planning - A Study from Coastal Southern India. AB - BACKGROUND: Over the years, India has emerged as one of the most populous countries in the world, next only to China. Unregulated fertility can compromise the economic development and political stability of a country. Family planning was always thought to be a woman's prerogative, especially in a male dominant society like India. Consequently, most of the studies on family planning focused on women as the subject of interest. PURPOSE: To assess the knowledge, attitude and practices of family planning amongst men who have been married for at least five years. MATERIALS AND METHODS: A cross-sectional study was carried out in the teaching hospitals of Kasturba Medical College (Manipal University), Mangalore; India among 156 men who had been married for at least five years. They were selected using non-random sampling method and were interviewed using a pretested semi structured validated questionnaire. Chi-square test was used for statistical analyses. RESULTS: Overall, 75.6% were aged between 26 and 34 years, 41.7% had one child, 92.3% subjects from upper and 86.9% from lower socio-economic status were aware about the male family planning services available in the market. Most husbands preferred that their spouse should be sterilized (53.8%). Family planning methods were actively practiced by 71.2 %. CONCLUSION: Most of the studies on family planning have focused mainly on females. This study throws light on the male perspective of family planning. Our study subjects were well aware about various family planning services and their attitude towards family planning was favorable, but the number of men practicing family planning was not high. PMID- 26023573 TI - Assessment of burden of depression during pregnancy among pregnant women residing in rural setting of chennai. AB - INTRODUCTION: Depression during perinatal period leads to adverse pregnancy outcome and of child growth. Our study aimed to examine the burden of antenatal depression and associated risk factors among pregnant women living in rural settings of Chennai, a southern state of India. MATERIALS AND METHODS: A pilot cross-sectional study was conducted in the rural settings of Chennai, one of the Southern States of India during August through September 2013. Hundred pregnant women who agreed to participate were enrolled in this study. Edinburg postnatal depression scale was used to assess the depression level of the study participants. Information was also gathered about socio-demographics, obstetric and disease history, social support and marital satisfaction was gathered. Descriptive analysis was performed using univariate statistics to report means and standard deviations for the continuous variables and frequency distribution for the categorical variables. RESULTS: Majority of the participants (65%) had scored 13 or higher on the Edinburg Depression Scale reflecting high likelihood of depression. Majority of the participants (66%) had been bothered due to low feeling, depressed or hopelessness during the previous month. Enriched marital satisfaction scale (p=.025) had shown significant association with Edinburg depression scale. CONCLUSION: Pregnancy is very crucial period not only for mother but whole family. This study has shown very high frequency of depression among the participants. There is a need for a longitudinal study to design interventions that can address emerging burden of antenatal depression among pregnant women living in rural settings. PMID- 26023574 TI - Unusual foreign body in nose and nasopharynx - a rare case. AB - Lodgment of foreign body in the nose/nasopharynx in a sane adult person is unusual. Here, we present the case of a patient who came with an unusual foreign body (fish) lodged in the nose & nasopharynx. It was removed successfully in the outpatient department transorally with aid of nasal endoscopy. PMID- 26023575 TI - Unicentric castlemans disease: unusual disorder of the neck a case review. AB - Castleman's disease (giant or angio follicular lymph node hyperplasia) was first described by Benjamin Castleman in the year 1957 and was named after him. It is an uncommon lympho proliferative disorder which is localised to single lymphnode (unicentric) or multiple lymph node level systemically (multicentric).It is a very rare disorder characterised by non-cancerous growths. The most common sites of this are mainly thorax (mediastinum or lung hilum) and abdomen. It rarely occurs in cervical area. We report a case of unicentric cervical castleman's disease of neck in an 18-year-old female, who came to ENT OPD with history of right sided neck mass since 6-8 months. After thorough clinical examination and investigations, complete excision of the mass was done. Histopathological examination confirmed the diagnosis of Castleman's disease. On follow-up for one year no recurrence has been seen. PMID- 26023576 TI - PCR detection and identification of bacterial contaminants in ocular samples from post-operative endophthalmitis. AB - BACKGROUND: Bacterial endophthalmitis is a sight-threatening complication of ocular surgery which requires urgent medical consideration including comprehensive diagnosis. Polymerase chain reaction (PCR) as a sensitive molecular method has been extensively used for detection of microbial species in clinical specimens. AIM: The aim of this study was to identify the causative organisms of endophthalmitis in our patient population using a procedure based on PCR. MATERIALS AND METHODS: Vitreous samples from 32 patients with post-operative endophthalmitis were collected. Total vitreous DNA was extracted and then assessed by agarose gel electrophoresis. Bacterial 16S rRNA gene was amplified from genomic DNA using PCR with a pair of HAD2 universal primers. Library of PCR products from 16S rRNA, cloned into the pTZ57R/T vector. The ligated products were then transformed into E. coli DH5alpha strain and grown in the LB ampicillin/X-Gal/IPTG plate. RESULTS: From the total of 32 vitreous samples, 18 specimens were positive, illustrating the presence of bacterial infection (56.4 %). Twelve species including Escherichia coli, Enterobacter cloacae, Bacillus subtilis, Neisseria gonorrhoeae, Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia trachomatis, Staphylococcus aureus, Neisseria meningitides, Staphylococcus epidermidis, Pseudomonas aeruginosa and Bacillus cereus were identified using BLAST for known 16S rRNA sequences. CONCLUSION: Polymerase chain reaction (PCR) accompanied with cloning and sequencing approved to be sensitive and specific. The rapid molecular technique was useful in detection of 12 major microbial species, in infectious endophthalmitis. PMID- 26023577 TI - Fractional excretion of sodium and its association with prognosis of decompensated heart failure patients. AB - INTRODUCTION: Diuretic resistance is a common problem in congestive heart failure patients. It has been defined clinically but can be defined objectively in terms of fractional excretion of sodium (FENa). AIM: Aim of the study was to find out the association of FENa with prognosis of decompensated heart failure patients. MATERIALS AND METHODS: One hundred and seventy eligible patients with a primary diagnosis of decompensated heart failure were enrolled and patients were categorized into two groups on the basis of baseline FENa- Group A (65 patients) with diuretic resistance with FENa <0.2% and Group B (105 patients) sensitive to diuretics with FENa >=0.2%. The patients were followed-up during the hospital stay for the time taken for improvement from NYHA functional class IV to class II. They were followed telephonically at 30 days post admission for all cause mortality. RESULT: The mean time taken to improve from NYHA functional class IV to class II were 146 hours for FENa<.2% and 60 h for FENa>=0.2% (p<0.0001). There was a fair negative correlation between FENa and time taken for improvement from NYHA functional class IV to class II with correlation coefficient being -0.4842. Multiple linear regression analysis showed FENa (standardized "B" is -0.480, p<0.001) and LVEF (standardized "B" is -0.182, p=0.007) as significant predictors of time taken for improvement from NYHA functional class IV to class II. The 30 days all cause mortality was significantly associated with level of Fena (p <0.001) and was inversely proportional. CONCLUSION: CHF patients with FENa <0.2% takes longer time to recover from NYHA functional class IV to class II. 30 days all cause mortality was also significantly higher among CHF patients with FENa <0.2%.Measuring baseline FENa and regulating diuretic dose accordingly at admission to hospital may probably improve the prognosis of CHF patients. PMID- 26023578 TI - Outcomes for emergency severity index triage implementation in the emergency department. AB - INTRODUCTION: Hospital triage scale in emergency departments needs to be valid and reliable. Lack of sufficient data exists on triage scale rigor in emergency departments of Iran. This study aimed to determine the impact of the emergency severity index (ESI) triage scale in the emergency department. MATERIALS AND METHODS: A single-center study was conducted. Proportion of triage categories allocated to high-risk patients admitted to high-acuity departments was examined in observational period in June 2012 and May 2013. True triage score was reported based on patients' paper- based scenario questionnaire. Interrater reliability was assessed using unweighted kappa. Concordance among experts, nurses and physicians was examined. The Chi-square test and Kappa statistics was used for statistical analysis. RESULTS: Triage decisions regarding high-risk patients before and after implementation period are independent from each other (chi2= 22.254; df=1; p<0.05) and more high-risk patients were recognized after implementation of the ESI. Overall agreement and concordance were (79%) and (kappa=0.54) among nurses; (71%) and (kappa=0.45) among physicians, (85%) and (kappa=0.81) among experts, respectively. Correct triage decisions among clinicians were increased after implementation of the ESI. CONCLUSION: The ESI as valid and reliable tool improving desirable outcomes' in the emergency department has been recommended but it may not reveal optimal outcomes in developing countries comparing to what have been achieved in the developed countries. In addition, patient influx in ESI level II could create considerable controversy with clinicians. PMID- 26023579 TI - Relationship between intracerebral hemorrhage and diabetes mellitus: a case control study. AB - INTRODUCTION: The role of diabetes mellitus in the pathogenesis of intracerebral hemorrhage (ICH) is controversial. Underlying comorbidities such as diabetes mellitus may increase the risk of intracerebral hemorrhage. In this study, we sought to assess the role of diabetes mellitus in the occurrence of intracerebral hemorrhage. MATERIALS AND METHODS: In this case-control study, the prevalence of diabetes mellitus was evaluated in 120 patients presenting with intracerebral hemorrhage and in a control group of 135 patients with low back pain. All patients were treated at the Departments of Neurology and Neurosurgery, Shohadaye Tajrish University Hospital, Tehran, Iran between 2008 and 2012. T-test was applied for analysing the quantitative variables and chi-square and Fisher's exact tests were used to analyse qualitative variables. RESULTS: The mean age was 67.5+/-12.7 y in patients with intracerebral hemorrhage and 70.5+/-12.6 y in the control group (p=0.201). Diabetes mellitus was found in 39 patients with intracerebral hemorrhage (33.1%) and 30 (22.2%) control subjects (p=0.054). The prevalence of diabetes mellitus in patients younger than 60 y was 7.4% in the control group and 27.8% in the case group (p=0.042). CONCLUSION: In our study, no significant relationship was found between diabetes mellitus and intracerebral hemorrhage (except in patients younger than 60 years) and diabetes mellitus did not cause bleeding in certain brain areas. However, more studies are required on the correlation of diabetes mellitus and intracerebral hemorrhage in the same population to reach a definite conclusion. PMID- 26023580 TI - Validation of the malaysian versions of parents and children health survey for asthma by using rasch-model. AB - CONTEXT: In recent years, health-related quality of life (HRQOL) has become an important outcome measure in epidemiologic studies and clinical trials. For patients with asthma there are many instruments but most of them have been developed in English. With the increase in research project, researchers working in other languages have two options; either to develop a new measure or to translate an already developed measure. Children Health Survey for Asthma is developed by American Academy of Paediatrics which has two versions one for the parents (CHSA) and the other for the child (CHSA-C). However, there is no Malay version of the CHSA or the CHSA-C. AIM: The aim of this study was to translate and determine the validity and reliability of the Malaysian versions of Parent and Children Health Survey for Asthma. MATERIALS AND METHODS: Questionnaires were translated to Bahasa Malayu using previously established guidelines, data from 180 respondents (asthmatic children and their parent) were analysed using Rasch Model; as, it is an approach that has been increasingly used in health field and also it explores the performance of each item rather than total set score. RESULTS: The internal consistency was high for the parent questionnaire (CHSA) (reliability score for persons = 0.88 and for items was 0.97), and good for child questionnaire (CHSA-C) (reliability score for persons = 0.83 and for items was 0.94). Also, this study shows that all items measure for both questionnaires (CHSA and CHSA-C) are fitted to Rasch-Model. CONCLUSION: This study produced questionnaires that are conceptually equivalent to the original, easy to understand for the children and their parents, and good in terms of internal consistency. Because of the questionnaire has two versions one for the child and the other for the parents, they could be used in clinical practice to measure the effect of asthma on the child and their families. This current research had translated two instruments to other language (BahasaMalayu) and evaluated their reliability and validity hence will help researchers from the same country to use these translated instruments in their studies. PMID- 26023582 TI - A Case of Autoimmune Polyglandular Syndrome (APS) Type II with Hypothyroidism, Hypoadrenalism, and Celiac Disease - A Rare Combination. AB - Autoimmune Polyglandular syndrome (APS) are rare condition characterised by presence of immune dysfunction of two or more endocrine glands and other non endocrine organs. APS is divided into 2 major subtypes based on age of presentation, pattern of disease combinations and mode of inheritance. APS 1(juvenile) usually manifest in early adolescence or in infancy. It is characterised by multiple endocrinal deficiency with mucocutaneous candidiasis and ectodermal dystrophy. Of the endocrine diseases, hypoparathyroidism form an important component followed by Addison's disease, type 1A diabetes, hypogonadism and thyroid disease. On the other hand APS II usually manifest in 3rd or 4th decade of life with female preponderance. Endocrine diseases commonly include autoimmune thyroid disease (graves or autoimmune thyroiditis), type 1A diabetes, and Addison's disease. Hypoparathyroidism is of rare occurrence and there is no mucocutaneous candidiasis. We report here a case of APS type II in a 29-year-old male who initially presented with hypothyroidism, which was soon followed by Addison's disease. The involvement of thyroid gland preceding the involvement of adrenal is of rare occurrence. The patient also had celiac disease which makes the combination further uncommon. PMID- 26023581 TI - Using an Artificial Neural Networks (ANNs) Model for Prediction of Intensive Care Unit (ICU) Outcome and Length of Stay at Hospital in Traumatic Patients. AB - INTRODUCTION: Currently applications of artificial neural network (ANN) models in outcome predicting of patients have made considerable strides in clinical medicine. This project aims to use a neural network for predicting survival and length of stay of patients in the ward and the intensive care unit (ICU) of trauma patients and to obtain predictive power of the current method. MATERIALS AND METHODS: We used Neuro-Solution software (NS), a leading-edge neural network software for data mining to create highly accurate and predictive models using advanced preprocessing techniques, intelligent automated neural network topology through cutting-edge distributed computing. This ANN model was used based on back propagation, feed forward, and fed by Trauma and injury severity score (TRISS) components, biochemical findings, risk factors and outcome of 95 patients. In the next step a trained ANN was used to predict outcome, ICU and ward length of stay for 30 test group patients by processing primary data. RESULTS: The sensitivity and specificity of an ANN for predicting the outcome of traumatic patients in this study calculated 75% and 96.26%, respectively. 93.33% of outcome predictions obtained by ANN were correct. In 3.33% of predictions, results of ANN were optimistic and 3.33% of cases predicted ANN results were worse than the actual outcome of patients. Neither difference in average length of stay in the ward and ICU with predicted ANN results, were statistically significant. Correlation coefficient of two variables of ANN prediction and actual length of stay in hospital was equal to 0.643. CONCLUSION: Using ANN model based on clinical and biochemical variables in patients with moderate to severe traumatic injury, resulted in satisfactory outcome prediction when applied to a test set. PMID- 26023583 TI - Disseminated cryptococcosis with adrenal and lung involvement in an immunocompetent patient. AB - Disseminated cryptococcosis usually occurs in immunocompromised patients. Occasionally, it affects immunocompetent persons and mimics tuberculosis in clinical presentation and radiological findings. Usually, it affects lungs and central nervous system. Rarely, it may affect adrenal glands. We present a case of 65-year-old gentleman with prolonged pyrexia. Computed Tomography (CT) scan of chest and abdomen showed miliary pattern in the chest with bilateral adrenal masses. On the basis of clinical and radiological findings, the case was initially diagnosed as disseminated tuberculosis and anti tubercular treatment was started. Subsequently, on histopathological examination, the diagnosis was confirmed as disseminated cryptococcosis. Even in a country with high prevalence of tuberculosis, other causes of miliary mottling should be considered and histopathological examination should be sought. PMID- 26023584 TI - Nafcillin implicated in a case of cutaneous and gastrointestinal leukocytoclastic vasculitis. AB - Leukocytoclastic vasculitis (LV) is a rare hypersensitive reaction involving the small vessels, which is usually mediated by drugs. Very few cases of nafcillin associated LV have been reported. Here, we reported a case of LV with the presentation of skin rashes and gastrointestinal bleeding after receiving nafcillin, evidenced by endoscopy and skin biopsy. The symptoms resolved after withdrawal of nafcillin and the addition of prednisone treatment. LV should be considered in the differential diagnosis of erythematous rash, especially with gastrointestinal symptoms after the exposure. PMID- 26023585 TI - Posterior reversible encephelopathy syndrome presenting as quadriparesis in pregnancy induced hypertension. AB - Pregnancy Induced Hypertension (PIH) is a condition characterised by raised blood pressure in pregnancy. It affects approximately one out of every 14 pregnant women. Although PIH more commonly occurs during first pregnancy, it can also occur in subsequent pregnancies. It can present with variable complications related to vasospasm. But focal neurologic deficits are extremely rare in patients with PIH. We report a case of quadriparesis due to posterior reversible encephalopathy syndrome (PRES). A 36 year old full term pregnant female was admitted for emergency lower segment caesarean section (LSCS) as a result of uncontrolled PIH with early clinical signs of left ventricular failure. She was recovering well from pulmonary oedema after being provided with mechanical ventilation. However on 4th day she developed sudden onset quadriparesis without any alteration in sensorium, bladder & bowel disturbance or any sensory deficit. Diffusion weighted neuroimaging (DWI) was carried out which revealed finding suggestive of PRES. The patient was treated with antihypertensive which followed improvement in neurological deficit. Although rare, PRES should be considered as a potential cause of acute onset focal neurological deficit in pregnant females with PIH. With this case report we have tried to create awareness and vigilance about rare but potentially serious yet salvageable condition like PRES. PMID- 26023586 TI - Role of IL-25 in Immunity. AB - IL-25 a 2o KDa protein mostly known as IL-17E, encoded by chromosome 14, and containing 117 amino acids. Cytokine IL-17 family consists of 6 members; IL-17A to IL-17F, among which IL-25 has a unique structure and function. The receptor of IL-25 (IL-17BR) is highly expressed in the main Th2 cells. IL-25 regulates the internal safety of adaptive immune responses which leads to begin allergic diseases and plays a role in stimulation of pulmonary mucosal cells and fibroblasts. IL-25 can also have some effects on production of other cytokines. For instance, production of IL-25 in human and mice or injection of IL-25 to animals has resulted in production of high concentrations of Th2 cytokines, including IL-4, IL-5, and IL-13. Pilot studies have shown that mRNA of IL-25 has a high expression in Th2 cells. However, the mechanism through which IL-25 leads to Th2 immune response is still unknown. Reaction between IL-25 and IL-17BR leads to activation of transcription factors, such as NF-KB, STAT6, GATA3, NF-ATC1, JUNNB, MAPK, and JNK. IL-25 has been used against the kidney damage in mice. A large number of researchers in various countries, including the U.S. and Taiwan, have stated that IL-25 is a strong inflammatory cytokine protein which is involved in allergic inflammations. PMID- 26023587 TI - Olfactory Agenesis in Kallmann Syndrome (KS). PMID- 26023588 TI - Endobronchial Foreign Body (FB): A Rare Cause of Empyema. PMID- 26023589 TI - A comparative study of colostrum dressing versus conventional dressing in deep wounds. AB - INTRODUCTION: Deep wounds are extending deeper, across deep fascia into muscles or deeper structures. Understanding of nutrition, immunology, psychological issues, the physiology and the metabolic interactions require for optimal treatment of deep wounds. Wound dressing plays one of the important roles in wound healing. Newer type of wound dressings - Biological dressings like colostrum powder, collagen granules create the physiological interface between the wound surface and environment which is impermeable to bacteria. AIM: To compare the efficacy and safety of colostrum dressing and conventional dressing in deep wounds. MATERIALS AND METHODS: Data was collected from all patients with deep wounds (stage II-IV), admitted during the period of April 2013 to March 2014, considering the inclusion and exclusion criteria. RESULTS: Less number of dressings, short healing time, rapid healing and decrease pain seen in colostrum dressing group compared to conventional dressing group. CONCLUSION: Colostrum powder dressings are safe, promoter of wound healing, more patient compliance in terms of less pain, less number of dressing required. This treatment though found to be more expensive than conventional dressings; results indicate that colostrum powder dressings may be used as an adjunct in management of deep wound. PMID- 26023590 TI - Total acquired vulval synechia: an unusual presentation. AB - An unusual case of Acquired Total vulval synechia due to vulvar Lichen planus is reported in an 18-year-old girl, which is an extremely rare condition. It has a potential for producing extensive scarring and narrowing of introitus resulting in dyspareunia and rarely carcinoma of vulva. Successful surgical management of total vulvar synechiae in patient suffering from Lichen Planus is being reported. PMID- 26023591 TI - Left Sided Hydro-pneumothorax in a Operated Case of Left Diaphragmatic Hernia Repair: A Diagnostic Dilemma. AB - Diaphragmatic hernia in adults often presents with overlapping respiratory and abdominal symptoms. They may be simple diaphragmatic eventrations or undiagnosed Bochdalek's hernias or may even be of post traumatic variety. Diaphragmatic hernias may be asymptomatic, present only with respiratory symptoms, or may present with obstruction and strangulation of involved bowel loops with faeco pneumothorax. The index case was operated for open diaphragmatic hernia repair six years back and admitted for breathlessness with absence of abdominal signs and symptoms. Patient subsequently developed hydro-pneumothorax during conservative management. Emergency laparotomy revealed a gastric ulcer which perforated into the left chest giving rise to hydro-pneumothorax. In present study we would like to report how this unusual presentation led to dilemma in diagnosis and surgical intervention thus increasing the morbidity and mortality of the patient at our institute. PMID- 26023592 TI - Gastro pleural fistula: a rare entity presenting as a complication of empyema thoracis following stab injury to the chest. AB - Gastro pleural fistula is an infrequently seen lesion. Here, a case of stab injury to the chest that led to the formation of a gastro pleural fistula has been presented. An intercostal drainage (ICD) tube was inserted after haemothorax was identified on this chest X-ray. The patient noticed the presence of ingested food particles at the site of ICD tube twelve days following the stab injury. The diagnosis of gastro pleural fistula was subsequently confirmed after a contrast enhanced computed tomography (CECT) of the chest and abdomen. Intraoperatively, a defect in the left hemi diaphragm with a fistulous tract between stomach and the left pleural cavity was identified. Closure of the gastric fundal perforation, excision of the fistulous tract and repair of the diaphragmatic defect was done. PMID- 26023593 TI - Secondary Spontaneous Pneumothorax (SSP) with Bronchopleural Fistula in A Patient with COPD. AB - The aim of this article is to report a case of secondary spontaneous pneumothorax (SSP) with bronchopleural fistula in a patient with chronic obstructive pulmonary disease (COPD). SSP is a common life threatening complication in a patient with COPD and usually creates confusion in the mind of the treating physician during an episode of acute exacerbation of COPD. A 52-year-old male presented with a three day history of dry cough and breathing difficulty. He had a history of COPD. A large pneumothorax on the left side was confirmed after chest X-ray. Tube thoracostomy was performed which showed a persistent air-leak suggesting a bronchopleural fistula. The patient was treated conservatively with patience and the leak sealed spontaneously. The patient recovered uneventfully. This case emphasizes that SSP should be considered in the differential diagnosis of patients having a history of long-term COPD who are in a relatively stable condition with non- critical respiratory distress and the importance of conducting a chest X-ray along with repeated clinical examination in a patient of COPD who does not improve with adequate therapy. PMID- 26023594 TI - Congenital interparietal encephalocele: a case report. AB - Encephalocele is a mesodermal defect in the skull bones and duramater. Parietal encephalocele is a rare congenital anomaly of newborn with variable prognostic value. The authors report a case of a very large inter parietal encephalocele with no associated other system malformations. A midline inter parietal encephalocele is much rare, earlier reported cases were posterior parietal in location. Such cases can be successfully operated upon with a very good outcome. A unique case of a 18 day neonate, with swelling over scalp was evaluated by the neurosurgical team and the patient underwent neurosurgery. In planning the strategy for management of encephalocele, one needs to take into consideration the site, size, contents, patency of CSF pathway, neurological status and other associated anomalies. Inspite of such a big encephalocele in an atypical location, excision and repair gave excellent results. PMID- 26023595 TI - A Large Cystic Variant of Gastro-intestinal Stromal Tumour arising from the Jejunum: A Case Report. AB - Gastrointestinal stromal tumours (GISTs) represent a mesenchymal neoplasm arising from the interstitial cells of cajal occurring mainly in the gastrointestinal tract. Here, we present a case of a large GIST arising from the jejunum with cystic presentation unlike the usual presentation as a solid mass. A 50-year-old male patient came with complaint of a painless mobile lump in abdomen of approximately 25 cm in size which had gradually increased over two years. Clinically mesenteric cyst was suspected. Intra-operatively the mass was a 30x25 cm cyst with approximately 2500 ml serous fluid present inside it arising from the anti-mesenteric border of the jejunum, adherent to the jejunum, appendix and the dome of the bladder. The fluid was aspirated and the mass excised along with resection of the involved jejunal segment and appendectomy was done. Diagnosis was confirmed on immunohistochemistry study. Imatinib Mesylate 400 mg OD was started as adjuvant therapy in view of the high risk of metastasis. PMID- 26023596 TI - Giant Cutaneous Horn Overlying A Verruca at an Uncommon Site: Medical Marvel vs Superstitious Dilemma. AB - Cutaneous horn has been a matter of discussion to mankind since time immemorial and a subject of fascination for the layman. There have been instances where certain groups saw it with angst and disgust, with a person having a large cutaneous horn on an exposed area getting a dismal look. We present a case of a 64-year-old man with a giant cutaneous horn over his left gluteal region. Cutaneous horns more commonly present in the sun-exposed areas. In our case it has presented in an uncommon site. The patient had delayed and denied medical treatment due to his superstitious beliefs, after having sought advice from faith healers leading to progression of the disease. This case has been presented for its giant size (rare variety), its location being over the gluteal region (photo protected site) and its benign histopathology suggestive of wart in spite of the giant size. PMID- 26023597 TI - Post Traumatic Delayed Bilateral Facial Nerve Palsy (FNP): Diagnostic Dilemma of Expressionless Face. AB - Bilateral facial nerve palsy [FNP] is a rare condition. Mostly it is idiopathic. Post traumatic bilateral FNP is even more rare and having unique neurosurgical considerations. Post traumatic delayed presentation of bilateral FNP is socially debilitating and also having diagnostic challenge. Due to lack of facial asymmetry as present in unilateral facial paralysis, it is difficult to recognize. We are presenting a case of delayed onset bilateral FNP who developed FNP after 12 days of head injury with a brief discussion of its diagnostic dilemma and management along with literature review. PMID- 26023598 TI - Colovesical fistula: a rare complication of diverticulitis in young male. AB - Herniation of colonic mucosa through the circular muscles at the point of penetration of blood vessels results in diverticuli formation. It is seen most commonly in the large bowel in sigmoid colon. Common complications of diverticular disease are inflammation and bleeding per rectum and rarely fistula formation which are seen mostly in elderly patients. A case of colovesical fistula with diverticulitis in young male aged 30 years is reported. PMID- 26023599 TI - Cecal volvulus-a diagnostic challenge. PMID- 26023600 TI - Feto-maternal Outcome Using New Screening Criteria of Serum TSH for Diagnosing Hypothyroidism in Pregnancy. AB - INTRODUCTION: Evidence suggests that by using the classical non pregnant reference range for serum TSH (STSH), one might miss hypothyroidism in pregnancy. Therefore, upper normal cut off value of S TSH should be taken as <2.5 mIU/L in the first trimester and <3mIU/L in the second and third trimester. However, two Indian studies have reported higher trimester specific reference ranges in the Indian pregnant women. OBJECTIVES: To assess the maternal and fetal outcomes using new screening criteria with upper S TSH cut off as >3mIU/L, for diagnosing hypothyroidism in pregnancy. MATERIALS AND METHODS: This study was a cross sectional study, carried out in the Department of Obstetrics and Gynaecology of a tertiary care hospital, in collaboration with the Department of Endocrinology. Pregnant women with <= 20 weeks gestation, attending antenatal OPD from December 2010 to January 2012 were included in the study. On the basis of S TSH level, women were divided into Study Group with S TSH level between 3.1 to 6.2 mIU/L, (new range to be studied) and an equal number of age and parity matched Control Group with S TSH levels between 0.4 to 3 mIU/L. The maternal and fetal outcomes were compared between study and control groups. RESULTS: During the study period, a total of 66 women had S TSH between 3.1-6.2 mIU/L. Maternal and fetal outcomes in both the groups were comparable. There was no difference in the mode of delivery between study and control groups. CONCLUSION: The lower S TSH cut off recommended for diagnosing hypothyroidism in pregnancy may not be applicable to pregnant Indian women. PMID- 26023601 TI - Comparative effect of cinnamon and Ibuprofen for treatment of primary dysmenorrhea: a randomized double-blind clinical trial. AB - BACKGROUND AND AIMS: Primary dysmenorrheal has a negative impact on women's quality of life. The purpose of this study was to compare the effect of Cinnamon and Ibuprofen for treatment of primary dysmenorrheal in a sample of Iranian female college students from Ilam University of Medical Sciences (western Iran). MATERIALS AND METHODS: In a randomized, double-blind trial, out of 114, control group received placebo (empty capsules contain starch, TDS, n= 38) a test group received Ibuprofen (capsule containing 400mg Ibuprofen, TDS, n=38), or another test group received Cinnamon (capsule containing 420 mg Cinnamon, TDS, n= 38) in 24 h. To determine severity of pain, we used the VAS scale. Pain intensity and duration of pain were monitored in the group during first 72 h of cycle. RESULTS: The mean pain severity score and mean duration of pain in Ibuprofen and Cinnamon were less than placebo group respectively (p< 0.001). Of 4 hours after the intervention there were no statistically significant differences between the Cinnamon and placebo group (p> 0.05). Of eight hours after the intervention, the mean pain severity in the cinnamon group was significantly lower than placebo group (p< 0.001). At various time intervals the mean pain severity in the Ibuprofen group were significantly less than Cinnamon and placebo groups (p< 0.001). CONCLUSION: Cinnamon compared with placebo significantly reduced the severity and duration of pain during menstruation, but this effect was lower compared with Ibuprofen. Cinnamon can be regarded as a safe and effective treatment for primary dysmenorrhea. More researches are recommended to study the efficacy of Cinnamon on reducing menstrual bleeding. PMID- 26023603 TI - Quadruplet pregnancy following spontaneous conception: a rare case report. AB - Quadruplets are a set of four offspring born at one birth which can be fraternal (multizygotic), identical (monozygotic) or a combination of both. Multizygotic quadruplets occur from fertilisation of four different sets of ovum and sperm. Monozygotic multiples are the result of a fertilized egg that splits into two or more embryos. Multizygotic quadruplets can be all male, all female, or a combination of both while monozygotic quadruplets will always be of the same gender. Here we present a case of 32-year-old G4P3L0 with previous history of three term intrauterine foetal death (IUFD) at 27 wk of gestation. After evaluation, she was found to carry three live foetuses with an IUFD. She was managed conservatively till 35 wk of gestation with regular monitoring of coagulation parameters. Elective caesarean section was done at 35 wk and three live female babies and one male still born were delivered. This case is unique due to the fact that our patient conceived a multizygotic quadruplet pregnancy spontaneously following a bad obstetric history (3 previous term intrauterine fetal deaths). One fetus died in utero and the pregnancy continued successfully resulting in 3 live born healthy babies. PMID- 26023602 TI - Role of 3D Ultrasound and Doppler in Differentiating Clinically Suspected Cases of Leiomyoma and Adenomyosis of Uterus. AB - INTRODUCTION: Adenomyosis and Leiomyoma are common disorders affecting females in their reproductive age. They mimic each other in clinical presentation. Due to similarities in clinical symptoms and signs, missing one diagnosis in favour of the other is not very uncommon. Accurate diagnosis of these two conditions is important for their management. In this study we evaluated role of 3D Ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus. MATERIALS AND METHODS: A total of 100 patients with symptoms of abnormal uterine bleeding (with or without dysmenorrhoea), lump abdomen, chronic pelvic pain or dysparaunia who were clinically diagnosed as leiomyoma of uterus and/or adenomyosis were enrolled in to the study. These patients underwent transvaginal sonography (TVS), trans abdominal sonography (TAS) along with color and spectral Doppler sonography. Scanning was done in follicular phase of the menstrual cycle to avoid bias due high vascularity of endometrium in secretory phase. The morphology of the lesion, its vascularity, and Pulsality Index (PI), Resistive Index (RI) and Vmax (maximum velocity) were measured. Only those patients who were chosen for operative treatment were included in the study. Radiological diagnosis was then correlated with intra operative and histopathological diagnosis. RESULTS: On imaging, while using morphological criteria and Doppler for diagnosing leiomyoma, it was found that "peripheral vascularity" was seen in 52 (89%) cases, which was the highest. Similarly while diagnosing adenomyosis it was, the criteria "central vascularity" was seen in 28 cases (93%) and "ill defined junctional zone in 3D ultrasound" was seen in 26 cases (86%), which was also observed to be highest. With the cut off values taken for PI,RI and Vmax, diagnosis of leiomyoma was found to be 93.4% sensitive, 95.6% specific and with a positive predictive value of 97.6% and negative predictive value of 88.6%. Diagnosis of adenomyosis showed a sensitivity of 95.6%, specificity of 93.4% and a positive predictive value of 88.6% and negative predictive value of 97.6%. Imaging dignosed the co-existence of both the conditions correctly in 8 (66%) cases. CONCLUSION: The parameters of blood flow impedance (that is PI, RI, and Vmax) of arteries within or around the uterine lesions revealed a consistent and significant difference between leiomyoma and adenomyosis. So apart from morphological criteria used in 3D TAS and TVS, aid of color Doppler can more accurately differentiate and diagnose these conditions. PMID- 26023604 TI - Placenta Percreta in First Trimester Leading to Disseminated Intravascular Coagulopathy (DIC): A Rare Case Report. AB - Placenta percreta is the most severe form of abnormal placental attachment. It is a variant of placenta accreta in which chorionic villi penetrate the entire thickness of the myometrium through the uterine serosa and may involve the adjacent structures. Literature review shows very few cases encountered during the first trimester of pregnancy. A-20-year-old woman with previous one cesarean section presented with continuous vaginal bleeding beginning after incomplete abortion at seven weeks and six days period of gestation for which she underwent dilatation and curettage. MRI revealed irregular heterogeneous signal intensity mass with large area of hemorrhage in lower anterior wall extending towards the endometrial cavity suggestive of morbid adherent placenta. Following continuous bleeding after repeated curettage for retained, adherent placenta her coagulation profile got deranged and DIC developed. Correction of coagulopathy and emergency hysterectomy as a life saving measure for placenta percreta was done in our case. PMID- 26023605 TI - Is interstitial pregnancy clinically different from cornual pregnancy? A case report. AB - Interstitial pregnancy is a rare form of ectopic pregnancy with significant risk for morbidity. A 32-year-old woman, was brought to the emergency department with severe abdominal pain and syncope. There was no history of menolipsis and usage of any contraceptive methods. Serum beta hCG arrival was 11224 IU/L. Trans vaginal ultrasound scan showed an empty uterus with a displaced 16 * 26 mm gestation sac on the left corn of the uterine cavity which surrounded by a thin myometrium. Free abdominal fluid and coagulum were also detected in the cul-de sac. She was haemodynamically unstable. A ruptured ectopic pregnancy was diagnosed in the left uterine cornu during emergency laparotomy. Cornual resection was performed. Interstitial and cornual pregnancies should be considered as two different clinical situations. It is important to enhance the clinician's suspicion about interstitial/cornual pregnancy. Thus, more detailed examination by transvaginal ultrasonography may contribute for accurate localization and diagnosis. PMID- 26023606 TI - Endometrial osseous metaplasia-a rare presentation of polymenorrhagia: a case report. AB - Endometrial ossification is a rare entity in which bones are found in the uterus. Exact aetiopathogenesis is not known but the most accepted theory is metaplasia of stromal cells into osteoblast cells result in the formation of bones. The possibility of malignant mixed mullerian tumour should be in the mind of clinician and pathologist while making diagnosis. We hereby report an extremely rare case, which is among very few reported cases in the world, in which endometrial ossification presented in a perimenopausal female with polymenorrhagia. A 41-year-old multiparous patient presented with irregular bleeding per vaginum for the past two years. She was found to be a case of endometrial calcification with osseous metaplasia with presence of bones varying from 7mm - 1.5 cms size in the uterine cavity. She was successfully managed by total abdominal hysterectomy. PMID- 26023607 TI - Lippes Loop Inserted 45 Years Back: The Dilemma to Remove It or Leave It in situ. A Case Report with Review of Literature. AB - IUD's like Lippes Loop (LL), intended for long term use are retained for years and menopausal ladies often present with LL in situ either deliberately or forgotten. We report a case of Lippes Loop removal inserted 45 years back in a woman complaining of post menopausal bleeding. The inserted LL thread was incidentally discovered during clinical examination and Ultrasonography. We also reviewed literature to determine the evidence for and against removal of an inert IUD. PMID- 26023608 TI - Ovarian struma - report of a rare case. PMID- 26023609 TI - Diagnostic dilemma in ovarian pregnancy: a case series. AB - Ovarian pregnancy is a rare form of ectopic pregnancy but it is the most common type of nontubal ectopic pregnancy. Many times it is operated with a misdiagnosis of ruptured tubal ectopic pregnancy or hemorrhagic corpus luteum. The high resolution transvaginal ultrasonography is a valuable tool for diagnosis of ectopic pregnancy but ovarian pregnancy still remains a diagnostic problem and a continuous challenge to the gynecologist. The correct diagnosis is made at the time of surgery and confirmation is by histopathological report. Here we report three cases of primary ovarian ectopic pregnancies, consistent with the Spiegelberg's criteria. Out of this, two cases have corroboration of ovarian ectopic pregnancy with use of intrauterine contraceptive device and one case by chance without any preexisting risk factors, probably due to interference in the release of ovum from the follicle. In all the three cases, emergency laparotomy was done for ruptured tubal ectopic pregnancy and the diagnosis of ruptured primary ovarian pregnancy was made at the time of surgery, this was subsequently confirmed by histopathology report. In the era where wider usage of intrauterine devices, ovulatory drugs and assisted reproductive techniques are rife, there is a possibility of an increase in the incidence of this rare entity, so ovarian ectopic pregnancy should be kept in mind as a possibility. Thereby early diagnosis by high resolution transvaginal ultrasound and laparoscopy can decrease the risk of complications like rupture, secondary implantation, hemorrhagic shock and maternal mortality. PMID- 26023610 TI - Comparison between external rotation method and milch method for reduction of acute anterior dislocation of shoulder. AB - BACKGROUND: Anterior dislocation of shoulder account for more than 50% of dislocation that occur in our body. Several methods of reduction are described in literature which are painful or require anaesthesia. AIM: This study was undertaken to compare the External Rotation Method and Milch method for reduction of anterior dislocation of shoulder. MATERIALS AND METHODS: There were total 52 patients with anterior dislocation of shoulder, distributed randomly into 2 groups. Reduction was done by External Rotation Method and Milch Method for each group and their outcome were compared. STATISTICAL ANALYSIS: The data was analysed by using SPSS for Windows (version 16.0) by applying the Chi-Square test. p-values of <0.05 was considered as significant. RESULTS: Among each group of 26 patients, three patients required anaesthesia in External Rotation Method and eight patients required anaesthesia in Milch Method. There was no statistically significant difference in success rate between external rotation (88.46%) and Milch (69.23%) methods of reduction (p=0.09). CONCLUSION: Both methods of reduction can be used for reduction of anterior dislocation of shoulder without anaesthesia but external rotation method was found to be easier and less painful. PMID- 26023611 TI - Bilateral distal radius fracture in third trimester of pregnancy with accelerated union: a rare case report. AB - Bilateral distal radius fracture is a rare entity. There is no literature reporting a bilateral distal radius fracture in pregnancy. Fracture healing is influenced by hormones. Hormonal changes of pregnancy will affect the healing of a fracture. A 28-year-old female at 34 wk of pregnancy sustained a bilateral distal radius fracture after a self fall. One side was managed conservatively and open reduction was done for the other side. Both fractures united at four weeks. This case is unique in three ways. First distal radius fractures commonly occur in elderly postmenopausal females due to oestrogen deficiency. In this case a distal radius fracture occurred following a self fall in third trimester of pregnancy - a hyperestrogenic state. Second the time taken for union was only four weeks signifying the hormonal effects on pregnancy on fracture healing. Third the occurrence of bilateral distal radius fracture itself is very rare in adults. In pregnancy there is a faster rate of fracture healing due to effects of oestrogen and increased cardiac output. Fractures in pregnancy require special attention. Surgical intervention should be done with a multidisciplinary approach. While management of fractures in pregnancy, effect of hormonal and physiological changes should be kept in mind. PMID- 26023612 TI - Fracture of the medial tibial sesamoid bone of the foot-case report. AB - The sesamoid bone ligament complex of foot contains two sesamoid bones one medial tibial sesamoid and other lateral fibular sesamoid bone, both embedded in the plantar ligament beneath first metatarsal head. The incidence of medial tibial sesamoid bone fracture is rare. Clinically they are often misdiagnosed as soft tissue injuries and often missed. We present a case of fracture medial tibial sesamoid bone in a young athlete who was diagnosed radiologically and treated conservatively with activity restriction and foot wear modification. Our case draws attention to this easily treatable fracture and outlines the investigative modalities in diagnosing this fracture. PMID- 26023613 TI - Grade-III Paraplegia in Spinal Tuberculosis. PMID- 26023614 TI - Absence of Nails, Deaf-mutism, Seizures, and Intellectual Disability: A Case Report. AB - Seizures coexists in children with intellectual disability and are often attributed to neural dysfunction associated with it. Often a careful clinical examination will unravel many diagnostic pointers as in this 8-year-old child with global development delay, deaf-mutism and moderate intellectual disability (mental retardation) who presented with seizures in the emergency department. General examination revealed dysmorphic features like anonychia, low set ears, long philtrum, large lower lips and abnormal dermatoglyphics with features of osteodystrophy on radiology. She was diagnosed as a case of DOORS syndrome, an extremely rare genetic condition affecting the TCA cycle, with just over 40 cases reported, worldwide till date, since its first description in 1961. Her genetic analysis did not reveal the common TBC1D24 mutation in 16p13.3 resulting often from substitutions affecting the arginine at position 242, in spite of all classical clinical features associated with it, suggesting genetic heterogeneity in DOORS syndrome. Though four year follow-up revealed changes in seizure pattern, there was no optic atrophy, change in IQ or peripheral nerve problem. This probably suggests that children with typical clinical features and TBC1D24 mutations may have more progressive deterioration than those without it and newer molecular techniques may identify unexplained phenotypic expressions. PMID- 26023615 TI - Conservative management of a large neonatal ovarian cyst: a case report. AB - We describe a case of a large simple neonatal ovarian cyst, which was managed successfully using "wait and watch" approach and serial ultrasound monitoring. A cystic lesion arising from right ovary was noted in antenatal ultrasound (USG) which was followed up with postnatal USG which revealed a large simple ovarian cyst without any complications. Patient was kept on expectant management with close clinical and USG monitoring. Cyst resolved spontaneously at 10 wk of age. A brief review of literature for likely aetio-pathogenesis and management is also presented. PMID- 26023616 TI - Role of ultraosonography in grading of penile fractures. AB - INTRODUCTION: Penile fracture is an uncommon and less reported condition. Early diagnosis with corrective measures is the order of the day. AIM: To perform ultrasonography of penis and to understand its role in making correct diagnosis of fractures. To know how it will help surgeon in its management and in adopting a grading system. MATERIALS AND METHODS: Emergency evaluation of 15 cases of penile fractures by ultrasonography before surgery. Entire penis was scanned all along its length and circumference. Tunica albugenia was seen as white covering of both corpora cavernosa and break in its continuity is seen as wedge shape defect. Hematoma on either sides of tunica was well appreciated. RESULTS: After ultrasonography all patients underwent emergency surgery, the defect in corpora was well appreciated. Repair of tunica albugenia was done which confirmed our findings. CONCLUSION: Ultrasonography is the modality of choice for quick diagnosis, and no other radiological workup is required before surgery. PMID- 26023617 TI - MRI evaluation of lumbar disc degenerative disease. AB - INTRODUCTION: Lower back pain secondary to degenerative disc disease is a condition that affects young to middle-aged persons with peak incidence at approximately 40 y. MRI is the standard imaging modality for detecting disc pathology due to its advantage of lack of radiation, multiplanar imaging capability, excellent spinal soft-tissue contrast and precise localization of intervertebral discs changes. AIMS AND OBJECTIVE: To evaluate the characterization, extent, and changes associated with the degenerative lumbar disc disease by Magnetic Resonance Imaging. STUDY DESIGN: Cross-sectional and observational study. MATERIALS AND METHODS: A total 109 patients of the lumbar disc degeneration with age group between 17 to 80 y were diagnosed & studied on 1.5 Tesla Magnetic Resonance Imaging machine. MRI findings like lumbar lordosis, Schmorl's nodes, decreased disc height, disc annular tear, disc herniation, disc bulge, disc protrusion and disc extrusion were observed. Narrowing of the spinal canal, lateral recess and neural foramen with compression of nerve roots observed. Ligamentum flavum thickening and facetal arthropathy was observed. RESULT: Males were more commonly affected in Degenerative Spinal Disease & most of the patients show loss of lumbar lordosis. Decreased disc height was common at L5-S1 level. More than one disc involvement was seen per person. L4 - L5 disc was the most commonly involved. Annular disc tear, disc herniation, disc extrusion, narrowing of spinal canal, narrowing of lateral recess, compression of neural foramen, ligamentum flavum thickening and facetal arthropathy was common at the L4 -L5 disc level. Disc buldge was common at L3 - L4 & L4 - L5 disc level. Posterior osteophytes are common at L3 - L4 & L5 -S1 disc level. L1- L2 disc involvement and spondylolisthesis are less common. CONCLUSION: Lumbar disc degeneration is the most common cause of low back pain. Plain radiograph can be helpful in visualizing gross anatomic changes in the intervertebral disc. But, MRI is the standard imaging modality for detecting disc pathology due to its advantage of lack of radiation, multiplanar imaging capability, excellent spinal soft-tissue contrast and precise localization of intervertebral discs changes. PMID- 26023618 TI - Multi-detector computed tomography in evaluating locally aggressive and malignant bone tumours. AB - OBJECTIVE: To evaluate the ability of Multi-Detector Computed Tomography in preoperative evaluation of locally aggressive and malignant bone tumours in correlation with histopathological findings. MATERIALS AND METHODS: Twenty patients suspected of malignant bone tumours on the basis of their clinical profile were selected. Following a plain radiograph evaluation, all of them were subjected to CT scan examination. Multi Planar Reconstruction (MPR) was done in sagittal and coronal planes and also three-dimensional Volume Rendering (VR) and Maximum Intensity Projection (MIP) images were obtained. RESULTS: Of the 20 patients, 18 underwent surgery, and their histopathological findings were compared and correlated with MDCT findings. MDCT was 92.8% sensitive and 100% specific in determining the vascularity of the tumour and also can detect displacement/ encasement/ involvement of adjacent vessels. It has a sensitivity and specificity of 100% in determining cortical break, calcification and periosteal reaction. However, it is less sensitive in detecting joint involvement. Post contrast enhancement gives details of the extent of the soft tissue component. CONCLUSION: Although MRI is a preferred modality in preoperative evaluation of bone tumours, CT may be used an alternative in case of non-availability of MRI, which has faster acquisition time and better resolution. Using three dimensional MPR imaging, the location and extent of the tumour can be studied. It is also useful in determining cortical discontinuity, periosteal reaction, and calcification. By virtue of MIP and VR imaging, vascularity of the tumour and its relationship with the adjacent vasculature can be established. However, it is inferior to MRI in soft tissue characterization and has poor sensitivity in detecting marrow and joint involvement. PMID- 26023620 TI - Morel-Lavallee Lesion (MLL) Mimicking A Soft Tissue Neoplasm. AB - Morel-lavallee lesion (MLL) represents post traumatic subcutaneous cyst generally overlying bony prominences like greater trochanter, lower back, knee and scapula. A 51-year-old man presented with a swelling in left thigh since six years which was insidious in onset, gradually progressive in size and not associated with pain, fever or discharge. There was no history of trauma or any associated constitutional symptoms. Since there was no history of trauma recalled by the patient the clinical dilemma was between soft tissue sarcoma and cold abscess. We report a case of slow growing painless mass lesion of thigh, diagnosed on Magnetic Resonance Imaging (MRI) as morel lavallee lesion and describe its salient imaging features with treatment options. PMID- 26023619 TI - Role of CT Colonography in Colonic Lesions and Its Correlation with Conventional Colonoscopic Findings. AB - BACKGROUND: Preoperative evaluation in patients with colorectal carcinoma is essential for a correct therapeutic plan. Conventional colonoscopy has certain limitations including its inability to detect synchronous lesions in case of distal obstructive mass and inaccurate tumour localization. CT colonography combines cross sectional imaging with virtual colonoscopic images and offers a comprehensive preoperative evaluation in patients with colorectal carcinoma including detection of synchronous lesions with accurate segmental localization and loco regional staging. AIM: The objective was to determine the role of CT colonography in various colonic lesions and to correlate the findings with conventional colonoscopy and histopathological findings. SETTINGS AND DESIGN: This prospective study included 50 patients with clinical symptoms suspicious of colonic pathology. MATERIALS AND METHODS: All the patients underwent both CT colonography and conventional colonoscopy on the same day. CT colonography was performed in supine and prone position. Considering histopathological and/or surgical findings as gold standard, sensitivity and specificity of both the modalities were calculated. RESULTS: Conventional colonoscopy missed two synchronous lesions proximal to occlusive mass and one lesion proximal to the anastomotic site; all were detected with CT colonography. One carpet lesion in rectum and one case of mild ulcerative colitis were missed by CT colonography. Sensitivity and specificity for detection of colorectal cancer were 97.56% and 100%, resp. with PPV and NPV of 100% and 93.75%, for CT colonography and 92.68% and 100%, respectively with PPV and NPV of 100% and 83.3% for conventional colonoscopy. Sensitivity for correct detection of acute and chronic ulcerative colitis of CT colonography was 66.6 % and 100 %, resp. CONCLUSION: CT colonography has higher sensitivity than conventional colonoscopy for detection of colorectal carcinoma, including its ability to detect abnormalities proximal to obstructing lesion, accurate segmental localization of lesions and staging. However, some limitations of CT colonography were difficulty in detection of flat lesions and lack of information about hyperemia and superficial mucosal erosion, where conventional colonoscopy scored over CT colonography. PMID- 26023621 TI - An infant with nasal regurgitation since birth and failure to thrive. AB - The condition achalasia cardia is rare in paediatric age group, especially in infants. An 11-month-old female infant presented with complaints of oronasal regurgitation since birth and failure to thrive. Upper GI contrast study was conducted which demonstrated massive dilatation of lower 2/3(rd) of oesophagus with abrupt narrowing at lower oesophageal sphincter and positive 'bird beak sign'. On the basis of radiological findings infantile achalasia cardia was diagnosed and patient underwent modified Heller's Oesophagocardiomyotomy with anti reflux procedure. Post operatively the symptoms subsided and weight gain was noted after six month follow up. Although functional infant regurgitation and Gastro-oesophageal reflux (GER) is common in infancy, uncommon causes like achalasia cardia should also be considered as a differential when symptoms are persisting. PMID- 26023622 TI - An early and rare second malignancy in a treated glioblastoma multiforme: is it radiation or temozolomide? AB - Glioblastoma Multiforme (GBM) is a high-grade brain tumour with the most dismal prognosis. There are very few reports on second malignancies occurring in GBM patients, as the survival has been short. Second malignancies have been reported after treatment of malignancies with radiation therapy and chemotherapy especially after 5 to 10 y of treatment. Here in, we present a very unique case where a patient succumbed to sinonasal carcinoma occurring one and half years after treatment of GBM. A 17-year-old boy was diagnosed to have GBM and underwent surgery followed by chemoradiation and adjuvant chemotherapy with Temozolamide. He presented with undifferentiated sinonasal carcinoma, in the sinonasal region outside the radiation field within two years of treatment. Here we discuss the histology and possible chances of it being a second malignancy. PMID- 26023623 TI - Case of cerebral venous thrombosis with unusual venous infarcts. AB - Cerebral venous thrombosis is a relatively rare condition when compared with vascular accidents of arterial origin representing 0.5-1% of all strokes. Unlike arterial infarcts parenchymal changes are seldom present and when present most of the times are reversible. We present a case report of 28-year-old female with thrombosis of internal cerebral veins and straight sinus and hemorrhagic infarcts in bilateral basal ganglia and bilateral thalami .The findings of bilateral symmetrical hyper intensities in basal ganglia and thalami on MRI may be due to various causes of diverse etiology and cerebral venous thrombosis remains an important cause. Early recognition and prompt anticoagulation therapy helps to reduce the mortality to a great extent. The MRI imaging features of straight sinus thrombosis and other imaging differentials are discussed. PMID- 26023624 TI - A rare case of prenatally detected craniopagus twin. PMID- 26023625 TI - Intraoperative BiPAP in OSA Patients. AB - Obstructive sleep apnea syndrome (OSA) is characterized by recurrent episodes of partial or complete upper airway obstructions during sleep. Severe OSA presents with a number of challenges to the anesthesiologist, the most life threatening being loss of the airway. We are reporting a case where we successfully used intraoperative bi level positive pressure ventilation (BiPAP) with moderate sedation and a regional technique in a patient with severe OSA posted for total knee replacement (TKR). A 55-year-old lady with osteoarthritis of right knee joint was posted for total knee replacement. She had severe OSA with an apnea hypopnea index of 35. She also had moderate pulmonary hypertension due to her long standing OSA. We successfully used in her a combined spinal epidural technique with intraoperative BiPAP and sedation. She had no complications intraoperatively or post operatively and was discharged on day 5. Patients with OSA are vulnerable to sedatives, anaesthesia and analgesia which even in small doses can cause complete airway collapse. The problem, with regional techniques is that it requires excellent patient cooperation. We decided to put our patient on intraoperative BiPAP hoping that this would allow us to sedate her adequately for the surgery. As it happened we were able to successfully sedate her with slightly lesser doses of the commonly used sedatives without any episodes of desaturation, snoring or exacerbation of pulmonary hypertension. Many more trials are required before we can conclusively say that intraoperative BiPAP allows us to safely sedate OSA patients but we hope that our case report draws light on this possibility. Planning ahead and having a BiPAP machine available inside the operating may allow us to use sedatives in these patients to keep them comfortable under regional anaesthesia. PMID- 26023626 TI - Valproate Induced Delirium due to Hyperammonemia in a Case of Acute Mania: A Diagnostic Dilemma. AB - Divalproex sodium is commonly used drug to treat variety of psychiatric and neurological disorders. Hyperammonemia is infrequent adverse affect of treatment with divalproex sodium. It needs high degree of clinical suspicion or else can lead to delirium of non hepatic origin in some group of patients and to medication errors or even death. We hereby report a case of mania who developed hyperammonemia with normal sodium valproate levels and liver function tests where delirium lead to diagnostic and medication errors. Withdrawal of divalproex sodium led to clinical recovery but delirium prolonged his hospital stay. This case report cautions the clinicians about hyperammonemia as the uncommon side effects and emphasizes the need of doing blood ammonia testing in patients treated with divalproex sodium where recovery is halted or clinical condition worsens despite normal liver function test and EEG. PMID- 26023627 TI - Ekbom syndrome occurring with multi infarct dementia. AB - Ekbom Syndrome is characterized by delusion that small living being infests skin. The clinical profile of this disorder has shown it to be associated with organic conditions. Neuroimaging studies implicate putamen as the brain structure involved in the pathophysiology. These are also known as organic delusional disorder and provide an opportunity to study biological causation of delusional disorder. We report a patient presented with a complaint of insects crawling on her body for last two years. She collected the peeled skin in a jar and claimed that these are insects. CT scan (brain) revealed multiple infarcts involving basal ganglia. She responded to Risperidone 4 mg daily. PMID- 26023628 TI - Immunoglobulin e, interleukin-18 and interleukin-12 in patients with atopic dermatitis: correlation with disease activity. AB - INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Immunological/inflammatory reactions are reported to play a role in AD but their role in disease activity has not been fully investigated. This study was done to investigate the role of immunoglobulin E (IgE), interleukin (IL)-18 and IL-12 in AD patients with different disease severities. MATERIALS AND METHODS: Sera from 50 AD infants with varying levels of disease activity according to the scoring index of atopic dermatitis (SCORAD) index and 30 age-matched healthy controls were evaluated for serum levels of IgE, IL-18 and IL-12/p40. RESULTS: Serum analysis showed higher levels of IgE, IL-18 or IL-12/p40 in AD patients compared with controls. Interestingly, not only was there an increased number of subjects positive for IgE, IL-18 or IL-12/p40, but also the levels of these parameters were higher among AD patients whose SCORAD scores were higher. In addition, a significant correlation was observed between the levels of these parameters and SCORAD scores. CONCLUSION: These findings support an association between IgE, IL 18 or IL-12/p40 and AD. The stronger response observed in serum samples from patients with higher SCORAD scores suggest that IgE, IL-18 and IL-12/p40 may be useful in evaluating the progression of AD and in elucidating the mechanisms of disease pathogenesis. PMID- 26023629 TI - Mycobacterial infection after cosmetic procedure with botulinum toxin a. AB - We report a case of mycobacterial infection at the sites of previous injections of botulinum toxin A in a 45-year-old woman. She presented with erythematous, swollen, warm, and tender plaques and nodules at the points of injection from which a biopsy was taken, demonstrating a deep dermal and hypodermal abscessified epithelioid granulomatous inflammatory infiltrate in which some acid-fast bacilli were identified with Ziehl-Neelsen and Fite-Faraco stains. The lesion was first treated with clarithromycin plus azithromycin, to which rifampicin was later added. A good therapeutic response was obtained. PMID- 26023630 TI - Primary Non Hodgkin's Lymphoma of Left Adrenal Gland - A Rare Presentation. AB - Primary adrenal lymphoma is rare and constitutes for 3% of extranodal lymphoma cases. Approximately 70% of patients present with bilateral disease and have adrenal insufficiency. Prognosis of primary adrenal lymphoma (PAL) is poor, most of patient die within one year of diagnosis. Moreover, there are no standard treatment protocols on such cases. Patients are generally treated with regimens similar to other nonhodgkin lymphoma which includes surgery, combination chemotherapy and or radiotherapy. We are presenting a successfully treated case of primary diffuse large B cell non Hodgkin lymphoma of adrenal gland in a 57 year-old patient. The patient had unilateral adrenal involvement (left adrenal gland), without adrenal insufficiency and normal Serum lactate dehyrogenase level. The patient was treated with left adrenalectomy followed by combination chemotherapy. Two years after diagnosis and treatment the patient is disease free on clinical and imaging studies. PMID- 26023631 TI - Giant exophytic renal angiomyolipoma mimicking as retroperitoneal sarcoma; a case report with review of literature. PMID- 26023632 TI - Assessment of tooth proportions in an aesthetically acceptable smile. AB - INTRODUCTION: Aesthetic facial animation is mostly reported to be due to a close relationship between soft and hard tissue i.e. dynamic smile with appropriate tooth proportions. But variations in tooth size have been seen among various ethnic populations globally. AIM: To evaluate the size and morphology of maxillary anterior teeth, the tooth with maximum variation both mesiodistally and cervicoincisally. Also, the tooth to tooth ratio in percentage of the mean tooth sizes in both genders in patients with aesthetically acceptable smile decided by a panel in North Indian population. MATERIALS AND METHODS: A total of 100 subjects (50 males and 50 females) were taken and a video clip of their dynamic smile was captured .The smiles were analyzed by a panel and the tooth proportions of the selected attractive smiles were evaluated in both males and females separately. STATISTICAL ANALYSIS: Data obtained was subjected to statistical analysis using Microsoft Excel 2007 software; test used was Unpaired t-test and also Mean +/- S.D., Variance, Ratio of W/L and its ranges were calculated. Significance is assessed at 5% level of significance. RESULTS: The mesiodistal width and cervicoincisal length of maxillary central incisor was greater compared to lateral incisor and canine in both males and females. There was a statistically significant difference between the width/length ratio of maxillary anterior teeth between males and females.Canine and Lateral incisor showed maximum variation mesio-distally and cervico-incisally. CONCLUSION: A smile is more pleasing if the visible teeth are in proper morphological proportions. Thus, it relates that teeth play a vital role in increasing the attractiveness of a smile. The mean coronal width/length ratio displayed a more square like tooth form for both males and females. PMID- 26023633 TI - Salivary Visfatin Concentration in Response to Non-surgical Periodontal Therapy. AB - INTRODUCTION: Visfatin is a pro-inflammatory cytokine that has been associated with several immunomodulating processes. The relationship between visfatin and periodontitis has been the subject of a few studies that have described visfatin as an inflammatory marker for periodontitis. However, studies on visfatin as a potential therapeutic target in periodontal diseases are scarce. In the present study, we evaluated the alterations in salivary visfatin levels in response to non-surgical periodontal treatment. MATERIALS AND METHODS: Twenty individuals with moderate to severe chronic periodontitis and twenty periodontally healthy individuals were selected for this study according to clinical parameters. Patients with chronic periodontitis were treated by non-surgical periodontal therapy. Clinical parameters were recorded and saliva samples were obtained from the control group and test group before (T1 group) and one month after periodontal treatment (T2 group). Salivary visfatin concentrations were measured by standard enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed with the statistical software SPSS, version 18. RESULTS: Visfatin was detectable in all samples. T1 and control groups were significantly different in terms of clinical parameters and visfatin levels. Visfatin concentrations were reduced significantly after non-surgical periodontal therapy. Periodontal treatment also resulted in significant reductions of all clinical parameters with the exception of clinical attachment level. CONCLUSION: The results demonstrated that salivary levels of visfatin are reduced after non-surgical periodontal therapy to the levels comparable with those found in healthy individuals. Therefore, the salivary visfatin level may have the potential to be a target marker for assessment of responses to non-surgical periodontal therapy. However, more studies with larger sample sizes are necessary to validate these findings. PMID- 26023634 TI - Hinged single piece putty index for preclinical demonstration of tooth preparation for fixed partial dentures and crowns. AB - INTRODUCTION: Different types of indices are being used for assessment of tooth preparation. All these indices are used to visualize tooth preparations in a particular plane. A single versatile index which could help to visualize tooth preparations in different planes is non-existent. The need for fabrication of such an index and its reliability is of utmost important to provide quality tooth preparations. PURPOSE: The purpose of the study is to fabricate a hinged single piece sectioned index which could be used to visualize tooth preparation in different planes and check its reliability in-vitro on phantom models. MATERIALS AND METHODS: Ten preclinical students were selected in random for preparing three teeth each. The three teeth preparations are classified as Group A, Group B and Group C based on the non-usage of index, usage of sectioned index and hinged single piece sectioned index respectively. Students were made to do provisional restorations after the tooth preparations. Then a questionnaire was given to students to score the duration/accuracy/comfort during tooth preparation and duration/accuracy of provisional restorations for each of the Groups A,B and C. RESULTS: In Group C, 90% of students found the final preparation to be very accurate. The time taken for fabrication of provisional restoration using sectioned hinged index by 60% of Group C students was 20 to 30 min. CONCLUSION: This hinged index is a viable option when accuracy of tooth preparation and speedy fabrication of provisional restoration is required. PMID- 26023635 TI - Quantification of Selenomonas sputigena in Chronic Periodontitis in Smokers Using 16S rDNA Based PCR Analysis. AB - BACKGROUND AND AIM: Selenomonas species have been associated with chronic periodontitis and have been implicated in converting periodontal health to disease. Scanty literature is available in Indian population. Hence, the objective of the study was to detect the prevalence of Selenomonas sputigena in healthy and chronic periodontitis by polymerase chain reaction (PCR) in Indian population and to check whether smoking affects the subgingival microflora of this organism in chronic periodontitis. MATERIALS AND METHODS: A total of 60 subjects with severe chronic periodontitis with or without smoking and periodontal healthy subjects underwent clinical and microbiological assessment. A deep subgingival plaque sample was collected and genomic DNA was extracted from each sample and analysed for detection of Selnomonas sputigena using PCR. The frequency and quantification of bacteria were also estimated. RESULTS: All groups differed statistically significant in the frequency of detection of Selenomonas sputigena. On comparison of patients with chronic periodontitis in smokers and non-smokers, there was no statistically significant difference. When the results were quantified, statistically non-significant results were seen among all groups. Plaque index, gingival index, probing pocket depth and clinical attachment level were statistically non-significant in chronic periodontitis with smokers and non-smokers. CONCLUSION: Prevalence of Selenomonas sputigena showed significant differences with respect to the frequency of detection when comparing the disease group to the healthy population. But no significant difference was seen when the results were quantified. Smoking has no influence on number of Selenomonas sputigena. This study highlights presence as well as quantity of the organism is very important in elucidating its role in causation and progression of the disease. PMID- 26023636 TI - Effect of Platelet Rich Fibrin (PRF) on Peri-implant Soft Tissue and Crestal Bone in One-Stage Implant Placement: A Randomized Controlled Trial. AB - INTRODUCTION: The viability of Platelet Rich Fibrin (PRF) on enhancement of osseous and associated tissue healing has been substantiated well in literature. However, paucity in the applicability of PRF to enhance peri-implant healing in oral region is not well-corroborated. PURPOSE: This prospective study evaluated the effect of Platelet PRF on peri-implant tissue response following one-stage implant placement with non-functional immediate provisionalization in maxillary anterior region. MATERIALS AND METHODS: A Prospective, Randomized Controlled Trial (RCT) was conducted across 20 (15 male, 5 Female) systemically healthy subjects with maintainable oral hygiene. Subjects were broadly divided into two groups i.e. Study group (PRF group) and Control group (Non-PRF group). Twenty standard SLA- AB/AE (alumina oxide blasted/acid etched surface treated) tapered threaded dental implants were randomly placed with and without PRF and immediately provisionalized. The subjects were evaluated clinically and radiographically at baseline (at time of implant placement), one month and three month post-operatively for peri-implant soft tissue and crestal bone responses. RESULTS: At 3 months, all implants remained osseointegrated. The mean marginal bone changes were observed from baseline to 3 months in both groups with lesser changes observed in PRF Group. No significant differences in probing depth and bleeding on probing were noted during follow-up. CONCLUSION: Within the limitations of this study, PRF could be considered as a healing biomaterial with potential beneficial effect on peri-implant tissue and can be used as a therapeutic adjuvant in clinical scenario of one stage, single tooth implant placement procedure in maxillary anterior region. PMID- 26023637 TI - The Changes in Dentists' Perception and Patient's Acceptance on Amalgam Restoration in Kurdistan-Iraq: A Questionnaire-based Cross-Sectional Study. AB - BACKGROUND: There has been considerable controversy concerning the health risks and benefits of utilizing mercury-containing amalgam. Across the developing countries, a reduction in the use of dental amalgam in oral health care provision is expected. PURPOSE: Assessment of dentists' and patient's attitude of dental amalgam regarding attractiveness, perceived health, and treatment preferences in Kurdistan, Iraq. MATERIALS AND METHODS: A 4-page questionnaire comprised two parts, specific for dentist and patient were structured and delivered to each dentist oneself. Both open-ended and close-ended questions about the treatment needs of patients, uses of amalgam and its alternative, the properties and usefulness of different materials. Patient's acceptance was assessed by means of structured questionnaire prepared based on commonly asked questions from routinely daily practice. Questions on the type of filling material in their mouth, previous knowledge of mercury in dental amalgam and disappointment due to mercury hazard and toxicity. They were to indicate their acceptance with filling their cavities by dental amalgam with or without prior information about its mercury content. This part was also accomplished by the dentists participated in this survey. RESULTS: Out of 185 dentists shared, only 39 (21.1%) indicated that amalgam presents no harm for the dentists and patients. While majority of dentists 85 (45.9%) were uncertain about this issue. Amalgam was selected most often 107 (57.8%) as the material of choice for restoring posterior teeth. About 94(50.8%) and 85(45.9%) of the practitioners primarily used glass ionomer/resin reinforced glass ionomer and composite, respectively. Among 1850 patients received treatment, only 450 (24.32%) claimed to have heard about adverse reactions to dental amalgams. Those who believed it to be safe were 200 (10.82%).Acceptance towards amalgam was 62%. CONCLUSION: While amalgam was the most common material used for posterior restorations, direct tooth-coloured restorative materials were also popular among dentists participated in this study. Awareness of toxicity of mercury in dental amalgam was slightly low among the respondents studied. This may be suggested to be a reflection of devoid of planetary amalgam controversy in Kurdistan. The level of acceptance toward amalgam appears to be related to economics, dental education, and aesthetic orientation of the residents. PMID- 26023638 TI - Comparison of Contamination of Low-Frictional Elastomeric Rings with That of Conventional Elastomeric Rings by Streptococcus mutans - An In-vivo Study. AB - INTRODUCTION: The presence of brackets and ligatures has been shown to be related to an increase in gingival inflammation and increased risk of decalcification. The various measures were taken to reduce the plaque accumulation and also lot of efforts were made by manufacturers that reduced the binding friction between the ligature rings and arch wire that facilitated easy sliding of the tooth through the wire. The low frictional ligatures rings manufactured by different manufacturers presumed to attract fewer bacteria due to greater reduction in surface roughness. Our study aimed to evaluate whether the low frictional elastomeric rings accumulate fewer bacteria than conventional ligature rings. MATERIALS AND METHODS: Thirty patients (15 males and 15 females) who underwent fixed appliance therapy were selected. The study was done using split-mouth design. In each volunteer, synergy low frictional elastomeric rings were tied to brackets bonded to the maxillary premolar on the right side and mandibular premolar on the left side. Conventional elastomeric rings that served as control group were tied to the contralateral teeth, with the same design. Samples were collected after four weeks (28 days) and cultured for bacteria Streptococcus mutans. RESULTS: There was no statistical difference between Streptococcus mutans count in low frictional elastomeric rings with that of conventional rings. CONCLUSION: We concluded that adherence of Streptococcus mutans is similar in both synergy low frictional elastomeric rings and conventional clear elastomeric rings and thus the manufacturer's claim of minimal bacterial adherence was discarded. PMID- 26023639 TI - Evaluation of Single File Systems Reciproc, Oneshape, and WaveOne using Cone Beam Computed Tomography -An In Vitro Study. AB - BACKGROUND: Successful endodontic therapy depends on many factor, one of the most important step in any root canal treatment is root canal preparation. In addition, respecting the original shape of the canal is of the same importance; otherwise, canal aberrations such as transportation will be created. AIM: The purpose of this study is to compare and evaluate Reciprocating WaveOne ,Reciproc and Rotary Oneshape Single File Instrumentation System On Cervical Dentin Thickness, Cross Sectional Area and Canal Transportation on First Mandibular Molar Using Cone Beam Computed Tomography. MATERIALS AND METHODS: Sixty Mandibular First Molars extracted due to periodontal reason was collected from the Department of Oral and Maxillofacial. Teeth were prepared using one rotary and two reciprocating single file system. Teeth were divided into 3 groups 20 teeth in each group. Pre instrumentation and Post instrumentation scans was done and evaluated for three parameters Canal Transportation, Cervical Dentinal Thickness, Cross-sectional Area. Results were analysed statistically using ANOVA, Post-Hoc Tukey analysis. RESULTS: The change in cross-sectional area after filing showed significant difference at 0mm, 1mm, 2mm and 7mm (p<0.001, p =0.006, 0.004 & <0.001 respectively). There was significant difference between wave one and oneshape; oneshape and reciproc at 0mm, 1mm, 2mm & 7mm (p-values for waveone and Oneshape <0.001, 0.022, 0.011 & <0.001 resp. and for oneshape and reciproc < 0.001, p= 0.011, p=0.008 & <0.001). On assessing the transportation of the three file system over a distance of 7 mm (starting from 0mm and then evaluation at 1mm, 2mm, 3mm, 5mm and 7mm), the results showed a significant difference among the file systems at various lengths (p= 0.014, 0.046, 0.004, 0.028, 0.005 & 0.029 respectively). Mean value of cervical dentinal removal is maximum at all the levels for oneshape and minimum for waveone showing the better quality of waveone and reciproc over oneshape file system. Significant difference was found at 9mm, 11mm and 12mm between all the three file systems (p<0.001,< 0.001, <0.001). CONCLUSION: It was concluded that reciprocating motion is better than rotary motion in all the three parameters Canal Transportation, Cross-sectional Area, Cervical Dentinal Thickness. PMID- 26023640 TI - Clinical Evaluation of Success of Primary Teeth Pulpotomy Using Mineral Trioxide Aggregate((r)), Laser and Biodentine(TM)- an In Vivo Study. AB - INTRODUCTION: Pulpotomy technique basically consists of removing the coronal pulp and fixing the radicular pulp with a medicament. It is the most widely accepted clinical procedure for treating primary teeth with coronal pulp inflammation caused by caries with no involvement of the radicular pulp. AIM: To evaluate the success and efficacy of Mineral Trioxide Aggregate (MTA), Lasers and Biodentine as pulpotomy agents both clinically and radiographically. MATERIALS AND METHODS: In the present study, 60 primary molars in children whose pulpal status warranted pulpotomy were selected and randomly assigned into three groups that included MTA, Laser and Biodentine allocating 20 teeth to each group. The pulpotomy procedure was then performed on all selected teeth followed by restoration with stainless steel crowns. Later the patients were recalled for 3 months and 6 months for clinical and radiographic evaluation. RESULTS: Statistical analysis was done using Fisher exact test to determine pair wise comparison of three agents with respect to clinical and radiographic criteria. Kruskal-Wallis ANOVA, Mc Nemars test was applied to evaluate the efficacy of each agent between 3 months and 6 months. The results showed that maximum success rate was found in MTA group. However, the comparison between three groups was statistically not significant (p<0.05). CONCLUSION: Pulpotomies performed with either MTA, Laser or Biodentine are equally efficient with similar clinical/radiographic success and hence can be considered as alternatives to Formocresol. PMID- 26023641 TI - Comparative assessment of sagittal skeletal discrepancy: a cephalometric study. AB - BACKGROUND AND OBJECTIVES: Evaluating the sagittal apical base relationship during orthodontic diagnosis and treatment planning is an important step. This study was aimed at comparison of Beta angle, ANB angle and Wit's appraisal for assessment of sagittal skeletal discrepancy. MATERIALS AND METHODS: Eighty six young adults (43 female and 43 male) were selected from the patient's reporting to Department of Orthodontics, College of Dental Sciences, Davangere, India. Family lineage was studied to know the nativity of Davangere. The standardized pre-treatment lateral cephalogram of the chosen sample was traced. The sample was divided into three skeletal pattern groups: Class I, Class II and Class III, based on the ANB angle and profile, Beta angle was assessed in each group. STATISTICAL ANALYSIS: The data was subjected to statistical analysis student's t test, ANOVA test and correlation and regression analysis, using the software namely SPSS Software version 13. Microsoft word and Excel were used to generate graphs and tables. RESULTS: In the local Davangere population, Class I skeletal pattern group exhibited Beta angle between 26 degrees -34 degrees , Beta angle less than 27 degrees was found in Class II skeletal pattern, and Beta angle greater than 32 degrees was seen Class III skeletal pattern. The coefficient of variation of Beta angle in all the three groups was significantly homogenous compared to ANB angle and Wits appraisal. The correlation and regression analysis of the total sample indicated a highly significant correlation between Beta angle and ANB angle (p<.001), and between Beta angle and Wits appraisal (p<.01). CONCLUSION: Beta angle can be used to classify subjects into different skeletal patterns. The Correlation and regression analysis for the total sample suggests a highly significant relation between Beta angle and ANB angle and, between Beta angle and Wits appraisal. It can be more reliably used to assess sagittal jaw discrepancies than ANB angle and Wits appraisal. PMID- 26023642 TI - Antimicrobial Efficacy of Ten Commercially Available Herbal Dentifrices against Specific Oral Microflora - In Vitro Study. AB - AIM: To determine and compare the antimicrobial efficacy of ten commercially available herbal dentifrices against specific strains of oral microflora using a standard diffusion method at full strength and 1:1 dilution at 24 h. MATERIALS AND METHODS: The standard strains of Streptococcus. mutans (ATCC 21293), Streptococcus sangius (MTCC 442), Actinomyces viscosus (ATCC 3268), Staphylococcus aureus (ATCC 2592), Streptococcus pyogenes (MTCC 442) and Candida albicans (ATCC 183) were obtained. Antimicrobial efficacy of the dentifrices was tested in triplicate, at full strength and 1:1 dilution with the sterile water using a standard diffusion method for 24 h at 37 degrees C. The antimicrobial efficacy was tested by observing the zones of inhibition in millimeters surrounding disk containing the dentifrice. Mean standard deviation and standard error of mean of the inhibitory zones was calculated for each herbal dentifrice. p<0.05 was considered statistically significant. RESULTS: Danth Kanthi (DK) was the most effective against all the microorganisms producing larger zones of inhibition at 24 h (F.S - 40+/-1.5; 1:1 dilution - 40+/-2.71). Amar Premium (AP) also produced larger zones of inhibition against all microorganisms except S. aureus. Of all the dentifrices, least zones of inhibitions i.e., around 5 mm was observed against S. aureus by Amar Premium (AP) and Dabur Babool (DB) at 24 h. CONCLUSION: Based on the results of the present study, it can be concluded that all herbal dentifrices exhibited antimicrobial activity against the selected oral microorganisms, with DK being the most effective. Hence, it can be inferred that herbal dentifrices can also be recommended like the conventional formulations. PMID- 26023643 TI - Bibliometric analysis of journal of clinical and diagnostic research (dentistry section; 2007-2014). AB - BACKGROUND: The role of scientific journals in diffusion of data concerning researches in the field of Public Health Dentistry is of premier importance. Bibliometric analysis involves analysis of publications reflecting the type of research work. AIM: The present study was conducted with an aim to determine the number and trends of published articles in Journal of Clinical and Diagnostic Research (JCDR) from Feb. 2007 to Oct.2014. SETTINGS AND DESIGN: A retrospective observational study was conducted for JCDR. MATERIALS AND METHODS: All issues of JCDR were electronically searched for the parameters : study design, area of interest of research, state /college where research was conducted, authorship pattern, source of articles published each year, changing study trends, disease under study and publication bias. STATISTICAL ANALYSIS USED: The data was organized and analyzed using software SPSS - version 21.0; descriptive statistics was used. RESULTS: Bibliometric analysis was done for 601 articles of JCDR published from Feb. 2007 to Oct. 2014. The total number of articles published under Dentistry section have tremendously increased from mere 2 articles in 2007 to 328 articles in 2014.Majority of the study designs published in both the journal were case reports (42.6%) followed by cross sectional studies (24.8%). 96.3% of the articles were from India. Majority of the articles published were of multi authors (65.2%) and from Educational institutes (98.4%). The trends of the articles published indicated that the case reports/series formed the major bulk (others=59.1%) followed by research studies (21.3%). CONCLUSION: It was concluded that most articles published were case reports followed by researches indicating an inclination towards better quality methodology. The SJR and the citation count of the articles published also indicated the quality of the scientific articles published. PMID- 26023644 TI - Aerosols how dangerous they are in clinical practice. AB - BACKGROUND AND OBJECTIVES: The purpose of the present study was to determine the microbial atmospheric contamination during initial periodontal treatment using a modern piezoelectric scaler and to evaluate the efficacy of two commercially available mouth rinses (0.2% Chlorhexidine mouth rinse and Listerine) in reducing bacterial contamination when used as a pre-procedural rinse, with and without high volume evacuation (Aerosol reduction device). MATERIALS AND METHODS: Subjects for the study were selected from the outpatient Department of Periodontics, Sri Siddhartha Dental College and Hospital, Tumkur, India. Total 60 patients were taken for the study and on the basis of inclusion and exclusion criteria's they were divided into three groups. The sampling was carried out in two stages before and after implementing a set protocol. Total duration of study was four months. MICROBIOLOGICAL EVALUATION: The samples (blood agar plates) were transported immediately to the Department of Microbiology, Sri Siddhartha Medical College, Tumkur for: Identification of microorganisms as per standard procedures (Gram stain, Biochemical Test, Species Identification).Counting the number of colonies formed on blood agar plates using colony counter unit. RESULTS: Out of all the three pre-procedural rinses 0.2% w/v Chlorhexidine is the best in reducing aerobic bacteria (CFU) followed by Listerine and then Water. CONCLUSION: The following conclusion was drawn that the use of pre-procedural rinses along with the use of high volume suction apparatus significantly reduced the aerosol contamination and hence chances of cross-infection in the dental units. PMID- 26023645 TI - Effect of Different Tube Potential Settings on Caries Detection using PSP Plate and Conventional Film. AB - PURPOSE: To compare intraoral Phosphor Stimulable Plate digital system and intraoral film using different tube settings on incipient proximal caries detection. MATERIALS AND METHODS: Five blocks, with five teeth each, were radiographically examined using phosphor plates and F-speed films. The images were acquired in 07 different tube potentials from 50-80 kV. The films were digitized. Three oral radiologists scored the images for the presence of caries using a 5-point rating scale. The areas under ROC curve were calculated. The influence of tube kilovoltage was verified by ANOVA and pair wise comparisons performed using Tukey test. RESULTS: Mean ROC curve areas varied from 0.446-0.628 for digital images and 0.494-0.559 for conventional images. The tube setting of 70 kV presented the best result both for digital and conventional images. Considering the image type separately, 70 kV scored highest followed by 75 and 65 kV for digital images (p=0.084). For conventional image modality, even though 70 kV presented the best result, it did not differ significantly from 80 kV, not differing from 60 and 55 kV, which did not differ from 75, 65 and 50 kV (p=0.53). CONCLUSION: Phosphor plate digital images seem to be more susceptible to tube setting potential variations then digitized film images. PMID- 26023646 TI - GCF Resistin As A Novel Marker in Patients with Chronic Periodontitis and Rheumatoid Arthritis. AB - BACKGROUND: The associational studies between periodontitis and rheumatoid arthritis are less documented, although they are found to have similar inflammatory pathogenesis. Resistin, a novel adipokine is suggested to be a common link between periodontitis and rheumatoid arthritis. The aim of the present study was to reinforce the inter-relationship between periodontitis and rheumatoid arthritis by using resistin as a potent inflammatory marker. MATERIALS AND METHODS: Hundred patients (aged >30 y) of either sex were selected for this study and were divided equally into four groups of 25 patients each. Group A consisted of healthy individuals, Group B consisted of patients with chronic periodontitis, Group C of patients with rheumatoid arthritis and Group D had patients suffering from both arthritis and periodontitis. Periodontal parameters assessed were plaque index (PI), modified gingival index (GI) and probing depth (PD). Panoramic radiographs were taken to confirm the diagnosis of periodontitis. Rheumatoid arthritis was confirmed by the rheumatologists and seropositivity for rheumatoid factor (RF) was checked. Resistin levels were analysed in GCF collected from all the four groups and statistical analysis was done by using Pearson correlation coefficient. RESULTS: The GCF of all the patients showed presence of resistin. The level of resistin was highest in Group D patients and least in Group A patients. On analysing the samples together positive co-relation was found between GCF resistin and PD, PI, GI and RF. CONCLUSION: Resistin levels are increased in both chronic periodontitis and rheumatoid arthritis. Therefore, the increased level of GCF resistin can be regarded as potential inflammatory marker for periodontitis and rheumatoid arthritis. PMID- 26023647 TI - Anaesthetic efficacy of 4% articaine mandibular buccal infiltration compared to 2% lignocaine inferior alveolar nerve block in children with irreversible pulpitis. AB - BACKGROUND: Lidocaine is the gold standard anaesthetic solution that has been used since its inception into dentistry till date. Around 80% of failures have been reported when lignocaine has been used for inferior alveolar nerve block in children and adults with irreversible pulpitis. There is a need to use newer drugs which are available which have been reported to be effective like lignocaine, such as articaine. Although articaine has been used in adults, literature supporting its use in children is sparse. AIM: The purpose of this study is to compare the anaesthetic efficacy of 4% articaine buccal infiltration and 2% lignocaine inferior alveolar nerve block in children with irreversible pulpitis. It also aims to assess the need for supplemental intrapulpal injections. MATERIALS AND METHODS: This study was designed as a randomized double blind cross over trial comparing the anaesthetic effectiveness of 4% articaine with 1:100,000 epinephrine in buccal infiltration and 2% lignocaine IAN block anaesthesia. The study subject and the pediatric dentist performing the pulpectomy procedures were blinded to the study. A sample size of 40 subjects in the age group of 5-8 y was included in the study. RESULTS: The onset of anaesthesia with 4% articaine was faster as compared to 2% lignocaine. The duration of anaesthesia with articaine infiltration was shorter. The need for supplemental injection in the articaine group was less. CONCLUSION: Four percent articaine infiltration can be used in children with irreversible pulpitis. It can be used to replace the IAN block in children thereby reducing the post anaesthetic complications like lip biting. PMID- 26023648 TI - Comparative Evaluation of Tensile - Bond Strength of An Orthodontic Adhesive with and without Fluoride Application, After Acid Etching -An Invitro Study. AB - BACKGROUND: Fixed appliances hinder the effective control of plaque accumulation and white spot lesions may develop under the ill fitting bands or adjacent to the stainless steel brackets during orthodontic treatment particularly the etching process. AIMS AND OBJECTIVES: Comparative study of tensile bond strength of an orthodontic adhesive with and without fluoride application after acid etching to know the effect of fluoride on bond strength. MATERIALS AND METHODS: This study is carried out on 90 non carious human premolar teeth, and divided in 6 groups with each group of 15 specimens. In those Groups I and IV were control group acid etch treatment, Group II and V is 1.23% APF gel (acid etch plus APF gel treatment,) and group III and VI is 8% SnF2 (acid etch plus SnF2 treatment). Samples of Group I, II and III bond strength were tested after 24 h and groups IV, V and VI after one month on microtechtensometer machine. The scanning electron microscope (SEM) investigation was carried out for the 2 specimens for the control group after acid etch and 4 specimens after acid etch with fluoride application for fluoride groups. RESULTS: Control and SnF2 treated groups was found to be nearly similar to the control group whereas APF treated group showed less focal holes than the other 2 groups. CONCLUSION: Fluoride application after acid etching without having an adverse effect on bond strength but we can prevent the white spot lesions and caries. PMID- 26023649 TI - Intramuscular cavernous haemangioma of masseter muscle - a case report of surgical excision. AB - Intramuscular haemangioma are rare benign congenital neoplasm of proliferative vascular in nature due to increased endothelial cell turnover. Less than 20% of these are found in head and neck region. The masseter muscle accounts for 5% of all intramuscular haemangioma of head and neck region. They are non metastasizing tumours which may suddenly start growing in later stages. The present article will discuss the clinical presentation, diagnostic modalities and surgical treatment of cavernous Haemangioma involving masseter muscle in a 15-year-old young female patient in whom a surgical excision of whole lesion was done under general anaesthesia and no reoccurrence of the lesion was observed after one year of follow up. PMID- 26023650 TI - Segmental alveolar osteotomy by palatal approach to correct excessive angulated dental implants in anterior and posterior maxilla. AB - Dental implants have been used for a long time to achieve better prosthetic and health conditions in the mouth. With the increase in their usage, more complications have occurred, and methods of solving these problems have been developed. One complication is insertion of the implant in the wrong direction. The aim of this case report is to describe an osteotomy technique to reposition a malpositioned dental implant. A female patient, aged 38 years, and a male patient aged 48 years, were referred complaining of the malpositioned osseointegrated implants, which had been placed in the region of the left maxillary first premolar and molar tooth, and in the region of the left maxillary lateral incisor. Due to severe buccal positioning of the implant fixtures, acceptable prosthetic treatment was not possible. Alveolar osteotomy procedure was used to reposition the implants. Satisfactory results were obtained by osteotomy for 18 month of follow up. We conclude that inadequately axially inclined implants can be successfully treated by alveolar osteotomy. The preservation of marginal gingiva permits obtaining better prosthetic results. To avoid the recession of attached gingiva, palatal approach technique may help the clinicians. PMID- 26023651 TI - Endodontic treatment of the mandibular first molar with six roots canals - two case reports and literature review. AB - The most common configuration of the mandibular first molar is the presence of two roots and three root canals. The objective of this work is to present two rare anatomic configurations with six root canals on two mandibular left first molars diagnosed during endodontic therapy. Root canal therapy was performed using a dental operating microscope. Ultrasonic troughing in the grooves in between the mesial root canals and in between the distal root canals was able to show the middle root canals. Large samples population characterization researches and systematic reviews were unable to detect a single case of six root canals configuration in a mandibular first molar in their investigations. Although it is a rare configuration, a six root canal configuration is possible to be found in the mandibular first molar. Three different pulp chamber configurations are possible to be found. Two or three roots may be present and the root configuration more common in the mesial root is the Type 8 and Type 12 for the distal root. Some concepts about the required technique to approach these cases are also debated. PMID- 26023652 TI - Langerhans histiocytosis in a child - diagnosed by oral manifestations. AB - Langerhans Histiocytosis (LCH) is a rare reactive and proliferative disease of histiocytes with unknown etiology, characterized by excessive proliferation of histiocytes called Langerhans cells. It occurs mainly in children but occurrence in adults has also been reported. It manifests as punched out lesions in the skull, maxilla, mandible, sternum and other flat bones and causes rapid resorption of the alveolar bone leading to floating teeth appearance in the radiographs. This disease manifests initially in the oral cavity in most of the cases and can be diagnosed by careful clinical and radiological examination. Here, we present a case of LCH in a child which was diagnosed by a swelling in the mandibular region. PMID- 26023653 TI - Microstomia-a treatment challenge to a prosthodontist. AB - The branch of Prosthodontics is not only a science but also an art of handling patients who present with limitations in continuing with normal procedures. An abnormally small mouth opening is called as microstomia. The common reasons for this condition include scleroderma, orofacial malignancies, surgery, burns and TMJ ankylosis. Impressions can be made for patients with restricted mouth opening with a sectional impression tray that can be assembled and disassembled in the mouth and reassembled outside the mouth. This article describes a sectional tray system for making preliminary and secondary impressions. Also an innovative technique of fabricating a sectional complete denture for a microstomic patient has been described. PMID- 26023654 TI - Osteochondroma of maxilla posterior region: a unique case. AB - Osteochondroma is the most common benign neoplasm of the skeleton commonly affecting the long bones due to endochondral growth. In the craniofacial region this tumour is very rare. The sites of predilection are the coronoid process and the mandibular condyle. Here, we report an exceptional case of osteochondroma originating from the maxillary posterior region in a 26-year-old male patient, mimicking an odontome, not reported earlier in the literature. We also discuss the importance of various imaging modalities, most importantly, computed tomography (CT) in the evaluation of such lesions. However, histopathology remains the mainstay for definitive diagnosis in such conditions. PMID- 26023655 TI - Endodontic management of maxillary first molar with type I canal configuration- a rare case report. AB - Thorough knowledge about the root canal variations is essential for the predictable endodontic treatment outcome. The root and root canal anatomy of maxillary first molar varies greatly. A Pub-med literature search about single rooted single canalled maxillary first molar was done to know its details such as incidence, diagnostic method used, age, sex and ethnic background of patient. This article presented report of a single rooted single canalled maxillary first molar in a 27-year-old healthy Asian female. PMID- 26023656 TI - Natal tooth associated with fibrous hyperplasia - a rare case report. AB - Eruption of tooth at about 6 months of age is a significant stage in child's life and is an emotional event for parents. However, a tooth present in the oral cavity of newborn can lead to a lot of delusions. Natal and neonatal teeth are of utmost importance not only for a dentist but also for a paediatrician due to parent's anxiety, folklore superstitions and numerous associated complications with it. This paper reports a rare case, wherein a natal tooth has led to the development of a reactive fibrous hyperplasia in an 8-week-old infant. PMID- 26023657 TI - A Rare Case Report of Neurofibromatosis I in HIV Positive Individual. AB - Neurofibroma is an uncommon benign tumour of neural tissue origin rarely presenting in the mouth and jaws and thereby attracting the attention of oral physicians. A 22-year-old male patient reported with a complaint of swelling in left middle one third region of face since 8-10 y which was slowly progressive in size. He had history of multiple dark brown pigmentation on skin associated with progressively enlarging multiple small nodular growths over the body and single firm nodular growth in left side of maxilla intraorally. He had history of tuberculosis at the age of one year which was treated completely and since last 2 3 y he was suffering from recurrent episodes of sore throat, fever, diarrhea, abdominal pain with vomiting and excessive weight loss. Radiographic findings showed irregular osteolytic lesions involving ramus and angle of mandible, zygomatic bone and posterior part of maxilla with displacement of teeth with abnormal soft tissue enhancement observed by advance imaging. On serological investigation he was HIV positive and histopathologically, diagnosed with Neurofibromatosis-1. Oral manifestations of neurofibromatosis have been reported in only 4% to 7% of affected persons. This article presents a rarest of rare case report of neurofibromatosis-I in HIV positive individual also involving maxilla, mandible as well as zygomatic arch. PMID- 26023658 TI - A rare case of mucopolysaccharidosis: hunter syndrome. AB - Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a member of a group of inherited metabolic disorders together termed mucopolysaccharidosis (MPSs). It is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. The prevalence of this syndrome is 1:100,000 births. Insufficient enzyme activity results in accumulation of glycosaminoglycans (GAGS) in the lysosomes of various tissues and organs and leading to progressive multisystem pathologies. Here, we report a case of 13-year old boy who presented with typical facial, skeletal and dental features without corneal clouding. It is possible that thorough and systematic clinical and radiological examination alone can help in diagnosis of this complex disorder. PMID- 26023659 TI - Effect of bisphosphonates on orthodontic tooth movement-an update. AB - Bisphosphonates are a synthetic class of pyrophosphate analogues that are powerful inhibitors of bone resorption which are commonly used as a medication for the prevention and therapy of osteoporosis and osteopenia, also used to treat tumor diseases. As it affects bone metabolism, it is said to have an influence on orthodontic treatment and tooth movement. Also, this review gives an insight into the reported effects of Bisphosphonate medication in literature highlighting the status quo of scientific research regarding effects of Bisphosphonates on orthodontic tooth movement. A systematic literature search was done in Medline database (Pubmed) for the appropriate keywords. Manual handsearch was also done. From the available evidence it can be concluded that the duration of orthodontic treatment is increased for patients under Bisphosphonate therapy as they interfere with the osteoclastic resorption. However, they may be beneficial for anchorage procedures. Further long term prospective randomized controlled trials are required to assess possible benefits and adverse effects of bisphosphonate treatment, before Bisphosphonates can be therapeutically used in orthodontics. PMID- 26023660 TI - Temporomandibular Disorders (TMD) in Edentulous Patients: A Review and Proposed Classification (Dr. Bader's Classification). AB - Temporomandibular disorders (TMD) are a collective term given to a number of clinical problems that involve the masticatory musculature, the temporomandibular joints and associated structures, or both. Although the aetiology of TMD has not been fully understood, in general it is considered to be multifactorial. The signs and symptoms of TMD which present in patients with natural teeth may also occur in edentulous patients. These symptoms may appear in various combinations and degrees. TMD has attained a prominent role within the context of dental care due to its high prevalence. The present paper is a review of the current literature on TMD in edentulous patients; with an attempt to propose a classification for the same. PMID- 26023661 TI - Systemic review of dry socket: aetiology, treatment, and prevention. AB - Our systemic review is to make a comprehensive review about the aetiology, treatment and the prevention of dry socket, the inclusion criteria were all the studies that discuss the dry socket and its etiology, treatment and prevention and exclusion criteria were all the studies that discuss the other complications of tooth extraction, the materials and methods used for this systemic review was to search in the Pub Medline database between 2008 to 2013, using specific words "dry socket, aetiology, treatment and prevention" and published in the English language, the articles were screened by abstract for relevance to aetiology, treatment and prevention of dry socket, 82 papers were identified in pub med but a total of 36 out of Publications were included in the final systemic review according to the specific keywords and materials mentioned above. The occurrence of dry socket in an everyday oral surgery or dental practice is unavoidable. The risk factors are smoking, surgical trauma, single extractions, age, sex, medical history, systemic disorder, extraction site, amount of anaesthesia, operator experience, antibiotics use prior to surgery, difficulty of the surgery and the previous surgical site infection in addition to oral Contraceptives, menstrual cycle and immediate postextraction socket irrigation with normal saline. The traditional options of treatment are directed toward palliative care, such as the irrigation of the surgical site, avoiding curetting the extraction socket, Packing with a zinc oxide- eugenol paste on iodoform gauze can be considered to relieve acute pain episodes, there is also new agents in the market can accelerate the healing of the socket such as PRGF and GECB. The prevention methods include avoiding smoking before and after surgery and a traumatic surgery, the use of antibiotics, such as, azithromycin, can be considered, the other preventive measures such as chlorhecidine rinse or gel can be effective in the reduction of dry socket incidence. PMID- 26023662 TI - Tuberous sclerosis. PMID- 26023663 TI - Non syndromic bilateral microdontia of maxillary second molars: a very rare finding. AB - Dental anomalies are the formative defects caused by genetic disturbances or environmental factors during tooth morphogenesis. The term microdontia is defined as the condition of having abnormally small teeth. Clinically, microdontia in the permanent dentition, excluding the third molars, is found in 0.8-8.4% of the population. One of the commonest forms of localized microdontia is that which affects the maxillary lateral incisor, a condition called Peg laterals. The next tooth which can be affected is the third molars. Few cases of microdontia in canines have been reported. Localised microdontia of maxillary second molar has never been reported in literature before. PMID- 26023664 TI - Anatomical abnormalities in multiple permanent teeth. PMID- 26023665 TI - Pulp Revascularization- It's your Future Whether you Know it or Not? AB - Pulpal regeneration after tooth injury is not easy to accomplish. In teeth with immature apices and exposed vital pulp tissue, partial or complete pulpotomy is indicated to preserve pulpal function and allow continued root development. In many cases, injury causes loss of pulp vitality and arrested root development leading to a tooth with poor crown root ratio, a root with very thin walls, an open blunderbuss apex and development of apical pathosis. The ideal treatment in such cases would be to obtain further root development and thickening of dentinal walls by stimulating the regeneration of a functional pulp dentin complex. This outcome has been observed after reimplantation in avulsed immature permanent teeth but has been thought impossible in a necrotic infected tooth. This case series evaluates the efficacy of revascularization procedure in immature, non vital permanent teeth. Pulp regeneration was attempted in four patients at Department of Conservative Dentistry, ESIC Dental College, New Delhi using blood clotting approach. The cases were treated and followed up regularly at regular intervals ranging from 6 months to 3 years to assess the treatment response clinically and radiographically. The patients remained clinically asymptomatic with three out of four patients even responding positively to pulp responsiveness tests. Radiographic examination also revealed increased root formation and thickening of dentinal walls. It was concluded that the triad of a disinfected canal, a matrix (blood clot) in to which new tissue could grow and an effective coronal seal produced the desirable environment for successful revascularization. PMID- 26023666 TI - Epithelial borderline ovarian tumor: Diagnosis and treatment strategy. AB - Epithelial borderline ovarian tumors (BOT) are distinctive from benign tumors and carcinoma. They occur in younger women more often than carcinoma, and there is some difficulty making correct diagnosis of BOT. Two subtypes of BOT, serous and mucinous borderline tumor have different characteristics and very different clinical behavior. Serous borderline tumor (SBT) with micropapillary pattern shows more incidence of extra ovarian disease and often coexists with invasive implant. SBT with micropapillary pattern in advanced stage has showed a worse prognosis than typical SBT. Huge mucinous borderline tumors have histologic heterogeneity, and the accuracy of frozen section diagnosis is relatively low. Extensive sampling is required to reach a correct pathological diagnosis. Mucinous adenoma (intestinal type) also runs the risk of recurrence after cystectomy, or intraoperative rupture of cyst. Laparoscopic procedure for BOT has not increased the risk of recurrence. Fertility preserving procedures are generally accepted, except in advanced stage SBT with invasive implants. Only cystectomy shows a significant risk of recurrence. Re-staging surgery and full staging surgery is not necessary for all BOT. We should not attempt to treat them uniformly, by the single diagnosis of "borderline tumor". It depends on histologic type. Close communication with the pathologist is necessary to gain more detail and ask more pathological samples in order to make the optimal treatment strategy for each individual patients. PMID- 26023667 TI - Sonographically accessed funneling of the uterine cervix as a predictor of successful labor induction. AB - OBJECTIVE: The Bishop score and length of the uterine cervix are good predictors of successful labor induction. However, little is known about the association between the funneling of the uterine cervix and successful labor induction. The study aimed to evaluate cervical funneling as a predictor of successful labor induction. METHODS: This study was designed as a prospective observational study. Subjects who delivered a baby by labor induction were enrolled in the study from July 2011 to August 2013. Cervical funneling and length were examined with transvaginal ultrasonography. The Bishop score was rated by digital pelvic examination. RESULTS: A total of 163 primigravida women were recruited for the study. Of these, 137 participants (84.0%) delivered vaginally by labor induction. Cervical funneling was observed in 93 women (57.1%). Successful labor induction was significantly higher in patients with cervical funneling than those without it (91.4% vs. 74.3%, P<0.01), and was significantly associated with cervical funneling, as well as the Bishop score and cervical length. In a multivariate analysis, cervical funneling was an independent predictor for successful vaginal delivery by labor induction ( odd ratio, 2.70; 95% confidence interval, 1.02 to 7.10; P=0.04). However, the Bishop score and cervical length had no association with successful vaginal delivery. CONCLUSION: This study showed that cervical funneling could be a predictive marker for vaginal delivery during labor induction. PMID- 26023668 TI - Prevalence of orofacial clefts in Korean live births. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of orofacial clefts and identify the characteristics of other birth defects associated with orofacial clefts in Korea. METHODS: This study used data from the Congenital Anomaly Survey conducted by the Korea Institute for Health and Social Affairs. The survey was conducted on birth defects documented during 2005 to 2006 in 2,348 medical institutes in Korea. This study was performed using data from medical insurance claims of the National Health Insurance Corporation. The prevalence of orofacial clefts was defined as the number of cases per 10,000 live births. RESULTS: Among the 883,184 live births, 25,335 infants had birth defects, which included 980 infants with orofacial clefts. The prevalence of total orofacial clefts in the total live births was 11.09 per 10,000, accounting for 3.9% of all birth defects. The most common orofacial cleft was cleft palate only (n=492), followed by cleft lip only (n=245) and cleft lip with cleft palate (n=243), with prevalence rates of 5.57, 2.77, 2.75 per 10,000 live births, respectively. While malformations of the circulatory system; digestive system; eyes, ears, face, and neck; and musculoskeletal system were most frequently encountered among infants with a cleft lip with or without a cleft palate, anomalies of most organ systems were notably observed among infants with cleft palate only. CONCLUSION: The prevalence of orofacial clefts in Korea was similar or slightly lower than that of other countries. This study informs present status of orofacial clefts and gives baseline data to lay the foundation stone for Korea's registry system of orofacial clefts. PMID- 26023669 TI - Practice patterns in the management of threatened preterm labor in Korea: A multicenter retrospective study. AB - OBJECTIVE: This study aimed to examine clinical practice patterns in the management of pregnant women admitted with threatened preterm labor (TPL) in Korea. METHODS: Data from women admitted with a diagnosis of TPL were collected from 22 hospitals. TPL was defined as regular uterine contractions with or without other symptoms such as pelvic pressure, backache, increased vaginal discharge, menstrual-like cramps, bleeding/show and cervical changes. Data on general patient information, clinical characteristics at admission, use of tocolytics, antibiotics, and corticosteroids, and pregnancy outcomes were collected using an online data collections system. RESULTS: A total of 947 women with TPL were enrolled. First-line tocolysis was administered to 822 (86.8%) patients. As a first-line tocolysis, beta-agonists were used most frequently (510/822, 62.0%), followed by magnesium sulfate (183/822, 22.3%), calcium channel blockers (91/822, 11.1%), and atosiban (38/822, 4.6%). Of the 822 women with first-line tocolysis, second-line tocolysis were required in 364 (44.3%). Of 364 with second-line, 199 had third-line tocolysis (37.4%). Antibiotics were administered to 29.9% of patients (284/947) with single (215, 22.7%), dual (26, 2.7%), and triple combinations (43, 4.5%). Corticosteroids were administered to 420 (44.4%) patients. Betamethasone was administered to 298 patients (71.0%), and dexamethasone was administered to 122 patients (29.0%). CONCLUSION: Practice patterns in the management of TPL in Korea were quite various. It is needed to develop standardized practice guidelines for TPL management. PMID- 26023670 TI - Long (27-nucleotides) small inhibitory RNAs targeting E6 protein eradicate effectively the cervical cancer cells harboring human papilloma virus. AB - OBJECTIVE: This study was to identify small inhibitory RNAs (siRNAs) that are effective in inhibiting growth of cervical cancer cell lines harboring human papilloma virus (HPV) and to examine how siRNAs interact with interferon beta (IFN-beta) and thimerosal. METHODS: The HPV18-positive HeLa and C-4I cell lines were used. Four types of siRNAs were designed according to their target (both E6 and E7 vs. E6 only) and sizes (21- vs. 27-nucleotides); Ex-18E6/21, Ex-18E6/27, Sp-18E6/21, and Sp-18E6/27. Each siRNA-transfected cells were cultured with or without IFN-b and thimerosal and their viability was measured. RESULTS: The viabilities of HPV18-positive tumor cells were reduced by 21- and 27-nucleotide siRNAs in proportion to the siRNA concentrations. Of the two types of siRNAs, the 27-nucleotide siRNA constructs showed greater inhibitory efficacy. Sp-18E6 siRNAs, which selectively downregulates E6 protein only, were more effective than the E6- and E7-targeting Ex-18E6 siRNAs. siRNAs and IFN-beta showed the synergistic effect to inhibit HeLa cell survival and the effect was proportional to both siRNA and IFN-beta concentrations. Thimerosal in the presence of siRNA exerted a dose-dependent inhibition of C-4I cell survival. Finally, co-treatment with siRNA, IFN-beta, and thimerosal induced the most profound decrease in the viability of both cell lines. CONCLUSION: Long (27-nucleotides) siRNAs targeting E6-E7 mRNAs effectively reduce the viability of HPV18-positive cervical cancer cells and show the synergistic effect in combination with IFN-b and thimerosal. It is necessary to find the rational design of siRNAs and effective co-factors to eradicate particular cervical cancer. PMID- 26023671 TI - Embryonic development in human oocytes fertilized by split insemination. AB - OBJECTIVE: To compare the laboratory outcomes of intracytoplasmic sperm injection (ICSI) and conventional insemination using sibling oocytes in poor prognosis IVF cycles where ICSI is not indicated. METHODS: Couples undergoing IVF with following conditions were enrolled: history of more than 3 years of unexplained infertility, history of >=3 failed intrauterine insemination, leukocytospermia or wide variation in semen analysis, poor oocyte quality, or >=50% of embryos had poor quality in previous IVF cycle(s). Couples with severe male factor requiring ICSI were excluded. Oocytes were randomly assigned to the conventional insemination (conventional group) or ICSI (ICSI group). Fertilization rate (FR), total fertilization failure, and embryonic development at day 3 and day 5 were assessed. RESULTS: A total of 309 mature oocytes from 37 IVF cycles (32 couples) were obtained: 161 were assigned to conventional group and 148 to ICSI group. FR was significantly higher in the ICSI group compared to the conventional group (90.5% vs. 72.7%, P<0.001). Total fertilization failure occurred in only one cycle in conventional group. On day 3, the percentage of cleavage stage embryos was higher in ICSI group however the difference was marginally significant (P=0.055). In 11 cycles in which day 5 culture was attempted, the percentage of blastocyst (per cleaved embryo) was significantly higher in the ICSI group than the conventional group (55.9% vs. 25.9%, P=0.029). CONCLUSION: Higher FR and more blastocyst could be achieved by ICSI in specific circumstances. Fertilization method can be tailored accordingly to improve IVF outcomes. PMID- 26023672 TI - Clinical features of thoracic endometriosis: A single center analysis. AB - OBJECTIVE: To analyze the diagnostic profiles and treatment outcomes of patients with thoracic endometriosis at a university hospital. METHODS: A retrospective review of medical records was performed for patients diagnosed with thoracic endometriosis at Gangnam Severance Hospital, Yonsei University College of Medicine, between January 2007 and January 2014. RESULTS: Fifteen patients (median age, 35 years; range, 23-48 years) were evaluated. Patients presented with catamenial hemoptysis (n=8), or catamenial pneumothorax (n=7). Patients with catamenial pneumothorax were significantly older than those presenting with hemoptysis (P=0.0002). Only 3 patients (20%) had coexisting pelvic endometriosis. All patients underwent chest computed tomography; lesions were shown to predominantly affect the right lung (right lung, n=13, 86.7%; left lung, n=2, 13.3%), and were mainly distributed on the right upper lobe (n=9, 60%). Ten patients underwent video-assisted thoracoscopic surgery, and 1 patient underwent a thoracotomy. Intraoperatively, endometriosis-specific findings were observed in 8/11 patients (72.7%); a further 5/11 patients (45.4%) had histologically detectable endometriosis. Over the follow-up period (mean, 18.4 months; range, 2 65 months) 5/15 patients (33%) had clinical signs of recurrence. Recurrence was not detected in any of the 5 catamenial pneumothorax patients that received adjuvant hormonal therapy after surgery. CONCLUSION: The diagnosis and management of thoracic endometriosis requires a multidisciplinary approach, based upon skillful differential diagnosis, and involving careful gynecologic evaluation and assessment of the cyclicity of pulmonary symptoms. Imaging findings are non specific, though there may be laterality towards the right lung. Since symptom recurrence is more common in those with presenting with pneumothorax, post operative adjuvant medical therapy is recommended. PMID- 26023673 TI - Relationship between phospholipase C zeta immunoreactivity and DNA fragmentation and oxidation in human sperm. AB - OBJECTIVE: The study aimed to evaluate the feasibility and reproducibility of measuring phospholipase C zeta (PLCzeta) using immunostaining in human sperm and to investigate the relationship between PLCzeta immunoreactivity and DNA fragmentation and oxidation in human sperm. METHODS: Semen samples were obtained from participants (n=44) and processed by the conventional swim-up method. Sperm concentration, motility, normal form by strict morphology, DNA fragmentation index assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling method and immunofluorescent expression for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and PLCzeta were assessed. RESULTS: When duplicate PLCzeta tests were performed on two sperm samples from each of the 44 participants, similar results were obtained (74.1+/-9.4% vs. 75.4+/-9.7%). Two measurements of PLCzeta were found to be highly correlated with each other (r=0.759, P<0.001). Immunoreactivity of PLCzeta was not associated with donor's age, sperm concentration, motility, and the percentage of normal form as well as DNA fragmentation index. However, immunoreactivity of PLCzeta showed a significant negative relationship with 8 OHdG immunoreactivity (r=-0.404, P=0.009). CONCLUSION: Measurement of PLCzeta by immunostaining is feasible and reproducible. Lower expression of PLCzeta in human sperm may be associated with higher sperm DNA oxidation status. PMID- 26023674 TI - Single-port access versus conventional multi-port access total laparoscopic hysterectomy for very large uterus. AB - OBJECTIVE: The aim of this study was to compare the surgical outcomes of single port access (SPA) and conventional multi-port access total laparoscopic hysterectomies (TLH) among patients with very large uteri (500 g or more). METHODS: Fifty consecutive patients who received TLH for large uterine myomas and/or adenomyoses weighing 500 g or more between February 2009 and December 2012 were retrospectively reviewed. SPA and conventional TLH were each performed in 25 patients. Surgical outcomes, including operation time, estimated blood loss, postoperative hemoglobin change, postoperative hospital stay, postoperative pain, and perioperative complications, were compared between the two groups. RESULTS: There were no significant demographic differences between the two groups. All operations were completed laparoscopically with no conversion to laparotomy. Total operation time, uterus weight, estimated blood loss, and postoperative hemoglobin change did not significantly differ between the two groups. Postoperative hospital stay was significantly shorter for the SPA-TLH group compared to that of the conventional TLH group (median [range], 3 [2.0-6.0] vs. 4 [3-7] days; P=0.004]. There were no inter-group differences in postoperative pain at 6, 24, and 72 hours after surgery. There was only one complicated case in each group. CONCLUSION: SPA-TLH in patients with large uteri weighing 500 g or more is as feasible as conventional TLH. SPA-TLH is associated with shorter hospital stays compared to that of conventional TLH. PMID- 26023675 TI - Primary peritoneal serous papillary carcinoma presenting as a large mesenteric mass mistaken for ovarian cancer: a case of primary peritoneal carcinoma. AB - Peritoneal origin serous papillary carcinoma is an uncommon primary malignancy occurring in the abdominal or pelvic peritoneum lining. It is characterized by peritoneal carcinomatosis with massive ascites, uninvolved or minimally involved ovary, and is histologically indistinguishable from ovarian serous tumors. Better recognition of this phenomenon in recent years has contributed to an increasing diagnostic frequency. We describe a rare case of peritoneal origin serous papillary carcinoma with unusual clinical presentations involving a solitary primary tumor originating from the peritoneal lining of the sigmoid colonal mesentery, without pelvic lymph node involvement or distant metastasis. Because of the location and morphological similarity, it was misdiagnosed as an ovarian malignancy. We aim to assist in the diagnosis of this disease with the following case report, thereby improving the management of patients with this condition. PMID- 26023676 TI - Carcinosarcoma of the uterine cervix arising from Mullerian ducts. AB - Carcinosarcomas of the uterine cervix are extremely rare. Cervical carcinosarcoma can be characterized by having two different origins: the Mullerian ducts and the mesonephric duct remnants. A 53-year-old Korean woman was admitted to the hospital because of pelvic mass detected on computed tomography scan done at private clinic. A Radical hysterectomy with bilateral salpingooophorectomy and pelvic lymphadenectomy was carried out upon a diagnosis of stage IB2 cervical sarcoma. Immunohistochemically, the epithelial component was positive for pancytokeratin and estrogen receptor, but negative for CD 10 and carletinin. The mesenchymal component was positive for vimentin. The histopathologic diagnosis was a carcinosarcoma of the uterine cervix arising from Mullerian ducts. She underwent chemotherapy. She developed systemic recurrence seven months after operation and died of disease. The origin of cervical carcinosarcoma needs to be verified and immunohistochemical studies using mesonephric marker (CD 10, carletinin, and estrogen receptor) is helpful. PMID- 26023677 TI - Pseudoaneurysm of uterine artery causing intra-abdominal and vaginal bleeding after cervical conization. AB - Uterine arterial pseudoaneurysm is a very rare condition usually associated with postpartum hemorrhage. It almost never occurs after cervical conization; however, since ruptured pseudoaneurysm could be life threatening, we should consider the possibility of vascular injury such as pseudoaneurysm when we find a patient with vaginal bleeding after the process of surgical operation. Emergency arterial embolization is a well established therapeutic option to control the ruptured pseudoaneurysm. This is a case report of uterine arterial pseudoaneurysm causing intra-abdominal bleeding followed by cervical conization, which was successfully treated by uterine artery embolization. PMID- 26023678 TI - Outcome of Carotid Endarterectomy after Regional Anesthesia versus General Anesthesia - A Retrospective Study Using Two Independent Databases. AB - BACKGROUND: Carotid endarterectomy (CEA) is effective in reducing stroke risk in selected patient groups. The ideal anesthetic technique remains controversial in light of literature between general anesthesia (GA) and regional anesthesia (RA) for CEA. METHODS: We studied the NSQIP data from 2005 to 2012. There were 32,718 patients receiving general anesthesia (GA) and 5,384 patients receiving regional anesthesia, local anesthesia, or monitored anesthesia care (RA). The outcome measurements of 30 days postoperative complications were death, stroke, coma, unplanned intubation, on ventilator > 48 hours, cardiac arrest, and myocardial infarction. We next studied NY-SID data from 2007 to 2011. There were 13,913 patients receiving GA and 3,145 patients receiving RA. The outcome measurements by discharge time were death, stroke, paraplegia, new neurological disorder, aspiration, respiratory failure, pulmonary resuscitation procedure (include intubation), cardiac arrest, cardiac resuscitation procedure, myocardial infarction, and congestive heart failure. All analyses were risk adjusted with propensity score matching algorithm. RESULTS: There were significant differences in incidences of un-expected intubation (1.21% vs. 0.55%, P=0.001), and myocardial infarction (0.80% vs. 0.35%, P=0.039) between GA and RA respectively in NSQIP data. GA group had significant higher incidences of aspiration (0.61% vs. 0.19%, P=0.014), and pulmonary resuscitation procedure (including intubation) (1.02% vs. 0.54%, P=0.044) than RA group in NY-SID data. CONCLUSIONS: In comparison to GA, patients receiving RA had significant lower risks of postoperative unplanned intubation and/or pulmonary resuscitation procedure after carotid endarterectomy. PMID- 26023679 TI - Human Cytomegalovirus interleukin-10 promotes proliferation and migration of MCF 7 breast cancer cells. AB - Breast cancer is the most common malignancy affecting women worldwide. While a small fraction of breast cancers have a hereditary component, environmental and behavioral factors also impact the development of cancer. Human cytomegalovirus (HCMV) is a member of the Herpesviridae family that is widespread in the general population and has been linked to several forms of cancer. While HCMV DNA has been found in some breast cancer tissue specimens, we wanted to investigate whether a secreted viral cytokine might have an effect on cancerous or even pre cancerous cells. HCMV encodes an ortholog of the human cellular cytokine interleukin-10 (IL-10). The HCMV UL111A gene product is cmvIL-10, which has 27% sequence identity to IL-10 and binds the cellular IL-10 receptor (IL-10R) to induce downstream cell signaling. We found that MCF-7 human breast cancer cells express IL-10R and that exposure to cmvIL-10 results in enhanced proliferation and increased chemotaxis of MCF-7 cells. PCR arrays revealed that treatment with cmvIL-10 alters expression of cell adhesion molecules and increases MMP gene expression. In particular, MMP-10 gene expression was found to be significantly up-regulated and this correlated with an increase in cell-associated MMP-10 protein produced by MCF-7 cells exposed to cmvIL-10. These results suggest that the presence of cmvIL-10 in the tumor microenvironment could contribute to the development of more invasive tumors. PMID- 26023680 TI - Tumor talk: understanding the conversation between the tumor and its microenvironment. AB - It was once believed that tumor growth, progression, and metastasis were intrinsically driven by the tumor. Instead, recent research has demonstrated that a solid tumor is surrounded by a complex matrix of cells, particularly fibroblasts, which support and even promote tumor progression. This matrix of stromal cells, also known as the tumor microenvironment (TME), plays a critical role in cancer and may represent a novel therapeutic target. As such, understanding the complex nature of how the tumor initiates and maintains communication, or a "conversation", with the TME is the focus of current investigations. We have previously shown that the most prevalent mutation found in melanoma, BRAFV600E, results in increased expression and secretion of several growth factors, cytokines, and matrix metalloproteinases, including factors that are able to activate fibroblasts. Targeted inhibition of the BRAFV600E mutation resulted in a decrease of secreted proteins into the TME and suggests that targeting the tumor also modifies the TME. Overall, this work, in combination with several additional studies discussed herein, provides strong evidence for the potential therapeutic benefits of targeting the TME, particularly signaling pathways within the fibroblasts, in conjunction with the tumor. This approach may result in extended drug resistance free survival, reduction in metastasis, and improved cytotoxic drug delivery. PMID- 26023681 TI - Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. AB - Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks. PMID- 26023682 TI - Region-Specific Disruption of Adenylate Cyclase Type 1 Gene Differentially Affects Somatosensorimotor Behaviors in Mice. AB - Adenylate cyclase type I (AC1) is primarily, and, abundantly, expressed in the brain. Intracellular calcium/ calmodulin increases regulate AC1 in an activity dependent manner. Upon stimulation, AC1 produces cAMP and it is involved in the patterning and the refinement of neural circuits. In mice, spontaneous mutations or targeted deletion of the Adcy1 gene, which encodes AC1, resulted in neuronal pattern formation defects. Neural modules in the primary somatosensory (SI) cortex, the barrels, which represent the topographic distribution of the whiskers on the snout, failed to form (Welker et al., 1996; Abdel-Majid et al., 1998). Cortex- or thalamus-specific Adcy1 deletions led to different cortical pattern phenotypes, with thalamus-specific disruption phenotype being more severe (Iwasato et al., 2008; Suzuki et al., 2013). Despite the absence of barrels in the "barrelless"/Adcy1 null mice, thalamocortical terminal bouton density and activation of cortical zones following whisker stimulation were roughly topographic (Abdel-Majid et al., 1998; Gheorghita et al., 2006). To what extent does patterning of the cortical somatosensory body map play a role in sensorimotor behaviors? In this study, we tested mice with global, cortical, or thalamic loss of AC1 function in a battery of sensorimotor and social behavior tests and compared them to mice with all of the whiskers clipped. Contrary to intuitive expectations that any region-specific or global disruption of the AC1 function would lead to similar behavioral phenotypes, we found significant differences in the degree of impairment between these strains. PMID- 26023683 TI - 3D Imaging of Axons in Transparent Spinal Cords from Rodents and Nonhuman Primates AB - The histological assessment of spinal cord tissue in three dimensions has previously been very time consuming and prone to errors of interpretation. Advances in tissue clearing have significantly improved visualization of fluorescently labelled axons. While recent proof-of-concept studies have been performed with transgenic mice in which axons were prelabeled with GFP, investigating axonal regeneration requires stringent axonal tracing methods as well as the use of animal models in which transgenic axonal labeling is not available. Using rodent models of spinal cord injury, we labeled axon tracts of interest using both adeno-associated virus and chemical tracers and performed tetrahydrofuran-based tissue clearing to image multiple axon types in spinal cords using light sheet and confocal microscopy. Using this approach, we investigated the relationships between axons and scar-forming cells at the injury site as well as connections between sensory axons and motor pools in the spinal cord. In addition, we used these methods to trace axons in nonhuman primates. This reproducible and adaptable virus-based approach can be combined with transgenic mice or with chemical-based tract-tracing methods, providing scientists with flexibility in obtaining axonal trajectory information from transparent tissue. PMID- 26023684 TI - Transgelin, a Novel Marker of Smooth Muscle Differentiation, Effectively Distinguishes Endometrial Stromal Tumors from Uterine Smooth Muscle Tumors. AB - Differentiation between endometrial stromal sarcomas (ESSs) and smooth muscle tumors of the uterus can be challenging. Transgelin, a 22 kDa actin-binding protein has recently been shown to be a smooth muscle specific marker. The goal of this study was to determine whether transgelin could accurately distinguish ESSs from smooth muscle tumors. The expression of transgelin, CD10 and smooth muscle actin (SMA) in 13 ESSs (4 low grade, 6 undifferentiated and 3 metastatic), 9 smooth muscle tumors (1 leiomyoma and 8 leiomyosarcomas (LMSs) and 15 soft tissue LMSs was studied. The diagnostic performance of transgelin compared to the other smooth muscle markers was assessed. Transgelin was diffusely strongly positive in all myometria, leiomyoma, and uterine and soft tissue LMSs. In contrast, transgelin expression was totally absent in all endometria, primary and metastatic ESSs. SMA positivity was noticed in 4 of the 13 ESSs. CD10 was positive in most ESSs. Transgelin appears to be a specific marker of smooth muscle differentiation in the uterus with 100% sensitivity and specificity and may be useful for distinguishing LMS from ESS. It could be used as an additional marker useful for decision making, especially in those tumors with questionable histology. PMID- 26023685 TI - HIV Tat 101-mediated loss of pericytes at the blood-brain barrier involves PDGF BB. AB - HIV-1-associated neurocognitive disorders (HAND) affect almost 30-50% of infected individuals, even in the presence of successful control of virus replication by combined antiretroviral therapy (cART).HIV Tat protein, a nuclear trans-activator of viral gene transcription, that is secreted by infected cells and can be taken up by the neighboring cells, is present in various tissues despite the presence of cART, and has been shown to break down the integrity of the blood-brain barrier (BBB). This, in turn, leads to disruption of the neovascular unit, affecting functioning of the brain microvascular endothelial cells as well as astrocytes. Pericytes, yet another important constituent of the BBB, play a critical role in the maintenance of the integrity of the BBB. Loss of pericytes resulting in disruption of BBB has been observed in several pathologies including HAND. Furthermore, while PDGF-BB is essential for pericyte generation, paradoxically, high concentrations of PDGF-BB lead to loss of pericytes in tumor vessels. In this research highlight, we provide a brief review of our recently published finding, which have demonstrated a novel role of PDGF-BB in HIV-Tat mediated migration of pericytes, leading ultimately to loss of pericyte coverage from the endothelium, with a subsequent breach of the BBB. These findings underpin yet another mechanism by which BBB integrity is disrupted in HAND. PMID- 26023686 TI - Cost-efficient and multi-functional systems for ultrasound measurement and imaging. AB - Two cost-efficient systems were designed and demonstrated for reconstructing ultrasound wave propagation and interference and for understanding the principles of ultrasound imaging and microbubble-enhanced ultrasound imaging. One of the systems was based on a needle hydrophone that was mechanically scanned in an ultrasound focal zone, and the other system was based on a metal wire or needle, with a small diameter, that was translated in an ultrasound focal zone. The advantages and disadvantages of both methods were discussed. These systems are useful for students, educators, and researchers for investigating ultrasound wave properties and understanding ultrasound imaging principles when the budget is limited. PMID- 26023687 TI - Optimal Thresholding of Classifiers to Maximize F1 Measure. AB - This paper provides new insight into maximizing F1 measures in the context of binary classification and also in the context of multilabel classification. The harmonic mean of precision and recall, the F1 measure is widely used to evaluate the success of a binary classifier when one class is rare. Micro average, macro average, and per instance average F1 measures are used in multilabel classification. For any classifier that produces a real-valued output, we derive the relationship between the best achievable F1 value and the decision-making threshold that achieves this optimum. As a special case, if the classifier outputs are well-calibrated conditional probabilities, then the optimal threshold is half the optimal F1 value. As another special case, if the classifier is completely uninformative, then the optimal behavior is to classify all examples as positive. When the actual prevalence of positive examples is low, this behavior can be undesirable. As a case study, we discuss the results, which can be surprising, of maximizing F1 when predicting 26,853 labels for Medline documents. PMID- 26023688 TI - U.S. asthma drug costs to jump 50% by 2023. PMID- 26023689 TI - Variations in the presence of chloride cells in the gills of lampreys (Petromyzontiformes) and their evolutionary implications. AB - Although confined to fresh water, non-parasitic species of lampreys and the landlocked parasitic sea lamprey, all of which were derived relatively recently from an adromous ancestors, still develop chloride cells, whose function in their ancestors was for osmoregulation in marine waters during the adult parasitic phase. In contrast, such cells are not developed by the non-parasitic least brook lamprey Lampetra aepyptera, which has been separated from its ancestor for >2 million years, nor by the freshwater parasitic species of the genus Ichthyomyzon. The length of time that a non-parasitic species or landlocked parasitic form or species has spent in fresh water is thus considered the overriding factor determining whether chloride cells are developed by those lampreys. PMID- 26023690 TI - Editor's response. PMID- 26023691 TI - proceedings of the 38th Annual Meeting of the Japanese Society for Biomedical Mass Spectrometry (JSBMS): New Applications of Mass Spectrometry in Biomedicine, September 26-27, 2013, Kobe City, Japan. PMID- 26023692 TI - Peanut consumption in infants at risk for peanut allergy. PMID- 26023693 TI - Proceedings of the NanoDDS 2013: The 11th International Nano Drug Delivery Symposium, October 25-27, 2014, San Diego, CA. PMID- 26023694 TI - Proceedings of the Neural Orchestration of Metabolism and Islet Function Symposium, March 27-29, 2014, St Jean Cap Ferrat, France. PMID- 26023695 TI - Abstracts of the 46th Annual Meeting of the German Society of Pediatric Cardiology, October 4-7, 2014, Weimar, Germany. PMID- 26023696 TI - Reply: To PMID 23989495. PMID- 26023697 TI - Reply: To PMID 23907692. PMID- 26023698 TI - Medical research: Subject to reflection. PMID- 26023699 TI - Author response. PMID- 26023700 TI - Discussion: "The kinetics of blood lactate in boys during and following a single and repeated all-out sprints of cycling are different than in men" - Do children indeed release and remove lactate faster than adults? PMID- 26023701 TI - Reply to "Discussion: The kinetics of blood lactate in boys during and following a single and repeated all-out sprints of cycling are different than in men - Do children indeed release and remove lactate faster than adults?". PMID- 26023702 TI - Embracing open access and offering greater choice for authors. PMID- 26023704 TI - Tag and Capture Flow Hydrogen Exchange Mass Spectrometry with a Fluorous Immobilized Probe. AB - Analysis of complex mixtures of proteins by hydrogen exchange (HX) mass spectrometry (MS) is limited by one's ability to resolve the protein(s) of interest from the proteins that are not of interest. One strategy for overcoming this problem is to tag the target protein(s) to allow for rapid removal from the mixture for subsequent analysis. Here we illustrate a new solution involving fluorous conjugation of a retrievable probe. The appended fluorous tag allows for facile immobilization on a fluorous surface. When a target protein is passed over the immobilized probe molecule, it can be efficiently captured and then exposed to a flowing stream of deuterated buffer for hydrogen exchange. The utility of this method is illustrated for a model system of the Elongin BC protein complex bound to a peptide from HIV Vif. Efficient capture is demonstrated, and deuteration when immobilized was identical to deuteration in conventional solution-phase hydrogen exchange MS. Protein captured from a crude bacterial cell lysate could also be deuterated without the need for separate purification steps before HX MS. The advantages and disadvantages of the method are discussed in light of miniaturization and automation. PMID- 26023705 TI - Platinum-Incorporating Poly(N-vinylpyrrolidone)-poly(aspartic acid) Pseudoblock Copolymer Nanoparticles for Drug Delivery. AB - Cisplatin-incorporating pseudoblock copolymer nanoparticles with high drug loading efficiency (ca. 50%) were prepared built on host-guest inclusion complexation between beta-cyclodextrin end-capped poly(N-vinylpyrrolidone) block and admantyl end-capped poly(aspartic acid) block, followed by the coordination between cisplatin and carboxyl groups in poly(aspartic acid). The host-guest interaction between the two polymer blocks was examined by two-dimensional nuclear overhauser effect spectroscopy. The size and morphology of nanoparticles formed were characterized by dynamic light scattering, zeta potential, transmission electron microscopy, and atomic force microscopy. The size control of nanoparticles was carried out by varying the ratio of poly(N-vinylpyrrolidone) to poly(aspartic acid). The nanoparticles were stable in the aqueous medium with different pH values but disintegrated in the medium containing Cl(-) ions. The in vitro and in vivo antitumor effects of cisplatin-loaded nanoparticles were evaluated. The biodistribution of the nanoparticles in vivo was studied by noninvasive near-infrared fluorescence imaging and ion-coupled plasma mass spectrometry. It was found that cisplatin-loaded nanoparticles could effectively accumulate in the tumor site and exhibited significant superior in vivo antitumor activity to the commercially available free cisplatin by combining the tumor volume, body weight, and survival rate measurements. PMID- 26023706 TI - Quantum dots: electrochemiluminescent and photoelectrochemical bioanalysis. AB - In this Feature, electrochemiluminescent (ECL) and photoelectrochemical (PEC) properties and mechanisms of semiconductor quantum dots (QDs) are reviewed, with emphasis on their specific fundamentals and concise comparison on their similarities and differences. With recent illustrative examples of bioanalytical applications, the main signaling strategies for QDs-based ECL and PEC bioanalysis are then highlighted. The future prospects in this field are also discussed. PMID- 26023707 TI - Virtual worlds for people with autism spectrum disorder: a case study in Second Life. AB - PURPOSE: The purpose of this study is to explore the use of virtual worlds by people with autism spectrum disorder (ASD), with a particular focus on the virtual world Second LifeTM. METHOD: Case study methodology was selected to explore the experiences of Wolf, a participant with ASD, in Second Life. Wolf participated in three in-depth interviews. The interviews were analyzed using a content analysis to identify themes and sub-themes. RESULTS: Analysis identified four main themes: social factors and communication, empowerment, virtual world versus physical world, and social cues and body language. CONCLUSION: Anecdotally Wolf's experiences suggest that people with ASD enjoy using a virtual world and may feel more comfortable communicating in the virtual world context than the physical world. Virtual worlds offer a venue for people with ASD to be a part of a virtual society, lowers communication barriers experienced in the physical world, and gives the participant a unique opportunity to create and maintain friendships. Virtual worlds offer an arena for people with ASD to meet their peers on equal terms, not being dependent on social cues, which in the physical world can be a barrier for communication for this group. Further research in this area is required. PMID- 26023708 TI - Copper-Catalyzed Oxidative C(sp(3))-H Functionalization for Facile Synthesis of 1,2,4-Triazoles and 1,3,5-Triazines from Amidines. AB - A facile and versatile catalytic system involving copper catalyst, K3PO4 as the base, and O2 as the oxidant has been developed to enable efficient synthesis of 2,4,6-trisubstituted and 2,6-disubstituted 1,3,5-triazines and 1,3-disubstituted 1,2,4-triazoles from amidines with trialkylamines, DMSO, and DMF as the reaction partners, respectively. This protocol features inexpensive metal catalyst, green oxidant, good functional group tolerance, and high regioselectivity, providing an efficient entry to those products that are challenging to prepare by traditional methods. A single-electron-transfer (SET) mechanism is proposed for these transformations. PMID- 26023709 TI - Stereochemistry and Mechanism of Undecylprodigiosin Oxidative Carbocyclization to Streptorubin B by the Rieske Oxygenase RedG. AB - The prodiginines are a group of specialized metabolites that share a 4 methoxypyrrolyldipyrromethene core structure. Streptorubin B is a structurally remarkable member of the prodiginine group produced by Streptomyces coelicolor A3(2) and other actinobacteria. It is biosynthesized from undecylprodigiosin by an oxidative carbocyclization catalyzed by the Rieske oxygenase-like enzyme RedG. Undecylprodigiosin derives from the RedH-catalyzed condensation of 2 undecylpyrrole and 4-methoxy-2, 2'-bipyrrole-5-carboxaldehyde (MBC). To probe the mechanism of the RedG-catalyzed reaction, we synthesized 2-(5-pentoxypentyl) pyrrole, an analogue of 2-undecylpyrrole with an oxygen atom next to the site of C-C bond formation, and fed it, along with synthetic MBC, to Streptomyces albus expressing redH and redG. This resulted in the production of the 6'-oxa analogue of undecylprodigiosin. In addition, a small amount of a derivative of this analogue lacking the n-pentyl group was produced, consistent with a RedG catalytic mechanism involving hydrogen abstraction from the alkyl chain of undecylprodigiosin prior to pyrrole functionalization. To investigate the stereochemistry of the RedG-catalyzed oxidative carbocyclization, [7'-(2)H](7'R) 2-undecylpyrrole and [7'-(2)H](7'S)-2-undecylpyrrole were synthesized and fed separately, along with MBC, to S. albus expressing redH and redG. Analysis of the extent of deuterium incorporation into the streptorubin B produced in these experiments showed that the pro-R hydrogen atom is abstracted from C-7' of undecylprodigiosin and that the reaction proceeds with inversion of configuration at C-7'. This contrasts sharply with oxidative heterocyclization reactions catalyzed by other nonheme iron-dependent oxygenase-like enzymes, such as isopenicillin N synthase and clavaminate synthase, which proceed with retention of configuration at the carbon center undergoing functionalization. PMID- 26023710 TI - Rapid Filament Supramolecular Chirality Reversal of HET-s (218-289) Prion Fibrils Driven by pH Elevation. AB - Amyloid fibril polymorphism is not well understood despite its potential importance for biological activity and associated toxicity. Controlling the polymorphism of mature fibrils including their morphology and supramolecular chirality by postfibrillation changes in the local environment is the subject of this study. Specifically, the effect of pH on the stability and dynamics of HET-s (218-289) prion fibrils has been determined through the use of vibrational circular dichroism (VCD), deep UV resonance Raman, and fluorescence spectroscopies. It was found that a change in solution pH causes deprotonation of Asp and Glu amino acid residues on the surface of HET-s (218-289) prion fibrils and triggers rapid transformation of one supramolecular chiral polymorph into another. This process involves changes in higher order arrangements like lateral filament and fibril association and their supramolecular chirality, while the fibril cross-beta core remains intact. This work suggests a hypothetical mechanism for HET-s (218-289) prion fibril refolding and proposes that the interconversion between fibril polymorphs driven by the solution environment change is a general property of amyloid fibrils. PMID- 26023711 TI - Modeling the Charging of Highly Oxidized Cyclohexene Ozonolysis Products Using Nitrate-Based Chemical Ionization. AB - Several extremely low volatility organic compounds (ELVOCs) formed in the ozonolysis of endocyclic alkenes have recently been detected in laboratory and field studies. These experiments have been carried out with chemical ionization atmospheric pressure interface time-of-flight mass spectrometers (CI-APi-TOF) with nitrate ions as reagent ions. The nitrate ion binds to the detected species through hydrogen bonds, but it also binds very strongly to one or two neutral nitric acid molecules. This makes the measurement highly selective when there is an excess amount of neutral nitric acid in the instrument. In this work, we used quantum-chemical methods to calculate the binding energies between a nitrate ion and several highly oxidized ozonolysis products of cyclohexene. These were then compared with the binding energies of nitrate ion-nitric acid clusters. Systematic configurational sampling of the molecules and clusters was carried out at the B3LYP/6-31+G* and omegaB97xD/aug-cc-pVTZ levels, and the final single point energies were calculated with DLPNO-CCSD(T)/def2-QZVPP. The binding energies were used in a kinetic simulation of the measurement system to determine the relative ratios of the detected signals. Our results indicate that at least two hydrogen bond donor functional groups (in this case, hydroperoxide, OOH) are needed for an ELVOC molecule to be detected in a nitrate ion CI-APi-TOF. Also, a double bond in the carbon backbone makes the nitrate cluster formation less favorable. PMID- 26023712 TI - Double-Bond Isomerization: Highly Reactive Nickel Catalyst Applied in the Synthesis of the Pheromone (9Z,12Z)-Tetradeca-9,12-dienyl Acetate. AB - A highly reactive nickel catalyst comprising NiCl2(dppp) or NiCl2(dppe) with zinc powder, ZnI2 and Ph2PH, was applied in the isomerization of terminal alkenes to Z 2-alkenes. The double-bond geometry of the 2-alkene can be controlled via the reaction temperature to yield the 2-Z-alkenes in excellent yields and high Z selectivities. The formation of other constitutional isomers, such as 3-alkenes, is suppressed on the basis of the proposed mechanism via a 1,2-hydride shift from the metal to the Ph2P ligand. The nickel-catalyzed isomerization reaction was then applied in the synthesis of (9Z,12Z)-tetradeca-9,12-dienyl acetate, a pheromone with a 2Z,5Z-diene subunit. PMID- 26023713 TI - Dysregulation of PAK1 Is Associated with DNA Damage and Is of Prognostic Importance in Primary Esophageal Small Cell Carcinoma. AB - Primary esophageal small cell carcinoma (PESCC) is a rare, but fatal subtype of esophageal carcinoma. No effective therapeutic regimen for it. P21-activated kinase 1 (PAK1) is known to function as an integrator and an indispensable node of major growth factor signaling and the molecular therapy targeting PAK1 has been clinical in pipeline. We thus set to examine the expression and clinical impact of PAK1 in PESCC. The expression of PAK1 was detected in a semi quantitative manner by performing immunohistochemistry. PAK1 was overexpressed in 22 of 34 PESCC tumors, but in only 2 of 18 adjacent non-cancerous tissues. Overexpression of PAK1 was significantly associated with tumor location (p = 0.011), lymph node metastasis (p = 0.026) and patient survival (p = 0.032). We also investigated the association of PAK1 with DNA damage, a driven cause for malignancy progression. gammaH2AX, a DNA damage marker, was detectable in 18 of 24 (75.0%) cases, and PAK1 expression was associated with gammaH2AX (p = 0.027). Together, PAK1 is important in metastasis and progression of PESCC. The contribution of PAK1 to clinical outcomes may be involved in its regulating DNA damage pathway. Further studies are worth determining the potentials of PAK1 as prognostic indicator and therapeutic target for PESCC. PMID- 26023714 TI - 1,8-Cineole Ameliorates Steatosis of Pten Liver Specific KO Mice via Akt Inactivation. AB - Hepatocyte-specific Phosphatase and tensin homolog (Pten)-knockout (KO) mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). 1,8 cineole is a monoterpene oxide and it has several biological effects including hepatoprotective effects. In this study we revealed that 1,8-cineole ameliorates NASH of Pten KO mice. Pten KO mice were assigned to a control group without any medication or to a 1,8-cineole group injected with 50 mg/kg i.p. twice per week for eight weeks. At eight weeks, livers from each group were processed to measure triglyceride (TG) content, gene expression analysis, western blot analysis, and histological examination including Oil red O staining. 1,8-cineole ameliorated hepatic steatosis in Pten KO mice, revealed by TG content and Oil red O staining. Moreover, 1,8-cineole downregulated collagen 1a1 expression and improved liver fibrosis. Thus, 1,8-cineole has potential as a candidate to treat NASH by inactivating the Akt/PI3-kinase pathway. PMID- 26023715 TI - The cross-bridge of skeletal muscle is not synchronized either by length or force step. AB - Force and length steps, applied to a muscle fiber in the isometric state, are believed to synchronize attached cross-bridges. This alleged synchronization facilitates the interpretation of the experiments. A rapid force step elicits an elastic response of the attached cross-bridges, followed by an isotonic phase. The decay of this second isotonic phase is of the first order. This excludes that the attached cross-bridges may decay all at the same time. The change of the X ray interference distance during the second phase measures the stroke size only in the unrealistic case that the cross-bridges are and remain all attached. A rapid force step does not synchronize attached cross-bridges. The change of X-ray interference during the second phase does not measure the stroke size. These conclusions significantly change the picture of the mechanism of skeletal muscle contraction. PMID- 26023716 TI - Human adipose-derived mesenchymal progenitor cells engraft into rabbit articular cartilage. AB - Mesenchymal stem cells (MSCs) are known to have the potential for articular cartilage regeneration, and are suggested for the treatment of osteoarthritis (OA). Here, we investigated whether intra-articular injection of xenogeneic human adipose-derived mesenchymal progenitor cells (haMPCs) promoted articular cartilage repair in rabbit OA model and engrafted into rabbit articular cartilage. The haMPCs were cultured in vitro, and phenotypes and differentiation characteristics of cells were evaluated. OA was induced surgically by anterior cruciate ligament transection (ACLT) and medical meniscectomy of knee joints. At six weeks following surgery, hyaluronic acid (HA) or haMPCs was injected into the knee joints, the contralateral knee served as normal control. All animals were sacrificed at the 16th week post-surgery. Assessments were carried out by macroscopic examination, hematoxylin/eosin (HE) and Safranin-O/Fast green stainings and immunohistochemistry. The data showed that haMPC treatment promoted cartilage repair. Signals of human mitochondrial can be directly detected in haMPC treated cartilage. The haMPCs expressed human leukocyte antigen I (HLA-I) but not HLA-II-DR in vivo. These results suggest that intra-articular injection of haMPCs promotes regeneration of articular cartilage in rabbit OA model, and support the notion that MPCs are transplantable between HLA-incompatible individuals. PMID- 26023717 TI - Anesthetic propofol overdose causes vascular hyperpermeability by reducing endothelial glycocalyx and ATP production. AB - Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions. PMID- 26023718 TI - Periostin expression and its prognostic value for colorectal cancer. AB - Integrin is important for cell growth, invasion and metastasis, which are frequently observed in malignant tumors. The periostin (POSTN) gene encodes the ligand for integrin, one of the key focal adhesion proteins contributing to the formation of a structural link between the extracellular matrix and integrins. High expression levels of the POSTN gene are correlated with numerous human malignancies. We examined POSTN protein in colorectal cancer specimens from 115 patients by strictly following up using immunohistochemistry. Cytoplasm immunohistochemical staining showed POSTN protein expression in colorectal cancers. The positive expression rate of POSTN protein (59.13%, 68/115) in colorectal cancers was significantly higher than that in adjacent normal colon mucosa (0.47%, 11/109). POSTN over-expression in colorectal cancers was positively correlated with tumor size, differentiation, lymph node metastasis, serosal invasion, clinical stage and five-year survival rates. Further analysis showed that patients with advanced stage colorectal cancer and high POSTN expression levels had lower survival rates than those with early stage colorectal cancer and low POSTN expression levels. Overall, our results showed that POSTN played an important role in the progression of colorectal cancers. PMID- 26023719 TI - Anti-Adhesive Activity of Cranberry Phenolic Compounds and Their Microbial Derived Metabolites against Uropathogenic Escherichia coli in Bladder Epithelial Cell Cultures. AB - Cranberry consumption has shown prophylactic effects against urinary tract infections (UTI), although the mechanisms involved are not completely understood. In this paper, cranberry phenolic compounds and their potential microbial-derived metabolites (such as simple phenols and benzoic, phenylacetic and phenylpropionic acids) were tested for their capacity to inhibit the adherence of uropathogenic Escherichia coli (UPEC) ATCC(r)53503TM to T24 epithelial bladder cells. Catechol, benzoic acid, vanillic acid, phenylacetic acid and 3,4-dihydroxyphenylacetic acid showed anti-adhesive activity against UPEC in a concentration-dependent manner from 100-500 uM, whereas procyanidin A2, widely reported as an inhibitor of UPEC adherence on uroepithelium, was only statistically significant (p < 0.05) at 500 uM (51.3% inhibition). The results proved for the first time the anti-adhesive activity of some cranberry-derived phenolic metabolites against UPEC in vitro, suggesting that their presence in the urine could reduce bacterial colonization and progression of UTI. PMID- 26023721 TI - Intracystic interferon-alpha treatment leads to neurotoxicity in craniopharyngioma: case report. AB - Craniopharyngioma is a benign, cystic suprasellar tumor that can be treated with intracystic chemotherapy. Interferon-alpha (IFN-alpha) has been gaining popularity as an intracystic treatment for craniopharyngioma because of its efficacy and supposed benign neurotoxicity profile. In this case report the authors describe a patient who, while receiving intracystic IFN-alpha, suffered a neurological event, which was believed to be related to drug leakage outside the cyst. This is the first report of a focal neurological deficit potentially attributable to intracystic IFN-alpha therapy, highlighting the fact that IFN alpha may have neurotoxic effects on the central nervous system. Given this case and the results of a literature review, the authors suggest that a positive leak test is a relative contraindication to intracystic IFN-alpha treatment. PMID- 26023720 TI - Structural Basis for the Stereochemical Control of Amine Installation in Nucleotide Sugar Aminotransferases. AB - Sugar aminotransferases (SATs) are an important class of tailoring enzymes that catalyze the 5'-pyridoxal phosphate (PLP)-dependent stereo- and regiospecific installation of an amino group from an amino acid donor (typically L-Glu or L Gln) to a corresponding ketosugar nucleotide acceptor. Herein we report the strategic structural study of two homologous C4 SATs (Micromonospora echinospora CalS13 and Escherichia coli WecE) that utilize identical substrates but differ in their stereochemistry of aminotransfer. This study reveals for the first time a new mode of SAT sugar nucleotide binding and, in conjunction with previously reported SAT structural studies, provides the basis from which to propose a universal model for SAT stereo- and regiochemical control of amine installation. Specifically, the universal model put forth highlights catalytic divergence to derive solely from distinctions within nucleotide sugar orientation upon binding within a relatively fixed SAT active site where the available ligand bound structures of the three out of four representative C3 and C4 SAT examples provide a basis for the overall model. Importantly, this study presents a new predictive model to support SAT functional annotation, biochemical study and rational engineering. PMID- 26023722 TI - Opportunities for Decarbonizing Existing U.S. Coal-Fired Power Plants via CO2 Capture, Utilization and Storage. AB - This study employs a power plant modeling tool to explore the feasibility of reducing unit-level emission rates of CO2 by 30% by retrofitting carbon capture, utilization, and storage (CCUS) to existing U.S. coal-fired electric generating units (EGUs). Our goal is to identify feasible EGUs and their key attributes. The results indicate that for about 60 gigawatts of the existing coal-fired capacity, the implementation of partial CO2 capture appears feasible, though its cost is highly dependent on the unit characteristics and fuel prices. Auxiliary gas-fired boilers can be employed to power a carbon capture process without significant increases in the cost of electricity generation. A complementary CO2 emission trading program can provide additional economic incentives for the deployment of CCS with 90% CO2 capture. Selling and utilizing the captured CO2 product for enhanced oil recovery can further accelerate CCUS deployment and also help reinforce a CO2 emission trading market. These efforts would allow existing coal fired EGUs to continue to provide a significant share of the U.S. electricity demand. PMID- 26023723 TI - Time-resolved imaging of pulse-induced magnetization reversal with a microwave assist field. AB - The reversal of the magnetization under the influence of a field pulse has been previously predicted to be an incoherent process with several competing phenomena such as domain wall relaxation, spin wave-mediated instability regions, and vortex-core mediated reversal dynamics. However, there has been no study on the direct observation of the switching process with the aid of a microwave signal input. We report a time-resolved imaging study of magnetization reversal in patterned magnetic structures under the influence of a field pulse with microwave assistance. The microwave frequency is varied to demonstrate the effect of resonant microwave-assisted switching. We observe that the switching process is dominated by spin wave dynamics generated as a result of magnetic instabilities in the structures, and identify the frequencies that are most dominant in magnetization reversal. PMID- 26023724 TI - Phytosiderophores revisited: 2'-deoxymugineic acid-mediated iron uptake triggers nitrogen assimilation in rice (Oryza sativa L.) seedlings. AB - Poaceae plants release phytosiderophores into the rhizosphere in order to chelate iron (Fe), which often exists in insoluble forms especially under high pH conditions. The impact of phytosiderophore treatment at the physiological and molecular levels in vivo remains largely elusive, although the biosynthesis of phytosiderophores and the transport of phytosiderophore-metal complexes have been well studied. We recently showed that the application of 30 MUM of the chemically synthesized phytosiderophore 2'-deoxymugineic acid (DMA) was sufficient for apparent full recovery of otherwise considerably reduced growth of hydroponic rice seedlings at high pH. Moreover, unexpected induction of high-affinity nitrate transporter gene expression as well as nitrate reductase activity indicates that the nitrate response is linked to Fe homeostasis. These data shed light on the biological relevance of DMA not simply as a Fe chelator, but also as a trigger that promotes plant growth by reinforcing nitrate assimilation. PMID- 26023725 TI - Capacity retention behavior and morphology evolution of SixGe1-x nanoparticles as lithium-ion battery anode. AB - Engineering silicon into nanostructures has been a well-adopted strategy to improve the cyclic performance of silicon as a lithium-ion battery anode. Here, we show that the electrode performance can be further improved by alloying silicon with germanium. We have evaluated the electrode performance of SixGe1-x nanoparticles (NPs) with different compositions. Experimentally, SixGe1-x NPs with compositions approaching Si50Ge50 are found to have better cyclic retention than both Si-rich and Ge-rich NPs. During the charge/discharge process, NP merging and Si-Ge homogenization are observed. In addition, a distinct morphology difference is observed after 100 cycles, which is believed to be responsible for the different capacity retention behavior. The present study on SixGe1-x alloy NPs sheds light on the development of Si-based electrode materials for stable operation in lithium-ion batteries (e.g., through a comprehensive design of material structure and chemical composition). The investigation of composition dependent morphology evolution in the delithiated Li-SiGe ternary alloy also significantly broadens our understanding of dealloying in complex systems, and it is complementary to the well-established understanding of dealloying behavior in binary systems (e.g., Au-Ag alloys). PMID- 26023728 TI - Arctic cyclone water vapor isotopes support past sea ice retreat recorded in Greenland ice. AB - Rapid Arctic warming is associated with important water cycle changes: sea ice loss, increasing atmospheric humidity, permafrost thaw, and water-induced ecosystem changes. Understanding these complex modern processes is critical to interpreting past hydrologic changes preserved in paleoclimate records and predicting future Arctic changes. Cyclones are a prevalent Arctic feature and water vapor isotope ratios during these events provide insights into modern hydrologic processes that help explain past changes to the Arctic water cycle. Here we present continuous measurements of water vapor isotope ratios (delta(18)O, delta(2)H, d-excess) in Arctic Alaska from a 2013 cyclone. This cyclone resulted in a sharp d-excess decrease and disproportional delta(18)O enrichment, indicative of a higher humidity open Arctic Ocean water vapor source. Past transitions to warmer climates inferred from Greenland ice core records also reveal sharp decreases in d-excess, hypothesized to represent reduced sea ice extent and an increase in oceanic moisture source to Greenland Ice Sheet precipitation. Thus, measurements of water vapor isotope ratios during an Arctic cyclone provide a critical processed-based explanation, and the first direct confirmation, of relationships previously assumed to govern water isotope ratios during sea ice retreat and increased input of northern ocean moisture into the Arctic water cycle. PMID- 26023726 TI - The Hedgehog signalling pathway in bone formation. AB - The Hedgehog (Hh) signalling pathway plays many important roles in development, homeostasis and tumorigenesis. The critical function of Hh signalling in bone formation has been identified in the past two decades. Here, we review the evolutionarily conserved Hh signalling mechanisms with an emphasis on the functions of the Hh signalling pathway in bone development, homeostasis and diseases. In the early stages of embryonic limb development, Sonic Hedgehog (Shh) acts as a major morphogen in patterning the limb buds. Indian Hedgehog (Ihh) has an essential function in endochondral ossification and induces osteoblast differentiation in the perichondrium. Hh signalling is also involved intramembrane ossification. Interactions between Hh and Wnt signalling regulate cartilage development, endochondral bone formation and synovial joint formation. Hh also plays an important role in bone homeostasis, and reducing Hh signalling protects against age-related bone loss. Disruption of Hh signalling regulation leads to multiple bone diseases, such as progressive osseous heteroplasia. Therefore, understanding the signalling mechanisms and functions of Hh signalling in bone development, homeostasis and diseases will provide important insights into bone disease prevention, diagnoses and therapeutics. PMID- 26023727 TI - Lipidome and transcriptome profiling of pneumolysin intoxication identifies networks involved in statin-conferred protection of airway epithelial cells. AB - Pneumonia remains one of the leading causes of death in both adults and children worldwide. Despite the adoption of a wide variety of therapeutics, the mortality from community-acquired pneumonia has remained relatively constant. Although viral and fungal acute airway infections can result in pneumonia, bacteria are the most common cause of community-acquired pneumonia, with Streptococcus pneumoniae isolated in nearly 50% of cases. Pneumolysin is a cholesterol dependent cytolysin or pore-forming toxin produced by Streptococcus pneumonia and has been shown to play a critical role in bacterial pathogenesis. Airway epithelium is the initial site of many bacterial contacts and its barrier and mucosal immunity functions are central to infectious lung diseases. In our studies, we have shown that the prior exposure to statins confers significant resistance of airway epithelial cells to the cytotoxicity of pneumolysin. We decided to take this study one step further, assessing changes in both the transcriptome and lipidome of human airway epithelial cells exposed to toxin, statin or both. Our current work provides the first global view in human airway epithelial cells of both the transcriptome and the lipid interactions that result in cellular protection from pneumolysin. PMID- 26023729 TI - Histone H1 Favors Folding and Parallel Fibrillar Aggregation of the 1-42 Amyloid beta Peptide. AB - Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases of the central nervous system. The aggregation of the amyloid-beta peptide, Abeta(1-42), is believed to play an important role in the pathogenesis of AD. Histone H1 is found in the cytoplasm of neurons in AD, and it has been shown to interact with aggregated amyloid-beta peptides and with amyloid fibrils. We have used Thioflavin T (ThT) fluorescence enhancement, circular dichroism spectroscopy (CD), coprecipitation, and transmission electron microscopy (TEM) to study the interaction of histone H1 with Abeta(1-42). Both freshly prepared (monomeric) Abeta(1-42) and histone H1 solutions showed negative CD bands typical of the random coil. Mixing Abeta(1-42) and histone H1 led to the loss of the random coil, which was replaced mostly by beta-structure. Therefore, both Abeta(1-42) and histone H1 behave as intrinsically disordered proteins with coupled binding and folding. Mutual structure induction demonstrates the interaction of Abeta(1 42) and histone H1. The interaction was confirmed by coprecipitation followed by SDS-PAGE. Mutual structure induction was also observed with the H1 terminal domains. Incubation of Abeta(1-42) for 1 week in the presence of histone H1 led to the formation of laminar aggregates and thick bundles, characterized by the parallel association of large numbers of fibrils. The aggregates were particularly large and ordered with the H1 subtype H1.2. Further aging of the complexes led to tight compaction of fibril bundles and to fiber growth. Stabilization of fibril-fibril interactions appeared to be determined by the C terminal domain of histone H1. In summary, these observations indicate that histone H1 has at least two effects: it helps the folding of Abeta monomers and stabilizes the parallel association of fibrils. PMID- 26023730 TI - Facile method for the synthesis of a magnetic CNTs-C@Fe-chitosan composite and its application in tetracycline removal from aqueous solutions. AB - A magnetic CNTs-C@Fe-chitosan composite (CNTs-C@Fe-CS) was prepared based on as prepared carbon nanotubes (APCNTs). The metal nanoparticles in APCNTs could be utilized directly without any purification treatment, and the carbon shells provide an effective barrier against oxidation, acid dissolution, and movement of the MNPs, thus ensuring the long-term stability of CNTs-C@Fe-CS. The results showed that CNTs-C@Fe-CS contained more abundant oxygen and nitrogen containing functional groups after chitosan modification and the composite had good magnetization characteristics, even in acidic solutions. Then CNTs-C@Fe-CS was used as an adsorbent for the removal of tetracycline from aqueous solutions. Adsorption experiments indicated that CNTs-C@Fe-CS have a good adsorption capacity (qe) of tetracycline (104 mg g(-1)). The Freundlich isotherm model fitted the experimental data better than the Langmuir isotherm model. Kinetic regression results showed that the adsorption kinetics was more accurately represented by a pseudo second-order model. Intra-particle diffusion was involved in the adsorption, but it was not the only rate-controlling step. Cu(2+) and humic acid could promote the adsorption of tetracycline on CNTs-C@Fe-CS. The CNTs C@Fe-CS adsorbents could be effectively and quickly separated by applying an external magnetic field and the adsorption capacity was still maintained at 99.3 mg g(-1) after being used 10 times. Therefore, CNTs-C@Fe-CS is a promising magnetic nanomaterial for preconcentration and separation of organic pollutants for environmental remediation. PMID- 26023731 TI - Stress levels in parents of children with and without attention deficit hyperactivity disorder during the back-to-school period: results of an international survey in Italy. AB - BACKGROUND: The back-to-school stress survey was an international, non-clinical opinion survey, which aimed to compare stress levels in parents of children with/without attention deficit hyperactivity disorder (ADHD) during the back-to school period. Here, we present results relating to the Italian sample, comparing them with European data. METHODS: The questionnaire was built using a modified Holmes and Rahe stress scale. Parents of children with/without ADHD evaluated potentially stress-causing situations on a scale from 1 (low stress) to 10 (high stress). RESULTS: In Italy, 107 parents of children with ADHD (mean age +/- SD 40.3+/-7.3 years) and 105 parents of children without ADHD (mean age 42.2+/-6.6 years) participated in the survey. The mean age of children with ADHD was 10.3+/ 3.1 years; 77.6% were male, 72.9% had been diagnosed with at least one comorbid condition - in particular conduct disorder (24.3%), learning disorders/dyslexia (23.4%) and language/communication disorder (19.6%) - and 32.7% were receiving ADHD medication. Parents of children with ADHD showed significantly higher stress levels (p<=0.005) compared with the non-ADHD group in all areas analyzed that were related to the return to school. Significant differences between groups (P<0.05) were also observed in most standard areas evaluated (e.g. personal life). These results were in agreement with data obtained for the overall European sample. CONCLUSIONS: Parents of children with ADHD suffer significantly higher stress levels compared with parents of children without ADHD. Considering parental stress is important for the management of children with ADHD, as stress can affect the control of behavioral symptoms of children. PMID- 26023732 TI - Parental opinions and level of knowledge regarding influenza immunization for high risk children: follow-up on two reminder methods. AB - BACKGROUND: The aim of this study was to compare influenza immunization rates in children who were defined as high risk for complications following a letter or a phone reminder, and to survey parental opinions about influenza. METHODS: The 198 families of 930 children were targeted. After the season for immunization, a phone survey was conducted. RESULTS: A letter was sent to the families of 444 children. A telephone reminder was successful with the families of 288 children. The rates of influenza immunization were 15.3% and 13.5%, respectively. In the 86 families that were interviewed, 46.7% of the children in the families who got a reminder letter were immunized compared to 32.1% in those who got a phone reminder (P=0.184). Better knowledge, older parents, and larger families were associated with higher immunization rates. Major reasons for non-immunization were: potential side effects, lack of knowledge, and opposition to influenza vaccine. CONCLUSIONS: A reminder letter or a phone call did not lead to high rates of influenza vaccination in children, nor was there significant difference between the two reminder methods. Parental knowledge, attitude, and barriers for vaccination should be addressed when a reminder method is chosen. PMID- 26023733 TI - CUEDC2 down-regulation is associated with tumor growth and poor prognosis in lung adenocarcinoma. AB - CUE domain-containing 2 (CUEDC2) is a multi-functional protein, which regulates cell cycle, growth factor signaling and inflammation. We found that CUEDC2 was low in lung adenocarcinoma cell lines and lung adenocarcinoma tissues at both mRNA and protein levels. Low levels of CUEDC2 were correlated with a shorter survival time in patients with lung adenocarcinoma (p = 0.004). CUEDC2 expression was correlated with tumor T classification (P = 0.001) at clinical stage (P = 0.001) and tumor size (P = 0.033). Multivariate analysis suggested that CUEDC2 expression is an independent prognostic indicator for patients with lung adenocarcinoma. Ectopic expression of CUEDC2 decreased cell proliferation in vitro and inhibited tumor growth in nude mice in vivo. Knockdown of endogenous CUEDC2 by short hairpin RNAs (shRNAs) increased tumor growth. Inhibition of proliferation by CUEDC2 was associated with inactivation of the PI3K/Akt pathway, induction of p21 and down-regulation of cyclin D1. Our results suggest that decreased expression of CUEDC2 contributes to tumor growth in lung adenocarcinoma, leading to a poor clinical outcome. PMID- 26023734 TI - ERalpha inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer. AB - In human breast cancer, estrogen receptor-alpha (ERalpha) suppresses epithelial mesenchymal transition (EMT) and stemness, two crucial parameters for tumor metastasis; however, the underlying mechanism by which ERalpha regulates these two processes remains largely unknown. Bmi1, the polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog, regulates EMT transition, maintains the self-renewal capacity of stem cells, and is frequently overexpressed in human cancers. In the present study, ERalpha upregulated the expression of the epithelial marker, E-cadherin, in breast cancer cells through the transcriptional down-regulation of Bmi1. Furthermore, ERalpha overexpression suppressed the migration, invasion, and EMT of breast cancer cells. Notably, overexpression of ERalpha significantly decreased the CD44high/CD24low cell population and inhibited the capacity for mammosphere formation in ERalpha-negative breast cancer cells. In addition, overexpression of Bmi1 attenuated the ERalpha-mediated suppression of EMT and cell stemness. Immunohistochemistry revealed an inverse association of ERalpha and Bmi1 expression in human breast cancer tissue. Taken together, our findings suggest that ERalpha inhibits EMT and stemness through the downregulation of Bmi1. PMID- 26023735 TI - miR-15b-5p induces endoplasmic reticulum stress and apoptosis in human hepatocellular carcinoma, both in vitro and in vivo, by suppressing Rab1A. AB - In human hepatocellular carcinoma (HCC), aberrant expression of miRNAs correlates with tumor cell proliferation, apoptosis, invasion, and migration by targeting downstream proteins. miR-15b levels are reported increased in HCC tissues; however, they negatively correlate to HCC recurrence. Our aim was to understand the reason for this phenomenon. We used the reverse transcription-polymerase chain reaction (RT-PCR) to measure miR-15b-5p expression in both HCC tissues and HCC cell lines. Our results were consistent with the report. Using bioinformatics and luciferase reporter assays, we identified Rab1A as a novel and direct target of miR-15b-5p. Inhibiting the function of Rab1A with shRab1A also inhibited the growth of HCC cells and induced endoplasmic reticulum stress (ERS) and apoptosis. Similarly, suppressing Rab1A by overexpression of miR-15b-5p also inhibited cell growth and induced ERS and apoptosis. Moreover, re-expression of Rab1A rescued the miR-15b-5p-induced ERS, apoptosis, and growth inhibition in HCC cells. In vivo assays were further performed to testify them. Taken together, our data suggest that miR-15b-5p induces ERS, apoptosis, and growth inhibition by targeting and suppressing Rab1A, acting as a tumor suppressor gene in HCC. This finding suggests a novel relation among Rabs, miRNAs, and apoptosis. PMID- 26023736 TI - Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition. AB - Proteins that promote epithelial to mesenchymal transition (EMT) are associated with cancer metastasis. Inhibition of EMT regulators may be a promising approach in cancer therapy. In this study, Thymoquinone (TQ) was used to treat cancer cell lines to investigate its effects on EMT-regulatory proteins and cancer metastasis. We show that TQ inhibited cancer cell growth, migration and invasion in a dose-dependent manner. At the molecular level, TQ treatment decreased the transcriptional activity of the TWIST1 promoter and the mRNA expression of TWIST1, an EMT-promoting transcription factor. Accordingly, TQ treatment also decreased the expression of TWIST1-upregulated genes such as N-Cadherin and increased the expression of TWIST1-repressed genes such as E-Cadherin, resulting in a reduction of cell migration and invasion. TQ treatment also inhibited the growth and metastasis of cancer cell-derived xenograft tumors in mice but partially attenuated the migration and invasion in TWIST1-overexpressed cell lines. Furthermore, we found that TQ treatment enhanced the promoter DNA methylation of the TWIST1 gene in BT 549 cells. Together, these results demonstrate that TQ treatment inhibits TWIST1 promoter activity and decreases its expression, leading to the inhibition of cancer cell migration, invasion and metastasis. These findings suggest TQ as a potential small molecular inhibitor of cancer growth and metastasis. PMID- 26023737 TI - In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma. AB - Glioblastoma (GBM) is the most lethal brain cancer with profound genomic alterations. While the bona fide tumor suppressor genes such as PTEN, NF1, and TP53 have high frequency of inactivating mutations, there may be the genes with GBM-suppressive roles for which genomic mutation is not a primary cause for inactivation. To identify such genes, we employed in vivo RNAi screening approach using the patient-derived GBM xenograft models. We found that Nemo-Like Kinase (NLK) negatively regulates mesenchymal activities, a characteristic of aggressive GBM, in part via inhibition of WNT/beta-catenin signaling. Consistent with this, we found that NLK expression is especially low in a subset of GBMs that harbors high WNT/mesenchymal activities. Restoration of NLK inhibited WNT and mesenchymal activities, decreased clonogenic growth and survival, and impeded tumor growth in vivo. These data unravel a tumor suppressive role of NLK and support the feasibility of combining oncogenomics with in vivo RNAi screen. PMID- 26023739 TI - Enhanced secretion of natto phytase by Bacillus subtilis. AB - Phytases comprise a group of phosphatases that trim inorganic phosphates from phytic acid (IP6). In this study, we aimed to achieve the efficient secretion of phytase by Bacillus subtilis. B. subtilis laboratory standard strain 168 and its derivatives exhibit no phytase activity, whereas a natto starter secretes phytase actively. The natto phytase gene was cloned into strain RIK1285, a protease defective derivative of 168, to construct a random library of its N-terminal fusions with 173 different signal peptides (SPs) identified in the 168 genome. The library was screened to assess the efficiency of phytase secretion based on clear zones around colonies on plates, which appeared when IP6 was hydrolyzed. The pbp SP enhanced the secretion of the natto phytase most efficiently, i.e. twice that of the original SP. Thus, the secreted natto phytase was purified and found to remove up to 3 phosphates from IP6. PMID- 26023738 TI - Establishing Duration-Specific Running Intensities From Match-Play Analysis in Rugby League. AB - Rugby league coaches often prescribe training to replicate the demands of competition. The intensities of running drills are often monitored in comparison with absolute match-play measures. Such measures may not be sensitive enough to detect fluctuations in intensity across a match or to differentiate between positions. PURPOSE: To determine the position- and duration-specific running intensities of rugby league competition, using a moving-average method, for the prescription and monitoring of training. METHODS: Data from a 15-Hz global positioning system (GPS) were collected from 32 professional rugby league players across a season. The velocity-time curve was analyzed using a rolling-average method, where maximum values were calculated for 10 different durations, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 min, for each player across each match. RESULTS: There were large differences between the 1- and 2-min rolling averages and all other rolling-average durations. Smaller differences were observed for rolling averages of greater duration. Fullbacks maintained a greater velocity than outside backs and middle and edge forwards over the 1- and 2-min rolling averages (ES 0.8-1.2, P < .05). For rolling averages 3 min and greater, the running demands of the fullbacks were greater than those of the middle forwards and outside backs (ES 1.1-1.4, P < .05). CONCLUSIONS: These findings suggest that the running demands of rugby league fluctuate vastly across a match. Fullbacks were the only position to exhibit a greater running intensity than any other position, and therefore training prescription should reflect this. PMID- 26023740 TI - Diterpenes and lignans from Viburnum odoratissimum var. odoratissimum. AB - A new diterpenoid, dehydrovibsanin G (1), a new lignan, (+)-9'-O senecioyllariciresinol (2), and six known compounds (3-8) were isolated from the branches and leaves of Viburnum odoratissimum var. odoratissimum. The structures of these compounds were elucidated by analysis of spectroscopic data. Both new compounds showed moderate inhibitory activity against human A431 and T47D tumor cell lines. PMID- 26023741 TI - Surface modification and endothelialization of biomaterials as potential scaffolds for vascular tissue engineering applications. AB - Surface modification and endothelialization of vascular biomaterials are common approaches that are used to both resist the nonspecific adhesion of proteins and improve the hemocompatibility and long-term patency of artificial vascular grafts. Surface modification of vascular grafts using hydrophilic poly(ethylene glycol), zwitterionic polymers, heparin or other bioactive molecules can efficiently enhance hemocompatibility, and consequently prevent thrombosis on artificial vascular grafts. However, these modified surfaces may be excessively hydrophilic, which limits initial vascular endothelial cell adhesion and formation of a confluent endothelial lining. Therefore, the improvement of endothelialization on these grafts by chemical modification with specific peptides and genes is now arousing more and more interest. Several active peptides, such as RGD, CAG, REDV and YIGSR, can be specifically recognized by endothelial cells. Consequently, graft surfaces that are modified by these peptides can exhibit targeting selectivity for the adhesion of endothelial cells, and genes can be delivered by targeting carriers to specific tissues to enhance the promotion and regeneration of blood vessels. These methods could effectively accelerate selective endothelial cell recruitment and functional endothelialization. In this review, recent developments in the surface modification and endothelialization of biomaterials in vascular tissue engineering are summarized. Both gene engineering and targeting ligand immobilization are promising methods to improve the clinical outcome of artificial vascular grafts. PMID- 26023742 TI - Exposure Assessment for Carbon Dioxide Gas: Full Shift Average and Short-Term Measurement Approaches. AB - Carbon dioxide (CO2) makes up a relatively small percentage of atmospheric gases, yet when used or produced in large quantities as a gas, a liquid, or a solid (dry ice), substantial airborne exposures may occur. Exposure to elevated CO2 concentrations may elicit toxicity, even with oxygen concentrations that are not considered dangerous per se. Full-shift sampling approaches to measure 8-hr time weighted average (TWA) CO2 exposures are used in many facilities where CO2 gas may be present. The need to assess rapidly fluctuating CO2 levels that may approach immediately dangerous to life or health (IDLH) conditions should also be a concern, and several methods for doing so using fast responding measurement tools are discussed in this paper. Colorimetric detector tubes, a non-dispersive infrared (NDIR) detector, and a portable Fourier transform infrared (FTIR) spectroscopy instrument were evaluated in a laboratory environment using a flow through standard generation system and were found to provide suitable accuracy and precision for assessing rapid fluctuations in CO2 concentration, with a possible effect related to humidity noted only for the detector tubes. These tools were used in the field to select locations and times for grab sampling and personal full-shift sampling, which provided laboratory analysis data to confirm IDLH conditions and 8-hr TWA exposure information. Fluctuating CO2 exposures are exemplified through field work results from several workplaces. In a brewery, brief CO2 exposures above the IDLH value occurred when large volumes of CO2 containing liquid were released for disposal, but 8-hr TWA exposures were not found to exceed the permissible level. In a frozen food production facility nearly constant exposure to CO2 concentrations above the permissible 8-hr TWA value were seen, as well as brief exposures above the IDLH concentration which were associated with specific tasks where liquid CO2 was used. In a poultry processing facility the use of dry ice to quickly freeze product produced a nearly constant CO2 concentration that caused exposures to approach the permissible 8-hr TWA exposure value. PMID- 26023744 TI - Transportation, dispersion and ordering of dense colloidal assemblies by magnetic interfacial rotaphoresis. AB - Colloidal systems exhibit intriguing assembly phenomena with impact in a wide variety of technological fields. The use of magnetically responsive colloids allows one to exploit interactions with an anisotropic dipolar nature. Here, we reveal magnetic interfacial rotaphoresis - a magnetically-induced rotational excitation that imposes a translational motion on colloids by a strong interaction with a solid-liquid interface - as a means to transport, disperse, and order dense colloidal assemblies. By balancing magnetic dipolar and hydrodynamic interactions at a symmetry-breaking interface, rotaphoresis effectuates a translational dispersive motion of the colloids and surprisingly transforms large and dense multilayer assemblies into single-particle layers with quasi-hexagonal ordering within seconds and with velocities of mm s(-1). We demonstrate the application of interfacial rotaphoresis to enhance molecular target capture, showing an increase of the molecular capture rate by more than an order of magnitude. PMID- 26023743 TI - The oxidant role of 4-hydroxynonenal in corneal epithelium. AB - 4-Hydroxynonenal (4-HNE or HNE) is a main endogenous product of cellular lipid peroxidation in tissues and is reported to play pathogenic roles in eye diseases. Here we investigated the association between 4-HNE and oxidative stress in the corneal epithelium. 4-HNE suppressed the cell viability of human corneal epithelial cells (HCE) in a concentration dependent manner. 4-HNE significantly increased the level of 3-Nitrotyrosine (3-NT), a marker of oxidative stress, in HCE cells and corneal epithelium of rats by immunofluorescent staining and Western blot analysis. To its underlying mechanistic on ROS system, 4-HNE elevated the ROS generation enzyme NADPH oxidase 4 (NOX4) and induced the activation of NF-E2-related factor-2 (NRF2) and its downstream effectors: NAD(P)H dehydrogenase (quinone 1) (NQO1) and glutathione S-transferase P (GSTP). Furthermore, N-acetylcysteine (NAC), an antioxidant and ROS scavenger, antagonized the inhibitory and oxidant effects of 4-HNE on the corneal epithelial cells. In conclusion, 4-HNE plays an oxidant role in the corneal epithelium and this work provides a new strategy for the pathogenesis and treatment of corneal diseases. PMID- 26023745 TI - Effect of training status on the changes in platelet parameters induced by short duration exhaustive exercise. AB - It is now well known that hemostasis is directly involved in the benefits induced by physical activity. It has recently been shown that the baseline mean platelet volume (MPV) may be a predictor of endurance performance. We aimed to explore whether platelet parameters are associated with VO2max as well as running duration and speed in a short-duration exhaustive exercise test. Thirty healthy male subjects (10 sedentary and 20 trained) performed an incremental running test until exhaustion. MPV, platelet distribution width (PDW), platelet (Plt) count, and plateletcrit (Pct) were determined before exercise, immediately after exercise and after 30' recovery. Training status did not produce any difference in the baseline levels or in the post-exercise increases found in all the parameters tested. VO2max, test duration, and running speed were not correlated with any baseline parameter. Although MPV was found to be a predictor of endurance performance in long-duration exercise, the results of the present study are consistent with the hypothesis that MPV may not be a significant marker of performance in short-duration exhaustive exercise. Likewise, more research is needed to ascertain whether platelet activation is a reliable performance predictor in other exercise settings. PMID- 26023746 TI - Angioplasty versus stenting for iliac artery lesions. AB - BACKGROUND: Atherosclerosis of the iliac artery may result in a stenosis or occlusion, which is defined as iliac artery occlusive disease. A range of surgical and endovascular treatment options are available. Open surgical procedures have excellent patency rates but at the cost of substantial morbidity and mortality. Endovascular treatment has good safety and short-term efficacy with decreased morbidity, complications and costs compared with open surgical procedures. Both percutaneous transluminal angioplasty (PTA) and stenting are commonly used endovascular treatment options for iliac artery occlusive disease. A stenotic or occlusive lesion of the iliac artery can be treated successfully by PTA alone. If PTA alone is technically unsuccessful, additional stent placement is indicated. Alternatively, a stent could be placed primarily to treat an iliac artery stenosis or occlusion (primary stenting, PS). However, there is limited evidence to prove which endovascular treatment strategy is superior for stenotic and occlusive lesions of the iliac arteries. OBJECTIVES: To assess the effects of percutaneous transluminal angioplasty versus primary stenting for stenotic and occlusive lesions of the iliac artery. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and Cochrane Register of Studies (CRS) (2015, Issue 3). The TSC searched trial databases for details of ongoing and unpublished studies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing percutaneous transluminal angioplasty and primary stenting for iliac artery occlusive disease. We excluded quasi-randomised trials, case reports, case control or cohort studies. We excluded no studies based on the language of publication. DATA COLLECTION AND ANALYSIS: Two authors (JB, NA) independently selected suitable trials. JB and HJ independently performed data extraction and trial quality assessment. When there was disagreement, consensus would be reached first by discussion among both authors and, if still no consensus could be reached, through consultation with BF. MAIN RESULTS: We identified two RCTs with a combined total of 397 participants as meeting the selection criteria. One study included mostly stenotic lesions (95%), whereas the second study included only iliac artery occlusions. Both studies were of moderate methodological quality with some risk of bias relating to selective reporting and non-blinding of participants and personnel. The overall quality of evidence was low due to the small number of included studies, the differences in study populations and definitions of the outcome variables. Due to the heterogeneity among these two studies it was not possible to pool the data. Percutaneous transluminal angioplasty (PTA) with selective stenting and primary stenting (PS) resulted in similar improvement in the stage of peripheral arterial occlusive disease according to Rutherford's criteria, resolution of symptoms and signs, improvement of quality of life, technical success of the procedure and patency of the treated vessel. Improvement in walking distance as reported by the patient, measured claudication distance, ulcer healing, major amputation-free survival and delayed complications (> 72 hours) were not reported in either of the studies. In one trial, PTA of iliac artery occlusions resulted in a significantly higher rate of major complications, especially distal embolisation. The other trial showed a significantly higher mean ankle brachial index (ABI) at two years in the PTA group (1.0) compared to the mean ABI in the PS group (0.91); mean difference (MD) 0.09 (95% confidence interval (CI) 0.04 to 0.14; P value = 0.001, analysis performed by review authors). However, at other time points there was no difference. We consider it unlikely that this difference is attributable to the study procedure, and also believe this difference may not be clinically relevant. AUTHORS' CONCLUSIONS: There is insufficient evidence to assess the effects of PTA versus PS for stenotic and occlusive lesions of the iliac artery. From one study it appears that PS in iliac artery occlusions may result in lower distal embolisation rates. More studies are required to come to a firm conclusion. PMID- 26023747 TI - Vacancy-controlled ultrastable nanoclusters in nanostructured ferritic alloys. AB - A new class of advanced structural materials, based on the Fe-O-vacancy system, has exceptional resistance to high-temperature creep and excellent tolerance to extremely high-dose radiation. Although these remarkable improvements in properties compared to steels are known to be associated with the Y-Ti-O-enriched nanoclusters, the roles of vacancies in facilitating the nucleation of nanoclusters are a long-standing puzzle, due to the experimental difficulties in characterizing vacancies, particularly in-situ while the nanoclusters are forming. Here we report an experiment study that provides the compelling evidence for the presence of significant concentrations of vacancies in Y-Ti-O-enriched nanoclusters in a nanostructured ferritic alloy using a combination of state-of the-art atom-probe tomography and in situ small angle neutron scattering. The nucleation of nanoclusters starts from the O-enriched solute clustering with vacancy mediation. The nanoclusters grow with an extremely low growth rate through attraction of vacancies and O:vacancy pairs, leading to the unusual stability of the nanoclusters. PMID- 26023749 TI - Evaluating assessment programmes using programme evaluation models. PMID- 26023748 TI - Complex Interactions Between the Macrophyte Acorus Calamus and Microbial Fuel Cells During Pyrene and Benzo[a]Pyrene Degradation in Sediments. AB - This study investigated the interaction of the macrophyte Acorus calamus and sediment microbial fuel cells (SMFC) during the degradation of high molecular weight-polycyclic aromatic hydrocarbons (HMW-PAHs) in sediments. Over 367-days, the combination of macrophyte and SMFC led to an increase in pyrene and benzo[a]pyrene degradation rates by at least 70% compared to SMFC or macrophyte alone. While either the macrophyte or SMFC increased redox potential in sediments, redox potentials near the anode (approximately 6 cm depth) in the macrophyte-SMFC combination were markedly lower than that in the only macrophyte treatment. Moreover, rhizospheric bacterial communities in macrophyte-SMFC and macrophyte treatments were distinctly different. Aerobic genera (Vogesella, Pseudomonas, Flavobacterium and Rhizobium) and anaerobic genera (Longilinea, Bellilinea, Desulfobacca and Anaeromyxobacter) became dominant in the rhizosphere in macrophyte and macrophyte-SMFC treatments, respectively. In addition, the macrophyte-SMFC combination improved the numbers of not only aerobic but anaerobic PAHs degraders in sediments. So, the SMFC employment facilitated the formation of anoxic zones in sediments with oxygen loss and exudates from the roots. As a result, cooperation of anaerobic/aerobic microbial metabolism for accelerating HMW-PAHs removal occurred within sediments after combining macrophytes with SMFC. PMID- 26023750 TI - Is it time to recognize excellence in faculty development programs? PMID- 26023752 TI - Student use of iPads at medical school. PMID- 26023751 TI - Enhancing the impact of BEME systematic reviews on educational practice. PMID- 26023753 TI - Memorable outpatient teaching: The sum of many teachable moments. PMID- 26023754 TI - A snapshot of clinical anaesthetics training in UK medical schools. PMID- 26023755 TI - Making room for the invisible: Teaching theory in medical education. PMID- 26023756 TI - Toxicopathology induced by microcystins and nodularin: a histopathological review. AB - Cyanobacteria are present in all aquatic ecosystems throughout the world. They are able to produce toxic secondary metabolites, and microcystins are those most frequently found. Research has displayed a negative influence of microcystins and closely related nodularin on fish, and various histopathological alterations have been observed in many organs of the exposed fish. The aim of this article is to summarize the present knowledge of the impact of microcystins and nodularin on the histology of fish. The observed negative effects of cyanotoxins indicate that cyanobacteria and their toxins are a relevant medical (due to irritation, acute poisoning, tumor promotion, and carcinogenesis), ecotoxicological, and economic problem that may affect both fish and fish consumers including humans. PMID- 26023757 TI - Metal nanoclusters: applications in environmental monitoring and cancer therapy. AB - Metal nanoclusters (NCs), with dimensions between metal atoms and nanoparticles, have attracted more and more attention due to their unique physical and chemical properties. With their size approaching the Fermi wavelength of electrons, metal NCs possess molecule-like properties and excellent fluorescence emission. Owing to their ultrasmall size, strong fluorescence, and excellent biocompatibility, they have been widely studied in environmental and biological fields concerning their applications. In this review, we will introduce the properties of metal NCs, mainly focusing on the synthesis of metal alloy NCs and the recent progress in their applications in environmental monitoring and cancer therapy. PMID- 26023758 TI - Molecular fingerprints of environmental carcinogens in human cancer. AB - Identification of specific molecular changes (fingerprints) is important to identify cancer etiology. Exploitable biomarkers are related to DNA, epigenetics, and proteins. DNA adducts are the turning point between environmental exposures and biological damage. DNA mutational fingerprints are induced by carcinogens in tumor suppressor and oncogenes. In an epigenetic domain, methylation changes occurs in specific genes for arsenic, benzene, chromium, and cigarette smoke. Alteration of specific microRNA has been reported for environmental carcinogens. Benzo(a)pyrene, cadmium, coal, and wood dust hits specific heat-shock proteins and metalloproteases. The multiple analysis of these biomarkers provides information on the carcinogenic mechanisms activated by exposure to environmental carcinogens. PMID- 26023759 TI - A current review for biological monitoring of manganese with exposure, susceptibility, and response biomarkers. AB - People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity. To regulate Mn exposure, many countries have performed biological monitoring of Mn with three major biomarkers: exposure, susceptibility, and response biomarkers. In this study, we review current statuses of Mn exposure via various exposure routes including food, high susceptible population, effects of genetic polymorphisms of metabolic enzymes or transporters (CYP2D6, PARK9, SLC30A10, etc.), alterations of the Mn-responsive proteins (i.e., glutamine synthetase, Mn-SOD, metallothioneins, and divalent metal trnsporter1), and epigenetic changes due to the Mn exposure. To minimize the effects of Mn exposure, further biological monitoring of Mn should be done with more sensitive and selective biomarkers. PMID- 26023760 TI - An Age-Calibrated Classification of Chronic Kidney Disease. PMID- 26023761 TI - Perceived anxiety control is associated with sleep disturbance in young and older adults. AB - OBJECTIVE: This study examined the extent to which perceived anxiety control was related to subjective sleep disturbance in young and older adults. METHOD: Fifty one young adults (18 to 30 years old) and 48 older adults (aged 65 years and older) completed questionnaires including the Pittsburgh Sleep Quality Index (PSQI) to assess sleep disturbance, Anxiety Control Questionnaire to assess perceived control over anxiety, a perceived health rating, and demographic questionnaire. Correlation and multivariable adjusted hierarchical regression analyses examined the extent to which anxiety control was associated with sleep disturbance. RESULTS: Anxiety control and health status were associated with global sleep quality on the PSQI, but no age differences in PSQI scores were found. In post hoc analyses, greater anxiety control was related to shorter sleep latency. Both older age and greater anxiety control were associated with less daytime dysfunction, whereas only older age was associated with better sleep quality. DISCUSSION: Although some variations in sleep quality by age were found, overall findings suggest that perceived anxiety control contributes to sleep disturbance in young and older adults. Greater anxiety control could lead to shorter sleep latency through reduced anxiety and worry symptoms at bedtime. Future studies should examine whether improved anxiety control with psychological treatments is one mechanism through which beneficial and lasting effects on sleep disturbance can be achieved. PMID- 26023762 TI - [Perioperative heart failure - preoperative approach]. AB - Heart failure is a common disease which is associated with an increased perioperative risk. In the following, we summarize pathophysiology, momentary treatment options and a preoperative approach to patients with heart failure. PMID- 26023763 TI - Highly Reproducible and Sensitive SERS Substrates with Ag Inter-Nanoparticle Gaps of 5 nm Fabricated by Ultrathin Aluminum Mask Technique. AB - Applicable surface enhanced Raman scattering (SERS) active substrates require high enhancement factor (EF), excellent spatial reproducibility, and low-cost fabrication method on a large area. Although several SERS substrates with high EF and relative standard deviation (RSD) of signal less than 5% were reported, reliable fabrication for large area SERS substrates with both high sensitivity and high reproducibility via low-cost routes remains a challenge. Here, we report a facile and cost-effective fabrication process for large-scale SERS substrate with Ag inter-nanoparticle (NP) gaps of 5 nm based on ultrathin alumina mask (UTAM) surface pattern technique. Such closely packed Ag NP arrays with high density of electromagnetic field enhancement ("hot spots") on large area exhibit high SERS activity and excellent reproducibility, simultaneously. Rhodamine 6G molecules with concentration of 1 * 10(-7) M are used to determine the SERS performance, and an EF of ~10(9) is obtained. It should be noted that we obtain RSDs about 2% from 10 random spots on an area of 1 cm(2), which implies the highly reproducible signals. Finite-difference time-domain simulations further suggest that the enhanced electric field originates from the narrow gap, which agrees well with the experimental results. The low value of RSD and the high EF of SERS signals indicate that the as-prepared substrate may be promising for highly sensitive and uniform SERS detection. PMID- 26023764 TI - Studies on the redox activity of iron N,O-complexes: Potential T1-contrast agents. AB - OBJECTIVES: The goal of this study was to determine the redox activity of iron (ethylenebis[2-(o-hydroxyphenyl)glycine]) (EHPG) and (ethylenebis[2-(o hydroxybenzyl)glycine]) (EHBG) (N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N' diacetic acid) derivative complexes and of some N,O-salan complexes of iron. The hexadentate chelate (EHPG and EHBG) ligands varied in their substituents (polar OMe, NHAc, or lipophilic Ph), while the latter had different charge and lipophilicity. The low redox activity of these complexes is important in their potential applications as magnetic resonance imaging contrast agents. METHODS: Redox activity was assessed in the entire Haber-Weiss cycle and separately in the Fenton reaction. The spin-trapping method with 5,5-dimethyl-1-pyrroline-N-oxide monitored in electron paramagnetic resonance was used. The standard Mn marker was applied as a reference for quantitative analysis. Additionally, ascorbate oxidation was analyzed with UV-Vis spectrophotometry. RESULTS: Both the Haber Weiss cycle and in particular the Fenton reaction showed low redox activity of the studied complexes, which did not exceed 30% of [Fe(EDTA)]- or FeCl3 activity. The N,O-salan complexes expressed even lower activity, i.e. 10-20% activity of [Fe(EDTA)]-. DISCUSSION: For the EHPG and EHBG complexes, it is likely that hydrophobicity and the possibility of H-bond formation play a major role in the resulting redox effects. For this reason, chelates equipped with phenyl groups in the majority belong to less redox-active complexes. For N,O-salan complexes, activity is not correlated with the charge of the coordination sphere, but again, the highly hydrophobic character of the groups and the non-pendant substituents capable of H-bonding that are present in these ligands limit the affinity of hydrophilic species. PMID- 26023765 TI - Fish beta-parvalbumin acquires allergenic properties by amyloid assembly. AB - PRINCIPLES: Amyloids are highly cross-beta-sheet-rich aggregated states that confer protease resistance, membrane activity and multivalence properties to proteins, all essential features for the undesired preservation of food proteins transiting the gastrointestinal tract and causing type I allergy. METHODS: Amyloid propensity of beta-parvalbumin, the major fish allergen, was theoretically analysed and assayed under gastrointestinal-relevant conditions using the binding of thioflavin T, the formation of sodium dodecyl sulphate- (SDS ) resistant aggregates, circular dichroism spectroscopy and atomic force microscopy fibril imaging. Impact of amyloid aggregates on allergenicity was assessed with dot blot. RESULTS: Sequences of beta-parvalbumin from species with commercial value contain several adhesive hexapeptides capable of driving amyloid formation. Using Atlantic cod beta-parvalbumin (rGad m 1) displaying high IgE cross-reactivity, we found that formation of amyloid fibres under simulated gastrointestinal conditions accounts for the resistance to acid and neutral proteases, for the presence of membrane active species under gastrointestinal relevant conditions and for the IgE-recognition in the sera of allergic patients. Incorporation of the anti-amyloid compound epigallocatechin gallate prevents rGad m 1 fibrillation, facilitates its protease digestion and impairs its recognition by IgE. CONCLUSIONS: the formation of amyloid by rGad m 1 explains its degradation resistance, its facilitated passage across the intestinal epithelial barrier and its epitope architecture as allergen. PMID- 26023766 TI - Gold-catalyzed selective oxidation of 4-oxahepta-1,6-diynes to 2H-pyran-3(6H) ones and chromen-3(4H)-ones via beta-gold vinyl cation intermediates. AB - alpha-Oxo gold carbenes generated in situ via the gold-catalyzed selective oxidation of 4-oxahepta-1,6-diynes were effectively trapped by internal alkynes, resulting in the formation of 2H-pyran-3(6H)-ones, , and chromen-3(4H)-ones, , upon facile trapping the vinyl cation intermediates by an external N-oxide and internal aryl ring system. PMID- 26023767 TI - Compact polar moieties induce lipid-water systems to form discontinuous reverse micellar phase. AB - The role of molecular interactions in governing lipid mesophase organization is of fundamental interest and has technological implications. Herein, we describe an unusual pathway for monoolein/water reorganization from a bicontinuous mesophase to a discontinuous reverse micellar assembly, directed by the inclusion of polar macromolecules. This pathway is very different from those reported earlier, wherein the Fd3m phase formed only upon addition of apolar oils. Experiments and molecular dynamics simulations indicate that hydrophilic ternary additives capable of inducing discontinuous phase formation must (i) interact strongly with the monoolein head group and (ii) have a compact molecular architecture. We present a detailed investigation that contrasts a monoolein water system containing polyamidoamine (PAMAM) dendrons with one containing their linear analogs. The Fd3m phase forms only on the addition of PAMAM dendrons but not their linear analogs. Thus, the dendritic architecture of PAMAM plays an important role in determining lipid mesophase behavior. Both dendrons and their linear analogs interact strongly with monoolein through their amine groups. However, while linear polymers adsorb and spread on monoolein, dendrons form aggregates that interact with the lipid. Dendrons induce formation of an intermediate reverse hexagonal phase, which subsequently restructures into the Fd3m phase. Finally, we demonstrate that other additives with compact structures that are known to interact with monoolein, such as branched polyethylenimine and polyhedral silsesquioxane cages, also induce the formation of the Fd3m phase. PMID- 26023768 TI - Survival analysis of patients with interval cancer undergoing gastric cancer screening by endoscopy. AB - AIMS: Interval cancer is a key factor that influences the effectiveness of a cancer screening program. To evaluate the impact of interval cancer on the effectiveness of endoscopic screening, the survival rates of patients with interval cancer were analyzed. METHODS: We performed gastric cancer-specific and all-causes survival analyses of patients with screen-detected cancer and patients with interval cancer in the endoscopic screening group and radiographic screening group using the Kaplan-Meier method. Since the screening interval was 1 year, interval cancer was defined as gastric cancer detected within 1 year after a negative result. A Cox proportional hazards model was used to investigate the risk factors associated with gastric cancer-specific and all-causes death. RESULTS: A total of 1,493 gastric cancer patients (endoscopic screening group: n = 347; radiographic screening group: n = 166; outpatient group: n = 980) were identified from the Tottori Cancer Registry from 2001 to 2008. The gastric cancer specific survival rates were higher in the endoscopic screening group than in the radiographic screening group and the outpatients group. In the endoscopic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer and the patients with interval cancer were nearly equal (P = 0.869). In the radiographic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer was higher than that of the patients with interval cancer (P = 0.009). For gastric cancer-specific death, the hazard ratio of interval cancer in the endoscopic screening group was 0.216 for gastric cancer death (95%CI: 0.054-0.868) compared with the outpatient group. CONCLUSION: The survival rate and the risk of gastric cancer death among the patients with screen-detected cancer and patients with interval cancer were not significantly different in the annual endoscopic screening. These results suggest the potential of endoscopic screening in reducing mortality from gastric cancer. PMID- 26023769 TI - Measurement of CD8+ and CD4+ T Cell Frequencies Specific for EBV LMP1 and LMP2a Using mRNA-Transfected DCs. AB - An EBV-specific cellular immune response is associated with the control of EBV associated malignancies and lymphoproliferative diseases, some of which have been successfully treated by adoptive T cell therapy. Therefore, many methods have been used to measure EBV-specific cellular immune responses. Previous studies have mainly used autologous EBV-transformed B-lymphoblastoid cell lines (B-LCLs), recombinant viral vectors transfected or peptide pulsed dendritic cells (DCs) as stimulators of CD8(+) and CD4(+) T lymphocytes. In the present study, we used an interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay by using isolated CD8(+) and CD4(+) T cells stimulated with mRNA-transfected DCs. The frequency of latent membrane protein 1 (LMP1)-specific IFN-gamma producing CD4(+) T cells was significantly higher than that of LMP2a. The frequency of IFN-gamma producing CD4(+) T cells was significantly correlated with that of CD8(+) T cells in LMP1-specific immune responses (r = 0.7187, Pc < 0.0001). To determine whether there were changes in LMP1- or LMP2a-specific immune responses, subsequent peripheral blood mononuclear cells (PBMCs) samples were analyzed. Significant changes were observed in 5 of the 10 donors examined, and CD4(+) T cell responses showed more significant changes than CD8(+) T cell responses. CD8(+) and CD4(+) T cells from EBV-seropositive donors secreted only the Th1 cytokines IFN-gamma, TNF alpha, and IL-2, while Th2 (IL-4) and Th17 (IL-17a) cytokines were not detected. CD4(+) T cells secreted significantly higher cytokine levels than did CD8(+) T cells. Analysis of EBV-specific T cell responses using autologous DCs transfected with mRNA might provide a comprehensive tool for monitoring EBV infection and new insights into the pathogenesis of EBV-associated diseases. PMID- 26023770 TI - The NMDA Receptor Promotes Sleep in the Fruit Fly, Drosophila melanogaster. AB - Considerable evidence indicates that sleep is essential for learning and memory. Drosophila melanogaster has emerged as a novel model for studying sleep. We previously found a short sleeper mutant, fumin (fmn), and identified its mutation in the dopamine transporter gene. We reported similarities in the molecular basis of sleep and arousal regulation between mammals and Drosophila. In aversive olfactory learning tasks, fmn mutants demonstrate defective memory retention, which suggests an association between sleep and memory. In an attempt to discover additional sleep related genes in Drosophila, we carried out a microarray analysis comparing mRNA expression in heads of fmn and control flies and found that 563 genes are differentially expressed. Next, using the pan-neuronal Gal4 driver elav-Gal4 and UAS-RNA interference (RNAi) to knockdown individual genes, we performed a functional screen. We found that knockdown of the NMDA type glutamate receptor channel gene (Nmdar1) (also known as dNR1) reduced sleep. The NMDA receptor (NMDAR) plays an important role in learning and memory both in Drosophila and mammals. The application of the NMDAR antagonist, MK-801, reduced sleep in control flies, but not in fmn. These results suggest that NMDAR promotes sleep regulation in Drosophila. PMID- 26023771 TI - Effects of G-gene Deletion and Replacement on Rabies Virus Vector Gene Expression. AB - The glycoprotein-gene (G gene) -deleted rabies virus (RV) vector is a powerful tool to examine the function and structure of neural circuits. We previously reported that the deletion of the G gene enhances the transgene expression level of the RV vector. However, the mechanism of this enhancement remains to be clarified. We presume that there are two possible factors for this enhancement. The first factor is the glycoprotein of RV, which shows cytotoxicity; thus, may cause a dysfunction in the translation process of infected cells. The second possible factor is the enhanced expression of the L gene, which encodes viral RNA polymerase. In the RV, it is known that the gene expression level is altered depending on the position of the gene. Since G-gene deletion displaces the L gene in the genome, the expression of the L gene and viral transcription may be enhanced. In this study, we compared the transgene expression level and viral transcription of three recombinant RV vectors. The effect of glycoprotein was examined by comparing the viral gene expression of G-gene-intact RV and G-gene replaced RV. Despite the fact that the L-gene transcription level of these two RV vectors was similar, the G-gene-replaced RV vector showed higher viral transcription and transgene expression level than the G-gene-intact RV vector. To examine the effect of the position of the L gene, we compared the viral gene expression of the G-gene-deleted RV and G-gene-replaced RV. The G-gene-deleted RV vector showed higher L-gene transcription, viral transcription, and transgene expression level than the G-gene-replaced RV vector. These results indicate that G-gene deletion enhances the transgene expression level through at least two factors, the absence of glycoprotein and enhancement of L-gene expression. These findings enable investigators to design a useful viral vector that shows a controlled desirable transgene expression level in applications. PMID- 26023772 TI - Assessing Odor Level when Using PrePex for HIV Prevention: A Prospective, Randomized, Open Label, Blinded Assessor Trial to Improve Uptake of Male Circumcision. AB - The PrePex is a WHO--prequalified medical device for adult male circumcision for HIV prevention. The Government of Rwanda was the first country to implement the PrePex device and acts as the leading center of excellence providing training and formal guidelines. As part of the Government's efforts to improve PrePex implementation, it made efforts to improve the psychological acceptability of device by men, thus increasing uptake with VMMC in sub-Saharan Africa. Some men who underwent the PrePex procedure complained of foreskin odor while wearing the PrePex 3-7 days after it was placed. This complaint was identified as potential risk for uptake of the device. Researchers from Rwanda assumed there is a possible relation between the level of foreskin odor and patient foreskin hygiene technique. The Government of Rwanda decided to investigate those assumptions in a scientific way and conduct a trial to test different hygiene-cleaning methods in order to increase the acceptability of PrePex and mitigate the odor concern. The main objective of the trial was to compare odor levels between three arms, having identical personal hygiene but different foreskin hygiene techniques using either clear water with soap during a daily shower, soapy water using a syringe, or chlorhexidine using a syringe. One hundred and one subjects were enrolled to the trial and randomly allocated into three trial arms. Using chlorhexidine solution daily almost completely eliminated odor, and was statistically significant more effective that the other two arms. The trial results suggest that odor from the foreskin, while wearing the PrePex device, could be related to the growth of anaerobic bacteria, which can be prevented by a chlorhexidine cleaning method. This finding can be used to increase acceptability by men when considering PrePex as one of the leading methods for HIV prevention in VMMC programs. PMID- 26023773 TI - Cooperative Action of Cdk1/cyclin B and SIRT1 Is Required for Mitotic Repression of rRNA Synthesis. AB - Mitotic repression of rRNA synthesis requires inactivation of the RNA polymerase I (Pol I)-specific transcription factor SL1 by Cdk1/cyclin B-dependent phosphorylation of TAF(I)110 (TBP-associated factor 110) at a single threonine residue (T852). Upon exit from mitosis, T852 is dephosphorylated by Cdc14B, which is sequestered in nucleoli during interphase and is activated upon release from nucleoli at prometaphase. Mitotic repression of Pol I transcription correlates with transient nucleolar enrichment of the NAD(+)-dependent deacetylase SIRT1, which deacetylates another subunit of SL1, TAFI68. Hypoacetylation of TAFI68 destabilizes SL1 binding to the rDNA promoter, thereby impairing transcription complex assembly. Inhibition of SIRT1 activity alleviates mitotic repression of Pol I transcription if phosphorylation of TAF(I)110 is prevented. The results demonstrate that reversible phosphorylation of TAF(I)110 and acetylation of TAFI68 are key modifications that regulate SL1 activity and mediate fluctuations of pre-rRNA synthesis during cell cycle progression. PMID- 26023774 TI - The 'Goldilocks Zone': getting the measure of manual asymmetries. AB - Some studies have shown that manual asymmetries decrease in older age. These results have often been explained with reference to models of reduced hemispheric specialisation. An alternative explanation, however, is that hand differences are subtle, and capturing them requires tasks that yield optimal performance with both hands. Whereas the hemispheric specialisation account implies that reduced manual asymmetries should be reliably observed in older adults, the 'measurement difficulty' account suggests that manual asymmetries will be hard to detect unless a task has just the right level of difficulty--i.e. within the 'Goldilocks Zone', where it is not too easy or too hard, but just right. Experiment One tested this hypothesis and found that manual asymmetries were only detected when participants performed in this zone; specifically, performance on a tracing task was only superior in the preferred hand when task constraints were high (i.e. fast speed tracing). Experiment Two used three different tasks to examine age differences in manual asymmetries; one task produced no asymmetries, whilst two tasks revealed asymmetries in both younger and older groups (with poorer overall performance in the old group across all tasks). Experiment Three revealed task dependent asymmetries in both age groups, but highlighted further detection difficulties linked with the metric of performance and compensatory strategies used by participants. Results are discussed with reference to structural learning theory, whereby we suggest that the processes of inter-manual transfer lead to relatively small performance differences between the hands (despite a strong phenomenological sense of performance disparities). PMID- 26023775 TI - Effect of energy under-reporting on secular trends of dietary patterns in a mediterranean population. AB - BACKGROUND: Diet is an important factor in the prevention of chronic diseases. Analysis of secular trends of dietary patterns can be biased by energy under reporting. Therefore, the objective of the present study was to analyse the impact of energy under-reporting on dietary patterns and secular trends in dietary patterns defined by cluster analysis. DESIGN AND METHODS: Two cross sectional population-based surveys were conducted in Spain, in 2000 and 2005, with 3058 and 6352 participants, respectively, aged 25 to 74 years. Validated questionnaire was used to collect dietary data. Cluster analysis was run separately for all participants, plausible energy reporters (PER), and energy under-reporters (EUR) to define dietary patterns. RESULTS: Three clusters, "healthy", "mixed" and "western", were identified for both surveys. The "mixed" cluster was the predominant cluster in both surveys. Excluding EUR reduced the proportion of the "mixed" cluster up to 6.40% in the 2000 survey; this caused secular trend increase in the prevalence of the "mixed" pattern. Cross classification analysis of all participants and PER' data showed substantial agreement in cluster assignments: 68.7% in 2000 and 84.4% in 2005. Excluding EUR did not cause meaningful (>= 15%) changes in the "healthy" pattern. It provoked changes in consumption of some food groups in the "mixed" and "western" patterns: mainly decreases of unhealthy foods within the 2000 and increases of unhealthy foods within the 2005 surveys. Secular trend effects of EUR were similar to those within the 2005 survey. Excluding EUR reversed the direction of secular trends in consumption of several food groups in PER in the "mixed" and "western" patterns. CONCLUSIONS: EUR affected distribution of participants between dietary patterns within and between surveys, secular trends in food group consumption and amount of food consumed in all, but not in the "healthy" pattern. Our findings emphasize threats from energy under-reporting in dietary data analysis. PMID- 26023776 TI - Studying Cat (Felis catus) Diabetes: Beware of the Acromegalic Imposter. AB - Naturally occurring diabetes mellitus (DM) is common in domestic cats (Felis catus). It has been proposed as a model for human Type 2 DM given many shared features. Small case studies demonstrate feline DM also occurs as a result of insulin resistance due to a somatotrophinoma. The current study estimates the prevalence of hypersomatotropism or acromegaly in the largest cohort of diabetic cats to date, evaluates clinical presentation and ease of recognition. Diabetic cats were screened for hypersomatotropism using serum total insulin-like growth factor-1 (IGF-1; radioimmunoassay), followed by further evaluation of a subset of cases with suggestive IGF-1 (>1000 ng/ml) through pituitary imaging and/ or histopathology. Clinicians indicated pre-test suspicion for hypersomatotropism. In total 1221 diabetic cats were screened; 319 (26.1%) demonstrated a serum IGF 1>1000 ng/ml (95% confidence interval: 23.6-28.6%). Of these cats a subset of 63 (20%) underwent pituitary imaging and 56/63 (89%) had a pituitary tumour on computed tomography; an additional three on magnetic resonance imaging and one on necropsy. These data suggest a positive predictive value of serum IGF-1 for hypersomatotropism of 95% (95% confidence interval: 90-100%), thus suggesting the overall hypersomatotropism prevalence among UK diabetic cats to be 24.8% (95% confidence interval: 21.2-28.6%). Only 24% of clinicians indicated a strong pre test suspicion; most hypersomatotropism cats did not display typical phenotypical acromegaly signs. The current data suggest hypersomatotropism screening should be considered when studying diabetic cats and opportunities exist for comparative acromegaly research, especially in light of the many detected communalities with the human disease. PMID- 26023777 TI - Correction: Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study. PMID- 26023778 TI - An Open Label Non-inferiority Trial Assessing Vibriocidal Response of a Killed Bivalent Oral Cholera Vaccine Regimen following a Five Year Interval in Kolkata, India. AB - BACKGROUND: The bivalent killed oral cholera vaccine (OCV) provides 65% cumulative protection over five years. It remains unknown whether a boosting regimen can maintain protection in previously immunized populations. This study examines the immunogenicity and safety of an OCV regimen given five years following initial dosing. METHODOLOGY/PRINCIPAL FINDINGS: An open label controlled trial was conducted in 426 healthy Indian participants previously enrolled in a large efficacy trial. To assess whether an OCV regimen given after five years can elicit an antibody response equal to that of a primary series, we compared vibriocidal antibody titers in previously immunized participants receiving a two dose booster regimen to participants receiving a primary two dose immunization series. Among participants receiving a two dose primary series of OCV (n = 186), 69% (95% CI 62%-76%) seroconverted. In the intervention arm (n = 184), 66% (95% CI 59%-73%) seroconverted following a two dose boosting schedule given five years following the initial series. Following a single boosting dose, 71% (95% CI 64%-77%) seroconverted. Children demonstrated 79% (95% CI 69%-86%) and 82% (95% CI 73%-88%) seroconversion after primary and boosting regimens, respectively. CONCLUSIONS/SIGNIFICANCE: Administration of an OCV boosting regimen elicits an immune response similar to those receiving a primary series in endemic areas. Though a single boosting dose induces a strong immune response, further investigations are needed to measure if these findings translate to clinical protection. PMID- 26023779 TI - Monosodium Urate Crystals Promote Innate Anti-Mycobacterial Immunity and Improve BCG Efficacy as a Vaccine against Tuberculosis. AB - A safer and more effective anti-Tuberculosis vaccine is still an urgent need. We probed the effects of monosodium urate crystals (MSU) on innate immunity to improve the Bacille Calmette-Guerin (BCG) vaccination. Results showed that in vitro MSU cause an enduring macrophage stimulation of the anti-mycobacterial response, measured as intracellular killing, ROS production and phagolysosome maturation. The contribution of MSU to anti-mycobacterial activity was also shown in vivo. Mice vaccinated in the presence of MSU showed a lower number of BCG in lymph nodes draining the vaccine inoculation site, in comparison to mice vaccinated without MSU. Lastly, we showed that MSU improved the efficacy of BCG vaccination in mice infected with Mycobacterium tuberculosis (MTB), measured in terms of lung and spleen MTB burden. These results demonstrate that the use of MSU as adjuvant may represent a novel strategy to enhance the efficacy of BCG vaccination. PMID- 26023781 TI - Seasonal effects on gene expression. AB - Many health conditions, ranging from psychiatric disorders to cardiovascular disease, display notable seasonal variation in severity and onset. In order to understand the molecular processes underlying this phenomenon, we have examined seasonal variation in the transcriptome of 606 healthy individuals. We show that 74 transcripts associated with a 12-month seasonal cycle were enriched for processes involved in DNA repair and binding. An additional 94 transcripts demonstrated significant seasonal variability that was largely influenced by blood cell count levels. These transcripts were enriched for immune function, protein production, and specific cellular markers for lymphocytes. Accordingly, cell counts for erythrocytes, platelets, neutrophils, monocytes, and CD19 cells demonstrated significant association with a 12-month seasonal cycle. These results demonstrate that seasonal variation is an important environmental regulator of gene expression and blood cell composition. Notable changes in leukocyte counts and genes involved in immune function indicate that immune cell physiology varies throughout the year in healthy individuals. PMID- 26023782 TI - High Concentrations of TNF-alpha Induce Cell Death during Interactions between Human Umbilical Cord Mesenchymal Stem Cells and Peripheral Blood Mononuclear Cells. AB - Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are currently being used as novel therapeutic agents in numerous clinical trials. Previous works have shown that hUC-MSCs possess profound immunomodulatory capacities through IL-1 stimulation produced by peripheral blood mononuclear cells (PBMCs), their main cellular partner in most pathophysiological and therapeutic situations. The present study was designed to explore the role of TNF-alpha in these interactions. In these experiments, we demonstrated that TNF-alpha originated from PBMCs under the influence of IL-1. We also showed that TNF-alpha acted differently depending upon the concentrations reached. At low concentrations it clearly contributed to IL-6 and monocyte chemotactic protein 1 (MCP-1) production. At high concentrations, used alone or in association with the TNF related apoptosis-inducing ligand, TNF-alpha also stimulated hUC-MSC IL-6 but, more intensely, MCP-1 production. This stimulation was associated but independent of apoptosis induction in a process involving Inhibitor of Apoptosis Proteins. Interferon gamma (IFN-gamma), tested to stimulate PBMC and tissue activation, amplified IL-6 and MCP-1 production and cell death by, apparently, a different process involving necrosis. Our findings bring new insights into the complex interactions between hUC-MSCs and PBMCs, involving cytokines, chemokines and cell death, and are of fundamental importance for tissue homeostasis. PMID- 26023780 TI - Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. AB - Eliciting broad tier 2 neutralizing antibodies (nAbs) is a major goal of HIV-1 vaccine research. Here we investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit nAbs. Unusually potent nAb titers developed in 2 of 8 rabbits immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and in 1 of 20 rabbits immunized with DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. Specifically, trimer VLP sera took advantage of the unusual absence of a glycan at residue 197 (present in 98.7% of Envs). Intriguingly, removing the N197 glycan (with no loss of tier 2 phenotype) rendered 50% or 16.7% (n = 18) of clade B tier 2 isolates sensitive to the two trimer VLP sera, showing broad neutralization via the surface masked by the N197 glycan. Neutralizing sera targeted epitopes that overlap with the CD4 binding site, consistent with the role of the N197 glycan in a putative "glycan fence" that limits access to this region. A bioinformatics analysis suggested shared features of one of the trimer VLP sera and monoclonal antibody PG9, consistent with its trimer-dependency. The neutralizing DNA trimer serum took advantage of the absence of a glycan at residue 230, also proximal to the CD4 binding site and suggesting an epitope similar to that of monoclonal antibody 8ANC195, albeit lacking tier 2 breadth. Taken together, our data show for the first time that strain-specific holes in the glycan fence can allow the development of tier 2 neutralizing antibodies to native spikes. Moreover, cross-neutralization can occur in the absence of protecting glycan. Overall, our observations provide new insights that may inform the future development of a neutralizing antibody vaccine. PMID- 26023783 TI - Staff perception on biomedical or health care waste management: a qualitative study in a rural tertiary care hospital in India. AB - BACKGROUND: Health care or biomedical waste, if not managed properly, can be of high risk to the hospital staff, the patients, the community, public health and the environment, especially in low and middle income settings where proper disposal norms are often not followed. Our aim was to explore perceptions of staff of an Indian rural tertiary care teaching hospital on hospital waste management. METHOD: A qualitative study was conducted using 10 focus group discussions (FGDs), with different professional groups, cleaning staff, nurses, medical students, doctors and administrators. The FGD guide included the following topics: (i) role of Health Care Waste Management (HCWM) in prevention of health care associated infections, (ii) awareness of and views about HCWM related guidelines/legislation, (iii) current HCWM practices, (iv) perception and preparedness related to improvements of the current practices, and (v) proper implementation of the available guidelines/legislation. The FGDs were recorded, transcribed verbatim, translated to English (when conducted in Hindi) and analysed using content analysis. RESULTS: Two themes were identified: Theme (A), 'Challenges in integration of HCWM in organizational practice,' with the categories (I) Awareness and views about HCWM, (II) Organizational practices regarding HCWM, and (III) Challenges in Implementation of HCWM; and Theme (B), 'Interventions to improve HCWM,' with three categories, (I) Educational and motivational interventions, (II) Organizational culture change, and (III) Policy related interventions. CONCLUSION: A gap between knowledge and actual practice regarding HCWM was highlighted in the perception of the hospital staff. The participants suggested organizational changes, training and monitoring to address this. The information generated is relevant not merely to the microsystem studied but to other institutions in similar settings. PMID- 26023784 TI - Hypothesis of Long-Term Outcome after Coronary Revascularization in Japanese Patients Compared to Multiethnic Groups in the US. AB - BACKGROUND: Ethnicity has a significant impact on coronary artery disease (CAD). This study investigated the long-term outcomes of Japanese patients undergoing revascularization compared with US patients belonging to multiple ethnic groups. METHODS AND RESULTS: We evaluated clinical outcomes, based on ethnicity, of patients included in the Coronary Revascularization Demonstrating Outcome (CREDO Kyoto) and the Texas (US) Heart Institute Research Database (THIRDBase) registries. For the analysis, we included 8871 patients from the CREDO-Kyoto registry (median follow-up period [FU], 3.5 years; interquartile range [IQR], 2.6 4.3) and 6717 patients from the THIRDBase registry (FU, 5.2 years; IQR, 3.8-6.5) who underwent percutaneous coronary intervention or bypass surgery. Cox proportional hazard models were constructed to compare the adjusted long-term outcomes for each ethnic group. A total of 8871 Japanese, 5170 Caucasians, 648 African-Americans, 817 Hispanics, and 82 Asian-Americans were identified. When adjusted, Japanese patients had significantly better outcomes than US patients, classified by ethnicity (Caucasians: hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.35-1.79; Hispanics: HR, 1.53; 95% CI, 1.22-1.93; African Americans: HR, 2.03; 95% CI, 1.62-2.56), except for Asian-Americans (HR, 0.84; 95% CI. 0.38-1.89) who had outcomes similar to Japanese patients. CONCLUSION: Our findings indicate better survival outcomes in re-vascularized Japanese CAD patients compared to major ethnic groups in the US, including Caucasian, Hispanic, and African-American CAD patients. The characteristics and outcomes of Japanese CAD patients were similar to those of Asian-Americans, despite the sample size limitations in the US dataset. PMID- 26023785 TI - Optimal design of river monitoring network in Taizihe River by matter element analysis. AB - The objective of this study is to optimize the river monitoring network in Taizihe River, Northeast China. The situation of the network and water characteristics were studied in this work. During this study, water samples were collected once a month during January 2009 - December 2010 from seventeen sites. Futhermore, the 16 monitoring indexes were analyzed in the field and laboratory. The pH value of surface water sample was found to be in the range of 6.83 to 9.31, and the average concentrations of NH4(+)-N, chemical oxygen demand (COD), volatile phenol and total phosphorus (TP) were found decreasing significantly. The water quality of the river has been improved from 2009 to 2010. Through the calculation of the data availability and the correlation between adjacent sections, it was found that the present monitoring network was inefficient as well as the optimization was indispensable. In order to improve the situation, the matter element analysis and gravity distance were applied in the optimization of river monitoring network, which were proved to be a useful method to optimize river quality monitoring network. The amount of monitoring sections were cut from 17 to 13 for the monitoring network was more cost-effective after being optimized. The results of this study could be used in developing effective management strategies to improve the environmental quality of Taizihe River. Also, the results show that the proposed model can be effectively used for the optimal design of monitoring networks in river systems. PMID- 26023787 TI - Defective Resensitization in Human Airway Smooth Muscle Cells Evokes beta Adrenergic Receptor Dysfunction in Severe Asthma. AB - beta2-adrenergic receptor (beta2AR) agonists (beta2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of betaARs by beta-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate beta-arrestin binding and betaAR internalization. Resensitization occurs by dephosphorylation of the endosomal betaARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in beta agonist response in asthma is due to altered betaAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs) isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to beta agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated beta2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and beta arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kgamma activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready beta2ARs as a measure of resensitization. Despite significant accumulation of beta2ARs in the endosomes of asthmatic HASMCs, endosomal beta2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kgamma and reduced PP2A activity that inhibits beta2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to beta2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control. PMID- 26023786 TI - Performance comparison of ultrasound-based methods to assess aortic diameter and stiffness in normal and aneurysmal mice. AB - OBJECTIVE: Several ultrasound-based methods are currently used to assess aortic diameter, circumferential strain and stiffness in mice, but none of them is flawless and a gold standard is lacking. We aimed to assess the validity and sensitivity of these methods in control animals and animals developing dissecting abdominal aortic aneurysm. METHODS AND RESULTS: We first compared systolic and diastolic diameters as well as local circumferential strains obtained in 47 Angiotensin II-infused ApoE(-/-) mice with three different techniques (BMode, short axis MMode, long axis MMode), at two different abdominal aortic locations (supraceliac and paravisceral), and at three different time points of abdominal aneurysm formation (baseline, 14 days and 28 days). We found that short axis BMode was preferred to assess diameters, but should be avoided for strains. Short axis MMode gave good results for diameters but high standard deviations for strains. Long axis MMode should be avoided for diameters, and was comparable to short axis MMode for strains. We then compared pulse wave velocity measurements using global, ultrasound-based transit time or regional, pressure-based transit time in 10 control and 20 angiotensin II-infused, anti-TGF-Beta injected C57BL/6 mice. Both transit-time methods poorly correlated and were not able to detect a significant difference in PWV between controls and aneurysms. However, a combination of invasive pressure and MMode diameter, based on radio-frequency data, detected a highly significant difference in local aortic stiffness between controls and aneurysms, with low standard deviation. CONCLUSIONS: In small animal ultrasound the short axis view is preferred over the long axis view to measure aortic diameters, local methods are preferred over transit-time methods to measure aortic stiffness, invasive pressure-diameter data are preferred over non invasive strains to measure local aortic stiffness, and the use of radiofrequency data improves the accuracy of diameter, strain as well as stiffness measurements. PMID- 26023788 TI - Risk of gastric cancer by water source: evidence from the Golestan case-control study. AB - BACKGROUND: Gastric cancer (GC) is the world's fifth most common cancer, and the third leading cause of cancer-related death. Over 70% of incident cases and deaths occur in developing countries. We explored whether disparities in access to improved drinking water sources were associated with GC risk in the Golestan Gastric Cancer Case Control Study. METHODS AND FINDINGS: 306 cases and 605 controls were matched on age, gender, and place of residence. We conducted unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, gender, ethnicity, marital status, education, head of household education, place of birth and residence, homeownership, home size, wealth score, vegetable consumption, and H. pylori seropositivity. Fully-adjusted ORs were 0.23 (95% CI: 0.05-1.04) for chlorinated well water, 4.58 (95% CI: 2.07-10.16) for unchlorinated well water, 4.26 (95% CI: 1.81-10.04) for surface water, 1.11 (95% CI: 0.61-2.03) for water from cisterns, and 1.79 (95% CI: 1.20-2.69) for all unpiped sources, compared to in-home piped water. Comparing unchlorinated water to chlorinated water, we found over a two fold increased GC risk (OR 2.37, 95% CI: 1.56-3.61). CONCLUSIONS: Unpiped and unchlorinated drinking water sources, particularly wells and surface water, were significantly associated with the risk of GC. PMID- 26023790 TI - Applications of shape memory alloys for neurology and neuromuscular rehabilitation. AB - Shape memory alloys (SMAs) are a very promising class of metallic materials that display interesting nonlinear properties, such as pseudoelasticity (PE), shape memory effect (SME) and damping capacity, due to high mechanical hysteresis and internal friction. Our group has applied SMA in the field of neuromuscular rehabilitation, designing some new devices based on the mentioned SMA properties: in particular, a new type of orthosis for spastic limb repositioning, which allows residual voluntary movement of the impaired limb and has no predetermined final target position, but follows and supports muscular elongation in a dynamic and compliant way. Considering patients in the sub-acute phase after a neurological lesion, and possibly bedridden, the paper presents a mobiliser for the ankle joint, which is designed exploiting the SME to provide passive exercise to the paretic lower limb. Two different SMA-based applications in the field of neuroscience are then presented, a guide and a limb mobiliser specially designed to be compatible with diagnostic instrumentations that impose rigid constraints in terms of electromagnetic compatibility and noise distortion. Finally, the paper discusses possible uses of these materials in the treatment of movement disorders, such as dystonia or hyperkinesia, where their dynamic characteristics can be advantageous. PMID- 26023791 TI - Body composition with bioelectrical impedance analysis and body growth in late diagnosed vesicoureteral reflux. AB - BACKGROUND: This study aimed to evaluate together body composition and growth in children with vesicoureteral reflux (VUR). METHODS: The study was performed in children presenting with recurrent urinary tract infection. The patients were grouped as VUR(+) (Group 1) and VUR(-) (Group 2). A group of healthy cases formed the control group (Group 3). The patients and control cases were evaluated from respect to age, gender, body weight, height, Z-scores of weight (WZ) and height (HZ), and Weight-for-Height Index (WHI). In addition, Body Mass Index, lean body mass, body fat mass, fat-free mass, and body cell mass were measured with bioimpedance analyzer. The parameters compared among groups. RESULTS: There were 53 patients in Group 1, 27 patients in Group 2, and 20 subjects in Group 3. While age, sex, weight, and height were not different among groups, WZ and HZ score were lower in the Group 1 than Group 2 and 3 (P=0.002 and P=0.012 to WZ score, P=0.003 and P=0.016 to HZ score, respectively). WHI was lower Group 1 than Group 2 (P=0.036). Among body composition values, only body cell mass was lower in Group 1 than Group 2 and 3 (P=0.015 and P=0.009, respectively). However, there was no difference between the Group 2 and Group 3. CONCLUSIONS: Deficit of body cell mass with body growth evident in patients with VUR in compared with other groups. Therefore, early evolution and treatment in terms of VUR of children with recurrent urinary tract infections may be important. PMID- 26023789 TI - In silico Neuropeptidome of Female Macrobrachium rosenbergii Based on Transcriptome and Peptide Mining of Eyestalk, Central Nervous System and Ovary. AB - Macrobrachium rosenbergii is the most economically important of the cultured freshwater crustacean species, yet there is currently a deficiency in genomic and transcriptomic information for research requirements. In this study, we present an in silico analysis of neuropeptide genes within the female M. rosenbergii eyestalk, central nervous system, and ovary. We could confidently predict 37 preproneuropeptide transcripts, including those that encode bursicons, crustacean cardioactive peptide, crustacean hyperglycemic hormones, eclosion hormone, pigment-dispersing hormones, diuretic hormones, neuropeptide F, neuroparsins, SIFamide, and sulfakinin. These transcripts are most prominent within the eyestalk and central nervous system. Transcript tissue distribution as determined by reverse transcription-polymerase chain reaction revealed the presence of selected neuropeptide genes of interest mainly in the nervous tissues while others were additionally present in the non-nervous tissues. Liquid chromatography-mass spectrometry analysis of eyestalk peptides confirmed the presence of the crustacean hyperglycemic hormone precursor. This data set provides a strong foundation for further studies into the functional roles of neuropeptides in M. rosenbergii, and will be especially helpful for developing methods to improve crustacean aquaculture. PMID- 26023792 TI - Is PCR for common viruses in pediatric acute respiratory infections really useful? PMID- 26023793 TI - Breastfeeding and its gamut of benefits. AB - Maternal milk is recommended as the optimal and exclusive source of early nutrition for all infants from birth and until at least their sixth month of age. Their nutritional virtues are due to potent immune factors and a unique composition which evolves in tandem with the infant's growth and developmental needs. Breast milk promotes sensory and cognitive development, and protects the infant against infectious and chronic diseases. Exclusive breastfeeding reduces infant mortality due to common childhood illnesses such as diarrhea or pneumonia, and improves recovery time during illness. Breastfeeding provides numerous short- and long-term health benefits for both the baby and its mother. Beyond the immediate benefits for infants, breastfeeding also contributes to a lifetime of good health. In this review we describe the influence of breastfeeding on mental and psychomotor development, on the risk of endocrine disorders, pediatric cancers and allergic diseases for the breastfed child. More prospective studies with comparable methodologies and longer periods of follow-up are necessary to allow firm conclusions on the effects of breastfeeding in some of these aspects. PMID- 26023794 TI - Inside and outside the liver: the challenge of hepatitis-associated aplastic anemia in children. PMID- 26023795 TI - TWIST-1 promotes cell growth, drug resistance and progenitor clonogenic capacities in myeloid leukemia and is a novel poor prognostic factor in acute myeloid leukemia. AB - Alterations of TWIST-1 expression are often seen in solid tumors and contribute to tumorigenesis and cancer progression. However, studies concerning its pathogenic role in leukemia are scarce. Our study shows that TWIST-1 is overexpressed in bone marrow mononuclear cells of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Gain-of-function and loss-of function analyses demonstrate that TWIST-1 promotes cell growth, colony formation and drug resistance of AML and CML cell lines. Furthermore, TWIST-1 is aberrantly highly expressed in CD34+CD38- leukemia stem cell candidates and its expression declines with differentiation. Down-modulation of TWIST-1 in myeloid leukemia CD34+ cells impairs their colony-forming capacity. Mechanistically, c-MPL, which is highly expressed in myeloid leukemia cells and associated with poor prognosis, is identified as a TWIST-1 coexpressed gene in myeloid leukemia patients and partially contributes to TWIST-1-mediated leukemogenic effects. Moreover, patients with higher TWIST-1 expression have shorter overall and event-free survival (OS and EFS) in AML. Multivariate analysis further demonstrates that TWIST-1 overexpression is a novel independent unfavourable predictor for both OS and EFS in AML. These data highlight TWIST-1 as a new candidate gene contributing to leukemogenesis of myeloid leukemia, and propose possible new avenues for improving risk and treatment stratification in AML. PMID- 26023796 TI - EGFR blockade prevents glioma escape from BRAFV600E targeted therapy. AB - Mutational activation of BRAF(BRAF(V600E)) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAF(V600E) displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAF(V600E) specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAF(V600E) inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAF(V600E) inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAF(V600E) to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAF(V600E) and EGFR targeted therapy in treating BRAF(V600E) glioma. PMID- 26023797 TI - Differential modulation of AMPK/PPARalpha/UCP2 axis in relation to hypertension and aging in the brain, kidneys and heart of two closely related spontaneously hypertensive rat strains. AB - OBJECTIVES: We examined expression protein of AMPK/SIRT1/PGC1alpha/PhoxO3a/PPARalpha/UCP2 pathway in brain, kidneys and heart of stroke-prone spontaneously hypertensive rat (SHRSP) vs stroke-resistant SHR (SHRSR) at different weeks of age, up to one year, in order to test the hypothesis that abnormalities within this pathway could associate with higher susceptibility of SHRSP to develop hypertension-related vascular damage. BACKGROUND: SHRSP develops severe hypertension and related target organ damage. Marked reduction of uncoupling protein 2 (UCP2) expression upon high salt-low potassium diet associates with increased renal injury in SHRSP. UCP2 may represent a key mitochondrial protein involved in cardiovascular damage. RESULTS: At 2 months of age a significant down-regulation of UCP2 expression at both mRNA and protein levels was found, along with reduced protein expression of all components of UCP2 regulatory pathway, in tissues of SHRSP but not of SHRSR, that progressed with hypertension development and aging. A significant increase of both oxidative stress and inflammation was detected in tissues of SHRSP as a function of age. SBP levels were significantly higher in SHRSP than SHRSR at 3 months of age and thereafter. At one year of age, higher degree of renal damage, with proteinuria and severe glomerular and tubulo-interstitial fibrosis, of cerebral damage, with significant vessel extravasation and stroke occurrence, and of myocardial damage was detected in SHRSP than SHRSR. CONCLUSIONS: The early significant reduced expression of the antioxidant AMPK/PPARalpha/UCP2 pathway that progressed throughout lifetime may contribute to explain higher predisposition of SHRSP to oxidative stress dependent target organ damage in the context of severe hypertension. PMID- 26023798 TI - A combination of YM-155, a small molecule survivin inhibitor, and IL-2 potently suppresses renal cell carcinoma in murine model. AB - YM155, a small molecule inhibitor of the antiapoptotic protein survivin, has been developed as a potential anti-cancer drug. We investigated a combination therapy of YM155 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). YM155 caused cell cycle arrest and apoptosis in renal cancer (RENCA) cells. Next, luciferase-expressing RENCA cells were implanted in the left kidney and the lung of BALB/c mice to develop RCC metastatic model. In this orthotopic renal and metastatic lung tumors models, YM155 and IL-2 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Also, the combination significantly suppressed regulatory T cells and myeloid-derived suppressor cells compared with single agent treatment. We suggest that a combination of YM155 and IL-2 can be tested as a potential therapeutic modality in patients with RCC. PMID- 26023800 TI - Accumulation and Distribution of Lead and Chromium in Laboratory-Scale Constructed Wetlands Inoculated with Metal-Tolerant Bacteria. AB - The accumulation and distribution of lead and chromium was tested in a laboratory scale constructed wetland (CW) inoculated with metal-tolerant bacteria. Two non inoculated systems also were evaluated, one planted and the other unplanted. Mass balances indicated that 57% of chromium input was accumulated into inoculated CW after 151 days of operation. The distribution was similar in support media and vegetation, in which 78% was transferred to aerial part. Similarly Pb was accumulated 29% in the support media and 39% in vegetation, which was distributed 52% in rhizome and 48% in aerial part. Significantly lower amounts of heavy metals were accumulated in non-inoculated systems than in the inoculated wetlands (p < 0.005). In addition, a markedly higher proportion of chromium in aerial vegetation and of lead in the suspended fraction of the effluent was exhibited, which raises a subsequent recovery of the metal by harvest and settling, respectively. Results indicate that CW inoculated with metal-tolerant bacteria might be a suitable option for treating wastewater with content of lead and chromium. PMID- 26023799 TI - Mitochondrial ribosomal protein S18-2 evokes chromosomal instability and transforms primary rat skin fibroblasts. AB - We have shown earlier that overexpression of the human mitochondrial ribosomal protein MRPS18-2 (S18-2) led to immortalization of primary rat embryonic fibroblasts. The derived cells expressed the embryonic stem cell markers, and cellular pathways that control cell proliferation, oxidative phosphorylation, cellular respiration, and other redox reactions were activated in the immortalized cells.Here we report that, upon overexpression of S18-2 protein, primary rat skin fibroblasts underwent cell transformation. Cells passed more than 300 population doublings, and two out of three tested clones gave rise to tumors in experimental animals. Transformed cells showed anchorage-independent growth and loss of contact inhibition; they expressed epithelial markers, such as E-cadherin and beta-catenin. Transformed cells showed increased telomerase activity, disturbance of the cell cycle, and chromosomal instability. Taken together, our data suggest that S18-2 is a newly identified oncoprotein that may be involved in cancerogenesis. PMID- 26023801 TI - An international study of how laboratories handle and evaluate patient samples after detecting an unexpected APTT prolongation. AB - BACKGROUND: An unexpectedly detected prolonged activated partial thromboplastin time (APTT) can be a harmless laboratory finding, but can also reflect a thrombotic tendency or a bleeding disorder. The assistance of laboratory professionals in the interpretation of an unexpectedly detected prolonged APTT (uAPTT) is often required. The way in which uAPTTs are evaluated in laboratories was assessed in this international study with the aim of determining whether laboratory professionals are able to fulfill this need. METHODS: Postanalytical practices after uAPTT were investigated and the mixing study methodology (if used) was studied by circulating a case report with a questionnaire to staff in the invited laboratories. In addition, the interpretations of those staff regarding the presence or absence of inhibitors in three APTT mixing study scenarios were examined. RESULTS: Large within- and between-country variations were detected in both postanalytical practices and mixing study methodologies among the 990 responding laboratories, 90% of which were in 13 countries. Shortcomings regarding the investigation of uAPTTs leading to potentially incorrect or delayed clinical diagnoses were found in 88% of the laboratories. Of the laboratories to which the interpretative questions were sent, 49% interpreted all mixing study scenarios correctly. uAPTTs were investigated appropriately and all mixing study scenarios interpreted correctly in parallel in only 9.6% of the participating laboratories. CONCLUSIONS: The clinical requirement for the assistance of laboratory professionals in the interpretation of uAPTTs cannot be met at most of the participating laboratories. Laboratory professionals should be trained in the evaluation of ordinary laboratory tests, such as that for uAPTTs. PMID- 26023804 TI - Clinical presentation and management of proatlas segmentation defect presenting with palatal myoclonus: case report. AB - Clinical presentation of craniovertebral junction disorders may range from acute catastrophic neurological deficits to insidious signs and symptoms that may mask the underlying etiology. Prompt recognition and treatment is essential to avert long-term neurological morbidity. Proatlas segmentation disorders are a rare group of developmental disorders involving the craniocervical junction. Abnormal bony segmentation leads to malformed bony structures that can in turn lead to neurological deficits through bony compression of the cervicomedullary junction. This report details a proatlas segmentation defect presenting as palatal myoclonus, a rare movement disorder. The clinical presentation, surgical management, and neuroanatomical basis for the disorder is presented. This report highlights the myriad clinical presentations of craniovertebral disorders and emphasizes a rare but treatable etiology for palatal myoclonus. PMID- 26023805 TI - Meta-analysis of studies examining medication adherence, persistence, and discontinuation of oral antihyperglycemic agents in type 2 diabetes. AB - OBJECTIVE: To estimate overall rates of adherence, persistence, and discontinuation for patients with type 2 diabetes mellitus (T2DM) prescribed oral antihyperglycemic agents (OAHAs) by combining results of published studies. RESEARCH DESIGN AND METHODS: A systematic literature review was conducted to identify articles published in English over the last 10 years evaluating the use of OAHAs for the treatment of T2DM. Databases searched included PubMed/MEDLINE, EMBASE, and the Cochrane Library. Seventy studies reporting adherence, persistence or discontinuation were identified by two independent reviewers and 40 reported relevant endpoints for the analysis. Outcomes included: (1) mean adherence defined as the average medication possession ratio (MPR); (2) proportion of adherent patients (MPR >= 80%); (3) discontinuation; and (4) persistence. Adherence and persistence were reported in observational studies only. Discontinuation was examined separately in randomized controlled trials (RCTs) and observational studies. Meta-analyses were conducted using both fixed and random effects models. When meta-analysis was not appropriate for a given outcome, descriptive statistics were provided. RESULTS: The pooled mean MPR (95% confidence interval [CI]) was 75.3% (68.8%-81.7%; n = 13) and the proportion of adherent patients (95% CI) was 67.9% (59.6%-76.3%; n = 12). The discontinuation rate (95% CI) in RCTs was 31.8% (17.0%-46.7%; n = 7). Persistence and discontinuation were not assessed via meta-analysis for observational studies due to the limited number of available studies and differences in outcome definitions. In these studies, persistence estimates ranged from 41.0% to 81.1%, with a mean (95% CI) of 56.2% (46.1%-66.3%; n = 6), while discontinuation estimates ranged from 9.9% to 60.1%, with a mean (95% CI) of 31.4% (17.6%-45.3%; n = 6). LIMITATIONS: Limitations include (1) the use of MPR as a proxy for adherence, (2) limited number of studies available, and (3) observed heterogeneity. CONCLUSION: The results of the analysis demonstrate that medication adherence, persistence, and discontinuation rates are suboptimal in patients with T2DM prescribed OAHAs. PMID- 26023803 TI - A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients. AB - Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer. PMID- 26023808 TI - The Effects of Frontal- and Sagittal-Plane Plyometrics on Change-of-Direction Speed and Power in Adolescent Female Basketball Players. AB - Plyometrics is a popular training modality for basketball players to improve power and change-of-direction speed. Most plyometric training has used sagittal plane exercises, but improvements in change-of-direction speed have been greater in multi-direction programs. PURPOSE: To determine the benefits of a 6-wk frontal plane plyometric (FPP) training program compared with a 6-wk sagittal-plane plyometric (SPP) training program with regard to power and change-of-direction speed. METHODS: Fourteen female varsity high school basketball players participated in the study. Multiple 2 * 2 repeated-measures ANOVAs were used to determine differences for the FPP and SPP groups from preintervention to postintervention on 4 tests of power and 2 tests of change-of-direction speed. RESULTS: There was a group main effect for time in all 6 tests. There was a significant group * time interaction effect in 3 of the 6 tests. The SPP improved performance of the countermovement vertical jump more than the FPP, whereas the FPP improved performance of the lateral hop (left) and lateral-shuffle test (left) more than the SPP. The standing long jump, lateral hop (right), and lateral-shuffle test (right) did not show a significant interaction effect. CONCLUSIONS: These results suggest that basketball players should incorporate plyometric training in all planes to improve power and change-of-direction speed. PMID- 26023810 TI - Venuloxanthone, a new pyranoxanthone from the stem bark of Calophyllum venulosum. AB - A new pyranoxanthone, venuloxanthone (1), was isolated from the stem bark of Calophyllum venulosum, together with three other xanthones, tovopyrifolin C (2), ananixanthone (3) and caloxanthone I (4), along with two common triterpenes, friedelin (5) and lupeol (6). The structures of these compounds were identified using several spectroscopic analyses which are NMR, GCMS and FTIR experiments. PMID- 26023811 TI - Electromagnetic Fields Associated with Commercial Solar Photovoltaic Electric Power Generating Facilities. AB - The southwest region of the United States is expected to experience an expansion of commercial solar photovoltaic generation facilities over the next 25 years. A solar facility converts direct current generated by the solar panels to three phase 60-Hz power that is fed to the grid. This conversion involves sequential processing of the direct current through an inverter that produces low-voltage three-phase power, which is stepped up to distribution voltage (~12 kV) through a transformer. This study characterized magnetic and electric fields between the frequencies of 0 Hz and 3 GHz at two facilities operated by the Southern California Edison Company in Porterville, CA and San Bernardino, CA. Static magnetic fields were very small compared to exposure limits established by IEEE and ICNIRP. The highest 60-Hz magnetic fields were measured adjacent to transformers and inverters, and radiofrequency fields from 5-100 kHz were associated with the inverters. The fields measured complied in every case with IEEE controlled and ICNIRP occupational exposure limits. In all cases, electric fields were negligible compared to IEEE and ICNIRP limits across the spectrum measured and when compared to the FCC limits (>=0.3 MHz). PMID- 26023809 TI - Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections. AB - Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts. PMID- 26023812 TI - Increased platelet activation in subjects chronically exposed to cadmium: A pilot study. AB - Cadmium exposure has been reported to be associated with the risk of vascular disorders. Here, we investigated platelet activity in subjects with chronic cadmium exposure. Eighteen and 15 women participated in this study as chronically cadmium-exposed and control non-exposed subjects, respectively. Plasma P-selectin and CD40 ligand (CD40L), soluble markers of platelet activation, were measured. Platelet aggregation in whole blood, P-selectin and activated glycoprotein (aGP) IIb/IIIa expression on platelets and platelet-leukocyte aggregates were determined. The levels of plasma P-selectin and CD40L increased in subjects with chronic cadmium exposure compared with control subjects. Platelet aggregation induced by adenosine diphosphate (ADP) was higher in cadmium-exposed subjects than control subjects. Cadmium-exposed subjects had higher baseline and ADP induced aGPIIb/IIIa expression on platelets than control subjects. Platelet neutrophil aggregates also increased in cadmium-exposed subjects. Blood cadmium correlated with ADP-induced aggregation, aGPIIb/IIIa expression and platelet neutrophil aggregates, while urinary cadmium correlated with soluble P-selectin. However, cadmium only at high concentration (15 uM) could potentiate ADP-induced platelet activation in vitro. In conclusion, our pilot data show that cadmium exposed subjects have increased baseline platelet activation and reactivity. PMID- 26023813 TI - Application of Statistical Thermodynamics To Predict the Adsorption Properties of Polypeptides in Reversed-Phase HPLC. AB - The theory of critical chromatography for biomacromolecules (BioLCCC) describes polypeptide retention in reversed-phase HPLC using the basic principles of statistical thermodynamics. However, whether this theory correctly depicts a variety of empirical observations and laws introduced for peptide chromatography over the last decades remains to be determined. In this study, by comparing theoretical results with experimental data, we demonstrate that the BioLCCC: (1) fits the empirical dependence of the polypeptide retention on the amino acid sequence length with R(2) > 0.99 and allows in silico determination of the linear regression coefficients of the log-length correction in the additive model for arbitrary sequences and lengths and (2) predicts the distribution coefficients of polypeptides with an accuracy from 0.98 to 0.99 R(2). The latter enables direct calculation of the retention factors for given solvent compositions and modeling of the migration dynamics of polypeptides separated under isocratic or gradient conditions. The obtained results demonstrate that the suggested theory correctly relates the main aspects of polypeptide separation in reversed-phase HPLC. PMID- 26023814 TI - Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential. AB - Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4 oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4 oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures. PMID- 26023815 TI - Polyphenolic Constituents of the Pericarp of Mangosteen (Garcinia mangostana L.). AB - Three new polyphenols, together with 14 known compounds, were isolated from a hot water extract of mangosteen (Garcinia mangostana L.) pericarp, a plant that has been used medicinally in Southeast Asia. The three new polyphenols were characterized as a 4-aryl-2-flavanylbenzopyran derivative (tentatively named GM 1), 1, 3,4,3',5'-tetrahydroxy-5-methoxybenzophenone (GM-2), 2, and 2,3 dihydrochromone derivative (GM-3), 3 on the basis of NMR and MS data. The relative stereostructure of GM-1 was assigned to have 2,3-cis-3,4-trans- and 2",3"-cis configurations on the basis of the coupling constants of heterocyclic ring protons in the (1)H NMR spectrum along with nuclear Overhauser effect correlations. The HPLC analysis indicated that major polyphenolic components in the hot water extract of mangosteen pericarp were epicatechin and procyanidin B2 (epicatechin dimer). PMID- 26023816 TI - Oxidative Cross-Coupling of Two Different Phenols: An Efficient Route to Unsymmetrical Biphenols. AB - An efficient synthesis of unsymmetrical biphenols via the oxidative cross coupling of two different phenols in the presence of K2S2O8 and Bu4N(+).HSO3(-) (10 mol %) in CF3COOH at ambient conditions is described. 1:1 Cross-coupling of substituted phenols with naphthols and 1:2 cross-coupling of naphthols with phenol are also disclosed. By using Bu4N(+).HSO3(-), the homocoupling of phenols or naphthols was controlled. In these reactions, the ortho C-H bond of two different phenols and the ortho and para C-H bond of phenols were coupled together. PMID- 26023817 TI - Use of CAD/CAM Healing Abutment Immediately After Dental Implant Placement for the Non-Esthetic Zone: A Guided Soft Tissue Healing Technique. PMID- 26023818 TI - Aldehyde as a Traceless Directing Group for Rh(III)-Catalyzed C-H Activation: A Facile Access to Diverse Indolo[1,2-a]quinolines. AB - The aldehyde group has been developed for the first time as a traceless directing group to promote regioselective Rh(III)-catalyzed C-H activation/cyclization of indolyl aldehydes with alkynes. This protocol streamlines access to a variety of appealing indolo[1,2-a]quinoline structures. As illustrative examples, a concise three-step synthesis of indolo[1,2-a]quinoline-based sensitizers is accomplished that exhibits the potential of C-H activation in the construction of organic optoelectronic materials. PMID- 26023819 TI - Highly Water-Stable Zirconium Metal-Organic Framework UiO-66 Membranes Supported on Alumina Hollow Fibers for Desalination. AB - In this study, continuous zirconium(IV)-based metal-organic framework (Zr-MOF) membranes were prepared. The pure-phase Zr-MOF (i.e., UiO-66) polycrystalline membranes were fabricated on alumina hollow fibers using an in situ solvothermal synthesis method. Single-gas permeation and ion rejection tests were carried out to confirm membrane integrity and functionality. The membrane exhibited excellent multivalent ion rejection (e.g., 86.3% for Ca(2+), 98.0% for Mg(2+), and 99.3% for Al(3+)) on the basis of size exclusion with moderate permeance (0.14 L m(-2) h(-1) bar(-1)) and good permeability (0.28 L m(-2) h(-1) bar(-1) MUm). Benefiting from the exceptional chemical stability of the UiO-66 material, no degradation of membrane performance was observed for various tests up to 170 h toward a wide range of saline solutions. The high separation performance combined with its outstanding water stability suggests the developed UiO-66 membrane as a promising candidate for water desalination. PMID- 26023820 TI - Binding of Fatty Acid Amide Amphiphiles to Bovine Serum Albumin: Role of Amide Hydrogen Bonding. AB - The study of protein-surfactant interactions is important because of the widespread use of surfactants in industry, medicine, and pharmaceutical fields. Sodium N-lauroylsarcosinate (SL-Sar) is a widely used surfactant in cosmetics, shampoos. In this paper, we studied the interactions of bovine serum albumin (BSA) with SL-Sar and sodium N-lauroylglycinate (SL-Gly) by use of a number of techniques, including fluorescence and circular dichroism spectroscopy and isothermal titration calorimetry. The binding strength of SL-Sar is stronger than that of structurally similar SL-Gly, which differs only by the absence of a methyl group in the amide nitrogen atom. Also, these two surfactants exhibit different binding patterns with the BSA protein. The role of the amide bond and hence the surfactant headgroup in the binding mechanism is discussed in this paper. It was observed that while SL-Sar destabilized, SL-Gly stabilized the protein structure, even at concentrations less than the critical micelle concentration (cmc) value. The thermodynamics of surfactant binding to BSA was studied by use of ITC. From the ITC results, it is concluded that three molecules of SL-Sar in contrast to only one molecule of SL-Gly bind to BSA in one set of binding sites at room temperature. However, on increasing temperature four molecules of SL-Gly bind to the BSA through H-bonding and van der Waals interactions, due to loosening of the BSA structure. In contrast, with SL-Sar the binding process is enthalpy driven, and very little structural change of BSA was observed at higher temperature. PMID- 26023821 TI - Detection of Penicillinase in Milk by Sandwich ELISA Based Polyclonal and Monoclonal Antibody. AB - A sandwich ELISA has been developed using polyclonal and monoclonal antibody for the determination of penicillinase in milk. For this purpose, specific polyclonal and monoclonal antibodies against penicillinase were generated and characterized. Using penicillinase standards prepared from 1-128 ng/mL, the method indicated that the detection limit of the sandwich ELISA, as measured in an ELISA plate reader, was as low as 0.86 ng/mL of penicillinase. For determine the accuracy, raw milk containing 2, 8, 32, and 64 ng/mL of penicillinase were tested by sandwich ELISA. Recoveries were from 93-97.5%, and the coefficient of variation [CV (%)] were from 5.55-8.38%. For interassay reproducibility, recoveries were from 89.5-95.1%, the coefficient of variation [CV (%)] were from 5.26-9.58%. This sandwich ELISA provides a useful screening method for quantitative detection of penicillinase in milk. PMID- 26023822 TI - Quantitative 3D shape description of dust particles from treated seeds by means of X-ray micro-CT. AB - Crop seeds are often treated with pesticides before planting. Pesticide-laden dust particles can be abraded from the seed coating during planting and expelled into the environment, damaging nontarget organisms. Drift of these dust particles depends on their size, shape and density. In this work, we used X-ray micro-CT to examine the size, shape (sphericity) and porosity of dust particles from treated seeds of various crops. The dust properties quantified in this work were very variable in different crops. This variability may be a result of seed morphology, seed batch, treatment composition, treatment technology, seed cleaning or an interaction of these factors. The intraparticle porosity of seed treatment dust particles varied from 0.02 to 0.51 according to the crop and generally increased with particle size. Calculated settling velocities demonstrated that accounting for particle shape and porosity is important in drift studies. For example, the settling velocity of dust particles with an equivalent diameter of 200 MUm may vary between 0.1 and 1.2 m s(-1), depending on their shape and density. Our analysis shows that in a wind velocity of 5 m s(-1), such particles ejected at 1 m height may travel between 4 and 50 m from the source before settling. Although micro-CT is a valuable tool to characterize dust particles, the current image processing methodology limits the number of particles that can be analyzed. PMID- 26023823 TI - Supramolecular Order of 2,5-Bis(dodecanoxy)phenyleneethynylene-Butadiyne Oligomers in the Solid State. AB - The supramolecular order of a 2,5-bis(dodecanoxy)phenyleneethynylene-butadiyne series of rod-like oligomers with 2, 4, 6, and 8 phenyleneethynylene moieties was studied in the solid state by differential scanning calorimetry (DSC), temperature-dependent small- and wide-angle X-ray scattering (SWAXS), selected area electron diffraction (SAED), polarized optical microscopy (POM), high resolution transmission microscopy (HRTEM), and scanning tunneling microscopy (STM). It was found that all of the oligomers self-assemble in blocks of molecules that resemble bricks that are randomly oriented. These oligomers are described as sanidic liquid crystals as a term to classify their mesomorphic behavior because of their brick or board-like structure. The strong pi-pi interaction that governs the package of conjugated backbones was evidenced by the reiterative distances of 0.36 +/- 0.017 nm found by SWAXS and 0.32 +/- 0.017 nm found by HRTEM. A STM study of a cast film of the tetramer deposited on highly oriented pyrolitic graphite (HOPG) allowed for the visualization and determination of the conjugated backbone length of 2.48 nm and a phenyl-phenyl distance of 0.34 nm, suggesting that the molecules are stacked in lamellae perpendicularly aligned to the substrate. PMID- 26023824 TI - Comparison of the effectiveness of rHVT-H5, inactivated H5 and rHVT-H5 with inactivated H5 prime/boost vaccination regimes in commercial broiler chickens carrying MDAs against HPAI H5N1 clade 2.2.1 virus. AB - Vaccination is the main tool implemented in Egypt since 2007 to control H5N1 avian influenza. The present study aimed at comparing the effectiveness of three avian influenza vaccination regimes in commercial broiler chickens carrying high levels of maternally derived antibodies (MDAs). Day-old chicks were divided into four experimental groups. Group I received only the rHVT-H5 vaccine (recombinant turkey herpesvirus (HVT) which carries a H5 clade 2.2 insert) administered at D1. Group II received only the KV-H5 (an oil emulsion killed vaccine prepared from reassortant HPAI virus (A/duck/Anhui/1/06)) vaccine (inactivated reverse genetic H5N1 clade 2.3.4 virus) administered at D8. Group III received rHVT-H5 and KV-H5 as prime/boost. Group IV served as unvaccinated control. Weekly serological monitoring was conducted using the haemagglutination inhibition test. Two challenge experiments were conducted at D28 and D35 using HPAI H5N1 clade 2.2.1 virus. Birds were monitored daily 14 days post-challenge for morbidity and mortality, and oropharyngeal swabs were collected for virological monitoring. Initially, day-old chicks had high mean MDA titres (9 + 0.9 log2). The MDA half life was >7 and <7 days, respectively, for unvaccinated and vaccinated birds. Group III showed the highest post-vaccination humoral immune response and seroconversion rate. The highest protection rate against morbidity (80-90%) and mortality (90-90%) was obtained in Group III after challenge at D28 and D35, respectively, as compared to Group I (70-70%) and (80-90%) and Group II (0-0%) and (30-30%). Groups I and III had lower number of shedder birds. The vaccination regime with prime/boost conferred the highest and earliest protection, and can hence be recommended for the broiler production sector in endemic and high HPAI H5N1 challenge areas. PMID- 26023826 TI - One-Step Preparation of Silver Hexagonal Microsheets as Electrically Conductive Adhesive Fillers for Printed Electronics. AB - A facile one-step solution-phase chemical reduction method has been developed to synthesize Ag microsheets at room temperature. The morphology of Ag sheets is a regular hexagon more than 1 MUm in size and about 200 nm in thickness. The hexagonal Ag microsheets possess a smoother and straighter surface compared with that of the commercial Ag micrometer-sized flakes prepared by ball milling for electrically conductive adhesives (ECAs). The function of the reagents and the formation mechanism of Ag hexagonal microsheets are also investigated. For the polyvinylpyrrolidone (PVP) and citrate facet-selective capping, the Ag atoms freshly reduced by N2H4 would orientationally grow alone on the {111} facet of Ag seeds, with the synergistically selective etching of irregular and small Ag particles by H2O2, to form Ag hexagonal microsheets. The hexagonal Ag microsheet filled epoxy adhesives, as electrically conductive materials, can be easily printed on various substrates such as polyethylene terephthalate (PET), epoxy, glass, and flexible papers. The hexagonal Ag microsheet filled ECAs demonstrate lower bulk resistivity (approximately 8 * 10(-5) Omega cm) than that of the traditional Ag micrometer-sized-flake-filled ECAs with the same Ag content of 80 wt % (approximately 1.2 * 10(-4) Omega cm). PMID- 26023825 TI - Notch Transmembrane Domain: Secondary Structure and Topology. AB - The Notch signaling pathway is critical in development, neuronal maintenance, and hematopoiesis. An obligate step in the activation of this pathway is cleavage of its transmembrane (TM) domain by gamma-secretase. While the soluble domains have been extensively studied, little has been done to characterize its TM and flanking juxtamembrane (JM) segments. Here, we present the results of nuclear magnetic resonance (NMR) studies of the human Notch1 TM/JM domain. The TM domain is largely alpha-helical. While the flanking JM segments do not adopt regular secondary structure, they interact with the membrane surface, suggesting membrane interactions may play a role in modulating its cleavage by gamma-secretase and subsequent NOTCH signaling function. PMID- 26023827 TI - A descriptive study of step alignment and foot positioning relative to the tee by professional rugby union goal-kickers. AB - This study describes foot positioning during the final two steps of the approach to the ball amongst professional rugby goal-kickers. A 3D optical motion capture system was used to test 15 goal-kickers performing 10 goal-kicks. The distance and direction of each step, as well as individual foot contact positions relative to the tee, were measured. The intra- and inter-subject variability was calculated as well as the correlation (Pearson) between the measurements and participant anthropometrics. Inter-subject variability for the final foot position was lowest (placed 0.03 +/- 0.07 m behind and 0.33 +/- 0.03 m lateral to the tee) and highest for the penultimate step distance (0.666 +/- 0.149 m), performed at an angle of 36.1 +/- 8.5 degrees external to the final step. The final step length was 1.523 +/- 0.124 m, executed at an external angle of 35.5 +/ 7.4 degrees to the target line. The intra-subject variability was very low; distances and angles for the 10 kicks varied per participant by 1.6-3.1 cm and 0.7-1.6 degrees , respectively. The results show that even though the participants had variability in their run-up to the tee, final foot position next to the tee was very similar and consistent. Furthermore, the inter- and intra subject variability could not be attributed to differences in anthropometry. These findings may be useful as normative reference data for coaching, although further work is required to understand the role of other factors such as approach speed and body alignment. PMID- 26023828 TI - Acute kidney injury KDIGO stage 2 to 3 in HIV-positive patients treated with cART -a case series over 11 years in a cohort of 1,153 patients. AB - OBJECTIVES: We aimed to explore acute kidney injury (AKI) Kidney Disease Improving Global Guidelines (KDIGO) stage 2 to 3 in a cohort of antiretroviral treated HIV-infected individuals. METHODS: HIV-infected individuals of the Swiss HIV Cohort Study (Basel site), treated with combination antiretroviral therapy (cART) 2002-2013, were included. AKI was defined and classified according to the KDIGO Clinical Practice Guidelines for AKI. Data were prospectively collected and reports of kidney biopsies obtained from records. RESULTS: Among 1,153 cART treated patients, 13 experienced AKI KDIGO stage 2 to 3 (1 patient stage 2, 12 patients stage 3; median age 46 years; 9 male; median CD4 count 366 cells/MUl), corresponding to an incidence rate of AKI of 0.77 (95% confidence interval 0.45 1.33) per 1000 patient-years. Baseline estimated glomerular filtration rate (eGFR) was 87 ml/min (interquartile range 66-100). Ten patients were treated with tenofovir (TDF). Nine patients (69%) had >=1 cardiovascular risk factor, only two patients had known pre-existing kidney disease. Three patients needed chronic and two temporary dialysis. AKI was associated with TDF therapy in 6 of 13 (46%) patients (mean TDF exposure time before AKI 41 months). Impaired renal function was partially reversible in all patients. In three patients with biopsy-proven pre-existing kidney disease (AA amyloidosis, calcineurin inhibitor-induced nephropathy and minimal change glomerulopathy), TDF potentially added to AKI. CONCLUSIONS: AKI KDIGO stage 2 to 3 demonstrates complex associations at the individual level and can occur without early signs. Although treatment with TDF and presence of cardiovascular risk factors were found frequently, predicting AKI seems very difficult. PMID- 26023829 TI - Measuring the optimal exposure for single particle cryo-EM using a 2.6 A reconstruction of rotavirus VP6. AB - Biological specimens suffer radiation damage when imaged in an electron microscope, ultimately limiting the attainable resolution. At a given resolution, an optimal exposure can be defined that maximizes the signal-to-noise ratio in the image. Using a 2.6 A resolution single particle cryo-EM reconstruction of rotavirus VP6, determined from movies recorded with a total exposure of 100 electrons/A(2), we obtained accurate measurements of optimal exposure values over a wide range of resolutions. At low and intermediate resolutions, our measured values are considerably higher than obtained previously for crystalline specimens, indicating that both images and movies should be collected with higher exposures than are generally used. We demonstrate a method of using our optimal exposure values to filter movie frames, yielding images with improved contrast that lead to higher resolution reconstructions. This 'high-exposure' technique should benefit cryo-EM work on all types of samples, especially those of relatively low-molecular mass. PMID- 26023830 TI - The Caenorhabditis elegans protein SAS-5 forms large oligomeric assemblies critical for centriole formation. AB - Centrioles are microtubule-based organelles crucial for cell division, sensing and motility. In Caenorhabditis elegans, the onset of centriole formation requires notably the proteins SAS-5 and SAS-6, which have functional equivalents across eukaryotic evolution. Whereas the molecular architecture of SAS-6 and its role in initiating centriole formation are well understood, the mechanisms by which SAS-5 and its relatives function is unclear. Here, we combine biophysical and structural analysis to uncover the architecture of SAS-5 and examine its functional implications in vivo. Our work reveals that two distinct self associating domains are necessary to form higher-order oligomers of SAS-5: a trimeric coiled coil and a novel globular dimeric Implico domain. Disruption of either domain leads to centriole duplication failure in worm embryos, indicating that large SAS-5 assemblies are necessary for function in vivo. PMID- 26023832 TI - Alkyl-aryl ketone synthesis via nickel-catalyzed reductive coupling of alkyl halides with aryl acids and anhydrides. AB - The present work disclosed a considerably improved method for the construction of alkyl-aryl ketones by the direct coupling of unactivated alkyl bromides with 1.5 equiv. of acids. In addition, the synthesis of aroyl C-glycosides was first achieved by the reductive coupling of 1-glycosyl bromides with acid derivatives, which may otherwise require multi-step synthesis. PMID- 26023831 TI - Speech encoding by coupled cortical theta and gamma oscillations. AB - Many environmental stimuli present a quasi-rhythmic structure at different timescales that the brain needs to decompose and integrate. Cortical oscillations have been proposed as instruments of sensory de-multiplexing, i.e., the parallel processing of different frequency streams in sensory signals. Yet their causal role in such a process has never been demonstrated. Here, we used a neural microcircuit model to address whether coupled theta-gamma oscillations, as observed in human auditory cortex, could underpin the multiscale sensory analysis of speech. We show that, in continuous speech, theta oscillations can flexibly track the syllabic rhythm and temporally organize the phoneme-level response of gamma neurons into a code that enables syllable identification. The tracking of slow speech fluctuations by theta oscillations, and its coupling to gamma-spiking activity both appeared as critical features for accurate speech encoding. These results demonstrate that cortical oscillations can be a key instrument of speech de-multiplexing, parsing, and encoding. PMID- 26023833 TI - Correction: Evaluation of water displacement energetics in protein binding sites with grid cell theory. PMID- 26023834 TI - Effects of thermal noise on the transitional dynamics of an inextensible elastic filament in stagnation flow. AB - We investigate the dynamics of a single inextensible elastic filament subject to anisotropic friction in a viscous stagnation-point flow, by employing both a continuum model represented by Langevin type stochastic partial differential equations (SPDEs) and a dissipative particle dynamics (DPD) method. Unlike previous works, the filament is free to rotate and the tension along the filament is determined by the local inextensible constraint. The kinematics of the filament is recorded and studied with normal modes analysis. The results show that the filament displays an instability induced by negative tension, which is analogous to Euler buckling of a beam. Symmetry breaking of normal modes dynamics and stretch-coil transitions are observed above the threshold of the buckling instability point. Furthermore, both temporal and spatial noise are amplified resulting from the interaction of thermal fluctuations and nonlinear filament dynamics. Specifically, the spatial noise is amplified with even normal modes being excited due to symmetry breaking, while the temporal noise is amplified with increasing time correlation length and variance. PMID- 26023835 TI - Structural and Functional Characterization of a Novel alpha-Conotoxin Mr1.7 from Conus marmoreus Targeting Neuronal nAChR alpha3beta2, alpha9alpha10 and alpha6/alpha3beta2beta3 Subtypes. AB - In the present study, we synthesized and, structurally and functionally characterized a novel alpha4/7-conotoxin Mr1.7 (PECCTHPACHVSHPELC-NH2), which was previously identified by cDNA libraries from Conus marmoreus in our lab. The NMR solution structure showed that Mr1.7 contained a 310-helix from residues Pro7 to His10 and a type I beta-turn from residues Pro14 to Cys17. Electrophysiological results showed that Mr1.7 selectively inhibited the alpha3beta2, alpha9alpha10 and alpha6/alpha3beta2beta3 neuronal nicotinic acetylcholine receptors (nAChRs) with an IC50 of 53.1 nM, 185.7 nM and 284.2 nM, respectively, but showed no inhibitory activity on other nAChR subtypes. Further structure-activity studies of Mr1.7 demonstrated that the PE residues at the N-terminal sequence of Mr1.7 were important for modulating its selectivity, and the replacement of Glu2 by Ala resulted in a significant increase in potency and selectivity to the alpha3beta2 nAChR. Furthermore, the substitution of Ser12 with Asn in the loop2 significantly increased the binding of Mr1.7 to alpha3beta2, alpha3beta4, alpha2beta4 and alpha7 nAChR subtypes. Taken together, this work expanded our knowledge of selectivity and provided a new way to improve the potency and selectivity of inhibitors for nAChR subtypes. PMID- 26023836 TI - Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer. AB - Protein phosphatase 2A (PP2A) is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa). However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients. PMID- 26023837 TI - Production of Chondroitin Sulphate from Head, Skeleton and Fins of Scyliorhinus canicula By-Products by Combination of Enzymatic, Chemical Precipitation and Ultrafiltration Methodologies. AB - This study illustrates the optimisation of the experimental conditions of three sequential steps for chondroitin sulphate (CS) recovery from three cartilaginous materials of Scyliorhinus canicula by-products. Optimum conditions of temperature and pH were first obtained for alcalase proteolysis of head cartilage (58 degrees C/pH 8.5/0.1% (v/w)/10 h of hydrolysis). Then, similar optimal conditions were observed for skeletons and fin materials. Enzymatic hydrolysates were subsequently treated with a combination of alkaline hydroalcoholic saline solutions in order to improve the protein hydrolysis and the selective precipitation of CS. Ranges of 0.53-0.64 M (NaOH) and 1.14-1.20 volumes (EtOH) were the levels for optimal chemical treatment depending on the cartilage origin. Finally, selective purification and concentration of CS and protein elimination of samples obtained from chemical treatment, was assessed by a combination of ultrafiltration and diafiltration (UF-DF) techniques at 30 kDa. PMID- 26023838 TI - Enantioselective total synthesis of (+)-lyngbyabellin M. AB - Lyngbyabellin M is a non-ribosomal peptide synthetase/polyketide synthase derived metabolite isolated from the cyanobacterium M. bouillonii displaying thiazole rings and a distinct chlorinated octanoic acid chain. Its absolute configuration was proposed based on the comparison of its spectroscopic data with those of other representatives of this family of marine natural products, as well as degradation and derivatization studies. Here the first total synthesis of (+) lyngbyabellin M is described based on the coupling of three key intermediates: two chiral thiazole moieties and an anti hydroxycarboxylic acid prepared stereoselectively via a boron enolate mediated aldol reaction directed by Masamune's chiral auxiliary. PMID- 26023839 TI - Influence of Core Oligosaccharide of Lipopolysaccharide to Outer Membrane Behavior of Escherichia coli. AB - Lipopolysaccharides, major molecules in the outer membrane of Gram-negative bacteria, play important roles on membrane integrity of the cell. However, how the core oligosaccharide of lipopolysaccharide affect the membrane behavior is not well understood. In this study, the relationship between the core oligosaccharide of lipopolysaccharide and the membrane behavior was investigated using a series of Escherichia coli mutants defective in genes to affect the biosynthesis of core oligosaccharide of lipopolysaccharide. Cell surface hydrophobicity, outer membrane permeability, biofilm formation and auto aggregation of these mutant cells were compared. Compared to the wild type W3110, cell surface hydrophobicities of mutant DeltawaaC, DeltawaaF, DeltawaaG, DeltawaaO, DeltawaaP, DeltawaaY and DeltawaaB were enhanced, outer membrane permeabilities of DeltawaaC, DeltawaaF, DeltawaaG and DeltawaaP were significantly increased, abilities of biofilm formation by DeltawaaC, DeltawaaF, DeltawaaG, DeltawaaO, DeltawaaR, DeltawaaP, DeltawaaQ and DeltawaaY decreased, and auto-aggregation abilities of DeltawaaC, DeltawaaF, DeltawaaG, DeltawaaO, DeltawaaR, DeltawaaU, DeltawaaP and DeltawaaY were strongly enhanced. These results give new insight into the influence of core oligosaccharide of lipopolysaccharide on bacterial cell membrane behavior. PMID- 26023840 TI - Seaweed hydrocolloid production: an update on enzyme assisted extraction and modification technologies. AB - Agar, alginate, and carrageenans are high-value seaweed hydrocolloids, which are used as gelation and thickening agents in different food, pharmaceutical, and biotechnological applications. The annual global production of these hydrocolloids has recently reached 100,000 tons with a gross market value just above US$ 1.1 billion. The techno-functional properties of the seaweed polysaccharides depend strictly on their unique structural make-up, notably degree and position of sulfation and presence of anhydro-bridges. Classical extraction techniques include hot alkali treatments, but recent research has shown promising results with enzymes. Current methods mainly involve use of commercially available enzyme mixtures developed for terrestrial plant material processing. Application of seaweed polysaccharide targeted enzymes allows for selective extraction at mild conditions as well as tailor-made modifications of the hydrocolloids to obtain specific functionalities. This review provides an update of the detailed structural features of kappa-, iota-, lambda-carrageenans, agars, and alginate, and a thorough discussion of enzyme assisted extraction and processing techniques for these hydrocolloids. PMID- 26023841 TI - Myrothecols g and h, two new analogues of the marine-derived quinone sesquiterpene penicilliumin A. AB - Two new quinone sesquiterpenes named myrothecols G and H (1 and 2), a pair of C 1' diastereomers of 13-hydroxyl penicilliumin A, were isolated from the mycelia solid cultures of Myrothecium sp. SC0265. Their structures, including the absolute configurations, were established on the basis of the spectroscopic data combining with the theoretical conformational analysis. The cytotoxic activities of 1 and 2 were tested against a panel of human tumor cell lines. PMID- 26023844 TI - Non-standard Hubbard models in optical lattices: a review. AB - Originally, the Hubbard model was derived for describing the behavior of strongly correlated electrons in solids. However, for over a decade now, variations of it have also routinely been implemented with ultracold atoms in optical lattices, allowing their study in a clean, essentially defect-free environment. Here, we review some of the vast literature on this subject, with a focus on more recent non-standard forms of the Hubbard model. After giving an introduction to standard (fermionic and bosonic) Hubbard models, we discuss briefly common models for mixtures, as well as the so-called extended Bose-Hubbard models, that include interactions between neighboring sites, next-neighbor sites, and so on. The main part of the review discusses the importance of additional terms appearing when refining the tight-binding approximation for the original physical Hamiltonian. Even when restricting the models to the lowest Bloch band is justified, the standard approach neglects the density-induced tunneling (which has the same origin as the usual on-site interaction). The importance of these contributions is discussed for both contact and dipolar interactions. For sufficiently strong interactions, the effects related to higher Bloch bands also become important even for deep optical lattices. Different approaches that aim at incorporating these effects, mainly via dressing the basis, Wannier functions with interactions, leading to effective, density-dependent Hubbard-type models, are reviewed. We discuss also examples of Hubbard-like models that explicitly involve higher p orbitals, as well as models that dynamically couple spin and orbital degrees of freedom. Finally, we review mean-field nonlinear Schrodinger models of the Salerno type that share with the non-standard Hubbard models nonlinear coupling between the adjacent sites. In that part, discrete solitons are the main subject of consideration. We conclude by listing some open problems, to be addressed in the future. PMID- 26023845 TI - Treating Urban Wastewater: Nutrient Removal by Using Immobilized Green Algae in Batch Cultures. AB - Essential roles of microalgae during the tertiary treatment of municipal wastewater have been proven. In order to avoid wash out of the biomass and also modify the quality of the treated wastewater; some techniques such as cell immobilization have been developed. To do so, in this study four samples from two species of microalgae (Chlorella vulgaris and Chlamydomonas sp.) were determined and confirmed by taxonomic identification. The samples were immobilized in calcium alginate beads. Within 10 days the amounts of nitrate (No3(-)-N) and orthophosphate (Po4(3-)-P) were measured to calculate the removal efficacy for each individual sample. Based on the standard methods, the amount of nitrate and orthophosphate were determined every 3 days within 10 days. The results indicate that immobilized microalgae are able to remove the nutrients and reduce the amount of nitrate and orthophosphate, significantly. Furthermore, the C. vulgaris (YG02) was the best species in this experience with 72% and 99% of reduction in the amount of nitrate and orthophosphate, respectively. PMID- 26023843 TI - Construction of Escherichia coli Mutant with Decreased Endotoxic Activity by Modifying Lipid A Structure. AB - Escherichia coli BL21 (DE3) and its derivatives are widely used for the production of recombinant proteins, but these purified proteins are always contaminated with lipopolysaccharide (LPS). LPS is recognized by the toll-like receptor 4 and myeloid differentiation factor 2 complex of mammalian immune cells and leads to release of pro-inflammatory cytokines. It is a vital step to remove LPS from the proteins before use for therapeutic purpose. In this study, we constructed BL21 (DE3) ?msbB28 ?pagP38 mutant, which produces a penta-acylated LPS with reduced endotoxicity. The plasmids harboring pagL and/or lpxE were then introduced into this mutant to further modify the LPS. The new strain (S004) carrying plasmid pQK004 (pagL and lpxE) produced mono-phosphoryated tetra acylated lipid A, which induces markedly less production of tumor necrosis factor alpha in the RAW264.7 and IL-12 in the THP1, but still retains ability to produce recombinant proteins. This study provides a strategy to decrease endotoxic activity of recombinant proteins purified from E. coli BL21 backgrounds and a feasible approach to modify lipid A structure for alternative purposes such as mono-phosphoryl lipid A (MPL) as vaccine adjuvants. PMID- 26023842 TI - Astaxanthin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy via the ROS/MAPK Pathway in Mice. AB - BACKGROUND: Hepatic ischemia reperfusion (IR) is an important issue in complex liver resection and liver transplantation. The aim of the present study was to determine the protective effect of astaxanthin (ASX), an antioxidant, on hepatic IR injury via the reactive oxygen species/mitogen-activated protein kinase (ROS/MAPK) pathway. METHODS: Mice were randomized into a sham, IR, ASX or IR + ASX group. The mice received ASX at different doses (30 mg/kg or 60 mg/kg) for 14 days. Serum and tissue samples at 2 h, 8 h and 24 h after abdominal surgery were collected to assess alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammation factors, ROS, and key proteins in the MAPK family. RESULTS: ASX reduced the release of ROS and cytokines leading to inhibition of apoptosis and autophagy via down-regulation of the activated phosphorylation of related proteins in the MAPK family, such as P38 MAPK, JNK and ERK in this model of hepatic IR injury. CONCLUSION: Apoptosis and autophagy caused by hepatic IR injury were inhibited by ASX following a reduction in the release of ROS and inflammatory cytokines, and the relationship between the two may be associated with the inactivation of the MAPK family. PMID- 26023846 TI - Semisynthesis and insecticidal activity of arylmethylamine derivatives of the neolignan honokiol against Mythimna separata Walker. AB - A series of novel arylmethylamine derivatives of honokiol (5a-m) was prepared. Their insecticidal activity was tested against the pre-third-instar larvae of the oriental armyworm (Mythimna separata Walker), a typical lepidopteran pest. Compounds 5a, 5b, 5e, 5h, and 5k exhibited insecticidal activity equal to, or higher than, that of the positive control toosendanin. PMID- 26023848 TI - Temporal evolution of medulloblastoma subgroups. PMID- 26023847 TI - Epigenetic landscape of amphetamine and methamphetamine addiction in rodents. AB - Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advances in our comprehension of epigenetic mechanisms underlying amphetamine- or methamphetamine-induced behavioral, transcriptional, and synaptic plasticity. Accumulating evidence demonstrated that drug exposure induces major epigenetic modifications-histone acetylation and methylation, DNA methylation-in a very complex manner. In rare instances, however, the regulation of a specific target gene can be correlated to both epigenetic alterations and behavioral abnormalities. Work is now needed to clarify and validate an epigenetic model of addiction to amphetamines. Investigations that include genome wide approaches will accelerate the speed of discovery in the field of addiction. PMID- 26023850 TI - Junk food thoughts. PMID- 26023849 TI - Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer. AB - Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC. PMID- 26023851 TI - Adverse childhood experiences: what can we do? PMID- 26023852 TI - A 4-year-old boy with pain in his left shoulder. PMID- 26023853 TI - The toddler gait--normal or not. AB - The first birthday is a time of great joy and relief for most parents as they celebrate the emergence of a toddler from the tiny newborn handed to them after entering the world. Along with this transition comes new conquests and concerns, including the milestone of walking. When parents view the toddler's ability to walk as delayed or abnormal, the pediatrician can be confronted with an anxious or confused parent. A thorough history with a detailed examination and reassurance will go a long way toward allaying parental fears and building trust. However, a sufficient understanding of the concerns most frequently voiced by parents and the ability to reassure them in an educated fashion is essential to the office clinician. PMID- 26023854 TI - A neonate with deformities of the bilateral lower extremities and bowel and urinary incontinence. PMID- 26023855 TI - A 15-year-old girl with painful, peeling skin. PMID- 26023856 TI - A new alternative therapy in dermatology: tocilizumab. AB - Tocilizumab (TCZ) is a recombinant-humanized anti-human interleukin 6 receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass with a H2L2 polypeptide structure. Even if it was approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis, satisfying results have also been reported with TCZ in various refractory dermatological diseases such as psoriasis, psoriatic arthritis, Behcet's disease, systemic lupus erythematosus, systemic sclerosis, relapsing polychondritis, vasculitis and atopic dermatitis. TCZ treatment in dermatology and adverse effects of the drug were reviewed here after the pharmacological properties, mechanism of action, dosage and administration of the drug were summarized. We estimate that by the help of newly well-designed studies with wider spectrum of subjects to comprehensively investigate the efficacy and safety will be able to contribute to the clinical management of the diseases especially refractory to the other treatments. Therefore, during the next decade, TCZ will be promising drugs in the treatment of refractory dermatological diseases. PMID- 26023857 TI - Resistance to pathogens in terpene down-regulated orange fruits inversely correlates with the accumulation of D-limonene in peel oil glands. AB - Volatile organic compounds (VOCs) are secondary metabolites acting as a language for the communication of plants with the environment. In orange fruits, the monoterpene D-limonene accumulates at very high levels in oil glands from the peel. Drastic down-regulation of D-limonene synthase gene expression in the peel of transgenic oranges harboring a D-limonene synthase transgene in antisense (AS) configuration altered the monoterpene profile in oil glands, mainly resulting in reduced accumulation of D-limonene. This led to fruit resistance against Penicillium digitatum (Pd), Xanthomonas citri subsp. citri (Xcc) and other specialized pathogens. Here, we analyze resistance to pathogens in independent AS and empty vector (EV) lines, which have low, medium or high D-limonene concentrations and show that the level of resistance is inversely related to the accumulation of D-limonene in orange peels, thus explaining the need of high D limonene accumulation in mature oranges in nature for the efficient attraction of specialized microorganism frugivores. PMID- 26023858 TI - Synthesis of PAMAM dendrimer-based fast cross-linking hydrogel for biofabrication. AB - Hydrogels possess great potential in biofabrication because they allow cell encapsulation and proliferation in a highly hydrated three-dimensional environment, and they provide biologically relevant chemical and physical signals. However, development of hydrogel systems that mimic the complexity of natural extracellular matrix remains a challenge. In this study, we report the development of a binary hydrogel system containing a synthetic poly(amido amine) (PAMAM) dendrimer and a natural polymer, i.e., hyaluronic acid (HA), to form a fast cross-linking hydrogel. Live cell staining experiment and cell viability assay of bone marrow stem cells demonstrated that cells were viable and proliferating in the in situ formed PAMAM/HA hydrogel system. Furthermore, introduction of a Arginylglycylaspartic acid (RGD) peptide into the hydrogel system significantly improved the cell viability, proliferation, and attachment. Therefore, this PAMAM/HA hydrogel system could be a promising platform for various applications in biofabrication. PMID- 26023859 TI - The postural and control-display gain effects of distal pointing on upper extremity fatigue. AB - Pointing at displays from a distance is becoming common in both work and domestic environments. Ray-casting interaction is easy for novices to learn and understand, but this technique can cause physiological fatigue. To address this issue, the present study aims to investigate the issue of fatigue caused by joint based pointing methods and Control-Display gains (CD gains) via Fitts' task. Ten healthy subjects participated in the experiment and performed multi-directional tapping tests with three joint-based pointing methods and three CD gains. The experimental results indicated that the joint-based pointing methods indeed affected the physiological and subjective fatigue of the upper limb muscles and measured body parts during distal pointing tasks. The wrist-based pointing method, which can induce substantially lower physiological and subjective fatigue, appears to be superior to the other two methods. There were no significant main effects of CD gains on either physiological fatigue or subjective Borg's CR-10 rating. PRACTITIONER SUMMARY: The present study investigates the issue of fatigue caused by joint-based pointing methods and CD gains via Fitts' task. The pointing methods affected the physiological and subjective fatigue of the upper-limb muscles. There were no significant main effects of CD gains on either physiological fatigue or subjective Borg's CR-10 rating. PMID- 26023860 TI - The Impact of 3 Different-Length Between-Matches Microcycles on Training Loads in Professional Rugby League Players. AB - PURPOSE: To examine the impact of varying between-matches microcycles on training characteristics (ie, intensity, duration, and load) in professional rugby league players and to report on match load related to these between-matches microcycles. METHODS: Training-load data were collected during a 26-wk competition period of an entire season. Training load was measured using the session rating of perceived exertion (session-RPE) method for every training session and match from 44 professional rugby league players from the same National Rugby League team. Using the category-ratio 10 RPE scale, the training intensity was divided into 3 zones (low <4 AU, moderate >= 4-<= 7 AU, and high >7 AU). Three different-length between-matches recovery microcycles were used for analysis: 5-6 d, 7-8 d, and 9 10 d. RESULTS: A total of 3848 individual sessions were recorded. During the shorter-length between-matches microcycles (5-6 d), significantly lower training load was observed. No significant differences for subsequent match load or intensity were identified between the various match recovery periods. Overall, 16% of the training sessions were completed at the low-intensity zone, 61% at the moderate-intensity zone, and 23% at the high-intensity zone. CONCLUSIONS: The findings demonstrate that rugby league players undertake higher training load as the length of between-matches microcycles is increased. The majority of in-season training of professional rugby league players was at moderate intensity, and a polarized approach to training that has been reported in elite endurance athletes does not occur in professional rugby league. PMID- 26023861 TI - Seasonal fluctuations in chemical defenses against macrofouling in Fucus vesiculosus and Fucus serratus from the Baltic Sea. AB - Macroalgae, especially perennial species, are exposed to a seasonally variable fouling pressure. It was hypothesized that macroalgae regulate their antifouling defense to fouling pressure. Over one year, the macrofouling pressure and the chemical anti-macrofouling defense strength of the brown algae Fucus vesiculosus and Fucus serratus were assessed with monthly evaluation. The anti-macrofouling defense was assessed by means of surface-extracted Fucus metabolites tested at near-natural concentrations in a novel in situ bioassay. Additionally, the mannitol content of both Fucus species was determined to assess resource availability for defense production. The surface chemistry of both Fucus species exhibited seasonal variability in attractiveness to Amphibalanus improvisus and Mytilus edulis. Of this variability, 50-60% is explained by a sinusoidal model. Only F. vesiculosus extracts originating from the spring and summer significantly deterred settlement of A. improvisus. The strength of macroalgal antifouling defense did not correlate either with in situ macrofouling pressure or with measured mannitol content, which, however, were never depleted. PMID- 26023862 TI - Single-Cell Analysis: Visualizing Pharmaceutical and Metabolite Uptake in Cells with Label-Free 3D Mass Spectrometry Imaging. AB - Detecting metabolites and parent compound within a cell type is now a priority for pharmaceutical development. In this context, three-dimensional secondary ion mass spectrometry (SIMS) imaging was used to investigate the cellular uptake of the antiarrhythmic agent amiodarone, a phospholipidosis-inducing pharmaceutical compound. The high lateral resolution and 3D imaging capabilities of SIMS combined with the multiplex capabilities of ToF mass spectrometric detection allows for the visualization of pharmaceutical compound and metabolites in single cells. The intact, unlabeled drug compound was successfully detected at therapeutic dosages in macrophages (cell line: NR8383). Chemical information from endogenous biomolecules was used to correlate drug distributions with morphological features. From this spatial analysis, amiodarone was detected throughout the cell, with the majority of the compound found in the membrane and subsurface regions and absent in the nuclear regions. Similar results were obtained when the macrophages were doped with amiodarone metabolite, desethylamiodarone. The fwhm lateral resolution measured across an intracellular interface in high lateral resolution ion images was approximately 550 nm. Overall, this approach provides the basis for studying cellular uptake of pharmaceutical compounds and their metabolites on the single cell level. PMID- 26023864 TI - Metabolomic Analysis Reveals Cyanidins in Black Raspberry as Candidates for Suppression of Lipopolysaccharide-Induced Inflammation in Murine Macrophages. AB - The extracts produced by multisolvent extraction and subfractionation with preparative liquid chromatography of black raspberry (Rubus coreanus Miquel) cultivated in Gochang, South Korea, were tested for their anti-inflammatory effects. The metabolomic profiling and analysis by orthogonal partial least squares discriminant analysis (OLPS-DA) suggested that cyanidin, cyanidin-3 glucoside (C3G), and cyanidin-3-rutinoside (C3R) were key components for the anti inflammatory responses in the most active fraction BF3-1, where they were present at 0.44, 1.26, and 0.56 MUg/mg of BF3-1, respectively. Both BF3-1 and mixture of these cyanidins at the same ratio reduced lipopolysaccharide (LPS)-induced protein level of iNOS expression and suppressed mRNA and protein expressions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta through inhibiting the phosphorylation of mitogen-activated protein kinases (MAPKs) and STAT3 in murine macrophage RAW264.7 cells. Overall, the results suggested that co administration of cyanidin, C3G, and C3R is more effective than that of cyanidin alone and that the coexistence of these anthocyanin components in black raspberry plays a vital role in regulating LPS-induced inflammation even at submicromolar concentrations, making it possible to explain the health beneficial activity of its extracts. PMID- 26023865 TI - Chemical derivatization processes applied to amine determination in samples of different matrix composition. PMID- 26023863 TI - Characterization of the antibody response against EV71 capsid proteins in Chinese individuals by NEIBM-ELISA. AB - Human enterovirus 71 (EV71) has become the major pathogen of hand, foot, and mouth disease (HFMD) worldwide, while the anti-EV71 antibody responses other than neutralizing epitopes have not been characterized. In this study, EV71 capsid proteins VP1, VP3, VP0 and various VP1 antigens were constructed to analyze anti EV71 response in severe HFMD cases, non-HFMD outpatient children and normal adults using a novel evolved immunoglobulin-binding molecule (NEIBM)-based ELISA. The high prevalence of antibody responses against all three capsid proteins was demonstrated, and anti-EV71 VP1 showed the main antibody response. Anti-EV71 VP1 antibody response was found to predominantly target to epitopes based on the common enterovirus cross-reactive sequence. Moreover, inhibition pattern against anti-EV71 VP1 reactions in three groups was obviously different. Taken together, these results firstly characterized the anti-EV71 antibody responses which are predominantly against VP1 epitopes based on common enterovirus cross-reactive sequence. This finding could be helpful for the better understanding of anti-EV71 humoral immunity and useful for seroepidemiological surveillance. PMID- 26023866 TI - The Bax inhibitor MrBI-1 regulates heat tolerance, apoptotic-like cell death, and virulence in Metarhizium robertsii. AB - Bax inhibitor 1 (BI-1) is a highly conserved protein originally identified as a suppressor of the proapoptotic protein Bax to inhibit cell death in animals and plants. The orthologs of BI-1 are widely distributed in filamentous fungi but their functions remain largely unknown. Herein, we report the identification and characterizations of MrBI-1, an ortholog of BI-1, in the entomopathogenic fungus Metarhizium robertsii. First, we found that MrBI-1 could partially rescue mammalian Bax-induced cell death in yeast. Deletion of MrBI-1 impaired fungal development, virulence and heat tolerance in M. robertsii. We also demonstrated that inactivation of MrBI-1 reduced fungal resistance to farnesol but not to hydrogen peroxide, suggesting that MrBI-1 contributes to antiapoptotic-like cell death via the endoplasmic reticulum stress-signaling pathway rather than the classical mitochondrium-dependent pathway. In particular, we found that unlike the observations in yeasts and plants, expression of mammalian Bax did not lead to a lethal effect in M. robertsii; however, it did aggravate the fungal apoptotic effect of farnesol. The results of this study advance our understanding of BI-1-like protein functions in filamentous fungi. PMID- 26023867 TI - Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity. AB - Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666 15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 +/- 0.04 MUM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target. PMID- 26023868 TI - Chronic Kidney Disease in Older People. PMID- 26023869 TI - Unravelling core microbial metabolisms in the hypersaline microbial mats of Shark Bay using high-throughput metagenomics. AB - Modern microbial mats are potential analogues of some of Earth's earliest ecosystems. Excellent examples can be found in Shark Bay, Australia, with mats of various morphologies. To further our understanding of the functional genetic potential of these complex microbial ecosystems, we conducted for the first time shotgun metagenomic analyses. We assembled metagenomic next-generation sequencing data to classify the taxonomic and metabolic potential across diverse morphologies of marine mats in Shark Bay. The microbial community across taxonomic classifications using protein-coding and small subunit rRNA genes directly extracted from the metagenomes suggests that three phyla Proteobacteria, Cyanobacteria and Bacteriodetes dominate all marine mats. However, the microbial community structure between Shark Bay and Highbourne Cay (Bahamas) marine systems appears to be distinct from each other. The metabolic potential (based on SEED subsystem classifications) of the Shark Bay and Highbourne Cay microbial communities were also distinct. Shark Bay metagenomes have a metabolic pathway profile consisting of both heterotrophic and photosynthetic pathways, whereas Highbourne Cay appears to be dominated almost exclusively by photosynthetic pathways. Alternative non-rubisco-based carbon metabolism including reductive TCA cycle and 3-hydroxypropionate/4-hydroxybutyrate pathways is highly represented in Shark Bay metagenomes while not represented in Highbourne Cay microbial mats or any other mat forming ecosystems investigated to date. Potentially novel aspects of nitrogen cycling were also observed, as well as putative heavy metal cycling (arsenic, mercury, copper and cadmium). Finally, archaea are highly represented in Shark Bay and may have critical roles in overall ecosystem function in these modern microbial mats. PMID- 26023870 TI - Marked seasonal variation in the wild mouse gut microbiota. AB - Recent studies have provided an unprecedented view of the microbial communities colonizing captive mice; yet the host and environmental factors that shape the rodent gut microbiota in their natural habitat remain largely unexplored. Here, we present results from a 2-year 16 S ribosomal RNA gene sequencing-based survey of wild wood mice (Apodemus sylvaticus) in two nearby woodlands. Similar to other mammals, wild mice were colonized by 10 bacterial phyla and dominated by the Firmicutes, Bacteroidetes and Proteobacteria. Within the Firmicutes, the Lactobacillus genus was most abundant. Putative bacterial pathogens were widespread and often abundant members of the wild mouse gut microbiota. Among a suite of extrinsic (environmental) and intrinsic (host-related) factors examined, seasonal changes dominated in driving qualitative and quantitative differences in the gut microbiota. In both years examined, we observed a strong seasonal shift in gut microbial community structure, potentially due to the transition from an insect- to a seed-based diet. This involved decreased levels of Lactobacillus, and increased levels of Alistipes (Bacteroidetes phylum) and Helicobacter. We also detected more subtle but statistically significant associations between the gut microbiota and biogeography, sex, reproductive status and co-colonization with enteric nematodes. These results suggest that environmental factors have a major role in shaping temporal variations in microbial community structure within natural populations. PMID- 26023871 TI - Can resistance against quorum-sensing interference be selected? AB - Quorum-sensing (QS) interference is a novel therapy to fight bacterial infections that, unlike conventional antibiotic treatments, is focused on reducing the damage caused by pathogens (virulence) rather than focused on inhibiting their growth. Given this ideal, it was predicted that this approach will be impervious to or at least much less prone to resistance in bacterial populations. However, recently, resistance mechanisms against well-characterized quorum quenchers (QQs) have been found in the laboratory as well as in clinical strains, demonstrating that the rise of resistance against these kinds of compounds is possible. Nevertheless, it has been argued that even if resistance mechanisms against QS interference exist, this fact does not guarantee that resistance will spread. In the present work, we discuss recent insights derived from the latest experiments to address this question. In addition, we explain how environmental conditions like the stress produced by the host immune system may influence the selection of resistance and eventually lead to the selection of QS interference-resistant bacteria in a clinical setting. PMID- 26023872 TI - Meta-omics uncover temporal regulation of pathways across oral microbiome genera during in vitro sugar metabolism. AB - Dental caries, one of the most globally widespread infectious diseases, is intimately linked to pH dynamics. In supragingival plaque, after the addition of a carbohydrate source, bacterial metabolism decreases the pH which then subsequently recovers. Molecular mechanisms supporting this important homeostasis are poorly characterized in part due to the fact that there are hundreds of active species in dental plaque. Only a few mechanisms (for example, lactate fermentation, the arginine deiminase system) have been identified and studied in detail. Here, we conducted what is to our knowledge, the first full transcriptome and metabolome analysis of a diverse oral plaque community by using a functionally and taxonomically robust in vitro model system greater than 100 species. Differential gene expression analyses from the complete transcriptome of 14 key community members revealed highly varied regulation of both known and previously unassociated pH-neutralizing pathways as a response to the pH drop. Unique expression and metabolite signatures from 400 detected metabolites were found for each stage along the pH curve suggesting it may be possible to define healthy and diseased states of activity. Importantly, for the maintenance of healthy plaque pH, gene transcription activity of known and previously unrecognized pH-neutralizing pathways was associated with the genera Lactobacillus, Veillonella and Streptococcus during the pH recovery phase. Our in vitro study provides a baseline for defining healthy and disease-like states and highlights the power of moving beyond single and dual species applications to capture key players and their orchestrated metabolic activities within a complex human oral microbiome model. PMID- 26023873 TI - Volatile affairs in microbial interactions. AB - Microorganisms are important factors in shaping our environment. One key characteristic that has been neglected for a long time is the ability of microorganisms to release chemically diverse volatile compounds. At present, it is clear that the blend of volatiles released by microorganisms can be very complex and often includes many unknown compounds for which the chemical structures remain to be elucidated. The biggest challenge now is to unravel the biological and ecological functions of these microbial volatiles. There is increasing evidence that microbial volatiles can act as infochemicals in interactions among microbes and between microbes and their eukaryotic hosts. Here, we review and discuss recent advances in understanding the natural roles of volatiles in microbe-microbe interactions. Specific emphasis will be given to the antimicrobial activities of microbial volatiles and their effects on bacterial quorum sensing, motility, gene expression and antibiotic resistance. PMID- 26023874 TI - Marine diatom proteorhodopsins and their potential role in coping with low iron availability. AB - Proteorhodopsins (PR) are retinal-binding membrane proteins that function as light-driven proton pumps to generate energy for metabolism and growth. Recently PR-like genes have been identified in some marine eukaryotic protists, including diatoms, dinoflagellates, haptophytes and cryptophytes. These rhodopsins are homologous to green-light-absorbing, ATP-generating PRs present within bacteria. Here we show that in the oceanic diatom Pseudo-nitzschia granii, PR-like gene and protein expressions increase appreciably under iron limitation. In a survey of available transcriptomes, PR-like genes in diatoms are generally found in isolates from marine habitats where seasonal to chronic growth limitation by the micronutrient iron is prevalent, yet similar biogeographical patterns are not apparent in other phytoplankton taxa. We propose that rhodopsin-based phototrophy could account for a proportion of energy synthesis in marine eukaryotic photoautotrophs, especially when photosynthesis is compromised by low iron availability. This alternative ATP-generating pathway could have significant effects on plankton community structure and global ocean carbon cycling. PMID- 26023875 TI - Fungal invasion of the rhizosphere microbiome. AB - The rhizosphere is the infection court where soil-borne pathogens establish a parasitic relationship with the plant. To infect root tissue, pathogens have to compete with members of the rhizosphere microbiome for available nutrients and microsites. In disease-suppressive soils, pathogens are strongly restricted in growth by the activities of specific rhizosphere microorganisms. Here, we sequenced metagenomic DNA and RNA of the rhizosphere microbiome of sugar beet seedlings grown in a soil suppressive to the fungal pathogen Rhizoctonia solani. rRNA-based analyses showed that Oxalobacteraceae, Burkholderiaceae, Sphingobacteriaceae and Sphingomonadaceae were significantly more abundant in the rhizosphere upon fungal invasion. Metatranscriptomics revealed that stress related genes (ppGpp metabolism and oxidative stress) were upregulated in these bacterial families. We postulate that the invading pathogenic fungus induces, directly or via the plant, stress responses in the rhizobacterial community that lead to shifts in microbiome composition and to activation of antagonistic traits that restrict pathogen infection. PMID- 26023879 TI - Optimal Sample Preparation for the Analysis of Micrometric Heterogeneous Samples. AB - Precise microanalytical techniques are essential in many fields such as cultural heritage materials, showing complex layered microstructures containing a wide range of materials of diverse nature and hardness. Noninvasive sample manipulation and preparation is required to avoid, as much as possible, sample contamination, which may strongly limit the materials identification. The method proposed consists in the application of thin gold or carbon protecting layers before embedding the samples in synthetic resin for microtoming. The validity and optimal procedure is checked for those materials most often found on the surface of paintings: varnishes (natural resins and wax). An artwork sample is similarly prepared and analyzed by optical microscopy (OM), scanning electron microscopy (SEM/EDS), micro-infrared spectroscopy (MUFTIR/MUSR-FTIR), and X-ray diffraction (MUSR-XRD) with synchrotron light. PMID- 26023877 TI - Sound can suppress visual perception. AB - In a single modality, the percept of an input (e.g., voices of neighbors) is often suppressed by another (e.g., the sound of a car horn nearby) due to close interactions of neural responses to these inputs. Recent studies have also suggested that close interactions of neural responses could occur even across sensory modalities, especially for audio-visual interactions. However, direct behavioral evidence regarding the audio-visual perceptual suppression effect has not been reported in a study with humans. Here, we investigated whether sound could have a suppressive effect on visual perception. We found that white noise bursts presented through headphones degraded visual orientation discrimination performance. This auditory suppression effect on visual perception frequently occurred when these inputs were presented in a spatially and temporally consistent manner. These results indicate that the perceptual suppression effect could occur across auditory and visual modalities based on close and direct neural interactions among those sensory inputs. PMID- 26023876 TI - Evolutionary transition in symbiotic syndromes enabled diversification of phytophagous insects on an imbalanced diet. AB - Evolutionary adaptations for the exploitation of nutritionally challenging or toxic host plants represent a major force driving the diversification of phytophagous insects. Although symbiotic bacteria are known to have essential nutritional roles for insects, examples of radiations into novel ecological niches following the acquisition of specific symbionts remain scarce. Here we characterized the microbiota across bugs of the family Pyrrhocoridae and investigated whether the acquisition of vitamin-supplementing symbionts enabled the hosts to diversify into the nutritionally imbalanced and chemically well defended seeds of Malvales plants as a food source. Our results indicate that vitamin-provisioning Actinobacteria (Coriobacterium and Gordonibacter), as well as Firmicutes (Clostridium) and Proteobacteria (Klebsiella) are widespread across Pyrrhocoridae, but absent from the sister family Largidae and other outgroup taxa. Despite the consistent association with a specific microbiota, the Pyrrhocoridae phylogeny is neither congruent with a dendrogram based on the hosts' microbial community profiles nor phylogenies of individual symbiont strains, indicating frequent horizontal exchange of symbiotic partners. Phylogenetic dating analyses based on the fossil record reveal an origin of the Pyrrhocoridae core microbiota in the late Cretaceous (81.2-86.5 million years ago), following the transition from crypt-associated beta-proteobacterial symbionts to an anaerobic community localized in the M3 region of the midgut. The change in symbiotic syndromes (that is, symbiont identity and localization) and the acquisition of the pyrrhocorid core microbiota followed the evolution of their preferred host plants (Malvales), suggesting that the symbionts facilitated their hosts' adaptation to this imbalanced nutritional resource and enabled the subsequent diversification in a competition-poor ecological niche. PMID- 26023878 TI - Development of biodegradable Zn-1X binary alloys with nutrient alloying elements Mg, Ca and Sr. AB - Biodegradable metals have attracted considerable attentions in recent years. Besides the early launched biodegradable Mg and Fe metals, Zn, an essential element with osteogenic potential of human body, is regarded and studied as a new kind of potential biodegradable metal quite recently. Unfortunately, pure Zn is soft, brittle and has low mechanical strength in the practice, which needs further improvement in order to meet the clinical requirements. On the other hand, the widely used industrial Zn-based alloys usually contain biotoxic elements (for instance, ZA series contain toxic Al elements up to 40 wt.%), which subsequently bring up biosafety concerns. In the present work, novel Zn-1X binary alloys, with the addition of nutrition elements Mg, Ca and Sr were designed (cast, rolled and extruded Zn-1Mg, Zn-1Ca and Zn-1Sr). Their microstructure and mechanical property, degradation and in vitro and in vivo biocompatibility were studied systematically. The results demonstrated that the Zn-1X (Mg, Ca and Sr) alloys have profoundly modified the mechanical properties and biocompatibility of pure Zn. Zn-1X (Mg, Ca and Sr) alloys showed great potential for use in a new generation of biodegradable implants, opening up a new avenue in the area of biodegradable metals. PMID- 26023880 TI - Development of the fentanyl iontophoretic transdermal system (ITS) for patient controlled analgesia of postoperative pain management. AB - The fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient activated drug delivery system used for patient-controlled analgesia in adult hospitalized patients with postoperative pain. The system design has been updated to a separated system consisting of a Controller and a Drug Unit, and has had regulatory submissions in USA and Europe in 2014. Fentanyl ITS has been shown to be therapeutically equivalent to morphine intravenous (iv.) patient-controlled analgesia. One of the advantages of fentanyl ITS is that patients have better mobility as there is no need for an iv. pump, iv. lines and pole. The introduction of the updated fentanyl ITS will add a versatile tool to the postoperative pain management armamentarium. PMID- 26023882 TI - Highly efficient red OLEDs using DCJTB as the dopant and delayed fluorescent exciplex as the host. AB - In this manuscript, we demonstrated a highly efficient DCJTB emission with delayed fluorescent exciplex TCTA:3P-T2T as the host. For the 1.0% DCJTB doped concentration, a maximum luminance, current efficiency, power efficiency and EQE of 22,767 cd m(-2), 22.7 cd A(-1), 21.5 lm W(-1) and 10.15% were achieved, respectively. The device performance is the best compared to either red OLEDs with traditional fluorescent emitter or traditional red phosphor of Ir(piq)3 doped into CBP host. The extraction of so high efficiency can be explained as the efficient triplet excitons up-conversion of TCTA:3P-T2T and the energy transfer from exciplex host singlet state to DCJTB singlet state. PMID- 26023883 TI - Silica-Supported Cationic Gold(I) Complexes as Heterogeneous Catalysts for Regio- and Enantioselective Lactonization Reactions. AB - An efficient method for the synthesis of heterogeneous gold catalysts has been developed. These catalysts were easily assembled from readily available silica materials and gold complexes. The heterogeneous catalysts exhibited superior reactivity in various reactions where protodeauration is the rate-limiting step. Dramatic enhancement in regio- and enantioselectivity was observed when compared to the homogeneous unsupported gold catalyst. The catalysts are easily recovered and recycled up to 11 times without loss of enantioselectivity. PMID- 26023881 TI - Structural transition in Bcl-xL and its potential association with mitochondrial calcium ion transport. AB - Bcl-2 family proteins are key regulators for cellular homeostasis in response to apoptotic stimuli. Bcl-xL, an antiapoptotic Bcl-2 family member, undergoes conformational transitions, which leads to two conformational states: the cytoplasmic and membrane-bound. Here we present the crystal and small-angle X-ray scattering (SAXS) structures of Bcl-xL treated with the mild detergent n-Octyl beta-D-Maltoside (OM). The detergent-treated Bcl-xL forms a dimer through three dimensional domain swapping (3DDS) by swapping helices alpha6-alpha8 between two monomers. Unlike Bax, a proapoptotic member of the Bcl-2 family, Bcl-xL is not converted to 3DDS homodimer upon binding BH3 peptides and ABT-737, a BH3 mimetic drug. We also designed Bcl-xL mutants which cannot dimerize and show that these mutants reduced mitochondrial calcium uptake in MEF cells. This illustrates the structural plasticity in Bcl-xL providing hints toward the probable molecular mechanism for Bcl-xL to play a regulatory role in mitochondrial calcium ion transport. PMID- 26023884 TI - Systematic Evaluation of the Relationship between Physical and Psychoacoustical Measurements of Hearing Protectors' Attenuation. AB - The most commonly used methods to measure hearing protectors attenuation can be divided into two categories: psychoacoustical (subjective) and physical (objective) methods. In order to better understand the relationship between these methods, this article presents various factors relating attenuation values obtained with these methods through a series of tests. Experiments on human subjects were carried out where the subjects were instrumented on both ears with miniature microphones outside and underneath the protector. The subjects were then asked to go through a series of hearing threshold measurements (psychoacoustical method) followed by microphone sound recordings using high level diffuse field broadband noises (physical method). The proposed test protocol allowed obtaining various factors relating the test methods as well as attenuation values and ratings for different protection conditions (open ear, earmuffs, earplugs, and dual protection). Results are presented for three models of passive earmuffs, three models of earplugs and all their combinations as dual hearing protectors. The validity and the relative importance of various terms used to correct the physical attenuation values when comparing with psychoacoustical attenuation values are examined. PMID- 26023885 TI - Asymmetric Transfer Hydrogenation of Imines in Water by Varying the Ratio of Formic Acid to Triethylamine. AB - Asymmetric transfer hydrogenation (ATH) of imines has been performed with variation in formic acid (F) and triethylamine (T) molar ratios in water. The F/T ratio is shown to affect both the reduction rate and enantioselectivity, with the optimum ratio being 1.1 in the ATH of imines with the Rh-(1S,2S)-TsDPEN catalyst. Use of methanol as a cosolvent enhanced reduction activity. A variety of imine substrates have been reduced, affording high yields (94-98%) and good to excellent enantioselectivities (89-98%). In comparison with the common azeotropic F-T system, the reduction with 1.1/1 F/T is faster. PMID- 26023886 TI - Nonadiabatic Photodissociation of the Hydroxymethyl Radical from the 2(2)A State. Surface Hopping Simulations Based on a Full Nine-Dimensional Representation of the 1,2,3(2)A Potential Energy Surfaces Coupled by Conical Intersections. AB - The nonadiabatic photodissociation CH2OH(1(2)A) + hv -> CH2OH(2,3(2)A) -> CH2O + H or HCOH(cis or trans) + H is addressed using trajectory surface hopping dynamics on a quasi-diabatic representation, H(d), of the 1,2,3(2)A coupled, adiabatic potential energy surfaces. We focus on dynamics originating on the 2(2)A potential energy surface. The H(d) is based exclusively on electronic structure data obtained from a multireference configuration interaction single and double excitation expansion, composed of over 67 million configuration state functions, and treats all nine internal degrees of freedom in an even-handed manner. Each simulation is based on bundles of 10000 trajectories randomly selected from harmonic Wigner distributions and propagated for up to 1 ps. The bimodal distribution in the kinetic energy release spectrum is explained in terms of direct versus quasi-statistical dissociation. PMID- 26023887 TI - Synthesis of Diaryliodonium Salts Having Pentafluorosulfanylarenes and Their Application to Electrophilic Pentafluorosulfanylarylation of C-, O-, N-, and S Nucleophiles. AB - Novel reagents for the electrophilic introduction of pentafluorosulfanyl (SF5) arenes into target molecules are disclosed. Unsymmetrical diaryliodonium salts 1 having SF5-arenes were synthesized by a one-pot process from iodo-SF5-benzenes 2 in good yields. The SF5-aryliodonium salts 1 were found to be efficient for the electrophilic SF5-arylation of carbon and heterocentered nucleophiles to furnish the corresponding substituted SF5-arenes in good to high yields. PMID- 26023888 TI - Chemical Environment Control and Enhanced Catalytic Performance of Platinum Nanoparticles Embedded in Nanocrystalline Metal-Organic Frameworks. AB - Chemical environment control of the metal nanoparticles (NPs) embedded in nanocrystalline metal-organic frameworks (nMOFs) is useful in controlling the activity and selectivity of catalytic reactions. In this report, organic linkers with two functional groups, sulfonic acid (-SO3H, S) and ammonium (-NH3(+), N), are chosen as strong and weak acidic functionalities, respectively, and then incorporated into a MOF [Zr6O4(OH)4(BDC)6 (BDC = 1,4-benzenedicarboxylate), termed UiO-66] separately or together in the presence of 2.5 nm Pt NPs to build a series of Pt NPs-embedded in UiO-66 (Pt?nUiO-66). We find that these chemical functionalities play a critical role in product selectivity and activity in the gas-phase conversion of methylcyclopentane (MCP) to acyclic isomer, olefins, cyclohexane, and benzene. Pt?nUiO-66-S gives the highest selectivity to C6-cyclic products (62.4% and 28.6% for cyclohexane and benzene, respectively) without acyclic isomers products. Moreover, its catalytic activity was doubled relative to the nonfunctionalized Pt?nUiO-66. In contrast, Pt?nUiO-66-N decreases selectivity for C6-cyclic products to <50% while increases the acyclic isomer selectivity to 38.6%. Interestingly, the Pt?nUiO-66-SN containing both functional groups gave different product selectivity than their constituents; no cyclohexane was produced, while benzene was the dominant product with olefins and acyclic isomers as minor products. All Pt?nUiO-66 catalysts with different functionalities remain intact and maintain their crystal structure, morphology, and chemical functionalities without catalytic deactivation after reactions over 8 h. PMID- 26023889 TI - Effect of lipid composition on incorporation of trastuzumab-PEG-lipid into nanoliposomes by post-insertion method: physicochemical and cellular characterization. AB - CONTEXT: Anti-HER2 immunoliposomes are promising nanotechnology based systems for active targeting of breast tumors, which depends on the amount of incorporated antibody. OBJECTIVE/AIM: In this work, we investigated the possible effect of lipid composition on the incorporation of trastuzumab-PEG-PE micelles into nanoliposomes and on their subsequent specific cellular targeting. MATERIALS AND METHODS: Trastuzumab (anti-HER2 monoclonal antibody) was monothiolated and conjugated to maleimide-PEG-PE micelles. Liposomes of different lipid compositions were prepared by the thin layer hydration. Trastuzumab-PEG-PE micelles were incorporated into the liposomes by the post-insertion method. The percentage of lipid mixing was determined based on fluorescence resonance energy transfer. Cellular binding and uptake of rhodamine-labeled immunoliposomes were studied in SKBR-3 (HER2(+++)) and MCF-7 (HER2(+)) cells. Also, antitumor cell activity of the immunoliposomes was compared to free trastuzumab and the liposomes. RESULTS: The lipid mixing of trastuzumab-PEG-PE micelles depended on the liposome composition. The immunoliposomes containing DPPC, cholesterol and PEG-PE showed prominent lipid mixing. The lipid mixing was consistent with the cell binding results which showed an efficient and specific binding of the immunoliposomes to SKBR-3 cells. Antitumor cell activity of the immunoliposomes in SKBR-3, unlike MCF-7 cells, depended on the content of trastuzumab. DISCUSSION: Cholesterol and PEG-PE in the liposome composition are prerequisites for a successful lipid mixing due to their ability to facilitate fusion. The higher lipid mixing results in higher antibody incorporation and consequently higher targeted cell binding. CONCLUSIONS: The lipid mixing depends on the liposome composition, which reflects targeted cell binding of the immunoliposomes. PMID- 26023890 TI - Silver Indium Telluride Semiconductors and Their Solid Solutions with Cadmium Indium Telluride: Structure and Physical Properties. AB - Ag0.8In2.4Te4 (= AgIn3Te5) and Ag0.5In2.5Te4 (= AgIn5Te8) form solid solutions with CdIn2Te4, which are interesting as materials for photovoltaics or with respect to their thermoelectric properties. The corresponding crystal structures are related to the chalcopyrite type. Rietveld refinements of high-resolution synchrotron powder diffraction data measured at K-absorption edges of Cd, Ag, In, and Te and electron diffraction reveal the symmetry as well as the element and vacancy distribution in Ag0.8In2.4Te4 (= AgIn3Te5)/Ag0.5In2.5Te4 (= AgIn5Te8) mixed crystals such as Ag0.25Cd0.5In2.25Te4 and Ag0.2Cd0.75In2.1Te4. All compounds of the solid solution series (CdIn2Te4)x(Ag0.5In2.5Te4)1-x exhibit the HgCu2I4 structure type (space group I42m) with completely ordered vacancies but disordered cations. The uniform cation distribution and thus the local charge balance are comparable to that of CdIn2Te4. In contrast, Ag0.8In2.4Te4 (= AgIn3Te5) crystallizes in the space group P42c with disordered cations and partially ordered vacancies. This is corroborated by bond-valence sum calculations and the fact that there is a Vegard-like behavior for compounds with 0.5 < x in the pseudobinary system (CdIn2Te4)x(Ag0.8In2.4Te4)1-x. Owing to the different structures, there is no complete solid solution series between CdIn2Te4 and AgIn3Te5. All compounds in this work are n-type semiconductors with a low electrical conductivity (~1 S/m) and rather high absolute Seebeck coefficients (up to -750 MUV/mK; 225 degrees C). Electrical band gaps (Eg) determined from the Seebeck coefficients as well as (more reliably) from the electrical conductivity range between 0.19 and 1.13 eV. PMID- 26023891 TI - Metabolomics Reveals that Aryl Hydrocarbon Receptor Activation by Environmental Chemicals Induces Systemic Metabolic Dysfunction in Mice. AB - Environmental exposure to dioxins and dioxin-like compounds poses a significant health risk for human health. Developing a better understanding of the mechanisms of toxicity through activation of the aryl hydrocarbon receptor (AHR) is likely to improve the reliability of risk assessment. In this study, the AHR-dependent metabolic response of mice exposed to 2,3,7,8-tetrachlorodibenzofuran (TCDF) was assessed using global (1)H nuclear magnetic resonance (NMR)-based metabolomics and targeted metabolite profiling of extracts obtained from serum and liver. (1)H NMR analyses revealed that TCDF exposure suppressed gluconeogenesis and glycogenolysis, stimulated lipogenesis, and triggered inflammatory gene expression in an Ahr-dependent manner. Targeted analyses using gas chromatography coupled with mass spectrometry showed TCDF treatment altered the ratio of unsaturated/saturated fatty acids. Consistent with this observation, an increase in hepatic expression of stearoyl coenzyme A desaturase 1 was observed. In addition, TCDF exposure resulted in inhibition of de novo fatty acid biosynthesis manifested by down-regulation of acetyl-CoA, malonyl-CoA, and palmitoyl-CoA metabolites and related mRNA levels. In contrast, no significant changes in the levels of glucose and lipid were observed in serum and liver obtained from Ahr null mice following TCDF treatment, thus strongly supporting the important role of the AHR in mediating the metabolic effects seen following TCDF exposure. PMID- 26023892 TI - Reassessing the educational environment among undergraduate students in a chiropractic training institution: A study over time. AB - OBJECTIVE: The aim of the study was twofold: (1) to compare the perceived educational environment at 2 points in time and (2) to longitudinally examine potential changes in perceptions of the educational environment over time. METHODS: The validated Dundee Ready Educational Environment Measure (DREEM), a 50 item, self-administered Likert-type inventory, was used in this prospective study. Employing convenience sampling, undergraduate chiropractic students were investigated at 2 points in time: 2009 (n = 124) and 2012 (n = 127). An analysis of 2 matching samples was performed on 27% (n = 34) of the respondents in 2009. RESULTS: A total of 251 students (79%) completed the inventory, 83% (n = 124) in 2009 and 75% (n = 127) in 2012. The overall DREEM scores in both years were excellent: 156 (78%) and 153 (77%), respectively. The students' perceptions of teachers differed significantly between the 2 cohort years, decreasing from 77% to 73%. Three items received deprived scores: limited support for stressed students, authoritarian teachers, and an overemphasis on factual learning; the latter significantly decreased in 2012. In the longitudinal sample these items also displayed scores below the expected mean. CONCLUSION: Students viewed the educational environment as excellent both in 2009 and 2012. The perceptions of teachers declined with time; however, this could be attributed to teachers' new roles. Certain aspects of the educational environment factored prominently during the comparative points in time, as well as longitudinally, and these ought to be further investigated and addressed to provide an enhanced educational environment. PMID- 26023893 TI - Participation strategies and student performance: An undergraduate health science retrospective study. AB - OBJECTIVE: This research explores participatory evidence-based teaching methods in a health science course to see if a relationship emerged between the level of student participation and course performance, the type of participation and course performance, or the amount of participation and course performance and level of demonstrated learning. METHODS: Level of student participation was dichotomous (100% or <100%), and differences between groups on a knowledge test were compared using an unpaired t test. Type of participation was also dichotomous (in class or out), and differences in course performance on the knowledge test were compared using the unpaired t test. Amount of participation and course performance and level of demonstrated learning were also tested after the knowledge test was measured using a matrix based upon Bloom's taxonomy. RESULTS: Students who participated 100% of the time scored 6% higher on average than students with less than 100% participation (t[183] = 3.55, p = .0005, d = 0.52). There was no difference between groups when assessing for differences in course performance by type of participation. Students with 100% participation scored higher on the short answer question section of the examination (t[183] = 4.58, p = .0001, d = 0.68), but there was no difference on the multiple choice question part of the examination. CONCLUSION: Full participation in the course was related to higher examination scores and higher scores on examination questions assessing higher levels in the cognitive domain. PMID- 26023894 TI - Degradable Polymer with Protein Resistance in a Marine Environment. AB - Protein resistance is the central issue in marine antibiofouling. We have prepared poly(epsilon-caprolactone) (PCL)-based polyurethane with 2 (dimethylamino) ethyl methacrylate (DEM) as pendant groups by a combination of the thiol-ene click reaction and the condensation reaction. By the use of quartz crystal microbalance with dissipation (QCM-D) and surface plasmon resonance (SPR), we have investigated the adsorption of fibrinogen, bovine serum albumin (BSA), and lysozyme on the polymer surface. The polymer exhibits protein resistance in seawater but not in fresh water because DEM pendant groups carry net neutral charges in the former. The evaluation of antibacterial adhesion of the polymer by using Micrococcus luteus demonstrates that the polymer can effectively inhibit the settlement of marine bacteria. Our studies also show that the polymer is degradable in marine environments. PMID- 26023896 TI - Preparation and Mechanism of Cu-Decorated TiO2-ZrO2 Films Showing Accelerated Bacterial Inactivation. AB - Antibacterial robust, uniform TiO2-ZrO2 films on polyester (PES) under low intensity sunlight irradiation made up by equal amounts of TiO2 and ZrO2 exhibited a much higher bacterial inactivation kinetics compared to pure TiO2 or ZrO2. The TiO2-ZrO2 matrix was found to introduce a drastic increase in the Cu dopant promoter enhancing bacterial inactivation compared to Cu sputtered in the same amount on PES. Furthermore, the bacterial inactivation was accelerated by a factor close to three, by Cu- on TiO2-ZrO2 at extremely low levels ~0.01%. Evidence is presented by X-ray photoelectron spectroscopy for redox catalysis taking place during bacterial inactivation. The TiO2-ZrO2-Cu band gap is estimated and the film properties were fully characterized. Evidence is provided for the photogenerated radicals intervening in the bacterial inactivation. The photoinduced TiO2-ZrO2-Cu interfacial charge transfer is discussed in term of the electronic band positions of the binary oxide and the Cu TiO2 intragap state. PMID- 26023895 TI - Expression and Characterization of Gly-317 Variants of Factor IX Causing Variable Bleeding in Hemophilia B Patients. AB - We recently identified two hemophilia B patients who carried Gly-317 to Arg (FIX G317R) or Gly-317 to Glu (FIX-G317E) substitutions in their FIX gene. The former mutation caused severe and the latter moderate bleeding in afflicted patients. To understand the molecular basis for the variable clinical manifestation of Gly-317 mutations, we prepared recombinant G317R and G317E derivatives of FIX and compared their kinetic properties to those of recombinant wild-type FIX in appropriate assay systems. Both physiological activators, factor XIa and extrinsic Tenase (factor VIIa-tissue factor), activated both zymogen variants with an ~1.5-fold elevated K(m); however, extrinsic Tenase activated FIX-G317E with an ~2-fold improved k(cat). By contrast to zymogen activation, the catalytic activities of both FIXa-G317R and FIXa-G317E enzymes toward the natural substrate, factor X, were dramatically (>4 orders of magnitude) impaired, but their apparent affinity for interaction with factor VIIIa was only slightly (<2 fold) decreased. Further studies revealed that the reactivity of FIXa-G317R and FIXa-G317E with antithrombin has been impaired 10- and 13-fold, respectively, in the absence and 166- and 500-fold, respectively, in the presence of pentasaccharide. As expected, the clotting activities of FIX variants could not be measured by the aPTT assay. These results implicate a critical role for Gly 317 in maintaining normal catalytic function for FIX/FIXa in the clotting cascade. The results further suggest that improved k(cat) of FIX-G317E activation in the extrinsic pathway together with dramatically impaired reactivity of FIXa G317E with antithrombin may account for the less severe bleeding phenotype of a hemophilia B patient carrying the FIX-G317E mutation. PMID- 26023897 TI - Comprehensive drilling of the C1-2 facets to achieve direct posterior reduction in irreducible atlantoaxial dislocation. AB - OBJECT: The cause of irreducibility in irreducible atlantoaxial dislocation (AAD) appears to be the orientation of the C1-2 facets. The current management strategies for irreducible AAD are directed at removing the cause of irreducibility followed by fusion, rather than transoral decompression and posterior fusion. The technique described in this paper addresses C1-2 facet mobilization by facetectomies to aid intraoperative manipulation. METHODS: Using this technique, reduction was achieved in 19 patients with congenital irreducible AAD treated between January 2011 and December 2013. The C1-2 joints were studied preoperatively, and particular attention was paid to the facet orientation. Intraoperatively, oblique C1-2 joints were opened widely, and extensive drilling of the facets was performed to make them close to flat and parallel to each other, converting an irreducible AAD to a reducible one. Anomalous vertebral arteries (VAs) were addressed appropriately. Further reduction was then achieved after vertical distraction and joint manipulation. RESULTS: Adequate facet drilling was achieved in all but 2 patients, due to VA injury in 1 patient and an acute sagittal angle operated on 2 years previously in the other patient. Complete reduction could be achieved in 17 patients and partial in the remaining 2. All patients showed clinical improvement. Two patients showed partial redislocation due to graft subsidence. The fusion rates were excellent. CONCLUSIONS: Comprehensive drilling of the C1-2 facets appears to be a logical and effective technique for achieving direct posterior reduction in irreducible AAD. The extensive drilling makes large surfaces raw, increasing fusion rates. PMID- 26023898 TI - Effects of sex on the incidence and prognosis of spinal meningiomas: a Surveillance, Epidemiology, and End Results study. AB - OBJECT: Most spinal meningiomas are intradural lesions in the thoracic spine that present with both local pain and myelopathy. By using the large prospective Surveillance, Epidemiology, and End Results (SEER) database, the authors studied the incidence of spinal meningiomas and examined demographic and treatment factors predictive of death. METHODS: Using SEER*Stat software, the authors queried the SEER database for cases of spinal meningioma between 2000 and 2010. From the results, tumor incidence and demographic statistics were computed; incidence was analyzed as a function of tumor location, pathology, age, sex, and malignancy code. Survival was analyzed by using a Cox proportional hazards ratio in SPSS for age, sex, marital status, primary site, size quartile, treatment modality, and malignancy code. In this analysis, significance was set at a p value of 0.05. RESULTS: The 1709 spinal meningiomas reported in the SEER database represented 30.7% of all primary intradural spinal tumors and 7.9% of all meningiomas. These meningiomas occurred at an age-adjusted incidence of 0.193 (95% CI 0.183-0.202) per 100,000 population and were closely related to sex (337 [19.7%] male patients and 1372 [80.3%] female patients). The Cox hazard function for mortality in males was higher (2.4 [95% CI1.7-3.5]) and statistically significant, despite the lower lesion incidence in males. All-cause survival was lowest in patients older than 80 years. Primary site and treatment modality were not significant predictors of mortality. CONCLUSIONS: Spinal meningiomas represent a significant fraction of all primary intradural spinal tumors and of all meningiomas. The results of this study establish the association of lesion incidence and survival with sex, with a less frequent incidence in but greater mortality among males. PMID- 26023899 TI - Traumatic anterior cervical pseudomeningocele causing intracranial hypotension successfully treated with blood patch: case report. AB - Cervical pseudomeningocele is a rare complication of trauma. It develops when an extradural collection of cerebrospinal fluid (CSF) develops after a dural breach. The authors present the unusual case of a 33-year-old man with progressive headache, neck pain, mental status changes, and cardiopulmonary instability after polytrauma sustained from a motorcycle-versus-deer collision, without improvement during a 5-day hospitalization. Magnetic resonance imaging revealed a collection of CSF anterior to the cervical thecal sac compatible with an anterior cervical pseudomeningocele. A nontargeted epidural blood patch was performed with subsequent resolution of the patient's symptoms. Anterior cervical pseudomeningoceles are usually asymptomatic; however, these lesions can cause orthostatic headaches, neck pain, and cardiopulmonary compromise, as it did in the featured patient. Pseudomeningoceles should be included in the differential diagnosis for posttrauma patients with progressive neurological decline or postural headache, and blood patch may be an effective minimally invasive treatment. PMID- 26023900 TI - Spinal intraarterial computed tomography angiography as an effective adjunct for spinal angiography. AB - OBJECT: Spinal digital subtraction angiography (DSA) is indispensable for the precise diagnosis of spinal vascular lesions and the assessment of blood supply to the spinal cord. However, comprehensive spinal DSA covering multiple segments requires repetition of selective catheterization into small segmental arteries, which is time consuming, sometimes difficult, and hazardous. The authors investigated the usefulness of CT angiography with intraarterial contrast injection (IA-CTA) as a preliminary study preceding spinal DSA. With the advent of multidetector CT, it is feasible to obtain images of the spinal cord vasculature instantaneously overa number of segments. METHODS: A total of 56 patients with lesions involving the spinal vasculature underwent IA-CTA with 64- or 320-row detector CT in advance of comprehensive spinal DSA. Contrast material was injected via a pigtail catheter placed at the aorta in proximity to the segments of interest. Scanning was repeated twice to obtain arterial- and venous phase images to differentiate between the arterial and venous components. The spinal arteries were identified by paging the various multiplanar reconstruction images and tracing the vessels from the aorta. Spinal DSA was subsequently performed by guiding selective catheterization to the feeding segments in reference to the IA-CTA findings. Visualization of the segmental arteries, normal spinal arteries, and abnormal vessels during IA-CTA was investigated and compared with that obtained during spinal DSA. RESULTS: In all 56 patients, spinal IA-CTA successfully enabled visualization of the spinal vessels, including the radicular arteries and the anterior spinal artery. Below the aortic arch, all segmental arteries were identified clearly. The segmental arteries, radiculomedullary arteries, spinal arteries, and abnormal vessels were traced from the aorta, which would be the target of selective catheterization. In 3 (6.8%) patients, IA-CTA revealed severe aortic atherosclerosis and occlusion of some segmental arteries. The information obtained was useful for directing selective catheterization studies. The findings of IA-CTA corresponded well with those of spinal DSA. CONCLUSIONS: IA-CTA is a useful adjunct to spinal DSA for surveying the vasculature surrounding the spinal cord and for orienting selective catheterization. IA-CTA can complement spinal DSA, curtail unnecessary segmental injections, and thus reduce procedural complications. PMID- 26023901 TI - Spontaneous resolution of idiopathic thoracic spinal cord herniation: case report. AB - Spinal cord herniation is a relatively rare but increasingly recognized clinical entity, with fewer than 200 cases reported in the literature to date. The etiology of this condition remains unknown, and surgery is used as the primary treatment to correct the herniation and consequent spinal cord compromise. Some patients without clinical progression have been treated with nonoperative measures, including careful follow-up and symptomatic physical therapy. To date, however, there has been no published report on the resolution of spinal cord herniation without surgical intervention. The patient in the featured case is a 58-year-old man who presented with mild thoracic myelopathy and imaging findings consistent with idiopathic spinal cord herniation. Surprisingly, updated MRI studies, obtained to better delineate the pathology, showed spontaneous resolution of the herniation. Subsequent MRI 6 months later revealed continued resolution of the previous spinal cord herniation. This is the first report of spontaneous resolution of a spinal cord herniation in the literature. At present, the treatment of this disorder is individualized, with microsurgical correction used in patients with progressive neurological impairment. The featured case highlights the potential variability in the natural history of this condition and supports considering an initial trial of nonoperative management for patients with mild, nonprogressive neurological deficits. PMID- 26023902 TI - Does atlantoaxial dislocation really cause Chiari? PMID- 26023903 TI - Low-Temperature Fabrication of Mesoporous Titanium Dioxide Thin Films with Tunable Refractive Indices for One-Dimensional Photonic Crystals and Sensors on Rigid and Flexible Substrates. AB - Highly transparent mesoporous titanium dioxide (TiO2; anatase) thin films were prepared at room temperature via ultraviolet (UV) irradiation of hybrid polymer TiO2 nanoparticle thin films. This approach utilized a UV-curable polymer in conjunction with the photocatalytic activity of TiO2 to form and degrade the organic component of the composite films in one step, producing films with well controlled porosity and refractive index. By adjustment of the loading of TiO2 nanoparticles in the host polymer, the refractive index was tuned between 1.53 and 1.73. Facile control of these properties and mild processing conditions was leveraged to fabricate robust one-dimensional photonic crystals (Bragg mirrors) consisting entirely of TiO2 on silicon and flexible poly(ethylene terephthalate) substrates. The mesoporous Bragg mirrors were shown to be effective chemical vapor sensors with strong optical responses. PMID- 26023904 TI - Quantitative Polymerase Chain Reaction to Assess Response to Treatment of Bacterial Vaginosis and Risk of Preterm Birth. AB - OBJECTIVE: The aim of this study was to determine whether quantitative polymerase chain reaction (qPCR) bacterial load measurement is a valid method to assess response to treatment of bacterial vaginosis and risk of preterm birth in pregnant women. STUDY DESIGN: Secondary analysis by utilizing stored vaginal samples obtained during a previous randomized controlled trial studying the effect of antibiotics on preterm birth (PTB). All women had risk factors for PTB: (1) positive fetal fibronectin (n=146), (2) bacterial vaginosis (BV) and a prior PTB (n=43), or (3) BV and a prepregnancy weight<50 kg (n=54). Total and several individual BV-related bacteria loads were measured using qPCR for 16S rRNA. Loads were correlated with Nugent scores (Spearman correlation coefficients). Loads were compared pre- and posttreatment with Wilcoxon rank-sum test. Individual patient differences were examined with Wilcoxon signed-rank test. RESULTS: A total of 243 paired vaginal samples were available for analysis: 123 antibiotics and 120 placebo. Groups did not differ by risk factors for PTB. For all samples, bacterial loads were correlated with Nugent score and each of its specific bacterial components (all p<0.01). Baseline total bacterial load did not differ by treatment group (p=0.87). Posttreatment total bacterial load was significantly lower in the antibiotics group than the placebo group (p<0.01). Individual patient total bacterial load decreased significantly posttreatment in the antibiotics group (p<0.01), but not in the placebo group (p=0.12). The rate of PTB did not differ between groups (p=0.24). PTB relative risks calculated for BV positive versus BV negative women and women with the highest quartile total and individual bacterial loads were not statistically significant. CONCLUSION: qPCR correlates with Nugent score and demonstrates decreased bacterial load after antibiotic treatment. Therefore, it is a valid method of vaginal flora assessment in pregnant women who are at high risk for PTB. PMID- 26023905 TI - Differential Morbidity in Preterm Small versus Appropriate for Gestational Age: Perhaps Unverifiable. AB - OBJECTIVE: The objective of this study was to determine the morbidity of preterm small for gestational age (SGA) infants compared with appropriate for GA (AGA). STUDY DESIGN: This is a secondary analysis of the randomized trial evaluating magnesium sulfate for the prevention of cerebral palsy (CP). We compared outcomes of preterm (< 37 weeks) nonanomalous infants who were SGA (birth weight < 10% for GA) versus AGA (birth weight 10-89% for GA). We compared (1) the parent trial primary outcome, a composite of stillbirth, infant death by 1 year of age, or moderate to severe CP at 2 years of age and (2) composite neonatal morbidity (CNM). RESULTS: Of the 1,948 infants who met inclusion criteria, 95% were AGA and 5% were SGA. The primary outcome was similar (10 and 15%, p = 0.08), as was the CNM (24 and 25%, p = 0.89). Sample size calculations indicate that detection of a one-third higher rate of CNM among SGA compared with AGA infants requires more than 93,900 preterm births; for a one-third difference in moderate to severe CP, more than 1.4 million infants. CONCLUSION: Owing to the prohibitive sample size required, ascertaining a difference in sequela between preterm SGA and AGA infants is possibly unverifiable. PMID- 26023906 TI - Sonographic Reference Ranges for the Thyroid Gland in Euthyroid Term Newborns. AB - OBJECTIVE: This study aims to establish the reference ranges for normal thyroid gland (length, width, depth, and volume) in healthy term Polish neonates within the first week of life to aid in the comparative evaluation of infants with suspected thyroid disease. STUDY DESIGN: A total of 148 term neonates from mothers with normal thyroid function were examined during their first week of life. Ultrasound examination was performed in both longitudinal and transverse projections to create reference value percentile charts for thyroid volume in healthy term neonates. RESULTS: Median (range) width, depth, and length were 0.714 (range, 0.470-0.959), 0.677 (range, 0.527-0.960), 2.07 (range, 1.540-2.870) cm for the right lobe of the thyroid: and 0.720 (range, 0.535-1.010), 0.678 (range, 0.521-0.952), 2.015 (range, 1.620-2.730) cm for the left. Volumes for right lobe, left lobe, and both lobes combined were 0.502 (range, 0.228-0.931), 0.511 (range, 0.294-0.959), and 1.014 (range, 0.526-1.849) mL. CONCLUSION: Diagnostic ultrasound examination of the thyroid in the neonate is a simple and useful method for assessment of thyroid gland disease and neonatal health. This study provides robust normative data for Polish newborns. Furthermore, we have found different values compared with other countries, particularly Scotland, which underlines the importance of establishing population-based data. PMID- 26023907 TI - Reconsidering the Current Preterm Premature Rupture of Membranes Antibiotic Prophylactic Protocol. AB - OBJECTIVE: The purpose of our study was to determine whether the current antibiotic regimen for preterm premature rupture of membranes (PPROM) is adequate for covering the current causative agents and sensitivities of chorioamnionitis and early-onset neonatal sepsis. STUDY DESIGN: During a 3-year period, we retrieved the results from placental and amniotic membrane cultures obtained at delivery in cases of maternal fever, chorioamnionitis, and PPROM, and from blood cultures obtained from neonates with early-onset sepsis (EOS) in three participating hospitals. Sensitivity of pathogens to antimicrobial agents was performed using routine microbiologic techniques. RESULTS: There were 1,133 positive placental or amniotic cultures, 740 (65.3%) were from gram-negative Enterobacteriaceae. There were 27 neonates diagnosed with EOS with positive blood cultures. Aerobic Enterobacteriaceae accounted for 14 cases (52%) and group B streptococcus for 7 cases (26%). Of the Escherichia coli and Klebsiella sp., only 38% were sensitive to ampicillin. CONCLUSION: Local pathogens and their antibiotic sensitivity profiles should be explored every few years and an effective antibiotic protocol chosen to cover the main pathogens causing chorioamnionitis and EOS. Consideration should be made for changing ampicillin in women with PPROM to a regimen with better coverage of gram-negative Enterobacteriaceae. PMID- 26023908 TI - Travelling activity and travel-related risks after allogeneic haematopoietic stem cell transplantation - a single centre survey. AB - BACKGROUND: Travel activity and travel-related risks of patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT) remain largely unknown. The aim of our study was to examine travel activity after allo-HSCT including travel behaviour and travel patterns. METHODS: We analysed travel characteristics of allo-HSCT recipients by using a retrospective cross-sectional survey. Allo-HSCT patients were asked to complete a questionnaire during their annual health visits from 2010 to 2012. RESULTS: Overall, 118/153 (77%) participating patients reported travel activity for a total of 201 travelling episodes. Travellers versus non-travellers were receiving immunosuppressive treatment in 35.6% versus 65.7% (p=0.002), and had graft-versus-host-disease (GvHD) in 52.5% versus 62.9% (p=0.17). In a multivariate analysis, the time between the transplantation and the survey was the only factor associated with travel activity (p<0.0001) and taking pretravel advice (p<0.0001). In 34.8% of travel episodes pretravel advice was sought. Patients with pretravel advice reported travel-related symptoms more frequently. Minor respiratory (27/201) and gastrointestinal (23/201) symptoms were most frequently indicated. Four percent (8/201) of the patients were hospitalised while travelling. CONCLUSION: We conclude that travelling after allo HSCT is frequent and linked to the time since transplantation. We could not define specific risks for any destination. Nevertheless, pretravel advice and preparation are highly recommended for immunosuppressed patients. PMID- 26023909 TI - Serine/threonine ligation for natural cyclic peptide syntheses. AB - Covering: 2000 to 2014Cyclic peptides are a class of abundant natural products, often exhibiting attractive biological activities. The challenges in the total synthesis of cyclic peptides lie in the preparation of unnatural amino acids if present and the peptide cyclization. Cyclization is an entropy-disfavoured process, with competition between intermolecular and intramolecular reactions. Biological methods can utilize the pre-organized conformation of the side chain unprotected peptide, which brings the reacting termini into proximity, while chemical synthesis requires protecting groups, often large-size and hydrophobic in nature. In this regard, performing peptide cyclization can be an arbitrary and trial-and-error practice. In this highlight, we discuss the application of chemoselective ligation-mediated peptide cyclization in the total synthesis of natural cyclic peptides. PMID- 26023910 TI - Efficient chemoenzymatic synthesis of novel galacto-N-biose derivatives and their sialylated forms. AB - Galacto-N-biose (GNB) derivatives were efficiently synthesized from galactose derivatives via a one-pot two-enzyme system containing two promiscuous enzymes from Bifidobacterium infantis: a galactokinase (BiGalK) and a d-galactosyl-beta1 3-N-acetyl-d-hexosamine phosphorylase (BiGalHexNAcP). Mono-sialyl and di-sialyl galacto-N-biose derivatives were then prepared using a one-pot two-enzyme system containing a CMP-sialic acid synthetase and an alpha2-3-sialyltransferase or an alpha2-6-sialyltransferase. PMID- 26023911 TI - Electrochemical imaging of hydrogen peroxide generation at individual gold nanoparticles. AB - Localised hydrogen peroxide generation at individual catalytic gold nanoparticles within ensemble electrodes is mapped for the first time using combined scanning electrochemical-scanning ion conductance microscopy (SECM-SICM). PMID- 26023912 TI - Rebamipide delivered by brushite cement enhances osteoblast and macrophage proliferation. AB - Many of the bioactive agents capable of stimulating osseous regeneration, such as bone morphogenetic protein-2 (BMP-2) or prostaglandin E2 (PGE2), are limited by rapid degradation, a short bioactive half-life at the target site in vivo, or are prohibitively expensive to obtain in large quantities. Rebamipide, an amino acid modified hydroxylquinoline, can alter the expression of key mediators of bone anabolism, cyclo-oxygenase 2 (COX-2), BMP-2 and vascular endothelial growth factor (VEGF), in diverse cell types such as mucosal and endothelial cells or chondrocytes. The present study investigates whether Rebamipide enhances proliferation and differentiation of osteoblasts when delivered from brushite cement. The reactive oxygen species (ROS) quenching ability of Rebampide was tested in macrophages as a measure of bioactivity following drug release incubation times, up to 14 days. Rebamipide release from brushite occurs via non fickian diffusion, with a rapid linear release of 9.70% +/- 0.37% of drug per day for the first 5 days, and an average of 0.5%-1% per day thereafter for 30 days. Rebamipide slows the initial and final cement setting time by up to 3 and 1 minute, respectively, but does not significantly reduce the mechanical strength below 4% (weight percentage). Pre-osteoblast proliferation increases by 24% upon exposure to 0.4 uM Rebamipide, and by up to 73% when Rebamipide is delivered via brushite cement. Low doses of Rebamipide do not adversely affect peak alkaline phosphatase activity in differentiating pre-osteoblasts. Rebamipide weakly stimulates proliferation in macrophages at low concentrations (118 +/- 7.4% at 1 uM), and quenches ROS by 40-60%. This is the first investigation of Rebamipide in osteoblasts. PMID- 26023913 TI - Use of brain MRI atlases to determine boundaries of age-related pathology: the importance of statistical method. AB - INTRODUCTION: Neurodegenerative disease diagnoses may be supported by the comparison of an individual patient's brain magnetic resonance image (MRI) with a voxel-based atlas of normal brain MRI. Most current brain MRI atlases are of young to middle-aged adults and parametric, e.g., mean +/- standard deviation (SD); these atlases require data to be Gaussian. Brain MRI data, e.g., grey matter (GM) proportion images, from normal older subjects are apparently not Gaussian. We created a nonparametric and a parametric atlas of the normal limits of GM proportions in older subjects and compared their classifications of GM proportions in Alzheimer's disease (AD) patients. METHODS: Using publicly available brain MRI from 138 normal subjects and 138 subjects diagnosed with AD (all 55-90 years), we created: a mean +/- SD atlas to estimate parametrically the percentile ranks and limits of normal ageing GM; and, separately, a nonparametric, rank order-based GM atlas from the same normal ageing subjects. GM images from AD patients were then classified with respect to each atlas to determine the effect statistical distributions had on classifications of proportions of GM in AD patients. RESULTS: The parametric atlas often defined the lower normal limit of the proportion of GM to be negative (which does not make sense physiologically as the lowest possible proportion is zero). Because of this, for approximately half of the AD subjects, 25-45% of voxels were classified as normal when compared to the parametric atlas; but were classified as abnormal when compared to the nonparametric atlas. These voxels were mainly concentrated in the frontal and occipital lobes. DISCUSSION: To our knowledge, we have presented the first nonparametric brain MRI atlas. In conditions where there is increasing variability in brain structure, such as in old age, nonparametric brain MRI atlases may represent the limits of normal brain structure more accurately than parametric approaches. Therefore, we conclude that the statistical method used for construction of brain MRI atlases should be selected taking into account the population and aim under study. Parametric methods are generally robust for defining central tendencies, e.g., means, of brain structure. Nonparametric methods are advisable when studying the limits of brain structure in ageing and neurodegenerative disease. PMID- 26023914 TI - Time regained: when people stop a physical activity program, how does their time use change? A randomised controlled trial. AB - The aim of this study was to investigate how previously inactive adults who had participated in a structured, partly supervised 6-week exercise program restructured their time budgets when the program ended. Using a randomised controlled trial design, 129 previously inactive adults were recruited and randomly allocated to one of three groups: a Moderate or Extensive six-week physical activity intervention (150 and 300 additional minutes of exercise per week, respectively) or a Control group. Additional physical activity was accumulated through both group and individual exercise sessions with a wide range of activities. Use of time and time spent in energy expenditure zones was measured using a computerised 24-h self-report recall instrument, the Multimedia Activity Recall for Children and Adults, and accelerometry at baseline, mid- and end-program and at 3- and 6-months follow up. At final follow up, all significant changes in time use domains had returned to within 20 minutes of baseline levels (Physical Activity 1-2 min/d, Active Transport 3-9 min/d, Self-Care 0-2 min/d, Television/Videogames 13-18 min/d in the Moderate and Extensive group, relative to Controls, respectively, p > 0.05). Similarly, all significant changes in time spent in the moderate energy expenditure zone had returned to within 1-3 min/d baseline levels (p > 0.05), however time spent in vigorous physical activity according to accelerometry estimates remained elevated, although the changes were small in magnitude (1 min/d in the Moderate and Extensive groups, relative to Controls, p = 0.01). The results of this study demonstrate strong recidivist patterns in physical activity, but also in other aspects of time use. In designing and determining the effectiveness of exercise interventions, future studies would benefit from considering the whole profile of time use, rather than focusing on individual activities, TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000248066. PMID- 26023915 TI - Effects of sowing date on phenotypic plasticity of fitness-related traits in two annual weeds on the Songnen Plain of China. AB - BACKGROUND: Phenotypic plasticity of fitness-related traits is vital for plant species to adapt to variable environments. Chenopodium glaucum L. and Amaranthus retroflexus L. are two common weed species globally. Understanding the plasticity in life-history traits, especially in reproductive allocation, within and among these species is important for predicting their success and for managing them in different environments. METHODOLOGY/PRINCIPAL FINDINGS: Seeds of the two plant species were sown every 10 days from 26 Jun to 15 Aug. Life-history and fitness related traits of both phenology and morphology were measured, and dry biomass of roots, stems, leaves, and reproductive tissues was determined at physiological maturity. Length of reproductive and total life period of the two species differed among six sowing-date treatments. Later germinating plants led to relatively reduced total life period, size, and earlier reproduction than earlier germinating plants. The ratio of reproductive biomass to total plant biomass increased with later planting dates in C. glaucum but declined in A. retroflexus. Mature plant height, crown diameter, and reproductive tissue biomass, and seed production of C. glaucum and A. retroflexus increased with delayed reproductive period. Both species displayed true plasticity in reproductive allocation. However, the sowing date had a far greater effect on rate of vegetative growth than on allocation to reproduction. CONCLUSIONS/SIGNIFICANCE: The fitness of both C. glaucum and A. retroflexus populations have an apparent increase when the period between germination and seed production is much longer. However, C. glaucum appears better adapted to later sowing than A. retroflexus. Controlling seedlings prior to reproduction will alleviate the negative effect not only in the present year but also in future years. PMID- 26023917 TI - Mechanism of testosterone deficiency in the transgenic sickle cell mouse. AB - Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi) exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease. PMID- 26023916 TI - Initial events in bacterial transcription initiation. AB - Transcription initiation is a highly regulated step of gene expression. Here, we discuss the series of large conformational changes set in motion by initial specific binding of bacterial RNA polymerase (RNAP) to promoter DNA and their relevance for regulation. Bending and wrapping of the upstream duplex facilitates bending of the downstream duplex into the active site cleft, nucleating opening of 13 bp in the cleft. The rate-determining opening step, driven by binding free energy, forms an unstable open complex, probably with the template strand in the active site. At some promoters, this initial open complex is greatly stabilized by rearrangements of the discriminator region between the -10 element and +1 base of the nontemplate strand and of mobile in-cleft and downstream elements of RNAP. The rate of open complex formation is regulated by effects on the rapidly reversible steps preceding DNA opening, while open complex lifetime is regulated by effects on the stabilization of the initial open complex. Intrinsic DNA opening-closing appears less regulated. This noncovalent mechanism and its regulation exhibit many analogies to mechanisms of enzyme catalysis. PMID- 26023918 TI - Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. AB - BACKGROUND: The associations between toll-like receptor 2 (TLR2) and toll-like receptor 4(TLR4) polymorphisms and inflammatory bowel disease (IBD) susceptibility remain controversial. A meta-analysis was performed to assess these associations. METHODS: A systematic search was performed to identify all relevant studies relating TLR2 and TLR4 polymorphisms and IBD susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by ethnicity and publication quality. RESULTS: Thirty eight eligible studies, assessing 10970 cases and 7061 controls were included. No TLR2 Arg677Trp polymorphism was found. No significant association was observed between TLR2 Arg753Gln polymorphism and Crohn's disease (CD) or ulcerative colitis (UC) in all genetic models. Interestingly, TLR4 Asp299Gly polymorphism was significantly associated with increased risk of CD and UC in all genetic models, except for the additive one in CD. In addition, a statistically significant association between TLR4 Asp299Gly polymorphism and IBD was observed among high quality studies evaluating Caucasians, but not Asians. Associations between TLR4 Thr399Ile polymorphisms and CD risk were found only in the allele and dominant models. The TLR4 Thr399Ile polymorphism was associated with UC risk in pooled results as well as subgroup analysis of high quality publications assessing Caucasians, in allele and dominant models. CONCLUSIONS: The meta analysis provides evidence that TLR2 Arg753Gln is not associated with CD and UC susceptibility in Asians; TLR4 Asp299Gly is associated with CD and UC susceptibility in Caucasians, but not Asians. TLR4 Thr399Ile may be associated with IBD susceptibility in Caucasians only. Additional well-powered studies of Asp299Gly and other TLR4 variants are warranted. PMID- 26023919 TI - TNF-alpha Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism. AB - Invasion by infectious pathogens can elicit a range of cytokine responses from host cells. These cytokines provide the initial host defense mechanism. In this report, we demonstrate that TNF-alpha, a pro-inflammatory cytokine, can be induced by hepatitis C virus (HCV) in its host cells in a biphasic manner. The initial induction of TNF-alpha by HCV was prompt and could be blocked by the antibody directed against the HCV E2 envelope protein and by chemicals that inhibit endocytosis, indicating the specificity of endocytic uptake of HCV in this induction. Further studies indicated that the induction of TNF-alpha was dependent on toll-like receptors 7 and 8 (TLR7/8) but not on other intracellular pattern recognition receptors. Consistently, siRNA-mediated gene silencing of the downstream effectors in the TLR7/8 signaling pathway including MyD88, IRAK1, TRAF6, TAK1 and p65 NF-kappaB suppressed the expression of TNF-alpha. The role of p65 NF-kappaB in the induction of TNF-alpha via transcriptional up-regulation was further confirmed by the chromatin immunoprecipitation assay. TNF-alpha induced by HCV could activate its own receptor TNFR1 on hepatocytes to suppress HCV replication. This suppressive effect of TNF-alpha on HCV was due to its role in supporting interferon signaling, as the suppression of its expression led to the loss of IFNAR2 and impaired interferon signaling and the induction of interferon stimulated genes. In conclusion, our results indicate that hepatocytes can sense HCV infection via TLR7/8 to induce the expression of TNF-alpha, which inhibits HCV replication via an autocrine mechanism to support interferon signaling. PMID- 26023921 TI - Correction: Longitudinal neurostimulation in older adults improves working memory. PMID- 26023922 TI - Multifarious facets of sugar-derived molecular gels: molecular features, mechanisms of self-assembly and emerging applications. AB - The remarkable capability of nature to design and create excellent self-assembled nano-structures, especially in the biological world, has motivated chemists to mimic such systems with synthetic molecular and supramolecular systems. The hierarchically organized self-assembly of low molecular weight gelators (LMWGs) based on non-covalent interactions has been proven to be a useful tool in the development of well-defined nanostructures. Among these, the self-assembly of sugar-derived LMWGs has received immense attention because of their propensity to furnish biocompatible, hierarchical, supramolecular architectures that are macroscopically expressed in gel formation. This review sheds light on various aspects of sugar-derived LMWGs, uncovering their mechanisms of gelation, structural analysis, and tailorable properties, and their diverse applications such as stimuli-responsiveness, sensing, self-healing, environmental problems, and nano and biomaterials synthesis. PMID- 26023920 TI - Intramembranous bone healing process subsequent to tooth extraction in mice: micro-computed tomography, histomorphometric and molecular characterization. AB - Bone tissue has a significant potential for healing, which involves a significant the interplay between bone and immune cells. While fracture healing represents a useful model to investigate endochondral bone healing, intramembranous bone healing models are yet to be developed and characterized. In this study, a micro computed tomography, histomorphometric and molecular (RealTimePCRarray) characterization of post tooth-extraction alveolar bone healing was performed on C57Bl/6 WT mice. After the initial clot dominance (0 h), the development of a provisional immature granulation tissue is evident (7 d), characterized by marked cell proliferation, angiogenesis and inflammatory cells infiltration; associated with peaks of growth factors (BMP-2-4-7,TGFbeta1,VEGFa), cytokines (TNFalpha, IL 10), chemokines & receptors (CXCL12, CCL25, CCR5, CXCR4), matrix (Col1a1-2, ITGA4, VTN, MMP1a) and MSCs (CD105, CD106, OCT4, NANOG, CD34, CD146) markers expression. Granulation tissue is sequentially replaced by more mature connective tissue (14 d), characterized by inflammatory infiltrate reduction along the increased bone formation, marked expression of matrix remodeling enzymes (MMP-2 9), bone formation/maturation (RUNX2, ALP, DMP1, PHEX, SOST) markers, and chemokines & receptors associated with healing (CCL2, CCL17, CCR2). No evidences of cartilage cells or tissue were observed, strengthening the intramembranous nature of bone healing. Bone microarchitecture analysis supports the evolving healing, with total tissue and bone volumes as trabecular number and thickness showing a progressive increase over time. The extraction socket healing process is considered complete (21 d) when the dental socket is filled by trabeculae bone with well-defined medullary canals; it being the expression of mature bone markers prevalent at this period. Our data confirms the intramembranous bone healing nature of the model used, revealing parallels between the gene expression profile and the histomorphometric events and the potential participation of MCSs and immune cells in the healing process, supporting the forthcoming application of the model for the better understanding of the bone healing process. PMID- 26023923 TI - Association between Hemoglobin Concentration and the Progression or Development of Albuminuria in Diabetic Kidney Disease. AB - AIMS: Anemia, which might contribute to pathogenesis of kidney dysfunction, is a common finding in patients with type 2 diabetes. The aim of this study was to investigate if hemoglobin concentration is associated with the degree of change in urinary albumin-creatinine ratio or the development of albuminuria in patients with type 2 diabetes. METHODS: We measured hemoglobin concentration in 470 (296 men and 174 women) consecutive type 2 diabetic patients without albuminuria. We performed a follow-up study to assess the progression or development of albuminuria, the interval of which was 3.0 years. Then we evaluated relationships between hemoglobin concentration and albuminuria, using multivariate linear regression analyses and logistic regression analyses. RESULTS: Eighty four patients developed albuminuria during follow-up duration. In multivariate analyses, hemoglobin concentration was negatively associated with a change in urinary albumin-creatinine ratio in men (beta = -0.259, P = 0.0002) and women (beta = -0.194, P = 0.030). Moreover, multivariate adjusted odds ratio associated with 1 g/L in hemoglobin for the development of albuminuria was 0.93 (95% confidence interval; 0.89-0.96) in men and 0.94 (95% confidence interval; 0.88 0.99) in women, respectively. And, multivariate analyses revealed that adjusted odds ratios for the development of albuminuria were 4.78 (95% confidence interval; 1.65-13.91) in men and 4.62 (95% confidence interval; 1.34-16.68) in women with anemia (hemoglobin < 130 g/L for men and < 120 g/L for women), which were higher than those without anemia. CONCLUSIONS: Low hemoglobin concentration could be a predictor for the progression and development of albuminuria in patients with type 2 diabetes. PMID- 26023924 TI - Novel Roles of GATA4/6 in the Postnatal Heart Identified through Temporally Controlled, Cardiomyocyte-Specific Gene Inactivation by Adeno-Associated Virus Delivery of Cre Recombinase. AB - GATA4 and GATA6 are central cardiac transcriptional regulators. The postnatal, stage-specific function of the cardiac transcription factors GATA4 and GATA6 have not been evaluated. In part, this is because current Cre-loxP approaches to cardiac gene inactivation require time consuming and costly breeding of Cre expressing and "floxed" mouse lines, often with limited control of the extent or timing of gene inactivation. We investigated the stage-specific functions of GATA4 and GATA6 in the postnatal heart by using adeno-associated virus serotype 9 to control the timing and extent of gene inactivation by Cre. Systemic delivery of recombinant, adeno-associated virus 9 (AAV9) expressing Cre from the cardiac specific Tnnt2 promoter was well tolerated and selectively and efficiently recombined floxed target genes in cardiomyocytes. AAV9:Tnnt2-Cre efficiently inactivated Gata4 and Gata6. Neonatal Gata4/6 inactivation caused severe, rapidly lethal systolic heart failure. In contrast, Gata4/6 inactivation in adult heart caused only mild systolic dysfunction but severe diastolic dysfunction. Reducing the dose of AAV9:Tnnt2-Cre generated mosaics in which scattered cardiomyocytes lacked Gata4/6. This mosaic knockout revealed that Gata4/6 are required cell autonomously for physiological cardiomyocyte growth. Our results define novel roles of GATA4 and GATA6 in the neonatal and adult heart. Furthermore, our data demonstrate that evaluation of gene function hinges on controlling the timing and extent of gene inactivation. AAV9:Tnnt2-Cre is a powerful tool for controlling these parameters. PMID- 26023925 TI - The ordinal effects of ostracism: a meta-analysis of 120 Cyberball studies. AB - We examined 120 Cyberball studies (N = 11,869) to determine the effect size of ostracism and conditions under which the effect may be reversed, eliminated, or small. Our analyses showed that (1) the average ostracism effect is large (d > |1.4|) and (2) generalizes across structural aspects (number of players, ostracism duration, number of tosses, type of needs scale), sampling aspects (gender, age, country), and types of dependent measure (interpersonal, intrapersonal, fundamental needs). Further, we test Williams's (2009) proposition that the immediate impact of ostracism is resistant to moderation, but that moderation is more likely to be observed in delayed measures. Our findings suggest that (3) both first and last measures are susceptible to moderation and (4) time passed since being ostracized does not predict effect sizes of the last measure. Thus, support for this proposition is tenuous and we suggest modifications to the temporal need-threat model of ostracism. PMID- 26023926 TI - LZ-207, a Newly Synthesized Flavonoid, Induces Apoptosis and Suppresses Inflammation-Related Colon Cancer by Inhibiting the NF-kappaB Signaling Pathway. AB - Flavonoids and flavonoid derivatives, which have significant biological and pharmacological activities, including antitumor and anti-inflammatory activities, have been widely used in human healthcare. To design a more effective flavonoid antitumor agent, we altered the flavonoid backbone with substitutions of piperazine and methoxy groups to synthesize a novel flavonoid derivative, LZ-207. The anticancer effect of LZ-207 against HCT116 colon cancer cells and the underlying mechanism of this effect were explored in this study. Specifically, LZ 207 exhibited inhibitory effects on growth and viability in several human colon cancer cell lines and induced apoptosis in HCT116 cells both in vitro and in vivo. LZ-207 treatment also suppressed the nuclear translocation of NF-kappaB and the phosphorylation of IkappaB and IKKalpha/beta in a dose-dependent manner in both HCT116 cells and human acute monocytic leukemia THP-1 cells. Moreover, LZ 207 also reduced the secretion of the pro-inflammatory cytokine interleukin-6 (IL 6) in LPS-induced THP-1 cells, and this effect was confirmed at the transcriptional level. Furthermore, LZ-207 significantly inhibited HCT116 cell proliferation that was elicited by LPS-induced THP-1 cells in a co-culture system. These findings elucidated some potential molecular mechanisms for preventing inflammation-driven colon cancer using the newly synthesized flavonoid LZ-207 and suggested the possibility of further developing novel therapeutic agents derived from flavonoids. PMID- 26023927 TI - A Pre-clinical Animal Model of Trypanosoma brucei Infection Demonstrating Cardiac Dysfunction. AB - African trypanosomiasis (AT), caused by Trypanosoma brucei species, results in both neurological and cardiac dysfunction and can be fatal if untreated. Research on the pathogenesis and treatment of the disease has centred to date on the characteristic neurological symptoms, whereas cardiac dysfunction (e.g. ventricular arrhythmias) in AT remains largely unstudied. Animal models of AT demonstrating cardiac dysfunction similar to that described in field cases of AT are critically required to transform our understanding of AT-induced cardiac pathophysiology and identify future treatment strategies. We have previously shown that T. brucei can interact with heart muscle cells (cardiomyocytes) to induce ventricular arrhythmias in ex vivo adult rat hearts. However, it is unknown whether the arrhythmias observed ex vivo are also present during in vivo infection in experimental animal models. Here we show for the first time the characterisation of ventricular arrhythmias in vivo in two animal models of AT infection using electrocardiographic (ECG) monitoring. The first model utilised a commonly used monomorphic laboratory strain, Trypanosoma brucei brucei Lister 427, whilst the second model used a pleomorphic laboratory strain, T. b. brucei TREU 927, which demonstrates a similar chronic infection profile to clinical cases. The frequency of ventricular arrhythmias and heart rate (HR) was significantly increased at the endpoint of infection in the TREU 927 infection model, but not in the Lister 427 infection model. At the end of infection, hearts from both models were isolated and Langendorff perfused ex vivo with increasing concentrations of the beta-adrenergic agonist isoproterenol (ISO). Interestingly, the increased frequency of arrhythmias observed in vivo in the TREU 927 infection model was lost upon isolation of the heart ex vivo, but re-emerged with the addition of ISO. Our results demonstrate that TREU 927 infection modifies the substrate of the myocardium in such a way as to increase the propensity for ventricular arrhythmias in response to a circulating factor in vivo or beta adrenergic stimulation ex vivo. The TREU 927 infection model provides a new opportunity to accelerate our understanding of AT-related cardiac pathophysiology and importantly has the required sensitivity to monitor adverse cardiac-related electrical dysfunction when testing new therapeutic treatments for AT. PMID- 26023928 TI - Genetic regulation of bone metabolism in the chicken: similarities and differences to Mammalian systems. AB - Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL) and expression QTL (eQTL) mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken) and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone. PMID- 26023930 TI - High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. AB - High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS 1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFkappaB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1alpha and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts profoundly on brain activity, i.e., synaptic plasticity. PMID- 26023931 TI - Glycosyltransferase family 43 is also found in early eukaryotes and has three subfamilies in Charophycean green algae. AB - The glycosyltransferase family 43 (GT43) has been suggested to be involved in the synthesis of xylans in plant cell walls and proteoglycans in animals. Very recently GT43 family was also found in Charophycean green algae (CGA), the closest relatives of extant land plants. Here we present evidence that non-plant and non-animal early eukaryotes such as fungi, Haptophyceae, Choanoflagellida, Ichthyosporea and Haptophyceae also have GT43-like genes, which are phylogenetically close to animal GT43 genes. By mining RNA sequencing data (RNA Seq) of selected plants, we showed that CGA have evolved three major groups of GT43 genes, one orthologous to IRX14 (IRREGULAR XYLEM14), one orthologous to IRX9/IRX9L and the third one ancestral to all land plant GT43 genes. We confirmed that land plant GT43 has two major clades A and B, while in angiosperms, clade A further evolved into three subclades and the expression and motif pattern of A3 (containing IRX9) are fairly different from the other two clades likely due to rapid evolution. Our in-depth sequence analysis contributed to our overall understanding of the early evolution of GT43 family and could serve as an example for the study of other plant cell wall-related enzyme families. PMID- 26023932 TI - The dilemma of heterogeneity tests in meta-analysis: a challenge from a simulation study. AB - INTRODUCTION: After several decades' development, meta-analysis has become the pillar of evidence-based medicine. However, heterogeneity is still the threat to the validity and quality of such studies. Currently, Q and its descendant I(2) (I square) tests are widely used as the tools for heterogeneity evaluation. The core mission of this kind of test is to identify data sets from similar populations and exclude those are from different populations. Although Q and I(2) are used as the default tool for heterogeneity testing, the work we present here demonstrates that the robustness of these two tools is questionable. METHODS AND FINDINGS: We simulated a strictly normalized population S. The simulation successfully represents randomized control trial data sets, which fits perfectly with the theoretical distribution (experimental group: p = 0.37, control group: p = 0.88). And we randomly generate research samples Si that fits the population with tiny distributions. In short, these data sets are perfect and can be seen as completely homogeneous data from the exactly same population. If Q and I(2) are truly robust tools, the Q and I(2) testing results on our simulated data sets should not be positive. We then synthesized these trials by using fixed model. Pooled results indicated that the mean difference (MD) corresponds highly with the true values, and the 95% confidence interval (CI) is narrow. But, when the number of trials and sample size of trials enrolled in the meta-analysis are substantially increased; the Q and I(2) values also increase steadily. This result indicates that I(2) and Q are only suitable for testing heterogeneity amongst small sample size trials, and are not adoptable when the sample sizes and the number of trials increase substantially. CONCLUSIONS: Every day, meta analysis studies which contain flawed data analysis are emerging and passed on to clinical practitioners as "updated evidence". Using this kind of evidence that contain heterogeneous data sets leads to wrong conclusion, makes chaos in clinical practice and weakens the foundation of evidence-based medicine. We suggest more strict applications of meta-analysis: it should only be applied to those synthesized trials with small sample sizes. We call upon that the tools of evidence-based medicine should keep up-to-dated with the cutting-edge technologies in data science. Clinical research data should be made available publicly when there is any relevant article published so the research community could conduct in-depth data mining, which is a better alternative for meta analysis in many instances. PMID- 26023933 TI - Phosphatidylcholine Specific PLC-Induced Dysregulation of Gap Junctions, a Robust Cellular Response to Environmental Toxicants, and Prevention by Resveratrol in a Rat Liver Cell Model. AB - Dysregulation of gap junctional intercellular communication (GJIC) has been associated with different pathologies, including cancer; however, molecular mechanisms regulating GJIC are not fully understood. Mitogen Activated Protein Kinase (MAPK)-dependent mechanisms of GJIC-dysregulation have been well established, however recent discoveries have implicated phosphatidylcholine specific phospholipase C (PC-PLC) in the regulation of GJIC. What is not known is how prevalent these two signaling mechanisms are in toxicant/toxin-induced dysregulation of GJIC, and do toxicants/toxins work through either signaling mechanisms or both, or through alternative signaling mechanisms. Different chemical toxicants were used to assess whether they dysregulate GJIC via MEK or PC-PLC, or both Mek and PC-PLC, or through other signaling pathways, using a pluripotent rat liver epithelial oval-cell line, WB-F344. Epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, thrombin receptor activating peptide-6 and lindane regulated GJIC through a MEK1/2-dependent mechanism that was independent of PC-PLC; whereas PAHs, DDT, PCB 153, dicumylperoxide and perfluorodecanoic acid inhibited GJIC through PC-PLC independent of Mek. Dysregulation of GJIC by perfluorooctanoic acid and R59022 required both MEK1/2 and PC-PLC; while benzoylperoxide, arachidonic acid, 18beta-glycyrrhetinic acid, perfluorooctane sulfonic acid, 1-monolaurin, pentachlorophenol and alachlor required neither MEK1/2 nor PC-PLC. Resveratrol prevented dysregulation of GJIC by toxicants that acted either through MEK1/2 or PC-PLC. Except for alachlor, resveratrol did not prevent dysregulation of GJIC by toxicants that worked through PC-PLC-independent and MEK1/2-independent pathways, which indicated at least two other, yet unidentified, pathways that are involved in the regulation of GJIC. IN CONCLUSION: the dysregulation of GJIC is a contributing factor to the cancer process; however the underlying mechanisms by which gap junction channels are closed by toxicants vary. Thus, accurate assessments of risk posed by toxic agents, and the role of dietary phytochemicals play in preventing or reversing the effects of these agents must take into account the specific mechanisms involved in the cancer process. PMID- 26023929 TI - Pseudomonas putida and Pseudomonas fluorescens Species Group Recovery from Human Homes Varies Seasonally and by Environment. AB - By shedding light on variation in time as well as in space, long-term biogeographic studies can help us define organisms' distribution patterns and understand their underlying drivers. Here we examine distributions of Pseudomonas in and around 15 human homes, focusing on the P. putida and P. fluorescens species groups. We describe recovery from 10,941 samples collected during up to 8 visits per home, occurring on average 2.6 times per year. We collected a mean of 141 samples per visit, from sites in most rooms of the house, from the surrounding yards, and from human and pet occupants. We recovered Pseudomonas in 9.7% of samples, with the majority of isolates being from the P. putida and P. fluorescens species groups (approximately 62% and 23% of Pseudomonas samples recovered respectively). Although representatives of both groups were recovered from every season, every house, and every type of environment sampled, recovery was highly variable across houses and samplings. Whereas recovery of P. putida group was higher in summer and fall than in winter and spring, P. fluorescens group isolates were most often recovered in spring. P. putida group recovery from soils was substantially higher than its recovery from all other environment types, while higher P. fluorescens group recovery from soils than from other sites was much less pronounced. Both species groups were recovered from skin and upper respiratory tract samples from healthy humans and pets, although this occurred infrequently. This study indicates that even species that are able to survive under a broad range of conditions can be rare and variable in their distributions in space and in time. For such groups, determining patterns and causes of stochastic and seasonal variability may be more important for understanding the processes driving their biogeography than the identity of the types of environments in which they can be found. PMID- 26023934 TI - Rice osa-miR171c Mediates Phase Change from Vegetative to Reproductive Development and Shoot Apical Meristem Maintenance by Repressing Four OsHAM Transcription Factors. AB - Phase change from vegetative to reproductive development is one of the critical developmental steps in plants, and it is regulated by both environmental and endogenous factors. The maintenance of shoot apical meristem (SAM) identity, miRNAs and flowering integrators are involved in this phase change process. Here, we report that the miRNA osa-miR171c targets four GRAS (GAI-RGA-SCR) plant specific transcription factors (OsHAM1, OsHAM2, OsHAM3, and OsHAM4) to control the floral transition and maintenance of SAM indeterminacy in rice (Oryza sativa). We characterized a rice T-DNA insertion delayed heading (dh) mutant, where the expression of OsMIR171c gene is up-regulated. This mutant showed pleiotropic phenotypic defects, including especially prolonged vegetative phase, delayed heading date, and bigger shoot apex. Parallel expression analysis showed that osa-miR171c controlled the expression change of four OsHAMs in the shoot apex during floral transition, and responded to light. In the dh mutant, the expression of the juvenile-adult phase change negative regulator osa-miR156 was up-regulated, expression of the flowering integrators Hd3a and RFT1 was inhibited, and expression of FON4 negative regulators involved in the maintenance of SAM indeterminacy was also inhibited. From these data, we propose that the inhibition of osa-miR171c-mediated OsHAM transcription factors regulates the phase transition from vegetative to reproductive development by maintaining SAM indeterminacy and inhibiting flowering integrators. PMID- 26023935 TI - Effect of coffee consumption on the risk of gastric cancer: a systematic review and meta-analysis of prospective cohort studies. AB - BACKGROUND AND OBJECTIVES: Results from observational epidemiologic studies on the relationship between coffee consumption and gastric cancer are inconsistent and inconclusive. To assess the association between coffee consumption and the risk of gastric cancer, we summarized evidence from prospective cohort studies. METHODS: Relevant studies were retrieved through computer searches (PubMed, EmBase and the Cochrane Library) and a review of references up to December 2014. The quality of the included studies was evaluated by Newcastle-Ottawa quality assessment scale. We used a meta-analytic approach to estimate overall hazard ratios (HRs) and 95% confidence intervals (CIs) for regular coffee drinkers versus individuals who seldom drank coffee. Sensitivity analysis and subgroup analysis were performed to assess the reliability of our results. A dose-response analysis was performed to assess the risk of gastric cancer based on the level of coffee consumption. RESULTS: Nine prospective cohort studies involving 1,250,825 participants and 3027 gastric cancer cases were included in this meta-analysis. The pooled HR of gastric cancer for the study-specific regularly versus seldom coffee drinking categories was 1.05 (95% CI, 0.88 to 1.25) with significant heterogeneity across studies (I(2) = 74.0%, P = 0.000). After the sensitivity analysis, three studies were deleted; however the association remained insignificant (HR, 0.99; 95% CI, 0.91 to 1.08). Subgroup analysis by anatomic location showed a risk for coffee consumption associated with cardia cancer (HR, 1.23; 95% CI, 1.04 to 1.45; heterogeneity, I(2) = 36.4, P = 0.207). In the dose response analysis, there was no significant association between coffee intake (in cups) and the risk of gastric cancer (P for linearity trend and non-linearity > 0.05). CONCLUSION: Our meta-analysis demonstrated that coffee consumption was not associated with overall gastric cancer risk; however, coffee consumption may be a risk factor for gastric cardia cancer. PMID- 26023936 TI - Theoretical Verification of Photoelectrochemical Water Oxidation Using Nanocrystalline TiO2 Electrodes. AB - Mesoscopic anatase nanocrystalline TiO2 (nc-TiO2) electrodes play effective and efficient catalytic roles in photoelectrochemical (PEC) H2O oxidation under short circuit energy gap excitation conditions. Interfacial molecular orbital structures of (H2O)3 &OH(TiO2)9H as a stationary model under neutral conditions and the radical-cation model of [(H2O)3&OH(TiO2)9H]+ as a working nc-TiO2 model are simulated employing a cluster model OH(TiO2)9H (Yamashita/Jono's model) and a H2O cluster model of (H2O)3 to examine excellent H2O oxidation on nc-TiO2 electrodes in PEC cells. The stationary model, (H2O)3&OH(TiO2)9H reveals that the model surface provides catalytic H2O binding sites through hydrogen bonding, van der Waals and Coulombic interactions. The working model, [(H2O)3&OH(TiO2)9H]+ discloses to have a very narrow energy gap (0.3 eV) between HOMO and LUMO potentials, proving that PEC nc-TiO2 electrodes become conductive at photo irradiated working conditions. DFT-simulation of stepwise oxidation of a hydroxide ion cluster model of OH-(H2O)3, proves that successive two-electron oxidation leads to hydroxyl radical clusters, which should give hydrogen peroxide as a precursor of oxygen molecules. Under working bias conditions of PEC cells, nc-TiO2 electrodes are now verified to become conductive by energy gap photo excitation and the electrode surface provides powerful oxidizing sites for successive H2O oxidation to oxygen via hydrogen peroxide. PMID- 26023937 TI - Molecular Interactions of beta-(1->3)-Glucans with Their Receptors. AB - beta-(1->3)-Glucans can be found as structural polysaccharides in cereals, in algae or as exo-polysaccharides secreted on the surfaces of mushrooms or fungi. Research has now established that beta-(1->3)-glucans can trigger different immune responses and act as efficient immunostimulating agents. They constitute prevalent sources of carbons for microorganisms after subsequent recognition by digesting enzymes. Nevertheless, mechanisms associated with both roles are not yet clearly understood. This review focuses on the variety of elucidated molecular interactions that involve these natural or synthetic polysaccharides and their receptors, i.e., Dectin-1, CR3, glycolipids, langerin and carbohydrate binding modules. PMID- 26023938 TI - Synthesis and Biological Evaluation of N-Alkoxyphenyl-3-hydroxynaphthalene-2 carboxanilides. AB - A series of fifteen new N-alkoxyphenylanilides of 3-hydroxynaphthalene-2 carboxylic acid was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium tuberculosis H37Ra and M. avium subsp. paratuberculosis. Some of the tested compounds showed antibacterial and antimycobacterial activity against the tested strains comparable with or higher than that of the standards ampicillin or rifampicin. 3-Hydroxy-N-(2 propoxyphenyl)naphthalene-2-carboxamide and N-[2-(but-2-yloxy)-phenyl]-3 hydroxynaphthalene-2-carboxamide had MIC = 12 uM against all methicillin resistant S. aureus strains; thus their activity is 4-fold higher than that of ampicillin. The second mentioned compound as well as 3-hydroxy-N-[3-(prop-2 yloxy)phenyl]-naphthalene-2-carboxamide had MICs = 23 uM and 24 uM against M. tuberculosis respectively. N-[2-(But-2-yloxy)phenyl]-3-hydroxynaphthalene-2 carboxamide demonstrated higher activity against M. avium subsp. paratuberculosis than rifampicin. Screening of the cytotoxicity of the most effective antimycobacterial compounds was performed using THP-1 cells, and no significant lethal effect was observed for the most potent compounds. The compounds were additionally tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. N-(3 Ethoxyphenyl)-3-hydroxynaphthalene-2-carboxamide (IC50 = 4.5 uM) was the most active PET inhibitor. The structure-activity relationships are discussed. PMID- 26023939 TI - Synthesis, Characterization and Biological Studies of Metal(II) Complexes of (3E) 3-[(2-{(E)-[1-(2,4-Dihydroxyphenyl) ethylidene]amino}ethyl)imino]-1-phenylbutan-1 one Schiff Base. AB - Co(II), Ni(II), Zn(II) and Cu(II) complexes of (3E)-3-[(2-{(E)-[1-(2,4 dihydroxyphenyl)ethylidene]amino}ethyl)imino]-1-phenylbutan-1-one (DEPH2) derived from ethylenediamine, 2',4'-dihydroxyacetophenone and 1-phenylbutane-1,3-dione have been synthesized and characterized by elemental analysis, FTIR, UV-Visible spectroscopy, and screened to establish their potential as antibacterial agents, antioxidants and DPPH radical scavengers. The FTIR spectra showed that the ligand behaves as a dibasic tetradentate ligand with the dioxygen-dinitrogen donor atom system oriented towards the central metal ion. The analytical and spectroscopic data suggest a square planar geometry for Cu(II) and Ni(II) complexes and an octahedral geometry for the Co(II) complex. The ligand and their metal complexes were screened for antibacterial activity against Gram (+) and Gram (-) bacteria by the agar well diffusion method. In addition, the antioxidant activities of the complexes were also investigated through their scavenging effect on DPPH and ABTS radicals. The obtained IC50 value of the DPPH activity for the copper complex (2.08 +/- 0.47 uM) and that of the ABTS activity for the copper complex (IC50 = 2.11 + 1.69 uM) were higher than the values obtained for the other compounds. PMID- 26023940 TI - Volatile profile of cashew apple juice fibers from different production steps. AB - This study aimed to determine the volatile profile of cashew apple fibers to verify which compounds are still present after successive washings and thus might be responsible for the undesirable remaining cashew-like aroma present in this co product, which is used to formulate food products like vegetarian burgers and cereal bars. Fibers were obtained from cashew apple juice processing and washed five times in an expeller press. Compounds were analyzed by the headspace solid phase micro extraction technique (HS-SPME) and gas chromatography-mass spectrometry (GC-MS), using a DB-5 column. Sensory analysis was also performed to compare the intensity of the cashew-like aroma of the fibers with the original juice. Altogether, 80 compounds were detected, being esters and terpenes the major chemical classes. Among the identified substances, 14 were classified as odoriferous in the literature, constituting the matrix used in the Principal Component Analysis (PCA). Odoriferous esters were substantially reduced, but many compounds were extracted by the strength used in the expeller press and remained until the last wash. Among them are the odoriferous compounds ethyl octanoate, gamma-dodecalactone, (E)-2-decenal, copaene, and caryophyllene that may contribute for the mild but still perceptible cashew apple aroma in the fibers that have been pressed and washed five times. Development of a deodorization process should include reduction of pressing force and stop at the second wash, to save water and energy, thus reducing operational costs and contributing to process sustainability. PMID- 26023941 TI - The Role of Lectin-Carbohydrate Interactions in the Regulation of ER-Associated Protein Degradation. AB - Proteins entering the secretory pathway are translocated across the endoplasmic reticulum (ER) membrane in an unfolded form. In the ER they are restricted to a quality control system that ensures correct folding or eventual degradation of improperly folded polypeptides. Mannose trimming of N-glycans on newly synthesized proteins plays an important role in the recognition and sorting of terminally misfolded glycoproteins for ER-associated protein degradation (ERAD). In this process misfolded proteins are retrotranslocated into the cytosol, polyubiquitinated, and eventually degraded by the proteasome. The mechanism by which misfolded glycoproteins are recognized and recruited to the degradation machinery has been extensively studied during last decade. In this review, we focus on ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family proteins that seem to play a key role in the discrimination between proteins undergoing a folding process and terminally misfolded proteins directed for degradation. We describe interactions of EDEM proteins with other components of the ERAD machinery, as well as with various protein substrates. Carbohydrate dependent interactions together with N-glycan-independent interactions seem to regulate the complex process of protein recognition and direction for proteosomal degradation. PMID- 26023944 TI - Multi-modality imaging of primary Extra-Hepatic Portal Vein Obstruction (EHPVO): What Every Radiologist Should Know. AB - Portal vein thrombosis (PVT) is a frequent complication of liver cirrhosis but it can also occur as a primary vascular disorder amid absent liver disease. Extra hepatic portal venous obstruction (EHPVO) refers to the obstruction of the extra hepatic portal vein with or without involvement of the intra-hepatic portal vein branches, splenic and/or superior mesenteric vein. It is a distinct disorder that excludes PVT occurring in concurrence with liver cirrhosis or hepatocellular carcinoma. The term 'EHPVO' implies chronicity and is principally reserved for a long-standing condition characterized by cavernous transformation of the portal vein. The most characteristic imaging manifestation is the formation of porto portal collaterals (via the venous plexi of Petren and Saint) which allow hepatopetal flow. However, this collateral circulation is insufficient resulting in clinically significant pre-hepatic portal hypertension, wherein the liver function and structure remain preserved until late. Although the long-term (>10 year) survival with controlled variceal bleeding is upto 100%, affected individuals have an impaired quality of life due to portal-cavernoma cholangiopathy, hypersplenism, neurocognitive dysfunction and growth retardation. Imaging diagnosis is not always straightforward as the collaterals can also present as a tumour-like solid-mass that can be inadvertently biopsied. Moreover, EHPVO has its implications on the biliary tree, arterial circulation, liver/splenic volumes and stiffness, which merit proper understanding but have not been so well described in literature. In this review we present the complete spectrum of the vascular, biliary and visceral changes with a particular emphasis on what our medical/surgical hepatology colleagues need to know in the pre-and post-operative settings. PMID- 26023943 TI - Pyrrole-pyridine and pyrrole-naphthyridine hosts for anion recognition. AB - The association constants of the complexes formed by two hosts containing pyrrole, amide and azine (pyridine and 1,8-naphthyridine) groups and six guests, all monoanions (Cl-, CH3CO2-, NO3-, H2PO4-, BF4-, PF6-), have been determined using NMR titrations. The X-ray crystal structure of the host N2,N5-bis(6 methylpyridin-2-yl)-3,4-diphenyl-1H-pyrrole- 2,5-dicarboxamide (1) has been solved (P21/c monoclinic space group). B3LYP/6-31G(d,p) and calculations were carried out in an attempt to rationalize the trends observed in the experimental association constants. PMID- 26023942 TI - Synthesis of S-layer conjugates and evaluation of their modifiability as a tool for the functionalization and patterning of technical surfaces. AB - Chemical functional groups of surface layer (S-layer) proteins were chemically modified in order to evaluate the potential of S-layer proteins for the introduction of functional molecules. S-layer proteins are structure proteins that self-assemble into regular arrays on surfaces. One general feature of S layer proteins is their high amount of carboxylic and amino groups. These groups are potential targets for linking functional molecules, thus producing reactive surfaces. In this work, these groups were conjugated with the amino acid tryptophan. In another approach, SH-groups were chemically inserted in order to extend the spectrum of modifiable groups. The amount of modifiable carboxylic groups was further evaluated by potentiometric titration in order to evaluate the potential efficiency of S-layer proteins to work as matrix for bioconjugations. The results proved that S-layer proteins can work as effective matrices for the conjugation of different molecules. The advantage of using chemical modification methods over genetic methods lies in its versatile usage enabling the attachment of biomolecules, as well as fluorescent dyes and inorganic molecules. Together with their self-assembling properties, S-layer proteins are suitable as targets for bioconjugates, thus enabling a nanostructuring and bio-functionalization of surfaces, which can be used for different applications like biosensors, filter materials, or (bio)catalytic surfaces. PMID- 26023947 TI - Diagnostic performance of diffusion-weighted magnetic resonance imaging for detection of pelvic metastatic lymph nodes in patients with cervical cancer: A systematic review and meta-analysis. AB - OBJECTIVE: In recent years, diffusion-weighted magnetic resonance imaging (DW MRI) has emerged as a new technique for detecting the pelvic lymph metastases in patients with cervical cancer. The aim of this meta-analysis was to assess the diagnostic value of DWI for benign/malignant discrimination of pelvic lymph nodes. METHODS: Studies about DWI for the detection of metastatic lymph nodes were searched in the PubMed, EMBASE, Web of science, EBSCO, the Cochrane Library and three Chinese databases. Based on the extracted data, we determined pooled sensitivities, specificities and diagnostic odds ratios (DORs) across studies, calculated positive and negative likelihood ratios, and constructed summary receiver operating characteristic curves with area under the curve (AUC) and Q* obtained. We also analyzed the heterogeneity between studies based on subgroup analysis, threshold effect and publication bias. RESULTS: In total, 15 studies involving 1021 patients met the inclusion criteria. The pooled sensitivity, specificity and DOR of DWI were 0.86 (95% CI, 0.84-0.89), 0.84 (95% CI, 0.83 0.86) and 47.21 (95% CI, 25.67-86.81), respectively. Likelihood ratio syntheses yielded overall PLR of 6.55 (95% CI, 4.77-9.01) and NLR of 0.17 (95% CI, 0.12 0.23). The AUC and Q* index were 0.9384 and 0.8754, respectively. The heterogeneity was relatively high between studies; however, there was no evidence for threshold effect and publication bias. CONCLUSION: DWI is beneficial in the pelvic nodal assessment in patients with cervical cancer. Large-scale, high quality trials with standard protocols are required to evaluate its clinical value for discrimination of metastatic from non-metastatic pelvic lymph nodes in cervical cancer patients. Advances in knowledge: Provide evidence to assess the role of DWI in nodal staging of cervical cancer. PMID- 26023949 TI - Diffusion-weighted MR imaging in the follow-up of chronic periaortitis. AB - OBJECTIVES: To evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DWI) for the assessment of the intra-individual follow-up in patients with chronic periaortitis under medication. METHODS: MRI data of 21 consecutive patients with newly diagnosed, untreated disease were retrospectively examined before and after medical therapy, with a median follow-up of 16 weeks. DWI parameters (b800-signal, ADC values) of the chronic periaortitis and psoas muscle were analysed together with the extent and contrast enhancement. Pre- and post treatment laboratory inflammation markers were acquired parallel to each MR examination. RESULTS: Statistically significant lower b800 signal intensities (p=<0.0001) and higher ADC values (p=<0.0001) were observed after medical treatment within the fibrous periaortic tissue. Extent and contrast enhancement of the chronic periaortitis showed also a statistically significant decrease (p=<0.0001) in the follow-up examinations. While the control parameters within the psoas muscle showed no differences. CONCLUSION: DWI seems to be a useful method for the evaluation of response to treatment without contrast agents. The technique may be helpful in the assessment of disease activity to guide further therapeutic strategies. Advances in knowledge: DWI detects significant differences in the intra-individual follow-up of chronic periaortitis under medical therapy. PMID- 26023950 TI - More food, low pollution (mo fo lo Po): a grand challenge for the 21st century. AB - Synthetic nitrogen fertilizer has been a double-edged sword, greatly improving human nutrition during the 20th century but also posing major human health and environmental challenges for the 21st century. In August 2013, about 160 agronomists, scientists, extension agents, crop advisors, economists, social scientists, farmers, representatives of regulatory agencies and nongovernmental organizations (NGOs), and other agricultural experts gathered to discuss the vexing challenge of how to produce more food to nourish a growing population while minimizing pollution to the environment. This collection of 14 papers authored by conference participants provides a much needed analysis of the many technical, economic, and social impediments to improving nitrogen use efficiency (NUE) in crop and animal production systems. These papers demonstrate that the goals of producing more food with low pollution (Mo Fo Lo Po) will not be achieved by technological developments alone but will also require policies that recognize the economic and social factors affecting farmer decision-making. Take home lessons from this extraordinary interdisciplinary effort include the need (i) to develop partnerships among private and public sectors to demonstrate the most current, economically feasible, best management NUE practices at local and regional scales; (ii) to improve continuing education to private sector retailers and crop advisers; (iii) to tie nutrient management to performance-based indicators on the farm and in the downwind and downstream environment; and (iv) to restore investments in research, education, extension, and human resources that are essential for developing the interdisciplinary knowledge and innovative skills needed to achieve agricultural sustainability goals. PMID- 26023951 TI - The economic and environmental consequences of implementing nitrogen-efficient technologies and management practices in agriculture. AB - Technologies and management practices (TMPs) that reduce the application of nitrogen (N) fertilizer while maintaining crop yields can improve N use efficiency (NUE) and are important tools for meeting the dual challenges of increasing food production and reducing N pollution. However, because farmers operate to maximize their profits, incentives to implement TMPs are limited, and TMP implementation will not always reduce N pollution. Therefore, we have developed the NUE Economic and Environmental impact analytical framework (NUE) to examine the economic and environmental consequences of implementing TMPs in agriculture, with a specific focus on farmer profits, N fertilizer consumption, N losses, and cropland demand. Our analytical analyses show that impact of TMPs on farmers' economic decision-making and the environment is affected by how TMPs change the yield ceiling and the N fertilization rate at the ceiling and by how the prices of TMPs, fertilizer, and crops vary. Technologies and management practices that increase the yield ceiling appear to create a greater economic incentive for farmers than TMPs that do not but may result in higher N application rates and excess N losses. Nevertheless, the negative environmental impacts of certain TMPs could be avoided if their price stays within a range determined by TMP yield response, fertilizer price, and crop price. We use a case study on corn production in the midwestern United States to demonstrate how NUE can be applied to farmers' economic decision-making and policy analysis. Our NUE framework provides an important tool for policymakers to understand how combinations of fertilizer, crop, and TMP prices affect the possibility of achieving win-win outcomes for farmers and the environment. PMID- 26023952 TI - Reducing Nitrogen Pollution while Decreasing Farmers' Costs and Increasing Fertilizer Industry Profits. AB - Nitrogen (N) pollution is emerging as one of the most important environmental issues of the 21st Century, contributing to air and water pollution, climate change, and stratospheric ozone depletion. With agriculture being the dominant source, we tested whether it is possible to reduce agricultural N pollution in a way that benefits the environment, reduces farmers' costs, and increases fertilizer industry profitability, thereby creating a "sweet spot" for decision makers that could significantly increase the viability of improved N management initiatives. Although studies of the economic impacts of improved N management have begun to take into account farmers and the environment, this is the first study to consider the fertilizer industry. Our "sweet spot" hypothesis is evaluated via a cost-benefit analysis of moderate and ambitious N use efficiency targets in U.S. and China corn sectors over the period 2015-2035. We use a blend of publicly available crop and energy price projections, original time-series modeling, and expert elicitation. The results present a mixed picture: although the potential for a "sweet spot" exists in both countries, it is more likely that one occurs in China due to the currently extensive overapplication of fertilizer, which creates a greater potential for farmers and the fertilizer industry to gain economically from improved N management. Nevertheless, the environmental benefits of improving N management consistently dwarf the economic impacts on farmers and the fertilizer industry in both countries, suggesting that viable policy options could include incentives to farmers and the fertilizer industry to increase their support for N management policies. PMID- 26023953 TI - Measures of nitrogen use efficiency and nitrogen loss from dairy production systems. AB - In dairy production systems, tradeoffs can occur between fertilizer N applications and crop N use, feed N consumption and manure N excretion, and environmental impacts. This paper examines (i) how stocking rates affect N imports and management on dairy farms, N use efficiency (NUE; i.e., the amount of applied N incorporated into product N), and N loss; (ii) how reductions in fertilizer N and feed N may affect crop and milk production, NUE, and N loss; and (iii) why tradeoffs in N use outcomes should be considered when attempting to enhance overall NUE and reduce N loss. The Integrated Farm Simulation Model simulations of two representative dairy farm types and analyses of regional studies, long-term field experiments, and cow nutrition trials were used to demonstrate that (i) stocking rate affects cropping patterns, fertilizer and feed imports, and N loss; (ii) although fertilizer N reductions of 20 kg N ha may reduce slightly the crude protein (CP) content of corn silage (which would require purchase of additional CP supplements), this practice should not affect long-term corn yield but would reduce nitrate (NO) and nitrous oxide (NO) losses by 13 to 38%; (iii) dietary CP could be reduced on many dairy farms, which would not affect milk production but would reduce ammonia (NH) and NO emissions by 15 to 43%; and (iv) greater recognition of the tradeoffs in N use and N loss are needed to provide a better understanding of the potentials to enhance overall NUE and reduce environmental N loss from dairy production systems. PMID- 26023954 TI - Future riverine nitrogen export to coastal regions in the United States: prospects for improving water quality. AB - Nitrogen (N) fluxes generated by an increasing human population have the potential to increase coastal riverine N loading, with implications for areas already degraded by elevated nutrient loads. Here we examine contemporary (year 2005) and future (year 2030) loading of total dissolved N (TDN) in the continental United States using the Nutrient Export from WaterSheds model (NEWS2 TDN). Model-derived TDN estimates compared well with measured export of 29 catchments that represent 65% of land surface area for the continental United States (Nash-Sutcliffe efficiency = 0.83). Future output is based on scenarios that reflect future population growth and "business as usual" (BAU) and "ambitious" (AMB) approaches to nutrient management. Model-derived TDN export was 2.1 Tg N yr in 2005 and 2.2 and 1.6 Tg N yr in 2030 for the BAU and AMB scenarios, respectively. Depending on year and scenario, agriculture supplies 44 to 48% of coastal TDN, atmospheric N deposition supplies 14 to 17%, human sewage supplies 13 to 18%, and background sources supply 21 to 29%. The AMB scenario suggests that reducing nutrient loads to coastal areas will require aggressive actions, including a 25% improvement in agricultural nutrient use efficiency, a 20% reduction in N runoff from croplands, a 30% reduction in ammonia emissions from agriculture, and a 40% reduction in nitrogen oxide emissions from vehicles. Together, these aggressive actions could reduce year 2030 TDN export by 24% from 2005 levels, even with a 20% larger population. PMID- 26023955 TI - Losses of Ammonia and Nitrate from Agriculture and Their Effect on Nitrogen Recovery in the European Union and the United States between 1900 and 2050. AB - Historical trends and levels of nitrogen (N) budgets and emissions to air and water in the European Union and the United States are markedly different. Agro environmental policy approaches also differ, with emphasis on voluntary or incentive-based schemes in the United States versus a more regulatory approach in the European Union. This paper explores the implications of these differences for attaining long-term policy targets for air and water quality. Nutrient surplus problems were more severe in the European Union than in the United States during the 1970s and 1980s. The EU Nitrates and National Emission Ceilings directives contributed to decreases in fertilizer use, N surplus, and ammonia (NH) emissions, whereas in the United States they stabilized, although NH emissions are still increasing. These differences were analyzed using statistical data for 1900-2005 and the global IMAGE model. IMAGE could reproduce NH emissions and soil N surpluses at different scales (European Union and United States, country and state) and N loads in the Rhine and Mississippi. The regulation-driven changes during the past 25 yr in the European Union have reduced public concerns and have brought agricultural N loads to the aquatic environment closer to US levels. Despite differences in agro-environmental policies and agricultural structure (more N-fixing soybean and more spatially separated feed and livestock production in the United States than in the European Union), current N use efficiency in US and EU crop production is similar. IMAGE projections for the IAASTD-baseline scenario indicate that N loading to the environment in 2050 will be similar to current levels. In the United States, environmental N loads will remain substantially smaller than in the European Union, whereas agricultural production in 2050 in the United States will increase by 30% relative to 2005, as compared with an increase of 8% in the European Union. However, in the United States, even rigorous mitigation with maximum recycling of manure N and a 25% reduction in fertilizer use will not achieve the policy target to halve the N export to the Gulf of Mexico. PMID- 26023956 TI - Navigating the socio-bio-geo-chemistry and engineering of nitrogen management in two illinois tile-drained watersheds. AB - Reducing nitrate loads from corn and soybean, tile-drained, agricultural production systems in the Upper Mississippi River basin is a major challenge that has not been met. We evaluated a range of possible management practices from biophysical and social science perspectives that could reduce nitrate losses from tile-drained fields in the Upper Salt Fork and Embarras River watersheds of east central Illinois. Long-term water quality monitoring on these watersheds showed that nitrate losses averaged 30.6 and 23.0 kg nitrate N ha yr (Embarras and Upper Salt Fork watersheds, respectively), with maximum nitrate concentrations between 14 and 18 mg N L. With a series of on-farm studies, we conducted tile monitoring to evaluate several possible nitrate reduction conservation practices. Fertilizer timing and cover crops reduced nitrate losses (30% reduction in a year with large nitrate losses), whereas drainage water management on one tile system demonstrated the problems with possible retrofit designs (water flowed laterally from the drainage water management tile to the free drainage system nearby). Tile woodchip bioreactors had good nitrate removal in 2012 (80% nitrate reduction), and wetlands had previously been shown to remove nitrate (45% reductions) in the Embarras watershed. Interviews and surveys indicated strong environmental concern and stewardship ethics among landowners and farmers, but the many financial and operational constraints that they operate under limited their willingness to adopt conservation practices that targeted nitrate reduction. Under the policy and production systems currently in place, large-scale reductions in nitrate losses from watersheds such as these in east-central Illinois will be difficult. PMID- 26023957 TI - Farmers' use of nutrient management: lessons from watershed case studies. AB - Nutrient enrichment of water resources has degraded coastal waters throughout the world, including in the United States (e.g., Chesapeake Bay, Gulf of Mexico, and Neuse Estuary). Agricultural nonpoint sources have significant impacts on water resources. As a result, nutrient management planning is the primary tool recommended to reduce nutrient losses from agricultural fields. Its effectiveness requires nutrient management plans be used by farmers. There is little literature describing nutrient management decision-making. Here, two case studies are described that address this gap: (i) a synthesis of the National Institute of Food and Agriculture, the Conservation Effects Assessment Project, and (ii) field surveys from three nutrient-impaired river basins/watersheds in North Carolina (Neuse, Tar-Pamlico, and Jordan Lake drainage areas). Results indicate farmers generally did not fully apply nutrient management plans or follow basic soil test recommendations even when they had them. Farmers were found to be hesitant to apply N at university-recommended rates because they did not trust the recommendations, viewed abundant N as insurance, or used recommendations made by fertilizer dealers. Exceptions were noted when watershed education, technical support, and funding resources focused on nutrient management that included easing management demands, actively and consistently working directly with a small group of farmers, and providing significant resource allocations to fund agency personnel and cost-share funds to farmers. Without better dialogue with farmers and meaningful investment in strategies that reward farmers for taking what they perceive as risks relative to nutrient reduction, little progress in true adoption of nutrient management will be made. PMID- 26023958 TI - Adoption of nitrogen-efficient technologies by u.s. Corn farmers. AB - Anthropogenically introduced nitrogen (N) has compromised environmental quality, but it is an essential element for crop production, particularly corn production. Increasing N use efficiency by adopting eco-innovations such as N soil testing, plant tissue testing, and N transformation inhibitors can ameliorate this problem. Data from the 2010 USDA Agricultural Resource Management Survey of corn producers was used to examine the factors affecting adoption of these practices. Twenty-one percent of the 1840 corn farmers had adopted N soil testing, 3% had adopted plant tissue testing, and 10% had adopted N inhibitors. A multivariate probit regression found significant results for each category of explanatory variable that was examined. Among the findings was the importance of information source for N recommendations. Farmers who did not obtain external recommendations were less likely to adopt all three practices than farmers who received recommendations from a crop consultant. Those who received recommendations from fertilizer dealers were less likely to adopt N soil testing and plant tissue testing. All regions were more likely to adopt N soil testing than the Midwest, and warmer regions were less likely to adopt B transformation inhibitors. Those who adopted conservation tillage were more likely to adopt plant tissue testing and N inhibitors, and those who received conservation payments were more likely to adopt N soil testing and plant tissue testing. Adoption of conservation tillage was also associated with the adoption of several other technologies. Implications for research and educational programs are discussed. PMID- 26023959 TI - Regulating farmer nutrient management: a three-state case study on the delmarva peninsula. AB - Growing concern about water quality issues, along with a series of fish kills in 1997, prompted Maryland, Delaware, and Virginia to adopt regulations to reduce nutrient pollution from agricultural nonpoint sources. All three states required farmers to follow a state-certified nutrient management plan that would "optimize crop yields and minimize environmental losses," although the policy-making processes in each state were different. The objective of this political and policy analysis research was to determine if the policy-making process affected farmer compliance and whether nutrient management practices have improved. Sixty farmers on the Delmarva Peninsula, which includes all three states, who grew corn and used poultry manure as a nutrient source were interviewed, as were 68 policy stakeholders. Analysis of state regulatory agency data indicated that the contentious policy-making process in Maryland resulted in initially poor administrative compliance (i.e., obtaining a plan), whereas collaborative approaches in Delaware resulted in very good initial compliance. Interviews with farmers indicated good adoption of four practices: possessing a current plan, taking soil and manure nutrient tests, and split-applying nitrogen fertilizer. Farmers reported poor adoption (60% or less) across all three states of other practices: taking residual nitrogen credits for previous use of legumes or manure, keeping manure-free setbacks next to surface waters, avoiding manure application in winter, and frequent calibration of manure spreaders. Although nutrient management plans were required, many aspects of implementation and enforcement meant that adherence to plans was largely voluntary. This research helped identify successes, shortcomings, and lessons learned about regulating farmers. PMID- 26023960 TI - Nitrous oxide emissions from anhydrous ammonia, urea, and polymer-coated urea in illinois cornfields. AB - The use of alternative N sources relative to conventional ones could mitigate soil-surface NO emissions. Our objective was to evaluate the effect of anhydrous ammonia (AA), urea, and polymer-coated urea (ESN) on NO emissions for continuous corn ( L.) production. Corn received 110 kg N ha in 2009 and 180 kg N ha in 2010 and 2011. Soil NO fluxes were measured one to three times per week early in the growing season and less frequently later, using vented non-steady state closed chambers and a gas chromatograph. Regardless of N source, NO emissions were largest immediately after substantial (>20 mm) rains, dropping to background levels thereafter. Averaged across N sources, 2.85% of the applied N was lost as NO. Emission differences for treatments only occurred in 2010, the year with maximum NO production. In the 2010 growing season, cumulative emissions (in kg NO N ha) were lowest for the check (2.21), followed by ESN (9.77), and ESN was lower than urea (14.07) and AA (16.89). Emissions in 2010 based on unit of corn yield produced followed a similar pattern, and NO emissions calculated as percent of applied N showed that AA losses were 1.9 times greater than ESN. Across years, relative to AA, ESN reduced NO emissions, emissions per unit of corn yield, and emissions per unit of N applied, whereas urea produced intermediate values. The study indicates that, under high N loss potential (wet and warm conditions), ESN could reduce NO emissions more that urea and AA. PMID- 26023961 TI - Enhanced-efficiency fertilizers in nitrous oxide emissions from urea applied to sugarcane. AB - The environmental benefits of producing biofuels from sugarcane have been questioned due to greenhouse gas emissions during the biomass production stage, especially nitrous oxide (NO) associated with nitrogen (N) fertilization. The objective of this work was to evaluate the use of nitrification inhibitors (NIs) dicyandiamide (DCD) and 3,4 dimethylpyrazole phosphate (DMPP) and a controlled release fertilizer (CRF) to reduce NO emissions from urea, applied at a rate of 120 kg ha of N. Two field experiments in ratoon cycle sugarcane were performed in Brazil. The treatments were (i) no N (control), (ii) urea, (iii) urea+DCD, (iv) urea+DMPP, and (v) CRF. Measurements of NO fluxes were performed using static chambers with four replications. The measurements were conducted three times per week during the first 3 mo and biweekly afterward for a total of 217 and 382 d in the first and second seasons, respectively. The cumulative NO-N emissions in the first ratoon cycle were 1098 g ha in the control treatment and 1924 g ha with urea (0.7% of the total N applied). Addition of NIs to urea reduced NO emissions by more than 90%, which did not differ from those of the plots without N. The CRF treatment showed NO emissions no different from those of urea. The results were similar in the second ratoon: the treatment with urea showed NO emissions of 0.75% of N applied N. Application of NIs resulted in a strong reduction in NO emissions, but CRF increased emissions compared with urea. We therefore conclude that both NIs can be options for mitigation of greenhouse gas emission in sugarcane used for bioenergy. PMID- 26023962 TI - Modeled nitrous oxide emissions from corn fields in iowa based on county level data. AB - The U.S. Corn Belt area has the capacity to generate high nitrous oxide (NO) emissions due to medium to high annual precipitation, medium- to heavy-textured soils rich in organic matter, and high nitrogen (N) application rates. The purpose of this work was to estimate NO emissions from cornfields in Iowa at the county level using the DeNitrification-DeComposition (DNDC) model and to compare the DNDC NO emission estimates with available results from field experiments. All data were acquired for 2007 to 2011. Weather Underground Network and the Iowa State University Iowa Soil Properties and Interpretation Database 7.3 were the data sources for DNDC inputs and for computing county soil parameters. The National Agriculture Statistic Service 5-yr averages for corn yield data were used to establish ex post fertilizer N input at the county level. The DNDC output suggested county-wide NO emissions in Iowa ranged from 2.2 kg NO-N ha yr in south central to 4.6 to 4.7 kg NO-N ha yr in north-central and eastern Iowa counties. In northern districts, the average direct NO emissions were 3.2, 4.4, and 3.6 kg NO-N ha yr for west, central, and east, respectively. In central districts, average NO emissions were 3.5, 3.9, and 3.4 kg NO-N ha yr for west, central, and east, respectively. For southern districts, NO emissions were 3.5, 2.6, and 3.1 kg NO-N ha yr for west, central, and east, respectively. Direct NO emissions estimated by the DNDC model were 1.93% of N fertilizer input to corn fields in Iowa, with values ranging from 1.66% in the northwest cropping district to 2.25% in the north-central cropping district. These values are higher than the average 1% loss rate used in the IPCC Tier 1 approach. PMID- 26023963 TI - The efficacy of winter cover crops to stabilize soil inorganic nitrogen after fall-applied anhydrous ammonia. AB - There is a dearth of knowledge on the ability of cover crops to increase the effectiveness of fall-applied nitrogen (N). The objective of this study was to investigate the efficacy of two cover crop species to stabilize inorganic soil N after a fall application of N. Fall N was applied at a rate of 200 kg N ha into living stands of cereal rye, tillage radish, and a control (no cover crop) at the Illinois State University Research and Teaching Farm in Lexington, Illinois. Cover crops were sampled to determine N uptake, and soil samples were collected in the spring at four depths to 80 cm to determine the distribution of inorganic N within the soil profile. Tillage radish (131.9-226.8 kg ha) and cereal rye (188.1-249.9 kg ha N) demonstrated the capacity to absorb a minimum of 60 to 80% of the equivalent rate of fall-applied N, respectively. Fall applying N without cover crops resulted in a greater percentage of soil NO-N (40%) in the 50- to 80 cm depth, compared with only 31 and 27% when tillage radish and cereal rye were present at N application. At planting, tillage radish stabilized an average of 91% of the equivalent rate of fall-applied N within the 0- to 20-cm, depth compared with 66 and 57% for the cereal rye and control treatments, respectively. This study has demonstrated that fall applying N into a living cover crop stand has the potential to reduce the vulnerability of soil nitrate and to stabilize a greater concentration of inorganic N within the agronomic depths of soil. PMID- 26023964 TI - Groundwater Quality and Nitrogen Use Efficiency in Nebraska's Central Platte River Valley. AB - Groundwater nitrate contamination has been an issue in the Platte River Valley of Nebraska since the 1960s, with groundwater nitrate-N concentrations frequently in excess of 10 mg L. This article summarizes education and regulatory efforts to reduce the environmental impact of irrigated crop production in the Platte River Valley. In 1988, a Groundwater Management Area (GWMA) was implemented in the Central Platte Natural Resources District to encourage adoption of improved management practices. Since 1988, there have been steady declines in average groundwater nitrate-N concentrations of about 0.15 mg NO-N L yr in much of the GWMA (from 19 to 15 mg NO-N L). However, N use efficiency (NUE) (partial factor productivity for N [PFP]) has increased very little from 1988 to 2012 (60-65 kg grain kg N), whereas statewide PFP increased from 49 to 67 kg grain kg N in the same period. Although growers are encouraged to credit N from sources besides fertilizer (e.g., soil residual, legumes, irrigation water, and manure), confidence in and use of credits tended to decrease as credits became larger; there was a tendency toward an average N rate regardless of credit-based recommendations. This information, coupled with data from other studies, suggests that much of the decline in groundwater nitrate can be attributed to improved irrigation management-especially conversion from furrow to sprinkler irrigation and to a lesser extent to improved timing of N application. The development and adoption of improved N management practices, such as fertigation, controlled release N formulation, and use of crop canopy sensors for in-season N application may be required for further significant NUE gains in these irrigated systems. PMID- 26023965 TI - Phosphorus fate, management, and modeling in artificially drained systems. AB - Phosphorus (P) losses in agricultural drainage waters, both surface and subsurface, are among the most difficult form of nonpoint source pollution to mitigate. This special collection of papers on P in drainage waters documents the range of field conditions leading to P loss in drainage water, the potential for drainage and nutrient management practices to control drainage losses of P, and the ability of models to represent P loss to drainage systems. A review of P in tile drainage and case studies from North America, Europe, and New Zealand highlight the potential for artificial drainage to exacerbate watershed loads of dissolved and particulate P via rapid, bypass flow and shorter flow path distances. Trade-offs are identified in association with drainage intensification, tillage, cover crops, and manure management. While P in drainage waters tends to be tied to surface sources of P (soil, amendments or vegetation) that are in highest concentration, legacy sources of P may occur at deeper depths or other points along drainage flow paths. Most startling, none of the major fate and-transport models used to predict management impacts on watershed P losses simulate the dominant processes of P loss to drainage waters. Because P losses to drainage waters can be so difficult to manage and to model, major investment are needed (i) in systems that can provide necessary drainage for agronomic production while detaining peak flows and promoting P retention and (ii) in models that can adequately describe P loss to drainage waters. PMID- 26023966 TI - Phosphorus transport in agricultural subsurface drainage: a review. AB - Phosphorus (P) loss from agricultural fields and watersheds has been an important water quality issue for decades because of the critical role P plays in eutrophication. Historically, most research has focused on P losses by surface runoff and erosion because subsurface P losses were often deemed to be negligible. Perceptions of subsurface P transport, however, have evolved, and considerable work has been conducted to better understand the magnitude and importance of subsurface P transport and to identify practices and treatments that decrease subsurface P loads to surface waters. The objectives of this paper were (i) to critically review research on P transport in subsurface drainage, (ii) to determine factors that control P losses, and (iii) to identify gaps in the current scientific understanding of the role of subsurface drainage in P transport. Factors that affect subsurface P transport are discussed within the framework of intensively drained agricultural settings. These factors include soil characteristics (e.g., preferential flow, P sorption capacity, and redox conditions), drainage design (e.g., tile spacing, tile depth, and the installation of surface inlets), prevailing conditions and management (e.g., soil test P levels, tillage, cropping system, and the source, rate, placement, and timing of P application), and hydrologic and climatic variables (e.g., baseflow, event flow, and seasonal differences). Structural, treatment, and management approaches to mitigate subsurface P transport-such as practices that disconnect flow pathways between surface soils and tile drains, drainage water management, in-stream or end-of-tile treatments, and ditch design and management-are also discussed. The review concludes by identifying gaps in the current understanding of P transport in subsurface drains and suggesting areas where future research is needed. PMID- 26023967 TI - Contributions of systematic tile drainage to watershed-scale phosphorus transport. AB - Phosphorus (P) transport from agricultural fields continues to be a focal point for addressing harmful algal blooms and nuisance algae in freshwater systems throughout the world. In humid, poorly drained regions, attention has turned to P delivery through subsurface tile drainage. However, research on the contributions of tile drainage to watershed-scale P losses is limited. The objective of this study was to evaluate long-term P movement through tile drainage and its manifestation at the watershed outlet. Discharge data and associated P concentrations were collected for 8 yr (2005-2012) from six tile drains and from the watershed outlet of a headwater watershed within the Upper Big Walnut Creek watershed in central Ohio. Results showed that tile drainage accounted for 47% of the discharge, 48% of the dissolved P, and 40% of the total P exported from the watershed. Average annual total P loss from the watershed was 0.98 kg ha, and annual total P loss from the six tile drains was 0.48 kg ha. Phosphorus loads in tile and watershed discharge tended to be greater in the winter, spring, and fall, whereas P concentrations were greatest in the summer. Over the 8-yr study, P transported in tile drains represented <2% of typical application rates in this watershed, but >90% of all measured concentrations exceeded recommended levels (0.03 mg L) for minimizing harmful algal blooms and nuisance algae. Thus, the results of this study show that in systematically tile-drained headwater watersheds, the amount of P delivered to surface waters via tile drains cannot be dismissed. Given the amount of P loss relative to typical application rates, development and implementation of best management practices (BMPs) must jointly consider economic and environmental benefits. Specifically, implementation of BMPs should focus on late fall, winter, and early spring seasons when most P loading occurs. PMID- 26023968 TI - Surface runoff and tile drainage transport of phosphorus in the midwestern United States. AB - The midwestern United States offers some of the most productive agricultural soils in the world. Given the cool humid climate, much of the region would not be able to support agriculture without subsurface (tile) drainage because high water tables may damage crops and prevent machinery usage in fields at critical times. Although drainage is designed to remove excess soil water as quickly as possible, it can also rapidly transport agrochemicals, including phosphorus (P). This paper illustrates the potential importance of tile drainage for P transport throughout the midwestern United States. Surface runoff and tile drainage from fields in the St. Joseph River Watershed in northeastern Indiana have been monitored since 2008. Although the traditional concept of tile drainage has been that it slowly removes soil matrix flow, peak tile discharge occurred at the same time as peak surface runoff, which demonstrates a strong surface connection through macropore flow. On our research fields, 49% of soluble P and 48% of total P losses occurred via tile discharge. Edge-of-field soluble P and total P areal loads often exceeded watershed-scale areal loadings from the Maumee River, the primary source of nutrients to the western basin of Lake Erie, where algal blooms have been a pervasive problem for the last 10 yr. As farmers, researchers, and policymakers search for treatments to reduce P loading to surface waters, the present work demonstrates that treating only surface runoff may not be sufficient to reach the goal of 41% reduction in P loading for the Lake Erie Basin. PMID- 26023969 TI - Tile drainage phosphorus loss with long-term consistent cropping systems and fertilization. AB - Phosphorus (P) loss in tile drainage water may vary with agricultural practices, and the impacts are often hard to detect with short-term studies. We evaluated the effects of long-term (>=43 yr) cropping systems (continuous corn [CC], corn oats-alfalfa-alfalfa rotation [CR], and continuous grass [CS]) and fertilization (fertilization [F] vs. no-fertilization [NF]) on P loss in tile drainage water from a clay loam soil over a 4-yr period. Compared with NF, long-term fertilization increased concentrations and losses of dissolved reactive P (DRP), dissolved unreactive P (DURP), and total P (TP) in tile drainage water, with the increments following the order: CS > CR > CC. Dissolved P (dissolved reactive P [DRP] and dissolved unreactive P [DURP]) was the dominant P form in drainage outflow, accounting for 72% of TP loss under F-CS, whereas particulate P (PP) was the major form of TP loss under F-CC (72%), F-CR (62%), NF-CS (66%), NF-CC (74%), and NF-CR (72%). Dissolved unreactive P played nearly equal roles as DRP in P losses in tile drainage water. Stepwise regression analysis showed that the concentration of P (DRP, DURP, and PP) in tile drainage flow, rather than event flow volume, was the most important factor contributing to P loss in tile drainage water, although event flow volume was more important in PP loss than in dissolved P loss. Continuous grass significantly increased P loss by increasing P concentration and flow volume of tile drainage water, especially under the fertilization treatment. Long-term grasslands may become a significant P source in tile-drained systems when they receive regular P addition. PMID- 26023970 TI - Turnover and losses of phosphorus in Swedish agricultural soils: long-term changes, leaching trends, and mitigation measures. AB - Transport of phosphorus (P) from agricultural fields to water bodies deteriorates water quality and causes eutrophication. To reduce P losses and optimize P use efficiency by crops, better knowledge is needed of P turnover in soil and the efficiency of best management practices (BMPs). In this review, we examined these issues using results from 10 Swedish long-term soil fertility trials and various studies on subsurface losses of P. The fertility trials are more than 50 years old and consist of two cropping systems with farmyard manure and mineral fertilizer. One major finding was that replacement of P removed by crops with fertilizer P was not sufficient to maintain soil P concentrations, determined with acid ammonium lactate extraction. The BMPs for reducing P leaching losses reviewed here included catch crops, constructed wetlands, structure liming of clay soils, and various manure application strategies. None of the eight catch crops tested reduced P leaching significantly, whereas total P loads were reduced by 36% by wetland installation, by 39 to 55% by structure liming (tested at two sites), and by 50% by incorporation of pig slurry into a clay soil instead of surface application. Trend analysis of P monitoring data since the 1980s for a number of small Swedish catchments in which various BMPs have been implemented showed no clear pattern, and both upward and downward trends were observed. However, other factors, such as weather conditions and soil type, have profound effects on P losses, which can mask the effects of BMPs. PMID- 26023971 TI - Phosphorus leaching from agricultural soils of the delmarva peninsula, USA. AB - Leaching of phosphorus (P) mobilizes edaphic and applied sources of P and is a primary pathway of concern in agricultural soils of the Delmarva Peninsula, which defines the eastern boundary of the eutrophic Chesapeake Bay. We evaluated P leaching before and after poultry litter application from intact soil columns (30 cm diameter * 50 cm depth) obtained from low- and high-P members of four dominant Delmarva Peninsula soils. Surface soil textures ranged from fine sand to silt loam, and Mehlich-3 soil P ranged from 64 to 628 mg kg. Irrigation of soil columns before litter application pointed to surface soil P controls on dissolved P in leachate (with soil P sorption saturation providing a stronger relationship than Mehlich-3 P); however, strong relationships between P in the subsoil (45-50 cm) and leachate P concentrations were also observed ( = 0.61-0.73). After poultry litter application (4.5 Mg ha), leachate P concentrations and loads increased significantly for the finest-textured soils, consistent with observations that well-structured soils have the greatest propensity to transmit applied P. Phosphorus derived from poultry litter appeared to contribute 41 and 76% of total P loss in leachate from the two soils with the finest textures. Results point to soil P, including P sorption saturation, as a sound metric of P loss potential in leachate when manure is not an acute source of P but highlight the need to factor in macropore transport potential to predict leaching losses from applied P sources. PMID- 26023972 TI - The role of subsoil as a source or sink for phosphorus leaching. AB - The importance of subsoil features for phosphorus (P) leaching is frequently mentioned, but subsoil effects are still poorly documented. This study examined whether the subsoil of four agricultural Swedish soils (two sand and two clay) functioned as a source or sink for P leaching by measuring P leaching from intact soil columns with topsoil (1.05 m deep) and without topsoil (0.77 m deep) over 3 yr. One sandy soil with high topsoil P content (Olsen P, 84 mg kg) and high subsoil sorption capacity (P sorption index [PSI], 3.7 mmol kg) had low leaching of dissolved reactive P (DRP) from full-length and subsoil lysimeters (0.12 and 0.08 kg ha yr, respectively). The other sandy soil, with high Olsen P content in the topsoil and subsoil (27 and 19 mg kg, respectively) and low PSI in the subsoil (1.4 mmol kg), had high DRP leaching from full-length and subsoil lysimeters (3.33 and 3.29 kg ha yr, respectively). High P content at depth (Olsen P, 21 mg kg) in one clay soil resulted in relatively higher subsoil DRP contribution (89%) to total leaching than observed in the other clay soil (71%). These results indicate that the subsoil can act as source or sink for P leaching, depending on P content, degree of P saturation, and P sorption capacity, and therefore subsoil properties should be considered when selecting mitigation measures to reduce P leaching. PMID- 26023973 TI - Extreme phosphorus losses in drainage from grazed dairy pastures on marginal land. AB - With the installation of artificial drainage and large inputs of lime and fertilizer, dairy farming can be profitable on marginal land. We hypothesized that this will lead to large phosphorus (P) losses and potential surface water impairment if the soil has little capacity to sorb added P. Phosphorous was measured in drainage from three "marginal" soils used for dairying: an Organic soil that had been developed out of scrub for 2 yr and used for winter forage cropping, a Podzol that had been developed into pasture for 10 yr, and an intergrade soil that had been in pasture for 2 yr. Over 18 mo, drainage was similar among all sites (521-574 mm), but the load leached to 35-cm depth from the Organic soil was 87 kg P ha (~89% of fertilizer-P added); loads were 1.7 and 9.0 kg ha from the Podzol and intergrade soils, respectively. Soil sampling to 100 cm showed that added P leached throughout the Organic soil profile but was stratified and enriched in the top 15 cm of the Podzol. Poor P sorption capacity (<5%) in the Organic soil, measured as anion storage capacity, and tillage (causing mineralization and P release) in the Organic and intergrade soils were thought to be the main causes of high P loss. It is doubtful that strategies would successfully mitigate these losses to an environmentally acceptable level. However, anion storage capacity could be used to identify marginal soils with high potential for P loss for the purpose of managing risk. PMID- 26023974 TI - Phosphorus losses from an irrigated watershed in the northwestern United States: case study of the upper snake rock watershed. AB - Watersheds using surface water for irrigation often return a portion of the water to a water body. This irrigation return flow often includes sediment and nutrients that reduce the quality of the receiving water body. Research in the 82,000-ha Upper Snake Rock (USR) watershed from 2005 to 2008 showed that, on average, water diverted from the Snake River annually supplied 547 kg ha of total suspended solids (TSS), 1.1 kg ha of total P (TP), and 0.50 kg ha of dissolved P (DP) to the irrigation tract. Irrigation return flow from the USR watershed contributed 414 kg ha of TSS, 0.71 kg ha of TP, and 0.32 kg ha of DP back to the Snake River. Significantly more TP flowed into the watershed than returned to the Snake River, whereas there was no significant difference between inflow and return flow loads for TSS and DP. Average TSS and TP concentrations in return flow were 71 and 0.12 mg L, respectively, which exceeded the TMDL limits of 52 mg L TSS and 0.075 mg L TP set for this section of the Snake River. Monitoring inflow and outflow for five water quality ponds constructed to reduce sediment and P losses from the watershed showed that TSS concentrations were reduced 36 to 75%, but DP concentrations were reduced only 7 to 16%. This research showed that continued implementation of conservation practices should result in irrigation return flow from the USR watershed meeting the total maximum daily load limits for the Snake River. PMID- 26023975 TI - Phosphorus and nitrogen leaching before and after tillage and urea application. AB - Leaching of nutrients through agricultural soils is a priority water quality concern on the Atlantic Coastal Plain. This study evaluated the effect of tillage and urea application on leaching of phosphorus (P) and nitrogen (N) from soils of the Delmarva Peninsula that had previously been under no-till management. Intact soil columns (30 cm wide * 50 cm deep) were irrigated for 6 wk to establish a baseline of leaching response. After 2 wk of drying, a subset of soil columns was subjected to simulated tillage (0-20 cm) in an attempt to curtail leaching of surface nutrients, especially P. Urea (145 kg N ha) was then broadcast on all soils (tilled and untilled), and the columns were irrigated for another 8 wk. Comparison of leachate recoveries representing rapid and slow flows confirmed the potential to manipulate flow fractions with tillage, albeit with mixed results across soils. Leachate trends in the finer-textured soil suggest that tillage impeded macropore flow and forced greater matrix flow. Despite significant vertical stratification of soil P that suggested tillage could prevent leaching of P via macropores from the surface to the subsoil, tillage had no significant impact on P leaching losses. Relatively high levels of soil P below 20 cm may have served as the source of P enrichment in leachate waters. However, tillage did lower losses of applied urea in leachate from two of the three soils, partially confirming the study's premise that tillage would destroy macropore pathways transmitting surface constituents to the subsoil. PMID- 26023976 TI - Impacts of soil conditioners and water table management on phosphorus loss in tile drainage from a clay loam soil. AB - Adoption of waste-derived soil conditioners and refined water management can improve soil physical quality and crop productivity of fine-textured soils. However, the impacts of these practices on water quality must be assessed to ensure environmental sustainability. We conducted a study to determine phosphorus (P) loss in tile drainage as affected by two types of soil conditioners (yard waste compost and swine manure compost) and water table management (free drainage and controlled drainage with subirrigation) in a clay loam soil under corn soybean rotation in a 4-yr period from 1999 to 2003. Tile drainage flows were monitored and sampled on a year-round continuous basis using on-site auto sampling systems. Water samples were analyzed for dissolved reactive P (DRP), particulate P (PP), and total P (TP). Substantially greater concentrations and losses of DRP, PP, and TP occurred with swine manure compost than with control and yard waste compost regardless of water table management. Compared with free drainage, controlled drainage with subirrigation was an effective way to reduce annual and cumulative losses of DRP, PP, and TP in tile drainage through reductions in flow volume and P concentration with control and yard waste compost but not with swine manure compost. Both DRP and TP concentrations in tile drainage were well above the water quality guideline for P, affirming that subsurface loss of P from fine-textured soils can be one critical source for freshwater eutrophication. Swine manure compost applied as a soil conditioner must be optimized by taking water quality impacts into consideration. PMID- 26023977 TI - Reducing phosphorus loss in tile water with managed drainage in a claypan soil. AB - Installing subsurface tile drain systems in poorly drained claypan soils to improve corn ( L.) yields could potentially increase environmental phosphorus (P) loss through the tile drainage system. The objectives of the study were to quantify the average concentration and loss of ortho-P in tile drain water from a claypan soil and to determine whether managed subsurface drainage (MD) could reduce ortho-P loss in tile water compared with free subsurface drainage (FD). Flow-weighted ortho-P concentration in the tile water was significantly lower with MD (0.09 mg L) compared with that of FD (0.15 mg L). Ortho-P loss in the tile water of this study was reduced with MD (36 g ha) by 80% compared with FD (180 g ha). Contrary to previous research, reduced ortho-P loss observed over the 4-yr study was not solely due to the reduced amount of water drained annually (63%) with MD compared with FD. During the spring period, when flow was similar between MD and FD, the concentration of ortho-P in the tile water generally was lower with MD compared with FD, which resulted in significantly less ortho-P loss with MD. We speculate that MD's ability to conserve water during the dry summer months increased corn's uptake of water and P, which reduced the amount of P available for leaching loss in the subsequent springs. PMID- 26023978 TI - Effect of replacing surface inlets with blind or gravel inlets on sediment and phosphorus subsurface drainage losses. AB - Open surface inlets that connect to subsurface tile drainage systems provide a direct pathway for movement of sediment, nutrients, and agrochemicals to surface waters. This study was conducted to determine the reduction in drainage effluent total suspended sediment (TSS) and phosphorus (P) concentrations and loads when open surface inlets were replaced with blind (in gravel capped with 30 cm of soil) or gravel (in very coarse sand/fine gravel) inlets. In Indiana, a pair of closed depressions in adjacent fields was fitted with open inlet tile risers and blind inlets in 2005 and monitored for flow and water chemistry. Paired comparisons on a storm event basis during the growing season for years 2006 to 2013 showed that TSS loads were 40.4 and 14.4 kg ha event for tile risers and blind inlets, respectively. Total P (TP) and soluble reactive P (SRP) loads were 66 and 50% less for the blind inlets, respectively. In Minnesota, TSS and SRP concentrations were monitored for 3 yr before and after modification of 24 open inlets to gravel inlets in an unreplicated large-field on-farm study. Median TSS concentrations were 97 and 8.3 mg L and median SRP concentrations were 0.099 and 0.064 mg L for the open inlet and gravel inlet periods, respectively. Median TSS and SRP concentrations were elevated for snowmelt vs. non-snowmelt seasons for open and gravel inlets. Both replacement designs reduced suspended sediment and P concentrations and loads. The Indiana study suggests blind inlets will be effective beyond a 10-yr service life. PMID- 26023979 TI - Enhanced nitrate and phosphate removal in a denitrifying bioreactor with biochar. AB - Denitrifying bioreactors (DNBRs) are an emerging technology used to remove nitrate-nitrogen (NO) from enriched waters by supporting denitrifying microorganisms with organic carbon in an anaerobic environment. Field-scale investigations have established successful removal of NO from agricultural drainage, but the potential for DNBRs to remediate excess phosphorus (P) exported from agricultural systems has not been addressed. We hypothesized that biochar addition to traditional woodchip DNBRs would enhance NO and P removal and reduce nitrous oxide (NO) emissions based on previous research demonstrating reduced leaching of NO and P and lower greenhouse gas production associated with biochar amendment of agricultural soils. Nine laboratory-scale DNBRs, a woodchip control, and eight different woodchip-biochar treatments were used to test the effect of biochar on nutrient removal. The biochar treatments constituted a full factorial design of three factors (biochar source material [feedstock], particle size, and application rate), each with two levels. Statistical analysis by repeated measures ANOVA showed a significant effect of biochar, time, and their interaction on NO and dissolved P removal. Average P removal of 65% was observed in the biochar treatments by 18 h, after which the concentrations remained stable, compared with an 8% increase in the control after 72 h. Biochar addition resulted in average NO removal of 86% after 18 h and 97% after 72 h, compared with only 13% at 18 h and 75% at 72 h in the control. Biochar addition also resulted in significantly lower NO production. These results suggest that biochar can reduce the design residence time by enhancing nutrient removal rates. PMID- 26023980 TI - Applicability of models to predict phosphorus losses in drained fields: a review. AB - Most phosphorus (P) modeling studies of water quality have focused on surface runoff loses. However, a growing number of experimental studies have shown that P losses can occur in drainage water from artificially drained fields. In this review, we assess the applicability of nine models to predict this type of P loss. A model of P movement in artificially drained systems will likely need to account for the partitioning of water and P into runoff, macropore flow, and matrix flow. Within the soil profile, sorption and desorption of dissolved P and filtering of particulate P will be important. Eight models are reviewed (ADAPT, APEX, DRAINMOD, HSPF, HYDRUS, ICECREAMDB, PLEASE, and SWAT) along with P Indexes. Few of the models are designed to address P loss in drainage waters. Although the SWAT model has been used extensively for modeling P loss in runoff and includes tile drain flow, P losses are not simulated in tile drain flow. ADAPT, HSPF, and most P Indexes do not simulate flow to tiles or drains. DRAINMOD simulates drains but does not simulate P. The ICECREAMDB model from Sweden is an exception in that it is designed specifically for P losses in drainage water. This model seems to be a promising, parsimonious approach in simulating critical processes, but it needs to be tested. Field experiments using a nested, paired research design are needed to improve P models for artificially drained fields. Regardless of the model used, it is imperative that uncertainty in model predictions be assessed. PMID- 26023981 TI - Using AnnAGNPS to Predict the Effects of Tile Drainage Control on Nutrient and Sediment Loads for a River Basin. AB - Controlled tile drainage (CTD) can reduce pollutant loading. The Annualized Agricultural Nonpoint Source model (AnnAGNPS version 5.2) was used to examine changes in growing season discharge, sediment, nitrogen, and phosphorus loads due to CTD for a ~3900-km agriculturally dominated river basin in Ontario, Canada. Two tile drain depth scenarios were examined in detail to mimic tile drainage control for flat cropland: 600 mm depth (CTD) and 200 mm (CTD) depth below surface. Summed for five growing seasons (CTD), direct runoff, total N, and dissolved N were reduced by 6.6, 3.5, and 13.7%, respectively. However, five seasons of summed total P, dissolved P, and total suspended solid loads increased as a result of CTD by 0.96, 1.6, and 0.23%. The AnnAGNPS results were compared with mass fluxes observed from paired experimental watersheds (250, 470 ha) in the river basin. The "test" experimental watershed was dominated by CTD and the "reference" watershed by free drainage. Notwithstanding environmental/land use differences between the watersheds and basin, comparisons of seasonal observed and predicted discharge reductions were comparable in 100% of respective cases. Nutrient load comparisons were more consistent for dissolved, relative to particulate water quality endpoints. For one season under corn crop production, AnnAGNPS predicted a 55% decrease (CTD) in dissolved N from the basin. AnnAGNPS v. 5.2 treats P transport from a surface pool perspective, which is appropriate for many systems. However, for assessment of tile drainage management practices for relatively flat tile-dominated systems, AnnAGNPS may benefit from consideration of P and particulate transport in the subsurface. PMID- 26023982 TI - Suburban groundwater quality as influenced by turfgrass and septic sources, delmarva peninsula, USA. AB - Suburban land use is expanding in many parts of the United States and there is a need to better understand the potential water-quality impacts of this change. This study characterized groundwater quality in a sandy, water-table aquifer influenced by suburban development and compared the results to known patterns in water chemistry associated with natural, background conditions and agricultural effects. Samples for nutrients, major ions, and isotopes of N and O in NO were collected in 2011 beneath turfgrass from 29 shallow wells (median depth 3.7 m) and from 18 deeper wells (median depth 16.9 m) in a long-term suburban development. Nitrate (as N) concentrations in groundwater beneath turfgrass were highly variable (0.02-22.3 mg L) with a median of 2.7 mg L, which is higher than natural water chemistry (>0.4 mg L; Na-Cl-HCO water type), but significantly lower than concentrations beneath a nearby agricultural area (median 16.9 mg L; < .0001). Dissolved Fe concentrations in shallow suburban groundwater, attributed to chelated Fe in turfgrass fertilizers, were significantly higher ( < .005) than concentrations from the agricultural site, although a Ca-Mg-Cl-NO water type was dominant in both areas. A Na-Cl-NO water type indicated a septic-system source for nitrate in deep suburban groundwater (0.06-6.0 mg L; median 1.5 mg L). Isotopic data indicated denitrification; however, geochemical techniques were more helpful in identifying nitrate sources. Results indicate that suburban expansion into agricultural areas may significantly decrease overall nitrate concentrations in groundwater, but excessive turfgrass fertilization could result in localized contamination. PMID- 26023983 TI - Mobility and uptake of zinc, cadmium, nickel, and lead in sludge-amended soils planted to dryland maize and irrigated maize-oat rotation. AB - Sludge application to agricultural lands is often limited mainly because of concerns about metal accumulation in soils and uptake by crops. The objective of the study was to test the following hypotheses: (i) in the short to medium term (5-10 yr), the application of good-quality sludge according to crop N requirements will not lead to significant accumulation of water-soluble metal fractions in soil, (ii) mobility and uptake of metals is higher under irrigated than dryland systems, and (iii) metal concentrations in plant tissue could reach phytotoxic levels before the soil reaches environmental threshold levels. Field plots were arranged in a randomized complete block design comprising four replications of three treatments (0, 8, and 16 Mg ha yr anaerobically digested municipal sludge) planted to dryland maize and irrigated maize-oat rotation. Soil and plant samples were collected after 7 yr of treatment application for selected metal analyses. A large fraction of the Zn, Ni, and Pb in the soil profile was ethylenediaminetetraacetic acid extractable (46-79%). Saturated paste-extractable fractions of Cd and Pb were <1 mg kg. Plant uptake of Cd, Pb, and Ni under irrigation was double that for dryland systems. Concentrations of the metals considered in plant tissue of both cropping systems remained well below phytotoxic levels, except for Zn under dryland maize, which received 16 Mg sludge ha yr. Metal concentrations in the soil remained far below total maximum threshold levels. Therefore, hypotheses 1 and 3 were accepted for the metals considered, and hypothesis 2 was rejected for Zn. PMID- 26023984 TI - The role of dissolved organic nitrogen in a nitrate-rich agricultural stream. AB - Agricultural activities have heavily altered the nitrogen (N) cycle in stream ecosystems draining croplands, particularly in the midwestern United States. However, our knowledge about dissolved organic N (DON) biogeochemistry in agricultural ecosystems is limited. From January 2011 to June 2012, we investigated DON dynamics in an agricultural headwater stream in the midwestern United States. We quantified the contribution of DON to the total dissolved N (TDN) pool and examined the role of DON as a source of N for microbial metabolism. For this we measured N-acquiring enzyme activities (aminopeptidases) and whole-stream DON uptake through short-term releases of amino acids. To investigate potential coupling between the N and C cycles occurring via simultaneous uptake of these two elements during assimilation of amino acids, seven of the short-term releases were performed concurrently with acetate. We found minimal contribution of DON to the TDN pool in this stream as a result of high concentrations of nitrate. Acetate uptake suggested that C was a limiting factor for microbial metabolism in this stream. In contrast, we were not able to detect amino acid uptake during any of the 13 short-term releases we conducted, likely as a result of high availability of dissolved inorganic N. Aminopeptidase (AMP) activity did not reflect N demand. Large spatial variability in AMP was observed within and among sites, possibly as result of physicochemical characteristics of the sediments. In contrast to other human-dominated streams, DON appeared to play a minor role in microbial metabolic processes and contributed minimally to the N pool of the study stream. PMID- 26023985 TI - Composting and gypsum amendment of broiler litter to reduce nutrient leaching loss. AB - The effect of composted litter relative to fresh litter on leaching losses of nutrients has not been well documented. Fresh and composted broiler litter was surface-applied to bermudagrass (hay) [ (L.) Pers.] established in undisturbed soil columns based on N need of the grass in the presence or absence of flue gas desulfurization (FGD) gypsum to evaluate an approach to reduce broiler litter nutrient leaching potential. Columns were periodically leached and biomass was harvested during the 60-d experiment. Total N applied to bermudagrass from broiler litter was 320 kg ha. Gypsum was mixed with fresh and composted litter at the rate based on 20% of litter weight. For composted broiler litter, NO-N, P, K, Cu, and Zn contents in the leachate obtained from the first leaching event were 58, 50, 40, 32, and 38% less than fresh broiler litter, respectively. Significant decreases in NO-N (13%), P (53%), Cu (17%), and Zn (28%) in leachate were obtained when gypsum was mixed with fresh broiler litter. Fresh broiler litter and composted broiler litter applications increased bermudagrass growth compared with the control and gypsum significantly increased yields when mixed with broiler litter. Composted broiler litter application significantly increased N and organic C in the soil compared with fresh litter. Results demonstrate that coapplication of composted broiler litter with FGD gypsum provide the most effective management option for minimizing leaching losses of nutrients while sustaining crop productivity. PMID- 26023986 TI - Aqueous leaching of organic acids and dissolved organic carbon from various biochars prepared at different temperatures. AB - Biochar has been used as a soil amendment, as a water treatment material, and for carbon (C) sequestration. Thirty-six biochars, produced from wood, agricultural residue, and manure feedstocks at different temperatures, were evaluated for the aqueous leaching of different forms of soluble C. The release of inorganic C (alkalinity), organic acids (OAs), and total dissolved organic C (DOC) was highly variable and dependent on the feedstock and pyrolysis temperature. The pH and alkalinity increased for the majority of samples. Higher pH values were associated with high-temperature (high-T) (600 and 700 degrees C) biochars. Statistically significant differences in alkalinity were not observed between low temperature (low-T) (300 degrees C) and high-T biochars, whereas alkalinity released from wood-based biochar was significantly lower than from others. Concentrations of OAs and DOC released from low-T biochars were greater than from high-T biochars. The C in the OAs represented 1 to 60% of the total DOC released, indicating the presence of other DOC forms. The C released as DOC represented up to 3% (majority <0.1%) of the total C in the biochar. Scanning electron microscopy with energy dispersive X-ray spectroscopy showed the high-T biochars had a greater proportion of micropores. Fourier transform infrared spectroscopy showed that hydroxyl, aliphatic, and quinone were the predominant functional groups of all biochars and that the abundance of other functional groups was dependent on the feedstock. The release of DOC, especially bioavailable forms such as OAs, may promote growth of organisms and heavy metal complexation and diminish the potential effectiveness of various biochars for C sequestration. PMID- 26023987 TI - Manganese-oxide-coated redox bars as an indicator of reducing conditions in soils. AB - Identification of reducing conditions in soils is of concern not only for pedogenesis but also for nutrient and pollutant dynamics. We manufactured manganese (Mn)-oxide-coated polyvinyl chloride bars and proved their suitability for the identification of reducing soil conditions. Birnessite was synthesized and coated onto white polyvinyl chloride bars. The dark brown coatings were homogenous and durable. As revealed by microcosm devices with adjusted redox potentials (E), under oxidizing conditions (E ~450 mV at pH 7) there was no Mn oxide removal. Reductive dissolution of Mn-oxides, which is expressed by the removal of the coatings, started under weakly reducing conditions (E ~175 mV) and was more intensive under moderately reducing conditions (~80 mV). According to thermodynamics, the removal of Mn-oxide coatings (225 mm d) exceeded the removal of iron (Fe)-oxide coatings (118 mm d) in soil column experiments. This was confirmed in a soil with a shallow and strongly fluctuating water table where both types of redox bars were inserted. Consequently, it was possible to identify reducing conditions in soils using Mn-oxide-coated bars. We recommend this methodology for short-term monitoring because tri- and tetravalent Mn is the preferred electron acceptor compared with trivalent Fe, and this additionally offers the possibility of distinguishing between weakly and moderately reducing conditions. If dissolved Fe is abundant in soils, the possibility of nonenzymatic reduction of Mn has to be taken into account. PMID- 26023988 TI - Removal of Less Commonly Addressed Metals via Passive Cotreatment. AB - The viability of removing less commonly addressed metals (e.g., Cd, Cu, Ni, and Pb) in a passive cotreatment concept was tested using a microcosm-scale, three stage batch reactor system in which acid mine drainage from an abandoned adit on Cerro Rico de Potosi and raw municipal wastewater from Potosi, Bolivia, were introduced at a 5:1 ratio. The acid mine drainage had pH 3.58, acidity 1080 mg L as CaCO equivalent, and elevated concentrations of dissolved Al, Fe, Mn, Zn, Cd, Cu, Ni, and Pb, among other metals/metalloids. The municipal wastewater had pH 9.05 and alkalinity 418 mg L as CaCO equivalent, with 5.6 and 38 mg L of nitrate and phosphate, respectively. Previous analyses noted substantial pH increase, phosphate removal, denitrification, and removal of Al, Fe, Mn, and Zn. Prompted by these results, subsequent analyses were conducted for the current study, which noted that dissolved concentrations of Cd, Cu, Ni, and Pb decreased by 78.5, 18.3, 25.5, and 45.9%, respectively. Additionally, concentrations of Ce, Cr, Gd, and La decreased throughout the system. The study revealed the broader applicability of passive cotreatment of acid mine drainage and municipal wastewater, specifically for removing metals that are often difficult to address with conventional passive treatment approaches, such as Cd, Cu, Ni, and Pb. Results could be applicable for treatment alternatives in developing and developed countries where these waste streams occur in close proximity. PMID- 26023990 TI - A novel C25 sterol peroxide from the endophytic fungus Phoma sp. EA-122. AB - A novel C25 sterol peroxide, phomasterol A (1), together with two known compounds (2-3), was isolated from the endophytic fungus Phoma sp. EA-122. The structure of phomasterol A (1) was elucidated by MS, 1D, and 2D NMR data analyses. Phomasterol A (1) was evaluated for its inhibitory activities against protein-tyrosine phosphatases MEG2 and PTP1Bc, showing moderate activities with identical IC50 values of 25 MUM. PMID- 26023989 TI - The promising effect of barberry (Zereshk) extract against experimental pulmonary microvascular remodeling and hypertension: A comparison with sildenafil. AB - CONTEXT: Despite the beneficial effects of barberry (Berberis integerrima Berberidaceae) on decreasing systemic hypertension, its influence has not been investigated on pulmonary hypertension. OBJECTIVE: The objective of this study is to examine the effect of barberry fruit, on monocrotaline-induced pulmonary hypertension. MATERIALS AND METHODS: Nine groups were arranged as follows: the control group, the monocrotaline (M) group, the barberry groups with doses of 50, 100, and 200 (mg/kg), the M plus barberry groups, and the M plus sildenafil group. Two weeks after a single injection of monocrotaline (60 mg/kg, s.c.), barberry water extracts or sildenafil (30 mg/kg/d) were gavaged daily for 2 weeks. At the end of the 4th week, hemodynamic, biochemical, and histopathological parameters were assessed. RESULTS: In comparison with the M group, barberry (200 mg/kg) or sildenafil significantly reduced the right ventricular systolic pressure (RVSP) (22.95 +/- 1.78 mm Hg and 30.71 +/- 1.64 mm Hg, versus 41.28 +/- 1.5 mm Hg), right ventricular hypertrophy (RVH) (0.39 +/- 0.03 and 0.42 +/- 0.02, versus 0.57 +/- 0.02), and the medial wall thickness (MWT) (4.56 +/- 0.15 um and 5.97 +/- 0.19 um, versus 7.02 +/- 0.43 um). Barberry or sildenafil had no significant effect on the plasma level of endothelin-1, glutathione peroxidase, and the malondialdehide of lung. CONCLUSION: 200 mg/kg of barberry has an improving effect on the monocrotaline-induced pulmonary hypertension. This effect was stronger than that of the sildenafil's and may have been mediated through mechanisms other than the modulation of the endothelin-1 or redox system. PMID- 26023991 TI - Development of a design space and predictive statistical model for capsule filling of low-fill-weight inhalation products. AB - The objectives of this study were to develop a predictive statistical model for low-fill-weight capsule filling of inhalation products with dosator nozzles via the quality by design (QbD) approach and based on that to create refined models that include quadratic terms for significant parameters. Various controllable process parameters and uncontrolled material attributes of 12 powders were initially screened using a linear model with partial least square (PLS) regression to determine their effect on the critical quality attributes (CQA; fill weight and weight variability). After identifying critical material attributes (CMAs) and critical process parameters (CPPs) that influenced the CQA, model refinement was performed to study if interactions or quadratic terms influence the model. Based on the assessment of the effects of the CPPs and CMAs on fill weight and weight variability for low-fill-weight inhalation products, we developed an excellent linear predictive model for fill weight (R(2 )= 0.96, Q(2 )= 0.96 for powders with good flow properties and R(2 )= 0.94, Q(2 )= 0.93 for cohesive powders) and a model that provides a good approximation of the fill weight variability for each powder group. We validated the model, established a design space for the performance of different types of inhalation grade lactose on low-fill weight capsule filling and successfully used the CMAs and CPPs to predict fill weight of powders that were not included in the development set. PMID- 26023992 TI - Coated biodegradable casein nanospheres: a valuable tool for oral drug delivery. AB - Biodegradable casein nanospheres for the sustained release of bioactive molecules in the gastro-intestinal tract were prepared by precipitation polymerization using sodium methacrylate (NaMA) and N,N'-methylene bis-acrylamide (MEBA) as pH responsive monomer and cross-linker. Three materials with different casein amount were obtained and characterized by scanning electron microscopy, dimensional analysis, water uptake, cytotoxicity and enzymatic degradation experiments. Nanospheres biodegradability was tuned by coating with polyacrylic acid. Coated and uncoated materials were investigated as delivery vehicles for diclofenac sodium salt. For un-coated samples, the release raise 100% in 30 h, while for coated specimens these values were lower than 70%, due to the diffusional constraints of polymer layer. PMID- 26023993 TI - Viscoelastic interactions between polydeoxyribonucleotide and ophthalmic excipients. AB - This study investigated the interaction between polydeoxyribonucleotide (PDRN) and several ionic and nonionic isotonic agents, thickeners and a preservative that were employed as excipients in ophthalmic preparations. Interaction of each individual excipient and PDRN aqueous solution was evaluated by analyzing their rheological properties. Rheological properties of PDRN solutions were evaluated by dynamic oscillatory shear tests and values of elastic modulus (G'), viscous modulus (G") and loss tangent (tan delta) were used to assess the relative changes in viscoelastic properties. At given concentrations, sodium chloride was found to show alteration in viscoelastic properties of PDRN solution while nonionic isotonic agents like d-glucose and d-sorbitol did not alter them. Similarly, nonionic water soluble polymers like polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) also did not interact with PDRN to alter the viscoelastic properties. However, there were changes observed when carbopol 940 was used as a thickener. Therefore, PDRN was found to interact with ionic excipients and the interactions were negligible when nonionic materials were examined, which suggests that nonionic excipients are suitable to be formulated with PDRN. PMID- 26023994 TI - 2D nanocomposite photoconductive sensors fully dry drawn on regular paper. AB - We proposed a new type of low-cost and environmentally friendly photoconductive sensor, based on GaSe/graphite nanocomposite fully dry drawn on paper. The proposed fully-drawn nanocomposite sensors successfully utilize the unique combination of structural and electrical properties of a layered semiconductor and graphite. In spite of the relatively pure photosensitivity of the proposed photodetectors, we believe that this work is the first step for the further development and enhancement of extremely simple and low-cost paper-based dry drawn layered semiconductor/graphite nanocomposite sensors. PMID- 26023995 TI - GM crops in the media. PMID- 26023996 TI - Perimesencephalic hemorrhage with negative angiography: case illustration. PMID- 26023997 TI - Stereotactic injection of nondiffusible dyes. PMID- 26023998 TI - Evaluation of a multiplex polymerase chain reaction for early diagnosis of ventriculostomy-related infections. AB - OBJECT: Diagnosis of ventriculostomy-related infections (VRIs) is challenging due to the lack of rapid, sensitive assays for pathogen detection. The authors report the development of a multiplex polymerase chain reaction (PCR) assay for differential diagnosis of common VRI pathogens. METHODS: MassTag PCR was used to develop a multiplex assay for detection of 11 VRI pathogens. The assay was established and optimized using cloned template standards and spiked samples and was then evaluated on CSF specimens from ventricular drains. Subjects were grouped into definite VRI, possible VRI, or no VRI based on conventional microbiology, CSF evaluation, and clinical parameters. RESULTS: CSF specimens were obtained from 45 subjects (median age 49 years, interquartile range 32-63 years; 51% were male). The assay detected 10-100 genome copies. It detected a pathogen in 100% (6 of 6) of definite VRI cases in which a pathogen targeted by the assay was present; these represented 67% of all definite VRIs (6 of 9). Among subjects with a possible VRI, the assay detected a pathogen in 29% (5 of 17). In subjects without overt infection the presence of a pathogen was detected in 32% of subjects (6 of 19), albeit with lower signal compared with the VRI group. CONCLUSIONS: MassTag PCR enabled parallel testing of CSF specimens for 11 pathogens of VRI. The high sensitivity of PCR combined with possible device colonization, specimen contamination, and concurrent antibiotic treatments limit the clinical value of the assay, similar to other current diagnostic approaches. With further optimization, multiplex PCR may provide timely identification of multiple possible VRI pathogens and guide management, complementing classic culture approaches. PMID- 26024000 TI - Perianeurysmal edema in giant intracranial aneurysms in relation to aneurysm location, size, and partial thrombosis. PMID- 26023999 TI - Improvement in cerebral hemodynamic parameters and outcomes after superficial temporal artery-middle cerebral artery bypass in patients with severe stenoocclusive disease of the intracranial internal carotid or middle cerebral arteries. AB - OBJECT: Both the older and the recent extracranial-intracranial (EC-IC) bypass trials for symptomatic carotid occlusion failed to demonstrate a reduction in stroke recurrence. However, the role of superficial temporal artery (STA)-middle cerebral artery (MCA) bypass in patients with symptomatic intracranial stenoocclusive disease has been rarely evaluated. The authors evaluated serial changes in various cerebral hemodynamic parameters in patients with severe stenoocclusive disease of the intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) and impaired cerebral vasodilatory reserve (CVR), treated by STA-MCA bypass surgery or medical treatment. METHODS: Patients with severe stenoocclusive disease of the intracranial ICA or MCA underwent transcranial Doppler (TCD) ultrasonography and CVR assessment using the breath holding index (BHI). Patients with impaired BHI (< 0.69) were further evaluated with acetazolamide-challenge technitium-99m hexamethylpropyleneamine oxime ((99m)Tc HMPAO) SPECT. STA-MCA bypass surgery was offered to patients with impaired CVR on SPECT. All patients underwent TCD and SPECT at 4 +/- 1 months and were followed up for cerebral ischemic events. RESULTS: A total of 112 patients were included. This total included 73 men, and the mean age of the entire study population was 56 years (range 23-78 years). (99m)Tc HMPAO SPECT demonstrated impaired CVR in 77 patients (69%). Of these 77 patients, 46 underwent STA-MCA bypass while 31 received best medical treatment. TCD and acetazolamide-challenge (99m)Tc HMPAO SPECT repeated at 4 +/- 1 months showed significant improvement in the STA-MCA bypass group. During a mean follow-up of 34 months (range 18-39 months), only 6 (13%) of 46 patients in the bypass group developed cerebral ischemic events, as compared with 14 (45%) of 31 patients receiving medical therapy (absolute risk reduction 32%, p = 0.008). CONCLUSIONS: STA-MCA bypass surgery in carefully selected patients with symptomatic severe intracranial stenoocclusive disease of the intracranial ICA or MCA results in significant improvement in hemodynamic parameters and reduction in stroke recurrence. PMID- 26024001 TI - Avoidance and management of perioperative complications of endoscopic third ventriculostomy: the Dhaka experience. AB - OBJECT: Although endoscopic third ventriculostomy (ETV) is a minimally invasive procedure, serious perioperative complications may occur due to the unique surgical maneuvers involved. In this paper the authors report the complications of elective and emergency ETV and their surgical management in 412 patients from July 2006 to October 2012 at Dhaka Medical College Hospital (a government hospital) and other private hospitals in Dhaka, Bangladesh. The authors attempted some previously undescribed simple maneuvers that may help to overcome the difficulties of managing complications. METHODS: The complication rate was determined by recording intraoperative changes in pulse and blood pressure, bleeding episodes, serum electrolyte abnormalities, CSF leakage, and neurological deterioration in the immediate postoperative period. RESULTS: Intraoperative complications included hemodynamic alterations in the form of tachycardia, bradycardia, and hypertension. Bleeding was categorized as major in 2 cases and minor in 68 cases. Delayed recovery from anesthesia occurred in 14 cases, CSF leakage from the wound in 11 cases, and electrolyte imbalance in 5 cases. Postoperatively, 2 patients suffered convulsions and 1 had evidence of third cranial nerve injury. Three patients died as a result of complications. CONCLUSIONS: Complications during endoscopy can lead to serious consequences that may sometimes be very difficult to manage. The authors have identified and managed a large number of complications in this series, although the rate of complications is consistent with that in other reported series. These complications should be kept in mind perioperatively by both surgeons and anesthesiologists, as prompt detection and action can help minimize the risks associated with neuroendoscopic procedures. PMID- 26024002 TI - The 6 thalamic regions: surgical approaches to thalamic cavernous malformations, operative results, and clinical outcomes. AB - OBJECT: The ideal surgical approach to thalamic cavernous malformations (CMs) varies according to their location within the thalamus. To standardize surgical approaches, the authors have divided the thalamus into 6 different regions and matched them with the corresponding surgical approach. METHODS: The regions were defined as Region 1 (anteroinferior), Region 2 (medial), Region 3 (lateral), Region 4 (posterosuperior), Region 5 (lateral posteroinferior), and Region 6 (medial posteroinferior). The senior author's surgical experience with 46 thalamic CMs was reviewed according to this classification. An orbitozygomatic approach was used for Region 1; anterior ipsilateral transcallosal for Region 2; anterior contralateral transcallosal for Region 3; posterior transcallosal for Region 4; parietooccipital transventricularfor Region 5; and supracerebellar infratentorial for Region 6. RESULTS: Region 3 was the most common location (17 [37%]). There were 5 CMs in Region 1 (11%), 9 in Region 2 (20%), 17 in Region 3 (37%), 3 in Region 4 (6%), 4 in Region 5 (9%), and 8 in Region 6 (17%). Complete resection was achieved in all patients except for 2, who required a second-stage operation. The mean follow-up period was 1.7 years (range 6 months-9 years). At the last clinical follow-up, 40 patients (87%) had an excellent or good outcome (modified Rankin Scale [mRS] scores 0-2) and 6 (13%) had poor outcome (mRS scores 3-4). Relative to their preoperative condition, 42 patients (91%) were unchanged or improved, and 4 (9%) were worse. CONCLUSIONS: The authors have presented the largest series reported to date of surgically treated thalamic CMs, achieving excellent results using this methodology. In the authors' experience, conceptually dividing the thalamus into 6 different regions aids in the selection of the ideal surgical approach fora specific region. PMID- 26024003 TI - "Unusual brain stone": heavily calcified primary neoplasm with some features suggestive of angiocentric glioma. AB - This 40-year-old man presented with a 5-month history of progressive right-sided headache associated with visual blurring. He also had a history of epilepsy but had been seizure free with medication for the past 10 years. An initial CT scan of his brain performed 16 years previously had revealed a small area of calcification in the right parietal region. In the current presentation, he had a left-sided homonymous hemianopia but no other neurological deficits. A CT scan of his brain showed a much larger calcified, partly cystic lesion in the right parietal region. Because he was symptomatic, the lesion was excised and the cyst was drained. Histological examination of the excised tissue showed an unusual primary tumor that was difficult to classify but had some features of angiocentric glioma. The heavy calcification, mixed-density cell population, and regions with features of angiocentric glioma were most unusual. The patient remained asymptomatic 5 years after surgery, and follow-up scans did not show recurrence. PMID- 26024004 TI - Dorsolateral subthalamic neuronal activity enhanced by median nerve stimulation characterizes Parkinson's disease during deep brain stimulation with general anesthesia. AB - OBJECT: Deep brain stimulation (DBS) surgery under general anesthesia is an alternative option for patients with Parkinson's disease (PD). However, few studies are available that report whether neuronal firing can be accurately recorded during this condition. In this study the authors attempted to characterize the neuronal activity of the subthalamic nucleus (STN) and elucidate the influence of general anesthetics on neurons during DBS surgery in patients with PD. The benefit of median nerve stimulation (MNS) for localization of the dorsolateral subterritory of the STN, which is involved in sensorimotor function, was explored. METHODS: Eight patients with PD were anesthetized with desflurane and underwent contralateral MNS at the wrist during microelectrode recording of the STN. The authors analyzed the spiking patterns and power spectral density (PSD) of the background activity along each penetration track and determined the spatial correlation to the target location, estimated mated using standard neurophysiological procedures. RESULTS: The dorsolateral STN spiking pattern showed a more prominent bursting pattern without MNS and more oscillation with MNS. In terms of the neural oscillation of the background activity, beta-band oscillation dominated within the sensorimotor STN and showed significantly more PSD during MNS (p < 0.05). CONCLUSIONS: Neuronal firing within the STN could be accurately identified and differentiated when patients with PD received general anesthetics. Median nerve stimulation can enhance the neural activity in beta band oscillations, which can be used as an index to ensure optimal electrode placement via successfully tracked dorsolateral STN topography. PMID- 26024005 TI - The double tunnels technique: an alternative minimally invasive approach for carpal tunnel syndrome. AB - OBJECT: The purpose of this study was to assess the effectiveness and safety of an alternative minimally invasive technique for the treatment of carpal tunnel syndrome (CTS). METHODS: This was designed as a prospective, randomized, open label, blinded end point evaluation (PROBE) study. The active comparison was double tunnels technique (DTT) (Group A, 110 patients) versus standard open decompression of the median nerve (control [Group B], 110 patients). Patient recruitment started in January 2011. The primary outcomes were the functional Boston Carpal Tunnel Syndrome Questionnaire (BCTSQ) scores and visual analog scale (VAS) scores for pain (pVAS) at Weeks 2 and 4, and at Months 3, 6, and 12. The secondary outcome was the aesthetics (aVAS) score at Weeks 2 and 4, and at Months 3, 6, and 12. RESULTS: The Student t-test and ANOVA were used, and the results were considered statistically significant if the p value was <=0.05 for continuous variables. The DTT is a tissue-sparing approach that allows the surgeon to limit the length of the incision (0.6+/-0.05 cm) and to respect the palmar fascia and the subcutaneous tissue. Recovery from wrist pain, night pain, numbness, stiffness, and weakness was achieved more effectively and quickly compared with the standard approach. Better BCTSQ, pVAS, and aVAS scores were observed in Group A. CONCLUSIONS: The DTT is a safe and effective approach for the treatment of CTS. This technique entails faster recovery times, better aesthetic outcomes, and lower risks of complications. PMID- 26024006 TI - Increased risk of intracerebral hemorrhage among patients with chronic osteomyelitis. AB - OBJECT: Inflammation may provoke cerebral arteriolar ectasia, inducing microaneurysm formation and further promoting intracerebral hemorrhage (ICH). Chronic osteomyelitis (COM) is an inflammatory disorder for which study of its role in ICH is lacking. This study explored whether COM increases the risk of ICH. METHODS: From Taiwan national insurance inpatient claims, 22,052 patients who were newly diagnosed with COM between 1997 and 2010 were identified; 88, 207 age and sex frequency-matched subjects without COM were selected at random for comparison. Risks of ICH associated with COM and comorbidities, including hypertension, diabetes, hyperlipidemia, chronic kidney disease, and drug abuse, were assessed by the end of 2010. RESULTS: The incidence of ICH was 1.68 times higher in the COM cohort than in the comparison cohort, with an adjusted hazard ratio (HR) of 1.50 (95% CI 1.29-1.74) estimated in the multivariable Cox model. Age-specific analysis showed that the HR of ICH for COM patients decreased with age, with an adjusted HR of 3.28 (95% CI 1.88-5.75) in the < 40-year age group, which declined to 1.11 (95% CI 0.88-1.40) in the elderly. The incidence of ICH increased with the severity of COM; for those with severe COM the adjusted HR was 4.42 (95% CI 3.31-5.89). For subjects without comorbidities, the incidence of ICH was 1.20-fold (95% CI 1.00-1.45) higher in the COM cohort than in the comparison cohort. CONCLUSIONS: This study suggests for the first time that COM is an inflammatory factor associated with increased risk of ICH, especially in younger patients. PMID- 26024007 TI - Comparisons between small intestinal and gastric feeding in severe traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECT: Nutritional support is highly recommended for reducing the risk of nosocomial infections, such as pneumonitis, in patients with severe traumatic brain injury (TBI). Currently, there is no consensus for the preferred route of feeding. The authors compared the risks of pneumonitis and other important outcomes associated with small intestinal and gastric feeding in patients with severe TBI. METHODS: This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Relevant randomized controlled trials (up to December 16, 2013) that compared small bowel to gastric feeding in patients with severe TBI were identified from searches in the PubMed and Embase databases. The primary outcome was risk of pneumonia. Secondary outcomes included ventilator associated pneumonia, mortality, length of intensive care unit stay, length of hospital stay, duration of mechanical ventilation, total number of complications, aspiration, diarrhea, distention, Glasgow Coma Scale score, Injury Severity Score, and Acute Physiology and Chronic Health Evaluation II score. RESULTS: Five randomized controlled trials with 325 participants in total were included in the meta-analysis. Compared with gastric feeding, small bowel feeding was associated with a significant reduction in the incidence of pneumonitis (risk ratio [RR] 0.67; 95% CI 0.52-0.87; p=0.002; I2=0.0%) and ventilator-associated pneumonia (RR 0.52; 95% CI 0.34-0.81; p=0.003; I2=0.0%). Small intestinal feeding was also associated with a decrease in the total number of complications (RR 0.43; 95% CI 0.20-0.93; p=0.03; I2=68%). However, small intestinal feeding did not seem to significantly convert any of the other end points in the meta-analysis. CONCLUSIONS: The limited evidence suggests that small bowel feeding in patients with severe TBI is associated with a risk of pneumonia that is lower than that with gastric feeding. From this result, the authors recommend the use of small intestinal feeding to reduce the incidence of pneumonitis in patients with severe TBI. PMID- 26024009 TI - The Effect of Fatigue-Induced Changes in Eggbeater-Kick Kinematics on Performance and Risk of Injury. AB - PURPOSE: To investigate the effects of fatigue on the vertical force and kinematics of the lower limbs during maximal water polo eggbeater kicking. METHODS: Twelve male water polo players maintained as high a position as possible while performing the eggbeater kick with the upper limbs raised out of the water until they were unable to keep the top of the sternum (manubrium) above water. Data comprising 27 complete eggbeater-kick cycles were extracted corresponding to 9 cycles of the initial nonfatigued (0%), 50% time point (50%), and final fatigued (100%) periods of the trial. Vertical force, foot speed, and hip-, knee , and ankle-joint angles were calculated. RESULTS: Mean vertical force (0%, 212.2 N; 50%, 184.5 N; 100%, 164.3 N) progressively decreased with time. Speed of the feet (0.4 m/s), hip abduction (2.9 degrees ), and flexion (3.6 degrees ) decreased with fatigue, while hip internal rotation (3.6 degrees ) and ankle inversion (4 degrees ) increased with fatigue. Average angular velocity decreased for all joint motions. CONCLUSIONS: Eggbeater-kick performance decreases with fatigue. Inability to maintain foot speeds and hip and ankle actions with progressing fatigue diminishes the ability of the player to produce vertical force during the cycle. Increased internal rotation of the hip when fatigued and the large eversion/abduction of the ankle during the cycle may be predisposing factors for the prevalence of patellofemoral pain syndrome observed among eggbeater-kick performers. Appropriate training interventions that can limit the effects of fatigue on performance and injury risk should be considered. PMID- 26024010 TI - Evaluation of holistic sexuality education: A European expert group consensus agreement. AB - OBJECTIVES: Holistic sexuality education (HSE) is a new concept in sexuality education (SE). Since it differs from other types of SE in a number of important respects, strategies developed for the evaluation of the latter are not necessarily applicable to HSE. In this paper the authors provide a basis for discussion on how to evaluate HSE. METHODS: First, the international literature on evaluation of SE in general was reviewed in terms of its applicability to HSE. Second, the European Expert Group on Sexuality Education extensively discussed the requirements of its evaluation and suggested appropriate indicators and methods for evaluating HSE. RESULTS: The European experience in SE is scarcely represented in the general evaluation literature. The majority of the literature focuses on impact and neglects programme and implementation evaluations. Furthermore, the current literature demonstrates that evaluation criteria predominantly focus on the public health impact, while there is not yet a consensus on sexual well-being criteria and aspects of positive sexuality, which are crucial parts of HSE. Finally, experimental designs are still considered the gold standard, yet several of the conditions for their use are not fulfilled in HSE. Realising that a new evaluation framework for HSE is needed, the European expert group initiated its development and agreed upon a number of indicators that provide a starting point for further discussion. CONCLUSIONS: Aside from the health impact, the quality of SE programmes and their implementation also deserve attention and should be evaluated. To be applicable to HSE, the evaluation criteria need to cover more than the typical public health aspects. Since they do not register long-term and multi-component characteristics, evaluation methods such as randomised controlled trials are not sufficiently suitable for HSE. The evaluation design should rely on a number of different information sources from mixed methods that are complemented and triangulated to build a plausible case for the effectiveness of SE in general and HSE in particular. PMID- 26024008 TI - Early treatment with metformin induces resistance against tumor growth in adult rats. AB - It is known that antidiabetic drug metformin, which is used worldwide, has anti cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer. PMID- 26024011 TI - Determination of oral mucosal Poisson's ratio and coefficient of friction from in vivo contact pressure measurements. AB - Despite their considerable importance to biomechanics, there are no existing methods available to directly measure apparent Poisson's ratio and friction coefficient of oral mucosa. This study aimed to develop an inverse procedure to determine these two biomechanical parameters by utilizing in vivo experiment of contact pressure between partial denture and beneath mucosa through nonlinear finite element (FE) analysis and surrogate response surface (RS) modelling technique. First, the in vivo denture-mucosa contact pressure was measured by a tactile electronic sensing sheet. Second, a 3D FE model was constructed based on the patient CT images. Third, a range of apparent Poisson's ratios and the coefficients of friction from literature was considered as the design variables in a series of FE runs for constructing a RS surrogate model. Finally, the discrepancy between computed in silico and measured in vivo results was minimized to identify the best matching Poisson's ratio and coefficient of friction. The established non-invasive methodology was demonstrated effective to identify such biomechanical parameters of oral mucosa and can be potentially used for determining the biomaterial properties of other soft biological tissues. PMID- 26024012 TI - Unusually high levels of bisphenol A (BPA) in thermal paper cash register receipts (CRs): development and application of a robust LC-UV method to quantify BPA in CRs. AB - We have developed a simple, reversed-phase high-performance liquid chromatography (RP-HPLC) method for the determination of bisphenol A (BPA) in thermal paper cash register receipts (CRs). The method is suitable for analysis of other types of bisphenols and it involves an overnight extraction of CRs with acetonitrile (AN) at 50 degrees C followed by the HPLC analysis on a Supelcosil LC18 column (150 * 4.6 mm, particle size: 5 MU) using 50% AN in water as the mobile phase (5 min, isocratic). The composition of AN in the mobile phase changed to 100% over a 10 min period (linear gradient) and then held at 100% AN for 10 min (isocratic). The flow rate was set at 1 mL/min (injection volume: 20 MUL) and the eluent was monitored at 234 nm. The authentic BPA eluted with a retention time of 5.9 min and gave a linear detector response in the concentration range of 0.23-50 mg/L. BPA in the CR extracts also eluted with the same retention and had identical absorbance properties as the standard. When CR extracts were co-injected with authentic BPA, they were resolved as a single peak. Further, GC/MS/EI analysis of authentic BPA and the HPLC-purified CR extracts have identical ion chromatograms and fragmentation of the molecular ion (m/z = 228). We have analyzed 170 CRs collected from 62 different vendors including supermarkets, fast food restaurants, gas stations and banking outlets. Almost all cash receipts (n = 168) showed the presence of BPA in the concentration range of 0.45-4.26% (M +/- SD, 1.54 +/- 0.73%). PMID- 26024013 TI - Recovery by N-acetylcysteine from subchronic exposure to Imidacloprid-induced hypothalamic-pituitary-adrenal (HPA) axis tissues injury in male rats. AB - Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor in insects, and potentially in mammals. N-Acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the recovery effect of NAC against Imidacloprid-induced oxidative stress and cholinergic transmission alteration in hypothalamic-pituitary-adrenal (HPA) axis of male rats following subchronic exposure. About 40 mg/kg of Imidacloprid was administered daily by intragastric intubation and 28 days later, the rats were sacrificed and HPA axis tissues were removed for different analyses. Imidacloprid increased adrenal relative weight and cholesterol level indicating an adaptive stage of the general alarm reaction to stress. Moreover, Imidacloprid caused a significant increase in malondialdehyde level, the antioxidants catalase, superoxide dismutase and glutathione-S-transferase showed various alterations following administration and significant depleted thiols content was only recorded in hypothalamic tissue. Furthermore, the hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased highlighting the alteration of cholinergic activity. The present findings revealed that HPA axis is a sensitive target to Imidacloprid (IMI). Interestingly, the use of NAC for only 7 days post-exposure to IMI showed a partial therapeutic effect against Imidacloprid toxicity. PMID- 26024014 TI - Aluminum ions alter the function of non-specific phospholipase C through the changes in plasma membrane physical properties. AB - The first indication of the aluminum (Al) toxicity in plants growing in acidic soils is the cessation of root growth, but the detailed mechanism of Al effect is unknown. Here we examined the impact of Al stress on the activity of non-specific phospholipase C (NPC) in the connection with the processes related to the plasma membrane using fluorescently labeled phosphatidylcholine. We observed a rapid and significant decrease of labeled diacylglycerol (DAG), product of NPC activity, in Arabidopsis seedlings treated with AlCl3. Interestingly, an application of the membrane fluidizer, benzyl alcohol, restored the level of DAG during Al treatment. Our observations suggest that the activity of NPC is affected by Al induced changes in plasma membrane physical properties. PMID- 26024015 TI - Study of the water structure in poly(methyl methacrylate-block-2-hydroxyethyl methacrylate) and its relationship to platelet adhesion on the copolymer surface. AB - The water structure and platelet compatibility of poly(methyl methacrylate (MMA) block-2-hydroxyethyl methacrylate (HEMA)) were investigated. The molecular weight (Mn) of the polyHEMA segment was kept constant (average: 9600), while the Mn of the polyMMA segment was varied from 1340 to 7390. The equilibrium water content of the copolymers was found to be mainly governed by the HEMA content. The water structure in the copolymers was characterized in terms of the amounts of non freezing and freezing water (abbreviated as Wnf and Wfz, respectively) using differential scanning calorimetry. It was found that the Wnf for the copolymers were higher than those estimated from the Wnf for the HEMA and MMA homopolymers and that the amount of excess non-freezing water depended on the polyMMA segment length. In addition, X-ray diffraction analysis revealed that some of the copolymers had cold-crystallizable water. These facts suggested that the polyMMA segments were involved in determining the water structures in the copolymers. Furthermore, the platelet compatibility of the copolymers was improved as compared to that of the HEMA homopolymer. It was therefore concluded that the platelet compatibility of the copolymer was related to the amount of excess non freezing water. PMID- 26024017 TI - Aerosol Analysis via Electrostatic Precipitation-Electrospray Ionization Mass Spectrometry. AB - Electrospray ionization (ESI) is the preferred mode of ion generation for mass analysis of many organic species, as alternative ionization techniques can lead to appreciable analyte fragmentation. For this reason, ESI is an ideal method for the analysis of species within aerosol particles. However, because of their low concentrations (~10 MUg/m(3)) in most environments, ESI has been applied sparingly in aerosol particle analysis; aerosol mass spectrometers typically employ analyte volatilization followed by electron ionization or chemical ionization, which can lead to a considerable degree of analyte fragmentation. Here, we describe an approach to apply ESI to submicrometer and nanometer scale aerosol particles, which utilizes unipolar ionization to charge particles, electrostatic precipitation to collect particles on the tip of a Tungsten rod, and subsequently, by flowing liquid over the rod, ESI and mass analysis of the species composing collected particles. This technique, which we term electrostatic precipitation-ESI-MS (EP-ESI-MS), is shown to enable analysis of nanogram quantities of collected particles (from aerosol phase concentrations as low as 10(2) ng m(-3)) composed of cesium iodide, levoglucosan, and levoglucosan within a carbon nanoparticle matrix. With EP-ESI-MS, the integrated mass spectrometric signals are found to be a monotonic function of the mass concentration of analyte in the aerosol phase. We additionally show that EP-ESI MS has a dynamic range of close to 5 orders of magnitude in mass, making it suitable for molecular analysis of aerosol particles in laboratory settings with upstream particle size classification, as well as analysis of PM 2.5 particles in ambient air. PMID- 26024016 TI - Polyphyly of nuclear lamin genes indicates an early eukaryotic origin of the metazoan-type intermediate filament proteins. AB - The nuclear lamina is a protein meshwork associated with the inner side of the nuclear envelope contributing structural, signalling and regulatory functions. Here, I report on the evolution of an important component of the lamina, the lamin intermediate filament proteins, across the eukaryotic tree of life. The lamins show a variety of protein domain and sequence motif architectures beyond the classical alpha-helical rod, nuclear localisation signal, immunoglobulin domain and CaaX motif organisation, suggesting extension and adaptation of functions in many species. I identified lamin genes not only in metazoa and Amoebozoa as previously described, but also in other opisthokonts including Ichthyosporea and choanoflagellates, in oomycetes, a sub-family of Stramenopiles, and in Rhizaria, implying that they must have been present very early in eukaryotic evolution if not even the last common ancestor of all extant eukaryotes. These data considerably extend the current perception of lamin evolution and have important implications with regard to the evolution of the nuclear envelope. PMID- 26024018 TI - Manitoba Lingonberry (Vaccinium vitis-idaea) Bioactivities in Ischemia Reperfusion Injury. AB - Evidence for the efficacy of dietary interventions in protecting against cardiovascular disease has grown significantly, with flavonoids and anthocyanins receiving special attention. Lingonberry (Vaccinium vitis-idaea L.) is a good source of these compounds, and this study examined the protective effects of wild lingonberry found in Manitoba, Canada, against ischemia-reperfusion (IR) injury. Manitoba lingonberry contained 3793 +/- 27 mg gallic acid equiv, 120,501 +/- 7651 MUmol trolox equiv, and 575 +/- 20 mg cyanidin-3-glucoside equiv per 100 g dry weight, which correspond with high total phenolic content, antioxidant activity, and anthocyanin content, respectively. A complete methanolic extract and both anthocyanin-rich and phenolic-rich fractions inhibited apoptosis in H9c2 cells during simulated IR. Lingonberry extract and fractions significantly inhibited several markers of apoptosis induced by IR, including nuclei condensation, caspase-3 activation, and MAP kinase signaling. These results provide the first analysis of Manitoba lingonberry and highlight the mechanistic importance of dietary berry compounds for cardiovascular health. PMID- 26024019 TI - QSAR studies on hydroxamic acids: a fascinating family of chemicals with a wide spectrum of activities. PMID- 26024020 TI - Ervatamines A-I, Anti-inflammatory Monoterpenoid Indole Alkaloids with Diverse Skeletons from Ervatamia hainanensis. AB - Nine new monoterpenoid indole alkaloids, ervatamines A-I (1-9), and five known ones (10-14), were isolated from Ervatamia hainanensis. The new structures were elucidated by extensive spectroscopic analysis and comparison to known compounds. Their absolute configurations were determined by various methods including computational methods, X-ray diffraction analysis, and electronic circular dichroism spectroscopy, as well as chemical transformations. Ervatamine A (1) is a ring-C-contracted ibogan-type monoterpenoid indole alkaloid with an unusual 6/5/6/6/6 pentacyclic rearranged ring system. Ervatamines B-E (2-5) display a nitrogen-containing 9/6 ring system, which is rarely observed in nature. The epimeric ervatamines B (2) and C (3) possess a 22-nor-monoterpenoid indole alkaloid carbon skeleton, which was only found in deformylstemmadenine. Compounds 10 and 14 exhibited significant anti-inflammatory activities, with IC50 values of 25.5 and 41.5 MUM, respectively, while the IC50 value of indomethacin as a positive control was found to be 42.6 MUM. Additionally, compound 9 showed mild activity against 786-O and HL-60 cell lines. PMID- 26024021 TI - Reduced Carrier Recombination in PbS - CuInS2 Quantum Dot Solar Cells. AB - Energy loss due to carrier recombination is among the major factors limiting the performance of TiO2/PbS colloidal quantum dot (QD) heterojunction solar cells. In this work, enhanced photocurrent is achieved by incorporating another type of hole-transporting QDs, Zn-doped CuInS2 (Zn-CIS) QDs into the PbS QD matrix. Binary QD solar cells exhibit a reduced charge recombination associated with the spatial charge separation between these two types of QDs. A ~30% increase in short-circuit current density and a ~20% increase in power conversion efficiency are observed in binary QD solar cells compared to cells built from PbS QDs only. In agreement with the charge transfer process identified through ultrafast pump/probe spectroscopy between these two QD components, transient photovoltage characteristics of single-component and binary QDs solar cells reveal longer carrier recombination time constants associated with the incorporation of Zn-CIS QDs. This work presents a straightforward, solution-processed method based on the incorporation of another QDs in the PbS QD matrix to control the carrier dynamics in colloidal QD materials and enhance solar cell performance. PMID- 26024024 TI - Size doesn't matter; in the stroma, little things make all the difference. AB - In recent years there has been an increase in the number of studies into the role of stromal cells and microRNAs (miRNAs) in kidney development. Nakagawa et al. combine the two in a study of a stromal cell-specific knockout of Dicer1. The work identifies many important roles for miRNAs in these cells and kidney development in general, partially through their modification of the beta-catenin signaling cascade. PMID- 26024025 TI - The vascular secret of Klotho. AB - Klotho is an evolutionarily highly conserved protein related to longevity. Increasing evidence of a vascular protecting effect of the Klotho protein has emerged and might be important for future treatments of uremic vascular calcification. It is still disputed whether Klotho is locally expressed in the vasculature or whether its vascular effects arise uniquely from its presence in the circulation. PMID- 26024026 TI - Urea and protein carbamylation in ESRD: surrogate markers or partners in crime? AB - Protein carbamylation may result from chronic exposure to elevated levels of urea in patients with chronic kidney disease. Carbamylation could cause conformational changes in proteins resulting in alterations in binding sites and disturbances in cellular functions. Elevated levels of carbamylated protein have been shown to be associated with increased risk of death from cardiac causes in patients with end stage renal disease. The precise mechanism by which carbamylated proteins mediate toxicity in uremia needs further investigation. PMID- 26024027 TI - Comparative health services research across populations: the unused opportunities in big data. AB - Large population registries present opportunities to understand the epidemiology of disease, study patters of care, and compare the effectiveness of different care practices. While these 'big data' tempt investigators to examine all available individuals, a targeted approach that restricts the study to an optimal sub-population may yield more relevant insights. We discuss how researchers might adapt their studies existing literature to generate additional insights. PMID- 26024028 TI - Simplified screening criteria for HNF1B analysis. PMID- 26024029 TI - The authors reply. PMID- 26024030 TI - Icodextrin skin rash incidence. PMID- 26024031 TI - Combined therapy using peritoneal dialysis and hemodialysis may increase the indications for peritoneal dialysis in the United States. PMID- 26024032 TI - The authors reply. PMID- 26024033 TI - Regarding mini-review on bicarbonate therapy for prevention of chronic kidney disease progression. PMID- 26024034 TI - The authors reply. PMID- 26024035 TI - The authors reply. PMID- 26024036 TI - Intravenous iron dose and mortality in hemodialysis patients. PMID- 26024037 TI - Low plasma magnesium and risk of developing chronic kidney disease: results from the PREVEND Study. PMID- 26024038 TI - The authors reply. PMID- 26024039 TI - Serum anti-PLA2R antibodies can be initially absent in idiopathic membranous nephropathy: seroconversion after prolonged follow-up. PMID- 26024040 TI - The growth of acute kidney injury: Eastern European perspective. PMID- 26024041 TI - A case of crystalline nephropathy. PMID- 26024042 TI - Nephrology image/primary localized amyloidosis of the ureter. PMID- 26024043 TI - The Case | Acute renal failure after antibiotic treatment for bronchitis. Diagnosis: Pigment nephropathy from cephalexin-induced immune hemolytic anemia. PMID- 26024045 TI - Chemical Dynamics Simulations of Benzene Dimer Dissociation. AB - Classical chemical dynamics simulations were performed to study the intramolecular and unimolecular dissociation dynamics of the benzene dimer, Bz2 > 2 Bz. The dissociation of microcanonical ensembles of Bz2 vibrational states, at energies E corresponding to temperatures T of 700-1500 K, were simulated. For the large Bz2 energies and large number of Bz2 vibrational degrees of freedom, s, the classical microcanonical (RRKM) and canonical (TST) rate constant expressions become identical. The dissociation rate constant for each T is determined from the initial rate dN(t)/dt of Bz2 dissociation, and the k(T) are well-represented by the Arrhenius eq k(T) = A exp(-E(a)/RT). The E(a) of 2.02 kcal/mol agrees well with the Bz2 dissociation energy of 2.32 kcal/mol, and the A-factor of 2.43 * 10(12) s(-1) is of the expected order-of-magnitude. The form of N(t) is nonexponential, resulting from weak coupling between the Bz2 intramolecular and intermolecular modes. With this weak coupling, large Bz2 vibrational excitation, and low Bz2 dissociation energy, most of the trajectories dissociate directly. Simulations, with only the Bz2 intramolecular modes excited at 1000 K, were also performed to study intramolecular vibrational energy redistribution (IVR) between the intramolecular and intermolecular modes. Because of restricted IVR, the initial dissociation is quite slow, but N(t) ultimately becomes exponential, suggesting an IVR time of 20.7 ps. PMID- 26024044 TI - A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity. AB - Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain. PMID- 26024046 TI - Biodistribution and function of extracellular miRNA-155 in mice. AB - Circulating miRNAs can be found in extracellular vesicles (EV) and could be involved in intercellular communication. Here, we report the biodistribution of EV associated miR-155 using miR-155 KO mouse model. Administration of exosomes loaded with synthetic miR-155 mimic into miR-155 KO mice resulted in a rapid accumulation and clearance of miR-155 in the plasma with subsequent distribution in the liver, adipose tissue, lung, muscle and kidney (highest to lowest, respectively). miR-155 expression was detected in isolated hepatocytes and liver mononuclear cells of recipient KO mice suggesting its cellular uptake. In vitro, exosome-mediated restoration of miR-155 in Kupffer cells from miR-155 deficient mice augmented their LPS-induced MCP1 mRNA increase. The systemic delivery of wild type plasma to miR-155 KO mice also resulted in a rapid accumulation of miR 155 in the circulation and distribution to the liver and adipose tissue. In summary, our results demonstrate tissue biodistribution and biologic function of EV-associated miR-155. PMID- 26024048 TI - Microwave-Assisted Copper-Catalyzed Four-Component Tandem Synthesis of 3-N Sulfonylamidine Coumarins. AB - Microwave-assisted copper-catalyzed four-component tandem synthesis of 3-N sulfonylamidine coumarins has been accomplished by the coupling of salicylaldehydes, propiolates, sulfonyl azides, and secondary amines. This one pot protocol affords an effective route for the construction of functionalized coumarin structural frameworks in a single operation with moderate to high yields. PMID- 26024047 TI - Slow Spin Dynamics in Superconducting Ca0.9Ce0.1Fe2As2. AB - Slow spin dynamics has been observed in superconducting under-doped Ca0.9Ce0.1Fe2As2 single crystal. Below 100 K, the system exhibits hysteresis in the cooling and warming protocols of temperature dependent resistivity due to first order tetragonal to orthorhombic structural transition with simultaneous magnetic transition from paramagnetic to spin density wave antiferromagnetic state of the iron (Fe) ions. Zero field cooled/field cooled (ZFC/FC) magnetization curves showed splitting at 32 K followed by a sharp increase of the FC curve and then FC plateau at low temperatures. Slow spin relaxation in both the ZFC and FC protocols was observed which is typical for spin-glass system. The system also showed features analogue to spin-glass behavior such as ZFC peak, FC plateau, ZFC slow spin relaxation, magnetic hysteresis, and ZFC ac memory effect. The spin-glass like behavior was rather weak and vanished at higher fields. The origin of the slow spin dynamics could be the inhomogeneous distribution of the cerium (Ce) spins ordered along the c-axis OR interactions between Fe and Ce spins which lead to magnetic frustration of Ce spins. All these findings support the coexistence of slow spin dynamics of Ce spins and superconductivity in Ca0.9Ce0.1Fe2As2 single crystal. PMID- 26024050 TI - Palladium-Catalyzed Monofluoromethylation of Arylboronic Esters with Fluoromethyl Iodide. AB - The first palladium-catalyzed direct monofluoromethylation of arylboronic esters to produce monofluoromethyl arenes is reported. The reaction is typically carried out at room temperature within 4 h and has a good functional group tolerance. The monofluoromethylating agent, CH2FI, was readily prepared via a halogen-exchange process. PMID- 26024049 TI - Effects of Abeta exposure on long-term associative memory and its neuronal mechanisms in a defined neuronal network. AB - Amyloid beta (Abeta) induced neuronal death has been linked to memory loss, perhaps the most devastating symptom of Alzheimer's disease (AD). Although Abeta induced impairment of synaptic or intrinsic plasticity is known to occur before any cell death, the links between these neurophysiological changes and the loss of specific types of behavioral memory are not fully understood. Here we used a behaviorally and physiologically tractable animal model to investigate Abeta induced memory loss and electrophysiological changes in the absence of neuronal death in a defined network underlying associative memory. We found similar behavioral but different neurophysiological effects for Abeta 25-35 and Abeta 1 42 in the feeding circuitry of the snail Lymnaea stagnalis. Importantly, we also established that both the behavioral and neuronal effects were dependent upon the animals having been classically conditioned prior to treatment, since Abeta application before training caused neither memory impairment nor underlying neuronal changes over a comparable period of time following treatment. PMID- 26024051 TI - Times are a-changing: Transitions at Nutrition Reviews. PMID- 26024053 TI - When do gain-framed health messages work better than fear appeals? AB - Past literature reviews of gain-framed versus loss-based health messages have been inconsistent and inconclusive. To resolve this and provide a clearer pattern, this review focuses on the individual or person-specific characteristics of target audiences. The results indicate that by answering the following four questions about a target audience, one can predict whether a gain-framed or a loss-based health message will be more effective. 1) Is there a low (versus high) level of involvement in the issue? 2) Is there a high (versus low) certainty of the outcome? 3) Is there a low (versus high) preference for risk? 4) Is there a heuristic (versus piecemeal) processing style? The profiling of audiences on these factors has two distinct benefits; it resolves many of the seeming inconsistencies in past positive-negative and gain-loss message research (such as fear appeals working better with experts than nonexperts) and it helps predict which type of message will be most effective with a given audience. PMID- 26024054 TI - Impact of oxidative stress during pregnancy on fetal epigenetic patterns and early origin of vascular diseases. AB - Epidemiological studies have led scientists to postulate the developmental origins of health and disease hypothesis for noncommunicable diseases such as diabetes, cardiovascular diseases, hypertension, and obesity. However, the cellular and molecular mechanisms involved in the development of these diseases are not well understood. In various animal models, it has been observed that oxidative stress during pregnancy is associated with the early development of endothelial dysfunction in offspring. This phenomenon suggests that endothelial dysfunction may initiate in the uterus and could lead to increased risk of cardiovascular disease later in life. Currently, it is known that many of the fetal adaptive responses to environmental factors are mediated by epigenetic changes in the genome, especially by the degree of methylation in cytosines in the promoter regions of genes. These findings suggest that the establishment of a particular epigenetic pattern in the genome may be generated by oxidative stress. PMID- 26024055 TI - Possible deleterious hormonal changes associated with low-sodium diets. AB - The average salt intake of people in Canada, the United States, and Europe is about 3,400 mg of sodium per day, which exceeds the recommended intake levels set by various health organizations. The World Health Organization recommends a worldwide reduction of sodium intake to less than 2,000 mg per day. Most research to date has focused on the negative effects of high-sodium intake; however, little information is available on the metabolic effects of low-sodium intakes. This review focuses on the hormonal changes associated with low-sodium diets, especially the hormones involved in metabolism and cardiovascular and renal function. Based largely on rodent studies, low-sodium diets have been associated with changes in glycemic control, energy metabolism, cardiovascular disease risk, cholesterol concentrations, inflammation, and functioning of the renin angiotensin-aldosterone system. Overall, research has revealed mixed results regarding the impact of dietary sodium intake on various hormones. Further research is required to assess the effects of sodium reduction on hormones and their associated pathways in order to determine the likelihood of any unintended effects. PMID- 26024056 TI - Protective role of dairy and its constituents on vascular function independent of blood pressure-lowering activities. AB - Greater intakes of dairy are frequently associated with reduced risk of cardiovascular disease. These observational studies have served as the basis for controlled interventions aimed at defining the cardioprotective mechanisms of dairy. Understanding these relationships is of public health importance because most of the US population fails to meet dietary recommendations for dairy, suggesting that many individuals could lower their cardiovascular disease risk by relatively simple dietary modification. Clinical studies investigating the acute ingestion of dairy or its constituents, including short-term (<=2 week) supplementation studies or those assessing postprandial responses, have largely shown benefits on vascular function without concomitant improvements in blood pressure. Chronic interventions have been less conclusive, with some showing benefits and others indicating a lack of improvement in vascular function regardless of blood pressure changes. Vasoprotective activities of dairy are likely mediated through improvements in nitric oxide bioavailability, oxidative stress, inflammation, and insulin resistance. Future controlled studies are needed to determine if these health benefits are mediated directly by dairy or indirectly by displacing other dietary components that otherwise impair vascular health. PMID- 26024057 TI - Quantifying the vitamin D economy. AB - Vitamin D enters the body through multiple routes and in a variety of chemical forms. Utilization varies with input, demand, and genetics. Vitamin D and its metabolites are carried in the blood on a Gc protein that has three principal alleles with differing binding affinities and ethnic prevalences. Three major metabolites are produced, which act via two routes, endocrine and autocrine/paracrine, and in two compartments, extracellular and intracellular. Metabolic consumption is influenced by physiological controls, noxious stimuli, and tissue demand. When administered as a supplement, varying dosing schedules produce major differences in serum metabolite profiles. To understand vitamin D's role in human physiology, it is necessary both to identify the foregoing entities, mechanisms, and pathways and, specifically, to quantify them. This review was performed to delineate the principal entities and transitions involved in the vitamin D economy, summarize the status of present knowledge of the applicable rates and masses, draw inferences about functions that are implicit in these quantifications, and point out implications for the determination of adequacy. PMID- 26024061 TI - An Industrial Hygienist Looks at Porn. PMID- 26024062 TI - Digital Breast Tomosynthesis in the Diagnostic Setting: Indications and Clinical Applications. AB - Digital breast tomosynthesis (DBT) is an emerging technology used in diagnostic breast imaging to evaluate potential abnormalities. In DBT, the compressed breast tissue is imaged in a quasi-three-dimensional manner by performing a series of low-dose radiographic exposures and using the resultant projection image dataset to reconstruct cross-sectional in-plane images in standard mammographic views. Improved visualization of breast detail at diagnostic DBT allows improved characterization of findings, including normal structures and breast cancer. This technology reduces the summation of overlapping breast tissue, which can mimic breast cancer, and provides improved detail of noncalcified mammographic findings seen in breast cancer. It also assists in lesion localization and determining mammographic extent of disease in women with known or suspected breast cancer. The authors review the potential uses, benefits, and limitations of DBT in the diagnostic setting and discuss how radiologists can best use DBT to characterize lesions, localize potential abnormalities, and evaluate the extent of known or suspected breast cancer. The authors' experience shows that DBT can be implemented effectively in the diagnostic workflow to evaluate and localize potential lesions more efficiently. DBT may potentially replace conventional supplemental mammography at diagnostic workup and obviate ultrasonography in select cases. PMID- 26024063 TI - Bronchiectasis: Mechanisms and Imaging Clues of Associated Common and Uncommon Diseases. AB - Bronchiectasis is permanent irreversible dilatation of the airways and occurs in a variety of pathologic processes. Recurrent infection and inflammation and the resulting chemical and cellular cascade lead to permanent architectural changes in the airways. Bronchiectasis can confer substantial potential morbidity, usually secondary to recurrent infection. In severe cases of bronchiectasis, massive hemoptysis can lead to death. Thin-section computed tomography is the most sensitive imaging modality for the detection of bronchiectasis; findings include bronchial diameter exceeding that of the adjacent pulmonary artery and lack of normal tapering of terminal bronchioles as they course toward the lung periphery. The authors will review various causes of bronchiectasis, including common causes, such as recurrent infection or aspiration, and uncommon causes, such as congenital immunodeficiencies and disorders of cartilage development. The authors will also present an approach emphasizing the distribution (apical versus basal and central versus peripheral) and concomitant findings, such as nodules, cavities, and/or lymphadenopathy, that can assist in narrowing the differential diagnosis. Although an adequate understanding of these underlying causes in conjunction with their specific imaging appearances will allow radiologists to more confidently determine the process causing this common radiologic finding, clinical history and patient demographic characteristics play an integral role in determining a pertinent and concise differential diagnosis. PMID- 26024064 TI - Influence of 4'-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin. AB - A series of 20 4'-O-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the d-pentopyranosides than for the l pentopyranosides and d-hexopyranosides. In particular, 4'-O-beta-d-xylopyranosyl paromomycin shows antibacterioribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome associated with hypersusceptibility to drug-induced ototoxicity. Compound antibacterioribosomal activity correlates with antibacterial activity, and the ribosomally more active compounds show activity against Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). The paromomycin glycosides retain activity against clinical strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4'-O-glycosylation blocking the action of 4'-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant. PMID- 26024065 TI - Epidemiology of Sepsis and Its Recognition by Emergency Medical Services Personnel in the Netherlands. AB - Little is known about the epidemiology of sepsis in the Netherlands. In addition, information regarding the ability of emergency medical services (EMS) personnel to recognize sepsis is lacking. The aim of this study is to determine epidemiological characteristics of sepsis and the recognition of sepsis by EMS personnel in an urban area in the Netherlands. We conducted a retrospective cohort study using transport information from EMS Amsterdam and admission diagnoses at the emergency department gathered through discharge data from two academic hospitals in Amsterdam for the year 2012. A total of 253 patients with sepsis were evaluated, of which 131 were transported by ambulance. The in hospital mortality rate of the total population was 21% and a mean length of hospital stay was of 13.5 days. Sixty-seven patients (26.5%) were admitted to the intensive care unit. Almost half of the patients were assigned to the internal medicine ward (117; 46.2%). The most common site of infection was the urinary tract (30%). E. coli was the most frequent cause of infections. EMS staff recognized 18/131 (13.7%) transported patients with (severe) sepsis or septic shock. In 52 cases (39.7%) sepsis went unrecognized, probably due to an incomplete primary survey. In 60 cases (45.8%) sepsis went unrecognized, although enough systemic inflammatory response syndrome criteria were present at initial presentation. Recognition of sepsis by EMS staff in the Netherlands is low, probably due to a lack of awareness of the syndrome and infrequent measurement of temperature and respiratory rate. As early initiation of treatment is crucial, the EMS staff, general practitioners, and other specialties could benefit from more education on this critical illness. PMID- 26024066 TI - Enhanced Performance of Polyurethane Hybrid Membranes for CO2 Separation by Incorporating Graphene Oxide: The Relationship between Membrane Performance and Morphology of Graphene Oxide. AB - Polyurethane hybrid membranes containing graphene oxide (GO) with different morphologies were prepared by in situ polymerization. The separation of CO2/N2 gas mixtures was studied using these novel membranes. The results from the morphology characterization of GO samples indicated that the oxidation process in the improved Hummers method introduced oxygenated functional groups into graphite, making graphite powder exfoliate into GO nanosheets. The surface defects on the GO sheets increased when oxidation increased due to the introduction of more oxygenated functional groups. Both the increase in oxygenated functional groups on the GO surface and the decrease in the number of GO layers leads to a better distribution of GO in the polymer matrix, increasing thermal stability and gas separation performance of membranes. The addition of excess oxidant destroyed the structure of GO sheets and forms structural defects, which depressed the separation performance of membranes. The hybrid membranes containing well-distributed GO showed higher permeability and permeability selectivity for the CO2. The formation of GO aggregates in the hybrid membranes depressed the membrane performance at a high content of GO. PMID- 26024067 TI - Rapid Slow Off-Rate Modified Aptamer (SOMAmer)-Based Detection of C-Reactive Protein Using Isotachophoresis and an Ionic Spacer. AB - We present an on-chip electrophoretic assay for rapid protein detection with a SOMAmer (Slow Off-Rate Modified Aptamer) reagent. We used isotachophoresis (ITP) coupled with an ionic spacer to both react and separate SOMAmer-protein complex from free SOMAmer reagent. ITP accelerates the reaction kinetics as the ionic spacer concurrently separates the reaction products. We developed a numerical and analytical model to describe ITP spacer assays, which involve low-mobility, nonfocusing targets that are recruited into the ITP zone by higher-mobility, ITP focused probes. We demonstrated a proof-of-concept of this assay using C-reactive protein (CRP) in buffer, and achieved a 2 nM limit of detection (LOD) with a combined 20 min assay time (10 min off-chip preparation of reagents and 10 min on chip run). Our findings suggest that this approach has potential as a simple and rapid alternative to other homogeneous immunoassays. We also explore the extension of this assay to a diluted serum sample spiked with CRP, where we observe decreased sensitivity (an LOD of 25 nM in 20-fold diluted serum). We describe the challenges in extending this assay to complex samples and achieving higher sensitivity and specificity for clinical applications. PMID- 26024068 TI - Colloidal 2D-0D Lateral Nanoheterostructures: A Case Study of Site-Selective Growth of CdS Nanodots onto Bi2Se3 Nanosheets. AB - Two-dimensional (2D) nanoheterostructure (2D NHS) with nanoparticles grown on 2D nanomaterial substrates could potentially enable many novel functionalities. Controlled site-selective growth of nanoparticles on either the lateral or the basal directions of 2D nanomaterial substrates is desirable but extremely challenging. Herein, we demonstrate the rational control of lateral- and basal selective attachment of CdS nanoparticles onto 2D Bi2Se3 nanosheets through solution phase reactions. The combination of experimental and theoretical efforts elucidate that site-relevant interfacial bonding and kinetic control of molecular precursors play vital roles for site selectivity. Furthermore, the electronic structures revealed from density functional theory calculations explain the superior performance of the lateral 2D NHSs compared to their basal counterpart in prototype photoelectrochemical cells. The present study will inspire the construction of other site-selective 2D NHSs with well-defined structure and unique properties. PMID- 26024070 TI - Retinal oxygen saturation in retinitis pigmentosa and macular dystrophies in asian-Indian eyes. AB - PURPOSE: To study the oxygen-saturation profiles in RP and macular dystrophies and compare them with age-matched healthy controls. METHODS: In a cross-sectional prospective study, 62 subjects with RP, 23 with macular dystrophies, and 78 controls were enrolled, and retinal oximetry was performed with the Oxymap T1 retinal oximeter. The images were analyzed for oxygen saturation and diameter of retinal vessels. RESULTS: All parameters showed a significant difference among the three groups. Patients with RP showed significantly lower diameters (98.4 MUm and 136.9 MUm arteriolar and venous) (P < 0.001), higher saturations (102.3% and 59.1%) (P < 0.001; 0.06), and higher arterio-venous saturation difference (AVSD) (43%) (P < 0.001) compared with the other two groups. Macular dystrophies showed higher global arteriolar values (96.7%) and AVSD (41.6%) but comparable venous values (54.9%) to the control group (90.6%, 57.4%, and 33.3%). CONCLUSIONS: Oximetry is sensitive in quantifying hemodynamic changes in retinal dystrophies. It is still unclear whether these hemodynamic changes are a cause or a result of the disease process. PMID- 26024069 TI - Effect of internal limiting membrane abrasion on retinal tissues in macular holes. AB - PURPOSE: The purpose of this study was to identify the structural and histological effects of a Tano diamond-dusted membrane scraper (DDMS) on the retinal surface after internal limiting membrane (ILM) abrasion in macular hole surgery. METHODS: Institutional experimental study was performed in 11 eyes. All eyes underwent ILM abrasion in the operating room with a DDMS for macular hole repair as an alternative to traditional ILM peeling. Three human donor eyes underwent an identical procedure in the laboratory. Retinal tissues were removed by ILM abrasion with a DDMS during vitrectomy for macular hole repair and retinal tissues remaining in human donor eyes. Main outcome measures were microscopic and immunohistological characteristics of instrument tip tissues and retinal structure after ILM abrasion. RESULTS: The tips of the Tano DDMS showed evidence of cellular membranes and ILM removal. The retinas showed distinct areas of lamellar ILM removal without penetration of the retinal nerve fiber layer (RNFL). CONCLUSIONS: Application of the Tano DDMS instrument is sufficient to remove membranes from the surface of the ILM and layers of the ILM without disruption of the underlying RNFL. Internal limiting membrane abrasion can be a useful and effective alternative to complete ILM removal for macular surgery. PMID- 26024071 TI - Regional assessment of energy-producing metabolic activity in the endothelium of donor corneas. AB - PURPOSE: We characterized mitochondrial respiration and glycolysis activity of human corneal endothelium, and compared metabolic activity between central and peripheral regions. METHODS: Endothelial keratoplasty-suitable corneas were obtained from donors aged 50 to 75 years. The endothelium-Descemet membrane complex (EDM) was isolated, and 3-mm punches were obtained from central and peripheral regions. Endothelium-Descemet membrane punches were assayed for mitochondrial respiration (oxygen consumption) and glycolysis (extracellular acidification) using an extracellular flux analyzer. Enzymatic (citrate synthase, glucose hexokinase) and mitochondrial density (MitoTracker) assays also were performed. RESULTS: Ten corneas were analyzed per assay. Metabolic activity for mitochondrial respiration and glycolysis showed expected changes to assay compounds (P < 0.01, all pairwise comparisons). Basal mitochondrial respiration and glycolysis activity did not differ between regions (P > 0.99). Similarly, central versus peripheral activity after assay compound treatment showed no significant differences (P > 0.99, all time points). The intracorneal coefficient of variation for basal readings between two and four peripheral punches was 18.5% of the mean. Although peripheral samples displayed greater enzymatic activity than central samples (P < 0.05), similar to extracellular flux results, mitochondrial density did not differ between regions (P = 0.78). CONCLUSIONS: Extracellular flux analysis of oxygen and pH is a valid technique for characterizing metabolic activity of human corneal endothelium. This technique demonstrates high reproducibility, allows quantification of metabolic parameters using small quantities of live cells, and permits estimation of overall metabolic output. Neither oxygen consumption nor extracellular acidification differed between central and peripheral regions of transplant suitable corneas in this series. Our results show that endothelial cell health can be quantified biochemically in transplant suitable corneas. PMID- 26024072 TI - Cross-coupled eye movement supports neural origin of pattern strabismus. AB - PURPOSE: Pattern strabismus describes vertically incomitant horizontal strabismus. Conventional theories emphasized the role of orbital etiologies, such as abnormal fundus torsion and misaligned orbital pulleys as a cause of the pattern strabismus. Experiments in animal models, however, suggested the role of abnormal cross-connections between the neural circuits. We quantitatively assessed eye movements in patients with pattern strabismus with a goal to delineate the role of neural circuits versus orbital etiologies. METHODS: We measured saccadic eye movements with high-precision video-oculography in 14 subjects with pattern strabismus, 5 with comitant strabismus, and 15 healthy controls. We assessed change in eye position in the direction orthogonal to that of the desired eye movement (cross-coupled responses). We used fundus photography to quantify the fundus torsion. RESULTS: We found cross-coupling of saccades in all patients with pattern strabismus. The cross-coupled responses were in the same direction in both eyes, but larger in the nonviewing eye. All patients had clinically apparent inferior oblique overaction with abnormal excylotorsion. There was no correlation between the amount of the fundus torsion or the grade of oblique overaction and the severity of cross-coupling. The disconjugacy in the saccade direction and amplitude in pattern strabismics did not have characteristics predicted by clinically apparent inferior oblique overaction. CONCLUSIONS: Our results validated primate models of pattern strabismus in human patients. We found no correlation between ocular torsion or oblique overaction and cross-coupling. Therefore, we could not ascribe cross-coupling exclusively to the orbital etiology. Patients with pattern strabismus could have abnormalities in the saccade generators. PMID- 26024073 TI - The impact of conjunctivochalasis on dry eye symptoms and signs. AB - PURPOSE: The purpose of this project was to study the relationship between conjunctivochalasis (Cch) and ocular signs and symptoms of dry eye. METHODS: Ninety-six patients with normal eyelid and corneal anatomy were prospectively recruited from a Veterans Administration hospital over 12 months. Symptoms (via the dry eye questionnaire 5 [DEQ5]) and signs of dry eye were assessed along with quality of life implications. Statistical analyses comparing the above metrics among the three groups included chi(2), analysis of variance, and linear regression tests. RESULTS: Participants were classified into three groups: nasal conjunctivochalasis (NCch; n = 31); nonnasal conjunctivochalasis (non-NCch; n = 41); and no conjunctivochalasis (no-Cch; n = 24). Patients with NCch had more dry eye symptoms than those with non-NCch (DEQ5: NCch = 13.8 +/- 5.0, non-NCch = 10.2 +/- 5.0, no-Cch = 11.6 +/- 5.8; P = 0.014), and more ocular pain than those with Non-NCch and no-Cch (numerical rating scale [NRS]: NCch = 4.5 +/- 3.0, non-NCch = 2.3 +/- 2.8, no-Cch = 3.3 +/- 2.6; P = 0.008). They also had worse dry eye signs compared to those with no-Cch measured by Schirmer score with anesthesia (NCch = 14.5 +/- 6.9, non-NCch = 16.8 +/- 8.2, no-Cch = 19.9 +/- 6.4; P = 0.039); meibomian gland dropout (NCch 1.8 +/- 0.9, non-NCch = 1.4 +/- 1.0, no-Cch = 1.0 +/- 1.0; P = 0.020); and eyelid vascularity (NCch = 0.84 +/- 0.8, non-NCch = 0.74 +/- 0.7, no-Cch = 0.33 +/- 0.6; P = 0.019). Moreover, those with NCch more frequently reported that dry eye symptoms moderately to severely impacted their quality of life (NCch = 87%, non-NCch = 51%, no-Cch = 58%; P = 0.005). CONCLUSIONS: The presence of NCch associates with dry eye symptoms, abnormal tear parameters, and impacts quality of life compared with non-NCch and no-Cch. Based on these data, it is important for clinicians to look for Cch in patients with symptoms of dry eye. PMID- 26024076 TI - Erratum. PMID- 26024074 TI - Progesterone treatment in two rat models of ocular ischemia. AB - PURPOSE: To determine whether the neurosteroid progesterone, shown to have protective effects in animal models of traumatic brain injury, stroke, and spinal cord injury, is also protective in ocular ischemia animal models. METHODS: Progesterone treatment was tested in two ocular ischemia models in rats: a rodent anterior ischemic optic neuropathy (rAION) model, which induces permanent monocular optic nerve stroke, and the middle cerebral artery occlusion (MCAO) model, which causes transient ischemia in both the retina and brain due to an intraluminal filament that blocks the ophthalmic and middle cerebral arteries. Visual function and retinal histology were assessed to determine whether progesterone attenuated retinal injury in these models. Additionally, behavioral testing and 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining in brains were used to compare progesterone's neuroprotective effects in both retina and brain using the MCAO model. RESULTS: Progesterone treatment showed no effect on visual evoked potential (VEP) reduction and retinal ganglion cell loss in the permanent rAION model. In the transient MCAO model, progesterone treatment reduced (1) electroretinogram (ERG) deficits, (2) MCAO-induced upregulation of glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), and (3) retinal ganglion cell loss. As expected, progesterone treatment also had significant protective effects in behavioral tests and a reduction in infarct size in the brain. CONCLUSIONS: Progesterone treatment showed protective effects in the retina following MCAO but not rAION injury, which may result from mechanistic differences with injury type and the therapeutic action of progesterone. PMID- 26024075 TI - Advanced glycation end-product accumulation reduces vitreous permeability. AB - PURPOSE: To evaluate the effect of nonenzymatic cross-linking (glycation) upon the permeability of the vitreous to small- and large-solute diffusion. METHODS: Vitreous from freshly excised porcine eyes was treated for 30 minutes with control or 0.01%, 0.1%, or 1% methylglyoxal (MG) solution. The efficacy of the glycation regimen was verified by measuring nonenzymatic cross-link density by fluorescence in the vitreous samples. Resistance to collagenase digestion as well as N(epsilon)-(carboxyethyl) lysine (CEL) content were also measured. The permeability coefficient for fluorescein and fluorescein isothiocyanate (FITC) IgG diffusion through 3 mL of the vitreous samples was determined by using a custom permeability tester. RESULTS: Vitreous cross-linking with MG treatment was confirmed by increased fluorescence, increased CEL concentration, and increased resistance to collagenase digestion. Vitreous glycation resulted in a statistically significant decrease in the permeability coefficient for fluorescein diffusion when either 0.1% or 1% MG solution was used (5.36 +/- 5.24 * 10(-5) cm s(-1), P = 0.04; and 4.03 +/- 2.1 * 10(-5) cm s(-1), P = 0.001; respectively, compared with control, 9.77 +/- 5.45 * 10(-5) cm s(-1)). The permeability coefficient for diffusion of FITC-IgG between control (9.9 +/- 6.37 * 10(-5) cm s(-1)) and treatment groups was statistically significant at all MG concentrations (0.01% MG: 3.95 +/- 3.44 * 10(-5) cm s(-1), P = 0.003; 0.1% MG: 4.27 +/- 1.32 * 10(-5) cm s(-1), P = 0.004; and 0.1% MG: 3.72 +/- 2.49 * 10(-5) cm s(-1), P = 0.001). CONCLUSIONS: Advanced glycation end-product (AGE) accumulation reduces vitreous permeability when glycation is performed in ex vivo porcine vitreous. The permeability change was more pronounced for the larger solute, suggesting a lower threshold for AGE-induced permeability changes to impact the movement of proteins through the vitreous when compared with smaller molecules. PMID- 26024077 TI - The Changing Profile of Astigmatism in Childhood: The NICER Study. AB - PURPOSE: We performed a prospective study of the changing profile of astigmatism in white school children in Northern Ireland. METHODS: Of the 399 6- to 7-year old and 669 12- to 13-year-old participants in Phase 1 of the Northern Ireland Childhood Errors of Refraction (NICER) study, 302 (76%) of the younger and 436 (65%) of the older cohort were re-examined three years later (Phase 2). Stratified random cluster sampling was used. Following cycloplegia (cyclopentolate HCl 1%) refractive error was recorded by the Shin-Nippon-SRW-5000 autorefractor. Astigmatism is defined as >= 1.00 diopters cylinder (DC). Right eye data only are presented. RESULTS: The prevalence of astigmatism was unchanged in both cohorts: younger cohort 17.1% (95% confidence intervals [CIs], 13.3-21.6) were astigmatic at 9 to 10 years compared to 22.9% (95% CIs, 18.3-28.2) at 6 to 7 years; older cohort, 17.5% (95% CIs, 13.9-21.7) of participants were astigmatic at 15-16 years compared to 18.4% (95% CIs, 13.4-24.8) at age 12 to 13 years. Although prevalence remained unchanged, it was not necessarily the same children who had astigmatism at both phases. Some lost astigmatism (10.0%; CIs, 7.5-13.3 younger cohort and 17.4%; CIs, 13.5-22.2 older cohort); others became astigmatic (9.1%; CIs, 6.7-12.2 younger cohort and 11.6%; CIs, 8.4-15.8 older cohort). CONCLUSIONS: This study presents novel data demonstrating that the astigmatic error of white children does not remain stable throughout childhood. Although prevalence of astigmatism is unchanged between ages 6 and 7 to 15 to 16 years; during this time period individual children are developing astigmatism while other children become nonastigmatic. It is difficult to predict from their refractive data who will demonstrate these changes, highlighting the importance of all children having regular eye examinations to ensure that their visual requirements are met. PMID- 26024078 TI - Experimental protocols for ex vivo lens stretching tests to investigate the biomechanics of the human accommodation apparatus. AB - PURPOSE: To explore alternative experimental protocols to investigate the biomechanical behavior of the crystalline lens and zonules using ex vivo stretching. METHODS: Radial stretching tests were conducted on the anterior segment (consisting of lens, zonules, ciliary body, and sclera) of four pairs of presbyopic human donor eyes. A simple mechanical model is used to describe the behavior of the anterior segment when tested in this way. Each pair of samples was initially stretched with the ciliary body intact. One sample was retested after cutting the ciliary body radially, and the other sample was retested after removing the lens. RESULTS: The external forces needed to stretch the sample with the ciliary body intact were significantly greater than for the tests in which the ciliary body had been cut. The forces measured with the ciliary body intact and lens in situ were comparable to the sum of the forces measured in the tests in which the ciliary body had been cut (lens in situ) and the forces measured in the tests on the intact ciliary body with the lens removed. CONCLUSIONS: When stretching tests are conducted on the anterior segment, significant circumferential tensions develop in the ciliary body. This means that the forces applied to the lens and zonules cannot be related directly to the forces applied by the external loading system. If radial cuts are introduced in the ciliary body prior to testing, however, then this difficulty does not arise. PMID- 26024079 TI - Laminin-511 and -521 enable efficient in vitro expansion of human corneal endothelial cells. AB - PURPOSE: The purpose of this study was to investigate the usefulness of laminin isoforms as substrates for culturing human corneal endothelial cells (HCECs) for clinical application of tissue engineering therapy. METHODS: Expression of specific laminin chains in human corneal endothelium and Descemet's membrane was analyzed at the mRNA and protein levels. The effect of laminin-511 and -521 on cell adhesion and proliferation was evaluated. Recombinant laminin E8 fragments (E8s), which represent functionally minimal forms of laminins, were also evaluated for their effects on cell density and cellular phenotype. The potential involvement of alpha3beta1 and alpha6beta1 integrins in laminin signal transduction was also investigated using neutralizing antibodies. RESULTS: Laminin-511 and -521 were expressed in Descemet's membrane and corneal endothelium. These laminin isoforms significantly enhanced the in vitro adhesion and proliferation, and differentiation of HCECs. A cell density of 2200 to 2400 cells/mm2 was achieved when HCECs were cultured on laminin-511 or -521, whereas the density was only 1100 cells/mm2 on an uncoated control. E8s also supported HCEC cultivation with a similar efficacy to that obtained with full-length laminin. Functional blocking of alpha3beta1 and alpha6beta1 integrins suppressed the adhesion of HCECs even in the presence of laminin-511. CONCLUSIONS: Laminin 511 and -521 were the laminin isoforms present in Descemet's membrane, and these laminins modulate the adhesion and proliferation of CECs. Laminin E8s represent an ideal xeno-free defined substrate for the culture of CECs for clinical applications. PMID- 26024080 TI - Diurnal Intraocular Pressure and the Relationship With Swept-Source OCT-Derived Anterior Chamber Dimensions in Angle Closure: The IMPACT Study. AB - PURPOSE: To evaluate diurnal intraocular pressure (DIOP) among individuals with primary angle closure (PAC) or primary angle-closure suspect (PACS). Additionally, the hypothesis that greater DIOP fluctuation is related to smaller angle parameters was investigated. METHODS: Forty Caucasian newly referred untreated patients with bilateral PAC or PACS were recruited. Intraocular pressure (IOP) was measured hourly between 9 AM and 4 PM with Goldmann applanation tonometry. Diurnal IOP fluctuation was defined as difference between maximum and minimum IOP. Angle opening distance (AOD), trabecular-iris angle (TIA), angle recess area (ARA), and trabecular-iris space area (TISA) were measured with anterior segment optical coherence tomography (AS-OCT) in dark (0.3 0.5 lux) and light (170-200 lux) on the same day as DIOP measurements in eight angle sections. RESULTS: Intraocular pressure declined as the day progressed (P < 0.001), unrelated to presence of peripheral anterior synechiae (PAS). At each time point, eyes with PAS (n = 31) had significantly higher IOPs than eyes without PAS (n = 49; P = 0.043). Diurnal IOP fluctuation varied from 1.50 to 14.50 mm Hg (mean 5.99 mm Hg, SD 2.70 mm Hg). Diurnal IOP fluctuation was unrelated to PAS. Multiple-predictor models investigating association of angle dimensions and greater DIOP fluctuation were statistically significant for AOD 750 (light), ARA 750 (light and dark), TISA 500 (light), TISA 750 (light), TIA 500 (light), and TIA 750 (light and dark). CONCLUSIONS: Diurnal IOP variation has clinical implications given that IOP level is used to distinguish between diagnostic categories of PACS and PAC. Optical coherence tomography angle parameter measurements may predict for magnitude of IOP diurnal fluctuations in at-risk patients, which may be clinically useful when a clinical intervention is being considered. PMID- 26024081 TI - What you see is what you step: the horizontal-vertical illusion increases toe clearance in older adults during stair ascent. AB - PURPOSE: Falls on stairs are a significant cause of morbidity and mortality in elderly people. A simple safety strategy to avoid tripping on stairs is increasing foot clearance. We determined whether a horizontal-vertical illusion superimposed onto stairs to create an illusory perceived increase in stair-riser height would increase stair ascent foot clearance in older participants. METHODS: Preliminary experiments determined the optimum parameters for the horizontal vertical illusion. Fourteen older adults (mean age +/- 1 SD, 68.5 +/- 7.4 years) ascended a three-step staircase with the optimized version of the horizontal vertical illusion (spatial frequency: 12 cycles per stair riser) positioned either on the bottom or top stair only, or on the bottom and top stair simultaneously. These were compared to a control condition, which had a plain stair riser with edge highlighters positioned flush with each stair-tread edge. Foot clearance and measures of postural stability were compared across conditions. RESULTS: The optimized illusion on the bottom and top stair led to a significant increase in foot clearance over the respective stair edge, compared to the control condition. There were no significant decreases in postural stability. CONCLUSIONS: An optimized horizontal-vertical visual illusion led to significant increases in foot clearance in older adults when ascending a staircase, but the effects did not destabilize their postural stability. Inclusion of the horizontal-vertical illusion on raised surfaces (e.g., curbs) or the bottom and top stairs of staircases could improve stair ascent safety in older adults. PMID- 26024082 TI - Effect of topical anesthesia on episcleral venous pressure in normal human subjects. AB - PURPOSE: Topical anesthetics can reduce episcleral venous pressure (EVP) and IOP in rabbits. In this study, we investigated the effect of topical anesthesia on EVP in normal human subjects. METHODS: We included in this study 30 eyes of 15 healthy volunteers who were habitual soft contact lens wearers. The EVP was measured before and at 5 and 10 minutes after instillation of topical proparacaine 0.5% in one eye. The EVP was measured by using a custom objective venomanometer. We compared EVP at 5 and 10 minutes after proparacaine to EVP before instilling proparacaine. RESULTS: There was no significant difference between EVP in eyes receiving topical anesthetic at 5 or 10 minutes (7.2 +/- 2.2 and 7.6 +/- 2.7 mm Hg, respectively; mean +/- SD) compared to contralateral eyes (6.9 +/- 2.5 and 7.3 +/- 2.6 mm Hg, respectively; P > 0.10). As well, EVP was not significantly different 5 or 10 minutes after topical anesthesia compared to baseline in either the eyes receiving anesthetic or the contralateral eyes (all P > 0.10; minimum detectable difference, 1.4-1.9 mm Hg, alpha = 0.05, beta = 0.20, n = 30 eyes). CONCLUSIONS: The EVP in human eyes is not affected significantly by topical anesthetics. PMID- 26024083 TI - Negligible impact on posture from 5-diopter vertical yoked prisms. AB - PURPOSE: Yoked prisms are used by some optometrists to adjust posture, but evidence to support this practice is sparse and low level. The aim of this research was to investigate whether vertical yoked prisms have an impact on posture in healthy adults. METHODS: Posture was assessed objectively in 20 healthy adults, by recording a range of joint angles or body segment locations at the ankle, hip, torso, neck, and head during participant observation of a straight-ahead target, and subsequently with eyes closed. Recording occurred before, during, and after wearing goggles with control plano lenses, and 5 diopter (D) base-up and 5-D base-down yoked prisms. In each viewing condition, the goggles were worn for 30 minutes. Interaction effects of lens/prism condition by time on joint angles and body orientation were determined. RESULTS: In the eyes-open and eyes-closed conditions, no significant lens/prism * time interaction effects were found at the torso, neck, hip, or ankle (P > 0.1). However, in both eyes-open and eyes-closed conditions a significant lens/prism * time interaction was found at the head (P = 0.031 and 0.006, respectively), with head extended (tilted backward) by up to 2.5 degrees more while viewing with base down prisms than with plano lenses. CONCLUSIONS: In healthy adults, 5-D base-down yoked prisms were not associated with a change in body posture. A small effect on head orientation and not at other locations suggests a minimal effect on posture. Research in a larger sample and in individuals with abnormal posture is needed to verify this. PMID- 26024084 TI - Lipotoxicity augments glucotoxicity-induced mitochondrial damage in the development of diabetic retinopathy. AB - PURPOSE: Although hyperglycemia is the main instigator in the development of diabetic retinopathy, dyslipidemia is also considered to play an important role. In the pathogenesis of diabetic retinopathy, cytosolic NADPH oxidase 2 (Nox2) is activated before retinal mitochondria are damaged. Our aim was to investigate the effect of lipids in the development of diabetic retinopathy. METHODS: Reactive oxygen species (ROS, by 2',7'-dichlorofluorescein diacetate) and activities of Nox2 (by a lucigenin-based method) and Rac1 (by G-LISA) were quantified in retinal endothelial cells incubated with 50 MUM palmitate in 5 mM glucose (lipotoxicity) or 20 mM glucose (glucolipotoxicity) for 6 to 96 hours. Mitochondrial DNA (mtDNA) damage was evaluated by extended-length PCR and its transcription by quantifying cytochrome b transcripts. RESULTS: Within 6 hours of exposure of endothelial cells to lipotoxicity, or glucotoxicity (20 mM glucose, without palmitate), significant increase in ROS, Nox2, and Rac1 was observed, which was exacerbated by glucolipotoxic insult. At 48 hours, neither lipotoxicity nor glucotoxicity had any effect on mtDNA and its transcription, but glucolipotoxicity significantly damaged mtDNA and decreased cytochrome b transcripts, and at 96 hours, glucotoxicity and glucolipotoxicity produced similar detrimental effects on mitochondrial damage. CONCLUSIONS: Although during initial exposure, lipotoxic or glucotoxic insult produces similar increase in ROS, addition of lipotoxicity in a glucotoxic environment further exacerbates ROS production, and also accelerates their damaging effects on mitochondrial homeostasis. Thus, modulation of Nox2 by pharmacological agents in prediabetic patients with dyslipidemia could retard the development of retinopathy before their hyperglycemia is observable. PMID- 26024087 TI - Changes in retinochoroidal thickness after vitrectomy for proliferative diabetic retinopathy. AB - PURPOSE: To evaluate the changes in the peripheral retinochoroidal thickness after pars plana vitrectomy (PPV) with scatter photocoagulation for proliferative diabetic retinopathy (PDR). METHODS: Small gauge PPV was performed on 22 eyes with PDR with scatter photocoagulation, and on 32 eyes with an epiretinal membrane (ERM) without photocoagulation as control. The peripheral retinochoroidal thickness was measured at 5 mm from the limbus in the four quadrants using anterior segment optical coherence tomography preoperatively, and 3 days and 1 and 2 weeks after the surgery. In eyes with a peripheral choroidal detachment, the retinochoroidal thickness and the height of choroidal detachment were measured separately. The total peripheral thickness was defined as the sum of retinochoroidal thickness and the height of choroidal detachment. RESULTS: A significant larger number of eyes developed a choroidal detachment in the PDR group than in the ERM group 3 days after surgery (P < 0.001). The total peripheral choroidal thickness 3 days after surgery was significantly thicker than that before surgery in the PDR group (P = 0.009). The increase in the total peripheral thickness in the PDR group was significantly greater than that in the ERM group at 3 days after surgery (P = 0.007). The number of photocoagulation burns was significantly and positively correlated with the total peripheral thickness (r = 0.57, P = 0.006). CONCLUSIONS: We conclude that the transient thickening of the total peripheral thickness in early postoperative stage for PDR was due to the intraoperative scatter photocoagulation. PMID- 26024085 TI - Aqueous humor outflow: dynamics and disease. PMID- 26024086 TI - Loss of corneal epithelial heparan sulfate leads to corneal degeneration and impaired wound healing. AB - PURPOSE: Heparan sulfate (HS) is a highly modified glycosaminoglycan (GAG) bound to a core protein to form heparan sulfate proteoglycans (HSPGs) that are vital in many cellular processes ranging from development to adult physiology, as well as in disease, through interactions with various protein ligands. This study aimed to elucidate the role of HS in corneal epithelial homeostasis and wound healing. METHODS: An inducible quadruple transgenic mouse model was generated to excise Ext1 and Ndst1, which encode the critical HS chain elongation enzyme and N deacetylase/N-sulfotransferase, respectively, in keratin 14-positive cells upon doxycycline induction. RESULTS: EXT(Delta/DeltaCEpi) mice (deletion of Ext1 in corneal epithelium) induced at P20 presented progressive thinning of the corneal epithelium with a significant loss in the number of epithelial layers by P55. EXT(Delta/DeltaCEpi) mice presented tight junction disruption, loss of cell basement membrane adhesion complexes, and impaired wound healing. Interestingly, EXT(Delta/DeltaCEpi) and NDST(Delta/DeltaCEpi) mice presented an increase in cell proliferation, which was assayed by both Ki67 staining and 5-ethynyl-2' deoxyuridine (EdU) incorporation. Moreover, EXT(Delta/DeltaCEpi) mice presented compromised epithelial stratification 7 days after a debridement wound. The conditional knockout of HS from keratocytes using the keratocan promoter led to no corneal abnormalities or any disruption in wound healing. CONCLUSIONS: Corneal epithelial cells require HS for maintaining corneal homeostasis, and the loss of epithelial HS leads to both impaired wound healing and impaired corneal stratification. PMID- 26024088 TI - High-fat diet induces toll-like receptor 4-dependent macrophage/microglial cell activation and retinal impairment. AB - PURPOSE: The toll-like receptor 4 (TLR4) signaling pathway is involved in chronic inflammation and insulin resistance, which are associated with obesity and diabetes mellitus. In the present study, a model of high-fat diet (HFD) feeding of mice was used to investigate the role of TLR4 in overnutrition- and obesity associated inflammation and infiltration of macrophages and microglia in the retina. METHODS: Wild-type C57BL/6 and TLR4 knockout (TLR4KO; B6.B10ScN-Tlr4(lps del)/JthJ) mice were fed a HFD or control chow diet (CD) for 6 months. The TLR4 expression, the relative increase in macrophages/microglia (CD11b(+) and CD45(+) cells), the presence of markers of oxidative stress (gp91phox and malondialdehyde; MDA), and DNA damage (phosphorylated histone H2AX; gammaH2AX) were assessed by real-time PCR and immunofluorescence studies. RESULTS: The HFD for 6 months showed increased obesity, glucose intolerance, and insulin resistance in mice. Toll-like receptor 4 expression was found in vascular pericytes at the inner retina. Increased CD11b(+) and CD45(+) cells, phosphorylated NF-kappaB, interleukin-6, gp91phox, MDA, and gammaH2AX were observed in the retina of mice fed a HFD compared to CD counterparts. TLR4KO mice did not show the adverse effects of HFD. CONCLUSIONS: Our results indicate that HFD-induced macrophage/microglial cell activation and retinal impairment were reduced in the absence of TLR4. The findings suggest that TLR4 is implicated in the pathogenesis of retinal diseases caused by metabolic disorders. PMID- 26024089 TI - Quantum dot labeling and tracking of cultured limbal epithelial cell transplants in vitro. AB - PURPOSE: Cultured human limbal epithelial cells (HLECs) have shown promise in the treatment of limbal stem cell deficiency but little is known about their survival, behavior, and long-term fate after transplantation. The aim of this research was to evaluate, in vitro, quantum dot (Qdot) technology as a tool for tracking transplanted HLECs. METHODS: In vitro cultured HLECs were labeled with Qdot nanocrystals. Toxicity was assessed using live-dead assays. The effect on HLEC function was assessed using colony-forming efficiency assays and expression of CK3, P63alpha, and ABCG2. Sheets of cultured HLECs labeled with Qdot nanocrystals were transplanted onto decellularized human corneoscleral rims in an organ culture model and observed to investigate the behavior of transplanted cells. RESULTS: Quantum dot labeling had no detrimental effect on HLEC viability or function in vitro. Proliferation resulted in a gradual reduction in Qdot signal but sufficient signal was present to allow tracking of cells through multiple generations. Cells labeled with Qdots could be reliably detected and observed using confocal microscopy for at least 2 weeks after transplantation in our organ culture model. In addition, it was possible to label and observe epithelial cells in intact human corneas by using the Rostock corneal module adapted for use with the Heidelberg HRA. CONCLUSIONS: This work demonstrates that Qdots combined with existing clinical equipment could be used to track HLEC for up to 2 weeks after transplantation; however, our model does not permit the assessment of cell labeling beyond 2 weeks. Further characterization in in vivo models are required. PMID- 26024090 TI - Phakic iris-fixated intraocular lens placement in the anterior chamber: effects on aqueous flow. AB - PURPOSE: Phakic intraocular lenses (pIOLs) are used for correcting vision; in this paper we investigate the fluid dynamical effects of an iris-fixated lens in the anterior chamber. In particular, we focus on changes in the wall shear stress (WSS) on the cornea and iris, which could be responsible for endothelial and pigment cell loss, respectively, and also on the possible increase of the intraocular pressure, which is known to correlate with the incidence of secondary glaucoma. METHODS: We use a mathematical model to study fluid flow in the anterior chamber in the presence of a pIOL. The governing equations are solved numerically using the open source software OpenFOAM. We use an idealized standard geometry for the anterior chamber and a realistic geometric description of the pIOL. RESULTS: We consider separately the main mechanisms that produce fluid flow in the anterior chamber. The numerical simulations allow us to obtain a detailed description of the velocity and pressure distribution in the anterior chamber, and indicated that implantation of the pIOL significantly modifies the fluid dynamics in the anterior chamber. However, lens implantation has negligible influence on the intraocular pressure and does not produce a significant increase of the shear stress on the cornea, while the shear stress on the iris, although increased, is not enough to cause detachment of cells. CONCLUSIONS: We conclude that alterations in the fluid dynamics in the anterior chamber as a result of lens implantation are unlikely to be the cause of medical complications associated with its use. PMID- 26024092 TI - Implications of sustained elevation in extracellular ATP in retina following chronic ocular hypertension. PMID- 26024091 TI - Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye. AB - PURPOSE: The cellular mechanisms linking elevated IOP with glaucomatous damage remain unresolved. Mechanical strains and short-term increases in IOP can trigger ATP release from retinal neurons and astrocytes, but the response to chronic IOP elevation is unknown. As excess extracellular ATP can increase inflammation and damage neurons, we asked if sustained IOP elevation was associated with a sustained increase in extracellular ATP in the posterior eye. METHODS: No ideal animal model of chronic glaucoma exists, so three different models were used. Tg Myoc(Y437H) mice were examined at 40 weeks, while IOP was elevated in rats following injection of hypertonic saline into episcleral veins and in cynomolgus monkeys by laser photocoagulation of the trabecular meshwork. The ATP levels were measured using the luciferin-luciferase assay while levels of NTPDase1 were assessed using qPCR, immunoblots, and immunohistochemistry. RESULTS: The ATP levels were elevated in the vitreal humor of rats, mice, and primates after a sustained period of IOP elevation. The ecto-ATPase NTPDase1 was elevated in optic nerve head astrocytes exposed to extracellular ATP for an extended period. NTPDase1 was also elevated in the retinal tissue of rats, mice, and primates, and in the optic nerve of rats, with chronic elevation in IOP. CONCLUSIONS: A sustained elevation in extracellular ATP, and upregulation of NTPDase1, occurs in the posterior eye of rat, mouse, and primate models of chronic glaucoma. This suggests the elevation in extracellular ATP may be sustained in chronic glaucoma, and implies a role for altered purinergic signaling in the disease. PMID- 26024093 TI - Differential Radiosensitivity of Uveal Melanoma Cell Lines After X-rays or Carbon Ions Radiation. AB - PURPOSE: We compared the radiosensitivity of uveal melanoma (UM) cell lines after x-ray or carbon-ions radiation (C-ions). METHODS: We characterized the radiosensitivity toward x-rays and C-ions of UM cell lines: 92.1, MEL270, SP6.5, MKT-BR, MU2, and TP17. Normal choroidal melanocytes and the retinal pigment epithelial cell line ARPE19 were used as controls for normal cells. X-rays were delivered with an energy of 6 MV at a dose rate of 2 Gy/min. X-rays served as a reference for Relative Biological Effectiveness (RBE) evaluation. Radiation with C-ions was delivered at 75 MeV/u (34 keV/MUm) at a dose rate of 2 Gy/min. After single-doses (0-8 Gy) of medical x-rays (6 MV) or C-ions (33 keV/MUm), cells sensitivity was measured using standard colony formation assay, and cell growth was examined by counting the cell colonies. The effect of x-rays or C-ions on the expression and activation of ERK1/2 was evaluated by Western Blot. RESULTS: C ions presented with regard to the x-rays a RBE of 1.9 to 2.5 at 10% of UM cells survival. The x-ray sensitivity of UM cells was neither influenced by the synchronization of cells in phase G0/G1 of the cell cycle nor by the level of oxygenation. X-ray and C-ions radiation had the same effects on cell cycle leading to a mitotic catastrophe that appeared earlier after C-ions than x-ray treatment. However, C-ions radiation induced a sustained inhibition of ERK1/2 activation compared to the transitory induction of that signalization pathway after x-ray radiation. CONCLUSIONS: This in vitro study shows that C-ions had a better biological effectiveness than x-rays leading to a sustained inhibition of the ERK1/2 pathway. PMID- 26024094 TI - Longitudinal changes in choroidal thickness and eye growth in childhood. AB - PURPOSE: To examine longitudinal changes in choroidal thickness and axial length in a population of children with a range of refractive errors. METHODS: One hundred and one children (41 myopes and 60 nonmyopes) aged 10 to 15 years participated in this prospective, observational longitudinal study. For each child, 6-month measures of choroidal thickness (using enhanced depth imaging optical coherence tomography) and axial ocular biometry were collected four times over an 18-month period. Linear mixed-models were used to examine the longitudinal changes in choroidal thickness and the relationship between changes in choroidal thickness and axial eye growth over the study period. RESULTS: A significant group mean increase in subfoveal choroidal thickness was observed over 18 months (mean increase 13 +/- 22 MUm, P < 0.001). Myopic children exhibited significantly thinner choroids compared with nonmyopic children (P < 0.001), although there was no significant time by refractive group interaction (P = 0.46), indicating similar changes in choroidal thickness over time in myopes and nonmyopes. However, a significant association between the change in choroidal thickness and the change in axial length over time was found (P < 0.001, beta = 0.14). Children showing faster axial eye growth exhibited significantly less choroidal thickening over time compared with children showing slower axial eye growth. CONCLUSIONS: A significant increase in choroidal thickness occurs over an 18-month period in normal 10- to 15-year-old children. Children undergoing faster axial eye growth exhibited less thickening and, in some cases, a thinning of the choroid. These findings support a potential role for the choroid in the mechanisms regulating eye growth in childhood. PMID- 26024095 TI - Eye growth in term- and preterm-born eyes modeled from magnetic resonance images. AB - PURPOSE: We generated a model of eye growth and tested it against an eye known to develop abnormally, one with a history of retinopathy of prematurity (ROP). METHODS: We reviewed extant magnetic resonance images (MRIs) from term and preterm-born patients for suitable images (n = 129). We binned subjects for analysis based upon postmenstrual age at birth (in weeks) and ROP history ("Term" >= 37, "Premature" <= 32 with no ROP, "ROP" <= 32 with ROP). We measured the axial positions and curvatures of the cornea, anterior and posterior lens, and inner retinal surface. We fit anterior chamber depth (ACD), posterior segment depth (PSD), axial length (AL), and corneal and lenticular curvatures with logistic growth curves that we then evaluated for significant differences. We also measured the length of rays from the centroid to the surface of the eye at 5 degrees intervals, and described the length versus age relationship of each ray, L(ray)(x), using the same logistic growth curve. We determined the rate of ray elongation, E(ray)(x), from L(ray)dy/dx. Then, we estimated the scleral growth that accounted for E(ray)(x), G(x), at every age and position. RESULTS: Relative to Term, development of ACD, PSD, AL, and corneal and lenticular curvatures was delayed in ROP eyes, but not Premature eyes. In Term infants, G(x) was fast and predominantly equatorial; in age-matched ROP eyes, maximal G(x) was offset by approximately 90 degrees . CONCLUSIONS: We produced a model of normal eye growth in term-born subjects. Relative to normal, the ROP eye is characterized by delayed, abnormal growth. PMID- 26024096 TI - Genetic dissection of horizontal cell inhibitory signaling in mice in complete darkness in vivo. AB - PURPOSE: To test the hypothesis that horizontal cell (HC) inhibitory signaling controls the degree to which rod cell membranes are depolarized as measured by the extent to which L-type calcium channels (LTCCs) are open in complete darkness in the mouse retina in vivo. METHODS: Dark-adapted wild-type (wt), CACNA1F (Ca(v)1.4(-/-)), arrestin-1 (Arr1(-/-)), and CACNA1D (Ca(v)1.3(-/-)) C57Bl/6 mice were studied. Manganese-enhanced MRI (MEMRI) evaluated the extent that rod LTCCs are open as an index of loss of HC inhibitory signaling. Subgroups were pretreated with D-cis-diltiazem (DIL) at a dose that specifically antagonizes Ca(v)1.2 channels in vivo. RESULTS: Knockout mice predicted to have impaired HC inhibitory signaling (Ca(v)1.4(-/-) or Arr1(-/-)) exhibited greater than normal rod manganese uptake; inner retinal uptake was also supernormal. Genetically knocking out a closely associated gene not expected to impact HC inhibitory signaling (CACNA1D) did not generate this phenotype. The Arr1(-/-) mice exhibited the largest rod uptake of manganese. Manganese-enhanced MRI of DIL-treated Arr1( /-) mice suggested a greater number of operant LTCC subtypes (i.e., Ca(v)1.2, 1.3, and 1.4) in rods and inner retina than that in DIL-treated Ca(v)1.4(-/-) mice (i.e., Ca(v)1.3). The Ca(v)1.3(-/-) + DIL-treated mice exhibited evidence for a compensatory contribution from Ca(v)1.2 LTCCs. CONCLUSIONS: The data suggest that loss of HC inhibitory signaling is the proximate cause leading to maximally open LTCCs in rods, and possibly inner retinal cells, in mice in total darkness in vivo, regardless of compensatory changes in LTCC subtype manifested in the mutant mice. PMID- 26024097 TI - Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease. AB - PURPOSE: The contribution of lymphangiogenesis (LA) to allergy has received considerable attention and therapeutic inhibition of this process via targeting VEGF has been considered. Likewise, certain inflammatory settings affecting the ocular mucosa can trigger pathogenic LA in the naturally avascular cornea. Chronic inflammation in allergic eye disease (AED) impacts the conjunctiva and cornea, leading to sight threatening conditions. However, whether corneal LA is involved is completely unknown. We addressed this using a validated mouse model of AED. METHODS: Allergic eye disease was induced by ovalbumin (OVA) immunization and chronic OVA exposure. Confocal microscopy of LYVE-1-stained cornea allowed evaluation of corneal LA, and qRT-PCR was used to evaluate expression of VEGF-C, D, and -R3 in these mice. Administration of VEGF receptor (R) inhibitor was incorporated to inhibit corneal LA in AED. Immune responses were evaluated by in vitro OVA recall responses of T cells, and IgE levels in the serum. RESULTS: Confocal microscopy of LYVE-1-stained cornea revealed the distinct presence of corneal LA in AED, and corroborated by increased corneal expression of VEGF-C, D, and -R3. Importantly, prevention of corneal LA in AED via VEGFR inhibition was associated with decreased T helper two responses and IgE production. Furthermore, VEGFR inhibition led a significant reduction in clinical signs of AED. CONCLUSIONS: Collectively, these data reveal that there is a distinct involvement of corneal LA in AED. Furthermore, VEGFR inhibition prevents corneal LA and consequent immune responses in AED. PMID- 26024098 TI - Effect of Topical 5-Aminoimidazole-4-carboxamide-1-beta-d-Ribofuranoside in a Mouse Model of Experimental Dry Eye. AB - PURPOSE: To investigate the efficacy of topical 5-aminoimidazole-4-carboxamide-1 beta-d-ribofuranoside (AICAR) in a mouse model of experimental dry eye (EDE). METHODS: Eye drops consisting of 0.001% or 0.01% AICAR, 0.05% cyclosporine A (CsA), or balanced salt solution (BSS) were applied for the treatment of EDE. Tear volume, tear film break-up time (BUT), and corneal fluorescein staining scores were measured 10 days after treatment. Levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interferon gamma induced protein 10 (IP-10), and monokine induced by interferon-gamma (MIG) were measured in the conjunctiva. In addition, Western blot, periodic acid-Schiff staining for evaluating goblet cell density, flow cytometry for counting the number of CD4+CXCR3+ T cells, and immunohistochemistry for detection of 4-hydroxy 2-nonenal (4HNE) were performed. RESULTS: Mice treated with 0.01% AICAR showed a significant improvement in all clinical parameters compared with the EDE control, vehicle control, and 0.001% AICAR groups (P < 0.001). A significant decrease in the levels of IL-1beta, IL-6, TNF-alpha, IFN-gamma, IP-10, and MIG, the number of CD4+CXCR3+ T cells, and the number of 4HNE-positive cells were also observed in the 0.01% AICAR group (P < 0.001). Although 0.05% CsA also led to an improvement in clinical parameters and inflammatory molecule levels, its therapeutic effects were comparable or inferior to those of 0.01% AICAR. CONCLUSIONS: Topical application of 0.01% AICAR can markedly improve clinical signs and decrease inflammation in the ocular surface of EDE, suggesting that AICAR eye drops may be used as a therapeutic agent for dry eye disease. PMID- 26024100 TI - Performance on the Farnsworth-Munsell 100-Hue Test Is Significantly Related to Nonverbal IQ. AB - PURPOSE: The Farnsworth-Munsell 100-Hue test (FM100) is a standardized measure of chromatic discrimination, based on colored cap-sorting, which has been widely used in both adults and children. Its dependence on seriation ability raises questions as to its universal suitability and accuracy in assessing purely sensory discrimination. This study investigates how general intellectual ability relates to performance on both the FM100 and a new computer-based chromatic discrimination threshold test, across different age groups in both typical and atypical development. METHODS: Participants were divided into two main age groups, children (6-15 years) and young adults (16-25 years), with each group further subdivided into typically developing (TD; three groups; TD 6-7 years, TD 8-9 years, TD Adult) individuals and atypically developing individuals, all but one carrying a diagnosis of Autism Spectrum Disorders (ASD; two groups; atypically developing [ATY] child 7-15 years, ASD Adult). General intelligence was measured using the Wechsler Abbreviated Intelligence Scale and Wechsler Intelligence Scale for Children. All participants completed the FM100. Both child groups also completed a computer-based chromatic discrimination threshold test, which assessed discrimination along cone-opponent ("red-green," "blue-yellow") and luminance cardinal axes using a controlled staircase procedure. RESULTS: Farnsworth-Munsell 100-Hue test performance was better in adults than in children. Furthermore, performance significantly positively correlated with nonverbal intelligence quotient (NVIQ) for all child groups and the young adult ASD group. The slope of this relationship was steeper for the ASD than TD groups. Performance on the chromatic discrimination threshold test was not significantly related to any IQ measure. Regression models reveal that chromatic discrimination threshold, although a significant predictor of FM100 performance when used alone, is a weaker predictor than NVIQ used alone or in combination. CONCLUSIONS: The results indicate that FM100 performance is not purely a measure of color discrimination but instead also reflects general nonverbal ability. Other measures of chromatic discrimination ability are therefore required for its accurate assessment, particularly in early or atypical development. PMID- 26024099 TI - Quantitative Fundus Autofluorescence and Optical Coherence Tomography in PRPH2/RDS- and ABCA4-Associated Disease Exhibiting Phenotypic Overlap. AB - PURPOSE: To assess whether quantitative fundus autofluorescence (qAF), a measure of RPE lipofuscin, and spectral-domain optical coherence tomography (SD-OCT) can aid in the differentiation of patients with fundus features that could either be related to ABCA4 mutations or be part of the phenotypic spectrum of pattern dystrophies. METHODS: Autofluorescence images (30 degrees , 488-nm excitation) from 39 patients (67 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference and were quantified as previously described. In addition, horizontal SD-OCT images through the fovea were obtained. Patients were screened for ABCA4 and PRPH2/RDS mutations. RESULTS: ABCA4 mutations were identified in 19 patients (mean age, 37 +/- 12 years) and PRPH2/RDS mutations in 8 patients (mean age, 48 +/- 13 years); no known ABCA4 or PRPH2/RDS mutations were found in 12 patients (mean age, 48 +/- 9 years). Differentiation of the groups using phenotypic SD-OCT and AF features (e.g., peripapillary sparing, foveal sparing) was not reliable. However, patients with ABCA4 mutations could be discriminated reasonably well from other patients when qAF values were corrected for age and race. In general, ABCA4 patients had higher qAF values than PRPH2/RDS patients, while most patients without mutations in PRPH2/RDS or ABCA4 had qAF levels within the normal range. CONCLUSIONS: The high qAF levels of ABCA4-positive patients are a hallmark of ABCA4-related disease. The reason for high qAF among many PRPH2/RDS-positive patients is not known; higher RPE lipofuscin accumulation may be a primary or secondary effect of the PRPH2/RDS mutation. PMID- 26024101 TI - Noninvasive vascular imaging of polypoidal choroidal vasculopathy by Doppler optical coherence tomography. AB - PURPOSE: To noninvasively investigate the vascular architecture of polypoidal lesions in polypoidal choroidal vasculopathy (PCV) using Doppler optical coherence tomography (OCT), and to evaluate the clinical usefulness of Doppler OCT for the assessment of therapeutic effects in PCV. METHODS: Fifteen eyes of 15 patients with treatment-naive PCV were prospectively studied. Vascular imaging was obtained using 1060-nm swept-source Doppler OCT, and compared with indocyanine green angiography (ICGA) images. The therapeutic effect of three consecutive intravitreal aflibercept injections was evaluated with ICGA and Doppler OCT. RESULTS: In Doppler OCT images, polypoidal lesions were clearly detected at the corresponding locations of lesions in the ICGA images. By being insensitive to dye leakage, Doppler OCT identified the complicated vascular structure in the polypoidal lesions. The identified mean area of the polypoidal lesions in the Doppler OCT images (0.04 mm(2)) was significantly smaller than that of the ICGA images (0.13 mm(2)). Polypoidal lesions were located in the retinal pigment epithelial detachment in 13 eyes, in the choroid in one eye, and in both the retinal pigment epithelial detachment and choroid in one eye. After intravitreal aflibercept treatment, areas of polypoidal lesions in the ICGA images were decreased in 14 of 15 eyes. This therapeutic effect was clearly confirmed in the Doppler OCT images. CONCLUSIONS: Doppler OCT imaging clearly detected fine vascular structures at the polypoidal lesions in PCV. Doppler OCT might be useful for the diagnosis and evaluation of therapeutic effects in PCV. PMID- 26024102 TI - Toward a specific classification of polypoidal choroidal vasculopathy: idiopathic disease or subtype of age-related macular degeneration. AB - PURPOSE: To suggest a clinical distinction between idiopathic polypoidal choroidal vasculopathy (PCV) and secondary polyps associated with neovascular age related macular degeneration (NV-AMD). METHODS: The study was a retrospective case series of 52 eyes of 52 consecutive patients (31 females and 21 males) diagnosed with PCV. Initial diagnosis was based on scanning laser ophthalmoscope indocyanine green angiography (SLO-ICGA) in association with fluorescein angiography (FA) and optical coherence tomography (OCT). All the data and images were analyzed in a masked fashion by four experienced examiners in two different sessions: the first, to classify patients into the two hypothesized groups (idiopathic polyps or NV-AMD-related polyps); the second, following a predetermined scheme, to describe objective features. The results obtained in each session underwent a cross multivariate analysis to identify statistically significant differences (P <= 0.05) between the two groups. RESULTS: The two groups were clinically different on the basis of FA (leakage origin [P = 0.001] and presence of drusen [P = 0.001]), ICGA (evidence of choroidal neovascularization [CNV; P = 0.001] and/or branching vascular network [BVN; P = 0.001]), OCT imaging (type of pigmented epithelium detachment [P = 0.001], presence of BVN [P = 0.001], and subfoveal choroidal thickness [P = 0.001]). Further significant differences were observed according to the location of lesion (uni- or multifocal) (P = 0.001), type of CNV (P = 0.001), and best-corrected visual acuity (P = 0.001). CONCLUSIONS: Our study demonstrated clinical and statistically significant differences between idiopathic PCV and NV-AMD-related polyps that could be considered as distinct entities. Although they share some similarities, mainly the sub-RPE location, the ability to identify a specific clinical pattern suggests a more specific therapeutic approach for these two entities. PMID- 26024103 TI - Repeatability of corneal phase retardation measurements by polarization-sensitive optical coherence tomography. AB - PURPOSE: Polarization-sensitive optical coherence tomography (PS-OCT) can evaluate internal tissue structures of the cornea, such as collagen fibers, by phase retardation measurement. In this study, we assessed the repeatability of corneal phase retardation measurements using anterior segment PS-OCT. METHODS: A total of 173 eyes of 173 patients were measured using PS-OCT. In total, 58 eyes of young subjects with normal corneas, 28 eyes of old subjects with normal corneas, 26 eyes with corneal dystrophy or degeneration, 37 eyes with corneal transplantation, and 24 eyes with keratoconus were evaluated. The 3-mm diameter average of en face phase retardation of the posterior corneal surface was examined using PS-OCT. To evaluate the repeatability, intraclass correlation coefficients (ICCs) were calculated for intraobserver repeatability and interobserver repeatability analysis. RESULTS: Polarization-sensitive OCT showed good repeatability for corneal measurements. Intraclass correlation coefficients of intraobserver and interobserver repeatability of all the subjects were 0.989 and 0.980, respectively. Intraclass correlation coefficients of the intraobserver for each group, that is, young and old subjects with normal cornea, cornea dystrophy/degeneration, corneal transplantation, and keratoconus, were 0.961, 0.975, 0.984, 0.978, and 0.996, respectively. Interobserver ICCs for the above mentioned respective groups were 0.952, 0.964, 0.988, 0.959, and 0.975, respectively. CONCLUSIONS: Polarization-sensitive OCT showed good repeatability for phase retardation measurements of central corneas not only for normal corneas, but also for various diseased corneas. Polarization-sensitive OCT might be useful for evaluating corneal phase retardation, which is one of the parameters that defines birefringence. PMID- 26024104 TI - Validity of Automated Choroidal Segmentation in SS-OCT and SD-OCT. AB - PURPOSE: To evaluate the validity of a novel fully automated three-dimensional (3D) method capable of segmenting the choroid from two different optical coherence tomography scanners: swept-source OCT (SS-OCT) and spectral-domain OCT (SD-OCT). METHODS: One hundred eight subjects were imaged using SS-OCT and SD OCT. A 3D method was used to segment the choroid and quantify the choroidal thickness along each A-scan. The segmented choroidal posterior boundary was evaluated by comparing to manual segmentation. Differences were assessed to test the agreement between segmentation results of the same subject. Choroidal thickness was defined as the Euclidian distance between Bruch's membrane and the choroidal posterior boundary, and reproducibility was analyzed using automatically and manually determined choroidal thicknesses. RESULTS: For SS-OCT, the average choroidal thickness of the entire 6- by 6-mm2 macular region was 219.5 MUm (95% confidence interval [CI], 204.9-234.2 MUm), and for SD-OCT it was 209.5 MUm (95% CI, 197.9-221.0 MUm). The agreement between automated and manual segmentations was high: Average relative difference was less than 5 MUm, and average absolute difference was less than 15 MUm. Reproducibility of choroidal thickness between repeated SS-OCT scans was high (coefficient of variation [CV] of 3.3%, intraclass correlation coefficient [ICC] of 0.98), and differences between SS-OCT and SD-OCT results were small (CV of 11.0%, ICC of 0.73). CONCLUSIONS: We have developed a fully automated 3D method for segmenting the choroid and quantifying choroidal thickness along each A-scan. The method yielded high validity. Our method can be used reliably to study local choroidal changes and may improve the diagnosis and management of patients with ocular diseases in which the choroid is affected. PMID- 26024106 TI - Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior-segment optical coherence tomography study. AB - PURPOSE: To analyze the correlation between photophobia and corneal crystal density in nephropathic cystinosis using in vivo confocal microscopy (IVCM) and anterior-segment optical coherence tomography (AS-OCT). METHODS: Forty eyes of 20 patients with nephropathic cystinosis aged 7 to 37 years were included in this study. Ophthalmologic investigations included clinician-assessed and self assessed evaluations of photophobia, slit-lamp biomicroscopy analysis, the depth of crystal deposition (DCD) and the central corneal thickness (CCT) in the central cornea measured with AS-OCT, and IVCM analysis of the crystal density score (IVCM-CysS), inflammatory cell density (IVCM-inf), and nerve damage (IVCM N). Age, sex, intraleukocyte cystine concentrations (ICC), and the need for renal transplantation were also recorded. RESULTS: The average subjective and objective photophobia scores were 2.10 +/- 1.28 and 1.70 +/- 1.41, respectively. Using AS OCT, the average percentage of crystal infiltration (OCT-CysP) and was 49.56 +/- 27.31% (range, 11.45%-95.81%). The mean IVCM-CysS was 8.84 +/- 4.34, the mean density of inflammatory cells (IVCM-inf) was 178.28 +/- 173.00 cells/mm2, and the mean IVCM-N score was 3.11 +/- 2.11. Clinician- and self-assessed estimations of photophobia were correlated (R2 = 0.61). No significant correlation was observed between clinician- and self-assessed photophobia scores and ICC or sex. There were significant correlations between clinician- and self-assessed photophobia scores and age, OCT-CysP, IVCM-CysS, IVCM-inf, and IVCM-N. The IVCM-CysS was also correlated with OCT-CysP (R2 = 0.27), IVCM-inf (R2 = 0.37), and IVCM-N (R2 = 0.56). CONCLUSIONS: In vivo confocal microscopy and AS-OCT are reliable tools to quantify cystinosis corneal crystals. In patients with nephropathic cystinosis, the intensity of photophobia is associated with the density of crystals, infiltration of inflammatory cells, and nerve damage within the cornea. PMID- 26024105 TI - Macular perfusion in healthy Chinese: an optical coherence tomography angiogram study. AB - PURPOSE: To investigate macular perfusion in healthy Chinese individuals and examine its dependence on age and sex. METHODS: Healthy adult Chinese individuals were recruited. Macular perfusion was measured by spectral-domain optical coherence tomography (OCT) using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. The parafoveal flow index and vessel area density as well as the area of the foveal capillary-free zone (CFZ) were quantified. RESULTS: A total of 76 eyes in 45 subjects were included (20 males and 25 females, mean age 36 +/- 11 years). The mean parafoveal flow index was 0.099 +/- 0.013; the mean vessel area density was 0.891 +/- 0.073; and the mean CFZ area was 0.474 +/- 0.172 mm2. All three parameters were significantly correlated with age (flow index: P = 0.00; vessel area density: P = 0.00; CFZ area: P = 0.02). The flow index and vessel area density decreased annually by 0.6% and 0.4%, respectively, and CFZ area increased by 1.48% annually. The CFZ area was larger in females than in males, while all three parameters seemed to change more rapidly with age in males than in females. CONCLUSIONS: In healthy Chinese eyes, macular perfusion decreased with increasing age, and decreased more rapidly in males than in females. The application of OCT angiograms may provide a useful approach for monitoring macular perfusion, although caution must be exercised with regard to age- and sex-related variations. PMID- 26024107 TI - Near-infrared autofluorescence: its relationship to short-wavelength autofluorescence and optical coherence tomography in recessive stargardt disease. AB - PURPOSE: We compared hypoautofluorescent (hypoAF) areas detected with near infrared (NIR-AF) and short-wavelength autofluorescence (SW-AF) in patients with recessive Stargardt disease (STGD1) to retinal structure using spectral domain optical coherence tomography (SD-OCT). METHODS: The SD-OCT volume scans, and SW AF and NIR-AF images were obtained from 15 eyes of 15 patients with STGD1 and registered to each other. Thickness maps of the total retina, receptor-plus layer (R+, from distal border of the RPE to outer plexiform/inner nuclear layer boundary), and outer segment-plus layer (OS+, from distal border of the RPE to ellipsoid zone [EZ] band) were created from SD-OCT scans. These were compared qualitatively and quantitatively to the hypoAF areas in SW-AF and NIR-AF images. RESULTS: All eyes showed a hypoAF area in the central macula and loss of the EZ band in SD-OCT scans. The hypoAF area was larger in NIR than SW-AF images and it exceeded the area of EZ band loss for 12 eyes. The thickness maps showed progressive thinning towards the central macula, with the OS+ layer showing the most extensive and severe thinning. The central hypoAF areas on NIR corresponded to the OS+ thinned areas, while the hypoAF areas on SW-AF corresponded to the R+ thinned areas. CONCLUSIONS: Since the larger hypoAF area on NIR-AF exceeded the region of EZ band loss, and corresponded to the OS+ thinned area, RPE cell loss occurred before photoreceptor cell loss. The NIR-AF imaging may be an effective tool for following progression and predicting loss of photoreceptors in STGD1. PMID- 26024108 TI - Ethnic variations in myopia and ocular biometry among adults in a rural community in China: the Yunnan minority eye studies. AB - PURPOSE: To determine the prevalence of myopia and ocular biometry in population based samples of ethnic Yi and Han people living in an inland rural community in China. METHODS: A random cluster sampling strategy was used to select ethnic Han and Yi adults aged 50 years or older living in Yunnan. Refractive error was determined by subjective refraction and ocular biometric parameters, including axial length (AL), anterior chamber depth (ACD), vitreous chamber depth (VCD), and lens thickness (LT), which were measured using an Echoscan. RESULTS: Adults of Yi ethnicity had lower prevalence of myopia (10.3% vs. 8.1%; P = 0.02) and high myopia (2.3% vs. 1.6%; P = 0.10) than their counterparts of Han ethnicity. The prevalence of myopia increased with age (P for trend < 0.05), whereas the mean AL did not differ significantly among age groups in both ethnic groups (both P for trend > 0.05). In multivariate analysis, time spent outdoors was associated with myopia (P = 0.003) and AL (P < 0.001) but not high myopia (P = 0.33). No interaction effect was detected between ethnicity and other risk factors on myopia (all P > 0.05). Adjustment for lens nuclear opacity score reduced the excess prevalence of myopia in Han ethnicity by 37.5%. CONCLUSIONS: There was little evidence showing that ethnic disparities existed in the prevalence and risk factors between the major and minor ethnic groups living in the same communities in rural China. The "cohort effect" on myopia observed in many other populations was not seen in this study. PMID- 26024109 TI - Subducted and melanotic cells in advanced age-related macular degeneration are derived from retinal pigment epithelium. AB - PURPOSE: To describe, illustrate, and account for two cell types plausibly derived from RPE in geographic atrophy (GA) and choroidal neovascularization (CNV) of AMD, using melanosomes, lipofuscin, and basal laminar deposit (BLamD) as anatomical markers. METHODS: Human donor eyes with GA (n = 13) or CNV (n = 39) were histologically processed, photodocumented, and analyzed for frequencies of occurrence. We defined RPE as cells containing spindle-shaped melanosomes and RPE lipofuscin, internal to basal lamina or BLamD, if present, or Bruch's membrane if not, and RPE-derived cells as those plausibly derived from RPE and not attached to basal lamina or BLamD. RESULTS: 'Subducted' cells contain RPE melanosomes and localize to the sub-RPE space, on Bruch's membrane. Credible transitional forms from RPE cells were seen. Grades of RPE overlying 'Subducted' cells were 'Atrophic with BLamD' (32.2% vs. 37.0% of 'Subducted,' for GA and CNV eyes, respectively), 'Dissociated' (22.0% vs. 21.7%), 'Nonuniform' (22.0% vs. 23.9%), and 'Sloughed' RPE (10.2% vs. 4.3%). Found exclusively in CNV scars, 'Melanotic' cells containing spherical melanosomes were adjacent to 'Entombed' RPE with spindle-shaped and spherical melanosomes. Of subretinal 'Melanotic' cells, 40.0% associated with 'Atrophy with BLamD,' 36.8% with 'Atrophy without BLamD,' and 20.6% with 'Entombed.' CONCLUSIONS: 'Dissociated' RPE within atrophic areas may be the source of 'Subducted' cells. 'Entombed' RPE within fibrovascular and fibrocellular scars may be the source of 'Melanotic' cells. An imaging correlate for 'Subducted' cells awaits discovery; 'Melanotic' cells appear gray-black in the CNV fundus. Results provide a basis for future molecular phenotyping studies. PMID- 26024110 TI - Systemic counterregulatory response of placental growth factor levels to intravitreal aflibercept therapy. AB - PURPOSE: Placental growth factor (PlGF) has been implicated as a contributor to resistance against anti-VEGF therapy. The purpose of the present study was to analyze the systemic levels of PlGF, VEGF-A, and VEGF-B in patients with neovascular age-related macular degeneration (AMD) after treatment with aflibercept, ranibizumab, or bevacizumab. METHODS: Totals of 19 patients were treated with intravitreal aflibercept, 19 with ranibizumab, and 18 with bevacizumab. The cytokine levels were measured by ELISA just before the injection, and 7 days and 1 month thereafter. Age- and sex-matched participants (n = 22) served as controls. RESULTS: The median PlGF plasma concentration at baseline was <12.0 pg/mL in the control group as well as in all three anti-VEGF treatment cohorts. After intravitreal aflibercept injection, a significant upregulation of systemic PlGF could be observed in all treated patients (38.0 [31.0-44.0] pg/mL after 1 week [P < 0.001] and 16.0 [0.0-19.0] pg/mL [P = 0.005] after 4 weeks). No significant effects on plasma PlGF concentrations could be detected in those treated with ranibizumab and bevacizumab. The systemic VEGF-A levels were significantly reduced 1 and 4 weeks after intravitreal aflibercept (P < 0.001, P < 0.001) and bevacizumab (P < 0.001, P < 0.01) injections. No significant effects on plasma cytokine concentrations could be observed in the ranibizumab cohort. No significant effects on systemic VEGF-B could be observed in any of the treatment groups. CONCLUSIONS: In this study, we report a significant systemic upregulation of the proangiogenic cytokine PlGF after intravitreal administration of aflibercept. This might represent a counter regulatory response to antiangiogenic therapy. PMID- 26024111 TI - Optical Coherence Tomography Angiography of Peripapillary Retinal Blood Flow Response to Hyperoxia. AB - PURPOSE: To measure the change in peripapillary retinal blood flow in response to hyperoxia by using optical coherence tomography (OCT) angiography. METHODS: One eye of each healthy human participants (six) was scanned with a commercial high speed (70 kHz) spectral OCT. Scans were captured twice after 10-minute exposures to normal breathing (baseline) and hyperoxia. Blood flow was detected by the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. Peripapillary retinal blood flow index and vessel density were calculated from en face maximum projections of the retinal layers. The experiment was performed on 2 separate days for each participant. Coefficient of variation (CV) was used to measure within-day repeatability and between-day reproducibility. Paired t-tests were used to compare means of baseline and hyperoxic peripapillary retinal blood flow. RESULTS: A decrease of 8.87% +/- 3.09% (mean +/- standard deviation) in flow index and 2.61% +/- 1.50% in vessel density was observed under hyperoxia. The within-day repeatability CV of baseline measurements was 5.75% for flow index and 1.67% for vessel density. The between-day reproducibility CV for baseline flow index and vessel density was 11.1% and 1.14%, respectively. The between-day reproducibility of the hyperoxic response was 3.71% and 1.67% for flow index and vessel density, respectively. CONCLUSIONS: Optical coherence tomography angiography with SSADA was able to detect a decrease in peripapillary retinal blood flow in response to hyperoxia. The response was larger than the variability of baseline measurements. The magnitude of an individual's hyperoxic response was highly variable between days. Thus, reliable assessment may require averaging multiple measurements. PMID- 26024112 TI - Photographic Reading Center of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT): Methods and Baseline Results. AB - PURPOSE: To describe the methods used by the Photographic Reading Center (PRC) of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and to report baseline assessments of papilledema severity in participants. METHODS: Stereoscopic digital images centered on the optic disc and the macula were collected using certified personnel and photographic equipment. Certification of the camera system included standardization and calibration using a model eye. Lay readers assessed disc photos of all eyes using the Frisen grade and performed quantitative measurements of papilledema. Frisen grades by PRC were compared with site investigator clinical grades. Spearman rank correlations were used to quantify associations among disc features and selected clinical variables. RESULTS: Frisen grades according to the PRC and site investigator's grades, matched exactly in 48% of the study eyes and 42% of the fellow eyes and within one grade in 94% of the study eyes and 92% of the fellow eyes. Frisen grade was strongly correlated (r > 0.65, P < 0.0001) with quantitative measures of disc area. Cerebrospinal fluid pressure was weakly associated with Frisen grade and disc area determinations (r <= 0.31). Neither Frisen grade nor any fundus feature was associated with perimetric mean deviation. CONCLUSIONS: In a prospective clinical trial, lay readers agreed reasonably well with physicians in assessing Frisen grade. Standardization of camera systems enhanced consistency of photographic quality across study sites. Images were affected more by sensors with poor dynamic range than by poor resolution. Frisen grade is highly correlated with quantitative assessment of disc area. (ClinicalTrials.gov number, NCT01003639.). PMID- 26024114 TI - In Vitro Modeling of Emulsification of Silicone Oil as Intraocular Tamponade Using Microengineered Eye-on-a-Chip. AB - PURPOSE: There is a lack of a standardized methodology or a physiologically realistic in vitro model to investigate silicone oil (SO) emulsification. In this study, we replicated the SO-aqueous interface within a microfluidic chip to study the formation of SO emulsion droplets in the eye cavity. METHODS: A chip made of poly(methylmethacrylate) was used to represent a cross-section of the posterior eye chamber. A retinal ganglion cell line was coated on the inner surface of the chamber to mimic the surface property of the retina. Silicone oil of different viscosities were tested. The SO-aqueous interface was created inside the chip, which, in turn, was affixed to a stepper-motor-driven platform and subjected to simulated saccadic eye movement for four days. Optical microscopy was used to quantify the count and size of SO emulsified droplets. RESULTS: Among SO of different viscosities, SO 5 centistokes (cSt) emulsifies readily, and a high number of droplets formed inside the chip. Silicone oil 100 cSt led to fewer droplets than 5 cSt, but the droplet count was still significantly higher than other SO of higher viscosities. There were no significant differences in the number of droplets among SO with viscosities of 500, 1000, and 5000 cSt. In all SOs tested, the number of droplets increased, whereas their size decreased with longer duration of simulated saccades. CONCLUSIONS: The study platform allows quantification of the number and size of emulsified SO droplets in situ. More importantly, this platform demonstrates the potential of microtechnology for constructing a more physiologically realistic in vitro eye model. Eye-on-a-chip technology presents exciting opportunities to study emulsification and potentially other phenomena in the human eye. PMID- 26024113 TI - Cannabinoid-induced chemotaxis in bovine corneal epithelial cells. AB - PURPOSE: Cannabinoid CB1 receptors are found in abundance in the vertebrate eye, with most tissue types expressing this receptor. However, the function of CB1 receptors in corneal epithelial cells (CECs) is poorly understood. Interestingly, the corneas of CB1 knockout mice heal more slowly after injury via a mechanism proposed to involve protein kinase B (Akt) activation, chemokinesis, and cell proliferation. The current study examined the role of cannabinoids in CEC migration in greater detail. METHODS: We determined the role of CB1 receptors in corneal healing. We examined the consequences of their activation on migration and proliferation in bovine CECs (bCECs). We additionally examined the mRNA profile of cannabinoid-related genes and CB1 protein expression as well as CB1 signaling in bovine CECs. RESULTS: We now report that activation of CB1 with physiologically relevant concentrations of the synthetic agonist WIN55212-2 (WIN) induces bCEC migration via chemotaxis, an effect fully blocked by the CB1 receptor antagonist SR141716. The endogenous agonist 2-arachidonoylglycerol (2 AG) also enhances migration. Separately, mRNA for most cannabinoid-related proteins are present in bovine corneal epithelium and cultured bCECs. Notably absent are CB2 receptors and the 2-AG synthesizing enzyme diglycerol lipase-alpha (DAGLalpha). The signaling profile of CB1 activation is complex, with inactivation of mitogen-activated protein kinase (MAPK). Lastly, CB1 activation does not induce bCEC proliferation, but may instead antagonize EGF-induced proliferation. CONCLUSIONS: In summary, we find that CB1-based signaling machinery is present in bovine cornea and that activation of this system induces chemotaxis. PMID- 26024115 TI - Structure-Function Relationship Between Bruch's Membrane Opening-Based Optic Nerve Head Parameters and Visual Field Defects in Glaucoma. AB - PURPOSE: This study was performed to evaluate the structure-function relationship between Bruch's membrane opening (BMO) parameters of the optic nerve head (ONH) and visual field (VF) sensitivity. METHODS: Forty-six right eyes of 46 patients with open-angle glaucoma (OAG) in the patient group and 12 right eyes in the control group were included. Standard automated perimetry (SAP) and spectral domain optical coherence tomography (SD-OCT) were assessed. Three BMO-based distances and two areas of the neuroretinal rim were used for correlation: the minimum rim width (MRW), the perpendicular rim width (PRW), the horizontal rim width (HRW), the minimum rim area (MRA) within the neuroretinal tissue defined by the MRW, and the perpendicular rim area (PRA) within the neuroretinal tissue defined by the PRW. These parameters were correlated with global and sectoral VF sensitivities. Spearman's correlation coefficients between BMO parameters and global and sectoral VF sensitivities were obtained. RESULTS: Within the patient group, significant correlations could be observed between global and sectoral VF sensitivities and BMO parameters, with PRW and PRA showing the highest values. In the sectoral analysis the highest correlations were found for the temporal inferior VF sector (MD-TI): PRW-TI (rho = 0.72394; P < 0.00001) and PRA-TI (rho = 0.77205; P < 0.00001). Minimum rim width and MRA performed more weakly than PRW and PRA. CONCLUSIONS: The BMO-based parameters PRW and PRA presented with a very good structure-function relationship in glaucoma patients, statistically at least equal to MRW and MRA. Using new BMO-based parameters might allow early objective assessments of functional glaucomatous impairments. PMID- 26024116 TI - Fluorescence lifetime imaging in retinal artery occlusion. AB - PURPOSE: Fluorescence lifetime imaging ophthalmoscopy is a technique to measure decay times of endogenous retinal fluorophores. The purpose of this study was to investigate fluorescence lifetimes in eyes with central and branch retinal artery occlusion. METHODS: Twenty-four patients with central or branch retinal artery occlusion were included in this study. The contralateral unaffected fellow eye was used as control. Measurements were performed using a fluorescence lifetime imaging ophthalmoscope based on a HRA Spectralis system. Fluorescence excitation wavelength was 473 nm, and mean lifetimes were measured in a short (498-560 nm) and in a long (560-720 nm) spectral channel. Fluorescence lifetimes in the area of retinal artery occlusion were measured and compared to corresponding areas in contralateral unaffected eyes. Additionally, findings were correlated to optical coherence tomography measurements. RESULTS: Retinal lifetime images of 24 patients with retinal artery occlusion were analyzed. Mean retinal fluorescence lifetimes were prolonged by 50% in the short and 20% in the long spectral channel in ischemic retinal areas up to 3 days after retinal artery occlusion compared to the contralateral unaffected eyes. In the postacute disease stage there was no difference between the lifetimes of affected areas and unaffected fellow eyes. CONCLUSIONS: Retinal artery occlusion leads to significantly longer fluorescence lifetimes of the retina in the acute phase and may serve as a useful indicator for acute ischemic retinal damage. PMID- 26024117 TI - Determinants of optical coherence tomography-derived minimum neuroretinal rim width in a normal Chinese population. AB - PURPOSE: To characterize an optical coherence tomography (OCT)-derived parameter, Bruch's membrane opening-minimum rim width (BMO-MRW), and its association with demographic and clinical parameters in normal Chinese subjects. METHODS: Right eyes of 466 consecutive healthy subjects from a population-based study of Singaporean Chinese underwent Cirrus OCT imaging. The retinal internal limiting membrane (ILM) and BMO were automatically delineated using the built-in Cirrus algorithm. The standard 36 interpolated radial B-scans (72 BMO points, 5 degrees increments) of each optic nerve head were manually extracted from the central circle (3.46-mm diameter). We used Matlab to measure the shortest distance from the BMO points to the ILM. Associations of BMO-MRW with demographic and clinical parameters were evaluated using marginal general estimating equations analysis. RESULTS: There was a slight preponderance of male subjects (50.9%), with a mean age of 54.8 +/- 7.63 years. Mean BMO-MRW was 304.67 +/- 58.96 MUm (range, 173.32 529.23 MUm), which was highly associated with OCT-derived disc area (DA) (beta = 91.78, P < 0.001) and rim area (RA) (beta = 194.31, P < 0.001), followed by spherical refractive error (SRE) (beta = -2.23, P = 0.02) and retinal nerve fiber layer (RNFL) thickness (beta = 0.5, P = 0.04), after adjusting for the associated factors such as age, sex, intraocular pressure (IOP), and vertical cup-disc ratio (VCDR). CONCLUSIONS: Disc area and RA had the strongest association with BMO-MRW, followed by SRE and RNFL thickness. The availability of this normative database will facilitate optic nerve head assessment using the BMO-MRW parameter in Chinese subjects. PMID- 26024118 TI - Erratum. PMID- 26024119 TI - Erratum. PMID- 26024120 TI - Corneal sensitivity following lacrimal gland excision in the rat. AB - PURPOSE: Dry eye disease (DED) produces ocular pain and irritation, yet a detailed characterization of ocular sensitivity in a preclinical model of DED is lacking. The aim of the present study was to assess nociceptive behaviors in an aqueous tear deficiency model of DED in the rat. METHODS: Spontaneous blinking, corneal mechanical thresholds, and eye wipe behaviors elicited by hypertonic saline (5.0 M) were examined over a period of 8 weeks following the unilateral excision of either the exorbital lacrimal gland or of the exorbital and infraorbital lacrimal glands, and in sham surgery controls. The effect of topical proparacaine on spontaneous blinking and of systemic morphine (0.5-3.0 mg/kg, subcutaneous [SC]) on spontaneous blinking and eye wipe responses were also examined. RESULTS: Lacrimal gland excision resulted in mechanical hypersensitivity and an increase in spontaneous blinking in the ipsilateral eye over an 8-week period that was more pronounced after infra- and exorbital gland excision. The time spent eye wiping was also enhanced in response to hypertonic saline (5.0 M) at both 1- and 8-week time-points, but only in infra- and exorbital gland excised animals. Morphine attenuated spontaneous blinking, and the response to hypertonic saline in dry eye animals and topical proparacaine application reduced spontaneous blinking down to control levels. CONCLUSIONS: These results indicate that aqueous tear deficiency produces hypersensitivity in the rat cornea. In addition, the increase in spontaneous blinks and their reduction by morphine and topical anesthesia indicate the presence of persistent irritation elicited by the activation of corneal nociceptors. PMID- 26024121 TI - Cdc42 and sec10 Are Required for Normal Retinal Development in Zebrafish. AB - PURPOSE: To characterize the function and mechanisms of cdc42 and sec10 in eye development in zebrafish. METHODS: Knockdown of zebrafish cdc42 and sec10 was carried out using antisense morpholino injection. The phenotype of morphants was characterized by histology, immunohistology, and transmission electron microscopy (TEM). To investigate a synergistic genetic interaction between cdc42 and sec10, we titrated suboptimal doses of cdc42 and sec10 morpholinos, and coinjected both morpholinos. To study trafficking, a melanosome transport assay was performed using epinephrine. RESULTS: Cdc42 and sec10 knockdown in zebrafish resulted in both abnormal eye development and increased retinal cell death. Cdc42 morphants had a relatively normal retinal structure, aside from the absence of most connecting cilia and outer segments, whereas in sec10 morphants, much of the outer nuclear layer, which is composed of the photoreceptor nuclei, was missing and RPE cell thickness was markedly irregular. Knockdown of cdc42 and sec10 also resulted in an intracellular transport defect affecting retrograde melanosome transport. Furthermore, there was a synergistic genetic interaction between zebrafish cdc42 and sec10, suggesting that cdc42 and sec10 act in the same pathway in retinal development. CONCLUSIONS: We propose a model whereby sec10 and cdc42 play a central role in development of the outer segment of the retinal photoreceptor cell by trafficking proteins necessary for ciliogenesis. PMID- 26024122 TI - Patient-Specific Induced Pluripotent Stem Cell-Derived RPE Cells: Understanding the Pathogenesis of Retinopathy in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency. AB - PURPOSE: Retinopathy is an important manifestation of trifunctional protein (TFP) deficiencies but not of other defects of fatty acid oxidation. The common homozygous mutation in the TFP alpha-subunit gene HADHA (hydroxyacyl-CoA dehydrogenase), c.1528G>C, affects the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of TFP and blindness in infancy. The pathogenesis of the retinopathy is unknown. This study aimed to utilize human induced pluripotent stem cell (hiPSC) technology to create a disease model for the disorder, and to derive clues for retinopathy pathogenesis. METHODS: We implemented hiPSC technology to generate LCHAD deficiency (LCHADD) patient-specific retinal pigment epithelial (RPE) monolayers. These patient and control RPEs were extensively characterized for function and structure, as well as for lipid composition by mass spectrometry. RESULTS: The hiPSC-derived RPE monolayers of patients and controls were functional, as they both were able to phagocytose the photoreceptor outer segments in vitro. Interestingly, the patient RPEs had intense cytoplasmic neutral lipid accumulation, and lipidomic analysis revealed an increased triglyceride accumulation. Further, patient RPEs were small and irregular in shape, and their tight junctions were disorganized. Their ultrastructure showed decreased pigmentation, few melanosomes, and more melanolysosomes. CONCLUSIONS: We demonstrate that the RPE cell model reveals novel early pathogenic changes in LCHADD retinopathy, with robust lipid accumulation, inefficient pigmentation that is evident soon after differentiation, and a defect in forming tight junctions inducing apoptosis. We propose that LCHADD-RPEs are an important model for mitochondrial TFP retinopathy, and that their early pathogenic changes contribute to infantile blindness of LCHADD. PMID- 26024123 TI - Hyperglycemia-suppressed expression of Serpine1 contributes to delayed epithelial wound healing in diabetic mouse corneas. AB - PURPOSE: Patients with diabetes mellitus (DM) are at an increased risk for developing corneal complications, including delayed wound healing. The purpose of this study was to characterize the expression and the function of Serpine1 and other components of urokinase plasminogen activator (uPA)-proteolytic system in delayed epithelial wound healing in diabetic mouse corneas. METHODS: Mice of the strain C57BL/6 were induced to develop diabetes by streptozotocin, and wound healing assays were performed 10 weeks afterward. Gene expression and/or distribution were assessed by real-time PCR, Western blotting, and/or immunohistochemistry. The role of Serpine1 in mediating epithelial wound closure was determined by subconjunctival injections of neutralizing antibodies in either normal or recombinant protein in diabetic corneas. Enzyme assay for matrix metalloproteinase (MMP)-3 was also performed. RESULTS: The expressions of Serpine1 (PAI-1), Plau (uPA), and Plaur (uPA receptor) were upregulated in response to wounding, and these upregulations were significantly suppressed by hyperglycemia. In healing epithelia, Plau and Serpine1 were abundantly expressed at the leading edge of the healing epithelia of normal and, to a lesser extent, diabetic corneas. Inhibition of Serpine1 delayed epithelial wound closure in normal corneas, whereas recombinant Serpine1 accelerated it in diabetic corneas. The Plau and MMP-3 mRNA levels and MMP-3 enzymatic activities were correlated to Serpine1 levels and/or the rates of epithelial wound closure. CONCLUSIONS: Serpine1 plays a role in mediating epithelial wound healing and its impaired expression may contribute to delayed wound healing in DM corneas. Hence, modulating uPA proteolytic pathway may represent a new approach for treating diabetic keratopathy. PMID- 26024125 TI - Increased levels of inflammatory immune mediators in vitreous from pseudophakic eyes. AB - PURPOSE: To determine if pseudophakic eyes have an increased and sustained level of inflammatory immune mediators in the vitreous compared to phakic eyes. METHODS: Vitreous fluid samples were obtained from 73 patients undergoing elective pars plana vitrectomy (PPV) as a result of a macular hole, epiretinal membrane, vitreous macular traction, or vitreous floaters. Forty eyes were pseudophakic and had previously undergone uncomplicated cataract surgery, ranging from a few months to several years prior to PPV. The vitreous samples were analyzed for 29 different inflammatory immune mediators using multiplex bead immunoassays. RESULTS: A total of 14 cytokines (eotaxin, interferon-gamma-induced protein-10 [IP-10], monocyte chemotactic protein-1 [MCP-1], macrophage derived chemokine [MDC], macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, thymus activation regulated chemokine [TARC], IL-12p40, IL-15, IL-16, IL-7, VEGF, IL-6, and IL-8) were detected in the vitreous of both study groups. Using multiple linear regression analysis, pseudophakia was significantly correlated with higher levels of vitreous immune mediators compared to phakia. Elevated vitreous levels were estimated to decrease over time for IL-6, IL-8, IL-15, IL-16, and VEGF, though they remained elevated for many months and even years compared to the levels detected in phakic eyes. CONCLUSIONS: This is the first study to demonstrate that cataract surgery and pseudophakia can induce increased vitreous levels of a substantial range of inflammatory immune mediators. The elevated levels seem to be maintained for a long period of time. These increased levels of cytokines may be involved in inflammatory processes leading to several complications to cataract surgery, both early and late. PMID- 26024124 TI - Autofluorescence imaging with near-infrared excitation:normalization by reflectance to reduce signal from choroidal fluorophores. AB - PURPOSE: We previously developed reduced-illuminance autofluorescence imaging (RAFI) methods involving near-infrared (NIR) excitation to image melanin-based fluorophores and short-wavelength (SW) excitation to image lipofuscin-based flurophores. Here, we propose to normalize NIR-RAFI in order to increase the relative contribution of retinal pigment epithelium (RPE) fluorophores. METHODS: Retinal imaging was performed with a standard protocol holding system parameters invariant in healthy subjects and in patients. Normalized NIR-RAFI was derived by dividing NIR-RAFI signal by NIR reflectance point-by-point after image registration. RESULTS: Regions of RPE atrophy in Stargardt disease, AMD, retinitis pigmentosa, choroideremia, and Leber congenital amaurosis as defined by low signal on SW-RAFI could correspond to a wide range of signal on NIR-RAFI depending on the contribution from the choroidal component. Retinal pigment epithelium atrophy tended to always correspond to high signal on NIR reflectance. Normalizing NIR-RAFI reduced the choroidal component of the signal in regions of atrophy. Quantitative evaluation of RPE atrophy area showed no significant differences between SW-RAFI and normalized NIR-RAFI. CONCLUSIONS: Imaging of RPE atrophy using lipofuscin-based AF imaging has become the gold standard. However, this technique involves bright SW lights that are uncomfortable and may accelerate the rate of disease progression in vulnerable retinas. The NIR-RAFI method developed here is a melanin-based alternative that is not absorbed by opsins and bisretinoid moieties, and is comfortable to view. Further development of this method may result in a nonmydriatic and comfortable imaging method to quantify RPE atrophy extent and its expansion rate. PMID- 26024126 TI - Localization of damage in progressive hydroxychloroquine retinopathy on and off the drug: inner versus outer retina, parafovea versus peripheral fovea. AB - PURPOSE: To evaluate the relative involvement of inner and outer retina in hydroxychloroquine (HCQ) retinopathy while on the drug, and after drug cessation, using data from spectral-domain optical coherence tomography (SD-OCT). METHODS: A total of 102 SD-OCT scans were obtained from 11 patients (classified as having early, moderate, or severe stages of toxicity) over a period of 4 years after cessation of HCQ. The inner and outer retina boundaries were identified automatically to measure thickness and characterize progression topographically. RESULTS: The segmentation of retinal layers was verified in SD-OCT cross-sections for all eyes and scans included in this study (a total of 102 scans). Topographic analysis showed that inner retina was not involved in HCQ toxicity to any meaningful degree, either between stages of retinopathy or after the drug is stopped. The characteristic bull's eye pattern of outer macula thinning appears when comparing moderate retinopathy (before any RPE damage) to the early stage. Later damage, as toxicity evolved to a severe stage, was diffuse across most of the macula. If the drug was stopped at an early or moderate stage, progression was limited to the first year and occurred diffusely without parafoveal localization. CONCLUSIONS: Hydroxychloroquine retinopathy primarily involves outer retina (photoreceptors). Outer retinal thinning while using HCQ initially involves the parafovea, but becomes diffuse across the macula as damage progresses or after drug cessation. When HCQ is stopped at an early or moderate stage (before RPE damage), progression seems to be limited to the first year. PMID- 26024127 TI - The complete mitochondrial genome of Ictidomys tridecemlineatus (Rodentia: Sciuridae). AB - The complete mitochondrial genome of the thirteen-lined ground squirrel, Ictidomys tridecemlineatus (Rodentia: Sciuridae) was sequenced to analyze the gene arrangement. It is a circular molecule of 16,458 bp in length including 37 genes typically found in other squirrels. The AT content of the overall base composition is 63.7% and the length of the control region is 1016 bp with 63.0% AT content. In BI and ML phylogenetic trees, I. tridecemlineatus is a sister clade to the genus Cynomys, and Tamias sibiricus is a sister clade to (Marmota himalayana + (I. tridecemlineatus + (C. leucurus + C. ludovicianus))). Ratufinae is well supported as the basal clade of Sciuridae. The monophyly of the family Sciuridae and its subfamilies Callosciurinae, Xerinae and Sciurinae are well supported. PMID- 26024128 TI - The complete mitogenome of Japanese swallow angelfish (Genicanthus semifasciatus) and Ornate angelfish (Genicanthus bellus) (Teleostei: Pomacanthidae). AB - In this study, we used the next-generation sequencing method to determine the complete mitogenome of Japanese swallow angelfish (Genicanthus semifasciatus) and Ornate angelfish (Genicanthus bellus) for the first time. The assembled mitogenome, 16,722 bp and 16,734 bp in length, shows 95% identity to each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes and a non-coding control region of D-loop. D-loop contains length of 1013 bp in G. semifasciatus and 1030 bp in G. bellus, and is located between tRNA-Pro and tRNA-Phe. The overall GC content is 46.4% for G. semifasciatus and 46.6% for G. bellus. The complete mitogenome of Japanese swallow angelfish and Ornate angelfish determined in this study provides essential and important DNA molecular data for further phylogenetic and evolutionary analyses for marine angelfish. PMID- 26024129 TI - Phylogenetic analysis of the endangered takin in the confluent zone of the Qinling and Minshan Mountains using mtDNA control region. AB - The takin (Budorcas taxicolor) is an Endangered ungulate. We analyzed the variation within mtDNA control region sequences of takin populations in the Qinling Mountains, the Minshan Mountains and the confluence of these two mountain ranges. We did not find any shared haplotypes among the populations. We observed apparent variation in the control region length among the three populations, and independent population expansions in the late of Pleistocene, which suggests these populations may have independent evolutionary histories. We found only one haplotype, and the lowest measures of genetic diversity (h = 0; pi = 0) in the population from the confluent zone, which suggests populations in the confluent zone may have grown from small founder populations and gene flow with other populations has ceased. Based on their phylogenetic relationships, we concluded that the takin population in the confluent zone was in the same clade as the Tangjiahe population, which suggests that these takin populations are Sichuan takin (Budorcas taxicolor tibetana). PMID- 26024130 TI - The complete mitochondrial genome of Cherskii's sculpin (Cottus czerskii) (Scorpaeniformes: Cottidae). AB - The complete mitogenome sequence of Cherskii's sculpin (Cottus czerskii) is determined using long PCR. The genome is 16,534 bp in length and contains 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and a control region. The overall base composition of the heavy strand is A (26.4%), C (30.1%), T (26.1%) and G (17.5%). The control region is 857 bp in length and the A + T content of the region is 61.5%. The extended termination-associated sequence domain, the central conserved domain and the conserved sequence block domain are defined in the mitochondrial genome control region of Cherskii's sculpin. Mitochondrial genome analyses based on MP, NJ and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the 21 Actinopterygii species. It appears that no less than two major phyletic lineages were present in Actinopterygii. The main clades within the Perciformes and Scorpaeniformes supported are: a clade including the Scombridae, Kyphosidae and Percichthyidae; a clade (Cottidae) with the Trichodontidae as the sister taxon to Pholidae, Anarhichadidae and Zoarcidae, which was supported by bootstrap values of 92%. The five Cottus species formed a paraphyletic group with the high bootstrap value (100%) in all examinations. PMID- 26024131 TI - Complete mitochondrial genome of blackedge greeneye Chlorophthalmus nigromarginatus (Aulopiformes, Chlorophthalmidae). AB - In this paper, the complete mitochondrial genome of Chlorophthalmus nigromarginatus has been determined. The mitochondrial genome (17,663 bp) had the canonical mitochondrial gene content and arrangement, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non-coding regions. The overall base composition of the heavy-strand is 25.66% A, 25.71% T, 17.82% G, and 30.81% C, with an AT content of 51.37%. It shared 86.6% identities with Chlorophthalmus agassizi. The phylogenetic analyses indicated the close relationship between the mitochondrial genome we presented and other species in order Aulopiformes. PMID- 26024132 TI - Sequence and organization of the complete mitochondrial genome of the Ussuri mamushi (Gloydius ussuriensis). AB - The mitochondrial genome sequence of Ussuri mamushi is analyzed and presented publically for the first time. The genome is 17,208 bp in length and contains 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 2 control regions. The overall base composition is A (32.4%), C (28.4%), T (26.3%) and G (12.9%). The base compositions clearly presented the A-C skew, which is the most obvious in the protein-coding genes. Mitochondrial genome analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the 13 Crotalinae species. It appeared that no less than two major phyletic lineages were present in Crotalinae. The main clades within the Crotalinae include Protobothrops. A clade (G. brevicaudus, G. ussuriensis, G. intermedius, and G. sahatilis) with the Ovophis as the sister taxon to Protobothrops was supported by bootstrap values of 88%. The four Gloydius species formed a paraphyletic group with the high bootstrap value (100%) in all examinations. PMID- 26024133 TI - The complete mitochondrial genome sequence of Trichopodus leerii (Perciformes: Osphronemidae) and phylogenetic studies of Osphronemidae. AB - Trichopodus leerii has been given many popular names in the ornament market, such as pearl gourami, lace gourami and mosaic gourami, which causes confusion in species identification. This species belongs in the family Osphronemidae of Perciformes. This species and its congeners are characterized by a brownish silver body, covered in a pearl-like pattern. In this study, we first determined and described the complete mitogenome sequence of T. leerii, which is 16,472 bp in length. The overall base composition is 29.2%, 27.3%, 28.0% and 15.5% for A, C, T and G, respectively, with a slight bias in the AT content (57.2%). All protein-coding genes share the start codon ATG and most of them have TAA or TAG as the stop codon, except ND4 and ND6 use an incomplete stop codon T. Maximum likelihood tree and Bayesian analyses based on partitioned nucleotide sequences of 12 mitochondrial protein-coding genes were constructed, and both yielded identical topologies. These results are expected to provide useful molecular data for species identification and further phylogenetic studies of Osphronemidae and Perciformes. PMID- 26024134 TI - Complete mitochondrial genome of Acrossocheilus yunnanensis (Cypriniformes, Barbinae, Acrossocheilus). AB - In this paper, the complete mitochondrial DNA sequence of Acrossocheilus yunnanensis collected from the Qingyi River is determined. The complete mitochondrial genome of A. yunnanensis is a circular molecule of 16,596 bp in length, and all genes showed the typical gene arrangement conforming to the vertebrate consensus. The 13 protein-coding genes of A. yunnanensis and other 21 Barbinae species from 3 genera were used for phylogenetic analysis using Bayesian inference and maximum likelihood methods. The topology demonstrated the genus Acrossocheilus is relatively close to the Labeo than Garra, the A. yunnanensis may have a common ancestor with A. monticola, where both belong to the non-barred group. PMID- 26024135 TI - The complete mitochondrial genome of the butterfly Euripus nyctelius (Lepidoptera: Nymphalidae). AB - The complete mitochondrial genome (mitogenome) of the butterfly, Euripus nyctelius, was determined in the present study. The mitogenome is a typical circular DNA molecule of 15,417 bp, containing 37 genes and a putative control region. Thirteen protein-coding genes all initiate with ATN codons and mostly terminate with TAA or TAG codons except for COII, ND4 and ND5 use a single T residue as the termination codon. All tRNAs have the classic clover-leaf structure, except that the dihydrouridine (DHU) arm of tRNA(Ser(AGN)) forms a simple loop. Both maximum likelihood and Bayesian analyses support the monophyly of butterflies and recover high supports for the following family level relationships: (Papilionidae + (Hesperioidea +(Pieridae (Lycaenidae + Nymphalidae)))). Euripus nycteliusis is placed as sister to the genus Sasakia within Nymphalidae. PMID- 26024136 TI - The complete chloroplast genome of Capsella rubella. AB - The whole nucleotide sequence of the chloroplast genome from Capsella rubella is determined in this study using short Illumina sequence data from public database. The circular double-stranded DNA, which consists of 154,601 base pairs (bp) in size, contains a pair of inverted repeats (IRa and IRb) of 26,462 bp each, which are separated by a small and large single-copies (SSC and LSC) of 17,855 and 83,822 bp, respectively. The overall GC content of the chloroplast genome is 36.54% and the GC contents of LSC, IRs and SSC are 34.33%, 42.38% and 29.61% separately. One hundred and twelve unique genes were annotated, including 78 protein-coding genes, 30 tRNA genes and 4 rRNA genes. Among these, 16 are duplicated in the inverted repeat regions, 15 genes contained 1 intron, and 3 genes (rps12, clpP and ycf3) comprised of 2 introns. Two protein genes (rps19 and ycf1) span in the boundaries of LSC-IR and IR-SSC to produce two partial pseudogenes. PMID- 26024137 TI - The complete mitochondrial genome of Bryodema miramae (Orthoptera: Oedipodidae). AB - The complete circular mitochondrial genome (mitogenome) of Bryodema miramae is 15,919 bp in length, containing 37 typical genes and 1 non-coding AT-rich region. The AT content of the AT-rich region is 84.7%. All protein-coding genes (PCGs) start with standard ATN initiation codon and end with complete termination codons TAG or TAA except for cox1 gene using an incomplete stop codon T. tRNA genes are predicted with a characteristic cloverleaf secondary structure except for trnS(AGN), whose dihydrouridine (DHU) arm is replaced by a simple loop. The lengths of the large and small ribosomal RNA genes are 1319 and 836 bp, respectively. Phylogenetic analysis found: (i) Bryodema miramae has a close relationship with Bryodema luctuosum luctuosum, but with low credibility, the bootstrap value was under 50% and (ii) the Bryodema clade forms a sister group with another clade containing Orinhippus tibetanus and Pacris xizangensis. PMID- 26024138 TI - The complete mitochondrial genome sequence of Tylototriton taliangensis (Amphibia: Caudata). AB - Tylototriton taliangensis was listed as a Near Threatened amphibian in IUCN red list. In this study, we sequenced the complete mitochondrial (mt) genome of this species (GenBank: KP979646) and found it contains 16,265 base pairs, which encode 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNA), 2 ribosomal RNA genes (rRNA) and 1 control region (CR). We also found that almost all PCGs and tRNA genes are located on the H-strand, except for ND6 subunit gene and eight tRNA genes, which were distributed on the L-strand. The PCGs used "ATG" and "GTG" as the start codon, while used four types of stop codons. Almost all tRNA genes were folded into typical cloverleaf secondary structures. The L-strand replication origin (OL) and a non-coding region were also found. The new mitogenomic phylogenetic tree confirms the reciprocally monophyly of the genus Tylototriton, Echinotriton and Pleurodeles with high bootstrap value. The present study will provide information for future studies on the conservation genetics and phylogeny of this species and its relatives. PMID- 26024139 TI - The complete mitochondrial genome of Stylodipus telum (Rodentia: Dipodidae) and its phylogenetic analysis. AB - Stylodipus telum belongs to the genus Stylodipus in the subfamily of Dipodinae. We got its complete genome first and it is 16,696 bp in length, the heavy strand contains 31.0% A, 13.8% G, 27.3% C, 27.9% T. Among them, protein-coding genes take up approximately 67.90% of the complete sequence. Trees constructed through phylogenetic analysis showed S. telum and Jaculus jaculus were clustered in one branch belonging to the family Dipodinae. This conclusion was identical to the former result by the methods of morphological taxonomy, and it would be convenient for further research on S. telum and other jerboa. PMID- 26024140 TI - The complete mitochondrial genome of the pumpkin fruit fly, Bactrocera tau (Diptera: Tephritidae). AB - The pumpkin fruit fly, Bactrocera tau, is an important quarantine pest in many countries because of its mass destructiveness to a variety of vegetable and fruit plants. In this study, we report the complete mitochondrial genome (mitogenome) of B. tau. Its complete mitogenome sequence is 15,687 bp in length, which contains a non-coding control region and all of the 37 genes of bilaterian animals (13 protein-coding genes, 22 tRNA genes and 2 rRNA genes). A phylogenetic tree of the complete mitogenome of all available Tephritidae species was established to approve the accuracy. The base composition of mitogenome sequence and the gene arrangement including directions are rather conservative, compared to other published mitogenomes of Bactrocera species. This first complete mitogenome of B. tau will facilitate the development of new DNA markers for species diagnosis, therefore improving accurate detection of quarantine species. PMID- 26024141 TI - The complete mitochondrial genome of the cold-adapted fungus Pseudogymnoascus pannorum syn. Geomyces pannorum. AB - In this study, the complete mitochondrial genome of a cold-adapted fungus, Pseudogymnoascus pannorum (=Geomyces pannorum), was sequenced. Its mitochondrial genome is 26,918 bp in length and consists of 13 standard protein-coding genes, 2 ribosomal RNA subunits and 27 transfer RNAs. The atp9 gene is absent from the mitochondrial DNA of P. pannorum. The mere intron present in the mitochondrial genome of P. pannorum is found within the rnl gene, and this group-IA intron carries an intronic ORF encoding for ribosomal protein S3. Phylogenetic analysis based on concatenated protein sequences support P. pannorum as a Leotiomycetes species, but its taxonomic resolution at the order level needs to be refined when additional mitochondrial genome data are available. PMID- 26024142 TI - The first complete mitochondrial genome of stag beetle from China, Prosopocoilus gracilis (Coleoptera, Lucanidae). AB - The complete mitochondrial genome (mitogenome) of Prosopocoilus gracilis (Coleoptera: Lucanidae) that is endemic to Southern China is determined. The circular genome is 736 bp in length and comprises 13 protein-coding genes, 22 tRNA, 2 rRNA genes and a control region. Gene order is identical to that of the putative ancestral arrangement of insects. The nucleotide composition of heavy strand is A (36.6%), C (22.6%), T (29.5%) and G (11.3%). All protein-coding genes start with a typical ATN codon except for the gene COI that uses AAC as the start codon. tRNA-Ser (AGN) uses the anticodon UCU instead of the commonly used GCU. Both maximum likelihood and Bayesian analyses support the monophyly of Lucanidae and the sister relationship of Nigidionus and the remaining sampled genera. Two species of Prosopocoilus were not recovered as a monophyletic group. PMID- 26024143 TI - Next generation sequencing yields complete mitogenomes of Leopard whipray (Himantura leoparda) and Blue-spotted stingray (Neotrygon kuhlii) (Chondrichthyes: Dasyatidae). AB - The Leopard whipray (Himantura leoparda) and Blue-spotted stingray (Neotrygon kuhlii) are distributed in the Indian and West Pacific Ocean and considered as complex species based on morphological and molecular evidences. In this study, we used the next-generation sequencing method to decode two complete mitogenomes of H. leoparda and N. kuhlii. The assembled mitogenome, consisting lengths of 17,690 bp for H. leoparda and 17,974 bp for N. kuhlii, shows 78% identity to each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes and a non-coding control region of D-loop. D-loop with the lengths 1931 bp (H. leoparda) and 2243 bp (N. kuhlii) is located between tRNA-Pro and tRNA-Phe. The overall GC content is 40.3% for H. leoparda and 39.8% for N. kuhlii. The complete mitogenome of H. leoparda and N. kuhlii provides essential and important DNA molecular data for further phylogenetic and evolutionary analyses for stingray species complex. PMID- 26024144 TI - Complete mitochondrial genome of the sheepshead minnow Cyprinodon variegatus (Cyprinodontiformes: Cyprinodontidae). AB - The complete mitochondrial genome of the sheepshead minnow (Cyprinodon variegatus) with the length of 16,498 bp was determined using long PCR and Sanger sequencing. The mitogenome contains 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and a D-loop region of 831 bp in length. All protein-coding genes except NADH dehydrogenase subunit 6 (nd6) are encoded on the heavy strand (H-strand). ATG acts as the start codon for all protein-coding genes except cytochrome c oxidase subunit I (coI), which has GTG as a start codon. Fourteen tRNA genes and both rRNA genes are also encoded on the H-strand, as observed in other Actinopterygiian fishes. This complete mitogenome sequence will facilitate studies on adaptation of C. variegates to local variation in temperature, salinity and chemical pollution conditions, as well as inform studies of genetic introgression by C. variegatus into other Cyprinodon species that have imperiled protection status. PMID- 26024145 TI - Complete mitochondrial genome of Coregonus autumnalis. AB - The complete mitochondrial genome of Coregonus autumnalis is determined in this study. The mitogenome is 16,736 bp in length and contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and a D-loop region. The overall base composition of the H-strand is 26.73% A, 29.44% C, 18.14% for G and 25.69% for T. The G+C content is 47.58%. In this article, the mitochondrial genome sequencing for Coregonus autumnalis is carried out for the first time. PMID- 26024146 TI - Complete mitochondrial genome of the Pere David's Vole, Eothenomys melanogaster (Rodentia: Arvicolinae). AB - The Pere David's Vole, Eothenomys melanogaster belongs to subfamily Arvicolinae. It is widespread in south China, and ranges into northern Southeast Asia. In this study, the complete mitochondrial genome sequence of Eothenomys melanogaster was determined. The mitogenome is 16,331 base pairs in length. The nucleotide sequence data of 12 heavy-strand protein-coding genes of E. melanogaster and other 17 rodents were used for phylogenetic analyses. Tree constructed using Bayesian phylogenetic methods demonstrated that E. melanogaster as a sister to E. chinensis, was clustered in subfamily Arvicolinae. The monophyly of the genus Eothenomys was supported as well with Eothenomys sister to the genus Myodes. PMID- 26024148 TI - The mitochondrial genome of Papilio demoleus Linnaeus (Lepidoptera: Papilionidae). AB - We determined the complete mitochondrial genome (mitogenome) sequence of Papilio demoleus (GenBank accession number KR024009) by long PCR and primer walking methods. The total length of mitochondrial DNA is 15,249 bp containing 13 protein coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and a control region. The overall base composition of the genome is A (39.31%), T (41.57%), C (11.33%) and G (7.78%) with an A + T-rich region, similar to other invertebrate mitochondrial genomes. The start codon was mainly ATG in most of the mitochondrial protein-coding genes such as COII, ATP6, COIII, ND4, ND4L, Cob and ND1, while ATA for ND2, COI, ATP8, ND3, ND5 and ND6 genes. The stop codon was mainly TAA in most of the mitochondrial protein-coding genes, whereas TAG was found in ND1 gene only. The A + T region is located between 12S rRNA and tRNA(M)(et) with a length of 403 bp. PMID- 26024147 TI - The complete chloroplast genome of Armand pine Pinus armandii, an endemic conifer tree species to China. AB - The complete chloroplast genome (cpDNA) sequence of an endemic conifer species, Armand pine Pinus armandii Franch., is determined in this study. The cpDNA was 117,265 bp in length, containing a pair of 475 bp inverted repeat (IR) regions those distinguished in large and small single copy (LSC and SSC) regions of 64,548 and 51,767 bp in length, respectively. The cpDNA contained 114 genes, including 74 protein-coding genes (74 PCG species), 4 ribosomal RNA genes (four rRNA species) and 36 transfer RNA genes (33 tRNA species). Out of these genes, 12 harbor a single intron and most of the genes occurred in a single copy. The overall AT content of the Armand pine cpDNA was 61.2%, while the corresponding values of the LSC, SSC and IR regions were 62.0%, 60.2% and 62.7%, respectively. A phylogenetic analysis revealed that P. armandii chloroplast genome is closely related to that of the P. koraiensis within the genus Pinus. PMID- 26024150 TI - Molecular Evolution of Poly(2-isopropyl-2-oxazoline) Aqueous Solution during the Liquid-Liquid Phase Separation and Phase Transition Process. AB - A detailed phase transition process of poly(2-isopropyl-2-oxazoline) (PIPOZ) in aqueous solution was investigated by means of DSC, temperature-variable (1)H NMR, Raman, optical micrographs, and FT-IR spectroscopy measurements. Gradual phase separation accompanied by large dehydration degree and big conformational changes above the lower critical solution temperature (LCST) and facile reversibility were identified. Based on the two-dimensional correlation (2Dcos) and perturbation correlation moving window (PCMW) analyses, the sequence order of chemical group motions in phase transition process was elucidated. Additionally, a newly assigned CH3...O?C intermolecular hydrogen bond at 3008 cm(-1) in the PIPOZ system provides extra information on the interactions between C-H and C?O groups. The formation of cross-linking "bridging" hydrogen bonds C?O...D-O D...O?C (1631 cm(-1)) is proposed as the key process to induce the liquid-liquid phase separation and polymer-rich phase formation of PIPOZ solution. With slow heating, more and more "bridging" hydrogen bonds were formed and D2O were expelled with an ordered and mostly all-trans conformation adopted in the PIPOZ chains. On the basis of these observations, a physical picture on the molecular evolution of PIPOZ solution during the phase transition process has been derived. PMID- 26024149 TI - The complete mitochondrial genome of Schizothorax yunnanensis paoshanensis (Cyprinidae: Schizothorax). AB - In this study, the complete mitochondrial DNA (mtDNA) sequence of Schizothorax yunnanensis paoshanensis is determined for the first time. The complete mtDNA genome sequence of S. yunnanensis paoshanensis is 16,585 bp in length. It consists of 13 protein-coding genes, 22 transfer RNA genes, 2 rRNA genes and a putative control region (D-loop region). The gene order of S. yunnanensis paoshanensis mtDNA is identical to most of the vertebrate mtDNAs. The complete mitogenome sequence information of S. yunnanensis paoshanensis can provide useful data for further studies on molecular systematics, taxonomic status and conservation genetics. PMID- 26024151 TI - Characterization and Luminescence Properties of Lanthanide-Based Polynuclear Complexes Nanoaggregates. AB - For the first time, hexanuclear complexes with general chemical formula [Ln6O(OH)8(NO3)6(H2O)n](2+) with n = 12 for Ln = Sm-Lu and Y and n = 14 for Ln = Pr and Nd were stabilized as nanoaggregates in ethylene glycol (EG). These unprecedented nanoaggregates were structurally characterized by (89)Y and (1)H NMR spectroscopy, UV-vis absorption and luminescence spectroscopies, electrospray ionization mass spectrometry, diffusion ordered spectroscopy, transmission electron microscopy, and dynamic light scattering. These nanoaggregates present a 200 nm mean solvodynamic diameter. In these nanoaggregates, hexanuclear complexes are isolated and solvated by EG molecules. The replacement of ethylene glycol by 2-hydroxybenzyl alcohol provides new nanoaggregates that present an antenna effect toward lanthanide ions. This results in a significant enhancement of the luminescence properties of the aggregates and demonstrates the suitability of the strategy for obtaining highly tunable luminescent solutions. PMID- 26024152 TI - Self-Assembly Synthesis of N-Doped Carbon Aerogels for Supercapacitor and Electrocatalytic Oxygen Reduction. AB - The rational design of high-performance and cheap nanomaterials for multiple sustainable energy storage applications is extremely urgent but remains challenging. Herein, a facile commercial melamine-sponge-directed multicomponent surface self-assembly strategy has been reported to synthesize N-doped carbon aerogels (NCAs) with low density (0.01 g cm(-3)), large open pores, and high surface area (1626 m2 g(-1)). The commercial melamine sponge simultaneously serves as a green N source for N-doping and a 3D scaffold to buffer electrolytes for reducing ion transport resistance and minimizing ion diffusion distance. With their tailored architecture characteristics, the NCAs-based supercapacitor and oxygen reduction electrocatalyst show excellent performance. PMID- 26024153 TI - Family of Bell-like Inequalities as Device-Independent Witnesses for Entanglement Depth. AB - We present a simple family of Bell inequalities applicable to a scenario involving arbitrarily many parties, each of which performs two binary-outcome measurements. We show that these inequalities are members of the complete set of full-correlation Bell inequalities discovered by Werner-Wolf-Zukowski-Brukner. For scenarios involving a small number of parties, we further verify that these inequalities are facet defining for the convex set of Bell-local correlations. Moreover, we show that the amount of quantum violation of these inequalities naturally manifests the extent to which the underlying system is genuinely many body entangled. In other words, our Bell inequalities, when supplemented with the appropriate quantum bounds, naturally serve as device-independent witnesses for entanglement depth, allowing one to certify genuine k-partite entanglement in an arbitrary n>=k-partite scenario without relying on any assumption about the measurements being performed, or the dimension of the underlying physical system. A brief comparison is made between our witnesses and those based on some other Bell inequalities, as well as quantum Fisher information. A family of witnesses for genuine k-partite nonlocality applicable to an arbitrary n>=k-partite scenario based on our Bell inequalities is also presented. PMID- 26024154 TI - Testing nonclassicality and non-gaussianity in phase space. AB - We theoretically propose and experimentally demonstrate a nonclassicality test of a single-mode field in phase space, which has an analogy with the nonlocality test proposed by Banaszek and Wodkiewicz [Phys. Rev. Lett. 82, 2009 (1999)]. Our approach to deriving the classical bound draws on the fact that the Wigner function of a coherent state is a product of two independent distributions as if the orthogonal quadratures (position and momentum) in phase space behave as local realistic variables. Our method detects every pure nonclassical Gaussian state, which can also be extended to mixed states. Furthermore, it sets a bound for all Gaussian states and their mixtures, thereby providing a criterion to detect a genuine quantum non-Gaussian state. Remarkably, our phase-space approach with invariance under Gaussian unitary operations leads to an optimized test for a given non-Gaussian state. We experimentally show how this enhanced method can manifest quantum non-Gaussianity of a state by simply choosing phase-space points appropriately, which is essentially equivalent to implementing a squeezing operation on a given state. PMID- 26024155 TI - Quantum algorithm for universal implementation of the projective measurement of energy. AB - A projective measurement of energy (PME) on a quantum system is a quantum measurement determined by the Hamiltonian of the system. PME protocols exist when the Hamiltonian is given in advance. Unknown Hamiltonians can be identified by quantum tomography, but the time cost to achieve a given accuracy increases exponentially with the size of the quantum system. In this Letter, we improve the time cost by adapting quantum phase estimation, an algorithm designed for computational problems, to measurements on physical systems. We present a PME protocol without quantum tomography for Hamiltonians whose dimension and energy scale are given but which are otherwise unknown. Our protocol implements a PME to arbitrary accuracy without any dimension dependence on its time cost. We also show that another computational quantum algorithm may be used for efficient estimation of the energy scale. These algorithms show that computational quantum algorithms, with suitable modifications, have applications beyond their original context. PMID- 26024156 TI - Nonperturbative leakage elimination operators and control of a three-level system. AB - Dynamical decoupling operations have been shown to reduce errors in quantum information processing. Leakage from an encoded subspace to the rest of the system space is a particularly serious problem for which leakage elimination operators (LEOs) were introduced. Here we provide an analysis of nonideal pulses, rather than the well-understood idealization or bang-bang controls. Under realistic conditions, we show that these controls will provide the same protection from errors as idealized controls. Our work indicates that the effectiveness of LEOs depends on the integral of the pulse sequence in the time domain, which has been missing because of the idealization of pulse sequences. Our results are applied to a three-level system for the nitrogen-vacancy centers under an external magnetic field and are illustrated by the fidelity dynamics of LEO sequences, ranging from regular rectangular pulses, random pulses, and even disordered (noisy) pulses. PMID- 26024157 TI - Columnar order and Ashkin-Teller criticality in mixtures of hard squares and dimers. AB - We show that critical exponents of the transition to columnar order in a mixture of 2*1 dimers and 2*2 hard squares on the square lattice depends on the composition of the mixture in exactly the manner predicted by the theory of Ashkin-Teller criticality, including in the hard-square limit. This result settles the question regarding the nature of the transition in the hard-square lattice gas. It also provides the first example of a polydisperse system whose critical properties depend on composition. Our ideas also lead to some interesting predictions for a class of frustrated quantum magnets that exhibit columnar ordering of the bond energies at low temperature. PMID- 26024158 TI - Three dimensional simulation of the magnetic stress in a neutron star crust. AB - We present the first fully self-consistent three dimensional model of a neutron star's magnetic field, generated by electric currents in the star's crust via the Hall effect. We find that the global-scale field converges to a dipolar Hall attractor state, as seen in recent axisymmetric models, but that small-scale features in the magnetic field survive even on much longer time scales. These small-scale features propagate toward the dipole equator, where the crustal electric currents organize themselves into a strong equatorial jet. By calculating the distribution of magnetic stresses in the crust, we predict that neutron stars with fields stronger than 10^{14} G can still be subject to starquakes more than 10^{5} yr after their formation. PMID- 26024159 TI - Infrared Renormalons versus Operator Product Expansions in Supersymmetric and Related Gauge Theories. AB - We use the connection between infrared (IR) renormalons and condensates in the operator product expansion for correlation functions to make predictions concerning the structure of singularities in the Borel plane for the perturbative series in quantum field theories with different levels of supersymmetry. The same conspiracy can be used for establishing the absence of condensates or IR renormalons in gauge theories with an IR conformal regime or gauge theories in the Higgs phase. The absence of the renormalon-induced factorial divergence implies that instanton contributions (where present) must be well defined. We show that the conventional bubble-chain method for detecting renormalon-induced factorial divergences in these theories is not sufficient. PMID- 26024160 TI - Holographic twin Higgs model. AB - We present the first realization of a "twin Higgs" model as a holographic composite Higgs model. Uniquely among composite Higgs models, the Higgs potential is protected by a new standard model (SM) singlet elementary "mirror" sector at the sigma model scale f and not by the composite states at m_{KK}, naturally allowing for m_{KK} beyond the LHC reach. As a result, naturalness in our model cannot be constrained by the LHC, but may be probed by precision Higgs measurements at future lepton colliders, and by direct searches for Kaluza-Klein excitations at a 100 TeV collider. PMID- 26024163 TI - Peak Locations and Relative Phase of Different Decay Modes of the a_{1} Axial Vector Resonance in Diffractive Production. AB - We show that a single I=1 spin-parity J^{PC}=1^{++} a_{1} resonance can manifest itself as two separated mass peaks, one decaying into an S-wave rhopi system and the second decaying into a P-wave f_{0}(980)pi system, with a rapid increase of the phase difference between their amplitudes arising mainly from the structure of the diffractive production process. This study clarifies questions related to the mass, width, and decay rates of the a_{1} resonance raised by the recent high statistics data of the COMPASS Collaboration on a_{1} production in piN->pipipiN at high energies. PMID- 26024168 TI - Origin of low-lying enhanced E1 strength in rare-Earth nuclei. AB - The experimental E1 strength distribution below 4 MeV in rare-earth nuclei suggests a local breaking of isospin symmetry. In addition to the octupole states, additional J^{pi}=1^{-} states with enhanced E1 strength have been observed in rare-earth nuclei by means of (gamma,gamma') experiments. By reproducing the experimental results, the spdf interacting boson model calculations provide further evidence for the formation of an alpha cluster in medium-mass nuclei and might provide a new understanding of the origin of low lying E1 strength. PMID- 26024172 TI - Experimental generation of squeezed cat States with an operation allowing iterative growth. AB - We present what is, to our knowledge, the first implementation of a "cat breeding" operation, which allows an iterative growth of cat states. We thus report the experimental generation of a squeezed cat state from two single photon Fock states, which can be seen as cat states with zero amplitude. These Fock states are mixed on a symmetrical beam splitter, and the generation is heralded by a homodyne measurement in one of the two output arms. The output state has a fidelity of 61% with an even squeezed cat state of amplitude alpha=1.63. This hybrid operation opens up new prospects in quantum optics, as the protocol depicted here can be iterated in order to produce new kinds of mesoscopic states. PMID- 26024170 TI - Efficient single photon emission and collection based on excitation of gap surface plasmons. AB - Combining the advantages of ultrahigh photon emission rates achievable in the gap surface plasmon polaritons with high extraction decay rates into low-loss nanofibers, we demonstrate theoretically the efficient photon emission of a single dipole emitter and one-dimensional nanoscale guiding in metallic nanorod coupled nanofilm structures coupled to dielectric nanofibers. We find that total decay rates and surface plasmon polariton channel decay rates orders of magnitude larger than those characteristic of metallic nanofilms alone can be achieved in ultrastrong hot spots of gap plasmons. For the requirement of practical applications, propagating single photons with decay rates of 290gamma_{0} 770gamma_{0} are guided into the phase-matched low-loss nanofibers. The proposed mechanism promises to have an important impact on metal-based optical cavities, on-chip bright single photon sources and plasmon-based nanolasers. PMID- 26024169 TI - Quantum-gas microscope for fermionic atoms. AB - We realize a quantum-gas microscope for fermionic ^{40}K atoms trapped in an optical lattice, which allows one to probe strongly correlated fermions at the single-atom level. We combine 3D Raman sideband cooling with high-resolution optics to simultaneously cool and image individual atoms with single-lattice-site resolution at a detection fidelity above 95%. The imaging process leaves the atoms predominantly in the 3D motional ground state of their respective lattice sites, inviting the implementation of a Maxwell's demon to assemble low-entropy many-body states. Single-site-resolved imaging of fermions enables the direct observation of magnetic order, time-resolved measurements of the spread of particle correlations, and the detection of many-fermion entanglement. PMID- 26024171 TI - Cavity-funneled generation of indistinguishable single photons from strongly dissipative quantum emitters. AB - We investigate theoretically the generation of indistinguishable single photons from a strongly dissipative quantum system placed inside an optical cavity. The degree of indistinguishability of photons emitted by the cavity is calculated as a function of the emitter-cavity coupling strength and the cavity linewidth. For a quantum emitter subject to strong pure dephasing, our calculations reveal that an unconventional regime of high indistinguishability can be reached for moderate emitter-cavity coupling strengths and high-quality factor cavities. In this regime, the broad spectrum of the dissipative quantum system is funneled into the narrow line shape of the cavity. The associated efficiency is found to greatly surpass spectral filtering effects. Our findings open the path towards on-chip scalable indistinguishable-photon-emitting devices operating at room temperature. PMID- 26024173 TI - Frequency combs with weakly lasing exciton-polariton condensates. AB - We predict the spontaneous modulated emission from a pair of exciton-polariton condensates due to coherent (Josephson) and dissipative coupling. We show that strong polariton-polariton interaction generates complex dynamics in the weak lasing domain way beyond Hopf bifurcations. As a result, the exciton-polariton condensates exhibit self-induced oscillations and emit an equidistant frequency comb light spectrum. A plethora of possible emission spectra with asymmetric peak distributions appears due to spontaneously broken time-reversal symmetry. The lasing dynamics is affected by the shot noise arising from the influx of polaritons. That results in a complex inhomogeneous line broadening. PMID- 26024166 TI - Evidence of soft dipole resonance in ^{11}li with isoscalar character. AB - The first conclusive evidence of a dipole resonance in ^{11}Li having isoscalar character observed from inelastic scattering with a novel solid deuteron target is reported. The experiment was performed at the newly commissioned IRIS facility at TRIUMF. The results show a resonance peak at an excitation energy of 1.03+/ 0.03 MeV with a width of 0.51+/-0.11 MeV (FWHM). The angular distribution is consistent with a dipole excitation in the distorted-wave Born approximation framework. The observed resonance energy together with shell model calculations show the first signature that the monopole tensor interaction is important in ^{11}Li. The first ab initio calculations in the coupled cluster framework are also presented. PMID- 26024165 TI - beta-Decay Half-Lives of 110 Neutron-Rich Nuclei across the N=82 Shell Gap: Implications for the Mechanism and Universality of the Astrophysical r Process. AB - The beta-decay half-lives of 110 neutron-rich isotopes of the elements from _{37}Rb to _{50}Sn were measured at the Radioactive Isotope Beam Factory. The 40 new half-lives follow robust systematics and highlight the persistence of shell effects. The new data have direct implications for r-process calculations and reinforce the notion that the second (A~130) and the rare-earth-element (A~160) abundance peaks may result from the freeze-out of an (n,gamma)?(gamma,n) equilibrium. In such an equilibrium, the new half-lives are important factors determining the abundance of rare-earth elements, and allow for a more reliable discussion of the r process universality. It is anticipated that universality may not extend to the elements Sn, Sb, I, and Cs, making the detection of these elements in metal-poor stars of the utmost importance to determine the exact conditions of individual r-process events. PMID- 26024174 TI - Axial momentum lost to a lateral wall of a helicon plasma source. AB - Momentum exerted to a lateral wall of a helicon plasma source is individually measured for argon, krypton, and xenon gases. A significant loss of the axial plasma momentum to the lateral wall, which has been assumed to be negligible, is experimentally identified when an axially asymmetric density profile is formed in the source. This indicates that the radially lost ions deliver not only the radial momentum but also the axial momentum to the lateral wall. The formation of the axial asymmetry causing the momentum loss is interpreted with competition between the magnetic field and neutral depletion effects. PMID- 26024167 TI - Precision Measurement of the p(e,e^{'}p)pi^{0} Reaction at Threshold. AB - New results are reported from a measurement of pi^{0} electroproduction near threshold using the p(e,e^{'}p)pi^{0} reaction. The experiment was designed to determine precisely the energy dependence of s- and p-wave electromagnetic multipoles as a stringent test of the predictions of chiral perturbation theory (ChPT). The data were taken with an electron beam energy of 1192 MeV using a two spectrometer setup in Hall A at Jefferson Lab. For the first time, complete coverage of the phi_{pi}^{*} and theta_{pi}^{*} angles in the ppi^{0} center of mass was obtained for invariant energies above threshold from 0.5 up to 15 MeV. The 4-momentum transfer Q^{2} coverage ranges from 0.05 to 0.155 (GeV/c)^{2} in fine steps. A simple phenomenological analysis of our data shows strong disagreement with p-wave predictions from ChPT for Q^{2}>0.07 (GeV/c)^{2}, while the s-wave predictions are in reasonable agreement. PMID- 26024175 TI - Direct heating of a laser-imploded core by ultraintense laser-driven ions. AB - A novel direct core heating fusion process is introduced, in which a preimploded core is predominantly heated by energetic ions driven by LFEX, an extremely energetic ultrashort pulse laser. Consequently, we have observed the D(d,n)^{3}He reacted neutrons (DD beam-fusion neutrons) with the yield of 5*10^{8} n/4pi sr. Examination of the beam-fusion neutrons verified that the ions directly collide with the core plasma. While the hot electrons heat the whole core volume, the energetic ions deposit their energies locally in the core, forming hot spots for fuel ignition. As evidenced in the spectrum, the process simultaneously excited thermal neutrons with the yield of 6*10^{7} n/4pi sr, raising the local core temperature from 0.8 to 1.8 keV. A one-dimensional hydrocode STAR 1D explains the shell implosion dynamics including the beam fusion and thermal fusion initiated by fast deuterons and carbon ions. A two-dimensional collisional particle-in-cell code predicts the core heating due to resistive processes driven by hot electrons, and also the generation of fast ions, which could be an additional heating source when they reach the core. Since the core density is limited to 2 g/cm^{3} in the current experiment, neither hot electrons nor fast ions can efficiently deposit their energy and the neutron yield remains low. In future work, we will achieve the higher core density (>10 g/cm^{3}); then hot electrons could contribute more to the core heating via drag heating. Together with hot electrons, the ion contribution to fast ignition is indispensable for realizing high-gain fusion. By virtue of its core heating and ignition, the proposed scheme can potentially achieve high gain fusion. PMID- 26024177 TI - Orbital angular momentum and spectral flow in two-dimensional chiral superfluids. AB - We study the orbital angular momentum (OAM) L_{z} in two-dimensional chiral (p_{x}+ip_{y})^{nu}-wave superfluids (SFs) of N fermions on a disk at zero temperature, in terms of spectral asymmetry and spectral flow. It is shown that L_{z}=nuN/2 for any integer nu, in the Bose-Einstein condensation regime. In contrast, in the BCS limit, while the OAM is L_{z}=N/2 for the p+ip-wave SF, for chiral SFs with nu>=2, the OAM is remarkably suppressed as L_{z}=N*O(Delta_{0}/epsilon_{F})?N, where Delta_{0} is the gap amplitude and epsilon_{F} is the Fermi energy. We demonstrate that the difference between the p+ip-wave SF and the other chiral SFs in the BCS regimes originates from the nature of edge modes and related depairing effects. PMID- 26024176 TI - Tunable all-optical quasimonochromatic thomson x-ray source in the nonlinear regime. AB - We present an all-laser-driven, energy-tunable, and quasimonochromatic x-ray source based on Thomson scattering from laser-wakefield-accelerated electrons. One part of the laser beam was used to drive a few-fs bunch of quasimonoenergetic electrons, while the remainder was backscattered off the bunch at weakly relativistic intensity. When the electron energy was tuned from 17-50 MeV, narrow x-ray spectra peaking at 5-42 keV were recorded with high resolution, revealing nonlinear features. We present a large set of measurements showing the stability and practicality of our source. PMID- 26024178 TI - Feshbach-stabilized insulator of bosons in optical lattices. AB - Feshbach resonances-namely, resonances between an unbound two-body (atomic) state and a bound (molecular) state, differing in magnetic moment-are a unique tool to tune the interaction properties of ultracold atoms. Here we show that the spin changing interactions, coherently coupling the atomic and molecular states, can act as a novel mechanism to stabilize an insulating phase-the Feshbach insulator for bosons in an optical lattice close to a narrow Feshbach resonance. Making use of quantum Monte Carlo simulations and mean-field theory, we show that the Feshbach insulator appears around the resonance, preventing the system from collapsing when the effective atomic scattering length becomes negative. On the atomic side of the resonance, the transition from condensate to Feshbach insulator has a characteristic first-order nature, due to the simultaneous loss of coherence in the atomic and molecular components. These features appear clearly in the ground-state phase diagram of, e.g., ^{87}Rb around its 414 G resonance, and they are therefore directly amenable to experimental observation. PMID- 26024179 TI - Vacuum channeling radiation by relativistic electrons in a transverse field of a laser-based Bessel beam. AB - Relativistic electrons counterpropagating through the center of a radially polarized J_{1} optical Bessel beam in vacuum will emit radiation in a manner analogous to the channeling radiation that occurs when charged particles traverse through a crystal lattice. However, since this interaction occurs in vacuum, problems with scattering of the electrons by the lattice atoms are eliminated. Contrary to inverse Compton scattering, the emitted frequency is also determined by the amplitude of the laser field, rather than only by its frequency. Adjusting the value of the laser field permits the tuning of the emitted frequency over orders of magnitude, from terahertz to soft X rays. High flux intensities are predicted (~100 MW/cm^{2}). Extended interaction lengths are feasible due to the diffraction-free properties of the Bessel beam and its radial field, which confines the electron trajectory within the center of the Bessel beam. PMID- 26024180 TI - Incommensurate systems as model compounds for disorder revealing low-temperature glasslike behavior. AB - We show that the specific heat of incommensurately modulated crystals with broken translational periodicity presents similar features at low temperatures to those of amorphous and glass materials. Here we demonstrate that the excess to the constant C_{p}(T)/T^{3} law (or Debye limit) is made up of an upturn below 1 K and of a broad bump at T~10 K that directly originates from the gapped phase and amplitude modes of the incommensurate structure. We argue that the low-energy dynamics of incommensurate systems constitute a plausible simplification of the landscape of interactions present in glasses, giving rise to their low temperature anomalies. PMID- 26024181 TI - Consolidation of Partially Stabilized ZrO_{2} in the Presence of a Noncontacting Electric Field. AB - Electric field-assisted sintering techniques demonstrate accelerated densification at lower temperatures than the conventional sintering methods. However, it is still debated whether the applied field and/or resulting currents are responsible for the densification enhancement. To distinguish the effects of an applied field from current flow, in situ scanning transmission electron microscopy experiments with soft agglomerates of partially stabilized yttria doped zirconia particles are carried out. A new microelectromechanical system based sample support is used to heat particle agglomerates while simultaneously exposing them to an externally applied noncontacting electric field. Under isothermal condition at 900 degrees C, an electric field strength of 500 V/cm shows a sudden threefold enhancement in the shrinkage of the agglomerates. The applied electrostatic potential lowers the activation energy for point defect formation within the space charge zone and therefore promotes consolidation. Obtaining similar magnitudes of shrinkage in the absence of any electric field requires a higher temperature and longer time. PMID- 26024182 TI - Understanding Anharmonicity in fcc Materials: From its Origin to ab initio Strategies beyond the Quasiharmonic Approximation. AB - We derive the Gibbs energy including the anharmonic contribution due to phonon phonon interactions for an extensive set of unary fcc metals (Al, Ag, Au, Cu, Ir, Ni, Pb, Pd, Pt, Rh) by combining density-functional-theory (DFT) calculations with efficient statistical sampling approaches. We show that the anharmonicity of the macroscopic system can be traced back to the anharmonicity in local pairwise interactions. Using this insight, we derive and benchmark a highly efficient approach which allows the computation of anharmonic contributions using a few T=0 K DFT calculations only. PMID- 26024184 TI - Hierarchy of modes in an interacting one-dimensional system. AB - Studying interacting fermions in one dimension at high energy, we find a hierarchy in the spectral weights of the excitations theoretically, and we observe evidence for second-level excitations experimentally. Diagonalizing a model of fermions (without spin), we show that levels of the hierarchy are separated by powers of R^{2}/L^{2}, where R is a length scale related to interactions and L is the system length. The first-level (strongest) excitations form a mode with parabolic dispersion, like that of a renormalized single particle. The second-level excitations produce a singular power-law line shape to the first-level mode and multiple power laws at the spectral edge. We measure momentum-resolved tunneling of electrons (fermions with spin) from or to a wire formed within a GaAs heterostructure, which shows parabolic dispersion of the first-level mode and well-resolved spin-charge separation at low energy with appreciable interaction strength. We find structure resembling the second-level excitations, which dies away quite rapidly at high momentum. PMID- 26024183 TI - Ultrafast Atomic Diffusion Inducing a Reversible (2sqrt[3]*2sqrt[3])R30 degrees < >(sqrt[3]*sqrt[3])R30 degrees Transition on Sn/Si(111)?B. AB - Dynamical phase transitions are a challenge to identify experimentally and describe theoretically. Here, we study a new reconstruction of Sn on silicon and observe a reversible transition where the surface unit cell divides its area by a factor of 4 at 250 degrees C. This phase transition is explained by the 24-fold degeneracy of the ground state and a novel diffusive mechanism, where four Sn atoms arranged in a snakelike cluster wiggle at the surface exploring collectively the different quantum mechanical ground states. PMID- 26024185 TI - Extraordinary exciton conductance induced by strong coupling. AB - We demonstrate that exciton conductance in organic materials can be enhanced by several orders of magnitude when the molecules are strongly coupled to an electromagnetic mode. Using a 1D model system, we show how the formation of a collective polaritonic mode allows excitons to bypass the disordered array of molecules and jump directly from one end of the structure to the other. This finding could have important implications in the fields of exciton transistors, heat transport, photosynthesis, and biological systems in which exciton transport plays a key role. PMID- 26024186 TI - Cavity-enhanced transport of excitons. AB - We show that exciton-type transport in certain materials can be dramatically modified by their inclusion in an optical cavity: the modification of the electromagnetic vacuum mode structure introduced by the cavity leads to transport via delocalized polariton modes rather than through tunneling processes in the material itself. This can help overcome exponential suppression of transmission properties as a function of the system size in the case of disorder and other imperfections. We exemplify massive improvement of transmission for excitonic wave packets through a cavity, as well as enhancement of steady-state exciton currents under incoherent pumping. These results may have implications for experiments of exciton transport in disordered organic materials. We propose that the basic phenomena can be observed in quantum simulators made of Rydberg atoms, cold molecules in optical lattices, as well as in experiments with trapped ions. PMID- 26024187 TI - Thermal vector potential theory of transport induced by a temperature gradient. AB - A microscopic formalism to calculate thermal transport coefficients is presented based on a thermal vector potential, whose time derivative is related to a thermal force. The formalism is free from the unphysical divergences reported to arise when Luttinger's formalism is applied naively, because the equilibrium ("diamagnetic") currents are treated consistently. The mathematical structure for the thermal transport coefficients is shown to be identical with that for the electric ones if the electric charge is replaced by the energy. The results indicate that the thermal vector potential couples to the energy current via the minimal coupling. PMID- 26024188 TI - Experimental Demonstration of Room-Temperature Spin Transport in n-Type Germanium Epilayers. AB - We report an experimental demonstration of room-temperature spin transport in n type Ge epilayers grown on a Si(001) substrate. By utilizing spin pumping under ferromagnetic resonance, which inherently endows a spin battery function for semiconductors connected with a ferromagnet, a pure spin current is generated in the n-Ge at room temperature. The pure spin current is detected by using the inverse spin-Hall effect of either a Pt or Pd electrode on n-Ge. From a theoretical model that includes a geometrical contribution, the spin diffusion length in n-Ge at room temperature is estimated to be 660 nm. Moreover, the spin relaxation time decreases with increasing temperature, in agreement with a recently proposed theory of donor-driven spin relaxation in multivalley semiconductors. PMID- 26024189 TI - Determination of formation and ionization energies of charged defects in two dimensional materials. AB - We present a simple and efficient approach to evaluate the formation energy and, in particular, the ionization energy (IE) of charged defects in two-dimensional (2D) systems using the supercell approximation. So far, first-principles results for such systems can scatter widely due to the divergence of the Coulomb energy with vacuum dimension, denoted here as L_{z}. Numerous attempts have been made in the past to fix the problem under various approximations. Here, we show that the problem can be resolved without any such assumption, and a converged IE can be obtained by an extrapolation of the asymptotic IE expression at large L_{z} (with a fixed lateral area S) back to the value at L_{z}=0. Application to defects in monolayer boron nitride reveal that defects in 2D systems can be unexpectedly deep, much deeper than the bulk. PMID- 26024190 TI - Phonon-assisted gain in a semiconductor double quantum dot maser. AB - We develop a microscopic model for the recently demonstrated double-quantum-dot maser. In characterizing the gain of this device we find that, in addition to the direct stimulated emission of photons, there is a large contribution from the simultaneous emission of a photon and a phonon, i.e., the phonon sideband. We show that this phonon-assisted gain typically dominates the overall gain, which leads to masing. Recent experimental data are well fit with our model. PMID- 26024191 TI - Coexistence of charge-density-wave and pair-density-wave orders in underdoped cuprates. AB - We analyze incommensurate charge-density-wave (CDW) and pair-density-wave (PDW) orders with transferred momenta (+/-Q,0)/(0,+/-Q) in underdoped cuprates within the spin-fermion model. Both orders appear due to an exchange of spin fluctuations before magnetic order develops. We argue that the ordered state with the lowest energy has nonzero CDW and PDW components with the same momentum. Such a state breaks C_{4} lattice rotational symmetry, time-reversal symmetry, and mirror symmetries. We argue that the feedback from CDW/PDW order on fermionic dispersion is consistent with ARPES data. We discuss the interplay between the CDW/PDW order and d_{x^{2}-y^{2}} superconductivity and make specific predictions for experiments. PMID- 26024192 TI - Theory of Electromagnons in CuO. AB - We develop a theory of electromagnons in CuO by combining a symmetry analysis based on irreducible corepresentations, ab initio calculations, and simulations of spin dynamics using a model Hamiltonian and the Landau-Lifshitz-Gilbert equation. We show that the electromagnon measured in [Jones et al., Nat. Commun. 5, 3787 (2014)] with the electric field along the [101] direction originates from a magnetoelectric coupling mediated by Dzyaloshinskii-Moriya interactions and consists of a rigid rotation of the Cu spins around the axis defined by the electric field. Furthermore we predict the existence of a second electromagnon originating from exchange striction and coupled to electric fields along the [010] direction in the AF2 phase. PMID- 26024193 TI - Microwave Magnetochiral Dichroism in the Chiral-Lattice Magnet Cu_{2}OSeO_{3}. AB - Through broadband microwave spectroscopy in Faraday geometry, we observe distinct absorption spectra accompanying magnetoelectric (ME) resonance for oppositely propagating microwaves, i.e., directional dichroism, in the multiferroic chiral lattice magnet Cu_{2}OSeO_{3}. The magnitude of the directional dichroism critically depends on the magnetic-field direction. Such behavior is well accounted for by considering the relative direction of the oscillating electric polarizations induced via the ME effect with respect to microwave electric fields. Directional dichroism in a system with an arbitrary form of ME coupling can be also discussed in the same manner. PMID- 26024194 TI - Microwave Magnetochiral Effect in Cu_{2}OSeO_{3}. AB - We theoretically find that in the multiferroic chiral magnet Cu_{2}OSeO_{3} resonant magnetic excitations are coupled to the collective oscillation of the electric polarization, and thereby attain simultaneous activity to the ac magnetic field and ac electric field. Because of the interference between these magnetic and electric activation processes, this material hosts a gigantic magnetochiral dichroism for microwaves, that is, a directional dichroism at gigahertz frequencies in the Faraday geometry. The absorption intensity of a microwave differs by as much as ~30% depending on whether its propagation direction is parallel or antiparallel to the external magnetic field. PMID- 26024195 TI - Coupling of chiralities in spin and physical spaces: the Mobius ring as a case study. AB - We show that the interaction of the magnetic subsystem of a curved magnet with the magnet curvature results in the coupling of a topologically nontrivial magnetization pattern and topology of the object. The mechanism of this coupling is explored and illustrated by an example of a ferromagnetic Mobius ring, where a topologically induced domain wall appears as a ground state in the case of strong easy-normal anisotropy. For the Mobius geometry, the curvilinear form of the exchange interaction produces an additional effective Dzyaloshinskii-like term which leads to the coupling of the magnetochirality of the domain wall and chirality of the Mobius ring. Two types of domain walls are found, transversal and longitudinal, which are oriented across and along the Mobius ring, respectively. In both cases, the effect of magnetochirality symmetry breaking is established. The dependence of the ground state of the Mobius ring on its geometrical parameters and on the value of the easy-normal anisotropy is explored numerically. PMID- 26024164 TI - Measurement of Long-Range Angular Correlation and Quadrupole Anisotropy of Pions and (Anti)Protons in Central d+Au Collisions at sqrt[s_{NN}]=200 GeV. AB - We present azimuthal angular correlations between charged hadrons and energy deposited in calorimeter towers in central d+Au and minimum bias p+p collisions at sqrt[s_{NN}]=200 GeV. The charged hadron is measured at midrapidity |eta|<0.35, and the energy is measured at large rapidity (-3.72.75 is observed in d+Au collisions. Using the event plane method applied to the Au-going energy distribution, we extract the anisotropy strength v_{2} for inclusive charged hadrons at midrapidity up to p_{T}=4.5 GeV/c. We also present the measurement of v_{2} for identified pi^{+/-} and (anti)protons in central d+Au collisions, and observe a mass-ordering pattern similar to that seen in heavy-ion collisions. These results are compared with viscous hydrodynamic calculations and measurements from p+Pb at sqrt[s_{NN}]=5.02 TeV. The magnitude of the mass ordering in d+Au is found to be smaller than that in p+Pb collisions, which may indicate smaller radial flow in lower energy d+Au collisions. PMID- 26024196 TI - Photon bunching in cathodoluminescence. AB - We have measured the second order correlation function [g^{(2)}(tau)] of the cathodoluminescence intensity resulting from the excitation by fast electrons of defect centers in wide band-gap semiconductor nanocrystals of diamond and hexagonal boron nitride. We show that the cathodoluminescence second order correlation function g^{(2)}(tau) of multiple defect centers is dominated by a large, nanosecond zero-delay bunching (g^{(2)}(0)>30), in stark contrast to their flat photoluminescence g^{(2)}(tau) function. We have developed a model showing that this bunching can be attributed to the synchronized emission from several defect centers excited by the same electron through the deexcitation of a bulk plasmon into few electron-hole pairs. PMID- 26024197 TI - Motional averaging of nuclear resonance in a field gradient. AB - The traditional view of nuclear-spin decoherence in a field gradient due to molecular self-diffusion is challenged on the basis of temperature dependence of the linewidth, which demonstrates different behaviors between liquids and gases. The conventional theory predicts that in a fluid, linewidth should increase with temperature; however, in gases we observed the opposite behavior. This surprising behavior can be explained using a more detailed theoretical description of the dephasing function that accounts for position autocorrelation effects. PMID- 26024198 TI - Core-level spectroscopy to probe the oxidation state of single europium atoms. AB - The valence of individual europium atoms confined in carbon nanotubes is successfully measured by using core-level electron energy loss spectroscopy. Changes in the oxidation state at the atomic scale have been observed in Eu atomic chains exposed to oxygen. A transitory behavior has been identified where multiple atoms show a signal consistent with a sum of Eu^{2+} and Eu^{3+}. This indicates that single atoms change their valence state multiple times during the reaction, suggesting that oxidation in confined spaces and with extra energy input (from the electron beam) might not be a simple one step electron transfer event. PMID- 26024199 TI - Cages and anomalous diffusion in vibrated dense granular media. AB - A vertically shaken granular medium hosts a blade rotating around a fixed vertical axis, which acts as a mesorheological probe. At high densities, independently of the shaking intensity, the blade's dynamics shows strong caging effects, marked by transient subdiffusion and a maximum in the velocity power density spectrum, at a resonant frequency ~10 Hz. Interpreting the data through a diffusing harmonic cage model allows us to retrieve the elastic constant of the granular medium and its collective diffusion coefficient. For high frequencies f, a tail ~1/f in the velocity power density spectrum reveals nontrivial correlations in the intracage microdynamics. At very long times (larger than 10 s), a superdiffusive behavior emerges, ballistic in the most extreme cases. Consistently, the distribution of slow velocity inversion times tau displays a power-law decay, likely due to persistent collective fluctuations of the host medium. PMID- 26024200 TI - Mortality, redundancy, and diversity in stochastic search. AB - We investigate a stochastic search process in one dimension under the competing roles of mortality, redundancy, and diversity of the searchers. This picture represents a toy model for the fertilization of an oocyte by sperm. A population of N independent and mortal diffusing searchers all start at x=L and attempt to reach the target at x=0. When mortality is irrelevant, the search time scales as tau_{D}/lnN for lnN?1, where tau_{D}~L^{2}/D is the diffusive time scale. Conversely, when the mortality rate MU of the searchers is sufficiently large, the search time scales as sqrt[tau_{D}/MU], independent of N. When searchers have distinct and high mortalities, a subpopulation with a nontrivial optimal diffusivity is most likely to reach the target. We also discuss the effect of chemotaxis on the search time and its fluctuations. PMID- 26024201 TI - Pressure and phase equilibria in interacting active brownian spheres. AB - We derive a microscopic expression for the mechanical pressure P in a system of spherical active Brownian particles at density rho. Our exact result relates P, defined as the force per unit area on a bounding wall, to bulk correlation functions evaluated far away from the wall. It shows that (i) P(rho) is a state function, independent of the particle-wall interaction; (ii) interactions contribute two terms to P, one encoding the slow-down that drives motility induced phase separation, and the other a direct contribution well known for passive systems; and (iii) P is equal in coexisting phases. We discuss the consequences of these results for the motility-induced phase separation of active Brownian particles and show that the densities at coexistence do not satisfy a Maxwell construction on P. PMID- 26024202 TI - Shape of dynamical heterogeneities and fractional Stokes-Einstein and Stokes Einstein-Debye relations in quasi-two-dimensional suspensions of colloidal ellipsoids. AB - We examine the influence of the shape of dynamical heterogeneities on the Stokes Einstein (SE) and Stokes-Einstein-Debye (SED) relations in quasi-two-dimensional suspensions of colloidal ellipsoids. For ellipsoids with repulsive interactions, both SE and SED relations are violated at all area fractions. On approaching the glass transition, however, the extent to which this violation occurs changes beyond a crossover area fraction. Quite remarkably, we find that it is not just the presence of dynamical heterogeneities but their change in the shape from stringlike to compact that coincides with this crossover. On introducing a suitable short-range depletion attraction between the ellipsoids, associated with the lack of morphological evolution of dynamical heterogeneities, the extent to which the SE and SED relations are violated remains unchanged even for deep supercooling. PMID- 26024203 TI - Concentrating genomic length DNA in a microfabricated array. AB - We demonstrate that a microfabricated bump array can concentrate genomic-length DNA molecules efficiently at continuous, high flow velocities, up to 40 MUm/s, if the single-molecule DNA globule has a sufficiently large shear modulus. Increase in the shear modulus is accomplished by compacting the DNA molecules to minimal coil size using polyethylene glycol (PEG) derived depletion forces. We map out the sweet spot, where concentration occurs, as a function of PEG concentration and flow speed using a combination of theoretical analysis and experiment. Purification of DNA from enzymatic reactions for next-generation DNA-sequencing libraries will be an important application of this development. PMID- 26024204 TI - HYSCORE Analysis of the Effects of Substrates on Coordination of Water to the Active Site Iron in Tyrosine Hydroxylase. AB - Tyrosine hydroxylase is a mononuclear non-heme iron monooxygenase found in the central nervous system that catalyzes the hydroxylation of tyrosine to yield L 3,4-dihydroxyphenylalanine, the rate-limiting step in the biosynthesis of catecholamine neurotransmitters. Catalysis requires the binding of tyrosine, a tetrahydropterin, and O2 at an active site that consists of a ferrous ion coordinated facially by the side chains of two histidines and a glutamate. We used nitric oxide as a surrogate for O2 to poise the active site iron in an S = 3/2 {FeNO}7 form that is amenable to electron paramagnetic resonance (EPR) spectroscopy. The pulsed EPR method of hyperfine sublevel correlation (HYSCORE) spectroscopy was then used to probe the ligands at the remaining labile coordination sites on iron. For the complex formed by the addition of tyrosine and nitric oxide, TyrH/NO/Tyr, orientation-selective HYSCORE studies provided evidence of the coordination of one H2O molecule characterized by proton isotropic hyperfine couplings (A(iso) = 0.0 +/- 0.3 MHz) and dipolar couplings (T = 4.4 and 4.5 +/- 0.2 MHz). These data show complex HYSCORE cross peak contours that required the addition of a third coupled proton, characterized by an A(iso) of 2.0 MHz and a T of 3.8 MHz, to the analysis. This proton hyperfine coupling differed from those measured previously for H2O bound to {FeNO}7 model complexes and was assigned to a hydroxide ligand. For the complex formed by the addition of tyrosine, 6-methyltetrahydropterin, and NO, TyrH/NO/Tyr/6-MPH4, the HYSCORE cross peaks attributed to H2O and OH- for the TyrH/NO/Tyr complex were replaced by a cross peak due to a single proton characterized by an A(iso) of 0.0 MHz and a dipolar coupling (T = 3.8 MHz). This interaction was assigned to the N5 proton of the reduced pterin. PMID- 26024205 TI - beta-Galactosidase from Ginkgo biloba seeds active against beta-galactose containing N-glycans: purification and characterization. AB - In this study, we purified an acidic beta-galactosidase to homogeneity from Ginkgo biloba seeds (beta-Gal'ase Gb-1) with approximately 270-fold purification. A molecular mass of the purified beta-Gal'ase Gb-1 was estimated about 35 kDa by gel filtration and 32 kDa by SDS-PAGE under non-reducing condition, respectively. On the other hand, beta-Gal'ase Gb-1 produced a single band with a molecular mass of 16 kDa by SDS-PAGE under reducing condition. The N-terminal amino acid sequences of 32 kDa and 16 kDa molecules were the same and identified as H-K-A-N X-V-T-V-A-F-V-M-T-Q-H-, suggesting that beta-Gal'ase Gb-1 may function as a homodimeric structure in vivo. When complex-type N-glycans containing beta galactosyl residues were used as substrates, beta-Gal'ase Gb-1 showed substantial activity for beta1-4 galactosyl residue and modest activity for beta1-3 galactosyl residue with an optimum pH near 5.0. Based on these results, the involvement of beta-Gal'ase Gb-1 in the degradation of plant complex-type N glycans is discussed. PMID- 26024206 TI - 2D Cross Sectional Analysis and Associated Electrochemistry of Composite Electrodes Containing Dispersed Agglomerates of Nanocrystalline Magnetite, Fe3O4. AB - When electroactive nanomaterials are fully incorporated into an electrode structure, characterization of the crystallite sizes, agglomerate sizes, and dispersion of the electroactive materials can lend insight into the complex electrochemistry associated with composite electrodes. In this study, composite magnetite electrodes were sectioned using ultramicrotome techniques, which facilitated the direct observation of crystallites and agglomerates of magnetite (Fe3O4) as well as their dispersal patterns in large representative sections of electrode, via 2D cross sectional analysis by Transmission Electron Microscopy (TEM). Further, the electrochemistry of these electrodes were recorded, and Transmission X-ray Microscopy (TXM) was used to determine the distribution of oxidation states of the reduced magnetite. Unexpectedly, while two crystallite sizes of magnetite were employed in the production of the composite electrodes, the magnetite agglomerate sizes and degrees of dispersion in the two composite electrodes were similar to each other. This observation illustrates the necessity for careful characterization of composite electrodes, in order to understand the effects of crystallite size, agglomerate size, and level of dispersion on electrochemistry. PMID- 26024207 TI - Y-Type Urethral Duplication: A True Variant of the Anomaly or a Misnomer? AB - Objectives The objective of this study was to define anatomical and radiological features of the so-called Y-type urethral duplication. Methods The study included four male patients and one female patient with congenital connection between the urogenital tract and the external anal orifice. Investigations included renal sonography, urethrograms, and magnetic resonance imaging pelvis in the last patient. The urethrograms of male patients were carefully reviewed, in addition to available urethrograms of similar cases that could be obtained through searching the literature. Results Unlike cases of urethral duplication, the male patients had always a complete prepuce and a functioning anterior urethra in 25%. The accessory uroanal channel had almost always a constant origin from the posterior urethra. Some tension seems to be exerted by the urethroanal tract pulling on and causing a kink in the posterior urethra. Management was simple in patients without anterior urethral hypoplasia (one male and the female patient). Both were treated by simple excision of the communicating ano-urogenital tract through a perineal approach with an excellent outcome. Histopathological examination of excised tracts revealed stratified squamous cell in the former and transitional cell lining in the latter. In patients with hypoplastic anterior urethra, staged urethral reconstruction was performed in two, and progressive dilatation of hypoplastic anterior urethra was tried in the last patient. Conclusion Several observations would support diagnosing the congenital connection between the urinary tract and the external anal orifice in the male as a congenital fistula rather than an accessory urethra. Confirming and accepting this information may have its impact on changing the current surgical approach. PMID- 26024208 TI - Intramural Injection with Botulinum Toxin Type A in Piglet Esophagus. The Influencer on Maximum Load and Elongation: A Dose Response Study. AB - Introduction The treatment of esophageal atresia (OA) is challenging. The main goal is to achieve primary anastomosis. We have previously demonstrated in a pig model that intramural injection of botulinum toxin type A (BTX-A) resulted in significant elongation of the esophagus during tensioning until bursting point. The objectives of the present study were to investigate the influence of different amounts of intramural BTX-A on the stretch-tension characteristics and histological changes of the esophagus in piglets. Materials and Methods A total of 52 piglets were randomized to four groups receiving 2, 4, or 8 units/kg of BTX A or isotonic saline (placebo). After a 1-hour of rest the esophagus was harvested and subjected to a stretch-tension test and histological examination to assess changes in the density of presynaptic vesicles in the nerve cells. Results Overall, 9 of the 52 animals were excluded from analysis due to problems with the stretch-tension test or death from anesthesia. The maximum loads were higher in the BTX-A groups (2 units/kg: +2.1 N; 4 units/kg: +1.3 N; 8 units/kg: +1.9 N) than the placebo (p = 0.046). There were no significant differences in percentage elongation, or histology. Conclusions This study demonstrated that injection of 2 units/kg BTX-A into a nonanastomosed esophageal wall resulted in a modest increase in the maximum load achieved before bursting; this may be due to the muscle-relaxant effect of BTX-A. BTX-A injection produced no significant effects on elongation or esophageal histology. The clinical usefulness of BTX-A in treatment of OA is still unclear. PMID- 26024209 TI - The Surgical Management of H-Type Rectovestibular Fistula: A Novel Modification. AB - Introduction H-type rectovestibular fistulas could be rare anorectal malformations or acquired diseases secondary to perianal infection. Various surgical procedures have been described in the literature, however the problem of recurrence still remains to be solved. We describe a novel modified surgical procedure and outcome in the management of these patients. Methods From 1999 to 2014, 14 patients who had an H-type rectovestibular fistula underwent the same surgical procedure performed by the same surgical team. Rectal-vestibular pull through inside-out and endorectal mucosal advancement flap was used, including circumferential incision of the fistula from the opening on the rectal side, pulling the fistula inside-out, ligating the fistula, and mobilizing a rectal mucosal flap to cover the internal opening. Results All the patients have been followed-up for 12 months to 15 years with no recurrences and no incontinence. Conclusion Our surgical management is a simple, safe, and probable choice for the treatment of H-type rectovestibular fistula with favorable outcomes. PMID- 26024210 TI - Aetiological blood biomarkers of ischaemic stroke. AB - Each year, over 5 million people die worldwide from stroke, and at least every sixth patient who survives will experience another stroke within five years [1]. We are therefore eager to advance early and rapid diagnosis, prognosis and optimal risk stratification, as well as secondary prevention. In this context, blood biomarkers may improve patient care, as they have already done in other fields in the past, for example, troponin T/I in patients with heart attacks, natriuretic peptides in patients with heart failure or PCT (procalcitonin) [2] in patients with pneumonia. In the setting of acute stroke, a blood biomarker can be any quantifiable entity that reflects the manifestation of a stroke-related process. The most fruitful implementation of stroke biomarkers is in areas where information from traditional clinical sources is limited. There may be markers, for example, to guide risk stratification, reveal stroke aetiology, identify patients who may benefit most from interventions, monitor treatment efficacy, and recognise the risk of short-term complications or unfavourable long-term outcomes. For this review we focus on blood biomarkers that could help distinguish the underlying aetiology of an ischaemic stroke. Stroke tends to be a much more heterogeneous condition than ischaemic heart disease, which is caused by atherosclerosis in the vast majority of cases. Causes of stroke include small and large vessel disease, cardioembolism, dissections, and rare vasculo- and coagulopathies, among others. Because of this heterogeneity among stroke patients, it is clear that a monolithic approach to stroke prevention or secondary prevention is not warranted. Aetiological classification is important specifically because prognosis, risk of recurrence and management options differ greatly between aetiological subtypes. Considering that today up to 30% of stroke patients still cannot be classified into a specific subtype [3], the ability to improve aetiological classification to direct prevention methods at the underlying mechanism would be of greatest interest. For this review we collected data from studies, on aetiological blood biomarkers in ischaemic stroke patients, listed in PubMed up to October 2014. We describe the potential role of 22 selected blood biomarkers in the context of stroke aetiology. Finally we provide the readers with an outlook in this research field. PMID- 26024211 TI - Nanosystems: the use of nanoalloys, metallic, bimetallic, and magnetic nanoparticles in biomedical applications. AB - There is a growing interest in the use of nanosystems such as nanoalloys, bimetallic nanoparticles, metallic nanoparticles and magnetic nanoparticles in biomedical applications. These applications can be as diverse as hyperthermic treatments; targeted drug delivery; bio-imaging; cell labelling and gene delivery. The use of nanoalloys in these applications has received only limited attention due to the fact that there were many unanswered questions and concerns regarding nanoparticles and nanoalloys such as their stability over time, tendency to agglomerate, chemical activity, ease of oxidation, biocompatibility and cytotoxicity. In this chapter we survey current applications and advances in magnetic nanoparticles used in these biomedical applications so as to understand the materials properties that can pave the way for the use of nanoalloys as a potential alternative or improve solutions that are offered by current materials. PMID- 26024212 TI - Novel ferrocene-anchored ZnO nanoparticle/carbon nanotube assembly for glucose oxidase wiring: application to a glucose/air fuel cell. AB - Glucose oxidase (GOx) is immobilized on ZnO nanoparticle-modified electrodes. The immobilized glucose oxidase shows efficient mediated electron transfer with ZnO nanoparticles to which the ferrocenyl moiety is pi-stacked into a supramolecular architecture. The constructed ZnO-Fc/CNT modified electrode exhibits high ferrocene surface coverage, preventing any leakage of the pi-stacked ferrocene from the newly described ZnO hybrid nanoparticles. The use of the new architecture of ZnO supported electron mediators to shuttle electrons from the redox centre of the enzyme to the surface of the working electrode can effectively bring about successful glucose oxidation. These modified electrodes evaluated as a highly efficient architecture provide a catalytic current for glucose oxidation and are integrated in a specially designed glucose/air fuel cell prototype using a conventional platinum-carbon (Pt/C) cathode at physiological pH (7.0). The obtained architecture leads to a peak power density of 53 MUW cm(-2) at 300 mV for the Nafion(r) based biofuel cell under "air breathing" conditions at room temperature. PMID- 26024214 TI - Efficient photocatalytic selective nitro-reduction and C-H bond oxidation over ultrathin sheet mediated CdS flowers. AB - We report here a visible light driven selective nitro-reduction and oxidation of saturated sp(3) C-H bonds using ultrathin (0.8 nm) sheet mediated uniform CdS flowers as catalyst under a household 40 W CFL lamp and molecular oxygen as oxidant. The CdS flowers were synthesized using a simple surfactant assisted hydrothermal method. PMID- 26024213 TI - Reducing Periconceptional Methylmercury Exposure: Cost-Utility Analysis for a Proposed Screening Program for Women Planning a Pregnancy in Ontario, Canada. AB - BACKGROUND: The assessment of neurodevelopmental effects in children associated with prenatal methylmercury exposure, from contaminated fish and seafood in the maternal diet, has recently been strengthened by adjustment for the negative confounding resulting from co-exposure to beneficial polyunsaturated fatty acids (PUFAs). OBJECTIVES: We aimed to determine the cost-effectiveness of a periconceptional screening program of blood mercury concentration for women planning to become pregnant in Ontario, Canada. Fish intake recommendations would be provided for those found to have blood mercury levels above the intervention threshold. METHODS: Analysis was conducted using a combined decision tree/Markov model to compare the proposed screening intervention with standard care from a societal perspective over a lifetime horizon. We used the national blood mercury distributions of women 20-49 years of age reported in the Canadian Health Measures Survey from 2009 through 2011 to determine the cognitive deficits associated with prenatal methylmercury exposure for successful planned pregnancies. Outcomes modeled included the loss in quality of life and the remedial education costs. Value of information analysis was conducted to assess the underlying uncertainty around the model results and to identify which parameters contribute most to this uncertainty. RESULTS: The incremental cost per quality-adjusted life year (QALY) gained for the proposed screening intervention was estimated to be Can$18,051, and the expected value for a willingness to pay of Can$50,000/QALY to be Can$0.61. CONCLUSIONS: Our findings suggest that the proposed periconceptional blood mercury screening program for women planning a pregnancy would be highly cost-effective from a societal perspective. The results of a value of information analysis confirm the robustness of the study's conclusions. PMID- 26024215 TI - Recent advances in elucidating the genetic mechanisms of nephrogenesis using zebrafish. AB - The kidney is comprised of working units known as nephrons, which are epithelial tubules that contain a series of specialized cell types organized into a precise pattern of functionally distinct segment domains. There is a limited understanding of the genetic mechanisms that establish these discrete nephron cell types during renal development. The zebrafish embryonic kidney serves as a simplified yet conserved vertebrate model to delineate how nephron segments are patterned from renal progenitors. Here, we provide a concise review of recent advances in this emerging field, and discuss how continued research using zebrafish genetics can be applied to gain insights about nephrogenesis. PMID- 26024216 TI - Analysis of personal and family factors in the persistence of attention deficit hyperactivity disorder: results of a prospective follow-up study in childhood. AB - OBJECTIVES: To study the course of ADHD during childhood and analyze possible personal and family predictor variables of the results. METHOD: Sixty-one children with ADHD who were between 6 and 12 years old at the baseline assessment were evaluated 30 months later (mean age at baseline: 8.70 +/- 1.97; mean age at follow-up: 10.98 +/- 2.19). Status of ADHD in follow-up was identified as persistent (met DSM-IV-TR criteria according to parents' and teachers' ratings), contextually persistent (met ADHD criteria according to one informant, and there was functional impairment) and remitted ADHD (with subthreshold clinical symptomatology). Associated psychological disorders of the three groups were analyzed in the follow-up with the Conners' Rating Scales. The groups were compared on ADHD characteristics (symptoms of ADHD and impairment), child psychopathology, executive functioning (EF; inhibition, working memory) and parenting characteristics (parental stress and discipline styles) at baseline. RESULTS: At the follow-up, 55.7% of the children continued to meet the DSM-IV-TR criteria for ADHD, 29.5% showed contextual persistence, and 14.8% presented remission of the disorder. The persistent and contextually persistent ADHD groups showed more associated psychological disorders. Inattention, oppositional problems, cognitive problems and impairment at baseline distinguished the remitted ADHD children from the persistent and contextually persistent ADHD children. Moreover, the persistent groups had significantly more emotional liability and higher parental stress than the group in remission, while no differences in EF where found among the groups. CONCLUSIONS: ADHD children continue to present symptoms, as well as comorbid psychological problems, during adolescence and early adulthood. These findings confirm that persistence of ADHD is associated with child psychopathology, parental stress and impairment in childhood. PMID- 26024217 TI - The effect of sampling and storage on the fecal microbiota composition in healthy and diseased subjects. AB - Large-scale cohort studies are currently being designed to investigate the human microbiome in health and disease. Adequate sampling strategies are required to limit bias due to shifts in microbial communities during sampling and storage. Therefore, we examined the impact of different sampling and storage conditions on the stability of fecal microbial communities in healthy and diseased subjects. Fecal samples from 10 healthy controls, 10 irritable bowel syndrome and 8 inflammatory bowel disease patients were collected on site, aliquoted immediately after defecation and stored at -80 degrees C, -20 degrees C for 1 week, at +4 degrees C or room temperature for 24 hours. Fecal transport swabs (FecalSwab, Copan) were collected and stored for 48-72 hours at room temperature. We used pyrosequencing of the 16S gene to investigate the stability of microbial communities. Alpha diversity did not differ between all storage methods and -80 degrees C, except for the fecal swabs. UPGMA clustering and principal coordinate analysis showed significant clustering by test subject (p < 0.001) but not by storage method. Bray-Curtis dissimilarity and (un)weighted UniFrac showed a significant higher distance between fecal swabs and -80 degrees C versus the other methods and -80 degrees C samples (p < 0.009). The relative abundance of Ruminococcus and Enterobacteriaceae did not differ between the storage methods versus -80 degrees C, but was higher in fecal swabs (p < 0.05). Storage up to 24 hours (at +4 degrees C or room temperature) or freezing at -20 degrees C did not significantly alter the fecal microbial community structure compared to direct freezing of samples from healthy subjects and patients with gastrointestinal disorders. PMID- 26024218 TI - Relationship between Expression of Cellular Receptor-27.8 kDa and Lymphocystis Disease Virus (LCDV) Infection. AB - The 27.8 kDa membrane protein from flounder (Paralichthys olivaceus) gill (FG) cells was previously identified as a putative cellular receptor involved in lymphocystis disease virus (LCDV) infection. In this paper, the expression of receptor-27.8 kDa (27.8R) and LCDV loads in FG cells and hirame natural embryo (HINAE) cells were investigated upon LCDV infection and anti-27.8R monoclonal antibody (MAb) treatment. The results showed the 27.8R was expressed and co localized with LCDV in both FG and HINAE cell surface. After LCDV infection, the expression of 27.8R exhibited a dose-dependent up-regulation with the increasing of LCDV titers, and demonstrated a tendency to increase firstly and then decrease during a time course up to 9 days; LCDV copies showed a similar variation trend to the 27.8R expression, however, it reached the highest level later than did the 27.8R expression. Additionally, the 27.8R expression and LCDV copies in FG cells were higher than those in HINAE cells. In the presence of increasing concentration of the anti-27.8R MAbs, the up-regulation of 27.8R expression and the copy numbers of LCDV significantly declined post LCDV infection, and the cytopathic effect induced by LCDV in the two cell lines was accordingly reduced, indicating anti-27.8R MAbs pre-incubation could inhibit the up-regulation of 27.8R expression and LCDV infection. These results suggested that LCDV infection could induce up-regulation of 27.8R expression, which in turn increased susceptibility and availability of FG and HINAE cells for LCDV entry, providing important new insights into the LCDV replication cycle and the interaction between this virus and the host cells. PMID- 26024219 TI - Acute Antibody-Mediated Rejection in Presence of MICA-DSA and Successful Renal Re Transplant with Negative-MICA Virtual Crossmatch. AB - The presence of donor-specific alloantibodies (DSAs) against the MICA antigen results in high risk for antibody-mediated rejection (AMR) of a transplanted kidney, especially in patients receiving a re-transplant. We describe the incidence of acute C4d+ AMR in a patient who had received a first kidney transplant with a zero HLA antigen mismatch. Retrospective analysis of post transplant T and B cell crossmatches were negative, but a high level of MICA alloantibody was detected in sera collected both before and after transplant. The DSA against the first allograft mismatched MICA*018 was in the recipient. Flow cytometry and cytotoxicity tests with five samples of freshly isolated human umbilical vein endothelial cells demonstrated the alloantibody nature of patient's MICA-DSA. Prior to the second transplant, a MICA virtual crossmatch and T and B cell crossmatches were used to identify a suitable donor. The patient received a second kidney transplant, and allograft was functioning well at one year follow-up. Our study indicates that MICA virtual crossmatch is important in selection of a kidney donor if the recipient has been sensitized with MICA antigens. PMID- 26024220 TI - Efficacy of oral cryotherapy on oral mucositis prevention in patients with hematological malignancies undergoing hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: Controversy exists regarding whether oral cryotherapy can prevent oral mucositis (OM) in patients with hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT). The aim of the present meta analysis was to evaluate the efficacy of oral cryotherapy for OM prevention in patients with hematological malignancies undergoing HSCT. METHODS: PubMed and the Cochrane Library were searched through October 2014. Randomized controlled trials (RCTs) comparing the effect of oral cryotherapy with no treatment or with other interventions for OM in patients undergoing HSCT were included. The primary outcomes were the incidence, severity, and duration of OM. The secondary outcomes included length of analgesic use, total parenteral nutrition (TPN) use, and length of hospital stay. RESULTS: Seven RCTs involving eight articles analyzing 458 patients were included. Oral cryotherapy significantly decreased the incidence of severe OM (RR = 0.52, 95% CI = 0.27 to 0.99) and OM severity (SMD = 2.07, 95% CI = -3.90 to -0.25). In addition, the duration of TPN use and the length of hospitalization were markedly reduced (SMD = -0.56, 95% CI = -0.92 to 0.19; SMD = -0.44, 95% CI = -0.76 to -0.13; respectively). However, the pooled results were uncertain for the duration of OM and analgesic use (SMD = -0.13, 95% CI = -0.41 to 0.15; SMD = -1.15, 95% CI = -2.57 to 0.27; respectively). CONCLUSIONS: Oral cryotherapy is a readily applicable and cost-effective prophylaxis for OM in patients undergoing HSCT. PMID- 26024223 TI - Correction: Application of the Phylogenetic Species Concept to Wallemia sebi from House Dust and Indoor Air Revealed by Multi-Locus Genealogical Concordance. PMID- 26024221 TI - A Method for 3D Histopathology Reconstruction Supporting Mouse Microvasculature Analysis. AB - Structural abnormalities of the microvasculature can impair perfusion and function. Conventional histology provides good spatial resolution with which to evaluate the microvascular structure but affords no 3-dimensional information; this limitation could lead to misinterpretations of the complex microvessel network in health and disease. The objective of this study was to develop and evaluate an accurate, fully automated 3D histology reconstruction method to visualize the arterioles and venules within the mouse hind-limb. Sections of the tibialis anterior muscle from C57BL/J6 mice (both normal and subjected to femoral artery excision) were reconstructed using pairwise rigid and affine registrations of 5 um-thick, paraffin-embedded serial sections digitized at 0.25 um/pixel. Low resolution intensity-based rigid registration was used to initialize the nucleus landmark-based registration, and conventional high-resolution intensity-based registration method. The affine nucleus landmark-based registration was developed in this work and was compared to the conventional affine high-resolution intensity-based registration method. Target registration errors were measured between adjacent tissue sections (pairwise error), as well as with respect to a 3D reference reconstruction (accumulated error, to capture propagation of error through the stack of sections). Accumulated error measures were lower (p < 0.01) for the nucleus landmark technique and superior vasculature continuity was observed. These findings indicate that registration based on automatic extraction and correspondence of small, homologous landmarks may support accurate 3D histology reconstruction. This technique avoids the otherwise problematic "banana into-cylinder" effect observed using conventional methods that optimize the pairwise alignment of salient structures, forcing them to be section-orthogonal. This approach will provide a valuable tool for high-accuracy 3D histology tissue reconstructions for analysis of diseased microvasculature. PMID- 26024222 TI - Chamber bioaerosol study: outdoor air and human occupants as sources of indoor airborne microbes. AB - Human occupants are an important source of microbes in indoor environments. In this study, we used DNA sequencing of filter samples to assess the fungal and bacterial composition of air in an environmental chamber under different levels of occupancy, activity, and exposed or covered carpeting. In this office-like, mechanically ventilated environment, results showed a strong influence of outdoor derived particles, with the indoor microbial composition tracking that of outdoor air for the 2-hour sampling periods. The number of occupants and their activity played a significant but smaller role influencing the composition of indoor bioaerosols. Human-associated taxa were observed but were not particularly abundant, except in the case of one fungus that appeared to be transported into the chamber on the clothing of a study participant. Overall, this study revealed a smaller signature of human body-associated taxa than had been expected based on recent studies of indoor microbiomes, suggesting that occupants may not exert a strong influence on bioaerosol microbial composition in a space that, like many offices, is well ventilated with air that is moderately filtered and moderately occupied. PMID- 26024225 TI - Scavenging rate ecoassay: a potential indicator of estuary condition. AB - Monitoring of estuary condition is essential due to the highly productive and often intensely impacted nature of these ecosystems. Assessment of the physico chemical condition of estuaries is expensive and difficult due to naturally fluctuating water quality and biota. Assessing the vigour of ecosystem processes is an alternative method with potential to overcome much of the variability associated with physico-chemical measures. Indicators of estuary condition should have small spatial and temporal variability, have a predictable response to perturbation and be ecologically relevant. Here, we present tests of the first criterion, the spatio-temporal variability of a potential ecoassay measuring the rate of scavenging in estuaries. We hypothesised that the proposed scavenging ecoassay would not vary significantly among A) sites in an estuary, B) trips separated by weeks, or C) days in a trip. Because not all habitats are present in all estuaries, this test was undertaken in two habitats. When conducted over bare substrate there were occasional significant differences, but no discernible patterns, within levels of the experiment. When conducted over vegetated substrate, days within a trip did not vary significantly, but later trips experienced greater scavenging. This scavenging ecoassay shows potential as a tool for assessing the condition of estuarine ecosystems, and further exploration of this protocol is warranted by implementation in estuaries across a gradient of anthropogenic stress. PMID- 26024224 TI - A spectral graph regression model for learning brain connectivity of Alzheimer's disease. AB - Understanding network features of brain pathology is essential to reveal underpinnings of neurodegenerative diseases. In this paper, we introduce a novel graph regression model (GRM) for learning structural brain connectivity of Alzheimer's disease (AD) measured by amyloid-beta deposits. The proposed GRM regards 11C-labeled Pittsburgh Compound-B (PiB) positron emission tomography (PET) imaging data as smooth signals defined on an unknown graph. This graph is then estimated through an optimization framework, which fits the graph to the data with an adjustable level of uniformity of the connection weights. Under the assumed data model, results based on simulated data illustrate that our approach can accurately reconstruct the underlying network, often with better reconstruction than those obtained by both sample correlation and l1-regularized partial correlation estimation. Evaluations performed upon PiB-PET imaging data of 30 AD and 40 elderly normal control (NC) subjects demonstrate that the connectivity patterns revealed by the GRM are easy to interpret and consistent with known pathology. Moreover, the hubs of the reconstructed networks match the cortical hubs given by functional MRI. The discriminative network features including both global connectivity measurements and degree statistics of specific nodes discovered from the AD and NC amyloid-beta networks provide new potential biomarkers for preclinical and clinical AD. PMID- 26024226 TI - Ear recognition from one sample per person. AB - Biometrics has the advantages of efficiency and convenience in identity authentication. As one of the most promising biometric-based methods, ear recognition has received broad attention and research. Previous studies have achieved remarkable performance with multiple samples per person (MSPP) in the gallery. However, most conventional methods are insufficient when there is only one sample per person (OSPP) available in the gallery. To solve the OSPP problem by maximizing the use of a single sample, this paper proposes a hybrid multi keypoint descriptor sparse representation-based classification (MKD-SRC) ear recognition approach based on 2D and 3D information. Because most 3D sensors capture 3D data accessorizing the corresponding 2D data, it is sensible to use both types of information. First, the ear region is extracted from the profile. Second, keypoints are detected and described for both the 2D texture image and 3D range image. Then, the hybrid MKD-SRC algorithm is used to complete the recognition with only OSPP in the gallery. Experimental results on a benchmark dataset have demonstrated the feasibility and effectiveness of the proposed method in resolving the OSPP problem. A Rank-one recognition rate of 96.4% is achieved for a gallery of 415 subjects, and the time involved in the computation is satisfactory compared to conventional methods. PMID- 26024227 TI - Significance of relative position of cellulases in designer cellulosomes for optimized cellulolysis. AB - Degradation of cellulose is of major interest in the quest for alternative sources of renewable energy, for its positive effects on environment and ecology, and for use in advanced biotechnological applications. Due to its microcrystalline organization, celluose is extremely difficult to degrade, although numerous microbes have evolved that produce the appropriate enzymes. The most efficient known natural cellulolytic system is produced by anaerobic bacteria, such as C. thermocellum, that possess a multi-enzymatic complex termed the cellulosome. Our laboratory has devised and developed the designer cellulosome concept, which consists of chimaeric scaffoldins for controlled incorporation of recombinant polysaccharide-degrading enzymes. Recently, we reported the creation of a combinatorial library of four cellulosomal modules comprising a basic chimaeric scaffoldin, i.e., a CBM and 3 divergent cohesin modules. Here, we employed selected members of this library to determine whether the position of defined cellulolytic enzymes is important for optimized degradation of a microcrystalline cellulosic substrate. For this purpose, 10 chimaeric scaffoldins were used for incorporation of three recombinant Thermobifida fusca enzymes: the processive endoglucanase Cel9A, endoglucanase Cel5A and exoglucanase Cel48A. In addition, we examined whether the characteristic properties of the T. fusca enzymes as designer cellulosome components are unique to this bacterium by replacing them with parallel enzymes from Clostridium thermocellum. The results support the contention that for a given set of cellulosomal enzymes, their relative position within a scaffoldin can be critical for optimal degradation of microcrystaline cellulosic substrates. PMID- 26024228 TI - Ex vivo host and parasite response to antileishmanial drugs and immunomodulators. AB - BACKGROUND: Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. METHODOLOGY: To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-alpha, IFN-gamma, IL-10 and IL 13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 MUg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 MUM HePC). Concentrations of 4 MUM of miltefosine and 8 MUg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. PRINCIPAL FINDINGS: Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine antimoniate. However, pentoxifylline diminished secretion of TNF-alpha, IFN-gamma and IL-13, cytokines associated with the outcome of infection by species of the Viannia subgenus. Exposure to CpG diminished the leishmanicidal effect of meglumine antimoniate, but not miltefosine, and significantly reduced secretion of IL-10, alone and in combination with either antileishmanial drug. IL-13 increased in response to CpG plus miltefosine. CONCLUSIONS AND SIGNIFICANCE: Human PBMCs allow integrated ex vivo assessment of antileishmanial treatments, providing information on host and parasite determinants of therapeutic response that may be used to tailor therapeutic strategies to optimize clinical resolution. PMID- 26024229 TI - TMEM120A and B: Nuclear Envelope Transmembrane Proteins Important for Adipocyte Differentiation. AB - Recent work indicates that the nuclear envelope is a major signaling node for the cell that can influence tissue differentiation processes. Here we present two nuclear envelope trans-membrane proteins TMEM120A and TMEM120B that are paralogs encoded by the Tmem120A and Tmem120B genes. The TMEM120 proteins are expressed preferentially in fat and both are induced during 3T3-L1 adipocyte differentiation. Knockdown of one or the other protein altered expression of several genes required for adipocyte differentiation, Gata3, Fasn, Glut4, while knockdown of both together additionally affected Pparg and Adipoq. The double knockdown also increased the strength of effects, reducing for example Glut4 levels by 95% compared to control 3T3-L1 cells upon pharmacologically induced differentiation. Accordingly, TMEM120A and B knockdown individually and together impacted on adipocyte differentiation/metabolism as measured by lipid accumulation through binding of Oil Red O and coherent anti-Stokes Raman scattering microscopy (CARS). The nuclear envelope is linked to several lipodystrophies through mutations in lamin A; however, lamin A is widely expressed. Thus it is possible that the TMEM120A and B fat-specific nuclear envelope transmembrane proteins may play a contributory role in the tissue specific pathology of this disorder or in the wider problem of obesity. PMID- 26024230 TI - Genetic mechanism of human neutrophil antigen 2 deficiency and expression variations. AB - Human neutrophil antigen 2 (HNA-2) deficiency is a common phenotype as 3-5% humans do not express HNA-2. HNA-2 is coded by CD177 gene that associates with human myeloproliferative disorders. HNA-2 deficient individuals are prone to produce HNA-2 alloantibodies that cause a number of disorders including transfusion-related acute lung injury and immune neutropenia. In addition, the percentages of HNA-2 positive neutrophils vary significantly among individuals and HNA-2 expression variations play a role in human diseases such as myelodysplastic syndrome, chronic myelogenous leukemia, and gastric cancer. The underlying genetic mechanism of HNA-2 deficiency and expression variations has remained a mystery. In this study, we identified a novel CD177 nonsense single nucleotide polymorphism (SNP 829A>T) that creates a stop codon within the CD177 coding region. We found that all 829TT homozygous individuals were HNA-2 deficient. In addition, the SNP 829A>T genotypes were significantly associated with the percentage of HNA-2 positive neutrophils. Transfection experiments confirmed that HNA-2 expression was absent on cells expressing the CD177 SNP 829T allele. Our data clearly demonstrate that the CD177 SNP 829A>T is the primary genetic determinant for HNA-2 deficiency and expression variations. The mechanistic delineation of HNA-2 genetics will enable the development of genetic tests for diagnosis and prognosis of HNA-2-related human diseases. PMID- 26024232 TI - Cyclophanes containing large polycyclic aromatic hydrocarbons. AB - Cyclophanes have been firmly entrenched as a distinct class of compounds for well over half a century. The two main factors that have kept this field of chemistry going so strongly for such a long time are tremendous structural diversity and the interesting behaviour that is often observed. Although a very large number cyclophanes has been reported, only a very small proportion of them contain polycyclic aromatic systems that can be thought of as "large", i.e. with >=4 rings. This Review puts the spotlight on such cyclophanes, illuminating both the chemistry that was used to synthesize them and what was learned from studying them. Context for the main body is provided by the careful consideration of the anatomy of a cyclophane and the classification of general synthetic approaches. The subsequent sections cover eleven different PAHs and are organized primarily according to increasing size of the aromatic system, starting with pyrene (C16, the only large polycyclic aromatic system to have been incorporated into numerous cyclophanes) and ending with hexabenzo[bc,ef,hi,kl,no,qr]coronene (C42). PMID- 26024231 TI - A Quantitative and Standardized Method for the Evaluation of Choroidal Neovascularization Using MICRON III Fluorescein Angiograms in Rats. AB - INTRODUCTION: In-vivo imaging of choroidal neovascularization (CNV) has been increasingly recognized as a valuable tool in the investigation of age-related macular degeneration (AMD) in both clinical and basic research applications. Arguably the most widely utilised model replicating AMD is laser generated CNV by rupture of Bruch's membrane in rodents. Heretofore CNV evaluation via in-vivo imaging techniques has been hamstrung by a lack of appropriate rodent fundus camera and a non-standardised analysis method. The aim of this study was to establish a simple, quantifiable method of fluorescein fundus angiogram (FFA) image analysis for CNV lesions. METHODS: Laser was applied to 32 Brown Norway Rats; FFA images were taken using a rodent specific fundus camera (Micron III, Phoenix Laboratories) over 3 weeks and compared to conventional ex-vivo CNV assessment. FFA images acquired with fluorescein administered by intraperitoneal injection and intravenous injection were compared and shown to greatly influence lesion properties. Utilising commonly used software packages, FFA images were assessed for CNV and chorioretinal burns lesion area by manually outlining the maximum border of each lesion and normalising against the optic nerve head. Net fluorescence above background and derived value of area corrected lesion intensity were calculated. RESULTS: CNV lesions of rats treated with anti-VEGF antibody were significantly smaller in normalised lesion area (p < 0.001) and fluorescent intensity (p < 0.001) than the PBS treated control two weeks post laser. The calculated area corrected lesion intensity was significantly smaller (p < 0.001) in anti-VEGF treated animals at 2 and 3 weeks post laser. The results obtained using FFA correlated with, and were confirmed by conventional lesion area measurements from isolectin stained choroidal flatmounts, where lesions of anti-VEGF treated rats were significantly smaller at 2 weeks (p = 0.049) and 3 weeks (p < 0.001) post laser. CONCLUSION: The presented method of in-vivo FFA quantification of CNV, including acquisition variable corrections, using the Micron III system and common use software establishes a reliable method for detecting and quantifying CNV enabling longitudinal studies and represents an important alternative to conventional CNV quantification methods. PMID- 26024233 TI - Acyclovir Has Low but Detectable Influence on HLA-B*57:01 Specificity without Inducing Hypersensitivity. AB - Immune mediated adverse drug reactions (IM-ADRs) remain a significant source of patient morbidity that have more recently been shown to be associated with specific class I and/or II human leukocyte antigen (HLA) alleles. Abacavir induced hypersensitivity syndrome is a CD8+ T cell dependent IM-ADR that is exclusively mediated by HLA-B*57:01. We and others have previously shown that abacavir can occupy the floor of the peptide binding groove of HLA-B*57:01 molecules, increasing the affinity of certain self peptides resulting in an altered peptide-binding repertoire. Here, we have identified another drug, acyclovir, which appears to act in a similar fashion. As with abacavir, acyclovir showed a dose dependent increase in affinity for peptides with valine and isoleucine at their C-terminus. In agreement with the binding studies, HLA B*57:01 peptide-elution studies performed in the presence of acyclovir revealed an increased number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we have hypothesized that acyclovir acts by the same mechanism as abacavir, although our data also suggest the overall effect is much smaller: the largest changes of peptide affinity for acyclovir were 2-5 fold, whereas for abacavir this effect was as much as 1000-fold. Unlike abacavir, acyclovir is not known to cause IM-ADRs. We conclude that the modest effect of acyclovir on HLA binding affinity in contrast to the large effect of abacavir is insufficient to trigger a hypersensitivity syndrome. We further support this by functional in vitro studies where acyclovir, unlike abacavir, was unable to produce an increase in IFN-gamma upon expansion of HLA-B*57:01+ PBMCs from healthy donors. Using abacavir and acyclovir as examples we therefore propose an in vitro pre-clinical screening strategy, whereby thresholds can be applied to MHC-peptide binding assays to determine the likelihood that a drug could cause a clinically relevant IM-ADR. PMID- 26024234 TI - Do we feel the same empathy for loved and hated peers? AB - Empathy allows us to understand and react to other people's feelings and sensations; we can more accurately judge another person's situation when we are aware of his/her emotions. Empathy for pain is a good working model of the behavioral and neural processes involved in empathy in general. Although the influence of perspective-taking processes (notably "Self" vs. "Other") on pain rating has been studied, the impact of the degree of familiarity with the person representing the "Other" perspective has not been previously addressed. In the present study, we asked participants to adopt four different perspectives: "Self", "Other-Most-Loved-Familiar", "Other-Most-Hated-Familiar" and "Other Stranger". The results showed that higher pain ratings were attributed to the Other-Most-Loved-Familiar perspective than to the Self, Other-Stranger and Other Most-Hated-Familiar perspectives. Moreover, participants were quicker to rate pain for the Other-Most-Loved-Familiar perspective and the Self-perspective than for the other two perspectives. These results for a perspective-taking task therefore more clearly define the role of familiarity in empathy for pain. PMID- 26024235 TI - The colonisation of exotic species does not have to trigger faunal homogenisation: lessons from the assembly patterns of arthropods on oceanic islands. AB - Human-caused disturbances can lead to the extinction of indigenous (endemic and native) species, while facilitating and increasing the colonisation of exotic species; this increase can, in turn, promote the similarity of species compositions between sites if human-disturbed sites are consistently invaded by a regionally species-poor pool of exotic species. In this study, we analysed the extent to which epigean arthropod assemblages of four islands of the Azorean archipelago are characterised by nestedness according to a habitat-altered gradient. The degree of nestedness represents the extent to which less ubiquitous species occur in subsets of sites occupied by the more widespread species, resulting in an ordered loss/gain of species across environmental or ecological gradients. A predictable loss of species across communities while maintaining others may lead to more similar communities (i.e. lower beta-diversity). In contrast, anti-nestedness occurs when different species tend to occupy distinct sites, thus characterising a replacement of species across such gradients. Our results showed that an increase in exotic species does not promote assemblage homogenisation at the habitat level. On the contrary, exotic species were revealed as habitat specialists that constitute new and well-differentiated assemblages, even increasing the species compositional heterogeneity within human altered landscapes. Therefore, contrary to expectations, our results show that both indigenous and exotic species established idiosyncratic assemblages within habitats and islands. We suggest that both the historical extinction of indigenous species in disturbed habitats and the habitat-specialised character of some exotic invasions have contributed to the construction of current assemblages. PMID- 26024236 TI - Potential measurement errors due to image enlargement in optical coherence tomography imaging. AB - The effect of interpolation and super-resolution (SR) algorithms on quantitative and qualitative assessments of enlarged optical coherence tomography (OCT) images was investigated in this report. Spectral-domain OCT images from 30 eyes in 30 consecutive patients with diabetic macular edema (DME) and 20 healthy eyes in 20 consecutive volunteers were analyzed. Original image (OR) resolution was reduced by a factor of four. Images were then magnified by a factor of four with and without application of one of the following algorithms: bilinear (BL), bicubic (BC), Lanczos3 (LA), and SR. Differences in peak signal-to-noise ratio (PSNR), retinal nerve fiber layer (RNFL) thickness, photoreceptor layer status, and parallelism (reflects the complexity of photoreceptor layer alterations) were analyzed in each image type. The order of PSNRs from highest to lowest was SR > LA > BC > BL > non-processed enlarged images (NONE). The PSNR was statistically different in all groups. The NONE, BC, and LA images resulted in significantly thicker RNFL measurements than the OR image. In eyes with DME, the photoreceptor layer, which was hardly identifiable in NONE images, became detectable with algorithm application. However, OCT photoreceptor parameters were still assessed as more undetectable than in OR images. Parallelism was not statistically different in OR and NONE images, but other image groups had significantly higher parallelism than OR images. Our results indicated that interpolation and SR algorithms increased OCT image resolution. However, qualitative and quantitative assessments were influenced by algorithm use. Additionally, each algorithm affected the assessments differently. PMID- 26024237 TI - A DJ-1 Based Peptide Attenuates Dopaminergic Degeneration in Mice Models of Parkinson's Disease via Enhancing Nrf2. AB - Drugs currently used for treating Parkinson's disease patients provide symptomatic relief without altering the neurodegenerative process. Our aim was to examine the possibility of using DJ-1 (PARK7), as a novel therapeutic target for Parkinson's disease. We designed a short peptide, named ND-13. This peptide consists of a 13 amino acids segment of the DJ-1-protein attached to 7 amino acids derived from TAT, a cell penetrating protein. We examined the effects of ND 13 using in vitro and in vivo experimental models of Parkinson's disease. We demonstrated that ND-13 protects cultured cells against oxidative and neurotoxic insults, reduced reactive oxygen species accumulation, activated the protective erythroid-2 related factor 2 system and increased cell survival. ND-13 robustly attenuated dopaminergic system dysfunction and in improved the behavioral outcome in the 6-hydroxydopamine mouse model of Parkinson's disease, both in wild type and in DJ-1 knockout mice. Moreover, ND-13 restored dopamine content in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model. These findings validate DJ-1 as a promising therapeutic target in Parkinson's disease and identify a novel peptide with clinical potential, which may be significant for a broader range of neurological diseases, possibly with an important impact for the neurosciences. PMID- 26024238 TI - A novel nanogel formulation of methotrexate for topical treatment of psoriasis: optimization, in vitro and in vivo evaluation. AB - CONTEXT: Although several formulation strategies have been developed for the treatment of psoriasis, there is an unmet need for optimization of its therapy. OBJECTIVE: The objective was to develop a nanogel composed of methotrexate (MTX) loaded nanostructured lipid carrier (MTX-NLC) and to evaluate its potential in imiquimod-induced psoriasis model to ameliorate symptoms of psoriasis. MATERIALS AND METHODS: MTX-NLC nanogel was prepared by hot-homogenization method and optimized by Design of Experiments. Particle size, polydispersity index (PDI) and entrapment efficiency were selected as the critical quality attributes. Antipsoriatic potential of MTX-NLC nanogel was evaluated by Psoriatic Area and Severity Index (PASI) score and histopathological examination in the imiquimod induced psoriasis model. RESULTS AND DISCUSSION: Optimized MTX-NLC exhibited particle size of 278 +/- 10 nm, PDI of 0.231 +/- 0.05 and EE of 22.29 +/- 1.23%. At the end of 48 h, MTX-NLC gel exhibited slow and prolonged release of MTX (47.32 +/- 0.94% versus 94.23 +/- 0.79%) compared to MTX gel. Furthermore, it significantly reduced the PASI score with recovery of normalcy of the mice's skin, while the MTX gel exhibited signs of hyper and parakeratosis at the end of the study. CONCLUSION: The developed MTX-NLC gel formulation can be a promising alternative to existing MTX formulation in treating psoriasis. PMID- 26024239 TI - Thermosensitive in situ nanogel as ophthalmic delivery system of curcumin: development, characterization, in vitro permeation and in vivo pharmacokinetic studies. AB - CONTEXT: The nanogel combining cationic nanostructured lipid carriers (CNLC) and thermosensitive gelling agent could enhance preocular retention and ocular permeation capacity of curcumin (CUR). OBJECTIVE: The purpose of the study was to develop and characterize a thermosensitive ophthalmic in situ nanogel of CUR-CNLC (CUR-CNLC-GEL) and evaluate in vitro and in vivo properties of the formulations. MATERIALS AND METHODS: The physicochemical properties, in vitro release and corneal permeation, were evaluated. Ocular irritation and preocular retention capacity were also conducted. Finally, pharmacokinetic study in the aqueous humor was investigated by microdialysis technique. RESULTS: The solution-gel transition temperature of the optimized formulation diluted by simulated tear fluid was 34 +/- 1.0 degrees C. The CUR-CNLC-GEL displayed zero-order release kinetics. The apparent permeability coefficient (Papp) and the area under the curve (AUC0 >infinity) of CUR-CNLC-GEL were 1.56-fold and 9.24-fold, respectively, than those of curcumin solution (CUR-SOL, p < 0.01). The maximal concentration (Cmax) was significantly improved (p < 0.01). The prolonged mean residence time (p < 0.01) indicated that CUR-CNLC-GEL is a controlled release formulation. DISCUSSION AND CONCLUSION: Those results demonstrated that CUR-CNLC-GEL could become a potential formulation for increasing the bioavailability of CUR in the aqueous humor by enhancing corneal permeation and retention capacity. PMID- 26024241 TI - Effective Community-Based Physical Activity Interventions for Older Adults Living in Rural and Regional Areas: A Systematic Review. AB - The purpose of this systematic review was to assess the characteristics and effectiveness of community-based interventions designed to increase physical activity participation in older adults (aged 65 years or more) living in rural or regional areas. Relevant peer-reviewed literature was obtained, using four primary electronic search engines, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement. The initial search identified 4,690 articles. After removal of duplicates and excluded articles, seven articles were included in the review. Few consistencies existed between intervention types, duration, outcome measures, and follow-up. Results provide some evidence to support the effectiveness of community-based interventions that include low- to moderate-intensity exercise to increase physical activity, physical function, and psychological state. However, without more rigorous studies it is difficult to identify the most critical characteristics of community-based interventions for older adults in rural and regional settings. PMID- 26024240 TI - Gas-saturated solution process to obtain microcomposite particles of alpha lipoic acid/hydrogenated colza oil in supercritical carbon dioxide. AB - Alpha lipoic acid (ALA), an active substance in anti-aging products and dietary supplements, need to be masked with an edible polymer to obscure its unpleasant taste. However, the high viscosity of the ALA molecules prevents them from forming microcomposites with masking materials even in supercritical carbon dioxide (scCO2). Therefore, the purpose of this study was to investigate and develop a novel production method for microcomposite particles for ALA in hydrogenated colza oil (HCO). Microcomposite particles of ALA/HCO were prepared by using a novel gas-saturated solution (PGSS) process in which the solid dispersion method is used along with stepwise temperature control (PGSS-STC). Its high viscosity prevents the formation of microcomposites in the conventional PGSS process even under strong agitation. Here, we disperse the solid particles of ALA and HCO in scCO2 at low temperatures and change the temperature stepwise in order to mix the melted ALA and HCO in scCO2. As a result, a homogeneous dispersion of the droplets of ALA in melted HCO saturated with CO2 is obtained at high temperatures. After the rapid expansion of the saturated solution through a nozzle, microcomposite particles of ALA/HCO several micrometers in diameter are obtained. PMID- 26024242 TI - Functionalized graphene and other two-dimensional materials for photovoltaic devices: device design and processing. AB - Graphene is the thinnest two-dimensional (2D) carbon material and has many advantages including high carrier mobilities and conductivity, high optical transparency, excellent mechanical flexibility and chemical stability, which make graphene an ideal material for various optoelectronic devices. The major applications of graphene in photovoltaic devices are for transparent electrodes and charge transport layers. Several other 2D materials have also shown advantages in charge transport and light absorption over traditional semiconductor materials used in photovoltaic devices. Great achievements in the applications of 2D materials in photovoltaic devices have been reported, yet numerous challenges still remain. For practical applications, the device performance should be further improved by optimizing the 2D material synthesis, film transfer, surface functionalization and chemical/physical doping processes. In this review, we will focus on the recent advances in the applications of graphene and other 2D materials in various photovoltaic devices, including organic solar cells, Schottky junction solar cells, dye-sensitized solar cells, quantum dot-sensitized solar cells, other inorganic solar cells, and perovskite solar cells, in terms of the functionalization techniques of the materials, the device design and the device performance. Finally, conclusions and an outlook for the future development of this field will be addressed. PMID- 26024243 TI - Swallowed glucocorticoid therapy for eosinophilic esophagitis in children does not suppress adrenal function. AB - OBJECTIVE: The purpose of this study was to examine the effect of chronic swallowed glucocorticoids on adrenal function during the treatment of eosinophilic esophagitis (EoE) in children. METHODS: Serum cortisol levels were obtained in children with EoE pre- and post-treatment with swallowed glucocorticoids. Exclusion criteria included those on any additional steroid therapy. Once diagnosed with EoE by esophageal biopsy, subjects were treated based on current standard of care with either swallowed fluticasone or budesonide. At the time of follow-up, esophagogastroduodenoscopy and blood sampling was repeated. Both pre- and post-treatment serum cortisol samples were collected fasting, between 07:00 and 10:00, and determined using a competitive binding method assay. The distribution of differences in cortisol levels between the pre- and post-treatment samples satisfied the assumption for normality and were subsequently analyzed using the paired t-test. RESULTS: Pre- and post treatment serum cortisol levels were examined in 14 children who met clinical and histological diagnostic criteria for EoE. Mean age was 10.1 years (range 2-17 years) with 71% male and 29% female subjects. Swallowed glucocorticoid treatment included fluticasone in 79% and budesonide in 21% of subjects. Mean dosage of fluticasone was 704 MUg daily (range 220-880 MUg daily) and budesonide 0.8 mg daily (range 0.5-1 mg daily), along with a mean treatment length of 17 weeks (range 8-43 weeks). No significant difference in serum cortisol was found following treatment with swallowed fluticasone or budesonide (mean change 1.9 MUg/dL, p=0.75, SD of the change=21.2). CONCLUSIONS: Swallowed glucocorticoid therapy does not appear to significantly affect the adrenal axis in children, and therefore, may represent a safe therapy for EoE. PMID- 26024244 TI - Insulin dynamics and biochemical markers for predicting impaired glucose tolerance in obese Thai youth. AB - BACKGROUND: Subjects with impaired glucose tolerance (IGT) are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. The predictors of IGT in obese youth are not well described. METHODS: We studied 115 obese Thai children who underwent an oral glucose tolerance test (OGTT). Plasma glucose and insulin levels were calculated for assessment of beta-cell function. Hemoglobin A1c (HbA1c), lipid profile, and clinical parameters were also used to determine predictors of IGT. RESULTS: We found that three patients had T2DM and 30 subjects had IGT. IGT patients had significantly higher fasting glucose (FG), 1-h postload glucose, 2-h postload insulin, and lower whole-body insulin sensitivity indices than in normal glucose tolerance subjects whereas other indices were comparable. By ROC curve analyses, 1-h postload glucose was the best predictor of IGT, but FG or HbA1c represented a poor diagnostic tool for prediabetes screening. Subjects with 1-h OGTT glucose > 155 mg/dL had significantly lower high-density lipoprotein levels, lower insulin sensitivity, and more insulin resistance than those with 1-h postload glucose of <= 155 mg/dL. CONCLUSIONS: Abnormal glucose tolerance is highly prevalent in obese Thai youth. Several fasting indices and HbA1c fail to predict IGT. An 1-h OGTT glucose of > 155 mg/dL appears to be more associated with adverse insulin dynamics and metabolic profile than 2-h postload glucose. PMID- 26024245 TI - A rare cause of fatal pulmonary alveolar proteinosis: Niemann-Pick disease type C2 and a novel mutation. AB - Niemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is NPC1 gene which is the cause of illness in 95% of the patients. The other gene is the rare type NPC2 which is the cause of illness in 5% of the patients. Patients with NPC2 usually present with respiratory distress in early infancy, which is rather unusual with NPC1. This article discusses about a patient who died at an early age from pulmonary involvement and who subsequently was found to have a novel homozygous mutation of NPC2 gene. PMID- 26024246 TI - Investigation of autoimmune diseases accompanying Hashimoto's thyroiditis in children and adolescents and evaluation of cardiac signs. AB - OBJECTIVE: In the present study, it was aimed to investigate the concomitance of additional cardiac problems, mainly mitral valve prolapse, in adolescents and pediatric patients with Hashimoto's thyroiditis, by screening autoimmune markers. MATERIALS AND METHODS: Fifty-seven euthyroid patients, who applied to the Pediatric Endocrinology clinic at our institution with marked symptoms of hypothyroidism at the time of diagnosis, and were diagnosed and treated for Hashimoto's thyroiditis, were included in the present study. All patients were evaluated by performing non-organ specific autoantibodies which could be tested at our institution, thyroid ultrasonography, two-dimensional echocardiography, and 24-h holter monitorization. RESULTS: Of the 57 cases with Hashimoto's thyroiditis, 48 (84.2%) were female, and nine (15.8%) were male. In the echocardiographic evaluation, mitral valve problems were detected in 10 (17.5%) of all cases; mitral valve prolapse was diagnosed in eight (seven females and one male) cases, and mitral insufficiency was diagnosed in two female cases. First degree atrioventricular block was observed in only two patients during 24-h holter monitorization. Different non-organ specific autoantibody positivity was distributed as antinuclear antibody in 15 (26.3%) cases, anticardiolipin IgG in two cases, anticardiolipin IgM in three cases, tissue transglutaminase IgA in one, glutamic acid decarboxylase in one, anti-insulin antibody in four cases, antiphospholipid IgG in one, and antiphospholipid IgM in one case. CONCLUSION: It should be underlined that patients with Hashimoto's thyroiditis should to be followed up closely for mitral valve prolapse and accompanying autoimmune diseases. PMID- 26024247 TI - Tamoxifen-associated hirsutism: an unusual side effect in a 5-year-old girl with McCune-Albright syndrome. AB - Tamoxifen, a selective estrogen receptor modulator, has been used in the treatment of peripheral precocious puberty. A 5-year and 3-month-old girl, diagnosed with McCune-Albright syndrome, came in with abnormal hair growth approximately 2 months after the initiation of tamoxifen. The pattern of terminal hair on the skin following the administration of the drug and the exclusion of other causes suggested tamoxifen-induced hirsutism. PMID- 26024248 TI - Combined Autodock and comparative molecular field analysis study on predicting 5 lipoxygenase inhibitory activity of flavonoids isolated from Spatholobus suberectus Dunn. AB - 5-Lipoxygenase (5-LOX) plays a key role in the pathway of leukotriene biosynthesis. To predict the inhibitory activity of flavonoid inhibitors against 5-LOX from Spatholobus suberectus Dunn, Autodock 4.2 and comparative molecular field analysis (CoMFA) were employed. For the positive inhibitors (n=7), the value of the coefficient of determination (R2) between the binding free energy, calculated using Autodock 4.2, and the experimental pIC50 is 0.838. In the training set (n=21) of inhibitors against 5-LOX, the R2 of non-cross-validated partial least squares analysis between the actual and predicted pIC50 values, using the no-validation with the optimum number of components set to 6, is 0.997 (p=0.000). For the model generated by CoMFA, the contribution of electrostatic and steric factors are 0.522 and 0.478, respectively. Among the flavonoids of S. suberectus, liquiritigenin, catechin, butin, 3',4',7-trihydroxyflavone, plathymenin, and gallocatechin are the more potent inhibitors of 5-LOX based on the calculated binding free energy and the predicted pIC50 value. PMID- 26024249 TI - Hepatitis C virus and autophagy. AB - Autophagy is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. It can also be used by cells to remove intracellular microbial pathogens, including viruses, in a process known as xenophagy. However, many viruses have developed mechanisms to subvert this intracellular antiviral response and even use this pathway to support their own replications. Hepatitis C virus (HCV) is one such virus and is an important human pathogen that can cause severe liver diseases. Recent studies indicated that HCV could activate the autophagic pathway to support its replication. This review summarizes the current knowledge on the interplay between HCV and autophagy and how this interplay affects HCV replication and host innate immune responses. PMID- 26024250 TI - Computational predictions of the site of metabolism of cytochrome P450 2D6 substrates: comparative analysis, molecular docking, bioactivation and toxicological implications. AB - Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme responsible for metabolizing approximately 25% of all drugs. CYP2D6 is highly expressed in the brain and plays a role as the major CYP in the metabolism of numerous brain-penetrant drugs, including antipsychotics and antidepressants. CYP2D6 activity and inhibition have been associated with numerous undesirable effects in patients, such as bioactivation, drug-associated suicidality and prolongation of the QTc interval. Several in silico tools have been developed in recent years to assist safety assessment scientists in predicting the structural identity of CYP2D6-derived metabolites. The first goal of this study was to perform a comparative evaluation on the ability of four commonly used in silico tools (MetaSite, StarDrop, SMARTCyp and RS-WebPredictor) to correctly predict the CYP2D6-derived site of metabolism (SOM) for 141 compounds, including 10 derived from the Genentech small molecule library. The second goal was to evaluate if a bioactivation prediction model, based on an indicator of chemical reactivity (ELUMO-EHOMO) and electrostatic potential, could correctly predict five representative compounds known to be bioactivated by CYP2D6. Such a model would be of great utility in safety assessment since unforeseen toxicities of CYP2D6 substrates may in part be due to bioactivation mechanisms. The third and final goal was to investigate whether molecular docking, using the crystal structure of human CYP2D6, had the potential to compliment or improve the results obtained from the four SOM in silico programs. PMID- 26024251 TI - "Please Know That You Are Not Alone with Your Pain": Responses to Newcomer Posts in an Online Grief Support Forum. AB - In an effort to better understand how the Internet can provide support to bereaved individuals, this discourse analysis study examined the responses to 107 initial posts in an online grief support group to understand how newcomers' bids for group membership were taken up by current members. Discursive features included validation and empathy through second stories, constructing grief through descriptions, and accepting bids for membership through advice giving and invitations to return to the group. These features illustrate how grief and being a griever are constructed in an online context and how they deviate from the "normal" grief expectations in the offline world. PMID- 26024252 TI - Does nitrogen fertilizer application rate to corn affect nitrous oxide emissions from the rotated soybean crop? AB - Little information exists on the potential for N fertilizer application to corn ( L.) to affect NO emissions during subsequent unfertilized crops in a rotation. To determine if N fertilizer application to corn affects NO emissions during subsequent crops in rotation, we measured NO emissions for 3 yr (2011-2013) in an Iowa, corn-soybean [ (L.) Merr.] rotation with three N fertilizer rates applied to corn (0 kg N ha, the recommended rate of 135 kg N ha, and a high rate of 225 kg N ha); soybean received no N fertilizer. We further investigated the potential for a winter cereal rye ( L.) cover crop to interact with N fertilizer rate to affect NO emissions from both crops. The cover crop did not consistently affect NO emissions. Across all years and irrespective of cover crop, N fertilizer application above the recommended rate resulted in a 16% increase in mean NO flux rate during the corn phase of the rotation. In 2 of the 3 yr, N fertilizer application to corn (0-225 kg N ha) did not affect mean NO flux rates from the subsequent unfertilized soybean crop. However, in 1 yr after a drought, mean NO flux rates from the soybean crops that received 135 and 225 kg N ha N application in the corn year were 35 and 70% higher than those from the soybean crop that received no N application in the corn year. Our results are consistent with previous studies demonstrating that cover crop effects on NO emissions are not easily generalizable. When N fertilizer affects NO emissions during a subsequent unfertilized crop, it will be important to determine if total fertilizer-induced NO emissions are altered or only spread across a greater period of time. PMID- 26024253 TI - Field measurement of beef pen manure methane and nitrous oxide reveals a surprise for inventory calculations. AB - Few data exist on direct greenhouse gas emissions from pen manure at beef feedlots. However, emission inventories attempt to account for these emissions. This study used a large chamber to isolate NO and CH emissions from pen manure at two Australian commercial beef feedlots (stocking densities, 13-27 m head) and related these emissions to a range of potential emission control factors, including masses and concentrations of volatile solids, NO, total N, NH, and organic C (OC), and additional factors such as total manure mass, cattle numbers, manure pack depth and density, temperature, and moisture content. Mean measured pen NO emissions were 0.428 kg ha d (95% confidence interval [CI], 0.252-0.691) and 0.00405 kg ha d (95% CI, 0.00114-0.0110) for the northern and southern feedlots, respectively. Mean measured CH emission was 0.236 kg ha d (95% CI, 0.163-0.332) for the northern feedlot and 3.93 kg ha d (95% CI, 2.58-5.81) for the southern feedlot. Nitrous oxide emission increased with density, pH, temperature, and manure mass, whereas negative relationships were evident with moisture and OC. Strong relationships were not evident between NO emission and masses or concentrations of NO or total N in the manure. This is significant because many standard inventory calculation protocols predict NO emissions using the mass of N excreted by the animal. PMID- 26024254 TI - Characterization of Chromium Bioremediation Products in Flow-Through Column Sediments Using Micro-X-ray Fluorescence and X-ray Absorption Spectroscopy. AB - Microbially mediated reductive immobilization of chromium is a possible remediation technique for sites contaminated with Cr(VI). This study is part of a broader effort investigating the biogeochemical mechanisms for Cr(VI) reduction in Hanford 100H aquifer sediments using flow-through laboratory columns. It had previously been shown that reduced chromium in the solid phase was in the form of freshly precipitated mixed-phase Cr(III)-Fe(III) (hydr)oxides, irrespective of the biogeochemical conditions in the columns. In this study, the reduced Cr phases in the columns were investigated further using spectroscopy to understand the structure and mechanisms involved in the formation of the end products. Several samples representing potential processes that could be occurring in the columns were synthesized in the laboratory and characterized using X-ray absorption near edge structure (XANES) and X-ray scattering. The XANES of Cr(III) particles in the columns most closely resembled those from synthetic samples produced by the abiotic reaction of Cr(VI) with microbially reduced Fe(II). Microbially mediated Cr-Fe reduction products were distinct from abiotic Cr-Fe (hydr)oxides [CrFe(OH)] and organically complexed Cr(III) sorbed onto the surface of a mixed ferrihydrite-goethite mineral phase. Furthermore, analyses of the abiotically synthesized samples revealed that even the end products of purely abiotic, iron-mediated reduction of Cr(VI) are affected by factors such as the presence of excess aqueous Fe(II) and cellular matter. These results suggest that CrFe(OH) phases made under realistic subsurface conditions or in biotic cultures are structurally different from pure Cr(OH) or laboratory-synthesized CrFe(OH). The observed structural differences imply that the reactivity and stability of biogenic CrFe(OH) could potentially be different from that of abiotic CrFe(OH). PMID- 26024255 TI - Soil phosphorus landscape models for precision soil conservation. AB - Phosphorus (P) enrichment in soils has been documented in the Santa Fe River watershed (SFRW, 3585 km) in north-central Florida. Yet the environmental factors that control P distribution in soils across the landscape, with potential contribution to water quality impairment, are not well understood. The main goal of this study was to develop soil-landscape P models to support a "precision soil conservation" approach combining fine-scale (i.e., site-specific) and coarse scale (i.e., watershed-extent) assessment of soil P. The specific objectives were to: (i) identify those environmental properties that impart the most control on the spatial distribution of soil Mehlich-1 extracted P (MP) in the SFRW; (ii) model the spatial patterns of soil MP using geostatistical methods; and (iii) assess model quality using independent validation samples. Soil MP data at 137 sites were fused with spatially explicit environmental covariates to develop soil MP prediction models using univariate (lognormal kriging, LNK) and multivariate methods (regression kriging, RK, and cokriging, CK). Incorporation of exhaustive environmental data into multivariate models (RK and CK) improved the prediction of soil MP in the SFRW compared with the univariate model (LNK), which relies solely on soil measurements. Among all tested environmental covariates, land use and vegetation related properties (topsoil) and geologic data (subsoil) showed the largest predictive power to build inferential models for soil MP. Findings from this study contribute to a better understanding of spatially explicit interactions between soil P and other environmental variables, facilitating improved land resource management while minimizing adverse risks to the environment. PMID- 26024256 TI - Agricultural conservation planning framework: 1. Developing multipractice watershed planning scenarios and assessing nutrient reduction potential. AB - Spatial data on soils, land use, and topography, combined with knowledge of conservation effectiveness, can be used to identify alternatives to reduce nutrient discharge from small (hydrologic unit code [HUC]12) watersheds. Databases comprising soil attributes, agricultural land use, and light detection and ranging-derived elevation models were developed for two glaciated midwestern HUC12 watersheds: Iowa's Beaver Creek watershed has an older dissected landscape, and Lime Creek in Illinois is young and less dissected. Subsurface drainage is common in both watersheds. We identified locations for conservation practices, including in-field practices (grassed waterways), edge-of-field practices (nutrient-removal wetlands, saturated buffers), and drainage-water management, by applying terrain analyses, geographic criteria, and cross-classifications to field- and watershed-scale geographic data. Cover crops were randomly distributed to fields without geographic prioritization. A set of alternative planning scenarios was developed to represent a variety of extents of implementation among these practices. The scenarios were assessed for nutrient reduction potential using a spreadsheet approach to calculate the average nutrient-removal efficiency required among the practices included in each scenario to achieve a 40% NO-N reduction. Results were evaluated in the context of the Iowa Nutrient Reduction Strategy, which reviewed nutrient-removal efficiencies of practices and established the 40% NO-N reduction as Iowa's target for Gulf of Mexico hypoxia mitigation by agriculture. In both test watersheds, planning scenarios that could potentially achieve the targeted NO-N reduction but remove <5% of cropland from production were identified. Cover crops and nutrient removal wetlands were common to these scenarios. This approach provides an interim technology to assist local watershed planning and could provide planning scenarios to evaluate using watershed simulation models. A set of ArcGIS tools is being released to enable transfer of this mapping technology. PMID- 26024257 TI - Agricultural conservation planning framework: 2. Classification of riparian buffer design types with application to assess and map stream corridors. AB - A watershed's riparian corridor presents opportunities to stabilize streambanks, intercept runoff, and influence shallow groundwater with riparian buffers. This paper presents a system to classify these riparian opportunities and apply them toward riparian management planning in hydrologic unit code 12 watersheds. In two headwater watersheds from each of three landform regions found in Iowa and Illinois, high-resolution (3-m grid) digital elevation models were analyzed to identify spatial distributions of surface runoff contributions and zones with shallow water tables (SWTs) (within 1.5 m of the channel elevation) along the riparian corridors. Results were tabulated, and a cross classification was applied. Classes of buffers include those primarily placed to (i) trap runoff and sediment, (ii) influence shallow groundwater, (iii) address both runoff and shallow groundwater, and (iv) maintain/improve stream bank stability. Riparian buffers occupying about 2.5% of these six watersheds could effectively intercept runoff contributions from 81 to 94% of the watersheds' contributing areas. However, extents of riparian zones where a narrow buffer (<10 m wide) would adequately intercept runoff but where >25 m width of buffer vegetation could root to a SWT varied according to landform region ( < 0.10). Yet, these wide-SWT riparian zones were widespread and occupied 23 to 53% of the lengths of stream banks among the six watersheds. The wide-SWT setting provides opportunities to reduce dissolved nutrients (particularly NO-N) carried via groundwater. This riparian classification and mapping system is part of a ArcGIS toolbox and could provide a consistent basis to identify riparian management opportunities in Midwestern headwater catchments wherever high-resolution elevation data are available. PMID- 26024258 TI - Relationships between Paddy Soil Radiocesium Interception Potentials and Physicochemical Properties in Fukushima, Japan. AB - The radiocesium interception potential (RIP) of bulk soil (RIP) can reliably be used to predict the magnitude of soil-to-plant radiocesium transfer. There has been some controversy about which soil properties control the RIP, although the RIP is theoretically proportional to the amount of frayed edge sites in micaceous clay minerals. The RIP was determined for 97 paddy soils in three regions (Hama dori, Naka-dori, and Aizu) in Fukushima Prefecture, Japan, and the relationships between selected physicochemical properties and the RIP were analyzed. The mean (+/- standard deviation) of the RIP for the 97 soils was 1.67 (+/-0.87) mol kg, and the range was 0.34 to 5.36 mol kg. Pearson correlation analysis revealed that the RIP positively correlated best ( < 0.01) with the clay fraction K content as a mass fraction of the bulk soil (clay-K) and negatively correlated with the total C content and the phosphate absorption coefficient ( < 0.05). Therefore, clay-K, an indicator of the amount of micaceous clay minerals in a soil, was confirmed as being useful for estimating the magnitude of the RIP for paddy soils in Fukushima. The RIP was invariably low if either the total C content exceeded 6.0% or the phosphate absorption coefficient exceeded 1500 mg kg, suggesting that these parameters could be useful for screening soils with particularly low RIP values. PMID- 26024259 TI - Evaluation of cesium-137 conversion models and parameter sensitivity for erosion estimation. AB - The Cs technique has been widely used to provide soil redistribution estimates since the 1970s. However, most Cs-conversion models remain theoretical and largely unvalidated. Our objectives were to validate the four widely used conversion models, examine model parameter sensitivity, and evaluate the potential of using kriging to improve soil redistribution estimation. Soil loss was measured from a 1.6-ha plot since 1978. Winter wheat ( L.) was grown primarily under conventional tillage. Soil samples in a 10-m grid were taken from the plot to estimate the Cs inventory. Soil redistribution rates were estimated using four models and were further interpolated using ordinary kriging. The parameter sensitivity analyses at the 95% confidence limits showed that reference inventory had the most impact on estimated water erosion, followed by particle size correction for erosion and tillage depth, with minimal impacts from mass depth, bulk density, and particle size correction for deposition. Compared with the measured water erosion, the relative errors of the mean net water erosion estimates across the entire plot without and with kriging were 28 and -17% for the proportional model (PM), 141 and 106% for the simplified mass balance model, 133 and 100% for the improved mass balance model (MBM2), and 109% for the extended MBM2 with tillage erosion (MBM3). Results indicated that the PM performed better than the mass balance models under the study conditions and that kriging improved mean soil redistribution estimates. However, the full potential of the MBM2 and MBM3 needs to be further evaluated under conditions where loss of newly deposited Cs exists. PMID- 26024260 TI - Tillage and corn residue harvesting impact surface and subsurface carbon sequestration. AB - Corn stover harvesting is a common practice in the western U.S. Corn Belt. This 5 yr study used isotopic source tracking to quantify the influence of two tillage systems, two corn ( L.) surface residue removal rates, and two yield zones on soil organic C (SOC) gains and losses at three soil depths. Soil samples collected in 2008 and 2012 were used to determine C enrichment during SOC mineralization, the amount of initial SOC mineralized (SOC), and plant C retained in the soil (PCR) and sequestered C (PCR - SOC). The 30% residue soil cover after planting was achieved by the no-till and residue returned treatments and was not achieved by the chisel plow, residue removed treatment. In the 0- to 15-cm soil depth, the high yield zone had lower SOC (1.49 Mg ha) than the moderate yield zone (2.18 Mg ha), whereas in the 15- to 30-cm soil depth, SOC was higher in the 60% (1.38 Mg ha) than the 0% (0.82 Mg ha) residue removal treatment. When the 0- to 15- and 15- to 30-cm soil depths were combined, (i) 0.91 and 3.62 Mg SOC ha were sequestered in the 60 and 0% residue removal treatments; (ii) 2.51 and 0.36 Mg SOC ha were sequestered in the no-till and chisel plow treatments, and (iii) 1.16 and 1.65 Mg SOC ha were sequestered in the moderate and high yield zone treatments, respectively. The surface treatments influenced C cycling in the 0- to 15- and 15- to 30-cm depths but did not influence SOC turnover in the 30- to 60-cm depth. PMID- 26024261 TI - Upper midwest climate variations: farmer responses to excess water risks. AB - Persistent above average precipitation and runoff and associated increased sediment transfers from cultivated ecosystems to rivers and oceans are due to changes in climate and human action. The US Upper Midwest has experienced a 37% increase in precipitation (1958-2012), leading to increased crop damage from excess water and off-farm loss of soil and nutrients. Farmer adaptive management responses to changing weather patterns have potential to reduce crop losses and address degrading soil and water resources. This research used farmer survey ( = 4778) and climate data (1971-2011) to model influences of geophysical context, past weather, on-farm flood and saturated soils experiences, and risk and vulnerability perceptions on management practices. Seasonal precipitation varied across six Upper Midwest subregions and was significantly associated with variations in management. Increased warm-season precipitation (2007-2011) relative to the past 40 yr was positively associated with no-till, drainage, and increased planting on highly erodible land (HEL). Experience with saturated soils was significantly associated with increased use of drainage and less use of no till, cover crops, and planting on HEL. Farmers in counties with a higher percentage of soils considered marginal for row crops were more likely to use no till, cover crops, and plant on HEL. Respondents who sell corn through multiple markets were more likely to have planted cover crops and planted on HEL in 2011.This suggests that regional climate conditions may not well represent individual farmers' actual and perceived experiences with changing climate conditions. Accurate climate information downscaled to localized conditions has potential to influence specific adaptation strategies. PMID- 26024262 TI - Equilibrium State of PAHs in Bottom Sediment-Water-Suspended Sediment System of a Large River Considering Freely Dissolved Concentrations. AB - In natural waters, the equilibrium state of hydrophobic organic compounds among bottom sediment (BS), suspended sediment (SPS), and water is fundamental to infer their transfer flux and aqueous bioavailability. However, this type of information remains scarce and fragmented. This study systematically evaluated the equilibrium state of polycyclic aromatic hydrocarbons (PAHs) in the Yangtze River. Total and freely dissolved concentrations of the 16 priority PAHs in pore water and overlying water (including surface and near-bottom) of the Yangtze middle reaches were investigated, as were the concentrations of attached PAHs in SPS and BS. Results showed that concentrations of total/freely dissolved PAHs, dissolved organic carbon (DOC), and SPS in surface water were not statistically different from those in near-bottom water, and the DOC-water distribution coefficients of PAHs in pore water were not statistically different from overlying water. However, significant disequilibrium was found at the sediment water interface; concentrations of total/freely dissolved PAHs in pore water were 1 to 2 orders of magnitude higher than those in overlying water. This study offers a complete analysis of the potential disequilibrium of PAHs in BS-water SPS system of large rivers and suggests that distribution of hydrophobic organic compounds between BS and overlying water is essential in controlling their equilibrium state in the BS-water-SPS system of natural waters. PMID- 26024263 TI - Factors affecting sorption of nitro explosives to biochar: pyrolysis temperature, surface treatment, competition, and dissolved metals. AB - The application of rice straw-derived biochar for removing nitro explosives, including 2,4-dinitrotoluene (DNT), 2,4,6-trinitrotoluene (TNT), and hexahydro 1,3,5-trinitro-1,3,5-triazine (RDX), from contaminated water was investigated through batch experiments. An increase in the pyrolysis temperature from 250 to 900 degrees C in general led to higher pH, surface area, cation exchange capacity (CEC), point of zero charge, and C:O ratio of biochar. The maximum sorption capacity estimated by a mixed sorption-partition model increased when pyrolysis temperatures were elevated from 250 to 900 degrees C, indicating that C content and aromaticity of biochar were strongly related to the sorption of nitro explosives to biochar. Surface treatment with acid or oxidant increased the sorption capacity of biochar for the two strong pi-acceptor compounds (DNT and TNT) but not for RDX. However, the enhancement of sorption capacity was not directly related to increased surface area and CEC. Compared with single-sorption systems, coexistence of explosives or cationic metals resulted in decreased sorption of each explosive to biochar, suggesting that sorption of nitro explosives and cationic metals to electron-rich portions in biochar was competitive. Our results suggest that pi-pi electron donor acceptor interactions are main sorption mechanisms and that changing various conditions can enhance or reduce the sorption of nitro explosives to biochar. PMID- 26024265 TI - Degradation of plant cuticles in soils: impact on formation and sorptive ability of humin-mineral matrices. AB - Plant cuticles are important precursors for soil organic matter, in particular for soil humin, which is considered an efficient sorbent for organic pollutants. In this study, we examined degradation and transformation of cuticles isolated from fruit and leaves in loamy sand and sandy clay loessial arid brown soils. We then studied sorption of phenanthrene and carbamazepine to humin-mineral matrices isolated from the incubated soils. Low degradation (22%) was observed for agave cuticle in a sandy clay soil system, whereas high degradation (68-78%) was obtained for agave cuticle in a loamy sand soil system and for loamy sand and sandy clay soils amended with tomato cuticle. During incubation, most of the residual organic matter was accumulated in the humin fraction. Sorption of phenanthrene was significantly higher for humin-mineral matrices obtained from soils incubated with plant cuticles as compared with soils without cuticle application. Sorption of carbamazepine to humin-mineral matrices was not affected by cuticle residues. Cooperative sorption of carbamazepine on humin-mineral matrices isolated from sandy clay soil is suggested. Sorption-desorption hysteresis of both phenanthrene and carbamazepine was lower for humin-mineral matrices obtained from soils incubated with plant cuticles as compared with nonamended soils. Our results show that cuticle composition significantly affects the rate and extent of cuticle degradation in soils and that plant cuticle application influences sorption and desorption of polar and nonpolar pollutants by humin-mineral matrices. PMID- 26024264 TI - Spatial and temporal distribution of fungicides applied to creeping bentgrass. AB - Turf managers often rely on fungicides to limit damage caused by root diseases. Because fungicides are applied to aboveground surfaces and do not move basipetally, they are effective against root pathogens only when fungitoxic concentrations migrate to the rhizosphere. This research focused on the distribution of modern fungicides in verdure, thatch, sand, and roots of creeping bentgrass [ L. var. (Huds.) Farw.] maintained as a putting green. The fungicides azoxystrobin (methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3 methoxyacrylate), propiconazole (1,2,4-triazole, 1-((2-(2,4-dichlorophenyl)-4 propyl-1,3-dioxolan-2-yl)methyl), pyraclostrobin (carbamic acid, [2-[[[1-(4 chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,methyl ester), and thiophanate-methyl (dimethyl 4,'4-o-phenylenebis[3-thioallophanate]) were applied to replicate field plots in a water volume of 815 L ha. Plots were sampled at 0, 3, 7, 10, 14, 17, and 21 d after application by extracting cores measuring 1.9 cm in diameter by 3.8 cm deep. Cores were separated into verdure/thatch, sand, and roots before quantitative determination (liquid chromatography, triple quadrupole mass spectrometry) of fungicide residues. Fungicide residues in verdure/thatch declined steadily with time and support previously reported results describing fungicide depletion. Fungicides were detected in roots and sand within 5 h of application at very low (1-15 mg kg) concentrations and remained at low levels throughout the sampling period. Fungicides differed with respect to amounts recovered per turfgrass component. Azoxystrobin and propiconazole were associated with roots for the duration of the experiment, but pyraclostrobin was nearly undetectable. Near-zero levels of all fungicides were detected in the sand component. Half-life values in the verdure/thatch component ranged from 2.3 to 18.9 d. PMID- 26024266 TI - Metal plaque on reeds from an Acid mine drainage site. AB - Studies were conducted to investigate the interactions among rhizosphere microorganisms, plaque formation, and metal accumulation in reeds [ (Cav.) Trin. ex Steud.] grown in an acid mine drainage-contaminated field. We found that Fe(II)-oxidizing bacteria (Fe(II)OB] played a key role in Fe plaque formation and pH decrease. The kinetics of Fe plaque formation were related to the abundance of rhizosphere Fe(II)OB, which mediated 66.0 to 93.3% Fe(II) oxidation. The Fe(II) concentration decreased from 14.24 to 0.94 mg L in nonsterile samples, with the most abundant Fe(II)OB activity (5.64 +/- 3.83 * 10 colony-forming units g) after 2 d, and pH decreased from 2.91 to 2.50. The amount of metal plaque was also positively correlated with metal levels in soil. No significant correlations were found between Fe, Mn, and Al concentration in the plaque. Reeds sequestered Al in the aboveground tissues, and Mn and Al were stored in the roots and rhizomes. Metal plaque did not affect the Mn uptake but inhibited the translocation of Fe and Al in reeds. To increase the phytoremediation efficiency of Fe, Mn, and Al from the acid mine drainage-contaminated site, further research may be needed to inhibit the Fe(II)OB growth and reduce the metal plaque formation, thereby increasing the metal accumulation in reeds. PMID- 26024267 TI - Nitrate leaching, yields and carbon sequestration after noninversion tillage, catch crops, and straw retention. AB - Crop management factors, such as tillage, rotation, and straw retention, need to be long-term to allow conclusions on effects on crop yields, nitrate leaching, and carbon sequestration. In 2002, two field experiments, each including four cash crop rotations, were established on soils with 9 and 15% clay, under temperate, coastal climate conditions. Direct drilling and harrowing to two different depths were compared to plowing with respect to yield, nitrate N leaching, and carbon sequestration. For comparison of yields across rotations, grain and seed dry matter yields for each crop were converted to grain equivalents (GE). Leaching was compared to yields by calculating yield-scaled leaching (YSL, g N kg GE), and N balances were calculated as the N input in manure minus the N output in products removed from the fields. Direct drilling reduced yields, but no effect on leaching was found. Straw retention did not significantly increase yields, nor did it reduce leaching, while fodder radish ( L.) as a catch crop was capable of reducing nitrate leaching to a low level. Thus, YSL of winter wheat ( L.) was higher than for spring barley ( L.) grown after fodder radish due to the efficient catch crop. Soil organic carbon (SOC) did not increase significantly after 7 yr of straw incorporation or noninversion tillage. There was no correlation between N balances calculated for each growing season and N leaching measured in the following percolation period. PMID- 26024161 TI - Measurement of J/psi and psi(2S) Prompt Double-Differential Cross Sections in pp Collisions at sqrt[s]=7 TeV. AB - The double-differential cross sections of promptly produced J/psi and psi(2S) mesons are measured in pp collisions at sqrt[s]=7 TeV, as a function of transverse momentum p_{T} and absolute rapidity |y|. The analysis uses J/psi and psi(2S) dimuon samples collected by the CMS experiment, corresponding to integrated luminosities of 4.55 and 4.90 fb^{-1}, respectively. The results are based on a two-dimensional analysis of the dimuon invariant mass and decay length, and extend to p_{T}=120 and 100 GeV for the J/psi and psi(2S), respectively, when integrated over the interval |y|<1.2. The ratio of the psi(2S) to J/psi cross sections is also reported for |y|<1.2, over the range 10 1:2 > 1:1 > CP alone > 2:1 > 3:1. Similarly, Olsen P was significantly higher ( < 0.05) where earthworms were added. The mean percentage increase in extractable P was in the order CP alone > 1:2 > 1:3 > 1:1 > 2:1 > 3:1, with earthworm addition almost doubling P release across the 1:1, 1:2, and CP alone treatments. Fly ash incorporation enhanced conversion of organic N to the plant-available inorganic forms, with the 1:3 treatment resulting in the highest conversion. Scanning electron micrograph images confirmed the extent of vermidegradation reflected by the various humification parameters determined. Fly ash incorporation at the 1:2 ratio proved to be the most appropriate because it allows processing of more fly ash while giving a vermicompost with desirable maturity and nutritional properties. PMID- 26024278 TI - Fate and Transport of 17beta-Estradiol beneath Animal Waste Holding Ponds. AB - Concentrated animal feeding operations typically store livestock waste in clay lined ponds. Although these ponds are regulated to include a liner with a small hydraulic conductivity to limit leaching, previous studies have traced surface and groundwater contamination from such regulated animal waste ponds. This research examined the transport of 17beta-estradiol (E2) and its primary metabolite, estrone (E1), through soil liners using field- and laboratory-based studies. Additionally, a potential engineering solution to limit hormone transport-applying biochar to new pond liners to act as a retardant-was studied. Soil cores 80 cm in length were collected beneath a mature dairy waste pond and analyzed for moisture content and hormone concentrations. Unsaturated conditions and E2 concentrations of 4 to 250 ng g were detected beneath the waste pond. In the laboratory portion of the study, hand-packed columns of sand or clay were subjected to infiltration by a 2.3-m head of dairy waste. A subset of the hand packed sand columns was amended with powdered biochar to test its ability to retard E2 and E1. For 3 mo, column leachate was analyzed for hormone concentrations, and at the conclusion of the study E2 and E1 concentrations in the soil were measured. In the 44 d after sealing, the clay, sand, sand with a thin layer of biochar, and sand mixed with a biochar amendment leached a total of 0.54, 1.3, 0.09, and 0.45 MUg of E2, respectively. The biochar amendments to the hand-packed columns considerably minimized E2 in the leachate. PMID- 26024279 TI - Porewater geochemistry of inland Acid sulfate soils with sulfuric horizons following postdrought reflooding with freshwater. AB - Following the break of a severe drought in the Murray-Darling Basin, rising water levels restored subaqueous conditions to dried inland acid sulfate soils with sulfuric horizons (pH <3.5). Equilibrium dialysis membrane samplers were used to investigate in situ changes to soil acidity and abundance of metals and metalloids following the first 24 mo of restored subaqueous conditions. The rewetted sulfuric horizons remained severely acidified (pH ~4) or had retained acidity with jarosite visibly present after 5 mo of continuous subaqueous conditions. A further 19 mo of subaqueous conditions resulted in only small additional increases in pH (~0.5-1 pH units), with the largest increases occurring within the uppermost 10 cm of the soil profile. Substantial decreases in concentrations of some metal(loid)s were observed with time most likely owing to lower solubility and sorption as a consequence of the increase in pH. In deeper parts of the profiles, porewater remained strongly buffered at low pH values (pH <4.5) and experienced little progression toward anoxic circumneutral pH conditions over the 24 mo of subaqueous conditions. It is proposed that low pH conditions inhibited the activity of SO-reducing bacteria and, in turn, the in situ generation of alkalinity through pyrite production. The limited supply of alkalinity in freshwater systems and the initial highly buffered low pH conditions were also thought to be slowing recovery. The timescales involved for a sulfuric horizon rewetted by a freshwater body to recover from acidic conditions could therefore be in the order of several years. PMID- 26024280 TI - Nitrogen removal and greenhouse gas emissions from constructed wetlands receiving tile drainage water. AB - Loss of nitrate from agricultural lands to surface waters is an important issue, especially in areas that are extensively tile drained. To reduce these losses, a wide range of in-field and edge-of-field practices have been proposed, including constructed wetlands. We re-evaluated constructed wetlands established in 1994 that were previously studied for their effectiveness in removing nitrate from tile drainage water. Along with this re-evaluation, we measured the production and flux of greenhouse gases (GHGs) (CO, NO, and CH). The tile inlets and outlets of two wetlands were monitored for flow and N during the 2012 and 2013 water years. In addition, seepage rates of water and nitrate under the berm and through the riparian buffer strip were measured. Greenhouse gas emissions from the wetlands were measured using floating chambers (inundated fluxes) or static chambers (terrestrial fluxes). During this 2-yr study, the wetlands removed 56% of the total inlet nitrate load, likely through denitrification in the wetland. Some additional removal of nitrate occurred in seepage water by the riparian buffer strip along each berm (6.1% of the total inlet load, for a total nitrate removal of 62%). The dominant GHG emitted from the wetlands was CO, which represented 75 and 96% of the total GHG emissions during the two water years. The flux of NO contributed between 3.7 and 13% of the total cumulative GHG flux. Emissions of NO were 3.2 and 1.3% of the total nitrate removed from wetlands A and B, respectively. These wetlands continue to remove nitrate at rates similar to those measured after construction, with relatively little GHG gas loss. PMID- 26024281 TI - Soil physicochemical conditions, denitrification rates, and abundance in north Carolina coastal plain restored wetlands. AB - Over the last century, North Carolina has seen a severe reduction in the percentage of wetlands and a rise in negative environmental impacts related to this loss. To counter these effects, efforts have been enacted to mitigate wetland loss and create new wetland areas. The objective of this study was to assess the impact of hydrological restoration at several sites in the North Carolina coastal plain. Nine sites were selected for study. Hydrologically restored wetlands were compared with natural wetlands and prior converted (PC) croplands (i.e., historic wetlands under agricultural production). Each site was analyzed along a relative wetness gradient, and physicochemical properties, denitrification enzyme activity, and NO reductase gene () abundances using real time PCR were measured. Physicochemically, restoration resulted in significantly increased levels of total C as compared with PC cropland sites. Restored wetland sites also saw pH, soil moisture, P, and NO+NO approximate levels similar to those of natural wetlands. Denitrification enzyme activity rates varied based on relative wetness within individual sites, generally increasing with increasing soil moisture. However, denitrification tended to be lower in restored wetland sites relative to natural wetlands. Gene abundances of saw statistically significant decreases in restored wetland soils. In conclusion, although analysis of restored wetlands reveals clear changes in several physicochemical characteristics and significant decreases in gene abundances, restoration efforts appear to have not significantly affected the denitrification component of the N cycle. PMID- 26024282 TI - ACS324.1 JOURNAL OF ENVIRONMENTAL QUALITY EDITORIAL BOARD 2014 Annual Reports. PMID- 26024284 TI - Epidemiology and emerging resistance in bacterial bloodstream infections in patients with hematologic malignancies. AB - BACKGROUND: The objective of this study was determine the frequency of bloodstream infections (BSIs) and the causative bacteria and their resistance patterns in patients with hematological malignancies (HMs) in a large tertiary care university hospital in Turkey over a 5-year period. METHODS: A total of 2098 patients with HMs with 3703 neutropenic episodes were included. Patients were classified as high-risk (n = 843) and low-risk (n = 1255) groups and evaluated for frequency of BSIs, causative bacteria, and their resistance patterns. RESULTS: The frequency of BSIs was 14.5%. The frequency of gram-negative BSIs in high-risk and low-risk groups was 10.7% and 5.4% (p < 0.001), respectively. The frequency of gram-positive BSIs in high-risk and low-risk groups was 7.0% and 3.9% (p < 0.001), respectively. Gram-negative bacteria predominated (52.6%), with Escherichia coli (17.3%) and Klebsiella spp. (11.0%) as the most frequent organisms. Coagulase-negative staphylococci (10.4%) and Corynebacterium spp. (6.3%) were the most common gram-positive bacteria (35.8%). The rate of extended spectrum beta-lactamase (ESBL) production was 45% for E. coli and 58% for Klebsiella spp. Quinolone resistance was 58% for E. coli and 11% for Klebsiella spp.. The overall frequency of ceftazidime resistance in Pseudomonas aeruginosa was 28%, and 87% of Acinetobacter spp. were multidrug-resistant. Of Staphylococcus aureus isolates, 24.8% were resistant to methicillin. CONCLUSION: The dominating causes of BSIs in patients with HMs in our hospital are resistant gram-negative bacteria, which has made empirical antimicrobial choice a highly challenging issue in this patient population. PMID- 26024285 TI - ESBL-producing enterobacteriaceae-related urinary tract infections in kidney transplant recipients: incidence and risk factors for recurrence. AB - BACKGROUND: Urinary tract infections (UTIs) represent the first cause of bacterial infections in renal transplant recipients. In a period of increasing resistance to antimicrobial agents, the factors leading to the development of UTI in previously urinary colonized renal transplant recipients as well as the factors associated with recurrence of UTIs have to be determined. The aims of this retrospective study were (1) to assess the incidence of extended-spectrum beta-lactamase-producing enterobacteriaceae (ESBL-PE)-related UTI in kidney transplant recipients, (2) to identify factors associated with ESBL-PE infection and (3) to determine the risk factors for recurrence. METHODS: We included all kidney transplant recipients admitted in our hospital between January 2009 and January 2012 who had a monobacterial ESBL-PE UTI or bacteriuria. RESULTS: During the study period, 659 patients underwent kidney transplantation; 72 patients had ESBL-PE bacteriuria, representing a 10.9% prevalence, and among the latter 34 (47.2%) presented an ESBL-PE-related UTI. Fourteen patients (41.2%) experienced a UTI relapse associated with two factors: advanced age (p = 0.032) and persistent bacteriuria 48 h after appropriate antibiotic therapy (p = 0.04). No other risk factor for recurrence was found, including the presence and management of a ureteral stent during the first UTI, causative microorganisms, or diabetes mellitus. CONCLUSIONS: In this specific population, regarding the risk of relapse there is an urgent need for prospective studies to test the best treatment strategy. PMID- 26024287 TI - Investigation of potential traces of pluripotency in germinal-center-derived B cell lymphomas driven by MYC. PMID- 26024286 TI - A novel antibody-drug conjugate targeting SAIL for the treatment of hematologic malignancies. AB - Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody-drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs. PMID- 26024289 TI - Inhibitors of alanine racemase enzyme: a review. AB - Alanine racemase is a fold type III PLP-dependent amino acid racemase enzyme catalysing the conversion of l-alanine to d-alanine utilised by bacterial cell wall for peptidoglycan synthesis. As there are no known homologs in humans, it is considered as an excellent antibacterial drug target. The standard inhibitors of this enzyme include O-carbamyl-d-serine, d-cycloserine, chlorovinyl glycine, alaphosphin, etc. d-Cycloserine is indicated for pulmonary and extra pulmonary tuberculosis but therapeutic use of drug is limited due to its severe toxic effects. Toxic effects due to off-target affinities of cycloserine and other substrate analogs have prompted new research efforts to identify alanine racemase inhibitors that are not substrate analogs. In this review, an updated status of known inhibitors of alanine racemase enzyme has been provided which will serve as a rich source of structural information and will be helpful in generating selective and potent inhibitor of alanine racemase. PMID- 26024288 TI - Inactivation of peptidylglycine alpha-hydroxylating monooxygenase by cinnamic acid analogs. AB - Peptidylglycine alpha-amidating monooxygenase (PAM) is a bifunctional enzyme that catalyzes the final reaction in the maturation of alpha-amidated peptide hormones. Peptidylglycine alpha-hydroxylating monooxygenase (PHM) is the PAM domain responsible for the copper-, ascorbate- and O2-dependent hydroxylation of a glycine-extended peptide. Peptidylamidoglycolate lyase is the PAM domain responsible for the Zn(II)-dependent dealkylation of the alpha-hydroxyglycine containing precursor to the final alpha-amidated peptide. We report herein that cinnamic acid and cinnamic acid analogs are inhibitors or inactivators of PHM. The inactivation chemistry exhibited by the cinnamates exhibits all the attributes of a suicide-substrate. However, we find no evidence for the formation of an irreversible linkage between cinnamate and PHM in the inactivated enzyme. Our data support the reversible formation of a Michael adduct between an active site nucleophile and cinnamate that leads to inactive enzyme. Our data are of significance given that cinnamates are found in foods, perfumes, cosmetics and pharmaceuticals. PMID- 26024290 TI - Influence of substrate orientation on the structural quality of GaAs nanowires in molecular beam epitaxy. AB - In this study, the effect of substrate orientation on the structural quality of Au-catalyzed epitaxial GaAs nanowires grown by a molecular beam epitaxy reactor has been investigated. It was found that the substrate orientations can be used to manipulate the nanowire catalyst composition and the catalyst surface energy and, therefore, to alter the structural quality of GaAs nanowires grown on different substrates. Defect-free wurtzite-structured GaAs nanowires grown on the GaAs (110) substrate have been achieved under our growth conditions. PMID- 26024291 TI - Fagopyrins and Protofagopyrins: Detection, Analysis, and Potential Phototoxicity in Buckwheat. AB - Buckwheat contains many healthy nutrients, and its consumption is therefore increasing. Buckwheat also contains fluorescent phototoxic fagopyrins. A systematic review of fagopyrins and the phototoxicity of buckwheat found that reliable quantitative data on fagopyrin toxicity are not yet available. Generally, buckwheat seeds, flour, and teas are safe in normal amounts. Diets extensively composed of buckwheat sprouts, herbs, and particularly flowers or of fagopyrin-rich buckwheat extracts may cause fagopyrism. A reference standard is needed, as it would enable the accurate evaluation of fagopyrin content in buckwheat products and would allow proper testing of their as yet unknown physical, chemical, and biological characteristics. PMID- 26024292 TI - Development of a UK Online 24-h Dietary Assessment Tool: myfood24. AB - Assessment of diet in large epidemiological studies can be costly and time consuming. An automated dietary assessment system could potentially reduce researcher burden by automatically coding food records. myfood24 (Measure Your Food on One Day) an online 24-h dietary assessment tool (with the flexibility to be used for multiple 24 h-dietary recalls or as a food diary), has been developed for use in the UK population. Development of myfood24 was a multi-stage process. Focus groups conducted with three age groups, adolescents (11-18 years) (n = 28), adults (19-64 years) (n = 24) and older adults (>= 65 years) (n = 5) informed the development of the tool, and usability testing was conducted with beta (adolescents n = 14, adults n = 8, older adults n = 1) and live (adolescents n = 70, adults n = 20, older adults n = 4) versions. Median system usability scale (SUS) scores (measured on a scale of 0-100) in adolescents and adults were marginal for the beta version (adolescents median SUS = 66, interquartile range (IQR) = 20; adults median SUS = 68, IQR = 40) and good for the live version (adolescents median SUS = 73, IQR = 22; adults median SUS = 80, IQR = 25). Myfood24 is the first online 24-h dietary recall tool for use with different age groups in the UK. Usability testing indicates that myfood24 is suitable for use in UK adolescents and adults. PMID- 26024293 TI - Glycemic responses, appetite ratings and gastrointestinal hormone responses of most common breads consumed in Spain. A randomized control trial in healthy humans. AB - The present study was carried out to determine the glycemic index (GI), glycemic load (GL), insulinemic index (InI), appetite ratings and postprandial plasma concentrations of gastrointestinal hormones related to the control of food intake after the ingestion of the five most common breads consumed in Spain with different compositions and manufacturing processes. Twenty-two healthy adults participated in a randomized crossover study. The breads tested were Ordinary, Precooked-Frozen, Candeal-flour, Alfacar whites and Wholemeal. All breads portions were calculated to supply 50 g of available carbohydrates. In addition, 50 g of glucose was used as a reference. A linear mixed-effects model was used to compare data calculated for all breads with glucose load. The GI value varied from 61 for the Wholemeal, to Alfacar 68, Ordinary 76, and 78 and 86 for the Precooked-Frozen and Candeal-flour breads, respectively. Wholemeal and Alfacar had lower GI than glucose. All tested breads had a lower GL (ranged 9 to 18) compared with glucose. Wholemeal GL was similar to Alfacar, but lower than the other white breads. InI were significantly lower for all breads (ranged 68 to 73) compared with glucose, and similar among them. The intake of the Wholemeal bread led to a higher release of gastric inhibitory polypeptide compared with the Ordinary and Precooked breads and to a higher release of pancreatic polypeptide compared with the Precooked-Frozen bread. All breads affected appetite ratings similarly. In conclusion, based on GL, the Wholemeal bread would be expected to exert a favorable glycemic response. PMID- 26024294 TI - Changes in the sodium content of New Zealand processed foods: 2003-2013. AB - Decreasing population sodium intake has been identified as a "best buy" for reducing non-communicable disease. The aim of this study was to explore 10-year changes in the sodium content of New Zealand processed foods. Nutrient data for nine key food groups were collected in supermarkets in 2003 (n = 323) and 2013 (n = 885). Mean (SD) and median (min, max) sodium content were calculated by food group, year and label type (private/branded). Paired t-tests explored changes in sodium content for all products available for sale in both years (matched; n = 182). The mean (SD) sodium content of all foods was 436 (263) mg (100 g)(-1) in 2003 and 433 (304) mg (100 g)(-1) in 2013, with no significant difference in matched products over time (mean (SD) difference, -56 (122) mg (100 g)(-1), 12%; p = 0.22). The largest percentage reductions in sodium (for matched products) were observed for Breakfast Cereals (28%; -123 (125) mg (100 g)(-1)), Canned Spaghetti (15%; -76 (111) mg (100 g)(-1)) and Bread (14%; -68 (69) mg (100 g)( 1)). The reduction in sodium was greater for matched private vs. branded foods ( 69 vs. -50 mg (100 g)(-1), both p < 0.001). There has been modest progress with sodium reduction in some New Zealand food categories over the past 10 years. A renewed focus across the whole food supply is needed if New Zealand is to meet its global commitment to reducing population sodium intake. PMID- 26024296 TI - Patterns of Food Parenting Practices and Children's Intake of Energy-Dense Snack Foods. AB - Most previous studies of parental influences on children's diets included just a single or a few types of food parenting practices, while parents actually employ multiple types of practices. Our objective was to investigate the clustering of parents regarding food parenting practices and to characterize the clusters in terms of background characteristics and children's intake of energy-dense snack foods. A sample of Dutch parents of children aged 4-12 was recruited by a research agency to fill out an online questionnaire. A hierarchical cluster analysis (n = 888) was performed, followed by k-means clustering. ANOVAs, ANCOVAs and chi-square tests were used to investigate associations between cluster membership, parental and child background characteristics, as well as children's intake of energy-dense snack foods. Four distinct patterns were discovered: "high covert control and rewarding", "low covert control and non-rewarding", "high involvement and supportive" and "low involvement and indulgent". The "high involvement and supportive" cluster was found to be most favorable in terms of children's intake. Several background factors characterized cluster membership. This study expands the current knowledge about parental influences on children's diets. Interventions should focus on increasing parental involvement in food parenting. PMID- 26024295 TI - PON1 and Mediterranean Diet. AB - The Mediterranean diet has been proven to be highly effective in the prevention of cardiovascular diseases. Paraoxonase 1 (PON1) has been implicated in the development of those conditions, especially atherosclerosis. The present work describes a systematic review of current evidence supporting the influence of Mediterranean diet and its constituents on this enzyme. Despite the differential response of some genetic polymorphisms, the Mediterranean diet has been shown to exert a protective action on this enzyme. Extra virgin olive oil, the main source of fat, has been particularly effective in increasing PON1 activity, an action that could be due to low saturated fatty acid intake, oleic acid enrichment of phospholipids present in high-density lipoproteins that favor the activity, and increasing hepatic PON1 mRNA and protein expressions induced by minor components present in this oil. Other Mediterranean diet constituents, such as nuts, fruits and vegetables, have been effective in modulating the activity of the enzyme, pomegranate and its compounds being the best characterized items. Ongoing research on compounds isolated from all these natural products, mainly phenolic compounds and carotenoids, indicates that some of them are particularly effective, and this may enhance the use of nutraceuticals and functional foods capable of potentiating PON1 activity. PMID- 26024297 TI - Blueberries improve endothelial function, but not blood pressure, in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial. AB - Blueberry consumption has been shown to have various health benefits in humans. However, little is known about the effect of blueberry consumption on blood pressure, endothelial function and insulin sensitivity in humans. The present study investigated the role of blueberry consumption on modifying blood pressure in subjects with metabolic syndrome. In addition, endothelial function and insulin sensitivity (secondary measurements) were also assessed. A double-blind and placebo-controlled study was conducted in 44 adults (blueberry, n = 23; and placebo, n = 21). They were randomized to receive a blueberry or placebo smoothie twice daily for six weeks. Twenty-four-hour ambulatory blood pressure, endothelial function and insulin sensitivity were assessed pre- and post intervention. The blood pressure and insulin sensitivity did not differ between the blueberry and placebo groups. However, the mean change in resting endothelial function, expressed as reactive hyperemia index (RHI), was improved significantly more in the group consuming the blueberries versus the placebo group (p = 0.024). Even after adjusting for confounding factors, i.e., the percent body fat and gender, the blueberry group still had a greater improvement in endothelial function when compared to their counterpart (RHI; 0.32 +/- 0.13 versus -0.33 +/- 0.14; p = 0.0023). In conclusion, daily dietary consumption of blueberries did not improve blood pressure, but improved (i.e., increased) endothelial function over six weeks in subjects with metabolic syndrome. PMID- 26024299 TI - Nitric oxide suppresses the inhibitory effect of abscisic acid on seed germination by S-nitrosylation of SnRK2 proteins. AB - Nitric oxide (NO) plays important roles in plant development, and biotic and abiotic stress responses. In a recent study, we showed that endogenous NO negatively regulates abscisic acid (ABA) signaling in guard cells by inhibiting sucrose nonfermenting 1 (SNF1)-related protein kinase 2.6 (SnRK2.6)/open stomata 1(OST1) through S-nitrosylation. Application of NO breaks seed dormancy and alleviates the inhibitory effect of ABA on seed germination and early seedling growth, but it is unclear how NO functions at the stages of seed germination and early seedling development. Here, we show that like SnRK2.6, SnRK2.2 can be inactivated by S-nitrosoglutathione (GSNO) treatment through S-nitrosylation. SnRK2.2 and the closely related SnRK2.3 are known to play redundant roles in ABA inhibition of seed germination in Arabidopsis. We found that treatment with the NO donor SNP phenocopies the snrk2.2snrk2.3 double mutant in conferring ABA insensitivity at the stages of seed germination and early seedling growth. Our results suggest that NO negatively regulates ABA signaling in germination and early seedling growth through S-nitrosylation of SnRK2.2 and SnRK2.3. PMID- 26024298 TI - Diabetic silkworms for evaluation of therapeutically effective drugs against type II diabetes. AB - We previously reported that sugar levels in the silkworm hemolymph, i.e., blood, increase immediately (within 1 h) after intake of a high-glucose diet, and that the administration of human insulin decreases elevated hemolymph sugar levels in silkworms. In this hyperglycemic silkworm model, however, administration of pioglitazone or metformin, drugs used clinically for the treatment of type II diabetes, have no effect. Therefore, here we established a silkworm model of type II diabetes for the evaluation of anti-diabetic drugs such as pioglitazone and metformin. Silkworms fed a high-glucose diet over a long time-period (18 h) exhibited a hyperlipidemic phenotype. In these hyperlipidemic silkworms, phosphorylation of JNK, a stress-responsive protein kinase, was enhanced in the fat body, an organ that functionally resembles the mammalian liver and adipose tissue. Fat bodies isolated from hyperlipidemic silkworms exhibited decreased sensitivity to human insulin. The hyperlipidemic silkworms have impaired glucose tolerance, characterized by high fasting hemolymph sugar levels and higher hemolymph sugar levels in a glucose tolerance test. Administration of pioglitazone or metformin improved the glucose tolerance of the hyperlipidemic silkworms. These findings suggest that the hyperlipidemic silkworms are useful for evaluating the hypoglycemic activities of candidate drugs against type II diabetes. PMID- 26024300 TI - Enantioselective Synthesis of alpha-Quaternary Amino Acids by Alkylation of Deprotonated alpha-Aminonitriles. AB - A series of alpha-quaternary arylglycines were prepared in high optical purity (up to 98% ee) by alpha-alkylation of deprotonated alpha-aminonitriles derived by the Strecker reaction from (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane. The procedure includes only chromatographic purification of the final products and is devoid of chromatography or crystallization operations on intermediates to raise the optical purity. PMID- 26024301 TI - Endotoxic shock-expanded murine CD11c low CD45RB + regulatory dendritic cells modulate inflammatory T cell responses through multiple mechanisms. AB - Changes in the number and function of dendritic cells (DCs) have been reported to play an important role in endotoxin tolerance. It has been reported that expansion of splenic CD11c(low)CD45RB(+) DCs occurs in mice injected with sublethal doses of lipopolysaccharide (LPS). However, the function of endotoxic shock-expanded CD11c(low)CD45RB(+) DCs has not been examined. In this work, we show that endotoxic shock promotes the expansion of CD11c(low)CD45RB(+) cells with dendritic morphology and the production of low levels of inflammatory cytokines and costimulatory molecules. The expanded cells induce the generation of regulatory T cells (Tregs), show incapability to stimulate T cells, and induce apoptosis of CD4(+) T cells in vitro. As compared to CD11c(hi)CD45RB(-) conventional DCs, the expanded cells exert better protection against colitis induction by CD4(+) CD25(-) T cells, even though both subpopulations show similar ability to induce Tregs in vivo. The better control of proinflammatory cytokine responses in vivo by the expanded cells is associated with more apoptosis in the Payer's patches and in colonic tissue-infiltrating cells. Thus, the expanded cells can modulate inflammatory T cell responses through multiple mechanisms. Our study facilitates a better understanding how innate immune responses may shape adaptive immunity and immune suppression following LPS-induced acute inflammation. PMID- 26024303 TI - Easy Tuning of Surface and Optical Properties of PDMS Decorated by Ag Nanoparticles. AB - Herein, we report a systematic study on the wetting and optical properties of a PDMS surface coated by silver nanoparticles. A uniform Ag nanoparticles distribution onto PDMS membrane was obtained through dc room-temperature sputtering. The effect of sputtering current and PDMS mixing ratio between oligomer and curing agent was investigated by means of UV-vis spectroscopy and contact angle measurements. The results clearly show that the wettability and optical properties of the silver-coated elastomeric substrate were strongly affected by the sputtering current and by the PDMS composition with a marked decrease of the water contact angle and the spectral shift of well-defined plasmonic dips in the transmittance spectra related to the nanoparticles morphology. The finite element method was employed to model the optical experimental results. The observed tunable properties can find huge applications in several technological fields in which PDMS was usually employed as the structural and/or plasmonic active element. PMID- 26024302 TI - Arsenic and Its Methylated Metabolites Inhibit the Differentiation of Neural Plate Border Specifier Cells. AB - Exposure to arsenic in food and drinking water has been correlated with adverse developmental outcomes, such as reductions in birth weight and neurological deficits. Additionally, studies have shown that arsenic suppresses sensory neuron formation and skeletal muscle myogenesis, although the reason why arsenic targets both of these cell types in unclear. Thus, P19 mouse embryonic stem cells were used to investigate the mechanisms by which arsenic could inhibit cellular differentiation. P19 cells were exposed to 0, 0.1, or 0.5 MUM sodium arsenite and induced to form embryoid bodies over a period of 5 days. The expression of transcription factors necessary to form neural plate border specifier (NPBS) cells, neural crest cells and their progenitors, and myocytes and their progenitors were examined. Early during differentiation, arsenic significantly reduced the transcript and protein expression of Msx1 and Pax3, both needed for NPBS cell formation. Arsenic also significantly reduced the protein expression of Sox 10, needed for neural crest progenitor cell production, by 31-50%, and downregulated the protein and mRNA levels of NeuroD1, needed for neural crest cell differentiation, in a time- and dose-dependent manner. While the overall protein expression of transcription factors in the skeletal muscle lineage was not changed, arsenic did alter their nuclear localization. MyoD nuclear translocation was significantly reduced on days 2-5 between 15 and 70%. At a 10 fold lower concentration, monomethylarsonous acid (MMA III) appeared to be just as potent as inorganic arsenic at reducing the mRNA levels Pax3 (79% vs84%), Sox10 (49% vs 65%), and Msx1 (56% vs 56%). Dimethylarsinous acid (DMA III) also reduced protein and transcript expression, but the changes were less dramatic than those with MMA or arsenite. All three arsenic species reduced the nuclear localization of MyoD and NeuroD1 in a similar manner. The early changes in the differentiation of neural plate border specifier cells may provide a mechanism for arsenic to suppress both neurogenesis and myogenesis. PMID- 26024304 TI - A variant of PSMD6 is associated with the therapeutic efficacy of oral antidiabetic drugs in Chinese type 2 diabetes patients. AB - The PSMD6 variant rs831571 has been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). This study aimed to investigate the association of this variant with therapeutic effects of oral antidiabetic drugs in Chinese T2DM patients. 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks, and the therapeutic effects were compared. In the rosiglitazone cohort, rs831571 showed significant associations with fasting plasma glucose (FPG), 2-h glucose and decrement of glycated haemoglobin (HbA1c) levels after 24 weeks of treatment (P = 0.0368, 0.0468 and 0.0247, respectively). The C allele was significantly associated with a better attainment of FPG at 24 and 32 weeks (P = 0.0172 and 0.0257, respectively). Survival analyses showed CC homozygotes were more likely to attain a standard FPG level (P = 0.0654). In the repaglinide cohort, rs831571 was significantly associated with decreased HbA1c levels after 24 weeks of treatment, the homeostatic model assessment of insulin resistance and fasting insulin level after 48 weeks of treatment with repaglinide (P = 0.0096, 0235 and 0.0212, respectively). In conclusion, we observed that the PSMD6 variant rs831571 might be associated with the therapeutic effects of rosiglitazone and repaglinide in Chinese T2DM patients. However, these findings need to be confirmed in the future. PMID- 26024306 TI - Zero Volt Paper Spray Ionization and Its Mechanism. AB - The analytical performance and a suggested mechanism for zero volt paper spray using chromatography paper are presented. A spray is generated by the action of the pneumatic force of the mass spectrometer (MS) vacuum at the inlet. Positive and negative ion signals are observed, and comparisons are made with standard kV paper spray (PS) ionization and nanoelectrospray ionization (nESI). While the range of analytes to which zero volt PS is applicable is very similar to kV PS and nESI, differences in the mass spectra of mixtures are interpreted in terms of the more significant effects of analyte surface activity in the gentler zero volt experiment than in the other methods due to the significantly lower charge. The signal intensity of zero volt PS is also lower than in the other methods. A Monte Carlo simulation based on statistical fluctuation of positive and negative ions in solution has been implemented to explain the production of ions from initially uncharged droplets. Uncharged droplets first break up due to aerodynamics forces until they are in the 2-4 MUm size range and then undergo Coulombic fission. A model involving statistical charge fluctuations in both phases predicts detection limits similar to those observed experimentally and explains the effects of binary mixture components on relative ionization efficiencies. The proposed mechanism may also play a role in ionization by other voltage-free methods. PMID- 26024305 TI - A novel inhibitory mechanism of MRTF-A/B on the ICAM-1 gene expression in vascular endothelial cells. AB - The roles of myocardin-related transcription factor A (MRTF-A) and MRTF-B in vascular endothelial cells are not completely understood. Here, we found a novel regulatory mechanism for MRTF-A/B function. MRTF-A/B tend to accumulate in the nucleus in arterial endothelial cells in vivo and human aortic endothelial cells (HAoECs) in vitro. In HAoECs, nuclear localization of MRTF-A/B was not significantly affected by Y27632 or latrunculin B, primarily due to the reduced binding of MRTF-A/B to G-actin and in part, to the low level of MRTF-A phosphorylation by ERK. MRTF-A/B downregulation by serum depletion or transfection of siRNA against MRTF-A and/or MRTF-B induced ICAM-1 expression in HAoECs. It is known that nuclear import of nuclear factor-kappaB (NF-kappaB) plays a key role in ICAM-1 gene transcription. However, nuclear accumulation of NF-kappaB p65 was not observed in MRTF-A/B-depleted HAoECs. Our present findings suggest that MRTF-A/B inhibit ICAM-1 mRNA expression by forming a complex with NF kappaB p65 in the nucleus. Conversely, downregulation of MRTF-A/B alleviates this negative regulation without further translocation of NF-kappaB p65 into the nucleus. These results reveal the novel roles of MRTF-A/B in the homeostasis of vascular endothelium. PMID- 26024308 TI - Parathyroid Adenomas and Hyperplasia on Four-dimensional CT Scans: Three Patterns of Enhancement Relative to the Thyroid Gland Justify a Three-Phase Protocol. AB - PURPOSE: To describe the prevalence of three relative enhancement patterns of parathyroid lesions on four-dimensional (4D) computed tomographic (CT) scans. MATERIALS AND METHODS: The institutional review board approved this HIPAA compliant study and waived the need for informed consent. The authors retrospectively reviewed preoperative 4D CT scans obtained from November 2012 to June 2014 in 94 patients with pathologically proven parathyroid adenomas or hyperplasia. Lesions were classified into one of three relative enhancement patterns. All patterns required lesions to be lower in attenuation than the thyroid on non-contrast material-enhanced images, but patterns differed in the two contrast-enhanced phases. Type A lesions were higher in attenuation than the thyroid in the arterial phase, type B lesions were not higher in attenuation than the thyroid in the arterial phase but were lower in attenuation than the thyroid in the delayed phase, and type C lesions were neither higher in attenuation than the thyroid in the arterial phase nor lower in attenuation than the thyroid in the delayed phase. The prevalence of the relative enhancement patterns was compared. The t test was used to compare mean attenuation differences in Hounsfield units between the relative enhancement patterns. RESULTS: Ninety-four patients had 110 parathyroid lesions, including 11 patients with multigland disease. The sensitivity for single-gland disease was 94% (78 of 83) and that for multigland disease was 59% (16 of 27). Type B enhancement was most common, with a prevalence of 57% (54 of 94), followed by type C (22% [21 of 94]) and type A (20% [19 of 94]). Five lesions were interpreted incorrectly as parathyroid adenoma (false-positive), and all lesions had the type C pattern. Relative to the thyroid, lesions categorized as type A by readers had mean attenuation difference (+/- standard deviation) of 39 HU +/- 13 in the arterial phase, and type B lesions had a difference of -58 HU +/- 26 in the delayed phase. These values differed from the mean attenuation difference of lesions not in these categories (P < .001). CONCLUSION: Parathyroid adenomas and hyperplasia can be grouped into three relative enhancement patterns based on a protocol with a non-contrast enhanced and two contrast-enhanced phases. The type B pattern is most common and could be diagnosed with two contrast-enhanced phases. However, almost one quarter of lesions have the type C pattern and thus could be missed without the non contrast-enhanced phase. PMID- 26024307 TI - Articular Cartilage of the Human Knee Joint: In Vivo Multicomponent T2 Analysis at 3.0 T. AB - PURPOSE: To compare multicomponent T2 parameters of the articular cartilage of the knee joint measured by using multicomponent driven equilibrium single-shot observation of T1 and T2 (mcDESPOT) in asymptomatic volunteers and patients with osteoarthritis. MATERIALS AND METHODS: This prospective study was performed with institutional review board approval and with written informed consent from all subjects. The mcDESPOT sequence was performed in the knee joint of 13 asymptomatic volunteers and 14 patients with osteoarthritis of the knee. Single component T2 (T2(Single)), T2 of the fast-relaxing water component (T2F) and of the slow-relaxing water component (T2S), and the fraction of the fast-relaxing water component (F(F)) of cartilage were measured. Wilcoxon rank-sum tests and multivariate linear regression models were used to compare mcDESPOT parameters between volunteers and patients with osteoarthritis. Receiver operating characteristic analysis was used to assess diagnostic performance with mcDESPOT parameters for distinguishing morphologically normal cartilage from morphologically degenerative cartilage identified at magnetic resonance imaging in eight cartilage subsections of the knee joint. RESULTS: Higher cartilage T2(Single) (P < .001), lower cartilage F(F) (P < .001), and similar cartilage T2F (P = .079) and T2S (P = .124) values were seen in patients with osteoarthritis compared with those in asymptomatic volunteers. Differences in T2(Single) and F(F) remained significant (P < .05) after consideration of age differences between groups of subjects. Diagnostic performance was higher with F(F) than with T2(Single) for distinguishing between normal and degenerative cartilage (P < .05), with greater areas under the curve at receiver operating characteristic analysis. CONCLUSION: Patients with osteoarthritis of the knee had significantly higher cartilage T2(Single) and significantly lower cartilage F(F) than did asymptomatic volunteers, and receiver operating characteristic analysis results suggested that F(F) may allow greater diagnostic performance than that with T2(Single) for distinguishing between normal and degenerative cartilage. PMID- 26024309 TI - A Prevalence and Management Study of Acute Pain in Children Attending Emergency Departments by Ambulance. AB - Pain is the most common symptom in the emergency setting and remains one of the most challenging problems for emergency care providers, particularly in the pediatric population. The primary objective of this study was to determine the prevalence of acute pain in children attending emergency departments (EDs) in Ireland by ambulance. In addition, this study sought to describe the prehospital and initial ED management of pain in this population, with specific reference to etiology of pain, frequency of pain assessment, pain severity, and pharmacological analgesic interventions. A prospective cross-sectional study was undertaken over a 12-month period of all pediatric patients transported by emergency ambulance to four tertiary referral hospitals in Ireland. All children (<16 years) who had pain as a symptom (regardless of cause) at any stage during the prehospital phase of care were included in this study. Over the study period, 6,371 children attended the four EDs by emergency ambulance, of which 2,635 (41.4%, 95% confidence interval 40.2-42.3%) had pain as a documented symptom on the ambulance patient care report (PCR) form. Overall 32% (n = 856) of children who complained of pain were subject to a formal pain assessment during the prehospital phase of care. Younger age, short transfer time to the ED, and emergency calls between midnight and 6 am were independently associated with decreased likelihood of having a documented assessment of pain intensity during the prehospital phase of care. Of the 2,635 children who had documented pain on the ambulance PCR, 26% (n = 689) received some form of analgesic agent prior to ED arrival. Upon ED arrival 54% (n = 1,422) of children had a documented pain assessment and some form of analgesic agent was administered to 50% (n = 1,324). Approximately 41% of children who attend EDs in Ireland by ambulance have pain documented as their primary symptom. This study suggests that the management of acute pain in children transferred by ambulance to the ED in Ireland is currently poor, with documentary evidence of only 26% receiving prehospital analgesic agents. PMID- 26024310 TI - Elucidating N2O Formation during the Cyclic NOx Storage and Reduction Process Using CO as a Reductant. AB - The N2O formation pathway and effect of H2O on N2O formation during the NOx storage and reduction (NSR) process using CO as a reductant were investigated over a Pt-BaO/Al2O3 catalyst. The NSR activity measurements and transient in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) experiments were performed to evaluate N2O evolution and elucidate the N2O formation mechanism. N2O is formed in the lean, rich, and delay2 phases. In the lean phase, N2O formation is related to the reactions between surface isocyanate and gaseous NO/O2 and NO is more responsible for N2O formation than O2. Moreover, N2O production decreases with H2O because of the hydrolysis of isocyanate species. In the rich phase, the amount of N2O formation also decreases in the presence of H2O at a higher temperature because of the high reduction ability of H2 generated from the water-gas shift (WGS) reaction. During the delay2 phase, N2O is mainly formed by nitrite species reacting with Pt(0)-CO. Furthermore, the presence of H2O decreases the stability of nitrites and results in more N2O production at a low temperature. PMID- 26024312 TI - Cu(0)/Selectfluor System-Mediated Mild Synthesis of Fluorinated Fluorenones from Nonaromatic Precursors (1,6-Enynes) Involving C-C Single Bond Cleavage. AB - A novel and facile method for the mild construction of fluorinated fluorenones from nonaromatic precursors (1,6-enynes) mediated by a Cu(0)/Selectfluor system has been successfully achieved. Preliminary mechanistic investigations indicate that the reaction may proceed via an unprecedented annulation/C-C single bond cleavage/fluorination sequence. PMID- 26024311 TI - Origin and evolution of lysyl oxidases. AB - Lysyl oxidases (LOX) are copper-dependent enzymes that oxidize primary amine substrates to reactive aldehydes. The best-studied role of LOX enzymes is the remodeling of the extracellular matrix (ECM) in animals by cross-linking collagens and elastin, although intracellular functions have been reported as well. Five different LOX enzymes have been identified in mammals, LOX and LOX like (LOXL) 1 to 4, showing a highly conserved catalytic carboxy terminal domain and more divergence in the rest of the sequence. Here we have surveyed a wide selection of genomes in order to infer the evolutionary history of LOX. We identified LOX proteins not only in animals, but also in many other eukaryotes, as well as in bacteria and archaea - which reveals a pre-metazoan origin for this gene family. LOX genes expanded during metazoan evolution resulting in two superfamilies, LOXL2/L3/L4 and LOX/L1/L5. Considering the current knowledge on the function of mammalian LOX isoforms in ECM remodeling, we propose that LOXL2/L3/L4 members might have preferentially been involved in making cross linked collagen IV-based basement membrane, whereas the diversification of LOX/L1/L5 forms contributed to chordate/vertebrate-specific ECM innovations, such as elastin and fibronectin. Our work provides a novel view on the evolution of this family of enzymes. PMID- 26024313 TI - Gold Nanoparticles-based Extraction-Free Colorimetric Assay in Organic Media: An Optical Index for Determination of Total Polyphenols in Fat-Rich Samples. AB - In this work, a rapid and simple gold nanoparticle (AuNPs)-based colorimetric assay meets a new type of synthesis of AuNPs in organic medium requiring no sample extraction. The AuNPs synthesis extraction-free approach strategically involves the use of dimethyl sulfoxide (DMSO) acting as an organic solvent for simultaneous sample analyte solubilization and AuNPs stabilization. Moreover, DMSO works as a cryogenic protector avoiding solidification at the temperatures used to block the synthesis. In addition, the chemical function as AuNPs stabilizers of the sample endogenous fatty acids is also exploited, avoiding the use of common surfactant AuNPs stabilizers, which, in an organic/aqueous medium, rise to the formation of undesirable emulsions. This is controlled by adding a fat analyte free sample (sample blank). The method was exhaustively applied for the determination of total polyphenols in two selected kinds of fat-rich liquid and solid samples with high antioxidant activity and economic impact: olive oil (n = 28) and chocolate (n = 16) samples. Fatty sample absorbance is easily followed by the absorption band of localized surface plasmon resonance (LSPR) at 540 nm and quantitation is refereed to gallic acid equivalents. A rigorous evaluation of the method was performed by comparison with the well and traditionally established Folin-Ciocalteu (FC) method, obtaining an excellent correlation for olive oil samples (R = 0.990, n = 28) and for chocolate samples (R = 0.905, n = 16). Additionally, it was also found that the proposed approach was selective (vs other endogenous sample tocopherols and pigments), fast (15-20 min), cheap and simple (does not require expensive/complex equipment), with a very limited amount of sample (30 MUL) needed and a significant lower solvent consumption (250 MUL in 500 MUL total reaction volume) compared to classical methods. PMID- 26024315 TI - Spithioneines A and B, Two New Bohemamine Derivatives Possessing Ergothioneine Moiety from a Marine-Derived Streptomyces spinoverrucosus. AB - Spithioneines A and B (1 and 2), two new bohemamine-type pyrrolizidine alkaloids possessing an unusual ergothioneine moiety, were isolated from a marine-derived Streptomyces spinoverrucosus. Their structures were elucidated by spectroscopic analysis, CD spectra, and chemical degradation and synthesis. Compounds 1 and 2 are rare natural products that incorporate the amino acid ergothioneine. PMID- 26024317 TI - Superovulation using the combined administration of inhibin antiserum and equine chorionic gonadotropin increases the number of ovulated oocytes in C57BL/6 female mice. AB - Superovulation is a reproductive technique generally used to produce genetically engineered mice. Superovulation in mice involves the administration of equine chorionic gonadotropin (eCG) to promote follicle growth and then that of human chorionic gonadotropin (hCG) to induce ovulation. Previously, some published studies reported that inhibin antiserum (IAS) increased the number of ovulated oocytes in ddY and wild-derived strains of mice. However, the effect of IAS on the C57BL/6 strain, which is the most widely used inbred strain for the production of genetically engineered mice, has not been investigated. In addition, the combined effect of IAS and eCG (IASe) on the number of ovulated oocytes in superovulation treatment has not been examined. In this study, we examined the effect of IAS and eCG on the number of ovulated oocytes in immature female mice of the C57BL/6 strain in superovulation treatment. Furthermore, we evaluated the quality of obtained oocytes produced by superovulation using IASe by in vitro fertilization (IVF) with sperm from C57BL/6 or genetically engineered mice. The developmental ability of fresh or cryopreserved embryos was examined by embryo transfer. The administration of IAS or eCG had a similar effect on the number of ovulated oocytes in C57BL/6 female mice. The number of ovulated oocytes increased to about 3-fold by the administration of IASe than by the administration of IAS or eCG alone. Oocytes derived from superovulation using IASe normally developed into 2-cell embryos by IVF using sperm from C57BL/6 mice. Fresh or cryopreserved 2-cell embryos produced by IVF between oocytes of C57BL/6 mice and sperm from genetically engineered mice normally developed into live pups following embryo transfer. In summary, a novel technique of superovulation using IASe is extremely useful for producing a great number of oocytes and offspring from genetically engineered mice. PMID- 26024316 TI - Genome-Wide Characterization of RNA Editing in Chicken Embryos Reveals Common Features among Vertebrates. AB - RNA editing results in a post-transcriptional nucleotide change in the RNA sequence that creates an alternative nucleotide not present in the DNA sequence. This leads to a diversification of transcription products with potential functional consequences. Two nucleotide substitutions are mainly described in animals, from adenosine to inosine (A-to-I) and from cytidine to uridine (C-to U). This phenomenon is described in more details in mammals, notably since the availability of next generation sequencing technologies allowing whole genome screening of RNA-DNA differences. The number of studies recording RNA editing in other vertebrates like chicken is still limited. We chose to use high throughput sequencing technologies to search for RNA editing in chicken, and to extend the knowledge of its conservation among vertebrates. We performed sequencing of RNA and DNA from 8 embryos. Being aware of common pitfalls inherent to sequence analyses that lead to false positive discovery, we stringently filtered our datasets and found fewer than 40 reliable candidates. Conservation of particular sites of RNA editing was attested by the presence of 3 edited sites previously detected in mammals. We then characterized editing levels for selected candidates in several tissues and at different time points, from 4.5 days of embryonic development to adults, and observed a clear tissue-specificity and a gradual increase of editing level with time. By characterizing the RNA editing landscape in chicken, our results highlight the extent of evolutionary conservation of this phenomenon within vertebrates, attest to its tissue and stage specificity and provide support of the absence of non A-to-I events from the chicken transcriptome. PMID- 26024320 TI - Electronically Excited States of Neutral, Protonated alpha-Naphthol and Their Water Clusters: A Theoretical Study. AB - The RI-MP2 and RI-CC2 methods have been employed to determine the potential energy profiles of neutral and protonated alpha-naphthol, in their individual forms and microhydrated with 1 and 3 water molecules, at different electronic states. According to calculated results, it has been predicted that dynamics of nonradiative processes in protonated alpha-naphthol is essentially different from that of its neutral homologue. In protonated alpha-naphthol, the calculations reveal that (1)sigmapi* state, is the most important photophysical state, having a bound nature with a broad potential curve along the OH coordinate of isolated system, while it is dissociative in monohydrated homologue. In neutral system, similar to phenol, the (1)pisigma* state, plays the fundamental relaxation role along the O-H stretching coordinate. Moreover, microhydration strongly affects the photophysical properties of alpha-naphthol, mostly by alteration of the (1)pipi* PE profile, from a bound state in an isolated analogue to a dissociative state in hydrated systems. Furthermore, it has been found that three water molecules are necessary for ground state proton transfer between protonated alpha naphthol and water; with a small barrier; (DeltaE< 0.1 eV). PMID- 26024319 TI - Identification of an Auxiliary Leader Peptide-Binding Protein Required for Azoline Formation in Ribosomal Natural Products. AB - Thiazole/oxazole-modified microcins (TOMMs) are a class of post-translationally modified peptide natural products bearing azole and azoline heterocycles. The first step in heterocycle formation is carried out by a two component cyclodehydratase comprised of an E1 ubiquitin-activating and a YcaO superfamily member. Recent studies have demonstrated that the YcaO domain is responsible for cyclodehydration, while the TOMM E1 homologue is responsible for peptide recognition during azoline formation. Although all characterized TOMM biosynthetic clusters contain this canonical TOMM E1 homologue (C domain), we also identified a second, highly divergent E1 superfamily member, annotated as an Ocin-ThiF-like protein (F protein), associated with more than 300 TOMM biosynthetic clusters. Here we describe the in vitro reconstitution of a novel TOMM cyclodehydratase from such a cluster and demonstrate that this auxiliary protein is required for cyclodehydration. Using a combination of biophysical techniques, we demonstrate that the F protein, rather than the C domain, is responsible for engaging the peptide substrate. The C domain instead appears to serve as a scaffolding protein, bringing the catalytic YcaO domain and the peptide binding Ocin-ThiF-like protein into proximity. Our findings provide an updated biosynthetic framework that provides a foundation for the characterization and reconstitution of approximately 25% of bioinformatically identifiable TOMM synthetases. PMID- 26024322 TI - Selective catalytic conversion of guaiacol to phenols over a molybdenum carbide catalyst. AB - An activated carbon supported alpha-molybdenum carbide catalyst (alpha-MoC1-x/AC) showed remarkable activity in the selective deoxygenation of guaiacol to substituted mono-phenols in low carbon number alcohol solvents. Combined selectivities of up to 85% for phenol and alkylphenols were obtained at 340 degrees C for alpha-MoC1-x/AC at 87% conversion in supercritical ethanol. The reaction occurs via consecutive demethylation followed by a dehydroxylation route instead of a direct demethoxygenation pathway. PMID- 26024318 TI - Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice. AB - BACKGROUND & AIMS: Accumulating evidence suggests that retinol and its metabolites are closely associated with liver fibrogenesis. Recently, we demonstrated that genetic ablation of alcohol dehydrogenase 3 (ADH3), a retinol metabolizing gene that is expressed in hepatic stellate cells (HSCs) and natural killer (NK) cells, attenuated liver fibrosis in mice. In the current study, we investigated whether pharmacological ablation of ADH3 has therapeutic effects on experimentally induced liver fibrosis in mice. METHODS: Liver fibrosis was induced by intraperitoneal injections of carbon tetrachloride (CCl4) or bile duct ligation (BDL) for two weeks. To inhibit ADH3-mediated retinol metabolism, 10 MUg 4-methylpyrazole (4-MP)/g of body weight was administered to mice treated with CCl4 or subjected to BDL. The mice were sacrificed at week 2 to evaluate the regression of liver fibrosis. Liver sections were stained for collagen and alpha smooth muscle actin (alpha-SMA). In addition, HSCs and NK cells were isolated from control and treated mice livers for molecular and immunological studies. RESULTS: Treatment with 4-MP attenuated CCl4- and BDL-induced liver fibrosis in mice, without any adverse effects. HSCs from 4-MP treated mice depicted decreased levels of retinoic acids and increased retinol content than HSCs from control mice. In addition, the expression of alpha-SMA, transforming growth factor-beta1 (TGF-beta1), and type I collagen alpha1 was significantly reduced in the HSCs of 4-MP treated mice compared to the HSCs from control mice. Furthermore, inhibition of retinol metabolism by 4-MP increased interferon-gamma production in NK cells, resulting in increased apoptosis of activated HSCs. CONCLUSIONS: Based on our data, we conclude that inhibition of retinol metabolism by 4-MP ameliorates liver fibrosis in mice through activation of NK cells and suppression of HSCs. Therefore, retinol and its metabolizing enzyme, ADH3, might be potential targets for therapeutic intervention of liver fibrosis. PMID- 26024321 TI - Targeting KRAS Oncogene in Colon Cancer Cells with 7-Carboxylate Indolo[3,2 b]quinoline Tri-Alkylamine Derivatives. AB - BACKGROUND: A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of KRAS transcription. We have previously identified indolo[3,2 b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression. METHODOLOGY/PRINCIPAL FINDINGS: IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC50 < 2.69 MUM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A compounds significantly reduced KRAS mRNA and protein steady-state levels at IC50 concentrations, and increased p53 protein steady-state levels and cell death by apoptosis in HCT116 cells (mut KRAS, wt p53). Furthermore, KRAS silencing in HCT116 p53 wild-type (p53(+/+)) and null (p53(-/-)) isogenic cell lines induced a higher level of cell death, and a higher IQ3A-induced cell death in HCT116 p53(+/+) compared to HCT116 p53(-/-). CONCLUSIONS: Herein we provide evidence that G4 ligands such as IQ3A compounds can target G4 motifs present in KRAS promoter, down-regulate the expression of the mutant KRAS gene through inhibition of transcription and translation, and induce cell death by apoptosis in colon cancer cell lines. Thus, targeting KRAS at the genomic level with G4 ligands may be a new anticancer therapy strategy for colon cancer. PMID- 26024323 TI - Synthesis and Ligand Exchange of Thiol-Capped Silicon Nanocrystals. AB - Hydride-terminated silicon (Si) nanocrystals were capped with dodecanethiol by a thermally promoted thiolation reaction. Under an inert atmosphere, the thiol capped nanocrystals exhibit photoluminescence (PL) properties similar to those of alkene-capped Si nanocrystals, including size-tunable emission wavelength, relatively high quantum yields (>10%), and long radiative lifetimes (26-280 MUs). X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy confirmed that the ligands attach to the nanocrystal surface via covalent Si-S bonds. The thiol-capping layer, however, readily undergoes hydrolysis and severe degradation in the presence of moisture. Dodecanethiol could be exchanged with dodecene by hydrosilylation for enhanced stability. PMID- 26024324 TI - Health issues among military populations: are we providing health care or health and care? PMID- 26024325 TI - Effectiveness of OMT for Carpal Tunnel Syndrome. PMID- 26024328 TI - Proposed Amendments to the AOA Constitution. PMID- 26024326 TI - Response. PMID- 26024329 TI - Perceptions of physicians in civilian medical practice on veterans' issues related to health care. AB - CONTEXT: The percentage of total US residents in the military is lower than ever before. Many civilians, including civilian physicians, have little knowledge of US military actions or the day-to-day experiences and working environments of veterans. OBJECTIVE: To assess civilian physician knowledge of veterans' issues using a survey. METHODS: A 10-item survey was distributed to physicians at 2 primary care-focused medical conferences in Ohio to determine self-reported levels of comfort and familiarity with veteran-oriented topics. RESULTS: Of 350 surveys that were distributed, 141 surveys were returned. Of the 141 respondents, 101 practiced primary care, 19 practiced internal medicine, 16 practiced other specialties, and 5 did not report a specialty affiliation and were excluded from final analysis. A single respondent reported pediatrics as a specialty but indicated "not applicable" for all answers. This individual was excluded from final analysis. Overall, physicians reported feeling moderately comfortable with military terminology and uncomfortable with the diagnosis and management of traumatic brain injury. More than half of the respondents indicated that they were not comfortable discussing health-related exposures and associated risks that veterans might experience and that they were unfamiliar with referral and consultation services for veterans. The data collected had a high degree of reliability (Cronbach alpha=0.88). Respondents of both primary care and internal medicine specialties scored statistically significantly higher than the other respondents in questions on veterans' medical conditions, military terminology, and military health risks (P<.05), although these 2 groups scored similarly (P>.05). Specialty orientation did not affect responses for questions on other topics (P>.05). CONCLUSION: The data indicated an overall moderate level of familiarity among civilian physicians with veterans' issues. The results did not reveal an overall high level of comfort with any issues included in the survey. More research is needed to determine reasons behind the findings and methods to improve civilian physician comfort with various veterans' issues. PMID- 26024330 TI - Relationships between polypharmacy and the sleep cycle among active-duty service members. AB - CONTEXT: Sleep disorders are frequent clinical presentations, especially among active-duty service members. Medications are one factor that can affect sleep in many ways. OBJECTIVE: To determine the effect of increasing numbers of medications on the sleep cycle of active-duty service members. METHODS: Medical records for active-duty service members who completed enhanced sleep assessments at the Psychiatry Continuity Service at Walter Reed National Military Medical Center from October 1, 2010, through November 30, 2013, were retrospectively reviewed. Data were collected on home sleep study findings, sleep-related self report instrument scores, and active medications. RESULTS: A total of 135 medical records were reviewed. One hundred patients (74.07%) had an active prescription for a psychoactive drug. Among all patients, the mean (SD) number of active medications per participant was 2.52 (2.09), with 118 patients (82.96%) having an active medication for depression or insomnia. As the number of prescribed medications increased, the percentage of the sleep cycle in deep sleep decreased (P=.049), the percentage of light sleep increased (P=.016), the percentage of rapid eye movement sleep decreased (P=.083), and the first episode of deep sleep was delayed (P=.056). An increased number of medications had no significant impact on total sleep time (P>.05). CONCLUSION: An increasing number of medications did not influence total sleep time but negatively affected the sleep cycle. PMID- 26024331 TI - Screening for at-risk drinking behavior in trauma patients. AB - CONTEXT: A blood alcohol level above 0 g/dL is found in up to 50% of patients presenting with traumatic injuries. The presence of alcohol in the blood not only increases the risk of traumatic injury, but it is also associated with worse outcomes and trauma recidivism. In light of these risks, the American College of Surgeons Committee on Trauma advocates screening for at-risk drinking. Although many institutions use blood alcohol levels to determine at-risk drinking in trauma patients, the Alcohol Use Disorders Identification Test (AUDIT) offers a cheap and easy alternative. Few direct comparisons have been made between these 2 tests in trauma patients. OBJECTIVE: To compare the utility of blood alcohol level and AUDIT score as indicators of at-risk drinking in trauma patients. METHODS: Records for all trauma patients aged 18 years or older who were admitted to a level I trauma center from May 2013 through June 2014 were reviewed in this retrospective cohort study. Inclusion criteria required patients to have undergone both blood alcohol level testing and AUDIT on admission. A blood alcohol level greater than 0 g/dL and an AUDIT score equal to or above 8 were considered positive for at-risk drinking. Performance of both tests was indexed against the National Institute of Alcohol Abuse and Alcoholism (NIAAA) criteria for at-risk drinking. RESULTS: Of 750 patients admitted for trauma, 222 records (30%) contained data on both blood alcohol level and AUDIT score. The patients were predominantly male (178 [80%]) and had a mean (SD) age of 40.1 (16.7) years. Most patients (178 [80%]) had sustained blunt trauma. Ninety-seven patients (44%) had a positive blood alcohol level, 70 (35%) had a positive AUDIT score, and 54 (24%) met NIAAA criteria for at-risk drinking. The sensitivity and specificity of having a positive blood alcohol level identify at-risk drinking were 61% and 62%, respectively. The sensitivity and specificity of having a positive AUDIT score identify at-risk drinking were 83% and 81%, respectively. CONCLUSION: As a stand alone indicator of at-risk drinking behavior in trauma patients, the AUDIT score was shown to be superior to blood alcohol level. The utility of obtaining routine blood alcohol levels in trauma patients as a screening tool for at-risk drinking should be reexamined. PMID- 26024332 TI - Age-related decline in chest wall mobility: a cross-sectional study among community-dwelling elderly women. AB - CONTEXT: Chest wall mobility is strongly related to respiratory function; however, the effect of aging on chest wall mobility-and the level at which this mobility is most affected-remains unclear. OBJECTIVE: To investigate age-related differences in chest wall mobility and respiratory function among elderly women in different age groups. METHODS: This cross-sectional observational study was performed in Himeji City in Hyogo Prefecture and Ayabe City in Kyoto Prefecture in Japan. Inclusion criteria were female sex, age 65 years or older, community resident, and ability to ambulate independently, with or without an assistive device. Thoracic excursion at the axillary and xiphoid levels and at the level of the tenth rib was measured with measuring tape. Respiratory function, including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), was assessed by spirometry, and FVC percent predicted (%FVC), FEV1 percent predicted (%FEV1), and FEV1/FVC were calculated. Chest wall mobility and respiratory function were compared among 4 age groups. RESULTS: Of 251 potential participants, 132 met the inclusion criteria. Participants were divided into 4 age groups: group 1, 65 to 69 years; group 2, 70 to 74 years; group 3, 75 to 79 years; and group 4, 80 years or older. Statistically significant differences were found in thoracic excursion at the axillary level between groups 1 and 4 and between groups 2 and 4 when adjusted for height and weight (F4.52, P=.01). In addition, statistically significant differences were found in the FVC and FEV1 values between groups 1 and 3 and between groups 2 and 3 (FVC: F4.97, P=.01; FEV1: F6.17, P=.01). CONCLUSION: Chest wall mobility at the axillary level and respiratory function decreased with age in community-dwelling women aged 65 years or older. Further longitudinal studies are required to clarify the effects of aging on chest wall mobility and respiratory function. PMID- 26024333 TI - The Doctors Hospital and Nationwide Children's Hospital Dually Accredited Pediatric Residency Program: A Potential Best Model for Pediatric Osteopathic GME Training. AB - With the commitment on the part of the American Osteopathic Association, the American Association of Colleges of Osteopathic Medicine, and the Accreditation Council for Graduate Medical Education to transition to a single graduate medical education accreditation system by 2020, a legitimate concern exists about the future of pediatric residency training that maintains an osteopathic focus. The authors describe a dually accredited pediatric residency program at one of the nation's largest children's hospitals, which may serve as a potential model of how to integrate a robust osteopathic-based education into a general pediatric residency program. PMID- 26024334 TI - Role of osteopathic manipulative treatment in the management of stiff person syndrome. AB - Stiff person syndrome (SPS) is a rare and disabling central nervous system disorder first described in 1956 and characterized by fluctuating rigidity and stiffness, gait impairment, and painful spasms of the axial and limb musculature. Although an underlying mechanism of impaired synaptic gamma-aminobutyric acid ergic inhibition has been proposed, the exact mechanism remains unclear. The glutamic acid decarboxylase antibody, a marker for SPS, is a strong indication of disease and has been reported in approximately 70% of patients. The current treatment of choice is benzodiazepines and baclofen, both of which reduce motor unit potential firing and, therefore, decrease stiffness and spasms. However, patients continue to have substantial disability with pharmacologic therapy alone. This case report demonstrates the potential of osteopathic manipulative treatment as an adjunct to medication in the management of SPS. By decreasing somatic dysfunction and reducing the frequency of exacerbations, osteopathic manipulative treatment may alleviate the symptoms and overall morbidity associated with this disease. PMID- 26024335 TI - Posterior reversible encephalopathy syndrome. PMID- 26024336 TI - Law #1: don't panic! PMID- 26024337 TI - Label-Free Detection of Sequence-Specific DNA Based on Fluorescent Silver Nanoclusters-Assisted Surface Plasmon-Enhanced Energy Transfer. AB - We have developed a label-free method for sequence-specific DNA detection based on surface plasmon enhanced energy transfer (SPEET) process between fluorescent DNA/AgNC string and gold nanoparticles (AuNPs). DNA/AgNC string, prepared by a single-stranded DNA template encoded two emitter-nucleation sequences at its termini and an oligo spacer in the middle, was rationally designed to produce bright fluorescence emission. The proposed method takes advantage of two strategies. The first one is the difference in binding properties of single stranded DNA (ssDNA) and double-stranded DNA (dsDNA) toward AuNPs. The second one is SPEET process between fluorescent DNA/AgNC string and AuNPs, in which fluorescent DNA/AgNC string can be spontaneously adsorbed onto the surface of AuNPs and correspondingly AuNPs serve as "nanoquencher" to quench the fluorescence of DNA/AgNC string. In the presence of target DNA, the sensing probe hybridized with target DNA to form duplex DNA, leading to a salt-induced AuNP aggregation and subsequently weakened SPEET process between fluorescent DNA/AgNC string and AuNPs. A red-to-blue color change of AuNPs and a concomitant fluorescence increase were clearly observed in the sensing system, which had a concentration dependent manner with specific DNA. The proposed method achieved a detection limit of ~2.5 nM, offering the following merits of simple design, convenient operation, and low experimental cost because of no chemical modification, organic dye, enzymatic reaction, or separation procedure involved. PMID- 26024338 TI - The Fifth Transmembrane Segment of Cystic Fibrosis Transmembrane Conductance Regulator Contributes to Its Anion Permeation Pathway. AB - Previous studies have identified several transmembrane segments (TMs), including TM1, TM3, TM6, TM9, TM11, and TM12, as pore-lining segments in cystic fibrosis transmembrane conductance regulator (CFTR), but the role of TM5 in pore construction remains controversial. In this study, we employed substituted cysteine accessibility methodology (SCAM) to screen the entire TM5 defined by the original topology model and its cytoplasmic extension in a Cysless background. We found six positions (A299, R303, N306, S307, F310, and F311) where engineered cysteines react to intracellular 2-sulfonatoethyl methanethiosulfonate (MTSES-). Quantification of the modification rate of engineered cysteines in the presence or absence of ATP suggests that these six residues are accessible in both the open and closed states. Whole-cell experiments with external MTSES- identified only two positive positions (L323 and A326), resulting in a segment containing 11 consecutive amino acids, where substituted cysteines respond to neither internal nor external MTSES-, a unique feature not seen previously in CFTR's pore-lining segments. The observation that these positions are inaccessible to channel permeant thiol-specific reagent [Au(CN)2]- suggests that this segment of TM5 between F311 and L323 is concealed from the pore by other TMs and/or lipid bilayers. In addition, our data support the idea that the positively charged arginine at position 303 poses a pure electrostatic action in determining the single-channel current amplitude of CFTR and the effect of an open-channel blocker glibencalmide. Collectively, we conclude that the cytoplasmic portion of CFTR's TM5 lines the pore. Our functional data are remarkably consistent with predicted structural arrangements of TM5 in some homology models of CFTR. PMID- 26024339 TI - Properties of water confined in ionic liquids. AB - The varying states of water confined in the nano-domain structures of typical room temperature ionic liquids (ILs) were investigated by (1)H NMR and by measurements of self-diffusion coefficients while systematically varying the IL cations and anions. The NMR peaks for water in BF4-based ILs were clearly split, indicating the presence of two discrete states of confined water (H2O and HOD). Proton and/or deuterium exchange rate among the water molecules was very slowly in the water-pocket. Notably, no significant changes were observed in the chemical shifts of the ILs. Self-diffusion coefficient results showed that water molecules exhibit a similar degree of mobility, although their diffusion rate is one order of magnitude faster than that of the IL cations and anions. These findings provide information on a completely new type of confinement, that of liquid water in soft matter. PMID- 26024340 TI - Environmental lung diseases--2015. PMID- 26024342 TI - Asbestos-related lung cancer and malignant mesothelioma of the pleura: selected current issues. AB - Asbestos-related diseases persist, because millions of workers have had prior exposure and many industrializing countries continue to use asbestos. Globally, an estimated 107,000 people die annually from lung cancer, malignant mesothelioma, and asbestosis due to occupational asbestos exposure. Malignant mesothelioma and lung cancer are caused by all major types of asbestos. Asbestos causes more lung cancer deaths than malignant mesothelioma of the pleura; most cases of the latter are due to asbestos exposure. The cancer risk increases with cumulative asbestos exposure, with increased risk even at low levels of exposure to asbestos. Based on empirical studies, an estimated cumulative occupational exposure to asbestos of 1 fiber/mL-year substantially raises malignant mesothelioma risk. No safe threshold for asbestos exposure has been established for lung cancer and mesothelioma. The validity of fiber-type risk assessments depends critically on the quality of exposure assessments, which vary considerably, leading to a high degree of uncertainty. Asbestos exposure without asbestosis and smoking increases the risk of lung cancer. The joint effect of asbestos and smoking is supra-additive, which may depend in part on the presence of asbestosis. Asbestos workers who cease smoking experience a dramatic drop in lung cancer risk, which approaches that of nonsmokers after 30 years. Studies to date show that longer, thinner fibers have a stronger association with lung cancer than shorter, less thin fibers, but the latter nonetheless also show an association with lung cancer and mesothelioma. Low-dose chest computed tomographic scanning offers an unprecedented opportunity to detect early-stage lung cancers in asbestos-exposed workers. PMID- 26024341 TI - Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of Distal Airway and Blood Biomarkers that Predict FEV1 Decline. AB - Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung's normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well-phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC-exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after WTC exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1 below the lower limit of normal known as WTC-Lung Injury (WTC-LI). We utilized a nested case-cohort control design of previously healthy never smokers who sought subspecialty pulmonary evaluation to explore predictive biomarkers of WTC-LI. We have identified biomarkers of inflammation, metabolic derangement, protease/antiprotease balance, and vascular injury expressed in serum within 6 months of WTC exposure that were predictive of their FEV1 up to 7 years after their WTC exposure. Predicting future risk of airway injury after particulate exposures can focus monitoring and early treatment on a subset of patients in greatest need of these services. PMID- 26024344 TI - Small airways involvement in coal mine dust lung disease. AB - Inhalation of coal mine dust results in a spectrum of symptoms, dysfunction, and pathological changes in the respiratory tract that collectively have been labeled coal mine dust lung disease. Recent reports from periodic health surveillance among underground and surface coal miners in the United States have demonstrated an increasing prevalence and severity of dust diseases, and have also documented that some miners experience rapid disease progression. The coal macule is an inflammatory lesion associated with deposited dust, and occurs in the region of the most distal conducting airways and proximal respiratory bronchioles. Inflammatory changes in the small airways have long been recognized as the signature lung pathology among coal miners. Human and laboratory studies have suggested oxidant injury, and increased recruitment and activity of macrophages play important roles in dust-induced lung injury. However, the functional importance of the small airway changes was debated for many years. We reviewed published literature that documents a pervasive occurrence of both physiologic and structural abnormalities in small airways among coal miners and other workers exposed to airborne particulates. There is increasing evidence supporting an important association of abnormalities in the small peripheral airways with the development of respiratory symptoms, deficits in spirometry values, and accelerated declines in ventilatory lung function. Pathologic changes associated with mineral dust deposition in the small airways may be of particular importance in contemporary miners with rapidly progressive respiratory impairment. PMID- 26024343 TI - Gene-environment interaction from international cohorts: impact on development and evolution of occupational and environmental lung and airway disease. AB - Environmental and occupational pulmonary diseases impose a substantial burden of morbidity and mortality on the global population. However, it has been long observed that only some of those who are exposed to pulmonary toxicants go on to develop disease; increasingly, it is being recognized that genetic differences may underlie some of this person-to-person variability. Studies performed throughout the globe are demonstrating important gene-environment interactions for diseases as diverse as chronic beryllium disease, coal workers' pneumoconiosis, silicosis, asbestosis, byssinosis, occupational asthma, and pollution-associated asthma. These findings have, in many instances, elucidated the pathogenesis of these highly complex diseases. At the same time, however, translation of this research into clinical practice has, for good reasons, proceeded slowly. No genetic test has yet emerged with sufficiently robust operating characteristics to be clearly useful or practicable in an occupational or environmental setting. In addition, occupational genetic testing raises serious ethical and policy concerns. Therefore, the primary objective must remain ensuring that the workplace and the environment are safe for all. PMID- 26024346 TI - Air contaminants associated with potential respiratory effects from unconventional resource development activities. AB - Unconventional natural gas development uses horizontal drilling in conjunction with hydraulic fracturing to gain access to natural gas deposits which may be tightly held in shale deposits and unavailable to conventional vertical drilling operations. The intensive work required to extract this source of energy results in higher than usual numbers of vehicles involved, potential release of emissions from those vehicles in congested zones surrounding the drill site, and release of other contaminants from materials drawn back out of the borehole after fracturing of the shale. Typical contaminants would be diesel exhaust particulate and gases, volatile organic compounds and other hydrocarbons both from diesels and the drilling process, crystalline silica, used as part of the hydraulic fracturing process in kiloton quantities, and methane escaping from the borehole and piping. A rise in respiratory disease with proximity to the process has been reported in nearby communities and both silica and diesel exposures at the worksite are recognized respiratory hazards. Because of the relatively short time this process has been used to the extent it is currently being used, it is not possible to draw detailed conclusions about the respiratory hazards that may be posed. However, based on the traffic volume associated with each drill site and the number of drill sites in any locale, it is possible at least to compare the effects to that of large traffic volume highways which are known to produce some respiratory effects in surrounding areas. PMID- 26024347 TI - Occupational asthma and work-exacerbated asthma. AB - Occupational asthma (OA) and work-exacerbated asthma (WEA), collectively known as work-related asthma (WRA), have been recognized as the most prevalent work related lung diseases in the industrialized world. OA is asthma caused by workplace conditions, and is subdivided into sensitizer-induced (allergic) OA and irritant-induced (nonallergic) OA. WEA is asthma that is made worse, but was not initially caused, by workplace conditions. Although WRA is rarely fatal, patients with WRA frequently experience excessive time lost from work, workplace-specific severe disability, loss of income, job loss, and related psychosocial and financial problems. More than 400 workplace environmental agents have been reported to cause WRA, and are classified by molecular weight and allergenic and irritant properties. Diagnosis of WRA requires confirmation of a diagnosis of asthma plus evidence that the asthma was caused or worsened by workplace conditions. Accuracy of diagnosis is important because either overdiagnosis or missed diagnosis of WRA can be problematic for the patient. Self-reported clinical symptoms alone have only fair sensitivity and specificity for OA. If possible, diagnostic assessment should also include objective evidence with functional and immunologic testing. Treatment and prevention of onset or worsening of WRA can be highly effective and typically include both optimal medical management (generally the same as for non-WRA) and, importantly, avoidance of sensitizer or irritant exposures that caused or exacerbate the asthma. In most cases of OA, prognosis is better with cessation rather than reduction of exposure, and this may require substantial changes in the workplace environment or change of job or even profession. PMID- 26024345 TI - Occupational and environmental bronchiolar disorders. AB - Occupational and environmental causes of bronchiolar disorders are recognized on the basis of case reports, case series, and, less commonly, epidemiologic investigations. Pathology may be limited to the bronchioles or also involve other components of the respiratory tract, including the alveoli. A range of clinical, functional, and radiographic findings, including symptomatic disease lacking abnormalities on noninvasive testing, poses a diagnostic challenge and highlights the value of surgical biopsy. Disease clusters in workplaces and communities have identified new etiologies, drawn attention to indolent disease that may otherwise have been categorized as idiopathic, and expanded the spectrum of histopathologic responses to an exposure. More sensitive noninvasive diagnostic tools, evidence based therapies, and ongoing epidemiologic investigation of at-risk populations are needed to identify, treat, and prevent exposure-related bronchiolar disorders. PMID- 26024348 TI - Chronic obstructive pulmonary disease secondary to household air pollution. AB - Approximately 3 billion people around the world cook and heat their homes using solid fuels in open fires and rudimentary stoves, resulting in household air pollution. Household air pollution secondary to indoor combustion of solid fuel is associated with multiple chronic obstructive pulmonary disease (COPD) outcomes. The exposure is associated with both chronic bronchitis and emphysema phenotypes of COPD as well as a distinct form of obstructive airway disease called bronchial anthracofibrosis. COPD from household air pollution differs from COPD from tobacco smoke with respect to its disproportionately greater bronchial involvement, lesser emphysematous change, greater impact on quality of life, and possibly greater oxygen desaturation and pulmonary hypertensive changes. Interventions that decrease exposure to biomass smoke may decrease the risk for incident COPD and attenuate the longitudinal decline in lung function, but more data on exposure-response relationships from well-designed longitudinal studies are needed. PMID- 26024349 TI - Ambient particulate matter air pollution and cardiopulmonary diseases. AB - Population exposures to ambient outdoor particulate matter (PM) air pollution have been assessed to represent a major burden on global health. Ambient PM is a diverse class of air pollution, with characteristics and health implications that can vary depending on a host of factors, including a particle's original source of emission or formation. The penetration of inhaled particles into the thorax is dependent on their deposition in the upper respiratory tract during inspiration, which varies with particle size, flow rate and tidal volume, and in vivo airway dimensions. All of these factors can be quite variable from person to person, depending on age, transient illness, cigarette smoke and other short-term toxicant exposures that cause transient bronchoconstriction, and occupational history associated with loss of lung function or cumulative injury. The adverse effects of inhaled PM can result from both short-term (acute) and long-term (chronic) exposures to PM, and can range from relatively minor, such as increased symptoms, to very severe effects, including increased risk of premature mortality and decreased life expectancy from long-term exposure. Control of the most toxic PM components can therefore provide major health benefits, and can help guide the selection of the most human health optimal air quality control and climate change mitigation policy measures. As such, a continued improvement in our understanding of the nature and types of PM that are most dangerous to health, and the mechanism(s) of their respective health effects, is an important public health goal. PMID- 26024351 TI - Surveillance for occupational respiratory diseases in developing countries. AB - The burden of chronic diseases, including occupational respiratory diseases (ORDs), is increasing worldwide. Nevertheless, epidemiological data on these conditions are scarce in most countries. Therefore, it is important to conduct surveillance to monitor ORDs, particularly in developing countries, where the working population is especially vulnerable and the health system infrastructure is usually weak. This article provides a general framework for the implementation of ORD surveillance in developing countries. The main objectives of surveillance are to describe incidence and prevalence of ORDs, as well as to identify sentinel events and new associations between occupational exposures and health outcomes. Diseases with high morbidity and mortality and those in which early diagnosis with standardized tests are available are especially suitable for surveillance activities. Simple strategies, preferably using existing resources and technology, are the best option for surveillance in developing countries. This article offers examples of specific surveillance systems that are in place in Brazil, China, Cuba, India, and South Africa. PMID- 26024350 TI - Role of chest computed tomography in prevention of occupational respiratory disease: review of recent literature. AB - This review provides an update on literature published over the past 5 years that is relevant to using chest computed tomography (CT) as a tool for preventing occupational respiratory disease. An important area of investigation has been in the use of low-dose CT (LDCT) to screen asbestos-exposed populations for lung cancer. Two recent systematic reviews have reached conclusions in support of screening. Based on the limited evidence that is currently available, the Finnish Institute of Occupational Health has recommended LDCT screening in asbestos exposed individuals if their personal combination of risk factors yields a risk for lung cancer equal to that needed for entry into the National Lung Screening Trial. It has also recommended further research, such as to document the optimal frequency of screening and the effectiveness of screening. Recent literature continues to support high-resolution CT (HRCT) as being more sensitive than chest radiography in detecting pneumoconiosis. However, there are insufficient data to determine the effectiveness of HRCT screening in improving individual outcomes if used in screening for pneumoconiosis and its routine use for this purpose cannot be recommended. However, if HRCT is used to evaluate populations, recent literature shows that the International Classification of HRCT for Occupational and Environmental Respiratory Diseases provides an important tool for reproducible evaluation and recording of findings. HRCT is an important tool for individual patient management and recent literature has documented that chest HRCT findings are significantly associated with outcomes such as pulmonary function and mortality. PMID- 26024352 TI - Amyloid beta Oligomeric Species Present in the Lag Phase of Amyloid Formation. AB - Alzheimer's disease (AD)-associated amyloid beta peptide (Abeta) is one of the main actors in AD pathogenesis. Abeta is characterized by its high tendency to self-associate, leading to the generation of oligomers and amyloid fibrils. The elucidation of pathways and intermediates is crucial for the understanding of protein assembly mechanisms in general and in conjunction with neurodegenerative diseases, e.g., for the identification of new therapeutic targets. Our study focused on Abeta42 and its oligomeric assemblies in the lag phase of amyloid formation, as studied by sedimentation velocity (SV) centrifugation. The assembly state of Abeta during the lag phase, the time required by an Abeta solution to reach the exponential growth phase of aggregation, was characterized by a dominant monomer fraction below 1 S and a population of oligomeric species between 4 and 16 S. From the oligomer population, two major species close to a 12 mer and an 18-mer with a globular shape were identified. The recurrence of these two species at different initial concentrations and experimental conditions as the smallest assemblies present in solution supports the existence of distinct, energetically favored assemblies in solution. The sizes of the two species suggest an Abeta42 aggregation pathway that is based on a basic hexameric building block. The study demonstrates the potential of SV analysis for the evaluation of protein aggregation pathways. PMID- 26024353 TI - Acrolein Exposure in U.S. Tobacco Smokers and Non-Tobacco Users: NHANES 2005 2006. AB - BACKGROUND: Acrolein is a highly reactive alpha,beta unsaturated aldehyde and respiratory irritant. Acrolein is formed during combustion (e.g., burning tobacco or biomass), during high-temperature cooking of foods, and in vivo as a product of oxidative stress and polyamine metabolism. No biomonitoring reference data have been reported to characterize acrolein exposure for the U.S. OBJECTIVES: Our goals were to a) evaluate two acrolein metabolites in urine--N-acetyl-S-(3 hydroxypropyl)-L-cysteine (3HPMA) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA)--as biomarkers of exposure to acrolein for the U.S. population by age, sex, race, and smoking status; and b) assess tobacco smoke as a predictor of acrolein exposure. METHODS: We analyzed urine from National Health and Nutrition Examination Survey (NHANES 2005-2006) participants >= 12 years old (n = 2,866) for 3HPMA and CEMA using ultra-high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC/ESI-MSMS). Sample weighted linear regression models stratified for non-tobacco users versus tobacco smokers (as defined by serum cotinine and self-report) characterized the association of urinary 3HPMA and CEMA with tobacco smoke exposure, adjusting for urinary creatinine, sex, age, and race/ethnicity. RESULTS: 3HPMA and CEMA levels were higher among tobacco smokers (cigarettes, cigars, and pipe users) than among non-tobacco users. The median 3HPMA levels for tobacco smokers and non-tobacco users were 1,089 and 219 MUg/g creatinine, respectively. Similarly, median CEMA levels were 203 MUg/g creatinine for tobacco smokers and 78.8 MUg/g creatinine for non-tobacco users. Regression analysis showed that serum cotinine was a significant positive predictor (p < 0.0001) of both 3HPMA and CEMA among tobacco smokers. CONCLUSIONS: Tobacco smoke was a significant predictor of acrolein exposure in the U.S. population. PMID- 26024354 TI - Trans-Activation between EphA and FGFR Regulates Self-Renewal and Differentiation of Mouse Embryonic Neural Stem/Progenitor Cells via Differential Activation of FRS2alpha. AB - Ephs and FGFRs belong to a superfamily of receptor tyrosine kinases, playing important roles in stem cell biology. We previously reported that EphA4 and FGFR form a heterodimer following stimulation with ligands, trans-activating each other and signaling through a docking protein, FRS2alpha, that binds to both receptors. Here, we investigated whether the interaction between EphA4 and FGFRs can be generalized to other Ephs and FGFRs, and, in addition, examined the downstream signal mediating their function in embryonic neural stem/progenitor cells. We revealed that various Ephs and FGFRs interact with each other through similar molecular domains. When neural stem/progenitor cells were stimulated with FGF2 and ephrin-A1, the signal transduced from the EphA4/FGFR/FRS2alpha complex enhanced self-renewal, while stimulation with ephrin-A1 alone induced neuronal differentiation. The downstream signal required for neuronal differentiation appears to be MAP kinase mainly linked to the Ras family of G proteins. MAP kinase activation was delayed and sustained, distinct from the transient activation induced by FGF2. Interestingly, this effect on neuronal differentiation required the presence of FGFRs. Specific FGFR inhibitor almost completely abolished the function of ephrin-A1 stimulation. These findings suggest that the ternary complex of EphA, FGFR and FRS2alpha formed by ligand stimulation regulates self-renewal and differentiation of mouse embryonic neural stem/progenitor cells by ligand-specific fine tuning of the downstream signal via FRS2alpha. PMID- 26024355 TI - Structural-Functional Analysis Reveals a Specific Domain Organization in Family GH20 Hexosaminidases. AB - Hexosaminidases are involved in important biological processes catalyzing the hydrolysis of N-acetyl-hexosaminyl residues in glycosaminoglycans and glycoconjugates. The GH20 enzymes present diverse domain organizations for which we propose two minimal model architectures: Model A containing at least a non catalytic GH20b domain and the catalytic one (GH20) always accompanied with an extra alpha-helix (GH20b-GH20-alpha), and Model B with only the catalytic GH20 domain. The large Bifidobacterium bifidum lacto-N-biosidase was used as a model protein to evaluate the minimal functional unit due to its interest and structural complexity. By expressing different truncated forms of this enzyme, we show that Model A architectures cannot be reduced to Model B. In particular, there are two structural requirements general to GH20 enzymes with Model A architecture. First, the non-catalytic domain GH20b at the N-terminus of the catalytic GH20 domain is required for expression and seems to stabilize it. Second, the substrate-binding cavity at the GH20 domain always involves a remote element provided by a long loop from the catalytic domain itself or, when this loop is short, by an element from another domain of the multidomain structure or from the dimeric partner. Particularly, the lacto-N-biosidase requires GH20b and the lectin-like domain at the N- and C-termini of the catalytic GH20 domain to be fully soluble and functional. The lectin domain provides this remote element to the active site. We demonstrate restoration of activity of the inactive GH20b GH20-alpha construct (model A architecture) by a complementation assay with the lectin-like domain. The engineering of minimal functional units of multidomain GH20 enzymes must consider these structural requirements. PMID- 26024356 TI - Idiopathic pulmonary fibrosis: the turning point is now! AB - Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with poor survival. Recent studies have improved understanding of IPF and new discoveries have led to novel treatment options, which now have become available for patients. In face of the newly available therapies we present an update on the pathophysiology and epidemiology of IPF. We discuss the typical clinical findings and elaborate diagnostic procedures according to current guidelines and our daily practice approach. The role of biomarkers will briefly be outlined. Finally, we discuss novel antifibrotic treatment options for IPF (pirfenidone, nintedanib) and the management of patients regarding to comorbidities and complications. Both pirfenidone and nintedanib were shown to reduce the progression of IPF and therefore represent novel therapeutic strategies in this so far untreatable chronic lung disease. PMID- 26024357 TI - Building-Related Symptoms among Office Employees Associated with Indoor Carbon Dioxide and Total Volatile Organic Compounds. AB - This study investigated whether sick building syndrome (SBS) complaints among office workers were associated with the indoor air quality. With informed consent, 417 employees in 87 office rooms of eight high-rise buildings completed a self-reported questionnaire for symptoms experienced at work during the past month. Carbon dioxide (CO2), temperature, humidity and total volatile organic compounds (TVOCs) in each office were simultaneously measured for eight office hours using portable monitors. Time-averaged workday difference between the indoor and the outdoor CO2 concentrations (dCO2) was calculated as a surrogate measure of ventilation efficiency for each office unit. The prevalence rates of SBS were 22.5% for eye syndrome, 15.3% for upper respiratory and 25.4% for non specific syndromes. Tiredness (20.9%), difficulty in concentrating (14.6%), eye dryness (18.7%) were also common complaints. The generalized estimating equations multivariate logistic regression analyses showed that adjusted odds ratios (aORs) and 95% confidence interval (CI) per 100 ppm increase in dCO2 were significantly associated with dry throat (1.10, 95% CI=(1.00-1.22)), tiredness (1.16, 95% CI=(1.04-1.29)) and dizziness (1.22, 95% CI=(1.08-1.37)). The ORs for per 100 ppb increases in TVOCs were also associated with upper respiratory symptoms (1.06, 95% CI=(1.04-1.07)), dry throat (1.06, 95% CI=(1.03-1.09)) and irritability (1.02, 95% CI=(1.01-1.04)). In conclusion, the association between some SBS symptoms and the exposure to CO2 and total VOCs are moderate but may be independently significant. PMID- 26024359 TI - The expansion of the economic frontier and the diffusion of violence in the Amazon. AB - Over the last few decades, the occupation of the Amazon and the expansion of large-scale economic activities have exerted a significant negative impact on the Amazonian environment and on the health of the Amazon's inhabitants. These processes have altered the context of the manifestation of health problems in time and space and changed the characteristics of the spatial diffusion of health problems in the region. This study analyzed the relationships between the various economic processes of territorial occupation in the Amazon and the spatial diffusion of homicidal violence through the configuration of networks of production, as well as the movements of population and merchandise. Statistical data on violence, deforestation, the production of agricultural items, and socio economic variables, georeferenced and available for the 771 municipalities of the Legal Amazon were used in this study. The results suggest that the diffusion of violence closely follows the economic expansion front, which is related to deforestation and livestock production but has little relation to grain production, demonstrating steps and typologies of recent occupation in the Amazon that promote violence. These spatial patterns reveal environmental and socio economic macro-determinants that materialize in geographic space through the construction of highways and the formation of city networks. PMID- 26024358 TI - Effect of pesticide exposure on immunological, hematological and biochemical parameters in thai orchid farmers- a cross-sectional study. AB - Various studies have found that many Thai orchid farmers used excessive amounts of pesticides without proper protective gear, but no toxicological study has been made. This cross-sectional study aimed to evaluate the immunological, hematological and biochemical statuses of these farmers. Sixty four orchid farmers and 60 controls were studied. Plasma cholinesterase activity, the percentage and absolute number of B lymphocytes (CD19+) were significantly lower in the farmers group (3966.32+/-1165.48 U/L, 11.61+/-4.09% and 312.26+/-164.83 cells/mm3, respectively) as compared to those of controls (5048.85+/-1139.40 U/L, 14.32+/-4.23%, 420.34+/-195.18 cells/mm3, respectively). There was a statistically significant higher level of serum IgE among the orchid farmers (0.031+/-0.011 mg/dL vs. 0.018+/-0.007 mg/dL) but not IgG, IgA and IgM, levels. Serum lysozyme level, lymphocyte proliferative responses to mitogens, hematological parameters and kidney function test, were not significantly different between the two groups. The liver function profiles showed significantly lower levels of albumin and serum protein in the farmer group. Thus frequent pesticide exposure resulted in subtle changes of some biological parameters. These changes, though may not be clinically significant, strongly indicated that caution in handing pesticides by these farmers is warranted. PMID- 26024360 TI - Assessment of Electromagnetic Interference with Active Cardiovascular Implantable Electronic Devices (CIEDs) Caused by the Qi A13 Design Wireless Charging Board. AB - Electromagnetic interference is a concern for people wearing cardiovascular implantable electronic devices (CIEDs). The aim of this study was to assess the electromagnetic compatibility between CIEDs and the magnetic field of a common wireless charging technology. To do so the voltage induced in CIEDs by Qi A13 design magnetic fields were measured and compared with the performance limits set by ISO 14117. In order to carry this out a measuring circuit was developed which can be connected with unipolar or bipolar pacemaker leads. The measuring system was positioned at the four most common implantation sites in a torso phantom filled with physiological saline solution. The phantom was exposed by using Helmholtz coils from 5 uT to 27 uT with 111 kHz sine-bursts or by using a Qi A13 design wireless charging board (Qi-A13-Board) in two operating modes "power transfer" and "pinging". With the Helmholtz coils the lowest magnetic flux density at which the performance limit was exceeded is 11 uT. With the Qi-A13 Board in power transfer mode 10.8% and in pinging mode 45.7% (2.2% at 10 cm distance) of the performance limit were reached at maximum. In neither of the scrutinized cases, did the voltage induced by the Qi-A13-Board exceed the performance limits. PMID- 26024361 TI - Simultaneous Exposure to Heavy Metals among Residents in the Industrial Complex: Korean National Cohort Study. AB - A survey was conducted to evaluate the multi-exposure level and correlation among toxic metal biomarkers (Cd, Pb, and Hg). A total of 592 individuals who participated in the survey were residents near an industrial complex in Gwangyang and Yeosu (exposed group) and of Hadong and Namhae (control group) in southern Korea from May 2007 to November 2010. The Gwangyang and Yeosu area exposed groups had slightly higher blood Pb (2.21 and 1.90 ug/dL), urinary Cd observed values (2.20 and 1.46 ug/L), urinary Cd with a urinary creatinine correction (1.43 and 1.25 ug/g Cr), and urinary Hg observed values (2.26 and 0.98 ug/L) in women participants than those in the Hadong and Namhae area (control group). Blood Pb (3.18 and 2.55 ug/dL), urinary Hg observed values (1.14 and 0.92 ug/L), and urinary Hg with a urinary creatinine correction (1.06 and 0.96 ug/L) for male participants were also slightly higher than those in the Hadong and Namhae area (control group). The correlation among urinary Cd, Hg and Pb concentrations in the blood was significant. We suggest that the exposed group of residents were simultaneously exposed to Pb, Cd, and Hg from contaminated ambient air originating from the iron manufacturing industrial complex. PMID- 26024362 TI - Cardiovascular mortality associated with low and high temperatures: determinants of inter-region vulnerability in China. AB - The objectives of this study were to estimate the effects of temperature on cardiovascular mortality in 26 regions in the south and west of China from 2008 to 2011, and to identify socioeconomic and demographic factors contributing to such inter-region variation in the temperature effect. A separate Poisson generalized additive model (GAM) was fitted to estimate percent changes in cardiovascular mortality at low and high temperatures on a daily basis for each region. The model used the smooth functions to model the nonlinear effects of temperature and humidity and to control for the seasonal factor using the calendar time variable. Given variation in the magnitude of the temperature effect on cardiovascular mortality, we employed a Bayesian network (BN) to identify potential region-specific socioeconomic and demographic factors that may explain the variation. In most regions, an increasing trend in high or low temperature was associated with an increase in cardiovascular mortality, with variation in the magnitude of the temperature effects across regions. Three factors, including per capita years of education (as an indicator of economic status), percentage of the population over 65 years of age and percentage of women had direct impact on cold-related cardiovascular mortality. Number of hospital beds (as an indicator of the availability of medical resources), percentage of population engaged in industrial occupations, and percentage of women showed direct impact on heat-related cardiovascular mortality. Due to the socioeconomic and demographic inequalities between regions, the development of customized prevention and adaptation programs to address the low/high temperatures in vulnerable regions should be prioritized. PMID- 26024364 TI - Anisotropic thermal transport in phosphorene: effects of crystal orientation. AB - As an intrinsic thermally anisotropic material, the thermal properties of phosphorene must vary with respect to the crystal chirality. Nevertheless, previous studies of heat transfer in phosphorene have been limited to the 0.0 degrees (zigzag, ZZ) and 90.0 degrees (armchair, AC) chiralities. In this study, we investigate the orientation-dependent thermal transport in phosphorene sheets with a complete set of crystal chirality ranging from 0.0 degrees to 90.0 degrees using the Boltzmann transport equation (BTE) associated with the first principles calculations. It was found that in the phosphorene sheets, the intrinsic thermal conductivity is a smooth monotonic decreasing function of the crystal chirality, which exhibits sinusoidal behavior bounded by the two terminated values 48.9 (0.0 degrees ) and 27.8 (90.0 degrees ) W m(-1) K(-1). The optical modes have unusually large contributions to heat transfer, which account for almost 30% of the total thermal conductivity of phosphorene sheets. This is because the optical phonons have comparable group velocities and relaxation times to the acoustic phonons. PMID- 26024363 TI - Study of the influence of the orientation of a 50-Hz magnetic field on fetal exposure using polynomial chaos decomposition. AB - Human exposure modelling is a complex topic, because in a realistic exposure scenario, several parameters (e.g., the source, the orientation of incident fields, the morphology of subjects) vary and influence the dose. Deterministic dosimetry, so far used to analyze human exposure to electromagnetic fields (EMF), is highly time consuming if the previously-mentioned variations are considered. Stochastic dosimetry is an alternative method to build analytical approximations of exposure at a lower computational cost. In this study, it was used to assess the influence of magnetic flux density (B) orientation on fetal exposure at 50 Hz by polynomial chaos (PC). A PC expansion of induced electric field (E) in each fetal tissue at different gestational ages (GA) was built as a function of B orientation. Maximum E in each fetal tissue and at each GA was estimated for different exposure configurations and compared with the limits of the International Commission of Non-Ionising Radiation Protection (ICNIRP) Guidelines 2010. PC theory resulted in an efficient tool to build accurate approximations of E in each fetal tissue. B orientation strongly influenced E, with a variability across tissues from 10% to 43% with respect to the mean value. However, varying B orientation, maximum E in each fetal tissue was below the limits of ICNIRP 2010 at all GAs. PMID- 26024365 TI - Correction: Genomic analysis of a Mycobacterium bovis bacillus Calmette-Guerin strain isolated from an adult patient with pulmonary tuberculosis. PMID- 26024366 TI - Room-Temperature Reactivity Of Silicon Nanocrystals With Solvents: The Case Of Ketone And Hydrogen Production From Secondary Alcohols: Catalysis? AB - Although silicon nanoparticles dispersed in liquids are used in various applications ranging from biolabeling to hydrogen production, their reactivities with their solvents and their catalytic properties remain still unexplored. Here, we discovered that, because of their surface structures and mechanical strain, silicon nanoparticles react strongly with their solvents and may act as catalysts for the dehydrogenation, at room temperature, of secondary alcohols (e.g., isopropanol) into ketones and hydrogen. This catalytic reaction was monitored by gas chromatography, pH measurements, mass spectroscopy, and solid-state NMR. This discovery provides new understanding of the role played by silicon nanoparticles, and nanosilicon in general, in their reactivity in solvents in general, as well as being candidates in catalysis. PMID- 26024367 TI - Magnetic and noble metal nanocomposites for separation and optical detection of biological species. AB - Nanoalloys and nanocomposites are widely studied classes of nanomaterials within the context of biological systems. They are of immense interest because of the possibility of tuning the optical, magnetic, electronic and chemical properties through particle composition and internal architecture. In principle these properties can therefore be optimized for application in biological detections such as of DNA sequences, bacteria, viruses, antibodies, antigens, and cancer cells. This article presents an overview of methods currently used for nanoalloy and nanocomposite synthesis and characterisation, focusing on Au-Ag and FexOy@Au structures as primary components in detection platforms for plasmonic and magnetically enabled plasmonic bio-sensing. PMID- 26024368 TI - Agrobacterium-mediated transient MaFT expression in mulberry (Morus alba L.) leaves. AB - To optimize Agrobacterium-mediated transient transformation assay in mulberry (Morus alba L.), various infiltration methods, Agrobacterium tumefaciens (A. tumefaciens) strains, and bacterial concentrations were tested in mulberry seedlings. Compared with LBA4404, GV3101 harboring pBE2133 plasmids presented stronger GUS signals at 3 days post infiltration using syringe. Recombinant plasmids pBE2133:GFP and pBE2133:GFP:MaFT were successfully constructed. Transient expression of MaFT:GFP protein was found in leaves, petiole (cross section), and shoot apical meristem (SAM) of mulberry according to the GFP signal. Moreover, MaFT:GFP mRNA was also detected in leaves and SAM via RT-PCR and qRT-PCR. An efficient transient transformation system could be achieved in mulberry seedlings by syringe using A. tumefaciens GV3101 at the OD600 of 0.5. The movement of MaFT expression from leaves to SAM might trigger the precocious flowering of mulberry. PMID- 26024369 TI - Dendrimers and hyperbranched polymers. PMID- 26024371 TI - Correction: Male Sexual Behavior and Pheromone Emission Is Enhanced by Exposure to Guava Fruit Volatiles in Anastrepha fraterculus. PMID- 26024370 TI - Phylogeography of Eastern Grey Kangaroos, Macropus giganteus, Suggests a Mesic Refugium in Eastern Australia. AB - Phylogeographic studies around the world have identified refugia where fauna were able to persist during unsuitable climatic periods, particularly during times of glaciation. In Australia the effects of Pleistocene climate oscillations on rainforest taxa have been well studied but less is known about the effects on mesic-habitat fauna, such as the eastern grey kangaroo (Macropus giganteus). The eastern grey kangaroo is a large mammal that is common and widespread throughout eastern Australia, preferring dry mesic habitat, rather than rainforest. As pollen evidence suggests that the central-eastern part of Australia (southeast Queensland and northern New South Wales) experienced cycles of expansion in mesic habitat with contraction in rainforests, and vice versa during glacial and interglacial periods, respectively, we hypothesise that the distribution of the eastern grey kangaroo was affected by these climate oscillations and may have contracted to mesic habitat refugia. From 375 mitochondrial DNA control region sequences from across the distribution of eastern grey kangaroos we obtained 108 unique haplotypes. Phylogenetic analysis identified two clades in Queensland, one of which is newly identified and restricted to a small coastal region in southern Queensland north of Brisbane, known as the Sunshine Coast. The relatively limited geographic range of this genetically isolated clade suggests the possibility of a mesic habitat refugium forming during rainforest expansion during wetter climate cycles. Other potential, although less likely, reasons for the genetic isolation of the highly distinct clade include geographic barriers, separate northward expansions, and strong local adaptation. PMID- 26024372 TI - Long-term weight change: association with impaired glucose metabolism in young Austrian adults. AB - Little is known about the associations between long-term weight change and the natural history of impaired fasting glucose (IFG) in young adults. We investigated the association between long-term body mass index (BMI) change and the risk of IFG using data of 24,930 20- to 40-year-old participants from the Vorarlberg Health Monitoring and Promotion Program (VHM&PP) cohort. Poisson models were applied to estimate the 10-year risk for new development of IFG (>= 5.6 mmol/L), and persistence of IFG. Over 10 years, most men (68.2%) and women (70.0%) stayed within their initial BMI category. The risk for incident IFG was highest for men and women with persisting obesity (37.4% and 24.1%) and lowest with persisting normal weight (15.7% and 9.3%). Men transitioning from normal to overweight increased their risk of incident IFG by factor 1.45 (95%-CI: 1.31, 1.62), women by 1.70 (95%-CI: 1.50, 1.93), whereas transitioning from overweight to normal weight decreased the risk in men by 0.69 (95%-CI: 0.53, 0.90) and 0.94 (95%-CI: 0.66, 1.33) in women. Relative risks for men and women transitioning from obesity to overweight were 0.58 and 0.44, respectively. In conclusion, 10 year weight increase was associated with an increased IFG risk, weight decrease with a decreased risk of IFG in young adults. PMID- 26024373 TI - Prognostic Role of Phospho-STAT3 in Patients with Cancers of the Digestive System: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The definite prognostic role of p-STAT3 has not been well defined. We performed a meta-analysis evaluating the prognostic role of p-STAT3 expression in patients with digestive system cancers. METHODS: We searched the available articles reporting the prognostic value of p-STAT3 in patients with cancers of the digestive system, mainly including colorectal cancer, gastric cancer, hepatocellular carcinoma, esophagus cancer and pancreatic cancer. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) of overall survival (OS) and disease-free survival (DFS) were used to assess the prognostic role of p STAT3 expression level in cancer tissues. And the association between p-STAT3 expression and clinicopathological characteristics was evaluated. RESULTS: A total of 22 studies with 3585 patients were finally enrolled in the meta analysis. The results showed that elevated p-STAT3 expression level predicted inferior OS (HR = 1.809, 95% CI: 1.442-2.270, P < 0.001) and DFS (HR = 1.481, 95% CI: 1.028-2.133, P = 0.035) in patients with malignant cancers of the digestive system. Increased expression of p-STAT3 is significantly related with tumor cell differentiation (Odds ratio (OR) = 1.895, 95% CI: 1.364-2.632, P < 0.001) and lymph node metastases (OR = 2.108, 95% CI: 1.104-4.024, P = 0.024). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Funnel plots and Egger's tests revealed there was no significant publication bias in the meta-analysis. CONCLUSION: Phospho-STAT3 might be a prognostic factor of patients with digestive system cancers. More well designed studies with adequate follow-up are needed to gain a thorough understanding of the prognostic role of p-STAT3. PMID- 26024374 TI - Cyclic Lipopeptide Biosynthetic Genes and Products, and Inhibitory Activity of Plant-Associated Bacillus against Phytopathogenic Bacteria. AB - The antibacterial activity against bacterial plant pathogens and its relationships with the presence of the cyclic lipopeptide (cLP) biosynthetic genes ituC (iturin), bmyB (bacillomycin), fenD (fengycin) and srfAA (surfactin), and their corresponding antimicrobial peptide products have been studied in a collection of 64 strains of Bacillus spp. isolated from plant environments. The most frequent antimicrobial peptide (AMP) genes were bmyB, srfAA and fenD (34-50% of isolates). Most isolates (98.4%) produced surfactin isoforms, 90.6% iturins and 79.7% fengycins. The antibacterial activity was very frequent and generally intense among the collection of strains because 75% of the isolates were active against at least 6 of the 8 bacterial plant pathogens tested. Hierarchical and correspondence analysis confirmed the presence of two clearly differentiated groups. One group consisted of Bacillus strains that showed a strong antibacterial activity, presented several cLPs genes and produced several isoforms of cLPs simultaneously, mainly composed of B. subtilis and B. amyloliquefaciens, although the last one was exclusive to this group. Another group was characterized by strains with very low or none antibacterial activity, that showed one or none of the cLP genes and produced a few or none of the corresponding cLPs, and was the most heterogenous group including B. subtilis, B. licheniformis, B. megaterium, B. pumilus, B. cereus and B. thuringiensis, although the last two were exclusive to this group. This work demonstrated that the antagonistic capacity of plant-associated Bacillus against plant pathogenic bacteria is related to the presence of cLP genes and to the production of the corresponding cLPs, and it is mainly associated to the species B. subtilis and B. amyloliquefaciens. Our findings would help to increase the yield and efficiency of screening methods to obtain candidate strains to biocontrol agents with a mechanism of action relaying on the production of antimicrobial cLPs. PMID- 26024376 TI - Correction: Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria. PMID- 26024375 TI - How to Determine the Accuracy of an Alternative Diagnostic Test when It Is Actually Better than the Reference Tests: A Re-Evaluation of Diagnostic Tests for Scrub Typhus Using Bayesian LCMs. AB - BACKGROUND: The indirect immunofluorescence assay (IFA) is considered a reference test for scrub typhus. Recently, the Scrub Typhus Infection Criteria (STIC; a combination of culture, PCR assays and IFA IgM) were proposed as a reference standard for evaluating alternative diagnostic tests. Here, we use Bayesian latent class models (LCMs) to estimate the true accuracy of each diagnostic test, and of STIC, for diagnosing scrub typhus. METHODS/PRINCIPAL FINDINGS: Data from 161 patients with undifferentiated fever were re-evaluated using Bayesian LCMs. Every patient was evaluated for the presence of an eschar, and tested with blood culture for Orientia tsutsugamushi, three different PCR assays, IFA IgM, and the Panbio IgM immunochromatographic test (ICT). True sensitivity and specificity of culture (24.4% and 100%), 56kDa PCR assay (56.8% and 98.4%), 47kDa PCR assay (63.2% and 96.1%), groEL PCR assay (71.4% and 93.0%), IFA IgM (70.0% and 83.8%), PanBio IgM ICT (72.8% and 96.8%), presence of eschar (42.7% and 98.9%) and STIC (90.5% and 82.5%) estimated by Bayesian LCM were considerably different from those obtained when using STIC as a reference standard. The IgM ICT had comparable sensitivity and significantly higher specificity compared to IFA (p=0.34 and p<0.001, respectively). CONCLUSIONS: The low specificity of STIC was caused by the low specificity of IFA IgM. Neither STIC nor IFA IgM can be used as reference standards against which to evaluate alternative diagnostic tests. Further evaluation of new diagnostic tests should be done with a carefully selected set of diagnostic tests and appropriate statistical models. PMID- 26024377 TI - A sketch of language history in the Korean Peninsula. AB - Among 7100 languages spoken on Earth, the Koreanic language is the 13th largest, with about 77 million speakers in and around the Korean Peninsula. In comparison to other languages of similar size, however, surprisingly little is known about the evolution of the Koreanic language. This is mainly due to two reasons. The first reason is that the genealogical relationship of the Koreanic to other neighboring languages remains uncertain, and thus inference from the linguistic comparative method provides only provisional evidence. The second reason is that, as the ancestral Koreanic speakers lacked their own writing system until around 500 years ago, there are scant historical materials to peer into the past, except for those preserved in Sinitic characters that we have no straightforward way of interpreting. Here I attempt to overcome these disadvantages and shed some light on the linguistic history of the Korean Peninsula, by analyzing the internal variation of the Koreanic language with methods adopted from evolutionary biology. The preliminary results presented here suggest that the evolutionary history of the Koreanic language is characterized by a weak hierarchical structure, and intensive gene/culture flows within the Korean Peninsula seem to have promoted linguistic homogeneity among the Koreanic variants. Despite the gene/culture flows, however, there are still three detectable linguistic barriers in the Korean Peninsula that appear to have been shaped by geographical features such as mountains, elevated areas, and ocean. I discuss these findings in an inclusive manner to lay the groundwork for future studies. PMID- 26024378 TI - Validity of a Self-Report Recall Tool for Estimating Sedentary Behavior in Adults. AB - BACKGROUND: Sedentary behavior is continuing to emerge as an important target for health promotion. The purpose of this study was to determine the validity of a self-report use of time recall tool, the Multimedia Activity Recall for Children and Adults (MARCA) in estimating time spent sitting/lying, compared with a device based measure. METHODS: Fifty-eight participants (48% female, [mean +/- standard deviation] 28 +/- 7.4 years of age, 23.9 +/- 3.05 kg/m(2)) wore an activPAL device for 24-h and the following day completed the MARCA. Pearson correlation coefficients (r) were used to analyze convergent validity of the adult MARCA compared with activPAL estimates of total sitting/lying time. Agreement was examined using Bland-Altman plots. RESULTS: According to activPAL estimates, participants spent 10.4 hr/day [standard deviation (SD) = 2.06] sitting or lying down while awake. The correlation between MARCA and activPAL estimates of total sit/lie time was r = .77 (95% confidence interval = 0.64-0.86; P < .001). Bland Altman analyses revealed a mean bias of +0.59 hr/day with moderately wide limits of agreement (-2.35 hr to +3.53 hr/day). CONCLUSIONS: This study found a moderate to strong agreement between the adult MARCA and the activPAL, suggesting that the MARCA is an appropriate tool for the measurement of time spent sitting or lying down in an adult population. PMID- 26024379 TI - Living with, managing and minimising treatment burden in long term conditions: a systematic review of qualitative research. AB - BACKGROUND: 'Treatment burden', defined as both the workload and impact of treatment regimens on function and well-being, has been associated with poor adherence and unfavourable outcomes. Previous research focused on treatment workload but our understanding of treatment impact is limited. This research aimed to systematically review qualitative research to identify: 1) what are the treatment generated disruptions experienced by patients across all chronic conditions and treatments? 2) what strategies do patients employ to minimise these treatment generated disruptions? METHODS AND FINDINGS: The search strategy centred on: treatment burden and qualitative methods. Medline, CINAHL, Embase, and PsychINFO were searched electronically from inception to Dec 2013. No language limitations were set. Teams of two reviewers independently conducted paper screening, data extraction, and data analysis. Data were analysed using framework synthesis informed by Cumulative Complexity Model. Eleven papers reporting data from 294 patients, across a range of conditions, age groups and nationalities were included. Treatment burdens were experienced as a series of disruptions: biographical disruptions involved loss of freedom and independence, restriction of meaningful activities, negative emotions and stigma; relational disruptions included strained family and social relationships and feeling isolated; and, biological disruptions involved physical side-effects. Patients employed "adaptive treatment work" and "rationalised non-adherence" to minimise treatment disruptions. Rationalised non-adherence was sanctioned by health professionals at end of life; at other times it was a "secret-act" which generated feelings of guilt and impacted on family and clinical relationships. CONCLUSIONS: Treatments generate negative emotions and physical side effects, strain relationships and affect identity. Patients minimise these disruptions through additional adaptive work and/or by non-adherence. This affects physical outcomes and care relationships. There is a need for clinicians to engage with patients in honest conversations about treatment disruptions and the 'adhere ability' of recommended regimens. Patient-centred practice requires management plans which optimise outcomes and minimise disruptions. PMID- 26024380 TI - Out of control!? How loss of self-control influences prosocial behavior: the role of power and moral values. AB - Lack of self-control has been suggested to facilitate norm-transgressing behaviors because of the operation of automatic selfish impulses. Previous research, however, has shown that people having a high moral identity may not show such selfish impulses when their self-control resources are depleted. In the present research, we extended this effect to prosocial behavior. Moreover, we investigated the role of power in the interaction between moral identity and self control depletion. More specifically, we expected that power facilitates the externalization of internal states, which implies that for people who feel powerful, rather than powerless, depletion decreases prosocial behavior especially for those low in moral identity. A laboratory experiment and a multisource field study supported our predictions. The present finding that the interaction between self-control depletion and moral identity is contingent upon people's level of power suggests that power may enable people to refrain from helping behavior. Moreover, the findings suggest that if organizations want to improve prosocial behaviors, it may be effective to situationally induce moral values in their employees. PMID- 26024381 TI - Chromosomal passports provide new insights into diffusion of emmer wheat. AB - Emmer wheat, Triticum dicoccon schrank (syn. T. dicoccum (schrank) schUbl.), is one of the earliest domesticated crops, harboring a wide range of genetic diversity and agronomically valuable traits. The crop, however, is currently largely neglected. We provide a wealth of karyotypic information from a comprehensive collection of emmer wheat and related taxa. In addition to C banding polymorphisms, we identified 43 variants of chromosomal rearrangements in T. dicoccon; among them 26 (60.4%) were novel. The T7A:5B translocation was most abundant in Western Europe and the Mediterranean. The plant genetic resources investigated here might become important in the future for wheat improvement. Based on cluster analysis four major karyotypic groups were discriminated within the T. dicoccon genepool, each harboring characteristic C-banding patterns and translocation spectra: the balkan, asian, european and ethiopian groups. We postulate four major diffusion routes of the crop and discuss their migration out of the Fertile Crescent considering latest archaeobotanical findings. PMID- 26024382 TI - The Association between Meditation Practice and Job Performance: A Cross Sectional Study. AB - Many previous studies have shown that meditation practice has a positive impact on cognitive and non-cognitive functioning, which are related to job performance. Thus, the aims of this study were to (1) estimate the prevalence of meditation practice, (2) identify the characteristics of individuals who practice meditation, and (3) examine the association between meditation practice and job performance. Two population-based, cross-sectional surveys were conducted. In study 1, we examined the prevalence of meditation practice and the characteristics of the persons practicing meditation; in Study 2, we examined the association between meditation practice and job performance. The outcome variables included work engagement, subjective job performance, and job satisfaction. The Utrecht Work Engagement Scale was used to assess work engagement, the World Health Organization Health and Work Performance Questionnaire (HPQ) was used to measure subjective job performance, and a scale developed by the Japanese government was used to assess job satisfaction. Hierarchical multiple regression analyses were used in Study 2. Demographic characteristics and behavioral risk factors were included as covariates in the analyses. The results of Study 1 indicated that 3.9% of persons surveyed (n = 30,665) practiced meditation; these individuals were younger and had a higher education, higher household income, higher stress level, and lower body mass index than those who did not practice meditation. The results of Study 2 (n = 1,470) indicated that meditation practice was significantly predictive of work engagement (beta = 0.112, p < .001), subjective job performance (beta = 0.116, p < .001), and job satisfaction (beta = 0.079, p = .002), even after adjusting for covariates (beta = 0.083, p < .001; beta = 0.104, p < .001; beta = 0.060, p = .015, respectively). The results indicate that meditation practice may positively influence job performance, including job satisfaction, subjective job performance, and work engagement. PMID- 26024384 TI - Remote ischemic preconditioning for kidney protection. PMID- 26024383 TI - Peptide 19-2.5 inhibits heparan sulfate-triggered inflammation in murine cardiomyocytes stimulated with human sepsis serum. AB - Myocardial dysfunction in sepsis has been linked to inflammation caused by pathogen-associated molecular patterns (PAMPs) as well as by host danger associated molecular patterns (DAMPs). These include soluble heparan sulfate (HS), which triggers the devastating consequences of the pro-inflammatory cascades in severe sepsis and septic shock. Thus, there is increasing interest in the development of anti-infective agents, with effectiveness against both PAMPs and DAMPs. We hypothesized that a synthetic antimicrobial peptide (peptide 19 2.5) inhibits inflammatory response in murine cardiomyocytes (HL-1 cells) stimulated with PAMPs, DAMPs or serum from patients with septic shock by reduction and/or neutralization of soluble HS. In the current study, our data indicate that the treatment with peptide 19-2.5 decreases the inflammatory response in HL-1 cells stimulated with either PAMPs or DAMPs. Furthermore, our work shows that soluble HS in serum from patients with Gram-negative or Gram positive septic shock induces a strong pro-inflammatory response in HL-1 cells, which can be effectively blocked by peptide 19-2.5. Based on these findings, peptide 19-2.5 is a novel anti-inflammatory agent interacting with both PAMPs and DAMPs, suggesting peptide 19-2.5 may have the potential for further development as a broad-spectrum anti-inflammatory agent in sepsis-induced myocardial inflammation and dysfunction. PMID- 26024386 TI - Are PEGylated liposomes better than conventional liposomes? A special case for vincristine. AB - Cancer poses a significant threat to human health worldwide, and many therapies have been used for its palliative and curative treatments. Vincristine has been extensively used in chemotherapy. However, there are two major challenges concerning its applications in various tumors: (1) Vincristine's antitumor mechanism is cell-cycle-specific, and the duration of its exposure to tumor cells can significantly affect its antitumor activity and (2) Vincristine is widely bio distributed and can be rapidly eliminated. One solution to these challenges is the encapsulation of vincristine into liposomes. Vincristine can be loaded into conventional liposomes, but it quickly leak out owing to its high membrane permeability. Numerous approaches have been attempted to overcome this problem. Vincristine has been loaded into PEGylated liposomes to prolong circulation time and improve tumor accumulation. These liposomes indeed prolong circulation time, but the payout characteristic of vincristine is severer, resulting in a compromised outcome rather than a better efficacy compared to conventional sphingomyelin (SM)/cholesterol (Chol) liposomes. In 2012, the USA Food and Drug Administration (FDA) approved SM/Chol liposomal vincristine (Marqibo(r)) for commercial use. In this review, we mainly focus on the drug's rapid leakage problem and the potentially relevant solutions that can be applied during the development of liposomal vincristine and the reason for conventional liposomal vincristine rather than PEGylated liposomes has access to the market. PMID- 26024387 TI - Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA. AB - In recent years, mRNA-based vaccines have emerged to be a great alternative to DNA-based vaccines due to the safety of not inserting into host genome. However, mRNA molecules are single-stranded nucleic acids that are vulnerable under RNase existing in human skin and tissues. In this study, a self-assembled cationic nanomicelles based on polyethyleneimine-stearic acid (PSA) copolymer were developed to delivery HIV-1 gag encoding mRNA to dendritic cells and BALB/c mice. We evaluated the transfection efficiency and cell uptake efficiency of naked EGFP mRNA, PSA, PEI-2k and PEI-25k nanoparticles format on DC2.4 cell lines. Immune responses after sub-cutaneous administration of gag mRNA to BALB/c mice were notably induced by PSA as compared with naked gag mRNA. We found the PSA/mRNA nanomicelles were potent systems that can effectively deliver mRNA and induce antigen-specific immune response, stimulating various new vaccine strategies using mRNA. PMID- 26024388 TI - HEDGEHOG/GLI-E2F1 axis modulates iASPP expression and function and regulates melanoma cell growth. AB - HEDGEHOG (HH) signaling is a key regulator of tissue development and its aberrant activation is involved in several cancer types, including melanoma. We and others have shown a reciprocal cross talk between HH signaling and p53, whose function is often impaired in melanoma. Here we present evidence that both GLI1 and GLI2, the final effectors of HH signaling, regulate the transcription factor E2F1 in melanoma cells, by binding to a functional non-canonical GLI consensus sequence. Consistently, we find a significant correlation between E2F1 and PATCHED1 (PTCH1), GLI1 and GLI2 expression in human melanomas. Functionally, we find that E2F1 is a crucial mediator of HH signaling and it is required for melanoma cell proliferation and xenograft growth induced by activation of the HH pathway. Interestingly, we present evidence that the HH/GLI-E2F1 axis positively modulates the inhibitor of apoptosis-stimulating protein of p53 (iASPP) at multiple levels. HH activation induces iASPP expression through E2F1, which directly binds to iASPP promoter. HH pathway also contributes to iASPP function, by the induction of Cyclin B1 and by the E2F1-dependent regulation of CDK1, which are both involved in iASPP activation. Our data show that activation of HH signaling enhances proliferation in presence of E2F1 and promotes apoptosis in its absence or upon CDK1 inhibition, suggesting that E2F1/iASPP dictates the outcome of HH signaling in melanoma. Together, these findings identify a novel HH/GLI-E2F1 iASPP axis that regulates melanoma cell growth and survival, providing an additional mechanism through which HH signaling restrains p53 proapoptotic function. PMID- 26024389 TI - Identification of synthetic lethality of PLK1 inhibition and microtubule destabilizing drugs. AB - Polo-like kinase 1 (PLK1) is frequently overexpressed in cancer, which correlates with poor prognosis. Therefore, we investigated PLK1 as therapeutic target using rhabdomyosarcoma (RMS) as a model. Here, we identify a novel synthetic lethal interaction of PLK1 inhibitors and microtubule-destabilizing drugs in preclinical RMS models and elucidate the underlying molecular mechanisms of this synergism. PLK1 inhibitors (i.e., BI 2536 and BI 6727) synergistically induce apoptosis together with microtubule-destabilizing drugs (i.e., vincristine (VCR), vinblastine (VBL) and vinorelbine (VNR)) in several RMS cell lines (combination index <0.9) including a patient-derived primary RMS culture. Importantly, PLK1 inhibitors and VCR cooperate to significantly suppress RMS growth in two in vivo models, including a mouse xenograft model, without causing additive toxicity. In addition, no toxicity was observed in non-malignant fibroblast or myoblast cultures. Mechanistically, BI 2536/VCR co-treatment triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by BAX/BAK activation, production of reactive oxygen species (ROS) and activation of caspase-dependent or caspase-independent effector pathways. This conclusion is supported by data showing that BI 2536/VCR-induced apoptosis is significantly inhibited by preventing cells to enter mitosis, by overexpression of BCL-2 or a non-degradable MCL-1 mutant, by BAK knockdown, ROS scavengers, caspase inhibition or endonuclease G silencing. This identification of a novel synthetic lethality of PLK1 inhibitors and microtubule-destabilizing drugs has important implications for developing PLK1 inhibitor-based combination treatments. PMID- 26024390 TI - TP53: an oncogene in disguise. AB - The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as 'amorph', 'hypomorph', 'hypermorph' 'neomorph' or 'antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene. PMID- 26024391 TI - NF-kappaB pathway controls mitochondrial dynamics. AB - The Optic atrophy 1 protein (OPA1) is a key element in the dynamics and morphology of mitochondria. We demonstrated that the absence of IkappaB kinase alpha, which is a key element of the nonclassical NF-kappaB pathway, has an impact on the mitochondrial network morphology and OPA1 expression. In contrast, the absence of NF-kappaB essential modulator (NEMO) or IkappaB kinase-beta, both of which are essential for the canonical NF-kappaB pathway, has no impact on mitochondrial dynamics. Whereas Parkin has been reported to positively regulate the expression of OPA1 through NEMO, herein we found that PARK2 overexpression did not modify the expression of OPA1. PARK2 expression reduced the levels of Bax, and it prevented stress-induced cell death only in Bak-deficient mouse embryonic fibroblast cells. Collectively, our results point out a role of the nonclassical NF-kappaB pathway in the regulation of mitochondrial dynamics and OPA1 expression. PMID- 26024392 TI - Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. AB - Mixed lineage kinase domain-like pseudokinase (MLKL) mediates necroptosis by translocating to the plasma membrane and inducing its rupture. The activation of MLKL occurs in a multimolecular complex (the 'necrosome'), which is comprised of MLKL, receptor-interacting serine/threonine kinase (RIPK)-3 (RIPK3) and, in some cases, RIPK1. Within this complex, RIPK3 phosphorylates the activation loop of MLKL, promoting conformational changes and allowing the formation of MLKL oligomers, which migrate to the plasma membrane. Previous studies suggested that RIPK3 could phosphorylate the murine MLKL activation loop at Ser345, Ser347 and Thr349. Moreover, substitution of the Ser345 for an aspartic acid creates a constitutively active MLKL, independent of RIPK3 function. Here we examine the role of each of these residues and found that the phosphorylation of Ser345 is critical for RIPK3-mediated necroptosis, Ser347 has a minor accessory role and Thr349 seems to be irrelevant. We generated a specific monoclonal antibody to detect phospho-Ser345 in murine cells. Using this antibody, a series of MLKL mutants and a novel RIPK3 inhibitor, we demonstrate that the phosphorylation of Ser345 is not required for the interaction between RIPK3 and MLKL in the necrosome, but is essential for MLKL translocation, accumulation in the plasma membrane, and consequent necroptosis. PMID- 26024393 TI - Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death. AB - The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression. PMID- 26024395 TI - Cardiovascular target organ damage could have been detected in sustained pediatric hypertension. AB - The aim of this study was to assess sustained hypertension in children and its impact on cardiovascular target organ damage (TOD). Blood pressure (BP) was measured in children in Beijing in 2009. Primary hypertension was diagnosed based on three separate visits. Hypertensive children and normotensive children were followed up in 2011. According to these evaluations, three groups were defined: sustained hypertension, non-sustained hypertension and normotensive. Cardiovascular TOD and metabolic disorders were evaluated using pulse-wave velocity (PWV), carotid intima-media thickness (cIMT), and assessments of left ventricular structure and kidney function. A total of 3032 children aged 9-15 years participated in this survey, of whom 128 were diagnosed with hypertension after three separate BP measurements. Eighty out of 128 (62.5%) hypertensive and 158 normotensive children were available for follow-up in 2011. Forty-eight children were defined as having sustained hypertension, 38 as non-sustained hypertension and 152 as normotensive. Mean levels of brachial-ankle PWV (baPWV), left ventricular mass, left ventricular mass index (LVMI) and cIMT were significantly different between the three groups (p < 0.01). Compared to normotensives, the odds ratios and 95% confidence intervals for elevated LVM and cIMT were 5.27 (1.57-17.66) and 2.88 (1.03-8.09) in the non-sustained hypertensive group, and 3.28 (1.00-10.74) and 7.25 (2.69-19.58) in the sustained hypertensive group. The children with sustained hypertension have the highest risk of developing arterial stiffness, left ventricular hypertrophy and early blood vessel endothelium damage. The indices of cIMT, LVMI and PWV were useful to identify children at high risk of cardiovascular TOD. PMID- 26024397 TI - Health effects of changes in the structure of dietary macronutrients intake in western societies. AB - A Western-type diet, characterized by a significant share of highly processed and refined foods and high content of sugars, salt, fat and protein from red meat, has been recognized as an important factor contributing to the development of metabolic disorders and the obesity epidemic around the world. Excessive body fat causes metabolic pathologies, such as insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular diseases, hypertension, non-alcoholic fatty liver disease and cancer. According to the World Health Organization 1.5 billion adults are overweight, nearly 500 million are obese and 220 million suffer from type 2 diabetes. The Western-type diet is also associated with an increased incidence of chronic kidney disease. It is known that a combination of nutrients typical for this diet contributes to impaired renal function, renal steatosis and inflammation, hypertension and dysfunctional renal hormonal regulation. The Western diet is also associated with a chronic inflammatory process that is involved in all stages of atherosclerosis development and is increasingly recognized as a universal mechanism of various chronic degenerative diseases, such as autoimmune diseases, some neoplasms or osteoporosis. The present article is focused on the results of the most recent research investigating the effects of dietary macronutrients and the type of fatty acids on selected mechanisms associated with the occurrence of the most common diet-related diseases. PMID- 26024394 TI - Molecular mechanisms of Ebola virus pathogenesis: focus on cell death. AB - Ebola virus (EBOV) belongs to the Filoviridae family and is responsible for a severe disease characterized by the sudden onset of fever and malaise accompanied by other non-specific signs and symptoms; in 30-50% of cases hemorrhagic symptoms are present. Multiorgan dysfunction occurs in severe forms with a mortality up to 90%. The EBOV first attacks macrophages and dendritic immune cells. The innate immune reaction is characterized by a cytokine storm, with secretion of numerous pro-inflammatory cytokines, which induces a huge number of contradictory signals and hurts the immune cells, as well as other tissues. Other highly pathogenic viruses also trigger cytokine storms, but Filoviruses are thought to be particularly lethal because they affect a wide array of tissues. In addition to the immune system, EBOV attacks the spleen and kidneys, where it kills cells that help the body to regulate its fluid and chemical balance and that make proteins that help the blood to clot. In addition, EBOV causes liver, lungs and kidneys to shut down their functions and the blood vessels to leak fluid into surrounding tissues. In this review, we analyze the molecular mechanisms at the basis of Ebola pathogenesis with a particular focus on the cell death pathways induced by the virus. We also discuss how the treatment of the infection can benefit from the recent experience of blocking/modulating cell death in human degenerative diseases. PMID- 26024398 TI - Pesticide residues in fruit and vegetable crops from the central and eastern region of Poland. AB - BACKGROUND: Fruit and vegetables have health and nutritional value, but can also be a source of toxic contaminants such as pesticide residues. OBJECTIVE: The aim of this study was to evaluate presence of pesticide residues in fruit and vegetable crops from the central and eastern region of Poland in order to check the compliance of these products with the maximum residue levels' (MRLs) requirements set in legal EU regulation for products present in the market. MATERIAL AND METHODS: Samples of fruit and vegetables were obtained from production farms as a part of an official premarket monitoring of pesticide residues conducted on behalf of the Ministry of Agriculture and Rural Development, implemented in cooperation with the regional Inspectorates of Plant Health and Seed Inspection. The tests covered determination of 207 pesticides. RESULTS: In 2014, a total of 317 samples of fruit and vegetables, collected from the central and eastern region of Poland, were analysed for the presence of pesticide residues. Pesticide residues were detected in 89 (28.1%) analysed samples: in 65 (38.2%) samples of fruit, and in 24 (16.3%) samples of vegetables. MRLs were exceeded in 2 samples (0.6%). Most often, the pesticide residues were found in gooseberry (100% of gooseberry samples) and apple (71.4%). CONCLUSIONS: Monitoring of pesticide residues in the agricultural crops at premarket stage should be continued to prevent market from the penetration by products with non acceptable residues of pesticides and to protect consumers against excessive exposure to pesticide residues. PMID- 26024399 TI - Antioxidant activity of rye bread enriched with milled buckwheat groats fractions. AB - BACKGROUND: Buckwheat, despite its broad nutritional benefits, is still not widely appreciated grain. It contains a protein with preferred amino acid composition and it is a valuable source of micronutrients and vitamins of the B group and vitamin E. Moreover, buckwheat groats have a high amount of polyphenols, including flavonoids and flavones. Eating rye bread is beneficial due to its high content of dietary fiber, phenolic acids and characteristic taste and aroma. Therefore, the use of rye flour and buckwheat mill products for bread may allow obtaining a product of high nutritional value and flavor. OBJECTIVE: The aim of the study was to evaluate the influence of buckwheat products addition and baking process on the antioxidant properties of rye-buckwheat blends and breads. MATERIAL AND METHODS: Experimental material was rye flour type 580 and buckwheat flour, wholegrain flour and bran obtained by grinding buckwheat groats. Buckwheat products share was 20 and 35%. The control was the rye flour. In the rye-buckwheat blends and bread loaves, the contents of selected flavonoids by HPLC method, total polyphenols content by Folin-Ciocalteu method and the antioxidant activity by the DPPH radical scavenging method were determined. RESULTS: Buckwheat bran was significantly richer in total polyphenols, rutin, quercetin, orientin and isoorientin than other buckwheat products and rye flour. Bread after baking contained similar amount of total polyphenols and quercetin and have a comparable ability to scavenge 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH) than the corresponding blends. Baking process negatively affected the amount of rutin, orientin and isoorientin. CONCLUSIONS: The use of buckwheat bran as a replacement for wheat flour in bread significantly increases its nutritional value. The process of baking unequally affects the content of particular groups of antioxidant compounds. PMID- 26024400 TI - Mineral supplements' effect on total nutrient intake in Warsaw adult population; cross-sectional assessment. AB - BACKGROUND: Mineral supplementation is important whenever any dietary deficiencies of these nutrients occur. However, an excessive consumption of such products can lead to the negative health consequences. OBJECTIVES: To estimate the mineral supplements contribution to total dietary intake for adults living in Warsaw. MATERIALS AND METHODS: Within the frame of the EHES JA Poland and WAW KARD Projects a representative sample of Warsaw population aged 20 years and above was screened in years 2011/2012. Nutrient intake and supplements use were available for 573 men and 497 women. The minerals levels were analyzed in reference to the Recommended Dietary Allowance (RDA) and the Tolerable Upper Intake Level (UL). RESULTS: In Warsaw population the intake of calcium, magnesium and potassium were lower than RDA, and supplementation didn't eliminate deficiency of these nutrients (except for magnesium in a group of women). Phosphorus intakes were somewhat higher than those recommended. Enriching the diet with zinc and copper supplements in both sexes were un- necessary, as was iron in men, as their daily dietary intakes closely met the recommended standards. Iron supplementation in women however proved effective, as their daily dietary intakes were rather low. CONCLUSIONS: The effectiveness of supplementing the diets of adults living in Warsaw with minerals depends on their type. PMID- 26024401 TI - Chemical analysis of minerals content in daily diets of children and adolescents grown up in Krakow orphanages. AB - BACKGROUND: Numerous studies attest to the role that inappropriate food product groups in the human diet, including children and adolescents diet, leading to abnormal intakes of many important nutrients, such as minerals. OBJECTIVES: These studies were undertaken to assess the coverage of the recommended values for chosen minerals by 205 children and adolescents between the ages of 4 and 20 years, grown up in Krakow orphanages. MATERIALS AND METHODS: Sodium, magnesium, zinc, iron, copper, calcium and potassium concentrations in 112 diets of children and adolescents from 7 selected orphanages in Krakow in every season of the year were performed using AAS method. Results obtained were compared to recommended standards in Poland. RESULTS: Intakes of calcium and potassium were usually too low whilst adequate levels of dietary magnesium and calcium were seen only for the youngest children. Recommended dietary levels of zinc were met in all cases and mostly also for iron and copper. Sodium intakes were however excessive. CONCLUSIONS: The study demonstrates that regular a monitoring and adjusting of the diet is necessary for the assessed children and adolescents in order to correct dietary abnormalities. PMID- 26024402 TI - Assessment of food intakes for women adopting the high protein Dukan diet. AB - BACKGROUND: Overweight and obesity are metabolic disorders affecting both adults and children. Effective treatment of these conditions is focused on decreasing the body mass, through individually tailored and well balanced diets, along with increasing physical activity. Obese persons often, however, choose high protein diets for losing weight. Recently in Poland, the high-protein Dukan-diet has become very popular. OBJECTIVES: To assess dietary consumption in women adopting the Dukan-diet, including intakes of protein, fat, carbohydrate as well as vitamins and minerals. MATERIALS AND METHODS: Subjects were 51 women aged 19-64 years on the Dukan-diet, who were surveyed by individually conducted interview. Women were asked to provide typical menus from each phase of their diets. Quantitative dietary intake assessment was achieved by an officially used 'Photograph album of foodstuffs and dishes' as custom-designed by the National Food and Nutrition Institute (IZZ) in Warsaw. RESULTS: Protein intakes in all subjects were excessive, especially those of animal origin when compared to recommended nutritional standards. In contrast, dietary carbohydrate intakes were low due to poor consumption of fruit and vegetables. Mineral and vitamin intakes revealed high potassium, iron and vitamins A, D and B2, but low vitamin C and folates. Women's average weight reduction after 8-10 weeks of dieting was approximately 15 kilograms. CONCLUSIONS: Many nutritional abnormalities were found in women on the high protein Dukan-diet. Adopting this diet in the long term may pose health threats through acquiring kidney and liver disease, osteoporosis and cardiovascular disease. PMID- 26024403 TI - Family influences on breakfast frequency and quality among primary school pupils in Warsaw and its surrounding areas. AB - BACKGROUND: Regular consumption of a well balanced breakfast is a pre-requisite for normal growth and child development, along with the acquisition of proper eating habits. The family environment is crucial place where children learn such patterns of behaviour that form the basis for their development. OBJECTIVES: To determine how family factors affect the regular eating of breakfast and types of foodstuffs consumed in primary school pupils, including food purchases made from vending machines and school tuck shops. MATERIALS AND METHODS: Subjects were 836 pupils (435 girls and 401 boys, aged 6 - 13) from Warsaw and the surrounding areas. Appropriate socio-demographic data and relevant eating habits were obtained from direct interviewing of the subjects by means of a custom designed questionnaire. Statistical analyses were performed by the Kohonen type cluster analysis model and Chi-square test (Chi(2)); (p<=0.05). RESULTS: Three clusters of pupils were identified by their differing socio-demographics and eating habits (eg. rates of breakfast consumption, buying from vending machines or school tuck shops). The first and third clusters were mainly pupils from two-parent families with parents proportionally spending similar times at work, where respective breakfast (87% and 91%) and second breakfast (77% and 72%) consumption rates were also similar together with food shopping rates during school time (respectively 69% and 63%). Pupils with single-parents, multi-generation families or if both parents were profession- ally active, predominated in the second cluster. These ate breakfast (73%) and second breakfast (67%) more rarely, but more frequently shopped for food at school (84%). A small number of pupils had a packed second breakfast from home, rarely ate sandwiches, fruit and/or vegetables and dairy products but ate more sweets, sweet rolls and savoury snacks. However, a large number of subjects bought sandwiches, fresh fruit and/or vegetables and fast-food at school. CONCLUSIONS: Family factors were found to affect eating habits in children and adolescents regarding how often breakfast was eaten and the type of foodstuffs consumed. High consumptions of unhealthy food items for second breakfast were also observed. Single-parent pupils, those in multi-generation families or if both parents are employed rarely brought second breakfasts from home but frequently bought food from vending machines and school tuck shops. The results of the presented findings are significant towards planning an appropriate educational campaigns and health programmes targeted at children, adolescents and their families. PMID- 26024404 TI - Assessment of the frequency of snack and beverages consumption and stimulants intake in children grown up in orphanages in Krakow. AB - BACKGROUND: Childhood is a particular period of life, when nutritional habits are emerging, so much attention should be paid to proper dietary habits, which become a nutritional pattern copied in the future. OBJECTIVE: The aim of this study was to evaluate selected dietary habits and preferences in a group of children living in Krakow orphanages (supervising by the Social Welfare Centre in Krakow), by assessing the frequency of snacks and beverages consumptions as well as an intake of beverages with caffeine, alcohol and smoking cigarettes. MATERIAL AND METHODS: Studies were performed in the years 2007-2008 in five orphanages located in Krakow. 181 children, 9 to 20 yrs of age, participated in this study. Assessment of dietary habits and preferences was performed based on anonymous questionnaire which included questions about snacking frequency, favorite and most frequently drank beverages without or with caffeine, alcohol and cigarettes smoking. RESULTS: The analysis of nutritional habits showed that the most popular high calorie snacks were eaten by the youngest children. Children and adolescents asked for the most commonly consumed beverages indicated on fizzy drinks and fruits juice. Among the youngest children (9-12 years old), 5% reported drinking alcohol, 10% of boys smoked cigarettes, 10% of girls and 21% of boys drank coffee. Among the oldest respondents, about 35% declared drinking coffee, 39% girls and 65% boys declared smoking cigarettes, whereas drinking alcohol reported 22 and 38% subjects, respectively. CONCLUSIONS: Results obtained in this study, indicate the necessity of intervention, consisting on running training courses and workshops of the assessed population, i.e. children, adolescents and instructing their educators. PMID- 26024405 TI - Selected indices of health status in preschool children from Pila and their families as a risk factor of diet-related diseases. AB - BACKGROUND: Diet-related diseases have their origin as early as in childhood; therefore, preventing them should start from the first years of life. Each assessment of dietary intake should be preceded by assessment of health status indices, especially familial diet-related diseases prevalence. OBJECTIVE: The objective of this study was to analyse selected indices of health status in preschool children from Pila and their families in order to assess the risk of developing diet-related diseases. MATERIAL AND METHODS: The studied population comprised 128 children aged 4 to 6 years, 63 girls and 65 boys, who at- tended two preschools in Pila. Parents filled in questionnaires concerning selected indices of health status of the children and their families. Statistical analysis was carried out by means of the IBM SPSS Statistics 21.0 computer programme. The studied children were divided according to gender. RESULTS: Statistically significantly higher percentage of boys than girls took medicines, 41.5% vs 21.0%. As many as 49.6% of mothers and 33.1% of fathers had higher education and most of the parents assessed the economic status of the family either as good or very good. Most of the studied children took dietary supplements. The highest percentage of both girls and boys, 34.2% and 33.8%, respectively, took vitamin and mineral supplements. The prevalence of familial diet-related diseases ranged from 3.2% in the case of hyperlipidaemia to 65.6% in the case of hypertension. CONCLUSIONS: The high percentage of the studied preschoolers who took dietary supplements shows the need to educate parents about the adverse effects of excessive intake of these nutrients and about the necessity to take such supplements only on recommendation of the paediatrician. The analysed indices of health status of the studied children and their families show the need to pay much attention to balanced diet and daily physical activity in order to prevent diet-related diseases in the studied preschoolers and their families. PMID- 26024406 TI - Prosthetic status and prosthetic needs amongst geriatric fishermen population of Kutch coast, Gujarat, India. AB - BACKGROUND: Literature among fishermen of India is scanty. The external factors like diet, quality of dental hygiene and environmental factors have an effect on oral health. Moreover elderly age group offer very little importance towards their oral health. OBJECTIVE: To assess the prosthetic status and prosthetic treatment needs among the geriatric fishermen population of Kutch coast, Gujarat, India. MATERIAL AND METHODS: A cross sectional descriptive study was conducted among 1200 elderly people (above 60 years) of Kutch coast, Gujarat, India. They were interviewed and examined using a proforma designed with the help of WHO Oral Health Survey 1997. Chi square test was used for comparisons. Confidence level and p-value were set at 95% and 5% respectively. RESULTS: Out of 1200 elderly people, 836 were males and 364 were females. Considering the prosthetic status, majority (76.7%) had no prosthesis followed by full removable dentures (12.3%). An insight into the prosthetic needs showed that majority (27.3%) had a need for multiunit prosthesis. CONCLUSION: In this study, it was seen that overall prosthetic status was low and prosthetic need was high. Therefore new avenues have to be discovered to make the prosthetic treatment readily available to the elderly. PMID- 26024407 TI - Antimicrobial effects of citrus sinensis peel extracts against periodontopathic bacteria: an in vitro study. AB - BACKGROUND: Use of plant extracts and phytochemicals with known antimicrobial properties may have great significance in therapeutic treatments. OBJECTIVE: To assess the in vitro antimicrobial potential and also determine the minimum inhibitory concentration (MIC) of Citrus sinensis peel extracts with a view of searching a novel extract as a remedy for periodontal pathogens. MATERIALS AND METHODS: Aqueous and ethanol (cold and hot) extracts prepared from peel of Citrus sinensis were screened for in vitro antimicrobial activity against Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia, using agar well diffusion method. The lowest concentration of every extract considered as the minimal inhibitory concentration (MIC) values were determined for both test organisms. Confidence level and level of significance were set at 95% and 5% respectively. RESULTS: Prevotella intermedia and Porphyromonas gingivalis were resistant to aqueous extracts while Aggregatibacter actinomycetemcomitans was inhibited at very high cncentrations. Hot ethanolic extracts showed significantly higher zone of inhibition than cold ethanolic extract. Minimum inhibitory concentration of hot and cold ethanolic extracts of Citrus sinensis peel ranged between 12-15 mg/ml against all three periodontal pathogens. CONCLUSIONS: Both extracts were found sensitive and contain compounds with therapeutic potential. Nevertheless, clinical trials on the effect of these plants are essential before advocating large-scale therapy. PMID- 26024408 TI - Anthropogenic impact of urban settlements on inorganic anions content in selected watercourses in the Subcarpathian Region of Poland. AB - BACKGROUND: Legislation for environmentally protecting surface waters in Poland and the EU is considered a priority because of the large human impact on this environmental feature in both highly industrialised countries as well as those that are agriculturally well developed. The biggest threats are regarded as being sewage arising from economic, industrial and agricultural pollution along with rain water run-off from fields treated with fertilizers. One of the most characteristic indicators of pollution exposure in surface waters are inorganic anions which form the principal components of town sew- age and fertilizers. OBJECTIVES: The estimate the effect that six selected sites of human settlement have on variously sized watercourses running through. The human environmental impact was based on determination of chlorides, nitrates and sulphates concentrations in such waters. MATERIALS AND METHODS: Water samples were obtained from the following rivers and towns, respectively; the Nil in Kolbuszowa, the Mleczka in Przeworsk, the San in Jaroslaw, the Wislok in Rzeszow, the Bystrzyca in Olimpow and an unnamed watercourse in Niwiska. Sampling sites were chosen at 4 6 points along each watercourse for a given locality. Analyte levels were measured by ion chromatography using the Dionex ICS 1000 instrument. RESULTS: Mean chlorides concentrations were found to vary from 8.52 (+/-0.17, n=3) mg/L to 78.41 (+/-0.19, n=3) mg/L, mean nitrates were 6.76 (+/-0.00, n=3) mg/L to 23.97 (+/-1.50, n=3) mg/L and mean sulphates from 29.89 (+/-1.57, n=3) mg/L to 62.48 (+/-2.99, n=3) mg/L. The clearest environmental effect of settlements on watercourses were observed for the small to medium sized towns of Kolbuszowa, Przeworsk and Jaroslaw in the form of frequently elevated chlorides levels from sewage. CONCLUSIONS: By designating various sampling locations, along the watercourses for measuring the human environmental impact of nearby settlements, it is possible to identify sources of river pollution and thus take appropriate remedial action, as and when required. PMID- 26024410 TI - Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design. AB - Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic xantine, a phtalimide, or a piperidine maleimide scaffold. PMID- 26024409 TI - A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells. AB - Cross-presentation is the process by which professional APCs load peptides from an extracellularly derived protein onto class I MHC molecules to trigger a CD8(+) T cell response. The ability to enhance this process is therefore relevant for the development of antitumor and antiviral vaccines. We investigated a new TLR2 based adjuvant, Small Molecule Immune Potentiator (SMIP) 2.1, for its ability to stimulate cross-presentation. Using OVA as model antigen, we demonstrated that a SMIP2.1-adjuvanted vaccine formulation induced a greater CD8(+) T cell response, in terms of proliferation, cytokine production and cytolytic activity, than a non adjuvanted vaccine. Moreover, using an OVA-expressing tumor model, we showed that the CTLs induced by the SMIP2.1 formulated vaccine inhibits tumor growth in vivo. Using a BCR transgenic mouse model we found that B cells could cross-present the OVA antigen when stimulated with SMIP2.1. We also used a flow cytometry assay to detect activation of human CD8(+) T cells isolated from human PBMCs of cytomegalovirus-seropositive donors. Stimulation with SMIP2.1 increased the capacity of human APCs, pulsed in vitro with the pp65 CMV protein, to activate CMV-specific CD8(+) T cells. Therefore, vaccination with an exogenous antigen formulated with SMIP2.1 is a successful strategy for the induction of a cytotoxic T cell response along with antibody production. PMID- 26024411 TI - Role of percutaneous transhepatic biliary drainage in patients with complications after gastrectomy. AB - OBJECTIVE: The aim of this study was to elucidate the role of PTBD in patients with DSL and ALS post-gastrectomy for malignancy or benign ulcer perforation. SUMMARY OF BACKGROUND DATA: Percutaneous transhepatic biliary drainage (PTBD) is an interventional radiologic procedure used to promote bile drainage. Duodenal stump leakage (DSL) and afferent loop syndrome (ALS) can be serious complications after gastrectomy. METHODS: From January 2002 through December 2014, we retrospectively reviewed 19 patients who underwent PTBD secondary to DSL and ALS post-gastrectomy. In this study, a PTBD tube was placed in the proximal duodenum near the stump or distal duodenum in order to decompress and drain bile and pancreatic fluids. RESULTS: Nine patients with DSL and 10 patients with ALS underwent PTBD. The mean hospital stay was 34.3 days (range, 12-71) in DSL group and 16.4 days (range, 6-48) in ALS group after PTBD. A liquid or soft diet was started within 2.6 days (range, 1-7) in the ALS group and within 3.4 days (range, 0-15) in the DSL group after PTBD. One patient with DSL had PTBD changed, and 2 patients with ALS underwent additional surgical interventions after PTBD. CONCLUSIONS: The PTBD procedure, during which the tube was inserted into the duodenum, was well-suited for decompression of the duodenum as well as for drainage of bile and pancreatic fluids. This procedure can be an alternative treatment for cases of DSL and ALS post-gastrectomy. PMID- 26024412 TI - Observation of nanoscale adhesion, friction and wear between ALD Al2O3 coated silicon MEMS sidewalls. AB - We report a novel investigation of the tribological properties of aluminum oxide (Al2O3) when it is used as protective coating on the sidewalls of microelectromechanical systems (MEMS). By using an in-house built optical displacement measurement system, we were able to measure the on-chip displacements with an unprecedented resolution of 2 nm. This corresponds to 2 nN and 9 nN force resolution, respectively, depending on whether an adhesion or a friction sensor MEMS device was used for the measurement. Al2O3 was deposited on the vertical etched sidewalls using atomic layer deposition (ALD). All tests were carried out in ambient conditions. The same tests carried out on uncoated polysilicon devices were not reproducible due to stiction, which sometimes prevented the interacting surfaces from moving once contact was made. The higher adhesion of silicon was also found to hinder the mobility of the slider. In the ALD-coated devices, we observed increasing adhesion after 50000 repeated contacts. We attribute this increase to the accumulation of aluminum hydroxide debris produced by the reaction with moisture in the environment. We also investigated the long-term effect of friction on the coated silicon sidewalls. The dissipated energy decreases, with a minimum lateral force occurring around the 1000th cycle. After 1000 cycles, the lateral displacement decreases, suggesting an additional lateral dragging force caused by the interaction between a mixture of aluminum hydroxides and water. However, the small overall amount of debris produced during the friction test indicates the outstanding characteristic of Al2O3 as a protective coating for MEMS that use contacting or sliding interfaces. PMID- 26024413 TI - Diverse Serum Manganese Species Affect Brain Metabolites Depending on Exposure Conditions. AB - Occupational and environmental exposure to increased concentrations of manganese (Mn) can lead to an accumulation of this element in the brain. The consequence is an irreversible damage of dopaminergic neurons leading to a disease called manganism with a clinical presentation similar to the one observed in Parkinson's disease. Human as well as animal studies indicate that Mn is mainly bound to low molecular mass (LMM) compounds such as Mn-citrate when crossing neural barriers. The shift toward LMM compounds might already take place in serum due to elevated Mn concentrations in the body. In this study, we investigated Mn-species pattern in serum in two different animal models by size exclusion chromatography inductively coupled plasma mass spectrometry (SEC-ICP-MS). A subchronic feeding of rats with elevated levels of Mn led to an increase in LMM compounds, mainly Mn citrate and Mn bound to amino acids. In addition, a single i.v. injection of Mn showed an increase in Mn-transferrin and Mn bound to amino acids 1 h after injection, while species values were more or less rebalanced 4 days after the injection. Results from Mn-speciation were correlated to the brain metabolome determined by means of electrospray ionization ion cyclotron resonance Fourier transform mass spectrometry (ESI-ICR/FT-MS). The powerful combination of Mn speciation in serum with metabolomics of the brain underlined the need for Mn speciation in exposure scenarios instead of the determination of whole Mn concentrations in blood. The progress of Mn-induced neuronal injury might therefore be assessed on the basis of known serum Mn-species. PMID- 26024414 TI - Development of a portable non-invasive swallowing and respiration assessment device. AB - Dysphagia is a condition that happens when a person cannot smoothly swallow food from the mouth to the stomach. It causes malnourishment in patients, or can even cause death due to aspiration pneumonia. Recently, more and more researchers have focused their attention on the importance of swallowing and respiration coordination, and the use of non-invasive assessment systems has become a hot research trend. In this study, we aimed to integrate the timing and pattern monitoring of respiration and swallowing by using a portable and non-invasive approach which can be applied at the bedside in hospitals or institutions, or in a home environment. In this approach, we use a force sensing resistor (FSR) to detect the motions of the thyroid cartilage in the pharyngeal phase. We also use the surface electromyography (sEMG) to detect the contraction of the submental muscle in the oral phase, and a nasal cannula to detect nasal airflow for respiration monitoring during the swallowing process. All signals are received and processed for swallowing event recognition. A total of 19 volunteers participated in the testing and over 57 measurements were made. The results show that the proposed approach can effectively distinguish the swallowing function in people of different ages and genders. PMID- 26024415 TI - Aperiodic linear networked control considering variable channel delays: application to robots coordination. AB - One of the main challenges in wireless cyber-physical systems is to reduce the load of the communication channel while preserving the control performance. In this way, communication resources are liberated for other applications sharing the channel bandwidth. The main contribution of this work is the design of a remote control solution based on an aperiodic and adaptive triggering mechanism considering the current network delay of multiple robotics units. Working with the actual network delay instead of the maximum one leads to abandoning this conservative assumption, since the triggering condition is fixed depending on the current state of the network. This way, the controller manages the usage of the wireless channel in order to reduce the channel delay and to improve the availability of the communication resources. The communication standard under study is the widespread IEEE 802.11g, whose channel delay is clearly uncertain. First, the adaptive self-triggered control is validated through the TrueTime simulation tool configured for the mentioned WiFi standard. Implementation results applying the aperiodic linear control laws on four P3-DX robots are also included. Both of them demonstrate the advantage of this solution in terms of network accessing and control performance with respect to periodic and non adaptive self-triggered alternatives. PMID- 26024416 TI - Ultrasonic sensor signals and optimum path forest classifier for the microstructural characterization of thermally-aged inconel 625 alloy. AB - Secondary phases, such as laves and carbides, are formed during the final solidification stages of nickel-based superalloy coatings deposited during the gas tungsten arc welding cold wire process. However, when aged at high temperatures, other phases can precipitate in the microstructure, like the gamma'' and delta phases. This work presents an evaluation of the powerful optimum path forest (OPF) classifier configured with six distance functions to classify background echo and backscattered ultrasonic signals from samples of the inconel 625 superalloy thermally aged at 650 and 950 degrees C for 10, 100 and 200 h. The background echo and backscattered ultrasonic signals were acquired using transducers with frequencies of 4 and 5 MHz. The potentiality of ultrasonic sensor signals combined with the OPF to characterize the microstructures of an inconel 625 thermally aged and in the as-welded condition were confirmed by the results. The experimental results revealed that the OPF classifier is sufficiently fast (classification total time of 0.316 ms) and accurate (accuracy of 88.75%" and harmonic mean of 89.52) for the application proposed. PMID- 26024417 TI - Impedance of the grape berry cuticle as a novel phenotypic trait to estimate resistance to Botrytis cinerea. AB - Warm and moist weather conditions during berry ripening provoke Botrytis cinerea (B. cinerea) causing notable bunch rot on susceptible grapevines with the effect of reduced yield and wine quality. Resistance donors of genetic loci to increase B. cinerea resistance are widely unknown. Promising traits of resistance are represented by physical features like the thickness and permeability of the grape berry cuticle. Sensor-based phenotyping methods or genetic markers are rare for such traits. In the present study, the simple-to-handle I-sensor was developed. The sensor enables the fast and reliable measurement of electrical impedance of the grape berry cuticles and its epicuticular waxes (CW). Statistical experiments revealed highly significant correlations between relative impedance of CW and the resistance of grapevines to B. cinerea. Thus, the relative impedance Zrel of CW was identified as the most important phenotypic factor with regard to the prediction of grapevine resistance to B. cinerea. An ordinal logistic regression analysis revealed a R2McFadden of 0.37 and confirmed the application of Zrel of CW for the prediction of bunch infection and in this way as novel phenotyping trait. Applying the I-sensor, a preliminary QTL region was identified indicating that the novel phenotypic trait is as well a valuable tool for genetic analyses. PMID- 26024418 TI - Optical detection of paraoxon using single-walled carbon nanotube films with attached organophosphorus hydrolase-expressed Escherichia coli. AB - In whole-cell based biosensors, spectrophotometry is one of the most commonly used methods for detecting organophosphates due to its simplicity and reliability. The sensor performance is directly affected by the cell immobilization method because it determines the amount of cells, the mass transfer rate, and the stability. In this study, we demonstrated that our previously-reported microbe immobilization method, a microbe-attached single walled carbon nanotube film, can be applied to whole-cell-based organophosphate sensors. This method has many advantages over other whole-cell organophosphate sensors, including high specific activity, quick cell immobilization, and excellent stability. A device with circular electrodes was fabricated for an enlarged cell-immobilization area. Escherichia coli expressing organophosphorus hydrolase in the periplasmic space and single-walled carbon nanotubes were attached to the device by our method. Paraoxon was hydrolyzed using this device, and detected by measuring the concentration of the enzymatic reaction product, p nitrophenol. The specific activity of our device was calculated, and was shown to be over 2.5 times that reported previously for other whole-cell organophosphate sensors. Thus, this method for generation of whole-cell-based OP biosensors might be optimal, as it overcomes many of the caveats that prevent the widespread use of other such devices. PMID- 26024419 TI - Strong ferromagnetically-coupled spin valve sensor devices for droplet magnetofluidics. AB - We report a magnetofluidic device with integrated strong ferromagnetically coupled and hysteresis-free spin valve sensors for dynamic monitoring of ferrofluid droplets in microfluidics. The strong ferromagnetic coupling between the free layer and the pinned layer of spin valve sensors is achieved by reducing the spacer thickness, while the hysteresis of the free layer is eliminated by the interplay between shape anisotropy and the strength of coupling. The increased ferromagnetic coupling field up to the remarkable 70 Oe, which is five-times larger than conventional solutions, brings key advantages for dynamic sensing, e.g., a larger biasing field giving rise to larger detection signals, facilitating the operation of devices without saturation of the sensors. Studies on the fundamental effects of an external magnetic field on the evolution of the shape of droplets, as enabled by the non-visual monitoring capability of the device, provides crucial information for future development of a magnetofluidic device for multiplexed assays. PMID- 26024420 TI - Target localization in wireless sensor networks using online semi-supervised support vector regression. AB - Machine learning has been successfully used for target localization in wireless sensor networks (WSNs) due to its accurate and robust estimation against highly nonlinear and noisy sensor measurement. For efficient and adaptive learning, this paper introduces online semi-supervised support vector regression (OSS-SVR). The first advantage of the proposed algorithm is that, based on semi-supervised learning framework, it can reduce the requirement on the amount of the labeled training data, maintaining accurate estimation. Second, with an extension to online learning, the proposed OSS-SVR automatically tracks changes of the system to be learned, such as varied noise characteristics. We compare the proposed algorithm with semi-supervised manifold learning, an online Gaussian process and online semi-supervised colocalization. The algorithms are evaluated for estimating the unknown location of a mobile robot in a WSN. The experimental results show that the proposed algorithm is more accurate under the smaller amount of labeled training data and is robust to varying noise. Moreover, the suggested algorithm performs fast computation, maintaining the best localization performance in comparison with the other methods. PMID- 26024421 TI - Characterization of wheat varieties using terahertz time-domain spectroscopy. AB - Terahertz (THz) spectroscopy and multivariate data analysis were explored to discriminate eight wheat varieties. The absorption spectra were measured using THz time-domain spectroscopy from 0.2 to 2.0 THz. Using partial least squares (PLS), a regression model for discriminating wheat varieties was developed. The coefficient of correlation in cross validation (R) and root-mean-square error of cross validation (RMSECV) were 0.985 and 1.162, respectively. In addition, interval PLS was applied to optimize the models by selecting the most appropriate regions in the spectra, improving the prediction accuracy (R = 0.992 and RMSECV = 0.967). Results demonstrate that THz spectroscopy combined with multivariate analysis can provide rapid, nondestructive discrimination of wheat varieties. PMID- 26024422 TI - Diamond nanowires: a novel platform for electrochemistry and matrix-free mass spectrometry. AB - Over the last decades, carbon-based nanostructures have generated a huge interest from both fundamental and technological viewpoints owing to their physicochemical characteristics, markedly different from their corresponding bulk states. Among these nanostructured materials, carbon nanotubes (CNTs), and more recently graphene and its derivatives, hold a central position. The large amount of work devoted to these materials is driven not only by their unique mechanical and electrical properties, but also by the advances made in synthetic methods to produce these materials in large quantities with reasonably controllable morphologies. While much less studied than CNTs and graphene, diamond nanowires, the diamond analogue of CNTs, hold promise for several important applications. Diamond nanowires display several advantages such as chemical inertness, high mechanical strength, high thermal and electrical conductivity, together with proven biocompatibility and existence of various strategies to functionalize their surface. The unique physicochemical properties of diamond nanowires have generated wide interest for their use as fillers in nanocomposites, as light detectors and emitters, as substrates for nanoelectronic devices, as tips for scanning probe microscopy as well as for sensing applications. In the past few years, studies on boron-doped diamond nanowires (BDD NWs) focused on increasing their electrochemical active surface area to achieve higher sensitivity and selectivity compared to planar diamond interfaces. The first part of the present review article will cover the promising applications of BDD NWS for label-free sensing. Then, the potential use of diamond nanowires as inorganic substrates for matrix-free laser desorption/ionization mass spectrometry, a powerful label-free approach for quantification and identification of small compounds, will be discussed. PMID- 26024423 TI - Chiral Recognition Studies of alpha-(Nonafluoro-tert-butoxy)carboxylic Acids by NMR Spectroscopy. AB - Three chiral alpha-(nonafluoro-tert-butoxy)carboxylic acids (R)-1, (RS)-2, (R)-3 were synthesized to examine their application as chiral solvating agents with amines. As a model compound, first (S)- and/or (RS)-alpha-phenylethylamine was used, and their diastereomeric salts were investigated by (1)H and (19)F NMR and ECD spectroscopy. The NMR spectroscopic studies were carried out at room temperature using the slightly polar CDCl3 and apolar C6D6 as solvents in 5 mM and 54 mM concentrations. The difference of the chemical shifts (Deltadelta) in the diastereomeric complexes is comparable with other, well-known chiral derivatizing and solvating agents (e.g., Mosher's acid, Pirkle's alcohol). Diastereomeric salts of racemic acids (RS)-1 and (RS)-2 with biologically active amines (1R,2S)-ephedrine and (S)-dapoxetine were also investigated by (19)F NMR spectroscopy. PMID- 26024424 TI - Gibberellin regulates infection and colonization of host roots by arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhiza (AM) is established by the entry of AM fungi into the host plant roots and the formation of symbiotic structures called arbuscules. The host plant supplies photosynthetic products to the AM fungi, which in return provide phosphate and other minerals to the host through the arbuscules. Both partners gain great advantages from this symbiotic interaction, and both regulate AM development. Our recent work revealed that gibberellic acids (GAs) are required for AM development in the legume Lotus japonicus. GA signaling interact with symbiosis signaling pathways, directing AM fungal colonization in host roots. Expression analysis showed that genes for GA biosynthesis and metabolism were induced in host roots around AM fungal hyphae, suggesting that the GA signaling changes with both location and time during AM development. The fluctuating GA concentrations sometimes positively and sometimes negatively affect the expression of AM-induced genes that regulate AM fungal infection and colonization. PMID- 26024425 TI - Quantification of the Influence of Endotoxins on the Mechanics of Adult and Neonatal Red Blood Cells. AB - In this study, we physically modeled the influence of endotoxin-induced sepsis symptoms on human red blood cells (RBCs) by quantifying the impact of endotoxins on the cell mechanics by the analysis of Fourier-transformed mean square amplitude of shape fluctuation, called flicker spectroscopy. With the aid of a microfluidic diffusion chamber, we noninvasively determined principal mechanical parameters of human RBCs in the absence and presence of endotoxins for individual RBCs for the first time. Because of the elongation of saccharide chain length of endotoxins, we found an increase in the morphological transition from discocytes to echinocytes, and monotonic changes in the mechanical parameters. Since septic shocks often cause lethal risks of neonates, we measured the mechanical parameters of neonatal RBCs, and compared them to those of adult RBCs. The quantitative comparison reveals that neonatal RBCs are more susceptible to the effect of endotoxins than adult RBCs. Furthermore, coincubation with the antiseptic peptide P19-2.5 (Aspidasept) with endotoxin results in a slight suppression of the impact of the endotoxin. The strategy proposed in our study can potentially be applied for the quantitative diagnosis of RBCs based on mechanical readouts. PMID- 26024426 TI - Surface plasmon resonance-induced stiffening of silver nanowires. AB - We report the results of a computational, atomistic electrodynamics study of the effects of electromagnetic waves on the mechanical properties, and specifically the Young's modulus of silver nanowires. We find that the Young's modulus of the nanowires is strongly dependent on the optical excitation energy, with a peak enhancement occurring at the localized surface plasmon resonance frequency. When the nanowire is excited at the plasmon resonance frequency, the Young's modulus is found to increase linearly with increasing nanowire aspect ratio, with a stiffening of nearly 15% for a 2 nm cross section silver nanowire with an aspect ratio of 3.5. Furthermore, our results suggest that this plasmon resonance induced stiffening is stronger for larger diameter nanowires for a given aspect ratio. Our study demonstrates a novel approach to actively tailoring and enhancing the mechanical properties of metal nanowires. PMID- 26024427 TI - Ethynyl, 2-Propynyl, and 3-Butynyl C-Phosphonate Analogues of Nucleoside Di- and Triphosphates: Synthesis and Reactivity in CuAAC. AB - The synthesis and reactivity of a novel class of clickable nucleotide analogues containing a C-phosphonate subunit that has an alkyne group at the terminal position of the oligophosphate chain are reported. The C-phosphonate subunits were prepared by simple one- or two-step procedures using commercially available reagents. Nucleotides were prepared by MgCl2-catalyzed coupling reactions and then subjected to CuAAC reactions with various azide compounds to afford 5'-gamma labeled nucleoside triphosphates in excellent yields. PMID- 26024429 TI - Mercury Adsorption and Oxidation over Cobalt Oxide Loaded Magnetospheres Catalyst from Fly Ash in Oxyfuel Combustion Flue Gas. AB - Cobalt oxide loaded magnetospheres catalyst from fly ash (Co-MF catalyst) showed good mercury removal capacity and recyclability under air combustion flue gas in our previous study. In this work, the Hg(0) removal behaviors as well as the involved reactions mechanism were investigated in oxyfuel combustion conditions. Further, the recyclability of Co-MF catalyst in oxyfuel combustion atmosphere was also evaluated. The results showed that the Hg(0) removal efficiency in oxyfuel combustion conditions was relative high compared to that in air combustion conditions. The presence of enriched CO2 (70%) in oxyfuel combustion atmosphere assisted the mercury oxidation due to the oxidation of function group of C-O formed from CO2. Under both atmospheres, the mercury removal efficiency decreased with the addition of SO2, NO, and H2O. However, the enriched CO2 in oxyfuel combustion atmosphere could somewhat weaken the inhibition of SO2, NO, and H2O. The multiple capture-regeneration cycles demonstrated that the Co-MF catalyst also present good regeneration performance in oxyfuel combustion atmosphere. PMID- 26024428 TI - Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms. AB - A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits. PMID- 26024430 TI - Relationship between serum DHEAS and oxidative stress levels of body mass index in healthy postmenopausal women. AB - OBJECTIVES: Menopause is a natural step in the process of aging. Postmenopausal women have decreased levels of antioxidants and increased oxidative stress, the latter of which plays an important role in atherogenesis. The aim of the present study was to evaluate the relationship of the body mass index (BMI) with serum catalase activity, malondialdehyde (MDA), and dehydroepiandrosterone sulfate (DHEAS) levels in healthy postmenopausal women and estimate whether the MDA/DHEAS ratio is a possible marker of oxidative stress for determining cardiovascular risk in these women. METHODS: We investigated serum catalase activity, MDA, and DHEAS levels, parity history, age, and BMI in 96 healthy postmenopausal women aged 50-82 years. The serum MDA levels and catalase activity were measured spectrophotometrically. The serum DHEAS levels were measured using an enzyme linked immunosorbent assay. The ratio percentage of the serum DHEAS levels to serum MDA levels was designated as a biomarker for oxidative stress. RESULTS: The mean BMI of the patients was 31.72 +/- 6.16 kg/m(2) (range = 20.5-47.94). The MDA/DHEAS ratio was significantly decreased in patients with a BMI over 30 compared to that of patients with a BMI between 25 and 30 (P = 0.025). Moreover, BMI was positively correlated with serum DHEAS levels (r = 0.285, P < 0.01) and negatively correlated with the MDA/DHEAS ratio (r = -0.241, P < 0.05) in postmenopausal women. Furthermore, BMI was observed to be a potential predictor of the MDA/DHEAS ratio based on covariance analysis (P = 0.039). CONCLUSIONS: Our results indicate that healthy, obese, postmenopausal women have a decreased MDA/DHEAS ratio. Additionally, BMI was observed to be a potential predictor of the MDA/DHEAS ratio. PMID- 26024433 TI - Hyphenation of Thermal Analysis to Ultrahigh-Resolution Mass Spectrometry (Fourier Transform Ion Cyclotron Resonance Mass Spectrometry) Using Atmospheric Pressure Chemical Ionization For Studying Composition and Thermal Degradation of Complex Materials. AB - In this study, the hyphenation of a thermobalance to an ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometer (UHR FTICR MS) is presented. Atmospheric pressure chemical ionization (APCI) is used for efficient ionization. The evolved gas analysis (EGA), using high-resolution mass spectrometry allows the time-resolved molecular characterization of thermally induced processes in complex materials or mixtures, such as biomass or crude oil. The most crucial part of the setup is the hyphenation between the thermobalance and the APCI source. Evolved gases are forced to enter the atmospheric pressure ionization interface of the MS by applying a slight overpressure at the thermobalance side of the hyphenation. Using the FTICR exact mass data, detailed chemical information is gained by calculation of elemental compositions from the organic species, enabling a time and temperature resolved, highly selective detection of the evolved species. An additional selectivity is gained by the APCI ionization, which is particularly sensitive toward polar compounds. This selectivity on the one hand misses bulk components of petroleum samples such as alkanes and does not deliver a comprehensive view but on the other hand focuses particularly on typical evolved components from biomass samples. As proof of principle, the thermal behavior of different fossil fuels: heavy fuel oil, light fuel oil, and a crude oil, and different lignocellulosic biomass, namely, beech, birch, spruce, ash, oak, and pine as well as commercial available softwood and birch-bark pellets were investigated. The results clearly show the capability to distinguish between certain wood types through their molecular patterns and compound classes. Additionally, typical literature known pyrolysis biomass marker were confirmed by their elemental composition, such as coniferyl aldehyde (C10H10O3), sinapyl aldehyde (C11H12O4), retene (C18H18), and abietic acid (C20H30O2). PMID- 26024432 TI - Prehospital Nitroglycerin Safety in Inferior ST Elevation Myocardial Infarction. AB - Patients with inferior ST elevation myocardial infarction (STEMI), associated with right ventricular infarction, are thought to be at higher risk of developing hypotension when administered nitroglycerin (NTG). However, current basic life support (BLS) protocols do not differentiate location of STEMI prior to NTG administration. We sought to determine if NTG administration is more likely to be associated with hypotension (systolic blood pressure < 90 mmHg) in inferior STEMI compared to non-inferior STEMI. We conducted a retrospective chart review of prehospital patients with chest pain of suspected cardiac origin and computer interpreted prehospital ECGs indicating "ACUTE MI." We included all local STEMI cases identified as part of our STEMI registry. Univariate analysis was used to compare differences in proportions of hypotension and drop in systolic blood pressure >= 30 mmHg after nitroglycerin administration between patients with inferior wall STEMI and those with STEMI in another region (non-inferior). Multiple variable logistic regression analysis was also used to assess the study outcomes while controlling for various factors. Over a 29-month period, we identified 1,466 STEMI cases. Of those, 821 (56.0%) received NTG. We excluded 16 cases because of missing data. Hypotension occurred post NTG in 38/466 inferior STEMIs and 30/339 non-inferior STEMIs, 8.2% vs. 8.9%, p = 0.73. A drop in systolic blood pressure >= 30 mmHg post NTG occurred in 23.4% of inferior STEMIs and 23.9% of non-inferior STEMIs, p = 0.87. Interrater agreement for chart review of the primary outcome was excellent (kappa = 0.94). NTG administration to patients with chest pain and inferior STEMI on their computer-interpreted electrocardiogram is not associated with a higher rate of hypotension compared to patients with STEMI in other territories. Computer interpretation of inferior STEMI cannot be used as the sole predictor for patients who may be at higher risk for hypotension following NTG administration. PMID- 26024431 TI - Cross-species comparative analysis of Dicer proteins during Sindbis virus infection. AB - In plants and invertebrates RNA silencing is a major defense mechanism against virus infections. The first event in RNA silencing is dicing of long double stranded RNAs into small interfering RNAs (siRNAs). The Dicer proteins involved in this process are phylogenetically conserved and have the same domain organization. Accordingly, the production of viral derived siRNAs has also been observed in the mouse, but only in restricted cell types. To gain insight on this restriction, we compare the dicing activity of human Dicer and fly Dicer-2 in the context of Sindbis virus (SINV) infection. Expression of human Dicer in flies inefficiently rescues the production of viral siRNAs but confers some protection against SINV. Conversely, expression of Dicer-2 in human cells allows the production of viral 21 nt small RNAs. However, this does not confer resistance to viral infection, but on the contrary results in stronger accumulation of viral RNA. We further show that Dicer-2 expression in human cells perturbs interferon (IFN) signaling pathways and antagonizes protein kinase R (PKR)-mediated antiviral immunity. Overall, our data suggest that a functional incompatibility between the Dicer and IFN pathways explains the predominance of the IFN response in mammalian somatic cells. PMID- 26024434 TI - Structured caustic vector vortex optical field: manipulating optical angular momentum flux and polarization rotation. AB - A caustic vector vortex optical field is experimentally generated and demonstrated by a caustic-based approach. The desired caustic with arbitrary acceleration trajectories, as well as the structured states of polarization (SoP) and vortex orders located in different positions in the field cross-section, is generated by imposing the corresponding spatial phase function in a vector vortex optical field. Our study reveals that different spin and orbital angular momentum flux distributions (including opposite directions) in different positions in the cross-section of a caustic vector vortex optical field can be dynamically managed during propagation by intentionally choosing the initial polarization and vortex topological charges, as a result of the modulation of the caustic phase. We find that the SoP in the field cross-section rotates during propagation due to the existence of the vortex. The unique structured feature of the caustic vector vortex optical field opens the possibility of multi-manipulation of optical angular momentum fluxes and SoP, leading to more complex manipulation of the optical field scenarios. Thus this approach further expands the functionality of an optical system. PMID- 26024435 TI - Race, Gender, and the Resources That Matter: An Investigation of Intersectionality and Health. AB - This study examined racial disparities in health among women, in particular, the relationship between social status and both the development of psychosocial resources and good health. These relationships were investigated using a sample of 869 women from the 2007 wave of the U.S. Panel Study of Income Dynamics, Child Development Supplement. While Black women developed the intrapersonal rewards of self-efficacy and self-esteem through socioeconomic status, they did not experience the same degree of health benefits with these advantages as White women. Models relating both self-rated health and chronic conditions suggested that, instead, highly educated Black women were at a persistent health disadvantage relative to Whites, even at the same levels of psychosocial resources. That being said, Black women with higher self-efficacy, and particularly, higher self-esteem, were more likely than Black women with lower levels of these resources to report being in better health. Thus, resources may improve health within a disadvantaged group while still not bringing them up to the level of health experienced by their advantaged counterparts. Overall, the findings demonstrated that research should not treat women as a homogenous group, assuming that mechanisms affecting health operate the same for women regardless of their race. PMID- 26024436 TI - Liquid Chromatography with Amperometric Detection at a Silver Based Detector for the Determination of Thiocompounds: Application to the Assay of Thiopurine Antimetabolites in Urine. AB - A silver amperometric detector coupled to liquid chromatography (LC) was used for the determination of 6-thioguanine (6-TG) and two of its metabolites, thiouric acid (TU) and 2-amino-6-mercaptopurine riboside (6-TGR). The silver detector coupled to LC operated at a low applied potential (0.08 V vs Ag/AgCl) and offered a chromatogram with peak responses corresponding to molecules interacting with silver, namely, chloride ions and small soluble biothiols in addition to the organothiol drug compounds investigated. Online electrochemical surface cleaning permitted the improvement of the repeatability and peak shape of the recorded signal compared to direct current amperometric detection (AD) when operating in chloride containing media. The studied molecules were eluted isocratically within 5 min on a reversed-phase C18 column without interference from endogenous biothiols present in urine samples. Diluted urine samples (1:1) were directly injected in the LC setup; a linear calibration curve was obtained between peak area and analyte concentration between 0.1 and 10 MUM for all the studied molecules. Limits of detection (LODs) were 0.03, 0.008, and 0.01 MUM, and the limits of quantification (LOQs) were 0.1, 0.02, and 0.03 MUM for TU, 6-TG, and 6 TGR, respectively. Within-day RSDs were 2%, 0.8%, and 1% and between-day RSDs were 2%, 0.9%, 2% for TU, 6-TG, and 6-TGR, respectively. Recoveries in spiked urine were 99.8%, 99.9%, and 99.0% for TU, 6-TG, and 6-TGR, respectively. PMID- 26024437 TI - Quantum Simulation of Dissipative Processes without Reservoir Engineering. AB - We present a quantum algorithm to simulate general finite dimensional Lindblad master equations without the requirement of engineering the system-environment interactions. The proposed method is able to simulate both Markovian and non Markovian quantum dynamics. It consists in the quantum computation of the dissipative corrections to the unitary evolution of the system of interest, via the reconstruction of the response functions associated with the Lindblad operators. Our approach is equally applicable to dynamics generated by effectively non-Hermitian Hamiltonians. We confirm the quality of our method providing specific error bounds that quantify its accuracy. PMID- 26024438 TI - Two New Classes of T-Type Calcium Channel Inhibitors with New Chemical Scaffolds from Ganoderma cochlear. AB - T-type calcium channel (TTCC) inhibitors hold great potential for the treatment of a variety of neurological disorders. Cochlearoids A-E (1-5), five pairs of dimeric meroterpenoid enantiomers, and cochlearines A (6) and B (7), two pairs of enantiomeric hybrid metabolites, were isolated and characterized from Ganoderma cochlear. Biological evaluation found that compounds (+)-1, (-)-3, and (+/-)-6 significantly inhibited Cav3.1 TTCC and showed noticeable selectivity against Cav1.2, Cav2.1, Cav2.2, and Kv11.1 (hERG) channels. PMID- 26024439 TI - Total synthesis and biological investigation of (-)-promysalin. AB - Compounds that specifically target pathogenic bacteria are greatly needed, and identifying the method by which they act would provide new avenues of treatment. Herein we report the concise, high-yielding total synthesis (eight steps, 35% yield) of promysalin, a natural product that displays antivirulence phenotypes against pathogenic bacteria. Guided by bioinformatics, four diastereomers were synthesized, and the relative and absolute stereochemistries were confirmed by spectral and biological analysis. Finally, we show for the first time that promysalin displays two antivirulence phenotypes: the dispersion of mature biofilms and the inhibition of pyoverdine production, hinting at a unique pathogenic-specific mechanism of action. PMID- 26024440 TI - Comparative Study on the Noble-Gas Binding Ability of BeX Clusters (X = SO4, CO3, O). AB - Ab initio computations are carried out to assess the noble gas (Ng) binding capability of BeSO4 cluster. We have further compared the stability of NgBeSO4 with that of the recently detected NgBeCO3 cluster. The Ng-Be bond in NgBeCO3 is somewhat weaker than that in NgBeO cluster. In NgBeSO4, the Ng-Be bond is found to be stronger compared with not only the Ng-Be bond in NgBeCO3 but also that in NgBeO, except the He case. The Ar-Rn-bound BeSO4 analogues are viable even at room temperature. The Wiberg bond indices of Be-Ng bonds and the degree of electron transfer from Ng to Be are somewhat larger in NgBeSO4 than those in NgBeCO3 and NgBeO. Electron density and energy decomposition analyses are performed in search of the nature of interaction in the Be-Ng bond in NgBeSO4. The orbital energy term (DeltaE(orb)) contributes the maximum (ca. 80-90%) to the total attraction energy. The Ar/Kr/Xe/Rn-Be bonds in NgBeSO4 could be of partial covalent type with a gradual increase in covalency along Ar to Rn. PMID- 26024442 TI - Small RNA Deep-Sequencing Analyses Reveal a New Regulator of Virulence in Agrobacterium fabrum C58. AB - Novel ways of regulating Ti plasmid functions were investigated by studying small RNAs (sRNAs) that are known to act as posttranscriptional regulators in plant pathogenic bacteria. sRNA-seq analyses of Agrobacterium fabrum C58 allowed us to identify 1,108 small transcripts expressed in several growth conditions that could be sRNAs. A quarter of them were confirmed by bioinformatics or by biological experiments. Antisense RNAs represent 24% of the candidates and they are over-represented on the pTi (with 62% of pTi sRNAs), suggesting differences in the regulatory mechanisms between the essential and accessory replicons. Moreover, a large number of these pTi antisense RNAs are transcribed opposite to those genes involved in virulence. Others are 5'- and 3'-untranslated region RNAs and trans-encoded RNAs. We have validated, by rapid amplification of cDNA ends polymerase chain reaction, the transcription of 14 trans-encoded RNAs, among which RNA1111 is expressed from the pTiC58. Its deletion decreased the aggressiveness of A. fabrum C58 on tomatoes, tobaccos, and kalanchoe, suggesting that this sRNA activates virulence. The identification of its putative target mRNAs (6b gene, virC2, virD3, and traA) suggests that this sRNA may coordinate two of the major pTi functions, the infection of plants and its dissemination among bacteria. PMID- 26024441 TI - Defense Responses to Mycotoxin-Producing Fungi Fusarium proliferatum, F. subglutinans, and Aspergillus flavus in Kernels of Susceptible and Resistant Maize Genotypes. AB - Developing kernels of resistant and susceptible maize genotypes were inoculated with Fusarium proliferatum, F. subglutinans, and Aspergillus flavus. Selected defense systems were investigated using real-time reverse transcription polymerase chain reaction to monitor the expression of pathogenesis-related (PR) genes (PR1, PR5, PRm3, PRm6) and genes protective from oxidative stress (peroxidase, catalase, superoxide dismutase and ascorbate peroxidase) at 72 h postinoculation. The study was also extended to the analysis of the ascorbate glutathione cycle and catalase, superoxide dismutase, and cytosolic and wall peroxidases enzymes. Furthermore, the hydrogen peroxide and malondialdehyde contents were studied to evaluate the oxidation level. Higher gene expression and enzymatic activities were observed in uninoculated kernels of resistant line, conferring a major readiness to the pathogen attack. Moreover expression values of PR genes remained higher in the resistant line after inoculation, demonstrating a potentiated response to the pathogen invasions. In contrast, reactive oxygen species-scavenging genes were strongly induced in the susceptible line only after pathogen inoculation, although their enzymatic activity was higher in the resistant line. Our data provide an important basis for further investigation of defense gene functions in developing kernels in order to improve resistance to fungal pathogens. Maize genotypes with overexpressed resistance traits could be profitably utilized in breeding programs focused on resistance to pathogens and grain safety. PMID- 26024443 TI - Brome mosaic virus Infection of Rice Results in Decreased Accumulation of RNA1. AB - Brome mosaic virus (BMV) (the Russian strain) infects monocot plants and has been studied extensively in barley and wheat. Here, we report BMV can systemically infect rice (Oryza sativa var. japonica), including cultivars in which the genomes have been determined. The BMV capsid protein can be found throughout the inoculated plants. However, infection in rice exhibits delayed symptom expression or no symptoms when compared with wheat (Triticum aestivum). The sequences of BMV RNAs isolated from rice did not reveal any nucleotide changes in RNA1 or RNA2, while RNA3 had only one synonymous nucleotide change from the inoculum sequence. Preparations of purified BMV virions contained RNA1 at a significantly reduced level relative to the other two RNAs. Analysis of BMV RNA replication in rice revealed that minus-strand RNA1 was replicated at a reduced rate when compared with RNA2. Thus, rice appears to either inhibit RNA1 replication or lacks a sufficient amount of a factor needed to support efficient RNA1 replication. PMID- 26024444 TI - Willingness-to-accept pharmaceutical retail inconvenience: evidence from a contingent choice experiment. AB - OBJECTIVES: Restrictions on retail purchases of pseudoephedrine are one regulatory approach to reduce the social costs of methamphetamine production and use, but may impose costs on legitimate users of nasal decongestants. This is the first study to evaluate the costs of restricting access to medications on consumer welfare. Our objective was to measure the inconvenience cost consumers place on restrictions for cold medication purchases including identification requirements, purchase limits, over-the-counter availability, prescription requirements, and the active ingredient. METHODS: We conducted a contingent choice experiment with Amazon Mechanical Turk workers that presented participants with randomized, hypothetical product prices and combinations of restrictions that reflect the range of public policies. We used a conditional logit model to calculate willingness-to-accept each restriction. RESULTS: Respondents' willingness-to-accept prescription requirements was $14.17 ($9.76-$18.58) and behind-the-counter restrictions was $9.68 ($7.03-$12.33) per box of pseudoephedrine product. Participants were willing to pay $4.09 ($1.66-$6.52) per box to purchase pseudoephedrine-based products over phenylephrine-based products. CONCLUSIONS: Restricting access to medicines as a means of reducing the social costs of non-medical use can imply large inconvenience costs for legitimate consumers. These results are relevant to discussions of retail access restrictions on other medications. PMID- 26024445 TI - Structural dynamics of the cereblon ligand binding domain. AB - Cereblon, a primary target of thalidomide and its derivatives, has been characterized structurally from both bacteria and animals. Especially well studied is the thalidomide binding domain, CULT, which shows an invariable structure across different organisms and in complex with different ligands. Here, based on a series of crystal structures of a bacterial representative, we reveal the conformational flexibility and structural dynamics of this domain. In particular, we follow the unfolding of large fractions of the domain upon release of thalidomide in the crystalline state. Our results imply that a third of the domain, including the thalidomide binding pocket, only folds upon ligand binding. We further characterize the structural effect of the C-terminal truncation resulting from the mental-retardation linked R419X nonsense mutation in vitro and offer a mechanistic hypothesis for its irresponsiveness to thalidomide. At 1.2A resolution, our data provide a view of thalidomide binding at atomic resolution. PMID- 26024447 TI - Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers. AB - The circulatory persistence, distribution, and metabolism of hemoglobin-based oxygen carriers (HBOCs) is a major determinant of their safety and efficacy. In this communication, published data on the pharmacokinetics and routes of plasma elimination of HBOCs are summarized and evaluated. The circulating half-life of HBOCs is dose-dependent in both animals and humans. Half-life also increases with molecular weight in animals, at least up to the MDa range. The functional half life of HBOCs is diminished by as much as 40% due to oxidation of the heme group relative to the overall rate of removal of hemoglobin (Hb) from plasma. Kidney excretion of HBOCs is greatly diminished compared to that of unmodified Hb, but the liver remains a primary site of catabolism. Both hepatocytes and Kupffer cells have been implicated in receptor-mediated HBOC uptake. Removal also occurs in the spleen and/or bone marrow and probably at dispersed sites in the endothelium as well. HBOCs extravasate into the lymph at a rate inversely proportional to their molecular weight and are taken up by monocyte/macrophage CD163 receptors, both as free Hb and in complexes with haptoglobin (Hp). The interactions with both Hp and the CD163 receptor are altered by Hb modification. However, monocyte/macrophage uptake may not be a quantitatively important route for the removal of clinically relevant doses of HBOCs. The relative contributions of different removal pathways have yet to be comprehensively determined, particularly in humans. PMID- 26024446 TI - Blast-Associated Shock Waves Result in Increased Brain Vascular Leakage and Elevated ROS Levels in a Rat Model of Traumatic Brain Injury. AB - Blast-associated shock wave-induced traumatic brain injury (bTBI) remains a persistent risk for armed forces worldwide, yet its detailed pathophysiology remains to be fully investigated. In this study, we have designed and characterized a laboratory-scale shock tube to develop a rodent model of bTBI. Our blast tube, driven by a mixture of oxygen and acetylene, effectively generates blast overpressures of 20-130 psi, with pressure-time profiles similar to those of free-field blast waves. We tested our shock tube for brain injury response to various blast wave conditions in rats. The results show that blast waves cause diffuse vascular brain damage, as determined using a sensitive optical imaging method based on the fluorescence signal of Evans Blue dye extravasation developed in our laboratory. Vascular leakage increased with increasing blast overpressures and mapping of the brain slices for optical signal intensity indicated nonhomogeneous damage to the cerebral vasculature. We confirmed vascular leakage due to disruption in the blood-brain barrier (BBB) integrity following blast exposure. Reactive oxygen species (ROS) levels in the brain also increased with increasing blast pressures and with time post-blast wave exposure. Immunohistochemical analysis of the brain sections analyzed at different time points post blast exposure demonstrated astrocytosis and cell apoptosis, confirming sustained neuronal injury response. The main advantages of our shock-tube design are minimal jet effect and no requirement for specialized equipment or facilities, and effectively generate blast-associated shock waves that are relevant to battle-field conditions. Overall data suggest that increased oxidative stress and BBB disruption could be the crucial factors in the propagation and spread of neuronal degeneration following blast injury. Further studies are required to determine the interplay between increased ROS activity and BBB disruption to develop effective therapeutic strategies that can prevent the resulting cascade of neurodegeneration. PMID- 26024449 TI - An Inverse Grip Starting Posture Gives Rise to Time-Dependent Adherence to Weber's Law: A Reply to Ganel et al. (2014). PMID- 26024448 TI - The Homeobox Genes of Caenorhabditis elegans and Insights into Their Spatio Temporal Expression Dynamics during Embryogenesis. AB - Homeobox genes play crucial roles for the development of multicellular eukaryotes. We have generated a revised list of all homeobox genes for Caenorhabditis elegans and provide a nomenclature for the previously unnamed ones. We show that, out of 103 homeobox genes, 70 are co-orthologous to human homeobox genes. 14 are highly divergent, lacking an obvious ortholog even in other Caenorhabditis species. One of these homeobox genes encodes 12 homeodomains, while three other highly divergent homeobox genes encode a novel type of double homeodomain, termed HOCHOB. To understand how transcription factors regulate cell fate during development, precise spatio-temporal expression data need to be obtained. Using a new imaging framework that we developed, Endrov, we have generated spatio-temporal expression profiles during embryogenesis of over 60 homeobox genes, as well as a number of other developmental control genes using GFP reporters. We used dynamic feedback during recording to automatically adjust the camera exposure time in order to increase the dynamic range beyond the limitations of the camera. We have applied the new framework to examine homeobox gene expression patterns and provide an analysis of these patterns. The methods we developed to analyze and quantify expression data are not only suitable for C. elegans, but can be applied to other model systems or even to tissue culture systems. PMID- 26024450 TI - Changes in apparent duration follow shifts in perceptual timing. AB - It is well established that the apparent duration of moving visual objects is greater at higher as compared to slower speeds. Here we report the effects of acceleration and deceleration on the perceived duration of a drifting grating with average speed kept constant (10 degrees /s).For acceleration, increasing the speed range progressively reduced perceived duration. The magnitude of apparent duration compression was determined by speed rather than temporal frequency and was proportional to speed range (independent of standard duration) rather than acceleration. The perceived duration reduction was also proportional to the standard length. The effects of increases and decreases in speed were highly asymmetric. Reducing speed through the interval induced a moderate increase in perceived duration. These results could not be explained by changes in apparent onset or offset or differences in perceived average speed between intervals containing increasing speed and intervals containing decreasing speed. Paradoxically, for intervals combining increasing speed and decreasing speed, compression only occurred when increasing speed occurred in the second half of the interval. We show that this pattern of results in the duration domain was concomitant with changes in the reported direction of apparent motion of Gaussian blobs, embedded in intervals of increasing or decreasing speed, that could be predicted from adaptive changes in the temporal impulse response function. We detected similar changes after flicker adaptation, suggesting that the two effects might be linked through changes in the temporal tuning of visual filters. PMID- 26024453 TI - Contour complexity and contour detection. AB - Itis well-known that "smooth" chains of oriented elements-contours-are more easily detected amid background noise than more undulating (i.e., "less smooth") chains. Here, we develop a Bayesian framework for contour detection and show that it predicts that contour detection performance should decrease with the contour's complexity, quantified as the description length (DL; i.e., the negative logarithm of probability integrated along the contour). We tested this prediction in two experiments in which subjects were asked to detect simple open contours amid pixel noise. In Experiment 1, we demonstrate a consistent decline in performance with increasingly complex contours, as predicted by the Bayesian model. In Experiment 2, we confirmed that this effect is due to integrated complexity along the contour, and does not seem to depend on local stretches of linear structure. The results corroborate the probabilistic model of contours, and show how contour detection can be understood as a special case of a more general process-the identification of organized patterns in the environment. PMID- 26024452 TI - Crowding, grouping, and object recognition: A matter of appearance. AB - In crowding, the perception of a target strongly deteriorates when neighboring elements are presented. Crowding is usually assumed to have the following characteristics. (a) Crowding is determined only by nearby elements within a restricted region around the target (Bouma's law). (b) Increasing the number of flankers can only deteriorate performance. (c) Target-flanker interference is feature-specific. These characteristics are usually explained by pooling models, which are well in the spirit of classic models of object recognition. In this review, we summarize recent findings showing that crowding is not determined by the above characteristics, thus, challenging most models of crowding. We propose that the spatial configuration across the entire visual field determines crowding. Only when one understands how all elements of a visual scene group with each other, can one determine crowding strength. We put forward the hypothesis that appearance (i.e., how stimuli look) is a good predictor for crowding, because both crowding and appearance reflect the output of recurrent processing rather than interactions during the initial phase of visual processing. PMID- 26024451 TI - The steady-state visual evoked potential in vision research: A review. AB - Periodic visual stimulation and analysis of the resulting steady-state visual evoked potentials were first introduced over 80 years ago as a means to study visual sensation and perception. From the first single-channel recording of responses to modulated light to the present use of sophisticated digital displays composed of complex visual stimuli and high-density recording arrays, steady state methods have been applied in a broad range of scientific and applied settings.The purpose of this article is to describe the fundamental stimulation paradigms for steady-state visual evoked potentials and to illustrate these principles through research findings across a range of applications in vision science. PMID- 26024455 TI - Connecting psychophysical performance to neuronal response properties I: Discrimination of suprathreshold stimuli. AB - One of the major goals of sensory neuroscience is to understand how an organism's perceptual abilities relate to the underlying physiology. To this end, we derived equations to estimate the best possible psychophysical discrimination performance, given the properties of the neurons carrying the sensory code.We set up a generic sensory coding model with neurons characterized by their tuning function to the stimulus and the random process that generates spikes. The tuning function was a Gaussian function or a sigmoid (Naka-Rushton) function.Spikes were generated using Poisson spiking processes whose rates were modulated by a multiplicative, gamma-distributed gain signal that was shared between neurons. This doubly stochastic process generates realistic levels of neuronal variability and a realistic correlation structure within the population. Using Fisher information as a close approximation of the model's decoding precision, we derived equations to predict the model's discrimination performance from the neuronal parameters. We then verified the accuracy of our equations using Monte Carlo simulations. Our work has two major benefits. Firstly, we can quickly calculate the performance of physiologically plausible population-coding models by evaluating simple equations, which makes it easy to fit the model to psychophysical data. Secondly, the equations revealed some remarkably straightforward relationships between psychophysical discrimination performance and the parameters of the neuronal population, giving deep insights into the relationships between an organism's perceptual abilities and the properties of the neurons on which those abilities depend. PMID- 26024454 TI - Spatiotemporal information during unsupervised learning enhances viewpoint invariant object recognition. AB - Recognizing objects is difficult because it requires both linking views of an object that can be different and distinguishing objects with similar appearance. Interestingly, people can learn to recognize objects across views in an unsupervised way, without feedback, just from the natural viewing statistics. However, there is intense debate regarding what information during unsupervised learning is used to link among object views. Specifically, researchers argue whether temporal proximity, motion, or spatiotemporal continuity among object views during unsupervised learning is beneficial. Here, we untangled the role of each of these factors in unsupervised learning of novel three-dimensional (3-D) objects. We found that after unsupervised training with 24 object views spanning a 180 degrees view space, participants showed significant improvement in their ability to recognize 3-D objects across rotation. Surprisingly, there was no advantage to unsupervised learning with spatiotemporal continuity or motion information than training with temporal proximity. However, we discovered that when participants were trained with just a third of the views spanning the same view space, unsupervised learning via spatiotemporal continuity yielded significantly better recognition performance on novel views than learning via temporal proximity. These results suggest that while it is possible to obtain view-invariant recognition just from observing many views of an object presented in temporal proximity, spatiotemporal information enhances performance by producing representations with broader view tuning than learning via temporal association. Our findings have important implications for theories of object recognition and for the development of computational algorithms that learn from examples. PMID- 26024456 TI - Connecting psychophysical performance to neuronal response properties II: Contrast decoding and detection. AB - The purpose of this article is to provide mathematical insights into the results of some Monte Carlo simulations published by Tolhurst and colleagues (Clatworthy, Chirimuuta, Lauritzen, & Tolhurst, 2003; Chirimuuta & Tolhurst, 2005a). In these simulations, the contrast of a visual stimulus was encoded by a model spiking neuron or a set of such neurons. The mean spike count of each neuron was given by a sigmoidal function of contrast, the Naka-Rushton function. The actual number of spikes generated on each trial was determined by a doubly stochastic Poisson process. The spike counts were decoded using a Bayesian decoder to give an estimate of the stimulus contrast. Tolhurst and colleagues used the estimated contrast values to assess the model's performance in a number of ways, and they uncovered several relationships between properties of the neurons and characteristics of performance. Although this work made a substantial contribution to our understanding of the links between physiology and perceptual performance, the Monte Carlo simulations provided little insight into why the obtained patterns of results arose or how general they are. We overcame these problems by deriving equations that predict the model's performance. We derived an approximation of the model's decoding precision using Fisher information. We also analyzed the model's contrast detection performance and discovered a previously unknown theoretical connection between the Naka-Rushton contrast response function and the Weibull psychometric function. Our equations give many insights into the theoretical relationships between physiology and perceptual performance reported by Tolhurst and colleagues, explaining how they arise and how they generalize across the neuronal parameter space. PMID- 26024458 TI - Comparing rapid scene categorization of aerial and terrestrial views: A new perspective on scene gist. AB - Scene gist, a viewer's holistic representation of a scene from a single eye fixation, has been extensively studied for terrestrial views, but not for aerial views. We compared rapid scene categorization of both views in three experiments to determine the degree to which diagnostic information is view dependent versus view independent.We found large differences in observers' ability to rapidly categorize aerial and terrestrial scene views, consistent with the idea that scene gist recognition is viewpoint dependent.In addition, computational modeling showed that training models on one view (aerial or terrestrial) led to poor performance on the other view, thereby providing further evidence of viewpoint dependence as a function of available information. Importantly, we found that rapid categorization of terrestrial views (but not aerial views) was strongly interfered with by image rotation, further suggesting that terrestrial-view scene gist recognition is viewpoint dependent, with aerial-view scene recognition being viewpoint independent. Furthermore, rotation-invariant texture images synthesized from aerial views of scenes were twice as recognizable as those synthesized from terrestrial views of scenes (which were at chance), providing further evidence that diagnostic information for rapid scene categorization of aerial views is viewpoint invariant. We discuss the results within a perceptual-expertise framework that distinguishes between configural and featural processing, where terrestrial views are more effectively processed due to their predictable view dependent configurations whereas aerial views are processed less effectively due to reliance on view-independent features. PMID- 26024457 TI - Crowding by a repeating pattern. AB - Theinability to recognize a peripheral target among flankers is called crowding. For a foveal target, crowding can be distinguished from overlap masking by its sparing of detection, linear scaling with eccentricity, and invariance with target size.Crowding depends on the proximity and similarity of the flankers to the target. Flankers that are far from or dissimilar to the target do not crowd it. On a gray page, text whose neighboring letters have different colors, alternately black and white, has enough dissimilarity that it might escape crowding. Since reading speed is normally limited by crowding, escape from crowding should allow faster reading. Yet reading speed is unchanged (Chung & Mansfield, 2009). Why? A recent vernier study found that using alternating-color flankers produces strong crowding (Manassi, Sayim, & Herzog, 2012). Might that effect occur with letters and reading? Critical spacing is the minimum center-to center target-flanker spacing needed to correctly identify the target. We measure it for a target letter surrounded by several equidistant flanker letters of the same polarity, opposite polarity, or mixed polarity: alternately white and black. We find strong crowding in the alternating condition, even though each flanker letter is beyond its own critical spacing (as measured in a separate condition). Thus a periodic repeating pattern can produce crowding even when the individual elements do not. Further, in all conditions we find that, once a periodic pattern repeats (two cycles), further repetition does not affect critical spacing of the innermost flanker. PMID- 26024459 TI - Training on spatiotemporal masking improves crowded and uncrowded visual acuity. AB - Spatial crowding impairs conscious visual perception and object recognition in clutter.Short presentation times produce crowding in the normal fovea, in young participants and in uncorrected presbyopes ("aging eye"), measured as reduced visual acuity (VA). On the other hand, perceptual learning improves near VA in healthy young adults, in presbyopia, and in amblyopia. Here we aimed at exploring the effects of perceptual training on crowded VA in uncorrected presbyopes with naturally decreased VA, with two specific objectives: (a) to objectively measure crowded VA, taking advantage of the natural deterioration of near visual acuity from being normal or better than normal (i.e., 20/20 or better) in young participants to naturally decreasing in uncorrected presbyopes; and (b) to explore whether perceptual training previously shown to improve visual functions as complex as reading will affect crowded VA. Visual acuity was measured under crowded and uncrowded conditions by having subjects identify letters presented for short durations ranging from 34 to 116 msec. Training consisted of detecting brief Gabor stimuli under spatial and temporal masking conditions, using the GlassesOff mobile application (GlassesOff, Inc., New York, NY)on iOS devices from a distance of 40 cm. Before training, a robust reduction in crowded VA was found in the fovea of presbyopes. Training resulted in significant improvement of letter identification under both crowded and uncrowded VA conditions for all stimulus durations. After training, the crowded condition threshold reached the level of the uncrowded threshold measured before training. Thus, training enabled the subjects to overcome the effect of reduced VA under the crowded condition. We suggest that more efficient spatial and temporal processing induced by perceptual learning allows one to improve crowded VA, including that found on naturally reduced near VA, and that this effect may transfer to improve complex visual functions, such as reading and object recognition. PMID- 26024460 TI - Color constancy supports cross-illumination color selection. AB - We rely on color to select objects as the targets of our actions (e.g., the freshest fish, the ripest fruit). To be useful for selection, color must provide accurate guidance about object identity across changes in illumination. Although the visual system partially stabilizes object color appearance across illumination changes, how such color constancy supports object selection is not understood. To study how constancy operates in real-life tasks, we developed a novel paradigm in which subjects selected which of two test objects presented under a test illumination appeared closer in color to a target object presented under a standard illumination. From subjects' choices, we inferred a selection based match for the target via a variant of maximum likelihood difference scaling, and used it to quantify constancy. Selection-based constancy was good when measured using naturalistic stimuli, but was dramatically reduced when the stimuli were simplified, indicating that a naturalistic stimulus context is critical for good constancy. Overall, our results suggest that color supports accurate object selection across illumination changes when both stimuli and task match how color is used in real life. We compared our selection-based constancy results with data obtained using a classic asymmetric matching task and found that the adjustment-based matches predicted selection well for our stimuli and instructions, indicating that the appearance literature provides useful guidance for the emerging study of constancy in natural tasks. PMID- 26024462 TI - Saccadic inhibition and the remote distractor effect: One mechanism or two? AB - It has been hotly debated whether a single mechanism underlies two established and highly robust oculomotor phenomena thought to index the competitive nature of eye movement plans: the remote distractor effect and saccadic inhibition (SI). It has been suggested that a transient mechanism underlying SI would not be able to account for the shift in the saccade latency distribution produced by early distractors (e.g., those appearing 60 ms before target onset) without additional assumptions or a more sustained source of inhibition. Here we tested this prediction with a model previously optimized to capture SI for late distractors. Where behavioral studies have intermingled stimulus onset asynchronies (SOAs) within the same block, the model captures the pattern of RDEs and SI effects with no parameter changes. Where SOAs have been blocked behaviorally, the pattern of RDEs can also be captured by the same model architecture, but requires changes to the inputs of the model between SOAs. Such changes plausibly reflect likely changes in participants' expectations and attentional strategy across block types. PMID- 26024463 TI - Reduction of interference effect by low spatial frequency information priming in an emotional Stroop task. AB - The affective prediction hypothesis assumes that visual expectation allows fast and accurate processing of emotional stimuli. The prediction corresponds to what an object is likely to be. It therefore facilitates its identification by setting aside what the object is unlikely to be. It has then been suggested that prediction might be inevitably associated with the inhibition of irrelevant possibilities concerning the object to identify. Several studies highlighted that the facilitation of emotional perception depends on low spatial frequency (LSF) extraction. However, most of them used paradigms in which only the object to identify was present in the scene. As a consequence, there have yet been no studies investigating the efficiency of prediction in the visual perception of stimuli among irrelevant information. In this study, we designed a novel priming emotional Stroop task in which participants had to identify emotional facial expressions (EFEs) presented along with a congruent or incongruent word. To further investigate the role of early extraction of LSF information in top-down prediction during emotion recognition, the target EFE was primed with the same EFE filtered in LSF or high spatial frequency (HSF). Results reveal a reduction of the Stroop interference in the LSF compared to the HSF priming condition, which supports that visual expectation, depending on early LSF information extraction, facilitates the inhibition of irrelevant information during emotion recognition. PMID- 26024461 TI - Spatial integration of optic flow information in direction of heading judgments. AB - While we know that humans are extremely sensitive to optic flow information about direction of heading, we do not know how they integrate information across the visual field. We adapted the standard cue perturbation paradigm to investigate how young adult observers integrate optic flow information from different regions of the visual field to judge direction of heading. First, subjects judged direction of heading when viewing a three-dimensional field of random dots simulating linear translation through the world. We independently perturbed the flow in one visual field quadrant to indicate a different direction of heading relative to the other three quadrants. We then used subjects' judgments of direction of heading to estimate the relative influence of flow information in each quadrant on perception. Human subjects behaved similarly to the ideal observer in terms of integrating motion information across the visual field with one exception: Subjects overweighted information in the upper half of the visual field. The upper-field bias was robust under several different stimulus conditions, suggesting that it may represent a physiological adaptation to the uneven distribution of task-relevant motion information in our visual world. PMID- 26024464 TI - The role of sensory ocular dominance on through-focus visual performance in monovision presbyopia corrections. AB - Monovision presbyopia interventions exploit the binocular nature of the visual system by independently manipulating the optical properties of the two eyes. It is unclear, however, how individual variations in ocular dominance affect visual function in monovision corrections. Here, we examined the impact of sensory ocular dominance on visual performance in both traditional and modified monovision presbyopic corrections. We recently developed a binocular adaptive optics vision simulator to correct subjects' native aberrations and induce either modified monovision (1.5 D anisometropia, spherical aberration of +0.1 and -0.4 MUm in distance and near eyes, respectively, over 4 mm pupils) or traditional monovision (1.5 D anisometropia). To quantify both the sign and the degree of ocular dominance, we utilized binocular rivalry to estimate stimulus contrast ratios that yield balanced dominance durations for the two eyes. Through-focus visual acuity and contrast sensitivity were measured under two conditions: (a) assigning dominant and nondominant eye to distance and near, respectively, and (b) vice versa. The results revealed that through-focus visual acuity was unaffected by ocular dominance. Contrast sensitivity, however, was significantly improved when the dominant eye coincided with superior optical quality. We hypothesize that a potential mechanism behind this observation is an interaction between ocular dominance and binocular contrast summation, and thus, assignment of the dominant eye to distance or near may be an important factor to optimize contrast threshold performance at different object distances in both modified and traditional monovision. PMID- 26024466 TI - Learning-based saliency model with depth information. AB - Most previous studies on visual saliency focused on two-dimensional (2D) scenes. Due to the rapidly growing three-dimensional (3D) video applications, it is very desirable to know how depth information affects human visual attention. In this study, we first conducted eye-fixation experiments on 3D images. Our fixation data set comprises 475 3D images and 16 subjects. We used a Tobii TX300 eye tracker (Tobii, Stockholm, Sweden) to track the eye movement of each subject. In addition, this database contains 475 computed depth maps. Due to the scarcity of public-domain 3D fixation data, this data set should be useful to the 3D visual attention research community. Then, a learning-based visual attention model was designed to predict human attention. In addition to the popular 2D features, we included the depth map and its derived features. The results indicate that the extra depth information can enhance the saliency estimation accuracy specifically for close-up objects hidden in a complex-texture background. In addition, we examined the effectiveness of various low-, mid-, and high-level features on saliency prediction. Compared with both 2D and 3D state-of-the-art saliency estimation models, our methods show better performance on the 3D test images. The eye-tracking database and the MATLAB source codes for the proposed saliency model and evaluation methods are available on our website. PMID- 26024465 TI - Functional magnetic resonance imaging adaptation reveals a noncategorical representation of hue in early visual cortex. AB - Color names divide the fine-grained gamut of color percepts into discrete categories. A categorical transition must occur somewhere between the initial encoding of the continuous spectrum of light by the cones and the verbal report of the name of a color stimulus. Here, we used a functional magnetic resonance imaging (fMRI) adaptation experiment to examine the representation of hue in the early visual cortex. Our stimuli varied in hue between blue and green. We found in the early visual areas (V1, V2/3, and hV4) a smoothly increasing recovery from adaptation with increasing hue distance between adjacent stimuli during both passive viewing (Experiment 1) and active categorization (Experiment 2). We examined the form of the adaptation effect and found no evidence that a categorical representation mediates the release from adaptation for stimuli that cross the blue-green color boundary. Examination of the direct effect of stimulus hue on the fMRI response did, however, reveal an enhanced response to stimuli near the blue-green category border. This was largest in hV4 and when subjects were engaged in active categorization of the stimulus hue. In contrast with a recent report from another laboratory (Bird, Berens, Horner, & Franklin, 2014), we found no evidence for a categorical representation of color in the middle frontal gyrus. A post hoc whole-brain analysis, however, revealed several regions in the frontal cortex with a categorical effect in the adaptation response. Overall, our results support the idea that the representation of color in the early visual cortex is primarily fine grained and does not reflect color categories. PMID- 26024467 TI - Sprayed P25 scaffolds for high-efficiency mesoscopic perovskite solar cells. AB - Uniform, thickness-controllable and large-size mesoscopic TiO2 films based on commercial P25 nanoparticles are prepared by a spray method, which have been applied in the perovskite solar cells, achieving a high efficiency of 16%. This spray method shows promising application in the large-scale production of mesoscopic solar cells. PMID- 26024468 TI - Molecular Determinants of N-Acetylglucosamine Recognition and Turnover by N Acetyl-1-D-myo-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside Deacetylase (MshB). AB - Actinobacteria such as Mycobacterium tuberculosis use the unique thiol mycothiol (MSH) as their primary reducing agent and in the detoxification of xenobiotics. N Acetyl-1-D-myo-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase (MshB) is the metal-dependent deacetylase that catalyzes the deacetylation of N acetyl-1-D-myo-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside, the committed step in MSH biosynthesis. We previously used docking studies to identify specific side chains that may contribute as molecular determinants of MshB substrate specificity [Huang, X., and Hernick, M. (2014) Biopolymers 101, 406-417]. Herein, we probe the molecular basis of N-acetylglucosamine (GlcNAc) recognition and turnover by MshB using a combination of site-directed mutagenesis and kinetic studies (mutants examined, L19A, E47A, R68A, D95A, M98A, D146N, and F216A). Results from these studies indicate that MshB is unable to catalyze the turnover of GlcNAc upon loss of the Arg68 or Asp95 side chains, consistent with the proposal that these side chains make critical hydrogen bonding interactions with substrate. The activity of the D146N mutant is ~10-fold higher than that of the D146A mutant, suggesting that the ability to accept a hydrogen bond at this position contributes to GlcNAc substrate specificity. Because there does not appear to be a direct contact between Asp146 and substrate, this effect is likely mediated via positioning of other catalytically important residues. Finally, we probed side chains located on mobile loops and in a hydrophobic cavity and identified two additional side chains (Met98 and Glu47) that contribute to GlcNAc recognition and turnover by MshB. Together, results from these studies confirm some of the molecular determinants of GlcNAc substrate specificity by MshB, which should aid the development of MshB inhibitors. PMID- 26024469 TI - Guided current-induced skyrmion motion in 1D potential well. AB - Magnetic skyrmions are particle-like magnetization configurations which can be found in materials with broken inversion symmetry. Their topological nature allows them to circumvent around random pinning sites or impurities as they move within the magnetic layer, which makes them interesting as information carriers in memory devices. However, when the skyrmion is driven by a current, a Magnus force is generated which leads to the skyrmion moving away from the direction of the conduction electron flow. The deflection poses a serious problem to the realization of skyrmion-based devices, as it leads to skyrmion annihilation at the film edges. Here, we show that it is possible to guide the movement of the skyrmion and prevent it from annihilating by surrounding and compressing the skyrmion with strong local potential barriers. The compressed skyrmion receives higher contribution from the spin transfer torque, which results in the significant increase of the skyrmion speed. PMID- 26024470 TI - Selective Formic Acid Production via CO2 Reduction with Visible Light Using a Hybrid of a Perovskite Tantalum Oxynitride and a Binuclear Ruthenium(II) Complex. AB - A hybrid material consisting of CaTaO2N (a perovskite oxynitride semiconductor having a band gap of 2.5 eV) and a binuclear Ru(II) complex photocatalytically produced HCOOH via CO2 reduction with high selectivity (>99%) under visible light (lambda>400 nm). Results of photocatalytic reactions, spectroscopic measurements, and electron microscopy observations indicated that the reaction was driven according to a two-step photoexcitation of CaTaO2N and the Ru photosensitizer unit, where Ag nanoparticles loaded on CaTaO2N with optimal distribution mediated interfacial electron transfer due to reductive quenching. PMID- 26024471 TI - Comparison of Biochemical Markers of Muscle Damage and Inflammatory Response Between the Open Discectomy, Microsurgical Discectomy, and Microsurgical Discectomy Using Tubular Retractor. AB - BACKGROUND: One of the methods to compare the invasiveness of different surgical techniques objectively is to measure the levels of biochemical markers of systemic inflammatory response and muscle damage. METHODS: A total of 120 patients undergoing surgery for symptomatic disc herniation at L4-L5 and L5-S1 were enrolled in the study. Patients were operated on using open discectomy (OD), microsurgical discectomy (MD), or microsurgical discectomy with tubular retractor (MD-TUB). Myoglobin (MYO) and creatine kinase (CK) levels were used as indicators of muscle damage, and interleukin-6 (IL-6) and C-reactive protein (CRP) levels were used as indicators of systemic inflammatory response. Sampling and analysis of samples were performed preoperatively and on postoperative days 1, 3, and 7. Levels of postoperative low back pain and radicular pain were recorded on a 10 grade visual analog scale. Statistical evaluation was performed using the analysis of variance test. RESULTS: MYO concentrations in the MD-TUB group on postoperative day 1 were significantly lower than in the MD and OD groups. CK values on postoperative day 1 were significantly lower in microsurgical techniques (MD and MD-TUB) than in the OD group. The lowest IL-6 levels were found in the MD-TUB group, followed by the MD and OD groups. Differences in the IL-6 levels were significant between the groups on postoperative day 1. On all postoperative days that were monitored, values of CRP in the MD-TUB group were significantly lower compared with the MD and OD groups. Lower values in the MD group versus OD group were not statistically significant. CONCLUSION: All studied techniques showed similar efficacy in reducing radicular pain. The microsurgical diskectomy using a retractor in comparison with MD and OD is friendlier toward the paraspinal muscles, but the difference is significant only for the MYO levels. The total stress inflammatory response exhibited by patients undergoing the MD-TUB technique is significantly lower compared with the MD and OD techniques. PMID- 26024472 TI - Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions: Catalyst Identification and Optimization. AB - A procedure for Ni-catalyzed cross-coupling of ketone enolates with alkenyl halides has been developed. Intermolecular coupling of aromatic and aliphatic ketone lithium enolates with a variety of alkenyl halides is achieved in the presence of Ni(cod)2 catalyst (5 mol %), an N-heterocyclic carbene (NHC) ligand, and LiI (10 mol %) at 6-22 degrees C for 0.5-12 h with yields of up to 90%. During the initial development of this reaction, a misleading result with respect to the actual active catalyst was obtained using commercially available Q-Phos ligand, which was found to contain a trace of Pd metal contaminant sufficient to catalyze the reaction. However, under the final conditions optimized for Ni(cod)2 in the presence of an NHC ligand, Pd was incompetent as a catalyst. PMID- 26024474 TI - An Opposite Pattern to the Conventional Thermal Hypothesis: Temperature-Dependent Variation in Coloration of Adults of Saccharosydne procerus (Homoptera: Delphacidae). AB - Melanism is a common polymorphism in many insect species that also influences immune function. According to the thermal melanin hypothesis, ectothermic individuals from cooler environments have darker cuticles and higher polyphenol oxidase (PO) levels, which represent a better immunocompetence. In this study, the links among environmental temperature, melanism, and PO activity of Saccharosydne procerus (Matsumura) were examined. Most S. procerus have a black spot on their forewings at high temperatures in the field and in the laboratory. In PO activity assay, a positive association between PO level and temperature was found. Our results showed that a diversification of melanism occurred under different temperatures and that melanism in S. procerus presented an opposite pattern to the one proposed by the thermal hypothesis. PMID- 26024473 TI - Does smoke from biomass fuel contribute to anemia in pregnant women in Nagpur, India? A cross-sectional study. AB - BACKGROUND: Anemia affects upwards of 50% of pregnant women in developing countries and is associated with adverse outcomes for mother and child. We hypothesized that exposure to smoke from biomass fuel--which is widely used for household energy needs in resource-limited settings--could exacerbate anemia in pregnancy, possibly as a result of systemic inflammation. OBJECTIVE: To evaluate whether exposure to smoke from biomass fuel (wood, straw, crop residues, or dung) as opposed to clean fuel (electricity, liquefied petroleum gas, natural gas, or biogas) is an independent risk factor for anemia in pregnancy, classified by severity. METHODS: A secondary analysis was performed using data collected from a rural pregnancy cohort (N = 12,782) in Nagpur, India in 2011-2013 as part of the NIH-funded Maternal and Newborn Health Registry Study. Multinomial logistic regression was used to estimate the effect of biomass fuel vs. clean fuel use on anemia in pregnancy, controlling for maternal age, body mass index, education level, exposure to household tobacco smoke, parity, trimester when hemoglobin was measured, and receipt of prenatal iron and folate supplements. RESULTS: The prevalence of any anemia (hemoglobin < 11 g/dl) was 93% in biomass fuel users and 88% in clean fuel users. Moderate-to-severe anemia (hemoglobin < 10 g/dl) occurred in 53% and 40% of the women, respectively. Multinomial logistic regression showed higher relative risks of mild anemia in pregnancy (hemoglobin 10-11 g/dl; RRR = 1.38, 95% CI = 1.19-1.61) and of moderate-to-severe anemia in pregnancy (RRR = 1.79, 95% CI = 1.53-2.09) in biomass fuel vs. clean fuel users, after adjusting for covariates. CONCLUSION: In our study population, exposure to biomass smoke was associated with higher risks of mild and moderate-to-severe anemia in pregnancy, independent of covariates. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01073475. PMID- 26024475 TI - Conditioned Media from Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibits Melanogenesis by Promoting Proteasomal Degradation of MITF. AB - Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) secrete various beneficial molecules, which have anti-apoptotic activity and cell proliferation. However, the effect of hUCB-MSCs in melanogenesis is largely unclear. In this study, we show that conditioned media (CM) derived from hUCB MSCs inhibit melanogenesis by regulating microphthalmia-associated transcription factor (MITF) expression via the ERK signalling pathway. Treatment of hUCB-MSC-CM strongly inhibited the alpha-melanocyte stimulating hormone-induced hyperpigmentation in melanoma cells as well as melanocytes. Treatment of hUCB-MSC CM induced ERK1/2 activation in melanocytes. In addition, inhibition of ERK1/2 suppressed the anti-pigmentation activity of the hUCB-MSC-CM in melanocytes and in vitro artificial skin models. We also found that the expression of MITF was appreciably diminished while expression of phosphorylated MITF, which leads to its proteasomal degradation, was increased in cells treated with hUCB-MSC-CM. These results suggested that hUCB-MSC-CM significantly suppresses melanin synthesis via MITF degradation by the ERK pathway activation. PMID- 26024476 TI - Impact evaluation of Swiss Medical Board reports on routine care in Switzerland: a case study of PSA screening and treatment for rupture of anterior cruciate ligament. AB - QUESTIONS UNDER STUDY: Evidence-based recommendations play an important role in medical decision-making, but barriers to adherence are common. In Switzerland, the Swiss Medical Board (SMB) publishes evidence reports that conclude with recommendations. We assessed the impact of two SMB reports on service provision (2009: Recommendation of conservative treatment as first option for rupture of the anterior cruciate ligament of the knee; 2011: Recommendation against PSA screening for prostate cancer). METHODS: We performed an observational study and assessed quantitative data over time via interrupted times series analyses. The primary outcome was the quarterly number of performed prostate-specific antigen (PSA) tests and the annual rates of surgical ACL repair in patients with ACL rupture. Data were adjusted for time trends and relevant confounders. RESULTS: We analysed PSA tests in 662,874 outpatients from 2005-2013 and treatment data in 101,737 patients with knee injury from 1990-2011. For the number of PSA tests, the secular trend before the intervention showed a continuous but diminishing increase over time. A statistically significant reduction in tests was estimated immediately after the intervention, but a later return to the trend before the intervention cannot be ruled out. The rate of surgical ACL repair had already declined after the late 1990s to about 55% in 2009. No relevant additional change emerged in this secular trend after the intervention. CONCLUSIONS: Despite some evidence of a possible change, we did not find a sustained and significant impact of SMB recommendations in our case study. Further monitoring is needed to confirm or refute these findings. PMID- 26024479 TI - Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH) formulation may improve drug response and economic efficiency. OBJECTIVE: To evaluate the cost-effectiveness from a societal perspective of a switch from IR MPH to ER-MPH in patients who are sub-optimally treated. METHODS: A daily Markov cycle model covering a time-span of 10 years was developed including four different health states: (1) optimal response, (2) sub-optimal response, (3) discontinued treatment, and (4) natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS) and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs). Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios. RESULTS: Switching sub optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of ?4200 and ?5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations. CONCLUSIONS: This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens. PMID- 26024478 TI - Exon organization and novel alternative splicing of Ank3 in mouse heart. AB - Ankyrin-G is an adaptor protein that links membrane proteins to the underlying cytoskeletal network. Alternative splicing of the Ank3 gene gives rise to multiple ankyrin-G isoforms in numerous tissues. To date, only one ankyrin-G isoform has been characterized in heart and transcriptional regulation of the Ank3 gene is completely unknown. In this study, we describe the first comprehensive analysis of Ank3 expression in heart. Using a PCR-based screen of cardiac mRNA transcripts, we identify two new exons and 28 alternative splice variants of the Ank3 gene. We measure the relative expression of each splice variant using quantitative real-time PCR and exon-exon boundary spanning primers that specifically amplify individual Ank3 variants. Six variants are rarely expressed (<1%), while the remaining variants display similar expression patterns in three hearts. Of the five first exons in the Ank3 gene, exon 1d is only expressed in heart and skeletal muscle as it was not detected in brain, kidney, cerebellum, and lung. Immunoblot analysis reveals multiple ankyrin-G isoforms in heart, and two ankyrin-G subpopulations are detected in adult cardiomyocytes by immunofluorescence. One population co-localizes with the voltage-gated sodium channel NaV1.5 at the intercalated disc, while the other population expresses at the Z-line. Two of the rare splice variants excise a portion of the ZU5 motif, which encodes the minimal spectrin-binding domain, and these variants lack beta spectrin binding. Together, these data demonstrate that Ank3 is subject to complex splicing regulation resulting in a diverse population of ankyrin-G isoforms in heart. PMID- 26024477 TI - The EBNA-2 N-Terminal Transactivation Domain Folds into a Dimeric Structure Required for Target Gene Activation. AB - Epstein-Barr virus (EBV) is a gamma-herpesvirus that may cause infectious mononucleosis in young adults. In addition, epidemiological and molecular evidence links EBV to the pathogenesis of lymphoid and epithelial malignancies. EBV has the unique ability to transform resting B cells into permanently proliferating, latently infected lymphoblastoid cell lines. Epstein-Barr virus nuclear antigen 2 (EBNA-2) is a key regulator of viral and cellular gene expression for this transformation process. The N-terminal region of EBNA-2 comprising residues 1-58 appears to mediate multiple molecular functions including self-association and transactivation. However, it remains to be determined if the N-terminus of EBNA-2 directly provides these functions or if these activities merely depend on the dimerization involving the N-terminal domain. To address this issue, we determined the three-dimensional structure of the EBNA-2 N-terminal dimerization (END) domain by heteronuclear NMR spectroscopy. The END domain monomer comprises a small fold of four beta-strands and an alpha-helix which form a parallel dimer by interaction of two beta-strands from each protomer. A structure-guided mutational analysis showed that hydrophobic residues in the dimer interface are required for self-association in vitro. Importantly, these interface mutants also displayed severely impaired self association and transactivation in vivo. Moreover, mutations of solvent-exposed residues or deletion of the alpha-helix do not impair dimerization but strongly affect the functional activity, suggesting that the EBNA-2 dimer presents a surface that mediates functionally important intra- and/or intermolecular interactions. Our study shows that the END domain is a novel dimerization fold that is essential for functional activity. Since this specific fold is a unique feature of EBNA-2 it might provide a novel target for anti-viral therapeutics. PMID- 26024480 TI - When your decisions are not (quite) your own: action observation influences free choices. AB - A growing number of studies have begun to assess how the actions of one individual are represented in an observer. Using a variant of an action observation paradigm, four experiments examined whether one person's behaviour can influence the subjective decisions and judgements of another. In Experiment 1, two observers sat adjacent to each other and took turns to freely select and reach to one of two locations. Results showed that participants were less likely to make a response to the same location as their partner. In three further experiments observers were asked to decide which of two familiar products they preferred or which of two faces were most attractive. Results showed that participants were less likely to choose the product or face occupying the location of their partner's previous reaching response. These findings suggest that action observation can influence a range of free choice preferences and decisions. Possible mechanisms through which this influence occurs are discussed. PMID- 26024481 TI - The Unique Non-Catalytic C-Terminus of P37delta-PI3K Adds Proliferative Properties In Vitro and In Vivo. AB - The PI3K/Akt pathway is central for numerous cellular functions and is frequently deregulated in human cancers. The catalytic subunits of PI3K, p110, are thought to have a potential oncogenic function, and the regulatory subunit p85 exerts tumor suppressor properties. The fruit fly, Drosophila melanogaster, is a highly suitable system to investigate PI3K signaling, expressing one catalytic, Dp110, and one regulatory subunit, Dp60, and both show strong homology with the human PI3K proteins p110 and p85. We recently showed that p37delta, an alternatively spliced product of human PI3K p110delta, displayed strong proliferation-promoting properties despite lacking the catalytic domain completely. Here we functionally evaluate the different domains of human p37delta in Drosophila. The N-terminal region of Dp110 alone promotes cell proliferation, and we show that the unique C terminal region of human p37delta further enhances these proliferative properties, both when expressed in Drosophila, and in human HEK-293 cells. Surprisingly, although the N-terminal region of Dp110 and the C-terminal region of p37delta both display proliferative effects, over-expression of full length Dp110 or the N-terminal part of Dp110 decreases survival in Drosophila, whereas the unique C-terminal region of p37delta prevents this effect. Furthermore, we found that the N-terminal region of the catalytic subunit of PI3K p110, including only the Dp60 (p85)-binding domain and a minor part of the Ras binding domain, rescues phenotypes with severely impaired development caused by Dp60 over expression in Drosophila, possibly by regulating the levels of Dp60, and also by increasing the levels of phosphorylated Akt. Our results indicate a novel kinase independent function of the PI3K catalytic subunit. PMID- 26024482 TI - Correction: Susceptibility to chronic mucus hypersecretion, a genome wide association study. PMID- 26024483 TI - The tobacco endgame: is it possible? PMID- 26024484 TI - 1H HR-MAS NMR Based Metabolic Profiling of Cells in Response to Treatment with a Hexacationic Ruthenium Metallaprism as Potential Anticancer Drug. AB - (1)H high resolution magic angle spinning (HR-MAS) NMR spectroscopy was applied in combination with multivariate statistical analyses to study the metabolic response of whole cells to the treatment with a hexacationic ruthenium metallaprism [1](6+) as potential anticancer drug. Human ovarian cancer cells (A2780), the corresponding cisplatin resistant cells (A2780cisR), and human embryonic kidney cells (HEK-293) were each incubated for 24 h and 72 h with [1](6+) and compared to untreated cells. Different responses were obtained depending on the cell type and incubation time. Most pronounced changes were found for lipids, choline containing compounds, glutamate and glutathione, nucleotide sugars, lactate, and some amino acids. Possible contributions of these metabolites to physiologic processes are discussed. The time-dependent metabolic response patterns suggest that A2780 cells on one hand and HEK-293 cells and A2780cisR cells on the other hand may follow different cell death pathways and exist in different temporal stages thereof. PMID- 26024485 TI - Preparatory Body State before Reacting to an Opponent: Short-Term Joint Torque Fluctuation in Real-Time Competitive Sports. AB - In a competitive sport, the outcome of a game is determined by an athlete's relationship with an unpredictable and uncontrolled opponent. We have previously analyzed the preparatory state of ground reaction forces (GRFs) dividing non weighted and weighted states (i.e., vertical GRFs below and above 120% of body weight, respectively) in a competitive ballgame task and demonstrated that the non-weighted state prevented delay of the defensive step and promoted successful guarding. However, the associated kinetics of lower extremity joints during a competitive sports task remains unknown. The present study aims to investigate the kinetic characteristics of a real-time competitive sport before movement initiation. As a first kinetic study on a competitive sport, we initially compared the successful defensive kinetics with a relatively stable preparatory state and the choice-reaction sidestep as a control movement. Then, we investigated the kinetic cause of the outcome in a 1-on-1 dribble in terms of the preparatory states according to our previous study. The results demonstrated that in successful defensive motions in the non-weighted state guarding trial, the times required for the generation of hip abduction and three extension torques for the hip, knee, and ankle joints were significantly shortened compared with the choice-reaction sidestep, and hip abduction and hip extension torques were produced almost simultaneously. The sport-specific movement kinetics emerges only in a more-realistic interactive experimental setting. A comparison of the outcomes in the 1-on-1 dribble and preparatory GRF states showed that, in the non weighted state, the defenders guarded successfully in 68.0% of the trials, and the defender's initiation time was earlier than that in the weighted state (39.1%). In terms of kinetics, the root mean squares of the derivative of hip abduction and three extension torques in the non-weighted state were smaller than those in the weighted state, irrespective of the outcome. These results indicate that the preparatory body state as explained by short-term joint torque fluctuations before the defensive step would help explain the performance in competitive sports, and will give insights into understanding human adaptive behavior in unpredicted and uncontrolled environments. PMID- 26024486 TI - Aggregation of asphaltene model compounds using a porphyrin tethered to a carboxylic acid. AB - A Ni(II) porphyrin functionalized with an alkyl carboxylic acid (3) has been synthesized to model the chemical behavior of the heaviest portion of petroleum, the asphaltenes. Specifically, porphyrin 3 is used in spectroscopic studies to probe aggregation with a second asphaltene model compound containing basic nitrogen (4), designed to mimic asphaltene behavior. NMR spectroscopy documents self-association of the porphyrin and aggregation with the second model compound in solution, and a Job's plot suggests a 1 : 2 stoichiometry for compounds 3 and 4. PMID- 26024487 TI - The mesh of civilizations in the global network of digital communication. AB - Conflicts fueled by popular religious mobilization have rekindled the controversy surrounding Samuel Huntington's theory of changing international alignments in the Post-Cold War era. In The Clash of Civilizations, Huntington challenged Fukuyama's "end of history" thesis that liberal democracy had emerged victorious out of Post-war ideological and economic rivalries. Based on a top-down analysis of the alignments of nation states, Huntington famously concluded that the axes of international geo-political conflicts had reverted to the ancient cultural divisions that had characterized most of human history. Until recently, however, the debate has had to rely more on polemics than empirical evidence. Moreover, Huntington made this prediction in 1993, before social media connected the world's population. Do digital communications attenuate or echo the cultural, religious, and ethnic "fault lines" posited by Huntington prior to the global diffusion of social media? We revisit Huntington's thesis using hundreds of millions of anonymized email and Twitter communications among tens of millions of worldwide users to map the global alignment of interpersonal relations. Contrary to the supposedly borderless world of cyberspace, a bottom-up analysis confirms the persistence of the eight culturally differentiated civilizations posited by Huntington, with the divisions corresponding to differences in language, religion, economic development, and spatial distance. PMID- 26024489 TI - Winter Conditions and Land Cover Structure the Subnivium, A Seasonal Refuge beneath the Snow. AB - In seasonally snow-covered environments, many organisms endure winter by using the subnivium, a below-snow thermally stable seasonal refugium. Because the insulation of snow is dependent on snow depth and density, the stability of temperatures within the subnivium varies across land cover types. Additionally, across much of the Northern Hemisphere snow extent, depth and duration are generally decreasing while snow density is increasing due to climate change. These changes are likely to destabilize the thermal profile of the subnivium, although they have not yet been quantified. To explore the effects of land cover and climate change on the subnivium, we measured snow pack characteristics (depth and density), and ambient and subnivium temperatures from three different land cover types (prairie, deciduous forest, and coniferous forest) and within a micro greenhouse (2.5 x 2.5 x 2 m) that maintained a temperature of 5 degrees C warmer than outdoor ambient temperatures, and automatically opened during snow events throughout the winter of 2013/14. We found that the mean daily subnivium temperature was significantly colder in the deciduous cover type than the prairie cover type, and that prairie had higher maximum subnivium temperatures than both of the other cover types. Our climate change simulation revealed that, although ambient temperatures within the micro-greenhouse were 5 degrees C warmer than outside the greenhouse, the daily minimum subnivium temperature was significantly lower inside the greenhouse. Our findings suggest that climate change could have considerable effects on the refuge quality of the subnivium, and that some cover types appear to be more susceptible to these effects than others. PMID- 26024488 TI - Increasing live birth rate by preimplantation genetic screening of pooled polar bodies using array comparative genomic hybridization. AB - Meiotic errors during oocyte maturation are considered the major contributors to embryonic aneuploidy and failures in human IVF treatment. Various technologies have been developed to screen polar bodies, blastomeres and trophectoderm cells for chromosomal aberrations. Array-CGH analysis using bacterial artificial chromosome (BAC) arrays is widely applied for preimplantation genetic diagnosis (PGD) using single cells. Recently, an increase in the pregnancy rate has been demonstrated using array-CGH to evaluate trophectoderm cells. However, in some countries, the analysis of embryonic cells is restricted by law. Therefore, we used BAC array-CGH to assess the impact of polar body analysis on the live birth rate. A disadvantage of polar body aneuploidy screening is the necessity of the analysis of both the first and second polar bodies, resulting in increases in costs for the patient and complex data interpretation. Aneuploidy screening results may sometimes be ambiguous if the first and second polar bodies show reciprocal chromosomal aberrations. To overcome this disadvantage, we tested a strategy involving the pooling of DNA from both polar bodies before DNA amplification. We retrospectively studied 351 patients, of whom 111 underwent polar body array-CGH before embryo transfer. In the group receiving pooled polar body array-CGH (aCGH) analysis, 110 embryos were transferred, and 29 babies were born, corresponding to live birth rates of 26.4% per embryo and 35.7% per patient. In contrast, in the control group, the IVF treatment was performed without preimplantation genetic screening (PGS). For this group, 403 embryos were transferred, and 60 babies were born, resulting in live birth rates of 14.9% per embryo and 22.7% per patient. In conclusion, our data show that in the aCGH group, the use of aneuploidy screening resulted in a significantly higher live birth rate compared with the control group, supporting the benefit of PGS for IVF couples in addition to the suitability and effectiveness of our polar body pooling strategy. PMID- 26024490 TI - The prognosis of breast cancer patients after mastectomy and immediate breast reconstruction: a meta-analysis. AB - BACKGROUND: An increasing number of patients with breast cancer are being offered immediate breast reconstruction (IBR). The aim of this study was to analyze the impact of IBR on the prognosis of patients with breast cancer. METHODS: We searched the electronic databases of Medline (Pubmed), ISI Web of Knowledge, Embase, and Google Scholar databases for studies reporting the overall recurrence, disease-free survival (DFS), and overall survival (OS) of patients after mastectomy only and mastectomy with IBR. With these data, we conducted a meta-analysis of the clinical outcomes. RESULTS: Fourteen studies, including 3641 cases and 9462 controls, matched our criteria. Relevant information was extracted from these 14 studies. There was no significant heterogeneity (P for Q-statistic > 0.10 and I2 < 25%). Patients who underwent IBR showed no increased risk of overall recurrence of breast cancer (RR = 0.89; 95% confidence interval [CI]: 0.75, 1.04; P = 0.14). Furthermore, patients receiving IBR had similar DFS (RR = 1.04; 95%CI: 0.99, 1.08); P = 0.10) and OS (RR = 1.02; 95%CI: 0.99, 1.05; P = 0.24)) as those of control patients. CONCLUSION: This meta-analysis provides evidence that IBR does not have an adverse effect on prognosis. These data suggest that IBR is an appropriate and safe choice for patients with breast cancer. PMID- 26024491 TI - Effects of dietary linseed oil and propionate precursors on ruminal microbial community, composition, and diversity in Yanbian yellow cattle. AB - The rumen microbial ecosystem is a complex system where rumen fermentation processes involve interactions among microorganisms. There are important relationships between diet and the ruminal bacterial composition. Thus, we investigated the ruminal fermentation characteristics and compared ruminal bacterial communities using tag amplicon pyrosequencing analysis in Yanbian yellow steers, which were fed linseed oil (LO) and propionate precursors. We used eight ruminally cannulated Yanbian yellow steers (510 +/- 5.8 kg) in a replicated 4 * 4 Latin square design with four dietary treatments. Steers were fed a basal diet that comprised 80% concentrate and 20% rice straw (DM basis, CON). The CON diet was supplemented with LO at 4%. The LO diet was also supplemented with 2% dl malate or 2% fumarate as ruminal precursors of propionate. Dietary supplementation with LO and propionate precursors increased ruminal pH, total volatile fatty acid concentrations, and the molar proportion of propionate. The most abundant bacterial operational taxonomic units in the rumen were related to dietary treatments. Bacteroidetes dominated the ruminal bacterial community and the genus Prevotella was highly represented when steers were fed LO plus propionate precursors. However, with the CON and LO diet plus malate or fumarate, Firmicutes was the most abundant phylum and the genus Ruminococcus was predominant. In summary, supplementing the diets of ruminants with a moderate level of LO plus propionate precursors modified the ruminal fermentation pattern. The most positive responses to LO and propionate precursors supplementation were in the phyla Bacteriodetes and Firmicutes, and in the genus Ruminococcus and Prevotella. Thus, diets containing LO plus malate or fumarate have significant effects on the composition of the rumen microbial community. PMID- 26024492 TI - Utilization of Bacillus sp. strain TAT105 as a biological additive to reduce ammonia emissions during composting of swine feces. AB - Bacillus sp. strain TAT105 is a thermophilic, ammonium-tolerant bacterium that grows assimilating ammonium nitrogen and reduces ammonia emission during composting of swine feces. To develop a practical use of TAT105, a dried solid culture of TAT105 (5.3 * 10(9) CFU/g of dry matter) was prepared as an additive. It could be stored for one year without significant reduction of TAT105. Laboratory-scale composting of swine feces was conducted by mixing the additive. When the additive, mixed with an equal weight of water one day before use, was added to obtain a TAT105 concentration of above 10(7) CFU/g of dry matter in the initial material, the ammonia concentration emitted was lower and nitrogen loss was approximately 22% lower in the treatment with the additive than in the control treatment without the additive. The colony formation on an agar medium containing high ammonium could be used for enumeration of TAT105 in the composted materials. PMID- 26024493 TI - Extraordinary aluminum coordination in a novel homometallic double complex salt. AB - We have characterized a novel aluminum-based homometallic double complex salt, incorporating discrete octa-coordinated cationic [Al(G3)2](3+) and hexa coordinated anionic [Al(TfO)4(OH)2](3-) complexes (G3 = triglyme, TfO = trifluoromethanesulfonate). X-ray crystallography, Raman spectra, and DFT calculations demonstrate extraordinary weak Al(3+) coordination in [Al(G3)2](3+). PMID- 26024494 TI - Effects of meal frequency on weight loss and body composition: a meta-analysis. AB - It has been hypothesized that eating small, frequent meals enhances fat loss and helps to achieve better weight maintenance. Several observational studies lend support to this hypothesis, with an inverse relationship noted between the frequency of eating and adiposity. The purpose of this narrative review is to present and discuss a meta-analysis with regression that evaluated experimental research on meal frequency with respect to changes in fat mass and lean mass. A total of 15 studies were identified that investigated meal frequency in accordance with the criteria outlined. Feeding frequency was positively associated with reductions in fat mass and body fat percentage as well as an increase in fat-free mass. However, sensitivity analysis of the data showed that the positive findings were the product of a single study, casting doubt as to whether more frequent meals confer beneficial effects on body composition. In conclusion, although the initial results of this meta-analysis suggest a potential benefit of increased feeding frequencies for enhancing body composition, these findings need to be interpreted with circumspection. PMID- 26024496 TI - Effects of glucose load on cognitive functions in elderly people. AB - Glucose is the main fuel for the brain, and manipulation of the glucose supply may consequently affect brain function. The present review was conducted to provide an overview of studies that investigated the acute effects of glucose load on memory and other cognitive functions in elderly people. The effects of sucrose on cognition and suggested mechanisms were also explored. A total of twenty studies met the inclusion criteria. In the majority of studies, episodic memory was investigated and a beneficial role for glucose in that specific cognitive domain was suggested. Other cognitive domains, i.e., working memory, semantic memory, visual memory, information-processing speed, attention, executive function, and visual/spatial function, have been studied less frequently and evidence for a beneficial effect of glucose was equivocal. Mechanisms are suggested to be mainly related to the human body's need for glucose as a metabolic substrate for physiological mechanisms in both central and peripheral processes. PMID- 26024497 TI - Vitamin B12 in meat and dairy products. AB - Vitamin B12 is synthesized exclusively by microorganisms; therefore, humans must absorb it from food. Excellent sources of B12 are foods of ruminant origin, so dairy and meat products play an important role in efforts to meet the official daily B12 intake recommendation of 3.0 MUg. Concentrations of the vitamin vary within foods of ruminant origin, with the highest concentrations found in offal such as liver and kidney. In comparison, dairy products have much lower quantities of the vitamin. In bovine milk, the B12 concentration is stable with regard to breed, feed, season, and stage of lactation, but in ruminant meat, the amount of B12 can vary based on the feeding and husbandry of the animal as well as the cut of meat chosen and its preparation. Processing of ruminant food, including thermal treatment, usually diminishes the vitamin B12 concentration. This review summarizes the vitamin B12 content of foods and discusses the impact of food processing on vitamin content. The contribution of ruminant food sources to B12 intake is specifically evaluated, with its bioavailability taken into account. PMID- 26024495 TI - Taste perception, associated hormonal modulation, and nutrient intake. AB - It is well known that taste perception influences food intake. After ingestion, gustatory receptors relay sensory signals to the brain, which segregates, evaluates, and distinguishes the stimuli, leading to the experience known as "flavor." It is well accepted that five taste qualities - sweet, salty, bitter, sour, and umami - can be perceived by animals. In this review, the anatomy and physiology of human taste buds, the hormonal modulation of taste function, the importance of genetic chemosensory variation, and the influence of gustatory functioning on macronutrient selection and eating behavior are discussed. Individual genotypic variation results in specific phenotypes of food preference and nutrient intake. Understanding the role of taste in food selection and ingestive behavior is important for expanding our understanding of the factors involved in body weight maintenance and the risk of chronic diseases including obesity, atherosclerosis, cancer, diabetes, liver disease, and hypertension. PMID- 26024498 TI - Emerging role of alpha-lipoic acid in the prevention and treatment of bone loss. AB - Osteoporosis is a chronic disease associated with decreased bone density that afflicts millions of people worldwide. Current pharmacological treatments are limited, costly, and linked to several negative side effects. These factors are driving current interest in the clinical use of naturally occurring bioactive compounds to mitigate bone loss. Alpha-lipoic acid, a potent antioxidant and essential member of mitochondrial dehydrogenases, has shown considerable promise as an antiosteoclastogenic agent due to its potent reactive oxygen species scavenging capabilities along with a proven clinical safety record. Collectively, current data indicate that alpha-lipoic acid protects from bone loss via a 2 pronged mechanism involving inhibition of osteoclastogenic reactive oxygen species generation and upregulation of redox gene expression. PMID- 26024503 TI - Mechanical and molecular basis for the symmetrical division of the fission yeast nuclear envelope. AB - In fission yeast Schizosaccharomyces pombe, the nuclear envelope remains intact throughout mitosis and undergoes a series of symmetrical morphological changes when the spindle pole bodies (SPBs), embedded in the nuclear envelope, are pushed apart by elongating spindle microtubules. These symmetrical membrane shape transformations do not correspond to the shape behavior of an analogous system based on lipid vesicles. Here we report that the symmetry of the dividing fission yeast nucleus is ensured by SPB-chromosome attachments, as loss of kinetochore clustering in the vicinity of SPBs results in the formation of abnormal asymmetric shapes with long membrane tethers. We integrated these findings in a biophysical model, which explains the symmetry of the nuclear shapes on the basis of forces exerted by chromosomes clustered at SPBs on the extending nuclear envelope. Based on this analysis we conclude that the fission yeast nuclear envelope exhibits the same mechanical properties as simple lipid vesicles, but interactions with other cellular components, such as chromosomes, influence the nuclear shape during mitosis, allowing the formation of otherwise energetically unfavorable symmetrical dumbbell structures upon spindle elongation. The model allows us to explain the appearance of abnormal asymmetric shapes in fission yeast mutants with mis-segregated chromosomes as well as with altered nuclear membrane composition. PMID- 26024502 TI - Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. AB - IMPORTANCE: No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery. OBJECTIVE: To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle. INTERVENTIONS: Patients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers. RESULTS: Acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; P = .02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; P = .01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (P = .04). There was no significant effect of remote ischemic preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL2/1000; difference, 0.61; 95% CI, 0.27-0.86; P < .001). No adverse events were reported with remote ischemic preconditioning. CONCLUSIONS AND RELEVANCE: Among high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation. TRIAL REGISTRATION: German Clinical Trials Register Identifier: DRKS00005333. PMID- 26024504 TI - Maintaining homeostasis by decision-making. AB - Living organisms need to maintain energetic homeostasis. For many species, this implies taking actions with delayed consequences. For example, humans may have to decide between foraging for high-calorie but hard-to-get, and low-calorie but easy-to-get food, under threat of starvation. Homeostatic principles prescribe decisions that maximize the probability of sustaining appropriate energy levels across the entire foraging trajectory. Here, predictions from biological principles contrast with predictions from economic decision-making models based on maximizing the utility of the endpoint outcome of a choice. To empirically arbitrate between the predictions of biological and economic models for individual human decision-making, we devised a virtual foraging task in which players chose repeatedly between two foraging environments, lost energy by the passage of time, and gained energy probabilistically according to the statistics of the environment they chose. Reaching zero energy was framed as starvation. We used the mathematics of random walks to derive endpoint outcome distributions of the choices. This also furnished equivalent lotteries, presented in a purely economic, casino-like frame, in which starvation corresponded to winning nothing. Bayesian model comparison showed that--in both the foraging and the casino frames -participants' choices depended jointly on the probability of starvation and the expected endpoint value of the outcome, but could not be explained by economic models based on combinations of statistical moments or on rank-dependent utility. This implies that under precisely defined constraints biological principles are better suited to explain human decision-making than economic models based on endpoint utility maximization. PMID- 26024505 TI - Quenched pinning and collective dislocation dynamics. AB - Several experiments show that crystalline solids deform in a bursty and intermittent fashion. Power-law distributed strain bursts in compression experiments of micron-sized samples, and acoustic emission energies from larger scale specimens, are the key signatures of the underlying critical-like collective dislocation dynamics - a phenomenon that has also been seen in discrete dislocation dynamics (DDD) simulations. Here we show, by performing large-scale two-dimensional DDD simulations, that the character of the dislocation avalanche dynamics changes upon addition of sufficiently strong randomly distributed quenched pinning centres, present e.g. in many alloys as immobile solute atoms. For intermediate pinning strength, our results adhere to the scaling picture of depinning transitions, in contrast to pure systems where dislocation jamming dominates the avalanche dynamics. Still stronger disorder quenches the critical behaviour entirely. PMID- 26024506 TI - Nonequilibrium fluctuations as a distinctive feature of weak localization. AB - Two-dimensional materials, such as graphene, topological insulators, and two dimensional electron gases, represent a technological playground to develop coherent electronics. In these systems, quantum interference effects, and in particular weak localization, are likely to occur. These coherence effects are usually characterized by well-defined features in dc electrical transport, such as a resistivity increase and negative magnetoresistance below a crossover temperature. Recently, it has been shown that in magnetic and superconducting compounds, undergoing a weak-localization transition, a specific low-frequency 1/f noise occurs. An interpretation in terms of nonequilibrium universal conductance fluctuations has been given. The universality of this unusual electric noise mechanism has been here verified by detailed voltage-spectral density investigations on ultrathin copper films. The reported experimental results validate the proposed theoretical framework, and also provide an alternative methodology to detect weak-localization effects by using electric noise spectroscopy. PMID- 26024507 TI - Activation of the TOR Signalling Pathway by Glutamine Regulates Insect Fecundity. AB - The target of rapamycin (TOR) positively controls cell growth in response to nutrients such as amino acids. However, research on the specific nutrients sensed by TOR is limited. Glutamine (Gln), a particularly important amino acid involved in metabolism in organisms, is synthesised and catalysed exclusively by glutamine synthetase (GS), and our previous studies have shown that Gln may regulate fecundity in vivo levels of the brown planthopper (BPH) Nilaparvata lugens. Until now, it has remained unclear whether Gln activates or inhibits the TOR signalling pathway. Here, we performed the combined analyses of iTRAQ (isobaric tags for relative and absolute quantification) and DGE (tag-based digital gene expression) data in N. lugens at the protein and transcript levels after GS RNAi, and we found that 52 pathways overlap, including the TOR pathway. We further experimentally demonstrate that Gln activates the TOR pathway by promoting the serine/threonine protein kinase AKT and inhibiting the 5'AMP-activated protein kinase AMPK phosphorylation activity in the pest. Furthermore, TOR regulates the fecundity of N. lugens probably by mediating vitellogenin (Vg) expression. This work is the first report that Gln activates the TOR pathway in vivo. PMID- 26024508 TI - Quantum Anomalous Hall Effect in Graphene-based Heterostructure. AB - Quantum anomalous Hall (QAH) effect, with potential applications in low-power consumption electronics, is predicted in the heterostructure of graphene on the (001) surface of a real antiferromagnetic insulator RbMnCl3, based on density functional theory and Wannier function methods. Due to the interactions from the substrate, a much large exchange field (about 280 meV) and an enhanced Rashba spin-orbit coupling are induced in graphene, leading to a topologically nontrivial QAH gap opened in the system. The avenues of enhancing the nontrivial gap are also proposed, from which nearly a gap one order large is achieved. Our work demonstrates that this graphene-based heterostructure is an appropriate candidate to be employed to experimentally observe the QAH effect and explore the promising applications. PMID- 26024510 TI - Probing intermediate stages of shape processing. AB - The visual system provides a representation of what and where objects are. This entails parsing the visual scene into distinct objects. Initially, the visual system encodes information locally. While interactions between adjacent cells can explain how local fragments of an object's contour are extracted from a scene, such computations are ill suited to capture extended objects. This article reviews some of the evidence in favor of intermediate-level computations, tuned to the shape of an object, in the transformation from discrete local sampling to representation of complex objects. Two main paradigms, employed to study how information about the position and orientation of local signals are combined at intermediate levels, are considered here: a shape detection task (measuring the number of signal elements required to detect a shape in noise) and a shape discrimination task (requiring observers to discriminate between shapes). Results support the notion of global mechanisms that integrate information beyond neighboring cells and are optimally tuned to a range of different shapes. These intermediate processing stages appear vulnerable to damage. Diverse clinical conditions (amblyopia, macular disease, migraine, premature birth) show specific deficits for these tasks. Taken together, evidence is converging in favor of intermediate levels of processing, at which sensitivity to the global shape of objects emerges. PMID- 26024509 TI - Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress. AB - Oxidative stress (OS) is caused by an imbalance between pro- and anti-oxidant reactions leading to accumulation of reactive oxygen species within cells. We here investigate the effect of OS on the transcriptome of human fibroblasts. OS causes a rapid and transient global induction of transcription characterized by pausing of RNA polymerase II (PolII) in both directions, at specific promoters, within 30 minutes of the OS response. In contrast to protein-coding genes, which are commonly down-regulated, this novel divergent, PolII pausing-phenomenon leads to the generation of thousands of long noncoding RNAs (lncRNAs) with promoter associated antisense lncRNAs transcripts (si-paancRNAs) representing the major group of stress-induced transcripts. OS causes transient dynamics of si-lncRNAs in nucleus and cytosol, leading to their accumulation at polysomes, in contrast to mRNAs, which get depleted from polysomes. We propose that si-lncRNAs represent a novel component of the transcriptional stress that is known to determine the outcome of immediate-early and later cellular stress responses and we provide insights on the fate of those novel mature lncRNA transcripts by showing that their association with polysomal complexes is significantly increased in OS. PMID- 26024511 TI - Adaptive shape coding for perceptual decisions in the human brain. AB - In its search for neural codes, the field of visual neuroscience has uncovered neural representations that reflect the structure of stimuli of variable complexity from simple features to object categories. However, accumulating evidence suggests an adaptive neural code that is dynamically shaped by experience to support flexible and efficient perceptual decisions. Here, we review work showing that experience plays a critical role in molding midlevel visual representations for perceptual decisions. Combining behavioral and brain imaging measurements, we demonstrate that learning optimizes feature binding for object recognition in cluttered scenes, and tunes the neural representations of informative image parts to support efficient categorical judgements. Our findings indicate that similar learning mechanisms may mediate long-term optimization through development, tune the visual system to fundamental principles of feature binding, and optimize feature templates for perceptual decisions. PMID- 26024512 TI - Low-level properties of natural images predict topographic patterns of neural response in the ventral visual pathway. AB - Neuroimaging research over the past 20 years has begun to reveal a picture of how the human visual system is organized. A key distinction that has arisen from these studies is the difference in the organization of low-level and high-level visual regions. Low-level regions contain topographic maps that are tightly linked to properties of the image. In contrast, high-level visual areas are thought to be arranged in modules that are tightly linked to categorical or semantic information in the image. To date, an unresolved question has been how the strong functional selectivity for object categories in high-level visual regions might arise from the image-based representations found in low-level visual regions. Here, we review recent evidence suggesting that patterns of response in high-level visual areas may be better explained by response to image properties that are characteristic of different object categories. PMID- 26024513 TI - From orientations to objects: Configural processing in the ventral stream. AB - The ventral or form vision hierarchy comprises a sequence of cortical areas in which successively more complex visual attributes are extracted, beginning with contour orientations in V1 and culminating in face and object representations at the highest levels. In addition, ventral areas exhibit increasing receptive field diameter by a factor of approximately three from area to area, and conversely neuron density decreases. We argue here that this is consistent with configural combination of adjacent orientations to form curves or angles, followed by combination of these to form descriptions of object shapes. Substantial data from psychophysics, functional magnetic resonance imaging (fMRI), and neurophysiology support this organization, and computational models consistent with it have also been proposed. We further argue that a key to the role of the ventral stream is dimensionality reduction in object representations. PMID- 26024514 TI - Extreme ultra-low lasing threshold of full-polymeric fundamental microdisk printed with room-temperature atmospheric ink-jet technique. AB - We experimentally demonstrated an extreme ultra-low lasing threshold from full polymeric fundamental microdisk cavities fabricated by a novel fabrication method, the ink-jet printing method, which is much simpler and easier than previous methods such as lithography. The ink-jet printing method provides additive, room-temperature atmospheric, rapid fabrication with only two steps: (i) stacking cladding pedestal and waveguiding disk spots using the ink-jet technique, and (ii) partial etching of the cladding pedestal envelope. Two kinds of low-viscosity polymers successfully formed microdisks with high surface homogeneity, and one of the polymers doped with LDS798 dye yielded whispering gallery-mode lasing. The fundamental disks exhibited an extremely ultra-low lasing threshold of 0.33 MUJ/mm(2) at a wavelength of 817.3 nm. To the best of our knowledge, this lasing threshold is the lowest threshold obtained among both organic and inorganic fundamental microdisk cavity lasers with a highly confined structure. PMID- 26024515 TI - Ethnic Disparities in Emergency Severity Index Scores among U.S. Veteran's Affairs Emergency Department Patients. AB - BACKGROUND: The goal of these analyses was to determine whether there were systematic differences in Emergency Severity Index (ESI) scores, which are intended to determine priority of treatment and anticipate resource needs, across categories of race and ethnicity, after accounting for patient-presenting vital signs and examiner characteristics, and whether these differences varied among male and female Veterans Affairs (VA) ED patients. METHODS AND FINDINGS: We used a large national database of electronic medical records of ED patients from twenty-two U.S. Department of Veterans Affairs ED stations to determine whether ESI assignments differ systematically by race or ethnicity. Multi-level, random effects linear modeling was used to control for demographic characteristics and patient's vital signs (heart rate, respiratory rate, and pain level), as well as age, gender, and experience of triage nurses. The dataset included 129,991 VA patients presenting for emergency care between 2008 and 2012 (91% males; 61% non Hispanic White, 28% Black, 7% Hispanic, 2% Asian, <1% American Indian/Alaska Native, 1% mixed ethnicity) and 774 nurses for a total of 359,642 patient/examiner encounters. Approximately 13% of the variance in ESI scores was due to patient characteristics and 21% was due to the nurse characteristics. After controlling for characteristics of nurses and patients, Black patients were assigned less urgent ESI scores than White patients, and this effect was more prominent for Black males compared with Black females. A similar interaction was found for Hispanic males. It remains unclear how these results may generalize to EDs and patient populations outside of the U.S. VA Health Care system. CONCLUSIONS: The findings suggest the possibility that subgroups of VA patients receive different ESI ratings in triage, which may have cascading, downstream consequences for patient treatment quality, satisfaction with care, and trust in the health equity of emergency care. PMID- 26024516 TI - Vitamin D Status: A Different Story in the Very Young versus the Very Old Romanian Patients. AB - BACKGROUND: In Romania (latitude 48 degrees 15'N to 43 degrees 40'N), vitamin D supplementation is common practice mostly in infants 0-1 year old. No published information is available regarding epidemiological data on vitamin D status in the Romanian population for a wide age range and geographical territory. In this context, we aimed to evaluate the seasonal and age variation of vitamin D status in a large Romanian population. METHODS: 6631 individuals from across Romania had performed 7544 vitamin D assessments (2012-2014) in a chain of private laboratories. Vitamin D (25-hydroxyvitamin D2 and 25-hydroxyvitamin D3) was measured using High Performance Liquid Chromatography. Vitamin D levels were classified as severe deficiency<10 ng/mL, deficiency 10-20 ng/mL, insufficiency 21-29 ng/mL, sufficiency >= 30 ng/mL and potentially harmful>100 ng/ml. RESULTS: Male to female ratio was 1:2.9. Age ranged from 0 to 85 years. Mean vitamin D levels increased from April (26.3n g/ml) to September (35.6 ng/ml) and decreased from October (33.5 ng/ml) to March (24.4 ng/ml). Overall 40% had sufficient vitamin D, while the rest were insufficient 33%, deficient 22%, severely deficient 4% and 1% potentially harmful (of them 81% under 1 year old). Males compared to females showed higher percentages of sufficiency (47% vs. 38%). Children 0- 2 years presented the highest percentage of vitamin D sufficiency (77%). Lowest percentages (21%) of sufficiency were in people 80-84 years. CONCLUSION: In Romania, suboptimal vitamin D levels are common (59%), especially in older age, wintertime and in women. Vitamin D supplementation would be most warranted from January to April in the Romanian population. 25-hydroxyvitamin D levels > 100 ng/ml were relatively prevalent in children 0-1 year old (17.3%). This was attributed to supplementation errors and the fact that high-risk individuals were more likely to visit for medical check-up. Nonetheless, it stresses the need to increase awareness of the importance of preventing Vitamin D supplementation administration errors in the young. PMID- 26024518 TI - Crystallographic Study of the LUMI Intermediate of Squid Rhodopsin. AB - Upon absorption of light, the retinal chromophore in rhodopsin isomerizes from the 11-cis to the trans configuration, initiating a photoreaction cycle. The primary photoreaction state, bathorhodopsin (BATHO), relaxes thermally through lumirhodopsin (LUMI) into a photoactive state, metarhodopsin (META), which stimulates the conjugated G-protein. Previous crystallographic studies of squid and bovine rhodopsins have shown that the structural change in the primary photoreaction of squid rhodopsin is considerably different from that observed in bovine rhodopsin. It would be expected that there is a fundamental difference in the subsequent thermal relaxation process between vertebrate and invertebrate rhodopsins. In this work, we performed crystallographic analyses of the LUMI state of squid rhodopsin using the P62 crystal. When the crystal was illuminated at 100 K with blue light, a half fraction of the protein was converted into BATHO. This reaction state relaxed into LUMI when the illuminated crystal was warmed in the dark to 170 K. It was found that, whereas trans retinal is largely twisted in BATHO, it takes on a more planar configuration in LUMI. This relaxation of retinal is accompanied by reorientation of the Schiff base NH bond, the hydrogen-bonding partner of which is switched to Asn185 in LUMI. Unlike bovine rhodopsin, the BATHO-to-LUMI transition in squid rhodopsin was accompanied by no significant change in the position/orientation of the beta-ionone ring of retinal. PMID- 26024517 TI - Involvement of Intracellular and Mitochondrial Abeta in the Ameliorative Effects of Huperzine A against Oligomeric Abeta42-Induced Injury in Primary Rat Neurons. AB - Considerable studies indicate huperzine A is a promising natural product to suppress neuronal damages induced by beta-amyloid (Abeta), a key pathogenic event in the Alzheimer's disease (AD). As an extension, the present study for the first time explored whether the beneficial profiles of huperzine A against oligomeric Abeta(42) induced neurotoxicity are associated with the accumulation and detrimental function of intraneuronal/mitochondrial Abeta, on the basis of the emerging evidence that intracellular Abeta is more relevant to AD progression as compared with extracellular Abeta. Huperzine A treatment was shown to significantly attenuate the neurotoxicity of oligomeric Abeta(42), as demonstrated by increased neuronal viability. Interestingly, our results proved that exogenous Abeta(42) could accumulate intraneuronally in a dose- and time dependent manner, while huperzine A treatment markedly reduced the level of intracellular Abeta(42). Moreover, huperzine A treatment rescued mitochondrial dysfunction induced by oligomeric Abeta(42), including adenosine triphosphate (ATP) reduction, reactive oxygen species (ROS) overproduction and membrane potential depolarization. Further study demonstrated that huperzine A also significantly reduced the level of Abeta(42) in the mitochondria-enriched subcellular fractions, as well as the Abeta(42) fluorescent signals colocalized with mitochondrial marker. This study indicates that interfering intracellular Abeta especially mitochondrial Abeta accumulation, together with ameliorating Abeta-associated mitochondrial dysfunction, may contribute to the protective effects of huperzine A against Abeta neurotoxicity. Above results may shed more light on the pharmacological mechanisms of huperzine A and provide important clues for discovering novel therapeutic strategies for AD. PMID- 26024519 TI - Isolation of Catharanthus roseus (L.) G. Don Nuclei and Measurement of Rate of Tryptophan decarboxylase Gene Transcription Using Nuclear Run-On Transcription Assay. AB - BACKGROUND: An accurate assessment of transcription 'rate' is often desired to describe the promoter activity. In plants, isolation of transcriptionally active nuclei and their subsequent use in nuclear run-on assays has been challenging and therefore limit an accurate measurement of gene transcription 'rate'. Catharanthus roseus has emerged as a model medicinal plant as it exhibits an unsurpassed spectrum of chemodiversity, producing over 130 alkaloids through the terpenoid indole alkaloid (TIA) pathway and therefore serves as a 'molecular hub' to understand gene expression profiles. RESULTS: The protocols presented here streamline, adapt and optimize the existing methods of nuclear run-on assay for use in C. roseus. Here, we fully describe all the steps to isolate transcriptionally active nuclei from C. roseus leaves and utilize them to perform nuclear run-on transcription assay. Nuclei isolated by this method transcribed at a level consistent with their response to external stimuli, as transcription rate of TDC gene was found to be higher in response to external stimuli i.e. when seedlings were subjected to UV-B light or to methyl jasmonate (MeJA). However, the relative transcript abundance measured parallel through qRT-PCR was found to be inconsistent with the synthesis rate indicating that some post transcriptional events might have a role in transcript stability in response to stimuli. CONCLUSIONS: Our study provides an optimized, efficient and inexpensive method of isolation of intact nuclei and nuclear 'run-on' transcription assay to carry out in-situ measurement of gene transcription rate in Catharanthus roseus. This would be valuable in investigating the transcriptional and post transcriptional response of other TIA pathway genes in C. roseus. Isolated nuclei may also provide a resource that could be used for performing the chip assay as well as serve as the source of nuclear proteins for in-vitro EMSA studies. Moreover, nascent nuclear run-on transcript could be further subjected to RNA-Seq for global nuclear run-on assay (GNRO-Seq) for genome wide in-situ measurement of transcription rate of plant genes. PMID- 26024521 TI - Effect of High-Flux Dialysis on Circulating FGF-23 Levels in End-Stage Renal Disease Patients: Results from a Randomized Trial. AB - BACKGROUND: In patients undergoing maintenance hemodialysis (HD), increased levels of circulating fibroblast growth factor-23 (FGF-23) are independently associated with cardiovascular events and mortality. Interventional strategies aiming to reduce levels of FGF-23 in HD patients are of particular interest. The purpose of the current study was to compare the impact of high-flux versus low flux HD on circulating FGF-23 levels. METHODS: We conducted a post-hoc analysis of the MINOXIS study, including 127 dialysis patients randomized to low-flux (n = 62) and high-flux (n = 65) HD for 52 weeks. Patients with valid measures for FGF 23 investigated baseline and after 52 weeks were included. RESULTS: Compared to baseline, a significant increase in FGF-23 levels after one year of low-flux HD was observed (Delta plasma FGF-23: +4026 RU/ml; p < 0.001). In contrast, FGF-23 levels remained stable in the high flux group (Delta plasma FGF-23: +373 RU/ml, p = 0.70). The adjusted difference of the absolute change in FGF-23 levels between the two treatment groups was statistically significant (p < 0.01). CONCLUSIONS: Over a period of 12 months, high-flux HD was associated with stable FGF-23 levels, whereas the low-flux HD group showed an increase of FGF-23. However, the implications of the different FGF 23 time-trends in patients on high flux dialysis, as compared to the control group, remain to be explored in specifically designed clinical trials. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00007612. PMID- 26024520 TI - Radiosynthesis of 6'-Deoxy-6'[18F]Fluorosucrose via Automated Synthesis and Its Utility to Study In Vivo Sucrose Transport in Maize (Zea mays) Leaves. AB - Sugars produced from photosynthesis in leaves are transported through the phloem tissues within veins and delivered to non-photosynthetic organs, such as roots, stems, flowers, and seeds, to support their growth and/or storage of carbohydrates. However, because the phloem is located internally within the veins, it is difficult to access and to study the dynamics of sugar transport. Radioactive tracers have been extensively used to study vascular transport in plants and have provided great insights into transport dynamics. To better study sucrose partitioning in vivo, a novel radioactive analog of sucrose was synthesized through a completely chemical synthesis route by substituting fluorine-18 (half-life 110 min) at the 6' position to generate 6'-deoxy 6'[(18)F]fluorosucrose ((18)FS). This radiotracer was then used to compare sucrose transport between wild-type maize plants and mutant plants lacking the Sucrose transporter1 (Sut1) gene, which has been shown to function in sucrose phloem loading. Our results demonstrate that (18)FS is transported in vivo, with the wild-type plants showing a greater rate of transport down the leaf blade than the sut1 mutant plants. A similar transport pattern was also observed for universally labeled [U-(14)C]sucrose ([U-(14)C]suc). Our findings support the proposed sucrose phloem loading function of the Sut1 gene in maize, and additionally demonstrate that the (18)FS analog is a valuable, new tool that offers imaging advantages over [U-(14)C]suc for studying phloem transport in plants. PMID- 26024522 TI - Evidence for a Novel Mechanism of Influenza Virus-Induced Type I Interferon Expression by a Defective RNA-Encoded Protein. AB - Influenza A virus (IAV) defective RNAs are generated as byproducts of error-prone viral RNA replication. They are commonly derived from the larger segments of the viral genome and harbor deletions of various sizes resulting in the generation of replication incompatible viral particles. Furthermore, small subgenomic RNAs are known to be strong inducers of pattern recognition receptor RIG-I-dependent type I interferon (IFN) responses. The present study identifies a novel IAV-induced defective RNA derived from the PB2 segment of A/Thailand/1(KAN-1)/2004 (H5N1). It encodes a 10 kDa protein (PB2?) sharing the N-terminal amino acid sequence of the parental PB2 protein followed by frame shift after internal deletion. PB2? induces the expression of IFNbeta and IFN-stimulated genes by direct interaction with the cellular adapter protein MAVS, thereby reducing viral replication of IFN sensitive viruses such as IAV or vesicular stomatitis virus. This induction of IFN is completely independent of the defective RNA itself that usually serves as pathogen-associated pattern and thus does not require the cytoplasmic sensor RIG I. These data suggest that not only defective RNAs, but also some defective RNA encoded proteins can act immunostimulatory. In this particular case, the KAN-1 induced defective RNA-encoded protein PB2? enhances the overwhelming immune response characteristic for highly pathogenic H5N1 viruses, leading to a more severe phenotype in vivo. PMID- 26024523 TI - MicroRNAs and Metabolites in Serum Change after Chemotherapy: Impact on Hematopoietic Stem and Progenitor Cells. AB - Hematopoietic regeneration after high dose chemotherapy necessitates activation of the stem cell pool. There is evidence that serum taken after chemotherapy comprises factors stimulating proliferation and self-renewal of CD34(+) hematopoietic stem and progenitor cells (HSPCs)--however, the nature of these feedback signals is yet unclear. Here, we addressed the question if specific microRNAs (miRNAs) or metabolites are affected after high dose chemotherapy. Serum taken from the same patients before and after chemotherapy was supplemented for in vitro cultivation of HSPCs. Serum taken after chemotherapy significantly enhanced HSPC proliferation, better maintained a CD34(+) immunophenotype, and stimulated colony forming units. Microarray analysis revealed that 23 miRNAs changed in serum after chemotherapy--particularly, miRNA-320c and miRNA-1275 were down-regulated whereas miRNA-3663-3p was up-regulated. miRNA-320c was exemplarily inhibited by an antagomiR, which seemed to increase proliferation. Metabolomic profiling demonstrated that 44 metabolites were less abundant, whereas three (including 2-hydroxybutyrate and taurocholenate sulphate) increased in serum upon chemotherapy. Nine of these metabolites were subsequently tested for effects on HSPCs in vitro, but none of them exerted a clear concentration dependent effect on proliferation, immunophenotype and colony forming unit formation. Taken together, serum profiles of miRNAs and metabolites changed after chemotherapy. Rather than individually, these factors may act in concert to recruit HSPCs into action for hematopoietic regeneration. PMID- 26024524 TI - Baseline Goblet Cell Mucin Secretion in the Airways Exceeds Stimulated Secretion over Extended Time Periods, and Is Sensitive to Shear Stress and Intracellular Mucin Stores. AB - Airway mucin secretion studies have focused on goblet cell responses to exogenous agonists almost to the exclusion of baseline mucin secretion (BLMS). In human bronchial epithelial cell cultures (HBECCs), maximal agonist-stimulated secretion exceeds baseline by ~3-fold as measured over hour-long periods, but mucin stores are discharged completely and require 24 h for full restoration. Hence, over 24 h, total baseline exceeds agonist-induced secretion by several-fold. Studies with HBECCs and mouse tracheas showed that BLMS is highly sensitive to mechanical stresses. Harvesting three consecutive 1 h baseline luminal incubations with HBECCs yielded equal rates of BLMS; however, lengthening the middle period to 72 h decreased the respective rate significantly, suggesting a stimulation of BLMS by the gentle washes of HBECC luminal surfaces. BLMS declined exponentially after washing HBECCs (t1/2 = 2.75 h), to rates approaching zero. HBECCs exposed to low perfusion rates exhibited spike-like increases in BLMS when flow was jumped 5 fold: BLMS increased >4 fold, then decreased within 5 min to a stable plateau at 1.5-2-fold over control. Higher flow jumps induced proportionally higher BLMS increases. Inducing mucous hyperplasia in HBECCs increased mucin production, BLMS and agonist-induced secretion. Mouse tracheal BLMS was ~6-fold higher during perfusion, than when flow was stopped. Munc13-2 null mouse tracheas, with their defect of accumulated cellular mucins, exhibited similar BLMS as WT, contrary to predictions of lower values. Graded mucous metaplasia induced in WT and Munc13-2 null tracheas with IL-13, caused proportional increases in BLMS, suggesting that naive Munc13-2 mouse BLMS is elevated by increased mucin stores. We conclude that BLMS is, [i] a major component of mucin secretion in the lung, [ii] sustained by the mechanical activity of a dynamic lung, [iii] proportional to levels of mucin stores, and [iv] regulated differentially from agonist-induced mucin secretion. PMID- 26024526 TI - Correction: The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study. PMID- 26024525 TI - Short-Term PTEN Inhibition Improves In Vitro Activation of Primordial Follicles, Preserves Follicular Viability, and Restores AMH Levels in Cryopreserved Ovarian Tissue From Cancer Patients. AB - INTRODUCTION: In vitro activation and growth of primordial dormant follicles to produce fertilizable oocytes would provide a useful instrument for fertility preservation. The employment of Phosphatase and TENsin homolog (PTEN) inhibitors, in combination with Protein kinase B (Akt) stimulating molecules, has been previously employed to increase follicular activation through the stimulation of the PTEN-Akt pathway. METHODS: We aim to establish improved in vitro activation also for cancer patients whose ovarian tissue has already been cryopreserved. Fresh and previously cryopreserved human ovarian cortex were exposed to short term, low-concentration and ovary-specific treatment with only a PTEN inhibitor. RESULTS: Our in vitro activation protocol enhances the activation mechanisms of primordial follicles in both fresh and cryopreserved samples, and enlarges growing populations without inducing apoptosis in either follicles or the surrounding stroma. Treatment augments estradiol secretion and restores the expression levels of the previously diminished Anti-Mullerian hormone by means of cryopreservation procedures. Genomic modulation of the relative expression of PTEN pathway genes was found in treated samples. CONCLUSION: The in vitro activation protocol offers new alternatives for patients with cryopreserved tissue as it increases the pool of viable activated follicles available for in vitro growth procedures. The combination of ovarian tissue cryopreservation and in vitro activation of primordial follicles, the main ovarian reserve component, will be a major advancement in fertility preservation. PMID- 26024527 TI - Cell kinetic studies fail to identify sequentially proliferating progenitors as the major source of epithelial renewal in the adult murine prostate. AB - There is evidence that stem cells and their progeny play a role in the development of the prostate. Although stem cells are also considered to give rise to differentiated progeny in the adult prostate epithelium ex vivo, the cohort of adult prostate stem cells in vivo as well as the mechanisms by which the adult prostate epithelium is maintained and regenerated remain highly controversial. We have attempted to resolve this conundrum by performing in vivo tracing of serially replicating cells after the sequential administration of two thymidine analogues to mice. Our results show that, during normal prostate homeostasis, sequentially proliferating cells are detected at a rate that is consistent with a stochastic process. These findings indicate that in vivo, under steady-state conditions, most adult prostate epithelial cells do not represent the progeny of a small number of specialized progenitors that generate sequentially replicating transit-amplifying (TA) cells but are formed by stochastic cell division. Similarly, no rapidly cycling TA cells were detected during regeneration following one cycle of androgen-mediated involution/regeneration of the prostate epithelium. These findings greatly enhance our understanding of the mechanisms regulating prostate epithelial cell renewal and may have significant implications in defining the cell of origin of proliferative prostatic diseases. PMID- 26024528 TI - Harnessing case isolation and ring vaccination to control Ebola. AB - As a devastating Ebola outbreak in West Africa continues, non-pharmaceutical control measures including contact tracing, quarantine, and case isolation are being implemented. In addition, public health agencies are scaling up efforts to test and deploy candidate vaccines. Given the experimental nature and limited initial supplies of vaccines, a mass vaccination campaign might not be feasible. However, ring vaccination of likely case contacts could provide an effective alternative in distributing the vaccine. To evaluate ring vaccination as a strategy for eliminating Ebola, we developed a pair approximation model of Ebola transmission, parameterized by confirmed incidence data from June 2014 to January 2015 in Liberia and Sierra Leone. Our results suggest that if a combined intervention of case isolation and ring vaccination had been initiated in the early fall of 2014, up to an additional 126 cases in Liberia and 560 cases in Sierra Leone could have been averted beyond case isolation alone. The marginal benefit of ring vaccination is predicted to be greatest in settings where there are more contacts per individual, greater clustering among individuals, when contact tracing has low efficacy or vaccination confers post-exposure protection. In such settings, ring vaccination can avert up to an additional 8% of Ebola cases. Accordingly, ring vaccination is predicted to offer a moderately beneficial supplement to ongoing non-pharmaceutical Ebola control efforts. PMID- 26024529 TI - Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis. AB - BACKGROUND: Chronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase. METHODS: Liver samples from patients with chronic HBV (n = 91), normal liver (n = 55) and regenerating liver (n = 15) were studied. Immunohistochemistry for cell cycle phase markers and HBV antigens was used to determine host cell cycle phase. Hepatocyte-specific telomere length was evaluated by quantitative fluorescent in-situ hybridization (Q-FISH) in conjunction with hepatocyte nuclear area and HBV antigen expression. The effects of induced cell cycle arrest and induced cellular senescence on HBV production were assessed in vitro. RESULTS: 13.7% hepatocytes in chronic HBV had entered cell cycle, but expression of markers for S, G2 and M phase was low compared with regenerating liver. Hepatocyte p21 expression was increased (10.9%) in chronic HBV and correlated with liver fibrosis. Mean telomere length was reduced in chronic HBV compared to normal. However, within HBV-affected livers, hepatocytes expressing HBV antigens had longer telomeres. Telomere length declined and hepatocyte nuclear size increased as HBV core antigen (HBcAg) expression shifted from the nucleus to cytoplasm. Nuclear co-expression of HBcAg and p21 was not observed. Cell cycle arrest induced in vitro was associated with increased HBV production, in contrast to in vitro induction of cellular senescence, which had no effect. CONCLUSION: Chronic HBV infection was associated with hepatocyte G1 cell cycle arrest and accelerated hepatocyte ageing, implying that HBV induced cellular senescence. However, HBV replication was confined to biologically younger hepatocytes. Changes in the cellular location of HBcAg may be related to the onset of cellular senescence. PMID- 26024530 TI - Deletion of a 4977-bp Fragment in the Mitochondrial Genome Is Associated with Mitochondrial Disease Severity. AB - Large deletions in mitochondrial DNA (mtDNA) may be involved in the pathogenesis of mitochondrial disease. In this study, we investigated the relationship between a 4,977-bp deletion in the mitochondrial genome (DeltamtDNA(4977)) and the severity of clinical symptoms in patients with mitochondrial disease lacking known point mutations. A total of 160 patients with mitochondrial disease and 101 healthy controls were recruited for this study. The copy numbers of DeltamtDNA(4977) and wild-type mtDNA were determined by real-time quantitative PCR and analyzed using Spearman's bivariate correlation analysis, t-tests, or one way ANOVA. The overall DeltamtDNA(4977) copy number per cell and the proportion of mtDNA(4977) relative to the total wild-type mtDNA, increased with patient age and symptom severity. Surprisingly, the total mtDNA copy number decreased with increasing symptom severity. Our analyses revealed that increases in the proportion and total copy number of DeltamtDNA(4977) in the blood may be associated with disease severity in patients with mitochondrial dysfunction. PMID- 26024531 TI - Application of a drug-induced apoptosis assay to identify treatment strategies in recurrent or metastatic breast cancer. AB - BACKGROUND: A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes. METHODS: In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users), or elect to not use the test (non-users). RESULTS: The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73%) used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR) rate compared to non users (38.1% vs 0%, p = 0.04) and a higher disease control (CR+PR+Stable) rate (81% vs 25%, p<0.01). Time to relapse was longer in users 7.4 mo compared to non users 2.2 mo (p<0.01). CONCLUSIONS: The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay. TRIAL REGISTRATION: Clinicaltrials.gov NCT00901264. PMID- 26024532 TI - Impact of a clinical decision model for febrile children at risk for serious bacterial infections at the emergency department: a randomized controlled trial. AB - OBJECTIVES: To assess the impact of a clinical decision model for febrile children at risk for serious bacterial infections (SBI) attending the emergency department (ED). METHODS: Randomized controlled trial with 439 febrile children, aged 1 month-16 years, attending the pediatric ED of a Dutch university hospital during 2010-2012. Febrile children were randomly assigned to the intervention (clinical decision model; n = 219) or the control group (usual care; n = 220). The clinical decision model included clinical symptoms, vital signs, and C reactive protein and provided high/low-risks for "pneumonia" and "other SBI". Nurses were guided by the intervention to initiate additional tests for high-risk children. The clinical decision model was evaluated by 1) area-under-the-receiver operating-characteristic-curve (AUC) to indicate discriminative ability and 2) feasibility, to measure nurses' compliance to model recommendations. Primary patient outcome was defined as correct SBI diagnoses. Secondary process outcomes were defined as length of stay; diagnostic tests; antibiotic treatment; hospital admission; revisits and medical costs. RESULTS: The decision model had good discriminative ability for both pneumonia (n = 33; AUC 0.83 (95% CI 0.75-0.90)) and other SBI (n = 22; AUC 0.81 (95% CI 0.72-0.90)). Compliance to model recommendations was high (86%). No differences in correct SBI determination were observed. Application of the clinical decision model resulted in less full-blood counts (14% vs. 22%, p-value < 0.05) and more urine-dipstick testing (71% vs. 61%, p-value < 0.05). CONCLUSIONS: In contrast to our expectations no substantial impact on patient outcome was perceived. The clinical decision model preserved, however, good discriminatory ability to detect SBI, achieved good compliance among nurses and resulted in a more standardized diagnostic approach towards febrile children, with less full blood-counts and more rightfully urine-dipstick testing. TRIAL REGISTRATION: Nederlands Trial Register NTR2381. PMID- 26024533 TI - The Role of PPARgamma in Advanced Glycation End Products-Induced Inflammatory Response in Human Chondrocytes. AB - OBJECTIVE: Advances made in the past ten years highlight the notion that peroxisome proliferator-activated receptors gamma (PPARgamma) has protective properties in the pathophysiology of osteoarthritis (OA). The aim of this study was to define the roles of PPARgamma in AGEs-induced inflammatory response in human chondrocytes. METHODS: Primary human chondrocytes were stimulated with AGEs in the presence or absence of neutralizing antibody against RAGE (anti-RAGE), MAPK specific inhibitors and PPARgamma agonist pioglitazone. The expression of IL 1, MMP-13, TNF-alpha, PPARgamma, nuclear NF-kappaB p65 and cytosol IkappaBalpha was determined by western blotting and real-time PCR. RESULTS: AGEs could enhance the expression of IL-1, TNF-alpha, and MMP-13, but the level of PPARgamma was decreased in a time- and dose-dependent manner, which was inhibited by anti-RAGE, SB203580 (P38 MAPK specific inhibitor) and SP600125 (a selective inhibitor of JNK). PPARgamma agonist pioglitazone could inhibit the effects of AGEs-induced inflammatory response and PPARgamma down-regulation. In human chondrocytes, AGEs could induce cytosol IkappaBalpha degradation and increase the level of nuclear NF-kappaB p65, which was inhibited by PPARgamma agonist pioglitazone. CONCLUSIONS: In primary human chondrocytes, AGEs could down-regulate PPARgamma expression and increase the inflammatory mediators, which could be reversed by PPARgamma agonist pioglitazone. Activation of RAGE by AGEs triggers a cascade of downstream signaling, including MAPK JNK/ p38, PPARgamma and NF-kappaB. Taken together, PPARgamma could be a potential target for pharmacologic intervention in the treatment of OA. PMID- 26024534 TI - Steadiness of Spinal Regions during Single-Leg Standing in Older Adults with and without Chronic Low Back Pain. AB - The aims of this study were to compare the steadiness index of spinal regions during single-leg standing in older adults with and without chronic low back pain (LBP) and to correlate measurements of steadiness index with the performance of clinical balance tests. Thirteen community-dwelling older adults (aged 55 years or above) with chronic LBP and 13 age- and gender-matched asymptomatic volunteers participated in this study. Data collection was conducted in a university research laboratory. Measurements were steadiness index of spinal regions (trunk, thoracic spine, lumbar spine, and pelvis) during single-leg standing including relative holding time (RHT) and relative standstill time (RST), and clinical balance tests (timed up and go test and 5-repetition sit to stand test). The LBP group had a statistically significantly smaller RHT than the control group, regardless of one leg stance on the painful or non-painful sides. The RSTs on the painful side leg in the LBP group were not statistically significantly different from the average RSTs of both legs in the control group; however, the RSTs on the non-painful side leg in the LBP group were statistically significantly smaller than those in the control group for the trunk, thoracic spine, and lumbar spine. No statistically significant intra-group differences were found in the RHTs and RSTs between the painful and non-painful side legs in the LBP group. Measurements of clinical balance tests also showed insignificant weak to moderate correlations with steadiness index. In conclusion, older adults with chronic LBP demonstrated decreased spinal steadiness not only in the symptomatic lumbar spine but also in the other spinal regions within the kinetic chain of the spine. When treating older adults with chronic LBP, clinicians may also need to examine their balance performance and spinal steadiness during balance challenging tests. PMID- 26024536 TI - Combined effects of interaction between physical activity and nutrition on bone health in children and adolescents: a systematic review. AB - CONTEXT: Osteoporosis is a major public health concern worldwide. Understanding the roles of diet and physical activity in ensuring adequate bone mass accrual during childhood and adolescence may help identify strategies to reduce the risk of osteoporotic fractures later in life. OBJECTIVE: The present systematic review was conducted to provide an overview of the current knowledge of the combined effects of physical activity and diet on bone mass accrual in children and adolescents. DATA SOURCES: Data were obtained via searches of the PubMed, EMBASE, SPORTDiscus, and ISI Web of Science databases. STUDY SELECTION: Studies published in English and Spanish between 1887 and August 2013 were eligible for inclusion. Two investigators evaluated the studies against the inclusion and exclusion criteria. A total of 14 studies (7 cross-sectional and 7 experimental) were included in the review. DATA EXTRACTION: The Pedro score and the Black and Down's checklist were used to evaluate the methodological quality of the experimental and the cross-sectional studies, respectively. Study characteristics were summarized in accordance with the review's PICO criteria. DATA SYNTHESIS: Significant exercise-by-calcium interaction was detected at several different bone sites. CONCLUSIONS: Although the results of cross-sectional studies were inconsistent, the results of randomized controlled trials showed that exercise has the potential to improve bone health under conditions of adequate calcium intake. PMID- 26024537 TI - Glucose transporters: cellular links to hyperglycemia in insulin resistance and diabetes. AB - Abnormal expression and/or function of mammalian hexose transporters contribute to the hallmark hyperglycemia of diabetes. Due to different roles in glucose handling, various organ systems possess specific transporters that may be affected during the diabetic state. Diabetes has been associated with higher rates of intestinal glucose transport, paralleled by increased expression of both active and facilitative transporters and a shift in the location of transporters within the enterocyte, events that occur independent of intestinal hyperplasia and hyperglycemia. Peripheral tissues also exhibit deregulated glucose transport in the diabetic state, most notably defective translocation of transporters to the plasma membrane and reduced capacity to clear glucose from the bloodstream. Expression of renal active and facilitative glucose transporters increases as a result of diabetes, leading to elevated rates of glucose reabsorption. However, this may be a natural response designed to combat elevated blood glucose concentrations and not necessarily a direct effect of insulin deficiency. Functional foods and nutraceuticals, by modulation of glucose transporter activity, represent a potential dietary tool to aid in the management of hyperglycemia and diabetes. PMID- 26024535 TI - Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. AB - Oxidative stress has been known to be involved in pathogenesis of dry eye disease. However, few studies have comprehensively investigated the relationship between hyperosmolarity and oxidative damage in human ocular surface. This study was to explore whether and how hyperosmolarity induces oxidative stress markers in primary human corneal epithelial cells (HCECs). Primary HCECs were established from donor limbal explants. The hyperosmolarity model was made in HCECs cultured in isosmolar (312 mOsM) or hyperosmotic (350, 400, 450 mOsM) media. Production of reactive oxygen species (ROS), oxidative damage markers, oxygenases and anti oxidative enzymes were analyzed by DCFDA kit, RT-qPCR, immunofluorescent and immunohistochemical staining and Western blotting. Compared to isosmolar medium, ROS production significantly increased at time- and osmolarity-dependent manner in HCECs exposed to media with increasing osmolarities (350-450 mOsM). Hyperosmolarity significantly induced oxidative damage markers in cell membrane with increased toxic products of lipid peroxidation, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and in nuclear and mitochondria DNA with increased aconitase-2 and 8-OHdG. Hyperosmotic stress also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), but reduced the levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), and glutathione peroxidase-1 (GPX1). In conclusion, our comprehensive findings demonstrate that hyperosmolarity induces oxidative stress in HCECs by stimulating ROS production and disrupting the balance of oxygenases and antioxidant enzymes, which in turn cause cell damage with increased oxidative markers in membrane lipid peroxidation and mitochondrial DNA damage. PMID- 26024538 TI - Curcumin and cancer: barriers to obtaining a health claim. AB - Curcumin is a highly pleiotropic molecule found in the rhizomes of Curcuma longa (turmeric). It is responsible for the yellow color of turmeric and has been shown to inhibit the proliferation of cancer cells and to be of use in preventing or treating a number of diseases. Curcumin has been shown to modulate multiple cell signaling pathways simultaneously, thereby mitigating or preventing many different types of cancers, including multiple myeloma and colorectal, pancreatic, breast, prostate, lung, head, and neck cancers, in both animal models and humans. Current therapeutic approaches using a single cancer drug for a single target can be expensive, have serious side effects, or both. Consequently, new approaches to the treatment and prevention of cancer, including the integration of curcumin as a viable treatment strategy where dysregulation of many pathways is involved, are warranted. A methodical review of the evidence was performed to evaluate the effects of curcumin in support of a health claim, as established through the regulatory framework of Health Canada, for a relationship between the consumption of curcumin and the prevention and treatment of cancer. PMID- 26024540 TI - Main characteristics of metabolically obese normal weight and metabolically healthy obese phenotypes. AB - In this review, the influence of fat depots on insulin resistance and the main characteristics of metabolically obese normal-weight and metabolically healthy obese phenotypes are discussed. Medline/PubMed and Science Direct were searched for articles related to the terms metabolically healthy obesity, metabolically obese normal weight, adipose tissue, and insulin resistance. Normal weight and obesity might be heterogeneous in regard to their effects. Fat distribution and lower insulin sensitivity are the main factors defining phenotypes within the same body mass index. Although these terms are interesting, controversies about them remain. Future studies exploring these phenotypes will help elucidate the roles of adiposity and/or insulin resistance in the development of metabolic alterations. PMID- 26024539 TI - Modulation of prenatal stress via docosahexaenoic acid supplementation: implications for child mental health. AB - Pregnant women living in poverty experience chronic and acute stressors that may lead to alterations in circulating glucocorticoids. Experimental evidence from animal models and correlational studies in humans support the hypothesis that prenatal exposure to high levels of glucocorticoids can negatively affect the developing fetus and later emotional and behavioral regulation in the offspring. In this integrative review, recent findings from research in psychiatry, obstetrics, and animal and human experimental studies on the role of docosahexaenoic acid in modulation of the stress response and brain development are discussed. The potential for an emerging field of nutritionally based perinatal preventive interventions for improving offspring mental health is described. Prenatal nutritional interventions may prove to be effective approaches to reducing common childhood mental disorders. PMID- 26024544 TI - Qualitative aspects of diet affecting visceral and subcutaneous abdominal adipose tissue: a systematic review of observational and controlled intervention studies. AB - CONTEXT: Knowledge of the role that qualitative as opposed to energy aspects of diet play in the accumulation of visceral abdominal adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAAT) is limited and not conclusive. OBJECTIVE: A systematic review was conducted to evaluate and summarize the existing literature investigating the relationships between qualitative aspects of diet, from single dietary components to overall dietary patterns, and VAT and SAAT. DATA SOURCES: The PubMed, Web of Science, Embase, and Cochrane databases were searched. STUDY SELECTION: Observational and controlled intervention studies that assessed healthy adults or adolescents using magnetic resonance imaging, computed tomography, dual-energy X-ray absorptiometry, or ultrasound were eligible for inclusion. After quality assessment of all eligible studies, 20 observational and 23 controlled intervention studies were included. DATA SYNTHESIS: Considering study quality, including nutritional and abdominal adipose tissue assessment, about 30 caloric and noncaloric qualitative aspects of diet were found "to be associated with or affect" VAT and/or SAAT, most notably, medium-chain triacylglycerols, dietary fiber, calcium, phytochemicals, and dietary patterns; for fructose and alcohol, the relationships were less clear. CONCLUSION: Additional well-designed prospective studies are warranted to confirm current findings and to identify further qualitative aspects of diet that may influence VAT and SAAT accumulation. PMID- 26024545 TI - Dietary flavonoids and nitrate: effects on nitric oxide and vascular function. AB - Emerging evidence highlights dietary flavonoids and nitrate as candidates that may explain at least part of the cardioprotective effect of a fruit and vegetable diet. Nitric oxide plays a pivotal role in cardiovascular health. Components of a fruit and vegetable diet that are cardioprotective, in part through effects on nitric oxide status, could substantially reduce the cardiovascular risk profile of the general population with increased intake of such a diet. Epidemiological evidence suggests that dietary flavonoids and nitrate have a cardioprotective effect. Clinical trials with flavonoid- and nitrate-rich foods have shown benefits on measures of vascular health. While the molecular mechanisms by which flavonoids and nitrate are cardioprotective are not completely understood, recent evidence suggests both nonspecific and specific effects through nitric oxide pathways. This review presents an overview of nitric oxide and its key role in cardiovascular health and discusses the possible vascular benefits of flavonoids and nitrate, individually and in combination, through effects on nitric oxide status. PMID- 26024546 TI - Effect of tea on blood pressure for secondary prevention of cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials. AB - CONTEXT: Tea has been proposed as an antihypertensive agent for individuals with elevated blood pressure, yet the evidence for this has not been systematically reviewed to date. OBJECTIVE: The aim of this review was to evaluate the effects of tea on blood pressure in individuals within the prehypertensive and hypertensive blood pressure ranges. DATA SOURCES: The CENTRAL, PubMed, Embase, and Web of Science databases were searched for all relevant studies published from 1946 to September 27, 2013. STUDY SELECTION: The selection criteria included randomized controlled trials of adults whose blood pressure was within hypertensive or prehypertensive ranges and in which the applied intervention was green or black tea; controls consisting of placebo, minimal tea intervention, or no intervention; and a follow-up period of at least 2 months. DATA EXTRACTION: Two reviewers independently extracted data on participants, interventions, comparators, outcomes, and study design. Mean differences (MDs) and 95% confidence intervals (95%CIs) were pooled to generate summary effect estimates. RESULTS: Meta-analyses of 10 trials (834 participants) showed statistically significant reductions in systolic blood pressure (MD -2.36 mmHg, 95%CI -4.20 to 0.52) and diastolic blood pressure (MD -1.77 mmHg, 95%CI -3.03 to -0.52) with tea consumption. CONCLUSIONS: Consumption of green or black tea can reduce blood pressure in individuals within prehypertensive and hypertensive ranges, although further investigation with studies of longer duration and stronger methodological quality is warranted to confirm these findings. PMID- 26024547 TI - Energy drinks and adolescents: what's the harm? AB - Concerns about potential dangers from energy drink consumption by youth have been raised by health experts, whereas energy drink manufacturers claim these products are safe and suitable for marketing to teens. This review summarizes the evidence used to support both sides of the debate. Unlike most beverage categories, sales of energy drinks and other highly caffeinated products continue to grow, and marketing is often targeted to youth under the age of 18 years. These products pose a risk of caffeine toxicity when consumed by some young people, and there is evidence of other troubling physiological and behavioral effects associated with their consumption by youth. The US Food and Drug Administration has indicated it will reexamine the safety of caffeine in the food supply; however, more research is needed to better understand youth consumption of energy drinks and caffeine in general, as well as the long-term effects on health. Meanwhile, policymakers and physician groups have called on energy drink manufacturers to take voluntary action to reduce the potential harm of their products, including placing restrictions on marketing to youth under the age of 18 years. Additional regulatory and legislative options are also being discussed. PMID- 26024551 TI - Effect of Carbohydrate and Caffeine Ingestion on Badminton Performance. AB - PURPOSE: To investigate the effect of ingesting carbohydrate and caffeine solutions on measures that are central to success in badminton. METHODS: Twelve male badminton players performed a badminton serve-accuracy test, coincidence anticipation timing (CAT), and a choice reaction-time sprint test 60 min before exercise. Participants then consumed 7 mL/kg body mass of either water (PLA), 6.4% carbohydrate solution (CHO), a solution containing a caffeine dose of 4 mg/kg, or 6.4% carbohydrate and 4 mg/kg caffeine (C+C). All solutions were flavored with orange-flavored concentrate. During the 33-min fatigue protocol, participants were provided with an additional 3 mL/kg body mass of solution, which was ingested before the end of the protocol. As soon as the 33-min fatigue protocol was completed, all measures were recorded again. RESULTS: Short-serve accuracy was improved after the ingestion of CHO and C+C compared with PLA (P = .001, eta(p)(2) = .50). Long-serve accuracy was improved after the ingestion of C+C compared with PLA (P < .001, eta(p)(2) = .53). Absolute error in CAT demonstrated smaller deteriorations after the ingestion of C+C compared with PLA (P < .05; slow, eta(p)(2) = .41; fast, eta(p)(2) = .31). Choice reaction time improved in all trials with the exception of PLA, which demonstrated a reduction (P < .001, eta(p)(2) = .85), although C+C was faster than all trials (P < .001, eta(p)(2) = .76). CONCLUSION: These findings suggest that the ingestion of a caffeinated carbohydrate solution before and during a badminton match can maintain serve accuracy, anticipation timing, and sprinting actions around the court. PMID- 26024552 TI - Biomechanical Analysis of a Change-of-Direction Task in Collegiate Soccer Players. AB - This study aimed to investigate biomechanical parameters during a change-of direction task in college soccer players. Fourteen male and 12 female players performed a 10-m sprint with a 60 degrees change of direction at 5 m. Vertical and mediolateral ground-reaction force (GRF) and contact time were measured by having the subjects run in both directions while contacting a force plate with either their preferred (kicking) or nonpreferred leg. Using the midpoint between 2 pelvic markers, further parameters were evaluated: performance cutting angle and horizontal distance. Relationships between parameters, sex, and leg preference were analyzed. Significant correlations emerged between vertical and mediolateral GRF (r = .660-.909) and between contact time and performance cutting angle (r = -.598 to -.793). Sex differences were found for mediolateral GRF (P = .005), performance cutting angle (P = .043), and horizontal distance (P = .020). Leg differences were observed for vertical GRF (P = .029), performance cutting angle (P = .011), and horizontal distance (P = .012). This study showed that a sharper change of direction corresponded to a longer contact time, while no relationships were found with GRF. Moreover, measuring the angle revealed that the real path traveled was different from the theoretical one, highlighting the performance of sharper or more rounded execution. In conclusion, this study showed that specific biomechanical measurements can provide details about the execution of a change of direction, highlighting the ability of the nonpreferred leg to perform better directional changes. PMID- 26024553 TI - DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries. AB - Complex mixtures of DNA encoded small molecules may be readily interrogated via high-throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules that interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small molecule moieties of DELs are generally synthesized though a multistep process, and each chemical step is accomplished while it is simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein, protocols for 24 reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multistep synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reactions including BOC deprotection (under pH neutral conditions), carbamylation, and Sonogashira coupling. Last, step-by-step protocols for synthesizing functionalized DELs from trichloronitropyrimidine and trichloropyrimidine scaffolds are detailed. PMID- 26024554 TI - Oral vinorelbine plus cisplatin followed by maintenance oral vinorelbine as first line treatment for advanced non-small cell lung cancer. AB - PURPOSE: Vinorelbine plus cisplatin is a commonly used doublet for the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy of oral vinorelbine as maintenance therapy in advanced NSCLC. METHODS: This multicenter phase II open-label, non-comparative study was designed to evaluate the three-weekly combination of cisplatin 80 mg/m(2) on day 1 in combination with oral vinorelbine on day 1 and 8 in advanced NSCLC. RESULTS: Thirty-nine patients were enrolled; median age was 63 years (range 42-82). In the response-evaluable population (n = 38), objective response after induction therapy was observed in 18 (47 %) patients with two (5 %) patients achieving complete response. Stable disease was observed in nine (24 %) patients. The median duration of response was 6 months. Eighteen (46 %) patients received oral vinorelbine as maintenance therapy. The median PFS for the whole population and for the maintenance therapy group was 4.9 [95 % CI (2.8-6.9)] and 6.7 [95 % CI (3.7-9.7)] months, respectively, while the overall survival was 8.7 [95 % CI (5.4 11.9)] and 11 [95 % CI (8.3-13.7)] months, respectively. The main observed overall hematologic toxicities were grade 3 anemia (8 %) and grade 3/4 neutropenia (8 %). CONCLUSION: Maintenance therapy with single-agent oral vinorelbine is feasible and well tolerated; it seems to extend the efficacy of the combination regimen with the advantage of being convenient to patients. PMID- 26024555 TI - Prediction of local proximal tibial subchondral bone structural stiffness using subject-specific finite element modeling: Effect of selected density-modulus relationship. AB - BACKGROUND: Quantitative computed tomography based subject-specific finite element modeling has potential to clarify the role of subchondral bone alterations in knee osteoarthritis initiation, progression, and pain initiation. Calculation of bone elastic moduli from image data is a basic step when constructing finite element models. However, different relationships between elastic moduli and imaged density (known as density-modulus relationships) have been reported in the literature. The objective of this study was to apply seven different trabecular-specific and two cortical-specific density-modulus relationships from the literature to finite element models of proximal tibia subchondral bone, and identify the relationship(s) that best predicted experimentally measured local subchondral structural stiffness with highest explained variance and least error. METHODS: Thirteen proximal tibial compartments were imaged via quantitative computed tomography. Imaged bone mineral density was converted to elastic moduli using published density-modulus relationships and mapped to corresponding finite element models. Proximal tibial structural stiffness values were compared to experimentally measured stiffness values from in-situ macro-indentation testing directly on the subchondral bone surface (47 indentation points). FINDINGS: Regression lines between experimentally measured and finite element calculated stiffness had R(2) values ranging from 0.56 to 0.77. Normalized root mean squared error varied from 16.6% to 337.6%. INTERPRETATION: Of the 21 evaluated density-modulus relationships in this study, Goulet combined with Snyder and Schneider or Rho appeared most appropriate for finite element modeling of local subchondral bone structural stiffness. Though, further studies are needed to optimize density-modulus relationships and improve finite element estimates of local subchondral bone structural stiffness. PMID- 26024556 TI - Development and validation of HPLC-DAD method for the simultaneous determination of amoxicillin, metronidazole and rabeprazole sodium. Application to spiked simulated intestinal fluid samples. AB - This work deals with the development, validation and application of an HPLC-DAD method for the determination of a ternary mixture containing amoxicillin (AX), metronidazole (MZ) and the proton pump inhibitor rabeprazole sodium (RB). This triple therapy is used for treatment of Helicobacter pylori infection. Effective chromatographic separation between the three drugs was achieved using Thermo Hypersil BDS-C8 (4.6*250mm, 5MUm particle size) column and a mobile phase composed of phosphate buffer pH 7 and acetonitrile (70: 30, by volume). The mobile phase was pumped isocratically at a flow rate of 1 mL/min. Quantification of the analytes was based on measuring their peak areas at 230nm for both AX and RB, and at 319nm for MZ. AX, MZ and RB eluted at retention times 2.36, 3.55 and 8.72min respectively. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to linearity, ranges, precision, accuracy, selectivity, robustness, detection and quantification limits. The linear dynamic ranges were 25-250, 25-250 and 5-50MUg/mL for AX, MZ and RB respectively with correlation coefficients>0.9998. The validated method was successfully applied to the analysis of several laboratory-prepared mixtures as well as simulated intestinal fluid samples spiked with the three drugs. PMID- 26024557 TI - Giant Solitary Synovial Osteochondroma of the Subtalar Joint. AB - A rapidly progressing calcified mass was found in the left sinus tarsi in a 12 year-old female after a trivial ankle sprain. The lesion mimicked an aggressive lesion clinically and radiographically. Ultrasound-guided biopsy confirmed the diagnosis of a synovial chondroma. Excision of the tumor and partial synovectomy were performed. The histologic diagnosis was a solitary synovial osteochondroma. The condition had not recurred after a follow-up period of 12 months. PMID- 26024558 TI - Pathogenesis and Treatment Strategies for Pilon Fractures With Ankle Dislocation. AB - The present study investigated the pathogenesis and treatment strategies for pilon fractures with ankle dislocation. A total of 58 patients (47 males and 11 females) who had sustained pilon fractures with ankle dislocation were treated. The mean patient age was 48.1 years. Using the AO classification, 8 cases were type B2, 17 were type B3, and 33 were type C3. The dislocation was medial in 13 cases, lateral in 9, anterior in 11, posterior in 14, and longitudinal in 9. Radiologic examinations were conducted to evaluate the postoperative reduction, dislocation correction, fracture healing, and internal fixation. Ankle function was evaluated according to the Kofoed and Danborg scoring system. The patients were followed up for 4 to 27 months. Anatomic reduction was achieved in 39 cases (67.24%), good reduction in 13 (22.41%), and poor reduction in 6 (10.34%). No internal implant failure occurred, and the fractures had healed after 2 to 4.3 (mean 2.8) months. The rate of good or excellent ankle recovery was 84.00% for those with type B fractures, 75.76% for those with type C, 76.92% for those with medial dislocation, 77.78% for lateral dislocation, 81.82% for anterior dislocation, 78.57% for posterior dislocation, and 81.82% for longitudinal dislocation. Pilon fractures often occur with ankle dislocation in different directions. In such cases, the original anatomy should be restored and the longitudinal alignment recovered to minimize complications as much as possible. PMID- 26024559 TI - Distally Based Saphenous Neurocutaneous Perforator Flap: A Versatile Donor Site for Reconstruction of Soft Tissue Defects of the Medial Malleolar Region. AB - Repair of both simple and complex defects in the medial malleolar region continues to be a challenging task for surgeons because of the local paucity of soft tissue available for transfer. The popular neurocutaneous flap has provided a reliable and less technically demanding method for resurfacing defects of the lower extremities. We present our experience with the versatile design of the distally based saphenous neurocutaneous perforator flap to provide coverage of complex post-traumatic medial malleolar defects by harvesting multiple tissue components in various combinations. Our series included 11 patients (8 males [72.7%] and 3 females [27.3%]); mean age 39.2 (range 22 to 58) years, who were followed for a mean duration of 13.3 (range 9 to 18) months. Three flaps (27.3%) were harvested with massive subcutaneous tissue to obliterate dead space. The procedure was uneventful in 10 patients (90.9%). Venous congestion was noted in 1 patient (9.1%), in whom secondary healing was achieved with conservative treatment. PMID- 26024560 TI - Enchondroma of the Foot. AB - The present study is a review of 20 patients with enchondroma of the foot treated from January 2005 to March 2012. All patients were examined clinically, followed by an evaluation of their enchondroma of the foot radiographically and an assessment of the outcome of their surgical intervention. The patients' sex and age, enchondroma location, findings from imaging studies such as plain radiography, computed tomography, and magnetic resonance imaging, clinical findings, operative findings, and treatment outcomes were recorded. The average postoperative follow-up period was 24 months. Eighty percent of the tumors were located in the proximal phalanx and 14 (70%) patients presented with pathologic fracture. The plain radiographs and computed tomography findings revealed 13 (65%) cases of internal calcification and 11 (55%) with endosteal scalloping. A periosteal reaction was seen only in 4 (20%) cases. Magnetic resonance imaging of 11 (55%) patients showed low T1-weighted and high T2-weighted signal intensity in all cases. Internal septa and nodules with low T2-weighted signal intensity were observed in 9 (82%) out of 11 cases, and adjacent soft tissue edema was noted in 9 (82%). All patients underwent curettage of the tumor and bone grafting as their surgical treatment. No recurrence or postoperative complications were observed during the 24-month follow-up period. Enchondroma of the foot most frequently involves the proximal phalangeal bone and is often associated with pathologic fracture. The unique clinical signs and characteristic radiographic images are easily recognized, making this a relatively easy diagnosis. With appropriate treatment, a good surgical outcome can be expected. PMID- 26024561 TI - On the second order spatiochromatic structure of natural images. AB - We provide a theoretical analysis of some empirical facts about the second order spatiochromatic structure of natural images in color. In particular, we show that two simple assumptions on the covariance matrices of color images yield eigenvectors made by the Kronecker product of Fourier features times the triad given by luminance plus color opponent channels. The first of these assumptions is second order stationarity while the second one is commutativity between color correlation matrices. The validity of these assumptions and the predicted shape of the PCA components of color images are experimentally observed on two large image databases. As a by-product of this experimental study, we also provide novel data to support an exponential decay law of the spatiochromatic covariance between pairs of pixels as a function of their spatial distance. PMID- 26024562 TI - Valuing Quiet: An Economic Assessment of U.S. Environmental Noise as a Cardiovascular Health Hazard. AB - INTRODUCTION: Environmental noise pollution increases the risk for hearing loss, stress, sleep disruption, annoyance, and cardiovascular disease and has other adverse health impacts. Recent (2013) estimates suggest that more than 100 million Americans are exposed to unhealthy levels of noise. Given the pervasive nature and significant health effects of environmental noise pollution, the corresponding economic impacts may be substantial. METHODS: This 2014 economic assessment developed a new approach to estimate the impact of environmental noise on the prevalence and cost of key components of hypertension and cardiovascular disease in the U.S. By placing environmental noise in context with comparable environmental pollutants, this approach can inform public health law, planning, and policy. The effects of hypothetical national-scale changes in environmental noise levels on the prevalence and corresponding costs of hypertension and coronary heart disease were estimated, with the caveat that the national-level U.S. noise data our exposure estimates were derived from are >30 years old. RESULTS: The analyses suggested that a 5-dB noise reduction scenario would reduce the prevalence of hypertension by 1.4% and coronary heart disease by 1.8%. The annual economic benefit was estimated at $3.9 billion. CONCLUSIONS: These findings suggest significant economic impacts from environmental noise-related cardiovascular disease. Given these initial findings, noise may deserve increased priority and research as an environmental health hazard. PMID- 26024563 TI - In vitro and in vivo studies of the endocrine disrupting potency of cadmium in roach (Rutilus rutilus) liver. AB - Cadmium has been reported to exert estrogenic, antiestrogenic or both effects in vertebrate species. To elucidate the endocrine disrupting action of CdCl2, ex vivo and in vivo experiments were performed in roach (Rutilus rutilus). Roach liver explants were exposed to a range of CdCl2 concentrations alone (0.1-50MUM) or with an effective concentration (100nM) of 17beta-estradiol (E2). In addition, juvenile roach were intraperitoneally injected with CdCl2 (0.1-2.5mg/kg) with or without 1mg E2/kg. Subsequent analysis evaluated the effect of CdCl2 on vitellogenin (VTG) synthesis both at the mRNA and protein level, on estrogen receptors (eralpha and erbeta1) and on androgen receptor (ar) mRNA expression. Ex vivo and in vivo experiments indicated that CdCl2 is strongly anti-estrogenic as, when co-exposed to E2, CdCl2 significantly inhibited VTG production as well as vtg and eralpha mRNA expressions. Moreover, CdCl2 compromised the E2-mediated induction of the ar mRNA expression in vivo. PMID- 26024564 TI - Composition and potential origin of marine debris stranded in the Western Indian Ocean on remote Alphonse Island, Seychelles. AB - The abundance, composition, and potential sources of marine debris were investigated on remote Alphonse Island, during the austral winter 2013. A total of 4743 items, weighing 142 kg, were removed from 1 km of windward beach, facing the prevailing southeasterly trade winds. Our study demonstrates the prevalence of plastic debris as a world-wide marine contaminant. Characteristics of the debris suggest it originated primarily from land-based sources. To determine their potential geographic sources we used the Surface Current from Diagnostic model of near-surface ocean currents, forced by satellite sea level and wind data. While preliminary evidence indicated the Southeast Asia to be the main source of the flotsam, the model highlighted Somalia as another potential primary source. Our study concludes that most of the collected debris entered the sea as a result of inadequate waste management and demonstrates how anthropogenic waste can negatively impact even the most remote environments. PMID- 26024565 TI - Enamel thickness trends in Plio-Pleistocene hominin mandibular molars. AB - Enamel thickness continues to be an important morphological character in hominin systematics and is frequently invoked in dietary reconstructions of Plio Pleistocene hominin taxa. However, to date, the majority of published data on molar enamel thickness of Pliocene and early Pleistocene hominins derive from naturally fractured random surfaces of a small number of specimens. In this study we systematically analyze enamel thickness in a large sample of Plio-Pleistocene fossil hominins (n = 99), extant hominoids (n = 57), and modern humans (n = 30). Based on analysis of 2D mesial planes of section derived from microtomography, we examine both average and relative enamel thickness, and the distribution of enamel across buccal, occlusal, and lingual components of mandibular molars. Our results confirm the trend of increasing enamel thickness during the Pliocene that culminates in the thick enamel of the robust Australopithecus species, and then decreases from early Homo to recent modern humans. All hominin taxa share a regional average enamel thickness pattern of thick occlusal enamel and greater buccal than lingual enamel thickness. Pan is unique in exhibiting the thinnest average enamel thickness in the occlusal basin. Statistical analysis indicates that among Pliocene hominins enamel thickness is a weak taxonomic discriminator. The data underlying these results are included in a table in the Supplementary Online Material. PMID- 26024566 TI - Episodes of environmental stability versus instability in Late Cenozoic lake records of Eastern Africa. AB - Episodes of environmental stability and instability may be equally important for African hominin speciation, dispersal, and cultural innovation. Three examples of a change from stable to unstable environmental conditions are presented on three different time scales: (1) the Mid Holocene (MH) wet-dry transition in the Chew Bahir basin (Southern Ethiopian Rift; between 11 ka and 4 ka), (2) the MIS 5-4 transition in the Naivasha basin (Central Kenya Rift; between 160 ka and 50 ka), and (3) the Early Mid Pleistocene Transition (EMPT) in the Olorgesailie basin (Southern Kenya Rift; between 1.25 Ma and 0.4 Ma). A probabilistic age modeling technique is used to determine the timing of these transitions, taking into account possible abrupt changes in the sedimentation rate including episodes of no deposition (hiatuses). Interestingly, the stable-unstable conditions identified in the three records are always associated with an orbitally-induced decrease of insolation: the descending portion of the 800 kyr cycle during the EMPT, declining eccentricity after the 115 ka maximum at the MIS 5-4 transition, and after ~ 10 ka. This observation contributes to an evidence-based discussion of the possible mechanisms causing the switching between environmental stability and instability in Eastern Africa at three different orbital time scales (10,000 to 1,000,000 years) during the Cenozoic. This in turn may lead to great insights into the environmental changes occurring at the same time as hominin speciation, brain expansion, dispersal out of Africa, and cultural innovations and may provide key evidence to build new hypotheses regarding the causes of early human evolution. PMID- 26024567 TI - Interpreting human behavior from depositional rates and combustion features through the study of sedimentary microfacies at site Pinnacle Point 5-6, South Africa. AB - Using fine and coarse resolution geoarchaeological studies at the Middle Stone Age site of PP5-6 at Pinnacle Point, Mossel Bay, South Africa, we discovered different patterns of anthropogenic input and changes in behavior through time. Through the microfacies approach, we documented the various geogenic and anthropogenic processes that formed the deposits of the site. By deciphering large scale rate differences in the production of these microfacies we estimated anthropogenic input rates and therefore gained understanding of occupational duration and intensity. The PP5-6 sediments document occupations characterized by small groups and short visits during Marine Isotope Stage (MIS) 5. This part of the sequence is characterized by numerous single (and mostly intact) hearth structures in a roofspall-rich matrix. During this time the sea was very close to the site and the people were focused on exploiting the rocky shores. With the advent of the glacial conditions of MIS4, the occupation of the site became much more intense. The occurrence of thick palimpsests of burnt remains, sometimes disturbed by small-scale sedimentary gravity processes, supports this conclusion. As sea level dropped and the coastline retreated, the geogenic input shifted to predominately aeolian sediments, implying an exposed shelf probably associated with a rich but more distant coastal environment. The occupants of PP5-6 turned their preference to silcrete as a raw material and they began to make microlithic stone tools. Since sites dating to MIS4 are abundant in the Cape, we suggest that populations during MIS4 responded to glacial conditions with either demographic stability or growth as well as technological change. PMID- 26024568 TI - Breakthrough Lactobacillus rhamnosus GG bacteremia associated with probiotic use in an adult patient with severe active ulcerative colitis: case report and review of the literature. AB - BACKGROUND: Probiotics are widely investigated in the treatment of various bowel diseases. However, they may also have a pathogenic potential, and the role of Lactobacillus spp. as opportunistic pathogens, mostly following disruption of the intestinal mucosa, is emerging. CASE REPORT: We report on a case of bacteremia caused by L. rhamnosus GG in an adult patient affected by severe active ulcerative colitis under treatment with corticosteroids and mesalazine. Lactobacillus bacteremia was associated with candidemia and occurred while the patient was receiving a probiotic formulation containing the same strain (as determined by PFGE typing), and was being concomitantly treated with i.v. vancomycin, to which the Lactobacillus strain was resistant. L. rhamnosus GG bacteremia, therefore, was apparently related with translocation of bacteria from the intestinal lumen to the blood. CONCLUSIONS: Pending conclusive evidence, use of probiotics should be considered with caution in case of active severe inflammatory bowel diseases with mucosal disruption. PMID- 26024569 TI - Sulfonylurea Prescribing Patterns After the Introduction of DPP-4 Inhibitors and GLP-1 Receptor Agonists. AB - PURPOSE: Although newer agents (dipeptidyl peptidase [DPP]-4 inhibitors and glucagon-like peptide [GLP]-1 receptor agonists) are available for the treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), the impact of the availability of these agents on the use of second-generation sulfonylureas (SUs) is unknown. This article presents percentages of patients prescribed SUs, using data from the National Ambulatory Medical Care Survey (NAMCS). The associations between SU prescribing and prespecified variables of interest were also explored. METHODS: The NAMCS database was queried for visits of patients aged >=18 years with an International Classification of Diseases, Ninth Revision diagnostic code relevant to T2DM. chi(2) tests were conducted to assess the associations between SU use and year-group (2003-2004, 2007-2008, or 2009-2010) and other variables of interest. A multivariate logistic regression model was constructed to jointly assess the value of these variables in predicting SU use. All analyses were weighted using procedures recommended by the National Center for Health Statistics. FINDINGS: Data from 7042 eligible visits were included, representing an extrapolated national estimate of 280,733,405 patient visits. The percentages of patients who received a prescription for an SU, by study year, were 25.7%, 23.4%, and 23.7% in 2003 to 2004, 2007 to 2008, and 2009 to 2010, respectively (P = 0.57). In the multivariate model, age >=70 years, male sex, nonwhite race, primary care physician seen, and concurrent DPP-4 inhibitor use were significantly associated with SU use. IMPLICATIONS: No significant decrease in the use of SUs was observed after the introduction of DPP-4 inhibitors and GLP 1 receptor agonists. However, patient-specific factors (eg, select demographic variables, site of care, and concurrent medication use) were associated with SU use. PMID- 26024570 TI - Response to "No clinically significant lymphocyte count change in pediatric patients treated with levetiracetam". PMID- 26024573 TI - Ginsenosides and their metabolites: a review of their pharmacological activities in the skin. AB - Ginsenosides are representative pharmaceutical compounds found in various forms in Panax ginseng, a traditional medicinal plant. They are converted to their metabolites Rg2, Rg3, compound K, and others by human intestinal microflora following ingestion. Numerous studies have demonstrated beneficial effects of ginsenosides against aberrant molecular processes responsible for cancer, metabolic diseases and neurodegenerative diseases. Recently, antiaging effects of ginsenosides in human skin have been reported from clinical trial and in vitro model data. Ginsenosides have hence been proposed as promising natural cosmeceutical agents. In this review, we will critically review the known biological effects of several ginsenosides (Rb1, Rg3, Rd and compound K), such as anti-inflammatory and anticancer activities, which arise from the modulation of diverse molecular pathways. The application potential of ginsenosides as cosmeceutical ingredients will also be reviewed. PMID- 26024572 TI - Histopathologic findings in children diagnosed with cow's milk protein allergy. AB - BACKGROUND: Cow's milk protein allergy is the most common cause of food allergy. The challenge test, either open or doubled-blind with a placebo control, is regarded as the criterion standard. Endoscopy and histologic findings are considered a method that can aid in the diagnosis of this entity. AIMS: The aim of this study was to describe the histopathologic findings in children suspected of cow's milk protein allergy that were seen at our hospital. MATERIAL AND METHODS: A descriptive, observational study was conducted on 116 children clinically suspected of presenting with cow's milk protein allergy that were seen at the Department of Gastroenterology and Nutrition of the Instituto Nacional de Pediatria. Upper endoscopy and rectosigmoidoscopy with biopsies were performed and the findings were described. RESULTS: Of the 116 patients, 64 (55.17%) were girls and 52 (44.83%) were boys. The rectum was the site with the greatest presence of eosinophils per field in both groups, followed by the duodenum. In general, more than 15 eosinophils were found in 46% of the patients. CONCLUSIONS: Between 40 and 45% of the cases had the histologic criterion of more than 15 to 20 eosinophils per field and the rectosigmoid colon was the most affected site. Therefore, panendoscopy and rectosigmoidoscopy with biopsy and eosinophil count are suggested. PMID- 26024574 TI - Spatial structural integrity is important for adipose regeneration after transplantation. AB - Advances in structural fat transplantation technology have significantly improved the survival rate and stability of grafts. This study investigated the importance of the spatial structural integrity of adipose tissue for adipose regeneration after fat transplantation. We sought to enhance understanding of structural fat transplantation and optimize procedures used for the clinical acquisition, purification, and transplantation of adipose tissue. In an inactivated structuration adipose tissue model established by freezing at -20 degrees C for 3 days, nearly all cells were dead but the structure was intact. We transplanted this adipose tissue model (group A) or non-treated adipose tissue (group B) into GFP-expressing mice. Group B showed a higher graft survival percentage and less fibrosis than group A. The macrophage infiltration (F4/80) peak period was longer in group A than in group B. The change in vessel density (CD31) was similar in the two groups: it peaked at 4 weeks after transplantation and decreased thereafter. In both groups, the number of Ki67+ cells showed a similar trend. In comparison to group B, group A had more Ki67+ cells at 4-8 weeks after transplantation, but fewer of these cells at 12 weeks after transplantation. The intact spatial structure of adipose tissue, which is supported by adipocytes and extracellular matrix, provides a niche for adipogenesis and angiogenesis after fat transplantation. PMID- 26024575 TI - Lycopene not in pill, nor in natura has photoprotective systemic effect. AB - Carotenoids are endogenous antioxidant agents. It has been reported that oral lycopene reduces immediate erythema induced by ultraviolet B radiation. The objective was to evaluate and compare the photoprotective effect of lycopene in capsule and tomato paste. This was an interventional, randomized, comparative 10 week study that included 20 subjects, divided in two groups: 10 for capsule and 10 for tomato paste intake. Blood samples were collected for serum lycopene dosage by high-performance liquid chromatography. Chromatometer was used to measure minimal erythematous dose 24 h after only ultraviolet B irradiation and the variation of color a (maximum erythema, 24 h after irradiation compared to normal skin). Evaluations were made at baseline and after 4, 8, and 10 weeks. Data were analyzed by ANOVA with repeated measures. Three subjects dropped out after 4 weeks. Serum lycopene demonstrated great variability; significant, higher levels for tomato after 4 weeks (p = 0.027) as compared to capsule and significant increase along the study just for tomato (p = 0.044) were detected. No visual change for minimal erythematous dose was observed in all evaluations, for both groups. Chromatometer measures showed no difference in the mean of minimal erythematous dose at baseline between groups. Slight variation of color a after 10 weeks was observed [marginally significant (p = 0.054)], with a tendency to be greater for capsule use [marginally significant (p = 0.066)] and no adverse effects. Lycopene regular intake was safe and demonstrated no effect for systemic photoprotection against ultraviolet B; no correlation with serum lycopene was detected. PMID- 26024576 TI - Short Personality and Life Event scale for detection of suicide attempters. AB - OBJECTIVE: To develop a brief and reliable psychometric scale to identify individuals at risk for suicidal behaviour. METHOD: DESIGN: Case-control study. SAMPLE AND SETTING: 182 individuals (61 suicide attempters, 57 psychiatric controls, and 64 psychiatrically healthy controls) aged 18 or older, admitted to the Emergency Department at Puerta de Hierro University Hospital in Madrid, Spain. MEASURES: All participants completed a form including their socio demographic and clinical characteristics, and the Personality and Life Events scale (27 items). To assess Axis I diagnoses, all psychiatric patients (including suicide attempters) were administered the Mini International Neuropsychiatric Interview. STATISTICAL ANALYSIS: Descriptive statistics were computed for the socio-demographic factors. Additionally, chi(2) independence tests were applied to evaluate differences in socio-demographic and clinical variables, and the Personality and Life Events scale between groups. A stepwise linear regression with backward variable selection was conducted to build the Short Personality Life Event (S-PLE) scale. In order to evaluate the accuracy, a ROC analysis was conducted. The internal reliability was assessed using Cronbach's alpha, and the external reliability was evaluated using a test-retest procedure. RESULTS: The S PLE scale, composed of just 6 items, showed good performance in discriminating between medical controls, psychiatric controls and suicide attempters in an independent sample. For instance, the S-PLE scale discriminated between past suicide and past non-suicide attempters with sensitivity of 80% and specificity of 75%. The area under the ROC curve was 88%. A factor analysis extracted only one factor, revealing a single dimension of the S-PLE scale. Furthermore, the S PLE scale provides values of internal and external reliability between poor (test retest: 0.55) and acceptable (Cronbach's alpha: 0.65) ranges. Administration time is about one minute. CONCLUSIONS: The S-PLE scale is a useful and accurate instrument for estimating the risk of suicidal behaviour in settings where the time is scarce. PMID- 26024577 TI - Immunohistochemical Mapping of Sensory Nerve Endings in the Human Triangular Fibrocartilage Complex. AB - BACKGROUND: The triangular fibrocartilage complex is the main stabilizer of the distal radioulnar joint. While static joint stability is constituted by osseous and ligamentous integrity, the dynamic aspects of joint stability chiefly concern proprioceptive control of the compressive and directional muscular forces acting on the joint. Therefore, an investigation of the pattern and types of sensory nerve endings gives more insight in dynamic distal radioulnar joint stability. QUESTIONS/PURPOSES: We aimed to (1) analyze the general distribution of sensory nerve endings and blood vessels; (2) examine interstructural distribution of sensory nerve endings and blood vessels; (3) compare the number and types of mechanoreceptors in each part; and (4) analyze intrastructural distribution of nerve endings at different tissue depth. METHODS: The subsheath of the extensor carpi ulnaris tendon sheath, the ulnocarpal meniscoid, the articular disc, the dorsal and volar radioulnar ligaments, and the ulnolunate and ulnotriquetral ligaments were dissected from 11 human cadaver wrists. Sensory nerve endings were counted in five levels per specimen as total cell amount/cm(2) after staining with low-affinity neurotrophin receptor p75, protein gene product 9.5, and S-100 protein and thereafter classified according to Freeman and Wyke. RESULTS: All types of sensory corpuscles were found in the various structures of the triangular fibrocartilage complex with the exception of the ulnolunate ligament, which contained only Golgi-like endings, free nerve endings, and unclassifiable corpuscles. The articular disc had only free nerve endings. Furthermore, free nerve endings were the predominant sensory nerve ending (median, 72.6/cm(2); range, 0-469.4/cm(2)) and more prevalent than all other types of mechanoreceptors: Ruffini (median, 0; range, 0-5.6/cm(2); difference of medians, 72.6; p < 0.001), Pacini (median, 0; range, 0-3.8/cm(2); difference of medians, 72.6; p < 0.001), Golgi-like (median, 0; range, 0-2.1/cm(2); difference of medians, 72.6; p < 0.001), and unclassifiable corpuscles (median, 0; range, 0 2.5/cm(2); difference of medians, 72.6; p < 0.001). The articular disc contained fewer free nerve endings (median, 1.8; range, 0-17.8/cm(2)) and fewer blood vessels (median, 29.8; range, 0-112.2/cm(2); difference of medians: 255.9) than all other structures of the triangular fibrocartilage complex (p <= 0.001, respectively) except the ulnolunate ligament. More blood vessels were seen in the volar radioulnar ligament (median, 363.62; range, 117.8-871.8/cm(2)) compared with the ulnolunate ligament (median, 107.7; range, 15.9-410.3/cm(2); difference of medians: 255.91; p = 0.002) and the dorsal radioulnar ligament (median, 116.2; range, 53.9-185.1/cm(2); difference of medians: 247.47; p = 0.001). Free nerve endings were obtained in each structure more often than all other types of sensory nerve endings (p < 0.001, respectively). The intrastructural analysis revealed no differences in mechanoreceptor distribution in all investigated specimens with the numbers available, showing a homogenous distribution of proprioceptive qualities in all seven parts of the triangular fibrocartilage complex. CONCLUSIONS: Nociception has a primary proprioceptive role in the neuromuscular stability of the distal radioulnar joint. The articular disc and ulnolunate ligament rarely are innervated, which implies mainly mechanical functions, whereas all other structures have pronounced proprioceptive qualities, prerequisite for dynamic joint stability. CLINICAL RELEVANCE: Lesions of the volar and dorsal radioulnar ligaments have immense consequences not only for mechanical but also for dynamic stability of the distal radioulnar joint, and surgical reconstruction in instances of radioulnar ligament injury is important. PMID- 26024578 TI - What Is the Role for Patelloplasty With Gullwing Osteotomy in Revision TKA? AB - BACKGROUND: Management of the patella in revision total knee arthroplasty (TKA) is challenging as a result of the deficient or unusable bone stock for patellar resurfacing that is frequently encountered. Options proposed in this setting include various patelloplasty procedures, patellectomy, and special patellar components. We sought to better define the role and results of one patelloplasty procedure, the gullwing osteotomy, used in revision TKA. QUESTIONS/PURPOSES: (1) How much improvement in the outcome measures of range of motion and Knee Society scores was seen after revision TKA with a gullwing osteotomy? (2) What are the radiographic results of this osteotomy as judged by patellar healing and patellar tracking? (3) What complications are associated with the gullwing osteotomy in revision TKA? METHODS: Between December 2003 and July 2012, we used a gullwing osteotomy on patients undergoing revision TKA (n = 238) in which the patellar remnant was avascular or less than 12 mm thick. This uncommon procedure was used in 17 of 115 (15%) of the patellae revised during this time. We performed manual chart reviews on all patients to collect preoperative and postoperative range of motion and Knee Society scores as well as radiographic review at last followup to assess patellar healing and tracking. RESULTS: In patients with at least 2 years of followup, the preoperative range of motion was a median -7.5 degrees of extension (interquartile range [IQR], -15 degrees -0 degrees ) and 90 degrees of flexion (IQR, 90 degrees -100 degrees ). Postoperative extension improved to 0 degrees (IQR, 0 degrees -0 degrees ; p = 0.015). With the numbers available, median flexion arc did not change at last followup (110 degrees ; IQR, 95 degrees -120 degrees ; p = 0.674). The Knee Society score improved from a combined (clinical + functional) mean of 86 (95% confidence interval [CI], 56-116) preoperatively to 142 (95% CI, 121-163; p < 0.001) postoperatively. Radiographically, 12 of 13 patients demonstrated healing of the osteotomy with osseous union and one patient healed with a fibrous union. Nine of the 10 patients with at least 2 years of followup had a centrally tracking gullwing osteotomized patella at last followup. One patient, with just over 3 years of followup, exhibited lateral subluxation without evidence of fracture. Three of the 10 patients with greater than 2 years of followup developed recurrent infections. One patient had avascular necrosis with fragmentation of the patella at 4 months postoperatively. CONCLUSIONS: Patellar bone stock is often compromised in revision TKA, leaving the surgeon with very few options for reconstruction. Using this technique, we found acceptable function, no aseptic rerevisions for patellofemoral complications, nine of 10 of patellae tracking within the trochlear groove, and radiographic healing of the majority of the osteotomies. The gullwing osteotomy may be considered an option in these difficult revisions, but further studies with more complete followup are needed. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26024579 TI - CORR Insights((r)): Wear and Osteolysis of Highly Crosslinked Polyethylene at 10 to 14 Years: The Effect of Femoral Head Size. PMID- 26024580 TI - What Are the Strength of Recommendations and Methodologic Reporting in Health Economic Studies in Orthopaedic Surgery? AB - BACKGROUND: Cost-effectiveness research is an increasingly used tool in evaluating treatments in orthopaedic surgery. Without high-quality primary-source data, the results of a cost-effectiveness study are either unreliable or heavily dependent on sensitivity analyses of the findings from the source studies. However, to our knowledge, the strength of recommendations provided by these studies in orthopaedics has not been studied. QUESTIONS/PURPOSES: We asked: (1) What are the strengths of recommendations in recent orthopaedic cost effectiveness studies? (2) What are the reasons authors cite for weak recommendations? (3) What are the methodologic reporting practices used by these studies? METHODS: The titles of all articles published in six different orthopaedic journals from January 1, 2004, through April 1, 2014, were scanned for original health economics studies comparing two different types of treatment or intervention. The full texts of included studies were reviewed to determine the strength of recommendations determined subjectively by our study team, with studies providing equivocal conclusions stemming from a lack or uncertainty surrounding key primary data classified as weak and those with definitive conclusions not lacking in high-quality primary data classified as strong. The reasons underlying a weak designation were noted, and methodologic practices reported in each of the studies were examined using a validated instrument. A total of 79 articles met our prespecified inclusion criteria and were evaluated in depth. RESULTS: Of the articles included, 50 (63%) provided strong recommendations, whereas 29 (37%) provided weak recommendations. Of the 29 studies, clinical outcomes data were cited in 26 references as being insufficient to provide definitive conclusions, whereas cost and utility data were cited in 13 and seven articles, respectively. Methodologic reporting practices varied greatly, with mixed adherence to framing, costs, and results reporting. The framing variables included clearly defined intervention, adequate description of a comparator, study perspective clearly stated, and reported discount rate for future costs and quality-adjusted life years. Reporting costs variables included economic data collected alongside a clinical trial or another primary source and clear statement of the year of monetary units. Finally, results reporting included whether a sensitivity analysis was performed. CONCLUSIONS: Given that a considerable portion of orthopaedic cost-effectiveness studies provide weak recommendations and that methodologic reporting practices varied greatly among strong and weak studies, we believe that clinicians should exercise great caution when considering the conclusions of cost-effectiveness studies. Future research could assess the effect of such cost-effectiveness studies in clinical practice, and whether the strength of recommendations of a study's conclusions has any effect on practice patterns. CLINICAL RELEVANCE: Given the increasing use of cost effectiveness studies in orthopaedic surgery, understanding the quality of these studies and the reasons that limit the ability of studies to provide more definitive recommendations is critical. Highlighting the heterogeneity of methodologic reporting practices will aid clinicians in interpreting the conclusions of cost-effectiveness studies and improve future research efforts. PMID- 26024581 TI - Does native combined anteversion influence pain onset in patients with dysplastic hips? AB - BACKGROUND: Combined anteversion is the sum of femoral and acetabular anteversion and represents their morphological relationship in the axial plane. Few studies have investigated the native combined anteversion in patients with symptomatic dysplastic hips. QUESTIONS/PURPOSES: We hypothesized the following: (1) dysplastic hips have two distinct populations, which differ from each other and from normal hips in their combined anteversion; and (2) these populations differ clinically in terms of correlation between age of onset of symptoms and amount of anteversion. METHODS: We measured radiographic parameters by CT of 100 dysplastic hips in 76 patients who were symptomatic enough to undergo periacetabular osteotomy and of 50 normal hips in 44 patients who had CT scans as part of preparation for computer-navigated TKAs; these patients had no visible hip arthritis or dysplasia and no hip symptoms. Dysplastic hips were divided into the anteversion (83 hips) and retroversion groups (17 hips) based on acetabular version. Age at pain onset was determined from their medical charts. RESULTS: Combined anteversion in the anteversion group was greater than that in the retroversion and control groups: 47 degrees +/- 12 degrees , 30 degrees +/- 16 degrees , and 36 degrees +/- 9 degrees , respectively. In the anteversion group, combined anteversion (r = -0.49; 95% confidence interval [CI], -0.66 to -0.27; p < 0.001) and femoral anteversion (r = -0.41; 95% CI, -0.60 to -0.19; p < 0.001) were associated with an earlier age at pain onset; however, no such relationships were observed in the retroversion group. After controlling for relevant potential confounding variables, we found that combined anteversion (hazard ratio [HR], 1.04; 95% CI, 1.01-1.07; p = 0.006) and Sharp angle (HR, 1.10; 95% CI, 1.02-1.17; p = 0.008) were associated with an earlier age of pain onset in the anteversion group. CONCLUSIONS: These results suggest that not only lateral coverage of the femoral head, but also axial joint morphology is important for the development of pain in the anteversion group. Optimal combined anteversion should be considered during periacetabular osteotomy. LEVEL OF EVIDENCE: Level IV, prognostic study. PMID- 26024582 TI - Primary ceramic-on-ceramic total hip arthroplasty using a 32-mm ceramic head with a titanium-alloy sleeve. AB - BACKGROUND: Modern ceramic-on-ceramic bearings have become attractive alternatives to conventional polyethylene in total hip arthroplasty (THA) as a result of their low wear and minimal particle production. However, 28-mm heads in ceramic-on-ceramic bearing couples have been associated with ceramic fracture. To address these issues, 32-mm and larger ceramic heads with a titanium-alloy sleeve have been introduced, although limited data are available on their durability and clinical outcomes. QUESTIONS/PURPOSES: We determined (1) the survivorship of the primary ceramic-on-ceramic THA using a 32-mm ceramic head with a titanium-alloy sleeve at a minimum followup of 5 years; (2) Harris hip scores; (3) the incidence of ceramic fracture and noisy hip; and (4) the proportion of hips showing radiographic evidence of osteolysis. METHODS: From November 2005 to August 2009, we performed 301 ceramic-on-ceramic THAs using a 32-mm ceramic head with a titanium-alloy sleeve in 270 patients. Of these, 12 patients (12 hips [4%]) died from problems unrelated to surgery and 13 patients (15 hips [5%]) were lost during followup before a minimum of 5 years had been reached, leaving 245 patients who had 274 THAs with a minimum followup of 5 years (mean, 6.5 years; range, 5-9 years) in this retrospective analysis. During the study period, 30% (301 of 997 hips) were performed with this articulation based on the operating surgeon's discretion. The mean patient age at the time of surgery was 55 years (range, 16-82 years). All operations were performed at a single center. All of the ceramic implants were hot isostatic-pressed, laser-marked, proof-tested third generation alumina. We determined the implant survival, Harris hip scores, incidence of ceramic fracture or noisy hips (based on a questionnaire), and presence of osteolysis. RESULTS: The survival rate of ceramic-on-ceramic bearings in primary THA using a 32-mm ceramic head with a titanium-alloy sleeve was 98% (95% confidence interval, 96%-100%) at 9 years. The Harris hip score improved from a mean of 47 points preoperatively to 93 points at last followup. One ceramic head fractured at 6 years postoperatively. No ceramic liners fractured. Audible hip clicking and squeaking were identified in four hips and one hip, respectively. Osteolysis was detected in three hips, but none had symptoms. CONCLUSIONS: Primary ceramic-on-ceramic THA using a 32-mm ceramic head with a titanium-alloy sleeve has a survivorship of 98% at 9-year followup. Nevertheless, surgeons should be aware of the potential risks of ceramic fracture, noise, and osteolysis associated with the use of a ceramic head with a titanium-alloy sleeve. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26024583 TI - A prospective, randomized study of the patency period of the plastic antireflux biliary stent: an interim analysis. AB - BACKGROUND: There is as yet no ideal design of a plastic biliary stent with the longest patency period. OBJECTIVE: To study the safety and effective patency period of a new plastic antireflux biliary stent in the clinical setting. DESIGN: We conducted a prospective, randomized trial to compare the patency of 2 similar plastic biliary stents, one of which has an antiduodenobiliary reflux property. SETTING: The study was conducted at 2 separate tertiary centers in 2 countries. PATIENTS: Patients with inoperable distal malignant biliary obstruction were recruited. INTERVENTIONS: One of the 2 types of plastic stents under study was randomly chosen and inserted in the common bile duct of the study subjects. The subjects were followed until the end of study or occlusion occurrence. MAIN OUTCOME MEASUREMENTS: Our primary endpoint was the time to stent occlusion in days, with stent-related adverse events and all-cause mortality the secondary endpoints. RESULTS: A total of 16 subjects were recruited for the study; 7 were allocated to group A (ordinary Tannenbaum stent) and 9 to group B (antireflux biliary stent). Five of 7 subjects (71%) in group B had stent occlusion within 8 days, and the primary end point was reached in all 7 subjects within 30 days, whereas the primary endpoint was not reached within 30 days in any of the subjects in group A. Our data showed a significantly shorter stent patency period in group B compared with group A (P < .003). LIMITATIONS: Small sample size. CONCLUSION: Routine use of antireflux plastic biliary stents in the palliative management of malignant biliary obstructions cannot be recommended at present. (Clinical trial registration number: NCT01142921.). PMID- 26024584 TI - Adenoma detection rate in high-risk patients differs from that in average-risk patients. AB - BACKGROUND: Adenoma detection rates (ADRs) are established as quality targets in average-risk (AR) individuals undergoing colorectal cancer (CRC) screening colonoscopy. Little is known about the ADR in high-risk (HR) individuals undergoing index or surveillance colonoscopy. OBJECTIVE: To determine and compare ADR in HR versus AR individuals undergoing colonoscopy. DESIGN AND SETTING: Retrospective study, tertiary care center. PATIENTS AND INTERVENTION: We reviewed records of 7357 patients who underwent colonoscopy by 66 multispecialty endoscopists at our institution during the period 2008 to 2009. Both screening and surveillance colonoscopies in AR and HR patients for CRC were studied. HR patients were further divided into 3 subgroups: those with a (1) personal history of polyps (PHP), (2) family history of polyps (FHP), and (3) family history of CRC (FHCRC). Multivariable logistic regression analysis was performed to evaluate differences in ADR between the groups after adjusting for possible confounders. MAIN OUTCOME MEASUREMENTS: ADR in HR patients. RESULTS: The study included 4141 patients, of whom 2170 were AR and 1971 were HR. Patients in the HR group were older (64.5 +/- 9.1 years vs 59.1 +/- 7.9 years, P < .001). HR patients were more likely to have adenomas (30.7% vs 25.6%, P < .001). Adenomas were detected more often in the proximal colon than in the distal colon (29.3% vs 21.0%, P < .001 and 22.8% vs 15.8%, P < .001, respectively). Patients with a PHP had the highest ADR (33.1%, P < .001). However, after adjusting for confounders, HR status was not found to be associated with ADR (odds ratio [OR] 1.2; 95% confidence interval [CI], 0.93-1.6; P = .15 for females and 0.93; 95% CI, 0.70-1.2; P = .61 for males). HR females were found to have a 40% greater likelihood of having proximal adenomas than AR females (1.4; 95% CI, 1.01-2; P = .04). LIMITATIONS: Retrospective design, single tertiary center. CONCLUSIONS: Patients with a PHP have a significantly higher ADR compared with AR patients. Defining a minimum target ADR for individuals with a PHP undergoing surveillance colonoscopy is important. PMID- 26024585 TI - Disparities in prevalence, location, and shape characteristics of colorectal neoplasia between South Korean and U.S. patients. AB - BACKGROUND: Colon cancer screening is being introduced in many countries, but standard Western screening approaches may not be appropriate for Asian societies if differences in colon cancer epidemiology exist. Comparative analysis of colorectal neoplasia patterns in South Korean and Western subjects has implications for appropriate screening approaches in non-Western societies. METHODS: The results of concurrent screening colonoscopies performed in average risk patients 50 to 69 years old in 2 teaching hospitals, Kyung Hee University Hospital (Seoul, South Korea) and Virginia Mason Medical Center (Seattle, Wash), were compared with respect to prevalence, histologic features, anatomic distribution, and shape characteristics of colorectal neoplasia. RESULTS: The U.S. (n = 3460) and South Korean (n = 2193) cohorts were similar with regard to the prevalence of adenomas (28.5% vs 29.8%, respectively, P = .312) and advanced neoplasia (6.4% vs 5.4%, respectively, P = .102), but the proportion of proximal adenomas was greater in the U.S. cohort (62.8% vs 45.9%, P < .001). The prevalence of adenomas and advanced neoplasia was similar in male patients, but there was a greater prevalence of neoplasia (23.5% vs 18.8%, P = .006) and advanced neoplasia (5.1% vs 2.7%, P < .001) in U.S. women than South Korean women. When large (>=10 mm) adenomas were considered, proximal location and nonpolypoid (flat) shape were more common in the U.S. cohort (79.4% vs 37.1%, P = .003 and 43.5% vs 12.3%, P < .001, respectively). The overall prevalence of large flat adenomas in the U.S. cohort was 5 times that of the South Korean cohort (2.6% vs 0.5%, P < .001). Adjustment for sex ratio discrepancies (48.3% men in the U.S. cohort vs 60.8% in the South Korean cohort, P < .001) did not result in any significant changes in the conclusions. CONCLUSION: Compared with Westerners, South Koreans have a more distal distribution of adenomas and advanced neoplasia and lower prevalence of large flat adenomas. South Korean women have a lower prevalence of colorectal neoplasia than Western women. Such disparities suggest that Western screening strategies cannot be directly adopted by other countries, but need to be customized by society. PMID- 26024586 TI - Osteoarticular cells tolerate short-term exposure to nitisinone-implications in alkaptonuria. AB - Alkaptonuria (AKU) is a rare genetic disease resulting in severe, rapidly progressing, early onset multi-joint osteoarthropathy. A potential therapy, nitisinone, is being trialled that reduces the causative agent; homogentisic acid (HGA) and in a murine model has shown to prevent ochronosis. Little is currently known about the effect nitisinone has on osteoarticular cells; these cells suffer most from the presence of HGA and its polymeric derivatives. This led us to investigate nitisinone's effect on chondrocytes and osteoblast-like cells in an in vitro model. Human C20/A4 immortalized chondrocytes, and osteosarcoma cells MG63 cultured in DMEM, as previously described. Confluent cells were then plated into 24-well plates at 4 * 10(4) cells per well in varying concentrations of nitisinone. Cells were cultured for 7 days with medium changes every third day. Trypan blue assay was used to determine viability and the effect of nitisinone concentration on cells. Statistical analysis was performed using analysis of variance, and differences between groups were determined by Newman-Keuls post test. Analysis of C20/A4 chondrocyte and MG63 osteoblast-like cell viability when cultured in different concentrations of nitisinone demonstrates that there is no statistically significant difference in cell viability compared to control cultures. There is currently no literature surrounding the use of nitisinone in human in vitro models, or its effect on chondrocytes or osteoblast like cells. Our results show that nitisinone does not appear detrimental to cell viability of chondrocytes or osteoblast-like cells, which adds to the evidence that this therapy could be useful in treating AKU. PMID- 26024587 TI - Secondary fracture prevention after femur fractures in the Gran Canaria North Health Area: A 2004-2014 comparison. PMID- 26024588 TI - Thrombopoietin-receptor agonist as a treatment of thrombocytopenia associated with systemic lupus erythematosus. PMID- 26024589 TI - A glycosyl hydrolase family 16 gene is responsible for the endogenous production of beta-1,3-glucanases within decapod crustaceans. AB - To identify the gene responsible for the production of a beta-1,3-glucanase (laminarinase) within crustacea, a glycosyl hydrolase family 16 (GHF16) gene was sequenced from the midgut glands of the gecarcinid land crab, Gecarcoidea natalis and the freshwater crayfish, Cherax destructor. An open reading frame of 1098 bp for G. natalis and 1095 bp for C. destructor was sequenced from cDNA. For G. natalis and C. destructor respectively, this encoded putative proteins of 365 and 364 amino acids with molecular masses of 41.4 and 41.5 kDa. mRNA for an identical GHF16 protein was also expressed in the haemolymph of C. destructor. These putative proteins contained binding and catalytic domains that are characteristic of a beta-1,3-glucanase from glycosyl hydrolase family 16. The amino acid sequences of two short 8-9 amino acid residue peptides from a previously purified beta-1,3-glucanase from G. natalis matched exactly that of the putative protein sequence. This plus the molecular masses of the putative proteins matching that of the purified proteins strongly suggests that the sequences obtained encode for a catalytically active beta-1,3-glucanase. A glycosyl hydrolase family 16 cDNA was also partially sequenced from the midgut glands of other amphibious (Mictyris platycheles and Paragrapsus laevis) and terrestrial decapod species (Coenobita rugosus, Coenobita perlatus, Coenobita brevimanus and Birgus latro) to confirm that the gene is widely expressed within this group. There are three possible hypothesised functions and thus evolutionary routes for the beta-1,3-glucanase: 1) a digestive enzyme which hydrolyses beta-1,3-glucans, 2) an enzyme which cleaves beta-1,3-glycosidic bonds within cell walls to release cell contents or 3) an immune protein which can hydrolyse the cell walls of potentially pathogenic micro-organisms. PMID- 26024590 TI - Mio acts in the Drosophila brain to control nutrient storage and feeding. AB - Animals recognize the availability of nutrients and regulate the intake and storage of these nutrients accordingly. However, the molecular mechanisms underlying nutrient sensing and subsequent changes in behavior and metabolism are not fully understood. Mlx interactor (Mio), the Drosophila homolog of carbohydrate response element binding protein (ChREBP), functions as a transcription factor in the fat body of the fly to control triglyceride storage as well as feeding, suggesting that Mio may act in a nutrient-sensing pathway to coordinate food consumption and metabolism. Here, we show that Mio functions in neurons in Drosophila to regulate feeding and nutrient storage. Pan-neuronal disruption of Mio function leads to increased triglyceride and glycogen storage, and this phenotype is not due to increased food consumption. Interestingly, targeted disruption of Mio specifically in the insulin-producing cells (IPCs) has little effect on nutrient storage, but increases food consumption suggesting that Mio acts in these neurons to control feeding behavior. Since Mio is a transcription factor, one possible way Mio may act in the IPCs to control feeding is through regulating the expression of Drosophila insulin-like peptides (dilps) or drosulfakinin (dsk), neuropeptides produced in the IPCs. Consistent with this hypothesis, IPC-specific knockdown of Mio leads to an increase in dilp3 expression, while not affecting dilp2, 5 or dsk levels. Together, this study indicates a new function for Mio in the Drosophila brain and specifically in the IPCs, controlling neuropeptide gene expression, feeding and metabolism in accordance with nutrient availability. PMID- 26024591 TI - Protective effect of Drosophila glutathione transferase omega 1 against hydrogen peroxide-induced neuronal toxicity. AB - Glutathione transferase omega (GSTO) belongs to a recently identified family of glutathione transferase (GST) and presents several known functions. In Drosophila, despite the high sequence identity among the four GstO isoforms, they present different physiological functions. Herein, we showed that GstO1, which is one of the Drosophila GstOs, is highly expressed in adult heads. We determined the three-dimensional structure of GstO1, by homology modeling. Furthermore, we show that GstO1 loss-of-function mutant flies display reduced survival than the control flies when subjected to H2O2 treatment. Interestingly, the neuronal specific expression of GstO1 in a GstO1 loss-of-function mutant background rescued H2O2-induced toxicity. We further showed that GstO1 inhibits H2O2 mediated activation of the mitogen-activated protein kinase (MAPK) pathway. Collectively, our findings provide valuable new insights into the tissue-specific protective mechanisms of Drosophila GstOs during oxidative stress. PMID- 26024592 TI - Genetic polymorphisms in Toll-like receptor 3 gene are associated with the risk of hepatitis B virus-related liver diseases in a Chinese population. AB - Toll-like receptors (TLRs) are well known to play a critical role in antiviral and antitumor response. Available evidence has demonstrated that TLRs are implicated in the immunopathogenesis of hepatitis B virus (HBV) infection and tumor carcinogenesis. Therefore, we performed the present study to investigate the relationship with TLR3 gene polymorphisms and the risk of HBV-related liver disease in a Chinese population. A total of 623 individuals were included: 172 chronic hepatitis B (CHB) patients, 91 HBV-related liver cirrhosis (LC) patients, 174 HBV-related hepatocellular carcinoma (HCC) patients, and 186 healthy controls. Allelic and genotypic frequencies of TLR3 rs1879026 and rs3775290 polymorphisms were detected by PCR-RFLP and DNA sequencing analysis. Association analysis showed that the TT genotype of TLR3 rs3775290 was associated with a decreased risk for CHB, HBV-related LC, and HCC (OR=0.52, 95% CI: 0.27-0.99, P=0.048; OR=0.32, 95% CI: 0.14-0.76, P=0.010; OR=0.49, 95% CI: 0.26-0.92, P=0.027). Nevertheless, a lack of association was found between TLR3 rs1879026 and HBV-related liver diseases. In addition, haplotype analysis revealed that individuals who carried the GT haplotype might have a decreased risk of HBV related liver diseases. The results indicated that genetic variant in TLR3 gene rs3775290 polymorphisms may be a protective factor for CHB, HBV-related LC, and HCC in the Chinese population. PMID- 26024593 TI - Genome-wide identification, evolution and expression analysis of nuclear receptor superfamily in Nile tilapia, Oreochromis niloticus. AB - The nuclear receptor (NR) superfamily, which is divided into 7 subfamilies, constitutes one of the largest classes of transcription factors. In this study, through comprehensive database search, we identified all NRs (including 4 novel members) from the tilapia (75), common carp (137), zebrafish (73), fugu (73), tetraodon (72), stickleback (70), medaka (69), coelacanth (55), spotted gar (51) and elephant shark (50). For 21 NRs, two duplicates were found in teleosts, while only one in tetrapods. These duplicates, except those of DAX1, SHP and GCNF found in the elephant shark, were derived from 3R (third round of genome duplication). The linkage duplication of 5 syntenic blocks (comprising 14 duplicated NR couples) in teleosts further supported their 3R origin. Based on transcriptome data from adult tilapia, 53 NRs were found to be expressed in more than one tissue (brain, head kidney, heart, liver, kidney, muscle, ovary and testis), and 4 were tissue-specific, indicating their essential roles in the corresponding tissue. Based on the XX and XY gonadal transcriptome data from four developmental stages, 65 NRs were detected in gonads, with 21, 31, 11 and 29 expressed sexual dimorphically at 5, 30, 90 and 180days after hatching, respectively. The expression of four selected genes was examined by in situ hybridization (ISH) and quantitative PCR (qPCR) to validate the spatial and temporal expression profiles of NRs. Comparative analyses of the expression profiles of duplicated NRs revealed divergence in gene expression as well as gene function. Our results demonstrated that NRs may play important roles in sex determination and gonadal development in teleosts. PMID- 26024594 TI - Reduced Wnt3a expression correlates with poor development of the hindgut in rats with anorectal malformations. AB - Embryogenesis is orchestrated by the wingless-type MMTV integration site family (WNT) signaling pathways, including Wnt3a. This study was performed to investigate the expression of Wnt3a in the terminal hindgut in ethylenethiourea (ETU)-exposed rat embryos with anorectal malformations (ARMs) and its potential association between Wnt3a and the maldevelopment of the terminal hindgut in ARMs. ARM rat embryos were induced by ethylenethiourea on embryonic day 10 (E10). The expression levels of protein and mRNA of Wnt3a were confirmed using immunohistochemistry staining, Western blotting analyses, and quantitative real time PCR (qRT-PCR) in normal rat and ARM embryos. Immunostaining revealed a variation in the expression of Wnt3a in the developing terminal hindgut of ARM embryos. The expression of Wnt3a in the terminal hindgut of ARM rat embryos decreased at both the mRNA level and protein level (P<0.05) compared with normal tissues. This study demonstrated that the expression of Wnt3a in the ARMs of ETU exposed rat embryos was remarkably reduced, which indicated its potential role in the pathogenesis of the terminal hindgut maldevelopment in ARMs. PMID- 26024596 TI - Approach to chest computed tomography. AB - Computed tomography (CT) is central to the detection and diagnosis of a wide variety of pulmonary, cardiovascular, and other diseases of the chest. Successful interpretation of thoracic CT requires both an appreciation of the spectrum of normal appearances of the chest and a systematic approach to the characterization of thoracic pathology. This article provides an introduction to basic CT techniques and protocols, a review of normal CT anatomy, and an overview of commonly encountered abnormalities. PMID- 26024595 TI - Histone deacetylase HDAC1 downregulates transcription of the serotonin transporter (5-HTT) gene in tumor cells. AB - Serotonin (5-HT) has been reported to be involved in cancer progression by stimulating angiogenesis and cell growth. In this study, we examined the expression of the serotonin transporter (5-HTT) and the role of histone deacetylases (HDACs) in regulating the 5-HTT gene in tumor cells. The 5-HTT gene expression was almost silenced in chicken lymphoma DT40, myelomonocytic tumor HD11 and hepatoma DU249 cells, compared to their physiological counterpart. In contrast, HDAC1 mRNA expression was increased in these cell lines. Indeed, the pan-HDAC inhibitor trichostatin A (TSA) enhanced the 5-HTT mRNA expression in several tumor cell lines including the human cell lines HepG2 and THP-1 and increased the 5-HT uptake in HD11 cells. In addition, treatment with parthenolide, which is capable of depleting HDAC1, and knockdown of HDAC1 using siRNA resulted in increased 5-HTT mRNA expression, confirming the role of HDAC1 in the down-regulation of 5-HTT in the tumor cells. Deletion analysis of the 5 HTT promoter and site-directed mutagenesis revealed that the transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta), in interacting with the 5-HTT promoter, mediated both the inhibition of the 5-HTT expression by HDAC1 and the activation by CREB-binding protein (CBP). Using a chromatin immunoprecipitation assay, we found increased acetylation of histone H4 associated with the 5-HTT promoter in cells treated with TSA. Our results suggest that the 5-HTT gene is epigenetically downregulated by HDAC1 in several types of cancer. PMID- 26024597 TI - Low-dose computed tomographic screening for lung cancer. AB - Low-dose computed tomographic (LDCT) screening is now moving from clinical trials to clinical practice, following the report from the National Lung Screening Trial that LDCT screening for lung cancer can reduce the number of deaths from lung cancer by 20% in current and former smokers, ages 55 to 74 years, with a 30 pack year smoking history. This article reviews the current evidence for screening, key elements of a successful lung cancer screening clinic, and reporting and management guidelines for LDCT screening findings. PMID- 26024598 TI - Imaging the solitary pulmonary nodule. AB - The development of widespread lung cancer screening programs has the potential to dramatically increase the number of thoracic computed tomography (CT) examinations performed annually in the United States, resulting in a greater number of newly detected, indeterminate solitary pulmonary nodules (SPNs). Additional imaging studies, such as fluorodeoxyglucose F 18 (FDG)-positron emission tomography (PET), have been shown to provide valuable information in the assessment of indeterminate SPNs. Newer technologies, such as contrast-enhanced dual-energy chest CT and FDG-PET/CT, also have the potential to facilitate diagnosis of potentially malignant SPNs. PMID- 26024599 TI - Staging of lung cancer. AB - Primary lung cancer is the leading cause of cancer mortality in the world. Thorough clinical staging of patients with lung cancer is important, because therapeutic options and management are to a considerable degree dependent on stage at presentation. Radiologic imaging is an essential component of clinical staging, including chest radiography in some cases, computed tomography, MRI, and PET. Multiplanar imaging modalities allow assessment of features that are important for surgical, oncologic, and radiation therapy planning, including size of the primary tumor, location and relationship to normal anatomic structures in the thorax, and existence of nodal and/or metastatic disease. PMID- 26024600 TI - Imaging infection. AB - Thoracic imaging is widely used to detect lower respiratory tract infections, identify their complications, and aid in differentiating infectious from noninfectious thoracic disease. Less commonly, the combination of imaging findings and a clinical setting can favor infection with a specific organism. This confluence can occur in cases of bronchiectatic nontuberculous mycobacterial infections in immune-competent hosts, invasive fungal disease among neutropenic patients, Pneumocystis jiroveci pneumonia in patients with AIDS, and in cytomegalovirus infections in patients with recent hematopoietic cell transplantation. These specific diagnoses often depend on computed tomography scanning rather than chest radiography alone. PMID- 26024601 TI - Intensive care unit imaging. AB - Chest radiography serves a crucial role in imaging of the critically ill. It is essential in ensuring the proper positioning of support and monitoring equipment, and in evaluating for potential complications of this equipment. The radiograph is useful in diagnosing and evaluating the progression of atelectasis, aspiration, pulmonary edema, pneumonia, and pleural fluid collections. Computed tomography can be useful when the clinical and radiologic presentations are discrepant, the patient is not responding to therapy, or in further defining the pattern and distribution of a radiographic abnormality. PMID- 26024602 TI - Pulmonary vascular diseases. AB - Pulmonary vascular diseases encompass a large and diverse group of underlying pathologies ranging from venous thromboembolism to congenital malformations to inflammatory vasculitides. As a result, patients can present either acutely with dyspnea and chest pain or chronically with dyspnea on exertion, hypoxia, and right heart failure. Imaging, particularly with multidetector CT, plays a key role in the evaluation and management of patients with suspected pulmonary vascular disease and, given the widespread routine use of high-quality CT pulmonary angiography, it is imperative that radiologists be familiar these pathologies. PMID- 26024603 TI - Occupational and environmental lung disease. AB - Occupational and environmental lung disease remains a major cause of respiratory impairment worldwide. Despite regulations, increasing rates of coal worker's pneumoconiosis and progressive massive fibrosis are being reported in the United States. Dust exposures are occurring in new industries, for instance, silica in hydraulic fracking. Nonoccupational environmental lung disease contributes to major respiratory disease, asthma, and COPD. Knowledge of the imaging patterns of occupational and environmental lung disease is critical in diagnosing patients with occult exposures and managing patients with suspected or known exposures. PMID- 26024604 TI - Radiologic evaluation of idiopathic interstitial pneumonias. AB - The idiopathic interstitial pneumonias are a group of inflammatory and fibrosing pulmonary conditions that share many clinical, radiologic, and histologic similarities. Radiologic evaluation can often help to make a more confident diagnosis of these conditions and may help in their management. Several specific radiologic findings can suggest a single best diagnosis or can help to differentiate between similar conditions. Imaging findings can also have important prognostic implications or identify complications. This review discusses the role of radiologic findings in the setting of the idiopathic interstitial pneumonias. PMID- 26024605 TI - Connective Tissue Disease-related Thoracic Disease. AB - Pulmonary involvement is a frequent manifestation of connective tissue disease (CTD)-related thoracic disease. It is important to characterize the underlying pattern when pulmonary involvement occurs in a patient with CTD, and to exclude other causes. A systematic approach, evaluating each compartment of the lung (airway, interstitium, pleura, pulmonary vasculature) may be helpful. In complex cases, a multidisciplinary approach should be considered, potentially including the pulmonologist, rheumatologist, radiologist, pathologist, and sometimes the infectious disease specialist or oncologist. New techniques, such as quantitative computed tomography and MRI, are expected to be helpful for evaluation and management of CTD-associated thoracic disease. PMID- 26024162 TI - Combined Measurement of the Higgs Boson Mass in pp Collisions at sqrt[s]=7 and 8 TeV with the ATLAS and CMS Experiments. AB - A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H->gammagamma and H->ZZ->4l decay channels. The results are obtained from a simultaneous fit to the reconstructed invariant mass peaks in the two channels and for the two experiments. The measured masses from the individual channels and the two experiments are found to be consistent among themselves. The combined measured mass of the Higgs boson is m_{H}=125.09+/-0.21 (stat)+/-0.11 (syst) GeV. PMID- 26024606 TI - Cystic and nodular lung disease. AB - Diffuse cystic and nodular lung diseases have characteristic imaging findings. The most common causes of cystic lung disease are lymphangioleiomyomatosis and Langerhans cell histiocytosis. Other less common cystic lung diseases include Birt-Hogg-Dube syndrome, lymphocytic interstitial pneumonitis, and light chain deposition disease. Computed tomography is used to differentiate cystic lung disease from emphysema, honeycombing, cavities, and bronchiectasis, which mimic cystic lung disease. Diffuse nodular lung disease are categorized as centrilobular, perilymphatic, and random types. In diffuse nodular lung disease, a specific diagnosis is achieved through a combination of history, physical examination, and imaging findings. PMID- 26024607 TI - Imaging of the central airways with bronchoscopic correlation: pictorial essay. AB - A wide variety of pathologic processes, both benign and malignant, affect the central airways. These processes may be classified into 4 distinct groups: anatomic variants, lesions that result in focal or diffuse airway narrowing, and those that result in multinodular airway disorder. Key to the accurate assessment of the central airways is meticulous imaging technique, especially the routine acquisition of contiguous high-resolution, 1-mm to 1.5-mm images. These images enable high-definition axial, coronal, and sagittal reconstructions, as well as advanced imaging techniques, including minimum intensity projection images and virtual bronchoscopy. Current indications most commonly include patients presenting with signs and symptoms of possible central airway obstruction, with or without hemoptysis. In addition to diagnosing airway abnormalities, computed tomography (CT) also serves a critical complementary role to current bronchoscopic techniques for both diagnosing and treating airway lesions. Advantages of CT include noninvasive visualization of the extraluminal extent of lesions, as well as visualization of airways distal to central airways obstructions. As discussed and illustrated later, thorough knowledge of current bronchoscopic approaches to central airway disease is essential for optimal correlative CT interpretation. PMID- 26024610 TI - Chest Imaging. Preface. PMID- 26024613 TI - Optimized removal of antibiotic drugs from aqueous solutions using single, double and multi-walled carbon nanotubes. AB - In this study, experiments were carried out to investigate the use of as synthesized single-walled (SWCNT), double-walled (DWCNT) and multi-walled carbon nanotubes (MWCNT) agglomerates for the removal of two antibiotics, Oxytetracycline (OXY) and Ciprofloxacin (CIP) from aqueous solution. The variations of key operating parameters on the removal process were assessed in order to find out the optimum conditions. It includes exposure time, solution pH, temperature, ultrasound assistance and desorption assays. The experimental results revealed that a moderate increase in adsorption was registered between pH 3 and 7 for both antibiotics. The application of ultrasound helped enhancing the removal capacities of OXY for all tested CNTs. For the case of MWCNTs, 1h of ultrasonication increased the adsorption capacity by 44.6%. As for CIP, the ultrasonic treatment did not enhance the overall adsorption, especially for the case of DWCNTS. The Brouers-Sotolongo equation was the best fitting isotherm model. The highest removal capacities were registered using SWCNTS for both antibiotics (724 mg/g for CIP and 554 mg/g for OXY). In addition, ethanol was the solvent that induced the highest desorption percent for the case of CIP (52% for MWCNTs). However, the desorption of OXY was negligible for all solvents (maximum 3.3% for DWCNTs using ethanol). PMID- 26024614 TI - Sulfate reduction in sulfuric material after re-flooding: Effectiveness of organic carbon addition and pH increase depends on soil properties. AB - Sulfuric material is formed upon oxidation of sulfidic material; it is extremely acidic, and therefore, an environmental hazard. One option for increasing pH of sulfuric material may be stimulation of bacterial sulfate reduction. We investigated the effects of organic carbon addition and pH increase on sulfate reduction after re-flooding in ten sulfuric materials with four treatments: control, pH increase to 5.5 (+pH), organic carbon addition with 2% w/w finely ground wheat straw (+C), and organic carbon addition and pH increase (+C+pH). After 36 weeks, in five of the ten soils, only treatment +C+pH significantly increased the concentration of reduced inorganic sulfur (RIS) compared to the control and increased the soil pore water pH compared to treatment+pH. In four other soils, pH increase or/and organic carbon addition had no significant effect on RIS concentration compared to the control. The RIS concentration in treatment +C+pH as percentage of the control was negatively correlated with soil clay content and initial nitrate concentration. The results suggest that organic carbon addition and pH increase can stimulate sulfate reduction after re flooding, but the effectiveness of this treatment depends on soil properties. PMID- 26024611 TI - Identification of xenobiotic biodegradation and metabolism-related genes in the copepod Tigriopus japonicus whole transcriptome analysis. AB - In this study, the whole transcriptome of Tigriopus japonicus was sequenced using next generation sequencing technology. De novo assembly was performed using Trinity, which assembled 140,130 contigs. Transdecoder found 54,761 candidate coding contigs, 39,507 of which showed homology to other species covering 15,310 genes by BLAST analysis. Functional gene annotation was performed by Gene Ontology, InterProScan, and KEGG pathway analyses. In addition to various metabolism-related pathways, xenobiotic biodegradation and metabolism were other interesting pathways in T. japonicus. Transcripts encoding various enzymes (e.g. superoxide dismutase, heat shock protein, and peroxidases) in response to a variety of stimuli were identified, which might be useful candidate biomarkers for ecotoxicology studies. PMID- 26024608 TI - Imaging of small airways and emphysema. AB - High-resolution chest computed tomography (CT) is one of the most useful techniques available for imaging bronchiolitis because it shows highly specific direct and indirect imaging signs. The distribution and combination of these various signs can further classify bronchiolitis as either cellular/inflammatory or fibrotic/constrictive. Emphysema is characterized by destruction of the airspaces, and a brief discussion of imaging findings of this class of disease is also included. Typical CT findings include destruction of airspace, attenuated vasculatures, and hyperlucent as well as hyperinflated lungs. PMID- 26024609 TI - Functional imaging: computed tomography and MRI. AB - Standard imaging for the lungs allow excellent visualization of normal and abnormal pulmonary patterns. Computed tomography (CT), however, has limitations. The recognized patterns have limited specificity, do not always diagnose the pathology at a treatable stage, and do not provide physiologic information. Advances allow more physiologic approaches in lung imaging, namely, functional imaging. The main functional lung imaging modalities are CT and MRI. Contrast and noncontrast imaging approaches study pulmonary perfusion, dynamics of the flow in the pulmonary artery, and motion. Noble gases allow assessment of regional pulmonary ventilation. We discuss the role of novel imaging techniques in the functional lung assessment. PMID- 26024612 TI - Draft genome of amylolytic actinobacterium, Sinomonas humi MUSC 117(T) isolated from intertidal soil. AB - The amylolytic actinobacterium, Sinomonas humi MUSC 117(T) was isolated from intertidal soil from Kuantan, Malaysia. MUSC 117(T) exhibited significant starch hydrolysis activity and was chosen for further analysis. Here we report approximately 4.4 Mbp high quality genome sequence of MUSC 117(T). Availability of the genome sequence will contribute to better understanding for the strain and allow further exploitation of its biotechnological potential. PMID- 26024617 TI - First record of a large-scale bloom-causing species Nannochloropsis granulata (Monodopsidaceae, Eustigmatophyceae) in China Sea waters. AB - Nannochloropsis is an ubiquitous genus, found in diverse aquatic environments including open ocean as well as fresh and brackish water. Recently, large-scale blooms occurred frequently along eutrophic coastal zone from the Bohai Sea to the northern Yellow Sea in China. The cell density reached 10(9) to 10(10)cells per liter during a bloom near Qinhuangdao, Hebei Province. The bloom forming species, a yellow-green microalgae was successfully isolated and cultivated in the laboratory. Microscopic observation indicated that the cells contained simple morphological characteristics with a diameter about 2 MUm. Pigment analyses confirmed that the pigment composition of the newly isolated strain BDH02 was similar to that of Nannochloropsis granulata. Phylogenetic analyses of 18S rRNA gene, ITS, and rbcL gene indicated that the strain was closely related to N. granulata. This is the first record of a bloom caused by N. granulata in China. PMID- 26024616 TI - Sequential processing in an auditory equiprobable Go/NoGo task with variable interstimulus interval. AB - A recent series of studies of the auditory equiprobable Go/NoGo task, using fixed interstimulus intervals (ISIs), proposed a processing schema relating observed event-related potential (ERP) components to sequential processing stages. However, it has been demonstrated that attention and ERP components can be affected by the predictable rhythmic timing of fixed ISIs. Hence the aim of the current study was to test the robustness of that processing schema with an unpredictable arrhythmic variable ISI. EEG was recorded from 30 university students at 30 scalp sites in an unwarned auditory equiprobable Go/NoGo task using a variable ISI. Following our previous studies, Go and NoGo ERP components were derived using temporal principal components analysis (PCA). Of the unrestricted Varimax-rotated factors, seven were identifiable as components based on their topography, polarity, and latency: two subcomponents of the N1 (N1-1, and processing negativity, PN), P2/N2b, N2c/P3a, P3b, and two subcomponents of the slow wave (SW-1 and SW-2). These components showed Go/NoGo effects comparable to those previously noted with fixed ISI, supporting the proposed processing schema. The Late Positivity (LP) component, previously speculated to mark cortical deactivation after processing the NoGo stimulus, was not present in the sequence of components. In its absence, activity underlying the observed sustained P300/late positive complex may be involved in processing temporally uncertain stimuli. PMID- 26024621 TI - Validation of genotyping protocols for diagnostic use. AB - This chapter contains some advice for first validating a new genotyping method and then continuing to ensure that it performs well when adopted for routine use. It should be applicable to most of the genotyping methods described in this volume; however, because the range of techniques is so wide and these recommendations have been written with PCR amplification in mind, the reader may need to adapt some of the recommendations for non-PCR based tests.It does not include any advice on how to handle unscreened human samples within the laboratory, and it assumes that the laboratory already has established good practice for DNA amplification and the avoidance of contamination. PMID- 26024615 TI - Photocatalytic degradation of sulfamethoxazole in aqueous solution using a floating TiO2-expanded perlite photocatalyst. AB - Photocatalytic degradation of an antibiotic, sulfamethoxazole (SMX), in aqueous solution using a novel floating TiO2-expanded perlite photocatalyst (EP-TiO2-773) and radiation from the near UV spectral range was studied. The process is important considering that SMX is known to be a widespread and highly persistent pollutant of water resources. SMX degradation was described using a pseudo-first order kinetic equation according to the Langmuir-Hinshelwood model. The products of the SMX photocatalytic degradation were identified. The effect of pH on the kinetics and mechanism of SMX photocatalytic degradation was explained. PMID- 26024619 TI - Select metal and metalloid surveillance of free-ranging Eastern box turtles from Illinois and Tennessee (Terrapene carolina carolina). AB - The Eastern box turtle (Terrapene carolina carolina) is a primarily terrestrial chelonian distributed across the eastern US. It has been proposed as a biomonitor due to its longevity, small home range, and reliance on the environment to meet its metabolic needs. Plasma samples from 273 free-ranging box turtles from populations in Tennessee and Illinois in 2011 and 2012 were evaluated for presence of heavy metals and to characterize hematologic variables. Lead (Pb), arsenic (As), zinc (Zn), chromium (Cr), selenium (Se), and copper (Cu) were detected, while cadmium (Cd) and silver (Ag) were not. There were no differences in any metal detected among age class or sex. However, Cr and Pb were higher in turtles from Tennessee, while As, Zn, Se, and Cu were higher in turtles from Illinois. Seasonal differences in metal concentrations were observed for Cr, Zn, and As. Health of turtles was assessed using hematologic variables. Packed cell volume was positively correlated with Cu, Se, and Pb in Tennessee. Total solids, a measure of plasma proteins, in Tennessee turtles were positively correlated with Cu and Zn. White blood cell count, a measure of inflammation, in Tennessee turtles was negatively correlated with Cu and As, and positively correlated with Pb. Metals are a threat to human health and the health of an ecosystem, and the Eastern Box Turtle can serve as a monitor of these contaminants. Differences established in this study can serve as baseline for future studies of these or related populations. PMID- 26024620 TI - Transitions of Care in Continuity Clinic--Lessons Learned and Next Steps. PMID- 26024618 TI - Bacterial growth efficiency in a partly eutrophicated bay of South China Sea: Implication for anthropogenic impacts and potential hypoxia events. AB - Bacterial metabolism plays a dual role [bacterial production (BP) and bacterial respiration (BR)] in the aquatic ecosystem and potentially leads to hypoxia in the coastal eutrophic area. Bacterial growth efficiency (BGE) is an important index showing the contribution of bacterial metabolism to marine biological production and carbon budget in the pelagic ecosystem. In this study, the spatial and seasonal variety as well as diurnal variation dynamics of BGE and associated ecological characteristics were investigated in a partly eutrophicated subtropical bay (the Daya Bay) located in the northern South China Sea. Furthermore, the relationship between bacterial metabolism and potential hypoxia event was analyzed. The average BGE was 0.14 and 0.22 in summer and winter, respectively, which was lower than the mean value ever reported in other coastal and estuarine waters. The diurnal variations of BGE and BP were widely fluctuated in the Daya Bay, with approximately 3-8 fold variation of BP and 2-3 fold variation of BR in different seasons, suggesting the importance of short-term ecological dynamics on evaluating the long-term ecological processes in the coastal waters. BR was the predominant contributor to the bacterial carbon demand; however, the variation of BGE was controlled by BP in both seasons. BGE was always high in the near-shore waters with higher eutrophic level and more active BP and BR. The bacterial metabolism could deplete dissolved oxygen (DO) in the Daya bay within about 9 days when the water body was enclosed and photosynthesis was prohibited. Therefore, low DO concentration and potential hypoxia was more likely to be found in the near-shore waters of the Daya Bay in summer, since the water was stratified and enclosed with poor water exchange capacity in this area. While in winter, hypoxia seldom occurred due to vertical mixing throughout the water column. Further biological-physical coupling research is recommended to find out the detailed formation mechanism of hypoxia in the bay, and to predict the potential hypoxia events and their environmental impacts in the future. PMID- 26024624 TI - Blood grouping based on PCR methods and agarose gel electrophoresis. AB - The study of erythrocyte antigens continues to be an intense field of research, particularly after the development of molecular testing methods. More than 300 specificities have been described by the International Society for Blood Transfusion as belonging to 33 blood group systems. The polymerase chain reaction (PCR) is a central tool for red blood cells (RBC) genotyping. PCR and agarose gel electrophoresis are low cost, easy, and versatile in vitro methods for amplifying defined target DNA (RBC polymorphic region). Multiplex-PCR, AS-PCR (Specific Allele Polymerase Chain Reaction), and RFLP-PCR (Restriction Fragment Length Polymorphism-Polymerase Chain Reaction) techniques are usually to identify RBC polymorphisms. Furthermore, it is an easy methodology to implement. This chapter describes the PCR methodology and agarose gel electrophoresis to identify the polymorphisms of the Kell, Duffy, Kidd, and MNS blood group systems. PMID- 26024622 TI - High-resolution melting analysis of single nucleotide polymorphisms. AB - The technology of Single Nucleotide Polymorphism (SNP) detection has evolved steadily through mobility shift studies, mass cleavage product evaluations, heterodimer differences in chemical, conformational, and enzymatic properties, mass spectroscopy and sequencing, to allele-specific hybridization probe methods. Each method presented challenges of labor intensity, unreliable efficiencies, complicated optimizations, and issues of sample quantity and quality. Concurrently the value of SNP detection in basic research and personalized medicine has continued to grow. Accessing the secrets of genetic individuality is the next frontier in moving medicine from the description of very low frequency and highly deleterious nucleotide changes to the study of very low frequency polymorphisms, lower penetrance polymorphisms, and polymorphisms with public health importance. High-Resolution Melting (HRM) analysis of SNP status became an option for high throughput settings with the development of double-stranded dyes that do not interfere with PCR amplification in saturation, eliminate dye jumping, and nearest neighbor sequence changes influence melt temperature via amplicon strand locking chemistry. This method is able to distinguish transitions, transversions, and identify novel changes at or near the SNP of interest rapidly, inexpensively, and without post-amplification assay techniques or extensive technical interpretation of data. For probe or solid matrix based assays, the investigator initially defines a set of target sequences for binding. These assays are not only difficult due to the optimization of binding conditions but are unable to detect sequences that were not included in the design, often have marginalized binding due to a "one size fits all" reaction, and are not distinct in the case of heterozygotes. PMID- 26024623 TI - High-speed droplet-allele-specific polymerase chain reaction for genotyping of single nucleotide polymorphisms. AB - Single nucleotide alternations such as single nucleotide polymorphisms (SNPs) or single nucleotide mutations are useful genetic markers for molecular diagnosis, prognosis, drug response, and predisposition to diseases. Rapid identification of SNPs or mutations is clinically important, especially for determining drug responses and selection of molecular-targeted therapy. Here, we describe a rapid genotyping assay based on the allele-specific polymerase chain reaction (AS-PCR) by using our droplet-PCR machine (droplet-AS-PCR). PMID- 26024625 TI - Parallel donor genotyping for 46 selected blood group and 4 human platelet antigens using high-throughput MALDI-TOF mass spectrometry. AB - Most blood group antigens are defined by single nucleotide polymorphisms (SNPs). Highly accurate MALDI-TOF MS has proven its potential in SNP genotyping and was therefore chosen for blood donor oriented genotyping with high-throughput capability, e.g., 380 samples per day. The Select Module covers a total of 36 SNPs in two single-tube reactions, representative of 46 blood group and 4 human platelet antigens. Using this tool, confirmatory blood group typing for RhD, RhCE, Kell, Kidd, Duffy, MN, Ss, and selected rare antigens is performed on a routine basis. PMID- 26024626 TI - PCR with sequence-specific primers for typing of diallelic blood groups. AB - PCR with sequence-specific primers (PCR-SSP) is a cost-effective and robust method for the analysis of single nucleotide polymorphisms (SNPs). Many blood group antigens and the antithetic antigens are based on a diallelic SNP in the coding region of the corresponding blood group gene. Here, we describe PCR-SSP protocols for genotyping 24 blood group antigens based on 12 diallelic SNPs. We also provide protocols for molecular determination of the rare blood group phenotypes Yk(a-) and Vel-. PMID- 26024627 TI - High-resolution melting analysis for genotyping Duffy blood group antigens. AB - Antigens of the Duffy (Fy) blood group are significant in medical transfusions since they may cause serious post-transfusion reactions and hemolytic disease of the fetus and newborn. Results of serotyping performed on donors with reduced or abolished erythrocyte Duffy expression may be misleading, since the Duffy antigen is also present on non-erythroid cells. In such cases only DNA-based genotyping may reveal the actual Duffy antigen status. Here we describe the high-resolution melting (HRM) method for Duffy genotyping, which is a new post-PCR analysis method used for identifying genetic variations in nucleic acid sequences. It is based on the PCR melting curve technique where single nucleotide polymorphism (SNP) in DNA determines a characteristic shape of the melting curve and melting temperature (Tm) of a sample. HRM analysis for FY genotyping can discriminate SNPs in the FY gene through detection of small differences in melting profiles of variants when compared to controls. Recently, we have shown the usefulness of HRM analysis in elucidation of the molecular basis of Duffy-negative phenotype in a Polish family and in large-scale Duffy genotyping. PMID- 26024628 TI - Molecular RHD-RHCE Analysis by Multiplex PCR of Short Fluorescent Fragments. AB - Several hundred variant alleles have been reported within the homologous RHD and RHCE genes that encode the antigens involved in the human Rh blood group system, which is of the main interest in the field of both transfusion and obstetrical medicine. Although these variants can be mostly characterized at the molecular level by sequence-specific primer polymerase chain reaction (SSP-PCR) and/or direct sequencing, some allelic combinations remain unresolved by conventional methods. Typically exon deletion or hybrid genes may be difficult to assess in a heterozygous context. Here we describe a qualitative and quantitative method to resolve copy number variations in the RH gene exons by quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF). PMID- 26024629 TI - Microarrays in blood group genotyping. AB - Thirty-five blood group systems, containing more than 300 antigens, are listed by the International Society of Blood Transfusion (ISBT). Most of these antigens result from a single-nucleotide polymorphism (SNP). Blood group typing is conventionally carried out by serology. However, this technique has certain limitations and cannot respond to the growing demand for blood products typed for a large number of antigens. Here we describe a blood group genotyping assay, from genomic DNA extraction from whole-blood samples to results. After DNA extraction, the on-chip test is based on the hybridization of targets beforehand amplified by multiplex polymerase chain reaction, followed by a revelation step allowing the simultaneous identification of up to 24 blood group antigens and leading to the determination of extended genotypes. PMID- 26024630 TI - Next-Generation Sequencing for Antenatal Prediction of KEL1 Blood Group Status. AB - The KEL1 antigen can give rise to immunization of KEL2 mothers. Maternal antibodies can be transferred to the fetus and destroy fetal red blood cells and their stem cell precursors and give rise to serious fetal disease. It is important to be able to predict the fetal KEL status in order to intervene in those pregnancies where the fetus is at risk, and to ascertain when the fetus is not at risk. Technically it can be demanding to predict KEL1 status from a maternal blood sample. The KEL1 allele is based on a single SNP present in about 1-10 % of cell-free maternal DNA after gestation week 10. Here we describe our protocol for antenatal prediction of fetal KEL1 status by NGS analysis of maternal DNA on a MiSeq instrument. PMID- 26024631 TI - 454-SequencingTM for the KEL, JR, and LAN Blood Groups. AB - The KEL (ISBT 006), JR (ISBT 032), and LAN (ISBT 033) blood group systems are defined by a complex genetics with a large number of exons, and numerous gene variants. In order to sequence the 53 coding exons and flanking intron regions of all three blood group genes we developed a next-generation-sequencing method using 454-sequencingTM on a Genome Sequencer (GS) JuniorTM system. Multiplex analysis of eight individual DNA samples was achieved using molecular identifiers. PMID- 26024633 TI - Genotyping of Human Platelet Antigens by BeadChip Microarray Technology. AB - Human platelet antigen (HPA) typing plays a critical role in the diagnosis of fetal/neonatal alloimmune thrombocytopenia, and the prevention of posttransfusion purpura and refractoriness to platelet transfusions. The recent development of high-throughput genotyping methods, allowing simultaneous genotyping of as many as 17 HPAs, is of utmost interest for saving time and money. Here, we describe a microarray technology named "BeadChip," designed for HPA-1 to -9, -11, and -15 genotyping of up to 96 individuals, in approximately 5 h. This technology was used to study allele frequencies in Brazilian blood donors, considering the heterogeneous ethnic composition. PMID- 26024632 TI - Noninvasive prenatal blood group genotyping. AB - Determination of fetal RHD from maternal plasma is increasingly used as a valuable tool for prenatal diagnosis. A remaining pitfall which hampers its use in situations with severe consequences is the following: (a) The reliability of negative results, however, is limited by difficulties to distinguish true negative results from false negative results due to insufficient amounts of free fetal DNA (ffDNA). False negative results can result in severe complications for the fetus and have to be reliably excluded. Large studies were performed in the last 10 years to investigate the reliability of noninvasive fetal RHD typing with real-time PCR. The majority of the assays were performed without internal controls. We present a protocol for inclusion of standards to assess the presence of adequate amounts of ffDNA for prenatal genotyping in maternal blood. PMID- 26024634 TI - Sequence-Based Typing for Platelet alloantigens. AB - Human platelet antigen (HPA) typing is largely performed by use of DNA-based techniques in patients that require assessing the risk of HPA alloimmunization. In this chapter, HPA typing by sequencing-based typing (SBT) techniques is described. PMID- 26024635 TI - Miniaturized technology for DNA typing: cassette PCR. AB - With the smaller size, low cost, and rapid testing capabilities, miniaturized lab on-a-chip devices can change the way medical diagnostics are currently performed in the health-care system. We have demonstrated such a device that is self contained, simple, disposable, and inexpensive. It is capable of performing DNA amplification on an inexpensive instrument suitable for near point of care settings. This technology will enable on the spot evaluation of patients in the clinic for faster medical decision-making and more informed therapeutic choices. Our device, a gel capillary cassette, termed cassette PCR, contains capillary reaction units each holding a defined primer set, with arrays of capillary reaction units for simultaneously detecting multiple targets. With the exception of the sample to be tested, each capillary reaction unit holds all the reagents needed for PCR in a desiccated form that can be stored at room temperature for up to 3 months and even longer in colder conditions. It relies on capillary forces for sample delivery of microliter volumes through capillaries, hence avoiding the need for pumps or valves. In the assembled cassette, the wax architecture supporting the capillaries melts during the PCR and acts as a vapor barrier as well as segregating capillaries with different primer sets. No other chip sealing techniques are required. Cassette PCR accepts raw samples such as urine, genital swabs, and blood. The cassette is made with off-the-shelf components and contains integrated positive and negative controls. PMID- 26024636 TI - Geno- and phenotyping of human neutrophil antigens. AB - For typing of human neutrophil antigens (HNA) usually genotyping techniques are used, except for HNA-2, which-due to a gene expression defect-requires phenotyping. For genotyping, several techniques have been described. Most reference laboratories use variations of the polymerase chain reaction (PCR) for antigen typing which showed good results in international quality assessment exercises. The granulocyte immunofluorescence test has been the gold standard technique for phenotyping for all HNA antigens except for HNA-3a and -3b phenotyping. The expression of the latter antigens on neutrophils is often better shown by the use of the granulocyte agglutination test. PMID- 26024637 TI - Allelic Discrimination by TaqMan-PCR for Genotyping of Human Neutrophil Antigens. AB - Neutrophil antigens are implicated in a variety of clinical conditions, including neonatal immune neutropenia, transfusion-related acute lung injury, refractoriness to granulocyte transfusions, febrile transfusion reactions, and autoimmune neutropenia. In this report, we describe simultaneous genotyping of human neutrophil antigens (HNA)-1, -3, -4, and -5 using PCR with allele-specific TaqMan probes and end-point fluorescence detection, which is a robust, rapid, and reproducible method, allowing for high-throughput genotyping. PMID- 26024638 TI - Novel Approaches and Technologies in Molecular HLA Typing. AB - The invention of the Polymerase Chain Reaction (PCR) has revolutionized molecular biology enabling gene isolation and characterization in hours rather than days. Scientists working in transplant diagnostics have proven to be pioneers in adapting this molecular technique to the clinical needs of histocompatibility testing. This chapter describes a number of novel genotyping technologies which have been used to address the challenges posed by genetic diversity seen in the extensive polymorphism in HLA genes. These novel approaches include single stranded and duplex conformational analyses, real-time PCR, microarray hybridization, RNA-based sequencing, and the present day Next Generation Sequencing. The chapter concludes with a brief look at a possible next, Next Generation Sequencing system. PMID- 26024639 TI - Luminex-Based Methods in High-Resolution HLA Typing. AB - Luminex-based technology has been applied to discriminate between the different Human Leukocyte Antigens (HLA) alleles. The typing method consists in a reverse SSO assay: Target DNA is PCR-amplified using biotinylated group-specific primers. A single PCR reaction is used for each HLA locus. The biotinylated PCR product is chemically denatured using a pH change and allowed to rehybridize to complementary DNA probes conjugated to microspheres. These beads are characterized by two internal fluorescent dyes that create a unique combination of color, make them identifiable. Washes are performed to eliminate any additional PCR product that does not exactly match the sequence detected by the probe. The biotinylated PCR product bound to the microsphere is labelled with streptavidin conjugated with R-phycoerythrin (SAPE). A flow analyzer identifies the fluorescent intensity SAPE on each microsphere. Software is used to assign positive or negative reactions based on the strength of the fluorescent signal. The assignment of the HLA typing is based on positive and negative probe reactions compared with published HLA gene sequences. Recently kits characterized by an extensive number of probes/beads designed to potentially reduce the number of ambiguities or to directly lead to an allele level typing, have been made available. PMID- 26024640 TI - In Silico HLA Typing Using Standard RNA-Seq Sequence Reads. AB - Next-generation sequencing (NGS) enables high-throughput transcriptome profiling using the RNA-Seq assay, resulting in billions of short sequence reads. Worldwide adoption has been rapid: many laboratories worldwide generate transcriptome sequence reads daily. Here, we describe methods for obtaining a sample's human leukocyte antigen (HLA) class I and II types and HLA expression using standard NGS RNA-Seq sequence reads. We demonstrate the application using our algorithm, seq2HLA, and a publicly available RNA-Seq dataset from the Burkitt lymphoma cell line Raji. PMID- 26024641 TI - Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency. AB - Complex I (CI) deficiency is the most common respiratory chain defect representing more than 30% of mitochondrial diseases. CI is an L-shaped multi subunit complex with a peripheral arm protruding into the mitochondrial matrix and a membrane arm. CI sequentially assembled into main assembly intermediates: the P (pumping), Q (Quinone) and N (NADH dehydrogenase) modules. In this study, we analyzed 11 fibroblast cell lines derived from patients with inherited CI deficiency resulting from mutations in the nuclear or mitochondrial DNA and impacting these different modules. In patient cells carrying a mutation located in the matrix arm of CI, blue native-polyacrylamide gel electrophoresis (BN-PAGE) revealed a significant reduction of fully assembled CI enzyme and an accumulation of intermediates of the N module. In these cell lines with an assembly defect, NADH dehydrogenase activity was partly functional, even though CI was not fully assembled. We further demonstrated that this functional N module was responsible for ROS production through the reduced flavin mononucleotide. Due to the assembly defect, the FMN site was not re-oxidized leading to a significant oxidative stress in cell lines with an assembly defect. These findings not only highlight the relationship between CI assembly and oxidative stress, but also show the suitability of BN-PAGE analysis in evaluating the consequences of CI dysfunction. Moreover, these data suggest that the use of antioxidants may be particularly relevant for patients displaying a CI assembly defect. PMID- 26024642 TI - Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration. AB - Auranofin is a gold based drug in clinical use since 1985 for the treatment of rheumatoid arthritis. Beyond its antinflammatory properties, auranofin exhibits other attractive biological and pharmacological actions such as a potent in vitro cytotoxicity and relevant antimicrobial and antiparasitic effects that make it amenable for new therapeutic indications. For instance, auranofin is currently tested as an anticancer agent in four independent clinical trials; yet, its mode of action is highly controversial. With the present study, we explore the effects of auranofin in Saccharomyces cerevisiae and its likely mechanism. Notably, auranofin is reported to induce remarkable yeast growth inhibition. Solid evidence is provided that growth inhibition is the consequence of a direct cytotoxic insult occurring at the mitochondrial level; a profound depression of cell respiration is indeed clearly documented as the main cause of cell death while induction of ROS plays only a secondary role. More in detail, the mitochondrial NADH kinase Pos5 is identified as a primary target for auranofin. The implications of these results are discussed in the frame of current mechanistic knowledge on the cellular effects of auranofin and of its role as a prospective anticancer drug. PMID- 26024643 TI - [Chronic myofacial pain. Reduced pain through psychoeducation and physiotherapy]. AB - BACKGROUND: Psychological factors are associated with the emergence and persistence of pain perception. The aim of this pilot study was to assess the psychological factors relating to pain perception in patients with chronic myofacial pain and to investigate the influence of patient information, education and physiotherapy on pain perception and functional jaw opening examined over a 6 month period. PATIENTS AND METHODS: In accordance with the research diagnostic criteria for temporomandibular disorders (RDC/TMD), 40 patients (31 females and 9 males, mean age 38.6 years) with chronic myofacial pain were assessed at 3 time points: on admission (T1), after 3 months (T2) and 6 months (T3). The study included a structured interview and five psychological questionnaires. At all time points patients were informed about the development of pain and the relationship between chronification of pain and psychological risk factors. RESULTS: After 6 months significant improvements in jaw function and quality of life, as well as a decrease in psychological parameters, such as fear and depression were found. Improvement was related to the severity of pain chronification. CONCLUSION: The results show the necessity of early identification of patients with severe pain chronification and the need for psychological pain therapy. PMID- 26024644 TI - [Pain measurement in cognitively impaired patients with the Doloshort scale]. AB - BACKGROUND: Until recently the measurement of pain in cognitively impaired patients represented a neglected field in the diagnostics and treatment of pain. Investigations indicate a prevalence of pain in nursing home residents of between 45 % and 80 %. MATERIAL AND METHODS: This study investigated the reliability of the German translation of the Doloshort scale and compared it with the visual analog scale (VS). The aim of this study was to determine the practical applicability of this scale in the clinical routine and to calculate the intrarater reliability (retest) and interrater reliability. RESULTS: The interrater and intrarater reliability of the Doloshort scale was between 0.949 and 0.970. There was a highly significant correlation between the values of the Doloshort scale and the VAS. CONCLUSION: The Doloshort scale is a well suited measurement instrument for the evaluation of pain in cognitively impaired patients. Because of the short form only simple instructions are necessary and it has a high acceptance with users. PMID- 26024645 TI - [Psychological assessment and psychotherapy for chronic pain in the elderly]. AB - Systematic reviews of psychosocial assessment and effectiveness of psychotherapy for chronic pain syndromes in older patients are rare. However, it is of particular importance to consider the psychosocial aspects of elderly people with chronic pain. This narrative review describes recommended German-language assessments of the psychosocial dimensions of pain and summarizes existing studies of psychological therapy approaches for chronic pain in old age. Effective psychometric instruments are available for the assessment of cognitive function, pain-specific attitudes, depression, fear of falling, interpersonal processes and social activities, pain management, pain acceptance, disability, psychological well-being, and quality of life. Further experience with the use of these instruments with cognitively impaired or geriatric patients is required. The efficacy of age-adapted cognitive behavioral therapy and multimodal therapy for older patients has been documented. However, there is often a lack of supporting documentation about important result parameters (e.g., quality of life, functioning in everyday life, or pain acceptance). Overall, chronic pain in elderly people requires a biopsychosocial-spiritual model of pain. More attention should be given in research and daily practice to religiosity/spirituality as a possible means of coping, while mindfulness- and acceptance-based therapies should be further explored. PMID- 26024646 TI - Total Cavopulmonary Connection is Superior to Atriopulmonary Connection Fontan in Preventing Thrombus Formation: Computer Simulation of Flow-Related Blood Coagulation. AB - The classical Fontan route, namely the atriopulmonary connection (APC), continues to be associated with a risk of thrombus formation in the atrium. A conversion to a total cavopulmonary connection (TCPC) from the APC can ameliorate hemodynamics for the failed Fontan; however, the impact of these surgical operations on thrombus formation remains elusive. This study elucidates the underlying mechanism of thrombus formation in the Fontan route by using a two-dimensional computer hemodynamic simulation based on a simple blood coagulation rule. Hemodynamics in the Fontan route was simulated with Navier-Stokes equations. The blood coagulation and the hemodynamics were combined using a particle method. Three models were created: APC with a square atrium, APC with a round atrium, and TCPC. To examine the effects of the venous blood flow velocity, the velocity at rest and during exercise (0.5 and 1.0 W/kg) was measured. The total area of the thrombi increased over time. The APC square model showed the highest incidence for thrombus formation, followed by the APC round, whereas no thrombus was formed in the TCPC model. Slower blood flow at rest was associated with a higher incidence of thrombus formation. The TCPC was superior to the classical APC in terms of preventing thrombus formation, due to significant blood flow stagnation in the atrium of the APC. Thus, local hemodynamic behavior associated with the complex channel geometry plays a major role in thrombus formation in the Fontan route. PMID- 26024648 TI - To the Editor. PMID- 26024647 TI - Quality of Life of Children with Congenital Heart Diseases: A Multicenter Controlled Cross-Sectional Study. AB - To assess the health-related quality of life (QoL) in children with congenital heart diseases (CHD) with a validated questionnaire in comparison with control children. We prospectively recruited 282 children with CHD aged from 8 to 18 years in two tertiary care centers (France and Belgium) and 180 same-age controls in randomly selected French schools. Children's QoL was self-reported with the KIDSCREEN-52 questionnaire and reported by parents with the KIDSCREEN-27. QoL scores of each dimension were compared between CHD and controls and between the classes of disease severity. Both centers were comparable for most demographic and clinical data. Age- and gender-adjusted self-reported QoL scores were lower in CHD children than in controls for physical well-being (mean +/- SEM 45.97 +/- 0.57 vs 50.16 +/- 0.71, p < 0.0001), financial resources (45.72 +/- 0.70 vs 48.85 +/- 0.87, p = 0.01), peers/social support (48.01 +/- 0.72 vs 51.02 +/- 0.88, p = 0.01), and autonomy in the multivariate analysis (47.63 +/- 0.69 vs 49.28 +/- 0.85, p = 0.04). Parents-reported scores were lower in CHD children for physical (p < 0.0001), psychological well-being (p = 0.04), peers/social support (p < 0.0001), and school environment (p < 0.0001) dimensions. Similarly, the disease severity had an impact on physical well-being (p < 0.001), financial resources (p = 0.05), and peers/social support (p = 0.01) for self-reported dimensions, and on physical well-being (p < 0.001), psychological well-being (p < 0.01), peers/social support (p < 0.001), and school environment (p < 0.001) for parents reported dimensions. However, in multivariate analysis on self-reported QoL, disease severity was significantly associated with the self-perception dimension only. Self-reported QoL of CHD children was similar to that of same-age healthy children in seven of 10 dimensions, but parents-reported QoL was impaired in four of five dimensions. PMID- 26024649 TI - [Irreversible electroporation. Current value for focal treatment of prostate cancer]. AB - BACKGROUND: Irreversible electroporation (IRE), a new tissue ablation procedure available since 2007, could meet the requirements for ideal focal therapy (FT) with its postulated features, especially the absence of a thermal ablative effect. Thus far, there is no adequate tumor-entity-specific proof of its effectiveness, and its clinical application has hitherto been confined to very small patient cohorts. This also holds true for prostate cancer (PCA). Nevertheless, it is now being increasingly applied outside clinical trials-to a certain extent due to active advertising in the lay press. AIM OF THE STUDY: In this study, current discrepancies between the clinical application and study situation and the approval and market implementation of the procedure are described. The media portrayal of IRE is discussed from different perspectives, particularly with reference to the FT of PCA. This is followed by a final clinical assessment of IRE using the NanoKnife(r) system. DISCUSSION: Strict requirements govern new drug approvals. According to the German Drug Act (AMG), evidence of additional benefit over existing therapy must be provided through comparative clinical trials. For medicotechnical treatment procedures, on the other hand, such trial-based proof is not required according to the Medical Devices Act (MPG). The use of IRE even outside clinical trials has been actively promoted since the NanoKnife(r) system was put on the market. This has led to an increase in the number of uncontrolled IRE treatments of PCA in the last 2 years. The patients have to cover the high treatment costs themselves in these cases. If articles in the lay press advertise the procedure with promising but unverified contents, false hopes are raised in those concerned. This is disastrous if it delays the use of truly effective treatment options. CONCLUSION: IRE basically still has high potential for the treatment of malignancies; however, whether it can really be used for FT remains unclear due to the lack of data. This also holds true for the treatment of PCA. Only carefully conducted scientific research studies can clarify the unresolved issues regarding IRE of PCA. The urgently needed development of universally valid treatment standards for IRE is unnecessarily hampered by the flow commercially driven patients. PMID- 26024650 TI - The High performance of nanocrystalline CVD diamond coated hip joints in wear simulator test. AB - The superior biotribological performance of nanocrystalline diamond (NCD) coatings grown by a chemical vapor deposition (CVD) method was already shown to demonstrate high wear resistance in ball on plate experiments under physiological liquid lubrication. However, tests with a close-to-real approach were missing and this constitutes the aim of the present work. Hip joint wear simulator tests were performed with cups and heads made of silicon nitride coated with NCD of ~10 MUm in thickness. Five million testing cycles (Mc) were run, which represent nearly five years of hip joint implant activity in a patient. For the wear analysis, gravimetry, profilometry, scanning electron microscopy and Raman spectroscopy techniques were used. After 0.5 Mc of wear test, truncation of the protruded regions of the NCD film happened as a result of a fine-scale abrasive wear mechanism, evolving to extensive plateau regions and highly polished surface condition (Ra<10nm). Such surface modification took place without any catastrophic features as cracking, grain pullouts or delamination of the coatings. A steady state volumetric wear rate of 0.02 mm(3)/Mc, equivalent to a linear wear of 0.27 MUm/Mc favorably compares with the best performance reported in the literature for the fourth generation alumina ceramic (0.05 mm(3)/Mc). Also, squeaking, quite common phenomenon in hard-on-hard systems, was absent in the present all-NCD system. PMID- 26024652 TI - Where is the radiobiology and pharmacology research to improve outcomes in glioblastoma? AB - Personalized medicine has been helpful for drug development in diseases with single and relatively stable gene mutations. The benefit for complex solid tumours with heterogeneous and changing genetic profiles is less clear. Whether it is efficient to continue diverting resources from combined biological and pharmacological approaches to trial new and existing genetic 'targeted therapies' for brain tumours is unknown but of developing concern in resource constrained environments. PMID- 26024651 TI - Silver nanoparticles activate endoplasmic reticulum stress signaling pathway in cell and mouse models: The role in toxicity evaluation. AB - Silver nanoparticles (AgNPs) attract considerable public attention both for their antimicrobial properties and their potential adverse effects. In the present study, endoplasmic reticulum (ER) stress was used as a sensitive and early biomarker to evaluate the toxic potential of AgNPs in three different human cell lines in vitro and in vivo in mice. In 16HBE cells, the activation of ER stress signaling pathway was observed by upregulated expression including xbp-1s, chop/DDIT3, TRIB3, ADM2, BIP, Caspase-12, ASNS and HERP at either the mRNA and/or protein levels. However, these changes were not observed in HUVECs or HepG2 cells. Furthermore, mice experiments showed that different tissues had various sensitivities to AgNPs following intratracheal instillation exposure. The lung, liver and kidney showed significant ER stress responses, however, only the lung and kidney exhibited apoptosis by TUNEL assay. The artery and tracheal tissues had lower ER stress and apoptosis after exposure. The lowest observable effect concentrations (LOEC) were proposed based on evaluation of AgNP induced ER stress response in cell and mouse models. In summary, preliminary evaluation of AgNP toxicity by monitoring the ER stress signaling pathway provides new insights toward the understanding the biological impacts of AgNPs. The adverse effects of exposure to AgNPs may be avoided by rational use within the safe dose. PMID- 26024653 TI - Re-resection for recurrent high-grade glioma in the setting of re-irradiation: more is not always better. AB - The optimal treatment for patients with recurrent high grade glioma (HGG) remains controversial. Available therapies include surgery, re-irradiation, alternating electric fields or systemic therapy. Here we investigate whether re-resection will improve survival in patients receiving repeat radiotherapy for tumor recurrence. 231 consecutive patients with recurrent HGG treated with re irradiation between 1994 and 2012 were analyzed. 105 patients underwent re resection. Re-irradiation was delivered using daily fractions of 3.5 Gy to a median total dose of 35 Gy. Survival was then analyzed comparing patients with and without re-resection. Overall survival (OS) and survival from the first recurrence are reported. Univariate and cox-proportional hazard modeling was performed in a step-wise multivariate analysis using known prognostic factors. The median follow-up time from initial diagnosis was 25.7 months. The median OS from initial diagnosis of the entire group was 22.5 months. There was no significant difference in median overall survival between patients who received re-resection versus no re-resection, 23 versus 21.9 months respectively (p = 0.6). Additionally, there was no difference in median survival from the time of first recurrence 10.5 months without re-resection versus 11.1 months with re resection (p = 0.09). After adjusting for known prognostic variables, only age remained significant. Re-irradiation is an effective salvage therapy for patients with localized, progressive high grade glioma, achieving a median survival of 10 11 months from re-irradiation. Our data reveals no significant improvement in survival with the addition of re-resection to re-irradiated patients with HGG. PMID- 26024654 TI - Incidence of vestibular schwannomas in the United States. AB - There is a paucity of population-based data evaluating the incidence of vestibular schwannomas according to age, gender, race, and ethnicity. Such data are necessary to assess the burden of vestibular schwannomas on varying populations and to inform future research and healthcare planning. The Central Brain Tumor Registry of the United States, which contains the largest aggregation of population-based data on the incidence of primary central nervous system tumors in the US, was used. Age-adjusted incidence rates and incidence rate ratios (IRR) of vestibular schwannomas from 2004 to 2010 were calculated by age at diagnosis, gender, race, and ethnicity. Annual percent change (APC) was calculated using Joinpoint to characterize temporal trends. From 2004 to 2010, there were 23,729 newly diagnosed vestibular schwannomas in the US; overall incidence was 1.09 per 100,000 population. Incidence was stable over time (APC 0.41 %, 95 % confidence interval -3.4, 2.7). Incidence increased with age to a peak of 2.93 per 100,000 in the 65-74 year old age group. Overall, there was no difference in incidence by gender. Compared to Whites, incidence was highest in Asian Pacific Islanders (IRR 1.37, p < 0.001) and lowest in African Americans (IRR 0.36, p < 0.001). Incidence was lower in Hispanics than non-Hispanics (IRR 0.69, p < 0.001). Over 3300 vestibular schwannomas are diagnosed per year in the US and incidence is 1.09 per 100,000 population. Incidence increases with age up to the 65-74 year old age group. Incidence is higher in Asian Pacific Islanders and lower in African Americans and Hispanics. PMID- 26024655 TI - Survival of children with medulloblastoma in Canada diagnosed between 1990 and 2009 inclusive. AB - The treatment of medulloblastoma, the most common malignant brain tumor in children, has evolved over the last few decades. The objectives of this paper were to determine the survival of pediatric medulloblastoma in Canada, to determine if there has been an improvement in the survival rates between the years of 1990 and 2009, inclusive, and to determine prognostic factors for survival. All patients under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009, inclusive, in Canada were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence and current status. From these, survival rates were determined. Data were obtained on 628 eligible patients. The overall 5-year survival rate for the study time period was 69.2 +/- 3.3 %. The survival rate increased during the interval of 1996-2000, then remained stable; 1990-1994: 60.2 +/- 4.3 %; 1995 1999: 73.2 +/- 3.5 %; 2000-2004: 68.8 +/- 3.7 %; and 2005-2009: 72.1 +/- 4.9 %, p = 0.05. Children over 14 years of age had a significantly better overall survival than those age 5-14 and those under 5 (85.7 +/- 5.5 % vs 76.1 +/- 2.7 % and 60.8 +/- 3 % respectively, p = 0.001). Histologic medulloblastoma subtype and M stage of disease did not result in significant differences in survival. Despite changes in approaches to therapy, we demonstrate a steady survival rate for children with medulloblastoma after 1996. In our analyses, age over 14 years was associated with a higher survival rate. PMID- 26024656 TI - Antibody Drug Conjugates: Nonclinical Safety Considerations. AB - Antibody drug conjugates (ADCs) are biopharmaceutical molecules consisting of a cytotoxic small molecule covalently linked to a targeted protein carrier via a stable cleavable or noncleavable linker. The process of conjugation yields a highly complex molecule with biochemical properties that are distinct from those of the unconjugated components. The impact of these biochemical differences on the safety and pharmacokinetic (PK) profile of the conjugate must be considered when determining the types of nonclinical safety studies required to support clinical development of ADCs. The hybrid nature of ADCs highlights the need for a science-based approach to safety assessment that incorporates relevant aspects of small and large molecule testing paradigms. This thinking is reflected in current regulatory guidelines, where sections pertaining to conjugates allow for a flexible approach to nonclinical safety testing. The aim of this article is to review regulatory expectations regarding early assessment of nonclinical safety considerations and discuss how recent advances in our understanding of ADC mediated toxicity can be used to guide the types of nonclinical safety studies needed to support ADC clinical development. The review will also explore nonclinical testing strategies that can be used to streamline ADC development by assessing the safety and efficacy of next generation ADC constructs using a rodent screen approach. PMID- 26024657 TI - Single-Laboratory Validation of a Multitoxin Ultra-Performance LC-Hydrophilic Interaction LC-MS/MS Method for Quantitation of Paralytic Shellfish Toxins in Bivalve Shellfish. AB - A single-laboratory validation study was conducted for the hydrophilic interaction-LC-MS/MS analysis of paralytic shellfish toxins (PSTs) in bivalve shellfish. The method was developed as an alternative to the precolumn oxidation AOAC 2005.06 and postcolumn oxidation AOAC 2011.02 LC with fluorescence detection methods, receptor binding assay AOAC 2011.27, as well as the mouse bioassay AOAC 959.08. PSTs assessed were saxitoxin, neosaxitoxin, deoxydecarbamoylsaxitoxin, decarbamoylsaxitoxin, decarbamoylneosaxitoxin, gonyautoxins 1-6, decarbamoylgonyautoxins 2-3, and N-sulfocarbamoyl gonyautoxins 2&3. The method also included the determination of decarbamoylgonyautoxins 1&4, N-sulfocarbamoyl gonyautoxins 1&4, and M toxins. Twelve commercially produced bivalve species from both New Zealand and the United Kingdom were assessed, including mussels, oysters, scallops, and clams. Validation studies demonstrated acceptable method performance characteristics for specificity, linearity, recovery, repeatability, and within-laboratory reproducibility. LOD and LOQ were significantly improved in comparison to current fluorescence-based detection methods, and the method was shown to be rugged. The method performed well in comparison to AOAC 2005.06, with evidence obtained from both comparative analysis of 1141 PST-contaminated samples and successful participation in proficiency testing schemes. The method is suitable for use in regulatory testing and will be submitted for an AOAC collaborative study. PMID- 26024658 TI - Quantification of three-dimensional computed tomography angiography for evaluating coronary luminal stenosis using digital subtraction angiography as the standard of reference. AB - OBJECTIVE: We sought to evaluate the accuracy of quantitative three-dimensional (3D) CT angiography (CTA) for the assessment of coronary luminal stenosis using digital subtraction angiography (DSA) as the standard of reference. METHOD: Twenty-three patients with 54 lesions were referred for CTA followed by DSA. The CTA scans were performed with 256-slice spiral CT. 3D CTA were reconstructed from two-dimensional CTA imaging sequences in order to extract the following quantitative indices: minimal lumen diameter, percent diameter stenosis (%DS), minimal lumen area, and percent area stenosis (%AS). Correlation and limits of agreement were calculated using Pearson correlation and Bland-Altman analysis, respectively. The diagnostic performance and the diagnostic concordance of 3D CTA derived anatomic parameters (%DS, %AS) for the detection of severe coronary arterial stenosis (as assessed by DSA) were presented as sensitivity, specificity, diagnostic accuracy, and Kappa statistics. Of which vessels with %DS >50% or with %AS >75% were identified as severe coronary arterial lesions. RESULT: The correlations of the anatomic parameters between 3D CTA and DSA were significant (r = 0.51-0.74, P < 0.001). Bland-Altman analysis confirmed that the mean differences were small (from -1.11 to 27.39%), whereas the limits of agreement were relatively wide (from +/-28.07 to +/-138.64%). Otherwise, the diagnostic accuracy (74.1% with 58.3% sensitivity and 86.7% specificity for DS%; 74.1% with 45.8% sensitivity and 96.7% specificity for %AS) and the diagnostic concordance (k = 0.46 for DS%; 0.45 for %AS) of 3D CTA-derived anatomic parameters for the detection of severe stenosis were moderate. CONCLUSION: 3D advanced imaging reconstruction technique is a helpful tool to promote the use of CTA as an alternative to assess luminal stenosis in clinical practice. PMID- 26024659 TI - Psychogenic fever in a patient with small cell lung cancer: a case report. AB - BACKGROUND: Fever is common in malignant tumors. We report an exceptional case of psychogenic fever in a patient with small cell lung cancer. This is the first case report of psychogenic fever in a patient with small cell lung cancer. CASE PRESENTATION: A 61-year-old Chinese man diagnosed with small cell carcinoma on June 30, 2012, came to our department with a complaint of fever lasting more than 1 month. He had undergone chemoradiotherapy for lung cancer 6 months previously. After admission, his body temperature fluctuated in the range of 37 degrees C to 39 degrees C. Somatic symptoms associated with anxiety were obvious. A 24-item Hamilton Anxiety Scale was used to assess the patient's condition. A score of 32 confirmed a diagnosis of severe anxiety. After a week of antianxiety treatment, the patient's temperature returned to normal. CONCLUSION: Psychogenic fever is common in cancer patients and deserves more attention. Patients with psychogenic fever must be distinguished from patients with infectious fever (including neutropenic fever), and tumor fever. Additionally, antianxiety or antidepression treatment should be provided. A concern is that continual anxiety may adversely affect anticancer therapy. PMID- 26024660 TI - ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis. AB - BACKGROUND: The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects; however, its role in GBM and the underlying mechanism are not clear. RESULTS: Here we found that salinomycin induced both apoptosis and necrosis in cultured glioma cells, and necrosis played a major role in contributing salinomycin's cytotoxicity. Salinomycin induced p53 translocation to mitochondria, where it formed a complex with cyclophilin-D (CyPD). This complexation was required for mitochondrial permeability transition pore (mPTP) opening and subsequent programmed necrosis. Blockade of Cyp-D by siRNA-mediated depletion or pharmacological inhibitors (cyclosporin A and sanglifehrin A) significantly suppressed salinomycin-induced glioma cell necrosis. Meanwhile, p53 stable knockdown alleviated salinomycin-induced necrosis in glioma cells. Reactive oxygen species (ROS) production was required for salinomycin-induced p53 mitochondrial translocation, mPTP opening and necrosis, and anti-oxidants n-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) inhibited p53 translocation, mPTP opening and glioma cell death. CONCLUSIONS: Thus, salinomycin mainly induces programmed necrosis in cultured glioma cells. PMID- 26024661 TI - An operational comparative study of quinine and artesunate for the treatment of severe malaria in hospitals and health centres in the Democratic Republic of Congo: the MATIAS study. AB - BACKGROUND: The Democratic Republic of the Congo (DRC) has the highest number of severe malaria cases in the world. In early 2012, the National Malaria Control Programme (NMCP) changed the policy for treating severe malaria in children and adults from injectable quinine to injectable artesunate. To inform the scaling up of injectable artesunate nationwide, operational research is needed to identify constraints and challenges in the DRC's specific setting. METHODS: The implementation of injectable quinine treatment in 350 patients aged 2 months or older in eight health facilities from October 2012 to January 2013 and injectable artesunate in 399 patients in the same facilities from April to June 2013 was compared. Since this was an implementation study, concurrent randomized controls were not possible. Four key components were evaluated during each phase: 1) clinical assessment, 2) time and motion, 3) feasibility and acceptability, and 4) financial cost. RESULTS: The time to discharge was lower in the artesunate (median=2, 90% central range 1-9) compared to the quinine group (3 (1-9) days; p<0.001). Similarly, the interval between admission and the start of intravenous (IV) treatment (2 (0-15) compared to 3 (0-20) hours; p<0.001) and parasite clearance time (23 (11-49) compared to 24 (10-82) hours; p<0.001) were lower in the artesunate group. The overall staff pre-administration time (13 (6-38) compared to 20 (7-50) minutes; p<0.001) and the personnel time spent on patient management (9 (1-24) compared to 12 (3-52) minutes; p<0.001) were lower in the artesunate group. In hospitals and health centres, the mean (standard deviation, SD) total cost per patient treated for severe malaria with injectable artesunate was USD 51.94 (16.20) and 19.51 (9.58); and USD 60.35 (17.73) and 20.36 (6.80) with injectable quinine. CONCLUSIONS: This study demonstrates that injectable artesunate in the DRC is easier to use and it costs less than injectable quinine. These findings provide the basis for practical recommendations for rapid national deployment of injectable artesunate in the DRC. PMID- 26024662 TI - Time elapsed after contrast injection is crucial to determine infarct transmurality and myocardial functional recovery after an acute myocardial infarction. AB - BACKGROUND: In acute myocardial infarction (MI), late Gadolinium enhancement (LGE) has been proposed to include the infarcted myocardium and area at risk. However, little information is available on the optimal timing after contrast injection to differentiate these 2 areas. Our aim was to determine in acute and chronic MI whether imaging time after contrast injection influences the LGE size that better predicts infarct size and functional recovery. METHODS: Subjects were evaluated by cardiovascular magnetic resonance (CMR) the first week (n = 60) and 3 months (n = 47) after a percutaneously revascularized STEMI. Inversion-recovery single-shot (ss-IR) imaging was acquired at multiple time points following contrast administration and compared to segmented inversion-recovery (seg-IR) sequences. Inversion time was properly adjusted and images were blinded, randomized and measured for LGE volumes. RESULTS: In acute MI, LGE volume decreased over several minutes (p = 0.005) with the greatest volume occurring at 3 minutes and the smallest at 25 minutes post-contrast injection; however, LGE volume remained constant over time in chronic MI (p = 0.886). Depending on the imaging time, in acute phase, a change in the transmurality index was also observed. A transmural infarction (>75%) at 25 minutes better predicted the absence of improvement in the wall motion score index (WMSI), a higher increase in left ventricular volumes and a lower ejection fraction compared to 10 minutes. CONCLUSIONS: A change was observed in LGE volume in the minutes following contrast administration in acute but not in chronic MI. Infarct transmurality 25 minutes post-contrast injection better predicted infarct size and functional recovery at follow-up. PMID- 26024664 TI - Rats: if you can't beat them eat them! (Tricks of the trade observed among the Adi and other North-East Indian tribals). AB - BACKGROUND: Since outside the tribal areas of North-East India it is not widely known, neither in the world nor in India itself, that rats are considered a delicious food item, this was one of several reasons why we decided to present this ethnographic account of rat procurement and preparation (together with some additional comments on the cultural role that rats have especially amongst members of the Adi tribe). Consumption of rats by humans as a biological control method far superior to the use of rodenticide poisoning and rat consumption as a way to reduce hunting pressure on rare wild animals were further considerations to publish this account. METHODS: Semi-structured interviews were conducted with male and female members of eight tribal communities in Arunachal Pradesh (North East India) on the uses of rats as food and as cultural objects. The construction of rat traps as well as the preparation of rat dishes were observed and recorded photographically. RESULTS: Numerous species of small rodents, collectively called "rats" by the locals of North-East Indian tribes and comprising the species Rattus rattus Linnaeus, R. nitidus Hodgson, R. burrus Miller, R. tanezumi Temminck as well as Bandicota bengalensis Gray and Hardwicke, B. indica Bechstein, and Mus musculus Linnaeus, are regularly trapped and consumed in roasted, cooked or smoked form. In this well-illustrated report the kinds of devices used to catch these animals are described and information is provided on how to prepare rats for human consumption. The role that rats as food and gift exchange items play in the context of local culture is explained and the locals' most highly appreciated meat dish, known as bule-bulak oying and consisting of boiled rat's tail, legs and inner organs, is introduced. CONCLUSION: Given the need to meet the world's future food demands and the environmental consequences of an expanding livestock production with regard to global warming, water availability, deforestation, soil erosion etc., rats as a food item, as our example shows, should not be overlooked. Using rats as food reduces hunting pressures on other wild and often already rare animals. It is a far superior method to control rat populations than poisoning the rodents and the artisanal construction of rat traps by local menfolk helps maintaining traditional skills and knowledge. PMID- 26024663 TI - Application of M13 phage display for identifying immunogenic proteins from tick (Ixodes scapularis) saliva. AB - BACKGROUND: Ticks act as vectors for a large number of different pathogens, perhaps most notably Borrelia burgdorferi, the causative agent of Lyme disease. The most prominent tick vector in the United States is the blacklegged tick, Ixodes scapularis. Tick bites are of special public health concern since there are no vaccines available against most tick-transmitted pathogens. Based on the observation that certain non-natural host animals such as guinea pigs or humans can develop adaptive immune responses to tick bites, anti-tick vaccination is a potential approach to tackle health risks associated with tick bites. RESULTS: The aim of this study was to use an oligopeptide phage display strategy to identify immunogenic salivary gland proteins from I. scapularis that are recognized by human immune sera. Oligopeptide libraries were generated from salivary gland mRNA of 18 h fed nymphal I. scapularis. Eight immunogenic oligopeptides were selected using human immune sera. Three selected immunogenic oligopeptides were cloned and produced as recombinant proteins. The immunogenic character of an identified metalloprotease (MP1) was validated with human sera. This enzyme has been described previously and was hypothesized as immunogenic which was confirmed in this study. Interestingly, it also has close homologs in other Ixodes species. CONCLUSION: An immunogenic protein of I. scapularis was identified by oligopeptide phage display. MP1 is a potential candidate for vaccine development. PMID- 26024665 TI - The Effects of Estrogen Receptors' Antagonist on Brain Edema, Intracranial Pressure and Neurological Outcomes after Traumatic Brain Injury in Rat. AB - BACKGROUND: In previous studies, the neuroprotective effect of 17beta-estradiol in diffuse traumatic brain injury has been shown. This study used ICI 182,780, a non-selective estrogen receptor antagonist, to test the hypothesis that the neuroprotective effect of 17beta-estradiol in traumatic brain injury is mediated by the estrogen receptors. METHODS: The ovariectomized rats were divided into eight groups. Brain injury was induced by Marmarou's method. Estrogen was injected 30 minutes after traumatic brain injury, and ICI 182,780 was injected before traumatic brain injury and also before estrogen treatment. In one group only ICI 182,780 was injected. The brain water content and Evans blue dye content were measured 24 and 5 hours after traumatic brain injury, respectively. The neurologic outcomes and intracranial pressure were assessed before, 4, and 24 hours after traumatic brain injury. RESULTS: Brain water content and Evans blue content were less in estrogen-treated group comparison to vehicle group. ICI 182,780 eliminated the effects of estrogen on brain edema and brain blood barrier permeability. Intracranial pressure was increased significantly after trauma, and estrogen decreased intracranial pressure at 4 and 24 hours after traumatic brain injury in comparison to vehicle. This inhibitory effect was also eliminated by treatment with ICI182,780. ICI 182,780 also inhibited the estrogen induced increase in neurologic outcomes following traumatic brain injury. However, the use of ICI 182,780 alone had no neuroprotective effect after traumatic brain injury. CONCLUSION: The results suggest that classical estrogen receptors have probably a role in the neuroprotective function of estrogen following traumatic brain injury. PMID- 26024666 TI - Adverse Drug Event Prevention: 2014 Action Plan Conference. AB - Adverse drug events (ADEs) have been highlighted as a national patient safety and public health challenge by the National Action Plan for Adverse Drug Event Prevention (ADE Action Plan), which was released by the Office of Disease Prevention and Health Promotion in August 2014. The following October, the ADE Prevention: 2014 Action Plan Conference provided an opportunity for federal agencies, national experts, and stakeholders to coordinate and collaborate in the initiative to reduce preventable ADEs. The single-day conference included morning plenary sessions focused on the surveillance, evidence-based prevention, incentives and oversights, and additional research needs of the drug classes highlighted in the ADE Action Plan: anticoagulants, diabetes agents, and opioids. Afternoon breakout sessions allowed for facilitated discussions on measures for tracking national progress in ADE prevention and the identification of opportunities to ensure safe and high-quality health care and medication use. PMID- 26024667 TI - MINT: software to identify motifs and short-range interactions in trajectories of nucleic acids. AB - Structural biology experiments and structure prediction tools have provided many high-resolution three-dimensional structures of nucleic acids. Also, molecular dynamics force field parameters have been adapted to simulating charged and flexible nucleic acid structures on microsecond time scales. Therefore, we can generate the dynamics of DNA or RNA molecules, but we still lack adequate tools for the analysis of the resulting huge amounts of data. We present MINT (Motif Identifier for Nucleic acids Trajectory) - an automatic tool for analyzing three dimensional structures of RNA and DNA, and their full-atom molecular dynamics trajectories or other conformation sets (e.g. X-ray or nuclear magnetic resonance derived structures). For each RNA or DNA conformation MINT determines the hydrogen bonding network resolving the base pairing patterns, identifies secondary structure motifs (helices, junctions, loops, etc.) and pseudoknots. MINT also estimates the energy of stacking and phosphate anion-base interactions. For many conformations, as in a molecular dynamics trajectory, MINT provides averages of the above structural and energetic features and their evolution. We show MINT functionality based on all-atom explicit solvent molecular dynamics trajectory of the 30S ribosomal subunit. PMID- 26024668 TI - Quinine Bitterness and Grapefruit Liking Associate with Allelic Variants in TAS2R31. AB - Multiple psychophysical gene-association studies suggest a single nucleotide polymorphism (SNP) within the bitter receptor gene TAS2R19 on chromosome 12 may be functional. Previously, the Arg299Cys SNP (rs10772420) has been associated with differential bitterness of quinine and differential liking for grapefruit juice. However, quinine does not activate TAS2R19 in vitro; likewise, limonin and naringin, bitter compounds in grapefruit, do not activate TAS2R19 in vitro. Here, we examined quinine bitterness (whole-mouth swish-and-spit stimuli and regionally delivered quinine across 4 loci) and remembered liking for grapefruit juice to test whether they associate with SNPs in another nearby gene, TASR2R31. We observed SNP-phenotype associations between whole-mouth quinine bitterness and self-reported liking for grapefruit juice with SNPs in TAS2R31, and regional quinine bitterness followed a similar trend, but did not reach significance. Present data provide independent replication of prior associations reported for TAS2R19. However, we also observed strong linkage disequilibrium (LD) between TAS2R19 and TAS2R31 SNPs. When present data are considered in light of existing functional expression data, this suggests phenotypic associations reported previously for rs10772420 may potentially be due to LD between this SNP and polymorphism(s) in, or closer to, TAS2R31. If confirmed, this would reduce the number of TAS2Rs with putatively functional polymorphisms to 5. PMID- 26024670 TI - The clinical course of patients with adrenal incidentaloma: is it time to reconsider the current recommendations? AB - OBJECTIVE: The current guidelines for the management of adrenal incidentaloma advise hormonal and radiological follow-up of patients for 2-5 years after the initial diagnosis. However, the vast majority of adrenal incidentaloma are non functional benign cortical adenomas that require no treatment, so the routine application of the current strategies often results in a number of unnecessary biochemical and radiological investigations. The aim of this study was to analyse the clinical course of patients with adrenal incidentaloma and to provide a critical review of the current management strategy of the disease. DESIGN AND METHODS: This was a retrospective study performed in the Croatian Referral Center for adrenal gland disorders. The study included 319 consecutive patients with adrenal incidentaloma, 174 of which were followed for at least 24 months. RESULTS: The vast majority of patients were diagnosed with benign adrenal masses, whereas in about 5% of them adrenal tumor corresponded to adrenal carcinoma or metastasis. Tumor density was found to be superior to tumor size in distinguishing benign adrenal masses from malignant tumors and pheochromocytomas. During the follow-up, no patient demonstrated a clinically significant increase in tumor size. In addition, no changes, either in metanephrines and normetanephrines or in the activity of renin-aldosterone axis, were observed during the follow-up. Six patients developed subclinical Cushing's syndrome (SCS) whereas eight patients with SCS showed biochemical remission during follow-up. CONCLUSION: The study suggests that the risk of an adrenal mass initially diagnosed as benign and non-functional becoming malignant or hormonally active is extremely low. Therefore, the clinical management of those patients should be tailored on an individual basis in order to avoid unnecessary procedures. PMID- 26024669 TI - Close To You? How Parent-Adult Child Contact Is Influenced by Family Patterns. AB - OBJECTIVES: Intergenerational contacts occur in the context of other family relationships. We examine how in-person contacts among parents and all adult children affect each other, focusing on proximity and other predictors to assess whether and how visiting is correlated across adult children. METHODS: We use a modeling approach derived from an adaptation of multilevel models to provide a convenient mechanism by which to write child-specific equations, each with its own set of predictors, and wherein one child's attribute values can be attached to other children's records. RESULTS: We find that parent-adult child visiting is positively correlated across siblings, but the frequency of visiting within families is not directly reciprocated. Rather, visiting responds to common family factors. Visiting declines with distance, but there are strong discontinuities in the effect. Distance between parents and a focal child is positively associated with visiting with other children. DISCUSSION: The empirical patterns we report can be framed within enhancement and compensation models. Positive correlations and cross-sibling interactions that juxtapose levels of visiting against not seeing a child in last 12 months are consistent with the enhancement model. The cross-sibling interaction for distance, whereby one child's farther distance leads to more visits reported with others, provides evidence of a countervailing, though, weaker, pattern of compensation for proximity. PMID- 26024671 TI - Notes From the Field: Changes in the Attentional Capacity and Emotional State of Physicians After Working at Busy Outpatient Clinics. AB - To examine changes in the performance of physicians after working in busy outpatient clinics, we conducted a prospective study, involving full-time clinicians who held morning and afternoon outpatient clinics on the same day. The participants completed three measures of attention, the psychomotor vigilance task, two-back test, and trail-making test, and a measure of emotion, the State Trait Anger Expression Inventory (STAXI), before and after the two clinic sessions. The physicians saw a mean of 91.3 patients in the two outpatient clinics on the day of testing. Overall, performance in the attention test did not deteriorate after the two successive outpatient sessions. However, we observed an increased STAXI score in 24 (54.3%) participants and saw a significant overall increase in STAXI scores. Our results indicate that busy outpatient sessions may increase physicians' anger although their attentional capacity appears to be maintained. PMID- 26024672 TI - The Role of Substance-Specific Skills and Cognitions in the Effectiveness of a School-Based Prevention Program on Smoking Incidence. AB - "Eigenstandig werden 5+6" (Becoming independent 5+6) is a German school-based smoking prevention program that draws on social competence and social influence approaches. It was investigated whether the program's effect on smoking onset is mediated by substance-specific skills and cognitions such as knowledge, attitudes/risk perception, normative expectations, resistance skills, and refusal self-efficacy. Multiple mediation analyses revealed a statistically significant total indirect effect that accounted for 30.8% of the total effect. When considered separately, significant indirect effects could be found for normative expectations concerning peer smoking and the resistance skill of saying 'no'. Between these two mediators, the percentage of total effect mediated varied between 9.8% and 10.3%. Results of the current study emphasize the importance of substance-specific skills and cognitions in the effectiveness of school-based programs combining social competence and social influence curricula in preventing adolescent smoking onset. PMID- 26024673 TI - Failed glaucoma drainage implant: long-term outcomes of a second glaucoma drainage device versus cyclophotocoagulation. AB - BACKGROUND/AIMS: To evaluate long-term efficacy of a second glaucoma drainage device (GDD) versus cyclophotocoagulation (CPC) after failure of primary drainage implant. METHODS: This is a non-randomised, retrospective cohort study. A chart review was conducted of patients who underwent GDD surgery between July 1986 and November 2012 requiring further glaucoma procedures for intraocular pressure (IOP) control. An additional GDD was placed in 15 eyes, while 32 eyes underwent CPC. The main outcome measurement was IOP control and/or time to failure of secondary intervention (IOP >18 mm Hg on two sequential measurements). RESULTS: Mean follow-up after the second procedure was 63+/-65.8 months (range 6-254 months) in the CPC group and 132+/-91.8 months (range 12-254 months) in the GDD group. Thirty-four per cent (11/32 eyes) undergoing CPC later required further treatment at a mean of 13.6+/-10.7 months with 10/11(91%) of additional interventions occurring within 2 years. Despite an initially high success rate for IOP control in the first 5 years, eventually 60% (9/15 eyes) that underwent a second tube required additional treatment at a mean of 73.4 months with only 2/9(22%) requiring this within the first 2 years. The risk of visual acuity worsening by 2 Snellen lines or more at 12 months was 5/14 for the GDD group (36%) and 4/23(17%) for the CPC group. CONCLUSIONS: After failure of an initial drainage implant to control IOP, a sequential tube had a high initial rate of success but a relatively high likelihood of long-term failure, generally after 6 years. Eyes that received CPC tended to fail earlier, often within the first year, but had relatively few late failures. PMID- 26024674 TI - Changes in ocular parameters depending on the motion-in-depth of a three dimensional display. AB - OBJECTIVE: To compare changes in ocular parameters after watching a display of three-dimensional (3D) images, with reference to motion-in-depth and viewer age. METHODS: A total of 30 healthy subjects were enrolled (of whom 17 were aged 20-30 years and 13, 40-50 years). All subjects watched 3D displays with binocular disparities of 1 degrees or 3 degrees run towards the viewer (who wore polarised glasses) at two defined velocities (slow, 105 mm/s; fast, 257 mm/s) for 15 min at intervals of 1 week. The viewing distance was 1.020 m. The near point of accommodation (NPA) and near point of convergence (NPC), and the tear break-up time (tBUT) of each subject, were measured before and after watching the 3D display. All parameters were repeatedly measured at intervals of 10 min after watching until baseline values became re-established. RESULTS: NPA and NPC deteriorated more, and tBUT decreased more, after watching a 3D display with fast rather than slow motion-in-depth (all p values <0.05). NPA deteriorated more in those aged 40-50 years as compared in those aged 20-30 years after watching a display of binocular disparity of 3 degrees at fast motion-in-depth (p=0.028). NPC deteriorated more in those aged 40-50 years as compared in those aged 20-30 years after watching a display of binocular disparity of 3 degrees at slow and fast motion-in-depth (p=0.001). The NPA and NPC recovery times were longer after watching at fast motion-in-depth than slow motion-in-depth (p<0.05). The decrease of tBUT was greater after watching at fast rather than slow motion-in-depth but only when the binocular disparity was 1 degrees . All parameters returned to baseline values within 80 min. CONCLUSIONS: Motion-in-depth has an important influence on ocular parameters when a 3D display is watched, and our information would provide some basis in manufacturing 3D equipment. PMID- 26024675 TI - N-Terminal Hypervariable Region of Muscle Type Isoforms of Troponin T Differentially Modulates the Affinity of Tropomyosin-Binding Site 1. AB - The troponin complex plays a central role in the contraction and relaxation of striated muscle by enacting Ca2+-regulated allosteric changes in the sarcomeric thin filaments. The troponin T subunit (TnT) contains two binding sites for tropomyosin (Tm) and is responsible for anchoring the troponin complex to the thin filament. While the amino acid sequences of the regions containing the Tm binding sites are highly conserved among the three muscle type isoforms of TnT, previous studies have observed significant discrepancies in the affinity of Tm binding site 1 in the chymotryptic fragment T1 of different TnT isoforms. Here we cross-examined the Tm-binding affinity of TnT isoforms and molecular engineered fragments using affinity chromatography and microplate protein binding assays to investigate the effects of the evolutionarily diverged N-terminal region that is significantly variable among muscle type isoforms. The results demonstrated that the C-terminal T2 fragment of TnT containing the Tm-binding site 2 had similarly high affinity across isoforms. In the absence of the N-terminal variable region, Tm-binding site 1 in the conserved middle region of TnT also exhibited high intrinsic affinity. The presence of isoform specific N-terminal variable region differentially reduced the binding affinity of TnT for Tm, primarily at binding site 1 in the middle region. These findings indicate that the N-terminal variable region of TnT plays a pivotal role in the functional difference of muscle type specific isoforms and the developmental and pathogenic splice variants by modulating the interaction with Tm during Ca2+ regulation of cardiac and skeletal muscle contraction and relaxation. PMID- 26024676 TI - Validation of a Screening Tool to Identify Undernutrition in Ambulatory Patients With Liver Cirrhosis. AB - BACKGROUND: The prevalence of chronic liver disease is increasing in the United States. Malnutrition is common as liver disease progresses. However, an accepted method to screen these patients for malnutrition is lacking. The 6-question undernutrition screening tool was developed for professionals without nutrition training to identify a decline in the nutrition status of patients with liver cirrhosis. A 3-phase validation study was completed to assess face, content, and clinical validity of the screening tool in ambulatory patients with liver cirrhosis. METHODS: In phase I, face validity was determined by surveying 13 liver disease professionals. In phase II, content validity was assessed by surveying 12 registered dietitians who specialize in liver disease. In phase III, a cross-sectional investigation was completed to compare the agreement between the undernutrition screening tool and nutrition assessment by a registered dietitian (RD). RESULTS: Twenty-two patients with a diagnosis of liver cirrhosis participated in phase III of the investigation. The RD assessment identified undernutrition in 82% of patients (95% CI, 60%-95%). The kappa statistic indicated a fair agreement between the screening tool and RD assessment. Sensitivity and specificity of the tool were 72% and 75%, respectively, and positive predictive value was 93%. CONCLUSIONS: Feedback from phase I, II, and III indicate that the undernutrition screening tool is simple, is easy to use, and measures the constructs that have the strongest link with undernutrition in liver disease. Additional minor adjustments to the screening tool and a multicenter investigation are indicated to confirm clinical effectiveness and cross-validity of the tool. PMID- 26024677 TI - Nutraceutical Supplements for Inflammatory Bowel Disease. PMID- 26024678 TI - Investigation of Bone Health Subsequent to Vitamin D Supplementation in Children Following Burn Injury. AB - BACKGROUND: The effect of supplemental vitamin D on fracture occurrence following burn injuries is unclear. The objective of this study was to evaluate postintervention incidence of fractures in children during the rehabilitative phase postburn (PB) following participation in a randomized clinical trial of vitamin D supplementation. MATERIALS AND METHODS: Follow-up for fracture evaluation was obtained in 39 of 50 patients randomized to daily enteral vitamin D2, D3, or placebo throughout the acute burn course. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, D2, D3, calcitonin, and bone alkaline phosphatase (BAP) measurements were obtained PB day 7, midpoint, discharge, and 1-year PB. Urinary calcium was obtained PB day 7 and midpoint. Dual-energy x-ray absorptiometry (DXA) was performed at discharge and 1-year PB. RESULTS: Fractures were reported in 6 of 39 respondents. Four fractures occurred in the placebo group, 2 in the D2 group, and none in the D3 group. Serum vitamin D, calcitonin, BAP, and urinary calcium were similar between fracture groups. The group with fracture morbidity had larger burn size (83.8% +/- 4.9% vs 53.0% +/- 2.9%, P < .0001), greater full thickness burn (69.7% +/- 9.4% vs 39.4% +/- 4.1%, P = .02), and increased incidence of inhalation injury (33% vs 6%, P = .04). Decreased bone mineral density z score was noted at discharge in the placebo fracture compared with no fracture group (P < .05). CONCLUSION: This preliminary report suggests there may be benefit of vitamin D3 in reducing postdischarge fracture risk. Results reaffirm the importance of monitoring bone health in pediatric patients postburn. PMID- 26024679 TI - Nutrition Assessment With Indirect Calorimetry in Patients Evaluated for Left Ventricular Assist Device Implantation. AB - BACKGROUND: Malnutrition is known to negatively impact the clinical course of advanced heart failure and is associated with increased mortality following left ventricular assist device (LVAD) implantation. Appropriate assessment of nutrition requirements in these patients is critical in their clinical care, yet there has been little discussion on how to best determine resting energy expenditure (REE) in the hospital setting. We investigated the use of indirect calorimetry in a group of patients with advanced heart failure. MATERIALS AND METHODS: Results from preoperative indirect calorimetry testing in 98 patients undergoing evaluation for LVAD candidacy were collected. REE was compared with 10 predictive equations that estimated caloric need based on a range of patient specific demographic and clinical variables. RESULTS: This study enrolled 22 female and 76 male patients with a mean age of 59.4 +/- 12.5 years, body mass index of 29.6 +/- 6.0 kg/m(2), and ejection fraction of 19.4 +/- 6.6%. The average REE by indirect calorimetry in this group was 1610.0 +/- 612.7 kcal/d. All predictive equations significantly overestimated REE. However, those equations intended for use in the critically ill demonstrated the greatest accuracy, with the Brandi equation achieving both the highest correlation (r = 0.605, P < .001) and the lowest standard error of the estimate (504.8 kcal/d). CONCLUSIONS: Indirect calorimetry may be reliably and safely used to determine caloric requirements in patients with advanced heart failure. The use of predictive equations based on demographic and clinical parameters appears to generate inaccurate estimations of REE in these patients. However, equations designed for use in critically ill patients better estimate nutrition requirements than those designed for healthy individuals. PMID- 26024680 TI - The art of limitations. PMID- 26024681 TI - In response to 'Medical Education Research: is participation fair?'. PMID- 26024682 TI - Myocardial ATP hydrolysis rates in vivo: a porcine model of pressure overload induced hypertrophy. AB - Left ventricular (LV) hypertrophy (LVH) and congestive heart failure are accompanied by changes in myocardial ATP metabolism. However, the rate of ATP hydrolysis cannot be measured in the in vivo heart with the conventional techniques. Here, we used a double-saturation phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol to monitor ATP hydrolysis rate in swine hearts as the hearts became hypertrophic in response to aortic banding (AOB). Animals that underwent AOB (n = 22) were compared with animals that underwent sham surgery (n = 8). AOB induced severe LVH (cardiac MRI). LV function (ejection fraction and systolic thickening fraction) declined significantly, accompanied by deferent levels of pericardial effusion, and wall stress increased in aorta banded animals at week 1 after AOB, suggesting acute heart failure, which recovered by week 8 when concentric LVH restored LV wall stresses. Severe LV dysfunction was accompanied by corresponding declines in myocardial bioenergetics (phosphocreatine-to-ATP ratio) and in the rate of ATP production via creatine kinase at week 1. For the first time, the same linear relationships of the rate increase of the constants of the ATP hydrolysis rate (kATP->Pi) vs. the LV rate-pressure product increase during catecholamine stimulation were observed in vivo in both normal and LVH hearts. Collectively, these observations demonstrate that the double-saturation, phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol can accurately monitor myocardial ATP hydrolysis rate in the hearts of living animals. The severe reduction of LV chamber function during the acute phase of AOB is accompanied by the decrease of myocardial bioenergetic efficiency, which recovers as the compensated LVH restores the LV wall stresses. PMID- 26024683 TI - Neural control of circulation and exercise: a translational approach disclosing interactions between central command, arterial baroreflex, and muscle metaboreflex. AB - The last 100 years witnessed a rapid and progressive development of the body of knowledge concerning the neural control of the cardiovascular system in health and disease. The understanding of the complexity and the relevance of the neuroregulatory system continues to evolve and as a result raises new questions. The purpose of this review is to articulate results from studies involving experimental models in animals as well as in humans concerning the interaction between the neural mechanisms mediating the hemodynamic responses during exercise. The review describes the arterial baroreflex, the pivotal mechanism controlling mean arterial blood pressure and its fluctuations along with the two main activation mechanisms to exercise: central command (parallel activation of central somatomotor and autonomic descending pathways) and the muscle metaboreflex, the metabolic component of exercise pressor reflex (feedback from ergoreceptors within contracting skeletal muscles). In addition, the role of the cardiopulmonary baroreceptors in modulating the resetting of arterial baroreflex is identified, and the mechanisms in the central nervous system involved with the resetting of baroreflex function during dynamic exercise are also described. Approaching a very relevant clinical condition, the review also presents the concept that the impaired arterial baroreflex function is an integral component of the metaboreflex-mediated exaggerated sympathetic tone in subjects with heart failure. This increased sympathetic activity has a major role in causing the depressed ventricular function observed during submaximal dynamic exercise in these patients. The potential contribution of a metaboreflex arising from respiratory muscles is also considered. PMID- 26024684 TI - Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells. AB - The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (~40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-gamma coactivator-1alpha small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis. PMID- 26024686 TI - The ambitious '95-95 by 2025' roadmap for the diagnosis and management of fungal diseases. PMID- 26024685 TI - VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function. AB - Angiogenesis induced by growth factor-releasing microspheres can be an off-the shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 * 10(6) 15-MUm microspheres at 0.5 * 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition. PMID- 26024687 TI - Incidental findings on chest CT imaging are associated with increased COPD exacerbations and mortality. AB - BACKGROUND: This study aimed to evaluate whether incidental CT findings of emphysema, airway thickening and bronchiectasis, as seen on CT scans performed for other non-pulmonary clinical indications, are associated with future acute exacerbations of COPD resulting in hospitalisation or death. METHODS: This multicentre prospective case-cohort study comprised 6406 subjects who underwent routine diagnostic chest CT for non-pulmonary indications. Using a case-cohort approach, we visually graded CT scans from cases and a random sample of ~10% of the baseline cohort (n=704) for emphysema severity (range 0-20), airway thickening (range 0-5) and bronchiectasis (range 0-5). We used weighted Cox proportional hazards analysis to assess the independent association between CT findings and hospitalisation or death due to COPD exacerbation. RESULTS: During a median follow-up of 4.4 years (maximum 5.2 years), 338 COPD events were identified. The risk of experiencing a future acute exacerbation of COPD resulting in hospitalisation or death was significantly increased in subjects with severe emphysema (score >=7) and severe airway thickening (score >=3). The respective HRs were 4.6 (95% CI 3.0 to 7.1) and 5.9 (95% CI 3.4 to 10.5). Severe bronchiectasis (score >=3) was not significantly associated with increased risk of adverse events (HR 1.5; 95% CI 0.9 to 2.5). CONCLUSIONS: Morphological correlates of COPD such as emphysema and airway thickening detected on CT scans obtained for other non-pulmonary indications are strong independent predictors of subsequent development of acute exacerbations of COPD resulting in hospitalisation or death. PMID- 26024688 TI - The relationship between Helicobacter pylori seropositivity and COPD. AB - RATIONALE: Chronic systemic infections such as those with Helicobacter pylori (H. pylori) may contribute to the evolution and progression of chronic obstructive pulmonary disease (COPD). Using data from the Lung Health Study (LHS), we determined the relationship of H. pylori infection with the severity and progression of COPD. METHODS: Using an immunoassay, we measured H. pylori immunoglobulin G (IgG) antibody titres in serum samples of 4765 patients with mild-to-moderate COPD. We then determined their relationship with the individual's FEV1 and the rate of decline in FEV1 and mortality over 11 years using multiple regression analysis. RESULTS: Approximately 18% of the patients were seropositive to H. pylori and these individuals demonstrated lower FEV1 (L) values at every study visit compared with individuals who were seronegative for H. pylori (p value=0.00012). However, patients with seropositivity to H. pylori were on average 0.012 m shorter than those with seronegativity (p value=0.0015). The significant relationship between FEV1 and H. pylori seropositivity disappeared when FEV1 per cent predicted (FEV1pp) was used (p value=0.45). H. pylori seropositive individuals had greater circulating C reactive protein (CRP) levels compared with H. pylori seronegative individuals (p value=0.012), and had increased risk of cardiovascular mortality (relative risk 1.61, p=0.05). CONCLUSIONS: H. pylori infection was associated with reduced lung function that is most likely due to the effect of the bacterium on lung growth earlier in life. It is also associated with systemic inflammation and increased risk of cardiovascular mortality in patients with COPD. TRIAL REGISTRATION NUMBERS: NCT00000568 and NCT00000569. PMID- 26024689 TI - Cerebral air embolism during CT-guided lung biopsy. PMID- 26024690 TI - Longitudinal shape irregularity of airway lumen assessed by CT in patients with bronchial asthma and COPD. AB - BACKGROUND: Airway remodelling in bronchial asthma (BA) and COPD has been quantitatively assessed by analysing the airway wall area and the luminal area on cross-sectional CT images. To date, there have been no reports on assessment of the longitudinal structure of the airway lumen. METHODS: Quantitative airway analysis using CT was performed on three groups consisting of 29 patients with BA, 58 patients with COPD and 59 healthy controls. To assess the longitudinal shape irregularity of the airway lumen, new quantitative CT parameters, validated by a phantom study, were established. The internal radii of imaginary inscribed spheres in the airway lumen were measured as a function of distance from the level of the carina to the fifth-order branches of the right posterior basal bronchus. The gaps of these radii from the regression line were calculated as parameters to reflect the longitudinal airway lumen shape irregularity. These new parameters were compared among the study groups as well as with the conventional parameters of airway wall thickening and luminal area. RESULTS: Longitudinal airway lumen shape irregularity was significantly greater in patients with COPD than in those with BA and healthy controls. Wall thickening was significantly greater, and luminal area smaller, in patients with BA than in those with COPD and healthy controls. These results were consistent even among the BA and COPD subgroups with similar airflow limitation. CONCLUSIONS: The combination of cross sectional and longitudinal airway structure analyses using CT images may suggest differences in the characteristics of airway remodelling between COPD and asthma. PMID- 26024691 TI - Waiting for what comes later: capuchin monkeys show self-control even for nonvisible delayed rewards. AB - Self-control tasks used with nonhuman animals typically involve the choice between an immediate option and a delayed, but more preferred option. However, in many self-control scenarios, not only does the more impulsive option come sooner in time, it is often more concrete than the delayed option. For example, studies have presented children with the option of eating a visible marshmallow immediately, or foregoing it for a better reward that can only be seen later. Thus, the immediately available option is visible and concrete, whereas the delayed option is not visible and more abstract. We tested eight capuchin monkeys to better understand this potential effect by manipulating the visibility of the response options and the visibility of the baiting itself. Monkeys observed two food items (20 or 5 g pieces of banana) each being placed either on top of or inside of one of the two opaque containers attached to a revolving tray apparatus, either in full view of monkeys or occluded by a barrier. Trials ended when monkeys removed a reward from the rotating tray. To demonstrate self control, monkeys should have allowed the smaller piece of food to pass if the larger piece was forthcoming. Overall, monkeys were successful on the task, allowing a smaller, visible piece of banana to pass from reach in order to access the larger, nonvisible banana piece. This was true even when the entire baiting process took place out of sight of the monkeys. This finding suggests that capuchin monkeys succeed on self-control tasks even when the delayed option is also more abstract than the immediate one-a situation likely faced by primates in everyday life. PMID- 26024692 TI - Feasibility and impact of a dedicated multidisciplinary rehabilitation program on health-related quality of life in advanced head and neck cancer patients. AB - In an observational prospective study, feasibility and outcomes of a dedicated multidisciplinary rehabilitation program (HNR) for head and neck cancer (HNC) patients were evaluated. HRQoL was assessed before and after HNR with EORTC C30 and H&N-35 QoL questionnaires in 52 consecutive patients. Initial HRQoL scores were compared with EORTC reference scores for HNC patients and post-HNR with those available for the general healthy population. Distress was assessed before and after HNR with the distress thermometer (DT). At completion of HNR with a mean duration of 7 months, overall HRQoL was significantly improved (p < 0.001). Role, Emotional, and Social function scales and most EORTC C30 and H&N35 symptom scale items showed a statistically significant (p < 0.01) and clinically relevant improvement. Mean distress score before HNR was above the cutoff value of 5, suggesting the need for referral to rehabilitation. After completing HNR, distress decreased significantly to 3.0 (p < 0.001). HRQoL pretreatment was poorer than that of the EORTC reference HNC population, whereas at the completion of the HNR program, the HRQoL was comparable to that of the general population reference level. We conclude that a dedicated multidisciplinary HNR program is feasible and suggest that it has a positive impact on HRQoL. The multidisciplinary approach may have added value over mono-disciplinary interventions. However, our results should be judged cautiously due to the observational nature of the study. PMID- 26024693 TI - The pathophysiological role of bacterial biofilms in chronic sinusitis. AB - Chronic rhinosinusitis (CRS) is a very common disorder that remains poorly understood from a pathogenic standpoint. Recent research on the pathogenesis of CRS has been focused on the potential role of biofilms in this chronic infection. The aim of this study was to assess the sinuses' microflora and biofilm formation on the sino-nasal mucosa in patients with CRS. Paranasal sinus mucosa specimens were harvested at the time of functional endoscopic sinus surgery (FESS). Classical microbiology techniques for the isolation and identification of sinus mucosa microbial flora were used. Scanning electron microscopy (SEM) was used to detect biofilm on the surface of mucosa. A microtiter plate assay for in vitro biofilm formation was employed, divided into three aliquots. One part was assessed for bacterial presence, utilizing an API manual system and the Vitek((r)) 2 Compact system. The two remaining aliquots were tested by in vitro conventional microbiological assay with the use of the Infinite M200 (Tecan) microtiter plate reader, and also by scanning electron microscopy (SEM). A microbiological examination of mucosal specimens had taken during FESS operation revealed the presence of various types of bacteria in 29 out of 30 tested samples. Out of 62 different strains isolated from patients with CRS, 23 strains of coagulase-negative Staphylococcus epidermidis and 6 strains of Escherichia coli were the most frequently isolated microorganisms, accounting for 37.1 and 9.7 %, respectively. Among the 62 isolated strains, 58 were used to assess biofilm formation. From the total of 58 isolates, 8.6 % were strong biofilm producers, 20.7 % were moderate, and 70.7 % of isolates were considered to be non or weak biofilm producers. SEM of the 30 nasal concha mucosal samples taken from patients with CRS revealed biofilm in 23 specimens. A marked destruction of the epithelium was observed, with variation in degrees of severity, from disarrayed cilia to complete absence of cilia. The vast majority of nasal concha mucosal samples of patients affected by chronic sinusitis presented with biofilm formation. Our study showed that 76.7 % of patients having FESS for CRS had evidence of biofilms on SEM micrographs. Although certain detection methods could lead to various discrepancies in the amount of biofilm produced, the consistent demonstration of biofilms in patients with CRS suggests that this convoluted three-dimensional structures might play a significant role in either the pathogenesis or persistence of chronic rhinosinusitis. PMID- 26024694 TI - Downbeat nystagmus: evidence for enhancement of utriculo-ocular pathways by ocular vestibular evoked myogenic potentials? AB - Downbeat nystagmus (DBN) is caused by an impairment of Purkinje cells in the flocculus. The decreased cerebellar inhibitory input affects otolith pathways. Since ocular and cervical vestibular evoked myogenic potentials (o-/cVEMP) test the otoliths, the VEMP were measured in DBN patients and in controls. Sixteen patients with DBN, 14 cerebellar oculomotor disorder patients without DBN (COMD), and 16 healthy controls were examined with o-/cVEMP. Computational modeling was used to predict VEMP differences between groups. DBN patients had significantly higher oVEMP peak-to-peak (PP) amplitudes than COMD patients without DBN and controls. Cervical VEMP did not differ. The computational model of DBN predicted a twofold oVEMP increase for DBN patients. These findings suggest an enhancement of the utriculo-ocular response. The unchanged cVEMP indicate no effect on the otolith-cervical reflex in DBN. Computational modeling suggests that the utriculo ocular enhancement is caused by an impaired vertical neural integrator resulting in the increased influence of utricular signals. This also explains the gravitational dependence of DBN. PMID- 26024695 TI - The Norwegian Voice Handicap Index (VHI-N) patient scores are dependent on voice related disease group. AB - The aim of this study is to determine to what extent the Voice Handicap Index Norwegian (VHI-N) is scored depending on specific laryngological disease. In a multi-center study, 126 healthy subjects and 355 patients with different voice related diseases answered the VHI-N. The VHI-N scores showed high Cronbach's alpha. Analyses of variance were performed with VHI-N dependent and specific voice-related disease as independent variable, and showed highly significant dependence by group allocation (F(7,461) = 28.0; p < 0.001). When studying post hoc analyses secondary to this ANOVA analysis, we have shown that the control group scored lower than the entire patient groups (all p < 0.001) except the dysplasia group. Aphonic patients scored higher than all the other groups (all p < 0.001) except those with spasmodic dysphonia. The cancer patient group furthermore scored lower than patient groups with recurrent palsy, dysfunctional disease or spasmodic dysphonia (all p < 0.001). In addition, patients with recurrent palsy scored higher than patients with degenerative/inflammatory disease (p < 0.001). No influences of patient age, gender, or smoking were observed in the VHI-N scores. The VHI-N is a psychometrically well-functioning instrument, also at disease-specific levels and discriminates well between health and voice diseases, as well as between different voice-related diseases. The VHI N may be recommended to be used when monitoring voice-related disease treatment. PMID- 26024696 TI - When is definitive radiotherapy the preferred treatment for head and neck squamous cell carcinoma? PMID- 26024697 TI - Effect of intratympanic application of efinaconazole 10 % solution in the guinea pig. AB - Efinaconazole 10 % solution is a new triazole antifungal agent developed for the topical treatment of fungal infections of the nails. The current study examined the effect of intratympanic application of efinaconazole 10 % solution in the guinea pig ear. Sixteen male Hartley guinea pigs (weight 501-620 g) were divided into 3 groups to be treated with efinaconazole 10 % solution, gentamicin (50 mg/mL), or saline solution. Topical solutions of 0.2 mL were applied through a small hole made at the tympanic bulla once daily for 7 consecutive days. Post intervention auditory brainstem responses were obtained 7 days after the last treatment. The extent of middle ear damage and hair cell loss was investigated. The efinaconazole- and gentamicin-treated groups showed severe deterioration in auditory brainstem response threshold. Middle ear examination revealed extensive changes in the efinaconazole-treated group and medium changes in the gentamicin treated group. Hair cells were preserved in the efinaconazole- and saline-treated groups, but severe damage was seen in the gentamicin group. In conclusion, efinaconazole 10 % solution applied intratympanically to the guinea pig middle ear caused significant middle ear inflammation and hearing impairment. PMID- 26024698 TI - The Epidemiology of Suicide Behaviors among the Countries of the Eastern Mediterranean Region of WHO: a Systematic Review. AB - This systematic review aimed to help better to understand the epidemiology of suicidal behaviors among Eastern Mediterranean Region (EMR) countries. The PubMed, EMR medex, Scopus, PsychInfo, ISI, and IMEMR were searched with no language limitation for papers on the epidemiology of suicidal behaviors in the general population, published up to August 2013. A total of 13 articles were reviewed. The incidence (per 100.000) of committed suicide ranged from 0.55 to 5.4. The lifelong prevalence of attempted suicide, suicidal plan and thoughts were 0.72-4.2%, 6.2-6.7%, and 2.9-14.1%, respectively. The figures for suicide are higher than those officially reported. Suicide behaviors' statistics is susceptible to underestimation presumably due to the socio-cultural, religious and legal barriers, not to mention the lack of well-organized registries and methodologically sound community-based surveys. PMID- 26024699 TI - The non-hyperemic coronary pressure notch as an indicator of the physiologic significance of coronary artery stenosis. AB - Myocardial fractional flow reserve (FFR) is a new index of the functional significance of intermediate coronary stenoses that is calculated from pressure measurements made during coronary arteriography. The aim of this study was to evaluate the correlation between non-hyperemic coronary pressure dicrotic notch and fractional flow reserve (FFR). A consecutive of 114 patients (73 men and 41 women) was enrolled in this study. Data were shown as means +/- SD. Statistical analyses were performed with SPSS software. The statistical significance of differences was determined by chi-square analysis with Yates correction. Significance was defined as P< 0.05. Positive dicrortic notch was observed in 97 patients (85%). Significant association was detected between coronary pressure notch (dicrotic notch), and FFR as loss of the dicrotic notch was detected in 93.8% (15/16) of patients with FFR less than 0.75 (P=0.001). Upon ROC curve, a cutoff FFR value of approximately 0.75 demonstrated sensivity and specifity of 93.8% and 98%, respectively for loss of the dicrotic notch. The positive predictive value for loss of the dicrotic notch was 88.2%. Our study demonstrated loss of non-hyperemic coronary pressure diacrotic notch correlates significantly with FFR and may predict an FFR < 0.75 with high accuracy. In patients with functionally significant coronary stenosis, loss of non-hyperemic diacrotic notch appears to be a useful index of the functional severity of the stenoses and the need for coronary revascularization. PMID- 26024700 TI - Correlates of memory complaints and personality, depression, and anxiety in a memory clinic. AB - The aim of the study was to find whether there is an association between subjective memory complaint and memory impairment and probable underlying psychological conditions. A total of 90 patients with subjective memory complaint enrolled in this study. Short history and demographic information were obtained and then the patients underwent memory and mental health assessments, using Wechsler Memory Scale (WMS), Hospital Anxiety and Depression Scale (HADS) and Minnesota Multiphasic Personality Inventory (MMPI) test tools. The mean age of the participants was 52.31 +/- 17.97. Forty patients out of 90 (44.4%) were male. The prevalence of depression, anxiety and memory impairment was 10%, 12.2%, and 28.8%, respectively. Memory impairment has only shown a significant association with the presence of anxiety disorder according to the HADS findings (P=0.001). Regarding the MMPI, considerable differences were observed in the average grade of hysteria among patients with and without memory impairment: 8.38 +/- 2.27 vs. 4.35 +/- 1.96. There was also significant statistical association between the average score of depression on the MMPI in patients with and without memory impairment that were 13.7 +/- 3.33 and 8.31 +/-3.86, (P=0.03). The result of the current study shows that underlying psychological conditions such as anxiety, depression, and histrionic personality are associated with memory impairment. PMID- 26024701 TI - Comparison of propranolol and pregabalin for prophylaxis of childhood migraine: a randomised controlled trial. AB - Migraine involves 5-10% of children and adolescents. Thirty percent of children with severe migraine attacks have school absence and reduced quality of life that need preventive therapy. The purpose of this randomised control trial study is to compare the effectiveness, safety and the tolerability of pregabalin toward Propranolol in migraine prophylaxis of children. From May 2011 to October 2012, 99 children 3-15 years referred to the neurology clinic of Mofid Children's Hospital with a diagnosis of migraine enrolled the study. Patients randomly divided into two groups (A&B). We treated children of group A with capsule of pregabalin as children of group B with tablet of propranolol for at least 8 weeks. In this study, 99 patients were examined that 91 children reached the last stage. The group A consistsed of 46 patients, 12(26.1%) girls, 34 (73.9%) boys and the group B consisted of 45 patients, 14(31.1%) girls, 31 (68.9%) boys. Basis of age, gender, headache onset, headache frequency, migraine type, triggering and relieving factors there was no significant difference among these groups (P>0.05). After 4 and 8 weeks of Pregabalin usage monthly headache frequency decreased to 2.2+/-4.5 and 1.76+/-6.2 respectively. Propranolol reduced monthly headache frequency up to 3.73+/-6.11 and 3.34+/-5.95 later 4 and 8 weeks respectively. There was a significant difference between these two groups according to headache frequency reduction (P=0.04). Pregabalin efficacy in reducing the frequency and duration of pediatric migraine headache is considerable in comparison with propranolol. PMID- 26024702 TI - Age-associated changes on axonal regeneration and functional outcome after spinal cord injury in rats. AB - This study was conducted to evaluate the association between aging and regenerative potential of spinal cord injury. Three groups of male Sprague-Dawley rats, including young (40 days), mature (5-6 months) and old (28-29 months) were spinally hemisected at the L1 level. The locomotor performance was assessed weekly for eight weeks after lesion using locomotors' rating scale developed by Basso, Bresnahan and Beattie (BBB). In the tracing study, retrograde labeled neuron was counted in the lateral vestibular nucleus for axonal regeneration. From 4-8 weeks, the functional recovery of the young and mature age rats was significantly increased in comparison to the old age group. At 8 weeks, young and mature animals achieved a plateau score of (mean +/- SD), 17 +/- 1.47 and 16.8 +/ 0.70 respectively, and the old rats reached an average score of 13.8+/-1.63 (P<0.05). The mean number of labeled neurons in the vestibular nucleus in the young group (mean +/- SD): 32.05 +/- 1.03 increase significantly compared to the older age group 5.01 +/- 1.31 (P<0.05). Current findings suggest that axonal repair and functional improvement decrease in aged animals after partial spinal cord injury. Thus, the aging process may affect the regenerative capacity of the injured central nervous system, and axonal regeneration is age dependent. PMID- 26024703 TI - Urinary 8-hydroxy-deoxyguanosine as a biomarker of oxidative DNA damage in employees of subway system. AB - Exposure to air pollutants, steel dust or other occupational and environmental hazards as oxidative stress have adverse effects on subway workers' health. Oxidative stress generates an excessive amount of reactive oxygen species (ROS) and Oxygen Free Radicals during their work time in the tunnels. Once DNA is repaired, Urinary 8-hydroxy-deoxyguanosine (8-OHdG) is excreted in the urine. Therefore, urinary level of 8-OHdG can reflect the extent of oxidative DNA damage. The aim of this study was to document the oxidative stress caused by exposure to these hazards by measuring 8-OHdG in workers urine. We collected urine samples of 81 male subway workers after their working shift. The concentration of urinary 8-OHdG was measured by ELISA method. We used linear regression analysis to compare the level of urinary 8-OHdG as a biomarker of oxidative stress between workers in tunnels and other staff. The mean concentration of urinary 8-OHdG for workers in the tunnel was 58.05 (SD=28.83) ng/mg creatinine and for another staff was 54.16 (SD =26.98) ng/mg creatinine. After adjustment for age, smoking, driving and a second job in a linear regression model, the concentration of 8-OHdG for the exposed group was significantly higher than unexposed group (P=0.038). These findings confirm that the concentration of urinary 8-OHdG for workers who work in tunnels was significantly higher than the other staff. Additional investigations should be performed to understand that which ones of occupational exposures are more important to cause oxidative stress. PMID- 26024704 TI - Parameters of lower extremities alignment view in Iranian adult population. AB - Normal axial alignment restoration in lower extremities is crucial for surgeons performing reconstructive surgeries. Since reference normal values of axial alignment are affected by age, sex, and ethical issues, we tried to scrutinize these parameters in Iranian adults and compare them with normal values in literatures. Through a cross-sectional design, standing axial alignment views of lower extremities were surveyed from 100 volunteers (50 males and 50 females) aged between 15-32 years. The lower extremities alignment variables were evaluated during two separate measurements. Total average values were used for comparison among genders. Tibiofemoral mechanical angle depicted mean varus of 1.5 degrees in an Iranian population that was significantly higher in male participants. The Mean angle between anatomical and mechanical axes of the femur was 5.7 +/- 1.2o. The Knee joint was shown to be medially inclined 3.6 +/- 1.7o in men comparing 2 +/- 2o of women with a significant difference. Joint line congruence angle was medially inclined in all of the study participants with a mean of 1 +/- 1.6o. To compare with anthropometric studies of western populations, Iranian participants had more varus lower limb alignment. It seemed mainly because of larger medially inclined knee joint (knee-joint obliquity). This finding along with more compensatory ankle valgus is similar to results of other Asian studies. Such racial variation should be considered in designing appropriate systems in reconstructive surgery. PMID- 26024705 TI - Does hypertension remain after kidney transplantation? AB - Hypertension is a common complication of kidney transplantation with the prevalence of 80%. Studies in adults have shown a high prevalence of hypertension (HTN) in the first three months of transplantation while this rate is reduced to 50- 60% at the end of the first year. HTN remains as a major risk factor for cardiovascular diseases, lower graft survival rates and poor function of transplanted kidney in adults and children. In this retrospective study, medical records of 400 kidney transplantation patients of Sina Hospital were evaluated. Patients were followed monthly for the 1st year, every two months in the 2nd year and every three months after that. In this study 244 (61%) patients were male. Mean +/- SD age of recipients was 39.3 +/- 13.8 years. In most patients (40.8%) the cause of end-stage renal disease (ESRD) was unknown followed by HTN (26.3%). A total of 166 (41.5%) patients had been hypertensive before transplantation and 234 (58.5%) had normal blood pressure. Among these 234 individuals, 94 (40.2%) developed post-transplantation HTN. On the other hand, among 166 pre-transplant hypertensive patients, 86 patients (56.8%) remained hypertensive after transplantation. Totally 180 (45%) patients had post-transplantation HTN and 220 patients (55%) didn't develop HTN. Based on the findings, the incidence of post transplantation hypertension is high, and kidney transplantation does not lead to remission of hypertension. On the other hand, hypertension is one of the main causes of ESRD. Thus, early screening of hypertension can prevent kidney damage and reduce further problems in renal transplant recipients. PMID- 26024706 TI - A comparative study of obsessive beliefs in obsessive-compulsive disorder, anxiety disorder patients and a normal group. AB - Cognitive models of obsessive-compulsive disorder (OCD) posit that specific kinds of dysfunctional beliefs underlie the development of this disorder. The aim of present study was to determine whether these beliefs are endorsed more strongly by OCD patients than by those with other anxiety disorders and by community samples. A battery of questionnaires, including the OBQ-44, MOCI, BDI-II, BAI, STAI, used to assess obsessive-compulsive symptoms, depression and anxiety in 39 OCD patients (OC), 46 anxious patients (AC) and 41 community controls (CC). Compared to CCs and ACs, OC patients more strongly endorsed beliefs related to importance and control of thoughts. Both OC and AC patients scored higher than CC participants did on belief domains about responsibility/threat estimation and perfectionism/certainty. Therefore, the domain that seems to be specific to OCD is a set of beliefs that revolves around the contention that it is possible and necessary to control one's thoughts. Results regarding group differences on particular items of the OBQ-44 indicated that 21 items discriminated between the OC and CC groups and 7 items discriminated between the OC and AC groups, suggesting that these items are more specific to the OC group. Additional research warranted because it is plausible that these cognitive factors relate differently to OCD phenomena across different cultures. PMID- 26024707 TI - Attenuation of alcohol withdrawal syndrome and blood cortisol level with forced exercise in comparison with diazepam. AB - Relieving withdrawal and post-abstinence syndrome of alcoholism is one of the major strategies in the treatment of alcohol addicted patients. Diazepam, chlordiazepoxide, and topiramate are the approved medications that were used for this object. To assess the role of non-pharmacologic therapy in the management of alcohol withdrawal syndrome, we analyzed effects of forced exercise by treadmill on alcohol dependent mice as an animal model. A total of 60 adult male mice were divided into 5 groups, from which 4 groups became dependent to alcohol (2 g/kg/day) for 15 days. From day 16, treatment groups were treated by diazepam (0.5mg/kg), forced exercise, and diazepam (0.5 mg/kg) concurrent with forced exercise for two weeks; And the positive control group received same dose of alcohol (2 g/kg/day) for two weeks. The negative control group received normal saline for four weeks. Finally, on day 31, all animals were observed for withdrawal signs, and Alcohol Total Withdrawal Score (ATWS) was determined. Blood cortisol levels were measured in non-fasting situations as well. Present findings showed that ATWS significantly decrease in all treatment groups in comparison with positive control group (P<0.05 for groups received diazepam and treated by forced exercise and P<0.001 for group under treatment diazepam + forced exercise). Moreover, blood cortisol level significantly decreased in all treatment groups (P<0.001). This study suggested that forced exercise and physical activity can be useful as adjunct therapy in alcoholism and can ameliorate side effects and stress situation of withdrawal syndrome periods. PMID- 26024708 TI - Insulinoma in a patient with type 2 diabetes mellitus. AB - Insulinoma in a patient with pre-existing diabetes is extremely rare. Only a small number of cases have been reported all over the world. We report a case of insulinoma in a patient with type 2 diabetes. A 63-year-old female was diagnosed to have diabetes mellitus six years ago, she was given metformin and sulphonylurea to control her glycemia, she had adequate glycemic control for many years, but thereafter, the patient has experienced hypoglycemia after cessation of the treatment since 8 months ago and was hospitalized for further examination, endogenous hypoglycemia was confirmed and the level of serum insulin and C peptide were elevated. Endoscopic ultrasound showed a heterogeneous lesion in the head of the pancreas. Head pancreatectomy was done. In the postoperative period diabetes again developed and required oral agents for control. PMID- 26024710 TI - Being knocked down after a blow to the head should end a boxing match. PMID- 26024709 TI - Hemosuccus pancreaticus as a rare cause of gastrointestinal bleeding: a report of two cases. AB - Pancreatic diseases are known to be associated with complications such as pseudocyst and abscess. A pseudoaneurysm associated with pancreatitis may develop as well. The pseudoaneurysm may rupture into various parts of the gastrointestinal tract; the peritoneal cavity, or the retroperitoneum. We report two cases of Hemosuccus pancreaticus admitted to our center in the past five years. One case was associated with acute pancreatitis, and another case was associated with chronic pancreatitis. A pseudocyst was found in two cases. Both were successfully managed by emergency surgery. So, Hemosuccus pancreaticus is a rare cause of gastrointestinal bleeding with difficult diagnosis, and surgery is the effective treatment for the patient with severe bleeding. However in cases with no life-threatening bleeding angiography and embolization can be performed. PMID- 26024711 TI - Erratum: The Correlation between Effective Factors of E-learning and Demographic Variables in a Post-Graduate Program of Virtual Medical Education in Tehran University of Medical Sciences. PMID- 26024712 TI - Characterization of Plant Peroxidases and Their Potential for Degradation of Dyes: a Review. AB - Peroxidases are ubiquitously found in all vascular plants and are promising biocatalysts for oxidization of wide range of aromatic substrates including various industrial dyes. Peroxidases can catalyze degradation of chemical structure of aromatic dyes either by precipitation or by opening the aromatic ring structure. Both soluble and immobilized peroxidases have been successfully used in batches as well as in continuous processes for the treatment of aromatic dyes present in industrial effluents. Plant peroxidases are stable catalysts that retain their activities over a broad range of pH and temperatures. The performance of an enzyme for degradation process depends upon the structure of dyes and the operational parameters like concentration of enzyme, H2O2 and dye, incubation time, pH, and temperature. Recalcitrant dyes can also be mineralized by plant peroxidases in the presence of redox mediators. Thus, plant peroxidases are easily available, inexpensive, and ecofriendly biocatalysts for the treatment of wastewaters containing a wide spectrum of textile and non-textile synthetic dyes. This article reviews the recent developments in isolation and characterization of plant peroxidases and their applications for bioremediation of synthetic dyes. PMID- 26024713 TI - Recombinant Multivalent EMMPRIN Extracellular Domain Induces U937 Human Leukemia Cell Apoptosis by Downregulation of Monocarboxylate Transporter 1 and Activation of Procaspase-9. AB - This study was carried out to understand the effect of the recombinant multivalent extracellular matrix metalloproteinase inducer (EMMPRIN) extracellular domain, designated as rmEMMPRINex, on the apoptotic cell death of human leukemia U937 cells. Expression of monocarboxylate transporter 1 (MCT1) and caspase-9 in U937 treated with rmEMMPRINex was investigated in this study. Levels of membrane MCT1 and intracellular procaspase-9 were decreased in rmEMMPRINex treated cells in comparison to controls. However, the expression of activated caspase-9 was undetectable. rmEMMPRINex also induced DNA fragmentation and apoptosis in U937 cells. Taken together, we concluded that interaction of rmEMMPRINex with U937 cells leads to inhibition of MCT1 membrane expression, intracellular activation of procaspase-9, followed by DNA fragmentation and apoptosis. This may contribute to the conceptual development of novel cancer drugs in the future. PMID- 26024714 TI - Disulfide Bonds of Proteins Displayed on Spores of Bacillus subtilis Can Occur Spontaneously. AB - Surface display using spores of Bacillus subtilis is widely used to anchor antigens and enzymes of different sources. One open question is whether anchored proteins are able to form disulfide bonds. To answer this important question, we anchored the Escherichia coli alkaline phosphatase PhoA on the spore surface using two different surface proteins, CotB and CotZ. This enzyme needs two disulfide bonds to become active. Subsequently, we purified the spores and assayed for alkaline phosphatase activity. In both cases, we were able to recover enzymatic activity. Next, we asked whether formation of disulfide bonds occurs spontaneous or is catalyzed by thiol-disulfide oxidoreductases upon lysis of the cells. The experiment was repeated in a double-knockout mutant DeltabdbC and DeltabdbD. Since the disulfide bonds are also present on spores prepared from the double knockout, we conclude that oxidative environment after cell lysis is sufficient for disulfide formation of alkaline phosphatase. PMID- 26024715 TI - Genetic differentiation analysis for the identification of complementary parental pools for sorghum hybrid breeding in Ethiopia. AB - KEY MESSAGE: The potential for exploiting heterosis for sorghum hybrid production in Ethiopia with improved local adaptation and farmers preferences has been investigated and populations suitable for initial hybrid development have been identified. Hybrids in sorghum have demonstrated increased productivity and stability of performance in the developed world. In Ethiopia, the uptake of hybrid sorghum has been limited to date, primarily due to poor adaptation and absence of farmer's preferred traits in existing hybrids. This study aimed to identify complementary parental pools to develop locally adapted hybrids, through an analysis of whole genome variability of 184 locally adapted genotypes and introduced hybrid parents (R and B). Genetic variability was assessed using genetic distance, model-based STRUCTURE analysis and pair-wise comparison of groups. We observed a high degree of genetic similarity between the Ethiopian improved inbred genotypes and a subset of landraces adapted to lowland agro ecology with the introduced R lines. This coupled with the genetic differentiation from existing B lines, indicated that these locally adapted genotype groups are expected to have similar patterns of heterotic expression as observed between introduced R and B line pools. Additionally, the hybrids derived from these locally adapted genotypes will have the benefit of containing farmers preferred traits. The groups most divergent from introduced B lines were the Ethiopian landraces adapted to highland and intermediate agro-ecologies and a subset of lowland-adapted genotypes, indicating the potential for increased heterotic response of their hybrids. However, these groups were also differentiated from the R lines, and hence are different from the existing complementary heterotic pools. This suggests that although these groups could provide highly divergent parental pools, further research is required to investigate the extent of heterosis and their hybrid performance. PMID- 26024716 TI - Pulmonary alveolar microlithiasis: an interesting case report with systematic review of Indian literature. AB - Pulmonary alveolar microlithiasis is a rare disease characterized by intra alveolar presence of microliths. This study reports an interesting case of pulmonary alveolar microlithiasis and provides a systematic review of cases reported from India. A 23-year-old female presented with a history of cough, wheeze, chest pain, and episodic wheeze for five months. Pulmonary function tests demonstrated an obstructive pattern, and chest Xray showed fine micronodular opacities predominantly involving the middle and lower zones of both lungs. Transbronchial lung biopsy revealed the diagnosis. She responded well to inhaled steroid therapy. A systematic review of literature was performed and identified 73 cases of pulmonary alveolar microlithiasis reported from India. The mean (SD) age of the patients was 28.8 (14.9) years, with an almost equal male:female ratio. Many patients were asymptomatic at presentation. Breathlessness and cough were the most common symptoms, and the disease progressed into respiratory failure associated with cor pulmonale. About one-third of the cases were initially misdiagnosed and treated as pulmonary tuberculosis. Extra-pulmonary manifestations and comorbidities were also evident in our series. This systematic review helps to determine epidemiological and clinical characteristics of pulmonary alveolar microlithiasis. Further research is needed to elucidate the etiopathogenesis, diagnosis, and therapeutic options, which are beneficial in developing and identifying cost-effective treatment for pulmonary alveolar microlithiasis. PMID- 26024717 TI - Correlation of CYP2C19 genotype with plasma voriconazole levels: a preliminary retrospective study in Indians. AB - BACKGROUND: Voriconazole is an antifungal drug essentially metabolized by cytochrome P450 (CYP2C19) isozyme. Plasma voriconazole levels exhibit wide inter individual variability due to several factors like age, weight, food or drug interactions or CYP2C19 polymorphisms. OBJECTIVE: In the present study, we assessed the correlation of voriconazole levels with CYP2C19 genotype in patients on voriconazole therapy. SETTING: Biochemistry Department of a 480 inpatient bed tertiary care hospital in India. METHODS: Plasma voriconazole estimation was done in seventy-two patients on standard weight based voriconazole therapy by High Performance Liquid Chromatography (HPLC) while genotype assessment for the CYP2C19*2 and *3 was done by PCR-RFLP and *17 by ARMS-PCR. Statistical analysis and genotype-phenotype correlation was done by comparing the drug levels with the CYP2C19 genotype. MAIN OUTCOME MEASURE: CYP2C19 polymorphisms influence voriconazole metabolism. RESULTS: A wide variability is seen in plasma levels with only 51% attaining therapeutic levels. The allele frequency of *2, *3 and *17 variant were found to be 33.3, 0.7 and 18% respectively. The drug levels in carriers of *2 allele (poor metabolizers) was twofold higher than that in extensive metabolizers. However, the influence of *2 allele was compromised in presence of *17 allele and patients had low voriconazole levels. In addition to the genotype, co-medication and clinical condition remarkably influenced voriconazole concentration. CONCLUSION: Plasma voriconazole levels are influenced by CYP2C19 variants, drug interactions and clinical condition of the patient. Genotype assessment at initiation of therapy followed by drug monitoring would help optimizing therapeutic efficacy and minimizing toxicity. PMID- 26024719 TI - Radiographic appearances of uncommon paediatric implants and devices. AB - As childhood survival of chronic illness improves, long-term implanted devices will be encountered more frequently in routine radiology. In our paediatric tertiary referral hospital, we have come across several types of implanted devices that were not confidently recognised or identified by front-line staff and were often only identified by discussion with the patient, family or clinical team. This pictorial review highlights the appearance of nonvascular devices on paediatric radiographs in order to help clinicians identify the most frequent complications and to improve awareness of these important devices. PMID- 26024721 TI - The "Friday effect": Can epidemiology tell us when to operate? PMID- 26024722 TI - Strategies of bringing drug product marketing applications to meet current regulatory standards. AB - In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts. PMID- 26024723 TI - Acceptance Probability (P a) Analysis for Process Validation Lifecycle Stages. AB - This paper introduces an innovative statistical approach towards understanding how variation impacts the acceptance criteria of quality attributes. Because of more complex stage-wise acceptance criteria, traditional process capability measures are inadequate for general application in the pharmaceutical industry. The probability of acceptance concept provides a clear measure, derived from specific acceptance criteria for each quality attribute. In line with the 2011 FDA Guidance, this approach systematically evaluates data and scientifically establishes evidence that a process is capable of consistently delivering quality product. The probability of acceptance provides a direct and readily understandable indication of product risk. As with traditional capability indices, the acceptance probability approach assumes that underlying data distributions are normal. The computational solutions for dosage uniformity and dissolution acceptance criteria are readily applicable. For dosage uniformity, the expected AV range may be determined using the s lo and s hi values along with the worst case estimates of the mean. This approach permits a risk-based assessment of future batch performance of the critical quality attributes. The concept is also readily applicable to sterile/non sterile liquid dose products. Quality attributes such as deliverable volume and assay per spray have stage-wise acceptance that can be converted into an acceptance probability. Accepted statistical guidelines indicate processes with C pk > 1.33 as performing well within statistical control and those with C pk < 1.0 as "incapable" (1). A C pk > 1.33 is associated with a centered process that will statistically produce less than 63 defective units per million. This is equivalent to an acceptance probability of >99.99%. PMID- 26024724 TI - Formation of dimethyldithioarsinic acid in a simulated landfill leachate in relation to hydrosulfide concentration. AB - Dimethyldithioarsinic acid (DMDTA(V)), present in such intense sources as municipal landfill leachate, has drawn a great deal of attention due to its abundant occurrence and different aspect of toxicity. The hydrosulfide (HS(-)) concentration in leachate was studied as a major variable affecting the formation of DMDTA(V). To this end, the HPLC-ICPMS system equipped with the reversed-phase C18 column was used to determine DMDTA(V). Simulated landfill leachates (SLLs) were prepared to cover a mature landfill condition with the addition of sodium sulfate and sulfide at varying concentrations in the presence of dimethylarsinic acid (DMA(V)). The concentration of sodium sulfide added in the SLLs generally exhibited a strong positive correlation with the concentration of DMDTA(V). As such, the formation of DMDTA(V) in the SLLs is demonstrated to be controlled by the interactive relationship between DMA(V) and the HS(-). PMID- 26024726 TI - Role of XmnIgG Polymorphism in Hydroxyurea Treatment and Fetal Hemoglobin Level at Isfahanian Intermediate beta-Thalassemia Patients. AB - BACKGROUND: beta-thalassemia is the most common monogenic disorder in human. The (C-->T) polymorphism at -158 upstream region of the gammaG-globin gene and pharmacological factors such as hydroxyurea have been reported to influence gamma globin gene expression and the severity of clinical symptoms of beta-thalassemia. METHODS: In the present study, 51 beta-thalassemia intermediate patients were studied. Xmn1gammaG polymorphism genotype was determined using Tetra-Primer ARMS PCR technique. Hemoglobin (Hb) and fetal hemoglobin (HbF) levels were determined by gel electrophoresis. RESULTS: Of 51 patients, 35 (68.6%) patients were heterozygous (CT) and 16 (31.4%) patients were homozygous (CC). Of 30 patients under treatment by hydroxyurea, 20 (66.7%) patients were heterozygous (CT) and 10 (33.3%) patients were homozygous (CC). Our results demonstrated that in the heterozygous (CT) genotype, the Hb (9.58 +/- 1.25 gm/dl) and HbF (89.30 +/- 21.87) levels were significantly higher in comparison with homozygous (CC) genotype (7.94 +/- 1.34 gm/dl and 70.32 +/- 40.56, respectively). Furthermore, we observed that after drug usage, the Hb and HbF levels in patients with heterozygous (CT) genotype (0.7 +/- 1.26 gm/dl and 5.95 +/- 14.8, respectively) raised more in comparison with homozygous (CC) genotype (0.26 +/- 1.43 gm/dl and 0.8 +/- 1.31, respectively). CONCLUSION: Hb and HbF levels in the patients carrying T allele are increased significantly, and they also response to hydroxyurea treatment. PMID- 26024727 TI - Evaluation of pharmacokinetic and pharmacodynamic interactions when lenalidomide is co-administered with warfarin in a randomized clinical trial setting. AB - BACKGROUND AND OBJECTIVE: Lenalidomide is an oral immunomodulatory drug used to treat multiple myeloma and some other hematological malignancies. Warfarin is often used concomitantly as prophylaxis against potential venous thromboembolism associated with lenalidomide treatment. The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic drug interactions between lenalidomide and warfarin in healthy volunteers. METHODS: This was a double blind, placebo-controlled, randomized, two-period crossover study. Eighteen healthy male and female subjects were treated with 10 mg/day lenalidomide or placebo for 9 days. A single oral 25 mg dose of warfarin was administered on Day 4 of each treatment period. Blood was sampled to determine international normalized ratio (INR), prothrombin time (PT), and area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max) warfarin and lenalidomide. RESULTS: The 90 % confidence intervals (CI) for the ratio of AUC or Cmax geometric means between co-administration with lenalidomide and placebo were within the 80-125 % bioequivalence bounds for R-warfarin and S warfarin. The 90 % CI for the ratio of area under the INR curve from time zero until 144 hours after dosing (AUCINR, 0-144) or the peak INR geometric means between co-administration with lenalidomide versus placebo was also within the 85 125 % bounds. Additionally, the AUC and C max values of lenalidomide were not altered by co-administration with warfarin. CONCLUSION: Co-administration of lenalidomide with warfarin did not alter the plasma exposure or anticoagulant effect to warfarin or the plasma exposure to lenalidomide, indicating that no dose adjustment of either drug is needed when these two drugs are co administered. PMID- 26024728 TI - Serum hepcidin concentrations correlate with serum iron level and outcome in patients with intracerebral hemorrhage. AB - Iron plays a detrimental role in the intracerebral hemorrhage (ICH)-induced brain damage, while hepcidin is the most important iron-regulated hormone. Here, we investigate the association between serum hepcidin and serum iron, outcome in patients with ICH. Serum samples of 81 cases with ICH were obtained on consecutive days to detect the levels of hepcidin, iron, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). The National Institutes of Health Stroke Scale score (NIHSS) was measured at admission and on days 7 and 30, and the modified Rankin Scale (mRS) score was evaluated at 3 months after ICH. Additionally, the correlations of serum hepcidin with serum iron and the mRS score were analyzed by a generalized linear model. Higher serum hepcidin levels were detected in patients with poor outcomes (P < 0.001), and the mRS score increased by a mean of 1.135 points (95% CI 1.021-1.247, P < 0.001) for every serum hepcidin quartile after adjusting for other prognostic variables. Pearson correlation analysis showed that serum hepcidin was negatively correlated with serum iron (r = -0.5301, P < 0.001), and a significantly lower concentration of serum iron was found in patients with poor outcomes (P = 0.007). Additionally, serum hepcidin was independently correlated with mRS scores of ICH patients (OR 1.115, 95% CI 0.995-1.249, P = 0.021). Our results suggest that serum hepcidin is closely related to the outcome of patients with ICH and may be a biological marker for outcome prediction. PMID- 26024729 TI - Occult dual pathology in mesial temporal lobe epilepsy. PMID- 26024730 TI - Infrared Spectrum and UV-Induced Photochemistry of Matrix-Isolated 5 Hydroxyquinoline. AB - The structure, infrared spectrum, and photochemistry of 5-hydroxyquinoline (5HQ) were studied by matrix isolation infrared spectroscopy, complemented by theoretical calculations performed at the DFT(B3LYP)/6-311++G(d,p) level of approximation. According to the calculations, the trans conformer of 5HQ (with the OH group pointing to the opposite direction of the pyridine ring of the molecule) is more stable than the cis form (by ~8.8 kJ mol(-1)). The main factors determining the relative stability of the two conformers were rationalized through natural bond orbital (NBO) and charge density analyses. The compound was trapped in solid nitrogen at 10 K, and its infrared spectra registered and interpreted, showing the sole presence in the matrix of the more stable trans conformer. Broadband in situ UV irradiations (lambda >= 288 nm and lambda >= 235 nm) allowed for the observation of different chemical transformations, which started by excitation to the S1 state of 5HQ, followed by homolytic cleavage of the O-H bond, and subsequent reattachment of the H atom to the 5HQ radical to form quinolin-5(6H)-one and quinolin-5(8H)-one. The first of these two quinolinones was found to convert to open-ring isomeric ketenes, especially when irradiation was performed at higher energy, whereas the second is rather stable under the used experimental conditions. As a whole, the observed photochemistry of matrix-isolated 5HQ closely matches those previously reported for phenol and thiophenol. A detailed mechanistic interpretation for the observed photochemical processes is here proposed, which received support from time-dependent DFT calculations. PMID- 26024731 TI - In memoriam--Walter J. Gehring. PMID- 26024732 TI - Catherine of Aragon (1485-1536): the red malar rash of familial SLE in a Tudor red rose queen. PMID- 26024733 TI - Circulating CD4+ T-cell number decreases in rheumatoid patients with clinical response to rituximab. PMID- 26024734 TI - Comparative Study of Serum Copper, Iron, Magnesium, and Zinc in Type 2 Diabetes Associated Proteinuria. AB - Trace element (TE) disturbances are well noted in type 2 diabetes mellitus (T2DM) and its associated complications. In present study, the effect of proteinuria on serum copper (Cu), iron (Fe), magnesium (Mg), and zinc (Zn) in T2DM patients with and without proteinuria was seen. Total subjects were aged between 30 and 90 years; 73 had proteinuria, 76 had T2DM with proteinuria, 76 had T2DM, and 75 were controls. Serum Cu(II), Fe(III), Mg(II), and Zn(II) were assayed by inductively coupled plasma optical emission spectrometer (ICP-OES). Urinary albumin estimation was performed by turbidimetric method. Other biochemical parameters were analyzed by ROCHE Module COBAS 6000 analyzer. Statistical analysis was performed using analysis of variance (ANOVA) at P<0.0001 followed by t test. Pearson correlation was applied to estimate the effect of proteinuria on TE. Serum Cu(II) level was increased in T2DM patients with proteinuria while Fe(III) was found elevated in T2DM (P<0.0001) compared to control groups. Zn(II) and Mg(II) were significantly low in proteinuria, T2DM with proteinuria, and T2DM (P<0.0001) compare to controls. Serum Cu(II) showed strong positive association with albumin creatinine ratio (ACR) in T2DM with proteinuria group and T2DM group (P<0.01). Fe(III) was positively and Zn(II) was negatively associated with ACR at P<0.10, in T2DM with proteinuria group. Mg(II) was negatively linked with ACR P<0.01 in proteinuria, T2DM with proteinuria, and T2DM group. TE were observed more disturbed in T2DM with proteinuria group, thus considered to be the part of T2DM routine checkup and restricts the disease towards its progression. PMID- 26024735 TI - A Thickness Calibration Device Is Needed to Determine Staple Height and Avoid Leaks in Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Leaks after sleeve gastrectomy (SG) may be due to a mismatch between staple height and tissue thickness. The aim of this study was to determine the range of gastric thicknesses in three areas of stapling. METHODS: SG was performed using a 40-Fr suction calibration system 4 cm from the pylorus. Measurement of combined gastric walls was accomplished with an applied pressure of 8 g/mm(2) on the fundus, midbody, and antrum. RESULTS: We enrolled 26 SG patients (15 women, 11 men; mean age 36.8 years). Body mass index (BMI) averaged 45.3 kg/m(2) overall, 44.7 kg/m(2) for males and 45.7 kg/m(2) for females. Although male patients had a thicker stomach antrum than female patients (3.12 vs. 3.09 mm), the midbody (2.57 vs. 3.09 mm) and proximal areas (1.67 vs. 1.72 mm) were thicker in female patients. However, some maximum fundus thicknesses were up to 2.83 mm in females and 2.28 mm in males. Some antra were as thick as 4.07 mm in females and 5.39 mm in males. Also, men had a longer average staple line (22.95 vs. 19.90 cm). CONCLUSION: Because of the range of gastric thicknesses, a single staple height cannot be used to appose the full range of gastric wall thicknesses without potentially causing necrosis or poor apposition. To help avoid leaks, a thickness calibration device is needed to determine correct staple height. PMID- 26024736 TI - Following Bariatric Surgery: an Exploration of the Couples' Experience. AB - BACKGROUND: Bariatric surgery is the most effective intervention for morbid obesity, resulting in substantial weight loss and the resolution of co-morbid conditions. It is not clear what impact bariatric surgery and the subsequent life style changes have on patients' couple relationships. The purpose of this phenomenological study was to examine the lived experience of couples after one member of the couple underwent bariatric surgery. METHODS: This study utilized a phenomenological approach of semi-structured interviews of the couples jointly (n = 10 couples). Colaizzi's method of analysis for phenomenological studies was utilized to elucidate the central themes and distill the essence of the participants' experience. RESULTS: All of the couples felt their post-operative success was due to a joint effort on both members of the couples' part. The participant couples described the following five emerging thematic experiences: (a) changes in physical health, (b) changes in emotional health, (c) changes in eating habits, (d) greater intimacy in the relationship, and (e) the joint journey. CONCLUSIONS: This research provides greater insight into the experience of the couple than has been previously reported. The use of qualitative research techniques offer new approaches to examine the biopsychosocial outcomes and needs of bariatric surgery patients. Further research is warranted in order to develop culturally appropriate interventions to improve the patient's surgical and biopsychosocial outcomes. PMID- 26024737 TI - Exclusion of the Distal Ileum Cannot Reverse the Anti-Diabetic Effects of Duodenal-Jejunal Bypass Surgery. AB - BACKGROUND: Duodenal-jejunal bypass (DJB) has been proven effective in glycemic control in various type 2 diabetes (T2DM) rat models. "Hindgut hypothesis" and "foregut hypothesis" are two prevailing theories to elucidate the weight independent anti-diabetic mechanisms of DJB, however, which mechanism plays the dominant role that has not been illuminated. OBJECTIVE: This paper aims to verify that exclusion of the foregut leads to loss of weight and remission of type 2 diabetes without expedited delivery of nutrients to the distal bowel. METHODS: Thirty-five diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ) were randomly assigned to the control, sham-DJB (S-DJB), DJB, ileal bypass (ILB), and DJB combined with ILB (DJB-ILB) groups. Effects of surgeries on body weight, food intake, blood glucose, glucose-stimulated insulin, and gastrointestinal hormones secretion were evaluated at indicated time points. RESULTS: Compared to the control and S-DJB groups, the DJB group had significant and sustained glycemic control independent of weight loss. Excluding part of the distal ileum did not reverse the diabetic control that followed DJB surgery. The glucagon-like peptide 1 (GLP-1) and PYY levels were significantly increased after DJB. Although GLP-1 and PYY are mainly secreted by L cells in the distal ileum, excluding part of the ileum did not decrease the levels of GLP-1 and PYY after DJB. CONCLUSIONS: The beneficial effects of DJB in glycemic control could not be reversed by excluding the distal ileum. PMID- 26024739 TI - Ethical Challenges in Psychiatric Administration and Leadership. AB - As with all professional ethical principles, those in psychiatry have to evolve over time and societal changes. The current ethical challenges for psychiatric administration and leadership, especially regarding for-profit managed care, need updated solutions. One solution resides in the development by the American Association of Psychiatric Administrators (AAPA) of the first set of ethical principles designed specifically for psychiatric administrators. These principles build on prior Psychological Theories of leadership, such as those of Freud, Kernberg, and Kohut. Supplementing these theories are the actual real life models of psychiatrist leadership as depicted in the memoirs of various psychiatrists. Appreciating these principles, theories, and models may help emerging leaders to better recognize the importance of ethical challenges. A conclusion is that psychiatrists should have the potential to assume more successful leadership positions once again. In such positions, making the skills and well-being of all in the organization seems now to be the foremost ethical priority. PMID- 26024738 TI - Insulin regulates Rab3-Noc2 complex dissociation to promote GLUT4 translocation in rat adipocytes. AB - AIMS/HYPOTHESIS: The glucose transporter GLUT4 is present mainly in insulin responsive tissues of fat, heart and skeletal muscle and is translocated from intracellular membrane compartments to the plasma membrane (PM) upon insulin stimulation. The transit of GLUT4 to the PM is known to be dependent on a series of Rab proteins. However, the extent to which the activity of these Rabs is regulated by the action of insulin action is still unknown. We sought to identify insulin-activated Rab proteins and Rab effectors that facilitate GLUT4 translocation. METHODS: We developed a new photoaffinity reagent (Bio-ATB-GTP) that allows GTP-binding proteomes to be explored. Using this approach we screened for insulin-responsive GTP loading of Rabs in primary rat adipocytes. RESULTS: We identified Rab3B as a new candidate insulin-stimulated G-protein in adipocytes. Using constitutively active and dominant negative mutants and Rab3 knockdown we provide evidence that Rab3 isoforms are key regulators of GLUT4 translocation in adipocytes. Insulin-stimulated Rab3 GTP binding is associated with disruption of the interaction between Rab3 and its negative effector Noc2. Disruption of the Rab3-Noc2 complex leads to displacement of Noc2 from the PM. This relieves the inhibitory effect of Noc2, facilitating GLUT4 translocation. CONCLUSIONS/INTERPRETATION: The discovery of the involvement of Rab3 and Noc2 in an insulin-regulated step in GLUT4 translocation suggests that the control of this translocation process is unexpectedly similar to regulated secretion and particularly pancreatic insulin-vesicle release. PMID- 26024741 TI - Chronic liver disease in alcohol-related chronic pancreatitis patients: Does lightning strike twice? PMID- 26024740 TI - Bacterial Diversity in Bentonites, Engineered Barrier for Deep Geological Disposal of Radioactive Wastes. AB - The long-term disposal of radioactive wastes in a deep geological repository is the accepted international solution for the treatment and management of these special residues. The microbial community of the selected host rocks and engineered barriers for the deep geological repository may affect the performance and the safety of the radioactive waste disposal. In this work, the bacterial population of bentonite formations of Almeria (Spain), selected as a reference material for bentonite-engineered barriers in the disposal of radioactive wastes, was studied. 16S ribosomal RNA (rRNA) gene-based approaches were used to study the bacterial community of the bentonite samples by traditional clone libraries and Illumina sequencing. Using both techniques, the bacterial diversity analysis revealed similar results, with phylotypes belonging to 14 different bacterial phyla: Acidobacteria, Actinobacteria, Armatimonadetes, Bacteroidetes, Chloroflexi, Cyanobacteria, Deinococcus-Thermus, Firmicutes, Gemmatimonadetes, Planctomycetes, Proteobacteria, Nitrospirae, Verrucomicrobia and an unknown phylum. The dominant groups of the community were represented by Proteobacteria and Bacteroidetes. A high diversity was found in three of the studied samples. However, two samples were less diverse and dominated by Betaproteobacteria. PMID- 26024742 TI - Expression of Amino Acid Transporters (LAT1 and ASCT2) in Patients with Stage III/IV Laryngeal Squamous Cell Carcinoma. AB - The aim of this study is to evaluate the clinicopathological significance of L type amino acid transporter 1 (LAT1) expression in patients with advanced laryngeal squamous cell carcinoma (LSCC). A total of 73 patients with advanced LSCC were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, 4F2hc, system ASC amino acid transporter-2 (ASCT2), cell proliferation by Ki-67, microvessel density (MVD) determined by CD34 and p53. A positive LAT1, 4F2hc and ASCT2 expression (staining more than a quarter) in the primary sites were recognized in 85, 80 and 45 %, respectively, and a high LAT1, 4F2hc and ASCT2 expression (staining more than a half) yielded 48, 31 and 18 %, respectively. High expression of LAT1 was significantly associated with lymph node metastasis, 4F2hc, ASCT2, Ki-67 and p53. The expression of LAT1 was significantly correlated with ASCT2, 4F2hc, cell proliferation, and MVD. By univariate analysis, there was no statistically significant relationship between LAT1 expression and prognosis in advanced LSCC. LAT1, 4F2hc and ASCT2 were highly expressed in patients with advanced laryngeal cancer. Our study suggests that the expression of LAT1 plays a crucial role in the metastasis and tumor progression in advanced LSCC. PMID- 26024743 TI - Incidence of bone pain in patients with breast cancer treated with lipegfilgrastim or pegfilgrastim: an integrated analysis from phase II and III studies. AB - PURPOSE: Lipegfilgrastim is a once-per-cycle, fixed-dose, glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF) recently approved in Europe to reduce the duration of chemotherapy-induced neutropenia and incidence of febrile neutropenia in patients with cancer receiving chemotherapy. Bone pain related (BPR) adverse events are commonly associated with G-CSF therapy. This post hoc analysis examined BPR treatment-emergent adverse events (TEAEs) in two comparative studies of lipegfilgrastim or pegfilgrastim in patients receiving chemotherapy. METHODS: A post hoc analysis was conducted using integrated data from two double-blind randomized studies in patients with breast cancer receiving docetaxel and doxorubicin and treated prophylactically with subcutaneous lipegfilgrastim 6 mg or pegfilgrastim 6 mg once per cycle. BPR TEAEs were defined as arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, noncardiac chest pain, and pain in extremity. Relationship of BPR TEAEs to study treatment or chemotherapy was also reported by the investigators. RESULTS: The analysis included 306 patients (lipegfilgrastim: n = 151; pegfilgrastim: n = 155). The proportion of patients experiencing BPR TEAEs was similar with lipegfilgrastim and pegfilgrastim (25.2 vs 21.9%, respectively), as was the proportion of patients experiencing BPR treatment-emergent adverse drug reactions (TEADRs) (18.5 vs 16.8%, respectively). No BPR TEADRs were serious, and none led to discontinuation. CONCLUSIONS: Nonsevere BPR TEAEs and TEADRs were observed in patients with breast cancer receiving chemotherapy and G-CSF; rates of BPR events were similar between lipegfilgrastim and pegfilgrastim. The similar BPR safety profile of lipegfilgrastim and pegfilgrastim provides support for use in patients with breast cancer receiving chemotherapy. PMID- 26024744 TI - Effects of a case management program on patients with oral precancerous lesions: a randomized controlled trial. AB - PURPOSE: The aim of this study is to identify the effects of a case management program on knowledge about oral cancer, preventive behavior for oral cancer, and level of uncertainty for patients with oral precancerous lesions. METHODS: A randomized controlled trial was conducted with two groups, using a pre- and posttest design. The experimental group received a case management program and telephone follow-up sessions; the control group received routine care. Patients were assessed at three time points: first visit to the otolaryngology clinic for biopsy examination (T0), and then at 2 weeks (T1) and 4 weeks (T2) after the biopsy examination. RESULTS: Patients in both groups had significantly higher levels of knowledge about oral cancer, preventive behavior for oral cancer, and lower level of uncertainty at T2 compared to T0. At T2, participants in the experimental group had significantly greater knowledge about oral cancer, more preventive behavior for oral cancer, and less uncertainty compared to those in the control group. CONCLUSIONS: The case management program with telephone counseling effectively improved knowledge about oral cancer, preventive behavior for oral cancer, and uncertainty levels in patients with oral precancerous lesions in the four weeks after receiving a biopsy examination. The case management program can be applied with positive results to patients receiving different types of cancer screening, including colorectal, breast, and cervical screening. PMID- 26024749 TI - Statistical characteristics of selected elements in vegetables from Kosovo. AB - Zinc, copper, iron, chromium and cobalt are essential elements for human health, showing toxicity only in high concentrations, while lead and cadmium are extremely toxic even as traces. Therefore, it is important to monitor the contents of toxic metals in vegetables. Large number of vegetables is grown and used in nutrition, in Kosovo. The concentrations of selected elements in vegetables (radish, onion, garlic and spinach) from Kosovo were determined using ICP-OES method. Oral intake of metals and health risk index were calculated. Statistical analysis indicated numerous positive correlations between concentrations of selected elements in vegetables. As a result of principal component analysis, 15 new variables were obtained which were characterized by eigenvalues. The sequence of health quotients for the heavy metals followed the decreasing order Zn = Mn > Pb > Cu > Ni > Fe > Cd > Co > Cr. The health quotients for all investigated heavy metals were below 1 (one), which is considered safe. The vegetables from Kosovo are mainly safe for use in everyday diet. PMID- 26024750 TI - Influence of the insecticides acetamiprid and carbofuran on arylamidase and myrosinase activities in the tropical black and red clay soils. AB - The objective of this study was to determine the effects of two insecticides, namely, acetamiprid and carbofuran on the enzymatic activities of arylamidase (as glucose formed from sinigrin) and myrosinase (as beta-naphthylamine formed from L leucine beta-naphthylamide) in the black and red clay soils collected from a fallow groundnut (Arachis hypogaea L.) fields in the Anantapur District, Andhra Pradesh, India. The study was realized within the framework of the laboratory experiments in which the acetamiprid and carbofuran were applied to the soils at different doses (1.0, 2.5, 5.0, 7.5, 10.0 kg ha(-1)). Initially, the physicochechemical properties of the soil samples were analyzed. After 10 days of pesticide application, the soil samples were analyzed for the enzyme activities. Acetamiprid and carbofuran stimulated the arylamidase and myrosinase activities at lower concentrations after 10 days incubation. Striking stimulation in soil enzyme activities was noticed at 2.5 kg ha(-1), persists for 20 days in both the soils. Overall, higher concentrations (5.0-10.0 kg ha(-1)) of acetamiprid and carbofuran were toxic or innocuous to the arylamidase and myrosinase activities. Nevertheless, the outcomes of the present study clearly indicate that the use of these insecticides (at field application rates) in the groundnut fields (black and red clay soils) stimulated the enzyme (arylamidase and myrosinase) activities. PMID- 26024751 TI - Performance Characteristics of AOAC Method 2005.06 for the Determination of Paralytic Shellfish Toxins in Manila Clams, European Otter Clams, Grooved Carpet Shell Clams, Surf Clams, and Processed King Scallops. AB - An approach was developed for the verification of method performance of the AOAC 2005.06 LC-fluorescence detector (FLD) method for determination of paralytic shellfish poisoning (PSP) toxins in bivalve shellfish. This was developed following advice published by the Analytical Laboratory Accreditation Criteria Committee and applied to shellfish species that had not been previously subjected to a full single-laboratory validation scheme. The refined approach was developed following the need to assess performance in a number of shellfish species infrequently monitored through the UK statutory monitoring program, while reducing the impact and cost of the studies, most notably in terms of the use of valuable reference standards. The species assessed were manila clams (Ruditapes philippinarum), European otter clams (Lutraria lutraria), grooved carpet shell clams (R. decussatus), surf clams (Spisula solida), and king scallops (Pecten maximus) presented as adductor only or adductor plus roe. The method was assessed for sensitivity in terms of LOD and LOQ, toxin recovery, and method precision in each species. It incorporated the PSP toxins deemed toxic and/or prevalent in UK samples and commercially available as certified reference standards. The toxins studied included GTX1-5, dcSTX, STX, C1&2, and NEO. The toxins dcGTX2&3 were included for surf clams due to the prevalence of these toxins in this species as a result of toxin decarbamoylation. Method performance targets were met for each of the characteristics investigated. Consequently, the method was deemed fit for purpose for the screening and quantification of these clam and scallop species for PSP toxins by AOAC Method 2005.06 LC-FLD. PMID- 26024752 TI - The Rationale for Treatment of Postresectional Bronchopleural Fistula: Analysis of 52 Patients. AB - BACKGROUND: Bronchopleural fistulas are a major therapeutic challenge. We have reviewed our experience to establish the best choice of treatment. METHODS: From January 2001 to December 2013, the records of 3,832 patients who underwent pulmonary anatomic resections were retrospectively reviewed. RESULTS: The overall incidence of bronchopleural fistulas was 1.4% (52 of 3,832): 1.2% after lobectomy and 4.4% after pneumonectomy. Pneumonectomy vs lobectomy, right-sided vs left sided resection, and hand-sewn closure of the stump vs stapling showed a statistically significant correlation with fistula formation. Primary bronchoscopic treatment was performed in 35 of 52 patients (67.3%) with a fistula of less than 1 cm and with a viable stump. The remaining 17 patients (32.7%) underwent primary operation. The fistula was cured with endoscopic treatment in 80% and with operative repair in 88.2%. Cure rates were 62.5% after pneumonectomy and 86.4% after lobectomy. The cure rate with endoscopic treatment was 92.3% in very small fistulas, 71.4% in small fistulas, and 80% in intermediate fistulas. The cure rate after surgical treatment was 100% in small fistulas, 75% in intermediate fistulas, and 100% in very large fistulas. Morbidity and mortality rates were 5.8% and 3.8%, respectively. CONCLUSIONS: The bronchoscopic approach shows very promising results in all but the largest bronchopleural fistulas. Very small, small, and intermediate fistulas with a viable bronchial stump can be managed endoscopically, using mechanical abrasion, polidocanol sclerosing agent, and cyanoacrylate glue. Bronchoscopic treatment can be repeated, and if it fails, does not preclude subsequent successful surgical treatment. PMID- 26024753 TI - A Review on the Hemodialysis Reliable Outflow (HeRO) Graft for Haemodialysis Vascular Access. AB - OBJECTIVES: With improved dialysis survival there are increasing numbers of patients who have exhausted definitive access options due to central venous stenosis and are maintaining dialysis on a central venous catheter. The Hemodialysis Reliable Outflow (HeRO) allows an alternative by providing a definitive access solution. The aim of this study is to systematically review the published outcomes of the HeRO graft and discuss the role in complex haemodialysis patients. METHODS: Electronic databases were searched for studies assessing the use of the HeRO graft for dialysis in accordance with PRISMA published up to December 31 2014. The primary outcomes for this study were 1-year primary and secondary patency rates. Secondary outcomes were rates of dialysis access associated steal syndrome, HeRO-related bacteraemia rates and rates of interventions. RESULTS: Following strict inclusion/exclusion criteria, eight studies including 409 patients were included in our review. Primary and secondary pooled patency rates in this complex cohort of dialysis patients were found to be 21.9% (9.6-37.2%) and 59.4% (39.4-78%). The rate of dialysis access associated steal syndrome was low at 6.3% (1-14.7%) as was the range of HeRO-related bacteraemia (0.13-0.7 events per 1000 days). CONCLUSIONS: This literature review shows that the HeRO graft is an acceptable option for complex dialysis patients who are catheter dependent. Owing to device availability, published data are predominantly North American and further longer-term studies in other populations may be necessary. In this challenging patient group, randomized controlled trials are required to allow comparisons with alternative access options. PMID- 26024754 TI - Re: 'more studies are needed to determine which exercise programmes for intermittent claudication should be funded'. PMID- 26024755 TI - Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL 8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a common disorder characterized by excessive hepatic fat accumulation, production of reactive oxygen species (ROS), inflammation and potentially resulting in non-alcoholic steatohepatitis (NASH), cirrhosis and end-stage liver disease. Recently, we have shown that niacin significantly prevented hepatic steatosis and regressed pre existing steatosis in high-fat fed rat model of NAFLD. To gain further insight into the cellular mechanisms, this study investigated the effect of niacin on human hepatocyte fat accumulation, ROS production, and inflammatory mediator IL-8 secretion. MATERIALS AND METHODS: Human hepatoblastoma cell line HepG2 or human primary hepatocytes were first stimulated with palmitic acid followed by treatment with niacin or control for 24 h. RESULTS: The data indicated that niacin (at 0.25 and 0.5 mmol/L doses) significantly inhibited palmitic acid induced fat accumulation in human hepatocytes by 45-62%. This effect was associated with inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression without affecting the mRNA expression of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1). Niacin attenuated hepatocyte ROS production and it also inhibited NADPH oxidase activity. Niacin reduced palmitic acid-induced IL-8 levels. CONCLUSIONS: These findings suggest that niacin, through inhibiting hepatocyte DGAT2 and NADPH oxidase activity, attenuates hepatic fat accumulation and ROS production respectively. Decreased ROS production, at least in part, may have contributed to the inhibition of pro inflammatory IL-8 levels. These mechanistic studies may be useful for the clinical development of niacin and niacin-related compounds for the treatment of NAFLD/NASH and its complications. PMID- 26024756 TI - Irisin-encoding gene (FNDC5) variant is associated with changes in blood pressure and lipid profile in type 2 diabetic women but not in men. AB - INTRODUCTION: Irisin has recently been described as a novel myokine, which reduces visceral obesity and improves glucose metabolism in mice. Thus, polymorphisms in the gene encoding irisin, fibronectin type III domain containing 5 (FNDC5), may be associated with type 2 diabetes mellitus (T2DM) and related disorders. However, to date, no study has investigated the association between FNDC5 polymorphisms and susceptibility to T2DM. OBJECTIVE: To investigate the association of FNDC5 rs3480 (A/G) and rs1746661 (G/T) polymorphisms, alone or in combination, with T2DM and its clinical features. METHODS: We analyzed 1006 T2DM patients and 434 nondiabetic subjects. Polymorphisms were genotyped by real-time PCR using TaqMan MGB probes. Haplotypes constructed from the combination of rs1746661 and rs3480 polymorphisms were inferred using the Phase 2.1 program. RESULTS: Genotype, allele and haplotype frequencies of rs1746661 and rs3480 polymorphisms did not differ significantly between nondiabetic subjects and T2DM patients. Women with T2DM carrying the G allele of rs3480 showed increased HbA1c levels compared with A/A carriers, adjusted for age. The T allele of rs1746661 was associated with increased systolic blood pressure, total cholesterol and LDL cholesterol and decreased HDL-cholesterol in women with T2DM, adjusted for covariates. Moreover, prevalence of hypercholesterolemia was higher in women carrying the T allele of rs1746661 than in G/G carriers (72.4% vs. 58.7%, OR=2.010, 95% CI=1.210-3.390), but it was not significantly different in men. CONCLUSIONS: These results indicate that, although not associated with T2DM, the G allele of rs3480 appears to be associated with increased HbA1c, while the T allele of rs1746661 appears to be associated with higher systolic blood pressure and dyslipidemia in women with T2DM. PMID- 26024757 TI - Influence of global change-related impacts on the mercury toxicity of freshwater algal communities. AB - The climatic-change related increase of temperatures, are expected to alter the distribution and survival of freshwater species, ecosystem functions, and also the effects of toxicants to aquatic biota. This study has thus assessed, as a first time, the modulating effect of climate-change drivers on the mercury (Hg) toxicity of freshwater algal photosynthesis. Natural benthic algal communities (periphyton) have been exposed to Hg under present and future temperature scenarios (rise of 5 degrees C). The modulating effect of other factors (also altered by global change), as the quality and amount of suspended and dissolved materials in the rivers, has been also assessed, exposing algae to Hg in natural river water or a synthetic medium. The EC50 values ranged from the 0.15-0.74 ppm for the most sensitive communities, to the 24-40 ppm for the most tolerant. The higher tolerance shown by communities exposed to higher Hg concentrations, as Jabarrella was in agreement with the Pollution Induced Community Tolerance concept. In other cases, the dominance of the invasive diatom Didymosphenia geminata explained the tolerance or sensitivity of the community to the Hg toxicity. Results shown that while increases in the suspended solids reduced Hg bioavailability, changes in the dissolved materials - such as organic carbon - may increase it and thus its toxic effects on biota. The impacts of the increase of temperatures on the toxicological behaviour of periphyton (combining both changes at species composition and physiological acclimation) would be certainly modulated by other effects at the land level (i.e., alterations in the amount and quality of dissolved and particulate substances arriving to the rivers). PMID- 26024758 TI - Methods of Analysis for Residues and Chemical Contaminants in Aquaculture. PMID- 26024759 TI - [Cutaneous manifestations in blastic plasmacytoid cell neoplasm: About two cases]. PMID- 26024760 TI - Biologics in vasculitides: Where do we stand, where do we go from now? AB - Biological agents represent a valid therapeutic option in patients with severe and/or relapsing vasculitis. Over the last years, some of these agents have become an established therapy (such as RTX in AAV or IFX for ocular BD), and some appear to hold promise to become so. In addition, there are a number of drugs in the pipeline that may contribute to further improve the prognosis of vasculitis. As the range of medications available for vasculitis widens, the need will also increase to define the best treatment schemes as well as to identify those patients that may benefit most from biological agents. PMID- 26024761 TI - Chemically Programmed Bispecific Antibody Targeting Legumain Protease and alphavbeta3 Integrin Mediates Strong Antitumor Effects. AB - A chemically programmed bispecific antibody (cp-bsAb) that targeted cysteine protease legumain and alphavbeta3 integrin has been prepared using the aldolase antibody chemical programming (AACP) strategy. In vitro evaluation of the anti legumain, anti-integrin cp-bsAb and its comparison with cpAbs targeting either integrin or legumain have shown that the former possesses superior functions, including receptor binding and inhibitory effects on cell proliferation as well as capillary tube formation, among all three cpAbs. The anti-legumain, anti integrin cp-bsAb also inhibited growth of primary tumor more effectively than either anti-legumain or anti-integrin cpAb as observed in the MDA-MB-231 human breast cancer mouse model. The AACP-based cp-bsAb, which contains a generic aldolase antibody, can also serve as a suitable platform for combination therapy, where two equally potent compounds are used to target extracellular receptors. PMID- 26024762 TI - The interaction between nitrogen availability and auxin, cytokinin, and strigolactone in the control of shoot branching in rice (Oryza sativa L.). AB - KEY MESSAGE: Nitrogen availability and cytokinin could promote shoot branching in rice, whereas auxin and strigolactone inhibited it. The interaction between nitrogen availability and the three hormones is discussed. Rice shoot branching is strongly affected by nitrogen availability and the plant hormones auxin, cytokinin, and strigolactone; however, the interaction of them in the regulation of rice shoot branching remains a subject of debate. In the present study, nitrogen and the three hormones were used to regulate rice tiller bud growth in the indica rice variety Yangdao 6. Both nitrogen and CK promoted shoot branching in rice, whereas auxin and SL inhibited it. We used HPLC to determine the amounts of endogenous IAA and CK, and we used quantitative real-time PCR analysis to quantify the expression levels of several genes. Nitrogen enhanced the amount of CK by promoting the expression levels of OsIPTs in nodes. In addition, both nitrogen and CK downregulated the expression of genes related to SL synthesis in root and nodes, implying that the inhibition of SL synthesis by nitrogen may occur at least partially through the CK pathway. SL did not significantly reduce the amount of CK or the expression levels of OsIPT genes, but it did significantly reduce the amount of auxin and the auxin transport capacity in nodes. Auxin itself inhibited CK synthesis and promoted SL synthesis in nodes rather than in roots. Furthermore, we found that CK and SL quickly reduced and increased the expression of FC1 in buds, respectively, implying that FC1 might be a common target for the CK and SL pathways. Nitrogen and auxin delayed expression change patterns of FC1, potentially by changing the downstream signals for CK and SL. PMID- 26024763 TI - Decline in macrolide resistance rates among Streptococcus pyogenes causing pharyngitis in children isolated in Italy. AB - Macrolides are often used to treat group A streptococcus (GAS) infections, but their resistance rates reached high proportions worldwide. The aim of the present study was to give an update on the characteristics and contemporary prevalence of macrolide-resistant pharyngeal GAS in Central Italy. A total of 592 isolates causing pharyngitis in children were collected in the period 2012-2013. Clonality was assessed by emm typing and pulsed-field gel electrophoresis (PFGE) for all macrolide-resistant strains and for selected susceptible isolates. Genetic determinants of resistance were screened by polymerase chain reaction (PCR). Forty-four GAS were erythromycin-resistant (7.4 %). Among them, 52.3 % and 50 % were clindamycin- and tetracycline-resistant, respectively. erm(B)-positive isolates (52.3 %) expressed the constitutive cMLSB phenotype. mef(A) and its associated M phenotype were recorded in 40.9 % of the cases. The remaining erm(A) positive isolates expressed the iMLSB phenotype. Seventeen tetracycline-resistant isolates carried tet(M) and five isolates carried tet(O). Twenty-five emm types were found among all strains, with the predominance of emm types 12, 89, 1, and 4. Eleven emm types and 12 PFGE clusters characterized macrolide-resistant strains, with almost two-thirds belonging to emm12, emm4, and emm11. Macrolide susceptible and -resistant emm types 12, 89, 11, and 4 shared related PFGE profiles. There was a dramatic decline in macrolide resistance in Central Italy among pharyngeal GAS isolates in 2012-2013 when compared to previous studies from the same region (p < 0.05), although macrolide consumption remained stable over the past 15 years. We observed a decrease in the proportion of macrolide resistant strains within emm types commonly associated with macrolide resistance in the past, namely emm12, 1, and 89. PMID- 26024764 TI - The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-beta. AB - Peripheral inflammation induced by lipopolysaccharide (LPS) causes behavioural changes indicative for depression. The possible mechanisms involve the interference with neuroinflammatory, neuroendocrine, and neurotrophic processes. Apart from heterogeneity in the molecular background, sexual context may be another factor relevant to the manifestation of mood disturbances upon an immune challenge. We investigated sex-dependent effects of a 7-day LPS treatment of adult Wistar rats on depressive-like behaviour and their relation with hypothalamic neuroendocrine factor, corticotrophin-releasing hormone (CRH), proplastic brain-derived neurotropic factor (BDNF), pro-inflammatory cyclooxygenase-2 (COX-2) and nuclear factor kappa beta (NFkB). Also, their regulators, the glucocorticoid receptor (GR) and CCAAT enhancer-binding protein (C/EBP) beta were followed. LPS induced depressive-like behaviour in females was associated with the increased hypothalamic CRH and decreased BDNF, but not with COX-2. These changes were paralleled by an increase in nuclear GR, NFkB and 20 kDa C/EBPbeta. LPS also altered behaviour in males and increased CRH expression, but in contrast to females, this was accompanied with the elevated COX-2, accumulation of cytosolic GR and elevated nuclear 38 kDa C/EBPbeta and NFkB. In conclusion, depressive-like phenotype induced by LPS in both sexes emerges from similar HPA axis activation and sex-specific alterations of hypothalamic molecular signalling: in males it is related to compromised control of neuroinflamation connected with cytoplasmic GR retention, while in females it is related to diminished proplastic capacity of BDNF. Sex-dependent mechanisms by which inflammation alters hypothalamic processes and cause pathological behaviour in animals, could be operative in the treatment of depression-related brain inflammation. PMID- 26024765 TI - Towards a biological monitoring guidance value for acrylamide. AB - Acrylamide is classified as a potential human carcinogen and neurotoxicant. Biological monitoring is a useful tool for monitoring worker exposure. However, other sources of exposure to acrylamide (including cigarette smoke and diet) also need to be considered. This study has performed repeat measurements of the urinary mercapturic acids of acrylamide (AAMA) and its metabolite glycidamide (GAMA) and determined globin adducts in 20 production-plant workers at a UK acrylamide production facility. The relationship between biomarker levels and environmental monitoring data (air levels and hand washes) was investigated. Good correlations were found between all of the biomarkers (r(2)=0.86-0.91) and moderate correlations were found between the biomarkers and air levels (r(2) = 0.56-0.65). Our data show that urinary AAMA is a reliable biomarker of acrylamide exposure. Occupational hygiene data showed that acrylamide exposure at the company was well within the current UK Workplace Exposure Limit. The 90th percentile of urinary AAMA in non-smoking production-plant workers (537 MUmol/mol creatinine (n = 59 samples)) is proposed as a possible biological monitoring guidance value. This 90th percentile increased to 798 MUmol/mol if smokers were included (n = 72 samples). These values would be expected following an airborne exposure of less than 0.07 mg/m(3), well below the current UK workplace exposure limit of 0.3mg/m(3). Comparison of biomarker levels in non-occupationally exposed individuals suggests regional variations (between UK and Germany), possibly due to differences in diet. PMID- 26024766 TI - Effect of race and histology on patterns of failure in women with early stage endometrial cancer treated with high dose rate brachytherapy. AB - BACKGROUND: Clinical trials have helped refine management of early stage endometrial cancer (EC). For patients with intermediate risk features, adjuvant radiation is considered, primarily vaginal cuff brachytherapy. For higher risk patients, there may be a role for chemotherapy and radiation. The purpose of this study is to examine patterns of failure for early stage EC patients treated with postoperative high dose rate brachytherapy. METHODS: In this single institution retrospective cohort study, 208 women with early stage endometrial cancer who received definitive therapy between January 1, 2000 and January 1, 2013 were identified. RESULTS: Median follow-up was 46.4 (range, 6.2-137.3) months. Thirteen (6.3%) patients developed with locoregional recurrent disease and 15 (7.2%) patients developed distant metastasis. Freedom from recurrence at 5 years was 88.6% for white patients and 60.5% for black patients (p=0.0093). Five year recurrence free survival (RFS) for white vs. black patients was 82.9% vs. 48.9% (p=0.0007). Five year overall survival (OS) was 86.8% for white patients and 59.5% for black patients (p=0.0023). Black patients with unfavorable histology treated with chemotherapy and vaginal brachytherapy had a 15% locoregional recurrence rate, more than double the rate of local recurrence compared to AA patients with endometrioid histology and white patients with any histology (6% locoregional recurrence rate). CONCLUSIONS: Black women with unfavorable histology early stage EC experience increased rates of recurrence and worse survival compared to white patients. Patterns of failure in this group also indicate a high locoregional failure rate for the black patients with unfavorable histology (type II). PMID- 26024767 TI - Characterization of Toll-like receptor transcriptome in squamous cell carcinoma of cervix: A case-control study. AB - OBJECTIVE: Human papillomavirus (HPV) is a proven etiological agent for cervical cancer However, not all HPV infections result in cervical cancer. The mechanisms of host immune system to prevent/control HPV infection remain poorly understood. Toll-like receptors (TLRs) are a system of innate immune defense. HPV has been demonstrated to modulate TLR expression and interfere in TLR signaling pathways, leading to persistent viral infection and carcinogenesis. The aim was to study the relative gene expression of TLRs in cervical squamous cell carcinoma (SCC). METHODS: Gene expression profile of TLRs 1 to 9 was examined in 30 cervical SCCs and an equal number of normal cervical tissue samples using a PCR array platform. Gene expression studies for TLRs 3 and 7 were validated by western blotting. RESULTS: HPV was detected in all cases and in none of the controls (p<0.0001). HPV16 was the preponderant (83.3%) subtype. A significant downregulation in the relative gene expression of TLR3 (p<0.0001), TLR4 (p<0.0005) and TLR5 (p<0.0001) was observed in cases. A significant upregulation for TLR1 was observed (p=0.006). Although TLRs 2, 7, 8 and 9 were upregulated and TLR6 was downregulated, it was not significant. The western blot performed with antibodies against TLRs 3 and 7 confirmed the findings of the gene expression studies. CONCLUSIONS: A significant downregulation in the gene expression of TLRs 3, 4 and 5 and upregulation of TLR1 was observed in cervical SCC as compared to controls. Study results evoke the proposition for investigating TLRs 3, 4 and 5 agonists for therapeutic exploration. PMID- 26024768 TI - SegWeigh: a mixed-method approach to segmenting potential contraceptive user groups and meeting Family Planning 2020 goals. AB - OBJECTIVE: To evaluate a low-cost mixed-method research tool (SegWeigh) that informs awareness raising and family planning interventions for potential contraceptive users. METHODS: A pilot study of SegWeigh was conducted in Uganda and Vietnam between September 3, 2012, and February 21, 2013. User archetypes were produced in four steps by triangulating Demographic and Health Survey (DHS) data; a secondary literature review; family planning service provision data; and primary qualitative investigation. RESULTS: Triangulation of DHS analysis, secondary literature and service data revealed three potential user profiles: Ugandan women wanting to space pregnancies; Ugandan men wanting to limit pregnancies; and unmarried Vietnamese women having infrequent sex. Archetypes were subsequently created of "Kibuuka," a 52-year-old semi-literate subsistence farmer in rural Uganda, and "Anh," a 20-year-old student in Hanoi, Vietnam. CONCLUSION: SegWeigh rapidly produced data-rich "real life" user profiles that might help to tailor family planning interventions. PMID- 26024769 TI - Atypical presentation of a schwannoma mimicking recurrence of primary peritoneal cancer. PMID- 26024770 TI - A case-control study of correlates of severe acute maternal morbidity in Kabul, Afghanistan. AB - OBJECTIVE: To identify correlates of severe acute maternal morbidity (SAMM) in Kabul, Afghanistan. METHODS: The present case-control study enrolled postpartum couples at four public maternity hospitals between September 2007 and December 2009. Eligibility was determined by: spousal consent; SAMM criteria from chart review for cases; and matching by age, parity, and time since previous delivery for controls (uncomplicated deliveries). Staff administered questionnaires to women and their husbands separately. SAMM correlates were analyzed with conditional logistic regression in models including (proximate) and excluding (distal) care factors. RESULTS: Among 285 case and 285 control couples, the most frequent SAMM diagnoses were obstructed labor (104 [36.5%]) and hemorrhage requiring transfusion (102 [35.8%]). In both models, SAMM was associated with the husband having more than one wife (distal: adjusted odds ratio [aOR] 48.6, 95% CI 5.4-436.5; proximate: 141.8, 3.5-5819.0), prior stillbirth(s) (distal: 16.2, 6.1 42.9; proximate: 8.0, 2.9-22.4), and complications in a prior pregnancy (distal: 5.4, 95% CI 2.5-12.1; proximate: 7.1, 2.5-20.4). In the proximate model, SAMM was associated with visiting another facility before hospitalization (aOR 7.5, 95% CI 3.1-17.9), male-reported planned home delivery (5.5, 1.5-20.0), and provider determined care-seeking (4.8, 1.6-14.9). CONCLUSION: Planned home delivery and referral to multiple facilities or by providers are factors associated with SAMM that are potentially amenable to intervention in Afghanistan. PMID- 26024771 TI - Differences in tissue proliferation and maturation between Matrix2 and bare platinum coil embolization in experimental swine aneurysms. AB - BACKGROUND AND PURPOSE: Recanalization of post-embolization cerebral aneurysms remains a serious problem that influences treatment outcomes. Matrix2 is a bioactive, bio-absorbable, detachable coil that was developed to reduce the risk of recanalization. We examined the short-term efficacy of the Matrix2 coil system, and evaluated the temporal profile of tissue proliferation in a swine experimental aneurysm model compared with the bare platinum (BP) coil. MATERIALS AND METHODS: Thirty-six experimental aneurysms were created in 18 swine. All aneurysms were tightly packed with Matrix2 or BP coils. Comparative histologic and morphologic analyses were undertaken 1, 2 and 4 weeks post-embolization. RESULTS: Endothelial-like cells were observed partially lining the aneurysmal opening one week post-embolization with both coil types. At two and four weeks post-embolization, the aneurysms treated with Matrix2 coils had more extensive areas of organized thrombus than those packed with BP coils, but the numbers of functional proliferating endothelial cells identified by immunohistochemistry in the tissue were broadly comparable between the groups. Moreover, morphological analysis suggested there were more mature endothelial cells in aneurysms treated with bare platinum rather than Matrix2 coils. CONCLUSIONS: Our results indicate that aneurysms embolized with Matrix2 coils build thicker scaffolds for endothelialization, but this is not necessarily evidence of earlier tissue proliferation and maturation than those embolized with BP coils. Matrix2 coils may not be superior to BP coils for preventing aneurysmal recanalization after endovascular treatment of cerebral aneurysms. PMID- 26024772 TI - Presurgical evaluation of mesial temporal lobe epilepsy with multiple advanced MR techniques at 3T. AB - BACKGROUND AND PURPOSE: Accurate localization of the epileptogenic zone is essential for successful surgical treatment of mesial temporal lobe epilepsy (MTLE). The aim of this study was to analyze and compare the hippocampal volumetry (HV), MR spectroscopy (MRS), Dynamic susceptibility contrast (DSC) and pulsed arterial spin labeling (pASL) perfusion techniques in a large sample size of refractory MTLE patients. MATERIALS AND METHODS: Forty-two patients with medically refractory MTLE who underwent preoperative evaluation and eleven normal controls were studied. Pathologic and control hippocampi were compared in terms of hippocampal volume, metabolite ratios and relative hippocampal perfusion values. By using cut-off points and asymmetry indexes, percentages of performance indicators for each technique were calculated in groups of MR (+), MR (-) and bilateral MTLE. RESULTS: For all techniques, a statistically significant difference was found between the pathologic and control hippocampus groups (P<0.001). Also, all of them except HV had diagnostic value in groups of MR (-) and bilateral MTLE. CONCLUSION: HV, MRS, DSC and pASL have achieved comparable performance and each of them provides important information about the lateralization of epileptogenic focus. Among those, pASL and MRS may easily be used as an adjunct to conventional MR. PMID- 26024773 TI - ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM DR) in Non-Hodgkin's Lymphomas. AB - Enolases are glycolytic enzymes responsible for the ATP-generated conversion of 2 phosphoglycerate to phosphoenolpyruvate. In addition to the glycolytic function, Enolase 1 (ENO1) has been reported up-regulation in several tumor tissues. In this study, we investigated the expression and biologic function of ENO1 in Non Hodgkin's Lymphomas (NHLs). Clinically, by western blot analysis we observed that ENO1 expression was apparently higher in diffuse large B-cell lymphoma than in the reactive lymphoid tissues. Subsequently, immunohistochemical staining of 144 NHLs suggested that the expression of ENO1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas. Further, we identified ENO1 as an independent prognostic factor, and it was significantly correlated with overall survival of NHL patients. In addition, we found that ENO1 could promote cell proliferation, regulate cell cycle associated gene and PI3K/AKT signaling pathway in NHLs. Finally, we verified that ENO1 participated in the process of lymphoma cell adhesion mediated drug resistance (CAM-DR). Adhesion to FN or HS5 cells significantly protected OCI-Ly8 and Daudi cells from cytotoxicity compared with those cultured in suspension, and these effects were attenuated when transfected with ENO1-siRNA. Based on the study, we propose that inhibition of ENO1 expression may be a novel strategy for therapy for NHLs patients, and it may be a target for drug resistance. PMID- 26024774 TI - Apoptosis induced by NAD depletion is inhibited by KN-93 in a CaMKII-independent manner. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme that catalyzes the synthesis of nicotinamide mononucleotide from nicotinamide (Nam) in the salvage pathway of mammalian NAD biosynthesis. Several potent NAMPT inhibitors have been identified and used to investigate the role of intracellular NAD and to develop therapeutics. NAD depletion induced by NAMPT inhibitors depolarizes mitochondrial membrane potential and causes apoptosis in a range of cell types. However, the mechanisms behind this depolarization have not been precisely elucidated. We observed that apoptosis of THP-1 cells in response to NAMPT inhibitors was reduced by the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 via an unknown mechanism. The inactive analog of KN-93, KN-92, exhibited the same activity, but the CaMKII-inhibiting cell-permeable autocamtide-2-related inhibitory peptide II did not, indicating that the inhibition of THP-1 cell apoptosis was not dependent on CaMKII. In evaluating the mechanism of action, we confirmed that KN-93 did not inhibit decreases in NAD levels but did inhibit decreases in mitochondrial membrane potential, indicating that KN-93 exerts inhibition upstream of the mitochondrial pathway of apoptosis. Further, qPCR analysis of the Bcl-2 family of proteins showed that Bim is efficiently expressed following NAMPT inhibition and that KN-92 did not inhibit this expression. The L type Ca(2+) channel blockers verapamil and nimodipine partially inhibited apoptosis, indicating that part of this effect is dependent on Ca(2+) channel inhibition, as both KN-93 and KN-92 are reported to inhibit L-type Ca(2+) channels. On the other hand, KN-93 and KN-92 did not markedly inhibit apoptosis induced by anti-cancer agents such as etoposide, actinomycin D, ABT-737, or TW 37, indicating that the mechanism of inhibition is specific to apoptosis induced by NAD depletion. These results demonstrate that NAD depletion induces a specific type of apoptosis that is effectively inhibited by the KN-93 series of compounds. PMID- 26024775 TI - Online social media: new data, new horizons in psychosis treatment. PMID- 26024776 TI - Advances in measuring single-cell pharmacology in vivo. AB - Measuring key pharmacokinetic and pharmacodynamic parameters in vivo at the single cell level is likely to enhance drug discovery and development. In this review, we summarize recent advances in this field and highlight current and future capabilities. PMID- 26024777 TI - Tolerance engineering in bacteria for the production of advanced biofuels and chemicals. AB - During microbial production of solvent-like compounds, such as advanced biofuels and bulk chemicals, accumulation of the final product can negatively impact the cultivation of the host microbe and limit the production levels. Consequently, improving solvent tolerance is becoming an essential aspect of engineering microbial production strains. Mechanisms ranging from chaperones to transcriptional factors have been used to obtain solvent-tolerant strains. However, alleviating growth inhibition does not invariably result in increased production. Transporters specifically have emerged as a powerful category of proteins that bestow tolerance and often improve production but are difficult targets for cellular expression. Here we review strain engineering, primarily as it pertains to bacterial solvent tolerance, and the benefits and challenges associated with the expression of membrane-localized transporters in improving solvent tolerance and production. PMID- 26024778 TI - [Residual limb and phantom pain : Causes and therapeutic approaches]. AB - INTRODUCTION: Residual limb pain and phantom pain are severe complications following an amputation. Various reasons are responsible for these complaints. It must be distinguished between amputation stump pain, phantom sensations and phantom pain. CAUSE AND THERAPY: In this paper we describe the most common reasons for stump pain and propose some non-operative therapeutic approaches. Furthermore path physiology and phantom pain therapy will be discussed. The recommendations offered in this paper are based on practical experience over three decades in a specialized out-patient department for patients with amputation injuries. PMID- 26024779 TI - Association of genetic variants with response to iron supplements in pregnancy. AB - The incidence of iron deficiency anemia in pregnancy is high in India where iron supplementation is a regular practice. The response to oral iron is influenced by several factors such as age, body mass index, gravida, socioeconomic status, food, vitamin deficiency and compliance to supplements. The major challenge is to understand the various modulators of iron status in this high-risk group so that we can improve the diagnosis and the management of these patients. The current study was designed to evaluate the iron status during pregnancy and to identify factors which might be influencing their response to oral iron. We investigated a total of 181 pregnant women with anemia (Hb < 11 g/dl) and evaluated the impact of probable factors on anemia and their iron status. Assessment of the response was based on hemoglobin and serum ferritin or transferrin saturation level after 8 and 20 weeks of iron supplementation. Socioeconomic, clinical, hematological, biochemical and genetic factors were all evaluated. Molecular analysis revealed that HFE variant allele (G) (rs1799945) was significantly associated with an adequate response to iron supplementation. We identified five subjects with a sustained poor response, and targeted re-sequencing of eleven iron-related genes was performed in them. We have identified seven novel variants in them, and in silico analysis suggested that these variants may have an iron regulatory effect. Taken together, our findings underscore the association of genetic variants with response to supplements in pregnancy, and they can be extended to other diseases where anemia and iron deficiency coexist. PMID- 26024780 TI - What are the barriers of quality survivorship care for haematology cancer patients? Qualitative insights from cancer nurses. AB - PURPOSE: Many haematological cancer survivors report long-term physiological and psychosocial effects beyond treatment completion. These survivors continue to experience impaired quality of life (QoL) as a result of their disease and aggressive treatment. As key members of the multidisciplinary team, the purpose of this study is to examine the insights of cancer nurses to inform future developments in survivorship care provision. METHODS: Open text qualitative responses from two prospective Australian cross-sectional surveys of nurses (n = 136) caring for patients with haematological cancer. Data were analysed thematically, using an inductive approach to identify themes. RESULTS: This study has identified a number of issues that nurses perceive as barriers to quality survivorship care provision. Two main themes were identified: the first relating to the challenges nurses face in providing care ('care challenges') and the second relating to the challenges of providing survivorship care within contemporary health care systems ('system challenges'). CONCLUSIONS: Cancer nurses perceive the nature of haematological cancer and its treatment and of the health care system itself, as barriers to the provision of quality survivorship care. Care challenges such as the lack of a standard treatment path and the relapsing or remitting nature of haematological cancers may be somewhat intractable, but system challenges relating to clearly defining and delineating professional responsibilities and exchanging information with other clinicians are not. IMPLICATIONS FOR CANCER SURVIVORS: Addressing the issues identified will facilitate cancer nurses' provision of survivorship care and help address haematological survivors' needs with regard to the physical and psychosocial consequences of their cancer and treatment. PMID- 26024781 TI - Mesenteric ischemia in acute aortic dissection. AB - Mesenteric ischemia complicated by acute aortic dissection (AAD) is uncommon, but serious, as there is no established treatment strategy and it can progress rapidly to multi-organ failure. Diagnosing mesenteric ischemia before necrotic change is difficult, not only for primary care physicians, but even for gastrointestinal or cardiovascular surgeons as it can occur at any time during surgery. Thus, measures need to be in place at the bedside to enable us to obtain information on visceral perfusion. It is often difficult to decide which of laparotomy or aortic repair should be performed first, especially when there is associated shock or malperfusion of other vital organs. The standard surgical procedures for mesenteric ischemia are prompt revascularization of the mesenteric artery and, if needed, resection of necrotic intestine. However, the development of endovascular treatment and the introduction of hybrid ORs have improved the treatment strategies for mesenteric ischemia. This article reviews the issues of "diagnosis" in relation to the mechanism of mesenteric ischemia, and discusses the current "treatment strategies". PMID- 26024782 TI - The modified Altemeier procedure for a loop colostomy prolapse. AB - Loop colostomy prolapse is associated with an impaired quality of life. Surgical treatment may sometimes be required for cases that cannot be closed by colon colostomy because of high-risk morbidities or advanced disease. We applied the Altimeter operation for patients with transverse loop colostomy. The Altemeier operation is therefore indicated for rectal prolapse. This technique involves a simple operation, which includes a circumferential incision through the full thickness of the outer and inner cylinder of the prolapsed limb, without incising the abdominal wall, and anastomosis with sutures using absorbable thread. We performed the Altemeier operation for three cases of loop stomal prolapse. Those patients demonstrated no postoperative complications (including obstruction, prolapse recurrence, or hernia). Our findings suggest that this procedure is useful as an optional surgical treatment for cases of transverse loop colostomy prolapse as a permanent measure in patients with high-risk morbidities or advanced disease. PMID- 26024783 TI - Alliances in Human Biology: The Harvard Committee on Industrial Physiology, 1929 1939. AB - In 1929 the newly-reorganized Rockefeller Foundation funded the work of a cross disciplinary group at Harvard University called the Committee on Industrial Physiology (CIP). The committee's research and pedagogical work was oriented towards different things for different members of the alliance. The CIP program included a research component in the Harvard Fatigue Laboratory and Elton May's interpretation of the Hawthorne Studies; a pedagogical aspect as part of Wallace Donham's curriculum for Harvard Business School; and Lawrence Henderson's work with the Harvard Pareto Circle, his course Sociology 23, and the Harvard Society of Fellows. The key actors within the CIP alliance shared a concern with training men for elite careers in government service, business leadership, and academic prominence. But the first communications between the CIP and the Rockefeller Foundation did not emphasize training in human biology. Instead, the CIP presented itself as a coordinating body that would be able to organize all the varied work going on at Harvard that did not fit easily into one department, and it was on this basis that the CIP became legible to the President of Harvard, A. Lawrence Lowell, and to Rockefeller's Division of Social Sciences. The members of the CIP alliance used the term human biology for this project of research, training and institutional coordination. PMID- 26024784 TI - Early clinical outcomes of ultrasound-guided CT-planned high-dose-rate interstitial brachytherapy for primary locally advanced cervical cancer. AB - PURPOSE: To report early clinical outcomes of high-dose-rate interstitial image guided brachytherapy (BT) in the definitive management of locally advanced cervical cancer. METHODS: We retrospectively analyzed 31 locally advanced cervical cancer patients treated at our institution between January 2010 and April 2013. About 88% had advanced disease based on the International Federation of Gynecology and Obstetrics guidelines, and 87% received concurrent chemotherapy. All patients were treated with external beam radiation therapy to a median dose of 45 Gy (range, 39.6-58 Gy) before receiving BT. High-dose-rate BT was delivered in a single implant to a median dose of 6 Gy * five fractions to a CT-defined volume. Median total equivalent 2-Gy dose, dose covered by 90% of the high-risk clinical target volume (HR-CTV D90), and HR-CTV were 84, 87.4, and 49.9 cc, respectively. Kaplan-Meier method was used for actuarial survival analysis, and toxicity was graded using Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Median followup was 19.3 months. Two-year actuarial local control, regional control, and distant metastasis (DM) were 90%, 93%, and 23.6%, respectively. Two-year disease-free survival was 55%. Genitourinary, gastrointestinal, or gynecologic Grade 3 toxicity was seen in 5 patients (3 T4a and 2 T3b) for crude rates of 13%, 7%, and 3%, respectively. Stratifying HR-CTV by <30 and >30 cc and then by HR-CTV D90 of <85, 85-90, and >90 Gy showed that 100% of the local failures, regional failures, DM, and G3 toxicity occurred in >30 cc group. The rate of DM was also significantly higher in the >30 cc group (p = 0.036). CONCLUSIONS: An interstitial approach can achieve excellent outcomes in cases where intracavitary and/or hybrid approaches are either not suitable or not available. PMID- 26024785 TI - New approach to relieving pain and distress during high-dose-rate intracavitary irradiation for cervical cancer. AB - BACKGROUND AND PURPOSE: To relieve the pain and distress experienced by women who undergo high-dose-rate intracavitary radiotherapy (HDR-ICRT) for cervical cancer and to improve the current status of gynecologic brachytherapy in Japan, a new intravenous anesthetic protocol involving the administration of a combination of propofol and ketamine was developed. The primary aim of this study is to investigate the efficacy and safety of this new anesthetic protocol during HDR ICRT for cervical cancer. METHODS AND MATERIALS: All the patients who were diagnosed with cervical cancer between December 2008 and February 2011, treated with three-channel brachytherapy and subjected to the new sedation protocol, were evaluated. A visual analog scale (VAS) was used to assess the pain during brachytherapy, and we collected VAS score at the next HDR-ICRT. Toxicities were graded using the Common Toxicity Criteria, version 3. RESULTS: A total of 178 sessions of HDR-ICRT were delivered to 57 patients. The patients' median VAS pain score was 0 (range, 0-10). The most frequent side effect was Grade 1-2 nausea, which occurred in 33 sessions (34%). However, 13 of 14 patients received concurrent cisplatin chemotherapy. None of the patients experienced Grade 3 or 4 adverse events. CONCLUSIONS: We have demonstrated that our new intravenous anesthetic protocol produces appropriate effects and can be performed by radiation oncologists who were required to finish training in basic life support and the cooperative system of emergency according to in-house guideline. PMID- 26024786 TI - The fluorescence properties and binding mechanism of SYTOX green, a bright, low photo-damage DNA intercalating agent. AB - DNA intercalators are widely used in cancer therapeutics, to probe protein-DNA interactions and to investigate the statistical-mechanical properties of DNA. Here, we employ single-molecule fluorescence microscopy, magnetic tweezers, and ensemble-binding assays to investigate the fluorescence properties and binding mechanism of SYTOX green, a DNA labeling dye previously used for staining dead cells and becoming of common use for single-molecule methodologies. Specifically, we show that SYTOX green presents several advantages with respect to other dyes: (1) binds DNA rapidly and with high affinity; (2) has a good signal-to-noise ratio even at low concentrations; (3) exhibits a low photobleaching rate; and (4) induces lower light-induced DNA degradation. Finally, we show that SYTOX green is a DNA intercalator that binds DNA cooperatively with a binding site of 3.5 bp, increasing the DNA length upon binding by 43%, while not affecting its mechanical properties. PMID- 26024787 TI - Predictors of waterpipe smoking progression among youth in Irbid, Jordan: A longitudinal study (2008-2011). AB - BACKGROUND: The predictors of waterpipe smoking progression are yet to be examined using a longitudinal study that is guided by a theoretical model of behavioral change. This study identifies the gender-specific predictors of waterpipe smoking progression among adolescents in Irbid, Jordan. METHODS: This study uses data from a school longitudinal study of smoking behavior in Irbid, Jordan. A random sample of 19 schools was selected by probability proportionate to size. A total of 1781 seventh graders were enrolled at baseline, and completed a questionnaire annually from 2008 through 2011. Students who reported ever smoking waterpipe (N=864) at any time point were assessed for progression (escalation in the frequency of waterpipe smoking) in the subsequent follow-up. Grouped-time survival analysis was used to identify the risk of progression. RESULTS: During the three years of follow-up, 29.6% of students progressed in waterpipe smoking. Predictors of waterpipe smoking progression were higher mother's education, enrollment in public school, frequent physical activity, and low refusal self-efficacy among boys, having ever smoked cigarettes, and having friends and siblings who smoke waterpipe among girls. Awareness of harms of waterpipe was protective among boys and seeing warning labels on the tobacco packs was protective among girls. CONCLUSIONS: Even at this early stage, about a third of waterpipe smokers progressed in their habit during the 3 year follow up. Factors predicting progression of use differed by gender, which calls for gender specific approaches to waterpipe interventions among Jordanian youth. PMID- 26024788 TI - Effects of concurrent physical and cognitive demands on arm movement kinematics in a repetitive upper-extremity precision task. AB - The effect of concurrent physical and cognitive demands on arm motor control is poorly understood. This exploratory study compared movement kinematics in a repetitive high-precision pipetting task with and without additional concurrent cognitive demands in the form of instructions necessary to locate the correct target tube. Thirty-five healthy female subjects performed a standardized pipetting task, transferring liquid repeatedly from one pick-up tube to different target tubes. In the reference condition, lights indicated the target tube in each movement cycle, while the target tube had to be deciphered from a row and column number on a computer screen in the condition with additional cognitive demands. Kinematics of the dominant arm was assessed using the central tendency and variability of the pipette-tip end-point trajectory and joint kinematics properties of the shoulder and elbow. Movements slowed down (lower velocities and higher area under the movement curves) and trajectory variability increased in the condition with additional cognitive demands, but there were no changes in the kinematics properties such as joint range of motion, times of acceleration and deceleration (as indicated by the time to peak velocity), average angles, or phase relationships between angle and angular velocity of shoulder or elbow movements between the two conditions. Further, there were also no differences in the size or structure of variability of the shoulder and elbow joint angles, suggesting that subjects could maintain the motor repertoire unaltered in the presence of these specific additional cognitive demands. Further studies should address motor control at other levels of concurrent cognitive demands, and with motor tasks that are less automated than the pipetting task used in the present study, so as to gain an increased understanding of the effect of concurrent cognitive demands for other activities of relevance to daily life. PMID- 26024789 TI - Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials. AB - Overdosing of parenteral antithrombotic therapies can increase the risk of bleeding. Cangrelor is a potent intravenous platelet P2Y12 receptor antagonist with rapid onset and offset of action. In patients undergoing percutaneous coronary interventions (PCI), compared with control, cangrelor (30 ug/kg bolus, followed immediately by a 4 ug/kg per minute infusion for 2-4 h or until the conclusion of the index PCI, whichever was longer) reduces periprocedural thrombotic complications without an increase in major bleeding complications, although minor bleeding is increased. The impact of cangrelor overdosing on bleeding is unknown and represented the aim of this analysis. Patients with cangrelor overdosing were identified among safety population patients enrolled in the CHAMPION program (n = 25,107). Overdose was defined as administration of an excess >20 % of the bolus dose (30 MUg/kg) and/or infusion rate (4 MUg/kg per min). Bleeding complications were assessed. Among the safety analysis population in the CHAMPION program, 12,565 patients received cangrelor. A total of 36 overdosed cangrelor patients (0.29 %) were identified in this pooled analysis (20 with both bolus and infusion, 5 with bolus only, and 11 with infusion only). In the majority of patients, the dose did not exceed 2.5 times the recommended dose. Bleeding events were balanced between treatment arms and were consistent with those in the overall CHAMPION program. Only one overdosed patient experienced a serious bleed. There was no correlation between bleeding and magnitude of cangrelor overdose. In a large clinical trial program of patients undergoing PCI, cangrelor overdosing was rare and not associated with an increase in bleeding complications, an observation that may be attributed to its very short-half life and rapid offset of action. PMID- 26024790 TI - Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells. AB - Aside from its role in cell membrane integrity, cholesterol is a key component in steroid hormone production. The vital functions of steroid hormones such as estrogen, testosterone, glucocorticoids (Gcrts) and mineralocorticoids (Mnrts) in perinatal and adult life are well understood; however, their role during early embryonic development remains largely unexplored. Here we show that siRNA mediated perturbation of steroid hormone production during mesoderm formation has important consequences on cardiac differentiation in mouse embryonic stem cells (mESC). Both Gcrts and Mnrts are capable of driving cardiac differentiation in mESC. Interestingly, the Gcrt receptor is widely expressed during gastrulation in the mouse, and is exclusively localized in the nuclei-and thus active-in visceral endoderm cells, suggesting that it functions much earlier than previously anticipated. We therefore studied Gcrt signaling in mESC as a model of the gastrulating embryo, and found that Gcrt signaling regulates expression of the transcription factor Hnf4a and the secreted Nodal and BMP inhibitor Cer1 in the early visceral endoderm. RNAi-mediated knockdown of Gcrt function blocked cardiomyocyte differentiation, with limited effects on other cardiovascular cell types including vascular endothelial cells and smooth muscle. Furthermore, the cardiogenic effect of Gcrts required Hnf4a and paracrine Cer1. These results establish a novel function for cholesterol-derived steroid hormones and identify Gcrt signaling in visceral endoderm cells as a regulator of Cer1 and cardiac fate. PMID- 26024791 TI - Obtaining appropriate interval estimates for age when multiple indicators are used: evaluation of an ad-hoc procedure. AB - When an estimate of age is needed, typically multiple indicators are present as found in skeletal or dental information. There exists a vast literature on approaches to estimate age from such multivariate data. Application of Bayes' rule has been proposed to overcome drawbacks of classical regression models but becomes less trivial as soon as the number of indicators increases. Each of the age indicators can lead to a different point estimate ("the most plausible value for age") and a prediction interval ("the range of possible values"). The major challenge in the combination of multiple indicators is not the calculation of a combined point estimate for age but the construction of an appropriate prediction interval. Ignoring the correlation between the age indicators results in intervals being too small. Boldsen et al. (2002) presented an ad-hoc procedure to construct an approximate confidence interval without the need to model the multivariate correlation structure between the indicators. The aim of the present paper is to bring under attention this pragmatic approach and to evaluate its performance in a practical setting. This is all the more needed since recent publications ignore the need for interval estimation. To illustrate and evaluate the method, Kohler et al. (1995) third molar scores are used to estimate the age in a dataset of 3200 male subjects in the juvenile age range. PMID- 26024792 TI - Everything clean? Transfer of DNA traces between textiles in the washtub. AB - Forensic genetic analysis of items possibly handled by a suspect or a victim is frequently inquired by the law enforcement authorities, since DNA left on touched objects can often be linked to an individual. Due to technical improvement, even poor traces, which seemed to be unsuitable for DNA analysis a few years ago, may be amplified successfully today. Yet, DNA can be transferred to a crime scene artificially or unintentionally without any primary contact between the individual and the object found at the crime scene, the so-called secondary transfer or indirect transfer in general. In this study, "secondary transfer" scenarios with cells and DNA of different origins under wet conditions were investigated. Transfer was simulated as either "washing by hand" in a washtub or as "machine laundry" in a washing machine. As expected, major differences were seen between blood stains and epithelial abrasions. DNA from blood donors could be detected clearly both on the donor and on the acceptor textile, regardless of washing method. Regarding epithelial abrasions, simulating worn clothes, after washing by hand, only little residual DNA was found, and partial profiles were displayed on the donor textile, while transfer to the acceptor textile occurred even less and not in noteworthy amount and quality. Single alleles could be found both on donor textiles and acceptor textiles after simulated machine wash, but no reliable DNA profile could be verified after laundry in machine. Therefore, a DNA transfer from one worn cloth (without blood stains) to another textile in the washing machine seems to be extremely unlikely. PMID- 26024793 TI - Carcass mass has little influence on the structure of gravesoil microbial communities. AB - Little is known about how variables, such as carcass mass, affect the succession pattern of microbes in soils during decomposition. To investigate the effects of carcass mass on the soil microbial community, soils associated with swine (Sus scrofa domesticus) carcasses of four different masses were sampled until the 15th day of decomposition during the month of June in a pasture near Lincoln, Nebraska. Soils underneath swine of 1, 20, 40, and 50 kg masses were investigated in triplicate, as well as control sites not associated with a carcass. Soil microbial communities were characterized by sequencing the archaeal, bacterial (16S), and eukaryotic (18S) rRNA genes in soil samples. We conclude that time of decomposition was a significant influence on the microbial community, but carcass mass was not. The gravesoil associated with 1 kg mass carcasses differs most compared to the gravesoil associated with other carcass masses. We also identify the 15 most abundant bacterial and eukaryotic taxa, and discuss changes in their abundance as carcass decomposition progressed. Finally, we show significant decreases in alpha diversity for carcasses of differing mass in pre-carcass rupture (days 0, 1, 2, 4, 5, and 6 postmortem) versus post-carcass rupture (days 9 and 15 postmortem) microbial communities. PMID- 26024794 TI - Genetic portrait of Tamil non-tribal and Irula tribal population using Y chromosome STR markers. AB - The 17 Y chromosomal short tandem repeat loci included in the AmpFlSTR(r) YfilerTM PCR Amplification Kit were used to analyse the genetic diversity of 517 unrelated males representing the non-tribal and Irula tribal population of Tamil Nadu. A total of 392 unique haplotypes were identified among the 400 non-tribal samples whereas 111 were observed among the 117 Irula tribal samples. Rare alleles for the loci DYS458, DYS635 and YGATAH4.1 were also observed in both population. The haplotype diversity for the non-tribal and Irula tribal population were found to be 0.9999, and the gene diversity ranged from 0.2041 (DYS391) to 0.9612 (DYS385). Comparison of the test population with 26 national and global population using principal coordinate analysis (PCoA) and determination of the genetic distance matrix using phylogenetic molecular analysis indicate a clustering of the Tamil Nadu non-tribal and Irula tribal population away from other unrelated population and proximity towards some Indo European (IE) and Asian population. Data are available in the Y chromosome haplotype reference database (YHRD) under accession number YA004055 for Tamil non tribal and YA004056 for the Irula tribal group. PMID- 26024795 TI - [Editors' corner: Anales de Pediatria annual report]. PMID- 26024796 TI - PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma. AB - OBJECTIVES: Immune checkpoint blockade using inhibitors of programmed death-1 have shown promise in early phase clinical trials in NSCLC and programmed death ligand 1 (PD-L1) tumoral expression could potentially be a useful predictive marker. Data reporting the prevalence of PD-L1 expression in NSCLC and clinicopathologic associations is very limited. We sought to determine the frequency of PD-L1 expression in NSCLC and investigate associations with clinicopathologic features and patient outcome. MATERIALS AND METHODS: PD-L1 expression was analyzed using immunohistochemistry (Merck; clone 22C3) in 678 stages I-III NSCLC and 52 paired nodal metastases using tissue microarrays. Tumors with >=50% cells showing positive membrane staining were considered to have high expression of PD-L1. RESULTS: PD-L1 expression of any intensity was identified in 32.8% of cases. High PD-L1 expression was found in 7.4% of NSCLC. Squamous cell carcinomas (8.1%) and large cell carcinomas (12.1%) showed high PD L1 expression more commonly than adenocarcinomas (5.1%) but this was not statistically significant (p=0.072). High PD-L1 expression was associated with younger patient age and high tumor grade (p<0.05). There was no association with gender, tumor size, stage, nodal status, EGFR or KRAS mutation status. In multivariate analysis, patients with high PD-L1 expression had significantly longer overall survival (p<0.05). CONCLUSIONS: PD-L1 is expressed at high levels in a significant proportion of NSCLC and appears to be a favorable prognostic factor in early stage disease. As there are potential sampling limitations using tissue microarrays to assess heterogeneously expressed biomarkers, and as the results may differ in advanced stage disease, further studies are recommended. PMID- 26024797 TI - The association of point-of-sale cigarette marketing with cravings to smoke: results from a cross-sectional population-based study. AB - OBJECTIVE: To examine the association between recalled exposure to point-of-sale (POS) cigarette marketing (ie, pack displays, advertisements and promotions such as discounts) and reported cravings to smoke while visiting a store. METHODS: Data were collected using a telephone survey of a cross-sectional sample of 999 adult smokers in Omaha, Nebraska. Recalled exposure to POS cigarette marketing was measured by asking respondents about noticing (a) pack displays, (b) advertisements and (c) promotions in store in their neighbourhood. A 3-item scale indicating the frequency of experiencing cravings to smoke in locations where cigarettes are sold was created by asking respondents: (1) "feel a craving for a cigarette?" (2) "feel like nothing would be better than smoking a cigarette?" and (3) "feel like all you want is a cigarette?" The association between recalled exposure to POS cigarette marketing and cravings was estimated using ordinary least squares linear regression models, controlling for nicotine dependence, gender, age, race/ethnicity, income, education, frequency of visiting stores in one's neighbourhood and method of recruitment into the study. RESULTS: Recalled exposure to POS cigarette displays (p<0.001) and advertisements (p=0.002), but not promotions (p=0.06), was associated with more frequent cravings to smoke. CONCLUSIONS: Recalled exposure to POS cigarette marketing is associated with cravings to smoke as predicted by laboratory studies on the effects of smoking cues on cigarette craving. Policies that reduce or eliminate POS cigarette marketing could reduce cigarette cravings and might attenuate impulse buying of cigarettes. PMID- 26024798 TI - Upregulation of a disintegrin and metalloprotease 8 is associated with progression and prognosis of patients with gastric cancer. AB - A disintegrin and metalloprotease 8 (ADAM8) is involved in the tumorigenesis of several types of solid tumors. However, its exact role in gastric cancer (GC) remains unclear. The aim of this study was to evaluate the clinical significance of ADAM8 in GC and to explore its biological effects on gastric carcinogenesis. In this study, quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical staining analysis revealed that ADAM8 messenger RNA expression was significantly upregulated in GC tissues compared with noncancerous tissues (P = 0.004), and that positive ADAM8 expression is much more common in tumor tissues compared with normal tissues (P < 0.001) and is correlated with T stage (P = 0.036), N stage (P = 0.048), vessel invasion (P = 0.002), and a shorter patient overall survival (P = 0.024). In vitro assay indicated that ADAM8 overexpression promoted cell growth and increased migration and invasion abilities by decreasing the p-p38/p-extracellular regulated protein kinases (p-ERK) ratio. In conclusion, ADAM8 promotes GC cell proliferation and invasion, and its expression is positively correlated with poor survival, indicating that it might be a promising target in GC therapy. PMID- 26024801 TI - Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut. AB - Adult tissue homeostasis requires a tight balance between the removal of old or damaged cells and the production of new ones. Such processes are usually driven by dedicated stem cells that reside within specific tissue locations or niches. The intestinal epithelium has a remarkable regenerative capacity, which has made it a prime paradigm for the study of stem cell-driven tissue self-renewal. The discovery of the presence of stem cells in the adult midgut of the fruit fly Drosophila melanogaster has significantly impacted our understanding of the role of stem cells in intestinal homeostasis. Here we will review the current knowledge of the main mechanisms involved in the regulation of tissue homeostasis in the adult Drosophila midgut, with a focus on the role of stem cells in this process. We will also discuss processes involving acute or chronic disruption of normal intestinal homeostasis such as damage-induced regeneration and ageing. PMID- 26024799 TI - Therapeutics targeting the inflammasome after central nervous system injury. AB - Innate immunity is part of the early response of the body to deal with tissue damage and infections. Because of the early nature of the innate immune inflammatory response, this inflammatory reaction represents an attractive option as a therapeutic target. The inflammasome is a component of the innate immune response involved in the activation of caspase 1 and the processing of pro interleukin 1beta. In this article, we discuss the therapeutic potential of the inflammasome after central nervous system (CNS) injury and stroke, as well as the basic knowledge we have gained so far regarding inflammasome activation in the CNS. In addition, we discuss some of the therapies available or under investigation for the treatment of brain injury, spinal cord injury, and stroke. PMID- 26024800 TI - The interface of inflammation and subclinical atherosclerosis in granulomatosis with polyangiitis (Wegener's): a preliminary study. AB - The objective of this study is to assess the relationship between inflammatory disease in granulomatosis with polyangiitis (GPA, Wegener's) and the development of subclinical atherosclerosis. A total of 46 adult patients with GPA were enrolled. Disease status was measured by Birmingham vasculitis assessment scores as modified for GPA, vasculitis damage index, disease duration, and number of relapses. Classic atherosclerotic risk factors, platelet aggregation responses, and circulating microparticle (MP) levels were recorded. All patients underwent carotid artery intima-media thickness (IMT) measurement as outcome for subclinical atherosclerosis. In univariate analyses, systolic and diastolic blood pressure, creatinine, and age were significantly associated with higher IMT (rho values 0.37, 0.38, 0.35, and 0.054, respectively [P < 0.02 for all]). In a multiple regression model, greater number of relapses, older age at the onset of disease, and higher diastolic blood pressure were found to be associated with higher IMT (P values 0.003, <0.001, and 0.031, respectively). MP counts and platelet reactivity correlated well with disease activity in GPA. Furthermore, MPs were found to activate vascular endothelial cells and platelets in vitro. The cumulative burden of systemic inflammation in GPA correlated with the development of subclinical atherosclerosis. The correlation with subclinical atherosclerosis could be because of glucocorticoid use and not the inflammatory process in GPA, giving the inherent bias that exits with the use of glucocorticoid with each relapse. The findings of increased levels of circulating leukocyte-derived MPs and enhanced platelet reactivity during relapse suggest possible roles for MPs and platelets in disease pathogenesis and support a growing literature that links inflammation, atherosclerosis, and platelet activation. This hypothesis is further substantiated by our demonstration that MPs isolated from plasma of GPA patients can activate platelets and vascular endothelial cells. PMID- 26024806 TI - Deficits in allergy knowledge among physicians at academic medical centers. AB - BACKGROUND: Allergic conditions have high prevalence in the general population. Misconceptions regarding the diagnosis and management of allergic disease among physicians can lead to suboptimal clinical care. OBJECTIVE: To determine the extent of allergy-related knowledge deficits among physicians. METHODS: Pediatric and internal medicine resident and attending physicians from 2 separate academic medical centers were asked to answer an anonymous electronic survey. Survey questions addressed 7 different allergy content areas. RESULTS: Four hundred eight physicians completed surveys (23.9% response rate). Respondents had few correct answers (mean +/- SD 1.91 +/- 1.43). Pediatric respondents had a larger number of correct answers compared with medicine-trained physicians (P < .001). No individual answered every survey question correctly, and 50 respondents (12.3%) had no correct answer. Three hundred seventy-eight respondents (92.6%) were unable to provide correct answers for at least 50% of survey questions. Level of residency training and prior rotation through an allergy and immunology elective correlated with a larger number of correct responses (P < .01). Only 1 survey question had an overall correct response rate higher than 50% (n = 261, 64%). Correct response rate was lower than 30% for 7 of the 9 possible questions. CONCLUSION: There are significant knowledge deficits in many areas of allergy related content among pediatric and internal medicine physicians and across all levels of training and specialty. Given the prevalence of allergic conditions, the potential implications of a negative impact on clinical care are staggering. PMID- 26024807 TI - Finite-time synchronization for memristor-based neural networks with time-varying delays. AB - Memristive network exhibits state-dependent switching behaviors due to the physical properties of memristor, which is an ideal tool to mimic the functionalities of the human brain. In this paper, finite-time synchronization is considered for a class of memristor-based neural networks with time-varying delays. Based on the theory of differential equations with discontinuous right hand side, several new sufficient conditions ensuring the finite-time synchronization of memristor-based chaotic neural networks are obtained by using analysis technique, finite time stability theorem and adding a suitable feedback controller. Besides, the upper bounds of the settling time of synchronization are estimated. Finally, a numerical example is given to show the effectiveness and feasibility of the obtained results. PMID- 26024808 TI - Effect of arsenite-oxidizing bacterium B. laterosporus on arsenite toxicity and arsenic translocation in rice seedlings. AB - Arsenite [As (III)] oxidation can be accelerated by bacterial catalysis, but the effects of the accelerated oxidation on arsenic toxicity and translocation in rice plants are poorly understood. Herein we investigated how an arsenite oxidizing bacterium, namely Brevibacillus laterosporus, influences As (III) toxicity and translocation in rice plants. Rice seedlings of four cultivars, namely Guangyou Ming 118 (GM), Teyou Hang II (TH), Shanyou 63 (SY) and Minghui 63 (MH), inoculated with or without the bacterium were grown hydroponically with As (III) to investigate its effects on arsenic toxicity and translocation in the plants. Percentages of As (III) oxidation in the solutions with the bacterium (100%) were all significantly higher than those without (30-72%). The addition of the bacterium significantly decreased As (III) concentrations in SY root, GM root and shoot, while increased the As (III) concentrations in the shoot of SY, MH and TH and in the root of MH. Furthermore, the As (III) concentrations in the root and shoot of SY were both the lowest among the treatments with the bacterium. On the other hand, its addition significantly alleviated the As (III) toxicity on four rice cultivars. Among the treatments amended with B. laterosporus, the bacterium showed the best remediation on SY seedlings, with respect to the subdued As (III) toxicity and decreased As (III) concentration in its roots. These results indicated that As (III) oxidation accelerated by B. laterosporus could be an effective method to alleviate As (III) toxicity on rice seedlings. PMID- 26024809 TI - ABC transporter and metallothionein expression affected by NI and Epichloe endophyte infection in tall fescue. AB - Epichloe endophytes are symbiotic fungi which unlike mycorrhiza grow within aerial parts of host plants. The fungi may increase host tolerance to both biotic and abiotic stresses. In this study, the effect of endophyte infection on growth and tolerance, carbohydrate contents and ABC (ABC transporter) and MET (metallothionein) expression in the leaves of tall fescue (Festuca arundinacea) plants cultivated in Ni polluted soil were evaluated. The endophyte infected (E+) and non-infected (E-) fescue plants were cultivated in soil under different Ni concentrations (30, 90 and 180mgkg(-1)). Growth parameters including root, shoot, total biomass, tiller number and total chlorophyll content of plants and H2O2 content of shoots were measured at the end of experiment. Ni translocation to the shoots, carbohydrate contents in roots and expression of ABC and MET of the leaves were also measured after 10 weeks of growth. Results demonstrated the beneficial effect of endophyte association on growth and Ni tolerance of tall fescue under Ni stress through an avoidance mechanism (reduction of Ni accumulation and translocation to the shoots). Endophyte infected plants showed less ABC and MET expression compared to the endophyte free plants. In endophyte free plants, H2O2 production had a significant positive correlation with genes expression, indicating that an increase in H2O2 might be involved in the up regulation of ABC and MET under Ni stress. PMID- 26024810 TI - Characterization of an epsilon-class glutathione S-transferase involved in tolerance in the silkworm larvae after long term exposure to insecticides. AB - This study assessed the effect of the pesticides on activity and expression of glutathione S-transferases (GSTs) in the midgut of the silkworm after intense selections by phoxim and fenpropathrin for five and four generations, respectively. GSTs activity towards cumene hydroperoxide (CHP), a substrate of GSH-dependent peroxidase, was significantly increased in the crude homogenate of midguts after long term exposure to the insecticides. An epsilon-class GST gene (BmGSTe2) was identified and showed elevated expression in the midguts of phoxim- and fenpropathrin-selected strains. Expression of BmGSTe2 was only detected in the midgut at transcriptional and translational levels. The recombinant BmGSTE2 possessed peroxidase activity and significantly inhibited by fenpropathrin, phoxim and chlorpyrifos in vitro. These results indicated that BmGSTE2 might be one of the enzymes involved in enhancing larval tolerance to the insecticides used. Furthermore, GST activity and expression level of BmGSTe2 might be used as biomarkers of organophosphorus and pyrethroid insecticide exposures. PMID- 26024811 TI - Effects of intra- and interspecific competition on the sensitivity of aquatic macroinvertebrates to carbendazim. AB - The Ecological Risk Assessment of pesticides and other potentially toxic chemicals is generally based on toxicity data obtained from single-species laboratory experiments. In the field, however, contaminant effects are ubiquitously co-occurring with ecological interactions such as species competition and predation, which might influence the sensitivity of the individuals exposed to toxicants. The present experimental study investigated how intra- and interspecific competition influence the response of sensitive aquatic organisms to a pesticide. For this, the effects of the fungicide carbendazim were assessed on the mortality and growth of the snail Bithynia tentaculata and the crustacean Gammarus pulex under different levels of intraspecific and interspecific competition for a food resource. Interspecific competition was created by adding individuals of Radix peregra and Asellus aquaticus, respectively. The interaction of competition and carbendazim exposure significantly influenced B. tentaculata growth, however, combined effects on survival and immobility were considered transient and were less easily demonstrated. Positive influence of competition on G. pulex survival was observed under low-medium carbendazim concentrations and under medium-high density pressures, being partly related to cannibalistic and predation compensatory mechanisms, enhanced under food limiting conditions. This study shows that intra- and interspecific competition pressure may influence the response of sensitive aquatic organisms in a more complex way (positive, non-significant and negative effects were observed) than just increasing the sensitivity of the studied species, as has generally been hypothesized. PMID- 26024812 TI - Involvement of fish immunomarkers in environmental biomonitoring approach: Urban and agri-viticultural context. AB - The Champagne region (France) is characterized by various chemical environmental pressures which could interfere with the immune status of natural populations of European bullhead, Cottus sp. Some adult fish were caught by electrofishing in spring, summer and autumn to determined immune effect of urban (Muizon), intensive agricultural (Bouy; Prunay) or viticultural (Serzy; Prunay) influences. The major results demonstrated an increase of cellular mortality and a decrease of phagocytosis activity in the stations impacted by agri-viticultural chemicals. These immunomodulations followed the temporal variability due to different treatments (agricultural impacts on spring; viticultural effects on autumn). At the present time, not enough data was provided to confirm the impact of agri viticultural chemicals on fish immune system without interaction with other environmental factors. For example, in summer, the immunomarkers seems to be not only correlated with water contamination but also with other environmental factors (pathogens, physical field degradation, nutrients, temperature ...). Nevertheless, immune parameters give a global view of organism and ecosystem health explaining growing interest for these biomarkers in environmental risk assessment. PMID- 26024813 TI - Analysis of estrogenic activity in environmental waters in Rio de Janeiro state (Brazil) using the yeast estrogen screen. AB - The estrogenicity of waters collected from an important hydrological system in Brazil (Paraiba do Sul and Guandu Rivers) was assessed using the yeast estrogen screen (YES) assay. Sampling was performed in rivers and at the outlets of conventional water treatment plants (WTP). The removal of estrogenic activity by ozonation and chlorination after conventional water treatment (clarification and sand filtration) was investigated employing samples of the Guandu River spiked with estrogens and bisphenol A (BPA). The results revealed a preoccupying incidence of estrogenic activity at levels higher than 1ngL(-1) along some points of the rivers. Another matter of concern was the number of samples from WTPs presenting estrogenicity surpassing 1ngL(-1). The oxidation techniques (ozonation and chlorination) were effective for the removal of estrogenic activity and the combination of both techniques led to good results using less amounts of oxidants. PMID- 26024814 TI - Analysis of Eisenia fetida earthworm responses to sub-lethal C60 nanoparticle exposure using (1)H-NMR based metabolomics. AB - The enhanced production and environmental release of Buckminsterfullerene (C60) nanoparticles will likely increase the exposure and risk to soil dwelling organisms. We used (1)H NMR-based metabolomics to investigate the response of Eisenia fetida earthworms to sub-lethal C60 nanoparticle exposure in both contact and soil tests. Principal component analysis of (1)H NMR data showed clear separation between controls and exposed earthworms after just 2 days of exposure, however as exposure time increased the separation decreased in soil but increased in contact tests suggesting potential adaptation during soil exposure. The amino acids leucine, valine, isoleucine and phenylalanine, the nucleoside inosine, and the sugars glucose and maltose emerged as potential bioindicators of exposure to C60 nanoparticles. The significant responses observed in earthworms using NMR based metabolomics after exposure to very low concentrations of C60 nanoparticles suggests the need for further investigations to better understand and predict their sub-lethal toxicity. PMID- 26024815 TI - Quantifying the health impacts of ambient air pollutants: recommendations of a WHO/Europe project. AB - OBJECTIVE: Quantitative estimates of air pollution health impacts have become an increasingly critical input to policy decisions. The WHO project "Health risks of air pollution in Europe--HRAPIE" was implemented to provide the evidence-based concentration-response functions for quantifying air pollution health impacts to support the 2013 revision of the air quality policy for the European Union (EU). METHODS: A group of experts convened by WHO Regional Office for Europe reviewed the accumulated primary research evidence together with some commissioned reviews and recommended concentration-response functions for air pollutant-health outcome pairs for which there was sufficient evidence for a causal association. RESULTS: The concentration-response functions link several indicators of mortality and morbidity with short- and long-term exposure to particulate matter, ozone and nitrogen dioxide. The project also provides guidance on the use of these functions and associated baseline health information in the cost-benefit analysis. CONCLUSIONS: The project results provide the scientific basis for formulating policy actions to improve air quality and thereby reduce the burden of disease associated with air pollution in Europe. PMID- 26024816 TI - Longitudinal associations between social relationships at age 30 and internalising symptoms at age 42: findings from the Northern Swedish Cohort. AB - OBJECTIVES: Little is known on long-term consequences of poor social relationships in adulthood. The study aimed to examine associations between social relationships at age 30 and internalising symptoms at age 42. METHODS: Data was drawn from four waves of the Northern Swedish cohort (n = 1001, 94 % response rate). The outcome internalising symptoms was measured by a composite index of depressiveness and anxiety. A cumulative measure was constructed to reflect various aspects of social relationships. Multivariate ordinal logistic regressions were used, controlling for socioeconomic indicators and previous level of internalising symptoms. RESULTS: An accumulation of poor social relationships indicators at age 30 is related to internalising symptoms at age 42 in women (OR 1.30; CI 1.11-1.52) and men (OR 1.17; CI 1.02-1.36). The associations remained significant after adjustment for covariates. CONCLUSIONS: Poor quality of social relationships at age 30 can predict internalising symptoms 12 years later in both men and women even when previous mental health as well as financial disadvantage is accounted for. More research is required to further examine pathways and mechanisms as well as suitable interventions. PMID- 26024818 TI - Pico Lantern: Surface reconstruction and augmented reality in laparoscopic surgery using a pick-up laser projector. AB - The Pico Lantern is a miniature projector developed for structured light surface reconstruction, augmented reality and guidance in laparoscopic surgery. During surgery it will be dropped into the patient and picked up by a laparoscopic tool. While inside the patient it projects a known coded pattern and images onto the surface of the tissue. The Pico Lantern is visually tracked in the laparoscope's field of view for the purpose of stereo triangulation between it and the laparoscope. In this paper, the first application is surface reconstruction. Using a stereo laparoscope and an untracked Pico Lantern, the absolute error for surface reconstruction for a plane, cylinder and ex vivo kidney, is 2.0 mm, 3.0 mm and 5.6 mm, respectively. Using a mono laparoscope and a tracked Pico Lantern for the same plane, cylinder and kidney the absolute error is 1.4 mm, 1.5 mm and 1.5 mm, respectively. These results confirm the benefit of the wider baseline produced by tracking the Pico Lantern. Virtual viewpoint images are generated from the kidney surface data and an in vivo proof-of-concept porcine trial is reported. Surface reconstruction of the neck of a volunteer shows that the pulsatile motion of the tissue overlying a major blood vessel can be detected and displayed in vivo. Future work will integrate the Pico Lantern into standard and robot-assisted laparoscopic surgery. PMID- 26024817 TI - Multifunctional Poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl beta-cyclodextrin Amphiphilic Copolymer as an Oral High-Performance Delivery Carrier of Tacrolimus. AB - In order to improve oral bioavailability of tacrolimus (FK506), a novel poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-beta cyclodextrin amphiphilic copolymer (CD-PVM/MA) is developed, combining the bioadhesiveness of PVM/MA, P-glycoprotein (P-gp), and cytochrome P450-inhibitory effect of CD into one. The FK506-loaded nanoparticles (CD-PVM/MA-NPs) were obtained by solvent evaporation method. The physiochemical properties and intestinal absorption mechanism of FK506-loaded CD-PVM/MA-NPs were characterized, and the pharmacokinetic behavior was investigated in rats. FK506-loaded CD-PVM/MA NPs exhibited nanometer-sized particles of 273.7 nm, with encapsulation efficiency as high as 73.3%. FK506-loaded CD-PVM/MA-NPs maintained structural stability in the simulated gastric fluid, and about 80% FK506 was released within 24 h in the simulated intestinal fluid. The permeability of FK506 was improved dramatically by CD-PVM/MA-NPs compared to its solution, probably due to the synergistic inhibition effect of P-gp and cytochrome P450 3A (CYP3A). The intestinal biodistribution of fluorescence-labeled CD-PVM/MA-NPs confirmed its good bioadhesion to the rat intestinal wall. Two endocytosis pathways, clathrin- and caveolae-mediated endocytosis, were involved in the cellular uptake of CD PVM/MA-NPs. The important role of lymphatic transport in nanoparticles' access to the systemic circulation, about half of the contribution to oral bioavailability, was observed in mesenteric lymph duct ligated rats. The AUC0-24 of FK506 loaded in nanoparticles was enhanced up to 20-fold compared to FK506 solutions after oral administration. The present study suggested that the novel multifunctional CD-PVM/MA is a promising efficient oral delivery carrier for FK506, due to its ability in solubilization, inhibitory effects on both P-gp and CYP 3A, high bioadhesion, and sustained release capability. PMID- 26024819 TI - Mechanical properties and in vivo healing evaluation of a novel Centella asiatica loaded hydrocolloid wound dressing. AB - To develop a novel sodium alginate based Centella asiatica (CA)-loaded hydrocolloid wound dressing (HCD) providing excellent mechanical properties and improved wound healing, numerous CA-loaded HCDs were prepared with various ingredients using the hot melting method. The effect of sodium alginate, styrene isoprene-styrene copolymer (SIS) and petroleum hydrocarbon resin (PHR) on the mechanical properties of CA-loaded HCDs was investigated. The effect of disintegrants on swelling and drug release was assessed. Moreover, the in vivo wound healing potentials of the selected CA-loaded HCD in various wound models such as abrasion, excision and infection were evaluated in comparison with the commercial product. Polyisobutylene and SIS hardly affected the mechanical properties, but PHR improved the tensile strength and elongation at break. Disintegrants such as croscarmellose sodium, sodium starch glycolate and crospovidone improved the swelling ratio of the CA-loaded HCD. Furthermore, the CA-loaded HCD without croscarmellose sodium poorly released the drug, but that with 2% croscarmellose sodium showed about 27% drug release in 24h. In particular, the CA-loaded HCD composed of CA/polyisobutylene/SIS/PHR/liquid paraffin/sodium alginate/croscarmellose sodium at the weight ratio of 1/8/25/25/12/27/2 furnished excellent mechanical properties and drug release. As compared with the commercial product, it offered improved healing effects in excision, infection and abrasion type wounds in rats. Thus, this novel CA-loaded HCD could be a potential candidate for the treatment of various wounds. PMID- 26024820 TI - Novel fenofibric acid-loaded controlled release pellet bioequivalent to choline fenofibrate-loaded commercial product in beagle dogs. AB - The objective of this study was to develop a novel fenofibric acid-loaded controlled release pellet showing enhanced, or equivalent to, bioavailability compared with two commercially available products containing fenofibrate or choline fenofibrate. The effect of solubilizing agents on drug solubility and the impact of fillers on core properties were investigated. Among them, magnesium carbonate most improved drug solubility, and kappa-carrageenan provided the best spherical cores. The fenofibric acid-loaded pellet was prepared with magnesium carbonate and kappa-carrageenan employing the extrusion/spheronizing technique followed by coating with ethylcellulose. Furthermore, dissolution and pharmacokinetic study in beagle dogs were performed compared to the fenofibrate loaded commercial tablet (FCT) and choline fenofibrate-loaded commercial mini tablet (CFCM). This fenofibric acid-loaded pellet showed controlled release of the drug in phosphate buffer (pH 6.8) and 0.025 M sodium laurylsulfate within 4h. Furthermore, this pellet and CFCM exhibited similar dissolution profiles. Plasma concentrations greater than 1,000 ng/ml were maintained from 30 min to 8h, suggesting a sustained release pattern. Also, the fenofibric acid-loaded pellet gave significantly higher AUC and Cmax values than FCT, indicating that it improved the bioavailability of fenofibrate due to enhanced solubility and sustained release. In addition, this pellet and CFCM were not significantly different in terms of pharmacokinetic parameters including AUC, Cmax and Tmax. Thus, this pellet was bioequivalent to CFCM in beagle dogs. In conclusion, this fenofibric acid-loaded controlled release pellet would be a potential alternative to the choline fenofibrate-loaded commercial product. PMID- 26024821 TI - Simplified formulations with high drug loads for continuous twin-screw granulation. AB - As different batches of the same excipients will be intermixed during continuous processes, the traceability of batches is complicated. Simplified formulations may help to reduce problems related to batch intermixing and traceability. Twin screw granulation with subsequent tableting was used to produce granules and tablets, containing drug, disintegrant and binder (binary and ternary mixtures), only. Drug loads up to 90% were achieved and five different disintegrants were screened for keeping their disintegration suitability after wetting. Granule size distributions were consistently mono-modal and narrow. Granule strength reached higher values, using ternary mixtures. Tablets containing croscarmellose-Na as disintegrant displayed tensile strengths up to 3.1MPa and disintegration times from 400 to 466s, resulting in the most robust disintegrant. Dissolution was overall complete and above 96% within 30 min. Na-starch glycolate offers tensile strengths up to 2.8MPa at disintegration times from 25s to 1031s, providing the broadest application window, as it corresponds in some parts to different definitions of orodispersible tablets. Tablets containing micronized crospovidone are not suitable for immediate release, but showed possibilities to produce highly drug loaded, prolonged release tablets. Tablets and granules from simplified formulations offer great opportunities to improve continuous processes, present performances comparable to more complicated formulations and are able to correspond to requirements of the authorities. PMID- 26024822 TI - Roller compactor: The effect of mechanical properties of primary particles. AB - In this study, the nano-indentation hardness of a single primary particle was measured for six different materials; microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin, lactose, sodium carbonate and calcium carbonate. This was linked to the properties of the ribbons produced by roller compactor at different hydraulic pressures in the range of 30-230 bar. The main investigated ribbon properties were strength, porosity and width. For the range of materials that were tested, it was found that the lower the nano-indentation hardness of the powder particles, the higher the strength, width and lower the ribbon porosity. This is because the applied pressure by the rollers was enough to plastically deform the particles and create bonds between them. A method was suggested to predict the workability of the powder in roller compactor by using the data of nano-indentation for three materials. PMID- 26024823 TI - Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists. PMID- 26024824 TI - Promising prognostic markers of preeclampsia: new avenues in waiting. AB - Preeclampsia is a pregnancy related condition identified by hypertension and either proteinuria or end-organ dysfunction after 20(th) week of gestation and complicates 2-8% pregnancies worldwide. Enigmatic pathophysiology and multi system involvement hinder accurate identification and clinical management of patients. Inadequate trophoblast invasion and subsequent inflammatory response have been implicated in the onset of PE. In absence of effective treatment of preeclampsia except delivery, recent research has been focused on identification of specific and sensitive biomarkers for early prediction of PE. Several angiogenic, anti-angiogenic, inflammatory, biophysical (mean arterial pressure and uterine artery Doppler) biomarkers, alone and in combination, have been proposed for prediction but limited predictive values have hindered their use in clinical settings. Current review summarizes some of relatively new biomarkers such as corin, copeptin, microparticles and miRNA, the prognostic efficiency of which are either analyzed in associated disorders or recently discovered. PMID- 26024825 TI - Medically-induced hemophilia C to treat thrombosis. PMID- 26024826 TI - [Impact of pulmonary rehabilitation after lung resection for cancer on patients' level of anxiety and depression]. AB - INTRODUCTION: Pulmonary rehabilitation (PR) for patients undergoing lung resection for cancer remains controversial. We studied the effects of PR, its impact on quality of life and the level of anxiety and depression. METHODS: In 2011 and 2012, PR was offered to all patients referred to our institution after lung resection for cancer. Patients were evaluated between admission and discharge by a 6 minutes walking test (6MWD), a Visual Analogue Pain Intensity Scale, a quality of life questionnaire (EORTC QLQ C30) and by the Hospital Anxiety and Depression Scale (HAD). The same questionnaires were mailed 6 months after completing PR. RESULTS: Between early 2011 and late 2012, 133 patients were admitted to our institution following lung resection for cancer. Of these, 59 (44%) patients completed PR and returned their questionnaires 6 months after discharge. During PR of these 59 patients, the mean quality of life score increased from 56.3 to 65.9 (P<0.05), the median anxiety score decreased from 5.5 to 4 (P<0.05) and that of depression from 3 to 2 (P<0.05). At 6 months post discharge, the mean quality of life score remained stable at 66.3 (P=0.8), the median anxiety score reverted to 6 (P<0.05) and the median depression score reverted to 4.5 (P<0.05). CONCLUSION: This observational study during PR, showed that quality of life and the levels of anxiety and depression were improved at the end of the course. After returning home, the average quality of life score remained stable but the level of anxiety and depression increased. PMID- 26024827 TI - [Tumor-bronchial actinomycosis simulating a recurrence of lung cancer 14 years after initial treatment: A case report]. AB - A patient with a history of squamous cell carcinoma of the right upper lung lobe treated 14 years before by concomitant chemo-radiotherapy was referred on account of dyspnea. Bronchial endoscopy revealed complete obstruction of the right main bronchus highly suggestive of a tumor recurrence. However, biopsy samples only showed inflammatory and necrotic tissue with no evidence of malignancy. Despite complete tissue resection by rigid bronchoscopy, a rapid and complete recurrence occurred requiring the placement of a Y-shaped bronchial prosthesis. Repeat histological, bacteriological and mycological analyses were negative. The patient was soon readmitted to hospital for a lung infection due to recurrence of obstruction inside and around the prosthesis. Bacterial examination of biopsy samples identified Actinomyces meyeri. Appropriate antibiotic therapy led to a complete regression of the bronchial obstruction. Unfortunately, the patient died a few months later due to massive hemoptysis after the removal of the prosthesis. Autopsy examination showed a fistula between the right main bronchus and pulmonary artery, with no evidence of neoplastic recurrence nor the persistence of lesions associated with actinomycosis. PMID- 26024829 TI - Spirituality in patients with advanced illness: The role of symptom control, resilience and social network. AB - In this study, we analyzed the relationships among clinical, emotional, social, and spiritual dimensions of patients with advanced illness. It was a cross sectional study, with a sample of 108 patients in an advanced illness situation attended by palliative care teams. Statistically significant correlations were found between some dimensions of spirituality and poor symptomatic control, resiliency, and social support. In the structural model, three variables predicted spirituality: having physical symptoms as the main source of discomfort, resiliency, and social support. This work highlights the relevance of the relationships among spirituality and other aspects of the patient at the end of life. PMID- 26024828 TI - Low-Dose Parenteral Soybean Oil for the Prevention of Parenteral Nutrition Associated Liver Disease in Neonates With Gastrointestinal Disorders. AB - BACKGROUND: Neonates with gastrointestinal disorders (GDs) are at high risk for parenteral nutrition-associated liver disease (PNALD). Soybean-based intravenous lipid emulsions (S-ILE) have been associated with PNALD. This study's objective was to determine if a lower dose compared with a higher dose of S-ILE prevents cholestasis without compromising growth. MATERIALS AND METHODS: This multicenter randomized controlled pilot study enrolled patients with GDs who were <=5 days of age to a low dose (~1 g/kg/d) (LOW) or control dose of S-ILE (~3 g/kg/d) (CON). The primary outcome was cholestasis (direct bilirubin [DB] >2 mg/dL) after the first 7 days of age. Secondary outcomes included growth, PN duration, and late onset sepsis. RESULTS: Baseline characteristics were similar between the LOW (n = 20) and CON groups (n = 16). When the LOW group was compared with the CON group, there was no difference in cholestasis (30% vs 38%, P = .7) or secondary outcomes. However, mean +/- SE DB rate of change over the first 8 weeks (0.07 +/- 0.04 vs 0.3 +/- 0.09 mg/dL/wk, P = .01) and entire study (0.008 +/- 0.03 vs 0.2 +/- 0.07 mg/dL/wk, P = .02) was lower in the LOW group compared with the CON group. CONCLUSION: In neonates with GDs who received a lower dose of S-ILE, DB increased at a slower rate in comparison to neonates who received a higher dose of S-ILE. Growth was comparable between the groups. This study demonstrates a need for a larger, randomized controlled trial comparing 2 different S-ILE doses for cholestasis prevention in neonates at risk for PNALD. PMID- 26024831 TI - A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide. AB - The study aims to compare serial changes in prostate-specific antigen (PSA), testosterone, dehydroepiandrosterone (DHEA), and androstenedione in patients treated with either of the antiandrogen agents, bicalutamide or flutamide, using a randomized controlled study. Patients had to meet the following inclusion criteria: (1) presence of histopathologically confirmed prostate cancer, (2) prostate cancer treatment naive, (3) no current treatment with luteinizing hormone-releasing hormone (LH-RH) agonist for sexual interest and physical capacity, (4) clinical stage T1-cT3N0M0, (5) Gleason score <= 7, and (6) Cooperative Oncology Group performance status 0-1. Patients were randomly allocated to two groups: flutamide and bicalutamide monotherapy group 1:1. PSA levels were significantly decreased in both groups at 4 weeks. PSA levels were significantly lower in the bicalutamide group compared with the flutamide group at 4 and 8 weeks. Testosterone levels in the bicalutamide group were significantly higher than the baseline levels between 4 and 24 weeks of treatment. Testosterone levels in the flutamide group were significantly increased at 4 and 12 weeks and returned to baseline levels at 16 and 24 weeks. DHEA levels in the bicalutamide group were unchanged from baseline at 4 and 24 weeks. However, DHEA levels in the flutamide group were decreased at 24 weeks. Androstenedione levels increased slightly in both groups, but the increase did not reach statistical significance. PSA, testosterone, and DHEA levels significantly differed between bicalutamide and flutamide monotherapy. PMID- 26024830 TI - Activity and growth of anammox biomass on aerobically pre-treated municipal wastewater. AB - Direct treatment of municipal wastewater (MWW) based on anaerobic ammonium oxidizing (anammox) bacteria holds promise to turn the energy balance of wastewater treatment neutral or even positive. Currently, anammox processes are successfully implemented at full scale for the treatment of high-strength wastewaters, whereas the possibility of their mainstream application still needs to be confirmed. In this study, the growth of anammox organisms on aerobically pre-treated municipal wastewater (MWW(pre-treated)), amended with nitrite, was proven in three parallel reactors. The reactors were operated at total N concentrations in the range 5-20 mg(N)?L(-1), as expected for MWW. Anammox activities up to 465 mg(N)?L(-1)?d(-1) were reached at 29 degrees C, with minimum doubling times of 18 d. Lowering the temperature to 12.5 degrees C resulted in a marked decrease in activity to 46 mg(N)?L(-1)?d(-1) (79 days doubling time), still in a reasonable range for autotrophic nitrogen removal from MWW. During the experiment, the biomass evolved from a suspended growth inoculum to a hybrid system with suspended flocs and wall-attached biofilm. At the same time, MWW(pre-treated) had a direct impact on process performance. Changing the influent from synthetic medium to MWW(pre-treated) resulted in a two-month delay in net anammox growth and a two to three-fold increase in the estimated doubling times of the anammox organisms. Interestingly, anammox remained the primary nitrogen consumption route, and high-throughput 16S rRNA gene-targeted amplicon sequencing analyses revealed that the shift in performance was not associated with a shift in dominant anammox bacteria ("Candidatus Brocadia fulgida"). Furthermore, only limited heterotrophic denitrification was observed in the presence of easily biodegradable organics (acetate, glucose). The observed delays in net anammox growth were thus ascribed to the acclimatization of the initial anammox population or/and the development of a side population beneficial for them. Additionally, by combining microautoradiography and fluorescence in situ hybridization it was confirmed that the anammox organisms involved in the process did not directly incorporate or store the amended acetate and glucose. In conclusion, these investigations strongly support the feasibility of MWW treatment via anammox. PMID- 26024832 TI - Is antenatal screening for hepatitis C virus cost-effective? A decade's experience at a London centre. AB - BACKGROUND & AIMS: This study aims to assess the cost-effectiveness of a routine universal antenatal hepatitis C virus (HCV) screening programme at a London centre. METHODS: Ten years' retrospective antenatal screening and outcome data informed a cost-effectiveness analysis using the previously validated MONARCH model. The cost and quality of life outcomes associated with the screening and treatment of newly identified hepatitis C cases were used to generate cost effectiveness estimates for the screening programme. RESULTS: A total of 35,355 women were screened between 1st November 2003 and 1st March 2013; 136 women (0.38%) were found to be HCV antibody positive. Of 78 (0.22%) viraemic cases, 44 (0.12%) were newly diagnosed. In addition, the screening programme identified three (6.8%) vertical transmissions in children of newly diagnosed mothers. Of 16 newly diagnosed mothers biopsied, all were in the F0-F2 METAVIR disease stages, and 50% had HCV genotype 1. Postnatal treatment with pegylated interferon and ribavirin was initiated in 19 women, with 14 (74%) achieving sustained virologic response. The total cost of screening and confirmation of diagnoses was estimated to be L240,641. This translates to L5469 per newly diagnosed individual. The incremental cost-effectiveness ratio of this screening and treatment strategy was L2400 per QALY gained. Treatment with newer direct-acting antiviral regimens would have a projected cost of L9139 per QALY gained, well below the L20,000 30,000/QALY gained willingness-to-pay threshold applied by policy advisory bodies. CONCLUSIONS: This study demonstrates that an antenatal screening and treatment programme is feasible and effective, at a cost considered acceptable. PMID- 26024833 TI - Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling. AB - BACKGROUND & AIMS: Long non-coding RNA Hotair has been considered as a pro oncogene in multiple cancers. Although there is emerging evidence that reveals its biological function and the association with clinical prognosis, the precise mechanism remains largely elusive. METHODS: We investigated the function and mechanism of Hotair in hepatocellular carcinoma (HCC) cell models and a xenograft mouse model. The regulatory network between miR-218 and Hotair was elucidated by RNA immunoprecipitation and luciferase reporter assays. Finally, the correlation between Hotair, miR-218 and the target gene Bmi-1 were evaluated in 52 paired HCC specimens. RESULTS: In this study, we reported that Hotair negatively regulated miR-218 expression in HCC, which might be mediated through an EZH2-targeting-miR 218-2 promoter regulatory axis. Further investigation revealed that Hotair knockdown dramatically inhibited cell viability and induced G1-phase arrest in vitro and suppressed tumorigenicity in vivo by promoting miR-218 expression. Oncogene Bmi-1 was shown to be a functional target of miR-218, and the main downstream targets signaling, P16(Ink4a) and P14(ARF), were activated in Hotair suppressed tumorigenesis. In primary human HCC specimens, Hotair and Bmi-1 were concordantly upregulated whereas miR-218 was downregulated in these tissues. Furthermore, Hotair was inversely associated with miR-218 expression and positively correlated with Bmi-1 expression in these clinical tissues. CONCLUSION: Hotair silence activates P16(Ink4a) and P14(ARF) signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HCC. PMID- 26024834 TI - Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci. AB - Previously, we have studied the effect of the gold-compound auranofin (AF) on both thioredoxin-glutathione reductasa (TGR) activity and viability of Taenia crassiceps cysticerci. It was demonstrated that micromolar concentrations of AF were high enough to fully inhibit TGR and kill the parasites. In this work, the dynamics of changes in the glutathione pool of T. crassiceps cysticerci following the addition of AF, was analyzed. A dose-dependent decrease in the internal glutathione concentration, concomitant with an increase in ROS production was observed. These changes were simultaneous with the formation of glutathione protein complexes and the export of glutathione disulfide (GSSG) to the culture medium. Incubation of cysticerci in the presence of both AF and N-acetyl cysteine (NAC) prevents all the above changes, maintaining cysticerci viability. By contrast, the presence of both AF and buthionine sulfoximine (BSO) resulted in a potentiation of the effects of the gold compound, jeopardizing cysticerci viability. These results suggest the lethal effect of AF on T. crassiceps cysticerci, observed at micromolar concentrations, can be explained as a consequence of major changes in the glutathione status, which results in a significant increase in the oxidative stress of the parasites. PMID- 26024836 TI - Effects of extraordinary snowfall on traffic safety. AB - Snowfall affects traffic safety by causing changes in roadway surface and visibility that result in crashes, spinouts, and breakdowns. Using data collected at a site that regularly receives nearly 1000 cm of snow during the snow season, this study examines the impact of snowfall quantity, gap between snow events, and weather conditions on crash and incident frequencies. Estimation results from regression analysis show that snowfall severity significantly impacts crashes and incidents but the impact diminishes marginally with each additional centimeter of snow. Gap has a significant fixed effect on crashes but its impact on incidents varies significantly across observations. The effect of the mixed precipitation condition is smaller in comparison to an all-snow condition. These results will help inform policy for snow removal and traffic enforcement in areas of high snowfall. PMID- 26024835 TI - mTOR, a new potential target for chronic pain and opioid-induced tolerance and hyperalgesia. AB - Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid therapy can produce opioid tolerance and hyperalgesia. Although the mechanisms underlying chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia remain to be uncovered, mammalian target of rapamycin (mTOR) is involved in these disorders. The mTOR complex 1 and its triggered protein translation are required for the initiation and maintenance of chronic pain (including cancer pain) and opioid-induced tolerance/hyperalgesia. Given that mTOR inhibitors are FDA-approved drugs and an mTOR inhibitor is approved for the treatment of several cancers, these findings suggest that mTOR inhibitors will likely have multiple clinical benefits, including anticancer, antinociception/anti-cancer pain, and antitolerance/hyperalgesia. This paper compares the role of mTOR complex 1 in chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia. PMID- 26024837 TI - Texting while driving using Google GlassTM: Promising but not distraction-free. AB - Texting while driving is risky but common. This study evaluated how texting using a Head-Mounted Display, Google Glass, impacts driving performance. Experienced drivers performed a classic car-following task while using three different interfaces to text: fully manual interaction with a head-down smartphone, vocal interaction with a smartphone, and vocal interaction with Google Glass. Fully manual interaction produced worse driving performance than either of the other interaction methods, leading to more lane excursions and variable vehicle control, and higher workload. Compared to texting vocally with a smartphone, texting using Google Glass produced fewer lane excursions, more braking responses, and lower workload. All forms of texting impaired driving performance compared to undistracted driving. These results imply that the use of Google Glass for texting impairs driving, but its Head-Mounted Display configuration and speech recognition technology may be safer than texting using a smartphone. PMID- 26024838 TI - Upper arm circumference development in Chinese children and adolescents: a pooled analysis. AB - BACKGROUND: Upper arm development in children is different in different ethnic groups. There have been few reports on upper arm circumference (UAC) at different stages of development in children and adolescents in China. The purpose of this study was to provide a reference for growth with weighted assessment of the overall level of development. METHODS: Using a pooled analysis, an authoritative journal database search and reports of UAC, we created a new database on developmental measures in children. In conducting a weighted analysis, we compared reference values for 0~60 months of development according to the World Health Organization (WHO) statistics considering gender and nationality and used Z values as interval values for the second sampling to obtain an exponential smooth curve to analyze the mean, standard deviation, and sites of attachment. RESULTS: Ten articles were included in the pooled analysis, and these articles included participants from different areas of China. The point of intersection with the WHO curve was 3.5 years with higher values at earlier ages and lower values at older ages. Boys curve was steeper after puberty. The curves in the studies had a merged line compatible. The Z values of exponential smoothing showed the curves were similar for body weight and had a right normal distribution. CONCLUSIONS: The integrated index of UAC in Chinese children and adolescents indicated slightly variations with regions. Exponential curve smoothing was suitable for assessment at different developmental stages. PMID- 26024840 TI - The interaction of electric field and hydrostatic pressure in an electrical double layer: A simple "first principle" model that accounts for the finite sizes of counterions. AB - A simple model describing the influence of ion size in the electrical double layer (EDL) near a highly charged plane is proposed here. This model is based on the Poisson-Boltzmann equation with a single additional term representing the mechanical response of bulky ions to hydrostatic pressure. This pressure is produced by Coulomb forces, and increases to several kilobars in the vicinity of a highly charged plane. Numerical simulations demonstrate close packing as a limit for counterion concentrations. Differential capacity reaches maximum at 0.1 0.3V and remains reasonably small in wide range of potentials. PMID- 26024839 TI - Comparison of cardiovascular magnetic resonance characteristics and clinical consequences in children and adolescents with isolated left ventricular non compaction with and without late gadolinium enhancement. AB - BACKGROUND: Although cardiovascular magnetic resonance (CMR) is showing increasingly diagnostic potential in left ventricular non-compaction (LVNC), relatively little research relevant to CMR is conducted in children with LVNC. This study was performed to characterize and compare CMR features and clinical outcomes in children with LVNC with and without late gadolinium enhancement (LGE). METHODS: A cohort of 40 consecutive children (age, 13.7 +/- 3.3 years; 29 boys and 11 girls) with isolated LVNC underwent a baseline CMR scan with subsequent clinical follow-up. Short-axis cine images were used to calculate left ventricular (LV) ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), myocardial mass, ratio of non-compacted-to-compacted myocardial thickness (NC/C ratio), and number of non-compacted segments. The LGE images were analyzed to assess visually presence and patterns of LGE. The primary end point was a composite of cardiac death and heart transplantation. RESULTS: The LGE was present in 10 (25%) children, and 46 (27%) segments were involved, including 23 non-compacted segments and 23 normal segments. Compared with LGE- cohort, LGE+ cohort had significantly lower LVEF (23.8 +/- 10.7% vs. 42.9 +/- 16.7%, p < 0.001) and greater LVEDV (169.2 +/- 65.1 vs. 118.2 +/- 48.9 mL/m2, p = 0.010), LVESV (131.3 +/- 55.5 vs. 73.3 +/- 46.7 mL/m2, p = 0.002), and sphericity indices (0.75 +/- 0.19 vs. 0.60 +/- 0.20, p = 0.045). There were no differences in terms of number and distribution of non-compacted segments, NC/C ratio, and myocardial mass index between LGE+ and LGE- cohort. In the LGE+ cohort, adverse events occurred in 6 patients compared to 2 events in the LGE- cohort. Kaplan-Meier analysis showed a significant difference in outcome between LGE+ and LGE- cohort for cardiac death and heart transplantation (p = 0.011). CONCLUSIONS: The LGE was present in up to one-fourth of children with LVNC, and the LGE+ children exhibited a more maladaptive LV remodeling and a higher incidence of cardiovascular death and heart transplantation. PMID- 26024841 TI - The implication of health insurance for child development and maternal nutrition: evidence from China. AB - We use the implementation of the new rural cooperative medical scheme (NCMS) in China to investigate the effect of health insurance on maternal nutrition and child health. Given the uneven roll-out of the NCMS across rural counties, we are able to deploy its implementation as a natural experiment in order to obviate problems of adverse selection that typically plague research on the effects of health insurance. We find that, among children, the NCMS has the greatest positive effect on infants between birth and 5 years of age. Also, with respect to female nutritional status, our models show that the NCMS has the greatest effect on women of childbearing age (aged between 16 and 35), indicating that women who benefit from the NCMS benefits may, in turn, give birth to healthier babies. Thus, taken together, our findings indicate that the NCMS plays an important role in health dynamics in rural China. PMID- 26024842 TI - StemBANCC: Governing Access to Material and Data in a Large Stem Cell Research Consortium. AB - This paper makes the case for implementing an internal governance framework for sharing materials and data in stem cell research consortia. A governance framework can facilitate a transparent and accountable system while building trust among partner institutions. However, avoiding excessive bureaucracy is essential. The development and implementation of a governance framework for materials and data access in the Stem cells for Biological Assays of Novel drugs and prediCtive toxiCology (StemBANCC) consortium is presented as a practical example. The StemBANCC project is a multi-partner European research consortium, which aims to build a resource of 1,500 well characterised induced pluripotent stem cell (iPSC) lines for in vitro disease modelling and toxicology studies. The project governance framework was developed in two stages. A small working group identified key components of a framework and translated the project legal agreements into a draft policy document. The second phase allowed input from all consortium partners to shape the iterative development of a final policy document that could be agreed by all parties. Careful time management strategies were needed to manage the duration of this component. This part of the process also served as an exploratory space where different options could be proposed, potential gaps in planning identified, and project co-ordination activities specified. PMID- 26024843 TI - Non-invasive detection of intracranial hypertension using a simplified intracranial hemo- and hydro-dynamics model. AB - BACKGROUND: Monitoring of intracranial pressure (ICP) is highly important for detecting abnormal brain conditions such as intracranial hemorrhage, cerebral edema, or brain tumor. Until now, the monitoring of ICP requires an invasive method which has many disadvantages including the risk of infections, hemorrhage, or brain herniation. Therefore, many non-invasive methods have been proposed for estimating ICP. However, these methods are still insufficient to estimate sudden increases in ICP. METHODS: We proposed a simplified intracranial hemo- and hydro dynamics model that consisted of two simple resistance circuits. From this proposed model, we designed an ICP estimation algorithm to trace ICP changes. First, we performed a simulation based on the original Ursino model with the real arterial blood pressure to investigate our proposed approach. We subsequently applied it to experimental data that were measured during the Valsalva maneuver (VM) and resting state, respectively. RESULTS: Simulation result revealed a small root mean square error (RMSE) between the estimated ICP by our approach and the reference ICP derived from the original Ursino model. Compared to the pulsatility index (PI) based approach and Kashif's model, our proposed method showed more statistically significant difference between VM and resting state. CONCLUSION: Our proposed method successfully tracked sudden ICP increases. Therefore, our method may serve as a suitable tool for non-invasive ICP monitoring. PMID- 26024844 TI - Tibial bowing in children - what is normal? A radiographic study. AB - PURPOSE: To define osseous landmarks on tibia radiographs in order to establish age-related normal values characterizing physiological tibial bowing in children. MATERIALS AND METHODS: Five hundred and twenty-six patients aged 0-17 years with normal radiographs of the lower legs were identified and retrospectively reviewed by two blinded radiologists. In anteroposterior (ap)/lateral (lat)-views, 3 lines defined tibial length and angulation. Line-A connecting proximal to distal corner of tibial metaphysic, lines B and C corresponding to corners of tibial metaphysis. Angle A/B defines proximal, A/C distal tibial-angulation. Tibial curvature is defined by distance of line-D parallel to A and tangential to tibial cortex. Normal values were calculated with linear-regression. Intra-/Interreader agreement were tested with a Bland-Altman-plot. RESULTS: Intrareader-agreement: Reader 1 showed a bias of -0.1, standard-deviation of bias was 1.9 and 95 % limits-of-agreement -3.9- 3.7. Reader 2: -0.01, 2.4 and -4.7- 4.7. Interreader: 0.2, 1.6 and -2.9- 3.3. Angle-A/B ap was 80-100 degrees , increasing with age (86.5-88); angle-AC ap was 82-107 degrees (96.8-90.5), angle-AB lat was 81-107 degrees (93.0-98.0); angle-AC lat was 76-102 (89.5-86.5); depth of curve ap was 0 11 % (8-3.5) and lat 2-13 %, (8.5-3.5). CONCLUSION: Age dependent tibial bowing can be assessed with this new measurement system and age-related normal-values characterizing physiological tibial bowing in children is established. KEY POINTS: * Tibial Bowing is diagnosed on conventional radiographs. * Existing Methods provide limited level of confidence. * New methods provide easy to assess landmarks in all patient ages. * Existing methods require higher radiation dose compared to new method presented. PMID- 26024845 TI - Early-stage differentiation between presenile Alzheimer's disease and frontotemporal dementia using arterial spin labeling MRI. AB - OBJECTIVE: To investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer's disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion changes. METHODS: Thirteen AD and 19 FTD patients, and 25 age-matched older and 22 younger controls underwent 3D pseudo-continuous ASL-MRI at 3 T. Gray matter (GM) volume and cerebral blood flow (CBF), corrected for partial volume effects, were quantified in the entire supratentorial cortex and in 10 GM regions. Sensitivity, specificity and diagnostic performance were evaluated in regions showing significant CBF differences between patient groups or between patients and older controls. RESULTS: AD compared with FTD patients had hypoperfusion in the posterior cingulate cortex, differentiating these with a diagnostic performance of 74 %. Compared to older controls, FTD patients showed hypoperfusion in the anterior cingulate cortex, whereas AD patients showed a more widespread regional hypoperfusion as well as atrophy. Regional atrophy was not different between AD and FTD. Diagnostic performance of ASL to differentiate AD or FTD from controls was good (78-85 %). Older controls showed global hypoperfusion compared to young controls. CONCLUSION: ASL-MRI contributes to early diagnosis of and differentiation between presenile AD and FTD. KEY POINTS: ASL-MRI facilitates differentiation of early Alzheimer's disease and frontotemporal dementia. Posterior cingulate perfusion is lower in Alzheimer's disease than frontotemporal dementia. Compared to controls, Alzheimer's disease patients show hypoperfusion in multiple regions. Compared to controls, frontotemporal dementia patients show focal anterior cingulate hypoperfusion. Global decreased perfusion in older adults differs from hypoperfusion in dementia. PMID- 26024846 TI - Peritumoral apparent diffusion coefficients for prediction of lymphovascular invasion in clinically node-negative invasive breast cancer. AB - OBJECTIVES: To evaluate whether visual assessment of T2-weighted imaging (T2WI) or an apparent diffusion coefficient (ADC) could predict lymphovascular invasion (LVI) status in cases with clinically node-negative invasive breast cancer. MATERIALS AND METHODS: One hundred and thirty-six patients with 136 lesions underwent MRI. Visual assessment of T2WI, tumour-ADC, peritumoral maximum-ADC and the peritumour-tumour ADC ratio (the ratio between them) were compared with LVI status of surgical specimens. RESULTS: No significant relationship was found between LVI and T2WI. Tumour-ADC was significantly lower in the LVI-positive (n = 77, 896 +/- 148 * 10(-6) mm(2)/s) than the LVI-negative group (n = 59, 1002 +/- 163 * 10(-6) mm(2)/s; p < 0.0001). Peritumoral maximum-ADC was significantly higher in the LVI-positive (1805 +/- 355 * 10(-6) mm(2)/s) than the LVI-negative group (1625 +/- 346 * 10(-6) mm(2)/s; p = 0.0003). Peritumour-tumour ADC ratio was significantly higher in the LVI-positive (2.05 +/- 0.46) than the LVI negative group (1.65 +/- 0.40; p < 0.0001). Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) of the peritumour tumour ADC ratio was the highest (0.81). The most effective threshold for the peritumour-tumour ADC ratio was 1.84, and the sensitivity, specificity, positive predictive value and negative predictive value were 77% (59/77), 76% (45/59), 81% (59/73) and 71% (45/63), respectively. CONCLUSIONS: We suggest that the peritumour-tumour ADC ratio can assist in predicting LVI status on preoperative imaging. KEY POINTS: * Tumour ADC was significantly lower in LVI-positive than LVI-negative breast cancer. * Peritumoral maximum-ADC was significantly higher in LVI-positive than LVI-negative breast cancer. * Peritumour-tumour ADC ratio was significantly higher in LVI-positive breast cancer. * Diagnostic performance of the peritumour-tumour ADC ratio was highest for positive LVI. * Peritumour-tumour ADC ratio showed higher diagnostic ability in postmenopausal than premenopausal patients. PMID- 26024847 TI - Assessment of CF lung disease using motion corrected PROPELLER MRI: a comparison with CT. AB - OBJECTIVES: To date, PROPELLER MRI, a breathing-motion-insensitive technique, has not been assessed for cystic fibrosis (CF) lung disease. We compared this technique to CT for assessing CF lung disease in children and adults. METHODS: Thirty-eight stable CF patients (median 21 years, range 6-51 years, 22 female) underwent MRI and CT on the same day. Study protocol included respiratory triggered PROPELLER MRI and volumetric CT end-inspiratory and -expiratory acquisitions. Two observers scored the images using the CF-MRI and CF-CT systems. Scores were compared with intra-class correlation coefficient (ICC) and Bland Altman plots. The sensitivity and specificity of MRI versus CT were calculated. RESULTS: MRI sensitivity for detecting severe CF bronchiectasis was 0.33 (CI 0.09 0.57), while specificity was 100% (CI 0.88-1). ICCs for bronchiectasis and trapped air were as follows: MRI-bronchiectasis (0.79); CT-bronchiectasis (0.85); MRI-trapped air (0.51); CT-trapped air (0.87). Bland-Altman plots showed an MRI tendency to overestimate the severity of bronchiectasis in mild CF disease and underestimate bronchiectasis in severe disease. CONCLUSIONS: Motion correction in PROPELLER MRI does not improve assessment of CF lung disease compared to CT. However, the good inter- and intra-observer agreement and the high specificity suggest that MRI might play a role in the short-term follow-up of CF lung disease (i.e. pulmonary exacerbations). KEY POINTS: PROPELLER MRI does not match CT sensitivity to assess CF lung disease. PROPELLER MRI has lower sensitivity than CT to detect severe bronchiectasis. PROPELLER MRI has good to very good intra- and inter-observer variability. PROPELLER MRI can be used for short-term follow up studies in CF. PMID- 26024848 TI - Impact of image denoising on image quality, quantitative parameters and sensitivity of ultra-low-dose volume perfusion CT imaging. AB - OBJECTIVES: To examine the impact of denoising on ultra-low-dose volume perfusion CT (ULD-VPCT) imaging in acute stroke. METHODS: Simulated ULD-VPCT data sets at 20 % dose rate were generated from perfusion data sets of 20 patients with suspected ischemic stroke acquired at 80 kVp/180 mAs. Four data sets were generated from each ULD-VPCT data set: not-denoised (ND); denoised using spatiotemporal filter (D1); denoised using quanta-stream diffusion technique (D2); combination of both methods (D1 + D2). Signal-to-noise ratio (SNR) was measured in the resulting 100 data sets. Image quality, presence/absence of ischemic lesions, CBV and CBF scores according to a modified ASPECTS score were assessed by two blinded readers. RESULTS: SNR and qualitative scores were highest for D1 + D2 and lowest for ND (all p <= 0.001). In 25 % of the patients, ND maps were not assessable and therefore excluded from further analyses. Compared to original data sets, in D2 and D1 + D2, readers correctly identified all patients with ischemic lesions (sensitivity 1.0, kappa 1.0). Lesion size was most accurately estimated for D1 + D2 with a sensitivity of 1.0 (CBV) and 0.94 (CBF) and an inter-rater agreement of 1.0 and 0.92, respectively. CONCLUSION: An appropriate combination of denoising techniques applied in ULD-VPCT produces diagnostically sufficient perfusion maps at substantially reduced dose rates as low as 20 % of the normal scan. KEY POINTS: Perfusion-CT is an accurate tool for the detection of brain ischemias. The high associated radiation doses are a major drawback of brain perfusion CT. Decreasing tube current in perfusion CT increases image noise and deteriorates image quality. Combination of different image denoising techniques produces sufficient image quality from ultra-low-dose perfusion CT. PMID- 26024849 TI - MR appearance of parathyroid adenomas at 3 T in patients with primary hyperparathyroidism: what radiologists need to know for pre-operative localization. AB - OBJECTIVES: To identify frequent MRI features of parathyroid adenomas (PTAs) in patients with primary hyperparathyroidism (PHPT) using a fast protocol with a 3 T magnet. METHODS: Thirty-eight patients with PHPT underwent a 3 T-MR. All patients had positive US and Tc-99 sestamibi, for a total number of 46 PTAs. T2-weighted IDEAL-FSE and T1 IDEAL-sequences, before and after contrast, were performed. Five features of PTAs were recognised: hyperintensity, homogeneous or "marbled" appearance and elongated morphology on T2-sequences; cleavage plane from thyroid gland on T2-outphase; rapid enhancement in post-contrast T1. Image quality for T2 weighted IDEAL FSE and usefulness for IDEAL post-contrast T1-weighted and T2 outphase sequences were also graded. RESULTS: PTAs were hyperintense in T2 sequences in 44/46 (95.7%), "marbled" in 30/46 (65.2%) and elongated in 38/46 (82.6%) patients. Cleavage plane was observed in 36/46 (78.3%), and rapid enhancement in 20/46 (43.5%) patients. T2-sequences showed both excellent fat suppression and image quality (average scores of 3.2 and 3.1). T2-outphase images demonstrated to be quite useful (score 2.8), whereas, post-contrast T1 images showed a lower degree of utility (score 2.4). CONCLUSIONS: A fast protocol with 3.0-T MRI, recognising most common features of PTAs, may be used as a second-line method in the preoperative detection of PTAs. KEY POINTS: 3 T MRI protocol based on T2-weighted IDEAL FSE sequences was used. T2-hyperintensity and elongated morphology are common features of PTAs. 3 T MRI could be used in the preoperative detection of PTAs. PMID- 26024850 TI - Distribution of naloxone for overdose prevention to chronic pain patients. AB - In this commentary, we reflect on the growing opioid overdose epidemic and propose that chronic pain patients prescribed opioids are contributing to growing mortality rates. We advocate for expanding naloxone access and overdose prevention training, which has historically been directed when available to injection drug users, to chronic pain patients who may be at high risk for accidental opioid overdose. PMID- 26024852 TI - Strong gun laws are not enough: the need for improved enforcement of secondhand gun transfer laws in Massachusetts. AB - OBJECTIVE: Research suggests that an overwhelming majority of crime guns were transferred by private sellers before recovery by law enforcement. Unfortunately, most states do not regulate these transactions. This study examines whether analyses of state-level private transfer data could be used to develop interventions to reduce the supply of handguns to violent criminals. METHODS: Traced Boston crime handguns first sold at Massachusetts license dealers were matched to state secondhand gun transfer data. Logistic regression and descriptive statistics were used to analyze the characteristics of recovered crime guns and in-state primary and secondary market transaction patterns. RESULTS: For crime handguns with records of secondary market transactions in Massachusetts, many rapidly move from private transfer to recovery by the police. Unfortunately, important transaction data on the in-state sources of nearly 63% of recovered handguns were not readily available to law enforcement agencies. CONCLUSIONS: Data on private transfers of guns could be used to prevent violent injuries by reducing criminal access. However, the passage of strong private transfer gun laws needs to be accompanied by investments in the vigorous enforcement of reporting requirements. PMID- 26024851 TI - The comparative efficacy of lifestyle intervention and metformin by educational attainment in the Diabetes Prevention Program. AB - OBJECTIVE: Educational attainment is inversely associated with type 2 diabetes risk, but it is unknown whether education impacts individuals' diabetes prevention efforts. We examined the comparative efficacy of intensive lifestyle intervention and metformin by educational attainment among participants in the Diabetes Prevention Program (DPP), an ongoing U.S. multi-site trial beginning in 1996. METHODS: We studied 2,910 DPP participants randomized to receive lifestyle intervention, metformin, or placebo. Stratifying by educational attainment, diabetes incidence and relative risk reductions by treatment assignment were estimated using Cox proportional hazards regression. RESULTS: 47% of participants had completed college and 53% had not. Compared to placebo, lifestyle participants who had completed college demonstrated a 68% reduction in diabetes incidence (95% CI=56, 77), whereas those with less education experienced a 47% risk reduction (95% CI=29, 61). For metformin participants, college graduates experienced a 49% relative risk reduction (95% CI=33, 62), compared to 23% (95% CI=1, 41) among those with lower educational attainment. There was a statistically significant education-by-treatment interaction with incident diabetes (p=0.03). CONCLUSIONS: Intensive lifestyle intervention and metformin have greater efficacy among highly educated individuals. Future efforts to deliver these treatments and study their dissemination may be more effective if tailored to individuals' educational background. PMID- 26024854 TI - An Ultra-Performance Liquid Chromatography Photodiode Array Detection Tandem Mass Spectrometric Method for Simultaneous Determination of Seven Major Bioactive Constituents in Xiaochaihutang and Its Application to Fourteen Compatibilities Study. AB - A rapid and sensitive ultra-performance liquid chromatography photodiode array detection tandem mass spectrometric method (UPLC-PDA-MS-MS) was developed and validated to simultaneously determine seven major bioactive constituents in the formula of traditional Chinese medicines Xiaochaihutang (XCHT). To investigate the discipline of compatibility in XCHT, 14 kinds of compatibilities designed by orthogonal array were also analyzed. The separation was performed on an ACQUITY UPLCTM BEH C18 column (100 * 2.1 mm, 1.7 um) using gradient elution with a mobile phase of 0.1% formic acid and acetonitrile at a flow rate of 0.2 mL/min. Two detection techniques of PDA detector and MS-MS detector were proposed, respectively. The concentrations of baicalin and wogonoside were high enough for PDA detection while low-concentration bioactive constituents including saikosaponin a, ginsenoside Rg1, liquiritin, baicalein and wogonin were quantified by MS-MS detection. The proposed method was fully validated in terms of sensitivity, linearity, specificity, precision, repeatability and recovery. This is the first report on the simultaneous determination of the major bioactive constituents of XCHT by UPLC-PDA-MS-MS, which could be used to evaluate the quality of XCHT and to investigate the discipline of compatibility in XCHT. PMID- 26024853 TI - Establishment of a free-mating, long-standing and highly productive laboratory colony of Anopheles darlingi from the Peruvian Amazon. AB - BACKGROUND: Anopheles darlingi is the main malaria vector in the Amazon region and is among the most efficient malaria vectors worldwide. However, due to the lack of a well-established laboratory colony, key control-relevant aspects of the bionomics, behaviour, genetics, and vector-parasite relationships of An. darlingi remain unknown. Here, biological parameters that had been successful in initiating other Anopheles colonies were optimized and improved for An. darlingi, with the aim of establish a free-mating, stable, and highly productive laboratory colony. METHODS: Wild An. darlingi adult females were field collected from Zungarococha, Loreto Department, Peru (03 degrees 49'32.40"S, 73 degrees 21'00.08"W), and taken to the NAMRU-6 Insectary in Iquitos where F(1) offspring were produced and reared. Natural copulation was successfully induced in F1 adults under a thermoperiod of 30 +/- 1 degrees C during the day and 25 +/- 1 degrees C at night, and with a 30-min LED light stimulation period at dusk. Oviposition success was enhanced using egg-laying containers with a dark-coloured surface. Larval feeding regimes were standardized for optimal larval development. Optimized copulation induction methods were used to facilitate mating in An. darlingi until the F(10) generation. No copulation induction assistance was needed in subsequent generations. RESULTS: In 19 generations, the An. darlingi colony produced a total of 763,775 eggs; 441,124 larvae; 248,041 pupae; and 231,591 adults. A mean of 0.56 sexual encounters/female/cage (n = 36 cages) was recorded across the first ten generations (F(1)-F(10)). A mean insemination rate of 54.7 % (n = 5,907 females) ranging from 43.6 % (F(2)) to 66.6 % (F(10)) was recorded across nine generations (F(2)-F(10)). Free-mating was casually observed in the F(8) generation, and subsequently confirmed in the F(9) and F(10) generations; comparable insemination rates and egg laying between stimulated (51.6 %, 12.9 eggs/female), and non-stimulated (52.3 %, 11.2 eggs/female) females were recorded. The time from egg to adult development ranged from 10 to 20 days. Moreover, the colony was relocated to a new laboratory within Iquitos in the F(14) generation without any noted changes in its productivity. By March 2015, the An. darlingi colony has been successfully reared to the F(26) generation. CONCLUSIONS: This constitutes the first report of a free-mating, highly productive, and long-standing An. darlingi laboratory colony established through natural copulation induction, which will support critical malaria research. This rearing methodology may be a transferable, cost-effective alternative to labour intensive forced mating practices widely used in maintaining other Anopheles colonies. PMID- 26024855 TI - Percutaneous Coronary Intervention Rates and Associated Independent Predictors for Progression of Nontarget Lesions in Patients With Diabetes Mellitus After Drug-Eluting Stent Implantation. PMID- 26024856 TI - Response to the comment by Vas P.R. et al.: "P.R. Vas, S. Sharma, G. Rayman, Utilizing the Ipswich Touch Test to simplify screening methods for identifying the risk of foot ulceration among diabetics: comment on the Saudi experience. Prim. Care Diabetes (2015) http://dx.doi.org/10.1016/j.pcd.2015.01.003.". PMID- 26024857 TI - Tuber shape and eye depth variation in a diploid family of Andean potatoes. AB - BACKGROUND: Tuber appearance is highly variable in the Andean cultivated potato germplasm. The diploid backcross mapping population 'DMDD' derived from the recently sequenced genome 'DM' represents a sample of the allelic variation for tuber shape and eye depth present in the Andean landraces. Here we evaluate the utility of morphological descriptors for tuber shape for identification of genetic loci responsible for the shape and eye depth variation. RESULTS: Subjective morphological descriptors and objective tuber length and width measurements were used for assessment of variation in tuber shape and eye depth. Phenotypic data obtained from three trials and male-female based genetic maps were used for quantitative trait locus (QTL) identification. Seven morphological tuber shapes were identified within the population. A continuous distribution of phenotypes was found using the ratio of tuber length to tuber width and a QTL was identified in the paternal map on chromosome 10. Using toPt-437059, the marker at the peak of this QTL, the seven tuber shapes were classified into two groups: cylindrical and non-cylindrical. In the first group, shapes classified as 'compressed', 'round', 'oblong', and 'long-oblong' mainly carried a marker allele originating from the male parent. The tubers in this group had deeper eyes, for which a strong QTL was found at the same location on chromosome 10 of the paternal map. The non-cylindrical tubers classified as 'obovoid', 'elliptic', and 'elongated' were in the second group, mostly lacking the marker allele originating from the male parent. The main QTL for shape and eye depth were located in the same genomic region as the previously mapped dominant genes for round tuber shape and eye depth. A number of candidate genes underlying the significant QTL markers for tuber shape and eye depth were identified. CONCLUSIONS: Utilization of a molecular marker at the shape and eye depth QTL enabled the reclassification of the variation in general tuber shape to two main groups. Quantitative measurement of the length and width at different parts of the tuber is recommended to accompany the morphological descriptor classification to correctly capture the shape variation. PMID- 26024858 TI - MiR-125b protects against ethanol-induced apoptosis in neural crest cells and mouse embryos by targeting Bak 1 and PUMA. AB - MicroRNAs are a class of small noncoding RNAs that have been implicated in regulation of a broad range of cellular and physiologic processes, including apoptosis. The objective of this study is to elucidate the roles of miR-125b in modulating ethanol-induced apoptosis in neural crest cells (NCCs) and mouse embryos. We found that treatment with ethanol resulted in a significant decrease in miR-125b expression in NCCs and in mouse embryos. We also validated that Bcl-2 antagonist killer 1 (Bak1) and p53-upregulated modulator of apoptosis (PUMA) are the direct targets of miR-125b in NCCs. In addition, over-expression of miR-125b significantly reduced ethanol-induced increase in Bak1 and PUMA protein expression, caspase-3 activation, and apoptosis in NCCs, indicating that miR-125b can modulate ethanol-induced apoptosis by the regulation of Bcl-2 and p53 pathways. Furthermore, microinjection of miR-125b mimic resulted in a significant increase in miR-125b expression and a decrease in the protein expression of Bak1 and PUMA in ethanol-exposed mouse embryos. Up-regulation of miR-125b also significantly reduced ethanol-induced caspase-3 activation and diminished ethanol induced growth retardation in mouse embryos. This is the first demonstration that miR-125b can prevent ethanol-induced apoptosis and that microinjection of miRNA mimic can prevent ethanol-induced embryotoxicity. PMID- 26024859 TI - Cellular prion protein directly interacts with and enhances lactate dehydrogenase expression under hypoxic conditions. AB - Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clarified, a PrP(c)-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion protein knockout mice (Prnp(0/0)) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrP(c). Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp(0/0) knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line. While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp(0/0) primary cortical neurons with concurrent less hypoxia-induced damage in the former group. Likewise, cerebral ischemia significantly increases LDH levels in WT vs. Prnp(0/0) mice with accompanying smaller lesions in the WT group. HEK293 cells overexpressing PrP(c) show significantly higher LDH expression/activity following 90-min of hypoxia as compared to control cells. Moreover, a cytoplasmic co localization of LDH and PrP(c) was recorded under both normoxic and hypoxic conditions. Interestingly, an expression of monocarboxylate transporter 1, responsible for cellular lactate uptake, increases with PrP(c)-overexpression under normoxic conditions. Our data suggest LDH as a direct PrP(c) interactor with possible physiological relevance under low oxygen conditions. PMID- 26024862 TI - Special issue on symposia organized by the American Society of Biomechanics at the 7th World Congress of Biomechanics. PMID- 26024860 TI - Modeling the complex pathology of Alzheimer's disease in Drosophila. AB - Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-beta (Abeta42) peptide revealed the critical role of amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncover the function and pathogenesis of human APP, Abeta42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Abeta42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Abeta42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Abeta42. PMID- 26024864 TI - Reply to: Occipital artery: a not so poor artery for the embolization of lateral sinus dural arteriovenous fistulas with Onyx. PMID- 26024861 TI - Transient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells. AB - Excitotoxicity plays a critical role in neurodegenerative disease. Cytosolic calcium overload and mitochondrial dysfunction are among the major mediators of high level glutamate-induced neuron death. Here, we show that the transient opening of mitochondrial permeability transition pore (tMPT) bridges cytosolic calcium signaling and mitochondrial dysfunction and mediates glutamate-induced neuron death. Incubation of the differentiated motor neuron-like NSC34D cells with glutamate (1mM) acutely induces cytosolic calcium transient (30% increase). Glutamate also stimulates tMPT opening, as reflected by a 2-fold increase in the frequency of superoxide flash, a bursting superoxide production event in individual mitochondria coupled to tMPT opening. The glutamate-induced tMPT opening is attenuated by suppressing cytosolic calcium influx and abolished by inhibiting mitochondrial calcium uniporter (MCU) with Ru360 (100 MUM) or MCU shRNA. Further, increased cytosolic calcium is sufficient to induce tMPT in a mitochondrial calcium dependent manner. Finally, chronic glutamate incubation (24h) persistently elevates the probability of tMPT opening, promotes oxidative stress and induces neuron death. Attenuating tMPT activity or inhibiting MCU protects NSC34D cells from glutamate-induced cell death. These results indicate that high level glutamate-induced neuron toxicity is mediated by tMPT, which connects increased cytosolic calcium signal to mitochondrial dysfunction. PMID- 26024863 TI - [Lepromatous leprosy revealed by palmoplantar papular lesions]. PMID- 26024865 TI - Initial experience with a new distal intermediate and aspiration catheter in the treatment of acute ischemic stroke: clinical safety and efficacy. AB - PURPOSE: To describe our initial experience with the novel 5 F SOFIA (Soft Torqueable catheter Optimized For Intracranial Access) intermediate and aspiration catheter for endovascular treatment of patients with acute ischemic stroke. METHODS: A retrospective review was performed in three centers of prospectively collected data of all stroke patients who underwent endovascular therapy using the SOFIA catheter. Patients were enrolled between November 2013 and December 2014. The primary endpoint of the study was accessibility of the thrombus with the SOFIA catheter. As a secondary endpoint, the study assessed recanalization success (Thrombolysis In Cerebral Infarction (TICI) >=2b). Clinical presentation on admission and discharge was also documented. In addition, catheter- and procedure-related complications (particularly thromboembolic complications) were recorded. RESULTS: The SOFIA catheter was used in 115 acute stroke procedures. In 110 cases (96%) the catheter could be advanced to the occlusion site. After mechanical thrombectomy, successful recanalization (TICI >=2b) was documented in 86.9%. There were no complications related to positioning of the catheter. Distal thrombus migration into a new vascular territory occurred in three patients following thrombectomy with a stent retriever (2.6%). The mean NIH Stroke Scale (NIHSS) score on admission was 16.8+/ 6 and at discharge the mean NIHSS score was 8.2+/-7.7. Sixteen patients died. CONCLUSIONS: The SOFIA catheter is a safe and efficient catheter for endovascular stroke therapy. PMID- 26024866 TI - Using Bayesian Multilevel Whole Genome Regression Models for Partial Pooling of Training Sets in Genomic Prediction. AB - Training set size is an important determinant of genomic prediction accuracy. Plant breeding programs are characterized by a high degree of structuring, particularly into populations. This hampers the establishment of large training sets for each population. Pooling populations increases training set size but ignores unique genetic characteristics of each. A possible solution is partial pooling with multilevel models, which allows estimating population-specific marker effects while still leveraging information across populations. We developed a Bayesian multilevel whole-genome regression model and compared its performance with that of the popular BayesA model applied to each population separately (no pooling) and to the joined data set (complete pooling). As an example, we analyzed a wide array of traits from the nested association mapping maize population. There we show that for small population sizes (e.g., <50), partial pooling increased prediction accuracy over no or complete pooling for populations represented in the training set. No pooling was superior; however, when populations were large. In another example data set of interconnected biparental maize populations either partial or complete pooling was superior, depending on the trait. A simulation showed that no pooling is superior when differences in genetic effects among populations are large and partial pooling when they are intermediate. With small differences, partial and complete pooling achieved equally high accuracy. For prediction of new populations, partial and complete pooling had very similar accuracy in all cases. We conclude that partial pooling with multilevel models can maximize the potential of pooling by making optimal use of information in pooled training sets. PMID- 26024867 TI - GATA Factor Regulation in Excess Nitrogen Occurs Independently of Gtr-Ego Complex Dependent TorC1 Activation. AB - The TorC1 protein kinase complex is a central component in a eukaryotic cell's response to varying nitrogen availability, with kinase activity being stimulated in nitrogen excess by increased intracellular leucine. This leucine-dependent TorC1 activation requires functional Gtr1/2 and Ego1/3 complexes. Rapamycin inhibition of TorC1 elicits nuclear localization of Gln3, a GATA-family transcription activator responsible for the expression of genes encoding proteins required to transport and degrade poor nitrogen sources, e.g., proline. In nitrogen-replete conditions, Gln3 is cytoplasmic and Gln3-mediated transcription minimal, whereas in nitrogen limiting or starvation conditions, or after rapamycin treatment, Gln3 is nuclear and transcription greatly increased. Increasing evidence supports the idea that TorC1 activation may not be as central to nitrogen-responsive intracellular Gln3 localization as envisioned previously. To test this idea directly, we determined whether Gtr1/2- and Ego1/3-dependent TorC1 activation also was required for cytoplasmic Gln3 sequestration and repressed GATA factor-mediated transcription by abolishing the Gtr-Ego complex proteins. We show that Gln3 is sequestered in the cytoplasm of gtr1Delta, gtr2Delta, ego1Delta, and ego3Delta strains either long term in logarithmically glutamine-grown cells or short term after refeeding glutamine to nitrogen-limited or -starved cells; GATA factor-dependent transcription also was minimal. However, in all but a gtr1Delta, nuclear Gln3 localization in response to nitrogen limitation or starvation was adversely affected. Our data demonstrate: (i) Gtr Ego-dependent TorC1 activation is not required for cytoplasmic Gln3 sequestration in nitrogen-rich conditions; (ii) a novel Gtr-Ego-TorC1 activation-independent mechanism sequesters Gln3 in the cytoplasm; (iii) Gtr and Ego complex proteins participate in nuclear Gln3-Myc(13) localization, heretofore unrecognized functions for these proteins; and (iv) the importance of searching for new mechanisms associated with TorC1 activation and/or the regulation of Gln3 localization/function in response to changes in the cells' nitrogen environment. PMID- 26024868 TI - Pharmacokinetics/pharmacodynamics of a beta-lactam and beta-lactamase inhibitor combination: a novel approach for aztreonam/avibactam. AB - OBJECTIVES: The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-beta-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for aztreonam/avibactam across multiple clinical Enterobacteriaceae strains. METHODS: Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollow-fibre infection model (HFIM) using various dosing regimens simulating human-like PK for aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains. RESULTS: MIC values of aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the aztreonam PK/PD index was observed as % fT >MIC. Studies performed in the presence of a fixed dose of aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2-2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target. CONCLUSIONS: PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for beta-lactam/beta-lactamase inhibitor combinations. PMID- 26024869 TI - Comparative outcomes of beta-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. AB - OBJECTIVES: beta-Lactam antibiotics are commonly used in outpatient parenteral antimicrobial therapy (OPAT), but data regarding outcomes of long-term therapy are limited. The purpose of this study was to compare treatment success, readmission and antibiotic switch rates in patients treated with beta-lactam antibiotics as OPAT. METHODS: We carried out a retrospective review of all patients, discharged from Tufts Medical Center with cefazolin, ceftriaxone, ertapenem or oxacillin, between January 2009 and June 2013. A competing risks analysis was used to compare the cumulative incidence of first occurrence of treatment success, antibiotic switch and 30 day readmission for each drug. RESULTS: Four hundred patients were identified (cefazolin n = 38, ceftriaxone n = 104, ertapenem n = 128 and oxacillin n = 130). Baseline demographics were similar. Treatment success rates were higher for ceftriaxone and ertapenem (cefazolin 61%, ceftriaxone 81%, ertapenem 73% and oxacillin 58%; P < 0.001). Thirty-day all-cause readmissions were similar (cefazolin 21%, ceftriaxone 14%, ertapenem 20% and oxacillin 15%; P = 0.46). In 400 OPAT courses, 37 out of 50 antibiotic switches were accomplished without readmission. Adverse drug events (ADEs) were the most common reason for outpatient antibiotic switches (31/37, 84%). The ADE rate was higher for the oxacillin group (cefazolin 2.0 versus ceftriaxone 1.5 versus ertapenem 2.9 versus oxacillin 8.4 per 1000 OPAT days; P < 0.001). CONCLUSIONS: OPAT with beta-lactam antibiotics is effective, but antibiotic switches for adverse events were more frequent with oxacillin use. Clinicians should be cognizant of the risk of readmissions and ADEs in OPAT patients, as the value of OPAT lies in reducing patient morbidity and readmissions by managing ADEs and preventing clinical failures. PMID- 26024870 TI - A Review of Aquaculture Practices and Their Impacts on Chemical Food Safety from a Regulatory Perspective. AB - Aquaculture is currently one of the most rapidly growing food production industries in the world. The increasing global importance for this industry stems primarily from the fact that it is reducing the gap between the supply and demand for fish products. Commercial aquaculture contributes significantly to the economies of many countries since high-value fish species are a major source of foreign exchange. This review looks at the aquaculture industry, the issues raised by the production of fish through aquaculture for food security, the sustainability of the practice to agriculture, what the future holds for the industry in the next 10-20 years, and why there is a need to have available analytical procedures to regulate the safe use of chemicals and veterinary drugs in aquaculture. PMID- 26024871 TI - Expansion of the Scope of AOAC First Action Method 2012.25--Single-Laboratory Validation of Triphenylmethane Dye and Leuco Metabolite Analysis in Shrimp, Tilapia, Catfish, and Salmon by LC-MS/MS. AB - Prior to conducting a collaborative study of AOAC First Action 2012.25 LC-MS/MS analytical method for the determination of residues of three triphenylmethane dyes (malachite green, crystal violet, and brilliant green) and their metabolites (leucomalachite green and leucocrystal violet) in seafood, a single-laboratory validation of method 2012.25 was performed to expand the scope of the method to other seafood matrixes including salmon, catfish, tilapia, and shrimp. The validation included the analysis of fortified and incurred residues over multiple weeks to assess analyte stability in matrix at -80 degrees C, a comparison of calibration methods over the range 0.25 to 4 MUg/kg, study of matrix effects for analyte quantification, and qualitative identification of targeted analytes. Method accuracy ranged from 88 to 112% with 13% RSD or less for samples fortified at 0.5, 1.0, and 2.0 MUg/kg. Analyte identification and determination limits were determined by procedures recommended both by the U. S. Food and Drug Administration and the European Commission. Method detection limits and decision limits ranged from 0.05 to 0.24 MUg/kg and 0.08 to 0.54 MUg/kg, respectively. AOAC First Action Method 2012.25 with an extracted matrix calibration curve and internal standard correction is suitable for the determination of triphenylmethane dyes and leuco metabolites in salmon, catfish, tilapia, and shrimp by LC-MS/MS at a residue determination level of 0.5 MUg/kg or below. PMID- 26024872 TI - Endogenous pro-thrombotic biomarkers from the arm and leg may not have the same value. AB - OBJECTIVE: Assessments of endogenous pro-thrombotic biomarkers are performed invariably on arm blood. However, the commonest site for thrombosis is in the leg. A leg blood sample may reflect local pro-thrombotic processes more accurately than systemic arm blood. The aim was to determine whether pro thrombotic biomarkers from standard venous arm samples differed significantly from leg samples. METHOD: Concurrent blood samples were taken from an ankle/lower calf varicose vein and an ante-cubital vein in 24 patients awaiting laser treatment as well as age approximated and sex matched healthy controls without venous disease. The following assays were performed: thrombin-antithrombin (ng/ml), antithrombin (%) activity, microparticles (nM), fibrinogen (mg/dl), prothrombin fragment 1.2 (F1.2) (pM) and P-selectin (ng/ml). RESULTS: Expressed as median (inter-quartile range). Significant arm/leg differences were observed in thrombin-antithrombin, antithrombin, prothrombin fragment 1.2 and P-selectin. The legs of patients had significantly reduced antithrombin activity and P selectin concentrations compared to their arms (leg: 101 (90-108) versus arm: 112 (99-126), P = 0.001 and leg: 42 (26-52) versus 45 (27-52), P = 0.044, respectively). Control leg samples had significantly increased thrombin antithrombin and P-selectin compared to control arm samples (leg: 2.1 (0.9-3.2) versus arm: 0.8 (0.5-1.7), P = 0.015 and leg: 36 (24-50) versus arm: 30 (23-41), P = 0.007, respectively). However, the control legs had significantly reduced F1.2 (leg: 265 (230-333) versus arm: 299 (236-361), P = 0.028). No significant arm/leg differences were detected in the microparticle or fibrinogen levels. CONCLUSIONS: These findings indicate that venous arm blood is significantly different from venous leg blood in four out of six biomarkers studied. Recognition of local venous leg sampling as a site for investigation may unravel why the leg has a greater predisposition to thrombosis and lead the way towards an arm/leg differential test. PMID- 26024874 TI - Race influences warfarin dose changes associated with genetic factors. AB - Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. PMID- 26024875 TI - Triallelic and epigenetic-like inheritance in human disorders of telomerase. AB - Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution. PMID- 26024876 TI - High-density preculture of PBMCs restores defective sensitivity of circulating CD8 T cells to virus- and tumor-derived antigens. AB - Peripheral blood mononuclear cells (PBMCs) are the only source of human lymphoid cells routinely available for immunomonitoring of T-cell responses to microbial and tumor-associated antigens. However, previous work in mice and humans had indicated that CD4 T cells transiently lose antigen sensitivity when cellular contacts are lost (eg, by entering the circulation). Using the simple and robust protocol for resetting T cells to original reactivity (RESTORE; ie, preculturing PBMCs for 2 days at a high cell density before initiation of antigenic stimulation), we show that CD8 T-cell responses to viral and tumor-associated antigens are greatly underestimated in blood, and sometimes even remain undetected, if conventional, unprocessed PBMC cultures are used. The latter finding is particularly striking with regard to the appearance of Wilms tumor 1 protein-specific CD8 T-cell responses in leukemia patients after allogeneic bone marrow transplantation. The dramatic increase in antigen sensitivity of "restored" CD8 T cells is associated with phosphorylation of proximal T-cell receptor signaling components, and with the upregulation of genes involved in aerobic glycolysis, thereby increasing T-cell functionality. The RESTORE protocol permits a more meaningful monitoring of CD8 memory T-cell responses to viral infections and tumors and vaccination success. Furthermore, when generating T cell lines for adoptive T-cell therapy, it avoids the loss of those clones, which strictly depend on the primed status conferred by cellular interactions in the tissue context for their initial reactivation by antigen. The data reported in this article have been deposited in the Gene Expression Omnibus database (accession number GSE63430). PMID- 26024877 TI - Multimorbidity and its social determinants among older people in southern provinces, Vietnam. AB - BACKGROUND: Developing countries are poorly equipped for health issues related to ageing populations making multimorbidity challenging. As in Vietnam the focus tends to be on single conditions. Hence little is known about burden of multimorbidity. This study aimed to examine the prevalence and the determinants of multimorbidity among older people in Southern Vietnam. METHODS: A cross sectional study was conducted in two provinces of Southern Vietnam with a sample of 2400 people aged 60 years and older. The presence of chronic disease was ascertained by medical examination done by physicians at commune health stations. Information on social and demographic factors was collected using structured questionnaire. Univariate and multivariable logistic regression analyses were used to examine the factors associated with multimorbidity. RESULTS: Nearly 40 % of older people had multimorbidity. Currently not working, and healthcare utilisation were associated with higher prevalence of multimorbidity. Living in urban areas and being literate were associated with lower prevalence of multimorbidity. CONCLUSION: The study found a high burden of multimorbidity among illiterate, especially those living in rural areas. This highlights the need for targeted community based programs aimed at reducing the burden of chronic disease. PMID- 26024878 TI - Utility of creatinine/cystatin C ratio as a predictive marker for adverse effects of chemotherapy in lung cancer: A retrospective study. AB - OBJECTIVE: To determine whether the creatinine/cystatin C (Cr/CysC) ratio, which is influenced by muscle mass, can be used as a predictive marker of the adverse effects of chemotherapy. METHODS: This single-centre, retrospective, observational study assessed patients with lung cancer. Serum Cr and CysC levels were measured once within 1 month prior the commencement of chemotherapy. RESULTS: A total of 25 patients with lung cancer were enrolled in the study: 22 received first-line therapy; three received second-line therapy. A significant difference was noted regarding the Cr/CysC ratios between patients with nonsmall cell lung cancer (NSCLC) and those with small-cell lung cancer (0.78 versus 0.92, respectively). A significant difference was also noted in the Cr/CysC ratios of patients with NSCLC with toxicity grades <3 and >=3 (0.84 versus 0.70, respectively). Similar findings were observed in patients with NSCLC who received platinum-based combination therapy (toxicity grade < 3, 0.85; toxicity grade >=3, 0.69). CONCLUSION: The Cr/CysC ratio could serve as a useful predictive marker for chemotherapy-related adverse effects in patients with NSCLC. PMID- 26024879 TI - Diagnosis of a granular cell tumour at the abdominal wall using fine needle aspiration cytology and histology: Case report. AB - This case report describes the use of fine needle aspiration cytology to diagnose a granular cell tumour (GCT) that presented as a painless, palpable mass at the abdominal wall in a 50-year-old woman who had had the mass for >=1 year prior to presentation. Routine haematoxylin and eosin staining of the cytological smears demonstrated that the specimen was predominantly cellular; it contained both cell clusters and single cells with abundant granular cytoplasm and indistinct cell borders. Cells were fragile and had fairly uniform naked nuclei that were scattered with vacuolated and prominent nucleoli. Background material on the smears included eosinophilic, granular cytoplasmic material and some adipose tissue. Neither mitoses nor necrosis were observed. A cytological diagnosis of a GCT was confirmed by histological examination of a surgical specimen stained with haematoxylin and eosin. This case report found that the GCT had a characteristic cytological appearance and that cells with prominent nucleoli can be present in benign GCTs. PMID- 26024880 TI - Determinants of price setting decisions on anti-malarial drugs at retail shops in Cambodia. AB - BACKGROUND: In many low-income countries, the private commercial sector plays an important role in the provision of malaria treatment. However, the quality of care it provides is often poor, with artemisinin combination therapy (ACT) generally being too costly for consumers. Decreasing ACT prices is critical for improving private sector treatment outcomes and reducing the spread of artemisinin resistance. Yet limited evidence exists on the factors influencing retailers' pricing decisions. This study investigates the determinants of price mark-ups on anti-malarial drugs in retail outlets in Cambodia. METHODS: Taking an economics perspective, the study tests the hypothesis that the structure of the anti-malarial market determines the way providers set their prices. Providers facing weak competition are hypothesized to apply high mark-ups and set prices above the competitive level. To analyse the relationship between market competition and provider pricing, the study used cross-sectional data from retail outlets selling anti-malarial drugs, including outlet characteristics data (e.g. outlet type, anti-malarial sales volumes), range of anti-malarial drugs stocked (e.g. dosage form, brand status) and purchase and selling prices. Market concentration, a measure of the level of market competition, was estimated using sales volume data. Market accessibility was defined based on travel time to the closest main commercial area. Percent mark-ups were calculated using price data. The relationship between mark-ups and market concentration was explored using regression analysis. RESULTS: The anti-malarial market was on average highly concentrated, suggesting weak competition. Higher concentration was positively associated with higher mark-ups in moderately accessible markets only, with no significant relationship or a negative relationship in other markets. Other determinants of pricing included anti-malarial brand status and generic type, with higher mark-ups on cheaper products. CONCLUSIONS: The results indicate that provider pricing as well as other key elements of anti-malarial supply and demand may have played an important role in the limited access to appropriate malaria treatment in Cambodia. The potential for an ACT price subsidy at manufacturer level combined with effective communications directed at consumers and supportive private sector regulation should be explored to improve access to quality malaria treatment in Cambodia. PMID- 26024881 TI - Association between body size and reservoir competence of mammals bearing Borrelia burgdorferi at an endemic site in the northeastern United States. AB - BACKGROUND: The reservoirs for the Lyme disease agent, Borrelia burgdorferi, are dominated by several different small to medium sized mammals in eastern North America. FINDINGS: To experimentally assess the competence of different mammalian species to transmit this pathogen to ticks, we carried out quantitative species specific PCR of individual nymphal Ixodes scapularis ticks, which had been collected as replete larvae from animals captured at a field site in eastern Connecticut and then allowed to molt in the laboratory. The mammals, in order of increasing body mass, were the white-footed mouse, pine vole, eastern chipmunk, gray squirrel, Virginia opossum, striped skunk, and common raccoon. The prevalence of infection in the nymphs and the counts of spirochetes in infected ticks allometrically scaled with body mass with exponents of -0.28 and -0.29, respectively. By species, the captured animals from the site differed significantly in the mean counts of spirochetes in the ticks recovered from them, but these associations could not be distinguished from an effect of body size per se. CONCLUSIONS: These empirical findings as well as inferences from modeling suggest that small mammals on the basis of their sizes are more competent as reservoirs of B. burgdorferi in this environment than medium-to large-sized mammals. PMID- 26024882 TI - A comparison of hierarchical cluster analysis and league table rankings as methods for analysis and presentation of district health system performance data in Uganda. AB - In 2003, the Uganda Ministry of Health introduced the district league table for district health system performance assessment. The league table presents district performance against a number of input, process and output indicators and a composite index to rank districts. This study explores the use of hierarchical cluster analysis for analysing and presenting district health systems performance data and compares this approach with the use of the league table in Uganda. Ministry of Health and district plans and reports, and published documents were used to provide information on the development and utilization of the Uganda district league table. Quantitative data were accessed from the Ministry of Health databases. Statistical analysis using SPSS version 20 and hierarchical cluster analysis, utilizing Wards' method was used. The hierarchical cluster analysis was conducted on the basis of seven clusters determined for each year from 2003 to 2010, ranging from a cluster of good through moderate-to-poor performers. The characteristics and membership of clusters varied from year to year and were determined by the identity and magnitude of performance of the individual variables. Criticisms of the league table include: perceived unfairness, as it did not take into consideration district peculiarities; and being oversummarized and not adequately informative. Clustering organizes the many data points into clusters of similar entities according to an agreed set of indicators and can provide the beginning point for identifying factors behind the observed performance of districts. Although league table ranking emphasize summation and external control, clustering has the potential to encourage a formative, learning approach. More research is required to shed more light on factors behind observed performance of the different clusters. Other countries especially low-income countries that share many similarities with Uganda can learn from these experiences. PMID- 26024884 TI - Obesity in school-aged children and its correlation with gut E.coli and Bifidobacteria: a case-control study. AB - BACKGROUND: To determine the correlation between obesity in school-aged children and imbalance of gut microbes by examining the ratio change of intestinal Bifidobacteria and E.coli in obese children compared to non-obese controls. METHODS: A hospital-based 1:1 case-control study was performed. Fecal samples of the subjects were collected for DNA extraction and analyzed by quantitative real time PCR (qPCR) to determine the copy number of Bifidobacteria and E.coli. The ratio of two microbes (B/E) was then calculated and statistically analyzed. RESULTS: Subjects of the obesity group and control group showed no significant difference in age, gender or height (P > 0.05); whereas they had significant differences in body weight and BMI. Copy numbers of Bifidobacteria and E.coli per gram of wet fecal samples were first determined using qPCR in both obese and normal groups, which were further used for the calculation of B/E ratio. We found that B/E ration in the two groups showed significant difference (P < 0.05). Corrected chi(2) test was performed for the two groups against B/E < 1, and it was found that there was a positive correlation (OR = 719.2, OR 95% C.I. = 81.57 6341.18) between B/E ratio decrease with childhood obesity. CONCLUSIONS: The obese children have a lower amount of Bifidobacteria and higher amount of E.coli (smaller B/E ratio) compared to normal non-obese children. It was suggested that obesity in children may be associated with the imbalance of gut microbes. PMID- 26024883 TI - Report of the AMIA EHR-2020 Task Force on the status and future direction of EHRs. PMID- 26024885 TI - A systematic review and thematic synthesis of quality of life in the informal carers of cancer patients with cachexia. AB - BACKGROUND: Informal carers of cancer patients with cachexia face additional challenges to those encountered by informal carers in general because of the central role food and eating play in everyday life. Patient weight loss and anorexia, core features of cancer cachexia, are frequent causes of distress in caregivers. Identification of quality of life issues can inform the development of interventions for both caregivers and patients and facilitate communication with healthcare professionals. AIM: To identify quality of life issues that are relevant to carers of cancer patients with cachexia. DESIGN: A systematic review and thematic synthesis of the qualitative literature were conducted. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: PubMed, ISI Web of Knowledge, EMBASE, MEDLINE, CINAHL, PsycINFO and PsycARTICLES were searched for publications dated from January 1980 to February 2015 using search terms relating to cancer, cachexia, quality of life and carers. Papers written in the English language, featuring direct quotes from the carers of adult patients with any cancer diagnosis and cachexia or problems with weight loss or anorexia, were included. RESULTS: Five themes were extracted from the 16 identified studies. These highlighted the impact on everyday life, the attempts of some carers to take charge, the need for healthcare professional's input, conflict with the patient and negative emotions. CONCLUSION: The complexity of caring for a cancer patient with cachexia translates into a range of problems and experiences for informal carers. By addressing the impact of caring for a patient with cancer cachexia on carers, both caregiver and patient quality of life may improve. PMID- 26024886 TI - Privacy preserving probabilistic record linkage (P3RL): a novel method for linking existing health-related data and maintaining participant confidentiality. AB - BACKGROUND: Record linkage of existing individual health care data is an efficient way to answer important epidemiological research questions. Reuse of individual health-related data faces several problems: Either a unique personal identifier, like social security number, is not available or non-unique person identifiable information, like names, are privacy protected and cannot be accessed. A solution to protect privacy in probabilistic record linkages is to encrypt these sensitive information. Unfortunately, encrypted hash codes of two names differ completely if the plain names differ only by a single character. Therefore, standard encryption methods cannot be applied. To overcome these challenges, we developed the Privacy Preserving Probabilistic Record Linkage (P3RL) method. METHODS: In this Privacy Preserving Probabilistic Record Linkage method we apply a three-party protocol, with two sites collecting individual data and an independent trusted linkage center as the third partner. Our method consists of three main steps: pre-processing, encryption and probabilistic record linkage. Data pre-processing and encryption are done at the sites by local personnel. To guarantee similar quality and format of variables and identical encryption procedure at each site, the linkage center generates semi-automated pre-processing and encryption templates. To retrieve information (i.e. data structure) for the creation of templates without ever accessing plain person identifiable information, we introduced a novel method of data masking. Sensitive string variables are encrypted using Bloom filters, which enables calculation of similarity coefficients. For date variables, we developed special encryption procedures to handle the most common date errors. The linkage center performs probabilistic record linkage with encrypted person identifiable information and plain non-sensitive variables. RESULTS: In this paper we describe step by step how to link existing health-related data using encryption methods to preserve privacy of persons in the study. CONCLUSION: Privacy Preserving Probabilistic Record linkage expands record linkage facilities in settings where a unique identifier is unavailable and/or regulations restrict access to the non-unique person identifiable information needed to link existing health-related data sets. Automated pre-processing and encryption fully protect sensitive information ensuring participant confidentiality. This method is suitable not just for epidemiological research but also for any setting with similar challenges. PMID- 26024887 TI - Development and performance evaluation of a novel immunofluorescence chromatographic assay for histidine-rich protein 2 of Plasmodium falciparum. AB - BACKGROUND: The low sensitivity and specificity of Plasmodium falciparum diagnostic tests pose a serious health threat to people living in endemic areas. The objective of the study was to develop a rapid assay for the detection of histidine-rich protein 2 (HRP2) of P. falciparum in whole blood by immunofluorescence chromatographic technology. METHODS: A total of 1163 positive and negative blood samples were screened. The double-antibody sandwich assay was used to establish the kit and its performance was evaluated for sensitivity, specificity, accuracy, precision, stability, and clinical effectiveness. RESULTS: The cut-off level of detection of the kit was 25 parasites/MUl. Common interfering substances in human blood specimens, such as bilirubin, triglyceride and cholesterol had no significant effect on HRP2 antigen detection. The precision of the kit was run with different concentration of standard calibrators and the values were less than 10 %. The performance of this diagnostic kit in the detection of the calibrators has shown that a shelf life of about 12 months gives a more reliable result. Among clinical samples tested, the HRP2 test kit and the reference products had good coincidence rate in a parallel experiment and this test kit had a more sensitive detecting level to the target protein than the reference kits used in this study. The specificity and sensitivity for this test were 99.6 % (800/803) and 99.7 % (1160/1163), respectively. CONCLUSIONS: A novel HRP2 immunofluorescence detection method was developed in this study. Overall performance evaluation indicated that the kit has a rapid, high sensitivity and on-spot method for detecting P. falciparum. PMID- 26024888 TI - Fast and reliable detection of toxic Crotalaria spectabilis Roth. in Thunbergia laurifolia Lindl. herbal products using DNA barcoding coupled with HRM analysis. AB - BACKGROUND: Nowadays, medicinal plants are used as a popular alternative to synthetic drugs. Many medicinal plant products have now been commercialized throughout various markets. These products are commonly sold in processed or modified forms such as powders, dried material and capsules, making it almost impossible to accurately identify the constituent species. The herbal plant known as 'Rang Chuet' in Thai has been widely used as remedies for various ailments. However, two medicinal plants species, Thunbergia laurifolia and Crotalaria spectabilis share this name. Duo to the similarity in nomenclature, the commercial products labeled as 'Rang Chuet' could be any of them. Recently, the evidence of hepatotoxic effects linked to use of C. spectabilis were reported and is now seriously concern. There is a need to find an approach that could help with species identification of these herbal products to ensure the safety and efficacy of the herbal drug. METHODS: Here DNA barcoding was used in combination with High Resolution Melting analysis (Bar-HRM) to authenticate T. laurifolia species. Four DNA barcodes including matK, rbcL, rpoC and trnL were selected for use in primers design for HRM analysis to produce standard melting profiles of the selected species. Commercial products labeled as 'Rang Chuet' were purchased from Thai markets and authentication by HRM analyses. RESULTS: Melting data from the HRM assay using the designed primers showed that the two 'Rang Chuet' species could easily be distinguished from each other. The melting profiles of the all four region amplicons of each species are clearly separated in all three replicates. The method was then applied to authenticate products in powdered form. HRM curves of all ten test samples indicated that three of the tested products did not only contain the T. laurifolia species. CONCLUSION: The herbal drugs derived from different plants must be distinguished from each other even they share the same vernacular name. The Bar-HRM method developed here proved useful in the identification and authentication of herbal species in processed samples. In the future, species authentication through Bar-HRM could be used to promote consumer trust, as well as raising the quality of herbal products. PMID- 26024890 TI - Parental smoking puts 400,000 UK children into poverty, researchers say. PMID- 26024889 TI - Genome-wide association study of platelet aggregation in African Americans. AB - BACKGROUND: We have previously shown that platelet aggregation has higher heritability in African Americans than European Americans. However, a genome-wide association study (GWAS) of platelet aggregation in African Americans has not been reported. We measured platelet aggregation in response to arachidonic acid, ADP, collagen, or epinephrine by optical aggregometry. The discovery cohort was 825 African Americans from the GeneSTAR study. Two replication cohorts were used: 119 African Americans from the Platelet Genes and Physiology Study and 1221 European Americans from GeneSTAR. Genotyping was conducted with Illumina 1 M arrays. For each cohort, age- and sex-adjusted linear mixed models were used to test for association between each SNP and each phenotype under an additive model. RESULTS: Six SNPs were significantly associated with platelet aggregation (P<5*10(-8)) in the discovery sample. Of these, three SNPs in three different loci were confirmed: 1) rs12041331, in PEAR1 (platelet endothelial aggregation receptor 1), replicated in both African and European Americans for collagen- and epinephrine-induced aggregation, and in European Americans for ADP-induced aggregation; 2) rs11202221, in BMPR1A (bone morphogenetic protein receptor type1A), replicated in African Americans for ADP-induced aggregation; and 3) rs6566765 replicated in European Americans for ADP-induced aggregation. The rs11202221 and rs6566765 associations with agonist-induced platelet aggregation are novel. CONCLUSIONS: In this first GWAS of agonist-induced platelet aggregation in African Americans, we discovered and replicated, novel associations of two variants with ADP-induced aggregation, and confirmed the association of a PEAR1 variant with multi-agonist-induced aggregation. Further study of these genes may provide novel insights into platelet biology. PMID- 26024891 TI - The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension. AB - The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKalpha is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKalpha in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKalpha antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKalpha was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the alpha isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease. PMID- 26024892 TI - Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. AB - This study was designed to determine whether cyclic stretch induces a persistent pulmonary hypertension of the newborn (PPHN) phenotype of increased NADPH oxidase (Nox) 4 signaling in control pulmonary artery smooth muscle cells (PASMC), and to identify the signal transduction molecules involved. To achieve this, PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and PASMC were isolated from control (twin) and PPHN lambs. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h. Stretch-induced Nox4 expression was attenuated by inhibition of mitochondrial complex III and NF-kappaB, and stretch-induced protein thiol oxidation was attenuated by Nox4 small interfering RNA and complex III inhibition. NF-kappaB activity was increased by stretch in a complex III dependent fashion, and stretch-induced cyclin D1 expression was attenuated by complex III inhibition and Nox4 small interfering RNA. This is the first study to show that cyclic stretch increases Nox4 expression via mitochondrial complex III induced activation of NF-kappaB in fetal PASMC, resulting in ROS signaling and increased cyclin D1 expression. Targeting these signaling molecules may attenuate pulmonary vascular remodeling associated with PPHN. PMID- 26024893 TI - Longitudinal in vivo microcomputed tomography of mouse lungs: No evidence for radiotoxicity. AB - Before microcomputed tomography (micro-CT) can be exploited to its full potential for longitudinal monitoring of transgenic and experimental mouse models of lung diseases, radiotoxic side effects such as inflammation or fibrosis must be considered. We evaluated dose and potential radiotoxicity to the lungs for long term respiratory-gated high-resolution micro-CT protocols. Free-breathing C57Bl/6 mice underwent four different retrospectively respiratory gated micro-CT imaging schedules of repeated scans during 5 or 12 wk, followed by ex vivo micro-CT and detailed histological and biochemical assessment of lung damage. Radiation exposure, dose, and absorbed dose were determined by ionization chamber, thermoluminescent dosimeter measurements and Monte Carlo calculations. Despite the relatively large radiation dose delivered per micro-CT acquisition, mice did not show any signs of radiation-induced lung damage or fibrosis when scanned weekly during 5 and up to 12 wk. Doubling the scanning frequency and once tripling the radiation dose as to mimic the instant repetition of a failed scan also stayed without detectable toxicity after 5 wk of scanning. Histological analyses confirmed the absence of radiotoxic damage to the lungs, thereby demonstrating that long-term monitoring of mouse lungs using high-resolution micro-CT is safe. This opens perspectives for longitudinal monitoring of (transgenic) mouse models of lung diseases and therapeutic response on an individual basis with high spatial and temporal resolution, without concerns for radiation toxicity that could potentially influence the readout of micro-CT derived lung biomarkers. This work further supports the introduction of micro-CT for routine use in the preclinical pulmonary research field where postmortem histological approaches are still the gold standard. PMID- 26024895 TI - Il-17A contributes to maintenance of pulmonary homeostasis in a murine model of cigarette smoke-induced emphysema. AB - Smoking is the main risk factor for the development of the chronic obstructive pulmonary disease (COPD) in Western countries. Recent studies suggest that IL-17A and Th17 cells play a role in the pathogenesis of COPD. We used a murine model of chronic cigarette smoke (CS) exposure to explore the contribution of IL-17A to CS induced lung damage and loss of pulmonary function. Histology and morphometry showed that IL-17A deficiency spontaneously resulted in a loss of lung structure under basal conditions. Even though inflammatory markers [IL-1beta and granulocyte colony-stimulating factor (G-CSF)] were decreased in IL-17A-deficient mice (IL-17A(-/-)) exposed to CS compared with wild-type (WT) mice, IL-17A(-/-) mice were per se not protected from CS-induced emphysematous disease. Assessment of pulmonary function showed that IL-17A(-/-) mice were partially protected from CS-induced changes in total lung capacity. However, the respiratory elastance decreased and respiratory compliance increased in IL-17A(-/-) mice after exposure to CS. Morphometry revealed destruction of lung tissue in CS-exposed IL-17A(-/-) mice similar to WT mice. The expression of elastin was decreased in air-exposed IL-17A(-/-) mice and in CS-exposed WT and IL-17A(-/-) mice. Thus, in the present model of sterile CS-exposure, IL-17A contributes to normal lung homeostasis and does not mediate CS-induced loss of lung structure and pulmonary function. PMID- 26024894 TI - Airway epithelial cell PPARgamma modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice. AB - Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-gamma activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARgamma activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARgamma activation-dependent fashion. The ability of PPARgamma to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE) mediated transactivation activity but was correlated with PPARgamma-mediated transrepression of NF-kappaB activity. Pharmacological or genetic activation of PPARgamma activity abrogated CS-dependent induction of NF-kappaB activity. Regulation of NF-kappaB activity involved direct PPARgamma-NF-kappaB interaction and PPARgamma-mediated effects on IKK activation, IkappaBalpha degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-kappaB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation. PMID- 26024896 TI - Analytical investigation of bilayer lipid biosensor based on graphene. AB - Graphene is another allotrope of carbon with two-dimensional monolayer honeycomb. Owing to its special characteristics including electrical, physical and optical properties, graphene is known as a more suitable candidate compared to other materials to be used in the sensor application. It is possible, moreover, to use biosensor by using electrolyte-gated field effect transistor based on graphene (GFET) to identify the alterations in charged lipid membrane properties. The current article aims to show how thickness and charges of a membrane electric can result in a monolayer graphene-based GFET while the emphasis is on the conductance variation. It is proposed that the thickness and electric charge of the lipid bilayer (LLP and QLP) are functions of carrier density, and to find the equation relating these suitable control parameters are introduced. Artificial neural network algorithm as well as support vector regression has also been incorporated to obtain other models for conductance characteristic. The results comparison between analytical models, artificial neural network and support vector regression with the experimental data extracted from previous work show an acceptable agreement. PMID- 26024897 TI - A rare complication of Epistats. AB - We report a 53-year-old man who sustained severe facial and base of skull fractures. At the scene of his accident he had Epistats (Medtronic Sofamor Danek, Memphis, TN, USA) placed for control of his severe nasal haemorrhage, subsequently resulting in the migration of one Epistat into the anterior cranial fossa. There are numerous reports of inadvertent intracranial placement of medical equipment, predominantly in association with complex facial and skull trauma. Other factors that can predispose to aberrant location include previous anterior cranial base surgery and lesions affecting structures in that area. PMID- 26024898 TI - Natalizumab to fingolimod: Questions answered, unanswered, and unasked. PMID- 26024899 TI - Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. AB - OBJECTIVE: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod. METHODS: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24. RESULTS: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6 2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred. CONCLUSIONS: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods. PMID- 26024900 TI - Clinical evaluation of an endorectal immobilization system for use in prostate hypofractionated Stereotactic Ablative Body Radiotherapy (SABR). AB - BACKGROUND: The objective of this study was to evaluate a novel prostate endorectal immobilization system (EIS) for improving the delivery of hypofractionated Stereotactic Ablative Body Radiotherapy (SABR) for prostate cancer. METHODS: Twenty patients (n = 20) with low- or intermediate-risk prostate cancer (T1-T2b, Gleason Score < 7, PSA <= 20 ng/mL), were treated with an EIS in place using Volumetric Modulated Arc Therapy (VMAT), to a prescription dose of 26 Gy delivered in 2 fractions once per week; the intent of the institutional clinical trial was an attempt to replicate brachytherapy-like dosimetry using SABR. EBT3 radiochromic film embedded within the EIS was used as a quality assurance measure of the delivered dose; additionally, prostate intrafraction motion captured using pre- and post-treatment conebeam computed tomography (CBCT) scans was evaluated. Treatment plans were generated for patients with- and without the EIS to evaluate its effects on target and rectal dosimetry. RESULTS: None of the observed 3-dimensional prostate displacements were >= 3 mm over the elapsed treatment time. A Gamma passing rate of 95.64 +/- 4.28 % was observed between planned and delivered dose profiles on EBT3 film analysis in the low-dose region. No statistically significant differences between treatment plans with- and without-EIS were observed for rectal, bladder, clinical target volume (CTV), and PTV contours (p = 0.477, 0.484, 0.487, and 0.487, respectively). A mean rectal V80% of 1.07 cc was achieved for plans using the EIS. CONCLUSIONS: The EIS enables the safe delivery of brachytherapy-like SABR plans to the prostate while having minimal impact on treatment planning and rectal dosimetry. Consistent and reproducible immobilization of the prostate is possible throughout the duration of these treatments using such a device. PMID- 26024901 TI - Evolution of Chemical Diversity in Echinocandin Lipopeptide Antifungal Metabolites. AB - The echinocandins are a class of antifungal drugs that includes caspofungin, micafungin, and anidulafungin. Gene clusters encoding most of the structural complexity of the echinocandins provided a framework for hypotheses about the evolutionary history and chemical logic of echinocandin biosynthesis. Gene orthologs among echinocandin-producing fungi were identified. Pathway genes, including the nonribosomal peptide synthetases (NRPSs), were analyzed phylogenetically to address the hypothesis that these pathways represent descent from a common ancestor. The clusters share cooperative gene contents and linkages among the different strains. Individual pathway genes analyzed in the context of similar genes formed unique echinocandin-exclusive phylogenetic lineages. The echinocandin NRPSs, along with the NRPS from the inp gene cluster in Aspergillus nidulans and its orthologs, comprise a novel lineage among fungal NRPSs. NRPS adenylation domains from different species exhibited a one-to-one correspondence between modules and amino acid specificity that is consistent with models of tandem duplication and subfunctionalization. Pathway gene trees and Ascomycota phylogenies are congruent and consistent with the hypothesis that the echinocandin gene clusters have a common origin. The disjunct Eurotiomycete Leotiomycete distribution appears to be consistent with a scenario of vertical descent accompanied by incomplete lineage sorting and loss of the clusters from most lineages of the Ascomycota. We present evidence for a single evolutionary origin of the echinocandin family of gene clusters and a progression of structural diversification in two fungal classes that diverged approximately 290 to 390 million years ago. Lineage-specific gene cluster evolution driven by selection of new chemotypes contributed to diversification of the molecular functionalities. PMID- 26024902 TI - Rgc2 Regulator of Glycerol Channel Fps1 Functions as a Homo- and Heterodimer with Rgc1. AB - The plasma membrane aquaglyceroporin Fps1 is responsible for glycerol transport in yeast in response to changes in extracellular osmolarity. Fps1 functions as a homotetramer, and control of its channel activity in response to hyperosmotic shock involves a redundant pair of fungus-specific regulators, Rgc1 and Rgc2 (regulators of the glycerol channel), and the mitogen-activatd protein kinase (MAPK) Hog1 (high-osmolarity glycerol response). Rgc1 and Rgc2 maintain Fps1 in an open-channel state by binding to its C-terminal cytoplasmic domain. Phosphorylation of Rgc1 and Rgc2 by Hog1 induces their eviction from Fps1 and consequent channel closure. In the absence of Fps1 channel function, cells experience chronic cell wall stress, which may be exploited for antifungal drug development. We show here that Rgc1 and Rgc2 form homodimers and heterodimers with each other and that dimer formation of Rgc2 is mediated by its N-terminal domain. Mutations that prevent Rgc2 dimerization block its ability to open Fps1. Therefore, the Rgc-Rgc dimer interface might be an attractive drug target. PMID- 26024903 TI - Candida albicans Kinesin Kar3 Depends on a Cik1-Like Regulatory Partner Protein for Its Roles in Mating, Cell Morphogenesis, and Bipolar Spindle Formation. AB - Candida albicans is a major fungal pathogen whose virulence is associated with its ability to transition from a budding yeast form to invasive hyphal filaments. The kinesin-14 family member CaKar3 is required for transition between these morphological states, as well as for mitotic progression and karyogamy. While kinesin-14 proteins are ubiquitous, CaKar3 homologs in hemiascomycete fungi are unique because they form heterodimers with noncatalytic kinesin-like proteins. Thus, CaKar3-based motors may represent a novel antifungal drug target. We have identified and examined the roles of a kinesin-like regulator of CaKar3. We show that orf19.306 (dubbed CaCIK1) encodes a protein that forms a heterodimer with CaKar3, localizes CaKar3 to spindle pole bodies, and can bind microtubules and influence CaKar3 mechanochemistry despite lacking an ATPase activity of its own. Similar to CaKar3 depletion, loss of CaCik1 results in cell cycle arrest, filamentation defects, and an inability to undergo karyogamy. Furthermore, an examination of the spindle structure in cells lacking either of these proteins shows that a large proportion have a monopolar spindle or two dissociated half spindles, a phenotype unique to the C. albicans kinesin-14 homolog. These findings provide new insights into mitotic spindle structure and kinesin motor function in C. albicans and identify a potentially vulnerable target for antifungal drug development. PMID- 26024904 TI - Lipid Biosynthetic Genes Affect Candida albicans Extracellular Vesicle Morphology, Cargo, and Immunostimulatory Properties. AB - Microbial secretion is integral for regulating cell homeostasis as well as releasing virulence factors during infection. The genes encoding phosphatidylserine synthase (CHO1) and phosphatidylserine decarboxylase (PSD1 and PSD2) are Candida albicans genes involved in phospholipid biosynthesis, and mutations in these genes affect mitochondrial function, cell wall thickness, and virulence in mice. We tested the roles of these genes in several agar-based secretion assays and observed that the cho1Delta/Delta and psd1Delta/Delta psd2Delta/Delta strains manifested less protease and phospholipase activity. Since extracellular vesicles (EVs) are surrounded by a lipid membrane, we investigated the effects of these mutations on EV structure, composition, and biological activity. The cho1Delta/Delta mutant releases EVs comparable in size to wild-type EVs, but EVs from the psd1Delta/Delta psd2Delta/Delta strain are much larger than those from the wild type, including a population of >100-nm EVs not observed in the EVs from the wild type. Proteomic analysis revealed that EVs from both mutants had a significantly different protein cargo than that of EVs from the wild type. EVs were tested for their ability to activate NF-kappaB in bone marrow-derived macrophage cells. While wild-type and psd1Delta/Delta psd2Delta/Delta mutant-derived EVs activated NF-kappaB, the cho1Delta/Delta mutant-derived EV did not. These studies indicate that the presence and absence of these C. albicans genes have qualitative and quantitative effects on EV size, composition, and immunostimulatory phenotypes that highlight a complex interplay between lipid metabolism and vesicle production. PMID- 26024905 TI - Presence of anti-Toxocara canis antibodies and risk factors in children from the Amecameca and Chalco regions of Mexico. AB - BACKGROUND: Toxocariasis is a zoonotic disease that poses a threat to public health worldwide. This disease primarily affects children and is caused by the presence in the digestive tract of a common roundworm of dogs, Toxocara canis, or cats, Toxocara cati. Toxocara is responsible for the presentation of various syndromes in humans depending on the affected organs. METHODS: In this study, the prevalence of anti-T. canis antibodies was investigated in children aged 3-16 years from semirural populations in the municipalities of Amecameca and Chalco in Mexico. An ELISA was used to determine the presence of anti-T. canis antibodies in blood samples. RESULTS: Of the 183 sera obtained for this study, 22 were positive for anti-T. canis antibodies (12.02%). Of these, 6.50% were from males and 5.4% were from females. Risk factors were investigated and it was found that living near a cattle operation had a statistically significant association with (Chi(2) = 5.51 and p = 0.01) and was a risk factor for (OR = 4.25, p = 0.02) seropositivity to T. canis. Keeping dogs with short hair (Chi(2) = 3.24 and p = 0.07) showed a tendency toward seropositivity for T. canis, as did the habit of sleeping with pets (Chi(2) = 3.46 and p = 0.06). CONCLUSIONS: Seropositivity to T. canis was confirmed in children in the Amecameca and Chalco regions of Mexico and the risk factors were identified. These findings provide important insight into the prevalence and spread of this zoonotic parasite. PMID- 26024906 TI - Factors associated with anti-phenolic glycolipid-I seropositivity among the household contacts of leprosy cases. AB - BACKGROUND: The diagnosis of leprosy is based on clinical symptoms of the disease, which may not be sufficient to ensure early diagnosis. The development of effective tools for the early detection of infection, such as rapid tests that can be applied by non-specialists for early-stage leprosy identification, has been considered a research priority and may contribute to overcoming the complications associated with late diagnosis. The aim of this study was to analyze the factors associated with anti-phenolic glycolipid-I (PGL-I) seropositivity among the household contacts of leprosy cases. METHODS: A cross sectional study of individuals from the northeastern municipalities of the state of Minas Gerais, Brazil, was performed. Anti-PGL-I seropositivity was evaluated by assessing specific antibody production using the ML Flow test. A Poisson regression with a robust error variance was used to evaluate the relationship between anti-PGL-I seropositivity and the independent variables investigated. RESULTS: The overall anti-PGL-I seropositivity was 13.5 %, and among the contacts of leprosy cases that were classified as paucibacillary or multibacillary, it was 8.4 and 17.3 %, respectively. The factors associated with the variation of anti PGL-I seropositivity among the study population were the presence of signs suggestive of leprosy (PR = 3.68; 95 % CI: 1.56-8.71), the operational leprosy classification (PR = 2.17; 95 % CI: 1.22-3.86) and grade 1 (PR = 1.83; 95 % CI: 1.02-3.26) or grade 2 disability (PR = 2.42; 95 % CI: 1.02-5.47) of the index leprosy case. CONCLUSIONS: The presence of signs suggestive of leprosy and the operational classification of leprosy cases were associated with anti-PGL-I seropositivity. The serological tests available for leprosy are not considered to be diagnostic tests but can be used as auxiliary assessments in combination with clinical parameters to identify exposed individuals at high risk of developing leprosy and those exhibiting the initial stages of this disease. PMID- 26024907 TI - Vaccination persuasion online: a qualitative study of two provaccine and two vaccine-skeptical websites. AB - BACKGROUND: Current concerns about vaccination resistance often cite the Internet as a source of vaccine controversy. Most academic studies of vaccine resistance online use quantitative methods to describe misinformation on vaccine-skeptical websites. Findings from these studies are useful for categorizing the generic features of these websites, but they do not provide insights into why these websites successfully persuade their viewers. To date, there have been few attempts to understand, qualitatively, the persuasive features of provaccine or vaccine-skeptical websites. OBJECTIVE: The purpose of this research was to examine the persuasive features of provaccine and vaccine-skeptical websites. The qualitative analysis was conducted to generate hypotheses concerning what features of these websites are persuasive to people seeking information about vaccination and vaccine-related practices. METHODS: This study employed a fully qualitative case study methodology that used the anthropological method of thick description to detail and carefully review the rhetorical features of 1 provaccine government website, 1 provaccine hospital website, 1 vaccine-skeptical information website focused on general vaccine safety, and 1 vaccine-skeptical website focused on a specific vaccine. The data gathered were organized into 5 domains: website ownership, visual and textual content, user experience, hyperlinking, and social interactivity. RESULTS: The study found that the 2 provaccine websites analyzed functioned as encyclopedias of vaccine information. Both of the websites had relatively small digital ecologies because they only linked to government websites or websites that endorsed vaccination and evidence based medicine. Neither of these websites offered visitors interactive features or made extensive use of the affordances of Web 2.0. The study also found that the 2 vaccine-skeptical websites had larger digital ecologies because they linked to a variety of vaccine-related websites, including government websites. They leveraged the affordances of Web 2.0 with their interactive features and digital media. CONCLUSIONS: By employing a rhetorical framework, this study found that the provaccine websites analyzed concentrate on the accurate transmission of evidence-based scientific research about vaccines and government-endorsed vaccination-related practices, whereas the vaccine-skeptical websites focus on creating communities of people affected by vaccines and vaccine-related practices. From this personal framework, these websites then challenge the information presented in scientific literature and government documents. At the same time, the vaccine-skeptical websites in this study are repositories of vaccine information and vaccination-related resources. Future studies on vaccination and the Internet should take into consideration the rhetorical features of provaccine and vaccine-skeptical websites and further investigate the influence of Web 2.0 community-building features on people seeking information about vaccine-related practices. PMID- 26024908 TI - Editorial Commentary: Critically Ill Patients With Clostridium difficile Infection: Are 2 Antibiotics Better Than One? PMID- 26024909 TI - The Addition of Intravenous Metronidazole to Oral Vancomycin is Associated With Improved Mortality in Critically Ill Patients With Clostridium difficile Infection. AB - BACKGROUND: The optimal therapy for critically ill patients with Clostridium difficile infection (CDI) is not known. We aimed to evaluate mortality among critically ill patients with CDI who received oral vancomycin (monotherapy) vs oral vancomycin with intravenous (IV) metronidazole (combination therapy). METHODS: A single-center, retrospective, observational, comparative study was performed. Patients with a positive C. difficile assay who received oral vancomycin while bedded in an intensive care unit (ICU) between June 2007 and September 2012 were evaluated. Patients meeting >=3 of the following criteria were included: albumin <2.5 g/dL, heart rate >90 bpm, mean arterial pressure <60 mmHg, white blood cell count >=15 000 cells/mL, age >60 years, serum creatinine >=1.5 times baseline, or temperature >=100.4 degrees F. Patients in the combination therapy group received IV metronidazole within 48 hours after initiating vancomycin. Patients <18 years or with unrelated gastrointestinal disease were excluded. The primary outcome was in-hospital mortality. Patients were matched using Acute Physiology and Chronic Health Evaluation II scores. RESULTS: Eighty-eight patients were included, 44 in each group. Patient characteristics were similar although more patients in the combination group had renal disease. Mortality was 36.4% and 15.9% in the monotherapy and combination therapy groups, respectively (P = .03). Secondary outcomes of clinical success, length of stay, and length of ICU stay did not differ between groups. CONCLUSIONS: Our data are supportive of the use of combination therapy with oral vancomycin and IV metronidazole in critically ill patients with CDI. However, prospective, randomized studies are required to define optimal treatment regimens in this limited population of CDI patients. PMID- 26024910 TI - The Mayo Clinic Arizona Spasmodic Dysphonia Experience: A Demographic Analysis of 718 Patients. AB - OBJECTIVE: Analyze demographic data collected over a 25-year experience of 718 patients with spasmodic dysphonia (SD) who have been treated with botulinum toxin A (BoNT-A) and compare our data with previously published studies. METHODS: Seven hundred eighteen patients with SD were treated with 6621 BoNT-A injections at Mayo Clinic Arizona between 1989 and 2014. All patients were treated by the same physician team. Background demographic data for each patient were recorded. RESULTS: Of 718 patients, 557 patients were female (77.6%). Six hundred sixty of 718 (91.8%) patients had adductor SD (AdSD), and 58 of 718 (8.1%) patients had abductor SD (AbSD). Average age of onset was 51 years. Of 718 patients, 378 (52.6%) had vocal tremor (VT); VT was present in 54.4% of AdSD patients and 32.1% of AbSD patients. Thirty-seven of 718 (5.2%) patients had other dystonias, including cervical dystonia (2.3%), blepharospasm (1.4%), limb dystonia (1.1%), and oromandibular dystonia (0.3%). A positive family history of SD was present in only 6 of 718 patients (0.8%) and of other dystonias in 11 of 718 patients (1.5%). CONCLUSIONS: Spasmodic dysphonia is a chronic and potentially disabling focal laryngeal dystonia. The Mayo Clinic Arizona SD experience compares to prior reports and reveals a female preponderance, onset in middle age, infrequent hereditary pattern, high co-occurrence of VT, and low co-occurrence of other dystonias. PMID- 26024911 TI - Average Ambulatory Measures of Sound Pressure Level, Fundamental Frequency, and Vocal Dose Do Not Differ Between Adult Females With Phonotraumatic Lesions and Matched Control Subjects. AB - OBJECTIVES: Clinical management of phonotraumatic vocal fold lesions (nodules, polyps) is based largely on assumptions that abnormalities in habitual levels of sound pressure level (SPL), fundamental frequency (f0), and/or amount of voice use play a major role in lesion development and chronic persistence. This study used ambulatory voice monitoring to evaluate if significant differences in voice use exist between patients with phonotraumatic lesions and normal matched controls. METHODS: Subjects were 70 adult females: 35 with vocal fold nodules or polyps and 35 age-, sex-, and occupation-matched normal individuals. Weeklong summary statistics of voice use were computed from anterior neck surface acceleration recorded using a smartphone-based ambulatory voice monitor. RESULTS: Paired t tests and Kolmogorov-Smirnov tests resulted in no statistically significant differences between patients and matched controls regarding average measures of SPL, f0, vocal dose measures, and voicing/voice rest periods. Paired t tests comparing f0 variability between the groups resulted in statistically significant differences with moderate effect sizes. CONCLUSIONS: Individuals with phonotraumatic lesions did not exhibit differences in average ambulatory measures of vocal behavior when compared with matched controls. More refined characterizations of underlying phonatory mechanisms and other potentially contributing causes are warranted to better understand risk factors associated with phonotraumatic lesions. PMID- 26024912 TI - Genome-wide association study on legendre random regression coefficients for the growth and feed intake trajectory on Duroc Boars. AB - BACKGROUND: Feed intake and growth are economically important traits in swine production. Previous genome wide association studies (GWAS) have utilized average daily gain or daily feed intake to identify regions that impact growth and feed intake across time. The use of longitudinal models in GWAS studies, such as random regression, allows for SNPs having a heterogeneous effect across the trajectory to be characterized. The objective of this study is therefore to conduct a single step GWAS (ssGWAS) on the animal polynomial coefficients for feed intake and growth. RESULTS: Corrected daily feed intake (DFI Adj) and average daily weight measurements (DBW Avg) on 8981 (n=525,240 observations) and 5643 (n=283,607 observations) animals were utilized in a random regression model using Legendre polynomials (order=2) and a relationship matrix that included genotyped and un-genotyped animals. A ssGWAS was conducted on the animal polynomials coefficients (intercept, linear and quadratic) for animals with genotypes (DFIAdj: n=855; DBWAvg: n=590). Regions were characterized based on the variance of 10-SNP sliding windows GEBV (WGEBV). A bootstrap analysis (n=1000) was conducted to declare significance. Heritability estimates for the traits trajectory ranged from 0.34-0.52 to 0.07-0.23 for DBWAvg and DFIAdj, respectively. Genetic correlations across age classes were large and positive for both DBWAvg and DFIAdj, albeit age classes at the beginning had a small to moderate genetic correlation with age classes towards the end of the trajectory for both traits. The WGEBV variance explained by significant regions (P<0.001) for each polynomial coefficient ranged from 0.2-0.9 to 0.3-1.01% for DBWAvg and DFIAdj, respectively. The WGEBV variance explained by significant regions for the trajectory was 1.54 and 1.95% for DBWAvg and DFIAdj. Both traits identified candidate genes with functions related to metabolite and energy homeostasis, glucose and insulin signaling and behavior. CONCLUSIONS: We have identified regions of the genome that have an impact on the intercept, linear and quadratic terms for DBWAvg and DFIAdj. These results provide preliminary evidence that individual growth and feed intake trajectories are impacted by different regions of the genome at different times. PMID- 26024913 TI - Evolution of V genes from the TRV loci of mammals. AB - Information concerning the evolution of T lymphocyte receptors (TCR) can be deciphered from that part of the molecule that recognizes antigen presented by major histocompatibility complex (MHC), namely the variable (V) regions. The genes that code for these variable regions are found within the TCR loci. Here, we describe a study of the evolutionary origin of V genes that code for the alpha and beta chains of the TCR loci of mammals. In particular, we demonstrate that most of the 35 TRAV and 25 TRBV conserved genes found in Primates are also found in other Eutheria, while in Marsupials, Monotremes, and Reptiles, these genes diversified in a different manner. We also show that in mammals, all TRAV genes are derived from five ancestral genes, while all TRBV genes originate from four such genes. In Reptiles, the five TRAV and three out of the four TRBV ancestral genes exist, as well as other V genes not found in mammals. We also studied the TRGV and TRDV loci from all mammals, and we show a relationship of the TRDV to the TRAV locus throughout evolutionary time. PMID- 26024914 TI - Many UK patients with gonorrhoea are given outdated antibiotics. PMID- 26024916 TI - Scientific journals and conflict of interest disclosure: what progress has been made? AB - The article addresses the failure of the scientific community to create an effective mechanism to protect the integrity of the scientific literature from improper influence by vested interests. The seriousness of this threat is increasingly recognized. Scientists willing to distort scientific research to serve vested interests receive millions of dollars for their services. Organizations such as the International Committee of Medical Journal Editors, the World Association of Medical Editors and the Committee on Publication Ethics (COPE) have launched initiatives to establish international standards for Conflict of Interest (COI) disclosure. COPE requires its 7,000 member journals to comply with its Code of Conduct for Journal Editors. While these initiatives are encouraging, they are internal educational endeavours only. Five examples are given showing failure of COPE member journals to comply with COPE's Code of Conduct. While COPE offers a complaint process, it involves only discussion and voluntary compliance. COPE neither polices nor enforces its Code. Instead of the current feeble, un-resourced process, which delivers neither transparency nor accountability, the article proposes the creation of a mechanism that will employ specific, effective measures to address contraventions of COI disclosure requirements. PMID- 26024915 TI - BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro. AB - BACKGROUND: BRCC3 has been found to be aberrantly expressed in breast tumors and involved in DNA damage response. The contribution of BRCC3 to nasopharyngeal carcinoma prognosis and radiosensitivity is still unclear. METHODS: Immunohistochemical analysis of BRCC3 was carried out in 100 nasopharyngeal carcinoma tissues, and the protein level was correlated to patient survival. BRCC3 expression of nasopharyngeal carcinoma cell lines was determined by Western blotting and real-time PCR. Additionally, the effects of BRCC3 knockdown on nasopharyngeal carcinoma cell clongenic survival, DNA damage repair, and cell cycle distribution after irradiation was assessed. RESULTS: The BRCC3 protein level was inversely correlated with nasopharyngeal carcinoma patient overall survival (P < 0.001) and 3-year loco-regional relapse-free survival (P = 0.034). Multivariate analysis demonstrated that BRCC3 expression was an independent prognostic factor (P = 0.010). The expression of BRCC3 was much higher in radioresistant nasopharyngeal carcinoma cells than in radiosensitive cells. Knockdown of BRCC3 increased the cell survival fraction, attenuated DNA damage repair and resulted in G2/M cell cycle arrest in radioresistant NPC cells. CONCLUSIONS: High BRCC3 expression in nasopharyngeal carcinoma patients is associated with poor survival. BRCC3 knockdown could abate the radioresistance in nasopharyngeal carcinoma cells. These findings suggest the utility of BRCC3 as a prognostic biomarker and novel target for nasopharyngeal carcinoma. PMID- 26024917 TI - An interpretive study of food, snack and beverage advertisements in rural and urban El Salvador. AB - BACKGROUND: Globalization and increased marketing of non-nutritious foods and beverages are driving a nutrition transition in developing countries, adversely affecting the health of vulnerable populations. This is a visual interpretive study of food, snack, and beverage advertisements (ads) in rural and urban El Salvador to discern the strategies and messages used to promote consumption of highly processed, commercialized products. METHODS: Digital photographs of billboard and wall advertisements recorded a convenience sample of 100 advertisements, including 53 from rural areas and 47 from urban areas in El Salvador. Advertisements were coded for location, type of product, visual details, placement and context. Qualitative methods were used to identify common themes used to appeal to consumers. RESULTS: Advertisements depicted "modern" fast foods, processed snacks and sugary beverages. Overall, the most prominent themes were: Cheap Price, Fast, Large Size, and Modern. Other themes used frequently in combination with these were Refreshment, Sports/Nationalism, Sex and Gender Roles, Fun/Happy Feelings, Family, Friendship and Community, and Health. In rural areas, beverage and snack food ads with the themes of cheap price, fast, and large size tended to predominate; in urban areas, ads for fast food restaurants and the theme of modernity tended to be more prominent. CONCLUSIONS: The advertisements represented a pervasive bombardment of the public with both explicit and subliminal messages to increase consumerism and shift dietary patterns to processed foods and beverages that are low in micronutrients and high in carbohydrates, sugar, fat and salt--dietary changes that are increasing rates of child and adult diseases including tooth decay, obesity, cardiovascular disease and cancer. Global food and beverage industries must be held accountable for the adverse public health effects of their products, especially in low-middle income countries where there are fewer resources to prevent and treat the health consequences. In addition, public health and governmental authorities should learn from the advertising strategies to promote social marketing of public health messages, and enact and enforce regulations to limit the advertisement and sale of unhealthy products, particularly for children in and around schools. This will create healthier social norms and environments for the entire population. PMID- 26024918 TI - State of the art of leadless pacing. AB - Despite undisputable benefits, conventional pacemaker therapy is associated with specific complications related to the subcutaneous device and the transvenous leads. Recently, two miniaturized leadless pacemakers, NanostimTM (St. Jude Medical) and MicraTM (Medtronic), which can be completely implanted inside the right ventricle using steerable delivery systems, entered clinical application. The WiCSTM-cardiac resynchronisation therapy (CRT) system (wireless cardiac stimulation for CRT, EBR Systems) delivers leadless left ventricular endocardial stimulation for cardiac resynchronization. In addition to obvious cosmetic benefits, leadless pacing systems may have the potential to overcome some complications of conventional pacing. However, acute and long-term complications still remains to be determined, as well as the feasibility of device explantation years after device placement. PMID- 26024919 TI - Semaphorin4A Is Cytotoxic to Oligodendrocytes and Is Elevated in Microglia and Multiple Sclerosis. AB - We have previously established that T cell immunoglobulin and mucin domain containing 2 (Tim2) is an H-ferritin receptor on oligodendrocytes (OLs). Tim2 also binds Semaphorin4A (Sema4A). Sema4A is expressed by lymphocytes, and its role in immune activation is known; however, its relationship to diseases that are known to have myelin damage has not been studied. In this study, we demonstrate that Sema4A is cytotoxic to OLs in culture: an effect accompanied by process collapse, membrane blebbing, and phosphatidylserine inversion. We further demonstrate that Sema4A preferentially binds to primary OLs but not astrocytes: an observation consistent with the lack of expression of Tim2 on astrocytes. We found that Sema4A protein levels are increased within multiple sclerosis plaques compared with normal-appearing white matter and that Sema4A induces lactate dehydrogenase release in a human OL cell line. The chief cellular source of Sema4A within the multiple sclerosis plaques appears to be infiltrating lymphocytes and microglia. Macrophages are known to express Sema4A, so we interrogated microglia as a potential source of Sema4A in the brain. We found that rat primary microglia express Sema4A which increased after lipopolysaccharide activation. Because activated microglia accumulate iron, we determined whether iron status influenced Sema4A and found that iron chelation decreased Sema4A and iron loading increased Sema4A in activated microglia. Overall, our data implicate Sema4A in the destruction of OLs and reveal that its expression is sensitive to iron levels. PMID- 26024920 TI - Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene. AB - BACKGROUND: The major disadvantage of using a stem cell-based bone morphogenetic protein-4 (BMP4) gene therapy for skull defect is the overgrowth of generated bone tissue in situ. In the present study, to overcome bony overgrowth of stem cell based-gene therapy, a new strategy of two-stage bone tissue engineering by an adeno-associated virus containing BMP4 gene (AAV-BMP4) gene therapy was used. METHODS: AAV-BMP4 was purposely implanted in the skeletal muscle of mice to generate ectopic bone tissues during the first stage. Next, the newly formed ectopic bone tissues were harvested and then transplanted to repair the mouse skull defect during the second stage. RESULTS: The results showed that skeletal muscle implantation of AAV-BMP4 yielded a large amount of new bone tissues. The ectopic bone tissues can be harvested as a bone graft and can successfully repair the mouse skull defect without any bony overgrowth in situ. CONCLUSION: The results indicate that the bone tissues purposely generated by AAV-BMP4 in the skeletal muscle may be a new alternative of bone grafting for clinical purposes. PMID- 26024921 TI - Social marketing of low dead space syringes in Vietnam: findings from a 1-year pilot program in Hanoi, Thai Nguyen, and Ho Chi Minh City. AB - BACKGROUND: Although a growing body of evidence suggests that low dead space syringes may reduce the risk of human immunodeficiency virus (HIV) and Hepatitis C virus infection associated with sharing syringes among people who inject drugs, there is little evidence of effective approaches to motivate people who inject drugs (PWID) to shift from high to low dead space syringes. METHODS: Using a mix of consumer and trade marketing approaches, informed by rapid assessments of both the syringe market and PWID preferences, practices, and behaviors in Hanoi and Ho Chi Minh City, Population Services International (PSI) Vietnam piloted an intervention to increase the use of low dead space syringes (LDSS) in the three provinces of Hanoi, Ho Chi Minh City, and Thai Nguyen, where an estimated 31% of PWID are HIV positive and 58% are living with hepatitis C virus (HCV). RESULTS: This paper provides a summary of the social marketing activities implemented and results achieved by PSI Vietnam during an initial 1-year pilot period from December 2012 to December 2013 in these three provinces to explore their effectiveness in motivating PWID to use low dead space syringes. We found major increases in sales of LDSS accompanied by increases in reported use and consistent use of LDSS among PWID in the three provinces included in the pilot program and a positive and independent association (odds ratio (OR) 21.08; 95% confidence interval (CI) 10.6-27.3) between LDSS use and exposure to social marketing activities. We also found that LDSS use had a stronger association with perceptions of LDSS product quality than with perceptions regarding LDSS potential to reduce HIV transmission risk and use. CONCLUSIONS: We conclude that social marketing interventions have an important role to play in widening access to and the use of LDSS for PWID, as they address the need for PWID to find LDSS when and where they need them and also promote the benefits of LDSS use to PWID. High coverage of these activities among PWID appears to be the key in achieving these successes. PMID- 26024922 TI - Online gambling's moderators: how effective? Study protocol for a randomized controlled trial. AB - BACKGROUND: Online gambling has been legalized in France in 2010. Licenses are issued to gambling operators who demonstrate their ability to respect the legal framework (security, taxation, consumer protection, etc.). The preventive measures to protect vulnerable gamblers include an obligation to provide online gambling moderators. These moderators should allow gamblers to limit their bets, exclude themselves from the website for 7 days, and consult the balance of the gambler's account at any time. However, there are only a few published reports of empirical research investigating the effectiveness of Internet-based protective measures implemented by French law. Moreover, no empirical research has yet studied the impact of bonuses on gambling behaviors. METHODS/DESIGN: This research is an experimental randomized controlled trial, risk prevention targeted. The research is divided into four sub-studies depending on the studied moderator: limiting bonuses, self-exclusion, self-limitation and information. The study sample consists of 485 volunteers. For each experimental condition and the control groups, the sample is composed of gamblers equally recruited from gamblers having preferences in each of the three major forms of games (lottery and scratch tickets, sports and horserace betting, and poker). For each form of gambling, the gamblers are recruited in order to obtain as many problem gamblers as non-problem gamblers. According to the randomization, the experimental session begins. The experimental session is a gambling situation on a computer in our research center. The gambler is invited to play on his favorite gambling site as usual, with his own gambler account and his own money. Data collected comprise sociodemographic characteristics, gambling habits, an interview about enjoyment and feeling out of control during the gambling session, moderator impact on gambling practice, statement of gambling parameters and questionnaires (BMIS, GRCS, CPGI, GACS). Moderator efficiency is assessed based on the two major characteristics of gambling behavior: money wagered and time spent in gambling. DISCUSSION: The results of this research will be important to prevent online problem gambling and influence policy-makers. TRIAL REGISTRATION NUMBER: NCT01789580. Registered 8 February 2013. PMID- 26024924 TI - Process evaluation of a practice nurse-led smoking cessation trial in Australian general practice: views of general practitioners and practice nurses. AB - BACKGROUND: Support in primary care can assist smokers to quit successfully, but there are barriers to general practitioners (GPs) providing this support routinely. Practice nurses (PNs) may be able to effectively take on this role. OBJECTIVES: The aim of this study was to perform a process evaluation of a PN-led smoking cessation intervention being tested in a randomized controlled trial in Australian general practice. METHODS: Process evaluation was conducted by means of semi-structured telephone interviews with GPs and PNs allocated in the intervention arm (Quit with PN) of the Quit in General Practice trial. Interviews focussed on nurse training, content and implementation of the intervention. RESULTS: Twenty-two PNs and 15 GPs participated in the interviews. The Quit with PN intervention was viewed positively. Most PNs were satisfied with the training and the materials provided. Some challenges in managing patient data and follow up were identified. CONCLUSION: The Quit with PN intervention was acceptable to participating PNs and GPs. Issues to be addressed in the planning and wider implementation of future trials of nurse-led intervention in general practice include providing ongoing mentoring support, integration into practice management systems and strategies to promote greater collaboration in GPs and PN teams in general practice. The ongoing feasibility of the intervention was impacted by the funding model supporting PN employment and the competing demands on the PNs time. PMID- 26024923 TI - Single nucleotide resolution RNA-seq uncovers new regulatory mechanisms in the opportunistic pathogen Streptococcus agalactiae. AB - BACKGROUND: Streptococcus agalactiae, or Group B Streptococcus, is a leading cause of neonatal infections and an increasing cause of infections in adults with underlying diseases. In an effort to reconstruct the transcriptional networks involved in S. agalactiae physiology and pathogenesis, we performed an extensive and robust characterization of its transcriptome through a combination of differential RNA-sequencing in eight different growth conditions or genetic backgrounds and strand-specific RNA-sequencing. RESULTS: Our study identified 1,210 transcription start sites (TSSs) and 655 transcript ends as well as 39 riboswitches and cis-regulatory regions, 39 cis-antisense non-coding RNAs and 47 small RNAs potentially acting in trans. Among these putative regulatory RNAs, ten were differentially expressed in response to an acid stress and two riboswitches sensed directly or indirectly the pH modification. Strikingly, 15% of the TSSs identified were associated with the incorporation of pseudo-templated nucleotides, showing that reiterative transcription is a pervasive process in S. agalactiae. In particular, 40% of the TSSs upstream genes involved in nucleotide metabolism show reiterative transcription potentially regulating gene expression, as exemplified for pyrG and thyA encoding the CTP synthase and the thymidylate synthase respectively. CONCLUSIONS: This comprehensive map of the transcriptome at the single nucleotide resolution led to the discovery of new regulatory mechanisms in S. agalactiae. It also provides the basis for in depth analyses of transcriptional networks in S. agalactiae and of the regulatory role of reiterative transcription following variations of intra-cellular nucleotide pools. PMID- 26024925 TI - Perivascular spaces and headache: A population-based imaging study (HUNT-MRI). AB - BACKGROUND: In four previous clinic-based MRI studies headache sufferers (in particular migraineurs) had more perivascular spaces (PVS) than individuals who were headache-free. METHODS: The present study was part of a large longitudinal, epidemiological study (Nord-Trondelag Health Survey (HUNT)). The 1006 participants, age 50-65 years at inclusion, had participated in all previous HUNT surveys (1-3), and been randomly selected to a population-based imaging study of the head (HUNT-MRI, 2007-2009). The number of visible PVS in the basal ganglia (BG) and hemispheric white matter (HWM) was compared in headache sufferers (migraine with and without aura, non-migrainous headache) and people who were headache-free. RESULTS: The results showed in general small differences between headache sufferers and headache-free participants. In the cross-sectional analysis migraineurs without aura had fewer PVS than headache-free individuals in BG (OR = 0.84, 95% CI = 0.76--0.94, p value = 0.003) and in BG and HWM together (OR = 0.97, 95% CI = 0.95-1.00, p value = 0.046). No difference between long-term headache sufferers and long-term headache-free individuals with regard to number of PVS was found. DISCUSSION: In contrast to previous studies, the present large, blinded, population-based study showed no increase in number of dilated PVS among headache sufferers. Fewer PVS among those with migraine without aura may be a spurious finding. PMID- 26024926 TI - Comparison of polyethylene glycol vs sodium picosulphate vs sodium biphosphonate by efficacy in bowel cleansing and patients' tolerability: a randomised trial. AB - INTRODUCTION: Adequate bowel preparation is necessary for a complete colonoscopy. Polyethylene glycol-electrolyte oral solution (PEG-EOS), sodium picosulphate (SS) and sodium biphosphonate (SP) are the three most commonly used purgative agents. We aimed to determine their efficacy and tolerability compared to each other in a randomised study. METHODS: 313 patients were randomly assigned to receive either PEG-EOS, SS or SP. Patients completed a tolerability score pre-colonoscopy. A cleanliness score was used to document adequacy of bowel preparation. A separate group of patients completed taste scores for the three cathartic agents before and after addition of flavour. RESULTS: PEG-EOS was the worst-tolerated regimen but achieved the highest rates of right colonic cleansing and the lowest rate of incomplete colonoscopies. There were no statistical differences in the rates of rectosigmoid and mid-gut cleansing among the three agents. SS was by far the preferred purgative in the taste assessment study. Addition of flavour increased significantly taste scores for PEG-EOS. CONCLUSION: For adequate bowel cleansing PEG-EOS is the most effective but is the least tolerated and least preferred among patients. Addition of flavour increases significantly patients' acceptance of PEG-EOS. PMID- 26024927 TI - Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet induced obese rodents. AB - The gastrointestinal tract plays a critical role in the regulation of energy homeostasis by initiating neural and hormonal responses to the ingestion of nutrients. In addition to peptide hormones, such as cholecystokinin (CKK) and peptide YY (PYY), the lipid-derived mediator oleoylethanolamide (OEA) has been implicated in the control of satiety. Previous studies in humans and rodent models have shown that obesity is associated with changes in CCK, PYY and other gut-derived peptide hormones, which may contribute to decreased satiety and increased energy intake. In the present study, we show that small-intestinal OEA production is disrupted in the gut of diet-induced obese (DIO) rats and mice. In lean rodents, feeding or duodenal infusion of Intralipid(r) or pure oleic acid stimulates jejunal OEA mobilization. This response is strikingly absent in DIO rats and mice. Confirming previous reports, we found that feeding rats or mice a high-fat diet for 7 days is sufficient to suppress jejunal OEA mobilization. Surprisingly, a similar effect is elicited by feeding rats and mice a high sucrose low-fat diet for 7 days. Collectively, our findings suggest that high fat induced obesity is accompanied by alterations in the post-digestive machinery responsible for OEA biosynthesis, which may contribute to reduced satiety and hyperphagia. PMID- 26024928 TI - CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment. AB - Persistent cognitive impairment in the euthymic state of bipolar disorder is increasingly recognized. Mounting evidence also suggests an association between neuroinflammation and cognitive dysfunction. The purpose of this study was to test if cerebrospinal fluid (CSF) markers of neuroinflammation could account for cognitive impairment in bipolar disorder. Hierarchical linear regression models were applied to account for performance in five cognitive domains using CSF neuroinflammatory biomarkers as predictors in patients with bipolar disorder type I and II (N=78). The associations between these biomarkers and cognition were further tested in healthy age- and sex-matched controls (N=86). In patients with bipolar disorder, the CSF biomarkers accounted for a significant proportion of the variance in executive functions (42.8%, p=<.0005) independently of age, medication, disease status, and bipolar subtype. The microglial marker YKL-40 had a high impact (beta=-.99), and was the only biomarker that contributed individually. CSF biomarkers were not associated with cognitive performance in healthy controls. The CSF neuroinflammation biomarker YKL-40 is associated with executive performance in euthymic bipolar disorder, but not in healthy controls. PMID- 26024929 TI - What regulatory science can bring for CNS drug development. PMID- 26024931 TI - Developmental changes of melatonin receptor expression in the spleen of the chicken, Gallus domesticus. AB - Melatonin plays an essential role in development and immunoregulation of the avian spleen through its receptors; however, the variations in the expression of the melatonin receptor subtypes in the developing avian spleen are still unclear. The objective of the present study was not only to investigate the distribution patterns and development changes of the expression of the melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) in the chicken spleen but also to identify the correlation between the plasma melatonin concentration and the expression of the melatonin receptor subtypes. The immunohistochemical results indicated that Mel1a was mainly distributed in the red pulp and capillaries, Mel1b was predominantly distributed in the periarterial lymphatic sheath (PALS) and splenic nodule, and Mel1c was widely located in the red pulp, PALS and splenic nodule. From P0 to P21, the mRNA and protein expressions of Mel1a, Mel1b and Mel1c in the spleen were increased (P<0.05); however, a slight increase in the expression of the three melatonin receptor subtypes was observed after P21 (P>0.05). Furthermore, the mRNA levels of Mel1b and Mel1c between P0 and P14 raised more quickly than Mel1a. The plasma melatonin concentration increased in an age-dependent manner in the chicken from P0 to P42 (P<0.05), and this increasing change was linear after P14 (P<0.05). The melatonin level in the plasma is strongly correlated with the protein expressions of Mel1a (r=0.938, P=0.005), Mel1b (r=0.912, P=0.011), and Mel1c (r=0.906, P=0.012) in the chicken spleen. These results suggest the existence of age-related and region-specific changes in the expression of the melatonin receptor subtypes within the spleen of the chicken, and this characteristic pattern may be involved in the development and functional maturation of the avian spleen. PMID- 26024932 TI - The relationship between the built environment and habitual levels of physical activity in South African older adults: a pilot study. AB - BACKGROUND: Previous research has shown that the built environment plays a role in habitual levels of physical activity (PA), however much of this research has been conducted in adults and higher income countries. The aim of this pilot study was to examine the strength of association between the built environment and PA in South African older adults. METHODS: Participants were recruited (n = 44, mean age 65 +/- 8.5 years) from two suburbs, representing either a high socioeconomic (HSA) or low socioeconomic area (LSA). Self-reported PA, and subjective assessments of neighborhood walkability (Neighborhood Environment Walkability Scale, NEWS) was measured. Participants wore Actigraph GT3x accelerometers to objectively quantify PA. RESULTS: HSA participants reported significantly more leisure-time and less transport PA. Objectively measured and self-reported MVPA was significantly higher in HSA participants. NEWS 'Land-use Mix' was negatively associated with leisure-time MVPA, (r(2) = 0.20; p < 0.02). In addition, neighborhood aesthetics was positively associated with leisure-time physical activity (r(2) = 0.33; p = 0.02). 'Safety from traffic' was inversely associated with travel-related PA (r(2) = 0.14, p = 0.01). None of the other NEWS scores were associated with PA for the total group. CONCLUSION: Leisure-time and transport-related PA was influenced by socio-economic status. Attributes of the perceived built environment associated with leisure-time and total MVPA in older South Africa adults were different in low- and high- income settings. PMID- 26024933 TI - Spontaneous Recovery of Ovarian Function in an Adolescent with Galactosemia and Apparent Premature Ovarian Insufficiency. AB - BACKGROUND: Galactosemia is an inborn error of metabolism resulting in premature ovarian insufficiency in 80-90% of females. There have been no reported cases of biochemical ovarian failure followed by normal menses. CASE: A 12-year-old girl with galactosemia presented for gynecologic consultation. Her follicle stimulating hormone (FSH) and estradiol levels were 52.9 U/L and less than 100 pmol/L, respectively. She started exogenous estrogen to stimulate puberty. At 16, she had spontaneous regular menstrual cycles. FSH and luteinizing hormone (LH) levels reflected normal ovarian function. Hormonal contraception was provided. One year later, she was found to be in ovarian failure (FSH 86.6 U/L, LH 33.3 U/L), and both estradiol and anti-Mullerian hormone were undetectable. SUMMARY AND CONCLUSIONS: This case documents spontaneous resumption of ovarian function after galactosemia-related ovarian failure. The use of FSH and LH is potentially limited in predicting ovarian function in this population. PMID- 26024934 TI - Psychological Distress and its Correlates among University Students: A Cross Sectional Study. AB - STUDY OBJECTIVE: Mental health disorders are common among university students. In addition to the normal stressors of everyday life, students must deal with stresses related to their education. Our aim was to identify the mental health status of university students and its correlation with socio-demographic, academic performance, and menstrual features. DESIGN: A cross sectional study was conducted among undergraduate health students using the Symptoms Checklist-90- Revised (SCL-90-R). The Global Severity Index (GSI), raw scores of SCL-90-R subscales, and correlated factors were reported and analyzed. RESULTS: A total of 171 health students completed the survey. Psychopathological symptoms were found in 23% of the student. Depression was the most prevalent mental reported symptom (100%). There was no significant association between the symptoms and variables such as age, gender, living in university dormitories, marital status, field of study, academic performance, and the day of menstrual cycle while filling the form. GSI scores were significantly related to regular menses. The odds of being identified as a mentally unhealthy individual was 0.37 times lower for those who experienced regular menstrual cycles. CONCLUSION: Psychological distress is prevalent among health students and tends to be reported more by female students with irregular periods and during luteal phase of menstrual cycle. Preventive and treatment programs need to be developed. It is also recommended that SCL-90-R be administered at least 7 days after the end of menstrual bleeding. PMID- 26024935 TI - Invasive Ductal Carcinoma in a 46,XY Partial Androgen Insensitivity Syndrome Patient on Hormone Therapy. AB - BACKGROUND: The hormonal management of patients with androgen insensitivity can be challenging. CASE: An illustrative case is presented of a newborn with ambiguous genitalia who was raised female. She was diagnosed as 46,XY Disorder of Sexual Development with partial androgen insensitivity. To induce puberty, conjugated equine estrogens were administered beginning at age 12. At age 13, she instead began taking combined oral contraceptives for maternal concerns about height and continued taking them for social reasons. Invasive ductal carcinoma was diagnosed at age 27, and the patient was treated with chemotherapy, radiation therapy, bilateral mastectomies, and endocrine therapy. SUMMARY AND CONCLUSION: The current literature is reviewed, and hormonal management and other risks for breast cancer are discussed. PMID- 26024936 TI - Do They Stand a Chance? Vaginal Birth after Cesarean Section in Adolescents Compared to Adult Women. AB - STUDY OBJECTIVE: To determine the rate of elective repeat cesarean delivery (CD), vaginal birth after cesarean (VBAC) attempt, and VBAC success in adolescent mothers presenting for delivery of a second child after a prior CD compared to their adult counterparts. DESIGN: Retrospective cohort study analyzing data from the Consortium on Safe Labor Database which includes data for 228,668 deliveries from 2002 to 2008. SETTING: 19 hospitals within 12 institutions in the United States. PARTICIPANTS: 10,791 women age <= 35 (428 adolescents, age <= 19 and 10,363 adults age 20-35) with history of prior CD presenting for delivery of a second child. METHODS: The database was accessed for information on patient characteristics, prenatal comorbidities, and delivery data. Rates of repeat CD, VBAC attempt, and VBAC success were calculated. Multiple logistic regression was applied to identify predictors of VBAC success. RESULTS: Adolescents had a lower overall repeat CD rate and higher VBAC attempt rate compared to adults (80.61% vs 85.32%, P = .0072; 40.42% vs 30.09%, P < .0001 respectively). VBAC success was similar between adolescents and adults (47.98% vs 48.78% P = .8368). Delivery at a teaching hospital and greater gestational age were predictive of VBAC success. Gestational diabetes mellitus, induction of labor, and higher maternal body mass index were predictive of VBAC failure. Adolescence was not an independent predictor of VBAC outcome. CONCLUSIONS: Adolescents are more likely to attempt VBAC and are likely to be as successful as their adult counterparts. Adolescents should be encouraged to attempt a trial of labor after prior CD when appropriate to lower the risks of lifelong maternal morbidity from numerous repeat CDs. PMID- 26024937 TI - Congenital Atresia of Uterine Isthmus: Successful Diagnosis and End-To-End Anastomosis. AB - BACKGROUND: Mullerian duct anomalies are rare and occasionally diagnosed in adolescents with primary amenorrhea, abdominal pain, and sexual difficulties. They are present in a variety of forms and sometimes difficult to appropriately classify. The management of malformations remains controversial. CASE: A 15-year old girl with primary amenorrhea and cyclic lower abdominal pain was found on laparoscopic examination to have an asymmetric ball-shaped uterus with isthmus stenosis suspended in the pelvis. The junction between the lower segment of uterus and the cervix was very thin and stenotic with scar-like tissue changes. Combined with pathologic evaluation, it was finally diagnosed as congenital atresia of uterine isthmus. Thus, an end-to-end anastomosis was performed instead of surgical resection. SUMMARY AND CONCLUSION: Mullerian duct anomalies in a variety of forms can be difficult to diagnosis correctly and treat appropriately. Preservation of reproductive ability is the first objective of all treatments. PMID- 26024938 TI - Physician Knowledge and Attitudes around Confidential Care for Minor Patients. AB - STUDY OBJECTIVE: Minor adolescent patients have a legal right to access certain medical services confidentially without parental consent or notification. We sought to assess physicians' knowledge of these laws, attitudes around the provision of confidential care to minors, and barriers to providing confidential care. DESIGN: An anonymous online survey was sent to physicians in the Departments of Family Medicine, Internal Medicine-Pediatrics, Obstetrics/Gynecology, and Pediatrics at the University of Michigan. RESULTS: Response rate was 40% (259/650). The majority of physicians felt comfortable addressing sexual health, mental health, and substance use with adolescent patients. On average, physicians answered just over half of the legal knowledge questions correctly (mean 56.6% +/- 16.7%). The majority of physicians approved of laws allowing minors to consent for confidential care (90.8% +/- 1.7% approval), while substantially fewer (45.1% +/- 4.5%) approved of laws allowing parental notification of this care at the physician's discretion. Most physicians agreed that assured access to confidential care should be a right for adolescents. After taking the survey most physicians (76.6%) felt they needed additional training on confidentiality laws. The provision of confidential care to minors was perceived to be most inhibited by insurance issues, parental concerns/relationships with the family, and issues with the electronic medical record. CONCLUSIONS: Physicians are comfortable discussing sensitive issues with adolescents and generally approve of minor consent laws, but lack knowledge about what services a minor can access confidentially. Further research is needed to assess best methods to educate physicians about minors' legal rights to confidential healthcare services. PMID- 26024939 TI - Guttate Psoriasis Following Streptococcal Vulvovaginitis in a Five-year-old Girl. AB - BACKGROUND: Guttate psoriasis is frequently associated with a preceding pharyngeal or perianal streptococcal infection in children. Despite Group A beta hemolytic streptococci (GABHS) being the most common cause of specific bacterial vulvovaginitis in prepubertal girls, there are no reports of streptococcal vulvovaginitis triggering guttate psoriasis. CASE: A five-year-old girl presented with guttate psoriasis following an episode of Streptococcal pyogenes vulvovaginitis. Following antibiotic treatment and bacterial eradication she developed vulvar psoriasis that resolved with high potency topical steroids. SUMMARY AND CONCLUSION: Identification of an antecedent streptoccocal infection can help predict the long term prognosis in children with guttate psoriasis. The vulvovaginal area should be considered as a source of GABHS infection in young girls with guttate psoriasis, and cultures should be considered if symptoms are present. PMID- 26024940 TI - Oral Tranexamic Acid versus Combined Oral Contraceptives for Adolescent Heavy Menstrual Bleeding: A Pilot Study. AB - STUDY OBJECTIVE: To compare the efficacy of oral tranexamic acid (TA) with combined oral contraceptives (COC) in reducing menstrual blood loss (MBL) and improving quality of life in adolescent heavy menstrual bleeding (HMB). DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized crossover trial with 17 postmenarchal girls aged 21 years and younger with HMB who were seen at our institution. INTERVENTIONS: Patients were randomized to group A (TA arm) or group B (COC arm), each for 3 cycles, with crossover to the second arm after 1-month washout. MAIN OUTCOME MEASURES: The primary end points were difference in improvement in MBL and QOL, from baseline to end of each therapy. RESULTS: Seventeen patients were enrolled (mean age 14.2 years, range 11.7 to 16.8 years). Nine patients completed both arms; 8 patients withdrew from the study due to adverse events or noncompliance. Compared with baseline, significant improvement (P < .05) was demonstrated by TA and COC in MBL (mean Pictorial Blood Assessment Chart score decrease: TA, 536.4; COC, 430.6) and quality of life (mean Pediatric Quality of Life Inventory(TM) version 4.0 Generic Scales score increase: TA, 15.6; COC, 16.75), but no significant difference was noted between TA and COC (P > .05). There was statistically significant reduction in the length of menstrual cycle for COC only (mean reduction 5.3 days; P = .04) and not for TA (P = .18). Ten patients (58%) experienced adverse events that were possibly drug related (TA: n = 3, 30%; COCP: n = 7, 64%). CONCLUSION: In this pilot study, oral TA appeared as efficacious as COC in the management of adolescent HMB by reducing MBL and improving quality of life. PMID- 26024941 TI - Strategically Timed Preventive Education and Media Strategies Reduce Seasonal Trends in Adolescent Conception. AB - STUDY OBJECTIVE: This study sought to analyze the effect of strategically timed local preventive education on reducing teen conception rates during known seasonal peaks in March and April. DESIGN: All teen conceptions (age <= 19) from March and April 2010, 2011, and 2012 were identified using medical records data. Teen conceptions occurring in January 2010, 2011, and 2012 were also identified to control for any new trends in the community. SETTING: A city of 160,000 with 1 tertiary care centre. PARTICIPANTS: Pregnant adolescents (age <= 19). INTERVENTIONS: During the month of February 2012, preventive education and media awareness strategies were aimed at parents, teachers, and teens. MAIN OUTCOME MEASURES: Adolescent conceptions in March and April 2012. RESULTS: Conception rates in teens <=18 years old were significantly reduced in March and April 2012 compared to March and April 2010 and 2011 (RR = 0.53, 95% CI = 0.32 - 0.88, P = .0132). There was an increase in conceptions in March and April 2012 compared to 2010 and 2011 among 19-year-olds (RR = 1.57, 95% CI = 0.84-2.9, P = .1500). Effect modification revealed our <=18-year-old group and our 19-year-old group were distinct groups with different risk estimates (P = .0075). CONCLUSIONS: Educational sessions were poorly attended and contraception clinic volume was static. We propose increased parental supervision in response to media reminders as a possible explanation for the reduction in adolescent conceptions (<=18 years old) seen in March 2012. PMID- 26024942 TI - Adolescent and Young Adult Women's Knowledge of and Attitudes Toward Etonogestrel Implants. AB - STUDY OBJECTIVE: Long acting reversible contraceptives, including etonogestrel implants, are top tier contraceptives for adolescents, yet they remained underutilized. This study aimed to assess awareness of and attitudes toward etonogestrel implants among adolescent and young adult women. DESIGN, MAIN OUTCOME MEASURES: This is a cross sectional study. We distributed an original, self-administered survey to a convenience sample of anonymous subjects. The survey assessed demographic information, pregnancy and sexual history, general contraceptive preferences, and awareness of implants. Subjects then read a brief description of implants before completing the section assessing attitudes toward them. We used chi-square and t-test analyses to identify factors associated with awareness of and positive attitudes toward implants. SETTING, PARTICIPANTS: Women aged 10-24 attending a birth control education group at an adolescent health center in New York City. RESULTS: Of the 129 participants, only 40% had heard of etonogestrel implants. Some (33%) reported positive attitudes toward implants. Positive attitudes were associated with preferences for birth control convenience (OR = 3.3, 95% CI = 1.1- 9.5) and privacy (OR = 2.2, 95% CI = 1.0- 4.8). Neutral or negative attitudes were associated with a preference for birth control that maintained menstrual regularity (OR = 0.4, 95% CI = 0.2- 0.8) and with having experienced at least 1 unintended pregnancy (OR = 0.4, 95% CI = 0.2- 0.9). Age, race, and education were not associated with participants' attitudes toward implants. CONCLUSIONS: Women who value convenience and privacy are more likely to report positive attitudes toward implants, and thus may represent especially receptive candidates for them. PMID- 26024943 TI - Silica-induced inflammasome activation in macrophages: role of ATP and P2X7 receptor. AB - Silicosis is a fibrotic lung disease caused by the inhalation of silica particles, and is considered an occupational disease, given that these particles are present in the working environment of many mining and civil construction industries. NLRP3 inflammasome activation is an important mechanism during the inflammatory process of silicosis, and it promotes the production of cytokines, such as IL-1beta and IL-18. ATP also plays an important role in silicosis. Specifically, extracellular ATP can activate P2X7 receptor, which then participates in the complete assembly of the NLRP3 inflammasome and its activation. Herein, we analyze the literature to provide a better understanding of the mechanisms underlying inflammasome activation and the role of P2X7 receptors in macrophages during silicosis. PMID- 26024944 TI - RNAi Screening with Self-Delivering, Synthetic siRNAs for Identification of Genes That Regulate Primary Human T Cell Migration. AB - Screening of RNA interference (RNAi) libraries in primary T cells is labor intensive and technically challenging because these cells are hard to transfect. Chemically modified, self-delivering small interfering RNAs (siRNAs) offer a solution to this problem, because they enter hard-to-transfect cell types without needing a delivery reagent and are available in library format for RNAi screening. In this study, we have screened a library of chemically modified, self delivering siRNAs targeting the expression of 72 distinct genes in conjunction with an image-based high-content-analysis platform as a proof-of-principle strategy to identify genes involved in lymphocyte function-associated antigen-1 (LFA-1)-mediated migration in primary human T cells. Our library-screening strategy identified the small GTPase RhoA as being crucial for T cell polarization and migration in response to LFA-1 stimulation and other migratory ligands. We also demonstrate that multiple downstream assays can be performed within an individual RNAi screen and have used the remainder of the cells for additional assays, including cell viability and adhesion to ICAM-1 (the physiological ligand for LFA-1) in the absence or presence of the chemokine SDF 1alpha. This study therefore demonstrates the ease and benefits of conducting siRNA library screens in primary human T cells using self-delivering, chemically modified siRNAs, and it emphasizes the feasibility and potential of this approach for elucidating the signaling pathways that regulate T cell function. PMID- 26024945 TI - A Cell-Based Internalization and Degradation Assay with an Activatable Fluorescence-Quencher Probe as a Tool for Functional Antibody Screening. AB - For the development of therapeutically potent anti-cancer antibody drugs, it is often important to identify antibodies that internalize into cells efficiently, rather than just binding to antigens on the cell surface. Such antibodies can mediate receptor endocytosis, resulting in receptor downregulation on the cell surface and potentially inhibiting receptor function and tumor growth. Also, efficient antibody internalization is a prerequisite for the delivery of cytotoxic drugs into target cells and is critical for the development of antibody drug conjugates. Here we describe a novel activatable fluorescence-quencher pair to quantify the extent of antibody internalization and degradation in the target cells. In this assay, candidate antibodies were labeled with a fluorescent dye and a quencher. Fluorescence is inhibited outside and on the surface of cells, but activated upon endocytosis and degradation of the antibody. This assay enabled the development of a process for rapid characterization of candidate antibodies potentially in a high-throughput format. By employing an activatable secondary antibody, primary antibodies in purified form or in culture supernatants can be screened for internalization and degradation. Because purification of candidate antibodies is not required, this method represents a direct functional screen to identify antibodies that internalize efficiently early in the discovery process. PMID- 26024946 TI - High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome. AB - Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention. PMID- 26024947 TI - Discovery of SIRT3 Inhibitors Using SAMDI Mass Spectrometry. AB - Lysine acetylation plays a critical role in cellular regulation and is implicated in human disease. Sirtuin deacetylases remove acetyl groups from modified lysine residues, and sirtuin 3 (SIRT3) has been identified as a target for cancer therapeutics. Robust and high-throughput screening methods for these targets will be important to the development of therapeutics. This article describes the use of self-assembled monolayer desorption/ionization mass spectrometry, or SAMDI-MS a label-free drug discovery tool--to characterize SIRT3 activity and discover inhibitors. SAMDI-MS was used to analyze a peptide array having 361 distinct acetylated peptides to identify an active SIRT3 substrate (GYK(Ac)RGC). This peptide was used in a screen of 100,000 small molecules to identify inhibitors of SIRT3. A total of 306 SIRT3 inhibitors were identified, with one compound, SDX 437, having an IC(50) of 700 nM with >100-fold selectivity for SIRT3 over SIRT1. PMID- 26024948 TI - [Position paper for a reform of medical emergency care in German emergency departments]. AB - The hospital emergency departments play a central role for the in- and outpatient care of patients with medical emergencies in Germany. In this position paper we point out some general financial and organizational problems of German emergency departments and urge for a higher significance of emergency care in the German health system as an element of public services. The corresponding reform proposals include a change in hospital financing towards a more budget-based system for the emergency departments, an improved structural planning for regional and transregional emergency care, an intensified cooperation with the emergency services of the ambulatory care physicians, a better organizational representation of emergency care within the hospitals and an advancement of emergency medicine in postgraduate medical education. PMID- 26024949 TI - Pilocytic astrocytoma of the lower thoracic spine in an adult patient. PMID- 26024950 TI - Matrix diffusion and sorption of Cs+, Na+, I- and HTO in granodiorite: Laboratory scale results and their extrapolation to the in situ condition. AB - Matrix diffusion and sorption are important processes controlling radionuclide transport in crystalline rocks. Such processes are typically studied in the laboratory using borehole core samples however there is still much uncertainty on the changes to rock transport properties during coring and decompression. It is therefore important to show how such laboratory-based results compare with in situ conditions. This paper focuses on laboratory-scale mechanistic understanding and how this can be extrapolated to in situ conditions as part of the Long Term Diffusion (LTD) project at the Grimsel Test Site, Switzerland. Diffusion and sorption of (137)Cs(+), (22)Na(+), (125)I(-) and tritiated water (HTO) in Grimsel granodiorite were studied using through-diffusion and batch sorption experiments. Effective diffusivities (De) of these tracers showed typical cation excess and anion exclusion effects and their salinity dependence, although the extent of these effects varied due to the heterogeneous pore networks in the crystalline rock samples. Rock capacity factors (alpha) and distribution coefficients (Kd) for Cs(+) and Na(+) were found to be sensitive to porewater salinity. Through diffusion experiments indicated dual depth profiles for Cs(+) and Na(+) which could be explained by a near-surface Kd increment. A microscopic analysis indicated that this is caused by high porosity and sorption capacities in disturbed biotite minerals on the surface of the samples. The Kd values derived from the dual profiles are likely to correspond to Kd dependence on the grain sizes of crushed samples in the batch sorption experiments. The results of the in situ LTD experiments were interpreted reasonably well by using transport parameters derived from laboratory data and extrapolating them to in situ conditions. These comparative experimental and modelling studies provided a way to extrapolate from laboratory scale to in situ condition. It is well known that the difference in porosity between laboratory and in situ conditions is a key factor to scale laboratory-derived De to in situ conditions. We also show that cation excess diffusion is likely to be a key mechanism in crystalline rocks and that high Kd in the disturbed surfaces is critically important to evaluate transport in both laboratory and in situ tests. PMID- 26024951 TI - Gaussian or non-Gaussian logconductivity distribution at the MADE site: What is its impact on the breakthrough curve? AB - The impact of the logconductivity (Y=ln K) distribution fY on transport at the MADE site is analyzed. Our principal interest is in non-Gaussian fY characterized by heavier tails than the Gaussian. Both the logconductivity moments and fY itself are inferred, taking advantage of the detailed measurements of Bohling et al. (2012). The resulting logconductivity distribution displays heavier tails than the Gaussian, although the departure from Gaussianity is not significant. The effect of the logconductivity distribution on the breakthrough curve (BTC) is studied through an analytical, physically based model. It is found that the non Gaussianity of the MADE logconductivity distribution does not strongly affect the BTC. Counterintuitively, assuming heavier tailed distributions for Y, with same variance, leads to BTCs which are more symmetrical than those for the Gaussian fY, with less pronounced preferential flow. Results indicate that the impact of strongly non-Gaussian, heavy tailed distributions on solute transport in heterogeneous porous formations can be significant, especially in the presence of high heterogeneity, resulting in reduced preferential flow and retarded peak arrivals. PMID- 26024952 TI - Variation analysis of transcriptome changes reveals cochlear genes and their associated functions in cochlear susceptibility to acoustic overstimulation. AB - Individual variation in the susceptibility of the auditory system to acoustic overstimulation has been well-documented at both the functional and structural levels. However, the molecular mechanism responsible for this variation is unclear. The current investigation was designed to examine the variation patterns of cochlear gene expression using RNA-seq data and to identify the genes with expression variation that increased following acoustic trauma. This study revealed that the constitutive expressions of cochlear genes displayed diverse levels of gene-specific variation. These variation patterns were altered by acoustic trauma; approximately one-third of the examined genes displayed marked increases in their expression variation. Bioinformatics analyses revealed that the genes that exhibited increased variation were functionally related to cell death, biomolecule metabolism, and membrane function. In contrast, the stable genes were primarily related to basic cellular processes, including protein and macromolecular syntheses and transport. There was no functional overlap between the stable and variable genes. Importantly, we demonstrated that glutamate metabolism is related to the variation in the functional response of the cochlea to acoustic overstimulation. Taken together, the results indicate that our analyses of the individual variations in transcriptome changes of cochlear genes provide important information for the identification of genes that potentially contribute to the generation of individual variation in cochlear responses to acoustic overstimulation. PMID- 26024953 TI - Cardiac stem cell therapy: Have we put too much hype in which cell type to use? AB - Injection of various stem cells has been tested with the hopes of improving cardiac function after a myocardial infarction (MI). However, there is continued controversy as to which cell type is best for repair. Due to technical differences in cell isolation, processing, delivery, and cardiac functional assessment by various investigators, it has been difficult to directly compare the results of different cells. Using same techniques to evaluate the efficacy of different cell types, we have separately delivered bone marrow cells (BMCs), cardiospheres (CSs), CS-derived Sca-1(+)/CD45(-) cells, human embryonic stem cell derived cardiomyocytes, and BMC extract into infarcted murine myocardium and found that all of these treatments reduce infarct size and improve cardiac function post-MI similarly without one regimen being superior to another. The beneficial effects appear to be via paracrine influences. Different progenitors lead to improved cardiac function post-MI, but it is premature to hype any specific cell type at this time. PMID- 26024954 TI - Titin mutations: the fall of Goliath. AB - Titin (TTN), the largest protein in the human body, forms powerful elastic filaments along the sarcomere of cardiomyocytes. This multifunctional protein is involved in numerous cellular processes, including sarcomeric assembly, stabilization and mechanosensing. Along physiological sarcomere lengths, TTN is also the most important determinant of the passive tension of cardiac muscle. However, as the giant Goliath was brought down by David's slingshot, so single base-pair mutations in the gene encoding TTN (TTN) can ultimately impair to some degree a normal cardiac function. Since the first report on the involvement of TTN mutations in the development of hypertrophic cardiomyopathy, in 1999, dozens of other mutations have been described and associated with the onset of cardiac disease. In this review, we aim to explore some of the mechanisms underlying the functions of TTN, as well as the pathophysiological consequences arising from the expression of abnormal TTN isoforms resulting from mutations located along TTN. PMID- 26024955 TI - Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat. AB - English-language literature cited in MEDLINE from January, 1980 to October 30, 2014 was searched by using terms of antipsychotic, generic and brand names of atypical antipsychotics, "bipolar depression/bipolar disorder", "placebo", and "trial". The parameters of response (>=50% improvement on MADRS, Montgomery Asberg Depression Rating Scale total score), remission (either <=12 or 8 on MADRS total score at endpoint), discontinuation due to adverse events (DAEs), somnolence, >=7% weight gain, overall extrapyramidal side-effects (EPSs), and akathisia, were extracted from originally published primary outcome papers. The number needed to treat to benefit (NNT) for response and remission or harm (NNH) for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95% confidence interval. Olanzapine monotherapy, olanzapine fluoxetine combination (OFC), quetiapine-IR monotherapy, quetiapine-XR monotherapy, lurasidone monotherapy, and lurasidone adjunctive therapy were superior to placebo with NNTs for responses of 11-12, 4, 7-8, 4, 4-5, and 7, and NNTs for remission of 11-12, 4, 5-11, 7, 6-7, and 6, respectively. There was no significant difference between OFC and lamotrigine, and between aripiprazole or ziprasidone and placebo in response and remission. Olanzapine monotherapy, quetiapine-IR, quetiapine-XR, aripiprazole, and ziprasidone 120-160 mg/day had significantly increased risk for DAEs with NNHs of 24, 8-14, 9, 12, and 10, respectively. For somnolence, quetiapine-XR had the smallest NNH of 4. For >=7% weight gain, olanzapine monotherapy and OFC had the smallest NNHs with both of 5. For akathisia, aripiprazole had the smallest NNH of 5. These findings suggest that among the FDA-approved agents including OFC, quetiapine-IR and -XR, lurasidone monotherapy and adjunctive therapy to a mood stabilizer, the differences in the NNTs for response and remission are small, but the differences in NNHs for DAEs and common side-effects are large. Therefore, the selection of an FDA-approved atypical antipsychotic for bipolar depression should be based upon safety and tolerability. PMID- 26024957 TI - Information entropy-based classification of triterpenoids and steroids from Ganoderma. AB - A set of 71 triterpenoid and steroid compounds from Ganoderma were periodically classified using a procedure based on information entropy with artificial intelligence. Six features were used in hierarchical order to classify the triterpenoids and steroids structurally. The phytochemicals belonging to the same group in the periodic table present similar antioxidant activity, and those compounds belonging to the same period exhibit maximum resemblance. The periodic classification is related to the experimental bioactivity and antioxidant potency data that are available in the literature: a steroid with a three-ketone group conjugated with two carbon-carbon double bonds in the right side of the periodic table exhibits the greatest antioxidant activity. PMID- 26024956 TI - Serological surveillance studies confirm the Rift Valley fever virus free status in South Korea. AB - Rift Valley fever is a mosquito-borne zoonotic disease of domestic ruminants. This disease causes abortions in pregnant animals, and it has a high mortality rate in newborn animals. Recently, a Rift Valley fever virus (RVFV) outbreak in the Arabian Peninsula increased its potential spread to new regions worldwide. In non-endemic or disease-free countries, early detection and surveillance are important for preventing the introduction of RVFV. In this study, a serological surveillance was conducted to detect antibodies against RVFV. A total of 2382 serum samples from goats and cattle were randomly collected from nine areas in South Korea from 2011 to 2013. These samples were tested for antibodies against RVFV, using commercial ELISA kits. None of the goats and cattle were positive for antibodies against RVFV. This finding suggests that this disease is not present in South Korea, and furthermore presents the evidence of the RVFV-free status of this country. PMID- 26024958 TI - The multi-tasked life of GM1 ganglioside, a true factotum of nature. AB - GM1 ganglioside occurs widely in vertebrate tissues, where it exhibits many essential functions, both in the plasma membrane and intracellular loci. Its essentiality is revealed in the dire consequences resulting from genetic deletion. This derives from its key roles in several signalosome systems, characteristically located in membrane rafts, where it associates with specific proteins that have glycolipid-binding domains. Thus, GM1 interacts with proteins that modulate mechanisms such as ion transport, neuronal differentiation, G protein-coupled receptors (GPCRs), immune system reactivities, and neuroprotective signaling. The latter occurs through intimate association with neurotrophin receptors, which has relevance to the etiopathogenesis of neurodegenerative diseases and potential therapies. Here, we review the current state of knowledge of these GM1-associated mechanisms. PMID- 26024959 TI - Microbiological study of bacteriophage induction in the presence of chemical stress factors in enhanced biological phosphorus removal (EBPR). AB - Polyphosphate accumulating organisms (PAOs) are responsible for carrying the enhanced biological phosphorus removal (EBPR). Although the EBPR process is well studied, the failure of EBPR performance at both laboratory and full-scale plants has revealed a lack of knowledge about the ecological and microbiological aspects of EBPR processes. Bacteriophages are viruses that infect bacteria as their sole host. Bacteriophage infection of polyphosphate accumulating organisms (PAOs) has not been considered as a main contributor to biological phosphorus removal upsets. This study examined the effects of different stress factors on the dynamics of bacteriophages and the corresponding effects on the phosphorus removal performance in a lab-scale EBPR system. The results showed that copper (heavy metal), cyanide (toxic chemical), and ciprofloxacin (antibiotic), as three different anthropogenic stress factors, can induce phages integrated onto bacterial genomes (i.e. prophages) in an enriched EBPR sequencing batch reactor, resulting in a decrease in the polyphosphate kinase gene ppk1 clades copy number, phosphorus accumulation capacity, and phosphorus removal performance. This study opens opportunities for further research on the effects of bacteriophages in nutrient cycles both in controlled systems such as wastewater treatment plants and natural ecosystems. PMID- 26024960 TI - A global analysis approach for investigating structural resilience in urban drainage systems. AB - Building resilience in urban drainage systems requires consideration of a wide range of threats that contribute to urban flooding. Existing hydraulic reliability based approaches have focused on quantifying functional failure caused by extreme rainfall or increase in dry weather flows that lead to hydraulic overloading of the system. Such approaches however, do not fully explore the full system failure scenario space due to exclusion of crucial threats such as equipment malfunction, pipe collapse and blockage that can also lead to urban flooding. In this research, a new analytical approach based on global resilience analysis is investigated and applied to systematically evaluate the performance of an urban drainage system when subjected to a wide range of structural failure scenarios resulting from random cumulative link failure. Link failure envelopes, which represent the resulting loss of system functionality (impacts) are determined by computing the upper and lower limits of the simulation results for total flood volume (failure magnitude) and average flood duration (failure duration) at each link failure level. A new resilience index that combines the failure magnitude and duration into a single metric is applied to quantify system residual functionality at each considered link failure level. With this approach, resilience has been tested and characterised for an existing urban drainage system in Kampala city, Uganda. In addition, the effectiveness of potential adaptation strategies in enhancing its resilience to cumulative link failure has been tested. PMID- 26024961 TI - Dynamics of dissolved organic carbon (DOC) through stormwater basins designed for groundwater recharge in urban area: Assessment of retention efficiency. AB - Managed aquifer recharge (MAR) has been developed in many countries to limit the risk of urban flooding and compensate for reduced groundwater recharge in urban areas. The environmental performances of MAR systems like infiltration basins depend on the efficiency of soil and vadose zone to retain stormwater-derived contaminants. However, these performances need to be finely evaluated for stormwater-derived dissolved organic matter (DOM) that can affect groundwater quality. Therefore, this study examined the performance of MAR systems to process DOM during its transfer from infiltration basins to an urban aquifer. DOM characteristics (fluorescent spectroscopic properties, biodegradable and refractory fractions of dissolved organic carbon -DOC-, consumption by micro organisms during incubation in slow filtration sediment columns) were measured in stormwater during its transfer through three infiltration basins during a stormwater event. DOC concentrations sharply decreased from surface to the aquifer for the three MAR sites. This pattern was largely due to the retention of biodegradable DOC which was more than 75% for the three MAR sites, whereas the retention of refractory DOC was more variable and globally less important (from 18% to 61% depending on MAR site). Slow filtration column experiments also showed that DOC retention during stormwater infiltration through soil and vadose zone was mainly due to aerobic microbial consumption of the biodegradable fraction of DOC. In parallel, measurements of DOM characteristics from groundwaters influenced or not by MAR demonstrated that stormwater infiltration increased DOC quantity without affecting its quality (% of biodegradable DOC and relative aromatic carbon content -estimated by SUVA254-). The present study demonstrated that processes occurring in soil and vadose zone of MAR sites were enough efficient to limit DOC fluxes to the aquifer. Nevertheless, the enrichments of DOC concentrations measured in groundwater below infiltration basins need to be considered in future studies to especially assess their impact on groundwater quality. PMID- 26024963 TI - Maternal metabolizable protein restriction during late gestation on uterine and umbilical blood flows and maternal and fetal amino acid concentrations near term in sheep. AB - To examine the effects of maternal metabolizable protein (MP) restriction during late gestation on uterine and umbilical blood flows, conceptus size, and amino acid concentrations in the uterine and umbilical vessels, 11 ewes with singleton pregnancies were assigned to one of three isocaloric diets formulated to provide 60% of MP (MP60), 80% of MP (MP80), or 100% of MP (MP100) requirements from days 100 to 130 of gestation. On day 130 of gestation, intraoperative uterine and umbilical blood flows were obtained as well as serum samples from the uterine artery, uterine vein, umbilical artery, and umbilical vein. Ewes on the MP60 diet had lighter (P=0.04) and smaller (P<=0.05) fetuses, but increased (P=0.02) uterine blood flow relative to fetal weight compared with MP100 ewes, with MP80 being intermediate. Umbilical blood flow was similar (P=0.70) across treatments. Glutamine, glycine, isoleucine, leucine, ornithine, serine, and valine concentrations were impacted (P<=0.02) by maternal treatment. While uterine flux of total serum nitrites was greater (P=0.03) in MP60 and MP80 ewes compared with MP100 ewes, fetal flux did not differ. Decreased maternal protein intake resulted in less (P<0.01) maternal cytochrome P450 1A enzyme activity. There were minimal impacts of maternal diet on steroid concentrations. Maternal dietary protein may alter fetal growth by impacting placental vasculature function and nutrient absorptive capabilities. PMID- 26024964 TI - Effect of Vitamin D on basal and Luteinizing Hormone (LH) induced testosterone production and mitochondrial dehydrogenase activity in cultured Leydig cells from immature and mature rams. AB - The objectives of this study were to investigate the potential effects of 1alpha,25-(OH)2VD3 (biologically active form of Vitamin D) on basal and LH induced testosterone production and mitochondrial dehydrogenase activity in Leydig cells from immature and mature rams cultured in vitro. Leydig cells were isolated from testes of immature and mature rams, treated without (control) or with increasing concentrations of LH (1, 10, 100ng/ml) and/or 1alpha,25-(OH)2VD3 (1, 10, 100nM). After 24h, concentrations of testosterone in culture media were measured. After 96h, mitochondrial dehydrogenase activity in Leydig cells were measured. In immature and mature ram Leydig cells, treatment with 10 and 100ng/ml LH increased testosterone production and mitochondrial dehydrogenase activity. Treatment with 1alpha,25-(OH)2VD3 in the absence of LH did not increase testosterone production, but 10 and 100nM 1alpha,25-(OH)2VD3 increased LH induced testosterone production for both immature and mature ram Leydig cells. Treatment with all doses of 1alpha,25-(OH)2VD3 in the absence of LH and 10 and 100ng/ml LH in the absence of 1alpha,25-(OH)2VD3 increased mitochondrial dehydrogenase activity for cultured Leydig cells from immature and mature rams and 1 and 10nM 1alpha,25-(OH)2VD3 treatment enhanced the LH induced increase in mitochondrial dehydrogenase activity. Result demonstrate Vitamin D3 induced regulation of function of Leydig cells from immature and mature rams cultured in the presence or absence of LH and support a potential role for Vitamin D3 in regulation of gonadal function in rams. PMID- 26024962 TI - Oxidative and nitrative stress in neurodegeneration. AB - Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage. PMID- 26024965 TI - Reproductive performance in ewes fed varying levels of cut lucerne pasture around conception. AB - Elevated intakes of protein and energy may increase embryo mortality, but it is not clear whether fresh lucerne (Medicago sativa) pasture poses a risk. A two year pen study using oestrous synchronised and artificially inseminated Merino ewes (n=175 in 2013 and 215 in 2014) evaluated whether feeding freshly cut lucerne pasture (mean crude protein 19.7%, metabolisable energy 9.4MJ/kg DM) at maintenance or ad libitum during different periods around insemination altered reproductive performance in comparison with ewes fed a Control diet (mean crude protein 7.8%, metabolisable energy 9.0MJ/kg DM) of pelleted faba bean hulls and oat grain hulls at maintenance. The proportion of pregnant ewes carrying multiple fetuses was reduced (P=0.026) when ewes were fed lucerne ad libitum between days 0 and 17 after insemination compared with the Control diet (0.18 and 0.34, respectively), but not when ewes were fed lucerne ad libitum between days 0 and 7 after insemination (0.22). Reproductive performance, including the proportion of ewes pregnant and the proportion with multiple fetuses, was not different (P>0.05) when ewes were fed lucerne at maintenance between days 0 and 7 compared with the Control diet. While reproductive performance was similar when ewes were fed lucerne at maintenance between 0 and 17 days after artificial insemination compared with pellets at maintenance, fetal numbers per pregnant ewe were reduced by feeding lucerne ad libitum after insemination. PMID- 26024967 TI - Incorrect predictions reduce switch costs. AB - In three experiments, we combined two sources of conflict within a modified task switching procedure. The first source of conflict was the one inherent in any task switching situation, namely the conflict between a task set activated by the recent performance of another task and the task set needed to perform the actually relevant task. The second source of conflict was induced by requiring participants to guess aspects of the upcoming task (Exps. 1 & 2: task identity; Exp. 3: position of task precue). In case of an incorrect guess, a conflict accrues between the representation of the guessed task and the actually relevant task. In Experiments 1 and 2, incorrect guesses led to an overall increase of reaction times and error rates, but they reduced task switch costs compared to conditions in which participants predicted the correct task. In Experiment 3, incorrect guesses resulted in faster performance overall and to a selective decrease of reaction times in task switch trials when the cue-target interval was long. We interpret these findings in terms of an enhanced level of controlled processing induced by a combination of two sources of conflict converging upon the same target of cognitive control. PMID- 26024966 TI - Development of a chronic kidney disease patient navigator program. AB - BACKGROUND: Chronic Kidney Disease (CKD) is a public health problem and there is a scarcity of type 2 CKD translational research that incorporates educational tools. Patient navigators have been shown to be effective at reducing disparities and improving outcomes in the oncology field. We describe the creation of a CKD Patient Navigator program designed to help coordinate care, address system barriers, and educate/motivate patients. METHODS: The conceptual framework for the CKD Patient Navigator Program is rooted in the Chronic Care Model that has a main goal of high-quality chronic disease management. Our established multidisciplinary CKD research team enlisted new members from information technology and data management to help create the program. It encompassed three phases: hiring, training, and implementation. For hiring, we wanted a non-medical or lay person with a college degree that possessed strong interpersonal skills and experience in a service-orientated field. For training, there were three key areas: general patient navigator training, CKD education, and electronic health record (EHR) training. For implementation, we defined barriers of care and created EHR templates for which pertinent study data could be extracted. RESULTS: We have hired two CKD patient navigators who will be responsible for navigating CKD patients enrolled in a clinical trial. They have undergone training in general patient navigation, specific CKD education through directed readings and clinical shadowing, as well as EHR and other patient related privacy and research training. CONCLUSIONS: The need for novel approaches like our CKD patient navigator program designed to impact CKD care is vital and should utilize team based care and health information technology given the changing landscape of our health systems. PMID- 26024968 TI - Controlling for conservation in genome-wide DNA methylation studies. AB - BACKGROUND: A commonplace analysis in high-throughput DNA methylation studies is the comparison of methylation extent between different functional regions, computed by averaging methylation states within region types and then comparing averages between regions. For example, it has been reported that methylation is more prevalent in coding regions as compared to their neighboring introns or UTRs, leading to hypotheses about novel forms of epigenetic regulation. RESULTS: We have identified and characterized a bias present in these seemingly straightforward comparisons that results in the false detection of differences in methylation intensities across region types. This bias arises due to differences in conservation rates, rather than methylation rates, and is broadly present in the published literature. When controlling for conservation at coding start sites the differences in DNA methylation rates disappear. Moreover, a re-evaluation of methylation rates at intronexon junctions reveals that the magnitude of previously reported differences is greatly exaggerated. We introduce two correction methods to address this bias, an inferencebased matrix completion algorithm and an averaging approach, tailored to address different underlying biological questions. We evaluate how analysis using these corrections affects the detection of differences in DNA methylation across functional boundaries. CONCLUSIONS: We report here on a bias in DNA methylation comparative studies that originates in conservation rate differences and manifests itself in the false discovery of differences in DNA methylation intensities and their extents. We have characterized this bias and its broad implications, and show how to control for it so as to enable the study of a variety of biological questions. PMID- 26024969 TI - Effects of artesunate against Trypanosma cruzi. AB - Therapy against Trypanosma cruzi relies on only two chemically related nitro derivative drugs, benznidazole and nifurtimox, both limited by poor efficacy and toxicity. It is suspected that with prolonged usage of these drugs, resistant parasites will be selected, which results in risk for treatment failure over the time. Herein, we studied the in vitro activity of artesunate, the most effective drug to treat severe P. falciparum and chloroquine-resistant P. vivax, on three strains of T. cruzi originated in different regions of Latin America (Argentina, Nicaragua and Brazil). The results of these assays showed that artesunate inhibits multiplication of epimastigotes (IC50 = 50, 6.10 and 23 uM, respectively) and intracellular amastigotes (IC50 = 15, 0.12 and 6.90 uM, respectively), indicating that it represents a potent anti-T. cruzi compound in terms of inhibiting parasite multiplication in vitro. We then tested the effect of artesunate in Balb/c mice infected with Brazil strain and found that it failed to cure the infection, suggesting that the drug may be unsuitable for in vivo treatment. When infected mice were treated with high doses AS + BZ, the outcome of infection was similar to that observed in mice treated with BZ alone. Nevertheless, understanding of structure-activity relationship of artesunate might lead to the development of new and effective drugs against T. cruzi. PMID- 26024971 TI - Programming the emergence in morphogenetically architected complex systems. AB - Large sets of elements interacting locally and producing specific architectures reliably form a category that transcends the usual dividing line between biological and engineered systems. We propose to call them morphogenetically architected complex systems (MACS). While taking the emergence of properties seriously, the notion of MACS enables at the same time the design (or "meta design") of operational means that allow controlling and even, paradoxically, programming this emergence. To demonstrate our claim, we first show that among all the self-organized systems studied in the field of Artificial Life, the specificity of MACS essentially lies in the close relation between their emergent properties and functional properties. Second, we argue that to be a MACS a system does not need to display more than weak emergent properties. Third, since the notion of weak emergence is based on the possibility of simulation, whether computational or mechanistic via machines, we see MACS as good candidates to help design artificial self-architected systems (such as robotic swarms) but also harness and redesign living ones (such as synthetic bacterial films). PMID- 26024970 TI - Turning the headlights on novel cancer biomarkers: Inspection of mechanics underlying intratumor heterogeneity. AB - Although the existence of intratumoral heterogeneity (ITH) in the expression of common biomarkers has been described by pathologists since the late 1890s, we have only recently begun to fathom the staggering extent and near ubiquity of this phenomenon. From the tumor's perspective, ITH provides a stabilizing diversity that allows for the evolution of aggressive cancer phenotypes. As the weight of the evidence correlating ITH to poor prognosis burgeons, it has become increasingly important to determine the mechanisms by which a tumor acquires ITH, find clinically-adaptable means to quantify ITH and design strategies to deal with the numerous profound clinical ramifications that ITH forces upon us. Elucidation of the drivers of ITH could enable development of novel biomarkers whose interrogation might permit quantitative evaluation of the ITH inherent in a tumor in order to predict the poor prognosis risk associated with that tumor. This review proposes centrosome amplification (CA), aided and abetted by centrosome clustering mechanisms, as a critical driver of chromosomal instability (CIN) that makes a key contribution to ITH generation. Herein we also evaluate how a tumor's inherent mitotic propensity, which reflects the cell cycling kinetics within the tumor's proliferative cells, functions as the indispensable engine underpinning CIN, and determines the rate of CIN. We thus expound how the forces of centrosome amplification and mitotic propensity collaborate to sculpt the genetic landscape of a tumor and spawn extensive subclonal diversity. As such, centrosome amplification and mitotic propensity profiles could serve as clinically facile and powerful prognostic biomarkers that would enable more accurate risk segmentation of patients and design of individualized therapies. PMID- 26024972 TI - Effects of ovarian dopaminergic receptors on ovulation. AB - Hormonal and neural signals regulate the ovarian follicular development. The present study's hypothesis is that the blockade of ovarian dopamine receptors locally will affect follicle development and ovulation. Groups of adult 4-day cyclic rats of the CII-ZV strain on estrus, diestrus-1, diestrus-2, or proestrus day were injected with vehicle, haloperidol (DA2 > DA1 blocker), sulpiride (DA2 blocker), or SCH-23390 (DA1 blocker) into the bursa of both ovaries at 08:00, 13:00, or 20:00 h. Animals were sacrificed the following predicted estrus day. The following treatments blocked ovulation: injecting haloperidol to rats on estrus or diestrus-1 at 8:00, 13:00, or 20:00 h and to rats on diestrus-2 at 08:00, or 20:00 h; injecting SCH-23390 to rats on diestrus-1 at 8:00, 13:00, or 20:00 h; injecting sulpiride to rats on estrus at 20:00 h, diestrus-1 at 08:00, 13:00, or 20:00 h and to rats on diestrus-2 at 08:00 h. In rats treated with any of the dopamine antagonists that blocked ovulation, injecting GnRH at 14.00 h on the next predicted proestrus day restored ovulation. Injecting estradiol benzoate at 14.00 h of the next predicted diestrus-2 restored ovulation in some animals treated with haloperidol on estrus or diestrus-2 and was ineffective in rats treated on diestrus-1. In rats treated with sulpiride or SCH-23390 ovulation occurred in most animals (SCH-23390: 6/8; SPD: 9/12). Present results suggest that dopamine ovarian receptors' participation in regulating follicular development and ovulation varies along the estrus cycle, with their most prominent activity occurring on diestrus-1. PMID- 26024973 TI - Quality of life in the patients with central diabetes insipidus assessed by Nagasaki Diabetes Insipidus Questionnaire. AB - Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia due to a deficiency of vasopressin. Currently, the treatment goal for CDI is improvement of quality of life (QOL) by desmopressin (DDAVP) without developing hyponatremia. However, there is no reliable measure for QOL in CDI patients. We evaluate our original questionnaire for QOL, consisting of 12 questions focusing on polyuria, polydipsia, and DDAVP treatment, in CDI patients who underwent a switch from nasal spray to oral disintegrating tablets of DDAVP. Twenty-five CDI patients under nasal DDAVP treatment, six with newly developed CDI, and 18 healthy individuals without known polyuric/polydipsic disorders as control subjects were enrolled. QOL scores were determined by our questionnaire at the enrollment and 3 months after the start of oral DDAVP treatment and were examined by the Wilcoxon signed-rank test. Eleven questions detected improvement in QOL. The sum of the QOL scores of the eleven questions increased from 29.2 +/- 5.6 under nasal to 36.8 +/- 4.5 under oral DDAVP (p < 0.001). There were no clinically relevant changes in serum levels of Na. After eliminating two questions about DDAVP treatment, the sum of QOL scores was 15.3 +/- 6.5 in untreated CDI patients, 24.4 +/- 5.2 in those with nasal treatment, 28.9 +/- 4.9 in those with oral DDAVP, and 29.5 +/- 3.6 in healthy controls. The difference among groups was significant (p < 0.05 in Steel-Dwass test) except between patients treated with oral DDAVP and healthy controls. Our questionnaire can be used to accurately assess QOL in CDI patients. PMID- 26024974 TI - Particulate matter pollutants and risk of type 2 diabetes: a time for concern? AB - The World Health Organization estimates that worldwide in 2012 around 7 million deaths occurred prematurely due to air pollution, which is now the world's largest single environmental health risk. The higher premature mortality associated with air pollution is due to exposure to small particulate matter of 10 microns (PM10) or less in diameter. Exposure to air pollution has also been suggested as a contributing to diabetes incidence and progression. There are a number of possible biological pathways linking air pollutants to diabetes, including endothelial dysfunction, dysregulation of the visceral adipose tissue through inflammation, hepatic insulin resistance, elevated hemoglobin A1c level, elevated blood pressure, and alterations in autonomic tone, which may increase insulin resistance. The risk of future diabetes associated with exposure to 10 MUg/m(3) increase of PM2.5 has been quantified in the range of 10 to 27%; the risk of diabetes mortality associated with PM2.5 appears to be quite lower, around 1% for each increment exposure of 10 MUg/m(3) of both PM2.5 and PM10. Limitations of the current epidemiological evidence include the complex mixture of pollutants, the different design of the studies, the limited data available for non Western populations, and the lack of demonstration that improvement of air quality is associated with a decrease incidence of type 2 diabetes. Although the most sources of outdoor air pollution are well beyond the control of individuals, people should be informed that there are means to reduce the burden of air pollutants on diabetes risk, including avoidance of passive smoking, adoption of an healthy diet, and increasing leisure-time physical activity. PMID- 26024975 TI - Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis? AB - Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "PCOS." Several cross-sectional and case-control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases. PMID- 26024976 TI - Longitudinal associations between lifestyle and vitamin D: A general population study with repeated vitamin D measurements. AB - Several lifestyle factors have been found to be associated with vitamin D status in cross-sectional studies, but it is not clear whether a change in these factors can actually affect the vitamin D level. We investigated the association between repeated measurements of physical activity, body mass index (BMI), diet, alcohol consumption, and smoking habits, and corresponding levels of vitamin D during 5 years of follow-up of a large general population sample. We included 4185 persons who participated and had vitamin D (serum-25-hydroxyvitamin D, 25-OH-D) measurements in the Inter99 study at baseline (1999-2001) and 5-year follow-up. In a subsample, 25-OH-D was also measured at 1- and 3-year follow-ups. We used mixed models to examine the association between repeated measurements of lifestyle factors and 25-OH-D levels. In multivariable analyses of repeated measurements, the difference in 25-OH-D was -0.32 ng/ml (95 % CI -0.37, -0.28) per 1 kg/m(2) increase in BMI; 4.50 ng/ml (95 % CI 3.84, 5.15) for persons moderately/vigorously physically active versus sedentary; 1.82 ng/ml (95 % CI 1.09, 2.56) for persons with healthy versus unhealthy dietary habits; 0.05 ng/ml (95 % CI 0.03, 0.07) per 1 standard drink/weak increase in alcohol consumption; and 0.86 ng/ml (95 % CI 0.36, 1.35) for never smokers versus daily smokers. Our study shows that lower BMI, a higher level of physical activity, a healthier diet and possibly a higher alcohol intake, and not smoking, are associated with higher 25-OH-D levels. PMID- 26024977 TI - MicroRNA-mediated immune modulation as a therapeutic strategy in host-implant integration. AB - The concept of implanting an artificial device into the human body was once the preserve of science fiction, yet this approach is now often used to replace lost or damaged biological structures in human patients. However, assimilation of medical devices into host tissues is a complex process, and successful implant integration into patients is far from certain. The body's immediate response to a foreign object is immune-mediated reaction, hence there has been extensive research into biomaterials that can reduce or even ablate anti-implant immune responses. There have also been attempts to embed or coat anti-inflammatory drugs and pro-regulatory molecules onto medical devices with the aim of preventing implant rejection by the host. In this review, we summarize the key immune mediators of medical implant reaction, and we evaluate the potential of microRNAs to regulate these processes to promote wound healing, and prolong host-implant integration. PMID- 26024980 TI - Exploring interactions between semantic and syntactic processes: The role of animacy in syntactic priming. AB - The current study addressed the relation between syntactic and semantic processes during language production in 5- and 6-year-old children. A priming paradigm was used to examine children's production of passives in describing transitive scenes (target pictures) following exposure to the experimenter's sentences (primes). The key question was whether the tendency to repeat the syntactic form of the prime was affected by the animacy features in the prime and the target picture. In Experiment 1, children heard either passive or active primes with varied animacy configurations (e.g., animate patient/inanimate agent vs. inanimate patient/animate agent). The animacy features of the prime matched those of the target. Similar to prior studies, results showed a greater use of passives following passive, as opposed to active, primes. Critically, the difference between the two priming conditions varied as a function of animacy; it was larger when the prime and the target included an animate patient/inanimate agent than with the reversed animacy. In Experiment 2, the animacy configuration of the prime either matched or did not match that of the target. Results showed a greater likelihood of producing a passive when the target picture contained an animate patient versus an inanimate patient, and this effect was stronger when the prime had the same animacy features. The findings indicating that syntactic priming is moderated by animacy are discussed in the broader context of understanding the role of semantics in guiding the choice of syntactic structure. PMID- 26024981 TI - Efficacy and time course of paired associative stimulation in cortical plasticity: Implications for neuropsychiatry. AB - OBJECTIVE: Paired associative stimulation (PAS) has been used to study normal and abnormal cortical plasticity. However, a normative review of PAS effects has not been provided so far. To this end, the magnitude and time course of PAS protocols was systematically evaluated here. METHODS: A literature search in PubMed using the search term paired associative stimulation was conducted. Main inclusion criteria were that experiments were conducted in primary motor cortex of healthy volunteers without motor training before intervention and motor evoked potentials as primary outcome measure. This search yielded in total 104 experiments, which were analyzed to examine the potentiating (PASLTP) and depressing effects of PAS (PASLTD) on cortical excitability levels in healthy volunteers. RESULTS: PASLTP induces reliable and stable potentiating effects (maximum +/- standard error 38.5 +/- 3.3%) on cortical excitability levels up to 90 min. PASLTP was most effective when applied at frequencies of 0.05 and 0.2 Hz. Analyses of the PASLTD studies demonstrated reliable and stable depression of cortical excitability levels up to 120 min (maximum +/- standard error -23.0 +/- 1.9%) CONCLUSIONS: PAS significantly modulates cortical excitability. The potentiating effects of PASLTP are stronger than the depressing effects for PASLTD. SIGNIFICANCE: Present findings offer normative insights into the magnitude and time course of PASLTP and PASLTD-induced changes in cortical excitability levels. PMID- 26024982 TI - Cortical correlates of response time slowing in older adults: ERP and ERD/ERS analyses during passive ankle movement. AB - OBJECTIVES: The response time (RT) to kinesthetic perception has been used as a proprioceptive measurement, for example, in older individuals. However, the RT cannot provide information on impairments at specific stages of the respective sensorimotor processing. In the present study, electroencephalographic (EEG) signals were recorded during passive ankle movement with and without an associated perceptual task of movement detection. The main purpose was to analyze differences between young and older adults both in terms of RT and cortical responses. Putative differences in the latter were expected to point to changes in the processing associated with neural pathways or cortical regions in the older subjects. METHODS: The EEG activity of nineteen older (OA, 65-76 years) and 19 young adults (YA, 21-32 years) was recorded during passive ankle movement, without motor voluntary response (NVR, sensory condition), and during a condition with voluntary motor response (VR, with measurement of the RT). Event-related potentials (ERP) and beta event-related desynchronization/synchronization (ERD/ERS) were recorded and analyzed in both experimental conditions. RESULTS: The RT in OA was larger than in YA (P<0.0001). EEG analyses showed that the N1 amplitude was larger in the VR than in the NVR condition (P=0.006), whereas no difference for latency was obtained between conditions (P=0.376). Comparisons between the groups revealed attenuated (P=0.019) and delayed (P=0.001) N1 in the OA group, irrespective of the condition (no interaction group vs condition). Only OA showed correlations between RT and N1, with significant correlation for both amplitude (r=-0.603, P=0.006) and latency (r=0.703, P=0.001). The ERD/ERS analyses revealed a task-dependent group effect: in NVR, significant differences were obtained only for the ERS amplitude, which was attenuated in OA (P=0.003). In VR, larger (P=0.004) and delayed (P=0.003) ERD and attenuated (P=0.029) and delayed (P=0.017) ERS peaks were observed in the older group. CONCLUSIONS: The results suggest that a larger response time to proprioceptive stimuli in older adults is associated with a weaker and delayed proprioceptive afferent inflow to the cortex. In this scenario, older adults would need a higher cognitive effort (larger ERD) to process the sensory inputs when attempting to properly perform a sensorimotor task. SIGNIFICANCE: ERP and ERD/ERS measurements during kinesthetic assessment provide new insights on identification of the origin of sensorimotor slowing in older adults. PMID- 26024979 TI - Basic biology and therapeutic implications of lncRNA. AB - Long non-coding RNAs (lncRNA), a class of non-coding RNA molecules recently identified largely due to the efforts of FANTOM, and later GENCODE and ENCODE consortia, have been a subject of intense investigation in the past decade. Extensive efforts to get deeper understanding of lncRNA biology have yielded evidence of their diverse structural and regulatory roles in protecting chromosome integrity, maintaining genomic architecture, X chromosome inactivation, imprinting, transcription, translation and epigenetic regulation. Here we will briefly review the recent studies in the field of lncRNA biology focusing mostly on mammalian species and discuss their therapeutic implications. PMID- 26024978 TI - MicroRNA delivery for regenerative medicine. AB - MicroRNA (miRNA) directs post-transcriptional regulation of a network of genes by targeting mRNA. Although relatively recent in development, many miRNAs direct differentiation of various stem cells including induced pluripotent stem cells (iPSCs), a major player in regenerative medicine. An effective and safe delivery of miRNA holds the key to translating miRNA technologies. Both viral and nonviral delivery systems have seen success in miRNA delivery, and each approach possesses advantages and disadvantages. A number of studies have demonstrated success in augmenting osteogenesis, improving cardiogenesis, and reducing fibrosis among many other tissue engineering applications. A scaffold-based approach with the possibility of local and sustained delivery of miRNA is particularly attractive since the physical cues provided by the scaffold may synergize with the biochemical cues induced by miRNA therapy. Herein, we first briefly cover the application of miRNA to direct stem cell fate via replacement and inhibition therapies, followed by the discussion of the promising viral and nonviral delivery systems. Next we present the unique advantages of a scaffold-based delivery in achieving lineage-specific differentiation and tissue development. PMID- 26024983 TI - B-mode transorbital ultrasononography for the diagnosis of acute optic neuritis. A systematic review. AB - OBJECTIVE: In patients with acute optic neuritis (AON) transorbital sonography may reveal a thickening of the retrobulbar portion of the optic nerve. Our aim was to systematically review the diagnostic accuracy of ultrasonography of optic nerve diameter (OND) for assessment of AON. METHODS: MEDLINE, EMBASE (1966 October 2014) was searched to identify studies reporting data on patients with AON (with/without multiple sclerosis) assessed by B-mode transorbital ultrasonography. Thereafter, the studies retrieved were screened based on predefined inclusion and exclusion criteria. Data were extracted and the quality of the included studies was evaluated. RESULTS: Seven studies (162 patients) were included. The OND was significantly thicker in the affected eye compared with its unaffected fellow or controls. An increased OND was found in 78-100% of patients. Four studies determined papilledema in 6-43% of patients. CONCLUSIONS: Transorbital sonography is a sensitive, highly accessible and user-friendly technique for the detection of significant optic nerve thickening on the side affected by AON and represents an adjunctive tool for the diagnosis of AON. Compared to visual evoked potentials, TOS may provide different, though complementary, information on the pathophysiology of AON. SIGNIFICANCE: B-mode transorbital ultrasonography provides promising support for the clinical diagnosis of AON. PMID- 26024984 TI - Forensic psychiatry in Pakistan. AB - This article reviews existing forensic psychiatric services in Pakistan highlighting the role played by the judicial and the medical fraternity in managing the legal and forensic issues of the population of patients with mental illnesses. Until 2001, all legal and forensic issues were dealt with the mental health legislation of 1912, the Lunacy Act of 1912. This was inherited from the British rulers in the Sub-Continent at the time. The Mental Health Ordinance of 2001 could not sustain following the 18th constitutional amendment in 2010, whereby psychiatric healthcare was devolved to the provinces from the previous federal authority. The article also highlights the difficulties and the barriers in implementation of the forensic psychiatric services in Pakistan at various levels within the healthcare system. This article also delves into the current framework of training in forensic psychiatry for postgraduates as well as the assessments and management schedules for the mentally ill offenders at tertiary care institutions in Pakistan. PMID- 26024988 TI - Reduced Length of Hospitalization in Primary Total Knee Arthroplasty Patients Using an Updated Enhanced Recovery After Orthopedic Surgery (ERAS) Pathway. AB - Decreasing hospital length of stay may attenuate costs associated with total knee arthroplasty. The purpose of this study was to determine if updates to an existing orthopedic enhanced recovery after surgery (ERAS) pathway would improve length of hospitalization. Clinical and demographic data were collected on 252 primary total knee arthroplasties between January 2012 and July 2013. Pre-updated and post-updated ERAS pathway cohorts were analyzed for length of stay, clinical outcomes, and re-admissions. The mean length of stay decreased from 76.6 hours to 56.1 hours after implementation of the evidence-based orthopedic enhanced recovery after surgery pathway (P<0.001). This improvement was possible without a concomitant increase in readmission rates. PMID- 26024989 TI - Fixation and Wear With Contemporary Acetabular Components and Cross-Linked Polyethylene at 10-Years in Patients Aged 50 and Under. AB - We evaluated the mid-term performance of a moderately cross-linked polyethylene THA bearing in younger patients. One hundred consecutive THAs performed in patients 50 years of age and under using the same cementless acetabular component and moderately cross-linked polyethylene were evaluated at minimum 10 year follow up. At final follow-up 75 patients (89 hips) were living, 7 patients (7 hips) were deceased and 4 patients (4 hips) were lost to follow-up. Average Tegner and UCLA scores were 3.7 and 5.8, respectively. Average steps per year were 1.84 million. The average linear wear rate was 0.05 mm/y and steady state wear rate was 0.033 mm/y. There was no detectable osteolysis. Minimum 10 year follow-up demonstrated durable fixation and reduced wear (P<0.001) when compared to our historical controls. PMID- 26024990 TI - Phosphatidylcholine covalently linked to a methacrylate-based monolith as a biomimetic stationary phase for capillary liquid chromatography. AB - In this study a strategy to immobilize phospholipids onto a polymer-based stationary phase is described. Methacrylate-based monoliths in capillary format (150*0.1mm) were modified by soybean phosphatidylcholine through 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide coupling to obtain stationary phases suitable to mimic cell surface membranes. The covalent coupling reaction involves the phosphate group in phospholipids; therefore, the described methodology is suitable for all types of phospholipids. Immobilization of soy bean phosphatidylcholine on the monolith was confirmed by attenuated total reflectance Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry of the fatty alcohol profile, generated upon reductive cleavage of the fatty acyl side chains of the phospholipid on the monolith surface with lithium aluminium hydride. The prepared stationary phases were evaluated through studies on the retention of low-molar mass model analytes including neutral, acidic, and basic compounds. Liquid chromatographic studies confirmed predominant hydrophobic interactions between the analytes and the synthesized stationary phase; however, electrostatic interactions contributed to the retention as well. The synthesized columns showed high stability even with fully aqueous mobile phases such as Dulbecco's phosphate-buffered saline solution. PMID- 26024991 TI - Effects of CD25siRNA gene transfer on high-risk rat corneal graft rejection. AB - BACKGROUND: Corneal graft rejection is the major cause of corneal failures. Previous studies have shown that the CD25 monoclonal antibody can inhibit corneal graft rejection during the acute phase of rejection in rat models. In the current study, we evaluated the safety and efficacy of the topical EntransterTM vector in rat corneal applications and further investigated the effects of CD25siRNA gene transfer on high-risk rat corneal graft rejection. METHODS: Fluorescence detection, clinical assessment, hematoxylin and eosin (HE), terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) and CD11b assays were used to evaluate the safety and efficacy of CD25siRNA gene transfer in normal SD rat corneas. Orthotopic corneal transplants were performed in alkali burned SD rats. Corneal recipients were divided into four groups that received different treatments. Clinical assessment, western blotting, quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry, HE and transmission electron microscopy (TEM) were performed on all grafts. RESULTS: Low toxicity, no immunogenicity and high transfection efficiency were observed in rat corneas treated with the EntransterTM vector. Reduced endothelial cell apoptosis, inflammatory cell infiltration and graft neovascularisation were observed in the CD25siRNA treatment groups. The graft survival curves showed that CD25siRNA treatment significantly prolonged graft survival time, with better graft transparency and less graft oedema. Lower CD25 and higher IL-10 expression were detected in the CD25siRNA treatment groups during the study period, and a higher FOXP3 level was found in the CD25siRNA group than in the CD25siRNA-twice group on days 14 and 21 post-operation. CONCLUSIONS: The EntransterTM vector is an effective vector for corneal gene therapy. CD25 siRNA gene transfer inhibits corneal graft rejection via upregulation of anti-inflammatory molecule expression. PMID- 26024992 TI - A safer disposal of hazardous phosphate coating sludge by formation of an amorphous calcium phosphate matrix. AB - Phosphate coating hazardous wastes originated from the automotive industry were efficiently encapsulated by an acid-base reaction between phosphates present in the sludge and calcium aluminate cement, yielding very inert and stable monolithic blocks of amorphous calcium phosphate (ACP). Two different compositions of industrial sludge were characterized and loaded in ratios ranging from 10 to 50 wt.%. Setting times and compressive strengths were recorded to establish the feasibility of this method to achieve a good handling and a safe landfilling of these samples. Short solidification periods were found and leaching tests showed an excellent retention for toxic metals (Zn, Ni, Cu, Cr and Mn) and for organic matter. Retentions over 99.9% for Zn and Mn were observed even for loadings as high as 50 wt.% of the wastes. The formation of ACP phase of low porosity and high stability accounted for the effective immobilization of the hazardous components of the wastes. PMID- 26024993 TI - Comparative assessment of compost and zeolite utilisation for the simultaneous removal of BTEX, Cd and Zn from the aqueous phase: Batch and continuous flow study. AB - The present study focuses on the comparison of two materials, compost from municipal solid waste and natural zeolite for the simultaneous removal of petroleum hydrocarbons (benzene, toluene, ethylbenzene, xylenes - BTEX) and toxic metals from groundwater. First, batch experiments were conducted to identify the optimal removal conditions. All of the kinetic experiments were fitted to the pseudo-second-order kinetic model; equilibrium was reached within approximately 8 h for the zeolite and 12 h for the compost. An increase in the adsorbent dose and the pH value as well as a decrease in the initial concentration enhanced the pollutants' removal. The removal selectivity of both materials with slight differences follows the order Cd > Zn & toluene > ethylbenzene > m- & p-xylene > o-xylene > benzene. According, to the results derived from the continuous flow experiments the maximum adsorption capacity of the compost (90%) referred to Cd (0.88 mmol/g) whereas the minimum refers to benzene (65%) with a capacity up to 0.065 mmol/g. Zeolite had lower efficiencies for the studied pollutants with a higher performance corresponding to Cd (0.26 mmol/g), whereas the minimum zeolite capacity (63%) corresponds to toluene (0.045 mmol/g). Thus, this paper provides evidence that compost, a low cost material produced from waste, is capable for the simultaneous removal of both organic and inorganic pollutants from wastewater, and its performance is superior to zeolite. PMID- 26024994 TI - Pesticide sorption and leaching potential on three Hawaiian soils. AB - On the Hawaiian Islands, groundwater is the principal source of potable water and contamination of this key resource by pesticides is of great concern. To evaluate the leaching potential of four weak acid herbicides [aminocyclopyrachlor, picloram, metsulfuron-methyl, biologically active diketonitrile degradate of isoxaflutole (DKN)] and two neutral non-ionizable herbicides [oxyfluorfen, alachlor], their sorption coefficients were determined on three prevalent soils from the island of Oahu. Metsulfuron-methyl, aminocylcopyrachlor, picloram, and DKN were relatively low sorbing herbicides (K(oc) = 3-53 mL g(-1)), alachlor was intermediate (K(oc) = 120-150 mL g(-1)), and oxyfluorfen sorbed very strongly to the three soils (K(oc) > 12,000 mL g(-1)). Following determination of K(oc) values, the groundwater ubiquity score (GUS) indices for these compounds were calculated to predicted their behavior with the Comprehensive Leaching Risk Assessment System (CLEARS; Tier-1 methodology for Hawaii). Metsulfuron-methyl, aminocyclopyrachlor, picloram, and DKN would be categorized as likely leachers in all three Hawaiian soils, indicating a high risk of groundwater contamination across the island of Oahu. In contrast, oxyfluorfen, regardless of the degradation rate, would possess a low and acceptable leaching risk due to its high sorption on all three soils. The leaching potential of alachlor was more difficult to classify, with a GUS value between 1.8 and 2.8. In addition, four different biochar amendments to these soils did not significantly alter their sorption capacities for aminocyclopyrachlor, indicating a relatively low impact of black carbon additions from geologic volcanic inputs of black carbon. Due to the fact that pesticide environmental risks are chiefly dependent on local soil characteristics, this work has demonstrated that once soil specific sorption parameters are known one can assess the potential pesticide leaching risks. PMID- 26024995 TI - Pre-service teachers' knowledge of phonemic awareness: relationship to perceived knowledge, self-efficacy beliefs, and exposure to a multimedia-enhanced lecture. AB - This study examined the relations among perceived and actual knowledge of phonemic awareness (PA), exposure to PA instruction during practicum, and self efficacy for teaching PA in a sample of 54 teacher candidates (TCs) enrolled in a 1-year Bachelor of Education program in a Canadian university. It also assessed the effects of a brief multimedia-enhanced lecture on TCs' actual knowledge of PA and efficacy ratings. Prior to the lecture, teacher candidates' scores on the PA assessment were relatively low with a mean percentage correct of 56.3%. Actual knowledge was not significantly correlated with perceived knowledge or self efficacy ratings. Perceived knowledge was significantly and positively correlated with efficacy ratings and students' rating of their exposure to PA instruction during their practicum experience. A path analysis revealed that the relationship between exposure to PA instruction and self-efficacy beliefs was mediated by perceived knowledge controlling for actual knowledge and general prior experience working with young children. Analyses also revealed that TCs made significant gains in self-efficacy as well as actual knowledge when re-assessed after the lecture with a mean post-lecture score of 71.4%. Written feedback from the TCs indicated that the digital video clips included in the lecture provided clarity regarding the type of instructional practices that teachers could use to support phonemic awareness development in children. Implications for practice and future research on teacher preparation are discussed. PMID- 26024996 TI - How willing are adolescents to record their dietary intake? The mobile food record. AB - BACKGROUND: Accurately assessing the diets of children and adolescents can be problematic. Use of technologies, such as mobile apps designed to capture food and beverages consumed at eating occasions with images taken using device embedded cameras, may address many of the barriers to gathering accurate dietary intake data from adolescents. OBJECTIVE: The objectives of this study were to assess the willingness of adolescents to take images of food and beverages at their eating occasions using a novel mobile food record (mFR) and to evaluate the usability of the user confirmation component of the mFR app, referred to as the "review process." METHODS: Mixed methods combining quantitative and qualitative protocols were used in this study. Adolescents (11-15-year olds) attending a summer camp were recruited to participate in the study. First, the participants were asked to take images of foods and beverages consumed as meals and snacks for 2 consecutive days using the mFR app running on an iPhone and the number of images taken was noted. This was followed by focus group sessions to evaluate usability, which was analyzed by content and themes. After using the mFR, a think aloud method was used to evaluate the usability of the mFR method for reviewing system-identified foods (ie, the review process). A usability questionnaire was administered at the end of all activities. RESULTS: The mFR was accepted by the majority of the 24 boys and 17 girls (n=41) but varied according to gender and eating occasion. Girls were significantly more likely than boys to capture images of their eating occasions (Fisher exact test, P=.03). Participants were more likely to take images of their breakfasts (90%, 36/40) and lunches (90%, 72/80) and least likely to capture afternoon and evening snacks, 54% (43/80) and 40% (32/80), respectively. The major themes from the focus groups with regard to using the mFR were games, rewards, and the need to know more about why they were using the app. Results of the usability questionnaire indicated that including a game component would be important to increase willingness to use the mFR, and a high majority of the participants indicated a willingness to use the mFR for 7 days or more. The image review process was found to be easy to use except for some confusion with overlapping markers on the screen. CONCLUSIONS: The adolescents' experiences with and feedback about the mFR highlighted the importance of increased training, reminders, entertainment (eg, games), and training with practice in using the device to capture complete dietary intake as part of their active lifestyles. PMID- 26024997 TI - "It's not healthy and it's decidedly not masculine": a media analysis of UK newspaper representations of eating disorders in males. AB - OBJECTIVES: Recent qualitative research found young men reporting that an expectation that eating disorders (EDs) mainly affect young women led them, and others, to only recognise their symptoms when their ED had become entrenched. This raises questions about how these stereotypes persist. We therefore explored how EDs in males were represented in articles published in UK newspapers over a 10-year period (7.12.2002-7.12.2012), specifically attending to whether newsprint media represent EDs in males as 'gender appropriate', 'gender anomalous' or 'gender neutral'. DESIGN: A qualitative thematic analysis of UK newspaper articles. METHODS: We searched two databases, Newsbank and LexisNexis, for newspaper articles including ED and male terms in the lead/first paragraph. Following de-duplication, 420 articles were scrutinised; 138 met inclusion criteria for detailed textual analysis and were imported into NVivo10. FINDINGS: The number of articles peaked in 2008 when a UK politician announced that he had experienced bulimia nervosa. Analysis of how the articles portrayed male ED related characterisations and experiences revealed that they conveyed ambiguous messages about EDs in males. Despite apparently aiming to dispel stereotypes that only young women experience EDs and to address stigma surrounding EDs in males, many aspects of the articles, including repetition of phrases such as 'a young woman's illness', serve to reinforce messages that EDs are inherently 'female' and so 'anomalous' for men. CONCLUSIONS: Newspaper articles represent men with EDs as atypical of men, as a result of having an ED (and any feminising or demasculinising characteristics associated with this), and as atypical of people with EDs, who are still usually portrayed as teenage girls. Such media representations frame a cultural paradigm in which there is an expectation that men may feel shame about or strive to conceal EDs, potentially contributing to men with EDs delaying help-seeking, gaining late access to treatments and reducing chances of successful outcomes. PMID- 26024998 TI - The relative risk of fatal poisoning by methadone or buprenorphine within the wider population of England and Wales. AB - OBJECTIVE: To examine the population-wide overdose risk emerging from the prescription of methadone and buprenorphine for opioid substitution treatment in England and Wales. DESIGN: Retrospective administrative data study. SETTING: National databases for England and Wales. PARTICIPANTS/CASES: Drug-related mortality data were drawn from the Office for National Statistics, and prescription data for methadone and buprenorphine were obtained from the National Health Service for the years 2007-2012. During this 6-year period, a total of 2366 methadone-related deaths and 52 buprenorphine-related deaths were registered, corresponding to 17,333,163 methadone and 2,602,374 buprenorphine prescriptions issued. The analysis encompassed poisoning deaths among members of the wider population of England and Wales who consumed, but were not prescribed these medications, in addition to patients prescribed methadone or buprenorphine. MAIN OUTCOME MEASURES: Mortality risk: substance-specific overdose rate per 1000 prescriptions issued; relative risk ratio of methadone in relation to buprenorphine. RESULTS: During the years 2007-2012, the pooled overdose death rate was 0.137/1000 prescriptions of methadone, compared to 0.022/1000 prescriptions of buprenorphine (including buprenorphine-naloxone). The analysis generated a relative risk ratio of 6.23 (95% CI 4.79 to 8.10) of methadone in relation to buprenorphine. UK Borders Agency data were taken into consideration and revealed that only negligible amounts of methadone and buprenorphine were seized on entering UK territory between 2007 and 2012, suggesting domestic diversion. CONCLUSIONS: Our analysis of the relative safety of buprenorphine and methadone for opioid substitution treatment reveals that buprenorphine is six times safer than methadone with regard to overdose risk among the general population. Clinicians should be aware of the increased risk of prescribing methadone, and tighter regulations are needed to prevent its diversion. PMID- 26024999 TI - The design of a multicentre Canadian surveillance study of sedation safety in the paediatric emergency department. AB - INTRODUCTION: Procedural sedation and analgesia have become standard practice in paediatric emergency departments worldwide. Although generally regarded as safe, serious adverse events such as bradycardia, asystole, pulmonary aspiration, permanent neurological injury and death have been reported, but their incidence is unknown due to the infrequency of their occurrence and lack of surveillance of sedation safety. To improve our understanding of the safety, comparative effectiveness and variation in care in paediatric procedural sedation, we are establishing a multicentre patient registry with the goal of conducting regular and ongoing surveillance for adverse events in procedural sedation. METHODS: This multicentre, prospective cohort study is enrolling patients under 18 years of age from six paediatric emergency departments across Canada. Data collection is fully integrated into clinical care and is performed electronically in real time by the healthcare professionals caring for the patient. The primary outcome is the proportion of patients who experience a serious adverse event as a result of their sedation. Secondary outcomes include the proportion of patients who experience an adverse event that could lead to a serious adverse event, proportion of patients who receive a significant intervention in response to an adverse event, proportion of patients who experience a successful sedation, and proportion of patients who experience a paradoxical reaction to sedation. There is no predetermined end date for data collection. ETHICS AND DISSEMINATION: Ethics approval has been obtained from participating sites. Results will be disseminated using a multifaceted knowledge translation strategy by presenting at international conferences, publication in peer-reviewed journals, and through established networks. PMID- 26025000 TI - A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects. AB - BACKGROUND: Although BRCA1 and BRCA2 mutations account for only ~27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. METHODS: We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. RESULTS: The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. CONCLUSIONS: The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process. PMID- 26025001 TI - Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels. AB - BACKGROUND: We previously reported that the low-frequency, loss-of-function variant p.R270H in FFAR4 encoding the lipid sensor GPR120 was associated with obesity. Gpr120-deficient mice develop obesity and both impaired fasting glucose and glucose intolerance under a high-fat diet. We aimed to assess the contribution of p.R270H to type 2 diabetes (T2D) risk and the variation of glucose-related traits. METHODS: We genotyped p.R270H in 8996 non-diabetic individuals (among whom 4523 had an oral glucose tolerance test (OGTT)) and in a T2D case-control study including 4725 cases and 4339 controls. The regression models were adjusted for age, sex and body mass index (BMI). RESULTS: We found a significant association between p.R270H and increased fasting glucose levels (beta=0.092+/-0.05 mmol/L; p=4.13*10(-4)). Furthermore, p.R270H nominally contributed to decreased homeostasis model of pancreatic beta-cell function (HOMA B; beta=-0.090+/-0.06; p=6.01*10(-3)). Despite a high statistical power, we did not find any significant association between p.R270H and T2D risk or the variation of fasting insulin levels, the homeostasis model of insulin resistance or OGTT-derived indices. CONCLUSIONS: These results suggest that the low frequency p.R270H variant which inhibits GPR120 activity might influence fasting glucose levels in a normal physiological range. This study does not exclude that other coding mutations in FFAR4 with stronger functional effect than p.R270H may be associated with T2D. PMID- 26025002 TI - Hereditary diffuse gastric cancer syndrome: improved performances of the 2015 testing criteria for the identification of probands with a CDH1 germline mutation. PMID- 26025003 TI - Review: Application of High Resolution Mass Spectrometry to Monitor Veterinary Drug Residues in Aquacultured Products. AB - High resolution MS (HRMS) instruments provide accurate mass measurements. With HRMS, virtually an unlimited number of compounds can be analyzed simultaneously because full-scan data are collected, rather than preselected ion transitions corresponding to specific compounds. This enables the development of methods that can monitor for a wide scope of residues and contaminants in aquacultured fish and shellfish including antibiotics, metabolites, and emerging contaminants. Applications of HRMS to the analysis of veterinary drug residues in aquacultured products are summarized in this review including methods for screening, quantifying, and identifying drug residues in these matrixes. The use of targeted, semi-targeted, and nontargeted analysis of HRMS data and the implications to the global aquaculture industry are also reviewed. PMID- 26025004 TI - Fluorescent tags influence the enzymatic activity and subcellular localization of procaspase-1. AB - Subcellular localization studies and life cell imaging approaches usually benefit from fusion-reporter proteins, such as enhanced green fluorescent protein (EGFP) and mCherry to the proteins of interest. However, such manipulations have several risks, including protein misfolding, altered protein shuttling, or functional impairment when compared to the wild-type proteins. Here, we demonstrate altered subcellular distribution and function of the pro-inflammatory enzyme procaspase-1 as a result of fusion with the reporter protein mCherry. Our observations are of central importance to further investigations of subcellular behavior and possible protein-protein interactions of naturally occurring genetic variants of human procaspase-1 which have recently been linked to autoinflammatory disorders. PMID- 26025005 TI - Progesterone mediates the late positive potentials evoked by affective pictures in high neuroticism females. AB - BACKGROUND: Neuroticism, which is a personality trait characterized by the tendency to experience negative affect, is associated with premenstrual negative emotion changes. The present ERP study intended to investigate how neuroticism and the menstrual cycle influence the evaluation of emotion as a function of the tested levels of ovarian hormones. METHOD: Forty-two healthy females with regular menstrual cycles were grouped by neuroticism (N): 16 were included in the high-N group, and 26 were included in the low-N group. Each female performed an emotion evaluation task in the early follicular phase, late follicular phase and luteal phase while the ERPs, hormone samples and Pleasure-Arousal-Dominance (PAD) mood ratings were measured. RESULTS: The PAD and behavioral data did not differ between the two groups during the three phases. However, the mean amplitude of the Late Positive Potentials (LPP, 300-1000ms post-stimulus) of ERPs was significantly larger in the high-N group than that in the low-N group. Moreover, the interaction between the group and phase was significant 2000-4000ms post stimulus: for the high-N group, the LPP of the luteal phase was the largest, followed by the late follicular phase and the early follicular phase; whereas the LPP of the luteal phase was the largest, followed by the early follicular phase and the late follicular phase for the low-N group. More importantly, the LPP (300 4000ms post-stimulus) evoked by positive pictures from the central or parietal area was significantly negatively correlated with the progesterone level in the early follicular phase. CONCLUSIONS: The present study provides electrophysiological evidence showing that both the menstrual cycle and neuroticism modulate the LPP evoked by emotional pictures. Furthermore, the negative correlation between progesterone and the amplitude of the LPP suggests that the effect of the menstrual cycle on the LPP may be primarily a function of progesterone. These findings suggest that the LPP evoked by emotional pictures for high and low neuroticism females change throughout the menstrual cycle and that this change is in part mediated by progesterone. PMID- 26025006 TI - Informed Mindfulness as the Foundation for Leadership. PMID- 26025007 TI - Semen Quality Improvement in a Man with Idiopathic Infertility Treated with Traditional Korean Medicine: A Case Report. AB - Approximately 45-50% of the cases of infertility result from deficiencies associated with male factors, and 30-45% of these deficiencies are idiopathic. A standardized approach for the treatment of idiopathic male infertility remains elusive. In Korea, male infertility has been treated with either acupuncture, herbal remedies, or pharmacopuncture. We report a case of male idiopathic infertility in which the patient's semen quality improved through traditional Korean medicine (TKM) therapies, which was evaluated according to the 2010 World Health Organization (WHO) standards. A 35-year-old infertile man visited the Conmaul Hospital from August 2013 to December 2013. He was diagnosed with asthenoteratozoospermia. The patient received 3 TKM therapies-acupuncture, pharmacopuncture, and herbal remedies-for 3 months. After 3 months of treatment, a second semen analysis of the patient was conducted. The sperm motility increased by 13%, and the normal sperm morphology increased by 4% over 3 months. In addition, the total motile sperm count was 2.5 times higher than that before treatment. The results of the present study support the clinical potency of treatment with acupuncture, pharmacopuncture, and herbal remedies in idiopathic infertile men, especially for the improvement of sperm motility and morphology. Further large-scale randomized controlled trials with elaborate designs should be performed to verify the clinical effect of TKM therapies. PMID- 26025008 TI - Nail-Patella Syndrome: A Report of a Saudi Arab Family With an Autosomal Recessive Inheritance. AB - BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant disorder with a variable interfamilial and intrafamilial clinical expressivity and penetrance. It is caused by loss-of-function heterozygous mutation in the LIM-homeodomain transcription factor (LMX1B) located on chromosome 9q. The pleiotropic LMB1X gene, a member of the homeogene family, is involved in the development of glomerular basement membrane, dorsoventral limb structures, along with the nails and the anterior segment of the eye. OBJECTIVE: Here, we report a Saudi Arab consanguineous family with 2 affected sisters presented with the typical nail changes of NPS. METHODS: DNA samples were collected from the sisters and their parents after consent. RESULTS: Both sisters were found to be homozygous for a previously described disease-causing mutation (c.268C>T) at the (LMX1B) gene. Both of the phenotypically normal parents were confirmed to be heterozygous for the same mutation. CONCLUSION: This finding supports the autosomal recessive mode of inheritance in this family. PMID- 26025009 TI - The Monitoring of Triphenylmethane Dyes in Aquaculture Products Through the European Union Network of Official Control Laboratories. AB - Aquaculture has been the fastest growing animal production industry for the past four decades, and almost half of the fish eaten in the world are now farmed fish. To prevent diseases in this more intensive aquaculture farming, use of therapeutic chemicals has become a basic choice. The monitoring of malachite green, a triphenylmethane dye and one of the oldest and widely used chemicals in fish production, has gained more interest since the mid 1990s when this substance was finally proven to be toxic enough to be prohibited in seafood products destined for human consumption. The enforcement of the European Union (EU) regulation of this banned substance along with some other triphenylmethane dye congeners and their metabolites in its domestic production and in seafood imports was undertaken through the National Residue Monitoring Plans implemented in nearly all of the 28 EU member states. The reliability of the overall European monitoring of this dye contamination in aquaculture products was assessed by using the results of proficiency testing (PT) studies provided by the EU Reference Laboratory (EU-RL) in charge of the network of the EU National Reference Laboratories (NRLs). The proficiency of each NRL providing analytical support services for regulating dye residues was carefully checked during three PT rounds. In the process, the analytical methods developed and validated for this purpose have gradually been improved and extended over the last two decades. PMID- 26025010 TI - Field size consistency of nominally matched linacs. AB - Given that there is increasing recognition of the effect that sub-millimetre changes in collimator position can have on radiotherapy beam dosimetry, this study aimed to evaluate the potential variability in small field collimation that may exist between otherwise matched linacs. Field sizes and field output factors were measured using radiochromic film and an electron diode, for jaw- and MLC collimated fields produced by eight dosimetrically matched Varian iX linacs (Varian Medical Systems, Palo Alto, USA). This study used nominal sizes from 0.6 * 0.6 to 10 * 10 cm(2), for jaw-collimated fields, and from 1 * 1 to 10 * 10 cm(2) for MLC-collimated fields, delivered from a zero (head up, beam directed vertically downward) gantry angle. Differences between the field sizes measured for the eight linacs exceeded the uncertainty of the film measurements and the repositioning uncertainty of the jaws and MLCs on one linac. The dimensions of fields defined by MLC leaves were more consistent between linacs, while also differing more from their nominal values than fields defined by orthogonal jaws. The field output factors measured for the different linacs generally increased with increasing measured field size for the nominal 0.6 * 0.6 to 1 * 1 cm(2) fields, and became consistent between linacs for nominal field sizes of 2 * 2 cm(2) and larger. The inclusion in radiotherapy treatment planning system beam data of small field output factors acquired in fields collimated by jaws (rather than the more-reproducible MLCs), associated with either the nominal or the measured field sizes, should be viewed with caution. The size and reproducibility of the fields (especially the small fields) used to acquire treatment planning data should be investigated thoroughly as part of the linac or planning system commissioning process. Further investigation of these issues, using different linac models, collimation systems and beam orientations, is recommended. PMID- 26025011 TI - What should not be in a manuscript submitted to a scientific journal. PMID- 26025013 TI - Individual differences in subcortical microstructure organization reflect reaction time performances during a flanker task: a diffusion tensor imaging study in children with and without ADHD. AB - The results of several previous magnetic resonance imaging studies suggest that the fronto-striato-thalamic circuitry is involved in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, few studies have investigated the putative association between quantitative diffusion tensor imaging measurements of subcortical gray matter and subject task performances in children with ADHD. Here, we examined whether reaction time (RT) parameters during a flanker task were correlated with mean diffusivity (MD) measurements in the basal ganglia and thalamus in children with ADHD and in controls. For the study group as a whole, both the mean RT and the intra-individual variability in RTs were found to be significantly correlated with MD measurements in the right and left caudate, putamen and thalamus. In contrast, the correlation between the interference effect and MD failed to reach statistical significance. The present results may advance our understanding of the anatomical substrates of ADHD. PMID- 26025012 TI - Selective cognitive and psychiatric manifestations in Wolfram Syndrome. AB - BACKGROUND: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. METHODS: Individuals with genetically confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. RESULTS: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. CONCLUSIONS: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well. TRIAL REGISTRATION: Current Clinicaltrials.gov Trial NCT02455414 . PMID- 26025014 TI - Grey matter morphological anomalies in the caudate head in first-episode psychosis patients with delusions of reference. AB - Delusions of reference (DOR) are theoretically linked with aberrant salience and associative learning. Previous studies have shown that the caudate nucleus plays a critical role in the cognitive circuits of coding prediction errors and associative learning. The current study aimed at testing the hypothesis that abnormalities in the caudate nucleus may be involved in the neuroanatomical substrate of DOR. Structural magnetic resonance imaging of the brain was performed in 44 first-episode psychosis patients (with diagnoses of schizophrenia or schizophreniform disorder) and 25 healthy controls. Patients were divided into three groups according to symptoms: patients with DOR as prominent positive symptom; patients with prominent positive symptoms other than DOR; and patients with minimal positive symptoms. All groups were age-, gender-, and education matched, and patient groups were matched for diagnosis, duration of illness, and antipsychotic treatment. Voxel-based morphometric analysis was performed to identify group differences in grey matter density. Relationships were explored between grey matter density and DOR. Patients with DOR were found to have reduced grey matter density in the caudate compared with patients without DOR and healthy controls. Grey matter density values of the left and right caudate head were negatively correlated with DOR severity. Decreased grey matter density in the caudate nucleus may underlie DOR in early psychosis. PMID- 26025015 TI - Quantitative evaluation of DNA damage and mutation rate by atmospheric and room temperature plasma (ARTP) and conventional mutagenesis. AB - DNA damage is the dominant source of mutation, which is the driving force of evolution. Therefore, it is important to quantitatively analyze the DNA damage caused by different mutagenesis methods, the subsequent mutation rates, and their relationship. Atmospheric and room temperature plasma (ARTP) mutagenesis has been used for the mutation breeding of more than 40 microorganisms. However, ARTP mutagenesis has not been quantitatively compared with conventional mutation methods. In this study, the umu test using a flow-cytometric analysis was developed to quantify the DNA damage in individual viable cells using Salmonella typhimurium NM2009 as the model strain and to determine the mutation rate. The newly developed method was used to evaluate four different mutagenesis systems: a new ARTP tool, ultraviolet radiation, 4-nitroquinoline-1-oxide (4-NQO), and N methyl-N'-nitro-N-nitrosoguanidine (MNNG) mutagenesis. The mutation rate was proportional to the corresponding SOS response induced by DNA damage. ARTP caused greater DNA damage to individual living cells than the other conventional mutagenesis methods, and the mutation rate was also higher. By quantitatively comparing the DNA damage and consequent mutation rate after different types of mutagenesis, we have shown that ARTP is a potentially powerful mutagenesis tool with which to improve the characteristics of microbial cell factories. PMID- 26025016 TI - Untargeted metabolomics analysis revealed changes in the composition of glycerolipids and phospholipids in Bacillus subtilis under 1-butanol stress. AB - 1-Butanol has been utilized widely in industry and can be produced or transformed by microbes. However, current knowledge about the mechanisms of 1-butanol tolerance in bacteria remains quite limited. Here, we applied untargeted metabolomics to study Bacillus subtilis cells under 1-butanol stress and identified 55 and 37 ions with significantly increased and decreased levels, respectively. Using accurate mass determination, tandem mass spectra, and synthetic standards, 86 % of these ions were characterized. The levels of phosphatidylethanolamine, diglucosyldiacylglycerol, and phosphatidylserine were found to be upregulated upon 1-butanol treatment, whereas those of diacylglycerol and lysyl phosphatidylglycerol were downregulated. Most lipids contained 15:0/15:0, 16:0/15:0, and 17:0/15:0 acyl chains, and all were mapped to membrane lipid biosynthetic pathways. Subsequent two-stage quantitative real-time reverse transcriptase PCR analyses of genes in the two principal membrane lipid biosynthesis pathways revealed elevated levels of ywiE transcripts in the presence of 1-butanol and reduced expression levels of cdsA, pgsA, mprF, clsA, and yfnI transcripts. Thus, the gene transcript levels showed agreement with the metabolomics data. Lastly, the cell morphology was investigated by scanning electron microscopy, which indicated that cells became almost twofold longer after 1.4 % (v/v) 1-butanol stress for 12 h. Overall, the studies uncovered changes in the composition of glycerolipids and phospholipids in B. subtilis under 1-butanol stress, emphasizing the power of untargeted metabolomics in the discovery of new biological insights. PMID- 26025017 TI - Genetic tools and techniques for Chlamydomonas reinhardtii. AB - The development of tools has always been a major driving force for the advancement of science. Optical microscopes were the first instruments that allowed discovery and descriptive studies of the subcellular features of microorganisms. Although optical and electron microscopes remained at the forefront of microbiological research tools since their inventions, the advent of molecular genetics brought about questions which had to be addressed with new "genetic tools". The unicellular green microalgal genus Chlamydomonas, especially the most prominent species C. reinhardtii, has become a frequently used model organism for many diverse fields of research and molecular genetic analyses of C. reinhardtii, as well as the available genetic tools and techniques, have become increasingly sophisticated throughout the last decades. The aim of this review is to provide an overview of the molecular key features of C. reinhardtii and summarize the progress related to the development of tools and techniques for genetic engineering of this organism, from pioneering DNA transformation experiments to state-of-the-art techniques for targeted nuclear genome editing and high-throughput screening approaches. PMID- 26025018 TI - Electronic Health Data for Postmarket Surveillance: A Vision Not Realized. AB - What has been learned about electronic health data as a primary data source for regulatory decisions regarding the harms of drugs? Observational studies with electronic health data for postmarket risk assessment can now be conducted in Europe and the US in patient populations numbering in the tens of millions compared with a few hundred patients in a typical clinical trial. With standard protocols, results can be obtained in a few months; however, extensive research published by scores of investigators has illuminated the many obstacles that prevent obtaining robust, reproducible results that are reliable enough to be a primary source for drug safety decisions involving the health and safety of millions of patients. The most widely used terminology for coding patient interactions with medical providers for payment has proved ill-suited to identifying the adverse effects of drugs. Directly conflicting results were reported in otherwise similar patient health databases, even using identical event definitions and research methods. Evaluation of some accepted statistical methods revealed systematic bias, while others appeared to be unreliable. When electronic health data studies detected no drug risk, there were no robust and accepted standards to judge whether the drug was unlikely to cause the adverse effect or whether the study was incapable of detecting it. Substantial investment and careful thinking is needed to improve the reliability of risk assessments based on electronic health data, and current limitations need to be fully understood. PMID- 26025019 TI - Microbial bet-hedging: the power of being different. AB - Bet-hedging is an evolutionary theory that describes how risk spreading can increase fitness of a genotype in an unpredictably changing environment. To achieve risk spreading, maladapted phenotypes develop within isogenic populations that may be fit for a future environment. In recent years, various observations of microbial phenotypic heterogeneity have been denoted as bet-hedging strategies, sometimes without sufficient evidence to support this claim. Here, we discuss selected examples of microbial phenotypic heterogeneity that so far do seem consistent with the evolutionary theory concept of bet-hedging. PMID- 26025020 TI - Adaptive strategies in the double-extremophilic prokaryotes inhabiting soda lakes. AB - Haloalkaliphiles are double extremophilic organisms thriving both at high salinity and alkaline pH. Although numerous haloalkaliphilic representatives have been identified among Archaea and Bacteria over the past 15 years, the adaptations underlying their prosperity at haloalkaline conditions are scarcely known. A multi-level adaptive strategy was proposed to occur in haloalkaliphilic organisms isolated from saline alkaline and soda environments including adjustments in the cell wall structure, plasma membrane lipid composition, membrane transport systems, bioenergetics, and osmoregulation. Isolation of chemolithoautotrophic sulfur-oxidizing gamma-Proteobacteria from soda lakes allowed the elucidation of the structural and physiological differences between haloalkaliphilic (prefer NaCl) and natronophilic (prefer NaHCO3/Na2CO3, i.e. soda) microbes. PMID- 26025021 TI - Functional microbiology of soda lakes. AB - Soda lakes represent unique permanently haloalkaline system. Despite the harsh conditions, they are inhabited by abundant, mostly prokaryotic, microbial communities. This review summarizes results of studies of main functional groups of the soda lake prokaryotes responsible for carbon, nitrogen and sulfur cycling, including oxygenic and anoxygenic phototrophs, aerobic chemolithotrophs, fermenting and respiring anaerobes. The main conclusion from this work is that the soda lakes are very different from other high-salt systems in respect to microbial richness and activity. The reason for this difference is determined by the major physico-chemical features of two dominant salts - NaCl in neutral saline systems and sodium carbonates in soda lakes, that are influencing the amount of energy required for osmotic adaptation. PMID- 26025022 TI - The Elusory Upward Spiral: A Reanalysis of Kok et al. (2013). PMID- 26025023 TI - Evidence for the Upward Spiral Stands Steady: A Response to Heathers, Brown, Coyne, and Friedman (2015). PMID- 26025025 TI - Design and evaluation of a software for the objective and easy-to-read presentation of new drug properties to physicians. AB - BACKGROUND: When new pharmaceutical products appear on the market, physicians need to know whether they are likely to be useful in their practices. Physicians currently obtain most of their information about the market release and properties of new drugs from pharmaceutical industry representatives. However, the official information contained in the summary of product characteristics (SPCs) and evaluation reports from health agencies, provide a more complete view of the potential value of new drugs, although they can be long and difficult to read. The main objective of this work was to design a prototype computer program to facilitate the objective appraisal of the potential value of a new pharmaceutical product by physicians. This prototype is based on the modeling of pharmaceutical innovations described in a previous paper. METHODS: The interface was designed to allow physicians to develop a rapid understanding of the value of a new drug for their practices. We selected five new pharmaceutical products, to illustrate the function of this prototype. We considered only the texts supplied by national or international drug agencies at the time of market release. The perceived usability of the prototype was evaluated qualitatively, except for the System Usability Scale (SUS) score evaluation, by 10 physicians differing in age and medical background. RESULTS: The display is based on the various axes of the conceptual model of pharmaceutical innovations. The user can select three levels of detail when consulting this information (highly synthetic, synthetic and detailed). Tables provide a comparison of the properties of the new pharmaceutical product with those of existing drugs, if available for the same indication, in terms of efficacy, safety and ease of use. The interface was highly appreciated by evaluators, who found it easy to understand and suggested no other additions of important, internationally valid information. The mean System Usability Scale score for the 10 physicians was 82, corresponding to a "good" user interface. CONCLUSIONS: This work led us to propose the selection, grouping, and mode of presentation for various types of knowledge on pharmaceutical innovations in a way that was appreciated by evaluators. It provides physicians with readily accessible objective information about new drugs. PMID- 26025024 TI - Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction. AB - BACKGROUND: Left ventricular noncompaction (LVNC) is an autosomal-dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co occur with cardiac hypertrophy. METHODS AND RESULTS: Here, we generated whole exome sequence data from multiple members from 5 families with LVNC. In 4 of 5 families, the candidate causative mutation segregates with disease in known LVNC genes MYH7 and TPM1. Subsequent sequencing of MYH7 in a larger LVNC cohort identified 7 novel likely disease causing variants. In the fifth family, we identified a frameshift mutation in NNT, a nuclear-encoded mitochondrial protein, not implicated previously in human cardiomyopathies. Resequencing of NNT in additional LVNC families identified a second likely pathogenic missense allele. Suppression of nnt in zebrafish caused early ventricular malformation and contractility defects, probably driven by altered cardiomyocyte proliferation. In vivo complementation studies showed that mutant human NNT failed to rescue nnt morpholino-induced heart dysfunction, indicating a probable haploinsufficiency mechanism. CONCLUSIONS: Together, our data expand the genetic spectrum of LVNC and demonstrate how the intersection of whole exome sequence with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders. PMID- 26025026 TI - Evaluation of ICON Maxx, a long-lasting treatment kit for mosquito nets: experimental hut trials against anopheline mosquitoes in Tanzania. AB - BACKGROUND: Insecticide-treated nets are the primary method of preventing malaria. To remain effective, the pyrethroid insecticide must withstand multiple washes over the lifetime of the net. ICON((r)) Maxx is a 'dip-it-yourself' kit for long-lasting treatment of polyester nets. The twin-sachet kit contains a slow release capsule suspension of lambda-cyhalothrin plus binding agent. To determine whether ICON Maxx meets the standards required by the World Health Organization Pesticide Evaluation Scheme (WHOPES), the efficacy and wash fastness of ICON Maxx was evaluated against wild, free-flying anopheline mosquitoes. METHODS: ICON Maxx was subjected to bioassay evaluation and experimental hut trial against pyrethroid-susceptible Anopheles gambiae, Anopheles arabiensis and Anopheles funestus. Mosquito mortality, blood feeding inhibition and personal protection were compared between untreated nets, conventional lambda-cyhalothrin treated nets (CTN) washed either four times (cut-off threshold) or 20 times, and ICON Maxx-treated nets either unwashed or washed 20 times. RESULTS: In bioassay, ICON Maxx demonstrated superior wash resistance to the CTN. In the experimental hut trial, ICON Maxx killed 75 % of An. funestus, 71 % of An. gambiae and 47 % of An. arabiensis when unwashed and 58, 66 and 42 %, respectively, when 20 times washed. The CTN killed 52 % of An. funestus, 33 % of An. gambiae and 30 % of An. arabiensis when washed to the cut-off threshold of four washes and 40, 40 and 36 %, respectively, when 20 times washed. Percentage mortality with ICON Maxx 20 times washed was similar (An. funestus) or significantly higher (An. gambiae, An. arabiensis) than with CTN washed to the WHOPES cut-off threshold. Blood-feeding inhibition with ICON Maxx 20 times washed was similar to the CTN washed to cut off for all three species. Personal protection was significantly higher with ICON Maxx 20 times washed (66-79 %) than with CTN washed to cut-off (48-60 %). CONCLUSIONS: Nets treated with ICON Maxx and washed 20 times met the approval criteria set by WHOPES for Phase II trials in terms of mortality and blood feeding inhibition. This finding raises the prospect of conventional polyester nets and other materials being made long-lastingly insecticidal through simple dipping in community or home, and thus represents a major advance over conventional pyrethroid treatments. PMID- 26025027 TI - How nanotechnology-enabled concepts could contribute to the prevention, diagnosis and therapy of bacterial infections. AB - This viewpoint summarizes a selection of nanotechnology-based key concepts relevant to critical care medicine. It focuses on novel approaches for a trigger dependent release of antimicrobial substances from degradable nano-sized carriers, the ultra-sensitive detection of analytes in body fluid samples by plasmonic and fluorescent nanoparticles, and the rapid removal of pathogens from whole blood using magnetic nanoparticles. The concepts presented here could significantly contribute to the prevention, diagnosis and therapy of bacterial infections in future and it is now our turn to bring them from the bench to the bedside. PMID- 26025028 TI - Molecular mechanisms of inter-organelle ER-PM contact sites. AB - Observed for decades by electron microscopy but mostly ignored, inter-organelle membrane contact sites (MCSs) are now emerging as major sites for the exchange of cellular components in eukaryotic cells. Although new MCSs are continually characterized, those formed between the endoplasmic reticulum (ER) and the plasma membrane (PM) are currently the best defined. Here, we focus on ER-PM contact sites as a model system for understanding the molecular mechanisms that govern inter-organelle junctions. Through tight inter-organelle tethering, ER-PM proteins generate a unique microenvironment optimized for processes like lipid and ion transport. Several MCS proteins also boast potential membrane remodeling domains, which may promote curvature and lipid transfer between juxtaposed bilayers. Finally, we discuss challenges and future directions for the MCS field. PMID- 26025029 TI - Can we predict outcome in schizophrenia? The need for prognostic biomarkers. PMID- 26025030 TI - Sitting with vs. across a patient. PMID- 26025031 TI - [OCT findings in X-linked retinoschisis]. PMID- 26025032 TI - [Sea fan neovascularization: Angiographic and tomographic (SD-OCT) appearance]. PMID- 26025033 TI - Influence on intraocular pressure of anti-inflammatory treatments after selective laser trabeculoplasty. AB - INTRODUCTION: Selective laser trabeculoplasty (SLT) is an effective and safe procedure to lower intraocular pressure (IOP) in the management of open-angle glaucoma. The post-laser inflammatory reaction could be positively implicated in SLT efficacy and the relevance of postoperative use of topical anti-inflammatory remains controversial. The goal of this study is to determine the effect of various anti-inflammatory treatments on intraocular pressure and on side effects following SLT. MATERIAL AND METHODS: A prospective, randomized, double-blind study with a control group was conducted. Ninety-six eyes of 67 patients with primary open-angle glaucoma who underwent SLT were enrolled in this study between March 2009 and March 2012. Eyes recruited in the study were randomized to receive either prednisolone acetate 1%, diclofenac 0.1% or a placebo. The 3 treatments were administered 4 times a day for 5 days following SLT. The intraocular pressures were measured at regular intervals during the 6-months follow-up period. Side effects were also evaluated with a questionnaire as well as with the ocular exam. RESULTS: The analysis of the relative IOP decrease over the 6-months period revealed a significant difference between the time points of follow-up (P<0.0001), but no group effect (P=0.2980). No significant difference regarding anterior chamber inflammation and discomfort was observed between the 3 groups. CONCLUSION: There was no difference in intraocular pressure reduction, intraocular inflammation or ocular discomfort post-SLT when comparing the 3 treatment modalities. PMID- 26025034 TI - Crosstalk between macrophages and astrocytes affects proliferation, reactive phenotype and inflammatory response, suggesting a role during reactive gliosis following spinal cord injury. AB - BACKGROUND: Large-scale macrophage infiltration and reactive astrogliosis are hallmarks of early spinal cord injury (SCI) pathology. The exact nature of the macrophage response and relationship between these phenomena have not been explored in detail. Here, we have investigated these responses using a combination of in vivo SCI models, organotypic and primary cultures. METHODS: In vivo macrophage response was investigated using a contusive injury mouse model. Interactions between astrocytes and macrophages were studied in primary or organotypic cultures. Proliferation was assessed though MTT assay and nucleotide incorporation and gene expression changes through qPCR. RESULTS: Seven days following contusive SCI, a mixed M1/M2 macrophage response was seen in the injury site. Conditioned medium from primary M1, but not M2, macrophages are able to induce astrocyte proliferation in both organotypic spinal cord cultures and primary astrocytes. Soluble factors from M1 macrophages induce a reactive astrocyte gene expression pattern, whereas M2 factors inhibit expression of these genes. M2-stimulated astrocytes are also able to decrease both M1 and M2 macrophage proliferation and decrease TNFalpha production in M1 macrophages. CONCLUSIONS: These results suggest a strong role of M1 macrophages in inducing reactive astrogliosis and the existence of an astrocyte-mediated negative feedback system in order to dampen the immune response. These results, combined with the poor outcomes of the current immunosuppressive steroid treatments in SCI, indicate the need for more targeted therapies, taking into account the significantly different effects of M1 and M2 macrophages, in order to optimise outcome. PMID- 26025035 TI - Predictors of marked weight gain in a population of health care and industrial workers following smoking cessation. AB - BACKGROUND: Concerns about postcessational weight gain might hamper rather than encourage smokers to quit smoking. METHODS: We conducted a comprehensive multi institutional smoking cessation program for health care and industrial workers (n = 654) employed at University Hospital Basel (Switzerland) and two local health industry companies (Novartis International AG, F. Hoffmann-La Roche AG). The program contained counselling with an option of pharmacological support. Changes in body weight were observed during 24 months of follow-up. Factors associated with longitudinal weight gain (> 5 % of baseline weight) were identified by cox regression analysis. RESULTS: In 51 % of permanent quitters no significant changes of mean body weight were observed after 12 (0.52 kg, SD +/- 2.87 kg) and 24 months (0.40 kg, SD +/- 2.99 kg). Marked weight gain following smoking cessation was characterized by a wide margin of changes. In more than a half of former smokers (58 %) weight increases were moderate (< 5 kg), whereas excessive increases (> 10 kg) were seen in only 10 % of quitters. Lower baseline BMI (HR 0.60, 95 % CI 0.40- 0.80, p = 0.03), daily consumption of less than ten cigarettes (HR 0.53, 95 % CI 0.27- 0.63, p = 0.04) and ischemic cardiopathy (HR 0.21, 95 % CI 0.07-0.62; p < 0.01) were associated with a lower risk for weight gain. Employees with lower educational levels (HR 2.60, 95 % CI 1.60-5.50, p < 0.01), diabetes mellitus (HR 3.05, 95 % CI 2.20-8.06, p = 0.02) and those smoking to reduce boredom in life (HR 1.68, 95 % CI 1.21-2.33, p < 0.01) were at highest risk. CONCLUSION: Marked postcessational weight gain occurs less often than expected, but remains difficult to be predicted. Our findings might be helpful to alleviate weight concerns in the average smoker willing to quit. PMID- 26025038 TI - Towards the design of 3D multiscale instructive tissue engineering constructs: Current approaches and trends. AB - The design of 3D constructs with adequate properties to instruct and guide cells both in vitro and in vivo is one of the major focuses of tissue engineering. Successful tissue regeneration depends on the favorable crosstalk between the supporting structure, the cells and the host tissue so that a balanced matrix production and degradation are achieved. Herein, the major occurring events and players in normal and regenerative tissue are overviewed. These have been inspiring the selection or synthesis of instructive cues to include into the 3D constructs. We further highlight the importance of a multiscale perception of the range of features that can be included on the biomimetic structures. Lastly, we focus on the current and developing tissue-engineering approaches for the preparation of such 3D constructs: top-down, bottom-up and integrative. Bottom-up and integrative approaches present a higher potential for the design of tissue engineering devices with multiscale features and higher biochemical control than top-down strategies, and are the main focus of this review. PMID- 26025037 TI - Panel docking of small-molecule libraries - Prospects to improve efficiency of lead compound discovery. AB - Computational docking as a means to prioritise small molecules in drug discovery projects remains a highly popular in silico screening approach. Contemporary docking approaches without experimental parametrisation can reliably differentiate active and inactive chemotypes in a protein binding site, but the absence of a correlation between the score of a predicted binding pose and the biological activity of the molecule presents a clear limitation. Several novel or improved computational approaches have been developed in the recent past to aid in screening and profiling of small-molecule ligands for drug discovery, but also more broadly in developing conceptual relationships between different protein targets by chemical probing. Among those new methodologies is a strategy known as inverse virtual screening, which involves the docking of a compound into different protein structures. In the present article, we review the different computational screening methodologies that employ docking of atomic models, and, by means of a case study, present an approach that expands the inverse virtual screening concept. By computationally screening a reasonably sized library of 1235 compounds against a panel of 48 mostly human kinases, we have been able to identify five groups of putative lead compounds with substantial diversity when compared to each other. One representative of each of the five groups was synthesised, and tested in kinase inhibition assays, yielding two compounds with micro-molar inhibition in five human kinases. This highly economic and cost effective methodology holds great promise for drug discovery projects, especially in cases where a group of target proteins share high structural similarity in their binding sites. PMID- 26025036 TI - A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin. AB - siRNA has the possibility to revolutionize medicine by enabling highly specific and efficient silencing of proteins involved in disease pathogenesis. Despite nearly 20 years of research dedicated to translating siRNA from a research tool into a clinically relevant therapeutic, minimal success has been had to date. Access to RNA interference machinery located in the cytoplasm is often overlooked, but must be considered when designing the next generation of siRNA delivery strategies. Peptide transduction domains (PTDs) have demonstrated moderate siRNA transfection, which is primarily limited by endosomal entrapment. Strategies aimed at overcoming endosomal entrapment associated with peptide vectors are reviewed here, including osmotic methods, lipid conjugation, and fusogenic peptides. As an alternative to traditional PTD, the hemolytic peptide melittin exhibits the native capacity for endosomal disruption but causes cytotoxicity. However, appropriate packaging and protection of melittin with activation and release in the endosomal compartment has allowed melittin-based strategies to demonstrate both in vitro and in vivo safety and efficacy. These data suggest that melittin's membrane disruptive properties can enable safe and effective endosomolysis, building a case for melittin as a key component in a new generation of siRNA therapeutics. PMID- 26025039 TI - Update on total intravenous anesthesia with special emphasis on cardiovascular anesthesia. PMID- 26025040 TI - Total intravenous anesthesia and anesthetic outcomes. PMID- 26025041 TI - Intraoperative Use of Remifentanil for TIVA: Postoperative Pain, Acute Tolerance, and Opioid-Induced Hyperalgesia. PMID- 26025042 TI - Remifentanil and opioid-induced cardioprotection. PMID- 26025043 TI - The current role of total intravenous anesthesia in cardiac surgery: total intravenous anesthesia and cardiopulmonary bypass. PMID- 26025044 TI - Total intravenous anesthesia versus inhalation anesthesia: a drug delivery perspective. PMID- 26025045 TI - Pharmacokinetic and pharmacodynamic concepts underpinning total intravenous anesthesia. PMID- 26025046 TI - Epicardial fat volume quantification by noncontrast CT: Trimming away the fat from the meat. PMID- 26025047 TI - The PROMISE trial: An inside perspective. PMID- 26025048 TI - In silico functional annotation of a hypothetical protein from Staphylococcus aureus. AB - Unknown proteins or hypothetical proteins exist but have not been characterized or linked to known genes. Domains of unknown function are experimentally identified proteins with no known functional or structural domain. In this paper, the investigation and characterization of the likely functional aspects of a hypothetical protein, YP_001317347.1, from Staphylococcus aureus was performed using various computational methods and tools. Based on the analysis, the protein has a YbbR domain and is expected to bind ribosomal subunits. The analysis reported here helps in understanding the importance of YbbR domains and will aid in the development of novel antibacterial agents. PMID- 26025049 TI - The WRKY45-Dependent Signaling Pathway Is Required For Resistance against Striga hermonthica Parasitism. AB - The root hemiparasite witchweed (Striga spp.) is a devastating agricultural pest that causes losses of up to $1 billion US annually in sub-Saharan Africa. Development of resistant crops is one of the cost-effective ways to address this problem. However, the molecular mechanisms underlying resistance are not well understood. To understand molecular events upon Striga spp. infection, we conducted genome-scale RNA sequencing expression analysis using Striga hermonthica-infected rice (Oryza sativa) roots. We found that transcripts grouped under the Gene Ontology term defense response were significantly enriched in up regulated differentially expressed genes. In particular, we found that both jasmonic acid (JA) and salicylic acid (SA) pathways were induced, but the induction of the JA pathway preceded that of the SA pathway. Foliar application of JA resulted in higher resistance. The hebiba mutant plants, which lack the JA biosynthesis gene allene oxide cyclase, exhibited severe S. hermonthica susceptibility. The resistant phenotype was recovered by application of JA. By contrast, the SA-deficient NahG rice plants were resistant against S. hermonthica, indicating that endogenous SA is not required for resistance. However, knocking down WRKY45, a regulator of the SA/benzothiadiazole pathway, resulted in enhanced susceptibility. Interestingly, NahG plants induced the JA pathway, which was down-regulated in WRKY45-knockdown plants, linking the resistant and susceptible phenotypes to the JA pathway. Consistently, the susceptibility phenotype in the WRKY45-knockdown plants was recovered by foliar JA application. These results point to a model in which WRKY45 modulates a cross talk in resistance against S. hermonthica by positively regulating both SA/benzothiadiazole and JA pathways. PMID- 26025050 TI - Lipid Peroxide-Derived Short-Chain Carbonyls Mediate Hydrogen Peroxide-Induced and Salt-Induced Programmed Cell Death in Plants. AB - Lipid peroxide-derived toxic carbonyl compounds (oxylipin carbonyls), produced downstream of reactive oxygen species (ROS), were recently revealed to mediate abiotic stress-induced damage of plants. Here, we investigated how oxylipin carbonyls cause cell death. When tobacco (Nicotiana tabacum) Bright Yellow-2 (BY 2) cells were exposed to hydrogen peroxide, several species of short-chain oxylipin carbonyls [i.e. 4-hydroxy-(E)-2-nonenal and acrolein] accumulated and the cells underwent programmed cell death (PCD), as judged based on DNA fragmentation, an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei, and cytoplasm retraction. These oxylipin carbonyls caused PCD in BY-2 cells and roots of tobacco and Arabidopsis (Arabidopsis thaliana). To test the possibility that oxylipin carbonyls mediate an oxidative signal to cause PCD, we performed pharmacological and genetic experiments. Carnosine and hydralazine, having distinct chemistry for scavenging carbonyls, significantly suppressed the increase in oxylipin carbonyls and blocked PCD in BY 2 cells and Arabidopsis roots, but they did not affect the levels of ROS and lipid peroxides. A transgenic tobacco line that overproduces 2-alkenal reductase, an Arabidopsis enzyme to detoxify alpha,beta-unsaturated carbonyls, suffered less PCD in root epidermis after hydrogen peroxide or salt treatment than did the wild type, whereas the ROS level increases due to the stress treatments were not different between the lines. From these results, we conclude that oxylipin carbonyls are involved in the PCD process in oxidatively stressed cells. Our comparison of the ability of distinct carbonyls to induce PCD in BY-2 cells revealed that acrolein and 4-hydroxy-(E)-2-nonenal are the most potent carbonyls. The physiological relevance and possible mechanisms of the carbonyl-induced PCD are discussed. PMID- 26025052 TI - The expression of interleukin-6 and its receptor in various brain regions and their roles in exploratory behavior and stress responses. AB - We examined the involvement of interleukin-6 (IL-6) and its receptor IL-6Ralpha on behavior and stress responses in mice. In the open field, both wild-type (WT) and IL-6 deficient mice displayed similar levels of locomotor activity; however, IL-6 deficient mice spent more time in the central part of the arena compared to control WT mice. After behavioral testing, mice were subjected to stress and then sacrificed. The levels of IL-6 and its receptor in their brains were determined. Immunohistochemical labeling of brain sections for IL-6 showed a high level of expression in the subventricular zone of the lateral ventricles and in the border zone of the third and fourth ventricles. Interestingly, 95% of the IL-6 expressing cells had an astrocytic phenotype, and the remaining 5% were microglial cells. A low level of IL-6 expression was observed in the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, cerebellum, midbrain and several brainstem structures. The vast majority of IL-6-expressing cells in these structures had a neuronal phenotype. Stress increased the number of IL-6 immunoreactive astrocytes and microglial cells. The levels of the IL-6Ralpha receptor were increased in the hypothalamus of stressed mice. Therefore, in this study, we describe for the first time the distribution of IL-6 in various types of brain cells and in previously unreported regions, such as the subventricular zone of the lateral ventricle. Moreover, we provide data on regional distribution and expression within specific cell phenotypes. This highly differential expression of IL-6 indicates its specific roles in the regulation of neuronal and astrocytic functions, in addition to the roles of IL-6 and its receptor IL 6Ralpha in stress responses. PMID- 26025051 TI - The Arabidopsis GAGA-Binding Factor BASIC PENTACYSTEINE6 Recruits the POLYCOMB REPRESSIVE COMPLEX1 Component LIKE HETEROCHROMATIN PROTEIN1 to GAGA DNA Motifs. AB - Polycomb-repressive complexes (PRCs) play key roles in development by repressing a large number of genes involved in various functions. Much, however, remains to be discovered about PRC-silencing mechanisms as well as their targeting to specific genomic regions. Besides other mechanisms, GAGA-binding factors in animals can guide PRC members in a sequence-specific manner to Polycomb responsive DNA elements. Here, we show that the Arabidopsis (Arabidopsis thaliana) GAGA-motif binding factor protein basic pentacysteine6 (BPC6) interacts with like heterochromatin protein1 (LHP1), a PRC1 component, and associates with vernalization2 (VRN2), a PRC2 component, in vivo. By using a modified DNA-protein interaction enzyme-linked immunosorbant assay, we could show that BPC6 was required and sufficient to recruit LHP1 to GAGA motif-containing DNA probes in vitro. We also found that LHP1 interacts with VRN2 and, therefore, can function as a possible scaffold between BPC6 and VRN2. The lhp1-4 bpc4 bpc6 triple mutant displayed a pleiotropic phenotype, extreme dwarfism and early flowering, which disclosed synergistic functions of LHP1 and group II plant BPC members. Transcriptome analyses supported this synergy and suggested a possible function in the concerted repression of homeotic genes, probably through histone H3 lysine 27 trimethylation. Hence, our findings suggest striking similarities between animal and plant GAGA-binding factors in the recruitment of PRC1 and PRC2 components to Polycomb-responsive DNA element-like GAGA motifs, which must have evolved through convergent evolution. PMID- 26025053 TI - MuSK autoantibodies in myasthenia gravis detected by cell based assay--A multinational study. AB - Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed. PMID- 26025054 TI - Dopamine receptors D3 and D5 regulate CD4(+)T-cell activation and differentiation by modulating ERK activation and cAMP production. AB - Dopamine receptors have been described in T-cells, however their signalling pathways coupled remain unknown. Since cAMP and ERKs play key roles regulating T cell physiology, we aim to determine whether cAMP and ERK1/2-phosphorylation are modulated by dopamine receptor 3 (D3R) and D5R, and how this modulation affects CD4(+) T-cell activation and differentiation. Our pharmacologic and genetic evidence shows that D3R-stimulation reduced cAMP levels and ERK2-phosphorylation, consequently increasing CD4(+) T-cell activation and Th1-differentiation, respectively. Moreover, D5R expression reinforced TCR-triggered ERK1/2 phosphorylation and T-cell activation. In conclusion, these findings demonstrate how D3R and D5R modulate key signalling pathways affecting CD4(+) T-cell activation and Th1-differentiation. PMID- 26025055 TI - Novel serum autoantibodies against talin1 in multiple sclerosis: Possible pathogenetic roles of the antibodies. AB - In the pathogenesis of multiple sclerosis (MS), B cell/antibody-related mechanisms have recently received attention. To investigate the role of autoantibody in MS, we performed SEREX which can identify autoantibody cyclopedically. We identified serum antibodies against cytoskeletal protein talin1, and the levels of whom were remarkably higher in 39 MS than 43 normal controls (P < 0.01) and 35 disease controls (P = 0.06), and in MS patients without oligoclonal bands than ones with them. Moreover, we found negative correlations between serum anti-talin1 antibody and IgG index in MS (P = 0.03). Anti-talin1 antibody exists in MS patients' sera, which may have some protective factor. PMID- 26025056 TI - Modified expression of peripheral blood lymphocyte muscarinic cholinergic receptors in asthmatic children. AB - Lymphocytes possess an independent cholinergic system. We assessed the expression of muscarinic cholinergic receptors in lymphocytes from 49 asthmatic children and 10 age matched controls using Western blot. We demonstrated that CD4+ and CD8+ T cells expressed M2 and M4 muscarinic receptors which density were significantly increased in asthmatic children in comparison with controls. M2 and M4 receptor increase was strictly related with IgE and fraction of exhaled nitric oxide (FeNO) measurements and with impairment in objective measurements of airway obstruction. Increased lymphocyte muscarinic cholinergic receptor expression may concur with lung cholinergic dysfunction and with inflammatory molecular framework in asthma. PMID- 26025057 TI - The role of PET/CT in the evaluation of patients affected by limbic encephalitis: A systematic review of the literature. AB - Autoimmune limbic encephalitis (LE) is a rare disorder affecting the medial temporal lobe of the brain. Although brain Magnetic Resonance (MR) has been widely evaluated and is currently considered essential in the suspicion of LE, Positron Emission Tomography/Computed Tomography (PET/CT) has been demonstrated to be useful also in the evaluation of brain inflammatory diseases such as encephalitis. We therefore aim to review the current literature about the role of PET/CT in the evaluation of patients affected by LE. PMID- 26025058 TI - Prenatal fluoxetine exposure affects cytokine and behavioral response to an immune challenge. AB - Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) is a commonly prescribed antidepressant drug in pregnant women. FLX readily crosses the placenta, consequently altering serotonergic neurotransmission in the fetus and causing physiological and behavioral disturbances in the newborn. Studies have shown that serotonin plays a role in modulating immune signaling. Thus, the goal of this study was to assess the effects of prenatal exposure to FLX on the response to an immune challenge in offspring mice. Male and female mice were prenatally exposed to FLX and later injected with lipopolysaccharide (LPS) at different stages of development. Results indicated that prenatal FLX modulated aspects of the response to the endotoxin challenge. Prenatal FLX diminished the secretion of interleukin (IL)-6 in adult male and female mice. Prenatal exposure to FLX further suppressed TNFalpha and augmented IL-1beta secretion in adult males. Early effects of LPS (within 24h of administration) on body weight and food consumption were diminished by prenatal exposure to FLX in adult mice. Delayed effects of LPS (within 60h of administration) were modulated by prenatal FLX in young animals. These results provide an indication that prenatal modulations of the serotonergic system had lasting implications for host response to an immune challenge. These findings may contribute to the understanding of the effects of prenatal environment on the development of physiological systems that are important to coping with infectious challenges, and assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy. PMID- 26025059 TI - Transitory loss of glia and the subsequent modulation in inflammatory cytokines/chemokines regulate paracellular claudin-5 expression in endothelial cells. AB - Signaling mechanisms involved in regulating blood-brain barrier (BBB) integrity during central nervous system (CNS) inflammation remain unclear. We show that an imbalance between pro-/anti-inflammatory cytokines/chemokines alters claudin-5 expression. In vivo, gliotoxin-induced changes in glial populations and an imbalance between pro-/anti-inflammatory cytokine/chemokine expression occurred as BBB integrity was compromised. The balance was restored as BBB integrity was re-established. In vitro, TNF-alpha, IL-6, and MCP-1 induced paracellular claudin 5 expression loss. TNF-alpha- and IL-6- effects were mediated through the PI3K pathway and IL-10 attenuated TNF-alpha's effect. This study shows that pro-/anti inflammatory modulators play a critical role in BBB integrity during CNS inflammation. PMID- 26025060 TI - Total glucosides of peony attenuates experimental autoimmune encephalomyelitis in C57BL/6 mice. AB - Total glucosides of peony (TGP), an active compound extracted from the roots of Paeonia lactiflora Pall, has wide pharmacological effects on nervous system. Here we examined the effects of TGP on experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). The results showed that TGP can reduce the severity and progression of EAE in C57 BL/6 mice. In addition, TGP also down-regulated the Th1/Th17 inflammatory response and prevented the reduced expression of brain-derived neurotrophic factor and 2',3'-cyclic nucleotide 3'-phosphodiesterase of EAE. These findings suggest that TGP could be a potential therapeutic agent for MS. PMID- 26025062 TI - A new 9,11-secosterol with a 1,4-quinone from a Korean marine sponge Ircinia sp. AB - An intensive investigation of chemical components for Ircinia sp. led to the isolation of a new 9,11-secosterol. The chemical structure of this compound was elucidated based on the interpretation of NMR and MS spectroscopic data. The isolated compound exhibited antibacterial activities against Staphylococcus epidermidis and Bacillus subtilis with MIC values of 6.3 and 25 MUg ml(-1), respectively. PMID- 26025061 TI - Methyl labeling and TROSY NMR spectroscopy of proteins expressed in the eukaryote Pichia pastoris. AB - (13)C Methyl TROSY NMR spectroscopy has emerged as a powerful method for studying the dynamics of large systems such as macromolecular assemblies and membrane proteins. Specific (13)C labeling of aliphatic methyl groups and perdeuteration has been limited primarily to proteins expressed in E. coli, preventing studies of many eukaryotic proteins of physiological and biomedical significance. We demonstrate the feasibility of efficient (13)C isoleucine delta1-methyl labeling in a deuterated background in an established eukaryotic expression host, Pichia pastoris, and show that this method can be used to label the eukaryotic protein actin, which cannot be expressed in bacteria. This approach will enable NMR studies of previously intractable targets. PMID- 26025063 TI - Risk factors for severe hypocalcemia after parathyroidectomy in prevalent dialysis patients with secondary hyperparathyroidism. AB - PURPOSE: Hypocalcemia is one of the common complications after parathyroidectomy (PTX). Severe hypocalcemia (SH) can lead to tetany, cardiac arrhythmia and even sudden death. However, predictors for the development of SH in patients with secondary hyperparathyroidism demonstrated in some small-scale studies with a limited sample size remain inconclusive. METHODS: A retrospective chart review of 420 consecutive dialysis patients who underwent PTX during a 12-year period was performed. We checked serum levels of calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) for three consecutive days postoperatively. SH was defined as the minimum values of serum calcium lower than 1.875 mmol/L (7.5 mg/dL) within 3 days after operation. RESULTS: The mean (+/-SD) age of our study population was 53 +/- 12 years, and more than half (57 %) were female. SH occurred in 37 % of the patients after PTX. Using a multivariate stepwise logistic regression analysis, lower preoperative levels of Ca (odds ratio 0.69, 95 % CI 0.60-0.79, P < 0.001), higher preoperative levels of iPTH (odds ratio 1.04, 95 % CI 1.00-1.07, P = 0.048), P (odds ratio 2.43, 95 % CI 1.49-3.95, P < 0.001) and ALP (odds ratio 1.08, 95 % CI 1.05-1.11, P < 0.001) were found to be independent predictors of occurrence of SH following PTX. CONCLUSIONS: The readily obtainable preoperative laboratory parameters including Ca, iPTH, P, and ALP will allow identification of a subgroup of patients who are at greater risk for the development of SH following PTX. PMID- 26025064 TI - Serum hyaluronic acid in chronic viral hepatitis B and C: a biomarker for assessing liver fibrosis in chronic hemodialysis patients. AB - PURPOSE: Serum hyaluronic acid (sHA) is studied as a noninvasive marker of liver fibrosis (F) in chronic B and C viral hepatitis in general population but less in end-stage renal disease patients undergoing hemodialysis. METHODS: We evaluated sHA as a noninvasive biomarker of F in a multicenter prospective, transversal, and observational study which included 52 end-stage renal disease patients with chronic B (14) and C (38) viral hepatitis (age 55.57 +/- 14.46 years, dialysis vintage 132.59 +/- 86.02 months). RESULTS: Of the noninvasive tests analyzed, only sHA, APRI, and FIB4 index were able to differentiate patients with F1 (sHA p = 0.006; APRI p = 0.031; FIB4 p = 0.016). No statistically significant differences were found between sHA and APRI, ASAT/ALAT ratio, and FIB4 index in detecting F1 a (p > 0.02). sHA seemed to be more efficient than APRI, ASAT/ALAT ratio, and FIB4 index, having the highest estimated AUC value. The sHA threshold value for F1 was equal to 33.46 ng/mL, with the following estimated values of the performance indicators: Se 88.46 % and Sp 50 %. sHA was the only noninvasive test of the studied tests that could determine F2 (p = 0.002), with a threshold value of 80.24 ng/mL (Se 63 %, Sp 88 %), and F3 (p = 0.008), with a threshold value of 88.54 ng/mL (Se 60 %, Sp 84 %). None of the studied noninvasive tests could determine F4. CONCLUSIONS: In patients with chronic B and C viral hepatitis undergoing hemodialysis, sHA may be a useful biomarker for the liver fibrosis grades: F1-mild, F2-moderate, and F3-severe, but it does not differentiate between chronic hepatitis (F1-F3) and liver cirrhosis (F4). PMID- 26025065 TI - Laparoscopic transgastric endoscopic retrograde cholangiopancreatography after biliopancreatic diversion. AB - Endoscopic retrograde cholangiopancreatography may be difficult in patients that have undergone Roux-en-Y gastric bypass. Due to the fact that prevalence of morbid obesity is increasing, and laparoscopic procedures for its treatment have increased, the incidence of biliary tract problems in patients of altered anatomy is also growing. We describe a laparoscopic technique to access the biliary tree by endoscope, through the excluded stomach. PMID- 26025066 TI - The forms and bioavailability of phosphorus in integrated vertical flow constructed wetland with earthworms and different substrates. AB - A sequential extraction method was utilized to analyze seven forms of P in an integrated vertical-flow constructed wetland (IVFCW) containing earthworms and different substrates. The aluminum-bound P (Al-P) content was found to be lower, and the occluded P (Oc-P) content was higher in the IVFCW. The addition of earthworms into the influent chamber of IVFCW increased the exchange P (Ex-P), iron-bound P (Fe-P), calcium bound P (Ca-P), Oc-P, detritus-bound (De-P) and organic P (Org-P) content in the influent chamber, and also enhanced P content uptake by wetland plants. A significantly positive correlation between P content of above-ground wetland plants and the Ex-P, Fe-P, Oc-P and Org-P content in the rhizosphere was found (P<0.05), which indicated that the Ex-P, Fe-P, Oc-P and Org P could be bio-available P. The Ex-P, Fe-P, De-P, Oc-P and Ca-P content of the influent chamber was higher where the substrate contained a mixture of Qing sand and river sand rather than only river sand. Also the IVFCW with earthworms and both Qing sand and river sand had a higher removal efficiency of P, which was related to higher P content uptake by wetland plants and P retained in IVFCW. These findings suggest that addition of earthworms in IVFCW increases the bioavailable P content, resulting in enhanced P content uptake by wetland plants. PMID- 26025067 TI - Nutritional status assessment in geriatrics: Consensus declaration by the Spanish Society of Geriatrics and Gerontology Nutrition Work Group. AB - Ongoing population ageing is one of the factors influencing the increase in the prevalence of undernutrition, because elderly people are a vulnerable group due to their biological, psychological and social characteristics. Despite its high prevalence, undernutrition is underdiagnosed in the geriatric sphere. For this reason, the aim of this consensus document is to devise a protocol for geriatric nutritional assessment. A multidisciplinary team has been set up within the Spanish Society of Geriatrics and Gerontology (in Spanish Sociedad Espanola de Geriatria y Gerontologia, SEGG) in order to address undernutrition and risk of undernutrition so that they can be diagnosed and treated in an effective manner. The MNA-SF is a practical tool amongst the many validated methods for nutritional screening. Following suspicion of undernutrition or after establishing the presence of undernutrition, a full assessment will include a detailed nutritional history of the patient. The compilation of clinical-nutritional and dietetic histories seeks to aid in identifying the possible risk factors at the root of a patient's undernutrition. Following this, an anthropometric assessment associated to laboratory data, will describe the patient's physical and metabolic changes associated to undernutrition. Currently, the tendency is to further nutritional assessment through the use of non-invasive techniques to study body composition in association with functional status. The latter is an indirect index for nutritional status which is very interesting from a geriatrician's point of view. To conclude, correct nutritional screening is the fundamental basis for an early undernutrition diagnosis and to assess the need for nutritional treatment. In order to achieve this, it is fundamental to foster research in the field of nutritional geriatrics, in order to expand our knowledge base and to increasingly practice evidence-based geriatrics. PMID- 26025068 TI - Menopausal hormone therapy for the prevention of cardiovascular disease: Evidence based customization. PMID- 26025069 TI - Yersinia pseudotuberculosis IP32953 survives and replicates in trophozoites and persists in cysts of Acanthamoeba castellanii. AB - Yersinia pseudotuberculosis is a foodborne enteric pathogen that causes a mild self-limiting diarrhea in humans. Yersinia pseudotuberculosis is able to persist in soil and water and in association with fresh produce, but the mechanism by which it persists is unknown. It has been shown that Y. pseudotuberculosis co occurs with protozoans in these environments; therefore, this study investigates if bacterivorous free-living amoeba (FLA) are able to support persistence of Y. pseudotuberculosis. Coculture studies of Y. pseudotuberculosis and the prototype FLA, Acanthamoeba castellanii revealed that bacteria had an enhanced capacity to survive in association with amoeba and in the absence of any cytotoxic effects. Yersinia pseudotuberculosis is able to survive and replicate in trophozoites specifically localized within vacuoles, and persists within cysts over a period of at least a week. These data present the first evidence that Y. pseudotuberculosis is able to resist the bacterivorous nature of FLA and instead exhibits an enhanced ability to replicate and persist in coculture with amoeba. This study sheds light on the potential role of FLA in the ecology of Y. pseudotuberculosis which may have implications for food safety. PMID- 26025070 TI - Methanogen communities in stools of humans of different age and health status and co-occurrence with bacteria. AB - Hydrogenotrophic methanogens live in a synthrophic relationship with the human gut microbiota as the terminal part of the anaerobic food chain. Methanobrevibacter smithii of the Methanobacteriales is the prevailing archaeal species. Recently, methylotrophic archaea of the novel order Methanomassiliicoccales were isolated from human stools. Few data exist on the prevalence, abundance, persistence and ecology of these methanogens in humans. This study investigated methanogen communities in 26 healthy and obese children (8-14 years) and 18 adults (28-78 years) using quantitative PCR. Samples were obtained from nine females before and after giving birth. Bacterial groups linked to the abundance of methanogens in adult females were identified using a 16S rRNA gene amplicon data set. A total of 89% and 65% of adults and children, respectively, carried Methanobacteriales. Methanomassiliicoccales were recovered from 50% of the adults and one child. Mean relative abundance of Methanomassiliicoccales in adults was lower than that of Methanobacteriales (0.10% versus 0.52%). Both Methanobacteriales and Methanomassiliicoccales formed stable communities in females before and after giving birth. Methanobacteriales co-occurred with bacterial taxonomic groups associated with the trophic chain from carbohydrate degradation to hydrogen and formate formation. Relative abundance was inversely correlated to Blautia. Negative correlation with little characterized groups within the Clostridiales indicated possible interactions of Methanomassiliicoccales with the bacterial community. PMID- 26025071 TI - Shigella flexneri cell-to-cell spread, and growth and inflammation in mice, is limited by the outer membrane protease IcsP. AB - The Shigella flexneri autotransporter protein IcsA is essential for intra- and intercellular spread, and icsA mutants are attenuated in several models. However, the pathogenic significance of the outer membrane protease IcsP, which orchestrates the polar distribution of IcsA on the bacterial surface, remains unclear. To further examine this point, we constructed icsP mutants in the two most commonly studied S. flexneri strains and evaluated their in vitro and in vivo performance relative to wild type. Both icsP mutants showed aberrant surface distribution of IcsA, but the in vitro consequences depended upon the cell line being used to assess bacterial motility and plaque formation. Evaluating the behaviour of the mutants in two mouse models suggested functional expression of icsP might limit bacterial persistence and the associated inflammation in host tissues, consistent with the findings in one of the three cell lines used. PMID- 26025072 TI - Influence of linker length in shape recognition of B* DNA by dimeric aminoglycosides. AB - DNA-protein recognition has shown us the importance of DNA shapes in the recognition process. Specific high-affinity targeting of DNA shapes by small molecules is desirable for many biological applications that involve regulation of DNA based processes. Here, the effect of linker length and rigidity on the affinity of a conjugated neomycin dimer for a specific DNA shape (B* form) AT rich DNA was explored. Binding constants approximating 10(8)M(-1) for optimal linker lengths of 18-19 atoms are reported herein. PMID- 26025073 TI - (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-beta aggregation with high antioxidant potency for Alzheimer's therapy. AB - The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-beta (Abeta) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Abeta self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. PMID- 26025075 TI - Vitamin A supplementation for the reduction of the risk of mother-to-child transmission of HIV. AB - Although advances in HIV prevention and treatment suggest the possibility of creating an AIDS-free generation, many areas of the world still suffer from high rates of mother-to-child transmission (MTCT) of HIV. Interventions proven to significantly decrease rates of MTCT of HIV are often unavailable in resource limited settings due to lack of reliable clean water, low numbers of hospital deliveries and inconsistent availability of antiretroviral medications. Vitamin A, with its multiple roles in epithelial, reproductive and immune function, has been evaluated as a possible intervention for preventing MTCT. Early observational studies suggested an association between vitamin A deficiency and increased rates of MTCT of HIV; however, the controlled studies that followed did not find a benefit for vitamin A in decreasing MTCT rates. Although vitamin A has some benefits for infants postpartum, it is not recommended for the reduction of the risk of MTCT of HIV. PMID- 26025074 TI - Comparative assessment of different reconstructive techniques of distal femur in revision total knee arthroplasty. AB - PURPOSE: Bone loss is often encountered in revision total knee arthroplasty. In particular, when the cortex of distal femur is breached, the surgical decision on the reconstructive options to be taken is challenging due to the variety of defects and the lack of data from clinical or experimental studies that can support it. The aim of the present work was to test the hypothesis that for an identical defect and bone condition, each reconstructive technique option has a dissimilar stress and stability behaviour, which may be related to differing longevity of the revision procedure. METHODS: Triaxial strain gauges and video extensometer were used to measure distal cortex strains and implant stability in eight reconstructive techniques replicated with synthetic femur under a load of 2030N. To assess the cancellous bone strains, finite element models were developed and validated. RESULTS: The measured strains showed that the distal cortex is not immune to the different reconstructive techniques, when applied to an identical defect; however, significant differences (P < 0.05) were found only between bone graft and metal augment on the 12-mm larger distal defect. The stem addition improves the stability of all reconstructive techniques; however, significant differences (P = 0.03) were found only on the bone-graft technique. CONCLUSIONS: Cement-fill and metal-augment techniques, applied to the 4-mm smaller defect, are not associated with different structural behaviour, while for the 12-mm larger defect, the metal-augment and bone-graft techniques presented distinct biomechanical effects. These effects, by themselves, may not be sufficient to be associated with a different longevity of the revision procedure among techniques, when the stem is added to the bone-graft technique. These findings, based on independent scientific understanding and advanced prediction tools, can improve the surgical decision-making process, when the peripheral cortex of the distal femur is breached. PMID- 26025076 TI - Structural elucidation of a polysaccharide from Chrysanthemum morifolium flowers with anti-angiogenic activity. AB - The flowers of Chrysanthemum morifolium were extracted with 5% sodium hydroxide, yielding a neutral polysaccharide (JHB0S2) with a molecular weight of 16 kDa by anion-exchange chromatography on a DEAE-cellulose column and gel permeation chromatography on a Sephacryl S-200 HR column. JHB0S2 was found to contain glucose, xylose, arabinose and galactose in molar ratio of 2.9:2.3:1.0:1.2. Through the linkage analysis, partial acid hydrolysis and NMR spectra and so forth, indicated that its backbone consisted of 1,4-linked beta-Glcp, nearly 50% of which was substituted at O-6 by 1,2-linked alpha-Xylp terminated with Galp or Xylp. Furthermore, some of 1,2-linked alpha-Xylp was substituted at O-4 by alpha Araf-(1->5)-alpha-Araf-(1->6)-beta-Galp. The biological test showed that JHB0S2 could inhibit the tube formation of HMEC-1 cells. PMID- 26025077 TI - Improvement of glycine oxidase by DNA shuffling, and site-saturation mutagenesis of F247 residue. AB - Glyphosate is a broad spectrum herbicide widely used throughout the world, and it could be degraded by glycine oxidase (GO) through CN bond cleavage. For a better understanding of the structure-function relationship and improving the activity of B3S1 (GO from Bacillus cereus), DNA shuffling was performed. A mutant B4S7 (The Km, Vmax, kcat and kcat/Km values on glyphosate were 0.1 mM, 0.002401 mM min(-1), 3.62 min(-1) and 36.2 mM(-1) min(-1), respectively. The four parameters on glycine were 50.34 mM, 0.001983 mM min(-1), 2.18 min(-1) and 0.04 mM(-1) min( 1), respectively) was obtained from 10,000 clones, which presented a 3.9-fold increase of the specificity constant (the kcat/Km ratio between glyphosate and glycine) compared with B3S1. Especially, the Km value of B4S7 to glyphosate was much less than those of the reported GO. Structure modeling and molecular docking indicated that the novel mutation point F247S was close to the active site of the enzyme. To identify the role of the site, the remaining 19 amino acids were introduced into the site by site-saturation mutagenesis. The result showed that compared with B3S1, the specificity constant of mutant F247S and F247R increased 0.64-fold and 1.04-fold, respectively. While the specificity constant of mutant F247E decreased 2.01-fold. Therefore, the site 247 plays a crucial role in regulating the substrate specificity. This study provides new information on the structure-function relationship of glycine oxidase and the development of glyphosate-tolerant crops. PMID- 26025078 TI - Ulcerative Colitis Care Pathway. PMID- 26025080 TI - Cultural sensitivity levels of university students receiving education in health disciplines. AB - Medical and nursing students are expected to be more competent in terms of being acquainted with different cultures and approaching culturally, compared to many other disciplines. This descriptive study was designed to evaluate the cultural sensitivity levels of nursing and medical students and the affecting factors. One hundred and eleven nursing and 164 medical students were included in the study. The data were collected by using a questionnaire questioning the variables that were thought to affect the cultural sensitivity of students and the intercultural sensitivity scale. According to results of the study; it was observed that university students receiving education in the fields of medicine and nursing had good cultural sensitivity levels and those interacting with people from other cultures and speaking a foreign language had significantly higher cultural sensitivity levels (p < 0.05). According to these results, it was thought that it would be useful to develop plannings aimed at increasing the language proficiency in university curriculums and abroad experience opportunities of students, and to design qualitative studies based on interviews and observations aimed at examining the factors affecting the intercultural sensitivity. PMID- 26025079 TI - Incidence and outcomes of acute kidney injury after cardiac surgery using either criteria of the RIFLE classification. AB - BACKGROUND: Adult cardiac surgery is significantly associated with the development of acute kidney injury (AKI). Still, the incidence and outcomes of AKI vary according to its definition. Our retrospective monocentric study comparatively investigates the yield of RIFLE definition, which is based on the elevation of serum creatinine levels (SCr) or the reduction of urine output (UO), taking into account only one or both criteria. Pre- and per-operative risk factors for post-operative AKI were evaluated. METHODS: All adult patients undergoing cardiac surgery, with or without cardiopulmonary bypass, from April 2008 to March 2009 were included. Clinical, biological and surgical features were recorded. Baseline serum creatinine was determined as its value on day 7 before surgery. Post-operative AKI was diagnosed and scored based upon the highest serum creatinine and/or the lowest urine output. RESULTS: 443 patients (Male/Female ratio, 2.3; median age, 69y) were included, with 221 (49.9%) developing postoperative AKI. Elevated serum creatinine (AKISCr) and oliguria (AKIUO) was observed in 9.7% and 40.2%, respectively. AKI patients had a significantly higher BMI and baseline SCr. In comparison to AKIUO, AKISCr mostly occurred in patients with co-morbidities, and was associated with an increased mortality at 1-year post surgery. CONCLUSIONS: The use of standard RIFLE definition of AKI in a cohort of 443 patients undergoing cardiac surgery resulted in an incidence reaching 50%. Still, significant discrepancies were found between AKISCr and AKIUO regarding the incidence and outcomes. In line with previous reports, our data questions the utility of urine output as a criterion for AKI diagnosis and management after cardiac surgery. PMID- 26025081 TI - Pericarditis-associated atrial fibrillation. PMID- 26025082 TI - Cochrane corner: cardiac rehabilitation for people with heart disease. PMID- 26025083 TI - Long-term outcomes in coarctation of the aorta: an evolving story of success and new challenges. PMID- 26025084 TI - Association of body mass index with mortality and cardiovascular events for patients with coronary artery disease: a systematic review and meta-analysis. AB - OBJECTIVES: The association between obesity and prognosis in patients with coronary artery disease (CAD) remains uncertain. We undertook a meta-analysis for the effects of body mass index (BMI) on mortality and cardiovascular events in these patients. METHODS: We identified studies that provided risk estimates for mortality or cardiovascular events on the basis of BMI in patients with CAD. Summary estimates of relative risks were obtained for five BMI groups: underweight, normal-weight, overweight, obese and grade II/III obese. Mortality was analysed separately as short-term (<6 months) and long-term (>=6 months). RESULTS: Data from 89 studies with 1 300 794 patients were included. Mean follow up of long-term estimates was 3.2 years. Using normal-weight as the reference, underweight was associated with higher risk of short-term mortality (2.24 (1.85 to 2.72)) and long-term mortality (1.70 (1.56 to 1.86)), overweight and obesity were both associated with lower risk of short-term mortality (0.69 (0.64 to 0.75); 0.68 (0.61 to 0.75)) and long-term mortality (0.78 (0.74 to 0.82); 0.79 (0.73 to 0.85)), but the long-term benefit of obesity disappeared after 5 years of follow-up (0.99 (0.91 to 1.08)). Grade II/III obesity was associated with lower risk of mortality in the short term (0.76 (0.62 to 0.91)) but higher risk after 5 years of follow-up (1.25 (1.14 to 1.38)). The similar J-shaped pattern was also seen for cardiovascular mortality and across different treatment strategies. Meta-regression found an attenuation of the inverse association between BMI and risk of mortality over longer follow-up. CONCLUSIONS: Our data support a J-shaped relationship between mortality and BMI in patients with CAD. The limitation of current literature warrants better design of future studies. PMID- 26025085 TI - Adiponectin: an accurate biomarker for patients at risk for atrial fibrillation? PMID- 26025086 TI - The effects of nutrition knowledge on food label use. A review of the literature. AB - Nutrition information on food labels is an important source of nutrition information but is typically underutilized by consumers. This review examined whether consumer nutrition knowledge is important for communication of nutrition information through labels on packaged foods. A cognitive processing model posits that consumers with prior knowledge are more likely to use label information effectively, that is, focus on salient information, understand information, and make healthful decisions based on this information. Consistent with this model, the review found that nutrition knowledge provides support for food label use. However, nutrition knowledge measures varied widely in terms of the dimensions they included and the extensiveness of the assessment. Relatively few studies investigated knowledge effects on the use of ingredient lists and claims, compared to nutrition facts labels. We also found an overreliance on convenience samples relying on younger adults, limiting our understanding of how knowledge supports food label use in later life. Future research should 1) investigate which dimensions, or forms, of nutrition knowledge are most critical to food label use and dietary decision making and 2) determine whether increases in nutrition knowledge can promote great use of nutrition information on food labels. PMID- 26025087 TI - Neighborhood fast food availability and fast food consumption. AB - Recent nutritional and public health research has focused on how the availability of various types of food in a person's immediate area or neighborhood influences his or her food choices and eating habits. It has been theorized that people living in areas with a wealth of unhealthy fast-food options may show higher levels of fast-food consumption, a factor that often coincides with being overweight or obese. However, measuring food availability in a particular area is difficult to achieve consistently: there may be differences in the strict physical locations of food options as compared to how individuals perceive their personal food availability, and various studies may use either one or both of these measures. The aim of this study was to evaluate the association between weekly fast-food consumption and both a person's perceived availability of fast food and an objective measure of fast-food presence - Geographic Information Systems (GIS) - within that person's neighborhood. A randomly selected population based sample of eight counties in South Carolina was used to conduct a cross sectional telephone survey assessing self-report fast-food consumption and perceived availability of fast food. GIS was used to determine the actual number of fast-food outlets within each participant's neighborhood. Using multinomial logistic regression analyses, we found that neither perceived availability nor GIS-based presence of fast-food was significantly associated with weekly fast food consumption. Our findings indicate that availability might not be the dominant factor influencing fast-food consumption. We recommend using subjective availability measures and considering individual characteristics that could influence both perceived availability of fast food and its impact on fast-food consumption. If replicated, our findings suggest that interventions aimed at reducing fast-food consumption by limiting neighborhood fast-food availability might not be completely effective. PMID- 26025088 TI - Effects of two cognitive regulation strategies on the processing of food cues in high restrained eaters. An event-related potential study. AB - This study tested the effects of cognitive regulation (CR) on the attentional processing of food cues in restrained eaters (RE) by means of event-related potentials (ERPs). In a within-subject-design, RE (n = 23) were presented pictures of highly palatable food and office items while ERPs were recorded. Prior to the presentation of the food stimuli, participants were either instructed to engage in reappraisal or to attempt to suppress cravings - both cognitive regulation (CR) strategies - or to simply watch the pictures. Prior to the presentation of the neutral stimuli, participants were instructed to simply watch them. Following each picture presentation, momentary craving was assessed. Main results showed that engaging in CR significantly reduced ERP amplitudes compared to the food watch condition. Passively attending to food pictures yielded significantly higher craving scores compared to engaging in CR. In addition, craving was significantly lower in the reappraisal than in the suppression condition. Therefore, reappraisal could potentially increase the ability to inhibit the appetitive motivation to eat. PMID- 26025089 TI - Infant and maternal predictors of early life feeding decisions. The timing of solid food introduction. AB - There is limited research on the maternal and infant characteristics associated with the timing of solid food introduction. The current study examined how maternal feeding style and infant temperament independently and interactively predicted the age at which infants were introduced to solid food. Data from 115 predominately white, middle-class mothers were collected when infants were 4 and 6 months of age. The timing of solid food introduction was positively correlated with mothers' age, education, breastfeeding at 4 months, self-reported responsiveness to infants' hunger and satiety cues, and negatively correlated with mothers' pre-pregnancy body mass index (BMI), beliefs about feeding infants solid food prior to 6 months of age, and infants' temperamental motor reactivity. When controlling for maternal age, education, pre-pregnancy BMI, and milk feeding method at 4 months, the timing of solid food introduction was negatively predicted by mothers' beliefs about feeding solid food prior to 6 months of age. Exploratory interaction analyses suggested that infant temperament marginally moderated maternal feeding style in predicting the timing of solid food introduction. PMID- 26025092 TI - Holistic Nursing in the Genetic/Genomic Era. AB - Holistic nursing practice is an ever-evolving transformative process with core values that require continued growth, professional leadership, and advocacy. Holistic nurses are required to stay current with all new required competencies, such as the Core Competencies in Genetics for Health Professional, and, as such, be adept at translating scientific evidence relating to genetics/genomics in the clinical setting. Knowledge of genetics/genomics in relation to nursing practice, policy, utilization, and research influence nurses' responsibilities. In addition to holistic nursing competencies, the holistic nurse must have basic knowledge and skills to integrate genetics/genomics aspects. It is important for holistic nurses to enhance their overall knowledge foundation, skills, and attitudes about genetics to prepare for the transformation in health care that is already underway. Holistic nurses can provide an important perspective to the application of genetics and genomics, focusing on health promotion, caring, and understanding the relationship between caring and families, community, and society. Yet there may be a lack of genetic and genomic knowledge to fully participate in the current genomic era. This article will explore the required core competencies for all health care professionals, share linkage of holistic nurses in practice with genetic/genomic conditions, and provide resources to further one's knowledge base. PMID- 26025091 TI - Determinants of EV71 immunogenicity and protection against lethal challenge in a mouse model. AB - Circulating enterovirus 71 (EV71)-associated hand, foot, and mouth disease (HFMD) is a major public health problem in the Asian-Pacific region. An EV71 vaccine for HFMD prevention is currently being developed. However, viral determinants that could influence the vaccine's efficacy have not been well characterized. In this study, we isolated and characterized several EV71 strains that are currently circulating in northern and southern China. We determined that VP1 variation is a major determinant of EV71 immunogenicity. A single amino acid variation in VP1 can lead to significant differences in the breadth and potency of immune responses against primary EV71 isolates as well as the sensitivity of EV71 to heterologous neutralizing antibody responses. We also identified EV71 strains that could induce potent immunogenic and cross-neutralizing antibody responses against diverse EV71 strains. Furthermore, these neutralizing antibodies could protect neonatal mice from lethal dose challenge with various circulating EV71 viruses. Our study provides useful information for EV71 vaccine development and evaluation. PMID- 26025090 TI - Quantitative proteomic analysis of host--pathogen interactions: a study of Acinetobacter baumannii responses to host airways. AB - BACKGROUND: Acinetobacter baumannii is a major health problem. The most common infection caused by A. baumannii is hospital acquired pneumonia, and the associated mortality rate is approximately 50%. Neither in vivo nor ex vivo expression profiling has been performed at the proteomic or transcriptomic level for pneumonia caused by A. baumannii. In this study, we characterized the proteome of A. baumannii under conditions that simulate those found in the airways, to gain some insight into how A. baumannii adapts to the host and to improve knowledge about the pathogenesis and virulence of this bacterium. A clinical strain of A. baumannii was grown under different conditions: in the presence of bronchoalveolar lavage fluid from infected rats, of RAW 264.7 cells to simulate conditions in the respiratory tract and in control conditions. We used iTRAQ labelling and LC-MALDI-TOF/TOF to investigate how A. baumannii responds on exposure to macrophages/BALF. RESULTS: 179 proteins showed differential expression. In both models, proteins involved in the following processes were over-expressed: (i) pathogenesis and virulence (OmpA, YjjK); (ii) cell wall/membrane/envelope biogenesis (MurC); (iii) energy production and conversion (acetyl-CoA hydrolase); and (iv) translation (50S ribosomal protein L9). Proteins involved in the following were under-expressed: (i) lipid metabolism (short-chain dehydrogenase); (ii) amino acid metabolism and transport (aspartate aminotransferase); (iii) unknown function (DNA-binding protein); and (iv) inorganic ion transport and metabolism (hydroperoxidase). CONCLUSIONS: We observed alterations in cell wall synthesis and identified 2 upregulated virulence-associated proteins with >15 peptides/protein in both ex vivo models (OmpA and YjjK), suggesting that these proteins are fundamental for pathogenesis and virulence in the airways. This study is the first comprehensive overview of the ex vivo proteome of A. baumannii and is an important step towards identification of diagnostic biomarkers, novel drug targets and potential vaccine candidates in the fight against pneumonia caused by A. baumannii. PMID- 26025093 TI - The Personal Narrative of a Nurse: A Journey Through Practice. AB - This article examines my phases of holistic learning concerning how I became a nurse, using story presented in a personal narrative style. I have incorporated my own stories to elaborate my journey. First, my early life in the East End of London and how this influenced my becoming a nurse. Second, I give an account of my journey through practice, where I examine how I developed my own learning from professional practice, drawing on some personal illustrations presented as stories. I have set out to explore how my stories of practice have influenced my progress, and I present a personal account of such learning in general from the lens of a nurse educator. PMID- 26025094 TI - The Use of Intercessory Prayer to Reduce Disruptive Behaviors of Patients With Dementia: A Pilot Feasibility Study. AB - A prospective longitudinal design was used to identify the feasibility, and preliminary efficacy of 12 weeks of intercessory prayer to reduce the disruptive behaviors of six late-stage dementia patients. One group of Catholic nuns offered the Lord's Prayer for assigned patients twice a day. Intercessory prayer for the entire subject group was also offered, by a second group of nuns, via a Latria (modality) called "Perpetual Adoration." Disruptions were documented from 3 weeks preintervention to 3 weeks postintervention. Consents were received for two thirds of invited patients. Retention was reduced by the death of two patients. Fidelity, assessed by retrospective report, was maintained throughout the study. Use of off-label antipsychotic medications was reduced or discontinued in four patients during the trial. The repeated measures analysis of variance, while indicative of a trend, did not reach a level of significance, likely due to small sample size. However, the average effect on behavior resulted in a reduction of disruptive incidents, for the group, in approximately 27 behavior categories/week. This study suggests that it is feasible to improve the life quality of patients in the terminal phase of their illness through prayer reducing their need to respond to life in a disturbed manner. PMID- 26025095 TI - Price and trade: World No Tobacco Day 2015. PMID- 26025096 TI - Yes-associated protein (YAP) is a negative regulator of chondrogenesis in mesenchymal stem cells. AB - INTRODUCTION: The control of differentiation of mesenchymal stromal/stem cells (MSCs) is crucial for tissue engineering strategies employing MSCs. The purpose of this study was to investigate whether the transcriptional co-factor Yes associated protein (YAP) regulates chondrogenic differentiation of MSCs. METHODS: Expression of total YAP, its paralogue transcriptional co-activator with PDZ binding motif (TAZ), and individual YAP transcript variants during in vitro chondrogenesis of human MSCs was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). YAP expression was confirmed by western blotting. To determine the effect of high YAP activity on chondrogenesis, C3H10T1/2 MSC-like cells were transduced with human (h)YAP and treated in micromass with bone morphogenetic protein-2 (BMP-2). Chondrogenic differentiation was assessed by alcian blue staining and expression of chondrocyte-lineage genes. BMP signalling was determined by detection of pSmad1,5,8 by western blotting and expression of BMP target genes by quantitative RT-PCR. Finally, YAP and pYAP were detected in mouse embryo hindlimbs by immunohistochemistry. RESULTS: YAP, but not TAZ, was downregulated during in vitro chondrogenesis of human MSCs. One of the YAP transcript variants, however, was upregulated in high-density micromass culture. Overexpression of hYAP in murine C3H10T1/2 MSCs inhibited chondrogenic differentiation. High YAP activity in these cells decreased Smad1,5,8 phosphorylation and expression of the BMP target genes Inhibitor of DNA binding/differentiation (Id)1, Id2 and Id3 in response to BMP-2. In developing mouse limbs, Yap was nuclear in the perichondrium while mostly phosphorylated and cytosolic in cells of the cartilage anlage, suggesting downregulation of Yap co transcriptional activity during physiological chondrogenesis in vivo. CONCLUSIONS: Our findings indicate that YAP is a negative regulator of chondrogenic differentiation of MSCs. Downregulation of YAP is required for chondrogenesis through derepression of chondrogenic signalling. Therapeutic targeting of YAP to promote cartilage repair and prevent secondary osteoarthritis is an exciting prospect in rheumatology. PMID- 26025097 TI - Intraocular Pressure in Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept or Ranibizumab. AB - PURPOSE: To assess change in intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (NVAMD) receiving intravitreal aflibercept injection (IAI) or ranibizumab in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies. DESIGN: Analyses from 2 randomized, active-controlled, phase III trials. PARTICIPANTS: A total of 2457 patients with NVAMD. METHODS: Patients received IAI 2 mg every (q) 4 weeks (2q4), 0.5 mg q4 weeks (0.5q4), 2 mg q8 weeks (after 3 monthly doses; 2q8), or ranibizumab 0.5 mg q4 weeks (Rq4) for 52 weeks. At week 52, patients were switched to a variable regimen requiring at least quarterly dosing and allowing interim injections based on anatomic and visual assessment. MAIN OUTCOME MEASURES: Pre-injection IOP was analyzed in study and uninjected fellow eyes from baseline to week 96. Prespecified end points included mean change in IOP from baseline and prevalence of a >21 mmHg and >10 mmHg increase in IOP from baseline. Cumulative incidence of sustained (at 2 consecutive visits) IOP >21 mmHg, a single event of IOP >25 mmHg, and sustained IOP increase from baseline (>=5 mmHg) was also evaluated. RESULTS: Mean IOP change from baseline over 96 weeks in all IAI groups was consistently lower than in the Rq4 group, and this finding was replicated in both trials. In an analysis integrating both studies, the proportion of study eyes with IOP >21 mmHg at week 96 was 20.2%, 14.2%, 12.1%, and 12.5% in Rq4, 2q4, 2q8, and 0.5q4, respectively. Reduction in risk, relative to Rq4, of having sustained IOP >21 mmHg over 96 weeks was 62% (95% confidence interval [CI], 36%-78%), 50% (95% CI, 19%-70%), and 69% (95% CI, 45%-84%) for 2q4, 2q8, and 0.5q4, respectively. Risk reduction in the IAI groups for a sustained IOP increase >=5 mmHg was 31% (95% CI, 8%-48%), 38% (95% CI, 17%-54%), and 47% (95% CI, 27%-61%), respectively. In uninjected fellow eyes, only sustained IOP >21 mmHg events were higher in the Rq4 group compared with all IAI groups. CONCLUSIONS: Incidence of elevated IOP in eyes with NVAMD was lower in all IAI groups than in the ranibizumab group. PMID- 26025099 TI - Comment on "Serum melatonin levels are associated with mortality in severe septic patients" by Lorente et al., J Crit Care (2015), http://dx.doi.org/10.1016/j.jcrc.2015.03.023. PMID- 26025098 TI - A new pattern of primordial germ cell migration in olive flounder (Paralichthys olivaceus) identified using nanos3. AB - The olive flounder (Paralichthys olivaceus) is an important cultured marine fish. However, little information is available on primordial germ cell (PGC) development and migration in this species; such information is vital for applications in artificial reproduction and for the preservation of genetic resources. Here, we sought to remedy this information deficit by isolating the germline-specific gene nanos3 and analyzing its expression in olive flounder. Sequencing analysis showed that olive flounder nanos3 contained a typical RNA binding zinc finger domain. A phylogenetic analysis demonstrated that nanos3 of the olive flounder grouped with that of the barfin flounder (Verasper moseri). In the olive flounder, nanos3 was consistently expressed during embryogenesis. Whole mount in situ hybridization showed that a new pattern of PGC migration was present in olive flounder, which combined elements of the PGC migration patterns of medaka, herring, and goby. In olive flounder, PGCs aligned along the lateral plate mesoderm in two loose, elongated lines at early embryogenesis, aggregated into a single loose cluster at mid-embryogenesis, then re-aligned into two tight clusters at late somitogenesis, and finally migrated to the genital ridge as two clusters. Furthermore, whole-mount in situ hybridization revealed that expression of stromal derived factor 1 (Sdf1) was important for guiding of PGC migration during somitogenesis. In particular, Sdf1 directed aggregation of PGCs into a single loose cluster from the two elongated lines during mid-embryogenesis. Additionally, PGCs in zebrafish were successfully visualized by injection of chimeric RNA containing the green fluorescent protein (GFP) and 3' untranslated region of olive flounder nanos3. These findings provide new insights into PGC migration and development in olive flounder and will also facilitate germ cell manipulation in this species. PMID- 26025100 TI - Association of tumor necrosis factor alpha -308G/A and interleukin-6 -174G/C gene polymorphism with pneumonia-induced sepsis. AB - PURPOSE: Sepsis is a lethal outcome of the inflammation and coagulation process. Human interleukin (IL)-6 and tumor necrosis factor (TNF) alpha are well-known inflammation factors closely associated with sepsis. In the present study, we aim to investigate the association of promoter-region polymorphisms IL-6 (-174G/C) rs1800795 and TNF-alpha (-308G/A) rs1800629 with pneumonia-induced sepsis. MATERIALS AND METHODS: A total of 277 Chinese patients with severe pneumonia induced sepsis were recruited into this study. All study participants were admitted to the intensive care unit until discharge or death in the First Affiliated Hospital of Zhengzhou University from July 2010 to July 2014. The patients were classified as severely septic, septic shock, and mortality. Clinical data and demographic information were recorded. TaqMan genotyping was performed to detect single nucleotide polymorphism distribution. RESULTS: The genotype results demonstrated that carriers of the TNF-alpha rs1800629 A allele had a 4.28-fold higher risk for septic shock (adjusted odds ratio [OR], 4.28; 95% confidence interval [CI], 2.24-8.18; P < .01) compared with severe sepsis, and carriers of the IL-6 rs1800795 C allele had a 2.42-fold higher risk for septic shock (OR, 2.42; 95% CI, 1.08-5.45; P < .01) compared with severe sepsis. No significant difference of SNP distribution was found between the survivors and the nonsurvivors. After the results were adjusted for age and the outcomes of blood cultures, a multivariate logistic regression analysis showed similar results. Individuals with the TNF-alpha 308 rs1800629 A allele (adjusted OR, 2.96; 95% CI, 1.30-7.87) or the IL-6 rs1800795 C allele (adjusted OR, 1.87; 95% CI, 1.03-3.61) had a higher prevalence of septic shock. However, these SNP distribution differences were not associated with mortality. CONCLUSIONS: In intensive care unit patients, the TNF-alpha -308A allele and the IL-6 rs1800795 allele variants were susceptibility risk factors for septic shock induced by pneumonia. PMID- 26025101 TI - Bit by bit: using design-based research to improve the health literacy of adolescents. AB - BACKGROUND: Although a low health literacy level has been found to be among the most powerful predictors of poor health outcomes, there is very little research focused on assessing and improving the health literacy skills of adolescents, particularly those from socioeconomically disadvantaged backgrounds. The vast majority of existing research focuses solely on reading comprehension, despite the fact that health literacy is actually a multifaceted concept, which entails many different types of skills. OBJECTIVE: The aim of this paper is to first mine existing literature to identify the many different skills that have been posited to constitute health literacy, and then, using this collection of skills as an overarching structure, to highlight the challenges that disadvantaged youth participating in our HackHealth after-school program encounter as they identify and articulate their health-related information needs, search for health-related information online, assess the relevance and credibility of this information, and manage and make use of it. METHODS: We utilized the design-based research method to design, implement, and revise our HackHealth program. To collect data regarding HackHealth participants' health literacy skills and associated challenges, we used a variety of methods, including participant observation, surveys, interviews, focus groups, and logging of Web browser activities. We also collected data through specialized instructional activities and data collection forms that we developed for this purpose. Quantitative and qualitative techniques were used to analyze this data, as well as all of the artifacts that each student produced, including their final projects. RESULTS: We identified the various challenges that the 30 HackHealth participants faced in completing various health related information activities during the course of the program. Based on these findings, we describe important implications for working with youth from socioeconomically disadvantaged backgrounds, how to assess and improve their health literacy skills, and offer specific recommendations for health literacy instruction aimed at this population. CONCLUSIONS: With an increased societal focus on health and a shift from viewing patients as passive recipients of medical care to viewing them as active arbiters of their own health, today's youth need to possess an array of health literacy skills to ensure that they can live long and healthy lives. Working with adolescents to help them develop and practice these skills will also help to break the cycle between poor health literacy and poor health outcomes, thereby reducing health disparities and improving the long-term outlook for the health of our nation. PMID- 26025106 TI - Orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence. AB - BACKGROUND: Urinary incontinence or the inability to void spontaneously after ileal orthotopic bladder substitution is a frequent finding in female patients. OBJECTIVE: To evaluate how hysterectomy and nerve sparing affect functional outcomes and whether these relate to pre- and postoperative urethral pressure profile (UPP) results. DESIGN, SETTING, AND PARTICIPANTS: Prospectively performed pre- and postoperative UPPs of 73 female patients who had undergone cystectomy and bladder substitution were correlated with postoperative voiding and continence status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome analyses were performed with the Kruskal-Wallis test, Wilcoxon-Mann-Whitney, or two-group post hoc testing with the Bonferroni correction. Chi-square or Fisher exact tests were applied for the categorical data. RESULTS AND LIMITATIONS: Of postoperatively continent or hypercontinent patients, 22 of 43 (51.2%) had the uterus preserved; of incontinent patients, only 4 of 30 (13.3%, p<0.01) had the uterus preserved. Of postoperatively continent or hypercontinent patients, 27 of 43 patients (62.8%) had bilateral and 15 of 43 (34.9%) had unilateral attempted nerve sparing. In incontinent patients, 11 of 30 (36.7%) had bilateral and 16 of 30 (53.3%) had unilateral attempted nerve sparing (p=0.02). When compared with postoperatively incontinent patients, postoperatively continent patients had a longer functional urethral length (median: 32mm vs 24mm; p<0.001), a higher postoperative urethral closing pressure at rest (56cm H2O vs 35cm H2O; p<0.001) as well as a higher preoperative urethral closing pressure at rest (74cm H2O vs 47.5cm H2O; p=0.01). The main limitation was the limited number of patients. CONCLUSIONS: In female patients undergoing radical cystectomy and bladder substitution, preservation of the uterus and attempted nerve sparing results in better functional outcomes. The preoperative UPPs correlate with postoperative voiding and continence status and may predict which patients are at a higher risk of functional failure after bladder substitution. PATIENT SUMMARY: If preservation of the urethra's innervation is not possible during cystectomy, poor functional results with bladder substitutes are likely. PMID- 26025105 TI - Viral and Antibody Prevalence of Hepatitis E in European Wild Boars (Sus scrofa) and Hunters at Zoonotic Risk in the Latium Region. AB - Hepatitis E virus (HEV) is a member of the genus Hepevirus within the family Hepeviridae. Hepatitis E is recognized as a zoonosis, and swine and wild boars (Sus scrofa) are known reservoirs of HEV infection. The aim of this study was to investigate the presence of HEV in wild boars and hunters exposed to infection in central Italy (Latium region). During the hunting season, blood samples were collected from 228 wild boars and 20 hunters. The seroprevalence of HEV infection was determined using a commercial enzyme-linked immunosorbent assay, previously validated for use in man, pigs and wild boars. The estimated HEV seroprevalence in wild boars and in hunters was 40.7% (93/228; 95% confidence interval [CI] 34.4 47.1%) and 25% (5/20; 95% CI 6.1-43.9%), respectively. Liver samples were collected from the boars and HEV RNA was detected by nested reverse transcriptase polymerase chain reaction. Fifty-five of 164 tested wild boar liver samples (33.5%; 95% CI 26.2-40.7%) and three of 20 (15.0%; 95% CI 1.3-28.7%) tested human serum samples were positive for HEV RNA. Phylogenetic analysis of the nucleotide sequences obtained from PCR products indicated that the HEV strains present in wild boars and the human population all belonged to genotype 3, supporting the zoonotic role of wild boars in the spread of HEV infection. PMID- 26025107 TI - Health Beliefs and Practices of African Immigrants in Canada. AB - A purposive sample of 14 immigrants living in Ontario, Canada, participated in two focus groups. The researchers used semi-structured interviews to collect data and five themes emerged from the data: beliefs about diabetes were centered on diverse factors, preserving culture through food preferences and preparation, cultural practices to stay healthy, cultural practices determined number of servings of fruit and vegetables per day, and engaging in physical activity to stay healthy. Findings indicated how health beliefs and cultural practices influenced behavior in preventing type 2 diabetes (T2D). Future research should focus on other high-risk minority groups (South Asian, Caribbean, and Latin American) to examine their health beliefs and cultural practices and use these finding to develop best practice guidelines, which should be incorporated into culturally tailored interventions. PMID- 26025108 TI - Unusual presentation of gastric carcinoma: back pain. PMID- 26025109 TI - Determination of Oxytetracycline from Salmon Muscle and Skin by Derivative Spectrophotometry. AB - A method was developed for the identification and quantification of oxytetracycline residues present in salmon muscle and skin using UV-Vis derivative spectrophotometry. With this method, it was possible to reduce the number of steps in the procedure typically required for instrumental analysis of a sample. The spectral variables, order of the derivative, scale factor, smoothing factor, and analytical wavelength were optimized using standard solutions of oxytetracycline dissolved in 900 mg/L oxalic acid in methanol. The matrix effect was significant; therefore, quantification for oxytetracycline residues was carried out using drug-free salmon muscle and skin samples fortified with oxytetracycline. The LOD and LOQ were found to be 271 and 903 MUg/kg, respectively. The precision and accuracy of the method were validated using drug free salmon muscle and skin tissues fortified at three different concentrations (8, 16, and 32 mg/kg) on 3 different days. The recoveries at all fortified concentrations were between 90 and 105%, and RSDs in all cases were less than 6.5%. This method can be used to screen out compliant samples and thereby reduce the number of suspect positive samples that will require further confirmatory analysis. PMID- 26025110 TI - Pharmacist provision of medication adherence services: More implementation and persistence research needed. PMID- 26025112 TI - Letter regarding Xiao WZ et al. entitled "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis". AB - With great interest, we read the article "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis" (by Xiao et al. Tumor Biol 35(7):6687-6693, 2014), which has reached important conclusions that the phosphatase and tensin homolog (PTEN) gene mutations were closely related to poor prognosis of glioma patients. Through quantitative analysis, the investigators (Xiao WZ et al.) showed that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95 % CI = 2.02~5.30, P < 0.001). Ethnicity-stratified subgroup analysis demonstrated that PTEN gene mutations were closely linked to poor prognosis in glioma among Americans (HR = 3.72, 95 % CI = 1.72~5.73, P < 0.001), while similar correlations were not observed among populations in Sweden, Italy, and Malaysia (all P > 0.05). The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise. PMID- 26025111 TI - Phenylketonuria screening and management in southeastern Europe - survey results from 11 countries. AB - BACKGROUND: We aimed to assess the current state of PKU screening and management in the region of southeastern Europe. METHODS: A survey was performed involving all identified professionals responsible for the PKU management in the 11 countries from South-Eastern region of Europe (Albania, Bulgaria, Bosnia and Herzegovina, Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, Slovenia). The questionnaire was designed to assess the characteristics regarding PKU management in three main areas: nation-wide characteristics, PKU screening, and characteristics of the PKU management in the responding centre. It consisted of 56 questions. The distribution and collection of the questionnaires (via e mail) was taking place from December 2013 to March 2014. RESULTS: Responses from participants from 11 countries were included; the countries cumulative population is approx. 52.5 mio. PKU screening was not yet introduced in 4 of 11 countries. Reported PKU incidences ranged from 1/7325 to 1/39338 (and were not known for 5 countries). National PKU guidelines existed in 5 of 11 countries and 7 of 11 countries had PKU registry (registries included 40 to 194 patients). The number of PKU centers in each country varied from 1 to 6. Routine genetic diagnostics was reported in 4 of 11 countries. Most commonly used laboratory method to assess phenylalanine levels was fluorometric. Tetrahydrobiopterine was used in only 2 of 11 countries. Most frequently, pediatricians were caring for the patients. Dietitian was a member of PKU team in only 4 of 11 countries, while regular psychological assessments were performed in 6 of 11 countries. Patient's PKU society existed in 7 of 11 countries. CONCLUSIONS: The region of southeastern Europe was facing certain important challenges of PKU screening and management. Neonatal PKU screening should be introduced throughout the region. Furthermore, PKU management was falling behind internationally established standards-of-care in many aspects. PMID- 26025113 TI - Platelet-to-lymphocyte ratio: a prognostic factor for patients with advanced hepatocellular carcinoma? PMID- 26025114 TI - Properly assessing CD133 as a risk factor for poor prognosis in patients with hepatocellular carcinoma after resection. PMID- 26025115 TI - Effect of slaughter age on the antioxidant enzyme activity, color, and oxidative stability of Korean Hanwoo (Bos taurus coreanae) cow beef. AB - This study investigated the effect of slaughter age on the antioxidant enzyme activity, lipid and protein oxidation, and color stability in striploins (M. longissimus lumborum) from Korean Hanwoo (Bos taurus coreanae) cows of different age groups (1.9 to 3.7, 4.0 to 4.8, 5.0 to 5.7, 6.0 to 6.9, and 7.5 to 11.5yr). Myoglobin content and the activities of catalase, superoxide dismutase, and glutathione peroxidase were significantly (P<0.05) increased in older cow beef. During refrigerated storage, 2-thiobarbituric acid reactive substances and protein carbonyls were significantly (P<0.05) increased in the meat from the older cows. The beef from older cows was darker and had lower color stability. These findings suggest that slaughter age has a negative effect on the color and lipid stability of Hanwoo cow beef. PMID- 26025116 TI - Management of Elderly Patients with Plasma Cell Myeloma. AB - Plasma cell myeloma (PCM) is a hematologic malignancy that primarily affects the elderly. Approximately two-thirds of patients are aged 65 years or older at diagnosis. Major advances in testing, treatment, and supportive care have resulted in substantial improvement in overall survival in younger, standard risk, PCM patients over the past 3 decades. However, this positive impact progressively diminishes with advancing age, with some studies showing no improvement in survival outcomes in the elderly. Slow improvement in survival for elderly PCM patients is likely multifactorial, influenced by factors such as age related physiologic changes, increased comorbidities, decreased treatment tolerance, socioeconomic barriers, and possible differences in disease biology. The standard approach of basing treatment decisions on age and performance status does not account for this complexity, and can be insufficient to determine the risks and benefits of treatment. Comprehensive geriatric assessment (CGA) produces a more thorough iteration of the factors influencing an individual's treatment risk, and can potentially identify targets for intervention to lower risk. Ongoing studies are looking at developing and refining the tools available for risk screening and assessment. Treating elderly PCM patients with novel agent based regimens with or without autologous stem cell transplantation has improved response rates and survival in some studies, but elderly PCM patients have benefitted less than their younger counterparts from recent advances in PCM treatment. Personalizing treatment decisions, based on predictions of risk, determined by geriatric assessment, and response, determined by precision medicine (our understanding of the genetic, molecular, and cellular pathways that drive an individual's cancer) will help maximize the benefit and minimize the risk of PCM treatment for each patient. Continued evaluation of new strategies and treatments for PCM in clinical trials specifically designed for elderly patients is needed to continue to improve outcomes for elderly PCM patients in the future. PMID- 26025117 TI - Pain in the Frail or Elderly Patient: Does Tapentadol Have a Role? AB - Persistent pain affects the elderly disproportionally, occurring in 50% of elderly community-dwelling patients and 80% of aged care residents. The management of pain in the elderly and frail patient is complicated because of the risks posed by changes in pharmacokinetics and pharmacodynamics, polypharmacy, and drug-disease interactions. Trials evaluating the efficacy of analgesics have often excluded elderly patients and universally excluded frail patients; therefore, the true efficacy and side-effect profiles in these population groups are largely unknown, especially for long-term use. A stepwise approach is recommended to managing pain, commencing with paracetamol and adding on opioids when needed to manage pain. However, because of the short duration of clinical trials, exclusion of frail patients, and minimal inclusion of elderly patients, the decision as to which opioid should be added on to paracetamol is a difficult one. This article reviews the evidence surrounding a newer opioid, tapentadol. Tapentadol acts on both the mu receptors and on neuronal reuptake of noradrenaline, and has no significant analgesically active metabolites, which theoretically presents some advantages, particularly in comparison with tramadol. However, the evidence to support tapentadol is weak and the trials were often methodologically poor and sponsored almost universally by the drug company. Currently, there is insufficient evidence to support the use of tapentadol over other opioids, which have been on the market longer, are less expensive, and have better established safety profiles. As a first-line agent after the failure of paracetamol alone, morphine, oxycodone, fentanyl, or buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for elderly or frail patients. PMID- 26025118 TI - Computerized Decision Support Improves Medication Review Effectiveness: An Experiment Evaluating the STRIP Assistant's Usability. AB - BACKGROUND: Polypharmacy poses threats to patients' health. The Systematic Tool to Reduce Inappropriate Prescribing (STRIP) is a drug optimization process for conducting medication reviews in primary care. To effectively and efficiently incorporate this method into daily practice, the STRIP Assistant--a decision support system that aims to assist physicians with the pharmacotherapeutic analysis of patients' medical records--has been developed. It generates context specific advice based on clinical guidelines. OBJECTIVE: The aim of this study was to validate the STRIP Assistant's usability as a tool for physicians to optimize medical records for polypharmacy patients. METHODS: In an online experiment, 42 physicians were asked to optimize medical records for two comparable polypharmacy patients, one in their usual manner and one using the STRIP Assistant. Changes in effectiveness were measured by comparing respondents' optimized medicine prescriptions with medication prepared by an expert panel of two geriatrician-pharmacologists. Efficiency was operationalized by recording the time the respondents took to optimize the two cases. User satisfaction was measured with the System Usability Scale (SUS). Independent and paired t tests were used for analysis. RESULTS: Medication optimization significantly improved with the STRIP Assistant. Appropriate decisions increased from 58% without the STRIP Assistant to 76% with it (p < 0.0001). Inappropriate decisions decreased from 42% without the STRIP Assistant to 24% with it (p < 0.0001). Participants spent significantly more time optimizing medication with the STRIP Assistant (24 min) than without it (13 min; p < 0.0001). They assigned it a below-average SUS score of 63.25. CONCLUSION: The STRIP Assistant improves the effectiveness of medication reviews for polypharmacy patients. PMID- 26025119 TI - Pharmacological Smoking Cessation Therapies in Older Adults: A Review of the Evidence. AB - Nearly 12% of adults 65 years and over in Europe and 9% in the USA are current cigarette smokers. Numerous studies have demonstrated tangible benefits of smoking cessation, regardless of advanced age. However, it is unclear which pharmacotherapy strategies are most effective in the elderly population. To that end, the literature on smoking cessation in older adults was reviewed with the aim of identifying the safest and most effective cessation pharmacotherapies. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for all articles pertaining to elderly smoking cessation strategies. Randomized controlled trials and cohort studies were included. Studies were included without regard to population or intervention, as long as results were analyzed with a group of smokers aged 60 years and above and at least one arm of the study involved a pharmacotherapy. Only 12 studies were identified that met our inclusion criteria. The limited existing literature does not allow for a definitive answer to the most effective pharmacotherapy for smoking cessation in older adult smokers. Nicotine replacement therapy (NRT) is the pharmacotherapy most studied in older adults, and the limited evidence that exists suggests that NRT is effective for smoking cessation among this population. Higher-quality studies that directly compare cessation strategies, including bupropion and varenicline, are needed in the older population in order to guide treatment decision making. PMID- 26025120 TI - Dual-energy computed tomography of cruciate ligament injuries in acute knee trauma. AB - OBJECTIVE: To examine dual-energy computed tomography (DECT) in evaluating cruciate ligament injuries. More specifically, the purpose was to assess the optimal keV level in DECT gemstone spectral imaging (GSI) images and to examine the usefulness of collagen-specific color mapping and dual-energy bone removal in the evaluation of cruciate ligaments and the popliteus tendon. MATERIALS AND METHODS: At a level 1 trauma center, a 29-month period of emergency department DECT examinations for acute knee trauma was reviewed by two radiologists for presence of cruciate ligament injuries, visualization of the popliteus tendon and the optimal keV level in GSI images. Three different evaluating protocols (GSI, bone removal and collagen-specific color mapping) were rated. Subsequent MRI served as a reference standard for intraarticular injuries. RESULTS: A total of 18 patients who had an acute knee trauma, DECT and MRI were found. On MRI, six patients had an ACL rupture. DECT's sensitivity and specificity to detect ACL rupture were 79% and 100%, respectively. The DECT vs. MRI intra- and interobserver proportions of agreement for ACL rupture were excellent or good (kappa values 0.72-0.87). Only one patient had a PCL rupture. In GSI images, the optimal keV level was 63 keV. GSI of 40-140 keV was considered to be the best evaluation protocol in the majority of cases. CONCLUSION: DECT is a usable method to evaluate ACL in acute knee trauma patients with rather good sensitivity and high specificity. GSI is generally a better evaluation protocol than bone removal or collagen-specific color mapping in the evaluation of cruciate ligaments and popliteus tendon. PMID- 26025121 TI - The utility of ultrasonographic bone age determination in detecting growth disturbances; a comparative study with the conventional radiographic technique. AB - OBJECTIVE: To test whether the conventional radiographic technique in determining bone age abnormalities can be replaced by ultrasonography. MATERIALS AND METHODS: A total of 54 Caucasian subjects up to 7 years of age with clinically suspected growth problems underwent left hand and wrist radiographic and ultrasonographic bone age estimations with the use of the Greulich-Pyle atlas. The ultrasonographic scans targeted the ossification centers in the radius and ulna distal epiphysis, carpal bones, epiphyses of the first and third metacarpals, and epiphysis of the middle phalanx, as described in previous reports. The degree of agreement between the two sets of data, as well as the accuracy of the ultrasonographic method in detecting radiographically suggested bone age abnormities, was examined. RESULTS: The mean chronological age, radiographic bone age, and ultrasonographic bone age (all in months) were 41.96 +/- 22.25, 26.68 +/ 14.08, and 26.71 +/- 13.50 in 28 boys and 43.62 +/- 24.63, 30.12 +/- 17.69, and 31.27 +/- 18.06 in 26 girls, respectively. According to the Bland-Altman plot there was high agreement between the results of the two methods with only three outliers. The deviations in bone age from the chronological age taken by the two techniques had the same sign in all patients. Supposing radiography to be the method of reference, the sensitivity, specificity, positive predictive value, and negative predictive value of sonography in detecting growth abnormalities were all 100% in males and 90.9, 100, 100, and 93.8%, respectively, in females. CONCLUSION: The conventional radiographic technique for determining bone age abnormalities could be replaced by ultrasonography. PMID- 26025122 TI - The popliteal fibular ligament in acute knee trauma: patterns of injury on MR imaging. AB - OBJECTIVE: To describe the patterns of injury associated with injury to the popliteofibular ligament injury. MATERIALS AND METHODS: A retrospective review was performed of 180 MRI scans undertaken for acute knee trauma. Scans were excluded if the time of injury was over 4 weeks from the time of the scan, or if there was a history of septic arthritis, inflammatory arthropathy, previous knee surgery, or significant artefact. An agreed criterion for assessing the structures of the posterolateral ligamentous complex was defined and in each scan, the popliteofibular ligament (PFL) was scored as normal or injured. The menisci, ligaments, and tendons of each knee were also assessed. RESULTS: The mean age was 25.7 years (range, 9-65 years) and 72.2% (n = 130) patients were male. The PFL was injured in 36 cases (20%). There is a significant association between PFL injury and ACL rupture (p = 0.0001), ITB injury (p = 0.0001), PCL injury (p = 0.0373), in addition to associations with injury to other posterolateral corner structures including the lateral collateral ligament (p = 0.0001), biceps femoris tendon (p = 0.0014), and popliteus tendon (p = 0.0014). Of our series of PFL injuries, nine cases (25%) were associated with further injuries of posterolateral corner structures and in 27 cases (75%) the PFL was the only posterolateral corner structure torn. CONCLUSIONS: PFL injury is not uncommon in acute knee trauma and is associated with significant internal derangement of the knee, especially anterior cruciate ligament rupture, ITB sprain, and injury to other structures within the posterolateral corner. PMID- 26025124 TI - A review of segmentation and deformable registration methods applied to adaptive cervical cancer radiation therapy treatment planning. AB - OBJECTIVE: Manual contouring and registration for radiotherapy treatment planning and online adaptation for cervical cancer radiation therapy in computed tomography (CT) and magnetic resonance images (MRI) are often necessary. However manual intervention is time consuming and may suffer from inter or intra-rater variability. In recent years a number of computer-guided automatic or semi automatic segmentation and registration methods have been proposed. Segmentation and registration in CT and MRI for this purpose is a challenging task due to soft tissue deformation, inter-patient shape and appearance variation and anatomical changes over the course of treatment. The objective of this work is to provide a state-of-the-art review of computer-aided methods developed for adaptive treatment planning and radiation therapy planning for cervical cancer radiation therapy. METHODS: Segmentation and registration methods published with the goal of cervical cancer treatment planning and adaptation have been identified from the literature (PubMed and Google Scholar). A comprehensive description of each method is provided. Similarities and differences of these methods are highlighted and the strengths and weaknesses of these methods are discussed. A discussion about choice of an appropriate method for a given modality is provided. RESULTS: In the reviewed papers a Dice similarity coefficient of around 0.85 along with mean absolute surface distance of 2-4mm for the clinically treated volume were reported for transfer of contours from planning day to the treatment day. CONCLUSIONS: Most segmentation and non-rigid registration methods have been primarily designed for adaptive re-planning for the transfer of contours from planning day to the treatment day. The use of shape priors significantly improved segmentation and registration accuracy compared to other models. PMID- 26025127 TI - Single allergen-induced oral tolerance inhibits airway inflammation in conjugated allergen immunized mice. PMID- 26025126 TI - IL-2 is a critical regulator of group 2 innate lymphoid cell function during pulmonary inflammation. AB - BACKGROUND: Group 2 innate lymphoid cells (ILC2) have been implicated in the pathogenesis of allergic lung diseases. However, the upstream signals that regulate ILC2 function during pulmonary inflammation remain poorly understood. ILC2s have been shown to respond to exogenous IL-2, but the importance of endogenous IL-2 in ILC2 function in vivo remains unclear. OBJECTIVE: We sought to understand the role of IL-2 in the regulation of ILC2 function in the lung. METHODS: We used histology, flow cytometry, immunohistochemistry, ELISA, and quantitative PCR with knockout and reporter mice to dissect pulmonary ILC2 function in vivo. We examined the role of ILC2s in eosinophilic crystalline pneumonia, an idiopathic type 2 inflammatory lung condition of mice, and the effect of IL-2 deficiency on this disease. We determined the effect of IL-2 administration on pulmonary ILC2 numbers and function in mice in the steady state and after challenge with IL-33. RESULTS: We discovered an unexpected role for innate cell-derived IL-2 as a major cofactor of ILC2 function during pulmonary inflammation. Specifically, we found that IL-2 was essential for the development of eosinophilic crystalline pneumonia, a type 2 disease characterized by increased numbers of activated ILC2s. We show that IL-2 signaling serves 2 distinct functions in lung ILC2s, namely promoting cell survival/proliferation and serving as a cofactor for the production of type 2 cytokines. We further demonstrate that group 3 innate lymphoid cells are an innate immune source of IL 2 in the lung. CONCLUSION: Innate cell-derived IL-2 is a critical cofactor in regulating ILC2 function in pulmonary type 2 pathology. PMID- 26025125 TI - Fine mapping of the myosin light chain kinase (MYLK) gene replicates the association with asthma in populations of Spanish descent. PMID- 26025128 TI - Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts. AB - BACKGROUND: Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). OBJECTIVE: We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. METHODS: We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts. RESULTS: We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin gamma pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 * 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 * 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin gamma gene expression in osteoblasts (P = 8.64 * 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased. CONCLUSIONS: We have identified 2 novel tubulin gamma pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts. PMID- 26025130 TI - A homozygous mutation of RTEL1 in a child presenting with an apparently isolated natural killer cell deficiency. PMID- 26025131 TI - Occupational allergic multiorgan disease induced by wheat flour. PMID- 26025129 TI - Single amino acid charge switch defines clinically distinct proline-serine threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. AB - BACKGROUND: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. RESULTS: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 +/- 1300 MUg/mL) compared with those with PAPA syndrome (116 +/- 74 MUg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. CONCLUSION: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E >K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family. PMID- 26025133 TI - Determination of Triphenylmethane Dyes and Their Metabolites in Salmon, Catfish, and Shrimp by LC-MS/MS Using AOAC First Action Method 2012.25: Collaborative Study. AB - A collaborative study was conducted to evaluate the AOAC First Action 2012.25 LC MS/MS analytical method for the determination of residues of three triphenylmethane dyes (malachite green, crystal violet, and brilliant green) and their metabolites (leucomalachite green and leucocrystal violet) in seafood. Fourteen laboratories from the United States, Canada, and the European Union member states participated in the study including national and state regulatory laboratories, university and national research laboratories, and private analytical testing laboratories. A variety of LC-MS/MS instruments were used for the analysis. Each participating laboratory received blinded test samples in duplicate of salmon, catfish, and shrimp consisting of negative control matrix; matrix fortified with residues at 0.42, 0.90, and 1.75 MUg/kg; and samples of incurred matrix. The analytical results from each participating laboratory were evaluated for both quantitative residue determination and qualitative identification of targeted analytes. Results from statistical analysis showed that this method provided excellent trueness (generally >=90% recovery) and precision (RSDr generally <=10%, HorRat<1). The Study Directors recommend Method 2012.25 for Final Action status. PMID- 26025132 TI - The Apicomplexan CDC/MACPF-like pore-forming proteins. AB - Pore-forming proteins (PFPs) encompass a broad family of proteins that are used for virulence or immune defense. Members of the cholesterol-dependent cytolysins (CDCs) and membrane attack complex/perforin (MACPF) family of PFPs form large beta-barrel pores in the membrane. The CDC/MACPF proteins contain a characteristic four-stranded beta-sheet that is flanked by two alpha-helical bundles, which unfold to form two transmembrane beta-hairpins. Apicomplexan eukaryotic parasites express CDC/MACPFs termed perforin-like proteins (PLPs). Here we review recent studies that provide key insights into the assembly and regulation of the Apicomplexan PLP (ApiMACPF) molecular pore-forming mechanisms, which are necessary for the osmotically driven rupture of the parasitophorous vacuole and host cell membrane, and cell traversal by these parasites. PMID- 26025134 TI - Parallel optical read-out of micromechanical pillars applied to prostate specific membrane antigen detection. AB - Micro and nanomechanical resonators represent a promising platform for proteins label-free detection because of their extreme sensitivity, fast response and low cost. Micro-pillars are columnar resonators that can be easily arranged in dense arrays of several thousand sensors in a squared mm. To exploit such a large density, however, a method for tracking independently micropillars resonance frequency is required. Here we present a detection method based on CCD imaging and software image analysis, which can measure the resonance frequency of tens of pillars in parallel. Acquiring simultaneously the frequency shift of up to 40 sensors and applying a proper statistical analysis, we were able to overcome the variability of the single measures improving the device sensitivity at low analyte concentration range. As a proof of concept, this method has been tested for the detection of a tumor marker, the Prostate Specific Membrane Antigen (PSMA). Pillars have been functionalized with an antibody against PSMA. The tumor marker (PSMA) has been detected in a range of concentrations between 300 pM and 100 nM, in buffer and in diluted bovine serum. The sensitivity of our method was limited only by the affinity constant of the antigen-antibody recognition. Moreover, this detection technique demonstrated to be effective in the 1-6 nM range, which is the window of PSMA concentration of clinical interest. PMID- 26025135 TI - Prognostic factors in dogs with protein-losing enteropathy. AB - Canine protein-losing enteropathy (PLE) is associated with severe gastrointestinal disorders and has a guarded to poor prognosis although little information is available regarding factors affecting prognosis. The purpose of this study was to identify the prognostic factors for survival of dogs with PLE. Ninety-two dogs diagnosed with PLE from 2006 to 2011 were included in a retrospective cohort study. Survival analysis was performed using the Kaplan Meier method and log-rank test. Variables recorded at the time of diagnosis were statistically analysed for possible prognostic factors in a univariate and multivariate Cox proportional hazard model. In the multivariate analysis, the predictors for mortality in dogs with PLE were more highly scored in terms of canine inflammatory bowel disease activity index (CIBDAI) (P = 0.0003), clonal rearrangement of lymphocyte antigen receptor genes (P = 0.003), and elevation of blood urea nitrogen (BUN) (P = 0.03). Using histopathological diagnosis, both small- and large-cell lymphomas were associated with significantly shorter survival times than chronic enteritis (CE) and intestinal lymphangiectasia (IL). Normalization of CIBDAI and plasma albumin concentration within 50 days of initial treatment was associated with a longer survival time. In conclusion, CIBDAI, clonal rearrangement of lymphocyte antigen receptor genes, histopathological diagnosis, and response to initial treatments would be valuable in separating the underlying causes and could be important in predicting prognosis in dogs with PLE. PMID- 26025136 TI - Variations in patient-reported physical health between cardiac and musculoskeletal diseases: systematic review and meta-analysis of population-based studies. AB - Population-based assessments of physical health are important to evaluate healthcare resource allocation. Normative data on the level of physical impairments attributable to specific diseases and severity levels within these diseases is critical to interpreting such data. Our objective, by means of a systematic review and meta-analysis, was to test the hypothesis that specific diseases which form cardiovascular and musculoskeletal disease spectra are associated with gradients of physical impairments. We examined a cardiovascular disease spectrum which consisted of hypertension, ischaemic heart disease and heart failure, and a musculoskeletal disease spectrum of lower back pain, osteoarthritis and rheumatoid arthritis. Using Medline, EMBASE and CINAHL databases, articles which had examined these morbidities and used either the SF 12 or SF-36 in general or primary care populations were selected; data was extracted independently by three reviewers. Study characteristics were described and the mean physical component summary scores of the SF-12 or SF-36 was analysed by disease, using random-effects meta-analysis. The association between disease and physical health (mean physical component summary scores) was assessed using multilevel meta-regression analysis, adjusting for age, health setting, country, disease definition and SF-12 or 36 format. From this search, 26 articles were identified, yielding 70 separate estimates of mean physical component summary scores across the morbidities from 14 different countries. For the selected conditions, pooled unadjusted mean physical component summary scores were: 44.4 for hypertension, 38.9 for ischaemic heart disease, 35.9 for heart failure, 39.5 for lower back pain, 36.0 for osteoarthritis and 36.5 for rheumatoid arthritis. The adjusted meta-regression showed mean physical component summary score difference for ischaemic heart disease of -4.6 (95 % confidence interval -6.0 to 3.2) and heart failure -7.5 (-9.1 to -5.9) compared to the hypertension category. For osteoarthritis -4.2 (-5.3 to -3.0) and rheumatoid arthritis -3.9 (-9.5 to 1.6) compared to the lower back pain category. Our findings provide the benchmark norms for the differences in physical health within and between disease spectra. Improved characterisation of the relative impact of individual conditions on physical health will facilitate public health assessments of chronic diseases as well as assessments of interventions using functional patient-reported outcomes. PMID- 26025137 TI - CREB expression mediates amyloid beta-induced basal BDNF downregulation. AB - In Alzheimer's disease, accumulation of amyloid-beta (Abeta) is associated with loss of brain-derived neurotrophic factor (BDNF), synapses, and memory. Previous work demonstrated that Abeta decreases activity-induced BDNF transcription by regulating cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation. However, the specific mechanism by which Abeta reduces basal BDNF expression remains unclear. Differentiated, unstimulated human neuroblastoma (SH-SY5Y) cells treated with oligomeric Abeta exhibited significantly reduced CREB messenger RNA compared with controls. Phosphorylated and total CREB proteins were decreased in both the cytoplasm and nucleus of Abeta-treated cells. However, neither pCREB129 nor pCREB133 levels were altered relative to total CREB levels. The protein kinase A activator forskolin increased pCREB133 levels and prevented Abeta-induced basal BDNF loss when administered before Abeta but did not rescue BDNF expression when administered later. These data demonstrate a new mechanism for Abeta-induced BDNF downregulation: in the absence of cell stimulation, Abeta downregulates basal BDNF levels via Abeta-induced CREB transcriptional downregulation, not changes in CREB phosphorylation. Thus, Abeta reduces basal and activity-induced BDNF expression by different mechanisms. PMID- 26025138 TI - Systematic Review of Retraction Devices for Laparoscopic Surgery. AB - BACKGROUND: Retraction plays a vital role in optimizing the field of vision in minimal-access surgery. As such, a number of devices have been marketed to aid the surgeon in laparoscopic retraction. This systematic review explores the advantages and disadvantages of the different instruments in order to aid surgeons and their institutions in selecting the appropriate device. Primary outcome measures include operation time, length of stay, use of staff, patient morbidity, ease of use, conversion rates to open surgery, and cost. METHODS: Systematic literature searches were performed in MEDLINE, EMBASE, The Cochrane Library, Current Controlled Trials, and ClinicalTrials.gov. The search strategy focused on studies testing a retraction device. The selection process was based on a predefined set of inclusion and exclusion criteria. Data were then extracted and analyzed. RESULTS: Out of 1360 papers initially retrieved, 12 articles were selected for data extraction and analysis. A total of 10 instruments or techniques were tested. Devices included the Nathanson's liver retractor, liver suspension tape, the V-List technique, a silicone disk with or without a snake retractor, the Endoloop, the Endograb, a magnetic retractor, the VaroLift, a laparoscope holder, and a retraction sponge. None of the instruments reported were associated with increased morbidity. No studies found increased rates of conversion to open surgery. All articles reported that the tested instruments might spare the use of an assistant during the procedure. It was not possible to determine the impact on length of stay or operation time. CONCLUSIONS: Each analyzed device facilitates retraction, providing a good field of view while allowing reduced staff numbers and minimal patient morbidity. Due to economic and environmental advantages, reusable devices may be preferable to disposable instruments, although the choice must be primarily based on clinical judgement. PMID- 26025139 TI - The effect of weight change on changes in breast density measures over menopause in a breast cancer screening cohort. AB - INTRODUCTION: High weight and high percentage mammographic breast density are both breast cancer risk factors but are negatively correlated. Therefore, we wanted to obtain more insight into this apparent paradox. METHODS: We investigated in a longitudinal study how weight change over menopause is related to changes in mammographic breast features. Five hundred ninety-one participants of the EPIC-NL cohort were divided into three groups according to their prospectively measured weight change over menopause: (1) weight loss (more than 3.0 %), (2) stable weight (between -3.0 % and +3.0 %), and (3) weight gain (more than 3.0 %). SPSS GLM univariate analysis was used to determine both the mean breast measure changes in, and the trend over, the weight change groups. RESULTS: Over a median period of 5 years, the mean changes in percent density in these groups were -5.0 % (95 % confidence interval (CI) -8.0; -2.1), -6.8 % (95 % CI 9.0; -4.5), and -10.2 % (95 % CI -12.5; -7.9), respectively (P-trend = 0.001). The mean changes in dense area were -16.7 cm(2) (95 % CI -20.1; -13.4), -16.4 cm(2) (95 % CI -18.9; -13.9), and -18.1 cm(2) (95 % CI -20.6; -15.5), respectively (P-trend = 0.437). Finally, the mean changes in nondense area were 6.1 cm(2) (95 % CI -11.9; -0.4), -0.6 cm(2) (95 % CI -4.9; 3.8), and 5.3 cm(2) (95 % CI 0.9; 9.8), respectively (P-trend < 0.001). CONCLUSIONS: Going through menopause is associated with a decrease in both percent density and dense area. Owing to an increase in the nondense tissue, the decrease in percent density is largest in women who gain weight. The decrease in dense area is not related to weight change. So the fact that both high percent density and high weight or weight gain are associated with high postmenopausal breast cancer risk can probably not be explained by an increase (or slower decrease) of dense area in women gaining weight compared with women losing weight or maintaining a stable weight. These results suggest that weight and dense area are presumably two independent postmenopausal breast cancer risk factors. PMID- 26025140 TI - Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase. AB - The present studies reports the synthesis of hydoxylated thymol analogues (4a-e) and (6a-c) as mushroom tyrosinase inhibitors. The title compounds were obtained in good yield and characterized by FTIR, (1)H NMR, (13)C NMR, Mass spectral data and X-ray crystallography in case of compound (6a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 2-[5-methyl 2-(propan-2-yl)phenoxy]-2-oxoethyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (6b) showed tyrosinase inhibitory activity (IC50 15.20 MUM) comparable to kojic acid (IC50 16.69 MUM) while 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl 3,4 dihydroxybenzoate (4d) exhibited higher antioxidant potential (IC50 11.30 MUM) than standard ascorbic acid (IC50 24.20 MUM). The docking studies of synthesized thymol analogues was also performed against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC50 values. The predicted binding affinities are in good agreement with the IC50 values as compound (6b) showed highest binding affinity -7.1 kcal/mol. The kinetic mechanism analyzed by Lineweaver-Burk plots exhibited that compound (4d) and (6b) inhibit the enzyme by two different pathways displayed mixed-type inhibition. The inhibition constants Ki calculated from Dixon plots for compounds (4d) and (6b) are 34 MUM and 25 MUM respectively. It was also found from kinetic analysis that derivative (6b) formed reversible enzyme inhibitor complex. It is propose on the basis of our investigation that title compound (6b) may serve as lead structure for the design of more potent tyrosinase inhibitors. PMID- 26025141 TI - Synthesis by microwave-assisted 1,3-dipolar cycloaddition of 1,2,3-triazole 1' homo-3'-isoazanucleosides and evaluation of their anticancer activity. AB - Racemic 1'-homo-3'-isoazanucleosides have been obtained by microwave-assisted 1,3 dipolar cycloaddition of 3,5-disubstituted proline derivative (+/-)-2 with different alkynes. The compounds obtained were evaluated for their cytotoxic activities in vitro against human breast carcinoma cell lines (MCF-7), human ovary carcinoma cell lines (A2780) and human lung carcinoma cell lines (NCI H460). PMID- 26025142 TI - Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans. AB - During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. METHODS: Twenty-eight patients with severe TBI (GCS <= 8, three patients had initial GCS = 9-10, but rapidly deteriorated to <=8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3 dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI. PMID- 26025143 TI - Adjuvant temozolomide-based chemoradiotherapy versus radiotherapy alone in patients with WHO III astrocytoma: The Mainz experience. AB - BACKGROUND: It is currently unclear whether adjuvant therapy for WHO grade III anaplastic astrocytomas (AA) should be carried out as combined chemoradiotherapy with temozolomide (TMZ)--analogous to the approach for glioblastoma multiforme- or as radiotherapy (RT) alone. PATIENTS AND METHODS: A retrospective analysis of data from 90 patients with AA, who were treated between November 1997 and February 2014. Assessment of overall (OS) and progression-free survival (PFS) was performed according to treatment categories: (1) 50%, RT + TMZ according to protocol, (2) 11%, RT + TMZ with dose reduction, (3) 26%, RT alone, and (4) 13%, individualized, primarily palliative therapy. No dose reduction was necessary in the RT alone group. RESULTS: Median OS was 85, 69, and 43 months for treatment categories 1/2, 3, and 4, respectively. These differences were not statistically significant. PFS was 35, 29, 48, and 33 months for categories 1, 2, 3, and 4, respectively; again without significant differences between categories. In a subgroup of 39 patients with known IDH1 R132H status, the presence of this mutation correlated with significantly longer OS (p = 0.01) and PFS (p = 0.002). Complete or partial tumor resection and younger age also correlated with a significantly better prognosis, and this influence persisted in multivariate analysis. In the IDH1 R132H subgroup analysis, only this marker retained an independent prognostic value. DISCUSSION AND CONCLUSION: A general superiority of combined chemoradiotherapy compared to RT alone could not be demonstrated. Biomarkers for predicting the benefits of combination therapy using RT and TMZ are needed for patients with AA. PMID- 26025144 TI - Tracking of maternal self-efficacy for limiting young children's television viewing and associations with children's television viewing time: a longitudinal analysis over 15-months. AB - BACKGROUND: Mothers' self-efficacy for limiting their children's television viewing is an important correlate of this behaviour in young children. However, no studies have examined how maternal self-efficacy changes over time, which is potentially important during periods of rapid child development. This study examined tracking of maternal self-efficacy for limiting young children's television viewing over 15-months and associations with children's television viewing time. METHODS: In 2008 and 2010, mothers (n = 404) from the Melbourne InFANT Program self-reported their self-efficacy for limiting their child's television viewing at 4- and 19-months of age. Tertiles of self-efficacy were created at each time and categorised into: persistently high, persistently low, increasing or decreasing self-efficacy. Weighted kappa and multinomial logistic regression examined tracking and demographic and behavioural predictors of change in self-efficacy. A linear regression model examined associations between tracking categories and children's television viewing time. RESULTS: Tracking of maternal self-efficacy for limiting children's television viewing was low (kappa = 0.23, p < 0.001). Mothers who had persistently high or increasing self-efficacy had children with lower television viewing time at 19-months (beta = -35.5; 95 % CI = -54.4,-16.6 and beta = 37.0; 95 % CI = -54.4,-19.7, respectively). Mothers of children with difficult temperaments were less likely to have persistently high self-efficacy. Mothers who met adult physical activity guidelines had 2.5 greater odds of increasing self-efficacy. CONCLUSIONS: Interventions to increase and maintain maternal self-efficacy for limiting children's television viewing time may result in lower rates of this behaviour amongst toddlers. Maternal and child characteristics may need to be considered when tailoring interventions. PMID- 26025145 TI - From the Editor's Perspective... PMID- 26025146 TI - Chronic venous disease and venous leg ulcers: An evidence-based update. AB - Chronic venous disease (CVD) is a complex chronic vascular condition with multifaceted primary and secondary etiologies leading to structural and functional changes in veins and valves and blood flow of the lower legs. As a consequence, a spectrum of clinical manifestations arise, ranging from symptoms of mild leg heaviness and achiness to debilitating pain, and signs of skin changes, such as eczema and hemosiderosis, to nonhealing, heavily draining venous leg ulcers (VLUs). Triggers such as trauma to the skin are responsible for a large majority of VLU recurrences. Diagnostic testing for venous reflux includes ultrasound imaging; unfortunately, there are no diagnostic tests to predict VLUs. The hallmark of treatment of both CVD and VLUs is compression. Leg elevation, exercise, and wound management with dressings and advanced healing technologies that provide an environment conducive to healing should focus on reducing pain, necrotic debris, drainage, and odor, as well as preventing infection. VLUs that become chronic without evidence of healing over a 4-week period respond best to multidisciplinary wound experts within a framework of patient-centered care. Nurses are in key positions to provide early recognition of the signs and symptoms as well as initiate prompt diagnostic and promote early treatment to offset the progression of the disease and improve quality of life. PMID- 26025148 TI - Venous leg ulcers: Impact and dysfunction of the venous system. AB - Management of chronic venous leg ulcers (VLU) can be frustrating for both patient and practitioner. It is a significant source of disability and cost of care. Before the practitioner enters the management phase of VLU care, it is helpful to understand the impact of VLUs. Additionally, it is essential to understand the structure and function of the venous system and manifestations indicative of a dysfunction of the system. This article focuses on the epidemiology, structure, and function of the venous system as well as clinical manifestations and prevention. PMID- 26025147 TI - Iliofemoral deep vein thrombosis: Percutaneous endovascular treatment options. AB - Venous thromboembolism is defined as an acute venous thrombotic event that targets two disease entities: deep vein thrombosis (DVT), pulmonary embolism, or both. The most common site of DVT origin is in the lower extremities, with 50% of patients exhibiting no symptoms. Although anticoagulation is the gold standard for DVT, early clot removal, especially of proximal iliofemoral DVT, is felt to reduce the incidence of postthrombotic syndrome (PTS) by preserving valve function. Up to one-half of all patients with an iliofemoral DVT treated only with anticoagulation subsequently develop long-term complications, including PTS. Beside anticoagulation, DVT treatment options may include pharmaceutical and/or mechanical therapies. Mechanical therapies consist of either endovascular percutaneous catheter-directed (PCD) interventions or open operative thrombectomy. There are several different PCD procedures available, consisting of catheter-directed thrombolysis, mechanical thrombectomy, combination pharmacomechanical devices, and postthrombus extraction (angioplasty and/or stenting). Endovascular therapies in the management of acute iliofemoral DVT are evolving with a variety of devices available to treat this disease entity. The purpose of this article is to provide an overview of the PCD therapies used when treating patients experiencing an acute iliofemoral DVT along with associated nursing considerations. Off-label device use is not included. PMID- 26025149 TI - Venous leg ulcers: Summary of new clinical practice guidelines published August 2014 in the Journal of Vascular Surgery. AB - The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) published guidelines for the management of venous leg ulcers in August 2014. The goal of this article (Part 2) is to summarize the guidelines that address diagnosis and treatment recommendations published jointly by the SVS and AVF that may affect the nursing practice of vascular nurses. Specific sections include wound evaluation, therapies used on the wound bed itself, compression, and operative or endovascular management. Part 1, published elsewhere in this issue, addressed the epidemiology and financial impact of ulcers, venous anatomy, pathophysiology of venous leg ulcer development, clinical manifestations, and prevention of venous leg ulcers. These 2 parts together provide a comprehensive summary of the joint SVS and AVF guidelines for care of venous leg ulcers. PMID- 26025150 TI - Assessment of the public's knowledge of venous thromboembolism. AB - Venous thromboembolism (VTE) is a major public health problem impacting 600,000 people and causing 100,000 deaths annually. Nurses are in a unique position in all health care settings to educate patients and the public to prevent and provide early detection for this devastating complication. A dearth of information exists regarding the knowledge level of those affected. This manuscript presents a study that investigates and quantifies the general public's knowledge level of VTE through a 13-question survey of 325 participants. The results indicate that >70% of the general, nonmedical participants involved in the survey were not familiar with VTE. The findings suggest the need for nurses to consistently and systematically educate patients and the public about VTE to decrease morbidity and mortality. PMID- 26025151 TI - Evaluation of venous thromboembolism prophylaxis after the introduction of an institutional guideline: Extent of application and implementation of its recommendations. AB - Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism. Although much is known about risk factors for VTE, there is failure in administration of appropriate prophylaxis to patients who are at risk for VTE. A paper-based reminder system is considered to be among the most effective methods of improving VTE prophylaxis in hospitalized patients. However, their success relies on choosing an evidence-based institutional guideline and implementation of its recommendations. This study was carried out to detect the extent of application of the institutional guideline (Caprini score risk assessment sheet). The study was carried out in the Jordan University Hospital; 354 patients were enrolled in the study and distributed among the following wards: nonorthopedic surgical (n = 119), medical (n = 220), and surgical orthopedic wards (n = 15). The risk assessment sheet was present in only 47.2% of the patient's' files, and the scores in the files were estimated correctly in only 52.1% of cases. Prophylaxis received by patients matched the recommendation of the Caprini score in 67.1% of the patients. The degree of concordance of the VTE prophylaxis with the Caprini score was 59.9%. This study showed that the institutional guideline was poorly implemented in the hospital. PMID- 26025152 TI - Translumbar inferior vena cava catheter: An unconventional dialysis access. PMID- 26025153 TI - Review of article: A randomized trial comparing treatments for varicose veins by Julie Brittenden, MD, Seonaidh C. Cotton, PhD, Andrew Elders, MSc, et al (N Engl J Med 2014; 371:1218-27). PMID- 26025154 TI - Dose finding of 3'deoxyadenosine and deoxycoformycin for the treatment of Trypanosoma evansi infection: An effective and nontoxic dose. AB - The aim of this study was to evaluate the therapeutic efficacy and safety of using 3'deoxyadenosine (Cordycepin - adenosine analogue) combined with deoxycoformycin (Pentostatin - an adenosine deaminase inhibitor) in mice infected with Trypanosoma evansi. We show that the combination of Cordycepin (2.0 mg kg( 1)) and Pentostatin (0.2, 0.5, 1.0, 2.0 mg kg(1)) is effective in the clearance of T. evansi, although at the higher concentrations of Pentostatin 2 mg kg(-1) some toxicity was observed in the liver and kidney. Since the Cordycepin 2.0 mg kg(-1) and Pentostatin 0.2 mg kg(-1) combination was effective and had low toxicity, we recommend this as a therapeutic option for a T. evansi mouse model. PMID- 26025155 TI - Delayed-onset enzootic bovine leukosis possibly caused by superinfection with bovine leukemia virus mutated in the pol gene. AB - Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leucosis (EBL), to which animals are most susceptible at 4-8 years of age. In this study, we examined tumor cells associated with EBL in an 18-year-old cow to reveal that the cells carried at least two different copies of the virus, one of which was predicted to encode a reverse transcriptase (RT) lacking ribonuclease H activity and no integrase. Such a deficient enzyme may exhibit a dominant negative effect on the wild-type RT and cause insufficient viral replication, resulting in delayed tumor development in this cow. PMID- 26025156 TI - Cymbidium chlorotic mosaic virus, a new sobemovirus isolated from a spring orchid (Cymbidium goeringii) in Japan. AB - Cymbidium chlorotic mosaic virus (CyCMV), isolated from a spring orchid (Cymbidium goeringii), was characterized molecularly. CyCMV isometric virions comprise a single, positive-strand RNA genome of 4,083 nucleotides and 30-kDa coat protein. The virus genome contains five overlapping open reading frames with a genomic organization similar to that of sobemoviruses. BLAST searches and phylogenetic analysis revealed that CyCMV is most closely related to papaya lethal yellowing virus, a proposed dicot-infecting sobemovirus (58.8 % nucleotide sequence identity), but has a relatively distant relationship to monocot infecting sobemoviruses, with only modest sequence identities. This suggests that CyCMV is a new monocot-infecting member of the floating genus Sobemovirus. PMID- 26025157 TI - Fusarium circinatum isolates from northern Spain are commonly infected by three distinct mitoviruses. AB - Pitch canker is a serious disease of pines caused by the ascomycete fungus Gibberella circinata (anamorph = Fusarium circinatum). Three distinct mitovirus strains have been described in this fungus: Fusarium circinatum mitovirus 1 (FcMV1), FcMV2-1 and FcMV2-2. Here, we investigated the frequency and population variation of these viruses and closely related sequence variants in northern Spain using RT-PCR and sequencing. Each virus strain and similar sequence variants shared >95 % sequence identity and were collectively designated as virus types. All virus types were relatively common in Spain, with estimated prevalence of 18.5 %, 8.9 % and 16.3 % for FcMV1, FcMV2-1 and FcMV2-2, respectively. PMID- 26025158 TI - Peripherally inserted central catheter placement in patients with coagulation disorders: A retrospective analysis. AB - OBJECTIVE: To assess the safety of peripherally inserted central venous catheter (PICC) placement in patients with altered and uncorrected coagulation parameters or receiving antiplatelet therapy. MATERIALS AND METHODS: Medical charts of all patients with major primary and secondary hemostasis disorders, combined hemostasis disorders or on antiplatelet therapy and who had undergone non tunneled PICC placement from December 2009 to December 2013, were retrospectively reviewed. A hemostatic disorder was defined as a platelet count (PC)<=50*10(9)/L, an international normalized ratio (INR) >= 2, or an activated partial thromboplastin time (aPTT)>=66s, alone or in combination. Underlying hemostasis disorders were not corrected and antiplatelet therapy was not interrupted before PICC placement in any patient. 4, and 5-Fr single and dual lumen PICCs were used. RESULTS: A total of 378 PICCs were placed in 271 patients (180 men and 91 women; mean age=62+/-13.4years; range, 18-93 years)) with coagulation disorders. Eighty nine (23%) PICCs were placed in patients who were receiving antiplatelet therapy (aspirin, clopidogrel, rivaroxaban). Thrombocytopenia was noted in 269PICC placements (71%). Among these patients, 23 had disseminated intravascular coagulation. Prolonged INR and aPTT were observed in 42 procedures (11.1%). PICC placement was achieved in all patients, with a mean number of 1.14 attempts. Peripheral venous access was obtained through the basilic and the brachial vein respectively in 295 (79.1%) and 83 (20.9%) of patients. The placements were performed by residents and fellows in 108 (28.5%) and 270 (71.5%) procedures, respectively. No early or late complications were reported after any procedure. No accidental puncture of the brachial artery occurred. CONCLUSION: In patients with severe primary and secondary hemostasis disorders, combined hemostasis disorders or on antiplatelet therapy, PICC placement is a feasible and safe procedure and does not require correction of coagulation parameters or discontinuation of antiplatelet therapy. PMID- 26025159 TI - Iatrogenic cardiac perforation due to pacing lead displacement: Imaging findings. AB - PURPOSE: Cardiac perforations due to pacing and implantable defibrillator lead displacement are rare and their detection may be difficult. The goal of this study was to review the clinical and imaging presentation of cardiac perforation related to pacing lead displacement. PATIENTS AND METHODS: The clinical and imaging files of four patients (two men and two women) who experienced cardiac perforation related to pacing lead displacement were reviewed. The four patients were investigated in our radiology department over a 24-month-period. RESULTS: Two patients had clinical symptoms at the time lead displacement was detected and the other two were free of symptoms. In all patients, lead displacement was visible on imaging examinations in retrospect but was not detected prospectively. CONCLUSION: Radiologists should pay attention to the position of the tips of the leads on chest X-ray and CT, even late after the implantation and in asymptomatic patients. PMID- 26025160 TI - Imaging before and after catheter ablation of atrial fibrillation. AB - Catheter ablation of arrhythmogenic triggers has been validated for the treatment of atrial fibrillation that is refractory to anti-arrhythmic medication. Imaging plays an important role in guiding the procedure as well as in planning and follow-up. The goal of pre-procedural imaging is to obtain a detailed anatomical description of the pulmonary veins, to eliminate a thrombus of the left atrium and to define the prognostic factors. MDCT angiography effectively and simply meets nearly all of these needs. Thus, a precise description of the left atrium anatomy before the procedure is a key factor to success and left atrium volume is a reliable prognostic factor of recurrence. Radiologists should be aware of early and late complications, sometimes severe such as pulmonary vein stenosis, cardiac tamponade or atrial-esophageal fistula, whose positive diagnosis is based on imaging. PMID- 26025161 TI - Solid Phase Micro-extraction (SPME) with In Situ Transesterification: An Easy Method for the Detection of Non-volatile Fatty Acid Derivatives on the Insect Cuticle. AB - Triacylglycerides (TAGs) and other non-volatile fatty acid derivatives (NFADs) occur in large amounts in the internal tissues of insects, but their presence on the insect cuticle is controversially discussed. Most studies investigating cuticular lipids of insects involve solvent extraction, which implies the risk of extracting lipids from internal tissues. Here, we present a new method that overcomes this problem. The method employs solid phase micro-extraction (SPME) to sample NFADs by rubbing the SPME fiber over the insect cuticle. Subsequently, the sampled NFADs are transesterified in situ with trimethyl sulfonium hydroxide (TMSH) into more volatile fatty acid methyl esters (FAMEs), which can be analyzed by standard GC/MS. We performed two types of control experiments to enable significant conclusions: (1) to rule out contamination of the GC/MS system with NFADs, and (2) to exclude the presence of free fatty acids on the insect cuticle, which would also furnish FAMEs after TMSH treatment, and thus might simulate the presence of NFADs. In combination with these two essential control experiments, the described SPME technique can be used to detect TAGs and/or other NFADs on the insect cuticle. We analyzed six insect species from four insect orders with our method and compared the results with conventional solvent extraction followed by ex situ transesterification. Several fatty acids typically found as constituents of TAGs were detected by the SPME method on the cuticle of all species analyzed. A comparison of the two methods revealed differences in the fatty acid compositions of the samples. Saturated fatty acids showed by trend higher relative abundances when sampled with the SPME method, while several minor FAMEs were detected only in the solvent extracts. Our study suggests that TAGs and maybe other NFADs are far more common on the insect cuticle than usually thought. PMID- 26025162 TI - Pressure algometry is a useful tool to quantify pain in the medial part of the knee: an intra- and inter-reliability study in healthy subjects. AB - PURPOSE: Pain quantification is essential for diagnostic and pain monitoring purposes in disorders around the knee. Pressure algometry is a method described to determine pressure pain threshold (PPT) by applying controlled pressure to a given body point. The purpose of this study was to determine the reliability of this method when it was applied to the medial part of the proximal tibia metaphysis and to evaluate the PPT levels between genders. METHODS: Fifty healthy (mean age; 46.9) volunteers were recruited, 25 men and 25 women. Pressure algometry was applied to a 1 cm(2)-probe area on the medial part of the knee by 2 raters. Intra- and interclass correlation (ICC) was obtained and differences between genders were evaluated. Bland-Altman plots were performed to evaluate the variability of the measures. RESULTS: The mean values of PPT obtained by rater 1 and 2 were 497.5 Kpa and 489 Kpa respectively. The intrarater reliability values (95% IC) for rater 1 and 2 were 0.97 (0.95-0.98) and 0.84 (0.73-0.90) respectively. With regard to interrater reliability, the ICC (95% IC) for the first measurement was 0.92 (0.87-0.95) and 0.86 (0.78-0.92) for the second one. Women showed significant lower values of PPT than men. The Bland-Altmand plots showed excellent agreement. CONCLUSIONS: Pressure algometry has excellent reliability when it is applied to the medial part of the proximal metaphysis of the tibia. Women have lower values of PTT than men. The high reliability of the PA in an individual volunteer makes it a more valuable tool for longitudinal assessment of a given patient than for comparison between them. LEVEL OF EVIDENCE: Level III. Prospective study. PMID- 26025163 TI - Simultaneous Determination of 11 Illicit Phenethylamines in Hair by LC-MS-MS: In Vivo Application. AB - Existing phenethylamines are a class of synthetic compounds that differ from each other only in small changes to a largely conserved chemical structure. The recreational and illicit use of phenethylamines is a widespread problem. A simple procedure for the simultaneous quantitative determination in hair of 11 phenethylamines that are officially recognized as illicit by Italian legislation (p-methoxyamphetamine; p-methoxymethamphetamine; 3,4,5-trimethoxyamphetamine; 2,5 dimethoxyamphetamine; 2,5-dimethoxy-4-methylamphetamine; 2,5-dimethoxy-4 ethylamphetamine; 2,5-dimethoxy-4-bromoamphetamine; 2,5-dimethoxy-4 bromophenethylamine; 2,5-dimethoxy-4-iodophenethylamine; 2,5-dimethoxy-4 ethylthiophenethylamine and 2,5-dimethoxy-4-n-propylthiophenethylamine) has been developed and validated. Extraction from the matrix was performed after incubation in methanolic HCl and filtered reconstituted extracts were injected into a liquid chromatography/tandem mass spectrometry system (LC-MS-MS) without any further purification steps. This validated LC-MS-MS method has been used to determine the in vivo accumulation/retention of the above target analytes in hair after repeat oral administration to rats. This experiment further permitted investigation of the effect of pigmentation on the uptake of these phenethylamines by hair and the effect of hair pigmentation. The developed method could potentially be used for forensic and toxicological purposes, in the detection and quantitation of these illicit substances in human hair in workplace drug testing; drug-facilitated crime investigation; driver re-licensing; determining drug abuse history and postmortem toxicology. PMID- 26025164 TI - Ethylone-Related Deaths: Toxicological Findings. AB - Synthetic cathinones are an emerging class of designer drugs, frequently with deceptive labels and a multitude of analogs to circumvent drug control regulations. Research regarding the pharmacological effects and toxicity of these amphetamine derivatives is scarce, heightening the risk to the public health and safety. The composition of synthetic cathinone products continually changes and laboratories began to notice ethylone-positive products in late 2011. This report presents nine postmortem cases in whom ethylone was identified. Ethylone was isolated using solid-phase extraction and detected by gas chromatography-mass spectrometry. Seven of the cases had measurable concentrations of ethylone in blood, ranging from 38 to 2,572 ng/mL; ethylone was detected in the blood sample of one case with a concentration below the assay limit of quantification (25 ng/mL), and one case did not have detectable ethylone in blood. Besides ethylone, all but one case were also positive for 11-nor-9-carboxy-Delta9 tetrahydrocannabinol; seven cases had other drugs quantified in blood, including ethanol, alprazolam, benzoylecgonine, diphenhydramine, morphine and tramadol. In five cases where ethylone was present at blood concentrations >400 ng/mL, no other drugs excluding ethanol, cannabis metabolite and doxylamine (one case) were found. The assay also tested for mephedrone, methylone and three dimethoxyamphetamine analogs; no case was positive for these analytes. The present report documents postmortem blood concentrations of ethylone, a novel synthetic cathinone, along with other concurrently identified substances. The findings provide valuable information for developing analytical assays and evaluating a toxic concentration range of ethylone. PMID- 26025166 TI - Enantiomer Profiling of Methamphetamine in White Crystal and Tablet Forms (Ma Old) Using LC-MS-MS. AB - At the global level, seizures of crystalline methamphetamine (MA) and MA tablets have risen to a new high, indicating that the substance is an imminent threat. MA enantiomer profiling was a useful tool to investigate the prevalence of MA abuse, the intrinsic characteristics of the seized samples and the trends of precursors. In this work, the distribution of enantiomers in clandestine MA crystals and tablets seized mainly in the Yangtze River Delta region, China, from 2008 to 2014 were identified. The MA samples were diluted with internal standard methanol solution, and analyzed by LC-MS-MS. The detection limits of the enantiomers were 0.04 MUg/L. The limit of quantification was 0.1 MUg/L. As little as 0.2% of the R enantiomer ratio could be determined. Standard calibration curves of S- and R-MA showed good linearity in the range of 0.1-80 MUg/L (r(2) > 0.995). All of the seizures were optically pure S-enantiomer in the years 2008 and 2009. Seized samples containing a slight amount of R-MA began to appear in 2010 and increased in the year 2014. No racemic mixture or R-isomer of MA was seized. From this study, we could find out that smuggling routes and/or precursors might be silently changing in the Yangtze River Delta region, China. PMID- 26025167 TI - Molecular architecture of the bacterial tripartite multidrug efflux pump focusing on the adaptor bridging model. AB - Gram-negative bacteria expel a wide range of toxic substances through tripartite drug efflux pumps consisting of an inner membrane transporter, an outer membrane channel protein, and a periplasmic adaptor protein. These pumps form tripartite assemblies which can span the entire cell envelope, including the inner and outer membranes. There have been controversial findings regarding the assembly of the individual components in tripartite drug efflux pumps. Recent structural and functional studies have advanced our understanding of the assembly and working mechanisms of the pumps. Here, we re-evaluate the assembly models based on recent structural and functional studies. In particular, this study focuses on the 'adaptor bridging model', highlighting the intermeshing cogwheel-like interactions between the tip regions of the outer membrane channel protein and the periplasmic adaptor protein in the hexameric assembly. PMID- 26025168 TI - Lysobacter tyrosinelyticus sp. nov. isolated from Gyeryongsan national park soil. AB - A novel Gram-negative, rod-shaped (0.2-0.5 MUm * 1.5-2.5 MUm), aerobic, non motile bacterium was isolated from Gyeryongsan national park soil, Republic of Korea. The novel isolate was designated as THG-DN8.2(T). The strain grows optimally at 28 degrees C, at pH 7 and in the absence of NaCl. Phylogenetic analysis based on 16S rRNA gene sequence showed that the novel isolate shared the highest sequence similarity with Lysobacter oryzae KCTC 22249(T) followed by Lysobacter yangpyeongensis KACC 11407(T) and Lysobacter niabensis KACC 11587(T). The DNA G+C content of strain THG-DN8.2T is 66.0 mol% and ubiquinone Q-8 is the main isoprenoid quinone. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidyl-N methylethanolamine. The major fatty acids of strain THG-DN8.2(T) were identified as iso-C15:0, iso-C16:0, and C16:1 omega7s alcohol. The phylogenetic distinctiveness and phenotypic characteristics differentiated strain THG-DN8.2(T) from closely related Lysobacter species. The results of polyphasic taxonomic analysis suggest that strain THG-DN8.2(T) represents a novel species of the genus Lysobacter, for which the name Lysobacter tyrosinelyticus sp. nov. is proposed. The type strain is THG-DN8.2(T) (= KCTC 42235(T) = JCM 30320(T)). PMID- 26025169 TI - Microbial communities inhabiting oil-contaminated soils from two major oilfields in Northern China: Implications for active petroleum-degrading capacity. AB - Although oilfields harbor a wide diversity of microorganisms with various metabolic potentials, our current knowledge about oil-degrading bacteria is limited because the vast majority of oil-degrading bacteria remain uncultured. In the present study, microbial communities in nine oil-contaminated soils collected from Daqing and Changqing, two of the largest oil fields in China, were characterized through highthroughput sequencing of 16S rRNA genes. Bacteria related to the phyla Proteobacteria and Actinobacteria were dominant in four and three samples, respectively. At the genus level, Alkanindiges, Arthrobacter, Pseudomonas, Mycobacterium, and Rhodococcus were frequently detected in nine soil samples. Many of the dominant genera were phylogenetically related to the known oil-degrading species. The correlation between physiochemical parameters within the microbial communities was also investigated. Canonical correspondence analysis revealed that soil moisture, nitrate, TOC, and pH had an important impact in shaping the microbial communities of the hydrocarbon-contaminated soil. This study provided an in-depth analysis of microbial communities in oilcontaminated soil and useful information for future bioremediation of oil contamination. PMID- 26025170 TI - Soil fungal communities of montane natural secondary forest types in China. AB - Distinctive plant communities may provide specific physical and chemical properties with soils by specific litters and root exudates to exert effects on soil microorganisms. Past logging activities in the Qinling Mountains induced diverse natural secondary forest types (NSFTs). How these recovered NSFTs regulate patterns of soil microbial communities remain limited. In the study, we used terminal-restriction fragment length polymorphism (T-RFLP) to precisely determine forest type-specific soil fungal diversity and composition in five NSFTs. Our results indicated that NSFTs had significant impacts on the soil fungal communities. The most diverse fungal species were found in the Armand pine (Pinus armandi) and Chinese pine (Pinus tabulaeformis) forest soils, followed by sharptooth oak (Quercus aliena var. acuteserrata) and Chinese pine-sharptooth oak forest soils, the wilson spruce (Picea wilsonii) forests had the lowest soil fungal diversity. The analyses of community composition suggested that the fungal communities of Armand pine forest soils were similar to those of Chinese pine forest soils, while other communities prominently differed from each other. Stepwise multiple regression analysis revealed that soil silt, clay, pH, and ammonium nitrogen had intimate linkages with soil fungal diversity. Furthermore, the patterns of soil fungal communities were strongly governed by the specific soil environments of the tested NSFTs, as described by canonical correspondence analysis (CCA). Finally, our study showed that soil fungal communities may be mediated by NSFTs via specific soil edaphic status. Hence, such a comparable study may provide fundamental information for fungal diversity and community structure of natural forests and assist with better prediction and understanding how soil fungal composition and function alter with forest type transformation. PMID- 26025171 TI - An endophytic Coniochaeta velutina producing broad spectrum antimycotics. AB - An endophyte (PC27-5) was isolated from stem tissue of Western hemlock (Tsuga heterophylla) in a Pacific Northwest temperate rainforest. Phylogenetic analyses, based on ITS-5.8S rDNA and 18S rDNA sequence data, combined with cultural and morphological analysis showed that endophyte PC27-5 exhibited all characteristics of a fungus identical to Coniochaeta velutina. Furthermore, wide spectrum antimycotics were produced by this endophyte that were active against such plant pathogens as Sclerotinia sclerotiorum, Pythium ultimum, and Verticillium dahliae and lethal to Phythophthora cinnamomi, Pythium ultimum, and Phytophthora palmivora in plate tests. The bioactive components were purified through organic solvent extraction, followed by silica column chromatography, and finally preparative HPLC. The minimum inhibitory concentration of the active fraction to Pythium ultimum, which was gained from preparative HPLC, was 11 MUg/ml. UPLC-HRMS analysis showed there were two similar components in the antimycotic fraction. Their molecular formulae were established as C30H22O11 (compound I) and C30H22O10 (compound II) respectively, and preliminary spectral results indicate that they are anthroquinone glycosides. Other non-biologically active compounds were identified in culture fluids of this fungus by spectral means as emodin and chrysophanol--anthroquinone derivatives. This is the first report that Coniochaeta velutina as an endophyte produces bioactive antifungal components. PMID- 26025172 TI - Effects of Lactobacillus salivarius Ren on cancer prevention and intestinal microbiota in 1, 2-dimethylhydrazine-induced rat model. AB - Probiotics have been suggested as a prophylactic measure in colon cancer. The aim of this study was to investigate the impact of Lactobacillus salivarius Ren (Ren) in modulating colonic microbiota structure and colon cancer incidence in a rat model after injection with 1,2-dimethyl hydrazine (DMH). The results indicated that oral administration of Ren could effectively suppress DMH-induced colonic carcinogenesis. A significant decrease in cancer incidence (87.5% to 25%) was detected in rats fed with a dose of 5 * 10(10) CFU/kg bodyweight per day. Using denaturing gradient gel electrophoresis and Real-time PCR combined with multivariate statistical methods, we demonstrated that injection with DMH significantly altered the rat gut microbiota, while Ren counteracted these DMH induced adverse effects and promoted reversion of the gut microbiota close to the healthy state. Tvalue biplots followed by band sequencing identified 21 bacterial strains as critical variables affected by DMH and Ren. Injection of DMH significantly increased the amount of Ruminococcus species (sp.) and Clostridiales bacteria, as well as decreasing the Prevotella sp. Administration of Ren reduced the amount of Ruminococcus sp., Clostridiales bacteria, and Bacteroides dorei, and increased the amount of Prevotella. Real-time PCR results were consistent with the results derived by t-value biplots. These findings suggested that Ren is a potential agent for colon cancer prevention. In conclusion, the results in the present study suggest a potential therapeutic approach based on the modulation of intestinal microflora by probiotics may be beneficial in the prevention of colorectal carcinogenesis. PMID- 26025173 TI - Morphological changes in human gastric epithelial cells induced by nuclear targeting of Helicobacter pylori urease subunit A. AB - Nuclear targeting of bacterial proteins and their pathological effects on host cells are an emerging pathogenic mechanism in bacteria. We have previously reported that urease subunit A (UreA) of Helicobacter pylori targets the nuclei of COS-7 cells through nuclear localization signals (NLSs). This study further investigated whether UreA of H. pylori targets the nuclei of gastric epithelial cells and then induces molecular and cellular changes in the host cells. H. pylori 26695 strain produced and secreted outer membrane vesicles (OMVs). UreA was translocated into gastric epithelial AGS cells through outer membrane vesicles (OMVs) and then targeted the nuclei of AGS cells. Nuclear targeting of rUreA did not induce host cell death, but resulted in morphological changes, such as cellular elongation, in AGS cells. In contrast, AGS cells treated with rUreA?NLS proteins did not show this morphological change. Next generation sequencing revealed that nuclear targeting of UreA differentially regulated 102 morphogenesis- related genes, of which 67 and 35 were up-regulated and down regulated, respectively. Our results suggest that nuclear targeting of H. pylori UreA induces both molecular and cellular changes in gastric epithelial cells. PMID- 26025174 TI - Therapeutic potential of an AcHERV-HPV L1 DNA vaccine. AB - Cervical cancer is strongly associated with chronic human papillomavirus infections, among which HPV16 is the most common. Two commercial HPV vaccines, Gardasil and Cervarix are effective for preventing HPV infection, but cannot be used to treat existing HPV infections. Previously, we developed a human endogenous retrovirus (HERV)-enveloped recombinant baculovirus capable of delivering the L1 genes of HPV types 16, 18, and 58 (AcHERV-HP16/18/58L1, AcHERV HPV). Intramuscular administration of AcHERVHPV vaccines induced a strong cellular immune response as well as a humoral immune response. In this study, to examine the therapeutic effect of AcHERV-HPV in a mouse model, we established an HPV16 L1 expressing tumor cell line. Compared to Cervarix, immunization with AcHERVHPV greatly enhanced HPV16 L1-specific cytotoxic T lymphocytes (CTL) in C57BL/6 mice. Although vaccination could not remove preexisting tumors, strong CTL activity retarded the growth of inoculated tumor cells. These results indicate that AcHERV-HPV could serve as a potential therapeutic DNA vaccine against concurrent infection with HPV 16, 18, and 58. PMID- 26025175 TI - Evaluation of the ecotoxicological impact of the organochlorine chlordecone on soil microbial community structure, abundance, and function. AB - The insecticide chlordecone applied for decades in banana plantations currently contaminates 20,000 ha of arable land in the French West Indies. Although the impact of various pesticides on soil microorganisms has been studied, chlordecone toxicity to the soil microbial community has never been assessed. We investigated in two different soils (sandy loam and silty loam) exposed to different concentrations of CLD (D0, control; D1 and D10, 1 and 10 times the agronomical dose) over different periods of time (3, 7, and 32 days): (i) the fate of chlordecone by measuring (14)C-chlordecone mass balance and (ii) the impact of chlordecone on microbial community structure, abundance, and function, using standardized methods (-A-RISA, taxon-specific quantitative PCR (qPCR), and (14)C compounds mineralizing activity). Mineralization of (14)C-chlordecone was inferior below 1 % of initial (14)C-activity. Less than 2 % of (14)C-activity was retrieved from the water-soluble fraction, while most of it remained in the organic-solvent-extractable fraction (75 % of initial (14)C-activity). Only 23 % of the remaining (14)C-activity was measured in nonextractable fraction. The fate of chlordecone significantly differed between the two soils. The soluble and nonextractable fractions were significantly higher in sandy loam soil than in silty loam soil. All the measured microbiological parameters allowed discriminating statistically the two soils and showed a variation over time. The genetic structure of the bacterial community remained insensitive to chlordecone exposure in silty loam soil. In response to chlordecone exposure, the abundance of Gram-negative bacterial groups (beta-, gamma-Proteobacteria, Planctomycetes, and Bacteroidetes) was significantly modified only in sandy loam soil. The mineralization of (14)C-sodium acetate and (14)C-2,4-D was insensitive to chlordecone exposure in silty loam soil. However, mineralization of (14)C-sodium acetate was significantly reduced in soil microcosms of sandy loam soil exposed to chlordecone as compared to the control (D0). These data show that chlordecone exposure induced changes in microbial community taxonomic composition and function in one of the two soils, suggesting microbial toxicity of this organochlorine. PMID- 26025176 TI - Exposing some important barriers to health care access in the rural USA. AB - OBJECTIVES: To review research published before and after the passage of the Patient Protection and Affordable Care Act (2010) examining barriers in seeking or accessing health care in rural populations in the USA. STUDY DESIGN: This literature review was based on a comprehensive search for all literature researching rural health care provision and access in the USA. METHODS: Pubmed, Proquest Allied Nursing and Health Literature, National Rural Health Association (NRHA) Resource Center and Google Scholar databases were searched using the Medical Subject Headings (MeSH) 'Rural Health Services' and 'Rural Health.' MeSH subtitle headings used were 'USA,' 'utilization,' 'trends' and 'supply and distribution.' Keywords added to the search parameters were 'access,' 'rural' and 'health care.' Searches in Google Scholar employed the phrases 'health care disparities in the USA,' inequalities in 'health care in the USA,' 'health care in rural USA' and 'access to health care in rural USA.' After eliminating non relevant articles, 34 articles were included. RESULTS: Significant differences in health care access between rural and urban areas exist. Reluctance to seek health care in rural areas was based on cultural and financial constraints, often compounded by a scarcity of services, a lack of trained physicians, insufficient public transport, and poor availability of broadband internet services. Rural residents were found to have poorer health, with rural areas having difficulty in attracting and retaining physicians, and maintaining health services on a par with their urban counterparts. CONCLUSIONS: Rural and urban health care disparities require an ongoing program of reform with the aim to improve the provision of services, promote recruitment, training and career development of rural health care professionals, increase comprehensive health insurance coverage and engage rural residents and healthcare providers in health promotion. PMID- 26025177 TI - Invasive epiglottic aspergillosis: A case report and literature review. AB - Invasive aspergillosis is a life-threatening infection in immunocompromised hosts and occurs most frequently in the lungs. Invasive laryngeal aspergillosis is extremely rare. Due to the potential progression of invasive aspergillosis, antifungal therapy must be started immediately in cases involving clinical suspicion of the disease. A 65-year-old male with agranulocytosis complained of sore throat and dysphagia. His epiglottis was covered with caseating granulomatous lesions and the tissue was easily disrupted. A histopathological examination showed an aggressive invasion of Aspergillus species and cartilage destruction. Therefore, we made a diagnosis of primary invasive epiglottic aspergillosis. The invasive aspergillosis resolved with antifungal therapy and an increase in neutrophils. It is therefore necessary to include invasive laryngeal aspergillosis in the differential diagnosis when encountering immunocompromised patients presenting with laryngeal granulomatous lesions and laryngitis-like symptoms. PMID- 26025178 TI - Quantification of the chromosomal radiation damage induced by labelling of leukocytes with [18F]FDG. AB - INTRODUCTION: The aim of our work is to quantify the radiation damage in lymphocytes after labelling with [18F]FDG. Comparison with gold standard [99mTc]HMPAO labelling is established. An approach to cellular dosimetry is proposed. METHODS: Mixed leukocytes were separated from fresh venous blood and labelled with [18F]FDG and [99mTc]HMPAO following published guidelines. Cytokinesis-block micronucleus (CBMN) assay was performed for both sets of experiments. Tests for quality control of labelling described in guidelines were followed. Cellular dosimetry was calculated according to MIRD. RESULTS: MN scored after labelling with 37 MBq of [18F]FDG were 956 +/- 172 and 347 +/- 26 for [99mTc]HMPAO (p < 0.05). Absorbed dose in cell nucleus was of 0.23 Gy for [18F]FDG and 0.08 Gy for [99mTc]HMPAO labelling. The CBMN assay after labelling with ~290 MBq of [18F]FDG showed radiation induced inhibition of proliferation capacity of the lymphocytes, confirmed by proliferation study. CONCLUSIONS: [18F]FDG labelling of mixed leukocytes causes severe radiation damage to the cell, higher than with [99mTc]HMPAO in accordance with the absorbed dose. Labelling of mixed leukocytes for clinical purpose induces high cytotoxicity reflected in the loss of proliferation capacity in lymphocytes this statement allows us to consider a low oncogenic risk however the association between MN formation in the PBL and subsequent risk of cancer is not well established. ADVANCES IN KNOWLEDGE: This is the first work about radiation damage with [18F]FDG labelled cells. We focused on [18F]FDG labelling of leukocytes due to the growing number of research and review articles about this technique. IMPLICATIONS FOR PATIENT CARE: The possibility of an increased risk of lymphoid malignancies associated with the administration of radiolabelled lymphocytes is a very controversial subject. Studies on radiation damage on new labelling procedures as the one exposed in this work must be considered. PMID- 26025179 TI - Responses to startling acoustic stimuli indicate that movement-related activation does not build up in anticipation of action. PMID- 26025180 TI - Reply to Maslovat et al. PMID- 26025181 TI - Corrigendum. PMID- 26025182 TI - Corrigendum. PMID- 26025183 TI - Association of lipoprotein lipase gene with coronary heart disease in Sudanese population. AB - Cardiovascular disease is stabilizing in high-income countries and has continued to rise in low-to-middle-income countries. Association of lipid profile with lipoprotein lipase gene was studied in case and control subject. The family history, hypertension, diabetes mellitus, smoking and alcohol consumption were the most risk factors for early-onset of coronary heart disease (CHD). Sudanese patients had significantly (P<0.05) lower TC and LDL-C levels compared to controls. Allele frequency of LPL D9N, N291S and S447X carrier genotype was 4.2%, 30.7% and 7.1%, respectively. We conclude that lipoprotein lipase polymorphism was not associated with the incidence of CHD in Sudan. PMID- 26025184 TI - Two variants of selenium-dependent glutathione peroxidase from the disk abalone Haliotis discus discus: Molecular characterization and immune responses to bacterial and viral stresses. AB - Glutathione peroxidase (GPx) is an essential member of the antioxidant systems of living organisms and may be involved in immune defense against pathogenic invasion. In the current study, two selenium-dependent glutathione peroxidases (AbSeGPxs) that shared 54.3% identity were identified from the disk abalone Haliotis discus discus. The open reading frames (ORFs) of AbSeGPx-a and AbSeGPx-b coded for 222 and 220 amino acids, respectively, with a characteristic selenocysteine residue encoded by an opal stop codon (TGA). The conserved selenocysteine insertion sequence (SECIS) element was predicted in the 3' untranslated region (UTR) of both isoforms, and they were found to form two stem loop structures. Amino acid comparison and phylogenetic studies revealed that the AbSeGPxs were closely related to those in other mollusk species and were evolutionarily distinct from those of other taxonomic groups. The SYBR Green qPCR was employed in investigating the transcripts of AbSeGPxs. The expression of AbSeGPxs mRNA was examined in different embryonic developmental stages and differential expression patterns for AbSeGPx-a and AbSeGPx-b were noted. Meanwhile, the highest expression of AbSeGPxs was detected in the hepatopancreas of healthy adult animals. Next, transcriptional levels were profiled in hemocytes of adults to determine the immune responses of AbSeGPxs to microbial infections. The results revealed the significant up-regulation of AbSeGPx-a in a time dependent manner after bacterial (Listeria monocytogenes and Vibrio parahaemolyticus) and viral (viral hemorrhagic septicemia virus) infections. Consequently, these findings indicate that AbSeGPx-a and AbSeGPx-b might be involved in the embryonic development of disk abalone and the regulation of immune defense system of adult animals. PMID- 26025186 TI - Selective adsorption mechanisms of antilipidemic and non-steroidal anti inflammatory drug residues on functionalized silica-based porous materials in a mixed solute. AB - The selective adsorption mechanisms of naproxen (NAP), acetaminophen (ACT), and clofibric acid (CFA) on silica-based porous materials were examined by single and mixed-batch adsorption. Effects of the types and densities of surface functional groups on adsorption capacities were determined, including the role of hydrophobic and hydrophilic dissolved organic matters (DOMs). Hexagonal mesoporous silica (HMS), superparamagnetic HMS (HMS-SP) and SBA-15 were functionalized and applied as adsorbents. Compared with powdered activated carbon (PAC), amine-functionalized HMS had a better adsorption capacity for CFA, but PAC possessed a higher adsorption capacity for the other pharmaceuticals than HMS and its two derivatives. In contrast to PAC, the adsorption capacity of the mesoporous silicas varied with the solution pH, being highest at pH 5. Electrostatic interactions and hydrogen bonding were found to be the main mechanisms. Increase in grafted amine group density on silica surfaces can enhance the CFA adsorption capacity. Further, hydrophilic DOM can decrease CFA adsorption capacities on amino-grafted adsorbents by adsorption site competition, while hydrophobic DOM can interfere with CFA adsorption by the interaction between hydrophobic DOM and CFA. Finally, in a competitive adsorption study, the adsorption capacity of hydrophilic adsorbents for acidic pharmaceuticals varied with their pKa values. PMID- 26025185 TI - Validation of a Mandarin Chinese version of the pelvic organ prolapse/urinary incontinence sexual questionnaire IUGA-revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: Sexual dysfunction has a high prevalence in women with pelvic organ disorders. Until recently, there has been no single one questionnaire translated or validated that can evaluate the sexual function of patients with a pelvic floor disorder, either for sexually active or inactive women. The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire IUGA Revised (PISQ-IR) was developed to fill this gap. The aim of this study was to translate and validate the Mandarin Chinese version of PISQ-IR for global use. METHODS: This study was conducted with a sample of 106 patients. The PISQ-IR was translated and back-translated by two bilingual urogynecological specialists, and the Mandarin Chinese version was approved by the PISQ-IR Working Group of the International Urogynecological Association (IUGA). Its reliability was assessed using test-retest reliability and internal consistency, and its criterion validity was assessed in relation to other currently valid Chinese questionnaires. Both exploratory and confirmatory factor analyses were assessed. RESULTS: The mean age of the participants was 52 +/- 10.6 years. The Cronbach alpha value for each subscale ranged from 0.65 to 0.84 and from 0.6 to 0.83 for the sexually active and inactive groups, respectively. The convergent validity test showed that the value of each subscale was positively correlated with those of other questionnaires (P < 0.05). Exploratory and confirmatory factor analysis illustrated both good factor extraction and model fit. CONCLUSION: This study demonstrated the Mandarin Chinese version of PISQ-IR is a valid, reliable and condition-specific instrument to assess sexual function in sexually active or inactive women with a pelvic floor disorder. PMID- 26025187 TI - Gold biorecovery from e-waste: An improved strategy through spent medium leaching with pH modification. AB - Rapid technological advancement and relatively short life time of electronic goods have resulted in an alarming growth rate of electronic waste which often contains significant quantities of toxic and precious metals. Compared to conventional recovery methods, bioleaching is an environmentally friendly process for metal extraction. Gold was bioleached from electronic scrap materials (ESM) via gold-cyanide complexation using cyanide produced from pure and mixed cultures of cyanogenic bacteria Chromobacterium violaceum, Pseudomonas aeruginosa and Pseudomonas fluorescens. As ESM was toxic to the bacteria, a two-step bioleaching approach was adopted where the solid waste was added to the bacterial culture after it has reached maximum growth and cyanide production during early stationary phase. Pure culture of C. violaceum showed the highest cyanide production, yielding maximum gold recovery of 11.3% at 0.5% w/v pulp density of ESM in two-step bioleaching. At the same pulp density of ESM, spent medium bioleaching using bacterial cell-free metabolites achieved gold recovery of 18%. Recovery increased to 30% when the pH of the spent medium was increased to shift the equilibrium in favor of cyanide ions production. It is demonstrated for the first time that pH modification of spent medium further improved metal solubilization and yielded higher metal recovery (compared to two-step bioleaching). PMID- 26025188 TI - UV/chlorine control of drinking water taste and odour at pilot and full-scale. AB - Advanced oxidation processes (AOPs) can be used to destroy taste and odour causing compounds in drinking water. This work investigated both pilot- and full scale performance of the novel ultraviolet (UV)/chlorine AOP for the destruction of geosmin, 2-methylisoborneol (MIB) and caffeine (as a surrogate) in two different surface waters. The efficiency of the UV/chlorine process at pH 7.5 and 8.5 was comparable to that of the UV/hydrogen peroxide (UV/H2O2) process under parallel conditions, and was superior at pH 6.5. Caffeine was found to be a suitable surrogate for geosmin and MIB, and could be used as a more economical alternative to geosmin or MIB spiking for site-specific full-scale testing. PMID- 26025189 TI - Prediction model for recurrence probabilities after intravesical chemotherapy in patients with intermediate-risk non-muscle-invasive bladder cancer, including external validation. AB - PURPOSE: To develop a model to predict recurrence for patients with intermediate risk (IR) non-muscle-invasive bladder cancer (NMIBC) treated with intravesical chemotherapy which can be challenging because of the heterogeneous characteristics of these patients. METHODS: Data from three Dutch trials were combined. Patients treated with intravesical chemotherapy with characteristics according to the IR definition of the EAU guideline 2013 were included. Uni- and multivariable Cox regression with selection methods were used to identify predictors of recurrence at 1, 2, and 5 years. An easy-readable table for recurrence probabilities was developed. An external validation was done using data from Spanish patients. RESULTS: A total of 724 patients were available for analyses, of which 305 were primary patients. Recurrences occurred in 413 patients (57%). History of recurrences, history of intravesical treatment, grade 2, multiple tumors, and adjuvant treatment with epirubicin were relevant predictors for recurrence-free survival with hazard ratios of 1.48, 1.38, 1.22, 1.56, and 1.27, respectively. A table for recurrence probabilities was developed using these five predictors. Based on the probability of recurrence, three risk groups were identified. Patients in each of the separate risk groups should be scheduled for less or more aggressive treatment. The model showed sufficient discrimination and good predictive accuracy. External validation showed good validity. CONCLUSION: In our model, we identified five relevant predictors for recurrence-free survival in IR-NMIBC patients treated with intravesical chemotherapy. These recurrence predictors allow the urologists to stratify patients in risk groups for recurrence that could help in deciding for an individualized treatment approach. PMID- 26025190 TI - Female stress urinary incontinence and the mid-urethral sling: is obstruction necessary to achieve dryness? AB - BACKGROUND: Recently, the American Urogynecologic Society and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction released position statements on the use of mid-urethral slings. The statement offers that the polypropylene mesh mid-urethral sling (retropubic and transobturator) is now the recognized worldwide standard of care for the surgical treatment of stress urinary incontinence. The purpose of the current manuscript is to examine whether the polypropylene mesh mid-urethral sling should be the standard of care. METHODS: Data for this review were acquired by a systematic search of the medical literature. RESULTS: The Trial of Mid-Urethral Slings found that retropubic and transobturator slings were associated with a significant rate of adverse events, despite being comprised of surgeons from high-volume, experienced centers. Stress urinary incontinence is not just a urethral disease due to intrinsic sphincteric deficiency. It can also be related to urethral hypermobility, which in turn is caused by anterior vaginal wall laxity. Often both hypermobility and intrinsic sphincter deficiency coexist. Recognizing the role of anterior vaginal wall support is important to understanding the role of procedures (such as Burch or needle suspension procedures) which have the potential of correcting stress incontinence without affecting voiding parameters. CONCLUSIONS: As a discipline, we need to conceptualize stress incontinence due to urethral hypermobility or intrinsic sphincter deficiency as separate entities and design our procedures to restore the underlying suspected pathology. PMID- 26025191 TI - Antibiotic resistance to Propionobacterium acnes: worldwide scenario, diagnosis and management. AB - Antibiotic resistance in cutaneous Propionobacterium is a global problem. As a general rule, resistance levels are high to macrolides, trimethoprim/sulfamethoxazole and clindamycin, while tetracyclines and levofloxacin have low resistance potential. Newer preparations like doxycycline MR and doxycycline 20 mg are subantimicrobial and may not lead to resistance. Sampling techniques are crucial to determine resistance. Genomic evaluation using 16S ribosomal RNA gene sequencing can be useful in diagnosing mutations and mapping phylotypes of Propionobacterium acnes. Resistance may lead to slow response and relapses. Apart from benzoyl peroxide, azelaic acid, topical dapsone, oral zinc and retinoids, novel molecules with little resistance potential include octadecenedioic acid, phytosphingosine, lauric acid, retapamulin, resveratrol, T-3912 and NB-003. The use of oral retinoids and non antibiotics like zinc can prevent resistance and help reduce the dependence on antibiotics. PMID- 26025193 TI - Barriers and Facilitators to HIV Testing in Migrants in High-Income Countries: A Systematic Review. AB - Migrants, particularly from low- and middle-income countries, are at a heightened risk of adverse HIV outcomes. HIV testing may improve these outcomes. We reviewed and synthesised studies into migrants and HIV testing (outcome variable), published between January 1997 and April 2014. Papers using quantitative, qualitative and mixed methods designs, and samples with adult (>=18 years) migrants from low- and middle-income countries in high-income countries were included in the paper. Of 3155 papers retrieved, 31 met the inclusion criteria and are included in the review. A large number of barriers and facilitators to HIV testing were identified across the individual, social and structural levels. A number of study design and methodological issues, however, inhibited a comprehensive synthesis. There is no doubt that addressing HIV testing in migrants in high-income countries is complex; however, it has important implications for individual, community and population health, and a strong, empirically based response is warranted. PMID- 26025192 TI - Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease. AB - BACKGROUND: We studied the association of inflammatory biomarkers including C reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6) with chronic kidney disease (CKD). METHODS: We conducted a case-control study among 201 CKD patients and 201 community-based controls in the greater New Orleans area. CKD was defined as estimated-glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or albuminuria >=30 mg/24-h. Serum CRP, TNF-alpha, and IL-6 were measured using standard methods. Multivariable regression models were used to examine associations between the inflammatory biomarkers and CKD adjusting for important CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin. RESULTS: The multivariable-adjusted medians (interquartile-range) were 2.91 (1.47, 5.24) mg/L in patients with CKD vs. 1.91 (0.99, 3.79) mg/L in controls without CKD (p = 0.39 for group difference) for CRP; 1.86 (1.51, 2.63) pg/mL vs. 1.26 (1.01, 1.98) pg/mL (p < 0.0001) for TNF-alpha; and 2.53 (1.49, 4.42) pg/mL vs. 1.39 (0.95, 2.15) pg/mL (p = 0.04) for IL-6, respectively. Compared to the lowest tertile, the highest tertile of TNF-alpha (OR 7.1, 95% CI 3.2 to 15.5) and IL-6 (OR 2.5, 95% CI 1.1 to 5.5) were significantly associated with higher odds of CKD in multivariable-adjusted models. Additionally, higher TNF-alpha and IL-6 were independently and significantly associated with lower eGFR and higher albuminuria. CONCLUSIONS: Our data suggest that TNF-alpha and IL-6, but not CRP, are associated with the prevalence and severity of CKD, independent from established CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin. PMID- 26025195 TI - Molecular cloning and expression studies of the adapter molecule myeloid differentiation factor 88 (MyD88) in turbot (Scophthalmus maximus). AB - Myeloid differentiation factor 88 (MyD88) is an adapter protein involved in the interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR)-mediated activation of nuclear factor-kappaB (NF-kappaB). In this study, a full length cDNA of MyD88 was cloned from turbot, Scophthalmus maximus. It is 1619 bp in length and contains an 858-bp open reading frame that encodes a peptide of 285 amino acid residues. The putative turbot (Sm)MyD88 protein possesses a N-terminal death domain and a C-terminal Toll/IL-1 receptor (TIR) domain known to be important for the functions of MyD88 in mammals. Phylogenetic analysis grouped SmMyD88 with other fish MyD88s. SmMyD88 mRNA was ubiquitously expressed in all examined tissues of healthy turbots, with higher levels observed in immune-relevant organs. To explore the role of SmMyD88, its gene expression profile in response to stimulation of lipopolysaccharide (LPS), CpG oligodeoxynucleotide (CpG-ODN) or turbot reddish body iridovirus (TRBIV) was studied in the head kidney, spleen, gills and muscle over a 7-day time course. The results showed an up-regulation of SmMyD88 transcript levels by the three immunostimulants in all four examined tissues, with the induction by CpG-ODN strongest and initiated earliest and inducibility in the muscle very weak. Additionally, TRBIV challenge resulted in a quite high level of SmMyD88 expression in the spleen, whereas the two synthetic immunostimulants induced the higher levels in the head kidney. These data provide insights into the roles of SmMyD88 in the TLR/IL-1R signaling pathway of the innate immune system in turbot. PMID- 26025194 TI - APOL1 G1 genotype modifies the association between HDLC and kidney function in African Americans. AB - BACKGROUND: Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term. RESULTS: Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 * HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies. CONCLUSIONS: Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan. PMID- 26025196 TI - Low-Dose Ketamine in Chronic Critical Illness. AB - We report a case series on the observed effects of low-dose ketamine infusions in 4 critically ill patients with varying complications related to prolonged critical illness. Doses of ketamine infusion ranged from 0.5 to 4 MUg/kg/min. A low-dose ketamine infusion was used to reduce agitation in a patient requiring high doses of sedatives and analgesics. In a second patient, ketamine improved depression and anxiety symptoms. In a third patient, ketamine may have facilitated liberation from mechanical ventilation. In a fourth patient, ketamine was used for palliation to avoid lethargy. Ketamine may be considered to help decrease agitation, manage pain, facilitate opioid and benzodiazepine withdrawal, prevent respiratory depression, and potentially manage depression and anxiety in chronically critically ill patients. PMID- 26025197 TI - Increasing metabolic rate despite declining body weight in an adult parasitoid wasp. AB - Metabolic rate is a positive function of body weight, a rule valid for most organisms and the basis of several theories of metabolic ecology. For adult insects, however, the diversity of relationships between body mass and respiration remains unexplained. The aim of this study is to relate the respiratory metabolism of a parasitoid with body weight and foraging activity. We compared the metabolic rate of groups of starving and host-fed females of the parasitoid Eupelmus vuilleti recorded with respirometry for 7days, corresponding to the mean lifetime of starving females and over half of the lifetime of foraging females. The dynamics of carbohydrate, lipid and protein in the body of foraging females were quantified with biochemical techniques. Body mass and all body nutrients declined sharply from the first day onwards. By contrast, the CO2 produced and the O2 consumed increased steadily. Starving females showed the opposite trend, identifying foraging as the reason for the respiration increase of feeding females. Two complementary physiological processes explain the unexpected relationship between increasing metabolic rate and declining body weight. First, host hemolymph is a highly unbalanced food, and the excess nutrients (protein and carbohydrate) need to be voided, partially through excretion and partially through respiration. Second, a foraging young female produces eggs at an increasing rate during the first half of its lifetime, a process that also increases respiration. We posit that the time-varying metabolic rate contributions of the feeding and reproductive processes supplements the contribution of the structural mass and lead to the observed trend. We extend our explanations to other insect groups and discuss the potential for unification using Dynamic Energy Budget theory. PMID- 26025198 TI - Bicaudal-C plays a vital role in oogenesis in Nilaparvata lugens (Hemiptera: Delphacidae). AB - Bicaudal-C (Bic-C) was originally identified in a Drosophila melanogaster mutagenesis screen and plays vital roles in embryogenesis. In this study, we characterized the Bic-C gene in the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae), an insect pest that undergoes incomplete metamorphosis. Our result showed that N. lugens Bic-C (NlBic-C) is a female-specific gene in this species. It is specifically expressed in developing oocytes and is not expressed in laid eggs. Ribonucleic acid interference (RNAi) of NlBic-C arrested the uptake of vitelline by oocytes, and resulted in undeveloped ovaries and the complete inhibition of oocyte growth in the ovarioles, suggesting that NlBic-C is required for oogenesis and oocyte maturation. NlBic-C is extremely highly sensitive to RNAi, suggesting that it may be a potential target in RNAi-based insect pest management. PMID- 26025200 TI - Age-related differences in task goal processing strategies during action cascading. AB - We are often faced with situations requiring the execution of a coordinated cascade of different actions to achieve a goal, but we can apply different strategies to do so. Until now, these different action cascading strategies have, however, not been examined with respect to possible effects of aging. We tackled this question in a systems neurophysiological study using EEG and source localization in healthy older adults and employing mathematical constraints to determine the strategy applied. The results suggest that older adults seem to apply a less efficient strategy when cascading different actions. Compared to younger adults, older adults seem to struggle to hierarchically organize their actions, which leads to an inefficient and more parallel processing of different task goals. On a systems level, the observed deficit is most likely due to an altered processing of task goals at the response selection level (P3 ERP) and related to changes of neural processes in the temporo-parietal junction. PMID- 26025199 TI - Voxelwise eigenvector centrality mapping of the human functional connectome reveals an influence of the catechol-O-methyltransferase val158met polymorphism on the default mode and somatomotor network. AB - Functional connections between brain regions constitute the substrate of the human functional connectome, whose topography has been discussed as an endophenotype for psychiatric disorders. Genetic influences on the entire connectome, however, have been rarely investigated so far. We tested for connectome-wide influences of the val158met (rs4860) polymorphism on the catechol O-methyltransferase (COMT) gene by applying formal network analysis and eigenvector centrality mapping on the voxel level to resting-state functional magnetic imaging data. This approach finds brain regions that are central in the network by aggregating local and global connectivity patterns, most importantly without the requirement to select regions or networks of interest. The COMT variant linked to high enzyme activity increased network centrality in distributed brain areas that are known to constitute the brain's default mode network. Further results also indicated a COMT influence on areas implicated in the somatomotor network. These findings are in line with the polymorphism's alleged role in cognitive processing and its role in psychotic disorders. The study is the first to demonstrate the influence of a functional and behaviorally relevant genetic variant on connectome-wide functional connectivity and is an important step toward establishing the functional connectome as an endophenotype for psychiatric and behavioral phenotypes. PMID- 26025201 TI - An in-silico analysis of the effect of heart position and orientation on the ECG morphology and vectorcardiogram parameters in patients with heart failure and intraventricular conduction defects. AB - AIM: The aim of this study was to investigate the influence of geometrical factors on the ECG morphology and vectorcardiogram (VCG) parameters. METHODS: Patient-tailored models based on five heart-failure patients with intraventricular conduction defects (IVCDs) were created. The heart was shifted up to 6 cm to the left, right, up, and down and rotated +/-30 degrees around the anteroposterior axis. Precordial electrodes were shifted 3 cm down. RESULTS: Geometry modifications strongly altered ECG notching/slurring and intrinsicoid deflection time. Maximum VCG parameter changes were small for QRS duration (-6% to +10%) and QRS-T angle (-6% to +3%), but considerable for QRS amplitude (-36% to +59%), QRS area (-37% to +42%), T-wave amplitude (-41% to +36%), and T-wave area (-42% to +33%). CONCLUSION: The position of the heart with respect to the electrodes is an important factor determining notching/slurring and voltage dependent parameters and therefore must be considered for accurate diagnosis of IVCDs. PMID- 26025202 TI - Comparison of model-based and expert-rule based electrocardiographic identification of the culprit artery in patients with acute coronary syndrome. AB - BACKGROUND AND PURPOSE: Culprit coronary artery assessment in the triage ECG of patients with suspected acute coronary syndrome (ACS) is relevant a priori knowledge preceding percutaneous coronary intervention (PCI). We compared a model based automated method (Olson method) with an expert-rule based method for the culprit artery assessment. METHODS: In each of the 53 patients who were admitted with the working diagnosis of suspected ACS, scheduled for emergent angiography with a view on revascularization as initial treatment and subsequently found to have an angiographically documented completely occluded culprit artery, culprit artery location was assessed in the preceding ECG by both the model-based Olson method and the expert-rule based method that considered either visual or computer measured J-point amplitudes. ECG culprit artery estimations were compared with the angiographic culprit lesion locations. Proportions of correct classifications were compared by a Z test at the 5% significance level. RESULTS: The Olson method performed slightly, but not significantly, better, when the expert-rule based method used visual assessment of J-point amplitudes (88.7% versus 81.1% correct; P=0.28). However, the Olson method performed significantly better when the expert rule based method used computer-measured J-point amplitudes (88.7% versus 71.7% correct; P<0.05). CONCLUSION: The automated model-based Olson method performed at least at the level of expert cardiologists using a manual rule-based method. PMID- 26025203 TI - Validation of PR interval length as a criterion for development of atrial fibrillation in non-Hispanic whites, African Americans and Hispanics. AB - BACKGROUND: PR interval prolongation on electrocardiogram (ECG) increases the risk of atrial fibrillation (AF). Non-Hispanic Whites are at higher risk of AF compared to African Americans and Hispanics. However, it remains unknown if prolongation of the PR interval for the development of AF varies by race/ethnicity. Therefore, we determined whether race affects the PR interval length's ability to predict AF and if the commonly used criterion of 200 ms in AF prediction models can continue to be used for non-White cohorts. METHODS: This is a retrospective epidemiological study of consecutive inpatient and outpatients. An ECG database was initially interrogated. Patients were included if their initial ECG demonstrated sinus rhythm and had two or more electrocardiograms and declared a race and/or ethnicity as non-Hispanic White, African American or Hispanic. Development of AF was stratified by race/ethnicity along varying PR intervals. Cox models controlled for age, gender, race/ethnicity, systolic blood pressure, BMI, QRS, QTc, heart rate, murmur, treatment for hypertension, heart failure and use of AV nodal blocking agents to assess PR interval's predictive ability for development of AF. RESULTS: 50,870 patients met inclusion criteria of which 5,199 developed AF over 3.72 mean years of follow-up. When the PR interval was separated by quantile, prolongation of the PR interval to predict AF first became significant in Hispanic and African Americans at the 92.5th quantile of 196-201 ms (HR: 1.42, 95% CI: 1.09-1.86, p=0.01; HR: 1.32, 95% CI: 1.07-1.64, p=0.01, respectively) then in non-Hispanic Whites at the 95th quantile at 203-212 ms (HR: 1.24, 95% CI: 1.24-1.53, p=0.04). For those with a PR interval above 200 ms, African Americans had a lower risk than non-Hispanic Whites to develop AF (HR: 0.80, 95% CI: 0.64-0.95, p=0.012), however, no significant difference was demonstrated in Hispanics. CONCLUSIONS: This is the first study to validate a PR interval value of 200 ms as a criterion in African Americans and Hispanics for the development of AF. However, a value of 200 ms may be less sensitive as a predictive measure for the development of AF in African Americans compared to non Hispanic Whites. PMID- 26025204 TI - Double hazards of ischemia and reperfusion arrhythmias in a patient with variant angina pectoris. AB - Variant angina pectoris, also called Prinzmetal's angina, is a syndrome caused by vasospasms of the coronary arteries. It can lead to myocardial infarction, ventricular arrhythmias, atrioventricular block and even sudden cardiac death. We report the case of a 53 year-old male patient with recurrent episodes of chest pain and arrhythmias in the course of related variant angina pectoris. It is likely that the reperfusion following myocardial ischemia was responsible for the ventricular fibrillation while the ST-segment returned to the baseline. This case showed that potential lethal arrhythmias could arise due to variant angina pectoris. It also indicated that ventricular fibrillation could be self terminated. PMID- 26025206 TI - Levels and sources of volatile organic compounds including carbonyls in indoor air of homes of Puertollano, the most industrialized city in central Iberian Peninsula. Estimation of health risk. AB - Twenty nine organic air pollutants including carbonyl compounds, alkanes, aromatic hydrocarbons and terpenes were measured in the indoor environment of different houses together with the corresponding outdoor measurements in Puertollano, the most industrialized city in central Iberian Peninsula. VOCs were sampled during 8 weeks using Radiello((r)) passive samplers, and a questionnaire on potential VOCs sources was filled out by the occupants. The results show that formaldehyde and hexanal was the most abundant VOCs measured in indoor air, with a median concentration of 55.5 and 46.4MUgm(-3), respectively followed by butanal (29.1MUgm(-3)), acetone (28.4MUgm(-3)) and acetaldehyde (21.4MUgm(-3)). After carbonyls, n-dodecane (13.1MUgm(-3)) and terpenes (alpha-pinene, 13.4MUgm(-3) and limonene, 13.4MUgm(-3)) were the compounds with higher median concentrations. The indoor/outdoor (I/O) ratios demonstrated that sources in the indoor environment are prevailing for most of the investigated VOCs especially for limonene, alpha pinene, hexanal, formaldehyde, pentanal, acetaldehyde, o-xylene, n-dodecane and acetone with I/O ratio >6. Multiple linear regressions were applied to investigate the indoor VOC determinants and Spearman correlation coefficients were used to establish common sources between VOCs. Finally, the lifetime cancer risk associated to formaldehyde, acetaldehyde and benzene exposure was estimated and they varied from 7.8*10(-5) to 4.1*10(-4) for formaldehyde, from 8.6*10(-6) to 3.5*10(-5) for acetaldehyde and from 2.0*10(-6) to 1.5*10(-5) for benzene. For formaldehyde, the attributed risk in most sampled homes was two orders of magnitude higher than the one (10(-6)) proposed as acceptable by risk management bodies. PMID- 26025208 TI - Grain boundary study of technically pure molybdenum by combining APT and TKD. AB - Molybdenum is an eligible material for high performance applications. However, its applicability is limited because of a brittle-to-ductile transition around room temperature, depending on the grain size and the content of interstitial impurities present at grain boundaries. The total amount of impurities in the current quality of molybdenum has become very small in the last decades. Therefore, the atom probe with its atomic resolution is the only suitable site specific analysis technique. Nevertheless, a site-specific specimen preparation by focused ion beam (FIB) is required to study the grain boundary chemistry effectively. With a novel method, which combines re-sharpening of pre-electro polished tips by FIB with transmission Kikuchi diffraction (TKD), a grain boundary can easily be positioned in the first 200 nm of an atom probe sample. Furthermore, the high resolution technique of TKD gives the opportunity to get crystallographic information of the mapped area and, therefore, an analysis of the grain boundary character to support the interpretation of the atom probe data files. In the present study, APT specimens of technically pure molybdenum which contain grain boundaries were prepared by FIB in support of TKD and subsequently were measured in the atom probe. The difference of segregation content at unequal types of grain boundaries in the as-deformed and recrystallized state is discussed. PMID- 26025209 TI - The correction of electron lens aberrations. AB - The progress of electron lens aberration correction from about 1990 onwards is chronicled. Reasonably complete lists of publications on this and related topics are appended. A present for Max Haider and Ondrej Krivanek in the year of their 65th birthdays. By a happy coincidence, this review was completed in the year that both Max Haider and Ondrej Krivanek reached the age of 65. It is a pleasure to dedicate it to the two leading actors in the saga of aberration corrector design and construction. They would both wish to associate their colleagues with such a tribute but it is the names of Haider and Krivanek (not forgetting Joachim Zach) that will remain in the annals of electron optics, next to that of Harald Rose. I am proud to know that both regard me as a friend as well as a colleague. PMID- 26025207 TI - Preparation of a polyclonal antibody that recognizes a unique galactosebeta1 4fucose disaccharide epitope. AB - Galactosebeta1-4fucose (Galbeta1-4Fuc) is a unique disaccharide unit that has been found only in the N-glycans of protostomia. We demonstrated that this unit has a role as an endogenous ligand for Caenorhabditis elegans galectins. This unit is also recognized by fungal and mammalian galectins possibly as a non-self glycomarker. In order to clarify its biological function, we made a polyclonal antibody using (Galbeta1-4Fuc)n-BSA as the antigen, which was prepared by crosslinking Galbeta1-4Fuc-O-(CH2)2-SH and BSA. The binding specificity of the antibody was analyzed by frontal affinity chromatography, and it was confirmed that it recognizes naturally occurring N-glycans containing the Galbeta1-4Fuc unit linked to the reducing-end GlcNAc via alpha1-6 linkage. By western blotting analysis, the antibody was also found to bind to (Galbeta1-4Fuc)n-BSA but not to BSA or asialofetuin, which has N-glycan chains containing Galbeta1-4GlcNAc. Western blotting experiments also revealed presence of stained proteins in crude extracts of C. elegans, the parasitic nematode Ascaris suum, and the allergenic mite Dermatophagoides pteronyssinus, while those from Drosophila melanogaster, Mus musculus, and the allergenic mites Dermatophagoides farinae and Tyrophagus putrescentiae were negative. This antibody should be a very useful tool for research on the distribution of the Galbeta1-4Fuc disaccharide unit in glycans in a wide range of organisms. PMID- 26025210 TI - Threshold of toxicological concern (TTC) for developmental and reproductive toxicity of anticancer compounds. AB - Pharmaceutical companies develop specialized therapies to treat late stage cancer. In order to accelerate life-saving treatments and reduce animal testing, compounds to treat life-threatening malignancies are allowed modified requirements for preclinical toxicology testing. Limited data packages in early drug development can present product quality challenges at multi-product manufacturing facilities. The present analysis established an endpoint-specific threshold of toxicological concern (TTC) for developmental and reproductive toxicity (DART) for anticancer compounds. A comprehensive database was created consisting of over 300 no-observed adverse effect levels (NOAELs) for DART of 108 anticancer compounds. The 5th percentile NOAEL for developmental and reproductive toxicity was 0.005 mg/kg/day (300 MUg/day), resulting in a human exposure threshold of 3 MUg/day assuming standard uncertainty factors and a 60 kg human bodyweight. The analysis shows this threshold is protective for developmental and reproductive toxicity of highly potent groups of anticancer compounds. There were similar TTC values calculated for direct-acting and indirect-acting anticancer compounds. PMID- 26025205 TI - The critical role of Akt in cardiovascular function. AB - Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat 3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKepsilon are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases. PMID- 26025211 TI - Making the connection-factors influencing implementation of evidence supported and non-evaluated lifestyle interventions in healthcare: a multiple case study. AB - Many implementation barriers relate to lifestyle interventions (LIs) being developed by scientists. Exploring whether implementation of non-evaluated LIs is less complicated, might offer insight how to improve the use of effective interventions. This study aimed to identify influencing factors for implementation and compare factors between evidence supported and non-evaluated LIs. Evidence-supported (n = 7) and non-evaluated LIs (n = 7) in hospitals, general practices and community care organizations were included as cases. Semi structured interviews (n = 46) were conducted. Additionally, documents (n = 207) were collected describing intervention, implementation process, and policy. We used a stepwise approach to inductively identify factors, organize them by diffusion phase, and an existing framework. A total of 37 factors were identified. 'Dissemination' factors were mainly observed in evidence-supported LIs. 'Compatibility to existing structures' ('adoption'), 'funding' and 'connection to existing care processes' ('implementation') was factors identified in all cases. 'Quality control' and 'ongoing innovation' ('maintenance') were reported in evidence-supported interventions. In all domains of the framework factors were observed. Factors identified in this study are in line with the literature. The findings do not support the assumption that implementation of non evaluated LIs is perceived as less complex. PMID- 26025212 TI - Tailored telephone counseling increases colorectal cancer screening. AB - To compare the efficacy of two interventions to promote colorectal cancer screening participation and forward stage movement of colorectal cancer screening adoption among first-degree relatives of individuals diagnosed with adenomatous polyps. One hundred fifty-eight first-degree relatives of individuals diagnosed with adenomatous polyps were randomly assigned to receive one of two interventions to promote colorectal cancer screening. Participants received either a tailored telephone counseling plus brochures intervention or a non tailored print brochures intervention. Data were collected at baseline and 3 months post-baseline. Group differences and the effect of the interventions on adherence and stage movement for colorectal cancer screening were examined using t-tests, chi-square tests, and logistic regression. Individuals in the tailored telephone counseling plus brochures group were significantly more likely to complete colorectal cancer screening and to move forward on stage of change for fecal occult blood test, any colorectal cancer test stage and stage of the risk appropriate test compared with individuals in the non-tailored brochure group at 3 months post-baseline. A tailored telephone counseling plus brochures intervention successfully promoted forward stage movement and colorectal cancer screening adherence among first-degree relatives of individuals diagnosed with adenomatous polyps. PMID- 26025213 TI - Early Therapy Intensity Level (TIL) Predicts Mortality in Spontaneous Intracerebral Hemorrhage. AB - BACKGROUND: Outcome from spontaneous intracerebral hemorrhage (sICH) may depend on patient-care variability. We developed as ICH-specific therapy intensity level (TIL) metric using evidence-based elements in a high severity sICH cohort. METHODS: This is a cohort study of 170 patients with sICH and any intraventricular hemorrhage treated in 2 academic neuroICUs. Pre-defined quality indicators were identified based on current guidelines, scientific evidence, and likelihood of care documentation in first 72 h of hospital admission. We assessed performance on each indicator and association with discharge mortality. Significant indicators were aggregated to develop a TIL score. The predictive validity of the best fit TIL score was tested with threefold cross-validation of multivariate logistic regression models of in-hospital survival and good outcome (modified Rankin score 0-3). RESULTS: Median ICH score was 3; discharge mortality was 51.2%. Five/19 tested variables were significantly associated with lower discharge mortality: no DNR/withdrawal of treatment within 24 h of admission, target glucose within 4 h of high glucose, no recurrent hyperpyrexia, clinical reversal of herniation/intracranial pressure >20 mmHg within 60 min of detection, and reversal of INR (<1.4) within 2 h of first elevation. One point was given for each or if not applicable. Median TIL score was significantly higher in survivors versus non-survivors (5[1] vs. 3[1]; P < 0.001). A 4-point aggregated TIL score was most predictive of discharge survival (area under receiving operating characteristic curve 0.85, 95% CI 0.80-0.90) and good outcome (AUC 0.84) and was an independent predictor of both (survival: OR 7.10; 95% CI 3.57-14.11; P < 0.001; good outcome: OR 3.10; 95% CI 1.06-8.79; P < 0.001). CONCLUSION: A simplified TIL score using evidenced-based patient-care parameters within first 3 days of admission after sICH was significantly associated with early mortality and good outcome. The next step is prospective validation of the simplified TIL score in a large clinical trial. PMID- 26025214 TI - Idiopathic non-cirrhotic portal hypertension: a review. AB - Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease characterized of intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis. The etiology of INCPH can be classified in five categories: 1) immunological disorders (i.e. association with common variable immunodeficiency syndrome, connective tissue diseases, Crohn's disease, etc.), 2) chronic infections, 3) exposure to medications or toxins (e.g. azathioprine, 6- thioguanine, arsenic), 4) genetic predisposition (i.e. familial aggregation and association with Adams-Oliver syndrome and Turner disease) and 5) prothrombotic conditions (e.g. inherited thrombophilias myeloproliferative neoplasm antiphospholipid syndrome). Roughly, INCPH diagnosis is based on clinical criteria and the formal exclusion of any other causes of portal hypertension. A formal diagnosis is based on the following criteria: 1) presence of unequivocal signs of portal hypertension, 2) absence of cirrhosis, advanced fibrosis or other causes of chronic liver diseases, and 3) absence of thrombosis of the hepatic veins or of the portal vein at imaging. Patients with INCPH usually present with signs or symptoms of portal hypertension such as gastro-esophageal varices, variceal bleeding or splenomegaly. Ascites and/or liver failure can occur in the context of precipitating factors. The development of portal vein thrombosis is common. Survival is manly limited by concomitant disorders. Currently, treatment of INCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied aimed to modify the natural history of the disease. Anticoagulation therapy can be considered in patients who develop portal vein thrombosis. PMID- 26025215 TI - Effect of a behavioral intervention of the SALdavel program to reduce salt intake among hypertensive women: A randomized controlled pilot study. AB - BACKGROUND: Excessive salt intake has been directly associated with cardiovascular diseases, especially hypertension, and non-cardiovascular diseases. Despite the current recommendations, salt intake remains high, indicating the need to develop theory-based interventions aimed at reducing this intake. AIM: The purpose of this study was to test the impact of a theory-based intervention - the SALdavel Program - to promote the use of less than 4 g of salt/day during cooking. METHODS: This was a two-arm parallel-group randomized study. A total of 92 hypertensive women were randomly assigned to an intervention or control group. The intervention was aimed at motivating participants to reduce salt addition by increasing self-efficacy and counteracting the negative influence of habit. Primary outcomes were the behavioral question of salt addition and total salt addition, secondary outcomes were overall salt intake, provided by 24-hour urinary sodium excretion, and psychosocial variables (intention, self-efficacy, and habit). RESULTS: At three-month follow-up, the intervention group improved significantly more than the control group regarding salt addition measures (p-values between 0.05 and 0.001) and psychosocial variables (all p-values ?0.001). The reduction in 24-hour urinary sodium excretion was not significant. CONCLUSION: The findings showed that this theory based intervention was effective to motivate and change the behavior of hypertensive women regarding daily salt use in cooking meals. This was accomplished by means of improvements in intention and self-efficacy and reduction of the habit of using more than 4 g of salt/day during cooking. PMID- 26025216 TI - Cluster-randomized clinical trial examining the impact of platelet function testing on practice: the treatment with adenosine diphosphate receptor inhibitors: longitudinal assessment of treatment patterns and events after acute coronary syndrome prospective open label antiplatelet therapy study. AB - BACKGROUND: Little is known about how clinicians use platelet function testing to guide choice and dosing of adenosine diphosphate receptor inhibitor (ADPri) therapy in routine community practice. METHODS AND RESULTS: The Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (ACS)-Prospective, Open Label, Antiplatelet Therapy Study (TRANSLATE-POPS) was a cluster-randomized trial in which 100 hospitals were assigned access to no-cost platelet function testing versus usual care for acute myocardial infarction patients treated with percutaneous coronary intervention. In both arms, ADPri treatment decisions were left up to the care team. The primary end point was the frequency of ADPri therapy adjustment before discharge. Secondary end points included 30-day rates of major adverse cardiovascular events and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries-defined bleeding events. Platelet function testing was performed in 66.9% of patients treated in intervention sites versus 1.4% of patients in usual care sites. Intervention arm patients were more likely to have ADPri therapy adjustment than usual care patients (14.8% versus 10.5%, P=0.004; odds ratio 1.68, 95% confidence interval 1.18-2.40); however, there were no significant differences in 30-day major adverse cardiovascular events (4.8% versus 5.4%, P=0.73; odds ratio 0.94, 95% confidence interval 0.66-1.34) or bleeding (4.3% versus 4.2%, P=0.33; odds ratio 0.86, 95% confidence interval 0.55-1.34). One-year outcomes were also not significantly different between groups. An as-treated analysis showed higher incidence of ADPri therapy adjustment among intervention arm patients who received platelet function testing than untested usual care arm (16.4% versus 10.2%, P<0.0001), but no significant differences in major adverse cardiovascular events or bleeding. CONCLUSIONS: TRANSLATE-POPS found that when clinicians routinely used platelet function testing, they were more likely to adjust their choice or dosing of ADPri therapy; yet with few changes in therapy overall, significant differences in clinical outcomes were not seen. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01088503. PMID- 26025217 TI - Change in coronary blood flow after percutaneous coronary intervention in relation to baseline lesion physiology: results of the JUSTIFY-PCI study. AB - BACKGROUND: Percutaneous coronary intervention (PCI) aims to increase coronary blood flow by relieving epicardial obstruction. However, no study has objectively confirmed this and assessed changes in flow over different phases of the cardiac cycle. We quantified the change in resting and hyperemic flow velocity after PCI in stenoses defined physiologically by fractional flow reserve and other parameters. METHODS AND RESULTS: Seventy-five stenoses (67 patients) underwent paired flow velocity assessment before and after PCI. Flow velocity was measured over the whole cardiac cycle and the wave-free period. Mean fractional flow reserve was 0.68+/-0.02. Pre-PCI, hyperemic flow velocity is diminished in stenoses classed as physiologically significant compared with those classed nonsignificant (P<0.001). In significant stenoses, flow velocity over the resting wave-free period and hyperemic flow velocity did not differ statistically. After PCI, resting flow velocity over the wave-free period increased little (5.6+/-1.6 cm/s) and significantly less than hyperemic flow velocity (21.2+/-3 cm/s; P<0.01). The greatest increase in hyperemic flow velocity was observed when treating stenoses below physiological cut points; treating stenoses with fractional flow reserve <=0.80 gained Delta28.5+/-3.8 cm/s, whereas those fractional flow reserve >0.80 had a significantly smaller gain (Delta4.6+/-2.3 cm/s; P<0.001). The change in pressure-only physiological indices demonstrated a curvilinear relationship to the change in hyperemic flow velocity but was flat for resting flow velocity. CONCLUSIONS: Pre-PCI physiology is strongly associated with post-PCI increase in hyperemic coronary flow velocity. Hyperemic flow velocity increases 6-fold more when stenoses classed as physiologically significant undergo PCI than when nonsignificant stenoses are treated. Resting flow velocity measured over the wave-free period changes at least 4-fold less than hyperemic flow velocity after PCI. PMID- 26025218 TI - Magnitude of troponin elevation and long-term clinical outcomes in acute coronary syndrome patients treated with and without revascularization. AB - BACKGROUND: In patients with non-ST-segment-elevation acute coronary syndrome (NSTE ACS), elevated troponin levels identify patients at high risk for adverse outcomes; however, it is unknown whether the magnitude of troponin elevation during hospitalization remains predictive of subsequent events in patients undergoing coronary revascularization. METHODS AND RESULTS: We studied 12 635 patients with NSTE ACS in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) study with at least 1 troponin measurement during index hospitalization. Cox proportional hazards regression was used to examine the relationship between peak troponin level (standardized as the ratio of peak troponin value measured during hospitalization and local laboratory upper reference limit [URL]) and revascularization on all-cause mortality at 2 years. Revascularization (percutaneous coronary intervention or coronary artery bypass graft) was performed during index hospitalization in 8586 patients (68.0%); revascularized patients had higher peak troponin ratios (median, 23 versus 9.5* URL). Among patients that did not undergo revascularization, the mortality rate at 2 years increased in a curvilinear fashion with increasing levels of peak troponin. In contrast, the mortality rate at 2 years remained constant irrespective of peak troponin levels among revascularized patients (P for interaction=0.004). This relationship was unchanged after multivariable adjustment. CONCLUSIONS: There is a differential relationship between the magnitude of troponin elevation and long-term mortality in ACS patients treated with and without revascularization. Although prognostically important in patients treated without revascularization, the prognostic implications of peak troponin level seem to be minimal in revascularized patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943. PMID- 26025219 TI - High event rate after a first percutaneous coronary intervention in patients with diabetes mellitus: results from the Swedish coronary angiography and angioplasty registry. AB - BACKGROUND: Patients with diabetes mellitus have reduced longevity after acute coronary syndromes and revascularization. However, knowledge of the long-term complication rates and patterns from an everyday life setting is lacking. METHODS AND RESULTS: Consecutive patients undergoing percutaneous coronary intervention included in the Swedish Coronary Angiography Angioplasty Registry (SCAAR) between 2006 and 2010 and with no previous revascularization were prospectively followed up for combined cardiovascular events (first of all-cause mortality, myocardial infarction, stroke, and heart failure) until December 31, 2010. The mean follow up period was 920 days (SD, 530 days). Differences in background and procedural characteristics were adjusted for in a multivariate Cox regression model. Of 58 891 patients, mean age 67 years, 19% had diabetes mellitus; 27% of them were on diet treatment, 33% on oral glucose lowering, and 40% on insulin treatment. At admission, cardiovascular risk factors, multiple coronary vessel, and left main stem disease were more frequent in patients with diabetes mellitus and their revascularization was less often complete. The adjusted risk for combined cardiovascular events was higher in patients on insulin (hazard ratio [95% confidence interval], 1.63 [1.55-1.72]), on oral treatment (1.23 [1.15-1.31]), and on diet alone (1.21 [1.12-1.29]) compared with patients without diabetes mellitus. Insulin-treated patients ran an increased risk of restenosis (1.54 [1.39-1.71]) and stent thrombosis (1.56 [1.25-1.96]). CONCLUSIONS: The prognosis after a first percutaneous coronary intervention is more severe in patients with diabetes mellitus, in particular, in patients treated with insulin, with higher rates of mortality, cardiovascular events, and stent thrombosis over the following 5 years. PMID- 26025220 TI - Platelet function test-guided strategy: lost in translation? PMID- 26025221 TI - Managing Treatment-Resistant Patients. AB - Treatment-resistant hypertension (TRH) has a prevalence of approximately 10-20 %, and up to 5 % of patients with TRH experience a major cardiovascular or cerebrovascular event each year. Effective management of real TRH is important but can present a significant clinical challenge. Utilisation of treatment options that maximise treatment compliance is recommended, particularly combinations that have supporting data from clinical studies. Renal denervation can be considered for a subset of truly resistant patients. PMID- 26025222 TI - Correction for Mishra et al., Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema. PMID- 26025223 TI - QnAs with Jane Lubchenco. PMID- 26025224 TI - QnAs with Madhav Gadgil. PMID- 26025225 TI - Identifying localized changes in large systems: Change-point detection for biomolecular simulations. AB - Research on change-point detection, the classical problem of detecting abrupt changes in sequential data, has focused predominantly on datasets with a single observable. A growing number of time series datasets, however, involve many observables, often with the property that a given change typically affects only a few of the observables. We introduce a general statistical method that, given many noisy observables, detects points in time at which various subsets of the observables exhibit simultaneous changes in data distribution and explicitly identifies those subsets. Our work is motivated by the problem of identifying the nature and timing of biologically interesting conformational changes that occur during atomic-level simulations of biomolecules such as proteins. This problem has proved challenging both because each such conformational change might involve only a small region of the molecule and because these changes are often subtle relative to the ever-present background of faster structural fluctuations. We show that our method is effective in detecting biologically interesting conformational changes in molecular dynamics simulations of both folded and unfolded proteins, even in cases where these changes are difficult to detect using alternative techniques. This method may also facilitate the detection of change points in other types of sequential data involving large numbers of observables--a problem likely to become increasingly important as such data continue to proliferate in a variety of application domains. PMID- 26025226 TI - Clinical profile and main comorbidities of Spanish adults with Down syndrome. AB - BACKGROUND: The life expectancy of adults with Down syndrome (DS) has significantly increased in the last decades. We aim to describe the main demographic and clinical characteristics of a cohort of adults with DS, and analyse their differences according to age and gender groups. METHODS: Cross sectional study of 144 adults with DS from the outpatient clinic of a tertiary care hospital in Madrid, Spain, recruited between February 2012 and March 2013. Demographic data (age, gender, living situation, caregivers, and working situation), clinical conditions, prior medications, and laboratory data were measured and compared between groups. RESULTS: Adults with DS were 35+/-12 years old (range 17-65), and 51% were males. Most subjects lived with their families (112, 78%), and parents were the main caregivers in 73% of cases. However, older adults with DS lived more frequently in residential facilities. Each subject presented an average of 5+/-2 clinical problems. Eye (117 adults, 81%), skin (86, 60%), thyroid (81, 56%), gastrointestinal (73, 51%), and psychopathological disorders (58, 40%) were amongst the most frequent clinical conditions of adults with DS. Cataracts (14, 61%), keratoconus (4, 17%), dementia (11, 48%), and seizures (6, 26%) were more frequent amongst individuals with DS over 50 years (p<0.001 for the comparisons). No relevant differences were found between genders. The medications most frequently prescribed were levothyroxine (70 subjects, 48.6%), vitamin D (50, 34.7%), antidepressants (32, 22%), and antipsychotics (31, 21.5%). CONCLUSIONS: Adults with DS present a wide spectrum of potentially treatable medical conditions, making specially-trained multidisciplinary teams a dire need for this population. PMID- 26025227 TI - A different role of angiotensin II type 1a receptor in the development and hypertrophy of plantaris muscle in mice. AB - The role of angiotensin II type 1 (AT1) receptors in muscle development and hypertrophy remains unclear. This study was designed to reveal the effects that a loss of AT1 receptors has on skeletal muscle development and hypertrophy in mice. Eight-week-old male AT1a receptor knockout (AT1a(-/-)) mice were used for this experiment. The plantaris muscle to body weight ratio, muscle fiber cross sectional area, and number of muscle fibers of AT1a(-/-) mice was significantly greater than wild type (WT) mice in the non-intervention condition. Next, the functional overload (OL) model was used to induce plantaris muscle hypertrophy by surgically removing the two triceps muscles consisting of the calf, soleus, and gastrocnemius muscles in mice. After 14 days of OL intervention, the plantaris muscle weight, the amount of fiber, and the fiber area increased. However, the magnitude of the increment of plantaris weight was not different between the two strains. Agtr1a mRNA expression did not change after OL in WT muscle. Actually, the Agt mRNA expression level of WT-OL was lower than WT-Control (C) muscle. An atrophy-related gene, atrogin-1 mRNA expression levels of AT1a(-/-)-C, WT-OL, and AT1a(-/-)-OL muscle were lower than that of WT-C muscle. Our findings suggest that AT1 receptor contributes to plantaris muscle development via atrogin-1 in mice. PMID- 26025228 TI - Metabolite profiling during cold acclimation of Lolium perenne genotypes distinct in the level of frost tolerance. AB - Abiotic stresses, including low temperature, can significantly reduce plant yielding. The knowledge on the molecular basis of stress tolerance could help to improve its level in species of relatively high importance to agriculture. Unfortunately, the complex research performed so far mainly on model species and also, to some extent, on cereals does not fully cover the demands of other agricultural plants of temperate climate, including forage grasses. Two Lolium perenne (perennial ryegrass) genotypes with contrasting levels of frost tolerance, the high frost tolerant (HFT) and the low frost tolerant (LFT) genotypes, were selected for comparative metabolomic research. The work focused on the analysis of leaf metabolite accumulation before and after seven separate time points of cold acclimation. Gas chromatography-mass spectrometry (GC/MS) was used to identify amino acids (alanine, proline, glycine, glutamic and aspartic acid, serine, lysine and asparagine), carbohydrates (fructose, glucose, sucrose, raffinose and trehalose) and their derivatives (mannitol, sorbitol and inositol) accumulated in leaves in low temperature. The observed differences in the level of frost tolerance between the analysed genotypes could be partially due to the time point of cold acclimation at which the accumulation level of crucial metabolite started to increase. In the HFT genotype, earlier accumulation was observed for proline and asparagine. The increased amounts of alanine, glutamic and aspartic acids, and asparagine during cold acclimation could be involved in the regulation of photosynthesis intensity in L. perenne. Among the analysed carbohydrates, only raffinose revealed a significant association with the acclimation process in this species. PMID- 26025230 TI - The NIH Toolbox Pattern Comparison Processing Speed Test: Normative Data. AB - The NIH Toolbox Pattern Comparison Processing Speed Test was developed to assess processing speed. While initial validation work provides preliminary support for this test in both children and adults, more work is needed to ensure dependability and generalizability. Thus, this replication study examines descriptive data (including age effects), test-retest reliability, and construct validity in n = 4,859 participants ages 3-85 years (matched to 2010 census data). Although the Pattern Comparison was not appropriate for all 3 and 4 years old, by ages 5 and 6, more meaningful scores were apparent. There was evidence for convergent and discriminant validity. There was also a moderate practice effect (i.e., increase of 5.5 points) over a 1-week time frame. Pattern Comparison exhibits a number of strengths: it is appropriate for use across the lifespan (ages 5-85), it is short and easy to administer, and there is support for construct validity. PMID- 26025231 TI - Verbal Fluency and Early Memory Decline: Results from the Wisconsin Registry for Alzheimer's Prevention. AB - This study examined the relationship between phonemic and semantic (category) verbal fluency and cognitive status in the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal cohort enriched for family history of Alzheimer's disease. Participants were 283 WRAP subjects (age 53.1[6.5] years at baseline); who had completed three waves of assessment, over ~6 years and met psychometric criteria either for "cognitively healthy" (CH) or for psychometric amnestic mild cognitive impairment (aMCI) using an approach that did not consider fluency scores. CH and aMCI groups differed significantly on phonemic total scores, category total scores, phonemic switching, and category mean cluster size. These results suggest that measures of both phonemic and semantic fluency yield lower scores in persons with evidence of psychometric aMCI compared with those who are CH. Differences have not previously been reported in a group this young, and provide evidence for the importance of including multiple verbal fluency tests targeting preclinical Alzheimer's disease. PMID- 26025233 TI - Testing for Sufficient-Cause Gene-Environment Interactions Under the Assumptions of Independence and Hardy-Weinberg Equilibrium. AB - To detect gene-environment interactions, a logistic regression model is typically fitted to a set of case-control data, and the focus is on testing of the cross product terms (gene * environment) in the model. A significant result is indicative of a gene-environment interaction under a multiplicative model for disease odds. Based on the sufficient-cause model for rates, in this paper we put forward a general approach to testing for sufficient-cause gene-environment interactions in case-control studies. The proposed tests can be tailored to detect a particular type of sufficient-cause gene-environment interaction with greater sensitivity. These tests include testing for autosomal dominant, autosomal recessive, and gene-dosage interactions. The tests can also detect trend interactions (e.g., a larger gene-environment interaction with a higher level of environmental exposure) and threshold interactions (e.g., gene environment interaction occurs only when environmental exposure reaches a certain threshold level). Two assumptions are necessary for the validity of the tests: 1) the rare-disease assumption and 2) the no-redundancy assumption. Another 2 assumptions are optional but, if imposed correctly, can boost the statistical powers of the tests: 3) the gene-environment independence assumption and 4) the Hardy-Weinberg equilibrium assumption. SAS code (SAS Institute, Inc., Cary, North Carolina) for implementing the methods is provided. PMID- 26025232 TI - Mechanisms and Mediators That Drive Arthritis Pain. AB - There are over 100 different types of arthritis and each can differ greatly in their aetiology and pathophysiology; however, one characteristic that is common to all arthritic conditions is joint pain. Musculoskeletal pain is the leading cause of disability in the world, and the number one reason arthritis patients visit their primary care physician. Despite the prevalence and burden of arthritis pain, current analgesics lack sufficient efficacy and are plagued by multiple adverse side effects. In this review, we outline the current landscape of research concerning joint pain, drawing from both preclinical and clinical studies. Specifically, this review is a discussion of the different neurophysiological processes that occur during joint disease and how inflammatory and neuropathic aspects contribute to the development of arthritis pain. PMID- 26025234 TI - Three Authors Reply. PMID- 26025235 TI - Re: "Elevated Lung Cancer In Younger Adults and Low Concentrations of Arsenic in Water". PMID- 26025236 TI - Social participation and depression in old age: a fixed-effects analysis in 10 European countries. AB - We examined whether changes in different forms of social participation were associated with changes in depressive symptoms in older Europeans. We used lagged individual fixed-effects models based on data from 9,068 persons aged >=50 years in wave 1 (2004/2005), wave 2 (2006/2007), and wave 4 (2010/2011) of the Survey of Health, Ageing and Retirement in Europe (SHARE). After we controlled for a wide set of confounders, increased participation in religious organizations predicted a decline in depressive symptoms (EURO-D Scale; possible range, 0-12) 4 years later (beta = -0.190 units, 95% confidence interval: -0.365, -0.016), while participation in political/community organizations was associated with an increase in depressive symptoms (beta = 0.222 units, 95% confidence interval: 0.018, 0.428). There were no significant differences between European regions in these associations. Our findings suggest that social participation is associated with depressive symptoms, but the direction and strength of the association depend on the type of social activity. Participation in religious organizations may offer mental health benefits beyond those offered by other forms of social participation. PMID- 26025237 TI - Re: "Elevated Lung Cancer in Younger Adults and Low Concentrations of Arsenic in Water". PMID- 26025239 TI - Misuse of 'trend' to describe 'almost significant' differences in anaesthesia research. PMID- 26025238 TI - Use of the Microbiome in the Practice of Epidemiology: A Primer on -Omic Technologies. AB - The term microbiome refers to the collective genome of the microbes living in and on our bodies, but it has colloquially come to mean the bacteria, viruses, archaea, and fungi that make up the microbiota (previously known as microflora). We can identify the microbes present in the human body (membership) and their relative abundance using genomics, characterize their genetic potential (or gene pool) using metagenomics, and describe their ongoing functions using transcriptomics, proteomics, and metabolomics. Epidemiologists can make a major contribution to this emerging field by performing well-designed, well-conducted, and appropriately powered studies and by including measures of microbiota in current and future cohort studies to characterize natural variation in microbiota composition and function, identify important confounders and effect modifiers, and generate and test hypotheses about the role of microbiota in health and disease. In this review, we provide an overview of the rapidly growing literature on the microbiome, describe which aspects of the microbiome can be measured and how, and discuss the challenges of including the microbiome as either an exposure or an outcome in epidemiologic studies. PMID- 26025240 TI - BIS and state entropy of the EEG - comparing apples and oranges. PMID- 26025241 TI - A hormone priming regimen and hibernation affect oviposition in the boreal toad (Anaxyrus boreas boreas). AB - Declines of the southern Rocky Mountain population of boreal toad (Anaxyrus boreas boreas) have led to the establishment of a captive assurance population and reintroduction program, in an attempt to preserve and propagate this geographically isolated population. One of the unique adaptations of this species is its ability to survive in cold environments by undergoing long periods of hibernation. In captivity, hibernation can be avoided altogether, decreasing morbidity caused by compromised immune systems. However, it is not entirely clear how essential hibernation is to reproductive success. In this study, the effects of hibernation versus nonhibernation, and exogenous hormones on oviposition, were examined in boreal toad females in the absence of males. In the summers of 2011 and 2012, 20 females housed at Mississippi State University were treated with a double priming dose of hCG and various ovulatory doses of hCG and LH-releasing hormone analog but denied hibernation. Exogenous hormones, in the absence of hibernation, could not induce oviposition over two breeding seasons (2011-2012). In contrast, during the summer of 2012 and 2013, 17 of 22 females (77%) housed at the Native Aquatic Species Restoration Facility (Alamosa, CO, USA) oviposited after they were treated with two priming doses of hCG (3.7 IU/g each) and a single ovulation dose of hCG (13.5 IU/g) and LH-releasing hormone analog (0.4 MUg/g) after hibernation. There was a significant difference in oviposition between females that were hibernated and received hormones (2012, P < 0.05 and 2013, P < 0.01) compared to hibernated control females. In 2013, 12 of 16 remaining Mississippi State University females from the same group used in 2011 and 2012 were hibernated for 1, 3, and 6 months, respectively and then treated with the same hormone regimen administered to females at the Native Aquatic Species Restoration Facility. Together, hibernation and hormone treatments significantly increased oviposition (P < 0.05), with 33% of females ovipositing. These results suggest that (1) hibernation is a key factor influencing oviposition that cannot be exclusively circumvented by exogenous hormones; (2) females do not require the presence of a male to oviposit after hormone treatments; and (3) longer hibernation periods are not beneficial for oviposition. The hormonal induction of oviposition in the absence of males and shorter hibernation periods could have important captive management implications for the boreal toad. Furthermore, the production of viable offspring by IVF where natural mating is limited could become an important tool for genetic management of this boreal toad captive population. PMID- 26025242 TI - Seasonal heat stress: Clinical implications and hormone treatments for the fertility of dairy cows. AB - Heat stress has consequences on both the physiology and reproductive performance of cows, but the most dramatic effect for dairy producers is the decrease produced in fertility. The effects of heat stress on fertility include an increased number of days open, reduced conception rate, and larger number of cows suffering different types of anestrus. Once becomes pregnant, heat stress affects also the reproductive success of the cow through its direct effects on the ovary, uterus, gametes, embryo, and early fetus. This article reviews current knowledge of the effects of heat stress on fertility in dairy cows and the hormonal strategies used to mitigate these effects at the farm level. Administration of GnRH at the moment of artificial insemination can improve the conception rate. Breeding synchronization protocols for fixed-time insemination may reduce the calving conception interval and the number of services per conception. Progesterone-based protocols seem resolve better the reproductive disorders related to a hot environment (anestrus) than GnRH-based protocols. The use of combinations of GnRH, eCG, and hCG in progesterone-based protocols can improve results. Progesterone supplementation during the late embryonic and/or early fetal period would be useful in curtailing pregnancy losses, mainly in single pregnancies, whereas a more positive effect of treatment with GnRH than progesterone has been found in twin pregnancies. Melatonin therapy is emerging as a promising strategy to improve the natural reproductive performance of cows suffering conditions of heat stress. PMID- 26025243 TI - In utero development of the fetal intestine: Sonographic evaluation and correlation with gestational age and fetal maturity in dogs. AB - Modern high-resolution ultrasound images enable earlier assessment of measures of fetal development, including identification of the bowel. The aim of this study was to describe the ultrasonographic development of fetal bowel and correlate this with gestational age; define whether ultrasonographic visualization of fetal intestinal peristalsis in utero is associated with fetal maturation and determine whether there is a difference in fetal intestinal peristalsis detection time between fetuses delivered by normal delivery and cesarean. A cohort study was conducted in pregnant bitches presented to a veterinary hospital, to assess fetal bowel development. Statistical analysis was used to establish the correlation of the stage of fetal bowel development, as recorded by ultrasound, with outcomes of normal delivery and cesarean section. The study was broken down into three stages: the first stage was a descriptive analysis of fetal bowel development by ultrasound; the second stage compared time (in days) of bowel development between groups (normal delivery vs. cesarean); and the third stage was correlated survival probability for fetuses born on any day after detection of intestinal peristalsis with fetal maturity. All statistical analyses were significant. It is possible to monitor pregnancy progression using ultrasonographic evaluation of bowel development and this can reliably identify the end of fetal organogenesis. However, ultrasonographic detection of bowel segments with visualization of wall layers and associated peristalsis should not be used as the sole indicator for cesarean section planning because it is not possible to determine ultrasonographically whether the bowel is functional (mature). PMID- 26025244 TI - Could semiquantitative FDG analysis add information to the prognosis in patients with stage II/III breast cancer undergoing neoadjuvant treatment? AB - PURPOSE: We investigated whether maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV), total lesion glycolysis (TLG) and whole-body (WB) SUVmax, WB MTV and WB TLG measured by (18)F-FDG PET/CT could improve prognostic stratification in patients with stage II/III breast cancer (BC). METHODS: We prospectively enrolled 99 consecutive women (median age 50 years, range 27 - 77 years) with pathologically proven stage II/III BC who underwent pretreatment FDG PET/CT. WB SUVmax, WB MTV and WB TLG were measured in all malignant lesions. Survival was analysed using the Kaplan-Meier method. Cox proportional hazards models were constructed to test for relationships among WB SUVmax, WB MTV, WB TLG, and overall survival (OS) and disease-free survival (DFS), after adjustment for age, and histopathological and immunohistochemical features (oestrogen/progesterone and HER2 expression, proliferation index and grade). RESULTS: The median values of WB SUVmax, WB MTV and WB TLG were 16.2 (range 1.5 - 33.1), 14 cm(3) (range 0.03 - 708.6 cm(3)) and 62.5 (0.06 - 3869.4), respectively. All WB semiquantitative values were higher in patients with higher TNM stage, although not significantly (all p > 0.05). The median follow-up for surviving patients was 30 months, with a range of 13 - 45 months. Both PFS and OS of patients with low WB SUVmax, WB MTV and WB TLG were longer than that of patients with high WB values for progression, although not statistically significant. However, stratifying the patients in accordance with the stage of disease, both PFS and OS were significantly lower in patients with high WB TLG and stage III than in patients with stage II (p < 0.05). In multivariate analyses, WB MTV and WB TLG were independent prognostic factors for PFS (hazard ratio 1.004, 95% confidence interval 1.002 - 1.006, p < 0.001, and hazard ratio 1.001, 95% confidence interval 1.000 - 1.001, p = 0.011, respectively). CONCLUSION: The addition of WB TLG to clinical data may provide a more detailed prediction of outcome in patients with stage III BC. Moreover, WB MTV and WB TLG are independent factors predicting recurrence of BC. On the contrary, WB SUVmax has poor prognostic significance in this cohort of patients. PMID- 26025246 TI - Introducing the Academy's 2015-2016 President: Evelyn Ford Crayton. PMID- 26025245 TI - Evaluation of a radioactive and fluorescent hybrid tracer for sentinel lymph node biopsy in head and neck malignancies: prospective randomized clinical trial to compare ICG-(99m)Tc-nanocolloid hybrid tracer versus (99m)Tc-nanocolloid. AB - PURPOSE: There is some controversy about the value of sentinel lymph node excision (SLNE) in patients with head and neck malignancies. The gold standard for detection and targeted extirpation of the SLN is lymphoscintigraphy with (99m)Tc-nanocolloid. The purpose of this prospective randomized study was to analyse the feasibility and clinical benefit of a hybrid tracer comprising the near-infrared (NIR) fluorescent indocyanine green (ICG) and (99m)Tc-nanocolloid (ICG-(99m)Tc-nanocolloid) in direct comparison with standard (99m)Tc-nanocolloid for guiding SLNE in patients with head and neck cutaneous malignancies. METHODS: We analysed the data from 40 clinically lymph node-negative patients with melanoma, high-risk cutaneous squamous cell carcinoma, Merkel cell carcinoma or sweat gland carcinoma who underwent SLNE with ICG-(99m)Tc-nanocolloid (cohort A) or with the standard (99m)Tc-nanocolloid (cohort B). RESULTS: Overall SLNs were identified preoperatively in all 20 patients (100%) in cohort A and in 18 of 20 patients (90%) in cohort B. The SLN basin was detected preoperatively in 18 patients (90%) in cohort A and also in 18 patients (90%) in cohort B. SLNs were identified intraoperatively in all 20 patients (100%) in cohort A and in 19 patients (95%) in cohort B (p = 0.487). Metastatic SLNs were detected in 9 patients (22.5%), 3 (15.0%) in cohort A and 6 (30.0%) in cohort B (p = 0.228). CONCLUSION: The hybrid tracer ICG-(99m)Tc-nanocolloid is an innovative imaging tracer, reliably and readily providing additional information for the detection and excision of SLN in the head and neck region. Therefore, SLNE with combined radioactive and NIR fluorescence guidance is an attractive option for improving the SLN detection rate in patients with cutaneous head and neck malignancies. PMID- 26025247 TI - Behind the Scenes at the US Department of Agriculture. PMID- 26025248 TI - Professional boundary issues in practice. PMID- 26025249 TI - The Essential Practice Competencies for the Commission on Dietetic Registration's Credentialed Nutrition and Dietetics Practitioners. PMID- 26025250 TI - A few days in autumn: the founding of the Academy of Nutrition and Dietetics. PMID- 26025251 TI - What are the current findings concerning arsenic in foods? PMID- 26025252 TI - Phenylboronic Acid Solid Phase Extraction Cleanup and Isotope Dilution Liquid Chromatography-Tandem Mass Spectrometry for the Determination of Florfenicol Amine in Fish Muscles. AB - Florfenicol (FFC) residues in foods are regulated as the sum of florfenicol and its metabolites measured as florfenicol amine (FFA). An isotope dilution LC-MS/MS method utilizing phenylboronic acid (PBA) SPE cleanup is established for the accurate determination of FFA in fish muscles (i.e., salmon and tilapia) after acid catalyzed hydrolysis. Comparisons of the PBA SPE cleanup procedure with other cleanup procedures such as mixed-mode cationic (MCX) SPE and solid supported liquid-liquid extraction were performed. Quantification of FFA in fish muscles was accomplished by using matrix-matched calibration with FFA-D3 as the internal standard. The method was validated with FFA fortified fish muscles at three different levels (50, 100, and 200 MUg/kg). Conversion of FFC to FFA by acid catalyzed hydrolysis was evaluated and found to be >=88%. The recoveries of FFA in fish muscles at the three fortification levels ranged from 89 to 106%, and RSDs were <=9% in all cases. The LOD values in salmon and tilapia muscles were 0.13 and 1.64 MUg/kg, respectively. The LOQ values in salmon and tilapia muscles were 0.29 and 4.13 MUg/kg, respectively. This method is suitable for the application in routine control of FFC in fishes according to its residue definition. PMID- 26025253 TI - Investigating the association between parental reflective functioning and distress tolerance in motherhood. AB - Parental reflective functioning, referring to the capacity of a parent to consider their child's mental states as they relate to their behavior, may support sensitive and adaptive parenting. We investigated the relationship between parental reflective functioning and tolerance of distress in a sample of recent mothers (N=59). Participants completed self-report measures of parental reflective functioning and distress tolerance, as well as two behavioral distress tolerance tasks. We also examined blood pressure and heart rate during the laboratory session. Mothers reporting more difficulty in recognizing and understanding their child's mental states displayed decreased tolerance of distress on our behavioral and self-report measures. Further, we found evidence of a relationship between these measures and assessments of peripheral physiology. These findings are discussed in the context of reflective functioning and distress tolerance in parenthood, and their implications for parenting interventions. PMID- 26025254 TI - Preparing for pre-exposure prophylaxis: perceptions and readiness of Canadian pharmacists for the implementation of HIV pre-exposure prophylaxis. AB - Pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV transmission but has the potential to cause harm if not used properly. Pharmacists are well-positioned to foster PrEP's efficacy but little is known whether they would endorse it as an HIV prevention tool. The objective of the study was to determine Canadian HIV pharmacists' support for PrEP and to identify current barriers to promoting PrEP. Canadian pharmacists with experience in HIV care were invited to complete an online survey about their experiences, opinions, and learning needs regarding PrEP from December 2012 to January 2013. Among the 59 surveys received, 48 met criteria for final analysis. Overall, 33 (69%) respondents would provide education positively supporting the use of PrEP and 26 (54%) believed Health Canada should approve PrEP for use in Canada. Familiarity with the concept of PrEP and practice characteristics examined did not appear to be significantly associated with support for PrEP in univariable analyses. The principal barriers to promoting PrEP included inadequate drug coverage and insufficient knowledge to educate others. Many Canadian HIV pharmacists would endorse PrEP for high-risk patients; however, wider dissemination of information and lower drug costs may be needed to make PrEP more widely promoted. PMID- 26025255 TI - [Diagnosis and treatment of diving accidents. New German guidelines for diving accidents 2014-2017]. AB - In 2015 the German Society for Diving and Hyperbaric Medicine (GTUM) and the Swiss Underwater and Hyperbaric Medical Society (SUHMS) published the updated guidelines on diving accidents 2014-2017. These multidisciplinary guidelines were developed within a structured consensus process by members of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), the Sports Divers Association (VDST), the Naval Medical Institute (SchiffMedInst), the Social Accident Insurance Institution for the Building Trade (BG BAU), the Association of Hyperbaric Treatment Centers (VDD) and the Society of Occupational and Environmental Medicine (DGAUM). This consensus-based guidelines project (development grade S2k) with a representative group of developers was conducted by the Association of Scientific Medical Societies in Germany. It provides information and instructions according to up to date evidence to all divers and other lay persons for first aid recommendations to physician first responders and emergency physicians as well as paramedics and all physicians at therapeutic hyperbaric chambers for the diagnostics and treatment of diving accidents. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose and the following key action statements: on-site 100% oxygen first aid treatment, still patient positioning and fluid administration are recommended. Hyperbaric oxygen (HBO) recompression remains unchanged the established treatment in severe cases with no therapeutic alternatives. The basic treatment scheme recommended for diving accidents is hyperbaric oxygenation at 280 kPa. For quality management purposes there is a need in the future for a nationwide register of hyperbaric therapy. PMID- 26025256 TI - Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression. AB - BACKGROUND: Selective maintenance of genomic epigenetic imprints during pre implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence. RESULTS: Here, we comprehensively map sequence-specific ZFP57 binding sites in an allele-specific manner using hybrid ES cell lines from reciprocal crosses between C57BL/6J and Cast/EiJ mice, assigning allele specificity to approximately two-thirds of all binding sites. While half of these are biallelic and include endogenous retrovirus (ERV) targets, the rest show monoallelic binding based either on parental origin or on genetic background of the allele. Parental-origin allele-specific binding is methylation-dependent and maps only to imprinting control differentially methylated regions (DMRs) established in the germline. We identify a novel imprinted gene, Fkbp6, which has a critical function in mouse male germ cell development. Genetic background-specific sequence differences also influence ZFP57 binding, as genetic variation that disrupts the consensus binding motif and its methylation is often associated with monoallelic expression of neighboring genes. CONCLUSIONS: The work described here uncovers further roles for ZFP57-mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined monoallelic gene expression. PMID- 26025257 TI - Neuronal self-injury mediated by IL-1beta and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia ischemia. AB - BACKGROUND: Inflammation due to remote pathogen exposure combined to hypoxia/ischemia (HI) is one of the most common causes of neonatal encephalopathy affecting at-term or near-term human newborn, which will consequently develop cerebral palsy. Within term-equivalent rat brains exposed to systemic lipopolysaccharide (LPS) plus HI, it was previously showed that neurons produce IL-1beta earlier than do glial cells, and that blocking IL-1 was neuroprotective. To further define the mechanisms whereby IL-1 exerts its neurotoxic effect, we hypothesize that IL-1beta plays a pivotal role in a direct and/or indirect mechanistic loop of neuronal self-injury through matrix metalloproteinase (MMP) 9. METHODS: An established preclinical rat model of LPS+HI-induced neonatal encephalopathy was used. In situ hybridization, ELISA, and immunolabeling techniques were employed. Selective blocking compounds allowed addressing the respective roles of IL-1 and MMP-9. RESULTS: In LPS+HI-exposed forebrains, neuronal IL-1beta was first detected in infarcted neocortical and striatal areas and later in glial cells of the adjacent white matter. Neuronal IL-1beta played a key role: (i) in the early post-HI exacerbation of neuroinflammation and (ii) in generating both core and penumbral infarcted cerebral areas. Systemically administered IL-1 receptor antagonist (IL-1Ra) reached the brain and bound to the neocortical and deep gray neuronal membranes. Then, IL-1Ra down-regulated IL 1beta mRNA and MMP-9 neuronal synthesis. Immediately post-HI, neuronal IL-1beta up-regulated cytokine-induced neutrophil chemoattractant (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and inducible nitric oxide synthase. MMP-9 would disrupt the blood-brain barrier, which, combined to CINC-1 up-regulation, would play a role in polymorphonuclear cell (PMN) infiltration into the LPS+HI exposed brain. IL-1beta blockade prevented PMN infiltration and oriented the phenotype of macrophagic/microglial cells towards anti-inflammatory and neurotrophic M2 profile. IL-1beta increased the expression of activated caspase-3 and of receptor-interacting-protein (RIP)-3 within infarcted forebrain area. Such apoptotic and necroptotic pathway activations were prevented by IL-1Ra, as well as ensuing cerebral palsy-like brain damage and motor impairment. CONCLUSIONS: This work uncovered a new paradigm of neuronal self-injury orchestrated by neuronal synthesis of IL-1beta and MMP-9. In addition, it reinforced the translational neuroprotective potential of IL-1 blockers to alleviate human perinatal brain injuries. PMID- 26025258 TI - Usual interstitial pneumonia end-stage features from explants with radiologic and pathological correlations. AB - Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe idiopathic interstitial pneumonia, with typical high-resolution computed tomography (HRCT) features and histologic pattern of usual interstitial pneumonia (UIP); its main differential diagnosis is fibrotic nonspecific interstitial pneumonia (F-NSIP). Usual interstitial pneumonia was mainly described from lung biopsies, and little is known on explants. Twenty-two UIP/IPF explants were analyzed histologically and compared with previous open lung biopsies (OLBs; n = 11) and HRCT (n = 19), when available. Temporospatial heterogeneity and subpleural and paraseptal fibrosis were similarly found in UIP/IPF explants and OLB (91%-95%). Fibroblastic foci were found in 82% of OLBs and 100% of explants, with a higher mean score in explants (P = .023). Honeycombing was present in 64% of OLBs and 95% of explants, with a higher mean score in explants (P = .005). Almost 60% of UIP/IPF explants showed NSIP areas and 41% peribronchiolar fibrosis; inflammation, bronchiolar metaplasia, and vascular changes were more frequent in UIP/IPF explants; and Desquamative Interstitial Pneumonia (DIP)-like areas were not common (18%-27%). Numerous large airspace enlargements with fibrosis were frequent in UIP/IPF explants (59%). On HRCT, honeycombing was observed in 95% of the cases and ground glass opacities in 53%, correlating with NSIP areas or acute exacerbation at histology. Six patients had combined IPF and emphysema. Lesions were more severe in UIP/IPF explants, reflecting the worsening of the disease. Usual interstitial pneumonia/IPF explants more frequently presented with confounding lesions such as NSIP areas, peribronchiolar fibrosis, and airspace enlargements with fibrosis sometimes associated with emphysema. PMID- 26025260 TI - 2015 American Thoracic Society International Conference. PMID- 26025259 TI - Cost-effectiveness of a multifaceted implementation strategy for the Dutch multidisciplinary guideline for nonspecific low back pain: design of a stepped wedge cluster randomised controlled trial. AB - BACKGROUND: Low back pain (LBP) is one of the most prevalent and expensive health care problems in industrialised countries. LBP leads to high health care utility and productivity losses; leaving the individual, the employer, and society with substantial costs. To improve the care for LBP patients and reduce the high societal and financial burden of LBP, in 2010 the 'Multidisciplinary care guideline for nonspecific low back pain' was developed in the Netherlands. The current paper describes the design of a study aiming to evaluate the (cost-) effectiveness of a multifaceted strategy to implement this guideline. METHODS: In a cluster-randomised controlled trial, the (cost-) effectiveness of a multifaceted implementation strategy will be compared to passive guideline dissemination. Using a stepped-wedge approach, participating general practitioners, physiotherapists, and occupational physicians are allocated into clusters and will attend a multidisciplinary continuing medical education training session. The timing these clusters receive the training is the unit of randomisation. LBP patients visiting the participating health care providers are invited to participate in the trial and will receive access to a multimedia intervention aimed at improving beliefs, cognitions, and self-management. The primary outcome measure of this study is patient back beliefs. Secondary outcome measures on patient level include pain, functional status, quality of life, health care utility, and productivity losses. Outcome measures on professional level include knowledge and attitude towards the guideline, and guideline adherence. A process evaluation for the implementation strategy will be performed among the health care providers and the patients. Furthermore, a qualitative subgroup analysis among patients with various ethnic backgrounds will be performed. DISCUSSION: This study will give insight into the (cost-) effectiveness of a multifaceted implementation strategy for the Dutch multidisciplinary guideline for non-specific back pain to improve outcomes on patient and professional level. The valuable information gained with this study may prove useful for policy-makers, health care providers, and researchers who are in the process of reducing the burden of back pain on individuals and society. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR4329. Registered December 20th, 2013. PMID- 26025261 TI - Seasonal occurrence of antibiotics and a beta agonist in an agriculturally intensive watershed. AB - We evaluated the occurrence of 12 veterinary antibiotics and a beta agonist over spatial and temporal scales in Shell Creek, an intensively agricultural watershed in Nebraska, using Polar Organic Chemical Integrative Samplers (POCIS). Twelve pharmaceuticals were detected with concentrations ranging from 0.0003 ng/L to 68 ng/L. The antibiotics measured at the highest time-weighted average concentrations were lincomycin (68 ng/L) and monensin (49 ng/L), and both compounds were detected at increased concentrations in summer months. Analysis of variance indicates that mean concentrations of detected pharmaceuticals have no significant (p > 0.01) spatial variation. However, significant temporal differences (p < 0.01) were observed. This study demonstrates the utility of passive samplers such as POCIS for monitoring ambient levels of pharmaceuticals in surface waters. PMID- 26025262 TI - Characterization of seed germination, seedling growth, and associated metabolic responses of Brassica juncea L. cultivars to elevated nickel concentrations. AB - Seed germination and seedling growth responses of three Brassica juncea L. cultivars, namely Varuna, Kranti, and Pusa Jai Kisan, to nickel have been characterized. Ni suppressed the seed germination differentially, suppression being greater in cv. Kranti than in others. On the basis of seedling growth performance, cv. Varuna proved most tolerant to Ni. The Ni accumulation in seedlings differed strongly among the three cultivars. The lowest and highest Ni contents were observed in the seedlings of cvs. Kranti and Pusa Jai Kisan, respectively. Despite substantial Ni accumulation, cv. Varuna was most tolerant to Ni. Ni accumulation in seedlings was accompanied by differentially altered Fe and K contents and increased levels of non-protein thiols and free proline. The O2- and H2O2 contents and their respective scavenging enzymes in the seedlings responded differentially to the Ni treatment suggesting the involvement of redox imbalance in the development of Ni toxicity. Interestingly, the greater Ni tolerance of cv. Varuna coincided with the elevated constitutive activities of superoxide dismutase (SOD) and ascorbate peroxidase (APX). The data have implications for seedling establishment under Ni-rich conditions and in turn for phytoremediation. PMID- 26025264 TI - The development of abiraterone acetate for castration-resistant prostate cancer. AB - Abiraterone acetate is a novel CYP17A1 inhibitor demonstrated to prolong survival in castration-resistant prostate cancer (CRPC). This review explores key stages in the almost 20-year history of abiraterone acetate's development, starting with a program aiming to develop inhibitors of androgen synthesis at the Institute of Cancer Research, London. Clinical development was initially slow owing to insufficient data supporting targeting of androgen synthesis as a therapeutic approach in CRPC and safety concerns of adrenocortical insufficiency from suppression of cortisol. Regulatory authorities approved abiraterone acetate in 2011 after a survival benefit was demonstrated when given in combination with prednisone as compared with prednisone alone in docetaxel-treated men. Licensing approval extended to include chemotherapy-naive patients with CRPC in 2012 following a significant increase in radiographic progression-free survival. Ongoing research focuses on identifying predictive biomarkers and understanding mechanisms of resistance to improve its administration. PMID- 26025263 TI - Unique features of myogenesis in Egyptian cobra (Naja haje) (Squamata: Serpentes: Elapidae). AB - During early stages of myotomal myogenesis, the myotome of Egyptian cobra (Naja haje) is composed of homogenous populations of mononucleated primary myotubes. At later developmental phase, primary myotubes are accompanied by closely adhering mononucleated cells. Based on localization and morphology, we assume that mononucleated cells share features with satellite cells involved in muscle growth. An indirect morphological evidence of the fusion of mononucleated cells with myotubes is the presence of numerous vesicles in the subsarcolemmal region of myotubes adjacent to mononucleated cell. As differentiation proceeded, secondary muscle fibres appeared with considerably smaller diameter as compared to primary muscle fibre. Studies on N. haje myotomal myogenesis revealed some unique features of muscle differentiation. TEM analysis showed in the N. haje myotomes two classes of muscle fibres. The first class was characterized by typical for fast muscle fibres regular distribution of myofibrils which fill the whole volume of muscle fibre sarcoplasm. White muscle fibres in studied species were a prominent group of muscles in the myotome. The second class showed tightly paced myofibrils surrounding the centrally located nucleus accompanied by numerous vesicles of different diameter. The sarcoplasm of these cells was characterized by numerous lipid droplets. Based on morphological features, we believe that muscle capable of lipid storage belong to slow muscle fibres and the presence of lipid droplets in the sarcoplasm of these muscles during myogenesis might be a crucial adaptive mechanisms for subsequent hibernation in adults. This phenomenon was, for the first time, described in studies on N. haje myogenesis. PMID- 26025265 TI - How Children Learn Their Mother Tongue: They Don't. AB - A new solution is offered to the Infant Language Acquisition Problem, rejecting both of Chomsky's alternatives. It proposes that the infant does not acquire his mother tongue by mastering its grammar, whether by inference from personal experience or via an innate Language Acquisition Device such as the UG, but that the language he hears is all saved in his extremely plastic and capacious brain, where it is stored in such a way as to organize it while populating it. The brain is thus transformed into a mind by language. Support for this theory is drawn from such topics as feral children and linguistic experiments with bonobos. PMID- 26025266 TI - Willingness of Japanese patients with breast cancer to have genetic testing of BRCA without burden of expenses. AB - BACKGROUND: Genetic analysis for individuals who are at risk for hereditary breast and ovarian cancer syndrome (HBOC) has becoming widely accepted. The poor introduction of the genetic testing of BRCA in Japan compared with western countries could be due to insufficient recognition of its importance, prejudice against a heredity disease, especially in non-urban districts, and its high cost. There is few available data regarding the acceptance or willingness to have genetic testing among Japanese who are at risk and living outside Tokyo. METHODS: Of 670 patients seen and detailed family history taken at our hospital, located non-urban, 30 (4 %) gave the family history of breast cancer in more than 2 members within the second degree relatives ("stronger" family history group), 92 (14 %) in 1 member ("weaker" group), and 548 (82 %) in none of members ("sporadic" group). Then, we selected 107 (24 from "stronger", 50 from "weaker", 33 from "sporadic" family history group) to see if they are willing to receive cost-free genetic testing of BRCA 1 and BRCA2. RESULTS: Ninety-two of 107 (86 %) patients agreed and 15 (14 %) refused. The rate of refusal for BRCA testing was higher in "stronger family history group" (6/24, 25 %) compared to "weaker" (7/50, 14 %) or "sporadic" (2/33, 6 %) (p = 0.04), respectively. CONCLUSIONS: These data indicate that the currently available preventive measures and/or counseling system may not be sufficient enough to convince the high risk population to receive the genetic testing or to overcome the prejudice in non urban area in Japan, even if served free. PMID- 26025267 TI - Isolation and characterization of tick-borne encephalitis virus from Ixodes persulcatus in Mongolia in 2012. AB - Tick-borne encephalitis virus (TBEV) is a zoonotic virus belonging to the genus Flavivirus, in the family Flaviviridae. The virus, which is endemic in Europe and northern parts of Asia, causes severe encephalitis. Tick-borne encephalitis (TBE) has been reported in Mongolia since the 1980s, but details about the biological characteristics of the endemic virus are lacking. In this study, 680 ticks (Ixodes persulcatus) were collected in Selenge aimag, northern Mongolia, in 2012. Nine Mongolian TBEV strains were isolated from tick homogenates. A sequence analysis of the envelope protein gene revealed that all isolates belonged to the Siberian subtype of TBEV. Two strains showed similar growth properties in cultured cells, but their virulence in mice differed. Whole genome sequencing revealed only thirteen amino acid differences between these Mongolian TBEV strains. Our results suggest that these naturally occurring amino acid mutations affected the pathogenicity of Mongolian TBEV. Our results may be an important platform for monitoring TBEV to evaluate the epidemiological risk in TBE endemic areas of Mongolia. PMID- 26025268 TI - Climate change influences on the annual onset of Lyme disease in the United States. AB - Lyme disease is the most commonly reported vector-borne illness in the United States. Lyme disease occurrence is highly seasonal and the annual springtime onset of cases is modulated by meteorological conditions in preceding months. A meteorological-based empirical model for Lyme disease onset week in the United States is driven with downscaled simulations from five global climate models and four greenhouse gas emissions scenarios to project the impacts of 21st century climate change on the annual onset week of Lyme disease. Projections are made individually and collectively for the 12 eastern States where >90% of cases occur. The national average annual onset week of Lyme disease is projected to become 0.4-0.5 weeks earlier for 2025-2040 (p<0.05), and 0.7-1.9 weeks earlier for 2065-2080 (p<0.01), with the largest shifts for scenarios with the highest greenhouse gas emissions. The more southerly mid-Atlantic States exhibit larger shifts (1.0-3.5 weeks) compared to the Northeastern and upper Midwestern States (0.2-2.3 weeks) by 2065-2080. Winter and spring temperature increases primarily cause the earlier onset. Greater spring precipitation and changes in humidity partially counteract the temperature effects. The model does not account for the possibility that abrupt shifts in the life cycle of Ixodes scapularis, the primary vector of the Lyme disease spirochete Borrelia burgdorferi in the eastern United States, may alter the disease transmission cycle in unforeseen ways. The results suggest 21st century climate change will make environmental conditions suitable for earlier annual onset of Lyme disease cases in the United States with possible implications for the timing of public health interventions. PMID- 26025270 TI - Neonatal Infant Pain Scale: Cross-Cultural Adaptation and Validation in Brazil. AB - CONTEXT: The Neonatal Infant Pain Scale (NIPS), initially developed in Canada, has been previously used but not adequately adapted and validated for use in Brazil. OBJECTIVES: The goal of the present study was to perform a cross-cultural adaptation and clinical validation of the NIPS for use in the Brazilian population. METHODS: The instrument was adapted based on the method outlined by Beaton et al., including the production and combination of translated versions, back-translation, committee review, and pilot testing. The psychometric properties of the adapted instrument, including its validity, reliability, and internal consistency, were tested in a clinical validation study. The sample comprised 60 at-term newborns who were evaluated by six nurses as they experienced vaccination. Psychometric properties were evaluated using Student's t tests, prevalence-adjusted and bias-adjusted kappa scores, the Bland-Altman method, and Cronbach's alpha coefficients. RESULTS: The Brazilian version of the NIPS (Escala de Dor no Recem-Nascido [NIPS-Brazil]) demonstrated excellent interobserver and intraobserver reliability. Total NIPS-Brazil scores yielded prevalence-adjusted and bias-adjusted kappa scores of 0.93, whereas the Bland Altman method revealed interobserver and intraobserver reliability values of 95% and 90%, respectively. The NIPS-Brazil had adequate internal consistency, as evidenced by a Cronbach's alpha of 0.762. CONCLUSION: The NIPS was successfully adapted for use in Brazil and is now available for use in the assessment of acute pain in at-term newborns in Brazil. PMID- 26025272 TI - Association Between "Good Death" of Cancer Patients and Post-Traumatic Growth in Bereaved Caregivers. PMID- 26025269 TI - Tick-borne encephalitis as a notifiable disease--Status quo and the way forward. Report of the 17th annual meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). AB - The 17th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE), a group of neurologists, general practicioners, clinicians, travel physicians, virologists, pediatricians, and epidemiologists, was held under the title "Tick-borne encephalitis as a notifiable disease--status quo and the way forward". The conference agenda was divided into three parts on the first day: "Epidemiology & Risk areas", "Poster Walk: Epidemiological Update in Europe", and "News in TBE Research". On the second day, a World Cafe Working Session took place where the participants could choose three tables out of six to join for discussion. Key topics on current epidemiological developments and investigations, risk areas, cases, travel and mobility, TBE in children, vaccination rates, and latest news on vaccination were presented and extensively discussed. PMID- 26025271 TI - Religion, Spirituality, and the Hidden Curriculum: Medical Student and Faculty Reflections. AB - CONTEXT: Religion and spirituality play an important role in physicians' medical practice, but little research has examined their influence within the socialization of medical trainees and the hidden curriculum. OBJECTIVES: The objective is to explore the role of religion and spirituality as they intersect with aspects of medicine's hidden curriculum. METHODS: Semiscripted, one-on-one interviews and focus groups (n = 33 respondents) were conducted to assess Harvard Medical School student and faculty experiences of religion/spirituality and the professionalization process during medical training. Using grounded theory, theme extraction was performed with interdisciplinary input (medicine, sociology, and theology), yielding a high inter-rater reliability score (kappa = 0.75). RESULTS: Three domains emerged where religion and spirituality appear as a factor in medical training. First, religion/spirituality may present unique challenges and benefits in relation to the hidden curriculum. Religious/spiritual respondents more often reported to struggle with issues of personal identity, increased self doubt, and perceived medical knowledge inadequacy. However, religious/spiritual participants less often described relationship conflicts within the medical team, work-life imbalance, and emotional stress arising from patient suffering. Second, religion/spirituality may influence coping strategies during encounters with patient suffering. Religious/spiritual trainees described using prayer, faith, and compassion as means for coping whereas nonreligious/nonspiritual trainees discussed compartmentalization and emotional repression. Third, levels of religion/spirituality appear to fluctuate in relation to medical training, with many trainees experiencing an increase in religiousness/spirituality during training. CONCLUSION: Religion/spirituality has a largely unstudied but possibly influential role in medical student socialization. Future study is needed to characterize its function within the hidden curriculum. PMID- 26025273 TI - Palliative Care Medical Education in European Universities: A Descriptive Study and Numerical Scoring System Proposal for Assessing Educational Development. AB - CONTEXT: The lack of palliative medicine (PM) education has been identified as a barrier to the development of the discipline. A number of international institutions have called for its implementation within undergraduate medical curricula. OBJECTIVES: The objectives are to describe the situation of undergraduate PM education in Europe and to propose a scoring system to evaluate its status. METHODS: This descriptive study was conducted with data provided by key experts from countries of the World Health Organization European Region (n = 53). A numerical scoring system was developed through consensus techniques. RESULTS: Forty-three countries (81%) provided the requested information. In 13 countries (30%), a PM course is taught in all medical schools, being compulsory in six of them (14%). In 15 countries (35%), PM is taught in at least one university. In 14 countries (33%), PM is not taught within medical curricula. A full professor of PM was identified in 40% of countries. Three indicators were developed to construct a scale (rank 0-100) of educational development: 1) proportion of medical schools that teach PM (weight = 32%); 2) proportion of medical schools that offer PM as a compulsory subject (weight = 40%); 3) total number of PM professors (weight = 28%). The highest level of PM educational development was found in Israel, Norway, the U.K., Belgium, France, Austria, Germany, and Ireland. CONCLUSION: PM is taught in a substantial number of undergraduate medical programs at European universities, and a qualified teaching structure is emerging; however, there is a wide variation in the level of PM educational development between individual countries. PMID- 26025274 TI - Goal Communication in Palliative Care Decision-Making Consultations. AB - CONTEXT: Palliative care (PC) promotes patient-centered outcomes, but the mechanisms underlying these effects remain poorly understood. Identifying, clarifying, and prioritizing patients' goals are conceptually fundamental to the process of patient-centeredness and are the main reasons for PC referral. However, very little is empirically known about the content or process of goal expression in the natural setting of PC. OBJECTIVES: To describe the frequency, types, and determinants of goal expression in PC consultations. METHODS: This was a cross-sectional direct observational study of 72 audiorecorded PC consultations with hospitalized patients (and families) referred for PC goals of care clarification or end-of-life decision making. We coded digital audio files using reliable methods and linked conversation codes to clinical record and brief clinician interview data. RESULTS: Goal expressions occurred frequently in PC consultations and addressed both length-of-life and quality-of-life domains. The presence of existential suffering in the conversation was associated with substantially more expressions and types of goals. CONCLUSION: Goal communication is common in PC decision-making settings and strongly influenced by existential suffering. PMID- 26025275 TI - Medical Oncology Patients: Are They Offered Help and Does It Provide Relief? AB - CONTEXT: Identifying modifiable gaps in the symptom management pathway, as perceived by patients, is the first step to relieving patient suffering. OBJECTIVES: The objective is to describe the proportion of patients experiencing treatable cancer-related symptoms who reported 1) a health care provider at the treatment center offered assistance for their symptom, 2) they accepted the assistance offered, and 3) the assistance relieved suffering. Variation in symptom management among treatment centers also was examined. METHODS: A survey was done with 528 medical oncology outpatients recruited from six treatment centers. Eight items explored management of prevalent, burdensome, and treatable cancer-related symptoms: pain, fatigue, other physical side effects, and emotional distress. Participants were asked about symptom management provided at the clinic from where they were recruited. Questions referred to the last occasion the patient experienced the symptom. RESULTS: Fewer patients were offered help to relieve fatigue (44%) and emotional distress (57%), than pain (90%) and other physical side effects (84%). In most cases, help was not offered as clinic staff were not aware of the patient's symptom. Although the vast majority of patients accepted the help that was offered, more patients accepted help for physical symptoms (pain, 97%; fatigue, 95%; and other side effects, 98%) than emotional symptoms (87%). When care was provided, most patients experienced at least a little relief from pain (99%), fatigue (94%), and emotional distress (96%). Symptom management did not vary significantly by treatment center (P = 0.073). CONCLUSION: Quality improvement initiatives must focus primarily on improving providers' awareness of their patients' symptoms and ensuring that patients are subsequently offered help. PMID- 26025276 TI - Recommendations to Surrogates at the End of Life: A Critical Narrative Review of the Empirical Literature and a Normative Analysis. AB - Physician recommendations have historically been a part of shared decision making. Recent literature has challenged the idea that physician recommendations should be part of shared decision making at the end of life, particularly the making of recommendations to surrogates of incapacitated patients. Close examination of the studies and the available data on surrogate preferences for decisional authority at the end of life, however, provide an empirical foundation for a style of shared decision making that includes a physician recommendation. Moreover, there are independent ethical reasons for arguing that physician recommendations enhance rather than detract from shared decision making. PMID- 26025277 TI - Hospice and Palliative Medicine Clinician Views of Deactivation of Ventricular Assist Devices at the End of Life. PMID- 26025278 TI - "The Patient Is Dying, Please Call the Chaplain": The Activities of Chaplains in One Medical Center's Intensive Care Units. AB - CONTEXT: Patients and families commonly experience spiritual stress during an intensive care unit (ICU) admission. Although most patients report that they want spiritual support, little is known about how these issues are addressed by hospital chaplains. OBJECTIVES: To describe the prevalence, timing, and nature of hospital chaplain encounters in ICUs. METHODS: This was a retrospective cross sectional study of adult ICUs at an academic medical center. Measures included days from ICU admission to initial chaplain visit, days from chaplain visit to ICU death or discharge, hospital and ICU lengths of stay, severity of illness at ICU admission and chaplain visit, and chart documentation of chaplain communication with the ICU team. RESULTS: Of a total of 4169 ICU admissions over six months, 248 (5.9%) patients were seen by chaplains. Of the 246 patients who died in an ICU, 197 (80%) were seen by a chaplain. There was a median of two days from ICU admission to chaplain encounter and a median of one day from chaplain encounter to ICU discharge or death. Chaplains communicated with nurses after 141 encounters (56.9%) but with physicians after only 14 encounters (5.6%); there was no documented communication in 55 encounters (22%). CONCLUSION: In the ICUs at this tertiary medical center, chaplain visits are uncommon and generally occur just before death among ICU patients. Communication between chaplains and physicians is rare. Chaplaincy service is primarily reserved for dying patients and their family members rather than providing proactive spiritual support. These observations highlight the need to better understand challenges and barriers to optimal chaplain involvement in ICU patient care. PMID- 26025279 TI - A Pilot Study of a Mobile Health Pain Coping Skills Training Protocol for Patients With Persistent Cancer Pain. AB - CONTEXT: Pain coping skills training (PCST) interventions have shown efficacy for reducing pain and providing other benefits in patients with cancer. However, their reach is often limited because of a variety of barriers (e.g., travel, physical burden, cost, time). OBJECTIVES: This study examined the feasibility and acceptability of a brief PCST intervention delivered to patients in their homes using mobile health (mHealth) technology. Pre-to-post intervention changes in pain, physical functioning, physical symptoms, psychological distress, self efficacy for pain management, and pain catastrophizing also were examined. METHODS: Patients with a diagnosis of breast, lung, prostate, or colorectal cancer who reported persistent pain (N = 25) participated in a four-session intervention delivered using mHealth technology (videoconferencing on a tablet computer). Participants completed measures of pain, physical functioning, physical symptoms, psychological distress, self-efficacy for pain management, and pain catastrophizing. We also assessed patient satisfaction. RESULTS: Participants completed an average of 3.36 (SD = 1.11) of the four intervention sessions for an overall session completion rate of 84%. Participants reported that the program was of excellent quality and met their needs. Significant preintervention to postintervention differences were found in pain, physical symptoms, psychological distress, and pain catastrophizing. CONCLUSION: The use of mHealth technology is a feasible and acceptable option for delivery of PCST for patients with cancer. This delivery mode is likely to dramatically increase intervention access for cancer patients with pain compared to traditional in person delivery. Preliminary data also suggest that the program is likely to produce pretreatment to post-treatment decreases in pain and other important outcomes. PMID- 26025280 TI - Accuracy of a Diagnostic Algorithm to Diagnose Breakthrough Cancer Pain as Compared With Clinical Assessment. AB - CONTEXT: Breakthrough cancer pain (BTCP) is a heterogeneous condition, and there are no internationally agreed standardized criteria to diagnose it. There are published algorithms to assist with diagnosis, but these differ in content. There are no comparative data to support use. OBJECTIVES: To compare the diagnostic ability of a simple algorithm against a comprehensive clinical assessment to diagnose BTCP and to assess if verbal rating descriptors can adequately discriminate controlled background pain. METHODS: Patients with cancer pain completed a three-step algorithm with a researcher to determine if they had controlled background pain and BTCP. This was followed by a detailed pain consultation with a clinical specialist who was blinded to the algorithm results and determined an independent pain diagnosis. The sensitivity, specificity, and positive and negative predictive values were calculated for the condition of BTCP. Further analysis determined which verbal pain severity descriptors corresponded with the condition of controlled background pain. RESULTS: The algorithm had a sensitivity of 0.54 and a specificity of 0.76 in the identification of BTCP. The positive predictive value was 0.7, and the negative predictive value was 0.62. The sensitivity of a background pain severity rating of mild or less to accurately categorize controlled background pain was 0.69 compared with 0.97 for severity of moderate or less; however, this was balanced by a higher specificity rating for mild or less, 0.78 compared with 0.2. CONCLUSION: The diagnostic breakthrough pain algorithm had a good positive predictive value but limited sensitivity using a cutoff score of "mild" to define controlled background pain. When the cutoff level was changed to moderate, the sensitivity increased, but specificity reduced. A comprehensive clinical assessment remains the preferred method to diagnose BTCP. PMID- 26025281 TI - Contribution of epigenetics in diabetic retinopathy. AB - Diabetes has become the epidemic of the 21st century, and with over 90% patients with diabetes becoming at a risk of developing retinopathy, diabetic retinopathy has emerged as a major public health concern. In spite of cutting edge research in the field, how retina and its vasculature are damaged by the diabetic milieu remains ambiguous. The environmental factors, life style or disease process can also bring in modifications in the DNA, and these epigenetic modifications either silence or activate a gene without altering the DNA sequence. Diabetic environment up- or downregulates a number of genes in the retina, and emerging research has shown that it also facilitates epigenetic modifications. In the pathogenesis of diabetic retinopathy, the genes associated with important enzymes (e.g., mitochondrial superoxide dismutase, matrix metalloproteinase-9 and thioredoxin interacting protein) and transcriptional factors are epigenetically modified, the enzymes responsible for these epigenetic modifications are either activated or inhibited, and the levels of microRNAs are altered. With epigenetic modifications taking an important place in diabetic retinopathy, it is now becoming critical to evaluate these modifications, and understand their impact on this slow progressing blinding disease. PMID- 26025282 TI - Innovative and propagable translational research model established for cell-based therapy at Chinese PLA General Hospital. PMID- 26025283 TI - Prostate cancer identification: quantitative analysis of T2-weighted MR images based on a back propagation artificial neural network model. AB - Computer-aided diagnosis (CAD) systems have been proposed to assist radiologists in making diagnostic decisions by providing helpful information. As one of the most important sequences in prostate magnetic resonance imaging (MRI), image features from T2-weighted images (T2WI) were extracted and evaluated for the diagnostic performances by using CAD. We extracted 12 quantitative image features from prostate T2-weighted MR images. The importance of each feature in cancer identification was compared in the peripheral zone (PZ) and central gland (CG), respectively. The performance of the computer-aided diagnosis system supported by an artificial neural network was tested. With computer-aided analysis of T2 weighted images, many characteristic features with different diagnostic capabilities can be extracted. We discovered most of the features (10/12) had significant difference (P<0.01) between PCa and non-PCa in the PZ, while only five features (sum average, minimum value, standard deviation, 10th percentile, and entropy) had significant difference in CG. CAD prediction by features from T2w images can reach high accuracy and specificity while maintaining acceptable sensitivity. The outcome is convictive and helpful in medical diagnosis. PMID- 26025284 TI - Health effects of fine particles (PM2.5) in ambient air. PMID- 26025285 TI - [Unilateral pleural effusion caused by vessel perforation due to peripherally inserted central catheter: Indocyanine green as a diagnostic tool]. AB - A peripherally inserted central catheter (PICC) was inserted into a 44-year-old man to provide parenteral nutrition in a protein-calorie malnutrition secondary to a benign pyloric stenosis. On the fifth day while monitoring the catheter, the patient presented with a massive whitish pleural effusion after undergoing gastric endoscopy in order to treat pyloric stenosis. Chylothorax was initially suspected, and the patient was admitted to a recovery unit. Indocyanine green was administered through the PICC, obtaining a greenish discoloration in the pleural effusion 30 min later. This led to the diagnosis of a pleural effusion caused by a vessel perforation due to the PICC, leading to parenteral nutrition extravasation. Thoraco-abdominal computed tomography was performed, which confirmed an innominate vein perforation due to the PICC. PICC insertion may be associated with severe complications, such as central vessel perforation, and therefore the correct position of a central catheter should be always checked. Intravenous computed tomography contrast is the gold standard for central vascular perforation diagnosis. However if a pleural effusion occurs in this context, it is possible to use a dye, which administered intravenously can lead us to the correct diagnosis in situ. Indocyanine green was used for this purpose in this case. PMID- 26025286 TI - [Ischemic stroke in childhood. A complication of tonsillectomy]. AB - Tonsillectomy is one of the most frequently performed otorhinolaryngological procedures on children. The postoperative complications are classified into primary or intermediate, which generally appear within 24h, and as secondary or delayed, after 48 h. We present the case of an ischemic stroke after performing a tonsillectomy on a 3 year-old boy, which was diagnosed in the immediate postoperative period. Using brain echo-doppler and angio-CT, an intraluminal clot was observed in the left internal carotid artery, probably as a result of direct vessel injury during arterial ligature for hemostasis. PMID- 26025287 TI - Magnesium sulphate and (123)I-MIBG in pheochromocytoma: Two useful techniques for a complicated disease. AB - Pheochromocytoma is a tumour of the chromaffin tissue. It may, through catecholamine release, have deleterious effects on myocardial structure. A 48 year-old woman with a history of hypertension and type II diabetes mellitus (ASA II) was diagnosed of pheochromocytoma-induced myocarditis, which caused severe cardiogenic shock, with an ejection fraction of 20%. Extreme blood pressure swings required aggressive therapy with vasoactive drugs (norepinephrine and dopamine) and an intra-aortic balloon pump, despite which severe haemodynamic instability persisted. Finally, the use of magnesium sulphate allowed for cardiovascular stabilization and weaning off vasoactive drugs prior to surgery. (123)I-metaiodobenzylguanidine scintigraphy helps not only to functionally confirm tumour tissue, but also to assess severity and prognosis of cardiac failure. Prognosis of pheochromocytoma-induced heart failure can be very poor. The use of these two well-known and relatively simple 'tools' for treatment and prognosis is a helpful option to keep in mind. PMID- 26025288 TI - Osteosarcopenic obesity is associated with reduced handgrip strength, walking abilities, and balance in postmenopausal women. AB - We determined the prevalence of osteosarcopenic obesity (loss of bone and muscle coexistent with increased adiposity) in overweight/obese postmenopausal women and compared their functionality to obese-only women. Results showed that osteosarcopenic obese women were outperformed by obese-only women in handgrip strength and walking/balance abilities indicating their higher risk for mobility impairments. INTRODUCTION: Osteosarcopenic obesity (OSO) is a recently defined triad of osteopenia/osteoporosis, sarcopenia, and adiposity. We identified women with OSO in overweight/obese postmenopausal women and evaluated their functionality comparing them with obese-only (OB) women. Additionally, women with osteopenic/osteoporotic obesity (OO), but no sarcopenia, and those with sarcopenic obesity (SO), but no osteopenia/osteoporosis, were identified and compared. We hypothesized that OSO women will have the lowest scores for each of the functionality measures. METHODS: Participants (n = 258; % body fat >=35) were assessed using a Lunar iDXA instrument for bone and body composition. Sarcopenia was determined from negative residuals of linear regression modeled on appendicular lean mass, height, and body fat, using 20th percentile as a cutoff. Participants with T-scores of L1-L4 vertebrae and/or total femur <-1, but without sarcopenia, were identified as OO (n = 99) and those with normal T-scores, but with sarcopenia, as SO (n = 28). OSO (n = 32) included women with both osteopenia/osteoporosis and sarcopenia, while those with normal bone and no sarcopenia were classified as OB (n = 99). Functionality measures such as handgrip strength, normal/brisk walking speed, and right/left leg stance were evaluated and compared among groups. RESULTS: Women with OSO presented with the lowest handgrip scores, slowest normal and brisk walking speed, and shortest time for each leg stance, but these results were statistically significantly different only from the OB group. CONCLUSION: These findings indicate a poorer functionality in women presenting with OSO, particularly compared to OB women, increasing the risk for bone fractures and immobility from the combined decline in bone and muscle mass, and increased fat mass. PMID- 26025289 TI - Multi-resolution statistical analysis of brain connectivity graphs in preclinical Alzheimer's disease. AB - There is significant interest, both from basic and applied research perspectives, in understanding how structural/functional connectivity changes can explain behavioral symptoms and predict decline in neurodegenerative diseases such as Alzheimer's disease (AD). The first step in most such analyses is to encode the connectivity information as a graph; then, one may perform statistical inference on various 'global' graph theoretic summary measures (e.g., modularity, graph diameter) and/or at the level of individual edges (or connections). For AD in particular, clear differences in connectivity at the dementia stage of the disease (relative to healthy controls) have been identified. Despite such findings, AD-related connectivity changes in preclinical disease remain poorly characterized. Such preclinical datasets are typically smaller and group differences are weaker. In this paper, we propose a new multi-resolution method for performing statistical analysis of connectivity networks/graphs derived from neuroimaging data. At the high level, the method occupies the middle ground between the two contrasts - that is, to analyze global graph summary measures (global) or connectivity strengths or correlations for individual edges similar to voxel based analysis (local). Instead, our strategy derives a Wavelet representation at each primitive (connection edge) which captures the graph context at multiple resolutions. We provide extensive empirical evidence of how this framework offers improved statistical power by analyzing two distinct AD datasets. Here, connectivity is derived from diffusion tensor magnetic resonance images by running a tractography routine. We first present results showing significant connectivity differences between AD patients and controls that were not evident using standard approaches. Later, we show results on populations that are not diagnosed with AD but have a positive family history risk of AD where our algorithm helps in identifying potentially subtle differences between patient groups. We also give an easy to deploy open source implementation of the algorithm for use within studies of connectivity in AD and other neurodegenerative disorders. PMID- 26025291 TI - Measuring directionality between neuronal oscillations of different frequencies. AB - It is well established that neuronal oscillations at different frequencies interact with each other in terms of cross-frequency coupling (CFC). In particular, the phase of slower oscillations modulates the power of faster oscillations. This is referred to as phase-amplitude coupling (PAC). Examples are alpha phase to gamma power coupling as observed in humans and theta phase to gamma power coupling as observed in the rat hippocampus. We here ask if the interaction between alpha and gamma oscillations is in the direction of the phase of slower oscillations driving the power of faster oscillations or conversely from the power of faster oscillations driving the phase of slower oscillations. To answer this question, we introduce a new measure to estimate the cross frequency directionality (CFD). This measure is based on the phase-slope index (PSI) between the phase of slower oscillations and the power envelope of faster oscillations. Further, we propose a randomization framework for statistically evaluating the coupling measures when controlling for multiple comparisons over the investigated frequency ranges. The method was firstly validated on simulated data and next applied to resting state electrocorticography (ECoG) data. These results demonstrate that the method works reliably. In particular, we found that the power envelope of gamma oscillations drives the phase of slower oscillations in the alpha band. This surprising finding is not easily reconcilable with theories suggesting that feedback controlled alpha oscillations modulate feedforward processing reflected in the gamma band. PMID- 26025290 TI - Decoupling of structural and functional brain connectivity in older adults with white matter hyperintensities. AB - Age-related impairments in the default network (DN) have been related to disruptions in connecting white matter tracts. We hypothesized that the local correlation between DN structural and functional connectivity is negatively affected in the presence of global white matter injury. In 125 clinically normal older adults, we tested whether the relationship between structural connectivity (via diffusion imaging tractography) and functional connectivity (via resting state functional MRI) of the posterior cingulate cortex (PCC) and medial prefrontal frontal cortex (MPFC) of the DN was altered in the presence of white matter hyperintensities (WMH). A significant correlation was observed between microstructural properties of the cingulum bundle and MPFC-PCC functional connectivity in individuals with low WMH load, but not with high WMH load. No correlation was observed between PCC-MPFC functional connectivity and microstructure of the inferior longitudinal fasciculus, a tract not passing through the PCC or MPFC. Decoupling of connectivity, measured as the absolute difference between structural and functional connectivity, in the high WMH group was related to poorer executive functioning and memory performance. These results suggest that such decoupling may reflect reorganization of functional networks in response to global white matter pathology and may provide an early marker of clinically relevant network alterations. PMID- 26025292 TI - FVGWAS: Fast voxelwise genome wide association analysis of large-scale imaging genetic data. AB - More and more large-scale imaging genetic studies are being widely conducted to collect a rich set of imaging, genetic, and clinical data to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. Several major big-data challenges arise from testing genome-wide (NC>12 million known variants) associations with signals at millions of locations (NV~10(6)) in the brain from thousands of subjects (n~10(3)). The aim of this paper is to develop a Fast Voxelwise Genome Wide Association analysiS (FVGWAS) framework to efficiently carry out whole-genome analyses of whole-brain data. FVGWAS consists of three components including a heteroscedastic linear model, a global sure independence screening (GSIS) procedure, and a detection procedure based on wild bootstrap methods. Specifically, for standard linear association, the computational complexity is O (nNVNC) for voxelwise genome wide association analysis (VGWAS) method compared with O ((NC+NV)n(2)) for FVGWAS. Simulation studies show that FVGWAS is an efficient method of searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. Finally, we have successfully applied FVGWAS to a large-scale imaging genetic data analysis of ADNI data with 708 subjects, 193,275voxels in RAVENS maps, and 501,584 SNPs, and the total processing time was 203,645s for a single CPU. Our FVGWAS may be a valuable statistical toolbox for large-scale imaging genetic analysis as the field is rapidly advancing with ultra-high-resolution imaging and whole-genome sequencing. PMID- 26025293 TI - Chorioamniotic membrane senescence: a signal for parturition? AB - OBJECTIVE: Senescence is an important biological phenomenon involved in both physiologic and pathologic processes. We propose that chorioamniotic membrane senescence is a mechanism associated with human parturition. The present study was conducted to explore the association between senescence and normal term parturition by examining the morphologic and biochemical evidences in chorioamniotic membranes. STUDY DESIGN: Chorioamniotic membranes were collected from normal term deliveries; group 1: term labor and group 2: term, not in labor. Senescence-related morphologic changes were determined by transmission electron microscopy and biochemical changes were studied by senescence-associated (SA) beta-galactosidase staining. Amniotic fluid samples collected from both term labor and term not in labor were analyzed for 14 SA secretory phenotype (SASP) markers. RESULTS: Morphologic evidence of cellular senescence (enlarged cells and organelles) and a higher number of SA beta-galactosidase-stained amnion and chorion cells were observed in chorioamniotic membranes obtained from women in labor at term, when compared to term not in labor. The concentration of proinflammatory SASP markers (granulocyte macrophage colony-stimulating factor, interleukin-6 and -8) was significantly higher in the amniotic fluid of women in labor at term than women not in labor. In contrast, SASP factors that protect against cell death (eotaxin-1, soluble Fas ligand, osteoprotegerin, and intercellular adhesion molecule-1) were significantly lower in the amniotic fluid samples from term labor. CONCLUSION: Morphologic and biochemical features of senescence were more frequent in chorioamniotic membranes from women who experienced term labor. Senescence of chorioamniotic membranes were also associated with amniotic fluid SASP markers. PMID- 26025294 TI - Knowledge and use of wild edible plants in rural communities along Paraguay River, Pantanal, Brazil. AB - BACKGROUND: Wild plants are used as food for human populations where people still depend on natural resources to survive. This study aimed at identifying wild plants and edible uses known in four rural communities of the Pantanal-Brazil, estimating the use value and understanding how distance to the urban areas, gender, age and number of different environments available in the vicinity can influence the knowledge and use of these plants by local people. METHODS: Data on edible plants with known uses by communities were obtained through semi structured interviews. A form with standardized information was used for all communities in order to obtain comparable data for analysis. For the quantitative analysis of the factors that could influence the number of species known by the population, a generalized linear model (GLM) was conducted using a negative binomial distribution as the data consisted of counts (number of citations). RESULTS: A total of 54 wild species were identified with food uses, included in 44 genera and 30 families of angiosperms. Besides food use, the species are also known as medicine, bait, construction, technology and other. The species with the highest use value was Acrocomia aculeata. Older people, aged more than 60 years, and those living in more remote communities farther from cities know more wild edible plants. Statistical analysis showed no difference regarding gender or number of vegetation types available in the vicinity and the number of plants known by locals. CONCLUSION: This study indicated more knowledge retained in communities more distant from the urban area, indifference in distribution of knowledge between genders and the higher cultural competence of elderly people in respect to knowledge of wild edible botanicals. PMID- 26025295 TI - Isomer-specific investigation of PCDD/F mobility and other fate processes in deep soil cores. AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) are highly hydrophobic compounds with low migration potential in soil-water. Nevertheless, they have been occasionally reported in subsurface soils hypothesised as the result of facilitated transport processes with colloids or surfactants, or yet unidentified in-situ formation processes. To date, however, the prevalence of deep soil contamination, involved processes and their kinetics remain poorly understood. This study investigated PCDD/F concentrations and isomer profiles through deep soil cores (to 20 m) from agricultural, industrial and urban sites in Queensland, Australia. Based on isomer profiles, a unique source common to all core soils (regardless of depth) was identified, dominated by octachlorodibenzo-p dioxin (OCDD). The source was consistent with contamination resulting from pesticide impurities. Elevated PCDD concentrations (MUg/kg range) to depths up to ~4-17 m and a continuous increase of peri-chlorinated (1,4,6,9-substituted) isomers through the cores suggested that vertical transport and lateral dechlorination were key post-depositional processes at these sites. The mobility of PCDDs in the present study is far greater than previously reported in soils in general. High estimated mass transport rates for OCDD in four agricultural cores (3.0-6.2% year(-1)) likely reflect significant levels of facilitating species, including surfactants, and intensive rainfall at these sites. The implications of such extensive subsurface transport of PCDD/Fs for groundwater contamination and load estimates may be significant. If the cores of the present study are assumed representative of the region, a total PCDD/F load in the order of 800 tonnes (1.6 tonnes TEQ) could be present in subsurface Queensland coastal soils. PMID- 26025296 TI - [In Process Citation]. PMID- 26025297 TI - [Fiberless miniature chandelier LED endoilluminator for pars plana vitrectomy]. AB - BACKGROUND: Currently available chandelier endoilluminators for pars plana vitrectomy consist of conventional optical fibers coupled to a light source. The light probes of these fibers now provide wide emittance angles but it is still often not possible to illuminate the whole intraocular space via just one incision. Therefore, several light probes or additional handheld endoilluminators have to be used simultaneously or the lights have to be repositioned during surgery. OBJECTIVE: The presented prototype of a fiberless chandelier light emitting diode (LED) endoilluminator aims at illuminating the whole intraocular space with just one incision while reducing the risk of harming the retina. MATERIAL AND METHODS: The light source is a white LED with a conical tip that allows stable fixation within an incision. The physical properties of these LEDs were determined and used for calculating the relevant irradiance to assess the risk of causing harm to the eye. The illumination of the intraocular space was investigated using porcine eyes. RESULTS: The illumination of porcine eyes with the modified LEDs was bright and homogeneous. Measurements and subsequent calculations proved that the expected thermal load and photochemical hazard were very low for human eyes. CONCLUSION: The hitherto existing experimental results on porcine eyes and the theoretical considerations on human eyes were found to be positive; therefore, it is expected that this new fiberless chandelier LED endoilluminator will prove to be advantageous for human patients. It promises a reduced number of incisions with a simplified handling and need to add handheld light sources only if minimal intensity oblique illumination is helpful together with the chandelier illumination. This contributes to a significant reduction of phototoxicity risks and additionally there is a chance for a cost reduction because expensive xenon or mercury lamps are no longer necessary. These expectations have to be verified by further studies on human eyes. PMID- 26025299 TI - HIV-associated lymphoma sub-type distribution, immunophenotypes and survival in an urban clinic population. AB - HIV-infected patients have an increased risk for both Hodgkin and non-Hodgkin lymphomas. A retrospective cohort of all HIV-infected patients diagnosed with lymphoma in urban clinics from 2000-2013 was evaluated to characterize the distribution and determine effects of sub-type and immunophenotype on survival. Of 160 cases identified, 131 (82%) had complete information and were analyzed. The most common sub-types were diffuse large B cell (41%), Burkitt (21%) and Hodgkin lymphoma (18%). Advanced (78% stage III/IV) and extranodal disease (82%) at presentation were common. CD20 was the most commonly expressed immunophenotypic marker (89%). Overall mortality rate was high (26.1 per 100 person-years). Lower mortality was noted in CD10 + and CD20 + lymphomas, but differences were not statistically significant. After adjustment, low CD4 count (<= 200) at diagnosis was associated with higher mortality (adjusted hazard ration (AHR) = 1.75; 95% CI = 1.00-3.61). Mortality in this cohort of patients with HIV-associated lymphomas was high and exceeds that from published data from the general population. PMID- 26025298 TI - [Influence of 20 % sulfur hexafluoride (SF6) on human corneal endothelial cells : An in vitro study]. AB - BACKGROUND: In posterior lamellar keratoplasties, such as Descemet membrane endothelial keratoplasty (DMEK) and Descemet's stripping automated endothelial keratoplasty (DSAEK) an air bubble is left inside the anterior chamber to promote graft attachment during the early postoperative period. In the case of insufficient graft adhesion a renewed intracameral air injection is often necessary. The use of sulfur hexafluoride diluted with air (SF6 20 %) as an alternative to pure air may further enhance graft attachment and reduce the rebubbling rate. The effect of SF6 20 % on corneal endothelium is currently unclear and was therefore examined in vitro. MATERIAL AND METHODS: For this study 12 human corneoscleral discs were mounted in artificial anterior chambers, the systems were continuously filled with culture medium and the anterior chambers with air (n = 5) or SF6 20 % (n = 7) as tamponade. After 6 days of storage in the incubator endothelial cell density, toxicity on endothelial cells and corneal thickness were evaluated. RESULTS: There were no significant differences in endothelial cell loss (p = 1.000), endothelial cell count (p = 0.648), toxicity on endothelial cells (p = 0.048) and central corneal thickness (p = 0.905) between the two groups after 1 week. The level of significance was defined as p <= 0.05 and adjusted to p <= 0.0056 according to the Bonferroni correction for multiple testing. CONCLUSION: The use of SF6 20 % as tamponade in the anterior chamber for posterior lamellar keratoplasty can be proposed as a safe alternative to pure air filling related to endothelial cell loss. Increased toxic effects on the corneal endothelium by SF6 20 % were not detected in this study; however, further prospective clinical trials are needed to examine the long-term effects in humans. PMID- 26025300 TI - Transplant of ex vivo incubated bone marrow with rIL -7 for the enhancement of immuno-hematopoietic reconstitution. AB - Interleukin-7 (IL-7) is a critical cytokine in early B and T cell development. Peripheral T cell expansion and thymopoiesis and is a result of the ongoing reconstitution from uncommitted stem cells after transplant. We investigated the efficacy of ex vivo incubated bone marrow cells treated with recombinant human IL 7 (rIL-7) on subsequent in vivo murine models of syngeneic bone marrow (BM) transplant. After ex vivo culture with rIL-7, we observed a 11/2-fold increase in BM cellularity; this increase was associated with an enhanced reconstitution of bone marrow cells and thymocytes at 45 days post-transplant. In addition to increased cellularity, lymphocytes from mice transplanted with cultured rIL-7 showed enhanced proliferative responses to mitogenic stimulation. These findings suggest rIL-7 to be a promising agent for the clinical application of treating immune deficiency and enhancing immuno-hematopoietic reconstitution of the stem cell auto/allograft. PMID- 26025301 TI - The effect of immunological status, in-vitro treatment and culture time on expression of eleven candidate reference genes in bovine blood mononuclear cells. AB - BACKGROUND: Technical feasibility of RNA quantification by real time RT-PCR has led to enormous utilization of this method. However, real time PCR results need to be normalized due to the high sensitivity of the method and also to eliminate technical variation. Normalization against a reference gene that is constitutively transcribed and has minimum variation among samples is the ideal method. Nevertheless, many studies have shown that there is no general reference gene(s) with ideal characteristics and candidate reference genes should be tested before being used as a "normalizer" in each study. METHODS: The current study investigated the effects of previous exposure of the host to experimental test antigens and culturing time on the expression of 11 candidate genes when blood mononuclear cells (BMCs) were cultured and treated in-vitro by hen egg white lysozyme, Candida albicans extract and a mitogen. Mononuclear cells were isolated and cultured from 12 bovine blood samples representing 3 different immunological statuses. The expression of candidate housekeeping genes were measured by real time RT-PCR at 4 and 24 hours post culture. The expression of candidate genes were first compared between the two time points in untreated samples. Constitutively expressed genes were further tested in linear mixed effects models to examine the effect of previous host exposure and in-vitro treatments. RESULTS: Our findings showed that the expression of the most common reference genes, beta actin, and Glyceraldehydes-3-phosphate dehydrogenase (GAPDH), are significantly decreased at 24 hours after culturing BMCs, even without any treatment. The effect of culturing time was also significantly influenced the expression of 18s ribosomal RNA, beta2-microglobulin, Tyrosine 3-monooxygenase/tryptophan 5 monoxygenase activation protein, zeta polypeptide (YWHAZ) in BMCs. Only the expression of C-terminal binding protein 1 (CTBP1) and RAD50 among all tested genes were consistent after treatment of cultured BMCs with C. albicans whole yeast extract and Hen Egg White Lysozyme (HEWL), respectively. In addition, expressions of CTBP1, and RAD50 were independent from previous exposure of the host to the antigen. CONCLUSIONS: The results of this study demonstrated inconsistent expression of commonly used reference genes in untreated cultured BMCs over time. As this condition applies to negative controls in real time RT PCR study designs, normalization against these genes can largely deceive the outcome, especially in kinetic studies. Moreover, the potential effects of immunological memory on the expression of reference genes should be considered if BMCs are collected from different individuals under different environmental conditions and if these cells are treated in-vitro by an antigen. PMID- 26025302 TI - Effects of polyunsaturated fatty acid intake and status during pregnancy, lactation, and early childhood on cardiometabolic health: A systematic review. AB - The importance of polyunsaturated fatty acid (PUFA) intake in fetal life and infancy has been widely studied in relation to child cognitive and visual development, but whether early life PUFA exposure is related to cardiometabolic risk factors is unclear. The focus of this systematic review was to evaluate the effects of PUFA dietary intake and blood levels during pregnancy, lactation, or early childhood (?5 y) on obesity, blood pressure, blood lipids, and insulin sensitivity. We identified 4302 abstracts in the databases Embase, Medline and Cochrane Central (April 2014), of which 56 articles, reporting on 45 unique studies, met all selection criteria. Many of the included studies focused on obesity as an outcome (33 studies), whereas studies on insulin sensitivity were relatively scarce (6 studies). Overall, results for obesity, blood pressure, and blood lipids were inconsistent, with a few studies reporting effects in opposite directions and other studies that did not observe any effects of PUFAs on these outcomes. Four studies suggested beneficial effects of PUFAs on insulin sensitivity. We conclude that there is insufficient evidence to support a beneficial effect of PUFAs in fetal life or early childhood on obesity, blood pressure, or blood lipids. More research is needed to investigate the potential favorable effects of PUFAs on insulin sensitivity, and to examine the role of specific fatty acids in early life on later cardiometabolic health. PMID- 26025304 TI - Two-component system YvqEC-dependent bacterial resistance against vancomycin in Bacillus thuringiensis. AB - YvqEC is one of the two-component signal transduction systems that may respond to cell envelope stress and enable cells to adjust multiple cellular functions. It consists of a histidine kinase YvqE and a response regulator YvqC. In this study, we separately constructed a single gene mutant DeltayvqE and a double gene mutant DeltayvqEC in Bacillus thuringiensis BMB171 through a homing endonucleases I-SceI mediated markerless gene deletion method. We found that the deletion of either yvqE or yvqEC weakened the resistance of B. thuringiensis against vancomycin. We also identified nine operons that may be involved in the cellular metabolism regulated by YvqC. This study not only enriches our understanding of bacterial resistance mechanisms against vancomycin, but also helps investigate the functions of YvqEC. PMID- 26025303 TI - Geodermatophilus aquaeductus sp. nov., isolated from the ruins of Hadrian's aqueduct. AB - An orange-black, Gram-positive, aerobic and gamma-ray resistant actinobacterium was isolated from the ruins of a Roman aqueduct located in Northern Tunisia. The optimal growth for the strain was found to be at 25-35 degrees C and at pH 6.0 9.5. Chemotaxonomic and molecular characteristics of the isolate matched those described for members of the genus Geodermatophilus. The peptidoglycan was found to contain meso-diaminopimelic acid as diagnostic diaminoacid. The main polar lipids were identified as phosphatidylcholine, diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, an unidentified glycolipid and an unidentified aminophospholipid; MK-9(H4) was found to be the dominant menaquinone and galactose was detected as the diagnostic sugar, with glucose, ribose and mannose also present. The major cellular fatty acids were identified as branched chain saturated acids iso-C16:0, iso-C15:0 and iso-H-C16:0. The 16S rRNA gene showed 95.4-99.6 % sequence identity with the type strains of the genus Geodermatophilus. DNA-DNA relatedness values with closely related species were 39.9 +/- 4.9, 33.9 +/- 1.9, 27.0 +/- 2.5 and 13.2 +/- 1.35 % with Geodermatophilus amargosae, G. normandii, G. saharensis and G. tzadiensis respectively. Based on phenotypic results and 16S rRNA gene sequence analysis, strain BMG801(T) (=DSM 46834(T) = CECT 8822(T)) is proposed to represent the type strain of a novel species, Geodermatophilus aquaeductus sp. nov. PMID- 26025305 TI - Description of Geodermatophilus bullaregiensis sp. nov. AB - The taxonomic position of an aerobic actinobacterial strain, BMG841(T), isolated from the Bulla Regia monument (Tunisia) and exhibiting a high resistance to gamma radiation (D10 ~9 kGy) was determined using polyphasic approach. The optimal growth range was found to be 25-35 degrees C at pH of 7.0-8.5. The strain was observed to form black dry colonies. Chemotaxonomic characteristics of the isolate showed a cell wall type III, with galactose and glucose as diagnostic sugars; phosphatidylcholine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylethanolamine and an unidentified glycolipid as main polar lipids; and MK-9(H4) as the predominant menaquinone. The major cellular fatty acids were identified as iso-C16:0 and iso-C15:0. Phylogenetic analysis indicated that strain BMG841(T) represents a novel member of the genus Geodermatophilus with high 16S rRNA gene sequence identity with Geodermatophilus saharensis (98.28 %). Based on phylogenetic and phenotypic analysis, strain BMG841(T) is proposed as the type strain (=DSM 46841(T) = CECT 8821(T)) of a novel species, Geodermatophilus bullaregiensis. PMID- 26025307 TI - Efficient suppression of biofilm formation by a nucleic acid aptamer. AB - Biofilms are microbial communities that are attached to a solid surface using extracellular polymeric substances. Motility and initial attachment mediated by flagella are required for biofilm formation. Therefore, blocking the motility of flagella is a potential strategy to inhibit biofilm formation. In this study, single-stranded DNA aptamers specific to the Salmonella choleraesuis were selected after 14 cycles of the systematic evolution of ligands by exponential enrichment. Among the selected aptamers, the aptamer 3 showed the highest affinity for S. choleraesuis with a dissociation constant (Kd) of 41 +/- 2 nM. Aptamer 3, conjugated with magnetic beads, was then used to capture its binding target on the bacteria. After mass spectrometry and specific binding analysis, the flagellin was identified as the target captured by aptamer 3. Furthermore, inhibition experiments, inverted microscopy and atomic force microscopy demonstrated that aptamer 3 was able to control the biofilm formation and promote the inhibitory effect of an antibiotic on bacterial biofilms. Single-stranded DNA aptamers therefore have great potential as inhibitors of biofilm formation. PMID- 26025306 TI - Combined effect of genetic background and gender in a mouse model of bleomycin induced skin fibrosis. AB - INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disorder characterised by the development of skin fibrosis. Our current understanding of the disease pathogenesis is incomplete and the study of SSc is hindered, at least partially, by a lack of animal models that fully replicate the complex state of human disease. Murine model of bleomycin-induced dermal fibrosis encapsulates important events that take place early in the disease course. METHODS: To characterise the optimum in vivo parameters required for the successful induction of dermal fibrosis we subjected three commonly used mouse strains to repeated subcutaneous bleomycin injections. We aimed to identify the effects of genetic background and gender on the severity of skin fibrosis. We used male and female Balb/C, C57BL/6, and DBA/2 strains and assessed their susceptibility to bleomycin induced fibrosis by measuring dermal thickness, hydroxyproline/collagen content and number of resident myofibroblasts, all of which are important indicators of the severity of skin fibrosis. All data are expressed as mean values +/- SEM. The Mann-Whitney U test was used for statistical analysis with GraphPad Prism 6.04 software. RESULTS: Dermal fibrosis was most severe in Balb/C mice compared to C57BL/6 and DBA/2 suggesting that Balb/C mice are more susceptible to bleomycin induced fibrosis. Analysis of the effect of gender on the severity of fibrosis showed that male Balb/C, C57BL/6, DBA/2 mice had a tendency to develop more pronounced fibrosis phenotype than female mice. Of potential importance, male Balb/C mice developed the most severe fibrosis phenotype compared to male C57BL/6 and male DBA/2 as indicated by significantly increased number of dermal myofibroblasts. CONCLUSION: Our study highlights the importance of genetic background and gender in the induction of murine dermal fibrosis. Robust and reproducible animal models of fibrosis are important research tools used in pharmacological studies which may lead to better understanding of the pathogenesis of fibrotic diseases and assist in identification of new drugs. PMID- 26025308 TI - Congenital Anomaly Detected During Work-up of Cystic Pancreatic Lesion. PMID- 26025310 TI - An Unusual Cause of a Pancreatic Mass. PMID- 26025311 TI - Reply: To PMID 25479138. PMID- 26025312 TI - Do Lay People Accept a Positive Diagnosis of Irritable Bowel Syndrome? PMID- 26025313 TI - Gut Serotonin Is a Regulator of Obesity and Metabolism. PMID- 26025314 TI - Abdominal Pain Caused by Spontaneous Rupture of a Liver Tumor. PMID- 26025315 TI - Macroparasites of introduced parakeets in Italy: a possible role for parasite mediated competition. AB - Alien species are considered a cause of biodiversity loss throughout the world. An important but often overlooked form of competition with native species is the parasite-mediated one. Introduced species may bring their own parasites from their native ranges (spillover) or get native parasites from native species, thus increasing the parasites' spread and transmission risk (spillback). Thus, a complete knowledge of parasites hosted by introduced species is important to assess and to possibly prevent impacts. Ring-necked and monk parakeets have been introduced in many European countries, where they established a number of alien reproductive populations. We sampled 21 ring-necked parakeets and 7 monk parakeets from Italy and identified 35 arthropod ectoparasites belonging to five species. Amongst those, one species was native to India (Neopsittaconirmus lybartota), where alien populations of ring-necked parakeet may have been originated, and one species from South America (Paragoniocotes fulvofasciatus), which is typically found of the monk parakeet in its native range. The other three species of arthropod parasites were native to Italy and commonly found on native species, suggesting the possibility of spillback processes. PMID- 26025316 TI - Systems approach to excitation-energy and electron transfer reaction networks in photosystem II complex: model studies for chlorophyll a fluorescence induction kinetics. AB - Photosystem II (PS II) is a protein complex which evolves oxygen and drives charge separation for photosynthesis employing electron and excitation-energy transfer processes over a wide timescale range from picoseconds to milliseconds. While the fluorescence emitted by the antenna pigments of this complex is known as an important indicator of the activity of photosynthesis, its interpretation was difficult because of the complexity of PS II. In this study, an extensive kinetic model which describes the complex and multi-timescale characteristics of PS II is analyzed through the use of the hierarchical coarse-graining method proposed in the authors' earlier work. In this coarse-grained analysis, the reaction center (RC) is described by two states, open and closed RCs, both of which consist of oxidized and neutral special pairs being in quasi-equilibrium states. Besides, the PS II model at millisecond scale with three-state RC, which was studied previously, could be derived by suitably adjusting the kinetic parameters of electron transfer between tyrosine and RC. Our novel coarse-grained model of PS II can appropriately explain the light-intensity dependent change of the characteristic patterns of fluorescence induction kinetics from O-J-I-P, which shows two inflection points, J and I, between initial point O and peak point P, to O-J-D-I-P, which shows a dip D between J and I inflection points. PMID- 26025317 TI - Optimal intervention strategy for prevention tuberculosis using a smoking tuberculosis model. AB - In this paper, we developed a dynamic model of smoking-tuberculosis (TB) transmission in South Korea, and investigated the effects of control strategies on the number of incidence of TB using optimal control theory. Model parameters regarding TB and smoking are estimated through least-squares fitting to real data. We considered three TB controls (distancing, case-finding, and case holding) and two smoking controls (distancing and quitting), in order to minimize the number of exposed and infectious individuals and the cost of control. Numerical simulations for the various control strategies highlight that implementing the smoking controls, not with TB controls, can effectively reduce the incidence of TB transmission. PMID- 26025318 TI - Four types of interference competition and their impacts on the ecology and evolution of size-structured populations and communities. AB - We investigate how four types of interference competition - which alternatively affect foraging, metabolism, survival, and reproduction - impact the ecology and evolution of size-structured populations. Even though all four types of interference competition reduce population biomass, interference competition at intermediate intensity sometimes significantly increases the abundance of adult individuals and the population's reproduction rate. We find that foraging and metabolic interference evolutionarily favor smaller maturation size when interference is weak and larger maturation size when interference is strong. The evolutionary response to survival interference and reproductive interference is always larger maturation size. We also investigate how the four types of interference competition impact the evolutionary dynamics and resultant diversity and trophic structure of size-structured communities. Like other types of trait mediated competition, all four types of interference competition can induce disruptive selection and thus promote initial diversification. Even though foraging interference and reproductive interference are more potent in promoting initial diversification, they catalyze the formation of diverse communities with complex trophic structure only at high levels of interference intensity. By contrast, survival interference does so already at intermediate levels, while reproductive interference can only support relatively smaller communities with simpler trophic structure. Taken together, our results show how the type and intensity of interference competition jointly affect coexistence patterns in structured population models. PMID- 26025319 TI - m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model. AB - Chronic pain and depression are two complex states that often coexist in the clinical setting and traditional antidepressants and analgesics have shown limited clinical efficacy. There is an intricate communication between the immune system and the central nervous system and inflammation has been considered a common mediator of pain-depression comorbidity. This study evaluated the effect of m-trifluoromethyl diphenyl diselenide [(m-CF3-PhSe)2], an organoselenium compound that has been reported to have both antinociceptive and antidepressant like actions, in the comorbidity of chronic pain and depression induced by partial sciatic nerve ligation (PSNL) in an inflammatory approach. Mice were submitted to PSNL during 4weeks and treated with (m-CF3-PhSe)2 acutely (0.1 10mg/kg, i.g.) or subchronically (0.1mg/kg, i.g., once a day during the 3rd and 4th weeks). Both treatments prevented PSNL-increased pain sensitivity and depressive-like behavior observed in Von-Frey hair (VFH) and forced swimming (FST) tests, respectively. These effects could be mainly associated with an anti inflammatory action of (m-CF3-PhSe)2 which reduced the levels of pro-inflammatory cytokines, NF-kappaB and COX-2, and p38 MAPK activation that were increased by PSNL. (m-CF3-PhSe)2 also increased the BDNF levels and reduced glutamate release and 5-HT uptake altered by PSNL. Although acute and subchronic treatments with (m CF3-PhSe)2 prevented these alterations induced by PSNL, the best results were found when (m-CF3-PhSe)2 was subchronically administered to mice. Considering the potential common mechanisms involved in the comorbidity of inflammation-induced depression and chronic pain, the results found in this study indicate that (m-CF3 PhSe)2 could become an interesting molecule to treat long-lasting pathological pain associated with depression. PMID- 26025320 TI - Comparison of scapular posterior tilting exercise alone and scapular posterior tilting exercise after pectoralis minor stretching on scapular alignment and scapular upward rotators activity in subjects with short pectoralis minor. AB - OBJECTIVES: To compare scapular posterior tilting exercise alone and scapular posterior tilting exercise after pectoralis minor (PM) stretching on the PM index (PMI), scapular anterior tilting index, scapular upward rotation angle, and scapular upward rotators' activity in subjects with a short PM. PARTICIPANTS: Fifteen subjects with a short PM participated in this study. MAIN OUTCOME MEASURES: The PMI, scapular anterior tilting index, and scapular upward rotation angle were measured after scapular posterior tilting exercise alone and scapular posterior tilting exercise after PM stretches. Scapular upward rotators' activities were collected during scapular posterior tilting exercise alone and scapular posterior tilting exercise after PM stretches. RESULTS: The PMI and scapular upward rotation angle, as well as the activity of the upper trapezius, lower trapezius, and serratus anterior muscles, were significantly greater for scapular posterior tilting exercise after PM stretching and the scapular anterior tilting index was significantly lower for scapular posterior tilting exercise after PM stretching than the scapular posterior tilting exercise alone. CONCLUSIONS: Scapular posterior tilting exercise after PM stretching in subjects with a short PM could be an effective method of modifying scapular alignment and scapular upward rotator activity. PMID- 26025321 TI - Splice variants and regulatory networks associated with host resistance to the intestinal worm Cooperia oncophora in cattle. AB - To elucidate the molecular mechanism of host resistance, we characterized the jejunal transcriptome of Angus cattle selected for parasite resistance for over 20 years in response to infection caused by the intestinal worm Cooperia oncophora. The transcript abundance of 56 genes, such as that of mucin 12 (MUC12) and intestinal alkaline phosphatase (ALPI), was significantly higher in resistant cattle. Novel splicing variants, exon skipping events, and gene fusion events, were also detected. An algorithm for the reconstruction of accurate cellular networks (ARACNE) was used to infer de novo regulatory molecular networks in the interactome between the parasite and host. Under a combined cutoff of an error tolerance (epsilon = 0.10) and a stringent P-value threshold of mutual information (1.0 * 10(-5)), a total of 229,100 direct interactions controlled by 20,288 hub genes were identified. Among these hub genes, 7651 genes had >= 100 direct neighbors while the top 9778 hub genes controlled more than 50% of total direct interactions. Three lysozyme genes (LYZ1, LYZ2, and LYZ3), which are co located in bovine chromosome 5 in tandem and are strongly upregulated in resistant cattle, shared a common regulatory network of 55 genes. These ancient antimicrobials were likely involved in regulating host-parasite interactions by affecting host gut microbiome. Notably, ALPI, known as a gut mucosal defense factor, controlled a molecular network consisting 410 genes, including 14 transcription factors (TF) and 10 genes that were significantly regulated in resistant cattle. Several large regulatory networks were controlled by TF, such as STAT6, SREBF1, and ELF4. Gene ontology (GO) processes significantly enriched in the regulatory network controlled by STAT6 included lipid metabolism. Our findings provide insights into the immune regulation of host-parasite interactions and the molecular mechanisms of host resistance in cattle. PMID- 26025322 TI - Digoxin therapy and associated clinical outcomes in the MADIT-CRT trial. AB - BACKGROUND: Digoxin's pharmacological, hemodynamic, and electrophysiological properties are well understood. However, in modern heart failure (HF) treatment, its effect has yet to be fully investigated. OBJECTIVE: The aim of the present study was to determine the effects of digoxin on outcomes in patients with mild HF implanted with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (CRT-D) device. METHODS: We investigated the effect of digoxin treatment on the end points of HF/death, HF alone, death alone, and ventricular tachycardia or ventricular fibrillation (VT/VF) in 1820 patients with mild HF (New York Heart Association class I and II), prolonged QRS duration (>=130 ms), and reduced left ventricular ejection fraction (<=30%) enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy trial. Multivariate Cox proportional hazards regression models were used to determine the effect of time-dependent digoxin usage on the end points. RESULTS: Digoxin therapy was not associated with an increased or decreased risk of HF/death (hazard ratio [HR] 1.07; 95% confidence interval [CI] 0.86-1.33; P = .0.56), HF alone (HR 1.1.04; 95% CI 0.82 1.32; P = .76), or death alone (HR 0.93; 95% CI 0.67-1.32; P = .71). However, digoxin was associated with a significant 41% increased risk of VT/VF (HR 1.41; 95% CI 1.14-1.75; P = .002), which was driven by a significantly increased risk of VT/VF with heart rate >=200 beats/min (HR 1.65; 95% CI 1.27-2.15; P <= .001), whereas no increased risk of VT/VF with heart rate <200 beats/min was evident (HR 1.20; 95% CI 0.92-1.57; P = .19). No significant differences in digoxin's effect on any of the end points were found between patients with ICD and patients with CRT-D (interaction P > .5). CONCLUSION: The use of digoxin in patients with mild HF implanted with an ICD or CRT-D device was not associated with reductions in HF/death events. However, digoxin therapy was associated with an increased risk of high-rate VT/VF (>=200 beats/min). PMID- 26025323 TI - Hydroxychloroquine reduces heart rate by modulating the hyperpolarization activated current If: Novel electrophysiological insights and therapeutic potential. AB - BACKGROUND: Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption. OBJECTIVES: The purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia. METHODS: We assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the "funny" current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 uM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1-30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography). RESULTS: In mouse atria, spontaneous beating rate was significantly (P < .05) reduced (by 9% +/- 3% and 15% +/- 2% at 3 and 10 uM HCQ, n = 7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17% +/- 6%, 1 MUM dose) and a dose-dependent reduction in If (13% +/- 3% at 1 uM; 19% +/- 2% at 3 uM). Effects were also observed on L-type calcium ion current (ICaL) (12% +/- 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% +/- 4%) at 3 uM. Intravenous HCQ decreased heart rate in anesthetized rats (14.3% +/- 1.1% at 15mg/kg; n = 6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function. CONCLUSIONS: We have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If. PMID- 26025325 TI - Predicting a response to FOLFIRINOX in pancreatic cancer. PMID- 26025324 TI - Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. METHODS: CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two sided. RESULTS: Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). CONCLUSION: Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy. PMID- 26025326 TI - Identification of the Avulsion-Injured Spinal Motoneurons. AB - In laboratory studies, counting the spinal motoneurons that survived axonal injury is a major method to estimate the severity and regenerative capacity of the injured motoneurons after the axonal injury and rehabilitation surgery. However, the typical motoneuron marker, the choline acetyltransferase (ChAT), could not be detected in the injured motoneurons within the first 3-4 weeks postinjury. It is necessary to explore the useful and reliable specific phenotypic markers to assess the fate of injured motoneurons in axonal injury. Here, we used the fluorogold to retrograde trace the injured motoneurons in the spinal cord and studied the expression patterns of the alpha-motoneuron marker, the neuronal nuclei DNA-binding protein (NeuN) and the peripheral nerve injury marker, the activating transcriptional factor (ATF-3), and the oxidative stress marker, the neuronal nitric oxide synthase (nNOS) within the first 4 weeks of the root avulsion of the right brachial plexus (BPRA) in the adult male Sprague Dawley rats. Our results showed that ATF-3 was rapidly induced and sustained to express only in the nuclei of the fluorogold-labeled injured motoneurons but none in the unaffected motoneurons from the 24 h of the injury; meanwhile, the NeuN almost disappeared in the avulsion-affected motoneurons within the first 4 weeks. The nNOS was not detected in the motoneurons until the second week of the injury. On the basis of the present data, we suggest that ATF-3 labels avulsion-injured motoneurons while NeuN and nNOS are poor markers within the first 4 weeks of BPRA. PMID- 26025327 TI - Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries. Defective autophagy of lipid droplets (LDs) in hepatocytes, also known as lipophagy, has recently been identified as a possible pathophysiological mechanism of NAFLD. Experimental and epidemiological evidence suggests that dietary polyphenols may prevent NAFLD. To address this hypothesis and analyze the underlying mechanisms, we supplemented bergamot polyphenol fraction (BPF) to cafeteria (CAF) diet-fed rats, a good model for pediatric metabolic syndrome and NAFLD. BPF treatment (50 mg/kg/day supplemented with drinking water, 3 months) potently counteracted the pathogenic increase of serum triglycerides and had moderate effects on blood glucose and obesity in this animal model. Importantly, BPF strongly reduced hepatic steatosis as documented by a significant decrease in total lipid content (-41.3% +/- 12% S.E.M.), ultrasound examination and histological analysis of liver sections. The morphometric analysis of oil-red stained sections confirmed a dramatic reduction in LDs parameters such as total LD area (48.5% +/- 15% S.E.M.) in hepatocytes from CAF+BPF rats. BPF-treated livers showed increased levels of LC3 and Beclin 1 and reduction of SQSTM1/p62, suggesting autophagy stimulation. Consistent with BPF stimulation of lipophagy, higher levels of LC3II were found in the LD subcellular fractions of BPF-expose livers. This study demonstrates that the liver and its lipid metabolism are the main targets of bergamot flavonoids, supporting the concept that supplementation of BPF is an effective strategy to prevent NAFLD. PMID- 26025328 TI - Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites. AB - Demand for the vital nutrient choline is high during lactation; however, few studies have examined choline metabolism and requirements in this reproductive state. The present study sought to discern the effects of lactation and varied choline intake on maternal biomarkers of choline metabolism and breast milk choline content. Lactating (n=28) and control (n=21) women were randomized to 480 or 930 mg choline/day for 10-12 weeks as part of a controlled feeding study. During the last 4-6 weeks, 20% of the total choline intake was provided as an isotopically labeled choline tracer (methyl-d9-choline). Blood, urine and breast milk samples were collected for choline metabolite quantification, enrichment measurements, and gene expression analysis of choline metabolic genes. Lactating (vs. control) women exhibited higher (P < .001) plasma choline concentrations but lower (P <= .002) urinary excretion of choline metabolites, decreased use of choline as a methyl donor (e.g., lower enrichment of d6-dimethylglycine, P <= .08) and lower (P <= .02) leukocyte expression of most choline-metabolizing genes. A higher choline intake during lactation differentially influenced breast milk d9- vs. d3-choline metabolite enrichment. Increases (P <= .03) were detected among the d3-metabolites, which are generated endogenously via the hepatic phosphatidylethanolamine N-methyltransferase (PEMT), but not among the d9 metabolites generated from intact exogenous choline. These data suggest that lactation induces metabolic adaptations that increase the supply of intact choline to the mammary epithelium, and that extra maternal choline enhances breast milk choline content by increasing supply of PEMT-derived choline metabolites. This trial was registered at clinicaltrials.gov as NCT01127022. PMID- 26025329 TI - Evaluation of targeting c-Src by the RGT-containing peptide as a novel antithrombotic strategy. AB - BACKGROUND: Interaction of integrin beta3 with c-Src plays critical roles in cellular signaling which is heavily implicated in platelet adhesion and aggregation, as well as in tumor cell proliferation and metastasis or in osteoclastic bone resorption. Selectively blocking integrin alphaIIbbeta3 outside in signaling in platelets has been a focus of attention because of its effective antithrombotic potential together with a sufficient hemostatic capacity. The myristoylated RGT peptide has been shown to achieve this blockade by targeting the association of c-Src with the integrin beta3 tail, but the lack of key information regarding the mechanisms of action prevents this strategy from being further developed into practical antithrombotics. Therefore, in-depth knowledge of the precise mechanisms for RGT peptide in regulating platelet function is needed to establish the basis for a potential antithrombotic therapy by targeting c-Src. METHODS: The reduction-sensitive peptides were applied to rule out the membrane anchorage after cytoplasmic delivery. The c-Src activity was assayed at living cell or at protein levels to assess the direct effect of RGT targeting on c-Src. Thrombus formation under flow in the presence of cytoplasmic RGT peptide was observed by perfusing whole blood through the collagen-coated micro-chamber. RESULTS: The RGT peptide did not depend on the membrane anchorage to inhibit outside-in signaling in platelets. The myr-AC ~ CRGT peptide readily blocked agonist-induced c-Src activation by disrupting the Src/beta3 association and inhibited the RhoA activation and collagen-induced platelet aggregation in addition to the typical outside-in signaling events. The myr-AC ~ CRGT had no direct effect on the kinase activity of c-Src in living cells as evidenced by its inability to dissociate Csk from c-Src or to alter the phosphorylation level of c Src Y(416) and Y(527), consistent results were also from in vitro kinase assays. Under flow conditions, the myr-AC~ CRGT peptide caused an inhibition of platelet thrombus formation predominantly at high shear rates. CONCLUSIONS: These findings provide novel insights into the molecular mechanisms by which the RGT peptide regulates integrin signaling and platelet function and reinforce the potential of the RGT peptide-induced disruption of Src/beta3 association as a druggable target that would finally enable in vivo and clinical studies using the structure-based small molecular mimetics. PMID- 26025330 TI - NTPDase and 5'-nucleotidase activities in synaptosomes of rabbits experimentally infected with BoHV-5. AB - Bovine herpesvirus type 5 (BoHV-5) is the causative agent of herpetic meningoencephalitis in cattle. The purinergic system is described as a modulator of the immune response and neuroinflammation. These functions are related to the extracellular nucleotides concentration. NTPDase and 5'-nucleotidase are enzymes responsible for controlling the extracellular concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine (ADO). The aim of this study is to determinate the ectonucleotidase activity in cortical synaptosomes and synaptosomes from the hippocampus of rabbits experimentally infected with BoHV-5. Rabbits were divided into four groups, two control groups (non-inoculated animals), and two infected groups (inoculated with BoHV-5). The infected groups received 0.5 ml of BoHV-5 suspension with 10(7.5)TCID50 of viral strain SV-507/99, per paranasal sinuses, and the control groups received 0.5 ml of minimum essential media per paranasal sinuses. Animals were submitted to euthanasia on days 7 and 12 post-inoculation (p.i.); cerebral cortex and hippocampus were collected for the synaptosomes isolation and posterior determination of the ectonucleotidase activities. The results showed a decrease (P < 0.05) in ectonucleotidase activity in synaptosomes from the cerebral cortex of infected rabbits, whereas an increased (P < 0.05) ectonucleotidase activity was observed in synaptosomes from the hippocampus. These differences may be related with the heterogeneous distribution of ectonucleotidases in the different brain regions and also with the viral infectivity. Therefore, it is possible to speculate that BoHV-5 replication results in changes in ectonucleotidase activity in the brain, which may contribute to the neurological signs commonly observed in this disease. PMID- 26025334 TI - Association between weight at birth and body composition in childhood: A Brazilian cohort study. AB - BACKGROUND AND AIM: Previous studies have shown that the association between birth weight and obesity later in life apparently follows a U-shaped curve. However, due to the continuous increase of mean birth weight in several countries worldwide, it is expected that higher birth weight will play a more important role as a risk factor for further obesity than low birth weight. This study investigated the association between birth weight and body composition of children in order to establish their relationship in an earlier period of life. STUDY DESIGN AND SUBJECTS: Prospective cohort study carried out from 1997 to 2006 in Jundiai city, Brazil, involving 486 children at birth and from 5 to 8 years of age. The following anthropometric measurements were determined: birth weight, weight, height, waist circumference and triceps skinfold thickness. Fat mass percentage, fat mass and fat-free mass were measured by electrical bioimpedance analysis by the 310 Body Composition Analyzer, Biodynamics((r)). Five multiple linear regression models were developed considering waist circumference, triceps skinfold thickness, fat mass percentage, fat mass and fat-free mass as markers of body composition, and outcomes. RESULTS: Significant positive associations were observed between birth weight and waist circumference (p<0.001), triceps skinfold thickness (p=0.006), fat mass (p=0.007) and fat-free mass (p<0.001). Approximately 10% of the children presented excess body fat assessed by bioimpedance, and 27.6% of them had central adiposity (waist circumference >=95th percentile). CONCLUSIONS: Intrauterine growth, assessed by weight at birth, was positively associated with body composition of children aged 5-8 years, indicating that those with the highest birth weight are more at risk for obesity, and probably to chronic diseases in adulthood. PMID- 26025333 TI - Neurodevelopmental outcome of extremely preterm infants born to rural and urban residents' mothers in Australia. AB - BACKGROUND: Rural and remote residents in Australia have long experienced unfavourable health outcomes compared to their urban counterparts. AIMS: To study neurodevelopmental outcome at 2-3 years of age, corrected for prematurity of extremely preterm infants admitted to a regional neonatal Australian network from rural and urban regions (based on usual location of maternal residence). METHODS: A multicenter population-based cohort study in which surviving urban and rural infants <29 weeks of gestation born between 1998 and 2004 underwent neurodevelopmental assessment at 2-3 years of age, corrected for prematurity by a developmental assessment team. Moderate/severe functional disability was defined as developmental delay (GQ or MDI>2 SD below the mean), cerebral palsy (aided for walking), sensorineural or conductive deafness (requiring amplification), and bilateral blindness (visual acuity <6/60 in the better eye). RESULTS: Of the 1970 infants alive at 2-3 years of age, 268 (63.8%) rural and 1205 (77.7%) urban infants were evaluated. Infants lost to follow-up were of slightly higher gestational age and birth weight. Both rural and urban assessed groups were comparable in gestation and birth weight percentile. In comparison to their urban counterparts, the rural group had more outborn infants (19.8% vs. 4.6%, p<0.001). They, however, did not have an increased risk of moderate/severe functional disability (OR 0.77, 95% CI 0.52-1.23, p=0.176). This finding was not significantly altered by limiting the analysis to different gestational ages. CONCLUSION: Extremely premature surviving young children from rural areas of residence do not seem to have an increased risk for moderate/severe functional disability. PMID- 26025335 TI - Digit ratio (2D:4D) and salivary testosterone, oestradiol and cortisol levels under challenge: Evidence for prenatal effects on adult endocrine responses. AB - BACKGROUND: Digit ratio (2D:4D) is a marker for prenatal sex steroids and a correlate of sporting performance. This association may exist because low 2D:4D is linked to high prenatal levels of testosterone (T) and low oestrogens (E). It was recently suggested that low 2D:4D, and particularly low right-left 2D:4D (or Dr-l), is a marker for T changes in response to physical and aggressive challenges. If correct, this link may in part explain the association between 2D:4D and sports performance. AIMS: We tested this hypothesis in adults. STUDY DESIGN: Three experimental treatments were completed using a randomised, cross over design; (i) cycle sprints plus an aggressive video (S+V), (ii) aggressive video plus cycle sprints (V+S), and (iii) a control session. SUBJECTS: 24 healthy adults (12 men and 12 women). OUTCOME MEASURES: Salivary T, oestradiol (E2) and cortisol (C) levels were measured on six occasions across each session and pooled for analysis. RESULTS: The S+V treatment was associated with a rise in T and C levels, and Dr-l was significantly and negatively correlated with T and E2 with these effects confined to men. The right 2D:4D and Dr-l were also negatively correlated with the T/C ratio and Dr-l negatively related to the E2/C ratio in men during the S+V treatment. CONCLUSIONS: We suggest that the hormonal responses to a challenge are programmed by prenatal levels of T and E with possible links to sporting performance in adulthood. PMID- 26025336 TI - Maternal PPARG Pro12Ala polymorphism is associated with infant's neurodevelopmental outcomes at 18 months of age. AB - BACKGROUND: Peroxisome proliferator activated receptors (PPARs) are ligand activated transcription factors with crucial functions in lipid homeostasis, glucose metabolism, anti-inflammatory processes, placental development, and are involved in cognitive functions and neurodegenerative diseases. Polymorphisms in PPAR genes are shown to influence the activity of these receptors. AIMS: 1) To examine the association of PPARG Pro12Ala polymorphism in pregnant women and their offspring on infant's neurodevelopmental outcomes during the first 18 months of life; 2) to determine the influence of Pro12Ala polymorphism on fatty acid concentrations in plasma phospholipids and placental tissue. STUDY DESIGN: 138 mother-infant pairs from the PREOBE observational study were genotyped for PPARG Pro12Ala. Plasma phospholipids and placental fatty acid concentrations were measured at delivery. Infants' neuropsychological assessment at 6 and 18 months of age was performed using Bayley III. RESULTS: The effect of Pro12Ala on infant's neurodevelopmental outcomes was detected at 18 months, but not at 6 months of age. 18 months old infants born to mothers with wild-type Pro12 genotype had better cognitive (OR=5.11, 95% CI: 1.379-18.96, p=0.015), language (OR=3.41, 95% CI: 1.35-11.24, p=0.044), and motor development scores (OR=4.77, 95% CI: 1.243-18.33, p=0.023) than the Ala allele carriers. Pro12Ala variants did not seem to affect fatty acids concentrations in blood nor in placenta at delivery. CONCLUSIONS: Infants born to mothers with Pro12 genotype have better neurodevelopmental outcomes at 18 months of age than Ala allele carriers, indicating a long-term transplacental action of PPARgamma variants on foetal brain development. PMID- 26025337 TI - Perfusion index in the preterm infant immediately after birth. AB - AIM: To evaluate PI in preterm infants during the first 10 min of life. DESIGN/METHODS: An observational study was conducted in the delivery room on preterm infants (less than 32 week gestation). PI values were obtained from a pre ductal saturation probe placed on the right wrist. Analysis was performed on the first 10 min of data to investigate the correlation of PI with gestational age, heart rate, blood pressure, and lactate values. RESULTS: 33 infants with a median gestational age of 29 wks (IQR, 26-30 wks) and median birth weight of 1205 g (IQR, 925-1520 g) were included for analysis. The overall median PI value for the first 10 min was 1.3 (IQR, 0.86-1.68). There was no significant correlation found between delivery room PI and gestational age(r=0.28, 95% CI: -0.09, 0.59), lactate levels (r=-0.25, 95% CI: -0.62, 0.18) and blood pressure values (r=-0.18, 95% CI: -0.46, 0.20). An average correlation value of r=-0.417 (95% CI: - 0.531, 0.253) was found between PI and heart rate values. There was no statistical difference between the median of the median PI value over the first 5 min of life compared to the second 5 min (p=0.22). Variability, as quantified by the IQR, was higher in the first 5 min compared to the second 5 min: median of 0.5(IQR, 0.27, 0.92) vs 0.2(IQR, 0.10, 0.30) (p<0.00). CONCLUSIONS: Delivery room PI values are easily obtained, however, have significant variability over the first 5 min of life and may add little to delivery room assessment. PMID- 26025338 TI - The CD38 genotype (rs1800561 (4693C>T): R140W) is associated with an increased risk of admission to the neonatal intensive care unit. AB - BACKGROUNDS: Preterm birth (PTB)/admission to the neonatal intensive care unit (NICU) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. AIM: Given the role of CD38 in term delivery through oxytocin (OXT) release, we hypothesized that OXT signaling may play a role in the etiology of PTB/admission to the NICU. This study was designed to identify genetic variation in the CD38-oxytocin pathway associated with PTB/admission to the NICU. METHODS: To identify common genetic variants predisposing individuals to PTB/admission to the NICU, we genotyped two single nucleotide polymorphisms (SNPs) in the CD38-oxytocin pathway in 63 case mothers, 55 control mothers, and 188 female volunteers in Nara Medical University Hospital, Japan. RESULTS: Maternal genetic effect analysis of the SNP genotype data revealed a significant association between an SNP in CD38 (rs1800561 (4693C>T): R140W), which was reported to be correlated with diabetes and autism, and the risk of NICU admission. On the other hand, an SNP in the oxytocin receptor (OXTR) (rs2254298) showed no correlation with the risk of NICU admission. CONCLUSION: Our study points to an association between maternal common polymorphisms in the CD38 (rs1800561) gene in Japanese women and susceptibility to PTB/admission to the NICU. Future studies with larger sample sizes are needed to confirm the findings of this study. PMID- 26025339 TI - Vaccinations in paediatric rheumatology: an update on current developments. AB - In 2011, the European League Against Rheumatism (EULAR) published recommendations regarding the vaccination of children with rheumatic diseases. These recommendations were based on a systematic literature review published in that same year. Since then, the evidence body on this topic has grown substantially. This review provides an update of the systematic literature study of 2011, summarizing all the available evidence on the safety and immunogenicity of vaccination in paediatric patients with rheumatic diseases. The current search yielded 21 articles, in addition to the 27 articles described in the 2011 review. In general, vaccines are immunogenic and safe in this patient population. The effect of immunosuppressive drugs on the immunogenicity of vaccines was not detrimental for glucocorticosteroids and methotrexate. Biologicals could accelerate a waning of antibody levels over time, although most patients were initially protected adequately. Overall, persistence of immunological memory may be reduced in children with rheumatic diseases, which shows the need for (booster) vaccination. This update of the 2011 systematic literature review strengthens the evidence base for the EULAR recommendations, and it must be concluded that vaccinations in patients with rheumatic diseases should be advocated. PMID- 26025340 TI - Influence of anode surface chemistry on microbial fuel cell operation. AB - Self-assembled monolayers (SAMs) modified gold anodes are used in single chamber microbial fuel cells for organic removal and electricity generation. Hydrophilic (N(CH3)3(+), OH, COOH) and hydrophobic (CH3) SAMs are examined for their effect on bacterial attachment, current and power output. The different substratum chemistry affects the community composition of the electrochemically active biofilm formed and thus the current and power output. Of the four SAM-modified anodes tested, N(CH3)3(+) results in the shortest start up time (15 days), highest current achieved (225 MUA cm(-2)) and highest MFC power density (40 MUW cm(-2)), followed by COOH (150 MUA cm(-2) and 37 MUW cm(-2)) and OH (83 MUA cm( 2) and 27 MUW cm(-2)) SAMs. Hydrophobic SAM decreases electrochemically active bacteria attachment and anode performance in comparison to hydrophilic SAMs (CH3 modified anodes 7 MUA cm(-2) anodic current and 1.2 MUW cm(-2) MFC's power density). A consortium of Clostridia and delta-Proteobacteria is found on all the anode surfaces, suggesting a synergistic cooperation under anodic conditions. PMID- 26025341 TI - Autoimmune Hepatitis Type 2 Associated With Positive Antimitochondrial Antibodies: An Overlap Syndrome? PMID- 26025343 TI - How Do Intimate Partner Violent Men Talk About Self-Control? AB - This study investigates discourses that male perpetrators of intimate partner violence (IPV) use regarding self-control when talking about their IPV. Literature addressing the role of self-control in committing and avoiding using violence toward partners is discussed; however, it is shown that self-control has not been investigated from a discursive psychological perspective, in which the function of talk, rather than what this talk says about speakers' cognitions, is analyzed. Discourse analysis of interviews with six male perpetrators, currently attending treatment and selected for their recent and multiple uses of IPV, revealed that talk of lacking self-control was used to account for situations when individuals engaged in violence. Conversely, talk about having self-control was used to account for refraining from IPV. An improvement narrative in which perpetrators of violence talked about moving from lacking to gaining self-control was also evident. Talk about self-control however was not as simple as this suggests because of particular note is the situation where perpetrators offered varying levels of self-control within their accounts of violence where having and lacking self-control was presented simultaneously. This demonstrates that talk about self-control is a discursive device that is used flexibly by perpetrators to manage their accountability for acts of IPV. PMID- 26025344 TI - Relation Between Sexual Assault and Negative Affective Conditions in Female College Students: Does Loss of Hope Account for the Association? AB - The present study examined dispositional hope as a potential mediator of the association between sexual assault and negative affective conditions, namely, depressive and anxious symptoms in a sample of 223 female college students. Results from conducting bootstrapped mediation analyses indicated that hope agency, but not hope pathways, mediated the link between sexual assault victimization and negative affective conditions in females. Importantly, the associations of sexual assault with both depressive and anxious symptoms remained highly significant independent of hope. Some implications of the present findings are discussed. PMID- 26025342 TI - Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity. AB - BACKGROUND: Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. METHODS AND RESULTS: Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure-volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3 butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. CONCLUSIONS: Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase. PMID- 26025345 TI - ADHD Symptoms as Risk Factors for Intimate Partner Violence Perpetration and Victimization. AB - Preliminary evidence underscores links between attention-deficit hyperactivity disorder (ADHD) symptoms and intimate partner violence (IPV) perpetration and victimization. However, little is known about whether ADHD symptoms are uniquely associated with IPV perpetration and victimization beyond well-established risk factors of IPV commonly associated with the disorder. In a cross-sectional design, 433 college students rated their ADHD symptoms as well as frequencies of psychological and physical IPV perpetration and victimization. Additional risk factors of IPV included childhood maltreatment, primary psychopathy, alcohol abuse, and illicit drug use. Correlational analyses indicated that students with greater ADHD symptom severity reported higher rates of psychological and physical IPV perpetration, and higher rates of psychological IPV victimization. Regression analyses indicated that ADHD symptoms were not additive risk factors of psychological IPV perpetration and victimization. Students reporting any alcohol abuse or illicit drug use endorsed high rates of psychological IPV perpetration and victimization, regardless of their level of ADHD symptoms. However, students who reported no alcohol abuse or drug use, but did report greater ADHD symptom severity-particularly inattention, indicated higher rates of psychological IPV perpetration and victimization than those reporting no alcohol abuse or drug use and low ADHD symptoms. These findings extend prior research by indicating that alcohol abuse and illicit drug use moderate associations between ADHD symptoms and psychological IPV perpetration and victimization. Investigations are needed to identify mechanisms of the association between ADHD symptoms and IPV perpetration and victimization, particularly those abusing alcohol and drugs, for appropriate prevention and intervention efforts to be developed. PMID- 26025346 TI - Evaluation of the Effect of Enterococcus faecalis Biofilm on the 2% Chlorhexidine Substantivity: An In Vitro Study. AB - INTRODUCTION: The aim of this study was to correlate the bacterial viability and the presence of 2% chlorhexidine (CHX) solution on dentin by means of confocal laser scanning microscopy and high-performance liquid chromatography for 48 hours, 7 days, and 30 days. METHODS: One hundred twenty-three extracted human teeth were used. Samples were divided into 4 groups according to the solution (CHX or saline) and the presence of Enterococus faecalis biofilm. Samples were kept in contact with 5 mL of the solution for 5 minutes. Each group was divided into 3 subgroups according to the evaluation period (n = 10). Statistical analysis was performed by using the Kruskal-Wallis test, the Mann-Whitney U test (P < .05), and the Spearman rank correlation coefficient (P < .01). RESULTS: There was a negative correlation between the percentage of live cells and the amount of remaining CHX (P = .000). CHX significantly reduced the percentage of viable cells compared with saline after 48 hours (P = .007). Differences were maintained in the 7-day evaluation period (P = .001). After 30 days, the CHX group presented an increase of viable cells, thereby becoming similar to saline (P = .623). Simultaneously, the remaining CHX was significantly reduced in the 30 day specimens (P = .000). CONCLUSIONS: The results of this study indicate that 2% CHX solution was detected for 48 hours and 7 days with a low percentage of viable cells. The presence of microorganisms on human dentin did not affect 2% CHX maintenance. PMID- 26025347 TI - Assessment of Root Perforation within Simulated Internal Resorption Cavities Using Cone-beam Computed Tomography. AB - INTRODUCTION: Internal root resorption lesions may perforate external root surfaces, which may not be detectable on conventional radiographic images. The purpose of this study was to evaluate the accuracy of cone-beam computed tomographic (CBCT) imaging in the detection of small perforations within simulated internal resorption cavities. METHODS: Artificial internal root resorption cavities with minimal (0.1-0.2 mm) wall thickness were prepared at 64 sites on buccal and lingual halves of 32 single-rooted mandibular teeth that had been split mesiodistally. Perforations with 0.5-mm diameters were produced using a #40 K-file in half of the specimens. All teeth were placed in dry sheep mandibles and imaged using a NewTomVGi CBCT scanner (6 * 6 cm field of view, 0.1 mm resolution; NewTomQR srl, Verona, Italy). Two observers evaluated the images. Interexaminer and intraexaminer agreement were assessed using the kappa statistic. Sensitivity, specificity, and predictive values were used to assess diagnostic accuracy. RESULTS: Intra- and interobserver agreement on perforation detection were high. The sensitivity and specificity of CBCT-based detection of perforation in internal root resorption were 81.3% and 84.4%, respectively. CONCLUSIONS: CBCT imaging is useful for perforation detection in internal root resorption defects. PMID- 26025348 TI - Whole-body FDG PET-MR oncologic imaging: pitfalls in clinical interpretation related to inaccurate MR-based attenuation correction. AB - Simultaneous data collection for positron emission tomography and magnetic resonance imaging (PET/MR) is now a reality. While the full benefits of concurrently acquiring PET and MR data and the potential added clinical value are still being evaluated, initial studies have identified several important potential pitfalls in the interpretation of fluorodeoxyglucose (FDG) PET/MRI in oncologic whole-body imaging, the majority of which being related to the errors in the attenuation maps created from the MR data. The purpose of this article was to present such pitfalls and artifacts using case examples, describe their etiology, and discuss strategies to overcome them. Using a case-based approach, we will illustrate artifacts related to (1) Inaccurate bone tissue segmentation; (2) Inaccurate air cavities segmentation; (3) Motion-induced misregistration; (4) RF coils in the PET field of view; (5) B0 field inhomogeneity; (6) B1 field inhomogeneity; (7) Metallic implants; (8) MR contrast agents. PMID- 26025349 TI - Impact of surfactant assisted acid and alkali pretreatment on lignocellulosic structure of pine foliage and optimization of its saccharification parameters using response surface methodology. AB - In present study, two hybrid methods such as surfactant assisted acid pretreatment (SAAP) and surfactant assisted base pretreatment (SABP) of pine foliage (PF) were found efficient for removal of 59.53 +/- 0.76% and 73.47 +/- 1.03% lignin, respectively. Assessment of the impact of pretreatment over the structure of PF were studied by scanning electron microscopy, Fourier transform infrared and X-ray diffraction analysis. Parameters for saccharification of SAAP and SABP biomass were optimized by Box-Behnken design method and 0.588 g/g and 0.477 g/g of reducing sugars were obtained, respectively. The ethanol fermentation efficiency of Saccharomyces cerevisiae (NCIM 3288) of hydrolysates was increased by 16.1% and 6.01% in SAAP-PFF and SABP-PFF after detoxification with XAD-4 resin. The mass balance analysis of the process showed that 67.7% and 70.12% cellulose were utilized during SAAP and SABP, respectively. These results indicated that SAAP would be more economic for bioethanol production. PMID- 26025350 TI - Degradation properties of protein and carbohydrate during sludge anaerobic digestion. AB - Degradation of protein and carbohydrate is vital for sludge anaerobic digestion performance. However, few studies focused on degradation properties of protein and carbohydrate. This study investigated detailed degradation properties of sludge protein and carbohydrate in order to gain insight into organics removal during anaerobic digestion. Results showed that carbohydrate was more efficiently degraded than protein and was degraded prior to protein. The final removal efficiencies of carbohydrate and protein were 49.7% and 32.2%, respectively. The first 3 days were a lag phase for protein degradation since rapid carbohydrate degradation in this phase led to repression of protease formation. Kinetics results showed that, after initial lag phase, protein degradation followed the first-order kinetic with rate constants of 0.0197 and 0.0018 d(-1) during later rapid degradation phase and slow degradation phase, respectively. Carbohydrate degradation also followed the first-order kinetics with a rate constant of 0.007 d(-1) after initial quick degradation phase. PMID- 26025351 TI - Tracking the dynamics of heterotrophs and nitrifiers in moving-bed biofilm reactors operated at different COD/N ratios. AB - In this study, the impact of COD/N ratio and feeding regime on the dynamics of heterotrophs and nitrifiers in moving-bed biofilm reactors was addressed. Based on DGGE analysis of 16S rRNA genes, the influent COD was found to be the main factor determining the overall bacterial diversity. The amoA-gene-based analysis suggested that the dynamic behavior of the substrate in continuous and pulse feeding reactors influenced the selection of specific ammonium-oxidizing bacteria (AOB) strains. Furthermore, AOB diversity was directly related to the applied COD/N ratio and ammonium-nitrogen load. Maximum specific ammonium oxidation rates observed under non-substrate-limiting conditions were observed to be proportional to the fraction of nitrifiers within the bacterial community. FISH analysis revealed that Nitrosomonas genus dominated the AOB community in all reactors. Moreover, Nitrospira was found to be the only nitrite-oxidizing bacteria (NOB) in the fully autotrophic system, whereas Nitrobacter represented the dominant NOB genus in the organic carbon-fed reactors. PMID- 26025352 TI - Continuous xylose fermentation by Clostridium acetobutylicum--Assessment of solventogenic kinetics. AB - This work deals with the specific butanol production rate of Clostridium acetobutylicum using xylose--a relevant fraction of lignocellulosic feedstock for biofuel production--as carbon source. The tests were carried out in a CSTR equipped with a microfiltration unit. The dilution rate (D) ranged between 0.02 and 0.22 h(-1) and the ratio R between the permeate stream rate and the stream fed to the reactor ranged between 14% and 88%. The biomass present in the broth was identified as a heterogeneous cell population consisting of: acidogenic cells, solventogenic cells and spores. The results were processed to assess the concentration of acidogenic cells, solventogenic cells and spores. The specific butanol production rate was also assessed. The max butanol productivity was 1.3 g L(-1) h(-1) at D = 0.17 h(-1) and R = 30%. A comparison between the results reported in a previous work carried out with lactose was made. PMID- 26025353 TI - The influence of cultivation period on growth and biodiesel properties of microalga Nannochloropsis gaditana 1049. AB - This work reported for the first time the detailed impacts of cultivation period on growth dynamics and biochemical composition of a microalga strain Nannochloropsis gaditana 1049. The results shown either the biomass accumulation, lipid content, neutral lipid content, monounsaturated fatty acids composition or the favorable fatty acid profile of C16-C18 increased along with the cultivation period extension, but the lipid productivity displayed a decrease since cultured for 16 days, with the highest value reached 289.51 +/- 16.34 mg L(-1) d(-1). Biodiesel properties of this microalga also changed with the cultivation period extension, with average unsaturated degree decreased from 1.24 +/- 0.03 to 0.59 +/- 0.02, cloud point increased from 3.39 +/- 0.40 degrees C to 12.14 +/- 0.32 degrees C, cetane number increased from 54.59 +/- 0.20 to 58.96 +/- 0.16 and iodine number reduced sharply from 105.15 +/- 2.24 gI2/100g to 56.44 +/- 1.76 gI2/100g, which all satisfied the specifications of biodiesel standard. PMID- 26025354 TI - Current indications for the osteoplastic flap. AB - INTRODUCTION AND OBJECTIVES: Endoscopic sinus surgery is the technique of choice in most of the frontal sinus diseases, both inflammatory and tumour-related. This is why the external approach using osteoplastic flap (OF) would be limited to cases with a difficult endoscopic approach. Our aim was to review the current indications of the osteoplastic flap in the treatment of frontal sinus pathology, through a retrospective study of patients undergoing this technique. METHODS: We performed a retrospective study of 14 patients who were treated with the osteoplastic flap procedure. All the surgical indication criteria, type of sinus disease, presence or absence of prior endoscopic surgery, surgical findings, complications and recurrence were reviewed. RESULTS: The pathologies found were 1 osteoma (7.1%), 3 inverted papilloma (21.4%) and 10 mucoceles (71.4%). Nine patients had a prior endoscopic surgery and 10 patients had an orbital dehiscence (9 mucocele, 1 papilloma). Frontal osteoma was Grade IV and the papilloma cases were Krouse Stage III. Surgical revision was required for 21.4%. CONCLUSIONS: The main indications for an OF in patients with inflammatory disease are lateral extension and frontal recess neo-osteogenesis. In osteoma cases, it depends on the size of the tumour. In inverted papilloma cases, the indication is multifocal implantation with origin in the anterior and lateral wall. In all cases, performing the osteoplastic flap must be individualised. PMID- 26025355 TI - Discharging mastoid cavity caused by necrosis of the modiolus. PMID- 26025356 TI - Extended high-frequency audiometry (9,000-20,000 Hz). Usefulness in audiological diagnosis. AB - Early detection and appropriate treatment of hearing loss are essential to minimise the consequences of hearing loss. In addition to conventional audiometry (125-8,000 Hz), extended high-frequency audiometry (9,000-20,000 Hz) is available. This type of audiometry may be useful in early diagnosis of hearing loss in certain conditions, such as the ototoxic effect of cisplatin-based treatment, noise exposure or oral misunderstanding, especially in noisy environments. Eleven examples are shown in which extended high-frequency audiometry has been useful in early detection of hearing loss, despite the subject having a normal conventional audiometry. The goal of the present paper was to highlight the importance of the extended high-frequency audiometry examination for it to become a standard tool in routine audiological examinations. PMID- 26025357 TI - Ear malformations, hearing loss and hearing rehabilitation in children with Treacher Collins syndrome. AB - OBJECTIVE: The aim of this study was to assess the main ear malformations, hearing loss and auditory rehabilitation in children with Treacher Collins syndrome. METHODS: We performed a retrospective study of 9 children with Treacher Collins syndrome treated in a central hospital between January 2003 and January 2013. RESULTS: This study showed a high incidence of malformations of the outer and middle ear, such as microtia, atresia or stenosis of the external auditory canal, hypoplastic middle ear cavity, dysmorphic or missing ossicular chain. Most patients had bilateral hearing loss of moderate or high degree. In the individuals studied, there was functional improvement in patients with bone anchored hearing aids in relation to conventional hearing aids by bone conduction. CONCLUSIONS: Treacher Collins syndrome is characterized by bilateral malformations of the outer and middle ear. Hearing rehabilitation in these children is of utmost importance, and bone-anchored hearing aids is the method of choice. PMID- 26025358 TI - Bilateral recurrent laryngeal nerve injury in total thyroidectomy with or without intraoperative neuromonitoring. Systematic review and meta-analysis. AB - INTRODUCTION AND OBJECTIVE: The risk of producing bilateral laryngeal paralysis (BLP) in total thyroidectomy (TT) is low, but it is a concern for the surgeon and a serious safety incident that may compromise the airway, require reintubation or tracheostomy and cause serious sequelae or death. Neuromonitoring (NM), as an early diagnostic tool for the existence of injury to the recurrent laryngeal nerve (RLN), has not been shown to have reduced the risk, even though published series show lower incidences. Our objective was to estimate the risk of bilateral RLN paralysis with and without NM TT by systematic review and meta-analysis. METHOD: We performed a systematic review of clinical trials, cohort studies and case series with total thyroidectomy without NM published in the period 2000 2014. A database search was performed using PubMed, Scopus (EMBASE) and the Cochrane Library. Heterogeneity between studies was explored and weighted risks grouped according to random effects models were estimated. RESULTS: We selected 40 articles and estimates of risk were identified in 54 case series (without NM, 25; with NM, 29) with 30,922 patients. The prevalence of BLP in the series with NM was lower compared to that without NM (2.430/00, [1.55 to 3.50/00] versus 5.180/00 [2.53 to 8.70/00]). This difference is equivalent to an absolute risk reduction of 2.750/00 with a number needed to treat of 364.13. The NM group was more homogeneous (I2=7.52%) than those without NM (I2=79.32%). The observed differences in the subgroup analysis were very imprecise because the number of observed paralysis was very low. CONCLUSIONS: The risk of bilateral paralysis is lower in studies with neuromonitoring. PMID- 26025359 TI - Structural, optical and magnetic properties of gamma-irradiated SiO2 xerogel doped Fe2O3. AB - The paper deals with the structure, morphology and magnetic properties of two different iron concentrations (20 and 33 mol.%) of Fe2O3-SiO2 nanocomposites, prepared by sol-gel technique and exposed to different gamma-irradiation doses (0, 30 and 60 kGy). The nanocomposites were investigated through XRD, TEM, SEM, FTIR and EPR measurements. Superparamagnetic iron (III) oxide nanoparticles with a narrow size distribution, dispersed over the amorphous silica matrix, are assumed to be present in all the samples before and after irradiation. Before irradiation, a lot of gamma-Fe2O3 crystalline ferromagnetic nanoparticles are assumed to be formed particularly for sample containing 33 mol.% Fe2O3, while exposing the samples to irradiation results in the transformation of gamma- to alpha-Fe2O3. Iron concentrations and/or irradiation of the samples are assumed to cause changes in the bond angles and/or bond lengths of the structural silicate units within network, as well, the increase of more defect centers induced by irradiation as evident through the variations of the IR bands intensity. The EPR results show both intensity and line width increase with increasing Fe2O3 concentration. The EPR signals for the samples consist of a well defined symmetrical broad signal at g~2.0 ascribed to antiferromagnetic interactions between the Fe(2+) and Fe(3+) clusters. Condensed clusters of Fe(3+) ions are observed to give rise to a resonance line at g~2 whose position and width do not depend on the Fe2O3 concentrations. The EPR signal intensity is observed to be significantly decreased in the sample 33 mol.% or stabilized in the sample 20 mol.% by gamma-irradiation. This reflects simultaneous spin transformation from the high-spin state of Fe III to the low-spin state of Fe II. As a final point, an effort has been given to found the possibility to use one of these studied nanocomposite materials as candidate for radiation shielding purposes. PMID- 26025360 TI - [Recommendations for management of acute pharyngitis in adults]. AB - Acute pharyngitis in adults is one of the most common infectious diseases seen in general practitioners' consultations. Viral aetiology is the most common. Among bacterial causes, the main agent is Streptococcus pyogenes or group A beta haemolytic streptococcus (GABHS), which causes 5%-30% of the episodes. In the diagnostic process, clinical assessment scales can help clinicians to better predict suspected bacterial aetiology by selecting patients who should undergo a rapid antigen detection test. If these techniques are not performed, an overdiagnosis of streptococcal pharyngitis often occurs, resulting in unnecessary prescriptions of antibiotics, most of which are broad spectrum. Consequently, management algorithms that include the use of predictive clinical rules and rapid tests have been set up. The aim of the treatment is speeding up symptom resolution, reducing the contagious time span and preventing local suppurative and non-suppurative complications. Penicillin and amoxicillin are the antibiotics of choice for the treatment of pharyngitis. The association of amoxicillin and clavulanate is not indicated as the initial treatment of acute infection. Neither are macrolides indicated as first-line therapy; they should be reserved for patients allergic to penicillin. The appropriate diagnosis of bacterial pharyngitis and proper use of antibiotics based on the scientific evidence available are crucial. Using management algorithms can be helpful in identifying and screening the cases that do not require antibiotic therapy. PMID- 26025361 TI - Ordered Regions of Channel Nucleoporins Nup62, Nup54, and Nup58 Form Dynamic Complexes in Solution. AB - Three out of ~30 nucleoporins, Nup62, Nup54, and Nup58, line the nuclear pore channel. These "channel" nucleoporins each contain an ordered region of ~150-200 residues, which is predicted to be segmented into 3-4 alpha-helical regions of ~40-80 residues. Notably, these segmentations are evolutionarily conserved between uni- and multicellular eukaryotes. Strikingly, the boundaries of these segments match our previously reported mapping and crystal data, which collectively identified two "cognate" segments of Nup54, each interacting with cognate segments, one in Nup58 and the other one in Nup62. Because Nup54 and Nup58 cognate segments form crystallographic hetero- or homo-oligomers, we proposed that these oligomers associate into inter-convertible "mid-plane" rings: a single large ring (40-50 nm diameter, consisting of eight hetero-dodecamers) or three small rings (10-20 nm diameter, each comprising eight homo-tetramers). Each "ring cycle" would recapitulate "dilation" and "constriction" of the nuclear pore complex's central transport channel. As for the Nup54.Nup62 interactome, it forms a 1:2 triple helix ("finger"), multiples of which project alternately up and down from mid-plane ring(s). Collectively, our previous crystal data suggested a copy number of 128, 64, and 32 for Nup62, Nup54, and Nup58, respectively, that is, a 4:2:1 stoichiometry. Here, we carried out solution analysis utilizing the entire ordered regions of Nup62, Nup54, and Nup58, and demonstrate that they form a dynamic "triple complex" that is heterogeneously formed from our previously characterized Nup54.Nup58 and Nup54.Nup62 interactomes. These data are consistent both with our crystal structure-deduced copy numbers and stoichiometries and also with our ring cycle model for structure and dynamics of the nuclear pore channel. PMID- 26025362 TI - Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation. AB - Albuminuria contributes to the development and progression of chronic kidney disease by inducing tubulointerstitial inflammation (TI) and fibrosis. However, the exact mechanisms of TI in response to albuminuria are unresolved. We previously demonstrated that NLRP3 and inflammasomes mediate albumin-induced lesions in tubular cells. Here, we further investigated the role of endocytic receptors and lysosome rupture in NLRP3 inflammasome activation. A murine proteinuric nephropathy model was induced by albumin overload as described previously. The priming and activation signals for inflammasome complex formation were evoked simultaneously by albumin excess in tubular epithelial cells. The former signal was dependent on a albumin-triggered NF-kappaB pathway activation. This process is mediated by the endocytic receptor, megalin and cubilin. However, the silencing of megalin or cubilin inhibited the albumin-induced NLRP3 signal. Notably, subsequent lysosome rupture and the corresponding release of lysosomal hydrolases, especially cathepsin B, were observed in tubular epithelial cells exposed to albumin. Cathepsin B release and distribution are essential for NLRP3 signal activation, and inhibitors of cathepsin B suppressed the NLRP3 signal in tubular epithelial cells. Taken together, our findings suggest that megalin/cubilin and lysosome rupture are involved in albumin-triggered tubular injury and TI. This study provides novel insights into albuminuria-induced TI and implicates the active control of albuminuria as a critical strategy to halt the progression of chronic kidney disease. PMID- 26025363 TI - Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced gamma-Secretase-dependent and -independent Apoptosis, Respectively. AB - Presenilin 1 (PS1) has been implicated in apoptosis; however, its mechanism remains elusive. We report that PS1-induced apoptosis was associated with cellular FLICE-like inhibitory protein (c-FLIP) turnover and that gamma-secretase inhibitor blocked c-FLIP turnover and also partially blocked PS1-induced apoptosis. A complete inhibition of PS1-induced apoptosis was achieved by knockdown of PS1-associated protein (PSAP), a mitochondrial proapoptotic protein that forms a complex with Bax upon induction of apoptosis, in the presence of gamma-secretase inhibitor. PS1-induced apoptosis was partially inhibited by knockdown of caspase-8, Fas-associated protein with death domain (FADD), or Bid. However, knockdown of Bax or overexpression of Bcl-2 resulted in complete inhibition of PS1-induced apoptosis. These data suggest that PS1 induces apoptosis through two pathways: the gamma-secretase-dependent pathway mediated by turnover of c-FLIP and the gamma-secretase-independent pathway mediated by PSAP Bax complex formation. These two pathways converge on Bax to activate mitochondria-dependent apoptosis. These findings provide new insight into the mechanisms by which PS1 is involved in apoptosis and the mechanism by which PS1 exerts its pathogenic effects. In addition, our results suggest that PS2 induces apoptosis through a pathway that is different from that of PS1. PMID- 26025364 TI - Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo. AB - The cascade of events that lead to cognitive decline, motor deficits, and psychiatric symptoms in patients with Huntington disease (HD) is triggered by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein. A significant mechanism in HD is the generation of mutant HTT fragments, which are generally more toxic than the full-length HTT. The protein fragments observed in human HD tissue and mouse models of HD are formed by proteolysis or aberrant splicing of HTT. To systematically investigate the relative contribution of the various HTT protein proteolysis events observed in vivo, we generated transgenic mouse models of HD representing five distinct proteolysis fragments ending at amino acids 171, 463, 536, 552, and 586 with a polyglutamine length of 148. All lines contain a single integration at the ROSA26 locus, with expression of the fragments driven by the chicken beta-actin promoter at nearly identical levels. The transgenic mice N171-Q148 and N552-Q148 display significantly accelerated phenotypes and a shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. We hypothesized that the accelerated phenotype was due to altered HTT protein interactions/complexes that accumulate with age. We found evidence for altered HTT complexes in caspase-2 fragment transgenic mice (N552 Q148) and a stronger interaction with the endogenous HTT protein. These findings correlate with an altered HTT molecular complex and distinct proteins in the HTT interactome set identified by mass spectrometry. In particular, we identified HSP90AA1 (HSP86) as a potential modulator of the distinct neurotoxicity of the caspase-2 fragment mice (N552-Q148) when compared with the caspase-6 transgenic mice (N586-Q148). PMID- 26025365 TI - Polyamines Stimulate the Level of the sigma38 Subunit (RpoS) of Escherichia coli RNA Polymerase, Resulting in the Induction of the Glutamate Decarboxylase dependent Acid Response System via the gadE Regulon. AB - To study the physiological roles of polyamines, we carried out a global microarray analysis on the effect of adding polyamines to an Escherichia coli mutant that lacks polyamines because of deletions in the genes in the polyamine biosynthetic pathway. Previously, we have reported that the earliest response to polyamine addition is the increased expression of the genes for the glutamate dependent acid resistance system (GDAR). We also presented preliminary evidence for the involvement of rpoS and gadE regulators. In the current study, further confirmation of the regulatory roles of rpoS and gadE is shown by a comparison of genome-wide expression profiling data from a series of microarrays comparing the genes induced by polyamine addition to polyamine-free rpoS(+)/gadE(+) cells with genes induced by polyamine addition to polyamine-free DeltarpoS/gadE(+) and rpoS(+)/DeltagadE cells. The results indicate that most of the genes in the E. coli GDAR system that are induced by polyamines require rpoS and gadE. Our data also show that gadE is the main regulator of GDAR and other acid fitness island genes. Both polyamines and rpoS are necessary for the expression of gadE gene from the three promoters of gadE (P1, P2, and P3). The most important effect of polyamine addition is the very rapid increase in the level of RpoS sigma factor. Our current hypothesis is that polyamines increase the level of RpoS protein and that this increased RpoS level is responsible for the stimulation of gadE expression, which in turn induces the GDAR system in E. coli. PMID- 26025366 TI - Outcomes associated with anxiety and depression among men who have sex with men in Estonia. AB - BACKGROUND: Evidence supports that gay, lesbian, and transgender populations are at increased risk for mental health problems. The current study was conducted to estimate the prevalence of anxiety and depressive symptoms and related factors among men who have sex with men (MSM) in Estonia. This is the only known study of its type in the Eastern European region. METHODS: In 2013, an Internet-based survey was conducted among men who have sex with men, collecting data on socio demographics, sexuality, drug and alcohol use, mental health, suicidality, and internalized homonegativity. RESULTS: 265 MSM completed the questionnaire (median age 31 years, 90% Estonian, 71% from the capital; 73% employed full-time, 42% with at least college education; 44% in a steady relationship; 72% gay, 23% bisexual; 23% reported illegal drug use in the last 12 months). One third met criteria for problem drinking and depressive symptoms with one quarter for anxiety symptoms. Suicidality was 44% reported lifetime suicidal thoughts and 11% with at least one suicide attempt. LIMITATIONS: The study instruments, EST-Q and CAGE, only measure symptoms and are not diagnostic tests. A non-random sample which could possibly include persons with easier internet access. Self-reported data and cross-sectional study design are prone to issues with recall bias and temporality. CONCLUSIONS: With demonstrated high rates of anxiety, depression, drinking, and drug use among MSM which is consistent with similar studies in Western countries, further research could help determine effective MSM focused interventions to address the broad spectrum of issues among MSM. PMID- 26025367 TI - EEG correlates of the severity of posttraumatic stress symptoms: A systematic review of the dimensional PTSD literature. AB - BACKGROUND: Considering the Research Domain Criteria (RDoC) framework, it is crucial to investigate posttraumatic stress disorder (PTSD) as a spectrum that ranges from normal to pathological. This dimensional approach is especially important to aid early PTSD detection and to guide better treatment options. In recent years, electroencephalography (EEG) has been used to investigate PTSD; however, reviews regarding EEG data related to PTSD are lacking, especially considering the dimensional approach. This systematic review examined the literature regarding EEG alterations in trauma-exposed people with posttraumatic stress symptoms (PTSS) to identify putative EEG biomarkers of PTSS severity. METHOD: A systematic review of EEG studies of trauma-exposed participants with PTSS that reported dimensional analyses (e.g., correlations or regressions) between PTSS and EEG measures was performed. RESULTS: The literature search yielded 1178 references, of which 34 studies were eligible for inclusion. Despite variability among the reviewed studies, the PTSS severity was often associated with P2, P3-family event-related potentials (ERPs) and alpha rhythms. LIMITATIONS: The search was limited to articles published in English; no information about non-published studies or studies reported in other languages was obtained. Another limitation was the heterogeneity of studies, which made meta-analysis challenging. CONCLUSIONS: EEG provides promising candidates to act as biomarkers, although further studies are required to confirm the findings. Thus, EEG, in addition to being cheaper and easier to implement than other central techniques, has the potential to reveal biomarkers of PTSS severity. PMID- 26025368 TI - Lifestyle change recommendations in major depression: Do they work? AB - BACKGROUND: Modifying some lifestyle factors can be useful in depression, at least as an adjuvant treatment. Combining different lifestyle interventions seems to be an adequate strategy to increase their antidepressant efficacy according with preliminary studies, but this issue has not been enough investigated. METHODS: The present study is a randomized, double-blinded, multicentre, two arm parallel clinical trials, with a 12 month follow-up. The sample consisted of 273 Primary Care patients. Four combined hygienic-dietary written recommendations were given to the patients about diet, exercise, light exposure and sleep hygiene. RESULTS: Both active and control interventions were associated with improvement on BDI (Beck Depression Inventory) scores. However, there were not statistically significant differences (7.0 vs. 7.6; p=0.594). LIMITATIONS: We were unable to monitor whether patients carry out recommendations. Intervention could be too difficult to accomplish for depressed patients without enough support and supervision. CONCLUSIONS: Just giving written lifestyle recommendations are not enough for depressive patients to benefit from them, so perhaps lifestyle change recommendations work or do not work on Depression depending on how they are presented to patients and on monitoring systems of their implementation. PMID- 26025369 TI - Identifying prevention strategies for adolescents to reduce their risk of depression: A Delphi consensus study. AB - BACKGROUND: Adolescence is a peak time for the onset of depression, but little is known about what adolescents can do to reduce their own level of risk. METHOD: This study employed the Delphi methodology to establish expert consensus on self help prevention strategies for adolescent depression. A literature search identified 194 recommendations for adolescents. These were presented over three questionnaire rounds to panels of 32 international research and practice experts and 49 consumer advocates, who rated the preventive importance of each recommendation and the feasibility of their implementation by adolescents. RESULTS: 145 strategies were endorsed as likely to be helpful in reducing adolescents' risk of developing depression by >=80% of both panels. Endorsed strategies included messages on mental fitness, personal identity, life skills, healthy relationships, healthy lifestyles, and recreation and leisure. 127 strategies were endorsed as likely to be helpful in reducing risks for depression for both junior and senior adolescents. One strategy was rated as likely to be helpful during the period of junior adolescence only, and 17 strategies were endorsed for the senior adolescent period only. Ratings of the ease of implementing the strategies during the adolescent period accorded by panellists were typically moderate. LIMITATIONS: This study used experts from developed, English-speaking countries; hence the strategies identified may not be for relevant or minority cultures within these countries or for other countries. CONCLUSIONS: This study produced a set of self-help preventive strategies for depression that are supported by research evidence and/or international experts, which can now be promoted in developed English-speaking communities to help adolescents reduce their risk of depression. PMID- 26025370 TI - Neural correlates of successful psychotherapy of depression in adolescents. AB - BACKGROUND: While major effort has been put in investigating neural correlates of depression and its treatment in adults, less is known about the effects of psychotherapy in adolescents. Given the concordance of the ventral striatum, amygdala, hippocampus and the subgenual anterior cingulate cortex (sgACC) as correlates of depression and their involvement in reward processing, we used functional magnetic resonance imaging (fMRI) during performance of a monetary reward task in an intervention versus waitlist-control design to investigate the clinical and neural effects of cognitive behavioral group therapy (CBT-G). METHODS: 22 medication naive adolescents with major depressive disorder were scanned before and after five sessions of CBT-G (PAT-I), or before and after five weeks of waiting (PAT-W). Changes in symptom scales were analyzed along with neural activation changes within the amygdala, hippocampus, sgACC and ventral striatum regions of interest (ROI). RESULTS: Psychometric assessments and ROI activation remained unchanged in PAT-W. In PAT-I, significant reduction in clinical symptoms accompanied significant changes in brain activation within the left amygdala, left hippocampus and bilateral sgACC. In line with previous findings in adults, pre-to-post-activation changes in the bilateral sgACC correlated with pre-to-post and pre-to-follow-up symptom improvement, and individual expressions of sgACC activation before treatment were related to pre to-follow-up therapeutic success. LIMITATIONS: Future studies should include larger sample sizes. CONCLUSIONS: Successful group psychotherapy of depression in adolescents was related to signal changes in brain regions previously demonstrated to be reliably linked with successful, particularly pharmacological treatment in adults. PMID- 26025371 TI - The validity of the symptom checklist depression and anxiety subscales: A general population study in Sweden. AB - BACKGROUND: The Symptom Checklist (SCL) is used as a screening tool in patient settings, but is also used as a diagnostic proxy for depression and anxiety in public health surveys. However, there are few validation studies based on general population samples. This study aims to validate the SCL subscales for depression and anxiety in a general population sample in Stockholm, Sweden. METHODS: We used a stratified random sample answering first a postal questionnaire covering SCL (n=8613) and then a semi-structured psychiatric interview based using Schedules for Clinical Assessment in Neuropsychiatry (SCAN, n=881). Agreement between SCL depression (SCL-DEP) and anxiety (SCL-ANX) scales and their respective DSM-IV disorder was examined by ROC analysis. Discriminant analysis was performed with factor analysis on the SCL depression and anxiety items. The SCL-DEP scale was also compared with the ability of the Major Depression Inventory (MDI) in detecting depressive disorders. RESULTS: A factor analysis with two factors differentiated the two subscales, with some cross loading items. The SCL-DEP and ANX subscales agreement with depression and anxiety disorders was good. SCL-DEP MDI performed better in detecting DSM-IV depression. LIMITATIONS: The questionnaire only included the SCL depression, anxiety and hostility subscales and not the full SCL-90. Also, no other anxiety scale was available for comparison. CONCLUSION: We conclude that depression and anxiety subscales are suitable instrument for proxies of depression and anxiety disorder in public health surveys. PMID- 26025372 TI - Residue Depletion Study of Danofloxacin in Cultured Tilapia (Oreochromis mossambicus). AB - Danofloxacin is an antibacterial drug of the fluoroquinolone group developed for therapeutic purposes in veterinary medicine. The studies described here include investigations of the residues following a single dose or multiple doses of danofloxacin. Residue depletion studies were performed to determine residues in plasma and tissues of saltwater tilapia fish (Oreochromis mossambicus) after a single oral administration of danofloxacin at the dose of 10 mg/kg body weight and also after daily dose of 10 mg/kg body weight for five consecutive days. Danofloxacin residues were analyzed by HPLC with fluorescence detection. Following a single oral dose, danofloxacin residues in 6 h postdosing tilapia were at a maximum of 1.44, 12.48, and 13.18 MUg/g in serum, liver, and kidney samples, respectively, while a peak muscle concentration of 2.15 MUg/g was reached at 12 h. From single-dose data, the concentration of danofloxacin in serum, muscle, liver, and kidney samples declined with half-lives of 29, 34, 49, and 44 h, respectively. Based on the maximum residue level (MRL) of 0.1 MUg/g in edible tissue for fin fish, the withdrawal times of danofloxacin in muscle were estimated to fall below the MRL after a withdrawal period of 21 days following the multiple-dose administration. These results may be helpful to regulatory agencies as they determine what tissues should be monitored to ensure that the established residue safety tolerance levels are not exceeded. PMID- 26025373 TI - [Lupus erythematosus]. AB - BACKGROUND: Lupus erythematosus is an autoimmune disease with a broad spectrum of cutaneous manifestations. The pathogenesis of lupus is based on a loss of tolerance against self antigens and can be mediated by defects in apoptosis, defects in eliminating cellular remnants and increased activation of the innate as well as the adaptive immune system. The increased activation of the innate immune system can be mediated by sensing of endogenous or exogenous nucleic acids, genetic variants in the components of the receptor cascade or disturbances in restriction of self nucleic acids. The inflammatory milieu is characterized by type I interferon expression and autoantibody production. The main trigger factors of the disease are sun exposure and viral infections. TREATMENT: Lupus erythematosus is effectively treated by glucocorticosteroids. Approved alternatives for long-term treatment are antimalarial agents and the B-cell inhibitor belimumab for patients with systemic lupus erythematosus. CONCLUSION: Future studies should more intensely analyse the effect of novel therapies on cutaneous manifestations to allow early detection of cutaneous lupus. Furthermore novel therapeutic strategies which specifically target the responsible pathogenetic mechanisms of the individual subtypes of lupus erythematosus are needed to improve the therapeutic success for this heterogeneous patient population. PMID- 26025374 TI - Contagious epididymitis due to Brucella ovis: relationship between sexual function, serology and bacterial shedding in semen. AB - BACKGROUND: Contagious Epididymitis (CE) due to Brucella ovis (B. ovis) is a contagious disease that impairs rams' fertility due to epididymis, testicle and accessory sexual gland alterations. An increased incidence of CE has been observed in South Eastern France ("PACA" region) since the Rev.1 vaccination against B. melitensis has been stopped in 2008. The objective of this study was to evaluate the relationship between the infection by B. ovis and the sexual function of rams. Two-hundred eighteen sexually-mature rams, from 11 seropositive flocks, were submitted to a clinical examination of the genital tract, a semen collection by electro-ejaculation for spermogram and culture, and a serological examination for anti-B. ovis antibodies by complement fixation test (CFT) and indirect ELISA (I-ELISA). The relationships between clinical, seminal, bacteriological and serological parameters were studied using the Fisher exact test and a logistic regression model (binomial logit). RESULTS: B. ovis shedding in semen was significantly associated with seropositivity (CFT and I-ELISA; p < 0.001 and 0.01 respectively), genital tract alterations (p < 0.05) and poor semen quality (p < 0.001). Seropositive rams presented significantly more genital tract alterations (p < 0.001) and a poor seminal score (p < 0.001) than seronegative rams. CONCLUSIONS: Since semen culture is not routinely feasible in field conditions, a control plan of CE should be based, where Rev.1 vaccination is not possible, on both systematic clinical and serological examination of rams, followed by the culling of seropositive and/or genital tract alterations carrier rams. PMID- 26025375 TI - Association between dietary patterns and metabolic syndrome in individuals with normal weight: a cross-sectional study. AB - BACKGROUND: The results of several papers have confirmed the existence of correlations between an unhealthy diet and the presence of metabolic syndrome. However, relationships between eating habits and metabolic obesity with normal weight have not yet been sufficiently studied. The aim of the study is to determine which dietary patterns are present in individuals with a normal BMI and to find out whether those patterns were connected with the risk of metabolic syndrome and its features. METHODS: A cross-sectional study was carried out in a group of 2479 subjects with a normal weight (BMI = 18.5-24.9 kg/m(2)), aged between 37-66. The study included the evaluation of eating habits, anthropometric measurements, blood pressure tests and the analysis of the collected fasting blood samples, on the basis of which cholesterol, triglycerides and glucose levels were determined. Dietary patterns were determined by means of factor analysis. RESULTS: In the group of individuals with a normal BMI, four dietary patterns were distinguished: "healthy", "fat, meat and alcohol", "prudent" and "coca cola, hard cheese and French fries". After controlling for potential confounders, subjects in the highest tertile of prudent dietary pattern scores had a lower odds ratio for the metabolic obesity normal weight) (odds ratio: 0.69; 95% CI: 0.53-0.89; p < 0.01) and low HDL cholesterol (odds ratio: 0.77; 95% CI: 0.59-0.99; p < 0.05), in comparison to those from the lowest tertile, whereas the individuals in the second tertile had a higher odds ratio for the increased blood glucose concentration than those in the lowest tertile (odds ratio: 0.74; 95% CI: 0.57-0.96; p < 0.05). CONCLUSION: A dietary pattern characterized by a high consumption of fish and whole grains, and a low consumption of refined grains, sugar, sweets and cold cured meat, is connected with lower risk of metabolic obesity normal weight as well as with the lower risk of low HDL cholesterol concentration and increased glucose concentration. PMID- 26025376 TI - Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain. AB - Astrocytes are the most abundant cell type in the mammalian brain and are important for the functions of the central nervous system. Glial fibrillary acidic protein (GFAP) is regarded as a hallmark of mature astrocytes, though some GFPA-positive cells may act as neural stem cells. Missense heterozygous mutations in GFAP cause Alexander disease that manifests leukodystrophy and intellectual disability. Here, we show that CUL4B, a scaffold protein that assembles E3 ubiquitin ligase, represses the expression of GFAP in neural progenitor cells (NPCs) during brain development. Lack of Cul4b in NPCs in cultures led to increased generation of astrocytes, marked by GFAP and S100beta. The GFAP+ cells were also found to be more abundant in the brains of nervous system-specific Cul4b knockout mice in vivo. Moreover, we demonstrated that the increased generation of GFAP+ cells from Cul4b-null NPCs was mediated by an upregulation of prostaglandin D2 synthase PTGDS. We showed that the increased GFAP expression can be attenuated by pharmacological inhibition of the PTGDS enzymatic activity or by shRNA-mediated knockdown of Ptgds. Importantly, exogenously added PTGDS could promote the generation of GFAP+ cells from wild-type NPCs. We further observed that Ptgds is targeted and repressed by the CUL4B/PRC2 complex. Together, our results demonstrate CUL4B as a negative regulator of GFAP expression during neural development. PMID- 26025377 TI - Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming. AB - Mitochondrial dysfunction caused by pathogenic mutations in mitochondrial tRNA genes emerges only when mutant mitochondrial DNA (mtDNA) proportions exceed intrinsic pathogenic thresholds; however, little is known about the actual proportions of mutant mtDNA that can affect particular cellular lineage determining processes. Here, we mainly focused on the effects of mitochondrial respiratory dysfunction caused by m.3243A>G heteroplasmy in MT-TL1 gene on cellular reprogramming. We found that generation of induced pluripotent stem cells (iPSCs) was drastically depressed only by high proportions of mutant mtDNA (>= 90% m.3243A>G), and these proportions were strongly associated with the degree of induced mitochondrial respiratory dysfunction. Nevertheless, all established iPSCs, even those carrying ~ 100% m.3243A>G, exhibited an embryonic stem cell-like pluripotent state. Therefore, our findings clearly demonstrate that loss of physiological integrity in mitochondria triggered by mutant mtDNA constitute a roadblock to cellular rejuvenation, but do not affect the maintenance of the pluripotent state. PMID- 26025379 TI - Genome-wide association study of toxic metals and trace elements reveals novel associations. AB - The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 * 10(-11), beta = -0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P value = 2.2 * 10(-14), beta = -0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 * 10(-10), beta = -1.2 and P = 1.8 * 10(-9), beta = -1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity. PMID- 26025380 TI - STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis. AB - One of the obstacles for cancer immunotherapy is the inefficiency of CD8(+) T cell recruitment to tumors. STAT3 has been shown to suppress CD8(+) T-cell antitumor functions in various cancer models, in part by restricting accumulation of CD8(+) T cells. However, the underlying molecular mechanism by which STAT3 in CD8(+) T cells inhibits their accumulation in tumors remains to be defined. Here, we show that STAT3 signaling in CD8(+) T cells inhibits chemokine CXCL10 production by tumor-associated myeloid cells by reducing IFNgamma expression by T cells. We further demonstrate that ablating STAT3 in T cells allows expression of CXCR3, the receptor of CXCL10, on CD8(+) T cells, resulting in efficient accumulation of CD8(+) T cells at tumor sites. Blocking IFNgamma or CXCR3 impairs the accumulation of STAT3-deficient CD8(+) T cells in tumor and their antitumor effects. Together, our study reveals a negative regulation by STAT3 signaling in T cells on cross-talk between myeloid cells and T cells through IFNgamma/CXCR3/CXCL10, which is important for CD8(+) T cells homing to tumors. Our results thus provide new insights applicable to cancer immunotherapy and adoptive T-cell strategies. PMID- 26025381 TI - Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. AB - Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. PMID- 26025382 TI - Intracellular signalling pathways associated with the glucose-lowering effect of ST36 electroacupuncture in streptozotocin-induced diabetic rats. AB - BACKGROUND AND AIM: Previous animal studies have reported a glucose-lowering effect of electroacupuncture (EA) and suggested that the mechanisms are closely related to intracellular signalling pathways. The aim of this study was to screen for potential intracellular signalling pathways that are upregulated by EA at ST36 bilaterally in rats with diabetes mellitus (DM) using microarray analysis. METHODS: Streptozotocin (STZ)-induced diabetic rats were randomly assigned to experimental (EA, n=8) or control (non-EA, n=8) groups. Plasma glucose levels were measured at baseline and after 30 and 60 min, and microarray analysis was performed on samples of gastrocnemius muscle. RESULTS: Relative to baseline values, EA significantly reduced plasma levels of glucose at 30 and 60 min. The microarray pathway analysis showed that cell adhesion molecules and type 1 DM gene sets were both upregulated in EA versus non-EA groups (p<0.05). CONCLUSIONS: Cell adhesion molecules might be related to the glucose-lowering effect induced by EA in rats with STZ-induced type 1 diabetes. Further research will be required to examine the involvement of related intracellular signalling pathways. PMID- 26025384 TI - Electroacupuncture plus metformin lowers glucose levels and facilitates insulin sensitivity by activating MAPK in steroid-induced insulin-resistant rats. AB - BACKGROUND: Type 2 diabetes mellitus is the predominant form of diabetes. Although metformin is the preferred first-line drug for treatment of the disease, it is associated with a risk of secondary failure. Electroacupuncture (EA) can enhance insulin sensitivity and reduce blood glucose levels. OBJECTIVES: To examine, in an animal study, whether EA combined with metformin (EA-metformin) results in a better glucose-lowering effect and greater insulin sensitivity than metformin alone in steroid-induced insulin-resistant rats. METHODS: Adult Wistar rats were injected with dexamethasone to induce diabetes and subsequently treated with EA plus metformin or metformin alone. Variations in plasma glucose, plasma insulin, and plasma free fatty acid levels were studied at the midpoint and end of the experimental course. Insulin receptor substrate 1 (IRS-1) and peroxisome proliferator-activated receptor gamma (PPAR-gamma), which are associated with glucose transporter type 4 (GLUT4) translocation, and mitogen-activated protein kinase (MAPK), which is related to GLUT4 activation, were measured after EA treatment. RESULTS: We found that EA-metformin resulted in a better glucose lowering effect, greater insulin sensitivity, lower plasma free fatty acid levels and higher levels of MAPK than metformin alone (p<0.05). There were no significant differences between treatment groups in expression of IRS-1 or PPAR gamma. CONCLUSIONS: The glucose-lowering effect and increased insulin sensitivity associated with EA-metformin administration is governed, at least in part, by its ability to stimulate the activation of GLUT4 via upregulation of MAPK expression. PMID- 26025383 TI - Transcutaneous electrical acupuncture stimulation as a countermeasure against cardiovascular deconditioning during 4 days of head-down bed rest in humans. AB - OBJECTIVE: Spaceflight is associated with cardiovascular deregulation. However, the influence of microgravity on the cardiovascular system and its mechanisms and countermeasures remain unknown. Our previous studies have demonstrated that transcutaneous electrical acupuncture stimulation (TEAS) is effective in improving orthostatic tolerance (OT). The purpose of this study was to determine if TEAS treatment can attenuate cardiovascular deconditioning induced by a 4-day 6 degrees head-down bed rest (HDBR). METHODS: Fourteen healthy male subjects were randomly allocated to a control group (control, n=6, 4 days HDBR without countermeasures) and a TEAS treatment group (TEAS, n=8, 4 days HDBR with TEAS at Neiguan (PC6) for 30 min each day for 4 consecutive days during HDBR). OT, plasma hormones, plasma volume and heart rate variability were assessed before and after HDBR. Cardiac function and cerebral blood flow were measured before, during and after HDBR. RESULTS: The data showed that TEAS treatment mitigated the decrease in OT that was observed in the control group and cardiac function, alleviated autonomic dysfunction, and partially prevented plasma volume reduction after HDBR. Angiotensin II and aldosterone were significantly increased by 129.3% and 133.3% after HDBR in the TEAS group (p<0.05). CONCLUSIONS: These results indicate that 30 min of daily TEAS treatment at PC6 is partially effective in maintaining OT, probably due to increased plasma volume-regulating hormones and activation of the peripheral sympathetic nervous system. TEAS treatment appears effective at reducing cardiovascular deconditioning induced by HDBR for 4 days. TRIAL REGISTRATION NUMBER: NCT02300207. PMID- 26025385 TI - Defining Action Levels for In Vivo Dosimetry in Intraoperative Electron Radiotherapy. AB - In vivo dosimetry is recommended in intraoperative electron radiotherapy (IOERT). To perform real-time treatment monitoring, action levels (ALs) have to be calculated. Empirical approaches based on observation of samples have been reported previously, however, our aim is to present a predictive model for calculating ALs and to verify their validity with our experimental data. We considered the range of absorbed doses delivered to our detector by means of the percentage depth dose for the electron beams used. Then, we calculated the absorbed dose histograms and convoluted them with detector responses to obtain probability density functions in order to find ALs as certain probability levels. Our in vivo dosimeters were reinforced TN-502RDM-H mobile metal-oxide semiconductor field-effect transistors (MOSFETs). Our experimental data came from 30 measurements carried out in patients undergoing IOERT for rectal, breast, sarcoma, and pancreas cancers, among others. The prescribed dose to the tumor bed was 90%, and the maximum absorbed dose was 100%. The theoretical mean absorbed dose was 90.3% and the measured mean was 93.9%. Associated confidence intervals at P = .05 were 89.2% and 91.4% and 91.6% and 96.4%, respectively. With regard to individual comparisons between the model and the experiment, 37% of MOSFET measurements lay outside particular ranges defined by the derived ALs. Calculated confidence intervals at P = .05 ranged from 8.6% to 14.7%. The model can describe global results successfully but cannot match all the experimental data reported. In terms of accuracy, this suggests an eventual underestimation of tumor bed bleeding or detector alignment. In terms of precision, it will be necessary to reduce positioning uncertainties for a wide set of location and treatment postures, and more precise detectors will be required. Planning and imaging tools currently under development will play a fundamental role. PMID- 26025386 TI - [Detection of adverse events in hospitalized adult patients by using the Global Trigger Tool method]. AB - OBJECTIVES: To identify and characterize adverse events (AE) in an Internal Medicine Department of a district hospital using an extension of the Global Trigger Tool (GTT), analyzing the diagnostic validity of the tool. METHODS: An observational, analytical, descriptive and retrospective study was conducted on 2013 clinical charts from an Internal Medicine Department in order to detect EA through the identification of 'triggers' (an event often related to an AE). The 'triggers' and AE were located by systematic review of clinical documentation. The AE were characterized after they were identified. RESULTS: A total of 149 AE were detected in 291 clinical charts during 2013, of which 75.3% were detected directly by the tool, while the rest were not associated with a trigger. The percentage of charts that had at least one AE was 35.4%. The most frequent AE found was pressure ulcer (12%), followed by delirium, constipation, nosocomial respiratory infection and altered level of consciousness by drugs. Almost half (47.6%) of the AE were related to drug use, and 32.2% of all AE were considered preventable. The tool demonstrated a sensitivity of 91.3% (95%CI: 88.9-93.2) and a specificity of 32.5% (95%CI: 29.9-35.1). It had a positive predictive value of 42.5% (95%CI: 40.1-45.1) and a negative predictive value of 87.1% (95%CI: 83.8 89.9). CONCLUSIONS: The tool used in this study is valid, useful and reproducible for the detection of AE. It also serves to determine rates of injury and to observe their progression over time. A high frequency of both AE and preventable events were observed in this study. PMID- 26025387 TI - HDL function as a predictor of coronary heart disease events: time to re-assess the HDL hypothesis? PMID- 26025388 TI - SGLT inhibition and euglycaemic diabetic ketoacidosis. PMID- 26025390 TI - How to learn places without spatial concepts: Does the what-and-where reaction time system in children regulate learning during stimulus repetition? AB - We investigated the role of repetition for place learning in children although the acquisition of organizing spatial concepts is often seen as more essential. In a reaction-time accuracy task, 7- and 9-year-old children were presented with a randomized sequence of objects-in-places. In a novelty condition (NC), memory sets in different colors were presented, while in a repetition condition (RC), the identical memory set was tested several times. Shape memory deteriorated more than place memory in the NC, but also stayed superior to place memory when both improved in the RC. False alarms occurred for objects and places in the same way in 7-year-olds in the NC, but were negligible for 9-year-olds. In contrast, false alarms in the RC occurred in both age groups mainly for place memory. The Common Region Test (CRT) predicted reaction times only in the novelty condition, indicating use of spatial concepts. Importantly, reaction times for shapes were faster than for places at the beginning of the experiment but slowed down thereafter, while reaction times for places were slow at the beginning of the experiment but accelerated considerably thereafter. False alarms and regulation of reaction times indicated that repetition facilitated true abstraction of information leading to place learning without spatial concepts. PMID- 26025389 TI - Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. AB - BACKGROUND: Although HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity-a prototypical measure of HDL function-has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain. METHODS: We measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40-79 years, assessed in 1993-97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB depleted serum from study participants. FINDINGS: Cholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0.40; p<0.0001) and apoA-I concentration (r=0.22; p<0.0001). It was also inversely correlated with type 2 diabetes (r=-0.18; p<0.0001) and positively correlated with alcohol consumption (r=0.12; p<0.0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0.64, 95% CI 0.51-0.80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0.80 (95% CI 0.70-0.90) for a per-SD change in cholesterol efflux capacity. INTERPRETATION: HDL cholesterol efflux capacity might provide an alternative mechanism for therapeutic modulation of the HDL pathway beyond HDL cholesterol concentration to help reduce risk of coronary heart disease. FUNDING: US National Institutes of Health, UK Medical Research Council, Cancer Research UK. PMID- 26025391 TI - TiF4 improves microtensile bond strength to dentin when using an adhesive system regardless of primer/bond application timing and method. AB - OBJECTIVES: This study evaluated the bond strength of a two-step conventional adhesive system to dentin pretreated with 2.5 % titanium tetrafluoride (TiF(4)) according to application timing (before or after acid conditioning) and primer/adhesive application method (active or passive). MATERIALS AND METHODS: Dentin surfaces were randomly treated with different adhesive procedures (n = 6): etching with phosphoric acid (PA) + primer/adhesive (Adper Single Bond 2/3M ESPE) actively applied; PA + primer/adhesive passively applied; TiF(4) before PA + primer/adhesive actively applied; TiF(4) before PA + primer/adhesive passively applied; TiF(4) after PA + primer/adhesive actively applied; and TiF(4) after PA + primer/adhesive passively applied. A composite block was built onto the tooth, which was sectioned into sticks (adhesive area of approximately 1 mm(2)). Microtensile bond strength tests and the failure mode were determined. RESULTS: Two-way ANOVA revealed no significant interaction between TiF(4) application timing and primer/adhesive application method (p = 0.184). The use of TiF(4), before or after PA significantly increased bond strength values (p < 0.001). There was no significant difference in bond strength values when using TiF4 before or after PA. The primer/adhesive application method had no influence on bond strength, regardless of whether TiF(4) was used (p = 0.906). Failure mode was predominantly adhesive. CONCLUSIONS: The use of TiF(4) promoted higher immediate bond strength to dentin. The conventional adhesive system may be applied either actively or passively, regardless of TiF(4) application timing. CLINICAL SIGNIFICANCE: Pretreatment with TiF(4) increased bond strength in a conventional two-step adhesive system to dentin, regardless of the primer/adhesive application method and the timing of dentin pretreatment. PMID- 26025393 TI - MMP-14 in skeletal muscle repair. AB - MMP-14 (also known as MT1-MMP) is a membrane-bound collagenase and member of the Matrix Metalloprotease (MMP) family known to target a broad range of extracellular matrix (ECM) proteins. Remodelling of the ECM is of particular importance following skeletal muscle injury involving myofiber necrosis, when satellite cells are activated to facilitate myogenesis and regeneration. Myogenesis (broadly encompassed by the processes of satellite cell activation, proliferation, migration, differentiation and fusion) requires the myoblast to move either on or through a changing milieu of ECM components. The ECM composition, and especially the degree of fibrosis, influences ability of satellite cells to mediate a successful regenerative program. As a result, MMP activity is central to this regeneration; its activity increases following skeletal muscle injury, while inhibition of MMP reduces regeneration in this tissue. Besides its direct effect on matrix invasion, MMP-14 itself can affect this regeneration via activation of other MMPs (MMP-2, -9 and -13) as well as cytokines, chemokines and growth factors. Indeed recent research suggests that MMP-14 is necessary for the migration of human myoblasts into a collagen I matrix. Here we provide a current review on MMP-14 in the context of its role as a critical mediator of skeletal muscle regeneration. PMID- 26025392 TI - The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. AB - The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future. PMID- 26025394 TI - Cardioprotective effect of miR-214 in myocardial ischemic postconditioning by down-regulation of hypoxia inducible factor 1, alpha subunit inhibitor. AB - To determine the significance of miR—214 expression in ischemic post—conditioning. Sixty rats were grouped to establish animal models. Immuno— luminescence and chemical methods were used to detect oxidative stress indicators. Hemodynamics indexes were measured by carotid artery intubation, and ischemia and infarction areas by Evans blue and 2,3—5 triphenyltetrazolium chloride(TTC) staining. TargetScan was used for identification and luciferase assays for verification of target genes.miR—214 and hypoxia inducible factor 1, alpha subunit inhibitor (HIF1AN) were analyzed by real—time quantitative polymerase chain reaction. Ischemia reperfusion significantly decreased left ventricular systolic pressure, +dp/dtmax, and —dp/dtmax and increased left ventricular end—diastolic pressure; ischemic post—conditioning had contrasting effects. Compared to the sham group, the ischemic/reperfusion (IR) group showed increased creatine kinase isoenzyme (CK—MB) and malondialdehyde (MDA) in the myocardium and decreased SOD. miR—214 in the IR group was down—regulated, and HIF1AN, up—regulated. Compared with the IR group, the ischemia postconditioning (IPC) group showed decreased CK—MB and MDA in the myocardium and increased SOD. The proportion of infarction area to ischemia area in IPC group declined compared to IR group. miR—214 and HIF1AN in the IPC group showed significant up— and down—regulation, respectively. Ischemic postconditioning can improve myocardial function, reduce myocardial infarction area, and prevent the ischemia reperfusion injury. miR—214 may participate in the protective function of ischemic post—conditioning by down—regulating HIF1AN. PMID- 26025395 TI - Conditional control of dendritic cell factor 1 expression by a tetracycline inducible system. AB - Dendritic cell factor 1 plays important roles in neural stem cells differentiation and in glioma cells proliferation, migration, and invasion. Here, we used a tetracycline—inducible system that regulates the expression of Dendritic cell factor 1 in glioma cells. We constructed two tet—inducible vectors, pTRE—EGFP—DCF1 and pTRE—LJM1—DCF1, by modifying the promoter PCMV. In the absence of tetracycline or doxycycline, the expression of Dendritic cell factor 1 in cells co—transfected with pTRE—EGFP—DCF1 or pTRE—LJM1—EGFP—DCF1 and ptTS—Neo was suppressed through binding of the tetracyline—controlled transcriptional suppressor to tetracycline response element, and the suppression was released by the addition of doxycycline. Our work has laid foundations for potential clinical application of cancer therapy in realizing artificial regulation of gene. PMID- 26025397 TI - Importance of CD44 on umbilical cord mesenchymal stem cells for expansion of hematopoietic cells. AB - Human umbilical cord mesenchymal stem cells (hUCMSCs) have important functions on the expansion of hematopoietic stem cells (HSCs) through providing the essential microenvironment for hematopoiesis. In order to test whether CD44 on hUCMSCs could have a key function for the ability of hUCMSCs to expand human HSCs, the soluble anti—CD44 antibody was added to the co—cultures of hUCMSCs and cord blood (CB) CD34+ cells, which blocked the ability of hUCMSCs to expand CB CD34+ cells significantly. Long—term culture initiating cell (LTC—IC) assay revealed that the ability of multipotent differentiation of CB CD34+ cells co—cultured with CD44 knockdown hUCMSCs could only retain lasting at most for 5 weeks in vitro. In vivo assay, based on non—obese diabetic/severe combined immunodeficient disease (NOD/SCID) mice, revealed that the hematopoietic reconstitution potential of CB CD34+ cells co—cultured with CD44 knockdown hUCMSCs is significantly reduced. The hematopoietic supporting ability of hUCMSCs in vivo and in vitro is reduced upon the knockdown of CD44. CD44 has important functions on the ability of hUCMSCs to expand human HSCs in the cell— extrinsic control. PMID- 26025396 TI - Lack of estrogen down-regulates CXCR4 expression on Treg cells and reduces Treg cell population in bone marrow in OVX mice. AB - Postmenopausal osteoporosis (PMO) is the most common metabolic bone disease in women after menopausal. Recent works focused on cross—talk between immune regulation and bone metabolism pathways and suggested Treg cells suppressed bone resorption and osteoclasts (OC) differentiation in bone marrow via cell—cell contact interaction and/or secreting of IL—10 and TGF—beta. In this study, we investigated the impact of estrogen on regulatory T cells (Treg cells) trafficking and staying in bone marrow and we found that a significant reduction of Treg cell population in bone marrow in estrogen deficiency ovariectomied (OVX) mice. We then studied the expressions of chemokines CXCL12/CXCR4 axes, which were critical to Treg cells migration and our data show the expression of CXCR4 on Treg cells was relative with oestrogen in vivo, however, the expression of CXCL12 was not. Furthermore, the loss of trafficking ability of Treg cells in OVX mice was recoverable in our system. These findings may mechanistically explain why Treg cells lose their suppressive functions on the regulation of OC cells and demonstrate a previously unappreciated role for estrogen, which may be critical to the novel therapy in clinical practice of PMO patients. PMID- 26025378 TI - Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. AB - Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ~38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region. PMID- 26025398 TI - Fibronectin chorused cohesion between endothelial progenitor cells and mesenchymal stem cells of mouse bone marrow. AB - Endothelial progenitor cells (EPCs) could function as niche cells to promote self—renewal of mesenchymal stem cells (MSCs) in the mouse bone marrow. Cohesion was the basis of the two cells to display their biological functions to each other. In this study, we investigated the mechanism of cohesion between MSCs and EPCs. And demonstrated that fibronectin (FN) in EPCs activated the integrin α5β1 of MSCs and further mediated cell-cell cohesion. Integrin α5β1 and its FN ligand played critical roles not only in single—cell line adhesion, but also in adhesion between stem and niche cells. This novel finding is important to understand the cross—talk between MSCs and their niche cells. PMID- 26025399 TI - Molecular events are associated with resistance to vinblastine in bladder cancer. AB - Bladder cancer occurs in the majority of cases in males, which represents the fourth highest incident cancer in men and tenth in women. It is associated with a high rate of recurrence, and prognosis is poor once the cancer metastasizes to distant sites. Transitional cell cancer (TCC) is the most predominant histological type. Bladder cancer is highly chemosensitive. However, the presence of acquired drug resistance is one of the primary impediments to the success of chemotherapy. To differentiate and delineate the molecular events, we developed drug resistant human transitional bladder cancer T24 cells (DRC) by treating cells with the increasing concentration of vinblastine. We found that DRC was resistant to vinblastine in comparison to parental T24 cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, expression of permeability glycoprotein (P—gp) was up—regulated in DRC. In addition, levels of Caveolin—1 (Cav—1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) were elevated in DRC. Downregulation of these proteins by respective specific pharmacological inhibitors and/or by siRNAs resensitized cells to vinblastine. These results suggested that differential levels of P—gp, Cav—1 and FASN except CYP450 play a major role in acquired resistant phenotype in bladder cancer. PMID- 26025400 TI - Vitis labrusca leaf extract prevents pentylenetetrazol-induced oxidative damage but not seizures in rats. AB - Epilepsy is a disorder of the central nervous system characterized by recurrent seizures. It is a very common disease in which approximately 30% of patients do not respond favorably to treatment with anticonvulsants. Oxidative stress is associated with neuronal damage arising from epileptic seizures. The present study investigated the possible anticonvulsant and antioxidant effects of a leaf extract of Vitis labrusca in an animal model of seizures induced by pentylenetetrazole (PTZ). The animals received injections of V. labrusca extract (10, 30 and 100 mg/kg) or vehicle and, 30 minutes later, they received an injection of PTZ, and were then observed for 30 minutes. The latency time and tonic—clonic seizure time were registered. Oxidative damage in lipids and proteins was quantified in the cerebellum, cerebral cortex and hippocampus. It was observed that the leaf extract were capable of reducing lipid peroxidation and protein oxidation caused by PTZ at all doses tested. PMID- 26025401 TI - Comparison of two codon optimization strategies enhancing recombinant Sus scrofa lysozyme production in Pichia pastoris. AB - Lysozyme has played an important role in animal feed additive industry, food additive industry and biological engineering. For improving expression efficiency of recombinant lysozyme from Sus scrofa, two genes respectively designed by the most used codon optimization strategies, "one amino acid one codon" and "codon randomization", were synthesized and expressed in Pichia pastoris X—33. At shaking flask level, Sus scrofa lysozyme (SSL) under two conditions had a highest activity of 153.33+/-10.41 and 538.33+/-15.18 U/mL after a 5 days induction of 1% methanol, with secreted protein concentration 80.03+/-1.94 and 239.60+/-4.16 mg/L, respectively. Compared with the original SSL gene, the expression of optimized SSL gene by the second strategy showed a 2.6 fold higher level, while the first method had no obvious improvement in production. In total secreted protein, the proportions of recombinant SSL encoded by the original gene, first method optimized gene and the second—strategy optimized one were 75.06+/ 0.25%, 74.56+/-0.14% and 79.00+/-0.14%, respectively, with the same molecular weight about 18 kDa, optimum acidity pH 6.0 and optimum temperature 35degC. PMID- 26025402 TI - Differentiation of transforming growth factor beta1-induced mesenchymal stem cells into nucleus pulposus-like cells under simulated microgravity conditions. AB - This study aims to observe the differentiation effects of transforming growth factor beta1 (TGF-beta1)-transfected bone marrow mesenchymal stem cells (BMMSCs) into the nucleus pulposus-like cells under simulated microgravity conditions. BMMSCs were isolated from the adult rabbits, then cultured and proliferated to the third generation. After transfected by TGF-beta1, these MMSCs were incubated in the calcium alginate gel microspheres and rotary cell culture system. The content changes of TGF-beta1 inside BMMSCs, as well as the proliferation abilities of BMMSCs, were detected. The immunohistochemistry and toluidine blue staining were performed to detect the type II collagen. The RT-PCR method was performed to detect the expressions of proteoglycan and type II collagen mRNA. Results found that, on the 14th day, the polygonal nucleus pulposus-like cells could be observed. The TGF-beta1 content inside the supernatant and the DNA content inside BMMSCs were significantly increased (P<0.05). The immunohistochemistry staining exhibited the positive results about the type II collagen. RT-PCR showed the expressions of proteoglycan and type II collagen mRNA inside BMMSCs. The TGF-beta1-transfected BMSCs exhibited the increased synthesizing abilities of proteoglycan and type II collagen under simulated microgravity conditions than the control group. PMID- 26025403 TI - Oligodendrocyte progenitor cells differentiation of nuclear transferred mouse embryonic stem cells. AB - Central nervous system (CNS) injuries cause to variable disorders in people around the world without any decisive treatment. Use of embryonic stem cells (ESCs) would be helpful in repairing of neural system damages. Somatic cell nuclear transfer (SCNT) is a way for implanting ESCs with lowest possible rejection. In the present study, mouse nuclear transfers ESCs (ntESCs) ability in differentiation to oligodendrocyte progenitor cells (OPCs) was investigated by morphological study, RT—PCR and flow cytometry analysis. Bi—polar and tri—polar, OPCs were observed in stem cells cultured in differentiation medium after four weeks. Result of gene expression analysis demonstrated that differentiated stem cells were expressed most important OPCs related gene markers after differentiation period. Moreover, flow cytometry analysis carried out to confirm other results that showed differentiated stem cells significantly expressed NG2 and O4 as critical OPC surface markers. Taken together, it seems that mouse ntESCs showed highly potential for OPC differentiation and could be an appropriate candidate for stem cell therapies. PMID- 26025404 TI - Arabidopsis thaliana SEPALLATA3 protein prokaryotic expression and purification. AB - SEPALLATA3 (SEP3) can be attributed to E class gene of the ABCE model of floral organ development. In order to reveal how SEP3 proteins form polymers, and the relationship between the polymers and their biological functions, the experiments of Arabidopsis thaliana AtSEP3 protein soluble expression in vitro were performed to construct a vector of prokaryotic expression, and investigate induced expression of recombinant proteins in Escherichia coli cells. The protein soluble expression was analyzed through the aspects of different protein domains, induction time, induction temperature, etc. Different structural domains and expression conditions were screened, and 0.1% IPTG inducing at 22 oC for 15 h was estimated as an optimal expression strategy. The nickel chelating resin was used to purify the protein in size exclusion chromatography (SEC) and the results indicated that AtSEP3 protein was present in the form of tetramer. PMID- 26025405 TI - Estrogen deficiency inducing shifted cytokines profile in bone marrow stromal cells inhibits Treg cells function in OVX mice. AB - The study aims to reveal the effect of estrogen deficiency on Treg cells population in bone marrow in the development of osteoclastogenis with comparing the differences about Treg cells phenotypes and cytokines related with the homeostasis and functions maintenance of Treg cells in bone marrow in OVX mice and health control group. Wide—type C57BL/6 mice were operated OVX to mimic estrogen deficiency in PMO women. Treg cells population and their surface markers expressions were detected by flow cytometry. Cytokines profiles in bone marrow with examined by real—time PCR and ELISA analysis. Signal pathways and key modulators responsible to inflammatory cytokines expressions in bone marrow stromal cells were also detected with using western blotting. Estrogen deficiency in OVX mice decreased Treg cells and their functions, and cytokines profile in bone marrow were found shifted in bone marrow when compared with control group. Consistent to these observations, signal pathways in bone marrow stromal cells were reported altered by estrogen deficiency in our model. Estrogen deficiency effects Treg cells population and their functions in OVX mice with altering cytokines profile in bone marrow stromal cells. PMID- 26025406 TI - Regulation of the Heme Oxygenase-1/carbon monoxide system by hydrogen sulfide in murine coxsackievirus B3-induced myocarditis. AB - To explore the impact of hydrogen sulfide (H2S) on the heme oxygenase—1 (HO—1)/carbon monoxide (CO) system in coxsackie virus B3 (CVB3)—induced myocarditis. A total of 80 Balb/c mice were divided randomly into four groups designated N, C, P and S. Group N served as the negative control while groups C, P, and S were infected with CVB3 to induce myocarditis. Group P was additionally treated with DL—propargylglycine (PAG) to inhibit the generation of H2S while Group S was treated with NaHS, an H2S donor. Ten days after infection, heart sections were scored for histopathology. We also measured carboxyhemoglobin (COHb) levels in the blood and HO—1 expression by immunohistochemistry. 1. Each CVB3—infected group (C, P, and S) exhibited increased pathology, COHb levels, and HO—1 expression compared to uninfected controls. 2. Regarding histopathology, the score of group P was worse, while that of group S was better, than that of group C. 3. The P group COHb level was lower than group C, while the S group COHb level was higher than group C. 4. Positive HO—1 expression was seen in group C with reduced expression in group P and increased expression in group S. 5. A positive correlation was observed between the COHb concentration and HO—1expression; alternatively, a negative correlation was found between the histopathologic scores and both the concentration of COHb and the expression level of HO—1. Modulation of H2S can play a regulatory role in the pathogenesis of VMC by impacting the HO—1/CO pathway. PMID- 26025407 TI - The association of PON1 192 Q/R polymorphism and the risk of female infertility. AB - Infertility is a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months of regular unprotected sexual intercourse. Both environmental and genetic factors are involved in female infertility. Paraoxonase (PON) is an oxidant enzyme which plays an important role in various diseases and is associated with inflammation, oxidative stress and lipid metabolism. The present study was aimed to evaluate the PON1 192 Q/R gene polymorphism in female infertility. Samples were obtained from 150 patients diagnosed with female infertility and 150 controls subjects and genotyped by Polymerase Chain Reaction—Restriction Fragment Length Polymorphism (PCR—RFLP). The PON genotype frequencies amongst the 70 cases were C/C=40%, C/T=52.8% and T/T=7.2%; the C and T allele frequencies were 66% and 34%, respectively. The PON genotype frequencies amongst the 73 controls were C/C=45.20%, C/T=50.70% and T/T=4.1%; the C and T allele frequencies were 70% and 30%, respectively. We observed a significant difference in the genotype distributions of PON1 192 Q/R polymorphism between patients and controls (P= 0.03). Our findings revealed that individuals with the variant QR had a significant decrease risk of female infertility (OR= 0.55, 95% CI= 0.33 - 0.91, P= 0.019). The data from this study indicates that the PON1 192 Q/R polymorphism may be associated with decreased risk of female infertility. Although more studies should be considered with larger number of patients and control subjects to confirm our results. PMID- 26025408 TI - MiR-30a suppresses non-small cell lung cancer progression through AKT signaling pathway by targeting IGF1R. AB - MicroRNAs play critical roles in the development and progression of human cancers. Although miR—30a has been suggested to function as a tumor repressor in several tumors, its role in non—small cell lung cancer (NSCLC) has not been investigated in detail. This study investigated the expression and role of miR—30a in human NSCLC. The expression of miR—30a is significantly decreased in clinical NSCLC tissues and cell lines. Overexpression of miR—30a inhibited NSCLC cell proliferation, G1/S and S/G2 transition in vitro, whereas suppression of miR—30a facilitated NSCLC cell proliferation, G1/S and S/G2 transition. Using a luciferase reporter assay, insulin—like growth factor 1 receptor (IGF1R) was determined to be a direct target of miR—30a. Furthermore, silencing IGF1R resulted in the same biologic effects of miR—30a overexpression in NSCLC cells, which included suppressed NSCLC cell proliferation and trigering cell cycle arrest through PI3K/AKT signaling pathway by inhibiting cell cycle regulators (CDK2, CDK4, Cyclin A2 , Cyclin D1). These results demonstrate that miR—30a influences NSCLC progression through PI3K/AKT signaling pathway by targeting IGF1R in A549 cells, which suggest miR—30a as a novel strategy for NSCLC diagnosis and treatment. PMID- 26025409 TI - Investigation of cell aggregation on the substrate of a parallel-plate flow chamber. AB - Adhesion of tumor cells (TCs) to polymorphonuclear neutrophils (PMNs) tethered on a monolayer of vascular endothelial cells (ECs) in shear flows is investigated theoretically. Both TC—PMN and PMN—EC aggregations are modeled using the population balance equations (PBEs). Parameters in the model obtained by curve fitting show that an increase of shear rate or viscosity will suppress the formation of aggregates and promote the breakage of them. Analysis on the collision frequency suggests that the averaged encounter duration is affected by viscosity. Based on the model, a nonlinear connection between the number of migrated TCs and the concentration of PMNs in the flow near the substrate is presented. PMID- 26025410 TI - Evaluation of FGFR2 gene polymorphism in women with breast cancer. AB - Breast cancer (BC) is one of the most frequent cancers among women worldwide. It is a complex polygenic disorder that genetic factors play an important role in disease etiology. The highly significant association of the Fibroblast growth factor receptor 2 (FGFR2) locus with breast cancer risk has been replicated in multiple genome association study; however, it's mechanism of action remains unclear. The aim of this study was to investigate whether the single nucleotide polymorphism (SNP) C-906T within intron 2 of FGFR2 is responsible for susceptibility to breast cancer. This case-control study included 108 breast cancer cases and 108 cancer-free controls. The prevalence of genotype frequencies of the FGFR2 CC/CT/TT was 5.5%, 90.7% and 3.7%, respectively, in cancer cases. Among controls, the distribution of CC, CT and TT genotype was 48.14%, 47.66% and 10.18% respectively. Significant differences in allele and genotype distribution among controls and patients were found (OR, 18.87 95% CI, 7.55-47.16; p = 0.0001). The results from this study suggest that the FGFR2 C-906T polymorphism may be associated to breast cancer in population studied. Well-designed studies with larger sample sizes are needed to confirm the role of FGFR2 SNP in breast cancer risk. PMID- 26025411 TI - siRNA-mediated silencing of MDR1 reverses the resistance to oxaliplatin in SW480/OxR colon cancer cells. AB - One of the most challenging aspects of colon cancer therapy is rapid acquisition of multidrug resistant phenotype. The multidrug resistance gene 1 (MDR1) product, p—glycoprotein (P—gp), pump out a variety of anticancer agents from the cell, giving rise to a general drug resistance against chemotherapeutic agents. The aim of this study was to investigate the effect of a specific MDR1 small interference RNA (siRNA) on sensitivity of oxaliplatin—resistant SW480 human colon cancer cell line (SW480/OxR) to the chemotherapeutic drug oxaliplatin. SW480 cells were made resistant by continuous incubation with stepwise serially increased concentrations of oxaliplatin over a 6—months period. Resistance cell were subsequently transfected with specific MDR1 siRNA. Relative MDR1 mRNA expression was measured by Quantitative real—time PCR. Western blot analysis was performed to determine the protein levels of P—gp. The cytotoxic effects of oxaliplatin and MDR1 siRNA, alone and in combination were assessed using MTT and the number of apoptotic cells was determined with the TUNEL assay. MDR1 siRNA effectively reduced MDR1 expression in both mRNA and protein levels. MDR1 down—regulation synergistically increased the cytotoxic effects of oxaliplatin and spontaneous apoptosis SW480/OxR. Our data demonstrates that RNA interference could down regulate MDR1 gene expression and reduce the P—gp level, and partially reverse the drug resistance in SW480/OxR cells in vitro. Therefore, the results could suggest that MDR1 silencing may be a potent adjuvant in human colon chemotherapy. PMID- 26025412 TI - Comparative prospective study of 2 ovarian stimulation protocols in poor responders: effect on implantation rate and ongoing pregnancy. AB - BACKGROUND: In patients treated with IVF, the incidence of poor ovarian response (POR) after ovarian stimulation varies from 9 to 25 %. However, at present, there are no clear guidelines for treating these poor responders. This study was designed to compare two different ovarian stimulation protocols and addresses future perspectives in the management of these unfortunate patients. METHOD: Four hundred and forty poor responders were studied during their second IVF cycle. They had all failed to become pregnant during their first IVF cycle where the long GnRH-agonist stimulation protocol (P1) was used. Patients were prospectively randomly assigned to 2 protocol groups (P2 or P3, 220 patients in each arm) at the start of ovarian stimulation according to the order of entry into the study including one patient per each stimulation protocols: The P2 group was treated with a contraceptive pill + flare-up GnRH-agonist protocol and the P3 group with the GnRH-antagonist protocol. The ovarian stimulation characteristics as well as the clinical and ongoing pregnancy rates were compared. RESULT(S): Although the numbers of embryos obtained and transferred were significantly higher with the P2 protocol, the implantation and ongoing pregnancy rates per transfer were the same in the two studied groups (8.9 % versus 14.6 % and 8.4 % versus 14.2 % for the P2 and P3 protocols, respectively). Good prognostic factors for ongoing pregnancy with both protocols were: a maternal age <36, no tobacco consumption, a total dose of gonadotropins injection <5000 IU and an endometrial thickness >10 mm. CONCLUSION(S): In poorly responding patients treated with IVF, the implantation and ongoing pregnancy rates per transfer were not significantly different between the two protocols studied: contraceptive pill + flare-up GnRH-agonist protocol and the GnRH-antagonist protocol. It is suggested that current strategies for the management of poor responders be reconsidered in the light of the potential contribution of age and the effect of life style changes on fertility potential. A customised policy of ovarian stimulation in these patients including mild stimulation protocols, sequential IVF cycles, oocytes-embryos freeze all protocols and blastocyst transfers after screening may improve the clinical outcome. PMID- 26025414 TI - Portal biliopathy as a complication of extrahepatic portal hypertension: etiology, presentation and management. AB - Portal biliopathy (PB) refers to the biliary abnormalities of the biliary ducts observed in patients with extrahepatic portal hypertension. Although majority of patients are asymptomatic, approximately 20% of these patients present with biliary symptoms (pain, pruritus, jaundice, cholangitis). The pathogenesis of PB is uncertain but compression by dilated veins into or around common bile duct may play the main role. CT-scan, MR cholangiopancreatography with MR portography should be the initial investigations in the evaluation of PB. Treatment is limited to symptomatic cases and is dictated by clinical manifestations and complications of the disease. Treatment of PB could be done by endoscopy (sphincterotomy, stone extraction or biliary stenting of the common bile duct) or surgery (definitive decompression by porto-systemic shunt followed by bilioenteric anastomosis, if necessary). This review describes pathogenesis, clinical features, investigation and management of portal biliopathy. PMID- 26025413 TI - Bridging the gap between gastric pouch and jejunum: a bariatric nightmare. AB - BACKGROUND: Even in a large volume bariatric centre, bariatric surgeons are sometimes confronted with intraoperative anatomical challenges which force even the most experienced surgeon into a pioneering position. In this video we present how a large gap of approximately 8 cm is bridged by applying several techniques that are not part of our standardized surgical procedure. CASE PRESENTATION: After creation of a 20 mL gastric pouch we discovered that the alimentary limb could not be advanced further cranially due to a very short a thick jejunal mesentery in a 49 year old male patient during laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. By dissecting the gastro-oesophageal junction form the crus, stretching the gastric pouch, transecting the jejunal mesentery, using a retrocolic/retrogastric route, and creating a fully hand-sewn gastrojejunostomy we were able to safely complete the LRYGB. Drains were left near the gastrojejunostomy and the patient was kept nil by mouth for 5 days. On the 5th postoperative day radiographic swallow series were obtained which revealed no sign of leakage. The patient was discharged in good clinical condition on the 6th postoperative day. To date, no complications have occurred. Weight loss results are -31.5 % of the preoperative total body weight. CONCLUSIONS: When confronted with a large distance between the gastric pouch and the alimentary limb, several techniques presented in this video may be of aid to the bariatric surgeon. We stress that only experienced bariatric surgeon should embark on these techniques. Inspecting the alimentary limb before the creation of the gastric pouch may prevent the need for such complex techniques. PMID- 26025415 TI - Transversus abdominis plane block-issues. PMID- 26025416 TI - Yessotoxin activates cell death pathways independent of Protein Kinase C in K-562 human leukemic cell line. AB - Protein Kinase C (PKC) is a group of enzymes involved in pro-survival or pro apoptotic events depending on the cellular model. Moreover, Yessotoxin (YTX) modulates its expression and activates different cell death pathways. In K-562 tumor cell line, YTX induces apoptosis and autophagy after 24 and 48 h of incubation, respectively, and the toxin carries out its action through the phosphodiesterase 4A (PDE4A). Therefore, the levels of two subtypes of PKC, conventional (cPKC) and delta isotype of novel PKC (PKCdelta) were studied at these times after YTX incubation. Also their involvement in the cell death activated by the toxin and their relationship with PDE4A was checked. The expression of cPKC and PKCdelta in cytosol, plasma membrane and nucleus was studied in normal and PDE4A-silenced cells. Furthermore, cell viability of normal cells, as well as cPKC-, PKCdelta- and PDE4A-silenced cells was tested by Lactate Dehydrogenase (LDH) assay. As a result, PKCdelta showed a key role in K-562 cell survive, since without this protein, K-562 cell decreased their viability. Furthermore, modulation of PKCs by YTX treatment was observed, however, the changes in the expression of these proteins are independent of cell death activated by the toxin. In addition, the modulation of PKCs detected is PDE4A dependent, since the silencing of this protein change PKC expression pattern. PMID- 26025417 TI - Effects of high-salinity seawater acclimation on the levels of D-alanine in the muscle and hepatopancreas of kuruma prawn, Marsupenaeus japonicus. AB - Changes in D- and L-alanine contents were determined in the muscle and hepatopancreas of kuruma prawn Marsupenaeus japonicus, during acclimation from seawater containing 100% salinity to artificial seawater containing 150% salinity. In the hepatopancreas, contents of both amino acids increased by approximately threefold. The activity of alanine racemase, which catalyzes the interconversion of D- and L-alanine, also increased in the high-salinity seawater. In addition, the expression of the gene encoding alanine racemase increased in the hepatopancreas with an increase in the alanine racemase activity. These data indicate that the biosynthesis of D- and L-alanine is controlled by the gene expression level of alanine racemase, and D-alanine in the hepatopancreas functions as a major osmolyte for isosmotic regulation. In contrast, the content of D-alanine and alanine racemase activity did not change in the muscle during hyper-osmotic acclimation. Therefore, we suggest that D alanine, which exists in the several tissues of M. japonicus, is considered to be utilized in some different physiological phenomena in different tissues. PMID- 26025418 TI - Virus Research. Foreword. Nidoviruses II. PMID- 26025419 TI - Percutaneous treatment of Hepatocellular carcinoma exceeding 3 cm: combined therapy or microwave ablation? Preliminary results. AB - PURPOSE: To compare MWA and RFA combined with TACE for HCC nodules exceeding 3 cm. METHODS: 19 lesions submitted to MWA (G1) were retrospectively compared with a combined treatment group (G2) matching by tumor characteristics (mean size 43 and 45 mm in G1 and G2, respectively). Technical success, complications, complete ablation (CA), and maintained CA (mCA) were evaluated. RESULTS: Technical success was achieved in all cases. Overall mortality was zero, both in G1 and G2. No significant differences were found in complications rates (3 in G1 and 2 in G2). CA was obtained in 11 (58 %) HCC in G1 and 15 (79 %) in G2 (p = n.s.). CA was obtained in 75.5 % (G1) and 89 % (G2) nodules up to 4 cm, 45 % and 70 % nodules >4 cm, respectively. At statistical analysis, size resulted as predictor for CA only in G1 (mean diameter of CA vs non-CA 39.9 vs. 47.7 mm, p = 0.021). During follow-up (13.1 and 14.4 months in G1 and G2), mCA occurred in 6/19 (32 %) nodules in G1, 8/19 (42 %) in G2. CONCLUSION: MWA and combined therapy are comparable as for safety. No significant differences were found in terms of technique effectiveness. Larger randomized studies should be designed to confirm MWA as a valid alternative to combined therapy. PMID- 26025421 TI - Spermatological characters of the digenean Lecithostaphylus retroflexus (Molin, 1859) (Microphalloidea: Zoogonidae), a parasite of the teleost fish Belone belone gracilis. AB - The ultrastructural organization of the spermatozoon of the digenean Lecithostaphylus retroflexus (Microphalloidea: Zoogonidae) was described. Alive digeneans were collected from Belone belone gracilis (Teleostei: Belonidae), caught from the Gulf of Gabes in Chebba (Tunisia). The mature spermatozoon of L. retroflexus exhibits two axonemes of different lengths with the 9+'1' Trepaxonematan pattern, a nucleus, two mitochondria, two bundles of parallel cortical microtubules and granules of glycogen. Additionally, the spermatozoon of L. retroflexus shows type 2 of the external ornamentation according to Quilichini et al. (2011), spine-like bodies and a continuous and submembranous layer of parallel cortical microtubules surrounding the axonemes at their anterior end. Moreover, the morphology of the posterior spermatozoon extremity in L. retroflexus corresponds to the fasciolidean type according to Quilichini et al. (2010). PMID- 26025420 TI - Effect of norbinaltorphimine on ?9-tetrahydrocannabinol (THC)-induced taste avoidance in adolescent and adult Sprague-Dawley rats. AB - RATIONALE: The aversive effects of ?(9)-tetrahydrocannabinol (THC) are mediated by activity at the kappa opioid receptor (KOR) as assessed in adult animals; however, no studies have assessed KOR involvement in the aversive effects of THC in adolescents. Given that adolescents have been reported to be insensitive to the aversive effects induced by KOR agonists, a different mechanism might mediate the aversive effects of THC in this age group. OBJECTIVES: The present study was designed to assess the impact of KOR antagonism on the aversive effects of THC in adolescent and adult rats using the conditioned taste avoidance (CTA) procedure. METHODS: Following a single pretreatment injection of norbinaltorphimine (norBNI; 15 mg/kg), CTAs induced by THC (0, 0.56, 1.0, 1.8, and 3.2 mg/kg) were assessed in adolescent (n = 84) and adult (n = 83) Sprague-Dawley rats. RESULTS: The KOR antagonist, norBNI, had weak and inconsistent effects on THC-induced taste avoidance in adolescent rats in that norBNI both attenuated and strengthened taste avoidance dependent on dose and trial. norBNI had limited impact on the final one-bottle avoidance and no effects on the two-bottle preference test. Interestingly, norBNI had no effect on THC-induced taste avoidance in adult rats as well. CONCLUSIONS: That norBNI had no significant effect on THC-induced avoidance in adults, and a minor and inconsistent effect in adolescents demonstrates that the aversive effects of THC are not mediated by KOR activity as assessed by the CTA design in Sprague-Dawley rats. PMID- 26025422 TI - Transplantation of differentiated umbilical cord mesenchymal cells under kidney capsule for control of type I diabetes in rat. AB - Nowadays, stem cells have been introduced as an appropriate source of regenerative medicine for treatment of type I diabetes. Human umbilical cord matrix-derived mesenchymal cells (hUCMC) have successfully been differentiated into insulin producing cells. The isolated hUCM cells were characterized by the expression of stem cell surface markers and by differentiation into adipocytes and osteocytes. The hUCMCs were cultured with different concentrations of neural conditional medium (NCM) and were induced to differentiate into insulin producing cells (IPCs). As 60% NCM concentration resulted in higher nestin and PDX1 expression, the cells were first exposed to 60% NCM and were then induced for IPCs differentiation. PDX1 and insulin gene expression was evaluated in the treated cells. Also, the secretion capacity of the IPCs was assessed by glucose challenge test. IPCs were transferred under the rat kidney capsule. Blood glucose level, weight gain and immunohistochemistry assessments were done in the treated animals. hUCMC expressed mesenchymal cell surface markers and successfully differentiated into adipocytes and osteocytes. Higher NCM concentration resulted in higher PDX1 and nestin expression. The IPCs expressed insulin and PDX1. IPCs were detectable under the kidney capsule 2 months after injection. IPCs transplantation resulted in a sharp decline of blood sugar level and less weight loss. Differentiated hUCM cells could alleviate the insulin deprivation in the rat model of type I diabetes. In addition, higher NCM concentration leads to more differentiation into IPCs and more nestin and PDX1 expression. Kidney capsule can serve as a suitable nominee for IPCs transplantation. PMID- 26025423 TI - Examining the Health Care Experiences of Women Living with Human Immunodeficiency Virus (HIV) and Perceived HIV-Related Stigma. AB - INTRODUCTION: The increased incidence of human immunodeficiency virus (HIV) in women, particularly marginalized women, prompted research to examine women's health service experiences at a local outpatient clinic. METHODS: A qualitative case study using semistructured interviews examined facilitators and barriers to health care services. Seventeen women living with HIV who accessed care at an outpatient HIV clinic in central west Ontario were interviewed. Thematic analysis was used to code health care experiences perceived as HIV-related stigma. RESULTS: Women perceived HIV-related stigma when health care providers lacked basic HIV knowledge and failed to uphold the ethical principles of patient provider relationships, resulting in women's disengagement from health care. CONCLUSIONS: We propose a community-based participatory research framework to reform health care educational curriculum toward a culture of health care safety that is inclusive of people living with HIV. PMID- 26025424 TI - Do Knowledge and Attitudes Regarding Intrauterine Devices Predict Interest in Their Use? AB - BACKGROUND: Increasing use of intrauterine devices (IUDs) is seen as a promising strategy to prevent unintended pregnancies, particularly among young women. In this study, we examined correlates of young women's interest in using an IUD, including sources of information about, knowledge of, and attitudes toward IUDs. METHODS: We conducted a national Web survey of young adults (ages 18-29) in 2012. Using a subset of data from 382 sexually experienced young women who had never used an IUD, we employed multinominal logit regression models to examine differences in IUD interest. FINDINGS: Twenty percent of women in the sample were interested in using an IUD in the future, 32% were not, and 48% were unsure. Women who thought IUDs were unattractive owing to the devices being inside their bodies, the need for provider insertion and removal, or the potential for pain during insertion were less likely to be interested in ever using an IUD. Those who found IUDs attractive owing to the ease of use, the ability to have sex without interruption or a barrier method, the option of a nonhormonal method, the potential length of use, the internal nature of the method, or the high level of effectiveness were more likely to be interested. CONCLUSIONS: These data suggest that young women's attitudes toward IUDs are strongly linked to their interest-or lack thereof-in using an IUD. Health care providers attuned to women's contraceptive preferences are well-poised to help their patients match with methods that best accommodate these preferences. PMID- 26025426 TI - Multilocus sequence data reveal dozens of putative cryptic species in a radiation of endemic Californian mygalomorph spiders (Araneae, Mygalomorphae, Nemesiidae). AB - We use mitochondrial and multi-locus nuclear DNA sequence data to infer both species boundaries and species relationships within California nemesiid spiders. Higher-level phylogenetic data show that the California radiation is monophyletic and distantly related to European members of the genus Brachythele. As such, we consider all California nemesiid taxa to belong to the genus Calisoga Chamberlin, 1937. Rather than find support for one or two taxa as previously hypothesized, genetic data reveal Calisoga to be a species-rich radiation of spiders, including perhaps dozens of species. This conclusion is supported by multiple mitochondrial barcoding analyses, and also independent analyses of nuclear data that reveal general genealogical congruence. We discovered three instances of sympatry, and genetic data indicate reproductive isolation when in sympatry. An examination of female reproductive morphology does not reveal species-specific characters, and observed male morphological differences for a subset of putative species are subtle. Our coalescent species tree analysis of putative species lays the groundwork for future research on the taxonomy and biogeographic history of this remarkable endemic radiation. PMID- 26025425 TI - Presbyopic LASIK using hybrid bi-aspheric micro-monovision ablation profile for presbyopic corneal treatments. AB - PURPOSE: To evaluate distance and near image quality after hybrid bi-aspheric multifocal central presbyLASIK treatments. DESIGN: Consecutive case series. METHODS: Sixty-four eyes of 32 patients consecutively treated with central presbyLASIK were assessed. The mean age of the patients was 51 +/- 3 years with a mean spherical equivalent refraction of -1.08 +/- 2.62 diopters (D) and mean astigmatism of 0.52 +/- 0.42 D. Monocular corrected distance visual acuity (CDVA), corrected near visual acuity (CNVA), and distance corrected near visual acuity (DCNVA) of nondominant eyes; binocular uncorrected distance visual acuity (UDVA); uncorrected intermediate visual acuity (UIVA); distance corrected intermediate visual acuity (DCIVA); and uncorrected near visual acuity (UNVA) were assessed pre- and postoperatively. Subjective quality of vision and near vision was assessed using the 10-item Rasch-scaled Quality of Vision and Near Activity Visual Questionnaire, respectively. RESULTS: At 1 year postoperatively, 93% of patients achieved 20/20 or better binocular UDVA; 90% and 97% of patients had J2 or better UNVA and UIVA, respectively; 7% lost 2 Snellen lines of CDVA; Strehl ratio reduced by ~-4% +/- 14%. Defocus curves revealed a loss of half a Snellen line at best focus, with no change for intermediate vergence (-1.25 D) and a mean gain of 2 lines for near vergence (-3 D). CONCLUSIONS: Presbyopic treatment using a hybrid bi-aspheric micro-monovision ablation profile is safe and efficacious. The postoperative outcomes indicate improvements in binocular vision at far, intermediate, and near distances with improved contrast sensitivity. A 19% retreatment rate should be considered to increase satisfaction levels, besides a 3% reversal rate. PMID- 26025427 TI - Gene fusion, fission, lateral transfer, and loss: Not-so-rare events in the evolution of eukaryotic ATP citrate lyase. AB - ATP citrate lyase (ACL) is an enzyme critical to the generation of cytosolic acetyl-CoA in eukaryotes. In most studied organisms, ACL activity is conferred in combination by two proteins, ACLA and ACLB (dsACL); however, animals encode a single-subunit ACL (ssACL) - the result of a gene fusion event. Through phylogenetic analyses, we investigated the evolution of ACL in a broad range of eukaryotes, including numerous microbes (protists). We show that the fused form is not restricted to animals, and is instead widely distributed among eukaryotes. Furthermore, ssACL and dsACL are patchily distributed and appear to be mutually exclusive; both types arose early in eukaryotic evolution. Finally, we present several compelling hypotheses of lateral gene transfer and gene loss, along with the secondary gene fission of ssACL in Ascomycota. Collectively, our in-depth analyses suggest that a complex suite of evolutionary events, usually considered rare, has shaped the evolution of ACL in eukaryotes. PMID- 26025428 TI - Oxytocin receptor gene sequences in owl monkeys and other primates show remarkable interspecific regulatory and protein coding variation. AB - The oxytocin (OT) hormone pathway is involved in numerous physiological processes, and one of its receptor genes (OXTR) has been implicated in pair bonding behavior in mammalian lineages. This observation is important for understanding social monogamy in primates, which occurs in only a small subset of taxa, including Azara's owl monkey (Aotus azarae). To examine the potential relationship between social monogamy and OXTR variation, we sequenced its 5' regulatory (4936bp) and coding (1167bp) regions in 25 owl monkeys from the Argentinean Gran Chaco, and examined OXTR sequences from 1092 humans from the 1000 Genomes Project. We also assessed interspecific variation of OXTR in 25 primate and rodent species that represent a set of phylogenetically and behaviorally disparate taxa. Our analysis revealed substantial variation in the putative 5' regulatory region of OXTR, with marked structural differences across primate taxa, particularly for humans and chimpanzees, which exhibited unique patterns of large motifs of dinucleotide A+T repeats upstream of the OXTR 5' UTR. In addition, we observed a large number of amino acid substitutions in the OXTR CDS region among New World primate taxa that distinguish them from Old World primates. Furthermore, primate taxa traditionally defined as socially monogamous (e.g., gibbons, owl monkeys, titi monkeys, and saki monkeys) all exhibited different amino acid motifs for their respective OXTR protein coding sequences. These findings support the notion that monogamy has evolved independently in Old World and New World primates, and that it has done so through different molecular mechanisms, not exclusively through the oxytocin pathway. PMID- 26025429 TI - Field isotopic study of lead fate and compartmentalization in earthworm-soil metal particle systems for highly polluted soil near Pb recycling factory. AB - Earthworms are important organisms in soil macrofauna and play a key role in soil functionality, and consequently in terrestrial ecotoxicological risk assessments. Because they are frequently observed in soils strongly polluted by metals, the influence of earthworm bioturbation on Pb fate could therefore be studied through the use of Pb isotopes. Total Pb concentrations and isotopic composition ((206)Pb, (207)Pb and (208)Pb) were then measured in earthworms, casts and bulk soils sampled at different distance from a lead recycling factory. Results showed decreasing Pb concentrations with the distance from the factory whatever the considered matrix (bulk soils, earthworm bodies or cast samples) with higher concentrations in bulk soils than in cast samples. The bivariate plot (208)Pb/(206)Pb ratios versus (206)Pb/(207)Pb ratios showed that all samples can be considered as a linear mixing between metallic process particulate matter (PM) and geochemical Pb background. Calculated anthropogenic fraction of Pb varied between approximately 84% and 100%. Based on Pb isotopic signatures, the comparison between casts, earthworms and bulk soils allowed to conclude that earthworms preferentially ingest the anthropogenic lead fraction associated with coarse soil organic matter. Actually, soil organic matter was better correlated with Pb isotopic ratios than with Pb content in soils. The proposed hypothesis is therefore a decrease of soil organic matter turnover due to Pb pollution with consequences on Pb distribution in soils and earthworm exposure. Finally, Pb isotopes analysis constitutes an efficient tool to study the influence of earthworm bioturbation on Pb cycle in polluted soils. PMID- 26025430 TI - The interactive biotic and abiotic processes of DDT transformation under dissimilatory iron-reducing conditions. AB - The objective of the study was to elucidate the biotic and abiotic processes under dissimilatory iron reducing conditions involved in reductive dechlorination and iron reduction. DDT transformation was investigated in cultures of Shewanella putrefaciens 200 with/without alpha-FeOOH. A modified first-order kinetics model was developed and described DDT transformation well. Both the alpha-FeOOH reduction rate and the dechlorination rate of DDT were positively correlated to the biomass. Addition of alpha-FeOOH enhanced reductive dechlorination of DDT by favoring the cell survival and generating Fe(II) which was absorbed on the surface of bacteria and iron oxide. 92% of the absorbed Fe(II) was Na-acetate (1M) extractable. However, alpha-FeOOH also played a negative role of competing for electrons as reflected by the dechlorination rate of DDT was inhibited when increasing the alpha-FeOOH from 1 g L(-1) to 5 g L(-1). DDT was measured to be toxic to S. putrefaciens 200. The metabolites DDD, DDE and DDMU were recalcitrant to S. putrefaciens 200. The results suggested that iron oxide was not the key factor to promote the dissipation of DDX (DDT and the metabolites), whereas the one-electron reduction potential (E1) of certain organochlorines is the main factor and that the E1 higher than the threshold of the reductive driving forces of DIRB probably ensures the occur of reductive dechlorination. PMID- 26025432 TI - Isolation and development of microsatellite loci in an African Woodpecker (Campethera nivosa) using polymerase chain reaction and DNA sequencing. AB - BACKGROUND: The Buff-spotted Woodpecker (Campethera nivosa) is a resident bird species that is distributed in lowland rainforest habitats from western to eastern Africa. We developed species-specific microsatellite markers to examine the population genetics of this species. FINDINGS: Twenty-one microsatellite loci were isolated from C. nivosa. Of these, 15 were found to amplify consistently. These loci were then tested for variability in 15 individuals from different lowland forest localities. The number of alleles ranged from 3 to 13 per locus, with observed and expected heterozygosity ranging from 0.100 to 0.917 and 0.485 to 0.901, respectively. Four loci exhibited significant heterozygote deficiency while one had an excess of heterozygotes. None of the loci exhibited linkage disequilibrium. CONCLUSION: These polymorphic microsatellite markers will be used to study genetic variability in populations of C. nivosa across either sides of the Congo River to evaluate the effect of the river as a barrier to gene flow. PMID- 26025433 TI - Assessment of malalignment at the metacarpophalangeal joint of the rheumatoid hand using three-dimensional computed tomogram. AB - OBJECTIVE: For the assessment of rheumatoid hand, three-dimensional (3D) malalignment including flexed or rotational deformities and dislocation at the finger joint is one of the important findings. The objective of this study is to prove usefulness of 3D computed tomography (3DCT) for the accurate measurement of palmoulnar flexion deformity at the metacarpophalangeal (MP) joint of the rheumatoid hand. METHODS: Swanson implant arthroplasty at the 2nd through the 5th MP joints was performed at 179 joints in 46 hands of 40 patients with rheumatoid arthritis. Pre-and postoperatively, evaluations included Larsen grade and ulnar flexion angle by an x-ray; and ulnar flexion angle, palmar flexion angle, and resected bone length by a 3DCT. RESULTS: With progression of Larsen grade and the joint dislocation, ulnar flexion angle increased. Average ulnar flexion angle was 18.7 +/- 16.0 degrees (mean +/- SD) in grade III, 38.4 +/- 21.2 degrees in grade IV, and 40.1 +/- 21.1 degrees in grade V, 29.6 +/- 16.0 degrees in "subluxation," 24.8 +/- 21.2 degrees in "dislocation," and 41.1 +/- 22.2 degrees in "severe dislocation." There was no significant difference between grade of the MP joint dislocation and palmar flexion angle. With progression of the MP joint dislocation, resected bone length increased. CONCLUSION: A 3DCT gives accurate information about deformity of the rheumatoid hand. Also, an appropriate length of bone resection can be determined in the preoperative planning. PMID- 26025431 TI - Thermoregulation in endotherms: physiological principles and ecological consequences. AB - In a seminal study published nearly 70 years ago, Scholander et al. (Biol Bull 99:259-271, 1950) employed Newton's law of cooling to describe how metabolic rates (MR) in birds and mammals vary predictably with ambient temperature (T a). Here, we explore the theoretical consequences of Newton's law of cooling and show that a thermoregulatory polygon provides an intuitively simple and yet useful description of thermoregulatory responses in endothermic organisms. This polygon encapsulates the region in which heat production and dissipation are in equilibrium and, therefore, the range of conditions in which thermoregulation is possible. Whereas the typical U-shaped curve describes the relationship between T a and MR at rest, thermoregulatory polygons expand this framework to incorporate the impact of activity, other behaviors and environmental conditions on thermoregulation and energy balance. We discuss how this framework can be employed to study the limits to effective thermoregulation and their ecological repercussions, allometric effects and residual variation in MR and thermal insulation, and how thermoregulatory requirements might constrain locomotor or reproductive performance (as proposed, for instance, by the heat dissipation limit theory). In many systems the limited empirical knowledge on how organismal traits may respond to environmental changes prevents physiological ecology from becoming a fully developed predictive science. In endotherms, however, we contend that the lack of theoretical developments that translate current physiological understanding into formal mechanistic models remains the main impediment to study the ecological and evolutionary repercussions of thermoregulation. In spite of the inherent limitations of Newton's law of cooling as an oversimplified description of the mechanics of heat transfer, we argue that understanding how systems that obey this approximation work can be enlightening on conceptual grounds and relevant as an analytical and predictive tool to study ecological phenomena. As such, the proposed approach may constitute a powerful tool to study the impact of thermoregulatory constraints on variables related to fitness, such as survival and reproductive output, and help elucidating how species will be affected by ongoing climate change. PMID- 26025434 TI - Characteristics of patients with intestinal Behcet's disease requiring treatment with immunosuppressants or anti-TNFalpha antibody. AB - OBJECTIVES: To identify the specific characteristics of patients with refractory intestinal Behcet's disease (BD) who required more than glucocorticoid (GC) and/or 5-aminosalicylic acid (5-ASA) treatment. METHODS: A retrospective review of the patient records in a university hospital identified 34 patients with intestinal BD. The patients treated only with glucocorticoid and/or 5-ASA (n = 8) were compared with refractory cases which required additional immunosuppressants, anti-TNFalpha antibodies, or surgery (n = 12). RESULTS: In the refractory group, ulcers were found outside the ileocecal region more often, and more active intestinal bleeding or melena was observed, than in the GC/5ASA-controlled group (75% vs 0%, p = 0.001), (58% vs 0%, p = 0.015). The refractory group also showed higher positivity for HLA-B51 (45% vs 0%, p = 0.044), higher blood C-reactive protein (CRP) levels (14.7 +/- 8.74 vs 3.93 +/- 6.33 mg/dL, p = 0.046), and a higher white blood cell or WBC count (14750 +/- 6760 vs 7210 +/- 1830/MUl, p = 0.025) at onset. The existence of either HLA-B51, melena, or elevated CRP of more than 4 mg/dL predicted the refractory form of BD with 100% sensitivity and 85.7% specificity. CONCLUSIONS: Refractory intestinal BD was distinguished from the non refractory form by distinct clinical and laboratory findings. These findings will be useful in identifying patients who require intensive therapy (e.g., anti TNFalpha antibodies) in addition to GC/5ASA. PMID- 26025435 TI - Antinuclear antibody-positive cohort constitutes homogeneous entity in juvenile idiopathic arthritis. AB - OBJECTIVE: To identify a homogeneous entity for antinuclear antibody (ANA) positive patients suffering from juvenile idiopathic arthritis (JIA). METHODS: All of the clinical features were recorded retrospectively. ANA positivity was defined as more than twice positive results at a titer of > 1:100. The correlation between ANA positivity and clinical parameters was assessed by multiple logistic regression analysis. RESULT: Of 120 patients, 49 patients were ANA positive (31 oligoarthritis, 18 rheumatoid factor [RF]-negative polyarthritis) and 71 patients were ANA negative (48 oligoarthritis, 23 RF negative polyarthritis), and were recruited retrospectively to this study according to the International League of Associations for Rheumatology (ILAR) criteria. In ANA-positive cohort, the characteristics of early-onset age, female predominance, and asymmetric arthritis were observed compared with ANA-negative cohort including oligoarthritis and RF-negative polyarthritis. Correspondingly, we found that ANA-positive cohort had higher cumulative number of joints affected at 9 and 12 months after disease presentation than ANA-negative cohort, had lower frequency of occurrence of image change, and had a different pattern of affected arthritis than ANA-negative cohort, which was more likely to have knee involvement and less likely to have hip and shoulder involvement. ANA positivity correlated strongly with asymmetric arthritis, female predominance and wrist involvement. CONCLUSION: This study demonstrates that ANA-positive cohort divided into different subgroups by present ILAR criteria share the similar features and suggests that ANA positivity might serve as a novel potential value for JIA classification. PMID- 26025436 TI - Risk of ischemic stroke in patients with systemic sclerosis: A systematic review and meta-analysis. AB - BACKGROUND: Several chronic inflammatory disorders, such as rheumatoid arthritis and idiopathic inflammatory myositis, have been shown to increase risk of ischemic stroke but the data on systemic sclerosis (SSc) remains unclear. METHODS: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio, or standardized incidence ratio comparing risk of ischemic stroke in patients with SSc versus non SSc participants. Pooled risk ratio and 95% confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Four retrospective cohort studies were identified and included in our data analysis. We found a statistically significant elevated ischemic stroke risk in patients with SSc with a pooled risk ratio of 1.68 (95% CI, 1.26-2.24). The statistical heterogeneity was moderate with an I(2) of 69%. CONCLUSIONS: Our study demonstrated a statistically significant increased ischemic stroke risk among patients with SSc. PMID- 26025437 TI - Association of beta-defensin gene copy number variations with ankylosing spondylitis in Chinese population: A case-control study. AB - OBJECTIVES: To explore the association of beta-defensin gene copy number variations (CNVs) with ankylosing spondylitis (AS). METHODS: In this study, 405 unrelated Chinese Han patients with AS and 401 unrelated healthy controls were enrolled. The copy numbers of DEFB4 gene (2 fragments) were measured by AccuCopyTM methods. The association of DEFB4 gene CNVs with AS susceptibility was analyzed by chi-square and logistic regression models. Besides, P values, odds ratio, and 95% confidence intervals (CIs) were used to estimate the effects of risk. RESULTS: The range of DEFB4_1 CN was 0-7 and the range of DEFB4_2 CN was 1 8 both in patients and controls. P values of chi(2) trend test for the association of DEFB4_1 and DEFB4_2 with AS were 0.607 and 0.005, respectively. The results of DEFB4_2, compared with the individual having median 3 copies, those carrying <= 2-copies [OR = 0.68, 95%CI: (0.46, 0.99), P = 0.049; adjusted OR = 0.69, 95%CI(0.47, 1.03), P = 0.067.]; and those carrying >= 4-copies [OR = 0.62, 95%CI: (0.45, 0.86), P = 0.004; adjusted OR = 0.64, 95%CI: (0.46, 0.88), P = 0.006], were significantly associated with decreasing risk of AS. Univariate analysis showed that both DEFB4_1 and DEFB4_2 were associated with Bath AS Disease Activity Index or BASDAI. After adjusted by age, sex, and disease duration, the results changed little, which demonstrated that high copies may be linked with decrease in the risk of disease severity [OR = 0.71, 95%CI: (0.56, 0.90), P = 0.005; OR = 0.75, 95%CI: (0.60, 0.94), P = 0.013, respectively]. CONCLUSIONS: The CNs of DEFB4 gene may be associated with AS and involved in disease progression. PMID- 26025438 TI - Clinical efficacy comparison of HA280 and DNA280 immunoadsorption column in treating systemic lupus erythematosus. AB - OBJECTIVE: The aim of this study was to compare the efficacy of HA280 and DNA280 immunoadsorption (IA) column in treating systemic lupus erythematosus (SLE), and provide the basis for seeking cost-effective solution for SLE. METHODS: Fifty seven severe SLE patients receiving IA treatment from January 2007 to December 2013 were selected. They were divided into HA280 group (31 cases) and DNA280 group (26 cases), which used HA280 and DNA280 IA column, respectively. The efficacy, adverse reactions, and hospitalization cost of the two groups were compared. RESULTS: Both two groups could effectively reduce the SLE-associated antibodies, immunoglobulins, complement levels, serum creatinine, blood urea nitrogen, and 24-h urine protein levels (P < 0.05). The efficiency and incidence of adverse reactions of two groups were similar (P > 0.05), while the hospitalization cost of HA280 group was significantly less than that of DNA280 group (P < 0.05). CONCLUSIONS: Application of HA280 IA column in IA treatment is relatively the most cost-effective adjuvant therapy to severe SLE. PMID- 26025439 TI - A novel method based on two cameras for accurate estimation of arterial oxygen saturation. AB - BACKGROUND: Photoplethysmographic imaging (PPGi) that is based on camera allows acquiring photoplethysmogram and measuring physiological parameters such as pulse rate, respiration rate and perfusion level. It has also shown potential for estimation of arterial oxygen saturation (SaO2). However, there are some technical limitations such as optical shunting, different camera sensitivity to different light spectra, different AC-to-DC ratios (the peak-to-peak amplitude to baseline ratio) of the PPGi signal for different portions of the sensor surface area, the low sampling rate and the inconsistency of contact force between the fingertip and camera lens. METHODS: In this paper, we take full account of the above-mentioned design challenges and present an accurate SaO2 estimation method based on two cameras. The hardware system we used consisted of an FPGA development board (XC6SLX150T-3FGG676 from Xilinx), with connected to it two commercial cameras and an SD card. The two cameras were placed back to back, one camera acquired PPGi signal from the right index fingertip under 660 nm light illumination while the other camera acquired PPGi signal from the thumb fingertip using an 800 nm light illumination. The both PPGi signals were captured simultaneously, recorded in a text file on the SD card and processed offline using MATLAB(r). The calculation of SaO2 was based on the principle of pulse oximetry. The AC-to-DC ratio was acquired by the ratio of powers of AC and DC components of the PPGi signal in the time-frequency domain using the smoothed pseudo Wigner-Ville distribution. The calibration curve required for SaO2 measurement was obtained by linear regression analysis. RESULTS: The results of our estimation method from 12 subjects showed a high correlation and accuracy with those of conventional pulse oximetry for the range from 90 to 100%. CONCLUSIONS: Our method is suitable for mobile applications implemented in smartphones, which could allow SaO2 measurement in a pervasive environment. PMID- 26025440 TI - Rapid draft sequencing and real-time nanopore sequencing in a hospital outbreak of Salmonella. AB - BACKGROUND: Foodborne outbreaks of Salmonella remain a pressing public health concern. We recently detected a large outbreak of Salmonella enterica serovar Enteritidis phage type 14b affecting more than 30 patients in our hospital. This outbreak was linked to community, national and European-wide cases. Hospital patients with Salmonella are at high risk, and require a rapid response. We initially investigated this outbreak by whole-genome sequencing using a novel rapid protocol on the Illumina MiSeq; we then integrated these data with whole genome data from surveillance sequencing, thereby placing the outbreak in a national context. Additionally, we investigated the potential of a newly released sequencing technology, the MinION from Oxford Nanopore Technologies, in the management of a hospital outbreak of Salmonella. RESULTS: We demonstrate that rapid MiSeq sequencing can reduce the time to answer compared to the standard sequencing protocol with no impact on the results. We show, for the first time, that the MinION can acquire clinically relevant information in real time and within minutes of a DNA library being loaded. MinION sequencing permits confident assignment to species level within 20 min. Using a novel streaming phylogenetic placement method samples can be assigned to a serotype in 40 min and determined to be part of the outbreak in less than 2 h. CONCLUSIONS: Both approaches yielded reliable and actionable clinical information on the Salmonella outbreak in less than half a day. The rapid availability of such information may facilitate more informed epidemiological investigations and influence infection control practices. PMID- 26025441 TI - Relationship between circulating syndecan-1 levels (CD138s) and serum free light chains in monoclonal gammopathies. AB - BACKGROUND: Monoclonal gammopathies encompass a wide range of diseases characterized by the monoclonal expansion of a B-cell clone. Despite emerging therapeutic strategies, chances of survival of patients who are affected are still scarce, which implies that new tools are necessary not only for the diagnosis but also for the follow-up of patients affected by such diseases. In this context, the use of free light chains (FLCs) has been incorporated into many guidelines. Likewise, tumor microenvironment is consistently gaining importance as role player in tumor pathogenesis. Specifically, Syndecan-1 (CD138), a heparan sulfate proteoglycan is attracting interests as it is highly expressed and shed by myeloma plasma-cells. The aim of our study was to analyze CD138 levels in the serum of patients affected by multiple myeloma or light chain only disease, and to compare the values obtained with free light chain (FLC) kappa, lambda and FLC ratio in both groups of patients. METHODS: 84 patients affected by Multiple Myeloma and Light Chain Myeloma were recruited for this study. Serum CD138 was assessed by ELISA (Diaclone Research, France) and FLC values were quantified by nephelometry (Freelite TM Human Kappa and Lambda Free Kits, The Binding Site, UK). Data was analyzed by GraphPad Prism software and Statgraph. RESULTS: We observed higher CD138 mean values in myeloma patients compared to the light chain only myeloma group. A positive linear regression of CD138 and FLC was observed in the light chain only cohort as opposed to myeloma patients which show an inverse trend. CONCLUSIONS: The study highlighted an existing relationship between FLCs and CD138 and wishes to seek also a correlation in order to rapidly and efficiently perform diagnosis and different diagnostic schemes. PMID- 26025442 TI - Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment. AB - BACKGROUND: The mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells. METHODS: We used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence. RESULTS: We report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21(CIP1) upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78(high)/CD138+ MM cells from patients suggested that high levels correlated with progressive disease. CONCLUSIONS: We conclude that Bz-surviving MM cells display a GRP78(HIGH)/p21(HIGH)/CDK6(LOW)/P Rb(LOW) profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz-induced apoptosis and quiescence stability. PMID- 26025443 TI - The effects of temporal neck cooling on cognitive function during strenuous exercise in a hot environment: a pilot study. AB - BACKGROUND: Heat stress potentially has detrimental effects on brain function. Hence, cognitive function may be impaired during physical activity in a hot environment. Skin cooling is often applied in a hot environment to counteract heat stress. However, it is unclear to what extent neck cooling is effective for cognitive impairment during exercise in a hot environment. The purpose of this study was to examine the effects of temporal neck cooling on cognitive function during strenuous exercise in a hot environment. METHODS: Eight male young participants (mean +/- SD, age = 26.1 +/- 3.2 years; peak oxygen uptake = 45.6 +/ 5.2 ml/kg/min) performed Spatial delayed response (DR) task (working memory) and Go/No-Go task (executive function) at rest and during exercise in the Hot and Hot + Cooling conditions. After the participants completed the cognitive tasks at rest, they cycled the ergometer until their heart rate (HR) reached 160 beats/min. Then, they cycled for 10 min while keeping their HR at 160 beats/min. The cognitive tasks were performed 3 min after their HR reached 160 beats/min. The air temperature was maintained at 35 degrees C and the relative humidity was controlled at 70%. Neck cooling was applied to the backside of the neck by a wet towel and fanning. We used accuracy of the Spatial DR and Go/No-Go tasks and reaction time in the Go/No-Go task to assess cognitive function. RESULTS: Neck cooling temporarily decreased the skin temperature during exercise. The accuracy of the cognitive tasks was lower during exercise than that at rest in the Hot and Hot + Cooling condition (p < 0.05). There were no differences in the accuracy between the Hot and Hot + Cooling conditions (p = 0.98). Neither exercise (p = 0.40) nor cooling (p = 0.86) affected reaction time. These results indicate that temporal neck cooling did not alter cognitive function during strenuous exercise in a hot environment. CONCLUSIONS: The present study suggests that temporal neck cooling with a wet towel and fanning is not effective for attenuating impairment of working memory and executive function during strenuous exercise with a short duration in a warm and humid environment. PMID- 26025444 TI - Envelope filter sequence to delete blinks and overshoots. AB - BACKGROUND: Eye movements have been used in control interfaces and as indicators of somnolence, workload and concentration. Different techniques can be used to detect them: we focus on the electrooculogram (EOG) in which two kinds of interference occur: blinks and overshoots. While they both draw bell-shaped waveforms, blinks are caused by the eyelid, whereas overshoots occur due to target localization error and are placed on saccade. They need to be extracted from the EOG to increase processing effectiveness. METHODS: This paper describes off- and online processing implementations based on lower envelope for removing bell-shaped noise; they are compared with a 300-ms-median filter. Techniques were analyzed using two kinds of EOG data: those modeled from our own design, and real signals. Using a model signal allowed to compare filtered outputs with ideal data, so that it was possible to quantify processing precision to remove noise caused by blinks, overshoots, and general interferences. We analyzed the ability to delete blinks and overshoots, and waveform preservation. RESULTS: Our technique had a high capacity for reducing interference amplitudes (>97%), even exceeding median filter (MF) results. However, the MF obtained better waveform preservation, with a smaller dependence on fixation width. CONCLUSIONS: The proposed technique is better at deleting blinks and overshoots than the MF in model and real EOG signals. PMID- 26025445 TI - Diagnostic and prognostic utility of tissue factor for severe sepsis and sepsis induced acute lung injury. AB - BACKGROUND: Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) play a central role in the endothelial permeability regulation and dysfunction, which is associated with the development of sepsis and acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The aim of this study is to assess the diagnostic and prognostic values of TF and TFPI in patients with sepsis and sepsis-induced ARDS. METHODS: A total of 62 patients with sepsis, 167 patients with severe sepsis and 32 healthy volunteers were enrolled in this prospective observational study. TF and TFPI levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with sepsis-induced ARDS showed significantly higher median levels of TF compared with patients without ARDS (1425.5 (1019.9 to 2595.2) pg/ml vs 916.2 (724.1 to 1618.2) pg/ml, P < 0.001), and compared with sepsis patients (943.5 (786.4 to 992.4) pg/ml, P < 0.001) on the day of admission. However, there was no significant difference between sepsis patients and healthy subjects, or between septic shock and non-septic shock patients (P > 0.05). The AUC of TF for the diagnosis of sepsis-induced ARDS was 0.749 (95% confidence interval (CI) 0.675-0.822). Plasma TF levels in the non-survivors of severe sepsis were significantly higher than those of survivors (1618.6 (1017.1 to 2900.8) pg/ml vs. 979.9 (757.2 to 1645.5) pg/ml, P < 0.001), and multivariate logistic regression showed the plasma value of TF was the independent predictor for 30-day mortality in patients with severe sepsis (P = 0.0022, odds ratio (OR) = 1.41, 95% CI 1.24-1.69). The AUC of TF for predicting 30-day mortality in severe sepsis patients was 0.718 (95% CI 0.641-0.794). However, there was no significant difference in the plasma TFPI values among the healthy control, sepsis and severe sepsis groups (P > 0.05). CONCLUSIONS: Our data showed that tissue factor is a valuable diagnostic biomarker for the diagnosis of sepsis induced ARDS. Moreover, tissue factor is a strong prognostic marker for short term mortality in severe sepsis and sepsis-induced ARDS patients. PMID- 26025446 TI - Sensitivity of initial biopsy or transurethral resection of bladder tumor(s) for detecting histological variants on radical cystectomy. AB - BACKGROUND: To investigate the efficacy of initial biopsy or transurethral resection of bladder tumor for detecting histological variants on radical cystectomy and to assess the prognostic significance of variant histology on urothelial carcinoma outcomes after radical cystectomy. METHODS: Clinical and histopathological characteristics of 147 patients with variant histology who underwent radical cystectomy for urothelial carcinoma between 2006 and 2012 were assessed. Sensitivity was calculated as the proportion of radical cystectomy specimens with a particular variant that also presented the variant in the biopsy or transurethral resection specimen. The Kaplan-Meier method and multivariate Cox proportional hazard regression analysis were used to estimate cancer-specific survival. RESULTS: Of the 147 patients, 116 (79 %) were diagnosed with a single variant histology, and 31 (21 %) had multiple patterns. Squamous differentiation (31 %) was the most common single variant histology, followed by glandular differentiation (28 %). Except for small cell variant (100 %), the sensitivity of biopsy and transurethral resection was most effective for the diagnosis of squamous differentiation, 19 % vs. 40 % respectively, followed by glandular differentiation, 11 % vs. 21 % respectively. A total of 6 % and 49 % patients could be variant-free partially due to biopsy or complete resection(s) respectively. Presence of variant differentiation in urothelial carcinoma at cystectomy was significantly associated with inferior survival both in univariate analysis (P = 0.005) and multivariate analysis (HR4.48, 95 % CI:1.03-19.53). CONCLUSIONS: Overall sensitivity of biopsy or transurethral resection to detect variant differentiation on cystectomy is relatively low. Patients with variant differentiation on cystectomy specimens have inferior survival. PMID- 26025447 TI - Ethnomedicinal plants used by traditional healers in Phatthalung Province, Peninsular Thailand. AB - BACKGROUND: In rural communities of Thailand, traditional healers still play an important role in local health care systems even though modern medicine is easily accessible. Meanwhile, natural forests in Thailand which are important sources of materia medica are being greatly destroyed. This has led to an erosion of traditional Thai medicine. Furthermore, the concept of medicinal plant selection as medicine based on their tastes is still an important component of traditional Thai medicine, but no or little publications have been reported. Thus the aim of the present study is to collect ethnomedicinal data, medicinal plant tastes and relevant information from experienced traditional healers before they are lost. METHODS: An ethnobotanical survey was carried out to collect information from nine experienced traditional healers on the utilization of medicinal plants in Phatthalung Province, Peninsular Thailand. Data were obtained using semi structured interviews and participant observations. Plant specimens were also collected and identified according to the plant taxonomic method. RESULTS: A total of 151 medicinal plants were documented and 98 of these are reported in the study. Local names, medicinal uses, parts used, modes of preparation, and the relationship between ailments and tastes of medicinal plant species are presented. CONCLUSIONS: This research suggests that traditional healers are still considered important for public health among Thai communities and that many people trust the healing properties of medicinal plants. In the future, it is hoped that traditional Thai medicine will be promoted and therefore will help reduce national public health expense. PMID- 26025449 TI - Coaggregation and biofilm growth of Granulicatella spp. with Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans. AB - BACKGROUND: Members of fastidious Granulicatella and Aggregatibacter genera belong to normal oral flora bacteria that can cause serious infections, such as infective endocarditis. Aggregatibacter actinomycetemcomitans has long been implicated in aggressive periodontitis, whereas DNA-based methods only recently showed an association between Granulicatella spp. and dental diseases. As bacterial coaggregation is a key phenomenon in the development of oral and nonoral multispecies bacterial communities it would be of interest knowing coaggregation pattern of Granulicatella species with A. actinomycetemcomitans in comparison with the multipotent coaggregator Fusobacterium nucleatum. The aim was to investigate coaggregation and biofilm formation of Granulicatella elegans and Granulicatella adiacens with A. actinomycetemcomitans and F. nucleatum strains. RESULTS: F. nucleatum exhibited significantly (p < 0.05) higher autoaggregation than all other test species, followed by A. actinomycetemcomitans SA269 and G. elegans. A. actinomycetemcomitans CU1060 and G. adiacens did not autoaggregate. G. elegans with F. nucleatum exhibited significantly (p < 0.05) higher coaggregation than most others, but failed to grow as biofilm together or separately. With F. nucleatum as partner, A. actinomycetemcomitans strains SA269, a rough-colony wild-type strain, and CU1060, a spontaneous smooth-colony laboratory variant, and G. adiacens were the next in coaggregation efficiency. These dual species combinations also were able to grow as biofilms. While both G. elegans and G. adiacens coaggregated with A. actinomycetemcomitans strain SA269, but not with CU1060, they grew as biofilms with both A. actinomycetemcomitans strains. CONCLUSIONS: G. elegans failed to form biofilm with F. nucleatum despite the strongest coaggregation with it. The ability of Granulicatella spp. to coaggregate and/or form biofilms with F. nucleatum and A. actinomycetemcomitans strains suggests that Granulicatella spp. have the potential to integrate into dental plaque biofilms. PMID- 26025448 TI - Association between fine particulate matter exposure and subclinical atherosclerosis: A meta-analysis. AB - BACKGROUND: Epidemiological studies in humans that have evaluated the association between fine particulate matter (PM2.5) and atherosclerosis have yielded mixed results. DESIGN: In order to further investigate this relationship, we conducted a comprehensive search for studies published through May 2014 and performed a meta-analysis of all available observational studies that investigated the association between PM2.5 and three noninvasive measures of clinical and subclinical atherosclerosis: carotid intima media thickness, arterial calcification, and ankle-brachial index. METHODS AND RESULTS: Five reviewers selected studies based on predefined inclusion criteria. Pooled mean change estimates and 95% confidence intervals were calculated using random-effects models. Assessment of between-study heterogeneity was performed where the number of studies was adequate. Our pooled sample included 11,947 subjects for carotid intima media thickness estimates, 10,750 for arterial calcification estimates, and 6497 for ankle-brachial index estimates. Per 10 ug/m(3) increase in PM2.5 exposure, carotid intima media thickness increased by 22.52 um but this did not reach statistical significance (p = 0.06). We did not find similar associations for arterial calcification (p = 0.44) or ankle-brachial index (p = 0.85). CONCLUSION: Our meta-analysis supports a relationship between PM2.5 and subclinical atherosclerosis measured by carotid intima media thickness. We did not find a similar relationship between PM2.5 and arterial calcification or ankle brachial index, although the number of studies was small. PMID- 26025450 TI - A systematic review of the use of an expertise-based randomised controlled trial design. AB - BACKGROUND: Under a conventional two-arm randomised trial design, participants are allocated to an intervention and participating health professionals are expected to deliver both interventions. However, health professionals often have differing levels of expertise in a skill-based interventions such as surgery or psychotherapy. An expertise-based approach to trial design, where health professionals only deliver an intervention in which they have expertise, has been proposed as an alternative. The aim of this project was to systematically review the use of an expertise-based trial design in the medical literature. METHODS: We carried out a comprehensive search of nine databases--AMED, BIOSIS, CENTRAL, CINAHL, Cochrane Methodology Register, EMBASE, MEDLINE, Science Citation Index, and PsycINFO--from 1966 to 2012 and performed citation searches using the ISI Citation Indexes and Scopus. Studies that used an expertise-based trial design were included. Two review authors independently screened the titles and abstracts and assessed full-text reports. Data were extracted and summarised on the study characteristics, general and expertise-specific study methodology, and conduct. RESULTS: In total, 7476 titles and abstracts were identified, leading to 43 included studies (54 articles). The vast majority (88%) used a pure expertise based design; three (7%) adopted a hybrid design, and two (5%) used a design that was unclear. Most studies compared substantially different interventions (79%). In many cases, key information relating to the expertise-based design was absent; only 12 (28%) reported criteria for delivering both interventions. Most studies recruited the target sample size or very close to it (median of 101, interquartile range of 94 to 118), although the target was reported for only 40% of studies. The proportion of participants who received the allocated intervention was high (92%, interquartile range of 82 to 99%). CONCLUSIONS: While use of an expertise-based trial design is growing, it remains uncommon. Reporting of study methodology and, particularly, expertise-related methodology was poor. Empirical evidence provided some support for purported benefits such as high levels of recruitment and compliance with allocation. An expertise-based trial design should be considered but its value seems context-specific, particularly when interventions differ substantially or interventions are typically delivered by different health professionals. PMID- 26025451 TI - Type 2 diabetes mellitus and myocardial ischemic preconditioning in symptomatic coronary artery disease patients. AB - BACKGROUND: The influence of diabetes mellitus on myocardial ischemic preconditioning is not clearly defined. Experimental studies are conflicting and human studies are scarce and inconclusive. OBJECTIVES: Identify whether diabetes mellitus intervenes on ischemic preconditioning in symptomatic coronary artery disease patients. METHODS: Symptomatic multivessel coronary artery disease patients with preserved systolic ventricular function and a positive exercise test underwent two sequential exercise tests to demonstrate ischemic preconditioning. Ischemic parameters were compared among patients with and without type 2 diabetes mellitus. Ischemic preconditioning was considered present when the time to 1.0 mm ST deviation and rate pressure-product were greater in the second of 2 exercise tests. Sequential exercise tests were analyzed by 2 independent cardiologists. RESULTS: Of the 2,140 consecutive coronary artery disease patients screened, 361 met inclusion criteria, and 174 patients (64.2 +/- 7.6 years) completed the study protocol. Of these, 86 had the diagnosis of type 2 diabetes. Among diabetic patients, 62 (72 %) manifested an improvement in ischemic parameters consistent with ischemic preconditioning, whereas among nondiabetic patients, 60 (68 %) manifested ischemic preconditioning (p = 0.62). The analysis of patients who demonstrated ischemic preconditioning showed similar improvement in the time to 1.0 mm ST deviation between diabetic and nondiabetic groups (79.4 +/- 47.6 vs 65.5 +/- 36.4 s, respectively, p = 0.12). Regarding rate pressure-product, the improvement was greater in diabetic compared to nondiabetic patients (3011 +/- 2430 vs 2081 +/- 2139 bpm x mmHg, respectively, p = 0.01). CONCLUSIONS: In this study, diabetes mellitus was not associated with impairment in ischemic preconditioning in symptomatic coronary artery disease patients. Furthermore, diabetic patients experienced an improvement in this significant mechanism of myocardial protection. PMID- 26025452 TI - Aftercare Services for Child Victims of Sex Trafficking: A Systematic Review of Policy and Practice. AB - OBJECTIVE: To explore aftercare services provided to child victims of sex trafficking globally based on the results of a systematic review of published and unpublished research, organizational policy, and current practice. This systematic review serves as a first step toward developing best practices for aftercare service providers. METHOD: A systematic search was conducted of four English language databases, two human trafficking resource libraries, and one Internet search engine for journal articles and "grey" literature published between January 2000 and May 2013 on the services offered to child sex trafficking victims globally. The search yielded 15 documents for inclusion in the review. RESULTS: The 15 documents emphasized the need for aftercare service provision to be founded on children's rights and trauma-informed service provision. They recommended delivery practices such as case management and multidisciplinary, multiagency and multinational coordination to ensure the child victims benefit fully from the services. The systematic review revealed that there are three phases to aftercare service provision: rescue, recover, and reintegration. Each of these phases is characterized by different needs and types of services provided. The recovery phase received the most attention compared to recovery and reintegration phases. CONCLUSION: The literature highlighted that aftercare service provision for child sex trafficking victims is a new area that needs an evidence base from which policy and practice can be formed. There is great need for further research and better documentation of service provision. While this research provides insight into this area, the gap in literature remains wide. The area of aftercare service provision for children who have been trafficked has experienced phenomenal growth within the last 10 years, and with more research and resources being directed to the area, the achievement of international minimum standards of care provision is possible. PMID- 26025454 TI - Local injection of mesenchymal stem cells protects testicular torsion-induced germ cell injury. AB - INTRODUCTION: Testicular torsion is a urological emergency and infertility is a common complication due to ischemic injury. Surgical reduction and orchiopexy is indicated, but to date there is no effective method for restoration of spermatogenesis. The effects of mesenchymal stem cells (MSCs) on acute tissue injury have been demonstrated, and the abilities of paracrine support, differentiation and immune-modulation may benefit to testicular torsion-induced infertility. We investigate the therapeutic efficacy and the mechanisms of MSCs in testicular torsion-induced germ cell injury when injected locally. METHODS: Six to eight-week-old Sprague-Dawley rats received surgical 720 degree torsion for 3 hours, followed by detorsion on the left testis. 20 MUl of phosphate buffered saline (PBS) without or with 3 x 10(4) MSCs from human orbital fat tissues (OFSCs) were given for 10 rats, respectively, via local injection into the left testis 30 minutes before detorsion. 20 MUl of PBS injection for 6 rats with surgical exposure without torsion served as sham control. Histopathology with Johnsen's score analysis, Western blot analysis for superoxide dismutase 2, Bax, Caspase-3, human insulin growth factor-1 and human stem cell factor, malondialdehyde (MDA) assay in testis and plasma, hormones level including testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by ELISA Kits, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and fluorescence staining for P450, Sox-9 and VASA were performed. RESULTS: Animals were sacrificed and bilateral orchiectomy was performed 7 days after torsion-detorsion. Local injections of OFSCs prevented torsion-induced infertility judging from Johnsen's score. TUNEL assay and Western blot analysis on caspase 3 and Bax demonstrated that OFSCs prevented ischemic/reperfusion induced intrinsic apoptosis. MDA assay revealed that OFSCs significantly reduced the oxidative stress in the damaged testicular tissues. After the OFSC injection, serum testosterone secretion was increased, while the elevation of FSH triggered by testicular injury was balanced. OFSCs also produced stem cell factor in the damaged testis. Immunofluorescence staining revealed that most transplanted cells surrounded the Leydig cells. Some of transplanted cells differentiated into p450 expressing cells within 7 days. CONCLUSIONS: Local injection of allogenic MSCs before surgical detorsion is a simple, clinical friendly procedure to rescue torsion-induced infertility. PMID- 26025455 TI - Psychometric Properties of the Sexual Excitation/Sexual Inhibition Inventory for Women in a German Sample. AB - The Sexual Excitation Sexual/Inhibition Inventory for Women (SESII-W) is a self report questionnaire for assessing propensities of sexual excitation (SE) and sexual inhibition (SI) in women. According to the dual control model of sexual response, these two factors differ between individuals and influence the occurrence of sexual arousal in given situations. Extreme levels of SE and SI are postulated to be associated with sexual problems or risky sexual behaviors. Psychometric evaluation of the original scale yielded two higher order and eight lower order factors as well as satisfactory to good construct validity and reliability. The present study was designed to assess the psychometric properties of a German version of the SESII-W utilizing a large convenience sample of 2206 women. Confirmatory factor analysis showed a satisfactory overall model fit, with support for the five lower order factors of SE (Arousability, Sexual Power Dynamics, Smell, Partner Characteristics, Setting) and the three lower order factors of SI (Relationship Importance, Arousal Contingency, and Concerns about Sexual Function). Additionally, the scale demonstrated good convergent and discriminant validity, internal consistency, and test-retest-reliability. The German SESII-W is a sufficiently reliable and valid measure for assessing SE and SI in women. Hence, its use can be recommended for future research in Germany that investigates women's sexual behaviors and experiences. PMID- 26025453 TI - Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway. AB - BACKGROUND: Prostaglandin E2 (PGE2) is an essential intrafollicular regulator of ovulation. In contrast with the one-gene, one-protein concept for synthesis of peptide signaling molecules, production and metabolism of bioactive PGE2 requires controlled expression of many proteins, correct subcellular localization of enzymes, coordinated PGE2 synthesis and metabolism, and prostaglandin transport in and out of cells to facilitate PGE2 action and degradation. Elevated intrafollicular PGE2 is required for successful ovulation, so disruption of PGE2 synthesis, metabolism or transport may yield effective contraceptive strategies. METHODS: This review summarizes case reports and studies on ovulation inhibition in women and macaques treated with cyclooxygenase inhibitors published from 1987 to 2014. These findings are discussed in the context of studies describing levels of mRNA, protein, and activity of prostaglandin synthesis and metabolic enzymes as well as prostaglandin transporters in ovarian cells. RESULTS: The ovulatory surge of LH regulates the expression of each component of the PGE2 synthesis metabolism-transport pathway within the ovulatory follicle. Data from primary ovarian cells and cancer cell lines suggest that enzymes and transporters can cooperate to optimize bioactive PGE2 levels. Elevated intrafollicular PGE2 mediates key ovulatory events including cumulus expansion, follicle rupture and oocyte release. Inhibitors of the prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme (also known as cyclooxygenase-2 or COX2) reduce ovulation rates in women. Studies in macaques show that PTGS2 inhibitors can reduce the rates of cumulus expansion, oocyte release, follicle rupture, oocyte nuclear maturation and fertilization. A PTGS2 inhibitor reduced pregnancy rates in breeding macaques when administered to simulate emergency contraception. However, PTGS2 inhibition did not prevent pregnancy in monkeys when administered to simulate monthly contraceptive use. CONCLUSION: PTGS2 inhibitors alone may be suitable for use as emergency contraceptives. However, drugs of this class are unlikely to be effective as monthly contraceptives. Inhibitors of additional PGE2 synthesis enzymes or modulation of PGE2 metabolism or transport also hold potential for reducing follicular PGE2 and preventing ovulation. Approaches which target multiple components of the PGE2 synthesis-metabolism-transport pathway may be required to effectively block ovulation and lead to the development of novel contraceptive options for women. Therapies which target PGE2 may also impact disorders of the uterus and could also have benefits for women's health in addition to contraception. PMID- 26025457 TI - Evaluation of convenient pretreatment protocols for RNA virus metagenomics in serum and tissue samples. AB - Viral metagenomic approaches are increasingly being used for viral discovery. Various strategies are applied to enrich viral sequences, but there is often a lack of knowledge about their effective influence on the viral discovery sensitivity. We evaluate some convenient and widely used approaches for RNA virus discovery in clinical samples in order to reveal their sensitivity and potential bias introduced by the enrichment or amplifications steps. An RNA virus was artificially spiked at a fixed titer in serum and lung tissue, respectively, low and high nucleic acid content matrices. For serum, a simple DNase treatment on the RNA extract gave the maximum gain in proportion of viral sequences (83*), and a subsequent ribosomal RNA removal nearly doubled once more the proportion of viral sequences. For lung tissue, a ribosomal RNA depletion step on the RNA extract had the biggest gain in proportion of viral sequences (32*). We show also that direct sequencing of cDNA is recommended above an extra random PCR amplification step, and a that the virion enrichment strategy (filtration and nuclease treatment) has a beneficial effect for sequencing-based virus discovery. Our findings provide sample-dependent guidelines for targeted virus discovery strategies. PMID- 26025456 TI - Ethnomedicinal survey of various communities residing in Garo Hills of Durgapur, Bangladesh. AB - BACKGROUND: Garo Hills represents one of earliest human habitation in Bangladesh preserving its ancient cultures due to the geographic location. It is situated in the most northern part of Durgapur sub-district having border with Meghalaya of India. Durgapur is rich in ethnic diversity with Garo and Hajong as the major ethnic groups along with Bangalee settlers from the mainstream population. Thus the ethnomedicinal practice in Garo Hills is considered rich as it encompasses three different groups. Present survey was undertaken to compile the medicinal plant usage among the various communities of the Garo Hills. METHODS: The ethnomedicinal data was collected through open and focussed group discussions, and personal interviews using semi-structured questionnaire. A total of 185 people were interviewed, including the three community people and their traditional health practitioners (THPs). The usage of the plants were further analysed and are presented as use value (UV), informant consensus factor (ICF) and fidelity level (FL). RESULTS: A total of 71 plants from 46 families and 64 genera were documented during our survey. Gastrointestinal disorders represented the major ailment category with the use of 36 plant species followed by dermatological problems (25 species). The ICF ranged from 0.90 to 0.99, with an average value of 0.96. Leaves (41) were the principle source of medication followed by fruits (27). Trees (33) were the major plant type used in the ethnobotanical practice. A total of 25 plants showed high FL (70.91 to 100 %) with 12 plants showing maximum FL (100 %). A number of the plants appear to have unique ethnomedicinal uses. CONCLUSION: Present investigation revealed a rich traditional practice in the studied region, which provides primary health care to the local community. This compilation of the ethnobotanical knowledge can help researchers to identify the uses of various medicinal plants that have a long history of use. PMID- 26025459 TI - A sensitive epitope-blocking ELISA for the detection of Chikungunya virus specific antibodies in patients. AB - Chikungunya fever (CHIKF) has re-emerged as an arboviral disease that mimics clinical symptoms of other diseases such as dengue, malaria, as well as other alphavirus-related illnesses leading to problems with definitive diagnosis of the infection. Herein we describe the development and evaluation of a sensitive epitope-blocking ELISA (EB-ELISA) capable of specifically detecting anti chikungunya virus (CHIKV) antibodies in clinical samples. The assay uses a monoclonal antibody (mAb) that binds an epitope on the E2 protein of CHIKV and does not exhibit cross-reactivity to other related alphaviruses. We also demonstrated the use of recombinant CHIK virus-like particles (VLPs) as a safe alternative antigen to infectious virions in the assay. Based on testing of 60 serum samples from patients in the acute or convalescent phase of CHIKV infection, the EB-ELISA provided us with 100% sensitivity, and exhibited 98.5% specificity when Ross River virus (RRV)- or Barmah Forest virus (BFV)-immune serum samples were included. This assay meets the public health demands of a rapid, robust, sensitive and specific, yet simple assay for specifically diagnosing CHIK-infections in humans. PMID- 26025458 TI - Detection of Zaire Ebola virus by real-time reverse transcription-polymerase chain reaction, Sierra Leone, 2014. AB - During the 2014 Ebola virus disease (EVD) outbreak, a real-time quantitative polymerase chain reaction was established to detect and identify the Zaire Ebola virus. We describe the use of this assay to screen 315 clinical samples from EVD suspected person in Sierra Leone. The detection rate in blood samples was 77.81% (207/266), and there were relatively higher detection rate (79.32% and 81.42%, respectively) during the first two weeks after onset of symptoms. In the two weeks that followed, the detection rate declined to 66.67% and 25.00%, respectively. There was the highest virus load at the first week and then decreased. The detection rate in swab samples was 89.79% (44/49). This may be benefit from the included patients. 46 of 49 swab samples were collected from died patients. Taken together, the results presented here indicate that the assay specifically and sensitively detects Zaire Ebola virus. PMID- 26025460 TI - Erythropoietin Reverses Sepsis-Induced Vasoplegia to Norepinephrine Through Preservation of alpha1D-Adrenoceptor mRNA Expression and Inhibition of GRK2 Mediated Desensitization in Mouse Aorta. AB - We investigated the effect of erythropoietin (EPO) posttreatment on survival time and vascular functions in a mouse model of sepsis. Sepsis was induced by cecal ligation and puncture. After 20 +/- 2 hours of sepsis, thoracic aorta was isolated for assessing its reactivity to norepinephrine (NE) and acetylcholine (ACh). We also measured the tissue nitric oxide (NO) level, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), G protein coupled receptor kinase 2 (GRK2), and alpha1D adrenoceptor messenger RNA (mRNA)/protein expression. In septic mice, EPO moderately improved the survival time from 19.68 +/- 0.75 to 34.7 +/- 3.2 hours. Sepsis significantly decreased the aortic contractile response to NE along with reduced alpha1D mRNA and protein expression. Erythropoietin significantly preserved the alpha1D receptor expression and restored NE-induced contractions to control levels in septic mice. Further, it attenuated the aortic alpha1D receptor desensitization in sepsis which was evident from reduced GRK2 mRNA expression. Accordingly, a selective GRK2 inhibitor markedly restored the contractile responses to NE in sepsis. Erythropoietin treatment attenuated iNOS mRNA expression and iNOS-induced overproduction of NO, but improved endothelium-dependent relaxation to ACh associated with increased eNOS mRNA expression. In conclusion, EPO seems to reverse sepsis-induced vasoplegia to NE through the preservation of alpha1D adrenoceptor mRNA/protein expression, inhibition of GRK2-mediated desensitization, and attenuation of NO overproduction in the mouse aorta. PMID- 26025461 TI - Comparison of kinematic variables obtained by inertial sensors among stroke survivors and healthy older adults in the Functional Reach Test: cross-sectional study. AB - BACKGROUND: Balance dysfunction is one of the most common problems in people who suffer stroke. To parameterize functional tests standardized by inertial sensors have been promoted in applied medicine. The aim of this study was to compare the kinematic variables of the Functional Reach Test (FRT) obtained by two inertial sensors placed on the trunk and lumbar region between stroke survivors (SS) and healthy older adults (HOA) and to analyze the reliability of the kinematic measurements obtained. METHODS: Cross-sectional study. Five SS and five HOA over 65. A descriptive analysis of the average range as well as all kinematic variables recorded was developed. The intrasubject and intersubject reliability of the measured variables was directly calculated. RESULTS: In the same intervals, the angular displacement was greater in the HOA group; however, they were completed at similar times for both groups, and HOA conducted the test at a higher speed and greater acceleration in each of the intervals. The SS values were higher than HOA values in the maximum and minimum acceleration in the trunk and in the lumbar region. CONCLUSIONS: The SS show less functional reach, a narrower, slower and less accelerated movement during the FRT execution, but with higher peaks of acceleration and speed when they are compared with HOA. PMID- 26025462 TI - Post-hoc validation of the Conley Scale in predicting the risk of falling with older in-hospital medical patients: findings from a multicentre longitudinal study. AB - BACKGROUND: The Conley Scale is one of the most widespread fall-risk screening tools in medical unit settings, despite the lack of data regarding its validity in patients currently admitted to these units. AIMS: Establishing the validity of the Conley Scale in identifying patients at risk of falling in an acute medical setting. METHODS: A 6-months longitudinal study in 12 acute medical units from September 2012 to March 2013, a total of 1464 patients with >=65 years of age were consecutively enrolled and evaluated with the Conley Scale within 24 h of admission. A construct validity, internal consistency, and a priori and a posteriori predictive validity study was performed. RESULTS: The explorative factor analysis showed a two-factor structure explaining a total variance of 48.3 %: previous history (30.41 %), and physical and cognitive impairment (17.9 %). The scale reported a poor internal consistency (Cronbach's alpha = 0.465) and the capability to correctly identify 18/649 patients as being at risk of falling, whereas the negative predictive value was 98.5 %. The sensitivity and specificity values were 60.0 and 55.9 %, respectively. No difference emerged between patients scored as at risk and those scored as not at risk in the time elapsed from admission to the first fall (HR = 0.600, 95 % CI 0.289-2.247 p = .166). DISCUSSION: The Conley Scale is not able to predict falls in elderly acute medical patients, and has reported poor internal consistency and accuracy. CONCLUSIONS: More studies are needed to develop appropriate tools to predict the risk of falling in elderly individuals admitted to an acute medical setting. PMID- 26025463 TI - Omega-3 fatty acids and risk of cognitive decline in the elderly: a meta-analysis of randomized controlled trials. AB - Evidence has demonstrated that omega-3 fatty acids intake may be associated with age-related cognitive decline. However, randomized controlled trials (RCTs) have drawn inconsistent conclusions. We performed a meta-analysis to assess the association between omega-3 fatty acids and risk of cognitive decline in the elderly. A strategic literature search of PubMed, EMBASE, and Cochrane Library (updated to December 2014) was performed. We retrieved six randomized controlled studies as eligible for our meta-analysis. Among these six studies, the duration time ranged from 3 to 40 months. The dose of omega-3 fatty acids (DHA + EPA) ranged from 400 to 1800 mg. The result of our meta-analysis expressed that omega 3 fatty acids statistically decrease the rate of cognitive decline in MMSE score (WMD = 0.15, [0.05, 0.25]; p = 0.003). In conclusion, our meta-analysis indicated that omega-3 fatty acids may help to prevent cognitive decline in the elderly. PMID- 26025464 TI - Prevalence and treatment of pain in non-institutionalized very old population: transversal study at national level. AB - BACKGROUND: In Europe, there is no conclusive data at national level about pain prevalence in non-institutionalized very old population. In USA, it has recently been reported a high prevalence (56 %); however, this data can not be extrapolated to other regions because the known influence of geographical and ethnic differences. Furthermore there are few data on use of treatments for pain in this population. AIMS: To explore prevalence and considered pharmacological treatments for pain in this population. METHODS: Transversal study on 551 participants aged 80 or more living in Spain (non-institutionalized). Probabilistic multistage sampling was carried out, stratified by sex and place of residence. All Spanish regions were considered for recruitment process. Pain (last 4 weeks), intensity (Face Pain Scale), localization and pharmacological treatments were evaluated by in-person interviews. RESULTS: Pain's prevalence was 52.5 % (CI 95 % 48.28-56.80) and 38.5 % experienced pain of at least moderate intensity. The most frequently involved body regions were lower limbs (26.6 %) and dorso-lumbar region (21.9 %). Only 40 % of participants with pain and 43.2 % with moderate or severe pain used analgesics, and paracetamol was less frequently used than non-steroidal anti-inflammatory drugs at any pain intensity. Age was not associated with higher prevalence [odds ratios 0.97 (CI 95 % 0.93-1.02) in females and 0.99 (CI 95 % 0.92-1.06) in males]. CONCLUSIONS: The prevalence of pain in non-institutionalized very old people is high. Pain is probably being undertreated, even moderate or severe pain. Guideline's recommendations are probably not being considered to select the analgesic therapy. PMID- 26025465 TI - Low 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 levels are independently associated with macroalbuminuria, but not with retinopathy and macrovascular disease in type 1 diabetes: the EURODIAB prospective complications study. AB - BACKGROUND: Low circulating levels of total vitamin D [25(OH)D] and 25(OH)D3 have been associated with vascular complications in few studies on individuals with type 1 diabetes. However, these measures are affected by UV light exposure. Circulating 25(OH)D2, however, solely represents dietary intake of vitamin D2, but its association with complications of diabetes is currently unknown. We investigated the associations between 25(OH)D2 and 25(OH)D3 and the prevalence of albuminuria, retinopathy and cardiovascular disease (CVD) in individuals with type 1 diabetes. METHODS: We measured circulating 25(OH)D2 and 25(OH)D3 in 532 individuals (40 +/- 10 years old, 51 % men) with type 1 diabetes who participated in the EURODIAB Prospective Complications Study. Cross-sectional associations of 25(OH)D2 and 25(OH)D3 with albuminuria, retinopathy and CVD were assessed with multiple logistic regression analyses adjusted for age, sex, season, BMI, smoking, HbA1c, total-HDL-cholesterol-ratio, systolic blood pressure, antihypertensive medication, eGFR, physical activity, alcohol intake, albuminuria, retinopathy and CVD, as appropriate. RESULTS: Fully adjusted models revealed that 1 nmol/L higher 25(OH)D2 and 10 nmol/L higher 25(OH)D3 were associated with lower prevalence of macroalbuminuria with ORs (95 % CI) of 0.56 (0.43;0.74) and 0.82 (0.72;0.94), respectively. These vitamin D species were not independently associated with microalbuminuria, non-proliferative and proliferative retinopathy or CVD. CONCLUSIONS: In individuals with type 1 diabetes, both higher 25(OH)D2 and 25(OH)D3 are associated with a lower prevalence of macroalbuminuria, but not of retinopathy and CVD. Prospective studies are needed to further examine the associations between 25(OH)D2 and 25(OH)D3 and the development of microvascular complications and CVD in type 1 diabetes. PMID- 26025466 TI - Rescue of a duck circovirus from an infectious DNA clone in ducklings. AB - BACKGROUND: Duck circovirus may predispose the host to immunosuppression and may serve as an immunological trigger for further complicated disease progression. Due to the lack of a cell culture system for propagating DuCV, little is known regarding the molecular biology and pathogenesis of DuCV. The aim of this study was to describe the construction and initial in vivo characterization of full length DNA clones of DuCV (pIC-Mu2DuCV) and its infectivity under in vivo conditions. METHOD: The constructed pIC-Mu2DuCV contained two copies of the whole DuCV genome and an introduced Xho I restriction enzyme site. Eighty-one 10-day old conventional ducklings that were free of DuCV were randomly divided equally into three groups (1, 2 and 3). The ducklings in groups 1, 2 and 3 were inoculated intramuscularly with pIC-Mu2DuCV, wild-type virus GH01 and PBS, respectively. Subsequently, all of the ducklings were examined clinically, which were each given a physical condition score, and their rectal temperatures were taken daily during the experimental period. DuCV genomes in serum samples and in various tissues from all of the ducklings at 0, 1, 3, 5, 7, 10, 15, 21 and 28 DPC were detected by PCR and real-time quantitative PCR, respectively. RESULTS: The average daily weight gain (ADWG) of group 3 was significantly higher than those of groups 1 and 2, and the temperature of all ducklings was stable between 41.7 degrees C and 42.2 degrees C. The clinical values (physical condition scores) of groups 1, 2 and 3 were 12.5, 15.6 and 0, respectively. In addition, viremia occurred at 15 and 10 days post-challenge (DPC) in groups 1 and 2, and antibodies could be detected in these ducklings at 21 and 15 DPC. Proliferation ability analysis showed that the viral titers of group 1 were lower than those of their parental viruses in group 2. CONCLUSION: This study shows that the rescued viruses are not significantly different but exhibit lower pathogenicity and proliferation ability compared with the parental virus. The results will facilitate future studies on DuCV pathogenesis and biology. PMID- 26025467 TI - Cholecystectomy vs. percutaneous cholecystostomy for the management of critically ill patients with acute cholecystitis: a protocol for a systematic review. AB - BACKGROUND: Acute cholecystitis is a common diagnosis. However, the heterogeneity of presentation makes it difficult to standardize management. Although surgery is the mainstay of treatment, critically ill patients have been managed via percutaneous cholecystostomy. However, the role of percutaneous cholecystostomy in the management of such patients has not been clearly established. This systematic review will compare the outcomes of critically ill patients with acute cholecystitis managed with percutaneous cholecystostomy to those of similar patients managed with cholecystectomy. METHODS/DESIGN: Systematic searches will be conducted across relevant health databases including the Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, Embase, and Scopus using the following keywords: (acute cholecystitis OR severe cholecystitis OR cholecystitis) AND (cholecystectomy OR laparoscopic cholecystectomy OR open cholecystectomy) AND (Cholecystostomy OR percutaneous cholecystectomy OR gallbladder drain OR gallbladder tube OR transhepatic gallbladder drain OR transhepatic gallbladder tube OR cholecystostomy tube). The reference lists of eligible articles will be hand searched. Articles from 2000 2014 will be identified using the key terms "acute cholecystitis, cholecystectomy, and percutaneous cholecystostomy". Studies including both interventions will be included. Relevant data will be extracted from eligible studies using a specially designed data extraction sheet. The Newcastle-Ottawa scale will be used to assess the quality of non-randomized studies. Central tendencies will be reported in terms of means and standard deviations where necessary, and risk ratios will be calculated where possible. All calculations will be performed with a 95 % confidence interval. Furthermore, the Fisher's exact test will be used for the calculation of significance, which will be set at p < 0.05. Pooled estimates will be presented after consideration of both clinical and methodological heterogeneity of included studies. Both interventions would be compared with regard to in-hospital mortality, 30-day mortality, procedure dependent complications, re-intervention, length of intensive care unit (ICU) stay, length of hospital stay, re-admission, and cost of treatment. The review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. DISCUSSION: This systematic review aims at identifying and evaluating the clinical value of percutaneous cholecystostomy in the management of critically ill patients with acute cholecystitis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015016205. PMID- 26025468 TI - Channel retention for fixed implant superstructures: A clinical report. AB - This clinical report describes the treatment of a patient with anatomic and biomechanical problems that made retrievability of an implant-supported prosthesis a design priority. During treatment, the patient was found to be intolerant of local anesthesia, prompting an alternative retrievable design from the screw-retained interim restoration. A channel retention technique for fixed implant superstructures is presented. PMID- 26025469 TI - Chest Pain and a Wide QRS Tachycardia. PMID- 26025470 TI - Reception of Aversive Taste. AB - Many organisms encounter noxious or unpalatable compounds in their diets. Thus, a robust reception-system for aversive taste is necessary for an individual's survival; however, mechanisms for perceiving aversive taste vary among organisms. Possession of a system sensitive to aversive taste allows for recognition of a vast array of noxious molecules via membrane-bound receptors, co-receptors, and ion channels. These receptor-ligand interactions trigger signal transduction pathways resulting in activation of nerves and in neural processing, which in turn dictates behavior, including rejection of the noxious item. The impacts of these molecular processes on behavior differ among species, and these differences have impacts at the ecosystem level by driving feeding-behavior, organization of communities, and ultimately, speciation. For example, when comparing mammalian carnivores and herbivores, it is not surprising that herbivores that encounter a variety of toxic plants in their diets express a larger number of aversive taste receptors than carnivores. Comparing the molecular mechanisms and ecological consequences of aversive-taste reception among organisms in a variety of types of ecosystems and ecological niches will illuminate the role of taste in ecology and evolution. PMID- 26025471 TI - The effect of thyroid autoimmunity on T-cell responses in early pregnancy. AB - Thyroid autoimmunity (TAI) is common in women of reproductive age. There is a relationship between TAI and recurrent pregnancy loss and infertility. In pregnant patients with thyroid autoimmunity, the T helper-1 (Th1)/T helper-2 (Th2) ratio may shift to a Th1-type response and these activated T lymphocytes may lead to implantation failure. The aims of this study were to investigate the serum levels of Th1-, Th2-, and T-helper-17-(Th17)-associated cytokines in pregnant patients with TAI, and to evaluate how these cytokines change with l thyroxin treatment during pregnancy. Twenty pregnant women with TAI diagnosed in the first trimester of pregnancy who were not on l-thyroxine treatment, 14 pregnant women with known TAI before pregnancy already been on l-thyroxine treatment, and 19 pregnant patients without TAI were included in this study. Thyroid function tests, thyroid autoantibodies, and cytokine levels were measured at the first and the second trimesters. In pregnant patients who were diagnosed with TAI in the first trimester, both serum IL-2 levels and IL-17 levels were significantly higher than those of the control group. There were no significant differences between groups for serum IL-4, IL-6, IL-23, IL-10, and IFNgamma levels. In the second trimester, no significant differences were found between groups for all the cytokines measured. There are significant differences in Th1- and Th17-associated cytokine levels between patients with TAI and the control group in the first trimester. In the second trimester cytokine levels were similar among all groups. This pattern may be associated with the clinical benefits of l-thyroxine treatment. PMID- 26025472 TI - NK Cells and Cancer Immunoediting. AB - Natural killer (NK) cells are innate lymphoid cells (ILC) known for their ability to recognize and rapidly eliminate infected or transformed cells. Consequently, NK cells are fundamental for host protection against virus infections and malignancies. Even though the critical role of NK cells in cancer immunosurveillance was suspected years ago, the underlying mechanisms took time to be unraveled. Today, it is clear that anti-tumor functions of NK cells are tightly regulated and expand far beyond the simple killing of malignant cells. In spite of tremendous steps made in understanding the NK cell biology, further work is warranted to fully exploit the anticancer potential of these cells. Indeed, tumor-mediated immune suppression hampers NK cell activity, thus complicating their stimulation for therapeutic purposes. Herein, we review the current knowledge of NK cell functions in anti-tumor immunity . We discuss NK cell activity in the cancer immunoediting process with particular emphasis on the elimination and escape phases. PMID- 26025473 TI - Dietary exposure to endocrine disrupting chemicals in metropolitan population from China: a risk assessment based on probabilistic approach. AB - The intake of contaminated foods is an important exposure pathway for endocrine disrupting chemicals (EDCs). However, data on the occurrence of EDCs in foodstuffs are sporadic and the resultant risk of co-exposure is rarely concerned. In this study, 450 food samples representing 7 food categories (mainly raw and fresh food), collected from three geographic cities in China, were analyzed for eight EDCs using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Besides estrone (E1), other EDCs including diethylstilbestrol (DES), nonylphenol (NP), bisphenol A (BPA), octylphenol (OP), 17beta-estradiol (E2), 17alpha-ethinylestradiol (EE2), and estriol (E3) were ubiquitous in food. Dose-dependent relationships were found between NP and EE2 (r=0.196, p<0.05), BPA (r=0.391, p<0.05). Moreover, there existed a correspondencebetween EDCs congener and food category. Based on the obtained database of EDCs concentration combined with local food consumption, dietary EDCs exposure was estimated using the Monte Carlo Risk Assessment (MCRA) system. The 50th and 95th percentile exposure of any EDCs isomer were far below the tolerable daily intake (TDI) value identically. However, the sum of 17beta-estradiol equivalents (?EEQs) exposure in population was considerably larger than the value of exposure to E2, which implied the underlying resultant risk of multiple EDCs in food should be concern. In conclusion, co-exposure via food consumption should be considered rather than individual EDCs during health risk evaluation. PMID- 26025474 TI - Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice. AB - Chronic and excessive alcohol consumption can lead to alcoholic liver disease (ALD), which is characterized by a spectrum of liver disorders, including fatty liver, alcoholic steatohepatitis (ASH), fibrosis/cirrhosis and hepatocellular carcinoma (HCC). The mechanism of the progression from alcoholic steatosis to steatohepatitis and fibrosis is still not fully understood. As a nuclear receptor, farnesoid X receptor (FXR) plays a critical role in maintaining hepatic lipid and bile acid homeostasis. To clarify the role of FXR in the progression of steatohepatitis, we studied the effect of ethanol feeding on FXR-deficient mice. Wild-type and FXR-deficient mice were fed with Lieber-DeCarli ethanol liquid diet or an isocaloric control diet. We found that FXR-deficient mice fed with ethanol diet developed more severe liver injury and steatosis, even progressed to steatohepatitis and moderate fibrosis. Whereas, wild-type (WT) mice only developed mild level of steatosis, with rarely observed inflammatory foci and collagen accumulation. We also found that ethanol induced hepatic bile acid accumulation and NF-kappaB activation in FXR-deficient mice, which could be attenuated by ursodeoxycholic acid (UDCA). Thus, FXR deficient mice were more prone to develop alcoholic steatohepatitis and fibrosis upon ethanol diet feeding. Our results highlight the role of FXR in hepatoprotection during ALD development. Moreover, attenuating alcoholic liver cholestasis would be beneficial in preventing the progression of hepatic hepatitis in patients with ALD. PMID- 26025475 TI - New insights on the organization and regulation of the fatty acid biosynthetic network in the model higher plant Arabidopsis thaliana. AB - In the plastids of plant cells, fatty acid (FA) production is a central biosynthetic process. It provides acyl chains for the formation of a variety of acyl lipids fulfilling different biological functions ranging from membrane synthesis to signaling or carbon and energy storage. The biochemical pathway leading to the synthesis of FA has been described for a long time. Over the last 15 years, and after the genome of the model higher plant Arabidopsis thaliana has been sequenced, the scientific community has deployed approaches of functional genomics to identify the actors comprising this pathway. One of the puzzling aspects of the emerging molecular biology of FA synthesis resided in the occurrence of multigene families encoding most enzymes of the pathway. Studies carried out to investigate these families led to the conclusion that most members have acquired non-redundant roles in planta. This is usually the consequence of divergent expression patterns of these isogenes and/or of different substrate specificities of the isoforms they encode. Nevertheless, much remains to be elucidated regarding the molecular bases underpinning these specificities. Protein biochemistry together with emerging quantitative proteomic technologies have then led to a better understanding of the structure of the network, which is composed of multiprotein complexes organized within the stromal compartment of plastids: whereas growing evidence suggests that the early steps of the pathway might be associated to the inner envelope membrane, several late enzymes might be localized next to the thylakoids. The question of the existence of a large integrated protein assembly channeling substrates through the whole pathway that would span the stroma remains uncertain. Finally, recent discoveries regarding the post-translational regulation of the pathway open new research horizons and may guide the development of relevant biotechnological strategies aimed at monitoring FA production in plant systems. PMID- 26025477 TI - Indocyanine green lymphography and lymphaticovenous anastomosis for generalized lymphatic dysplasia with pleural effusion and ascites in neonates. AB - BACKGROUND: The fatality rate of generalized lymphatic dysplasia (GLD) with chylous pleural effusion and ascites is particularly high when it persists over a prolonged period. The purpose of this report was to determine the utility of indocyanine green (ICG) lymphography and lymphaticovenous anastomosis (LVA) in GLD with chylous pleural effusion and ascites in neonates. METHODS: We tested the lymphatic function in the 4 extremities for 8 GLD neonate patients using ICG lymphography, and on the basis of the results, we performed LVA for 5 of them. LVA was performed at the extremities under general anesthesia using incisions <1 cm in length. The outcome of LVA was evaluated with the amount of ascites discharged from thoracostomy tube or abdominal tube, except for 1 patient who had no drainage tube. RESULTS: In all cases, ICG lymphography showed varying degrees of dermal backflow in the limbs with lymphostasis. After LVA surgery, effusion stopped in 2 cases and decreased in 1 case. In the cases where effusion stopped, backflow as observed with ICG lymphography was minimal, and in the case where effusion decreased but did not stop, backflow was moderate. CONCLUSIONS: The application of ICG and LVA could possibly be used to diagnose and treat lymphatic pleural effusion or ascites. PMID- 26025476 TI - Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease. AB - Environmental variations have strong influences in the etiology of type 2 diabetes mellitus. In this study, we investigated the genetic basis of diabetes in patients with sickle cell disease (SCD), a Mendelian disorder accompanied by distinct physiological conditions of hypoxia and hyperactive erythropoiesis. Compared to the general African American population, the prevalence of diabetes as assessed in two SCD cohorts of 856 adults was low, but it markedly increased with older age and overweight. Meta-analyses of over 5 million single-nucleotide polymorphisms (SNPs) in the two SCD cohorts identified a SNP, rs59014890, the C allele of which associated with diabetes risk at P = 3.2 * 10(-8) and, surprisingly, associated with decreased APOB expression in peripheral blood mononuclear cells (PBMCs). The risk allele of the APOB polymorphism was associated with overweight in 181 SCD adolescents, with diabetes risk in 592 overweight, non-SCD African Americans >= 45 years of age, and with elevated plasma lipid concentrations in general populations. In addition, lower expression level of APOB in PBMCs was associated with higher values for percent hemoglobin A1C and serum total cholesterol and triglyceride concentrations in patients with Chuvash polycythemia, a congenital disease with elevated hypoxic responses and increased erythropoiesis at normoxia. Our study reveals a novel, environment specific genetic polymorphism that may affect key metabolic pathways contributing to diabetes in SCD. PMID- 26025478 TI - A comparison of femorocrural bypasses performed with modified heparin-bonded expanded polytetrafluorethylene grafts and those with great saphenous vein grafts to treat critical limb ischemia. AB - BACKGROUND: The purpose of this study was to evaluate our results involving femorocrural bypasses by comparing heparin-bonded expanded polytetrafluoroethylene (HePTFE) graft (Propaten) modified with handmade distal compliant HePTFE cuffs (mHePTFE graft) to great saphenous vein (GSV) graft. METHODS: A retrospective study involving 74 femorocrural bypasses performed from January 2010 to May 2013 at a single institution was carried out. The indication for revascularization was critical limb ischemia (Rutherford stages 4-6. Forty one femorocrural bypasses were created in 37 patients with unavailable GSVs using modified ringed HePTFE grafts with a handmade distal radial stretch HePTFE cuff to reduce the mismatch compliance between the graft and the artery wall. Thirty three femorocrural bypasses were created using a reversed GSV graft. The results were analyzed in terms of primary graft patency, limb salvage, and patient survival using univariate (Kaplan-Meier curves and log-rank test) and multivariate (Cox regression) analyses. RESULTS: The 2 groups were statistically comparable for main risk factors, Rutherford stage, and target artery for distal anastomoses. The run-off anatomy did not significantly differ between the prosthetic and the vein bypass group. The cumulative 30-day operative mortality rate was 2.9%. At 1, 2, and 3 years, the 2 groups were equivalent in primary graft patency (the mHePTFE group: 84%, 80%, and 70%, respectively; the GSV group: 84%,71%, and 71%, respectively; P = 0.93) and were also equivalent in terms of limb salvage (the mHePTFE group: 87%, 87%, and 76%, respectively; the GSV group: 84%, 75%, and 75%, respectively; P = 0.78) and patient survival (the mHePTFE group: 87%, 75%, and 75%, respectively; the GSV group: 87%, 73%, and 65%, respectively; P = 0.86). At Cox regression analysis, only postoperative treatment with warfarin therapy compared with double antiplatelet therapy was independently associated with poorer primary patency (P = 0.003; 95% confidence interval, 1.80 18.00; hazard ratio, 5.7). CONCLUSIONS: In this retrospective study regarding femorocrural bypasses, the mHePTFE grafts had 1-, 2-, and 3-year primary patency and limb salvage results which were not significantly different from those in the GSV grafts. Additional randomized data and larger studies are needed to confirm these results. PMID- 26025479 TI - Incidental diagnosis of tumor thrombosis on FDG PET/CT imaging. AB - OBJECTIVE: Clinical data are presented on patients with tumor thrombosis (TT) incidentally detected on FDG PET/CT imaging, as well as determining its prevalence and metabolic characteristics. MATERIALS AND METHODS: Out of 12,500 consecutive PET/CT examinations of patients with malignancy, the PET/CT images of 15 patients with TT as an incidental finding were retrospectively investigated. A visual and semiquantitative analyses was performed on the PET/CT scans. An evaluation was made of the pattern of FDG uptake in the involved vessel as linear or focal via visual analyses. For the semiquantitative analyses, the metabolic activity was measured using SUVmax by drawing the region of interest at the site of the thrombosis and tumor (if any). RESULTS: The prevalence of occult TT was 0.12%. A total of 15 patients had various malignancies including renal (1 patient), liver (4), pancreas (2), stomach (1), colon (1), non-Hodgkin lymphoma (1), leiomyosarcoma (1), endometrial (1), ovarian (1), malign melanoma (1) and parotid (1). Nineteen vessels with TT were identified in 15 patients; three patients had more than one vessel. Various vessels were affected; the most common was the inferior vena cava (n=7) followed by the portal (n=5), renal (n=3), splenic (n=1), jugular (n=1), common iliac (n=1) and ovarian vein (n=1). The FDG uptake pattern was linear in 12 and focal in 3 patients. The mean SUVmax values in the TT and primary tumors were 8.40+/-4.56 and 13.77+/-6.80, respectively. CONCLUSION: Occult TT from various malignancies and locations was found incidentally in 0.12% of patients. Interesting cases with malign melanoma and parotid carcinoma and with TT in ovarian vein were first described by FDG PET/CT. Based on the linear FDG uptake pattern and high SUVmax value, PET/CT may accurately detect occult TT, help with the assessment of treatment response, contribute to correct tumor staging, and provide additional information on the survival rates of oncology patients. PMID- 26025480 TI - Influenza infection in the intensive care unit: Four years after the 2009 pandemic. AB - The role of influenza viruses in severe acute respiratory infection (SARI) in Intensive Care Units (ICU) remains unknown. The post-pandemic influenza A(H1N1)pdm09 period, in particular, has been poorly studied. OBJECTIVE: To identify influenza SARI patients in ICU, to assess the usefulness of the symptoms of influenza-like illness (ILI), and to compare the features of pandemic vs. post pandemic influenza A(H1N1) pdm09 infection. METHODS: A prospective observational study with SARI patients admitted to ICU during the first three post-pandemic seasons. Patient demographics, characteristics and outcomes were recorded. An influenza epidemic period (IEP) was defined as >100 cases/100,000 inhabitants per week. RESULTS: One hundred sixty-three patients were diagnosed with SARI. ILI was present in 65 (39.9%) patients. Influenza infection was documented in 41 patients, 27 (41.5%) ILI patients, and 14 (14.3%) non-ILI patients, 27 of them during an IEP. Influenza A viruses were mainly responsible. Only five patients had influenza B virus infection, which were non-ILI during an IEP. SARI overall mortality was 22.1%, and 15% in influenza infection patients. Pandemic and post pandemic influenza infection patients shared similar clinical features. CONCLUSIONS: During influenza epidemic periods, influenza infection screening should be considered in all SARI patients. Influenza SARI was mainly caused by subtype A(H1N1)pdm09 and A(H3N2) in post-pandemic seasons, and no differences were observed in ILI and mortality rate compared with a pandemic season. PMID- 26025481 TI - The paradox of control: An ethnographic analysis of opiate maintenance treatment in a Norwegian prison. AB - BACKGROUND: Opiate maintenance treatment (OMT) is increasingly being offered in prisons throughout Europe. The benefits of OMT in prison have been found to be similar to those produced by OMT in community settings. However, prison-based OMT has been a controversial issue because of fear of the diversion of OMT medications and the development of black markets for prescription drugs such as buprenorphine and methadone. Prison-based OMT thus involves a delicate balance between the considerations of control and treatment. METHODS: This article reports on an ethnographic study of a prison-based OMT programme in a closed Norwegian prison. The data include field notes from eight months of participant observation in the prison as well as qualitative interviews with 23 prisoners and 12 prison staff. Midway through the fieldwork, the prison authorities established a separate unit for OMT-enrolled prisoners to reduce the widespread diversion of buprenorphine. This "natural experiment" is explored in the analysis. RESULTS: The prison-based OMT programme was characterised by strict and repressive control to prevent the diversion of buprenorphine, and the control became even stricter after the establishment of the OMT unit. However, the diversion of buprenorphine increased rather than decreased after the establishment of the OMT unit. To understand this "paradox of control", the article engages with theories of legitimacy, power and resistance. The excessive and repressive control was perceived as illegitimate and unfair by the majority of study participants. In various ways, many prisoners protested, confronted and subverted the OMT programme. The increase in buprenorphine diversion is interpreted as a form of collective resistance towards the perceived unfairness of the OMT programme. CONCLUSION: The article demonstrates that an unbalanced and control-dominated approach to prison-based OMT may have the opposite effect of what is intended. PMID- 26025482 TI - Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation. AB - Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 MUMol*minute per day in a first cohort (n = 12) and 5000 MUMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 +/- 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 +/- 1239 in the AUC 4000 cohort and 4884 +/- 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 MUMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 MUMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants. PMID- 26025483 TI - Assessment of HEMA and TEGDMA induced DNA damage by multiple genotoxicological endpoints in human lymphocytes. AB - OBJECTIVES: Residual unbound resin monomers of 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) are known to diffuse in the saliva and through dentin and pulp into the blood and may affect cellular integrity. The current study was performed to investigate the genotoxic potential of both monomers in distinctly lower concentrations than known to cause cytotoxic damage. METHODS: Lymphocytes from 10 healthy volunteers were treated with HEMA (10MUM 1mM) and TEGDMA (1MUM-100MUM) for 24h. Cell viability, apoptosis and influence on cell cycle kinetics were assessed by flowcytometry. DNA damage was determined by the alkali version of the comet assay in combination with the FPG protein and by the cytokinesis-block micronucleus (CBMN) test. Additionally, the chromosome aberration (CA) test and sister chromatid exchange (SCE) test were performed. RESULTS: A slight decrease in cell viability was detected only at the highest concentration of TEGDMA. Genotoxic effects were measurable in the comet assay at 1mM of HEMA and 100MUM of TEGDMA, with and without FPG protein, but not in the CBMN test or the cell cycle analysis. Contrary to these findings, a significant dose-dependent increase in the frequency of CAs and SCEs could be demonstrated in all tested concentrations. SIGNIFICANCE: This is the first time clastogenic responses to HEMA and TEGDMA have been detected in concentrations distinctly lower than those reported for causing cytotoxic or even genotoxic effects. These findings underline the importance of using test batteries with different genotoxicological endpoints to describe the multiple effects of both resin monomers. PMID- 26025484 TI - CEBPA methylation and mutation in myelodysplastic syndrome. AB - Aberrant methylation of CCAAT/enhancer-binding protein alpha (CEBPA) promoter has been observed in acute myeloid leukemia. However, little is known about CEBPA promoter in myelodysplastic syndrome (MDS). The purpose of this study was to investigate the alteration of CEBPA promoter in MDS patients and further determine the association with CEBPA expression and mutation. CEBPA promoter was significantly methylated in 105 MDS patients compared to 22 controls (median 0.016 vs. 0.000) (P < 0.0001). Receiver operating characteristic curve analysis discriminated all patients or cytogenetically normal patients from normal controls. Three cases (3 %) were identified with single-mutated CEBPA and one (1 %) with double-mutated CEBPA. CEBPA methylation and mutation occurred mutually exclusive. No significant correlation was found between CEBPA expression and methylation (P = 0.586). Our findings indicate that CEBPA methylation is a common event in MDS, but could not act as a prognostic biomarker for MDS patients. PMID- 26025485 TI - Phase I study of postoperative radiotherapy concurrent with S-1 in patients with gastric cancer. AB - Postoperative chemoradiotherapy (CRT) with concurrent 5-fluorouracil is the standard care for gastric cancer patients after curative surgery. The previous studies revealed that the subgroup of patients with high recurrence risk would benefit most from adjuvant CRT. S-1, a novel oral fluorouracil, has showed very effective in metastatic gastric cancer and became the standard option for gastric cancer with D2 dissection. The safety and dosage of S-1 combined with postoperative radiotherapy have not yet been evaluated. This study is to determine the maximum tolerate dose (MTD) and dose-limiting toxicity (DLT) of S-1 given concurrently with postoperative high-dose radiotherapy in gastric cancer. Patients with more advanced stage (pT4 and/or pN+) after R0 resection were recruited. Eligible patients received one cycle standard SOX (S-1 plus oxaliplatin) chemotherapy, then S-1 monotherapy with concurrent radiotherapy for 6 weeks, followed by additional three cycles of SOX. During the concurrent CRT, S 1 was administered on every radiotherapy treatment day according to a predefined dose-escalation schedule. Radiotherapy (3D-RT or IMRT) was given to a total dose of 50.4 Gy in 28 fractions. DLT was defined as grade 3 or 4 hematologic and non hematologic toxicity. From March 2011 to October 2012, 21 patients were enrolled at five dose levels: 40 (n = 3), 50 (n = 3), 60 (n = 6), 70 (n = 6) and 80 mg/m(2)/day (n = 3). D2-dissection was performed in 18 patients (85.7 %) and 15 patients (71.4 %) had stage III disease. The most common dose-related toxicity was anorexia, nausea and vomiting, fatigue and leucopenia. DLT was occurred in one patient at 60 mg/m(2)/day (grade 3 fatigue), one patient at 70 mg/m(2)/day (grade 3 vomiting and anorexia), two patients at 80 mg/m(2)/day (one with grade 3 vomiting and anorexia; another with grade 3 febrile leucopenia). Four patients did not complete CRT as planned. Overall, this phase I study demonstrated that postoperative CRT with daily S-1 was feasible in gastric cancer and the MTD of S 1 concurrent with radiotherapy was 70 mg/m(2)/day. This S-1-based postoperative CRT will be investigated in a multicenter phase III study in West China. PMID- 26025486 TI - Crizotinib-loaded polymeric nanoparticles in lung cancer chemotherapy. AB - The study describes the development of polylactide-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS)-based nanosystem as a carrier of crizotinib (CZT) to achieve superior anticancer efficacy in lung cancer therapy. We have demonstrated that block copolymer and hydrophobic drug is capable of self-assembling into a very stable nanocarrier, with suitable properties that allow their application for cancer drug delivery. Drug release study showed a sustained release pattern as a result of entrapment in the hydrophobic core of micelles. CZT/PT NP showed a noticeable cytotoxic effect in NCIH3122 lung cancer cells in a dose-dependent manner. Furthermore, morphological imaging and Live/Dead assay revealed a superior anticancer efficacy for nanoformulations. The polymeric nanoparticle showed a predominant presence in the cytoplasmic region of cell, indicating a typical endocytosis-mediated cellular uptake. The annexin V/PI staining-based apoptosis assay showed a remarkable ~40 % apoptosis (early and late apoptosis cells) comparing to only ~25 % apoptosis by free CZT. Taken together, Vitamin E TPGS-modified PLA nanoparticles would be a potential drug delivery system to increase the chemotherapeutic efficacy of CZT in lung cancer chemotherapy. PMID- 26025487 TI - Endometriosis and Ascites: A Strategy to Achieve Pregnancy. AB - Deep endometriosis presenting with ascites and preserved fertility is an unusual combination. This report describes a unique case of deep endometriosis and primary infertility, with a successful pregnancy after an optimal surgical approach and personalized ovarian stimulation protocol for in vitro fertilization, which shows the importance of a multidisciplinary approach in these patients. PMID- 26025488 TI - Spontaneous Ruptured Uterus in an Adolescent With Polycystic Ovarian Syndrome and Endometrial Hyperplasia. AB - Uterine diverticula and rudimentary horns are rare forms of uterine anomalies that occur during embryogenesis. They can communicate with the endometrial cavity and may have the potential to develop pathology. This case report presents an obese, anovulatory adolescent with polycystic ovarian syndrome who was admitted with acute abdominal pain and found to have radiological findings that were concerning for a ruptured mass contiguous with the uterine cavity, which was likely a uterine horn or diverticulum. Further evaluation revealed simple hyperplasia without atypia on endometrial sampling, supporting the surgical resection and subsequent medical management of this young patient. PMID- 26025489 TI - Experience of People With Disabilities in Haiti Before and After the 2010 Earthquake: WHODAS 2.0 Documentation. AB - OBJECTIVE: To describe the functioning and participation of people with disabilities seen in Haiti Team Canada Healing Hands clinics before and after the 2010 earthquake. DESIGN: Cross-sectional survey. SETTING: Rehabilitation clinics. PARTICIPANTS: A convenience sample of individuals attending Team Canada Healing Hands clinics (N=194): individuals who completed the survey before the 2010 earthquake (n=72) and individuals who completed the survey after the 2010 earthquake (n=122). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). RESULTS: Overall WHODAS 2.0 scores before and after the 2010 earthquake were in the top 10th percentile of population normative data, where higher scores reflect greater disability. A median increase (6.6 points) in disability was reported after the earthquake (Mann-Whitney U, P=.055). There was a significant increase (Mann-Whitney U, P<.001) in WHODAS 2.0 scores related to mobility (18.8 points), life activities (30 points), and participation (16.7 points) domains after the earthquake. CONCLUSIONS: Persons in Haiti with a disability attending Team Canada Healing Hands clinics reported a low level of functioning. The increase in WHODAS 2.0 scores related to mobility, life activities, and participation domains suggests that the 2010 earthquake had a negative impact on functioning of this population and provides additional information on the responsiveness of the WHODAS 2.0 in limited resource settings. Future work can include using WHODAS 2.0 to monitor the impact of rehabilitation service and advocacy initiatives in Haiti and similar locations. PMID- 26025490 TI - Identifying predation on rodent teeth through structure and composition: A case from Morocco. AB - Predation by nocturnal birds of prey is one of the most frequent modes leading to the concentration of rodents in fossil assemblages. This mode of accumulation leaves characteristic surface alterations on bones and teeth. In order to evaluate and characterize the effects of these pre-diagenesis alterations on rodent fossil samples, we have carried out microstructural and chemical analyses on incisors collected from present day Moroccan wild animals and owl pellets. The microstructure of both dentine and enamel was well preserved, but chemical changes were evident in pellet samples and depended on the particular tissue and the nature of the predator. The comparison of compositional data obtained from electron microprobe chemical analyses and infrared spectrometry has allowed us to assign a possible predator to an incisor extracted from a pellet of an unknown origin. This method has further implications for the understanding of taphonomy and palaeoecology of archaeological and fossil sites. PMID- 26025491 TI - Laparoscopy and transseptal orchiopexy in the management of transverse testicular ectopia. AB - Transverse testicular ectopia (TTE) is a rare congenital anomaly in which both testes descend through the same inguinal canal. The most frequent clinical presentation is undescended testis (UDT) with ipsilateral inguinal hernia and contralateral non-palpable testis. This condition is often diagnosed during surgery and is frequently associated with other anomalies. There is controversy in the surgical management of TTE. Considerations for TTE repair include avoiding damage to the testes or vas deferens and detection of other congenital anomalies. Frequently, the vas deferens and testicular tissues are joined, and dissection of these structures can cause damage. In this article, we report four patients with TTE, describe the surgical approach made in each case, and provide a review of the literature. PMID- 26025492 TI - Bone marrow mesenchymal stem cell therapy for voiding dysfunction. AB - Lower urinary tract symptoms can significantly impact quality of life. Current standard treatments are not always effective and are associated with complications and side effects. The discovery of stem cells led to research into cell-based therapies for treatment of disorders of voiding dysfunction. Bone marrow mesenchymal stem cells are particularly promising given their ability to differentiate into a variety of cell types. Recent studies have investigated bone marrow stem cells to treat a number of functional voiding pathologies including bladder outlet obstruction, neurogenic bladder, and stress urinary incontinence. Experiments in tissue regeneration have also attempted to create artificial bladders and urethras. The purpose of this article is to critically review the literature regarding the use of bone marrow mesenchymal stem cells in treatment of voiding dysfunction. PMID- 26025493 TI - Techniques for Minimizing Radiation Exposure During Evaluation, Surgical Treatment, and Follow-up of Urinary Lithiasis. AB - Patients receive significant radiation exposure during the diagnosis, treatment, and follow-up of urinary stone disease. This radiation exposure may result in patient harm and is believed to contribute to the risk for malignancy. This review will present current information to allow surgeons to optimize their diagnostic, treatment, and follow-up regimens to allow optimal care of stone disease patients at the lowest radiation dose possible. PMID- 26025494 TI - The nutrition consult for recurrent stone formers. AB - Diet is implicated in stone formation and growth. Whether alone or in concert with pharmacologics, dietary changes may be useful in reducing recurrence but only when they correct dietary stone-forming risks. Patients benefit from recommendations individualized to their food preferences as well as to lifestyle, age, food knowledge and access, preparation skills, and cultural and ethnic identities. Urologists can provide general dietary recommendations but often lack the time to provide the full complement of individualized nutrition care offered by a registered dietitian nutritionist (RDN). Urologists can partner with and refer patients to a RDN for any component of the nutrition care process: assessment of diet, diagnosis of dietary factors that contribute to stone risk factors, intervention formulation and implementation, and monitoring the effectiveness of the intervention and modifying it as needed to maintain suitably low dietary risk for stone recurrence. PMID- 26025495 TI - Management of neurogenic lower urinary tract dysfunction in multiple sclerosis patients. AB - Multiple sclerosis (MS) can be a debilitating neurological condition that attributes significant morbidity to bladder dysfunction. Although many effective treatment options exist, symptomatic patients are often underdiagnosed and undertreated. The purpose of this article is to give an overview of the current literature including new screening tools to identify symptomatic patients and updates on treatment options including medications, botulinum toxin, and neuromodulation. PMID- 26025496 TI - Do circulating tumor cells have a role in deciding on adjuvant chemotherapy after radical cystectomy? AB - Radical cystectomy (RC) with bilateral pelvic lymphadenectomy with or without perioperative chemotherapy is the golden standard treatment in muscle invasive and recurrent high-grade non-muscle invasive urothelial carcinoma of the bladder (UCB). Despite treatment with curative intent, up to 50% of patients develop metastasis and die from UCB due to micro-metastatic disease undetectable for current staging techniques prior to definitive therapy. Tumor cell dissemination is a crucial step in the natural history of the metastatic cascade. Circulating tumor cells (CTC) are malignant epithelial cells detectable in the peripheral blood of patients with various malignancies. In UCB, CTC are detectable in a significant number of patients prior to RC and associated with inferior outcomes. In this review, we summarize the current literature regarding CTC in UCB, discussing their potential on clinical decision-making regarding multimodal treatment and implications on the application of novel targeted therapies in the future. There is reliable evidence that presence of CTC in clinically non metastatic UCB patients treated with RC are a powerful predictor for unfavorable outcomes and may be useful for adjuvant chemotherapy decision-making and monitoring. However, currently, the evidence is limited, and thus, integration of CTC in future UCB clinical trials is strongly recommended to shed more light on the potential of this promising biomarker. PMID- 26025497 TI - Telemedicine in Surgery: What are the Opportunities and Hurdles to Realising the Potential? AB - Since the first telegraphic transmission of an electrocardiogram in 1906, technological developments have allowed telemedicine to flourish. It has become a multi-billion pound industry encompassing many areas of medical practice and education. Telemedicine is now widely used in surgery from performing operations to teaching and can be divided into three main components; telesurgery, telementoring and teleconsultation. Developments across these fields have led to remarkable achievements such as intercontinental telesurgery and telementoring. However, barriers to the further implementation of telemedicine remain. In this review, the developments and recent advances of telemedicine across the three domains are discussed together with the challenges and limitations that need to be overcome. PMID- 26025498 TI - [Sleep and sleep disorders in the elderly: Part 3: Restless legs syndrome]. AB - Restless legs syndrome (RLS) is a commonly occurring condition with a prevalence of approximately 10%. Women are more often affected than men. There is a primary and a secondary form. Secondary RLS is triggered by iron deficiency, severe renal insufficiency and many drugs and medications. The treatment for RLS is always symptomatic. In addition to treating associated diseases, dopaminergic therapy is paramount. Pharmacotherapy encompasses levodopa (L-dopa) and dopamine agonists, such as pramipexole, ropinirole and rotigotine. A serious complication of dopaminergic therapy is the so-called augmentation. In the case of insufficient efficacy, severe discomfort or augmentation, oxycodone/naloxone is now approved for the treatment of RLS. PMID- 26025499 TI - A log rank type test in observational survival studies with stratified sampling. AB - In randomized clinical trials, the log rank test is often used to test the null hypothesis of the equality of treatment-specific survival distributions. In observational studies, however, the ordinary log rank test is no longer guaranteed to be valid. In such studies we must be cautious about potential confounders; that is, the covariates that affect both the treatment assignment and the survival distribution. In this paper, two cases were considered: the first is when it is believed that all the potential confounders are captured in the primary database, and the second case where a substudy is conducted to capture additional confounding covariates. We generalize the augmented inverse probability weighted complete case estimators for treatment-specific survival distribution proposed in Bai et al. (Biometrics 69:830-839, 2013) and develop the log rank type test in both cases. The consistency and double robustness of the proposed test statistics are shown in simulation studies. These statistics are then applied to the data from the observational study that motivated this research. PMID- 26025500 TI - Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer. AB - PURPOSE: Limited literature exists regarding the safety of testosterone therapy in men treated for prostate cancer. We present multi-institutional data on testosterone therapy in hypogonadal men with prostate cancer treated with radiation therapy. MATERIALS AND METHODS: We retrospectively reviewed the records of hypogonadal men treated with testosterone therapy after radiation therapy for prostate cancer at 4 institutions. Serum testosterone, free testosterone, estradiol, sex hormone-binding globulin, prostate specific antigen, prostate specific antigen velocity and prostate biopsy findings were analyzed. RESULTS: A total of 98 men were treated with radiation therapy. Median age was 70.0 years (range 63.0 to 74.3) at initiation of testosterone therapy. Median baseline testosterone was 209 ng/dl (range 152 to 263) and median baseline prostate specific antigen was 0.08 ng/ml (range 0.00 to 0.33). In the cohort the tumor Gleason score was 5 in 3 men (3.1%), 6 in 44 (44.9%), 7 in 28 (28.6%), 8 in 7 (7.1%) and 9 in 4 (4.1%). Median followup was 40.8 months (range 1.5 to 147). Serum testosterone increased to a median of 420 ng/dl (range 231 to 711) during followup (p <0.001). Overall a nonsignificant increase in mean prostate specific antigen was observed from 0.08 ng/ml at baseline to 0.09 ng/ml (p = 0.05). Among patients at high risk prostate specific antigen increased from 0.10 to 0.36 ng/ml (p = 0.018). Six men (6.1%) met criteria for biochemical recurrence. CONCLUSIONS: Testosterone therapy in men following radiation therapy for prostate cancer was associated with a minor increase in serum prostate specific antigen and a low rate of biochemical recurrence. PMID- 26025501 TI - Methodological Quality of Systematic Reviews Published in the Urological Literature from 1998 to 2012. AB - PURPOSE: Systematic reviews synthesize the current best evidence to address a clinical question. Given the growing emphasis on evidence-based clinical practice, systematic reviews are being increasingly sought after and published. We previously reported limitations in the methodological quality of 57 individual systematic reviews published from 1998 to 2008. We provide an update to our previous study, adding systematic reviews published from 2009 to 2012. MATERIALS AND METHODS: We systematically searched PubMed(r) and hand searched the table of contents of 4 major urological journals to identify systematic reviews related to questions of prevention and therapy. Two independent reviewers with prior formal evidence-based medicine training assessed the methodological quality using the validated 11-point AMSTAR (A Measurement Tool to Assess Systematic Reviews) instrument. We performed predefined statistical hypothesis testing for differences by publication period (1998 to 2008 vs 2009 to 2012) and journal of publication. We performed statistical testing using SPSS(r), version 23.0 with a 2-sided alpha of 0.05 using the Student t-test, ANOVA and the chi-square test. RESULTS: A total of 113 systematic reviews published from 2009 to 2012 met study inclusion criteria. The most common topics were oncology (44 reviews or 38.9%), voiding dysfunction (26 or 23.0%) and stones/endourology (13 or 11.5%). The largest contributor was European Urology (46 reviews or 40.7%), followed by BJU International (31 or 27.4%) and The Journal of Urology(r) (22 or 19.5%). The mean +/- SD AMSTAR score for the 2009 to 2012 period was 5.3 +/- 2.3 compared to 4.8 +/- 2.0 for 1998 to 2008 with a mean difference of 0.5 (95% CI 0.2 to 1.2, p = 0.133). CONCLUSIONS: While the number of systematic reviews published in the urological literature has increased substantially, the methodological quality of these studies remains suboptimal. Systematic review authors and editors should make every effort to adhere to well established methodological standards to enhance the impact of their research efforts. PMID- 26025502 TI - Multi-Institutional Validation of an OSATS for the Assessment of Cystoscopic and Ureteroscopic Skills. AB - PURPOSE: We evaluated the internal and construct validity of an assessment tool for cystoscopic and ureteroscopic cognitive and psychomotor skills at a multi institutional level. MATERIALS AND METHODS: Subjects included a total of 30 urology residents at Ohio State University, Columbus, Ohio; Penn Presbyterian Medical Center, Philadelphia, Pennsylvania; and Mayo Clinic, Rochester, Minnesota. A single external blinded reviewer evaluated cognitive and psychomotor skills associated with cystoscopic and ureteroscopic surgery using high fidelity bench models. Exercises included navigation, basketing and relocation; holmium laser lithotripsy; and cystoscope assembly. Each resident received a total cognitive score, checklist score and global psychomotor skills score. Construct validity was assessed by calculating correlations between training year and performance scores (both cognitive and psychomotor). Internal validity was confirmed by calculating correlations between test components. RESULTS: The median total cognitive score was 91 (IQR 86.25, 97). For psychomotor performance residents had a median total checklist score of 7 (IQR 5, 8) and a median global psychomotor skills score of 21 (IQR 18, 24.5). Construct validity was supported by the positive and statistically significant correlations between training year and total cognitive score (r = 0.66, 95% CI 0.39-0.82, p = 0.01), checklist scores (r = 0.66, 95% CI 0.35-0.84, p = 0.32) and global psychomotor skills score (r = 0.76, 95% CI 0.55-0.88, p = 0.002). The internal validity of OSATS was supported since total cognitive and checklist scores correlated with the global psychomotor skills score. CONCLUSIONS: In this multi-institutional study we successfully demonstrated the construct and internal validity of an objective assessment of cystoscopic and ureteroscopic cognitive and technical skills, including laser lithotripsy. PMID- 26025504 TI - We Want You: Nurse educators. A message for nursing academia in the U.S. PMID- 26025503 TI - Role of Lynx1 and related Ly6 proteins as modulators of cholinergic signaling in normal and neoplastic bronchial epithelium. AB - The ly-6 proteins are a large family of proteins that resemble the snake three finger alpha toxins such as alpha-bungarotoxin and are defined by their multiple cysteine residues. Multiple members of the ly-6 protein family can modulate nicotinic signaling including lynx1, lynx2, slurp-1, slurp-2 and prostate stem cell antigen (PSCA). Consistent with the expression of multiple nicotinic receptors in bronchial epithelium, multiple members of the nicotinic-modulatory ly-6 proteins are expressed in lung including lynx1 and lynx2. We studied the role of lynx1 as an exemplar of the role of ly-6 proteins in lung. Our data demonstrates that lynx1 acts as a negative modulator of nicotinic signaling in normal and neoplastic lung. In normal lung lynx1 serves to limit the ability of chronic nicotine exposure to increase levels of nicotinic receptors and also serves to limit the ability of nicotine to upregulate levels of GABAA receptors in lung. In turn this allows lynx1 to limit the ability of nicotine to upregulate levels of mucin which is mediated by GABAergic signaling. This suggests that lynx1-mimetics may have potential for treatment of asthma and COPD. In that most lung cancer cells also express nicotinic receptor and lynx1 we examined the role of lynx-1 in lung cancer. Lynx1 levels are decreased in lung cancers compared to adjacent normal lung. Knockdown of lynx1 by siRNAs increased growth of lung cancer cells while expression of lynx1 in lung cancer cell decreased cell proliferation. This suggests that lynx1 is an endogenous regulator of lung cancer growth. Given that multiple small molecule negative and positive allosteric modulators of nicotinic receptors have already been developed, this suggests that lynx1 is a highly druggable target both for development of drugs that may limit lung cancer growth as well as for drugs that may be effective for asthma or COPD treatment. PMID- 26025505 TI - Curriculum development through understanding the student nurse experience of suicide intervention education--A phenomenographic study. AB - Suicide remains a global public health issue and a major governmental concern. The World Health Organisation argues for continued investment in education for front-line professionals, with a particular focus on nurses, to address the rising suicide levels. Considering this rate, it could be argued that suicide has impacted on the lives of many, including the student nurse population. Understanding the psychological impact, and influence on learning, whilst developing suicide intervention knowledge is crucial. However, little is known of the student experience in this complex and challenging area of skills development. This phenomenographic study examines the experiences of second year Bachelor of Nursing (mental health) students who participated in the Applied Suicide Intervention Skills Training (ASIST). Experiences were illuminated through two focus groups, Experiences were distilled and categorised through hierarchically relationships to construct a group experiential field to illustrate understandings of the impact this approach has on learning Students found ASIST to be emotionally challenging yet an extremely positive experience through bonding, peer learning, and class cohesion. The supportive workshop facilitation was essential allowing for full immersion into role simulation thus developing student confidence. Appropriate pedagogy and student support must be considered whilst developing suicide intervention in the pre-registration curricula. PMID- 26025506 TI - [Nurse prescribing within the Spanish national Health Service: fact or fiction?]. PMID- 26025507 TI - Streaming flow from ultrasound contrast agents by acoustic waves in a blood vessel model. AB - To elucidate the effects of streaming flow on ultrasound contrast agent (UCA) assisted drug delivery, streaming velocity fields from sonicated UCA microbubbles were measured using particle image velocimetry (PIV) in a blood vessel model. At the beginning of ultrasound sonication, the UCA bubbles formed clusters and translated in the direction of the ultrasound field. Bubble cluster formation and translation were faster with 2.25MHz sonication, a frequency close to the resonance frequency of the UCA. Translation of bubble clusters induced streaming jet flow that impinged on the vessel wall, forming symmetric vortices. The maximum streaming velocity was about 60mm/s at 2.25MHz and decreased to 15mm/s at 1.0MHz for the same acoustic pressure amplitude. The effect of the ultrasound frequency on wall shear stress was more noticeable. Maximum wall shear stress decreased from 0.84 to 0.1Pa as the ultrasound frequency decreased from 2.25 to 1.0MHz. The maximum spatial gradient of the wall shear stress also decreased from 1.0 to 0.1Pa/mm. This study showed that streaming flow was induced by bubble cluster formation and translation and was stronger upon sonication by an acoustic wave with a frequency near the UCA resonance frequency. Therefore, the secondary radiant force, which is much stronger at the resonance frequency, should play an important role in UCA-assisted drug delivery. PMID- 26025508 TI - A scanning-mode 2D shear wave imaging (s2D-SWI) system for ultrasound elastography. AB - Ultrasound elastography is widely used for the non-invasive measurement of tissue elasticity properties. Shear wave imaging (SWI) is a quantitative method for assessing tissue stiffness. SWI has been demonstrated to be less operator dependent than quasi-static elastography, and has the ability to acquire quantitative elasticity information in contrast with acoustic radiation force impulse (ARFI) imaging. However, traditional SWI implementations cannot acquire two dimensional (2D) quantitative images of the tissue elasticity distribution. This study proposes and evaluates a scanning-mode 2D SWI (s2D-SWI) system. The hardware and image processing algorithms are presented in detail. Programmable devices are used to support flexible control of the system and the image processing algorithms. An analytic signal based cross-correlation method and a Radon transformation based shear wave speed determination method are proposed, which can be implemented using parallel computation. Imaging of tissue mimicking phantoms, and in vitro, and in vivo imaging test are conducted to demonstrate the performance of the proposed system. The s2D-SWI system represents a new choice for the quantitative mapping of tissue elasticity, and has great potential for implementation in commercial ultrasound scanners. PMID- 26025510 TI - Gene and stress history interplay in emergence of PTSD-like features. AB - Systematically distinguishing genetic liability from other contributing factors is critical for designing a preventive strategy for post-traumatic stress disorder (PTSD). To address this issue, we investigated a murine model exposing C57BL/6j, DBA/2j and BALB/cj mice to repeated stress via exposure to conspecific aggressors (Agg-E). Naive mice from each strain were subjected to the proximity of aggressor (Agg) mice for 6h using a 'cage-within-a-cage' paradigm, which was repeated for 5 or 10 days with intermittent and unpredictable direct contact with Agg mice. During the Agg-E stress, DBA/2j developed a different strategy to evade Agg mice, which potentially contributed to its phenotypic resilience to Agg-E stress. Although Agg mice inflicted C57BL/6j and BALB/cj with equivalent numbers of strikes, BALB/cj displayed a distinct behavioral phenotype with delayed exhibition of a number of PTSD-like features. By contrast, C57BL/6j mice displayed unique vulnerability to Agg-E stress induced myocardopathy, possibly attributable to their particular susceptibility to hypoxia. A group of genes (Bdnf, Ngf, Zwint, Cckbr, Slc6a4, Fkbp5) linked to PTSD and synaptic plasticity were significantly altered in C57BL/6j and BALB/cj Agg-E mice. Contributions of Agg-E stress history and genotypic heterogeneity emerged as the key mediators of PTSD-like features. Linking genetic components to specific phenotypic and pathological features could have potential clinical implications. PMID- 26025511 TI - Altered local field potential activity and serotonergic neurotransmission are further characteristics of the Flinders sensitive line rat model of depression. AB - A significant portion of patients suffering from major depression remains refractory to available antidepressant treatment strategies. This highlights the need for a better understanding of the underlying neuropathology in order to develop rationale-based treatments. Here we aimed to further characterize neurobiological abnormalities of the Flinders Sensitive Line (FSL) rat model of depression. Biochemically, in FSL rats we mainly found increased levels of serotonin in most cortical and subcortical brain regions when compared to controls. Using electrophysiological measurements, in FSL rats we found decreased alpha, beta and low gamma oscillatory activity in the medial prefrontal cortex and nucleus accumbens and decreased alpha and beta as well as increased low gamma oscillatory activity in the subthalamicus nucleus when compared to controls. In summary, we show distinct neurochemical properties in combination with particular oscillatory activity patterns for brain areas thought to be pathophysiologically relevant for depression. Our data contribute to the further understanding of neurobiological alterations in the FSL rat model of depression that could provide a basis for research into future therapeutic strategies. PMID- 26025509 TI - Anterior cingulate cortex surface area relates to behavioral inhibition in adolescents with and without heavy prenatal alcohol exposure. AB - Prenatal alcohol exposure is associated with behavioral disinhibition, yet the brain structure correlates of this deficit have not been determined with sufficient detail. We examined the hypothesis that the structure of the anterior cingulate cortex (ACC) relates to inhibition performance in youth with histories of heavy prenatal alcohol exposure (AE, n = 32) and non-exposed controls (CON, n = 21). Adolescents (12-17 years) underwent structural magnetic resonance imaging yielding measures of gray matter volume, surface area, and thickness across four ACC subregions. A subset of subjects were administered the NEPSY-II Inhibition subtest. MANCOVA was utilized to test for group differences in ACC and inhibition performance and multiple linear regression was used to probe ACC-inhibition relationships. ACC surface area was significantly smaller in AE, though this effect was primarily driven by reduced right caudal ACC (rcACC). AE also performed significantly worse on inhibition speed but not on inhibition accuracy. Regression analyses with the rcACC revealed a significant group * ACC interaction. A smaller rcACC surface area was associated with slower inhibition completion time for AE but was not significantly associated with inhibition in CON. After accounting for processing speed, smaller rcACC surface area was associated with worse (i.e., slower) inhibition regardless of group. Examining processing speed independently, a decrease in rcACC surface area was associated with faster processing speed for CON but not significantly associated with processing speed in AE. Results support the theory that caudal ACC may monitor reaction time in addition to inhibition and highlight the possibility of delayed ACC neurodevelopment in prenatal alcohol exposure. PMID- 26025512 TI - Childhood leukemia and residential proximity to industrial and urban sites. AB - BACKGROUND: Few risk factors for the childhood leukemia are well established. While a small fraction of cases of childhood leukemia might be partially attributable to some diseases or ionizing radiation exposure, the role of industrial and urban pollution also needs to be assessed. OBJECTIVES: To ascertain the possible effect of residential proximity to both industrial and urban areas on childhood leukemia, taking into account industrial groups and toxic substances released. METHODS: We conducted a population-based case-control study of childhood leukemia in Spain, covering 638 incident cases gathered from the Spanish Registry of Childhood Tumors and for those Autonomous Regions with 100% coverage (period 1990-2011), and 13,188 controls, individually matched by year of birth, sex, and autonomous region of residence. Distances were computed from the respective subject's residences to the 1068 industries and the 157 urban areas with >=10,000 inhabitants, located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables. RESULTS: Excess risk of childhood leukemia was observed for children living near (<=2.5 km) industries (OR=1.31; 95%CI=1.03-1.67) - particularly glass and mineral fibers (OR=2.42; 95%CI=1.49 3.92), surface treatment using organic solvents (OR=1.87; 95%CI=1.24-2.83), galvanization (OR=1.86; 95%CI=1.07-3.21), production and processing of metals (OR=1.69; 95%CI=1.22-2.34), and surface treatment of metals (OR=1.62; 95%CI=1.22 2.15) - , and urban areas (OR=1.36; 95%CI=1.02-1.80). CONCLUSIONS: Our study furnishes some evidence that living in the proximity of industrial and urban sites may be a risk factor for childhood leukemia. PMID- 26025516 TI - Got to hide your Zn away: Molecular control of Zn accumulation and biotechnological applications. AB - Zinc (Zn) is an essential micronutrient for all organisms, with key catalytic and structural functions. Zn deficiency in plants, common in alkaline soils, results in growth arrest and sterility. On the other hand, Zn can become toxic at elevated concentrations. Several studies revealed molecules involved with metal acquisition in roots, distribution within the plant and translocation to seeds. Transmembrane Zn transport proteins and Zn chelators are involved in avoiding its toxic effects. Plant species with the capacity to hyperaccumulate and hypertolerate Zn have been characterized. Plants that accumulate and tolerate high amounts of Zn and produce abundant biomass may be useful for phytoremediation, allowing cleaning of metal-contaminated soils. The study of Zn hyperaccumulators may provide indications of genes and processes useful for biofortification, for developing crops with high amounts of nutrients in edible tissues. Future research needs to focus on functional characterization of Zn transporters in planta, elucidation of Zn uptake and sensing mechanisms, and on understanding the cross-talk between Zn homeostasis and other physiological processes. For this, new research should use multidisciplinary approaches, combining traditional and emerging techniques, such as genome-encoded metal sensors and multi-element imaging, quantification and speciation using synchrotron-based methods. PMID- 26025517 TI - Dwarf and tiller-enhancing 1 regulates growth and development by influencing boron uptake in boron limited conditions in rice. AB - Boron (B) is essential for plant growth, and B deficiency causes severe losses in crop yield. Here we isolated and characterized a rice (Oryza sativa L.) mutant named dwarf and tiller-enhancing 1 (dte1), which exhibits defects under low-B conditions, including retarded growth, increased number of tillers and impaired pollen fertility. Map-based cloning revealed that dte1 encodes a NOD26-LIKE INTRINSIC PROTEIN orthologous to known B channel proteins AtNIP5;1 in Arabidopsis and TASSEL-LESS1 in maize. Its identity was verified by transgenic complementation and RNA-interference. Subcellular localization showed DTE1 is mainly localized in the plasma membrane. The accumulation of DTE1 transcripts both in roots and shoots significantly increased within 3h of the onset of B starvation, but decreased within 1h of B replenishment. GUS staining indicated that DTE1s are expressed abundantly in exodermal cells in roots, as well as in nodal region of adult leaves. Although the dte1 mutation apparently reduces the total B content in plants, it does not affect in vivo B concentrations under B deficient conditions. These data provide evidence that DTE1 is critical for vegetative growth and reproductive development in rice grown under B-deficient conditions. PMID- 26025518 TI - Biochemical and physiological analyses of NADPH-dependent thioredoxin reductase isozymes in Euglena gracilis. AB - At least four peroxiredoxins that are coupled with the thioredoxin (Trx) system have been shown to play a key role in redox metabolism in the unicellular phytoflagellate Euglena gracilis. In order to clarify Trx-mediated redox regulation in this alga, we herein identified three NADPH-dependent thioredoxin reductases (NTRs) using a homologous search and characterized their enzymatic properties and physiological roles. Each Euglena NTR protein belonged to the small, large, and NTRC types, and were named EgNTR1, EgNTR2, and EgNTRC, respectively. EgNTR2 was phylogenetically different from the known NTRs in eukaryotic algae. EgNTR1 was predicted to be localized in mitochondria, EgNTR2 in the cytosol, and EgNTRC in plastids. The catalytic efficiency of EgNTR2 for NADPH was 30-46-fold higher than those of EgNTR1 and truncated form of EgNTRC, suggested that large type EgNTR2 reduced Trx more efficiently. The silencing of EgNTR2 gene expression resulted in significant growth inhibition and cell hypertrophy in Euglena cells. These results suggest that EgNTRs function in each cellular compartment and are physiologically important, particularly in the cytosol. PMID- 26025519 TI - Constitutively expressed ERF-VII transcription factors redundantly activate the core anaerobic response in Arabidopsis thaliana. AB - Plant adaptation to hypoxic conditions is mediated by the transcriptional activation of genes involved in the metabolic reprogramming of plant cells to cope with reduced oxygen availability. Recent studies indicated that members of the group VII of the Ethylene Responsive Transcription Factor (ERFs) family act as positive regulators of this molecular response. In the current study, the five ERF-VII transcription factors of Arabidopsis thaliana were compared to infer a hierarchy in their role with respect to the anaerobic response. When the activity of each transcription factor was tested on a set of hypoxia-responsive promoters, RAP2.2, RAP2.3 and RAP2.12 appeared to be the most powerful activators. RAP2.12 was further dissected in transactivation assays in Arabidopsis protoplasts to identify responsible regions for transcriptional activation. An ultimate C terminal motif was identified as sufficient to drive gene transcription. Finally, using realtime RT-PCR in single and double mutants for the corresponding genes, we confirmed that RAP2.2 and RAP2.12 exert major control upon the anaerobic response. PMID- 26025520 TI - Physiological and proteome analysis suggest critical roles for the photosynthetic system for high water-use efficiency under drought stress in Malus. AB - Water use efficiency is an important indicator for plant adaptation and resistance to drought conditions. We previously found that under moderate drought stress, the water use efficiency of cv. 'Qinguan' apple (Malus domestica Borkh.) (tolerant to drought) was enhanced, while that of cv. 'Naganofuji No. 2' was not enhanced. In this research, we also found that instantaneous water-use efficiency of cv. 'Qinguan' was higher than that of cv. 'Naganofuji No. 2', mainly because of its higher net photosynthesis rate. To dissect the potential mechanisms underlying this phenomenon, we performed a comparative iTRAQ-based proteomics analysis with leaves of drought-treated cv. 'Qinguan' and 'Naganofuji No. 2'. We identified 4078 proteins, of which 594 were differentially abundant between drought and well-watered leaves. The majority of increased proteins were predicted to be involved in photosynthetic pathway in drought treated cv. 'Qinguan' leaves, indicating that regulation of photosynthesis plays an important role for higher water use efficiency under drought stress. Enzyme activity assays were performed to validate the proteomics data. Our results suggested that the main regulatory mechanisms for high water use efficiency of cv. 'Qinguan' under moderate drought stress included the maintaining of Calvin cycle function by increasing key enzymes, stabilization of photosynthetic electron transfer and keeping reactive oxygen species at normal level by regulation of photosynthetic electron transfer chain, photorespiration and reactive oxygen species scavenging capability, thus prevented photoinhibition, reduced reactive oxygen species production and enhanced net photosynthesis rate. In addition, the response of signal regulatory proteins and abiotic stress-responsive proteins to drought also helped plants to cope with such stress. PMID- 26025521 TI - Constitutive expression of DaCBF7, an Antarctic vascular plant Deschampsia antarctica CBF homolog, resulted in improved cold tolerance in transgenic rice plants. AB - Deschampsia antarctica is an Antarctic hairgrass that grows on the west coast of the Antarctic peninsula. In this report, we have identified and characterized a transcription factor, D. antarctica C-repeat binding factor 7 (DaCBF7), that is a member of the monocot group V CBF homologs. The protein contains a single AP2 domain, a putative nuclear localization signal, and the typical CBF signature. DaCBF7, like other monocot group V homologs, contains a distinct polypeptide stretch composed of 43 amino acids in front of the AP2 motif. DaCBF7 was predominantly localized to nuclei and interacted with the C-repeat/dehydration responsive element (CRT/DRE) core sequence (ACCGAC) in vitro. DaCBF7 was induced by abiotic stresses, including drought, cold, and salinity. To investigate its possible cellular role in cold tolerance, a transgenic rice system was employed. DaCBF7-overexpressing transgenic rice plants (Ubi:DaCBF7) exhibited markedly increased tolerance to cold stress compared to wild-type plants without growth defects; however, overexpression of DaCBF7 exerted little effect on tolerance to drought or salt stress. Transcriptome analysis of a Ubi:DaCBF7 transgenic line revealed 13 genes that were up-regulated in DaCBF7-overexpressing plants compared to wild-type plants in the absence of cold stress and in short- or long-term cold stress. Five of these genes, dehydrin, remorin, Os03g63870, Os11g34790, and Os10g22630, contained putative CRT/DRE or low-temperature responsive elements in their promoter regions. These results suggest that overexpression of DaCBF7 directly and indirectly induces diverse genes in transgenic rice plants and confers enhanced tolerance to cold stress. PMID- 26025522 TI - The rice RCN11 gene encodes beta1,2-xylosyltransferase and is required for plant responses to abiotic stresses and phytohormones. AB - Seed germination rates and plant development and growth under abiotic stress are important aspects of crop productivity. Here, our characterization of the rice (Oryza sativa L.) mutant reduced culm number11 (rcn11) showed that RCN11 controls growth of plants exposed to abnormal temperature, salinity and drought conditions. RCN11 also mediates root aerenchyma formation under oxygen-deficient conditions and ABA sensitivity during seed germination. Molecular studies showed that the rcn11 mutation resulted from a 966-bp deletion that caused loss of function of beta1,2-xylosyltransferase (OsXylT). This enzyme is located in the Golgi apparatus where it catalyzes the transfer of xylose from UDP-xylose to the core beta-linked mannose of N-glycans. RCN11/OsXylT promoter activity was observed in the basal part of the shoot containing the shoot and axillary meristems and in the base of crown roots. The level of RCN11/OsXylT expression was regulated by multiple phytohormones and various abiotic stresses suggesting that plant specific N-glycosylation is regulated by multiple signals in rice plants. The present study is the first to demonstrate that rice beta1,2-linked xylose residues on N-glycans are critical for seed germination and plant development and growth under conditions of abiotic stress. PMID- 26025523 TI - Analysis of transcriptional regulation and tissue-specific expression of Avicennia marina Plasma Membrane Protein 3 suggests it contributes to Na(+) transport and homoeostasis in A. marina. AB - Plasma membrane proteins (PMP3) play a role in cation homoeostasis. The 5' flanking sequence of stress inducible, Avicennia marina PMP3 (AmPMP3prom) was transcriptionally fused to (a) GUS or (b) GFP-AmPMP3 and analyzed in transgenic tobacco. Tissue-histochemical GUS and GFP:AmPMP3 localization are co-incident under basal and stress conditions. AmPMP3prom directed GUS activity is highest in roots. Basal transcription is conferred by a 388bp segment upstream of the translation start site. A 463bp distal enhancer in the AmPMP3prom confers enhanced expression under salinity in all tissues and also responds to increases in salinity. The effect of a central, stem-specific negative regulatory region is suppressed by the distal enhancer. The A. marina rhizosphere encounters dynamic changes in salinity at the inter-tidal interface. The complex, tissue-specific transcriptional responsiveness of AmPMP3 to salinity appears to have evolved in response to these changes. Under salinity, guard cell and phloem-specific expression of GFP:AmPMP3 is highly enhanced. Mesophyll, trichomes, bundle sheath, parenchymatous cortex and xylem parenchyma also show GFP:AmPMP3 expression. Cis elements conferring stress, root and vascular-specific expression are enriched in the AmPMP3 promoter. Pronounced vascular-specific AmPMP3 expression suggests a role in salinity induced Na(+) transport, storage, and secretion in A. marina. PMID- 26025524 TI - Quantification of expression of dehydrin isoforms in the desiccation tolerant plant Craterostigma plantagineum using specifically designed reference genes. AB - Craterostigma plantagineum is a desiccation tolerant resurrection plant. Many genes are induced during desiccation. Dehydrins are a group of dehydration induced genes present in all higher plants. The current study aims at classifying the most abundantly expressed dehydrin genes from vegetative tissues of C. plantagineum and quantifying their expression. To identify variations between dehydrin isoforms at different stages of desiccation and rehydration by RT-qPCR, the target mRNA requires an accurate and reliable normalization. Previously we reported that RNAs from leaves and roots of C. plantagineum are not degraded during desiccation and subsequent rehydration thus allowing the use of RT-qPCR to test the stability of reference genes. The expression stability of eight candidate reference genes was tested in leaves, roots and callus. These genes were ranked according to their stability of gene expression using GeNorm(PLUS) and RefFinder. The most consistently expressed reference genes in each tissue were identified and used to normalize gene expression data. Dehydrin isoforms were divided in three groups based on the expression level during the desiccation process in three different tissues (leaves, roots and callus). PMID- 26025525 TI - Role of B3 domain transcription factors of the AFL family in maize kernel filling. AB - In the dicot Arabidopsis thaliana, the B3 transcription factors, ABA-INSENSITIVE 3 (ABI3), FUSCA 3 (FUS3) and LEAFY COTYLEDON 2 (LEC2) are key regulators of seed maturation. This raises the question of the role of ABI3/FUS3/LEC2 (AFL) proteins in cereals, where not only the embryo but also the persistent endosperm accumulates reserve substances. Among the five ZmAFL genes identified in the maize genome, ZmAFL2 and ZmAFL3/ZmVp1 closely resemble FUS3 and ABI3, respectively, in terms of their sequences, domain structure and gene activity profiles. Of the three genes that fall into the LEC2 phylogenetic sub-clade, ZmAFL5 and ZmAFL6 have constitutive gene activity, whereas ZmAFL4, like LEC2, has preferential gene activity in pollen and seed, although its seed gene activity is restricted to the endosperm during reserve accumulation. Knock down of ZmAFL4 gene activity perturbs carbon metabolism and reduces starch content in the developing endosperm at 20 DAP. ZmAFL4 and ZmAFL3/ZmVp1 trans-activate a maize oleosin promoter in a heterologous moss system. In conclusion our results suggest, based on gene activity profiles, that the functions of FUS3 and ABI3 could be conserved between dicot and monocot species. In contrast, LEC2 function may have partially diverged in cereals where our findings provide first evidence of the specialization of ZmAFL4 for roles in the endosperm. PMID- 26025527 TI - Autofluorescence: Biological functions and technical applications. AB - Chlorophylls are the most remarkable examples of fluorophores, and their fluorescence has been intensively studied as a non-invasive tool for assessment of photosynthesis. Many other fluorophores occur in plants, such as alkaloids, phenolic compounds and porphyrins. Fluorescence could be more than just a physicochemical curiosity in the plant kingdom, as several functional roles in biocommunication occur or have been proposed. Besides, fluorescence emitted by secondary metabolites can convert damaging blue and UV into wavelengths potentially useful for photosynthesis. Detection of the fluorescence of some secondary phytochemicals may be a cue for some pollinators and/or seed dispersal organisms. Independently of their functions, plant fluorophores provide researchers with a tool that allows the visualization of some metabolites in plants and cells, complementing and overcoming some of the limitations of the use of fluorescent proteins and dyes to probe plant physiology and biochemistry. Some fluorophores are influenced by environmental interactions, allowing fluorescence to be also used as a specific stress indicator. PMID- 26025526 TI - The genomics of plant sex chromosomes. AB - Around six percent of flowering species are dioecious, with separate female and male individuals. Sex determination is mostly based on genetics, but morphologically distinct sex chromosomes have only evolved in a few species. Of these, heteromorphic sex chromosomes have been most clearly described in the two model species - Silene latifolia and Rumex acetosa. In both species, the sex chromosomes are the largest chromosomes in the genome. They are hence easily distinguished, can be physically separated and analyzed. This review discusses some recent experimental data on selected model dioecious species, with a focus on S. latifolia. Phylogenetic analyses show that dioecy in plants originated independently and repeatedly even within individual genera. A cogent question is whether there is genetic degeneration of the non-recombining part of the plant Y chromosome, as in mammals, and, if so, whether reduced levels of gene expression in the heterogametic sex are equalized by dosage compensation. Current data provide no clear conclusion. We speculate that although some transcriptome analyses indicate the first signs of degeneration, especially in S. latifolia, the evolutionary processes forming plant sex chromosomes in plants may, to some extent, differ from those in animals. PMID- 26025528 TI - The R2R3-type MYB gene OsMYB91 has a function in coordinating plant growth and salt stress tolerance in rice. AB - Plants have evolved a number of different mechanisms to respond and to adapt to abiotic stress for their survival. However, the regulatory mechanisms involved in coordinating abiotic stress tolerance and plant growth are not fully understood. Here, the function of OsMYB91, an R2R3-type MYB transcription factor of rice was explored. OsMYB91 was induced by abiotic stress, especially by salt stress. Analysis of chromatin structure of the gene revealed that salt stress led to rapid removal of DNA methylation from the promoter region and rapid changes of histone modifications in the locus. Plants over-expressing OsMYB91 showed reduced plant growth and accumulation of endogenous ABA under control conditions. Under salt stress, the over-expression plants showed enhanced tolerance with significant increases of proline levels and a highly enhanced capacity to scavenge active oxygen as well as the increased induction of OsP5CS1 and LOC_Os03g44130 compared to wild type, while RNAi plants were less sensitive. In addition, expression of OsMYB91 was also induced by other abiotic stresses and hormone treatment. More interestingly, SLR1, the rice homolog of Arabidopsis DELLA genes that have been shown to integrate endogenous developmental signals with adverse environmental conditions, was highly induced by OsMYB91 over expression, while the salt-induction of SLR1 expression was impaired in the RNAi plants. These results suggested that OsMYB91 was a stress-responsive gene that might be involved in coordinating rice tolerance to abiotic stress and plant growth by regulating SLR1 expression. PMID- 26025529 TI - AtUGT76C2, an Arabidopsis cytokinin glycosyltransferase is involved in drought stress adaptation. AB - The Arabidopsis uridine diphosphate (UDP)-glycosyltransferase 76C2 (UGT76C2), a member of family 1 UGTs, is described as a cytokinin glycosyltransferase. In this study, we demonstrate a novel role of UGT76C2 in response to water deficit. QRT PCR assay identified that the expression of this gene was downregulated by drought, osmotic stress and abscisic acid (ABA). Compared with wild type (WT) plants, transgenic lines ectopically expressing UGT76C2 exhibited reduced tolerance to ABA and osmotic stress during postgermination growth, while enhanced adaptation to drought stress at mature stage. Consistently, the ugt76c2 mutant plants showed opposite responses to these conditions. To explore the possible mechanisms of UGT76C2 contributing to drought stress adaptation, six stress inducible genes including DREB2A, RD22, RD29B, LEA, COR47 and KIN1 were detected, which showed significant upregulation in UGT76C2 overexpression plants under drought stress. Besides, five cytokinin marker genes AHK2, AHK3, AHK4, ARR1 and ARR2 were also evaluated, which showed less induced in UGT76C2 overexpression plants in response to drought stress. Our results reveal that UGT76C2, as a cytokinin glycosyltransferase, is involved in the plant response to drought stress and might represent novel cues in abiotic stress adaptation. PMID- 26025530 TI - Climate change conditions (elevated CO2 and temperature) and UV-B radiation affect grapevine (Vitis vinifera cv. Tempranillo) leaf carbon assimilation, altering fruit ripening rates. AB - The increase in grape berry ripening rates associated to climate change is a growing concern for wine makers as it rises the alcohol content of the wine. The present work studied the combined effects of elevated CO2, temperature and UV-B radiation on leaf physiology and berry ripening rates. Three doses of UV-B: 0, 5.98, 9.66 kJm(-2)d(-1), and two CO2-temperature regimes: ambient CO2-24/14 degrees C (day/night) (current situation) and 700 ppm CO2-28/18 degrees C (climate change) were imposed to grapevine fruit-bearing cuttings from fruit set to maturity under greenhouse-controlled conditions. Photosynthetic performance was always higher under climate change conditions. High levels of UV-B radiation down regulated carbon fixation rates. A transient recovery took place at veraison, through the accumulation of flavonols and the increase of antioxidant enzyme activities. Interacting effects between UV-B and CO2-temperature regimes were observed for the lipid peroxidation, which suggests that UV-B may contribute to palliate the signs of oxidative damage induced under elevated CO2-temperature. Photosynthetic and ripening rates were correlated. Thereby, the hastening effect of climate change conditions on ripening, associated to higher rates of carbon fixation, was attenuated by UV-B radiation. PMID- 26025531 TI - Polysaccharide deposition during cytokinesis: Challenges and future perspectives. AB - De novo formation of a new cell wall partitions the cytoplasm of the dividing cell during plant cytokinesis. The development of the cell plate, a transient sheet-like structure, requires the accumulation of vesicles directed by the phragmoplast to the cell plate assembly matrix. Fusion and fission of the accumulated vesicles are accompanied by the deposition of polysaccharides and cell wall structural proteins; together, they are leading to the stabilization of the formed structure which after insertion into the parental wall lead to the maturation of the nascent cross wall. Callose is the most abundant polysaccharide during cell plate formation and during maturation is gradually replaced by cellulose. Matrix polysaccharides such as hemicellulose, and pectins presumably are present throughout all developmental stages, being delivered to the cell plate by secretory vesicles. The availability of novel chemical probes such as endosidin 7, which inhibits callose formation at the cell plate, has proved useful for dissecting the temporal accumulation of vesicles at the cell plate and establishing the critical role of callose during cytokinesis. The use of emerging approaches such as chemical genomics combined with live cell imaging; novel techniques of polysaccharide detection including tagged polysaccharide substrates, newly characterized polysaccharide antibodies and vesicle proteomics can be used to develop a comprehensive model of cell plate development. PMID- 26025532 TI - Rubisco accumulation is important for the greening of the fln2-4 mutant in Arabidopsis. AB - The fructokinase-like protein2 (FLN2) is a component of the PEP complex. FLN2 knockout mutants displayed a delayed greening phenotype on sucrose-containing medium. Our previous work indicated that partial PEP activity is essential for its greening phenotype. In this study, we further report that sufficient Rubisco accumulation is critical for fln2-4 greening. Sugar serves many important functions, such as an energy source and signaling molecule. Through pharmacological experiments using a sugar analog and sugar signaling inhibitor, we demonstrate that sugar serves as energy to support the fln2-4 greening. Seed reserve and photosynthetic CO2-fixation are the primary energy sources for early seedling growth. No obvious differences were observed in the seed-reserve of the wild-type and fln2-4 by comparing their seed size and dark-germination, indicating that the defective carbon fixation may account for the energy deficit in fln2-4 during its early seedling growth. The Rubisco content was low in fln2 4, but it rapidly accumulated during the greening of fln2-4. Expression of a nuclear-encoded rbcL gene facilitates Rubisco accumulation and partially complements the mutant defects. These results suggest that the Rubisco accumulation is critical for fln2-4 greening. In summary, the rapid Rubisco accumulation that depends on sufficient PEP activity is important for normal seedling growth. PMID- 26025533 TI - Differences in the cell walls and extracellular polymers of the two Trebouxia microalgae coexisting in the lichen Ramalina farinacea are consistent with their distinct capacity to immobilize extracellular Pb. AB - Trebouxia TR1 and T. TR9 are the two microalgae that coexist within Ramalina farinacea thalli. In the presence of Pb, TR9 formed extracellular aggregates, while TR1 showed a lower wall lead retention capability. Herein, we studied the cell walls and extracellular polymers (EPS) of TR1 and TR9, and their possible implication in the different Pb retention capacity of these microalgae. The proportion of cell walls on the overall cell biomass was 2.6 times higher in TR9 than in TR1. Glycosyl linkage analysis indicated the presence of hot-water soluble beta-galactofuranan(s) in both cell walls, distinct from that previously described in Asterochloris, with increased rhamnose content in TR9 and a higher substitution by side chains in TR1. In the EPS of both microalgae, monosaccharide composition resembled their cell walls; however, TR9 produced two times more EPS than TR1. EPS also contained proteins, displaying distinct polypeptide patterns, modulated by Pb in TR9. Uronic acid content in EPS was higher in TR9, and increased in this phycobiont after the addition of Pb. Our findings suggest that the differential extracellular Pb retention capabilities of TR1 and TR9 microalgae can be related to differences in the main features of their cell walls and EPS. PMID- 26025534 TI - WRKY13 acts in stem development in Arabidopsis thaliana. AB - Stems are important for plants to grow erectly. In stems, sclerenchyma cells must develop secondary cell walls to provide plants with physical support. The secondary cell walls are mainly composed of lignin, xylan and cellulose. Deficiency of overall stem development could cause weakened stems. Here we prove that WRKY13 acts in stem development. The wrky13 mutants take on a weaker stem phenotype. The number of sclerenchyma cells, stem diameter and the number of vascular bundles were reduced in wrky13 mutants. Lignin-synthesis-related genes were repressed in wrky13 mutants. Chromatin immunoprecipitation assays proved that WRKY13 could directly bind to the promoter of NST2. Taken together, we proposed that WRKY13 affected the overall development of stem. Identification of the role of WRKY13 may help to resolve agricultural problems caused by weaker stems. PMID- 26025535 TI - Three WRKY transcription factors additively repress abscisic acid and gibberellin signaling in aleurone cells. AB - Members of the WRKY transcription factor superfamily are essential for the regulation of many plant pathways. Functional redundancy due to duplications of WRKY transcription factors, however, complicates genetic analysis by allowing single-mutant plants to maintain wild-type phenotypes. Our analyses indicate that three group I WRKY genes, OsWRKY24, -53, and -70, act in a partially redundant manner. All three showed characteristics of typical WRKY transcription factors: each localized to nuclei and yeast one-hybrid assays indicated that they all bind to W-boxes, including those present in their own promoters. Quantitative real time-PCR (qRT-PCR) analyses indicated that the expression levels of the three WRKY genes varied in the different tissues tested. Particle bombardment-mediated transient expression analyses indicated that all three genes repress the GA and ABA signaling in a dosage-dependent manner. Combination of all three WRKY genes showed additive antagonism of ABA and GA signaling. These results suggest that these WRKY proteins function as negative transcriptional regulators of GA and ABA signaling. However, different combinations of these WRKY genes can lead to varied strengths in suppression of their targets. PMID- 26025536 TI - The beta subunit of glyceraldehyde 3-phosphate dehydrogenase is an important factor for maintaining photosynthesis and plant development under salt stress Based on an integrative analysis of the structural, physiological and proteomic changes in chloroplasts in Thellungiella halophila. AB - Thellungiella halophila, a new model halophyte, can survive under highly saline conditions. We performed comparative proteomics of chloroplasts from plants grown under different saline conditions. Seventy-five salt-responsive proteins were positively identified by mass spectrometry, which represented 43 unique ones. These proteins were categorized into 7 main pathways: light reaction, carbon fixation, energy metabolism, antenna proteins, cell structure, and protein degradation and folding. Saline conditions increased the abundance of proteins involved in photosynthesis, energy metabolism and cell structure. The results indicated that Thellungiella could withstand high salinity by maintaining normal or high photosynthetic capacity, reducing ROS production, as well as enhancing energy usage. Meanwhile, the ultrastructural and physiological data also agree with chloroplast proteomics results. Subsequently, the glyceraldehydes 3 phosphate dehydrogenase beta subunit (GAPB) involved in carbon fixation was selected and its role in salt tolerance was clarified by over-expressing it in Arabidopsis. ThGAPB-overexpressing plants had higher total chlorophyll contents, dry weights, water contents and survival rates than that of wild type plants. These results indicated that ThGAPB might improve plant salt tolerance by maintaining higher recycling rates of ADP and NADP(+) to decrease ROS production, helping to maintain photosynthetic efficiency and plant development under saline conditions. PMID- 26025537 TI - Expression patterns of C- and N-metabolism related genes in wheat are changed during senescence under elevated CO2 in dry-land agriculture. AB - Projected climatic impacts on crop yield and quality, and increased demands for production, require targeted research to optimise nutrition of crop plants. For wheat, post-anthesis carbon and nitrogen remobilisation from vegetative plant parts and translocation to grains directly affects grain carbon (C), nitrogen (N) and protein levels. We analysed the influence of increased atmospheric CO2 on the expression of genes involved in senescence, leaf carbohydrate and nitrogen metabolism and assimilate transport in wheat under field conditions (Australian Grains Free Air CO2 Enrichment; AGFACE) over a time course from anthesis to maturity, the key period for grain filling. Wheat grown under CO2 enrichment had lower N concentrations and a tendency towards greater C/N ratios. A general acceleration of the senescence process by elevated CO2 was not confirmed. The expression patterns of genes involved in carbohydrate metabolism, nitrate reduction and metabolite transport differed between CO2 treatments, and this CO2 effect was different between pre-senescence and during senescence. The results suggest up-regulation of N remobilisation and down-regulation of C remobilisation during senescence under elevated CO2, which is consistent with greater grain N sink strength of developing grains. PMID- 26025538 TI - NnSR1, a class III non-S-RNase specifically induced in Nicotiana alata under phosphate deficiency, is localized in endoplasmic reticulum compartments. AB - A combined strategy of phosphate (Pi) remobilization from internal and external RNA sources seems to be conserved in plants exposed to Pi starvation. Thus far, the only ribonucleases (RNases) reported to be induced in Nicotiana alata undergoing Pi deprivation are extracellular S-like RNase NE and NnSR1. NnSR1 is a class III non S-RNase of unknown subcellular location. Here, we examine the hypothesis that NnSR1 is an intracellular RNase derived from the self incompatibility system with specific expression in self-incompatible Nicotiana alata. NnSR1 was not induced in self-compatible Nicotiana species exposed to Pi deprivation. NnSR1 conjugated with a fluorescent protein and transiently expressed in Arabidopsis protoplasts and Nicotiana leaves showed that the fusion protein co-localized with an endoplasmic reticulum (ER) marker. Subcellular fractionation by ultracentrifugation of roots exposed to Pi deprivation revealed that the native NnSR1 migrated in parallel with the BiP protein, a typical ER marker. To our knowledge, NnSR1 is the first class III RNase reported to be localized in ER compartments. The induction of NnSR1 was detected earlier than the extracellular RNase NE, suggesting that intracellular RNA may be the first source of Pi used by the cell under Pi stress. PMID- 26025539 TI - Genetic analyses of the interaction between abscisic acid and gibberellins in the control of leaf development in Arabidopsis thaliana. AB - Although abscisic acid (ABA) and gibberellins (GAs) play pivotal roles in many physiological processes in plants, their interaction in the control of leaf growth remains elusive. In this study, genetic analyses of ABA and GA interplay in leaf growth were performed in Arabidopsis thaliana. The results indicate that for the ABA and GA interaction, leaf growth of both the aba2/ga20ox1 and aba2/GA20ox1 plants, which were derived from the crosses of aba2*ga20ox1 and aba2*GA20ox1 overexpressor, respectively, exhibits partially additive effects but is similar to the aba2 mutant. Consistently, the transcriptome analysis suggests that a substantial proportion (45-65%) of the gene expression profile of aba2/ga20ox1 and aba2/GA20ox1 plants overlap and share a pattern similar to the aba2 mutant. Thus, these data suggest that ABA deficiency dominates leaf growth regardless of GA levels. Moreover, the gene ontology (GO) analysis indicates gene enrichment in the categories of hormone response, developmental and metabolic processes, and cell wall organization in these three genotypes. Leaf developmental genes are also involved in the ABA-GA interaction. Collectively, these data support that the genetic relationship of ABA and GA interaction involves multiple coordinated pathways rather than a simple linear pathway for the regulation of leaf growth. PMID- 26025540 TI - Cell wall modifications triggered by the down-regulation of Coumarate 3 hydroxylase-1 in maize. AB - Coumarate 3-hydroxylase (C3H) catalyzes a key step of the synthesis of the two main lignin subunits, guaiacyl (G) and syringyl (S) in dicotyledonous species. As no functional data are available in regards to this enzyme in monocotyledonous species, we generated C3H1 knock-down maize plants. The results obtained indicate that C3H1 participates in lignin biosynthesis as its down-regulation redirects the phenylpropanoid flux: as a result, increased amounts of p-hydroxyphenyl (H) units, lignin-associated ferulates and the flavone tricin were detected in transgenic stems cell walls. Altogether, these changes make stem cell walls more degradable in the most C3H1-repressed plants, despite their unaltered polysaccharide content. The increase in H monomers is moderate compared to C3H deficient Arabidopsis and alfalfa plants. This could be due to the existence of a second maize C3H protein (C3H2) that can compensate the reduced levels of C3H1 in these C3H1-RNAi maize plants. The reduced expression of C3H1 alters the macroscopic phenotype of the plants, whose growth is inhibited proportionally to the extent of C3H1 repression. Finally, the down-regulation of C3H1 also increases the synthesis of flavonoids, leading to the accumulation of anthocyanins in transgenic leaves. PMID- 26025541 TI - Redox homeostasis and reactive oxygen species scavengers shift during ontogenetic phase changes in apple. AB - The change from juvenile to adult phase is a universal phenomenon in perennial plants such as apple. To validate the changes in hydrogen peroxide (H2O2) levels and scavenging during ontogenesis in apple seedlings, the H2O2 contents, its scavenging capacity, and the expression of related genes, as well as miR156 levels, were measured in leaf samples from different nodes in seedlings of 'Zisai Pearl' (Malus asiatica)*'Red Fuji' (M. domestica). Then in vitro shoots were treated with redox modulating chemicals to verify the response of miR156 to redox alteration. The expression of miR156 decreased gradually during ontogenesis, indicating a progressive loss of juvenility. During the phase changes, H2O2 and ascorbate contents, the ratio of ascorbate to dehydroascorbate, the ascorbate peroxidase, catalase and glutathione reductase activities, and the expressions of some MdGR and MdAPX gene family members increased remarkably. However, the glutathione content and glutathione to glutathione disulfide ratio declined. In chemicals treated in vitro shoots, the changes in miR156 levels were coordinated with GSH contents and GSH/GSSG ratio but not H2O2 contents. Conclusively, the relative reductive thiol redox status is critical for the maintenance of juvenility and the reductive ascorbate redox environment was elevated and sustained during the reproductive phase. PMID- 26025542 TI - Arabidopsis casein kinase 2 alpha4 subunit regulates various developmental pathways in a functionally overlapping manner. AB - Casein kinase 2 (CK2) is an essential and well-conserved Ser/Thr kinase that regulates proteins in a posttranslational manner. CK2 has been shown to affect a large number of developmental processes across eukaryotes. It is a tetrameric protein composed of a dimer of alpha (catalytic) and beta (regulatory) subunit each. In our previous study we showed that three of the four CK2 alpha subunits in Arabidopsis act in a functionally redundant manner to regulate various developmental pathways. In this study we constructed two independent CK2 alpha4 RNAi lines in the CK2 alpha triple mutant background. Through functional characterization of these RNAi lines we show that the fourth alpha subunit in Arabidopsis also functions redundantly in regulating ABA response, lateral root formation and flowering time. CK2 alpha4-GFP localizes to the chloroplast in transgenic Arabidopsis seedlings, consistent with the presence of a chloroplast localization signal at the amino-terminus of CK2 alpha4 subunit. Taken together, our results suggest a functionally overlapping role for the CK2 alpha4 subunit in regulating various developmental processes in plants. PMID- 26025543 TI - OsIAA6, a member of the rice Aux/IAA gene family, is involved in drought tolerance and tiller outgrowth. AB - Auxin signaling is a fundamental part of many plant growth processes and stress responses and operates through Aux/IAA protein degradation and the transmission of the signal via auxin response factors (ARFs). A total of 31 Aux/IAA genes have been identified in rice (Oryza sativa), some of which are induced by drought stress. However, the mechanistic link between Aux/IAA expression and drought responses is not well understood. In this study we found that the rice Aux/IAA gene OsIAA6 is highly induced by drought stress and that its overexpression in transgenic rice improved drought tolerance, likely via the regulation of auxin biosynthesis genes. We observed that OsIAA6 was specifically expressed in the axillary meristem of the basal stem, which is the tissue that gives rise to tillers. A knock-down mutant of OsIAA6 showed abnormal tiller outgrowth, apparently due to the regulation of the auxin transporter OsPIN1 and the rice tillering inhibitor OsTB1. Our results confirm that the OsIAA6 gene is involved in drought stress responses and the control of tiller outgrowth. PMID- 26025544 TI - De novo sequencing of root transcriptome reveals complex cadmium-responsive regulatory networks in radish (Raphanus sativus L.). AB - Cadmium (Cd) is a nonessential metallic trace element that poses potential chronic toxicity to living organisms. To date, little is known about the Cd responsive regulatory network in root vegetable crops including radish. In this study, 31,015 unigenes representing 66,552 assembled unique transcripts were isolated from radish root under Cd stress based on de novo transcriptome assembly. In all, 1496 differentially expressed genes (DEGs) consisted of 3579 transcripts were identified from Cd-free (CK) and Cd-treated (Cd200) libraries. Gene Ontology and pathway enrichment analysis indicated that the up- and down regulated DEGs were predominately involved in glucosinolate biosynthesis as well as cysteine and methionine-related pathways, respectively. RT-qPCR showed that the expression profiles of DEGs were in consistent with results from RNA-Seq analysis. Several candidate genes encoding phytochelatin synthase (PCS), metallothioneins (MTs), glutathione (GSH), zinc iron permease (ZIPs) and ABC transporter were responsible for Cd uptake, accumulation, translocation and detoxification in radish. The schematic model of DEGs and microRNAs-involved in Cd-responsive regulatory network was proposed. This study represents a first comprehensive transcriptome-based characterization of Cd-responsive DEGs in radish. These results could provide fundamental insight into complex Cd responsive regulatory networks and facilitate further genetic manipulation of Cd accumulation in root vegetable crops. PMID- 26025545 TI - Lower antibiotic costs attributable to clinical microbiology rounds. AB - OBJECTIVE: At our institution, our microbiologist, pharmacist, and infectious disease (ID) team meet to discuss ID patients, and this meeting is referred to as microbiology rounds. We hypothesized that our microbiology rounds reduce antibiotic costs. The study involved a review of 80 patients with an ID consultation order at each of the 3 hospitals: hospital A (HA) (only HA has microbiology rounds), hospital B (HB), and hospital C (HC). Of this population, we included patients with a positive blood culture. Thirty-six patients who met the above criteria were included in the study. The average antibiotic cost/patient/day at HA, HB, and HC were $66.0, $123, and $109, respectively. Also, we found that change in antibiotics was appropriate when compared to the final microbiology results in 90%, 44%, and 40% of the time at HA, HB, and HC, respectively. Herein, we found an association between conducting microbiology rounds and reduction of antibiotic cost. PMID- 26025546 TI - Multi-subject atlas-based auto-segmentation reduces interobserver variation and improves dosimetric parameter consistency for organs at risk in nasopharyngeal carcinoma: A multi-institution clinical study. AB - BACKGROUND AND PURPOSE: To assess whether consensus guideline-based atlas-based auto-segmentation (ABAS) reduces interobserver variation and improves dosimetric parameter consistency for organs at risk (OARs) in nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Eight radiation oncologists from 8 institutes contoured 20 OARs on planning CT images of 16 patients via manual contouring and manually-edited ABAS contouring. Interobserver variation [volume coefficient of variation (CV), Dice similarity coefficient (DSC), three-dimensional isocenter difference (3D-ICD)] and dosimetric parameters were compared between the two methods of contouring for each OAR. RESULTS: Interobserver variation was significant for all OARs in manual contouring, resulting in significant dosimetric parameter variation (P<0.05). Edited ABAS significantly improved multiple metrics and reduced dosimetric parameter variation for most OARs; brainstem, spinal cord, cochleae, temporomandibular joint (TMJ), larynx and pharyngeal constrictor muscle (PCM) obtained most benefit (range of mean DSC, volume CV and main ICD values was 0.36-0.83, 12.1-84.3%, 2.2-5.0mm for manual contouring and 0.42-0.86, 7.2-70.6%, 1.2-3.5mm for edited ABAS contouring, respectively; range of dose CV reduction: 1.0-3.0%). CONCLUSION: Substantial objective interobserver differences occur during manual contouring, resulting in significant dosimetric parameter variation. Edited ABAS reduced interobserver variation and improved dosimetric parameter consistency, particularly for brainstem, spinal cord, cochleae, TMJ, larynx and PCM. PMID- 26025549 TI - Unfolded partial least squares/residual bilinearization combined with the Successive Projections Algorithm for interval selection: enhanced excitation emission fluorescence data modeling in the presence of the inner filter effect. AB - The use of the successive projections algorithm (SPA) for elimination of uninformative variables in interval selection, and unfold partial least squares regression (U-PLS) modeling of excitation-emission matrices (EEM), when under the inner filter effect (IFE) is reported for first time. Post-calibration residual bilinearization (RBL) was employed against events of unknown components in the test samples. The inner filter effect can originate changes in both the shape and intensity of analyte spectra, leading to trilinearity losses in both modes, and thus invalidating most multiway calibration methods. The algorithm presented in this paper was named iSPA-U-PLS/RBL. Both simulated and experimental data sets were used to compare the prediction capability during: (1) simulated EEM; and (2) quantitation of phenylephrine (PHE) in the presence of paracetamol (PAR) (or acetaminophen) in water samples. Test sets containing unexpected components were built in both systems [a single interference was taken into account in the simulated data set, while water samples were added with varying amounts of ibuprofen (IBU), and acetyl salicylic acid (ASA)]. The prediction results and figures of merit obtained with the new algorithm were compared with those obtained with U-PLS/RBL (without intervals selection), and with the well-known parallel factors analysis (PARAFAC). In all cases, U-PLS/RBL displayed better EEM handling capability in the presence of the inner filter effect compared with PARAFAC. In addition, iSPA-U-PLS/RBL improved the results obtained with the full U-PLS/RBL model, in this case demonstrating the potential of variable selection. PMID- 26025547 TI - Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency. AB - BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially. PMID- 26025550 TI - Optimization and comparison of several extraction methods for determining perfluoroalkyl substances in abiotic environmental solid matrices using liquid chromatography-mass spectrometry. AB - In this study, four extraction methods of perfluoroalkyl substances (PFASs) in soils and sediments were validated and compared in order to select the one that provides the best recoveries and the highest sensitivity. The determination of PFASs was carried out by liquid chromatography-tandem mass spectrometry. The extraction methods compared were based on (i) an aqueous solution of acetic acid and methanol (recoveries 44-125%, relative standard deviation (RSD) <25%), (ii) methanol (34-109%, <25%), (iii) sodium hydroxide digestion (24-178%, <49%), and (iv) ion pair (35-179%, <31%). The best results were obtained with methanol extraction, which recovered a greater number of PFASs and provided values between 45-103% in sediment and 34-109% in soil with RSDs <25% and limits of quantification (LOQs) between 0.02-0.31 and 0.01-6.00 ng g(-1), respectively. The selected method was successfully applied to Segura River sediments and soil samples taken near the Turia River. This study demonstrates the presence of PFASs in the studied rivers of the Valencian Community (0.07-14.91 ng g(-1) in Segura River sediments; 0.02-64.04 ng g(-1) in Turia River soils). Graphical Abstract Selected matrices and extraction methods for determination of perfluoroalkyl substances. PMID- 26025551 TI - G-quadruplex-based structural transitions in 15-mer DNA oligonucleotides varying in lengths of internal oligo(dG) stretches detected by voltammetric techniques. AB - Electrochemical methods, particularly when applied in connection with mercury containing electrodes, are excellent tools for studying nucleic acids structure and monitoring structural transitions. We studied the effect of the length of the central (dG) n stretch (varying from 0 to 15 guanine residues) in 15-mer oligodeoxynucleotides (ODN, G0 to G15) on their electrochemical and interfacial behavior at mercury and carbon electrodes. The intensity of guanine oxidation signal at the carbon electrode (peak G(ox)) was observed to increase continuously with number of guanines between 0 and 15, with only a slight positive shift for ODNs with seven or more guanines in the central segment. Very different effects were observed when the peak G(HMDE) was measured at the mercury electrode. Intensity of the latter signal increased with number of guanines up to G5, and decreased sharply with further elongation of the (dG) n stretch. CD spectroscopy and electrophoresis experiments revealed formation of parallel intermolecular quadruplex structures for ODNs containing five or more G residues. Further measurements made by cyclic and alternating-current voltammetry revealed a strong influence of the ODN structure on their behavior at electrically charged surfaces. PMID- 26025548 TI - Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. AB - Mitochondria play a key role in overall cell physiology and health by integrating cellular metabolism with cellular defense and repair mechanisms in response to physiological or environmental changes or stresses. In fact, dysregulation of mitochondrial stress responses and its consequences in the form of oxidative stress, has been linked to a wide variety of diseases including inborn errors of metabolism. In this review we will summarize how the functional state of mitochondria -- and especially the concentration of reactive oxygen species (ROS), produced in connection with the respiratory chain -- regulates cellular stress responses by redox regulation of nuclear gene networks involved in repair systems to maintain cellular homeostasis and health. Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death. We suggest that this model may have important implications for those inborn errors of metabolism, where mitochondrial dysfunction plays a major role, as it allows the explanation of oxidative stress, metabolic reprogramming and altered signalling growth pathways that have been reported in many of the diseases. It is our hope that the model may facilitate novel ideas and directions that can be tested experimentally and used in the design of future new approaches for pre-symptomatic diagnosis and prognosis and perhaps more effective treatments of inborn errors of metabolism. PMID- 26025552 TI - High-internal-phase-emulsion polymeric monolith coupled with liquid chromatography-electrospray tandem mass spectrometry for enrichment and sensitive detection of trace cytokinins in plant samples. AB - High-internal-phase-emulsion polymers (polyHIPEs) show great promise as solid phase-extraction (SPE) materials because of the tremendous porosity and highly interconnected framework afforded by the high-internal-phase-emulsion (HIPE) technique. In this work, polyHIPE monolithic columns as novel SPE materials were prepared and applied to trace enrichment of cytokinins (CKs) from complex plant samples. The polyHIPE monoliths were synthesized via the in-situ polymerization of the continuous phase of a HIPE containing styrene (STY) and divinylbenzene (DVB) in a stainless column, and revealed highly efficient and selective enrichment ability for aromatic compounds. Under the optimized experimental conditions, a method using a monolithic polyHIPE column combined with liquid chromatography-electrospray tandem mass spectrometry (LC-MS-MS) was developed for the simultaneous extraction and sensitive determination of trans-zeatin (tZ), meta-topolin (mT), kinetin (K), and kinetin riboside (KR). The proposed method had good linearity, with correlation coefficients (R (2)) from 0.9957 to 0.9984, and low detection limits (LODs, S/N = 3) in the range 2.4-47 pg mL(-1) for the four CKs. The method was successfully applied to the determination of CKs in real plant samples, and obtained good recoveries ranging from 68.8 % to 103.0 % and relative standard deviations (RSDs) lower than 16 %. PMID- 26025553 TI - New approach to the determination of contaminants of emerging concern in natural water: study of alprazolam employing adsorptive cathodic stripping voltammetry. AB - Contaminants of emerging concern (CECs) are chemicals, including pharmaceutical and personal care products, not commonly monitored in the aquatic environment. Pharmaceuticals are nowadays considered as an important environmental contaminant. Chromatography methods which require expensive equipment and complicated sample pretreatment are used for detection of CECs in natural water. Thus, in this study we proposed a simple, fast, and low-cost voltammetric method as a screening tool for the determination of CECs in natural water prior to chromatography. A case study was conducted with alprazolam (benzodiazepine). The method was optimized and validated in-house. The limit of quantification was 0.4 MUg L(-1) for a 120 s preconcentration time. The recoveries ranged from 93 to 120 % for accuracy tests. A further proposal aim was to determine for the first time the occurrence of alprazolam in Brazilian river water and to evaluate its potential use as a marker of contamination by wastewater. PMID- 26025554 TI - Navigating 3D electron microscopy maps with EM-SURFER. AB - BACKGROUND: The Electron Microscopy DataBank (EMDB) is growing rapidly, accumulating biological structural data obtained mainly by electron microscopy and tomography, which are emerging techniques for determining large biomolecular complex and subcellular structures. Together with the Protein Data Bank (PDB), EMDB is becoming a fundamental resource of the tertiary structures of biological macromolecules. To take full advantage of this indispensable resource, the ability to search the database by structural similarity is essential. However, unlike high-resolution structures stored in PDB, methods for comparing low resolution electron microscopy (EM) density maps in EMDB are not well established. RESULTS: We developed a computational method for efficiently searching low-resolution EM maps. The method uses a compact fingerprint representation of EM maps based on the 3D Zernike descriptor, which is derived from a mathematical series expansion for EM maps that are considered as 3D functions. The method is implemented in a web server named EM-SURFER, which allows users to search against the entire EMDB in real-time. EM-SURFER compares the global shapes of EM maps. Examples of search results from different types of query structures are discussed. CONCLUSIONS: We developed EM-SURFER, which retrieves structurally relevant matches for query EM maps from EMDB within seconds. The unique capability of EM-SURFER to detect 3D shape similarity of low resolution EM maps should prove invaluable in structural biology. PMID- 26025555 TI - The Development and Single-Laboratory Validation of a Method for the Determination of Steroid Residues in Fish and Fish Products. AB - Due to potential use in aquacultured fish products, the Canadian Food Inspection Agency has identified residue testing for steroids as a priority. These compounds are used in aquaculture primarily to direct sexual differentiation with both androgens and estrogens applied depending on the desired outcome. Published research is lacking with respect to steroid residue testing in fish; however, recent studies in other matrixes provided transferable cleanup techniques. A simple, rapid, and sensitive method was developed and validated for use in monitoring aquacultured fish products for the presence of methyltestosterone, nandrolone, epi-nandrolone, boldenone, and epi-boldenone residues. The developed method consists of solvent extraction followed by cleanup using hexane and dual cartridge SPE with analysis by ultra-HPLC-MS/MS. The method is capable of detecting and confirming steroid residue levels ranging from 0.05 to 25 ng/g in salmon and tilapia, depending on the analyte. Recoveries ranged from 88 to 130% for the analytes. Instrument repeatability was less than 13% for all compounds, while intermediate precision ranged from 5 to 25% RSD. HorRat values were within acceptable ranges. PMID- 26025556 TI - The time course of explicit and implicit categorization. AB - Contemporary theory in cognitive neuroscience distinguishes, among the processes and utilities that serve categorization, explicit and implicit systems of category learning that learn, respectively, category rules by active hypothesis testing or adaptive behaviors by association and reinforcement. Little is known about the time course of categorization within these systems. Accordingly, the present experiments contrasted tasks that fostered explicit categorization (because they had a one-dimensional, rule-based solution) or implicit categorization (because they had a two-dimensional, information-integration solution). In Experiment 1, participants learned categories under unspeeded or speeded conditions. In Experiment 2, they applied previously trained category knowledge under unspeeded or speeded conditions. Speeded conditions selectively impaired implicit category learning and implicit mature categorization. These results illuminate the processing dynamics of explicit/implicit categorization. PMID- 26025557 TI - Human exposure to soil contaminants in subarctic Ontario, Canada. AB - BACKGROUND: Chemical contaminants in the Canadian subarctic present a health risk with exposures primarily occurring via the food consumption. OBJECTIVE: Characterization of soil contaminants is needed in northern Canada due to increased gardening and agricultural food security initiatives and the presence of known point sources of pollution. DESIGN: A field study was conducted in the western James Bay Region of Ontario, Canada, to examine the concentrations of polychlorinated biphenyls, dichlorodiphenyltrichloroethane and its metabolites (SigmaDDT), other organochlorines, and metals/metalloids in potentially contaminated agriculture sites. METHODS: Exposure pathways were assessed by comparing the estimated daily intake to acceptable daily intake values. Ninety soil samples were collected at random (grid sampling) from 3 plots (A, B, and C) in Fort Albany (on the mainland), subarctic Ontario, Canada. The contaminated soil samples were analysed by gas chromatography with an electron capture detector or inductively coupled plasma mass spectrometer. RESULTS: The range of SigmaDDT in 90 soil samples was below the limit of detection to 4.19 mg/kg. From the 3 soil plots analysed, Plot A had the highest SigmaDDT mean concentration of 1.12 mg/kg, followed by Plot B and Plot C which had 0.09 and 0.01 mg/kg, respectively. Concentrations of other organic contaminants and metals in the soil samples were below the limit of detection or found in low concentrations in all plots and did not present a human health risk. CONCLUSION: Exposure analyses showed that the human risk was below regulatory thresholds. However, the SigmaDDT concentration in Plot A exceeded soil guidelines set out by the Canadian Council of Ministers of the Environment of 0.7 mg/kg, and thus the land should not be used for agricultural or recreational purposes. Both Plots B and C were below threshold limits, and this land can be used for agricultural purposes. PMID- 26025558 TI - The Treatment of VIP Patients in Academic Teaching Settings: Applying the "Difficult Patient Framework" to Guide Therapeutic Response. PMID- 26025559 TI - Molecular Diversity and Gene Evolution of the Venom Arsenal of Terebridae Predatory Marine Snails. AB - Venom peptides from predatory organisms are a resource for investigating evolutionary processes such as adaptive radiation or diversification, and exemplify promising targets for biomedical drug development. Terebridae are an understudied lineage of conoidean snails, which also includes cone snails and turrids. Characterization of cone snail venom peptides, conotoxins, has revealed a cocktail of bioactive compounds used to investigate physiological cellular function, predator-prey interactions, and to develop novel therapeutics. However, venom diversity of other conoidean snails remains poorly understood. The present research applies a venomics approach to characterize novel terebrid venom peptides, teretoxins, from the venom gland transcriptomes of Triplostephanus anilis and Terebra subulata. Next-generation sequencing and de novo assembly identified 139 putative teretoxins that were analyzed for the presence of canonical peptide features as identified in conotoxins. To meet the challenges of de novo assembly, multiple approaches for cross validation of findings were performed to achieve reliable assemblies of venom duct transcriptomes and to obtain a robust portrait of Terebridae venom. Phylogenetic methodology was used to identify 14 teretoxin gene superfamilies for the first time, 13 of which are unique to the Terebridae. Additionally, basic local algorithm search tool homology-based searches to venom-related genes and posttranslational modification enzymes identified a convergence of certain venom proteins, such as actinoporin, commonly found in venoms. This research provides novel insights into venom evolution and recruitment in Conoidean predatory marine snails and identifies a plethora of terebrid venom peptides that can be used to investigate fundamental questions pertaining to gene evolution. PMID- 26025561 TI - Does It MEK a Difference? Understanding Immune Effects of Targeted Therapy. AB - BRAF inhibitor (BRAFi) treatment enhances antitumor immunity, but is associated with increased intratumoral PD-L1 expression. MEK inhibitors (MEKi) may alter T cell function; however, recent studies demonstrate preserved T-cell infiltrate during treatment with BRAFi/MEKi. These data have important implications for combining BRAFi/MEKi and checkpoint blockade in the treatment of melanoma. PMID- 26025562 TI - Changes in cognitive symptoms after a buspirone-melatonin combination treatment for Major Depressive Disorder. AB - Cognitive deficits are often associated with acute depressive episodes and contribute to the functional impairment seen in patients with Major Depressive Disorder (MDD). Many patients sustain residual cognitive deficits after treatment that may be independent of the core MDD disorder. We tracked changes in cognitive deficits relative to antidepressant treatment response using the patient self rated Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) during a 6-week, double-blind trial of a combination antidepressant treatment (buspirone 15 mg with melatonin-SR 3 mg) versus buspirone (15 mg) monotherapy versus placebo in MDD patients with acute depressive episodes. The CPFQ includes distinct cognitive and physical functioning dimension subscales. Treatment response was determined using the Inventory of Depressive Symptomatology (IDSc30). Treatment responders improved significantly more on the total CPFQ than non-responders (p < 0.0001) regardless of treatment assignment. The cognitive dimension of the CPFQ score favored the combination treatment over the other two groups (ANCOVA: p = 0.050). Among the treatment non-responders, the effect size for the CPFQ cognitive dimension was 0.603 favoring the combination treatment over the over two groups and 0.113 for the CPFQ physical dimension. These preliminary findings suggest that a combination of buspirone with melatonin may benefit cognitive function distinct from mood symptoms and that some aspects of cognition may be specific targets for treatment within a population of patients with MDD. PMID- 26025560 TI - Distinctive Genome Reduction Rates Revealed by Genomic Analyses of Two Coxiella Like Endosymbionts in Ticks. AB - Genome reduction is a hallmark of symbiotic genomes, and the rate and patterns of gene loss associated with this process have been investigated in several different symbiotic systems. However, in long-term host-associated coevolving symbiont clades, the genome size differences between strains are normally quite small and hence patterns of large-scale genome reduction can only be inferred from distant relatives. Here we present the complete genome of a Coxiella-like symbiont from Rhipicephalus turanicus ticks (CRt), and compare it with other genomes from the genus Coxiella in order to investigate the process of genome reduction in a genus consisting of intracellular host-associated bacteria with variable genome sizes. The 1.7-Mb CRt genome is larger than the genomes of most obligate mutualists but has a very low protein-coding content (48.5%) and an extremely high number of identifiable pseudogenes, indicating that it is currently undergoing genome reduction. Analysis of encoded functions suggests that CRt is an obligate tick mutualist, as indicated by the possible provisioning of the tick with biotin (B7), riboflavin (B2) and other cofactors, and by the loss of most genes involved in host cell interactions, such as secretion systems. Comparative analyses between CRt and the 2.5 times smaller genome of Coxiella from the lone star tick Amblyomma americanum (CLEAA) show that many of the same gene functions are lost and suggest that the large size difference might be due to a higher rate of genome evolution in CLEAA generated by the loss of the mismatch repair genes mutSL. Finally, sequence polymorphisms in the CRt population sampled from field collected ticks reveal up to one distinct strain variant per tick, and analyses of mutational patterns within the population suggest that selection might be acting on synonymous sites. The CRt genome is an extreme example of a symbiont genome caught in the act of genome reduction, and the comparison between CLEAA and CRt indicates that losses of particular genes early on in this process can potentially greatly influence the speed of this process. PMID- 26025563 TI - Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy. AB - CONTEXT: Prostate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of traditional short term markers of treatment response observed with chemotherapy and contemporary hormonal treatments. Therefore, it is essential that clinicians understand the mechanism of action of sipuleucel-T and how this can translate in the clinic. OBJECTIVE: This article aims to summarize the current knowledge of sipuleucel-T therapy and its effects in mCRPC. EVIDENCE ACQUISITION: Relevant publications describing sipuleucel-T clinical data and information relating to immunotherapies were identified. EVIDENCE SYNTHESIS: Treatment with sipuleucel-T extends survival, with side effects being usually mild or moderate and manageable within the outpatient setting. The long-term immune responses generated by sipuleucel-T correlate with a survival benefit. Sipuleucel-T shows a greater magnitude of clinical benefit when used in patients earlier in the mCRPC setting. CONCLUSIONS: Sipuleucel-T stimulates long-lived immune responses that translate into long-term clinical benefit. The treatment course (three infusions at weeks 0, 2, and 4) is associated with manageable side effects. Short-term markers of future benefit would be clinically useful, and information on effective treatment combinations or sequences is awaited. Sipuleucel-T treatment directs the patient's own immune system to target and remove prostate cancer cells and increases life expectancy. Patients whose cancer is less advanced generally have a more 'active' immune system and may benefit the most from this treatment. PMID- 26025564 TI - Local and systemic XAGE-1b-specific immunity in patients with lung adenocarcinoma. AB - XAGE-1b is a cancer/testis antigen aberrantly expressed in pulmonary adenocarcinoma. Systemic antibody and T cell responses have been demonstrated in adenocarcinoma patients, but so far, local antigen-specific immunity has not been reported. In this study, XAGE-1b expression by tumor cells as well as the presence of systemic and/or local XAGE-1b-specific immunity was assessed in peripheral blood, tumor tissue and tumor-draining lymph nodes of Caucasian patients with pulmonary adenocarcinoma. XAGE-1b protein expression was detected in 43.6% (17 of 39) of patients when at least two different parts of a resected tumor were assessed. In 20 patients, analysis of T cells isolated and expanded from the primary tumor and its draining lymph node demonstrated XAGE-1b-specific responses in two patients. XAGE-1b-specific immunoglobulin G antibodies were found in 3 of 40 patients. These three antibody-positive patients had also mounted a systemic T cell response to XAGE-1b, measured by proliferation, cytokine production and expression of T cell activation markers on peripheral blood mononuclear cells. The population of XAGE-1b-specific T cells comprised both CD4+ and CD8+ T cells secreting both type I and II cytokines. Epitope mapping showed that T cells predominantly targeted the N-terminal part of the XAGE-1b protein, while the B cell response was directed against the C-terminal domain. Our study for the first time provides evidence for the presence of XAGE 1b-specific T cells within adenocarcinoma tissue, which supports the concept that XAGE-1b acts as a genuine tumor antigen and, therefore, might form an attractive target for a vaccine-based approach of immunotherapy. PMID- 26025565 TI - Measures of follow-up in time-to-event studies: Why provide them and what should they be? AB - BACKGROUND/AIMS: There is some consensus among authors of reports of clinical studies that a measure of follow-up time is informative for the interpretation of the Kaplan-Meier estimate of the survivor function of the event time of interest. Previous authors have suggested that length of follow-up is important to report because the findings of a study should be extracted from the time frame in which most of the subjects have had the event or have remained under observation. This time frame is where the Kaplan-Meier estimate is most stable. This concept of stability is relative to the potential maximum information about the event time distribution contained in the sample; it is not relative to the true, population survivor function. A measure of stability is useful for the interpretation of an interim analysis in which an immature survivor function is presented. Our interest in this article lies in characterizing the unobserved, complete follow up Kaplan-Meier estimate based on the observed, partial follow-up estimate. Our focus is not on characterizing the true event time distribution relative to its estimate. The concept of stability has not been well-defined in the literature, which has led to inconsistency and lack of transparency across trials in their attempts to capture it through a variety of measures of follow-up. METHODS: We report the results of a survey of recent literature on cancer clinical trials and summarize whether follow-up is reported and if so, whether it is well-defined. We define commonly used measures of follow-up in clinical studies. RESULTS: We explain how each measure should be assessed to evaluate the stability of the Kaplan-Meier estimate for the event, and we identify relationships among measures. We propose a new measure that better conveys the desired information about the stability of the current Kaplan-Meier estimate relative to one based on complete follow-up. We apply the proposed measure to a meningioma study for illustration. CONCLUSION: It is useful for reports of clinical studies to supplement Kaplan-Meier estimates with quantitative assessments of the stability of those estimates relative to the potential follow-up of study participants. We justify the use of one commonly used measure, and we propose a new measure that most directly accomplishes this goal. PMID- 26025566 TI - Cooling rate of 9.4 degrees C in an hour in an avalanche victim. PMID- 26025567 TI - Is time to recurrence of ventricular fibrillation a constant? PMID- 26025568 TI - Reply to Letter: "Is time to recurrence of ventricular fibrillation a constant?". PMID- 26025569 TI - Development and validation of the Cerebral Performance Categories-Extended (CPC E). AB - BACKGROUND: Optimizing resuscitation efforts after cardiac arrest (CA) requires valid and reliable measurements of functional outcomes. The Cerebral Performance Category (CPC), the historical "gold" standard outcome measure post-CA, lacks psychometric validation. The purpose of this study was to establish the psychometric properties of a revised CPC: the CPC-Extended (CPC-E). METHODS: The study had two phases: We established content validity of the CPC-E by identifying existing domains in the CPC, by adding new domains following a literature review, and iterative input from a panel of CA and rehabilitation experts. We tested the CPC-E's feasibility, intra-rater (IR) reliability and inter-rater reliability (IRR) using retrospective reviews of the electronic medical records (EMR) and "in person" in-hospital administration. RESULTS: The CPC-E has 10 domains. For both IR and IRR record reviews, 5/10 domains had frequent missing data and in three instances, intraclass correlation coefficients (ICC) could not be calculated. Of the scores that could be calculated, ICC ranged from poor to high (n=30; 0.46 1.0) and poor to high (n=50; -0.16 to 0.93) for IR and IRR, respectively. No data were missing for the "in-person" IRR for the 10 domains and ICC ranged from good to excellent (n=26; 0.79-1.00). In-hospital and post-discharge domains were completed in under 7 min. CONCLUSIONS: The CPC-E is a valid and clinically feasible outcome measure for describing post-CA impairment and disability status. In-person hospital administration of the CPC-E yields more complete data and good to excellent inter-rater reliability compared to retrospective EMR review. PMID- 26025571 TI - Getting the algorithm right--Not as simple as linear or circular but a more complex matter. PMID- 26025570 TI - Post-discharge outcomes after resuscitation from out-of-hospital cardiac arrest: A ROC PRIMED substudy. AB - IMPORTANCE: Assessment of morbidity is an important component of evaluating interventions for patients with out-of-hospital cardiac arrest (OHCA). OBJECTIVE: We evaluated among survivors of OHCA cognition, functional status, health-related quality of life and depression as functions of patient and emergency medical services (EMS) factors. DESIGN: Prospective cohort sub-study of a randomized trial. SETTING: The parent trial studied two comparisons in persons with non traumatic OHCA treated by EMS personnel participating in the Resuscitation Outcomes Consortium. PARTICIPANTS: Consenting survivors to discharge. MAIN OUTCOME MEASURES: Telephone assessments up to 6 months after discharge included neurologic function (modified Rankin score, MRS), cognitive impairment (Adult Lifestyle and Function Mini Mental Status Examination, ALFI-MMSE), health-related quality of life (Health Utilities Index Mark 3, HUI3) and depression (Telephone Geriatric Depression Scale, T-GDS). RESULTS: Of 15,794 patients enrolled in the parent trial, 729 (56% of survivors) consented. About 644 respondents (88% of consented) completed >= 1 assessment. Likelihood of assessment was associated with baseline characteristics and study site. Most respondents had MRS <= 3 (82.7%), no cognitive impairment (82.7% ALFI-MMSE >= 17), no severe impairment in health (71.6%, HUI3 >= 0.7) and no depression (90.1% T-GDS<=10). Outcomes did not differ by trial intervention or time from hospital discharge. CONCLUSIONS AND RELEVANCE: The majority of patients in this large cohort who survived cardiac arrest and were interviewed had no, mild or moderate health impairment. Concern about poor quality of life is not a valid reason to abandon efforts to improve an EMS system's response to cardiac arrest. PMID- 26025572 TI - Diabetes mellitus and platelet reactivity in patients under prasugrel or ticagrelor treatment: an observational study. AB - BACKGROUND: The influence of diabetes mellitus (DM) on platelet reactivity (PR) in prasugrel or ticagrelor treated patients is not well studied. METHODS: In an observational study involving 777 patients with acute coronary syndrome undergoing percutaneous coronary intervention treated by either prasugrel 10 mg od (n = 315) or ticagrelor 90 mg bid (n = 462), platelet function was assessed using the VerifyNow P2Y12 function assay (in PRU) at one month post intrvention. RESULTS: In the overall population, ticagrelor and insulin-treated DM affected PR, with a decrease in log by 0.88 (corresponding to a 58 % decrease in PR) compared to prasugrel-treated patients (p < 0.001), and an increase in log by 0.26 (corresponding to a 30 % increase in PR) compared to non-diabetic patients (p = 0.01), respectively. PR in prasugrel-treated patients differed significantly by DM status: 70.0 (36.3-113.0) in non-diabetic vs 69.0 (44.5-115.3) in non insulin-treated diabetic vs 122.0 (69.0-161.0) in insulin-treated diabetic patients, p for trend = 0.01. No differences were observed in ticagrelor-treated patients. By multivariate analysis, in prasugrel-treated patients insulin-treated DM was the only factor predicting PR, with log of PR increased by 0.42 (corresponding to a 52 % increase in PR) compared to non-diabetic patients (p = 0.001). No factor was found to affect PR in ticagrelor-treated patients. CONCLUSIONS: Patients with insulin-treated DM treated with prasugrel post PCI have higher PR, than patients without DM or non insulin-treated diabetic patients treated with this drug. Ticagrelor treated patients have overall lower PR than patients on prasugrel, independent of DM status or insulin treatment. TRIAL REGISTRATION: Clinical Trials Gov. NCT01774955. PMID- 26025573 TI - Diverse patterns of stored water use among saplings in seasonally dry tropical forests. AB - Tree species in seasonally dry tropical forests likely vary in their drought survival mechanisms. Drought-deciduousness, which reduces water loss, and low wood density, which may permit dependence on stored water, are considered key traits. For saplings of six species at two distinct sites, we studied these and two associated traits: the seasonal amount of water released per stem volume ("water released") and the hydraulic capacitance of the stem (C). Two deciduous species with low stem density, Cavanillesia platanifolia and Bursera simaruba, had high C and high dry-season stem water potential (Psi(stem)), but differed in dry-season water released. C. platanifolia did not use stored water during the dry season whereas B. simaruba, in a drier forest, released stored water. In both, water released was highest while flushing leaves, suggesting that stored water supports leaf flushing. In contrast, two deciduous species with intermediate stem density, Annona hayesii and Genipa americana, had intermediate C, low dry-season Psi(stem), and high seasonal change in water released. Meanwhile, two evergreen species with intermediate stem density, Cojoba rufescens and Astronium graveolens, had relatively low C, low dry-season Psi(stem), and intermediate seasonal change in water released. Thus, at least three, distinct stored-water-use strategies were observed. Additionally, bark relative water content (RWC) decreased along with Psi(stem) during the dry season while xylem RWC did not change, suggesting that bark-stored water buffers Psi(stem) seasonally. Together these results suggest that seasonal use of stored water and change in Psi(stem) are associated with functional groups that are characterized by combinations of deciduousness and stem density. PMID- 26025574 TI - Herbivores with similar feeding modes interact through the induction of different plant responses. AB - Plants respond to attacks by herbivores with various defences, which are mounted through the activation of different biochemical pathways that are known to interact. Thus, the attack of a plant by one herbivore species may result in changes in the performances of other species on the same plant. It has been suggested that species with comparable feeding modes induce similar plant defences and such herbivores are therefore expected to have a negative effect on each other's performance. We studied two closely related phytophagous mite species with identical feeding modes. Yet, one of the species (Tetranychus urticae) induces tomato plant defences, whereas the other (T. evansi) reduces them. We found that the "inducing" species benefits from the downregulation of defences by the "reducing" species, which, in turn, suffers from the induction of defences by the inducing species. Moreover, the performances of the two mite species on leaves that were previously attacked by both species simultaneously were intermediate between that on leaves previously attacked by each of the mites separately. The activity of proteinase inhibitor, a defensive compound, was not found to be intermediate in leaves attacked by both species simultaneously--it was almost as high as the activity seen in leaves with defences induced by T. urticae. Oviposition rates of T. urticae showed a nonlinear correlation with inhibitor activity, suggesting that it is potentially problematic to use this activity as an indicator of the level of plant defence. Our results show that herbivores with similar feeding modes have opposite effects on plant defence and differentially affect each other's performance on co-infested plants. PMID- 26025575 TI - Feeding damage to plants increases with plant size across 21 Brassicaceae species. AB - Plant size is a major predictor of ecological functioning. We tested the hypothesis that feeding damage to plants increases with plant size, as the conspicuousness of large plants makes resource finding and colonisation easier. Further, large plants can be attractive to herbivores, as they offer greater amounts and ranges of resources and niches, but direct evidence from experiments testing size effects on feeding damage and consequently on plant fitness is so far missing. We established a common garden experiment with a plant size gradient (10-130 cm height) using 21 annual Brassicaceae species, and quantified plant size, biomass and number of all aboveground components (flowers, fruits, leaves, stems) and their proportional feeding damage. Plant reproductive fitness was measured using seed number, 1000 seed weight and total seed weight. Feeding damage to the different plant components increased with plant size or component biomass, with mean damage levels being approximately 30 % for flowers, 5 % for fruits and 1 % for leaves and stems. Feeding damage affected plant reproductive fitness depending on feeding damage type, with flower damage having the strongest effect, shown by greatly reduced seed number, 1000 seed weight and total seed weight. Finally, we found an overall negative effect of plant size on 1000 seed weight, but not on seed number and total seed weight. In conclusion, being conspicuous and attractive to herbivores causes greater flower damage leading to higher fitness costs for large plants, which might be partly counterbalanced by benefits such as enhanced competitive/compensatory abilities or more mutualistic pollinator visits. PMID- 26025576 TI - Context-dependent effects of feather corticosterone on growth rate and fledging success of wild passerine nestlings in heterogeneous habitat. AB - Life history theory seeks answers to questions about how suites of traits, like growth rate, body mass and survival, have coevolved to maximize the fitness of individuals. In stochastic environments, individual fitness may be closely linked to environmental conditions experienced early in life. When conditions deteriorate, animals have to adapt physiologically to avoid detrimental effects to growth and survival. Hormones such as glucocorticoids are potentially important mediators of developmental plasticity, although their function is quite poorly understood in free-living animals to date. In this study, we used brood size manipulation in wild great tits (Parus major) to see whether resource (e.g. food) availability can change feather corticosterone levels, somatic growth and fledging success in nestlings raised in habitats of different quality. Recent studies suggest that feather corticosterone offers a long-term hormonal measure for the main avian glucocorticoid by integrating the plasma levels of corticosterone over the whole nestling period. We showed that feather corticosterone, growth rate and fledging success were significantly affected by the treatment only in coniferous forests where growth conditions had a tendency to be poorer than in deciduous forests. We also found that feather corticosterone was negatively related to fledging success, and this effect was more pronounced in coniferous habitat. Our results suggest that feather corticosterone could offer an important physiological measure for nestling performance, mediated by a context-dependent developmental trade-off between immediate and future survival. PMID- 26025577 TI - Application of Computer-Aided Diagnosis to the Sonographic Evaluation of Cervical Lymph Nodes. AB - We initiated an observer study to evaluate a computerized system developed in our previous study for automatic extraction of 10 features and estimation of the malignancy probability of cervical nodes in sonograms. In the present study, five expert radiologists and five resident radiologists interpreted the sonograms of 178 nodes. The malignancy rating and patient management recommendation (biopsy or follow-up) were made without and then with the computer aid. Under these two reading conditions, the performances of radiologists and agreement among a group of radiologists were evaluated by using the receiver operating characteristic (ROC) analysis and the kappa statistic, respectively. With the computer aid, the performances of radiologists improved significantly, as indicated by the increase in the area under the ROC curve (Az) from 0.843 to 0.896 (p = 0.031) and from 0.705 to 0.822 (p < 0.001), for the expert and resident groups, respectively. Agreement among all 10 radiologists improved from slight to moderate as indicated by an increase in the kappa value from 0.195 to 0.421 (p < 0.001). The average performance of residents with aid (Az = 0.822) was close to that of experts without aid (Az = 0.843). Results indicate that computer-aided diagnosis is useful to improve radiologist performance (especially that of inexperienced radiologists) in the ultrasonographic evaluation of cervical nodes and to reduce variability among radiologists. PMID- 26025578 TI - Improved Correlation of Strain Indices with Cognitive Dysfunction with Inclusion of Adventitial Layer with Carotid Plaque. AB - Plaque instability may lead to chronic embolization, which in turn may contribute to progressive cognitive decline. Accumulated strain tensor indices over a cardiac cycle within a pulsating carotid plaque may be viable biomarkers for the diagnosis of plaque instability. Using plaque-only carotid artery segmentations, we recently demonstrated that impaired cognitive function correlated significantly with maximum axial and lateral strain indices within a localized region of interest in plaque. Inclusion of the adventitial layer focuses our strain or instability measures on the vessel wall-plaque interface hypothesized to be a region with increased shearing forces and measureable instability. A hierarchical block-matching motion tracking algorithm developed in our laboratory was used to estimate accumulated axial, lateral, and shear strain distribution in plaques identified with the plaque-with-adventitia segmentation. Correlations of strain indices to the Repeatable Battery for the Assessment of Neuropsychological Status Total score were performed and compared with previous results. Overall, correlation coefficients (r) and significance (p) values improved for axial, lateral, and shear strain indices. Shear strain indices, however, demonstrated the largest improvement. The Pearson correlation coefficients for maximum shear strain and cognition improved from the previous plaque-only analyses of -0.432 and -0.345 to -0.795 and -0.717 with the plaque-with-adventitia segmentation for the symptomatic group and for all patients combined, respectively. Our results demonstrate the advantage of including adventitia for ultrasound carotid strain imaging providing improved association to parameters assessing cognitive impairment in patients. This supports theories of the importance of the vessel wall plaque interface in the pathophysiology of embolic disease. PMID- 26025580 TI - Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact. AB - The role of the tight junctions (TJ) in controlling paracellular traffic of ions and molecules, through the regulation of claudin proteins, is now established. However, it has also become increasingly evident that claudin proteins, as integral components of the TJs, play crucial role in maintaining the cell-cell integrity. In conformity, deregulation of claudin expression and cellular distribution in cancer tissues has been widely documented and correlated with cancer progression and metastasis. However, this correlation is not unidirectional and rather suggests tissue specific regulations. Irrespective, if the widely described correlations between altered claudin expression and cancer initiation/progression could be established, they may serve as important markers for prognostic purposes and potential therapeutic targets. In this review, we summarize data from screening of the cancer tissues, manipulation of claudin expression in cells and animals subjected to cancer models, and how claudins are regulated in cancer. The focus of this article remains analysis of the association between cancer and the claudins and to decipher clinical relevance. PMID- 26025581 TI - Psoriasis. AB - Psoriasis is an immune-mediated, genetic disease manifesting in the skin or joints or both. A diverse team of clinicians with a range of expertise is often needed to treat the disease. Psoriasis provides many challenges including high prevalence, chronicity, disfiguration, disability, and associated comorbidity. Understanding the role of immune function in psoriasis and the interplay between the innate and adaptive immune system has helped to manage this complex disease, which affects patients far beyond the skin. In this Seminar, we highlight the clinical diversity of psoriasis and associated comorbid diseases. We describe recent developments in psoriasis epidemiology, pathogenesis, and genetics to better understand present trends in psoriasis management. Our key objective is to raise awareness of the complexity of this multifaceted disease, the potential of state-of-the-art therapeutic approaches, and the need for early diagnosis and comprehensive management of patients with psoriasis. PMID- 26025579 TI - Sulforaphane protects the heart from doxorubicin-induced toxicity. AB - Cardiotoxicity is one of the major side effects encountered during cancer chemotherapy with doxorubicin (DOX) and other anthracyclines. Previous studies have shown that oxidative stress caused by DOX is one of the primary mechanisms for its toxic effects on the heart. Since the redox-sensitive transcription factor, Nrf2, plays a major role in protecting cells from the toxic metabolites generated during oxidative stress, we examined the effects of the phytochemical sulforaphane (SFN), a potent Nrf2-activating agent, on DOX-induced cardiotoxicity. These studies were carried out both in vitro and in vivo using rat H9c2 cardiomyoblast cells and wild type 129/sv mice, and involved SFN pretreatment followed by SFN administration during DOX exposure. SFN treatment protected H9c2 cells from DOX cytotoxicity and also resulted in restored cardiac function and a significant reduction in DOX-induced cardiomyopathy and mortality in mice. Specificity of SFN induction of Nrf2 and protection of H9c2 cells was demonstrated in Nrf2 knockdown experiments. Cardiac accumulation of 4 hydroxynonenal (4-HNE) protein adducts, due to lipid peroxidation following DOX induced oxidative stress, was significantly attenuated by SFN treatment. The respiratory function of cardiac mitochondria isolated from mice exposed to DOX alone was repressed, while SFN treatment with DOX significantly elevated mitochondrial respiratory complex activities. Co-administration of SFN reversed the DOX-associated reduction in nuclear Nrf2 binding activity and restored cardiac expression of Nrf2-regulated genes at both the RNA and protein levels. Together, our results demonstrate for the first time that the Nrf2 inducer, SFN, has the potential to provide protection against DOX-mediated cardiotoxicity. PMID- 26025582 TI - Student paramedic experience of transition into the workforce: A scoping review. AB - OBJECTIVES: In this article we present the findings from a scoping review that sought to identify what is known about the experiences of paramedic students transitioning into the workforce. BACKGROUND: Within the emergency healthcare sector, paramedics are primarily tasked with the assessment, treatment and safe transport of patients to hospital. New paramedics entering the workforce are exposed to the full extent of human emotion, injury and suffering as part of their everyday work. There is evidence from other healthcare disciplines that the transition to practice period can be difficult for new graduates. METHODS: We utilised Arksey and O'Malley's five-stage scoping review framework to identify what is known about the transition of paramedicine graduates to the workplace. The framework involves identifying relevant studies; study selection; charting the data; and collating, summarizing and reporting results. RESULTS: We identified eleven articles that explored transition of newly qualified paramedics. Thematic content was identified and discussed into four separate categories. Each theme revealing the emotional, physical and social impacts new paramedics face as they strive to find acceptance in a new workplace and culture. CONCLUSION: Given the significant role that paramedics have in modern healthcare, the transition from student to practitioner is a period of significant stress to the new paramedic. Limited research in this field though inhibits a thorough understanding of these issues. PMID- 26025583 TI - Accelerated carbonation using municipal solid waste incinerator bottom ash and cold-rolling wastewater: Performance evaluation and reaction kinetics. AB - Accelerated carbonation of alkaline wastes including municipal solid waste incinerator bottom ash (MSWI-BA) and the cold-rolling wastewater (CRW) was investigated for carbon dioxide (CO2) fixation under different operating conditions, i.e., reaction time, CO2 concentration, liquid-to-solid ratio, particle size, and CO2 flow rate. The MSWI-BA before and after carbonation process were analyzed by the thermogravimetry and differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy equipped with energy dispersive X-ray spectroscopy. The MSWI-BA exhibits a high carbonation conversion of 90.7%, corresponding to a CO2 fixation capacity of 102g perkg of ash. Meanwhile, the carbonation kinetics was evaluated by the shrinking core model. In addition, the effect of different operating parameters on carbonation conversion of MSWI-BA was statistically evaluated by response surface methodology (RSM) using experimental data to predict the maximum carbonation conversion. Furthermore, the amount of CO2 reduction and energy consumption for operating the proposed process in refuse incinerator were estimated. Capsule abstract: CO2 fixation process by alkaline wastes including bottom ash and cold-rolling wastewater was developed, which should be a viable method due to high conversion. PMID- 26025584 TI - Isolated Jejunal Crohn's Disease in an Adolescent Girl. PMID- 26025585 TI - Measuring psoriatic disease in clinical practice. An expert opinion position paper. AB - Psoriasis is a common, immune-mediated chronic inflammatory disease with a primary involvement of skin and joints, affecting approximately 2% of the population worldwide. Up to one third of patients with psoriasis are diagnosed with psoriatic arthritis (PsA). Psoriasis and PsA are heterogeneous diseases whose severity depends on a number of clinical factors, such as areas affected and pattern of involvement, and are associated with a range of comorbid diseases and risk factors, including obesity, metabolic syndrome, cardiovascular disease and liver disease. Thus measuring the severity of psoriatic disease needs to take into account the multidimensional aspects of the disease. Subjective measures including the impairment in quality of life or in daily living activities as well as the presence of cardio-metabolic comorbidities, are important for the outcome and add further levels of complexity that, to a certain extent, need to be assessed. Because of the wide range of comorbid conditions associated with psoriasis, comprehensive screening and treatment must be implemented for a most effective managing of psoriasis patients. A joint dermatologist-rheumatologist roundtable discussion was convened to share evidence on the real-life use of methods for measuring psoriasis severity comprehensively. Our objective was to provide an expert position on which clinical variables are to be taken into account when considering patients affected by psoriasis and/or PsA globally and on the assessment tools more suitable for measuring disease activity and/or severity in clinical practice. PMID- 26025586 TI - Antimicrobial peptide dendrimer interacts with phosphocholine membranes in a fluidity dependent manner: A neutron reflection study combined with molecular dynamics simulations. AB - The interaction mechanism of a novel amphiphilic antimicrobial peptide dendrimer, BALY, with model lipid bilayers was explored through a combination of neutron reflection and molecular dynamics simulations. 1-Palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phos-phocholine (DPPC) lipid bilayers were examined at room temperature to extract information on the interaction of BALY with fluid and gel phases, respectively. Furthermore, a 1:4 mixture of POPC and DPPC was used as a model of a phase-separated membrane. Upon interaction with fluid membranes, BALY inserted in the distal leaflet and caused thinning and disordering of the headgroups. Membrane thinning and expansion of the lipid cross-sectional area were observed for gel phase membranes, also with limited insertion to the distal leaflet. However, dendrimer insertion through the entire lipid tail region was observed upon crossing the lipid phase transition temperature of DPPC and in phase separated membranes. The results show clear differences in the interaction mechanism of the dendrimer depending on the lipid membrane fluidity, and suggest a role for lipid phase separation in promoting its antimicrobial activity. PMID- 26025587 TI - Structural features and dynamic investigations of the membrane-bound cytochrome P450 17A1. AB - Cytochrome P450 (CYP) 17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones. The enzyme is an important target for treatment of breast and prostate cancers that proliferate in response to estrogens and androgens. Despite the crystallographic structures available for CYP17A1, no membrane-bound structural features of this enzyme at atomic level are available. Accumulating evidence has indicated that the interactions between bounded CYPs and membrane could contribute to the recruitment of lipophilic substrates. To this end, we have investigated the effects on structural characteristics in the presence of the membrane for CYP17A1. The MD simulation results demonstrate a spontaneous insertion process of the enzyme to the lipid. Two predominant modes of CYP17A1 in the membrane are captured, characterized by the depths of insertion and orientations of the enzyme to the membrane surface. The measured heme tilt angles show good consistence with experimental data, thereby verifying the validity of the structural models. Moreover, conformational changes induced by the membrane might have impact on the accessibility of the active site to lipophilic substrates. The dynamics of internal aromatic gate formed by Trp220 and Phe224 are suggested to regulate tunnel opening motions. The knowledge of the membrane binding characteristics could guide future experimental and computational works on membrane-bound CYPs so that various investigations of CYPs in their natural, lipid environment rather than in artificially solubilized forms may be achieved. PMID- 26025588 TI - Binding structure and kinetics of surfactin monolayer formed at the air/water interface to counterions: A molecular dynamics simulation study. AB - The binding structure and kinetics of ionized surfactin monolayer formed at the air/water interface to five counterions, Li+, Na+, K+, Ca2+, and Ba2+ (molar ratios of surfactin to monovalent and divalent counterions are 1:2 and 1:1 respectively), have been studied using molecular dynamics simulation. The results show that surfactin exhibits higher binding affinity to divalent counterions, Ca2+, and Ba2+, and smaller monovalent counterion, Li+, than Na+ and K+. Both carboxyl groups in surfactin are accessible for counterions, but the carboxyl group in Glu1 is easier to access by counterions than Asp5. Salt bridges are widely built between carboxyl groups by counterions, and the probability of the formation of intermolecular salt bridge is markedly larger than that of intramolecular salt bridge. Divalent counterions perform well in forming salt bridges between carboxyl groups. The salt bridges mediated by Ca2+ are so rigid that the lifetimes are about 0.13 ns, and the break rates of these salt bridges are 1-2 orders of magnitude smaller than those mediated by K+ which is about 5 ps in duration. The positions of the hydration layer of carboxyl groups are independent of counterions, but the bound counterions induce the dehydration of carboxyl groups and disturb the hydrogen bonds built between carboxyl group and hydration water. PMID- 26025589 TI - Catalytic oxidation of carbon nanotubes with noble metal nanoparticles. AB - Catalytic oxidation of multi-walled carbon nanotubes (MWNCTs) with some noble metal nanoparticles was observed by environmental transmission electron microscopy (E-TEM). Amoeba-like movement of the nanoparticles was observed even at a temperature of ~400 degrees C, which is much lower than the melting points of any of the metals. In particular, rhodium particles reacted intensely with MWCNTs, and assumed a droplet-like shape. On the other hand, gold particles caused very little erosion of the MWCNTs under the conditions of this study. PMID- 26025590 TI - Acupuncture-brain interactions as hypothesized by mood scale recordings. AB - Mood expressions encompassing positive scales like "activity, elation, contemplation, calmness" and negative scales like "anger, excitement, depression, fatigue" were applied for introducing a new tool to assess the effects of acupuncture on brain structures. Traditional acupuncture points defined in the literature for their effects on task negative and task positive brain structures were applied to chronic disease patients supposed to have dominant negative mood scales. Burn-out syndrome (n=10) and female chronic pain patients (n=22) showed a significant improvement on positive mood scales and a decline in negative mood scales after 10 acupuncture sessions. We observed a direct effect of acupuncture on brain structures in 5 burn-out syndrome patients showing an immediate, fast suppression of unusual slow high amplitude EEG waves in response to acupuncture needle rotation. These EEG waves described here for the first time in awake patients disappeared after 10 sessions but gradually returned after 1-1.5 years without acupuncture. This was accompanied with deterioration of positive mood scales and a return to negative mood scales. Both male (n=16) and female chronic pain patients reported a significant decrease of pain intensity after 10 sessions. Female patients only, however, showed a linear correlation between initial pain intensity and pain relief as well as a linear correlation between changes in pain intensity and mood scales accompanied by a drop of their heart rate during the acupuncture sessions. We hypothesized that mood scale recordings are a sensitive and specific new tool to reveal individual acupuncture-brain interaction. PMID- 26025591 TI - High prevalence of vitamin D deficiency and cancer in Saudi Arabian populations: Can we hypothesize a link? AB - Inspite of having so much sunshine, Saudi Arabian population is suffering from the deficiency of the 'sunshine vitamin', vitamin D, measured in the serum as 25 OHD level. According to a recent report, about 83.6% of Saudi population is vitamin D deficient. 31.9% have severe, 32% have moderate and 19.7% have mild vitamin D deficiency (VDD). The severity of VDD differs with age, gender and region. Females are more severely vitamin D deficient than males. Various factors contributing towards it deficiency are linked to their housing designs, religious practices, lifestyle choices and dark skin color. The increasing incidences of breast, prostate and colon cancer among this society are also raising an alarm. The presence of vitamin D receptor (VDR) and the enzyme responsible for conversion of the 25(OH)D in its active metabolite 25(OH)2D3 in extra renal tissue shows the involvement of vitamin D in other diseases like cancer, diabetes, multiple sclerosis etc. About 2000 genes related to various types of diseases are found to be regulated by VDRs. These genes possess vitamin D responsive elements (VDREs) in their promoters. Studies on population of other regions also have shown correlation with low serum levels of 25(OH)D and certain diseases So, we hypothesized that vitamin D deficiencies might cause a higher prevalence of these diseases in the Kingdom. PMID- 26025592 TI - Association between ventricular arrhythmias and myocardial mechanical dispersion assessed by strain analysis in patients with nonischemic cardiomyopathy. AB - BACKGROUND: Mechanical dispersion (MD), defined as the standard deviation of time to maximum myocardial shortening assessed by 2D speckle tracking echocardiographic strain imaging (2DS), has been recently proposed as a predictor for ventricular tachycardia or fibrillation (VT/VF) in patients with ischemic cardiomyopathy and long QT syndrome. However, the role of MD in patients with non ischemic cardiomyopathy (NICM) has not yet been studied. METHODS AND RESULTS: In 20 patients with NICM (mean age 62 +/- 11 years, 75 % male, mean EF 32 +/- 6 %, mean QRS duration 102 +/- 14 ms), we measured longitudinal strain by 2DS in a 16 segment left ventricular model and calculated the MD. Patients were divided into two groups, defined by the presence or absence of documented VT/VF. In 11 patients (55 %), VT/VF was documented. The median time from VT/VF to echocardiographic examination was 26 (IQR 15-58) months. There were no significant differences in baseline characteristics between patients with and without index events. MD was significantly greater in patients with VT/VF as compared to those without arrhythmias (84 +/- 31 ms vs. 53 +/- 16 ms, p = 0.017). The analysis of the ROC curve (AUC 0.81, 95 % CI 0.63-1.00, p = 0.017) revealed that dispersion >50 ms is associated with twelve times higher risk of VT/VF in patients with NICM (OR 12.5, 95 % CI 1.1-143.4, p = 0.024). CONCLUSIONS: In this small cohort of NICM patients, greater MD was associated with a higher incidence of VT/VF. PMID- 26025594 TI - The role of leptin in the pathophysiology of rheumatoid arthritis. AB - The past 20 years of research on leptin has provided important insights into its role in rheumatoid arthritis (RA). Leptin is one of the different adipokines produced by the adipose tissue that influences the endocrine system, energy homeostasis and the immune response in several ways. Leptin is known to have predominantly pro-inflammatory effects, especially in the setting of chronic inflammation. Animal models of arthritis have illustrated well the participation of leptin in the inflammatory response within the joints. In patients with RA, numerous studies have evaluated the concentrations of leptin in the bloodstream and/or the joint cavity, showing higher levels compared to control populations. Leptin has also been found to correlate with clinical or biological measurements of disease activity of RA. Conversely, the relationship between serum leptin and joint structural damage is less evident. Leptin may also promote the development of atherosclerosis in RA and may contribute to the cardiovascular consequences of the metabolic syndrome that coexists with RA. Indeed, leptin could be a link between inflammation, metabolic risk factors and cardiovascular diseases in RA. Finally, due to abnormal body composition phenotypes with an increased prevalence of obesity in RA, the therapeutic response to traditional DMARDs and/or biological agents may be attenuated. This review discusses the multiple interplays that have been described between leptin and the clinical, radiographic and therapeutic aspects of RA. PMID- 26025595 TI - Concomitant coronary artery bypass graft and aortic and mitral valve replacement for rheumatic heart disease: short- and mid-term outcomes. AB - OBJECTIVES: It has been reported that the short-term mortality of concomitant aortic and mitral valve replacement (AVR and MVR) is considerable and concomitant coronary artery bypass graft (CABG) has adverse effects on the survival of patients with valve replacement surgery. We summarize the short- and mid-term outcome after concomitant CABG, AVR and MVR in our centre. METHODS: Between 2003 and 2013, 103 patients (68 males, 35 females, age: 60.1 +/- 10.1 years) underwent CABG, AVR and MVR for rheumatic heart disease (RHD) and coronary artery disease (CAD). The median follow-up was 47.6 months. Most of the patients were asymptomatic at rest. We analysed demographic, clinical and operative data of patients to define independent predictors of overall survival, cardiac event-free survival as well as cardiac death. RESULTS: The rate of 30-day survival was 93% (n = 96). The corresponding rates of overall survival and cardiac event-free survival and the cumulative incidence rate of cardiac death at 1 year were 80.2, 77.3 and 10.9%; the same at 4 years were 73.7, 64.6 and 15.8%. The corresponding freedom rates from anticoagulation-associated major haemorrhage; a composite of major bleeding events, thromboemboli and valvular thrombosis; cardiac rehospitalization; major adverse valve-associated events; and significant malfunction of the prosthetic valve were 96.2, 95.3, 94.7, 81.6 and 97.7% at 1 year. The corresponding freedom rates from anticoagulation-associated major haemorrhage; a composite of major bleeding events, thromboemboli and valvular thrombosis; cardiac rehospitalization; major adverse valve-associated events; and significant malfunction of the prosthetic valve were 93.5, 91.0, 91.4, 73.5 and 95.5% at 4 years. The independent predictors of overall survival were age, cigarette smoking, chronic kidney diseases and balloon pump insertion. The independent predictors of cardiac event-free survival were age and previous myocardial infarction, while age, cigarette smoking, history of cerebrovascular accident and balloon pump insertion were the independent predictors of cardiac death. CONCLUSIONS: Concomitant CABG, AVR and MVR for rheumatic heart disease accompanied by CAD appear to have acceptable short- and mid-term outcomes with symptomatic amelioration. PMID- 26025596 TI - Development and application of single-tube multiplex real-time PCR for lineage classification of Mycobacterium tuberculosis based on large sequence polymorphism in Northeast Thailand. AB - An appreciation of the genetic diversity of Mycobacterium tuberculosis (Mtb) is needed for effective planning of strategies in tuberculosis (TB) control. Large sequence polymorphisms (LSPs) are the molecular epidemiological and evolutionary markers for classification of Mtb into East Asian (EA) or Beijing, Indo-Oceanic (IO), Euro-American (EuA) and East African-Indian (EAI) lineages. We aimed to develop a single-tube multiplex real-time PCR assay using melting curve analysis for lineage classification of Mtb based on LSPs. The technique was optimized and tested with well-characterized strains (n = 89). The developed technique was then applied to classify Mtb isolates from TB patients (n = 256) randomly recruited from 19 provinces covering Northeast Thailand in 2013-2014. The technique demonstrated 100% sensitivity and specificity based on well-characterized strains compared to conventional techniques. The detection limit of the technique is 0.05 ng of genomic DNA of Mtb. The 256 Mtb isolates represented IO (n = 178, 70%), Beijing (n = 60, 23%) and EuA (n = 18, 7%) lineages. Significant associations of the Beijing lineage with drug resistance (p < 0.001) and younger average age of TB patients (p < 0.001) compared to other lineages were shown. The single-tube multiplex real-time PCR technique provides a simple, rapid and high performance tool for characterizing Mtb based on LSPs. PMID- 26025598 TI - Binding energies of tyrosine kinase inhibitors: Error assessment of computational methods for imatinib and nilotinib binding. AB - The binding energies of imatinib and nilotinib to tyrosine kinase have been determined by quantum mechanical (QM) computations, and compared with literature binding energy studies using molecular mechanics (MM). The potential errors in the computational methods include these critical factors. Errors in X-ray structures such as structural distortions and steric clashes give unrealistically high van der Waals energies, and erroneous binding energies.MM optimization gives a very different configuration to the QM optimization for nilotinib, whereas the imatinib ion gives similar configurations. Solvation energies are a major component of the overall binding energy. The QM based solvent model (PCM/SMD) gives different values from those used in the implicit PBSA solvent MM models. A major error in inhibitor-kinase binding lies in the non-polar solvation terms. Solvent transfer free energies and the required empirical solvent accessible surface area factors for nilotinib and imatinib ion to give the transfer free energies have been reverse calculated. These values differ from those used in the MM PBSA studies.An intertwined desolvation-conformational binding selectivity process is a balance of thermodynamic desolvation and intramolecular conformational kinetic control.The configurational entropies (TDeltaS) are minor error sources. PMID- 26025597 TI - A real-time PCR signature to discriminate between tuberculosis and other pulmonary diseases. AB - The goal of this study was to identify a host gene signature that can distinguish tuberculosis (TB) from other pulmonary diseases (OPD). We conducted real-time PCR on whole blood samples from patients in Brazil. TB and OPD patients (asthma and non-TB pneumonia) differentially expressed granzyme A (GZMA), guanylate binding protein 5 (GBP5) and Fc gamma receptor 1A (CD64). Receiver operating characteristic, tree classification and random forest analyses were applied to evaluate the discriminatory power of the three genes and find the gene panel most predictive of patients' disease classification. Tree classification produced a model based on GBP5 and CD64 expression. In random forest analysis, the combination of the three genes provided a robust biosignature to distinguish TB from OPD with 95% specificity and 93% sensitivity. Our results suggest that GBP5 and CD64 in tandem may be the most predictive combination. However, GZMA contribution to the prediction model requires further investigation. Regardless, these three genes show promise as a rapid diagnostic marker separating TB from OPD. PMID- 26025599 TI - A systematic study on the effect of substrate acidification degree and acidogenic biomass on sludge filterability. AB - The influence of substrate acidification on sludge filtration characteristics was systematically investigated by using short term filtration tests. Four reactors were operated with raw and acidified whey permeate in order to evaluate the effect of acidogens on sludge filterability. The results showed that feeding non acidified substrate promoted the growth of acidogens which in return decreased the median particle size of the sludge and adversely influenced specific resistance to filtration (SRF). In addition to the presence of acidogens, the food to mass (F:M) ratio was found as an important operation parameter on sludge filterability. Various filterability indicators, such as capillary suction time (CST), SRF and supernatant filterability, tended to became worse at increased F:M ratios. The decreased filterability at high F:M ratio was attributed to the accumulation of soluble microbial products (SMP) in the reactors. Interestingly, impact of acidogens on short term critical flux tests was not significant, but this may be a consequence of the experimental set-up. PMID- 26025600 TI - Evaluation of solar sludge drying alternatives by costs and area requirements. AB - Thermal drying is a common method to reach above 90% dry solids content (DS) in sludge. However, thermal drying requires high amount of energy and can be expensive. A greenhouse solar dryer (GSD) can be a cost-effective substitute if the drying performance, which is typically 70% DS, can be increased by additional heat. In this study feasibility of GSD supported with solar panels is evaluated as an alternative to thermal dryers to reach 90% DS. Evaluations are based on capital and O&M costs as well as area requirements for 37 wastewater treatment plants (WWTPs) with various sludge production rates. Costs for the supported GSD system are compared to that of conventional and co-generation thermal dryers. To calculate the optimal costs associated with the drying system, an optimization model was developed in which area limitation was a constraint. Results showed that total cost was minimum when the DS in the GSD (DS(m,i)) was equal to the maximum attainable value (70% DS). On average, 58% of the total cost and 38% of total required area were associated with the GSD. Variations in costs for 37 WWTPs were due to differences in initial DS (DS(i,i)) and sludge production rates, indicating the importance of dewatering to lower drying costs. For large plants, GSD supported with solar panels provided savings in total costs especially in long term when compared to conventional and co-generation thermal dryers. PMID- 26025601 TI - Substrate-immobilized electrospun TiO2 nanofibers for photocatalytic degradation of pharmaceuticals: The effects of pH and dissolved organic matter characteristics. AB - A substrate-immobilized (SI) TiO2 nanofiber (NF) photocatalyst for multiple uses was prepared through electrospinning and hot pressing. The rate of furfuryl alcohol degradation under UV irradiation was found to be the highest when the anatase to rutile ratio was 70:30; the rate did not linearly increase as a function of the NF film thickness, mainly due to diffusion limitation. Even after eight repeated cycles, it showed only a marginal reduction in the photocatalytic activity for the degradation of cimetidine. The effects of pH and different organic matter characteristics on the photodegradation of cimetidine (CMT), propranolol (PRP), and carbamazepine (CBZ) were investigated. The pH-dependence of the photocatalytic degradation rates of PRP was explained by electrostatic interactions between the selected compounds and the surface of TiO2 NFs. The degradation rates of CMT showed the following order: deionized water > l-tyrosine > secondary wastewater effluent (effluent organic matter) > Suwannee River natural organic matter, demonstrating that the characteristics of the dissolved organic matter (DOM) can affect the photodegradation of CMT. Photodegradation of CBZ was affected by the presence of DOM, and no significant change was observed between different DOM characteristics. These findings suggest that the removal of CMT, PRP, and CBZ during photocatalytic oxidation using SI TiO2 NFs is affected by the presence of DOM and/or pH, which should be importantly considered for practical applications. PMID- 26025602 TI - Thick heel pads. PMID- 26025607 TI - Impact of family history of alcoholism on glutamine/glutamate ratio in anterior cingulate cortex in substance-naive adolescents. AB - Neuroimaging studies of individuals with family histories of alcoholism provide evidence suggesting neurobiological risk factors for alcoholism. Youth family history positive (FH+) for alcoholism exhibit increased impulsivity compared to family history negative (FH-) peers in conjunction with altered functional activation in prefrontal cortex, including anterior cingulate cortex (ACC). This study examined glutamate (Glu) and glutamine (Gln), amino acids vital to protein synthesis, cellular metabolism and neurotransmission, acquired from ACC and parieto-occipital cortex (POC) using magnetic resonance spectroscopy (MRS) at 4T. Participants were 28 adolescents (13 male, 12-14 yrs) and 31 emerging adults (16 male, 18-25 yrs), stratified into FH- and FH+ groups. Significantly higher ACC Gln/Glu was observed in emerging adults versus adolescents in FH- but not FH+ groups. In FH- adolescents, higher impulsivity was significantly associated with higher ACC Gln/Glu. In FH+ emerging adults, higher impulsivity was negatively associated with ACC Gln/Glu. No differences or associations were observed for POC. These findings provide preliminary evidence that family history of alcoholism is associated with a neurochemical profile that may influence normative age differences in glutamatergic metabolites and their association with impulse control, which together could confer greater genetic risk of addiction later in life. PMID- 26025609 TI - TPX2 Level Correlates with Hepatocellular Carcinoma Cell Proliferation, Apoptosis, and EMT. AB - BACKGROUND: Targeting protein for Xklp2 (TPX2) is a microtubule-associated protein involved in targeting the motor protein Xklp2 to microtubules. TPX2 overexpression plays a key role in the progression of human cancers. But the underlying mechanism remains unclear. AIMS: This study aimed to investigate the effects and mechanisms of TPX2 on the cell cycle, apoptosis, and epithelial mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). METHODS: The tissue TPX2 mRNA and protein were assessed by quantitative reverse transcriptase PCR and immunoblot. Cell proliferation, cell cycle, apoptosis, and invasion were determined by CCK-8, FACS, TdT-UTP nick end-labeling, and transwell assays. Immunoblotting was performed to detect the expression of target proteins. RESULTS: TPX2 was highly expressed in tumor tissues compared with non-tumoral tissues, and TPX2 overexpression was positively correlated with poor prognosis. Knockdown TPX2 effectively reduced cell growth, G2/M arrest, induced apoptosis and cell death, and inhibited EMT. Mechanistically, in the TPX2-siRNA-treated groups, cell-cycle-related proteins cyclin A1, cyclin B1, cyclin E1, and cdk4 were up-regulated, while cyclin D1, cdk2, and p21 proteins were down-regulated. Cell-apoptosis-related proteins Bax, p53, caspase-3, and caspase-8 levels were increased. EMT-related proteins E-cadherin was up-regulated, while N-cadherin, beta-catenin, MMP-9, MMP-2, and Slug were down-regulated. We also found that knockdown TPX2 in HCC cell lines caused a significant decrease in the level of p Akt and p-ERK which are important signaling pathways in tumor formation. CONCLUSIONS: TPX2 expression is associated with proliferation, apoptosis, and EMT in hepatocellular carcinoma cell and patients. PMID- 26025610 TI - Effects of body weight unloading on electromyographic activity during overground walking. AB - BACKGROUND: Body weight unloading (BWU) on treadmills is a common method of gait rehabilitation. However, treadmills slightly but significantly modify gait biomechanical parameters thus confound the effects of BWU. By conducting our experiments under conditions that replicate daily walking and controlling for speed variability, with a mechanical device designed to pull the BWU system at a constant speed, this study could assess the unique effects of BWU on gait electromyography (EMG) of healthy subjects. METHODS: Fifteen healthy subjects walked overground in a control (no suspension vest) and three (0%, 15%, 30%) BWU experimental conditions. The EMG activity of the Tibialis Anterior (TA), Lateral Gastrocnemius (LG), Vastus Lateralis (VL), and Rectus Femoris (RF) were recorded (six trials per condition). RESULTS: ANOVA showed significant differences in the peak activity and integrated EMG of the TA, LG and VL. Pairwise comparisons of EMG parameters under 0% vs. 15% and 15% vs. 30% BWU levels showed that the increase in BWU levels decreased the peak and integrated EMG of the TA, LG, and VL without pattern modification. CONCLUSION: Overground gait with up to 30% BWU reduces joint loads without modifying the muscle activation patterns. Several clinical applications for overground gait reeducation with BWU are suggested. PMID- 26025608 TI - Elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork. AB - Rodents are increasingly being used as glaucoma models to study ocular hypertension, optic neuropathy, and retinopathy. A number of different techniques are used to elevate intraocular pressure in rodent eyes by artificially obstructing the aqueous outflow pathway. Another successful technique to induce ocular hypertension is to transduce the trabecular meshwork of rodent eyes with viral vectors expressing glaucoma associated transgenes to provide more relevant models of glaucomatous damage to the trabecular meshwork. This technique has been used to validate newly discovered glaucoma pathogenesis pathways as well as to develop rodent models of primary open angle glaucoma. Ocular hypertension has successfully been induced by adenovirus 5 mediated delivery of mutant MYOC, bioactivated TGFbeta2, SFRP1, DKK1, GREM1, and CD44. Advantages of this approach are: selective tropism for the trabecular meshwork, the ability to use numerous mouse strains, and the relatively rapid onset of IOP elevation. Disadvantages include mild-to-moderate ocular inflammation induced by the Ad5 vector and sometimes transient transgene expression. Current efforts are focused at discovering less immunogenic viral vectors that have tropism for the trabecular meshwork and drive sufficient transgene expression to induce ocular hypertension. This viral vector approach allows rapid proof of concept studies to study glaucomatous damage to the trabecular meshwork without the expensive and time consuming generation of transgenic mouse lines. PMID- 26025611 TI - Mediastinal paraganglioma. AB - We present a case of mediastinal paraganglioma with radiologic-pathologic correlation. A 48-year-old woman was found incidentally to have a middle mediastinal mass on CT. The mass showed iso-signal intensity compared to that of muscle on T1-weighted images and high signal intensity on T2-weighted images. The lesion showed intermediate intensity on diffusion-weighted imaging, and its apparent diffusion coefficient was 1.72 * 10(-3) mm(2)/s. A contrast-enhanced dynamic study revealed a rapid peak and washout enhancement pattern. (18)F-FDG PET revealed abnormal uptake in the mediastinal tumor with a maximal standardized uptake value of 7.88. (123)I-meta-iodobenzylguanidine scintigraphy also showed abnormal uptake in the tumor. These findings corresponded to the hypervascularity, rich stroma, low nuclear/cytoplasmic ratio, and nest-forming proliferation of tumor cells with positive neuroendocrine markers. PMID- 26025612 TI - Motion sickness is associated with an increase in vestibular modulation of skin but not muscle sympathetic nerve activity. AB - We have previously shown that sinusoidal galvanic vestibular stimulation (sGVS), delivered bilaterally at frequencies of 0.08-2.00 Hz, causes a pronounced modulation of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA), together with robust frequency-dependent illusions of side-to side motion. At low frequencies of sGVS (<=0.2 Hz), some subjects report nausea, so we tested the hypothesis that vestibular modulation of MSNA and SSNA is augmented in individuals reporting nausea. MSNA was recorded via tungsten microelectrodes inserted into the left common peroneal nerve in 22 awake, seated subjects; SSNA was recorded in 14 subjects. Bipolar binaural sGVS (+/-2 mA, 100 cycles) was applied to the mastoid processes at 0.08, 0.13, and 0.18 Hz. Nausea was reported by 21 out of 36 subjects (58 %), but across frequencies of sGVS there was no difference in the magnitude of the vestibular modulation of MSNA in subjects who reported nausea (27.1 +/- 1.8 %) and those who did not (30.4 +/- 2.9 %). This contrasts with the significantly greater vestibular modulation of SSNA with nausea (41.1 +/- 2.0 vs. 28.7 +/- 3.1 %) and indicates an organ-specific modulation of sympathetic outflow via the vestibular system during motion sickness. PMID- 26025613 TI - Temporal profile of the effects of regional anesthesia on the cutaneous reflexes of foot muscles. AB - We analyzed the effects of an anesthetic sciatic nerve block on the cutaneomuscular reflex (cMR) and the cutaneous silent period (cSP) of foot muscles, in order to investigate further the type of fibers involved in their generation. In 14 neurologically normal patients with indication for surgical treatment of hallux valgus, we recorded from the extensor digitorum brevis muscle the reflex responses elicited by high-intensity electrical stimulation of the big toe at various time periods, ranging from 0 to 20 min, after ultrasound-guided sciatic nerve popliteal anesthetic block. The first effect was a delay in cSP onset latency, with no changes in end latency. The cMR remained unaltered up to when subjects were no longer able to maintain the contraction. The effects of local anesthetics on peripheral nerves allow for recognition of the different types of fibers contributing to the cMR and the cSP in muscles of the lower limb. PMID- 26025615 TI - Erratum to: New Dimeric and seco-Abietane Diterpenoids from Salvia wardii. PMID- 26025614 TI - Experimental orofacial pain and sensory deprivation lead to perceptual distortion of the face in healthy volunteers. AB - Patients suffering from persistent orofacial pain may sporadically report that the painful area feels "swollen" or "differently," a phenomenon that may be conceptualized as a perceptual distortion because there are no clinical signs of swelling present. Our aim was to investigate whether standardized experimental pain and sensory deprivation of specific orofacial test sites would lead to changes in the size perception of these face areas. Twenty-four healthy participants received either 0.2 mL hypertonic saline (HS) or local anesthetics (LA) into six regions (buccal, mental, lingual, masseter muscle, infraorbital and auriculotemporal nerve regions). Participants estimated the perceived size changes in percentage (0 % = no change, -100 % = half the size or +100 % = double the size), and somatosensory function was checked with tactile stimuli. The pain intensity was rated on a 0-10 Verbal Numerical Rating Scale (VNRS), and sets of psychological questionnaires were completed. HS and LA were associated with significant self-reported perceptual distortions as indicated by consistent increases in perceived size of the adjacent face areas (P <= 0.050). Perceptual distortion was most pronounced in the buccal region, and the smallest increase was observed in the auriculotemporal region. HS was associated with moderate levels of pain VNRS = 7.3 +/- 0.6. Weak correlations were found between HS-evoked perceptual distortion and level of dissociation in two regions (P < 0.050). Experimental pain and transient sensory deprivation evoked perceptual distortions in all face regions and overall demonstrated the importance of afferent inputs for the perception of the face. We propose that perceptual distortion may be an important phenomenon to consider in persistent orofacial pain conditions. PMID- 26025616 TI - Quantitation of Chloramphenicol and Nitrofuran Metabolites in Aquaculture Products Using Microwave-Assisted Derivatization, Automated SPE, and LC-MS/MS. AB - This paper describes a rapid and robust method utilizing microwave-assisted derivatization, automated SPE, and LC-MS/MS for the quantitation and confirmation of chloramphenicol (CAP) and nitrofuran metabolites in various aquaculture matrixes. The use of equipment presented in this work allowed extractions to be completed on average within 6 h, with quantitation accuracy ranging from 89 to 107% and RSD<=8.3%. The demonstrated detection limits for all the nitrofuran metabolites of interest in three different matrixes were <=0.06 ng/g, with a quantitation limit of <=0.2 ng/g. Additionally, the method exhibited a CAP detection limit for all matrixes<=0.01 ng/g and an LOQ of <=0.03 ng/g. PMID- 26025617 TI - A Review of Training Opportunities for Singing Voice Rehabilitation Specialists. AB - OBJECTIVES: Training opportunities for singing voice rehabilitation specialists are growing and changing. This is happening despite a lack of agreed-on guidelines or an accredited certification acknowledged by the governing bodies in the fields of speech-language pathology and vocal pedagogy, the American Speech Language Hearing Association and the National Association of Teachers of Singing, respectively. The roles of the speech-language pathologist, the singing teacher, and the person who bridges this gap, the singing voice rehabilitation specialist, are now becoming better defined and more common among the voice care community. To that end, this article aims to review the current opportunities for training in the field of singing voice rehabilitation. METHODS: A review of available university training programs, private training programs and mentorships, clinical fellowships, professional organizations, conferences, vocal training across genres, and self-study opportunities was conducted. All institutional listings are with permission from program leaders. RESULTS/CONCLUSIONS: Although many avenues are available for training of singing voice rehabilitation specialists, there is no accredited comprehensive training program at this point. This review gathers information on current training opportunities from across various modalities. The listings are not intended to be comprehensive but rather representative of possibilities for interested practitioners. PMID- 26025618 TI - Prevalence of Vocal Tract Discomfort in the Flemish Population Without Self Perceived Voice Disorders. AB - OBJECTIVES: The main aim of this study was to assess the prevalence of Vocal Tract Discomfort (VTD) in the Flemish population without self-perceived voice disorders using the VTD scale and to examine the relationship between vocal load and VTD symptoms. In addition, consistency between the VTD scale and the Voice Handicap Index (VHI) and the Corporal Pain scale was evaluated. METHODS: A total of 333 participants completed the VTD scale, the VHI, and the Corporal Pain scale. Patient information about study and voice-related hobbies (for students), state of (non)professional voice user (for employees), smoking, shouting, allergy, and voice therapy was taken into account. RESULTS: A median number of three VTD symptoms was reported, and 88% of the participants showed at least one symptom of VTD. Dryness (70%), tickling (62%), and lump in the throat (54%) were the most frequently occurring symptoms. The frequency and severity of VTD were significantly higher in participants who followed voice-related studies, played a team sport, were part of a youth movement, shouted frequently, and received voice therapy in the past (P < 0.05). Finally, low correlations were obtained between frequency and severity of the VTD scale and total VHI score (r = 0.226-0.411) or frequency and intensity of the Corporal Pain scale (r = 0.016-0.408). CONCLUSIONS: The prevalence of VTD is relatively high in the Flemish population without self-perceived voice disorders, although the frequency and severity of the symptoms are rather low. Vocal load seems to influence the frequency and severity of VTD. Finally, the VTD scale seems to reveal clinically important information that cannot be gathered from any other protocol. PMID- 26025619 TI - Myc regulates programmed cell death and radial glia dedifferentiation after neural injury in an echinoderm. AB - BACKGROUND: Adult echinoderms can completely regenerate major parts of their central nervous system even after severe injuries. Even though this capacity has long been known, the molecular mechanisms that drive fast and complete regeneration in these animals have remained uninvestigated. The major obstacle for understanding these molecular pathways has been the lack of functional genomic studies on regenerating adult echinoderms. RESULTS: Here, we employ RNA interference-mediated gene knockdown to characterize the role of Myc during the early (first 48 hours) post-injury response in the radial nerve cord of the sea cucumber Holothuria glaberrima. Our previous experiments identified Myc as the only pluripotency-associated factor, whose expression significantly increased in the wounded CNS. The specific function(s) of this gene, however, remained unknown. Here we demonstrate that knockdown of Myc inhibits dedifferentiation of radial glia and programmed cell death, the two most prominent cellular events that take place in the regenerating sea cucumber nervous system shortly after injury. CONCLUSIONS: In this study, we show that Myc overexpression is required for proper dedifferentiation of radial glial cells and for triggering the programmed cell death in the vicinity of the injury. Myc is thus the first transcription factor, whose functional role has been experimentally established in echinoderm regeneration. PMID- 26025620 TI - Inducible Transgene Expression in Human iPS Cells Using Versatile All-in-One piggyBac Transposons. AB - Transgenics is a mainstay of functional genomics. Conditionally overexpressing genes of interest (GOIs) helps to reveal their roles in the control of complex biological processes. Complemented by findings in classic animal model systems, recent advances in human embryonic stem cell (hESC) and patient-specific induced pluripotent stem cell (hiPSC) differentiation have led to sophisticated in vitro models of human development and disease. Yet, as transgenic elements encoding inducible systems must be introduced de novo into each genetically unique human stem cell line, robust and straightforward solutions to gene delivery are required. Transposons are a family of mobile DNA elements that have been adapted as experimental tools for stable genomic integration of transgenes. The piggyBac (PB) transposon from Trichoplusia ni presents a number of benefits over classic viral or BAC transgenesis: ease of application, simple integration-site mapping, and the unique capacity for traceless excision. Moreover, their large capacity permits the consolidation of multiple transgene components in a single vector system. In this chapter, we outline the features of a panel of "All-in-One" PB transposons designed for drug-inducible gene expression and provide guidelines to establish and validate populations or clones of transgenic hiPSCs. PMID- 26025621 TI - Determining Epigenetic Targets: A Beginner's Guide to Identifying Genome Functionality Through Database Analysis. AB - There can now be little doubt that the cis-regulatory genome represents the largest information source within the human genome essential for health. In addition to containing up to five times more information than the coding genome, the cis-regulatory genome also acts as a major reservoir of disease-associated polymorphic variation. The cis-regulatory genome, which is comprised of enhancers, silencers, promoters, and insulators, also acts as a major functional target for epigenetic modification including DNA methylation and chromatin modifications. These epigenetic modifications impact the ability of cis regulatory sequences to maintain tissue-specific and inducible expression of genes that preserve health. There has been limited ability to identify and characterize the functional components of this huge and largely misunderstood part of the human genome that, for decades, was ignored as "Junk" DNA. In an attempt to address this deficit, the current chapter will first describe methods of identifying and characterizing functional elements of the cis-regulatory genome at a genome-wide level using databases such as ENCODE, the UCSC browser, and NCBI. We will then explore the databases on the UCSC genome browser, which provides access to DNA methylation and chromatin modification datasets. Finally, we will describe how we can superimpose the huge volume of study data contained in the NCBI archives onto that contained within the UCSC browser in order to glean relevant in vivo study data for any locus within the genome. An ability to access and utilize these information sources will become essential to informing the future design of experiments and subsequent determination of the role of epigenetics in health and disease and will form a critical step in our development of personalized medicine. PMID- 26025622 TI - Library Construction for High-Throughput Mobile Element Identification and Genotyping. AB - Mobile genetic elements are discrete DNA elements that can move around and copy themselves in a genome. As a ubiquitous component of the genome, mobile elements contribute to both genetic and epigenetic variation. Therefore, it is important to determine the genome-wide distribution of mobile elements. Here we present a targeted high-throughput sequencing protocol called Mobile Element Scanning (ME Scan) for genome-wide mobile element detection. We will describe oligonucleotides design, sequencing library construction, and computational analysis for the ME Scan protocol. PMID- 26025623 TI - Calcium Imaging in Pluripotent Stem Cell-Derived Cardiac Myocytes. AB - The possibility to generate cardiomyocytes (CMs) from disease-specific induced pluripotent stem cells (iPSCs) is a powerful tool for the investigation of various cardiac diseases in vitro. The pathological course of various cardiac conditions, causatively heterogeneous, often converges into disturbed cellular Ca(2+) cycling. The gigantic Ca(2+) channel of the intracellular Ca(2+) store of CMs, the ryanodine receptor type 2 (RyR2), controls Ca(2+) release and therefore plays a crucial role in Ca(2+) cycling of CMs. In the present protocol we describe ways to measure and analyze global as well as local cellular Ca(2+) release events in CMs derived from a patient carrying a CPVT-causing RyR2 mutation. PMID- 26025624 TI - Quantitative Analysis of Intra-chromosomal Contacts: The 3C-qPCR Method. AB - The chromosome conformation capture (3C) technique is fundamental to many population-based methods investigating chromatin dynamics and organization in eukaryotes. Here, we provide a modified quantitative 3C (3C-qPCR) protocol for improved quantitative analyses of intra-chromosomal contacts. We also describe an algorithm for data normalization which allows more accurate comparisons between contact profiles. PMID- 26025625 TI - Size-exclusion chromatography-based enrichment of extracellular vesicles from urine samples. AB - Renal biopsy is the gold-standard procedure to diagnose most of renal pathologies. However, this invasive method is of limited repeatability and often describes an irreversible renal damage. Urine is an easily accessible fluid and urinary extracellular vesicles (EVs) may be ideal to describe new biomarkers associated with renal pathologies. Several methods to enrich EVs have been described. Most of them contain a mixture of proteins, lipoproteins and cell debris that may be masking relevant biomarkers. Here, we evaluated size-exclusion chromatography (SEC) as a suitable method to isolate urinary EVs. Following a conventional centrifugation to eliminate cell debris and apoptotic bodies, urine samples were concentrated using ultrafiltration and loaded on a SEC column. Collected fractions were analysed by protein content and flow cytometry to determine the presence of tetraspanin markers (CD63 and CD9). The highest tetraspanin content was routinely detected in fractions well before the bulk of proteins eluted. These tetraspanin-peak fractions were analysed by cryo-electron microscopy (cryo-EM) and nanoparticle tracking analysis revealing the presence of EVs.When analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, tetraspanin-peak fractions from urine concentrated samples contained multiple bands but the main urine proteins (such as Tamm-Horsfall protein) were absent. Furthermore, a preliminary proteomic study of these fractions revealed the presence of EV-related proteins, suggesting their enrichment in concentrated samples. In addition, RNA profiling also showed the presence of vesicular small RNA species.To summarize, our results demonstrated that concentrated urine followed by SEC is a suitable option to isolate EVs with low presence of soluble contaminants. This methodology could permit more accurate analyses of EV-related biomarkers when further characterized by -omics technologies compared with other approaches. PMID- 26025626 TI - Conceptualizing smartphone use in outpatient wound assessment: patients' and caregivers' willingness to use technology. AB - BACKGROUND: Information technology is transforming health care communication. Using smartphones to remotely monitor incisional wounds via digital photos as well as collect postoperative symptom information has the potential to improve patient outcomes and transitional care. We surveyed a vulnerable patient population to evaluate smartphone capability and willingness to adopt this technology. METHODS: We surveyed 53 patients over a 9-mo period on the vascular surgery service at a tertiary care institution. Descriptive statistics were calculated to describe survey item response. RESULTS: A total of 94% of recruited patients (50 of 53) participated. The cohort was 50% female, and the mean age was age 70 y (range: 41-87). The majority of patients owned cell phones (80%) and 23% of these cell phones were smartphones. Ninety percent of patients had a friend or family member that could help take and send photos with a smartphone. Ninety-two percent of patients reported they would be willing to take a digital photo of their wound via a smartphone (68% daily, 22% every other day, 2% less than every other day, and 8% not at all). All patients reported they would be willing to answer questions related to their health via a smartphone. Patients identified several potential difficulties with regard to adopting a smartphone wound monitoring protocol including logistics related to taking photos, health-related questions, and coordination with caretakers. CONCLUSIONS: Our survey demonstrates that an older patient cohort with significant comorbidity is able and willing to adopt a smartphone-based postoperative monitoring program. Patient training and caregiver participation will be essential to the success of this intervention. PMID- 26025627 TI - MicroRNA expression profile of surgical removed mandibular bone tissues from patients with mandibular prognathism. AB - BACKGROUND: Mandibular prognathism (MP) or skeletal class III malocclusion with a prognathic mandible is one of the most severe facial deformities. Recent work has revealed certain circulating microRNAs (miRNAs) are associated with MP, we conducted this study to characterize the miRNAs expression profile in surgically removed mandibular bone tissue in patients with MP and explored the role of miRNA regulation in the pathogenesis of MP. METHODS: Affymetrix GeneChip miRNA 3.0 Array was used to examine the miRNA expression in mandibular bone tissues from MP patients and control subjects. A variety of bioinformatic approaches were used to predict the target genes of the miRNAs, find the potential functions and pathways of the target genes, analyze their intersection with differentially expressed mRNAs, and establish miRNA-gene network. RESULTS: Eleven upregulated and 11 downregulated miRNAs with a fold change >= 2 and a P value <0.05 were identified in bone specimens of MP patients. A total of 3569 genes were predicted as targets of hsa-miR-10a-5p, hsa-miR-150-5p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-197 3p, hsa-miR-30 d-5p, hsa-miR-342-5p and hsa-miR-629-5p, hsa-miR-1202, and hsa-miR 638. The target genes were predicted to be involved in biological functions and signaling pathways related to osteogenesis. Hsa-miR-30 d-5p was the key node of miRNA-gene network. CONCLUSIONS: Our results indicated a possible association between the differentially expressed miRNAs and MP pathogenesis, and the precise mechanisms are needed to be further validated. PMID- 26025628 TI - Impact of the new payment system on laparoscopic appendectomy in Korea. AB - BACKGROUND: Korea has a nationalized health system. The aim of this study was to evaluate the impact of the Korea diagnosis related group-based prospective payment system (K-DRG/PPS) on the use of medical resources and the rate of adverse events during laparoscopic appendectomy. METHODS: We included patients who underwent laparoscopic appendectomy at Dongtan Sacred Heart Hospital, Korea, between November 2012 and February 2014. The patients were divided into two groups: before-DRG/PPS or after-DRG/PPS groups. The length of the postoperative hospital stay (LOS) and medical costs were indicators of the medical resources. Medical costs included those of the initial hospital stay, outpatient clinic, readmission, and the sum of these charges. Complication and readmission rates were indicators of the rates of adverse events. RESULTS: After the implementation of the DRG/PPS, length of the hospital stay decreased by 10% (4.9 d before versus 4.4 d after DRG/PPS; P < 0.001). The initial hospital stay and total cost were significantly lower in the after-DRG/PPS group (both P < 0.001). The complication rates during the initial hospital stay (3.5% before versus 2.3% after DRG/PPS; P = 0.225) and the readmission rates (4.3% versus 2.5%, respectively; P = 0.227) were statistically similar. CONCLUSIONS: This study shows that the K-DRG/PPS for laparoscopic appendectomy had no negative effect on the rate of adverse events and reduced the use of medical resources. Further evaluation of other procedures is required to determine the overall effects of the K-DRG/PPS. PMID- 26025629 TI - Spirituality, Religiosity, and Health: a Comparison of Physicians' Attitudes in Brazil, India, and Indonesia. AB - BACKGROUND: One of the biggest challenges in the spirituality, religiosity, and health field is to understand how patients and physicians from different cultures deal with spiritual and religious issues in clinical practice. PURPOSE: The present study aims to compare physicians' perspectives on the influence of spirituality and religion (S/R) on health between Brazil, India, and Indonesia. METHOD: This is a cross-sectional, cross-cultural, multi-center study carried out from 2010 to 2012, examining physicians' attitudes from two continents. Participants completed a self-rated questionnaire that collected information on sociodemographic characteristics, S/R involvement, and perspectives concerning religion, spirituality, and health. Differences between physicians' responses in each country were examined using chi-squared, ANOVA, and MANCOVA. RESULTS: A total of 611 physicians (194 from Brazil, 295 from India, and 122 from Indonesia) completed the survey. Indonesian physicians were more religious and more likely to address S/R when caring for patients. Brazilian physicians were more likely to believe that S/R influenced patients' health. Brazilian and Indonesians were as likely as to believe that it is appropriate to talk and discuss S/R with patients, and more likely than Indians. No differences were found concerning attitudes toward spiritual issues. CONCLUSION: Physicians from these different three countries had very different attitudes on spirituality, religiosity, and health. Ethnicity and culture can have an important influence on how spirituality is approached in medical practice. S/R curricula that train physicians how to address spirituality in clinical practice must take these differences into account. PMID- 26025630 TI - Effects of Aquatic Exercise on Sleep in Older Adults with Mild Sleep Impairment: a Randomized Controlled Trial. AB - BACKGROUND: Exercise has been found to be associated with improved sleep quality. However, most of the evidence is based on resistance exercise, walking, or gym based aerobic activity. PURPOSE: This study aimed to examine the effects of an 8 week aquatic exercise program on objectively measured sleep parameters among older adults with mild sleep impairment. METHODS: A total of 67 eligible older adults with sleep impairment were selected and randomized to exercise and control groups, and 63 participants completed the study. The program involved 2 * 60-min sessions of aquatic exercise for 8 weeks. Participants wore wrist actigraphs to assess seven parameters of sleep for 1 week before and after the intervention. Mixed-design analysis of variance (ANOVA) was used to assess the differences between groups in each of the sleep parameters. RESULTS: No significant group differences on demographic variables, life satisfaction, percentage of body fat, fitness, seated blood pressure, and any parameter of sleep were found at baseline. Significant group * time interaction effects were found in sleep onset latency, F(1,58) = 6.921, p = .011, partial eta squared = .011, and in sleep efficiency, F(1, 61) = 16.909, p < 0.001, partial eta squared = .217. The exercise group reported significantly less time on sleep onset latency (mean difference = 7.9 min) and greater sleep efficiency (mean difference = 5.9 %) than the control group at posttest. There was no significant difference between groups in change of total sleep time, wake after sleep onset, activity counts, or number and length of awakenings. CONCLUSIONS: An 8-week aquatic exercise has significant benefits on some sleep parameters, including less time for sleep onset latency and better sleep efficiency in older adults with mild sleep impairment. PMID- 26025632 TI - Anti-coagulation assessment with prothrombin time and anti-Xa assays in real world patients on treatment with rivaroxaban. AB - Monitoring of anti-coagulation with the direct factor Xa inhibitor rivaroxaban is considered unnecessary in a routine clinical setting. However, assessment of its anti-coagulant effect may be desirable in certain clinical situations. We assessed prothrombin time (PT) reagents and commercially available anti-Xa assays (Biophen) calibrated for rivaroxaban and heparin in comparison to liquid chromatography-mass spectrometry (LC-MS/MS) measurements of rivaroxaban concentration in samples from patients on treatment with rivaroxaban for stroke prevention in atrial fibrillation. Citrate plasma samples were obtained from 30 randomly selected patients on uninterrupted treatment with rivaroxaban for a minimum of 1 month. The anti-Xa assays, direct Xa inhibitor (DiXa-I(r)), and Heparin LRT(r) were conducted for both wide and low calibrations for rivaroxaban. Measurements were compared to LC-MS/MS using correlation, linear regression, intra-class correlation, and Bland-Altman analysis. In 30 patients (9 female) of median age 71.5 years and BMI 26.5 kg/m(2), rivaroxaban concentrations between 2.4 and 625 ng/ml (median 82 ng/ml) were measured by LC-MS/MS. PT reagents were poorly correlated with rivaroxaban concentrations (r (2) = 0.52 and 0.09). Anti Xa assays DiXa-I (r (2) = 0.95) and Heparin LRT (r (2) = 0.97) were correlated with rivaroxaban in all concentrations, but especially in low concentrations with low calibrations (r (2) = 0.97 and 0.98, respectively). The highest agreement occurred between Heparin LRT and low rivaroxaban concentrations with a mean difference of -5.3 ng/ml (limits of agreement, 12.9 to 2.4 ng/ml). Anti-Xa assays can indirectly determine the concentration of rivaroxaban for a wide range of concentrations in real-world patients. An interpretation of anti-Xa and PT measurements in treatment with rivaroxaban requires knowledge of the local reagents. PMID- 26025631 TI - The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells. AB - We studied the role of miRNA-200 family members in cellular sensitivity to paclitaxel and carboplatin, using two ovarian cancer cell lines, OVCAR-3 and MES OV, and their paclitaxel resistant variants OVCAR-3/TP and MES-OV/TP. Both resistant variants display a strong epithelial-mesenchymal transition (EMT) phenotype, with marked decreases in expression of miR-200c and miR-141 in OVCAR 3/TP, and down-regulation of all five members of the miR-200 family in MES-OV/TP. Lentiviral transfection of inhibitors of miR-200c or miR-141 in parental OVCAR-3 triggered EMT and rendered the cells resistant to paclitaxel and carboplatin. Conversely, the infection of OVCAR-3/TP cells with retroviral particles carrying the miR-200ab429 and 200c141 clusters triggered a partial mesenchymal to epithelial transition (MET). This partial MET was not sufficient to re-sensitize OVCAR-3/TP cells to paclitaxel. However, the miR-200c/miR-141 cluster transfectants became 6-8x resistant to carboplatin, an unexpected result, whereas miR-200a/miR-200b/miR-429 had no effect. Transfecting the OVCAR-3/TP GFP cells with specific miRNA mimics confirmed these data. MiR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells. PMID- 26025633 TI - Synchronous Hodgkin's lymphoma and schwannomas mimicking refractory Hodgkin's lymphoma. PMID- 26025634 TI - Comment to: A systematic review of the surgical treatment of large incisional hernia. Deerenberg EB, Timmermans L, Hogerzeil DP, Slieker JC, Eilers PH, Jeekel J, Lange JF. Hernia 2015; 19:89-101. PMID- 26025635 TI - Is routine reinforcement of the posterior inguinal wall necessary for laparoscopic inguinal hernia repair in children? Comment to: Technical refinement of mini-laparoscopic hernia repair in infants and children. Tsai YC, Da Lin C, Chueh SC (2014) Hernia, DOI 10.1007/s10029-014-1327-4. PMID- 26025636 TI - FASCIN and alpha-actinin can regulate the conformation of actin filaments. AB - BACKGROUND: Actin filament bundling proteins mediate numerous processes in cells such as the formation of cell membrane protrusions or cell adhesions and stress fiber based locomotion. Among them alpha-actinin and fascin are the most abundant ones. This work characterizes differences in molecular motions in actin filaments due to the binding of these two actin bundling proteins. METHODS: We investigated how alpha-actinin and fascin binding modify the conformation of actin filaments by using conventional and saturation transfer EPR methods. RESULTS: The result characteristic for motions on the microsecond time scale showed that both actin bundling proteins made the bending and torsional twisting of the actin filaments slower. When nanosecond time scale molecular motions were described the two proteins were found to induce opposite changes in the actin filaments. The binding of one molecule of alpha-actinin or fascin modified the conformation of numerous actin protomers. CONCLUSION: As fascin and alpha-actinin participates in different cellular processes their binding can serve the proper tuning of the structure of actin by establishing the right conformation for the interactions with other actin binding proteins. Our observations are in correlation with the model where actin filaments fulfill their biological functions under the regulation by actin-binding proteins. GENERAL SIGNIFICANCE: Supporting the general model for the cellular regulation of the actin cytoskeleton we showed that two abundant actin bundling proteins, fascin and alpha-actinin, alter the conformation of actin filaments through long range allosteric interactions in two different ways providing the structural framework for the adaptation to specific biological functions. PMID- 26025637 TI - Impact of wastewater infrastructure upgrades on the urban water cycle: Reduction in halogenated reaction byproducts following conversion from chlorine gas to ultraviolet light disinfection. AB - The municipal wastewater treatment facility (WWTF) infrastructure of the United States is being upgraded to expand capacity and improve treatment, which provides opportunities to assess the impact of full-scale operational changes on water quality. Many WWTFs disinfect their effluent prior to discharge using chlorine gas, which reacts with natural and synthetic organic matter to form halogenated disinfection byproducts (HDBPs). Because HDBPs are ubiquitous in chlorine disinfected drinking water and have adverse human health implications, their concentrations are regulated in potable water supplies. Less is known about the formation and occurrence of HDBPs in disinfected WWTF effluents that are discharged to surface waters and become part of the de facto wastewater reuse cycle. This study investigated HDBPs in the urban water cycle from the stream source of the chlorinated municipal tap water that comprises the WWTF inflow, to the final WWTF effluent disinfection process before discharge back to the stream. The impact of conversion from chlorine-gas to low-pressure ultraviolet light (UV) disinfection at a full-scale (68,000 m(3) d(-1) design flow) WWTF on HDBP concentrations in the final effluent was assessed, as was transport and attenuation in the receiving stream. Nutrients and trace elements (boron, copper, and uranium) were used to characterize the different urban source waters, and indicated that the pre-upgrade and post-upgrade water chemistry was similar and insensitive to the disinfection process. Chlorinated tap water during the pre upgrade and post-upgrade samplings contained 11 (mean total concentration=2.7 MUg L(-1); n=5) and 10 HDBPs (mean total concentration=4.5 MUg L(-1)), respectively. Under chlorine-gas disinfection conditions 13 HDBPs (mean total concentration=1.4 MUg L(-1)) were detected in the WWTF effluent, whereas under UV disinfection conditions, only one HDBP was detected. The chlorinated WWTF effluent had greater relative proportions of nitrogenous, brominated, and iodinated HDBPs than the chlorinated tap water. Conversion of the WWTF to UV disinfection reduced the loading of HDBPs to the receiving stream by >90%. PMID- 26025638 TI - Dishwashing water recycling system and related water quality standards for military use. AB - As the demand for reliable and safe water supplies increases, both water quality and available quantity are being challenged by population growth and climate change. Greywater reuse is becoming a common practice worldwide; however, in remote locations of limited water supply, such as those encountered in military installations, it is desirable to expand its classification to include dishwashing water to maximize the conservation of fresh water. Given that no standards for dishwashing greywater reuse by the military are currently available, the current study determined a specific set of water quality standards for dishwater recycling systems for U.S. military field operations. A tentative water reuse standard for dishwashing water was developed based on federal and state regulations and guidelines for non-potable water, and the developed standard was cross-evaluated by monitoring water quality data from a full-scale dishwashing water recycling system using an innovative electrocoagulation and ultrafiltration process. Quantitative microbial risk assessment (QMRA) was also performed based on exposure scenarios derived from literature data. As a result, a specific set of dishwashing water reuse standards for field analysis (simple, but accurate) was finalized as follows: turbidity (<1 NTU), Escherichia coli (<50 cfu mL(-1)), and pH (6-9). UV254 was recommended as a surrogate for organic contaminants (e.g., BOD5), but requires further calibration steps for validation. The developed specific water standard is the first for dishwashing water reuse and will be expected to ensure that water quality is safe for field operations, but not so stringent that design complexity, cost, and operational and maintenance requirements will not be feasible for field use. In addition the parameters can be monitored using simple equipment in a field setting with only modest training requirements and real-time or rapid sample turn-around. This standard may prove useful in future development of civilian guidelines. PMID- 26025639 TI - Significance of anionic functional group in betaine-type metabolite analogs on the facilitation of enzyme reactions. AB - Using synthetic sulfobetaine library, the enzyme activation behavior has been investigated. Comparison of enzyme activation behavior revealed that sulfobetaines equally facilitate enzyme reactions, being consistent with that of carboxybetaines. The subsequent kinetic and solution property analyses clarified that both the kinetic parameter and hydration property changes are identical with those of carboxybetaines, indicating that the difference in the anionic functional group of the betaine structure scarcely affects the enzyme activation. On the other hand, comparison of carboxy- or sulfo-betaines with tetraalkylammonium salts, whose counteranion binds to the ammonium cation intermolecularly, revealed that the activation ability for enzymes of tetraalkylammonium salts is considerably smaller than that of carboxy- or sulfo betaines. These findings give us a hint to design the useful betaine-type enzyme activators. PMID- 26025640 TI - Identification and genomic analysis of temperate Pseudomonas bacteriophage PstS-1 from the Japan trench at a depth of 7000 m. AB - Viruses play important roles in aquatic ecosystems, but deep-sea bacteriophages remain largely unexplored. A temperate bacteriophage (termed vB_PstS-1) was identified from the psychrotolerant gammaproteobacterium Pseudomonas stutzeri 1-1 1b, which was isolated from hadopelagic water (depth of 7000 m) of the Japan Trench in the Northwest Pacific Ocean. The genome size of PstS-1 was 48,666 bp; its genome displayed a 59.8% G + C content and a total of 79 coding sequences were identified in its genome. The PstS-1 phage belongs to the family Siphoviridae, but its genomic sequence and organization are distinct from those of any other well-known Siphoviridae phage. The mosaic genomic structure of PstS 1 suggests the occurrence of genetic exchange between distinct temperate phages in deep-sea Pseudomonas populations. The PstS-1 genome also harbors three distinct sequence regions corresponding to spacers within a single clustered regularly interspaced short palindromic repeat (CRISPR) locus in the rhizosphere associated diazotrophic P. stutzeri A1501 genome. The extension of these spacers to the soil environment and the presence of many homologs of both the hadal deep sea phage PstS-1 and terrestrial Pseudomonas phages suggest the early co evolution of temperate phages and their host genus Pseudomonas prior to the divergence of their habitational and physiological adaptation. PMID- 26025641 TI - Anti-oxidative responses of zebrafish (Danio rerio) gill, liver and brain tissues upon acute cold shock. AB - The present study seeks to detect oxidative damage and to compare anti-oxidative responses among liver, gills and brain of adult zebrafish that were cooled from 28 degrees C (control) to 12 degrees C (treatment) for 0-24 h. The lipid peroxidation of liver, gill and brain tissues significantly increased at 1h after transfer, but reactive oxygen species in the treatment group increased significantly after 24 h as compared to the control. The fish were found to develop a cascading anti-oxidative mechanism beginning with an increase in Cu/Zn SOD levels, followed by increased CAT and GPx mRNA expressions in the three tissue types. Both smtB and mt2 mRNAs increased in the hepatic and brain tissues following 1h of cold stress, but only smtB exhibited a significant increase in the gills at 1 h and 6 h after transfer to 12 degrees C. Furthermore, cellular apoptosis in the brain was not evident after cold shock, but liver and gills showed cellular apoptosis at 1-3 h, with another peak in the liver at 6 h after cold shock. The results suggest that the cold shock induced oxidative stress, and the enzymatic (SOD, GPx and CAT) and non-enzymatic (mt-2 and smt-B) mRNA expressions all play a role in the resulting anti-oxidation within 1-6 h of cold shock. A functional comparison showed that the brain had the most powerful antioxidant defense system of the three tissue types since it had the highest smtB mRNA expression and a lower level of cell apoptosis than the liver and gills after exposure to cold stress. PMID- 26025642 TI - Highlight-stacking the deck: heritage and environment shape nucleotide composition in prokaryotes. PMID- 26025643 TI - Green technology effect of injection pressure, timing and compression ratio in constant pressure heat addition cycle by an eco-friendly material. AB - Present energy strategies focus on environmental issues, especially environmental pollution prevention and control by eco-friendly green technologies. This includes, increase in the energy supplies, encouraging cleaner and more efficient energy management, addressing air pollution, greenhouse effect, global warming, and climate change. Biofuels provide the panorama of new fiscal opportunities for people in rural area for meeting their need and also the demand of the local market. Biofuels concern protection of the environment and job creation. Renewable energy sources are self-reliance resources, have the potential in energy management with less emissions of air pollutants. Biofuels are expected to reduce dependability on imported crude oil with connected economic susceptibility, reduce greenhouse gases, other pollutants and invigorate the economy by increasing demand and prices for agricultural products. The use of neat paradise tree oil and induction of eco-friendly material Hydrogen through inlet manifold in a constant pressure heat addition cycle engine (diesel engine) with optimized engine operating parameters such as injection timing, injection pressure and compression ratio. The results shows the heat utilization efficiency for neat vegetable oil is 29% and neat oil with 15% Hydrogen as 33%. The exhaust gas temperature (EGT) for 15% of H2 share as 450 degrees C at full load and the heat release of 80J/deg. crank angle for 15% Hydrogen energy share. PMID- 26025644 TI - Nanocrystalline semiconductor doped rare earth oxide for the photocatalytic degradation studies on Acid Blue 113: A di-azo compound under UV slurry photoreactor. AB - Preventive measures for the control of environmental pollution and its remediation has received much interest in recent years due to the world-wide increase in the contamination of water bodies. Contributions of these harmful effluents are caused by the leather processing, pharmaceutical, cosmetic, textile, agricultural and other chemical industries. Nowadays, advanced oxidation processes considered to be better option for the complete destruction of organic contaminants in water and wastewater. Acid Blue 113 is a most widely used di-azo compound in leather, textile, dying and food industry as a color rending compound. In the present study, we have reported the photo catalytic degradation of Acid Blue 113 using a nanocrystalline semiconductor doped rare earth oxide as a photo catalyst under UV light irradiation. The photocatalyst was prepared by a simple precipitation technique and were characterized by XRD, FT-IR, UV-DRS and FE-SEM analysis. The experimental results proved that the prepared photo catalyst was nanocrystalline and highly active in the UV region. The UV-DRS results showed the band gap energy was 3.15eV for the prepared photo catalyst. The photodegradation efficiency was analyzed by various experimental parameters such as pH, catalyst dosage, variation of substrate concentration and effect of electrolyte addition. The photo degradation process followed a pseudo first order kinetics and was continuously monitored by UV-visible spectrophotometer. The experimental results proved the efficacy of the nanocrystalline zinc oxide doped dysprosium oxide which are highly active under UV light irradiations. It is also suggested that the prepared material would find wider applications in environmental remediation technologies to remove the carcinogenic and toxic moieties present in the industrial effluents. PMID- 26025645 TI - Validity of the mediastinum as a reference region to evaluate cardiac accumulation of iodine-123 metaiodobenzylguanidine. AB - OBJECTIVE: The heart-to-mediastinum (H/M) ratio, the heart count normalized for the mediastinum count, is commonly used in cardiac (123)I-metaiodobenzylguanidine (MIBG) imaging. However, there are reports describing age-dependent increases in the mediastinum count with or without correction for the injected dose (ID) and a poor correlation between the H/M ratio and heart count normalized for ID. We evaluated the validity of the mediastinum count as a reference in comparison with the ID. METHODS: Results of cardiac (123)I-MIBG imaging in 200 patients were analyzed. The mean counts for the heart and mediastinum were estimated to calculate the H/M ratio. Additionally, the heart and mediastinum counts were normalized for ID measured with a dose calibrator. ID was corrected for body size represented by body weight, body surface area, or lean body mass. RESULTS: The coefficient of variance of the ID-normalized mediastinum count was reduced by correcting ID for body size. The indicators of body size showed significant negative correlations with age. Although a positive correlation was found between age and the ID-normalized mediastinum counts, the age-dependence was reduced by body size correction. There was a close correlation between the H/M ratio and ID normalized heart counts, and body size correction improved the correlation. CONCLUSION: The results of this study indicate the validity of the mediastinum as a reference region and support the use of the H/M ratio as an index of cardiac accumulation of (123)I-MIBG. PMID- 26025646 TI - Functional and radiological outcomes of operative management of displaced talar neck fractures. AB - AIM: To evaluate functional and radiological results of internal fixation of displaced talar neck fractures. MATERIALS AND METHODS: Twenty patients with displaced talar neck fractures who underwent surgery and fixation by cancellous screws were evaluated. Patients were evaluated by American Orthopedic Foot and Ankle Society score which is based on pain (40 points), function (50 points) and alignment (10 points) with excellent (90-100 points), good (75-89 points), fair (60-74 points) and poor scores (<60 points) and radiographically for assessment of union, osteonecrosis and osteoarthritic changes in the subtalar and ankle joint. RESULTS: Among the 20 cases, 13 cases had closed injuries and 7 had open fractures. The most common etiology of injury was road traffic accidents. The average follow up time was 28 months. Osteonecrosis was evident on follow up X rays in 7 cases of which 2 progressed to talar dome collapse. Post traumatic arthritis was observed in 11 cases. Based on American Orthopedic Foot and Ankle Society scores, excellent result was obtained in 4 cases, good 7 cases, fair 5 cases and poor 4 cases. CONCLUSION: Talar neck fractures are associated with high rates of morbidity and complications. Post traumatic arthritis is more common complication than osteonecrosis following surgery. PMID- 26025647 TI - TMS-evoked silent periods in scalene and parasternal intercostal muscles during voluntary breathing. AB - Transcranial magnetic stimulation (TMS) during voluntary muscle contraction causes a period of reduced electromyographic (EMG) activity (EMG). This is attributed to cortical inhibition and is known as the 'silent period'. Silent periods were compared in inspiratory muscles following TMS during voluntary inspiratory efforts during normocapnia, hypercapnia, and hypocapnia. TMS was delivered during isometric and dynamic contractions of scalenes and parasternal intercostals at 25% maximum inspiratory pressure. Changing end-tidal CO2 did not affect the duration of the silent period nor suppression of EMG activity during the silent period. In scalenes, silent periods were shorter for dynamic compared to isometric contractions (p<0.05); but contraction type did not alter the degree of suppression of EMG during the silent period. In parasternal intercostal, no significant differences in silent period parameters occurred for the different contraction types. The lack of effect of end-tidal CO2 suggests that descending drive from the medullary respiratory centres does not independently activate the inspiratory muscles during voluntary inspiratory efforts. PMID- 26025648 TI - Synthesis, spectral, structural characterization and biological investigation of m-Xylylenediaminium-bis (p-toluenesulfonate) monohydrate. AB - Novel organic charge transfer complex, m-xylylenediaminium-bis (p toluenesulfonate) monohydrate (XDPTS) have been synthesized and crystallized to the triclinic system with space group P-1 and the lattice parameters obtained are a=9.9265(7) A, b=9.9676(6) A, c=13.4948(10) A, alpha=71.95(6) degrees , beta=77.02(6) degrees , gamma=76.851(5) degrees . The synthesized complex structure was confirmed by IR, (1)H NMR and (13)C NMR spectral analysis. Pharmacology activities of charge transfer complex were evaluated through antimicrobial, DNA binding/cleavage, antioxidant and cytotoxicity studies. The results reveal that the compound shows good antimicrobial activity against various antibacterial and antifungal species. The DNA interaction indicated that the compound could interact with DNA through intercalation, which is further confirmed by viscosity measurements. The compound should have weak to moderate capacity of scavenging with DPPH, Hydroxyl and ABTS radicals. The cytotoxicity has been evaluated by MTT assay method against MCF-7 cancer cell line. PMID- 26025649 TI - Downregulating HMGA2 attenuates epithelial-mesenchymal transition-induced invasion and migration in nasopharyngeal cancer cells. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is associated with invasion and metastasis of cancer cells. High-mobility group AT-hook 2 (HMGA2) has been found to play a critical role in EMT in a number of malignant tumors. However, whether HMGA2 regulates the EMT in human nasopharyngeal carcinoma (NPC) is unclear. OBJECTIVE: The aim of this study was to investigate the effect and mechanism of HMGA2 in inducing invasion and migration in NPC. METHODS: In NPC tissues samples, the association of HMGA2 mRNA expression with clinicopathological characteristics were estimated by real-time quantitative RT PCR(qRT-PCR). In vitro, following the silencing of HMGA2 in CNE-1 and CNE-2 cell lines, the viability and metastatic ability were analyzed using Cell Counting Kit 8 (CCK8), colony formation assay, and transwell assay. EMT and transforming growth factor-beta (TGFbeta)/Smad3 signaling pathway-related protein expression changes were evaluated using western blot. RESULTS: HMGA2 was upregulated in NPC cell lines and clinical specimens (P < 0.01), and HMGA2 expression correlated significantly with metastasis (P = 0.02) and disease-free survival of NPC (hazard ratio: 3.52; 95% confidence interval: 1.34-7.79; P = 0.01). In addition, following in vitro knockdown of HMGA2, the aggressiveness of cells was markedly inhibited, Vimentin and Snail level was downregulated and E-cadherin expression was upregulated. Moreover, the expression of key proteins TGFbetaRII and p-Smad3 of the TGFbeta/Smad3 signaling pathway was inhibited by the downregulation of HMGA2. CONCLUSION: HMGA2 might maintain EMT-induced invasion and migration through the TGFbeta/Smad3 signaling pathway in NPC cell lines. PMID- 26025650 TI - Erbin loss promotes cancer cell proliferation through feedback activation of Akt Skp2-p27 signaling. AB - Erbin localizes at the basolateral membrane to regulate cell junctions and polarity in epithelial cells. Dysregulation of Erbin has been implicated in tumorigenesis, and yet it is still unclear if and how disrupted Erbin regulates the biological behavior of cancer cells. We report here that depletion of Erbin leads to cancer cell excessive proliferation in vitro and in vivo. Erbin deficiency accelerates S-phase entry by down-regulating CDK inhibitors p21 and p27 via two independent mechanisms. Mechanistically, Erbin loss promotes p27 degradation by enhancing E3 ligase Skp2 activity though augmenting Akt signaling. Interestingly, we also show that Erbin is an unstable protein when the Akt-Skp2 signaling is aberrantly activated, which can be specifically destructed by SCF Skp2 ligase. Erbin loss facilitates cell proliferation and migration in Skp2 dependent manner. Thus, our finding illustrates a novel negative feedback loop between Erbin and Akt-Skp2 signaling. It suggests disrupted Erbin links polarity loss, hyperproliferation and tumorigenesis. PMID- 26025651 TI - Hepatic fibrosis and angiogenesis after bile duct ligation are endogenously expressed vasohibin-1 independent. AB - Liver fibrosis is linked to VEGF-induced angiogenesis. Overexpression of exogenous vasohibin-1, a feedback inhibitor of angiogenesis, has been reported to reduce liver fibrosis after bile duct ligation (BDL). To uncover the function of endogenous vasohibin-1, we performed BDL using vasohibin-1-deficient mice and analyzed liver fibrosis, injury, and angiogenesis. Liver fibrosis was induced by 14-days of BDL in both wild-type and vasohibin-1-deficient mice. The liver sections were stained with anti-CD31 to visualize endothelial cells and with Sirius red to observe fibrotic regions. Total RNAs were purified from the livers and expression of collagen I alpha1 mRNA was measured by quantitative PCR. Plasma ALT activity was determined to assess liver injury. Surprisingly, the same extents of increases were seen in anti-CD31 and Sirius red stainings, collagen I alpha1 mRNA expressions, hepatic hydroxyproline contents, and ALT activity after 14-days of BDL in both wild-type and vasohibin-1-deficient mice. There was unexpectedly no difference between these mice, suggesting that anti-fibrogenic and angiogenic activities of the endogenous vasohibin-1 might be masked in the normal liver at early stage of hepatic fibrosis in mice. PMID- 26025652 TI - Adaptive traits of indigenous cattle breeds: The Mediterranean Baladi as a case study. AB - Generally taken, breeds of Bos taurus ancestry are considered more productive, in comparison with Bos indicus derived breeds that present enhanced hardiness and disease resistance, low nutritional requirements and higher capability of feed utilization. While breeds of B. taurus have been mostly selected for intensive production systems, indigenous cattle, developed mostly from indicine and African taurines, flourish in extensive habitats. Worldwide demographic and economic processes face animal production with new challenges - the increasing demand for animal food products. Intensification of animal husbandry is thus a desired goal in stricken parts of the world. An introduction of productive traits to indigenous breeds might serve to generate improved biological and economic efficiencies. For this to succeed, the genetic merit of traits like efficiency of feed utilization and product quality should be revealed, encouraging the conservation initiatives of indigenous cattle populations, many of which are already extinct and endangered. Moreover, to overcome potential genetic homogeneity, controlled breeding practices should be undertaken. The Baladi cattle are a native local breed found throughout the Mediterranean basin. Purebred Baladi animals are rapidly vanishing, as more European breeds are being introduced or used for backcrosses leading to improved production. The superiority of Baladi over large-framed cattle, in feedlot and on Mediterranean pasture, with respect to adaptability and efficiency, is highlighted in the current review. PMID- 26025653 TI - Coping with the Conflict-of-Interest Pandemic by Listening to and Doubting Everyone, Including Yourself. AB - In light of the widespread existence of financial and non-financial issues that contribute to the appearance or fact of conflict of interest, it is proposed that conflict of interest should generally be assumed, no matter the source of financial support or the expressed declarations of conflicts and even with respect to one's own work. No new model is advanced for modification of peer review processes or for elaboration of author declarations of interest. Researchers should be assessing the quality of published work as best they can and make their own decisions on the appropriate use of the work. While some apparent sources of conflict are likely more obvious and serious than others, even subtler biases can influence scientific reports. Ignoring peer-reviewed contributions because of conflict-of-interest concerns is discouraged. Listening skeptically to all sources, including yourself, is encouraged. PMID- 26025654 TI - The Moral Dimensions of Infrastructure. AB - Moral issues in urban planning involving technology, residents, marginalized groups, ecosystems, and future generations are complex cases, requiring solutions that go beyond the limits of contemporary moral theory. Aside from typical planning problems, there is incongruence between moral theory and some of the subjects that require moral assessment, such as urban infrastructure. Despite this incongruence, there is not a need to develop another moral theory. Instead, a supplemental measure that is compatible with existing moral positions will suffice. My primary goal in this paper is to explain the need for this supplemental measure, describe what one looks like, and show how it works with existing moral systems. The secondary goal is to show that creating a supplemental measure that provides congruency between moral systems that are designed to assess human action and non-human subjects advances the study of moral theory. PMID- 26025656 TI - Storage of washed platelets in BRS-A platelet additive solutions based on two types of clinically available bicarbonated Ringer's solutions with different electrolyte concentrations. AB - BACKGROUND: In Japan, no platelet (PLT) additive solutions (PASs) are officially approved for clinical use although blood centers often receive requests for washed PLTs to reduce adverse reactions. Recently, we developed a novel PAS called BRS-A based on clinically available bicarbonated Ringer's solution (BRS), Bicanate and acid-citrate-dextrose formula A (ACD-A), which has been shown to maintain the in vitro properties of PLTs in the condition of <5% residual plasma during 7-day storage. The aim of this study was to evaluate whether another clinically available BRS, Bicarbon with different electrolyte concentrations can be used as a PAS. STUDY DESIGN AND METHODS: Two types of BRS-As were prepared by adding 25 mL of ACD-A to 500 mL of Bicanate or Bicarbon BRSs. Bicanate-based BRS A and Bicarbon-based BRS-A contain 0.9 or 0.5 mmol/L of magnesium chloride, 95.2 or 100.1 mmol/L of sodium chloride, 4.2 or 5.1 mmol/L of trisodium citrate, and 26.6 or 23.8 mmol/L of sodium bicarbonate, respectively; the other components were identical. Apheresis PLTs stored in these solutions with less than 5% plasma for 7-day storage were compared with regard to their in vitro properties. RESULTS: The pH levels of all units were above 7 throughout storage. The mean PLT volume, hypotonic shock response, glucose consumption, lactate production, swirling, and CD62P and CD42b expression were similar during 7-day storage. The bicarbonate levels in Bicarbon-based BRS-A were lower than those in Bicanate based BRS-A. CONCLUSION: Differences in concentrations of electrolytes such as magnesium, sodium, citrate, and bicarbonate salts in BRS-A do not affect the in vitro properties of PLTs during 7-day storage. These results indicate that the use of another type of BRS-A based on Bicarbon as a PAS is feasible. Thus, BRS-A can be used in hospitals that do not stock Bicanate but have Bicarbon. PMID- 26025658 TI - Neuronal histamine and cognitive symptoms in Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'. PMID- 26025657 TI - Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy. AB - Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP. PMID- 26025659 TI - Lack of support for bexarotene as a treatment for Alzheimer's disease. AB - Bexarotene has been reported to reduce brain amyloid-beta (Abeta) levels and to improve cognitive function in transgenic mouse models of Alzheimer's disease (AD). Four groups failed to fully replicate the primary results but the original authors claimed overall support for the general conclusions. Because of its potential clinical importance, the current work studied the effects of bexarotene using two animal species and highly relevant paradigms. Rats were tested for the ability of bexarotene to prevent changes induced by an Abeta challenge in the form intracerebroventricular (i.c.v) administration of 7PA2 conditioned medium (7PA2 CM) which contains high levels of Abeta species. Bexarotene had no effect on the long-term potentiation of evoked extracellular field excitatory postsynaptic potentials induced by i.c.v. 7PA2 CM. It also had no effect following subcutaneous administration of 2, 5, 10 and 15 mg/kg on behavioral/cognitive impairment using an alternating-lever cyclic-ratio schedule of operant responding in the rat. The effects of bexarotene were further tested using the APPSwFILon, PSEN1*M146L*L286V transgenic mouse model of AD, starting at the time Abeta deposits first begin to develop. Mice were sacrificed after 48 days of exposure to 100 mg bexarotene per day. No significant difference between test and control mice was found using a water-maze test, and no significant difference in the number of Abeta deposits in cerebral cortex, using two different antibodies, was apparent. These results question the potential efficacy of bexarotene for AD treatment, even if instigated in the preclinical period prior to the onset of cognitive deficits reported for human AD. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. PMID- 26025660 TI - Co-operative binding assay for the characterization of mGlu4 allosteric modulators. AB - The interest in the role of metabotropic glutamate receptor 4 (mGlu4) in CNS related disorders has increased the need for methods to investigate the binding of allosteric drug candidates. Our aim is to present the first fully characterized in vitro binding assay of mGlu4 positive allosteric modulators (PAMs). Results suggest that mGlu4 PAMs have characteristic co-operative binding with orthosteric glutamate, which offers a notable insight to the further development of mGlu4 targeted therapies. PMID- 26025662 TI - A Case of Fungus Ball-Type Pansinusitis Due to Fusarium proliferatum. AB - Incidence of fungal sinusitis due to the genus Fusarium has increased during the last two decades. We report a case of fungus ball sinusitis with multiple sinuses involvement in an Iranian 21-year-old woman. The patient was diagnosed as having a fungus ball-type sinusitis in computed tomography scan. The sinus biopsy revealed fungal structures on histopathological and direct microscopic examinations and a Fusarium species arose in culture. Partial sequencing of the translation elongation factor 1-alpha identified the isolate as F. proliferatum. Removal of all lesions by endoscopic surgery resulted in a favorable outcome. To the best of our knowledge, this is the first case of F. proliferatum-associated fungus ball which involved multi-sinus and highlights the efficiency of molecular methods for discrimination of fungal agents involved. PMID- 26025661 TI - Cryptococcus gattii-Induced Infections in Dogs from Southern Brazil. AB - Cryptococcus gattii-induced cryptococcosis is an emerging infectious disease of humans and animals worldwide, with rare descriptions of this infection in domestic animals from Brazil. This study presents the findings associated with C. gattii in dogs from Londrina, Parana, Southern Brazil. Two dogs, a 3-year-old, female German shepherd and a 6-year-old, male Boxer, were evaluated by a combination of pathological, mycological, and molecular diagnostic techniques. Significant pathological alterations included cryptococcal lymphadenitis, meningoencephalitis, tonsillitis, and rhinitis with nasal cryptococcomas in the German shepherd dog, while cryptococcal lymphadenitis and pneumonia were observed in the Boxer; both dogs had pseudocystic cryptococcosis. The mucicarmine histochemical stain readily identified the intralesional cryptococcal budding organisms in all affected tissues. Mycological culture and isolation confirmed the yeasts as C. gattii due to positive reaction with the L-canavanine glycine bromothymol blue agar. A PCR assay using the internal transcribed spacers (ITS)1 and ITS2 primers, which target the ITS1 and 2 regions including the 5.8S rRNA gene, amplified the desired amplicons; direct sequencing confirmed the isolate as C. gattii. ITS nucleotide differentiation demonstrated that the isolate forms part of the ITS type 4 Cryptococcus organisms which corresponds to the C. gattii VGII molecular subtype or the RAPD type 2 Cryptococcus organisms. Collectively, these findings confirmed the participation of C. gattii in the etiopathogenesis of the lesions observed in these dogs and expanded the epidemiological niche of this important mycotic agent to include Southern Brazil. It is noteworthy to mention that previous epidemiological studies have suggested that C. gattii induced cryptococcosis is more frequently diagnosed in Northern relative to Southern Brazil, so these findings might suggest an expansion of the distribution of this agent within continental Brazil. PMID- 26025663 TI - Endothelial progenitor cell dysfunction in myelodysplastic syndromes: possible contribution of a defective vascular niche to myelodysplasia. AB - We set a model to replicate the vascular bone marrow niche by using endothelial colony forming cells (ECFCs), and we used it to explore the vascular niche function in patients with low-risk myelodysplastic syndromes (MDS). Overall, we investigated 56 patients and we observed higher levels of ECFCs in MDS than in healthy controls; moreover, MDS ECFCs were found variably hypermethylated for p15INK4b DAPK1, CDH1, or SOCS1. MDS ECFCs exhibited a marked adhesive capacity to normal mononuclear cells. When normal CD34+ cells were co-cultured with MDS ECFCs, they generated significant lower amounts of CD11b+ and CD41+ cells than in co-culture with normal ECFCs. At gene expression profile, several genes involved in cell adhesion were upregulated in MDS ECFCs, while several members of the Wingless and int (Wnt) pathways were underexpressed. Furthermore, at miRNA expression profile, MDS ECFCs hypo-expressed various miRNAs involved in Wnt pathway regulation. The addition of Wnt3A reduced the expression of intercellular cell adhesion molecule-1 on MDS ECFCs and restored the defective expression of markers of differentiation. Overall, our data demonstrate that in low-risk MDS, ECFCs exhibit various primary abnormalities, including putative MDS signatures, and suggest the possible contribution of the vascular niche dysfunction to myelodysplasia. PMID- 26025664 TI - Transmembrane-Bound IL-15-Promoted Epithelial-Mesenchymal Transition in Renal Cancer Cells Requires the Src-Dependent Akt/GSK-3beta/beta-Catenin Pathway. AB - Intrarenal interleukin-15 (IL-15) plays a major role controlling epithelial survival and polarization both in physiological and pathologic conditions. Herein, we confirmed that human renal cell carcinomas (RCCs) express a membrane bound IL-15 isoform displaying an unusual molecular weight of 27 kDa. Its stimulation with soluble IL-15 receptor alpha chain (s-IL-15Ralpha) triggers epithelial-mesenchymal transition (EMT) process as shown by the down-regulation of E-cadherin and zona occludens 1 and the up-regulation of vimentin and N cadherin and promotes the migratory and invasive properties of RCC. S-IL-15Ralpha treatment triggered the Src/PI3K/Akt/GSK-3beta pathway and promoted beta-catenin nuclei translocation. Deactivation of this pathway by using Src-specific inhibitor PP2, PI3K inhibitor LY294002, and AKT inhibitor MK2206 hampered beta catenin nuclei translocation and suppressed EMT, migration, and invasion of RCC. S-IL-15Ralpha treatment also enhanced Src-dependent phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (Erk1/2). FAK knockdown significantly decreased the migration and invasion of RCC, which suggest that Src-FAK signaling was involved in s-IL-15Ralpha-favored migration and invasion of RCC. At the same time, inhibitors of Erk1/2 also significantly decreased the migration and invasion of RCC but could not reverse s-IL-15Ralpha induced EMT. Taken together, our results reveal that Src-dependent PI3K/Akt/GSK3b/beta-catenin pathway is required for s-IL-15Ra-dependent induction of EMT in RCC, while Src-FAK and Src-Erk1/2 signaling were involved in s-IL 15Ralpha-promoted migration and invasion properties of RCC. Our study provides a better understanding of IL-15 signaling in RCC tumor progression, which may lead to novel targeted therapies and provide some suggestions when using IL-15 in clinic. PMID- 26025665 TI - Presence of insulin-like growth factor binding proteins correlates with tumor promoting effects of matrix metalloproteinase 9 in breast cancer. AB - The stroma of breast cancer can promote the disease's progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV)-Neu] and a triple-negative/basal-like [C3(1)-Simian virus 40 large T antigen (Tag)] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9), an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1)-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1), an MMP9 substrate, were increased in C3(1) Tag;Mmp9(-/-) compared to C3(1)-Tag;Mmp9(+/+) tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1)-Tag;Mmp9(-/-) mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed. PMID- 26025666 TI - Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. AB - Targeting the tumor microenvironment is critical toward improving the effectiveness of cancer therapeutics. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types of the tumor microenvironment, playing an important role in tumor progression. Multiple origins for CAFs have been proposed including resident fibroblasts, adipocytes, and bone marrow. Our laboratory previously identified a novel hematopoietic stem cell (HSC) origin for CAFs; however, the functional roles of HSC-derived CAFs (HSC-CAFs) in tumor progression have not yet been examined. To test the hypothesis that HSC-CAFs promote tumor progression through contribution to extracellular matrix (ECM) and paracrine production of pro-angiogenic factors, we developed a method to isolate HSC-CAFs. HSC-CAFs were profiled on the basis of their expression of hematopoietic and fibroblastic markers in two murine tumor models. Profiling revealed production of factors associated with ECM deposition and remodeling. Functional in vivo studies showed that co-injection of HSC-CAFs with tumor cells resulted in increased tumor growth rate and significantly larger tumors than tumor cells alone. Immunohistochemical studies revealed increased blood vessel density with co injection, demonstrating a role for HSC-CAFs in tumor vascularization. Mechanistic in vitro studies indicated that HSC-CAFs play a role in producing vascular endothelial growth factor A and transforming growth factor-beta1 in endothelial tube formation and patterning. In vitro and in vivo findings suggest that HSC-CAFs are a critical component of the tumor microenvironment and suggest that targeting the novel HSC-CAF may be a promising therapeutic strategy. PMID- 26025668 TI - An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function. AB - Heterozygous, germline nonsense mutations in AXIN2 have been reported in two families with oligodontia and colorectal cancer (CRC) predisposition, including an AXIN2 1989G>A mutation. Somatic AXIN2 mutations predicted to generate truncated AXIN2 (trAXIN2) proteins have been reported in some CRCs. Our studies of cells from an AXIN2 1989G>A mutation carrier showed that the mutant transcripts are not significantly susceptible to nonsense-mediated decay and, thus, could encode a trAXIN2 protein. In transient transfection assays, trAXIN2 was more abundant than wild-type AXIN2 protein, and in contrast to AXIN2, glycogen synthase kinase 3beta inhibition did not increase trAXIN2 levels. Like AXIN2, the trAXIN2 protein interacts with beta-catenin destruction complex proteins. When ectopically overexpressed, trAXIN2 inhibits beta-catenin/T-cell factor-dependent reporter gene activity and SW480 CRC cell colony formation. These findings suggest the trAXIN2 protein may retain some wild-type functions when highly expressed. However, when stably expressed in rat intestinal IEC-6 cells, the trAXIN2 protein did not match AXIN2's activity in inhibiting Wnt mediated induction of Wnt-regulated target genes, and SW480 cells with stable expression of trAXIN2 but not AXIN2 could be generated. Our data suggest the AXIN2 1989G>A mutation may not have solely a loss-of-function role in CRC. Rather, its contribution may depend on context, with potential loss-of-function when AXIN2 levels are low, such as in the absence of Wnt pathway activation. However, given its apparent increased stability in some settings, the trAXIN2 protein might have gain-of-function in cells with substantially elevated AXIN2 expression, such as Wnt pathway-defective CRC cells. PMID- 26025669 TI - Leachate water quality of soils amended with different swine manure-based amendments. AB - In the face of the rising level of manure production from concentrated animal feeding operations (CAFOs), management options are being sought that can provide nutrient recycling for plant growth and improved soil conditions with minimal environmental impacts. Alternatives to direct manure application are composting and thermochemical conversion which can destroy pathogens and improve handling and storage. The effect of four forms of swine manure-based soil amendments (raw, compost, hydrochar, and pyrochar) on soil fertility and leachate water quality characteristics of a sandy soil were investigated in soil incubation experiments. All four amendments significantly increased soil carbon, cation exchange capacity and available nutrient contents of the soil. However, hydrochar amended soil leached lower amounts of N, P, and K compared to the other amendments including the control. On the other hand, pyrochar amended soil leached higher concentrations of P and K. Subsequent tests on the hydrochar for K and N adsorption isotherms and surface analysis via XPS suggested that these nutrients were not sorbed directly to the hydrochar surface. Although it is still not clear how these nutrients were retained in the soil amended with hydrochar, it suggests a great potential for hydrochar as an alternative manure management option as the hydrochar can be soil applied while minimizing potential environmental issues from the leaching of high nutrient concentrations to water bodies. PMID- 26025667 TI - STAT1: A Novel Target of miR-150 and miR-223 Is Involved in the Proliferation of HTLV-I-Transformed and ATL Cells. AB - We have previously reported on the deregulation of cellular microRNAs involved in hematopoiesis and inflammation in human T-cell lymphotropic virus type 1 (HTLV-I) transformed cells. In this study, we demonstrate that miR-150 and miR-223 specifically target the signal transducer and activator of transcription 1 (STAT1) 3' untranslated region, reducing STAT1 expression and dampening STAT1 dependent signaling in human T cells. The effects of miR-150 and miR-223 on endogenous STAT1 were confirmed using inducible cell lines. Our studies also showed that miR-150 expression is upregulated by interleukin-2 signaling in adult T cell leukemia/lymphoma (ATL) cells. HTLV-I-transformed and ATL-derived cells have reduced levels of miR150 and miR223 expression, which coincide with increased STAT1 expression and STAT1-dependent signaling. Knockdown of STAT1 by short hairpin RNA demonstrated that the constitutive activation of STAT1 is required for the continuous proliferation of HTLV-I-transformed cells. Our studies further demonstrate that increased expression of STAT1 in ATL cells is associated with higher levels of major histocompatibility complex class I expression. Previous studies have demonstrated that the pressure exerted by natural killer (NK) cells in vivo can edit leukemic tumor cells by forcing an increased expression of major histocompatibility complex class I to escape immune clearance. STAT1-expressing tumor cells produce more aggressive tumors because they cannot be eliminated by NK cells. Our results suggest that therapeutic approaches using combined targeting of STAT1 and MHC class I may be an effective approach to activate NK cell-mediated clearance of ATL tumor cells. PMID- 26025674 TI - Cell-cell fusion induced by the Ig3 domain of receptor FGFRL1 in CHO cells. AB - FGFRL1 is a single-pass transmembrane protein with three extracellular Ig domains. When overexpressed in CHO cells or related cell types, it induces cell cell fusion and formation of large, multinucleated syncytia. For this fusion promoting activity, only the membrane-proximal Ig domain (Ig3) and the transmembrane domain are required. It does not matter whether the transmembrane domain is derived from FGFRL1 or from another receptor, but the distance of the Ig3 domain to the membrane is crucial. Fusion can be inhibited with soluble recombinant proteins comprising the Ig1-Ig2-Ig3 or the Ig2-Ig3 domains as well as with monoclonal antibodies directed against Ig3. Mutational analysis reveals a hydrophobic site in Ig3 that is required for fusion. If a single amino acid from this site is mutated, fusion is abolished. The site is located on a beta-sheet, which is part of a larger beta-barrel, as predicted by computer modeling of the 3D structure of FGFRL1. It is possible that this site interacts with a target protein of neighboring cells to trigger cell-cell fusion. PMID- 26025675 TI - Identification and functional characterization of Trypanosoma brucei peroxin 16. AB - Protozoan parasites of the family Trypanosomatidae infect humans as well as livestock causing devastating diseases like sleeping sickness, Chagas disease, and Leishmaniasis. These parasites compartmentalize glycolytic enzymes within unique organelles, the glycosomes. Glycosomes represent a subclass of peroxisomes and they are essential for the parasite survival. Hence, disruption of glycosome biogenesis is an attractive drug target for these Neglected Tropical Diseases (NTDs). Peroxin 16 (PEX16) plays an essential role in peroxisomal membrane protein targeting and de novo biogenesis of peroxisomes from endoplasmic reticulum (ER). We identified trypanosomal PEX16 based on specific sequence characteristics and demonstrate that it is an integral glycosomal membrane protein of procyclic and bloodstream form trypanosomes. RNAi mediated partial knockdown of Trypanosoma brucei PEX16 in bloodstream form trypanosomes led to severe ATP depletion, motility defects and cell death. Microscopic and biochemical analysis revealed drastic reduction in glycosome number and mislocalization of the glycosomal matrix enzymes to the cytosol. Asymmetry of the localization of the remaining glycosomes was observed with a severe depletion in the posterior part. The results demonstrate that trypanosomal PEX16 is essential for glycosome biogenesis and thereby, provides a potential drug target for sleeping sickness and related diseases. PMID- 26025676 TI - PAK1 is involved in sensing the orientation of collagen stiffness gradients in mouse fibroblasts. AB - Migrating cells sense variations of stiffness in connective tissue matrices but how cells detect and respond to stiffness orientation is not defined. We examined cell extension formation on collagen with underlying support (vertical stiffness gradient) or on collagen laterally supported by nylon (lateral stiffness gradient). At 6 h after plating, cells plated on laterally-supported collagen exhibited >2-fold more abundant and ~2-fold longer cell extensions than cells plated on collagen with underlying support. We examined whether p21-activated kinase 1 (PAK1) influences extension formation that is dependent on the orientation of support. At 6 h after plating on collagen with underlying support, wild-type cell extensions were 40% shorter than PAK1 knockdown cells. In contrast, on laterally-supported collagen, wild-type cell extensions were 2-fold longer than PAK1 knockdown cells. In cells plated on laterally-supported collagen, there were ~2-fold reductions of collagen fiber alignment and compaction in PAK1 knockdown cells compared with wild-type cells. PAK1 knockdown did not affect collagen fiber alignment or compaction by cells plated on collagen with underlying support. Wild-type cells with lateral support of collagen exhibited 3-fold increases of phospho-myosin staining at 6h, which was 2-fold lower in PAK1 knockdown cells. In contrast, cells on collagen with underlying support showed no increase of phospho-myosin staining at any times. PAK1 knockdown did not affect alpha2 or beta1 integrin expression or function. We conclude that PAK1 is involved in the ability of cells to sense the orientation of stiffness in collagen substrates and generate contractile forces that affect cell extension formation. PMID- 26025677 TI - Active cell mechanics: Measurement and theory. AB - Living cells are active mechanical systems that are able to generate forces. Their structure and shape are primarily determined by biopolymer filaments and molecular motors that form the cytoskeleton. Active force generation requires constant consumption of energy to maintain the nonequilibrium activity to drive organization and transport processes necessary for their function. To understand this activity it is necessary to develop new approaches to probe the underlying physical processes. Active cell mechanics incorporates active molecular-scale force generation into the traditional framework of mechanics of materials. This review highlights recent experimental and theoretical developments towards understanding active cell mechanics. We focus primarily on intracellular mechanical measurements and theoretical advances utilizing the Langevin framework. These developing approaches allow a quantitative understanding of nonequilibrium mechanical activity in living cells. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26025678 TI - Protein kinase CK2 is necessary for the adipogenic differentiation of human mesenchymal stem cells. AB - CK2 is a serine/threonine protein kinase, which is so important for many aspects of cellular regulation that life without CK2 is impossible. Here, we analysed CK2 during adipogenic differentiation of human mesenchymal stem cells (hMSCs). With progress of the differentiation CK2 protein level and the kinase activity decreased. Whereas CK2alpha remained in the nucleus during differentiation, the localization of CK2beta showed a dynamic shuttling in the course of differentiation. Over the last years a large number of inhibitors of CK2 kinase activity were generated with the idea to use them in cancer therapy. Our results show that two highly specific inhibitors of CK2, CX-4945 and quinalizarin, reduced its kinase activity in proliferating hMSC with a similar efficiency. CK2 inhibition by quinalizarin resulted in nearly complete inhibition of differentiation whereas, in the presence of CX-4945, differentiation proceeded similar to the controls. In this case, differentiation was accompanied by the loss of CX-4945 inhibitory function. By analysing the subcellular localization of PPARgamma2, we found a shift from a nuclear localization at the beginning of differentiation to a more cytoplasmic localization in the presence of quinalizarin. Our data further show for the first time that a certain level of CK2 kinase activity is required for adipogenic stem cell differentiation and that inhibition of CK2 resulted in an altered localization of PPARgamma2, an early regulator of differentiation. PMID- 26025679 TI - Mechanics of lipid bilayers: What do we learn from pore-spanning membranes? AB - The mechanical properties of biological membranes have become increasingly important not only from a biophysical viewpoint but also as they play a substantial role in the information transfer in cells and tissues. This minireview summarizes some of our recent understanding of the mechanical properties of artificial model membranes with particular emphasis on membranes suspending an array of pores, so called pore-spanning membranes. A theoretical description of the mechanical properties of these membranes might pave the way to biophysically describe and understand the complex behavior of native biological membranes. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26025680 TI - JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation. AB - JMJD5 is a Jumonji C domain-containing demethylase/hydroxylase shown to be essential in embryological development, osteoclastic maturation, circadian rhythm regulation and cancer metabolism. However, its role and underlying mechanisms in oncogenesis remain unclear. Here, we demonstrate that JMJD5 forms complex with the tumor suppressor p53 by interacting with p53 DNA-binding domain (DBD), and negatively regulates its activity. Downregulation of JMJD5 resulted in increased expression of multiple p53 downstream genes, such as the cell cycle inhibitor CDKN1A and DNA repair effector P53R2, only in p53-proficient lung cancer cells. Upon DNA damage, the JMJD5-p53 association decreased, and thereby, promoted p53 recruitment to the target genes and stimulated its transcriptional activity. Furthermore, JMJD5 facilitated the cell cycle progression in a p53-dependent manner under both normal and DNA damage conditions. Depletion of JMJD5 inhibited cell proliferation and enhanced adriamycin-induced cell growth suppression in the presence of p53. Collectively, our results reveal that JMJD5 is a novel binding partner of p53 and it functions as a positive modulator of cell cycle and cell proliferation mainly through the repression of p53 pathway. Our study extends the mechanistic understanding of JMJD5 function in cancer development and implicates JMJD5 as a potential therapeutic target for cancer. PMID- 26025681 TI - Identification of lipid droplet structure-like/resident proteins in Caenorhabditis elegans. AB - The lipid droplet (LD) is a cellular organelle that stores neutral lipids in cells and has been linked with metabolic disorders. Caenorhabditis elegans has many characteristics which make it an excellent animal model for studying LDs. However, unlike in mammalian cells, no LD structure-like/resident proteins have been identified in C. elegans, which has limited the utility of this model for the study of lipid storage and metabolism. Herein based on three lines of evidence, we identified that MDT-28 and DHS-3 previously identified in C. elegans LD proteome were two LD structure-like/resident proteins. First, MDT-28 and DHS-3 were found to be the two most abundant LD proteins in the worm. Second, the proteins were specifically localized to LDs and we identified the domains responsible for this targeting in both proteins. Third and most importantly, the depletion of MDT-28 induced LD clustering while DHS-3 deletion reduced triacylglycerol content (TAG). We further characterized the proteins finding that MDT-28 was ubiquitously expressed in the intestine, muscle, hypodermis, and embryos, whereas DHS-3 was expressed mainly in intestinal cells. Together, these two LD structure-like/resident proteins provide a basis for future mechanistic studies into the dynamics and functions of LDs in C. elegans. PMID- 26025683 TI - Smart Clothes to Take Care of People or Smart People Who Use Clothes to Take Care of Themselves? PMID- 26025682 TI - Rhinosinusitis and disseminated cutaneous infection caused by Mycobacterium chelonae in an immunocompromised patient. AB - Mycobacterium chelonae frequently involves the skin, and the disseminated form can be observed in immunocompromised patients. In contrast, rhinosinusitis caused by the bacterium is a rare manifestation, which occurs independently of immune status. We report here a rare case of M. chelonae infection presenting as both disseminated cutaneous infection and rhinosinusitis in an immunocompromised patient. He had received systemic corticosteroids for 11 months due to cryptogenic organizing pneumonia. Before admission, he sustained injuries to his left arm and hand; those injuries succumbed to an infection that would subsequently spread to his other limbs, face, and even nasal cavities. This valuable case suggests that disseminated cutaneous infection by M. chelonae could spread to other organs. PMID- 26025684 TI - Structural Damage to Jailed Guidewire During the Treatment of Coronary Bifurcations: Microscopic Evaluation. AB - INTRODUCTION AND OBJECTIVES: The use of the jailed guidewire technique is highly useful when treating bifurcation lesions by provisional stenting. However, at the time of withdrawal, the guidewire can suffer damage and even fracture. The aim of this study was to evaluate structural damage in both polymer-coated and nonpolymer-coated jailed guidewires. METHODS: Between January 2011 and December 2012, an observational study was conducted using stereoscopic microscopy to evaluate 135 jailed guidewires (45 nonpolymer-coated and 90 polymer-coated) previously used in the percutaneous treatment of bifurcation lesions. Damage after withdrawal was classified as mild, moderate, or severe. RESULTS: Age and sex distributions were similar in both groups of patients treated with polymer coated and nonpolymer-coated guidewires. However, operators selected polymer coated guidewires more frequently when treating more complex bifurcations and in diabetic patients. Some type of microscopic damage was observed in 25 of the guidewires analyzed (18%). Paradoxically, damage was more common in nonpolymer coated guidewires (53.0% vs 1.1%; P<.001). None of the guidewires suffered complete fracture. CONCLUSIONS: Coronary guidewires that are jailed during the treatment of bifurcations using provisional stenting often suffer nonsevere microscopic damage. Although polymer-coated guidewires were used in more complex bifurcation lesions, paradoxically, they were damaged less frequently. PMID- 26025685 TI - Lower limb ischemia, Candida parapsilosis and prosthetic valve endocarditis. PMID- 26025686 TI - Physics for physicians. PMID- 26025687 TI - Sclerocornea. PMID- 26025688 TI - Musculoskeletal manifestations of diabetes mellitus. AB - The prevalence of Type 1 and Type 2 diabetes are increasing significantly worldwide. Whilst vascular complications of diabetes are well recognized, and account for principle mortality and morbidity from the condition, musculoskeletal manifestations of diabetes are common and whilst not life threatening, are an important cause of morbidity, pain and disability. Joints affected by diabetes include peripheral joints and the axial skeleton. Charcot neuroarthropathy is an important cause of deformity and amputation associated with peripheral neuropathy. A number of fibrosing conditions of the hands and shoulder are recognized, including carpal tunnel syndrome, adhesive capsulitis, tenosynovitis and limited joint mobility. People with diabetes are more prone to gout and osteoporosis. Management of these conditions requires early recognition and close liaison between diabetes and rheumatology specialists. PMID- 26025689 TI - Short telomere syndrome and fibrosis. PMID- 26025690 TI - The Asian Network for Obstructive Lung Disease (ANOLD)-COPD from an Asian perspective. PMID- 26025691 TI - Symptom-to-door times in patients presenting with ST elevation myocardial infarction--do ethnic or gender differences exist? AB - BACKGROUND: Studies have shown higher in-hospital mortality for female patients and ethnic minorities admitted to hospital with acute ST elevation myocardial infarction (STEMI). Pre-hospital delay is thought to be associated with increased in-hospital mortality. AIM: To assess the impact of gender and ethnicity on symptom-to-door time (STDT) in patients presenting with STEMI. DESIGN: Retrospective survey of consecutive patients receiving primary percutaneous coronary intervention between January 2008 and January 2013. A multivariate model was used to adjust for confounders. MAIN OUTCOME MEASURE: Influence of gender and ethnicity on STDT. RESULTS: We analysed 1020 patients (75% male, 263 South Asians, 38 Afro Caribbeans and 719 White Europeans.) There was a trend towards longer unadjusted median STDT in women compared with men (132 min vs. 113 min P = 0.07) which disappeared after correction for age and ethnicity (P = 0.15). There was no gender difference in hospital mortality after correction for age (odds ratio 0.69, 95% confidence interval 0.40-1.18, P = 0.17). On linear regression analysis South Asians showed a trend towards longer STDT than other ethnic groups (P = 0.08) however after adjustment for diabetes there was no association between South Asian ethnicity and hospital mortality. CONCLUSIONS: Neither female gender nor ethnicity were shown to be associated with significant pre-hospital delay. PMID- 26025692 TI - Decreased risk of intracerebral hemorrhage among patients with milder allergic rhinitis. AB - BACKGROUND: This study investigated whether allergic rhinitis (AR) increases the risk of intracerebral hemorrhage (ICH). METHODS: Using Taiwanese insurance outpatient claims data, 52,870 patients with new diagnoses of AR between 2000 and 2010 were identified, and 105,680 age- and sex-frequency matched people without AR were chosen randomly as controls. Risks of ICH were correlated with AR and comorbidities, such as diabetes, hypertension, coronary artery disease, hyperlipidemia, disease and chronic kidney disease, and were estimated by the end of 2011. RESULTS: The risk of ICH was lower in the AR cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 0.58 (95% confidence interval [CI] = 0.50-0.66), assessed using the multivariable Cox model. Age specific analysis demonstrated that the aHR for ICH in the AR patients increased with age, with an aHR of 0.53 (95% CI = 0.39-0.71) in the <=49-year age group, which increased to 0.72 (95% CI = 0.59-0.89) in the elderly age group. The risk of ICH increased with the severity of AR, from an aHR of 0.47 (95% CI = 0.40 0.56) in mild AR patients to 2.55 (95% CI = 1.88-3.47) in severe ones. For patients without comorbidities, the risk of ICH was 0.46 times (95% CI = 0.34 0.63) lower in the AR cohort than in the comparison cohort. CONCLUSION: This study showed for the first time that milder AR is correlated with a reduction in the risk of ICH, particularly for elderly patients. PMID- 26025693 TI - Bardet-Biedl syndrome in two siblings: a rare entity revisited. PMID- 26025694 TI - The selective outpatient treatment of adults with imported falciparum malaria: a prospective cohort study. AB - BACKGROUND: Current UK malaria treatment guidelines recommend admission for all patients diagnosed with falciparum malaria. However, evidence suggests that certain patients are at lower risk of severe malaria and death and may be managed as outpatients. AIM: To prospectively assess the risk of post-treatment severe falciparum malaria in selected cases managed as outpatients. The readmission rate and treatment tolerability were assessed as secondary outcomes. DESIGN: Prospective cohort study. METHODS: Adults (>15 years old) diagnosed with falciparum malaria between May 2008 and July 2012 were selected for outpatient treatment using locally defined clinical and laboratory indicators based on known risk factors for severity and death. Treatment outcomes were assessed in clinic or by telephone 4-6 weeks after treatment. RESULTS: 269 adults were diagnosed with falciparum malaria on blood film between May 2008 and July 2012. Of 255 eligible participants, 106 patients were offered ambulatory treatment, of which 95 completed the study. The severe malaria rate was 0% (95% confidence interval (CI) 0-3.8%) and the readmission rate was 5.3% (95% CI 1.7-11.9) in the outpatient group. In addition, 10.6% (95% CI 5.2-18.7%) of outpatients reported drug-related side effects. CONCLUSIONS: The outpatient treatment of selected cases of falciparum malaria is effective in our high volume UK setting. We recommend adopting a similar approach to managing this infection in other non endemic settings where immediate access to specialist advice is available. PMID- 26025695 TI - Octreotide for hypoglycemia caused by sulfonylurea and DPP-4 inhibitor. AB - We describe a type 2 diabetes patient with persistent hypoglycemia caused by sulfonylurea misuse on top of a DPP-4 inhibitor. Hyperinsulinemia was exaggerated by dextrose administration, but was successfully treated with octreotide. Since many patients are currently treated with DPP-4 inhibitors, the importance of octreotide has been increasing. For refractory sulfonylurea-induced hypoglycemia, especially when the patient is also being given an incretin-based therapy, octreotide should be considered. PMID- 26025696 TI - Genotype screening of APLN rs3115757 variant in Egyptian women population reveals an association with obesity and insulin resistance. AB - AIMS: Apelin is one of adipokines that plays a pivotal role in energy metabolism, insulin sensitivity and vascular integrity. A definite genetic variant of apelin gene (APLN), rs3115757, was recently introduced to potentially influence apelin expression in adipocytes. The aim of our study was to explore the sights of a potential association of this functional variant with obesity traits, insulin resistance indices as well as type 2 diabetes mellitus (T2DM) prevalence. METHODS: Genotype screening for rs3115757 variant in 151 Egyptian female samples was conducted. Fasting levels of serum insulin and lipid profile, in addition to plasma glucose were measured. Cochran-Armitage trend test was used to decide the risk allele and evaluate the association between the candidate variant and obesity using a case-control design. RESULTS: The homozygous G risk allele carriers showed higher values of body mass index (BMI) and waist circumference (P=0.001,0.02, respectively) as compared to CC or CG genotypes. As for GG genotype carriers, the risk of developing morbid obesity in lean subjects, (BMI<25), is twelve times the risk in subjects carrying other genotypes (OR=12.09, 95% CI: 1.4, 104.8, P=0.024). On the other hand, GG carriers are shown to be more resistant to insulin. Significantly after correction for BMI and age effects, GG genotype carriers showed 14% and 41% increment in insulin level and resistance (OR=1.14, 95% CI: 1.06, 1.23, P=0.001), (OR=1.42, 95% CI: 1.19, 1.70, P<0.001), respectively. CONCLUSION: These results suggest a prospective role mediated by this variant in mounting obesity disorders and as significant as insulin resistance complications. PMID- 26025697 TI - Oxidative stress and antioxidant status in women with gestational diabetes mellitus diagnosed by IADPSG criteria. AB - AIMS: The relationship between oxidative stress and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria diagnosed gestational diabetes mellitus GDM isn't well known. Our aim is to evaluate the oxidative stress in women diagnosed by the IADPSG criteria versus the American Diabetes Association (ADA) criteria in China. METHODS: Malondialdehyde (MDA), 8 isoprostane (8IsoP), xanthine oxidize (XO), lipid peroxides (LPO), superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC), vitamin C (Vc) and vitamins E (Ve) were determined in maternal and cord plasma and placenta of 68 pregnant women. Among these, 28 were diagnosed with GDM while the other 40 were controls. RESULTS: The maternal, cord and placental MDA, XO and 8IsoP levels were significantly higher while SOD and TAC levels were significantly lower in GDM women by either criterion (P < 0.05). XO and 8IsoP levels were higher in ADA group than IADPSG only group while TAC levels significant lower (P < 0.05). Cord MDA, cord and placental XO, and maternal and cord 8IsoP showed significant positive relationship with HbA1c values (P < 0.05). Cord XO levels increased (P < 0.05) while maternal and placental SOD levels decreased (P < 0.05) in women who received cesarean section compared with those delivered normally. Increased XO levels and decreased Ve levels in cord plasma were also found in macrosomia (P < 0.05). CONCLUSIONS: Oxidative stress is present in women diagnosed by IADPSG but to a lesser degree than by ADA. All these women should be monitored and perhaps antioxidant supplemented. PMID- 26025699 TI - The effect of electronic reminders on risk management among diabetic patients in low resourced settings. AB - BACKGROUND: Information technology has potential to improve health care delivery particularly among individuals with chronic diseases such as diabetes in low and middle-income countries (LMIC). Research on the usefulness of information technology to manage persons living with chronic diseases is scarce in LMIC. We sought to evaluate the effect of an electronic reminder system on cardiovascular risk factors (blood pressure, heart rate, and fasting plasma glucose) and adherence to clinical appointments among persons living with diabetes. RESEARCH DESIGN AND METHODS: A randomized controlled design was used to recruit 200 diabetic patients (intervention n=100, control n=100) from the National Diabetes Management Research Centre, Accra. All patients received usual diabetes care. The intervention group was given electronic reminders for their clinical appointments and their physicians were prompted with abnormal laboratory results for six months. RESULTS: Baseline characteristics were largely similar for both groups. At six months follow up, the mean reductions of all the cardiovascular risk factors in the intervention group were significantly greater than in the control group: -1.7 kg/m(2) versus -1.1 kg/m(2)(p=0.002) for BMI; -4.7 mmHg versus -2.8 mmHg (p=0.002) for SBP; -5.3 mmH versus -3.1 mmHg (p=0.001) for DBP; -1.7 bpm versus -0.1 bpm (p=0.001) for heart rate and -2.3 mmol/L versus -1.6 mmol/L (p=0.001) for fasting plasma glucose, respectively. Adherence to appointment schedules was also significantly higher in the intervention group compared with the control group (97.8% versus 89.4%, p=0.010). CONCLUSIONS: Locally developed electronic initiatives such as this resulted in improved cardiovascular risk factors and effective compliance to clinical practices and improved quality of care for persons living with diabetes. PMID- 26025698 TI - A possible relationship between renal impairment and complications development in type 2 diabetes mellitus: a prospective, observational study in Italy. AB - BACKGROUND: We investigated the relationship between complications development and estimated glomerular filtration rate (eGFR), in a cohort of type 2 diabetes mellitus (T2DM) outpatients. METHODS: This observational study considered 1284 T2DM outpatients, who had been followed-up for 4.5 +/- 1.6 years. eGFR was estimated using Chronic Kidney Disease Epidemiology Collaboration equation. The independent relationship between development of complications and clinical data was evaluated, and hazard ratio (HR) by Cox regression analysis calculated. RESULTS: Mean age of the population was 66.8 +/- 10.4 years; mean serum creatinine and eGFR were 1.05 +/- 0.36 mg/dl and 71.6 +/- 21.6 ml/min/1.73 m(2), respectively. Complications including death (14.2% of the whole population) were recorded in 504 subjects (39.3%). Patients with complications were older and more frequently male with history of hypertension, coronary heart disease, congestive heart disease, retinopathy, nephropathy and had higher levels of glycated hemoglobin. At Cox regression analysis, eGFR was the major risk factor for development of complications, and the HR increased according with lower eGFR (HR 1.53 and 1.86, for eGFR<45 and<30 ml/min/1.73 m(2), respectively). CONCLUSIONS: In our cohort of T2DM outpatients, a reduced eGFR was associated with an increased risk of complications development. PMID- 26025700 TI - Matrix metalloproteinase-2 (MMP-2) gene polymorphism and cardiovascular comorbidity in type 2 diabetes patients. AB - OBJECTIVE: Matrix metalloproteinases (MMPs) play an important role in pathogenesis of atherosclerosis and vascular disease. We hypothesized that MMP-2 might be a susceptibility gene for cardiovascular disease (CVD) in diabetes. The aim of this study was to evaluate the association between C(-1306)T functional polymorphism in the MMP-2 gene and risk of CVD in type 2 diabetes patients. METHODS: We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the C(-1306)T polymorphism by polymerase chain reaction (PCR) and restriction analysis. RESULTS: A significant decrease of T allele frequency was observed in patients with CVD versus those with no CVD (OR 0.44, 95% CI 0.36 0.52, p<0.0001). In contrast, OR for CC genotype was 2.19 (1.79-2.68, p<0.0001), conferring 2-fold greater odds for CVD. When the distribution of C(-1306)T was compared in subgroups with different clinical phenotypes of CVD, patients with stroke had the lowest frequency of T allele (6% vs. 11%), compared to entire CVD+ group (p<0.05). CONCLUSIONS: T2DM patients carrying the T allele of MMP-2 C( 1306)T polymorphism have a significantly reduced risk of CVD. The C(-1306)T polymorphism is associated with susceptibility to stroke in T2DM patients. PMID- 26025701 TI - Use of DNA sequences to identify forensically important fly species and their distribution in the coastal region of Central California. AB - Forensic entomology has gained prominence in recent years, as improvements in DNA technology and molecular methods have allowed insect and other arthropod evidence to become increasingly useful in criminal and civil investigations. However, comprehensive faunal inventories are still needed, including cataloging local DNA sequences for forensically significant Diptera. This multi-year fly-trapping study was built upon and expanded a previous survey of these flies in Santa Clara County, including the addition of genetic barcoding data from collected species of flies. Flies from the families Calliphoridae, Sarcophagidae, and Muscidae were trapped in meat-baited traps set in a variety of locations throughout the county. Flies were identified using morphological features and confirmed by molecular analysis. A total of 16 calliphorid species, 11 sarcophagid species, and four muscid species were collected and differentiated. This study found more species of flies than previous area surveys and established new county records for two calliphorid species: Cynomya cadaverina and Chrysomya rufifacies. Differences were found in fly fauna in different areas of the county, indicating the importance of microclimates in the distribution of these flies. Molecular analysis supported the use of DNA barcoding as an effective method of identifying cryptic fly species. PMID- 26025703 TI - Peer bids for protection of title 'veterinary nurse'. PMID- 26025702 TI - The Relationship of Bone Mineral Density to Oxidant/Antioxidant Status and Inflammatory and Bone Turnover Markers in a Multicenter Cross-Sectional Study of Young Men with Ankylosing Spondylitis. AB - Low bone mineral density (BMD) is an important complication of ankylosing spondylitis (AS) that seriously affects men and their quality of life, even in young patients. However, the relationships among redox; levels of bone turnover markers (BTMs), inflammatory markers and disease activity; and low BMD in AS require clarification. We recruited 102 men aged 30-39 year with AS and 102 healthy, sex- and age-matched controls for this cross-sectional study. The subjects were analyzed for lumbar spine and femoral neck BMD by dual-energy X-ray absorptiometry. Significantly lower BMD and corresponding T-scores were observed in the AS patients compared with the controls (P < 0.05). The oxidant biomarker and antioxidant levels were significantly (P < 0.05) higher and lower, respectively, in the AS subjects compared with the controls, and the bone resorption and inflammatory marker levels were higher (P < 0.05). In subgroup analyses, the patients with osteoporosis or active disease had the highest levels of oxidant biomarkers (P < 0.05). Furthermore, the BMD T-scores in AS were found to be negatively correlated with oxidative status (P < 0.05). Multivariate binary logistic analysis showed that low BMD in the AS patients was associated with higher levels of advanced oxidation protein products, malondialdehyde and C terminal telopeptide of type I collagen; lower levels of glutathione peroxidase; and higher scores of a bath ankylosing spondylitis metrology index. In conclusion, imbalanced redox was independently associated with low BMD in young men with AS and may play an important role in the pathogenesis of AS-related low BMD. PMID- 26025704 TI - Grant for an online resource to support evidence-based veterinary medicine. PMID- 26025706 TI - Animal welfare 'a priority' in most GB slaughterhouses. PMID- 26025705 TI - Rabies confirmed in an illegally imported dog in France. PMID- 26025707 TI - Setting out a vision for rabbit welfare. PMID- 26025708 TI - Guidance for Welsh farmers on protecting cattle from disease. PMID- 26025710 TI - Recognition for services to the RSPCA. PMID- 26025709 TI - Supporting equine welfare projects at home and abroad. PMID- 26025711 TI - BBC Panorama programme paints clear picture of antibiotic use in people. PMID- 26025713 TI - Survey suggests public trusts vets. PMID- 26025714 TI - Excavating the history of ancient veterinary practices. AB - People have lived alongside animals for many centuries, and it can be assumed that they also treated them when they were sick. There are some texts that describe early veterinary care, but details are lacking and medical instruments are hard to come by in archaeological sites. However, as ANNELISE BINOIS: explains, archaeological findings can provide a lot more information than might be thought, and can start to give a glimpse of the vast history of veterinary medicine. PMID- 26025715 TI - Using early neutering to control unwanted litters. PMID- 26025716 TI - Alternative dispute resolution trial. PMID- 26025717 TI - Pain relief after calf disbudding. PMID- 26025718 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 26025719 TI - Veterinary relief after Nepal earthquake. PMID- 26025720 TI - Equine health questionnaire. PMID- 26025721 TI - Postcards from the front. PMID- 26025722 TI - Masters in veterinary professional studies. AB - Kate Thompson and Dan Shaw will soon become the first graduates of the University of Liverpool's Postgraduate Masters in Veterinary Professional Studies. Catherine McGowan, director of veterinary postgraduate education, and Rebekah Tee, lecturer in small animal practice, believe that the programme marks a new phase in postgraduate education. PMID- 26025723 TI - Online learning for all. AB - Last year, Simon Doherty, president of the North of Ireland Veterinary Association and the BVA's NI Branch, completed a number of MOOCs (massive open online courses) having read about them in Vet Record Careers; here, he describes his experiences. PMID- 26025725 TI - Authors' Reply. PMID- 26025724 TI - Left Ventricular Involvement in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Assessed by Echocardiography Predicts Adverse Clinical Outcome. AB - BACKGROUND: Among studies describing the phenotype of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), significant discrepancy exists regarding the extent and impact of left ventricular (LV) involvement. The capability of conventional and new quantitative echocardiographic techniques to accurately detect LV involvement in ARVD/C remains unknown. The aim of this study was to test the hypothesis that accurate detection of LV involvement on echocardiography identifies patients at additional risk for cardiac events during follow-up. METHODS: Thirty-eight patients with ARVD/C, 16 pathogenic mutation positive relatives, and 55 healthy control subjects were prospectively enrolled. Conventional echocardiography with additional deformation imaging was performed in all subjects to detect LV involvement. In a subgroup (n = 27), cardiac magnetic resonance imaging was performed with late enhancement. All patients and relatives were prospectively followed for events (sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator intervention, sudden cardiac death, and heart transplantation). RESULTS: Conventional echocardiography detected LV involvement in 32% of patients with ARVD/C and in none of the relatives. Deformation imaging revealed LV involvement in 68% of patients with ARVD/C and 25% of relatives and was correlated closely with late enhancement on cardiac magnetic resonance imaging. During a mean follow-up period of 5.9 +/- 2.3 years, 20 patients with ARVD/C (53%) experienced events, and no events occurred in the relatives. LV involvement detected by deformation imaging (hazard ratio, 4.9; 95% CI, 1.7-14.2) and right ventricular outflow tract enlargement (hazard ratio, 1.2; 95% CI, 1.1-1.3) were the only independent predictors of outcomes. CONCLUSIONS: Deformation imaging detected a high incidence of LV involvement in patients with ARVD/C and their relatives. Compared with conventional echocardiography, deformation imaging is superior in detecting minor LV involvement. LV involvement and an enlarged right ventricular outflow tract are independent prognostic markers of outcomes. PMID- 26025726 TI - Quantitative Modeling of the Mitral Valve by Three-Dimensional Transesophageal Echocardiography in Patients Undergoing Mitral Valve Repair: Correlation with Intraoperative Surgical Technique. AB - BACKGROUND: Mitral valve (MV) repair is the procedure of choice for patients with degenerative MV disease (DMVD) with severe mitral regurgitation. The aim of this study was to identify specific quantitative MV parameters from preoperative three dimensional (3D) transesophageal echocardiography that are associated with the length of the mitral annuloplasty band implanted and the performance of leaflet resection in patients with DMVD undergoing MV repair. METHODS: Ninety-four patients (mean age, 60 +/- 11 years; 68% men) referred for MV surgery with adequate-quality preoperative 3D transesophageal echocardiographic studies were retrospectively identified. Parametric maps of the MV were generated using semiautomated MV modeling software. Annular and valvular parameters were measured and indexed to body surface area. The implanted annuloplasty band size and leaflet resection were determined on the basis of surgical reports. RESULTS: Three-dimensional annular circumference correlated best (r = 0.74) with the implanted annuloplasty band length and remained an independent predictor on multivariate linear regression analysis. A third of our cohort (n = 33) had posterior leaflet resection. On receiver operating characteristic curve analysis, P2 segment length >= 20 mm (area under the curve, 0.86; sensitivity, 88%; specificity, 74%) and P2 leaflet area >= 3.4 cm(2) (area under the curve, 0.84; sensitivity, 85%; specificity, 74%) best discriminated the need for leaflet resection. CONCLUSIONS: In DMVD, quantitative 3D annular circumference obtained from semiautomatically generated parametric maps of the MV from 3D transesophageal echocardiographic data was associated with the surgically implanted annuloplasty band length, while P2 leaflet length >= 20 mm and area >= 3.4 cm(2) were associated with the performance of leaflet resection. These parameters should be further investigated for preoperative planning in patients with DMVD undergoing MV repair. PMID- 26025727 TI - Maturational Changes in Diastolic Longitudinal Myocardial Velocity in Preterm Infants. AB - BACKGROUND: Doppler tissue imaging (DTI) has been used to evaluate myocardial velocity during ventricular filling, a means of characterizing diastolic function. Previous studies in older children have shown age-related increases in early diastolic tissue velocities, but there are limited data in preterm infants. The aim of this study was to prospectively determine maturational changes in diastolic tissue velocities at two points in time: (1) 7 days of age and (2) 36 weeks' postmenstrual age (PMA). It was further determined whether DTI measures were altered in infants who developed bronchopulmonary dysplasia with or without pulmonary hypertension. METHODS: A total of 277 preterm infants born at <34 weeks' PMA, with birth weights between 500 and 1,250 g, were prospectively enrolled. Echocardiograms were obtained at 7 days of age and repeated at 36 weeks' PMA. Measurements included DTI assessment of early (E') and late (A') annular velocities of the left ventricular free wall, septum and the right ventricular free wall. Statistical analysis included the Wilcoxon rank sum test, simple linear regression, and the chi(2) test. RESULTS: At 7 days of age, there was a statistically significant increase in the E'/A' ratio as a function of gestational age at birth. At 36 weeks' PMA, E'/A' ratio was increased, but there was no association with gestational age. DTI measures were not different between infants who did or did not develop bronchopulmonary dysplasia or pulmonary hypertension at either time point. CONCLUSIONS: A gestational age-related increase was found in the early diastolic tissue velocities of preterm infants. At a gestational age equivalent to near term, no difference was observed in diastolic tissue velocities, regardless of gestational age at birth. These findings suggest that maturational changes in diastolic function occur relatively independently of the timing of birth. PMID- 26025728 TI - The Effect of Thrombolytic Use and Mechanical Ventilation on Echocardiographic Parameters of Survival after Acute Pulmonary Embolism. PMID- 26025729 TI - Simultaneous Determination of Nitrofuran Metabolites and Chloramphenicol in Shrimp with a Single Extraction and LC-MS/MS Analysis. AB - A method has been developed to quantify the nitrofuran metabolites 3-amino-5 morphorinomethyl-1,3-oxazolidinone, 3-amino-oxazolidinone, 1-aminohydantoin, and semicarbazide, as well as chloramphenicol in shrimp with a single extraction procedure followed by LC-MS/MS analysis. Dynamic selected reaction monitoring with positive and negative ionization mode switching was used. The method LODs were 0.5 ng/g for the nitrofuran metabolites and 0.3 ng/g for chloramphenicol. PMID- 26025731 TI - Is the use of surgical checklists thriving in your OR? PMID- 26025732 TI - Professional versus predatory publishing: cautions for perioperative nurse authors. PMID- 26025730 TI - Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide. AB - Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide, but the disease inevitably recurs in a drug-resistant form after initial treatment. Here, we report that in GBM cells, even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sensitivity. RNAi mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of temozolomide resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress temozolomide-induced tumor regression. Using The Cancer Genome Atlas to analyze mRNA expression patterns in tumors from temozolomide-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial temozolomide therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades temozolomide sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of temozolomide resistance and argue that MMR activity offers a predictive marker for initial therapeutic response to temozolomide treatment. PMID- 26025733 TI - Financing a perioperative nursing education course. PMID- 26025734 TI - Author response. PMID- 26025735 TI - Communicating with a transgender patient. PMID- 26025736 TI - Author response. PMID- 26025737 TI - AORN Surgical Conference & Expo highlights. PMID- 26025740 TI - Using OR patient classification for staffing assignments. AB - Traditionally, one nurse is assigned per OR. Recent health care reforms and the AORN "Position statement on perioperative safe staffing and on-call practices" require managers to rethink this practice. Staffing levels that are insufficient have been linked to sentinel events. A patient classification system that includes patient acuity and procedure complexity can be used to determine which surgical procedures require more than one RN circulator and offer a scientific basis for increasing staff budgetary requests. The goal is to experience fewer sentinel events while providing better patient care and achieving higher nurse retention. PMID- 26025741 TI - Concept analysis: wrong-site surgery. AB - A concept analysis was conducted on the concept of wrong-site surgery (WSS) using the principle-based method by Penrod and Hupcey. It included analysis of WSS within the context of epistemological, pragmatic, linguistic, and logical principles. The analysis found that WSS is an important concept that is universally accepted, but the definition could be improved with inclusion of comprehensive labeling for types of WSS that may occur, such as wrong patient, wrong site, wrong level/part, wrong procedure, and wrong side. Wrong-site surgery falls into the domains of both nursing and medicine, and there is limited research on the topic specific to nursing interventions, perceptions, and contributions to prevent WSS. PMID- 26025742 TI - Reducing surgical errors: implementing a three-hinge approach to success. AB - Surgical errors can have serious consequences including patient deaths, and recent reports suggest that surgical errors continue to occur at unacceptable rates. Studies indicate that causative factors for surgical error include human factors, OR interruptions, staffing issues, and error-reporting trends. A "three hinge" approach can be used to implement a safety program that emphasizes use of a safe surgery checklist and the Centers for Medicare & Medicaid Services reporting requirements for ambulatory surgery centers. The three hinges are the assignment of a change agent, ideally an RN with a doctorate in nursing practice; team cohesiveness; and continuous quality monitoring. PMID- 26025743 TI - The Effect of an Interdisciplinary QI Project to Reduce OR Foot Traffic. AB - We instituted a multidisciplinary educational and operational quality improvement initiative to assess the effect of process interventions on reducing OR door openings and, by extension, surgical site infections. From 2009 to 2012, we conducted an initial trial to gather information and identify reasons for door openings followed by a three-phase investigation that evaluated a total of 102 orthopedic hip and knee procedures in which we counted door openings from the time of incision to the closing of the capsule. We analyzed the effectiveness of door opening deterrents (eg, a pull shade, magnetic yellow caution tape across the door frame) and changes in traffic processes (eg, clear-covered implant carts). The interventions and process changes showed a 50% reduction in door openings compared to the baseline. PMID- 26025744 TI - Guideline implementation: local anesthesia. AB - It is not uncommon in perioperative settings for patients to receive local anesthesia for a variety of procedures. It is imperative for patient safety that the perioperative RN has a comprehensive understanding of best practices associated with the use of local anesthesia. The updated AORN "Guideline for care of the patient receiving local anesthesia" provides guidance on perioperative nursing assessments and interventions to safely care for patients receiving local anesthesia. This article focuses on key points of the guideline to help perioperative personnel become knowledgeable regarding best practice as they care for this patient population. The key points address patient assessment, the importance of having an overall understanding of the local agent being used, recommended monitoring requirements, and potential adverse events, including life threatening events. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 26025745 TI - Local anesthetic systemic toxicity: perioperative implications. PMID- 26025747 TI - An easily forgotten tube. PMID- 26025748 TI - Deterioration of pre-existing hemiparesis due to an ipsilateral internal capsule infarction after a contralateral stroke. PMID- 26025749 TI - Olfactory hallucinations as primary symptom for ischemia in the right posterior insula. PMID- 26025750 TI - Can old dogs learn new "transfusion requirements in critical care": a survey of packed red blood cell transfusion practices among members of The American Association for the Surgery of Trauma. AB - BACKGROUND: The objective of this study was to characterize variations in packed red blood cell (PRBC) transfusion practices in critically ill patients and to identify which factors influence such practices. We hypothesized that significant variation in transfusion triggers exists among acute care surgeons. METHODS: A survey of PRBC transfusion practices was administered to the American Association for the Surgery of Trauma members. The scenarios examined hemoglobin thresholds for which participants would transfuse PRBCs. RESULTS: A hemoglobin threshold of less than or equal to 7 g/dL was adopted by 45% of respondents in gastrointestinal bleeding, 75% in penetrating trauma, 66% in sepsis, and 62% in blunt trauma. Acute care surgeons modified their transfusion trigger significantly in the majority of the modifications of these scenarios, often inappropriately so. CONCLUSIONS: This study documents continued evidence-practice gaps and wide variations in the PRBC transfusion practices of acute care surgeons. Numerous clinical factors altered such patterns despite a lack of supporting evidence (for or against). PMID- 26025751 TI - Framework for a critical evaluation of surgical literature. PMID- 26025752 TI - Introduction of a fresh cadaver laboratory during the surgery clerkship improves emergency technical skills. AB - BACKGROUND: Student acquisition of technical skills during the clinical years of medical school has been steadily declining. To address this issue, the authors instituted a fresh cadaver-based Emergency Surgical Skills Laboratory (ESSL). METHODS: Sixty-three medical students rotating through the third-year surgery clerkship participated in a 2-hour, fresh cadaver-based ESSL conducted during the first 2 days of the clerkship. The authors evaluated students utilizing both surgical skills and written examination before the ESSL and at 4 weeks post ESSL. RESULTS: Students demonstrated a mean improvement of 64% (+/-11) (P < .001) and 38% (+/-17) (P < .001) in technical skills and clinical knowledge, respectively. When technical skills were compared between cohorts, there were no differences observed in both pre- and post-testing (P = .08). CONCLUSIONS: A fresh cadaver laboratory is an effective method to provide proficiency in emergency technical skills not acquired during the clinical years of medical school. PMID- 26025753 TI - Transgenic potato plants expressing cry3A gene confer resistance to Colorado potato beetle. AB - The Colorado potato beetle (Leptinotarsa decemlineata Say, CPB) is a fatal pest, which is a quarantine pest in China. The CPB has now invaded the Xinjiang Uygur Autonomous Region and is constantly spreading eastward in China. In this study, we developed transgenic potato plants expressing cry3A gene. Quantitative real time polymerase chain reaction (qRT-PCR) analysis indicated that the cry3A gene expressed in leaves, stems and roots of the transgenic plants under the control of CaMV 35S promoter, while they expressed only in leaves and stems under the control of potato leaf and stem-specific promoter ST-LS1. The mortality of the larvae was higher (28% and 36%) on the transgenic plant line 35S1 on the 3rd and 4th days, and on ST3 (48%) on the 5th day after inoculation with instar larvae. Insect biomass accumulation on the foliage of the transgenic plant lines 35S1, 35S2 and ST3 was significantly lower (0.42%, 0.43% and 0.42%). Foliage consumption was lowest on transgenic lines 35S8 and ST2 among all plant foliage (7.47 mg/larvae/day and 12.46 mg/larvae/day). The different transgenic plant foliages had varied inhibition to larval growth. The survivors on the transgenic lines obviously were smaller than their original size and extremely weak. The transgenic potato plants with CPB resistance could be used to develop germplasms or varieties for controlling CPB damage and halting its spread in China. PMID- 26025754 TI - Population-level consequences of complementary sex determination in a solitary parasitoid. AB - BACKGROUND: Sex determination mechanisms are known to be evolutionarily labile but the factors driving transitions in sex determination mechanisms are poorly understood. All insects of the Hymenoptera are haplodiploid, with males normally developing from unfertilized haploid eggs. Under complementary sex determination (CSD), diploid males can be produced from fertilized eggs that are homozygous at the sex locus. Diploid males have near-zero fitness and thus represent a genetic load, which is especially severe under inbreeding. Here, we study mating structure and sex determination in the parasitoid Cotesia vestalis to investigate what may have driven the evolution of two complementary sex determination loci in this species. RESULTS: We genotyped Cotesia vestalis females collected from eight fields in four townships in Western Taiwan. 98 SNP markers were developed by aligning Illumina sequence reads of pooled DNA of eight different females against a de novo assembled genome of C. vestalis. This proved to be an efficient method for this non-model species and provides a resource for future use in related species. We found significant genetic differentiation within the sampled population but variation could not be attributed to sampling locations by AMOVA. Non-random mating was detected, with 8.1% of matings between siblings. Diploid males, detected by flow cytometry, were produced at a rate of 1.4% among diploids. CONCLUSIONS: We think that the low rate of diploid male production is best explained by a CSD system with two independent sex loci, supporting laboratory findings on the same species. Fitness costs of diploid males in C. vestalis are high because diploid males can mate with females and produce infertile triploid offspring. This severe fitness cost of diploid males combined with non-random mating may have resulted in evolution from single locus CSD to CSD with two independent loci. PMID- 26025755 TI - Combined therapy with shock wave and autologous bone marrow-derived mesenchymal stem cells alleviates left ventricular dysfunction and remodeling through inhibiting inflammatory stimuli, oxidative stress & enhancing angiogenesis in a swine myocardial infarction model. AB - BACKGROUND: We hypothesized that combined therapy with shock wave (SW) and autologous bone marrow-derived mesenchymal stem cells (BMDMSCs) is superior to either therapy alone for alleviating left ventricular (LV) dysfunction. METHODS AND RESULTS: Male mini-pigs (n=30) equally divided into group 1 (sham control), group 2 [acute myocardial infarction (AMI) by left coronary artery ligation], group 3 (AMI-SW), group 4 (AMI-BMDMSC), and group 5 (AMI-SW-BMDMSC) were sacrificed by day 60 and the hearts were collected for studies. Baseline LV injection fraction [LVEF (%)] and LV chamber size did not differ among the five groups (p>0.5). By day 60, LVEF was highest in group 1 and lowest in group 2, significantly higher in group 5 than that in groups 3 and 4, and significantly higher in group 4 than that in group 3 (p<0.001). Cellular and protein levels of VEGF, CXCR4, and SDF-1alpha were significantly increased progressively from groups 1 to 5 (all p<0.05). Small vessel number and protein expressions of CD31 and eNOS were highest in groups 1 and 5, lowest in group 2, and significantly higher in group 4 than those in group 3 (p<0.001). Protein (MMP-9, TNF-1alpha and NF-kappaB) and cellular (CD14+, CD40+) levels of inflammatory biomarkers, protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), apoptosis (Bax, caspase-3, PARP), infarct size, and LV dimensions showed a pattern opposite to that of LVEF among all groups (all p<0.001). CONCLUSIONS: Combined SW-BMDMSC therapy is superior to either therapy alone for improving LVEF, reducing infarct size, and inhibiting LV remodeling. PMID- 26025756 TI - 5-HT1A receptor blockade targeting the basolateral amygdala improved stress induced impairment of memory consolidation and retrieval in rats. AB - The aim of the present study was to investigate the possible role of basolateral amygdala (BLA) 5-HT1A receptors in memory formation under stress. We also examined whether the blockade of these receptors is involved in stress-induced state-dependent memory. Adult male Wistar rats received cannula implants that bilaterally targeted the BLA. Long-term memory was examined using the step through type of passive avoidance task. Behavioral stress was evoked by exposure to an elevated platform (EP) for 10, 20 and 30min. Post-training exposure to acute stress (30min) impaired the memory consolidation. In addition, pre-test exposure to acute stress-(20 and 30min) induced the impairment of memory retrieval. Interestingly, the memory impairment induced by post-training exposure to stress was restored in the animals that received 20- or 30-min pre-test stress exposure, suggesting stress-induced state-dependent memory retrieval. Post training BLA-targeted injection of a selective 5-HT1A receptor antagonist, (S) WAY-100135 (2MUg/rat), prevented the impairing effect of stress on memory consolidation. Pre-test injection of the same doses of (S)-WAY-100135 that was targeted to the BLA also reversed stress-induced memory retrieval impairment. It should be considered that post-training or pre-test BLA-targeted injection of (S) WAY-100135 (0.5-2MUg/rat) by itself had no effect on the memory formation. Moreover, pre-test injection of (S)-WAY-100135 (2MUg/rat) that targeted the BLA inhibited the stress-induced state-dependent memory retrieval. Taken together, our findings suggest that post-training or pre-test exposure to acute stress induced the impairment of memory consolidation, retrieval and state-dependent learning. The BLA 5-HT1A receptors have a critical role in learning and memory under stress. PMID- 26025757 TI - The Effect of Radiation Dose on Swallowing: Evaluation of Aspiration and Kinematics. AB - Radiation oncologists have focused on the pharyngeal constrictors as the primary muscles of concern for dysphagia. However, our prior investigations have demonstrated that radiation dose to the geniohyoid rather than the constrictor muscles was more closely related to penetration aspiration scores (PAS). We examined the relationship between (1) radiation dose and swallowing temporal kinematics, and (2) between PAS and swallowing kinematics in these patients. Videofluoroscopic swallowing studies of 41 patients following radiation therapy for oropharyngeal cancer were analyzed for thin liquid boluses. Timing measures included duration of laryngeal vestibule closure (DLVC), duration to maximum hyoid elevation (DTMHE), duration to cricopharyngeal opening (DTCPO), and pharyngeal transit time (PTT). PAS was extracted for each swallow and considered normal if <= 2. As minimum and mean dose to the geniohyoid increased, DTMHE, DTCPO, and PTT increased. Worse PA scores were most strongly correlated with radiation dose received by geniohyoid (r = 0.445, p < 0.0001). Mean DLVC varied according to PAS group (normal PAS mean = 0.67 s, abnormal PAS mean = 0.13 s; p < 0.001). Similarly, DTCPO was significantly different based upon PAS (normal PAS mean = 0.22 s, abnormal PAS mean = 0.37 s, p = 0.016). As PAS increased, DTPCO and PTT increased (r = 0.208, p = 0.04; r = 0.204, p = 0.043). A negative correlation was noted between PAS and DLVC (r = -0.375, p = 0.001). Higher doses of radiation to the geniohyoid muscles are associated with increased severity of dysphagia as measured through both kinematics and PAS. Consideration of dose to the geniohyoid should be considered when planning radiation. PMID- 26025758 TI - Use of Thickened Liquids to Manage Feeding Difficulties in Infants: A Pilot Survey of Practice Patterns in Canadian Pediatric Centers. AB - Improved survival rates of sick or preterm infants have resulted in an increase of observed feeding difficulties. One common method for managing feeding difficulties in infants is to manipulate liquid viscosity by adding thickening agents to formula or expressed breast milk. Concerns regarding the lack of clinical practice guidelines for the use of this strategy have been raised in the literature and in clinical settings for several years. This study aimed to survey feeding clinicians working in major Canadian pediatric centers to identify current practice patterns for use of thickened liquids in managing feeding difficulties of infants and to justify the need for standardization of this practice. A web-based pilot survey was developed using Fluidsurveys software. The questionnaire contained 37 questions targeting the process of prescribing thickeners, choice of thickener, awareness of issues, and inconsistencies raised in the literature about thickener use and how to address them. A total of 69 questionnaire responses were analyzed using descriptive statistics and inductive thematic analysis methods. Our study results indicate that thickened liquids continue to be broadly used to manage feeding difficulties in Canadian infants, despite numerous areas of concern related to their use raised by our respondents. While clear practice patterns for assessment and management were observed among the respondents, some areas of practice did not reflect recent published research or experts' opinion. Further research to develop a systematic approach for assessment, intervention, and follow-up is warranted to guide clinicians in this complex decision-making process. PMID- 26025759 TI - fMRI reveals lateralized pattern of brain activity modulated by the metrics of stimuli during auditory rhyme processing. AB - Our fMRI study investigates auditory rhyme processing in spoken language to further elucidate the topic of functional lateralization of language processing. During scanning, 14 subjects listened to four different types of versed word strings and subsequently performed either a rhyme or a meter detection task. Our results show lateralization to auditory-related temporal regions in the right hemisphere irrespective of task. As for the left hemisphere we report responses in the supramarginal gyrus as well as in the opercular part of the inferior frontal gyrus modulated by the presence of regular meter and rhyme. The interaction of rhyme and meter was associated with increased involvement of the superior temporal sulcus and the putamen of the right hemisphere. Overall, these findings support the notion of right-hemispheric specialization for suprasegmental analyses during processing of spoken sentences and provide neuroimaging evidence for the influence of metrics on auditory rhyme processing. PMID- 26025760 TI - The p38 MAPK signalling pathway is required for glucose metabolism, lineage specification and embryo survival during mouse preimplantation development. AB - Preimplantation embryo development is an important and unique period and is strictly controlled. This period includes a series of critical events that are regulated by multiple signal-transduction pathways, all of which are crucial in the establishment of a viable pregnancy. The p38 mitogen-activated protein kinase (MAPK) signalling pathway is one of these pathways, and inhibition of its activity during preimplantation development has a deleterious effect. The molecular mechanisms underlying the deleterious effects of p38 MAPK suppression in early embryo development remain unknown. To investigate of the effect of p38 MAPK inhibition on late preimplantation stages in detail, we cultured 2-cell stage embryos in the presence of SB203580 for 48 h and analysed the 8-cell, morula, and blastocyst stages. We determined that prolonged inhibition of the p38 MAPK altered the expression levels of Glut1 and Glut4, decreased glucose uptake during the 8-cell to blastocyst transition, changed the expression levels of transcripts which will be important to lineage commitment, including Oct4/Pou5f1, Nanog, Sox2, and Gata6, and increased cell death in 8-16 cell stage embryos onwards. Strikingly, while the expression levels of Nanog, Gata6 and Oct4/Pou5f1 mRNAs were significantly decreased, Sox2 mRNA was increased in SB203580-treated blastocysts. Taken together, our results provide important insight into the biological processes controlled by the p38 MAPK pathway and its critical role during preimplantation development. PMID- 26025761 TI - Acute cholecystitis associated with infection of Enterobacteriaceae from gut microbiota. AB - Acute cholecystitis (AC) is one of the most common surgical diseases. Bacterial infection accounts for 50% to 85% of the disease's onset. Since there is a close relationship between the biliary system and the gut, the aims of this study were to characterize and determine the influence of gut microbiota on AC, to detect the pathogenic microorganism in the biliary system, and to explore the relationship between the gut and bile microbiota of patients with AC. A total of 185 713 high-quality sequence reads were generated from the faecal samples of 15 patients and 13 healthy controls by 16S rRNA gene pyrosequencing. Patients' samples were significantly enriched in Akkermansia, Enterobacter and Escherichia/Shigella group. The healthy controls, however, showed significant enrichment of Clostridiales, Coprococcus, Coprobacillaceae, Paraprevotella, Turicibacter and TM7-3 in their faecal samples. Escherichia coli was the main biliary pathogenic microorganism, among others such as Klebsiella spp., Clostridium perfringens, Citrobacter freundii and Enterobacter cloacae in the bile of the patients. Additionally, the amount of bile endotoxin significantly correlated with the number of Enterobacteriaceae, especially E. coli. Our data indicate that Enterobacteriaceae might play essential role in the pathogenesis and/or progress of AC. This was verified in an in vivo model using a pathogenic E. coli isolated from one of the patients in guinea pigs and observed marked gallbladder inflammation and morphologic changes. This study thus provides insight which could be useful for the prevention, diagnosis and treatment of AC and related diseases by controlling the growth of Enterobacteriaceae to alleviate the infection. PMID- 26025762 TI - Attitudes of healthcare professionals providing pulmonary rehabilitation toward partnership in care. AB - OBJECTIVES: This multicenter study sought to explore attitudes of pulmonary rehabilitation (PR) professionals toward self-management and which patients' competencies are considered important. BACKGROUND: Self-management in patients with chronic obstructive pulmonary disease (COPD) requires a patients' active role. Whether patient-clinician partnership in care is supported by PR professionals remains unknown. METHODS: Attitudes of 75 PR professionals were assessed using an online version of the Clinician Support - Patient Activation Measure (CS-PAM) 13TM. RESULTS: Mean CS-PAM 13TM activation score was 66.5 (11.9) points - professionals support patient's participation in the care process. However, competencies related to patient as member of a care team and patient as an independent information seeker were only extremely important for 30.7-38.7% and 9.3-17.3% of the professionals, respectively. CONCLUSION: PR professionals embrace the idea of a patients' active role in the process of COPD self management. Nonetheless, endorsement of the patient's involvement as an independent information seeker is needed. PMID- 26025763 TI - Emergent echocardiography and extracorporeal membrane oxygenation: Lifesaving in massive pulmonary embolism. AB - Massive pulmonary embolism is a life-threatening emergency that results in circulatory failure. The main challenges in management are early diagnosis and maintenance of hemodynamic stability. We present a case of a 63-year-old male who was in cardiac arrest. After resuscitation, massive pulmonary embolism was diagnosed with the help of bedside echocardiography and extracorporeal membrane oxygenation (ECMO). We were able to maintain hemodynamic stability and improve hypoxia until the patient underwent embolectomy. This case demonstrates a common presentation of massive pulmonary embolism highlighting the main challenges in its management and the role of echocardiography and ECMO in improving outcomes in such scenarios. PMID- 26025764 TI - Effect of the Schneiderian membrane on the formation of bone after lifting the floor of the maxillary sinus: an experimental study in dogs. AB - A titanium membrane was used to isolate the Schneiderian membrane of the bony walls of the sinus so that we could investigate their role on the formation of bone after sinus lifts compared with a control group (conventional raising of the sinus floor) in which we did not use a membrane to isolate any area. Three canine models of lifting the sinus floor using the lateral window technique were established: conventional lifting of the floor (control group), raising of the floor with the mucosa shielded (mucosal shielding group), and raising of the floor with the bony wall shielded (bony wall shielding group). The formation of bone one and three months after the sinus floor had been lifted was compared in each group both grossly and by histopathological examination. An appreciable amount of new bone had formed in the control group, with abundant areas near the inferior bony wall, and some near the raised Schneiderian membrane. Similarly, new bone had also formed in the mucosal shielding group, with abundant new bone near the inferior bony wall, but none near the raised Schneiderian membrane. However, there was considerably less new bone in the bony wall shielding group, with none in tissues adjacent to the inferior bony wall and little in tissues near the raised Schneiderian membrane. The Schneiderian membrane has osteogenic capability and participates in the formation of bone after the sinus floor has been lifted. However, its osteogenic role is weaker than that of the surrounding bony wall of the maxillary sinus. PMID- 26025765 TI - Interplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer. AB - The WNT/beta-catenin signalling implies its significance in maintaining an epithelial cell phenotype, proper cell-cell junctions, and tissue homeostasis. Dysregulation of the members of this pathway involves in the development of cancer and an epithelial-mesenchymal transition (EMT) required for metastasis. Loss of E-cadherin is the major contributor to an EMT process and is largely influenced by the WNT/beta-catenin signalling. An E-cadherin/beta-catenin complex maintains epithelial integrity and disturbance of this complex and WNT/beta catenin pathway will ultimately lead to the nuclear translocation of beta-catenin and transcription of EMT-promoting genes. WNT/beta-catenin signalling is controlled by microRNAs (miRNAs), several of which are either up- or downregulated during EMT. The strong association between the expression of the WNT signalling components with miRNAs in the initiation and achievement of an EMT phenotype is suggestive of introducing these miRNAs as therapeutic targets against metastatic tumours. Therefore, this review aims to describe these putative miRNAs in altering the WNT/beta-catenin signalling in EMT, and whether targeting them is a useful therapeutic option for human invasive tumours. PMID- 26025767 TI - Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ - The LORD study. AB - BACKGROUND: The current debate on overdiagnosis and overtreatment of screen detected ductal carcinoma in situ (DCIS) urges the need for prospective studies to address this issue. A substantial number of DCIS lesions will never form a health hazard, particularly if it concerns non- to slow-growing low-grade DCIS. The LORD study aims to evaluate the safety of active surveillance in women with low-risk DCIS. DESIGN: This is a randomised, international multicentre, open label, phase III non-inferiority trial, led by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organization for Research and Treatment of Cancer (EORTC-BCG 1401). Standard treatment will be compared to active surveillance in 1240 women aged ? 45 years with asymptomatic, screen-detected, pure low-grade DCIS based on vacuum-assisted biopsies of microcalcifications only. Both study arms will be monitored with annual digital mammography for a period of 10 years. The primary end-point is 10-year ipsilateral invasive breast cancer free percentage. Secondary end-points include patient reported outcomes, diagnostic biopsy rate during follow-up, ipsilateral mastectomy rate and translational research. FEASIBILITY: To explore interest in and feasibility of the LORD study we conducted a survey among EORTC and BOOG centres. A vast majority of EORTC and BOOG responding centres expressed interest in participation in the LORD study. The proposed study design is endorsed by nearly all centres. PMID- 26025766 TI - A model for predicting clinical outcome in patients with human papillomavirus positive tonsillar and base of tongue cancer. AB - AIM: To combine clinical and molecular markers into an algorithm for predicting outcome for individual patients with human papillomavirus (HPV) DNA/p16(INK4a) positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC). BACKGROUND: Head-neck cancer treatment has become more intensified, comprising not only surgery and radiotherapy, but also induction/concomitant chemotherapy and targeted therapy. With less treatment, 3-year disease free survival (DFS) is 80% for HPV-positive TSCC and BOTSCC. An 85-100% 3-year DFS is observed for HPV(+) TSCC and BOTSCC with absence of HLA class I, or CD44 expression, or high CD8(+) tumour-infiltrating lymphocyte (TIL) counts suggesting that therapy could be tapered for many if patients could be identified individually. PATIENTS AND METHODS: Patients treated curatively, with HPV DNA/p16(INK4a) positive tumours examined for HLA class I and II, CD44 and CD8(+)TILs, were included. An L1 regularised logistic regression was used to evaluate the effect of the biomarker data, age, stage, diagnosis, smoking and treatment on 3-year risk of death or relapse on a training cohort of 197 patients diagnosed 2000-2007 and validated on a cohort of 118 patients diagnosed 2008-2011. RESULTS: The variables finally included in the model were HLA class I, CD8(+) TILs, age, stage and diagnosis (TSCC or BOTSCC). The model showed acceptable discrimination and calibration. The discriminative ability of the model did not diminish after validation (AUC=0.77). CONCLUSION: To our knowledge, this is the first model to utilise information from several markers to predict an individual probability of clinical outcome for patients with HPV DNA/p16(INK4a) positive tumours. PMID- 26025768 TI - Bacterial expression and re-engineering of Gaussia princeps luciferase and its use as a reporter protein. AB - Bioluminescence, the generation of visible light in a living organism, is widely observed in nature, and a large variety of bioluminescent proteins have been discovered and characterized. Luciferase is a generic term for bioluminescent enzymes that catalyze the emission of light through the oxidization of a luciferin (also a generic term). Luciferase are not necessarily evolutionary related and do not share sequence or structural similarities. Some luciferases, such as those from fireflies and Renilla, have been thoroughly characterized and are being used in a wide range of applications in bio-imaging. Gaussia luciferase (GLuc) from the marine copepod Gaussia princeps is the smallest known luciferase, and it is attracting much attention as a potential reporter protein. GLuc identification is relatively recent, and its structure and its biophysical properties remain to be fully characterized. Here, we review the bacterial production of natively folded GLuc with special emphasis on its disulfide bond formation and the re-engineering of its bioluminescence properties. We also compare the bioluminescent properties under a strictly controlled in vitro condition of selected GLuc's variants using extensively purified proteins with native disulfide bonds. Furthermore, we discuss and predict the domain structure and location of the catalytic core based on literature and on bioinformatics analysis. Finally, we review some examples of GLuc's emerging use in biomolecular imaging and biochemical assay systems. PMID- 26025770 TI - Advances in protein complex analysis by chemical cross-linking coupled with mass spectrometry (CXMS) and bioinformatics. AB - For the analysis of protein-protein interactions and protein conformations, cross linking coupled with mass spectrometry (CXMS) has become an essential tool in recent years. A variety of cross-linking reagents are used to covalently link interacting amino acids to identify protein-binding partners. The spatial proximity of cross-linked amino acid residues is used to elucidate structural models of protein complexes. The main challenges for mapping protein-protein interaction are low stoichiometry and low frequency of cross-linked peptides relative to unmodified linear peptides as well as accurate and efficient matches to corresponding peptide sequences with low false discovery rates for identifying the site of cross-link. We evaluate the current state of chemical cross-linking and mass spectrometry applications with the special emphasis on the recent development of informatics data processing and analysis tools that help complexity of interpreting CXMS data. This article is part of a Special Issue entitled:Physiological Enzymology and Protein Functions. PMID- 26025769 TI - Subcellular functions of proteins under fluorescence single-cell microscopy. AB - A cell is a highly organized, dynamic, and intricate biological entity orchestrated by a myriad of proteins and their self-assemblies. Because a protein's actions depend on its coordination in both space and time, our curiosity about protein functions has extended from the test tube into the intracellular space of the cell. Accordingly, modern technological developments and advances in enzymology have been geared towards analyzing protein functions within intact single cells. We discuss here how fluorescence single-cell microscopy has been employed to identify subcellular locations of proteins, detect reversible protein-protein interactions, and measure protein activity and kinetics in living cells. Considering that fluorescence single-cell microscopy has been only recently recognized as a primary technique in enzymology, its potentials and outcomes in studying intracellular protein functions are projected to be immensely useful and enlightening. We anticipate that this review would inspire many investigators to study their proteins of interest beyond the conventional boundary of specific disciplines. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions. PMID- 26025771 TI - Effect of pyrrolidinium based ionic liquid on the channel form of gramicidin in lipid vesicles. AB - The present work is focused on the interaction between membrane bound gramicidin and 1-butyl-1-methyl-2-oxopyrrolidinium bromide (BMOP) ionic liquid. Ionic liquids (ILs) are solvents that are often liquid at room temperature and composed of organic cation and appropriate anion. The gramicidin peptide forms prototypical ion channels for cations, which have been extensively used to study the organization, dynamics, and function of membrane spanning channels. The interaction was studied by circular dichroism, steady state, time-resolved fluorescence spectroscopy in combination with dynamic surface tension and field emission scanning electron microscopic methods (FESEM). The results obtained from circular dichroism shows that the BMOP interacts with the channel form of gramicidin in lipid vesicle without any considerable effect on its conformation. The Red-edge excitation shift (REES) also supported the above findings. In addition, the fluorescence studies suggested that BMOP makes ground state complex with ion channel, which was further supported by time resolved measurements. Furthermore, dynamic surface tension analysis shows the faster adsorption of BMOP with membrane bound gramicidin at the air-water interface. Additionally, FESEM results indicated that BMOP forms a film around the membrane bound gramicidin at higher concentration. These results are potentially useful to analyze the effect of ionic liquids on the behaviour of membrane proteins. PMID- 26025772 TI - Stability of urine specimens stored with and without preservatives at room temperature and on ice prior to urinalysis. AB - OBJECTIVES: Laboratories determine the most appropriate approach for the collection and transport of urine specimens. We investigated the effect of a chlorhexidine-based preservative tube on sample stability, compared the results of refrigerated polystyrene tubes with no additives, and investigated the effect of temperature on the performance of preservative tubes. DESIGN AND METHODS: Fresh urine specimen (n=48) aliquots in BD Vacutainer(r) Plus Urinalysis Preservative Tubes and polystyrene tubes were analyzed on an Iris Diagnostics iQ200. Samples in polystyrene tubes were refrigerated for 4 and 8h. Four aliquots in preservative tubes were kept at room temperature for 4, 8, 24, and 72h, while two aliquots were kept on ice for 4 and 8h. RESULTS: There was good agreement for all chemistry and microscopy parameters with the exceptions of white blood cells (WBCs) at 24 and 72h and red blood cells (RBCs) at 72h. Preservative tubes on ice showed a significant decrease in concordance of WBCs and calcium oxalate (CaOx) parameters compared with the results at room temperature. Results of refrigerated polystyrene tubes showed good agreement with the exceptions of WBC clumps and amorphous crystal at 8h. CONCLUSIONS: A chlorhexidine-containing preservative tube seems advantageous for urine sample transport from outside healthcare services. A preservative tube offers comparable results with urine samples kept in a refrigerator for 4-8h for the majority of parameters. Keeping samples at room temperature is recommended when preservative tubes are used because ice produces a negative effect on WBCs and CaOx. PMID- 26025773 TI - Characterization of endogenously circulating IGFBP-4 fragments-Novel biomarkers for cardiac risk assessment. AB - BACKGROUND: Recent findings show that circulating N- and C-terminal fragments of IGF-binding protein-4 (NT-IGFBP-4 and CT-IGFBP-4) can be utilized as biomarkers for cardiac risk assessment in acute coronary syndrome (ACS) patients. The fragments are thought to be the products of pregnancy-associated plasma protein A (PAPP-A)-dependent proteolysis. Two immunoassays for the measurement of IGFBP-4 fragments have been proposed. However, properties of the endogenous IGFBP-4 fragments that could influence the performance of the immunoassays were still not investigated. METHODS: NT- and CT-IGFBP-4 were extracted from pooled ACS plasma using affinity purification, and their concentrations were measured using sandwich immunoassays utilizing antibodies specific to their proteolytic neo epitopes or internal epitopes. The extracted fragments were characterized by Western blots (WB) and mass-spectrometry. ACS plasma samples were analyzed by size exclusion chromatography (SEC). RESULTS: Immunoassays utilizing the neo epitope-specific and the internal epitope-specific antibodies measured equal concentrations of the analyte in the endogenous IGFBP-4 fragments preparations. Only the 18 kDa NT-IGFBP-4 and 14 kDa CT-IGFBP-4 were detected in the WB analysis. Using mass-spectrometry, peaks corresponding to intact non-truncated and non-modified NT-IGFBP-4 (14626 Da) and CT-IGFBP-4 (11346 Da) were observed. The absence of complexed forms of IGFBP-4 in patients' plasma was demonstrated using SEC. CONCLUSIONS: Endogenous NT- and CT-IGFBP-4 from ACS patients' plasma correspond to the PAPP-A-derived IGFBP-4 fragments and do not undergo any truncation, modification, or complex formation in the patients' blood. Because of the demonstrated intact state of the circulating IGFBP-4 fragments, the neo epitope-specific immunoassays perform reliably, allowing further clinical validation of these novel biomarkers. PMID- 26025774 TI - Serum neurogranin measurement as a biomarker of acute traumatic brain injury. AB - OBJECTIVES: Neurogranin (NRGN) is a small neuronal protein that plays an important role in synaptic signaling by regulating calmodulin (CaM) availability. In this study, we developed an ELISA to measure NRGN quantitatively in serum samples from a cohort of acute traumatic brain injury (TBI) patients and a non TBI control cohort, and explored the potential value of NRGN as a circulating biomarker for TBI. DESIGN AND METHODS: Recombinant His-NRGN protein was used to develop mouse monoclonal capture and rabbit polyclonal detection antibodies, and they were used to develop a sandwich ELISA. After validation, we used this ELISA to measure serum samples from a cohort of typical adult acute TBI patients (N=76 TBI cases) and non-TBI control patients (N=150 controls). RESULTS: The NRGN ELISA lower limit of detection was 0.055ng/mL, lower limit of quantification was 0.2ng/mL, and interassay CVs were <=10.7%. The average recovery was 99.9% (range from 97.2-102%). Serum NRGN concentrations in TBI cases were significantly higher than in controls (median values were 0.18ng/mL vs. 0.02ng/mL, p<0.0001), but did not discriminate TBI cases with intracranial hemorrhage (p=0.09). CONCLUSIONS: We have developed a highly sensitive and reproducible ELISA for measuring circulating NRGN in blood samples. Serum NRGN concentrations in acute TBI patients were significantly higher than in controls, indicating that NRGN could have utility as a circulating biomarker for acute TBI. This report provides evidence to support larger and controlled TBI clinical studies for NRGN validation and prediction of outcomes. PMID- 26025776 TI - Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy. AB - PURPOSE: Stereotactic ablative radiation therapy (SABR) is increasingly used to treat lung oligometastases. We set out to determine the safety and efficacy of this approach and to identify factors associated with outcomes. METHODS AND MATERIALS: We conducted a retrospective study of patients treated with SABR for metastatic lung tumors at our institution from 2003 to 2014. We assessed the association between various patient and treatment factors with local failure (LF), progression, subsequent treatment, systemic treatment, and overall survival (OS), using univariate and multivariate analyses. RESULTS: We identified 122 tumors in 77 patients meeting inclusion criteria for this study. Median follow-up was 22 months. The 12- and 24-month cumulative incidence rates of LF were 8.7% and 16.2%, respectively; the 24-month cumulative incidence rates of progression, subsequent treatment, and subsequent systemic treatment were 75.2%, 64.5%, and 35.1%, respectively. Twenty-four-month OS was 74.6%, and median OS was 36 months. Colorectal metastases had a significantly higher cumulative incidence of LF at 12 and 24 months (25.5% and 42.2%, respectively), than all other histologies (4.4% and 9.9%, respectively; P<.0004). The 24-month cumulative incidences of LF for colorectal metastases treated with a biologically effective dose at alpha/beta = 10 (BED10) of <100 Gy versus BED10 of >=100 Gy were 62.5% and 16.7%, respectively (P=.08). Toxicity was minimal, with only a single grade 3 or higher event observed. CONCLUSIONS: SABR for metastatic lung tumors appears to be safe and effective with excellent local control, treatment-free intervals, and OS. An exception is metastases from colorectal cancer, which have a high LF rate consistent with a radioresistant phenotype, suggesting a potential role for dose escalation. PMID- 26025775 TI - Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma. AB - PURPOSE: Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. METHODS AND MATERIALS: From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/MUL within the first 3 months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. RESULTS: Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2 months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46 11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V25Gy) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V25Gy <56% appeared to be the optimal threshold (OR: 2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). CONCLUSIONS: Female sex, older age, lower baseline TLC, and higher brain V25Gy are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V25Gy of brain below 56% may reduce the risk of ASL. PMID- 26025777 TI - Outcomes for Spine Stereotactic Body Radiation Therapy and an Analysis of Predictors of Local Recurrence. AB - PURPOSE: To investigate local control, survival outcomes, and predictors of local relapse for patients treated with spine stereotactic body radiation therapy. METHODS AND MATERIALS: We reviewed the records of 332 spinal metastases consecutively treated with stereotactic body radiation therapy between 2002 and 2012. The median follow-up for all living patients was 33 months (range, 0-111 months). Endpoints were overall survival and local control (LC); recurrences were classified as either in-field or marginal. RESULTS: The 1-year actuarial LC and overall survival rates were 88% and 64%, respectively. Patients with local relapses had poorer dosimetric coverage of the gross tumor volume (GTV) compared with patients without recurrence (minimum dose [Dmin] biologically equivalent dose [BED] 23.9 vs 35.1 Gy, P<.001; D98 BED 41.8 vs 48.1 Gy, P=.001; D95 BED 47.2 vs 50.5 Gy, P=.004). Furthermore, patients with marginal recurrences had poorer prescription coverage of the GTV (86% vs 93%, P=.01) compared with those with in field recurrences, potentially because of more upfront spinal canal disease (78% vs 24%, P=.001). Using a Cox regression univariate analysis, patients with a GTV BED Dmin >=33.4 Gy (median dose) (equivalent to 14 Gy in 1 fraction) had a significantly higher 1-year LC rate (94% vs 80%, P=.001) compared with patients with a lower GTV BED Dmin; this factor was the only significant variable on multivariate Cox analysis associated with LC (P=.001, hazard ratio 0.29, 95% confidence interval 0.14-0.60) and also was the only variable significant in a separate competing risk multivariate model (P=.001, hazard ratio 0.30, 95% confidence interval 0.15-0.62). CONCLUSIONS: Stereotactic body radiation therapy offers durable control for spinal metastases, but there is a subset of patients that recur locally. Patients with local relapse had significantly poorer tumor coverage, which was likely attributable to treatment planning directives that prioritized the spinal cord constraints over tumor coverage. When possible, we recommend maintaining a GTV Dmin above 14 Gy in 1 fraction and 21 Gy in 3 fractions. PMID- 26025778 TI - p53-Based Strategy for Protection of Bone Marrow From Y-90 Ibritumomab Tiuxetan. AB - PURPOSE: The main drawbacks of radioimmunotherapy have been severe hematological toxicity and potential development of myelodysplastic syndrome and secondary leukemia. Activation of p53 follows a major pathway by which normal tissues respond to DNA-damaging agents, such as chemotherapy and radiation therapy, that result in injuries and pathological consequences. This pathway is separate from the tumor suppressor pathway of p53. We have previously reported that use of low dose arsenic (LDA) temporarily and reversibly suppresses p53 activation, thereby ameliorating normal tissue toxicity from exposure to 5-fluorouracil and X rays. We have also demonstrated that LDA-mediated protection requires functional p53 and thus is selective to normal tissues, as essentially every cancer cell has dysfunctional p53. Here we tested the protective efficacy of LDA for bone marrow tissue against radioimmunotherapy through animal experiments. METHODS AND MATERIALS: Mice were subjected to LDA pretreatment for 3 days, followed by treatment with Y-90 ibritumomab tiuxetan. Both dose course (10, 25, 50, 100, and 200 MUCi) and time course (6, 24, and 72 hours and 1 and 2 weeks) experiments were performed. The response of bone marrow cells to LDA was determined by examining the expression of NFkappaB, Glut1, and Glut3. Staining with hematoxylin and eosin, gamma-H2AX, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to examine morphology, DNA damage response, and apoptotic cell populations. RESULTS: Elevated levels of NFkappaB, Glut1, and Glut3 were observed in bone marrow cells after LDA treatment. Bone marrow damage levels induced by Y-90 ibritumomab tiuxetan were greatly reduced by LDA pretreatment. Consistent with this observation, significantly less DNA damage and fewer apoptotic cells were accumulated after Y-90 ibritumomab tiuxetan treatment in LDA-pretreated mice. Furthermore, in the mouse xenograft model implanted with human Karpas-422 lymphoma cells, LDA pretreatment did not have any detectable effect on either tumor growth or Y-90 ibritumomab tiuxetan (200 MUCi)-induced tumor suppression. CONCLUSIONS: LDA pretreatment protected bone marrow without compromising tumor control caused by Y-90 ibritumomab tiuxetan. PMID- 26025779 TI - Assessing the Clinical Impact of Approximations in Analytical Dose Calculations for Proton Therapy. AB - PURPOSE: To assess the impact of approximations in current analytical dose calculation methods (ADCs) on tumor control probability (TCP) in proton therapy. METHODS: Dose distributions planned with ADC were compared with delivered dose distributions as determined by Monte Carlo simulations. A total of 50 patients were investigated in this analysis with 10 patients per site for 5 treatment sites (head and neck, lung, breast, prostate, liver). Differences were evaluated using dosimetric indices based on a dose-volume histogram analysis, a gamma-index analysis, and estimations of TCP. RESULTS: We found that ADC overestimated the target doses on average by 1% to 2% for all patients considered. The mean dose, D95, D50, and D02 (the dose value covering 95%, 50% and 2% of the target volume, respectively) were predicted within 5% of the delivered dose. The gamma-index passing rate for target volumes was above 96% for a 3%/3 mm criterion. Differences in TCP were up to 2%, 2.5%, 6%, 6.5%, and 11% for liver and breast, prostate, head and neck, and lung patients, respectively. Differences in normal tissue complication probabilities for bladder and anterior rectum of prostate patients were less than 3%. CONCLUSION: Our results indicate that current dose calculation algorithms lead to underdosage of the target by as much as 5%, resulting in differences in TCP of up to 11%. To ensure full target coverage, advanced dose calculation methods like Monte Carlo simulations may be necessary in proton therapy. Monte Carlo simulations may also be required to avoid biases resulting from systematic discrepancies in calculated dose distributions for clinical trials comparing proton therapy with conventional radiation therapy. PMID- 26025780 TI - Abnormal Anterior Cingulate N-Acetylaspartate and Executive Functioning in Treatment-Resistant Depression After rTMS Therapy. AB - BACKGROUND: Cognitive impairment is a key feature of treatment-resistant depression (TRD) and can be related to the anterior cingulate cortex (ACC) function. Repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the last two decades. However, no studies to date have investigated the association between neurobiochemical changes within the anterior cingulate and executive dysfunction measured in TRD being treated with rTMS. METHODS: Thirty-two young depressed patients with treatment-resistant unipolar depression were enrolled in a double blind, randomized study [active (n=18) vs. sham (n=14)]. ACC metabolism was investigated before and after high-frequency (15 Hz) rTMS using 3-tesla proton magnetic resonance spectroscopy (1H-MRS). The results were compared with 28 age- and gender-matched healthy controls. Executive functioning was measured with the Wisconsin Card Sorting Test (WCST) among 34 subjects with TRD and 28 healthy subjects. RESULTS: Significant reductions in N-acetylaspartate (NAA) and choline containing Compound levels in the left ACC were found in subjects with TRD pre rTMS when compared with healthy controls. After successful treatment, NAA levels increased significantly in the left ACC of subjects and were not different from those of age-matched controls. In the WCST, more perseverative errors and fewer correct numbers were observed in TRD subjects at baseline. Improvements in both perseverative errors and correct numbers occurred after active rTMS. In addition, improvement of perseverative errors was positively correlated with enhancement of NAA levels in the left ACC in the active rTMS group. CONCLUSIONS: Our results suggest that the NAA concentration in the left ACC is associated with an improvement in cognitive functioning among subjects with TRD response to active rTMS. PMID- 26025782 TI - Multiple system atrophy in the USA: another piece in the jigsaw. PMID- 26025781 TI - The Female Encounter Test: A Novel Method for Evaluating Reward-Seeking Behavior or Motivation in Mice. AB - BACKGROUND: Reduced motivation is an important marker of psychiatric disorders, including depression. We describe the female encounter test, a novel method of evaluating reward-seeking behavior in mice. METHODS: The test apparatus consists of three open chambers, formed with partitions that allow the animal to move freely from one chamber to another. A test male mouse is habituated in the apparatus, and subsequently a female and male mouse are introduced into a wire mesh box in the left and right chamber, respectively. The time the test male mouse spends in the female or male area is measured for 10 min. RESULTS: All six strains of mice tested showed a significant preference for female encounters. The preference was observed in 7-30-week-old mice. The preference was blocked by castration of the resident male test mouse, and was not affected by the phase of the menstrual cycle of the female intruder. The preference was impaired in mouse models of depression, including social isolation-reared, corticosterone-treated, and lipopolysaccharide-treated mice. The impairment was alleviated by fluvoxamine in isolation-reared and lipopolysaccharide-treated mice, and it was improved by the metabotropic glutamate 2/3 receptor antagonist LY341495 in corticosterone treated mice. Encounter with a female, but not male, mouse increased c-Fos expression in the nucleus accumbens shell of test male mice. Furthermore, both the preference and encounter-induced increases in c-Fos expression were blocked by dopamine D1 and D2 receptor antagonists. CONCLUSIONS: These findings indicate that motivation in adult male mice can be easily evaluated by quantitating female encounters. PMID- 26025784 TI - Estimation of human heat loss in five Mediterranean regions. AB - This study investigates the effects of seasonal weather differences on the human body's heat losses in the Mediterranean region of Turkey. The provinces of Adana, Antakya, Osmaniye, Mersin and Antalya were chosen for the research, and monthly atmospheric temperatures, relative humidity, wind speed and atmospheric pressure data from 2007 were used. In all these provinces, radiative, convective and evaporative heat losses from the human body based on skin surface and respiration were analyzed from meteorological data by using the heat balance equation. According to the results, the rate of radiative, convective and evaporative heat losses from the human body varies considerably from season to season. In all the provinces, 90% of heat loss was caused by heat transfer from the skin, with the remaining 10% taking place through respiration. Furthermore, radiative and convective heat loss through the skin reached the highest values in the winter months at approximately between 110 and 140W/m(2), with the lowest values coming in the summer months at roughly 30-50W/m(2). PMID- 26025785 TI - Cold exposure and/or fasting modulate the relationship between sleep and body temperature rhythms in mice. AB - We assessed the relationship between core temperature (Tc) and sleep rhythms in mice, and examined the effects of ambient temperature and fasting. Tc, electroencephalograms (EEG), electromyograms (EMG), and spontaneous activity in male ICR mice (n=9) were measured by telemetry for 3 days under a 12:12h dark light cycle. Mice were fed or fasted at an ambient temperature (Ta) of 27 degrees C or 20 degrees C for the final 30h of the experiment. The vigilance state was categorized into a wake state, rapid-eye movement (REM) sleep, and non-REM (NREM) sleep, and the total sleep time (TST) was assessed. Relationships between Tc and TST, NREM periods, and REM sleep were estimated using Pearson's correlation coefficient. During cold exposure, Tc decreased during the dark and light phases, and TST and the periods of NREM and REM sleep decreased during the dark phase. Throughout the fasting period, Tc also decreased during the dark and light phases. Furthermore, the decrease in Tc was augmented when fasting and cold were combined. TST and NREM sleep periods decreased in the light and dark phases, respectively, whereas REM sleep periods decreased in both phases. Negative linear correlations (r=-0.884 to -0.987) were observed between Tc and TST, NREM sleep periods, and REM sleep periods, except for Tc and REM sleep periods where fasting and cold conditions were combined. The correlations between sleep and Tc rhythms were well maintained during cold exposure and fasting. However, when cold and fasting were combined, REM sleep and Tc rhythms were desynchronized. PMID- 26025783 TI - Natural history of multiple system atrophy in the USA: a prospective cohort study. AB - BACKGROUND: Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. METHODS: We recruited participants with probable multiple system atrophy-of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. FINDINGS: We recruited 175 participants. Mean age at study entry was 63.4 years (SD 8.6). Median survival from symptom onset was 9.8 years (95% CI 8.8-10.7) and median survival from enrolment was 1.8 years (0.9-2.7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8.0 years, 95% CI 6.5-9.5 vs 10.3 years, 9.3-11.4; p=0.021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25.2 (SD 8.08) versus 24.6 (8.34; p=0.835); mean UMSARS II 26.4 (8.8) versus 25.4 (10.5; p=0.764); COMPASS-select 43.5 (18.7) versus 42.8 (19.6; p=0.835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. INTERPRETATION: Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. FUNDING: US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation. PMID- 26025786 TI - Event-related alpha perturbations related to the scaling of steering wheel corrections. AB - Previously we derived a new measure relating the driver's steering wheel responses to the vehicle's heading error velocity. This measure, the relative steering wheel compensation (RSWC), changes at times coincident with an alerting stimulus, possibly representing shifts in control strategy as measured by a change in the gain between visual input and motor output. In the present study, we sought to further validate this novel measure by determining the relationship between the RSWC and electroencephalogram (EEG) activity in brain regions associated with sensorimotor transformation processes. These areas have been shown to exhibit event-related spectral perturbation (ERSP) in the alpha frequency band that occurs with the onset of corrective steering wheel maneuvers in response to vehicle perturbations. We hypothesized that these regions would show differential alpha activity depending on whether the RSWC was high or low, reflecting changes in gain between visual input and motor output. Interestingly, we find that low RSWC is associated with significantly less peak desynchronization than larger RSWC. In addition we demonstrate that these differences are not attributable to the amount the steering wheel is turned nor the heading error velocity independently. Collectively these results suggest that neural activity in these sensorimotor regions scales with alertness and may represent differential utilization of multisensory information to control the steering wheel. PMID- 26025787 TI - Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: Results from an artificial selection experiment. AB - We evaluated the effect of voluntary exercise on spontaneous physical activity (SPA) and food consumption in mice from 4 replicate lines bred for 57 generations for high voluntary wheel running (HR) and from 4 non-selected control (C) lines. Beginning at ~24 days of age, mice were housed in standard cages or in cages with attached wheels. Wheel activity and SPA were monitored in 1-min intervals. Data from the 8th week of the experiment were analyzed because mice were sexually mature and had plateaued in body mass, weekly wheel running distance, SPA, and food consumption. Body mass, length, and masses of the retroperitoneal fat pad, liver, and heart were recorded after the 13th week. SPA of both HR and C mice decreased with wheel access, due to reductions in both duration and average intensity of SPA. However, total activity duration (SPA+wheel running; min/day) was ~1/3 greater when mice were housed with wheels, and food consumption was significantly increased. Overall, food consumption in both HR and C mice was more strongly affected by wheel running than by SPA. Duration of wheel running had a stronger effect than average speed, but the opposite was true for SPA. With body mass as a covariate, chronic wheel access significantly reduced fat pad mass and increased heart mass in both HR and C mice. Given that both HR and C mice housed with wheels had increased food consumption, the energetic cost of wheel running was not fully compensated by concomitant reductions in SPA. The experiment demonstrates that both duration and intensity of both wheel running and SPA were significant predictors of food consumption. This sort of detailed analysis of the effects of different aspects of physical activity on food consumption has not previously been reported for a non-human animal, and it sets the stage for longitudinal examination of energy balance and its components in rodent models. PMID- 26025788 TI - Do the crystallographic forms of prethrombin-2 revert to a single form in solution? AB - It has been earlier established (Pozzi et al. Biochemistry 50 (2011) 10195-10202) that prethrombin-2 crystallizes into two similar but distinct forms: a collapsed form and an alternative form. We employed long molecular dynamics (MD) simulations for these two forms to obtain solvent-equilibrated forms. We find that, at 200ns, the simulated solution collapsed form is quite similar to the X ray crystal collapsed form, while the simulated solution alternative form deviates from the X-ray crystal alternative form as well as from the solution collapsed form. A detailed structural analysis suggests that the fluctuation of the 140s-loop, in cross-talk with the 220s-loop, may alter the conformation of the W215-E217 segment near the nascent thrombin active site. A rationale is provided for the manner in which interactions of prethrombin-2 with FVa may affect the equilibrium between the two forms of prethrombin-2. PMID- 26025790 TI - Twenty-five years in the blink of an eye. PMID- 26025789 TI - A neglected modulator of insulin-degrading enzyme activity and conformation: The pH. AB - Insulin-degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease, has multiple activities in addition to insulin degradation and its malfunction is believed to connect type 2 diabetes with Alzheimer's disease. IDE has been found in many different cellular compartments, where it may experience significant physio-pathological pH variations. However, the exact role of pH variations on the interplay between enzyme conformations, stability, oligomerization state and catalysis is not understood. Here, we use ESI mass spectrometry, atomic force microscopy, surface plasmon resonance and circular dichroism to investigate the structure-activity relationship of IDE at different pH values. We show that acidic pH affects the ability of the enzyme to bind the substrate and decrease the stability of the protein by inducing an alpha-helical bundle conformation with a concomitant dissociation of multi-subunit IDE assemblies into monomeric units and loss of activity. These effects suggest a major role played by electrostatic forces in regulating multi-subunit enzyme assembly and function. Our results clearly indicate a pH dependent coupling among enzyme conformation, assembly and stability and suggest that cellular acidosis can have a large effect on IDE oligomerization state, inducing an enzyme inactivation and an altered insulin degradation that could have an impact on insulin signaling. PMID- 26025791 TI - Nurses' attitudes toward patients with sickle cell disease: a worksite comparison. AB - Individuals with sickle cell disease (SCD) have reported being stigmatized when they seek care for pain. Nurse attitudes contribute to stigmatization and may affect patients' response to sickle cell cues, care-seeking, and ultimately patient outcomes. The purpose of this cross-sectional, descriptive, comparative design study was to determine whether there are significant differences in nurse attitudes toward patients with SCD by worksite-medical-surgical units compared with emergency departments/intensive care units (ED/ICU). The sample consisted of 77 nurses (36 nurses from the ED/ICU and 41 from medical-surgical units) who completed an anonymous online survey. No significant differences were noted in attitudes by worksite, with nurses from both sites demonstrating high levels of negative attitudes toward patients with SCD. Findings suggest that nurses from both worksites need additional education about SCD and care of this vulnerable, patient population. PMID- 26025792 TI - The Effectiveness of Vitamin B12 for Relieving Pain in Aphthous Ulcers: A Randomized, Double-blind, Placebo-controlled Trial. AB - Aphthous ulcers, the most common oral mucosal lesions seen in primary care, occur in up to ~2%-50% of the general population. Our objective was to confirm the analgesic benefit of treatment of mouth ulcers with vitamin B12 as adjunctive therapy. A randomized, double-blind, placebo-controlled trial was performed with primary care patients. The intervention group received vitamin B12 ointment for 2 days. In total, 42 patients suffering from aphthous ulcers participated in the study: 22 were included in the intervention group and 20 in the control group. All parameters of aphthous ulcers of patients in the intervention group were recorded and compared with those in the control group. We assessed the patients' pain levels before and after treatment using a visual analog scale. The statistical analyses were performed using a nonparametric Mann-Whitney test. Statistically significant differences in pain levels were found between the intervention group and the control group after 2 days of treatment (mean visual analog scale, 0.36 [95% CI, 0.01-0.71] vs. 1.80 [1.16-2.44]; p < .001). In conclusion, the results of this research study provide evidence that vitamin B12 is an effective analgesic treatment for aphthous ulcers. This study indicates that healthcare providers could use vitamin B12 as an adjunctive therapy for mouth ulcers, providing more effective pain management and improving the quality of life for patients with mouth ulcers. PMID- 26025793 TI - Pediatric procedural pain: how far have we come? An ethnographic account. AB - The aim of this ethnographic study was to explore the pediatric procedural pain management practice of health care providers in a non-pediatric emergency department. Data were collected for 5 months and included more than 100 hours of observation. Six key informants were interviewed, and 44 pediatric procedural interactions with 27 health care providers during the treatment of children aged 2 to 8 years undergoing procedures were observed. Other information gathered included documents from the institution, and pain-related information from the patient's medical record. Two major themes with categories are discussed, the treatment of pain, and procedural pain. The findings of this study provide insight into the everyday practice of emergency department health care providers for pediatric pain in a non-pediatric setting, and identify practice issues that may adversely affect the management of pediatric procedural pain, notably the nonuse of pharmacologic techniques for simple needle procedures and the common use of physical restraint during painful procedures. PMID- 26025794 TI - Effect of cyclooxygenase-2-specific inhibitors on postoperative analgesia after major open abdominal surgery. AB - The aim of this study was to examine the effect of cyclooxygenase-2 (COX-2) specific medications on postoperative analgesia after major open abdominal surgery. This is was a prospective, randomized controlled, double-blind study conducted on 90 patients who underwent major open abdominal surgery between September 2011 and June 2012, in the General Surgery Department, Jinling Hospital. After written informed consent, patients were prospectively and randomly assigned to one of three treatment groups before surgery, and were scheduled to receive different analgesic drugs according to randomization. We assessed the patients' pain levels using pain intensity score and adverse events during our study period. The group that received intravenous parecoxib for 3 days, and continued oral celecoxib for 4 days had better postoperative analgesia than other groups. COX-2-specific inhibitors are safe and effective in reducing postoperative pain in patients who have undergone major open abdominal surgery. Additionally, sufficient postoperative analgesia, lasting for 1 week, was necessary for patients to obtain satisfactory pain control after major open abdominal surgery. PMID- 26025795 TI - Evaluation of the preliminary effectiveness of hand massage therapy on postoperative pain of adults in the intensive care unit after cardiac surgery: a pilot randomized controlled trial. AB - Although many intensive care unit patients experience significant pain, very few studies explored massage to maximize their pain relief. This study aimed to evaluate the preliminary effects of hand massage on pain after cardiac surgery in the adult intensive care unit. A pilot randomized controlled trial was used for this study. The study was conducted in a Canadian medical-surgical intensive care unit. Forty adults who were admitted to the intensive care unit after undergoing elective cardiac surgery in the previous 24 hours participated in the study. They were randomly assigned to the experimental (n = 21) or control (n = 19) group. The experimental group received a 15-minute hand massage, and the control group received a 15-minute hand-holding without massage. In both groups the intervention was followed by a 30-minute rest period. The interventions were offered on 2-3 occasions within 24 hours after surgery. Pain, muscle tension, and vital signs were assessed. Pain intensity and behavioral scores were decreased for the experimental group. Although hand massage decreased muscle tension, fluctuations in vital signs were not significant. This study supports potential benefits of hand massage for intensive care unit postoperative pain management. Although larger randomized controlled trials are necessary, this low-cost nonpharmacologic intervention can be safely administered. PMID- 26025796 TI - Comparison of the efficacy and safety of different doses of propacetamol for postoperative pain control after breast surgery. AB - Intravenous propacetamol has been shown to be effective for postoperative pain control. However, the recommendations regarding propacetamol doses for pain control are vague. The present study was performed to compare the efficacy and safety of propacetamol at a dose of 1 g or 2 g. After breast-conserving surgery, patients received 1 g or 2 g intravenous propacetamol. Treatment efficacy for pain control was assessed using a 100 mm visual analog scale at 15, 30, 45, and 60 minutes and 4 hours after surgery, and global evaluation was assessed by a 4 point categorical scale at the end of the 4-hour study period. Safety was monitored through adverse event reporting. Patients were allowed rescue analgesia, and the timing of requests was recorded. A total of 111 patients were enrolled in the study. There were no differences in efficacy variables, including visual analog scale, the 4-point categorical scale, and requests for rescue analgesia, between propacetamol doses of 1 g and 2 g. Adverse events were similar in the two groups. Intravenous propacetamol at a dose of 2 g is not superior to the lower dose of 1 g with regard to postoperative analgesia or the incidence of side effects in breast-conserving surgery. PMID- 26025797 TI - Validity and reliability of a pain location tool for pediatric abdominal surgery. AB - For children with surgical problems, pain location conveys important clinical information. We developed a Location and Level of Intensity of Postoperative Pain (Lolipops) tool consisting of a body outline with a seven-sector abdominal grid, the International Association for the Study of Pain Revised Faces Pain Scale, and a recording chart. The aim of the study was to assess the validity and reliability of Lolipops. Children aged 5-14 years who had undergone laparoscopic appendectomy took both nurse- and investigator-administered Lolipops, and an investigator administered Varni Thompson Pediatric Pain Questionnaires, within 24 hours of surgery. The average age of the 42 participants was 10.7 years; 64% were boys; 24 (57.1%) had acute appendicitis, 13 (31%) had perforated appendicitis, and 5 (11.9%) were uninflamed. Pain scores were higher at the laparoscopic port incision sites than in upper abdominal sites distant from incisions or expected inflammation, mean (SD) 3.3 (2.3) and 1.1 (1.8), respectively (p < .0001). In children with acute appendicitis, pain scores were higher in the right iliac fossa than in upper abdominal sites, mean (SD) 3.3 (2.5) and 0.4 (0.7), respectively (p = .001). In children with perforated appendicitis, Lolipops demonstrated a more widespread pain pattern. Correlations between nurse and investigator were fair to moderate with an overall intraclass correlation coefficient of 0.597. This study presents a new tool to measure the location of pain in pediatric surgical patients and shows it to be valid and reliable. PMID- 26025798 TI - Effects of Reiki on Post-cesarean Delivery Pain, Anxiety, and Hemodynamic Parameters: A Randomized, Controlled Clinical Trial. AB - The aim of this study was to investigate the effect of Reiki on pain, anxiety, and hemodynamic parameters on postoperative days 1 and 2 in patients who had undergone cesarean delivery. The design of this study was a randomized, controlled clinical trial. The study took place between February and July 2011 in the Obstetrical Unit at Odemis Public Hospital in Izmir, Turkey. Ninety patients equalized by age and number of births were randomly assigned to either a Reiki group or a control group (a rest without treatment). Treatment applied to both groups in the first 24 and 48 hours after delivery for a total of 30 minutes to 10 identified regions of the body for 3 minutes each. Reiki was applied for 2 days once a day (in the first 24 and 48 hours) within 4-8 hours of the administration of standard analgesic, which was administered intravenously by a nurse. A visual analog scale and the State Anxiety Inventory were used to measure pain and anxiety. Hemodynamic parameters, including blood pressure (systolic and diastolic), pulse and breathing rates, and analgesic requirements also were recorded. Statistically significant differences in pain intensity (p = .000), anxiety value (p = .000), and breathing rate (p = .000) measured over time were found between the two groups. There was a statistically significant difference between the two groups in the time (p = .000) and number (p = .000) of analgesics needed after Reiki application and a rest without treatment. Results showed that Reiki application reduced the intensity of pain, the value of anxiety, and the breathing rate, as well as the need for and number of analgesics. However, it did not affect blood pressure or pulse rate. Reiki application as a nursing intervention is recommended as a pain and anxiety-relieving method in women after cesarean delivery. PMID- 26025799 TI - Patient- and family caregiver-related barriers to effective cancer pain control. AB - Cancer is a worldwide health problem. In Jordan, cancer is the second leading cause of death. Approximately 2,000 people die from cancer every year, 70% of them experiencing varying high levels of pain as a result of ineffective pain relief. The purpose of this study was to identify the attitudinal barriers to effective cancer pain relief in patients and their family caregivers in Jordan. A cross-sectional questionnaire survey was used. A convenience sample of 300 cancer patients and 246 family caregivers were recruited from four different Jordanian hospitals between August 2009 and May 2010. Patients completed the Arabic version of the Barriers Questionnaire II (ABQ-II), the Arabic Brief Pain Inventory (A BPI), and a demographic questionnaire. Family caregivers completed the ABQ-II and a demographic questionnaire. The A-BPI results identified that more than 70% of cancer patients in localized stage and more than 90% of patients with advanced cancer experienced substantial pain. Four major barriers to pain control were highlighted: fears related to addiction, side effects, communication concerns, and fatalistic beliefs. This study provides baseline information about the barriers to effective cancer pain control in Jordan. PMID- 26025800 TI - The effectiveness of therapeutic play intervention in reducing perioperative anxiety, negative behaviors, and postoperative pain in children undergoing elective surgery: a systematic review. AB - Children undergoing surgical procedures commonly experience stress and anxiety, exhibit negative behaviors, and complain of postoperative pain. Parents also experience anxiety when their children undergo surgery. Therapeutic play intervention has been used to prepare hospitalized children for invasive medical procedures for decades. However, there has been no systematic review to examine the effectiveness of therapeutic play intervention for improving children's health-related outcomes such as perioperative anxiety and postoperative pain. The aim of this review was to synthesize current empirical evidence on the effectiveness of therapeutic play intervention in reducing perioperative anxiety, negative behaviors, and postoperative pain in children undergoing elective surgery and in reducing their parents' perioperative anxiety. Systematic searches of electronic databases of the Cumulative Index to Nursing and Allied Health Literature, PubMed, ProQuest Dissertations and Theses, Scopus, and Web of Science and screening of the reference lists of included articles from these databases identified studies on the topic. Relevant studies were methodologically assessed and appraised by two independent reviewers using the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument. Six studies were identified. The outcome measurements were heterogeneous across all six studies. These studies had conflicting outcomes regarding the effectiveness of therapeutic play intervention in children's perioperative anxiety, negative behaviors, and postoperative pain. Two studies showed that the intervention significantly reduced parents' preoperative anxiety. The current empirical evidence on the effectiveness of therapeutic play intervention in children's perioperative anxiety, negative behaviors, and postoperative pain is inconclusive. More studies on the effectiveness of therapeutic play intervention using rigorous designs and involving parents are needed. PMID- 26025801 TI - Knowledge about Sterile Water Injections for Pain Relief in Labor. PMID- 26025802 TI - Analysis of dynamic changes in retinoid-induced transcription and epigenetic profiles of murine Hox clusters in ES cells. AB - The clustered Hox genes, which are highly conserved across metazoans, encode homeodomain-containing transcription factors that provide a blueprint for segmental identity along the body axis. Recent studies have underscored that in addition to encoding Hox genes, the homeotic clusters contain key noncoding RNA genes that play a central role in development. In this study, we have taken advantage of genome-wide approaches to provide a detailed analysis of retinoic acid (RA)-induced transcriptional and epigenetic changes within the homeotic clusters of mouse embryonic stem cells. Although there is a general colinear response, our analyses suggest a lack of strict colinearity for several genes in the HoxA and HoxB clusters. We have identified transcribed novel noncoding RNAs (ncRNAs) and their cis-regulatory elements that function in response to RA and demonstrated that the expression of these ncRNAs from both strands represent some of the most rapidly induced transcripts in ES cells. Finally, we have provided dynamic analyses of chromatin modifications for the coding and noncoding genes expressed upon activation and suggest that active transcription can occur in the presence of chromatin modifications and machineries associated with repressed transcription state over the clusters. Overall, our data provide a resource for a better understanding of the dynamic nature of the coding and noncoding transcripts and their associated chromatin marks in the regulation of homeotic gene transcription during development. PMID- 26025804 TI - Unraveling predictors affecting compliance to MRI in Parkinson's disease. AB - INTRODUCTION: Magnetic resonance imaging (MRI) is a sensitive, noninvasive and widely available technique for studying Parkinson's disease (PD) from both research and clinical perspective. Several issues may physically impede execution of MRI. Moreover, the severity of motor or non-motor symptoms of PD might reduce compliance to MRI. Here we investigated predictors affecting compliance to MRI in PD patients. METHODS: Two-hundred-thirty-six PD patients underwent clinical, neuropsychological and neuropsychiatric investigations. Accordingly to their ability/inability to perform MRI scan, they were divided into 3 groups. Forty-two patients had physical incompatibility to MRI (PI); 51 patients refused to undergo scan during the MRI evaluation session (RR); 143 patients accepted to undergo and successfully completed MRI (SP). Multivariate/Univariate Analyses of Variance, followed by Bonferroni's post-hoc comparisons, were used to assess differences among groups. To identify predictors of compliance to MRI scan in the whole PD sample (SP vs. RR + PI) we carried out a logistic regression analysis. RESULTS: PI subjects were significantly older, had higher UPRDRS-III score, received lower daily dopamine agonist doses, and displayed worse cognitive performances than SP. RR subjects had significantly higher anxiety severity than SP. Lower daily dopamine agonist equivalents and higher anxiety scores were the significant whole predictors of not compliance to MRI in the logistic regression analysis. CONCLUSIONS: These results show that demographic, neuropsychological and neuropsychiatric features may limit compliance to MRI in PD, and provide valuable aid for setting and interpreting research and clinical MRI studies in PD. PMID- 26025806 TI - Strangles in horses can be caused by vaccination with Pinnacle I. N. AB - The differentiation of live attenuated vaccine strains from their progenitor and wild-type counterparts is important for ongoing surveillance of product safety and improved guidelines on their use. We utilised a genome sequencing approach to confirm that two cases of strangles in previously healthy horses that had received the Pinnacle I. N. vaccine (Zoetis) were caused by the vaccine strain. Our data shed new light on the safety of this vaccine and suggest that factors beyond the maturity of the animal's immune system influence the development of adverse reactions. PMID- 26025805 TI - A novel method for separation of Rickettsiales-like organism "Candidatus Xenohaliotis californiensis" from host abalone tissue. AB - Filtrations were applied to separate vacuoles of Rickettsiales-like organism Candidatus Xenohaliotis californiensis. Vacuoles were visualized by staining with nucleic acid fluorochrome and their identity was confirmed by Laser Capture Microdissection and PCR. This methodology separates vacuoles and allows studies without the need of isolation in synthetic media or cell lines. PMID- 26025803 TI - Genome-wide specificity of DNA binding, gene regulation, and chromatin remodeling by TALE- and CRISPR/Cas9-based transcriptional activators. AB - Genome engineering technologies based on the CRISPR/Cas9 and TALE systems are enabling new approaches in science and biotechnology. However, the specificity of these tools in complex genomes and the role of chromatin structure in determining DNA binding are not well understood. We analyzed the genome-wide effects of TALE- and CRISPR-based transcriptional activators in human cells using ChIP-seq to assess DNA-binding specificity and RNA-seq to measure the specificity of perturbing the transcriptome. Additionally, DNase-seq was used to assess genome wide chromatin remodeling that occurs as a result of their action. Our results show that these transcription factors are highly specific in both DNA binding and gene regulation and are able to open targeted regions of closed chromatin independent of gene activation. Collectively, these results underscore the potential for these technologies to make precise changes to gene expression for gene and cell therapies or fundamental studies of gene function. PMID- 26025807 TI - Safety and immunogenicity of a four-component meningococcal group B vaccine (4CMenB) and a quadrivalent meningococcal group ACWY conjugate vaccine administered concomitantly in healthy laboratory workers. AB - Safety precautions for laboratory staff working with meningococci should primarily rely on laboratory procedures preventing exposure to aerosols containing viable meningococci. Despite this, vaccination is a key component of protection in the occupational setting. In the UK in 2009, there were no licensed vaccines for meningococcal capsular group B or conjugate vaccines for capsular groups A, C, W and Y. We therefore undertook a Phase II trial in laboratory workers to investigate the safety and immunogenicity of a four component group B vaccine (4CMenB) and a quadrivalent group A, C, W and Y conjugate vaccine (ACWY CRM). Enrolment was open to staff aged 18-65 years at the Public Health Laboratory, Manchester who may have had a potential occupational exposure risk to meningococci. 4CMenB was administered at 0, 2 and 6 months in the non-dominant arm and ACWY-CRM concomitantly at 0 months in the dominant arm. Pre- and post vaccination blood samples were taken and analysed by the serum bactericidal antibody (SBA) assay against A, C, W and Y strains and a panel of seven diverse group B strains. Diary cards were used to record any local and systemic reactions following each vaccination. In total, 38 staff were enrolled and received initial vaccinations with 31 completing the trial per protocol. Both vaccines were proven safe, with local reactogenicity being more commonly reported following 4CMenB than ACWY-CRM. High proportions of subjects had putative protective SBA titres pre-vaccination, with 61-84 and 61-87% protected against A, C, W and Y strains and diverse MenB strains, respectively. Post-vaccination, SBA titres increased with 95-100 and 90-100% of subjects with protective SBA titres against A, C, W and Y strains and diverse MenB strains, respectively. These data suggest that 4CMenB and ACWY-CRM are safe when administered concomitantly and have the potential to enhance protection for laboratory workers. www.clinicaltrials.gov identifier: NCT00962624. PMID- 26025808 TI - Macular retinal sensitivity using MP-1 in healthy Malaysian subjects of different ages. AB - PURPOSE: To determine the influence of age and gender on macular sensitivity to light in healthy subjects of 4 age groups using the MP-1 microperimeter. METHODS: A prospective study was carried out on 50 healthy subjects (age range: 18-60 years) divided into 4 age groups; 18-30 years, 31-40 years, 41-50 years and 51-60 years. Full-threshold microperimetry of the central 10 degrees of retina was performed utilizing 32 points with the MP-1. Macula area was divided into four quadrants, which were superior nasal (SN), inferior nasal (IN), inferior temporal (IT) and superior temporal (ST). RESULTS: Total mean sensitivity at 10 degrees for age groups 18-30 years, 31-40 years, 41-50 years and 51-60 years were 19.46 +/- 0.30, 19.40 +/- 0.39, 19.47 +/- 0.35 and 18.73 +/- 0.75 (dB), respectively. There was a significant difference in total mean retinal sensitivity at 10 degrees and at the four quadrants with age but not for gender. The retinal sensitivity was highest in the IT quadrant and lowest in the SN quadrant for all age groups. The linear regression analysis revealed that there was a 0.019 dB, 0.016 dB, 0.022 dB, 0.029 dB and 0.029 dB per year age-related decline in mean macular sensitivity within the central 10 degrees diameter in the SN, IN, IT and ST quadrants respectively. CONCLUSION: Among normal healthy subjects, there was a linear decline in retinal light sensitivity with increasing age with the highest reduction in the superior nasal quadrant and lowest in the inferior temporal quadrant. PMID- 26025810 TI - Probabilities of benefit and harms of preoperative radiotherapy for rectal cancer: What do radiation oncologists tell and what do patients understand? AB - OBJECTIVE: Probabilities of benefits and harms of treatment may help patients when making a treatment decision. This study aimed to examine (1) whether and how radiation oncologists convey probabilities to rectal cancer patients, and (2) patients' estimates of probabilities of major outcomes of rectal cancer treatment. METHODS: First consultations of oncologists and patients eligible for preoperative radiotherapy (PRT) (N=90) were audio taped. Tapes were transcribed verbatim and coded to identify probabilistic information presented. Patients (N=56) filled in a post-consultation questionnaire on their estimates of probabilities. RESULTS: Probabilities were mentioned in 99% (local recurrence), 75% (incontinence), 72% and 40% (sexual dysfunction in males and females, respectively) of cases. Most patients (89%) correctly estimated that PRT decreases the probability of local recurrence, and 10% and 38%/54% that it increases the probability of incontinence and sexual dysfunction in males/females, respectively. Patients tended to underestimate the probabilities of harms of treatment. CONCLUSION: Our results show that oncologists almost always mention probabilities of benefit of PRT. In contrast, probabilities of harms often go unmentioned. The effect of PRT on adverse events is often underestimated. PRACTICE IMPLICATIONS: Oncologists should stay alert to patients' possible misunderstanding of probabilistic information and should check patients' perceptions of probabilities. PMID- 26025809 TI - Visual impairment attributable to uncorrected refractive error and other causes in the Ghanaian youth: The University of Cape Coast Survey. AB - PURPOSE: To determine the prevalence of visual impairment attributable to refractive error and other causes in a youthful Ghanaian population. METHODS: A prospective survey of all consecutive visits by first-year tertiary students to the Optometry clinic between August, 2013 and April, 2014. Of the 4378 first-year students aged 16-39 years enumerated, 3437 (78.5%) underwent the eye examination. The examination protocol included presenting visual acuity (PVA), ocular motility, and slit-lamp examination of the external eye, anterior segment and media, and non-dilated fundus examination. Pinhole acuity and fundus examination were performed when the PVA<=6/12 in one or both eyes to determine the principal cause of the vision loss. RESULTS: The mean age of participants was 21.86 years (95% CI: 21.72-21.99). The prevalence of bilateral visual impairment (BVI; PVA in the better eye <=6/12) and unilateral visual impairment UVI; PVA in the worse eye <=6/12) were 3.08% (95% CI: 2.56-3.72) and 0.79% (95% CI: 0.54-1.14), respectively. Among 106 participants with BVI, refractive error (96.2%) and corneal opacity (3.8%) were the causes. Of the 27 participants with UVI, refractive error (44.4%), maculopathy (18.5%) and retinal disease (14.8%) were the major causes. There was unequal distribution of BVI in the different age groups, with those above 20 years having a lesser burden. CONCLUSION: Eye screening and provision of affordable spectacle correction to the youth could be timely to eliminate visual impairment. PMID- 26025811 TI - Comparison of markers of ovarian reserve between patients with complete mullerian agenesis and age-matched fertile and infertile controls. AB - OBJECTIVE: To investigate ovarian reserve in complete mullerian agenesis (CMA) patients and to compare the ovarian reserve of CMA patients with that of age matched fertile and infertile controls. DESIGN: Prospective cohort study. SETTING: University gynecology outpatient clinic. PATIENT(S): Fifty-eight typical CMA (type A) patients, 8 atypical CMA (type B) patients, 39 fertile patients, and 38 infertile patients were compared for ovarian reserve. INTERVENTION(S): Ovarian reserve was evaluated via antimullerian hormone (AMH) levels and antral follicle counts (AFCs). MAIN OUTCOME MEASURE(S): Investigation of ovarian reserve in CMA patients and a comparison of the ovarian reserve of the CMA patients with that of age-matched fertile and infertile controls. RESULT(S): Fifty-eight type A and eight type B CMA patients and 39 fertile and 38 infertile control patients were assessed for ovarian reserve. The mean (+/-SD) ages of the type A and type B CMA patients and the fertile and infertile groups were 25.8 +/- 5.3, 33.3 +/- 5.9, 32.6 +/- 4.8, and 33.9 +/- 3.3 years, respectively. After age standardization of the groups, AMH levels and AFCs were found to be lower in the atypical CMA group. The differences in AMH levels and AFC were found to be highly significant. CONCLUSION(S): The present study showed that atypical CMA patients had decreased ovarian reserve compared with age-matched fertile and infertile controls. PMID- 26025812 TI - Capillary isoelectric focusing method development and validation for investigation of recombinant therapeutic monoclonal antibody. AB - Capillary isoelectric focusing (cIEF) is a basic and highly accurate routine analytical tool to prove identity of protein drugs in quality control (QC) and release tests in biopharmaceutical industries. However there are some "out-of-the box" applications commercially available which provide easy and rapid isoelectric focusing solutions for investigating monoclonal antibody drug proteins. However use of these kits in routine testings requires high costs. A capillary isoelectric focusing method was developed and validated for identification testing of monoclonal antibody drug products with isoelectric point between 7.0 and 9.0. A method was developed providing good pH gradient for internal calibration (R(2)>0.99) and good resolution between all of the isoform peaks (R=2), minimizing the time and complexity of sample preparation (no urea or salt used). The method is highly reproducible and it is suitable for validation and method transfer to any QC laboratories. Another advantage of the method is that it operates with commercially available chemicals which can be purchased from any suppliers. The interaction with capillary walls (avoid precipitation and adsorption as far as possible) was minimized and synthetic isoelectric small molecular markers were used instead of peptide or protein based markers. The developed method was validated according to the recent ICH guideline (Q2(R1)). Relative standard deviation results were below 0.2% for isoelectric points and below 4% according to the normalized migration times. The method is robust to buffer components with different lot numbers and neutral capillaries with different type of inner coatings. The fluoro-carbon coated column was chosen because of costs-effectivity aspects. PMID- 26025813 TI - Development and validation of UHPLC-MS/MS method for determination of eight naturally occurring catechin derivatives in various tea samples and the role of matrix effects. AB - A complete analytical procedure combining optimized tea infusion preparation and validated UHPLC-MS/MS method was developed for routine quantification of eight naturally occurring catechin derivatives in various tea samples. The preparation of tea infusions was optimized in terms of temperature, time and water-to-tea ratio in green, white and black teas. The catechins were analyzed using ultra high performance liquid chromatography coupled with triple quadrupole mass spectrometry in a run of only 4 min including equilibration of the system. The UHPLC-MS/MS method was fully validated in terms of inter/intra-day precision, accuracy, linearity (r(2)>0.9991), range (50-5000 ng/ml), LOD (1.5-7.5 ng/ml) and LOQ (5-25 ng/ml). Validation of the method included also the determination of the matrix effects that were evaluated in both flavored and unflavored green, white and black teas. Dilution of the resulting tea infusions appeared to be crucial for the matrix effects and also for subsequent catechin quantification in real tea samples in order to fit into the linear range of the UHPLC-MS/MS method. This complete procedure for catechin quantification was finally applied to real sample analysis represented by 70 commercial tea samples. PMID- 26025814 TI - Profiling a gut microbiota-generated catechin metabolite's fate in human blood cells using a metabolomic approach. AB - The microbial catechin metabolite delta-(3,4-dihydroxy-phenyl)-gamma valerolactone (M1) has been found in human plasma samples after intake of maritime pine bark extract (Pycnogenol). M1 has been previously shown to accumulate in endothelial and blood cells in vitro after facilitated uptake and to exhibit anti-inflammatory activity. The purpose of the present research approach was to systematically and comprehensively analyze the metabolism of M1 in human blood cells in vitro and in vivo. A metabolomic approach that had been successfully applied for drug metabolite profiling was chosen to detect 19 metabolite peaks of M1 which were subsequently further analyzed and validated. The metabolites were categorized into three levels of identification according to the Metabolomics Standards Initiative with six compounds each confirmed at levels 1 and 2 and seven putative metabolites at level 3. The predominant metabolites were glutathione conjugates which were rapidly formed and revealed prolonged presence within the cells. Although a formation of an intracellular conjugate of M1 and glutathione (M1-GSH) was already known two GSH conjugate isomers, M1-S-GSH and M1-N-GSH were observed in the current study. Additionally detected organosulfur metabolites were conjugates with oxidized glutathione and cysteine. Other biotransformation products constituted the open-chained ester form of M1 and a methylated M1. Six of the metabolites determined in in vitro assays were also detected in blood cells in vivo after ingestion of the pine bark extract by two volunteers. The present study provides the first evidence that multiple and structurally heterogeneous polyphenol metabolites can be generated in human blood cells. The bioactivity of the M1 metabolites and their contribution to the previously determined anti-inflammatory effects of M1 now need to be elucidated. PMID- 26025815 TI - Impact on the pharyngeal airway space of different orthognathic procedures for the prognathic mandible. AB - The study objective was to evaluate, through a meta-analysis, the impact on the pharyngeal airway space (PAS) of different orthognathic surgeries for the treatment of the prognathic mandible. An electronic search of three databases and hand searches were carried out up to December 2014. The inclusion criteria were clinical human studies, including randomized controlled trials (RCTs), controlled clinical trials (CCTs), and retrospective studies, with the aim of comparing bilateral sagittal split osteotomy (BSSO) to intraoral vertical ramus osteotomy (IVRO), or one-jaw to two-jaw surgery for the treatment of the prognathic mandible. The PAS changes (anterior-posterior dimensions and cross-sectional area) at the level of the nasopharynx, oropharynx, and hypopharynx were analyzed. A statistically significant difference was found between BSSO and IVRO groups and one-jaw surgery and two-jaw surgery with regard to PAS changes after the treatment of mandibular prognathism. The results of this meta-analysis indicate that BSSO presents less change in the PAS after mandibular setback surgery compared to IVRO. Furthermore, the results of this study suggest that bimaxillary surgery is superior to mandibular setback surgery alone for the correction of the prognathic mandible, particularly in patients with factors predisposing them to the development of breathing problems. PMID- 26025816 TI - The vital role of research funding in preserving the oral health of the public and the dental profession. PMID- 26025817 TI - Prophylactic antibiotics. PMID- 26025818 TI - Authors' response. PMID- 26025819 TI - The dental marketplace. PMID- 26025820 TI - Improving salivary flow. PMID- 26025821 TI - Responsibility and sugary drinks. PMID- 26025822 TI - Author's response. PMID- 26025823 TI - Disparities in dental care associated with disability and race and ethnicity. AB - BACKGROUND: Both racial and ethnic and disability-related disparities in dental care exist, yet little is known about the cumulative effect of these 2 characteristics. The purpose of this study was to determine how the combination of disability and race and ethnicity is associated with dental examinations, delays in receiving needed care, and inability to obtain needed care among noninstitutionalized working-age adults in the United States. METHODS: The authors conducted cross-sectional analyses of Medical Expenditure Panel Survey data pooled across the years 2002 to 2012, yielding a sample of 208,548. Multivariable logistic regression analyses were used to examine the association of disability (including physical, sensory, and cognitive limitations) and race and ethnicity with each of the dependent variables. RESULTS: Compared with non Hispanic whites, other racial and ethnic groups were less likely to receive annual dental examinations. There were significant disparities for people with disabilities in receipt of examinations, delays in obtaining needed care, and being unable to obtain needed care. The combination of disability status and membership in an underserved racial or ethnic group was associated with a greater magnitude of disparity in all 3 areas, especially for American Indian, Alaska Native, and multiracial people with disabilities. CONCLUSIONS: Community-dwelling adults with disabilities in underserved racial and ethnic groups have higher levels of delayed and unmet needs for dental care and lower receipt of routine dental examinations. PRACTICAL IMPLICATIONS: As the United States population ages and grows more diverse, the population of people with disabilities in underserved racial and ethnic groups will expand. Dentists need to be aware of, and be prepared to address, the needs of these people. PMID- 26025824 TI - Risk factors for bleeding after oral surgery in patients who continued using oral anticoagulant therapy. AB - BACKGROUND: The authors assessed the incidence of postoperative bleeding in patients who were highly anticoagulated and in patients who underwent extensive oral surgical procedures and who continued using oral anticoagulant therapy. METHODS: The authors placed 125 patients receiving anticoagulant therapy into 1 of 3 groups. Group A had 54 patients who were highly anticoagulated (international normalized ratio [INR] >= 3.5) in whom up to 3 teeth were extracted. Group B had 60 patients with INR 2.0 to less than 3.5 in whom higher risk dentoalveolar surgery (extraction of more than 3 teeth or other oral surgery procedure involving raising a mucoperiosteal flap, osteotomy, or biopsy) was performed. Group C had 11 patients whose INR values were 3.5 or higher and who required higher-risk dentoalveolar surgery. Eighty-five healthy participants who underwent surgical procedures similar to those performed in group A and group B were the control group. RESULTS: Two patients in group A (3.7%), 3 in group B (5.0%), and 2 in group C (18.2%) experienced postoperative bleeding. In the control group, a single bleeding event (1.2%) occurred. All cases of hemorrhage were mild and easily controlled using local hemostatic measures. CONCLUSIONS: Dental extractions in patients who are highly anticoagulated (INR, 3.5-4.2), as well as more extensive oral surgical procedures in patients who are therapeutically anticoagulated, can be performed safely without interruption or modification of the therapy. PRACTICAL IMPLICATIONS: Tooth extractions and even more extensive surgical procedures can be performed safely in patients who continue using anticoagulant therapy if proper local hemostatic measures are used and if no other coagulopathies are present. PMID- 26025825 TI - Association of periodontitis and human papillomavirus in oral rinse specimens: Results from the National Health and Nutrition Survey 2009-2012. AB - BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas are increasing in incidence and are becoming significant public health concerns. Periodontitis is a chronic condition in which the affected tissue may facilitate oral HPV infection and persistence. The purpose of this study was to determine if an association of the presence of HPV in oral rinse specimens and periodontal disease exists. METHODS: The authors combined the National Health and Nutrition Examination Survey (NHANES) data for years 2009-2010 and 2011-2012. The authors included participants aged 30-69 years who had clinically assessed periodontal and HPV data (n = 6,004). The authors analyzed the data using the Rao Scott chi(2) test and logistic regression. RESULTS: There were 498 participants who had the presence of HPV in oral rinse specimens. The adjusted odds ratio for the presence of HPV in oral rinse specimens with relation to periodontal disease was 1.04 (95% confidence interval, 0.63-1.73), adjusting for sex, race and ethnicity, education, age, income-to-poverty ratio, smoking, alcohol use, and number of sex partners during their lifetime. CONCLUSIONS: The authors failed to reject the hypothesis of no association of the presence of HPV in oral rinse specimens and periodontitis. PRACTICAL IMPLICATIONS: Although oral HPV infection is a serious concern, the authors found that periodontitis was not shown to be related to the presence of HPV in oral rinse specimens in adjusted analyses in this study. PMID- 26025827 TI - What about narrative dentistry? AB - BACKGROUND AND OVERVIEW: Narrative medicine strives toward a humanized form of medicine in which empathy and the ability to listen are developed with the same emphasis as scientific rigor. We hypothesize that the adoption of narrative medicine in dentistry would be an excellent method to cultivate the philosophy behind the emerging clinical concept of patient-centered dentistry. CONCLUSIONS: Reading literary works, reflective writing, and creative writing would sensitize practitioners to the daily lives of people, human uniqueness, and alterity. Narrative dentistry could lead to more empathic and self-aware practices, and improve dental professionals' observational abilities by making them more perceptive and more attentive to image, metaphor, and meaning. PRACTICAL IMPLICATIONS: The introduction of narrative dentistry would enrich the clinical clerkship of dentists by bringing the often-missing humanities to the dental professional, academic, and scientific environment. PMID- 26025826 TI - Attitudes toward and beliefs about the use of a dental diagnostic terminology: A survey of dental care providers in a dental practice. AB - BACKGROUND: Attitudes and views are critical to the adoption of innovation. Although there have been broadening calls for a standardized dental diagnostic terminology, little is known about the views of private practice dental team members regarding the adoption of such a terminology. METHODS: The authors developed a survey by using validated questions identified through literature review. Domain experts' input allowed for further modifications. The authors administered the final survey electronically to 814 team members at a multioffice practice based in the US Pacific Northwest. RESULTS: Response proportion was 92%. The survey had excellent reliability (Cronbach alpha coefficient = 0.87). Results suggested that participants showed, in general, positive attitudes and beliefs about using a standardized diagnostic terminology in their practices. Additional written comments by participants highlighted the potential for improved communication with use of the terminology. CONCLUSIONS: Dental care providers and staff in 1 multioffice practice showed positive attitudes about the use of a diagnostic terminology; specifically, they believed it would improve communication between the dentist and patient, as well as among providers, while expressing some concerns about whether using standardized dental diagnostic terms helps clinicians to deliver better dental care. PRACTICAL IMPLICATIONS: As the dental profession is advancing toward the use of standardized diagnostic terminology, successful implementation will require that dental team leaders prepare their teams by gauging their attitude about the use of such a terminology. PMID- 26025828 TI - Restoring lost gingival pigmentation in the esthetic zone: A case report. AB - BACKGROUND AND OVERVIEW: There is insufficient literature on the lack of oral pigmentation in the esthetic zone. The aim of this case report was to illustrate the potential impact of loss of gingival pigmentation in the esthetic zone, describe its surgical treatment, and discuss the limited literature on this topic. CASE DESCRIPTION: An African American woman with high smile line had localized loss of gingival melanin pigmentation as a complication after implant failure and attempted guided bone regeneration in site 8. A highly pigmented free gingival graft was collected from the facial-attached gingiva of the maxillary posterior teeth and placed onto the previously de-epithelialized recipient bed in the maxillary front. Some pigmentation of the graft was preserved and was visible a few weeks after surgery; some pigmentation recovered over time. At 6 months after surgery, the patient was satisfied with the esthetics. Complete recovery of pigmentation took 12 months, at which time the patient was ready to proceed with the final prosthetic work. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Gingival pigmentation can be restored using a free gingival graft from a highly pigmented area. When surgical procedures are performed in such cases, loss of gingival pigmentation should be part of the informed consent. However, further research, including histology, is needed. PMID- 26025829 TI - Nonodontogenic toothaches. PMID- 26025830 TI - Sealing pits and fissures of permanent molars in children and adolescents is effective in controlling dental caries. PMID- 26025831 TI - Where have all the dental care visits gone? PMID- 26025832 TI - How to evaluate dental insurance plans. PMID- 26025833 TI - FOR THE PATIENT. Bridges, implants, and dentures. PMID- 26025834 TI - Quantitative Analysis of Nitrofuran Metabolites and Chloramphenicol in Shrimp Using Acetonitrile Extraction and Liquid Chromatograph-Tandem Mass Spectrometric Detection: A Single Laboratory Validation. AB - A method was developed and validated for the simultaneous analysis of chloramphenicol and nitrofuran metabolites in shrimp according to the guideline established by the U.S. Food and Drug Administration Office of Foods and Veterinary Medicine. The extraction steps following the overnight hydrolysis and derivatization are simpler than the conventional ethyl acetate extraction method. The main steps are neutralization of hydrolysates, addition of acetonitrile for extraction, and salting out of organic phase from the acetonitrile-aqueous mixture. Extracts are analyzed for chloramphenicol and nitrofuran metabolites by LC-MS/MS in a single injection with polarity switching between the positive electrospray ionization (ESI) mode for the nitrofurans and the negative ESI mode for chloramphenicol. Recoveries calculated using an extracted matrix calibration curve and labeled internal standards for chloramphenicol and nitrofurans ranged from 98.6 to 109.2% with RSDs less than 18%. This method that combines the analysis of chloramphenicol with the nitrofurans was shown to generate analytical results similar to those obtained using the individual drug-class analytical methods currently used for the analysis of chloramphenicol or nitrofurans in shrimp. PMID- 26025835 TI - [Inconsistency between the level of care in Neonatal Units and the patients in care]. PMID- 26025836 TI - John P Peters (1887-1955): McCarthyism and the Unfinished Revision of Quantitative Clinical Chemistry. AB - John P Peters is considered one of the founders of modern clinical chemistry. In more than 200 research articles, he brought clinical biochemistry to the bedside, advancing the use of laboratory medicine in diagnosis and disease management. His two-volume landmark textbook Quantitative Clinical Chemistry, coauthored with Donald Dexter van Slyke (1883-1971) and released in 1931-1932, defined clinical chemistry as a distinct professional discipline within medicine. A three-volume revision was begun in 1937. Peters took on the task of revising Volumes I and II but never finished Volume II. His outspoken public advocacy for social reform, world peace, and universal health care made him a target in the era of McCarthyism. Three times between 1949 and 1953 he was brought before the Loyalty Review Board with charges of being a communist and a sympathetic supporter of subversive organizations. According to his family, the turmoil of the McCarthyism persecution shortened his life and prevented him from completing the one thing he wanted to do in his professional life, finish the revision of his landmark clinical chemistry textbook. PMID- 26025837 TI - Dr Girolamo Fracastoro (1478-1553) and the poetry of Syphilis. PMID- 26025838 TI - Louis Pasteur (1822-1895), his friendships with the artists Max Claudet (1840 1893) and Paul Dubois (1829-1905), and his public image in the 1870s and 1880s. AB - Biographers have largely ignored Louis Pasteur's many and varied connections with art and artists. This article is the third in a series of the authors' studies of Pasteur's friendships with artists. This research project has uncovered data that enlarge the great medical chemist's biography, throwing new light on a variety of topics including his work habits, his social life, his artistic sensibilities, his efforts to lobby on behalf of his artist friends, his relationships to their patrons and to his own patrons, and his use of works of art to foster his reputation as a leader in French medical science. In their first article, the authors examined his unique working relationship with the Finnish painter Albert Edelfelt and the creation of the famous portrait of Pasteur in his laboratory in the mid-1880s. A second study documented his especially warm friendship with three French artists who came from Pasteur's home region, the Jura, or from neighbouring Alsace. The present study explores Pasteur's friendships with Max Claudet and Paul Dubois, both of whom created important representations of Pasteur. These friendships and others with patrons reveal an active pursuit of patronage and reputation building from 1876 into the late 1880s. Yet, although Pasteur actively used public art to raise his status, it becomes clear in these stories that for Pasteur beauty was an ideal and art a pleasure for its own sake. PMID- 26025840 TI - Alice Welford (1887-1918), a nurse in World War I: The impact of kindness and compassion. AB - The contribution of nurses to the morale of wounded and dying young men during World War 1 was immense. Alice Welford came from the small North Yorkshire village of Crathorne, joined the Queen Alexandra Imperial Military Nursing Service in 1915 and spent the following two and one half years in nursing casualties from some of the fiercest battles of the war including Gallipoli and Salonika. She kept an autograph book inscribed by wounded and dying soldiers, with poignant verses and humorous drawings showing love, wit and tragedy. Despite the dreadful conditions, kindness and compassion brought them comfort and raised their morale - a critical message for today, and Alice's gift to us from World War I. PMID- 26025839 TI - Louis Pasteur's three artist compatriots-Henner, Pointelin, and Perraud: A story of friendship, science, and art in the 1870s and 1880s. AB - Biographers have largely ignored Louis Pasteur's many and varied connections with art and artists. This article is the second in a series of the authors' studies of Pasteur's friendships with artists. This research project has uncovered data that enlarge the great medical chemist's biography, throwing new light on a variety of topics including his work habits, his social life, his artistic sensibilities, his efforts to lobby on behalf of his artist friends, his relationships to their patrons and to his own patrons, and his use of works of art to foster his reputation as a leader in French medical science. In a prior article, the authors examined his unique working relationship with the Finnish painter Albert Edelfelt and the creation of the famous portrait of Pasteur in his laboratory in the mid-1880s. The present study documents his especially warm friendship with three French artists who came from Pasteur's home region, the Jura, or from neighboring Alsace. A forthcoming study gives an account of his friendships with Max Claudet and Paul Dubois, both of whom made important images of Pasteur, and it offers further illustrations of his devotion to the fine arts. PMID- 26025841 TI - Letter to the Editor. PMID- 26025842 TI - Ralph Albert Blakelock (1847-1919): Psychiatric hospitalization and the abduction of an American landscape artist. AB - Ralph Blakelock was a leading American landscape painter. Much of his life was lived in obscurity and destitution. He developed late onset paranoid schizophrenia, resulting in prolonged hospitalization. During his time in hospital, demand for Blakelock's works grew, but he was unable to enjoy any of this success. Instead, the artist fell prey to unscrupulous and unlikely exploitation by a self-appointed guardian, aided and abetted by Blakelock's psychiatrists, which broke his spirit and may well have hastened his demise. PMID- 26025843 TI - Alexander Falconer Sr Seamen's missionary in New Zealand, son Alexander Falconer medical superintendent for mentally ill, grandson Murray Falconer neurosurgeon. AB - Alexander Falconer Sr (1843-1915) came from Scotland to New Zealand. A practical Christian, he set up places of relaxation for miners, sailors and soldiers; he became the Seamen's Missionary. Son, Dr Alexander Falconer (1874-1955) trained at Otago University Medical School. As medical superintendent for the mentally ill, he urged the early introduction of psychotherapy. His son, Murray Falconer (1910 1977) was the first Nuffield Dominions Clinical Fellow, training in neurosurgery in Oxford. He was the first director of the Guy's-Maudsley Neurosurgical Unit in London and was internationally known for the surgical management of temporal lobe epilepsy in adults and children. PMID- 26025844 TI - Frederick, Duke of York (1763-1827) - Medical Patron. AB - Frederick, Duke of York, was the hardest working prince of his day. He was Commander-in-Chief of the British Army for almost the entire period of the French revolutionary and Napoleonic wars and he used his position to implement important reforms to benefit the health of troops. He encouraged hygiene initiatives and improved medical treatment, steadily seeking to enhance the quality of medical officers and facilities. Frederick was particularly involved in the spread of vaccination, authorising the very earliest clinical trials of the process and doing all he could to promote the practice. He also played an active role in the fight to prevent and treat the ophthalmia that was decimating the British Army. As the favourite son of George III and ultimately his carer, he developed an interest in mental health and he sponsored the pioneering work of Alexander Morison (1779-1866) to expand understanding of the subject. Although not a medical man himself, Frederick was one of the most important patrons of the day and his efforts were the key to enabling others to make important advances that saved thousands of lives. PMID- 26025845 TI - Morris Young, pioneer physician. AB - This concise biography of Morris Young shows how he developed the medical services of the Anglo-Persian Oil Company in the first three decades of the twentieth century, and ended his career working with Sir Alexander Fleming at St Mary's Hospital in London. Young is an important figure in the history of medicine in Persia, and this biography introduces the achievements of this modest man who devoted his life to medicine. PMID- 26025846 TI - Paul Klee (1879-1940) as a tragic figure: What the artist learned from his illness. AB - Paul Klee was a major contributor to the development of modern European art. An ethnic German (although born in Switzerland) and a German citizen, he was persecuted by the Nazi government on political rather than racial grounds because of his allegedly "degenerate" artistic style. Dismissed from his teaching position, he emigrated to Switzerland in 1933; shortly afterward he became ill with systemic sclerosis and struggled with this condition for the remaining years of his life. Many publications have examined the effect of social rejection and illness on his art, but the present study considers the effect of these adversities on Klee's attitude toward his fellow humans. After being an extreme misanthrope in his early adult years, he developed an attitude of cosmic indifference toward humanity during the First World War, which he then maintained until the end of 1939. Although his rejection by Germany had been a significant emotional blow, it was the physical suffering caused by his illness that led him, at the end of his life, to show compassion toward the suffering of other individuals. In this he was like tragic figures such as King Lear who learned from their great misfortunes to value humanity. PMID- 26025847 TI - Felicjan Slawoj-Skladkowski (1885-1962): The only known doctor-soldier-politician with an outdoor-wooden-toilet named after him. AB - Felicjan Slawoj-Skladkowski was a Polish physician, General and politician who served as Polish Minister of Internal Affairs and was the last Prime Minister of Poland before the Second World War. The lack of basic sanitation in many of Poland's villages caused him to issue a decree that every household in Poland must have a latrine in working order. Wooden sheds were built in the backyards, subsequently named 'slawojkis'. PMID- 26025848 TI - Edward Elgar (1857-1934): Moaner or loner? PMID- 26025849 TI - Serendipity: a personal tale of two biographies, William Richard Gowers (1845 1915) and his son Ernest (1880-1966). AB - Between 2004 and 2012, the author wrote two biographies, the first of 20th century civil servant Ernest Gowers and the second of his father the Victorian neurologist William Richard Gowers. This article describes the author's experience conducting the research for two biographies at a time when the research tools available were rapidly shifting from paper-based to digital records. Technological aids have made the preliminary research of historians easier, but they have not taken the place of hard copy archive-based research. While the paper will focus primarily on the biography of William Richard Gowers, the author describes the research methods she employed to help reveal the personalities, strengths and weaknesses of both men, each of whom left his own intellectual legacy. PMID- 26025850 TI - Contributions of Antoine Barthelemy Clot (1793-1868): A historiographical reflection of public health in Ottoman Egypt. AB - This paper reviews the selected historiographic and contemporary literature that discussed the medical and public health contribution of Antoine Barthelemy Clot (Clot Bey) and how these contributions shaped modern public health in Ottoman Egypt, and the major features that led to the development of the public health infrastructure of early modern Egypt based on the contributions of Clot Bey. The literature discussed the establishment of Egypt's first modern public health and medical schools under the direct administration and guidance of Clot Bey, and his major contribution in the fields of vaccination, quarantine, the development of a culturally congruent curriculum for medical students, and the public health policies and practices enacted during the reign of Muhammad Ali Pasha that addressed major communicable diseases affecting Egypt. With considerable support from the viceroy of Egypt despite popular resistance, Clot Bey significantly modernized Egyptian medicine, medical education and reformed the public health infrastructure. He became one of the preeminent medical figures of nineteenth century Ottoman Egypt. PMID- 26025851 TI - 'A certain instability of mind': Herbert Mayo, 1796-1852, Surgeon and Physiologist. AB - Herbert Mayo was a significant physiologist and an important figure in the London medical world of the 1820s and 1830s. And yet, a combination of poor decision making and dabbling in heterodox medicine damaged his reputation. The life of Herbert Mayo illustrates that during the critical period before the 1858 Medical Act the boundary between orthodox and alternative medicine was porous. It also gives important insights into the politics of medicine at this time, particularly the significance of character to becoming a successful medical practitioner. PMID- 26025852 TI - Merlin's 'invalid or gouty chair' and the origin of the self-propelled wheelchair. AB - Wheelchairs are a major advance in enabling independence for people with walking difficulties. The first self-propelled wheelchair has been attributed to John Joseph Merlin, the 'ingenious mechanick', in the early 19th century and his 'gouty chair' is exhibited at Kenwood House. Research would suggest that comparable chairs existed in France as early as 1751 and the French Revolutionary, Georges Couthon, used one to get around Paris. A later design, also attributed to Merlin, the invalid wheelchair, features large wheels with outer hoops for the occupant to grasp and this is the true ancestor of the modern wheelchair. PMID- 26025853 TI - Dorothy Davison (1890-1984): Manchester medical artist and her work for neurosurgeon Sir Geoffrey Jefferson (1886-1961). AB - Miss Davison was a medical artist at the Manchester Royal Infirmary and the University of Manchester from around 1918 until her retirement in 1957. She illustrated books and scientific papers on anthropology, anatomy and surgery, and became well known for her striking pictures produced by the 'Ross board technique'- a difficult process that she helped pioneer from the 1930s and which forms the bulk of the work she undertook for neurosurgeon Geoffrey Jefferson during the 1930s-1950s. His Neurosurgical Department became the main base for her work until his retirement in 1953. She was an active member of the Medical Artist Association (MAA) which she helped found in 1949. PMID- 26025854 TI - Sulfated phenolic compounds from Limonium caspium: Isolation, structural elucidation, and biological evaluation. AB - Three new compounds, (2S,3S)-5-methyldihydromyricetin (1), (2S,3S)-5 methyldihydromyricetin-3'-O-sulfate (2) and beta-d-glucopyranoside, 3-methyl, but 3-en-1-yl 4-O-alpha-l-rhamnopyranosyl (3) have been isolated from the Limonium caspium, together with dihydromyricetin (4), dihydromyricetin-3'-O-sulfate (5), myricetin-3'-O-sulfate (6), 5-methylmyricetin (7), myricetin (8), myricetin-3-O beta-glucoside (9), as well as phloridzin (10), and tyramine (11). Compounds 5 and 6 were isolated for the first time as acids. This is the first report of all these compounds from this plant. Their structures were established by extensive NMR studies ((1)H NMR, (13)C NMR, DEPT, (1)H-(1)H COSY, HSQC, HMBC) as well as HRESIMS. All isolated compounds were evaluated for their antibacterial, antifungal, antimalarial and antileishmanial activities. Compounds 7, 8 and 9 exhibited good antifungal activity against Candida glabrata with IC50 values of 6.79, 15.37 and 8.53MUg/mL, respectively. Compound 8 displayed significant antimalarial activity against resistant and sensitive strains of Plasmodium falciparum with IC50 values of 1.82 and 1.51MUg/mL, respectively. Compounds 1, 4, 6, 8 and 9 showed excellent activity against Trypanosoma brucei with IC50 values of 6.93, 9.65, 8.52, 7.67 and 6.31MUg/mL, respectively. To date, this is the first report on the phytochemical and biological activity of secondary metabolites from L. caspium. PMID- 26025855 TI - New flavonoids with cytotoxicity from the roots of Flemingia latifolia. AB - Flemingia latifolia is a folk medicine in China, which is used for treating rheumatism, arthropathy, chronic nephritis and menopausal syndrome. The phytochemicals of the plant have seldom been studied so far. In present study, three new compounds, a flavanone quinone (flemingiquinone A) (1), a prenylated dihydroflavonoid (khonklonginol I) (2) and an isoflavonoid (flemilatifolin B) (3) were isolated from the roots of F. latifolia. Their structures were established by (1)H and (13)C NMR spectra and 2D NMR experiments, including COSY, HMQC, HMBC and ROESY. Meanwhile, the compounds were evaluated for cytotoxicity against two human cancer cell lines, SMMC-7721 and A-549. The results showed that compounds 1 and 2 possessed moderate antiproliferative effects on SMMC-7721 and A-549 cell lines. PMID- 26025857 TI - A Rare Etiology of Severe Acute Heart Failure: Subacute Spinal Subdural Hematoma in a Young Woman. PMID- 26025856 TI - Fargesin as a potential beta1 adrenergic receptor antagonist protects the hearts against ischemia/reperfusion injury in rats via attenuating oxidative stress and apoptosis. AB - Fargesin displayed similar chromatographic retention peak to metoprolol in the cardiac muscle/cell membrane chromatography (CM/CMC) and beta1 adrenergic receptor/cell membrane chromatography (beta1AR/CMC) models. To provide more biological information about fargesin, we investigated the effects of fargesin on isoproterenol-(ISO-) induced cells injury in the high expression beta1 adrenergic receptor/Chinese hamster ovary-S (beta1AR/CHO-S) cells and occluding the left coronary artery- (LAD-) induced myocardial ischemia/reperfusion (MI/R) injury in rats. The results in vitro showed that ISO-induced canonical cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) levels were decreased by fargesin in beta1AR/CHO-S cells. Fargesin attenuated the serum creatine kinase (CK), lactate dehydrogenase (LDH), and improved histopathological changes of ischemic myocardium compared with the I/R rats. Similar results were obtained with Evans Blue/TTC staining, in which fargesin notably reduced infarct size. Moreover, compared with the I/R group, fargesin increased COX release and the activities of some endogenous antioxidative enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), but suppressed malondialdehyde (MDA), and intracellular ROS release. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated fargesin suppressed myocardial apoptosis, which may be related to inhibition of caspase-3 activity. Taken together, these results provided substantial evidences that fargesin as a potential beta1AR antagonist through cAMP/PKA pathway could protect against myocardial ischemia/reperfusion injury in rats. The underlining mechanism may be related to inhibiting oxidative stress and myocardial apoptosis. PMID- 26025858 TI - Diastolic dysfunction reduces stroke volume during daily's life activities in patients with severe aortic stenosis. PMID- 26025859 TI - Optimal blood pressure for favorable neurological outcome in adult patients following in-hospital cardiac arrest. AB - BACKGROUND: Adequate cerebral blood flow maintained by optimal blood pressure is important in neurological recovery for patients sustaining transient brain ischemia. Few clinical studies have investigated the relationship between blood pressure and neurological outcomes of patients resuscitated following cardiac arrest. METHODS: This was a retrospective observational study, from a single medical center, of adult patients between 2006 and 2012 who had in-hospital cardiac arrest and achieved sustained return of spontaneous circulation (ROSC). Multivariable logistic regression analysis was used to identify factors associated with a favorable neurological outcome at hospital discharge. Maximal mean arterial pressure (MAP) during the initial 24h after sustained ROSC was used for analysis. RESULTS: Of the 319 study patients, 56 (17.6%) achieved a favorable neurologic outcome. The mean MAP was 95 mmHg. MAP above 85 mmHg was found to correlate with a favorable neurological outcome (odds ratio [OR] 4.12, 95% confidence interval [CI] 1.47-14.39, p = 0.01). For patients without arterial hypertension, the optimal MAP was between 85 and 115 mmHg (OR 8.80, 95% CI 3.13 28.55, p < 0.001); for patients with arterial hypertension, the threshold MAP for achieving a favorable neurological outcome was above 88 mmHg (OR 4.04, 95% CI 1.41-13.03, p = 0.01). CONCLUSIONS: The blood pressure over the first 24h following resuscitation was correlated with neurological outcome. There may be a threshold blood pressure required to affect a favorable neurological outcome. The optimal blood pressure may be dependent on the presence or absence of arterial hypertension. PMID- 26025861 TI - Association of atrial fibrillation and erectile dysfunction. PMID- 26025860 TI - Mitral valve prolapse caused from ruptured mitral chordae tendineae due to an infective endocarditis in cancer patient. PMID- 26025862 TI - Clinical impact of USPSTF screening recommendations for abdominal aortic aneurysm: Analysis of Nationwide Inpatient Sample data. PMID- 26025863 TI - Five-year outcomes of percutaneous coronary intervention versus coronary artery bypass graft surgery in patients with left main coronary artery disease: An updated meta-analysis of randomized trials and adjusted observational studies. PMID- 26025864 TI - Successful heart transplantation from a donor with takotsubo syndrome. PMID- 26025865 TI - FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy. AB - BACKGROUND: Congestive heart failure (CHF) is a significant health care burden in developed countries. However, the molecular events leading from cardiac hypertrophy to CHF are unclear and preventive therapeutic approaches are limited. We have previously described that microphthalmia-associated transcription factor (MITF) is a key regulator of cardiac hypertrophy, but its cardiac targets are still uncharacterized. METHODS AND RESULTS: Gene array analysis of hearts from MITF-mutated mice indicated that ErbB2 interacting protein (Erbin) is a candidate target gene for MITF. We have recently demonstrated that Erbin is decreased in human heart failure and plays a role as a negative modulator of pathological cardiac hypertrophy. Here we show that Erbin expression is regulated by MITF. Under basal conditions MITF activates Erbin expression by direct binding to its promoter. However, under beta-adrenergic stimulation Erbin expression is decreased only in wild type mice, but not in MITF-mutated mice. Yeast two-hybrid screening, using MITF as bait, identified an interaction with the cardiac predominant four-and-a-half LIM domain protein 2 (FHL2), which was confirmed by co-immunoprecipitation in both mouse and human hearts. Upon beta-adrenergic stimulation, FHL2 and MITF bind Erbin promoter as a complex and repress MITF directed Erbin expression. Overexpression of FHL2 alone had no effect on Erbin expression, but in the presence of MITF, Erbin expression was decreased. FHL2 MITF association was also increased in biopsies of heart failure patients. CONCLUSION: MITF unexpectedly regulates both the activation and the repression of Erbin expression. This ligand mediated fine tuning of its gene expression could be an important mechanism in the process of cardiac hypertrophy and heart failure. PMID- 26025866 TI - How far do we want to go in the treatment of obstruction in Hypertrophic Cardiomyopathy? PMID- 26025867 TI - Pericardial fat and atrial fibrillation: Epidemiology, mechanisms and interventions. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and is associated with major morbidity and mortality. AF prevalence has been projected to increase in the coming decades and is expected to affect over 7.5 million Americans by the year 2050. There is growing evidence that obesity represents an important risk factor for new onset AF, with each increment in BMI associated with a 3-8% higher risk for new-onset of AF, independent of other conventional AF risk factors such as age, hypertension and heart failure. Several recent studies have also reported that obesity is also a risk factor for AF severity & chronicity. Although obesity may impact AF incidence via several mechanisms, a relation between local pericardial fat depots surrounding the heart and AF has been recently described which may have important pathophysiological implications. Pericardial fat represents one of several localized, fat depots, with unique properties due to its contiguity with cardiac structures and its shared blood supply with the heart microcirculation. Pericardial fat is also highly metabolically active and is an important source of several adipokines and cytokines. Importantly, pericardial fat appears to be more closely linked with metabolic risk than indices of systemic obesity such as BMI or waist circumference. Therefore, pericardial fat may partially explain the increased risk of AF seen in obesity and may promote AF arrhythmogenesis by local mechanisms. In this article, we review the characteristics of pericardial fat, the evidence of an association between pericardial fat and AF and the potential mechanisms for this association. We also summarize the evidence from several recent reports that have linked pericardial fat to AF prevalence, severity as well as outcome after AF ablation. We also briefly review whether interventions targeting pericardial fat could reduce AF incidence and recurrence. PMID- 26025868 TI - Diastolic mitral and tricuspid regurgitation in a patient with 2:1 AV block. PMID- 26025869 TI - Assessment of carotid plaque neovascularization using quantitative analysis of contrast-enhanced ultrasound imaging is useful for risk stratification in patients with coronary artery disease. AB - BACKGROUND: Contrast-enhanced ultrasound (CEUS) of the carotid artery is a potential technique for imaging plaque neovascularization, a feature of unstable atherosclerotic plaques. This study examined whether assessment of intra-plaque neovascularization of the carotid artery using CEUS provides prognostic information in patients with coronary artery disease (CAD). METHODS: A total of 206 patients with stable CAD underwent a CEUS examination of the carotid artery and were followed up prospectively for <38 months or until a cardiac event (cardiac death, non-fatal myocardial infarction (MI), unstable angina pectoris (uAP) requiring unplanned coronary revascularization, or heart failure requiring hospitalization). The degree of contrast signals measured within the carotid plaque was quantified by calculating the mean gray scale level within the region of interest of the carotid plaque, expressed as plaque enhanced intensity. RESULTS: During the follow-up period, 31 events occurred (2 cardiac deaths, 7 non fatal MIs, 16 uAP, and 6 heart failure). Multivariate Cox proportional hazard analysis showed that plaque enhanced intensity was a significant predictor of cardiac events independent of traditional risk factors (HR, 1.13; 95% CI, 1.05 1.21; p<0.001). The addition of the plaque enhanced intensity to traditional risk factors resulted in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.62, p=0.001; and IDI 0.106, p=0.002). CONCLUSIONS: The assessment of carotid plaque neovascularization using quantitative analysis of CEUS may be useful for risk stratification in patients with CAD. PMID- 26025870 TI - Is strengthening the endothelial barrier a therapeutic strategy for Ebola? PMID- 26025871 TI - 'No Man's Land': An exploration of the traumatic experiences of student midwives in practice. AB - BACKGROUND: the role of being 'with woman' during traumatic birth has been identified as having an emotional cost for midwives, but to date no research has explored traumatic experiences of student midwives. AIM: to explore student midwives' perceptions of what was traumatic for them and how they were supported with such events. DESIGN: a qualitative descriptive approach, using semi structured interviews. SETTING: one university in the North West of England. PARTICIPANTS: 11 student midwives recruited by poster campaign. FINDINGS: five main themes emerged from the analysis. Wearing your Blues depicted what participants described as the 'bleak' landscape of practice. No Man's Land was concerned with traumatic tensions in the student role. 'Get the Red Box! ' and The Aftermath concerned traumatic events in practice and the impact of these on students. Learning to cope related to the way students coped with such incidents, as well as other stresses in the role. KEY CONCLUSIONS: the student midwife inhabits a vulnerable position in the 'No Man's Land' of hospital practice. Her strong identification with the woman renders her potentially more vulnerable in traumatic situations. The study revealed a paradigmatic clash between the manualised care of a busy obstetric unit and the individualised woman-led approach they were expecting. IMPLICATIONS FOR PRACTICE: it seems important for the profession to recognise that distressing events are not always the obvious critical incidents in care, and that a culture of support and/or debriefing after adverse events may assist students to articulate their needs and develop resilience. Educators may need to appreciate that the student midwife role in an emergency may heighten her vulnerability. This study also highlighted the potential alienation of students when placed in the maelstrom of a busy obstetric unit. The Birthplace study (Brocklehurst et al., 2011), NHS England's Five Year Forward View (NHS England, 2014) and NICE (2014) all recommend increasing the numbers of out-of-hospital births: it seems likely that such a reorganisation of care would improve the experiences of mothers and those who care for them during birth. As part of a 'design for compassionate care' (Crawford et al., 2014) it is important to foster spaces, processes and resources which are compassionate to practitioners and students. PMID- 26025872 TI - Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting. AB - The role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and that of antibodies neutralizing virus epithelial infection (AbNEI) in the control of CMV DNAemia were investigated in 39 CMV-seropositive allogeneic stem-cell transplant (Allo-SCT) recipients with (n = 24) or without (n = 15) CMV DNAemia. AbNEI levels were monitored prospectively by means of a neutralization assay employing retinal epithelial cells (ARPE-19) and the recombinant CMV strain BADrUL131-Y4. Quantification of CMV-specific polyfunctional CD8+ T-cells (expressing two or three of the following markers: IFN-gammagamma, TNF-alpha and CD107a) in whole blood was performed by flow cytometry for intracellular cytokine staining. We found no differences in the dynamic pattern of AbNEI in patients with or without subsequent CMV DNAemia. Baseline and peak AbNEI titres were not predictive of the dynamics of CMV replication within episodes. No correlation was found between CMV DNA loads and AbNEI levels during episodes of CMV DNAemia (rho = 0.09; 95 % confidence interval - 0.52 to 0.64; P = 0.78). The detection of pp65/IE-1 CMV-specific polyfunctional CD8+ T-cells was associated with low-level virus replication within subsequent episodes of CMV DNAemia. Interestingly, the presence of AbNEI titres (inverse) >4.7 log2 was predictive of the occurrence of CMV DNAemia (sensitivity, 83 %; specificity, 80 %). Our findings provide an insight to the role of humoral and cellular immunity in the control of CMV infection in an Allo-SCT setting. PMID- 26025873 TI - Epidemiological dynamics of norovirus GII.4 variant New Orleans 2009. AB - Norovirus (NoV) is one of the major causes of diarrhoeal disease with epidemic, outbreak and sporadic patterns in humans of all ages worldwide. NoVs of genotype GII.4 cause nearly 80-90 % of all NoV infections in humans. Periodically, some GII.4 strains become predominant, generating major pandemic variants. Retrospective analysis of the GII.4 NoV strains detected in Italy between 2007 and 2013 indicated that the pandemic variant New Orleans 2009 emerged in Italy in the late 2009, became predominant in 2010-2011 and continued to circulate in a sporadic fashion until April 2013. Upon phylogenetic analysis based on the small diagnostic regions A and C, the late New Orleans 2009 NoVs circulating during 2011-2013 appeared to be genetically different from the early New Orleans 2009 strains that circulated in 2010. For a selection of strains, a 3.2 kb genome portion at the 3' end was sequenced. In the partial ORF1 and in the full-length ORF2 and ORF3, the 2011-2013 New Orleans NoVs comprised at least three distinct genetic subclusters. By comparison with sequences retrieved from the databases, these subclusters were also found to circulate globally, suggesting that the local circulation reflected repeated introductions of different strains, rather than local selection of novel viruses. Phylogenetic subclustering did not correlate with changes in residues located in predicted putative capsid epitopes, although several changes affected the P2 domain in epitopes A, C, D and E. PMID- 26025874 TI - Click reaction based synthesis, antimicrobial, and cytotoxic activities of new 1,2,3-triazoles. AB - Three-motif pharmacophoric models 20a-e and 21-25 were prepared in good yields by CuAAC of two azido substrates 2 and 11 with seven terminal acetylenic derivatives including chalcones 17a-e, theophylline 18 and cholesterol 19. The structure of these compounds was elucidated by NMR, MS, IR spectroscopy and micro analyses. This series was screened as antimicrobial and cytotoxic agents in vitro. Most derivatives showed appreciable antibacterial activity, but they displayed weak cytotoxic, and antifungal activities. Notably, conjugate 25 (cream of the crop) was found to be more active than Ampicillin against Escherichia coli and Staphylococcus aureus and showed appreciable antifungal and cytotoxic activities as well. PMID- 26025875 TI - New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies. AB - A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 MUM, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme. PMID- 26025876 TI - Peroxisome proliferator-activated receptor gamma (PPARgamma) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARgamma partial agonists bind to PPARgamma LBD in different conformations. AB - In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARgamma) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARgamma partial agonist 2. Co-crystallization of 3 with the hPPARgamma ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARgamma LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180 degrees away from that of bound 2. These results support our previous proposal that the hPPARgamma LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands. PMID- 26025877 TI - Improvement of solid material for affinity resins by application of long PEG spacers to capture the whole target complex of FK506. AB - Solid materials for affinity resins bearing long PEG spacers between a functional group used for immobilization of a bio-active compound and the solid surface were synthesized to capture not only small target proteins but also large and/or complex target proteins. Solid materials with PEG1000 or PEG2000 as spacers, which bear a benzenesulfonamide derivative, exhibited excellent selectivity between the specific binding protein carbonic anhydrase type II (CAII) and non specific ones. These materials also exhibited efficacy in capturing a particular target at a maximal amount. Affinity resins using solid materials with PEG1000 or PEG2000 spacers, bear a FK506 derivative, successfully captured the whole target complex of specific binding proteins at the silver staining level, while all previously known affinity resins with solid materials failed to achieve this objective. These novel affinity resins captured other specific binding proteins such as dynamin and neurocalcin delta as well. PMID- 26025878 TI - The identification of proteomic markers of sperm freezing resilience in ram seminal plasma. AB - The source and composition of seminal plasma has previously been shown to alter the ability of spermatozoa to survive cryopreservation. In the present study, the ionic and proteomic composition of seminal plasma from rams with high (HSP; n = 3) or low (LSP; n = 3) freezing resilient spermatozoa was assessed. 75 proteins were identified to be more abundant in HSP and 48 proteins were identified to be more abundant in LSP. Individual seminal plasma proteomes were established for each of the six rams examined. For each ram, correlations were conducted between previously recorded freezing resilience [1] and individual spectral counts in order to identify markers of freezing resilience. 26S proteasome complex, acylamino acid releasing enzyme, alpha mannosidase class 2C, heat shock protein 90, tripeptidyl-peptidase 2, TCP-1 complex, sorbitol dehydrogenase and transitional endoplasmic reticulum ATPase were found to be positively correlated (r(2) > 0.7) with freezing resilience. Cystatin, zinc-2-alpha glycoprotein, angiogenin-2-like protein, cartilage acidic protein-1, cathepsin B and ribonuclease 4 isoform 1 were found to be negatively correlated (r(2) > 0.7) with freezing resilience. Several negative markers were found to originate from the accessory sex glands, whereas many positive markers originated from spermatozoa and were part of or associated with the 26S proteasome or CCT complex. PMID- 26025879 TI - Chromatographic behavior of peptides containing oxidized methionine residues in proteomic LC-MS experiments: Complex tale of a simple modification. AB - On average, the oxidation of a single Met residue to Mso (methionine S-oxide, methionine sulfoxide) and Msn (methionine S,S-dioxide, methionine sulfone) decreases peptide retention in RP HPLC by 2.37 and 1.95 Hydrophobicity Index units (% acetonitrile), respectively. At the same time, the magnitude of the retention shift varies greatly (-9.1 to +0.4% acetonitrile for Mso) depending on peptide sequence. The latter effects are mostly associated with the stabilization of secondary structures upon peptide interaction with the hydrophobic stationary phase: when an oxidized residue is located in the hydrophobic face of an amphipathic helix, the decrease in retention is profound. The same amino acid positioning leads to complete or partial resolution of pairs of peptides containing diastereomeric Mso residues. Contrary to all previously reported observations, and the nature of this modification, we also demonstrate for the first time that methionine oxidation may increase peptide hydrophobicity. This behavior is characteristic for Met residues in the N3 position of an N-capping box stabilization motif prior to the amphipathic helix. All these findings indicate that the prediction of peptide secondary structures upon interaction with hydrophobic surfaces must become an integral part of peptide retention modeling in proteomic applications going forward. PMID- 26025880 TI - Effects of leukemia inhibitory factor and insulin-like growth factor-I on the cell allocation and cryotolerance of bovine blastocysts. AB - The present study examined the developmental capacity and cryotolerance of cultured bovine embryos in defined media (synthetic oviduct fluid, SOF) supplemented with insulin-like growth factor I (IGF-I) and leukemia inhibitor factor (LIF). The objectives of the present study were: (1) to examine the effects IGF-I and LIF on bovine embryo development potential and (2) to investigate the cryotolerance and survivability of vitrified blastocysts obtained from embryos cultured in a defined media. We studied the development of bovine embryos produced in vitro and cultured (in four different treatments) until Day 7 after fertilization. In Experiment 1, zygotes were cultured to the blastocyst stage and differentially stained for determine the count of cells. In Experiment 2, zygotes were vitrified before staining. LIF alone or combined with IGF-I was significantly effective on in vitro bovine embryo development especially ratio to reach blastocyst. The cells for both ICM and TE decreased by the effect of freezing in all treatment groups in the Experiment 2 compared with Experiment 1. Interestingly, the LIF treatment showed fewest variations. In addition to this, for average number of ICM and TE cells, LIF treatment showed fewest variation compared with other treatments (ICM: 23.5 vs 19.5, TE: 53.6 vs 51). These results are the first to demonstrate that the addition of IGF-I along with LIF to the culture medium was found to be beneficial for bovine embryonic development based on cellular cryotolerance after vitrification. PMID- 26025882 TI - Burnout in Radiology. AB - Burnout is a psychological syndrome that arises in the setting of prolonged work related stress. Although its specific manifestations are highly variable, the core features of burnout include emotional exhaustion, callousness or apathy towards patients or peers, and feelings of personal inadequacy. Burnout can have profound consequences for the affected physician, his or her patients, and the health care system at large. Increased rates of substance abuse, depression, and suicide have been linked to physician burnout, as have medical errors and lapses in patient safety. Disruptive workplace behaviors, such as presenteeism (which is reduced productivity due to physical or emotional dysfunction), absenteeism (which is nonparticipation in work), high employment turnover, and early retirement also have been linked to physician burnout and depression. In this article, we review causes, preventive measures and possible solutions for physician burnout. PMID- 26025881 TI - Efficient cryopreservation of mouse embryos by modified droplet vitrification (MDV). AB - The aim of this study was to assess modified droplet vitrification (MDV) for the cryopreservation of early developmental mouse embryos. Mouse embryos were equilibrated in holding solution for 3 min followed by immersion in vitrification solution for 30-45 s, and then three embryos per 3-MUL vitrification droplet were directly dropped into liquid nitrogen. Vitrified embryos were warmed to examine their developmental potential both in vitro and in vivo. The results demonstrated that MDV vitrified and warmed embryos had a survival rate of 98.1-99.6% (P>0.05); however, blastocyst development post warming and culture in vitro demonstrated that vitrified 4-celled, 8-celled, 16-celled, morulae, and blastocyst embryos had significant higher developmental potentials (94.7-99.5%) than those from zygotes (9.2%) and 2-celled embryos (85.7%) (P<0.05). Compared to CryoLoop and CryoTech vitrification, MDV showed similar results with regards to rates of survival, blastocyst development, but with the higher hatching rate (76.1% vs. 64.0-67.3%) (P<0.05). Cryopreservation by MDV resulted in a similar blastocyst developmental potential in 4-celled and 16 celled embryos from ICR (94.7-99.5%), C57BL/6J (94.7 96.4%), and their crossbred F1 strain (97.9-98.9%) (P>0.05). After embryo transfer of vitrified ICR embryos from 4-celled, 16-celled, morulae and blastocyst stage, 40.7-43.7% of the embryos developed into live offspring (P>0.05), but MDV vitrification resulted in the highest birth rate (43.8%) compared to CryoLoop (38.3%) and CryoTech (35.4%) (P<0.05), when 4-celled mouse embryos were used for vitrification. Our study clearly demonstrated that MDV is the most efficient vitrification to cryopreserve embryos at least 4-celled and advanced stages, which can be used to preserve important mouse genomes from different strains and different developmental stages. PMID- 26025884 TI - Mixing times towards demographic equilibrium in insect populations with temperature variable age structures. AB - In this study, we use entropy related mixing rate modules to measure the effects of temperature on insect population stability and demographic breakdown. The uncertainty in the age of the mother of a randomly chosen newborn, and how it is moved after a finite act of time steps, is modeled using a stochastic transformation of the Leslie matrix. Age classes are represented as a cycle graph and its transitions towards the stable age distribution are brought forth as an exact Markov chain. The dynamics of divergence, from a non equilibrium state towards equilibrium, are evaluated using the Kolmogorov-Sinai entropy. Moreover, Kullback-Leibler distance is applied as information-theoretic measure to estimate exact mixing times of age transitions probabilities towards equilibrium. Using empirically data, we show that on the initial conditions and simulated projection's trough time, that population entropy can effectively be applied to detect demographic variability towards equilibrium under different temperature conditions. Changes in entropy are correlated with the fluctuations of the insect population decay rates (i.e. demographic stability towards equilibrium). Moreover, shorter mixing times are directly linked to lower entropy rates and vice versa. This may be linked to the properties of the insect model system, which in contrast to warm blooded animals has the ability to greatly change its metabolic and demographic rates. Moreover, population entropy and the related distance measures that are applied, provide a means to measure these rates. The current results and model projections provide clear biological evidence why dynamic population entropy may be useful to measure population stability. PMID- 26025883 TI - Adjuvant Metronomic CMF in a Contemporary Breast Cancer Cohort: What's Old Is New. AB - BACKGROUND: Commonly used adjuvant systemic therapies harbor high rates of severe short-term and long-term side effects but are often justified to patients because of curative intent in early-stage breast cancer. One of the oldest and least toxic adjuvant regimens, CMF (oral cyclophosphamide given with intravenous methotrexate and 5-fluorouracil), has been largely abandoned because of the perception that it underperforms for survival outcomes compared with modern regimens containing anthracycline and/or taxanes. MATERIALS AND METHODS: To address this misperception, we performed a review of all consecutive breast cancer patients at the Seattle Cancer Care Alliance over the past decade who received 6 months of adjuvant CMF as their sole chemotherapy regimen and determined rates for relapse-free survival (RFS), overall survival (OS), and major organ toxicity. From January 2003 to August 2013, 248 patients (median age of 52 years at the start of chemotherapy) met criteria for inclusion in this series and had a median follow-up of 67 months. RESULTS: RFS and OS at 5 years was 94.5% (91.3%-97.9%) and 98% (96%-100%), respectively. The only major organ toxicity that occurred in > 5% of patients was Grade 3 neutropenia (18.1%, 24 patients). One patient died during therapy from pneumocystis pneumonia attributed to previously undiagnosed AIDS. CONCLUSION: In a modern cohort of patients thoroughly characterized for Grade and hormone receptor status, CMF was a well tolerated and effective adjuvant regimen for early-stage breast cancer and should be considered for appropriately selected patients. PMID- 26025885 TI - Predictors of reoperation-free survival following decompression-alone lumbar spine surgery for on-the-job injuries. AB - INTRODUCTION: Workers' compensation patients are known to be associated with inferior outcomes following lumbar surgery. We investigated demographics and clinical characteristics between the reoperative and non-reoperative group of patients undergoing decompression-alone lumbar surgery (discectomy and/or laminectomy) for on-the-job injuries (OJI) at our institute, and evaluated its possible impact on the reoperation-free survival (RFS). METHODS: A retrospective analysis of patients undergoing lumbar surgery for OJI between 2003 through 2010 by a single surgeon (A.N.) was performed. A comparison of baseline clinical and demographic parameters between the two groups was compared using Fisher's exact test for the categorical variables and the independent t-test (2-tailed) for the continuous variables. Overall, RFS was presented in Kaplan-Meier curves and the RFS difference was compared using log-rank (Mantel-Cox) test. Cox proportional hazard model was used for the univariate and multivariate analysis and hazard ratios with 95% confidence intervals were reported. RESULTS: About 92 patients with mean age 48.07 +/- 10.10 years and mean follow-up of 36.4 (range 24.3-66.0) months were included. About 38 (41.3%) patients underwent reoperation for failed decompression-alone procedures whereas the non-reoperative cohort comprises 54 (58.7%) patients. Female gender (p = 0.015) and history of previous surgery (p = 0.05) were associated with a higher chance of reoperation. Majority of the reoperations (20/38, 52.6%) were performed within the first 2 years, with a RFS at the end of 2 years being 78.3% (n = 72) and 58.9% (n = 53) at 5 years. Cox regression analysis did not demonstrate any influence of patients and treatment related factors on the RFS. CONCLUSION: There is a substantial risk of redo surgeries following decompression-alone lumbar procedures for OJI. As patient and treatment-related factors did not influence the reoperation rates and RFS in this study, it appears that workman compensation status of patients is inherently associated with poor outcomes following spine surgeries. PMID- 26025887 TI - Circular economy and global secondary material supply chains. PMID- 26025886 TI - Quantification of beta-hydroxymethylbutyrate and leucine by ultrahigh performance liquid chromatography tandem mass spectrometry at different situations and stages of a rodent life. AB - The main objective of this work was to develop a method to measure Leucine (Leu) and beta-hydroxymethylbutyrate (HMB) at basal levels in serum, urine, milk and brain microdialysates in rats. Ultrahigh performance liquid chromatography electrospray-tandem mass spectrometry (UHPLC-ESI-MS/MS) was used as analytical technique. The sample treatment was simple and consisted of dilution with methanol and centrifugation for serum and urine, dilution with water and filtration with an Amicon filter for milk, and treatment with formic acid with no further dilution for microdialyzates. The procedures for sampling and the UHPLC MS/MS parameters were accurately optimized to achieve the highest recoveries and to enhance the analytical characteristics of the method. For chromatographic separation, an Acquity UPLC BEH Amide column using acetonitrile-water gradient with formic acid as additive was used. The total run time was 4min. The analytical characteristics (accuracy, selectivity and sensitivity) of the proposed method were evaluated. The limits of detection (LODs) obtained ranged from 0.4 to 7ngmL(-1) and the limits of quantification (LOQs) from 1 to 22ngmL( 1). Precision, expressed as relative standard deviation (% RSD), was lower than 15% in all cases, and the determination coefficient (R(2)) was equal or higher than 99.0% with a residual deviation for each calibration point lower than +/ 25%. Mean recoveries were between 85 and 115%. The method was successfully applied to these matrices being able to detect significant differences between physiological situations, strains and stages of life. PMID- 26025888 TI - Structural and Mechanistic Insights into the Pseudomonas fluorescens 2 Nitrobenzoate 2-Nitroreductase NbaA. AB - The bacterial 2-nitroreductase NbaA is the primary enzyme initiating the degradation of 2-nitrobenzoate (2-NBA), and its activity is controlled by posttranslational modifications. To date, the structure of NbaA remains to be elucidated. In this study, the crystal structure of a Cys194Ala NbaA mutant was determined to a 1.7-A resolution. The substrate analog 2-NBA methyl ester was used to decipher the substrate binding site by inhibition of the wild-type NbaA protein. Tandem mass spectrometry showed that 2-NBA methyl ester produced a 2-NBA ester bond at the Tyr193 residue in the wild-type NbaA but not residues in the Tyr193Phe mutant. Moreover, covalent binding of the 2-NBA methyl ester to Tyr193 reduced the reactivity of the Cys194 residue on the peptide link. The Tyr193 hydroxyl group was shown to be essential for enzyme catalysis, as a Tyr193Phe mutant resulted in fast dissociation of flavin mononucleotide (FMN) from the protein with the reduced reactivity of Cys194. FMN binding to NbaA varied with solution NaCl concentration, which was related to the catalytic activity but not to cysteine reactivity. These observations suggest that the Cys194 reactivity is negatively affected by a posttranslational modification of the adjacent Tyr193 residue, which interacts with FMN and the substrate in the NbaA catalytic site. PMID- 26025889 TI - Dynamics of the Streptococcus gordonii Transcriptome in Response to Medium, Salivary alpha-Amylase, and Starch. AB - Streptococcus gordonii, a primary colonizer of the tooth surface, interacts with salivary alpha-amylase via amylase-binding protein A (AbpA). This enzyme hydrolyzes starch to glucose, maltose, and maltodextrins that can be utilized by various oral bacteria for nutrition. Microarray studies demonstrated that AbpA modulates gene expression in response to amylase, suggesting that the amylase streptococcal interaction may function in ways other than nutrition. The goal of this study was to explore the role of AbpA in gene regulation through comparative transcriptional profiling of wild-type KS1 and AbpA(-) mutant KS1OmegaabpA under various environmental conditions. A portion of the total RNA isolated from mid log-phase cells grown in 5% CO2 in (i) complex medium with or without amylase, (ii) defined medium (DM) containing 0.8% glucose with/without amylase, and (iii) DM containing 0.2% glucose and amylase with or without starch was reverse transcribed to cDNA and the rest used for RNA sequencing. Changes in the expression of selected genes were validated by quantitative reverse transcription PCR. Maltodextrin-associated genes, fatty acid synthesis genes and competence genes were differentially expressed in a medium-dependent manner. Genes in another cluster containing a putative histidine kinase/response regulator, peptide methionine sulfoxide reductase, thioredoxin protein, lipoprotein, and cytochrome c-type protein were downregulated in KS1OmegaabpA under all of the environmental conditions tested. Thus, AbpA appears to modulate genes associated with maltodextrin utilization/transport and fatty acid synthesis. Importantly, in all growth conditions AbpA was associated with increased expression of a potential two-component signaling system associated with genes involved in reducing oxidative stress, suggesting a role in signal transduction and stress tolerance. PMID- 26025890 TI - Transcriptomic and Proteomic Profiling of Anabaena sp. Strain 90 under Inorganic Phosphorus Stress. AB - Inorganic phosphorus (Pi) is one of the main growth-limiting factors of diazotrophic cyanobacteria. Due to human activity, the availability of Pi has increased in water bodies, resulting in eutrophication and the formation of massive cyanobacterial blooms. In this study, we examined the molecular responses of the cyanobacterium Anabaena sp. strain 90 to phosphorus deprivation, aiming at the identification of candidate genes to monitor the Pi status in cyanobacteria. Furthermore, this study increased the basic understanding of how phosphorus affects diazotrophic and bloom-forming cyanobacteria as a major growth-limiting factor. Based on RNA sequencing data, we identified 246 differentially expressed genes after phosphorus starvation and 823 differentially expressed genes after prolonged Pi limitation, most of them related to central metabolism and cellular growth. The transcripts of the genes related to phosphorus transport and assimilation (pho regulon) were most upregulated during phosphorus depletion. One of the most increased transcripts encodes a giant protein of 1,869 amino acid residues, which contains, among others, a phytase-like domain. Our findings predict its crucial role in phosphorus starvation, but future studies are still needed. Using two-dimensional difference in gel electrophoresis (2D-DIGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found 43 proteins that were differentially expressed after prolonged phosphorus stress. However, correlation analysis unraveled an association only to some extent between the transcriptomic and proteomic abundances. Based on the present results, we suggest that the method used for monitoring the Pi status in cyanobacterial bloom should contain wider combinations of pho regulon genes (e.g., PstABCS transport systems) in addition to the commonly used alkaline phosphatase gene alone. PMID- 26025891 TI - CysK Plays a Role in Biofilm Formation and Colonization by Vibrio fischeri. AB - A biofilm, or a matrix-embedded community of cells, promotes the ability of the bacterium Vibrio fischeri to colonize its symbiotic host, the Hawaiian squid Euprymna scolopes. Biofilm formation and colonization depend on syp, an 18-gene polysaccharide locus. To identify other genes necessary for biofilm formation, we screened for mutants that failed to form wrinkled colonies, a type of biofilm. We obtained several with defects in genes required for cysteine metabolism, including cysH, cysJ, cysK, and cysN. The cysK mutant exhibited the most severe wrinkling defect. It could be complemented with a wild-type copy of the cysK gene, which encodes O-acetylserine sulfhydrolase, or by supplementing the medium with additional cysteine. None of a number of other mutants defective for biosynthetic genes negatively impacted wrinkled colony formation, suggesting a specific role for CysK. CysK did not appear to control activation of Syp regulators or transcription of the syp locus, but it did influence production of the Syp polysaccharide. Under biofilm-inducing conditions, the cysK mutant retained the same ability as that of the parent strain to adhere to the agar surface. The cysK mutant also exhibited a defect in pellicle production that could be complemented by the cysK gene but not by cysteine, suggesting that, under these conditions, CysK is important for more than the production of cysteine. Finally, our data reveal a role for cysK in symbiotic colonization by V. fischeri. Although many questions remain, this work provides insights into additional factors required for biofilm formation and colonization by V. fischeri. PMID- 26025892 TI - Comparison of Quantitative PCR and Droplet Digital PCR Multiplex Assays for Two Genera of Bloom-Forming Cyanobacteria, Cylindrospermopsis and Microcystis. AB - The increasing occurrence of harmful cyanobacterial blooms, often linked to deteriorated water quality and adverse public health effects, has become a worldwide concern in recent decades. The use of molecular techniques such as real time quantitative PCR (qPCR) has become increasingly popular in the detection and monitoring of harmful cyanobacterial species. Multiplex qPCR assays that quantify several toxigenic cyanobacterial species have been established previously; however, there is no molecular assay that detects several bloom-forming species simultaneously. Microcystis and Cylindrospermopsis are the two most commonly found genera and are known to be able to produce microcystin and cylindrospermopsin hepatotoxins. In this study, we designed primers and probes which enable quantification of these genera based on the RNA polymerase C1 gene for Cylindrospermopsis species and the c-phycocyanin beta subunit-like gene for Microcystis species. Duplex assays were developed for two molecular techniques qPCR and droplet digital PCR (ddPCR). After optimization, both qPCR and ddPCR assays have high linearity and quantitative correlations for standards. Comparisons of the two techniques showed that qPCR has higher sensitivity, a wider linear dynamic range, and shorter analysis time and that it was more cost effective, making it a suitable method for initial screening. However, the ddPCR approach has lower variability and was able to handle the PCR inhibition and competitive effects found in duplex assays, thus providing more precise and accurate analysis for bloom samples. PMID- 26025893 TI - Tulane Virus as a Potential Surrogate To Mimic Norovirus Behavior in Oysters. AB - Oyster contamination by noroviruses is an important health and economic problem. The present study aimed to compare the behaviors of Norwalk virus (the prototype genogroup I norovirus) and two culturable viruses: Tulane virus and mengovirus. After bioaccumulation, tissue distributions were quite similar for Norwalk virus and Tulane virus, with the majority of viral particles detected in digestive tissues, while mengovirus was detected in large amounts in the gills and mantle as well as in digestive tissues. The levels of persistence of all three viruses over 8 days were comparable, but clear differences were observed over longer periods, with Norwalk and Tulane viruses displaying rather similar half-lives, unlike mengovirus, which was cleared more rapidly. These results indicate that Tulane virus may be a good surrogate for studying norovirus behavior in oysters, and they confirm the prolonged persistence of Norwalk virus in oyster tissues. PMID- 26025894 TI - Resistance to Bacillus thuringiensis Toxin Cry2Ab in Trichoplusia ni Is Conferred by a Novel Genetic Mechanism. AB - The resistance to the Bacillus thuringiensis (Bt) toxin Cry2Ab in a greenhouse originated Trichoplusia ni strain resistant to both Bt toxins Cry1Ac and Cry2Ab was characterized. Biological assays determined that the Cry2Ab resistance in the T. ni strain was a monogenic recessive trait independent of Cry1Ac resistance, and there existed no significant cross-resistance between Cry1Ac and Cry2Ab in T. ni. From the dual-toxin-resistant T. ni strain, a strain resistant to Cry2Ab only was isolated, and the Cry2Ab resistance trait was introgressed into a susceptible laboratory strain to facilitate comparative analysis of the Cry2Ab resistance with the susceptible T. ni strain. Results from biochemical analysis showed no significant difference between the Cry2Ab-resistant and -susceptible T. ni larvae in midgut proteases, including caseinolytic proteolytic activity and zymogram profile and serine protease activities, in midgut aminopeptidase and alkaline phosphatase activity, and in midgut esterases and hemolymph plasma melanization activity. For analysis of genetic linkage of Cry2Ab resistance with potential Cry toxin receptor genes, molecular markers for the midgut cadherin, alkaline phosphatase (ALP), and aminopeptidase N (APN) genes were identified between the original greenhouse-derived dual-toxin-resistant and the susceptible laboratory T. ni strains. Genetic linkage analysis showed that the Cry2Ab resistance in T. ni was not genetically associated with the midgut genes coding for the cadherin, ALP, and 6 APNs (APN1 to APN6) nor associated with the ABC transporter gene ABCC2. Therefore, the Cry2Ab resistance in T. ni is conferred by a novel but unknown genetic mechanism. PMID- 26025895 TI - Inactivation of Escherichia coli Cells in Aqueous Solution by Atmospheric Pressure N2, He, Air, and O2 Microplasmas. AB - Atmospheric-pressure N2, He, air, and O2 microplasma arrays have been used to inactivate Escherichia coli cells suspended in aqueous solution. Measurements show that the efficiency of inactivation of E. coli cells is strongly dependent on the feed gases used, the plasma treatment time, and the discharge power. Compared to atmospheric-pressure N2 and He microplasma arrays, air and O2 microplasma arrays may be utilized to more efficiently kill E. coli cells in aqueous solution. The efficiencies of inactivation of E. coli cells in water can be well described by using the chemical reaction rate model, where reactive oxygen species play a crucial role in the inactivation process. Analysis indicates that plasma-generated reactive species can react with E. coli cells in water by direct or indirect interactions. PMID- 26025896 TI - SnPKS19 Encodes the Polyketide Synthase for Alternariol Mycotoxin Biosynthesis in the Wheat Pathogen Parastagonospora nodorum. AB - Alternariol (AOH) is an important mycotoxin from the Alternaria fungi. AOH was detected for the first time in the wheat pathogen Parastagonospora nodorum in a recent study. Here, we exploited reverse genetics to demonstrate that SNOG_15829 (SnPKS19), a close homolog of Penicillium aethiopicum norlichexanthone (NLX) synthase gene gsfA, is required for AOH production. We further validate that SnPKS19 is solely responsible for AOH production by heterologous expression in Aspergillus nidulans. The expression profile of SnPKS19 based on previous P. nodorum microarray data correlated with the presence of AOH in vitro and its absence in planta. Subsequent characterization of the DeltaSnPKS19 mutants showed that SnPKS19 and AOH are not involved in virulence and oxidative stress tolerance. Identification and characterization of the P. nodorum SnPKS19 cast light on a possible alternative AOH synthase gene in Alternaria alternata and allowed us to survey the distribution of AOH synthase genes in other fungal genomes. We further demonstrate that phylogenetic analysis could be used to differentiate between AOH synthases and the closely related NLX synthases. This study provides the basis for studying the genetic regulation of AOH production and for development of molecular diagnostic methods for detecting AOH-producing fungi in the future. PMID- 26025897 TI - Novel N4 Bacteriophages Prevail in the Cold Biosphere. AB - Coliphage N4 is a lytic bacteriophage discovered nearly half a century ago, and it was considered to be a "genetic orphan" until very recently, when several additional N4-like phages were discovered to infect nonenteric bacterial hosts. Interest in this genus of phages is stimulated by their unique genetic features and propagation strategies. To better understand the ecology of N4-like phages, we investigated the diversity and geographic patterns of N4-like phages by examining 56 Chesapeake Bay viral communities, using a PCR-clone library approach targeting a diagnostic N4-like DNA polymerase gene. Many new lineages of N4-like phages were found in the bay, and their genotypes shift from the lower to the upper bay. Interestingly, signature sequences of N4-like phages were recovered only from winter month samples, when water temperatures were below 4 degrees C. An analysis of existing metagenomic libraries from various aquatic environments supports the hypothesis that N4-like phages are most prolific in colder waters. In particular, a high number of N4-like phages were detected in Organic Lake, Antarctica, a cold and hypersaline system. The prevalence of N4-like phages in the cold biosphere suggests these viruses possess yet-to-be-determined mechanisms that facilitate lytic infections under cold conditions. PMID- 26025898 TI - Living in an Extremely Polluted Environment: Clues from the Genome of Melanin Producing Aeromonas salmonicida subsp. pectinolytica 34melT. AB - Aeromonas salmonicida subsp. pectinolytica 34mel(T) can be considered an extremophile due to the characteristics of the heavily polluted river from which it was isolated. While four subspecies of A. salmonicida are known fish pathogens, 34mel(T) belongs to the only subspecies isolated solely from the environment. Genome analysis revealed a high metabolic versatility, the capability to cope with diverse stress agents, and the lack of several virulence factors found in pathogenic Aeromonas. The most relevant phenotypic characteristics of 34mel(T) are pectin degradation, a distinctive trait of A. salmonicida subsp. pectinolytica, and melanin production. Genes coding for three pectate lyases were detected in a cluster, unique to this microorganism, that contains all genes needed for pectin degradation. Melanin synthesis in 34mel(T) is hypothesized to occur through the homogentisate pathway, as no tyrosinases or laccases were detected and the homogentisate 1,2-dioxygenase gene is inactivated by a transposon insertion, leading to the accumulation of the melanin precursor homogentisate. Comparative genome analysis of other melanogenic Aeromonas strains revealed that this gene was inactivated by transposon insertions or point mutations, indicating that melanin biosynthesis in Aeromonas occurs through the homogentisate pathway. Horizontal gene transfer could have contributed to the adaptation of 34mel(T) to a highly polluted environment, as 13 genomic islands were identified in its genome, some of them containing genes coding for fitness related traits. Heavy metal resistance genes were also found, along with others associated with oxidative and nitrosative stresses. These characteristics, together with melanin production and the ability to use different substrates, may explain the ability of this microorganism to live in an extremely polluted environment. PMID- 26025899 TI - Development of Multiple-Locus Variable-Number Tandem-Repeat Analysis for Molecular Subtyping of Campylobacter jejuni by Using Capillary Electrophoresis. AB - Campylobacter jejuni is a common cause of the frequently reported food-borne diseases in developed and developing nations. This study describes the development of multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) using capillary electrophoresis as a novel typing method for microbial source tracking and epidemiological investigation of C. jejuni. Among 36 tandem repeat loci detected by the Tandem Repeat Finder program, 7 VNTR loci were selected and used for characterizing 60 isolates recovered from chicken meat samples from retail shops, samples from chicken meat processing factory, and stool samples. The discrimination ability of MLVA was compared with that of multilocus sequence typing (MLST). MLVA (diversity index of 0.97 with 31 MLVA types) provided slightly higher discrimination than MLST (diversity index of 0.95 with 25 MLST types). The overall concordance between MLVA and MLST was estimated at 63% by adjusted Rand coefficient. MLVA predicted MLST type better than MLST predicted MLVA type, as reflected by Wallace coefficient (Wallace coefficient for MLVA to MLST versus MLST to MLVA, 86% versus 51%). MLVA is a useful tool and can be used for effective monitoring of C. jejuni and investigation of epidemics caused by C. jejuni. PMID- 26025900 TI - Genes Associated with Desiccation and Osmotic Stress in Listeria monocytogenes as Revealed by Insertional Mutagenesis. AB - Listeria monocytogenes is a foodborne pathogen whose survival in food processing environments may be associated with its tolerance to desiccation. To probe the molecular mechanisms used by this bacterium to adapt to desiccation stress, a transposon library of 11,700 L. monocytogenes mutants was screened, using a microplate assay, for strains displaying increased or decreased desiccation survival (43% relative humidity, 15 degrees C) in tryptic soy broth (TSB). The desiccation phenotypes of selected mutants were subsequently assessed on food grade stainless steel (SS) coupons in TSB plus 1% glucose (TSB-glu). Single transposon insertions in mutants exhibiting a change in desiccation survival of >0.5 log CFU/cm(2) relative to that of the wild type were determined by sequencing arbitrary PCR products. Strain morphology, motility, and osmotic stress survival (in TSB-glu plus 20% NaCl) were also analyzed. The initial screen selected 129 desiccation-sensitive (DS) and 61 desiccation-tolerant (DT) mutants, out of which secondary screening on SS confirmed 15 DT and 15 DS mutants. Among the DT mutants, seven immotile and flagellum-less strains contained transposons in genes involved in flagellum biosynthesis (fliP, flhB, flgD, flgL) and motor control (motB, fliM, fliY), while others harbored transposons in genes involved in membrane lipid biosynthesis, energy production, potassium uptake, and virulence. The genes that were interrupted in the 15 DS mutants included those involved in energy production, membrane transport, protein metabolism, lipid biosynthesis, oxidative damage control, and putative virulence. Five DT and 14 DS mutants also demonstrated similar significantly (P < 0.05) different survival relative to that of the wild type when exposed to osmotic stress, demonstrating that some genes likely have similar roles in allowing the organism to survive the two water stresses. PMID- 26025901 TI - Total Biosynthesis and Diverse Applications of the Nonribosomal Peptide Polyketide Siderophore Yersiniabactin. AB - Yersiniabactin (Ybt) is a mixed nonribosomal peptide-polyketide natural product natively produced by the pathogen Yersinia pestis. The compound enables iron scavenging capabilities upon host infection and is biosynthesized by a nonribosomal peptide synthetase featuring a polyketide synthase module. This pathway has been engineered for expression and biosynthesis using Escherichia coli as a heterologous host. In the current work, the biosynthetic process for Ybt formation was improved through the incorporation of a dedicated step to eliminate the need for exogenous salicylate provision. When this improvement was made, the compound was tested in parallel applications that highlight the metal chelating nature of the compound. In the first application, Ybt was assessed as a rust remover, demonstrating a capacity of ~40% compared to a commercial removal agent and ~20% relative to total removal capacity. The second application tested Ybt in removing copper from a variety of nonbiological and biological solution mixtures. Success across a variety of media indicates potential utility in diverse scenarios that include environmental and biomedical settings. PMID- 26025902 TI - Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities. AB - Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs. PMID- 26025903 TI - Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior. AB - Phenotypic heterogeneity describes the occurrence of "nonconformist" cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. PMID- 26025904 TI - Activation of Histidine Kinase SpaK Is Mediated by the N-Terminal Portion of Subtilin-Like Lantibiotics and Is Independent of Lipid II. AB - The biosynthesis of the lantibiotic subtilin is autoinduced in a quorum-sensing mechanism via histidine kinase SpaK. Subtilin-like lantibiotics, such as entianin, ericin S, and subtilin, specifically activated SpaK in a comparable manner, whereas the structurally similar nisin did not provide the signal for SpaK activation at nontoxic concentrations. Surprisingly, nevertheless, nisin if applied together with entianin partly quenched SpaK activation. The N-terminal entianin1-20 fragment (comprising N-terminal amino acids 1 to 20) was sufficient for SpaK activation, although higher concentrations were needed. The N-terminal nisin1-20 fragment also interfered with entianin-mediated activation of SpaK and, remarkably, at extremely high concentrations also activated SpaK. Our data show that the N-terminal entianin1-20 fragment is sufficient for SpaK activation. However, if present, the C-terminal part of the molecule further strongly enhances the activation, possibly by its interference with the cellular membrane. As shown by using lipid II-interfering substances and a lipid II-deficient mutant strain, lipid II is not needed for the sensing mechanism. PMID- 26025905 TI - DNA Microarray-Based Identification of Genes Regulated by NtrC in Bradyrhizobium japonicum. AB - The Bradyrhizobium japonicum NtrBC two-component system is a critical regulator of cellular nitrogen metabolism, including the acquisition and catabolism of nitrogenous compounds. To better define the roles of this system, genome-wide transcriptional profiling was performed to identify the NtrC regulon during the response to nitrogen limitation. Upon cells perceiving low intracellular nitrogen, they stimulate the phosphorylation of NtrC, which induces genes responsible for alteration of the core glutamine synthetase/glutamate synthase nitrogen assimilation pathway, including the genes for the glutamine synthetases and PII proteins. In addition, genes responsible for the import and utilization of multiple nitrogen sources, specifically nitrate and nitrite, were upregulated by NtrC activation. Mutational analysis of a candidate nitrite reductase revealed a role for NtrC in regulating the assimilation of nitrite, since mutations in both ntrC and the gene encoding the candidate nitrite reductase abolished the ability to grow on nitrite as a sole nitrogen source. PMID- 26025906 TI - Dual-Color Bioluminescence Imaging for Simultaneous Monitoring of the Intestinal Persistence of Lactobacillus plantarum and Lactococcus lactis in Living Mice. AB - Lactic acid bacteria are found in the gastrointestinal tract of mammals and have received tremendous attention due to their health-promoting properties. We report the development of two dual-color luciferase-producing Lactobacillus (Lb.) plantarum and Lactococcus (Lc.) lactis strains for noninvasive simultaneous tracking in the mouse gastrointestinal tract. We previously described the functional expression of the red luciferase mutant (CBRluc) from Pyrophorus plagiophthalamus in Lb. plantarum NCIMB8826 and Lc. lactis MG1363 (C. Daniel, S. Poiret, V. Dennin, D. Boutillier, and B. Pot, Appl Environ Microbiol 79:1086 1094, 2013, http://dx.doi.org/10.1128/AEM.03221-12). In this study, we determined that CBRluc is a better-performing luciferase for in vivo localization of both lactic acid bacteria after oral administration than the green click beetle luciferase mutant construct developed in this study. We further established the possibility to simultaneously detect red- and green-emitting lactic acid bacteria by dual-wavelength bioluminescence imaging in combination with spectral unmixing. The difference in spectra of light emission by the red and green click beetle luciferase mutants and dual bioluminescence detection allowed in vitro and in vivo quantification of the red and green emitted signals; thus, it allowed us to monitor the dynamics and fate of the two bacterial populations simultaneously. Persistence and viability of both strains simultaneously administered to mice in different ratios was studied in vivo in anesthetized mice and ex vivo in mouse feces. The application of dual-luciferase-labeled bacteria has considerable potential to simultaneously study the interactions and potential competitions of different targeted bacteria and their hosts. PMID- 26025908 TI - Repair synthesis step involving ERCC1-XPF participates in DNA repair of the Top1 DNA damage complex. AB - Topoisomerase 1 (Top1) is the intercellular target of camptothecins (CPTs). CPT blocks DNA religation in the Top1-DNA complex and induces Top1-attached nick DNA lesions. In this study, we demonstrate that excision repair cross complementing 1 protein-xeroderma pigmentosum group F (ERCC1-XPF) endonuclease and replication protein A (RPA) participate in the repair of Top1-attached nick DNA lesions together with other nucleotide excision repair (NER) factors. ERCC1-XPF shows nuclease activity in the presence of RPA on a 3'-phosphotyrosyl bond nick containing DNA (Tyr-nick DNA) substrate, which mimics a Top1-attached nick DNA lesion. In addition, ERCC1-XPF and RPA form a DNA/protein complex on the nick DNA substrate in vitro, and co-localize in CPT-treated cells in vivo. Moreover, the DNA repair synthesis of Tyr-nick DNA lesions occurred in the presence of NER factors, including ERCC1-XPF, RPA, DNA polymerase delta, flap endonuclease 1 and DNA ligase 1. Therefore, some of the NER repair machinery might be an alternative repair pathway for Top1-attached nick DNA lesions. Clinically, these data provide insights into the potential of ERCC1 as a biomarker during CPT regimens. PMID- 26025907 TI - "Wigglesworthia morsitans" Folate (Vitamin B9) Biosynthesis Contributes to Tsetse Host Fitness. AB - Closely related ancient endosymbionts may retain minor genomic distinctions through evolutionary time, yet the biological relevance of these small pockets of unique loci remains unknown. The tsetse fly (Diptera: Glossinidae), the sole vector of lethal African trypanosomes (Trypanosoma spp.), maintains an ancient and obligate mutualism with species belonging to the gammaproteobacterium Wigglesworthia. Extensive concordant evolution with associated Wigglesworthia species has occurred through tsetse species radiation. Accordingly, the retention of unique symbiont loci between Wigglesworthia genomes may prove instrumental toward host species-specific biological traits. Genome distinctions between "Wigglesworthia morsitans" (harbored within Glossina morsitans bacteriomes) and the basal species Wigglesworthia glossinidia (harbored within Glossina brevipalpis bacteriomes) include the retention of chorismate and downstream folate (vitamin B9) biosynthesis capabilities, contributing to distinct symbiont metabolomes. Here, we demonstrate that these W. morsitans pathways remain functionally intact, with folate likely being systemically disseminated through a synchronously expressed tsetse folate transporter within bacteriomes. The folate produced by W. morsitans is demonstrated to be pivotal for G. morsitans sexual maturation and reproduction. Modest differences between ancient symbiont genomes may still play key roles in the evolution of their host species, particularly if loci are involved in shaping host physiology and ecology. Enhanced knowledge of the Wigglesworthia-tsetse mutualism may also provide novel and specific avenues for vector control. PMID- 26025909 TI - Body size, physical activity, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk. AB - Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in The Netherlands Cohort Study. Participants (n = 120852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19 and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12 and <8 kJ/min in the job and >90, >60-90, >30-60 and <=30 min/day) were analyzed by Cox regression. Increasingly higher hazard ratios (HRs) for CRC were observed for a larger adult body mass index, larger trouser size and tallness in the presence of more unfavorable alleles in men. HRs (95% confidence intervals) for joint effects were 1.55 (1.06 2.25), 1.78 (1.29-2.46) and 1.48 (1.01-2.17), respectively. In women, variant repeat alleles halved CRC risk irrespective of body size and physical activity. Almost no interactions tested significant. To conclude, a larger body size was a CRC risk factor in men in the presence of an accumulation of unfavorable alleles in IGF-related genes, but interactions were generally nonsignificant. PMID- 26025910 TI - Telomere length, genetic variants and gastric cancer risk in a Chinese population. AB - Telomeres maintain chromosomal stability and integrity and are crucial in carcinogenesis. Telomere length is implicated in multiple cancer risk, but the results are conflicting. Genome-wide association studies have identified several genetic loci associated with telomere length in Caucasians. However, the roles of telomere length and related variants on gastric cancer development are largely unknown. We conducted a case-control study including 1136 gastric cancer cases and 1012 controls to evaluate the associations between telomere length, eight telomere length-related variants identified in Caucasians and gastric cancer risk in Chinese population. We observed an obvious U-shaped association between telomere length and gastric cancer risk (P < 0.001), with odds ratios (95% confidence intervals) being 3.81 (2.82-5.13), 1.65 (1.21-2.26), 1.28 (0.93-1.77) and 1.78 (1.30-2.44) for individuals in the first (the shortest), second, third and fifth (the longest) quintile as compared with those in the fourth quintile as reference group. The weighted genetic score (WGS) of eight variants was significantly associated with telomere length (P < 0.001), and in particular, the G allele of rs2736100 in TERT at 5p15.33 exhibited a significant association with long telomeres (P = 0.047). However, we did not observe significant associations between these genetic variants and gastric cancer risk for both single-variant and WGS analyses. These findings suggest that either short or extreme long telomeres may be risk factor for gastric cancer. Genetic variants identified in Caucasians may also contribute to the variation of telomere length in Chinese but seems not to gastric cancer susceptibility. PMID- 26025911 TI - Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway. AB - The DNA damage response (DDR) is activated by various genotoxic stresses. Base lesions, which are structurally simple and predominantly fixed by base excision repair (BER), can trigger the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway, a DDR component. How these lesions trigger DDR remains unclear. Here we show that, for alkylation damage, methylpurine-DNA glycosylase (MPG) and apurinic/apyrimidinic endonuclease 1, both of which function early in BER, are required for ATM-Chk2-dependent DDR. In addition, other DNA glycosylases, including uracil-DNA glycosylase and 8-oxoguanine glycosylase, which are involved in repairing deaminated bases and oxidative damage, also induced DDR. The early steps of BER therefore play a vital role in modulating the ATM-Chk2 DDR in response to base lesions, facilitating downstream BER processing for repair, in which the formation of a single-strand break was shown to play a critical role. Moreover, MPG knockdown rescued cell lethality, its overexpression led to cell death triggered by DNA damage and, more interestingly, higher MPG expression in breast and ovarian cancers corresponded with a greater probability of relapse-free survival after chemotherapy, underscoring the importance of glycosylase-dependent DDR. This study highlights the crosstalk between BER and DDR that contributes to maintaining genomic integrity and may have clinical applications in cancer therapy. PMID- 26025913 TI - Erratum. PMID- 26025912 TI - beta-Caryophyllene potently inhibits solid tumor growth and lymph node metastasis of B16F10 melanoma cells in high-fat diet-induced obese C57BL/6N mice. AB - We reported previously that high-fat diet (HFD) feeding stimulated solid tumor growth and lymph node (LN) metastasis in C57BL/6N mice injected with B16F10 melanoma cells. beta-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in many essential oils and has been shown to exert anti-inflammatory activities. To examine whether BCP inhibits HFD-induced melanoma progression, 4 weeks old, male C57BL/6N mice were fed a control diet (CD, 10 kcal% fat) or HFD (60 kcal% fat + 0, 0.15 or 0.3% BCP) for the entire experimental period. After 16 weeks of feeding, B16F10s were subcutaneously injected into mice. Three weeks later, tumors were resected, and mice were killed 2 weeks post-resection. Although HFD feeding increased body weight gain, fasting blood glucose levels, solid tumor growth, LN metastasis, tumor cell proliferation, angiogenesis and lymphangiogenesis, it decreased apoptotic cells, all of which were suppressed by dietary BCP. HFD feeding increased the number of lipid vacuoles and F4/80+ macrophage (MPhi) and macrophage mannose receptor (MMR)+ M2-MPhis in tumor tissues and adipose tissues surrounding the LN, which was suppressed by BCP. HFD feeding increased the levels of CCL19 and CCL21 in the LN and the expression of CCR7 in the tumor; these changes were blocked by dietary BCP. In vitro culture results revealed that BCP inhibited lipid accumulation in 3T3-L1 preadipocytes; monocyte migration and monocyte chemoattractant protein-1 secretion by B16F10s, adipocytes and M2-MPhis; angiogenesis and lymphangiogenesis. The suppression of adipocyte and M2-cell accumulation and the inhibition of CCL19/21-CCR7 axis may be a part of mechanisms for the BCP suppression of HFD-stimulated melanoma progression. PMID- 26025914 TI - Theory of mind impairment in patients with behavioural variant fronto-temporal dementia (bv-FTD) increases caregiver burden. AB - BACKGROUND: Theory of mind (ToM), the capacity to infer the intention, beliefs and emotional states of others, is frequently impaired in behavioural variant fronto-temporal dementia patients (bv-FTDp); however, its impact on caregiver burden is unexplored. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health. SUBJECTS: bv-FTDp (n = 28), a subgroup of their caregivers (n = 20) and healthy controls (n = 32). METHODS: we applied a faux-pas (FP) task as a ToM measure in bv-FTDp and healthy controls and the Zarit Burden Interview as a measure of burden in patients' caregivers. Patients underwent structural MRI; we used voxel-based morphometry to examine relationships between regional atrophy and ToM impairment and caregiver burden. RESULTS: FP task performance was impaired in bv-FTDp and negatively associated with caregiver burden. Atrophy was found in areas involved in ToM. Caregiver burden increased with greater atrophy in left lateral premotor cortex, a region associated in animal models with the presence of mirror neurons, possibly involved in empathy. CONCLUSION: ToM impairment in bv-FTDp is associated with increased caregiver burden. PMID- 26025915 TI - Environmental complexity and feeding enrichment can mitigate effects of space constraints in captive callitrichids. AB - Non-human primates housed in zoos and laboratories often exhibit reduced activity and this poses welfare concerns. We examined the effects of enclosure types of differing size and environmental complexity on the activities of two species of callitrichids. We found that cotton-top tamarins housed in an enclosure of larger size and more environmental complexity showed higher activity levels, which was mainly contributed by more feeding/foraging activity. By contrast, Goeldi's monkeys housed in an enclosure of larger size and more environmental complexity showed lower activity levels, which was mainly contributed by less locomotory activity. In both species, off-exhibit groups housed in smaller enclosures did not show significantly less locomotory activity which would have been expected, as larger availability spaces should allow more opportunities for locomotion. Furthermore, the feeding enrichment had significant effects on increased feeding/foraging activity for both cotton-top tamarins and Goeldi's monkeys, irrespective of enclosure type. These results suggested that environmental complexity (or application of feeding enrichment) that provided more opportunities for natural foraging could have a larger effect on overall activity levels compared with larger enclosure sizes that should provide more locomotion opportunities. More importantly, it showed that even when enclosure space and complexity were limited, increased opportunities for foraging through the application of enrichment could increase species-typical behaviours. Such inexpensive, easy to implement enrichment methods should be applied to provide more complex environments for captive non-human primates, particularly in situations where there are logistical and/or cost constraints to the modification of physical exhibits. PMID- 26025916 TI - The effect of anaesthesia on somatosensory evoked potential measurement in a rat model. AB - Somatosensory evoked potentials (SEPs) are widely used to study the functional integrity of ascending sensory pathways. For animal studies, SEPs provide a convenient method to quantitatively assess the functionality of the nervous system with low invasiveness. Even though they are frequently used in animal models, little attention is paid to the fact that SEPs are vulnerable to contamination from experimental factors such as anaesthetic delivery. In this study, the effect of isoflurane on SEP measurement was investigated in a rat model. The aim was to find out the adjustments for anaesthetic delivery optimizing the quality of the recordings. Two aspects were studied: the effect of isoflurane dosage on the SEP parameters and on the repeatability of the measurements. The SEP quality was found to be best when 1.5% isoflurane concentration was used. This dosage resulted in the best signal-to-noise ratio and equal repeatability of the measurements compared with the others. Our findings can help in refining the anaesthetic protocols related to SEP recordings in a rat model and, by improving the quality of the measurements, potentially reducing the number of subjects needed to carry out studies. PMID- 26025918 TI - MDM2 and P53 polymorphisms contribute together to the risk and survival of prostate cancer. AB - The p53 gene and MDM2 gene play critical roles in cell cycle arrest and apoptosis together. Here, we evaluated the associations of prostate cancer risk and survival with the joint effects of mdm2 and p53 polymorphisms. Totally 1,193 cases and 1,310 age frequency-matched controls were included in the study. Prostate cancer patients were followed to determine the intervals of overall survival and disease-free survival. The Pro72Arg Pro allele (homozygous and heterozygous) were significantly associated with prostate cancer risk with an odds ratio (OR) of 0.77 [95% confidence interval(CI), 0.64-0.93]. SNP309 T alleles were associated with a significantly decreased prostate cancer risk among Pro72Arg Pro alleles carriers (OR=0.79, 95% CI, 0.64-0.98). In addition, compared with the Pro72Arg Pro alleles and SNP309 G homozygous, patients carrying both SNP309 T alleles and Pro72Arg Arg homozygous had more favorable disease-free survival (hazard ratio [HR] = 0.59, 95% CI, 0.38-0.93). Our results indicated that SNP309 and Pro72Arg polymorphisms may jointly contribute to the etiology and prognosis of prostate cancer. PMID- 26025917 TI - The evolutionary diversity of insect retinal mosaics: common design principles and emerging molecular logic. AB - Independent evolution has resulted in a vast diversity of eyes. Despite the lack of a common Bauplan or ancestral structure, similar developmental strategies are used. For instance, different classes of photoreceptor cells (PRs) are distributed stochastically and/or localized in different regions of the retina. Here, we focus on recent progress made towards understanding the molecular principles behind patterning retinal mosaics of insects, one of the most diverse groups of animals adapted to life on land, in the air, under water, or on the water surface. Morphological, physiological, and behavioral studies from many species provide detailed descriptions of the vast variation in retinal design and function. By integrating this knowledge with recent progress in the characterization of insect Rhodopsins as well as insight from the model organism Drosophila melanogaster, we seek to identify the molecular logic behind the adaptation of retinal mosaics to the habitat and way of life of an animal. PMID- 26025919 TI - Assessment and diagnostic relevance of novel serum biomarkers for early decision of ST-elevation myocardial infarction. AB - Blood transcriptome reflects the status of diseases, and characteristic molecular signature provides a novel window on gene expression preceding acute coronary events. We aim to determine blood transcriptome-based molecular signature of acute coronary syndrome (ACS), and to identify novel serum biomarkers for early stage ST-segment-elevation myocardial infarction (STEMI). We obtained peripheral blood from the patients with ACS who visited emergency department within 4 hours after the onset of chest pain: STEMI (n = 10), Non-ST-segment-elevation MI (NSTEMI, n = 10) and unstable angina (UA, n = 11). Blood transcriptome scans revealed that a characteristic gene expression change exists in STEMI, resulting in 531 outlier genes as STEMI molecular signature (Welch's t test, P < 0.05). Another analysis with a set of blood samples of patients with STEMI (n = 7) before and 7 days after the primary percutaneous coronary intervention (n = 7) and normal control (n = 10) evidenced that STEMI molecular signature directly reflects the onset of STEMI pathogenesis. From the two sets of transcriptome based STEMI signatures, we identified 10 genes encoding transmembrane or secretory proteins that are highly expressed in STEMI. We validated blood protein expression levels of these 10 putative biomarkers in 40 STEMI and 32 healthy subjects by ELISA. Data suggested that PGLYRP1, IRAK3 and VNN3 are more specific and sensitive diagnostic biomarkers for STEMI than traditional CK-MB or troponin.Blood transcriptome scans of ACS evidenced early stage molecular markers for STEMI. Here, we report novel biomarkers to diagnose STEMI at emergency department in hospitals by a simple ELISA method. PMID- 26025921 TI - Patient Violence Towards Counselors in Substance Use Disorder Treatment Programs: Prevalence, Predictors, and Responses. AB - Workplace violence disproportionately impacts healthcare and social service providers. Given that substance use and abuse are documented risk factors for the perpetration of violence, SUD treatment personnel are at risk for patient initiated violence. However, little research has addressed SUD treatment settings. Using data nationally representative of the U. S., the present study explores SUD counselors' experiences of violent behaviors perpetrated by patients. More than half (53%) of counselors personally experienced violence, 44% witnessed violence, and 61% had knowledge of violence directed at a colleague. Counselors reported that exposure to violence led to an increased concern for personal safety (29%), impacted their treatment of patients (15%), and impaired job performance (12%). In terms of organizational responses to patient violence, 70% of organizations increased training on de-escalation of violent situations, and 58% increased security measures. Exposure to verbal assault was associated with age, minority, tenure, recovery status, 12-step philosophy, training in MI/MET, and higher caseloads of patients with co-occurring disorders. Exposure to physical threats was associated with age gender, minority, tenure, recovery status, and higher caseloads of patients with co-occurring disorders. Exposure to physical assault was associated with age, gender, and sample. Implications of these findings for organizations and individuals are discussed. PMID- 26025920 TI - Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells. AB - Although melatonin oncostatic and cytotoxic effects have been described in different types of cancer cells, the specific mechanisms leading to its antitumoral effects and their metabolic context specificity are still not completely understood. Here, we evaluated the effects of melatonin in P19 embryonal carcinoma stem cells (CSCs) and in their differentiated counterparts, cultured in either high glucose medium or in a galactose (glucose-free) medium which leads to glycolytic suppression and increased mitochondrial metabolism. We found that highly glycolytic P19 CSCs were less susceptible to melatonin antitumoral effects while cell populations relying on oxidative metabolism for ATP production were more affected. The observed antiproliferative action of melatonin was associated with an arrest at S-phase, decreased oxygen consumption, down-regulation of BCL-2 expression and an increase in oxidative stress culminating with caspase-3-independent cell death. Interestingly, the combined treatment of melatonin and dichloroacetate had a synergistic effect in cells grown in the galactose medium and resulted in an inhibitory effect in the highly resistant P19 CSCs. Melatonin appears to exert its antiproliferative activity in P19 carcinoma cells through a mitochondrially-mediated action which in turn allows the amplification of the effects of dichloroacetate, even in cells with a more glycolytic phenotype. PMID- 26025924 TI - 2015 BSDB Spring Meeting report. PMID- 26025922 TI - Rectification of muscle and nerve deficits in paralyzed ryanodine receptor type 1 mutant embryos. AB - Locomotion and respiration require motor axon connectivity and activation of the neuromuscular junction (NMJ). Through a forward genetic screen for muscle weakness, we recently reported an allele of ryanodine receptor type 1 (Ryr1(AG)). Here we reveal a role for functional RyR1 during acetylcholine receptor (AChR) cluster formation and embryonic synaptic transmission. Ryr1(AG) homozygous embryos are non-motile. Motor axons extend past AChR clusters and enlarged AChR clusters are found under fasciculated nerves. Using physiological and pharmacological methods, we show that contractility can be resumed through the masking of a potassium leak, and evoked vesicular release can be resumed via bypassing the defect in RyR1 induced calcium release. Moreover, we show the involvement of ryanodine receptors in presynaptic release at the NMJ. This data provides evidence of a role for RyR1 on both the pre- and postsynaptic sides of the NMJ. PMID- 26025923 TI - A pipeline for the systematic identification of non-redundant full-ORF cDNAs for polymorphic and evolutionary divergent genomes: Application to the ascidian Ciona intestinalis. AB - Genome-wide resources, such as collections of cDNA clones encoding for complete proteins (full-ORF clones), are crucial tools for studying the evolution of gene function and genetic interactions. Non-model organisms, in particular marine organisms, provide a rich source of functional diversity. Marine organism genomes are, however, frequently highly polymorphic and encode proteins that diverge significantly from those of well-annotated model genomes. The construction of full-ORF clone collections from non-model organisms is hindered by the difficulty of predicting accurately the N-terminal ends of proteins, and distinguishing recent paralogs from highly polymorphic alleles. We report a computational strategy that overcomes these difficulties, and allows for accurate gene level clustering of transcript data followed by the automated identification of full ORFs with correct 5'- and 3'-ends. It is robust to polymorphism, includes paralog calling and does not require evolutionary proximity to well annotated model organisms. We developed this pipeline for the ascidian Ciona intestinalis, a highly polymorphic member of the divergent sister group of the vertebrates, emerging as a powerful model organism to study chordate gene function, Gene Regulatory Networks and molecular mechanisms underlying human pathologies. Using this pipeline we have generated the first full-ORF collection for a highly polymorphic marine invertebrate. It contains 19,163 full-ORF cDNA clones covering 60% of Ciona coding genes, and full-ORF orthologs for approximately half of curated human disease-associated genes. PMID- 26025926 TI - The Role of Metacognitive Reading Strategies, Metacognitive Study and Learning Strategies, and Behavioral Study and Learning Strategies in Predicting Academic Success in Students With and Without a History of Reading Difficulties. AB - We examined the self-reported use of reading, study, and learning strategies in university students with a history of reading difficulties (HRD; n = 77) and with no history of reading difficulties (NRD; n = 295). We examined both between groups differences in strategy use and strategy use as a predictive measure of academic success. Participants completed online questionnaires regarding reading history and strategy use. GPA and frequency of use of academic support services were also obtained for all students. University students with HRD reported a different profile of strategy use than their NRD peers, and self-reported strategy use was differentially predictive of GPA for students with HRD and NRD. For students with HRD, the use of metacognitive reading strategies and the use of study aids predicted academic success. Implications for university student services providers are discussed. PMID- 26025927 TI - TAT-ODD-p53 enhances the radiosensitivity of hypoxic breast cancer cells by inhibiting Parkin-mediated mitophagy. AB - Radiation therapy has an important role in the treatment of breast cancer. Dysfunction p53 and hypoxia are typical biological characteristics of breast cancer that constitute barriers to the efficacy of radiotherapy. Mitophagy plays a protective role in cellular homeostasis under hypoxic conditions, while mitophagy is inhibited by p53 in normal cells. We explored the effects of a p53 fusion protein, TAT-ODD-p53, on the radiosensitivity of hypoxic breast cancer cells both in vitro and in vivo, as well as investigating the related molecular mechanisms. We found that selective accumulation of TAT-ODD-p53 occurred under hypoxic conditions and significantly increased tumor cell radiosensitivity both in vitro and in vivo. Mitophagy had an important role in maintaining hypoxia induced radioresistance. Mitophagy was inhibited by TAT-ODD-p53 and this inhibition was suppressed by over-expression of Parkin in hypoxic irradiated breast cancer cells. In addition, mitophagy was induced by deletion of p53, with this effect being weakened by Parkin knockdown at a low oxygen tension. By interacting with Parkin, p53 inhibited the translocation of Parkin to the mitochondria, disrupting the protective mitophagy process. These results suggest that TAT-ODD-p53 has a significant and preferential radiosensitizing effect on hypoxic breast cancer cells by inhibition of Parkin-mediated mitophagy. PMID- 26025929 TI - Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Kruppel-like factor 8 in breast cancer. AB - Kruppel-like factor 8 (KLF8) is a dual transcriptional factor critical for breast cancer progression. Epidermal growth factor receptor (EGFR) is frequently overexpressed in aggressive such as triple-negative breast cancer and associated with poor clinical outcomes. Here we report a novel KLF8-EGFR signaling axis in breast cancer. We identified a highly correlated co-overexpression between KLF8 and EGFR in invasive breast cancer cells and patient tumor samples. Overexpression of KLF8 in the non-tumorigenic MCF-10A cells induced the expression of EGFR, whereas knockdown of KLF8 from the MDA-MB-231 cells decreased it. Promoter activation and binding assays indicated that KLF8 promotes the EGFR expression by directly binding its gene promoter. We also revealed that KLF8 directly represses the promoter of miR141 and miR141 targets the 3' untranslational region of EGFR transcript to inhibit EGFR translation. Treatment with the EGFR inhibitor AG1478 or overexpression of miR141 blocked the activity of ERK downstream of EGFR and inhibited KLF8-depndent cell invasiveness, proliferation and viability in cell culture and invasive growth and lung metastasis in nude mice. Conversely, overexpression of an inhibitory sponge of miR141 led to the opposite phenotypes. Taken together, these findings demonstrate a novel KLF8 to miR141/EGFR signaling pathway potentially crucial for breast cancer malignancy. PMID- 26025928 TI - Pharmacological inactivation of CHK1 and WEE1 induces mitotic catastrophe in nasopharyngeal carcinoma cells. AB - Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. As radiotherapy is the primary treatment for NPC, this offers a rationale to investigate if uncoupling the DNA damage responses can sensitize this cancer type. The G2 DNA damage checkpoint is controlled by a cascade of protein kinases: ATM/ATR, which phosphorylates CHK1/CHK2, which in turn phosphorylates WEE1. A number of small molecule inhibitors have been developed against these kinases as potential therapeutic agents. Here we demonstrated that compare to that in immortalized nasopharyngeal epithelial cells, ATR, CHK1, and WEE1 were overexpressed in NPC cell lines. Inhibitors of these kinases were unable to promote extensive mitotic catastrophe in ionizing radiation-treated NPC cells, indicating that they are not very effective radiosensitizer for this cancer. In the absence of prior irradiation, however, mitotic catastrophe could be induced with inhibitors against CHK1 (AZD7762) or WEE1 (MK-1775). NPC cells were more sensitive to WEE1 inactivation than nasopharyngeal epithelial cells. Targeting CHK1 and WEE1 together induced more extensive mitotic catastrophe than the individual components alone. Taken together, our results show that NPC cells depend on CHK1 and WEE1 activity for growth and that inhibitors of these kinases may serve as potential therapeutics for NPC. PMID- 26025930 TI - MDM2 mediates p73 ubiquitination: a new molecular mechanism for suppression of p73 function. AB - The protein p73, a homologue of the tumor suppressor protein p53, is capable of inducing apoptosis and cell cycle arrest. MDM2 is transcriptionally activated by p73 and represses the functions of p73, including p73-dependent transactivation and growth suppression. However, the molecular mechanism of this repression is unknown. In this study, we show that MDM2 mediates p73 ubiquitination. MDM2 mainly utilizes K11, K29 and K63-linked chains to mediate p73 ubiquitination in vivo and in vitro. However, MDM2 is unable to promote p73 degradation in most tested cell lines. Surprisingly, we observe that overexpression of Mdm2 promotes p73 degradation mainly through Itch in Mdm2-null MEFs. We further find that Itch interacts with the transfected Mdm2 in Mdm2-null cells. Moreover, our findings reveal that the E3 ligase activity of MDM2 is required to repress p73-dependent apoptosis and cell cycle arrest but not p73-dependent transcriptional activity. Furthermore, the data suggest a link between p73 ubiquitination/MDM2 E3 ligase activity and p73 biological functions. PMID- 26025931 TI - Molecular Phenotype of Breast Cancer According to Time Since Last Pregnancy in a Large Cohort of Young Women. AB - BACKGROUND: The increase in breast cancer risk during pregnancy and postpartum is well known; however, the molecular phenotype of breast cancers occurring shortly after pregnancy has not been well studied. Given this, we investigated whether nulliparity and the time interval since pregnancy among parous women affects the breast cancer phenotype in young women. MATERIALS AND METHODS: We examined molecular phenotype in relation to time since pregnancy in a prospective cohort of 707 young women (aged <=40 years) with breast cancer. Parity was ascertained from study questionnaires. Using tumor histologic grade on central review and biomarker expression, cancers were categorized as luminal A- or B-like, HER2 enriched, and triple negative. RESULTS: Overall, 32% were luminal A-like, 41% were luminal B-like, 9% were HER2 enriched, and 18% were triple negative. Although, numerically, patients diagnosed >5 years after pregnancy had more luminal A-like subtypes than women with shorter intervals since pregnancy, there was no evidence of a relationship between these intervals and molecular subtypes once family history of breast cancer and age at diagnosis were considered. CONCLUSION: Distribution of breast cancer molecular phenotype did not differ significantly among young women by parity or time interval since parturition when important predictors of tumor phenotype such as age and family history were considered. IMPLICATIONS FOR PRACTICE: Distribution of breast cancer molecular phenotype did not differ among parous young women by time interval since pregnancy. The implication of these findings for clinical practice suggests that pregnancy-associated breast cancers may be seen up to 5 years beyond parturition. PMID- 26025933 TI - Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma. AB - LESSONS LEARNED: Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. BACKGROUND: Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. METHODS: Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28 day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. RESULTS: Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months). CONCLUSION: Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM. PMID- 26025934 TI - Imaging Radiation Doses and Associated Risks and Benefits in Subjects Participating in Breast Cancer Clinical Trials. AB - BACKGROUND: Medical imaging is commonly required in breast cancer (BC) clinical trials to assess the efficacy and/or safety of study interventions. Despite the lack of definitive epidemiological data linking imaging radiation with cancer development in adults, concerns exist about the risks of imaging radiation induced malignancies (IRIMs) in subjects exposed to repetitive imaging. We estimated the imaging radiation dose and IRIM risk in subjects participating in BC trials. MATERIALS AND METHODS: The imaging protocol requirements in 10 phase III trials in the adjuvant and advanced settings were assessed to estimate the effective radiation dose received by a typical and fully compliant subject in each trial. For each study, the excess lifetime attributable cancer risk (LAR) was calculated using the National Cancer Institute's Radiation Risk Assessment Tool, version 3.7.1. Dose and risk calculations were performed for both imaging intensive and nonintensive approaches to reflect the variability in imaging performed within the studies. RESULTS: The total effective imaging radiation dose was 0.4-262.2 mSv in adjuvant trials and 26-241.3 mSv in metastatic studies. The dose variability resulted from differing protocol requirements and imaging intensity approaches, with computed tomography, multigated acquisition scans, and bone scans as the major contributors. The mean LAR was 1.87-2,410/100,000 in adjuvant trials (IRIM: 0.0002%-2.41% of randomized subjects) and 6.9-67.3/100,000 in metastatic studies (IRIM: 0.007%-0.067% of subjects). CONCLUSION: IRIMs are infrequent events. In adjuvant trials, aligning the protocol requirements with the clinical guidelines' surveillance recommendations and substituting radiating procedures with equivalent nonradiating ones would reduce IRIM risk. No significant risk has been observed in metastatic trials, and potential concerns on IRIMs are not justified. IMPLICATIONS FOR PRACTICE: Medical imaging is key in breast cancer (BC) clinical trials. Most of these procedures expose patients to ionizing radiation, and the risk of second cancer development after imaging has prompted recent concerns and controversy. Using accepted calculation models, the number of malignancies were estimated that were potentially attributable to the imaging procedures performed during a patient's participation in BC clinical trials. The results show that for patients participating in metastatic trials, the risk of imaging radiation-induced malignancies is negligible. In adjuvant trials, some second cancers due to imaging could be expected, and measures can be taken to reduce their risk. PMID- 26025936 TI - Dollars and sense. PMID- 26025932 TI - Molecular Targets in Biliary Carcinogenesis and Implications for Therapy. AB - Biliary tract cancers (BTCs) encompass a group of invasive carcinomas, including cholangiocarcinoma (intrahepatic, perihilar, or extrahepatic), and gallbladder carcinoma. Approximately 90% of patients present with advanced, unresectable disease and have a poor prognosis. The latest recommendation is to treat advanced or metastatic disease with gemcitabine and cisplatin, although chemotherapy has recorded modest survival benefits. Comprehension of the molecular basis of biliary carcinogenesis has resulted in experimental trials of targeted therapies in BTCs, with promising results. This review addresses the emerging role of targeted therapy in the treatment of BTCs. Findings from preclinical studies were reviewed and correlated with the outcomes of clinical trials that were undertaken to translate the laboratory discoveries. IMPLICATIONS FOR PRACTICE: Biliary tract cancers are rare. Approximately 90% of patients present with advanced, unresectable disease and have a poor prognosis. Median overall and progression free survival are 12 and 8 months, respectively. Because chemotherapy has recorded modest survival benefits, targeted therapies are being explored for personalized treatment of these cancers. A comprehensive review of targeted therapies in biliary tract cancers was undertaken to present emerging evidence from laboratory and/or molecular studies as they translate to clinical trials and outcomes. The latest evidence on this topic is presented to clinicians and practitioners to guide decisions on treatment of this disease. PMID- 26025935 TI - Transvenous implantable cardioverter-defibrillator lead reliability: implications for postmarket surveillance. AB - BACKGROUND: As implantable cardioverter-defibrillator technology evolves, clinicians and patients need reliable performance data on current transvenous implantable cardioverter-defibrillator systems. In addition, real-world reliability data could inform postmarket surveillance strategies directed by regulators and manufacturers. METHODS AND RESULTS: We evaluated Medtronic Sprint Quattro, Boston Scientific Endotak, and St Jude Medical Durata and Riata ST Optim leads implanted by participating center physicians between January 1, 2006 and September 1, 2012. Our analytic sample of 2653 patients (median age 65, male 73%) included 445 St Jude, 1819 Medtronic, and 389 Boston Scientific leads. After a median of 3.2 years, lead failure was 0.28% per year (95% CI, 0.19 to 0.43), with no statistically significant difference among manufacturers. Simulations based on these results suggest that detecting performance differences among generally safe leads would require nearly 10 000 patients or very long follow-up. CONCLUSIONS: Currently marketed implantable cardioverter-defibrillator leads rarely fail, which may be reassuring to clinicians advising patients about risks and benefits of transvenous implantable cardioverter-defibrillator systems. Regulators should consider the sample size implications when designing comparative effectiveness studies and evaluating new technology for preventing sudden cardiac death. PMID- 26025937 TI - It takes more than timing: letter to the editor. PMID- 26025938 TI - It takes more than timing: response. PMID- 26025939 TI - IKBKE Upregulation is Positively Associated with Squamous Cell Carcinoma of the Lung In Vivo and Malignant Transformation of Human Bronchial Epithelial Cells In Vitro. AB - BACKGROUND: The IkappaB kinase inhibitor of kappaB kinase epsilon (IKBKE) is overexpressed in several human cancers. Although IKBKE plays an important role in smoking-induced non-small cell lung cancer carcinogenesis, its role in squamous cell carcinoma of the lung (SCCL) remains unclear. MATERIAL AND METHODS: IKBKE protein expression was assessed by immunohistochemistry in 288 paraffinized SCCL specimens (with adjacent squamous dysplastic and normal tissue). IKBKE mRNA expression was assessed by reverse transcription PCR in 66 fresh SCCL specimens (with adjacent squamous dysplastic and normal tissue). Separately, immortalized human bronchial epithelial cells were cultured in 7 groups: untreated control, ethanol-treated, and cigarette smoke condensate (CSC)-exposed for 10, 20, 30, 40, and 50 generations (P10, P20, P30, P40, and P50, respectively). Malignant transformation was assessed by serum resistance and colony formation assays. IKBKE protein and mRNA expression were detected by Western blotting and reverse transcription PCR, respectively. RESULTS: IKBKE protein expression showed a significant upward trend from normal bronchial epithelium to squamous cell dysplasia to SCCL. IKBKE protein expression in SCCL was significantly associated with smoking status, smoking index, degree of differentiation, and clinical stage. Current and former smokers displayed significantly higher IKBKE protein and mRNA expression than non-smokers. IKBKE protein and mRNA expression displayed a significant upward trend with the smoking index. P30, P40, and P50 CSC-exposed cells displayed malignant transformation with increasing IKBKE mRNA and protein expression from P20 through P50. CONCLUSIONS: IKBKE upregulation is positively associated with SCCL and smoking indices as well as CSC-induced malignant transformation of human bronchial epithelial cells. PMID- 26025940 TI - Rhizobium anhuiense sp. nov., isolated from effective nodules of Vicia faba and Pisum sativum. AB - Four rhizobia-like strains, isolated from root nodules of Pisum sativum and Vicia faba grown in Anhui and Jiangxi Provinces of China, were grouped into the genus Rhizobium but were distinct from all recognized species of the genus Rhizobium by phylogenetic analysis of 16S rRNA and housekeeping genes. The combined sequences of the housekeeping genes atpD, recA and glnII for strain CCBAU 23252(T) showed 86.9 to 95% similarity to those of known species of the genus Rhizobium. All four strains had nodC and nifH genes and could form effective nodules with Pisum sativum and Vicia faba, and ineffective nodules with Phaseolus vulgaris, but did not nodulate Glycine max, Arachis hypogaea, Medicago sativa, Trifolium repens or Lablab purpureus in cross-nodulation tests. Fatty acid composition, DNA-DNA relatedness and a series of phenotypic tests also separated these strains from members of closely related species. Based on all the evidence, we propose a novel species, Rhizobium anhuiense sp. nov., and designate CCBAU 23252(T) ( = CGMCC 1.12621(T) = LMG 27729(T)) as the type strain. This strain was isolated from a root nodule of Vicia faba and has a DNA G+C content of 61.1 mol% (Tm). PMID- 26025941 TI - Cyberlindnera xylosilytica sp. nov., a xylitol-producing yeast species isolated from lignocellulosic materials. AB - Independent surveys of yeasts associated with lignocellulosic-related materials led to the discovery of a novel yeast species belonging to the Cyberlindnera clade (Saccharomycotina, Ascomycota). Analysis of the sequences of the internal transcribed spacer (ITS) region and the D1/D2 domains of the large subunit rRNA gene showed that this species is related to C. japonica, C. maesa and C. easanensis. Six isolates were obtained from different sources, including rotting wood, tree bark and sugar cane filter cake in Brazil, frass from white oak in the USA and decayed leaf in Taiwan. A novel species is suggested to accommodate these isolates, for which the name C. xylosilytica sp. nov. is proposed. The type strain of C. xylosilytica sp. nov. is NRRL YB-2097(T) ( = CBS 13984(T) = UFMG-CM Y347(T)) and the allotype is UFMG-CM-Y409 ( = CBS 14083). The novel species is heterothallic and complementary mating types are represented by the type and allotype strains. The MycoBank number is MB 811428. PMID- 26025942 TI - Eionea flava sp. nov., isolated from coastal seawater, and emended description of the genus Eionea. AB - A Gram-staining-negative, non-motile, catalase- and oxidase-positive, facultatively aerobic bacterium, designated IMCC1962(T) was isolated from a surface seawater sample from the Yellow Sea. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain IMCC1962(T )belonged to the genus Eionea, forming a robust clade with members of the genus, and was most closely related to Eionea nigra (97.3% similarity). DNA-DNA relatedness between strain IMCC1962(T) and Eionea nigra DSM 19752(T) was 21.8-26.3%, which indicated strain IMCC1962(T) represents a novel genomic species of the genus Eionea. The G+C content of the DNA of strain IMCC1962(T) was 48.7 mol%. The major isoprenoid quinone was ubiquinone Q-8 and major fatty acids were C16 : 1omega7c and/or C16 : 1omega6c (43.4%), C18 : 1omega7c and/or C18 : 1omega6c (19.3%) and C16 : 0 (17.2%). The polar lipids found in strain IMCC1962(T) were phosphatidylethanolamine, phosphatidylglycerol, aminophospholipid, unknown phospholipid, and four unknown polar lipids. Strain IMCC1962(T) and Eionea nigra DSM 19752(T) differed from each other in diverse phenotypic characteristics including motility, colony colour and enzyme activities. On the basis of phenotypic and genotypic data, strain IMCC1962(T) ( = KACC 17481(T)= NBRC 109703(T)) represents a novel species of the genus Eionea, for which the name Eionea flava sp. nov. is proposed. An emended description of the genus Eionea is also provided. PMID- 26025943 TI - Allochromatium humboldtianum sp. nov., isolated from soft coastal sediments. AB - A novel purple sulfur bacterium, strain AX1YPE(T), was isolated from marine sediments sampled at 47 m depth in Callao Bay, Peru. Strain AX1YPE grew anaerobically, synthesizing bacteriochlorophyll a and carotenoid pigments of the spirilloxanthin series. Cells were Gram-stain-negative rods and actively motile by a polar flagellum. Strain AX1YPE was able to grow photolithoautotrophically with sulfide and thiosulfate as electron donors. This new phototrophic organism utilized ammonium salt, N2, urea and glutamate as nitrogen sources. Strain AX1YPE had a DNA base composition of 63.9 mol% G+C. Analysis of the 16S rRNA gene sequence indicated that strain AX1YPE clusters in a separate branch within the genus Allochromatium of the family Chromatiaceae. Strain AX1YPE showed 16S rRNA gene sequence similarities of 98.2% with Allochromatium vinosum DSM 180(T) and Allochromatium minutissimum DSM 1376(T), 98.1% with Allochromatium phaeobacterium JA144(T), 97.3% with Allochromatium renukae DSM 18713(T) and 96.8% with Allochromatium warmingiiDSM 173(T). DNA-DNA hybridization values to the type strains of its closest relatives, A. vinosum and A. minutissimum, were 59 and 64%, respectively. The predominant fatty acid of strain AX1YPE(T) was C18 : 1omega;7c and it notably possessed C20 : 1 as a minor component. PCR-based molecular typing (Box A1R and randomly amplified polymorphic DNA) produced a unique banding pattern for strain AX1YPE(T) in comparison with the type strains of A. vinosum and A. minutissimum. Based on data from this polyphasic taxonomic study, which also includes average nucleotide identity comparison of five concatenated housekeeping genes, strain AX1YPE(T) is considered to represent a novel species of the genus Allochromatium for which the name Allochromatiumhumboldtianum sp. nov. is proposed. The type strain is AX1YPE(T) ( = DSM 21881(T) = KCTC 15448(T)). PMID- 26025945 TI - Halovulum dunhuangense gen. nov., sp. nov., isolated from a saline terrestrial spring. AB - A bacterial strain, YYQ-30(T), isolated from a mixed water-sand-sediment sample collected from a terrestrial spring located in Dunhuang, China, was characterized with respect to its morphology, physiology and taxonomy. Cells of the strain were Gram-stain-negative, aerobic, oxidase- and catalase-positive, non-flagellated, oval to rod-shaped (0.5-1.0 MUm wide and 1.1-6.6 MUm long) and divided by binary fission. Growth was observed in the presence of 0-10.0% (w/v) NaCl with optimal growth at 0-3.0%, at pH 6.0-9.0 (optimum pH 7.0-8.5) and at 10-45 degrees C (optimum 30-37 degrees C). The isolate could reduce nitrate to nitrite and hydrolyse aesculin and gelatin (weakly), but was unable to degrade Tween 80 or starch. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain YYQ-30(T) belongs to the family Rhodobacteraceae and forms a distinct lineage with the type strain of Albimonas donghaensis and forms a branch within a cluster constituted by the type strains of species of the genera Albimonas, Rhodovulum, Albidovulum, Haematobacter and Tropicimonas; levels of 16S rRNA gene sequence similarity between strain YYQ-30(T) and members of related genera ranged from 94.1 to 89.7%. Strain YYQ-30(T) contained Q-10 as the predominant ubiquinone and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c; 70.0%), C18 : 0 (9.5%), summed feature 2 (one or more of C14 : 0 3-OH, iso-C16 : 1 I and C12 : 0 aldehyde; 6.9%) and 11-methyl C18 : 1omega7c (6.0%) as the principal fatty acids. The polar lipids comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, three unidentified phospholipids, two unidentified aminolipids and five unknown lipids. The pufLM gene was detected. The G+C content of the genomic DNA was 71.7 mol%. Based on the phylogenetic, chemotaxonomic and phenotypic data obtained in this study, strain YYQ-30T is considered to represent a novel species in a new genus within the family Rhodobacteraceae, for which the name Halovulum dunhuangense gen. nov., sp. nov. is proposed. The type strain of Halovulum dunhuangense is YYQ-30(T) ( = LMG 27418(T) = MCCC 1A06483(T)). PMID- 26025946 TI - Sphingomonas psychrolutea sp. nov., a psychrotolerant bacterium isolated from glacier ice. AB - A Gram-stain-negative, rod-shaped, orange bacterium (strain MDB1-A(T)) was isolated from ice samples collected from Midui glacier in Tibet, south-west China. Cells were aerobic and psychrotolerant (growth occurred at 0-25 degrees C). Phylogenetic analysis based on 16S rRNA gene sequences showed that it was a member of the genus Sphingomonas, with its closest relative being Sphingomonas glacialis C16y(T) (98.9% similarity). Q-10 was the predominant ubiquinone. C17 : 1omega6c and summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c) were the major cellular fatty acids. The predominant polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and sphingoglycolipid. The polyamines detected were sym-homospermidine, spermidine and spermine. The G+C content of the genomic DNA was 63.6%. Based on data from this polyphasic analysis, strain MDB1-A(T) represents a novel species of the genus Sphingomonas, for which the name Sphingomonas psychrolutea sp. nov. is proposed. The type strain is MDB1-A(T) ( = CGMCC 1.10106(T) = NBRC 109639(T)). PMID- 26025947 TI - Cystatin C for therapeutic drug monitoring. PMID- 26025950 TI - Direct bilirubin higher than total bilirubin? PMID- 26025951 TI - Stacking the odds to detect dengue from saliva. PMID- 26025952 TI - Variation: gilmorehill. PMID- 26025953 TI - Individuality in science:Richard Feynman. PMID- 26025954 TI - Molecular Genetic Analysis of the Variable Number of Tandem-Repeat Alleles at the Phenylalanine Hydroxylase Gene in Iranian Azeri Turkish Population. AB - BACKGROUND: The variable numbers of tandem-repeat (VNTR) alleles at the phenylalanine hydroxylase (PAH) gene have been used in carrier detection and prenatal diagnosis in phenylketonuria families. This study was carried out to analyze VNTR alleles at the PAH gene in Iranian Azeri Turkish population. METHODS: In this study, 200 alleles from general population were studied by PCR. RESULTS: The frequencies of VNTR alleles were 45%, 46%, 2%, 3%, 1%, and 3% in studied group regarding 3, 8, 9, 11, 12, and 13 repeat copies, respectively. Statistically significant differences were not found between expected and observed frequencies of VNTR genotypes (P > 0.05). CONCLUSIONS: VNTR alleles with three and eight repeats were frequent, and the VNTR alleles with 13 repeats showed 3% frequency in the tested group. This study is the first report on tested population genetic structure using VNTR alleles at the PAH gene. PMID- 26025955 TI - MicroRNA-1298 is regulated by DNA methylation and affects vascular smooth muscle cell function by targeting connexin 43. AB - AIMS: Growing evidence links microRNA to the process of peripheral vascular disease. Recently, we have found that microRNA-1298(miR-1298) is one of the most significantly down-regulated microRNAs in human arteries with arteriosclerosis obliterans (ASO) of the lower extremities. However, little is known regarding its role in the process of ASO. The present study aimed to investigate the expression, regulatory mechanisms, and functions of miR-1298 in the process of ASO. METHODS AND RESULTS: Using quantitative reverse-transcription PCR and in situ hybridization assays, miR-1298 was observed predominantly expressed in the vascular smooth muscle cells (VSMCs) and was significantly down-regulated in ASO compared with normal arteries. Pyrosequencing analysis revealed that the miR-1298 DNA upstream of CpG sites were hypermethylated in ASO compared with normal arteries. Next, the luciferase reporter assay revealed that miR-1298 down regulation is related with upstream DNA CpG site hypermethylation. Introducing a miR-1298 mimic into cultured VSMCs significantly attenuated cell proliferation and migration. Connexin 43 (Cx43) was validated to be a functional target of miR 1298 that was involved in the miR-1298-mediated cellular effects. Finally, lentivirus-mediated delivery of miR-1298 and its target Cx43 into a rat carotid balloon injury model indicated that re-overexpression of miR-1298 significantly decreased neointimal formation by targeting connexin 43. CONCLUSION: Our data demonstrate a specific role of the upstream DNA methylation/miR-1298/Cx43 pathway in regulating VSMC function and suggest that modulation of miR-1298 levels may offer a novel therapeutic approach for ASO. PMID- 26025956 TI - Human epicardial cell-conditioned medium contains HGF/IgG complexes that phosphorylate RYK and protect against vascular injury. AB - AIMS: The aim of this study was to evaluate the paracrine activity of human epicardial-derived cells (hEPDCs) to screen for secreted vasoprotective factors and develop therapeutics to treat vascular reperfusion injury. METHODS AND RESULTS: Epicardial cells support cardiac development, repair, and remodelling after injury in part, through paracrine activity. We hypothesized that secreted ligands from hEPDCs would protect vascular integrity after myocardial infarction (MI) with reperfusion. During simulated ischaemia in culture (24-48 h), concentrated hEPDC-conditioned medium (EPI CdM) increased survival of primary cardiac endothelial cells. In a rat MI model, EPI CdM treatment reduced vascular injury in vivo after reperfusion. By phospho-receptor tyrosine kinase (RTK) arrays, ELISA, and neutralizing antibody screens, we identified hepatocyte growth factor (HGF) as a key vasoprotective factor in EPI CdM. Unexpectedly, we observed that some of the HGF in EPI CdM formed complexes with polyclonal IgG. Following reperfusion, preparations of HGF/IgG complexes provided greater vascular protection than free HGF with IgG. HGF/IgG complexes localized to blood vessels in vivo and increased HGF retention time after administration. In subsequent screens, we found that 'related to tyrosine kinase' (RYK) receptor was phosphorylated after exposure of cardiac endothelial cells to HGF/IgG complexes, but not to free HGF with IgG. The enhanced protection conferred by HGF/IgG complexes was lost after antibody blockade of RYK. Notably, the HGF/IgG complex is the first 'ligand' shown to promote phosphorylation of RYK. CONCLUSION: Early treatment with HGF/IgG complexes after myocardial ischaemia with reperfusion may rescue tissue through vasoprotection conferred by c-Met and RYK signalling. PMID- 26025957 TI - Whole-Body PET/MR Imaging: Quantitative Evaluation of a Novel Model-Based MR Attenuation Correction Method Including Bone. AB - In routine whole-body PET/MR hybrid imaging, attenuation correction (AC) is usually performed by segmentation methods based on a Dixon MR sequence providing up to 4 different tissue classes. Because of the lack of bone information with the Dixon-based MR sequence, bone is currently considered as soft tissue. Thus, the aim of this study was to evaluate a novel model-based AC method that considers bone in whole-body PET/MR imaging. METHODS: The new method ("Model") is based on a regular 4-compartment segmentation from a Dixon sequence ("Dixon"). Bone information is added using a model-based bone segmentation algorithm, which includes a set of prealigned MR image and bone mask pairs for each major body bone individually. Model was quantitatively evaluated on 20 patients who underwent whole-body PET/MR imaging. As a standard of reference, CT-based MU-maps were generated for each patient individually by nonrigid registration to the MR images based on PET/CT data. This step allowed for a quantitative comparison of all MU-maps based on a single PET emission raw dataset of the PET/MR system. Volumes of interest were drawn on normal tissue, soft-tissue lesions, and bone lesions; standardized uptake values were quantitatively compared. RESULTS: In soft-tissue regions with background uptake, the average bias of SUVs in background volumes of interest was 2.4% +/- 2.5% and 2.7% +/- 2.7% for Dixon and Model, respectively, compared with CT-based AC. For bony tissue, the -25.5% +/- 7.9% underestimation observed with Dixon was reduced to -4.9% +/- 6.7% with Model. In bone lesions, the average underestimation was -7.4% +/- 5.3% and -2.9% +/- 5.8% for Dixon and Model, respectively. For soft-tissue lesions, the biases were 5.1% +/- 5.1% for Dixon and 5.2% +/- 5.2% for Model. CONCLUSION: The novel MR-based AC method for whole-body PET/MR imaging, combining Dixon-based soft tissue segmentation and model-based bone estimation, improves PET quantification in whole-body hybrid PET/MR imaging, especially in bony tissue and nearby soft tissue. PMID- 26025958 TI - Imaging of Apoptosis: The Need to Distinguish Tracer Uptake Rate from Regional Contribution of Blood Flow. PMID- 26025959 TI - Simplified Methods for Quantification of 18F-Fluoromethylcholine Uptake: Is SUVAUC,PP Actually an SUV? PMID- 26025960 TI - Optimized Quantification of Translocator Protein Radioligand 18F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers. AB - Translocator protein (TSPO) is expressed at a low level in healthy brain and is upregulated during inflammatory processes that may occur in neurodegenerative diseases. Thus, TSPO may be a suitable in vivo indicator of neurodegeneration. Here, we quantified the (18)F-DPA-714 radioligand in healthy TSPO-genotyped volunteers and developed a method to eliminate the need for invasive arterial blood sampling. METHODS: Ten controls (7 high-affinity binders [HABs] and 3 mixed affinity binders [MABs]) underwent (18)F-DPA-714 PET with arterial and venous sampling. (18)F-DPA-714 binding was quantified with a metabolite-corrected arterial plasma input function, using the 1- and 2-tissue-compartment models (TCMs) as well as the Logan analysis to estimate total volume distribution (V(T)) in the regions of interest. Alternative quantification methods were tested, including tissue-to-plasma ratio or population-based input function approaches normalized by late time points of arterial or venous samples. RESULTS: The distribution pattern of (18)F-DPA-714 was consistent with the known distribution of TSPO in humans, with the thalamus displaying the highest binding and the cerebellum the lowest. The 2-TCM best described the regional kinetics of (18)F DPA-714 in the brain, with good identifiability (percentage coefficient of variation < 5%). For each region of interest, V(T) was 47.6% +/- 6.3% higher in HABs than in MABs, and estimates from the 2-TCM and the Logan analyses were highly correlated. Equilibrium was reached at 60 min after injection. V(T) calculated with alternative methods using arterial samples was strongly and significantly correlated with that calculated by the 2-TCM. Replacement of arterial with venous sampling in these methods led to a significant but lower correlation. CONCLUSION: Genotyping of subjects is a prerequisite for a reliable quantification of (18)F-DPA-714 PET images. The 2-TCM and the Logan analyses are accurate methods to estimate (18)F-DPA-714 V(T) in the human brain of both HAB and MAB individuals. Population-based input function and tissue-to-plasma ratio with a single arterial sample are promising alternatives to classic arterial plasma input function. Substitution with venous samples is promising but still requires methodologic improvements. PMID- 26025963 TI - Gastrointestinal Motility, Part 1: Esophageal Transit and Gastric Emptying. AB - Although not as well standardized as gastric emptying (GE) scintigraphy, esophageal transit scintigraphy, if performed in a comprehensive manner including both quantitative and qualitative analysis of single- and multiple-swallow studies, is clinically useful when expertise in esophageal manometry is not available or not tolerated and when esophageal manometry or barium videofluoroscopy results are equivocal or nondiagnostic. GE scintigraphy has undergone much-needed standardization. Both solid and liquid GE studies play an important role in assessing patients with upper gastrointestinal symptoms. Because measurement of simple total GE is often not sufficient to explain patient symptoms, there is a need to expand the analysis of GE scintigraphy to include the separate roles of the fundus and antrum and to include the complex interactions the stomach has with other organ systems. PMID- 26025962 TI - Comparative Analysis of T Cell Imaging with Human Nuclear Reporter Genes. AB - Monitoring genetically altered T cells is an important component of adoptive T cell therapy in patients, and the ability to visualize their trafficking/targeting, proliferation/expansion, and retention/death using highly sensitive reporter systems that do not induce an immunologic response would provide useful information. Therefore, we focused on human reporter gene systems that have the potential for translation to clinical studies. The objective of the in vivo imaging studies was to determine the minimum number of T cells that could be visualized with the different nuclear reporter systems. We determined the imaging sensitivity (lower limit of T cell detection) of each reporter using appropriate radiolabeled probes for PET or SPECT imaging. METHODS: Human T cells were transduced with retroviral vectors encoding for the human norepinephrine transporter (hNET), human sodium-iodide symporter (hNIS), a human deoxycytidine kinase double mutant (hdCKDM), and herpes simplex virus type 1 thymidine kinase (hsvTK) reporter genes. After viability and growth were assessed, 10(5) to 3 * 10(6) reporter T cells were injected subcutaneously on the shoulder area. The corresponding radiolabeled probe was injected intravenously 30 min later, followed by sequential PET or SPECT imaging. Radioactivity at the T cell injection sites and in the thigh (background) was measured. RESULTS: The viability and growth of experimental cells were unaffected by transduction. The hNET/meta-(18)F-fluorobenzylguanidine ((18)F-MFBG) reporter system could detect less than 1 * 10(5) T cells because of its high uptake in the transduced T cells and low background activity. The hNIS/(124)I-iodide reporter system could detect approximately 1 * 10(6) T cells; (124)I-iodide uptake at the T cell injection site was time-dependent and associated with high background. The hdCKDM/2'-(18)F fluoro-5-ethyl-1-beta-d-arabinofuranosyluracil ((18)F-FEAU) and hsvTK/(18)F-FEAU reporter systems detected approximately 3 * 10(5) T cells, respectively. (18)F FEAU was a more efficient probe (higher uptake, lower background) than (124)I-1 (2-deoxy-2-fluoro-1-d-arabinofuranosyl)-5-iodouracil for both hdCKDM and hsvTK. CONCLUSION: A comparison of different reporter gene-reporter probe systems for imaging of T cell number was performed, and the hNET/(18)F-MFBG PET reporter system was found to be the most sensitive and capable of detecting approximately 35-40 * 10(3) T cells at the site of T cell injection in the animal model. PMID- 26025964 TI - An Enterovirus-Like RNA Construct for Colon Cancer Suicide Gene Therapy. AB - BACKGROUND: In gene therapy, the use of RNA molecules as therapeutic agents has shown advantages over plasmid DNA, including higher levels of safety. However, transient nature of RNA has been a major obstacle in application of RNA in gene therapy. METHODS: Here, we used the internal ribosomal entry site of encephalomyocarditis virus and the 3' non-translated region of Poliovirus to design an enterovirus-like RNA for the expression of a reporter gene (enhanced green fluorescent protein) and a suicide gene (thymidine kinase of herpes simplex virus). The expression of these genes was evaluated by flow cytometry and cytotoxicity assay in human colorectal adenocarcinoma cell line (SW480). We then armed RNA molecules with a target sequence for hsa-miR-143 to regulate their expression by microRNA (miRNA) mimics. RESULTS: The results showed effective expression of both genes by Entrovirus-like RNA constructs. The data also showed that the restoration of hsa-miR-143 expression in SW480 leads to a significant translation repression of the introduced reporter and suicide genes. CONCLUSION: Collectively, our data suggest the potential use of Entrovirus-like RNA molecules in suicide gene therapy. Additionally, as a consequence of the possible downregulated miRNA expression in cancerous tissues, a decreased expression of gene therapy constructs armed with target sequences for such miRNA in cancer tissue is expected. PMID- 26025966 TI - Has the time come for genomic tests to guide the use of adjuvant chemotherapy in node-positive breast cancer? PMID- 26025965 TI - Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. AB - BACKGROUND: Enhanced phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key adaptive changes accounting for epidermal growth factor receptor (EGFR) inhibitor-resistant growth in head and neck squamous cell carcinoma (HNSCC). We designed a phase II clinical trial of EGFR tyrosine kinase inhibitor (TKI), erlotinib, in association with the mTOR inhibitor, everolimus, based on the hypothesis that the downstream effects of Akt through inhibition of mTOR may enhance the effectiveness of the EGFR-TKI in patients with recurrent/metastatic HNSCC. PATIENTS AND METHODS: Patients with histologically or cytologically confirmed platinum-resistant HNSCC received everolimus 5 mg and erlotinib 150 mg daily orally until disease progression, intolerable toxicity, investigator or patient decision. Cytokines and angiogenic factors profile, limited mutation analysis and p16 immunohistochemistry status were included in the biomarker analysis. RESULTS: Of the 35 assessable patients, 3 (8%) achieved partial response at 4 weeks, 1 confirmed at 12 weeks; overall response rate at 12 weeks was 2.8%. Twenty-seven (77%) patients achieved disease stabilization at 4 weeks, 11 (31%) confirmed at 12 weeks. Twelve-week progression free survival (PFS) was 49%, median PFS 11.9 weeks and median overall survival (OS) 10.25 months. High neutrophil gelatinase lipocalin (P = 0.01) and vascular endothelial growth factor (VEGF) (P = 0.04) plasma levels were significantly associated with worse OS. CONCLUSIONS: The combination of erlotinib and everolimus did not show significant benefit in unselected patients with platinum resistant metastatic HNSCC despite a manageable toxicity profile. Markers of tumor invasion and hypoxia identify a group of patients with particularly poor prognosis. CLINICAL TRIAL NUMBER: NCT00942734. PMID- 26025967 TI - Desformylflustrabromine Modulates alpha4beta2 Neuronal Nicotinic Acetylcholine Receptor High- and Low-Sensitivity Isoforms at Allosteric Clefts Containing the beta2 Subunit. AB - Alterations in expression patterns of alpha4beta2 nicotinic acetylcholine receptors have been demonstrated to alter cholinergic neurotransmission and are implicated in neurologic disorders, including autism, nicotine addiction, Alzheimer's disease, and Parkinson's disease. Positive allosteric modulators (PAMs) represent promising new leads in the development of therapeutic agents for the treatment of these disorders. This study investigates the involvement of the beta2-containing subunit interfaces of alpha4beta2 receptors in the modulation of acetylcholine (ACh)-induced responses by the PAM desformylflustrabromine (dFBr). Eight amino acids on the principal face of the beta2 subunit were mutated to alanine to explore the involvement of this region in the potentiation of ACh induced currents by dFBr. ACh-induced responses obtained from wild-type and mutant alpha4beta2 receptors expressed in Xenopus laevis oocytes were recorded in the presence and absence of dFBr using two-electrode voltage clamp electrophysiology. Wild-type and mutant receptors were expressed in both high and low ACh sensitivity isoforms by using biased injection ratios of 1:5 or 5:1 alpha4 to beta2 complementary RNA. Mutations were made in the B, C, and A loops of the principal face of the beta2 subunit, which are regions not involved in the binding of ACh. Mutant beta2(Y120A) significantly eliminated dFBr potency in both isoform preparations. Several other mutations altered dFBr potentiation levels in both preparations. Our findings support the involvement of the principal face of the beta2 subunit in dFBr modulation of ACh-induced responses. Findings from this study will aid in the improved design of dFBr-like PAMs for potential therapeutic use. PMID- 26025968 TI - Effect of Oxidized Low Density Lipoprotein on the Expression of Runx2 and SPARC Genes in Vascular Smooth Muscle Cells. AB - BACKGROUND: Vascular calcification is an important stage in atherosclerosis. During this stage, vascular smooth muscle cells (VSMC) synthesize many osteogenic factors such as osteonectin (encoded by SPARC). Oxidative stress plays a critical role in atherosclerosis progression, and its accumulation in the vascular wall stimulates the development of atherosclerosis and vascular calcification. The osteonectin overexpression has been observed in the arterial wall during the course of atherosclerosis. However, the regulatory mechanism of oxidized low density lipoprotein (oxLDL)-mediated vascular calcification remains to be clarified. The aim of this study was to investigate the effect of oxLDL on the osteonectin gene expression through the Runx2 transcription factor. METHODS: In this experimental study, VSMC were cultured in F-12K media and then treated with oxLDL. The expression of Runx2 and osteonectin genes was determined by real-time PCR method. Protein levels were investigated by the western blotting technique. The Runx2 gene was knocked down using siRNA in order to determine whether Runx2 regulates the osteonectin expression in VSMC induced by oxLDL. Then transfected cells were treated with oxLDL, and the expression levels of Runx2 and osteonectin were determined again. RESULTS: oxLDL was found to increase Runx2 and osteonectin gene expression (4.8+/-0.47- and 9.2+/-1.96-fold, respectively) after 48 h. Western blotting analysis confirmed the induced levels of Runx2 and osteonectin proteins. However, oxLDL-induced osteonectin expression was not observed to be blocked by Runx2 knockdown. CONCLUSION: The up-regulation of osteonectin by oxLDL is independent of Runx2, and it may be mediated by other transcription factors. PMID- 26025970 TI - Response to 'dual training in general internal medicine and rheumatology: the Irish context' by Dr Sheane. PMID- 26025969 TI - Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation. AB - Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free one-dimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post re-aeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to prevent reactivation of latent tuberculosis. PMID- 26025971 TI - RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. AB - OBJECTIVE: RANKL is mainly expressed by synovial fibroblasts and T cells within the joints of rheumatoid arthritis patients. The relative importance of RANKL expression by these cell types for the formation of bone erosions is unclear. We therefore aimed to quantify the contribution of RANKL by each cell type to osteoclast differentiation and bone destruction during inflammatory arthritis. METHODS: RANKL was specifically deleted in T cells (Tnfsf11(flox/Delta) Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11(flox/Delta) Col6a1-Cre) and in collagen II expressing cells including articular chondrocytes (Tnfsf11(flox/Delta) Col2a1-Cre). Erosive disease was induced using the collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA) models. Osteoclasts and cartilage degradation were assessed by histology and bone erosions were assessed by micro-CT. RESULTS: The inflammatory joint score during CAIA was equivalent in all mice regardless of cell-targeted deletion of RANKL. Significant increases in osteoclast numbers and bone erosions were observed in both the Tnfsf11(flox/Delta) and the Tnfsf11(flox/Delta) Lck-Cre groups during CAIA; however, the Tnfsf11(flox/Delta) Col6a1-Cre mice showed significant protection against osteoclast formation and bone erosions. Similar results on osteoclast formation and bone erosions were obtained in CIA mice. The deletion of RANKL on any cell type did not prevent articular cartilage loss in either model of arthritis used. CONCLUSIONS: The expression of RANKL on synovial fibroblasts rather than T cells is predominantly responsible for the formation of osteoclasts and erosions during inflammatory arthritis. Synovial fibroblasts would be the best direct target in RANKL inhibition therapies. PMID- 26025973 TI - Muscle paralysis in thyrotoxicosis. AB - Thyrotoxic periodic paralysis (TPP) is a condition characterised by muscle paralysis due to hypokalaemia usually secondary to thyrotoxicosis. We report a case of a 31-year-old man with no known comorbidities who presented to a tertiary healthcare unit with a 1-month history of difficulty in breathing, palpitations, weight loss and hoarseness of voice. On examination, his thyroid gland was palpable and fine hand tremors were present. An initial provisional diagnosis of hyperthyroidism was made. Three months after initial presentation, the patient presented in emergency with severe muscle pain and inability to stand. Laboratory results revealed hypokalaemia. All the symptoms reverted over the next few hours on administration of intravenous potassium. A diagnosis of TTP was established. After initial presentation, the patient was treated with carbimazole and propranolol. Once he was euthyroid, radioactive iodine ablation therapy (15 mCi) was carried out as definitive therapy, after which the patient's symptoms resolved; he is currently doing fine on levothyroxine replacement and there has been no recurrence of muscle paralysis. PMID- 26025972 TI - Systemic aspergilloma post aortic root surgery following coronary artery stenting: diagnostic and management dilemma. AB - Aspergillus infections such as Aspergillus endocarditis were once relatively rare occurrences, however, due to the increased use of intracardiac devices, the incidence has grown. With mortality rates close to 100%, in medically treated cases, it is paramount that early diagnosis and treatment are performed. An immunocompetent aviculturist presented 8 months post aortic root replacement for severe aortic regurgitation with a composite graft, with central crushing chest pain. Investigations confirmed ST elevation inferior myocardial infarction due to stenosis of the origin of the right coronary artery, which was stented. Echocardiogram demonstrated a mobile mass posterior to the left ventricular outflow tract. Following referral to our cardiothoracic surgeons, a polypoidal mass covering the right ostial button was noted along with systemic complications of the disease. Emergency redo aortic valve replacement with a homograft and coronary artery bypass was performed. Histological analysis confirmed A. fumigatus and the patient was started on intravenous voriconazole. PMID- 26025974 TI - Adynamic ileus and diarrhoea: a rare adverse effect of antidepressants. AB - Antidepressants can cause a variety of gastrointestinal effects, including nausea, dyspepsia, anorexia, constipation, and, rarely, diarrhoea and adynamic ileus. There is a lack of cases associating antidepressants to adynamic ileus and diarrhoea. We report a case of an elderly woman in whom the use of several antidepressants apparently induced adynamic ileus with diarrhoea. PMID- 26025975 TI - Flow diversion in vasculitic intracranial aneurysms? Repair of giant complex cavernous carotid aneurysm in polyarteritis nodosa using Pipeline embolization devices: first reported case. AB - Intracranial aneurysms in polyarteritis nodosa (PAN) are exceedingly rare lesions with unpredictable behavior that pose real challenges to microsurgical and endovascular interventions owing to their inflammatory nature. We introduce a safe and effective alternative for treating these aneurysms using Pipeline embolization devices (PEDs). A 20-year-old man presented with diplopia, headaches, chronic abdominal pain, and weight loss. Diagnostic evaluations confirmed PAN, including bilateral giant cavernous carotid aneurysms. Cyclophosphamide and steroids achieved significant and sustained clinical improvement, with a decision to follow the aneurysms serially. Seven years later the left unruptured aneurysm enlarged, causing a sudden severe headache and a cavernous sinus syndrome. Treatment of the symptomatic aneurysm was pursued using flow diversion (PED) and the internal carotid artery was successfully reconstructed with a total of four overlapping PEDs. At 6 months follow-up, complete exclusion of the aneurysm was demonstrated, with symptomatic recovery. This is the first description of using a flow-diverting technique in an inflammatory vasculitis. In this case, PEDs not only attained a definitive closure of the aneurysm but also reconstructed the damaged and fragile arterial segment affected with vasculitis. PMID- 26025976 TI - AML transformation after autologous stem cell transplant for multiple myeloma. AB - A 59-year-old male patient was diagnosed as multiple myeloma in 2005 and received chemotherapy consisting of thalidomide, cyclophosphamide, and dexamethasone. The patient subsequently received high-dose melphalan followed by autologous stem cell transplantation and maintenance therapy with thalidomide. During the follow up, the patient developed fever and cytopenias in 2012. The work up revealed 55% blasts in the marrow with myeloid phenotype leading to a diagnosis of acute myeloma leukaemia (AML). The karyotype was normal (46,XY) on conventional cytogenetics. The therapy was initiated, however, the patient expired within 1 month of diagnosis. The treatment related factors like alkylating agents are usually taken as the responsible agents for therapy-related AML, however, recent studies have proposed a multifactorial pathogenesis of leukaemic transformation in multiple myeloma. PMID- 26025977 TI - Surgical repair of a giant idiopathic macular hole by inverted internal limiting membrane flap. AB - A 22-year-old male patient presented with gradual outward deviation of the right eye following corneal tear repair in that eye 8 years prior. He was asymptomatic in the left eye. On examination, his best corrected visual acuity was counting fingers at 2 m in the right eye and 20/80 in the left eye. The left eye showed a large macular hole, 2845 um in diameter, with a retinal detachment at the posterior pole. The patient underwent pars plana vitrectomy, internal limiting membrane (ILM) peeling with inverted ILM flap technique and silicone oil injection. At the 1-week follow-up visit, there was growth of retinal tissue under the ILM flap. At 2-month follow-up, there was a complete closure of the macular hole and visual acuity was 20/100. At this time, the patient underwent removal of the silicone oil, following which visual acuity was maintained at 20/100. PMID- 26025979 TI - The Kinetic and Thermodynamic Aftermath of Horizontal Gene Transfer Governs Evolutionary Recovery. AB - Shared host cells can serve as melting pots for viral genomes, giving many phylogenies a web-like appearance due to horizontal gene transfer. However, not all virus families exhibit web-like phylogenies. Microviruses form three distinct clades, represented by phiX174, G4, and alpha3. Here, we investigate protein based barriers to horizontal gene transfer between clades. We transferred gene G, which encodes a structural protein, between phiX174 and G4, and monitored the evolutionary recovery of the resulting chimeras. In both cases, particle assembly was the major barrier after gene transfer. The G4phiXG chimera displayed a temperature-sensitive assembly defect that could easily be corrected through single mutations that promote productive assembly. Gene transfer in the other direction was more problematic. The initial phiXG4G chimera required an exogenous supply of both the phiX174 major spike G and DNA pilot H proteins. Elevated DNA pilot protein levels may be required to compensate for off-pathway reactions that may have become thermodynamically and/or kinetically favored when the foreign spike protein was present. After three targeted genetic selections, the foreign spike protein was productively integrated into the phiX174 background. The first adaption involved a global decrease in gene expression. This was followed by modifications affecting key protein-protein interactions that govern assembly. Finally, gene expression was re-elevated. Although the first selection suppresses nonproductive reactions, subsequent selections promote productive assembly and ultimately viability. However, viable chimeric strains exhibited reduced fitness compared with wild-type. This chimera's path to recovery may partially explain how unusual recombinant viruses could persist long enough to naturally emerge. PMID- 26025978 TI - Identification of Allorecognition Loci in Neurospora crassa by Genomics and Evolutionary Approaches. AB - Understanding the genetic and molecular bases of the ability to distinguish self from nonself (allorecognition) and mechanisms underlying evolution of allorecognition systems is an important endeavor for understanding cases where it becomes dysfunctional, such as in autoimmune disorders. In filamentous fungi, allorecognition can result in vegetative or heterokaryon incompatibility, which is a type of programmed cell death that occurs following fusion of genetically different cells. Allorecognition is genetically controlled by het loci, with coexpression of any combination of incompatible alleles triggering vegetative incompatibility. Herein, we identified, characterized, and inferred the evolutionary history of candidate het loci in the filamentous fungus Neurospora crassa. As characterized het loci encode proteins carrying an HET domain, we annotated HET domain genes in 25 isolates from a natural population along with the N. crassa reference genome using resequencing data. Because allorecognition systems can be affected by frequency-dependent selection favoring rare alleles (i.e., balancing selection), we mined resequencing data for HET domain loci whose alleles displayed elevated levels of variability, excess of intermediate frequency alleles, and deep gene genealogies. From these analyses, 34 HET domain loci were identified as likely to be under balancing selection. Using transformation, incompatibility assays and genetic analyses, we determined that one of these candidates functioned as a het locus (het-e). The het-e locus has three divergent allelic groups that showed signatures of positive selection, intra- and intergroup recombination, and trans-species polymorphism. Our findings represent a compelling case of balancing selection functioning on multiple alleles across multiple loci potentially involved in allorecognition. PMID- 26025980 TI - Bystander Effect Fuels Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells to Quickly Attenuate Early Stage Neurological Deficits After Stroke. AB - : Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA's effectiveness is limited in that the drug not only must be administered less than 3-5 hours after stroke but often exacerbates blood-brain barrier (BBB) leakage and increases hemorrhagic incidence. A potentially promising therapy for stroke is transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs). To date, the effects of iPSCs on injuries that take place during early stage ischemic stroke have not been well studied. Consequently, we engrafted iPSC-NSCs into the ipsilesional hippocampus, a natural niche of NSCs, at 24 hours after stroke (prior to secondary BBB opening and when inflammatory signature is abundant). At 48 hours after stroke (24 hours after transplant), hiPSC-NSCs had migrated to the stroke lesion and quickly improved neurological function. Transplanted mice showed reduced expression of proinflammatory factors (tumor necrosis factor-alpha, interleukin 6 [IL-6], IL-1beta, monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha), microglial activation, and adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and attenuated BBB damage. We are the first to report that engrafted hiPSC-NSCs rapidly improved neurological function (less than 24 hours after transplant). Rapid hiPSC-NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and BBB damage. SIGNIFICANCE: Clinically, cerebral vessel occlusion is rarely permanent because of spontaneous or thrombolytic therapy-mediated reperfusion. These results have clinical implications indicating a much extended therapeutic window for transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs; 24 hours after stroke as opposed to the 5-hour window with tissue plasminogen activator [tPA]). In addition, there is potential for a synergistic effect by combining hiPSC-NSC transplantation with tPA to attenuate stroke's adverse effects. PMID- 26025981 TI - A Stem Cell-Derived Platform for Studying Single Synaptic Vesicles in Dopaminergic Synapses. AB - The exocytotic release of dopamine is one of the most characteristic but also one of the least appreciated processes in dopaminergic neurotransmission. Fluorescence imaging has yielded rich information about the properties of synaptic vesicles and the release of neurotransmitters in excitatory and inhibitory neurons. In contrast, imaging-based studies for in-depth understanding of synaptic vesicle behavior in dopamine neurons are lagging largely because of a lack of suitable preparations. Midbrain culture has been one of the most valuable preparations for the subcellular investigation of dopaminergic transmission; however, the paucity and fragility of cultured dopaminergic neurons limits their use for live cell imaging. Recent developments in stem cell technology have led to the successful production of dopamine neurons from embryonic or induced pluripotent stem cells. Although the dopaminergic identity of these stem cell derived neurons has been characterized in different ways, vesicle-mediated dopamine release from their axonal terminals has been barely assessed. We report a more efficient procedure to reliably generate dopamine neurons from embryonic stem cells, and it yields more dopamine neurons with more dopaminergic axon projections than midbrain culture does. Using a collection of functional measurements, we show that stem cell-derived dopamine neurons are indistinguishable from those in midbrain culture. Taking advantage of this new preparation, we simultaneously tracked the turnover of hundreds of synaptic vesicles individually using pH-sensitive quantum dots. By doing so, we revealed distinct fusion kinetics of the dopamine-secreting vesicles, which is consistent within both preparations. PMID- 26025983 TI - Health centers embrace clinical pharmacy services. PMID- 26025982 TI - Effect of TGF-beta1 Stimulation on the Secretome of Human Adipose-Derived Mesenchymal Stromal Cells. AB - Adipose tissue is an attractive source of mesenchymal stromal cells (MSCs) owing to the relative ease of obtaining large volumes with more MSC abundance compared with other sources. Increasing evidence supports the fact that trophic factors secreted by MSCs play a pivotal therapeutic role. Several strategies in regenerative medicine use MSCs, mainly exploiting their immunosuppressive effect and homing capacity to sites of damage. Transforming growth factor-beta1 (TGF beta1) is a pleiotropic cytokine that, depending on the cell niche, can display either anti-inflammatory or proinflammatory effects. TGF-beta1 expression increases in various tissues with damage, especially when accompanied by inflammation. Thus, we analyzed the effect of TGF-beta1 on the secretion by adipose-derived mesenchymal stromal cells (ASCs) of a panel of 80 cytokines/chemokines using an antibody array. To avoid a possible effect of fetal bovine serum (FBS) on ASCs secretion, we performed our analysis by culturing cells in FBS-free conditions, only supplemented with 0.1% of bovine serum albumin. We report the cytokine profile secreted by ASCs. We also found that TGF beta1 exposure modulates 8 chemokines and 18 cytokines, including TGF-beta1 and beta2, and other important cytokines involved in immunosuppression, allergic responses, and bone resorption. PMID- 26025984 TI - Failure to heed incompatibility information can result in CSTD leaking hazardous drug. PMID- 26025985 TI - ASHP's election communications guidelines balance visibility with fairness. PMID- 26025986 TI - Correction. Personal reflections 30 years after the Hilton Head Conference. PMID- 26025987 TI - Involving pharmacy technicians and students in the emergency department to expand care provided by clinical pharmacists. PMID- 26025988 TI - Remeasuring job satisfaction among pharmacy residents. PMID- 26025989 TI - Activities of palliative care and pain management clinical pharmacists. PMID- 26025990 TI - ASHP Connect community. PMID- 26025991 TI - Clostridium difficile infection: A brief update on emerging therapies. AB - PURPOSE: Established and investigational antibiotic, monoclonal antibody, vaccine, and microbe-based approaches to the prevention and treatment of Clostridium difficile infection (CDI) are reviewed. SUMMARY: CDI is increasingly prevalent in the United States and other countries, particularly among hospitalized patients and the elderly, who are at high risk for potentially fatal CDI-related enterotoxic diarrhea. Established therapies for CDI such as vancomycin and metronidazole (an off-label use) are limited by poor efficacy and high recurrence rates. An investigational antibiotic with potent in vitro activity against all C. difficile strains (including the hypervirulent BI/NAP1/027 strain) has yielded encouraging results in early clinical trials. Another promising approach involves the use of monoclonal antibodies with selective activity against toxins responsible for CDI-associated diarrhea; in a small Phase II clinical trial, a single monoclonal antibody infusion in combination with vancomycin or metronidazole therapy was more effective than antibiotic therapy alone in preventing CDI relapse. Other emerging approaches to CDI treatment and prophylaxis include the use of vaccines against C. difficile toxins (several C. difficile-targeted vaccines are under development in Europe and the United States); microbe-based strategies such as fecal microbiota transplants, "microbial ecosystem therapeutics," and probiotic supplements; and an investigational encapsulated form of beta-lactamase designed to prevent C. difficile colonization from progressing to CDI. CONCLUSION: The current antibiotic therapies for CDI, mainly vancomycin and (off-label) metronidazole and the newer agent fidaxomicin, have limitations with respect to efficacy, recurrence rates, and adverse effects, but a variety of promising approaches are emerging. PMID- 26025992 TI - Role of intravenous immune globulin in streptococcal toxic shock syndrome and Clostridium difficile infection. AB - PURPOSE: The use of intravenous immune globulin (IVIG) in the management of streptococcal toxic shock syndrome (STSS) and Clostridium difficile infection (CDI) is reviewed. SUMMARY: IVIG has a wide range of uses in clinical practice, including STSS and CDI. It is an attractive option for these two infections because both infections are toxin mediated, and IVIG may contain antibodies that neutralize these toxins. For STSS and CDI, IVIG is often considered for use in critically ill patients who are not responding to traditional therapies. Several encouraging case reports and retrospective chart reviews have been published, highlighting the potential benefit of IVIG in such patients. However, its definitive role remains unclear, mainly due to the lack of high-level evidence. Data supporting its use have been extrapolated from retrospective chart reviews and case reports in which profound heterogeneity in patient populations and treatment modalities exist. The use of IVIG must be weighed carefully because it is not a benign product. As with the use of IVIG for STSS, the role of IVIG for CDI is unclear. Nonetheless, IVIG may serve as a useful adjunct therapy for patients suffering from severe complicated CDI (shock, ileus, or megacolon) who do not respond to conventional treatment. Adverse reactions to IVIG are mild and transitory and occur during or immediately after drug infusion. CONCLUSION: Although randomized, controlled trials supporting the use of IVIG for STSS and CDI are lacking, IVIG may be considered a last-line adjunct therapy in those patients for whom the clinical benefit outweighs the potential adverse effects of therapy. PMID- 26025993 TI - Indomethacin for treatment of refractory intracranial hypertension secondary to acute liver failure. AB - PURPOSE: Successful use of i.v. indomethacin for urgent management of elevated intracranial pressure (ICP) due to acute liver failure is reported. SUMMARY: A 42 year-old woman receiving intensive care for fulminant hepatic failure secondary to acetaminophen toxicity developed cerebral edema and intracranial hypertension refractory to standard pharmacotherapy and respiratory support measures. A computed tomography (CT) scan of the patient's head was ordered as part of an evaluation for liver transplantation, but the patient's severely elevated ICP precluded supine positioning for the CT study (throughout the hospital stay, the head of the patient's bed was kept at a 30 degrees angle to optimize cerebral venous outflow). With administration of indomethacin 10 mg by i.v. injection, the ICP decreased from 29 to 13 mm Hg and remained at goal after the patient was placed in a fully supine position for a period long enough to permit the CT scan. Indomethacin was used a second time to facilitate CT imaging several days later. No adverse effects attributable to indomethacin use were documented. Although the patient underwent successful liver transplantation, her mental status and overall clinical status continued to deteriorate and she died on postoperative day 12. CONCLUSION: Despite the poor overall patient outcome in this case, i.v. indomethacin was successfully used to decrease ICP in order to facilitate CT imaging as part of a transplantation eligibility workup. PMID- 26025994 TI - Clinical outcomes and treatment cost comparison of levalbuterol versus albuterol in hospitalized adults with chronic obstructive pulmonary disease or asthma. AB - PURPOSE: Results of a prospective study comparing clinical outcomes and costs of levalbuterol versus albuterol therapy for exacerbations of asthma or chronic obstructive pulmonary disease (COPD) are presented. METHODS: In a single-center open-label study, selected adults hospitalized for asthma or COPD exacerbations over a 21-month period were randomly assigned to receive levalbuterol 1.25 mg three times daily (n = 55) or albuterol 2.5 mg four times daily (n = 57); dosage reductions and other respiratory therapies were permitted. Study outcomes included scheduled and rescue nebulizations, total treatment costs, hospital length of stay, and change in heart rate from baseline. RESULTS: The numbers of scheduled nebulizations were similar in the levalbuterol and albuterol groups (mean +/- S.D., 19.6 +/- 13.4 versus 20.7 +/- 14.4; p = 0.692), as were the numbers of rescue nebulizations (mean +/- S.D., 0.7 +/- 1.4 versus 0.8 +/- 2.0; p = 0.849). The mean change from baseline in heart rate did not differ significantly between groups. Mean total treatment costs per patient were significantly greater with the use of levalbuterol ($8003, bootstrap 95% confidence interval [CI], $6628-$9379) versus albuterol ($5772, bootstrap 95% CI, $5051-$6494; p = 0.006). Hospital length of stay was significantly greater in the levalbuterol group (mean +/- S.D., 8.5 +/- 5.2 days versus 6.8 +/- 3.6 days with albuterol use; p = 0.040). CONCLUSION: Clinical outcomes were similar with the use of levalbuterol versus albuterol for exacerbations of COPD or asthma. On average, patients receiving levalbuterol had longer and more costly hospital stays. PMID- 26025995 TI - A three-year study of a first-generation chemotherapy-compounding robot. AB - PURPOSE: Results of a performance evaluation of an automated system for compounding antineoplastic preparations are reported. METHODS: Three years after the pharmacy department of a hospital in Saudi Arabia installed an i.v. compounding robot (CytoCare, Health Robotics), data captured by the pharmacy information system and the machine's integrated software were analyzed to assess the performance of the robot in terms of compounding accuracy, days of operation, and downtime. RESULTS: The robot was used to prepare 3.82%, 10.80%, and 13.79% of selected antineoplastics compounded in 2010, 2011, and 2012, respectively. The robot failed to meet the specified dose accuracy range of +/-5% in compounding 3 of 337 chemotherapy preparations (0.9%) in 2010, 349 of 1516 preparations (23%) in 2011, and 460 of 2993 preparations (15%) in 2012. The robot was operational on 40%, 39%, and 61% of available workdays in 2010, 2011, and 2012, respectively. Robot throughput relative to the pharmacy's manual compounding process was low, with substantial medication waste resulting from dose preparation failures. Implementation challenges included workflow disruptions due to robot downtime, mechanical issues (e.g., robot arm-clamping failures), difficulty obtaining gravimetric data for some drugs, and the need to recalibrate the device to accept i.v. bags, syringes, and medication vials incompatible with manufacturer specifications. CONCLUSION: The introduction of a chemotherapy-compounding robot for preparation of patient-specific i.v. antineoplastic drugs had a limited efficiency impact in practice. This solution, with its numerous limitations and technical difficulties, is not yet mature enough for universal adoption. PMID- 26025996 TI - Implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit to reduce medication expenditures. AB - PURPOSE: The implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit (ICU) is described. METHODS: This retrospective study compared the use of i.v. chlorothiazide and i.v. ethacrynic acid in pediatric cardiovascular surgery patients before and after implementation of a diuretic stewardship program. All pediatric patients admitted to the pediatric cardiovascular service were included. The cardiovascular surgery service was educated on formal indications for specific diuretic agents, and the diuretic stewardship program was implemented on January 1, 2013. Under the stewardship program, i.v. ethacrynic acid was indicated in patients with a sulfonamide allergy, and i.v. chlorothiazide was considered appropriate in patients receiving maximized i.v. loop diuretic doses. A detailed review of the pharmacy database and medical records was performed for each patient to determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. RESULTS: After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of $91,398 in expenditures on these diuretics over the six-month study period and an estimated annual saving of over $182,000. The median number of days using a ventilator and the length of ICU stay did not differ significantly during the study period. CONCLUSION: Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as ventilator days and length of stay in a pediatric cardiovascular ICU. PMID- 26025997 TI - Pharmacy Practice Model Initiative task force report: Improving participation in a survey on hospital pharmacy practices in Texas. AB - PURPOSE: Results of an initiative to increase participation in a survey on hospital pharmacy practices are reported. METHODS: In an initiative led by pharmacy residents at the University of Houston College of Pharmacy, a task force was created to boost the rate of response to the Hospital-Assessment Survey (HSA), an online benchmarking tool developed as part of the ASHP-sponsored Pharmacy Practice Model Initiative (PPMI). Under the guidance of leaders from ASHP's Texas affiliate and state health-system pharmacy leaders, an 11-member team of residents targeted Texas hospitals that had not responded to the HSA as of December 2013 and used phone and e-mail methods to encourage survey participation. Data obtained from newly responding institutions were aggregated with previously collected data on Texas facilities and compared with national data. RESULTS: During the 11-week initiative, 66 new HSA responses were received from Texas hospitals, raising the total number of respondents to 89 and boosting the overall participation rate from 4.3% to 16.7% (p <0.001). Analysis of the survey data indicated broad similarities among small and large Texas hospitals with regard to six optimal practice characteristics. Pharmacy practice models and characteristics in Texas overall were largely consistent with national statistics. CONCLUSION: The involvement of the PPMI task force was associated with a substantial increase in the survey response rate. The survey results indicated that, with a few exceptions, practice models and the use of optimal practices were similar at Texas hospitals of various sizes and between Texas hospitals overall and sampled hospitals nationwide. PMID- 26025999 TI - Translocation of heme oxygenase-1 to mitochondria is a novel cytoprotective mechanism against non-steroidal anti-inflammatory drug-induced mitochondrial oxidative stress, apoptosis, and gastric mucosal injury. PMID- 26025998 TI - Addition of tranexamic acid to a traumatic injury massive transfusion protocol. AB - PURPOSE: The development of eligibility criteria and use of tranexamic acid in conjunction with a massive transfusion protocol (MTP) are described. SUMMARY: The trauma surgery and pharmacy departments collaborated to operationalize tranexamic acid administration in trauma patients for whom an MTP was activated. The MTP at Boston Medical Center, an urban, tertiary, academic medical center, is activated by the attending physician when the patient is expected to require at least 10 units of packed red blood cells in 24 hours. Tranexamic acid was considered in MTP trauma patients who arrived at the medical center within 8 hours of traumatic injury, were 15 years of age or older, and weighed at least 40 kg. Eligible patients were to receive a loading dose of tranexamic acid 1 g i.v. over 10 minutes followed by a maintenance dose of 1 g infused over 8 hours. To ensure that tranexamic acid use was limited to trauma patients, both its location of use and physician-ordering privileges were restricted by the pharmacy department. A 16-month assessment revealed that 16 patients received tranexamic acid, 13 (81%) of whom met all criteria for use. Tranexamic acid was used in 13 (38%) of 34 eligible MTP patients. Barriers to the use of tranexamic acid include a lack of familiarity with the medication among staff, drug availability, the complexity of administration, and the critical setting of MTP activation. CONCLUSION: Multidisciplinary collaboration and standardization of tranexamic acid use in conjunction with an MTP promoted use of the drug within a trauma population. PMID- 26026001 TI - Software solutions alone cannot guarantee useful radiology requests. AB - Background The availability of clinical information and a pertinent clinical question can improve the diagnostic accuracy of the imaging process. Purpose To examine if an electronic request form forcing referring clinicians to provide separate input of both clinical information and a clinical question can improve the quality of the request. Material and Methods A total of 607 request forms in the clinical worklists for a computed tomography (CT) scan of the thorax, the abdomen or their combination, were examined. Using software of our own making, we examined the presence of clinical information and a clinical question before and after the introduction of a new, more compelling order method. We scored and compared the quality of the clinical information and the clinical question between the two systems and we examined the effect on productivity. Results Both clinical information and a clinical question were present in 76.7% of cases under the old system and in 95.3% under the new system ( P < 0.001). Individual characteristics of the clinical information and the clinical question however, with the exception of incompleteness, showed little improvement under the new system. There was also no significant difference between the two systems in the number of requests requiring further search. Conclusion The introduction of electronic radiology request forms compelling referring clinicians to provide separate input of clinical information and a clinical question provides only limited benefit to the quality of the request. Raising awareness among clinicians of the importance of a well-written request remains essential. PMID- 26026000 TI - Preanalytical ammonia generation: a race with time but not with temperature. PMID- 26026002 TI - Use of pulmonary embolism rule-out criteria (PERC) in the emergency department. PMID- 26026003 TI - Helping patients and the emergency department: enhanced patient care and reduced hospital admission rates with a pilot rapid access neurology clinic (RANC). PMID- 26026004 TI - Improving identification of malnutrition in older patients admitted acutely to hospital. PMID- 26026005 TI - Direct access echocardiography to a district general hospital: are patients being screened appropriately? PMID- 26026006 TI - Impact of early comprehensive geriatric assessment in the acute medical unit. PMID- 26026007 TI - An unusual aetiology of 'collapse query cause': penetrating chest trauma. PMID- 26026008 TI - BMPR-II mutations promote pulmonary arterial hypertension via a hyperinflammatory response. PMID- 26026009 TI - Measurement and recording errors of the respiratory rate. PMID- 26026010 TI - Tackling blood culture contamination rates in the acute setting. PMID- 26026011 TI - Venous thromboembolism prophylaxis post-discharge in hip fracture surgery patients: what to do if the patient is taking antiplatelets. PMID- 26026012 TI - Heart failure management in high-risk patient groups. PMID- 26026013 TI - HEADS-UP: a novel intervention to improve clinical outcomes with daily, team based risk recognition. PMID- 26026014 TI - Use of a modified Clinical Institute Withdrawal Assessment (CIWA) for symptom triggered management of alcohol withdrawal syndrome. PMID- 26026015 TI - Thrombotic thrombocytopenic purpura specialist centres: providing better outcomes for patients with rare but life-threatening conditions. PMID- 26026016 TI - Can a perioperative physician improve care and reduce length of stay in a surgical emergency admission unit? PMID- 26026017 TI - Extending the definition of quality for non-tunnelled central venous catheter insertion. PMID- 26026018 TI - What are the barriers to improving care for patients with sepsis? PMID- 26026019 TI - Early outcome after implantation of bioresorbable vascular scaffolds in elderly patients. PMID- 26026020 TI - Non-standardised treatment rooms present an obstacle to efficient and prompt patient care. PMID- 26026021 TI - 'Mini-GEMs': short, focused e-learning videos in geriatric medicine. PMID- 26026022 TI - Male and female faculty members' perceptions of organisational culture in academic medicine at 26 representative US academic health centres: implications for delivering the future hospital. PMID- 26026023 TI - Developing the first UK integrated respiratory registrar role in an inner city integrated care organisation. PMID- 26026024 TI - Early triaging using the Modified Early Warning Score (MEWS) and dedicated emergency teams leads to improved clinical outcomes in acute emergencies. PMID- 26026025 TI - Learning to make a difference: facilitating improvements in care by enabling core medical trainees to develop skills in quality improvement. PMID- 26026026 TI - Moving from reactive to proactive patient safety training in the future hospital: making learning a normal part of the working day. PMID- 26026027 TI - 'Unblocking flow constraints' within a medical directorate at a large acute NHS trust. PMID- 26026028 TI - Tracking failure to rescue in the future hospital. PMID- 26026029 TI - Delivering electronic prescribing and medicines administration in challenging areas such as paediatrics and maternity at King's College Hospital NHS Foundation Trust. PMID- 26026030 TI - Teaching prescribing skills to foundation trainees: a pilot study evaluating the impact of a prescribing training session for foundation year two doctors. PMID- 26026031 TI - Intravenous therapy. PMID- 26026032 TI - Developing a clinical screening tool for frailty in the acute care setting. PMID- 26026033 TI - Is it time to replace the Abbreviated Mental Test Score as a screening tool for dementia? PMID- 26026034 TI - Electrical aspects of the osmorespiratory compromise: TEP responses to hypoxia in the euryhaline killifish (Fundulus heteroclitus) in freshwater and seawater. AB - The osmorespiratory compromise, the trade-off between the requirements for respiratory and ionoregulatory homeostasis at the gills, becomes more intense during environmental hypoxia. One aspect that has been previously overlooked is possible change in transepithelial potential (TEP) caused by hypoxia, which will influence branchial ionic fluxes. Using the euryhaline killifish, we show that acute hypoxia reduces the TEP across the gills by approximately 10 mV in animals acclimated to both freshwater (FW) and seawater (SW), with a higher PO2 threshold in the former. TEP becomes negative in FW, and less positive in SW. The effects are immediate, stable for at least 3 h, and reverse immediately upon return to normoxia. Hypoxia also blocks the normal increase in TEP that occurs upon transfer from FW to SW, but does not reduce the fall in TEP that occurs with transfer in the opposite direction. These effects may be beneficial in FW but not in SW. PMID- 26026035 TI - The human iliotibial band is specialized for elastic energy storage compared with the chimp fascia lata. AB - This study examines whether the human iliotibial band (ITB) is specialized for elastic energy storage relative to the chimpanzee fascia lata (FL). To quantify the energy storage potential of these structures, we created computer models of human and chimpanzee lower limbs based on detailed anatomical dissections. We characterized the geometry and force-length properties of the FL, tensor fascia lata (TFL) and gluteus maximus (GMax) in four chimpanzee cadavers based on measurements of muscle architecture and moment arms about the hip and knee. We used the chimp model to estimate the forces and corresponding strains in the chimp FL during bipedal walking, and compared these data with analogous estimates from a model of the human ITB, accounting for differences in body mass and lower extremity posture. We estimate that the human ITB stores 15- to 20-times more elastic energy per unit body mass and stride than the chimp FL during bipedal walking. Because chimps walk with persistent hip flexion, the TFL and portions of GMax that insert on the FL undergo smaller excursions (origin to insertion) than muscles that insert on the human ITB. Also, because a smaller fraction of GMax inserts on the chimp FL than on the human ITB, and thus its mass-normalized physiological cross-sectional area is about three times less in chimps, the chimp FL probably transmits smaller muscle forces. These data provide new evidence that the human ITB is anatomically derived compared with the chimp FL and potentially contributes to locomotor economy during bipedal locomotion. PMID- 26026036 TI - Pre-landing wrist muscle activity in hopping toads. AB - Coordinated landing requires preparation. Muscles in the limbs important for decelerating the body should be activated prior to impact so that joints may be stiffened and limbs stabilized during landing. Moreover, because landings vary in impact force and timing, muscle recruitment patterns should be modulated accordingly. In toads, which land using their forelimbs, previous work has demonstrated such modulation in muscles acting at the elbow, but not at the shoulder. In this study, we used electromyography and high-speed video to test the hypothesis that antagonistic muscles acting at the wrists of toads are activated in advance of impact, and that these activation patterns are tuned to the timing and force of impact. We recorded from two wrist extensors: extensor carpi ulnaris (ECU) and extensor digitorum communis longus (EDCL), and two wrist flexors: flexor carpi ulnaris (FCU) and palmaris longus (PL). Each muscle was recorded in 4-5 animals (>=15 hops per animal). In all muscles, activation intensity was consistently greatest shortly before impact, suggesting the importance of these muscles during landing. Pre-landing recruitment intensity regularly increased with aerial phase duration (i.e. hop distance) in all muscles except PL. In addition, onset timing in both wrist flexors was also modulated with hop distance, with later onset times being associated with longer hops. Thus, activation patterns in major flexors and extensors of the wrist are tuned to hop distance with respect to recruitment intensity, onset timing or both. PMID- 26026037 TI - Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis? AB - Neonatal mice have a greater thermogenic need than adult mice and may require additional means of heat production, other than the established mechanism of brown adipose tissue (BAT). We and others recently discovered a novel mediator of skeletal muscle-based thermogenesis called sarcolipin (SLN) that acts by uncoupling sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA). In addition, we have shown that SLN expression is downregulated during neonatal development in rats. In this study we probed two questions: (1) is SLN expression developmentally regulated in neonatal mice?; and (2) if so, will cold adaptation override this? Our data show that SLN expression is higher during early neonatal stages and is gradually downregulated in fast twitch skeletal muscles. Interestingly, we demonstrate that cold acclimation of neonatal mice can prevent downregulation of SLN expression. This observation suggests that SLN-mediated thermogenesis can be recruited to a greater extent during extreme physiological need, in addition to BAT. PMID- 26026038 TI - Skeletal muscle phenotype affects fasting-induced mitochondrial oxidative phosphorylation flexibility in cold-acclimated ducklings. AB - Starvation is particularly challenging for endotherms that remain active in cold environments or during winter. The aim of this study was to determine whether fasting-induced mitochondrial coupling flexibility depends upon the phenotype of skeletal muscles. The rates of oxidative phosphorylation and mitochondrial efficiency were measured in pectoralis (glycolytic) and gastrocnemius (oxidative) muscles from cold-acclimated ducklings (Cairina moschata). Pyruvate and palmitoyl l-carnitine were used in the presence of malate as respiratory substrates. Plasma metabolites, skeletal muscle concentrations of triglycerides, glycogen and total protein and mitochondrial levels of oxidative phosphorylation complexes were also quantified. Results from ad libitum fed ducklings were compared with those from ducklings that were fasted for 4 days. During the 4 days of nutritional treatment, birds remained in the cold, at 4 degrees C. The 4 days of starvation preferentially affected the pectoralis muscles, inducing an up-regulation of mitochondrial efficiency, which was associated with a reduction of both total muscle and mitochondrial oxidative phosphorylation protein, and with an increase of intramuscular lipid concentration. By contrast, fasting decreased the activity of oxidative phosphorylation but did not alter the coupling efficiency and protein expression of mitochondria isolated from the gastrocnemius muscles. Hence, the adjustment of mitochondrial efficiency to fasting depends upon the muscle phenotype of cold-acclimated birds. Furthermore, these results suggest that the reduced cost of mitochondrial ATP production in pectoralis muscles may trigger lipid storage within this tissue and help to sustain an important metabolic homeostatic function of skeletal muscles, which is to maintain levels of amino acids in the circulation during the fast. PMID- 26026039 TI - Visual ecology of directed aerial descent in first-instar nymphs of the stick insect Extatosoma tiaratum. AB - Many wingless insects perform directed aerial descent (DAD) to return to vegetational structures after falling. Given the complex visual environment and spatial structures of tree canopies, those visual signals used as directional cues are not fully understood. Here, we address the role of visual contrast for DAD in newly hatched nymphs of the stick insect Extatosoma tiaratum under controlled laboratory conditions. Landing preferences of gliding E. tiaratum in various visual environments were studied. We used a single vertical stripe defined by variable contrast edges to test the use of contrast consistency and sharpness. We also used aggregate patterns to examine the effects of target size and the effectiveness of luminance contrast and chromatic contrast. E. tiaratum nymphs were attracted to single stripes with well-defined edges, and particularly favored narrow dark targets. The directionality and accuracy of landing were dependent on target size. Lastly, luminance contrasts were more effective in attracting landings than were chromatic contrasts. Visual contrasts are therefore used as spatial references for landing behavior in DAD. These behaviors may enable nymphs to quickly locate dark or shaded sides of vertically oriented vegetation in natural habitats. PMID- 26026040 TI - Ontogenetic propulsive transitions by Sarsia tubulosa medusae. AB - While swimming in their natural environment, marine organisms must successfully forage, escape from predation, and search for mates to reproduce. In the process, planktonic organisms interact with their fluid environment, generating fluid signatures around their body and in their downstream wake through ontogeny. In the early stages of their life cycle, marine organisms operate in environments where viscous effects dominate and govern physical processes. Ontogenetic propulsive transitions in swimming organisms often involve dramatic changes in morphology and swimming behavior. However, for organisms that do not undergo significant changes in morphology, swimming behavior or propulsive mode, how is their swimming performance affected? We investigated the ontogenetic propulsive transitions of the hydromedusa Sarsia tubulosa, which utilizes jet propulsion and possesses a similar bell morphology throughout its life cycle. We used digital particle image velocimetry and high-speed imaging to measure the body kinematics, velocity fields and wake structures induced by swimming S. tubulosa with bell exit diameters from 1 to 10 mm. Our experimental observations revealed three distinct classes of hydrodynamic wakes: elongated vortex rings for 1030 (larger than 2 mm bell exit diameter) and elliptical vortex rings (or leading vortex rings) followed by trailing jets for most instances where Re>100 (larger than 4 or 5 mm bell exit diameter). The relative travel distance and propulsive efficiency remained unchanged throughout ontogeny, and the swimming proficiency and hydrodynamic cost of transport decreased non-linearly. PMID- 26026041 TI - Experimental manipulations of tissue oxygen supply do not affect warming tolerance of European perch. AB - A progressive inability of the cardiorespiratory system to maintain systemic oxygen supply at elevated temperatures has been suggested to reduce aerobic scope and the upper thermal limit of aquatic ectotherms. However, few studies have directly investigated the dependence of thermal limits on oxygen transport capacity. By manipulating oxygen availability (via environmental hyperoxia) and blood oxygen carrying capacity (via experimentally induced anaemia) in European perch (Perca fluviatilis Linneaus), we investigated the effects of oxygen transport capacity on aerobic scope and the critical thermal maximum (CT(max)). Hyperoxia resulted in a twofold increase in aerobic scope at the control temperature of 23 degrees C, but this did not translate to an elevated CT(max) in comparison with control fish (34.6+/-0.1 versus 34.0+/-0.5 degrees C, respectively). Anaemia (~43% reduction in haemoglobin concentration) did not cause a reduction in aerobic scope or CT(max) (33.8+/-0.3 degrees C) compared with control fish. Additionally, oxygen consumption rates of anaemic perch during thermal ramping increased in a similar exponential manner to that in control fish, highlighting that perch have an impressive capacity to compensate for a substantial reduction in blood oxygen carrying capacity. Taken together, these results indicate that oxygen limitation is not a universal mechanism determining the CT(max) of fishes. PMID- 26026042 TI - Sensory processing within cockroach antenna enables rapid implementation of feedback control for high-speed running maneuvers. AB - Animals are remarkably stable during high-speed maneuvers. As the speed of locomotion increases, neural bandwidth and processing delays can limit the ability to achieve and maintain stable control. Processing the information of sensory stimuli into a control signal within the sensor itself could enable rapid implementation of whole-body feedback control during high-speed locomotion. Here, we show that processing in antennal afferents is sufficient to act as the control signal for a fast sensorimotor loop. American cockroaches Periplaneta americana use their antennae to mediate escape running by tracking vertical surfaces such as walls. A control theoretic model of wall following predicts that stable control is possible if the animal can compute wall position (P) and velocity, its derivative (D). Previous whole-nerve recordings from the antenna during simulated turning experiments demonstrated a population response consistent with P and D encoding, and suggested that the response was synchronized with the timing of a turn executed while wall following. Here, we record extracellularly from individual mechanoreceptors distributed along the antenna and show that these receptors encode D and have distinct latencies and filtering properties. The summed output of these receptors can be used as a control signal for rapid steering maneuvers. The D encoding within the antenna in addition to the temporal filtering properties and P dependence of the population of afferents support a sensory-encoding notion from control theory. Our findings support the notion that peripheral sensory processing can enable rapid implementation of whole-body feedback control during rapid running maneuvers. PMID- 26026043 TI - Daily temperature extremes play an important role in predicting thermal effects. AB - Organisms in natural environments experience diel temperature fluctuations, including sporadic extreme conditions, rather than constant temperatures. Studies based mainly on model organisms have tended to focus on responses to average temperatures or short-term heat stress, which overlooks the potential impact of daily fluctuations, including stressful daytime periods and milder night-time periods. Here, we focus on daily maximum temperatures, while holding night-time temperatures constant, to specifically investigate the effects of high temperature on demographic parameters and fitness in the English grain aphid Sitobion avenae. We then compared the observed effects of different daily maximum temperatures with predictions from constant temperature-performance expectations. Moderate daily maximum temperatures depressed aphid performance while extreme conditions had dramatic effects, even when mean temperatures were below the critical maximum. Predictions based on daily average temperature underestimated negative effects of temperature on performance by ignoring daily maximum temperature, while predictions based on daytime maximum temperatures overestimated detrimental impacts by ignoring recovery under mild night-time temperatures. Our findings suggest that daily maximum temperature will play an important role in regulating natural population dynamics and should be considered in predictions. These findings have implications for natural population dynamics, particularly when considering the expected increase in extreme temperature events under climate change. PMID- 26026044 TI - Multiple-stressor interactions influence embryo development rate in the American horseshoe crab, Limulus polyphemus. AB - Fertilized eggs of the American horseshoe crab, Limulus polyphemus, are buried in shallow nests above the high tide line, where they are exposed to variations in abiotic conditions during early development. Using a multiple-stressors approach, we examined whether the rate of embryonic development is affected by exposure to combinations of three factors: temperature (25, 30 and 35 degrees C), salinity (5, 15 and 34 ppt) and ambient O2 (5%, 13% and 21% O2). Newly fertilized eggs were incubated under 27 fully factorial stressor combinations for 14 days, then allowed to recover in control conditions (30 degrees C, 34 ppt, 21% O2) for an additional 14 days. Growth rate was measured every 2 days throughout the experiment (N=1289). We found that the effect of isolated stressors (high temperature, low salinity or low O2) reduced developmental success by up to 72% (low salinity), and that stressor combinations showed stronger effects and evidence of complex interactions. For example, low O2 had little effect individually but was lethal in combination with high temperature, and low temperature in isolation slightly decreased the rate of development but reduced the negative effects of low salinity and low O2. Development was delayed under exposure to low O2 but resumed upon return to control conditions after a 10 day lag. These data demonstrate that complex, synergistic interactions among abiotic stressors can substantially alter the development of a coastal invertebrate in ways that may not be predicted from the effects of the stressors in isolation. PMID- 26026046 TI - Genome-Wide Association Study of Insect Bite Hypersensitivity in Swedish-Born Icelandic Horses. AB - Insect bite hypersensitivity (IBH) is the most common allergic skin disease in horses and is caused by biting midges, mainly of the genus Culicoides. The disease predominantly comprises a type I hypersensitivity reaction, causing severe itching and discomfort that reduce the welfare and commercial value of the horse. It is a multifactorial disorder influenced by both genetic and environmental factors, with heritability ranging from 0.16 to 0.27 in various horse breeds. The worldwide prevalence in different horse breeds ranges from 3% to 60%; it is more than 50% in Icelandic horses exported to the European continent and approximately 8% in Swedish-born Icelandic horses. To minimize the influence of environmental effects, we analyzed Swedish-born Icelandic horses to identify genomic regions that regulate susceptibility to IBH. We performed a genome-wide association (GWA) study on 104 affected and 105 unaffected Icelandic horses genotyped using Illumina(r) EquineSNP50 Genotyping BeadChip. Quality control and population stratification analyses were performed with the GenABEL package in R (lambda = 0.81). The association analysis was performed using the Bayesian variable selection method, Bayes C, implemented in GenSel software. The highest percentage of genetic variance was explained by the windows on X chromosomes (0.51% and 0.36% by 73 and 74 mb), 17 (0.34% by 77 mb), and 18 (0.34% by 26 mb). Overlapping regions with previous GWA studies were observed on chromosomes 7, 9, and 17. The windows identified in our study on chromosomes 7, 10, and 17 harbored immune system genes and are priorities for further investigation. PMID- 26026045 TI - Recombinant interleukin-1beta dilates steelhead trout coronary microvessels: effect of temperature and role of the endothelium, nitric oxide and prostaglandins. AB - Interleukin (IL)-1beta is associated with hypotension and cardiovascular collapse in mammals during heat stroke, and the mRNA expression of this pro-inflammatory cytokine increases dramatically in the blood of Atlantic cod (Gadus morhua) at high temperatures. These data suggest that release of IL-1beta at high temperatures negatively impacts fish cardiovascular function and could be a primary determinant of upper thermal tolerance in this taxa. Thus, we measured the concentration-dependent response of isolated steelhead trout (Oncorhynchus mykiss) coronary microvessels (<150 MUm in diameter) to recombinant (r) IL-1beta at two temperatures (10 and 20 degrees C). Recombinant IL-1beta induced a concentration-dependent vasodilation with vessel diameter increasing by approximately 8 and 30% at 10(-8) and 10(-7) mol l(-1), respectively. However, this effect was not temperature dependent. Both vessel denudation and cyclooxygenase blockade (by indomethacin), but not the nitric oxide (NO) antagonist L-NIO, inhibited the vasodilator effect of rIL-1beta. In contrast, the concentration-dependent dilation caused by the endothelium-dependent calcium ionophore A23187 was completely abolished by L-NIO and indomethacin, suggesting that both NO and prostaglandin signaling mechanisms exist in the trout coronary microvasculature. These data: (1) are the first to demonstrate a functional link between the immune and cardiovascular systems in fishes; (2) suggest that IL 1beta release at high temperatures may reduce systemic vascular resistance, and thus, the capacity of fish to maintain blood pressure; and (3) provide evidence that both NO and prostaglandins play a role in regulating coronary vascular tone, and thus, blood flow. PMID- 26026051 TI - Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells. AB - mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0-G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027-induced cell cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. Mol Cancer Ther; 14(8); 1805-15. (c)2015 AACR. PMID- 26026052 TI - The TMPRSS2-ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition. AB - Exposure to genotoxic agents, such as ionizing radiation (IR), produces DNA damage, leading to DNA double-strand breaks (DSB); IR toxicity is augmented when the DNA repair is impaired. We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer cells expressing the TMPRSS2-ERG gene fusion protein. Here, we show that TMPRSS2-ERG blocks nonhomologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2-ERG and PC3 cells that stably express it, displayed gammaH2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2-ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2-ERG's ability to inhibit DNA-PKcs function, as indicated by its own phosphorylation (Thr2609, Ser2056) and that of its substrate, Ser1778-53BP1. DNA-PKcs deficiency caused by TMPRSS2-ERG destabilized critical NHEJ components on chromatin. Thus, XRCC4 was not recruited to chromatin, with retention of other NHEJ core factors being reduced. DNA-PKcs autophosphorylation was restored to the level of parental cells when TMPRSS2-ERG was depleted by siRNA. Following IR, TMPRSS2-ERG-expressing PC3 cells had elevated Rad51 foci and homologous recombination (HR) activity, indicating that HR compensated for defective NHEJ in these cells, hence addressing why TMPRSS2 ERG alone did not lead to radiosensitization. However, the presence of TMPRSS2 ERG, by inhibiting NHEJ DNA repair, enhanced PARPi-mediated radiosensitization. IR in combination with PARPi resulted in enhanced DNA damage in TMPRSS2-ERG expressing cells. Therefore, by inhibiting NHEJ, TMPRSS2-ERG provides a synthetic lethal interaction with PARPi in prostate cancer patients expressing TMPRSS2-ERG. PMID- 26026054 TI - Airway-Resident Memory CD8 T Cells Provide Antigen-Specific Protection against Respiratory Virus Challenge through Rapid IFN-gamma Production. AB - CD8 airway resident memory T (TRM) cells are a distinctive TRM population with a high turnover rate and a unique phenotype influenced by their localization within the airways. Their role in mediating protective immunity to respiratory pathogens, although suggested by many studies, has not been directly proven. This study provides definitive evidence that airway CD8 TRM cells are sufficient to mediate protection against respiratory virus challenge. Despite being poorly cytolytic in vivo and failing to expand after encountering Ag, airway CD8 TRM cells rapidly express effector cytokines, with IFN-gamma being produced most robustly. Notably, established airway CD8 TRM cells possess the ability to produce IFN-gamma faster than systemic effector memory CD8 T cells. Furthermore, naive mice receiving intratracheal transfer of airway CD8 TRM cells lacking the ability to produce IFN-gamma were less effective at controlling pathogen load upon heterologous challenge. This direct evidence of airway CD8 TRM cell-mediated protection demonstrates the importance of these cells as a first line of defense for optimal immunity against respiratory pathogens and suggests they should be considered in the development of future cell-mediated vaccines. PMID- 26026053 TI - Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia. AB - Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5MUmol/L) and Stat5b (IC50 = 3.5 MUmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies. PMID- 26026056 TI - Deficiency of CD40 Reveals an Important Role for LIGHT in Anti-Leishmania Immunity. AB - We previously showed that LIGHT and its receptor herpes virus entry mediator (HVEM) are important for development of optimal CD4(+) Th1 cell immunity and resistance to primary Leishmania major infection in mice. In this study, we further characterized the contributions of this molecule in dendritic cell (DC) maturation, initiation, and maintenance of primary immunity and secondary anti Leishmania immunity. Flow-cytometric studies showed that CD8alpha(+) DC subset was mostly affected by HVEM-Ig and lymphotoxin beta receptor-Ig treatment. LIGHT signaling is required at both the priming and the maintenance stages of primary anti-Leishmania immunity but is completely dispensable during secondary immunity in wild type mice. However, LIGHT blockade led to impaired IL-12 and IFN-gamma responses and loss of resistance in healed CD40-deficient mice after L. major challenge. The protective effect of LIGHT was mediated primarily via its interaction with lymphotoxin beta receptor on CD8alpha(+) DCs. Collectively, our results show that although LIGHT is critical for maintenance of primary Th1 response, it is dispensable during secondary anti-Leishmania immunity in the presence of functional CD40 signaling as seen in wild type mice. PMID- 26026055 TI - Structural Analysis of Der p 1-Antibody Complexes and Comparison with Complexes of Proteins or Peptides with Monoclonal Antibodies. AB - Der p 1 is a major allergen from the house dust mite, Dermatophagoides pteronyssinus, that belongs to the papain-like cysteine protease family. To investigate the antigenic determinants of Der p 1, we determined two crystal structures of Der p 1 in complex with the Fab fragments of mAbs 5H8 or 10B9. Epitopes for these two Der p 1-specific Abs are located in different, nonoverlapping parts of the Der p 1 molecule. Nevertheless, surface area and identity of the amino acid residues involved in hydrogen bonds between allergen and Ab are similar. The epitope for mAb 10B9 only showed a partial overlap with the previously reported epitope for mAb 4C1, a cross-reactive mAb that binds Der p 1 and its homolog Der f 1 from Dermatophagoides farinae. Upon binding to Der p 1, the Fab fragment of mAb 10B9 was found to form a very rare alpha helix in its third CDR of the H chain. To provide an overview of the surface properties of the interfaces formed by the complexes of Der p 1-10B9 and Der p 1-5H8, along with the complexes of 4C1 with Der p 1 and Der f 1, a broad analysis of the surfaces and hydrogen bonds of all complexes of Fab-protein or Fab-peptide was performed. This work provides detailed insight into the cross-reactive and specific allergen Ab interactions in group 1 mite allergens. The surface data of Fab-protein and Fab-peptide interfaces can be used in the design of conformational epitopes with reduced Ab binding for immunotherapy. PMID- 26026057 TI - Cutting Edge: Developmental Regulation of IFN-gamma Production by Mouse Neutrophil Precursor Cells. AB - Neutrophils are an emerging cellular source of IFN-gamma, a key cytokine that mediates host defense to intracellular pathogens. Production of IFN-gamma by neutrophils, in contrast to lymphoid cells, is TLR- and IL-12-independent and the events associated with IFN-gamma production by neutrophils are not understood. In this study, we show that mouse neutrophils express IFN-gamma during their lineage development in the bone marrow niche at the promyelocyte stage independently of microbes. IFN-gamma accumulates in primary neutrophilic granules and is released upon induction of degranulation. The developmental mechanism of IFN-gamma production in neutrophils arms the innate immune cells prior to infection and assures the potential for rapid release of IFN-gamma upon neutrophil activation, the first step during responses to many microbial infections. PMID- 26026058 TI - Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation. AB - Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk. In this study, we sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. rHDL bound to CC and inhibited the CC induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. rHDL attenuated the amount of CC-induced complement receptor 3 (CD11b/CD18) expression on monocytes and granulocytes, as well as reactive oxygen species generation. Moreover, addition of CC to whole blood resulted in release of proinflammatory cytokines that were inhibited by rHDL. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC induced inflammatory responses by inhibiting complement deposition on the crystals. PMID- 26026059 TI - PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation. AB - Protein arginine methyltransferase (PRMT)1, methylating both histones and key cellular proteins, has emerged as a key regulator of various cellular processes. This study aimed to identify the mechanism that regulates PRMT1 in chronic Ag induced pulmonary inflammation (AIPI) in the E3 rat asthma model. E3 rats were challenged with OVA for 1 or 8 wk to induce acute or chronic AIPI. Expression of mRNAs was detected by real-time quantitative PCR. PRMT1, TGF-beta, COX2, and vascular endothelial growth factor protein expression in lung tissues was determined by immunohistochemistry staining and Western blotting. In the in vitro study, IL-4-stimulated lung epithelial cell (A549) medium (ISEM) with or without anti-TGF-beta Ab was applied to human fibroblasts from lung (HFL1). The proliferation of HFL1 was determined by MTT. AMI-1 (pan-PRMT inhibitor) was administered intranasally to chronic AIPI rats to determine PRMT effects on asthmatic parameters. In lung tissue sections, PRMT1 expression was significantly upregulated, mainly in epithelial cells, in acute AIPI lungs, whereas it was significantly upregulated mainly in fibroblasts in chronic AIPI lungs. The in vitro study revealed that ISEM elevates PRMT1, COX2, and vascular endothelial growth factor expressions, and it promoted fibroblast proliferation. The application of anti-TGF-beta Ab suppressed COX2 upregulation by ISEM. AMI-1 inhibited the expression of COX2 in TGF-beta-stimulated cells. In the in vivo experiment, AMI-1 administered to AIPI rats reduced COX2 production and humoral immune response, and it abrogated mucus secretion and collagen generation. These findings suggested that TGF-beta-induced PRMT1 expression participates in fibroblast proliferation and chronic airway inflammation in AIPI. PMID- 26026060 TI - Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models. AB - The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues to regulate cell growth and survival through various mechanisms. However, how mTORC1 responds to acute inflammatory signals to regulate bowel regeneration is still obscure. In this study, we investigated the role of mTORC1 in acute inflammatory bowel disease. Inhibition of mTORC1 activity by rapamycin treatment or haploinsufficiency of Rheb through genetic modification in mice impaired intestinal cell proliferation and induced cell apoptosis, leading to high mortality in dextran sodium sulfate- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis models. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1-deficient Rheb(+/-) mice. Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease. PMID- 26026063 TI - Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T Lineage Commitment. AB - Extrathymic T cell precursors can be detected in many tissues and represent an immediately competent population for rapid T cell reconstitution in the event of immunodeficiencies. Blood T cell progenitors have been detected, but their source in the bone marrow (BM) remains unclear. Prospective purification of BM-resident and circulating progenitors, together with RT-PCR single-cell analysis, was used to evaluate and compare multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). Molecular analysis of circulating progenitors in comparison with BM-resident progenitors revealed that CCR9(+) progenitors are more abundant in the blood than CCR7(+) progenitors. Second, although Flt3(-) CLPs are less common in the BM, they are abundant in the blood and have reduced Cd25(+) expressing cells and downregulated c-Kit and IL-7Ralpha intensities. Third, in contrast, stage 3 MPP (MPP3) cells, the unique circulating MPP subset, have upregulated Il7r, Gata3, and Notch1 in comparison with BM-resident counterparts. Evaluation of the populations' respective abilities to generate splenic T cell precursors (Lin(-)Thy1.2(+)CD25(+)IL7Ralpha(+)) after grafting recipient nude mice revealed that MPP3 cells were the most effective subset (relative to CLPs). Although several lymphoid genes are expressed by MPP3 cells and Flt3(-) CLPs, the latter only give rise to B cells in the spleen, and Notch1 expression level is not modulated in the blood, as for MPP3 cells. We conclude that CLPs have reached the point where they cannot be a Notch1 target, a limiting condition on the path to T cell engagement. PMID- 26026062 TI - The Tec Kinase-Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages. AB - Previous work has shown conflicting roles for Tec family kinases in regulation of TLR-dependent signaling in myeloid cells. In the present study, we performed a detailed investigation of the role of the Tec kinases Btk and Tec kinases in regulating TLR signaling in several types of primary murine macrophages. We demonstrate that primary resident peritoneal macrophages deficient for Btk and Tec secrete less proinflammatory cytokines in response to TLR stimulation than do wild-type cells. In contrast, we found that bone marrow-derived and thioglycollate-elicited peritoneal macrophages deficient for Btk and Tec secrete more proinflammatory cytokines than do wild-type cells. We then compared the phosphoproteome regulated by Tec kinases and LPS in primary peritoneal and bone marrow-derived macrophages. From this analysis we determined that Tec kinases regulate different signaling programs in these cell types. In additional studies using bone marrow-derived macrophages, we found that Tec and Btk promote phosphorylation events necessary for immunoreceptor-mediated inhibition of TLR signaling. Taken together, our results are consistent with a model where Tec kinases (Btk, Tec, Bmx) are required for TLR-dependent signaling in many types of myeloid cells. However, our data also support a cell type-specific TLR inhibitory role for Btk and Tec that is mediated by immunoreceptor activation and signaling via PI3K. PMID- 26026061 TI - Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma. AB - Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-alpha. Apart from IFN alpha production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-alpha secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naive mice can be effectively activated and loaded with SIINFEKL Ag in vitro. Upon intradermal injection in the hindleg, a fraction of both types of DCs migrate to the brain and lymph nodes. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generate a robust Th1 type immune response, characterized by high frequency of CD4(+)T-bet(+) T cells and CD8(+)SIINFEKEL(+) T cells. This robust antitumor T cell response results in tumor eradication and long-term survival in 60% of the animals (p < 0.001). PMID- 26026064 TI - A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor beta Subunit, Glycoprotein 130. AB - IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6 stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-alpha production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL 6, IL-6Ralpha, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL 6/IL-6Ralpha complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130. PMID- 26026065 TI - Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery. AB - Assessment of immune responses in lymph nodes (LNs) is routine in animals, but rarely done in humans. We have applied minimally invasive ultrasound-guided fine needle aspiration of the LN to a before-and-after study of the immune response to intradermally delivered Ag in healthy volunteers (n = 25). By comparison with PBMCs from the same individual, LN cells (LNCs) were characterized by reduced numbers of effector memory cells, especially CD8(+) TEMRA cells (3.37 +/- 1.93 in LNCs versus 22.53 +/- 7.65 in PBMCs; p = 0.01) and a marked increased in CD69 expression (27.67 +/- 7.49 versus 3.49 +/- 2.62%, LNCs and PBMCs, respectively; p < 0.0001). At baseline, there was a striking absence of IFN-gamma ELISPOT responses to recall Ags (purified protein derivative, Tetanus toxoid, or flu/EBV/CMV viral mix) in LN, despite strong responses in the peripheral blood. However, 48 h after tuberculin purified protein derivative administration in the ipsilateral forearm resulting in a positive skin reaction, a clear increase in IFN-gamma ELISPOT counts was seen in the draining LN but not in PBMCs. This response was lost by 5 d. These data suggest that the low levels of effector memory cells in the LN may explain the low background of baseline ELISPOT responses in LNs as compared with PBMCs, and the appearance of a response after 48 h is likely to represent migration of effector memory cells from the skin to the LN. Hence, it appears that the combination of intradermal Ag administration and draining LN sampling can be used as a sensitive method to probe the effector memory T cell repertoire in the skin. PMID- 26026066 TI - Reduced Fluorescence versus Forward Scatter Time-of-Flight and Increased Peak versus Integral Fluorescence Ratios Indicate Receptor Clustering in Flow Cytometry. AB - Clustering of surface receptors is often required to initiate signal transduction, receptor internalization, and cellular activation. To study the kinetics of clustering, we developed an economic high-throughput method using flow cytometry. The quantification of receptor clustering by flow cytometry is based on the following two observations: first, the fluorescence signal length (FL time-of-flight [ToF]) decreases relative to the forward scatter signal length (FSc-ToF), and second, the peak FL (FL-peak) increases relative to the integral FL (FL-integral) upon clustering of FL-labeled surface receptors. Receptor macroclustering can therefore be quantified using the ratios FL-ToF/FSc-ToF (method ToF) or FL-peak/FL-integral (method Peak). We have used these methods to analyze clustering of two immune receptors known to undergo different conformational and oligomeric states: the BCR and the complement receptor 3 (CR3), on murine splenocytes, purified B cells, and human neutrophils. Engagement of both the BCR and CR3, on immortalized as well as primary murine B cells and human neutrophil, respectively, resulted in decreased FL-ToF/FSc-ToF and increased FL-peak/FL-integral ratios. Manipulation of the actin-myosin cytoskeleton altered BCR clustering which could be measured using the established parameters. To confirm clustering of CR3 on neutrophils, we applied imaging flow cytometry. Because receptor engagement is as a biological process dependent on cell viability, energy metabolism, and temperature, receptor clustering can only be quantified by gating on viable cells under physiological conditions. In summary, with this novel method, receptor clustering on nonadherent cells can easily be monitored by high-throughput conventional flow cytometry. PMID- 26026067 TI - Primordial germ cell development in the marmoset monkey as revealed by pluripotency factor expression: suggestion of a novel model of embryonic germ cell translocation. PMID- 26026070 TI - Aortic wall thickness in patients with ascending aortic aneurysm versus acute aortic dissection. AB - OBJECTIVES: Recent studies have shown that aortic diameter alone is an insufficient parameter to identify patients at risk for aortic dissection. The aim of this study was to determine the value of the ratio of aortic diameter to medial wall thickness as a new marker of risk. METHODS: We obtained data from 181 patients with an ascending aortic aneurysm (n = 94) or an acute type A aortic dissection (n = 87), surgically treated at our institution (1996-2012). Measurements of the maximum aortic diameter and the medial wall thickness were conducted by retrospective review of preoperative imaging studies and histological specimens, respectively. RESULTS: Nearly 60% of the dissection patients had aortic diameters smaller than 50 mm. There was a significant negative linear correlation between medial wall thickness and aortic diameter (P = 0.01) in the dissection group only. Among patients with aortic diameters above 50 mm, dissection patients had significantly thinner aortic media (P = 0.04). Among patients with a mildly dilated aorta (>45 mm), the aortic diameter to medial wall thickness ratio was significantly higher in the dissection group (P = 0.04). CONCLUSIONS: Among patients with a dilatation of the ascending aorta of more than 45 and 49 mm, patients experiencing aortic dissection have a significantly higher aortic diameter to wall thickness ratio and a thinner aortic media, respectively. In the subset of patients with mild aortic dilatation, wall thickness might in the future serve as an additional parameter to help identify those patients who would benefit from prophylactic aortic surgery. PMID- 26026068 TI - Interferon at the crossroads of allergy and viral infections. AB - IFN-alpha/beta was first described as a potent inhibitor of viral replication, but it is now appreciated that IFN signaling plays a pleiotropic role in regulating peripheral T cell functions. Recently, IFN-alpha/beta was shown to block human Th2 development by suppressing the transcription factor GATA3. This effect is consistent with the role for IFN-alpha/beta in suppressing allergic inflammatory processes by blocking granulocyte activation and IL-4-mediated B cell isotype switching to IgE. With the consideration of recent studies demonstrating a defect in IFN-alpha/beta secretion in DCs and epithelial cells from individuals with severe atopic diseases, there is an apparent reciprocal negative regulatory loop in atopic individuals, whereby the lack of IFN alpha/beta secretion by innate cells contributes to the development of allergic Th2 cells. Is it possible to overcome these events by treating with IFN alpha/beta or by inducing its secretion in vivo? In support of this approach, case studies have documented the therapeutic potential of IFN-alpha/beta in treating steroid-resistant allergic asthma and other atopic diseases. Additionally, individuals with asthma who are infected with HCV and respond to IFN therapy showed a reduction in symptoms and severity of asthma attacks. These findings support a model, whereby allergic and antiviral responses are able to cross-regulate each other, as IgER cross-linking of pDCs prevents IFN-alpha/beta production in response to viral infection. The clinical importance of upper respiratory viruses in the context of allergic asthma supports the need to understand how these pathways intersect and to identify potential therapeutic targets. PMID- 26026069 TI - alpha-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein. AB - alpha-Tocopherol (vitamin E) has attracted considerable attention as a potential protective or palliative agent. In vitro, its free radical-scavenging antioxidant action has been widely demonstrated. In vivo, however, vitamin E treatment exhibits negligible benefits against oxidative stress. alpha-Tocopherol influences lipid ordering within biological membranes and its derivatives have been suggested to inhibit the multi-drug efflux pump, P-glycoprotein (P-gp). This study employs the fluorescent membrane probe, 1-(3-sulfonatopropyl)-4-[beta[2-(di n-octylamino)-6-naphthyl]vinyl] pyridinium betaine, to investigate whether these effects are connected via influences on the membrane dipole potential (MDP), an intrinsic property of biological membranes previously demonstrated to modulate P gp activity. alpha-Tocopherol and its non-free radical-scavenging succinate analog induced similar decreases in the MDP of phosphatidylcholine vesicles. alpha-Tocopherol succinate also reduced the MDP of T-lymphocytes, subsequently decreasing the binding affinity of saquinavir for P-gp. Additionally, alpha tocopherol succinate demonstrated a preference for cholesterol-treated (membrane microdomain enriched) cells over membrane cholesterol-depleted cells. Microdomain disruption via cholesterol depletion decreased saquinavir's affinity for P-gp, potentially implicating these structures in the influence of alpha-tocopherol succinate on P-gp. This study provides evidence of a microdomain dipole potential dependent mechanism by which alpha-tocopherol analogs influence P-gp activity. These findings have implications for the use of alpha-tocopherol derivatives for drug delivery across biological barriers. PMID- 26026071 TI - Emergency fertility preservation for female patients with cancer: clinical perspectives. AB - To explore the new as well as the currently available options and strategies that can be used for emergency fertility preservation of female cancer patients, a systematic literature review was performed for all full-text articles published in PubMed in English language in the past 15 years according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Although under-utilized, several established, experimental and debatable options exist and can be used for emergency fertility preservation in females. Such options include emergency ovarian stimulation, embryo freezing, egg freezing, ovarian tissue freezing and autotransplantation, in vitro maturation, and ovarian protection techniques. This article describes and evaluates in detail the advantages and disadvantages of each option and suggests a new comprehensive multi-step strategy for emergency fertility preservation of female patients with cancer. PMID- 26026072 TI - Histone Deacetylase (HDAC) Inhibitors: Current Evidence for Therapeutic Activities in Pancreatic Cancer. AB - Pancreatic carcinoma is one of the leading causes of cancer death. Current standard treatments include surgical resection, chemotherapy and radiotherapy but patient's prognosis remains poor and present severe side-effects. Contemporary oncology found a wide variety of novel anticancer drugs that regulate the epigenetic mechanisms of tumor genesis. Histone deacetylases (HDACs) are enzymes with pleiotropic activities that control critical functions of the cell through regulation of the acetylation states of histone proteins and other non-histone protein targets. They are divided into four groups, each with different localization in the cell, role and structure. Histone deacetylase inhibitors (HDACIs) are substances, which inhibit the function of HDACs. We recognize four leading groups (hydroxamic acid, cyclic tetrapeptide, benzamide, aliphatic acid). There are many HDACIs currently in pre-clinical and two (vorinostat, romidepsin) in clinical stages of investigation for pancreatic cancer. Numerous studies argue for the use HDACIs as monotherapy, others suggest that combination of HDACIs with other antitumor drugs has better therapeutic results. This review focuses on the use of HDACIs as novel anticancer drugs and will explain the mechanisms of therapeutic effect on pancreatic cancer. PMID- 26026073 TI - Anticancer Effects of Sandalwood (Santalum album). AB - Effective management of tumorigenesis requires development of better anticancer agents with greater efficacy and fewer side-effects. Natural products are important sources for the development of chemotherapeutic agents and almost 60% of anticancer drugs are of natural origin. alpha-Santlol, a sesquiterpene isolated from Sandalwood, is known for a variety of therapeutic properties including anti-inflammatory, anti-oxidant, anti-viral and anti-bacterial activities. Cell line and animal studies reported chemopreventive effects of sandalwood oil and alpha-santalol without causing toxic side-effects. Our laboratory identified its anticancer effects in chemically-induced skin carcinogenesis in CD-1 and SENCAR mice, ultraviolet-B-induced skin carcinogenesis in SKH-1 mice and in vitro models of melanoma, non-melanoma, breast and prostate cancer. Its ability to induce cell-cycle arrest and apoptosis in cancer cells is its most reported anticancer mechanism of action. The present review discusses studies that support the anticancer effect and the mode of action of sandalwood oil and alpha-santalol in carcinogenesis. PMID- 26026074 TI - The Story of MCF-7 Breast Cancer Cell Line: 40 years of Experience in Research. AB - Breast cancer is the most frequent malignancy in females. Due to its major impact on population, this disease represents a critical public health problem that requires further research at the molecular level in order to define its prognosis and specific treatment. Basic research is required to accomplish this task and this involves cell lines as they can be widely used in many aspects of laboratory research and, particularly, as in vitro models in cancer research. MCF-7 is a commonly used breast cancer cell line, that has been promoted for more than 40 years by multiple research groups but its characteristics have never been gathered in a consistent review article. The current paper provides a broad description of the MCF-7 cell line, including the molecular profile, proliferation, migration, invasion, spheroid formation, its involvement in angiogenesis and lymphangiogenesis and its interaction with the mesenchymal stem cells. PMID- 26026075 TI - Whole-genome Linkage Analysis and Sequence Analysis of Candidate Loci in Familial Breast Cancer. AB - BACKGROUND: Known breast cancer-predisposing genes account for fewer than 25% of all familial breast cancer cases and further studies are required to find the remaining high- and moderate-risk genes. We set-out to couple linkage analysis using microsatellite marker data and sequence analysis of linked regions in 13 non-BRCA1/2 families in order to find novel susceptibility loci and high penetrant genes. MATERIALS AND METHODS: Genotyping with 540 fluorescently-labeled microsatellite markers located on the 23 chromosomes at 7.25 cM resolution was used for primary linkage analysis and an additional 40 markers were used for fine mapping of loci with a logarithm of odds (LOD) or heterogeneity LOD (HLOD) score greater than one. Whole-exome sequencing data of 28 members from all 13 families were used for the bioinformatics sequence analysis on the linked regions of these families. RESULTS: Linkage analysis identified three loci on chromosome 18q as a putative region of interest (overall LOD=1, HLOD=1.2). Sequencing analysis of the three linked regions on 18q and mutation prediction algorithms did reveal three probable damaging variants. CONCLUSION: Overall, our study identified three weakly linked loci on 18q and three probable damaging variants of interest in the 13 families with breast cancer. PMID- 26026076 TI - Genistein Suppresses Growth of Human Uterine Sarcoma Cell Lines via Multiple Mechanisms. AB - BACKGROUND: The estrogen-like soy isoflavone genistein can suppress the growth of a number of different types of cancer cells, but its effect on uterine sarcoma is unknown. MATERIALS AND METHODS: The impact of genistein on the proliferation of three uterine sarcoma cell lines, MES-SA, MES-SA-Dx5 and SK-UT-1, was evaluated. TOPflash luciferase reporter assay and western blotting were used to assess the influence of genistein on cellular signaling; DNA fragmentation was assessed as a measure of genistein-induced apoptosis. RESULTS: Genistein inhibited the proliferation of all three cell lines, with half-maximal inhibitory concentrations of 19.2 MUM, 13.1 MUM and 9.3 MUM for SK-UT-1, MES-SA-Dx5, and MES SA, respectively. This inhibitory activity was accompanied by induction of DNA fragmentation at 48 h. Western blot analyses revealed three major expression patterns: induction of p53 and Dickkopf-related protein 1 (DKK1) and suppression of histone deacetylase 4/5/7 (HDAC4/5/7), dishevelled protein (DVL), BAX, survivin and phosphorylated mitogen-activated protein kinase kinase (phospho-MEK) in all three lines; suppression of p27 and beta-catenin in the more resistant lines MES-SA-Dx5 and SK-UT-1; and suppression of Protein kinase B (AKT) and extracellular signal-regulated kinases (ERKs) phosphorylation and activation of caspase-3 in the parental derived lines MES-SA and MES-SA-Dx5. Down-regulation of beta-catenin expression also coincided with decreases in TOPflash activity. CONCLUSION: Genistein reduces sarcoma cell numbers through inhibition of proliferative signaling and through induction of programmed or non-programmed cell death. Genistein-mediated signaling changes were unique in each individual cell line, and the differential signaling responses in these three cell lines may contribute to their different levels of susceptibility to this compound. PMID- 26026077 TI - Expression and Tissue Distribution of MicroRNA-21 in Malignant and Benign Breast Tissues>. AB - BACKGROUND/AIM: miR-21 is a common OncomiR in human cancer. The present study analyzed the distribution and expression of miR-21 in breast tumor tissues so as to examine the role of miR-21 in the carcinogenesis of breast cancer. MATERIALS AND METHODS: Sixteen malignant and 10 benign breast tissue specimens were analyzed using a miRNA chromogenic in situ hybridization (CISH) assay. The locations of miR-21 CISH-positive cells in breast tissues were observed and its expression level was semi-quantified by ISH scoring. RESULTS: Positive in situ staining of miR-21 was detected in the cytoplasm of malignant epithelial cells in most of the high-grade infiltrating ductal carcinoma specimens. miR-21-positive spindle-like cells were found to surround tumor cell islands. High miR-21 ISH scores were correlated with positive lymph node status. miR-21 expression was low in most types of benign breast tissues. CONCLUSION: miR-21 is a potential biomarker for breast cancer prognosis. PMID- 26026078 TI - Reduced Expression of RECK Protein May Help Differentiate Cutaneous Malignant Melanoma from Melanocytic Nevus. AB - BACKGROUND: Differentiating between vertical growth cutaneous malignant melanoma (CMM) and predominantly intradermal benign melanocytic nevus (BMN) can be extremely challenging. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an endogenous inhibitor of many proteins that promote tumor invasion and progression. We investigated the difference in expression of RECK between CMM and BMN to determine whether RECK could assist in their differentiation. MATERIALS AND METHODS: The expression of RECK in skin biopsies of 39 cases, including 20 cases of CMM and 19 cases of BMN, was evaluated by immunohistochemistry. RESULTS: Two out of 20 cases (10%) of CMM were positive for RECK, and all (100%) 19 cases of BMN exhibited positivity at different levels. In 7/8 cases of CMM adjacent to benign nevus cells, malignant melanoma cells did not express RECK, but benign nevus cells stained positively. CONCLUSION: These findings suggest that immunohistochemical staining for RECK could be useful in the differential diagnosis between CMM and BMN. PMID- 26026079 TI - Combination Efficacy of Astragalus membranaceus and Curcuma wenyujin at Different Stages of Tumor Progression in an Imageable Orthotopic Nude Mouse Model of Metastatic Human Ovarian Cancer Expressing Red Fluorescent Protein. AB - BACKGROUND/AIM: The present study determined the efficacy of extracts of Astragalus membranaceus (AM) and Curcuma wenyujin (CW), a traditional Chinese medicine herbal mixture, at different tumor stages of an orthotopic nude mouse model of human ovarian cancer expressing red fluorescent protein. MATERIALS AND METHODS: The tumor-bearing mice were treated with cisplatinum (CDDP), AM, CW, or a combination of AM and CW in each of three tumor stages, using the same regimen. Group 1 received saline as negative control. Group 2 received CDDP i.p. as positive control with a dose of 2 mg/kg, every three days. Group 3 received AM daily via oral gavage, at a dose of 9120 mg/kg. Group 4 received CW daily via oral gavage, at a dose of 4560 mg/kg. Groups 5, 6 and 7 received combinations of AM and CW daily via oral gavage at low (AM, 2280 mg/kg; CW, 1140 mg/kg), medium (AM, 4560 mg/kg; CW 2280 mg/kg), and high (AM, 9120 mg/kg; CW, 4560 mg/kg) doses. The expression of angiogenesis- and apoptosis-related genes in the tumors were analyzed by immunohistochemistry for matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF) fibroblast growth factor 2 (FGF-2), B-cell lymphoma 2 (Bcl-2) and cyclooxygenase 2 (Cox-2), and by polymerase chain reaction for MMP-2, FGF-2 and Bcl-2. RESULTS: CDDP, AM, and its combination with CW induced significant growth inhibition of Stage I tumors. Strong efficacy of the combination of AM and CW at high dose was observed. Monotherapy with CDDP, AM, CW, and the combination treatments did not significantly inhibit Stage II and III tumors. The expression of MMP-2, VEGF, FGF-2, and Cox-2 was significantly reduced in Stage I tumors treated with AM, CW, and their combination, suggesting a possible role of these angiogenesis- and apoptosis-related genes in the observed efficacy of the agents tested. CONCLUSION: This study is the first report on the efficacy of anticancer agents at different stages of ovarian cancer in an orthotopic mouse model. As the tumor progressed, it became treatment-resistant, similar to the clinical situation, further demonstrating the utility of the model and the need for agents acrtive in advanced-stage ovarian cancer. PMID- 26026080 TI - MicroRNA-145 Promotes the Phenotype of Human Glioblastoma Cells Selected for Invasion. AB - BACKGROUND/AIM: Novel treatment strategies aiming to eliminate or attenuate the invasive phenotype of glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, could offer a profound therapeutic benefit to patients. We previously demonstrated one method to create invasive sub populations of GBM cells (IM3 cells) and a positive regulatory role for the miR 143/-145 locus in enhancing the invasion of GBM cells. Herein, we investigated the correlation between miR-145 and srGAP1 (SLIT-ROBO Rho GTPase-activating protein1) that is purported to be a target of miR-145 and involved in migration and invasion. MATERIALS AND METHODS: IM3 cells were created by a serial selection by using Boyden chambers(r). Antisense-miR-145 was transfected into IM3 cells by using lipofectamine 2000. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot were employed to analyze the expression of srGAP1. RESULTS: The invasiveness of U87-IM3 and U251-IM3 is attenuated by transfection of antisense miR-145. In addition, srGAP1 was down-regulated in U87 IM3 and U251-IM3 cells compared to parental cells. CONCLUSION: The elevated miR 145 present in invasive glioblastoma cells (IM3 cells) targets and down-regulated srGAP1, thereby allowing downstream G-proteins to remain in their active state and promote the observed invasive phenotype. PMID- 26026081 TI - Inflammation-Related Tumor Progression in Murine Fibrosarcoma Exhibited Over expression of Sex-determining Region Y-box 2 (Sox2) Compared to Parental Regressor Cells. AB - BACKGROUND/AIM: Tumor progression is one of the most serious issues to overcome cancer disease. As a model of inflammation-induced tumor progression, we used the regressive murine fibrosarcoma cell clone QR-32 and the progressive malignant clone QRsP-11, that was derived from QR-32. Heat shock protein beta-1 (Hspb1) is a molecular chaperone. Hspb1 plays roles in not only cell protection but also chemo-resistance, tumorigenicity and protection from apoptosis. In a recent study, we showed that Hspb1 was up-regulated in QRsP-11 compared to QR-32. MATERIALS AND METHODS: We compared the expression levels of Hspb1, Hsf1 and Sox2 in QR-32 and QRsP-11 cells by means of western blotting. RESULTS: Hsf1, a transcription factor for Hspb1 was not increased in QRsP-11. Sex determining region Y-box 2 (Sox2) is a transcription factor, reported to interact with Hspb1. Sox2 was up-regulated in QRsP-11 compared to QR-32. CONCLUSION: These results suggest that Sox2-Hspb1 signaling is a possible pathway responsible to tumor progression of QRsP-11. PMID- 26026082 TI - Gene Expression Profiling of MCF10A Breast Epithelial Cells Exposed to IOERT. AB - BACKGROUND/AIM: Intraoperative electron radiation therapy (IOERT) is a therapeutic approach that delivers a single high dose of ionizing radiation (IR) directly to the tumor bed during cancer surgery. The main goal of IOERT is to counteract tumor growth by acting on residual cancer cells as well as to preserve healthy surrounding tissue from the side-effects of radiation therapy. The radiobiology of the healthy tissue response to IR is a topic of interest which may contribute to avoiding impairment of normal tissue and organ function and to reducing the risks of secondary cancer. The purpose of the study was to highlight cell and gene expression responses following IOERT treatment in the human non tumorigenic MCF10A cell line in order to find new potential biomarkers of radiosensitivity/radioresistance. MATERIAL AND METHODS: Gene-expression profiling of MCF10A cells treated with 9 and 23 Gy doses (IOERT boost and exclusive treatment, respectively), was performed by whole-genome cDNA microarrays. Real time quantitative reverse transcription (qRT-PCR), immunofluorescence and immunoblot experiments were carried out to validate candidate IOERT biomarkers. Clonogenic tests and morphological evaluations to examine cellular effects induced by radiation were also conducted. RESULTS: The study revealed a dose dependent gene-expression profile and specific key genes that may be proposed as novel markers of radiosensitivity. Our results show consistent differences in non tumorigenic cell tolerance and in the molecular response of MCF10A cells to different IOERTs. In particular, after 9 Gy of exposure, the selection of a radioresistant cell fraction was observed. CONCLUSION: The possibility of clarifying the molecular strategies adopted by cells in choosing between death or survival after IR-induced damage opens-up new avenues for the selection of a proper personalized therapy schedule. PMID- 26026083 TI - Induction of G1 Arrest by SB265610 Involves Cyclin D3 Down-regulation and Suppression of CDK2 (Thr160) Phosphorylation. AB - BACKGROUND/AIM: The current study investigated the mechanisms underlying the antitumor activity of SB265610, a cysteine-amino acid-cysteine (CXC) chemokines receptor 2 (CXCR2) antagonist. MATERIALS AND METHODS: Cell-cycle progression and regulatory molecules were assessed by flow cytometry, immunoblotting, real-time PCR and immunoprecipitation. Target validation was achieved via RNA interference. RESULTS: G1 arrest induced by SB265610 occurred at concentrations lacking CXCR2 selectivity, persisted upon interleukin 8 (IL8) challenge, and did not affect IL8 downstream target expression. Profiling of G1 regulators revealed cyclin dependent kinase 2 (CDK2) (Thr160) hypophosphorylation, cyclin D3 gene down regulation, and p21 post-translational induction. However, only cyclin D3 and CDK2 contributed towards G1 arrest. Furthermore, SB265610 induced a sustained phosphorylation of the p38MAPK. Pharmacological interference with p38MAPK significantly abrogated SB265610-induced G1 arrest and normalized the expression of cyclin D3, with restoration of its exclusive binding to CDK6, but with weak recovery of CDK2 (Thr160) hypo-phosphorylation. CONCLUSION: The present study described the mechanisms for the anti-proliferative activity of SB265610 which may be of value in IL8-rich tumor microenvironments. PMID- 26026084 TI - Reversal of ABCB1-related Multidrug Resistance of Colonic Adenocarcinoma Cells by Phenothiazines. AB - BACKGROUND: The most common mechanism that reduces the efficacy of anticancer agents is overexpression of ATP-binding cassette (ABC) drug transporters. Phenothiazines and structurally-related compounds can sensitize multidrug resistant (MDR) cells to chemotherapeutics. MATERIALS AND METHODS: Phenothiazine derivatives were investigated regarding their anticancer and MDR-reversing effect on colonic adenocarcinoma cells. The anti-proliferative and cytotoxic effects of the derivatives were assessed by the thiazolyl blue tetrazolium bromide (MTT) method, the modulation of the ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. RESULTS: All phenothiazines exhibited potent cytotoxic effect on the sensitive and MDR colon adenocarcinoma cell lines. The inhibition of the ABCB1 transporter was greater in the presence of the phenothiazine derivatives than for the known ABCB1 inhibitor verapamil. CONCLUSION: It can be concluded that these derivatives show synergism in the presence of doxorubicin and could have potential as ABCB1 inhibitors. PMID- 26026085 TI - Differential Gene Regulation in Fibroblasts in Co-culture with Keratinocytes and Head and Neck SCC Cells. AB - BACKGROUND: While carcinoma-associated fibroblasts (CAFs) support tumorigenesis, normal tissue fibroblasts suppress tumor progression. Mechanisms behind conversion of fibroblasts into a CAF phenotype are largely unrevealed. MATERIALS AND METHODS: Transwell co-cultures with fibroblasts in collagen gels and squamous cell carcinoma (SCC) cells or normal oral keratinocytes (NOKs) in inserts. Differences in fibroblast global gene expression were analyzed using Affymetrix arrays and subsequent functional annotation and cluster analysis, as well as gene set enrichment analysis were performed. RESULTS: There were 52 up-regulated and 30 down-regulated transcript IDs (>2-fold, p<0.05) in fibroblasts co-cultured with SCC compared to NOKs. Functional analysis demonstrated an enrichment of collagen-related genes. There were similarities with gene sets reflecting a non specific, innate-type response with activation of both interferon pathways and connective tissue turnover. CONCLUSION: There were distinct differences in fibroblast gene expression between the co-culture types. Many were in genes related to an innate-type of response and to connective tissue turnover. PMID- 26026086 TI - ROCK I Has More Accurate Prognostic Value than MET in Predicting Patient Survival in Colorectal Cancer. AB - BACKGROUND: Colorectal cancer remains the second leading cause of death in the United States despite improvements in incidence rates and advancements in screening. The present study evaluated the prognostic value of two tumor markers, MET and ROCK I, which have been noted in other cancers to provide more accurate prognoses of patient outcomes than tumor staging alone. MATERIALS AND METHODS: We constructed a tissue microarray from surgical specimens of adenocarcinomas from 108 colorectal cancer patients. Using immunohistochemistry, we examined the expression levels of tumor markers MET and ROCK I, with a pathologist blinded to patient identities and clinical outcomes providing the scoring of MET and ROCK I expression. We then used retrospective analysis of patients' survival data to provide correlations with expression levels of MET and ROCK I. RESULTS: Both MET and ROCK I were significantly over-expressed in colorectal cancer tissues, relative to the unaffected adjacent mucosa. Kaplan-Meier survival analysis revealed that patients' 5-year survival was inversely correlated with levels of expression of ROCK I. In contrast, MET was less strongly correlated with five year survival. CONCLUSION: ROCK I provides better efficacy in predicting patient outcomes, compared to either tumor staging or MET expression. As a result, ROCK I may provide a less invasive method of assessing patient prognoses and directing therapeutic interventions. PMID- 26026087 TI - Cellular Vaccines Modified with Hyper IL6 or Hyper IL11 Combined with Docetaxel in an Orthotopic Prostate Cancer Model. AB - BACKGROUND: Whole-cell-based vaccines modified with Hyper-IL-6 (H6) and Hyper-IL 11 (H11) have demonstrated high activity in murine melanoma and renal cancer models. MATERIALS AND METHODS: H6 and H11 cDNA was transduced into TRAMP cells (TRAMP-H6 and TRAMP-H11). An orthotopic TRAMP model was employed. The efficacy of TRAMP-H6 and TRAMP-H11 in combination with docetaxel was evaluated. Immune cells infiltrating tumors were assessed. RESULTS: Immunization with TRAMP-H6 and TRAMP H11 vaccines extended OS of mice. Addition of docetaxel to TRAMP-H6 and TRAMP-H11 vaccines further extended OS of the animals. Vaccination with TRAMP-H6 alone and TRAMP-H11 combined with docetaxel augmented tumor infiltration by activated CD8(+) and CD4(+) T-cells and attracted higher number of activated, mature DCs infiltrating tumors. Addition of docetaxel to TRAMP-H6, TRAMP-H11, TRAMP-Adv700 vaccines enhanced the infiltration of the tumor by NK cells. CONCLUSION: Addition of docetaxel to modified TRAMP vaccines improved clinical benefit of treated mice and enhanced anti-tumor immune response. PMID- 26026088 TI - Microarray analysis reveals distinct gene set profiles for gastric and intestinal gastrointestinal stromal tumors. AB - AIM: We sought to address the mechanisms by which intestinal gastrointestinal stromal tumors (GIST) have a markedly higher risk of recurrence than gastric GISTs. MATERIALS AND METHODS: Gene expression levels were compared among six primary gastric, three intestinal and six metastatic liver GISTs using cDNA microarray. Protein levels of Slit homolog 2 (SLIT2) were analyzed by immunohistochemistry in 25 primary gastric and 10 intestinal GIST. RESULTS: Intestinal GIST had gene expression profiles similar to clinically malignant and metastatic GIST. In gene set-enrichment analysis, the gene sets MITOTIC_CELL CYCLE and NEURON_DIFFERENTIATION were up-regulated and down-regulated, respectively, in intestinal GIST compared to gastric GIST. High-risk gastric GISTs and intestinal GIST, expressed similar levels of SLIT2 protein, which were lower than those of low-risk gastric GISTs. CONCLUSION: The gene-expression profile of intestinal GISTs was similar to that of metastatic liver GISTs. Besides higher proliferative activity, down-regulation of SLIT2 might be involved in clinically malignant phenotypes of intestinal GIST. PMID- 26026089 TI - MCP1-Induced Epithelial-Mesenchymal Transition in Head and Neck Cancer by AKT Activation. AB - AIM: To explore whether monocyte chemotactic protein-1 (MCP1) is associated with the epithelial-mesenchymal transition (EMT) and neck metastases in head and neck cancer (HNC). MATERIALS AND METHODS: MCP1 and its related protein were evaluated using western blotting, and a migration assay for HNC cell lines. Thirty-five patients with HNC were recruited for the evaluation of MCP1 expression and pathologically-proven neck metastases from their tissue specimens. RESULTS: MCP1 changed the phenotype of OML-1 cells to a spindle shape, with increased mobility. In OML3 cells, MCP1 knockdown with siRNA blocked EMT. Activation of protein kinase B (AKT) was positively associated with the EMT phenotype, and this transition was abrogated with a phosphoinositide 3 kinase (PI3K) inhibitor. By comparing clinical outcomes, the histological MCP1 score was associated with pathological neck metastases (p=0.027). CONCLUSION: The overexpression of MCP1 in HNC cells may partially induce EMT through the AKT pathway. A high cellular expression of MCP1 was associated with pathological neck metastases. PMID- 26026090 TI - Bortezomib Causes ER Stress-related Death of Acute Promyelocytic Leukemia Cells Through Excessive Accumulation of PML-RARA. AB - BACKGROUND/AIM: The success of proteasome inhibitors in therapy of multiple myeloma has led to their use for other malignancies. For the proteasome inhibitor bortezomib, combination therapies with histone deacetylase inhibitors, which up regulate ubiquitin-proteasome system (UPS)-related enzymes, produce a beneficial effect. However, the mechanisms underlying the effect of bortezomib are not completely understood. We hypothesized that bortezomib causes excessive accumulation of aberrant proteins, which augments endoplasmic reticulum (ER) stress, leading to death of malignant cells. MATERIALS AND METHODS: The NB4 cell line established from a patient with acute promyelocytic leukemia (APL) expressing the promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) fusion protein was used to assess changes in cell viability and apoptosis caused by bortezomib, as well as alterations in PML-RARA and UPS-related enzymes via western blotting and immunoprecipitation assays. RESULTS: Bortezomib time- and dose-dependently reduced cell viability and induced apoptosis. Bortezomib significantly increased the abundance of ubiquitinated-PML-RARA (Ub-PML-RARA), ubiquitin-conjugating human enzyme 8 (UbcH8), and Ub-UbcH8, indicating that UbcH8 is the E2 ubiquitin-conjugating enzyme for PML-RARA. Moreover, UbcH8 abundance was dose-dependently increased in the culture supernatant of bortezomib-treated cells. CONCLUSION: UbcH8 may have a utility as a biomarker of treatment response to bortezomib in patients with APL. Furthermore, bortezomib impairs the UPS that controls normal protein homeostasis by causing excessive accumulation of PML-RARA augmenting ER stress and leading to APL cell death. The study provides a rationale for incorporating proteasome inhibitors in the treatment of diseases expressing aberrant proteins. Furthermore, monitoring of UPS-related enzymes might have use in predicting the treatment response to proteasome inhibitors and in assessing their therapeutic effects. PMID- 26026091 TI - Correlation of HIWI and HILI Expression with Cancer Stem Cell Markers in Colorectal Cancer. AB - BACKGROUND/AIM: Cancer stem cells (CSCs) constitute a sub-population of tumor cells that possess stem cell properties, such as self-renewal and the ability of differentiation. The presence of CSCs is associated with metastatic potential, treatment resistance and poor patient prognosis. Recently, aberrant expression of P-element induced wimpy testis proteins-PIWI (HIWI and HILI) has been identified in various types of tumors. The aim of the study was to evaluate the clinical significance of the HIWI and HILI expression and its relationship with cancer stem cells markers in 72 patients with colorectal carcinoma (CRC). MATERIALS AND METHODS: The expression level of HIWI and HILI and cancer stem cells markers in paired cancerous and non-cancerous tissues was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. Immunohistochemistry was performed to confirm the observed changes on mRNA level and detect tissue localization of PIWI proteins. RESULTS: Significantly higher mRNA levels of HIWI and decreased HILI mRNA were measured in colorectal cancer tissues compared to corresponding non-cancerous samples. The changes in HIWI mRNA level in cancer tissues were correlated with OCT4 expression. Positive correlations between HILI level and SOX2 were also observed in cancerous tissues. CONCLUSION: Our results indicate a reciprocal regulation between HIWI, HILI and some CSCs markers in colorectal cancer. PMID- 26026092 TI - Differential genomic damage in different tumor lines induced by prodigiosin. AB - Prodigiosin is a secondary metabolite produced by Serratia marcercens. As this pigment is suggested to be a cancer drug, genotoxicity studies are necessary. The aim of the present investigation was to evaluate the genotoxic effects of prodigiosin on tumoral and normal cell lines, NCIH-292, MCF-7 and HL-60. A normal line BGMK was used as control. Genomic damage induced by prodigiosin was observed in all tumor lines as well as the control line. The pigment induced the formation of micronuclei in tumor cells. The present data confirm the antitumor potential of prodigiosin. However, these findings also raise concerns regarding its target specific action, as genotoxic effects on normal cells also occurred. PMID- 26026093 TI - Microarray Gene-expression Profiling Analysis Comparing PCNSL and Non-CNS Diffuse Large B-Cell Lymphoma. AB - AIM: The purpose of the present study was to compare microarray gene-expression profiling data between primary central nervous system (CNS) lymphoma and non-CNS lymphomas. MATERIALS AND METHODS: We performed whole-genomic cDNA-mediated annealing, selection and ligation assay with 177 formalin-fixed paraffin-embedded tumor samples. RESULTS: We identified 20 differentially expressed genes out of which 5 were predominantly expressed in CNS DLBCL compared to non-CNS DLBCL (C16orf59, SLC16A9, HPDL, SPP1, and MAG). SLC16A9 may be involved in aerobic glycolysis of malignant tumors. The alteration in gene expression of SPP1 in primary CNS lymphoma is involved in biological activity, such as CNS tropism, B cell migration, proliferation, and aggressive clinical behavior. MAG may be an important adhesion molecule that contributes to perineural cancer invasion. CONCLUSION: Genomic differences between CNS and non-CNS DLBCL exist and the most prominent genes are SPP1 and MAG. SPP1 may play a key role in CNS tropism of primary CNS lymphoma. PMID- 26026094 TI - Characterization of cells cultured from chylous effusion from a patient with sporadic lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a progressive, rare interstitial lung disease that almost exclusively affects women. It is caused by a mutation in one of the tuberous sclerosis genes, TSC1 or TSC2, and constitutive activation of the mammalian target of rapamycin (mTOR) pathway in smooth muscle-like cells (LAM cells). The heightened proliferation and accumulation of LAM cells leads to the destruction of lung tissue. MATERIALS AND METHODS: In the present study, we developed a cell line (S-LAM1) derived from a chylous effusion obtained from a patient with sporadic, pulmonary LAM and evaluated its phenotype using immunofluorescence, flow cytometry, and an image stream system. Ultrastructure was assessed using a transmission electron microscope. To assess the ability of LAM cells to move and migrate (which is strictly associated with the ability to metastasize), we carried-out a real-time polymerase chain reaction (PCR) array analysis of 84 genes involved in cell motility. In order to evaluate the effect of rapamycin, a natural inhibitor of mTOR kinase, on S-LAM1 cells, a sulforhodamine B cell viability assay was performed with different concentrations of rapamycin. RESULTS AND CONCLUSION: The phenotype of these cells is consistent with the biology of LAM cells. S-LAM1 cells present combined smooth muscle, melanocytic, and lymphatic endothelium lineage, as well as the presence of mesenchymal differentiation markers. A particular pattern of gene expression, including high expression of ezrin (EZR), myosin heavy chain 10, non-muscle (MYH10), and myosin light chain kinase (MYLK) and a greatly decreased expression of supervillin (SVIL), when compared to controls, indicates a high potential motility activity, especially of cell spreading. Rapamycin significantly, although only partially, inhibited S-LAM1 cell proliferation in vitro, and should, perhaps, be considered in the future in combination with other agents. PMID- 26026095 TI - Immunohistochemical evaluation of pulmonary lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare interstitial lung disease characterized by abnormal smooth muscle-like cell (LAM cell) proliferation in the lung stroma. The origin of LAM cells is still unknown. The gold-standard immunohistochemical diagnostic for LAM is an immunopositive reaction to the HMB 45 antibody. MATERIALS AND METHODS: We aimed to evaluate 15 diagnostic open-lung biopsy specimens of pulmonary LAM. Based on the LAM histologic score (LHS), we distinguished two groups of histological severity: early- and advanced-stage LAM. The expression of HMB-45, estrogen receptor (ER), progesterone receptor (PR), beta-catenin, E-cadherin, podoplanin (D2-40), mini-chromosome maintenance protein 3 (MCM3), and epidermal growth factor receptor (EGFR) was evaluated immunohistochemically. Fluorescence in situ hybridization (FISH) was performed in order to investigate amplification of the EGFR gene in LAM cells. RESULTS: The expression of ER and EGFR was significantly higher in advanced than in early stage LAM. Amplification of the EGFR gene was not detected in any of the 15 studied cases. There was a strong-positive correlation between the expression of PR, ER, beta-catenin, E-cadherin, and the standard marker of LAM, HMB45. CONCLUSION: We conclude that together with LHS, ER may be considered a useful tool for evaluating the progression of LAM. beta-Catenin and E-cadherin seem to be new potential specific markers of LAM cells. The increased expression of EGFR in LAM cells is not associated with EGFR gene amplification, although it may be a marker of disease progression; the role of this receptor in LAM pathogenesis should be further investigated. Positive reaction of LAM cells with podoplain demonstrates the existence of an additional lymphatic endothelial lineage in LAM cells. PMID- 26026096 TI - Characterization of alpha-, beta- and p120-Catenin Expression in Feline Mammary Tissues and their Relation with E- and P-Cadherin. AB - BACKGROUND: Abnormal catenin expression has been related to mammary carcinogenesis in both human and canine species and they are considered tumor- and invasion-suppressor molecules; however, in feline mammary tissues they have been scarcely studied. MATERIALS AND METHODS: The immunohistochemical expression of alpha-, beta- and p120-catenin was studied in a series of normal feline mammary glands, hyperplastic/dysplastic lesions and benign and malignant mammary tumors. Their relationship with clinicopathological parameters and with E- and P cadherin expression was assessed. RESULTS: Normal tissues, hyperplastic/dysplastic lesions and benign tumors expressed alpha-, beta- and p120-catenin in the membrane of more than 75% of the luminal epithelial cells, while in malignant tumors, there was a reduction in their membranous expression and a p120-catenin cytoplasmic expression in 40%. Reduced alpha-catenin expression was related to tumor features with prognostic value, namely tumor size (p=0.0203) and necrosis (p=0.0205). The expression of alpha-, beta- and p120 catenin were individually related to each other and collectively associated with E-cadherin expression. CONCLUSION: The results demonstrate a relationship between feline mammary carcinogenesis and decreased expression of catenins, suggesting that they may represent a valuable tool in the diagnosis of feline mammary neoplasms. PMID- 26026097 TI - Biochemical action of new complexes of ruthenium with quinolones as potential antitumor agents. AB - BACKGROUND: The aim of the present study paper was to identify the role of reactive oxygen species (ROS) in apoptosis signaling mechanisms. We used for this purpose two ruthenium complex compounds based on that overproduce these reactive species by their metabolism thus manifesting their antitumor activity too. MATERIALS AND METHODS: In vivo studies were performed in Walker 256 carcinoma bearing Wistar rats treated with two ruthenium (III) (Ru(III)) complexes with fluoroquinolones norfloxacin and ofloxacin. The treatment started 7 days after tumor grafting. We assayed the dynamics of apoptosis by flow-cytometry and the biochemical oxidative status parameters. The biological samples used were serum and whole-tumor tissues; the results were compared to the untreated control group. RESULTS: The results showed an increase of apoptosis from 14.79% to 59.72% 14.79% to 59.72% in tumor cells treated with the most active combination, ruthenium complex with norfloxacin. We also noted an increase of the oxidative status and ROS production during treatment. CONCLUSION: The newly-synthesized complexes are less toxic and their activity is based on the induction of oxidative stress. PMID- 26026098 TI - Circulating Cytokine Levels in Patients with Prostate Cancer: Effects of Neoadjuvant Hormonal Therapy and External-beam Radiotherapy. AB - AIM: The aim of the study was to better characterize the temporal induction of inflammatory cytokines in the serum of patients with prostate cancer (PCa) treated with radiotherapy and to ascertain the influence of hormonal therapy upon those expressions. PATIENTS AND METHODS: Between May 2007 and December 2009, 30 patients with localized PCa were treated with 3-dimensional conformal external beam radiotherapy. Fifteen patients had received neoadjuvant hormonal therapy using a leuteinizing hormone-releasing hormone (LH-RH) analog for six months prior to radiotherapy. The cytokine levels were collectively measured using a multiplex assay system. RESULTS: Seventeen cytokines were at detectable levels throughout the blood sampling times before and during radiotherapy. Hormonal therapy for six months significantly decreased the serum levels of fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). The levels of epidermal growth factor (EGF), granulocyte-colony stimulating factor (G-CSF), and interferon-gamma (IFNgamma) significantly increased during radiotherapy. Most cytokine levels, except for eotaxin, G-CSF, growth-related oncogene (GRO), transforming growth factor-beta (TGFbeta)-1 and TGFbeta2, significantly increased during radiotherapy compared to the levels observed before radiotherapy. CONCLUSION: The present study revealed the influence of hormonal, and of radiation therapy on the proinflammatory cytokine levels in the sera of patients with PCa. In addition, neoadjuvant hormonal therapy amplified the radiation induced alteration of serum cytokines. Further studies to characterize the mechanism underlying a radiation- or hormone-induced inflammatory state are, therefore, necessary. PMID- 26026100 TI - Cyclin E Expression Correlates with Cancer-specific Survival in Endometrial Endometrioid Adenocarcinoma. AB - AIM: The aim of the present study was to investigate the impact of cyclin E expression on cancer-specific survival, as well as on conventional clinocopathological and prognostic factors in endometrial endometrioid adenocarcinoma. MATERIALS AND METHODS: The study consisted of 211 patients surgically treated for endometrial endometrioid adenocarcinoma at the Oulu University Hospital between 1992-2000. Tissue samples were immunohistochemically stained for cyclin E and clinicopathological data were retrospectively retrieved from the patients' records. RESULTS: Cyclin E expression correlated with grade but not with the Federation Internationale de Gynecologie Obstetrique (FIGO) stage or myometrial invasion. Univariate and multivariate survival analyses were performed between patients grouped according to a receiver operating characteristic (ROC) curve-derived cut-off value. A statistically significant difference in survival was demonstrated between patient groups in Kaplan-Meier analysis. CONCLUSION: Contrary to previous literature, we found a correlation between cyclin E expression and prognosis. Further large-scale studies are required to confirm our findings. PMID- 26026099 TI - Effective Treatment of Transmissible Venereal Tumors in Dogs with Vincristine and IL2. AB - AIM: To improve treatment of inoperable transmissible venereal tumors (TVTs) in dogs. Recently, we showed that TVT is sensitive to intratumoral treatment with interleukin-2 (IL2). In addition it is known that TVT is sensitive to intravenous treatment with vincristine. In the present study we tried to establish the therapeutic effect of intratumoral treatment with vincristine and IL2. PATIENTS AND METHODS: We treated 12 dogs with TVT with 1-4 intratumoral treatments with vincristine and IL-2. Per treatment we used vincristine (0.5-0.7 mg/m(2)) and IL2 (2*10(6) units). The injections were given at weekly intervals. RESULTS: Early therapeutic effects were: three complete regressions, four partial regressions, three stable disease, and two progressive disease. Late therapeutic effects were established 45-60 months after the first presentation; there were five complete regressions, no partial regressions, nor stable or progressive diseases. Interestingly, all five dogs with late therapeutic effects were in good health. No tumor recurrence was noted. CONCLUSION: Intratumoral treatment of TVT with vincristine and IL2 appears to have impressive therapeutic effects. PMID- 26026101 TI - Effective Therapeutic Intervention and Comprehensive Genetic Analysis of mTOR Signaling in PEComa: A Case Report. AB - BACKGROUND/AIM: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms. The exact genetic alterations underlying the pathophysiology of PEComas are largely unknown, although it has been shown that activation of the Mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role. Herein we describe the successful treatment of a patient with metastatic PEComa with the mTOR inhibitor everolimus and a comprehensive analysis to identify mechanisms for response. MATERIALS AND METHODS: Immunohistochemistry, array comparative genomic hybridization (aCGH) and genetic analyses were performed. RESULTS: Immunohistochemistry confirmed constitutive activation of mTOR. aCGH revealed a hyperdiploid karyotype affecting large regions of the genome. Next-generation sequencing did not reveal any tumor-specific mutations in mTOR-related genes. CONCLUSION: Our results show the complexity of determining causal genetic alterations that can predict responsiveness to mTOR inhibition, even for a tumor with a complete remission to this specific treatment. PMID- 26026102 TI - Atypical paracaval recurrence of uterine endometrial stromal sarcoma: a case report. AB - Endometrial stromal sarcomas are rare uterine malignancies with a high capacity for recurrence, even in cases diagnosed at an early stage of the disease. Recurrence is usually confined to the pelvic space but sometimes accelerated growth and extension into the upper abdomen can be found. In such cases, an aggressive surgical approach might be needed in order to provide complete resection of the recurrent tumor. We present the case of a 51-year-old patient who was diagnosed with an atypical spindle-shaped recurrence stretching from the pelvic floor to the right renal hilum along the inferior vena cava following total interadnexial hysterectomy for a presumed benign uterine tumor. An R0 resection of the recurrent tumor was performed and the histopathological study revealed the presence of a low-grade endometrial stromal sarcoma. PMID- 26026103 TI - Liver transplantation followed by pulmonary resection complicated with end-stage liver cirrhosis: a case report. AB - BACKGROUND: With the recent popularization of living-donor liver transplantation (LDLT), it has become important to provide treatment for comorbidities in recipients. We report the case of a patient who was successfully treated with LDLT, followed by left upper lobectomy for lung cancer concomitant with decompensated liver cirrhosis. CASE REPORT: A 67-year-old female was admitted for treatment for severe liver cirrhosis. The lung cancer was identified preoperatively using computed tomography. We initially performed LDLT to improve liver function and coagulopathy; the patient was discharged postoperatively on day 39 without complication. Three months after LDLT, we performed a left upper lobectomy. RESULTS: The patient's postoperative course was uneventful and she was discharged after 11 days. CONCLUSION: We conclude that an aggressive and appropriate surgical strategy, including LDLT, is an effective curative treatment in patients with controllable malignancy, concomitant with severe liver dysfunction. PMID- 26026104 TI - Duration of First-line Treatment with Molecular Targeted-Therapy Is a Prognostic Factor in Metastatic Renal Cell Carcinoma. AB - AIM: We investigated the prognostic factors associated with overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who received molecular targeted-therapies. MATERIAL AND METHODS: A total of 66 patients underwent molecular targeted-therapies at the Kurume University between May 2008 and April 2014. Medical records were retrieved and analyzed retrospectively. RESULTS: The median OS was 25.9 [95% confidence interval (CI)=18.3-33.7] months. The median OS stratified by the Memorial Sloan Kettering Cancer Center risk classification was 49.3, 28.6 and 18.3 months for the favorable-, intermediate- and poor-risk groups, respectively. Univariate analyses for various factors revealed gender, pre-treatment C-reactive protein (CRP) level, best response to first-line treatment, the number of molecular targeted agents and the duration of first-line treatment with a median of 6 months, as prognostic variables. Multivariate analyses showed than two or more than three molecular targeted agents [two: hazard ratio (HR)=0.351, 95% CI=0.121-0.901; more than three: HR=0.193, 95% CI=0.069-0.495] and a duration of first-line treatment of more than 6 months (HR=0.203, 95% CI=0.078-0.498) to be independent prognostic factors. CONCLUSION: Our results suggest that the duration of first-line treatment with molecular targeted-therapies is the strongest prognostic factor in patients with mRCC. PMID- 26026105 TI - AGO Score As a Predictor of Surgical Outcome at Secondary Cytoreduction in Patients with Ovarian Cancer. AB - AIM: The present study aimed to compare the outcome of secondary cytoreductive surgery retrospectively in patients with positive and negative Arbeitsgemeinschaft Gynakologische Onkologie (AGO) score that were operated on at the Department of Gynecology, Charite Comprehensive Cancer Center, Medical University, between 2006 and 2013. PATIENTS AND METHODS: A total of 209 consecutive patients presenting a first recurrence of epithelial ovarian cancer were enrolled: 139 patients had a positive AGO score, and 70 patients had at least one negative criterion of the AGO score. All patients underwent secondary cytoreductive surgery and data were evaluated retrospectively. RESULTS: Total macroscopic tumor resection was obtained during secondary cytoreductive surgery in 127 patients (61%), 93 (67%) in the AGO-positive group and 34 (48.5%) in the AGO-negative group. Overall (OS) and progression-free survival (PFS) were identical in both groups of patients when secondary cytoreductive surgery succeeded in achieving complete tumor resection. PFS was 22 months in AGO positive patients who were tumor-free after secondary cytoreductive surgery and 21 months in AGO-negative patients with complete resection after secondary cytoreductive surgery. There were no significant differences in morbidity and mortality rates for both groups. CONCLUSION: AGO score is a useful predictor for operability in patients with a first recurrence of ovarian cancer. Patients with negative scores may still have a 50% chance of achieving optimal tumor resection after secondary cytoreductive surgery. This will be a pivotal factor when counseling patients with recurrent disease regarding further management options. PMID- 26026106 TI - A cohort study evaluating the role of surgery for lung metastases from colorectal cancer. AB - BACKGROUND/AIM: Surgery may be curative in some patients with metastatic colorectal cancer (mCRC). We analyzed the role of lung metastatectomy in this population. PATIENTS AND METHODS: In this retrospective cohort study, cases were defined as mCRC patients with lung metastases (LM's) who underwent metastatectomy. Controls had LM's but did not undergo resection. RESULTS: There were 28 cases and 46 controls. The median overall survival (OS) was 53 months among the cases and 26.3 months for the controls. The cases were more likely to have 1 or 2 lung metastases, unilateral versus bilateral LM's, metachronous versus synchronous presentation of LM's and more likely to have a carcinoembryonic antigen (CEA) level less than 10 ng/ml at diagnosis. The interval from diagnosis to the development of lung metastases was significantly longer in cases versus controls (22.9 versus 8.5 months). CONCLUSION: Patients selected using these criteria may have prolonged survival with therapy that includes lung metastatectomy. PMID- 26026107 TI - Second Primary Malignancies in Mantle Cell Lymphoma: A US Population-based Study. AB - BACKGROUND/AIM: The risk of second primary malignancy (SPM) in mantle cell lymphoma (MCL) is not well-known. In this population-based study, we analyzed rates of SPM in adult patients with MCL. PATIENTS AND METHODS: We selected adult (>=18 years) patients with MCL as first primary malignancy diagnosed during January 1992 to December 2011 from National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) 13 database. We used multiple standardized incidence ratio (MP-SIR) session of SEER(*) stat software to calculate the risk of second primary malignancies. RESULTS: Among 3,149 patients, 261 (8.29%) developed 287 second primary malignancies with observed/expected (O/E) ratio of 1.32 (95% confidence interval (CI=1.17-1.48, p<0.001). The median time to SPM from the time of diagnosis was 47 months (range=6 months to 17.91 years). The significant excess risks were observed for skin, excluding basal and squamous cancer, (N=22, O/E=2.24, CI=1.4-3.39, p<0.001), thyroid malignancy (O/E=3, CI=1.1 6.52, p<0.01), acute myeloid leukemia (O/E=7.74, CI=4.54-13.94, p<0.001), chronic lymphocytic leukemia (O/E=7.27, CI=4.44-11.23, p<0.001) and Non-Hodgkin's lymphoma (NHL) (O/E=3.79, CI=2.64-5.27, p<0.001). The risk of malignancies of brain, thyroid, rectum and anal canal were higher within the first two years of diagnosis of MCL. Risk of skin cancer, excluding basal and squamous cancer, was higher after two years of latency. CONCLUSION: There is significantly higher risk of second primary malignancies in patients with mantle cell lymphoma compared to the general population. Patients may benefit from cancer-specific screening during follow-up. PMID- 26026108 TI - Adjuvant Chemoradiation in Pancreatic Cancer: A Pooled Analysis in Elderly (>=75 years) Patients. AB - AIM: To determine the impact of postoperative chemoradiation (POCR) on overall survival (OS) after resection of pancreatic adenocarcinoma (PAC) in elderly (>=75 years) patients. MATERIALS AND METHODS: A multi-center retrospective review of 1248 patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive PAC was performed. Exclusion criteria included age <75 years, metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiotherapy (IORT) and postoperative death. RESULTS: A total of 98 patients were included in the analysis (males=39.8%, females=60.2%; R1 resections=33.7%; pN1=61.2%); 63 patients received POCR and 26 patients received adjuvant chemotherapy alone. The median follow-up was 25.6 months. The mean age for the entire cohort of patients was 78.1+/-2.9 (SD) years. No differences were observed between patients receiving or not receiving POCR in terms of age (p=0.081), tumor diameter (p=0.412), rate of R1 resection (p=0.331) and incidence of lymph node-positive disease (p=0.078). The only factor predicting an improved OS was POCR. The median OS was 69.0 months in patients treated by POCR and 23.0 months in patients treated without POCR (p=0.008). Even by Cox multivariate analysis, the only significant predictor of OS was POCR (hazard ratio=0.449; 95% confidence interval=0.212-0.950; p=0.036). CONCLUSION: The study represents the first comparative approach on POCR in elderly patients after resection of PAC. OS was higher in patients who received POCR. Further analyses are warranted to evaluate the toxicity rate/grade and the impact of POCR on patient quality of life. PMID- 26026109 TI - Retrospective Analysis of Concurrent Chemoradiation with Triweekly Cisplatin plus 5-Fluorouracil Versus Weekly Cisplatin in Cervical Cancer. AB - BACKGROUND/AIM: Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced cervical cancer. The purpose of the study was to compare the outcomes of triweekly cisplatin plus 5-fluorouracil and weekly cisplatin regimens. PATIENTS AND METHODS: We retrospectively reviewed data from 91 patients with stage IB1-IVA cervical cancer. RESULTS: Out of 91 patients, 48 received triweekly CCRT and 43 received weekly CCRT. For triweekly CCRT, patients received a median of two chemotherapy cycles and median total doses of cisplatin and 5 fluorouracil were 210 mg/body and 8,525 mg/body, respectively. For weekly CCRT, patients received a median of five chemotherapy cycles and the median total dose of cisplatin was 252 mg/body. No statistically significant differences in overall survival or progression-free survival were noted between the two groups. CONCLUSION: Both triweekly CCRT and weekly CCRT appear to have similar efficacy for cervical cancer patients, but the toxicities were better tolerable in weekly CCRT. PMID- 26026110 TI - Bevacizumab with FOLFIRI or XELIRI in the First-line Therapy of Metastatic Colorectal Carcinoma: Results from Czech Observational Registry. AB - AIM: To retrospectively compare the efficacy of two irinotecan-based chemotherapy regimens combined with bevacizumab in first-line therapy of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The data of 558 patients with mCRC treated with first-line bevacizumab plus irinotecan-containing regimen were obtained from the national CORECT registry that collects data of all patients with mCRC treated with targeted-agents. The treatment outcomes of patients treated with bevacizumab plus irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) were compared to patients treated with bevacizumab plus irinotecan and capecitabine (XELIRI). RESULTS: Among 4,312 patients with CRC treated with bevacizumab, only 13% (558) received irinotecan-based chemotherapy. No significant differences were observed in terms of progression-free survival and overall survival between FOLFIRI and XELIRI groups. Moreover, the toxicity of both regimens was also comparable. CONCLUSION: This retrospective analysis confirms the comparable activity of FOLFIRI and XELIRI regimens when combined with bevacizumab. PMID- 26026111 TI - Preoperative Leucocytosis, Thrombocytosis and Anemia as Potential Prognostic Factors in Non-metastatic Renal Cell Carcinoma. AB - BACKGROUND: To validate the potential prognostic significance of preoperatively assessed inflammatory parameters leucocytosis, thrombocytosis and anemia in patients with non-metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: We retrospectively evaluated a cohort comprising 736 consecutive patients with non-metastatic RCC, operated on between 2004 and 2012 with curative radical or partial nephrectomy at a single tertiary academic centre. Laboratory parameters were assessed within one week before surgical intervention. Patients were categorized using laboratory parameter cut-off values according to receiver operating characteristics (ROC) analyses. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method. To evaluate the potential prognostic significance of the preoperative laboratory parameters, multivariate Cox regression models were applied. RESULTS: Multivariable analysis identified preoperative thrombocytosis (>=285,000/MUl) as an independent prognostic factor for CSS (Hazard ratio=2.28, 95% confidence interval=1.24-4.20, p=0.008). CONCLUSION: Regarding CSS, an elevated preoperative platelet count represented an independent prognostic factor of poor survival. Our findings strengthen the potential prognostic significance of preoperative thrombocytosis in patients with non-metastatic RCC. PMID- 26026112 TI - Non-menopausal Status, High Nuclear Grade, Tumor Size >30 mm and Positive Resection Margins Are Predictors of Residual Tumor After Lumpectomy for Ductal Carcinoma In Situ of the Breast. AB - AIM: Breast-conserving surgery with radiation therapy is the primary treatment for ductal carcinoma in situ (DCIS). Re-excision is indicated when clear resection margins have not been achieved, although in some cases the procedure may be unnecessary as there is no residual tumor. The purpose of our three-Center retrospective study was to identify predictors of positive re-excision findings following breast-conserving surgery for DCIS. PATIENTS AND METHODS: A total of 285 patients underwent re-excision following conservative treatment for DCIS between 01/01/08 and 12/31/13 at three breast-cancer referral Centers. We conducted a retrospective, comparative review of the factors that differentiated patients with a residual tumor from those without. The study was based on clinical, radiological, surgical and pathological criteria. RESULTS: A total of 180 patients (63%) had residual tumor after conservative treatment. Six factors were predictive on univariate analysis: young age (p=0.025), non-menopausal status (p=0.016), absence of preoperative biopsy (p=0.0029), high nuclear grade (p=0.0181), lesion size >30 mm (p=0.032), and positive surgical margins (p=0.0016). Four factors remained independently predictive on multivariate analysis: non-menopausal status (p=0.0017), high nuclear grade (p=0.0031), lesion size >30 mm (p=0.012) and positive surgical margins (p=0.0013). We calculated a 93% probability of positive re-excision findings if all four factors were combined. On the other hand, if none of the factors were present, the rate fell to 18%. CONCLUSION: In cases of DCIS, where risk factors for both involved lumpectomy margins and recurrence are carefully studied, knowledge of the risk factors for residual tumor can help guide therapeutic choices. PMID- 26026113 TI - Role of Pelvic and Para-aortic Lymph Node Metastases in Optimally Cytoreduced Advanced Ovarian Cancer. AB - AIM: To delineate the role of pelvic and para-aortic node involvement in patients with optimally cytoreduced (R<=1 cm; R=residual tumor) stage IIIC ovarian cancer. PATIENTS AND METHODS: Ninety-five consecutive optimally cytoreduced patients with primary stage IIIc ovarian cancer underwent stage-related surgery and adjuvant platinum-based chemotherapy, with a median follow-up of 53.5 months. All patients underwent systematic lymphadenectomy. On average, 24.7 pelvic and para-aortic lymph nodes were removed per patient (range=1-60 nodes); Patients were stratified into three groups to evaluate nodal involvement (ratio of affected to resected nodes): 0: no lymph node metastases; >0-0.5: >0 and fewer than 50% of involved nodes; >0.5-1: more than 50% of nodes involved. Clinical parameters were retrospectively evaluated. RESULTS: Most often, serous histology, histological grade 3 and a node ratio >0-<=0.5 (61.1%) were detected. Complete cytoreduction (R=0 mm) had significant best prognostic impact compared to R>0 mm-1 cm (overall survival: p=0.047, progression-free survival: p<0.001). Nodal involvement was associated with serous histology and grade 3 tumor. Best overall survival was associated with a node ratio >0-<=0.5 (p=0.011). A solitary affection of the pelvic or rather para-aortic nodes was detected in 22.1% vs. 16.%, respectively; a combined affection of pelvic and paraaortic nodes were detected in 34.8%. CONCLUSION: The goal is optimal cytoreduction in advanced ovarian cancer. More extensive pelvic and para-aortic lymphadenectomy seems to play an important role in providing accurate staging in optimally-cytoreduced advanced ovarian cancer and the node ratio might give prognostic information. Current prospective studies should investigate if these data have therapeutic implications and may be considered in future staging. PMID- 26026114 TI - Serrated adenoma of the gallbladder: a case report. AB - A case of serrated adenomatous polyp found in a cholecystectomy specimen is reported. The adenoma was built with mucosal crypts exhibiting unlocked serrations lined with up to high-grade dysplastic cells. A desmoplastic sclerotic tissue having multiple stromal hubs with branched thin spokes replaced the subjacent lamina propia, muscularis mucosae, and submucosa. The generous serrated configurations covering a multi-branched sclerotic stroma, gave the adenoma a papillary appearance. Review of the literature indicates that this appears to be the first reported case of serrated adenoma of the gallbladder. PMID- 26026115 TI - Sentinel node navigation surgery for lower rectal cancer. AB - BACKGROUND: Lateral pelvic lymph node metastasis is generally present in 17% of patients with T3 lower rectal cancer. However, such lymph node metastases cannot be accurately detected before surgery. Since 2001, we have performed sentinel node navigation surgery for patients with T3 lower rectal cancer considering the lymph nodes located between the vesicohypogastric fascia and the pelvic nerve plexus as the lateral sentinel lymph node (LSN). PATIENTS AND METHODS: Between 2001 and 2010, 101 patients with T3 lower rectal cancer without distant metastasis or peritoneal dissemination were prospectively enrolled in the study. Patients with negative lymph nodes in the mesorectum underwent only LSN dissection in the lateral pelvic space. Patients with metastatic lymph nodes detected in the mesorectum underwent lateral pelvic lymph node dissection (LPLD). RESULTS: Fifty-three out of the 101 patients with pathologically-negative lymph nodes in the mesorectum and a negative LSN were clinically judged as having stage II disease because no recurrence was detected in the lateral pelvic space during the three years following surgery. The other 48 patients underwent LPLD because of a positive lymph node in the mesorectum, and were further divided into two sub groups, 40 with a negative and 8 with a positive LSN. Only the eight patients with a positive LSN also had positive lymph nodes in the lateral pelvic space. CONCLUSION: Patients with T3 lower rectal cancer in stage III may not require LPLD. LSN may be very useful to determine stage II disease during surgery. PMID- 26026116 TI - Prognostic Value of Total Lesion Glycolysis Measured by 18F-FDG-PET/CT in Patients with Colorectal Cancer. AB - AIM: [(18)F]Fluorodeoxyglucose positron-emission tomography with computed tomography ((18)F-FDG-PET/CT) was assessed regarding its utility in prediction of outcomes after curative resection of colorectal cancer. PATIENTS AND METHODS: Preoperative (18)F-FDG-PET/CT was performed in 325 patients with colorectal cancer. Maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic volume (MV), and total lesion glycolysis (TLG) were measured. Patients were divided into groups using cut-offs for overall survival (OS). (18)F-FDG-PET/CT parameters and other clinicopathological factors were investigated as prognostic factors. RESULTS: The 5-year OS rates in the low and high SUVmax, SUVmean, MV, and TLG groups were 91.4% and 87.0% (p=0.238), 90.8% and 88.2% (p=0.453), 91.7% and 83.8% (p=0.006), and 92.1% and 70.1% (p=0.001), respectively, indicating poorer outcomes in patients with high MV and TLG. In multivariate analysis, high TLG, age >=65 years, rectal tumor location, and pN(+) were independent factors predicting a poor prognosis. CONCLUSION: TLG in (18)F-FDG-PET/CT is a prognostic parameter for colorectal cancer after curative resection. PMID- 26026117 TI - Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors. AB - Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs. PMID- 26026118 TI - Preoperative prediction of peritoneal metastasis in gastric cancer as an indicator for neoadjuvant treatment. AB - AIM: The aim of the present study was to investigate whether serum markers and clinical factors could be used for preoperative prediction of peritoneal metastasis in gastric cancer (GC) as an indicator for neoadjuvant treatment. PATIENTS AND METHODS: We enrolled 493 patients with GC for whom preoperative serum tumor markers [carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9], systemic inflammatory marker C-reactive protein (CRP), host immune markers [neutrophil and lymphocyte counts and their ratio (NLR)], albumin as a nutritional marker, and objective preoperative clinical factors were available as indicators of postoperative peritoneal metastasis. RESULTS: Specific clinical factors, including tumor size, histopathology of biopsy sample, and tumor morphology, were significantly correlated with peritoneal metastasis. CA19-9, lymphocyte count and NLR were also predictive factors for peritoneal metastasis. Multivariate analysis identified the clinical factors tumor morphology and histopathology, and laboratory markers CA19-9 and lymphocyte count as independent factors predictive for peritoneal metastasis. A combination of independent predictive factors achieved high predictive accuracy (0.882) for peritoneal metastasis preoperatively. CONCLUSION: A combination of specific factors is an alternative method to preoperatively discriminate patients with GC with peritoneal metastasis from those without. PMID- 26026119 TI - The Role of Quaternary Cytoreduction in Recurrent Epithelial Ovarian Cancer: A Single-center Experience. AB - AIM: to evaluate the efficacy and to determine safety and survival benefit after quaternary cytoreduction in recurrent epithelial ovarian cancer. PATIENTS AND METHODS: We retrospectively reviewed data of all patients submitted to quaternary cytoreduction at the Dan Setlacec Center of Gastrointestinal Disease and Liver Transplantation, Fundeni Clinical Institute between January 2002 and May 2014. RESULTS: Twenty patients with a mean age of 54.3 years were submitted to quaternary cytoreduction. At the time of initial diagnosis, International Federation of Gynaecology and Obstetrics stages were IA in four cases, IIA in three cases, IIC in two cases, IIIA in three cases, IIIB in two cases and IIIC in six cases. At the time of quaternary cytoreduction, R0 resection was achieved in seven cases. Postoperative complications occurred in three cases (15%), while the 30-day mortality was 0. The median overall survival after quaternary cytoreduction was 16 months. CONCLUSION: quaternary cytoreduction in recurrent epithelial ovarian cancer appears to be a safe procedure and may bring survival benefit in selected cases. PMID- 26026120 TI - Local therapy improvement of outcome in a patient with recurrent hepatocellular carcinoma after living donor liver transplantation: a case report. AB - We describe a very rare case of recurrent hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT). A 47-year-old female underwent LDLT for HCC within Milan criteria, receiving a left liver lobe from her 38-year-old husband with an incompatible blood type. Thirty months after LDLT, however, enhanced computed tomography (CT) showed a tumor in her left adrenal gland; after another six months, enhanced CT and positron-emission tomography detected a frontal head bone tumor; enhanced CT performed 54 months after LDLT revealed a recurrent HCC in the liver graft. Each of these three tumors was surgically resected. Two months after hepatic partial resection, an enhanced CT showed another HCC in her liver graft, which was treated with local ablation therapy. One year after the last ablation treatment, the recipient is doing well without evidence of recurrence. At the time of detection of each of these tumors, the patient's serum concentration of hepatitis B virus surface antigen was elevated. Pathological examination showed that the resected tumors were moderately differentiated HCCs. Genotyping by microsatellite analysis confirmed their origin to be metastases of the primary HCC. PMID- 26026121 TI - Multi-center Randomized Phase II Study of Weekly Docetaxel Versus Weekly Docetaxel-plus-Oxaliplatin as a Second-line Chemotherapy for Patients with Advanced Gastric Cancer. AB - AIM: The current phase II clinical study was conducted to evaluate the efficacy and safety of weekly docetaxel alone, and weekly docetaxel-plus-oxaliplatin, as a second-line chemotherapy in patients with cisplatin-refractory advanced gastric cancer. PATIENTS AND METHODS: We enrolled patients with histologically confirmed gastric adenocarcinoma whose disease had progressed after cisplatin-based regimens. Patients were randomly assigned to receive docetaxel alone (36 mg/m(2), days 1 and 8) or docetaxel (36 mg/m(2), days 1 and 8) and oxaliplatin (80 mg/m(2), day 1) combination therapy every three weeks. RESULTS: This trial was terminated early due to poor patient accrual rate. From January 2009 to January 2012, a total of 52 patients were enrolled in the current study from six centers: 27 patients in the docetaxel monotherapy arm and 25 patients in the docetaxel/oxaliplatin combination arm. Fifty-two patients were assessable for efficacy, and response rates as follows (response rate: 14.8% in the monotherapy arm, 24.0% in the combination arm; disease control rate: 48.1% in the monotherapy arm, 76.0% in the combination arm. The median progression-free survival was 2.0 (95% confidence interval=1.2-2.9) months in the monotherapy arm and 4.9 (95% confidence interval=3.6-6.6) months in the combination arm (p=0.002). The most common grade 3 or 4 adverse event was neutropenia (14% for monotherapy versus 32% for combination). No treatment-related mortality was observed. CONCLUSION: Weekly docetaxel and weekly docetaxel-plus-oxalipaltin regimens were found to be well tolerated and effective as a second-line chemotherapy for patients with advanced gastric cancer. PMID- 26026122 TI - Evaluation of IL-2, IL-6, IL-8 and IL-10 in Malignant Melanoma Diagnostics. AB - AIM: The aim of the present study was to evaluate the usefulness of four interleukins (IL-2, IL-6, IL-8 and IL-10) for melanoma detection and correlate these interleukins with sentinel node metastasis positivity. PATIENTS AND METHODS: A group of 236 persons was assessed: 175 patients with melanomas and 61 healthy persons. Melanoma patients were divided to four groups according to Breslow score. We determined IL-2, IL-6, IL-8 and IL-10 in each plasma sample. Interleukin plasma levels were assayed using a Human Cytokine Milliplex Map kit. Measurements were performed using the Bio-Plex MAGPIX Multiplex Reader. Plasma samples were collected prior to surgery or any other form of treatment. All melanoma diagnoses were histologically verified. RESULTS: We compared interleukin plasma levels in the healthy group and plasma levels in each Breslow score stage. In the first Breslow score stage, IL-2 (p<0.0001), IL-6 (p=0.0004) and IL-10 (p<0.0001) were positive. In the second Breslow score, stage IL-2 (p<0.0001), IL 6 (p<0.0001), IL-8 (p=0.0017) and IL-10 (p<0.0001) were positive. By comparing the group of positive and negative sentinel node metastasis, we observed a statistically significant difference in two interleukins: The median of IL-2 levels in the negative group was 5.88 pg/ml compared to 32.57 pg/ml in the positive group (p=0.0005). The median of IL-6 levels in the negative group was 4.80 pg/ml compared to 32.02 pg/ml in the positive group (p=0.0048). CONCLUSION: Interleukins IL-2, IL-6 and IL-10 are promising biomarkers of early-stage melanoma. IL-2 and IL-6 appear to be prognostic biomarkers. PMID- 26026123 TI - Suicidal Ideation Versus Hopelessness/Helplessness in Healthy Individuals and in Patients with Benign Breast Disease and Breast Cancer: A Prospective Case-control Study in Finland. AB - BACKGROUND/AIM: The relation between suicidal ideation versus hopelessness/helplessness in healthy study subjects (HSS) and in patients with benign breast disease (BBD) and breast cancer (BC) has not been compared to date in a prospective study. We, therefore, investigated suicidal ideation versus hopelessness/helplessness in 115 patients. PATIENTS AND METHODS: In the Kuopio Breast Cancer Study, 115 women with breast symptoms were evaluated for hopelessness and helplessness versus suicidal/pessimistic thoughts before any diagnostic procedures were carried-out. RESULTS: In the self-rating score (SRS), hopelessness and the helplessness versus pessimistic thoughts were significantly correlated in the HSS, BBD and BC groups. In the SRS, the weighted kappa-values for hopelessness versus pessimistic thoughts in the BBD group were also statistically significant. There was also a significant positive correlation in the examiner-rating score (ERS) in the hopelessness versus pessimistic thoughts in the HSS, BBD and BC groups, as well as in the ERS, in the helplessness versus pessimistic thoughts in the HSS and BBD groups. In SRS, the hopelessness and the helplessness versus suicidal thoughts were significantly correlated in the HSS, BBD and BC groups. There was also a significant positive correlation in the ERS in the hopelessness versus suicidal thoughts in the HSS, BBD and BC groups, as well as in the ERS, in the helplessness versus suicidal thoughts in the BBD group. CONCLUSION: A new finding with clinical relevance in the present work is the agreement between hopelessness/helplessness versus suicidal/pessimistic thoughts in the self-rating and examiner-rating. In the breast cancer diagnostic Unit, the identification of suicidal ideation is essential in suicide prevention and it is important to assess and treat depression even though a subject reports little suicidal ideation. PMID- 26026124 TI - The impact of perioperative allogeneic blood transfusion on survival in elderly patients with colorectal cancer. AB - BACKGROUND: The relationship between perioperative allogeneic blood transfusion (ABT) and survival following curative surgery for colorectal cancer (CRC) in elderly patients has not been elucidated to date. PATIENTS AND METHODS: The cases of 108 patients aged 75 years or more who underwent curative surgery for CRC between 2004 and 2011 were retrospectively reviewed. The association between perioperative ABT requirements and other clinicopathological variables was examined. Subsequently, perioperative ABT was compared with other variables concerning overall survival (OS) by univariate and multivariate analyses. RESULTS: Tumor depth, lymph node metastasis and hemoglobin levels were significantly associated with perioperative ABT. Transfused patients had significantly worse OS compared to non-transfused patients. In the multivariate analysis, perioperative ABT (hazard ratio=3.16, 95% confidence interval=1.11 8.98, p=0.031) was the only independent indicator of OS. CONCLUSION: Perioperative ABT was significantly associated with increased mortality in elderly patients with CRC. PMID- 26026125 TI - Cerebral relapsing meningioma: a surgical series with lack of reliability of standard parameters establishing prognosis. AB - BACKGROUND/AIM: Meningioma is the most frequent meningeal neoplasm, usually without relapse or metastasis. Patient follow-up is challenging, not standardized and is decided in multidisciplinary case discussion. Our aim was to determine the clinical and histological factors influencing the time to relapse. PATIENTS AND METHODS: We conducted a single-Center retrospective study on 38 patients with surgically-excised relapsing meningiomas and collected clinical and pathological data. RESULTS: Our results show that none of the histological factors included in the WHO classification, nor those not included are related to a shorter time to relapse. CONCLUSION: In our study, none of the histological, immunohistochemical and clinical parameters evaluated seem to be able to predict the time to relapse in meningioma. PMID- 26026126 TI - Short-term Survival of Patients with Lung Metastases from Colorectal and Non colorectal Cancer Who Underwent Pulmonary Metastasectomy. AB - The lung is a common site of metastases, whose prevalence varies as a function of the primary tumor site, which is usually colorectal cancer (CRC), breast carcinoma, or genitourinary cancers, such as ovary, urinary bladder and renal cell carcinomas. The aim of the present study was to analyze whether the site of primitive tumor affects overall survival (OS) of patients with lung metastases (LMs) who underwent pulmonary metastasectomy. The data of 41 patients with surgically treated CRC (Group A=22 patients) and non-colorectal carcinomas (Group B=19 patients), who developed matachronous LMs and underwent pulmonary metastasectomy with curative intent, were analyzed. The origin of non-colorectal LMs was genitourinary cancer in nine and breast cancer in 10 patients. Overall, there were 22 men and 19 women, with a median age of 65 years (range=31-80); 18 patients had a solitary metastatic tumor, while 23 had two or more LMs. Twenty nine patients underwent wedge resection, through thoracotomy or video-assisted thoracic surgery, while 12 underwent pulmonary lobectomy. Seventy-five LMs were resected with a 5-tear OS of 48.8%. No difference was found between elderly (>=65 year-old) and younger patients (p=0.26), and between those with solitary or multiple LMs (p=0.62) in terms of survival rate. The female patients had a worse OS (31.6% vs. 63.6%; odds ratio (OR)=3.79, 95% confidence interval (CI)=1.03 13.91, p=0.003) compared to males, independent of the origin of primary cancer. There was no difference in the cumulative survival rates (OR=1.65, 95%CI=0.48 5.69, p=0.42) between Groups and the log-rank test (p=0.75) was not significant. In conclusion, the main pathological characteristics of metastatic lesions and advanced age do not appear to be associated with a poor prognosis in patients with LMs, while the female gender is a negative prognostic factor. Thus, the primary tumor site should not be considered a major criterion in selecting patients for pulmonary metastasectomy. PMID- 26026127 TI - PSA Isoforms' Velocities for Early Diagnosis of Prostate Cancer. AB - Free prostate-specific antigen (fPSA) and its molecular isoforms are suggested for enhancement of PSA testing in prostate cancer (PCa). In the present study we evaluated whether PSA isoforms' velocities might serve as a tool to improve early PCa diagnosis. Our study population included 381 men who had undergone at least one ultrasound-guided prostate biopsy whose pathologic examination yielded PCa or showed no evidence of prostatic malignancy. Serial PSA, fPSA, and proPSA measurements were performed on serum samples covering 7 years prior to biopsy using Beckmann Coulter Access immunoassays. Afterwards, velocities of PSA (PSAV), fPSA% (fPSA%V), proPSA% (proPSA%V) and the ratio proPSA/PSA/V were calculated and their ability to discriminate cancer from benign disease was evaluated. Among 381 men included in the study, 202 (53%) were diagnosed with PCa and underwent radical prostatectomy at our Department. PSAV, fPSA%V, proPSA%V as well as proPSA/PSA/V were able to differentiate significantly between PCa and non cancerous prostate. The highest discriminatory power between cancer and benign disease has been observed two and one year prior to diagnosis with all measured parameters. Among all measured parameters, fPSA%V showed the best cancer specificity of 45.3% with 90% of sensitivity. In summary, our results highlight the value of PSA isoforms' velocity for early detection of PCa. Especially fPSA%V should be used in the clinical setting to increase cancer detection specificity. PMID- 26026128 TI - Impact of stereotactic radiosurgery dose on control of cerebral metastases from renal cell carcinoma. AB - AIM: Renal cell carcinoma (RCC) is a relatively radioresistant tumor and may require for higher radiation doses than other tumor types. PATIENTS AND METHODS: Nineteen patients treated with 20 Gy of stereotactic radiosurgery (SRS) alone for one to three cerebral metastases were compared to nine patients treated with 16 18 Gy. RESULTS: SRS with 20 Gy led to significantly better local control than did 16-18 Gy (81% vs. 50% at 12 months; p<0.001). Results were also significant on multivariate analysis (risk ratio: 6.30; p=0.033). SRS dose did not associate with freedom from new cerebral metastases (75% vs. 62% at 12 months; p=0.42) or survival (16% vs. 56% at 12 months; p=0.46). On multivariate analyses, better survival was associated with higher Karnofsky performance score (p<0.001) and absence of extracranial metastatic disease (p=0.006). CONCLUSION: In patients treated with SRS alone, local control of cerebral metastases from RCC was better after 20 Gy than after 16-18 Gy. PMID- 26026129 TI - Frequent High Expression of Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1) in Gastric Cancer. AB - BACKGROUND: The tumor-associated antigen Kita-Kyushu lung cancer antigen-1 (KK-LC 1) has been reported as not being expressed in normal tissues, except for the testis, and in the setting of non-small cell lung cancer. The present study demonstrated that KK-LC-1 is expressed in gastric cancer. MATERIALS AND METHODS: We analyzed the expression of KK-LC-1 and cancer/testis antigens (CTAs) in surgical specimens of 49 gastric carcinomas. The expression of KK-LC-1 and CTAs was assessed using reverse transcription-polymerase chain reaction. RESULTS: KK LC-1 expression was observed in gastric carcinomas. The number of lesions with expression of KK-LC-1, Melanoma antigen gene encoding-A1 (MAGE-A1), MAGE-A3 and New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) was 40 (81.6%), 17 (34.7%), 22 (44.9%) and 8 (16.3%) out of the 49 specimens, respectively. CONCLUSION: KK-LC-1 should be categorized as a CTA. The frequency of KK-LC-1 expression was higher than that of the other CTAs. KK-LC-1 might be a useful target for immunotherapy and in diagnosis of gastric cancer. PMID- 26026130 TI - Significance of lymphatic invasion combined with size of primary tumor for predicting sentinel lymph node metastasis in patients with breast cancer. AB - BACKGROUND/AIM: Lymphatic invasion (ly) may mainly reflect the selective affinity of breast cancer cells for lymph nodes. We conducted the present study to investigate whether the presence of lymphatic invasion is a predictor of sentinel lymph node (SLN) metastasis in clinically node-negative breast cancer. PATIENTS AND METHODS: We retrospectively evaluated the cases of 202 consecutive female patients with clinically node-negative primary breast cancer who underwent a radical breast operation with SLN biopsy. We examined the relationship between SLN metastasis and the significance of clinicopathological factors, including lymphatic invasion. RESULTS: Among the 202 patients, 49 (24.3%) had SLN metastasis. The univariate and multivariate analyses revealed that the size of the tumor and lymphatic invasion were independent risk factors for SLN metastasis. Among the 96 patients who were ly-negative and had a tumor size of less than 20 mm, only 5 (5.2%) had 1-2 metastases within the SLN. Among the 34 patients who were ly-negative and had a tumor size of less than 10 mm, there were no patients with SLN metastasis. CONCLUSION: Our results suggest that the presence of lymphatic invasion combined with the size of the primary cancer could be considered a strong risk factor for SLN metastasis in clinically node-negative breast cancer, and patients with a tumor size of less than 20 mm and clinically node-negative breast cancer may avoid axillary lymph node dissection after SLN biopsy. There is also a possibility that SLN biopsy could be unnecessary for patients with clinically node-negative breast cancer who are ly-negative and have a tumor size of less than 10 mm. PMID- 26026131 TI - New Approach to Complete Video-assisted Thoracoscopic Lobectomy in T2 and T3 Non Small Cell Lung Cancer. AB - Complete video-assisted thoracoscopic surgery (c-VATS) for lung cancer is minimally invasive because of the small incision required. c-VATS has recently become a standard procedure for treatment of stage IA/IB lung cancer. However, a long thoracic incision or extensive costal rib resection is required in patients with large lung tumors. We herein introduce an improved VATS lobectomy procedure for patients with T2 and T3 lung cancer. In this technique, resected tissue is removed through a small upper abdominal midline incision below the xiphoid through the retrosternal-extraperitoneal pathway. Five patients who underwent this new procedure were compared against 10 control patients who underwent hybrid VATS lobectomy. Significantly fewer patients who underwent c-VATS lobectomy complained of severe postoperative pain; however, there was no significant difference in the postoperative hospital stay between the two groups. The present study demonstrates that c-VATS lobectomy can be performed with minimal operative pain and without need for a long thoracic incision or extensive rib resection, even in patients with large lung tumors (T2 and T3). These results suggest that the indications for c-VATS lobectomy in patients with T2 and T3 non-small cell lung cancer can be expanded by implementation of our approach, which involves removal of the freed lobe through an abdominal incision. PMID- 26026133 TI - Errata. PMID- 26026132 TI - Treatment Outcome of Radiotherapy for Localized Primary Ocular Adnexal MALT Lymphoma--Prognostic Effect of the AJCC Tumor-Node-Metastasis Clinical Staging System. AB - AIM: To analyze the treatment outcome of radiotherapy for localized primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) and evaluate the prognostic effect of the American Joint Committee on Cancer (AJCC) tumor-node metastasis (TNM) clinical staging system for POAML. PATIENTS AND METHODS: Seventy three patients with Ann Arbor stage IE POAML who were treated with radiotherapy alone were analyzed. T-Factor based on the AJCC staging system was T1 in 28, T2 in 33 and T3 in 12 patients. RESULTS: Out of nine patients with relapse, six had distant and three had contralateral ocular adnexal relapse. One patient died of lymphoma progression. The 5-year local control and progression-free survival (PFS) rates were 100% and 81.5%, respectively. T-Factor was not significantly associated with PFS. CONCLUSION: Radiotherapy achieved excellent local control and survival rates for stage IE POAML. The AJCC TNM clinical staging system was not significantly predictive for PFS of stage IE POAML. PMID- 26026135 TI - A Complication of Management of Closed Incision with Negative-Pressure Wound Therapy. PMID- 26026136 TI - Differential protein expression and peak selection in mass spectrometry data by binary discriminant analysis. AB - MOTIVATION: Proteomic mass spectrometry analysis is becoming routine in clinical diagnostics, for example to monitor cancer biomarkers using blood samples. However, differential proteomics and identification of peaks relevant for class separation remains challenging. RESULTS: Here, we introduce a simple yet effective approach for identifying differentially expressed proteins using binary discriminant analysis. This approach works by data-adaptive thresholding of protein expression values and subsequent ranking of the dichotomized features using a relative entropy measure. Our framework may be viewed as a generalization of the 'peak probability contrast' approach of Tibshirani et al. (2004) and can be applied both in the two-group and the multi-group setting. Our approach is computationally inexpensive and shows in the analysis of a large-scale drug discovery test dataset equivalent prediction accuracy as a random forest. Furthermore, we were able to identify in the analysis of mass spectrometry data from a pancreas cancer study biological relevant and statistically predictive marker peaks unrecognized in the original study. AVAILABILITY AND IMPLEMENTATION: The methodology for binary discriminant analysis is implemented in the R package binda, which is freely available under the GNU General Public License (version 3 or later) from CRAN at URL http://cran.r-project.org/web/packages/binda/. R scripts reproducing all described analyzes are available from the web page http://strimmerlab.org/software/binda/. CONTACT: k.strimmer@imperial.ac.uk. PMID- 26026134 TI - Shaping of the Unaffected Breast with Brava-Assisted Autologous Fat Grafting to Obtain Symmetry after Breast Reconstruction. AB - BACKGROUND: In breast reconstruction, symmetry is a vital issue. However, when the original breast is unusually shaped or the patient desires augmentation at the time of reconstruction, obtaining symmetrical breasts becomes difficult. OBJECTIVES: The authors performed shaping of unaffected breasts by Brava-assisted autologous fat grafting to enhance breast symmetry, and evaluated the clinical results to validate this new approach. METHODS: Brava-assisted autologous fat grafting was performed to the unaffected breasts of 12 patients who had undergone unilateral breast reconstruction. The procedure was used for augmentation in six patients and to correct ptosis, volume, and tuberous breast deformity in three, two, and one patient, respectively. Clinical outcomes were assessed in all 12 patients. RESULTS: All patients could complete fat grafting within two sessions (one session in nine patients and two sessions in three patients). The mean volume of grafted fat per session was 211 cc in all patients. The mean retention rate of grafted fat was 58.9% in the 10 patients for whom the retention rate could be calculated using preoperative and postoperative magnetic resonance imaging (MRI). Postoperative MRI revealed small benign foci in two patients (16.7%), which were not palpable and did not become a clinical problem. A postoperative mammography revealed a small agglutinate calcification in one patient, which was determined to be benign through biopsy. CONCLUSIONS: Shaping the unaffected breast by autologous fat grafting combined with Brava is predictable, effective, and feasible as an aesthetic adjunct to unilateral breast reconstruction to achieve breast symmetry. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26026137 TI - ACE: accurate correction of errors using K-mer tries. AB - The quality of high-throughput next-generation sequencing data significantly influences the performance and memory consumption of assembly and mapping algorithms. The most ubiquitous platform, Illumina, mainly suffers from substitution errors. We have developed a tool, ACE, based on K-mer tries to correct such errors. On real MiSeq and HiSeq Illumina archives, ACE yields higher gains in terms of coverage depth, outperforming state-of-the-art competitors in the majority of cases. AVAILABILITY AND IMPLEMENTATION: ACE is licensed under the GPL license and can be freely obtained at https://github.com/sheikhizadeh/ACE/. The program is implemented in C++ and runs on most Unix-derived operating systems. CONTACT: siavash.sheikhizadehanari@wur.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26026139 TI - Vitamin C: It Isn't Just for Cancer Anymore. PMID- 26026138 TI - QVZ: lossy compression of quality values. AB - MOTIVATION: Recent advancements in sequencing technology have led to a drastic reduction in the cost of sequencing a genome. This has generated an unprecedented amount of genomic data that must be stored, processed and transmitted. To facilitate this effort, we propose a new lossy compressor for the quality values presented in genomic data files (e.g. FASTQ and SAM files), which comprise roughly half of the storage space (in the uncompressed domain). Lossy compression allows for compression of data beyond its lossless limit. RESULTS: The proposed algorithm QVZ exhibits better rate-distortion performance than the previously proposed algorithms, for several distortion metrics and for the lossless case. Moreover, it allows the user to define any quasi-convex distortion function to be minimized, a feature not supported by the previous algorithms. Finally, we show that QVZ-compressed data exhibit better performance in the genotyping than data compressed with previously proposed algorithms, in the sense that for a similar rate, a genotyping closer to that achieved with the original quality values is obtained. AVAILABILITY AND IMPLEMENTATION: QVZ is written in C and can be downloaded from https://github.com/mikelhernaez/qvz. CONTACT: mhernaez@stanford.edu or gmalysa@stanford.edu or iochoa@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26026140 TI - Vitamin D: dosages to optimize serum levels. PMID- 26026141 TI - Humors Effect on Short-term Memory in Healthy and Diabetic Older Adults. AB - CONTEXT: With aging, the detrimental effects of stress can impair a person's ability to learn and sustain memory. Humor and its associated mirthful laughter can reduce stress by decreasing the hormone cortisol. Chronic release of cortisol can damage hippocampal neurons, leading to impairment of learning and memory. Objectives * The study intended to examine the effect of watching a humor video on short-term memory in older adults. Design * The research team designed a randomized, controlled trial. SETTING: The study took place at Loma Linda University in Loma Linda, CA, USA. PARTICIPANTS: The study included 30 participants: 20 normal, healthy, older adults-11 males and 9 females-and 10 older adults with type 2 diabetes mellitus (T2DM)-6 males and 4 females. INTERVENTION: The study included 2 intervention groups of older adults who viewed humorous videos, a healthy group (humor group), aged 69.9 +/- 3.7 y, and the diabetic group, aged 67.1 +/- 3.8 y. Each participant selected 1 of 2 humorous videos that were 20 min in length, either a Red Skeleton comedy or a montage of America's Funniest Home Videos. The control group, aged 68.7 +/- 5.5 y, did not watch a humor video and sat in quiescence. OUTCOME MEASURES: A standardized, neuropsychological, memory-assessment tool, the Rey Auditory Verbal Learning Test (RAVLT), was used to assess the following abilities: (1) learning, (2) recall, and (3) visual recognition. The testing occurred twice, once before (RAVLT1) and once after (RAVLT2) the humorous video for the humor and diabetic groups, and once before (RAVLT1) and once after (RAVLT2) the period of quiescence for the control group. At 5 time points, measurements of salivary cortisol were also obtained. The Kruskal-Wallis test was used to measure significance of the data based on the 3 groups. RESULTS: In the humor, diabetic, and control groups, (1) learning ability improved by 38.5%, 33.4%, and 24.0%, respectively (P = .025); (2) delayed recall improved by 43.6%, 48.1%, and 20.3%, respectively (P = .064); and (3) visual recognition increased by 12.6%, 16.7%, and 8.3%, respectively (P = .321). For levels of salivary cortisol, the research team found significant and borderline decreases for the humor group between baseline and (1) post-RAVLT1 (P = .047), (2) postvideo (P = .046), and (3) post-RAVLT2 (P = .062). The diabetic group showed significant decreases between baseline and (1) post-RAVLT1 (P = .047), (2) postvideo (P = .025), and (3) post-RAVLT2 (P = .034). The study found no significant changes for the control group. CONCLUSION: The research findings supported potential clinical and rehabilitative benefits for humor that can be applied to whole-person wellness programs for older adults. The cognitive components-learning ability and delayed recall-become more challenging as individuals age and are essential to older adults for providing a high quality of life: mind, body, and spirit. Because older adults can experience age-related memory deficits, complementary, enjoyable, and beneficial humor therapies should be implemented for them. PMID- 26026142 TI - The influence of traditional and complementary and alternative medicine on medication adherence in Honduras. AB - BACKGROUND: Adherence to medication is a worldwide problem and deserves country specific attention. Honduras, like many other countries, has allopathic providers, traditional medicine (TM), and complementary and alternative medicine (CAM). Understanding a population's health behaviors is essential to satisfactory integration of these systems and successful patient care. STUDY OBJECTIVE: The objective was to identify factors that influence medication adherence in Honduras. DESIGN: The research team administered a cross-sectional, 25-item questionnaire to various neighborhoods based on national demographic statistics in order to obtain a quota sample. Setting * The survey took place in Tegucigalpa, Honduras, Central America. PARTICIPANTS: The research team surveyed 614 Hondurans, aged >= 18 y, within the general population of Tegucigalpa, the largest and capital city of Honduras, in neighborhoods representing areas where primarily the lower and middle classes lived. OUTCOME MEASURES: The primary outcome measure was a modified Medication Adherence Report Scale (MARS). Results * The research team collected 610 surveys that had complete answers to questions about adherence (610/614, 99.3%) total complete responses to other items varied. The prevalence of use of TM was 62.8% (381/607). Nearly one-half, 47.3% (287/607), of all the respondents had used herbs or teas for health in the prior year, and 26.1% (159/607) of all respondents had received a sobada (therapeutic rubbing). Respondents with daily private spiritual devotions (OR = 0.610, P = .018) and diabetes (OR = 0.154, P = .004) were less likely to report low adherence. Receiving a sobada and a history of fever were independently associated with low adherence (OR = 1.718, P = .017 and OR = 2.226, P < .001, respectively). CONCLUSIONS: Hondurans use both allopathic and TM. Although private spiritual devotion may help improve adherence to medication, only use of traditional massage therapy, the sobada, was associated with decreased adherence. Effective integration of alternative therapies in Central America will require proper counseling on how to combine multiple therapies to maximize the health benefits. PMID- 26026143 TI - Ten-year Retrospective Study on the Efficacy of a Manual Physical Therapy to Treat Female Infertility. AB - BACKGROUND: Female infertility is a complex issue encompassing a wide variety of diagnoses, many of which are caused or affected by adhesions. OBJECTIVES: The study intended to examine the rates of successful treatment of infertile women using a protocol of manual physical therapy to address underlying adhesive disease leading to infertility. Methods * The research team designed a retrospective chart review. SETTING: The study took place in a private physical therapy clinic. PARTICIPANTS: Participants were 1392 female patients who were treated at the clinic between the years of 2002 and 2011. They had varying diagnoses of infertility, including occluded fallopian tubes, hormonal dysfunction, and endometriosis, and some women were undergoing in vitro fertilization (IVF). Intervention * All patients underwent whole-body, patient centered treatments that used a protocol of manual physical therapy, which focused on restoring mobility and motility to structures affecting reproductive function. OUTCOME MEASURES: Improvements demonstrated in the condition(s) causing infertility were measured by improvements in tubal patency and/or improved hormone levels or by pregnancy. Results * The results included a 60.85% rate of clearing occluded fallopian tubes, with a 56.64% rate of pregnancy in those patients. Patients with endometriosis experienced a 42.81% pregnancy rate. The success rate was 49.18% for lowering elevated levels of follicle stimulating hormone (FSH), with a 39.34% pregnancy rate in that group, and 53.57% of the women with polycystic ovarian syndrome (PCOS) achieved pregnancy. The reported pregnancy rate for patients who underwent IVF after the therapy was 56.16%. The results also suggested that the treatment was effective for patients with premature ovarian failure (POF). CONCLUSION: The manual physical therapy represented an effective, conservative treatment for women diagnosed as infertile due to mechanical causes, independent of the specific etiology. PMID- 26026144 TI - Global water fluoridation: what is holding us back? AB - Artificial water fluoridation was introduced more than 60 y ago as a public health intervention to control dental caries. Despite wide recommendations for its use from the World Health Organization (WHO) and studies showing the benefits of water fluoridation, many countries have opted out. Currently, only 25 countries, including the United Kingdom, the United States, and Australia have schemes for artificial water fluoridation. The issues faced in efforts to promote the global uptake of water fluoridation and the factors that affect the decision to implement it are unique in both developed and developing countries and must be explored. This article addresses the benefits and challenges of artificial water fluoridation. Further, it tackles the complexities faced with uptake of water fluoridation globally, such as ethical and political controversies and the use of alternative fluoride therapies. Potential future strategies to encourage the uptake of artificial water fluoridation are also discussed. PMID- 26026145 TI - Nutritional aspects of detoxification in clinical practice. AB - Detoxification is a vital cellular task that, if lacking, can lead to early morbidity and mortality. The process of detoxification involves the mobilization, biotransformation, and elimination of toxicants of exogenous and endogenous origin. This article discusses the phase I and phase II detoxification and biotransformation pathways and promotes using food to support these highly complex processes. The author identifies the comprehensive elimination diet as a useful therapeutic tool for clinicians and patients to use to achieve detoxification. Using this diet, the patient removes the most common allergenic foods and beverages from the diet and replaces them with nonallergenic choices for a period of 4 wk, gradually adding back the eliminated foods and observing their effects. Another effective clinical tool that the author discusses is the detox-focused core food plan, which identifies the variety of foods required to supply key nutrients that can maximize the effectiveness of detoxification. Finally, the author provides a case study in which these tools were used to help a patient suffering from major, debilitating illnesses that resulted from exposure to malathion, including severe vomiting and diarrhea, headaches, night sweats, severe arthralgias and myalgias, episcleritis, and shortness of breath. The article details the interventions used and the clinical results (ie, successful resolution of most issues after 3 mo). PMID- 26026146 TI - Guillain-Barre syndrome mistaken for a common spinal disorder: a case report. AB - CONTEXT: Many patients with musculoskeletal issues seek traditional Korean medicine or complementary and alternative medicine (CAM) to treat or help deal with their health conditions. Practitioners and patients should be aware of diseases that can exhibit similar symptoms, consequently complicating diagnosis and treatment. OBJECTIVE: The study intended to examine a case of Guillain-Barre syndrome (GBS), in which the patient presented with back pain, leg pain, and weakness that gave cause for diagnostic error at onset. Design * The research team has reported a case study. SETTING: The study was conducted at Jaseng Hospital of Korean Medicine in Seoul, Korea. PARTICIPANT: After initially being prescribed back surgery for lumbar disc herniation, as confirmed by lumbar magnetic resonance imaging (MRI) at a previous hospital, a 54-y-old female with low back and leg pain as her chief complaint chose to transfer to a Korean medicine hospital for nonsurgical treatment. INTERVENTION: The patient became nonambulatory owing to a sudden decrease in muscle strength during admission and underwent a cervical MRI to assess for cervical myelopathy because she developed additional neck pain and upper-limb symptoms. She then was diagnosed with GBS and received a regime of symptomatic treatment with CAM, including acupuncture, electroacupuncture, pharmacopuncture, and herbal medicine. RESULTS: The cervical MRI results showed that the symptoms were not due to myelopathy or radiculopathy, and GBS was suspected because of the progressive ascending weakness, absence of myotatic reflexes in the lower limbs, and preceding flu-like symptoms. The patient showed swift recuperation after the CAM treatments, recovering motor strength and ambulation. CONCLUSIONS: A seemingly typical patient with musculoskeletal symptoms may turn out to have a completely different pathology, and clinicians should keep such potential confounders and comorbidities in mind when diagnosing patients. PMID- 26026147 TI - Leslie Ray Matthews, MD: Enhanced Surgical Outcomes and Boosted Soft-tissue Wellness From Vitamin D Supplementation. PMID- 26026148 TI - Kinetochore-independent chromosome segregation driven by lateral microtubule bundles. AB - During cell division, chromosomes attach to spindle microtubules at sites called kinetochores, and force generated at the kinetochore-microtubule interface is the main driver of chromosome movement. Surprisingly, kinetochores are not required for chromosome segregation on acentrosomal spindles in Caenorhabditis elegans oocytes, but the mechanism driving chromosomes apart in their absence is not understood. In this study, we show that lateral microtubule-chromosome associations established during prometaphase remain intact during anaphase to facilitate separation, defining a novel form of kinetochore-independent segregation. Chromosome dynamics during congression and segregation are controlled by opposing forces; plus-end directed forces are mediated by a protein complex that forms a ring around the chromosome center and dynein on chromosome arms provides a minus-end force. At anaphase onset, ring removal shifts the balance between these forces, triggering poleward movement along lateral microtubule bundles. This represents an elegant strategy for controlling chromosomal movements during cell division distinct from the canonical kinetochore-driven mechanism. PMID- 26026150 TI - Autism: environmental triggers. PMID- 26026151 TI - Improving access to yoga: barriers to and motivators for practice among health professions students. AB - BACKGROUND: Yoga is gaining momentum as a popular and evidence-based, integrative health care and self-care practice. The characteristics of yoga practitioners are not proportional to the demographics of the general population, especially with respect to gender and ethnicity. Several access barriers have been implicated (eg, time, cost, and access to teachers). No studies have explored the barriers to practice among health professions students. Their participation in yoga is deemed important because they are future health professionals who will make referrals to other services. Research has shown that providers who practice yoga refer more patients to yoga. OBJECTIVE: To increase yoga practice among health professions students, an understanding must be developed of factors that interfere with or facilitate a regular yoga practice. The current study intended to identify such barriers and motivators. DESIGN: This study was a small population survey. SETTING: The setting was a private university in the northwestern United States, including students in 3 of its colleges and 10 professional programs. PARTICIPANTS: All students (N = 1585) in the programs of the 10 health professions received e-mail requests for participation. OUTCOME MEASURES: The Acceptability of Yoga Survey was developed for purposes of a larger yoga perceptions study and implemented with health professions students. Participants were solicited via e-mail; the survey was administered online. The current study used data from that survey. RESULTS: Of the 498 usable, completed surveys (ie, a response rate of approximately 30%), 478 were relevant to the current study. The sample's demographics--78% women and 79% white--did not differ significantly from the population's demographics. The findings revealed the existence of common barriers that were related to (1) time; (2) cost; (3) lack of pragmatic information about access to yoga classes and teachers; and (4) stereotypes related to flexibility, athleticism, and typical yoga practitioners. Motivators included athleticism, health promotion, and emotional well-being as well as the seeking of pain relief and a sense of community. A referral by health care providers was the least-frequently cited motivator. CONCLUSIONS: The findings have implications for strategies that may help motivate health professionals toward a yoga practice, because having done yoga personally may be related to a willingness to perceive the benefits of and to refer patients to yoga as a viable integrative treatment for patients. Improved access can be developed in 3 ways: (1) integration of yoga research into health curricula to acquaint care providers with yoga's benefits to patients and care givers; (2) have yoga available as close to the workplace as possible to obviate some of the larger access barriers; and (3) societally, project yoga as a healing art and science, not simply as a weight loss strategy or athletic endeavor. PMID- 26026152 TI - The influence of personal patterns of behavior on the physiological effects of woodland walking. AB - CONTEXT: The effects of forest walking are once again being recognized; however, few studies have investigated individual variations in the effects of forest walking. OBJECTIVE: The objective of the current study was to investigate the influence of individual patterns of behavior on the physiological effects of walking through woodland. DESIGN: The study employed a crossover, open-label, single-group, self-controlled design. SETTING: This study was conducted in the forest on Ikoma Mountain, at the eastern edge of Osaka Prefecture in Japan. PARTICIPANTS: Participants were 20 healthy males, selected randomly from a population of members at a nonprofit organization with a mean age of 67.6 y. INTERVENTION: Moving from the start of a mountain path to an observation platform, participants took a 1000-m walk through the forest. On another day, participants remained in their offices. PRIMARY OUTCOME MEASURES: Patterns of personal behavior were assessed preintervention by written questionnaire, identifying type A and type B behavior patterns. Salivary chromogranin A (CgA) levels were determined immediately before and after the walk as well as at 20 min after and 40 min after its end. On the day when participants sat in their offices, control samples were collected at the same times as on the day of the walk. RESULTS: In the type B-behavior pattern group, a significant increase in the levels of CgA occurred after the walk. No change was observed in the type A behavior pattern group. CONCLUSIONS: The findings suggest that walking in woodland may bring about positive health benefits, particularly to individuals with type B characteristics. PMID- 26026153 TI - Religion, spirituality, and health: a review and update. AB - This article summarizes research prior to 2010 and more recent research on religion, spirituality, and health, including some of the latest work being done by research teams at Columbia University, Harvard University, Duke University, and other academic medical centers. First, terms such as religion, humanism, and spirituality are defined. Second, based on his research team's previous systematic review of quantitative studies published in the peer-reviewed literature prior to 2010, the author discusses the findings from that research on the effects of religion and spirituality (R/S) on (1) mental health-well-being, purpose in life, hope, optimism, self-esteem, depression, anxiety, suicide, and substance abuse; (2) health behaviors-exercise, diet, cigarette smoking, and risky sexual activity; and (3) physical health-coronary artery disease, cancer, and all-cause mortality. Third, the author examines the latest research on the prevalence of spiritual needs among individuals with serious or terminal medical illnesses, the consequences of ignoring those needs, and the results of clinical trials that have examined the effects of spiritual assessments by physicians. Finally, the author reviews the research currently being conducted at Duke University on the efficacy of religious cognitive-behavioral therapies and on the effects of religious involvement on telomere length in stressed caregivers. Resources are provided that will assist seasoned researchers and clinicians who might be interested in doing research in this novel and expanding area of whole person medicine. PMID- 26026154 TI - Increasing the Social Communication of a Boy With Autism Using Animal-assisted Play Therapy: A Case Report. AB - CONTEXT: Although research has shown that animal-assisted play therapy (AAPT) is associated with increased positive social behaviors in children with autism, the related literature on AAPT and autism is very limited. OBJECTIVES: The study tested the effectiveness of AAPT in increasing the social communication of a boy with autism. The treatment's effects on specific types of social communication were also investigated. DESIGN: An A-B-A single-subject design was adopted to examine treatment effectiveness. Follow-up assessments were made at 1 mo posttreatment. SETTING: The videotaped treatment sessions were held in the multipurpose room of the participant's school. PARTICIPANT: A 7-y-old boy who had a diagnosis of autism and mild-grade intellectual disability participated in the study. INTERVENTION: AAPT was implemented in 20-min sessions held 3 */wk. The 14 AAPT sessions occurred in 4 phases, covering child-dog relationship building and interaction in the presence of the therapist, with the diminishing presence of the dog occurring in phase 4. OUTCOME MEASURES: Naturally occurring social behaviors were measured in 3 baseline sessions, during the 14 AAPT sessions, during 3 posttreatment sessions, and again during 3 follow-up sessions. Momentary time sampling was used to estimate the frequency of target behaviors, using a 15 s interval. Behavioral categories were checked at every interval during each 20 min session in all 23 sessions. RESULTS: The study showed that the boy's social communication increased during treatment and remained higher than baseline at follow-up. An analysis of specific types of social communication showed that the benefits of AAPT were most apparent in the joint-attention and waiting behaviors. CONCLUSIONS: The findings provide support for using AAPT as an intervention to facilitate the social communication of children with autism. PMID- 26026155 TI - Pharmacological treatments for fatigue associated with palliative care. AB - BACKGROUND: This review updates the original review, 'Pharmacological treatments for fatigue associated with palliative care' and also incorporates the review 'Drug therapy for the management of cancer-related fatigue'.In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients' fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Fatigue frequently occurs in patients with advanced disease (e.g. cancer-related fatigue) and modalities used to treat cancer can often contribute. Further complicating issues are the multidimensionality, subjective nature and lack of a consensus definition of fatigue. The pathophysiology is not fully understood and evidence-based treatment approaches are needed. OBJECTIVES: To evaluate the efficacy of pharmacological treatments for fatigue in palliative care, with a focus on patients at an advanced stage of disease, including patients with cancer and other chronic diseases. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and EMBASE, and a selection of cancer journals up to 28 April 2014. We searched the references of identified articles and contacted authors to obtain unreported data. To validate the search strategy we selected sentinel references. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) concerning adult palliative care with a focus on pharmacological treatment of fatigue compared to placebo, application of two drugs, usual care or a non-pharmacological intervention. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). We did not include studies on fatigue related to antineoplastic treatment (e.g. chemotherapy, radiotherapy, surgical intervention). We also included secondary outcomes that were assessed in fatigue-related studies (e.g. exhaustion, tiredness). DATA COLLECTION AND ANALYSIS: Two review authors (MM and MC) independently assessed trial quality and extracted data. We screened the search results and included studies if they met the selection criteria. If we identified two or more studies that investigated a specific drug with the same dose in a population with the same disease and using the same assessment instrument or scale, we conducted meta-analysis. In addition, we compared the type of drug investigated in specific populations, as well as the frequent adverse effects of fatigue treatment, by creating overview tables. MAIN RESULTS: For this update, we screened 1645 publications of which 45 met the inclusion criteria (20 additional studies to the previous reviews). In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials and we discuss the reasons for this in the review. There were some sources of potential bias in the included studies, including a lack of description of the methods of blinding and allocation concealment, and the small size of the study populations. We included studies investigating pemoline and modafinil in participants with multiple sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue in meta-analysis. Treatment results pointed to weak and inconclusive evidence for the efficacy of amantadine, pemoline and modafinil in multiple sclerosis and for carnitine and donepezil in cancer-related fatigue. Methylphenidate and pemoline seem to be effective in patients with HIV, but this is based only on one study per intervention, with only a moderate number of participants in each study. Meta-analysis shows an estimated superior effect for methylphenidate in cancer-related fatigue (standardised mean difference (SMD) 0.49, 95% confidence interval (CI) 0.15 to 0.83). Therapeutic effects could not be described for dexamphetamine, paroxetine or testosterone. There were a variety of results for the secondary outcomes in some studies. Most studies had low participant numbers and were heterogeneous. In general, adverse reactions were mild and had little or no impact. AUTHORS' CONCLUSIONS: Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials. PMID- 26026156 TI - The impact of culturally responsive self-management interventions on health outcomes for minority populations: A systematic review. AB - OBJECTIVES: The health of people from Indigenous and ethnic minorities is poorer than the remainder of the population. Frequently, Westernized health systems respond by introducing self-management interventions to improve chronic illness health outcomes. The aim of this study was to answer the research question: "Can self-management programs that have been adapted or modified still be effective for ethnic minority and Indigenous populations?" METHODS: A systematic review across four databases was conducted. RESULTS: Twenty-three publications met the inclusion criteria. As the studies were heterogeneous, meta-analysis was not possible. Overall, interventions resulted in more positive health outcomes than usual care, but findings were inconsistent. DISCUSSION: We argue that rather than focusing on individual skills, knowledge, self-efficacy, and attitudes toward self-management, it may be more important to explore the structures and processes that underpin the sharing of information and skills within clinical or education encounters. Given that self-management is a Western cultural construct, creating empathic and responsive systems might be more effective for improving health of Indigenous and ethnic minority groups rather than relying predominantly on individual skill development. PMID- 26026157 TI - Epigenetics, Darwin, and Lamarck. AB - It is not really helpful to consider modern environmental epigenetics as neo Lamarckian; and there is no evidence that Lamarck considered the idea original to himself. We must all keep learning about inheritance, but attributing modern ideas to early researchers is not helpful, and can be misleading. PMID- 26026149 TI - Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome. AB - Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies. PMID- 26026158 TI - Smartphone-based diagnostic for preeclampsia: an mHealth solution for administering the Congo Red Dot (CRD) test in settings with limited resources. AB - OBJECTIVE: Morbidity and mortality due to preeclampsia in settings with limited resources often results from delayed diagnosis. The Congo Red Dot (CRD) test, a simple modality to assess the presence of misfolded proteins in urine, shows promise as a diagnostic and prognostic tool for preeclampsia. We propose an innovative mobile health (mHealth) solution that enables the quantification of the CRD test as a batch laboratory test, with minimal cost and equipment. METHODS: A smartphone application that guides the user through seven easy steps, and that can be used successfully by non-specialized personnel, was developed. After image acquisition, a robust analysis runs on a smartphone, quantifying the CRD test response without the need for an internet connection or additional hardware. In the first stage, the basic image processing algorithms and supporting test standardizations were developed using urine samples from 218 patients. In the second stage, the standardized procedure was evaluated on 328 urine specimens from 273 women. In the third stage, the application was tested for robustness using four different operators and 94 altered samples. RESULTS: In the first stage, the image processing chain was set up with high correlation to manual analysis (z-test P < 0.001). In the second stage, a high agreement between manual and automated processing was calculated (Lin's concordance coefficient rhoc = 0.968). In the last stage, sources of error were identified and remedies were developed accordingly. Altered samples resulted in an acceptable concordance with the manual gold-standard (Lin's rhoc = 0.914). CONCLUSION: Combining smartphone-based image analysis with molecular-specific disease features represents a cost-effective application of mHealth that has the potential to fill gaps in access to health care solutions that are critical to reducing adverse events in resource-poor settings. PMID- 26026159 TI - Denoising DNA deep sequencing data-high-throughput sequencing errors and their correction. AB - Characterizing the errors generated by common high-throughput sequencing platforms and telling true genetic variation from technical artefacts are two interdependent steps, essential to many analyses such as single nucleotide variant calling, haplotype inference, sequence assembly and evolutionary studies. Both random and systematic errors can show a specific occurrence profile for each of the six prominent sequencing platforms surveyed here: 454 pyrosequencing, Complete Genomics DNA nanoball sequencing, Illumina sequencing by synthesis, Ion Torrent semiconductor sequencing, Pacific Biosciences single-molecule real-time sequencing and Oxford Nanopore sequencing. There is a large variety of programs available for error removal in sequencing read data, which differ in the error models and statistical techniques they use, the features of the data they analyse, the parameters they determine from them and the data structures and algorithms they use. We highlight the assumptions they make and for which data types these hold, providing guidance which tools to consider for benchmarking with regard to the data properties. While no benchmarking results are included here, such specific benchmarks would greatly inform tool choices and future software development. The development of stand-alone error correctors, as well as single nucleotide variant and haplotype callers, could also benefit from using more of the knowledge about error profiles and from (re)combining ideas from the existing approaches presented here. PMID- 26026160 TI - Outwitting EF-Tu and the ribosome: translation with d-amino acids. AB - Key components of the translational apparatus, i.e. ribosomes, elongation factor EF-Tu and most aminoacyl-tRNA synthetases, are stereoselective and prevent incorporation of d-amino acids (d-aa) into polypeptides. The rare appearance of d aa in natural polypeptides arises from post-translational modifications or non ribosomal synthesis. We introduce an in vitro translation system that enables single incorporation of 17 out of 18 tested d-aa into a polypeptide; incorporation of two or three successive d-aa was also observed in several cases. The system consists of wild-type components and d-aa are introduced via artificially charged, unmodified tRNA(Gly) that was selected according to the rules of 'thermodynamic compensation'. The results reveal an unexpected plasticity of the ribosomal peptidyltransferase center and thus shed new light on the mechanism of chiral discrimination during translation. Furthermore, ribosomal incorporation of d-aa into polypeptides may greatly expand the armamentarium of in vitro translation towards the identification of peptides and proteins with new properties and functions. PMID- 26026161 TI - A Pressure-dependent Model for the Regulation of Lipoprotein Lipase by Apolipoprotein C-II. AB - Apolipoprotein C-II (apoC-II) is the co-factor for lipoprotein lipase (LPL) at the surface of triacylglycerol-rich lipoproteins. LPL hydrolyzes triacylglycerol, which increases local surface pressure as surface area decreases and amphipathic products transiently accumulate at the lipoprotein surface. To understand how apoC-II adapts to these pressure changes, we characterized the behavior of apoC II at multiple lipid/water interfaces. ApoC-II adsorption to a triacylglycerol/water interface resulted in large increases in surface pressure. ApoC-II was exchangeable at this interface and desorbed on interfacial compressions. These compressions increase surface pressure and mimic the action of LPL. Analysis of gradual compressions showed that apoC-II undergoes a two-step desorption, which indicates that lipid-bound apoC-II can exhibit at least two conformations. We characterized apoC-II at phospholipid/triacylglycerol/water interfaces, which more closely mimic lipoprotein surfaces. ApoC-II had a large exclusion pressure, similar to that of apoC-I and apoC-III. However, apoC-II desorbed at retention pressures higher than those seen with the other apoCs. This suggests that it is unlikely that apoC-I and apoC-III inhibit LPL via displacement of apoC-II from the lipoprotein surface. Upon rapid compressions and re-expansions, re-adsorption of apoC-II increased pressure by lower amounts than its initial adsorption. This indicates that apoC-II removed phospholipid from the interface upon desorption. These results suggest that apoC-II regulates the activity of LPL in a pressure-dependent manner. ApoC-II is provided as a component of triacylglycerol-rich lipoproteins and is the co-factor for LPL as pressure increases. Above its retention pressure, apoC-II desorbs and removes phospholipid. This triggers release of LPL from lipoproteins. PMID- 26026162 TI - A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). AB - The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Evidence for clinical benefit from new treatment options is derived from clinical research, in particular phase III randomised trials, which generate unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented, discussed and promoted as major advances or 'breakthroughs'. Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high-quality clinical trials, the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the magnitude of clinical benefit for cancer medicines, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost effective and affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis. PMID- 26026164 TI - Ictal SPECT in patients with rapid eye movement sleep behaviour disorder. PMID- 26026163 TI - Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. AB - Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes. PMID- 26026166 TI - miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts. AB - There is increasing evidence that the expression of microRNA (miRNA) in cancer is associated with chemosensitivity but the mechanism of miRNA-induced chemoresistance has not been fully elucidated. The aim of this study was to examine the role of extracellular miRNA in the response to chemotherapy in esophageal cancer. First, serum expression of miRNAs selected by miRNA array was measured by quantitative reverse transcription-polymerase chain reaction in 68 patients with esophageal cancer who received cisplatin-based chemotherapy to examine the relationship between miRNA expression and response to chemotherapy. The serum expression levels of 18 miRNAs were different between responders and non-responders by miRNA array. Of these, high expression levels of miR-27a/b correlated with poor response to chemotherapy in patients with esophageal cancer. Next, in vitro assays were conducted to investigate the mechanism of miRNA induced chemoresistance. Although transfection of miR-27a/b to cancer cells had no significant impact on chemosensitivity, esophageal cancer cells cultured in supernatant of miR-27a/b-transfected normal fibroblast showed reduced chemosensitivity to cisplatin, compared with cancer cells cultured in supernatant of normal fibroblast. MiR-27a/b-transfected normal fibroblast showed alpha-smooth muscle actin (alpha-SMA) expression, a marker of cancer-associated fibroblasts (CAF) and increased production of transforming growth factor-beta (TGF-beta). Chemosensitivity recovered after administration of neutralizing antibody of TGF beta to the supernatant transfer experiments. Our results indicated that miR 27a/b is involved in resistance to chemotherapy in esophageal cancer, through miR 27a/b-induced transformation of normal fibroblast into CAF. PMID- 26026167 TI - RPdb: a database of experimentally verified cellular reprogramming records. AB - Many cell lines can be reprogrammed to other cell lines by forced expression of a few transcription factors or by specifically designed culture methods, which have attracted a great interest in the field of regenerative medicine and stem cell research. Plenty of cell lines have been used to generate induced pluripotent stem cells (IPSCs) by expressing a group of genes and microRNAs. These IPSCs can differentiate into somatic cells to promote tissue regeneration. Similarly, many somatic cells can be directly reprogrammed to other cells without a stem cell state. All these findings are helpful in searching for new reprogramming methods and understanding the biological mechanism inside. However, to the best of our knowledge, there is still no database dedicated to integrating the reprogramming records. We built RPdb (cellular reprogramming database) to collect cellular reprogramming information and make it easy to access. All entries in RPdb are manually extracted from more than 2000 published articles, which is helpful for researchers in regenerative medicine and cell biology. AVAILABILITY AND IMPLEMENTATION: RPdb is freely available on the web at http://bioinformatics.ustc.edu.cn/rpdb with all major browsers supported. CONTACT: aoli@ustc.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26026168 TI - lpNet: a linear programming approach to reconstruct signal transduction networks. AB - With the widespread availability of high-throughput experimental technologies it has become possible to study hundreds to thousands of cellular factors simultaneously, such as coding- or non-coding mRNA or protein concentrations. Still, extracting information about the underlying regulatory or signaling interactions from these data remains a difficult challenge. We present a flexible approach towards network inference based on linear programming. Our method reconstructs the interactions of factors from a combination of perturbation/non perturbation and steady-state/time-series data. We show both on simulated and real data that our methods are able to reconstruct the underlying networks fast and efficiently, thus shedding new light on biological processes and, in particular, into disease's mechanisms of action. We have implemented the approach as an R package available through bioconductor. AVAILABILITY AND IMPLEMENTATION: This R package is freely available under the Gnu Public License (GPL-3) from bioconductor.org (http://bioconductor.org/packages/release/bioc/html/lpNet.html) and is compatible with most operating systems (Windows, Linux, Mac OS) and hardware architectures. CONTACT: bettina.knapp@helmholtz-muenchen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26026165 TI - A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues. AB - Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardized framework for such in vitro evaluation. We tested human insulin; the super mitogenic insulin, X10 and insulin-like growth factor I, in four cancer cell lines with a range of insulin-like growth factor-I receptor (IGF-IR)/IR (insulin receptor) ratios (HCT 116, HT-29, COLO 205 and MCF7) and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IR-A isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time varying experiments, and performed mitogenic dose-response equivalent assays to derive EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 values onto data from the literature in a meta-analysis. The IGF IR/IR ratios varied from <1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for insulin like growth factor I (IGF-I) and correlated with IGF-IR/IR ratios. The meta analysis, adding data from five additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bioassays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities. PMID- 26026169 TI - DisVis: quantifying and visualizing accessible interaction space of distance restrained biomolecular complexes. AB - We present DisVis, a Python package and command line tool to calculate the reduced accessible interaction space of distance-restrained binary protein complexes, allowing for direct visualization and quantification of the information content of the distance restraints. The approach is general and can also be used as a knowledge-based distance energy term in FFT-based docking directly during the sampling stage. AVAILABILITY AND IMPLEMENTATION: The source code with documentation is freely available from https://github.com/haddocking/disvis. CONTACT: a.m.j.j.bonvin@uu.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26026171 TI - Prospective evaluation of azole resistance in Aspergillus fumigatus clinical isolates in France. AB - OBJECTIVES: Several studies, especially in Europe, have recently reported the emerging phenomenon of azole resistance in Aspergillus fumigatus, but very few data are available in France. Our study aimed to determine the resistance prevalence in A. fumigatus isolates recovered from clinical samples over a 1-year period in two university hospital centers. METHODS: All A. fumigatus isolates were screened for azole resistance using RPMI agar plates supplemented with itraconazole and voriconazole. Resistance was then confirmed by the EUCAST method. A part of the beta-tubulin gene was amplified for resistant isolates to confirm the A. fumigatus species, and the Cyp51A gene and its promoter were afterward sequenced to detect mutations potentially responsible for this resistance. RESULTS: One hundred sixty-five A. fumigatus isolates were recovered from 134 patients. Three isolates recovered from three patients were found resistant with MICs of >8 mg/l, 4 mg/l, and 1 mg/l for itraconazole, voriconazole, and posaconazole, respectively. The TR34/L98H mutation, previously and largely described in other countries, was detected in the three isolates. CONCLUSION: Our study demonstrated the occurrence of azole resistance among unselected A. fumigatus clinical isolates, with an overall prevalence of 1.8%. PMID- 26026170 TI - Polymorphonuclear neutrophils and granulocytic myeloid-derived suppressor cells inhibit natural killer cell activity toward Aspergillus fumigatus. AB - Invasive aspergillosis is a devastating infectious disease in immunocompromised patients. Besides neutrophils and macrophages, natural killer (NK) cells have recently emerged as important players in immunity to this infection. It was shown that NK cells comprise an essential role in the clearance of Aspergillus fumigatus (A. fumigatus) in neutropenic but not in nonneutropenic mice. However, the antifungal activity of NK cells and their regulation have not been fully characterized. In this study, we investigated the interplay between polymorphonuclear neutrophils (PMNs) or granulocyte myeloid-derived suppressor cells (Gr-MDSCs) with NK cells. Both cell types exhibited an equal inhibitory effect on NK cell activation through downregulation of NKp30 expression on the cell surface and cytotoxicity towards the cell line K562. Furthermore, we showed that NK cell activation and antifungal cytotoxicity were impaired when NK cells had been cultured in the presence of PMNs or Gr-MDSCs before fungal stimulation. Besides the reduced cytotoxicity a decreased release of interferon gamma (IFNgamma), a key player in the clearance of an A. fumigatus infection, was observed. Thus, inhibition of NK cell activity by PMNs or Gr-MDSCs might impair an effective anti-fungal immune response during recovery from conditions such as hematopoietic stem cell transplantation. PMID- 26026172 TI - Analysis of asthma patients for cryptococcal seroreactivity in an urban German area. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised patients but is also able to asymptomatically infect immunocompetent individuals. C. neoformans is found ubiquitously especially in urban areas where it is spread by pigeons, and fungal exposure may predispose for asthma development already at an early age, as soon as confronted with pigeon droppings. In the study presented here, we investigated the presence of specific immunoglobulin G (IgG) against C. neoformans in sera from patients suffering from asthma in comparison to a healthy control cohort, accrued from the Leipzig Research Centre for Civilization Diseases (LIFE). For serological analysis we developed a flow cytometry (FACS) based assay specific for an acapsular strain of C. neoformans to comprehensively analyze different cryptococcal serotypes. Compared with the non-asthmatic cohort, asthmatics exhibited, as expected, an elevated level of total serum immunoglobulin E (IgE), whereas the IgG seroreactivity against C. neoformans was not significantly different among the two groups (P = .118). Nevertheless, there was a trend toward increased Cryptococcus-specific IgG antibodies in the serum of asthmatics. Additionally, in male asthmatics an increased IgG-mediated seroreactivity compared to female asthmatics was found. This points to a higher prevalence of subclinical C. neoformans infection in male asthmatics and may support the hypothesis of C. neoformans as a risk factor for the development of asthma in urban areas. PMID- 26026173 TI - Allergic fungal rhino sinusitis with granulomas: A new entity? AB - INTRODUCTION: Allergic fungal rhino sinusitis (AFS) is classically described as allergic manifestation to the fungal antigen present in sinuses with no evidence of invasion. Granulomas in histopathology, suspicious of invasion, are occasionally observed in AFS and the disease in these patients behaves like invasive fungal sinusitis even without histologic evidence of invasion. We retrospectively studied AFS patients to analyze whether AFS should be continued to be designated as an allergic entity. MATERIAL AND METHODS: AFS patients operated from January 2009 to July 2013 were retrospectively reviewed. Of the total 57 cases operated in last 4 years, nine showing presence of granuloma in histology were included in the AFS with granuloma Group (group 1) and the rest 48 were included in the AFS group (group 2). Both the groups were compared in terms of various parameters at presentation, treatment course and rate of recurrence. RESULTS: Group 1 had significantly high rates of orbital erosion (P = .000), with positive association of skull base erosion (P = .092) and high rates of telecanthus (P = .000), diplopia (P = .000), proptosis (P = .161) and facial pain. Recurrent surgery was needed in 8 of 9 patients in the group 1 as compared to 1 of 48 patients group 2. CONCLUSION: Granulomas suggests a more severe disease with a trend toward the invasive fungal sinusitis and alerts the clinician regarding the nature of progression. AFS seems to be a part of a continuous spectrum of fungal sinusitis rather than an allergic form as a distinct entity. PMID- 26026174 TI - The use of biomarkers and molecular methods for the earlier diagnosis of invasive aspergillosis in immunocompromised patients. AB - Invasive aspergillosis (IA) is an opportunistic infection that is often life threatening in the immunocompromised host. Early diagnosis is critical, especially given the efficacy and availability of several new anti-fungal therapies. Current (2008) diagnostic criteria have limited ability to detect early infection and are aimed at establishing disease. Although histopathology and culture techniques have traditionally been used to make a proven diagnosis of IA, their dependence on tissue samples and slow turnaround times hamper early confirmation of IA. Serologic detection of circulating galactomannan and 1,3-beta D-glucan fungal biomarkers show promise for improving the diagnosis of IA, and their use is included in the EORTC/MSG diagnostic criteria for IA. Numerous studies have evaluated the diagnostic performance of these two biomarkers and shown that they have suboptimal sensitivity when used alone for early diagnosis of proven IA. Currently available molecular assays also suffer from a lack of standardization. Evaluation of the use of different combinations of test methods to enhance diagnostic accuracy is also being done but prompt, accurate diagnosis of IA remains a clinical and diagnostic challenge. The clinical validity and limitations of biomarkers and current molecular methods for the early diagnosis of IA are summarized in this review with respect to the different patient populations at risk for this serious infection. PMID- 26026175 TI - Designing and evaluating a patient-centred health management system for seniors. AB - INTRODUCTION: Telehealth has been widely promoted as a technology to make healthcare more effective and affordable. However, current telehealth systems suffer from vendor lock-in and high cost, and are designed for managing chronic diseases rather than preventing them. METHODS: We address shortcomings of existing consumer-level health informatics applications in supporting senior health consumers, and provide designers of such systems with a design framework. We assess the feasibility of patient-centred health management systems (HMSs) that are designed based on the proposed framework. In contrast to traditional telehealth, HMSs are patient centred and aim at enabling health consumers to take control of their own health by providing functionality for health self management. Quantitative and qualitative methods were adopted in evaluating a prototype HMS. RESULTS: Senior healthcare consumers viewed our HMS prototype positively, and experienced a positive change in their attitude towards their health. We identified requirements and challenges for HMSs. In particular, participants indicated that social networking features must have a clear purpose beyond simple broadcasting of emotions and opinions. DISCUSSION: Our study indicates that seniors are able and motivated to leverage a web-based patient centred HMS, provided that there are suitable health support applications tailored to their needs. This could be achieved by making it attractive for third party application developers to contribute HMS content. PMID- 26026176 TI - The impact of a text messaging service on orthopaedic clinic Did Not Attend rates. AB - BACKGROUND: Missed clinic appointments cause delays in treatment of other patients, under utilization of clinical manpower or facilities and impact upon hospital finances. AIMS: The primary aim of this study is to evaluate whether a text messaging reminder service reduces the Did Not Attend rate. The secondary aim is to evaluate the cost-effectiveness of a mobile text message reminder service. METHODS: The study focused on the outpatient department of a district general hospital. In January 2011 a patient text messaging reminder service was implemented across the outpatient departments in the trust. Data were collected prospectively 24 months prior and 24 months following the implementation of this service. A reminder was sent to patients one week prior to the scheduled appointment as a text message. All patients attending the orthopaedic department were included in the study. Patients who had an appointment and cancelled/rescheduled it prior to their original consultation date were excluded. Children were also excluded from the study. RESULTS: The overall Did Not Attend rate was reduced by 12% following the intervention (p < 0.0001). The new appointment follow-up rate was reduced by 2% (p = 0.74) and the follow-up rate decreased by 13.7% (p < 0.0001). The economic analysis revealed a saving of L19,853 over a two-year period following the intervention. CONCLUSION: Thus mobile technology is a feasible tool in improving attendance rates at outpatient clinics and is economically viable. PMID- 26026177 TI - Assessing the impact of telestration on surgical telementoring: A randomized controlled trial. AB - INTRODUCTION: Using graphical annotations in surgical telementoring promises vast improvements in both clinical and educational outcomes. However, these assumptions do not consider the potential patient safety risks resulting from this feature. Major differences in regulations regarding the implementation of telestration encourage an assessment of the utility of this feature on the outcomes of telementoring sessions. METHODS: Eight students participated in a randomized controlled trial, comparing verbal with annotation-supplemented telementoring via video conferencing. A remote mentor guided the participants through four localization exercises, identifying the features in a still laparoscopic surgery scene using a laparoscopic simulator. Clinical and educational outcomes were assessed; the time consumption and quality of mentoring were determined. RESULTS: The study revealed no significant difference in localizing the intervention between the studied methods, while educational outcomes favoured verbal mentoring. Telestration-supplemented guidance was considerably faster and resulted in fewer miscommunications between the mentor and mentee. DISCUSSION: The initial hypothesis of the major clinical and education benefits of telestration in telementoring was not supported. A potential 33% decrease in the duration of the mentored episodes is expected due to the ability to annotate live video content. However, the impact of time saving on the outcome of the procedure remains unclear. Regardless of the quantitative measures, most of the participants and the mentor agreed that graphical annotations provide advantages over verbal guidance. PMID- 26026178 TI - Association of time on outcome after intravenous thrombolysis in the elderly in a telestroke network. AB - BACKGROUND: Recent studies showed that the safety and benefit of early intravenous (IV) thrombolysis on favourable outcomes in acute ischemic stroke are also seen in the elderly. Furthermore, it has shown that age increases times for pre- and in-hospital procedures. We aimed to assess the applicability of these findings to telestroke. METHODS: We retrospectively analysed 542 of 1659 screened consecutive stroke patients treated with IV thrombolysis in our telestroke network in East-Saxony, Germany from 2007 to 2012. Outcome data were symptomatic intracranial hemorrhage (sICH) by ECASS-2-criteria, survival at discharge and favourable outcome, defined as a modified Rankin scale (mRS) of 0-2 at discharge. RESULTS: Thirty-three percent of patients were older than 80 years (elderly). Being elderly was associated with higher risk of sICH (p = 0.003), less favourable outcomes (p = 0.02) and higher mortality (p = 0.01). Using logistic regression analysis, earlier onset-to-treatment time was associated with favourable outcomes in not elderly patients (adjusted odds ratio (OR) 1.18; 95% CI 1.03-1.34; p = 0.01), and tended to be associated with favourable outcomes (adjusted OR 1.13; 95% CI 0.92-1.38; p = 0.25) and less sICH (adjusted OR 0.88; 95% CI 0.76-1.03; p = 0.11) in elderly patients. Age caused no significant differences in onset-to-door-time (p = 0.25), door-to-treatment-time (p = 0.06) or onset-to-treatment-time (p = 0.29). CONCLUSION: Treatment time seems to be critical for favourable outcome after acute ischemic stroke in the elderly. Age is not associated with longer delivery times for thrombolysis in telestroke. PMID- 26026179 TI - Use of and interest in mobile health for diabetes self-care in vulnerable populations. AB - OBJECTIVE: We aimed to assess use of and interest in mobile health (mHealth) technology and in-person services for diabetes self-care in vulnerable populations. METHODS: We delivered a self-administered cross-sectional survey. Participants were recruited at two primary care practices (P1 and P2) with P1 located in a medically underserved area and P2 in an affluent suburb. Two-sample t-tests and chi-square tests were used with p < 0.05 significant. In addition, a secondary analysis was performed to analyse differences in use and interest in mHealth by age. RESULTS: Of 75 eligible patients, 60 completed the survey (80% response rate). P1 patients had significantly higher interest in three of five categories of in-person diabetes support services, one of four categories of health-related text messages (TM), and three of eight categories of mHealth applications (p < 0.05). Smartphone users reported higher interest in TM (p = 0.004) and mHealth applications for diabetes self-care (p = 0.004). Younger patients were more likely to have a smartphone (p < 0.006), use the Internet (p < 0.0012), use smartphone applications (p < 0.0004), and to be interested in using applications to manage their diabetes (p < 0.004). DISCUSSION: This study shows substantial patient interest in TM and mHealth applications for diabetes self care and suggests that patients in underserved areas may have particularly high interest in using mHealth solutions in primary care. Younger patients and smartphone users were more likely to be interested in using applications to manage their diabetes. As more patients use smartphones, interest in using mHealth to support patient self-care and strengthen primary care infrastructure will continue to grow. PMID- 26026180 TI - Internet health seeking behaviour of parents attending a general paediatric outpatient clinic: A cross-sectional observational study. AB - INTRODUCTION: Our aim was to examine the internet health seeking behaviour of parents attending a general paediatric outpatient clinic. For this purpose, the proportion of parents going online to obtain child health information, the most commonly used online resources, and factors having an influence on internet usage were identified. METHODS: This cross-sectional observational study was conducted at a general paediatric outpatient clinic in Vienna, Austria. Data collection was done by means of an anonymous questionnaire containing 14 items. A total number of 500 questionnaires were collected. RESULTS: Among parents visiting the outpatient clinic, 94.4% use the internet to obtain child health information in general and 21% to be informed about the reason for consultation. Most commonly used online resources are Google (91.4%), websites run by doctors (84.8%), Wikipedia (84.7%), health portals (76.4%), the outpatient clinic's homepage (76.4%), as well as health forums and communities (61.9%). Younger parents (p = 0.022) and parents of younger children (p < 0.01) display a higher tendency to use the internet for child health information purposes. Mothers and fathers (p = 0.151) as well as parents with different completed educational levels (mothers: p = 0.078; fathers: p = 0.388) do not differ in this behaviour. DISCUSSION: Important reasons for high internet use might be the inexperience of young parents regarding child health as well as the frequent infections, vaccinations, and preventive check-ups which are associated with young age of children. In contrast to former findings relating to health seekers in general, internet usage of parents is independent of their sex and educational level. PMID- 26026181 TI - A systematic review of the use of telehealth in speech, language and hearing sciences. AB - INTRODUCTION: We conducted a systematic literature review to investigate the domain of speech-language and hearing sciences (SLHS) in telehealth. METHODS: The databases used for the literature search were Web of Knowledge, Pubmed, Scopus, Embase and Scielo. The inclusion criteria consisted of papers published up to August 2014. Papers without peer-review evaluation, and those without abstracts or available full texts were excluded. RESULTS: A total of 103 papers were selected. The selected studies have focused primarily on hearing (32.1%), followed by speech (19.4%), language (16.5%), voice (8.7%), swallowing (5.8%), multiple areas (13.6%) and others (3.9%). The majority of the studies focused on assessment (36.9%) or intervention (36.9%). The use of telehealth in SLHS has been increasing in many countries, especially in the last 5 years. The country with the largest number of published studies was the United States of America (32.03%), followed by Australia (29.12%). The remaining studies were distributed in lower numbers among other countries. DISCUSSION: The advancement of information and communication technologies provides more favourable conditions for providing distance care in several areas. Most of studies concluded that the telehealth procedure had advantages over the non-telehealth alternative approach (85.5%); however, 13.6% reported that it was unclear whether the telehealth procedure had advantages. Some barriers still need to be overcome, such as technology, training, regulation, acceptance and recognition of the benefits of this practice by the public and professionals. The need for speech-language pathologists and audiologists to adapt to this new health care modality is evident. PMID- 26026182 TI - Speed and accuracy of text-messaging emergency department electrocardiograms from a small community hospital to a provincial referral center. AB - BACKGROUND: Currently, transmission of electrocardiograms (EKGs) from a small emergency department (ED) to specialists at referral hospitals can be a time consuming and laborious process. We investigate whether text messaging by use of short message service (SMS) of EKGs from a small hospital to consultants at a large hospital is rapid and accurate. METHODS: This study involved a one-month prospective evaluation of consecutive EKGs recorded in a small community ED. Investigators obtained de-identified photographs of each EKG via a mobile phone camera. Each EKG picture, along with a brief patient clinical history, was sent via SMS to on-call emergency physicians located at a large referral care site. All images were evaluated solely on a mobile phone. The primary outcome was the proportion of SMS that were received within two minutes of being sent. As a secondary outcome, the intra-rater evaluation of the initial EKG and the SMS EKG image were compared on 13 standardized features. The tertiary outcome was cost of text messaging. RESULTS: A total of 298 patients (14.6%) had 409 EKGs performed and a total of 926 SMS were sent. 921 SMS (99.5%, 95% confidence interval (CI) 98.7-99.8%) arrived within two minutes with a median transmission time of nine seconds (interquartile range (IQR) 3-32 s). Between the gold standard original EKG, and the interpretation of the texted image, six out of 409 (1.5%, 95% CI 0.6 3.3%) had any differences recorded, across all 13 categories. Overall, the study cost 4.1 cents per texted image. CONCLUSIONS: Systematic text messaging of ED EKGs from a small community hospital to a referral center is a rapid, accurate, portable, and inexpensive method of data transfer. This may be a safe and effective strategy to communicate vital patient information. PMID- 26026183 TI - A comparative study on the effectiveness of one-way printed communication versus videophone interactive interviews on health promotion. AB - INTRODUCTION: We performed a comparative study of a health education programme that was delivered either through one-way communication with printed media, or through interactive videophone interviews. We aimed to ascertain which mode of counselling, when used in combination with telemonitoring, is more effective at lifestyle modification intended to improve health status. METHODS: Participants, who were residents of Kurihara city in Miyagi prefecture, Japan, were randomized into two groups: one group received individualized monthly documented reports (n = 33; 22 females; average age: 67.2 years), and the other received interactive videophone communication (n = 35; 22 females; average age: 65.1 years) for three months. Telemonitoring was conducted on both groups, using a pedometer, weighing scale and a sphygmomanometer. Pre- and post-intervention, anthropometric measurements and blood tests were performed; the participants also completed self administered questionnaires. RESULTS AND DISCUSSION: The two groups showed similar degrees of health status improvement and satisfaction levels. However, the participants in the videophone group were more aware of improvements in their lifestyles than were the participants in the document group. The individualized printed communication programme was less time-consuming compared to videophone communication. Further studies are needed to formulate a balanced protocol for a counselling-cum-telemonitoring programme that provides optimal health improvement and cost performance with the available human resources. PMID- 26026184 TI - Consumer preferences for teledermoscopy screening to detect melanoma early. AB - INTRODUCTION: 'Store and forward' teledermoscopy is a technology with potential advantages for melanoma screening. Any large-scale implementation of this technology is dependent on consumer acceptance. AIM: To investigate preferences for melanoma screening options compared with skin self-examination in adults considered to be at increased risk of developing skin cancer. METHODS: A discrete choice experiment was completed by 35 consumers, all of whom had prior experience with the use of teledermoscopy, in Queensland, Australia. Participants made 12 choices between screening alternatives described by seven attributes including monetary cost. A mixed logit model was used to estimate the relative weights that consumers place on different aspects of screening, along with the marginal willingness to pay for teledermoscopy as opposed to screening at a clinic. RESULTS: Overall, participants preferred screening/diagnosis by a health professional rather than skin self-examination. Key drivers of screening choice were for results to be reviewed by a dermatologist; a higher detection rate; fewer non-cancerous moles being removed in relation to every skin cancer detected; and less time spent away from usual activities. On average, participants were willing to pay AUD110 to have teledermoscopy with dermatologist review available to them as a screening option. DISCUSSION AND CONCLUSIONS: Consumers preferentially value aspects of care that are more feasible with a teledermoscopy screening model, as compared with other skin cancer screening and diagnosis options. This study adds to previous literature in the area which has relied on the use of consumer satisfaction scales to assess the acceptability of teledermoscopy. PMID- 26026185 TI - The effectiveness of telephone counselling in the treatment of illicit drug and alcohol use concerns. AB - INTRODUCTION: Technology-assisted substance use interventions such as 'high-tech' internet-based treatments are thought to be effective; however, the relatively 'low-tech' use of telephone counselling does not yet have an established evidence base. This paper reviews the literature including articles with information on the use of telephone counselling for the treatment of illicit drug or alcohol use. METHODS: A systematic literature search using a set of telephone counselling and substance-related terms was conducted across four electronic databases. English studies prior to June 2014 that involved the use of telephone counselling with the treatment of illicit drug or alcohol use as a primary or secondary outcome were included. Review papers, opinion pieces, letters or editorials, case studies, published abstracts, and posters were excluded. In all, 94 publications were included in the review. RESULTS AND DISCUSSION: The literature was supportive of telephone counselling for the treatment of alcohol use in the short term; however, literature regarding illicit drug use was particularly scarce. The generalisability of findings was limited by evident methodological issues in the included studies. PMID- 26026187 TI - Home spirometry: Assessment of patient compliance and satisfaction and its impact on early diagnosis of pulmonary symptoms in post-lung transplantation patients. AB - Telemedicine is useful in monitoring patients, and in particular those, such as lung transplant recipients, suffering from chronic illnesses. This prospective cohort study was conducted on 15 lung transplant recipients. The patients provided physicians with data from spirometry as well as their clinical respiratory symptoms via SMS messages. In cases where spirometry results or clinical symptoms required follow-up, the monitoring physician contacted the patient according to guidelines and gave appropriate instructions. Qualitative assessment of satisfaction showed that the sense of increased support from medical staff was rated highest (92.9%). Telespirometry is an efficient method of monitoring lung transplant recipients which leads to patient satisfaction, compliance, adherence to study and sense of security. Nevertheless, for optimal implementation of this method, thorough training of both medical staff and patients is required. PMID- 26026186 TI - Treating rural paediatric obesity through telemedicine vs. telephone: Outcomes from a cluster randomized controlled trial. AB - OBJECTIVE: The objective of the current study was to examine the feasibility of telemedicine vs. telephone for the delivery of a multidisciplinary weekly family based behavioural group intervention to treat paediatric obesity delivered to families living in rural areas using a randomized controlled trial methodology. METHODS: 103 rural children and their families were recruited. Feasibility measures included participant satisfaction, session attendance and retention. Treatment outcome measures included child Body Mass Index z-score (BMIz), parent BMI, 24-hour dietary recalls, accelerometer data, the child behavior checklist and the behavioral pediatrics feeding assessment scale. RESULTS: Participants were highly satisfied with the intervention both via telemedicine and via telephone. Completion rates were much higher than for other paediatric obesity intervention programmes, and both methodologies were highly feasible. There were no differences in telemedicine and telephone groups on primary outcomes. CONCLUSION: Both telemedicine and telephone intervention appear to be feasible and acceptable methods of delivering paediatric obesity treatment to rural children. PMID- 26026188 TI - A meta-review of Internet computer-based psychological treatments for anxiety disorders. AB - INTRODUCTION: Internet computer-based psychological treatments have enjoyed rapid growth. Today, there are a number of them available for many mental disorders and psychological problems. Internet-based psychological treatments for anxiety disorders and phobias are amongst the most frequently observed. Treatment results with these resources are promising, but inconclusive. METHODS: This paper reviews 11 systematic reviews and meta-analyses about the efficacy of Internet-based psychological treatments for anxiety disorders, including studies and clinical trials covering the majority of anxiety disorders and phobias, usually with adult patient samples. RESULTS: In general, these reviews agree on the efficacy of Internet-based psychological treatment as compared with non-treatment groups (with large effect sizes), finding similar efficacy compared with face-to-face therapies. Internet-based psychological treatments are further improved when combined with some type of therapist contact. On the negative side, some systematic reviews highlight high attrition rates of Internet-based psychological treatments. DISCUSSION: These findings remain inconclusive and more refined reviews (involving patient samples, therapy comparisons, type of therapist contact, etc.) are needed, in order to establish the scope and limits of Internet based psychological treatments for anxiety disorders. PMID- 26026189 TI - Tele-emergency utilization: In what clinical situations is tele-emergency activated? AB - INTRODUCTION: Tele-emergency provides audio/visual communication between a central emergency care centre (tele-emergency hub) and a distant emergency department (remote ED) for real-time emergency care consultation. The purpose of this mixed methods study is to examine how often tele-emergency is activated in usual practice and in what circumstances it is used. METHODS: Tele-emergency log data and merged electronic medical record data from Avera Health (Sioux Falls, SD) were analysed for 60,193 emergency department (ED) encounters presenting over a two-and-a-half year period at 21 critical access hospitals using the tele emergency service. Of these, tele-emergency was activated for 1512 ED encounters. RESULTS: Analyses indicated that patients presenting at rural EDs with circulatory, injury, mental and symptoms diagnoses were significantly more likely to have tele-emergency department services activated as were patients who were transferred to another hospital. Interviews conducted with 85 clinicians and administrators at 26 rural hospitals that used this service indicated that this pattern of utilization facilitated rapid transfers and followed recommended clinical protocols for patients needing serious and/or urgent attention (e.g. stroke symptoms, chest pain). DISCUSSION: Although only used in 3.5% of ED encounters on average, our findings provide evidence that tele-emergency activation is well reasoned and related to those situations when extra expert assistance is particularly beneficial. PMID- 26026190 TI - A cost comparison of travel models and behavioural telemedicine for rural, Native American populations in New Mexico. AB - OBJECTIVE: The purpose of this study was to model the cost of delivering behavioural health services to rural Native American populations using telecommunications and compare these costs with the travel costs associated with providing equivalent care. METHODS: Behavioural telehealth costs were modelled using equipment, transmission, administrative and IT costs from an established telecommunications centre. Two types of travel models were estimated: a patient travel model and a physician travel model. These costs were modelled using the New Mexico resource geographic information system program (RGIS) and ArcGIS software and unit costs (e.g. fuel prices, vehicle depreciation, lodging, physician wages, and patient wages) that were obtained from the literature and US government agencies. RESULTS: The average per-patient cost of providing behavioural healthcare via telehealth was US$138.34, and the average per-patient travel cost was US$169.76 for physicians and US$333.52 for patients. Sensitivity analysis found these results to be rather robust to changes in imputed parameters and preliminary evidence of economies of scale was found. CONCLUSION: Besides the obvious benefits of increased access to healthcare and reduced health disparities, providing behavioural telehealth for rural Native American populations was estimated to be less costly than modelled equivalent care provided by travelling. Additionally, as administrative and coordination costs are a major component of telehealth costs, as programmes grow to serve more patients, the relative costs of these initial infrastructure as well as overall per-patient costs should decrease. PMID- 26026191 TI - Brain MRI findings in aspartylglucosaminuria. AB - BACKGROUND AND PURPOSE: The aim of this study was to identify characteristic 3.0 T brain MRI findings in patients with aspartylglucosaminuria (AGU), a rare lysosomal storage disorder. Previous AGU patient material imaged at 1.0 and 1.5 T was also re-evaluated. MATERIALS AND METHODS: Twenty-five brain MRI examinations from 20 AGU patients were included in the study. Thirteen patients underwent a prospective 3.0 T MRI (5 male, 8 female, aged 9-45 years). Twelve examinations from nine patients (4 male, 5 female, aged 8-33 years) previously imaged at 1.0 or 1.5 T were re-evaluated. Two patients were included in both the prospective and the retrospective groups. Visual analysis of the T1- and T2-weighted images was performed by two radiologists. RESULTS: The previously reported signal intensity changes in T2-weighted images were visible at all field strengths, but they were more distinct at 3.0 T than at 1.0 or 1.5 T. These included signal intensity decrease in the thalami and especially in the pulvinar nuclei, periventricular signal intensity increase and juxtacortical high signal foci. Poor differentiation between gray and white matter was found in all patients. Some degree of cerebral and/or cerebellar atrophy and mild ventricular dilatation were found in nearly all patients. This study also disclosed various unspecific findings, including a higher than normal incidence of dilated perivascular spaces, arachnoid cysts, pineal cysts and mildly dilated cavum veli interpositi. CONCLUSION: This study revealed particular brain MRI findings in AGU, which can raise the suspicion of this rare disease in clinical practice. PMID- 26026192 TI - Use of a prototype radioprotection cabin in vascular neuroradiology: Dosimetry and ergonomics. AB - OBJECTIVES: The aim of this work was to compare the performance of a prototype radioprotection cabin in interventional neuroradiology, and to assess its suitability for routine use. MATERIALS AND METHODS: The radioprotection cabin was a prototype derived from the CATHPAX AF((r)) model. Three operators carried out 21 procedures (19 brain arteriographies and 2 embolizations) using the radioprotection cabin and not wearing the usual lead individual protection equipment (IPE), and 17 procedures (16 brain arteriographies and 1 embolization) wearing the standard lead IPE (vest, skirt, thyroid shield and goggles), and not using the radioprotection cabin. In all cases, thermoluminescent dosimeters (TLDs) were positioned at head, trunk, pelvic region, and upper and lower limbs to measure the dose equivalent for Hp(0.07) or Hp(3) that they received, attenuated by either the cabin or the lead IPE. Parallel to these dosimetric measurements, the ergonomics of the protection cabin were appraised by each radiologist after each procedure. RESULTS AND CONCLUSION: The cabin procured an overall reduction of 74% of the dose received on the whole body with Hp(0.07)=0.04 mSv +/- 0.01 (CL=95%) against Hp(0.07)=0.12 mSv +/- 0.04 (CL=95%) for the IPE. Body protection with the cabin was near complete, and close to 100% for the regions not protected by the usual IPE (e.g. the head). We also showed that design weaknesses noted by the operators that hampered procedures (light reflections, reduced hand mobility, awkward access to radioscopy pedal) could be remedied by maker's improvements to the prototype and minor changes in work habits. PMID- 26026193 TI - A unique combination of Dyke-Davidoff-Masson syndrome and Down syndrome: Diffusion tensor tractography findings. PMID- 26026195 TI - Design, recruitment, and microbiological considerations in human challenge studies. AB - Since the 18th century a wealth of knowledge regarding infectious disease pathogenesis, prevention, and treatment has been accumulated from findings of infection challenges in human beings. Partly because of improvements to ethical and regulatory guidance, human challenge studies-involving the deliberate exposure of participants to infectious substances-have had a resurgence in popularity in the past few years, in particular for the assessment of vaccines. To provide an overview of the potential use of challenge models, we present historical reports and contemporary views from experts in this type of research. A range of challenge models and practical approaches to generate important data exist and are used to expedite vaccine and therapeutic development and to support public health modelling and interventions. Although human challenge studies provide a unique opportunity to address complex research questions, participant and investigator safety is paramount. To increase the collaborative effort and future success of this area of research, we recommend the development of consensus frameworks and sharing of best practices between investigators. Furthermore, standardisation of challenge procedures and regulatory guidance will help with the feasibility for using challenge models in clinical testing of new disease intervention strategies. PMID- 26026194 TI - Parenchymal FLAIR hyperintensity before thrombolysis is a prognostic factor of ischemic stroke outcome at 3 Tesla. AB - BACKGROUND: The goal of the present study was to determine whether the presence or absence of parenchymal FLAIR hyperintensity alone, before thrombolysis, might be a predictive factor of ischemic stroke outcomes after the acute phase of stroke and at 3 months. MATERIALS AND METHODS: We retrospectively included 84 patients with an ischemic stroke between November 2007 and March 2012, who underwent 3T MRI, were treated by thrombolysis, and had medical follow-up at 3 months. Two readers analyzed parenchymal FLAIR visibility. Logistic regressions were performed for NIHSS difference (NIHSS at admission - NIHSS at the end of hospitalization) and for 3 months modified Ranking Score (mRS). Predictive values of positive parenchymal FLAIR for identifying poor outcome at discharge and at 3 months were estimated. RESULTS: Parenchymal FLAIR positivity was not predictive of NIHSS difference but it predicted poor outcome at 3 months (sensitivity: 0.49 [0.37-0.60], specificity: 0.69 [0.46-0.91], positive predictive value: 0.87 [0.76 0.98] and negative predictive value: 0.24 [0.12-0.36]). CONCLUSIONS: At 3 Tesla, the presence of a parenchymal hyperintense FLAIR signal before thrombolysis is predictive of a poor clinical outcome at 3 months. PMID- 26026196 TI - Comparison patterns of 4 T1 antigens recognized by humoral immune response mediated by IgG and IgM antibodies in female and male mice with breast cancer using 2D-immnunoblots. AB - The early detection of cancer is one of the most promising approaches to reduce its growing burden and develop a curative treatment before the tumor is established. The early diagnosis of breast cancer is the most demanding of all tumors, because it is the most common cancer in women worldwide. We have described a new approach to analyze humoral immune reactions against 4 T1 cell antigens in female mice, reporting that the IgG and IgM responses differed and varied over time and between individuals. In this study, we compared and analyzed the detection of tumor antigens with IgG and IgM from the sera of male mice that were injected with 4 T1 cells into the mammary gland nipple in 2D immunoblot images. The variability in IgM and IgG responses in female and male mice with breast cancer at various stages of disease was characterized, and the properties with regard to antigen recognition were correlated statistically with variables that were associated with the individuals and tumors. The ensuing IgG and IgM responses differed. Only the IgG response decreased over time in female mice--not in male mice. The IgM response was maintained during tumor development in both sexes. Each mouse had a specific pattern of antigen recognition--ie, an immunological signature--represented by a unique set of antigen spots that were recognized by IgM or IgG. These data would support that rationale IgM is a better tool for early diagnosis, because it is not subject to immunosuppression like IgG in female mice with breast cancer. PMID- 26026197 TI - Social networking sites (SNS); exploring their uses and associated value for adolescent mothers in Western Australia in terms of social support provision and building social capital. AB - OBJECTIVE: to explore the use of social networking sites (SNS) by adolescent mothers in Western Australia (WA) in relation to social support and the building of social capital. DESIGN: a constructionist narrative inquiry approach was employed to guide the research design and processes. Approval was gained from the university human ethics department. Sampling was purposeful and data were collected using in-depth interviews with seven adolescent mothers in WA. SETTING: interviews were undertaken within the homes of adolescent mothers across WA. FINDINGS: from within three fundamental domains of social support; tangible, emotional and informational support, provided by SNS use, five key themes were identified from the narratives. 'Social connectedness' was identified as a form of tangible support, sometimes termed 'practical' or 'instrumental' support. This theme incorporates connectedness with family, friends, and peers and across new and existing social groups. Three themes were identified that relate to emotional support; 'increased parenting confidence'; 'reduced parental stress' and 'enhanced self-disclosure' afforded by use of SNS. 'Access to information' was identified in terms of informational support, with participants often highlighting SNS use as their primary portal for information and advice. CONCLUSIONS: the findings of this study suggest that SNS use affords adolescent mothers in WA access to tangible, informational and emotional support and thus is a valuable source of social capital for these mothers. This study provides a platform for further exploration into this phenomenon, and possible implications include the potential for midwives and health care professionals to promote the benefits of SNS use with, and for, this group of mothers, or to incorporate SNS use into modern health care practices to further develop the potential for improved social capital related outcomes for them. PMID- 26026198 TI - Factors associated with antenatal depression and obstetric complications in immigrant women in Geneva. AB - OBJECTIVE: immigrant women are at increased risk for health problems during pregnancy, and for antenatal and postnatal depression. This study aimed to identify sociodemographic and specific psychosocial risk factors of antenatal depression and obstetric complications in an economically and culturally heterogeneous sample. DESIGN: prospective cross-sectional design. SETTING: the study was conducted in a midwifery office. PARTICIPANTS: the community sample included 228 immigrant pregnant women with low French proficiency referred to birth preparation classes between 2006 and 2014 in Geneva, Switzerland. MEASUREMENT: depressive symptoms were measured during the third trimester of pregnancy using the Edinburgh Postnatal Depression Scale. A cut-off score >=12 was considered to be indicative of antenatal depression. FINDINGS: more than half of the participants had been living in Switzerland for less than five years and had a short-term residence permit. Thirty-seven per cent of women scored above the clinical cut-off score. Women with several risk factors, such as a precarious legal status, lack of marital support, difficult living conditions and being a newcomer to Switzerland, were at higher risk of depression. Women who encountered difficult living conditions were at higher risk of obstetric complications. IMPLICATIONS FOR PRACTICE: these results confirm the findings of previous research, and highlight the need for early detection. Public health prevention policies should consist of multidimensional programmes to address simultaneously psychosocial, cultural and obstetric issues in pregnant immigrant women. PMID- 26026199 TI - Reply: To PMID 25640408. PMID- 26026200 TI - Evaluating breast lymphoplasmacytic infiltrates: a multiparameter immunohistochemical study, including assessment of IgG4. AB - Lymphoplasmacytic infiltrates in the breast, a modified skin appendage, include lymphocytic lobulitis, other nonspecific benign proliferations, and mucosa associated lymphoid tissue (MALT)-type lymphoma. Distinguishing these entities, all of which may be B-cell rich and may have associated sclerosis, can be difficult. In addition, the proportion that represents IgG4-related disease is unknown, and the similarity of MALT lymphomas to primary cutaneous marginal zone lymphoma is uncertain. To address these questions, the clinical, histologic, and immunohistochemical features of 50 benign and malignant breast lymphoplasmacytic infiltrates (10 lymphocytic lobulitis, 1 granulomatous, 19 not otherwise specified, 20 MALT lymphomas) were evaluated. Compared with the MALT lymphomas, benign cases had a less dense infiltrate (P < .001), fewer but more histologically apparent germinal centers (P < .001), and more marked fibrosis (P < .0001). Greater than 60% B cells were present in 23% (7/30) benign cases versus 75% (15/20) MALT lymphomas (P = .0003). Plasma cells were predominantly IgG+ in 83% (24/29) benign cases and predominantly IgM+ in 73% (14/19) MALT lymphomas (P < .0001). None of the benign cases had greater than 50 IgG4+ plasma cells/high power field, and only 1 lymphocytic lobulitis case had an IgG4/IgG ratio exceeding 40% and no clinical evidence for extramammary IgG4-related disease. Although there may be some overlapping features, routine histopathology together with limited immunohistochemical stains can distinguish benign from neoplastic lymphoplasmacytic infiltrates in the breast. Despite frequent sclerosis, the breast is not a common site of unrecognized IgG4-related sclerosing disease. Although there are similarities, breast MALT lymphomas can be separated from cutaneous marginal zone lymphoma. PMID- 26026201 TI - Risk factors for nonunion after intramedullary nailing of femoral shaft fractures: Remaining controversies. AB - INTRODUCTION: Intramedullary nailing (IMN) is the preferred treatment for femoral shaft fractures in adults. Although previous studies published good outcomes, some controversies remain. The purpose of this retrospective study was to identify factors that influence outcome after IMN for femoral shaft fractures. MATERIALS AND METHODS: Between July 1998 and July 2013, we treated 230 patients with 248 femoral shaft fractures. Statistical analyses were performed to determine predictors of nonunion. The following set of variables was selected based on the speculation that they would contribute to the outcome: sex (male or female), smoking, obesity, polytrauma, fracture type, open fractures, Gustilo type, primary external fixation (EF) and reaming. RESULTS: Initial fracture stabilization was performed by IMN in 161 (64.9%) and by EF in 87 (35.1%) fractures. There were no documented cases of deep infection. Nonunion was diagnosed in 27 patients with 28 fractures (11.3%). Factors affecting nonunion in the univariate analysis were Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) fracture type (odds ratio [OR] 25.0; p<0.0001), Gustilo type (OR 0.64; p=0.0358), and EF (OR 0.42; p=0.0401). Multiple logistic regression analysis only identified AO/OTA fracture type (OR 22.0; p<0.0001) as a risk factor for nonunion. Fracture reaming did not change the outcome (OR 0.80; p=0.6073). A separate analysis showed that damage control EF was not a risk factor in polytrauma patients (OR 0.76; p=0.5825). CONCLUSIONS: Fracture stabilisation with IMN is a good treatment option for femoral shaft fractures in adults. The purpose of this study was to evaluate risk factors of poor outcome after IMN of femoral shaft fractures. The present analysis revealed that there was no difference in the outcome whether the fracture was reamed or not. Univariate and multivariate analysis could only correlate AO/OTA fracture type with the occurrence of nonunion. Therefore, in this study, unreamed nailing and damage control EF were not associated with a negative outcome. PMID- 26026202 TI - Discharge of emergency patients to the clinical wards or intensive care units: An assessment of complications and possible shortcomings. AB - OBJECTIVE: We aimed to evaluate the most common complications and possible shortcomings in the emergency patients who were admitted to the clinical wards or intensive care units. MATERIALS AND METHODS: 1000 patients were included in this study. The patients's complication rates were compared with the clinical diagnosis, age groups, the section of the emergency department initially managed the patients, the time of the shift (daytime or night), the accompanying medical staff and specific type of patient populations. Also the interventions of the complications were recorded. RESULTS: 37.5% of the patients who were included in the study were female and 62.5% were male. The median age of the patients was 54.2 year (min:1 max:92). The vital signs that were recorded prior to transport of the patients did not interfere with the complication rates (p>0.05). Complication rates in the night were found to be higher as more admissions took place during the night shift (p<0.05). The complication rates were found higher in patients who were admitted to coronary care unit. The most frequent complication was the dislocation of the intravenous catheter. Replacing the dislocated intravenous catheter was the most frequently noted intervention. However, initiating inotropic agents to the hypotensive patients was done more frequently in the admitted clinical departments. CONCLUSION: The overall complication rate was low in this series of patients. The majority of them can be prevented by having in house guidelines. PMID- 26026203 TI - Clinical and functional outcomes and treatment options for paediatric elbow dislocations: Experiences of three trauma centres. AB - Although elbow dislocations are seen rarely in children, their management remains controversial. In this study, over a 7 years period, we evaluated retrospectively the clinical and functional results of paediatric elbow dislocations managed in three different trauma centres. Pure dislocations and dislocations with associated injuries were evaluated separately. In total 56 patients met the inclusion criteria. The number of patients without additional injury was 22 out of which according to the Robert's criteria, 15 children (68%) had an excellent, four (18%) a good, one (5%) a fair, and two (9%) a poor outcome. From the thirty four patients that had associated injuries, two (6%) had an excellent, 6 (18%) a good, 10 (29%) a fair and 16 (47%) a poor result. Overall, patients with pure dislocation were found to have a better range of motion compared to patients with dislocation and associated injuries. Prolonged follow ups, and effective rehabilitation programs are required in order to expect good outcomes. PMID- 26026205 TI - Warfarin use and the risks of stroke and bleeding in hemodialysis patients with atrial fibrillation: A systematic review and a meta-analysis. AB - BACKGROUND AND AIM: The efficacy and safety of warfarin therapy in hemodialysis (HD) patients with atrial fibrillation (AF) remains controversial. Thus, we performed, up to date, the first meta-analysis on the risks of stroke and bleeding in warfarin treatment in these populations. METHODS AND RESULTS: The relevant literature was searched using the following electronic databases without any language restrictions: the Cochrane Library Database, PubMed, ISI, Ovid, and Chinese Biomedical Database from the establishment of the database to October 2014. The studies were included if (a) studies described the risk of stroke or bleeding with or without warfarin in dialysis patients with AF, (b) studies provided information about hazard ratio (HR) and 95% confidence interval (CI) of stroke or bleeding, and (c) the study design was a clinical cohort. The inverse variance method was used to obtain overall HRs and 95% CIs. Sensitivity analyses and publication bias were also performed. We identified six eligible studies with a total of 9816 patients. Combined HRs showed that warfarin cannot prevent strokes in HD patients with AF (HR = 1.23, 95% CI 0.80-1.87; P = 0.347), but its use was associated with a higher risk of bleeding (HR = 1.20, 95% CI 1.03-1.39; P = 0.019). CONCLUSION: This meta-analysis suggested that warfarin should not be recommended for the routine treatment of HD patients with AF. PMID- 26026204 TI - Adiponectin is independently associated with NT-proBNP: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND AND AIMS: To investigate the associations between selected adipokines and the N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). METHODS AND RESULTS: As many as 1489 individuals enrolled in the Multi-Ethnic Study of Atherosclerosis were evaluated at 4 clinic visits about every 2 years. The evaluation included fasting venous blood, which was analyzed for NT-proBNP (at visits 1 and 3) and the adipokines adiponectin and leptin (at visits 2 and 3). The mean age was 64.8 +/- 9.6 years and 48% were female. After multivariable adjustment, a 1-SD increment in adiponectin was associated with a 14 pg/ml higher NT-proBNP level (p < 0.01), while, compared to the 1st quartile of adiponectin, the 2nd, 3rd and 4th quartiles had 28, 45 and 67% higher NT-proBNP levels (p < 0.01 for all). For changes in NT-proBNP over the follow-up period, and after multivariable adjustment including baseline NT-proBNP, a 1-SD increment in adiponectin was associated with a 25 pg/ml absolute increase in NT-proBNP (p < 0.01), while those in the 2nd, 3rd and 4th quartiles of adiponectin were associated with increases of 5, 28 and 65 pg/ml (p = 0.74, 0.09 and <0.01, respectively). There was a significant interaction between adiponectin and sex for visit 3 NT-proBNP (p-interaction < 0.01), with significantly stronger associations in men. Leptin was not associated with NT-proBNP. CONCLUSION: Higher adiponectin, but not leptin, is significantly associated with higher levels of NT proBNP, as well as with greater longitudinal increases in NT-proBNP. The associations were stronger in men. PMID- 26026206 TI - Echocardiographic findings in patients with eating disorders: A case-control study. PMID- 26026207 TI - Centella asiatica and lipoic acid, or a combination thereof, inhibit monocyte adhesion to endothelial cells from umbilical cords of gestational diabetic women. AB - BACKGROUND AND AIMS: Diabetes mellitus is associated with inflammatory endothelial activation and increased vascular leukocyte adhesion molecule expression, both playing a prominent role in the development of vascular complications. Centella asiatica (CA) and Lipoic Acid (LA) have shown anti inflammatory and anti-oxidant properties in a variety of experimental models; however, their action on human umbilical vein endothelial cells (HUVECs), chronically exposed to hyperglycemia and pro-inflammatory environment during pregnancy, is still unknown. METHODS AND RESULTS: In HUVECs from umbilical cords of gestational diabetic (GD) or healthy (C) women, both CA and LA affected tumor necrosis factor-alpha (TNF-alpha)-induced inflammation, being associated with a significant decrease in vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression (western blot) and exposure (flow cytometry), as well as monocyte-HUVECs interaction (adhesion assay). Notably, this was associated with a significant reduction of an index of nitro oxidative stress, such as the intracellular peroxynitrite levels (fluorescence detection by cytometric analysis), Mitogen-Activated Protein kinase (p44/42 MAPK) expression/phosphorylation levels and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB p65) cytoplasm-nucleus translocation (flow cytometry). Overall our results indicate that both CA and LA used separately, and even better when combined, are effective to reduce the inflammatory response in TNF-alpha-treated HUVECs. Notably, this was more significant in GD than in C HUVECs and also evident at baseline. CONCLUSION: In conclusion, our in vitro study demonstrates that both CA and LA, or a combination thereof, are able to mitigate the potentially dangerous effects on the endothelium of chronic exposure to hyperglycemia in vivo. PMID- 26026209 TI - Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p-cresyl sulfate in chronic kidney disease patients. AB - BACKGROUND AND AIMS: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are uremic toxins derived solely from colonic bacterial fermentation of protein. Dietary fiber may counteract this by limiting proteolytic bacterial fermentation. However, the influence of dietary intake on the generation of IS and PCS has not been adequately explored in chronic kidney disease (CKD). METHODS AND RESULTS: This cross-sectional study included 40 CKD participants (60% male; age 69 +/- 10 years; 45% diabetic) with a mean estimated glomerular filtration rate (eGFR) of 24 +/- 8 mL/min/1.73 m(2), who enrolled in a randomized controlled trial of synbiotic therapy. Total and free serum IS and PCS were measured at baseline by ultra-performance liquid chromatography. Dietary intake was measured using in depth diet histories collected by a dietitian. Associations between each toxin, dietary fiber (total, soluble and insoluble), dietary protein (total, and amino acids: tryptophan, tyrosine and phenylalanine), and the protein-fiber index (ratio of protein to fiber) were assessed using linear regression. Dietary fiber was associated with free and total serum PCS (r = -0.42 and r = -0.44, both p < 0.01), but not IS. No significant association was observed between dietary protein and either toxin. The protein-fiber index was associated with total serum IS (r = 0.40, p = 0.012) and PCS (r = 0.43, p = 0.005), independent of eGFR, sex and diabetes. CONCLUSION: Dietary protein-fiber index is associated with serum IS and PCS levels. Such association, beyond fiber and protein alone, highlights the importance of the interplay between these nutrients. We speculate that dietary modification towards a lower protein-fiber index may contribute to lowering IS and PCS. PMID- 26026208 TI - Identification of a dietary pattern associated with greater cardiometabolic risk in adolescence. AB - BACKGROUND AND AIMS: Energy dense, high fat, low fibre diets may contribute to obesity in young people, however their relationships with other cardiometabolic risk factors are unclear. We examined associations between an 'energy-dense, high fat and low-fibre' dietary pattern (DP) and cardiometabolic risk factors, and the tracking of this DP in adolescence. METHODS AND RESULTS: Data was sourced from participants in the Western Australian Pregnancy (Raine) Cohort Study. At 14 and 17 y, dietary intake, anthropometric and biochemical data were measured and z scores for an 'energy dense, high fat and low fibre' DP were estimated using reduced rank regression (RRR). Associations between DP z-scores and cardiometabolic risk factors were examined using regression models. Tracking of DP z-scores was assessed using Pearson's correlation coefficient. A 1 SD unit increase in DP z-score between 14 and 17 y was associated with a 20% greater odds of high metabolic risk (95% CI: 1.01, 1.41) and a 0.04 mmol/L higher fasting glucose in boys (95% CI: 0.01, 0.08); a 28% greater odds of a high-waist circumference (95% CI: 1.00, 1.63) in girls. An increase of 3% and 4% was observed for insulin and HOMA (95% CI: 1%, 7%), respectively, in boys and girls, for every 1 SD increase in DP z-score and independently of BMI. The DP showed moderate tracking between 14 and 17 y of age (r = 0.51 for boys, r = 0.45 for girls). CONCLUSION: An 'energy dense, high fat, low fibre' DP is positively associated with cardiometabolic risk factors and tends to persist throughout adolescence. PMID- 26026210 TI - Fish, omega-3 long-chain fatty acids, and all-cause mortality in a low-income US population: Results from the Southern Community Cohort Study. AB - BACKGROUND: We examined associations between fish and n-3 LCFA and mortality in a prospective study with a large proportion of blacks with low socio-economic status. METHODS AND RESULTS: We observed 6914 deaths among 77,604 participants with dietary data (follow-up time 5.5 years). Of these, 77,100 participants had available time-to-event data. We investigated associations between mortality with fish and n-3 LCFA intake, adjusting for age, race, sex, kcal/day, body mass index (BMI), smoking, alcohol consumption, physical activity, income, education, chronic disease, insurance coverage, and meat intake. Intakes of fried fish, baked/grilled fish and total fish, but not tuna, were associated with lower mortality among all participants. Analysis of trends in overall mortality by quintiles of intake showed that intakes of fried fish, baked/grilled fish and total fish, but not tuna, were associated with lower risk of total mortality among all participants. When participants with chronic disease were excluded, the observed association remained only between intakes of baked/grilled fish, while fried fish was associated with lower risk of mortality in participants with prevalent chronic disease. The association between n-3 LCFA intake and lower risk of mortality was significant among those with diabetes at baseline. There was an inverse association of mortality with fried fish intake in men, but not women. Total fish and baked/grilled fish intakes were associated with lower mortality among blacks while fried fish intake was associated with lower mortality among whites. Effect modifications were not statistically significant. CONCLUSION: Our findings suggest a modest benefit of fish consumption on mortality. PMID- 26026211 TI - Quantitative assessment of the effects of beta-glucan consumption on serum lipid profile and glucose level in hypercholesterolemic subjects. AB - BACKGROUND & AIMS: A growing body of evidence suggests that beta-glucan derived from oats or barley can reduce cardiovascular disease risk through reductions in serum lipids. However, the effects of beta-glucan on lipid changes in hypercholesterolemic patient groups are inconsistent. The objective of this study was to identify and quantify the effect of beta-glucan, a marker of water-soluble fiber, on various lipid parameters and glucose level in hypercholesterolemic subjects. METHODS AND RESULTS: We performed a comprehensive literature search to identify the relevant randomized controlled trials (RCTs) that investigated the effects of beta-glucan consumption in hypercholesterolemic subjects. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for net changes in lipid concentrations by using fixed-effects or random-effects models according to heterogeneity. Publication bias, sensitivity analysis and subgroup analyses were also performed. Seventeen eligible RCTs with 916 subjects were included in the meta-analysis. The pooled result showed that beta-glucan consumption in hypercholesterolemic population significantly lowered the total cholesterol (TC) (MD, -0.26 mmol/L; 95% CI, -0.33 to -0.18; P < 0.00001) and low density lipoprotein (LDL)-cholesterol concentration (MD, -0.21 mmol/L; 95% CI, 0.27 to -0.14; P < 0.00001). However, there were no significant differences in high-density lipoprotein (HDL)-cholesterol, triglycerides (TG) and glucose. No adverse effects were reported among the eligible trials. CONCLUSION: Our meta analysis showed that beta-glucan consumption significantly decreased TC and LDL cholesterol concentrations but did not affect TG, HDL-cholesterol, and glucose concentrations in hypercholesterolemic subjects. PMID- 26026212 TI - Clinical significance of serum bilirubin and gamma-glutamyltransferase levels on coronary atherosclerosis assessed by multidetector computed tomography. AB - BACKGROUND AND AIMS: Low bilirubin and high gamma-glutamyltransferase (GGT), which are endogenous markers of oxidative stress, confer a higher risk of cardiovascular disease (CVD). We investigated associations between serum concentrations of bilirubin, GGT and coronary atherosclerosis. METHODS AND RESULTS: A cross-sectional analysis was performed on 1520 subjects who underwent multidetector computed tomography scans. Coronary atherosclerosis was assessed by coronary artery calcium score (CACS) and obstructive coronary artery disease (OCAD), was defined as the presence of coronary artery stenosis of >=50%. Total bilirubin (TB) level was negatively correlated with CACS and coronary stenosis whereas GGT level was positively correlated with CACS in men. However, there was no correlation between TB, GGT levels and either CACS or coronary artery stenosis in women. In a multivariate-adjusted model, TB level was inversely associated with a CACS > 100 [odds ratio (OR) per log standard deviation (SD), 0.67; 95% confidence interval (CI), 0.52-0.87], and OCAD (OR per log SD, 0.77; 95% CI, 0.62 0.95) in men. By contrast, GGT level was positively associated with a CACS > 100 (OR per log SD, 1.35; 95% CI, 1.05-1.73) but not with OCAD. Adding TB and GGT to the conventional risk factors increased predictive accuracy for CACS > 100 (net reclassification improvement index [NRI] = 13.1%, P = 0.026; integrated discrimination index [IDI] = 0.024, P = 0.001) and for OCAD (NRI = 12.6%, P = 0.026; IDI = 0.010, P = 0.013). CONCLUSIONS: Low TB and high GGT levels were concomitantly associated with coronary atherosclerosis in Korean men. Future studies are needed to elucidate the causal associations of TB and GGT with CVD. PMID- 26026214 TI - A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Very little information is available on whether docosahexaenoic acid (DHA) supplementation has a beneficial effect on liver fat and cardiovascular disease (CVD) risk factors in children with nonalcoholic fatty liver disease (NAFLD). In a double-blind, placebo-controlled randomized trial we investigated whether 6-month treatment with DHA improves hepatic fat and other fat depots, and their associated CVD risk factors in children with biopsy-proven NAFLD. METHODS AND RESULTS: Of 58 randomized children, 51 (25 DHA, 26 placebo) completed the study. The main outcome was the change in hepatic fat fraction as estimated by magnetic resonance imaging. Secondary outcomes were changes in visceral adipose tissue (VAT), epicardial adipose tissue (EAT), and left ventricular (LV) function, as well as alanine aminotransferase (ALT), triglycerides, body mass index-standard deviation score (BMI-SDS), and insulin sensitivity. At 6 months, the liver fat was reduced by 53.4% (95% CI, 33.4-73.4) in the DHA group, as compared with 22.6% (6.2-39.0) in the placebo group (P = 0.040 for the comparison between the two groups). Likewise, in the DHA group VAT and EAT were reduced by 7.8% (0-18.3) and 14.2% (0-28.2%), as compared with 2.2% (0-8.1) and 1.7% (0-6.8%) in the placebo group, respectively (P = 0.01 for both comparisons). There were no significant between-group changes for LV function as well as BMI-SDS and ALT, while fasting insulin and triglycerides significantly decreased in the DHA-treated children (P = 0.028 and P = 0.041, respectively). CONCLUSIONS: DHA supplementation decreases liver and visceral fat, and ameliorates metabolic abnormalities in children with NAFLD. PMID- 26026215 TI - Individual and contextual determinants of resident-on-resident abuse in nursing homes: a random sample telephone survey of adults with an older family member in a nursing home. AB - Few empirical investigations of elder abuse in nursing homes address the frequency and determinants of resident-on-resident abuse (RRA). A random sample of 452 adults with an older adult relative, >=65 years of age, in a nursing home completed a telephone survey regarding elder abuse experienced by that elder family member. Using a Linear Structural Relations (LISREL) modeling design, the study examined the association of nursing home resident demographic characteristics (e.g., age, gender), health and behavioral characteristics (e.g., diagnosis of Alzheimer's Disease, Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), types of staff abuse (e.g., physical, emotional), and factors beyond the immediate nursing home setting (e.g., emotional closeness of resident with family members) with RRA. Mplus statistical software was used for structural equation modeling. Main findings indicated that resident-on-resident mistreatment of elderly nursing home residents is associated with the age of the nursing home resident, all forms of staff abuse, all ADLs and IADLs, and emotional closeness of the older adult to the family. PMID- 26026216 TI - The association between orthostatic hypotension, falling and successful rehabilitation in a nursing home population. AB - PURPOSE OF THE STUDY: Our objectives were to identify the prevalence of orthostatic hypotension (OH) in frail, elderly nursing home residents, and assess its possible association with falling and chances of successful rehabilitation. MATERIALS AND METHODS: A prospective observational cohort study. A total of 290 patients participated in this study, of which 128 were admitted to the rehabilitation department. OH was defined as a drop in systolic blood pressure of >20mmHg and diastolic blood pressure of >10mmHg after postural change within 3min. The analyses regarding falling and successful rehabilitation were only performed in the rehabilitation group. Multivariate binary logistic regression analyses were used to describe risk factors related with falling. Cox proportional hazard modeling was used to investigate the relation between OH and the time to successful rehabilitation. RESULTS: The prevalence of OH in the studied nursing home population was 36.6% (95% CI (confidence interval): 31.1 42.1%). The prevalence varied from 28.6% (95% CI: 16.8-40.4%) in somatic patients, 36.7% (95% CI: 28.4-45.1%) in rehabilitation patients, to 40.6% (95% CI: 31.3-50.0%) in psychogeriatric patients. The association between orthostatic hypotension and previous falling was not significant; Odds ratio 0.66 (95% CI: 0.30-1.48). The Hazard ratio of the relationship between OH and successful rehabilitation was 2.88 (95% CI:1.77-4.69). CONCLUSIONS: OH is highly prevalent in nursing home residents. Surprisingly, patients with OH were found to have a higher chance of successful rehabilitation compared to patients without OH. If confirmed in other studies, these results may change our view of the implications of OH. PMID- 26026213 TI - Prognostic role of LDL cholesterol in non-dialysis chronic kidney disease: Multicenter prospective study in Italy. AB - BACKGROUND AND AIMS: The prognostic role of LDL in non-dialysis chronic kidney disease (CKD) is still undefined. We addressed this question in a multicenter prospective study including patients referred to nephrologist for management. METHODS AND RESULTS: 1306 patients with CKD stage III-V were studied at basal visit in 79 Italian nephrology clinics in 2004-2006, and then followed for survival analyses. Study endpoints were incident cardiovascular -CV events (fatal and major non-fatal) and renal events (start of renal replacement therapy or eGFR halving). Mean age was 67.6 +/- 11.8 years, male 65%, diabetes 25%, CV disease 27%, and eGFR 35.8 +/- 12.5 mL/min/1.73 m(2). LDL was 119 +/- 40 mg/dL, with high levels in 50.1% and 82.8% defined on the basis of the individual CV risk profile estimated according to ATPIII 2001 and ESC 2012 guidelines (LDL 100 to 160, and >70 or >100 mg/dL, respectively). Over a median follow up of 2.87 years, 178 CV and 181 renal events occurred. At multivariable Cox analyses, CV risk linearly increased with higher LDL (hazard ratio-HR per 40 mg/dL higher LDL: 1.20, 95% confidence intervals-CI 1.03-1.39); risk doubled when considering high LDL defined according to ESC 2012 (HR 2.37, 95%CI 1.39-4.03) while this association was not significant when considering the higher threshold levels of ATPIII 2001 (HR 1.10, 95%CI 0.82-1.49). No association emerged between LDL and renal risk. CONCLUSION: In non-dialysis CKD patients, CV risk increases linearly with higher LDL and is more than doubled when considering the lower threshold values currently indicated for defining optimal LDL level. PMID- 26026217 TI - Racial Disparities in Poststroke Activity Limitations Are Not due to Differences in Prestroke Activity Limitation. AB - BACKGROUND: African Americans experience greater poststroke disability than whites. We explored whether these differences are because of differences in prestroke function. METHODS: The Panel Study of Income Dynamics (PSID) is a nationally representative US panel survey of families and their descendants. We included all PSID respondents who reported an incident stroke between 2001 and 2011. Our primary outcome was an index representing the sum of total activities of daily living (ADL) limitations (0-7), and the secondary outcome was an index of instrumental activities of daily living (IADL) limitations (0-6). Survey weighted descriptive statistics and Poisson regression were used to estimate racial differences in ADL and IADL before, with, and after the wave when incident stroke was reported. RESULTS: A total of 534 incident strokes were identified, 198 (37%) in African Americans. There were no prestroke racial differences in activity limitations (.7 versus .7, P = .99). In the wave of the incident stroke (between 0 and 2 years from incident stroke), African Americans had considerably more ADL limitations than whites (2.2 versus 1.5, P = .048). These racial differences persisted after adjusting for age, sex, and comorbidities. For IADLs, adjusted models suggested small prestroke racial differences and larger poststroke differences. CONCLUSIONS: Racial disparities in poststroke ADL limitations are not due to prestroke activity limitations. Instead, differences appear largest in the first 2 years after stroke. PMID- 26026218 TI - Cervical Cancer Screening Rates in a Chart Review of Adolescent Patients at an Academic Institution before and after the Publication of the 2009 American College of Obstetricians and Gynecologists' Recommendations. AB - OBJECTIVE: Evaluation of compliance with ACOG guidelines against screening for cervical cancer in women before age 21; identification of factors associated with lack of compliance with guidelines. METHODS: A review of 799 charts of women age 14-21 seen for care at our institution in 2009-2010 to determine baseline cervical cytology rates, compliance with publication of 2009 ACOG guidelines recommending against testing in this age group. Clinical data was gathered to identify patient and physician characteristics associated with testing. RESULTS: The baseline rate of cervical cytology testing for women age 14-21 in our chart review (20%, 2009) dropped significantly (10.8%, 2010, P < .005) after publication of new guidelines. Among those patients tested, factors associated with higher screening rates included: patients seen by obstetrician/gynecologist (59% patients tested 2009/38% 2010), who were sexually active (83%/88%) and seen for routine care (68%/95%). Other associated factors: prior screening (61% all patients tested), hormonal contraceptives (58%), private insurance (72%). Patients with history of previous cervical intraepithelial neoplasia had cytology testing done at high rates (72%). CONCLUSION: The rate of cervical cytology screening in women ages 14-21 was higher than expected given ACOG recommendations. There was a significant decrease in screening rates after publication of guidelines. Patient and physician characteristics were identified which were associated with an increased screening rate. There are no databases that track cervical cancer testing in this age group. This information can be utilized for physician and patient education in order to improve compliance. PMID- 26026219 TI - Helping Clinicians Prevent Pregnancy among Sexually Active Adolescents: U.S. Medical Eligibility Criteria for Contraceptive Use and U.S. Selected Practice Recommendations for Contraceptive Use. AB - The United States has made substantial progress in reducing teenage birth rates in recent decades, but rates remain high. Teen pregnancy can increase the risk of poor health outcomes and lead to decreased educational attainment, increased poverty, and welfare use, as well as increased cost to taxpayers. One of the most effective ways to prevent teenage pregnancy is through the use of effective birth control methods. The Centers for Disease Control (CDC) and Prevention has made the prevention of teenage pregnancy 1 of its 10 winnable battles. The CDC has released 2 evidence-based clinical guideline documents regarding contraceptive use for adolescents and adults. The first guideline, US Medical Eligibility Criteria for Contraceptive Use, 2010, helps clinicians recognize when a contraceptive method may not be safe to use for a particular adolescent but also when not to withhold a contraceptive method that is safe to use. The second document, US Selected Practice Recommendations for Contraceptive Use, 2013, provides guidance for how to use contraceptive methods safely and effectively once they are deemed safe. Health care providers are encouraged to use these documents to provide safe and effective contraceptive care to patients seeking family planning, including adolescents. PMID- 26026220 TI - Paratubal Borderline Malignancy: A Case of a 17-Year-Old Adolescent Female Treated with Laparo-Endoscopic Single-Site Surgery and a Review of the Literature. AB - BACKGROUND: Although paratubal cysts are common, borderline paratubal cysts are extremely rare. We describe the case of a large borderline paratubal cyst in a 17 year-old adolescent female treated with laparo-endoscopic single-site surgery (LESS), and review the literature. CASE: A 17-year-old female was referred due to a large right adnexal cyst on pelvic sonogram. A CT scan showed a 19-cm cystic lesion with enhancing papillary projection along the wall. Laparo-endoscopic single-site surgery confirmed a large cystic mass that originated from the right salpinx. Right salpingectomy and right ovarian wedge resection were performed, and intraoperative frozen section analysis was conducted. The result of the frozen section analysis and final pathologic review indicated that the cyst was a serous papillary-type borderline tumor in a paratubal cyst. SUMMARY AND CONCLUSION: To the best of our knowledge, this is the first case report of a BPC treated with LESS. We suggest that minimally invasive, fertility-preserving surgery should be considered as a standard treatment of borderline paratubal cysts if patients desire future fertility. PMID- 26026221 TI - Aesthetic auricular reconstruction with autologous rib cartilage grafts in adult microtia patients. AB - BACKGROUND: Cartilage calcification is an important factor in aesthetic auricular reconstruction using autologous rib cartilage grafts in adults, a technique that involves difficult manipulation and unexpected absorption. As a result, artificial implants or prosthetics are considered for auricular reconstruction in adult patients despite the limitations of artificial material. In this article, we present our experience with auricular reconstruction using autologous rib cartilage grafts in adult microtia patients with reliable aesthetic results and minimal complications. METHODS: A retrospective chart review was performed for 84 microtia patients ranging in age from 21 to 56 (average: 29.9) years who underwent auricular reconstruction using autologous rib cartilage grafts from March 2001 to March 2013. To validate our acceptable reconstructive results, two independent observers performed postoperative photographic evaluation of two groups (adults and children) using non-inferiority tests in addition to patient questionnaires. RESULTS: The mean operation time for rib cartilage grafts was 3 h and 53 min, and the follow-up time for all patients ranged from 6 months to 8 years. Surgery-related complications occurred in only three cases. On objective photographic evaluation, the adult group was not inferior to the child group in auricular shape, location, or symmetry. The subjective patient satisfaction evaluation reported a high satisfaction rate. CONCLUSIONS: As this study shows, aesthetic auricular reconstruction using rib cartilage grafts in adult microtia patients is possible even in cases with advanced cartilage calcification. Modification of the fabricating framework, well-preserved flap vascularity, and complete understanding of physiological aspects of rib cartilage are essential for aesthetic auricular reconstruction. PMID- 26026222 TI - Double-powered free gracilis muscle transfer for smile reanimation: A longitudinal optoelectronic study. AB - The choice of the motor donor nerve is a crucial point in free flap transfer algorithms. In the case of unilateral facial paralysis, the contralateral healthy facial nerve can provide coordinated smile animation and spontaneous emotional expression, but with unpredictable axonal ingrowth into the recipient muscle. Otherwise, the masseteric nerve ipsilateral to the paralysis can provide a powerful neural input, without a spontaneous trigger of the smile. Harvesting a bulky muscular free flap may enhance the quantity of contraction but esthetic results are unpleasant. Therefore, the logical solution for obtaining high amplitude of smiling combined with spontaneity of movement is to couple the neural input: the contralateral facial nerve plus the ipsilateral masseteric nerve. Thirteen patients with unilateral dense facial paralysis underwent a one stage facial reanimation with a gracilis flap powered by a double donor neural input, provided by both the ipsilateral masseteric nerve (coaptation by an end-to end neurorrhaphy with the obturator nerve) and the contralateral facial nerve (coaptation through a cross-face nerve graft: end-to-end neurorrhaphy on the healthy side and end-to-side neurorrhaphy on the obturator nerve, distal to the masseteric/obturator neurorrhaphy). Their facial movements were evaluated with an optoelectronic motion analyzer. Before surgery, on average, the paretic side exhibited a smaller total three-dimensional mobility than the healthy side, with a 52% activation ratio and >30% of asymmetry. After surgery, the differences significantly decreased (analysis of variance (ANOVA), p < 0.05), with an activation ratio between 75% (maximum smile) and 91% (maximum smile with teeth clenching), and <20% of asymmetry. Similar modifications were seen for the performance of spontaneous smiles. The significant presurgical asymmetry of labial movements reduced after surgery. The use of a double donor neural input permitted both movements that were similar in force to that of the healthy side, and spontaneous movements elicited by emotional triggering. PMID- 26026223 TI - Acylated neo-clerodanes and 19-nor-neo-clerodanes from the aerial parts of Scutellaria coleifolia (Lamiaceae). AB - Scutefolides A1 and A2, two acylated neo-clerodanes with a 19,18-gamma-lactone, scutefolides B1, B2 and C, three 19-nor-neo-clerodanes, together with scutefolides D, E1, E2 and F, four neo-clerodanes, were isolated from the EtOAc soluble fraction of the aerial parts of Scutellaria coleifolia. Their structures were established on the basis of spectroscopic analysis. The absolute configurations of four of these compounds were elucidated by the CD exciton chirality method. Cytotoxic activities of scutefolides D-F against four cancer cell lines (KB, A549, HeLa, and MCF7) were also evaluated, but they were inactive. PMID- 26026224 TI - Prosthetic joint infection: A pluridisciplinary multi-center audit bridging quality of care and outcome. AB - BACKGROUND: Care to patients with prosthetic joint infections (PJI) is provided after pluridisciplinary collaboration, in particular for complex presentations. Therefore, to carry out an audit in PJI justifies using pluridisciplinary criteria. We report an audit for hip or knee PJI, with emphasis on care homogeneity, length of hospital stay (LOS) and mortality. PATIENTS AND METHODS: Fifteen criteria were chosen for quality of care: 5 diagnostic tools, 5 therapeutic aspects, and 5 pluridisciplinary criteria. Among these, 6 were chosen: surgical bacterial samples, surgical strategy, pluridisciplinary discussion, antibiotic treatment, monitoring of antibiotic toxicity, and prevention of thrombosis. They were scored on a scale to 20 points. We included PJI diagnosed between 2010 and 2012 from 6 different hospitals. PJI were defined as complex in case of severe comorbid conditions or multi-drug resistant bacteria, or the need for more than 1 surgery. RESULTS: Eighty-two PJI were included, 70 of which were complex (85%); the median score was 15, with a significant difference among hospitals: from 9 to 17.5 points, P < 0.001. The median LOS was 17 days, and not related to the criterion score; 16% of the patients required intensive care and 13% died. The cure rate was 41%, lost to follow-up 33%, and therapeutic failure 13%. Cure was associated with a higher score than an unfavorable outcome in the univariate analysis (median [range]): 16 [9-18] vs 13 [4-18], P = 0.002. CONCLUSIONS: Care to patients with PJI was heterogeneous, our quality criteria being correlated to the outcome. PMID- 26026225 TI - [Panton-Valentine leukocidin-positive methicillin susceptible Staphylococcus aureus necrotizing pneumonia at Reunion Island]. PMID- 26026226 TI - An update on pediatric invasive aspergillosis. AB - Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised adults and children, the number of which has been continuously increasing in the last decades. The purpose of our review was to provide epidemiological, clinical, and biological data and antifungal treatment options in the pediatric population. Several biological assays (galactomannan enzyme immunoassay, beta-D-glucan, detection of Aspergillus spp. DNA) have proven useful adjuncts for the diagnosis of IA in adult studies. However, data on these assays in children is limited by small sample sizes and sometimes conflicting results concerning their sensitivity/specificity. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. It is thus necessary to develop new antifungal formulations specifically adapted to the pediatric population and to evaluate their pharmacokinetic/pharmacodynamic profile, their safety, and their effectiveness in infants and children. PMID- 26026228 TI - [Detection of virulence genes of the enteroaggregative pathotype in Escherichia coli strains isolated from groundwater sources in the province of Chaco, Argentina]. AB - Groundwater is an important source of drinking water for many communities in Northern Argentina; particularly, in the province of Chaco, where about 14% of households use this natural resource. Enteroaggregative Escherichia coli is an emerging pathogen whose global importance in public health has increased in recent years. Despite the significant risk of disease linked to contaminated water exposure, the prevalence of E. coli pathotypes in aquatic environments is still not so well defined. The aim of the present study was to detect the presence of typical enteroaggregative E. coli through the recognition of its virulence factors aap, AA probe and aggR by molecular techniques. A total of 93 water samples from different small communities of Chaco were analyzed. E. coli was identified in 36 (38.7%) of the tested samples. Six strains isolated from different samples harbored the studied genes. Of these 6 isolates, 3 carried the aap gene, 2 the AA probe and the last one the combination of aap/aggR genes. The prevalence of E. coli isolates harboring enteroaggregative virulence genes in groundwater sources was 6.4%. This work represents the first contribution to the study of the presence and distribution of virulence genes of EAEC in groundwater sources in this region of Argentina. PMID- 26026227 TI - Impact of advice given to travelers concerning the main infectious risks associated with traveling in the tropics. AB - INTRODUCTION: The prevention of sanitary risks related to traveling in the tropics implies delivering a large amount of information to travelers. The objective of our study was to assess the knowledge acquired by travelers during a pre-travel consultation. METHODS: A before and after study was conducted among 202 travelers having consulted at the Tours international vaccine center. We used self-administrated questionnaires (score out of 100 marks) concerning diet, hygiene, anti-vectorial prevention (AVP), and sexual-transmitted infections (STI). The scores obtained before and after consultation were compared globally and for each topic. RESULTS: The travelers' global knowledge had improved after consultation (66.1 vs. 75.5%; P < 0.0001) as well as for each topic. The most important improvement concerned hygiene (+12.5%; P < 0.0001) and the lowest concerned STI (+5.8%; P < 0.0001). The multivariate analysis revealed that not having searched for information before consulting was the main factor associated with global knowledge improvement (P < 0.0001) (unplanned professional traveling compared to humanitarian mission prepared ahead of departure time). The recommendations for diet were less well acquired in travelers > 50 years of age than in those < 30 years of age (P < 0.002). CONCLUSION: A specialized pre-travel consultation improves the travelers' knowledge for the main prevention measures but does not allow them to acquire all required knowledge. Taking into account the travelers' initial knowledge and their ability to learn could improve the impact of the pre-travel consultation. PMID- 26026229 TI - [Shigelosis outbreak in the city of Lujan, Argentina]. AB - The aim of this study was to describe an outbreak of Shigella sonnei that occurred in the city of Lujan, Buenos Aires, Argentina, in July 2012. Five individuals were affected after eating a hand-made Viennese-style pastry at a family gathering. All of them presented with fever, joint pain, chills and non bloody diarrhea containing mucus. Stool cultures were performed in all cases and the samples taken from the pastry ingredients were analyzed microbiologically. S.sonnei was isolated and identified in all the patients involved as well as in the almond cream filling. The isolates were analyzed for determining the antimicrobial susceptibility and genetic profiles by pulsed field gel electrophoresis (PFGE). The results showed the genetic relationship among the isolates, confirming that the cases occurred due to the patients' exposure to the same source of infection, i.e., the almond cream. Being the almond cream an industrially-manufactured ingredient, an initial contamination could have been unlikely; however contamination might have occurred as a result of manipulation in the bakery. PMID- 26026230 TI - [Isolation and characterization of Escherichia coli O157 in bovine meat products and cattle in the province of Tucuman]. AB - Escherichia coli O157 is an emergent pathogen associated with diarrhea, hemorrhagic colitis and hemolytic uremic syndrome. Meat products constitute an important transmission source of this microorganism. The aims of this study were to characterize E. coli O157 isolated from cattle and meat products collected from abattoirs and retail stores, to establish the clonal relatedness among regional isolates and to compare them with those in the national database. Between 2004 and 2013, 169 minced meat, 35 sausage and 216 carcass samples were analyzed. Thirteen E. coli O157 isolates were identified; 6 of which were O157:H7 and characterized as stx2c(vh-a)/eae/ehxA (n = 5) and stx2/eae/ehxA (n = 1). The 7 remaining isolates were non-toxigenic E. coli strains, and serotyped as O157:NT (n = 4), O157:NM (n = 1), O157:ND (n = 1) and O157:H16 (n = 1). The strains yielded different XbaI-PFGE patterns. Compared to the E. coli O157 isolates in the National Database, none of these patterns have been previously detected in strains of different origin in Argentina. PMID- 26026231 TI - Molecular screening of pathogenic Escherichia coli strains isolated from dairy neonatal calves in Cordoba province, Argentina. AB - The aim of this study was to perform a current molecular characterization of bovine pathogenic Escherichia coli strains isolated from random samplings in Argentinean dairy farms. Rectal swabs were obtained from 395 (63.7%) healthy and 225 (36.3%) diarrheic calves, belonging to 45 dairy farms in Cordoba Province, Argentina. E. coli isolates were examined for virulence genes (f5, f41, f17, sta, stb, lt, eae, vt) using PCR and the prevalence of E. coli virulence profiles was spatially described in terms of spatial distribution. A total of 30.1% isolates were found to be positive for at least one of the virulence genes. Depending on the different gene combinations present, 11 virulence profiles were found. Most of the isolates analyzed had a single gene, and no combination of fimbrial and enterotoxin gene was predominant. There was no association between the frequency and distribution of E. coli virulence genes and calf health status. Most of the virulence profiles were compatible with ETEC strains and showed a homogeneous distribution over the sampled area. A clustering pattern for E. coli virulence profiles could not be recognized. This work provides updated information on the molecular characterization of pathogenic E. coli strains from dairy herds in Cordoba, Argentina. These findings would be important to formulate prevention programs and effective therapies for diarrhea in calves caused by E. coli. PMID- 26026232 TI - Integrating membrane filtration into bioelectrochemical systems as next generation energy-efficient wastewater treatment technologies for water reclamation: A review. AB - Bioelectrochemical systems (BES) represent an energy-efficient approach for wastewater treatment, but the effluent still requires further treatment for direct discharge or reuse. Integrating membrane filtration in BES can achieve high-quality effluents with additional benefits. Three types of filtration membranes, dynamic membrane, ultrafiltration membrane and forward osmosis membrane that are grouped based on pore size, have been studied for integration in BES. The integration can be accomplished either in an internal or an external configuration. In an internal configuration, membranes can act as a separator between the electrodes, or be immersed in the anode/cathode chamber as a filtration component. The external configuration allows BES and membrane module to be operated independently. Given much progress and interest in the integration of membrane filtration into BES, this paper has reviewed the past studies, described various integration methods, discussed the advantages and limitations of each integration, and presented challenges for future development. PMID- 26026233 TI - Dynamic observation of the biodegradation of lignocellulosic tissue under solid state anaerobic conditions. AB - The solid-state anaerobic digestion (SS-AD) of wheat straw was characterized under low inoculated batch tests during 244 days. High levels of degradation of the cellulose (52%+/-1) and hemicelluloses (55%+/-2) were observed at the final stages and associated to a methane yield of 204+/-16 NmL gTS(-1). Ultrastructural observations, using transmission electronic microscopy, indicated that microorganisms degraded wheat straw from the central to the outer tissue (i.e. parenchyma to epidermis), depending on cell chemical, physical accessibility and the degree of lignification. Furthermore, major degradation of sclerenchyma secondary walls was observed. The bioaccessibility of lignocellulosic structures of wheat straw is mainly limited by the external waxy layer (cuticle), tertiary cell walls, high silica content and access to the cell lumen. PMID- 26026234 TI - Transforming river basins: Post-livelihood transition agricultural landscapes and implications for natural resource governance. AB - The agricultural and livelihood transitions post globalization are redefining resource relations and redrawing landscapes in the Global South and have major implications for nascent natural resource governance regimes such as Integrated River Basin Management (IRBM). A mosaic of divergent reciprocations in resource relations were noticed due to livelihood transitions in the rural areas where previous resource uses and relations had been primarily within agriculture. The reconstitution of rural spaces and the attendant changes in the resource equations are observed to be creating new sites of conformity, contestation and conflicts that often move beyond local spaces. This paper critically reviews studies across the Global South to explore the nature and extent of changes in resource relations and agricultural landscapes post livelihood diversification and the implication and challenges of these changes for natural resource governance. Though there is drastic reduction in agricultural livelihoods throughout the Global South, changes in agricultural area are found to be inconsistent and heterogeneous in the region. Agriculture continues in the countrysides but in widely differentiated capacities and redefined value systems. The transformed agrarian spaces are characterized by a mosaic of scenarios from persistence and sustainable subsistence to differentiation and exploitative commercial practices to abandonment and speculation. The reconfigured resource relations, emergent multiple and multi-scalar interest groups, institutional and policy changes and altered power differentials in these diversified landscapes are yet to be incorporated into natural resource governance frameworks such as IRBM. PMID- 26026235 TI - Communication between primary care and physician specialist: is it improving? AB - BACKGROUND AND OBJECTIVE: Efforts have recently been made in Spain to improve the communication model between primary care and specialized care. The aim of our study was to analyze the impact of a change in the communication model between the two areas when comparing a traditional system to a consulting system in terms of satisfaction of general practitioners and the number of patient referrals. METHODS: A questionnaire was used to assess the point of view on the relations with the endocrinologist team of 20 general practitioners from one primary care center at baseline and 18 months after the implementation of the new method of communication. In addition, we counted the number of referrals during the two periods. RESULTS: We analyzed 30 questionnaires; 13 before and 17 after the consulting system was established. Consulting system was preferred to other alternatives as a way of communication with endocrinologists. After the consulting system was implemented, general practitioners were more confident in treating hypothyroidism and diabetes. There was a decrease in the number of patient referrals to specialized care from 93.8 to 34.6 per month after implementation of the consultant system. CONCLUSIONS: The consultant system was more efficient in resolving problems and responding to general practitioners than the traditional system. General practitioners were more confident in self management of hypothyroidism and diabetes. A very large decrease in the number of patient referrals was observed after implementation of the consultant system. PMID- 26026237 TI - Small bowel obstruction in a young adult. PMID- 26026236 TI - Occult hepatitis B virus infection among chronic hemodialysis patients in Alexandria, Egypt. AB - The prevalence of end-stage renal disease has increased dramatically in developing countries. Hepatitis B virus (HBV) infection is a global health problem that represents a significant co-morbidity event that has led to outbreaks of hepatitis B. There are inadequate data concerning occult HBV infection among Egyptian chronic hemodialysis patients. This study aimed to detect occult HBV infection among chronic hemodialysis patients in Alexandria, Egypt. A cross-sectional study was performed on 100 patients with end-stage renal disease that received maintenance hemodialysis and had tested negative for HBV surface antigen. Blood samples were collected before the initiation of hemodialysis. Sera were tested for hepatitis C virus (HCV) and hepatitis B core (HBc) antibodies using ELISA, and HBV DNA was detected by SYBR Green real-time PCR using specific primers for the s and c genes and by nested PCR using pol gene specific primers. The serum activity of alanine and aspartate aminotransferase (ALT and AST) were also measured. Anti-HCV and anti-HBc antibodies were detected in 34% and 48% of patients, respectively, and 70.6% of anti-HCV positive patients were also positive for anti-HBc antibodies. This association was statistically significant (p=0.001). HBV DNA was detected in 32% of the hemodialysis patients. A significant association was determined between the presence of HBV DNA and anti HCV positivity (p=0.021). Aminotransferases were elevated in 21% of the studied patients, more often in patients with positive anti-HCV profiles than in patients negative for anti-HCV (p<0.05). In conclusion, the serological markers of HBV infection should be verified with molecular tests to investigate possible occult infections, especially among anti-HBc-positive hemodialysis patients, to improve our understanding of their clinical, laboratory, and epidemiological characteristics. PMID- 26026238 TI - Langerhans cell histiocytosis presenting as bilateral pneumothorax. PMID- 26026239 TI - [Safety culture assessment in a university pulmonary medicine department]. AB - INTRODUCTION: Improvement in treatment safety is a major issue in Western healthcare systems, with the aim of reducing the number of treatment associated undesirable events. The safety culture, defined as an integrated and coherent collection of individual and organizational behavior that seeks continuously to reduce harm to patients, possibly related to treatment, could fulfill this aim. METHODS: We have used an adaption of the American "Hospital Survey on Patient Safety" questionnaire (HSOPSC), which examines professionals' perception of treatment safety, to assess the safety culture in our respiratory medicine service in the Strasbourg University Hospital. RESULTS: Of the 110 questionnaires distributed to the service personnel, 93 were returned (85 %). The level of treatment safety was judged "acceptable" for 56 % of the personnel, "very good" for 32 %, against "weak" or "failing" for 10 %. Of the 10 dimensions explored, 8 were considered to need improvement and 2 had a level of positive responses greater than 50 %. CONCLUSIONS: Treatment safety culture seems to be an area to develop in our service. A strong safety culture should allow health care professionals to adhere better to treatment safety mechanisms. PMID- 26026240 TI - Developmental abnormalities and neurotoxicological effects of CuO NPs on the black sea urchin Arbacia lixula by embryotoxicity assay. AB - The embryotoxicity of CuO NPs was evaluated in the black sea urchin Arbacia lixula embryos, by using 24-well plates. Fertilized eggs were exposed to five doses of CuO NPs ranging from 0.07 to 20 ppb, until pluteus stage. CuO NPs suspensions in artificial seawater formed agglomerates of 80-200 nm size, and copper uptake was 2.5-fold up in larvae exposed to high NP concentrations in respect to control. Developmental delay and morphological alteration, including skeletal abnormalities, were observed, as well as impairment in cholinergic and serotonergic nervous systems. These findings suggest the potential of CuO NPs to interfere with the normal neurotransmission pathways, thus affecting larval morphogenesis. Overall, the embryotoxicity tests are effective for evaluation of nanoparticle effects on the health of aquatic biota. Furthermore, as the black sea urchin A. lixula demonstrated to be vulnerable to NP exposure, it may be a valid bioindicator in marine biomonitoring and ecotoxicological programmes. PMID- 26026241 TI - Development of a quantitative PCR assay for rapid detection of Lactobacillus plantarum and Lactobacillus fermentum in cocoa bean fermentation. AB - To monitor dominant species of lactic acid bacteria during cocoa bean fermentation, i.e. Lactobacillus plantarum and Lactobacillus fermentum, a fast and reliable culture-independent qPCR assay was developed. A modified DNA isolation procedure using a commercial kit followed by two species-specific qPCR assays resulted in 100% sensitivity for L. plantarum and L. fermentum. Kruskal Wallis and post-hoc analyses of data obtained from experiments with cocoa beans that were artificially spiked with decimal concentrations of L. plantarum and L. fermentum strains allowed the calculation of a regression line suitable for the estimation of both species with a detection limit of 3 to 4 Log cells/g cocoa beans. This process was successfully tested for efficacy through the analyses of samples from laboratory-scale cocoa bean fermentations with both the qPCR assay and a culture-dependent method which resulted in comparable results. PMID- 26026242 TI - Lost in translocation: the functions of the 18-kD translocator protein. AB - Research spanning nearly four decades has assigned to the translocator protein (18 kDa) (TSPO) a critical role, among others, in the mitochondrial import of cholesterol, the subsequent steps of (neuro)steroid production, and systemic endocrine regulation, with implications for the pathophysiology of immune, inflammatory, neurodegenerative, and psychiatric as well as neoplastic diseases. Recent knockout studies in mice unexpectedly report normal or latent phenotypes, raising doubts about the protein's role in steroidogenesis and other previously postulated functions and challenging the validity of earlier data on the selectivity of TSPO-binding drugs. Here we provide a synthesis of the current debate from a structural and molecular biology perspective, discuss the limits of inference in loss-of-function (gene knockout) studies, and suggest new functions of TSPO. PMID- 26026243 TI - Involvement of Relish gene from Macrobrachium rosenbergii in the expression of anti-microbial peptides. AB - Relish is an NF-kB transcription factor involved in immune-deficiency (IMD) signal pathway. In this study, a Relish gene (MrRelish) was identified from Macrobrachium rosenbergii. The full length of MrRelish comprises 5072 bp, including a 3510 bp open reading frame encoding a 1169 bp amino acid protein. MrRelish contains a Rel homology domain (RHD), a nucleus localization signal, an IkappaB-like domain (6 ankyrin repeats), and a death domain. Phylogenetic analysis showed that MrRelish and other Relish from crustaceans belong to one group. MrRelish was expressed in all detected tissues, with the highest expression level in hemocytes and intestines. MrRelish was also upregulated in hepatopancreas at 6 h after Vibrio anguillarum challenge. The over-expression of MrRelish could induce the expression of antimicrobial peptides (AMPs), such as Drosophila Metchnikowin (Mtk), Attacin (Atta), Drosomycin (Drs), and Cecropin (CecA) and shrimp Penaeidin (Pen4). The RNAi of MrRelish in gills showed that the expression of crustin (cru) 2, Cru5, Cru8, lysozyme (Lyso) 1, and Lyso2 was inhibited. However, the expression of anti-lipopolysaccharide factor (ALF) 1 and ALF3 did not change when MrRelish was knocked down. These results indicate that MrRelish may play an important role in innate immune defense against V. anguillarum in M. rosenbergii. PMID- 26026244 TI - IL-17 signaling components in bivalves: Comparative sequence analysis and involvement in the immune responses. AB - The recent discovery of soluble immune-regulatory molecules in invertebrates takes advantage of the rapid growth of next generation sequencing datasets. Following protein domain searches in the transcriptomes of 31 bivalve spp. and in few available mollusk genomes, we retrieved 59 domains uniquely identifying interleukin 17 (IL-17) and 96 SEFIR domains typical of IL-17 receptors and CIKS/ACT1 proteins acting downstream in the IL-17 signaling pathway. Compared to the Chordata IL-17 family members, we confirm a separate clustering of the bivalve domain sequences and a consistent conservation pattern of amino acid residues. Analysis performed at transcript and genome level allowed us to propose an updated view of the components outlining the IL-17 signaling pathway in Mytilus galloprovincialis and Crassostrea gigas (in both species, homology modeling reduced the variety of IL-17 domains to only two 3D structures). Digital expression analysis indicated more heterogeneous expression levels for the mussel and oyster IL-17 ligands than for IL-17 receptors and CIKS/CIKSL proteins. Besides, new qPCR analyses confirmed such gene expression trends in hemocytes and gills of mussels challenged with heat-killed bacteria. These results uphold the involvement of an ancient IL-17 signaling pathway in the bivalve immune responses and, likewise in humans, suggest the possibility of distinctive modulatory roles of individual IL-17s/IL-17 receptors. Overall, the common evidence of pro inflammatory cytokines and inter-related intracellular signaling pathways in bivalves definitely adds complexity to the invertebrate immunity. PMID- 26026245 TI - The broad pattern recognition spectrum of the Toll-like receptor in mollusk Zhikong scallop Chlamys farreri. AB - Toll-like receptors (TLRs) are among the most studied pattern recognition receptors (PRRs) playing essential roles in innate immune defenses. In the present study, the basic features of CfTLR in mollusk Zhikong scallop Chlamys farreri, including sequence homology, tissue distribution, subcellular localization and ligands spectrum, were investigated to elucidate its pattern recognition. The elements of extracellular domains (ECD) in CfTLR displayed high homology to the corresponding parts of the ECDs in TLRs from Homo sapiens. CfTLR protein was detected in hemocytes, mantle, gills, hepatopancreas, kidney and gonad of the scallops, and it was localized in both the plasma membranes and the lysosomes in HEK293T cells. CfTLR could activate NFkappaB in response to multiple HsTLR ligands including Pam3CSK4, glucan (GLU), peptidoglycan (PGN), polyriboinosinic:polyribocytidylic acid (poly I:C), Imiquimod and three types of CpG. Additionally, the scallop serum could enhance the induction of NFkappaB in the CfTLR expressing cells elicited by most PAMPs, including GLU, PGN, Imiquimod and four types of CpG. It could be concluded that this primitive mollusk TLR shared a hybrid function in pattern recognition and could recognize broader ligands than mammalian TLRs, and its mosaic capability of pathogen associated molecular pattern (PAMP) recognition might be based on the basic features of its structure, ligand properties and the assistance of some components in scallop serum. PMID- 26026246 TI - Effect of the synthetic Toll-like receptor ligands LPS, Pam3CSK4, HKLM and FSL-1 in the function of bovine polymorphonuclear neutrophils. AB - Toll-like receptors (TLR) are a family of pattern recognition receptors that sense microbial associated molecular patterns (MAMP) such as microbial membrane components and nucleic acids of bacterial origin. Polymorphonuclear neutrophils (PMN) are the first cell of the innate immune system to arrive at the site of infection or injury and elicit oxidative and non-oxidative microbicidal mechanisms. Observations in human and mouse suggest that TLR ligands can induce direct responses in PMN. So far, there is no information of the effect of synthetic TLR ligands on the response of bovine PMN. The objective of this study was to evaluate the functional response of bovine PMN incubated with four synthetic TLR ligands: ultrapure LPS (TLR4), Pam(3)CSK(4) (TLR2/1), HKLM (TLR2) and FSL-1 (TLR2/6). The results show that all the ligands increment cells size as identified by changes in the FSC-SSC as part of the flow cytometric analysis. Interestingly, only Pam(3)CSK(4) consistently induced a calcium influx, increased ROS production and secretion of gelatinase granules, whereas no response was seen using other ligands. Furthermore, exposure of bovine PMN to ultrapure LPS, Pam(3)CSK(4), HKLM or FSL-1 for 24 hours did not impact on apoptosis of these cells. Our data provide evidence for a selective response of bovine PMNs to TLR ligands. PMID- 26026247 TI - NADPH oxidase, MPO, NE, ERK1/2, p38 MAPK and Ca2+ influx are essential for Cryptosporidium parvum-induced NET formation. AB - Cryptosporidium parvum causes a zoonotic infection with worldwide distribution. Besides humans, cryptosporidiosis affects a wide range of animals leading to significant economic losses due to severe enteritis in neonatal livestock. Neutrophil extracellular trap (NET) formation has been demonstrated as an important host effector mechanism of PMN acting against several invading pathogens. In the present study, C. parvum-mediated NET formation was investigated in human and bovine PMN in vitro. We here demonstrate that C. parvum sporozoites indeed trigger NET formation in a time-dependent manner. Thereby, the classical characteristics of NETs were demonstrated by co-localization of extracellular DNA with histones, neutrophil elastase (NE) and myeloperoxidase (MPO). A significant reduction of NET formation was measured following treatments of PMN with NADPH oxidase-, NE- and MPO-inhibitors, confirming the key role of these enzymes in C. parvum-induced NETs. Additionally, sporozoite-triggered NETosis revealed as dependent on intracellular Ca(++) concentration and the ERK 1/2 and p38 MAPK-mediated signaling pathway. Moreover, sporozoite-triggered NET formation led to significant parasite entrapment since 15% of the parasites were immobilized in NET structures. Consequently, PMN-pre-exposed sporozoites showed significantly reduced infectivity for epithelial host cells confirming the capability of NETs to prevent active parasite invasion. Besides NETs, we here show that C. parvum significantly up-regulated CXCL8, IL6, TNF-alpha and of GM CSF gene transcription upon sporozoite confrontation, indicating a pivotal role of PMN not only in the bovine and human system but most probably in other final hosts for C. parvum. PMID- 26026248 TI - Public attitudes to GM foods. The balancing of risks and gains. AB - In the paper we study the variables influencing attitudes to the use of two biotechnologies related to gene transfer within apples. Using Eurobarometer 73.1 survey data on biotechnology, science and technology, with 15,650 respondents, we study the extent these attitudes are determined by socio-economic and other variables. We found that attitudes to the risks and gains are determined by socio economic variables and also by the individual's knowledge, scientific background, their parent's education in science and their religion. Perceptions of naturalness and of environmental impact combined with perceived risks and gains in determining overall approval, proxied by views on whether the technologies should be encouraged, for GMTs. However there are substantial differences in attitudes to transgenesis and cisgenesis. PMID- 26026249 TI - Impairment of mitochondrial energy metabolism of two marine fish by in vitro mercuric chloride exposure. AB - The goal of this work was to understand the extent of mercury toxic effects in liver metabolism under an episode of acute contamination. Hence, the effects of in vitro mercuric chloride in liver mitochondria were assessed in two commercial marine fish: Senegalese sole (Solea senegalensis) and gilthead seabream (Sparus aurata). Liver mitochondria were exposed to 0.2mgL(-1) of mercury, the average concentration found in fish inhabiting contaminated areas. Mercuric chloride depressed mitochondrial respiration state 3 and the maximal oxygen consumption in the presence of FCCP indicating inhibitory effects on the oxidative phosphorylation and on the electron transport chain, respectively. The inhibition of F1Fo-ATPase and succinate-dehydrogenase activities also corroborated the ability of mercury to inhibit ADP phosphorylation and the electron transport chain. This study brings new understanding on the mercury levels able to impair fish mitochondrial function, reinforcing the need for further assessing bioenergetics as a proxy for fish health status. PMID- 26026250 TI - Distribution of Alexandrium fundyense and A. pacificum (Dinophyceae) in the Yellow Sea and Bohai Sea. AB - This study characterizes the distribution of two closely related, causative species of paralytic shellfish poisoning - Alexandrium fundyense and A. pacificum - within the Yellow Sea (YS) and Bohai Sea (BS). These two Alexandrium species are distinguished for the first time in a regional field study using species specific, quantitative PCR (qPCR) based assays. Both qPCR assays target the large subunit ribosomal DNA gene and were used to analyze net-concentrated phytoplankton samples collected in May 2012. A. fundyense was mainly distributed in YS, while A. pacificum was confined to an area adjacent to the Changjiang River estuary. The different distribution of the two species is interpreted as evidence of their distinct bloom ecology. Expanded efforts implementing these assays offer the ability to discriminate the dynamics of A. fundyense and A. pacificum blooms and provide a more sound basis for monitoring toxic Alexandrium species in this region. PMID- 26026251 TI - Investigating the cubosomal ability for transnasal brain targeting: In vitro optimization, ex vivo permeation and in vivo biodistribution. AB - The aim of this study was to enhance the risperidone delivery to the brain through the transnasal route via optimization of cubosomal gel. Cubosomes were prepared using glycerol mono-oleate (GMO), Pluronic F127 (PF127) and Tween 80 (T80). The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro drug release and transmission electron microscopy. Central composite design was planned for the formulae optimization and the selected formula (containing PF127 with concentration 15 mg/g GMO and T80 with concentration of 20mg/L) was re prepared in presence of gelling polymer (gellan gum or polyox). The optimal cubosomal gel (containing 0.4% w/v polyox) had been subjected to ex-vivo permeation, histopathological evaluation and in vivo biodistribution studies. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control (drug solution and/or suspension). Finally, the cubosomal gel could be considered as a promising carrier for brain targeting of CNS acting drugs through the transnasal route. PMID- 26026252 TI - Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats. AB - A glass solution of the amorphous sodium salt of furosemide (ASSF) and polyvinylpyrrolidone (PVP) (80:20 w/w%) was prepared by spray drying. It was investigated if PVP was able to stabilise ASSF during storage and dissolution and whether this influenced the in vivo performance of the glass solution after oral dosing to rats. The glass solution had a glass transition temperature of 121.3 +/ 0.5 degrees C, which was significantly higher than that of the pure drug (101.2 degrees C). ASSF in the glass solution was stable for at least 168 days when stored at 20 degrees C and 0% relative humidity. The glass solution exhibited fast dissolution in simulated intestinal medium, pH 6.5; the intrinsic dissolution rate was found to be 10.1 +/- 0.6 mg/cm(2)/min, which was significantly faster than the pure ASSF. When investigating the stability during dissolution in stimulated intestinal medium at pH 6.5, the ASSF in the glass solution showed signs of crystallinity after 1 min of dissolution, but crystallised to a lesser extent than pure ASSF. The stabilising effect of PVP on ASSF, led to improved relative oral bioavailability in rats of 263%, when compared to the pure ASSF. PMID- 26026253 TI - Cationic triblock copolymer micelles enhance antioxidant activity, intracellular uptake and cytotoxicity of curcumin. AB - The aim of the present study was to develop curcumin loaded cationic polymeric micelles and to evaluate their loading, preservation of curcumin antioxidant activity and intracellular uptake ability. The micelles were prepared from a triblock copolymer consisting of poly(epsilon-caprolactone) and very short poly(2 (dimethylamino) ethyl methacrylate) segments (PDMAEMA9-PCL70-PDMAEMA9). The micelles showed monomodal size distribution, mean diameter of 145 nm, positive charge (+72 mV), critical micellar concentration around 0.05 g/l and encapsulation efficiency of 87%. The ability of the micellar curcumin to scavenge the ABTS radical and hypochlorite ions was higher than that of the free curcumin. Confocal microscopy revealed that the uptake of curcumin by chronic myeloid leukemia derived K-562 cells and human multiple myeloma cells U-266 was more intensive when curcumin was loaded into the micelles. These results correlated with the higher cytotoxicity of the micellar curcumin compared to free curcumin. Intraperitoneal treatment of Wistar rats indicated that PDMAEMA-PCL-PDMAEMA copolymer, comprising very short cationic chains, did not change the levels of malondialdehyde and glutathione in livers indicating an absence of oxidative stress. Thus, PDMAEMA-PCL-PDMAEMA triblock micelles could be considered efficient and safe platform for curcumin delivery. PMID- 26026254 TI - Recommendations for the Diagnosis and Management of Bladder Pain Syndrome. Spanish Urological Association Consensus Document. AB - INTRODUCTION: Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) and other bladder pathologies share common manifestations, such as the presence of mictional symptoms and a negative impact on the patient's quality of life. To be properly diagnosed and clinically managed, it is important to distinguish between its clinical modalities and diagnostic criteria for adequate exclusion. OBJECTIVE: The purpose of this study was to standardize criteria for making decisions in BPS management, for its diagnosis, initial treatment and follow-up. MATERIAL AND METHOD: A nominal group methodology was employed, using scientific evidence on BPS taken from a systematic (non-exhaustive) literature review for developing recommendations along with specialist expert opinions. RESULTS: The diagnosis of BPS should be made based on the patient's clinical history, with emphasis on pain and mictional symptoms as well as excluding other pathologies with similar symptomatology. BPS treatment should be directed towards restoring normal bladder function, preventing symptom relapse and improving patients' quality of life. It is therefore advisable to start with conservative treatment and to adopt less conservative treatments as the level of clinical severity increases. It is also recommended to abandon ineffective treatments and reconsider other therapeutic options. CONCLUSIONS: Quickly identifying the pathology is important when trying to positively influence morbidity and care quality for these patients. PMID- 26026255 TI - Neural correlates of active vision: An fMRI comparison of natural reading and scene viewing. AB - Theories of eye movement control during active vision tasks such as reading and scene viewing have primarily been developed and tested using data from eye tracking and computational modeling, and little is currently known about the neurocognition of active vision. The current fMRI study was conducted to examine the nature of the cortical networks that are associated with active vision. Subjects were asked to read passages for meaning and view photographs of scenes for a later memory test. The eye movement control network comprising frontal eye field (FEF), supplementary eye fields (SEF), and intraparietal sulcus (IPS), commonly activated during single-saccade eye movement tasks, were also involved in reading and scene viewing, suggesting that a common control network is engaged when eye movements are executed. However, the activated locus of the FEF varied across the two tasks, with medial FEF more activated in scene viewing relative to passage reading and lateral FEF more activated in reading than scene viewing. The results suggest that eye movements during active vision are associated with both domain-general and domain-specific components of the eye movement control network. PMID- 26026256 TI - Partial dissociation in the neural bases of VSTM and imagery in the early visual cortex. AB - Visual short-term memory (VSTM) and visual imagery are believed to involve overlapping neuronal representations in the early visual cortex. While a number of studies have provided evidence for this overlap, at the behavioral level VSTM and imagery are dissociable processes; this begs the question of how their neuronal mechanisms differ. Here we used transcranial magnetic stimulation (TMS) to examine whether the neural bases of imagery and VSTM maintenance are dissociable in the early visual cortex (EVC). We intentionally used a similar task for VSTM and imagery in order to equate their assessment. We hypothesized that any differential effect of TMS on VSTM and imagery would indicate that their neuronal bases differ at the level of EVC. In the "alone" condition, participants were asked to engage either in VSTM or imagery, whereas in the "concurrent" condition, each trial required both VSTM maintenance and imagery simultaneously. A dissociation between VSTM and imagery was observed for reaction times: TMS slowed down responses for VSTM but not for imagery. The impact of TMS on sensitivity did not differ between VSTM and imagery, but did depend on whether the tasks were carried concurrently or alone. This study shows that neural processes associated with VSTM and imagery in the early visual cortex can be partially dissociated. PMID- 26026257 TI - Targeted arginine metabolomics: A rapid, simple UPLC-QToF-MS(E) based approach for assessing the involvement of arginine metabolism in human disease. AB - BACKGROUND: Nitric oxide synthase (NOS) mediated conversion of arginine (ARG) to citrulline (CIT) is a key pathway for nitric oxide synthesis. ARG is also metabolised by alternate pathways to ornithine (ORN), homoarginine (HMA), N(G) monomethyl-L-arginine (MMA), N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G),N(G)' dimethyl-L-arginine (SDMA), all of which have the capacity to alter NOS activity. Simultaneous assessment of these analytes, when assessing the impact of arginine metabolism in human disease states, is desirable. METHODS: Analytes (ARG, ADMA, SDMA, MMA, HMA, CIT and ORN) were isolated from human plasma by solvent extraction, evaporated and reconstituted. Ultra-performance liquid chromatography (UPLC) was performed on a 150mm*2.1mm T3 HSS column using a gradient mobile phase comprising ammonium formate (10mM, pH3.8) in methanol (1% to 63%). Analytes were detected by time-of-flight mass spectrometry (Q-ToF-MS) in positive ion mode with electrospray ionisation (ESI+). Data were collected using MS(E). RESULTS: Solvent extraction provided high recovery (>95%). UPLC-QToF-MS(E) facilitated the separation and quantification of the 7 analytes in an analysis time of 6min. The approach has high sensitivity; LOQ range from 0.005MUM (NMMA) to 0.25MUM (ARG and ORN), and good precision; intra- and inter-day %RSD are <6% for all analytes. CONCLUSIONS: This approach provides the capacity to quantify 7 key compounds involved in ARG metabolism in a small sample volume, with a short total analysis time. These characteristics make this approach ideal for undertaking a comprehensive characterisation of this pathway in large data sets (e.g. population studies). PMID- 26026258 TI - A high throughput passive dosing format for the Fish Embryo Acute Toxicity test. AB - High throughput testing according to the Fish Embryo Acute Toxicity (FET) test (OECD Testing Guideline 236) is usually conducted in well plates. In the case of hydrophobic test substances, sorptive and evaporative losses often result in declining and poorly controlled exposure conditions. Therefore, our objective was to improve exposure conditions in FET tests by evaluating a passive dosing format using silicone O-rings in standard 24-well polystyrene plates. We exposed zebrafish embryos to a series of phenanthrene concentrations until 120h post fertilization (hpf), and obtained a linear dilution series. We report effect values for both mortality and sublethal morphological effects based on (1) measured exposure concentrations, (2) (lipid normalized) body residues and (3) chemical activity. The LC50 for 120hpf was 310MUg/L, CBR50 (critical body residue) was 2.72mmol/kg fresh wt and La50 (lethal chemical activity) was 0.047. All values were within ranges expected for baseline toxicity. Impaired swim bladder inflation was the most pronounced morphological effect and swimming activity was reduced in all exposure concentrations. Further analysis showed that the effect on swimming activity was not attributed to impaired swim bladder inflation, but rather to baseline toxicity. We conclude that silicone O-rings (1) produce a linear dilution series of phenanthrene in the 120hpf FET test, (2) generate and maintain aqueous concentrations for reliable determination of effect concentrations, and allow for obtaining mechanistic toxicity information, and (3) cause no toxicity, demonstrating its potential as an extension of the FET test when testing hydrophobic chemicals. PMID- 26026259 TI - Quasi-SMILES and nano-QFAR: united model for mutagenicity of fullerene and MWCNT under different conditions. AB - Simplified molecular input-line entry system (SMILES) are a tool to represent molecular features of various compounds. Quasi-SMILES is a tool to represent various eclectic features of interaction between complex substances and bio targets (cells, organs, organisms). The construction and the application of quasi SMILES in order to build up a model for prediction of mutagenicity of fullerene and multi-walled carbon-nanotubes (MWCNTs) are described in this work: instead of paradigm "endpoint is a mathematical function of molecular structure", the paradigm "endpoint is a mathematical function of eclectic data (features)" is used. PMID- 26026260 TI - Direct Visualization of the Antiangiogenic Effects of Sunitinib During the Treatment of Metastatic Clear Cell Renal Cell Carcinoma. PMID- 26026262 TI - Lipid Production from Hemicellulose and Holocellulose Hydrolysate of Palm Empty Fruit Bunches by Newly Isolated Oleaginous Yeasts. AB - Palm empty fruit bunches (EFBs) are abundant lignocellulosic wastes from palm oil mills. They are potential sources of sugars which can be converted to microbial lipids by oleaginous yeasts. To produce sugars from EFB, two-step and one-step hydrolysis reactions were performed. In the first step, the use of diluted sulfuric acid (0.5 % w/v) hydrolyzed hemicelluloses and released mainly pentoses, and in the second step of hydrolysis of residual pulp using 2.5 % (w/v), sulfuric acid released more hexoses. The use of 2.5 % (w/v) sulfuric acid in one-step hydrolysis of holocelluloses released the highest amount of sugars (38.3 g/L), but it also produced high concentration of potential inhibitors (>1 g/L). Three oleaginous yeasts, Rhodotorula mucilaginosa, Kluyveromyces marxianus, and Candida tropicalis, were isolated and screened for their ability to convert EFB hydrolysates into lipids. These yeasts grew well and produced lipids from EFB hemicellulose and holocellulose hydrolysate after potential inhibitors were removed. This study shows that EFB can be used for lipid production. PMID- 26026261 TI - The influence of a mild thermal challenge and severe hypoxia on exercise performance and serum BDNF. AB - AIM: To examine the isolated and combined effects of severe hypoxia and a mild thermal challenge on performance, physiological measures, cognition, and serum brain-derived neurotrophic factor (BDNF). METHODS: Nine trained male athletes (age: 23 +/- 3 years; W max: 333 +/- 45 W) completed four experimental trials (CON: 15 degrees C/0 m, ALT: 15 degrees C/3800 m, TEMP: 25 degrees C/0 m, ALT + TEMP: 25 degrees C/3800 m) in a double blind, randomized, cross-over design. Subjects cycled for 30 min in a self-paced test starting at 75% W max, their goal was to 'perform as much work as possible in 30 min.' Power output, heart rate, blood lactate, pulse oximetry, core and skin temperature, thermal sensation, ratings of perceived exertion, reaction time (RT), and BDNF were assessed. RESULTS: The amount of work produced in 30 min was reduced by temperature (F(1,8) = 7.1; p = 0.029; 360 +/- 19 kJ in 15 degrees C; 344 +/- 18 kJ in 25 degrees C) and altitude (F(1,8) = 94.2; p < 0.001; 427 +/- 24 kJ at sea level; 277 +/- 15 kJ at altitude), yet there was no interaction effect. Altitude increased mean RT (F(1,8) = 8.0; p = 0.022; 281.9 +/- 9.4 ms at sea level; 289.3 +/- 10.0 ms at altitude) and RT variability (F(1,8) = 8.5; p = 0.020; 44 +/- 3 ms at sea level: 50 +/- 4 ms at altitude). Exercise increased BDNF (F(1,8) = 15.2; p = 0.005; PRE: 21.8 +/- 1.3 ng/mL; POST: 26.5 +/- 2.1 ng/mL). CONCLUSION: Exercise capacity was significantly reduced due to an increase in altitude (3800 m; -34.3%) or a 10 degrees C increase in ambient temperature (-3.2%). The combination of both stressors showed to be additive (-38.0 %). Altitude induced an increase in RT and RT variability presenting a deterioration in cognitive functioning during acute hypoxia. Exercise significantly increased BDNF, but no effect of altitude on the BDNF concentration was observed. PMID- 26026263 TI - DNA-Binding Domain of DNA Ligase from the Thermophilic Archaeon Pyrococcus abyssi: Improving Long-Range PCR and Neutralization of Heparin's Inhibitory Effect. AB - The DNA-binding domain of the DNA ligase from Pyrococcus abyssi (PabDBD) was mapped and cloned into two expression vectors. The resulting 6X His-tagged proteins, with a predicted molecular mass of approximately 30 kDa, were overexpressed, purified using Ni-NTA resin, and biochemically characterized. Both PabDBD derivatives bound to double-stranded DNA fragments at the temperature range of 40-70 degrees C, and both were inactivated via heating at 95 degrees C for 15 min. Complexes of the PabDBD variants with either double- and single stranded DNA fragments were less stable than the native DNA ligase of P. abyssi. Inclusion of the C-terminally 6X His-tagged PabDBD in the reaction mixture during long-range polymerase chain reaction (PCR) increased the efficacy of amplification and eliminated the inhibitory effect of heparin. PMID- 26026264 TI - Intraoperative optical coherence tomography-assisted descemet membrane endothelial keratoplasty in the DISCOVER study. AB - PURPOSE: To investigate the utility of intraoperative optical coherence tomography (OCT) for Descemet membrane endothelial keratoplasty (DMEK) surgery. DESIGN: Prospective consecutive interventional case series. METHODS: DISCOVER (NCT02423213) is a prospective consecutive interventional case series examining the feasibility and utility of microscope-integrated intraoperative OCT in ophthalmic surgery. This report focuses on those eyes in the DISCOVER study undergoing DMEK surgery. The 8 cases were the first DMEK cases performed by the primary surgeon (J.M.G.) with microscope-integrated intraoperative OCT feedback. Qualitative OCT analysis was performed at multiple surgeon-defined time points, including host and donor tissue preparation, graft orientation, graft apposition, and tissue interface fluid dynamics. RESULTS: Correct graft orientation was confirmed by intraoperative OCT prior to unscrolling in 100% of cases. Seven of 8 grafts were fully attached at the conclusion of surgery and on postoperative day 1. One graft had a linear paracentral fixed area of interface separation corresponding to posterior stromal irregularities that was visible during surgery and unchanged on postoperative day 1. Two eyes developed significant peripheral graft dehiscence visible by the first postoperative week. Both grafts were successfully reattached with repeat gas injection. All eyes demonstrated improvement in best-corrected visual acuity and there was a 100% graft survival rate at last follow-up (minimum 4 months). Surgeon feedback indicated that intraoperative OCT provided valuable information in all 8 cases. CONCLUSIONS: Real-time intraoperative OCT can provide useful information that may directly impact surgical decision making during DMEK surgery. Intraoperative OCT may facilitate the transition for novice DMEK surgeons by increasing surgeon confidence and reducing the risk of iatrogenic graft failure. PMID- 26026265 TI - An economic passive sampling method to detect particulate pollutants using magnetic measurements. AB - Identifying particulate matter (PM) emitted from industrial processes into the atmosphere is an important issue in environmental research. This paper presents a passive sampling method using simple artificial samplers that maintains the advantage of bio-monitoring, but overcomes some of its disadvantages. The samplers were tested in a heavily polluted area (Linfen, China) and compared to results from leaf samples. Spatial variations of magnetic susceptibility from artificial passive samplers and leaf samples show very similar patterns. Scanning electron microscopy suggests that the collected PM are mostly in the range of 2 25 MUm; frequent occurrence of spherical shape indicates industrial combustion dominates PM emission. Magnetic properties around power plants show different features than other plants. This sampling method provides a suitable and economic tool for semi-quantifying temporal and spatial distribution of air quality; they can be installed in a regular grid and calibrate the weight of PM. PMID- 26026266 TI - A validated LC-MS/MS method of total and unbound lenvatinib quantification in human serum for protein binding studies by equilibrium dialysis. AB - A sensitive method for the determination of total and unbound lenvatinib (LenvimaTM), a novel tyrosine kinase inhibitor, in human serum was developed for protein binding studies using an equilibrium dialysis and liquid chromatography with tandem mass spectrometry. Serum samples (0.8 mL) were dialyzed against phosphate buffered saline (PBS) in dialyzer for 18 h at 37 degrees C to obtain dialysate and serum for unbound and total lenvatinib, respectively. After extraction by organic solvent, separation was achieved on a Symmetry Shield RP8 column with isocratic elution of 2 mM ammonium acetate (pH 4.0)-acetonitrile (3:2, v/v) at the flow rate of 0.2 mL/min. Detection was performed using API4000 with multiple reaction monitoring mode using positive electrospray ionization. The standard curve ranged from 0.0400 to 16.0 ng/mL and 0.0800 to 400 ng/mL as lenvatinib free base in PBS and serum, respectively. Accuracy and precision in the intra- and inter-batch reproducibility study were within the acceptance criteria. Various stability assessments including bench-top, freeze/thaw, processed samples, and frozen stability confirmed that lenvatinib was stable in serum and PBS. Application to in vivo protein binding studies in clinical studies was successfully performed and results showed that lenvatinib was highly protein bound in serum. PMID- 26026267 TI - Spectrophotometric pKa determination of ionizable pharmaceuticals: Resolution of molecules with weak pH-dependent spectral shift. AB - The extent of ionization of a drug molecule at different pH values can be characterized by its pKa (acid dissociation constants). It is an important parameter in pharmaceutical development to rationalize the physiochemical and biopharmaceutical properties of the drug molecule. UV titration for pKa determination is one of the popular methods. The success of this method requires the molecule exhibiting strong pH-dependent spectral shift related to the ionization process. Depending on the proximity between the ionizable group and the chromophore, the spectral shift may not be strong enough to warrant a successful determination. In a previous study, it has been reported that a distance of three sigma bonds between the chromophore and the ionizable group was the limit for a precise pKa determination. In this work, a UV titration method for pKa determination, with a particular emphasis on molecules with weak pH dependent spectral shift is investigated. It has been shown that the pKa values determined from this study are in good agreement with those determined using potentiometric method and literature data (R(2)=0.998). Our methodology revealed that successful pKa determination is feasible even with a separation distance of five sigma bonds between the chromophore and the ionizable group. PMID- 26026268 TI - Nuclear termination of STAT3 signaling through SIPAR (STAT3-Interacting Protein As a Repressor)-dependent recruitment of T cell tyrosine phosphatase TC-PTP. AB - STAT3 is associated with embryo development and survival as well as proliferation and metastasis of tumor cells. In a previous study, we demonstrated that STAT3 Interacting Protein As a Repressor (SIPAR) enhances the dephosphorylation of STAT3 and negatively regulates its activity. However, it remains unclear how SIPAR inhibits phosphorylation of STAT3. Here we demonstrate that SIPAR directly interacts with T cell protein tyrosine phosphatase TC45 and enhances its association with STAT3. This interaction triggers an accelerated dephosphorylation process for STAT3. Furthermore, SIPAR inhibits the transcriptional activity of STAT3 in wild-type MEF cells but not in TC45 null MEF cells. These results suggest that SIPAR terminates the activation of STAT3 through a dephosphorylation process that is dependent upon interaction with TC45 in the nucleus. PMID- 26026269 TI - The PqqD homologous domain of the radical SAM enzyme ThnB is required for thioether bond formation during thurincin H maturation. AB - Thurincin H is a 31-residue, ribosomally synthesized bacteriocin originating from the thn operon of Bacillus thuringiensis SF361. It is the only known sactipeptide carrying four thioether bridges between four cysteines and the alpha-carbons of a serine, an asparagine and two threonine residues. By analysis of the thn operon and use of in vitro studies we now reveal that ThnB is a radical S adenosylmethionine (SAM) enzyme containing two [4Fe-4S] clusters. Furthermore, we confirm the involvement of ThnB in the formation of the thioether bonds present within the structure of thurincin H. Finally, we show that the PqqD homologous N terminal domain of ThnB is essential for maturation of the thurincin H precursor peptide, but not for the SAM cleavage activity of ThnB. PMID- 26026270 TI - Innate immunity: Bacterial cell-wall muramyl peptide targets the conserved transcription factor YB-1. AB - The bacterial cell wall muramyl dipeptides MDP and glucosaminyl-MDP (GMDP) are powerful immunostimulators but their binding target remains controversial. We previously reported expression cloning of GMDP-binding polypeptides and identification of Y-box protein 1 (YB-1) as their sole target. Here we show specific binding of GMDP to recombinant YB-1 protein and subcellular colocalization of YB-1 and GMDP. GMDP binding to YB-1 upregulated gene expression levels of NF-kappaB2, a mediator of innate immunity. Furthermore, YB-1 knockdown abolished GMDP-induced Nfkb2 expression. GMDP/YB-1 stimulation led to NF-kappaB2 cleavage, transport of activated NF-kappaB2 p52 to the nucleus, and upregulation of NF-kappaB2-dependent chemokine Cxcr4 gene expression. Therefore, our findings identify YB-1 as new target for muramyl peptide signaling. PMID- 26026271 TI - The N2-Src neuronal splice variant of C-Src has altered SH3 domain ligand specificity and a higher constitutive activity than N1-Src. AB - N2-Src is a poorly understood neuronal splice variant of the ubiquitous C-Src tyrosine kinase, containing a 17 amino acid insert in its Src homology 3 (SH3) domain. To characterise the properties of N2-Src we directly compared its SH3 domain specificity and kinase activity with C- and N1-Src in vitro. N2- and N1 Src had a similar low affinity for the phosphorylation of substrates containing canonical C-Src SH3 ligands and synaptophysin, an established neuronal substrate for C-Src. N2-Src also had a higher basal kinase activity than N1- and C-Src in vitro and in cells, which could be explained by weakened intramolecular interactions. Therefore, N2-Src is a highly active kinase that is likely to phosphorylate alternative substrates to C-Src in the brain. PMID- 26026272 TI - The Potential Role of an Extended-Release, Abuse-Deterrent Oxycodone/Acetaminophen Fixed-Dose Combination Product for the Treatment of Acute Pain. AB - Acute pain, prevalent as part of postoperative and traumatic pain, is often sub optimally or inadequately treated. Fixed-dose combination analgesic products that combine a reduced amount of opioid with a nonopioid analgesic such as acetaminophen (paracetamol) in a single tablet offer potential pharmacodynamic and/or pharmacokinetic benefits, and may also result in an opioid-sparing effect. A new analgesic product (XARTEMISTM XR, Mallinckrodt Brand Pharmaceuticals, Dublin, Ireland) combines oxycodone (7.5 mg) with acetaminophen (325 mg) in an immediate-release/extended-release (ER) formulation that is indicated for the treatment of acute pain. The ER formulation of this product provides stable serum drug concentrations that in this case lasts 12 h. Oxycodone/acetaminophen is a drug combination that offers safe and effective pain relief in a variety of acute pain syndromes such as postoperative pain. The combination formulation allows a smaller amount of oxycodone per tablet and the biphasic-layered matrix of the pill for ER may present obstacles to potential abusers. No opioid is totally abuse resistant, but the lower opioid content and tamper-resistant formulation of this product might discourage abuse. Clinicians must still be mindful of the acetaminophen part of this product in the patient's overall daily intake (in light of acetaminophen hepatotoxicity). The new product appears to provide an important new choice in the armamentarium against acute pain. PMID- 26026273 TI - Oral Administration of Lactococcus lactis Expressing Synthetic Genes of Myelin Antigens in Decreasing Experimental Autoimmune Encephalomyelitis in Rats. AB - BACKGROUND: Multiple sclerosis is a human autoimmunological disease that causes neurodegeneration. One of the potential ways to stop its development is induction of oral tolerance, whose effect lies in decreasing immune response to the fed antigen. It was shown in animal models that administration of specific epitopes of the three main myelin proteins - myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and proteolipid protein (PLP) - results in induction of oral tolerance and suppression of disease symptoms. Use of bacterial cells to produce and deliver antigens to gut mucosa seems to be an attractive method for oral tolerance induction in treatment of diseases with autoimmune background. MATERIAL AND METHODS: Synthetic genes of MOG35-55, MBP85-97, and PLP139-151 myelin epitopes were generated and cloned in Lactococcus lactis under a CcpA regulated promoter. The tolerogenic effect of bacterial preparations was tested on experimental autoimmune encephalomyelitis, which is the animal model of MS. EAE was induced in rats by intradermal injection of guinea pig spinal cord homogenate into hind paws. RESULTS: Rats were administered preparations containing whole-cell lysates of L. lactis producing myelin antigens using different feeding schemes. Our study demonstrates that 20-fold, but not 4-fold, intragastric administration of autoantigen-expressing L. lactis cells under specific conditions reduces the clinical symptoms of EAE in rats. CONCLUSIONS: The present study evaluated the use of myelin antigens produced in L. lactis in inhibiting the onset of experimental autoimmune encephalomyelitis in rats. Obtained results indicate that application of such recombinant cells can be an attractive method of oral tolerance induction. PMID- 26026274 TI - Adverse events and survival after closing- and opening-wedge high tibial osteotomy: a comparative study of 412 patients. AB - PURPOSE: Varus medial knee osteoarthritis (OA) can be treated with a closing wedge (CW) or opening-wedge (OW) high tibial osteotomy (HTO). Little is known about the adverse event (AE) rate of these techniques. The purpose of this study was to examine the AE rate and survival rate of a consecutive series of 412 patients undergoing CW- or OW-HTO. METHODS: Medical records were retrospectively screened, and all patients who underwent HTO from 1993 to 2012 at the Erasmus University Medical Centre were assessed with a self-administered questionnaire. Patients filled in the intermittent and constant osteoarthritis pain score, knee injury and osteoarthritis outcome score, and a general questionnaire focusing on AE. RESULTS: Medical records of 412 patients (354 CW- and 112 OW-HTOs) were screened. Of the 358 eligible patients, 291 (81 %) returned their questionnaire. A total of 80 AE (17 %) were found in 466 osteotomies. In the CW-group, 47 (13 %) serious adverse events (SAE) and 2 (0.6 %) AE were found. In the OW-group, 17 (15 %) SAE and 14 (13 %) AE were found. The most common AE was in 14 (4 %) patients of the CW-group sensory palsy of the common peroneal nerve. The most common AE in the OW-group was persistent pain at the iliac crest [11 (9.8 %) patients]. Hardware was removed in 48 % of the CW-osteotomies and 71 % of the OW-osteotomies (p < 0.05). The probability of survival was 75 % after 10 years in the CW-group versus 90 % in the OW-group (p < 0.05). In both groups, an equal number of patients were "in need for prosthesis" according to OARSI criteria. CONCLUSION: OW-HTO was associated with more AE than CW-HTO. OW-HTO resulted in better survival than CW-HTO. However, in both groups an equal number of patients were in need for prosthesis. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 26026275 TI - Patient Experience in Health Center Medical Homes. AB - The Human Resource and Services Administration, Bureau of Primary Health Care Health Center program was developed to provide comprehensive, community-based quality primary care services, with an emphasis on meeting the needs of medically underserved populations. Health Centers have been leaders in adopting innovative approaches to improve quality care delivery, including the patient centered medical home (PCMH) model. Engaging patients through patient experience assessment is an important component of PCMH evaluation and a vital activity that can help drive patient-centered quality improvement initiatives. A total of 488 patients from five Health Center PCMHs in south Florida were surveyed in order to improve understanding of patient experience in Health Center PCMHs and to identify quality improvement opportunities. Overall patients reported very positive experience with patient-centeredness including being treated with courtesy and respect (85 % responded "always") and communication with their provider in a way that was easy to understand (87.7 % responded "always"). Opportunities for improvement included patient goal setting, referrals for patients with health conditions to workshops or educational programs, contact with the Health Center via phone and appointment availability. After adjusting for patient characteristics, results suggest that some patient experience components may be modified by educational attainment, years of care and race/ethnicity of patients. Findings are useful for informing quality improvement initiatives that, in conjunction with other patient engagement strategies, support Health Centers' ongoing transformation as PCMHs. PMID- 26026276 TI - Does an AHEC-Sponsored Clerkship Experience Strengthen Medical Students' Intent to Provide Care for Medically Underserved Patients? AB - The mission of Area Health Education Centers (AHECs) is to recruit and educate students to serve as practicing health care professionals in rural, primary care, and medically underserved communities. We sought to determine if participation in an AHEC-sponsored family medicine clerkship experiences during medical school are significantly associated with a self-reported intent to practice primary care in a medically underserved environment upon graduation. The study was a prospective cohort study comparing third-year family medicine students with the Indiana University School of Medicine who participated in either an AHEC-sponsored family medicine clerkship to those who completed their required family medicine clerkship outside of the AHEC setting. Following the 160-h clinical clerkship, all students completed a mandatory, electronic survey and were asked to self report their intent to the following question: "Which of the following statements best describes the impact of the family medicine clerkship on your intention to provide care to underserved patients when you complete residency training?" The question was integrated into a mandatory post-clerkship evaluation form required by the Indiana University School of Medicine, Department of Family Medicine. A Chi square test of independence as well as a multivariate logistic regression analysis was used to determine the independent association of AHEC clerkship participation and reported intent. A total of 1138 students completed the survey. There were not significant differences in age, gender, race, and ethnicity between students that completed an AHEC clerkship and those that did not. After adjusting for gender, race, and ethnicity, AHEC participants were significantly more likely to report an intention to practice primary care in a medically underserved setting upon graduation. Female students were found to be 1.2-3.4 times as likely to report increased intent compared to male students (95 % CI 1.241-3.394). Participation in an AHEC-supported clerkship was associated with a significant increase in self-reported intent to practice primary care in a medically underserved setting. Additional research is required to determine if participation and/or reported intent are predictive of practice selection after graduation. PMID- 26026277 TI - Effect of Educational Intervention on Cervical Cancer Prevention and Screening in Hispanic Women. AB - To evaluate the effect of an educational intervention on four domains of health care utilization and cervical cancer prevention and screening in a Hispanic population. Data collected from a survey were used to design education strategies focused on four domains of interest. A second survey was conducted to measure the impact of the intervention. Following the intervention, respondents were more likely to have any knowledge of human papillomavirus (HPV). Respondents living in the United States (US) for <5 years were more likely to have had a Papanicolaou smear in the preceding 3 years (p = 0.0314), to report knowledge of HPV vaccination (p = 0.0258), and to be willing to vaccinate themselves (p = 0.0124) and their children (p = 0.0341) after the intervention. Educational interventions designed to meet the needs identified by the sample group led to an increase in HPV awareness throughout the entire population surveyed and an increase in health care service utilization and HPV vaccine acceptance for women living in the US for <5 years. These tools should be promoted to reduce the cervical cancer burden on vulnerable populations. PMID- 26026278 TI - Novel Halomonas sp. B15 isolated from Larnaca Salt Lake in Cyprus that generates vanillin and vanillic acid from ferulic acid. AB - Vanillin is a high value added product with many applications in the food, fragrance and pharmaceutical industries. A natural and low-cost method to produce vanillin is by microbial bioconversions through ferulic acid. Until now, limited microorganisms have been found capable of bioconverting ferulic acid to vanillin at high yield. This study aimed to screen halotolerant strains of bacteria from Larnaca Salt Lake which generate vanillin and vanillic acid from ferulic acid. From a total of 50 halotolenant/halophilic strains 8 grew in 1 g/L ferulic acid and only 1 Halomonas sp. B15 and 3 Halomonas elognata strains were capable of bioconverting ferulic acid to vanillic acid at 100 g NaCl/L. The highest vanillic acid (365 mg/L) at these conditions generated by Halomonas sp. B15 which corresponds to ferulic acid bioconversion yield of 36.5%. Using the resting cell technique with an initial ferulic acid concentration of 0.5 g/L at low salinity, the highest production of vanillin (245 mg/L) took place after 48 h, corresponding to a bioconversion yield of 49%. This is the first reported Halomonas sp. with high yield of vanillin production from ferulic acid at low salinity. PMID- 26026279 TI - A review of the enzymatic hydrolysis of mannans and synergistic interactions between beta-mannanase, beta-mannosidase and alpha-galactosidase. AB - Mannan is an important polysaccharide found in softwoods and many other plant sources. Mannans from various sources display large differences in composition, structure and complexity. To hydrolyse mannan into its monomer sugars requires a number of enzymes working in synergy. This review examines mannan structure and the enzymes required for its hydrolysis. Several studies have investigated the effect of supplementing beta-mannanases with beta-mannosidases and alpha galactosidases in binary and ternary combinations. Synergistic enhancement of hydrolysis has been found in some, but not all cases. In the case of mannosidases, they sometimes display an anti-synergistic effect with mannanases, most likely due to competition for binding sites. Most importantly, in the case of alpha-galactosidases, the same enzyme from different families display differences in synergistic interactions due to different specificities. An improved understanding of enzyme interactions will aid in achieving enhanced hydrolysis of mannans and higher sugar yields. This review highlights areas which require further research in order to gain a better understanding of mannan hydrolysis and utilisation. Such knowledge is very important as this can be used in the optimisation of commercial or purified enzyme mixtures to improve the economic viability of the conversion of high mannan-containing biomass such as softwoods into fermentable sugars for bioethanol production. PMID- 26026280 TI - Phloretin derived from apple can reduce alpha-hemolysin expression in methicillin resistant Staphylococcus aureus USA300. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly important because it is the most common cause of hospital-acquired infections, which have become globally epidemic. Our study specifically focused on the MRSA strain USA300, which was shown in 2014 to be responsible for the most current pandemic of highly virulent MRSA in the United States. We aimed to evaluate the in vitro effect of phloretin on USA300. Susceptibility testing, western blotting assays, hemolysis assays and real-time RT-PCR were employed to examine the in vitro effects of phloretin on alpha-hemolysin (Hla) production when the bacterium was co-cultured with phloretin. The protective effect of phloretin against the USA300-mediated injury of human alveolar epithelial cells (A549) was tested using the live/dead analysis and cytotoxicity assays. We showed that sub-inhibitory concentrations of phloretin have no effect on bacterial viability; however, they can markedly inhibit the production of Hla in culture supernatants and the transcriptional levels of hla (the gene encoding Hla) and agrA (the accessory gene regulator). Phloretin, at a final concentration of 16 ug/ml, could protect A549 cells from injury caused by USA300 in the co-culture system. Our study suggests that phloretin might have a potential application in the development of treatment for MRSA infections. PMID- 26026281 TI - Epigenetic dynamics in immunity and autoimmunity. AB - A tightly synchronized and spatial-temporal interaction among regulatory proteins within genomic DNA and chromatin is essential for cellular commitment and differentiation. During development and activation of the immune system, a complex regulatory network that involves induction of lineage instructive transcription factors, installation or removal of histone modifications and changes in DNA methylation patterns locally orchestrate the three-dimensional chromatin structure and determine immune cell fate and immune responses. In autoimmune diseases, disease associated epigenetic marks and dynamic changes control the dysregulated immune system, thus determining the disease development and clinical phenotype. In this review, we introduce the dynamic epigenetic regulation of DNA and histones, summarize the epigenetic regulatory mechanisms in the development and differentiation of some important immune cell subsets and provide new insights for the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and Type 1 diabetes. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 26026282 TI - MicroRNA: Key regulators of oligodendrocyte development and pathobiology. AB - MicroRNAs (miRNAs or miRs) are a group of small non-coding RNAs that function through binding to messenger RNA (mRNA) targets and downregulating gene expression. miRNAs have been shown to regulate many cellular functions including proliferation, differentiation, development and apoptosis. Recently, evidence has grown which shows the involvement of miRs in oligodendrocyte (OL) specification and development. In particular, miRs-138, -219, -338, and -9 have been classified as key regulators of OL development, acting at various points in the OL lineage and influencing precursor cell transit into mature myelinating OLs. Many studies have emerged which link miRNAs with OL and myelin pathology in various central nervous system (CNS) diseases including multiple sclerosis (MS), ischemic stroke, spinal cord injury, and adult-onset autosomal dominant leukodystrophy (ADLD). PMID- 26026283 TI - Inter-subject Variability in Electric Fields of Motor Cortical tDCS. AB - BACKGROUND: The sources of inter-subject variability in the efficacy of transcranial direct current stimulation (tDCS) remain unknown. One potential source of variations is the brain's electric field, which varies according to each individual's anatomical features. OBJECTIVE: We employed an approach that combines imaging and computational modeling to quantitatively study the extent and primary causes of inter-subject variation in tDCS electric fields. METHODS: Anatomically-accurate models of the head and brain of 24 males (age: 38.63 +/- 11.24 years) were constructed from structural MRI. Finite-element method was used to computationally estimate the electric fields for tDCS of the motor cortex. Surface-based inter-subject registration of the electric field and functional MRI data was used for group level statistical analysis. RESULTS: We observed large differences in each individual's electric field patterns. However, group level analysis revealed that the average electric fields concentrated in the vicinity of the primary motor cortex. The variations in the electric fields in the hand motor area could be characterized by a normal distribution with a standard deviation of approximately 20% of the mean. The cerebrospinal fluid (CSF) thickness was the primary factor influencing an individual's electric field, thereby explaining 50% of the inter-individual variability, a thicker layer of CSF decreasing the electric field strength. CONCLUSIONS: The variability in the electric fields is related to each individual's anatomical features and can only be controlled using detailed image processing. Age was found to have a slight negative effect on the electric field, which might have implications on tDCS studies on aging brains. PMID- 26026284 TI - Single-pulse Transcranial Magnetic Stimulation Reveals Contribution of Premotor Cortex to Object Shape Recognition. AB - BACKGROUND: It is known that ventral premotor cortex responds selectively to the visual perception of object shapes. However, it is unclear whether this activation also contributes to visual processing. OBJECTIVE: In this study we want to assess whether activation in premotor areas contributes to visual perception of objects. METHODS: We measure performance on a perception task while delivering single pulse transcranial magnetic stimulation (TMS) to the left premotor cortex at different latencies after stimulus onset. RESULTS: We show that in cases of limited visual consciousness, disturbing the left premotor cortex 150 ms after stimulus onset results in a decrease in the capacity to recognize shapes, compared both to other latencies and to stimulation of the vertex. CONCLUSION: Premotor cortex plays a constitutive role in object shape recognition. PMID- 26026285 TI - Supplemental S1 fixation for type C pelvic ring injuries: biomechanical study of a long iliosacral versus a transsacral screw. AB - BACKGROUND: A single iliosacral screw placed into the S1 vertebral body has been shown to be clinically unreliable for certain type C pelvic ring injuries. Insertion of a second supplemental iliosacral screw into the S1 or S2 vertebral body has been widely used. However, clinical fixation failures have been reported using this technique, and a supplemental long iliosacral or transsacral screw has been used. The purpose of this study was to compare the biomechanical effect of a supplemental S1 long iliosacral screw versus a transsacral screw in an unstable type C vertically oriented sacral fracture model. MATERIALS AND METHODS: A type C pelvic ring injury was created in ten osteopenic/osteoporotic cadaver pelves by performing vertical osteotomies through zone 2 of the sacrum and the ipsilateral pubic rami. The sacrum was reduced maintaining a 2-mm fracture gap to simulate a closed-reduction model. All specimens were fixed using one 7.0-mm iliosacral screw into the S1 body. A supplemental long iliosacral screw was placed into the S1 body in five specimens. A supplemental transsacral S1 screw was placed in the other five. Each pelvis underwent 100,000 cycles at 250 N, followed by loading to failure. Vertical displacements at 25,000, 50,000, 75,000, and 100,000 cycles and failure force were recorded. RESULTS: Vertical displacement increased significantly (p < 0.05) within each group with each increase in the number of cycles. However, there was no statistically significant difference between groups in displacement or load to failure. CONCLUSIONS: Although intuitively a transsacral screw may seem to be better than a long iliosacral screw in conveying additional stability to an unstable sacral fracture fixation construct, we were not able to identify any biomechanical advantage of one method over the other. PMID- 26026286 TI - Rationale and design of a randomized, controlled multicentre clinical trial to evaluate the effect of bromocriptine on left ventricular function in women with peripartum cardiomyopathy. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is an idiopathic heart disease that develops in the last month of pregnancy and/or the first months following delivery in previously healthy women and may lead to acute heart failure. A cleaved fragment of the nursing hormone prolactin is considered essential in the pathophysiology of PPCM. To date, no specific therapy has been tested for PPCM in a randomized controlled trial of adequate size. AIMS: The purpose of this trial is to investigate the safety of the dopamin-D2-receptor agonist bromocriptine and its effects on left ventricular (LV) function in women with PPCM. METHODS: This is an 11 center German trial with a prospective randomized controlled open-label design. The trial enrolls females with newly diagnosed PPCM according to European Society of Cardiology criteria with a LV ejection fraction (LVEF) <35 %. Patients are randomized 1:1 to either best supportive care (BSC) including standard heart failure therapy plus 8 weeks of bromocriptine therapy (2.5 mg b.i.d. for 14 days and 2.5 mg q.d. from day 15 to 56) or to BSC plus 1 week of low-dose bromocriptine (2.5 mg q.d.) with anticoagulant therapy at a prophylactic dose administered during the period of bromocriptine treatment in both groups. The primary endpoint is change in LVEF from baseline to 6 months follow-up as assessed by cardiac magnetic resonance imaging (or echocardiography if CMR is not tolerated). The secondary endpoints are hospitalization for worsening heart failure, heart transplantation, and all-cause mortality during follow-up or a combination of these endpoints. A total of 60 patients will be recruited (including 6 potential dropouts) giving a power of 0.9 for an expected LVEF change of 10.8 % between treatment groups at 6 months. PERSPECTIVE: This trial will provide important knowledge on potential benefits and safety of prolonged inhibition of prolactin release with bromocriptine in addition to standard heart failure therapy in newly diagnosed PPCM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00998556. PMID- 26026287 TI - Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol. AB - Epithelial damage caused by intestinal permeation enhancers is a source of debate concerning safety. The medium chain fatty acid, sodium caprate (C10), causes reversible membrane perturbation at high dose levels required for efficacy in vivo, so the aim was to model it in vitro. Exposure of Caco-2 monolayers to 8.5mM C10 for 60min followed by incubation in fresh buffer led to (i) recovery in epithelial permeability (i.e. transepithelial electrical resistance (TEER) and apparent permeability coefficient (Papp) of [(14)C]-mannitol), (ii) recovery of cell viability parameters (monolayer morphology, plasma membrane potential, mitochondrial membrane potential, and intracellular calcium) and (iii) reduction in mRNA expression associated with inflammation (IL-8). Pre-incubation of monolayers with a mucosal prostaglandin cytoprotectant was attempted in order to further decipher the mechanism of C10. Misoprostol (100nM), inhibited C10-induced changes in monolayer parameters, an effect that was partially attenuated by the EP1 receptor antagonist, SC51322. In rat isolated intestinal tissue mucosae and in situ loop instillations, C10-induced respective increases in the [(14)C] mannitol Papp and the AUC of FITC-dextran 4000 (FD-4) were similarly inhibited by misoprostol, with accompanying morphological damage spared. These data support a temporary membrane perturbation effect of C10, which is linked to its capacity to mainly increase paracellular flux, but which can be prevented by pre-exposure to misoprostol. PMID- 26026288 TI - A pilot study in prostate cancer patients treated with the AE37 Ii-key-HER-2/neu polypeptide vaccine suggests that HLA-A*24 and HLA-DRB1*11 alleles may be prognostic and predictive biomarkers for clinical benefit. AB - Recently, several types of immunotherapies have been shown to induce encouraging clinical results, though in a restricted number of patients. Consequently, there is a need to identify immune biomarkers to select patients who will benefit from such therapies. Such predictive biomarkers may be also used as surrogates for overall survival (OS). We have recently found correlations between immunologic parameters and clinical outcome in prostate cancer patients who had been vaccinated with a HER-2/neu hybrid polypeptide vaccine (AE37) and received one booster 6 months post-primary vaccinations. Herein, we aimed to expand these retrospective analyses by studying the predictive impact of HLA-A*24 and HLA DRB1*11 alleles, which are expressed at high frequencies among responders in our vaccinated patients, for clinical and immunological responses to AE37 vaccination. Our data show an increased OS of patients expressing the HLA-DRB1*11 or HLA-A*24 alleles, or both. Vaccine-induced immunological responses, measured as interferon gamma (IFN-gamma) responses in vitro or delayed-type hypersensitivity reactions in vivo, were also higher in these patients and inversely correlated with suppressor elements. Preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-gamma immunity and plasma TGF-beta, among the HLA-A*24 and/or HLA-DRB1*11 positive patients, were strong indicators for immunological responses to AE37 treatment. These data suggest that HLA-DRB1*11 and HLA-A*24 are likely to be predictive factors for immunological and clinical responses to vaccination with AE37, though prospective validation in larger cohorts is needed. PMID- 26026289 TI - Mechanisms Underlying Motivational Deficits in Psychopathology: Similarities and Differences in Depression and Schizophrenia. AB - Motivational and hedonic impairments are core aspects of a variety of types of psychopathology. These impairments cut across diagnostic categories and may be critical to understanding major aspects of the functional impairments accompanying psychopathology. Given the centrality of motivational and hedonic systems to psychopathology, the Research Domain Criteria (RDoC) initiative includes a "positive valence" systems domain that outlines a number of constructs that may be key to understanding the nature and mechanisms of motivational and hedonic impairments in psychopathology. These component constructs include initial responsiveness to reward, reward anticipation or expectancy, incentive or reinforcement learning, effort valuation, and action selection. Here, we review behavioral and neuroimaging studies providing evidence for impairments in these constructs in individuals with psychosis versus in individuals with depressive pathology. There are important differences in the nature of reward-related and hedonic deficits associated with psychosis versus depression that have major implications for our understanding of etiology and treatment development. In particular, the literature strongly suggests the presence of impairments in in the-moment hedonics or "liking" in individuals with depressive pathology, particularly among those who experience anhedonia. Such deficits may propagate forward and contribute to impairments in other constructs that are dependent on hedonic responses, such as anticipation, learning, effort, and action selection. Such hedonic impairments could reflect alterations in dopamine and/or opioid signaling in the striatum related to depression or specifically to anhedonia in depressed populations. In contrast, the literature points to relatively intact in the-moment hedonic processing in psychosis, but provides much evidence for impairments in other components involved in translating reward to action selection. Particularly, individuals with schizophrenia exhibit altered reward prediction and associated striatal and prefrontal activation, impaired reward learning, and impaired reward-modulated action selection. PMID- 26026290 TI - Optimal technique for maximal forward rotating vaults in men's gymnastics. AB - In vaulting a gymnast must generate sufficient linear and angular momentum during the approach and table contact to complete the rotational requirements in the post-flight phase. This study investigated the optimization of table touchdown conditions and table contact technique for the maximization of rotation potential for forwards rotating vaults. A planar seven-segment torque-driven computer simulation model of the contact phase in vaulting was evaluated by varying joint torque activation time histories to match three performances of a handspring double somersault vault by an elite gymnast. The closest matching simulation was used as a starting point to maximize post-flight rotation potential (the product of angular momentum and flight time) for a forwards rotating vault. It was found that the maximized rotation potential was sufficient to produce a handspring double piked somersault vault. The corresponding optimal touchdown configuration exhibited hip flexion in contrast to the hyperextended configuration required for maximal height. Increasing touchdown velocity and angular momentum lead to additional post-flight rotation potential. By increasing the horizontal velocity at table touchdown, within limits obtained from recorded performances, the handspring double somersault tucked with one and a half twists, and the handspring triple somersault tucked became theoretically possible. PMID- 26026291 TI - Real-time MRI comparisons of brass players: A methodological pilot study. AB - This paper describes the use of real-time MRI at 30 frames/s in studying motor function within the oropharyngeal cavity of a trumpet, horn, trombone, and tuba player. Using Image J and customized MB-Ruler Pro software, analyses of discrete 33.3 ms snapshots of motion extracted from real-time MRI films obtained during an ascending five note sequence performed on a plastic practice device (B.E.R.P.) revealed inter-instrument differences in oropharyngeal cavity size and tongue conformation when moving from lower to higher notes. Tuba and trombone show a progressive decrease in oropharyngeal area featuring an upward and forward displacement of the tongue. Trumpet showed progressive increases in oropharyngeal area, with the posterior compartment showing the largest change, while horn essentially showed no change. A novel dynamic quantitative analysis method is also described utilizing Matlab. This method employs user-specified line profiles, aligned to the direction of the movement of interest. It takes advantage of time-varying pixel luminescence to derive spatial and temporal gradients. These gradients make possible the acquisition of kinematic data to describe movement in terms of slower position changes (spatial gradient) as well as fast, articulatory movements (temporal gradient). Spatial gradient analysis for the trumpet player demonstrates a progressive raising of the tongue during the ascending five note exercise. Temporal gradient analysis of double-tonguing revealed similarities in range of motion, anti-phase behavior, and frequency across instruments with respect to movements of the tongue tip and back of tongue. The paper concludes by making recommendations for extending these methods to studying musician's dystonia. PMID- 26026292 TI - Influence of temperature on carbon and nitrogen dynamics during in situ aeration of aged waste in simulated landfill bioreactors. AB - The effect of temperature on carbon and nitrogen compounds during in situ aeration of aged waste was investigated in lab-scale simulated landfill bioreactors at 35, 45 and 55 degrees C, respectively. The bioreactor operated at 55 degrees C presented the highest carbon mineralization rate in the initial stage, suggesting accelerated biodegradation rates under thermophilic conditions. The nitrogen speciation study indicated that organic nitrogen was the dominant species of total N in aerobic bioreactors due to ammonia removal. Leachate organic nitrogen was further fractionated to elucidate the fate of individual constituent. Detailed investigation revealed the higher bioconversion rates of N humic and N-fulvic compounds compared to hydrophilic compounds in thermophilic conditions. At the end, waste material in 55 degrees C bioreactor was richer in highly matured humic substances (HS) verifying the high bioconversion rates. PMID- 26026293 TI - Pretreatment of lignocellulosic biomass with renewable cholinium ionic liquids: Biomass fractionation, enzymatic digestion and ionic liquid reuse. AB - Pretreatment of lignocelluloses is a key step in the biorefinery for production of biofuels and valuable platform chemicals. In this work, various lignocelluloses were pretreated using cholinium ionic liquids (ILs) that are wholly composed of biomaterials, and fractionated into carbohydrate-rich materials (CRMs) and lignin-rich materials (LRMs). Cholinium ILs were found to be effective pretreatment solvents for grass lignocelluloses as well as eucalyptus, resulting in significant improvements in the glucose yields (58-75%) in subsequent enzymatic hydrolysis, while they were inefficient to make pine susceptible to biodegradation. Approximately 46% of lignin in native rice straw was fractionated as LRM after pretreatment using cholinium argininate ([Ch][Arg]). [Ch][Arg] showed excellent recyclability, and the total recovery was as high as 75% after reused for 8 cycles. Besides, rice straw pretreated by the recycled IL remained highly digestible, and good glucose yields (63-75%) were achieved after its enzymatic hydrolysis. PMID- 26026294 TI - Density of biogas digestate depending on temperature and composition. AB - Density is one of the most important physical properties of biogas digestate to ensure an optimal dimensioning and a precise design of biogas plant components like stirring devices, pumps and heat exchangers. In this study the density of biogas digestates with different compositions was measured using pycnometers at ambient pressure in a temperature range from 293.15 to 313.15K. The biogas digestates were taken from semi-continuous experiments, in which the marine microalga Nannochloropsis salina, corn silage and a mixture of both were used as feedstocks. The results show an increase of density with increasing total solid content and a decrease with increasing temperature. Three equations to calculate the density of biogas digestate were set up depending on temperature as well as on the total solid content, organic composition and elemental composition, respectively. All correlations show a relative deviation below 1% compared to experimental data. PMID- 26026295 TI - A new flat sheet membrane bioreactor hybrid system for advanced treatment of effluent, reverse osmosis pretreatment and fouling mitigation. AB - This paper introduces a new hybrid electro membrane bioreactor (HEMBR) for reverse osmosis (RO) pretreatment and advanced treatment of effluent by simultaneously integrating electrical coagulation (EC) with a membrane bioreactor (MBR) and its performance was compared with conventional MBR. Experimental results and their statistical analysis showed removal efficiency for suspended solids (SS) of almost 100% for both reactors. HEMBR removal of chemical oxygen demand (COD) improved by 4% and membrane fouling was alleviated according to transmembrane pressure (TMP). The average silt density index (SDI) of HEMBR permeate samples was slightly better indicating less RO membrane fouling. Moreover, based on the SVI comparison of two reactor biomass samples, HEMBR showed better settling characteristics which improved the dewaterability and filterability of the sludge. Analysis the change of membrane surfaces and the cake layer formed over them through field emission scanning electron microscopy (FESEM) and X-ray fluorescence spectrometer (XRF) were also discussed. PMID- 26026296 TI - Changes in vasotocin levels in relation to ovarian development in the catfish Heteropneustes fossilis exposed to altered photoperiod and temperature. AB - Photoperiod and temperature are the major proximate factors that activate the brain-pituitary-gonadal-endocrine axis stimulating gonadal recrudescence. Vasotocin (VT), the basic nonapeptide hormone, is secreted by the nucleus preopticus in the hypothalamus and released from the pituitary into circulation as a neurohormone for physiological actions. Additionally, VT is secreted de novo in the ovary of the catfish and has been implicated in ovarian functions. In the present study, we evaluated the changes in VT secretion during altered photoperiod and temperature exposure. The ovarian changes were monitored over gonadosomatic index (GSI) and plasma steroid hormone levels. Exposure of the catfish to long photoperiod (LP, 16L:08D) daily, alone or in combination with high temperature (HT, 28 +/- 2 degrees C), for 14 or 28 days resulted in a decrease in brain-pituitary VT level with a concomitant increase in plasma and ovarian VT levels. The changes were greater in the LP + HT group on day 28. Concurrently, the treatments stimulated the GSI and plasma estradiol-17beta (E2), testosterone (T) and progesterone (P4) levels with higher more responses in the LP + HT group. Exposure of the catfish to short photoperiod (SP, 08L:16D) daily or total darkness (TD, 24L:00D) daily, with or without changing the ambient temperature, for 14 or 28 days produced a depressing effect on VT, GSI and steroid hormone levels, the range of the response varied with the temperature. The brain VT level was low except in the TD + NT group. Plasma and ovarian VT levels decreased more in the SP and TD groups under ambient temperature than in the groups at the raised temperature. The GSI and plasma steroid hormones (E2, T and P4) responded in a similar manner. Plasma cortisol level registered a significant increase in all the groups compared to the initial control groups, and the increase was significantly higher on day 28. The simultaneous activation of VT secretion and ovarian recrudescence by photoperiod and temperature suggests the peptide's involvement in the hormonal control of gametogenesis. PMID- 26026297 TI - A comparison of single and multiple stressor protocols to assess acute stress in a coastal shark species, Rhizoprionodon terraenovae. AB - Elasmobranch stress responses are traditionally measured in the field by either singly or serially sampling an animal after a physiologically stressful event. Although capture and handling techniques are effective at inducing a stress response, differences in protocols could affect the degree of stress experienced by an individual, making meaningful comparisons between the protocols difficult, if not impossible. This study acutely stressed Atlantic sharpnose sharks, Rhizoprionodon terraenovae, by standardized capture (rod and reel) and handling methods and implemented either a single or serial blood sampling protocol to monitor four indicators of the secondary stress response. Single-sampled sharks were hooked and allowed to swim around the boat until retrieved for a blood sample at either 0, 15, 30, 45, or 60 min post-hooking. Serially sampled sharks were retrieved, phlebotomized, released while still hooked, and subsequently resampled at 15, 30, 45, and 60 min intervals post-hooking. Blood was analyzed for hematocrit, and plasma glucose, lactate, and osmolality levels. Although both single and serial sampling protocols resulted in an increase in glucose, no significant difference in glucose level was found between protocols. Serially sampled sharks exhibited cumulatively heightened levels for lactate and osmolality at all time intervals when compared to single-sampled animals at the same time. Maximal concentration differences of 217.5, 9.8, and 41.6 % were reported for lactate, osmolality, and glucose levels, respectively. Hematocrit increased significantly over time for the single sampling protocol but did not change significantly during the serial sampling protocol. The differences in resultant blood chemistry levels between implemented stress protocols and durations are significant and need to be considered when assessing stress in elasmobranchs. PMID- 26026298 TI - Microfluidics and numerical simulation as methods for standardization of zebrafish sperm cell activation. AB - Sperm cell activation plays a critical role in a range of biological and engineering processes, from fertilization to cryopreservation protocol evaluation. Across a range of species, ionic and osmotic effects have been discovered that lead to activation. Sperm cells of zebrafish (Danio rerio) initiate motility in a hypoosmotic environment. In this study, we employ a microfluidic mixer for the purpose of rapidly diluting the extracellular medium to initiate the onset of cell motility. The use of a microchannel offers a rapid and reproducible mixing profile throughout the device. This greatly reduces variability from trial to trial relative to the current methods of analysis. Coupling these experiments with numerical simulations, we were able to investigate the dynamics of intracellular osmolality as each cell moves along its path through the micromixer. Our results suggest that intracellular osmolality, and hence intracellular ion concentration, only slightly decreases, contrary to the common thought that larger changes in these parameters are required for activation. Utilizing this framework, microfluidics for controlled extracellular environments and associated numerical modeling, has practical applicability in standardizing high-throughput aquatic sperm activation, and more fundamentally, investigations of the intracellular environment leading to motility. PMID- 26026299 TI - TDDFT prediction of UV-vis absorption and emission spectra of tocopherols in different media. AB - We use the TDDFT/PBE0/6-31+G* method to determine the electronic absorption and emission energies, in different media, of the four forms of tocopherol, which differ by the number and the position of methyl groups on the chromanol. Geometries of the ground state S0 and the first singlet excited state S1 were optimized in the gas phase, and various solvents. The solvent effect is evaluated using an implicit solvation model (IEF-PCM). Our results are compared to the experimental ones obtained for the vitamin E content in several vegetable oils. For all forms of tocopherols, the HOMO-LUMO first vertical excitation is a pi-pi* transition. Gas phase and non-polar solvents (benzene and toluene) give higher absorption wavelengths than polar solvents (acetone, ethanol, methanol, DMSO, and water); this can be interpreted by a coplanarity between the O-H group and the chroman, allowing a better electronic resonance of the oxygen lone pairs and the aromatic ring, and therefore giving an important absorption wavelength, whereas the polar solvents give high emission wavelengths comparatively to gas phase and non-polar solvents. Fluorescence spectra permit the determination, the separation, and the identification of the four forms of tocopherols by a large difference in emission wavelength values. Graphical Abstract Scheme from process methodological to obtain the absorption and emission spectra for tocopherols. PMID- 26026300 TI - Quantum chemistry investigation on the reaction mechanism of the elemental mercury, chlorine, bromine and ozone system. AB - Ab initio calculations were performed to study the quantum chemistry reactions mechanisms among Hg(0), elemental halogen and O3. The geometry of reactions, transition states (TS), intermediates (M) and products were optimized using the MP2 method at the SDD basis function level for Hg, and using 6-311++G (3df, 3pd) for other species. Molecular energies were calculated at QCISD (T) level with zero point energy. Activation energies were calculated along with pre-exponential factors . The reaction rate constants within 298-1800 K were calculated according to transition state theory (TST). The influences of O3 on the reaction of Hg(0) with halogen are discussed. Hg(0) can be oxidized to Hg(1+) by halogen and O3, and halogen and O3 can be arranged in decreasing order as: Br2 > BrO > O3 > Br > Cl, BrCl > HBr > HCl, Br2 > Cl2 according to reaction rate constants. When O3 is presented, Br2, HBr, BrCl, Cl2 and HCl react with O3 and are initially converted to BrO and ClO. O3 is unfavorable for oxidation of Hg(0) by Br2. The mixture of HBr and O3 has better oxidizing Hg(0) performance than HBr and O3. Cl is less effective than Br for oxidation of Hg(0). PMID- 26026301 TI - Ligand effects due to resonance character in LAuCCH(-) (L = F, Cl, Br, I, CCH) complexes: an NBO/NRT analysis. AB - The organogold complexes of LAuCCH(-) (L = F, Cl, Br, I, CCH) were investigated using natural bond orbital/natural resonance theory (NBO/NRT) methods. The NBO/NRT results strongly support the general resonance-type three-center-four electron (3c/4e) picture of LAuCCH: L(-): Au-CCH <-> L-Au :CCH(-), arising from hyperconjugation interactions. The sums of ionic and covalent contributions to both L-Au and Au-CCH bonds are all slightly larger than that due to the additional pi-back bonding within the 3c/4e hyperbonded triad. This complementary relationship between L-Au and Au-CCH bond orders implies a competing relationship between the ancillary ligand and CCH around the gold atom. We discuss the ligand effects in the LAuCCH(-) series on the basis of this competing relationship. PMID- 26026302 TI - Calorimetry investigations of milled alpha-tricalcium phosphate (alpha-TCP) powders to determine the formation enthalpies of alpha-TCP and X-ray amorphous tricalcium phosphate. AB - One alpha-tricalcium phosphate (alpha-TCP) powder was either calcined at 500 degrees C to obtain fully crystalline alpha-TCP or milled for different durations to obtain alpha-TCP powders containing various amounts of X-ray amorphous tricalcium phosphate (ATCP). These powders containing between 0 and 71wt.% ATCP and up to 2.0+/-0.1wt.% beta-TCP as minor phase were then hydrated in 0.1M Na2HPO4 aqueous solution and the resulting heat flows were measured by isothermal calorimetry. Additionally, the evolution of the phase composition during hydration was determined by in situ XRD combined with the G-factor method, an external standard method which facilitates the indirect quantification of amorphous phases. Maximum ATCP hydration was reached after about 1h, while that of crystalline alpha-TCP hydration occurred between 4 and 11h, depending on the ATCP content. An enthalpy of formation of -4065+/-6kJ/mol (T=23 degrees C) was calculated for ATCP (Ca3(PO4)2), while for crystalline alpha-TCP (alpha Ca3(PO4)2) a value of -4113+/-6kJ/mol (T=23 degrees C) was determined. PMID- 26026303 TI - The armored carapace of the boxfish. AB - The boxfish (Lactoria cornuta) has a carapace consisting of dermal scutes with a highly mineralized surface plate and a compliant collagen base. This carapace must provide effective protection against predators as it comes at the high cost of reduced mobility and speed. The mineralized hydroxyapatite plates, predominantly hexagonal in shape, are reinforced with raised struts that extend from the center toward the edges of each scute. Below the mineralized plates are non-mineralized collagen fibers arranged in through-the-thickness layers of ladder-like formations. At the interfaces between scutes, the mineralized plates form suture-like teeth structures below which the collagen fibers bridge the gap between neighboring scutes. These sutures are unlike most others as they have no bridging Sharpey's fibers and appear to add little mechanical strength to the overall carapace. It is proposed that the sutured interface either allows for accommodation of the changing pressures of the boxfish's ocean habitat or growth, which occurs without molting or shedding. In both tension and punch testing the mineralized sutures remain relatively intact while most failures occur within the collagen fibers, allowing for the individual scutes to maintain their integrity. This complex structure allows for elevated strength of the carapace through an increase in the stressed area when attacked by predators in both penetrating and crushing modes. PMID- 26026304 TI - Efficient RNA delivery by integrin-targeted glutathione responsive polyethyleneimine capped gold nanorods. AB - RNA interference (RNAi) mediated gene silencing holds significant promises in gene therapy. A major obstacle to efficient RNAi is the systemic delivery of the therapeutic RNAs into the cytoplasmon without being trapped in intracellular endo /lyso-somes. Herein we report the development of a PEGylated, RGD peptide modified, and disulfide cross-linked short polyethylenimines (DSPEIs) functionalized gold nanorod (RDG) for targeted small hairpin (sh)RNA delivery. The RDG effectively condensed shRNAs into stable nanoparticles, allowing for highly specific targeting of model human brain cancer cells (U-87 MG-GFP) via the alphavbeta3 integrins-mediated endocytosis. The combined effects of endosomal escape (via the proton-sponge effect of the PEIs) and efficient cleavage of the disulfide-cross-linked DSPEIs by the high intracellular glutathione content triggered rapid cytoplasma shRNAs release resulting in excellent RNAi efficiency and low cytotoxicity. Furthermore, the high stability and prolonged blood circulation afforded by PEGylation allowed for highly effective, targeted tumor accumulation and internalization of the carriers, resulting in outstanding intra tumor gene silencing efficiency in U-87 MG-GFP tumor bearing BALB/c mice. Combining the capabilities of both passive and active targeting, intracellular glutathione-triggered "off-on" release and endosomal escape, the RDG nanocarrier developed herein appears to be a highly promising non-viral vector for efficient RNAi. PMID- 26026306 TI - Molecular structure, spectroscopic characterization, HOMO and LUMO analysis of 3,3'-diaminobenzidine with DFT quantum chemical calculations. AB - In this work, infrared, Raman and UV spectra of 3,3'-diaminobenzidine (3,3-DAB) were carried out by using density functional theory (DFT)/B3LYP method with 6 311G(d,p) basis set. FT-IR and FT-Raman spectra were recorded in the region 4000 400 and 4000-50 cm(-1), respectively. The geometrical parameters, energies and wavenumbers were obtained and fundamental vibrations were assigned on the basis of the potential energy distribution (PED) of the vibrational modes. The UV spectrum of the investigated compound was recorded in the range of 200-400 nm in ethanol and water solutions. The electronic properties, such as excitation energies, absorption wavelengths, HOMO and LUMO energies were performed by DFT/B3LYP approach and the results were compared with experimental observations. Thermodynamic properties, Mulliken atomic charges and molecular electrostatic potential (MEP) were calculated for the title molecule. Also the nonlinear optical properties of 3,3-DAB molecule were explored theoretically. As a result, the calculated results were compared with the observed values and generally found to be in good agreement. PMID- 26026305 TI - Combinatorial effect of substratum properties on mesenchymal stem cell sheet engineering and subsequent multi-lineage differentiation. AB - Cell sheet engineering has been exploited as an alternative approach in tissue regeneration and the use of stem cells to generate cell sheets has further showed its potential in stem cell-mediated tissue regeneration. There exist vast interests in developing strategies to enhance the formation of stem cell sheets for downstream applications. It has been proved that stem cells are sensitive to the biophysical cues of the microenvironment. Therefore we hypothesized that the combinatorial substratum properties could be tailored to modulate the development of cell sheet formation and further influence its multipotency. For validation, polydimethylsiloxane (PDMS) of different combinatorial substratum properties (including stiffness, roughness and wettability) were created, on which the human bone marrow derived mesenchymal stem cells (BMSCs) were cultured to form cell sheets with their multipotency evaluated after induced differentiation. The results showed that different combinatorial effects of these substratum properties were able to influence BMSC behavior such as adhesion, spreading and proliferation during cell sheet development. Collagen formation within the cell sheet was enhanced on substrates with lower stiffness, higher hydrophobicity and roughness, which further assisted the induced chondrogenesis and osteogenesis, respectively. These findings suggested that combinatorial substratum properties had profound effects on BMSC cell sheet integrity and multipotency, which had significant implications for future biomaterials and scaffold designs in the field of BMSC-mediated tissue regeneration. PMID- 26026307 TI - Thiophene aldehyde-diamino uracil Schiff base: A novel fluorescent probe for detection and quantification of cupric, silver and ferric ions. AB - A new Schiff base from the condensation of 5,6-diamino-1,3-dimethyluracil with 5 methylthiophene-2-carboxaldehyde was synthesized. The compound was characterized by spectral data (UV-Vis, IR, (1)H NMR, fluorescence, MS). Ethanolic solutions of the Schiff base exhibit a strong fluorescence emission at 385 nm (lambdaex=341 nm), and have been employed as a "turn-off" fluorescent probe for selective detection of Ag(+), Cu(2+) and Fe(3+) ions in presence of other cations such as Na(+), K(+), Ca(2+) and Mg(2+) ions abundant in natural water. The interaction between the tested compound and copper, silver or iron ions is associated with a significant fluorescence decrease, showing detection limits of 2.1-14.2 ppb. Under optimal conditions, the developed sensor was successfully employed to determine Ag(+), Cu(2+) and Fe(3+) ions in real samples and proved to be selective and sensitive. PMID- 26026309 TI - Discrepancies between the K-ras mutational status of primary colorectal cancers and corresponding liver metastases are found in codon 13. AB - K-ras mutation status has remained elusive in the metastatic liver tumors of colorectal cancer (CRC) in contrast to the primary CRC tumors. In this study, K ras mutational status of the primary and corresponding liver metastatic tumors was investigated in the 43 CRC patients. Codons 12 and 13 of K-ras were directly sequenced, and a K-ras mutation was evident in 17 cases (39.5%). In 6 cases, the K-ras mutation was evident only in the liver metastasis, but not in the primary CRC, where the mutation was found in codon 13. This discrepancy between primary and metastatic lesions with regard to codon 13 of the K-ras gene may explain the clinical discrepancy of EGFR antibody therapy. In conclusion, the current data may lead to the development of personalized medicine for recurrent CRC, although further validation study is still required. PMID- 26026308 TI - The value of preoperative screening colonoscopies in patients with biliary tract cancer. AB - BACKGROUND: The purpose of this study was to evaluate the value of preoperative screening colonoscopies in patients with biliary tract cancer. METHODS: A total of 544 patients with biliary tract cancer who underwent preoperative screening colonoscopies between January 2005 and December 2012 were retrospectively analyzed. RESULTS: Synchronous colorectal neoplasia was detected in 199 patients (36.7 %), with adenocarcinomas detected in 21 (3.9 %) patients, carcinoids in two (0.4 %) patients, and adenomas in 176 (32.4 %) patients. Of those with adenomas, 32 patients were diagnosed with advanced adenomas, defined as adenomas with a maximum diameter of >1 cm, villous histology, or high-grade dysplasia because these characteristics implied the risk of malignant transformation. Fifty-five (10.1 %) of the patients with colorectal neoplasia required resection (11 surgical and 44 endoscopic resections). There were no major adverse events related to the resection. Univariate and multivariate analyses revealed that smoking status [ex-smoker + current smoker vs. non-smoker: odds ratio (OR) 2.32; 95 % confidence interval (CI) 1.30-4.21] and advanced age (>=70 vs. <=69 years: OR 2.22; 95 % CI 1.24-3.91) were independent risk factors of having a colorectal neoplasia that required resection. CONCLUSIONS: In patients with biliary tract cancer, preoperative screening colonoscopy was feasible and provided valuable clinical information. Synchronous colorectal neoplasia was detected in a substantial number of patients. Preoperative screening colonoscopies should be considered especially in high-risk patients such as smokers and elderly patients. PMID- 26026310 TI - Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans. AB - Humans maintain core temperature through a complex neuroendocrine circuitry, coupling environmental thermal and nutritional cues to heat-producing and dissipating mechanisms. Up to 40% of resting energy expenditure contributes to thermal homeostasis maintenance. Recent re-discovery of thermogenic brown adipose tissue (BAT) has brought the relation between ambient temperature, thermogenesis and systemic energy and substrate metabolism to the forefront. In addition to well-known pituitary-thyroid-adrenal axis, new endocrine signals, such as FGF21 and irisin, orchestrate crosstalk between white adipose tissue (WAT), BAT and muscle, tuning non-shivering and shivering thermogenesis responses. Cold exposure modulates the endocrine milieu, and cold-induced hormones cause bioenergetics transformation sufficient to impact whole body metabolism. This review will appraise the nature of human BAT and the basis of BAT-centred therapeutics, highlighting how the interaction between hormones and adipose tissue impacts metabolic responses. Non-pharmacological and pharmacological strategies of BAT recruitment and/or fat browning for metabolic benefits will be discussed. PMID- 26026311 TI - CONSORT in China: past development and future direction. AB - The Consolidated Standards of Reporting Trials (CONSORT) Statement was published in 1996, and first introduced to China in 2001. Although CONSORT has been widely accepted in high-quality international journals, we still need to have more investigation on how many Chinese journals have adopted the CONSORT Statement, and whether the quality of reporting has improved. A systematic search of the "Instructions to authors" in all Chinese medical journals in China Academic Journals (CAJ) Full-text Database was conducted up to February 2012 and only 7 journals officially listed the requirements of the CONSORT Statement. The research articles about randomized controlled trials (RCTs) published in 2002, 2004, 2006, 2008, and 2010 from journals which had specifically adopted the CONSORT Statement, and from 30 top journals based on the Chinese Science Citation Index (CSCI) 2011 as the control group, were identified. The quality of both cohorts of articles was assessed using the revised CONSORT Checklist and Jadad scale. A total of 1221 Chinese medical journals was identified. Only seven journals stated clearly in the "Instructions to authors" that authors should adopt the CONSORT requirement in the clinical trial paper. None of these journals is among the control group in the CSCI 2011. In the selected years, a total of 171 articles from 7 journals which had adopted CONSORT and 232 articles in the control were identified as including RCT trials. The average scores according to the revised CONSORT Checklist were 29.47 for the CONSORT-adopting journals and 25.57 for the control group; while the average scores based on the Jadad scale were 2.53 for CONSORT-adopting journals and 1.97 for the control group. Few journals among Chinese medical journals have adopted the CONSORT Statement. The overall quality of RCT reports in the 7 journals which have adopted CONSORT was better than those in the top 30 journals which have not adopted CONSORT. The quality of RCT reports in Chinese journals needs further improvement, and the CONSORT Statement could be a very helpful guideline. PMID- 26026313 TI - Time lagged ordinal partition networks for capturing dynamics of continuous dynamical systems. AB - We investigate a generalised version of the recently proposed ordinal partition time series to network transformation algorithm. First, we introduce a fixed time lag for the elements of each partition that is selected using techniques from traditional time delay embedding. The resulting partitions define regions in the embedding phase space that are mapped to nodes in the network space. Edges are allocated between nodes based on temporal succession thus creating a Markov chain representation of the time series. We then apply this new transformation algorithm to time series generated by the Rossler system and find that periodic dynamics translate to ring structures whereas chaotic time series translate to band or tube-like structures-thereby indicating that our algorithm generates networks whose structure is sensitive to system dynamics. Furthermore, we demonstrate that simple network measures including the mean out degree and variance of out degrees can track changes in the dynamical behaviour in a manner comparable to the largest Lyapunov exponent. We also apply the same analysis to experimental time series generated by a diode resonator circuit and show that the network size, mean shortest path length, and network diameter are highly sensitive to the interior crisis captured in this particular data set. PMID- 26026314 TI - Dynamics of a relativistic charge in the Penning trap. AB - We are interested in the motion of a classical charge within a processing chamber of a Penning trap. We examine the relativistic Lagrangian and Hamiltonian dynamics without any approximations. We show that the radial and axial motions are non-linearly coupled to each other whenever the special relativity is taken into account. As the restoring quadruple potential has the axial symmetry, the dynamics of the system can be reduced to two degrees of freedom. If all the energy of a charge belongs to the axial oscillating mode, its time evolution is described by the nonlinear equation of motion for a simple pendulum. If the whole energy is accumulated in radial oscillating mode, the dynamical system resembles a double pendulum. We demonstrate that the Hamiltonian system is not integrable in the Liouville sense in the class of functions meromorphic in coordinates and momenta. Using Poincare sections, we show that, in spite of the non integrability, a large part of the phase space is filled by quasi-periodic solutions that encircle some periodic solutions. We determine numerically characteristic frequencies of these periodic solutions. PMID- 26026312 TI - The value of local malaria strains for serological studies: local strains versus Palo Alto reference strain. AB - BACKGROUND: The standardization of the type of crude Plasmodium falciparum extracts for assays to evaluate the overall anti-blood-stage immune response in humans may be beneficial to malaria pre-elimination programmes. However, there is no consensus on which strain is appropriate for routine analyses. This study aimed to compare the responses of malaria IgG antibodies in serum collections from Dielmo and Ndiop to crude extracts of merozoites and schizonts of local and reference strains of P. falciparum. METHODS: Malaria antibodies were evaluated using serological tests for exposure to three local strains (0703, F15 and F16) and the P. falciparum reference Palo Alto strain (PA). A total of 218 sera collected in 2000 from inhabitants of the villages of Dielmo and Ndiop were used: 142 from Dielmo and 76 from Ndiop. The biological collection was used to evaluate by ELISA the prevalence of IgG antibodies against crude merozoite and schizont extracts. The genetics of the local and reference strains were compared. RESULTS: There was genetic divergence between strains 0703, F15, F16 and PA. IgG responses against local and reference strains correlated well (0.6 to 0.8; p<0.01). Ig G responses were highest to schizont and merozoite extracts from the field strain of P. falciparum 0703 adapted to in vitro culture. Extracts of P. falciparum strain 0703 isolated from a subject in Dielmo was the most widely recognized [91.3% (199/218) and 81.2% (177/218) for schizonts and merozoites, respectively], although the responses were high for merozoites from PA [85.3% (186/218)] the reference strain, and the two strains isolated from subjects living in Dakar: F15 [90.4% (197/218)] and F16 [72.5% (158/218)]. CONCLUSIONS: For serological studies, the local strain provided the most complete picture of exposure to transmission and malaria prevalence in the local context. However, for the standardization of this method by different laboratories, the reference strain appeared to perform sufficiently well to be used for the evaluation of malaria control programmes. PMID- 26026315 TI - Algebraic geometrization of the Kuramoto model: Equilibria and stability analysis. AB - Finding equilibria of the finite size Kuramoto model amounts to solving a nonlinear system of equations, which is an important yet challenging problem. We translate this into an algebraic geometry problem and use numerical methods to find all of the equilibria for various choices of coupling constants K, natural frequencies, and on different graphs. We note that for even modest sizes (N ~ 10 20), the number of equilibria is already more than 100 000. We analyze the stability of each computed equilibrium as well as the configuration of angles. Our exploration of the equilibrium landscape leads to unexpected and possibly surprising results including non-monotonicity in the number of equilibria, a predictable pattern in the indices of equilibria, counter-examples to conjectures, multi-stable equilibrium landscapes, scenarios with only unstable equilibria, and multiple distinct extrema in the stable equilibrium distribution as a function of the number of cycles in the graph. PMID- 26026316 TI - A cubic map chaos criterion theorem with applications in generalized synchronization based pseudorandom number generator and image encryption. AB - This paper sets up a chaos criterion theorem on a kind of cubic polynomial discrete maps. Using this theorem, Zhou-Song's chaos criterion theorem on quadratic polynomial discrete maps and generalized synchronization (GS) theorem construct an eight-dimensional chaotic GS system. Numerical simulations have been carried out to verify the effectiveness of theoretical results. The chaotic GS system is used to design a chaos-based pseudorandom number generator (CPRNG). Using FIPS 140-2 test suit/Generalized FIPS 140-2, test suit tests the randomness of two 1000 key streams consisting of 20 000 bits generated by the CPRNG, respectively. The results show that there are 99.9%/98.5% key streams to have passed the FIPS 140-2 test suit/Generalized FIPS 140-2 test. Numerical simulations show that the different keystreams have an average 50.001% same codes. The key space of the CPRNG is larger than 2(1345). As an application of the CPRNG, this study gives an image encryption example. Experimental results show that the linear coefficients between the plaintext and the ciphertext and the decrypted ciphertexts via the 100 key streams with perturbed keys are less than 0.00428. The result suggests that the decrypted texts via the keystreams generated via perturbed keys of the CPRNG are almost completely independent on the original image text, and brute attacks are needed to break the cryptographic system. PMID- 26026317 TI - Ergodic theory and visualization. II. Fourier mesochronic plots visualize (quasi)periodic sets. AB - We present an application and analysis of a visualization method for measure preserving dynamical systems introduced by I. Mezic and A. Banaszuk [Physica D 197, 101 (2004)], based on frequency analysis and Koopman operator theory. This extends our earlier work on visualization of ergodic partition [Z. Levnajic and I. Mezic, Chaos 20, 033114 (2010)]. Our method employs the concept of Fourier time average [I. Mezic and A. Banaszuk, Physica D 197, 101 (2004)], and is realized as a computational algorithms for visualization of periodic and quasi periodic sets in the phase space. The complement of periodic phase space partition contains chaotic zone, and we show how to identify it. The range of method's applicability is illustrated using well-known Chirikov standard map, while its potential in illuminating higher-dimensional dynamics is presented by studying the Froeschle map and the Extended Standard Map. PMID- 26026318 TI - Nonlinear transient waves in coupled phase oscillators with inertia. AB - Like the inertia of a physical body describes its tendency to resist changes of its state of motion, inertia of an oscillator describes its tendency to resist changes of its frequency. Here, we show that finite inertia of individual oscillators enables nonlinear phase waves in spatially extended coupled systems. Using a discrete model of coupled phase oscillators with inertia, we investigate these wave phenomena numerically, complemented by a continuum approximation that permits the analytical description of the key features of wave propagation in the long-wavelength limit. The ability to exhibit traveling waves is a generic feature of systems with finite inertia and is independent of the details of the coupling function. PMID- 26026319 TI - Riemann equation for prime number diffusion. AB - This study makes the first attempt to propose the Riemann diffusion equation to describe in a manner of partial differential equation and interpret in physics of diffusion the classical Riemann method for prime number distribution. The analytical solution of this equation is the well-known Riemann representation. The diffusion coefficient is dependent on natural number, a kind of position dependent diffusivity diffusion. We find that the diffusion coefficient of the Riemann diffusion equation is nearly a straight line having a slope 0.99734 in the double-logarithmic axis. Consequently, an approximate solution of the Riemann diffusion equation is obtained, which agrees well with the Riemann representation in predicting the prime number distribution. Moreover, we interpret the scale free property of prime number distribution via a power law function with 1.0169 the scale-free exponent in respect to logarithmic transform of the natural number, and then the fractal characteristic of prime number distribution is disclosed. PMID- 26026320 TI - Basin structure of optimization based state and parameter estimation. AB - Most data based state and parameter estimation methods require suitable initial values or guesses to achieve convergence to the desired solution, which typically is a global minimum of some cost function. Unfortunately, however, other stable solutions (e.g., local minima) may exist and provide suboptimal or even wrong estimates. Here, we demonstrate for a 9-dimensional Lorenz-96 model how to characterize the basin size of the global minimum when applying some particular optimization based estimation algorithm. We compare three different strategies for generating suitable initial guesses, and we investigate the dependence of the solution on the given trajectory segment (underlying the measured time series). To address the question of how many state variables have to be measured for optimal performance, different types of multivariate time series are considered consisting of 1, 2, or 3 variables. Based on these time series, the local observability of state variables and parameters of the Lorenz-96 model is investigated and confirmed using delay coordinates. This result is in good agreement with the observation that correct state and parameter estimation results are obtained if the optimization algorithm is initialized with initial guesses close to the true solution. In contrast, initialization with other exact solutions of the model equations (different from the true solution used to generate the time series) typically fails, i.e., the optimization procedure ends up in local minima different from the true solution. Initialization using random values in a box around the attractor exhibits success rates depending on the number of observables and the available time series (trajectory segment). PMID- 26026321 TI - Transient and chaotic low-energy transfers in a system with bistable nonlinearity. AB - The low-energy dynamics of a two-dof system composed of a grounded linear oscillator coupled to a lightweight mass by means of a spring with both cubic nonlinear and negative linear components is investigated. The mechanisms leading to intense energy exchanges between the linear oscillator, excited by a low energy impulse, and the nonlinear attachment are addressed. For lightly damped systems, it is shown that two main mechanisms arise: Aperiodic alternating in well and cross-well oscillations of the nonlinear attachment, and secondary nonlinear beats occurring once the dynamics evolves solely in-well. The description of the former dissipative phenomenon is provided in a two-dimensional projection of the phase space, where transitions between in-well and cross-well oscillations are associated with sequences of crossings across a pseudo separatrix. Whereas the second mechanism is described in terms of secondary limiting phase trajectories of the nonlinear attachment under certain resonance conditions. The analytical treatment of the two aformentioned low-energy transfer mechanisms relies on the reduction of the nonlinear dynamics and consequent analysis of the reduced dynamics by asymptotic techniques. Direct numerical simulations fully validate our analytical predictions. PMID- 26026322 TI - Josephson phase diffusion in the superconducting quantum interference device ratchet. AB - We study diffusion of the Josephson phase in the asymmetric superconducting quantum interference device (SQUID) subjected to a time-periodic current and pierced by an external magnetic flux. We analyze a relation between phase diffusion and quality of transport characterized by the dc voltage across the SQUID and efficiency of the device. In doing so, we concentrate on the previously reported regime [J. Spiechowicz and J. Luczka, New J. Phys. 17, 023054 (2015)] for which efficiency of the SQUID attains a global maximum. For long times, the mean-square displacement of the phase is a linear function of time, meaning that diffusion is normal. Its coefficient is small indicating rather regular phase evolution. However, it can be magnified several times by tailoring experimentally accessible parameters like amplitudes of the ac current or external magnetic flux. Finally, we prove that in the deterministic limit this regime is essentially non-chaotic and possesses an unexpected simplicity of attractors. PMID- 26026323 TI - Model reduction for networks of coupled oscillators. AB - We present a collective coordinate approach to describe coupled phase oscillators. We apply the method to study synchronisation in a Kuramoto model. In our approach, an N-dimensional Kuramoto model is reduced to an n-dimensional ordinary differential equation with n?N, constituting an immense reduction in complexity. The onset of both local and global synchronisation is reproduced to good numerical accuracy, and we are able to describe both soft and hard transitions. By introducing two collective coordinates, the approach is able to describe the interaction of two partially synchronised clusters in the case of bimodally distributed native frequencies. Furthermore, our approach allows us to accurately describe finite size scalings of the critical coupling strength. We corroborate our analytical results by comparing with numerical simulations of the Kuramoto model with all-to-all coupling networks for several distributions of the native frequencies. PMID- 26026324 TI - Extreme multistability: Attractor manipulation and robustness. AB - The coexistence of infinitely many attractors is called extreme multistability in dynamical systems. In coupled systems, this phenomenon is closely related to partial synchrony and characterized by the emergence of a conserved quantity. We propose a general design of coupling that leads to partial synchronization, which may be a partial complete synchronization or partial antisynchronization and even a mixed state of complete synchronization and antisynchronization in two coupled systems and, thereby reveal the emergence of extreme multistability. The proposed design of coupling has wider options and allows amplification or attenuation of the amplitude of the attractors whenever it is necessary. We demonstrate that this phenomenon is robust to parameter mismatch of the coupled oscillators. PMID- 26026325 TI - Regular and irregular patterns of self-localized excitation in arrays of coupled phase oscillators. AB - We study a system of phase oscillators with nonlocal coupling in a ring that supports self-organized patterns of coherence and incoherence, called chimera states. Introducing a global feedback loop, connecting the phase lag to the order parameter, we can observe chimera states also for systems with a small number of oscillators. Numerical simulations show a huge variety of regular and irregular patterns composed of localized phase slipping events of single oscillators. Using methods of classical finite dimensional chaos and bifurcation theory, we can identify the emergence of chaotic chimera states as a result of transitions to chaos via period doubling cascades, torus breakup, and intermittency. We can explain the observed phenomena by a mechanism of self-modulated excitability in a discrete excitable medium. PMID- 26026326 TI - Generalized permutation entropy analysis based on the two-index entropic form Sq,delta. AB - Permutation entropy (PE) is a novel measure to quantify the complexity of nonlinear time series. In this paper, we propose a generalized permutation entropy ( PEq,delta) based on the recently postulated entropic form, Sq,delta, which was proposed as an unification of the well-known Sq of nonextensive statistical mechanics and Sdelta, a possibly appropriate candidate for the black hole entropy. We find that PEq,delta with appropriate parameters can amplify minor changes and trends of complexities in comparison to PE. Experiments with this generalized permutation entropy method are performed with both synthetic and stock data showing its power. Results show that PEq,delta is an exponential function of q and the power ( k(delta)) is a constant if delta is determined. Some discussions about k(delta) are provided. Besides, we also find some interesting results about power law. PMID- 26026327 TI - Unusual spiral wave dynamics in the Kessler-Levine model of an excitable medium. AB - The Kessler-Levine model is a two-component reaction-diffusion system that describes spatiotemporal dynamics of the messenger molecules in a cell-to-cell signaling process during the aggregation of social amoeba cells. An excitation wave arising in the model has a phase wave at the wave back, which simply follows the wave front after a fixed time interval with the same propagation velocity. Generally speaking, the medium excitability and the refractoriness are two important factors which determine the spiral wave dynamics in any excitable media. The model allows us to separate these two factors relatively easily since the medium refractoriness can be changed independently of the medium excitability. For rigidly rotating waves, the universal relationship has been established by using a modified free-boundary approach, which assumes that the front and the back of a propagating wave are thin in comparison to the wave plateau. By taking a finite thickness of the domain boundary into consideration, the validity of the proposed excitability measure has been essentially improved. A novel method of numerical simulation to suppress the spiral wave instabilities is introduced. The trajectories of the spiral tip observed for a long refractory period have been investigated under a systematic variation of the medium refractoriness. PMID- 26026328 TI - Comment on "Dynamical glucometry: Use of multiscale entropy analysis in diabetes" [Chaos 24, 033139 (2014)]. PMID- 26026329 TI - Response to "Comment on 'Dynamical glucometry: Use of multiscale entropy analysis in diabetes'" [Chaos 25, 058101 (2015)]. PMID- 26026330 TI - Alternative management of the left subclavian artery in thoracic endovascular aortic repair for aortic dissection: a single-center experience. AB - BACKGROUND: Since the new 2009 guidelines for left subclavian artery (LSA) management using thoracic endovascular aortic repair (TEVAR), a few studies have been published about alternative LSA management. The objective of this study was to present the follow-up results of covered or revascularized LSA during TEVAR. METHODS: From January 2010 to August 2012, 109 consecutive patients were treated with TEVAR at the Department of Vascular Surgery, Changhai Hospital, for aortic dissection extending near the LSA. After evaluating the bilateral vertebral arteries, fifty-two LSAs were covered and not revascularized (covered group), while 57 LSAs were preserved (revascularized group). Complications were stratified according to the time of occurrence after surgery. RESULTS: Emergency operations were more common (17.3 vs. 3.5 %, P = 0.017) and operation time was shorter (96.9 +/- 16.3 vs. 135.3 +/- 38.4 min, P < 0.001) in the covered group. Pulselessness and intermittent claudication of the left arm occurred in most patients in the covered group (P < 0.001). Incidence of stroke and cold shoulder feeling were higher in the covered group compared with the revascularized group (P = 0.026 and <0.001, respectively). There were five aorta-related deaths in the covered group and one in the revascularized group. Eight endoleaks were observed in the revascularized group (P = 0.006). CONCLUSIONS: The results of this study suggest that due to occurrence of complications, LSA should be preserved or revascularized to reduce complications and to improve patients' quality of life. PMID- 26026331 TI - Leiomyoma of the Trachea: a case report. AB - We present a surgical case of a rare primary tracheal tumor. In a 44-year-old asymptomatic man, computed tomography (CT), performed as part of health check-up, revealed a tumor measuring 1.5 cm in diameter in the mediastinal trachea. Biopsy failed to yield a definitive diagnosis, but the tumor tended to grow rapidly; therefore, surgery was performed. Five tracheal rings were resected through median sternotomy, followed by interrupted suture with 3-0 absorbable thread. The postoperative course has been favorable with no evidence of recurrence. The pathological diagnosis was leiomyoma. We report this case with literature review. PMID- 26026332 TI - Neurologists are key to the WHO global dementia strategy. PMID- 26026333 TI - How a network of conservationists and population control activists created the contemporary US anti-immigration movement. AB - Continuing historical narratives of the early twentieth century nexus of conservationism, eugenics, and nativism (exemplified by Madison Grant), this paper traces the history of the contemporary US anti-immigration movement's roots in environmentalism and global population control activism, through an exploration of the thoughts and activities of the activist, John Tanton, who has been called "the most influential unknown man in America." We explore the "neo Malthusian" ideas that sparked a seminal moment for population control advocacy in the late 1960s and early 1970s, leading to the creation of Zero Population Growth (ZPG). After rising to the presidency of ZPG, Tanton, and ZPG spun off the Federation for American Immigration Reform. After leaving ZPG's leadership, Tanton created additional anti-immigration advocacy groups and built up connections with existing organizations such as the Pioneer Fund. We trace Tanton's increasingly radical conservative network of anti-immigration advocates, conservationists, and population control activists to the present day. Tanton's archived papers illustrate, among other things, his interactions with collaborators such as ecologist Garrett Hardin (author of the famous "Tragedy of the Commons") and his documented interest in reviving eugenics. We contend that this history of Tanton's network provides key insights into understanding how there came to be an overlap between the ideologies and activist communities of immigration restrictionism, population control, conservationism and eugenics. PMID- 26026335 TI - Comments on "ESR dating of the Majuangou and Banshan Paleolithic sites in the Nihewan Basin, North China" by Liu et al. (2014). PMID- 26026334 TI - Adverse events resulting in withdrawal of biologic therapy for psoriasis in real world clinical practice: A Canadian multicenter retrospective study. AB - BACKGROUND: Safety profiles of biologics for treatment of psoriasis are limited to data from randomized controlled trials. There is a need for comparative safety reports of biologics based on data from clinical practice. OBJECTIVE: We sought to estimate and compare the incidence of adverse events (AEs) leading to withdrawal of biologics (etanercept, infliximab, adalimumab, and ustekinumab) in the treatment of psoriasis. METHODS: We conducted a multicenter retrospective chart review from September 2005 to September 2014. Incidence proportion and rate of AEs leading to withdrawal by biologic agent and AE were calculated. RESULTS: For 545 treatments administered in 398 patients, 22 (4.04%) AEs were associated with withdrawal, for a rate of 1.97/100 patient-years (95% confidence interval [CI] 1.32-2.94). Common AEs were injection-/infusion-site reactions (0.55%, 0.92%, 0%, and 0% for etanercept, infliximab, adalimumab, and ustekinumab, respectively); infections (0%, 0.18%, 0.55%, 0.18%); and malignancies (0.18%, 0.18%, 0%, 0.37%). LIMITATIONS: Possible incompleteness of chart details and small study population limit the conclusiveness of findings. CONCLUSION: Biologic agents for treatment of psoriasis are safe; AEs associated with withdrawal occurred in 4% of all administered biologic therapies. It does not appear that real-world patients encounter more AEs with biologics than patients in clinical trials. PMID- 26026336 TI - Do past mortality rates predict future hospital mortality? AB - BACKGROUND: This study aimed to determine whether hospitals with higher historical mortality rates are independently associated with worse patient outcomes. METHODS: Observational study of in-hospital mortality in open abdominal aortic aneurysm repair, aortic valve replacement, and coronary artery bypass graft surgery in a California in-patient database was conducted. Hospitals' annual historical mortality rates between 1998 and 2010 were calculated based on 3 years of data before each year. Results were adjusted for race, sex, age, hospital teaching status, admission year, insurance status, and Charlson comorbidity index. RESULTS: Hospitals were divided into quartiles based on historical mortality rates. For abdominal aortic aneurysm repair, the odds ratio (OR) of in-hospital mortality for hospitals within the highest quartile of prior mortality was 1.30 compared with the lowest quartile (95% confidence interval [CI] 1.03 to 1.63). For aortic valve replacement, the OR was 1.41 for the 3rd quartile (95% CI 1.15 to 1.73) and 1.54 for the highest quartile (95% CI 1.27 to 1.87). For coronary artery bypass graft surgery, the OR was 1.33 for the 3rd (95% CI 1.2 to 1.49) and 1.58 for the highest (95% CI 1.41 to 1.76) quartiles. CONCLUSION: Patients presenting to hospitals with high historical mortality rates have a 30% to 60% increased mortality risk compared with patients presenting to hospitals with low historical mortality rates. PMID- 26026337 TI - Arterial clamping leads to stenosis at clamp sites after femoropopliteal bypass surgery. AB - BACKGROUND: To date, the incidence and clinical relevance of arterial stenosis at clamp sites after femoropopliteal bypass surgery is unknown. METHODS: Ninety-four patients underwent a femoropopliteal bypass in which the arterial inflow and outflow clamp sites were controlled by the Fogarty-Soft-Inlay clamp and marked with an hemoclip. The number of pre-existing atherosclerotic segments, clamp force, and clamp time were recorded and the occurrence of a stenosis at the clamp site was determined. RESULTS: After a mean follow-up of 83 months, a significant stenosis was confirmed at 23 of the 178 clamp sites (12.9%; 95% confidence interval 8.4 to 18.8). The mean number of pre-existing atherosclerotic segments (P = .28) and the mean clamp force (P = .55) was similar between the groups with and without a stenosis. There was a significant difference regarding clamp time between the group with and without a stenosis (38 minutes and 26 minutes, P = .001). CONCLUSION: Arterial clamping, even with the Fogarty-Soft-Inlay clamp, can lead to clamp stenosis and seems to be related to the duration of clamping, but not to pre-existent atherosclerotic burden. PMID- 26026338 TI - Thyroid swellings in the art of the Italian Renaissance. AB - BACKGROUND: Thyroid swellings in the art of the Italian Renaissance are sporadically reported in the medical literature. METHODS: Six hundred paintings and sculptures from the Italian Renaissance, randomly selected, were analyzed to determine the prevalence of personages with thyroid swellings and its meaning. RESULTS: The prevalence of personages with thyroid swellings in the art of Italian Renaissance is much higher than previously thought. This phenomenon was probably secondary to iodine deficiency. The presence of personages with thyroid swelling was related to specific meanings the artists wanted to show in their works. CONCLUSIONS: Even if the function and the role of the thyroid were discovered only after thyroidectomy was started to be performed, at the beginning of the 19th century, artists of the Italian Renaissance had the intuition that thyroid swellings were related to specific psychological conditions. Artistic intuition and sensibility often comes before scientific demonstration, and it should be a guide for science development. PMID- 26026339 TI - The impact of a surgical boot camp on early acquisition of technical and nontechnical skills by novice surgical trainees. AB - BACKGROUND: Acquisition of skills early in surgical training represents a significant challenge at present because of training time constraints. The aim of this study was to investigate if an intensive surgical boot camp was effective in transferring skills at the beginning of a surgical training program. METHODS: New core surgical trainees (n = 58) took part in a 5-day boot camp. There were pretest and posttest assessments of knowledge, technical skills, and confidence levels. The boot camp used simulation and senior surgical faculty to teach a defined range of technical and nontechnical skills. RESULTS: The scores for knowledge (53.8% vs 68.4%, P < .01), technical skills (35.9% to 60.6% vs 50.6% to 78.2%, P < .01), and confidence levels improved significantly during boot camp. Skills improvements were still present a year later. CONCLUSION: The 5-day surgical boot camp proved to be an effective way to rapidly acquire surgical knowledge and skills while increasing the confidence levels of trainees. PMID- 26026340 TI - Risk-based testing of imported animals: A case study for bovine tuberculosis in The Netherlands. AB - In intra-EU trade, the health status of animals is warranted by issuing a health certificate after clinical inspection in the exporting country. This certificate cannot provide guarantee of absence of infection, especially not for diseases with a long incubation period and no overt clinical signs such as bovine tuberculosis (bTB). The Netherlands are officially free from bTB since 1999. However, frequent reintroductions occurred in the past 15 years through importation of infected cattle. Additional testing (AT) of imported cattle could enhance the probability of detecting an imported bTB infection in an early stage. The goal of this study was to evaluate the effectiveness of risk-based AT for bTB in cattle imported into The Netherlands. A generic stochastic import risk model was developed that simulates introduction of infection into an importing country through importation of live animals. Main output parameters are the number of infected animals that is imported (Ninf), the number of infected animals that is detected by testing (Ndet), and the economic losses incurred by importing infected animals (loss). The model was parameterized for bTB. Model calculations were optimized to either maximize Ndet or to minimize loss. Model results indicate that the risk of bTB introduction into The Netherlands is very high. For the current situation in which Dutch health checks on imported cattle are limited to a clinical inspection of a random sample of 5-10% of imported animals, the calculated annual Ninf=99 (median value). Random AT of 8% of all imported cattle results in Ndet=7 (median value), while the median Ndet=75 if the sampling strategy for AT is optimized to maximize Ndet. However, in the latter scenario, loss is more than twice as large as in the current situation, because only calves are tested for which cost of detection is higher than the expected gain of preventing a possible outbreak. When optimizing the sampling strategy for AT to minimize loss, only breeding and production cattle are selected for AT resulting in Ndet=1 (median value). Loss is; however, reduced by 75% if compared to the current situation. We conclude that the effectiveness of AT can greatly be improved by risk-based sampling. The optimal sampling strategy for risk-based AT for bTB is highly dependent on the objective of AT. If economic losses are to be contained, AT should focus on breeding and production cattle originating from high-risk countries. PMID- 26026341 TI - Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal regulated kinase (ERK) phosphorylation in keratinocytes. PMID- 26026343 TI - A meta-analysis of risk of pregnancy loss and caffeine and coffee consumption during pregnancy. AB - BACKGROUND: Previous reports of the relationship between pregnancy loss and caffeine/coffee consumption have been inconsistent. OBJECTIVES: To evaluate the association between pregnancy loss and caffeine and coffee consumption. SEARCH STRATEGY: PubMed was searched for reports published before September 2014, with the keywords "caffeine," "coffee," "beverage," "miscarriage," "spontaneous abortion," and "fetal loss." SELECTION CRITERIA: Case-control and cohort studies were included when they had been reported in English, the exposure of interest was caffeine/coffee consumption during pregnancy, the outcome of interest was spontaneous abortion or fetal death, and multivariate-adjusted odds ratios (ORs) or risk ratios were provided or could be calculated. DATA COLLECTION AND ANALYSIS: Data were extracted and combined ORs calculated. MAIN RESULTS: Overall, 26 studies were included (20 of caffeine and eight of coffee). After adjustment for heterogeneity, caffeine consumption was associated with an increased risk of pregnancy loss (OR 1.32, 95% confidence interval [CI] 1.24-1.40), as was coffee consumption (OR 1.11, 95% CI 1.02-1.21). A dose-response analysis suggested that risk of pregnancy loss rose by 19% for every increase in caffeine intake of 150 mg/day and by 8% for every increase in coffee intake of two cups per day. CONCLUSIONS: Consumption of caffeine and coffee during pregnancy seems to increase the risk of pregnancy loss. PMID- 26026344 TI - Hyperbaric oxygen therapy in a case of vaginal and uterine necrosis after embolization for postpartum hemorrhage. PMID- 26026342 TI - Cockroach sensitization mitigates allergic rhinoconjunctivitis symptom severity in patients allergic to house dust mites and pollen. AB - BACKGROUND: Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. OBJECTIVE: We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. METHODS: Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. RESULTS: The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C- > M+P+C+ > M+P-C- > M+P-C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C- participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C- status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). CONCLUSIONS: C+ status is associated with mitigation of AR symptom severity in adults with AR. PMID- 26026345 TI - Current trends in the surgical treatment of pediatric ovarian torsion: we can do better. AB - INTRODUCTION: Current literature strongly recommends ovarian preservation for pediatric patients with ovarian torsion. The purpose of this study was to evaluate national trends in the surgical management of pediatric ovarian torsion and to compare outcomes between pediatric surgeons (PED) and gynecologists (GYN). METHODS: We queried Pediatric Health Information System (PHIS) data from 2007 to 2011 for patients <18years old with a diagnosis of ovarian torsion who underwent a surgical procedure. Patients with malignant disease were excluded. Outcomes were compared between pediatric surgeons and gynecologists. RESULTS: A total of 1151 patients were identified with a mean age of 10.7+/-4.1years with a bimodal distribution. Pediatric surgeons performed the majority of procedures (81%) and were more likely to use a laparoscopic approach (PED 27% vs. GYN 17%, p<.05). Pediatric surgeons were more likely to perform an oophorectomy (PED 38% vs. GYN 27%, p<.01), and more likely to administer antibiotics for this clean procedure (PED 61% vs. GYN 29%, p<.001). The overall reoperation rate was 5.1% and did not differ significantly by subspecialty (PED 4.4% vs. GYN 7.8%, p>.05). CONCLUSIONS: These data demonstrate a significant opportunity for pediatric surgeons and gynecologists to improve ovarian salvage rates and to reduce unnecessary antibiotic utilization for children with ovarian torsion. PMID- 26026346 TI - Molecular signature of amniotic fluid derived stem cells in the fetal sheep model of myelomeningocele. AB - Abnormal cord development results in spinal cord damage responsible for myelomeningocele (MMC). Amniotic fluid-derived stem cells (AFSCs) have emerged as a potential candidate for applications in regenerative medicine. However, their differentiation potential is largely unknown as well as the molecular signaling orchestrating the accurate spinal cord development. Fetal lambs underwent surgical creation of neural tube defect and its subsequent repair. AFSCs were isolated, cultured and characterized at the 12th (induction of MMC), 16th (repair of malformation), and 20th week of gestation (delivery). After performing open hysterectomy, AF collections on fetuses with sham procedures at the same time points as the MMC creation group have been used as controls. Cytological analyses with the colony forming unit assay, XTT and alkaline-phosphatase staining, qRT PCR gene expression analyses (normalized with aged match controls) and NMR metabolomics profiling were performed. Here we show for the first time the metabolomics and molecular signature variation in AFSCs isolated in the sheep model of MMC, which may be used as diagnostic tools for the in utero identification of the neural tube damage. Intriguingly, PAX3 gene involved in the murine model for spina bifida is modulated in AFSCs reaching the peak of expression at 16 weeks of gestation, 4 weeks after the intervention. Our data strongly suggest that AFSCs reorganize their differentiation commitment in order to generate PAX3-expressing progenitors to counteract the MMC induced in the sheep model. The gene expression signature of AFSCs highlights the plasticity of these cells reflecting possible alterations of embryonic development. PMID- 26026347 TI - Influenza A(H1N1)pdm09 infection in pregnant and non-pregnant women hospitalized in Singapore, May - December 2009. AB - OBJECTIVES: The aim of this study was to compare the demographic and clinical characteristics of pregnant women and non-pregnant women of childbearing age hospitalized with laboratory-confirmed influenza A(H1N1)pdm09 infection in Singapore, and to assess whether pregnancy was a risk factor associated with the development of influenza-related complications. STUDY DESIGN: Retrospective observational study. METHODS: We retrospectively identified and collected information from available medical records of all women admitted to three tertiary hospitals between 26 May 2009 and 31 December 2009 with laboratory confirmed influenza A(H1N1)pdm09 infection who were either pregnant or non pregnant and of childbearing age between 15 and 50 years. RESULTS: A total of 222 women, of whom 81 (36.5%) were pregnant, were hospitalized during the study period. Pregnant women were significantly more likely to be hospitalized with influenza A(H1N1)pdm09 infection than non-pregnant women of childbearing age (relative risk 26.3; 95% confidence interval: 20.1-34.6). Among those hospitalized, the proportion of pregnant women having at least one underlying medical condition that could predispose them to influenza-related complications was significantly lower than that of non-pregnant women (32.1% versus 56.0%, P < 0.001). The median time from onset of symptoms to administration of anti-viral drugs was significantly shorter among pregnant women than among non-pregnant women (three days versus five days, P < 0.001). The median length of stay in hospital was also significantly shorter among pregnant women than that of non pregnant women (two days versus three days, P = 0.002). About 4.9% of pregnant women developed influenza-related complications, compared with 12.8% among non pregnant women (P = 0.066). CONCLUSIONS: Pregnant women with influenza A(H1N1)pdm09 infection were at a higher risk of hospitalization. Upon hospitalization, they were not at a higher risk of developing influenza-related complications. PMID- 26026348 TI - The effect of body mass index on endometrial cancer: a meta-analysis. AB - BACKGROUND: Several epidemiological studies have investigated the association between body mass index (BMI) and endometrial cancer in recent years. This up-to date meta-analysis was conducted to obtain an overall effect estimate based on current evidence. STUDY DESIGN: A meta-analysis was conducted until March 2015. METHODS: Major electronic databases including PubMed, Web of Science, and Scopus were searched. The reference lists and related scientific conference databases were searched for additional data. Cohort and case-control studies addressing the association between BMI and endometrial cancer were included. The exposure of interest was overweight and obesity. The outcome of interest was endometrial cancer of any type confirmed pathologically. The effect measure of choice was rate ratio (RR) for cohort studies and odds ratio (OR) for case-control studies. The random effect model was reported. RESULTS: Of 6241 retrieved references, 40 studies were included in the meta-analysis including 20 prospective cohort studies and 20 case-control studies involving 32,281,242 participants. The results of both cohort and case-control studies showed a significant association. Based on random effect model, compared to normal weight people, the estimated RR and OR of endometrial cancer was 1.34 (95% CI: 1.20, 1.48) and 1.43 (95% CI: 1.30, 1.56) for the overweight and 2.54 (95% CI: 2.27, 2.81) and 3.33 (95% CI: 2.87, 3.79) for the obese, respectively. CONCLUSIONS: The results of this meta analysis indicated that BMI is strongly associated with an increased risk of endometrial cancer. Further investigations are required to expect the pathophysiology of the endometrial cancer caused by overweight and obesity. PMID- 26026349 TI - Non-fatal injury occurrence in Southern California Thoroughbred racehorses 2009 2010. AB - Private-practice racetrack veterinarians in southern California recorded non fatal injuries meeting defined criteria in Thoroughbreds for 1 year. Injury incidence was 2.29 injury events per 100 horse-months, which was lower than other studies where trainer reported injury data were collected. Of 477 injuries recorded, 344 (72.1%) were acute and 133 (27.9%) were chronic. Fractures were common (47.6% of injuries), with stress fractures accounting for 14% of injuries. Superficial digital flexor tendonitis and suspensory ligament desmitis accounted for 15.3 and 11.5% of injuries, respectively. Agreement between non-fatal injuries recorded in the current study and those recorded via an existing regulatory system (Equine Injury Database) was poor, with neither system capturing all injuries. Non-fatal injuries occurred 17-29 times more often than fatal injuries. Non-fatal musculoskeletal injury remains an ongoing issue for Thoroughbred racehorses, and an accurate, comprehensive system for recording these injuries is needed. PMID- 26026350 TI - Analgesic and antihyperalgesic effects of dipyrone, meloxicam or a dipyrone meloxicam combination in bitches undergoing ovariohysterectomy. AB - The analgesic and antihyperalgesic effects of dipyrone, meloxicam or a dipyrone meloxicam combination were compared in dogs undergoing elective ovariohysterectomy. In a double-blinded, prospective, randomised design, 40 bitches premedicated with intramuscular pethidine (4 mg/kg) and anaesthetised with isoflurane received one of four intravenous treatments (n = 10 per group) before ovariohysterectomy: control (physiological saline), meloxicam (0.2 mg/kg), dipyrone (25 mg/kg) or dipyrone-meloxicam (25 mg/kg and 0.2 mg/kg, respectively). Glasgow composite measure pain scale (GCMPS) and mechanical nociceptive thresholds (MNT) were assessed before anaesthesia and at 1, 2, 3, 4, 6, 8, 12 and 24 h postoperatively. Rescue analgesia (0.5 mg/kg morphine) was administered intramuscularly if the GCMPS was >=3. The GCMPS and MNT did not differ among groups. The frequency of rescue analgesia was significantly (P <0.05) lower in the dipyrone group (30%) than in controls (50%), but there were no significant differences from the control group in bitches treated with meloxicam (70%) or dipyrone-meloxicam (40%). There was a significant reduction in the total number of rescue treatments in the dypyrone (n = 5) and dipyrone-meloxicam (n = 5) groups when compared with the control (n = 17) and meloxicam (n = 19) groups. Meloxicam and dipyrone-meloxicam significantly reduced the percentage of animals exhibiting severe pain during MNT measurements (30% and 0%, respectively) compared with the control group (50%). Dipyrone produced superior analgesia (reduced morphine consumption), while meloxicam produced better antihyperalgesia (fewer episodes of severe pain) in contrast to controls. When used in tandem, the beneficial effects were combined. PMID- 26026351 TI - The Association of the H-Index and Academic Rank Among Full-Time Academic Hand Surgeons Affiliated With Fellowship Programs. AB - PURPOSE: To evaluate the association between the Hirsch index (a measure of publications and citations) and academic rank among hand surgeons. METHODS: This was a cross-sectional study of full-time academic hand surgeons within Accreditation Council for Graduate Medical Education-approved hand surgery fellowship programs in the United States and Canada. The study variables were classified as bibliometric (h-index, I-10 index, total number of publications, total number of citations, maximum number of citations for a single work) and demographics (gender, training factors). The outcome was academic rank (instructor, assistant professor, associate professor, professor, endowed professor). Descriptive, bivariate, and multiple regression statistics were computed. RESULTS: The sample was composed of 366 full-time academic hand surgeons; 86% were male and 98% had formal hand surgery fellowship training. The mean time since completion of surgical training was 17 +/- 11 years. The distribution of primary faculty appointments was orthopedic surgery (70%) and plastic surgery (30%). Two hundred fifty surgeons (68%) were members of the American Society for Surgery of the Hand. The mean h-index was 10.2 +/- 9.9 and was strongly correlated with academic rank. Gender was not associated with academic rank. Distribution of academic ranks was as follows: instructor (4%), assistant professor (28%), associate professor (40%), professor (22%), and endowed professor (5%). The h-index, years since completion of training, and American Society for Surgery of the Hand membership were associated with academic rank. The h-index had a high sensitivity and specificity for predicting academic rank. CONCLUSIONS: The h-index is a reliable tool for quantitatively assessing research productivity and should be considered for use in academic hand surgery. CLINICAL RELEVANCE: When evaluating candidates for academic promotion in hand surgery, the h-index is a potentially valuable tool for assessing research productivity and impact. PMID- 26026352 TI - A Comparison of Plain Radiographs and Computed Tomography for Determining Canal Diameter of the Distal Phalanx. AB - PURPOSE: To compare plain radiographs and computed tomography (CT) when determining the narrowest diameter of the medullary canal of the distal phalanx. METHODS: A database review identified 48 patients (23 male, 25 female) who underwent a CT scan of the hand and plain radiographs of the same hand. Using digital imaging software, the smallest diameter of the medullary canal was measured for each finger (index, middle, ring, little) on CT and on radiographs. RESULTS: The narrowest diameter of the medullary canal was measured on the axial CT and lateral hand radiograph at the transition between the tuft and the distal phalanx shaft. The mean narrowest diameters on plain radiographs for the index, middle, ring, and little fingers were 1.4 mm, 1.4 mm, 1.4 mm, and 1.1 mm, respectively. The mean diameters on CT were 1.2 mm, 1.3 mm, 1.2 mm, and 1.0 mm, respectively. Men had larger medullary canal dimensions (1.5-1.7 mm) than women (0.8-1.2 mm). CONCLUSIONS: The differences in canal diameter measurements between plain radiograph and CT were small and likely clinically insignificant. CLINICAL RELEVANCE: Lateral radiographs can be used for preoperative planning when estimating the size of the distal phalanx intramedullary canal. PMID- 26026353 TI - Ergonomic Strategies for Computer Users With Upper Limb Problems. PMID- 26026354 TI - Prenatal Detection of Upper Limb Differences With Obstetric Ultrasound. AB - PURPOSE: To determine the sensitivity, specificity, and predictive values of prenatal ultrasound detection of fetal upper extremity anomalies at a single tertiary care center in a large patient cohort. Our secondary purpose was to assess factors affecting prenatal detection including the presence of associated anomalies. METHODS: We performed a retrospective review of prenatal ultrasound and postnatal clinical records from each pregnancy evaluated with a prenatal ultrasound at the Washington University Department of Obstetrics and Gynecology over a 20-year period. We searched for upper extremity anomaly diagnosis codes pre- and postnatally and correlated with clinical postnatal follow-up to determine prevalence, sensitivity, specificity, predictive values, and associated conditions. RESULTS: A total of 100,856 pregnancies were evaluated by prenatal ultrasound, which included 843 fetuses diagnosed with a musculoskeletal anomaly (prevalence, 1 of 120) and 642 with an upper extremity anomaly (prevalence, 1 of 157). The postnatally confirmed sensitivity for prenatal ultrasound detection of an upper extremity anomaly was 42%. Sensitivity was lower in cases isolated to the upper extremity (25% vs 55%). Sensitivity was highest for conditions affecting the entire upper extremity (70%-100%) and lowest for those affecting the digits alone (4%-19%). Fetuses with limb reduction defects, radial longitudinal deficiency, phocomelia, arthrogryposis, abnormal hand positioning, and cleft hand had a higher likelihood of having an associated anomaly. CONCLUSIONS: At our tertiary referral center, there was a notable prevalence of upper extremity anomalies; however, the overall sensitivity for detecting them with prenatal ultrasound was low. This was disappointing given the value of prenatal identification of anomalies for parental counseling. Prenatal diagnosis of anomalies affecting the entire upper limb was more reliable than diagnosis of more distal anomalies. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 26026355 TI - Early Versus Delayed Fourth Ray Amputation With Fifth Ray Transposition for Management of Mutilating Ring Finger Injuries. AB - PURPOSE: To compare hand function after early versus delayed fourth ray amputation and transposition of the fifth ray in mutilating ring finger injuries. METHODS: We prospectively compared 2 groups of patients who sustained either isolated mutilating ring finger or complex hand injuries between January 2008 and December 2013. The first group (12 patients; 10 male and 2 female) was managed by early (within 14 d) fourth ray amputation with fifth ray transposition, and the second group (13 patients; 9 male and 4 female) was managed similarly but on a delayed basis (after 20 d). The postoperative fifth metacarpophalangeal joint active range of motion was recorded and compared with the preoperative value. Function was evaluated by measuring grip and key pinch strengths, supination and pronation strengths, and hand breadth. All parameters were evaluated by comparing the injured and the noninjured hands. RESULTS: Group 1 patients exhibited superior results to group 2 patients regarding the postoperative grip and key pinch strength and pronation and supination strength in addition to the mean postoperative active range of motion of the transposed ray metacarpophalangeal joint. However, the results were statistically significant regarding only grip and pronation strengths. Postoperative active range of motion of the transposed ray metacarpophalangeal joint was significantly reduced in the cases having preoperative compromise of the transposed digit in group 1. The final subjective cosmetic satisfaction was better in group 1. CONCLUSIONS: Our results support early fourth ray amputation with fifth ray transposition for mutilating ring finger injuries. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 26026357 TI - Single-Stage Flexor Tendon Grafting: Refining the Steps. AB - Single-stage tendon grafting for reconstruction of zone I and II flexor tendon injuries is a challenging procedure in hand surgery. Careful patient selection, strict indications, and adherence to sound surgical principles are mandatory for return of digital motion. PMID- 26026356 TI - Force in the Scapholunate Interosseous Ligament During Active Wrist Motion. AB - PURPOSE: To examine the force experienced by the scapholunate interosseous ligament (SLIL) during movements of the wrist. METHODS: Six fresh-frozen cadaveric wrists were freed of soft tissue and tested in a computer controlled, servohydraulic simulator. Each wrist was tested cyclically through simulated active arcs of flexion-extension and dart throw motion. Tensile forces were recorded across the scapholunate joint with the SLIL cut through a cable placed through the scaphoid to the lunate and fixed to a force transducer external to the wrist. RESULTS: The average recorded maximal tensile force across the scapholunate joint during all tested motions was 20 N. During wrist flexion extension and the dart throw motion, SLIL force was greater at maximum extension than at maximum flexion. No significant differences among the different motions at maximum flexion or extension or for maximal force during motion were found. CONCLUSIONS: Forces during the flexion-extension and dart throw motions were significantly higher in extension than in flexion. However, during simple unresisted wrist motions, the force did not exceed 20 N. CLINICAL RELEVANCE: This information can be used to evaluate surgical methods used for SLIL repairs and thus provide better outcomes for patients. PMID- 26026358 TI - The Heart: Pressure-Propulsion Pump or Organ of Impedance? PMID- 26026359 TI - Parenting and proximity to social services: Lessons from Los Angeles County in the community context of child neglect. AB - Using a sample of 438 parents in Los Angeles County, CA, this study examines the role of proximity to social services in child neglect. In an extension of social disorganization theory, it seeks to understand the potential sources of support in neighborhoods for families. It uses ordinary least squares regression to examine driving distance from parents' residences to four types of services (child care, domestic violence, mental health/substance abuse, and poverty). The results show an association between proximity to mental health and substance abuse services and parents' self-reported neglectful behaviors. Additionally, higher levels of socioeconomic disadvantage (poverty, unemployment, and low education), having older children, respondents being male, and respondents being older parents are associated with higher levels of child neglect, while being white is associated with lower levels. Overall, the findings suggest a potentially protective role of geographic access to mental health and substance abuse services in child maltreatment. Additional research on the pathways through which proximity to services influences child neglect is needed. PMID- 26026360 TI - Child maltreatment and adult psychopathology in an Irish context. AB - One-hundred-ninety-nine adult mental health service users were interviewed with a protocol that included the Childhood Trauma Questionnaire, the Structured Clinical Interviews for Axis I and II DSM-IV disorders, the Global Assessment of Functioning scale, the SCORE family assessment measure, the Camberwell Assessment of Need Short Appraisal Schedule, and the Readiness for Psychotherapy Index. Compared to a U.S. normative sample, Irish clinical cases had higher levels of maltreatment. Cases with comorbid axis I and II disorders reported more child maltreatment than those with axis I disorders only. There was no association between types of CM and types of psychopathology. Current family adjustment and service needs (but not global functioning and motivation for psychotherapy) were correlated with a CM history. It was concluded that child maltreatment may contribute to the development of adult psychopathology, and higher levels of trauma are associated with co-morbid personality disorder, greater service needs and poorer family adjustment. A history of child maltreatment should routinely be determined when assessing adult mental health service users, especially those with personality disorders and where appropriate evidence-based psychotherapy which addresses childhood trauma should be offered. PMID- 26026361 TI - [The effect of using 13-valent pneumococcal vaccine in American children (and adults)]. PMID- 26026362 TI - Antiproliferative activity of O4-benzo[c]phenanthridine alkaloids against HCT-116 and HL-60 tumor cells. AB - The O4-benzo[c]phenanthridine alkaloids exhibit potent antiproliferative activity against cancer cells, which is derived from their ability to inhibit of topoisomerase I and II. It has been reported that in the alkaloids a cationic quaternary ammonium atom, which results in resonance effects between ring A and B, is necessary for increased antiproliferative activity. These findings indicate the role of their substituents at ring A on inhibition of tumor cell proliferation. In the present study, we systematically assessed the cytotoxic activities of naturally occurring alkaloids and their derivatives containing various ring A substituents against two tumor cell lines, HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells. Among the cationic iminium alkaloids, which displayed more potent activity than the corresponding neutral derivatives, and the 7,8-oxygenated benzo[c]phenanthridine alkaloids, chelerythrine and NK109, exhibited stronger antiproliferative activity than the 8,9- and 9,10-oxygenated alkaloids. The activity of cationic iminium alkaloids could be correlated with the bond lengths of their ring A substituents and the electrostatic potentials of their ammonium molecules by DFT calculation. PMID- 26026363 TI - C-Aryl glucoside SGLT2 inhibitors containing a biphenyl motif as potential anti diabetic agents. AB - A series of highly active C-aryl glucoside SGLT2 inhibitors containing a biphenyl motif were designed and synthesized for biological evaluation. Among the compounds tested, compound 16l demonstrated high inhibitory activity against SGLT2 (IC50=1.9 nM) with an excellent pharmacokinetic profile. Further study indicated that the in vivo efficacy of compound 16l was comparable to that of dapagliflozin, suggesting that further development would be worthwhile. PMID- 26026364 TI - Boehmenan, a lignan from Hibiscus ficulneus, showed Wnt signal inhibitory activity. AB - The Wnt signal pathway modulates numerous biological processes, and its aberrant activation is related to various diseases. Therefore, inhibition of the Wnt signal may provide an effective (or efficient) strategy for these diseases. Cell based luciferase assay targeting the Wnt signal (TOP assay) revealed that Hibiscus ficulneus extract inhibited the Wnt signal. The activity-guided isolation of the MeOH extract of H. ficulneus stems yielded four known (1-4) lignans along with myriceric acid (5). Compounds 1-4 potently inhibited the Wnt signal with TOPflash IC50 values of 1.0, 4.5, 6.3, and 1.9 MUM, respectively. Compound 1 exhibited cytotoxicity against both Wnt-dependent (HCT116) and Wnt independent (RKO) cells. Western blot analysis showed that 1 decreased the expression of full, cytosolic and nuclear beta-catenin along with c-myc in STF/293 cells. Our results suggested that 1 may have inhibited the Wnt signal by decreasing beta-catenin levels. PMID- 26026365 TI - Pediatric craniomaxillofacial injuries after road traffic crashes: characteristics of injuries and protective equipment use. AB - OBJECTIVE: A cross-sectional study to determine the pattern of craniomaxillofacial (CMF) injuries among children involved in road traffic crashes was performed. The association of protective equipment use with the CMF injuries was evaluated. METHODS: Retrospective records of children treated in the University Malaya Medical Centre, Kuala Lumpur, Malaysia, after road traffic crashes between January 1, 2008 and December 31, 2012 were reviewed, and, after that, telephone interviews were made. RESULTS: Seventy-one children were included in this study. Fifty-two (73.6%) were involved in a motorcycle injury and 19 (23.4%) in a car crash. Their mean age was 6.02 years; SD, 3.46 (range between 0 to 13 years old). More male children were observed (52.1%) compared with females (47.9%). Thirty-nine point four percent of the children sustained CMF injuries, 33.8% body injuries, and 23.9% had both CMF and other body parts injuries. The highest injury severity score was 26, whereas the lowest was 0. Many children did not use protective equipment during traveling, 44.2% of children among motorcycle pillion riders, and 78.9% among car passengers. The association between helmet use and CMF injuries was shown to be statistically significant (P < .001). CONCLUSION: Craniomaxillofacial injuries could be prevented with the use of motorcycle helmet and seat belt. PMID- 26026366 TI - Splenectomy attenuates obesity and decreases insulin hypersecretion in hypothalamic obese rats. AB - OBJECTIVE: Obesity-induced abnormalities, such as insulin resistance, dyslipidemia and hypertension, are frequently correlated with low-grade inflammation, a process that may depend on normal spleen function. This study investigated the role of the spleen in the obesity induced by monosodium glutamate (MSG) treatment. MATERIALS/METHODS: MSG-obese and lean control (CON) rats were subjected to splenectomy (SPL) or non-operated (NO). RESULTS: MSG-NO rats presented a high adipose tissue content, insulin resistance, dyslipidemia and islet hypersecretion, accompanied by hypertrophy of both pancreatic islets and adipocytes when compared with CON-NO rats. In addition, changes in nitric oxide response were found in islets from the MSG-NO group without associated alterations in inducible nitric oxide synthase (iNOS) or IL1beta expression. MSG NO also presented increased leukocyte counts and augmented LPS-induced nitric oxide production in macrophages. Splenectomy of MSG-obese animals decreased insulin hypersecretion, normalized the nitric oxide response in the pancreatic islets, improved insulin sensitivity and reduced hypertrophy of both adipocytes and islets, when compared with MSG-NO rats. CONCLUSION: Results show that splenectomy attenuates the progression of the obesity modulating pancreas functions in MSG-obese rats. PMID- 26026367 TI - Glycemic control paradox: Poor glycemic control associated with higher one-year and eight-year risks of all-cause hospitalization but lower one-year risk of hypoglycemia in patients with type 2 diabetes. AB - OBJECTIVE: The relationship between glycemic control and adverse outcomes found in a population with diabetes has seldom been evaluated in patients with type 2 diabetes. We explored the association between hemoglobin A1c (HbA1c) and hospitalization risks within one-year and eight-year follow-up periods. METHODS: We conducted a retrospective cohort study on 57,061 patients with type 2 diabetes from National Diabetes Case Management Program during 2002-2004 in Taiwan. HbA1c at baseline and in-hospital mortality, all-cause and cause-specific hospitalization over one year and eight years were analyzed. RESULTS: After multivariate adjustment, one-year risk was higher for cases with HbA1c level <6%, 9-10%, >=10% versus 6-7% for all-cause hospitalization (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.03-1.20; 1.08, 1.01-1.16, and 1.19, 1.12-1.26, respectively) and for >=10% for diabetes-related hospitalization (1.68, 1.46 1.92). Yet each 1-step increment in HbA1c category (<6.0, 6.0-6.9, 7.0-7.9, 8.0 8.9, 9.0-9.9 and >=10.0%) showed linkage with lower risk of hypoglycemia hospitalization (0.81, 95% CI: 0.74-0.88). For eight-year risk, subjects with HbA1c level <6%, and >=10% were more likely to have in-hospitality mortality (1.16, 1.03-1.31, and 1.23, 1.11-1.35, respectively). Each 1-step increment in HbA1c category showed an association with higher risks of all-cause and diabetes related hospitalization (1.04, 1.03-1.05, and 1.15, 1.14-1.17, respectively). CONCLUSIONS: Higher HbA1c level correlated with lower one-year risk due to hypoglycemia hospitalization but increased one-year and eight-year risks due to all-cause and diabetes-specific hospitalization among Chinese people with type 2 diabetes in Taiwan. Future study must ascertain how to meet HbA1c targets and improve outcome without risk to this population. PMID- 26026370 TI - Ethnomedicinal plants of Sarigol district (Manisa), Turkey. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper provides new and significant ethnopharmacological information on medicinal plants used by native people who live in Sarigol and its surroundings in Turkey. AIM OF THE STUDY: To compile herbal remedies from the area of Sarigol with their traditional uses, parts of the plant used and form of administration as well as to calculate ethnobotanical indices and validate its therapeutic use. MATERIALS AND METHODS: Plant samples that have been collected by herbalists or informants from Sarigol and its surroundings for medical purposes were studied by visiting the villages during the study period, and then brought to the laboratory to identify the species. The relative frequency citation (RFC), use value (UV), informant consensus factor (ICF) and fidelity level (FL) were computed for the plants included in the study as well as a pharmacological validation from International Official sources by using WHO, ESCOP and EMA monographs. RESULTS: In this research conducted between 2010 and 2013, 141 taxa affiliated with 55 families, including 3 Gymnosperms, were determined as they used for medical purposes. The study was carried out by visiting 15 villages and 4 herbalist shops identified in Sarigol and its surroundings. Asteraceae, Lamiaceae, Fabaceae, Rosaceae and Apiaceae have been detected as the most consumed families for medical purposes. The research showed that most of the informants agreed on the use of Vitis vinifera fruits to cure gastrointestinal diseases that demonstrated the highest fidelity level (0.62). Only 31, out of 141, of the species recorded in this study, currently have a monograph with a validated use. CONCLUSION: During the survey, it was observed that local people consumed plants in the form of the infusion, whereas when using hard organs such as bark or branches, decoctions were preferred. It was identified that most of the medicinal plants have been used for gastrointestinal and respiratory disorders, and they are mainly utilized in the form of infusion or decoction. Vitis vinifera has a different traditional use compared to therapeutic indication proposed by monographs from Official sources like ESCOP or EMA. PMID- 26026368 TI - High level PHGDH expression in breast is predominantly associated with keratin 5 positive cell lineage independently of malignancy. AB - We have previously reported the 2D PAGE-based proteomic profiling of a prospective cohort of 78 triple negative breast cancer (TNBC) patients, and the establishment of a cumulative TNBC protein database. Analysis of this database identified a number of proteins as being specifically overexpressed in TNBC samples. One such protein was D-3-phosphoglycerate dehydrogenase (Phgdh), a candidate oncogene. We analysed expression of Phgdh in normal and TNBC mammary tissue samples by 2D gel-based proteomics and immunohistochemistry (IHC), and show here that high-level expression of Phgdh in mammary epithelial cells is primarily associated with cell lineage, as we found that Phgdh expression was predominant in CK5-positive cells, normal as well as malignant, thus identifying an association of this protein with the basal phenotype. Quantitative IHC analysis of Phgdh expression in normal breast tissue showed high-level expression of Phgdh in normal CK5-positive mammary epithelial cells, indicating that expression of this protein was not associated with malignancy, but rather with cell lineage. However, proteomic profiling of Phgdh showed it to be expressed in two major protein forms, and that the ratio of expression between these variants was associated with malignancy. Overexpression of Phgdh in CK5-positive cell lineages, and differential protein isoform expression, was additionally found in other tissues and cancer types, suggesting that overexpression of Phgdh is generally associated with CK5 cells, and that oncogenic function may be determined by isoform expression. PMID- 26026369 TI - Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model. AB - Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. PMID- 26026371 TI - Plant species as a therapeutic resource in areas of the savanna in the state of Pernambuco, Northeast Brazil. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical studies have contributed significantly in research of plants with therapeutic potential. The aim of the present study was to learn about the use of native medicinal plants cited by the traditional population in "cerradao" (savanna woodland) areas in Northeast Brazil, providing data on therapeutic indications of the species used and their versatility. MATERIALS AND METHODS: Semi-structured interviews were conducted on the basis of a standardized questionnaire designed for key informants selected using the "snowball" technique. The selection of plants species with therapeutic potential was performed on the basis of the relative importance (RI) and informant consensus fator (ICF). RESULTS: A total of 78 species were indicated for 87 therapeutic purposes. Of these, 11 species presented great versatility of use (RI>1), as e.g.including Copaifera langsdorffii Desf., Hybanthus calceolaria (Mart.) Plumel., Heliotropium cf. indicum L., Croton zehntneri, Croton heliotropiifolius, Myracrodruon urundeuva, Stryphnodendro rotundifolium. Medicinal uses could be generalized Pax & K. Hoffm and Hymenaea courbaril L. The therapeutic indications were grouped into 14 use 15 categories with 594 species category combinations. The largest number of medicinal species was indicated for illnesses or undefined pain, followed by diseases associated with respiratory, digestive and genitourinaryof body systems. The factor informant consensus highlighted the agreement in the use of plants and showed that the, of which Diseases of the Nervous System and, Diseases of the Circulatory System had the greatest agreement 1.0 and 0.87 repectively, Disorders of the Visual Sensory System - Eyes and Respiratory System Disorder showed the highest agreement of use. CONCLUSIONS: Most of the species cited by the key informants are well known scientifically, but it is interesting that some have been studied little or not all with regard to confirming their purported medicinal properties and can contribute substantially to pharmacological and phytochemical investigations in the search for new drugs. PMID- 26026372 TI - Posterior EEG alpha at rest and during task performance: Comparison of current source density and field potential measures. AB - Resting and task-related EEG alpha are used in studies of cognition and psychopathology. Although Laplacian methods have been applied, apprehensions about loss of global activity dissuade researchers from greater use except as a supplement to reference-dependent measures. The unfortunate result has been continued reliance on reference strategies that differ across labs, and a systemic preference for a montage-dependent average reference over true reference free measures. We addressed these concerns by comparing resting- and task-related EEG alpha using three EEG transformations: nose- (NR) and average-referenced (AR) EEG, and the corresponding CSD. Amplitude spectra of resting and prestimulus task related EEG (novelty oddball) and event-related spectral perturbations were scaled to equate each transformation. Alpha measures quantified for 8-12 Hz bands were: 1) net amplitude (eyes-closed minus eyes-open) and 2) overall amplitude (eyes-closed plus eyes-open); 3) task amplitude (prestimulus baseline) and 4) task event-related desynchronization (ERD). Mean topographies unambiguously represented posterior alpha for overall, net and task, as well as poststimulus alpha ERD. Topographies were similar for the three transformations, but differed in dispersion, CSD being sharpest and NR most broadly distributed. Transformations also differed in scale, AR showing less attenuation or spurious secondary maxima at anterior sites, consistent with simulations of distributed posterior generators. Posterior task alpha and alpha ERD were positively correlated with overall alpha, but not with net alpha. CSD topographies consistently and appropriately represented posterior EEG alpha for all measures. PMID- 26026373 TI - Abnormal regional homogeneity and its correlations with personality in first episode, treatment-naive somatization disorder. AB - BACKGROUND: Structural and functional abnormalities of the default mode network (DMN) and their correlations with personality have been found in somatization disorder (SD). However, no study is conducted to identify regional neural activity and its correlations with personality in SD. In this study, regional homogeneity (ReHo) was applied to explore whether abnormal regional neural activity is present in patients with SD and its correlations with personality measured by Eysenck Personality Questionnaire (EPQ). METHODS: Twenty-five first episode, treatment-naive patients with SD and 28 sex-, age-, and education matched healthy controls participated in the whole study. During the scanning, all subjects were instructed to lie still with their eyes closed and remain awake. A ReHo approach was employed to analyze the data. RESULTS: The SD group had a significantly increased ReHo in the left angular gyrus (AG) compared to healthy controls. The increased ReHo positively correlated to the neuroticism scores of EPQ (EPQ-N). No other correlations were detected between the ReHo values and other related factors, such as symptom severity and education level. CONCLUSIONS: Our results suggest that abnormal regional neural activity of the DMN may play a key role in SD with clinical implications and emphasize the importance of the DMN in the pathophysiological process of SD. PMID- 26026374 TI - Is a GRACE 3.0 needed? PMID- 26026375 TI - Advances in quantitative muscle ultrasonography using texture analysis of ultrasound images. AB - Musculoskeletal ultrasound imaging can be used to investigate the skeletal muscle structure in terms of architecture (thickness, cross-sectional area, fascicle length and fascicle pennation angle) and texture. Gray-scale analysis is commonly used to characterize transverse scans of the muscle. Gray mean value is used to distinguish between normal and pathologic muscles, but it depends on the image acquisition system and its settings. In this study, quantitative ultrasonography was performed on five muscles (biceps brachii, vastus lateralis, rectus femoris, medial gastrocnemius and tibialis anterior) of 20 healthy patients (10 women, 10 men) to assess the characterization performance of higher-order texture descriptors to differentiate genders and muscle types. A total of 53 features (7 first-order descriptors, 24 Haralick features, 20 Galloway features and 2 local binary pattern features) were extracted from each muscle region of interest (ROI) and were used to perform the multivariate linear regression analysis (MANOVA). Our results show that first-order descriptors, Haralick features (energy, entropy and correlation measured along different angles) and local binary pattern (LBP) energy and entropy were highly linked to the gender, whereas Haralick entropy and symmetry, Galloway texture descriptors and LBP entropy helped to distinguish muscle types. Hence, the combination of first-order and higher-order texture descriptors (Haralick, Galloway and LBP) can be used to discriminate gender and muscle types. Therefore, multi-texture analysis may be useful to investigate muscle damage and myopathic disorders. PMID- 26026376 TI - Interplay among cytokines and T cell subsets in the progression and control of immune-mediated diseases. AB - Cytokines serve as key mediators of inflammation and tissue damage in a variety of immune-mediated disorders. The induction, progression, and resolution of inflammation in such disorders are characterized by a dynamic balance between both the pro-inflammatory and anti-inflammatory cytokines as well as the pathogenic and protective T cell subsets. Over the past two decades, the roles of the interleukin-17 (IL-17) /IL-23 axis and the T helper 17 (Th17)/ T regulatory (Treg) cell balance in the pathogenesis of autoimmunity and other inflammatory diseases have extensively been analyzed, and their significance validated. However, these studies, coupled with others devoted to well-established Th1/Th2 cytokines, have unraveled some challenging issues including the dual action of cytokines and the plasticity of T cell subsets. Nevertheless, major positive advances have also been made regarding cytokines and T cell subsets as therapeutic targets/agents. In this special issue, "Cytokines in Immune Pathology and Therapy," leading experts have shared their research work and perspectives on the roles of cytokines in the development and control of immune-mediated diseases. An outline of 14 articles in the first volume is presented here. The second volume will follow soon. PMID- 26026377 TI - Inhibition of HIV infection by caerin 1 antimicrobial peptides. AB - The major mode of transmission of the human immunodeficiency virus (HIV) is by sexual intercourse. In the effort to halt the spread of HIV, one measure that holds great promise is the development of effective microbicides that can prevent transmission. Previously we showed that several amphibian antimicrobial peptides (AMPs) completely inhibit HIV infection of T cells while maintaining good viability of the T cell targets. These peptides also inhibited the transfer of HIV by dendritic cells (DCs) to T cells when added up to 8h after virus exposure. Here we report on the anti-HIV activity of 18 additional structurally related caerin 1 family peptides in comparison with our previous best candidate caerin 1.9. Nine peptides were equally effective or more effective in the inhibition of T cell infection and disruption of the HIV envelope as caerin 1.9. Of those nine peptides, three peptides (caerin 1.2, caerin 1.10, and caerin 1.20) exhibited excellent inhibition of HIV infectivity at low concentrations (12-25MUM) and limited toxicity against target T cells and endocervical epithelial cells. There was a direct correlation between the effectiveness of the peptides in disruption of the viral envelope and their capacity to inhibit infection. Thus, several additional caerin 1 family peptides inhibit HIV infection have limited toxicity for vaginal epithelial cells, and would be good candidates for inclusion in microbicide formulations. PMID- 26026379 TI - [Geriatrics: Frailty care, chronic disease and dependence for activities of daily living in the community]. PMID- 26026378 TI - Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses. AB - Current influenza virus vaccines provide solid protection from infection with viruses that are well matched with the vaccine strains. However, they do not protect efficiently against drifted or shifted strains. We developed an antigen based on the conserved stalk domain of the influenza virus hemagglutinin and tested its efficacy as a vaccine in a mouse virus challenge model. Although the antigen lacked the correct conformation of the native stalk domain and was not recognized by a panel of neutralizing stalk-reactive antibodies, it did induce considerable protection against H1N1, H5N1 and H6N1 challenge strains. Protection was enhanced when mice had pre-existing immunity against the stalk domain. Since pre-existing immunity is also present in the human population, we hypothesize that a similar antigen could show efficacy in humans as well. PMID- 26026380 TI - Utilization of recombinant Trichoderma reesei expressing Aspergillus aculeatus beta-glucosidase I (JN11) for a more economical production of ethanol from lignocellulosic biomass. AB - The capacity of Trichoderma reesei cellulase to degrade lignocellulosic biomass has been enhanced by the construction of a recombinant T. reesei strain expressing Aspergillus aculeatus beta-glucosidase I. We have confirmed highly efficient ethanol production from converge-milled Japanese cedar by recombinant T. reesei expressing A. aculeatus beta-glucosidase I (JN11). We investigated the ethanol productivity of JN11 and compared it with the cocktail enzyme T. reesei PC-3-7 with reinforced cellobiase activity by the commercial Novozyme 188. Results showed that the ethanol production efficiency under enzymatic hydrolysis of JN11 was comparable to the cocktail enzyme both on simultaneous saccharification and fermentation (SSF) or separate hydrolysis and fermentation (SHF) processes. Moreover, the cocktail enzyme required more protein loading for attaining similar levels of ethanol conversion as JN11. We propose that JN11 is an intrinsically economical enzyme that can eliminate the supplementation of BGL for PC-3-7, thereby reducing the cost of industrial ethanol production from lignocellulosic biomass. PMID- 26026381 TI - Cloning, expression and characterization of a novel GH5 exo/endoglucanase of Thermobifida halotolerans YIM 90462(T) by genome mining. AB - The 1389-bp thcel5A gene, which encodes a family 5 of glycoside hydrolases (GH5), was screened from the draft genome of Thermobifida halotolerans YIM 90462(T). ThCel5A was most similar (77% identity) to a GH5 endoglucanase from Thermobifida fusca YX, followed by cellulases from Nocardiopsis dassonvillei subsp. dassonvillei DSM 43111, Nocardiopsis alba ATCC BAA-2165, and Kribbella flavida DSM 17836. The deduced amino acid sequence of ThCel5A, which consisted of 462 amino acid residues, encompassed a family 2 cellulose-binding module and a GH5 catalytic domain. Notably, ThCel5A hydrolysed soluble as well as insoluble cellulose substrates. The enzymatic hydrolysis assay showed that the activity of recombinant ThCel5A was optimized at pH 8.0 and 50 degrees C. Moreover, it retained hydrolytic activity in the presence of various metal ions and >90% activity within the range of pH 8.0-9.0 after 30 min at 50 degrees C. These results suggested that this enzyme has considerable potential in industrial applications. PMID- 26026382 TI - What baboons can (not) tell us about natural language grammars. AB - Rey et al. (2012) present data from a study with baboons that they interpret in support of the idea that center-embedded structures in human language have their origin in low level memory mechanisms and associative learning. Critically, the authors claim that the baboons showed a behavioral preference that is consistent with center-embedded sequences over other types of sequences. We argue that the baboons' response patterns suggest that two mechanisms are involved: first, they can be trained to associate a particular response with a particular stimulus, and, second, when faced with two conditioned stimuli in a row, they respond to the most recent one first, copying behavior they had been rewarded for during training. Although Rey et al. (2012) 'experiment shows that the baboons' behavior is driven by low level mechanisms, it is not clear how the animal behavior reported, bears on the phenomenon of Center Embedded structures in human syntax. Hence, (1) natural language syntax may indeed have been shaped by low level mechanisms, and (2) the baboons' behavior is driven by low level stimulus response learning, as Rey et al. propose. But is the second evidence for the first? We will discuss in what ways this study can and cannot give evidential value for explaining the origin of Center Embedded recursion in human grammar. More generally, their study provokes an interesting reflection on the use of animal studies in order to understand features of the human linguistic system. PMID- 26026383 TI - Hedgehog signaling regulates imaginal cell differentiation in a basally branching holometabolous insect. AB - The evolution of imaginal cells, or stem cell-like cells, contributed to the spectacular diversification of holometabolous insects, which undergo complete metamorphosis. The proliferation and differentiation of these imaginal cells is under the control of juvenile hormone (JH), but which patterning genes respond to JH is currently unknown. Here, the role of Hedgehog (Hh) signaling in the development of imaginal cells was investigated. RNA interference-mediated knockdown of the components of the Hh signaling pathway showed that Hh is required for the proliferation of polymorphic and imaginal cells in Tribolium castaneum. Hh was also necessary for the regeneration of larval appendages. In contrast, knockdown of Hh signaling antagonists, patched and costal 2 led to the overgrowth and precocious maturation of structures derived from imaginal cells and the occasional appearance of ectopic appendages from the head epidermis. In addition, JH suppressed the expression of hh both in vivo and in vitro. Our findings suggest that imaginal cells are created and maintained by modulating Hh signaling. Thus, Hh signaling may have played a critical role during the evolution of complete metamorphosis. PMID- 26026384 TI - Patterns of concurrent substance use among adolescent nonmedical ADHD stimulant users. AB - OBJECTIVES: There are growing concerns about nonmedical use of ADHD stimulants among adolescents; yet, little is known whether there exist heterogeneous subgroups among adolescents with nonmedical ADHD stimulant use according to their concurrent substance use. METHODS: We used latent class analysis (LCA) to examine patterns of past-year problematic substance use (meeting any criteria for abuse or dependence) in a sample of 2203 adolescent participants from the National Surveys on Drug Use and Health 2006-2011 who reported past-year nonmedical use of ADHD stimulants. Multivariable latent regression was used to assess the association of socio-demographic characteristics, mental health and behavioral problems with the latent classes. RESULTS: The model fit indices favored a four class model, including a large class with frequent concurrent use of alcohol and marijuana (Alcohol/marijuana class; 41.2%), a second large class with infrequent use of other substances (Low substance class, 36.3%), a third class characterized by more frequent misuse of prescription drugs as well as other substances (Prescription drug+class; 14.8%), and finally a class characterized by problematic use of multiple substances (Multiple substance class; 7.7%). Compared with individuals in Low substance class, those in the other three classes were all more likely to report mental health problems, deviant behaviors and substance abuse service use. CONCLUSIONS: Adolescent nonmedical ADHD stimulants users are a heterogeneous group with distinct classes with regard to concurrent substance use, mental health and behavioral problems. The findings have implications for planning of tailored prevention and treatment programs to curb stimulant use for this age group. PMID- 26026385 TI - Implicit associations in cybersex addiction: Adaption of an Implicit Association Test with pornographic pictures. AB - Recent studies show similarities between cybersex addiction and substance dependencies and argue to classify cybersex addiction as a behavioral addiction. In substance dependency, implicit associations are known to play a crucial role, and such implicit associations have not been studied in cybersex addiction, so far. In this experimental study, 128 heterosexual male participants completed an Implicit Association Test (IAT; Greenwald, McGhee, & Schwartz, 1998) modified with pornographic pictures. Further, problematic sexual behavior, sensitivity towards sexual excitation, tendencies towards cybersex addiction, and subjective craving due to watching pornographic pictures were assessed. Results show positive relationships between implicit associations of pornographic pictures with positive emotions and tendencies towards cybersex addiction, problematic sexual behavior, sensitivity towards sexual excitation as well as subjective craving. Moreover, a moderated regression analysis revealed that individuals who reported high subjective craving and showed positive implicit associations of pornographic pictures with positive emotions, particularly tended towards cybersex addiction. The findings suggest a potential role of positive implicit associations with pornographic pictures in the development and maintenance of cybersex addiction. Moreover, the results of the current study are comparable to findings from substance dependency research and emphasize analogies between cybersex addiction and substance dependencies or other behavioral addictions. PMID- 26026386 TI - A colorimetric-based amplification system for proteinases including MMP2 and ADAM8. AB - We have developed a new amplification system for proteinases that is sensitive, simple, and inexpensive to run, exemplified by a horseradish peroxidase (HRP) conjugated, dual MMP2 (matrix metalloproteinase 2) and ADAM8 (a disintegrin and metalloproteinase 8) peptide substrate assay presented herein. The HRP-conjugated substrate is attached to beads through a 6* histidine tag and then incubated with the target enzyme, cleaving the HRP reporter. This product is subsequently removed from the unreacted bound portions of the substrate by magnetic deposition of the beads. The amount of product is then quantified using a standard HRP color development assay employing 3,3',5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide (H2O2). This HRP amplification system represents a new approach to proteinase assays and could be applied to other enzymes, such as lipases, esterases, and kinases, as long as the unreacted substrate can be physically separated from the product and catalysis by the enzyme to be quantified is not impaired dramatically by steric hindrance from the HRP entity. PMID- 26026387 TI - Development of a novel immunoassay specific for mouse intact proinsulin. AB - The blood concentration of intact proinsulin, but not total proinsulin, has been suggested to be a diagnostic marker for type 2 diabetes mellitus (T2DM), but a sensitive assay specific for rodent intact proinsulin is lacking. Here, a novel enzyme-linked immunosorbent assay (ELISA) for mouse intact proinsulin was developed. The developed ELISA detected mouse intact proinsulin with the working range of 8.3 to 2700pg/ml. Cross-reactivity with mouse split-32,33 proinsulin was approximately 100times lower than the reactivity with mouse intact proinsulin, and no cross-reactivity with mouse insulin was detected. The developed ELISA was sufficiently sensitive to detect low levels of intact proinsulin in normal mouse plasma. The measurement by the developed ELISA revealed that intact proinsulin was elevated in the plasma of type 2 diabetic db/db mice as mice aged, and the ratio of intact proinsulin/insulin in plasma was correlated with levels of glycated hemoglobin A1c as seen in T2DM patients. These results suggest that the plasma level of intact proinsulin, but not total proinsulin, is a sensitive marker for pancreatic dysfunction and the ensuring diabetic disease progression of db/db mice. This ELISA could aid nonclinical evaluation of therapeutic interventions in T2DM. PMID- 26026388 TI - Sequential extractions: A new way for protein quantification-data from peanut allergens. AB - Quantification of certain protein contents in the matrix is essential in protein analyses. The amount of total protein in the matrix can be determined by the Kjeldahl method. However, few methods can quantify certain protein contents in the matrix without extracting all of them in solution. Extracting all of the contents is difficult for proteins, especially relatively insoluble ones. A five step sequential extraction method was developed for the quantification of certain proteins in defatted peanut flour based on the relationship between the extracted protein contents and the extraction times. The extracted proteins (i.e., total protein, Ara h 1, and Ara h 2) were quantitatively analyzed in each extraction of the same condition. An exponential equation was obtained between the extraction times and the respective amount of extracted protein as well as both the total protein and a particular protein. In particular, the amount of protein extracted each time can be a geometric sequence. If all proteins can be extracted with sufficient extraction times, the protein contents in the peanut matrix can be calculated using a mathematical summation formula. This sum should be all proteins in the matrix. The five-step sequential extraction method can provide a means to quantify certain proteins in the matrix. PMID- 26026389 TI - Pouch Inflammation Is Associated With a Decrease in Specific Bacterial Taxa. AB - BACKGROUND & AIMS: Pouchitis is a common long-term complication in patients with ulcerative colitis (UC) undergoing proctocolectomy with ileal pouch-anal anastomosis. Because the inflammation occurs in a previously normal small bowel, studies of this process might provide information about the development of Crohn's disease. Little is known about the intestinal microbiome of patients with pouchitis. We investigated whether specific bacterial populations correlate with the pouch disease phenotype and inflammatory activity. METHODS: We performed a prospective study of patients with UC who underwent pouch surgery (N = 131) from 1981 through 2012 and were followed at Tel Aviv Medical Center. Patients were assigned to groups based on their degree and type of pouch inflammation. Patients with familial adenomatous polyposis after pouch surgery (n = 9), individuals with intact colons undergoing surveillance colonoscopy (n = 10), and patients with UC who did not undergo surgery (n = 9) served as controls. We collected demographic and disease activity data (based on the Pouchitis Disease Activity Index) and measured levels of C-reactive protein. Fecal samples were collected, levels of calprotectin were measured, and microbiota were analyzed by 16S ribosomal RNA gene amplicon pyrosequencing. RESULTS: Increased proportions of the Fusobacteriaceae family correlated with increased disease activity and levels of C-reactive protein in patients with UC who underwent pouch surgery. In contrast, proportions of Faecalibacterium were reduced in patients with pouchitis vs controls; there was a negative correlation between proportion of Faecalibacterium and level of C-reactive protein. There was an association between antibiotic treatment, but not biologic or immunomodulatory therapy, with reduced proportions of 11 genera and with increased proportions of Enterococcus and Enterobacteriaceae. CONCLUSIONS: Reductions in protective bacteria and increases in inflammatory bacteria are associated with pouch inflammation in patients with UC who underwent pouch surgery. The finding that antibiotics exacerbate dysbiosis indicates that these drugs might not provide long-term benefit for patients with pouchitis. Additional studies of this form of dysbiosis could provide information about the pathogenesis of Crohn's disease. PMID- 26026390 TI - High Prevalence of Nonalcoholic Fatty Liver Disease in Adolescents Undergoing Bariatric Surgery. AB - BACKGROUND & AIMS: Little is known about the prevalence of nonalcoholic fatty liver disease (NAFLD) among severely obese adolescents or factors that determine its development. We investigated the prevalence of NAFLD in a multicenter cohort of adolescents undergoing bariatric surgery and the factors associated with it. METHODS: We enrolled 242 adolescents undergoing bariatric surgery between March 2007 and February 2012 at 5 tertiary care centers into a multicenter, prospective observational cohort study. Intraoperative core liver biopsies were collected from 165 subjects; 17 were excluded because of insufficient liver tissue or use of hepatotoxic medications, so 148 remained in the study (mean age, 16.8 +/- 1.6 years; median body mass index = 52 kg/m(2)). Liver tissues were analyzed by histology using validated criteria. Hepatic gene expression was analyzed in 67 samples. RESULTS: NAFLD was present in 59% of this predominantly female (72%), white (68%), non-Hispanic (91%) cohort. Of subjects with NAFLD, 24% had borderline and 10% had definite nonalcoholic steatohepatitis (NASH). Mild fibrosis (stage 2 or lower) was observed in 18% of liver biopsies and stage 3 was observed in 0.7%, but cirrhosis was not detected. Dyslipidemia was present in 78% of subjects, hypertension in 44%, and diabetes in 14%. More severe NAFLD was associated with increasing levels of alanine aminotransferase, fasting glucose level, hypertension (each P < .01), and white blood cell count (P = .04). Only diabetes was associated with detection of fibrosis (odds ratio = 3.56; 95% confidence interval: 1.93-6.56). Microarray analysis associated presence of NASH with altered expression of genes that regulate macrophage chemotaxis, cholesterol absorption, and fatty acid binding. CONCLUSIONS: More than half of adolescents undergoing bariatric surgery in this cohort had NAFLD, yet the prevalence of severe or fibrotic NASH was low. Increasing severity of NAFLD was associated with level of alanine aminotransferase and cardiometabolic risk factors, but not body mass index. Based on gene expression analysis, borderline and definite NASH were associated with abnormal immune function, intestinal cholesterol absorption, and lipid metabolism. PMID- 26026392 TI - High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies. AB - BACKGROUND & AIMS: There is much interest in wheat sensitivity among people without celiac disease (CD), but little is known about any risks associated with the condition. We evaluated the prevalence of autoimmune diseases (ADs) among patients with nonceliac wheat sensitivity (NCWS), and investigated whether they carry antinuclear antibodies (ANA). METHODS: We performed a retrospective study of 131 patients diagnosed with NCWS (121 female; mean age, 29.1 years) at 2 hospitals in Italy from January 2001 through June 2011. Data were also collected from 151 patients with CD or irritable bowel syndrome (IBS) (controls). Patient medical records were reviewed to identify those with ADs. We also performed a prospective study of 42 patients (38 female; mean age, 34 years) diagnosed with NCWS from July 2011 through March 2014 at 3 hospitals in Italy. One hundred age- and sex-matched subjects with CD or IBS served as controls. Serum samples were collected from all subjects and ANA levels were measured by immunofluorescence analysis. Participants completed a questionnaire and their medical records were reviewed to identify those with ADs. RESULTS: In the retrospective analysis, similar portions of subjects with NCWS (29%) and CD (29%) developed ADs (mainly Hashimoto's thyroiditis, 29 cases), compared with a smaller proportion of subjects with IBS (4%) (P < .001). In the prospective study, 24% of subjects with NCWS, 20% of subjects with CD, and 2% of subjects with IBS developed ADs (P < .001). In the retrospective study, serum samples tested positive for ANA in 46% of subjects with NCWS (median titer, 1:80), 24% of subjects with CD (P < .001), and 2% of subjects IBS (P < .001); in the prospective study, serum samples were positive for ANA in 28% of subjects with NCWS, 7.5% of subjects with CD (P = .02), and 6% of subjects with IBS (P = .005 vs patients with NCWS). ANA positivity was associated with the presence of the HLA DQ2/DQ8 haplotypes (P < .001). CONCLUSIONS: Higher proportions of patients with NCWS or CD develop autoimmune disorders, are ANA positive, and showed DQ2/DQ8 haplotypes compared with patients with IBS. PMID- 26026391 TI - KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up Regulated in a Subset of Human Colon Cancers. AB - BACKGROUND & AIMS: Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer. METHODS: An array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 DM colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. Cells were analyzed by real time quantitative reverse transcription polymerase chain reaction, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. Some mice were given the RTK inhibitor imatinib after injection of cancer cells; tumor growth was measured based on bioluminescence. We assessed tumorigenicity using limiting dilution analysis. RESULTS: KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. Knockdown of KIT decreased proliferation of colon cancer cell lines and growth of xenograft tumors in mice compared with control cells. KIT knockdown cells had increased expression of enterocyte markers, decreased expression of cycling genes, and, unexpectedly, increased expression of LGR5 associated genes. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. Imatinib inhibited growth of KIT(+) colon cancer organoids in culture and growth of xenograft tumors in mice. Cancer cells with endogenous KIT expression were more tumorigenic in mice. CONCLUSIONS: KIT and KITLG are expressed by a subset of human colon tumors. KIT signaling promotes growth of colon cancer cells and organoids in culture and xenograft tumors in mice via its ligand, KITLG, in an autocrine or paracrine manner. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors. PMID- 26026394 TI - Reflex syncope in classic Greek literature. PMID- 26026393 TI - Association Between Plasma Levels of Macrophage Inhibitory Cytokine-1 Before Diagnosis of Colorectal Cancer and Mortality. AB - BACKGROUND & AIMS: Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or growth differentiation factor 15), a marker of inflammation that might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality. METHODS: We collected data on survival of 618 participants diagnosed with CRC who provided prediagnosis blood specimens in 1990 (Nurses' Health Study) and 1994 (Health Professionals' Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by enzyme-linked immunosorbent assay and then were categorized into quartiles based on the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or cyclooxygenase-2), measured in 245 tumor samples by immunohistochemistry. RESULTS: Compared with participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval: 1.33-4.34; P for linear trend = .009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples (Pinteraction = .04). For individuals with PTGS2-positive tumors, the hazard ratio for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% confidence interval: 0.99-4.58) compared with participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate hazard ratio = 0.61; 95% confidence interval: 0.13-2.93). CONCLUSIONS: Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (growth differentiation factor 15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors. PMID- 26026395 TI - Purinergic signalling and the autonomic nervous system in health and disease. PMID- 26026396 TI - Exploring the autonomic correlates of personality. AB - The aim of this study was to investigate the relationship between personality and resting heart rate variability (HRV) indices. Healthy volunteers (n=106) completed a 240-item Big Five personality inventory, the state/Trait Anxiety inventory, and a ten minute electrocardiographic recording. Time and frequency domain estimates of HRV were derived from the cardiac time series and related to the Big Five dimensions of personality, to personality types extracted from a cluster analysis, and to Trait Anxiety. Frequency domain measures of HRV (HRV-HF, LF/HF) were associated with specific dimensions of personality, but significance was not noted for the time domain measure (STD-RR). Furthermore, distressed personality types exhibited significantly greater autonomic imbalance (LF/HF) than other personality types. However, significance was not noted for the time domain measure (STD-RR). These results can be explained with reference to a contemporary model of neurovisceral integration. PMID- 26026397 TI - Down-regulation of mir-542-3p promotes neointimal formation in the aging rat. AB - AIM: To explore mir-542-3p mediated inhibition of vascular smooth muscle cell (VSMC) proliferation through the inhibition of Syk activation. METHODS AND RESULTS: MicroRNA (mir)-542-3p was selected for analysis based on miRNA microarray and qRT-PCR results. In vitro mir-542-3p expression was significantly downregulated in old (o)VSMCs compared with young (y)VSMCs under serum stimulation conditions. Upregulation of mir-542-3p in oVSMCs significantly inhibited VSMC proliferation, whereas downregulation of mir-542-3p in yVSMCs increased VSMC proliferation. We identified spleen tyrosine kinase (Syk) as a direct target of mir-542-3p by database search, and showed that its expression and phosphorylation were higher in oVSMCs than in yVSMCs after serum stimulation. Luciferase assays confirmed that Syk is a direct target of miR-3542-3p. Knock down of mir-542-3p in yVSMCs inhibited the activation of the Syk downstream effectors STAT3 and STAT5, whereas mir-542-3p overexpression enhanced STAT3 and STAT5 activities. In a rat balloon injury model, mir-542-3p inhibited neointima formation and proliferating cell nuclear antigen (PCNA) protein expression. CONCLUSION: Mir-542-3p modulates VSMC proliferation via the Syk/STAT3-STAT5 axis. Downregulation of mir-542-3p may explain age-related neointimal hyperplasia in rats. PMID- 26026398 TI - The cardiovascular benefits of dark chocolate. AB - Dark chocolate contains many biologically active components, such as catechins, procyanidins and theobromine from cocoa, together with added sucrose and lipids. All of these can directly or indirectly affect the cardiovascular system by multiple mechanisms. Intervention studies on healthy and metabolically dysfunctional volunteers have suggested that cocoa improves blood pressure, platelet aggregation and endothelial function. The effect of chocolate is more convoluted since the sucrose and lipid may transiently and negatively impact on endothelial function, partly through insulin signalling and nitric oxide bioavailability. However, few studies have attempted to dissect out the role of the individual components and have not explored their possible interactions. For intervention studies, the situation is complex since suitable placebos are often not available, and some benefits may only be observed in individuals showing mild metabolic dysfunction. For chocolate, the effects of some of the components, such as sugar and epicatechin on FMD, may oppose each other, or alternatively in some cases may act together, such as theobromine and epicatechin. Although clearly cocoa provides some cardiovascular benefits according to many human intervention studies, the exact components, their interactions and molecular mechanisms are still under debate. PMID- 26026399 TI - Immune dysregulation in Alagille syndrome: A new feature of the evolving phenotype. AB - Alagille syndrome (ALGS) is a rare autosomal dominant, multi-system disease caused by mutations in one of two NOTCH signaling pathway genes. Mutations in JAG1 are found in more than 94% of patients, with associated Jagged1 defects. We previously showed that CD46, which is a complement and immune regulator, regulates NOTCH expression during T cell activation after binding to C3b/C4b. We have identified 25% of our ALGS cohort with frequent infections and studied a subgroup of 4 in detail who were not showing current features of infections in order to show if Jagged1 abnormalities could affect immune function. We used cytometric bead arrays and FACS to measure cytokines and cell membrane expression. Resting and activated T cells were studied in both low and high IL-2 concentration to assess the TH1 ability to shift from INFgamma to IL-10 production. In vitro initial PBMC cell population and subpopulation assessment were normal but further assessment of the lymphocytes revealed that while NOTCH1 expression and regulation was normal on resting TH1, Jagged1 expression was exaggerated. Resting TH1 cells from some patients exhibited high CD132 levels. Upon activating T cells, TH1 cells managed to produce TNF but failed to produce sufficient IFNgamma levels (in two patients TH1 produced no IFNgamma). TH2 exhibited exaggerated response with high IL-4 and IL-5 levels. TH1 were unable to down-regulate CD127, resulting in prolonged immune activation, and failed to shift from IFNgamma to IL-10 production maintaining high IL-2 levels suggesting an impaired T cell response. Disturbed CD46-Jagged1 interaction may explain recurrent infections among ALGS patients, and could predispose to Th2-driven conditions such as asthma, eczema, food allergies and airway atopy and otitis media. The ALGS description could now be extended to include immune dysregulation. PMID- 26026400 TI - Improving health worker performance: The patient-perspective from a PBF program in Rwanda. AB - The effect of performance-based financing (PBF) on patients' perception of primary health care services in developing countries in not well documented. Data from a randomized impact evaluation in Rwanda conducted between 2006 and 2008 in 157 primary level facilities is used to explore patients' satisfaction with clinical and non-clinical services and quantify the contribution of individual and facility characteristics to satisfaction including PBF. Improvements in productivity, availability and competences of the health workforce following the implementation of PBF have a positive effect on patients' satisfaction with clinical services even if patients' satisfaction is not tied to a reward. The positive effect of PBF on non-clinical dimensions of satisfaction also suggests that PBF incentivizes providers to raise patients' satisfaction with non-clinical services if it is associated with future financial gains. It is recommended that low and middle income countries build on the experience from high income countries to better listen to patients' voice in general and include an assessment of patients' satisfaction in incentive mechanisms as a way to increase the benefits of the strategy. PMID- 26026401 TI - Butanol production from hexoses and pentoses by fermentation of Clostridium acetobutylicum. AB - The present paper reports the characterization of ABE (acetone-butanol-ethanol) production by Clostridium acetobutylicum DSM 792 for sugars representative of hydrolysed lignocellulosic biomass (glucose, mannose, arabinose, xylose). The attention was focused on: the selection of an optimal medium for the simultaneous conversion of the investigated sugars; the assessment of interference-synergistic effects during the fermentation of mixtures of the investigated sugars. The synthetic medium was optimised in terms of nutritional factors: the KH2PO4-K2HPO4 concentration was increased up to 5 g/L; the MgSO4 concentration was increased up to 2 g/L; the MnSO4 concentration was increased up to 0.1 g/L; the FeSO4 concentration ranged between 0.002 and 0.01 g/L); the CaCO3 concentration was increased up to 10 g/L. The optimal concentration of the investigated factors was assessed and it varied from one sugar to another. The batch fermentations of a mixture of the four sugars highlighted their synergistic effects. Once set the initial concentration of the sugars (60 g/L), the butanol and solvent concentration increased up to 14.6 and 20.6 g/L, respectively, when the four sugars were present. PMID- 26026402 TI - Late effects of low blood lead concentrations in children on school performance and cognitive functions. AB - BACKGROUND: Although it is known that lead is a neurotoxin that negatively impacts cognitive functions at low blood concentrations (B-Pb), little is known about the impact of early exposure on later cognitive functions. OBJECTIVES: This study assesses the effects of very low lead exposure in early childhood on teenage cognitive performance. METHODS: Using data collected between 1978 and 2007, we analyzed B-Pb (median 30 MUg/L; six-fold decrease over time) in 3176 Swedish children (age 7-12). School performance in grade 9 (age 16; boys and girls) and over-all IQs measured during conscription examinations (age 18-19; mainly boys) were obtained from registers. In multivariate models, potential confounders (age at blood sampling, sex, parents' education, family economy, and country of birth of child and parents) and effect modifiers (socioeconomic; father's IQ at conscription examination) were included. RESULTS: There were statistically significant adjusted negative associations between school performance (Grades up to 1991: P<0.0001; Merits 1992-2007:P<0.0001) and IQ (P=0.03) and B-Pb. The dose-response relationships were non-linear. Effects were more pronounced for B-Pb<=50 MUg/L than for higher levels. In the B-Pb range 5-50 MUg/L, the average IQ loss corresponded to about 5 IU. There was no significant effect modification associated with socioeconomic factors. CONCLUSIONS: Lead causes neurotoxic effects at very low exposures (B-Pb<50 MUg/L) in childhood and these effects remain for many years. PMID- 26026403 TI - NSAID-manufacturing plant effluent induces geno- and cytotoxicity in common carp (Cyprinus carpio). AB - The pharmaceutical industry generates wastewater discharges of varying characteristics and contaminant concentrations depending on the nature of the production process. The main chemicals present in these effluents are solvents, detergents, disinfectants - such as sodium hypochlorite (NaClO) - and pharmaceutical products, all of which are potentially ecotoxic. Therefore, this study aimed to evaluate the geno- and cytotoxicity induced in the common carp Cyprinus carpio by the effluent emanating from a nonsteroidal anti-inflammatory drug (NSAID)-manufacturing plant. Carp were exposed to the lowest observed adverse effect level (LOAEL, 0.1173%) for 12, 24, 48, 72 and 96 h, and biomarkers of genotoxicity (comet assay and micronucleus test) and cytotoxicity (caspase-3 activity and TUNEL assay) were evaluated. A significant increase with respect to the control group (p<0.05) occurred with all biomarkers from 24h on. Significant positive correlations were found between NSAID concentrations and biomarkers of geno- and cytotoxicity, as well as among geno- and cytotoxicity biomarkers. In conclusion, exposure to this industrial effluent induces geno- and cytotoxicity in blood of C. carpio. PMID- 26026404 TI - Diversity of enterococcal species and characterization of high-level aminoglycoside resistant enterococci of samples of wastewater and surface water in Tunisia. AB - One hundred-fourteen samples of wastewater (n=64) and surface-water (n=50) were inoculated in Slanetz-Bartley agar plates supplemented or not with gentamicin (SB Gen and SB plates, respectively) for enterococci recovery. Enterococci were obtained from 75% of tested samples in SB media (72% in wastewater; 78% in surface-water), and 85 enterococcal isolates (one/positive-sample) were obtained. Enterococcus faecium was the most prevalent species (63.5%), followed by Enterococcus faecalis (20%), Enterococcus hirae (9.4%), Enterococcus casseliflavus (4.7%), and Enterococcus gallinarum/Enterococcus durans (2.4%). Antibiotic resistance detected among these enterococci was as follows [percentage/detected gene (number isolates)]: kanamycin [29%/aph(3')-IIIa (n=22)], streptomycin [8%/ant(6)-Ia (n=4)], erythromycin [44%/erm(B) (n=34)], tetracycline [18%/tet(M) (n=6)/tet(M)-tet(L) (n=9)], chloramphenicol [2%/cat(A) (n=1)], ciprofloxacin [7%] and trimethoprim-sulfamethoxazole [94%]. High-level gentamicin resistant (HLR-G) enterococci were recovered from 15 samples in SB-Gen or SB plates [12/64 samples of wastewater (19%) and 3/50 samples of surface-water (6%)]; HLR-G isolates were identified as E. faecium (n=7), E. faecalis (n=6), and E. casseliflavus (n=2). These HLR-G enterococci carried the aac(6')-Ie-aph(2")-Ia and erm(B) genes, in addition to aph(3')-IIIa (n=10), ant(6)-Ia (n=9), tet(M) (n=13), tet(L) (n=8) and cat(A) genes (n=2). Three HLR-G enterococci carried the esp virulence gene. Sequence-types detected among HLR-G enterococci were as follows: E. faecalis (ST480, ST314, ST202, ST55, and the new ones ST531 and ST532) and E. faecium (ST327, ST12, ST296, and the new ones ST985 and ST986). Thirty-two different PFGE patterns were detected among 36 high-level aminoglycoside-resistant enterococci recovered in water samples. Diverse genetic lineages of HLR-G enterococci were detected in wastewater and surface-water in Tunisia. Water can represent an important source for the dissemination of these antibiotic resistant microorganisms to other environments. PMID- 26026405 TI - Concentration and sources of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in surface soil near a municipal solid waste (MSW) landfill. AB - Due to a continuous demand of land for infrastructural and residential development there is a public concern about the condition of surface soil near municipal solid waste landfills. A total of 12 surface (0-20 cm) soil samples from a territory near a landfill were collected and the concentration of 16 PAHs and 7 PCB congeners were investigated in these samples. Limits of detection were in the range of 0.038-1.2 MUg/kg for PAHs and 0.025-0.041 MUg/kg for PCBs. The total concentration of ? PAHs ranged from 892 to 3514 MUg/kg with a mean of 1974 MUg/kg. The total concentration of ? PCBs ranged from 2.5 to 12 MUg/kg with a mean of 4.5 MUg/kg. Data analyses allowed to state that the PAHs in surface soils near a landfill were principally from pyrogenic sources. Due to air transport, PAHs forming at the landfill are transported outside the landfill. PCB origin is not connected with the landfill. Aroclor 1242 can be the source of PCBs in several samples. PMID- 26026406 TI - An integrated approach using high time-resolved tools to study the origin of aerosols. AB - Long-range transport of natural and/or anthropogenic particles can contribute significantly to PM10 and PM2.5 concentrations and some European cities often fail to comply with PM daily limit values due to the additional impact of particles from remote sources. For this reason, reliable methodologies to identify long-range transport (LRT) events would be useful to better understand air pollution phenomena and support proper decision-making. This study explores the potential of an integrated and high time-resolved monitoring approach for the identification and characterization of local, regional and long-range transport events of high PM. In particular, the goal of this work was also the identification of time-limited event. For this purpose, a high time-resolved monitoring campaign was carried out at an urban background site in Bari (southern Italy) for about 20 days (1st-20th October 2011). The integration of collected data as the hourly measurements of inorganic ions in PM2.5 and their gas precursors and of the natural radioactivity, in addition to the analyses of aerosol maps and hourly back trajectories (BT), provided useful information for the identification and chemical characterization of local sources and trans boundary intrusions. Non-sea salt (nss) sulfate levels were found to increase when air masses came from northeastern Europe and higher dispersive conditions of the atmosphere were detected. Instead, higher nitrate and lower nss-sulfate concentrations were registered in correspondence with air mass stagnation and attributed to local traffic source. In some cases, combinations of local and trans-boundary sources were observed. Finally, statistical investigations such as the principal component analysis (PCA) applied on hourly ion concentrations and the cluster analyses, the Potential Source Contribution Function (PSCF) and the Concentration Weighted Trajectory (CWT) models computed on hourly back trajectories enabled to complete a cognitive framework and confirm the influence of aerosol transported from heavily polluted areas on the receptor site. PMID- 26026407 TI - A predictive method for volatile organic compounds emission from soil: Evaporation and diffusion behavior investigation of a representative component of crude oil. AB - Pipelines are convenient, economical and widely used mode of transportation of crude oil. However, the inevitable or otherwise accidents during such transport of crude oil lead to large scale oil spills, which consequently result in both soil and air pollution. When such pollution occurs, crude oil VOC concentrations in air, soil pollution evaluation and VOC propagation in soil provide important evidence for airborne detection of oils spills. Therefore, several issues, including determination method for VOC, isotherm parameters of VOC sorption on soil surfaces, and VOC diffusion flux simulation, are significant. In our previous study, n-butane and n-pentane were proved to be the maximum VOCs in studied crude oils. Therefore, a predictive method using n-pentane as a representative component is proposed in this paper. Firstly, a headspace solid phase microextraction (SPME) method was developed for determination of n-pentane in non-equilibrium mass transfer conditions. Secondly, Brunauer-Emmett-Teller (BET) analysis with liquid nitrogen was carried out to predict isotherm parameters for n-pentane. Finally, two models were used to predict the emission process. Probably influenced by gas vapor density below and above the soil layer, the experimental data amounted to 74% of the deduced value from the simplified analytical model. However, the free diffusion model fitted well with the experimental results. PMID- 26026408 TI - The assessment of daily dietary intake reveals the existence of a different pattern of bioaccumulation of chlorinated pollutants between domestic dogs and cats. AB - Pet dogs and cats have been proposed as sentinel species to assess environmental contamination and human exposure to a variety of pollutants, including POPs. However, some authors have reported that dogs but not cats exhibit intriguingly low levels of some of the most commonly detected POPs, such as DDT and its metabolites. This research was designed to explore these differences between dogs and cats. Thus, we first determined the concentrations of 53 persistent and semi persistent pollutants (16 polycyclic aromatic hydrocarbons (PAHs), 18 polychlorinated biphenyls (PCBs) and 19 organochlorine pesticides (OCPs)) in samples of the most consumed brands of commercial feed for dogs and cats, and we calculated the daily dietary intake of these pollutants in both species. Higher levels of pollutants were found in dog food and our results showed that the median values of intake were about twice higher in dogs than in cats for all the three groups of pollutants (SigmaPAHs: 274.8 vs. 141.8; SigmaOCPs: 233.1 vs. 83; SigmaPCBs: 101.8 vs. 43.8 (ng/kg bw/day); respectively). Additionally, we determined the plasma levels of the same pollutants in 42 and 35 pet dogs and cats, respectively. All these animals lived indoors and were fed on the commercial brands of feed analyzed. As expected (considering the intake), the plasma levels of PAHs were higher in dogs than in cats. However, for organochlorines (OCPs and PCBs) the plasma levels were much higher in cats than in dogs (as much as 23 times higher for DDTs), in spite of the higher intake in dogs. This reveals a lower capacity of bioaccumulation of some pollutants in dogs, which is probably related with higher metabolizing capabilities in this species. PMID- 26026409 TI - Feasibility analysis of wastewater and solid waste systems for application in Indonesia. AB - Indonesia is one of many developing countries with a backlog in achieving targets for the implementation of wastewater and solid waste collection, treatment and recovery systems. Therefore a technical and financial feasibility analysis of these systems was performed using Indonesia as an example. COD, BOD, nitrogen, phosphorus and pathogen removal efficiencies, energy requirements, sludge production, land use and resource recovery potential (phosphorus, energy, duckweed, compost, water) for on-site, community based and off-site wastewater systems were determined. Solid waste systems (conventional, centralized and decentralized resource recovery) were analyzed according to land requirement, compost and energy production and recovery of plastic and paper. In the financial analysis, investments, operational costs & benefits and Total Lifecycle Costs (TLC) of all investigated options were compared. Technical performance and TLC were used to guide system selection for implementation in different residential settings. An analysis was undertaken to determine the effect of price variations of recoverable resources and land prices on TLC. A 10-fold increase in land prices for land intensive wastewater systems resulted in a 5 times higher TLC, whereas a 4-fold increase in the recovered resource selling price resulted in maximum 1.3 times higher TLC. For solid waste, these impacts were reversed - land price and resource selling price variations resulted in a maximum difference in TLC of 1.8 and 4 respectively. Technical and financial performance analysis can support decision makers in system selection and anticipate the impact of price variations on long-term operation. The technical analysis was based on published results of international research and the approach can be applied for other tropical, developing countries. All costs were converted to per capita unit costs and can be updated to assess other countries' estimated costs and benefits. Consequently, the approach can be used to guide wastewater and solid waste system planning in developing countries. PMID- 26026410 TI - Assessing potential harmful effects of CdSe quantum dots by using Drosophila melanogaster as in vivo model. AB - Since CdSe QDs are increasingly used in medical and pharmaceutical sciences careful and systematic studies to determine their biosafety are needed. Since in vivo studies produce relevant information complementing in vitro data, we promote the use of Drosophila melanogaster as a suitable in vivo model to detect toxic and genotoxic effects associated with CdSe QD exposure. Taking into account the potential release of cadmium ions, QD effects were compared with those obtained with CdCl2. Results showed that CdSe QDs penetrate the intestinal barrier of the larvae reaching the hemolymph, interacting with hemocytes, and inducing dose/time dependent significant genotoxic effects, as determined by the comet assay. Elevated ROS production, QD biodegradation, and significant disturbance in the conserved Hsps, antioxidant and p53 genes were also observed. Overall, QD effects were milder than those induced by CdCl2 suggesting the role of Cd released ions in the observed harmful effects of Cd based QDs. To reduce the observed side effects of Cd based QDs biocompatible coats would be required to avoid cadmium's undesirable effects. PMID- 26026411 TI - Simulation of nitrous oxide emissions at field scale using the SPACSYS model. AB - Nitrous oxide emitted to the atmosphere via the soil processes of nitrification and denitrification plays an important role in the greenhouse gas balance of the atmosphere and is involved in the destruction of stratospheric ozone. These processes are controlled by biological, physical and chemical factors such as growth and activity of microbes, nitrogen availability, soil temperature and water availability. A comprehensive understanding of these processes embodied in an appropriate model can help develop agricultural mitigation strategies to reduce greenhouse gas emissions, and help with estimating emissions at landscape and regional scales. A detailed module to describe the denitrification and nitrification processes and nitrogenous gas emissions was incorporated into the SPACSYS model to replace an earlier module that used a simplified first-order equation to estimate denitrification and was unable to distinguish the emissions of individual nitrogenous gases. A dataset derived from a Scottish grassland experiment in silage production was used to validate soil moisture in the top 10 cm soil, cut biomass, nitrogen offtake and N2O emissions. The comparison between the simulated and observed data suggested that the new module can provide a good representation of these processes and improve prediction of N2O emissions. The model provides an opportunity to estimate gaseous N emissions under a wide range of management scenarios in agriculture, and synthesises our understanding of the interaction and regulation of the processes. PMID- 26026412 TI - Decay characteristics and erosion-related transport of glyphosate in Chinese loess soil under field conditions. AB - The decay characteristics and erosion-related transport of glyphosate and aminomethylphosphonic acid (AMPA) were monitored for 35 d at different slope gradients and rates of application in plots with loess soil on the Loess Plateau, China. The initial glyphosate decayed rapidly (half-life of 3.5d) in the upper 2 cm of soil following a first-order rate of decay. AMPA content in the 0-2 cm soil layer correspondingly peaked 3d after glyphosate application and then gradually decreased. The residues of glyphosate and AMPA decreased significantly with soil depth (p<0.05) independently of the slope inclination and application rate. About 0.36% of the glyphosate initially applied was transported from plots after one erosive rain 2d after the application. Glyphosate and AMPA concentrations in runoff were low while the contents in the sediment were much higher than in the upper 2 cm of the soil. CAPSULE: Although the rate of glyphosate decay is rapid in Chinese loess soil, the risks of glyphosate and AMPA need to be taken into account especially in the area with highly erosive rainfall. PMID- 26026413 TI - Characterization of toxicants in urban road dust by Toxicity Identification Evaluation using ostracod Heterocypris incongruens direct contact test. AB - The current study involves characterization of organic compounds, heavy metals, and ammonia as potential toxicants in one arterial road (St. 3) and two highway (St. 7 and 8) urban road dust (URD) collected in Tokyo, Japan. URD toxicity was evaluated by Toxicity Identification Evaluation using the ostracod Heterocypris incongruens direct contact test. URDs were treated with resins (10% XAD-4, 20% SIR-300 and 20% SIR-600) to determine the reduction in mortality after treatment. The mortality of ostracods exposed to St. 3 URD (baseline 80%) was significantly (p<0.05) reduced to 0% and 47% after XAD-4 and SIR-300 treatment respectively. This reduction led us to suspect hydrophobic organic compounds and heavy metals as potential toxicants. Subsequent elution of the recovered XAD-4 with polar (methanol, acetone) and non-polar (dichloromethane) solvents confirmed the dominance of relatively polar hydrophobic organic toxicants. The dissolved concentration of Cu and Zn after SIR-300 treatment exceeded the 50% lethal concentration (LC50) for ostracods, which led us to suspect Cu and Zn as other probable toxicants. The concentration of Zn in a SIR-300 acidic elutriate, recovered after the termination of toxicity test, confirmed Zn as one of the toxicants in St. 3. The baseline mortality (100%) of St. 7 was significantly reduced (23%) by SIR-300 treatment. This indicated the presence of heavy metals as the probable toxicant. However, the concentration of dissolved heavy metals (Cd, Cr, Cu, Ni, Pb and Zn) in the overlying water was below previously reported LC50 values for each metal in St. 7. Recovery of Zn concentrations exceeding the LC50 in the St. 7 SIR-300 elutriate led us to suspect a dietary exposure route of Zn to the ostracod during the direct contact test. The overall results indicate that the toxicant types can vary widely depending on the road sampled. PMID- 26026414 TI - Disentangling the effects of feedback structure and climate on Poaceae annual airborne pollen fluctuations and the possible consequences of climate change. AB - Pollen allergies are the most common form of respiratory allergic disease in Europe. Most studies have emphasized the role of environmental processes, as the drivers of airborne pollen fluctuations, implicitly considering pollen production as a random walk. This work shows that internal self-regulating processes of the plants (negative feedback) should be included in pollen dynamic systems in order to give a better explanation of the observed pollen temporal patterns. This article proposes a novel methodological approach based on dynamic systems to investigate the interaction between feedback structure of plant populations and climate in shaping long-term airborne Poaceae pollen fluctuations and to quantify the effects of climate change on future airborne pollen concentrations. Long-term historical airborne Poaceae pollen data (30 years) from Cordoba city (Southern Spain) were analyzed. A set of models, combining feedback structure, temperature and actual evapotranspiration effects on airborne Poaceae pollen were built and compared, using a model selection approach. Our results highlight the importance of first-order negative feedback and mean annual maximum temperature in driving airborne Poaceae pollen dynamics. The best model was used to predict the effects of climate change under two standardized scenarios representing contrasting temporal patterns of economic development and CO2 emissions. Our results predict an increase in pollen levels in southern Spain by 2070 ranging from 28.5% to 44.3%. The findings from this study provide a greater understanding of airborne pollen dynamics and how climate change might impact the future evolution of airborne Poaceae pollen concentrations and thus the future evolution of related pollen allergies. PMID- 26026415 TI - Characteristics and major sources of carbonaceous aerosols in PM2.5 from Sanya, China. AB - PM2.5 samples were collected in Sanya, China in summer and winter in 2012/2013. Organic carbon (OC), elemental carbon (EC), and non-polar organic compounds including n-alkanes (n-C14-n-C40) and polycyclic aromatic hydrocarbons (PAHs) were quantified. The concentrations of these carbonaceous matters were generally higher in winter than summer. The estimated secondary organic carbon (OCsec) accounted for 38% and 54% of the total organic carbon (TOC) in winter and summer, respectively. The higher value of OCsec in addition to the presences of photochemically-produced PAHs in summer supports that photochemical conversions of organics are much active at the higher air temperatures and with stronger intense solar radiation. Carbon preference index (CPI) and percent contribution of wax n-alkanes suggest that anthropogenic sources were more dominant than derivation from terrestrial plants in Sanya. Diagnostic ratios of atmospheric PAHs further indicate that there was a wide mix of pollution sources in winter while fossil fuel combustion was the most dominant in summer. Positive Matrix Factorization (PMF) analysis with 18 PAHs in the winter samples found that motor vehicle emissions and biomass burning were the two main pollution sources, contributing 37.5% and 24.6% of the total quantified PAHs, respectively. PMID- 26026416 TI - Assessment of biomarkers for contaminants of emerging concern on aquatic organisms downstream of a municipal wastewater discharge. AB - Contaminants of emerging concern (CECs), including pharmaceuticals, personal care products and estrogens, are detected in wastewater treatment plant (WWTP) discharges. However, analytical monitoring of wastewater and surface water does not indicate whether CECs are affecting the organisms downstream. In this study, fathead minnows (Pimephales promelas) and freshwater mussels Pyganodon grandis Say, 1829 (synonym: Anodonta grandis Say, 1829) were caged for 4 weeks in the North Saskatchewan River, upstream and downstream of the discharge from the WWTP that serves the Edmonton, AB, Canada. Passive samplers deployed indicated that concentrations of pharmaceuticals, personal care products, an estrogen (estrone) and an androgen (androstenedione) were elevated at sites downstream of the WWTP discharge. Several biomarkers of exposure were significantly altered in the tissues of caged fathead minnows and freshwater mussels relative to the upstream reference sites. Biomarkers altered in fish included induction of CYP3A metabolism, an increase in vitellogenin (Vtg) gene expression in male minnows, elevated ratios of oxidized to total glutathione (i.e. GSSG/TGSH), and an increase in the activity of antioxidant enzymes (i.e. glutathione reductase, glutathione-S-transferase). In mussels, there were no significant changes in biomarkers of oxidative stress and the levels of Vtg-like proteins were reduced, not elevated, indicating a generalized stress response. Immune function was altered in mussels, as indicated by elevated lysosomal activity per hemocyte in P. grandis caged closest to the wastewater discharge. This immune response may be due to exposure to bacterial pathogens in the wastewater. Multivariate analysis indicated a response to the CECs Carbamazepine (CBZ) and Trimethoprim (TPM). Overall, these data indicate that there is a 1 km zone of impact for aquatic organisms downstream of WWTP discharge. However, multiple stressors in municipal wastewater make measurement and interpretation of impact of CECs difficult since water temperature, conductivity and bacteria are also inducing biomarker responses in both fish and mussels. PMID- 26026417 TI - Geochemical processes regulating F-, as and NO3- content in the groundwater of a sector of the Pampean Region, Argentina. AB - The presence of F(-) and As in groundwater is common in volcanic aquifers. Excessive concentrations of these ions affect the quality of drinking water and can be harmful to health. When there is an anthropogenic source in phreatic aquifers, NO3(-) is incorporated to the groundwater components, deteriorating its quality. The objective of this work is to assess the geochemical processes that regulate the contents of F(-), As and NO3(-) of the groundwater in a sector of the Pampean Region in Argentina. This area is supplied with water by exploiting a multilayer aquifer, composed of a phreatic aquifer occurring in loess sediments and a fluvial semi-confined aquifer, separated by an aquitard. The results obtained show that the phreatic aquifer has a higher concentration of F(-), As and NO3(-) than the semi-confined aquifer. Fluoride derives from the dissolution of volcanic glass at a slightly alkaline pH and from anion exchange; however, it may also be absorbed by the reprecipitating carbonates. The As is released by desorption, with the main source being the glass and lithic fragments of the loess. The NO3(-) originates from the decomposition of organic matter, mainly in the septic tanks of the peri-urban areas. Meanwhile, the As and F(-) content in the semi-confined aquifer is lower and its origin is the result of water inflow by vertical downward infiltration from the phreatic aquifer through the aquitard. The Pampean Region is one of the areas with the largest volume of agricultural exports in the world and at present it is undergoing a strong social and economic growth. Understanding the geochemical processes that regulate the quality of drinking water is of vital importance to generate water management guidelines aiming at minimizing the deterioration of drinking water sources. PMID- 26026419 TI - Statistical downscaling of CMIP5 outputs for projecting future changes in rainfall in the Onkaparinga catchment. AB - A generalized linear model was fitted to stochastically downscaled multi-site daily rainfall projections from CMIP5 General Circulation Models (GCMs) for the Onkaparinga catchment in South Australia to assess future changes to hydrologically relevant metrics. For this purpose three GCMs, two multi-model ensembles (one by averaging the predictors of GCMs and the other by regressing the predictors of GCMs against reanalysis datasets) and two scenarios (RCP4.5 and RCP8.5) were considered. The downscaling model was able to reasonably reproduce the observed historical rainfall statistics when the model was driven by NCEP reanalysis datasets. Significant bias was observed in the rainfall when downscaled from historical outputs of GCMs. Bias was corrected using the Frequency Adapted Quantile Mapping technique. Future changes in rainfall were computed from the bias corrected downscaled rainfall forced by GCM outputs for the period 2041-2060 and these were then compared to the base period 1961-2000. The results show that annual and seasonal rainfalls are likely to significantly decrease for all models and scenarios in the future. The number of dry days and maximum consecutive dry days will increase whereas the number of wet days and maximum consecutive wet days will decrease. Future changes of daily rainfall occurrence sequences combined with a reduction in rainfall amounts will lead to a drier catchment, thereby reducing the runoff potential. Because this is a catchment that is a significant source of Adelaide's water supply, irrigation water and water for maintaining environmental flows, an effective climate change adaptation strategy is needed in order to face future potential water shortages. PMID- 26026418 TI - Change of water sources reduces health risks from heavy metals via ingestion of water, soil, and rice in a riverine area, South China. AB - This study evaluates the effect of water source change on heavy metal concentrations in water, paddy soil, and rice, as well as the health risks to residents of three riverine communities in South China. The results show that after substituting the sources of drinking water, heavy metal levels (except for Pb at Tangjun) in drinking water were below WHO guideline values and the potential risk from drinking water may be negligible. The As (46.2-66.8%), Pb (65.7-82.6%), Cd (50.8-55.0%), and Hg (28.3-32.6%) concentrations in paddy soils in Sanhe and Lasha significantly (p<0.05) decreased with a change of irrigation water sources compared to Tangjun, without change of irrigation water source. Similarly, the Cd (39.1-81.3%) and Hg (60.0-75.0%) concentrations in rice grown at Sanhe and Lasha significantly (p<0.05) decreased compared to those at Tangjun. Consequently, replacing irrigation water source significantly (p<0.05) reduced the hazard quotient (HQ) and cancer risk for the corresponding single metal via soil ingestion and rice consumption. Despite that total non-carcinogenic and carcinogenic risks at Sanhe and Lasha were significantly decreased, they still exceeded the maximum acceptable limits recommended by US EPA, indicating that residents of these two communities remain at high risks of both non-cancer and cancer effects. PMID- 26026421 TI - Cognitive flexibility in young children: General or task-specific capacity? AB - Cognitive flexibility is the ability to adapt to changing tasks or problems. To test whether cognitive flexibility is a coherent cognitive capacity in young children, we tested 3- to 5-year-olds' performance on two forms of task switching, rule-based (Three Dimension Changes Card Sorting, 3DCCS) and inductive (Flexible Induction of Meaning-Animates and Objects, FIM-Ob and FIM-An), as well as tests of response speed, verbal working memory, inhibition, and reasoning. Results suggest that cognitive flexibility is not a globally coherent trait; only the two inductive word-meaning (FIM) tests showed high inter-test coherence. Task and knowledge-specific factors also determine children's flexibility in a given test. Response speed, vocabulary size, and causal reasoning skills further predicted individual and age differences in flexibility, although they did not have the same predictive relation with all three flexibility tests. PMID- 26026422 TI - Environmental stability modulates the role of path integration in human navigation. AB - Path integration has long been thought of as an obligatory process that automatically updates one's position and orientation during navigation. This has led to the hypotheses that path integration serves as a back-up system in case landmark navigation fails, and a reference system that detects discrepant landmarks. Three experiments tested these hypotheses in humans, using a homing task with a catch-trial paradigm. Contrary to the back-up system hypothesis, when stable landmarks unexpectedly disappeared on catch trials, participants were completely disoriented, and only then began to rely on path integration in subsequent trials (Experiment 1). Contrary to the reference system hypothesis, when stable landmarks unexpectedly shifted by 115 degrees on catch trials, participants failed to detect the shift and were completely captured by the landmarks (Experiment 2). Conversely, when chronically unstable landmarks unexpectedly remained in place on catch trials, participants failed to notice and continued to navigate by path integration (Experiment 3). In the latter two cases, they gradually sensed the instability (or stability) of landmarks on later catch trials. These results demonstrate that path integration does not automatically serve as a back-up system, and does not function as a reference system on individual sorties, although it may contribute to monitoring environmental stability over time. Rather than being automatic, the roles of path integration and landmark navigation are thus dynamically modulated by the environmental context. PMID- 26026420 TI - The code of non-coding RNAs in lung fibrosis. AB - The pathogenesis of pulmonary fibrosis is a complicated and complex process that involves phenotypic abnormalities of a variety of cell types and dysregulations of multiple signaling pathways. There are numerous genetic, epigenetic and post transcriptional mechanisms that have been identified to participate in the pathogenesis of this disease. However, efficacious therapeutics developed from these studies have been disappointingly limited. In the past several years, a group of new molecules, i.e., non-coding RNAs (ncRNAs), has been increasingly appreciated to have critical roles in the pathological progression of lung fibrosis. In this review, we summarize the recent findings on the roles of ncRNAs in the pathogenesis of this disorder. We analyze the translational potential of this group of molecules in treating lung fibrosis. We also discuss challenges and future opportunities of studying and utilizing ncRNAs in lung fibrosis. PMID- 26026425 TI - A facile method to determine pore size distribution in porous scaffold by using image processing. AB - Image processing permits scientists to investigate morphological properties of three-dimensional structures starting from their bi-dimensional gray-scale representation. In many cases porous structure with complex architecture has to be designed in order to attempt specific properties such in the case of scaffold for tissue engineering. Traditional morphological characterization, like scanning electron microscopy, should be coupled with quantitative information such as pore size distribution (PSD) in order to get a deeper understanding of the influence of the porous structure on tissue regeneration processes and on other related applications, it is remarkable to study a quantitative analysis of porosity and of pores dimension. In this work it was developed as a software able to accomplish the segmentation of images containing pores of any geometry in a semi automatic way with the aim to measure the PSD. Case study constituted by PLA porous scaffolds with different pore size was adopted. Results indicate that image processing methods well fit the pore size features of PLA scaffolds, overcoming the limits of the more invasive porosimetry techniques. PMID- 26026424 TI - The strategies for treating primary hepatocellular carcinoma with portal vein tumor thrombus. AB - PURPOSE: To further improve the effectiveness and prognosis of primary hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT), the current status of treatment for HCC with PVTT was reviewed. METHODS: A Medline search was undertaken to identify articles using the keywords "HCC", "PVTT" and "therapy". Additional papers were identified by a manual search of the references from the key articles. RESULTS: PVTT, as a common complication of HCC, was divided into type I ~ IV. The therapeutic approach is mainly composed of five types: surgical resection, regional interventional therapy, radiotherapy, combination therapy, targeted therapy. All of these therapeutic approaches were separately evaluated in detail. CONCLUSIONS: For those resectable tumors, the better choice for treatment of HCC with PVTT should be hepatectomy and removal of PVTT. For those unresectable tumors, TACE (especially the super-selective TACE) has been the preferred palliative treatment, the other regional interventional therapy and/or radiotherapy could improve the therapeutic effects. The multidisciplinary treatments may further improve the quality of life and prolong the survival period for the HCC patients associated with PVTT. PMID- 26026423 TI - Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms. AB - Abnormal high frequency oscillations (HFOs) in EEG recordings are thought to be reflections of mechanisms responsible for focal seizure generation in the temporal lobe and neocortex. HFOs have also been recorded in patients and animal models of infantile spasms. If HFOs are important contributors to infantile spasms then anticonvulsant drugs that suppress these seizures should decrease the occurrence of HFOs. In experiments reported here, we used long-term video/EEG recordings with digital sampling rates capable of capturing HFOs. We tested the effectiveness of vigabatrin (VGB) in the TTX animal model of infantile spasms. VGB was found to be quite effective in suppressing spasms. In 3 of 5 animals, spasms ceased after a daily two week treatment. In the other 2 rats, spasm frequency dramatically decreased but gradually increased following treatment cessation. In all animals, hypsarrhythmia was abolished by the last treatment day. As VGB suppressed the frequency of spasms, there was a decrease in the intensity of the behavioral spasms and the duration of the ictal EEG event. Analysis showed that there was a burst of high frequency activity at ictal onset, followed by a later burst of HFOs. VGB was found to selectively suppress the late HFOs of ictal complexes. VGB also suppressed abnormal HFOs recorded during the interictal periods. Thus VGB was found to be effective in suppressing both the generation of spasms and hypsarrhythmia in the TTX model. Vigabatrin also appears to preferentially suppress the generation of abnormal HFOs, thus implicating neocortical HFOs in the infantile spasms disease state. PMID- 26026428 TI - Similarity-transformed perturbation theory on top of truncated local coupled cluster solutions: Theory and applications to intermolecular interactions. AB - Your correspondents develop and apply fully nonorthogonal, local-reference perturbation theories describing non-covalent interactions. Our formulations are based on a Lowdin partitioning of the similarity-transformed Hamiltonian into a zeroth-order intramonomer piece (taking local CCSD solutions as its zeroth-order eigenfunction) plus a first-order piece coupling the fragments. If considerations are limited to a single molecule, the proposed intermolecular similarity transformed perturbation theory represents a frozen-orbital variant of the "(2)" type theories shown to be competitive with CCSD(T) and of similar cost if all terms are retained. Different restrictions on the zeroth- and first-order amplitudes are explored in the context of large-computation tractability and elucidation of non-local effects in the space of singles and doubles. To accurately approximate CCSD intermolecular interaction energies, a quadratically growing number of variables must be included at zeroth-order. PMID- 26026426 TI - Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model. AB - One critical approach to preclinical evaluation of anti-tuberculosis (anti-TB) drugs is the study of correlations between drug exposure and efficacy in animal TB infection models. While such pharmacokinetic/pharmacodynamic (PK/PD) studies are useful for the identification of optimal clinical dosing regimens, they are resource intensive and are not routinely performed. A mathematical model capable of simulating the PK/PD properties of drug therapy for experimental TB offers a way to mitigate some of the practical obstacles to determining the PK/PD index that best correlates with efficacy. Here, we present a preliminary physiologically based PK/PD model of rifampin therapy in a mouse TB infection model. The computational framework integrates whole-body rifampin PKs, cell population dynamics for the host immune response to Mycobacterium tuberculosis infection, drug-bacteria interactions, and a Bayesian method for parameter estimation. As an initial application, we calibrated the model to a set of available rifampin PK/PD data and simulated a separate dose fractionation experiment for bacterial killing kinetics in the lungs of TB-infected mice. The simulation results qualitatively agreed with the experimentally observed PK/PD correlations, including the identification of area under the concentration-time curve as best correlating with efficacy. This single-drug framework is aimed toward extension to multiple anti-TB drugs in order to facilitate development of optimal combination regimens. PMID- 26026429 TI - Ion aggregation in high salt solutions. III. Computational vibrational spectroscopy of HDO in aqueous salt solutions. AB - The vibrational frequency, frequency fluctuation dynamics, and transition dipole moment of the O-D stretch mode of HDO molecule in aqueous solutions are strongly dependent on its local electrostatic environment and hydrogen-bond network structure. Therefore, the time-resolved vibrational spectroscopy the O-D stretch mode has been particularly used to investigate specific ion effects on water structure. Despite prolonged efforts to understand the interplay of O-D vibrational dynamics with local water hydrogen-bond network and ion aggregate structures in high salt solutions, still there exists a gap between theory and experiment due to a lack of quantitative model for accurately describing O-D stretch frequency in high salt solutions. To fill this gap, we have performed numerical simulations of Raman scattering and IR absorption spectra of the O-D stretch mode of HDO in highly concentrated NaCl and KSCN solutions and compared them with experimental results. Carrying out extensive quantum chemistry calculations on not only water clusters but also ion-water clusters, we first developed a distributed vibrational solvatochromic charge model for the O-D stretch mode in aqueous salt solutions. Furthermore, the non-Condon effect on the vibrational transition dipole moment of the O-D stretch mode was fully taken into consideration with the charge response kernel that is non-local polarizability density. From the fluctuating O-D stretch mode frequencies and transition dipole vectors obtained from the molecular dynamics simulations, the O-D stretch Raman scattering and IR absorption spectra of HDO in salt solutions could be calculated. The polarization effect on the transition dipole vector of the O-D stretch mode is shown to be important and the asymmetric line shapes of the O-D stretch Raman scattering and IR absorption spectra of HDO especially in highly concentrated NaCl and KSCN solutions are in quantitative agreement with experimental results. We anticipate that this computational approach will be of critical use in interpreting linear and nonlinear vibrational spectroscopies of HDO molecule that is considered as an excellent local probe for monitoring local electrostatic and hydrogen-bonding environment in not just salt but also other confined and crowded solutions. PMID- 26026430 TI - Theoretical analysis of co-solvent effect on the proton transfer reaction of glycine in a water-acetonitrile mixture. AB - The co-solvent effect on the proton transfer reaction of glycine in a water acetonitrile mixture was examined using the reference interaction-site model self consistent field theory. The free energy profiles of the proton transfer reaction of glycine between the carboxyl oxygen and amino nitrogen were computed in a water-acetonitrile mixture solvent at various molar fractions. Two types of reactions, the intramolecular proton transfer and water-mediated proton transfer, were considered. In both types of the reactions, a similar tendency was observed. In the pure water solvent, the zwitterionic form, where the carboxyl oxygen is deprotonated while the amino nitrogen is protonated, is more stable than the neutral form. The reaction free energy is -10.6 kcal mol(-1). On the other hand, in the pure acetonitrile solvent, glycine takes only the neutral form. The reaction free energy from the neutral to zwitterionic form gradually increases with increasing acetonitrile concentration, and in an equally mixed solvent, the zwitterionic and neutral forms are almost isoenergetic, with a difference of only 0.3 kcal mol(-1). The free energy component analysis based on the thermodynamic cycle of the reaction also revealed that the free energy change of the neutral form is insensitive to the change of solvent environment but the zwitterionic form shows drastic changes. In particular, the excess chemical potential, one of the components of the solvation free energy, is dominant and contributes to the stabilization of the zwitterionic form. PMID- 26026431 TI - Development of efficient time-evolution method based on three-term recurrence relation. AB - The advantage of the real-time (RT) propagation method is a direct solution of the time-dependent Schrodinger equation which describes frequency properties as well as all dynamics of a molecular system composed of electrons and nuclei in quantum physics and chemistry. Its applications have been limited by computational feasibility, as the evaluation of the time-evolution operator is computationally demanding. In this article, a new efficient time-evolution method based on the three-term recurrence relation (3TRR) was proposed to reduce the time-consuming numerical procedure. The basic formula of this approach was derived by introducing a transformation of the operator using the arcsine function. Since this operator transformation causes transformation of time, we derived the relation between original and transformed time. The formula was adapted to assess the performance of the RT time-dependent Hartree-Fock (RT-TDHF) method and the time-dependent density functional theory. Compared to the commonly used fourth-order Runge-Kutta method, our new approach decreased computational time of the RT-TDHF calculation by about factor of four, showing the 3TRR formula to be an efficient time-evolution method for reducing computational cost. PMID- 26026432 TI - Linear-scaling implementation of the direct random-phase approximation. AB - We report the linear-scaling implementation of the direct random-phase approximation (dRPA) for closed-shell molecular systems. As a bonus, linear scaling algorithms are also presented for the second-order screened exchange extension of dRPA as well as for the second-order Moller-Plesset (MP2) method and its spin-scaled variants. Our approach is based on an incremental scheme which is an extension of our previous local correlation method [Rolik et al., J. Chem. Phys. 139, 094105 (2013)]. The approach extensively uses local natural orbitals to reduce the size of the molecular orbital basis of local correlation domains. In addition, we also demonstrate that using natural auxiliary functions [M. Kallay, J. Chem. Phys. 141, 244113 (2014)], the size of the auxiliary basis of the domains and thus that of the three-center Coulomb integral lists can be reduced by an order of magnitude, which results in significant savings in computation time. The new approach is validated by extensive test calculations for energies and energy differences. Our benchmark calculations also demonstrate that the new method enables dRPA calculations for molecules with more than 1000 atoms and 10,000 basis functions on a single processor. PMID- 26026433 TI - Lagrangian formulation of irreversible thermodynamics and the second law of thermodynamics. AB - We show that the equations which describe irreversible evolution of a system can be derived from a variational principle. We suggest a Lagrangian, which depends on the properties of the normal and the so-called "mirror-image" system. The Lagrangian is symmetric in time and therefore compatible with microscopic reversibility. The evolution equations in the normal and mirror-imaged systems are decoupled and describe therefore independent irreversible evolution of each of the systems. The second law of thermodynamics follows from a symmetry of the Lagrangian. Entropy increase in the normal system is balanced by the entropy decrease in the mirror-image system, such that there exists an "integral of evolution" which is a constant. The derivation relies on the property of local equilibrium, which states that the local relations between the thermodynamic quantities in non-equilibrium are the same as in equilibrium. PMID- 26026434 TI - The study of basis sets for the calculation of the structure and dynamics of the benzene-Kr complex. AB - An ab initio intermolecular potential energy surface (PES) has been constructed for the benzene-krypton (BKr) van der Waals (vdW) complex. The interaction energy has been calculated at the coupled cluster level of theory with single, double, and perturbatively included triple excitations using different basis sets. As a result, a few analytical PESs of the complex have been determined. They allowed a prediction of the complex structure and its vibrational vdW states. The vibrational energy level pattern exhibits a distinct polyad structure. Comparison of the equilibrium structure, the dipole moment, and vibrational levels of BKr with their experimental counterparts has allowed us to design an optimal basis set composed of a small Dunning's basis set for the benzene monomer, a larger effective core potential adapted basis set for Kr and additional midbond functions. Such a basis set yields vibrational energy levels that agree very well with the experimental ones as well as with those calculated from the available empirical PES derived from the microwave spectra of the BKr complex. The basis proposed can be applied to larger complexes including Kr because of a reasonable computational cost and accurate results. PMID- 26026436 TI - Relaxation time in disordered molecular systems. AB - Relaxation time is the typical time it takes for a closed physical system to attain thermal equilibrium. The equilibrium is brought about by the action of a thermal reservoir inducing changes in the system micro-states. The relaxation time is intuitively expected to increase with system disorder. We derive a simple analytical expression for this dependence in the context of electronic equilibration in an amorphous molecular system model. We find that the disorder dramatically enhances the relaxation time but does not affect its independence of the nature of the initial state. PMID- 26026435 TI - Adaptive deployment of model reductions for tau-leaping simulation. AB - Multiple time scales in cellular chemical reaction systems often render the tau leaping algorithm inefficient. Various model reductions have been proposed to accelerate tau-leaping simulations. However, these are often identified and deployed manually, requiring expert knowledge. This is time-consuming and prone to error. In previous work, we proposed a methodology for automatic identification and validation of model reduction opportunities for tau-leaping simulation. Here, we show how the model reductions can be automatically and adaptively deployed during the time course of a simulation. For multiscale systems, this can result in substantial speedups. PMID- 26026437 TI - Accompanying coordinate expansion and recurrence relation method using a transfer relation scheme for electron repulsion integrals with high angular momenta and long contractions. AB - An efficient algorithm for the rapid evaluation of electron repulsion integrals is proposed. The present method, denoted by accompanying coordinate expansion and transferred recurrence relation (ACE-TRR), is constructed using a transfer relation scheme based on the accompanying coordinate expansion and recurrence relation method. Furthermore, the ACE-TRR algorithm is extended for the general contraction basis sets. Numerical assessments clarify the efficiency of the ACE TRR method for the systems including heavy elements, whose orbitals have long contractions and high angular momenta, such as f- and g-orbitals. PMID- 26026438 TI - Representing the thermal state in time-dependent density functional theory. AB - Classical molecular dynamics (MD) provides a powerful and widely used approach to determining thermodynamic properties by integrating the classical equations of motion of a system of atoms. Time-Dependent Density Functional Theory (TDDFT) provides a powerful and increasingly useful approach to integrating the quantum equations of motion for a system of electrons. TDDFT efficiently captures the unitary evolution of a many-electron state by mapping the system into a fictitious non-interacting system. In analogy to MD, one could imagine obtaining the thermodynamic properties of an electronic system from a TDDFT simulation in which the electrons are excited from their ground state by a time-dependent potential and then allowed to evolve freely in time while statistical data are captured from periodic snapshots of the system. For a variety of systems (e.g., many metals), the electrons reach an effective state of internal equilibrium due to electron-electron interactions on a time scale that is short compared to electron-phonon equilibration. During the initial time-evolution of such systems following electronic excitation, electron-phonon interactions should be negligible, and therefore, TDDFT should successfully capture the internal thermalization of the electrons. However, it is unclear how TDDFT represents the resulting thermal state. In particular, the thermal state is usually represented in quantum statistical mechanics as a mixed state, while the occupations of the TDDFT wavefunctions are fixed by the initial state in TDDFT. We work to address this puzzle by (A) reformulating quantum statistical mechanics so that thermodynamic expectations can be obtained as an unweighted average over a set of many-body pure states and (B) constructing a family of non-interacting (single determinant) TDDFT states that approximate the required many-body states for the canonical ensemble. PMID- 26026439 TI - Equivalence between a generalized dendritic network and a set of one-dimensional networks as a ground of linear dynamics. AB - It has been shown by some existing studies that some linear dynamical systems defined on a dendritic network are equivalent to those defined on a set of one dimensional networks in special cases and this transformation to the simple picture, which we call linear chain (LC) decomposition, has a significant advantage in understanding properties of dendrimers. In this paper, we expand the class of LC decomposable system with some generalizations. In addition, we propose two general sufficient conditions for LC decomposability with a procedure to systematically realize the LC decomposition. Some examples of LC decomposable linear dynamical systems are also presented with their graphs. The generalization of the LC decomposition is implemented in the following three aspects: (i) the type of linear operators; (ii) the shape of dendritic networks on which linear operators are defined; and (iii) the type of symmetry operations representing the symmetry of the systems. In the generalization (iii), symmetry groups that represent the symmetry of dendritic systems are defined. The LC decomposition is realized by changing the basis of a linear operator defined on a dendritic network into bases of irreducible representations of the symmetry group. The achievement of this paper makes it easier to utilize the LC decomposition in various cases. This may lead to a further understanding of the relation between structure and functions of dendrimers in future studies. PMID- 26026441 TI - Ab initio kinetics and thermal decomposition mechanism of mononitrobiuret and 1,5 dinitrobiuret. AB - Mononitrobiuret (MNB) and 1,5-dinitrobiuret (DNB) are tetrazole-free, nitrogen rich, energetic compounds. For the first time, a comprehensive ab initio kinetics study on the thermal decomposition mechanisms of MNB and DNB is reported here. In particular, the intramolecular interactions of amine H-atom with electronegative nitro O-atom and carbonyl O-atom have been analyzed for biuret, MNB, and DNB at the M06-2X/aug-cc-pVTZ level of theory. The results show that the MNB and DNB molecules are stabilized through six-member-ring moieties via intramolecular H bonding with interatomic distances between 1.8 and 2.0 A, due to electrostatic as well as polarization and dispersion interactions. Furthermore, it was found that the stable molecules in the solid state have the smallest dipole moment amongst all the conformers in the nitrobiuret series of compounds, thus revealing a simple way for evaluating reactivity of fuel conformers. The potential energy surface for thermal decomposition of MNB was characterized by spin restricted coupled cluster theory at the RCCSD(T)/cc-pVinfinity Z//M06-2X/aug-cc-pVTZ level. It was found that the thermal decomposition of MNB is initiated by the elimination of HNCO and HNN(O)OH intermediates. Intramolecular transfer of a H atom, respectively, from the terminal NH2 group to the adjacent carbonyl O-atom via a six-member-ring transition state eliminates HNCO with an energy barrier of 35 kcal/mol and from the central NH group to the adjacent nitro O-atom eliminates HNN(O)OH with an energy barrier of 34 kcal/mol. Elimination of HNN(O)OH is also the primary process involved in the thermal decomposition of DNB, which processes C2v symmetry. The rate coefficients for the primary decomposition channels for MNB and DNB were quantified as functions of temperature and pressure. In addition, the thermal decomposition of HNN(O)OH was analyzed via Rice-Ramsperger Kassel-Marcus/multi-well master equation simulations, the results of which reveal the formation of (NO2 + H2O) to be the major decomposition path. Furthermore, we provide fundamental interpretations for the experimental results of Klapotke et al. [Combust. Flame 139, 358-366 (2004)] regarding the thermal stability of MNB and DNB, and their decomposition products. Notably, a fundamental understanding of fuel stability, decomposition mechanism, and key reactions leading to ignition is essential in the design and manipulation of molecular systems for the development of new energetic materials for advanced propulsion applications. PMID- 26026440 TI - Dynamics-based selective 2D (1)H/(1)H chemical shift correlation spectroscopy under ultrafast MAS conditions. AB - Dynamics plays important roles in determining the physical, chemical, and functional properties of a variety of chemical and biological materials. However, a material (such as a polymer) generally has mobile and rigid regions in order to have high strength and toughness at the same time. Therefore, it is difficult to measure the role of mobile phase without being affected by the rigid components. Herein, we propose a highly sensitive solid-state NMR approach that utilizes a dipolar-coupling based filter (composed of 12 equally spaced 90 degrees RF pulses) to selectively measure the correlation of (1)H chemical shifts from the mobile regions of a material. It is interesting to find that the rotor synchronized dipolar filter strength decreases with increasing inter-pulse delay between the 90 degrees pulses, whereas the dipolar filter strength increases with increasing inter-pulse delay under static conditions. In this study, we also demonstrate the unique advantages of proton-detection under ultrafast magic-angle spinning conditions to enhance the spectral resolution and sensitivity for studies on small molecules as well as multi-phase polymers. Our results further demonstrate the use of finite-pulse radio-frequency driven recoupling pulse sequence to efficiently recouple weak proton-proton dipolar couplings in the dynamic regions of a molecule and to facilitate the fast acquisition of (1)H/(1)H correlation spectrum compared to the traditional 2D NOESY (Nuclear Overhauser effect spectroscopy) experiment. We believe that the proposed approach is beneficial to study mobile components in multi-phase systems, such as block copolymers, polymer blends, nanocomposites, heterogeneous amyloid mixture of oligomers and fibers, and other materials. PMID- 26026442 TI - A permutationally invariant full-dimensional ab initio potential energy surface for the abstraction and exchange channels of the H + CH4 system. AB - We report a permutationally invariant global potential energy surface (PES) for the H + CH4 system based on ~63,000 data points calculated at a high ab initio level (UCCSD(T)-F12a/AVTZ) using the recently proposed permutation invariant polynomial-neural network method. The small fitting error (5.1 meV) indicates a faithful representation of the ab initio points over a large configuration space. The rate coefficients calculated on the PES using tunneling corrected transition state theory and quasi-classical trajectory are found to agree well with the available experimental and previous quantum dynamical results. The calculated total reaction probabilities (Jtot = 0) including the abstraction and exchange channels using the new potential by a reduced dimensional quantum dynamic method are essentially the same as those on the Xu-Chen-Zhang PES [Chin. J. Chem. Phys. 27, 373 (2014)]. PMID- 26026444 TI - The benzene radical anion: A computationally demanding prototype for aromatic anions. AB - The benzene radical anion is studied with ab initio coupled-cluster theory in large basis sets. Unlike the usual assumption, we find that, at the level of theory investigated, the minimum energy geometry is non-planar with tetrahedral distortion at two opposite carbon atoms. The anion is well known for its instability to auto-ionization which poses computational challenges to determine its properties. Despite the importance of the benzene radical anion, the considerable attention it has received in the literature so far has failed to address the details of its structure and shape-resonance character at a high level of theory. Here, we examine the dynamic Jahn-Teller effect and its impact on the anion potential energy surface. We find that a minimum energy geometry of C2 symmetry is located below one D2h stationary point on a C2h pseudo-rotation surface. The applicability of standard wave function methods to an unbound anion is assessed with the stabilization method. The isotropic hyperfine splitting constants (Aiso) are computed and compared to data obtained from experimental electron spin resonance experiments. Satisfactory agreement with experiment is obtained with coupled-cluster theory and large basis sets such as cc-pCVQZ. PMID- 26026443 TI - Quantum scattering calculations for ro-vibrational de-excitation of CO by hydrogen atoms. AB - We present quantum-mechanical scattering calculations for ro-vibrational relaxation of carbon monoxide (CO) in collision with hydrogen atoms. Collisional cross sections of CO ro-vibrational transitions from v = 1, j = 0 - 30 to v' = 0, j' are calculated using the close coupling method for collision energies between 0.1 and 15,000 cm(-1) based on the three-dimensional potential energy surface of Song et al. [J. Phys. Chem. A 117, 7571 (2013)]. Cross sections of transitions from v = 1, j >= 3 to v' = 0, j' are reported for the first time at this level of theory. Also calculations by the more approximate coupled states and infinite order sudden (IOS) methods are performed in order to test the applicability of these methods to H-CO ro-vibrational inelastic scattering. Vibrational de excitation rate coefficients of CO (v = 1) are presented for the temperature range from 100 K to 3000 K and are compared with the available experimental and theoretical data. All of these results and additional rate coefficients reported in a forthcoming paper are important for including the effects of H-CO collisions in astrophysical models. PMID- 26026445 TI - B27(-): Appearance of the smallest planar boron cluster containing a hexagonal vacancy. AB - Photoelectron spectroscopy and ab initio calculations have been carried out to probe the structures and chemical bonding of the B27 (-) cluster. Comparison between the experimental spectrum and the theoretical results reveals a two dimensional (2D) global minimum with a triangular lattice containing a tetragonal defect (I) and two low-lying 2D isomers (II and III), each with a hexagonal vacancy. All three 2D isomers have 16 peripheral boron atoms and 11 inner boron atoms. Isomer I is shown to be mainly responsible for the observed photoelectron spectrum with isomers II and III as minor contributors. Chemical bonding analyses of these three isomers show that they all feature 16 localized peripheral B-B sigma-bonds. Additionally, isomer I possesses 16 delocalized sigma bonds and nine delocalized pi bonds, while isomers II and III each contain 17 delocalized sigma bonds and eight delocalized pi bonds. It is found that the hexagonal vacancy is associated generally with an increase of delocalized sigma bonds at the expense of delocalized pi bonds in 2D boron clusters. The hexagonal vacancy, characteristic of borophenes, is found to be a general structural feature for mid sized boron clusters. The current study shows that B27 (-) is the first boron cluster, where a hexagonal vacancy appears among the low-lying isomers accessible experimentally. PMID- 26026446 TI - Heavy Rydberg behaviour in high vibrational levels of some ion-pair states of the halogens and inter-halogens. AB - We report the identification of heavy Rydberg resonances in the ion-pair spectra of I2, Cl2, ICl, and IBr. Extensive vibrational progressions are analysed in terms of the energy dependence of the quantum defect delta(Eb) rather than as Dunham expansions. This is shown to define the heavy Rydberg region, providing a more revealing fit to the data with fewer coefficients and leads just as easily to numbering data sets separated by gaps in the observed vibrational progressions. Interaction of heavy Rydberg states with electronic Rydberg states at avoided crossings on the inner wall of the ion-pair potential is shown to produce distinctive changes in the energy dependence of delta(Eb), with weak and strong interactions readily distinguished. Heavy Rydberg behaviour is found to extend well below near-dissociation states, down to vibrational levels ~18,000 20,000 cm(-1) below dissociation. The rapid semi-classical calculation of delta(Eb) for heavy Rydberg states is emphasised and shows their absolute magnitude to be essentially the volume of phase space excluded from the vibrational motion by avoiding core-core penetration of the ions. PMID- 26026447 TI - Accurate ab initio potential for the krypton dimer and transport properties of the low-density krypton gas. AB - A new highly accurate potential energy curve for the krypton dimer was constructed using coupled-cluster calculations up to the singles, doubles, triples, and perturbative quadruples level, including corrections for core-core and core-valence correlation and for relativistic effects. The ab initio data points were fitted to an analytic potential which was used to compute the most important transport properties of the krypton gas. The viscosity, thermal conductivity, self-diffusion coefficient, and thermal diffusion factor were calculated by the kinetic theory at low density and temperatures from 116 to 5000 K. The comparisons with literature experimental data as well as with values from other pair potentials indicate that our new potential is superior to all previous ones. The transport property values computed in this work are recommended as standard values over the complete temperature range. PMID- 26026448 TI - Diffusion anisotropy of poor metal solute atoms in hcp-Ti. AB - Atom migration mechanisms influence a wide range of phenomena: solidification kinetics, phase equilibria, oxidation kinetics, precipitation of phases, and high temperature deformation. In particular, solute diffusion mechanisms in alpha-Ti alloys can help explain their excellent high-temperature behaviour. The purpose of this work is to study self- and solute diffusion in hexagonal close-packed (hcp)-Ti, and its anisotropy, from first-principles using the 8-frequency model. The calculated diffusion coefficients show that diffusion energy barriers depend more on bonding characteristics of the solute rather than the size misfit with the host, while the extreme diffusion anisotropy of some solute elements in hcp Ti is a result of the bond angle distortion. PMID- 26026449 TI - Microsolvation of NO(+) in Ar(n) clusters: A theoretical treatment. AB - At present, we investigate the structure and the stability of NO(+)Arn (n <= 54) ionic clusters using analytical potential functions. The energy of these systems is described using additive potentials with VNO(+)Ar and VAr-Ar representing the pair potential interactions. To find the geometry of the lowest energy isomers of the NO(+)Arn clusters, we use the so-called basin hopping method of Wales et al. which combines a Monte-Carlo exploration and deformation method. The reliability of our model was checked by deriving the structures of the NO(+)Arn systems (n = 1, 2, 3 and 4) using ab initio Moller-Plesset perturbation theory up to second order (MP2) in connection with the aug-cc-pVTZ basis set. Magic numbers for sizes n = 8, 12, 18, 22, and 25 are found and they show a high relative stability. Our results reveal that a transition in the NO(+) ion coordination from 8 (square antiprism) to 12 (icosahedrons) occurs for n = 11. Examination of the stable structures of the ionic clusters demonstrates that the first solvation shell closes at n = 12. Furthermore, we found that the NO(+)Arn (n = 12-54) clusters are structurally very similar to the homogenous rare gas clusters with a polyicosahedral packing pattern. The distribution exhibits an additional magic number at n = 54, consistent with the completion of a second solvation sphere around NO(+). The effects of microsolvation of NO(+) cation in Ar clusters are also discussed. Generally, our results agree with the available experimental and theoretical findings on NO(+)Arn clusters and more generally on diatomics solvated in Ar clusters. PMID- 26026450 TI - Rotationally inelastic scattering of OH by molecular hydrogen: Theory and experiment. AB - We present an experimental and theoretical investigation of rotationally inelastic transitions of OH, prepared in the X(2)Pi, v = 0, j = 3/2 F1f level, in collisions with molecular hydrogen (H2 and D2). In a crossed beam experiment, the OH radicals were state selected and velocity tuned over the collision energy range 75-155 cm(-1) using a Stark decelerator. Relative parity-resolved state-to state integral cross sections were determined for collisions with normal and para converted H2. These cross sections, as well as previous OH-H2 measurements at 595 cm(-1) collision energy by Schreel and ter Meulen [J. Chem. Phys. 105, 4522 (1996)], and OH-D2 measurements for collision energies 100-500 cm(-1) by Kirste et al. [Phys. Rev. A 82, 042717 (2010)], were compared with the results of quantum scattering calculations using recently determined ab initio potential energy surfaces [Ma et al., J. Chem. Phys. 141, 174309 (2014)]. Good agreement between the experimental and computed relative cross sections was found, although some structure seen in the OH(j = 3/2 F1f -> j = 5/2 F1e) + H2(j = 0) cross section is not understood. PMID- 26026451 TI - Real-space representation of electron correlation in pi-conjugated systems. AB - pi-electron conjugation and aromaticity are commonly associated with delocalization and especially high mobility of the pi electrons. We investigate if also the electron correlation (pair density) exhibits signatures of the special electronic structure of conjugated systems. To that end the shape and extent of the pair density and derived quantities (exchange-correlation hole, Coulomb hole, and conditional density) are investigated for the prototype systems ethylene, hexatriene, and benzene. The answer is that the effects of pi electron conjugation are hardly discernible in the real space representations of the electron correlation. We find the xc hole to be as localized (confined to atomic or diatomic regions) in conjugated systems as in small molecules. This result is relevant for density functional theory (DFT). The potential of the electron exchange-correlation hole is the largest part of vxc, the exchange-correlation Kohn-Sham potential. So the extent of the hole directly affects the orbital energies of both occupied and unoccupied Kohn-Sham orbitals and therefore has direct relevance for the excitation spectrum as calculated with time-dependent DFT calculations. The potential of the localized xc hole is comparatively more attractive than the actual hole left behind by an electron excited from a delocalized molecular orbital of a conjugated system. PMID- 26026452 TI - Heterogeneity in (2-butoxyethanol + water) mixtures: Hydrophobicity-induced aggregation or criticality-driven concentration fluctuations? AB - Micro-heterogeneity in aqueous solutions of 2-butoxyethanol (BE), a system with closed loop miscibility gap, has been explored via absorption and time-resolved fluorescence measurements of a dissolved dipolar solute, coumarin 153 (C153), in the water-rich region at various BE mole fractions (0 <= XBE <= 0.25) in the temperature range, 278 <= T/K <= 320. Evidences for both alcohol-induced H-bond strengthening and subsequent structural transition of H-bond network have been observed. Analyses of steady state and time-resolved spectroscopic data for these aqueous mixtures and comparisons with the results for aqueous solutions of ethanol and tertiary butanol indicate that alcohol aggregation in BE/water mixtures is driven by hydrophobic interaction with no or insignificant role for criticality-driven concentration fluctuations preceding phase separation. Excitation energy dependence of fluorescence emission of C153 confirms formation of aggregated structures at very low BE mole fractions. No asymptotic critical power law dependence for relaxation rates of the type, k ? (|T - Tc|/Tc)(gamma), with gamma denoting universal critical constant, has been observed for both solute's rotational relaxation and population relaxation rates in these mixtures upon either approaching to critical concentration or critical temperature. Estimated activation energies for rotational relaxation rate of C153 and solution viscosity have been found to follow each other with no abrupt changes in either of them at any mixture composition. In addition, measured C153 rotation times at various compositions and temperatures reflect near-hydrodynamic viscosity coupling through the dependence,? (eta/T)(p), with p = 0.8-1.0, suggesting solute's orientational relaxation dynamics being, on an average, temporally homogeneous. PMID- 26026453 TI - Structural and elastic anisotropy of crystals at high pressures and temperatures from quantum mechanical methods: The case of Mg2SiO4 forsterite. AB - We report accurate ab initio theoretical predictions of the elastic, seismic, and structural anisotropy of the orthorhombic Mg2SiO4 forsterite crystal at high pressures (up to 20 GPa) and temperatures (up to its melting point, 2163 K), which constitute earth's upper mantle conditions. Single-crystal elastic stiffness constants are evaluated up to 20 GPa and their first- and second-order pressure derivatives reported. Christoffel's equation is solved at several pressures: directional seismic wave velocities and related properties (azimuthal and polarization seismic anisotropies) discussed. Thermal structural and average elastic properties, as computed within the quasi-harmonic approximation of the lattice potential, are predicted at high pressures and temperatures: directional thermal expansion coefficients, first- and second-order pressure derivatives of the isothermal bulk modulus, and P-V-T equation-of-state. The effect on computed properties of five different functionals, belonging to three different classes of approximations, of the density functional theory is explicitly investigated. PMID- 26026454 TI - Dynamics of [C3H5N2]6[Bi4Br18] by means of (1)H NMR relaxometry and quadrupole relaxation enhancement. AB - (1)H spin-lattice field cycling relaxation dispersion experiments in the intermediate phase II of the solid [C3H5N2]6[Bi4Br18] are presented. Two motional processes have been identified from the (1)H spin-lattice relaxation dispersion profiles and quantitatively described. It has been concluded that these processes are associated with anisotropic reorientations of the imidazolium ring, characterized by correlation times of the order of 10(-8) s-10(-9) s and of about 10(-5) s. Moreover, quadrupole relaxation enhancement (QRE) effects originating from slowly fluctuating (1)H-(14)N dipolar interactions have been observed. From the positions of the relaxation maxima, the quadrupole coupling parameters for the (14)N nuclei in [C3H5N2]6[Bi4Br18] have been determined. The (1)H-(14)N relaxation contribution associated with the slow dynamics has been described in terms of a theory of QRE [Kruk et al., Solid State Nucl. Magn. Reson. 40, 114 (2011)] based on the stochastic Liouville equation. The shape of the QRE maxima (often referred to as "quadrupole peaks") has been consistently reproduced for the correlation time describing the slow dynamics and the determined quadrupole coupling parameters. PMID- 26026455 TI - Adsorption and self-assembled structures of sexithiophene on the Si(111)-?3*?3-Ag surface. AB - The adsorption and self-assembled structures of alpha-sexithiophene (alpha-6T) have been investigated on a Si(111)-Ag surface using scanning tunneling microscopy (STM), low-energy electron diffraction, and density functional theory calculations. The adsorbed alpha-6T molecules are arranged into unidirectional molecular rows with a side-by-side orientation. The molecular rows reveal three kinds of appearances in the filled-state STM images, which reflect the distinct adsorption sites. From tunneling spectroscopy, we find that the filled-state STM images of alpha-6T should be influenced by the surface states of Si(111)-Ag. At one monolayer coverage, sequentially ordering of the triple molecular rows results in the close-packed arrangement of the alpha-6T overlayer. PMID- 26026456 TI - Mono- and polynucleation, atomistic growth, and crystal phase of III-V nanowires under varying group V flow. AB - We present a refined model for the vapor-liquid-solid growth and crystal structure of Au-catalyzed III-V nanowires, which revisits several assumptions used so far and is capable of describing the transition from mononuclear to polynuclear regime and ultimately to regular atomistic growth. We construct the crystal phase diagrams and calculate the wurtzite percentages, elongation rates, critical sizes, and polynucleation thresholds of Au-catalyzed GaAs nanowires depending on the As flow. We find a non-monotonic dependence of the crystal phase on the group V flow, with the zincblende structure being preferred at low and high group V flows and the wurtzite structure forming at intermediate group V flows. This correlates with most of the available experimental data. Finally, we discuss the atomistic growth picture which yields zincblende crystal structure and should be very advantageous for fabrication of ternary III-V nanowires with well-controlled composition and heterointerfaces. PMID- 26026457 TI - Photoinduced reduction of surface states in Fe:ZnO. AB - We report on the electronic structure of nano-crystalline Fe:ZnO, which has recently been found to be an efficient photocatalyst. Using resonant photoemission spectroscopy, we determine the binding energy of Fe 3d states corresponding to different valencies and coordination of the Fe atoms. The photo activity of ZnO reduces Fe from 3+ to 2+ in the surface region of the nano crystalline material due to the formation of oxygen vacancies. Electronic states corresponding to low-spin Fe(2+) are observed and attributed to crystal field modification at the surface. These states are potentially important for the photocatalytic sensitivity to visible light due to their location deep in the ZnO bandgap. X-ray absorption and x-ray photoemission spectroscopy suggest that Fe is only homogeneously distributed for concentrations up to 3%. Increased concentrations does not result in a higher concentration of Fe ions in the surface region. This is limiting the photocatalytic functionality of ZnO, where the most efficient Fe doping concentration has been shown to be 1%-4%. PMID- 26026458 TI - Copper dimer interactions on a thermomechanical superfluid (4)He fountain. AB - Laser induced fluorescence imaging and frequency domain excitation spectroscopy of the copper dimer (B(1)Sigmag (+) <-X(1)Sigmau (+)) in thermomechanical helium fountain at 1.7 K are demonstrated. The dimers penetrate into the fountain provided that their average propagation velocity is ca. 15 m/s. This energy threshold is interpreted in terms of an imperfect fountain liquid-gas interface, which acts as a trap for low velocity dimers. Orsay-Trento density functional theory calculations for superfluid (4)He are used to characterize the dynamics of the dimer solvation process into the fountain. The dimers first accelerate towards the fountain surface and once the surface layer is crossed, they penetrate into the liquid and further slow down to Landau critical velocity by creating a vortex ring. Theoretical lineshape calculations support the assignment of the experimentally observed bands to Cu2 solvated in the bulk liquid. The vibronic progressions are decomposed of a zero-phonon line and two types of phonon bands, which correlate with solvent cavity interface compression (t < 200 fs) and expansion (200 < t < 500 fs) driven by the electronic excitation. The presented experimental method allows to perform molecular spectroscopy in bulk superfluid helium where the temperature and pressure can be varied. PMID- 26026459 TI - Mechanical unfolding pathway of a model beta-peptide foldamer. AB - Foldamers constructed from oligomers of beta-peptides form stable secondary helix structures already for small chain lengths, which makes them ideal candidates for the investigation of the (un)folding of polypeptides. Here, the results of molecular simulations of the mechanical unfolding of a beta-heptapeptide in methanol solvent revealing the detailed unfolding pathway are reported. The unfolding process is shown to proceed via a stable intermediate even for such a small system. This result is arrived at performing non-equilibrium force ramp simulations employing different pulling velocities and also using standard calculations of the potential of mean force, i.e., the free energy as a function of the helix elongation. It is thus demonstrated that even with the rather large pulling velocities employed in the force ramp simulations relevant information about the equilibrium kinetics can be obtained. The smallness of the system allows a detailed analysis of the unfolding pathway, which is characterized by an opening of the terminal loops followed by the unfolding of the center. This sequence is in accord with the configurational preferences of the system that also are responsible for the stability of the 314-helix. From an analysis of the distributions of rupture forces and the force spectra, the kinetic rates for both transitions were determined and common models were used to extract geometric quantities describing the free energy landscape of the system. PMID- 26026460 TI - Complexation behavior of oppositely charged polyelectrolytes: Effect of charge distribution. AB - Complexation behavior of oppositely charged polyelectrolytes in a solution is investigated using a combination of computer simulations and experiments, focusing on the influence of polyelectrolyte charge distributions along the chains on the structure of the polyelectrolyte complexes. The simulations are performed using Monte Carlo with the replica-exchange algorithm for three model systems where each system is composed of a mixture of two types of oppositely charged model polyelectrolyte chains (EGEG)5/(KGKG)5, (EEGG)5/(KKGG)5, and (EEGG)5/(KGKG)5, in a solution including explicit solvent molecules. Among the three model systems, only the charge distributions along the chains are not identical. Thermodynamic quantities are calculated as a function of temperature (or ionic strength), and the microscopic structures of complexes are examined. It is found that the three systems have different transition temperatures, and form complexes with different sizes, structures, and densities at a given temperature. Complex microscopic structures with an alternating arrangement of one monolayer of E/K monomers and one monolayer of G monomers, with one bilayer of E and K monomers and one bilayer of G monomers, and with a mixture of monolayer and bilayer of E/K monomers in a box shape and a trilayer of G monomers inside the box are obtained for the three mixture systems, respectively. The experiments are carried out for three systems where each is composed of a mixture of two types of oppositely charged peptide chains. Each peptide chain is composed of Lysine (K) and glycine (G) or glutamate (E) and G, in solution, and the chain length and amino acid sequences, and hence the charge distribution, are precisely controlled, and all of them are identical with those for the corresponding model chain. The complexation behavior and complex structures are characterized through laser light scattering and atomic force microscopy measurements. The order of the apparent weight-averaged molar mass and the order of density of complexes observed from the three experimental systems are qualitatively in agreement with those predicted from the simulations. PMID- 26026461 TI - Multiblock copolymers prepared by patterned modification: Analytical theory and computer simulations. AB - We describe a special type of multiblock copolymers which are synthesized by a hypothetic procedure of the modification of monomer units in a polymer melt according to a certain geometrical criterion. In particular, we explore the case of lamellar-like structures: the sequence statistics of the resulting multiblock copolymers is described and their ability to self-assemble is studied. It is found that the block-size distribution P(k) for such random copolymers contains a large fraction of short blocks with the asymptotic dependence ~k(-3/2), where k is the block size. A characteristic feature of such multiblock copolymers is their extremely high block-size polydispersity with the polydispersity index being proportional to the space period of the modification. The morphological behavior of such copolymers is simulated by means of dissipative particle dynamics. A stable self-assembled lamellar structure is observed, but the domain size appears to be sufficiently larger than the initial pattern period. PMID- 26026462 TI - Effects of rigid or adaptive confinement on colloidal self-assembly. Fixed vs. fluctuating number of confined particles. AB - The effects of confinement on colloidal self-assembly in the case of fixed number of confined particles are studied in the one dimensional lattice model solved exactly in the grand canonical ensemble (GCE) in Pekalski et al. [J. Chem. Phys. 142, 014903 (2015)]. The model considers a pair interaction defined by a short range attraction plus a longer-range repulsion. We consider thermodynamic states corresponding to self-assembly into clusters. Both fixed and adaptive boundaries are studied. For fixed boundaries, there are particular states in which, for equal average densities, the number of clusters in the GCE is larger than in the canonical ensemble. The dependence of pressure on density has a different form when the system size changes with fixed number of particles and when the number of particles changes with fixed size of the system. In the former case, the pressure has a nonmonotonic dependence on the system size. The anomalous increase of pressure for expanding system is accompanied by formation of a larger number of smaller clusters. In the case of elastic confining surfaces, we observe a bistability, i.e., two significantly different system sizes occur with almost the same probability. The mechanism of the bistability in the closed system is different to that of the case of permeable walls, where the two equilibrium system sizes correspond to a different number of particles. PMID- 26026463 TI - Simple theory of transitions between smectic, nematic, and isotropic phases. AB - The transitions between smectic, nematic, and isotropic phases are investigated in the framework of a unified molecular-statistical approach. The new translational order parameter is different from the one introduced in K. Kobayashi [Phys. Lett. A 31, 125 (1970)] and W. L. McMillan [Phys. Rev. A 4, 1238 (1971)]. The variance of the square sine of intermolecular shift angle along the director is introduced to take self-consistently into account the most probable location of the molecules with respect to each other, which is unique for every liquid crystal (LC) material and is mainly responsible for the order parameters and phase sequences. The mean molecular field was treated in terms of only two parameters specific to any intermolecular potential of elongated molecules: (1) its global minimum position with respect to the shift of two interacting molecules along the director and (2) its inhomogeneity/anisotropy ratio. A simple molecular model is also introduced, where the global minimum position is determined by the linking groups elongation Delta/d, while the inhomogeneity/anisotropy ratio Gbeta/Ggamma is determined by the ratio of electrostatic and dispersion contributions. All possible phase sequences, including abrupt/continuous transformation between the smectic and nematic states and the direct smectic-isotropic phase transition, are predicted. The theoretical prediction is in a good agreement with experimental data for some simple materials correlating with our molecular model, but it is expected to be valid for any LC material. PMID- 26026464 TI - Chitotriosidase Expression during Monocyte-Derived Dendritic Cells Differentiation and Maturation. AB - The chitotriosidase (CHIT-1) is a glycosyl hydrolase (GH), which has been found highly expressed in activated macrophages and in different monocyte-derived cell lines such as Kupffer cells and osteoclasts, as well is differently produced in diverse stages of macrophage polarization (M1 and M2). Recent finding suggests that CHIT-1 plays a crucial role in innate and acquired immunity. Dendritic cells (DCs) are a complex group of cells that play a critical role in immune response. The aim of this study was to investigate the presence of CHIT-1 during the differentiation and maturation of DCs. Magnetically-isolated peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs). Our results showed, for the first time, that CHIT-1 is expressed during the process of differentiation and maturation of DCs in a time-dependent manner. We found that CHIT1 is evenly distributed in cytoplasm of both the iDCs and mDCs. Additionally, a significantly increased expression of CHIT1 mRNA and protein was observed in mature DCs. These results suggest that CHIT-1 play an important role in the DCs immunoresponse. PMID- 26026465 TI - Utero-vaginal suspension using bilateral vaginal anterior sacrospinous fixation with mesh: intermediate results of a cohort study. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse is a major burden for the public health system, affecting up to 30 % of all women. One mesh kit has been introduced for pelvic organ prolapse surgery that can be inserted via a single anterior incision with the mesh arms driven through the sacrospinous ligament in a tension-free manner. The aim of this study was to describe the medium-term results of this vaginal mesh kit procedure for the combined treatment of the anterior vaginal wall and vault prolapse. METHODS: This is a longitudinal case series of patients undergoing an anterior mesh operation between 2009 and 2013. All patients presenting with symptomatic stage II prolapse or higher were included when a minimum follow-up of 12 months was achieved. A structured interview and clinical examination were performed pre- and postoperatively. RESULTS: One hundred and eighteen consecutive patients were operated with the Uphold(r) system during the study period. Three patients did not complete the 12 month follow-up and were excluded from the analysis, leaving 115 patients. Anatomical success at a mean follow-up of 23 months was 93 %, with a patient satisfaction rate of 95 %. Four patients (8 %) experienced de novo dyspareunia related to the mesh. The reoperation rate for mesh-related complications was 3.4 %; no patients were re-operated for POP recurrence. CONCLUSIONS: The subjective and objective cure rates were high and the mesh-related re-operation rate was 3 % in the medium term, suggesting that this surgical technique may be an option for women requiring anterior and apical prolapse repair. PMID- 26026466 TI - Erosion of prolene sutures into the bladder after abdominal sacrocolpopexy. PMID- 26026467 TI - Adjuvant taxane-based chemotherapy for early stage breast cancer: a real-world comparison of chemotherapy regimens in Ontario. AB - The purpose of this study was to compare survival and risk of adverse events in women with early stage breast cancer (BC) treated with (1) doxorubicin (A), cyclophosphamide (C) + paclitaxel (P), (2) fluorouracil (F), epirubicin (E), cyclophosphamide (C) + docetaxel (D), or (3) dose-dense AC-P. Retrospective cohort study including 8462 women aged >=18 years, with resected stage I-III BC, diagnosed between 2003 and 2009 in Ontario, identified through linkage of administrative databases. Primary outcome is overall survival (OS). Secondary outcomes are emergency room (ER) visits/hospitalizations, heart failure (HF), and leukemia. 4710 women were treated with FEC-D, 2065 with AC-P, and 1687 with dd AC P. Adjusted 5-year OS was 92.1, 87.7, and 90.3 %, for each regimen, respectively (p = 0.0006). There was no difference in OS for FEC-D and dd AC-P in the propensity score-matched analyses (HR 1.24, 95 % CI 0.99-1.55). Five-year risk of HF was also similar (HR 1.09; 0.66-1.791.4 % for dd AC-P and 1.3 % for FEC-D and, p = 0.72). Treatment with FEC-D was significantly associated with ER visits and hospital admissions (p < 0.0001). The risks of leukemia were low and similar among the 3 groups (AC-P: 0.34 %, FEC-D: 0.08 %, dd AC-P: 0.12 %; p = 0.09). Although the efficacy of the three regimens was similar to that observed in randomized trials, we report higher toxicity with the use of these regimens in clinical practice. This was especially concerning for the docetaxel-containing regimen. PMID- 26026468 TI - Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer. AB - Progression or recurrence due to resistance to aromatase inhibitors (AIs) is a significant clinical problem for a considerable number of patients with breast cancer. Programmed cell death 4 (PDCD4), a tumor suppressor protein, is targeted for degradation during tumor progression. In the current study, we aimed to examine PDCD4 expression and regulation in AI-resistant breast cancer cells, and its association with survival in patients with estrogen receptor (ER)-positive breast cancer. We determined PDCD4 expression levels in AI-resistant breast cancer cell lines and ER-positive breast cancer tumors, investigated the regulation of PDCD4 in AI-resistant breast cancer cell lines, and carried out a Kaplan-Meier survival analysis in two independent cohorts that included a total of 420 patients with ER-positive breast cancer. We found that PDCD4 expression was down-regulated in AI-resistant breast cancer cells, and this down-regulation was inversely correlated with activation of HER2 signaling. Moreover, lower expression of PDCD4 was significantly associated with HER2 positive status in ER positive breast tumors. Down-regulation of PDCD4 was mediated through up regulation of HER2 via the mitogen-activated protein kinase (MAPK), protein kinase B (PKB/AKT), and miR-21 in AI-resistant breast cancer cells. MiR-21 inhibitor and the ER down-regulator fulvestrant induced PDCD4 expression and decreased cell proliferation in AI-resistant breast cancer cells. Furthermore, forced overexpression of PDCD4 resensitized AI-resistant cells to AI or hormone deprivation. Finally, we identified that down-regulation of PDCD4 was associated with a lower rate of disease-free survival in patients with ER-positive breast cancer and high histologic grade of breast tumors. In summary, our study shows that expression of PDCD4 is down-regulated by HER2 signaling in AI-resistant breast cancer. Down-regulation of PDCD4 is associated with AI resistance and a poor prognosis in patients with ER-positive breast cancer. PMID- 26026470 TI - Substrate specificities of two tau class glutathione transferases inducible by 2,4,6-trinitrotoluene in poplar. AB - BACKGROUND: The genome of poplar (Populus trichocarpa) encodes 81 glutathione transferases (GSTs) annotated in eight distinct classes. The tau class is considered the most versatile in the biotransformation of xenobiotics and is composed of 58 GSTs. Two of the enzymes, GSTU16 and GSTU45, have particular interest since their expression is induced by exposure of poplar tissues to 2,4,6 trinitrotoluene (TNT) and could potentially be involved in the metabolism of this toxic environmental contaminant. RESULTS: DNA encoding these GSTs was synthesized and the proteins were heterologously expressed in Escherichia coli and the purified enzymes were characterized. MAJOR CONCLUSIONS: GSTU16 assayed with a number of conventional GST substrates showed the highest specific activity (60MUmolmin-1 mg-1) with phenethyl isothiocyanate, 150-fold higher than that with CDNB. By contrast, GSTU45 showed CDNB as the most active substrate (3.3MUmolmin-1 mg-1) whereas all of the 16 alternative substrates tested yielded significantly lower activities. Homology modeling suggested that the aromatic residues Phe10 and Tyr107 in the active site of GSTU16 are promoting the high activity with PEITC and other substrates with aromatic side-chains. Nonetheless, TNT was a poor substrate for GSTU16 as well as for GSTU45 with a specific activity of 0.05nmolmin-1 mg-1 for both enzymes. GENERAL SIGNIFICANCE: GSTU16 and GSTU45 do not play a major role in the degradation of TNT in poplar. PMID- 26026469 TI - Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration. AB - BACKGROUND: alphaA- and alphaB crystallins are principal members of the small heat shock protein family and elicit both a cell protective function and a chaperone function. alpha-Crystallins have been found to be prominent proteins in normal and pathological retina emphasizing the importance for in-depth understanding of their function and significance. SCOPE OF REVIEW: Retinal pigment epithelial cells (RPE) play a vital role in the pathogenesis of age related macular degeneration (AMD). This review addresses a number of cellular functions mediated by alpha-crystallins in the retina. Prominent expression of alphaB crystallin in mitochondria may serve to protect cells from oxidative injury. alphaB crystallin as secretory protein via exosomes can offer neuroprotection to adjacent RPE cells and photoreceptors. The availability of chaperone-containing minipeptides of alphaB crystallin could prove to be a valuable new tool for therapeutic treatment of retinal disorders. MAJOR CONCLUSIONS: alpha-Crystallins are expressed in cytosol and mitochondria of RPE cells and are regulated during oxygen-induced retinopathy and during development. alpha-Crystallins protect RPE from oxidative-and ER stress-induced injury and autophagy. alphaB-Crystallin is a modulator of angiogenesis and vascular endothelial growth factor. alphaB Crystallin is secreted via exosomal pathway. Minichaperone peptides derived from alphaB Crystallin prevent oxidant induced cell death and have therapeutic potential. GENERAL SIGNIFICANCE: Overall, this review summarizes several novel properties of alpha-crystallins and their relevance to maintaining normal retinal function. In particular, the use of alpha crystallin derived peptides is a promising therapeutic strategy to combat retinal diseases such as AMD. This article is part of a Special Issue entitled Crystallin biochemistry in health and disease. PMID- 26026471 TI - Low back pain status of female university students in relation to different sport activities. AB - PURPOSE: To investigate the prevalence of low back pain (LBP) and its absence rate among female university student athletes in different types of sports. METHODS: A cross-sectional study based on a standard self-reporting questionnaire was performed among 1335 athletes. Participants were female athletes who attended the National Sports Olympiad of Female University Students in basketball, volleyball, futsal, tennis, badminton, swimming, track and field, shooting, and karate. RESULTS: One thousand and fifty-nine athletes with the mean (SD) age of 23.1 (3.8) years responded to the questionnaire (response rate 79%). The 12-month prevalence of LBP was 39.0%; in addition, lifetime and point prevalence of LBP were 59.7 and 17.8%, respectively. Basketball (47.9 %) and karate (44.0 %) players had reported the highest 12-month prevalence of LBP. Also, LBP prevalences in shooting (29.7 %) and badminton (42.4 %) players were not negligible. Results show that, LBP led to relatively high absence rate from training sessions (27.9%) and matches (13.0%). CONCLUSION: While most of the existing literatures regarding female athletes' LBP have focused on particular sports with specific low back demands (such as skiing and rowing), many other sports have not been studied very well in this regard. Investigating LBP prevalence and related factors in other types of sports, such as combat sports, badminton and shooting, can help us better understand the prevalence of low back pain and provide us with necessary insight to take effective steps towards its prevention in athletes. PMID- 26026472 TI - Use of PET/CT in the early diagnosis of implant related wound infection and avoidance of wound debridement. AB - PURPOSE: Delayed infections after spinal instrumentation typically require complete implant removal and extensive wound debridement due to the difficulties in establishing an early diagnosis. We report a case of occult late infection after posterior spinal instrumentation that was detected early using PET/CT and therefore was successfully treated with antibiotics alone. METHODS: A 26-year-old woman who underwent posterior spinal instrumentation and fusion for scoliosis correction had superficial pseudomonal infection that healed with ceftazidime and levofloxacin and was admitted 4 months later with mild back pain. She had no fever and the surgical wound healed well. Laboratory tests were compatible with late infection but radiographs showed no signs of implant infection. The patient was suspected of having ongoing occult late infection and thus, underwent a PET/CT. RESULTS: PET/CT revealed a significant pathological FDG uptake at the T5 vertebral body and the area surrounding proximal end of the T5 instrumentation. The maximal standardized uptake value (SUV) was 7.9 for the T5 vertebra and only 2.3 for the patient's liver, suggesting an infection pathology. A conclusive diagnosis of delayed onset infection after spinal instrumentation was established and the patient was immediately started on oral anti-pseudomonal treatment. The scoliosis correction was well maintained 10 months after the index surgery and she had no signs of implant infection. CONCLUSIONS: PET/CT provides detailed diagnostic information for occult infections in the absence of morphological changes and thus, is valuable for an early diagnosis of late infection after spinal instrumentation. It is possible to retain the instrumentation in the case of late infection, if early detection and efficacious treatment can be achieved timely. PMID- 26026473 TI - A preclinical large animal study on a novel intervertebral fusion cage covered with high porosity titanium sheets with a triple pore structure used for spinal fusion. AB - PURPOSE: To evaluate the osteoconductivity and the bonding strength of the newly developed interbody cage covered with the porous titanium sheet (porous Ti cage) to vertebral bodies in a sheep model. METHODS: Twelve sheep underwent anterior lumbar interbody fusion at L2-3 and L4-5 using either the new porous Ti cages (Group-P) or conventional Ti cages with autogenous iliac bone (Group-C). The animals were euthanized at 2 or 4 months postoperatively and subjected to radiological, biomechanical, and histological examinations. RESULTS: Computed tomography analyses showed that the ratio of bone contact area in Group-P was significantly increased at 4 months compared with that at 2 months (p = 0.01). Although the ratio of bone contact area in Group-C was significantly higher than Group-P at 2 months (p < 0.001), there was no statistically significant difference between the two groups at 4 months. Biomechanical test showed that there was no significant difference in bonding strength between the two groups at either 2 or 4 months. Histological analyses revealed that the bone apposition ratio increased significantly with time in Group-P (p < 0.001). Although Group-C showed significantly higher bone apposition ratio than Group-P at 2 months (p = 0.001), there was no statistical difference between the two groups at 4 months. CONCLUSIONS: There was bone ingrowth into the porous Ti sheet, and bonding capacity of the porous Ti cage to the host bone increased with time. However, the speed of union to the bone with a porous Ti cage was marginally lower than a conventional cage along with an autogenous bone graft. Although it needs further experiment with a larger sample size, the results of the current study suggested that this material could achieve interbody fusion without the need for bone grafts. PMID- 26026474 TI - Analysis of an unexplored group of sagittal deformity patients: low pelvic tilt despite positive sagittal malalignment. AB - PURPOSE: In adult spinal deformity (ASD), patients increase pelvic tilt (PT) to maintain standing alignment. Previously, ASD patients with low PT and high disability were described. This study investigates this unusual population in terms of demographic, radiographic, and clinical features after three-column osteotomy (3CO). METHODS: In this multicenter retrospective study, ASD patients underwent single lumbar 3CO. Since PT is proportional to pelvic incidence (PI), the low PT group (LowPT) was defined as having a baseline (BL) PT/PI <25th percentile. HRQOL and full spine x-rays were analyzed at BL and 1 year. LowPT patients were compared to those with high PT/PI (HighPT) in a matched range of T1 pelvic angle. RESULTS: LowPT group had PT/PI <0.4 (n = 31). High disability was reported at baseline for both groups with significant improvement postoperatively, but without difference between groups. LowPT had significantly smaller lack lumbar lordosis but larger SVA, T1 spinopelvic inclination. Postoperatively, there were improvements in all sagittal modifiers except PT in LowPT. 33 % of LowPT had an increase in PT (>5 degrees ) postoperatively. This subset had more deformity at baseline, achieving good T1SPi postoperative correction but without achieving the SRS-Schwab target SVA at 1 year. CONCLUSION: LowPT group had high levels of disability. After 3CO surgery, low PT patients experience only partial improvements in sagittal vertical axis (SVA) and 33 % of the group increased their PT. Further work is necessary to determine optimal realignment approaches for this unusual set of patients. It is unclear if neuromuscular pathology plays a role in the setting of high SVA without pelvic retroversion. PMID- 26026475 TI - Case report of chylous ascites with strangulated ileus and review of the literature. AB - We describe a case of chylous ascites with strangulated ileus, and review all 22 cases (including our case) of chylous ascites with strangulated ileus reported in the English and Japanese literature. The patient we describe was a 51-year-old woman with medical history of radiotherapy for cervical cancer of the uterus 15 months prior to being admitted to our hospital with abdominal pain after consuming a meal. A computed tomography (CT) scan revealed ascites, expansion of the small intestine, and whirl sign. Laparotomy revealed chylous ascites with an incarcerated internal hernia of the small intestine, which was released without intestinal resection. In our case the postoperative phase was uneventful, and as in the other 21 literature cases reviewed, treatment by either detorsion, release of the incarcerated internal hernia, or incision of the adhesion band without intestinal resection resulted in rapid improvement in the color of the intestine. It is considered that minimally invasive laparoscopic laparotomy should be selected as the treatment of first choice, because the degree of strangulation is slight in cases where chylous ascites is associated with strangulated ileus. PMID- 26026476 TI - Attention Deficit Hyperactivity Disorder Medication Use Among Teens and Young Adults. AB - PURPOSE: The purpose of this study was to determine rates of stimulant/atomoxetine use among teens (aged 12-17 years) and young adults (aged 18-23 years) and to investigate associations in medication use before and after the transition from teen to young adult. METHODS: Repeated cross-sectional analyses using the nationally representative Medical Expenditure Panel Survey. The sample included all teens and young adults between 2003 and 2012. Within this group, a staggered sample of individuals between 2006 and 2012 born during a 5 year range was used to minimize false positive findings due to temporal trends. The primary outcome was attention deficit hyperactivity disorder (ADHD) medication use (two or more prescriptions and >=60 tablets). A multivariable logistic regression was utilized to determine associations between ADHD medication use and race/ethnicity and other sociodemographic factors. RESULTS: A total of 62,699 individuals were included between 2003 and 2012. Rates of ADHD medication use increased for both teens (4.2%-6.0%) and young adults (1.2%-2.6%) between 2003-2004 and 2011-2012. In adjusted analysis, blacks, Hispanics, and Asians had lower rates of use compared with whites. The decrease in use among young adults was more pronounced among blacks compared with whites. A usual source of care and health insurance were less common among young adults, and both were associated with ADHD medication use. CONCLUSIONS: Although there has been an increase in the use of ADHD medications in both teens and young adults, we found a drop-off in levels of ADHD treatment among young adults when compared with teens. A portion of this decrease appears to be related to race/ethnicity, usual source of care, and health insurance status. PMID- 26026477 TI - Cervical Cancer Screening, Pelvic Examinations, and Contraceptive Use Among Adolescent and Young Adult Females. AB - PURPOSE: The purpose of this study was to characterize the association between pelvic examination and adolescent contraceptive method use in two time periods in the 2006-2010 National Survey of Family Growth (NSFG). METHODS: Using data from the 2006-2010 NSFG, we used descriptive statistics and multivariable regression models to examine the association between pelvic examination and/or Pap smear and use of effective or highly effective contraceptive methods during two time periods (2006-2008 and 2008-2010). We used the design characteristics of the NSFG to produce population estimates. RESULTS: More than half (57.3%) of our target population reported that they had a pelvic examination and/or Pap smear in the preceding 12 months. After considering health service use, pregnancy history, and demographic characteristics, receipt of pelvic/Pap remained significantly associated with use of effective or highly effective methods of contraception. Adjusted odds ratio = 1.86; 95% confidence interval (CI), 1.17-2.97. When we examined the relationship between pelvic/Pap and use of effective or highly effective methods within time periods, we found that the odds of effective contraception use were higher among adolescents who had received a Pap/pelvic examination in Period 1 (June 2006-May 2008) but not in Period 2 (June 2008-May 2010). Odds ratio = 3.05; 95% CI, 1.53-6.03 and odds ratio = 1.52; 95% CI, .88 2.62, Periods 1 and 2 respectively. CONCLUSIONS: This finding provides some reassurance that although indications for pelvic examination and Pap smear among adolescents have decreased, the previously documented association between pelvic examination and effective or highly effective contraception appears to have decreased. PMID- 26026478 TI - Chinese travellers visiting friends and relatives--A review of infectious risks. AB - BACKGROUND: Travellers are potential vectors in the transmission of infectious diseases across international borders. Travellers visiting friends and relatives (VFR) have a particularly high risk of acquiring certain infections during travel. Chinese VFR travellers account for a substantial proportion of all travel in Western countries with high migrant populations. METHODS: A literature review was undertaken regarding major infectious disease risks for VFR travellers visiting China. This included an examination of the previous pandemics arising in China, the likelihood of future outbreaks in China from H5N1 and H7N9 avian influenza viruses, the potential role of travellers in disease transmission, and the special risks for VFR travellers. RESULTS: China has been the origin of several influenza pandemics in past few decades, and the origin of several emerging infectious diseases with pandemic potential, including SARS. Travel to and from China has the potential for global spread of emergent infectious diseases, as seen in the SARS outbreak in 2003. For VFR travellers, the risk of other infectious diseases may also be greater in China compared to their countries of migration, including hepatitis A and B, dengue fever, typhoid, and other diseases. CONCLUSIONS: VFR travel to China may be associated with increased risk of acquiring a range of infectious diseases, and also poses a potential risk for importation of future pandemics to other countries. Chinese VFR travellers need to be cognisant of these risks and health professionals should consider educational interventions to minimise these risks. PMID- 26026479 TI - Extraordinary cerebral venous drainage pathway with mastoid emissary and posterior external jugular veins detected by contrast-enhanced neck computed tomography. AB - An extraordinary cerebral venous drainage pathway and dilated vein at the left posterior cervical region were detected with routine contrast-enhanced neck computed tomography exam. The left sigmoid sinus was drained by dilated mastoid emissary vein (MEV). The MEV continued as posterior auricular and posterior external jugular veins (PEJVs). The left PEJV directly drained into subclavian vein. Atretic right transverse sinus, left facial vein forming the external jugular vein, atresia and hypoplasia of upper internal jugular veins at the right and left sides, respectively, were the other uncommon findings in our case. Detecting venous variations may prevent complications during surgical and interventional procedures, so the radiologists should examine the superficial cervical veins closely. PMID- 26026480 TI - Analysis of microsamples of human faeces: a non-invasive approach to study the bioavailability of fat-soluble bioactive compounds. AB - INTRODUCTION: Bioavailability is a critical feature in the assessment of the role of micronutrients in human health. Poorly bioavailable micronutrients like carotenoids may reach significant concentrations in the gastrointestinal tract where they may exert biological actions. PURPOSE: We evaluated a simple collection protocol to determine vitamin A, E and carotenoids in microsamples of human faeces as a non-invasive approach for nutritional studies. METHODS: Microsamples of human faeces were collected using a commercially available device, extracted and analysed on two LC systems. Suitability of the protocol was assessed by evaluating several factors including the effect of simulated colonic conditions and two nutritional scenarios with different dietary components, chemical forms, nutritional goals and target groups. RESULTS: The protocol was reproducible and representative of a faeces sample. The major dietary and serum carotenoids, and several "unidentified" compounds (possibly metabolites) could be detected, and cis-/trans-beta-carotene profile reflected dietary intervention. In faeces of neonates, free retinol, retinyl and alpha-tocopheryl acetate (from infant formula), long-chain fatty acid retinyl esters (from human milk), free gamma-tocopherol and alpha-tocopherol could be detected. CONCLUSION: Our results show that the analysis of vitamin A, E and carotenoids in microsamples of human faeces is a suitable, non-invasive approach that may provide relevant information regarding responsiveness, nutrient stability and metabolism and may help assess adequacy of chemical forms and delivery systems reaching the colon. PMID- 26026482 TI - Perisynaptic astroglial processes: dynamic processors of neuronal information. AB - Neuroglial interactions are now recognized as essential to brain functions. Extensive research has sought to understand the modalities of such dialog by focusing on astrocytes, the most abundant glial cell type of the central nervous system. Neuron-astrocyte exchanges occur at multiple levels, at different cellular locations. With regard to information processing, regulations occurring around synapses are of particular interest as synaptic networks are thought to underlie higher brain functions. Astrocytes morphology is tremendously complex in that their processes exceedingly branch out to eventually form multitudinous fine leaflets. The latter extremities have been shown to surround many synapses, forming perisynaptic astrocytic processes, which although recognized as essential to synaptic functioning, are poorly defined elements due to their tiny size. The current review sums up the current knowledge on their molecular and structural properties as well as the functional characteristics making them good candidates for information processing units. PMID- 26026481 TI - Estimated intake and major food sources of flavonoids among US adults: changes between 1999-2002 and 2007-2010 in NHANES. AB - PURPOSE: This study was conducted to: (1) demonstrate an updated method for estimating flavonoid intake of US adults by combining USDA flavonoid databases and NHANES food consumption data; (2) document the intake and major food sources of flavonoids among US adults; and (3) determine whether the intake and major sources of dietary flavonoids have changed during the past decade in the USA. METHODS: A cross-sectional population-based study. Differences over time in the average daily intake and food sources of flavonoids were estimated using food consumption data from NHANES 1999-2002 (n = 8833) and 2007-2010 (n = 9801). RESULTS: The total flavonoid intake of US adults aged 19 years and older remained unchanged between 1999-2002 (201.9 mg/d) and 2007-2010 (200.1 mg/d), with tea being the top food source of flavonoids. However, intake of anthocyanidins increased during this period, mainly due to greater consumption of berries and wine, which was consistent with the increase in per capita consumption of these foods based on USDA food availability data. CONCLUSIONS: The results of this study provide updated information on flavonoid intake and food contributors and warrant further studies on the health implications of flavonoid intake. PMID- 26026483 TI - Application of hollow fiber liquid phase microextraction for simultaneous determination of regulated and emerging iodinated trihalomethanes in drinking water. AB - Trihalomethanes (THMs) are regulated disinfection by-products (DBPs) most commonly analyzed in quality control water supply due to their harmful effects on health. However, few data exist about the content of emerging iodo trihalomethanes (I-THMs) which are present in drinking water at very low concentrations (in the order of ngL(-1)). For this reason a two-phase hollow fiber liquid phase microextraction method for the simultaneous determination of four regulated trihalomethanes and six emerging iodo-trihalomethanes using GC MUECD and GC-MS with detection limits in the range of few ngL(-1) has been developed. A central composite design was used to optimize conditions for simultaneous extraction. The best extraction recovery was obtained with 19.2min at 27.1 degrees C and 900rpm, without salt addition, using a supported hollow fiber membrane of 10.5cm (0.6mm id) and 1-octanol as acceptor phase. The limits of detection for the regulated THMs and I-THMs were 3-44ngL(-1) and 1-3ngL(-1), respectively. The calibration curves showed good linearity (R(2)>0.995) and good repeatibility (3-22%). The relative recoveries in water were between 96.5% and 105.2%. The method was applied for the simultaneous determination of trihalomethanes in supply water samples from seven water distribution systems (WDS) in the Huelva area, located at the southwest Spain, which use different water-treatment processes. The highest concentrations of I-THMs, particularly CHBrClI and CHCl2I, were detected in water treated with advanced treatment process using pre-ozonation, however these compounds were not detected or decreased along distribution system. In the samples of treated water with conventional treatment, using pre-oxidation by permanganate and distribution network, CHCl2I, CHBrClI, CHClI2, CHBrI2 and CHI3 were detected at very low concentrations (1-18ngL(-1)). Finally, in water samples from underground origin without oxidation treatment, in which only disinfection with sodium hypochlorite was applied, I-THMs were not detected. PMID- 26026484 TI - A moving blocker-based strategy for simultaneous megavoltage and kilovoltage scatter correction in cone-beam computed tomography image acquired during volumetric modulated arc therapy. AB - PURPOSE: To evaluate a moving blocker-based approach in estimating and correcting megavoltage (MV) and kilovoltage (kV) scatter contamination in kV cone-beam computed tomography (CBCT) acquired during volumetric modulated arc therapy (VMAT). METHODS AND MATERIALS: During the concurrent CBCT/VMAT acquisition, a physical attenuator (i.e., "blocker") consisting of equally spaced lead strips was mounted and moved constantly between the CBCT source and patient. Both kV and MV scatter signals were estimated from the blocked region of the imaging panel, and interpolated into the unblocked region. A scatter corrected CBCT was then reconstructed from the unblocked projections after scatter subtraction using an iterative image reconstruction algorithm based on constraint optimization. Experimental studies were performed on a Catphan(r) phantom and an anthropomorphic pelvis phantom to demonstrate the feasibility of using a moving blocker for kV-MV scatter correction. RESULTS: Scatter induced cupping artifacts were substantially reduced in the moving blocker corrected CBCT images. Quantitatively, the root mean square error of Hounsfield units (HU) in seven density inserts of the Catphan phantom was reduced from 395 to 40. CONCLUSIONS: The proposed moving blocker strategy greatly improves the image quality of CBCT acquired with concurrent VMAT by reducing the kV-MV scatter induced HU inaccuracy and cupping artifacts. PMID- 26026486 TI - The evaluation of insufficient cognitive effort in schizophrenia in light of low IQ scores. AB - Low IQ has recently been shown to predict neuropsychological effort test failure in healthy and neurological populations. Although low IQ is common in schizophrenia (SZ), its effect on effort test performance remains unclear in this population. The current study examined the role of IQ in effort test performance in a sample of 60 outpatients with SZ and 30 demographically matched healthy controls (CN). Participants were administered a battery of neuropsychological tests, and insufficient effort was calculated using two embedded effort indices: the Reliable Digit Span Effort Index and the Finger Tapping Effort Index. Results indicated that 16.1% of SZ patients and 0% CN failed both effort measures and that 32.1% of SZ and 3.3% of CN failed one measure. In SZ, IQ in the <70 or 70-79 range was associated with the highest rates of falling below the effort cut-off scores; however, patients with IQs in the low-average or higher range (>80) did not fall below effort cut-offs. Findings suggest that low IQ is a significant predictor of insufficient effort during neuropsychological test performance in schizophrenia, calling into question the validity of neuropsychological effort testing in SZ patients with low IQ. PMID- 26026485 TI - IAEA randomised trial of optimal single dose radiotherapy in the treatment of painful bone metastases. AB - BACKGROUND: To determine the optimal single-dose radiotherapy schedule for pain from bone metastases in a multi-centre, international, randomised trial. PATIENTS AND METHODS: 651 patients were randomised to either 8Gy (n=325) or 4Gy (n=326) radiotherapy. Pain at 4, 8, 12, 24 and 52weeks was assessed using a Categorical Scale (CS) and a Visual Analogue Scale (VAS). The primary endpoint was response at 4weeks. RESULTS: There was no significant difference in patient demographics and other co-variates. The complete response (CR) rate and ORR (complete or partial response) for all follow-up times were higher after 8Gy (p=0.02). The Kaplan-Meier actuarial rate (categorical scale) at 4weeks for ORR was 80% after 8Gy compared to 68% after 4Gy (p=0.0015). 117 re-treatments were given of which 72 were in the 4Gy group and 45 in 8Gy arm (p=0.01). CONCLUSIONS: There was a marked consistent difference in pain relief at all time points in favour of 8Gy. These data reinforce the case for single dose 8Gy radiotherapy to be recommended for metastatic bone pain in all healthcare settings. PMID- 26026487 TI - Memory and brain-derived neurotrophic factor after subchronic or chronic amphetamine treatment in an animal model of mania. AB - Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala. PMID- 26026488 TI - Investigation of spatial and temporal metal atmospheric deposition in France through lichen and moss bioaccumulation over one century. AB - Lichens and mosses were used as biomonitors to assess the atmospheric deposition of metals in forested ecosystems in various regions of France. The concentrations of 17 metals/metalloids (Al, As, Cd, Co, Cr, Cs, Cu, Fe, Mn, Ni, Pb, Sb, Sn, Sr, Ti, V, and Zn) indicated overall low atmospheric contamination in these forested environments, but a regionalism emerged from local contributions (anthropogenic activities, as well as local lithology). Taking into account the geochemical background and comparing to Italian data, the elements from both natural and anthropogenic activities, such as Cd, Pb, or Zn, did not show any obvious anomalies. However, elements mainly originating from lithogenic dust (e.g., Al, Fe, Ti) were more prevalent in sparse forests and in the Southern regions of France, whereas samples from dense forests showed an accumulation of elements from biological recycling (Mn and Zn). The combination of enrichment factors and Pb isotope ratios between current and herbarium samples indicated the historical evolution of metal atmospheric contamination: the high contribution of coal combustion beginning 150 years ago decreased at the end of the 20th century, and the influence of car traffic during the latter observed period decreased in the last few decades. In the South of France, obvious local influences were well preserved during the last century. PMID- 26026489 TI - Paternal postnatal depression in Japan: an investigation of correlated factors including relationship with a partner. AB - BACKGROUND: A negative effect of paternal depression on child development has been revealed in several previous studies. The aims of this study were to examine the prevalence and relevant factors associated with paternal postnatal depression at four months postpartum, including age, part-time work or unemployment, experience of visiting a medical institution due to a mental health problem, economic anxiety, unexpected pregnancy, pregnancy with infertility treatment, first child, partner's depression, and lower marital relationship satisfaction. METHODS: We distributed 2032 self-report questionnaires to couples (one mother and one father) with a 4-month old infant between January and April 2013. Data from 807 couples (39.7 %) were analyzed. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS). In order to clarify the factors related with paternal depression, a logistic regression analysis was conducted. RESULTS: One hundred and ten fathers (13.6 %) and 83 mothers (10.3 %) were depressed. According to the logistic regression analysis, paternal depression was positively associated with partner's depression (adjusted odds ratio (AOR) 1.91, 95 % confidence interval (CI) 1.05-3.47), and negatively with marital relationship satisfaction (AOR 0.83, 95 % CI 0.77-0.89). History of infertility treatment (AOR 2.37, 95 % CI 1.32-4.24), experience of visiting a medical institution due to a mental health problem (AOR 4.56, 95 % CI 2.06-10.08), and economic anxiety (AOR 2.15, 95 % CI 1.34-3.45) were also correlated with paternal depression. CONCLUSIONS: This study showed that the prevalence of paternal depression at four months after childbirth was 13.6 % in Japan. The presence of partner's depression and low marital relationship satisfaction were significantly correlated with paternal postpartum depression, suggesting that health professionals need to pay attention to the mental status of both fathers and mothers, and to their relationship. PMID- 26026490 TI - Reading, listening and memory-related brain activity in children with early-stage temporal lobe epilepsy of unknown cause-an fMRI study. AB - BACKGROUND AND AIMS: The changes in functional brain organization associated with paediatric epilepsy are largely unknown. Since children with epilepsy are at risk of developing learning difficulties even before or shortly after the onset of epilepsy, we assessed the functional organization of memory and language in paediatric patients with temporal lobe epilepsy (TLE) at an early stage in epilepsy. METHODS: Functional magnetic resonance imaging was used to measure the blood oxygenation level-dependent (BOLD) response to four cognitive tasks measuring reading, story listening, memory encoding and retrieval in a population based group of children with TLE of unknown cause (n = 21) and of normal intelligence and a healthy age and gender-matched control group (n = 21). RESULTS: Significant BOLD response differences were found only in one of the four tasks. In the story listening task, significant differences were found in the right hemispheric temporal structures, thalamus and basal ganglia. Both activation and deactivation differed significantly between the groups, activation being increased and deactivation decreased in the TLE group. Furthermore, the patients with abnormal electroencephalograms (EEGs) showed significantly increased activation bilaterally in the temporal structures, basal ganglia and thalamus relative to those with normal EEGs. The patients with normal interictal EEGs had a significantly stronger deactivation than those with abnormal EEGs or the controls, the differences being located outside the temporal structures. CONCLUSIONS: Our results suggest that TLE entails a widespread disruption of brain networks. This needs to be taken into consideration when evaluating learning abilities in patients with TLE. The thalamus seems to play an active role in TLE. The changes in deactivation may reflect neuronal inhibition. PMID- 26026491 TI - Comparison of dual-antiplatelet therapy durations after endovascular revascularization of infrainguinal arteries. AB - BACKGROUND: The optimal dual-antiplatelet therapy (DAPT) duration after endovascular revascularization of infrainguinal arteries is uncertain. METHODS: This study examines DAPT prescription trends and 12-month major adverse limb events (MALEs; a composite of repeat endovascular or surgical revascularization, acute vessel thrombosis, or amputation of the target limb), major adverse cardiovascular events (MACEs; all-cause mortality, nonfatal myocardial infarction [MI], stroke, or coronary revascularization), fatal bleeding events, and those requiring interruption or discontinuation of DAPT (hemorrhagic complications) for patients enrolled into the Excellence in Peripheral Artery Disease (XLPAD) registry. RESULTS: Data on 368 patients prescribed antiplatelet therapy were analyzed; 8.2% were prescribed antiplatelet monotherapy, 48.6% DAPT for <=3 months, and 43.2% for >3 months. Patients in the >3 DAPT prescribed group were older, had preexisting coronary artery disease (CAD), and prior MI (all P < 0.001). Overall MALE in the <=3 and >3-month DAPT prescribed groups were 22.3% and 23.9%, respectively (P = 0.541). Survival analysis showed significantly higher rates of MACE in patients prescribed >3-month DAPT (17.6% vs. 9.5%; P = 0.019). An "as-treated" analysis excluded 10 patients who were prescribed DAPT for >3 months and revealed similar rates of MALE (24.9% vs. 20.8%; P = 0.386) and MACE (12.2% vs. 14.8%; P = 0.443) in patients receiving <=3 and >3 DAPT. Hemorrhagic complications were similar across all prescribed and "as-treated" DAPT groups. CONCLUSIONS: After infrainguinal endovascular procedures, patients with underlying CAD were prescribed longer (>3 months) duration of DAPT and experienced more cardiovascular events compared with those prescribed <=3 months of DAPT. Adverse limb events were similar in both groups. PMID- 26026492 TI - Patterns of major depression and nonmedical use of prescription opioids in the United States. AB - INTRODUCTION: Recent epidemiologic studies have shown that nonmedical use of prescription opioids (NMUPO) and major depression frequently co-occur. Comorbid forms of drug use and mental illness such as NMUPO and depression pose a greater disease burden than either condition alone. However, sociodemographic and substance use differences between individuals with either NMUPO or depression and those with comorbid conditions have not yet been fully investigated. METHODS: Data came from the 2011 and 2012 National Survey on Drug Use and Health (NSDUH). Adolescents and adults were examined independently because of differences in screening for major depressive episodes (MDE). Weighted multinomial logistic regression investigated differences between persons with either past-year NMUPO (4.0%) or MDE (5.5%) and those with comorbid NMUPO and MDE (0.6%), compared to persons with neither condition. RESULTS: Females were more likely than males to report either MDE-alone and comorbid NMUPO and MDE, whereas adult men were marginally more likely to report NMUPO-alone (not significant among adolescents). Polydrug use and alcohol use disorders were more pronounced among those with comorbid NMUPO and MDE than persons with either NMUPO-alone or MDE-alone. Persons with independent and comorbid NMUPO and MDE were more likely to report lower income and unemployment versus employment. CONCLUSIONS: This study found that independent and comorbid NMUPO and MDE were disproportionately clustered with burdens of lower socioeconomic position, suggesting that a population-based approach to address NMUPO would target these social determinants of health, whereas a high-risk approach to prevention should be tailored to females experiencing MDE symptoms and polydrug users. PMID- 26026493 TI - Comparison of the characteristics of long-term users of electronic cigarettes versus nicotine replacement therapy: A cross-sectional survey of English ex smokers and current smokers. AB - BACKGROUND: Electronic cigarettes (ECs) and nicotine replacement therapy (NRT) are non-combustible nicotine delivery devices being widely used as a partial or a complete long-term substitute for smoking. Little is known about the characteristics of long-term users, their smoking behaviour, attachment to smoking, experience of nicotine withdrawal symptoms, or their views on these devices. This study aimed to provide preliminary evidence on this and compare users of the different products. METHODS: UK participants were recruited from four naturally occurring groups of long-term (>=6 months) users of either EC or NRT who had stopped or continued to smoke (N=36 per group, total N=144). Participants completed a questionnaire assessing socio-demographic and smoking characteristics, nicotine withdrawal symptoms, smoker identity and attitudes towards the products they were using. RESULTS: Adjusting for relevant confounders, EC use was associated with a stronger smoker identity (Wald X(2)(1)=3.9, p=0.048) and greater product endorsement (Wald X(2)(1)=4.6, p=0.024) than NRT use, irrespective of smoking status. Among ex-smokers, EC users reported less severe mood and physical symptoms (Wald X(2)(1)=6.1, p=0.014) and cravings (Wald X(2)(1)=8.5, p=0.003), higher perceived helpfulness of the product (Wald X(2)(1)=4.8, p=0.028) and lower intentions to stop using the product (Wald X(2)(1)=17.6, p<0.001) than NRT users. CONCLUSIONS: Compared with people who use NRT for at least 6 months, those who use EC over that time period appear to have a stronger smoker identity and like their products more. Among long-term users who have stopped smoking, ECs are perceived as more helpful than NRT, appear more effective in controlling withdrawal symptoms and continued use may be more likely. PMID- 26026495 TI - Rehabilitation during mechanical ventilation: Review of the recent literature. AB - Mechanically ventilated patients are at increased risk of developing physical and psychological complications that are associated with prolonged weaning from mechanical ventilation, increased morbidity and mortality. These complications include intensive care unit acquired weakness, delirium and a loss of physical function that may persist well beyond ICU and hospital discharge. Factors such as the requirement for intubation and mechanical ventilation, sedation, systemic inflammation and immobility are associated with the development of these physical and psychological complications. Implementation of rehabilitation in mechanically ventilated patients has been demonstrated to be both safe and feasible and provide benefits in terms of physical and psychological function and assist with weaning from mechanical ventilation. The recent relevant literature on the role of rehabilitation interventions in the mechanically ventilated patient will be discussed. PMID- 26026494 TI - An economic evaluation of a contingency-management intervention for stimulant use among community mental health patients with serious mental illness. AB - BACKGROUND: This study examines the cost-effectiveness of contingency-management (CM) for stimulant dependence among community mental health patients with serious mental illness (SMI) METHODS: Economic evaluation of a 12-week randomized controlled trial investigating the efficacy of CM added to treatment-as-usual (CM+TAU), relative to TAU without CM, for treating stimulant dependence among patients with a SMI. The trial included 176 participants diagnosed with SMI and stimulant dependency who were receiving community mental health and addiction treatment at one community mental health center in Seattle, Washington. Participants were also assessed during a 12-week follow-up period. Positive and negative syndrome scale (PANSS) scores were used to calculate quality-adjusted life-years (QALYs) for the primary economic outcome. The primary clinical outcome, the stimulant-free year (SFY) is a weighted measure of time free from stimulants. Two perspectives were adopted, those of the provider and the payer. RESULTS: At 12-weeks neither the provider ($2652, p=0.74) nor the payer ($2611, p=0.99) cost differentials were statistically significant. This was also true for the payer at 24-weeks (-$125, p=1.00). QALYs gained were similar across groups, resulting in small, insignificant differences (0.04, p=0.23 at 12-weeks; 0.01, p=0.70 at 24 weeks). CM+TAU experienced significantly more SFYs, 0.24 (p<0.001) at 12 weeks and 0.20 (p=0.002) at 24 weeks, resulting in at least an 85% chance of being considered cost-effective at a threshold of $200,000/SFY. CONCLUSION: Contingency management appears to be a wise investment for both the provider and the payer with regard to the clinical outcome of time free from stimulants. PMID- 26026496 TI - Performing both propensity score and instrumental variable analyses in observational studies often leads to discrepant results: a systematic review. AB - OBJECTIVES: Propensity score (PS) and instrumental variable (IV) are analytical techniques used to adjust for confounding in observational research. More and more, they seem to be used simultaneously in studies evaluating health interventions. The present review aimed to analyze the agreement between PS and IV results in medical research published to date. STUDY DESIGN AND SETTING: Review of all published observational studies that evaluated a clinical intervention using simultaneously PS and IV analyses, as identified in MEDLINE and Web of Science. RESULTS: Thirty-seven studies, most of them published during the previous 5 years, reported 55 comparisons between results from PS and IV analyses. There was a slight/fair agreement between the methods [Cohen's kappa coefficient = 0.21 (95% confidence interval: 0.00, 0.41)]. In 23 cases (42%), results were nonsignificant for one method and significant for the other, and IV analysis results were nonsignificant in most situations (87%). CONCLUSION: Discrepancies are frequent between PS and IV analyses and can be interpreted in various ways. This suggests that researchers should carefully consider their analytical choices, and readers should be cautious when interpreting results, until further studies clarify the respective roles of the two methods in observational comparative effectiveness research. PMID- 26026497 TI - Hedgehog/GLI-mediated transcriptional activity inhibitors from Crinum asiaticum. AB - The inhibition of the hedgehog (Hh) signaling pathway has emerged as an attractive anti-cancer strategy. As part of our continuing search for natural inhibitors of the Hh/GLI1 signaling pathway, we isolated three alkaloids (1-3) from Crinum asiaticum. Compounds 1 and 3 showed potent Hh/GLI1-mediated transcriptional inhibitory activity and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compounds 1 and 3 clearly inhibited the Hh signaling pathway by down-regulating the expression of GLI-related proteins (PTCH and BCL2) in DU145 cells. PMID- 26026500 TI - Short Time Exposure (STE) test in conjunction with Bovine Corneal Opacity and Permeability (BCOP) assay including histopathology to evaluate correspondence with the Globally Harmonized System (GHS) eye irritation classification of textile dyes. AB - Eye irritation evaluation is mandatory for predicting health risks in consumers exposed to textile dyes. The two dyes, Reactive Orange 16 (RO16) and Reactive Green 19 (RG19) are classified as Category 2A (irritating to eyes) based on the UN Globally Harmonized System for classification (UN GHS), according to the Draize test. On the other hand, animal welfare considerations and the enforcement of a new regulation in the EU are drawing much attention in reducing or replacing animal experiments with alternative methods. This study evaluated the eye irritation of the two dyes RO16 and RG19 by combining the Short Time Exposure (STE) and the Bovine Corneal Opacity and Permeability (BCOP) assays and then comparing them with in vivo data from the GHS classification. The STE test (first level screening) categorized both dyes as GHS Category 1 (severe irritant). In the BCOP, dye RG19 was also classified as GHS Category 1 while dye RO16 was classified as GHS no prediction can be made. Both dyes caused damage to the corneal tissue as confirmed by histopathological analysis. Our findings demonstrated that the STE test did not contribute to arriving at a better conclusion about the eye irritation potential of the dyes when used in conjunction with the BCOP test. Adding the histopathology to the BCOP test could be an appropriate tool for a more meaningful prediction of the eye irritation potential of dyes. PMID- 26026501 TI - Perioperative Acid-Base and Electrolyte Disturbances. AB - Obtaining and interpreting blood gas and electrolyte levels is essential in the management of perioperative veterinary patients. Metabolic and electrolyte alterations are common in critically ill surgical patients, and can lead to alterations in cardiovascular function, neurologic status, respiratory function, and even response to various drug therapies. Several common perioperative conditions are discussed in this article, including metabolic disturbances, electrolyte abnormalities (hyponatremia and hypernatremia, hyperkalemia), and respiratory abnormalities. PMID- 26026499 TI - Structural findings of phenylindoles as cytotoxic antimitotic agents in human breast cancer cell lines through multiple validated QSAR studies. AB - Antimitotic agents are potential compounds for the treatment of breast cancer. Cytotoxicity is one of the parameters required for anticancer activity. A validated comparative molecular modeling study was performed on a set of phenylindole derivatives through R-group QSAR (RQSAR), regression-based and linear discriminant analysis (LDA)-based 2D QSAR studies and kernel-based partial least square (KPLS) analyses as well as CoMSIA 3D-QSAR study. Antiproliferative activities against two breast cancer cell lines (MDA-MB-231 and MCF7) were separately used as dependent variables. The RQSAR analysis highlighted different E-state indices and pharmacophoric requirements of important substitutions. The best 2D-QSAR model is established on the basis of three machine learning tools - MLR, SVM and ANN. The 2D-QSAR models depicted importance of different structural, physicochemical and topological descriptors. While RQSAR analyses demonstrated the fingerprint requirements of various substitutions, the KPLS analyses showed these requirements for the entire molecule. The CoMSIA model further refines these interpretations and reveals how subtle variations in these structures may influence biological activities. Observations of different modeling techniques complied with each other. The current QSAR study may be used to design potential antimitotic agents. It also demonstrates the utilities of different molecular modeling tools to elucidate the SAR. PMID- 26026498 TI - Protective effect of (+/-)alpha-tocopherol on brominated diphenyl ether-47 stimulated prostaglandin pathways in human extravillous trophoblasts in vitro. AB - Brominated diphenyl ether (BDE)-47 is a prevalent flame retardant chemical found in human tissues and is linked to adverse pregnancy outcomes in humans. Because dysregulation of the prostaglandin pathway is implicated in adverse pregnancy outcomes, the present study investigates BDE-47 induction of prostaglandin synthesis in a human extravillous trophoblast cell line, HTR-8/SVneo, examining the hypothesis that BDE-47 increases generation of reactive oxygen species (ROS) to stimulate the prostaglandin response. Treatment with 20 MUM BDE-47 significantly increased mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2) at 4, 12 and 24 h, and 24-h treatment significantly increased cyclooxygenase (COX)-2 cellular protein expression and prostaglandin E2 (PGE2) concentration in culture medium. The BDE-47-stimulated PGE2 release was inhibited by the COX inhibitors indomethacin and NS398, implicating COX activity. Exposure to 20 MUM BDE-47 significantly increased ROS generation as measured by carboxydichlorofluorescein fluorescence, and this response was blocked by cotreatment with the peroxyl radical scavenger (+/-)-alpha-tocopherol. (+/-) alpha-Tocopherol cotreatment suppressed BDE-47-stimulated increases of PGE2 release without significant effects on COX-2 mRNA and protein expression, implicating a role for ROS in post-translational regulation of COX activity. Because prostaglandins regulate trophoblast functions necessary for placentation and pregnancy, further investigation is warranted of BDE-47 impacts on trophoblast responses. PMID- 26026502 TI - The immunomodulatory effects of fish-oil supplementation in elite paddlers: A pilot randomized double blind placebo-controlled trial. AB - BACKGROUND: Physical exercise can induce imbalance of different cytokines by leading them towards an inflammatory and immunosuppressive milieu. Fish-oil (FO) supplementation may modulate the mentioned skewed balance following intense exercise. Therefore, we decided to investigate the effect of intense physical exercise and FO supplementation on cytokine production and helper T (Th) cell phenotype in male elite paddlers. SUBJECTS AND METHODS: Male elite paddlers consumed 6 g/day of either FO capsules (n=11) containing 3.6 g long chain n-3 polyunsaturated fatty acids (1.2 g docosahexaenoic acid and 2.4 g eicosapentaenoic acid) or placebo capsules (n=11) for 4 weeks. The paddlers simultaneously undertook a program of increasing exercise. Blood samples were taken from all the subjects 48 h before and after the 4 weeks of supplementation. RESULTS: Our results show that while FO supplementation decreases the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in the elite paddlers, it increases the production of IL-6. On the other hand, while there was no change in IL-4 secretion, the production of interferon (IFN)-gamma was significantly decreased after 4 weeks FO consumption. We also showed that the production of IL-10 was significantly higher in the FO group compared to the placebo. Finally, we found that fish-oil consumption shifts the balance between Th cells towards Th2 phenotype during intensive exercise. CONCLUSION: Our results suggest that the consumption of n-3 polyunsaturated fatty acids during intense exercise can induce the anti-inflammatory and immunosuppressive cytokine networks that are associated with a reduced Th1/Th2 ratio in elite paddlers. PMID- 26026503 TI - Impact of anesthesia on cancer recurrence. AB - Surgery remains the mainstay treatment in the majority of solid cancers. Anesthetics and analgesics used during the perioperative period may modulate the innate and adaptive immune system, inflammation and angiogenesis, and have a direct effect on cancer cells that could ultimately modify oncological outcomes. For instance, volatile anesthetics and opioid analgesics have shown predominantly pro-tumor effects, while propofol, non-steroid anti-inflammatory drugs have mostly anticancer effects. Researchers have been especially interested in investigating the association between the use of regional anesthesia techniques and the postoperative survival of patients with cancers. Since the results of the current retrospective studies are conflicting, several researchers are conducting prospective randomized trials. PMID- 26026504 TI - Origin and Pawn scaling for adults who do and do not stutter: A preliminary comparison. AB - PURPOSE: In order to determine whether adults who stutter (AWS) would show changes in locus of causality during stuttering treatment and approximate those of adults who do not stutter (AWNS) this preliminary study compared the locus of causality as indicated by Origin and Pawn scaling procedures from two groups of young adults who do and do not stutter. METHOD: A total of 20 age- and gender matched undergraduate and graduate students who did (n = 10) and did not (n = 10) stutter participated. The AWS took part in a three week intensive stuttering treatment provided by the American Institute for Stuttering (AIS). Along with measures of treatment outcome, writing samples were analyzed for Origin and Pawn statements that indicated the participant's locus of causality. RESULTS: At the outset of treatment the AWS showed significantly greater Pawn scores than the control group of AWNS and similar occurrences of Origin statements. The AWS showed a statistically significant increase in pre- to post-treatment Origin scores and a statistically significant decrease in Pawn scores. Following treatment the AWS showed the Origin and Pawn score ratios similar to those of AWNS. CONCLUSION: A pattern of increasing Origin and decreasing Pawn scores may indicate a pattern of increasing agency during successful stuttering treatment. Moreover the post-treatment Origin and Pawn score ratios of AWS, which were not significantly different from those of AWNS, may indicate a change trend toward normalization. Further research will determine whether such change patterns are predictive of long-term maintenance. EDUCATIONAL OBJECTIVES: By reading this article the reader will be able to: (a) describe advantages of content analysis measure such as the Origin and Pawn Scales; (b) discuss the purposes and procedures of the Origin and Pawn Scales; (c) describe typical change pattern of Origin and Pawn scores of adults who stutter while receiving treatment; (d) discuss how successful treatment for stuttering can result in the normalization of one's locus of causality. PMID- 26026505 TI - An approach to ingredient screening and toxicological risk assessment of flavours in e-liquids. AB - Flavour ingredients are an essential part of e-liquids. Their responsible selection and inclusion levels in e-liquids must be guided by toxicological principles. We propose an approach to the screening and toxicological risk assessment of flavour ingredients for e-liquids. The screening involves purity requirements and avoiding ingredients that are carcinogenic, mutagenic or toxic to reproduction. Additionally, owing to the uncertainties involved in potency determination and the derivation of a tolerable level for respiratory sensitisation, we propose excluding respiratory sensitisers. After screening, toxicological data on the ingredients should be reviewed. Inhalation-specific toxicological issues, for which no reliable safe levels can currently be derived, can lead to further ingredient exclusions. We discuss the use of toxicological thresholds of concern for flavours that lack inhalation data suitable for quantitative risk assessment. Higher toxicological thresholds of concern are suggested for flavour ingredients (170 or 980MUg/day) than for contaminant assessment (1.5MUg/day). Analytical detection limits for measurements of potential reaction and thermal breakdown products in vaping aerosol, should be informed by the contaminant threshold. This principle leads us to recommend 5ng/puff as an appropriate limit of detection for untargeted aerosol measurements. PMID- 26026507 TI - Invited Article: Single-shot THz detection techniques optimized for multidimensional THz spectroscopy. AB - Multidimensional spectroscopy at visible and infrared frequencies has opened a window into the transfer of energy and quantum coherences at ultrafast time scales. For these measurements to be performed in a manageable amount of time, one spectral axis is typically recorded in a single laser shot. An analogous rapid-scanning capability for THz measurements will unlock the multidimensional toolkit in this frequency range. Here, we first review the merits of existing single-shot THz schemes and discuss their potential in multidimensional THz spectroscopy. We then introduce improved experimental designs and noise suppression techniques for the two most promising methods: frequency-to-time encoding with linear spectral interferometry and angle-to-time encoding with dual echelons. Both methods, each using electro-optic detection in the linear regime, were able to reproduce the THz temporal waveform acquired with a traditional scanning delay line. Although spectral interferometry had mediocre performance in terms of signal-to-noise, the dual echelon method was easily implemented and achieved the same level of signal-to-noise as the scanning delay line in only 4.5% of the laser pulses otherwise required (or 22 times faster). This reduction in acquisition time will compress day-long scans to hours and hence provides a practical technique for multidimensional THz measurements. PMID- 26026506 TI - Regional brain activation supporting cognitive control in the context of reward is associated with treated adolescents' marijuana problem severity at follow-up: A preliminary study. AB - This preliminary study examined the extent to which regional brain activation during a reward cue antisaccade (AS) task was associated with 6-month treatment outcome in adolescent substance users. Antisaccade performance provides a sensitive measure of executive function and cognitive control, and generally improves with reward cues. We hypothesized that when preparing to execute an AS, greater activation in regions associated with cognitive and oculomotor control supporting AS, particularly during reward cue trials, would be associated with lower substance use severity at 6-month follow-up. Adolescents (n=14, ages 14-18) recruited from community-based outpatient treatment completed an fMRI reward cue AS task (reward and neutral conditions), and provided follow-up data. Results indicated that AS errors decreased in reward, compared to neutral, trials. AS behavioral performance, however, was not associated with treatment outcome. As hypothesized, activation in regions of interest (ROIs) associated with cognitive (e.g., ventrolateral prefrontal cortex) and oculomotor control (e.g., supplementary eye field) during reward trials were inversely correlated with marijuana problem severity at 6-months. ROI activation during neutral trials was not associated with outcomes. Results support the role of motivational (reward cue) factors to enhance cognitive control processes, and suggest a potential brain-based correlate of youth treatment outcome. PMID- 26026508 TI - An electrically tunable plenoptic camera using a liquid crystal microlens array. AB - Plenoptic cameras generally employ a microlens array positioned between the main lens and the image sensor to capture the three-dimensional target radiation in the visible range. Because the focal length of common refractive or diffractive microlenses is fixed, the depth of field (DOF) is limited so as to restrict their imaging capability. In this paper, we propose a new plenoptic camera using a liquid crystal microlens array (LCMLA) with electrically tunable focal length. The developed LCMLA is fabricated by traditional photolithography and standard microelectronic techniques, and then, its focusing performance is experimentally presented. The fabricated LCMLA is directly integrated with an image sensor to construct a prototyped LCMLA-based plenoptic camera for acquiring raw radiation of targets. Our experiments demonstrate that the focused region of the LCMLA based plenoptic camera can be shifted efficiently through electrically tuning the LCMLA used, which is equivalent to the extension of the DOF. PMID- 26026509 TI - Improved x-ray detection and particle identification with avalanche photodiodes. AB - Avalanche photodiodes are commonly used as detectors for low energy x-rays. In this work, we report on a fitting technique used to account for different detector responses resulting from photoabsorption in the various avalanche photodiode layers. The use of this technique results in an improvement of the energy resolution at 8.2 keV by up to a factor of 2 and corrects the timing information by up to 25 ns to account for space dependent electron drift time. In addition, this waveform analysis is used for particle identification, e.g., to distinguish between x-rays and MeV electrons in our experiment. PMID- 26026510 TI - Sub-nanometer periodic nonlinearity error in absolute distance interferometers. AB - Periodic nonlinearity which can result in error in nanometer scale has become a main problem limiting the absolute distance measurement accuracy. In order to eliminate this error, a new integrated interferometer with non-polarizing beam splitter is developed. This leads to disappearing of the frequency and/or polarization mixing. Furthermore, a strict requirement on the laser source polarization is highly reduced. By combining retro-reflector and angel prism, reference and measuring beams can be spatially separated, and therefore, their optical paths are not overlapped. So, the main cause of the periodic nonlinearity error, i.e., the frequency and/or polarization mixing and leakage of beam, is eliminated. Experimental results indicate that the periodic phase error is kept within 0.0018 degrees . PMID- 26026511 TI - Closing the pressure gap in x-ray photoelectron spectroscopy by membrane hydrogenation. AB - Comprehensive studies of gas-solid reactions require the in-situ interaction of the gas at a pressure beyond the operating pressure of ultrahigh vacuum (UHV) X ray photoelectron spectroscopy (XPS). The recent progress of near ambient pressure XPS allows to dose gases to the sample up to a pressure of 20 mbar. The present work describes an alternative to this experimental challenge, with a focus on H2 as the interacting gas. Instead of exposing the sample under investigation to gaseous hydrogen, the sample is in contact with a hydrogen permeation membrane, through which hydrogen is transported from the outside to the sample as atomic hydrogen. Thereby, we can reach local hydrogen concentrations at the sample inside an UHV chamber, which is equipped with surface science tools, and this corresponds to a hydrogen pressure up to 1 bar without affecting the sensitivity or energy resolution of the spectrometer. This experimental approach is validated by two examples, that is, the reduction of a catalyst precursor for CO2 hydrogenation and the hydrogenation of a water reduction catalyst for photocatalytic H2 production, but it opens the possibility of the new in situ characterisation of energy materials and catalysts. PMID- 26026513 TI - Accurate convergence of transient-absorption spectra using pulsed lasers. AB - Transient-absorption spectroscopy is a common and well-developed technique for measuring time-dependent optical phenomena. One important aspect, especially for measurements using pulsed lasers, is how to average multiple data acquisition events. Here, we use a mathematical analysis method based on covariance to evaluate various averaging schemes. The analysis reveals that the baseline and the signal converge to incorrect values without balanced detection of the probe, shot-by-shot detection, and a specific method of averaging. Experiments performed with sub-7 fs pulses confirm the analytic results and reveal insights into molecular excited-state vibrational dynamics. PMID- 26026512 TI - A Q-switched Ho:YAG laser assisted nanosecond time-resolved T-jump transient mid IR absorbance spectroscopy with high sensitivity. AB - Knowledge of dynamical structure of protein is an important clue to understand its biological function in vivo. Temperature-jump (T-jump) time-resolved transient mid-IR absorbance spectroscopy is a powerful tool in elucidating the protein dynamical structures and the folding/unfolding kinetics of proteins in solution. A home-built setup of T-jump time-resolved transient mid-IR absorbance spectroscopy with high sensitivity is developed, which is composed of a Q switched Cr, Tm, Ho:YAG laser with an output wavelength at 2.09 MUm as the T-jump heating source, and a continuous working CO laser tunable from 1580 to 1980 cm( 1) as the IR probe. The results demonstrate that this system has a sensitivity of 1 * 10(-4) DeltaOD for a single wavelength detection, and 2 * 10(-4) DeltaOD for spectral detection in amide I' region, as well as a temporal resolution of 20 ns. Moreover, the data quality coming from the CO laser is comparable to the one using the commercial quantum cascade laser. PMID- 26026514 TI - Imaging of transient surface acoustic waves by full-field photorefractive interferometry. AB - A stroboscopic full-field imaging technique based on photorefractive interferometry for the visualization of rapidly changing surface displacement fields by using of a standard charge-coupled device (CCD) camera is presented. The photorefractive buildup of the space charge field during and after probe laser pulses is simulated numerically. The resulting anisotropic diffraction upon the refractive index grating and the interference between the polarization rotated diffracted reference beam and the transmitted signal beam are modeled theoretically. The method is experimentally demonstrated by full-field imaging of the propagation of photoacoustically generated surface acoustic waves with a temporal resolution of nanoseconds. The surface acoustic wave propagation in a 23 mm * 17 mm area on an aluminum plate was visualized with 520 * 696 pixels of the CCD sensor, yielding a spatial resolution of 33 MUm. The short pulse duration (8 ns) of the probe laser yields the capability of imaging SAWs with frequencies up to 60 MHz. PMID- 26026515 TI - A chopper system for shortening the duration of pulsed supersonic beams seeded with NO or Br2 down to 13 MUs. AB - A chopper wheel construct is used to shorten the duration of a molecular beam to 13 MUs. Molecular beams seeded with NO or with Br2 and an initial pulse width of >=200 MUs were passed through a spinning chopper wheel, which was driven by a brushless DC in vacuo motor at a range of speeds, from 3000 rpm to 80,000 rpm. The resulting duration of the molecular-beam pulses measured at the laser detection volume ranged from 80 MUs to 13 MUs and was the same for both NO and Br2. The duration is consistent with a simple analytical model, and the minimum pulse width measured is limited by the spreading of the beam between the chopper and the detection point as a consequence of the longitudinal velocity distribution of the beam. The setup adopted here effectively eliminates buildup of background gas without the use of a differential pumping stage, and a clean narrow pulse is obtained with low rotational temperature. PMID- 26026516 TI - High efficiency positron accumulation for high-precision magnetic moment experiments. AB - Positrons are accumulated within a Penning trap designed to make more precise measurements of the positron and electron magnetic moments. The retractable radioactive source used is weak enough to require no license for handling radioactive material, and the radiation dosage 1 m from the source gives an exposure several times smaller than the average radiation dose on the earth's surface. The 100 mK trap is mechanically aligned with the 4.2 K superconducting solenoid that produces a 6 T magnetic trapping field with a direct mechanical coupling. PMID- 26026517 TI - Magnetized retarding field energy analyzer measuring the particle flux and ion energy distribution of both positive and negative ions. AB - This paper presents the development of a magnetized retarding field energy analyzer (MRFEA) used for positive and negative ion analysis. The two-stage analyzer combines a magnetic electron barrier and an electrostatic ion energy barrier allowing both positive and negative ions to be analyzed without the influence of electrons (co-extracted or created downstream). An optimal design of the MRFEA for ion-ion beams has been achieved by a comparative study of three different MRFEA configurations, and from this, scaling laws of an optimal magnetic field strength and topology have been deduced. The optimal design consists of a uniform magnetic field barrier created in a rectangular channel and an electrostatic barrier consisting of a single grid and a collector placed behind the magnetic field. The magnetic barrier alone provides an electron suppression ratio inside the analyzer of up to 6000, while keeping the ion energy resolution below 5 eV. The effective ion transparency combining the magnetic and electrostatic sections of the MRFEA is measured as a function of the ion energy. It is found that the ion transparency of the magnetic barrier increases almost linearly with increasing ion energy in the low-energy range (below 200 eV) and saturates at high ion energies. The ion transparency of the electrostatic section is almost constant and close to the optical transparency of the entrance grid. We show here that the MRFEA can provide both accurate ion flux and ion energy distribution measurements in various experimental setups with ion beams or plasmas run at low pressure and with ion energies above 10 eV. PMID- 26026518 TI - A confocal microscope position sensor for micron-scale target alignment in ultra intense laser-matter experiments. AB - A diagnostic tool for precise alignment of targets in laser-matter interactions based on confocal microscopy is presented. This device permits precision alignment of targets within the Rayleigh range of tight focusing geometries for a wide variety of target surface morphologies. This confocal high-intensity positioner achieves micron-scale target alignment by selectively accepting light reflected from a narrow range of target focal planes. Additionally, the design of the device is such that its footprint and sensitivity can be tuned for the desired chamber and experiment. The device has been demonstrated to position targets repeatably within the Rayleigh range of the Scarlet laser system at The Ohio State University, where use of the device has provided a marked increase in ion yield and maximum energy. PMID- 26026519 TI - Peculiarities of measuring ion energy distribution in plasma with a retarding field analyzer. AB - Presented are the results from tailoring the retarding field energy analyzer to measure the degree of charge compensation and regular patterns in the separations of ions of different mass, with the multicomponent ion flow spreading out in the plasma-optical mass separator model. PMID- 26026520 TI - Fast valve based on double-layer eddy-current repulsion for disruption mitigation in Experimental Advanced Superconducting Tokamak. AB - A fast valve based on the double-layer eddy-current repulsion mechanism has been developed on Experimental Advanced Superconducting Tokamak (EAST). In addition to a double-layer eddy-current coil, a preload system was added to improve the security of the valve, whereby the valve opens more quickly and the open-valve time becomes shorter, making it much safer than before. In this contribution, testing platforms, open-valve characteristics, and throughput of the fast valve are discussed. Tests revealed that by choosing appropriate parameters the valve opened within 0.15 ms, and open-valve times were no longer than 2 ms. By adjusting working parameter values, the maximum number of particles injected during this open-valve time was estimated at 7 * 10(22). The fast valve will become a useful tool to further explore disruption mitigation experiments on EAST in 2015. PMID- 26026521 TI - Response measurement of single-crystal chemical vapor deposition diamond radiation detector for intense X-rays aiming at neutron bang-time and neutron burn-history measurement on an inertial confinement fusion with fast ignition. AB - A neutron bang time and burn history monitor in inertial confinement fusion with fast ignition are necessary for plasma diagnostics. In the FIREX project, however, no detector attained those capabilities because high-intensity X-rays accompanied fast electrons used for plasma heating. To solve this problem, single crystal CVD diamond was grown and fabricated into a radiation detector. The detector, which had excellent charge transportation property, was tested to obtain a response function for intense X-rays. The applicability for neutron bang time and burn history monitor was verified experimentally. Charge collection efficiency of 99.5% +/- 0.8% and 97.1% +/- 1.4% for holes and electrons were obtained using 5.486 MeV alpha particles. The drift velocity at electric field which saturates charge collection efficiency was 1.1 +/- 0.4 * 10(7) cm/s and 1.0 +/- 0.3 * 10(7) cm/s for holes and electrons. Fast response of several ns pulse width for intense X-ray was obtained at the GEKKO XII experiment, which is sufficiently fast for ToF measurements to obtain a neutron signal separately from X-rays. Based on these results, we confirmed that the single-crystal CVD diamond detector obtained neutron signal with good S/N under ion temperature 0.5-1 keV and neutron yield of more than 10(9) neutrons/shot. PMID- 26026522 TI - Power supply and impedance matching to drive technological radio-frequency plasmas with customized voltage waveforms. AB - We present a novel radio-frequency (RF) power supply and impedance matching to drive technological plasmas with customized voltage waveforms. It is based on a system of phase-locked RF generators that output single frequency voltage waveforms corresponding to multiple consecutive harmonics of a fundamental frequency. These signals are matched individually and combined to drive a RF plasma. Electrical filters are used to prevent parasitic interactions between the matching branches. By adjusting the harmonics' phases and voltage amplitudes individually, any voltage waveform can be approximated as a customized finite Fourier series. This RF supply system is easily adaptable to any technological plasma for industrial applications and allows the commercial utilization of process optimization based on voltage waveform tailoring for the first time. Here, this system is tested on a capacitive discharge based on three consecutive harmonics of 13.56 MHz. According to the Electrical Asymmetry Effect, tuning the phases between the applied harmonics results in an electrical control of the DC self-bias and the mean ion energy at almost constant ion flux. A comparison with the reference case of an electrically asymmetric dual-frequency discharge reveals that the control range of the mean ion energy can be significantly enlarged by using more than two consecutive harmonics. PMID- 26026523 TI - Visible wide angle view imaging system of KTM tokamak based on multielement image fiber bundle. AB - In the paper, new visible wide angle view imaging system of KTM tokamak is described. The system has been designed to observe processes inside of plasma and the processes occurring due to plasma-wall interactions through the long equatorial port. Imaging system is designed based on special image fiber bundle and entrance wide angle lens, which provide image of large section of the vacuum chamber, both poloidal half-section and divertor through the sufficiently long equatorial port. The system also consists of two video cameras: slow and fast with image intensifier. Commercial equipment had been used in design of the system that allowed reducing the cost and time for research and development. The paper also discusses advantages and disadvantages of the system in comparison with conventional endoscopes based on a lens system and considers its promising utilization in future tokamaks and future steady state fusion reactors. PMID- 26026524 TI - A method for in situ absolute DD yield calibration of neutron time-of-flight detectors on OMEGA using CR-39-based proton detectors. AB - Neutron time of flight (nTOF) detectors are used routinely to measure the absolute DD neutron yield at OMEGA. To check the DD yield calibration of these detectors, originally calibrated using indium activation systems, which in turn were cross-calibrated to NOVA nTOF detectors in the early 1990s, a direct in situ calibration method using CR-39 range filter proton detectors has been successfully developed. By measuring DD neutron and proton yields from a series of exploding pusher implosions at OMEGA, a yield calibration coefficient of 1.09 +/- 0.02 (relative to the previous coefficient) was determined for the 3m nTOF detector. In addition, comparison of these and other shots indicates that significant reduction in charged particle flux anisotropies is achieved when bang time occurs significantly (on the order of 500 ps) after the trailing edge of the laser pulse. This is an important observation as the main source of the yield calibration error is due to particle anisotropies caused by field effects. The results indicate that the CR-39-nTOF in situ calibration method can serve as a valuable technique for calibrating and reducing the uncertainty in the DD absolute yield calibration of nTOF detector systems on OMEGA, the National Ignition Facility, and laser megajoule. PMID- 26026525 TI - A resistively heated CeB6 emissive probe. AB - The plasma potential, V(p), is a key quantity in experimental plasma physics. Its spatial gradients directly yield the electrostatic field present. Emissive probes operating under space-charge limited emission conditions float close to V(p) even under time-varying conditions. Throughout their long history in plasma physics, they have mostly been constructed with resistively heated tungsten wire filaments. In high density plasmas (>10(12) cm(-3)), hexaboride emitters are required because tungsten filaments cannot be heated to sufficient emission without component failure. A resistively heated emissive probe with a cerium hexaboride, CeB6, emitter has been developed to work in plasma densities up to 10(13) cm(-3). To show functionality, three spatial profiles of V(p) are compared using the emissive probe, a cold floating probe, and a swept probe inside a plasma containing regions with and without current. The swept probe and emissive probe agree well across the profile while the floating cold probe fails in the current carrying region. PMID- 26026526 TI - Mode-mismatched confocal thermal-lens microscope with collimated probe beam. AB - We report a thermal lens microscope (TLM) based on an optimized mode-mismatched configuration. It takes advantage of the coaxial counter propagating tightly focused excitation and collimated probe beams, instead of both focused at the sample, as it is in currently known TLM setups. A simple mathematical model that takes into account the main features of the instrument is presented. The confocal detection scheme and the introduction of highly collimated probe beam allow enhancing the versatility, limit of detection (LOD), and sensitivity of the instrument. The theory is experimentally verified measuring ethanol's absorption coefficient at 532.8 nm. Additionally, the presented technique is applied for detection of ultra-trace amounts of Cr(III) in liquid solution. The achieved LOD is 1.3 ppb, which represents 20-fold enhancement compared to transmission mode spectrometric techniques and a 7.5-fold improvement compared to previously reported methods for Cr(III) based on thermal lens effect. PMID- 26026527 TI - Automatic real time evaluation of red blood cell elasticity by optical tweezers. AB - Optical tweezers have been used to trap, manipulate, and measure individual cell properties. In this work, we show that the association of a computer controlled optical tweezers system with image processing techniques allows rapid and reproducible evaluation of cell deformability. In particular, the deformability of red blood cells (RBCs) plays a key role in the transport of oxygen through the blood microcirculation. The automatic measurement processes consisted of three steps: acquisition, segmentation of images, and measurement of the elasticity of the cells. An optical tweezers system was setup on an upright microscope equipped with a CCD camera and a motorized XYZ stage, computer controlled by a Labview platform. On the optical tweezers setup, the deformation of the captured RBC was obtained by moving the motorized stage. The automatic real-time homemade system was evaluated by measuring RBCs elasticity from normal donors and patients with sickle cell anemia. Approximately 150 erythrocytes were examined, and the elasticity values obtained by using the developed system were compared to the values measured by two experts. With the automatic system, there was a significant time reduction (60*) of the erythrocytes elasticity evaluation. Automated system can help to expand the applications of optical tweezers in hematology and hemotherapy. PMID- 26026528 TI - Fast and reliable method of conductive carbon nanotube-probe fabrication for scanning probe microscopy. AB - We demonstrate the procedure of scanning probe microscopy (SPM) conductive probe fabrication with a single multi-walled carbon nanotube (MWNT) on a silicon cantilever pyramid. The nanotube bundle reliably attached to the metal-covered pyramid is formed using dielectrophoresis technique from the MWNT suspension. It is shown that the dimpled aluminum sample can be used both for shortening/modification of the nanotube bundle by applying pulse voltage between the probe and the sample and for controlling the probe shape via atomic force microscopy imaging the sample. Carbon nanotube attached to cantilever covered with noble metal is suitable for SPM imaging in such modulation regimes as capacitance contrast microscopy, Kelvin probe microscopy, and scanning gate microscopy. The majority of such probes are conductive with conductivity not degrading within hours of SPM imaging. PMID- 26026529 TI - Design and optimization of arrays of neodymium iron boron-based magnets for magnetic tweezers applications. AB - We present the design methodology for arrays of neodymium iron boron (NdFeB) based magnets for use in magnetic tweezers devices. Using finite element analysis (FEA), we optimized the geometry of the NdFeB magnet as well as the geometry of iron yokes designed to focus the magnetic fields toward the sample plane. Together, the magnets and yokes form a magnetic array which is the basis of the magnetic tweezers device. By systematically varying 15 distinct shape parameters, we determined those features that maximize the magnitude of the magnetic field gradient as well as the length scale over which the magnetic force operates. Additionally, we demonstrated that magnetic saturation of the yoke material leads to intrinsic limitations in any geometric design. Using this approach, we generated a compact and light-weight magnetic tweezers device that produces a high field gradient at the image plane in order to apply large forces to magnetic beads. We then fabricated the optimized yoke and validated the FEA by experimentally mapping the magnetic field of the device. The optimization data and iterative FEA approach outlined here will enable the streamlined design and construction of specialized instrumentation for force-sensitive microscopy. PMID- 26026530 TI - A method for the monitoring of metal recrystallization based on the in-situ measurement of the elastic energy release using neutron diffraction. AB - A method is proposed for the monitoring of metal recrystallization using neutron diffraction that is based on the measurement of stored energy. Experiments were performed using deformed metal specimens heated in-situ while mounted at the sample position of the High Resolution Powder Diffractometer, HRPD (ISIS Facility), UK. Monitoring the breadth of the resulting Bragg lines during heating not only allows the time-dependence (or temperature-dependence) of the stored energy to be determined but also the recrystallized fraction. The analysis method presented here was developed using pure nickel (Ni270) specimens with different deformation levels from 0.29 to 0.94. In situ temperature ramping as well as isothermal annealing was undertaken. The method developed in this work allows accurate and quantitative monitoring of the recrystallization process. The results from neutron diffraction are satisfactorily compared to data obtained from calorimetry and hardness measurements. PMID- 26026531 TI - Thin film cryogenic thermometers defined with optical lithography for thermomagnetic measurements on films. AB - Resistance thermometers are common secondary thermometers in cryogenic applications. Bulk RuO2 thermometers are used in dilution refrigerators because of their low magnetoresistances in addition to their temperature sensitivity. Thermoelectric and thermomagnetic measurements require multiple thermometers to measure temperature differences. Here, we present a method to fabricate thin film RuO2 thermometers directly onto an experimental substrate. This enhances thermal contact between thermometers and films whose thermoelectric or thermomagnetic properties may be measured. Commercial thermometers have higher temperature sensitivities than the thermometers presented in this study, but commercial thermometers must be carefully heat sunk to the cryostat or sample to be useful. Thin film thermometers can be patterned with ultraviolet (UV) lithography. This allows both the size of the thermometer and its distance from the sample, when also patterned with UV lithography, to be on the order of micrometers. A universal calibration curve for these thin film thermometers has not been produced. The efficacy of these thermometers has been demonstrated through measurements of the Nernst effect in Nb. In this study, the thin film thermometers were calibrated using the cryostat thermometers. PMID- 26026532 TI - Development of micro-four-point probe in a scanning tunneling microscope for in situ electrical transport measurement. AB - Electrons at surface may behave differently from those in bulk of a material. Multi-functional tools are essential in comprehensive studies on a crystal surface. Here, we developed an in situ microscopic four-point probe (4PP) transport measurement system on the basis of a scanning tunneling microscope (STM). In particular, convenient replacement between STM tips and micro-4PPs enables systematic investigations of surface morphology, electronic structure, and electrical transport property of a same sample surface. Performances of the instrument are demonstrated with high-quality STM images, tunneling spectra, and low-noise electrical I-V characteristic curves of a single-layer FeSe film grown on a conductive SrTiO3 surface. PMID- 26026533 TI - Piston pressure cell for low-temperature infrared investigations. AB - The design of a piston pressure cell ranging up to approximately 11 kilobars is reported, which allows for optical reflection measurements in the infrared spectral range from 100 to 8000 cm(-1) down to temperatures as low as 6 K. The mechanical alignment and vacuum considerations are discussed before details of the sample preparation are given, with particular emphasis on small and fragile single crystals, mosaics, and pressed powder. A few examples of one- and two dimensional organic conductors illustrate the performance. PMID- 26026534 TI - Rapid determination of Faraday rotation in optical glasses by means of secondary Faraday modulator. AB - A rapid high sensitive method for determining the Faraday rotation of optical glasses is proposed. Starting from an experimental setup based on a Faraday rod coupled to a lock-in amplifier in the detection chain, two methodologies were developed for providing reliable results on samples presenting low and large Faraday rotations. The proposed methodologies were critically discussed and compared, via results obtained in transmission geometry, on a new series of aluminophosphate glasses with or without rare-earth doping ions. An example on how the method can be used for a rapid examination of the optical homogeneity of the sample with respect to magneto-optical effects is also provided. PMID- 26026535 TI - A compact and low-weight sputtering unit for in situ investigations of thin film growth at synchrotron radiation beamlines. AB - In this work, we report on a highly variable, compact, and light high-vacuum sputter deposition unit designed for in situ experiments using synchrotron radiation facilities. The chamber can be mounted at various synchrotron beamlines for scattering experiments in grazing incidence geometry. The sample position and the large exit window allow to perform x-ray experiments up to large q values. The sputtering unit is easy to mount on existing experimental setups and can be remote-controlled. In this paper, we describe in detail the design and the performance of the new sputtering chamber and present the installation of the apparatus at different 3rd generation light sources. Furthermore, we describe the different measurement options and present some selected results. The unit has been successfully commissioned and is now available for users at PETRA III at DESY. PMID- 26026536 TI - A technique for continuous measurement of the quality factor of mechanical oscillators. AB - Thermal noise is a limit to precision measurement in many fields. The relationship of the quality factor of mechanical systems to the thermal noise has compelled many researchers to search for materials with low mechanical losses. Typical measurements of mechanical quality factor involve exciting a mechanical resonator and observing the exponential decay of the amplitude under free oscillations. Estimation of the decay time allows one to infer the quality factor. In this article, we describe an alternative technique in which the resonator is forced to oscillate at constant amplitude, and the quality factor is estimated by measuring the drive amplitude required to maintain constant oscillation amplitude. A straightforward method for calibration of the quality factor is presented, along with an analysis of the propagation of measurement uncertainties. Such a technique allows the quality factor to be measured continuously in real time and at constant signal to noise ratio. PMID- 26026537 TI - Single Hit Energy-resolved Laue Diffraction. AB - In situ white light Laue diffraction has been successfully used to interrogate the structure of single crystal materials undergoing rapid (nanosecond) dynamic compression up to megabar pressures. However, information on strain state accessible via this technique is limited, reducing its applicability for a range of applications. We present an extension to the existing Laue diffraction platform in which we record the photon energy of a subset of diffraction peaks. This allows for a measurement of the longitudinal and transverse strains in situ during compression. Consequently, we demonstrate measurement of volumetric compression of the unit cell, in addition to the limited aspect ratio information accessible in conventional white light Laue. We present preliminary results for silicon, where only an elastic strain is observed. VISAR measurements show the presence of a two wave structure and measurements show that material downstream of the second wave does not contribute to the observed diffraction peaks, supporting the idea that this material may be highly disordered, or has undergone large scale rotation. PMID- 26026538 TI - Enhancement of molecular sensitivity in positron emission tomography with quantum correlation of gamma-ray photons. AB - Enhancement of molecular sensitivity in positron emission tomography (PET) has long been discussed with respect to imaging instrumentation and algorithms for data treatment. Here, the molecular sensitivity in PET is discussed on the basis of 2-dimensional coincident measurements of 511 keV gamma ray photons resultant from two-photon annihilation. Introduction of an additional selection window based on the energy sum and difference of the coincidently measured gamma ray photons, without any significant instrumental and algorithmic changes, showed an improvement in the signal-to-noise ratio (SNR) by an order of magnitude. Improvement of performance characteristics in the PET imaging system was demonstrated by an increase in the noise equivalent count rate (NECR) which takes both the SNR and the detection efficiency into consideration. A further improvement of both the SNR and the NECR is expected for the present system in real clinical and in-vivo environments, where much stronger positron sources are employed. PMID- 26026539 TI - An integrated time-of-flight versus residual energy subsystem for a compact dual ion composition experiment for space plasmas. AB - We have developed a novel concept for a Compact Dual Ion Composition Experiment (CoDICE) that simultaneously provides high quality plasma and energetic ion composition measurements over 6 decades in ion energy in a wide variety of space plasma environments. CoDICE measures the two critical ion populations in space plasmas: (1) mass and ionic charge state composition and 3D velocity and angular distributions of ~10 eV/q-40 keV/q plasma ions-CoDICE-Lo and (2) mass composition, energy spectra, and angular distributions of ~30 keV-10 MeV energetic ions-CoDICE-Hi. CoDICE uses a common, integrated Time-of-Flight (TOF) versus residual energy (E) subsystem for measuring the two distinct ion populations. This paper describes the CoDICE design concept, and presents results of the laboratory tests of the TOF portion of the TOF vs. E subsystem, focusing specifically on (1) investigation of spill-over and contamination rates on the start and stop microchannel plate (MCP) anodes vs. secondary electron steering and focusing voltages, scanned around their corresponding model-optimized values, (2) TOF measurements and resolution and angular resolution, and (3) cross contamination of the start and stop MCPs' singles rates from CoDICE-Lo and -Hi, and (4) energy resolution of avalanche photodiodes near the lower end of the CoDICE-Lo energy range. We also discuss physical effects that could impact the performance of the TOF vs. E subsystem in a flight instrument. Finally, we discuss advantages of the CoDICE design concept by comparing with capabilities and resources of existing flight instruments. PMID- 26026540 TI - Parametric design of tri-axial nested Helmholtz coils. AB - This paper provides an optimal parametric design for tri-axial nested Helmholtz coils, which are used to generate a uniform magnetic field with controllable magnitude and direction. Circular and square coils, both with square cross section, are considered. Practical considerations such as wire selection, wire wrapping efficiency, wire bending radius, choice of power supply, and inductance and time response are included. Using the equations provided, a designer can quickly create an optimal set of custom coils to generate a specified field magnitude in the uniform-field region while maintaining specified accessibility to the central workspace. An example case study is included. PMID- 26026541 TI - Effect of BaTiO3 nano-particles on breakdown performance of propylene carbonate. AB - As an alternative to water, propylene carbonate (PC) has a good application prospect in the compact pulsed power sources for its breakdown strength higher than that of water, resistivity bigger than 10(9) Omega m, and low freezing temperature (-49 degrees C). In this paper, the investigation into dielectric breakdown of PC and PC-based nano-fluids (NFs) subjected to high amplitude electric field is presented with microsecond pulses applied to a 1 mm gap full of PC or NFs between spherical electrodes. One kind of NF is composed of PC mixed with 0.5-1.4 vol. % BaTiO3 (BT) nano-particles of mean diameter ~100 nm and another is mixed with 0.3-0.8 vol. % BT nano-particles of mean diameter ~30 nm. The experimental results demonstrate the rise of permittivity and improvement of the breakdown strength of NFs compared with PC. Moreover, it is found that there exists an optimum fraction for these NFs corresponding to tremendous surface area in nano-composites with finite mesoscopic thickness. In concrete, the dielectric breakdown voltage of NFs is 33% higher than that of PC as the volume concentration of nano-particles with a 100 nm diameter is 0.9% and the breakdown voltage of NFs is 40% higher as the volume concentration of nano-particles with a 30 nm diameter is 0.6%. These phenomena are considered as the dielectric breakdown voltage of PC-based NFs is increased because the interfaces between nano-fillers and PC matrices provide myriad trap sites for charge carriers, which play a dominant role in the breakdown performance of NFs. PMID- 26026542 TI - Performance analysis of a digital capacitance measuring circuit. AB - This paper presents the design and study of a digital capacitance measuring circuit with theoretical analysis, numerical simulation, and experimental evaluation. The static and dynamic performances of the capacitance measuring circuit are first defined, including signal-to-noise ratio (SNR), standard deviation, accuracy, linearity, sensitivity, and response time, within a given measurement range. Then numerical simulation is carried out to analyze the SNR and standard deviation of the circuit, followed by experiments to validate the overall performance of the circuit. The simulation results show that when the standard deviation of noise is 0.08 mV and the measured capacitance decreases from 6 pF to 3 fF, the SNR decreases from 90 dB to 22 dB and the standard deviation is between 0.17 fF and 0.24 fF. The experimental results show that when the measured capacitance decreases from 6 pF to 40 fF and the data sampled in a single period are used for demodulation, the SNR decreases from 88 dB to 40 dB and the standard deviation is between 0.18 fF and 0.25 fF. The maximum absolute error and relative error are 5.12 fF and 1.26%, respectively. The SNR and standard deviation can be further improved if the data sampled in more than one period are used for demodulation by the circuit. PMID- 26026543 TI - Portable microwave frequency dissemination in free space and implications on ground-to-satellite synchronization. AB - Frequency dissemination and synchronization in free space play an important role in global navigation satellite system, radio astronomy, and synthetic aperture radar. In this paper, we demonstrated a portable radio frequency dissemination scheme via free space using microwave antennas. The setup has a good environment adaptability and high dissemination stability. The frequency signal was disseminated at different distances ranging from 10 to 640 m with a fixed 10 Hz locking bandwidth, and the scaling law of dissemination stability on distance and averaging time was discussed. The preliminary extrapolation shows that the dissemination stability may reach 1 * 10(-12)/s in ground-to-satellite synchronization, which far exceeds all present methods, and is worthy for further study. PMID- 26026544 TI - Experimental tests of a 263 GHz gyrotron for spectroscopic applications and diagnostics of various media. AB - A 263 GHz continuous-wave (CW) gyrotron was developed at the IAP RAS for future applications as a microwave power source in Dynamic Nuclear Polarization / Nuclear magnetic resonance (DNP/NMR) spectrometers. A new experimental facility with a computerized control was built to test this and subsequent gyrotrons. We obtained the maximum CW power up to 1 kW in the 15 kV/0.4 A operation regime. The power about 10 W, which is sufficient for many spectroscopic applications, was realized in the low current 14 kV/0.02 A regime. The possibility of frequency tuning by variation of the coolant temperature about 4 MHz/1 degrees C was demonstrated. The spectral width of the gyrotron radiation was about 10(-6). PMID- 26026545 TI - The study of frequency-scan photothermal reflectance technique for thermal diffusivity measurement. AB - A frequency scan photothermal reflectance technique to measure thermal diffusivity of bulk samples is studied in this manuscript. Similar to general photothermal reflectance methods, an intensity-modulated heating laser and a constant intensity probe laser are used to determine the surface temperature response under sinusoidal heating. The approach involves fixing the distance between the heating and probe laser spots, recording the phase lag of reflected probe laser intensity with respect to the heating laser frequency modulation, and extracting thermal diffusivity using the phase lag-(frequency)(1/2) relation. The experimental validation is performed on three samples (SiO2, CaF2, and Ge), which have a wide range of thermal diffusivities. The measured thermal diffusivity values agree closely with the literature values. Compared to the commonly used spatial scan method, the experimental setup and operation of the frequency scan method are simplified, and the uncertainty level is equal to or smaller than that of the spatial scan method. PMID- 26026546 TI - A 3 omega method to measure an arbitrary anisotropic thermal conductivity tensor. AB - Previous use of the 3 omega method has been limited to materials with thermal conductivity tensors that are either isotropic or have their principal axes aligned with the natural cartesian coordinate system defined by the heater line and sample surface. Here, we consider the more general case of an anisotropic thermal conductivity tensor with finite off-diagonal terms in this coordinate system. An exact closed form solution for surface temperature has been found for the case of an ideal 3 omega heater line of finite width and infinite length, and verified numerically. We find that the common slope method of data processing yields the determinant of the thermal conductivity tensor, which is invariant upon rotation about the heater line's axis. Following this analytic result, an experimental scheme is proposed to isolate the thermal conductivity tensor elements. Using two heater lines and a known volumetric heat capacity, the arbitrary 2-dimensional anisotropic thermal conductivity tensor can be measured with a low frequency sweep. Four heater lines would be required to extend this method to measure all 6 unknown tensor elements in 3 dimensions. Experiments with anisotropic layered mica are carried out to demonstrate the analytical results. PMID- 26026547 TI - Burst design and signal processing for the speed of sound measurement of fluids with the pulse-echo technique. AB - The pulse-echo technique determines the propagation time of acoustic wave bursts in a fluid over a known propagation distance. It is limited by the signal quality of the received echoes of the acoustic wave bursts, which degrades with decreasing density of the fluid due to acoustic impedance and attenuation effects. Signal sampling is significantly improved in this work by burst design and signal processing such that a wider range of thermodynamic states can be investigated. Applying a Fourier transformation based digital filter on acoustic wave signals increases their signal-to-noise ratio and enhances their time and amplitude resolutions, improving the overall measurement accuracy. In addition, burst design leads to technical advantages for determining the propagation time due to the associated conditioning of the echo. It is shown that the according operation procedure enlarges the measuring range of the pulse-echo technique for supercritical argon and nitrogen at 300 K down to 5 MPa, where it was limited to around 20 MPa before. PMID- 26026548 TI - High-temperature fiber-optic Fabry-Perot interferometric sensors. AB - A photonic crystal fiber (PCF) based high-temperature fiber-optic sensor is proposed and experimentally demonstrated. The sensor head is a Fabry-Perot cavity manufactured with a short section of endless single-mode photonic crystal fiber (ESM PCF). The interferometric spectrum of the Fabry-Perot interferometer is collected by a charge coupled device linear array based micro spectrometer. A high-resolution demodulation algorithm is used to interrogate the peak wavelengths. Experimental results show that the temperature range of 1200 degrees C and the temperature resolution of 1 degrees C are achieved. PMID- 26026549 TI - Damped leaf flexure hinge. AB - Flexure-based mechanism like compliant actuation system embeds complex dynamics that will reduce the control bandwidth and limits their dynamic positioning precision. This paper presents a theoretical model of a leaf flexure hinge with damping layers using strain energy method and Kelvin damping model. The modified loss factor of the damped leaf flexure hinge is derived, and the equivalent viscous damping coefficient of the damped leaf hinge is obtained, which could be used to improve the pseudo-rigid-model. The free vibration signals of the hinge in three different damping configurations are measured. The experimental modal analysis also is performed on the three kinds of damped leaf flexure hinges in order to evaluate their 1st order bending natural frequency and vibration suppressing effects. The evaluation of modified loss factor model also is performed. The experimental results indicate that the constrained layer damping can enhance the structure damping of the hinge even if only single damping layer each side, the modified loss factor model can get good predicts of a damped leaf flexure hinge in the frequency range below 1st order natural frequency, and it is necessary that the dimensional parameters of the damping layers and basic layer of the hinge should be optimized for simplification at the mechanism's design stage. PMID- 26026550 TI - A differential electromagnetic induction torque sensor and its finite element analysis. AB - Torque is an important parameter for condition monitoring and fault diagnosis for rotary machines. This paper describes a new structure differential torque sensor based on the principle of electromagnetic induction. The method involves the construction of a pulsating flux by the excitation winding of the sensor, and the torsion angle produced by the load torque is converted into the angle displacements of the excitation winding and the output winding. Last, the output winding of sensor generates an induction potential force, which is proportional to the load torque as seen through electromagnetic coupling. Sensor sensitivity would be reduced by load effect; therefore, this paper presents a suppression method that can ensure the sensitivity is not affected. The transfer function of the sensor is constructed through Laplace transformation. The sensor characteristics are simulated by finite elements, including the influence of winding coil numbers and excitation voltage frequency. The sensor was calibrated by a torsion testing machine, and the experimental results indicated that the sensitivity of the sensor is about 18.2 mV/Nm, the non-repeatability error is about 2.3%, the non-linear error is about 3.3%, and the hysteresis error is about 2.6%. PMID- 26026551 TI - A fast and reliable readout method for quantitative analysis of surface-enhanced Raman scattering nanoprobes on chip surface. AB - Surface-enhanced Raman scattering techniques have been widely used for bioanalysis due to its high sensitivity and multiplex capacity. However, the point-scanning method using a micro-Raman system, which is the most common method in the literature, has a disadvantage of extremely long measurement time for on chip immunoassay adopting a large chip area of approximately 1-mm scale and confocal beam point of ca. 1-MUm size. Alternative methods such as sampled spot scan with high confocality and large-area scan method with enlarged field of view and low confocality have been utilized in order to minimize the measurement time practically. In this study, we analyzed the two methods in respect of signal-to noise ratio and sampling-led signal fluctuations to obtain insights into a fast and reliable readout strategy. On this basis, we proposed a methodology for fast and reliable quantitative measurement of the whole chip area. The proposed method adopted a raster scan covering a full area of 100 MUm * 100 MUm region as a proof of-concept experiment while accumulating signals in the CCD detector for single spectrum per frame. One single scan with 10 s over 100 MUm * 100 MUm area yielded much higher sensitivity compared to sampled spot scanning measurements and no signal fluctuations attributed to sampled spot scan. This readout method is able to serve as one of key technologies that will bring quantitative multiplexed detection and analysis into practice. PMID- 26026553 TI - Simultaneous measurements of X-ray reflectivity and grazing incidence fluorescence at BL-16 beamline of Indus-2. AB - A new multipurpose x-ray reflectometer station has been developed and augmented at the microfocus beamline (BL-16) of Indus-2 synchrotron radiation source to facilitate synchronous measurements of specular x-ray reflectivity and grazing incidence x-ray fluorescence emission from thin layered structures. The design and various salient features of the x-ray reflectometer are discussed. The performance of the reflectometer has been evaluated by analyzing several thin layered structures having different surface interface properties. The results reveal in-depth information for precise determination of surface and interface properties of thin layered materials demonstrating the immense potential of the combined measurements of x-ray reflectivity and grazing incidence fluorescence on a single reflectometer. PMID- 26026552 TI - A slow neutron polarimeter for the measurement of parity-odd neutron rotary power. AB - We present the design, description, calibration procedure, and an analysis of systematic effects for an apparatus designed to measure the rotation of the plane of polarization of a transversely polarized slow neutron beam as it passes through unpolarized matter. This device is the neutron optical equivalent of a crossed polarizer/analyzer pair familiar from light optics. This apparatus has been used to search for parity violation in the interaction of polarized slow neutrons in matter. Given the brightness of existing slow neutron sources, this apparatus is capable of measuring a neutron rotary power of dphi/dz = 1 * 10(-7) rad/m. PMID- 26026554 TI - Laboratory surface astrochemistry experiments. AB - Although several research groups have studied the formation of H2 on interstellar dust grains using surface science techniques, few have explored the formation of more complex molecules. A small number of these reactions produce molecules that remain on the surface of interstellar dust grains and, over time, lead to the formation of icy mantles. The most abundant of these species within the ice is H2O and is of particular interest as the observed molecular abundance cannot be accounted for using gas-phase chemistry alone. This article provides a brief introduction to the astronomical implications and motivations behind this research and the requirement for a new dual atomic beam ultrahigh vacuum (UHV) system. Further details of the apparatus design, characterisation, and calibration of the system are provided along with preliminary data from atomic O and O2 beam dosing on bare silica substrate and subsequent temperature programmed desorption measurements. The results obtained in this ongoing research may enable more chemically accurate surface formation mechanisms to be deduced for this and other species before simulating the kinetic data under interstellar conditions. PMID- 26026555 TI - Mechanical characterization between room temperature and 1000 degrees C of SiC free-standing thin films by a novel high-temperature micro-tensile setup. AB - A novel high-temperature micro-tensile setup allows the characterization of the elastic and plastic as well as creep behavior of free-standing thin films at temperatures of up to 1000 degrees C. Correspondingly, a new layout for free standing thin film tensile test structures has been developed, enabling accurate self-alignment upon loading. Furthermore, a differential optical strain measurement technique as well as optimizations of the optical path has been implemented, providing a strain resolution of well below 1 * 10(-4) at 1000 degrees C. Two different polycrystalline SiC free-standing thin films have been investigated in tension to acquire stress-strain data and corresponding Young's modulus at up to 1000 degrees C. The high sensitivity of the strain measurement technique makes it also possible to identify creep strains in the high temperature regime. PMID- 26026556 TI - Humidity scanning quartz crystal microbalance with dissipation monitoring setup for determination of sorption-desorption isotherms and rheological changes. AB - A new method to determine water sorption-desorption isotherms with high resolution in the complete range of water activities (relative humidities) is presented. The method is based on quartz crystal microbalance with dissipation monitoring (QCM-D). The QCM-D is equipped with a humidity module in which the sample film is kept in air with controlled humidity. The experimental setup allows for continuous scanning of the relative humidity from either dry to humid conditions or vice versa. The amount of water sorbed or desorbed from the sample is determined from the resonance frequencies of the coated quartz sensor, via analysis of the overtone dependence. In addition, the method allows for characterization of hydration induced changes of the rheological properties from the dissipation data, which is closely connected to the viscoelasticity of the film. The accuracy of the humidity scanning setup is confirmed in control experiments. Sorption-desorption isotherms of pig gastric mucin and lysozyme, obtained by the new method, show good agreement with previous results. Finally, we show that the deposition technique used to coat the quartz sensor influences the QCM-D data and how this issue can be used to obtain further information on the effect of hydration. In particular, we demonstrate that spin-coating represents an attractive alternative to obtain sorption-desorption isotherms, while drop-coating provides additional information on changes of the rheological properties during hydration. PMID- 26026557 TI - System overview and characterization of a high-temperature, high-pressure, entrained-flow, laboratory-scale gasifier. AB - The high-temperature, high-pressure, entrained-flow, laboratory-scale gasifier at the Colorado School of Mines, including the primary systems and the supporting subsystems, is presented. The gasifier is capable of operating at temperatures and pressures up to 1650 degrees C and 40 bar. The heated section of the reactor column has an inner diameter of 50 mm and is 1 m long. Solid organic feedstock (e.g., coal, biomass, and solid waste) is ground into batches with particle sizes ranging from 25 to 90 MUm and is delivered to the reactor at feed rates of 2-20 g/min. The maximum useful power output of the syngas is 10 kW, with a nominal power output of 1.2 kW. The initial characterization and demonstration results of the gasifier system with a coal feedstock are also reported. PMID- 26026558 TI - A compact Raman converter for UV-VIS spectrometers. AB - A small form factor, easily constructed converter that adapts fiber coupled UV/VIS CCD detector-based spectrometers into a right angle scattering Raman spectrometer is described. Its design philosophy and design are discussed. An example measurement, the depolarization ratio of carbon tetrachloride, a classic Raman test compound, is presented. The unique instrument features a blue-violet (405 nm wavelength) diode laser that takes advantage of the inverse fourth power wavelength dependence of Raman scattering. The converter also features Glan Thompson polarizing prisms that enable measurement of depolarization ratios. The spectrometer is also capable of measuring a standard Raman spectrum. A fiber optic link offers flexibility when adapting the converter to any spectrometer system that accepts a fiber optic input. The performance of the instrument is critically discussed in the context of an example measurement. PMID- 26026559 TI - Overlay accuracy on a flexible web with a roll printing process based on a roll to-roll system. AB - For high-quality flexible devices from printing processes based on Roll-to-Roll (R2R) systems, overlay alignment during the patterning of each functional layer poses a major challenge. The reason is because flexible substrates have a relatively low stiffness compared with rigid substrates, and they are easily deformed during web handling in the R2R system. To achieve a high overlay accuracy for a flexible substrate, it is important not only to develop web handling modules (such as web guiding, tension control, winding, and unwinding) and a precise printing tool but also to control the synchronization of each unit in the total system. A R2R web handling system and reverse offset printing process were developed in this work, and an overlay between the 1st and 2nd layers of +/-5MUm on a 500 mm-wide film was achieved at a sigma level of 2.4 and 2.8 (x and y directions, respectively) in a continuous R2R printing process. This paper presents the components and mechanisms used in reverse offset printing based on a R2R system and the printing results including positioning accuracy and overlay alignment accuracy. PMID- 26026560 TI - Development of a vector-tensor system to measure the absolute magnetic flux density and its gradient in magnetically shielded rooms. AB - Several experiments in fundamental physics demand an environment of very low, homogeneous, and stable magnetic fields. For the magnetic characterization of such environments, we present a portable SQUID system that measures the absolute magnetic flux density vector and the gradient tensor. This vector-tensor system contains 13 integrated low-critical temperature (LTc) superconducting quantum interference devices (SQUIDs) inside a small cylindrical liquid helium Dewar with a height of 31 cm and 37 cm in diameter. The achievable resolution depends on the flux density of the field under investigation and its temporal drift. Inside a seven-layer mu-metal shield, an accuracy better than +/-23 pT for the components of the static magnetic field vector and +/-2 pT/cm for each of the nine components of the gradient tensor is reached by using the shifting method. PMID- 26026561 TI - A compact 300 kV solid-state high-voltage nanosecond generator for dielectric wall accelerator. AB - Compact solid-state system is the main development trend in pulsed power technologies. A compact solid-state high-voltage nanosecond pulse generator with output voltage of 300 kV amplitude, 10 ns duration (FWHM), and 3 ns rise-time was designed for a dielectric wall accelerator. The generator is stacked by 15 planar plate Blumlein pulse forming lines (PFL). Each Blumlein PFL consists of two solid state planar transmission lines, a GaAs photoconductive semiconductor switch, and a laser diode trigger. The key components of the generator and the experimental results are reported in this paper. PMID- 26026562 TI - Note: Rapid reduction of graphene oxide paper by glow discharge plasma. AB - This note reports on a novel method for the rapid reduction of graphene oxide (GO) paper using a glow discharge plasma reactor. Glow discharge is produced and sustained between two parallel-plate graphite electrodes at a pressure of 240 mTorr. By exposing GO paper at the junction of negative-glow and Faraday-dark area for 4 min, the oxygen-containing groups can be effectively removed (C/O ratio increases from 2.6 to 7.9), while the material integrality and flexibility are kept well. Electrochemical measurements demonstrate that the as-obtained reduced GO paper can be potentially used for supercapacitor application. PMID- 26026563 TI - Note: Inverted heat pulse method to measure heat capacity during cooling: A counterpart of conventional quasi-adiabatic heat pulse method. AB - A simple method to extract known amount of heat from a sample within a given time interval has been proposed. Using this method, which we call inverted heat pulse (IHP) method, absolute values of heat capacity (C(P)) during cooling can be measured in a manner similar to conventional quasi-adiabatic heat pulse method of measuring C(P) during warming. Absolute accuracy of the measured C(P) using IHP method is found to be better than 2% in the temperature range 100-300 K. Applicability of this method to a broad and hysteretic first order transition is tested by measuring C(P) of Rh doped FePt sample, which shows a antiferromagnetic to ferromagnetic first order transition with a transition width of ~35 K and hysteresis of ~6 K. The peak value of the measured C(P) using IHP during cooling as well as entropy change calculated from measured data is found to be in good agreement with that measured during warming using conventional quasi-adiabatic heat pulse method. PMID- 26026564 TI - Note: Application of CR-39 plastic nuclear track detectors for quality assurance of mixed oxide fuel pellets. AB - A CR-39 plastic nuclear track detector was used for quality assurance of mixed oxide fuel pellets for next-generation nuclear power plants. Plutonium (Pu) spot sizes and concentrations in the pellets are significant parameters for safe use in the plants. We developed an automatic Pu detection system based on dense alpha radiation tracks in the CR-39 detectors. This system would greatly improve image processing time and measurement accuracy, and will be a powerful tool for rapid pellet quality assurance screening. PMID- 26026565 TI - Note: Measuring capacitance and inductance of a helical resonator and improving its quality factor by mutual inductance alteration. AB - Narrow bandwidth and high voltage radio frequency (RF) is an essential requirement for stable confinement of ions within a RF trap and helical resonators are commonly used for that purpose. Effective capacitance and inductance of a helical resonator are estimated by measuring resonant frequencies for different external loads. Load capacitance of an ion trap can be estimated from this method and a resonator can be constructed for desired resonant frequency. We demonstrate a very simple method to achieve higher Q-factor of a resonator by optimizing mutual separation between the primary antenna and helical coil. We also formulate a set of analytical equations for calculating overall inductance, resistance, and Q-factor of a loaded helical resonator. PMID- 26026566 TI - Note: Simple leak sealing technique for ultra-high vacuum cryostat by using freezable liquid. AB - Here we introduce a simple, low-cost, contamination-free, and highly reliable technique for sealing an ultra-high vacuum (UHV) cryostat by using cryogenically freezable liquid. We demonstrate it by sealing an UHV cryostat with dry leaks in the high vacuum range; ethanol was utilized to fill and block the leakage pathways through the subsequent in situ solidification by LN2. The seal is reversible and can be maintained as long as the cryostat is kept at cryogenic temperature. PMID- 26026567 TI - Note: Improved calibration of atomic force microscope cantilevers using multiple reference cantilevers. AB - Overall precision of the simplified calibration method in J. E. Sader et al., Rev. Sci. Instrum. 83, 103705 (2012), Sec. III D, is dominated by the spring constant of the reference cantilever. The question arises: How does one take measurements from multiple reference cantilevers, and combine these results, to improve uncertainty of the reference cantilever's spring constant and hence the overall precision of the method? This question is addressed in this note. Its answer enables manufacturers to specify of a single set of data for the spring constant, resonant frequency, and quality factor, from measurements on multiple reference cantilevers. With this data set, users can trivially calibrate cantilevers of the same type. PMID- 26026568 TI - Note: Fiber optic transport probe for Hall measurements under light and magnetic field at low temperatures: Case study of a two dimensional electron gas. AB - A fiber optic based probe is designed and developed for electrical transport measurements in presence of quasi-monochromatic (360-800 nm) light, varying temperature (T = 1.8-300 K), and magnetic field (B = 0-7 T). The probe is tested for the resistivity and Hall measurements performed on a LaAlO3-SrTiO3 heterointerface system with a conducting two dimensional electron gas. PMID- 26026569 TI - Note: An analyzer for field detection of H2S by using cavity ring-down at 1.57 MUm. AB - A prototype analyzer for the detection of hydrogen sulfide (H2S), based on cavity ring-down spectroscopy, is described. The device exploits, whenever possible, optical fibers, in order to simplify the alignment and to improve the stability. A trade-off between low detection level and simplicity has been pursued. The experimental results obtained during tests on different kinds of H2S samples are shown. PMID- 26026570 TI - Note: A portable Raman analyzer for microfluidic chips based on a dichroic beam splitter for integration of imaging and signal collection light paths. AB - An integrated and portable Raman analyzer featuring an inverted probe fixed on a motor-driving adjustable optical module was designed for the combination of a microfluidic system. It possesses a micro-imaging function. The inverted configuration is advantageous to locate and focus microfluidic channels. Different from commercial micro-imaging Raman spectrometers using manual switchable light path, this analyzer adopts a dichroic beam splitter for both imaging and signal collection light paths, which avoids movable parts and improves the integration and stability of optics. Combined with surface-enhanced Raman scattering technique, this portable Raman micro-analyzer is promising as a powerful tool for microfluidic analytics. PMID- 26026571 TI - Note: A new regulation method of stable operation of high power cathode ion source. AB - The hot cathode ion source will tend to be unstable when operated with high power and long pulse. In order to achieve stable operation, a new regulation method based on the arc power (discharge power) feedback control was designed and tested on the hot cathode ion source test bed with arc discharge and beam extraction. The results show that the new regulation method can achieve stable arc discharge and beam extraction. It verifies the success of feedback control of arc source with arc power. PMID- 26026572 TI - Note: Work function change measurement via improved Anderson method. AB - We propose the modification to the Anderson method of work function change (Deltaphi) measurements. In this technique, the kinetic energy of the probing electrons is already low enough for non-destructive investigation of delicate molecular systems. However, in our implementation, all electrodes including filament of the electron gun are polarized positively. As a consequence, electron bombardment of any elements of experimental system is eliminated. Our modification improves cleanliness of the ultra-high vacuum system. As an illustration of the solution capabilities, we present Deltaphi of the Ag(100) surface induced by cobalt phthalocyanine layers. PMID- 26026574 TI - Sweet's Syndrome. PMID- 26026575 TI - A new scorpion species of genus Diplocentrus Peters, 1861 (Scorpiones: Diplocentridae) endemic to Islas de la Bahia, Honduras. AB - Three species of genus Diplocentrus are found in north-northwestern Honduras. These species represent the southern east limits of Diplocentrus' distribution. In recent years, a broad survey of arachnids in Honduras has yielded a collection of several specimens of an undescribed species from two islands in northern Honduras. This new species represents the second species of the genus inhabiting an island. The present contribution describes this new species, and compares it against its most similar relatives. A dichotomous key for the identification of the species of Diplocentrus in Honduras is also included. PMID- 26026577 TI - The role of Pleistocene glaciations in shaping the evolution of polar and brown bears. Evidence from a critical review of mitochondrial and nuclear genome analyses. AB - In this report, I review recent molecular studies dealing with the origin and evolution of polar bears (Ursus maritimus), with special emphasis on their relationships with brown bears (U. arctos). On the basis of mitochondrial and nuclear data, different hypotheses have been proposed, including rapid morphological differentiation of U. maritimus, genetic introgression from U. arctos into U. maritimus, or inversely from U. maritimus into U. arctos, involving either male- or female-mediated gene flow. In the light of available molecular and eco-ethological data, I suggest, firstly, that all divergences among major clades of large bears can be linked to glacial periods, secondly, that polar bears diverged from brown bears before 530 thousand years ago (ka), during one of the three glacial marine isotope stages (MIS) 14, 15.2 or 16, and, thirdly, that genetic introgression had occurred from female polar bears into brown bear populations during at least two glacial periods, at 340 +/- 10 ka (MIS 10) in western Europe, and at 155 +/- 5 ka (MIS 6) on the ABC islands of southeastern Alaska, and probably also in Beringia and Ireland based on ancient DNA sequences. PMID- 26026578 TI - Preclinical safety testing for cell-based products using animals. AB - The objectives of preclinical testing include to show why there might be therapeutic benefit in patients and to provide information on the product's toxicity. For cell-based products, given even once, there may be long term exposure and this could imply, unlike for conventional drugs, that all preclinical studies may be needed prior to first human use. The duration of exposure to cells should be studied in animals to guide toxicity assessments. Distribution of cells after administration by a route resembling that intended in humans should be studied to understand potential risks. Risk of tumour formation with the product may also need to be characterised. To the extent that this information can be generated by in vitro testing, studies in animals may not be needed and limitations on the capability of preclinical data to predict human toxicity are recognised: species-specificity make some cell products act only in humans and a human cell-product might be expected to be rejected by immunocompetent animals. Does this suggest testing in immunosuppressed animals or of development of an animal-cell product supposedly similar to the human cell product? No single answer seems to fit every situation. PMID- 26026576 TI - Intraspecific variability of the facultative meiotic parthenogenetic root-knot nematode (Meloidogyne graminicola) from rice fields in Vietnam. AB - Twenty years ago, the facultative meiotic parthenogenetic root-knot nematode (RKN), Meloidogyne graminicola, was recognised as an important rice pathogen in South Vietnam. Although this country is one of the most important rice exporters worldwide, a comprehensive picture of the occurrence of M. graminicola in Vietnamese rice fields is still not available. Therefore a nematode survey was carried out with the aim of better understanding the geographical distribution, and the pathogenic and genetic variability of the RKN in Vietnam. From the fields surveyed in a range of ecosystems, 21 RKN populations were recovered from infected rice roots. A diagnostic SCAR marker was developed showing that all Vietnamese populations belong to M. graminicola. Furthermore, sequencing of the Internal Transcribed Spacer (ITS) of the rDNA genes confirmed this identification. These populations were then characterised using morphometrics and pathogenicity tests (host plant range diversity, reproduction and virulence diversity) revealing intraspecific variability. We showed that morphometric traits are mainly genetically heritable characters with significant differences among the studied populations. Finally, a distinctive trait signature was found for the populations isolated from the upland rice cultures. All together, our study reveals the prevalence of M. graminicola populations in Vietnamese rice. Further investigations need to be developed to explore the population dynamics and evolutionary history of this species in South East Asia. PMID- 26026579 TI - Therapies for Cognitive Deficits Associated With Chemotherapy for Breast Cancer: A Systematic Review of Objective Outcomes. AB - OBJECTIVE: To systematically review evidence of treatments for cognitive impairments experienced by at least 20% of all women who undergo chemotherapy for breast cancer. DATA SOURCES: Searches of 5 databases (PubMed, Embase, Cochrane CENTRAL, PsycINFO, CINAHL), with no date or language restrictions, identified 1701 unique results. Search terms included breast cancer, chemotherapy, chemobrain, chemofog, and terms on cognition and language deficits. STUDY SELECTION: Included only peer-reviewed journal articles that described therapies for cognitive dysfunction in women undergoing (or who had undergone) chemotherapy for breast cancer and provided objective measurements of cognition or language. DATA EXTRACTION: Data were extracted according to Cochrane recommendations, including characteristics of participants, interventions, outcomes, and studies. Quality assessment of all 12 eligible studies was performed using the Physiotherapy Evidence Database scale and treatment fidelity criteria. Screening, data extraction, and quality assessment reliability were performed. DATA SYNTHESIS: Six articles described interventions for cognition that took place during cancer treatment; 6, afterward. Five interventions were medical (including a strength-training program), 2 were restorative, and 5 were cognitive. Medicinal treatments were ineffective; restorative and exercise treatments had mixed results; cognitive therapy had success in varying cognitive domains. The domains most tested and most successfully treated were verbal memory, attention, and processing speed. CONCLUSIONS: Cognitive therapy protocols delivered after chemotherapy and aimed at improving verbal memory, attention, and processing speed hold the most promise. Future research is needed to clarify whether computerized cognitive training can be effective in treating this population, and to identify objective assessment tools that are sensitive to this disorder. PMID- 26026580 TI - Pilot Study on the Effect of Ramelteon on Sleep Disturbance After Traumatic Brain Injury: Preliminary Evidence From a Clinical Trial. AB - OBJECTIVE: To investigate the effect of ramelteon on sleep and daytime functioning among individuals with traumatic brain injury (TBI). DESIGN: A double blind, placebo-controlled study with a crossover design. SETTING: A research facility attached to an acute rehabilitation hospital. PARTICIPANTS: Individuals with TBI (N=13) complaining of sleep difficulties with a Pittsburgh Sleep Quality Index score >5. INTERVENTIONS: A nightly dosage of ramelteon (8 mg) was given over a period of 3 weeks. MAIN OUTCOME MEASURES: An actigraph and a daily sleep log were used to measure sleep/wake patterns. Daytime functioning was measured after 3 weeks of treatment using a computer-administrated neuropsychological test battery in conjunction with subjective questionnaires measuring mood, daytime sleepiness, and fatigue. RESULTS: A significant increase in objectively measured total sleep time and a small increase in sleep latency were observed after 3 weeks of treatment compared with placebo. Treatment also showed a significant increase in standardized neuropsychological test scores, with a particular improvement on an index of executive functioning. CONCLUSIONS: Preliminary evidence for the effectiveness of 8 mg of ramelteon taken nightly over a 3-week period was found in the treatment of sleep difficulties among individuals with TBI. Improvements in total sleep time and some aspects of cognitive functioning are discussed. PMID- 26026581 TI - Near-field electromagnetic holography for high-resolution analysis of network interactions in neuronal tissue. AB - BACKGROUND: Brain function is dependent upon the concerted, dynamical interactions between a great many neurons distributed over many cortical subregions. Current methods of quantifying such interactions are limited by consideration only of single direct or indirect measures of a subsample of all neuronal population activity. NEW METHOD: Here we present a new derivation of the electromagnetic analogy to near-field acoustic holography allowing high resolution, vectored estimates of interactions between sources of electromagnetic activity that significantly improves this situation. In vitro voltage potential recordings were used to estimate pseudo-electromagnetic energy flow vector fields, current and energy source densities and energy dissipation in reconstruction planes at depth into the neural tissue parallel to the recording plane of the microelectrode array. RESULTS: The properties of the reconstructed near-field estimate allowed both the utilization of super-resolution techniques to increase the imaging resolution beyond that of the microelectrode array, and facilitated a novel approach to estimating causal relationships between activity in neocortical subregions. COMPARISON WITH EXISTING METHODS: The holographic nature of the reconstruction method allowed significantly better estimation of the fine spatiotemporal detail of neuronal population activity, compared with interpolation alone, beyond the spatial resolution of the electrode arrays used. Pseudo-energy flow vector mapping was possible with high temporal precision, allowing a near-realtime estimate of causal interaction dynamics. CONCLUSIONS: Basic near-field electromagnetic holography provides a powerful means to increase spatial resolution from electrode array data with careful choice of spatial filters and distance to reconstruction plane. More detailed approaches may provide the ability to volumetrically reconstruct activity patterns on neuronal tissue, but the ability to extract vectored data with the method presented already permits the study of dynamic causal interactions without bias from any prior assumptions on anatomical connectivity. PMID- 26026582 TI - Accelerometer-based automatic voice onset detection in speech mapping with navigated repetitive transcranial magnetic stimulation. AB - BACKGROUND: The use of navigated repetitive transcranial magnetic stimulation (rTMS) in mapping of speech-related brain areas has recently shown to be useful in preoperative workflow of epilepsy and tumor patients. However, substantial inter- and intraobserver variability and non-optimal replicability of the rTMS results have been reported, and a need for additional development of the methodology is recognized. In TMS motor cortex mappings the evoked responses can be quantitatively monitored by electromyographic recordings; however, no such easily available setup exists for speech mappings. NEW METHOD: We present an accelerometer-based setup for detection of vocalization-related larynx vibrations combined with an automatic routine for voice onset detection for rTMS speech mapping applying naming. COMPARISON WITH EXISTING METHOD(S): The results produced by the automatic routine were compared with the manually reviewed video recordings. RESULTS: The new method was applied in the routine navigated rTMS speech mapping for 12 consecutive patients during preoperative workup for epilepsy or tumor surgery. The automatic routine correctly detected 96% of the voice onsets, resulting in 96% sensitivity and 71% specificity. Majority (63%) of the misdetections were related to visible throat movements, extra voices before the response, or delayed naming of the previous stimuli. The no-response errors were correctly detected in 88% of events. CONCLUSION: The proposed setup for automatic detection of voice onsets provides quantitative additional data for analysis of the rTMS-induced speech response modifications. The objectively defined speech response latencies increase the repeatability, reliability and stratification of the rTMS results. PMID- 26026583 TI - Combretastatin A4 phosphate treatment induces vasculogenic mimicry formation of W256 breast carcinoma tumor in vitro and in vivo. AB - The purpose of this study was to investigate the effect of combretastatin A4 phosphate (CA4P) on vasculogenic mimicry (VM) channel formation in vitro and in vivo after a single-dose treatment and the underlying mechanism involved in supporting VM. In vitro model of three-dimensional cultures was used to test the effect of CA4P on the tube formation of Walker 256 cells. Western blot analysis was conducted to assess the expression of hypoxia-inducible factor (HIF)-1alpha and VM-associated markers. W256 tumor-bearing rat model was established to demonstrate the effect of CA4P on VM formation and tumor hypoxia by double staining and a hypoxic marker pimonidazole. Anti-tumor efficacy of CA4P treatment was evaluated by tumor growth curve. Under hypoxic conditions for 48 h in vitro, W256 cells formed VM network associated with increased expression of VM markers. Pretreatment with CA4P did not influence the amount of VM in 3-D culture as well as the expression of these key molecules. In vivo, W256 tumors showed marked intratumoral hypoxia after CA4P treatment, accompanied by increased VM formation. CA4P exhibited only a delay in tumor growth within 2 days but rapid tumor regrowth afterward. VM density was positively related to tumor volume and tumor weight at day 8. CA4P causes hypoxia which induces VM formation in W256 tumors through HIF-1alpha/EphA2/PI3K/matrix metalloproteinase (MMP) signaling pathway, resulting in the consequent regrowth of the damaged tumor. PMID- 26026584 TI - Effects of sorafenib on lung metastasis in rats with hepatocellular carcinoma: the role of microRNAs. AB - Many patients with advanced hepatocellular carcinoma (HCC) develop lung metastasis and available treatments are limited. The anticancer drug sorafenib has opened a window of hope for patients with advanced hepatocellular carcinoma. However, the effect of sorafenib is limited by drug resistance. MicroRNAs have been reported to play an important role in HCC, but the effect of sorafenib on microRNAs (miRNAs) and on lung metastasis is not clear. This report employed a high-throughput deep sequencing technique to detect the difference of miRNAs and immunohistochemical technique to detect the difference of protein in implanted primary tumors and in metastatic HCC tumors after treatment with sorafenib. Among the detected miRNAs, we identified rno-miR-122-3p and rmo-miR-122-5p that were downregulated and rno-miR-383-5p and rno-miR-34a-5p that were upregulated and one novel miRNAs is reported as downregulated here for the first time. Immunohistochemical analysis of known miRNAs identified CMYC protein expression as inhibited, MDM2 protein was expressed, and NM23 and GST protein were upregulated. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of novel miRNA found that the targeted genes were concentrated in pathways of metabolism, especially in cytochrome P450. These results indicate that these miRNAs are likely to be involved in the treatment response of lung metastases of HCC to sorafenib. They may be useful as biomarkers to predict the clinical treatment response of sorafenib. PMID- 26026585 TI - Zerumbone induces mitochondria-mediated apoptosis via increased calcium, generation of reactive oxygen species and upregulation of soluble histone H2AX in K562 chronic myelogenous leukemia cells. AB - Zerumbone, a natural cyclic sesquiterpene, is known to exhibit selective toxicity toward various cancer cells. Sustained efforts to explore the potential of new agents for effective therapy are critical in the context of development of drug resistance especially in cancers like chronic myelogenous leukemia (CML). The present study evaluated the effect of zerumbone on CML-K562 cells. The cell viability of zerumbone-treated K562 cells was detected by MTT assay, and morphological changes were observed by light microscopy and scanning electron microscopy (SEM). Staining with Hoechst 33258, acridine orange/ethidium bromide, and AnnexinV-FITC were used to detect apoptosis. Intracellular reactive oxygen species (ROS), Ca(2+), and changes in mitochondrial membrane potential were measured using Dichloro-dihydro-fluorescein diacetate (DCFH-DA), Fluo-3AM, and Rhodamine-123, respectively. Western blot analysis was carried out to detect key proteins involved in apoptosis. Zerumbone inhibited K562 cell proliferation with an IC50 value of 3.5 MUg/mL and colony formation capability (P < 0.001). Interestingly, zerumbone did not affect the growth of normal human peripheral blood lymphocytes (hPBLs). Distinct morphological changes observed by light microscopy and fluorescent staining with Hoechst-33258, AO/EtBr, annexin V-FITC, and cytotoxicity evaluation by comet assay indicated induction of DNA damage and apoptosis. This was further confirmed by demonstration of pro-caspase-3, -9 activation and Poly(ADP-ribose) polymerase (PARP) cleavage on western blots. Apoptosis induction was found to be mitochondria mediated, involving increased free intracellular Ca(2+), ROS, and upregulation of soluble histone H2AX. Our results suggest that zerumbone holds promise as a potential candidate drug for CML. PMID- 26026586 TI - High density of tryptase-positive mast cells in patients with multiple myeloma: correlation with parameters of disease activity. AB - Multiple myeloma (MM) is a plasma cell neoplasm characterized by bone marrow infiltration from malignant plasma cells. Mast cells play an important role in inflammation and angiogenesis in malignant diseases. The aim of the study was to evaluate the mast cell density in bone marrow of untreated MM patients with markers of disease activity such as serum interleukin-6 (IL-6), B2M, and C reactive protein (CRP), the grade of bone marrow infiltration, and the levels of produced paraprotein. We studied 86 newly diagnosed MM patients (46 males, 40 females, mean age 59 +/- 13.7 years). Thirty of them reached plateau phase after chemotherapy and 20 healthy volunteers. According to the criteria of International Staging System (ISS) staging system, 23 patients had stage I, 30 had stage II, and 33 had stage III. The serum concentrations of CRP, B2M, and IL 6, and the mast cell density (MCD) values were significantly higher in MM patients' group (1.6 +/- 1.8, 4.3 +/- 2.9, 7.1 +/- 5.1, and 9 +/- 4.8), in comparison with those found in control group (0.4 +/- 0.1, 1.5 +/- 0.6, 1.1 +/- 0.5, and 1.9 +/- 0.7; p < 0.001 in all the cases). Significant differences were found between the grade of infiltration in bone marrow, and the paraprotein values in patients' serum before and after chemotherapy. Furthermore, there was a significant correlation between the MCD values and the prognostic markers CRP (r = 0.452, p < 0.0001), IL-6 (r = 0.475, p < 0.0001), bone marrow infiltration (r = 0.333, p < 0.0002), and serum paraprotein levels(r = 0.221, p < 0.04). High MCD values strengthen the hypothesis that mast cells participate in the pathogenesis of disease progression and may be used as an indicator of the disease activity. PMID- 26026587 TI - The impact of immunohistochemical staining with ezrin-carbonic anhydrase IX and neuropilin-2 on prognosis in patients with metastatic renal cell cancer receiving tyrosine kinase inhibitors. AB - The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. In this retrospective study, we evaluated the prognostic role of carbonic anhydrase-IX, ezrin, and neuropilin in metastatic RCC patients. The expression of several biomarkers were measured by immunohistochemistry (IHC) in 45 patients with advanced stage RCC treated with second-line tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) after failure of interferon-alpha between January 2007 and June 2012. Kaplan-Meier curves and log-rank tests were used for analysis of progression-free survival (PFS) and overall survival (OS), and a multivariate Cox proportional hazard model was employed to identify factors with an independent effect on the survival. Age, ezrin and neuropilin-2 overexpression were found to be statistically significant factors (P < 0.05) for PFS in the univariate analysis. Ezrin and neuropilin-2 overexpression, hemoglobin and albumin level were statistically significant factors (P < 0.05) for OS in the univariate analysis. Multivariate analysis revealed that low expression of ezrin and neuropilin-2 was an independent prognostic factor for PFS and OS. The median PFS was 4 months for patients overexpressing neuropilin-2 versus 11 months for those with lower expression of neuropilin-2 (p = 0.033). The median OS was longer in patients with low levels of neuropilin-2 expression (26 months) compared to patients overexpressing neuropilin-2 (13 months) (p = 0.023). Increased expression of ezrin was associated with poor prognosis in patients treated with TKIs targeting VEGF (PFS, 3 vs 7 months; p = 0.012). High ezrin expression was associated with shorter OS (p = 0.009). This is the first study in the literature showing that neuropilin-2 and ezrin are related with prognosis in patients with advanced RCC. PMID- 26026588 TI - High pretreatment serum C-reactive protein level predicts a poor prognosis for combined small-cell lung cancer. AB - High serum C-reactive protein (CRP) level is related to poor prognosis in several tumors. The aim of this study was to explore the prognosis value of serum CRP in patients with combined small-cell lung cancer (C-SCLC). The clinicopathological parameters of 112 C-SCLC patients from January 2000 to March 2009 were collected. The pretreatment serum CRP level was measured at diagnosis, and the correlation between serum CRP and clinicopathological characters was analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters for C-SCLC. The pretreatment serum CRP level was elevated in 52.7% of patients (E-CRP; n = 59), while (47.3%) within the normal range (N-CRP; n = 53). There was a significantly worse disease stage (p = 0.037) and higher neuronal specific enolase (NSE) level (p = 0.014) in the E-CRP group. The median overall survival (OS) was significantly longer in the N-CRP group than in the E CRP group (22.0 vs. 11.5 months, respectively; p < 0.001). Multivariate analyses indicated serum CRP (hazard ratio (HR) = 2.1; p < 0.001), the extent of disease (HR = 1.3; p = 0.039), performance status (HR = 1.8; p = 0.012), and NSE (HR = 1.2; p < 0.001) as independent prognostic factors. High pretreatment serum CRP level predicts a poor long-term prognosis for C-SCLC, which should be considered in defining the prognosis with other prognosticators in C-SCLC patients. PMID- 26026589 TI - Statistical analyses of the results of 25 years of beach litter surveys on the south-eastern North Sea coast. AB - In the North Sea, the amount of litter present in the marine environment represents a severe environmental problem. In order to assess the magnitude of the problem and measure changes in abundance, the results of two beach litter monitoring programmes were compared and analysed for long-term trends applying multivariate techniques. Total beach litter pollution was persistently high. Spatial differences in litter abundance made it difficult to identify long-term trends: Partly more than 8000 litter items year(-1) were recorded on a 100 m long survey site on the island of Scharhorn, while the survey site on the beach on the island of Amrum revealed abundances lower by two orders of magnitude. Beach litter was dominated by plastic with mean proportions of 52%-91% of total beach litter. Non-parametric time series analyses detected many significant trends, which, however, did not show any systematic spatial patterns. Cluster analyses partly led to groupings of beaches according to their expositions to sources of litter, wind and currents. Surveys in short intervals of one to two weeks were found to give higher annual sums of beach litter than the quarterly surveys of the OSPAR method. Surveys at regular intervals of four weeks to five months would make monitoring results more reliable. PMID- 26026590 TI - Translational Research--The Imperative for Articulating Linkages Between Research Evidence and Pediatric Nursing Practice. PMID- 26026591 TI - Lymphomas and microenvironment: Impact on lymphomagenesis. Foreword. PMID- 26026592 TI - Glutamate neurotransmission is affected in prenatally stressed offspring. AB - Previous studies from our laboratory have shown that male adult offspring of stressed mothers exhibited higher levels of ionotropic and metabotropic glutamate receptors than control rats. These offspring also showed long-lasting astroglial hypertrophy and a reduced dendritic arborization with synaptic loss. Since metabolism of glutamate is dependent on interactions between neurons and surrounding astroglia, our results suggest that glutamate neurotransmitter pathways might be impaired in the brain of prenatally stressed rats. To study the effect of prenatal stress on the metabolism and neurotransmitter function of glutamate, pregnant rats were subjected to restrain stress during the last week of gestation. Brains of the adult offspring were used to assess glutamate metabolism, uptake and release as well as expression of glutamate receptors and transporters. While glutamate metabolism was not affected it was found that prenatal stress (PS) changed the expression of the transporters, thus, producing a higher level of vesicular vGluT-1 in the frontal cortex (FCx) and elevated levels of GLT1 protein and messenger RNA in the hippocampus (HPC) of adult male PS offspring. We also observed increased uptake capacity for glutamate in the FCx of PS male offspring while no such changes were observed in the HPC. The results show that changes mediated by PS on the adult glutamatergic system are brain region specific. Overall, PS produces long-term changes in the glutamatergic system modulating the expression of glutamate transporters and altering synaptic transmission of the adult brain. PMID- 26026593 TI - Biological warfare: Microorganisms as drivers of host-parasite interactions. AB - Understanding parasite strategies for evasion, manipulation or exploitation of hosts is crucial for many fields, from ecology to medical sciences. Generally, research has focused on either the host response to parasitic infection, or the parasite virulence mechanisms. More recently, integrated studies of host-parasite interactions have allowed significant advances in theoretical and applied biology. However, these studies still provide a simplistic view of these as mere two-player interactions. Host and parasite are associated with a myriad of microorganisms that could benefit from the improved fitness of their partner. Illustrations of such complex multi-player interactions have emerged recently from studies performed in various taxa. In this conceptual article, we propose how these associated microorganisms may participate in the phenotypic alterations induced by parasites and hence in host-parasite interactions, from an ecological and evolutionary perspective. Host- and parasite-associated microorganisms may participate in the host-parasite interaction by interacting directly or indirectly with the other partner. As a result, parasites may develop (i) the disruptive strategy in which the parasite alters the host microbiota to its advantage, and (ii) the biological weapon strategy where the parasite-associated microorganism contributes to or modulates the parasite's virulence. Some phenotypic alterations induced by parasite may also arise from conflicts of interests between the host or parasite and its associated microorganism. For each situation, we review the literature and propose new directions for future research. Specifically, investigating the role of host- and parasite-associated microorganisms in host-parasite interactions at the individual, local and regional level will lead to a holistic understanding of how the co-evolution of the different partners influences how the other ones respond, both ecologically and evolutionary. The conceptual framework we propose here is important and relevant to understand the proximate basis of parasite strategies, to predict their evolutionary dynamics and potentially to prevent therapeutic failures. PMID- 26026594 TI - Changes in the distribution of lineage constellations of G2P[4] Rotavirus A strains detected in Japan over 32 years (1980-2011). AB - Rotavirus A (RVA) is a leading cause of acute gastroenteritis in young children worldwide. Most human RVA strains are classified into three major genotype constellations: Wa-like, DS-1-like and AU-1-like. The evolution of G2P[4] strains possessing the DS-1-like genetic background was described in a few recent studies. However, the strains analyzed in these studies were almost exclusively the ones detected after 2000. In recognition of the scarcity of G2P[4] strains detected before 2000 for which whole genome information was available, this study was undertaken to characterize 19 Japanese G2P[4] strains detected between 1983 and 1990 (14 strains) and between 2001 and 2011 (5 strains), and to compare them with 131 G2P[4] strains from across the world. The Japanese strains along with the strains elsewhere in the world underwent stepwise changes from lineage I to IVa in 5 genes (the VP7, VP4, VP2, NSP1 and NSP5 genes) and from lineage I to V in 6 genes (the VP6, VP1, VP3, NSP2, NSP3 and NSP4 genes). Furthermore, G2P[4] strains detected after 2004 appeared to have undergone further intragenotype reassortment, resulting in the emergence of lineage V in the VP7 gene, and VI and VII in the VP3 and NSP4 genes. The time of the most recent common ancestor (tMRCA) for the emergent lineages VI and VII was estimated to be around the early 2000s. However, the year when the ancestor of the emergent lineages diverged from that of the rest of the lineages in the respective genes preceded the tMRCA 80-90 years. The origin of the emergent lineages is likely to be human RVA strains possessing genotypes other than G2P[4], and not RVA strains of an animal origin. In conclusion, stepwise changes in lineages imparted new genomic constellations to G2P[4] strains, which appears to have contributed to their successful spread across the globe, most notably since 2004. PMID- 26026595 TI - Does des-acyl ghrelin improve glycemic control by decreasing acylated ghrelin levels? PMID- 26026596 TI - Response to inquiry by Gaylinn et al. on 'Administration of UAG improves glycemic control in obese subjects with diabetes'. PMID- 26026597 TI - Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient. AB - Recent evidence has shown that 346million people in the world have diabetes mellitus (DM); this number will increase to 439million by 2030. In addition, current data indicate an increase in DM cases in the population between 40 and 59years of age. Diabetes is associated with the development of micro- and macro vascular complications, derived from chronic hyperglycemia on the endothelium. Some reports demonstrate that people in a prediabetic state have a major risk of developing early endothelial dysfunction (ED). Today, it is accepted that individuals considered as prediabetic patients are in a pro-inflammatory state associated with endothelial and mitochondrial dysfunction. It is important to mention that impaired mitochondrial functionality has been linked to endothelial apoptosis and release of mitochondrial DNA (mtDNA) in patients with sepsis, cardiac disease, or atherosclerosis. This free mtDNA could promote ED, as well as other side effects on the vascular system through the activation of the toll-like receptor 9 (TLR9). TLR9 is expressed in different cell types (e.g., T or B lymphocytes, mastocytes, and epithelial and endothelial cells). It is localized intracellularly and recognizes non-methylated dinucleotides of viral, bacterial, and mitochondrial DNA. Recently, it has been reported that TLR9 is associated with the pathogenesis of lupus erythematosus, rheumatoid arthritis, and autoimmune diabetes. In this work, it is hypothesized that the increase in the levels of circulating mtDNA is the trigger of early ED in the prediabetic patient, and later on in the older patient with diabetes, through activation of the TLR9 present in the endothelium. PMID- 26026598 TI - Young adolescents' perceived activity space risk, peer networks, and substance use. AB - Adolescent substance use is a developmentally contingent social practice that is constituted within the routine social-environment of adolescents' lives. Few studies have examined peer networks, perceived activity space risk (risk of substance use at routine locations), and substance use. We examined the moderating influence of peer network characteristics on the relationship between perceived activity space risk and substance use among a sample of 250 urban adolescents. Significant interactions were found between peer networks and perceived activity space risk on tobacco and marijuana use, such that protective peer networks reduced the effect of activity place risk on substance use. A significant 3-way interaction was found on marijuana use indicating that gender moderated peer network's effect on activity space risk. Conditional effect analysis found that boys' peer networks moderated the effect of perceived activity space risk on marijuana use, whereas for girls, the effect of perceived activity space risk on marijuana use was not moderated by their peer networks. These findings could advance theoretical models to inform social-environmental research among adolescents. PMID- 26026599 TI - Geographic variation of dental utilization among low income children. AB - Spatial accessibility of dental care is mediated by dentist workforce availability and travel costs. In this study, we generated dental service areas through small area analysis of Medicaid administrative data and claims. Service areas were then used to assess dimensions of spatial accessibility, including dentist-to-population ratios, and examine relationships in geographic variation of routine dental care among Medicaid-enrolled children. Our findings indicate significant geographic differences in accessibility for Hispanic children compared to other children, even after controlling for individual and service area characteristics. PMID- 26026601 TI - Immunotherapy Applied to Neuropsychiatric Disorders: a New Perspective of Treatment. AB - Manipulation of the immunological system has lead to groundbreaking discoveries that have had deep impact in demographic and health worldwide. Newer research has made it clear that immunological treatment of neurological and neuropsychiatric diseases may present itself as a viable solution to many ailments. In this mini review, results of immunotherapeutic studies are presented, indicating that this field may be important in elucidating the etiology of many neurological conditions, and presenting a therapeutic alternative to current treatments. PMID- 26026603 TI - Housing under abnormal light-dark cycles attenuates day/night expression rhythms of the clock genes Per1, Per2, and Bmal1 in the amygdala and hippocampus of mice. AB - Although the results of previous studies have suggested that disruptions in circadian rhythms are involved in the pathogenesis of depression, no studies have examined the interaction of clock gene expression deficit and depression state. In this study, we examined clock gene expression levels and depressive-like behavior in mice housed under 3.5h light, 3.5h dark (T = 7) conditions to investigate the association between clock gene expression and depressive state. C57BL/6J mice were housed under a T = 24 cycle (12h light, 12h dark) or a T = 7 cycle and clock gene expression levels in the hippocampus and the amygdala were measured by real-time RT-PCR. Depressive state was evaluated by the forced swim test (FST). Although circadian rhythms of Per1 and Per2 clock gene expression in the hippocampus and amygdala were still detected under T = 7 conditions, rhythmicity and expression levels of both significantly decreased. Mice housed with a T = 7 cycle showed increased immobile time in the FST than those with a T = 24 cycle. The present results suggest that the presence of a depressive state around the early active phase of activity may be related to impairment of rhythmicity and expression levels of Per1 and Per2 genes under abnormal light dark conditions. PMID- 26026600 TI - Multigenerational and transgenerational effects of endocrine disrupting chemicals: A role for altered epigenetic regulation? AB - Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of an individual. Moreover, recent studies have revealed that early life perturbations can affect the health of subsequent generations. Hypothesized mechanisms of multi- and transgenerational inheritance of abnormal developmental phenotypes include epigenetic misregulation in germ cells. In this review, we will focus on the available data demonstrating the ability of endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, and parabens, to alter epigenetic marks in rodents and humans. These epigenetic marks include DNA methylation, histone post-translational modifications, and non-coding RNAs. We also review the current evidence for multi and transgenerational inheritance of abnormal developmental changes in the offspring following EDC exposure. Based on published results, we conclude that EDC exposure can alter the mouse and human epigenome, with variable tissue susceptibilities. Although increasing data suggest that exposure to EDCs is linked to transgenerational inheritance of reproductive, metabolic, or neurological phenotypes, more studies are needed to validate these observations and to elucidate further whether these developmental changes are directly associated with the relevant epigenetic alterations. PMID- 26026602 TI - Attenuation of Colitis by Serum-Derived Bovine Immunoglobulin/Protein Isolate in a Defined Microbiota Mouse Model. AB - BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) is complex and multifaceted including genetic predisposition, environmental components, microbial dysbiosis, and inappropriate immune activation to microbial components. Pathogenic bacterial provocateurs like adherent and invasive E. coli have been reported to increase susceptibility to Crohn's disease. Serum-derived bovine immunoglobulin/protein isolate (SBI) is comprised primarily of immunoglobulins (Igs) that bind to conserved microbial components and neutralize exotoxins. AIM: To demonstrate that oral administration of SBI may modulate mucosal inflammation following colonization with E. coli, LF82, and exposure to dextran sodium sulfate (DSS). METHODS: Defined microbiota mice harboring the altered Schaedler flora (ASF) were administered SBI or hydrolyzed collagen twice daily starting 7 days prior to challenge with E. coli LF82 and continuing for the remainder of the experiment. Mice were treated with DSS for 7 days and then evaluated for evidence of local and peripheral inflammation. RESULTS: Igs within SBI bound multiple antigens from all eight members of the ASF and E. coli LF82 by western blot analysis. Multiple parameters of LF82/DSS-induced colitis were reduced following administration of SBI, including histological lesion scores, secretion of cytokines and chemokines from cecal biopsies, intestinal fatty acid binding protein (I-FABP) and serum amyloid A from plasma. CONCLUSIONS: Oral administration of SBI attenuated clinical signs of LF82/DSS-induced colitis in mice. The data are consistent with the hypothesis that SBI immunoglobulin binding of bacterial antigens in the intestinal lumen may inhibit the inflammatory cascades that contribute to IBD, thus attenuating DSS-induced colitis. PMID- 26026604 TI - Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis. AB - The multi-biomarker disease activity (MBDA) score measures 12 proteins involved in the pathophysiology of rheumatoid arthritis (RA) to assess disease activity (DA). Previous studies demonstrated correlations between MBDA and clinical DA scores with some RA therapies. In this analysis, the relationship between DA and MBDA scores and changes in MBDA component biomarkers were evaluated in tocilizumab (TCZ)-treated patients. Patients from the ACT-RAY study were included in this analysis if they had DA measures and serum collected at pre-specified time points with sufficient serum for MBDA testing at >=1 visit. Descriptive statistics, associations between outcomes, and percentage agreement between DA categories were calculated. Seventy-eight patients were included and were similar to the ACT-RAY population. Correlations between MBDA score and DAS28-CRP were rho = 0.50 at baseline and rho = 0.26 at week 24. Agreement between low/moderate/high categories of MBDA score and DAS28-CRP was observed for 77.1 % of patients at baseline and 23.7 % at week 24. Mean changes from baseline to weeks 4, 12, and 24 were proportionately smaller for MBDA score than DAS28-CRP. Unlike some other MBDA biomarkers, interleukin-6 (IL-6) concentrations increased in most patients during TCZ treatment. Correlations and agreement between MBDA and DAS28-CRP or CDAI scores were lower at week 24 versus baseline. The proportionately smaller magnitude of response observed for MBDA score versus DAS28-CRP may be due to the influence of the increase in IL-6 concentrations on MBDA score. Thus, MBDA scores obtained during TCZ treatment should be interpreted cautiously and in the context of available clinical information. PMID- 26026605 TI - Childhood cancer mortality in Japan, 1980-2013. AB - BACKGROUND: This study aimed to provide an updated analysis of childhood cancer mortality rates and long-term trends to 2013 to describe the current level of deaths and identify changes in recent decades. METHODS: Data on number of deaths from cancer in children aged under 15 years were derived from Vital Statistics in Japan and the World Health Organization (WHO) mortality database for comparison countries. Trends in mortality were examined by fitting a joinpoint regression model. RESULTS: For all cancers combined, the mortality rate during 2010-2013 was 19.9 per 1,000,000 population for boys and 17.5 for girls in Japan. Mortality from all cancers combined decreased significantly from 1980 to 2003 for boys and from 1980 to 2001 for girls. Afterwards, the rates remained stable for both sexes. Mortality from leukemia declined over the entire study period by 4.6% per year (p<0.05) in boys and 4.3% per year (p<0.05) in girls. For central nervous system (CNS) tumors, a slight increase in mortality was observed for both sexes, with a statistically significant annual percent change (APC) of 0.5% (p<0.05) for boys and 0.6% (p<0.05) for girls. CONCLUSIONS: We provided updated information on recent trends of childhood cancer death. The establishment of a nationwide, childhood cancer registry is required in Japan. Moreover, trends in cancer mortality should be monitored continuously. PMID- 26026607 TI - Revise and resubmit: how real-time parsing limitations influence grammar acquisition. AB - We present the results from a three-day artificial language learning study on adults. The study examined whether sentence-parsing limitations, in particular, difficulties revising initial syntactic/semantic commitments during comprehension, shape learners' ability to acquire a language. Findings show that both comprehension and production of morphology pertaining to sentence argument structure are delayed when this morphology consistently appears at the end, rather than at the beginning, of sentences in otherwise identical grammatical systems. This suggests that real-time processing constraints impact acquisition; morphological cues that tend to guide linguistic analyses are easier to learn than cues that revise these analyses. Parallel performance in production and comprehension indicates that parsing constraints affect grammatical acquisition, not just real-time commitments. Properties of the linguistic system (e.g., ordering of cues within a sentence) interact with the properties of the cognitive system (cognitive control and conflict-resolution abilities) and together affect language acquisition. PMID- 26026606 TI - Bisphenol A and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence. AB - Bisphenol A (BPA) is suspected to be associated with several chronic metabolic diseases. The aim of the present study was to review the epidemiological literature on the relation between BPA exposure and the risk of cardiometabolic disorders. PubMed and Embase databases were searched up to August 2014 by two independent investigators using standardized subject terms. We included observational studies (cohort, case-control and cross-sectional studies) carried out in children or adults, measuring urinary BPA (uBPA), including at least 100 participants and published in English. The health outcomes of interest were diabetes, hyperglycemia, measures of anthropometry, cardiovascular disease (CVD) and hypertension. Data were extracted and meta-analyzed when feasible, using a random-effects model. Thirty-three studies with sample size ranging from 239 to 4811 met the inclusion criteria, including five with a prospective design. Twelve studies reported on diabetes or hyperglycemia, 16 on anthropometry, 6 on CVD and 3 on hypertension. Evidence for a positive association between uBPA concentrations and diabetes, overweight, obesity, elevated waist circumference (WC), CVD and hypertension was found in 7/8, 2/7, 6/7, 5/5, 4/5 and 2/3 of the cross-sectional studies, respectively. We were able to conduct outcome-specific meta-analyses including 12 studies. When comparing the highest vs. the lowest uBPA concentrations, the pooled ORs were 1.47 (95% CI: 1.21-1.80) for diabetes, 1.21 (95% CI: 0.98-1.50) for overweight, 1.67 (95% CI: 1.41-1.98) for obesity, 1.48 (95% CI: 1.25-1.76) for elevated WC, and 1.41 (95% CI: 1.12-1.79) for hypertension. Moreover, among the five prospective studies, 3 reported significant findings, relating BPA exposure to incident diabetes, incident coronary artery disease, and weight gain. To conclude, there is evidence from the large body of cross-sectional studies that individuals with higher uBPA concentrations are more likely to suffer from diabetes, general/abdominal obesity and hypertension than those with lower uBPA concentrations. Given the potential importance for public health, prospective cohort studies with proper adjustment for dietary characteristics and identification of critical windows of exposure are urgently needed to further improve knowledge about potential causal links between BPA exposure and the development of chronic disease. PMID- 26026608 TI - Moojenactivase, a novel pro-coagulant PIIId metalloprotease isolated from Bothrops moojeni snake venom, activates coagulation factors II and X and induces tissue factor up-regulation in leukocytes. AB - Coagulopathies following snakebite are triggered by pro-coagulant venom toxins, in which metalloproteases play a major role in envenomation-induced coagulation disorders by acting on coagulation cascade, platelet function and fibrinolysis. Considering this relevance, here we describe the isolation and biochemical characterization of moojenactivase (MooA), a metalloprotease from Bothrops moojeni snake venom, and investigate its involvement in hemostasis in vitro. MooA is a glycoprotein of 85,746.22 Da, member of the PIIId group of snake venom metalloproteases, composed of three linked disulfide-bonded chains: an N glycosylated heavy chain, and two light chains. The venom protease induced human plasma clotting in vitro by activating on both blood coagulation factors II (prothrombin) and X, which in turn generated alpha-thrombin and factor Xa, respectively. Additionally, MooA induced expression of tissue factor (TF) on the membrane surface of peripheral blood mononuclear cells (PBMC), which led these cells to adopt pro-coagulant characteristics. MooA was also shown to be involved with production of the inflammatory mediators TNF-alpha, IL-8 and MCP-1, suggesting an association between MooA pro-inflammatory stimulation of PBMC and TF up-regulation. We also observed aggregation of washed platelets when in presence of MooA; however, the protease had no effect on fibrinolysis. Our findings show that MooA is a novel hemostatically active metalloprotease, which may lead to the development of coagulopathies during B. moojeni envenomation. Moreover, the metalloprotease may contribute to the development of new diagnostic tools and pharmacological approaches applied to hemostatic disorders. PMID- 26026610 TI - Dual effect of red wine on liver redox status: a concise and mechanistic review. AB - Chronic ethanol consumption is a strong risk factor for the development of liver disease. Multiple mechanisms are involved in ethanol-mediated liver injury; oxidative stress being pointed has an important factor. However, it should be noted that moderate consumption of red wine has been associated with hepatoprotective effects, mainly due to the antioxidant effect of resveratrol, one of its polyphenolic compounds. In this paper, the potential molecular mechanisms through which the protective effects of resveratrol counteract the oxidative effect of ethanol and the way as this dual effect impacts liver oxidative stress are reviewed. Mechanistic evaluation of modulation of oxidative signaling pathways by ethanol and resveratrol may explain the pathogenesis of various liver diseases and ultimately to disclose possible pharmacological therapies. PMID- 26026609 TI - Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-kappaB activation and sensitizes toward TNFalpha-induced cytotoxicity. AB - Drug-induced liver injury (DILI) is an important problem both in the clinic and in the development of new safer medicines. Two pivotal adaptation and survival responses to adverse drug reactions are oxidative stress and cytokine signaling based on the activation of the transcription factors Nrf2 and NF-kappaB, respectively. Here, we systematically investigated Nrf2 and NF-kappaB signaling upon DILI-related drug exposure. Transcriptomics analyses of 90 DILI compounds in primary human hepatocytes revealed that a strong Nrf2 activation is associated with a suppression of endogenous NF-kappaB activity. These responses were translated into quantitative high-content live-cell imaging of induction of a selective Nrf2 target, GFP-tagged Srxn1, and the altered nuclear translocation dynamics of a subunit of NF-kappaB, GFP-tagged p65, upon TNFR signaling induced by TNFalpha using HepG2 cells. Strong activation of GFP-Srxn1 expression by DILI compounds typically correlated with suppression of NF-kappaB nuclear translocation, yet reversely, activation of NF-kappaB by TNFalpha did not affect the Nrf2 response. DILI compounds that provided strong Nrf2 activation, including diclofenac, carbamazepine and ketoconazole, sensitized toward TNFalpha-mediated cytotoxicity. This was related to an adaptive primary protective response of Nrf2, since loss of Nrf2 enhanced this cytotoxic synergy with TNFalpha, while KEAP1 downregulation was cytoprotective. These data indicate that both Nrf2 and NF-kappaB signaling may be pivotal in the regulation of DILI. We propose that the NF-kappaB-inhibiting effects that coincide with a strong Nrf2 stress response likely sensitize liver cells to pro-apoptotic signaling cascades induced by intrinsic cytotoxic pro-inflammatory cytokines. PMID- 26026611 TI - Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3beta enzyme, beta-amyloid and tau protein levels. AB - Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer's disease (AD). However, the mechanism through which cadmium induces this effect remains unknown. In this regard, we described in a previous work that cadmium blocks cholinergic transmission and induces a more pronounced cell death on cholinergic neurons from basal forebrain which is partially mediated by AChE overexpression. Degeneration of basal forebrain cholinergic neurons, as happens in AD, results in memory deficits attributable to the loss of cholinergic modulation of hippocampal synaptic circuits. Moreover, cadmium has been described to activate GSK-3beta, induce Abeta protein production and tau filament formation, which have been related to a selective loss of basal forebrain cholinergic neurons and development of AD. The present study is aimed at researching the mechanisms of cell death induced by cadmium on basal forebrain cholinergic neurons. For this purpose, we evaluated, in SN56 cholinergic mourine septal cell line from basal forebrain region, the cadmium toxic effects on neuronal viability through muscarinic M1 receptor, AChE splice variants, GSK 3beta enzyme, Abeta and tau proteins. This study proves that cadmium induces cell death on cholinergic neurons through blockade of M1 receptor, overexpression of AChE-S and GSK-3beta, down-regulation of AChE-R and increase in Abeta and total and phosphorylated tau protein levels. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on cholinergic neurons and suggest that cadmium could mediate these mechanisms by M1R blockade through AChE splices altered expression. PMID- 26026612 TI - DECODE: an integrated differential co-expression and differential expression analysis of gene expression data. AB - BACKGROUND: Both differential expression (DE) and differential co-expression (DC) analyses are appreciated as useful tools in understanding gene regulation related to complex diseases. The performance of integrating DE and DC, however, remains unexplored. RESULTS: In this study, we proposed a novel analytical approach called DECODE (Differential Co-expression and Differential Expression) to integrate DC and DE analyses of gene expression data. DECODE allows one to study the combined features of DC and DE of each transcript between two conditions. By incorporating information of the dependency between DC and DE variables, two optimal thresholds for defining substantial change in expression and co expression are systematically defined for each gene based on chi-square maximization. By using these thresholds, genes can be categorized into four groups with either high or low DC and DE characteristics. In this study, DECODE was applied to a large breast cancer microarray data set consisted of two thousand tumor samples. By identifying genes with high DE and high DC, we demonstrated that DECODE could improve the detection of some functional gene sets such as those related to immune system, metastasis, lipid and glucose metabolism. Further investigation on the identified genes and the associated functional pathways would provide an additional level of understanding of complex disease mechanism. CONCLUSIONS: By complementing the recent DC and the traditional DE analyses, DECODE is a valuable methodology for investigating biological functions of genes exhibiting disease-associated DE and DC combined characteristics, which may not be easily revealed through DC or DE approach alone. DECODE is available at the Comprehensive R Archive Network (CRAN): http://cran.r project.org/web/packages/decode/index.html . PMID- 26026614 TI - Unique contributions of individual eating disorder symptoms to eating disorder related impairment. AB - This study examined the unique contribution of individual eating disorder symptoms and related features to overall eating disorder-related impairment. Participants (N=113) from the community with eating disorders completed assessments including the Clinical Impairment Assessment (CIA) and the Eating Disorder Examination Questionnaire. A multiple linear regression analysis indicated that 58.6% of variance in the CIA was accounted for by binge eating frequency, weight and shape concerns, and depression. These findings indicate that certain eating disorder symptoms uniquely account for impairment and that depression is a substantial contributor. It is possible that purging, restrictive eating, and body mass index did not significantly contribute to impairment because these features are consistent with many individuals' weight and shape goals. The results imply that eating disorder-related impairment may be more a result of cognitive features and binge eating rather than body weight and compensatory behaviors. PMID- 26026613 TI - The Chinese version of the Yale Food Addiction Scale: An examination of its validation in a sample of female adolescents. AB - INTRODUCTION: The present study developed and tested a Chinese version of the Yale Food Addiction Scale (YFAS-R-C) in a sample of female normal-school students, with the aim of producing a psychometrically sound tool for assessing food addiction in female adolescents. METHODS: A preliminary study of 72 normal school students tested the YFAS-R-C and collected suggestions to improve it. Twenty days later, the formal YFAS-R-C, the Binge Eating Scale (BES), Eating Attitude Test (EAT-26), BIS/BAS Reactivity (BIS/BAS) scale, and Regulatory Emotional Self-efficacy (RES) scale were administrated to a sample of 950 normal school students. Test-retest reliability was assessed in 53 students who took the YFAS-R-C twice. RESULTS: The single factor structure of the YFAS-R-C could be confirmed in our study. The internal consistency (KR-20) for 21 original items (0.857) and diagnostic criteria (0.75) were good. Confirmatory factor analysis verified a one-factor structure with an acceptable fit. The test-retest reliability of the YFAS-R-C was good, with interclass correlations of 0.72 for symptom items and 0.69 for the diagnostic criteria. The YFAS-R-C had good convergent and discriminant validity: symptom and diagnosis versions both had significant correlations with measures of related eating behavior constructs (BES and EAT-26), but had no or moderate correlations with measures of related, yet separate constructs (BIS/BAS and RES). DISCUSSION: The results indicate the YFAS R-C has a good psychometric validity to differentiate population with and without food addiction in a group of female normal-school students. Future studies should validate the YFAS-R-C in diverse samples. PMID- 26026615 TI - Smoking relapse and weight gain prevention program for postmenopausal weight concerned women: A pilot study. AB - OBJECTIVE: Postmenopausal women have substantial concerns about weight gain when quitting smoking, which may contribute smoking relapse. There is a need for smoking cessation and weight gain prevention programs effective in this population. METHODS: Two formats of a smoking cessation/weight gain prevention follow-up intervention in postmenopausal weight concerned women were compared: a minimally-tailored group format and a highly tailored, multidisciplinary individual format. Effects on sustained abstinence and postcessation weight gain were assessed. Postmenopausal smokers received 6 sessions of behavioral counseling over a 2-week period, 8weeks of the nicotine transdermal patch, and subsequent random assignment to receive follow-up relapse prevention sessions at 1, 3, 8, and 16weeks postcessation in either group or individual format. RESULTS: The sample (N=98) was 67% Caucasian and 33% African-American. Age: m=52.3 (7.8) years, follicle stimulating hormone: m=42.6 (25.7), body mass index (BMI): m=27.4 (6.2), daily smoking rate: m=20.3 (11.5), for m=29.4 (10.7) years, Fagerstrom Test for Nicotine Dependence (FTND): m=6.4 (2.1), and carbon monoxide: m=23.8 (13.0) ppm. Abstinence rates in the group condition were significantly higher at 8weeks posttreatment. Group format significantly predicted abstinence rates at 8 and 16weeks posttreatment, even while controlling for age, race, BMI, CPD, years smoking, FTND, and weight concern. Weight concern predicted postcessation weight gain at 8 and 16weeks posttreatment. CONCLUSIONS: Results indicate that smoking cessation programs for postmenopausal women may best be delivered in a group format and that postcessation weight concerns be dealt with prior to a quit date. PMID- 26026617 TI - Response of endothelial cells and pericytes to hypoxia and erythropoietin in a co culture assay dedicated to soft tissue repair. AB - The increasing mean life expectancy of the citizens of the western world countries leads to an increase of the age-related diseases, among them soft tissue defects exhibiting inadequate healing. In order to develop new therapeutic strategies to support disturbed soft tissue repair, there is a strong need of sophisticated in vitro assays. A new assay combining scratch wounding with co cultures of primary human microvascular endothelial cells (HDMEC) and pericytes (HPC) focuses on basic characteristics of cell interaction against the background of soft tissue repair. The cell parameters proliferation, migration and differentiation, and the release of monocyte chemoattractant protein-1 (MCP-1) were analysed in response to hypoxia (pO2 < 5 mmHg) and to erythropoietin (EPO; 50 IU/ml), a glycoprotein hormone having shown promising effects in soft tissue repair. As basic characteristics of the assay, direct cell contact in co-culture led to a weakened proliferation of both cell types, an increase of the percentage of myofibroblast-like pericytes and to a higher release of MCP-1. Hypoxia caused a proliferation decrease of HPC in co-culture, which was slightly attenuated by EPO. Hypoxia also reduced the MCP-1 release of co-cultured cells, when EPO had been added. In addition, EPO had a rather positive effect on HPC migration under hypoxia. These in vitro results allow new insights into the interaction of pericytes with endothelial cells in the context of soft tissue repair. PMID- 26026618 TI - Erratum to: Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells. PMID- 26026616 TI - The role of brain somatostatin receptor 2 in the regulation of feeding and drinking behavior. AB - Somatostatin was discovered four decades ago as hypothalamic factor inhibiting growth hormone release. Subsequently, somatostatin was found to be widely distributed throughout the brain and to exert pleiotropic actions via interaction with five somatostatin receptors (sst1-5) that are also widely expressed throughout the brain. Interestingly, in contrast to the predominantly inhibitory actions of peripheral somatostatin, the activation of brain sst2 signaling by intracerebroventricular injection of stable somatostatin agonists potently stimulates food intake and independently, drinking behavior in rodents. The orexigenic response involves downstream orexin-1, neuropeptide Y1 and MU receptor signaling while the dipsogenic effect is mediated through the activation of the brain angiotensin 1 receptor. Brain sst2 activation is part of mechanisms underlying the stimulation of feeding and more prominently water intake in the dark phase and is able to counteract the anorexic response to visceral stressors. PMID- 26026620 TI - [Quality of registration of dementia diagnosis in primary care: The situation in Spain in 2002-2011]. AB - OBJECTIVE: To ascertain the diagnosis associated with specific treatment for dementia in the Primary Care Electronic Clinical Record (PC-ECR) and to analyse the factors associated with the quality of registration. METHODS: Descriptive study of patients taking cholinesterase inhibitors or memantine registered in Database for pharmacoepidemiological research in PC (BIFAP) 2011: 24,575 patients between 2002 and 2011. Diagnoses associated with first prescription of these drugs were grouped into 5 categories: "dementia", "memory impairment", "dementia related diseases", "intercurrent processes" and "convenience codes". We calculated the prevalence of each category by age and sex for each study year (95%CI) and analysed the associations and trend for 2002-2011 using difference in proportions in independent samples and binary logistic regression. RESULTS: A code of "dementia" was associated with first prescription in 56.5% (95%CI: 55.8 57.1) of patients. It was higher in women [OR1.09 (95%CI: 1.03-1.15)] and with increasing follow-up time [OR1.07 (95%CI: 1.06-1.08) for each year of follow-up]. "Convenience codes" [16.3% (95%CI: 15.8-16.7)] were coded more frequently in women and in those >=80 years; "Memory impairment" [12.4% (95%CI: 12.0-12.8)], "related diseases" [4.6% (95%CI: 4.4-4.8)] and "intercurrent processes" [10.3% (95%CI: 9.9-10.6)] were used more in men and in persons <80 years. Between 2002 and 2011 improved the use of "convenience codes". CONCLUSIONS: Almost half of the patients taking cholinesterase inhibitors or memantine do not have a diagnosis of dementia registered in their PC-ECR. Registration improves with increasing time of follow-up. Improvements are needed in the PC-ECR, adequate care coordination, and proactive approach to increase the quality of dementia registration. PMID- 26026619 TI - Converging evidence from fMRI and aphasia that the left temporoparietal cortex has an essential role in representing abstract semantic knowledge. AB - While the neural underpinnings of concrete semantic knowledge have been studied extensively, abstract conceptual knowledge remains enigmatic. We present two experiments that provide converging evidence for the involvement of key regions in the temporoparietal cortex (TPC) in abstract semantic representations. First, we carried out a neuroimaging study in which participants thought deeply about abstract and concrete words. A functional connectivity analysis revealed a cortical network, including portions of the TPC, that showed coordinated activity specific to abstract word processing. In a second experiment, we tested participants with lesions involving the left TPC on a spoken-to-written word matching task using abstract and concrete target words presented in arrays of related or unrelated distractors. The results revealed an interaction between concreteness and relatedness: participants with TPC lesions were significantly less accurate for abstract words presented in related arrays than in unrelated arrays, but exhibited no effect of relatedness for concrete words. These results confirm that the TPC plays an important role in abstract concept representation and that it is part of a larger network of functionally cooperative regions needed for abstract word processing. PMID- 26026621 TI - Prevalence of ciguatoxins in lionfish (Pterois spp.) from Guadeloupe, Saint Martin, and Saint Barthelmy Islands (Caribbean). AB - Lionfish (Pterois spp.) are invasive species that have recently spread throughout the Caribbean. Lionfish are available for purchase in local markets for human consumption in several islands of the region. We examined the prevalence of ciguatoxins (CTXs) in lionfish from the French Antilles, a ciguatera-endemic region. The neuroblastoma-2a (N2a) cell assay was used to assess composite cytotoxicity in 120 fish samples collected from the surrounding waters of Guadeloupe (n = 60), Saint Barthelemy Islands (n = 55) and Saint Martin (n = 5). Twenty-seven of these samples exhibited CTX-like activity by the N2a assay. Ciguatoxin (CTX) was confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple samples that presented highest composite toxicity levels by N2a. Those fish found to contain CTXs were all from Saint Barthelemy. Lionfish from Guadeloupe and Saint Martin did not exhibit toxin activity, although the sample size from Saint Martin was insufficient to draw any conclusions as to the incidence of CTXs. In this study, we provide information about the potential hazard of ciguatera associated with the consumption of lionfish from known endemic areas. We also demonstrate the utility of the cell-based assay combined with LC-MS/MS to assess activity and to provide structural confirmation of CTXs respectively. PMID- 26026622 TI - TaqMan qPCR for detection and quantification of mitochondrial DNA from toxic pufferfish species. AB - Outbreaks of pufferfish food poisoning have been reported worldwide, most were from unsuitable food preparation and adulteration. In order to rapidly detect pufferfish adulterant in processed foods, we developed and proposed the use of a TaqMan probe-based quantitative PCR. The designed detection oligos targeted a unique region in 16S rDNA of toxic marine pufferfish in Tetraodontidae Family and gave a positive signal at >=1.75 pg of genomic DNA. Non-target DNA samples from other fish, chicken, and beef were negative. PMID- 26026623 TI - Rho-modifying bacterial protein toxins from Photorhabdus species. AB - Photorhabdus bacteria live in symbiosis with entomopathogenic nematodes. The nematodes invade insect larvae, where they release the bacteria, which then produce toxins to kill the insects. Recently, the molecular mechanisms of some toxins from Photorhabdus luminescens and asymbiotica have been elucidated, showing that GTP-binding proteins of the Rho family are targets. The tripartite Tc toxin PTC5 from P. luminescens activates Rho proteins by ADP-ribosylation of a glutamine residue, which is involved in GTP hydrolysis, while PaTox from Photorhabdus asymbiotica inhibits the activity of GTPases by N-acetyl glucosaminylation at tyrosine residues and activates Rho proteins indirectly by deamidation of heterotrimeric G proteins. PMID- 26026624 TI - Is restless legs syndrome associated with chronic mountain sickness? AB - BACKGROUND: Restless legs syndrome (RLS) and chronic mountain sickness (CMS) share physiological traits. Our objective was to explore a possible association between RLS and CMS. METHODS: We carried a cross-sectional study with male subjects living between 4100 and 4300 m above sea level. Participants underwent a clinical interview, physical examination, electrocardiographic (EKG) recording, and spirometry. We classified subjects into CMS, Limbo, and healthy high-altitude dwellers (hHAD), according to their Quinghai score and hematocrit levels. We applied the "Paradigm of questions for epidemiological studies of RLS," The International Restless Leg Syndrome Study Group Scale, and the Pittsburgh Sleep Quality Index. Logistic regression analysis was used to determine the association between variables. RESULTS: Seventy-eight male subjects were included. Forty subjects were hHAD, 23 were CMS patients, and 15 participants were considered as Limbo. CMS and Limbo subjects had a higher frequency of RLS (p <0.05). Limbo subjects had the highest severity score for RLS. There were no differences in age, body mass index (BMI), or tobacco use between RLS patients and non sufferers. In the multivariate analysis, CMS was not associated with RLS diagnosis. Oxygen saturation (p = 0.019), poor sleep quality (p <0.01), and Quinghai score of >=6 (p = 0.026) were independently associated with RLS diagnosis. CONCLUSIONS: Our results did not show a direct association between RLS and CMS; however, RLS was associated with reduced oxygen saturation. Hence, RLS could represent an early clinical manifestation of hypoxia, or, in CMS natural history, an early sign of maladaptation to high altitude. PMID- 26026627 TI - Deficits of attention and cognition in narcoleptic patients--is it hypocretin dependent? PMID- 26026626 TI - Differences in electroencephalographic findings among categories of narcolepsy spectrum disorders. AB - OBJECTIVE: To clarify the differences in quantitative electroencephalographic (EEG) measures and their relation to clinical symptoms among narcolepsy-spectrum disorders. METHODS: The enrolled patients were: 28 with narcolepsy with cataplexy (NA-CA); 16 with NA without cataplexy (NA w/o CA) and HLA-DRB1*1501/DQB1*0602 positive (NA w/o CA HLA+); 22 with NA w/o CA and HLA negative (NA w/o CA HLA-); and 22 with idiopathic hypersomnia without long sleep time (IHS w/o LST). Nocturnal polysomnography (n-PSG) and quantitative EEG evaluation, as well as the Multiple Sleep Latency test (MSLT), were conducted for all patients. RESULTS: Patients with NA-CA or NA w/o CA HLA+ showed lower alpha power, higher delta and theta power during wakefulness, and higher alpha and beta power during rapid eye movement (REM) sleep, compared to those with NA w/o CA HLA- or IHS w/o LST. The former two groups also showed lower sleep efficiency and a higher rate of positivity of REM-related symptoms than the other two groups. CONCLUSIONS: In narcolepsy, the presence of cataplexy and HLA positivity are associated with EEG slowing during wakefulness and increased fast EEG activity during REM sleep, REM related symptoms and disrupted nocturnal sleep in narcolepsy. PMID- 26026625 TI - Self-reported memory problems in adult-onset cancer survivors: effects of cardiovascular disease and insomnia. AB - BACKGROUND: Cancer and its treatments can deleteriously affect memory. Cardiac function and insomnia can exacerbate memory problems. OBJECTIVE: To examine the relationships among cardiovascular disease, insomnia, and self-reported memory problems (SRMP) in adult-onset cancer survivors. METHODS: We included data from participants (41-64 year-old) of the 2007-2008 National Health and Nutrition Examination Survey, a nationally representative probability sample of the civilian, non-institutionalized population of the US. We excluded participants with brain cancer/stroke history since these conditions are expected to cause cognitive problems. Using binary logistic regression, we determined the prevalence of SRMP relative to cardiac problems and insomnia by weighting our results proportionally. We adjusted for predictors of memory problems: age, sex, race, education and general health. RESULTS: The sample included 2289 adults (49% females), 9% with a cancer history. The results pertain only to cancer survivors. Those with insomnia were 16 times as likely to have SRMP. Only insomnia symptoms (OR, 15.74; 95% CI, 1.73-143.30; p < 0.01) significantly predicted SRMP, uniquely explaining 12% of the variance. Insomnia accounted for 18.8% of the association between cardiac issues and SRMP, demonstrating mediation (Sobel p < 0.05). The large CI is a consequence of analyzing a sub-group of a subpopulation. Among participants without a cancer history, cardiovascular disease and insomnia were not associated with SRMP (p > 0.05). LIMITATIONS: We could not determine severity and time-related changes in SRMP. CONCLUSION: Likelihood of SRMP was higher in cancer survivors with a history of cardiovascular disease and insomnia symptoms. Future studies are needed to delineate the cardiac-insomnia-memory interrelationships. PMID- 26026628 TI - Cerebral Arteriovenous Malformations and Epilepsy, Part 2: Predictors of Seizure Outcomes Following Radiosurgery. AB - OBJECTIVE: Seizure outcomes after arteriovenous malformation (AVM) management with radiosurgery are incompletely understood. In this case-control study, we aim to determine the incidences and define the predictors of seizure improvement and de novo seizures in patients with AVM with and without seizures at presentation, respectively. METHODS: We evaluated our institutional AVM radiosurgery database to determine the factors that were associated with favorable seizure outcome (seizure improvement or lack of de novo seizures). In patients with seizures at presentation, seizure improvement was defined as decreased seizure frequency or complete seizure remission. In patients without seizures at presentation, de novo seizures were defined as new-onset seizures after radiosurgery. Logistic regression analyses were performed to identify predictors of favorable seizure outcome. RESULTS: In 229 patients with seizures at presentation, the rates of seizure improvement and seizure remission were 57% and 20%, respectively. Prior AVM hemorrhage (P = 0.015), longer follow-up (P < 0.0001), and lack of hemorrhage after radiosurgery (P = 0.048) were independent predictors of seizure improvement in the multivariate analysis. In 778 patients without seizures at presentation, the overall rate of de novo seizures was 1.7%. Prior AVM hemorrhage (P = 0.001) and higher Spetzler-Martin grade (P = 0.018) were independent predictors of the absence of de novo seizures in the multivariate analysis. AVM obliteration was not significantly associated with seizure outcomes after radiosurgery. CONCLUSIONS: Radiosurgery provides reasonable rates of seizure improvement for patients with AVM who present with seizures. For patients with AVM without seizures at presentation, the risk of de novo seizures after radiosurgery is very low, obviating the need for prophylactic antiepileptic drug therapy. Further investigation of epilepsy in patients with AVM undergoing stereotactic radiosurgery should be considered with validated outcome measures and prospective study design. PMID- 26026629 TI - Neurosurgical Management of Brainstem Hemangioblastomas: A Single-Institution Experience with 116 Patients. AB - OBJECTIVE: Brainstem hemangioblastomas (HBs) are considered one of the most challenging lesions in surgical procedures. We present our institutional experience with 116 patients over a period of 20 years in the treatment of HBs. METHODS: We evaluated the results of microsurgical treatment and highlighted the management strategies. There were 60 male and 56 female patients including 13 cases with clinical evidence of von Hippel-Lindau disease. Tumors were solid in 99 cases and cystic in 17 cases. Tumors were small (<=2 cm) in 43 cases, large (2 4 cm) in 45 cases, and giant (>=4 cm) in 28 cases. RESULTS: Radical removal was achieved in 111 patients (95.7%), and incomplete removal was achieved in 5 cases (4.3%). The immediate postoperative mortality and morbidity were 7.8% and 17.2%, respectively. Detailed analyses of outcomes showed that surgical complications were related to some tumor characteristics. Follow-up study was available in 83 patients by Karnofsky performance scale scores. Most patients maintained their preoperative neurologic status. There were 17 patients with surgical disability who demonstrated a clear improvement with rehabilitation treatment. Worsening of neurologic deficits occurred in 2 patients. Ectopic recurrent lesions developed in 2 patients. CONCLUSIONS: Based on our experience, microsurgery is safe and effective, and excellent outcomes can be obtained for cystic or small tumors. We advocate early surgical intervention for sporadic HBs; giant solid HBs remain a challenge, and meticulous microsurgical technique and perioperative management are vital. Long-term monitoring also is recommended. PMID- 26026630 TI - Affective Symptoms and White Matter Changes in Brain Tumor Patients. AB - BACKGROUND: Affective symptoms are frequent in patients with brain tumors. The origin of such symptoms is unknown; either focal brain injury or reactive emotional distress may be responsible. This cross-sectional pilot study linked depressive symptoms and anxiety to white matter integrity. The objective was to test the hypothesis of a relationship between tissue damage and brain function in patients with brain tumors and to provide a basis for further studies in this field. METHODS: Diffusion tensor imaging was performed in 39 patients with newly diagnosed supratentorial primary brain tumor. Patients completed the Beck Depression Inventory, and examiners rated them on the Hamilton Depression Rating Scale (HDRS). State and trait anxiety were measured using the State-Trait Anxiety Inventory. Correlations between fractional anisotropy (FA) and psychological measures were assessed on the basis of regions of interest; the defined regions of interest corresponded to clearly specified white matter tracts. RESULTS: Statistical analysis revealed correlations between FA in the left internal capsule and scores on the HDRS, Beck Depression Inventory, and State-Trait Anxiety Inventory (P < 0.05). HDRS scores were also correlated with FA in the right medial uncinate fasciculus, and state anxiety scores were significantly correlated with FA in the left lateral and medial uncinate fasciculus (P < 0.05). CONCLUSIONS: Our results suggest that neurobiologic mechanisms related to the integrity of tissue in specific white matter tracts may influence affective symptoms in patients with brain tumors, and these mechanisms can be investigated with diffusion tensor imaging. However, prospective observational studies are needed to investigate further the links between brain structures and the severity of affective symptoms in this patient population. PMID- 26026632 TI - Sellar Toxoplasmosis and Nonfunctioning Pituitary Adenoma. AB - BACKGROUND: Sellar toxoplasmosis is associated with congenital infections or immunodeficiency. The finding of Toxoplasma bradycysts in a pituitary adenoma is very unusual. CASE DESCRIPTION: An otherwise healthy 27-year-old woman presented with secondary amenorrhea and moderately elevated prolactin levels. A macroprolactinoma was suspected on magnetic resonance imaging, and cabergoline was initiated. Although dopamine levels decreased, the tumor did not show significant shrinkage; after 2 years, transsphenoidal resection was indicated to clarify the diagnosis and to cure hyperprolactinemia. Histology showed an inactive pituitary adenoma and Toxoplasma bradycysts. Seropositivity for Toxoplasma gondii, but neither immunodeficiency nor intracerebral spread, was found. During a postoperative follow-up period of 15 months, the patient did not show any recurrence. CONCLUSIONS: Sellar toxoplasmosis in conjunction with pituitary adenoma is extremely rare. Nonfunctioning lesions should be suspected in cases of sellar masses and moderate hyperprolactinemia. PMID- 26026631 TI - Bilateral Choroid Plexus Metastasis from Papillary Thyroid Carcinoma: Case Report and Review of the Literature. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. It has an indolent clinical course and favorable prognosis. Brain metastasis is uncommon and complicates about 0.1%-5% of PTCs. Metastasis to the choroid plexus of the lateral ventricles has been reported in 7 cases of thyroid malignancies, all of which were unilateral. METHODS: We report a case of a 52 year-old woman with a history of PTC who presented with severe headache, nausea and vomiting, right hemiparesis, and speech disturbance. Imaging studies depicted lesions in both lateral ventricles. RESULTS: The patient underwent microsurgical tumor resection. Histopathologic examination revealed choroid plexus metastasis from PTC. CONCLUSIONS: Metastases to the choroid plexus from extracranial tumors are very rare, with only a few cases reported thus far. A demographic analysis of these cases suggests there may be a tropism of some extracranial carcinomas, such as renal cell carcinoma, for choroid plexus, especially in the lateral ventricles. We report the eighth case of choroid plexus metastasis, but it is the first bilateral one arising from thyroid cancer. PMID- 26026633 TI - Loading and removal of PAHs in a wastewater treatment plant in a separated sewer system. AB - The loading and removal of polycyclic aromatic hydrocarbons (PAHs) were measured and estimated in a wastewater treatment plant in a separated sewer system in a suburban area of Japan. The influent 16 PAHs concentration was 219 +/- 210 ng L( 1), whereas the effluent concentration was 43.5 +/- 42.5 ng L(-1) (mean +/- sd). No clear diurnal or weekly fluctuation was observed. However, evaluation of long term changes revealed PAH fluctuations continuing for more than 1 week. Half of the PAHs (63%) were biologically or chemically transformed, or vaporized in the treatment plant, while the remainder were discharged with effluent (28%) and excess sludge (9%). Measurement of the per capita loading of the treatment plant revealed values of 142 +/- 53 and 28 +/- 11 MUg person(-1)day(-1) (mean +/- 95% confidence interval) for influent and effluent, respectively. Isomer ratio analysis revealed that the PAHs originated from a mixture of petroleum, petroleum combustion, and burning of biomass residues. PMID- 26026634 TI - A retrospective analysis of outcomes of dalteparin use in pediatric patients: a single institution experience. AB - BACKGROUND: Dalteparin is a commonly used low molecular weight heparin (LMWH) with extensive safety data in adults. With distinct advantages of once daily dosing and relative safety in renal impairment, it has been used off-label in pediatric practice; however, age-based dosing guidelines, safety and efficacy data in children are evolving. OBJECTIVES: To report our institutional experience with the use of dalteparin in the treatment and prophylaxis of venous thromboembolism (VTE) in pediatric patients. PATIENTS/METHODS: Retrospective chart review of all children (0-18years) that received dalteparin from December 1, 2000 through December 31, 2011. Doses per unit body weight per day (units/kg/day) were calculated for age-based group comparisons. RESULTS: Of 166 patients identified, 116 (70%) received prophylactic doses while 50 (30%) received therapeutic doses of dalteparin. Infants (<1year) required significantly higher weight-based dosing to achieve therapeutic anti-Xa levels compared to children (1-10years) or adolescents (>10-18years) (mean dose units/kg/day; 396.6 versus 236.7 and 178.8 respectively, p<0.0001). Overall response rate, including complete and partial thrombus resolution, was 83%. Bleeding complications were minor and the rates were similar in therapeutic and prophylaxis patients. No significant differences in dosing or bleeding events were noted based on obesity or malignancy. CONCLUSIONS: In our experience, dalteparin is effective for prophylaxis and therapy of VTE in pediatric patients. Dosing should be customized in an age-based manner with close monitoring of anti-Xa activity in order to achieve optimal levels, prevent bleeding complications, and to allow full benefit of prevention or therapy of thrombotic complications. PMID- 26026635 TI - Does tranexamic acid alter the risk of thromboembolism following primary total knee arthroplasty with sequential earlier anticoagulation? A large, single center, prospective cohort study of consecutive cases. AB - INTRODUCTION: In order to decrease the blood loss and transfusion requirement, tranexamic acid (TXA) has attracted the public's attention in total knee arthroplasty (TKA). However, the safety profile of TXA hindered its wide adoption. And the balance of anti-coagulation sequential anti-fibrinolysis has not yet been explored. This large, single center, prospective cohort study of consecutive cases aimed to investigate the epidemiology of vascular occlusive events associated with TXA and introduce our preliminary results of novel thromboprophylaxis. MATERIALS AND METHODS: We prospectively collected patients' data of our institution through National Health Database. The primary outcome was the incidence of venous thromboembolism and mortality within 30days following primary TKA. Subgroup analysis was performed on the basis of TXA administration methods. RESULTS: During 2012 to 2014, a total of 2532 unilateral TKA procedures were conducted in our institution, 2222 with TXA, 310 without TXA. The total occurrence of vascular occlusive events was statistically significantly higher (17.55% Vs 9.35%, p<0.001) in the TXA group but this finding was confined to the calf veins, with the main difference being the incidence in the calf muscular veins (13.68% Vs 6.77%, p=0.001). Statistical difference was not detected neither in the incidence of symptomatic DVT nor asymptomatic DVT. No episode of symptomatic PE and all-cause mortality within 30days occurred postoperatively. Subgroup analysis revealed no significant difference with regard to the incidence of DVT (p>0.05). CONCLUSION: This study confirmed that the incidence of postoperative VTE was unchanged when TXA was administered in primary unilateral TKA. And our study further indicated that earlier anticoagulation should be adopted to keep the balance between anti-fibrinolysis and anti-coagulation after administering TXA. PMID- 26026636 TI - Accuracy of X-ray with perfusion scan in young patients with suspected pulmonary embolism. AB - BACKGROUND: Computed tomography pulmonary angiogram (CTPA) has become the standard test in the diagnostic workup of patients with suspected pulmonary embolism (PE). However, young patients may have an increased risk of cancer with CTPA. Perfusion scanning combined with chest X-ray (X/Q) may offer an adequate alternative, but has never been prospectively validated. We directly compared this strategy with CTPA in patients aged <=50years with suspected PE. METHODS: Consecutive patients with a likely clinical probability or an abnormal D-dimer level underwent both CTPA and X/Q. Two trained and experienced nuclear physicians independently analyzed the X/Q-scans. The accuracy of X/Q according to the PISAPED criteria was calculated in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Seventy-six patients were included, with a PE rate of 33%. The inter-observer agreement for X/Q-scan reading was high (kappa=0.89). After consensus reading, 21 patients (28%) were categorized as 'PE present', 53 (70%) as 'PE absent', and two (2.6%) as 'non-diagnostic'. In 22%, there was a discrepancy between the X/Q-scan and CPTA for the diagnosis or exclusion of PE. The PPV and NPV were 71% and 83%, respectively. CONCLUSION: In patients with a high risk of PE, a diagnostic strategy of chest X-ray and perfusion scanning using the PISAPED criteria seems less safe than CTPA. Additional studies should further investigate this diagnostic algorithm. PMID- 26026637 TI - Plasma visfatin levels are associated with major adverse cardiovascular events in patients with acute ST-elevation myocardial infarction. AB - PURPOSE: Circulating levels of visfatin, a ubiquitous adipokine, may reflect both the severity of plaque as well as degree of plaque stabilization in acute myocardial injury. The purpose of this study was to test whether the level of visfatin is associated with the occurrence of major adverse cardiovascular events (MACEs) in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: Consecutive patients (n=185) with acute STEMI were prospectively enrolled in the study. ELISA was used to measure plasma visfatin concentrations. Composite MACEs included death, recurrent myocardial infarction, target lesion revascularization or re-advanced heart failure. RESULTS: Plasma visfatin levels were significantly higher in composite MACE patients than in non-MACE patients. A multivariate Cox hazard regression model revealed that the predictive independent risk factors for the occurrence of composite MACEs were visfatin level (relative risk = 1.04) and age (relative risk = 6.05). When patients were grouped according to their plasma visfatin levels, composite MACEs occurred more frequently in patients presenting with high visfatin levels. Moreover, Kaplan-Meier analysis revealed that high visfatin levels were significantly associated with the occurrence of composite MACEs. CONCLUSIONS: The level of plasma visfatin may be associated with risk of composite MACEs in STEMI patients, and may be useful for risk stratification. PMID- 26026638 TI - Remote ischemic conditioning and renal function after contrast-enhanced CT scan: A randomized trial. AB - PURPOSE: Remote ischemic conditioning has been shown to protect against kidney injury in animal and human studies of ischemia-reperfusion. Recent evidence suggests that conditioning may also provide protection against kidney injury caused by contrast medium. The purpose of this study was to determine if conditioning protected against increases in serum creatinine (SCr) after contrast enhanced computed tomography (CECT). METHODS: A randomised controlled trial (NCT 01741896) was performed with institutional review board approval and informed patient consent. Adult in-patients undergoing abdomino-pelvic CECT were allocated to conditioned or control groups. Conditioning consisted of four cycles of five minutes of cuff-induced arm ischemia with three minutes of reperfusion applied ~40 minutes before CECT. The primary outcome was SCr change after CECT. RESULTS: Baseline characteristics were similar in both groups. For all patients, conditioning reduced the risk ratio (RR) of increased SCr; RR 0.65 (95% confidence intervals 0.41 to 1.04). The protective effect was greater and the evidence for protection stronger when analysis was restricted to patients with pre-scan reduced renal function (eGFR. PMID- 26026639 TI - Comparison of Pressure- and Volume-Controlled Ventilation in Laparoscopic Surgery: A Meta-analysis of Randomized Controlled Trial. AB - PURPOSE: Volume-controlled ventilation (VCV) has been the traditional mechanical ventilation mode in laparoscopic surgery. Pressure-controlled ventilation (PCV) has been used more frequently in recent years, especially for patients with complicated conditions; however, evidence on whether PCV is superior to VCV is still lacking. A meta-analysis was used to compare the effects of PCV and VCV on respiratory and hemodynamic parameters during laparoscopic surgery. METHODS: PubMed and Embase were each searched from their inception to December 2014 for randomized controlled trials comparing the effects of PCV and VCV on respiratory and hemodynamic parameters during laparoscopic surgery. Standard mean difference (SMD) with 95% confidence interval (CI) was calculated using a random effect model. Outcomes were assessed at three times: preoperative (T1), intraoperative (T2) and postoperative (T3). Respiratory mechanics (including peak airway pressure, plateau pressure, mean airway pressure, compliance, airway resistance, minute volume, end-tidal CO2 tension and tidal volume) and hemodynamic parameters (including heart rate and mean arterial pressure) were calculated. RESULTS: Eight randomized controlled trials with a total of 428 participants, 214 cases using PCV and 214 cases using VCV, were included in the meta-analysis. No significant differences were detected between the groups in terms of hemodynamic parameters. In contrast, with respiratory mechanics, PCV was slightly but significantly associated with lower peak airway pressure, higher compliance, lower airway resistance at T1, lower peak airway pressure, higher compliance, higher mean airway pressure at T2, lower peak airway pressure, lower mean airway pressure and higher end-tidal CO2 tension at T3. For the rest of respiratory parameters, there were no statistical differences between the groups. Subgroup analysis by morbidly obese, type of operations and quality of studies, showed similar results. CONCLUSIONS: Our meta-analysis suggests that hemodynamic parameters are similar in patients who underwent laparoscopic surgery with PCV and VCV, but patients who had PCV exhibited mildly better respiratory data. PMID- 26026640 TI - Letter of retraction. AB - It has come to our attention that the a manuscript published in CIM: JianXin J, Cha Y, ZhiPeng L, Jie X, Hao Z, Meiyuan C, ChengYi S "GOLP3 is a predictor of survival in patients with hepatocellular carcinoma" Clin Invest Med. 2014 Aug 1;37(4):E233-42 contains text identical to a manuscript published in Tumour Biology: Hu GS, Li YQ, Yang YM, Shi W, Liao AJ, Yao YH, Zeng B, Yuan J "High expression of Golgi phosphoprotein-3 is associated with poor survival in patients with hepatocellular carcinoma" Tumour Biol. 2014 Sep;35(9):8625-32. doi: 10.1007/s13277-014-2105-8. Epub 2014 May 28. For this reason, the publication in CIM has been retracted. Jonathan Angel, MD?Editor, CIM. PMID- 26026641 TI - Challenges in pharmacotherapeutics education for diabetes in real-world clinical settings: views from family medicine and internal medicine residents. AB - PURPOSE: Pharmacotherapy for diabetes in real-world clinical settings is very complex and is posing a challenge for residents in training. The purpose of this study was to explore the views of residents in Canada regarding educational priorities for pharmacotherapy in diabetes management. METHODS: A questionnaire was developed to explore different domains of pharmacotherapy in diabetes management, including different clinic>al settings, combination pharmacotherapy with different classes of medications and patients' characteristics, including comorbidities and cardiovascular risk factors. The questionnaire and the letter of invitation was sent to residents through their program directors. The results were gathered through an online survey system. Due to the study design, response rate could not be determined. For data analysis, SPSS Software was used for statistical analysis. Chi-square testing was utilized for comparisons of proportions. RESULTS: Thirty-four residency programs in Canada were contacted and 165 residents completed the study. A significant number of the residents (59%) viewed combination pharmacotherapy for diabetes management as the most important educational priority (p < 0.001). Regarding insulin therapy, combination of insulin with another class of agents was recognized as the most important educational priority by 51% of residents (p < 0.001). Among all classes of medication for blood glucose management the education on the use of newer class of medication such as GLP1 agonists, DPP4 inhibitors and SGLT2 inhibitors was recognized as a priority by 77% of residents (p < 0.001). CONCLUSION: This study provides new data and insights into residents' views on diabetes pharmacotherapy. Educational curriculums may incorporate these views from residents on the educational priorities that were identified in this study. PMID- 26026642 TI - Serum and urinary biomarkers for predicting acute kidney injury after partial nephrectomy. AB - PURPOSE: The purpose of this study was to evaluate the ability of specific biomarkers to predict acute kidney injury (AKI) after partial nephrectomy. METHODS: A prospective study of 89 patients undergoing partial nephrectomy was conducted in the First Affiliated Hospital of Fujian Medical University. The patients were divided into two groups according to AKI status: an AKI group and non-AKI group. Receiver operator characteristic (ROC) curves were generated and the areas under the curve (AUCs) were compared. RESULTS: Twenty-eight subjects (31.5%) developed AKI while sixty-one subjects (68.5%) did not. Vascular clamping time in the AKI group was longer than that in the non-AKI group (29 +/- 17 min vs. 24 +/- 9 min, P = 0.042). Eight patients (28.6%) received blood infusion in the AKI group compared with five patients (8.2%) in the non-AKI group (P = 0.021). The area under ROC curve for AKI prediction was 0.792 [95% confidence interval (CI) 0.697 to 0.888, P < 0.000] for serum cystatin C 24 hours after surgery and 0.756 (95% CI 0.656 to 0.857, P < 0.000) for serum cystatin C 48 hours after surgery. Multivariate regression analysis showed transfusion [Hazard ratio (HR) 3.712, P = 0.044] and 24 hours serum cystatin C (HR 41.594, P = 0.001) correlated with AKI. CONCLUSIONS: Postoperative serum cystatin C may be an early predictor for AKI after partial nephrectomy. Transfusion may be an independent risk factor for AKI after partial nephrectomy. PMID- 26026643 TI - High resolution multi-arterial phase MRI improves lesion contrast in chronic liver disease. AB - PURPOSE: To determine the reliability of arterial phase capture and evaluate hypervascular lesion contrast kinetics with a combined view-sharing and parallel imaging dynamic contrast-enhanced acquisition, DIfferential Sub-sampling with Cartesian Ordering (DISCO), in patients with known chronic liver disease. METHODS: A retrospective review of 3T MR images from 26 patients with known chronic liver disease referred for hepatocellular carcinoma surveillance or post treatment follow up was performed. After administration of a gadolinium-based contrast agent, a multiphasic acquisition was obtained in a 28 s breath-hold, from which seven sequential post-contrast image volumes were reconstructed. RESULTS: The late arterial phase was successfully captured in all cases (26/26, 95% CI 87-100%). Images obtained 26 s post-injection had the highest frequency of late arterial phase capture (20/26) and lesion detection (23/26) of any individual post-contrast time; however, the multiphasic data resulted in a significantly higher frequency of late arterial phase capture (26/26, p=0.03) and a higher relative contrast (5.37+/-0.97 versus 7.10+/-0.98, p < 0.01). CONCLUSION: Multiphasic acquisition with combined view-sharing and parallel imaging reliably captures the late arterial phase and provides sufficient temporal resolution to characterize hepatic lesion contrast kinetics in patients with chronic liver disease while maintaining high spatial resolution. PMID- 26026644 TI - Small molecule TBTC as a new selective retinoid X receptor alpha agonist improves behavioral deficit in Alzheimer's disease model mice. AB - Alzheimer's disease (AD) is a neurodegenerative disease, which is characterized by progressive cognitive impairments. The beta-amyloid (Abeta)-induced neurodegeneration is determined as the main pathogenesis of AD, and either decrease of Abeta production or increase of Abeta clearance is beneficial in the treatment of AD, while Abeta clearance regulation seems to be more attractive as a promising therapeutic strategy against AD based on the fact that the insufficient clearance of Abeta is tightly associated with the late onset of AD that is represented as the majority of AD cases. Here, we report that the small molecular compound, methyl 2-amino-6-(tert-butyl)-4,5,6,7 tetrahydrobenzo[b]thiophene-3-carboxylate (TBTC), as a selective agonist of retinoid X receptor alpha (RXRalpha) can effectively activate the heterodimerization of RXRalpha with either liver X receptor alpha (LXRalpha) or peroxisome proliferator activated receptor gamma (PPARgamma), stimulate the expressions of the genes of apoE, ABCA1 and ABCG1, and decrease Abeta content both in cells and animal models. In addition, administration of TBTC (30mg/kg/day) in the transgenic APP-PS1 mice could also reduce the formation of senile plaques and improve the daily living activity of the mice. Therefore, our findings have suggested that TBTC might hold the potential as a drug lead compound for the treatment of AD. PMID- 26026645 TI - Modulation of osteoblast differentiation and bone mass by 5-HT2A receptor signaling in mice. AB - Recent studies reported that serotonin (5-hydroxytryptamine, 5-HT) may be an endogenous paracrine and/or autocrine factor that is used for intercellular communication in bone cells and between multiple organs regulating bone homeostasis. In the present study, we showed that the administration of MDL11939, a selective 5-HT2A receptor antagonist, reduced bone mass in mice. The loss of bone mass in MDL11939-treated mice was associated with impaired bone formation in vivo, as demonstrated by the lower expression of osterix (Osx) and osteocalcin than that in vehicle-treated mice. On the other hand, no significant differences were observed in osteoclast numbers between MDL11939- and vehicle-treated mice. The pharmacological blockade of 5-HT2A receptor signaling significantly decreased alkaline phosphatase activity in osteoblastic cells. In addition, the knockdown of the 5-HT2A receptor by a siRNA treatment decreased Osx, but not Runx2 gene expression in MC3T3-E1 cells. These results suggest that 5-HT2A receptor signaling mediated bone mass by regulating osteoblast differentiation. PMID- 26026646 TI - Repetition, response mobilization, and face: Analysis of group interactions with a 19-year-old with Asperger syndrome. AB - This Conversation Analytic study examined the talk of an adolescent with Asperger syndrome (under previously used diagnostic criteria), Nathan, as he interacts with peers in a small group setting. We focused on Nathan's repetition aimed at pursuing response, and rely on analytical frameworks including response mobilization, face-work, and agreement preference. We found that while Nathan's repetitions resembled 'topic perseveration' previously described in the literature, they showed evidence of interactional awareness as they were employed when peers offered little or no response to his original utterance. However, we also found that while much of Nathan's talk was sophisticatedly structured, his repetition to pursue response eschewed interaction rituals that work to maintain social cohesion. As a result, Nathan's interactional priorities appeared mis aligned with those of his peers, and failed to produce extended interactions in most cases. LEARNING OUTCOMES: Readers will be able to describe features of conversational interaction, including response mobilization, agreement preference, and face work. They will understand the relevance of conversation analysis to the study of interaction in individuals with autism spectrum disorder. Lastly, they will be able to describe the conditions under which the subject used repetition within peer interactions, and the effects of his repetition on interaction. PMID- 26026647 TI - Shortening the PHQ-9: a proof-of-principle study of utilizing Stochastic Curtailment as a method for constructing ultrashort screening instruments. AB - OBJECTIVE: In primary care, screening instruments for mental health should be ultrashort to allow for routine usage. In this paper, Stochastic Curtailment is introduced as a method for constructing ultrashort screeners. METHOD: In a post hoc diagnostic accuracy study using the item scores on the Patient Health Questionnaire depression module (PHQ-9) of a large sample (N=20, 685), Stochastic Curtailment was compared with two existing ultrashort versions of PHQ-9. The first was PHQ-2 (which includes the first two items of PHQ-9), and the second was a 'two-step' method (only if the PHQ-2 screened positive were all nine PHQ items administered). For PHQ-2 and two-step, both cut scores 2 and 3 were evaluated. RESULTS: PHQ-2 showed the lowest and Stochastic Curtailment the highest diagnostic accuracy with reference to the classifications based on the full PHQ 9. To do so, Stochastic Curtailment used 3.08 items on average (S.D.=1.98), which was slightly less than two-step (M=3.18, S.D.=2.62) under its most accurate cut score (>=2). CONCLUSIONS: It was concluded that Stochastic Curtailment is a promising method for constructing ultrashort screeners. PMID- 26026648 TI - Cardiac output method comparison studies: the relation of the precision of agreement and the precision of method. AB - Cardiac output (CO) plays a crucial role in the hemodynamic management of critically ill patients treated in the intensive care unit and in surgical patients undergoing major surgery. In the field of cardiovascular dynamics, innovative techniques for CO determination are increasingly available. Therefore, the number of studies comparing these techniques with a reference, such as pulmonary artery thermodilution, is rapidly growing. There are mainly two outcomes of such method comparison studies: (1) the accuracy of agreement and (2) the precision of agreement. The precision of agreement depends on the precision of each method, i.e., the precision that the studied and the reference technique are able to achieve. We call this "precision of method". A decomposition of variance shows that method agreement does not only depend on the precision of method but also on another important source of variability, i.e., the method's general variability about the true values. Ignorance of that fact leads to falsified conclusions about the precision of method of the studied technique. In CO studies, serial measurements are frequently confused with repeated measurements. But as the actual CO of a subject changes from assessment to assessment, there is no real repetition of a measurement. This situation equals a scenario in which single measurements are given for multiple true values per subject. In such a case it is not possible to assess the precision of method. PMID- 26026650 TI - Activating schoolyards: study design of a quasi-experimental schoolyard intervention study. AB - BACKGROUND: The aim of the Activating Schoolyards Study is to develop, implement, document and assess a comprehensive schoolyard intervention to promote physical activity (PA) during school recess for primary school children (grade 4-8). The intervention is designed to implement organizational and structural changes in the physical environment. METHOD: The study builds on a quasi-experimental study design using a mixed method approach including: 1) an exploratory study aimed at providing input for the developing process; 2) an evaluation of the effect of the interventions using a combination of accelerometer, GPS and GIS; 3) a process evaluation facilitating the intervention development process and identifying barriers and facilitators in the implementation process; 4) a post-intervention end-user evaluation aimed at exploring who uses the schoolyards and how the schoolyards are used. The seven project schools (cases) were selected by means of an open competition and the interventions were developed using a participatory bottom-up approach. DISCUSSION: The participatory approach and case selection strategy make the study design novel. The use of a mixed methods design including qualitative as well as quantitative methods can be seen as a strength, as the different types of data complement each other and results of one part of the study informed the following parts. A unique aspect of our study is the use of accelerometers in combination with GPS and GIS in the effect evaluation to objectively determine where and how active the students are in the schoolyard, before and after the intervention. This provides a type of data that, to our knowledge, has not been used before in schoolyard interventions. Exploring the change in behavior in relation to specific intervention elements in the schoolyard will lead to recommendations for schools undergoing schoolyard renovations at some point in the future. PMID- 26026649 TI - Satisfaction with primary care provider involvement is associated with greater weight loss: Results from the practice-based POWER trial. AB - OBJECTIVE: To evaluate the association between the patient-provider relationship, satisfaction with primary care provider's (PCP) involvement and weight loss in a practice-based weight loss trial. METHODS: POWER was a practice-based randomized controlled behavioral weight loss trial. Participants completed questionnaires about patient-provider relationship and satisfaction with their PCPs' involvement in the trial. PCPs completed a demographics and practice survey. The main outcome was the mean weight change from baseline to 24 months. We created mixed-effect models, accounting for the random effects of patients clustering with the PCP and the repeated outcome assessments within patient over time, and adjusted for randomization assignment, age, gender, race and clinical site. RESULTS: 347 (of 415) were included. Mean age was 54.8 years, mean BMI was 36.3 kg/m(2). Participants reported high quality patient-provider relationships (mean summary score=29.1 [range 14-32]). Patient-provider relationship quality was not associated weight loss in either the intervention or control groups. Among intervention participants, higher ratings of the helpfulness of the PCPs' involvement was associated with greater weight loss (p=0.005). CONCLUSION: Patient-provider relationship quality was not associated with weight loss in a practice-based weight loss trial but rating PCPs as helpful in the intervention was associated with weight loss. PRACTICE IMPLICATIONS: Partnering with PCPs to deliver weight loss programs may promote greater participant satisfaction and weight loss. PMID- 26026651 TI - The Nuances of Health Literacy, Nutrition Literacy, and Food Literacy. AB - Health literacy, defined as the ability to access, understand, and use health information, has been identified as an international public health goal. The term nutrition literacy has emerged as a distinct form of health literacy, yet scholars continue to reflect on constituent skills and capabilities in light of discussions regarding what it means to be food literate and health literate. This viewpoint argues that a comprehensive conceptualization of nutrition literacy should reflect key elements of health literacy and food literacy constructs. Nutbeam's tripartite model of health literacy is employed to explore competencies that are likely to facilitate healthy food relationships. PMID- 26026652 TI - Variable effects of statins on glucose homeostasis parameters and their diabetogenic role. PMID- 26026654 TI - Analysis of peri-islet CD45-positive leucocytic infiltrates in long-standing type 1 diabetic patients: additional data regarding cause of death. PMID- 26026653 TI - Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs. AB - AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9(+) transgenic minipig. METHODS: Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs' weight gain and cholesterol intake. After 49 weeks of high-fat feeding, the major arteries were harvested for a detailed analysis of the plaque burden and histological plaque type. RESULTS: Stable hyperglycaemia was achieved in the diabetic minipigs, while the plasma total and LDL-cholesterol and creatinine levels were unaffected. Diabetes failed to increase atherosclerosis in any of the vessels examined. The plaque burden in the aorta and right coronary artery was comparable between the groups, and was even reduced in the left anterior descending (LAD) coronary and iliofemoral arteries in the diabetic pigs compared with the controls. The distribution of plaque types and the collagen and macrophage contents were similar between the groups, except for a reduced infiltration of macrophages in the LAD arteries of the diabetic pigs. CONCLUSIONS/INTERPRETATION: Poorly controlled diabetes with no alterations in plasma cholesterol or creatinine concentrations did not augment the plaque burden or promote the development of more advanced lesions in this large-animal model of human-like atherosclerosis. This is consistent with clinical studies in patients with type 1 diabetes, indicating that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important. PMID- 26026655 TI - Perioperative Complications and Length of Stay After Revision Total Hip and Knee Arthroplasties: An Analysis of the NSQIP Database. AB - Goals of this study were (1) to determine the 30-day complications after aseptic revision hip arthroplasty (RHA) and aseptic revision knee arthroplasty (RKA) and (2) to identify patient-related risk factors predicting major complications and prolonged hospital stay beyond 7 days. The National Surgical Quality Improvement Program (NSQIP) database was used to identify patients with RHA (n=2643) or RKA (n=2425) from 2011 to 2012. The 30-day mortality rates for RHA and RKA were 1.0% and 0.1% (P<0.001) and the overall complication rates were 7.4% and 4.7% (P<0.001) for RHA and RKA, respectively. Multivariable analysis showed that preoperative anemia is the most important modifiable independent predictor for both major complications and prolonged hospital stay after RHA and RKA. PMID- 26026656 TI - Ethnicity-stratified analysis of the association between IL-18 polymorphisms and systemic lupus erythematosus in a European population: a meta-analysis. AB - We performed a meta-analysis to identify the association between polymorphisms in the promoter of interleukin-18 (IL-18) and susceptibility for systemic lupus erythematosus (SLE) . Genotype data for three single-nucleotide polymorphisms (SNPs rs360719, rs1946518, and rs187238) in the IL-18 promoter were extracted from 20 studies of three different ethnicities (European, Asian, and South American). Data from each ethnicity group and their combinations were analyzed. We found distinct evidence of an association between rs360719 and SLE (P = 0.001) in the European/South American group [odds ratio (OR) 1.31 per C allele, 95% confidence interval (CI) 1.11-1.53]. Stratification analysis by ethnicity showed a significant association between rs360719 and SLE in the European population (OR 1.33 per C allele, 95% CI 1.11-1.61, P = 0.003) and a lesser effect in the same direction in the South American population (OR 1.18). A significant association was also identified between rs1946518 and SLE in the European population (OR 1.16 per A allele, 95% CI 1.03-1.30, P = 0.017), although there was no association in the Asian or the combined European/Asian population. We also examined genome-wide association study (GWAS) data from an Asian subpopulation (Chinese) for the association between rs1946518 and SLE, but found no association (P = 0.83). The third SNP, rs187238, was not significantly associated with SLE in any of the populations examined. In summary, this study identified a significant association between SLE and two SNPs within the IL-18 gene promoter region (rs360719 and rs1946518) in a European population, but not in populations of Asian origin. PMID- 26026657 TI - [The French National Professional Council: An underrated structure]. PMID- 26026658 TI - [Desmoplastic ameloblastoma and histopathological features: A case report]. PMID- 26026659 TI - Automated 3D-2D registration of X-ray microcomputed tomography with histological sections for dental implants in bone using chamfer matching and simulated annealing. AB - We propose a novel 3D-2D registration approach for micro-computed tomography (MUCT) and histology (HI), constructed for dental implant biopsies, that finds the position and normal vector of the oblique slice from MUCT that corresponds to HI. During image pre-processing, the implants and the bone tissue are segmented using a combination of thresholding, morphological filters and component labeling. After this, chamfer matching is employed to register the implant edges and fine registration of the bone tissues is achieved using simulated annealing. The method was tested on n=10 biopsies, obtained at 20 weeks after non-submerged healing in the canine mandible. The specimens were scanned with MUCT 100 and processed for hard tissue sectioning. After registration, we assessed the agreement of bone to implant contact (BIC) using automated and manual measurements. Statistical analysis was conducted to test the agreement of the BIC measurements in the registered samples. Registration was successful for all specimens and agreement of the respective binary images was high (median: 0.90, 1.-3. Qu.: 0.89-0.91). Direct comparison of BIC yielded that automated (median 0.82, 1.-3. Qu.: 0.75-0.85) and manual (median 0.61, 1.-3. Qu.: 0.52-0.67) measures from MUCT were significant positively correlated with HI (median 0.65, 1.-3. Qu.: 0.59-0.72) between MUCT and HI groups (manual: R(2)=0.87, automated: R(2)=0.75, p<0.001). The results show that this method yields promising results and that MUCT may become a valid alternative to assess osseointegration in three dimensions. PMID- 26026660 TI - Risk factors of multidrug-resistant, extensively drug-resistant and pandrug resistant Acinetobacter baumannii ventilator-associated pneumonia in a Medical Intensive Care Unit of University Hospital in Thailand. AB - Ventilator-associated pneumonia (VAP) caused by Acinetobacter baumannii remains a significant cause of morbidity and mortality. Increasing antimicrobial resistance influences the selection of antibiotic treatment especially pandrug-resistant A. baumannii. A retrospective cohort study was conducted in the Medical Intensive Care Unit to identify the risk factors of VAP caused by multidrug-resistant A. baumannii (MDR-AB), extensively drug-resistant A. baumannii (XDR-AB) and pandrug resistant A. baumannii (PDR-AB). All 337 adult patients with confirmed A. baumannii VAP were included. The incidence of MDR-AB, XDR-AB and PDR-AB were 72 (21.4%), 220 (65.3%) and 12 (3.6%), respectively. The risk factor for MDR-AB was prior use of carbapenems (OR 5.20; 95% CI 1.41-19.17). Risk factors for XDR-AB were the prior use of carbapenems (OR, 6.30; 95% CI, 1.80-21.97) and a high Sequential Organ Failure Assessment (SOFA) score (OR 1.35; 95% CI 1.07-1.71). In PDR-AB, the risk factors were the prior use of colistin (OR, 155.95; 95% CI, 8.00 3041.98), carbapenems (OR, 12.84; 95% CI, 1.60-103.20) and a high Simplified Acute Physiology Score (SAPS II) (OR 1.10; 95% CI 1.01-1.22). In conclusion, previous exposure to antibiotics and severity of VAP were risk factors of drug resistant A. baumannii. Judicious use of carbapenems and colistin is recommended to prevent the antimicrobial-resistant strains of this organism. PMID- 26026661 TI - Clinical characteristics of pneumonia in bedridden patients receiving home care: a 3-year prospective observational study. AB - BACKGROUND: The aim of the study was to describe the epidemiology, clinical features, antimicrobial treatment, and outcomes of bedridden pneumonia patients receiving home healthcare. METHODS: A 3-year prospective observational study of poor performance status (PS) 3-4 patients receiving long-term home healthcare and hospitalized at a single center with pneumonia between October 2010 and September 2013 was conducted, and their clinical characteristics were compared with non bedridden community-acquired pneumonia (CAP) patients. RESULTS: A total of 131 CAP patients with PS 3-4, and 400 CAP patients with PS 0-2 were evaluated. The PS 3-4 patients were older, and exhibited a higher frequency of underlying diseases. Aspiration was thought to be associated with pneumonia in 77.1% of the PS 3-4 patients. Streptococcus pneumoniae was the leading pathogen in both groups, whereas the frequency of streptococci and polymicrobial infections was higher in the PS 3-4 group. The incidence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa was lower than in previous healthcare-associated pneumonia reports. The in-hospital mortality and recurrence rates were significantly higher in the PS 3-4 group than in the good PS group (17.6% vs. 6.0%, p < 0.001 and 15.3% vs. 7.5%, p = 0.008, respectively). CONCLUSIONS: The clinical characteristics of pneumonia in poor PS patients were similar to healthcare-associated pneumonia (HCAP), except for the frequency of drug-resistant pathogens. Hence, it might be beneficial to categorize pneumonia in home residents with poor PS separately from pneumonia in CAP patients who were previously healthy or experienced mild comorbidities. PMID- 26026662 TI - Phagocytosis by human monocytes is required for the secretion of presepsin. AB - BACKGROUND: Presepsin, a soluble CD14 subtype, is increasingly recognized as a useful biomarker for sepsis. However, little is known about the biological characteristics of presepsin in humans. Furthermore, there are no studies evaluating clinical validity of measuring the presepsin levels in patients after allogeneic hematopoietic cell transplantation, irrespective of the high frequency of sepsis. METHODS: For in vitro assays, neutrophils and monocytes were isolated from the peripheral blood of healthy controls and treated with bacteria or inflammatory stimuli. Presepsin levels in the culture supernatants were measured by enzyme linked immunosorbent assay (ELISA). For a cohort study of patients undergoing allogeneic hematopoietic cell transplantation, serum samples were subjected to ELISA for presepsin, and the relationship of presepsin levels with the incidence of transplantation-related complications was statistically analyzed. RESULTS: We found that monocytes were the main source of presepsin in humans. Presepsin secretion by human monocytes was triggered by bacterial phagocytosis or sterile phagocytic stimulus, such as monosodium urate crystals, rather than soluble inflammatory stimuli. Elastase, a serine protease in human monocytes, mediated CD14 cleavage to produce presepsin. The cohort study demonstrated that high presepsin values were significantly associated with an increased incidence of hemophagocytic syndrome, as well as bacteremia. Moreover, patients with higher presepsin values revealed inferior overall survival, suggesting that presepsin can also be a prognostic marker for transplantation. CONCLUSIONS: In this study, we clarified the biological features of presepsin in humans. Our study may be useful for increasing the clinical application of presepsin as a biomarker. PMID- 26026663 TI - Intraspecific genetic lineages of a marine mussel show behavioural divergence and spatial segregation over a tropical/subtropical biogeographic transition. AB - BACKGROUND: Intraspecific variability is seen as a central component of biodiversity. We investigated genetic differentiation, contemporary patterns of demographic connectivity and intraspecific variation of adaptive behavioural traits in two lineages of an intertidal mussel (Perna perna) across a tropical/subtropical biogeographic transition. RESULTS: Microsatellite analyses revealed clear genetic differentiation between western (temperate) and eastern (subtropical/tropical) populations, confirming divergence previously detected with mitochondrial (COI) and nuclear (ITS) markers. Gene flow between regions was predominantly east-to-west and was only moderate, with higher heterozygote deficiency where the two lineages co-occur. This can be explained by differential selection and/or oceanographic dynamics acting as a barrier to larval dispersal. Common garden experiments showed that gaping (periodic closure and opening of the shell) and attachment to the substratum differed significantly between the two lineages. Western individuals gaped more and attached less strongly to the substratum than eastern ones. CONCLUSIONS: These behavioural differences are consistent with the geographic and intertidal distributions of each lineage along sharp environmental clines, indicating their strong adaptive significance. We highlight the functional role of diversity below the species level in evolutionary trends and the need to understand this when predicting biodiversity responses to environmental change. PMID- 26026664 TI - Evaluation of two commercially available chromogenic media for confirmation of methicillin-resistant Staphylococcus aureus from human, animal, and food samples. AB - We compared the diagnostic performance of two chromogenic media, Brilliance MRSA 2 agar (Thermo Fisher Scientific) and ChromID MRSA agar (bioMerieux), for MRSA confirmation of 239 Staphylococcus aureus isolates from clinical, animal and food samples. Statistically significant differences were not observed between MRSA confirmation by mecA/mecC PCR, and by culture in both chromogenic media. However, a statistically significant difference was observed between the results obtained by both chromogenic media (p = 0.003). Segregated analysis of the results depending on the origin of the isolates (clinical, animal, and food) revealed a significant lower performance in the MRSA confirmation of food-derived isolates by using Brilliance MRSA 2 agar in comparison to PCR confirmation (p = 0.003) or ChromID MRSA agar (p<0.001). Both chromogenic media provided a good diagnostic performance for detection of MRSA isolates of human and animal origin. In conclusion, the use of chromogenic agar plates for MRSA confirmation of S. aureus isolates can provide a good diagnostic performance (sensitivity >92% and specificity >89%) regardless of the type of chromogenic media used or the origin of the S. aureus isolates. However, our results revealed a lower diagnostic performance for MRSA confirmation of S. aureus isolates from food samples by using Brilliance MRSA 2 agar. PMID- 26026665 TI - Enhanced suppression of adenovirus replication by triple combination of anti adenoviral siRNAs, soluble adenovirus receptor trap sCAR-Fc and cidofovir. AB - Adenoviruses (Ad) generally induce mild self-limiting respiratory or intestinal infections but can also cause serious disease with fatal outcomes in immunosuppressed patients. Antiviral drug therapy is an important treatment for adenoviral infections but its efficiency is limited. Recently, we have shown that gene silencing by RNA interference (RNAi) is a promising new approach to inhibit adenoviral infection. In the present in vitro study, we examined whether the efficiency of an RNAi-based anti-adenoviral therapy can be further increased by combination with a virus receptor trap sCAR-Fc and with the antiviral drug cidofovir. Initially, three siRNAs, siE1A_4, siIVa2_2 and Pol-si2, targeting the adenoviral E1A, IVa2 and DNA polymerase mRNAs, respectively, were used for gene silencing. Replication of the Ad was inhibited in a dose dependent manner by each siRNA, but the efficiency of inhibition differed (Pol-si2>siIVa2_2>siE1A_4). Double or triple combinations of the siRNAs compared with single siRNAs did not result in a measurably higher suppression of Ad replication. Combination of the siRNAs (alone or mixes of two or three siRNAs) with sCAR-Fc markedly increased the suppression of adenoviral replication compared to the same siRNA treatment without sCAR-Fc. Moreover, the triple combination of a mix of all three siRNAs, sCAR-Fc and cidofovir was about 23-fold more efficient than the combination of siRNAs mix/sCAR-Fc and about 95-fold more efficient than the siRNA mix alone. These data demonstrate that co-treatment of cells with sCAR-Fc and cidofovir is suitable to increase the efficiency of anti-adenoviral siRNAs. PMID- 26026666 TI - Pharmacodynamics of folic acid receptor targeted antiretroviral nanotherapy in HIV-1-infected humanized mice. AB - Long-acting nanoformulated antiretroviral therapy (nanoART) can sustain plasma drug levels and improve its biodistribution. Cell targeted-nanoART can achieve this and bring drug efficiently to viral reservoirs. However, whether such improvements affect antiretroviral responses remains unknown. To these ends, we tested folic acid (FA)-linked poloxamer407-coated ritonavir-boosted atazanavir (FA-nanoATV/r) nanoparticles for their ability to affect chronic HIV-1 infection in humanized mice. Following three, 100mg/kg FA-nanoATV/r intramuscular injections administered every other week to infected animals, viral RNA was at or below the detection limit, cell-associated HIV-1p24 reduced and CD4+ T cell counts protected. The dosing regimen improved treatment outcomes more than two fold from untargeted nanoATV/r. We posit that these nanoformulations have potential for translation to human use. PMID- 26026668 TI - Reply to comment to article: Posterior component separation with transversus abdominis release successfully addresses recurrent ventral hernias following anterior component separation. Bruce Tulloh, Andrew Charles de Beaux, DOI 10.1007/s10029-015-1391-4. PMID- 26026667 TI - A Checklist for Reporting Valuation Studies of Multi-Attribute Utility-Based Instruments (CREATE). AB - Multi-attribute utility-based instruments (MAUIs) assess health status and provide an index score on the full health-dead scale, and are widely used to support reimbursement decisions for new healthcare interventions worldwide. A valuation study is a key part of the development of MAUIs, with the primary goal of developing a scoring algorithm through eliciting societal preferences. We developed the 21-item Checklist for REporting VAluaTion StudiEs (CREATE) by following a modified two-round Delphi panel approach plus an email survey. CREATE is intended to promote good reporting practice as well as guiding developers to thoroughly and carefully think through key methodological elements in designing valuation studies. PMID- 26026669 TI - Input of molecular analysis in medical management of primary brain tumor patients. AB - Primary brain tumors comprise a large group of malignant and non-malignant tumors including heterogeneous entities with various biological and clinical behaviors. Up till recently, diagnosis of brain cancers, that drives treatment decision making, was based on integration of clinical, radiological and pathological features of patients and tumors. Over the last years, practical neuro-oncology has entered an era of molecular-based personalized medicine. Indeed, molecular features of tumors provide critical information to physicians for daily clinical management of patients and for design of relevant clinical research. Sporadic gliomas or glial tumors are the most common primary brain tumors in adults. Recently, their medical management has been revolutionized by molecular data. Indeed, optimal therapeutic management of grade III glioma patients now requires assessment of chromosome arms 1p/19q copy number and IDH mutational statuses as predictive and prognostic biomarkers. Indeed, two large phase III clinical trials have demonstrated that early chemotherapy plus radiotherapy, versus radiotherapy alone, doubles median overall survival of patients suffering from 1p/19q co deleted and/or IDH mutated anaplastic oligodendroglial tumor. Interestingly, both biomarkers have been identified in a large proportion of WHO grade II gliomas. Their clinical value, in this population, is under investigation through multiple phase III clinical trials. In sporadic WHO grade I gliomas, and specifically in pilocytic astrocytomas, MAPK signaling pathway activation is a frequent event, mainly due to genetic alterations involving BRAF gene. This characteristic opens new therapeutic perspectives using MAPK signaling pathway inhibitors. Finally, in the most aggressive gliomas, WHO grade IV gliomas, two critical biomarkers have been identified: (i) MGMT promoter methylation associated with longer survival and better response to chemotherapy and (ii) IDH mutations predicting better prognosis. Although, further studies are needed, MGMT promoter methylation will undoubtedly be transferred soon to clinical practice. Molecular characteristics are beginning to be valuable and indispensable in neuro-oncology for better management of brain tumors patients. The near future will be marked by identification of novel molecular biomarkers and their validation for clinical practice. PMID- 26026670 TI - Variable infection of stream salamanders in the southern Appalachians by the trematode Metagonimoides oregonensis (family: Heterophyidae). AB - Many factors contribute to parasites varying in host specificity and distribution among potential hosts. Metagonimoides oregonensis is a digenetic trematode that uses stream-dwelling plethodontid salamanders as second intermediate hosts in the Eastern US. We completed a field survey to identify which stream salamander species, at a regional level, are most likely to be important for transmission to raccoon definitive hosts. We surveyed six plethodontid species (N = 289 salamanders) from 23 Appalachian headwater sites in North Carolina: Desmognathus quadramaculatus (n = 69), Eurycea wilderae (n = 160), Desmognathus ocoee (n = 31), Desmognathus monticola (n = 3), Eurycea guttolineata (n = 7), and Gyrinophilus porphyriticus (n = 19). We found infection in all species except D. monticola. Further analysis focused on comparing infection in the two most abundant species, D. quadramaculatus and E. wilderae. We found that D. quadramaculatus had significantly higher infection prevalence and intensity, probably due to a longer aquatic larval period and larger body sizes and thus greater cumulative exposure to the parasite. PMID- 26026671 TI - Lethal and sub-lethal chronic effects of the herbicide diuron on seagrass. AB - Photosystem II herbicides from agricultural sources have been detected throughout nearshore tropical habitats including seagrass meadows. While PSII herbicides have been shown to inhibit growth in microalgae at low concentrations, the potential impacts of chronic low concentration exposures to seagrass health and growth have not been investigated. Here we exposed two tropical seagrass species Halodule uninervis and Zostera muelleri to elevated diuron concentrations (from 0.3 to 7.2MUgl(-1)) over a 79-day period followed by a 2-week recovery period in uncontaminated seawater. PAM fluorometry demonstrated rapid effect of diuron on photosystem II (PSII) in both seagrass species at 0.3MUgl(-1). This effect included significant inhibition of photosynthetic efficiency (DeltaF/Fm') and inactivation of PSII (Fv/Fm) over the 11 week exposure period. Significant mortality and reductions in growth was only observed at the highest exposure concentration of 7.2MUgl(-1) diuron. However, biochemical indicators demonstrated that the health of seagrass after this prolonged exposure was significantly compromised at lower concentrations. For example, the drop in C:N ratios (0.6MUgl(-1)) and reduced delta(13)C (1.7MUgl(-1)) in seagrass leaves indicated reduced C-assimilation from photosynthesis. Critically, the energetic reserves of the plants (as measured by starch content in the root-rhizome complex) were approximately halved following diuron exposure at and above 1.7MUgl(-1). During the 2-week recovery period, the photosynthetic capacity of the seagrass improved with only plants from the highest diuron treatment still exhibiting chronic damage to PSII. This study shows that, although seagrass may survive prolonged herbicide exposures, concentrations >=0.6MUgl(-1) diuron equivalents cause measureable impacts on energetic status that may leave the plants vulnerable to other simultaneous stressors. For example, tropical seagrasses have been heavily impacted by reduced light from coastal flood plumes and the effects on plant energetics from light limitation and diuron exposure (highest in flood plumes) are very similar, potentially leading to cumulative negative effects. PMID- 26026672 TI - Developmental exposures to waterborne abused drugs alter physiological function and larval locomotion in early life stages of medaka fish. AB - Environmental pollution by neuroactive pharmaceuticals from wastewater discharge is a major threat to aquatic ecosystems. However, the ecotoxicologic effect of waterborne abused drugs remains unclear. Embryos of medaka fish (Oryzias latipes) were exposed to aqueous solutions of 2 hallucinogenic drugs, ketamine (KET) and methamphetamine (MET) (0.004-40MUM) to assess developmental toxicity, oxidative stress and behavioral alteration in early life stages. The environmentally relevant concentration (0.004MUM) of both KET and MET significantly delayed blood circulation and hatching time in embryos and altered larval swimming behavior (e.g., maximum velocity and relative turn angle). KET and MET induced similar oxidative stress responses in embryos, which were unrecoverable in hatchlings in drug-free solutions. Early life exposure to the 2 drugs conferred distinct patterns in larval locomotion: KET induced hyperactivity and a less tortuous swimming path, but MET-treated larvae showed hypoactivity and a clockwise swimming direction at high doses. The alteration in locomotor responses were generally similar in mammals and zebrafish. We report sensitive biomarkers (e.g., heartbeat, hatching and swimming behavior) by developmental stage of medaka that reflect environmentally relevant exposures of abused drugs. They could be useful for ecological risk assessment of waterborne neuroactive drugs. The toxicity results implicate a potential ecotoxicological impact of controlled or abused drugs on fish development and populations in aquatic environments. PMID- 26026673 TI - Progesterone is actively metabolized to 5alpha-pregnane-3,20-dione and 3beta hydroxy-5alpha-pregnan-20-one by the marine mussel Mytilus galloprovincialis. AB - Progesterone (P4) and synthetic progestins enter the aquatic environment through wastewater treatment plant effluents and agricultural run-off, posing potential risks to aquatic organisms due to their biological activity. P4 is a precursor of a number of steroids in vertebrates, including estrogens and androgens. Mussels Mytilus galloprovincialis were exposed to P4 at the ng to low MUg/L range (0.02 10MUg/L) for 7 days with the aim of (a) assessing potential alterations on endogenous steroids as a consequence of exposure, and (b) describing the enzymatic pathways involved in P4 metabolism in mussels. No significant alteration of the levels of testosterone (T) and estradiol (E2) was observed in mantle/gonad tissue of exposed mussels, in spite of a 5.6-fold increase in immunoreactive T in those exposed to 10MUg P4/L, which was attributed to cross reactivity. P4 was actively metabolized to 5alpha-pregnane-3,20-dione (5alpha DHP) and 3beta-hydroxy-5alpha-pregnan-20-one (3beta,20-one) in digestive gland, with no evidence for the synthesis of 17alpha-hydroxyprogesterone or androstenedione. The metabolism of P4 to 5alpha-DHP was not altered by exposure. Histological examination of the gonads suggested that exposure to 10MUg/L P4 induced gamete maturation and release in mussels. Nonetheless, environmental concentrations of P4 are unlikely to have an endocrine action in mussels. PMID- 26026674 TI - Thrombin receptor PAR-1 activation on endothelial progenitor cells enhances chemotaxis-associated genes expression and leukocyte recruitment by a COX-2 dependent mechanism. AB - BACKGROUND: Endothelial colony forming cells (ECFC) represent a subpopulation of endothelial progenitor cells involved in endothelial repair. The activation of procoagulant mechanisms associated with the vascular wall's inflammatory responses to injury plays a crucial role in the induction and progression of atherosclerosis. However, little is known about ECFC proinflammatory potential. AIMS: To explore the role of the thrombin receptor PAR-1 proinflammatory effects on ECFC chemotaxis/recruitment capacity. METHODS AND RESULTS: The expression of 30 genes known to be associated with inflammation and chemotaxis was quantified in ECFC by real-time qPCR. PAR-1 activation with the SFLLRN peptide (PAR-1-ap) resulted in a significant increase in nine chemotaxis-associated genes expression, including CCL2 and CCL3 whose receptors are present on ECFC. Furthermore, COX-2 expression was found to be dramatically up-regulated consequently to PAR-1 activation. COX-2 silencing with the specific COX-2-siRNA also triggered down-regulation of the nine target genes. Conditioned media (c.m.) from control-siRNA- and COX-2-siRNA-transfected ECFC, stimulated or not with PAR 1-ap, were produced and tested on ECFC capacity to recruit leukocytes in vitro as well in the muscle of ischemic hindlimb in a preclinical model. The capacity of the c.m. from ECFC stimulated with PAR-1-ap to recruit leukocytes was abrogated when COX-2 gene expression was silenced in vitro (in terms of U937 cells migration and adhesion to endothelial cells) as well as in vivo. Finally, the postnatal vasculogenic stem cell derived from infantile hemangioma tumor (HemSC) incubated with PAR-1-ap increased leukocyte recruitment in Matrigel((r)) implant. CONCLUSIONS: PAR-1 activation in ECFC increases chemotactic gene expression and leukocyte recruitment at ischemic sites through a COX-2-dependent mechanism. PMID- 26026675 TI - Hot Topics: Chemical Burns in the Emergency Department. PMID- 26026676 TI - Comparative study on bioremediation of heavy metals by solitary ascidian, Phallusia nigra, between Thoothukudi and Vizhinjam ports of India. AB - Ascidians belonging to the sub-phylum Uro-chordata are used as potential model organisms in various parts of the world for biosorption of metals. The sedentary nature, filter feeding habits, presence of vanadocytes and the absence of kidneys cause them to accumulate metals. The present study was aimed to compare biosorption of metals such as cadmium, copper, lead, mercury and vanadium in test and mantle body of solitary ascidian Phallusia nigra between two ecologically significant stations such as Thoothukudi (Station 1) and Vizhinjam (Station 2) ports of India. Monthly samplings of water and P. nigra were done for a period of one year from September 2010 to August 2011 and subjected to analysis of metal accumulation. The average metal concentrations except mercury in the Thoothukudi water were found to be higher of comparable magnitudes than the Vizhinjam water. One-way ANOVA showed significant differences between the stations. A comparison of average metal concentrations in the test and mantle body of P. nigra between two stations showed that the enrichment of V, Cd, Pb, Cu and Hg in the Thoothukudi samples may be due to high bioaccumulation factors of these elements as compared to other species of ascidians. The bioaccumulation factors were in the order of V>Pb>Cd>Cu> Hg for the test and mantle body in stations 1 and 2. Application of one-way ANOVA for the concentration of these metals between test and mantle body showed significant differences in both stations. Similarly, ANOVA for biosorption of these trace metals by P. nigra showed significant difference between stations. Metal concentrations recorded in this ascidian could effectively be used as good reference material for monitoring metal contamination in Indian sea waters. PMID- 26026677 TI - The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production. AB - In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1 phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. PMID- 26026678 TI - Spliced XBP1 promotes macrophage survival and autophagy by interacting with Beclin-1. AB - Macrophage autophagy plays an important role in the development of atherosclerosis, but the precise mechanism mediating this process is unclear. The potential role of the X-box binding protein 1 (XBP1), a crucial transduction factor that is involved in endoplasmic reticulum stress and the unfolded protein response, in bone marrow-derived macrophage autophagy is unknown. This study mainly explores the roles of XBP1 mRNA splicing in bone marrow-derived macrophage autophagy. The present study shows that the transient overexpression of spliced XBP1 via adenovirus-mediated gene transfer induces autophagy and promotes proliferation in bone marrow-derived macrophages via the down-regulation of Beclin-1, but that the sustained overexpression of spliced XBP1 leads to apoptosis. When XBP1 is down-regulated in bone marrow-derived macrophages using siRNA, rapamycin-induced autophagosome formation is ablated. Furthermore, we have detected the overexpression of XBP1 in areas of atherosclerotic plaques in the arteries of ApoE-/- mice. These results demonstrate that XBP1 mRNA splicing plays an important role in maintaining the function of bone marrow-derived macrophages and provide new insight into the study and treatment of atherosclerosis. PMID- 26026679 TI - Fluency-dependent cortical activation associated with speech production and comprehension in second language learners. AB - This functional magnetic resonance imaging (fMRI) study investigated the brain regions underlying language task performance in adult second language (L2) learners. Specifically, we identified brain regions where the level of activation was associated with L2 fluency levels. Thirty Japanese-speaking adults participated in the study. All participants were L2 learners of English and had achieved varying levels of fluency, as determined by a standardized L2 English proficiency test, the Versant English Test (Pearson Education Inc., 2011). When participants performed the oral sentence building task from the production tasks administered, the dorsal part of the left inferior frontal gyrus (dIFG) showed activation patterns that differed depending on the L2 fluency levels: The more fluent the participants were, the more dIFG activation decreased. This decreased activation of the dIFG might reflect the increased automaticity of a syntactic building process. In contrast, when participants performed an oral story comprehension task, the left posterior superior temporal gyrus (pSTG) showed increased activation with higher fluency levels. This suggests that the learners with higher L2 fluency were actively engaged in post-syntactic integration processing supported by the left pSTG. These data imply that L2 fluency predicts neural resource allocation during language comprehension tasks as well as in production tasks. This study sheds light on the neural underpinnings of L2 learning by identifying the brain regions recruited during different language tasks across different modalities (production vs. comprehension). PMID- 26026682 TI - Exploration of binding of bisphenol A and its analogues with calf thymus DNA by optical spectroscopic and molecular docking methods. AB - Bisphenol A and its analogues have carcinogenic potentials and toxicities. However, there are lacks of studies elucidating gene toxic interactions of bisphenols with DNA. In this work, the binding modes of five bisphenol compounds with calf thymus DNA were characterized. The multi-spectroscopic experimental results indicated that the fluorescence quenching of bisphenols by calf thymus DNA point to groove binding. The ultraviolet visible and circular dichroism spectral data displayed that bisphenols partly induced conformational changes of calf thymus DNA. In addition, the binding constants of bisphenol A, diphenolic acid, bisphenol AF, bisphenol AP, bisphenol fluorine with calf thymus DNA obtained from fluorescence emission spectra were 1.09*10(4), 3.65*10(4), 4.46*10(4), 1.69*10(4), 4.49*10(4)Lmol(-1) at 298.15K, which indicated that the multi-noncovalent binding forces were involved in the binding processes. In silico investigations indicated that DNA has the preferable binding sites binding with bisphenols by minor groove binding and electrons transfer from DNA bases to bisphenols occurred. In addition, the structural differences of these five bisphenols partly affected the binding ability of them with DNA. PMID- 26026681 TI - Cardiovascular and single-unit responses to microinjection of angiotensin II into the bed nucleus of the stria terminalis in rat. AB - The bed nucleus of the stria terminalis (BST) is part of the limbic system located in the rostral forebrain. BST is involved in behavioral, neuroendocrine and autonomic functions, including cardiovascular regulation. The angiotensin II (Ang II) receptor, AT1, was found in the BST, however its effects on the cardiovascular system and on single-unit responses have not been studied yet. In the present study, Ang II was microinjected into the BST of anesthetized rats and cardiovascular and single-unit responses were recorded simultaneously. Furthermore the responses were re-tested after the microinjection of a blocker of the AT1 receptor, losartan, into the BST. We found that microinjection of Ang II into the BST produced a pressor response of 11+/-1mmHg for a duration of 2-8min. Ang II had no consistent effect on heart rate. It also produced two types of single-unit responses in the BST, short excitatory and long inhibitory. Blockade of AT1 receptors abolished both the cardiovascular and single-unit responses, indicating that the responses were mediated through AT1 receptors. These findings imply that Ang II may be utilized as a neurotransmitter and may play a role in returning blood pressure toward normal during hypotension. PMID- 26026680 TI - Tract-based analysis of white matter degeneration in Alzheimer's disease. AB - Although much prior work has focused on the known cortical pathology that defines Alzheimer's disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated microstructural differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that (1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and (2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition. PMID- 26026684 TI - Vestibular compensation following vestibular neurotomy. AB - OBJECTIVES: Four studies assessing vestibular compensation in Meniere's disease patients undergoing unilateral vestibular neurotomy, using different analysis methods, are reviewed, with a focus on the different strategies used by patients according to their preoperative sensory preference. MATERIAL AND METHODS: Four prospective studies performed in a university tertiary referral center were reviewed, measuring the pattern of vestibular compensation in Meniere's disease patients before and after unilateral vestibular neurotomy on various assessment protocols: postural syndrome assessed on static posturography and gait analysis; perceptual syndrome assessed on subjective visual vertical perception; and oculomotor syndrome assessed on ocular cyclotorsion. RESULTS: Vestibular compensation occurred at variable intervals depending on the parameter investigated. Open-eye postural control and gait/walking returned to normal one month after neurotomy. Fine balance analysis found that visual perception of the vertical and ocular cyclotorsion impairment persisted at long-term follow-up. Clinical postural disturbance persisted only when visual afferents were cut off (eyes closed). These impairments were the expression of a postoperative change in postural strategy related to the new use of visual and non-visual references. CONCLUSIONS: Understanding pre-operative interindividual variation in balance strategy is critical to screening for postural instability and tailoring vestibular rehabilitation. PMID- 26026683 TI - Can low-level laser therapy when associated to exercise decrease adipocyte area? AB - Obesity affects approximately 20% of the world population, and exercise is the primary non-pharmacological therapy. The combined use of exercise and low-level laser therapy (LLLT) may potentiate the effects promoted by exercise. The objective of this study was to investigate the effects of exercise in combination with phototherapy on adipocyte area, activity of the enzyme citrate synthase and muscle morphological analysis. We used 64 Wistar rats, which were divided into eight groups with 8 rats each: sedentary chow-diet (SC); sedentary chow-diet plus laser therapy (SCL), exercised chow-diet (EC); exercised chow-diet plus laser therapy (ECL); sedentary high-fat diet (SH); sedentary high-fat diet plus laser therapy (SHL); exercised high-fat diet (EH); exercised high-fat diet, laser therapy (EHL). The animals were submitted to a program of swimming training for 90min/5 times per week for 8weeks and LLLT (GA-Al-AS, 830nm) at a dose of 4.7J/point and a total energy of 9.4J/animal, with duration of 47s, which was applied to both gastrocnemius muscles after exercise. We conclude that the combined use of exercise and phototherapy increases the activity of the enzyme citrate synthase and decreases the white adipocyte area epididymal, retroperitoneal and visceral in obese rats, enhancing the effects of exercise. PMID- 26026686 TI - What was the impact of the Spanish COPD guidelines (GesEPOC) and how can they be improved? PMID- 26026685 TI - Validation of the Spanish Version of the COPD-Q Questionnaire on COPD Knowledge. AB - RATIONALE: Although recognition of the importance of educating chronic obstructive pulmonary disease (COPD) patients has grown in recent years, their understanding of this disease is not being measured due to a lack of specific instruments. The aim of this study was to validate the COPD-Q questionnaire, a 13 item instrument for determining COPD knowledge. METHODS: The COPD-Q was translated and backtranslated, and subsequently submitted to logic and content validation by a group of COPD experts and 8 COPD patients. Reliability was studied in an independent group of 59 patients with severe COPD seen in the pulmonology ward or clinics of 6 hospitals in Spain (Andalusia, Baleares, Castilla-La Mancha, Galicia and Madrid). This sample was also used for other internal and external validations. RESULTS: The mean age of the group was approximately 70 years and their health awareness was low-to-medium. The number of correct answers was 8.3 (standard deviation: 1.9), median 8, range 3-13. Floor and ceiling effects were 0% and 1.5%, respectively. Internal consistency of the questionnaire was good (Cronbach's alpha=0.85) and reliability was also high, with a kappa coefficient >0.6 for all items and an intraclass correlation efficient of 0.84 for the total score. CONCLUSION: The 13-item COPD-Q is a valid, applicable and reliable instrument for determining patients' knowledge of COPD. PMID- 26026687 TI - Congenital pulmonary sequestration supplied by the right coronary artery. PMID- 26026688 TI - Prestige and quality control of medical journals. PMID- 26026689 TI - First series of patients with XDR and pre-XDR TB treated with regimens that included meropenen-clavulanate in Argentina. AB - XDR (extensively drug-resistant) and pre-XDR tuberculosis (TB) seriously compromise prognosis and treatment possibilities, and inevitably require the use of group V drugs (World Health Organization). The progress of all patients with XDR and pre-XDR TB seen in a specialized unit during 2012 and 2013 and treated with regimens that included at least 6 months of meropenem-clavulanate (MPC), capreomycin, moxifloxacin, linezolid, clofazimine, high-dose isoniazid, PAS, and bedaquiline in 1 case, were retrospectively analysed. Ten patients were treated, 9 with an extensive pattern of resistance to at least 6 drugs, and 1 because of adverse reactions and drug interactions leading to a similar situation. Eight of the 10 patients treated achieved bacteriological sputum conversion (2 consecutive negative monthly cultures) over a period of 2-7 months, while 2 died. No adverse reactions attributable to prolonged administration of MPC were observed. PMID- 26026690 TI - High-flow nasal cannula oxygen therapy: preliminary study in hospitalized patients. PMID- 26026691 TI - Paraneoplastic cerebellar degeneration associated with small cell neuroendocrine mediastinal carcinoma. PMID- 26026693 TI - Evaluation of alignment in total knee arthroplasty: a prospective study. AB - BACKGROUND: Successful results of knee arthroplasty demand precise surgical technique, sound implant design, kinematics, appropriate materials and patient compliance with rehabilitation. The precision with which the implants are placed directly affects patient outcome as implant position and alignment influence the stability, durability and patellar tracking. Evaluating the alignment in total knee arthroplasty and functional outcome with respect to the alignment is the need of the hour. AIM AND OBJECTIVE OF THE STUDY: (1) To evaluate the accuracy of the overall limb alignment and component alignment in jig-assisted TKR. (2) To evaluate the functional outcome with respect to the alignment parameters. METHODOLOGY: This is a prospective study of 120 knees in 80 patients that underwent total knee replacement at Victoria and Bowring and Lady Curzon hospitals. Patients were selected according to the inclusion and exclusion criteria and evaluated using knee society score at regular follow-up. Preoperative and postoperative standing 'long-leg radiographs' and postoperative CT scans were taken from all the patients. In our study, we had 54 female patients and 26 male patients. Indications were OA in 72 and RA in 48 knees. The average follow-up period was 36 months. RESULTS: Preoperatively, all the patients had moderate to severe pain. Mechanical and tibiofemoral axes were outside the acceptable range. Postoperatively, with respect to mechanical axis, the inliers had significantly better knee score (p = 0.026) compared to the outliers. But the functional score did not show any significant difference between these two groups (p = 0.2093). Inliers in tibiofemoral axis alignment parameter had extremely significant better knee score (p = 0.0001) and also functional score (p = 0.0082) compared to outliers group. Sagittal and rotational femoral component angles in all 120 cases were coming within the 'inliers group'. Similarly, the sagittal, the coronal and the rotational component angles of tibia were also coming under inliers group in all 120 replaced knees. CONCLUSION: Aligning the mechanical axis, tibiofemoral angle within (0 degrees +/- 3 degrees ) and placement of prostheses within (0 degrees +/- 3 degrees ) to the normal alignment in all the three planes significantly produce excellent result with respect to functional outcome. PMID- 26026692 TI - Identification, characterization, and functional studies of a Pelle gene in the Chinese mitten crab, Eriocheir sinensis. AB - The toll-like receptor/NF-kappaB signaling pathways play an important role in the innate immune system. In the present study, one Pelle gene (named EsPelle) was identified for the first time from the Chinese mitten crab Eriocheir sinensis. The full-length cDNA of EsPelle is 3797 bp with a 3156 bp-long open reading frame that encodes a 1051 amino acid protein. EsPelle protein contains a death domain at the N-terminal and a serine/threonine kinase domain at the C-terminal. A neighbor joining phylogenetic tree showed that the EsPelle protein, which is closest to those of Scylla paramamosain Pelle and Litopenaeus vannamei Pelle, was clustered to a group of crustacean Pelle proteins. EsPelle was expressed in all tested tissues of normal crabs, and its expression was regulated in hemocytes and hepatopancreas of crabs challenged with lipopolysaccharide, peptidoglycan, Staphyloccocus aureus, Vibrio parahaemolyticus, and Aeromonas hydrophila. Overexpression of EsPelle in Drosophila Schneider 2 cells could upregulate the expression of Drosophila antimicrobial peptides, namely, metchnikowin (Mtk), attacinA (Atta), drosomycin (Drs), and cecropinA (CecA). Moreover, EsPelle silencing by siRNA reduced the transcription of anti-lipopolysaccharide factor 1 and 2, crustin 2, and lysozyme in crabs challenged with V. parahaemolyticus. From the results, we speculated that EsPelle was involved in innate immune defense against V. parahaemolyticus in E. sinensis. PMID- 26026694 TI - Diagnosis and monitoring of IgA nephropathy: the role of biomarkers as an alternative to renal biopsy. AB - IgA nephropathy (IgAN) is the most prevalent form of chronic glomerulonephritis in the world. The underlying pathogenesis of this autoimmune disease comprises the formation of immune complexes, including glycan-specific IgA1 or IgG antibodies and an aberrant glycosylation of IgA1. Until now, anatomopathological analysis of renal biopsies is essential for the diagnosis of IgAN and different histological classification systems have been proposed, e.g. the Oxford classification. However, a percutaneous renal biopsy is frequently not performed for several reasons and the Oxford classification system has some limitations. Since the poor prognosis of IgAN patients is partly the result of a delayed diagnosis, there is an urgent need for reliable noninvasive biomarkers that might be applicable in routine clinical practice. This article reviews the advances on the understanding of the underlying pathophysiological mechanisms of IgAN and discusses in depth the recent development of new biomarkers, including the use of proteomics and microRNAs. PMID- 26026695 TI - Epigenetics in autoimmune diseases: Pathogenesis and prospects for therapy. AB - Epigenetics is the study of heritable changes in genome function without underlying modifications in their nucleotide sequence. Disorders of epigenetic processes, which involve DNA methylation, histone modification, non-coding RNA and nucleosome remodeling, may influence chromosomal stability and gene expression, resulting in complicated syndromes. In the past few years, it has been disclosed that identified epigenetic alterations give rise to several typical human autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis (MS). These emerging epigenetic studies provide new insights into autoimmune diseases. The identification of specific epigenetic dysregulation may inspire more discoveries of other uncharacterized mechanisms. Further elucidation of the biological functions and clinical significance of these epigenetic alterations may be exploited for diagnostic biomarkers and therapeutic benefits. PMID- 26026696 TI - Functional limitations in functional somatic syndromes and well-defined medical diseases. Results from the general population cohort LifeLines. AB - OBJECTIVE: Functional somatic syndromes (FSS), defined as physical syndromes without known underlying organic pathology, are sometimes regarded as less serious conditions than well-defined medical diseases (MD). The aims of this study were to evaluate functional limitations in FSS, and to compare the results to MD patients with the same core symptoms. METHODS: This study was performed in 89,585 participants (age: 44.4+/-12.4 years, 58.5% female) of the general population cohort LifeLines. Quality of Life (QoL) and work participation were examined as indicators of functional limitations. QoL was assessed with two summary scales of the RAND-36: the physical component summary (PCS) and the mental component summary (MCS). Work participation was assessed with a self reported questionnaire. QoL and work participation were compared between FSS and MD patients, using Chi-squared tests and ANCOVA-analyses, adjusted for age, sex, educational level, and mental disorders. RESULTS: Of the participants, 11.0% (n=9861) reported a FSS, and 2.7% (n=2395) reported a MD. Total QoL, PCS and MCS were significantly lower in all separate FSS and MD compared to controls (P<=.001). Clinically relevant differences in QoL were found between chronic fatigue syndrome and multiple sclerosis patients, and between fibromyalgia syndrome and rheumatoid arthritis patients. Compared to controls, FSS and MD patients reported a comparably reduced working percentage, increased sick absence, early retirement due to health-related reasons, and disability percentage (P<=.001). CONCLUSION: Functional limitations in FSS patients are common, and as severe as those in patients with MD when looking at QoL and work participation, emphasizing that FSS are serious health conditions. PMID- 26026697 TI - Real-time ultrasound image classification for spine anesthesia using local directional Hadamard features. AB - PURPOSE: Injection therapy is a commonly used solution for back pain management. This procedure typically involves percutaneous insertion of a needle between or around the vertebrae, to deliver anesthetics near nerve bundles. Most frequently, spinal injections are performed either blindly using palpation or under the guidance of fluoroscopy or computed tomography. Recently, due to the drawbacks of the ionizing radiation of such imaging modalities, there has been a growing interest in using ultrasound imaging as an alternative. However, the complex spinal anatomy with different wave-like structures, affected by speckle noise, makes the accurate identification of the appropriate injection plane difficult. The aim of this study was to propose an automated system that can identify the optimal plane for epidural steroid injections and facet joint injections. METHODS: A multi-scale and multi-directional feature extraction system to provide automated identification of the appropriate plane is proposed. Local Hadamard coefficients are obtained using the sequency-ordered Hadamard transform at multiple scales. Directional features are extracted from local coefficients which correspond to different regions in the ultrasound images. An artificial neural network is trained based on the local directional Hadamard features for classification. RESULTS: The proposed method yields distinctive features for classification which successfully classified 1032 images out of 1090 for epidural steroid injection and 990 images out of 1052 for facet joint injection. In order to validate the proposed method, a leave-one-out cross-validation was performed. The average classification accuracy for leave-one-out validation was 94 % for epidural and 90 % for facet joint targets. Also, the feature extraction time for the proposed method was 20 ms for a native 2D ultrasound image. CONCLUSION: A real-time machine learning system based on the local directional Hadamard features extracted by the sequency-ordered Hadamard transform for detecting the laminae and facet joints in ultrasound images has been proposed. The system has the potential to assist the anesthesiologists in quickly finding the target plane for epidural steroid injections and facet joint injections. PMID- 26026698 TI - Prognostic role of atrial fibrillation in patients affected by chronic heart failure. Data from the MECKI score research group. AB - BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF). It is unclear whether AF has an independent prognostic role in HF. The aim of the present study was to assess the prognostic role of AF in HF patients with reduced ejection fraction (EF). METHODS: HF patients were followed in 17 centers for 3.15years (1.51-5.24). Study endpoints were the composite of cardiovascular (CV) death and heart transplant (HTX) and all-cause death. Data analysis was performed considering the entire population and a 1 to 1 match between sinus rhythm (SR) and AF patients. Match process was done for age+/-5, gender, left ventricle EF+/ 5, peakVO2+/-3 (ml/min/kg) and recruiting center. RESULTS: A total of 3447 patients (SR=2882, AF=565) were included in the study. Considering the entire population, CV death and HTX occurred in 114 (20%) AF vs. 471 (16%) SR (p=0.026) and all-cause death in 130 (23%) AF vs. 554 (19.2%) SR patients (p=0.039). At univariable Cox analysis, AF was significantly related to prognosis. Applying a multivariable model based on all variables significant at univariable analysis (EF, peakVO2, ventilation/carbon dioxide relationship slope, sodium, kidney function, hemoglobin, beta-blockers and digoxin) AF was no longer associated with adverse outcomes. Matching procedure resulted in 338 couples. CV death and HTX occurred in 63 (18.6%) AF vs. 74 (21.9%) SR (p=0.293) and all-cause death in 71 (21%) AF vs. 80 (23.6%) SR (p=0.406), with no survival differences between groups. CONCLUSION: In systolic HF AF is a marker of disease severity but not an independent prognostic indicator. PMID- 26026702 TI - Percutaneous ultrasound-guided alcohol ablation of solitary parathyroid adenoma in a patient with primary hyperparathyroidism. AB - Parathyroidectomy is considered the definitive cure for primary hyperparathyroidism due to a single parathyroid adenoma, which represents the most common cause of chronic hypercalcemia. However, in few cases, surgery may be technically difficult or risky. We report the use of percutaneous ultrasound guided alcohol ablation of a parathyroid adenoma as an alternative to surgery in an 88-year-old male patient with significant medical comorbidities. PMID- 26026699 TI - A comprehensive evaluation of catalase-like activity of different classes of redox-active therapeutics. AB - Because of the increased insight into the biological role of hydrogen peroxide (H2O2) under physiological and pathological conditions and the role it presumably plays in the action of natural and synthetic redox-active drugs, there is a need to accurately define the type and magnitude of reactions that may occur with this intriguing and key species of redoxome. Historically, and frequently incorrectly, the impact of catalase-like activity has been assigned to play a major role in the action of many redox-active drugs, mostly SOD mimics and peroxynitrite scavengers, and in particular MnTBAP(3-) and Mn salen derivatives. The advantage of one redox-active compound over another has often been assigned to the differences in catalase-like activity. Our studies provide substantial evidence that Mn(III) N-alkylpyridylporphyrins couple with H2O2 in actions other than catalase-related. Herein we have assessed the catalase-like activities of different classes of compounds: Mn porphyrins (MnPs), Fe porphyrins (FePs), Mn(III) salen (EUK-8), and Mn(II) cyclic polyamines (SOD-active M40403 and SOD inactive M40404). Nitroxide (tempol), nitrone (NXY-059), ebselen, and MnCl2, which have not been reported as catalase mimics, were used as negative controls, while catalase enzyme was a positive control. The dismutation of H2O2 to O2 and H2O was followed via measuring oxygen evolved with a Clark oxygen electrode at 25 degrees C. The catalase enzyme was found to have kcat(H2O2)=1.5*10(6)M(-1) s(-1). The yield of dismutation, i.e., the maximal amount of O2 evolved, was assessed also. The magnitude of the yield reflects an interplay between the kcat(H2O2) and the stability of compounds toward H2O2-driven oxidative degradation, and is thus an accurate measure of the efficacy of a catalyst. The kcat(H2O2) values for 12 cationic Mn(III) N-substituted (alkyl and alkoxyalkyl) pyridylporphyrin-based SOD mimics and Mn(III) N,N'-dialkylimidazolium porphyrin, MnTDE-2-ImP(5+), ranged from 23 to 88M(-1) s(-1). The analogous Fe(III) N-alkylpyridylporphyrins showed ~10-fold higher activity than the corresponding MnPs, but the values of kcat(H2O2) are still ~4 orders of magnitude lower than that of the enzyme. While the kcat(H2O2) values for Fe ethyl and n-octyl analogs were 803.5 and 368.4M(-1) s(-1), respectively, the FePs are more prone to H2O2-driven oxidative degradation, therefore allowing for similar yields in H2O2 dismutation as analogous MnPs. The kcat(H2O2) values are dependent on the electron deficiency of the metal site as it controls the peroxide binding in the first step of the dismutation process. SOD-like activities depend on electron deficiency of the metal site also, as it controls the first step of O2(?-) dismutation. In turn, the kcat(O2(?-)) parallels the kcat(H2O2). Therefore, the electron-rich anionic non-SOD mimic MnTBAP(3-) has essentially very low catalase-like activity, kcat(H2O2)=5.8M(-1) s(-1). The catalase-like activities of Mn(III) and Fe(III) porphyrins are at most, 0.0004 and 0.05% of the enzyme activity, respectively. The kcat(H2O2) values of 8.2 and 6.5M(-1) s(-1) were determined for electron-rich Mn(II) cyclic polyamine-based compounds, M40403 and M40404, respectively. The EUK 8, with modest SOD-like activity, has only slightly higher kcat(H2O2)=13.5M(-1) s(-1). The biological relevance of kcat(H2O2) of MnTE-2-PyP(5+), MnTDE-2-ImP(5+), MnTBAP(3-), FeTE-2-PyP(5+), M40403, M40404, and Mn salen was evaluated in wild type and peroxidase/catalase-deficient E. coli. PMID- 26026700 TI - Are blood vessels a target to treat lower urinary tract dysfunction? AB - Bladder dysfunction is common in the general population (Stewart et al. 2010) and even more so among patients seeing a physician for any reason (Goepel et al. 2002). It often manifests as lower urinary tract symptoms (LUTS), a term originally coined to describe voiding and storage symptoms in men with benign prostatic hyperplasia (BPH) but now more universally used to describe any type of voiding and storage symptoms in both sexes. Studies into possible causes of urinary bladder dysfunction have long focused on detrusor smooth muscle cells (Turner and Brading 1999). More recently, it became clear that several other types of cells and organs contribute to regulating detrusor smooth muscle function. These include the urothelium (Andersson and McCloskey 2014; Michel 2015), afferent nerves (Michel and Igawa 2015; Yoshimura et al. 2014b), and the central and autonomic nervous systems (Fowler and Griffiths 2010; Yoshimura et al. 2014a). Alterations in any of these may at least partly be responsible for detrusor dysfunction and, accordingly, be potential targets for the treatment of bladder dysfunction. As highlighted by an article in this issue of Naunyn Schmiedeberg's Archives of Pharmacology (Bayrak et al. 2015), there is an additional suspect, the bladder vasculature. This article will discuss the currently available experimental and clinical evidence for a role of the vasculature in causing bladder dysfunction, and how existing and emerging treatments may modulate bladder function by acting on blood vessels. Due to a similarity in concept, data on prostate perfusion will also be discussed to some extent. PMID- 26026701 TI - Tumor necrosis factor inhibition increases the revascularization of ischemic hind limbs in diabetic mice. AB - Tumor necrosis factor (TNF) is first identified as a mediator of lethal endotoxin poisoning. The anti-TNF therapy in the treatment of rheumatoid arthritis is based on the recognition of the role of TNF as the master regulator. Type II diabetes is characterized with altered stem cells and reduced vasculogenesis. Therefore, we aimed to determine if TNF inhibitor would improve vasculogenesis in ischemic hind-limbs of diabetic mice. Fifty male type 2 diabetic and their control (8-10 weeks old mice) were used, and ischemia was induced in the hind-limbs of all mice for 28 days. Vessel density was assessed by high-definition microangiography at the end of the treatment period. After 4 weeks, vessel density displayed no difference between the ischemic and the non-ischemic legs in control mice. However, in diabetic mice, the ischemic hind-limb vessel density was significantly decreased. Interestingly, diabetic mice displayed a significant improved vasculogenesis when treated with TNF inhibitor. Moreover, this data was confirmed by capillary density determined by immunostaining. TNF inhibitors are able to improve the formation of microvessels in response to ischemia in type 2 diabetes. PMID- 26026703 TI - Production of (S)-3-hydroxybutyrate by metabolically engineered Saccharomyces cerevisiae. AB - (S)-3-Hydroxybutyrate (S-3HB) can be used as a precursor for the synthesis of biodegradable polymers such as polyhydroxyalkanoate and stereo-specific fine chemicals such as antibiotics, pheromones, and drugs. For the production of S-3HB in yeast, the biosynthetic pathway of S-3HB from acetyl-CoA, consisting of the three enzymes, acetyl-CoA C-acetyltransferase (ACCT), acetoacetyl-CoA reductase (ACR), and 3-hydroxybutyryl-CoA thioesterase (HBT), was introduced into Saccharomyces cerevisiae. An engineered yeast strain overexpressing ERG10, hbd, and tesB genes not only exhibited enzyme activities of AACT, ACR, and HBT, but also produced S-3HB from ethanol. In order to increase the titer of S-3HB, a fed batch fermentation based on pulse feeding of ethanol as a carbon source was performed, and a final S-3HB titer of 12.0g/L was achieved. This is the first report on the production of 3HB by engineered yeast, utilizing ethanol as the carbon source, suggesting that the industrially preferred S. cerevisiae can be a promising host for producing S-3HB. PMID- 26026704 TI - Single step purification of recombinant proteins using the metal ion-inducible autocleavage (MIIA) domain as linker for tag removal. AB - For fast and easy purification, proteins are typically fused with an affinity tag, which often needs to be removed after purification. Here, we present a method for the removal of the affinity tag from the target protein in a single step protocol. The protein VIC_001052 of the coral pathogen Vibrio coralliilyticus ATCC BAA-450 contains a metal ion-inducible autocatalytic cleavage (MIIA) domain. Its coding sequence was inserted into an expression vector for the production of recombinant fusion proteins. Following, the target proteins MalE and mCherry were produced as MIIA-Strep fusion proteins in Escherichia coli. The target proteins could be separated from the MIIA-Strep part simply by the addition of calcium or manganese(II) ions within minutes. The cleavage is not affected in the pH range from 5.0 to 9.0 or at low temperatures (6 degrees C). Autocleavage was also observed with immobilized protein on an affinity column. The protein yield was similar to that achieved with a conventional purification protocol. PMID- 26026705 TI - Is it me or is it you? Behavioral and electrophysiological effects of oxytocin administration on self-other integration during joint task performance. AB - The neuropeptide oxytocin has been associated with promoting various social behaviors in humans including cooperation and trust. Surprisingly little, however, is known about the possible role of oxytocin in processes required for social interactive behavior such as joint task performance. The current study investigated whether intranasal administration of oxytocin leads to increased self-other integration using a social Simon task. A placebo-controlled double blind between-subjects design was used. Behavioral and EEG measures were obtained from 63 healthy male volunteers who either received 24 intranasal units (IU) oxytocin or a placebo while they performed the social Simon task in an individual and a joint/social context. The behavioral results demonstrated an enhanced Simon effect in the social context after oxytocin administration. At the electrophysiological level, the stimulus-locked N2 component, reflecting response conflict, was increased in the social compared to the individual context for Go trials, but only after oxytocin administration. The P3 component, reflecting response inhibition, was increased for social compared to individual contexts, irrespective of condition. Both the behavioral and N2 findings suggest that oxytocin enhances self-other integration. While more inhibition is needed in the social context, this process seems less sensitive to changes in self-other integration. To conclude, the current study is the first to show oxytocin-induced modulations of processes that play a central role in joint task performance and thus importantly adds to our understanding of the neurocognitive mechanisms underlying the diverse social effects of oxytocin. PMID- 26026706 TI - The challenged but indispensable role of ethical committees for human clinical experimentation. PMID- 26026707 TI - This is your brain on Scrabble: Neural correlates of visual word recognition in competitive Scrabble players as measured during task and resting-state. AB - Competitive Scrabble players devote considerable time to studying words and practicing Scrabble-related skills (e.g., anagramming). This training is associated with extraordinary performance in lexical decision, the standard visual word recognition task (Hargreaves, Pexman, Zdrazilova & Sargious, 2012). In the present study we investigated the neural consequences of this lexical expertise. Using both event-related and resting-state fMRI, we compared brain activity and connectivity in 12 competitive Scrabble experts with 12 matched non expert controls. Results showed that when engaged in the lexical decision task (LDT), Scrabble experts made use of brain regions not generally associated with meaning retrieval in visual word recognition, but rather those associated with working memory and visual perception. The analysis of resting-state data also showed group differences, such that a different network of brain regions was associated with higher levels of Scrabble-related skill in experts than in controls. PMID- 26026708 TI - Mechanistic Analysis of Activation of the Innate Immune Sensor PKR by Bacterial RNA. AB - The protein kinase PKR (protein kinase R) is a sensor in innate immunity. PKR autophosphorylates in the presence of double-stranded RNA enabling it to phosphorylate its substrate, eIF2alpha (eukaryotic initiation factor 2alpha), halting cellular translation. Classical activators of PKR are long viral double stranded RNAs, but recently, PKR has been found to be activated by bacterial RNA. However, the features of bacterial RNA that activate PKR are unknown. We studied the Bacillus subtilis trp 5'-UTR (untranslated region), which is an indirect riboswitch with secondary and tertiary RNA structures that regulate gene function. Additionally, the trp 5'-UTR binds a protein, TRAP (tryptophan RNA binding attenuation protein), which recognizes l-tryptophan. We present the first evidence that multiple structural features in this RNA, which are typical of bacterial RNAs, activate PKR in TRAP-free and TRAP/l-Trp-bound forms. Segments from the 5'-UTR, including the terminator 5'-stem-loop and Shine-Dalgarno blocking hairpins, demonstrated 5'-triphosphate and flanking RNA tail dependence on PKR activation. Disruption of long-distance tertiary interactions in the 5' UTR led to partial loss in activation, consistent with highly base-paired regions in bacterial RNA activating PKR. One physiological change a bacterial RNA would face in a human cell is a decrease in the concentration of free magnesium. Upon lowering the magnesium concentration to human physiological conditions of 0.5mM, the trp 5'-UTR continued to activate PKR potently. Moreover, total RNA from Escherichia coli, depleted of rRNA, also activated PKR under these ionic conditions. This study demonstrates that PKR can signal the presence of bacterial RNAs under physiological ionic conditions and offers a potential explanation for the apparent absence of riboswitches in the human genome. PMID- 26026711 TI - In-situ tryptophan-like fluorescence: A real-time indicator of faecal contamination in drinking water supplies. AB - Enteric pathogens are typically inferred from the presence of surrogate indicator organisms such as thermotolerant (faecal) coliforms (TTCs). The analysis of TTCs requires time-consuming incubation in suitable laboratories, which can limit sampling resolution, particularly during critical pollution events. Here, we demonstrate the use of in-situ fluorimeters targeting tryptophan-like compounds as a rapid, reagentless indicator of TTCs in groundwater-derived potable water supplies in Africa. A range of other common indicators of TTCs were also determined including nitrate, turbidity, and sanitary risk survey scores. Sampling was conducted during both the dry and wet seasons to investigate seasonality. Tryptophan-like fluorescence was the most effective predictor of both presence/absence and number of TTCs during both seasons. Seasonal changes in tryptophan-like fluorescence in deeper supplies suggest it is transported more efficiently through the aquifer than TTCs. Moreover, the perennial elevated concentrations in some wells suggest it is more resilient than TTCs in groundwater. Therefore tryptophan-like fluorescence could also be a better indicator of some smaller, more easily transported, and long-lived, pathogenic enteric viruses. These sensors have the potential to be included in real-time pollution alert systems for drinking water supplies throughout the world, as well as for mapping enteric pathogen risks in developing regions. PMID- 26026710 TI - A Modified Method of Proximal Segment Alignment After Sagittal Split Ramus Osteotomy for Patients With Mandibular Asymmetry. AB - PURPOSE: The purpose of this study was to evaluate a modified method of aligning the proximal segment after bilateral sagittal split ramus osteotomy (BSSO) in the treatment of patients with facial asymmetry. PATIENTS AND METHODS: Eleven patients with mandibular excess and facial asymmetries were enrolled in this prospective study. The surgery was planned according to a computer-aided surgical simulation protocol. In addition, the proximal segment on the hypoplastic side was intentionally flared out after the distal segment was rotationally set back. If the gap between the proximal and distal segments was too wide, then bone grafts were used. The surgery was completed according to the computerized plan. The proximal segment on the hypoplastic side was fixed with bicortical lag screws, and the proximal segment on the hyperplastic side was fixed with a 4-hole titanium miniplate. Postoperative evaluation was performed 6 months after surgery. Statistical analyses were performed. RESULTS: All surgeries were completed uneventfully. Of the 11 patients, 4 also underwent genioplasty and 3 underwent bone grafting to fill in the gap and smooth the anterior step. The physicians and patients were satisfied with the surgical outcomes. Only 1 patient underwent a secondary revision using an onlay hydroxyapatite implant. Results of statistical analyses showed that the computerized surgical plan could be accurately transferred to the patients at the time of surgery and the surgical outcomes achieved with this modified method were better than with the routine method of aligning the proximal and distal segments in maximal contact. CONCLUSION: The present modified method of aligning the proximal segment for BSSO can effectively correct mandibular asymmetry and obviate a secondary revision surgery. PMID- 26026712 TI - Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced atherosclerosis? AB - Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of intermittent hypoxia. This disease is associated with premature atherosclerosis and consequently with increased cardiovascular morbidity and mortality. Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway. In particular, OSA is associated with activation of the thromboxane A2 (TXA2)-pathway, in which obesity seems to be a major confounding factor. Moreover, TXA2-pathway activation is related to the vascular remodeling associated with OSA. In view of the modest effect of the conventional treatment of OSA by continuous positive airway pressure on the cardiovascular risk in obese OSA patients, the identification of new therapeutic targets to treat OSA-induced atherosclerosis seems essential. As disruption of the TXA2-pathway has been suggested to be of potential interest to prevent atherosclerosis progression, we have reviewed the recent findings on the intricate interaction between the TXA2-pathway, chronic intermittent hypoxia and atherosclerosis and suggest promising therapeutic strategies to treat OSA-related atherogenesis, including pharmacological and/or nutritional approaches. PMID- 26026713 TI - On the biosynthesis of 15-HETE and eoxin C4 by human airway epithelial cells. AB - Several lines of evidence indicate that 15-lipoxygenase type 1 (15-LO-1) plays a pathophysiological role in asthma. The aim for this study was to investigate the 15-LO-1 expression and activity in primary human airway epithelial cells cultivated on micro-porous filters at air-liquid interface. Incubation of human airway epithelial cells with arachidonic acid led to the formation of 15(S) hydroxy-eicosatetraenoic acid (15-HETE) and exposing the cells to bacteria or physical injury markedly increased their production of 15-HETE. The cells were also found to convert arachidonic acid to eoxin C4 (EXC4). Subcellular fractionation revealed that the conversion of EXA4 to EXC4 was catalyzed by a soluble glutathione transferase (GST). The GST P1-1 enzyme was found to possess the highest activity of the investigated soluble GSTs. Following IL-4 treatment of airway epithelial cells, microarray analysis confirmed high expression of 15 LO-1 and GST P1-1, and immunohistochemical staining of bronchial biopsies revealed co-localization of 15-LO-1 and GST P1-1 in airway epithelial cells. These results indicate that respiratory infection and cell injury may activate the 15-LO pathway in airway epithelial cells. Furthermore, we also demonstrate that airway epithelial cells have the capacity to produce EXC4. PMID- 26026714 TI - Leptospirosis in Greece. AB - Leptospirosis is a zoonotic disease with increased public health concern worldwide. The disease occurs more often in temperate and tropical regions. The present study analyzes the demographic, epidemiological and clinical data of 168 leptospirosis cases laboratory diagnosed in northern Greece during 1998-2014. Most patients were males, aged 50-69 years, working in animal husbandry or farming. Cases were observed more frequently in summer and autumn. Severity of the disease was correlated with presence of pulmonary involvement and hemorrhagic manifestations. PMID- 26026709 TI - Cracking the nodule worm code advances knowledge of parasite biology and biotechnology to tackle major diseases of livestock. AB - Many infectious diseases caused by eukaryotic pathogens have a devastating, long term impact on animal health and welfare. Hundreds of millions of animals are affected by parasitic nematodes of the order Strongylida. Unlocking the molecular biology of representatives of this order, and understanding nematode-host interactions, drug resistance and disease using advanced technologies could lead to entirely new ways of controlling the diseases that they cause. Oesophagostomum dentatum (nodule worm; superfamily Strongyloidea) is an economically important strongylid nematode parasite of swine worldwide. The present article reports recent advances made in biology and animal biotechnology through the draft genome and developmental transcriptome of O. dentatum, in order to support biological research of this and related parasitic nematodes as well as the search for new and improved interventions. This first genome of any member of the Strongyloidea is 443 Mb in size and predicted to encode 25,291 protein-coding genes. Here, we review the dynamics of transcription throughout the life cycle of O. dentatum, describe double-stranded RNA interference (RNAi) machinery and infer molecules involved in development and reproduction, and in inducing or modulating immune responses or disease. The secretome predicted for O. dentatum is particularly rich in peptidases linked to interactions with host tissues and/or feeding activity, and a diverse array of molecules likely involved in immune responses. This research progress provides an important resource for future comparative genomic and molecular biological investigations as well as for biotechnological research toward new anthelmintics, vaccines and diagnostic tests. PMID- 26026715 TI - Molecular mechanism of serine/threonine protein phosphatase 1 (PP1calpha-PP1r7) in spermatogenesis of Toxocara canis. AB - Toxocariasis is one of the most important, but neglected, zoonoses, which is mainly caused by Toxocara canis. To better understand the role of serine/threonine protein phosphatase 1 (PP1) in reproductive processes of male adult T. canis, differential expression analysis was used to reveal the profiles of PP1 catalytic subunit alpha (PP1calpha) gene Tc-stp-1 and PP1 regulatory subunit 7 (PP1r7) gene TcM-1309. Indirect fluorescence immunocytochemistry was carried out to determine the subcellular distribution of PP1calpha. Double stranded RNA interference (RNAi) assays were employed to illustrate the function and mechanism of PP1calpha in male adult reproduction. Real-time quantitative PCR (qPCR) showed transcriptional consistency of Tc-stp-1 and TcM-1309 in sperm producing germline tissues and localization research showed cytoplasmic distribution of PP1calpha in sf9 cells, which indicated relevant involvements of PP1calpha and PP1r7 in spermatogenesis. Moreover, spatiotemporal transcriptional differences of Tc-stp-1 were determined by gene knockdown analysis, which revealed abnormal morphologies and blocked meiotic divisions of spermatocytes by phenotypic aberration scanning, thereby highlighting the crucial involvement of PP1calpha in spermatogenesis. These results revealed a PP1calpha-PP1r7 mechanism by which PP1 regulates kinetochore-microtubule interactions in spermatogenesis and provided important clues to identify novel drug or vaccine targets for toxocariasis control. PMID- 26026716 TI - Molecular epidemiological study of cutaneous leishmaniasis in Beni Mellal and Fquih Ben Saleh provinces in Morocco. AB - Leishmaniases are parasitic diseases frequent in the Mediterranean Basin. Cutaneous leishmaniasis (CL) has been recently emerged in several new foci, causing a public health problem in Morocco. This study was performed to evaluate the epidemiological status of cutaneous leishmaniasis (CL) in Beni Mellal and Fquih Ben Saleh Provinces and to identify the causative agent. A total of 584 (56% female, 44% male) confirmed cases of CL were enrolled during the study period 2000-2012. Majority of cases (56%) were recorded in three sectors: Zaouiat Cheikh, Beni Mellal and Oulad Ayad. Fisher statistical test showed that there is a significant effect of the total cases of CL affected in the 185 localities. The age distribution of CL cases was relatively stable, with the majority of patients (62.34%) aged less than 9 years old with significant differences (p-value<2.2e 16). CL lesions were mostly located on the face (89%). The average number of lesions per patient was 1.38. Leishmania tropica was identified as the causative agent based on species-specific ITS1-PCR-RFLP assay. PMID- 26026717 TI - Immunological cross-reactivity and neutralization of the principal toxins of Naja sumatrana and related cobra venoms by a Thai polyvalent antivenom (Neuro Polyvalent Snake Antivenom). AB - The low potency of cobra antivenom has been an area of concern in immunotherapy for cobra envenomation. This study sought to investigate factors limiting the neutralizing potency of cobra antivenom, using a murine model. We examined the immunological reactivity and neutralizing potency of a Thai polyvalent antivenom against the principal toxins of Naja sumatrana (Equatorial spitting cobra) venom and two related Asiatic cobra venom alpha-neurotoxins. The antivenom possesses moderate neutralizing potency against phospholipases A2 (P, potency of 0.98mg/mL) and moderately weak neutralizing potency against long-chain alpha-neurotoxins (0.26-0.42mg/mL) but was only weakly effective in neutralizing the short-chain alpha-neurotoxins and cardiotoxins (0.05-0.08mg/mL). The poor neutralizing potency of the antivenom on the low molecular mass short-chain neurotoxins and cardiotoxins is presumably the main limiting factor of the efficacy of the cobra antivenom. Our results also showed that phospholipase A2, which exhibited the highest ELISA reactivity and avidity, was most effectively neutralized, whereas N. sumatrana short-chain neurotoxin, which exhibited the lowest ELISA reactivity and avidity, was least effectively neutralized by the antivenom. These observations suggest that low immunoreactivity (low ELISA reactivity and avidity) is one of the reasons for poor neutralization of the cobra venom low molecular mass toxins. Nevertheless, the overall results show that there is a lack of congruence between the immunological reactivity of the toxins toward antivenom and the effectiveness of toxin neutralization by the antivenom, indicating that there are other factors that also contribute to the weak neutralization capacity of the antivenom. Several suggestions have been put forward to overcome the low efficacy of the cobra antivenom. The use of a 'proper-mix' formulation of cobra venoms as immunogen, whereby the immunogen mixture used for hyperimmunization contains a mix of various types of alpha-neurotoxins and cardiotoxins in sufficient amount, may also help to improve the efficacy and broaden the neutralization spectrum of the antivenom. PMID- 26026718 TI - SDF-1/CXCR4 promotes F5M2 osteosarcoma cell migration by activating the Wnt/beta catenin signaling pathway. AB - Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, lacks an effective therapy. Stromal cell-derived factor (SDF-1) and its receptor, CXCR4, play multiple roles in migration, proliferation, and survival of different tumor cells. This study aimed to investigate whether the functional SDF-1/CXCR4 signaling mediates chemotaxis in F5M2 OS cells as well as the underlying mechanisms. Immunohistochemistry and immunofluorescence microscopy were used. RNA expression was detected by real-time quantitative polymerase chain reaction, and protein expression was examined by Western blotting. Migration assays were carried out in F5M2 cells. The results showed that the expression of CXCR4 and beta-catenin mRNA and protein was significantly higher in OS tissues compared to the surrounding non-neoplastic tissues. SDF-1 promoted F5M2 cell migration by activating the AKT and Wnt/beta-catenin signaling pathway, which was abrogated by preincubation with AMD3100 and LY294002. In conclusion, SDF-1/CXCR4 axis-promoted F5M2 cell migration was regulated by the Wnt/beta-catenin signaling pathway. PMID- 26026720 TI - The aspartate aminotransferase-like domain of Firmicutes MocR transcriptional regulators. AB - Bacterial MocR transcriptional regulators possess an N-terminal DNA-binding domain containing a conserved helix-turn-helix module and an effector-binding and/or oligomerization domain at the C-terminus, homologous to fold type-I pyridoxal 5'-phosphate (PLP) enzymes. Since a comprehensive structural analysis of the MocR regulators is still missing, a comparisons of Firmicutes MocR sequences was undertook to contribute to the understanding of the structural characteristics of the C-terminal domain of these proteins, and to shed light on the structural and functional relationship with fold type-I PLP enzymes. Results of this work suggest the presence of at least three subgroups within the MocR sequences and provide a guide for rational site-directed mutagenesis studies aimed at deciphering the structure-function relationships in this new protein family. PMID- 26026719 TI - Cervical spine involvement in rheumatoid arthritis over time: results from a meta analysis. AB - INTRODUCTION: Complications in rheumatoid arthritis (RA) seem less common than they were years ago. The prevalence and progression of anterior atlantoaxial subluxations (aAASs), vertical subluxations (VSs), subaxial subluxations (SASs), and associated cervical myelopathy in RA over the past 50 years were determined. METHODS: A literature search was performed by using Medline-OVID/EMBASE, PubMed, and Scopus (from 1960 to June 21, 2014). Prevalence studies were included if the sample size was at least 100 or the prevalence/progression of cervical subluxations was reported. Study quality was assessed by using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Prevalence of cervical subluxations was calculated for each study. Student's t test and meta-regression were used to evaluate for significance. RESULTS: In total, 12,249 citations were identified and 59 studies were included. The prevalence of aAAS decreased from 36% (95% confidence interval (CI) 30% to 42%) before the 1980s to 24% (95% CI 13% to 36%) in the 2000s (P = 0.04). The overall prevalence rates were 11% (95% CI 10% to 19%) for VS, 13% (95% CI 12% to 20%) for SAS, and 5% (95% CI 3% to 9%) for cervical myelopathy, and there were no significant temporal changes. Rates of progression of aAAS, VS, and SAS were 4, 6, and 3 lesions per 100 patients per year, respectively. The incidence of new or progressive cervical myelopathy was 2 cases per 100 patients with known cervical subluxations per year. CONCLUSIONS: Since the 1960s, only aAAS has decreased dramatically. It is still more than twice as common as VS or SAS. No temporal changes in the development of cervical myelopathy in affected patients with RA were noted. The progression rates of cervical subluxations and myelopathy were unchanged over time. PMID- 26026721 TI - Structural correlates for fatigue in early relapsing remitting multiple sclerosis. AB - OBJECTIVES: Fatigue is a common symptom in multiple sclerosis (MS) patients, even early in the disease, but the pathophysiology remains unclear. We aimed to determine morphologic and microstructural correlates and neuropsychological parameters of cognitive fatigue in early relapsing-remitting MS patients. METHODS: Seventy-nine early relapsing-remitting MS patients (38 with fatigue and 41 without), none of whom suffered from depression, underwent neuropsychological testing. Magnetic resonance imaging was performed using anatomical and diffusion tensor imaging sequences on all patients and 40 controls. Voxel-based morphologic analysis and tract-based spatial statistics were performed. RESULTS: Only patients with cognitive fatigue, but not those without, exhibited alterations in the thalamic region, showing reduced thalamic fractional anisotropy and increased mean diffusivity values. No differences in lesion volume and lesion distribution were observed between patient groups. In cognitive tests, no significant differences were found between the two groups in the number of patients with pathologic scores; however, subjective cognitive impairment differed. CONCLUSION: Morphological alterations and distinct microstructural changes (mainly in the thalamus) but not typical MS lesions were found to be related to cognitive fatigue in early MS. We suggest that compensatory processes adapting to these changes could initially facilitate normal cognitive performance, but also result in a feeling of fatigue. KEY POINTS: * Morphological alterations and microstructural changes are related to fatigue in multiple sclerosis * Thalamic alterations in particular were related to fatigue in early MS * Fatigued patients exhibited subjective but not measurable cognitive impairment * Compensatory processes help preserve or maintain cognitive performance but also contribute to fatigue. PMID- 26026722 TI - Using scan statistics for congenital anomalies surveillance: the EUROCAT methodology. AB - Scan statistics have been used extensively to identify temporal clusters of health events. We describe the temporal cluster detection methodology adopted by the EUROCAT (European Surveillance of Congenital Anomalies) monitoring system. Since 2001, EUROCAT has implemented variable window width scan statistic for detecting unusual temporal aggregations of congenital anomaly cases. The scan windows are based on numbers of cases rather than being defined by time. The methodology is imbedded in the EUROCAT Central Database for annual application to centrally held registry data. The methodology was incrementally adapted to improve the utility and to address statistical issues. Simulation exercises were used to determine the power of the methodology to identify periods of raised risk (of 1-18 months). In order to operationalize the scan methodology, a number of adaptations were needed, including: estimating date of conception as unit of time; deciding the maximum length (in time) and recency of clusters of interest; reporting of multiple and overlapping significant clusters; replacing the Monte Carlo simulation with a lookup table to reduce computation time; and placing a threshold on underlying population change and estimating the false positive rate by simulation. Exploration of power found that raised risk periods lasting 1 month are unlikely to be detected except when the relative risk and case counts are high. The variable window width scan statistic is a useful tool for the surveillance of congenital anomalies. Numerous adaptations have improved the utility of the original methodology in the context of temporal cluster detection in congenital anomalies. PMID- 26026723 TI - Size at birth and risk of breast cancer: update from a prospective population based study. AB - Birth size variables (birth weight, birth length and head circumference) have been reported to be positively associated with adult breast cancer risk, whereas a possible association of placental weight has not been adequately studied. It has also been suggested that maternal height may modify the association of birth size with adult breast cancer risk, but this has not been studied in detail. We updated a long-term follow-up of 22,931 Norwegian women (average of 51 years of follow up during which 870 women were diagnosed with breast cancer) and assessed placental weight in relation to breast cancer risk, in addition to providing updated analyses on breast cancer risk in relation to birth weight, birth length and head circumference. Placental weight was not associated with risk for breast cancer in adulthood, but there was a positive association of breast cancer risk with birth length (HR 1.13, 95% CI 1.05-1.21, per 2 cm increment), though not with birth weight (HR 1.02, 95% CI 0.95-1.10 per 0.5 kg increment). For birth length, the graded increase in risk was particularly strong among women whose mothers were relatively tall (p for trend, 0.001), compared to the trend among women whose mothers were relatively short (p for trend, 0.221). The results showed a robust and positive association of birth length with breast cancer risk, and may be especially strong in women whose mothers were relatively tall. We found no association of placental weight with risk for breast cancer. PMID- 26026724 TI - Finding the missing gene-environment interactions. PMID- 26026725 TI - [Something is wrong in the way we inform patients of an adverse event]. AB - OBJECTIVE: To analyze which actions are carried out in hospitals and primary care to ensure open disclosure to the patient after an adverse event (AE). METHODS: We surveyed 633 managers and patient safety coordinates (staff) and 1340 physicians and nurses from eight autonomous communities. The level of implementation of open disclosure recommendations was explored. RESULTS: A total of 112 (27.9%) staff and 386 (35.9%) professionals considered that patients were correctly informed after an EA; 30 (7.4%) staff claimed to have a guideline on how to report EA; only 92 medical professionals (17.4%) and 93 nurses (19.1%) had received training on open disclosure. CONCLUSIONS: There are gaps in the way of planning, organizing and ensuring that patients who suffer an AE will receive an apology with honest information about what has happened and what could subsequently happen. PMID- 26026726 TI - [Is youth-friendly primary care feasible in Spain?]. PMID- 26026727 TI - Prevalence of Chagas disease in the Bolivian population of Majorca (Spain). AB - OBJECTIVE: To establish the prevalence of Trypanosoma cruzi infection in Bolivian (Spain) participants. METHODS: A cross sectional study was carried out in Majorca. Bolivian residents older than 18 years assigned to the family physicians of two primary care centers were randomly selected from the health card population database. Participants were invited to attend a serology test and an interview. T. cruzi infection was confirmed after two positive ELISA tests. If the result was positive or dubious, the serological test was sent to the National Microbiology Center for confirmation. RESULTS: A total of 251 participants were included (response rate 36.3%). The overall seroprevalence of Chagas infection was 19.1% (95% CI: 14.06-24.19). Seroprevalence was higher in participants from highly endemic provinces, those from rural areas, those who had lived in mud houses, and in those whose mother or a family member had contracted this infection. CONCLUSION: This study demonstrates a high prevalence of T. cruzi in Bolivian residents, which was strongly associated with established risk factors. PMID- 26026728 TI - Evaluation of the clinical significance of human papillomavirus (HPV) 53. AB - OBJECTIVE: Human papillomaviruses (HPV) are classified according to their potential for the development of cervical neoplasia. However, the carcinogenicity of HPV types forms an evolving continuum based on the newly available data especially regarding the role of probable and possible high-risk HPV types (pHR HPV). The objective of the present work was to evaluate clinical significance of the pHR-HPV53. STUDY DESIGN: An observational cohort study of potential aetiological association between infection with HPV53 and development of high grade cervical cytology was performed. The study was conducted in two geographically remoted hospitals, in Belgium and Democratic Republic of Congo, as an attempt to collect data from regions with different geographical distribution of HPV genotypes. The samples were taken during routine gynaecological visit in outpatient clinics of both participating hospitals. RESULTS: A total of 2283 liquid-Pap samples were taken from 1465 women at Ghent University Hospital, Belgium, and from 660 women at General Hospital and Ngaliema Hospital of Kinshasa, DRC. "HPV53-only"-pattern as evaluated by full HPV genotyping was found in samples from only 34 (1.6%) samples. The initial cytology represented next to non-dysplastic, undetermined and low-grade lesions also high-grade lesions (12%). For 26 (76.5%) from the 34 women presented with "HPV53-only"-pattern follow-up results were available showing no progression to malignancy. CONCLUSION: Our findings support very low to lacking carcinogenic potential of HPV53. Recognising extreme rarity in cervical cancer next to high prevalence in general population of HPV53, further studies investigating progression to high-grade lesions are needed to elucidate the oncogenic potential of pHR-HPV53. PMID- 26026729 TI - Development of a forensically useful age prediction method based on DNA methylation analysis. AB - Forensic DNA phenotyping needs to be supplemented with age prediction to become a relevant source of information on human appearance. Recent progress in analysis of the human methylome has enabled selection of multiple candidate loci showing linear correlation with chronological age. Practical application in forensic science depends on successful validation of these potential age predictors. In this study, eight DNA methylation candidate loci were analysed using convenient and reliable pyrosequencing technology. A total number of 41 CpG sites was investigated in 420 samples collected from men and women aged from 2 to 75 years. The study confirmed correlation of all the investigated markers with human age. The five most significantly correlated CpG sites in ELOVL2 on 6p24.2, C1orf132 on 1q32.2, TRIM59 on 3q25.33, KLF14 on 7q32.3 and FHL2 on 2q12.2 were chosen to build a prediction model. This restriction allowed the technical analysis to be simplified without lowering the prediction accuracy significantly. Model parameters for a discovery set of 300 samples were R(2)=0.94 and the standard error of the estimate=4.5 years. An independent set of 120 samples was used to test the model performance. Mean absolute deviation for this testing set was 3.9 years. The number of correct predictions +/-5 years achieved a very high level of 86.7% in the age category 2-19 and gradually decreased to 50% in the age category 60-75. The prediction model was deterministic for individuals belonging to these two extreme age categories. The developed method was implemented in a freely available online age prediction calculator. PMID- 26026730 TI - Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation. AB - Osteoporosis is the consequence of altered bone metabolism resulting in the systemic reduction of bone strength and increased risk of fragility fractures. MicroRNAs (miRNAs) regulate gene expression on a post-transcriptional level and are known to take part in the control of bone formation and bone resorption. In addition, it is known that miRNAs are secreted by many cell types and can transfer "messages" to recipient cells. Thus, circulating miRNAs might not only be useful as surrogate biomarkers for the diagnosis or prognosis of pathological conditions, but could be actively modulating tissue physiology. Therefore, the aim of this study was to test whether circulating miRNAs that exhibit changes in recent osteoporotic fracture patients could be causally related to bone metabolism. In the first step we performed an explorative analysis of 175 miRNAs in serum samples obtained from 7 female patients with recent osteoporotic fractures at the femoral neck, and 7 age-matched female controls. Unsupervised cluster analysis revealed a high discriminatory power of the top 10 circulating miRNAs for patients with recent osteoporotic fractures. In total 6 miRNAs, miR 10a-5p, miR-10b-5p, miR-133b, miR-22-3p, miR-328-3p, and let-7g-5p exhibited significantly different serum levels in response to fracture (adjusted p value<0.05). These miRNAs were subsequently analyzed in a validation cohort of 23 patients (11 control, 12 fracture), which confirmed significant regulation for miR-22-3p, miR-328-3p, and let-7g-5p. A set of these and of other miRNAs known to change in the context of osteoporotic fractures were subsequently tested for their effects on osteogenic differentiation of human mesenchymal stem cells (MSCs) in vitro. The results show that 5 out of 7 tested miRNAs can modulate osteogenic differentiation of MSCs in vitro. Overall, these data suggest that levels of specific circulating miRNAs change in the context of recent osteoporotic fractures and that such perturbations of "normal" levels might affect bone metabolism or bone healing processes. PMID- 26026731 TI - Molecular characterization and pathogenicity of a genogroup GVI feline norovirus. AB - Norovirus (NoV) has been classified into 6 genogroups, GI-GVI. In the present study, we identified novel feline NoV (FNoV) M49-1 strain. The C-terminal of RNA dependent RNA polymerase of the FNoV M49-1 strain was highly homologous with GIV FNoV and GIV lion norovirus, whereas VP1 was highly homologous with GVI canine NoV (CNoV). Based on the results of the Simplot analysis, the FNoV M49-1 strain may have been produced by recombination between GIV.2 FNoV and GVI.1 CNoV. In addition, specific pathogen-free cats inoculated with FNoV gene-positive-fecal samples developed diarrhea symptoms, and the viral gene was detected in their feces and blood. PMID- 26026732 TI - Low Voltage Transmission Electron Microscopy in Cell Biology. AB - Low voltage transmission electron microscopy (LVTEM) was employed to examine biological tissues with accelerating voltages as low as 5kV. Tissue preparation was modified to take advantage of the low-voltage techniques. Treatments with heavy metals, such as post-fixation with osmium tetroxide, on block and counterstaining were omitted. Sections (40nm) were thinner than usual and generated highly contrasted images. General appearance of the cells remains similar to that of conventional TEM. New features were however revealed. The matrix of the pancreatic granules displays heterogeneity with partitions that may correspond to the inner-segregation of their secretory proteins. Mitochondria revealed the presence of the ATP synthase granules along their cristea. The nuclear dense chromatin displayed a honeycomb organization while distinct beads, nucleosomes, aligned along thin threads were seen in the dispersed chromatin. Nuclear pore protein complexes revealed their globular nature. The intercalated disks in cardiac muscle displayed their fine structural organization. These features correlate well with data described or predicted by cell and molecular biology. These new aspects are not revealed when thicker and conventionally osmicated tissue sections were examined by LVTEM, indicating that major masking effects are associated with standard TEM techniques. Immunogold was adapted to LVTEM further enhancing its potential in cell biology. PMID- 26026733 TI - Acceptability of self-sample human papillomavirus testing among medically underserved women visiting the emergency department. AB - OBJECTIVE: Self-sample human papillomavirus (HPV) testing in public emergency departments (EDs) may be a viable strategy to opportunistically screen women who otherwise do not attend for regular Papanicolaou test-based cervical cancer screening. We describe the acceptability of self-sample HPV testing among women presenting to two high-volume, urban EDs that primarily care for the medically underserved. METHODS: In 2014, a total of 210 women 21 years of age and older were recruited from two public ED waiting areas following a two-stage cluster sampling design. Questionnaire items inquired about demographics, healthcare access and utilization, history of cervical cancer screening, and acceptability of self-sample HPV testing. Descriptive analyses were performed. RESULTS: Overall, 34.8% of participants were considered screening non-attendees based on their adherence to the current guidelines for Pap testing every three years. Acceptability of self-sample HPV testing was high, with over 85% of participants reporting that they would be willing to use the test if available. A smaller proportion (58%) was deemed likely to accept self-sample HPV testing in a public ED restroom setting. Primary concerns expressed by women were that the sampling may not be done correctly (64%) and that they may not know how to perform the sampling (39%). CONCLUSIONS: Opportunistic self-sample HPV testing is acceptable to women seeking care at a high-volume, urban emergency care center. The use of this intervention potentially offers a unique strategy to improve cervical cancer screening among high-risk women who otherwise do not attend for regular screening. PMID- 26026735 TI - Association of specific PTEN/10q haplotypes with endometrial cancer phenotypes in African-American and European American women. AB - OBJECTIVE: Endometrial carcinoma (EC), the most common gynecologic malignancy in the United States, affects European American (EA) women more frequently than African-American (AA) women. Yet, AA women are more likely to die from EC. Proposed etiologies for this racial disparity, such as socioeconomic status, aggressive, non-endometrioid tumor histology, and comorbid conditions, do not account for the entire disparity experienced by AA women, suggesting an unexplored genetic component. Germline mutations in PTEN cause Cowden syndrome (CS), which increases lifetime risk of endometrial cancer. In addition, somatic PTEN silencing is one of the most common initiating events in sporadic EC. Therefore, we hypothesized that specific PTEN haplotypes in the AA population may directly predispose AA women to unfavorable tumor characteristics when diagnosed with EC. METHODS: We conducted a case-control association study of germline variations in and around the PTEN/10q region between 53 EA and 51 AA EC cases and ethnic controls. RESULTS: Eighteen tag SNPs with minor allele frequency >=0.1, were genotyped and used to reconstruct haplotypes. Forty-eight ancestry informative markers were genotyped control for population stratification. Two haplotypes were overrepresented in AA, and there was a trend towards tumors with higher stage and grade in patients with these haplotypes. One haplotype was overrepresented in the EA population with a trend towards more endometrioid tumors. CONCLUSIONS: We show that specific PTEN/10q haplotypes are significantly different between EA and AA individuals (p<=0.02), and specific haplotypes may increase the risk of unfavorable tumor phenotypes in AA women diagnosed with EC. PMID- 26026734 TI - Cardiorespiratory fitness in survivors of cervical, endometrial, and ovarian cancers: The Cooper Center Longitudinal Study. AB - BACKGROUND: Cardiorespiratory fitness (CRF), a strong predictor of mortality, is impaired among cancer patients. There is limited data, however, regarding CRF levels in women diagnosed with gynecologic cancers. METHODS: We compared CRF among ovarian, endometrial, and cervical cancer cases (n=89) to age-matched controls (n=89) in the Cooper Center Longitudinal Study (CCLS). CRF was evaluated by a maximal treadmill exercise tolerance test using a modified-Balke protocol. Conditional logistic regression was used to test for case-control differences in cardiorespiratory fitness, after controlling for age and body mass index, and adhering to the matched pairs design. RESULTS: The mean ages of cancer cases and controls were 50.9 years and 51.1 years, respectively (p=0.81). Peak METs (1 MET=3.5 mL kg(-1)min(-1)) were 9.2 +/- 2.0 in cancer cases compared to 10.0 +/- 2.2 in controls (p=0.03). When stratifying by type of cancer, peak METs were 8.9 +/- 2.2, 8.4 +/- 1.9, 9.5 +/- 2.0 for patients with ovarian, endometrial, and cervical cancer, respectively. A gynecological cancer diagnosis was associated with greater odds of having 1-MET lower CRF compared to controls (OR 1.31, 95% CI: 1.05-1.64, p=0.018), after controlling for age and BMI. CONCLUSION: Gynecologic cancer survivors were more likely to have a 1-MET lower CRF than controls. Given a 1-MET change in CRF is associated with a significant, we advocate for more robust research regarding CRF in gynecologic cancer patients. PMID- 26026736 TI - Ovarian and cervical cancer patient derived xenografts: The past, present, and future. AB - Preclinical research in gynecologic malignancies has largely relied upon cloned cancer-derived cell lines and tumor xenografts derived from these cell lines. Unfortunately, the use of cell lines for translational research has disadvantages because genetic and phenotypic alterations from serial passaging have resulted in expression profiles that are different from the original patient tumors. The patient-derived xenograft (PDX) model derived from human tumor not previously cultured has shown better representation of the heterogeneity of gynecologic malignancies and the human tumor microenvironment with preservation of cytogenetics, cellular complexity, and vascular and stromal tumor architecture. Studies have shown promise with these models to analyze tumor development and adaptation, test drug efficacy, and predict clinical outcomes. Their ultimate value may be seen with preclinical drug screening including novel targeted therapies, biomarker identification, and the development of individualized treatment plans. This article reviews PDX model development, current studies testing chemotherapeutics and targeted therapies, and limitations of the PDX model in gynecologic malignancies. PMID- 26026737 TI - Physical activity and sedentary behavior in breast cancer survivors: New insight into activity patterns and potential intervention targets. AB - BACKGROUND: Inactivity and sedentary behavior are related to poorer health outcomes in breast cancer survivors. However, few studies examining these behaviors in survivors have used objective measures, considered activities other than moderate-to-vigorous intensity activity (MVPA) and/or sedentary behavior (i.e. low intensity activities) or compared survivors to healthy controls. The purpose of the present study is to compare accelerometer-measured activity of various intensities (total, light, lifestyle, MVPA) and sedentary behavior between breast cancer survivors and non-cancer controls. METHODS: An imputation based approach of independent sample t-tests adjusting for multiple comparisons was used to compare estimates of participation in each activity and sedentary behavior between survivors [n=398; M(SD)age=56.95 (9.11)] and block-matched non cancer controls [n=1120; M(SD)age=54.88 (16.11)]. Potential moderating effects of body mass index (BMI), age, and education were also examined. RESULTS: Breast cancer survivors registered less daily total (282.8 v. 346.9) light (199.1 v. 259.3) and lifestyle (62.0 v. 71.7) activity minutes and more MVPA (21.6 v. 15.9) and sedentary behavior (555.7 v. 500.6) minutes than controls (p<0.001 for all). These relationships were largely consistent across BMI, age and education. On average, survivors spent an estimated 66.4% of their waking time sedentary and 31.1% in light/lifestyle activity and 2.6% in MVPA. CONCLUSIONS: Breast cancer survivors are more sedentary and participate in less low intensity activity than controls. Although survivors registered more MVPA, these levels were insufficient. Future research should explore these differences and potential benefits of targeting low intensity activities and reducing sedentary time in this population. PMID- 26026739 TI - Heart disease in pregnancy. AB - Cardiac disease is the leading cause of maternal mortality in the developed world. The majority of women with heart disease are able to successfully undergo pregnancy. However, in women with severely impaired ventricular function, severe left heart obstruction, pulmonary hypertension and aortopathy, such as Marfan syndrome, with significant aortic dilatation, pregnancy is associated with a significant risk, and these women should be counselled against pregnancy if there is no option for treatment that reduces risk. Although there are increasing numbers of women with congenital heart disease who are considering pregnancy, as a result of joint expert specialist cardiac and obstetric care, maternal mortality is low. Most of the observed mortality occurs in women with structurally normal hearts who were not known to have heart disease before their pregnancy. It is therefore important that those caring for pregnant women are aware of the risk factors for and presentation of cardiac conditions in pregnancy. We review the presentation and management of both congenital and acquired heart diseases in pregnancy. PMID- 26026738 TI - A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. AB - OBJECTIVES: The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. METHODS: This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks). RESULTS: 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). CONCLUSIONS: Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested. PMID- 26026740 TI - Development of resistance to antiglioma agents in rat C6 cells caused collateral sensitivity to doxorubicin. AB - Chemoresistance is a severe limitation to glioblastoma (GBM) therapy and there is a strong need to understand the underlying mechanisms that determine its response to different chemotherapeutics. Therefore, we induced resistance in C6 rat glioma cell line, which considerably resembles the characteristics of human GBM. The resistant phenotype was developed by 3-bis (2-chloroethyl)-1-nitrosourea (BCNU), one of the most commonly used therapeutic drug in the course of GBM treatment. After confirmation of the cross-resistance to cisplatin (CPt) and temozolomide (TMZ) in newly established RC6 cell line, we examined cell death induction and DNA damage by these drugs. Resistance to apoptosis and deficiency in forming DNA double-strand breaks was followed by significant decrease in the mRNA expression of pro-apoptotic and anti-apoptotic genes. The development of drug resistance was associated with significant increase in reactive oxygen species (ROS) and decrease in oxidized to reduced gluthatione ratio in RC6 cell line indicating a reduced level of oxidative stress. The mRNA expression levels of manganese superoxid dismutase (MnSOD), inducible nitric oxide synthase (iNOS) and gluthatione peroxidase (GPx) were increased while hypoxia-inducible factor 1 alpha (HIF-1alpha) was decreased in RC6 compared to C6 cells. This was in line with obtained changes in ROS content and increased antioxidative capacity of RC6 cells. Importantly, RC6 cells demonstrated collateral sensitivity to doxorubicin (DOX). The analysis of this phenomenon revealed increased accumulation of DOX in RC6 cells due to their adaptation to high ROS content and acidification of cytoplasm. In conclusion, newly established RC6 rat glioma cell line could be used as a starting material for the development of allogenic animal model and preclinical evaluation of new antiglioma agents. Collateral sensitivity to DOX obtained after BCNU treatment may prompt new studies aimed to find efficient delivery of DOX to the glioma site in brain. PMID- 26026741 TI - Lack of association between COMT polymorphism rs4680 and risk of Alzheimer's disease in Asians: Evidence from a meta-analysis. PMID- 26026742 TI - The role of baseline inflammatory-based scores and serum tumor markers to risk stratify pseudomyxoma peritonei patients treated with cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - AIMS: Inflammation-based scores such as neutrophil-lymphocyte ratio (NLR) and Onodera nutritional index (ONI) have been identified as new prognosticators in several tumors. We conducted a prognostic analysis of these markers and performed a risk stratification of PMP patients submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: 226 patients from two peritoneal surface malignancies centers participated in this study. Cox proportional modeling was used to select predictors of overall survival (OS) among baseline inflammation-based scores, serum tumor markers, clinical and surgical variables. Risk stratification was done using conditional inference tree model. RESULTS: One hundred eighty-two cases had diffuse peritoneal adenomucinosis subtype. Fifty-four cases had received previous systemic chemotherapy. The means of ONI and NLR were 51.4 (SD = 9.8) and 3.2 (SD = 2.3), respectively. Two hundred ten cases were optimally cytoreduced. Cox analysis identified completeness of cytoreduction, histological subtype, previous systemic chemotherapy, NLR, and CA 19-9 as independent prognosticators. Conditional inference tree method identified two poor prognostic subsets: NLR <=2.7 and CA 19 9>336 (5yr-OS = 15%) and NLR >2.7 and ONI <=42 (5yr-OS = 30%). CONCLUSIONS: NLR, ONI, and CA 19-9 are new prognosticators that contributed to improve prediction of OS in PMP patients treated by CRS and HIPEC. These markers allowed a risk stratification that could optimize therapeutic management of PMP patients. PMID- 26026743 TI - Mosquito Attraction: Crucial Role of Carbon Dioxide in Formulation of a Five Component Blend of Human-Derived Volatiles. AB - Behavioral responses of the malaria mosquito Anopheles coluzzii (An. gambiae sensu stricto molecular 'M form') to an expanded blend of human-derived volatiles were assessed in a dual-port olfactometer. A previously documented attractive three-component blend consisting of NH3, (S)-lactic acid, and tetradecanoic acid served as the basis for expansion. Adding 4.5% CO2 to the basic blend significantly enhanced its attractiveness. Expansion of the blend with four human derived C4-volatiles was then assessed, both with and without CO2. Only when CO2 was offered simultaneously, did addition of a specific concentration of 3-methyl 1-butanol or 3-methyl-butanoic acid significantly enhance attraction. The functional group at the terminal C of the 3-methyl-substituted C4 compounds influenced behavioral effectiveness. In the absence of CO2, addition of three concentrations of butan-1-amine caused inhibition when added to the basic blend. In contrast, when CO2 was added, butan-1-amine added to the basic blend strongly enhanced attraction at all five concentrations tested, the lowest being 100,000 times diluted. The reversal of inhibition to attraction by adding CO2 is unique in the class Insecta. We subsequently augmented the three-component basic blend by adding both butan-1-amine and 3-methyl-1-butanol and optimizing their concentrations in the presence of CO2 in order to significantly enhance the attractiveness to An. coluzzii compared to the three- and four-component blends. This novel blend holds potential to enhance malaria vector control based on behavioral disruption. PMID- 26026744 TI - An Unusual Cause of Upper Gastrointestinal Bleeding. PMID- 26026745 TI - Tail Tale: nNOSdel1203-1434 Predicts Global Defects in Esophagogastrointestinal Transit. PMID- 26026746 TI - Peculiar Pigmented Polyp. PMID- 26026747 TI - A B-wildering Case of Recurrent Acute Pancreatitis. PMID- 26026748 TI - Progressive Abdominal Distention in an Immunosuppressed Woman. PMID- 26026749 TI - Hematochezia and a Mesenteric Mass. PMID- 26026750 TI - A Rare Cause of Esophageal Ulcers. PMID- 26026751 TI - Genotype by environment interactions on culling rates and 305-day milk yield of Holstein cows in 3 US regions. AB - The objective of this study was to investigate genotype by environment interactions for culling rates and milk production in large and small dairy herds in 3 US regions, using genotypes, pedigree, and phenotypes. Single nucleotide polymorphism (SNP) marker variances were also estimated in these different environments. Culling rates including cow mortality were based on 6 Dairy Herd Improvement termination codes reported by dairy producers. Separate data sets for culling rates and 305-d milk yield were created for large and small dairy herds in the US regions of the Southeast (SE), Southwest (SW), and Northeast (NE) for the first 3 lactation cows that calved between 1999 and 2008. Genomic information from 42,503 SNP markers on 34,506 bulls was included in the analysis to predict genomic estimated breeding value (GEBV) of culling rates and 305-d milk yield with a single-step genomic BLUP using a bivariate threshold-linear model. Cow replacement rates in large SE and NE herds were higher. Heritability estimates of culling rates ranged from 0.03 to 0.11, but the differences were small between large and small herds and among the 3 US regions. Genetic correlations between culling rates and 305-d milk yield were medium to high for cows sold for poor production and reproduction problems. Correlations of GEBV for culling rates among the 3 US regions ranged from 0.34 to 0.92 and were lower between the SW and the other regions, especially in small herds. Correlations of GEBV between large and small herds ranged from 0.44 to 0.90 and were lower in the SW. These results indicate genotype by environment interactions of cow culling rate between the US regions and between large and small herds. Correlations of top 30 SNP marker effects for culling rates between 2 US regions ranged from 0.64 to 0.98 and were higher than those of more SNP marker effects except for a culling reason "sold for dairy purpose." Those correlations between large and small herds ranged from 0.67 to 0.98. High correlations of top SNP marker effects on culling reasons between the US regions and between large and small herds suggest that major markers can be useful for selection in different environments. The SNP variance shown in a marker gene segment on chromosome 14 was strongly associated with milk production in large and small herds in the NE but not in the SE and SW. Marker genes on chromosome 14 also showed a strong association with cow culling rates due to poor production and mortality in large herds in the NE. PMID- 26026752 TI - A standard bacterial isolate set for research on contemporary dairy spoilage. AB - Food spoilage is an ongoing issue that could be dealt with more efficiently if some standardization and unification was introduced in this field of research. For example, research and development efforts to understand and reduce food spoilage can greatly be enhanced through availability and use of standardized isolate sets. To address this critical issue, we have assembled a standard isolate set of dairy spoilers and other selected nonpathogenic organisms frequently associated with dairy products. This publicly available bacterial set consists of (1) 35 gram-positive isolates including 9 Bacillus and 15 Paenibacillus isolates and (2) 16 gram-negative isolates including 4 Pseudomonas and 8 coliform isolates. The set includes isolates obtained from samples of pasteurized milk (n=43), pasteurized chocolate milk (n=1), raw milk (n=1), cheese (n=2), as well as isolates obtained from samples obtained from dairy-powder production (n=4). Analysis of growth characteristics in skim milk broth identified 16 gram-positive and 13 gram-negative isolates as psychrotolerant. Additional phenotypic characterization of isolates included testing for activity of beta-galactosidase and lipolytic and proteolytic enzymes. All groups of isolates included in the isolate set exhibited diversity in growth and enzyme activity. Source data for all isolates in this isolate set are publicly available in the FoodMicrobeTracker database (http://www.foodmicrobetracker.com), which allows for continuous updating of information and advancement of knowledge on dairy-spoilage representatives included in this isolate set. This isolate set along with publicly available isolate data provide a unique resource that will help advance knowledge of dairy-spoilage organisms as well as aid industry in development and validation of new control strategies. PMID- 26026753 TI - Simulation, prediction, and genetic analyses of daily methane emissions in dairy cattle. AB - This study presents an approach combining phenotypes from novel traits, deterministic equations from cattle nutrition, and stochastic simulation techniques from animal breeding to generate test-day methane emissions (MEm) of dairy cows. Data included test-day production traits (milk yield, fat percentage, protein percentage, milk urea nitrogen), conformation traits (wither height, hip width, body condition score), female fertility traits (days open, calving interval, stillbirth), and health traits (clinical mastitis) from 961 first lactation Brown Swiss cows kept on 41 low-input farms in Switzerland. Test-day MEm were predicted based on the traits from the current data set and 2 deterministic prediction equations, resulting in the traits labeled MEm1 and MEm2. Stochastic simulations were used to assign individual concentrate intake in dependency of farm-type specifications (requirement when calculating MEm2). Genetic parameters for MEm1 and MEm2 were estimated using random regression models. Predicted MEm had moderate heritabilities over lactation and ranged from 0.15 to 0.37, with highest heritabilities around DIM 100. Genetic correlations between MEm1 and MEm2 ranged between 0.91 and 0.94. Antagonistic genetic correlations in the range from 0.70 to 0.92 were found for the associations between MEm2 and milk yield. Genetic correlations between MEm with days open and with calving interval increased from 0.10 at the beginning to 0.90 at the end of lactation. Genetic relationships between MEm2 and stillbirth were negative (0 to 0.24) from the beginning to the peak phase of lactation. Positive genetic relationships in the range from 0.02 to 0.49 were found between MEm2 with clinical mastitis. Interpretation of genetic (co)variance components should also consider the limitations when using data generated by prediction equations. Prediction functions only describe that part of MEm which is dependent on the factors and effects included in the function. With high probability, there are more important effects contributing to variations of MEm that are not explained or are independent from these functions. Furthermore, autocorrelations exist between indicator traits and predicted MEm. Nevertheless, this integrative approach, combining information from dairy cattle nutrition with dairy cattle genetics, generated novel traits which are difficult to record on a large scale. The simulated data basis for MEm was used to determine the size of a cow calibration group for genomic selection. A calibration group including 2,581 cows with MEm phenotypes was competitive with conventional breeding strategies. PMID- 26026754 TI - Brown midrib corn shredlage in diets for high-producing dairy cows. AB - A novel method of harvesting whole-plant corn silage, shredlage, may increase kernel processing and physically effective fiber. Improved fiber effectiveness may be especially advantageous when feeding brown midrib (BMR) corn hybrids, which have reduced lignin content. The objective of this study was to determine the effect of feeding TMR containing BMR corn shredlage (SHRD) compared with BMR conventionally processed corn silage (KP) or KP plus chopped alfalfa hay (KPH) on intake, lactation performance, and total-tract nutrient digestibility in dairy cows. The KP was harvested using conventional rolls (2-mm gap) and the self propelled forage harvester set at 19mm of theoretical length of cut, whereas SHRD was harvested using novel cross-grooved rolls (2-mm gap) and the self-propelled forage harvester set at 26mm of theoretical length of cut. Holstein cows (n=120; 81+/-8 d in milk at trial initiation), stratified by parity, days in milk, and milk yield, were randomly assigned to 15 pens of 8 cows each. Pens were randomly assigned to 1 of 3 treatment diets, SHRD, KP, or KPH, in a completely randomized design using a 2-wk covariate period with cows fed a common diet followed by a 14 wk treatment period with cows fed their assigned treatment diet. The TMR contained (dry matter basis) KP or SHRD forages (45%), alfalfa silage (10%), and a concentrate mixture (45%). Hay replaced 10% of KP silage in the KPH treatment TMR (dry matter basis). Milk, protein, and lactose yields were 3.4, 0.08, and 0.16kg/d greater, respectively, for cows fed KP and SHRD than KPH. A week by treatment interaction was detected for milk yield, such that cows fed SHRD produced or tended to produce 1.5kg/d per cow more milk, on average, than cows fed KP during 6 of the 14 treatment weeks. Component-corrected milk yields were similar among treatments. Cows fed KPH had greater milk fat concentration than cows fed KP and SHRD (3.67 vs. 3.30% on average). Consumption of dry matter, rumination activity, and sorting behavior were similar among treatments. Ruminal in situ starch digestibility was greater for SHRD than KP forages, and total tract dietary starch digestibility was greater for SHRD than KP. Milk yield and starch digestibility were greater for SHRD than KP. Lack of improvement in milk fat content and rumination activity for SHRD compared with KP and reduced milk fat content for SHRD compared with KPH, however, suggest no improvement in physically effective fiber from the longer theoretical length of cut used with SHRD in a BMR hybrid. PMID- 26026755 TI - The effect of buffering dairy cow diets with limestone, calcareous marine algae, or sodium bicarbonate on ruminal pH profiles, production responses, and rumen fermentation. AB - Six ruminally cannulated Holstein cows were used to evaluate the effect of 2 dietary buffers on rumen pH, milk production, milk composition, and rumen fermentation parameters. A high concentrate total mixed ration [35.2% forage dry matter (DM)], formulated to be potentially acidotic, was used to construct 3 dietary treatments in which calcareous marine algae (calcified remains of the seaweed Lithothamnium calcareum) was compared with limestone (control) and sodium bicarbonate plus limestone. One basal diet was formulated and the treatment diets contained either 0.4% of dietary DM as Acid Buf, a calcified marine algae product (AB treatment), or 0.8% of dietary DM as sodium bicarbonate and 0.37% as limestone (BC treatment), or 0.35% of dietary DM as limestone [control (CON) treatment]. Cows were randomly allocated to treatments according to a double 3*3 Latin square design, with 3 treatments and 3 periods. The total experimental period was 66 d during which each cow received each treatment for a period of 15 d before the data collection period of 7 d. Rumen fluid was collected to determine volatile fatty acids, lactic acid, and ammonia concentrations. Rumen pH was monitored every 10min for 2 consecutive days using a portable data logging system fitted with in-dwelling electrodes. Milk samples were analyzed for solid and mineral contents. The effect of treatment on acidity was clearly visible, especially from the period from midday to midnight when rumen pH dropped below 5.5 for a longer period of time (13 h) in the CON treatment than in the BC (8.7 h) and AB (4 h) treatments. Daily milk, 4% fat-corrected milk, and energy corrected milk yields differed among treatments, with AB being the highest, followed by BC and CON. Both buffers increased milk fat content. Treatment had no effect on milk protein content, but protein yield was increased in the AB treatment. Total rumen volatile fatty acids and acetate concentrations were higher and propionate was lower in the AB treatment than in CON. The molar proportion of acetate was higher in AB than in CON, but that of propionate was lower in both buffer treatments than in CON. The acetate:propionate ratio was increased in the AB and BC treatments compared with CON. Lactic acid concentration was higher in the CON treatment than in the buffer treatments. Treatment had no effect on rumen ammonia concentrations. Results indicated that buffer inclusion in high concentrate diets for lactating dairy cows had a positive effect on milk production and milk composition. Calcareous marine algae, at a level of 90 g/cow per day, had a greater effect on rumen pH, milk production and milk composition, and efficiency of feed conversion into milk than sodium bicarbonate at a level of 180 g/cow per day. PMID- 26026756 TI - Short communication: Noninvasive indicators to identify lactating dairy cows with a greater risk of subacute rumen acidosis. AB - The objective of the current study was to evaluate if milk urea nitrogen (MUN) and milk fat content could be used as the noninvasive indicator to identify cows with greater or lower risk of subacute ruminal acidosis (SARA). Our hypothesis was that cows with lower MUN and milk fat content would have greater risk of SARA, whereas cows with higher MUN and milk fat content would have lower risk of SARA. In the screening study, 35 late-lactating Holstein cows (DIM=250+/-71.1; BW=601+/-45.4kg) were fed a high-grain diet containing 35% forage and 65% concentrate mix ad libitum for 21 d. Concentration of MUN ranged from 5.7 to 13.9Mg/dL among the 35 cows, and the average milk fat content was 3.5%. Then, 5 cows with highest MUN concentrations with milk fat higher than 3.5% were selected as animals that presumably have low risk of SARA, and 5 cows with lowest MUN concentrations with milk fat less than 3.5% were selected as animals that presumably have high risk of SARA. These 10 animals were ruminally cannulated during the subsequent dry period. As 1 low-risk cow was culled due to fatty liver, 9 animals (DIM=122+/-33.2; BW=615+/-49.1kg) were used in the subsequent study in the following lactation. All cows were fed a high-grain diet consisting of 35% forage and 65% concentrate mix ad libitum for 21 d. Ruminal pH was measured every 30 s for 72 h. Minimum (5.75 vs. 5.30) and mean ruminal pH (6.35 vs. 6.04) was higher for low- compared with high-risk animals. In addition, duration of rumen pH below 5.8 was shorter in low-risk animals (52.5 vs. 395min/d). These results suggested that MUN and milk fat content in late lactating cows fed a high-grain diet may be used to identify cows that have higher or lower risk of SARA. PMID- 26026757 TI - Short communication: Effects of Bos taurus autosome 9-located quantitative trait loci haplotypes on enzymatic mastitis indicators of milk from dairy cows experimentally inoculated with Escherichia coli. AB - The aim of this study was to investigate the effect of a quantitative trait locus associated with mastitis caused by Escherichia coli, with one haplotype being more susceptible (HH) and another being more resistant (HL) to E. coli mastitis, on the activity of 4 inflammatory related milk enzymes. In particular, we investigated the suitability of beta-glucuronidase (GLU) as an early indicator of E. coli mastitis. Besides GLU, the enzymes l-lactate dehydrogenase (LDH), N acetyl-beta-d-glucosaminidase (NAGase), and alkaline phosphatase were included. The study was conducted in an experimental setup with 31 Holstein cows divided into 4 groups representing repeated experiments and, within group, divided according to quantitative trait locus haplotype. All cows were inoculated with viable E. coli, and milk samples were collected 27 times from -6 to 396 h post-E. coli inoculation (PI). Activity of the 4 enzymes in milk, somatic cell count (SCC), daily milk yield, viable E. coli counts, and results of a semiquantitative polymerase chain reaction for pathogen detection, were all analyzed with a repeatability model. The response variables all expressed a strong reaction to the E. coli infection. Daily milk yield decreased significantly at 12 h PI and bacteria counts increased 100-fold and peaked at 18 h PI, which was validated by PCR. Also, SCC started to increase at 12 h PI and increased on average 70 times; however, no significant differences in SCC level were detected between HH and HL cows at any sampling point. The enzymes LDH, NAGase, and alkaline phosphatase showed similar responses, with a significantly increased activity and higher peak values for the HH than the HL cows. Significant differences between HH and HL cows were detected at different time points for these 3 enzymes, but not after adjusting P-values for multiple testing. A different pattern was also observed for GLU, where HL cows expressed the highest peak activity. Indication of differences in GLU activity between the 2 haplotype groups was only seen at 60 h PI. It was concluded that HL and HH cows expressed similar response patterns after E. coli infection but with differences in the size and profile of the activity of the 4 enzymes. The enzyme GLU was an equally good indicator of E. coli mastitis compared with the other studied enzymes, although it showed a slower response compared with LDH and NAGase. PMID- 26026758 TI - Short communication: Use of a mixture of sodium nitrite, sodium benzoate, and potassium sorbate in aerobically challenged silages. AB - Aerobic instability is still a common problem with many types of silages, particularly well-fermented silages. This study evaluated the effect of adding an additive mixture based on sodium nitrite, sodium benzoate, and potassium sorbate to a variety of crop materials on fermentation quality and aerobic stability of silages. Ensiling conditions were challenged by using a low packing density (104+/-4.3kg of dry matter/m(3)) of forage and allowing air ingression into silos (at 14 and 7 d before the end of the storage, for 8 h per event). Additive treated silages were found to have significantly lower pH and reduced formation of ammonia-N, 2.3-butanediol, and ethanol compared with untreated control silages. Yeast growth was significantly reduced by additive treatment in comparison with untreated control silage. Consequently, additive-treated silages were considerably more aerobically stable (6.7 d) than untreated control silages (0.5 d). Overall, adding 5mL/kg of fresh crop of the additive based on sodium nitrite, sodium benzoate, and potassium sorbate reduced undesirable microorganisms in silages and thereby provided suitable ensiling conditions and prolonged aerobic stability, even under air-challenged laboratory ensiling conditions. PMID- 26026759 TI - Technical note: Intraobserver, interobserver, and test-retest reliabilities of an assessment of vaginal discharge from cows with and without acute puerperal metritis. AB - Acute puerperal metritis (APM) in dairy cows is a common disease occurring in the first 10 d after calving. According to a widely accepted definition, the diagnosis is primarily based on body temperature and sensorial assessment of vaginal discharge. The scope of this study was to evaluate the reliability for color, smell, and viscosity of vaginal discharge from healthy cows and cows with APM. Fifteen investigators evaluated 6 vaginal discharge samples 10 times. Subsequently, the investigators rated the health status of the cows and the diagnostic value of color, smell, and viscosity. In a final questionnaire, the investigators estimated their ability to diagnose APM correctly and the influence of experience. Reliability was tested using Cohen's kappa (kappa). Our study revealed slight to moderate reliabilities concerning the assessment of vaginal discharge. Overall interobserver reliability for color, smell, and viscosity was kappa=0.15, 0.27, and 0.44, respectively. Overall intraobserver reliability for color, smell, and viscosity was kappa=0.35, 0.39, and 0.6, respectively. By means of a questionnaire, overall personal expertise to detect cows suffering from APM correctly as such was estimated to be 59%, whereas the diagnostic value of a combination of color, smell, and viscosity to detect cows with APM correctly was estimated to be 91.1% perfect. We found a discrepancy between reliability and the personal perception of diagnostic value. Our study shows that the sensorial assessment of color, smell, and viscosity of vaginal discharge in cows postpartum is subjective. PMID- 26026760 TI - Short communication: The effect of 4 antiseptic compounds on umbilical cord healing and infection rates in the first 24 hours in dairy calves from a commercial herd. AB - The objective of this study was to compare the effect of 4 antiseptic compounds on the healing rate and incidence of infection of umbilical cords in newborn calves (n=60). Late gestation Jersey cows were monitored at a commercial farm (Sioux Jersey, Salix, IA) and newborn purebred (n=30) and crossbred (n=30) calves were obtained within 30min after birth. Calves were alternately assigned by birth order to 4 treatment groups: 7% tincture of iodine, 0.1% chlorine created using a novel chlorine disinfectant technology, chlorohexidine gluconate 4.0% wt/vol, and 10% trisodium citrate. Prior to dipping (within 30min of birth), diameter of the umbilical cords (as an indicator of cord drying and healing) were determined using digital calipers. In addition, as an indicator of umbilical infections, surface temperature of the umbilical stump (along with a reference point at the midpoint of the sternum) was determined using a dual-laser infrared thermometer. These measurements were all repeated at 24+/-1 h of age. All data were analyzed using mixed model methods. All models included fixed effects of breed (Jersey or Jersey cross), sex (bull or heifer), and treatment. Fixed effect interactions were not included in the statistical model due to the relatively small sample size. No treatment differences were noted for healing rate of umbilical cords. Initially, mean umbilical cord diameter was 22.84+/-3.89mm and cords healed to a mean diameter of 7.64+/-4.12mm at 24 h of age. No umbilical infections were noted for calves on any treatment during the course of this study. Mean surface temperature of the umbilical stump was 33.1+/-2.2 degrees C at birth (1.5+/-1.6 degrees C higher than the sternal reference temperature), and at 24+/-1 h of age the mean temperature of the umbilical stump was 33.0+/-4.3 degrees C (0.5+/-1.8 degrees C lower than the sternal reference temperature). These data suggest that these antiseptic compounds are equally effective for preventing infections and permitting healing of the umbilical cord when used within 30min of birth. PMID- 26026761 TI - Hot topic: Innovative lactation-stage-dependent prediction of methane emissions from milk mid-infrared spectra. AB - The main goal of this study was to develop, apply, and validate a new method to predict an indicator for CH4 eructed by dairy cows using milk mid-infrared (MIR) spectra. A novel feature of this model was the consideration of lactation stage to reflect changes in the metabolic status of the cow. A total of 446 daily CH4 measurements were obtained using the SF6 method on 142 Jersey, Holstein, and Holstein-Jersey cows. The corresponding milk samples were collected during these CH4 measurements and were analyzed using MIR spectroscopy. A first derivative was applied to the milk MIR spectra. To validate the novel calibration equation incorporating days in milk (DIM), 2 calibration processes were developed: the first was based only on CH4 measurements and milk MIR spectra (independent of lactation stage; ILS); the second included milk MIR spectra and DIM information (dependent on lactation stage; DLS) by using linear and quadratic modified Legendre polynomials. The coefficients of determination of ILS and DLS equations were 0.77 and 0.75, respectively, with standard error of calibration of 63g/d of CH4 for both calibration equations. These equations were applied to 1,674,763 milk MIR spectra from Holstein cows in the first 3 parities and between 5 and 365 DIM. The average CH4 indicators were 428, 444, and 448g/d by ILS and 444, 467, and 471g/d by DLS for cows in first, second, and third lactation, respectively. Behavior of the DLS indicator throughout the lactations was in agreement with the literature with values increasing between 0 and 100 DIM and decreasing thereafter. Conversely, the ILS indicator of CH4 emission decreased at the beginning of the lactation and increased until the end of the lactation, which differs from the literature. Therefore, the DLS indicator seems to better reflect biological processes that drive CH4 emissions than the ILS indicator. The ILS and DLS equations were applied to an independent data set, which included 59 respiration chamber measurements of CH4 obtained from animals of a different breed across a different production system. Results indicated that the DLS equation was much more robust than the ILS equation allowing development of indicators of CH4 emissions by dairy cows. Integration of DIM information into the prediction equation was found to be a good strategy to obtain biologically meaningful CH4 values from lactating cows by accounting for biological changes that occur throughout the lactation. PMID- 26026762 TI - Chemical characterization of milk after treatment with thermal (HTST and UHT) and nonthermal (turbulent flow ultraviolet) processing technologies. AB - As a result of growing interest to nonthermal processing of milk, the purpose of this study was to characterize the chemical changes in raw milk composition after exposure to a new nonthermal turbulent flow UV process, conventional thermal pasteurization process (high-temperature, short-time; HTST), and their combinations, and compare those changes with commercially UHT-treated milk. Raw milk was exposed to UV light in turbulent flow at a flow rate of 4,000L/h and applied doses of 1,045 and 2,090 J/L, HTST pasteurization, and HTST in combination with UV (before or after the UV). Unprocessed raw milk, HTST-treated milk, and UHT-treated milk were the control to the milk processed with the continuous turbulent flow UV treatment. The chemical characterization included component analysis and fatty acid composition (with emphasis on conjugated linoleic acid) and analysis for vitamin D and A and volatile components. Lipid oxidation, which is an indicator to oxidative rancidity, was evaluated by free fatty acid analysis, and the volatile components (extracted organic fraction) by gas chromatography-mass spectrometry to obtain mass spectral profile. These analyses were done over a 14-d period (initially after treatment and at 7 and 14 d) because of the extended shelf-life requirement for milk. The effect of UV light on proteins (i.e., casein or lactalbumin) was evaluated qualitatively by sodium dodecyl sulfate-PAGE. The milk or liquid soluble fraction was analyzed by sodium dodecyl sulfate-PAGE for changes in the protein profile. From this study, it appears that continuous turbulent flow UV processing, whether used as a single process or in combination with HTST did not cause any statistically significant chemical changes when compared with raw milk with regard to the proximate analysis (total fat, protein, moisture, or ash), the fatty acid profile, lipid oxidation with respect to volatile analysis, or protein profile. A 56% loss of vitamin D and a 95% loss of vitamin A content was noted after 7 d from the continuous turbulent flow UV processing, but this loss was equally comparable to that found with traditional thermal processing, such as HTST and UHT. Chemical characterization of milk showed that turbulent flow UV light technology can be considered as alternative nonthermal treatment of pasteurized milk and raw milk to extend shelf life. PMID- 26026763 TI - Strain diversity and phage resistance in complex dairy starter cultures. AB - The compositional stability of the complex Gouda cheese starter culture Ur is thought to be influenced by diversity in phage resistance of highly related strains that co-exist together with bacteriophages. To analyze the role of bacteriophages in maintaining culture diversity at the level of genetic lineages, simple blends of Lactococcus lactis strains were made and subsequently propagated for 152 generations in the absence and presence of selected bacteriophages. We first screened 102 single-colony isolates (strains) from the complex cheese starter for resistance to bacteriophages isolated from this starter. The collection of isolates represents all lactococcal genetic lineages present in the culture. Large differences were found in bacteriophage resistance among strains belonging to the same genetic lineage and among strains from different lineages. The blends of strains were designed such that 3 genetic lineages were represented by strains with different levels of phage resistance. The relative abundance of the lineages in blends with phages was not stable throughout propagation, leading to continuous changes in composition up to 152 generations. The individual resistance of strains to phage predation was confirmed as one of the factors influencing starter culture diversity. Furthermore, loss of proteolytic activity of initially proteolytic strains was found. Reconstituted blends with only 4 strains with a variable degree of phage resistance showed complex behavior during prolonged propagation. PMID- 26026764 TI - Effect of prepartal ad libitum feeding of grass silage on transcriptional adaptations of the liver and subcutaneous adipose tissue in dairy cows during the periparturient period. AB - Prepartal energy overfeeding may predispose cows to a state of increased insulin resistance with greater lipolysis after parturition. The aim of the study was to evaluate the effects of prepartal overfeeding in terms of abundant grass silage ration on the liver and subcutaneous adipose tissue (SAT) gene expression around parturition. Sixteen multiparous Finnish Ayrshire dairy cows were fed ad libitum either grass silage [high energy, HE; 144 MJ/d of metabolizable energy (ME) intake, n=8] or a mixture of grass silage, wheat straw, and rapeseed meal [55:40:5 (CON), 109 MJ/d of ME, n=8] during the dry period (58.2+/-4.89 d, mean +/- standard deviation). Tissue biopsies and blood samples were collected at -14 (+/-4.98), 1, and 7 d relative to the actual parturition date. The HE cows had greater total dry matter intake, ME intake, and ME balance during the dry period than the CON cows. Compared with CON, the increases in body weight and body condition score were greater in HE during the dry period. Milk yield during the first 2 wk of lactation was not different between the groups. Plasma glucose, nonesterified fatty acids, insulin, glucagon, and beta-hydroxybutyrate did not differ between the groups during the transition period. Dietary treatment did not affect hepatic triglyceride content; however, a delayed increase in hepatic total lipid content was observed in the HE cows at d 1 postpartum. Hepatic cytosolic phosphoenolpyruvate carboxykinase 1 mRNA expression was lower in HE than in CON at d 1 and 7 postpartum. Adiponectin receptor 1 and 2 mRNA abundance tended to be lower in SAT of HE than CON. Lower lipoprotein lipase, leptin, and stearoyl coenzyme A desaturase mRNA abundances were observed at d 7 postpartum in SAT of the HE cows compared with the CON cows. We concluded that prepartal ad libitum feeding of grass silage may decrease insulin sensitivity and lipogenesis in SAT during peripartal period and may attenuate the increase of hepatic gluconeogenic capacity from propionate compared with a controlled-energy diet. PMID- 26026765 TI - The effect of transient, moderate dietary phosphorus deprivation on phosphorus metabolism, muscle content of different phosphorus-containing compounds, and muscle function in dairy cows. AB - Hypophosphatemia is a common finding in periparturient and anorectic cattle. Although the clinical relevance of hypophosphatemia in cattle is uncertain, it has been empirically associated with persistent recumbency, specifically in periparturient dairy cows. The objective of the present study was to determine if transient dietary phosphorus (P) deprivation over a course of 5 wk, by feeding an approximately 40% P-deficient ration to lactating dairy cows, would result in altered muscle function or muscle P metabolism severe enough to present a risk for animal health and well-being. In addition, we wanted to determine the association between the plasma phosphate concentration ([Pi]) and muscle tissue P content to assess to what extent intracellular P deprivation of muscle cells could be extrapolated from subnormal plasma [Pi]. Ten healthy multiparous, mid lactating dairy cows received a ration with a P content of 0.18% over a period of 5 wk. Following the P-deprivation phase, the same ration supplemented with P to obtain a dietary P content of 0.43% was fed for 2 wk. Blood and urine samples were collected regularly and muscle biopsies were obtained repeatedly to determine the P content in muscle tissue. Function of skeletal and heart muscles was evaluated by electrocardiography and electromyography conducted repeatedly throughout the study. Feeding the P-deficient ration resulted in the rapid development of marked hypophosphatemia. The lowest plasma [Pi] were measured after 9 d of P depletion and were, on average, 60% below predepletion values. Plasma [Pi] increased thereafter, despite ongoing dietary P depletion. None of the animals developed clinical signs commonly associated with hypophosphatemia or any other health issues. Urine analysis revealed increasing renal calcium, pyridinoline, and hydroxypyridinoline excretion with ongoing P deprivation. Biochemical muscle tissue analysis showed that dietary P depletion and hypophosphatemia were not associated with a decline in muscle tissue P content. Electromyographic examination revealed increased occurrence of pathological spontaneous activity in striated muscles after 2 wk of dietary P depletion in several cows, which could be suggestive of neuromuscular membrane instability. No effect on heart muscle activity was identified electrocardiographically. These results suggest that counter-regulatory mechanisms were sufficient to maintain normal muscle tissue P content during transient and moderate P deprivation. Muscle function was not grossly affected, although the increased occurrence of pathological spontaneous activity suggests that subclinical neuropathy or myopathy, or both, may have occurred with ongoing P deprivation. The results presented here indicate that plasma [Pi] is unsuitable for assessing muscle tissue P content in cattle. PMID- 26026766 TI - Prepartal dietary energy level affects peripartal bovine blood neutrophil metabolic, antioxidant, and inflammatory gene expression. AB - During the dry period, cows can easily overconsume higher-grain diets, a scenario that could impair immune function during the peripartal period. Objectives were to investigate the effects of energy overfeeding on expression profile of genes associated with inflammation, lipid metabolism, and neutrophil function, in 12 multiparous Holstein cows (n=6/dietary group) fed control [CON, 1.34 Mcal/kg of dry matter (DM)] or higher-energy (HE, 1.62 Mcal/kg of DM) diets during the last 45 d of pregnancy. Blood was collected to evaluate 43 genes in polymorphonuclear neutrophil leukocytes (PMNL) isolated at -14, 7, and 14 d relative to parturition. We detected greater expression of inflammatory-related cytokines (IL1B, STAT3, NFKB1) and eicosanoid synthesis (ALOX5AP and PLA2G4A) in HE cows than in CON cows. Around parturition, all cows had a close balance in mRNA expression of the pro-inflammatory IL1B and the anti-inflammatory IL10, with greater expression of both in cows fed HE than CON. The expression of CCL2, LEPR, TLR4, IL6, and LTC4S was undetectable. Cows in the HE group had greater expression of genes involved in PMNL adhesion, motility, migration, and phagocytosis, which was similar to expression of genes related to the pro inflammatory cytokine. This response suggests that HE cows experienced a chronic state of inflammation. The greater expression of G6PD in HE cows could have been associated with the greater plasma insulin, which would have diverted glucose to other tissues. Cows fed the HE diet also had greater expression of transcription factors involved in metabolism of long-chain fatty acids (PPARD, RXRA), suggesting that immune cells might be predisposed to use endogenous ligands such as nonesterified fatty acids available in the circulation when glucose is in high demand for milk synthesis. The lower overall expression of SLC2A1 postpartum than prepartum supports this suggestion. Targeting interleukin-1beta signaling might be of value in terms of controlling the inflammatory response around calving. The present study revealed that overfeeding cows during late pregnancy results in activation, ahead of parturition, of PMNL responses associated with stress and inflammation. These adaptations observed in PMNL did not seem to be detrimental for production. PMID- 26026767 TI - A patient-derived subrenal capsule xenograft model can predict response to adjuvant therapy for cancers in the head of the pancreas. AB - BACKGROUND: Although gemcitabine is commonly used as adjuvant therapy for pancreatic adenocarcinoma and pancreaticobiliary-type periampullary cancers, not all patients appear to benefit. This translational study evaluates the potential of a patient-derived subrenal capsule pancreatic cancer xenograft (SRCPCX) model to identify within eight weeks after surgery those tumours which will respond to gemcitabine. METHODS: SRCPCXs from 32 pancreatectomy patients were established in six to ten NOD/SCID mice per patient. After four weeks the mice were randomly assigned to receive gemcitabine or saline for four more weeks. After eight weeks, gemcitabine response in the grafts was evaluated by the percentage of tumour growth inhibition (%TGI), histological morphology and immunohistochemical markers (Ki-67, CK7 and cleaved caspase-3). These were collated into an Overall Response. Survival was assessed by Kaplan-Meier and Cox multivariate analyses. RESULTS: 375 of 450 pieces of tissue from 27 of 31 patients were evaluable. In 90% of patients, histopathological and immunostaining features of saline-treated control grafts were concordant with their original tumours. At follow up, six of 15 patients whose tumours had an Overall Response to gemcitabine died, compared with ten of 12 whose tumours did not respond (P = 0.025, Fisher's exact test). This was associated with improved survival on Kaplan-Meier analysis (P = 0.013). Cox multivariate analysis indicated that Overall Response, stage and grade were independent predictors of survival. CONCLUSION: This SRCPCX model retains major histopathological and immunohistochemical characteristics of the original tumour and when a combination of measures is used, enables early assessment of tumour sensitivity to gemcitabine in pancreatic cancers. PMID- 26026768 TI - Novel Raman-tagged sphingomyelin that closely mimics original raft-forming behavior. AB - Three Raman probes of sphingomyelin (SM) were synthesized and evaluated for their applicability to imaging experiments. One probe containing a hydroxymethyl-1,3 butadiyne moiety in the polar head group showed strong scattering. The solid state (2)H NMR spectra of this probe in oriented bilayer membrane revealed excellent compatibility with natural SM in phase behavior since the probe undergoes phase separation to form raft-like liquid ordered (Lo) domains in the raft-mimicking mixed bilayers. PMID- 26026769 TI - Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. AB - The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5 ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with beta-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5 ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6 naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5 ones showed excellent inhibition of the tankyrases, with some examples having IC50=2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6 naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2. PMID- 26026771 TI - Sequential evaluation for bone union of transferred fibula flaps in reconstructed mandibles: panoramic X-ray versus computed tomography. AB - The purpose of this study was to sequentially evaluate bone union of fibular grafts in mandibular reconstruction. Patients who underwent routine follow-up computed tomography (CT) and panoramic X-ray imaging during a period of >=2 years were enrolled. On panoramic X-ray images, bone union was scored as 0 (absent callus formation) or 1 (complete callus formation). On CT images, a scale of 0 to 2 was used (0, absent callus formation; 1, complete callus formation only on the labial side; 2, complete callus formation on both the labial and lingual side). A total of 56 bone junctions were evaluated in 20 patients. Five of 56 junctions (9%) in four of 20 patients (20%) showed radiological non-union (panoramic X-ray score=0, CT score=0 or 1) at 2 years after surgery. All bone junctions with radiological non-union were located at the mandibular angle. No categorical values, including diabetes mellitus and radiation therapy, were significantly associated with radiological non-union. In conclusion, assessing at least two sides (i.e. labial and lingual sides) on CT images is adequate to evaluate bone union in transferred fibula flaps. Careful fixation at the mandibular angle may improve the rate of bone union. PMID- 26026770 TI - Altered Central Sensitization and Pain Modulation in the CNS in Chronic Joint Pain. AB - Musculoskeletal pain disorders are the second largest contributor to global disability underlining the significance of effective treatments. However, treating chronic musculoskeletal pain, and chronic joint pain (osteoarthritis (OA)) in particular, is challenging as the underlying peripheral and central pain mechanisms are not fully understood, and safe and efficient analgesic drugs are not available. The pain associated with joint pain is highly individual, and features from radiological imaging have not demonstrated robust associations with the pain manifestations. In recent years, a variety of human quantitative pain assessment tools (quantitative sensory testing (QST)) have been developed providing new opportunities for profiling patients and reaching a greater understanding of the mechanisms involved in chronic joint pain. As joint pain is a complex interaction between many different pain mechanisms, available tools are important for patent profiling and providing the basic knowledge for development of new drugs and for developing pain management regimes. PMID- 26026773 TI - Nail psoriasis as a predictor of the development of psoriatic arthritis. AB - Psoriatic arthritis is a psoriasis-related spondyloarthropathy that occurs in 20 30% of patients with psoriasis. Various imaging studies have demonstrated that there is a considerable proportion of undiagnosed psoriatic arthritis among patients with psoriasis. Since early detection and treatment of psoriatic arthritis could, ultimately, allow the prevention of clinical and radiologic progression of the disease, there is the need to establish clinical indicators to detect this risk. Nail psoriasis has been proposed as a predictor for the development of psoriatic arthritis. The inflammation involving the entheses, called enthesitis, is an early inflammatory change seen in psoriatic arthritis, and nail changes appear to result from the close relationship between the nail and the enthesis of the distal interphalangeal extensor tendon, one of the main entheseal compartments affected in psoriatic arthritis. As skin lesions precede articular symptoms in more than 75-80% of patients with psoriatic arthritis, dermatologists may play a key role in the early detection and management of psoriatic arthritis. PMID- 26026774 TI - A comment on "Improving rehabilitation following critical illness through outpatient physiotherapy classes and essential amino acid supplement: a randomised, controlled trial". PMID- 26026772 TI - Head and neck solitary fibrous tumors: a rare and challenging entity. AB - The objective of this study is to analyze the outcome of treatment for solitary fibrous tumors (SFTs) in the head and neck area. SFTs present as slow-growing masses, often with local compressive symptoms that are difficult to distinguish from other soft-tissue tumors. SFTs are commonly treated using local excision without adjuvant therapy. To date, only heterogeneous small series have been published, documenting the treatment results and outcome with these tumors. Retrospective study of patients with histopathologically confirmed SFT treated at two tertiary referral hospitals between 2004 and 2014. Eight men and four women with histologically confirmed SFT were identified in the records. Their age range was 37-82 years (mean 57.8 years). The mean follow-up period for eight patients was 6.75 years (range 1-24 years). Four patients were lost to follow-up. Sublocalizations were neck (n = 3), orbit (n = 2), paranasal sinus (n = 2), cheek (n = 2), hard palate (n = 1), parotid gland (n = 1), and tongue (n = 1). The first-line treatment for all of the tumors identified was surgical excision. In four cases, the surgical margins were narrow or unclear due to piecemeal resection in the paranasal sinus and orbit (n = 3) or a tumor location deep in the parapharyngeal space (n = 1). Recurrences developed in two of these cases (in the orbit and parapharyngeal space), and the other two patients were lost to follow-up. Radiotherapy and chemotherapy were not administered as first-line treatments. Overall, the local recurrence rate (n = 2/8) was 25 %. The disease specific survival rate was 100 %. These results are consistent with the literature data and show that safe surgical excision, without opening of the tumor capsule, reduces the risk of local recurrence and leads to a favorable outcome. Tumors in the head and neck often represent a surgical challenge, and wide surgical margins are rarely possible due to the complex three-dimensional anatomic compartments in the region. Head and neck surgeons should therefore be aware that there is an increased risk of recurrence in these patients; tightly scheduled follow-up visits are mandatory for at least 10 years, if not longer. Radiotherapy only appears to be an option in patients with unresectable tumors or when wide surgical excision would cause severe functional morbidity. PMID- 26026776 TI - Effects of two retraining strategies on nursing students' acquisition and retention of BLS/AED skills: A cluster randomised trial. AB - AIM: To determine and compare the effects of two different retraining strategies on nursing students' acquisition and retention of BLS/AED skills. METHODS: Nursing students (N = 177) from two European universities were randomly assigned to either an instructor-directed (IDG) or a student-directed (SDG) 4-h retraining session in BLS/AED. A multiple-choice questionnaire, the Cardiff Test, Laerdal SkillReporter((r)) software and a self-efficacy scale were used to assess students' overall competency (knowledge, psychomotor skills and self-efficacy) in BLS/AED at pre-test, post-test and 3-month retention-test. GEE, chi-squared and McNemar tests were performed to examine statistical differences amongst groups across time. RESULTS: There was a significant increase in the proportion of students who achieved competency for all variables measuring knowledge, psychomotor skills and self-efficacy between pre-test and post-test in both groups (all p-values<0.05). However, at post-test, significantly more students in the SDG achieved overall BLS/AED competency when compared to IDG. In terms of retention at 3 months, success rates of students within the IDG deteriorated significantly for all variables except >= 70% of chest compressions with correct hand position (p-value = 0.12). Conversely, the proportion of students who achieved competency within the SDG only decreased significantly in 'mean no flow time <= 5s' (p-value = 0.02). Furthermore, differences between groups' success rates at retention-test also proved to be significantly different for all variables measured (all p-values < 0.05). CONCLUSION: This study demonstrated that using a student-directed strategy to retrain BLS/AED skills has resulted in a higher proportion of nursing students achieving and retaining competency in BLS/AED at three months when compared to an instructor-directed strategy. PMID- 26026775 TI - Managing the identification of the mortal victims run over by a train in the Castelldefels railway accident (Barcelona). AB - The identification of disaster victims is the formal, organized process of identifying multiple bodies after an incident with multiple victims. The appropriate management of these incidents, particularly of the bodies, is one of the most crucial aspects of disaster response and its importance has led to the evolution of the concept of Disaster Victim Management. The aim of this study is to report how the process of identifying the 12 mortal victims of a railway accident in June 2010 in Castelldefels (Barcelona) was managed. The methodology used complied with the National Protocol for medical forensic and scientific police response to mass casualty incidents. The family assistance center also served as an ante mortem (AM) office. Despite the fragmentation of the bodies, all the victims were identified satisfactorily. The main problems observed during the management of the disaster were due to the state of the bodies, which raised many doubts as to the number of fatalities. The experience prompted a proposal to establish some recommendations on limiting the number of fragments to be analyzed genetically. We would like to stress the importance of setting up a Data Integration Center which brought together all the participating institutions, and collected and supervised all the different identification reports in a single comprehensive text addressed to the competent legal authority. PMID- 26026777 TI - Frequency and number of resuscitation related rib and sternum fractures are higher than generally considered. PMID- 26026778 TI - A hybrid method for airway segmentation and automated measurement of bronchial wall thickness on CT. AB - Inflammatory and infectious lung diseases commonly involve bronchial airway structures and morphology, and these abnormalities are often analyzed non invasively through high resolution computed tomography (CT) scans. Assessing airway wall surfaces and the lumen are of great importance for diagnosing pulmonary diseases. However, obtaining high accuracy from a complete 3-D airway tree structure can be quite challenging. The airway tree structure has spiculated shapes with multiple branches and bifurcation points as opposed to solid single organ or tumor segmentation tasks in other applications, hence, it is complex for manual segmentation as compared with other tasks. For computerized methods, a fundamental challenge in airway tree segmentation is the highly variable intensity levels in the lumen area, which often causes a segmentation method to leak into adjacent lung parenchyma through blurred airway walls or soft boundaries. Moreover, outer wall definition can be difficult due to similar intensities of the airway walls and nearby structures such as vessels. In this paper, we propose a computational framework to accurately quantify airways through (i) a novel hybrid approach for precise segmentation of the lumen, and (ii) two novel methods (a spatially constrained Markov random walk method (pseudo 3-D) and a relative fuzzy connectedness method (3-D)) to estimate the airway wall thickness. We evaluate the performance of our proposed methods in comparison with mostly used algorithms using human chest CT images. Our results demonstrate that, on publicly available data sets and using standard evaluation criteria, the proposed airway segmentation method is accurate and efficient as compared with the state-of-the-art methods, and the airway wall estimation algorithms identified the inner and outer airway surfaces more accurately than the most widely applied methods, namely full width at half maximum and phase congruency. PMID- 26026779 TI - "Adolescent metabolic phenotypes and early adult metabolic syndrome: Tehran lipid and glucose study". AB - OBJECTIVE: To investigate the predictive role of adolescent metabolic phenotypes in development of early adult metabolic syndrome (MetS). STUDY DESIGN: A group of 1446 adolescents (44.8% boys), participants of the Tehran Lipid and Glucose Study, with a mean (SD) of age 14.6 (2.2) years, followed for 10.4 years. Logistic regression models were developed to evaluate the predictive power of different metabolic phenotypes for adult MetS. Moreover, areas under the receiver operating characteristic (ROC) curve were estimated to compare the prediction power of metabolic phenotypes for adult MetS. RESULTS: The prevalence of MetS was 14.6% (29.7% and 2.4% for adult males and females, respectively) at the end of follow up. The most frequent metabolic phenotype in adolescent was high TGs/low HDL-C (23.7%), while the prevalence of high TGs/high WC was 10.4% and the other phenotypes were less than 10%. After adjustment for baseline BMI Z-Score and BMI change, high TGs/low HDL-C (OR: 1.70, 95%CI: 1.23-2.37), high WC/high BP (OR: 1.75., 95%CI: 1.08-2.84), high BP/low HDL-C (OR:1.68, 95%CI: 1.05-2.60) and high WC/low HDL-C (OR: 2.41, 95% CI: 1.37-4.23) phenotypes were associated with adult MetS. However, their AUCs were significantly lower than overweight or obesity. CONCLUSION: Some combinations of metabolic abnormalities in adolescence predict early adult MetS, independent of baseline BMI Z-Score and BMI change. However, the discriminative power of these phenotypes was weak, in comparison to adolescent overweight or obesity. PMID- 26026780 TI - Retrospective analysis of the relationship between elevated plasma levels of TXNIP and carotid intima-media thickness in subjects with impaired glucose tolerance and early Type 2 diabetes mellitus. AB - AIMS: Accelerated atherosclerosis is the major cause of mortality in diabetic patients and increased oxidative stress probably plays an important role in its development. The aim of our study was to evaluate the relationship between thioredoxin-interacting protein (TXNIP) as an oxidative stress parameter and carotid artery intima-media thickness (CIMT) as an indicator of atherosclerosis in patients with early-state diabetes and impaired glucose tolerance. METHODS: The study was a retrospective analysis of 90 patients with impaired glucose regulation (IGR), 80 patients with early Type 2 diabetes mellitus (T2DM), and 80 subjects with normal glucose tolerance (NGT) as the control group. It was conducted at the endocrine out-patient clinic and hospital department of Cangzhou Central Hospital (Cangzhou, China) from June 2012 to Oct. 2013. Plasma TXNIP was measured to evaluate the level of oxidative stress. CIMT was assessed by carotid artery ultrasonography. Soluble vascular cell adhesion molecule-1 (sVCAM-1), a risk indicator for endothelial dysfunction, was also measured. RESULTS: Compared to the NGT control, patients with IGR showed significantly higher plasma levels of TXNIP (P<0.05). Compared to the IGR group, patients with T2DM also had significantly higher plasma levels of TXNIP (P<0.05). CIMT was significantly higher in the subjects with abnormal glucose metabolism than in the NGT group (P<0.05). CIMT showed positive correlations with both TXNIP and sVCAM-1 levels (r = 0.56 and r = 0.49, respectively, both P<0.01). CONCLUSIONS: The present study showed that plasma levels of TXNIP may be a useful predictor of subclinical atherosclerosis in Type 2 diabetic patients. PMID- 26026781 TI - Using computer modelled life expectancy to evaluate the impact of Australian Primary Care Incentive programs for patients with type 2 diabetes. AB - AIMS: To evaluate the impact of enhanced primary care and practice incentive programs on the care of patients with type 2 diabetes in the Australian primary care setting using routinely collected data and computer modelling software. METHODS: Primary care patient data were electronically extracted from practices and inputted into the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes model. A retrospective cohort study design was employed with predicted life expectancies compared between patients who had a recorded diabetes cycle of care (DCoC) and those who did not. Changes in glycated haemoglobin (HbA1c) were also analysed using a mixed-effects regression model. Potential life expectancy gains were estimated by inputting theoretical risk factors data consistent with current guidelines. RESULTS: Twelve primary care practices were recruited and suitable data were available for 559 people with type 2 diabetes. Two hundred and twenty five patients (40%) were identified as having completed at least one DCoC and as a group had a predicted additional life expectancy of 0.65 years (95% CI, -0.22 to 1.5). However, once this was adjusted for comorbidities the difference reduced to 0.03 years. There was no significant difference in HbA1c levels attributable to the intervention. An estimated 0.5 year of additional life expectancy was predicted should all patients have complied with current risk factor guideline recommendations. CONCLUSIONS: Computer modelling using routinely collected primary care data can be used to evaluate the effectiveness of primary care programs. However, there are some data availability and linkage limitations in the Australian setting. PMID- 26026782 TI - Adiponectin, leptin, interleukin-6 and HbA1c in the prediction of incident type 2 diabetes: A nested case-control study in Asian Indian men with impaired glucose tolerance. AB - AIMS: The aims of this study were: (1) to assess the association of adiponectin, leptin and interleukin-6 (IL-6) with incidence of type 2 diabetes (T2DM) in Asian Indian men with impaired glucose tolerance (IGT) and (2) to evaluate the additional contribution of these with the well-established glycaemic marker HbA1c. METHODS: This is an ancillary analyses of a nested case-control study derived from a prospective, prevention trial in India. All the participants had IGT at baseline. For this subanalysis a total of 147 (T2DM: 71; nondiabetic: 76) participants were selected based on the final glycemic outcomes. Association of these selected adipokines with T2DM were assessed using logistic regression analyses. Clinical usefulness of adding adipokine markers with HbA1c on prediction of T2DM was assessed using the area under the curve (AUC) of the receiver operating characteristics. RESULTS: Baseline levels of adiponectin were lower and the levels of IL-6 were higher in T2DM cases when compared with non diabetic cases (P<0.05). Levels of leptin were similar in both groups. In fully adjusted models, adiponectin (odds ratio (OR): 0.55 [95%CI: 0.33-0.91]; P=0.019) and IL-6 (OR: 2.27 [95%CI: 1.40-3.691]; P=0.001) were associated with diabetes. Addition of adiponectin to HbA1c improved the AUC (DeltaAUC: 0.0619; P=0.0251), whereas addition of IL-6 did not improve the predictive power of HbA1c alone. CONCLUSIONS: Adiponectin and IL-6 are independently associated with incident diabetes. However, they are unlikely to serve as simple tools to predict future risk of diabetes but may have a role in understanding the pathogenesis. PMID- 26026784 TI - Interactions among attention-deficit hyperactivity disorder (ADHD) and problem gambling in a probabilistic reward-learning task. AB - Problem gambling is thought to be highly comorbid with attention-deficit hyperactivity disorder (ADHD). We propose that the neurobiological pathologies underlying problem gambling overlap with those in ADHD. In this study, we used a simplified computerized version of the Iowa Gambling Task (IGT) to assess differences in reinforcement-driven choice adaptation among participants with pathological gambling and/or ADHD. The task contained two choice options with different net payouts over the session; a good bet that resulted in a win of +50 points on 60% of trials (and -50 points on 40%), and a bad bet that resulted in +100 points on 40% of the trials (and -100 points on 60%). We quantified participants' preference for the good bet over the session and their sensitivity to reinforcement. Both the control subjects and medicated ADHD nongamblers significantly increased the proportion of good bets over the 400-trial session. Subjects with problem gambling performed worse than controls and ADHD nongamblers, but better than our limited sample of unmedicated ADHD gamblers. Control subjects, medicated ADHD nongamblers, and unmedicated ADHD nongamblers tended to tolerate losses following good bets, whereas unmedicated ADHD gamblers tended to tolerate losses following bad bets. These data reveal that ADHD, particularly when treated with medication, is not associated with poor choices on the IGT, but may exacerbate pathological choices in problem gamblers. It seems that stabilization of dopamine signaling that occurs when ADHD is treated is itself also a treatment for certain forms of problem gambling. PMID- 26026783 TI - Examining the reinforcement-enhancement effects of phencyclidine and its interactions with nicotine on lever-pressing for a visual stimulus. AB - Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: (1) it produces discrepant results on overall reward, similar to that seen with nicotine and (2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances. PMID- 26026785 TI - Relationships among rat ultrasonic vocalizations, behavioral measures of striatal dopamine loss, and striatal tyrosine hydroxylase immunoreactivity at acute and chronic time points following unilateral 6-hydroxydopamine-induced dopamine depletion. AB - Voice deficits in Parkinson disease (PD) emerge early in the disease process, but do not improve with standard treatments targeting dopamine. Experimental work in the rat shows that severe and chronic unilateral nigrostriatal dopamine depletion with 6-OHDA results in decreased intensity, bandwidth, and complexity of ultrasonic vocalizations. However, it is unclear if mild/acute dopamine depletion, paralleling earlier stages of PD, results in vocalization deficits, or to what degree vocalization parameters are correlated with other dopamine dependent indicators of lesion severity or percent of tyrosine hydroxylase (%TH) loss. Here, we assayed ultrasonic vocalizations, forelimb asymmetry, and apomorphine rotations in rats with a range of unilateral dopamine loss resulting from 6-OHDA or vehicle control infusions to the medial forebrain bundle at acute (72 h) and chronic (4 weeks) time points post-infusion. The %TH loss was evaluated at 4 weeks. At 72 h, forelimb asymmetry and %TH loss were significantly correlated, while at 4 weeks, all measures of lesion severity were significantly correlated with each other. Call complexity was significantly correlated with all measures of lesion severity at 72 h but only with %TH loss at 4 weeks. Bandwidth was correlated with forelimb asymmetry at both time points. Duration was significantly correlated with all dopamine depletion measures at 4 weeks. Notably, not all parameters were affected universally or equally across time. These results suggest that vocalization deficits may be a sensitive index of acute and mild catecholamine loss and further underscores the need to characterize the neural mechanisms underlying vocal deficits in PD. PMID- 26026786 TI - Positive effects of beta-amyrin on pentobarbital-induced sleep in mice via GABAergic neurotransmitter system. AB - Sleep loss, insomnia, is considered a sign of imbalance of physiological rhythm, which can be used as pre-clinic diagnosis of various neuropsychiatric disorders. The aim of the present study is to understand the pharmacological actions of alpha- or beta-amyrin, natural triterpene compound, on the sleep in mice. To analyze the sleeping behavior, we used the well-known pentobarbital-induced sleeping model after single administration of either alpha- or beta-amyrin. The sleeping onset time was remarkably decreased and duration was prolonged by beta amyrin (1, 3, or 10mg/kg) but not by alpha-amyrin (1, 3, or 10mg/kg). These effects were significantly blocked by GABAA receptor antagonist, bicuculline. Moreover, beta-amyrin increased brain GABA level compared to the vehicle administration. Overall, the present study suggests that beta-amyrin would enhance the total sleeping behavior in pentobarbital-induced sleeping model via the activation of GABAergic neurotransmitter system through GABA content in the brain. PMID- 26026787 TI - Muscarinic, but not nicotinic, acetylcholine receptor blockade in the ventral tegmental area attenuates cue-induced sucrose-seeking. AB - The mesolimbic dopamine (DA) system is known to play a role in cue-mediated reward-seeking for natural rewards and drugs of abuse. Specifically, cholinergic and glutamatergic receptors in the ventral tegmental area (VTA) have been shown to regulate cue-induced drug-seeking. However, the potential role of these VTA receptors in regulating cue-induced reward seeking for natural rewards is unknown. Here, we examined whether blockade of VTA acetylcholine receptors (AChRs) and N-methyl-d-aspartate receptors (NMDARs) would alter cue-induced sucrose seeking in male Sprague-Dawley rats. Subjects underwent 10 days of sucrose self-administration training (fixed ratio 1 schedule) followed by 7 days of forced abstinence. On withdrawal day 7, rats received bilateral VTA infusion of vehicle, the muscarinic AChR antagonist scopolamine (2.4 or 24 MUg/side), the nicotinic AChR antagonist mecamylamine (3 or 30 MUg/side), or the NMDAR antagonist AP-5 (0.1 or 1 MUg/side) immediately prior to examination of cue induced sucrose-seeking. Scopolamine infusion led to robust attenuation, but did not completely block, sucrose-seeking behavior. In contrast, VTA administration of mecamylamine or AP-5 did not alter cue-induced sucrose-seeking. Together, the data suggest that VTA muscarinic AChRs, but not nicotinic AChRs nor NMDARs, facilitate the ability of food-associated cues to drive seeking behavior for a food reward. PMID- 26026788 TI - Inflammatory damage on respiratory and nervous systems due to hRSV infection. AB - The exacerbated inflammatory response elicited by human Respiratory Syncytial Virus (hRSV) in the lungs of infected patients causes a major health burden in the pediatric and elderly population. Since the discovery of hRSV, the exacerbated host immune-inflammatory response triggered by this virus has been extensively studied. In this article, we review the effects on the airways caused by immune cells and cytokines/chemokines secreted during hRSV infection. While molecules such as interferons contribute at controlling viral infection, IL-17 and others produce damage to the hRSV-infected lung. In addition to affecting the airways, hRSV infection can cause significant neurologic abnormalities in the host, such as seizures and encephalopathy. Although the origin of these symptoms remains unclear, studies from patients suffering neurological alteration suggest an involvement of the inflammatory response against hRSV. PMID- 26026789 TI - Pulp management after traumatic injuries with a tricalcium silicate-based cement (BiodentineTM): a report of two cases, up to 48 months follow-up. AB - BACKGROUND: Apexogenesis after traumatic exposure in vital young permanent teeth can be accomplished by implementing the appropriate vital pulp therapy such as pulp capping (direct or indirect) or pulpotomy (partial or complete) depending on the time between the trauma and treatment of the patient, degree of root development, and size of the pulp exposure. CASE REPORT: Two children with respectively 2 and 1 complicated enamel dentine fractures in immature permanent incisors were treated with new tricalcium silicate cement (BiodentineTM). The treatment plan in these cases was to maintain pulp vitality aiming for apexogenesis which allows continued root development along the entire root length. Endodontic management included partial pulpotomy or pulpotomy using BiodentineTM. Clinical and radiographical evaluation (up to 48 months) showed continual apexogenesis with no periodontal or periapical pathology. The appropriate restorations were functionally acceptable and aesthetically satisfying. The three traumatised teeth showed complete success both clinically (vitality and aesthetic outcome) as well as radiographically (apexogenesis and absence of pathological findings) after up to 48 months follow-up. CONCLUSION: BiodentineTM is a suitable alternative to MTA for vital pulpotomy in traumatised permanent incisors. It is also beneficial as a temporary filling without any risk of discolouration. PMID- 26026790 TI - A novel cell-containing device for regenerative medicine: biodegradable nonwoven filters with peripheral blood cells promote wound healing. AB - The efficacy of skin regeneration devices consisting of nonwoven filters and peripheral blood cells was investigated for wound healing. We previously found that human peripheral blood cells enhanced their production of growth factors, such as transforming growth factor beta1 (TGF-beta1) and vascular endothelial growth factor, when they were captured on nonwoven filters. Cells on biodegradable filters were expected to serve as a local supply of growth factors and cell sources when they were placed in wounded skin. Nonwoven filters made of biodegradable polylactic acid (PLA) were cut out as 13-mm disks and placed into cell-capturing devices. Mouse peripheral blood was filtered, resulting in PLA filters with mouse peripheral blood cells (m-PBCs) at capture rates of 65.8 +/- 5.2%. Then, the filters were attached to full-thickness surgical wounds in a diabetic db/db mouse skin for 14 days as a model of severe chronic wounds. The wound area treated with PLA nonwoven filters with m-PBCs (PLA/B+) was reduced to 8.5 +/- 12.2% when compared with day 0, although the non-treated control wounds showed reduction only to 60.6 +/- 27.8%. However, the PLA filters without m-PBCs increased the wound area to 162.9 +/- 118.7%. By histopathological study, the PLA/B+ groups more effectively accelerated formation of epithelium. The m-PBCs captured on the PLA filters enhanced keratinocyte growth factor (FGF-7) and TGF beta1 productions in vitro, which may be related to wound healing. This device is useful for regeneration of wounded skin and may be adaptable for another application. PMID- 26026791 TI - Diversifying selection and color-biased dispersal in the asp viper. AB - BACKGROUND: The presence of intraspecific color polymorphism can have multiple impacts on the ecology of a species; as a consequence, particular color morphs may be strongly selected for in a given habitat type. For example, the asp viper (Vipera aspis) shows a high level of color polymorphism. A blotched morph (cryptic) is common throughout its range (central and western Europe), while a melanistic morph is frequently found in montane populations, presumably for thermoregulatory reasons. Besides, rare atypical uniformly colored individuals are known here and there. Nevertheless, we found in a restricted treeless area of the French Alps, a population containing a high proportion (>50%) of such specimens. The aim of the study is to bring insight into the presence and function of this color morph by (i) studying the genetic structure of these populations using nine microsatellite markers, and testing for (ii) a potential local diversifying selection and (iii) differences in dispersal capacity between blotched and non-blotched vipers. RESULTS: Our genetic analyses support the occurrence of local diversifying selection for the non-blotched phenotype. In addition, we found significant color-biased dispersal, blotched individuals dispersing more than atypical individuals. CONCLUSION: We hypothesize that, in this population, the non-blotched phenotype possess an advantage over the typical one, a phenomenon possibly due to a better background matching ability in a more open habitat. In addition, color-biased dispersal might be partly associated with the observed local diversifying selection, as it can affect the genetic structure of populations, and hence the distribution of color morphs. PMID- 26026793 TI - The financial impact of intraoperative adverse events in abdominal surgery. AB - BACKGROUND: Little evidence currently exists regarding the clinical or financial impact of intraoperative adverse events (iAEs). We sought to study the additional health care charges attributable to the occurrence of an iAE. METHODS: The administrative and ACS-NSQIP databases at our tertiary academic medical center were linked for all patients undergoing abdominal surgery (January 2007-October 2012). The ICD-9-CM-based Patient Safety Indicator "accidental puncture/laceration" was used to screen the linked database for potential iAEs. All iAEs were confirmed subsequently through standardized review of all flagged medical records. Multivariate analyses controlling for demographics, comorbidities/laboratory values, procedure type, and approach and complexity of surgery were performed to assess the increase in health care charges independently predicted by the occurrence of iAEs. RESULTS: Of 9,111 patients, 183 were confirmed to have iAEs. Patients in the iAE group had higher median total charges ($27,169 [IQR, 17,302-44,952] vs $13,312 [IQR, 8,586-22,012]; P < .001), direct charges ($17,808 [IQR, 11,520-28,930] vs $8,738 [IQR, 5,686 14,227]; P < .001) and indirect charges ($9,396 [IQR, 5,932-16,144] vs $4,568 [IQR, 2,887-7,824]; P < .001) when compared with patients without iAEs. Multivariate analyses demonstrated that iAEs independently predict an increase in total hospitalization charges by 41% (95% CI, 30-52%; P < .001). Specifically, the direct, indirect, operating room, laboratory/radiology, and alimentation/medical therapy charges increased by 42, 39, 27, 54, and 48%, respectively (all P < .001). CONCLUSION: In addition to the morbidity incurred by patients, the occurrence of an iAE is associated with major additional health care charges. In an era of value-based health care, understanding and preventing iAEs can lead to major cost savings alongside improvements in patient safety and surgical quality. PMID- 26026794 TI - Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome. AB - Pyridoxine-dependent epilepsy (PDE) is an epileptic encephalopathy characterized by response to pharmacologic doses of pyridoxine. PDE is caused by deficiency of alpha-aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of alpha-aminoadipic semialdehyde. Despite adequate seizure control with pyridoxine monotherapy, 75% of individuals with PDE have significant developmental delay and intellectual disability. We describe a new combined therapeutic approach to reduce putative toxic metabolites from impaired lysine metabolism. This approach utilizes pyridoxine, a lysine restricted diet to limit the substrate that leads to neurotoxic metabolite accumulation and L-arginine to compete for brain lysine influx and liver mitochondrial import. We report the developmental and biochemical outcome of six subjects who were treated with this triple therapy. Triple therapy reduced CSF, plasma, and urine biomarkers associated with neurotoxicity in PDE. The addition of arginine supplementation to children already treated with dietary lysine restriction and pyridoxine further reduced toxic metabolites, and in some subjects appeared to improve neurodevelopmental outcome. Dietary lysine restriction was associated with improved seizure control in one subject, and the addition of arginine supplementation increased the objective motor outcome scale in two twin siblings, illustrating the contribution of each component of this treatment combination. Optimal results were noted in the individual treated with triple therapy early in the course of the disease. Residual disease symptoms could be related to early injury suggested by initial MR imaging prior to initiation of treatment or from severe epilepsy prior to diagnosis. This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the cognitive impairment in PDE. PMID- 26026796 TI - Anticancer compounds from cyanobacterium Lyngbya species: a review. AB - The use of synthetic anticancer drugs and other methods followed in cancer therapy have several side effects; and ineffective methods or drugs give a way to the emergence of drug resistant cancer cells, with the intrinsic metastasis as the aftermath. Anticancer efficacy of many cyanobacterial compounds has been claimed in literature. This review considers 144 compounds isolated and characterized from seven species of the non-nitrogen fixing filamentous cyanobacterium Lyngbya, as the source of antineoplastic agents, which have been screened primarily with cancer cell lines. Structure and information of Lyngbya compounds were retrieved from databases, PubChem, ChemSpider and ChEBI. Information and clinical status of Lyngbya compounds are summarized, and those might be the future anticancer drugs for drug-resistant cancer cells even, as complementary/adduct drugs, if pursued thoroughly in pharmacology and pharmaceutics. PMID- 26026797 TI - Actinospica durhamensis sp. nov., isolated from a spruce forest soil. AB - Seven acidophilic actinobacteria isolated from humus and mineral layers of a spruce forest soil were examined using a polyphasic approach. Chemotaxonomic properties of the isolates were found to be consistent with their classification in the genus Actinospica. The strains formed a distinct phyletic line in the Actinospica 16S rRNA gene tree being most closely related to Actinospica robiniae DSM 44927(T) (98.7-99.3 % similarity). DNA:DNA relatedness between isolate CSCA57(T) and the type strain of A. robiniae was found to be low at 40.8 (+/-6.6) %. The isolates were shown to have many phenotypic properties in common and were distinguished readily from the type strains of Actinospica acidiphila and A. robiniae using a range of phenotypic features. On the basis of these data the seven isolates were considered to represent a new species for which the name Actinospica durhamensis sp. nov. is proposed. The type strain of the species is CSCA 57(T) (=DSM 46820(T) = NCIMB 14953(T)). PMID- 26026798 TI - Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure. AB - The ketogenic diet is known to have an anti-epileptic effect; in fact it is currently used to treat drug resistant epilepsies. The efficacy of this diet is thought to be correlated to the elevation of blood ketone bodies. Because of problems with compliance to this diet, there is an interest in evaluating alternative pharmacological treatments that can have anti-seizure effects by elevating ketone bodies. In the present experiment, an orally administered synthetic ketone ester (R,S - 1,3-butanediol acetoacetate diester, or BD-AcAc2) was evaluated for its anti-seizure efficacy in a rat model. The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats two hours after a single 1 ml intragastric administration of BD-AcAc2 (i.e. 4 g/kg b.w., treated group) or water (control group). After correction for the dose of anesthetic, the results showed that the administration of BD-AcAc2 induced an elevation of the PTZ threshold (140 +/- 11 mg/kg for the treated group, 122 +/- 6 mg/kg for the control group), along with an increased level of blood beta-hydroxybutyrate (2.7 +/- 0.3mM for the treated group, 1.4 +/- 0.1mM for the control group). This result suggests that ketone esters may pave the road towards the establishment of a "ketogenic diet in a pill". PMID- 26026795 TI - Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease. AB - PURPOSE: 3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS). METHODS: Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals. RESULTS: Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients' fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals. CONCLUSION: We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy C4-carnitine found in the retrospective analysis of our patient's NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS. PMID- 26026800 TI - Together nurses have a renewed focus on ethical issues. PMID- 26026792 TI - Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. AB - Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2 ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2 positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans. PMID- 26026799 TI - Evaluation of cell responses toward adhesives with different photoinitiating systems. AB - OBJECTIVES: The photoinitiator diphenyl-(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) is more reactive than a camphorquinone/amine (CQ) system, and TPO-based adhesives obtained a higher degree of conversion (DC) with fewer leached monomers. The hypothesis tested here is that a TPO-based adhesive is less toxic than a CQ-based adhesive. METHODS: A CQ-based adhesive (SBU-CQ) (Scotchbond Universal, 3M ESPE) and its experimental counterpart with TPO (SBU-TPO) were tested for cytotoxicity in human pulp-derived cells (tHPC). Oxidative stress was analyzed by the generation of reactive oxygen species (ROS) and by the expression of antioxidant enzymes. A dentin barrier test (DBT) was used to evaluate cell viability in simulated clinical circumstances. RESULTS: Unpolymerized SBU-TPO was significantly more toxic than SBU-CQ after a 24h exposure, and TPO alone (EC50=0.06mM) was more cytotoxic than CQ (EC50=0.88mM), EDMAB (EC50=0.68mM) or CQ/EDMAB (EC50=0.50mM). Cultures preincubated with BSO (l-buthionine sulfoximine), an inhibitor of glutathione synthesis, indicated a minor role of glutathione in cytotoxic responses toward the adhesives. Although the generation of ROS was not detected, a differential expression of enzymatic antioxidants revealed that cells exposed to unpolymerized SBU-TPO or SBU-CQ are subject to oxidative stress. Polymerized SBU-TPO was more cytotoxic than SBU-CQ under specific experimental conditions only, but no cytotoxicity was detected in a DBT with a 200MUm dentin barrier. SIGNIFICANCE: Not only DC and monomer-release determine the biocompatibility of adhesives, but also the cytotoxicity of the (photo-)initiator should be taken into account. Addition of TPO rendered a universal adhesive more toxic compared to CQ; however, this effect could be annulled by a thin dentin barrier. PMID- 26026801 TI - Caregiving tasks and caregiver burden; effects of an psycho-educational intervention in partners of patients with post-operative heart failure. AB - OBJECTIVE: To evaluate the effects of a psycho-educational intervention on caregiver burden in partners of patients with postoperative heart failure. BACKGROUND: Since partners of cardiac surgery patients play a significant role in the patient's recovery, it is important to address their needs during hospitalization and after discharge. METHODS: Forty-two patients with postoperative heart failure and their partners participated in a randomized controlled pilot study. Dyads in the intervention group received psycho educational support from a multidisciplinary team. Dyads in the control group received usual care. RESULTS: No significant differences were found in the performance of caregiving tasks and perceived caregiver burden in the control versus the intervention group. CONCLUSION: A pilot study exploring the effects of a psycho-educational intervention in patients and their partners did not reveal significant effects with regard to reduced feelings of burden in partners. Alleviating caregiver burden in partners may need a more intense or specific approach. PMID- 26026802 TI - Effect of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of classical antiepileptic drugs against maximal electroshock-induced seizures in mice. AB - The effects of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Results indicate that xanthotoxin (50 and 100 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures (P<0.05 and P<0.001, respectively). Similarly, xanthotoxin (100 mg/kg, i.p.) markedly enhanced the anticonvulsant action of valproate in the maximal electroshock seizure test (P<0.001). In contrast, xanthotoxin (100 mg/kg, i.p.) did not affect the protective action of phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Moreover, xanthotoxin (100 mg/kg, i.p.) significantly increased total brain concentrations of carbamazepine (P<0.001) and valproate (P<0.05), but not those of phenytoin and phenobarbital, indicating pharmacokinetic nature of interactions between drugs. In conclusion, the combinations of xanthotoxin with carbamazepine and valproate, despite their beneficial effects in terms of seizure suppression in mice, were probably due to a pharmacokinetic increase in total brain concentrations of these antiepileptic drugs in experimental animals. PMID- 26026803 TI - Little-known Aspects in Hypertrophic Cardiomyopathy. PMID- 26026804 TI - Comments on the Long-term Prognosis of Patients With Non-ST-segment Elevation Acute Myocardial Infarction and Coronary Arteries Without Significant Stenosis. PMID- 26026805 TI - Impact on survival of the number of lymph nodes resected in patients with lymph node-negative gastric cancer. AB - BACKGROUND: Patients with lymph node-negative gastric cancer show a better overall survival rate than those who have a pathological lymph node-positive gastric cancer. But a large number of patients still develop recurrence. We aimed to explore the significant prognostic factors of lymph node-negative gastric cancer and determine how many lymph nodes should be removed. METHODS: A total of 3103 patients who underwent radical operation are identified from the Surveillance, Epidemiology, and End Results database. Standard survival methods and restricted multivariable Cox regression models were applied. RESULTS: The overall survival rate was significantly higher with an increasing number of negative lymph node resected. Among the 843 patients who had the exact T stage, the overall survival rate was significantly better in T3-4 group with more than 15 lymph nodes resected (P < 0.001) but not in T1-2 stage patients (P = 0.44). A further 25 more lymph nodes resection did not show additional survival benefits. Multivariate analysis of patients demonstrated that age, depth of tumor invasion, and the number of lymph nodes resected were the significant and independent prognostic factors. CONCLUSIONS: A lymphadenectomy with more than 15 lymph nodes removal should be performed for T3-4 lymph node-negative gastric cancer. But the survival benefit of a lymphadenectomy with more than 25 lymph nodes removal is disputed. And the further treatment should refer to the prognostic indicators. PMID- 26026806 TI - Rhoptry-associated protein (rap-1) genes in the sheep pathogen Babesia sp. Xinjiang: Multiple transcribed copies differing by 3' end repeated sequences. AB - Sheep babesiosis occurs mainly in tropical and subtropical areas. The sheep parasite Babesia sp. Xinjiang is widespread in China, and our goal is to characterize rap-1 (rhoptry-associated protein 1) gene diversity and expression as a first step of a long term goal aiming at developing a recombinant subunit vaccine. Seven different rap-1a genes were amplified in Babesia sp. Xinjiang, using degenerate primers designed from conserved motifs. Rap-1b and rap-1c gene types could not be identified. In all seven rap-1a genes, the 5' regions exhibited identical sequences over 936 nt, and the 3' regions differed at 28 positions over 147 nt, defining two types of genes designated alpha and beta. The remaining 3' part varied from 72 to 360 nt in length, depending on the gene. This region consists of a succession of two to ten 36 nt repeats, which explains the size differences. Even if the nucleotide sequences varied, 6 repeats encoded the same stretch of amino acids. Transcription of at least four alpha and two beta genes was demonstrated by standard RT-PCR. PMID- 26026807 TI - Independent effects of reward expectation and spatial orientation on the processing of emotional facial expressions. AB - The present study investigated the effect of reward expectation and spatial orientation on the processing of emotional facial expressions, using a spatial cue-target paradigm. A colored cue was presented at the left or right side of the central fixation point, with its color indicating the monetary reward stakes of a given trial (incentive vs. non-incentive), followed by the presentation of an emotional facial target (angry vs. neutral) at a cued or un-cued location. Participants were asked to discriminate the emotional expression of the target, with the cue-target stimulus onset asynchrony being 200-300 ms in Experiment 1 and 950-1250 ms in Experiment 2a (without a fixation cue) and Experiment 2b (with a fixation cue), producing a spatial facilitation effect and an inhibition of return effect, respectively. The results of all the experiments revealed faster reaction times in the monetary incentive condition than in the non-incentive condition, demonstrating the effect of reward to facilitate task performance. An interaction between reward expectation and the emotion of the target was evident in all the three experiments, with larger reward effects for angry faces than for neutral faces. This interaction was not affected by spatial orientation. These findings demonstrate that incentive motivation improves task performance and increases sensitivity to angry faces, irrespective of spatial orienting and reorienting processes. PMID- 26026808 TI - The configural properties of task stimuli do influence vigilance performance. AB - Sixty-one participants performed a sustained attention task in which they were required to respond to a critical signal requiring feature discrimination. Three separate groups performed the task with different global display configurations. The local feature elements (directional arrow shapes) were displayed on either a circle, a circle broken apart or a reconnected figure. For two of the groups, the entire display consisted of a clear global shape (circle and reconnected), and for one of the groups, the display had no discernible global element (broken circle) despite the critical signal being the same for all the groups. Analyses of hit rate and A' scores indicated that the broken circle group had impaired performance compared to the global figure groups. A configural superiority effect was found in which performance was improved by having a global shape property to the entire display. These results provide a behavioural base for further research utilizing measures of cerebral activation, as cerebral activity during vigilance tasks may be dependent on both task difficulty and hierarchical aspects of the display. The configurable or hierarchical aspects of vigilance displays may be critical in understanding sustained attention performance and its hemispheric lateralization. PMID- 26026809 TI - Hand position influences perceptual grouping. AB - Over the past decade, evidence has accumulated that performance in attention, perception, and memory-related tasks are influenced by the distance between the hands and the stimuli (i.e., placing the observer's hands near or far from the stimuli). To account for existing findings, it has recently been proposed that processing of stimuli near the hands is dominated by the magnocellular visual pathway. The present study tests an implication of this hypothesis, whether perceptual grouping is reduced in hands-proximal space. Consistent with previous work on the object-based capture of attention, a benefit for the visual object in the hands-distal condition was observed in the present study. Interestingly, the object-based benefit did not emerge in the hands-proximal condition, suggesting perceptual grouping is impaired near the hands. This change in perceptual grouping processes provides further support for the hypothesis that visual processing near the hands is subject to increased magnocellular processing. PMID- 26026810 TI - Reduced motor preparation during dual-task performance: evidence from startle. AB - Previous studies have used a secondary probe reaction time (RT) task to assess attentional demands of a primary task. The current study used a startling acoustic stimulus (SAS) in a probe RT paradigm to test the hypothesis that attentional resources would be directly related to limitations in response preparation. Participants performed an easy or difficult version of a continuous primary task that was either primarily motor in nature (pursuit tracking) or cognitive (counting backward). Concurrently, participants responded to an auditory cue as fast as possible by performing a wrist extension secondary movement. On selected trials, the auditory cue was replaced with a SAS (120 dB), which is thought to involuntarily trigger a prepared response and thus bypass any response initiation bottleneck that may be present when trying to perform two movements. Although startle trials were performed at a shorter latency, both non startle and startle probe trials resulted in a delayed RT, as compared to single task trials, consistent with reduced preparation of the secondary task. In addition, analysis of SAS trial RT when a startle indicator was present versus absent provided evidence that the secondary task was at a lowered state of preparation when engaged in the cognitive primary task as compared to a motor primary task, suggesting a facilitative effect on preparatory activation when both the primary and secondary tasks are motoric in nature. PMID- 26026811 TI - Results of the modified bi-pectoral muscle flap procedure for post-sternotomy deep wound infection. AB - PURPOSE: Post-sternotomy deep sternal wound infection (DSWI) is a severe complication of cardiac surgery. The introduction of omental and muscle flaps has resulted in a significant decrease in morbidity and mortality. In this article, we present the findings for a series of 55 consecutive patients with DSWI treated using an alternative bi-pectoral musculofascial flap technique. METHODS: The patients were stratified into two groups (one-or two-stage intervention). Patients with septic wounds initially underwent debridement and wound treatment, while vacuum therapy was used in a subset of the subjects. All patients were treated with wound debridement and bi-pectoral advancement flap reconstruction. RESULTS: 30-day mortality was 5.4%. Most patients (72%) were treated in two stages, while vacuum therapy was used in 20% of the patients. The mean number of hospitalization days was 8 and 12 for the one- and the two-stage groups, respectively. Reconstruction was successful in all but three patients, each of whom developed recurrent infection. No major morbidity was reported at a mean follow-up of 82 months with excellent functional and aesthetic outcomes. CONCLUSIONS: Pectoralis-major muscle flaps remain relevant in the modern management of post-sternotomy mediastinitis. The addition of an omental flap should be considered in cases in which the lower sternum is involved. Prompt diagnosis and a meticulous surgical technique ensure favorable results for the majority of patients. PMID- 26026812 TI - [Universal cytomegalovirus infection screening in premature newborns less than 1,500 g]. PMID- 26026813 TI - Visuotactile motion congruence enhances gamma-band activity in visual and somatosensory cortices. AB - When touching and viewing a moving surface our visual and somatosensory systems receive congruent spatiotemporal input. Behavioral studies have shown that motion congruence facilitates interplay between visual and tactile stimuli, but the neural mechanisms underlying this interplay are not well understood. Neural oscillations play a role in motion processing and multisensory integration. They may also be crucial for visuotactile motion processing. In this electroencephalography study, we applied linear beamforming to examine the impact of visuotactile motion congruence on beta and gamma band activity (GBA) in visual and somatosensory cortices. Visual and tactile inputs comprised of gratings that moved either in the same or different directions. Participants performed a target detection task that was unrelated to motion congruence. While there were no effects in the beta band (13-21Hz), the power of GBA (50-80Hz) in visual and somatosensory cortices was larger for congruent compared with incongruent motion stimuli. This suggests enhanced bottom-up multisensory processing when visual and tactile gratings moved in the same direction. Supporting its behavioral relevance, GBA was correlated with shorter reaction times in the target detection task. We conclude that motion congruence plays an important role for the integrative processing of visuotactile stimuli in sensory cortices, as reflected by oscillatory responses in the gamma band. PMID- 26026814 TI - Reproducibility of multiphase pseudo-continuous arterial spin labeling and the effect of post-processing analysis methods. AB - Arterial spin labeling (ASL) is an emerging MRI technique for non-invasive measurement of cerebral blood flow (CBF). Compared to invasive perfusion imaging modalities, ASL suffers from low sensitivity due to poor signal-to-noise ratio (SNR), susceptibility to motion artifacts and low spatial resolution, all of which limit its reliability. In this work, the effects of various state of the art image processing techniques for addressing these ASL limitations are investigated. A processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, partial volume effect correction, and CBF quantification was developed and assessed. To further improve the SNR for pseudo-continuous ASL (PCASL) by accounting for errors in tagging efficiency, the data from multiphase (MP) acquisitions were analyzed using a novel weighted-averaging scheme. The performances of each step in terms of SNR and reproducibility were evaluated using test-retest ASL data acquired from 12 young healthy subjects. The proposed processing pipeline was shown to improve the within-subject coefficient of variation and regional reproducibility by 17% and 16%, respectively, compared to CBF maps computed following motion correction but without the other processing steps. The CBF measurements of MP PCASL compared to PCASL had on average 23% and 10% higher SNR and reproducibility, respectively. PMID- 26026815 TI - Predictions to motion stimuli in human early visual cortex: Effects of motion displacement on motion predictability. AB - Recently, several studies showed that fMRI BOLD responses to moving random dot stimuli are enhanced at the location of dot appearance, i.e., the motion trailing edge. Possibly, BOLD activity in human visual cortex reflects predictability of visual motion input. In the current study, we investigate to what extent fMRI BOLD responses reflect estimated predictions to visual motion. We varied motion displacement parameters (duration and velocity), while measuring BOLD amplitudes as a function of distance from the trailing edge. We have found that for all stimulus configurations, BOLD signals decrease with increasing distance from the trailing edge. This finding indicates that neural activity directly reflects the predictability of moving dots, rather than their appearance within classical receptive fields. However, different motion displacement parameters exerted only marginal effects on predictability, suggesting that early visual cortex does not literally predict motion trajectories. Rather, the results reveal a heuristic mechanism of motion suppression from trailing to leading edge, plausibly mediated through short-range horizontal connections. Simple heuristic suppression allows the visual system to recognize novel input among many motion signals, while being most energy efficient. PMID- 26026816 TI - Mapping cortical responses to speech using high-density diffuse optical tomography. AB - The functional neuroanatomy of speech processing has been investigated using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) for more than 20years. However, these approaches have relatively poor temporal resolution and/or challenges of acoustic contamination due to the constraints of echoplanar fMRI. Furthermore, these methods are contraindicated because of safety concerns in longitudinal studies and research with children (PET) or in studies of patients with metal implants (fMRI). High-density diffuse optical tomography (HD-DOT) permits presenting speech in a quiet acoustic environment, has excellent temporal resolution relative to the hemodynamic response, and provides noninvasive and metal-compatible imaging. However, the performance of HD-DOT in imaging the brain regions involved in speech processing is not fully established. In the current study, we use an auditory sentence comprehension task to evaluate the ability of HD-DOT to map the cortical networks supporting speech processing. Using sentences with two levels of linguistic complexity, along with a control condition consisting of unintelligible noise vocoded speech, we recovered a hierarchically organized speech network that matches the results of previous fMRI studies. Specifically, hearing intelligible speech resulted in increased activity in bilateral temporal cortex and left frontal cortex, with syntactically complex speech leading to additional activity in left posterior temporal cortex and left inferior frontal gyrus. These results demonstrate the feasibility of using HD-DOT to map spatially distributed brain networks supporting higher-order cognitive faculties such as spoken language. PMID- 26026817 TI - Extent of pelvic lymph node dissection in penile cancer may impact survival. AB - INTRODUCTION: Current guidelines on management of penile carcinoma (PC) recommend ipsilateral pelvic lymph node dissection (PLND) in patients with inguinal lymph node metastasis (LNM) who meet specific criteria. The aim of this article was to assess outcomes in patients treated with bilateral PLND in the presence of unilateral metastatic pelvic nodes. METHODS: After IRB approval, four international centers contributed to this study. Men with PC and unilateral inguinal LNM and pelvic node metastases were retrospectively analyzed. Estimates of overall survival (OS) and cancer-specific survival were provided by the Kaplan Meier method. Comparisons between subgroups were made using the log-rank test, and Cox regression analysis was used to adjust comparisons for covariates of interest. RESULTS: From 1978 to 2012, fifty-one men with unilateral inguinal LNM and positive pelvic nodes on PLND were identified. Thirty-eight (75 %) had ipsilateral and 13 (25 %) had bilateral PLND. Except the extent of the PLND, patients were comparable with respect to disease and therapeutic interventions. The Kaplan-Meier estimated median OS was significantly longer in the bilateral PLND patients (21.7 vs. 13.1, p = 0.051). On Cox regression analysis, bilateral PLND [HR 0.25, (95 % CI 0.10-0.64)], multiple pelvic node involvement [HR 2.12 (95 % CI 1.02-4.43)], neoadjuvant chemotherapy [HR 0.01, (95 % CI 0.02-0.44)] and adjuvant therapies [HR 0.16, (95 % CI 0.06-0.45)] (compared to no additional therapy) were independent predictors of OS. CONCLUSIONS: Men with PC and pelvic node metastases may benefit from a bilateral PLND. This hypothesis requires further confirmation. PMID- 26026818 TI - Efficacy and safety of a new device for intravesical thermochemotherapy in non grade 3 BCG recurrent NMIBC: a phase I-II study. AB - PURPOSE: We report for the first time the activity and safety of Unithermia((r)) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia((r)) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia((r)) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC. PMID- 26026819 TI - Activation of human inspiratory muscles in an upside-down posture. AB - During quiet breathing, activation of obligatory inspiratory muscles differs in timing and magnitude. To test the hypothesis that this coordinated activation can be modified, we determined the effect of the upside-down posture compared with standing and lying supine. Subjects (n=14) breathed through a pneumotachometer with calibrated inductance bands around the chest wall and abdomen. Surface electromyographic activity (EMG) was recorded from the scalene muscles. Crural diaphragmatic EMG and oesophageal and gastric pressures were measured in a subset of six subjects. Quiet breathing and standard lung function manoeuvres were performed. The upside-down posture reduced end-expiratory lung volume. During quiet breathing, for the same inspiratory airflow and tidal volume, ribcage contribution decreased, abdominal contribution increased and transdiaphragmatic pressure swing doubled in the upside-down posture compared to standing (p<0.05). Despite this, crural diaphragm EMG was unchanged, whereas scalene muscle EMG was reduced by ~half (p<0.05). Thus, the mechanical effect of an upside-down posture differentially affects inspiratory muscle activation. PMID- 26026820 TI - The role of CCN family genes in haematological malignancies. AB - Haematological malignancies, although a broad range of specific disease types, continue to show considerable overlap in classification, and patients are treated using similar chemotherapy regimes. In this review we look at the role of the CCN family of matricellular proteins and indicate their role in nine haematological malignancies including both myeloid and lymphoid neoplasms. The potential for further haematological neoplasms with CCN family associations is argued by summarising the demonstrated role of CCN family genes in the differentiation of haematopoietic stem cells (HSC) and mesenchymal stem cells. The expanding field of knowledge encompassing CCN family genes and cancers of the HSC-lineage highlights the importance of extracellular matrix-interactions in both normal physiology and tumorigenesis of the blood, bone marrow and lymph nodes. PMID- 26026821 TI - Vaginal Radical Trachelectomy for early stage cervical cancer. Results of the Danish National Single Center Strategy. AB - OBJECTIVE: To present and evaluate an unselected national single center strategy with fertility preserving trachelectomy in cervical cancer. In 2003 nationwide single-center referral of women for trachelectomies was agreed upon between all Danish departments performing cervical cancer surgery with the purpose of increasing volume, to increase surgical safety and facilitate follow-up. METHODS: Prospective data were recorded in the Danish Gynecological Cancer Database of all Vaginal Radical Trachelectomies (VRT) performed in Denmark between 2002 and 2013. Oncologic, fertility and obstetrical outcomes of 120 unselected consecutive VRTs were assessed. To obtain complete follow-up about fertility treatment, pregnancy and obstetric outcome the women filled out an electronic questionnaire. Median follow-up: 55.7 months. RESULTS: 85.8% of the patients had stage IB1 disease, 68.3% squamous cell carcinomas, 30.0% adenocarcinomas and 1.7% adenosquamous carcinomas. Six recurrences (5.1%) and 2 deaths (1.7%) occurred. Four women with adenocarcinomas (10.5%) had recurrences, compared to two women with squamous cell carcinomas (2.5%). Seventy-two women (60.0%) desired to conceive and 55 women obtained a total of 77 pregnancies. Of the 72 women 40 were referred to fertility treatment. First and second trimester miscarriage rates were 21.6% and 2.7%, respectively. A total of 53 children were born of which 41 were delivered after gestational week 34. CONCLUSION: This unselected national single center referral study confirms the oncological safety of Vaginal Radical Trachelectomy. The complete follow-up regarding reproductive data, reveals a surprisingly extensive need of fertility treatment and due to the rate of prematurity, these pregnancies must be regarded as high-risk pregnancies. PMID- 26026822 TI - An outbreak of joint and cutaneous infections caused by non-tuberculous mycobacteria after corticosteroid injection. AB - OBJECTIVES: An outbreak of joint and cutaneous infections among patients who had been injected at a single clinic in South Korea was investigated. METHODS: In this retrospective case-control study, 61 cases were diagnosed based on symptoms and signs of septic arthritis or cutaneous infection that developed after injections at the clinic between April and September 2012; 64 controls were investigated by administering questionnaires on risk factors and analyzing the clinic medical records. An environmental investigation was performed, and clinical specimens of the cases were analyzed by pulsed-field gel electrophoresis. RESULTS: All cases were injected with triamcinolone. A greater number of triamcinolone injections (adjusted odds ratio 4.3, 95% confidence interval 1.5-12.1 for six or more visits, compared with one or two visits) was associated with the development of an infection. In the clinic, only the triamcinolone injection was prepared by mixing with lidocaine and normal saline, and an alcohol swab was prepared using boiled tap water by members of the clinic staff. Although injected medications and environmental cultures were not found to be responsible, a single strain of Mycobacterium massiliense was isolated from the affected sites of 16 cases. CONCLUSIONS: Repeated injection of triamcinolone contaminated with NTM from the clinic environment may have caused this post injection outbreak. PMID- 26026823 TI - Clinical significance of serotype V among infants with invasive group B streptococcal infections in South Korea. AB - BACKGROUND: Group B Streptococcus (GBS) strains are classified by the polysaccharide capsule, which is an important virulence factor and stimulator of antibody-associated immunity. As GBS infections in neonates may be life threatening, GBS screening and intrapartum antibiotic prophylaxis have been implemented for prevention. In Korea, there are few reports on the GBS serotype distribution and antibiotic resistance patterns because GBS screening and intrapartum prophylaxis are not done routinely. METHODS: The serotype distribution and antibiotic resistance of GBS in infants in Korea with invasive bacterial infections were examined for the 19-year period 1995-2013. Isolates obtained previously from hospitals located in three different regions were analyzed for capsular serotype by PCR and sequencing and for antimicrobial susceptibility. RESULTS: Among 56 isolates serotyped, the most common serotypes were III (44.6%) and V (28.6%), followed by Ia (14.3%), Ib (10.7%), and VI (1.8%). No penicillin-resistant strains were detected, however 51.8% of the strains had resistance to erythromycin and 55.4% showed clindamycin resistance. Resistance was highest (93.8%) to both erythromycin and clindamycin for serotype V; all 15 isolates resistant to erythromycin were cMLSB phenotype and had a high level of resistance to both erythromycin and clindamycin with MIC levels >256MUg/ml, and all but one were positive for ermB. CONCLUSION: In this study in Korea, serotype V was identified in a relatively large proportion of GBS isolates and this serotype showed a high level of resistance to erythromycin and clindamycin in a statistically significant majority. Continuous monitoring of changes in clinical disease and molecular characteristics is important for the treatment and prevention of invasive GBS disease in infants. PMID- 26026824 TI - Inclusion of social media-based strategies in a health care worker influenza immunization campaign. PMID- 26026825 TI - Blood culture contamination rate in an intensive care setting: Effectiveness of an education-based intervention. AB - BACKGROUND: Blood culture (BC) contamination rate is an indicator of quality of care scarcely explored in intensive care units (ICUs). We analyzed the BC contamination rate in our ICU to assess the effectiveness of an education-based intervention. METHODS: We conducted an interventional study with concurrent controls. Consecutive BCs drawn during a 6-month period were included. An education-based intervention was presented to case nurses (optimal technique). The remaining nurses comprised the control group (standard technique). Two independent observers assessed clinical significance of saprophytic skin bacteria isolated in BCs. RESULTS: Six hundred fifty-six BCs were obtained: 308 (47%) via optimal technique and 348 (53%) via standard technique (47%). One hundred eighty seven BCs were positive for saprophytic microorganisms; 127 (89%) were considered unrelated to infection. Coagulase-negative staphylococci isolation was lower in the optimal technique group (14% vs 26%; P < .001), as well as contamination due to coagulase-negative staphylococci (12% vs 21%; P = .002) or Acinetobacter baumannii (0.3% vs 2%; P = .013). BC contamination rate was 13% in the optimal technique group versus 23% in the standard group (P < .005). In the optimal technique group, BC contamination rate was higher in BCs drawn through the catheter (17% vs 7%; P = .028). CONCLUSIONS: An education-based intervention significantly reduced the BC contamination rate in our ICU. It seems necessary to design a tool to extract BCs through the catheter to minimize the risk of contamination. PMID- 26026826 TI - Central line-associated bloodstream infections in Australian intensive care units: Time-trends in infection rates, etiology, and antimicrobial resistance using a comprehensive Victorian surveillance program, 2009-2013. AB - BACKGROUND: The epidemiology of central line-associated bloodstream infections (CLABSI) in Australian intensive care units (ICUs) has not previously been reported. We sought to describe time-trends in CLABSI rates, infections by ICU peer-groups, etiology, and antimicrobial susceptibility of pathogens in a large cohort of Australian ICUs for the period January 1, 2009-December 31, 2013. METHODS: Using National Healthcare Safety Network methods, CLABSI surveillance in adult patients was performed by hospitals participating in the Victorian Healthcare Associated Infection Surveillance System (n = 29). Hospitals were grouped by location, sector, and teaching status. RESULTS: Overall, 384 CLABSI events were reported over 303,968 central venous catheter (CVC)-days, corresponding to a rate of 1.26/1,000 CVC-days (95% confidence interval, 1.14 1.40). Every 1-year increase was associated with a 26% reduction in CLABSI risk (risk ratio, 0.74, 95% confidence interval, 0.69-0.80; P < .001). The most frequently identified pathogens were Enterococcus spp (26.3%), followed by Candida spp (15.4%) and Staphylococcus aureus (13.3%). CLABSI due to Enterococcus spp, S aureus, and coagulase-negative Staphylococcus spp displayed significant reductions over time. CONCLUSIONS: Internationally accepted surveillance methods have been employed in Australia, demonstrating CLABSI rates comparable to medical/surgical ICUs in the United States and a reduction in pathogen-specific infections over a 5-year period. PMID- 26026828 TI - Identifying the psychological determinants of handwashing: Results from two cross sectional questionnaire studies in Haiti and Ethiopia. AB - BACKGROUND: Diarrheal disease kills around 760,000 infants every year. Many of these deaths could have been prevented by handwashing with soap. However, the whole range of psychological factors encouraging handwashing is not yet identified and handwashing campaigns are often limited to awareness-raising and education. The purpose of this article was to identify the psychological determinants of handwashing in Haiti (study 1) and Ethiopia (study 2). METHODS: Data were collected cross-sectionally by administering face-to-face interviews with the primary caregiver in a participating household (NHaiti = 811; NEthiopia = 463). Hierarchical multiple regression analyses were performed on self-reported handwashing. RESULTS: In both countries, risk factors-meaning awareness and health knowledge-accounted for only 11%-19% of variance in handwashing and were not consistently associated with handwashing. The inclusion of additional factor groups, namely attitude, norm, ability, and self-regulation factors, led to significant increases in explained variance (P <= .01), accounting for 25%-44% of additionally explained variance. The attitude factor disgust, the norm factor, the ability factors motivational self-efficacy and perceived impediments, and the self-regulation factors coping planning and commitment emerged as especially relevant. CONCLUSIONS: Handwashing campaigns should focus especially on attitudes and norms and not only on risk. PMID- 26026827 TI - Norovirus prevention and the prevalence of asymptomatic norovirus infection in kindergartens and primary schools in Changzhou, China: Status of the knowledge, attitudes, behaviors, and requirements. AB - BACKGROUND: We estimated the status of norovirus infection and prevention in kindergartens and primary schools and identified poor areas for which future education is needed. We evaluated the knowledge, attitude, behavior, requirements of outbreak prevention, and rate of asymptomatic carriers. METHODS: Two self administered questionnaires were conducted for data collection. Five hundred seventy-four teachers from kindergartens and primary schools and 3,114 students from primary schools in Changzhou city were sampled for questionnaire investigation. In addition, 511 rectal swabs from healthy children were taken for norovirus detection. RESULTS: Twenty-one of 511 children were asymptomatically infected with norovirus. The rate of asymptomatic norovirus infection children in kindergartens was 2.7% and 4.7% in primary schools. Nineteen of 21 positive samples were GII strains, the other 2 were GI strains. In addition, we found that primary schools were less prepared to prevent norovirus outbreaks than kindergartens. Settings in the suburban counties needed more education on norovirus prevention. CONCLUSIONS: The results of this study emphasize the need for training of primary schools and suburban schools about norovirus prevention. Asymptomatic norovirus infection should receive more attention. PMID- 26026829 TI - Stickers used for the identification of intravenous lines could be a portal of entry of microorganisms through the catheter: Results from a clinical study. AB - We evaluated the colonization of stickers used to identify intravenous access lines in a clinical practice setting. We isolated the same microorganisms in colonized catheters and on the stickers in 77.8% of cases. Therefore, stickers could be a portal of entry of microorganisms through the catheter. Alternative methods for labeling intravenous lines are required. PMID- 26026830 TI - Identification of lung cancer miRNA-miRNA co-regulation networks through a progressive data refining approach. AB - Co-regulations of miRNAs have been much less studied than the research on regulations between miRNAs and their target genes, although these two problems are equally important for understanding the entire mechanisms of complex post transcriptional regulations. The difficulty to construct a miRNA-miRNA co regulation network lies in how to determine reliable miRNA pairs from various resources of data related to the same disease such as expression levels, gene ontology (GO) databases, and protein-protein interactions. Here we take a novel integrative approach to the discovery of miRNA-miRNA co-regulation networks. This approach can progressively refine the various types of data and the computational analysis results. Applied to three lung cancer miRNA expression data sets of different subtypes, our method has identified a miRNA-miRNA co-regulation network and co-regulating functional modules common to lung cancer. An example of these functional modules consists of genes SMAD2, ACVR1B, ACVR2A and ACVR2B. This module is synergistically regulated by let-7a/b/c/f, is enriched in the same GO category, and has a close proximity in the protein interaction network. We also find that the co-regulation network is scale free and that lung cancer related miRNAs have more synergism in the network. According to our literature survey and database validation, many of these results are biologically meaningful for understanding the mechanism of the complex post-transcriptional regulations in lung cancer. PMID- 26026831 TI - Objects and processes: Two notions for understanding biological information. AB - In spite of being ubiquitous in life sciences, the concept of information is harshly criticized. Uses of the concept other than those derived from Shannon's theory are denounced as metaphoric. We perform a computational experiment to explore whether Shannon's information is adequate to describe the uses of said concept in commonplace scientific practice. Our results show that semantic sequences do not have unique complexity values different from the value of meaningless sequences. This result suggests that quantitative theoretical frameworks do not account fully for the complex phenomenon that the term "information" refers to. We propose a restructuring of the concept into two related, but independent notions, and conclude that a complete theory of biological information must account completely not only for both notions, but also for the relationship between them. PMID- 26026832 TI - Seaweed on the Beach: Reducing the Burden of Healthcare Waste. PMID- 26026833 TI - The role of a phospholipase (PLD) in virulence of Purpureocillium lilacinum (Paecilomyces lilacinum). AB - Phospholipases are key enzymes in pathogenic fungi that cleave host phospholipids, resulting in membrane destabilization and host cell penetration. However, understanding the role of phospholipases on the virulence of the filamentous fungus Purpureocillium lilacinum has been still rather limited. In this study, pld gene was characterized. It encodes the protein phospholipase D (PLD) in P. lilacinum. This gene, 3303 bp open reading frame fragment (ORF), encodes a protein of 1100 amino acids with high similarity to the same gene from Penicillium oxalicum and Aspergillus fumigatus. Secondary structure prediction showed two PLD phosphodiesterase domains (437-464 bp and 885-912 bp). The pld gene was significantly regulated during infection of Meloidogyne incognita eggs by P. lilacinum. The expression of pld gene using RT-PCR was the highest at 36 and 48 h, which introduce evidence that the presence of M. incognita may induce the expression of the pld gene in P. lilacinum. In addition, maltose and l alanine were found to increase the expression of pld gene. An acidic environment (pH 3.0-4.0) and moderate temperatures (27-29 degrees C) are favorable for pld expression in P. lilacinum. PMID- 26026834 TI - SufC may promote the survival of Salmonella enterica serovar Typhi in macrophages. AB - The sufC gene of Escherichia coli (E. coli) is required for the biogenesis of iron-sulfur (Fe-S) cluster under oxidative stress conditions. In order to investigate the roles of sufC in Salmonella enterica serovar Typhi (S. Typhi), isogenic S. Typhi strain GIFU10007 harboring a non-polar mutation of sufC (DeltasufC) was constructed and the results showed that the sufC deleted mutant grew more slowly than the wild type strain when encounter oxidative stresses. Moreover, the deletion of sufC gene decreased S. Typhi survival within macrophages. After macrophages infected by sufC deleted mutant and wild type strain, we detected IL-6 and TNF-alpha released into the supernatant, and found the expression of IL-6 and TNF-alpha decreased in the supernatant of sufC deleted mutant infected groups than the wild type strain infected ones. In summary, our results showed that SufC may promote S. Typhi coping oxidative stress and help S. Typhi survival in macrophages. PMID- 26026835 TI - Virulence factors genes of Staphylococcus spp. isolated from caprine subclinical mastitis. AB - The aim of this study was to investigate genes involved in adhesion expression, biofilm formation, and enterotoxin production in isolates of Staphylococcus spp. from goats with subclinical mastitis and associate these results with the staphylococcal species. One hundred and twenty-four isolates were identified and polymerase chain reaction (PCR) was performed to detect the following genes: cna, ebpS, eno, fib, fnbA, fnbB, bap, sea, seb, sec, sed and see. The most commonly Staphylococcus species included S. epidermidis, S. lugdunensis, S. chromogenes, S. capitis ss capitis and S. intermedius. With the exception of fnbB, the genes were detected in different frequencies of occurrence in 86.3% of the Staphylococcus spp. isolates. Eno (73.2%) and bap (94.8%) were more frequently detected in coagulase-negative staphylococci (CNS); ebpS (76%), fib (90.9%) and fnbA (87%) were the most frequent genes in coagulase-positive staphylococci (CPS). Regarding enterotoxins, genes sed (28.2%) and see (24.2%) had a higher frequency of occurrence; sec gene was more frequently detected in CPS (58.8%). There was no association between the presence of the genes and the Staphylococcus species. Different virulence factors genes can be detected in caprine subclinical mastitis caused by CNS and CPS. The knowledge of the occurrence of these virulence factors is important for the development of effective control and prevention measures of subclinical mastitis caused by CNS and CPS in goats. PMID- 26026836 TI - Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation. AB - Consumption of a high-fat diet causes an increase in bile acid deoxycholic acid (DCA) in colon lumen and colon cancer risk, while butyrate, an intestinal microbiota metabolite of dietary fiber, has been shown to exhibit colon cancer preventive effects. To distinguish these opposing effects of DCA and butyrate (two major metabolites in colon lumen), we examined the effects of physiologically relevant doses of butyrate (0.5-2 mmol/l) and DCA (0.05-0.3 mmol/l) on colon cell proliferation. We hypothesize that butyrate and DCA each modulates the cell cycle and apoptosis via common and distinct cellular signaling targets. In this study, we demonstrated that both butyrate and DCA inhibited cell proliferation by up to 89% and 92% and increased cell apoptosis rate by up to 3.1 and 4.5-fold, respectively. Cell cycle analyses revealed that butyrate led to an increase in G1 and G2 fractions with a concomitant drop in the S-phase fraction, but DCA induced an increase in only G1 fraction with a concomitant drop in the S phase fraction when compared with the untreated cells. The examination of early cellular signaling revealed that DCA but not butyrate increased intracellular reactive oxygen species, genomic DNA breakage, the activation of ERK1/2, caspase 3 and PARP. In contrast, DCA decreased activated Rb protein level, and butyrate but not DCA increased p21 expression. Collectively, although both butyrate and DCA inhibit colonic cell proliferation, butyrate increases tumor suppressor gene expression, whereas DCA decreases tumor suppressor activation in cell cycle and apoptosis pathways. PMID- 26026837 TI - Pan-colonic pharmacokinetics of catechins and procyanidins in male Sprague-Dawley rats. AB - Poor absorption and bioavailability of procyanidins from the upper gastrointestinal tract result in the majority of the dose reaching the colon. During colonic transit, progressive microbial metabolism likely produces gradients of procyanidins and microbial metabolites along the length of the colon, suggesting that proximal and distal regions are exposed to different profiles of procyanidins and metabolites. However, previous studies have largely treated the colon as a single organ or looked at fecal profiles, and differences in the profiles of native and metabolite compounds between regions have not been observed. The metabolism kinetics of procyanidins larger than trimers and formation of metabolites in the colon have not been well characterized. Therefore, the objective of this study was to determine the kinetics of delivery and microbial metabolism of monomeric, dimeric and oligomeric procyanidins in the cecum and proximal, mid and distal colon. Sprague-Dawley rats were gavaged grape seed extract and sacrificed over 18 h. Analysis of luminal contents showed distinct native and metabolite profiles for each region. Procyanidins had maximum concentrations at approximately 3h postgavage for all sections. Metabolites reached maximum concentrations from 3 to 18 h postgavage. The appearance of metabolites was highly dependent on species: larger metabolites were found at earlier times in the more proximal segments, and smaller metabolites were found at later times in more distal regions. This study allowed for the observation of regions in the lower gastrointestinal tract, giving insight into the distribution and delivery of procyanidins and their microbial metabolites throughout the colon. PMID- 26026838 TI - Tissue distribution of rat flavanol metabolites at different doses. AB - Flavanols are metabolized in the small intestine and the liver to produce their glucuronidated, sulfated or methylated conjugates that can be body distributed or excreted in the urine. However, the intake of large amounts of flavanols is not directly related to their bioavailability. This study aims to investigate the administered dose dependence of flavanols' conjugation and body distribution. In this study, different doses of a grape seed proanthocyanidin extract (GSPE; 125, 250, 375 and 1000 mg/kg) were orally administered to male Wistar rats. Tissues were collected 2h after GSPE administration. Flavanols were quantified by HPLC MS/MS. Results show that the majority of GSPE metabolites are located in the kidney, followed by the liver. Lower concentrations were found in mesenteric white adipose tissue (MWAT) and the brain. Moreover, flavanol metabolites followed a tissue-specific distribution pattern independent of dosage. In the kidney, glucuronidated metabolites were the most abundant; however, in the liver, it was mainly methyl-glucuronidated metabolites. In MWAT, free flavanols were dominant, and methylated metabolites were dominant in the brain. Concentration within a tissue was dependent on the administered dose. In conclusion, flavanol metabolites follow a tissue-specific distribution pattern and only the tissue concentration of flavanol metabolites is dependent on the administered dose. PMID- 26026839 TI - Successive bioanode regenerations to maintain efficient current production from biowaste. AB - The long-term operation of efficient bioanodes supplied with waste-derived organics is a key challenge for using bioelectrochemical systems as a waste valorization technology. Here, we describe a simple procedure that allowed maintaining highly efficient bioanodes supplied with biowaste. Current densities up to 14.8 A/m(2) were obtained with more than 40% of the electrons introduced as biowaste being recovered in the electrical circuit. Three fed-batch reactors were started at different biowaste loading rates. A decline of coulombic efficiencies between 22 and 31% was recorded depending on the reactor over the first 3 weeks of operation. A renewal procedure of the anode was thereafter implemented, which led to a recovery of initial performances. The second and the third renewal, allowed maintaining stable high level performances with coulombic efficiency of approximately 40% over at least 3 weeks. Electroactive biofilm dynamics were monitored using 16S rRNA-gene amplicon sequencing. Retrieved sequences were dominated by Geobacter sulfurreducens-related reads (37% of total sequences), which proportion however varied along the experiment. Interestingly, sequences affiliated to various Bacteroidetes groups were also abundant, suggesting an adaptation of the anodic biofilm to the degradation of biowaste through metabolic interactions between microbial community members. PMID- 26026840 TI - The effect of hydrodynamic cavitation on Microcystis aeruginosa: Physical and chemical factors. AB - The various effects of hydrodynamic cavitation (HC) on algal growth inhibition were investigated. The gas-vacuolate species Microcystis aeruginosa responded differently to the gas-vacuole-negative alga Chlorella sp. When M. aeruginosa was subjected to HC, both its cell density and photosynthetic activity were subsequently reduced by nearly 90% after three days culture. However, the cell density of Chlorella sp. was reduced by only 63%, and its final photosynthetic activity was unaffected. Electron microscopy confirmed that HC had a minimal impact on algal cells that lack gas vacuoles. Shear stress during recirculation only modestly inhibited the growth of M. aeruginosa. The relative malondialdehyde (MDA) content, a quantitative indicator of lipid peroxidation, increased significantly during HC treatment, indicating the production of free radicals. Accordingly, the addition of H2O2 to the HC process promoted the production of free radicals, which also improved algal reduction. A comparison of the outcomes and energy efficiency of HC and ultrasonic cavitation indicated that HC gives the best performance: under 10 min cavitation treatment, the algal removal rate of HC could reach 88% while that of sonication was only 39%. PMID- 26026841 TI - Thermophilic hydrogen-producing bacteria inhabiting deep-sea hydrothermal environments represented by Caloranaerobacter. AB - Hydrogen is an important energy source for deep-sea hydrothermal vent ecosystems. However, little is known about microbes and their role in hydrogen turnover in the environment. In this study, the diversity and physiological characteristics of fermentative hydrogen-producing microbes from deep-sea hydrothermal vent fields were described for the first time. Seven enrichments were obtained from hydrothermal vent sulfides collected from the Southwest Indian Ocean, East Pacific and South Atlantic. 16S rRNA gene analysis revealed that members of the Caloranaerobacter genus were the dominant component in these enrichments. Subsequently, three thermophilic hydrogen producers, strains H363, H53214 and DY22619, were isolated. They were phylogenetically related to species of the genus Caloranaerobacter. The H2 yields of strains H363, H53214, DY22619 and MV107, which was the type species of genus Caloranaerobacter, were 0.11, 1.21, 3.13 and 2.85 mol H2/mol glucose, respectively. Determination of the main soluble metabolites revealed that strains H363, H53214 and MV107 performed heterolactic fermentations, while strain DY22619 performed butyric acid fermentation, indicating distinct fermentation patterns among members of the genus. Finally, a diversity of forms of [FeFe]-hydrogenase with different modular structures was revealed based on draft genomic data of Caloranaerobacter strains. This highlights the complexity of hydrogen metabolism in Caloranaerobacter, reflecting adaptations to environmental conditions in hydrothermal vent systems. Collectively, results suggested that Caloranaerobacter species might be ubiquitous and play a role in biological hydrogen generation in deep-sea hydrothermal vent fields. PMID- 26026842 TI - Methemoglobinemia: a diagnosis not to be missed. PMID- 26026843 TI - Pharmacoepidemiology of chronic noncancer pain patients requiring chronic opioid therapy: A nationwide population-based study. AB - OBJECTIVE: This study was aimed to explore the pharmacoepidemiology of chronic noncancer pain (CNCP) patients who required chronic opioid therapy (COT) in the Taiwanese population. METHODS: Using the Taiwan National Health Insurance Research Database during 2008-2009, COT-requiring CNCP patients were identified by the inclusion criteria of both chronic analgesic requirement for >3 months per year and long-term use of controlled opioids for >28 therapeutic days during any 3-month period in ambulatory visits with malignancy-related pain excluded. Their demographic data and pharmacoepidemiological characteristics of opioid consumption and opioid prescriptions issued in ambulatory visits were analyzed. RESULTS: In total, 159 patients were enrolled as COT-requiring CNCP patients, and the prevalence was calculated at 0.016% in a 2-year period. Females were outnumbered by males (45.3% vs. 54.7%). Almost 60% of them were of working age and 93.7% belonged to low-income households, as in the health insurance claims, probably implying socioeconomic disadvantages associated with CNCP. The leading three diagnoses were unspecified myalgia and myositis, lumbago, and abdominal pain of unspecified site. The most common department from where these 159 CNCP patients obtained their opioid prescriptions was the emergency department (27.6%), ensued by a pain clinic (25.3%), but they could acquire only a few opioid therapeutic days through emergency department visits. Moreover, pain clinic satisfied the majority of opioid therapeutic days. Among all opioids, morphine was the most frequently prescribed in opioid-obtaining ambulatory visits, accounting for most of the opioid therapeutic days as well as opioid consumption. CONCLUSION: COT-requiring CNCP patients were easily associated with adverse socioeconomic liabilities and often visited emergency department as well as pain clinics. Morphine was the main opioid used for their chronic pain. Transfer of COT-requiring CNCP patients to appropriate departments is strongly recommended for efficient long-term pharmacotherapy for their chronic pain. PMID- 26026844 TI - Surface topography enhances differentiation of mesenchymal stem cells towards osteogenic and adipogenic lineages. AB - Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared in vitro differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ridge structures. Micro- and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively. These structures affected cell spreading and orientation of human MSCs, which was also reflected in focal adhesions morphology and size. Time-lapse demonstrated directed migration parallel to the nano-patterns. Overall, surface patterns clearly enhanced differentiation of MSCs towards specific lineages: 15 MUm ridges increased adipogenic differentiation whereas 2 MUm ridges enhanced osteogenic differentiation. Notably, nano-patterns with a periodicity of 650 nm increased differentiation towards both osteogenic and adipogenic lineages. However, in absence of differentiation media surface structures did neither induce differentiation, nor lineage-specific gene expression changes. Furthermore, nanostructures did not affect the YAP/TAZ complex, which is activated by substrate stiffness. Our results provide further insight into how structuring of tailored biomaterials and implant interfaces - e.g. by multi beam laser interference in sub-micrometer scale - do not induce differentiation of MSCs per se, but support their directed differentiation. PMID- 26026845 TI - Dissipation kinetics and residues of triazolopyrimidine herbicides flumetsulam and florasulam in corn ecosystem. AB - The dynamic and residues of florasulam and flumetsulam in corn field ecosystem were investigated using quick, easy, cheap, effective, rugged, and safe (QuEChERS) procedure with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The limits of quantification (LOQs) of the proposed method ranged from 0.005 to 0.01 mg/kg. Mean recoveries and relative standard deviations (RSDs) of the two compounds in all samples at three spiking levels ranged 94-110 % and 2.0-9.2 %, respectively. Florasulam and flumetsulam degradation followed first-order kinetics with half-lives 1.7-2.9 and 3.3-8.7 days in soil and 1.3-1.8 and 0.9-1.7 days in plant, respectively. The residues in all the samples were found to be less than the LOQs at preharvest intervals of 53 and 78 days. The results suggest that the combined use of florasulam and flumetsulam on corn is considered to be safe under the recommended conditions and can be utilized for establishing the maximum residue limit (MRL) of florasulam in corn in China. PMID- 26026846 TI - Suspended particulate matter estimates using optical and acoustic sensors: application in Nestos River plume (Thracian Sea, North Aegean Sea). AB - The present study investigates the use of combined methods of optical and acoustic sensors, in collaboration with direct in situ measurements, for the calibration and validation of a model transforming acoustic backscatter intensity series into suspended particulate matter (SPM) concentration datasets. The model follows previously elaborated techniques, placing particular attention to the parameterization of the acoustic absorption index as a function of water physical properties. Results were obtained from the annual deployment (during 2007-2008) of an upward-facing acoustic Doppler current profiler (ADCP) (307 kHz), equipped with a Wave Array, and an optical backscatter sensor (OBS), at the bottom of Thassos Passage near Nestos River plume (Thracian Sea, Northern Greece). The OBS was calibrated through linear regression, using 2007 and 2012 field sampling data, exhibiting an error of 13-14 % due to chlorophyll presence. The ADCP signal was calibrated through simultaneous measurements of backscatter intensity and turbidity profiles. Harmonic analysis on the model-produced SPM concentrations explained the tidal influence on their variability, especially during the summer. Empirical orthogonal functions analysis revealed the impact of waves and wave induced currents on SPM variability. Finally, Nestos River sediment load was found uncorrelated to the SPM change in Thassos Passage, due to the dispersal and sediment deposition near the river mouth. PMID- 26026847 TI - Identification and analysis of polyaromatic hydrocarbons (PAHs)--biodegrading bacterial strains from refinery soil of India. AB - Polyaromatic hydrocarbons (PAHs) utilizing bacteria were isolated from soils of seven sites of Mathura refinery, India. Twenty-six bacterial strains with different morphotypes were isolated. These strains were acclimatized to utilize a mixture of four polycyclic aromatic hydrocarbons, i.e., anthracene, fluorene, phenanthrene, and pyrene, each at 50 mg/L concentration as sole carbon source. Out of total isolates, 15 potent isolates were subjected to 16S rDNA sequencing and identified as a member of diverse genera, i.e., Bacillus, Acinetobacter, Stenotrophomonas, Alcaligenes, Lysinibacillus, Brevibacterium, Serratia, and Streptomyces. Consortium of four promising isolates (Acinetobacter, Brevibacterium, Serratia, and Streptomyces) were also investigated for bioremediation of PAH mixture. This consortium was proved to be efficient PAH degrader resulting in 40-70 % degradation of PAH within 7 days. Results of this study indicated that these genera may play an active role in bioremediation of PAHs. PMID- 26026848 TI - Effects of oral hypoglycemic agents on platelet function. AB - Platelet dysfunction plays a role in diabetic macrovascular complications. Several studies have assessed the effect of oral hypoglycemic agents (OHAs) on platelet function. Data from both in vivo and in vitro studies show a favorable effect for most of the traditional glucose-lowering therapies, while evidence is limited for the newer ones. Metformin, sulfonylureas, glitazones and acarbose exert a favorable effect on platelet function. Among incretin therapies, only sitagliptin has so far been demonstrated to have a beneficial effect on platelet aggregation. More in vivo and in vitro evidence is required to increase our knowledge on any potential beneficial effects of OHAs on platelet function. Any such effect may have implications for the reduction of cardiovascular risk in type 2 diabetes mellitus. PMID- 26026849 TI - Explaining high and low performers in complex intervention trials: a new model based on diffusion of innovations theory. AB - BACKGROUND: Complex intervention trials may require health care organisations to implement new service models. In a recent cluster randomised controlled trial, some participating organisations achieved high recruitment, whereas others found it difficult to assimilate the intervention and were low recruiters. We sought to explain this variation and develop a model to inform organisational participation in future complex intervention trials. METHODS: The trial included 40 general practices in a London borough with high HIV prevalence. The intervention was offering a rapid HIV test as part of the New Patient Health Check. The primary outcome was mean CD4 cell count at diagnosis. The process evaluation consisted of several hundred hours of ethnographic observation, 21 semi-structured interviews and analysis of routine documents (e.g., patient leaflets, clinical protocols) and trial documents (e.g., inclusion criteria, recruitment statistics). Qualitative data were analysed thematically using--and, where necessary, extending--Greenhalgh et al.'s model of diffusion of innovations. Narrative synthesis was used to prepare case studies of four practices representing maximum variety in clinicians' interest in HIV (assessed by level of serological testing prior to the trial) and performance in the trial (high vs. low recruiters). RESULTS: High-recruiting practices were, in general though not invariably, also innovative practices. They were characterised by strong leadership, good managerial relations, readiness for change, a culture of staff training and available staff time ('slack resources'). Their front-line staff believed that patients might benefit from the rapid HIV test ('relative advantage'), were emotionally comfortable administering it ('compatibility'), skilled in performing it ('task issues') and made creative adaptations to embed the test in local working practices ('reinvention'). Early experience of a positive HIV test ('observability') appeared to reinforce staff commitment to recruiting more participants. Low-performing practices typically had less good managerial relations, significant resource constraints, staff discomfort with the test and no positive results early in the trial. CONCLUSIONS: An adaptation of the diffusion of innovations model was an effective analytical tool for retrospectively explaining high and low-performing practices in a complex intervention research trial. Whether the model will work prospectively to predict performance (and hence shape the design of future trials) is unknown. TRIAL REGISTRATION: ISRCTN Registry number: ISRCTN63473710. Date assigned: 22 April 2010. PMID- 26026850 TI - The mechanism of uranium transformation from U(VI) into nano-uramphite by two indigenous Bacillus thuringiensis strains. AB - The mechanism of uranium transformation from U(VI) into nano-uramphite by two indigenous Bacillus thuringiensis strains was investigated in the present work. Our data showed that the bacteria isolated from uranium mine possessed highly accumulation ability to U(VI), and the maximum accumulation capacity was around 400 mg U/g biomass (dry weight). X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FT-IR) analyzes indicated that the U(VI) was adsorbed on the bacterial surface firstly through coordinating with phosphate, CH2 and amide groups, and then needle-like amorphous uranium compounds were formed. With the extension of time, the extracellular crystalline substances were disappeared, but some particles were appeared in the intracellular region, and these particles were characterized as tetragonal-uramphite. Moreover, the disrupted experiment indicated that the cell-free extracts had better uranium immobilization ability than cell debris. Our findings provided the understanding of the uranium transformation process from amorphous uranium to crystalline uramphite, which would be useful in the regulation of uranium immobilization process. PMID- 26026851 TI - Hygienic treatment and energy recovery of dead animals by high solid co-digestion with vinasse under mesophilic condition: feasibility study. AB - In the present study, the feasibility of hygienic treatment and energy recovery of dead animals (pork as an experimental alternative) by high solid co-digestion with vinasse under mesophilic condition was investigated. A lab-scale digester was operated for 125 days with SRT of 20 days. The volatile solid (VS) reduction, biogas yield, and CH4 content finally achieved stability after two obvious fluctuations, and were 55+/-1%, 0.40+/-0.02 m(3)/kg VS feed and 68%, respectively. Meanwhile, the shifts of microbial communities of the samples taken on typical days with different performance (day 40 (stable), day 65 (deteriorated), day 75 (in recovery), day 90 (recovered) and day 110 (stable)) were monitored by the application of pyrosequencing technology and the bioinformatical analysis with QIIME 1.8. In consequence, the details of changes in bacterial and archaeal communities elaborately explained the intrinsic reasons for the deterioration and recovery of the digester, and provided the proofs for the feasibility of hygienic treatment and energy recovery of dead animals by high solid co-digestion with vinasse under mesophilic condition. PMID- 26026852 TI - Iterative ensemble Kalman filter for atmospheric dispersion in nuclear accidents: An application to Kincaid tracer experiment. AB - Information about atmospheric dispersion of radionuclides is vitally important for planning effective countermeasures during nuclear accidents. Results of dispersion models have high spatial and temporal resolutions, but they are not accurate enough due to the uncertain source term and the errors in meteorological data. Environmental measurements are more reliable, but they are scarce and unable to give forecasts. In this study, our newly proposed iterative ensemble Kalman filter (EnKF) data assimilation scheme is used to combine model results and environmental measurements. The system is thoroughly validated against the observations in the Kincaid tracer experiment. The initial first-guess emissions are assumed to be six magnitudes underestimated. The iterative EnKF system rapidly corrects the errors in the emission rate and wind data, thereby significantly improving the model results (>80% reduction of the normalized mean square error, r=0.71). Sensitivity tests are conducted to investigate the influence of meteorological parameters. The results indicate that the system is sensitive to boundary layer height. When the heights from the numerical weather prediction model are used, only 62.5% of reconstructed emission rates are within a factor two of the actual emissions. This increases to 87.5% when the heights derived from the on-site observations are used. PMID- 26026853 TI - Costs of hepato-pancreato-biliary surgery and readmissions in privately insured US patients. AB - BACKGROUND: Surgical costs are influenced by perioperative care, readmissions, and further therapies. We aimed to characterize costs in hepato-pancreato-biliary surgery in the United States. METHODS: The MarketScan database (2008-2010) was used to identify privately insured patients undergoing pancreatectomy (n = 2254) or hepatectomy (n = 1702). Costs associated with the index surgery, readmissions, and total short-term costs were assessed from a third party payer perspective using generalized linear regression models. RESULTS: Mean total costs of pancreatectomy and hepatectomy were $107,600 (95% confidence interval [CI], 101,200-114,000) and $81,300 (95% CI, 77,600-85,000), respectively, with corresponding surgical costs of 69.2% and 60.9%. Ninety-day readmission costs were $36,200 (95% CI, 32,000-40,400) and $34,100 (95% CI, 28,100-40,100), respectively. In multivariate analysis, readmissions were associated with an almost two-fold increase in total costs in both pancreatectomy (cost ratio = 1.98; P < 0.001) and hepatectomy (cost ratio = 1.92; P < 0.001). CONCLUSIONS: Hepato-pancreato-biliary surgery is associated with significant economic burden in the privately insured population. Substantial costs are incurred beyond the index surgical admission, with readmissions representing a major source of potentially preventable health care spending. Sustained efforts in defining high risk populations and decreasing the burden of postoperative complications through a combination of prevention and improved outpatient management offer promising strategies to reduce readmissions and control costs. PMID- 26026854 TI - Growth differentiation factor 11 supports migration and sprouting of endothelial progenitor cells. AB - BACKGROUND: Neovascularization plays an important role in tissue engineering applications. In animal models, it was demonstrated that implantation of endothelial progenitor cells (EPCs) from cord blood led to the formation of a complex functional neovasculature, whereas EPCs isolated from peripheral blood (pbEPCs) showed a limited vasculogenic potential, which may be attributed to age related dysfunction. Growth differentiation factor 11 (GDF11) was recently identified as a rejuvenation factor, which was able to reverse age-related dysfunction of stem cells. Therefore, we hypothesized that GDF11 may improve the vasculogenesis-related phenotype of pbEPCs. MATERIALS AND METHODS: pbEPCs were isolated from adult peripheral blood. Transforming growth factor (TGF)-beta type I receptor expression was analyzed by immunostaining. pbEPCs were treated with recombinant GDF11 for various time periods. Thereafter, phosphorylation of Smad2/Smad3, adhesion, proliferation, cell survival, migration, and in vitro sprout formation was investigated. RESULTS: pbEPCs express the TGF-beta type-I receptors ALK4 and ALK5, but not ALK7. Treatment of pbEPCs with recombinant GDF11 resulted in activation of the Smad2/Smad3 pathway and in increased migration, which was inhibited by the TGF-beta1 superfamily type-I activin receptor-like kinase inhibitor SB431542, demonstrating that the TGF-beta receptor-Smad2/Smad3 pathway is involved in GDF11 induced migration. Moreover, in vitro sprout formation was increased as well by GDF11 treatment. However, other parameters such as adherence, proliferation, and apoptosis were not affected by GDF11. CONCLUSIONS: This study provides evidence that GDF11 improves vasculogenesis related growth parameters in pbEPCs and may represent a therapeutic option to ameliorate the angiogenic and vasculogenic properties of pbEPCs. PMID- 26026855 TI - Evaluation of Leukocyte Threshold Values in Semen to Detect Inflammation Involving Seminal Interleukin-6 and Interleukin-8. AB - OBJECTIVE: To evaluate leukocyte threshold values in semen to detect inflammation involving seminal interleukin (IL)-6 and IL-8. MATERIALS AND METHODS: The levels of leukocytes, IL-6, and IL-8 in semen were determined. The 75th and 90th percentiles of seminal IL-6 and IL-8 were considered as "high" and "very high" concentrations, respectively. Inflammatory semen was defined based on high levels of IL-6 (>=86.75 pg/mL) or IL-8 (>=4460 pg/mL). Very high levels of IL-6 (>=228 pg/mL) or IL-8 (>=12,480 pg/mL) were used to define acute seminal inflammation. On the basis of high and very high levels of IL-6 or IL-8, receiver operating characteristic curves were generated to evaluate leukocyte threshold values. RESULTS: Leukocytes at a cutoff level of 1 * 10(6)/mL had 51% sensitivity and 95% specificity to detect high levels of IL-6, whereas on the basis of very high levels of IL-6, the same cutoff level revealed 82% sensitivity and 90% specificity. Similarly, leukocytospermia demonstrated low sensitivity (56%) to detect high levels of IL-8 but acceptable sensitivity (94%) and specificity (92%) to predict very high levels of IL-8. The cutoff level of 0.315 * 10(6) leukocytes/mL had optimal sensitivity and specificity for predicting high levels of inflammatory cytokines. CONCLUSION: Leukocytospermia demonstrated poor sensitivity to detect seminal inflammation, as defined by high levels of inflammatory cytokines. The optimal threshold value to detect inflammation was found to be 0.315 * 10(6) leukocytes/mL. On the basis of very high levels of IL-6 or IL-8, leukocytospermia is a sensitive and specific marker to predict acute seminal inflammation. PMID- 26026857 TI - Removal of Polypropylene Sling Mesh From the Urethra: An Anatomic Technique. AB - OBJECTIVE: To describe a technique for removal of intraurethral mesh with minimal disruption of the periurethral anatomy. MATERIALS AND METHODS: Through a midline transvaginal approach the sling is located lateral to the urethra and divided. The medial portion of the divided sling is carefully dissected back to its entrance laterally into the urethral lumen. A stay suture is placed on the dissected sling. The sling is located on the contralateral side and likewise divided and dissected back to the urethral lumen. The completely dissected sling is pulled through such that the holding stitch is through and through the urethral lumen, allowing easy localization of the urethral defect on lateral walls of the urethra. These defects are closed with an absorbable suture and the vaginal incision is closed. RESULTS: Three patients have undergone a transvaginal removal of their intraurethral mesh using the described technique. At a mean follow-up of 6.0 months, there were no intraoperative or postoperative complications. All patients were obstructed preoperatively and all developed stress urinary incontinence postoperatively requiring 0-1 pads per day. CONCLUSION: Current approaches to the surgical repair of chronic intraurethral mesh have significant limitations that are minimized by the described technique. This anatomic removal of mesh from the urethra has several advantages including no disruption of the ventral wall of the urethra, complete removal of foreign body from the urethra, and simplified localization of the urethral wall defect to allow for anatomic closure. PMID- 26026856 TI - Physician Use of Sacral Neuromodulation Among Medicare Beneficiaries With Overactive Bladder and Urinary Retention. AB - OBJECTIVE: To identify physician-level factors associated with high rates of sacral neuromodulation testing. MATERIALS AND METHODS: We performed a retrospective cohort study using a 20% sample of national Medicare claims to identify physicians who performed sacral neuromodulation procedures between 2005 and 2010. Physician-level rates of device testing were determined based on the number of patients seen for overactive bladder and urinary retention diagnoses in the office in each calendar year. These rates were then used to fit a Poisson model to examine factors associated with high rates of device testing. RESULTS: The number of physicians performing test procedures increased 4-fold from 2005 to 2010. Average rates of test procedures increased from 4.0 to 6.4 procedures per physician per year (P <.001), whereas rates of device implantation remained stable (P = .23). Physicians who had higher rates of device testing were associated with lower rates of device implantation (estimate, -1.76, P <.01). Other predictors of physicians with higher test rates included more recent calendar year, testing done in any setting other than an ambulatory surgery center, gynecology subspecialty, and geographic location in the South and West (all P values <.01). CONCLUSION: Over time, physicians are testing more patients but are not implanting more devices. Additionally, there is an inverse relationship between rates of device testing and implantation, suggesting opportunities to improve efficiency and resource utilization. PMID- 26026858 TI - Retraining running gait to reduce tibial loads with clinician or accelerometry guided feedback. AB - OBJECTIVES: Reducing tibial acceleration through gait retraining is thought to reduce the risk of stress fracture development, however current approaches require the use of advanced accelerometry equipment not readily available in the clinical setting. The aim was to compare the effect of clinician guided feedback with accelerometry guided feedback on peak tibial accelerations during running. DESIGN: Repeated measures randomised design. METHODS: Twenty-two healthy male runners were randomised to receive either tibial accelerometry or clinician guided feedback. Peak tibial accelerations were obtained for all participants (i) prior to intervention, (ii) after 10min of feedback, (iii) after a further 10min without feedback, and (iv) 1 week later. RESULTS: Across groups, significant reductions in peak tibial acceleration were observed from baseline to each of the subsequent time points in the order of 19-29% (p=0.001). No between-group differences in peak tibial acceleration were observed at any of the follow-up time points (p=0.434). CONCLUSIONS: These data indicate that in the short term the low cost, low technology, clinician guided approach to retraining running gait may be equally as effective as the more expensive accelerometry guided solution in reducing peak tibial accelerations. Longer term follow-up is required to evaluate the efficacy of both approaches in reducing the risk of stress fracture development. PMID- 26026859 TI - Prognostic implication of progression pattern after anti-VEGF bevacizumab treatment for recurrent malignant gliomas. AB - Malignant glioma treated with anti-vascular endothelial growth factor (VEGF) bevacizumab show progression patterns that vary with different mechanisms of resistance. We evaluated the clinico-radiological data of 71 patients with progressive malignant glioma treated with bevacizumab to determine the prognostic value of the differential outcome of each progression pattern. Progression patterns were categorized as three types based on the initial response to bevacizumab and serious changes of MR images i.e., non-enhancing infiltration, flare-up of contrast enhancement (CE) and primary non-responder progression. We analyzed the clinical outcome in each type of progression using Kaplan-Meier survival analysis. Analysis of progression patterns showed that incidence of non enhancing infiltration progression (28.1 %) was less common than flare-up of CE or primary non-responder pattern. The time from initiation of bevacizumab to development of non-enhancing infiltration or flare-up of CE progression was longer than for progression in primary non-responders. There was no significant difference of overall survival, progression-free survival from start of bevacizumab therapy, survival after bevacizumab failure between non-enhancing infiltration and flare-up of CE patterns. However, in the non-enhancing infiltration pattern, early appearance of enhancement was observed after bevacizumab was discontinued, resulting in poor survival, as compared to flare-up of CE pattern (P = 0.01). Although the appearance of non-enhancing infiltration after bevacizumab does not imply a worse prognosis, discontinuation of therapy can aggravate the clinical course. PMID- 26026860 TI - Health-related quality of life in patients with high-grade gliomas: a quantitative longitudinal study. AB - The diagnosis of a high-grade glioma usual is followed by functional impairment(s), cognitive decline and an impaired psycho-social well-being. This might well have a significant and negative impact on the health related quality of life. The purpose of this study was to explore physical activity levels, prevalence and severity of anxiety and depressive symptoms and health-related quality of life among patients with a highgrade glioma. This paper is based on a longitudinal mixed methods study. Patients (n = 30) completed questionnaires at 5 time points from time of diagnosis until the final follow-up after 1 year. Scores of Karnofsky Performance Status (KPS), physical activity, anxiety and depression and health-related quality of life (FACT-Br) are obtained. Patients' physical activity level and KPS decrease during the disease- and treatment trajectory. The majority of patients did not report any depressive symptoms, eight individuals (26.7 %) being depressed at various time points. Among a sub-group of participants who completed all study requirements for the entire study period the level of anxiety decreased significantly during the study. The FACT-Br sub-scale of emotional well-being increased significant, indicating a better HRQOL attend of followup. The diagnosis of a HGG leads to an ongoing functional decline measured as a decline of the KPS and a reduced physical activity during leisure time. Supportive care combined with rehabilitative and palliative approaches might well be valuable along the trajectory especially during the post-surgery period when anxiety is at its highest peak. PMID- 26026861 TI - Adult medulloblastoma: clinical characters, prognostic factors, outcomes and patterns of relapse. AB - To analyze the clinical characters, prognostic factors, patterns of relapse and treatment outcomes for medulloblastoma in adults. The clinical materials of 73 consecutive adult patients (age, >=16 years) with medulloblastoma were analyzed retrospectively. Follow-up data were available in 62 patients, ranging from 10 to 142 months (median, 78.4 months). Outcome in survival was assessed by the progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analysis were performed to determine the prognostic factors. Total or near-total tumor resection was achieved in 37 cases (59.7 %), subtotal in 19 cases (30.6 %), and partial resection in 6 cases (9.7 %).Twenty-two patients experienced recurrences, and 45 % percent of all recurrences occurred more than 4 years after initial surgery. The PFS rates at 5 and 8 years were 60.1 and 37.0 %, respectively. The OS rates at 5 and 8 years were 82.6 and 57.3 %, respectively. In univariate analysis, less tumor resection, non-desmoplastic pathology, and brainstem involvement were risk factors for worse PFS and OS (P < 0.05). High risk category was associated with just lower PFS, but not OS. In multivariate analysis, complete resection and desmoplastic pathology were independently predictive factors of improved PFS and OS. In adult medulloblastoma, late relapse is common and therefore long-term follow-up is important for evaluating the real impact of treatments. Risk category had prognostic value just for PFS, but not for OS. Complete resection and desmoplastic histology are independently predictive factors for favorable outcomes. PMID- 26026862 TI - Impact of Acute Kidney Injury on Early to Long-Term Outcomes in Patients Who Underwent Surgery for Type A Acute Aortic Dissection. AB - Acute kidney injury (AKI) is relatively common after cardiothoracic surgery for type A acute aortic dissection (TA-AAD) and increases mortality. We investigated the incidence and risk factors for AKI in patients with TA-AAD and its impact on their outcomes. The records of 375 consecutive patients who underwent surgical treatment for TA-AAD from October 2007 to March 2013 were analyzed retrospectively. We defined AKI using the Kidney Disease Improving Global Outcomes criteria, which are based on serum creatinine concentration or glomerular filtration rate. We used Kaplan-Meier methods and multivariate Cox proportional hazards regression to assess the impact of AKI on both mortality and major adverse cardiovascular and cerebrovascular events. We also examined the association between risk factors and AKI using logistic regression modeling. Postoperative AKI was observed in 165 patients (44.0%). The overall 30-day and mid- to long-term mortality was 1.6% and 8.8%, respectively. Mortality and major adverse cardiovascular and cerebrovascular events correlated significantly with the severity of AKI, and multivariate analysis showed that AKI stage 3 (the most sever stage) was an independent risk factor for mortality (hazard ratio 6.83, 95% confidence interval 2.52 to 18.52) after adjustment for important confounding factors. Extracorporeal circulation time, body mass index, perioperative peak serum C-reactive protein concentration, renal malperfusion, and perioperative sepsis were found to be risk factors for AKI. In conclusion, AKI was common in patients who underwent surgery for type A acute aortic dissection. The severity of AKI strongly influences patient outcomes, so it should be recognized promptly and treated aggressively when possible. PMID- 26026863 TI - Significance of Late Gadolinium Enhancement at Right Ventricular Attachment to Ventricular Septum in Patients With Hypertrophic Cardiomyopathy. AB - Cardiovascular magnetic resonance (CMR) with extensive late gadolinium enhancement (LGE) is a novel marker for increased risk for sudden death (SD) in patients with hypertrophic cardiomyopathy (HC). Small focal areas of LGE confined to the region of right ventricular (RV) insertion to ventricular septum (VS) have emerged as a frequent and highly visible CMR imaging pattern of uncertain significance. The aim of this study was to evaluate the prognostic significance of LGE confined to the RV insertion area in patients with HC. CMR was performed in 1,293 consecutive patients with HC from 7 HC centers, followed for 3.4 +/- 1.7 years. Of 1,293 patients (47 +/- 14 years), 134 (10%) had LGE present only in the anterior and/or inferior areas of the RV insertion to VS, occupying 3.7 +/- 2.9% of left ventricular myocardium. Neither the presence nor extent of LGE in these isolated areas was a predictor of adverse HC-related risk, including SD (adjusted hazard ratio 0.82, 95% confidence interval 0.45 to 1.50, p = 0.53; adjusted hazard ratio 1.16/10% increase in LGE, 95% confidence interval 0.29 to 4.65, p = 0.83, respectively). Histopathology in 20 HC hearts show the insertion areas of RV attachment to be composed of a greatly expanded extracellular space characterized predominantly by interstitial-type fibrosis and interspersed disorganized myocyte patterns and architecture. In conclusion, LGE confined to the insertion areas of RV to VS was associated with low risk of adverse events (including SD). Gadolinium pooling in this region of the left ventricle does not reflect myocyte death and repair with replacement fibrosis or scarring. PMID- 26026864 TI - The Necessity of Comprehensive Searching and Quality Assessment in Meta-analyses. PMID- 26026865 TI - Predictors of Access Site Crossover in Patients Who Underwent Transradial Coronary Angiography. AB - Despite increasing use of the transradial approach (TRA) for coronary angiography, TRA failure and subsequent access site crossover remain a barrier to TRA adoption. The aim of this study was to elucidate patient and procedural characteristics associated with TRA to transfemoral approach (TFA) crossover and examine TRA to TFA crossover by operator experience over time. This retrospective analysis identified 1,600 patients who underwent coronary angiography with possible percutaneous coronary intervention through TRA by operators with varied TRA experience in an urban tertiary care center from October 2010 to August 2013. Univariate and multivariable logistic regression were used to identify independent predictors of access site crossover, from TRA to TFA, and strength of association is presented as odds ratio (OR, 95% confidence interval [CI]). Access site crossover was noted in 166 patients (10.4%). Multivariable predictors of access site crossover included age >75 years (OR 1.90, 95% CI 1.23 to 2.91, p = 0.004) and operator experience (OR 2.98, 95% CI 1.96 to 4.52, p <0.0001). Less experienced operators (<=5 years TRA experience) had a decrease in access site crossover over time (quartile 1: 8.9%, quartile 2: 18.8%, quartile 3: 16.4%, and quartile 4: 8.6%, p <0.001), which paralleled an increase in the proportion of procedures using initial TRA over time (quartile 1: 38.0%, quartile 2: 53.7%, quartile 3: 54.8%, and quartile 4: 70.3%, p <0.001). Experienced operators (>5 years TRA experience) had no significant change in proportion of access site crossover over time (quartile 1: 2.8%, quartile 2: 6.4%, quartile 3: 5.6%, quartile 4: 5.8%, p = 0.54). In conclusion, rate of access site crossover in the contemporary era is relatively low and can be mitigated with operator experience. PMID- 26026866 TI - Effect of Varying Definitions of Contrast-Induced Acute Kidney Injury and Left Ventricular Ejection Fraction on One-Year Mortality in Patients Having Transcatheter Aortic Valve Implantation. AB - The prognostic relevance of direct contrast toxicity in patients treated with transcatheter aortic valve implantation (TAVI) remains unclear because of the confounding hemodynamic effect of acute left ventricular ejection fraction (LVEF) impairment on kidney function estimation. In addition, different definitions of contrast-induced acute kidney injury (CI-AKI) may have different prognostic stratification potential. In the present study, 240 consecutive patients who underwent TAVI were prospectively enrolled. CI-AKI was defined (1) according to the postprocedural creatinine increase of >=0.3 mg/dl or (2) according to the postprocedural decrease of the creatinine clearance of at least 25%. Primary end point of the study was 1-year all-cause mortality. At a mean follow-up of 1.7 +/- 1.4 years, all-cause mortality was significantly higher in the CI-AKI patient group, using both CI-AKI definitions (for (1) and (2) p = 0.025 and p <0.001, respectively). In the Cox regression multivariate analysis, CI-AKI was an independent predictor of mortality (hazard ratio 2.244, 95% CI 1.064 to 4.732, p = 0.034), along with LVEF (hazard ratio 0.974, 95% CI 0.946 to 0.993, p = 0.012). Although LVEF and creatinine values at admission were not significantly associated with CI-AKI, their interaction term significantly defined CI-AKI (p = 0.033). The prognostic accuracy of definition (2) was higher (area under the curve 0.704; p <0.001) as with respect to definition (1) (area under the curve 0.602; p = 0.037) for the primary end point of 1-year mortality. In conclusion, in a nonselected patient population who underwent TAVI, CI-AKI was confirmed as an independent predictor of clinical outcome. Only the interaction between LVEF and baseline creatinine values was found to determine CI-AKI. Definition of CI AKI based to creatinine clearance values had higher prognostic accuracy in comparison with the CI-AKI definition based on creatinine absolute value changes. PMID- 26026868 TI - Fate of Mitral Regurgitation After Transcatheter Closure of Atrial Septal Defect in Adults. AB - Although the volume overload of pulmonary circulation improves after atrial septal defect (ASD) closure, the increasing left ventricular preload may contribute to mitral regurgitation (MR) deterioration. We aimed to evaluate the impact of MR after transcatheter ASD closure on clinical outcomes in adults. A total of 288 consecutive patients who underwent transcatheter ASD closure were enrolled. Changes in MR were assessed at 1 month after the procedure. The end point was defined as cardiovascular events. After the procedure, MR ameliorated in 3 patients and unchanged in 253, whereas MR deteriorated in 32. During a median follow-up of 24 months, patients with MR deterioration had no cardiovascular events, and the event-free survival rate was not different between patients with MR deterioration and those with MR amelioration or no-change (p = 0.355). Even in patients with MR deterioration, the New York Heart Association functional class improved after the procedure, with no cases of worsening functional class. Multivariate logistic regression analysis showed that MR deterioration was independently related to advanced age and female gender. The degree of enlargement of mitral valve annulus diameter after the procedure was greater in patients with MR deterioration than in those with MR amelioration or no-change, and it was correlated with the degree of MR deterioration. In conclusion, MR deterioration occurs in a minority of adult patients after transcatheter ASD closure; however, it is not linked with adverse outcomes. MR deterioration may be provoked by geometric changes in mitral valve annulus, especially in women with advanced age. PMID- 26026867 TI - Medication Adherence Based on Part D Claims for Patients With Heart Failure After Hospitalization (from the Atherosclerosis Risk in Communities Study). AB - Medication nonadherence is a common precipitant of heart failure (HF) hospitalization and is associated with poor outcomes. Recent analyses of national data focus on long-term medication adherence. Little is known about adherence of patients with HF immediately after hospitalization. Hospitalized patients with HF were identified from the Atherosclerosis Risk in Communities study. Atherosclerosis Risk in Communities data were linked to Medicare inpatient and part D claims from 2006 to 2009. Inclusion criteria were a chart-adjudicated diagnosis of acute decompensated or chronic HF; documentation of angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), beta blocker (BB), or diuretic prescription at discharge; and Medicare part D coverage. Proportion of ambulatory days covered was calculated for up to twelve 30-day periods after discharge. Adherence was defined as >=80% proportion of ambulatory days covered. We identified 402 participants with Medicare part D: mean age 75, 30% men, and 41% black. Adherence at 1, 3, and 12 months was 70%, 61%, and 53% for ACEI/ARB; 76%, 66%, and 62% for BB; and 75%, 68%, and 59% for diuretic. Adherence to any single drug class was positively correlated with being adherent to other classes. Adherence varied by geographic site/race for ACEI/ARB and BB but not diuretics. In conclusion, despite having part D coverage, medication adherence after discharge for all 3 medication classes decreases over 2 to 4 months after discharge, followed by a plateau over the subsequent year. Interventions should focus on early and sustained adherence. PMID- 26026869 TI - Sonodynamic action of curcumin on foodborne bacteria Bacillus cereus and Escherichia coli. AB - Bacterial contamination is an important cause of foodborne diseases. The present study aimed to investigate sonodynamic action of curcumin on foodborne bacteria Bacillus cereus (B. cereus) and Escherichia coli (E. coli). The uptake of curcumin was measured for optimizing the concentration incubation time before ultrasound sonication, and colony forming units (CFU) were counted after ultrasound treatment. The chromosomal DNA fragmentation of bacteria was analyzed and the effect of hypoxic condition on the antibacterial efficacy of sonodynamic action of curcumin was also assessed in this study. The results showed that the maximum uptake of curcumin in B. cereus and E. coli occurred in 50min after curcumin incubation. Curcumin had sonodynamic bactericidal activity in a curcumin dose-dependent manner, and 5.6-log reduction in CFU of B. cereus was observed after curcumin treatment (2.0MUM), however, only 2-log reduction in CFU of E. coli after 40MUM curcumin treatment. No significant change in chromosomal DNA was found after the combined treatment of curcumin and ultrasound. The survival of B. cereus and E. coli after sonodynamic treatment in hypoxic group was significantly higher than that in normal oxygen group. These findings indicated that sonodynamic action of curcumin had significant inactivation effect on foodborne bacteria, and B. cereus was more sensitive to sonodynamic treatment of curcumin than E. coli. Sonodynamic antibacterial activity of curcumin might be dependent on the oxygen environment. PMID- 26026870 TI - Screen-printed ultrasonic 2-D matrix array transducers for microparticle manipulation. AB - This paper reports the development of a two-dimensional thick film lead zirconate titanate (PZT) ultrasonic transducer array, operating at frequency approximately 7.5MHz, to demonstrate the potential of this fabrication technique for microparticle manipulation. All layers of the array are screen-printed then sintered on an alumina substrate without any subsequent patterning processes. The thickness of the thick film PZT is 139+/-2MUm, the element pitch of the array is 2.3mm, and the dimension of each individual PZT element is 2*2mm(2) with top electrode 1.7*1.7mm(2). The measured relative dielectric constant of the PZT is 2250+/-100 and the dielectric loss is 0.09+/-0.005 at 10kHz. Finite element analysis was used to predict the behaviour of the array and to optimise its configuration. Electrical impedance spectroscopy and laser vibrometry were used to characterise the array experimentally. The measured surface motion of a single element is on the order of tens of nanometres with a 10Vpeak continuous sinusoidal excitation. Particle manipulation experiments have been demonstrated with the array by manipulating O10MUm polystyrene microspheres in degassed water. The simplified array fabrication process and the bulk production capability of screen-printing suggest potential for the commercialisation of multilayer planar resonant devices for ultrasonic particle manipulation. PMID- 26026871 TI - Brugada ECG patterns in athletes. AB - Brugada syndrome is responsible for up to 4% of all sudden cardiac deaths worldwide and up to 20% of sudden cardiac deaths in patients with structurally normal hearts. Heterogeneity of repolarization and depolarization, particularly over the right ventricle and the outflow tract, is responsible for the arrhythmogenic substrate. The coved Type I ECG pattern is considered diagnostic of the syndrome but its prevalence is very low. Distinguishing between a saddle back Type 2 Brugada pattern and one of many "Brugada-like" patterns presents challenges especially in athletes. A number of criteria have been proposed to assess Brugada ECG patterns. Proper precordial ECG lead placement is paramount. This paper reviews Brugada syndrome, Brugada ECG patterns, and recently proposed criteria. Recommendations for evaluating a Brugada ECG pattern are provided. PMID- 26026872 TI - Phytotrapy of cyclophosphamide-induced immunosuppression. AB - Cyclophosphamide (CP) is a cytotoxic drug that can suppress both humoral and cellular immunity. Combining traditional medicinal herbs and chemotherapy drugs are used to improve immunity and quality of life performance status. In this paper, the effects of plant extracts, active components and their derivatives on immunosuppression of CP are discussed. Appropriate keywords were used to search through PubMed, Google Scholar, and Sciverse. All relevant results published from 1990 to date were chosen for final review. Over 50 references were found in which plant extracts, active components and their derivatives have been tested for their immune protective effects against CP-induced immune toxicity. Although there are several plants shown to be effective in animal models, no study was carried out on human subjects. According to the results; we can claim that plants and their active ingredients are good candidates for alternative adjuvant chemotherapy in reducing the immunotoxicity of CP. PMID- 26026873 TI - Hepatitis B virus induces RNR-R2 expression via DNA damage response activation. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) infects and replicates in quiescent hepatocytes, which are deficient in dNTPs, the critical precursors of HBV replication. Most tumor viruses promote dNTP production in host cells by inducing cell proliferation. Although HBV is known as a major cause of hepatocellular carcinoma, it does not lead to cellular proliferation. Instead, HBV acquires dNTPs by activating the expression of the R2 subunit of the Ribonucleotide Reductase (RNR) holoenzyme, the cell cycle gene that is rate-limiting for generation of dNTPs, without inducing the cell cycle. We wished to elucidate the molecular basis of HBV-dependent R2 expression in quiescent cells. METHODS: Quiescent HepG2 cells were transduced with an HBV-containing lentiviral vector, and primary human hepatocytes were infected with HBV. DNA damage response and RNR R2 gene expression were monitored under this condition. RESULTS: We report here that HBV-induced R2 expression is mediated by the E2F1 transcription factor, and that HBV induces E2F1 accumulation, modification and binding to the R2 promoter. We found that Chk1, a known E2F1 kinase that functions in response to DNA damage, was activated by HBV. In cells where Chk1 was pharmacologically inhibited, or depleted by shRNA-mediated knockdown, HBV-mediated R2 expression was severely attenuated. Furthermore, we found that HBV attenuates DNA repair, thus reducing cellular dNTP consumption. CONCLUSIONS: Our findings demonstrate that HBV exploits the Chk1-E2F1 axis of the DNA damage response pathway to induce R2 expression in a cell cycle-independent manner. This suggests that inhibition of this pathway may have a therapeutic value for HBV carriers. PMID- 26026875 TI - Can we use HCC risk scores to individualize surveillance in chronic hepatitis B infection? AB - Chronic hepatitis B is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Accurate prediction of HCC risk is important for decisions on antiviral therapy and HCC surveillance. In the last few years, a number of Asian groups have derived and validated several HCC risk scores based on well-known risk factors such as cirrhosis, age, male sex and high viral load. Overall, these scores have high negative predictive values of over 95% in excluding HCC development in 3 to 10 years. The REACH-B score was derived from a community cohort of non-cirrhotic patients and is better applied in the primary care setting. In contrast, the GAG-HCC and CU-HCC scores were derived from hospital cohorts and include cirrhosis as a major integral component. While the latter scores may be more applicable to patients at specialist clinics, the diagnosis of cirrhosis based on routine imaging and clinical parameters can be inaccurate. To this end, recent developments in non-invasive tests of liver fibrosis may further refine the risk prediction. The application of HCC risk scores in patients on antiviral therapy and in other ethnic groups should be evaluated in future studies. PMID- 26026874 TI - Sirt1 mediates the effect of the heme oxygenase inducer, cobalt protoporphyrin, on ameliorating liver metabolic damage caused by a high-fat diet. AB - BACKGROUND & AIMS: Heme oxygenase 1 (HO-1)-mediated increases in adiponectin, ameliorate the deleterious effects of obesity and metabolic syndrome; however, the effect of HO-1 on hepatic lipid metabolism remains elusive. The aim of this study is to evaluate the role of HO-1 in hepatic lipid metabolism. METHODS: Functional studies were performed using C57BL/6J (WT) mice and Sirt1 liver specific mutant (Sirt1-deficient) mice. The molecular mechanism was explored in primary hepatocytes and mouse liver. RESULTS: Chronic exposure to high-fat diet (HFD) induced hepatic steatosis in WT mice. Treatment of WT mice on HFD with cobalt protoporphyrin (CoPP), an inducer of HO-1 activity, decreased body weight and visceral fat content, reduced intracellular hepatic triglyceride and serum total cholesterol concentrations, and decreased liver lipid droplet formation. Compared with WT mice, the administration of CoPP to Sirt1-deficient mice on HFD increased visceral fat content, and slightly promoted liver lipid droplet formation. CoPP improved glucose tolerance and insulin sensitivity in WT mice on HFD, but compromised insulin sensitivity in Sirt1-deficient mice on HFD. Furthermore, CoPP-induced Sirt1 expression and decreased sterol regulatory element binding protein 1c (SREBP-1c) expression in WT mice on HFD. However, CoPP promoted SREBP-1c expression in Sirt1-deficient hepatocytes, which was reversed by a protein tyrosine phosphatase 1b inhibitor. Additionally, while the administration of CoPP to WT mice on HFD improved antioxidant and anti inflammatory states, these CoPP-mediated effects were abolished in Sirt1 deficient mice. CONCLUSIONS: Sirt1 mediates the effect of CoPP on ameliorating liver metabolic damage caused by HFD. PMID- 26026876 TI - Dietary glycotoxins induce RAGE and VEGF up-regulation in the retina of normal rats. AB - Exogenous intake of glycotoxins present in western diet accelerates the accumulation of advanced glycation end products (AGEs) in multiple organs leading to potential tissue damage. Advanced ageing and diabetic conditions have been associated with AGEs deposition in multiple eye compartments including Bruch's membrane, optic nerve, lens and cornea. However, the impact of dietary AGEs in ocular physiology has not been extensively studied. The present study investigates the direct effects of a high AGE content diet in the ocular tissues of normal rats of different age. Two groups of baby (4 weeks of age) and adult (12 weeks of age) female Wistar rats (n = 73) were allocated to high- or low-AGE diet for 3 months. Upon completion of experimental protocol, somatometric, hormonal and biochemical parameters were evaluated in all groups. Circulating and tissue AGE levels were estimated along with their signaling receptor (receptor for AGEs, RAGE) and vascular endothelial growth factor A (VEGF-A) expression in ocular tissues of the different subgroups. High AGE intake was associated with elevated serum AGEs (p = 0.0001), fructosamine (p = 0.0004) and CRP levels (p = 0.0001) compared to low AGE. High peripheral AGE levels were positively correlated with significant increased tissue immunoreactivity of AGEs and RAGE in retinal and uveal tissues as well as retinal VEGF-A expression. Up-regulation of RAGE and VEGF-A expression was observed in the ocular tissue of both baby and adult animals fed with high-AGE diet. Co-localization of AGEs and RAGE staining was observed mainly in the inner retinal layers and the retinal pigment epithelium (RPE) of all groups. VEGF-A expression was elevated in the RPE, the inner nuclear layer and the retinal ganglion cell layer of the animals exposed to high-AGE diet. In conclusion, dietary AGEs intake affects the physiology of ocular tissues by up-regulating RAGE and VEGF-A expression contributing to enhanced inflammatory responses and pathologic neovascularization in normal organisms independent of ageing. PMID- 26026877 TI - Iron accumulation in Bruch's membrane and melanosomes of donor eyes with age related macular degeneration. AB - Iron (Fe) accumulation in cytoplasmic storages of the retina and retinal pigment epithelium (RPE) with age has been reported to be a contributing factor to the onset and progression of Age-related Macular Degeneration (AMD). This work investigated whether iron can also be stored in specialized metal-binding melanosomes of the RPE and choroid and in age pigments of the RPE (lipofuscin and melanolipofuscin). As accumulation of debris in Bruch's membrane is an additional hallmark of AMD, the elemental composition of Bruch's membrane was also investigated. Perimacular sections of the retina-choroid complex of six eyes of AMD donors and of seven age-matched healthy controls were investigated using Analytical Electron Microscopy (AEM). The melanosomes of the RPE and choroidal melanocytes of all AMD donors contained about two times higher iron mole fractions (0.06-0.07 at%) compared to the controls, which showed only minor iron mole fractions at or below the detection limit of 0.02 at%. Only melanosomes that contained iron, showed also significant lead peaks (both AMD and control about 0.08 at%). In addition, the electron-dense part of melanolipofuscin granules in the RPE accumulated iron and lead, both for control and AMD donors. Iron in lipofuscin was below the detection limit. The elastic layer of Bruch's membrane of all AMD donors also contained significantly higher iron mole fractions compared to controls (about 0.08 at% Fe), predominantly in areas that were also rich in calcium (Ca) and phosphorus (P), suggesting calcification. Indeed, five of the six AMD donors but only one of the seven controls showed nanocrystalline hydroxyapatite calcifications. Note that such nanocrystalline material can only be detected in EM samples without heavy metal (osmiumtetroxide, uranylacetate) staining. In conclusion, iron accumulation in melanosomal storages and within calcified Bruch's membrane is more pronounced in donors suffering from AMD compared to age-matched controls. This work underlines the common hypothesis that heavy metal homeostasis plays an important role in age-related neuropathy. PMID- 26026878 TI - Evaluation of the relationship of corneal biomechanical metrics with physical intraocular pressure and central corneal thickness in ex vivo rabbit eye globes. AB - The relationship of corneal biomechanical metrics provided by the Ocular Response Analyzer (ORA) and Corvis ST (CVS) with physical intraocular pressure (IOPp) and central corneal thickness (CCT) was evaluated. Thirty fresh enucleated eyes of 30 rabbits were used in ex vivo whole globe inflation experiments. IOPp was measured with a pressure transducer and increased from 7.5 to 37.5 mmHg in steps of 7.5 mmHg while biomechanical data was acquired using the ORA and CVS. At least 3 examinations were performed at each pressure level, where CCT and twelve biomechanical metrics were recorded and analyzed as a function of IOPp. The biomechanical metrics included corneal hysteresis (CH) and corneal resistance factor (CRF), obtained by the ORA. They also included the applanation times (A1T, A2T), lengths (A1L, A2L) and velocities (A1V, A2V), in addition to the highest concavity time (HCT), peak distance (PD), radius (HR) and deformation amplitude (DA), obtained by the CVS. The variation of CCT and the twelve biomechanical metrics for the 30 rabbit eyes tested across the 5 pressure stages considered (inter-pressure differences) were statistically significant (P = 0.00). IOPp was highly to moderately correlated with most biomechanical metrics, especially CRF, A1T, A1V, A2V, PD and DA, while the relationships with CH, A2T, A1L and HCT were poor. IOP has important influences on most corneal biomechanical metrics provided by CVS and ORA. Two biomechanical metrics A1V and HR were influenced by CCT after correcting for the effect of IOP in most pressure stages, while the correlation with others were weak. Comparisons of research groups based on ORA and CVS with different IOPs and CCTs may lead to possible misinterpretations if both or one of which are not considered in the analysis. PMID- 26026881 TI - Microbiological survey of birds of prey pellets. AB - A microbiological survey of 73 pellets collected from different birds of prey species housed at the Wildlife Rescue and Rehabilitation Center of Napoli (southern Italy) was performed. Pellets were analyzed by culture and biochemical methods as well as by serotyping and polymerase chain reaction. We isolated a wide range of bacteria some of them also pathogens for humans (i.e. Salmonella enterica serotype Typhimurium, Campylobacter coli, Escherichia coli O serogroups). This study highlights the potential role of birds of prey as asymptomatic carriers of pathogenic bacteria which could be disseminated in the environment not only through the birds of prey feces but also through their pellets. PMID- 26026880 TI - Gastrointestinal stromal tumor of the stomach and hepatocellular carcinoma: An unusual association. AB - INTRODUCTION: Gastrointestinal stromal tumors (GIST) are uncommon, potentially malignant tumors, that arise in the wall of the gastrointestinal tract. Up to 50% can develop metastasis, mainly in the liver, but the occurrence of synchronous primary liver tumors is a rare event in these patients. PRESENTATION OF CASE: The authors report a case of the association of gastric GIST and hepatocellular carcinoma (HCC) in a non-cirrhotic liver in a 76 year-old patient. DISCUSSION: The appearance of an hepatic lesion in a GIST patient does not necessarily imply its secondary nature. CONCLUSION: In diagnosed GIST patients, all efforts should be pursued to characterize synchronous hepatic lesions, in order to plan a correct and tailored treatment of the patients. PMID- 26026879 TI - Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2. AB - Feingold syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various learning disabilities. Heterozygous deletion of the miR-17-92 cluster is responsible for a subset of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize this disorder are partially recapitulated in mice that harbor a heterozygous deletion of this cluster (miR-17-92?/+ mice). Although Feingold patients develop a wide array of learning disabilities, no scientific description of learning/cognitive disabilities, intellectual deficiency, and brain alterations have been described in humans and animal models of FS2. The aim of this study was to draw a behavioral profile, during development and in adulthood, of miR-17-92?/+ mice, a genetic mouse model of FS2. Moreover, dopamine, norepinephrine and serotonin tissue levels in the medial prefrontal cortex (mpFC), and Hippocampus (Hip) of miR-17-92?/+ mice were analyzed.Our data showed decreased body growth and reduced vocalization during development. Moreover, selective deficits in spatial ability, social novelty recognition and memory span were evident in adult miR-17-92?/+ mice compared with healthy controls (WT). Finally, we found altered dopamine as well as serotonin tissue levels, in the mpFC and Hip, respectively, of miR-17 92?/+ in comparison with WT mice, thus suggesting a possible link between cognitive deficits and altered brain neurotransmission. PMID- 26026882 TI - Generation of Corneal Keratocytes from Human Embryonic Stem Cells. AB - Human Embryonic Stem Cells (hESC) offer an important resource as a limitless supply of any differentiated cell type of the human body. Keratocytes, cells from the corneal stroma, may have the potential for restoration of vision in cell therapy and biomedical engineering applications, but these specialized cells are not readily expanded in vitro. Here we describe a two-part method to produce keratocytes from the H1 hESC cell line. The hESC cells, maintained and expanded in feeder-free culture medium are first differentiated to neural crest cells using the stromal-derived inducing activity (SDIA) of the PA6 mouse embryonic fibroblast cell line. The resulting neural crest cells are selected by their expression of cell-surface CD271 and subsequently cultured as 3D pellets in a defined differentiation medium to induce a keratocyte phenotype. PMID- 26026883 TI - Maximizing Clonal Embryonic Stem Cell Derivation by ERK Pathway Inhibition. AB - Since the development of inhibitor-based defined culture conditions (known as "2i"), multiple clonal embryonic stem cell (ESC) lines can be readily derived from single cells isolated directly from mouse embryos. In addition to providing an efficient means to generate ES cells from compound transgenic or murine disease models on any genetic background, this technology can be used to investigate the process of ESC derivation at both a functional and molecular level. Here, we provide details of the procedure for both maximizing the number of cells in the donor tissue and subsequent effective derivation of multiple clonal ES cell lines. PMID- 26026884 TI - Resolving Heterogeneity: Fluorescence-Activated Cell Sorting of Dynamic Cell Populations from Feeder-Free Mouse Embryonic Stem Cell Culture. AB - Embryonic stem cell (ESC) culture comprises a mixture of cells that are primed to differentiate into different lineages. In conditions where ESCs self-renew, these primed populations continuously interconvert and consequently show highly dynamic coordinated changes in their expression of different sets of pluripotency and differentiation markers. It has become increasingly apparent that this transcriptional heterogeneity is an important characteristic of ESC culture. By sorting for specific populations of ESCs it is possible to enrich for cells with a capacity to colonize the embryo proper or the extra-embryonic lineages such as the descendents of the primitive endoderm or trophoblast. Here, we describe a method of isolating specific sub-sets of ESCs from the pluripotent cells present in in vitro ESC culture using SSEA1 antibody staining in combination with reporter lines and fluorescence activated cell sorting (FACS). PMID- 26026885 TI - Cold denaturation as a tool to measure protein stability. AB - Protein stability is an important issue for the interpretation of a wide variety of biological problems but its assessment is at times difficult. The most common parameter employed to describe protein stability is the temperature of melting, at which the populations of folded and unfolded species are identical. This parameter may yield ambiguous results. It would always be preferable to measure the whole stability curve. The calculation of this curve is greatly facilitated whenever it is possible to observe cold denaturation. Using Yfh1, one of the few proteins whose cold denaturation occurs at neutral pH and low ionic strength, we could measure the variation of its full stability curve under several environmental conditions. Here we show the advantages of gauging stability as a function of external variables using stability curves. PMID- 26026886 TI - Three-dimensional position changes of the midface following Le Fort III advancement in syndromic craniosynostosis. AB - Little is known about the positional change of the Le Fort III segment following advancement. To study this, pre- and postoperative computed tomography scans of 18 craniosynosthosis patients were analyzed. The Le Fort III segment movement was measured by creating a reference coordinate system and by superpositioning the postoperative over the preoperative scan. On both the pre- and postoperative scans, four anatomical landmarks were marked: the most anterior point of the left and right foramen infraorbitale, the nasion, and the anterior nasal spine. A significant anterior movement of the four reference points was observed. No significant transversal differences were found. A significant difference between the anterior movement of the nasion and anterior nasal spine was found. In vertical dimension, there was a significant cranial movement of nasion in the study group. In addition, from all patients standardized lateral X-rays were viewed to determine the location and direction of force application that were linked to the outcomes of the three-dimensional movement of the nasion and anterior nasal spine (ANS) and the surgical technique. Conclusively, a significant advancement of the midface can be achieved with Le Fort III distraction osteogenesis in this specific patient group. Counterclockwise movement seemed to be the most dominant movement despite different modes of anchorage. PMID- 26026887 TI - Histopathological features of hypertrophic bone mass of temporomandibular joint ankylosis (TMJA): An explanation of pathogenesis of TMJA. AB - Temporomandibular joint ankylosis (TMJA) is a severe organic disease with progressive limitation of the mouth opening. Histopathologically, a residual joint space is reported to consist of fibrous tissue and/or cartilage, indicating two types of interface (osteo-fibrous and osteo-chondral) of residual joint space. It is well known that adverse mechanical stress results in pathological changes of osteoarthritis and enthesopathy in these interfaces. What would happen pathologically in these interfaces of TMJA under repeated mandible movement has not been elucidated. Fourteen tissue samples of residual joint space and temporal and condylar bone were stained with hematoxylin and eosin and evaluated by collagen I and II immunohistochemistry. A pathological study of 14 TMJA patients showed that the residual joint space presented a fibrocartilage entheses structure and an articular cartilage structure. Moreover, these two structures were associated with pathological alterations of both osteoarthritis and enthesopathy, including degenerated and necrotized tissue, chondrocyte cloning, crack and fissure, various bone scleroses, and inflammatory granulation tissue. It is suggested that the pathological alterations of both osteoarthritis and enthesopathy occurred in TMJA, which hints at mechanical stress on TMJA development. PMID- 26026888 TI - Cytoprotective effects of melatonin on zoledronic acid-treated human mesenchymal stem cells in vitro. AB - OBJECTIVE: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a common clinical complication in patients receiving bisphosphonate therapy. Furthermore, melatonin has been proposed as a therapeutic drug for the oral cavity due to its antioxidant properties. This study aimed to evaluate the cytoprotective effects of melatonin on zoledronic acid (ZA)-treated human mesenchymal stem cells from periodontal ligament (PDLSCs) and bone marrow (BMMSCs). METHODS: PDLSCs and BMMSCs were exposed to ZA, melatonin or ZA + melatonin for 72 h. Cell proliferation was measured by a colorimetric assay, whereas their mesenchymal phenotype was analyzed by flow cytometry. RESULTS: Proliferation assays showed that BMMSCs presented higher ZA resistance than PDLSCs, as well as a difference in response to the simultaneous treatment of ZA + melatonin. Using PDLSCs, high doses of melatonin significantly increased their proliferation, whereas lower concentrations were enough to enhance ZA-treated BMMSC proliferation. Moreover, PDLSCs displayed a CD90/CD105 downregulation and CD73 upregulation in response to ZA, which was more pronounced in response to melatonin. Furthermore, ZA or ZA + low doses of melatonin induced a decrease of expression of CD90/CD105/CD73 on BMMSCs, while a higher concentration recovered CD73 levels. CONCLUSION: These results suggest that melatonin has a cytoprotective effect on ZA-treated PDLSCs and BMMSCs. Thus, it could be used for BRONJ prevention. PMID- 26026889 TI - Traction force microscopy on soft elastic substrates: A guide to recent computational advances. AB - The measurement of cellular traction forces on soft elastic substrates has become a standard tool for many labs working on mechanobiology. Here we review the basic principles and different variants of this approach. In general, the extraction of the substrate displacement field from image data and the reconstruction procedure for the forces are closely linked to each other and limited by the presence of experimental noise. We discuss different strategies to reconstruct cellular forces as they follow from the foundations of elasticity theory, including two- versus three-dimensional, inverse versus direct and linear versus non-linear approaches. We also discuss how biophysical models can improve force reconstruction and comment on practical issues like substrate preparation, image processing and the availability of software for traction force microscopy. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26026890 TI - National Institute of Nursing Research commentary on the Idea Festival for Nursing Science Education. PMID- 26026891 TI - Intranasal midazolam for anxiolysis in closed reduction of nasal fractures in children. AB - OBJECTIVES: Nasal fractures can result in obstruction of the nasal airflow and cosmetic deformities, and are treated either with observation, closed reduction, or a delayed rhinoplasty. In the pediatric patient, closed reduction is challenging due to anxiety and poor patient cooperation. Here, we describe the unique topical use of intranasal midazolam for anxiolysis in two pediatric patients at the time of closed reduction of nasal fractures, which has not been previously described. METHODS: Retrospective case series. RESULTS: In this case series, intranasal midazolam was used in two pediatric patients with isolated nasal fractures during closed reduction for anxiolysis in the Emergency department at a single academic medical institution between 2012 and 2013. There were no adverse outcomes and anxiolysis was achieved in both patients. CONCLUSIONS: Intranasal midazolam can provide effective anxiolysis for pediatric patients during closed reduction of nasal fractures. PMID- 26026892 TI - Chronic suppurative otitis media due to nontuberculous mycobacteria: A case of successful treatment with topical boric acid. AB - Nontuberculous mycobacteria (NTM) are an increasingly recognized cause of chronic suppurative otitis media in children with tympanostomy tubes. Treatment of this condition is difficult and typically requires a combination of systemic antibiotics and surgical debridement. We present the first case of a 2-year-old male with chronic suppurative otitis media due to NTM who failed systemic antibiotic therapy and was successfully managed with topical boric acid powder. This report highlights the challenges involved in treating this infection, and introduces boric acid as a potentially valuable component of therapy. PMID- 26026894 TI - Subjective pain perception mediated by alpha rhythms. AB - Suppression of spontaneous alpha oscillatory activities, interpreted as cortical excitability, was observed in response to both transient and tonic painful stimuli. The changes of alpha rhythms induced by pain could be modulated by painful sensory inputs, experimental tasks, and top-down cognitive regulations such as attention. The temporal and spatial characteristics, as well as neural functions of pain induced alpha responses, depend much on how these factors contribute to the observed alpha event-related desynchronization/synchronization (ERD/ERS). How sensory-, task-, and cognitive-related changes of alpha oscillatory activities interact in pain perception process is reviewed in the current study, and the following conclusions are made: (1) the functional inhibition hypothesis that has been proposed in auditory and visual modalities could be applied also in pain modality; (2) the neural functions of pain induced alpha ERD/ERS were highly dependent on the cortical regions where it is observed, e.g., somatosensory cortex alpha ERD/ERS in pain perception for painful stimulus processing; (3) the attention modulation of pain perception, i.e., influences on the sensory and affective dimensions of pain experience, could be mediated by changes of alpha rhythms. Finally, we propose a model regarding the determinants of pain related alpha oscillatory activity, i.e., sensory-discriminative, affective-motivational, and cognitive-modulative aspects of pain experience, would affect and determine pain related alpha oscillatory activities in an integrated way within the distributed alpha system. PMID- 26026893 TI - Determination of Tumor Heterogeneity in Colorectal Cancers Using Heterogeneity Tissue Microarrays. AB - Cancer is often heterogeneous both on a morphological and on a genetic level. Though resected tumors are often large, molecular tumor analysis is usually restricted to one tissue block. In this project we introduce a new tool for a high-throughput heterogeneity analysis of colorectal cancer. A heterogeneity tissue microarray (TMA) was manufactured from tissues of 340 patients with colorectal cancer. For this purpose 8 different tissue spots were taken from as many different cancer blocks per patient as possible (at least 4 different blocks). Additional tissue samples from 1 to 4 corresponding lymph node metastases were added from 134 patients. The system was then validated by analysing one parameter each known for minimal (p53) or substantial (HER2) heterogeneity in colorectal cancer. P53 alterations as detected by immunohistochemistry were seen in 174 (51.3 %) of 339 analyzable primary tumors of which 23 (13.2 % of positive cases) showed a heterogeneous distribution pattern. HER2 overexpression was seen in 18 (5.4 %) of 336 evaluable tumors. HER2 amplification occurred in 6 (33.3 %) of the 18 cases with HER2 overexpression. Genomic heterogeneity was more prevalent for HER2 alterations than for p53 alterations. For immunohistochemical expression analysis, 16 of 18 positive cases were heterogeneous (88.9 %) and for amplification 3 of 6 cases (50 %) were heterogeneous. Large section validation revealed, however a considerable fraction of heterogeneous cases were due to technical artifacts. In summary, our data suggest, that heterogeneity TMAs are a powerful tool to rapidly screen for molecular heterogeneity in colorectal cancer. PMID- 26026895 TI - "Observational Medicine" should be replaced by "Real Science". AB - Science is defined by fundamental principles that can be modeled to explain observations and predict new findings. Clinical trials have not achieved this status. The trials generate new observations and lack the ability to predict future outcomes. The following hypotheses are generated: 1. Biology has no defined fundamental principles that can be modeled to explain observations and predict new findings. 2. Observational Medicine has advanced our knowledge but has not elicited fundamental principles that could predict future outcomes in individual patients. 3. A biologic model of regeneration/degeneration moderated by inflammation framed by 6 laws of biology can make predictions. 4. Biology can be quantified. Observational Medicine from Hippocrates, through Framingham and the Women's Health Initiative are examined. These trials have advanced our knowledge but have not elicited fundamental principles that could predict future outcomes. A set of fundamental principles of biology and a model based on regeneration/degeneration modified by inflammation has been previously reported. These laws represent empirical facts and no exceptions to these laws have been realized. The model suggests the observations from Framingham could be explained by the quantity of circulating stem cells and the inflammatory status of the patient. Clinical trials that select patients by their quantity of stem cells and inflammatory status would be more efficient than selection by risk factors. This same model can explain the inability of the Women's Health Initiative to determine the female advantage over men in coronary heart disease. This model is exploited to make predictions in coronary disease, heart failure, and is used to explain disease processes, paradoxes and make predictions. Mechanical statistical entropy is method that can quantify biologic processes. PMID- 26026896 TI - Identification of miR-199a-5p target genes in the skin keratinocyte and their expression in cutaneous squamous cell carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that mediate the biological cellular processes via regulation of target genes through translational repression or mRNA degradation. Among various miRNAs, miRNA-199a (miR-199a) has been known to be involved in cancer development and progression, protection of cardiomyocyte, and skeletal formation. OBJECTIVE: Although miR-199a 5p was studied in various cell types, the role of miR-199a-5p and its target genes in skin keratinocyte have not been documented. In this study, we identified target genes of miR-199a-5p in skin keratinocyte. METHODS: In order to identify the target of miR-199a-5p in keratinocyte, microarray analysis was performed. The relative expression of candidate target genes was investigated using quantitative RT-PCR and western blot analysis. To determine whether their expression was directly regulated by miR-199a-5p, luciferase reporter assay was performed. In order to investigate expression of target genes in cutaneous squamous cell carcinoma, immunohistochemistry was performed. RESULTS: We identified new target genes, Bcam, Fzd6, and Wnt7a, as well as previously known targets, Ddr1 and Podxl. We found that their expressions were directly regulated by miR-199a-5p in the skin keratinocyte using in vitro study and observed that expression of miR 199a-5p was inversely correlated with those of BCAM, FZD6 and DDR1 in the cSCC. In addition, overexpression of miR-199a-5p resulted in inhibition of the migratory capability of the skin keratinocyte. CONCLUSION: These results suggested that miR-199a-5p plays a role in pathogenesis of cSCC via inhibition of invasiveness through regulation of BCAM, FZD6 and DDR1 expression. PMID- 26026897 TI - Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger Than Age 18 Years. AB - BACKGROUND: There have been no clinical trials for approval of medications for treating multiple sclerosis in patients younger than age 18 years. All treatments are based on personal experience and data from open observational studies. Fingolimod is an oral drug for multiple sclerosis that has been shown to be efficient and safe in adults. The aim of our study is to describe patients with multiple sclerosis who started treatment with fingolimod before the age of 18 years. PARTICIPANTS AND METHODS: Seventeen patients treated with fingolimod were identified in the Brazilian database of children and adolescents with multiple sclerosis. The average time of use of the drug was 8.6 months. RESULTS: Fingolimod showed a good safety and efficacy profile in these patients, all of whom had very active multiple sclerosis. After starting treatment with fingolimod, only one patient had a relapse and a new lesion on magnetic resonance imaging. The patients' degree of disability did not progress. No major adverse events were reported in relation to the first dose of the drug, nor in the short- and medium-term treatment. No patient has been followed for longer than 18 months, thus limiting long-term conclusions. CONCLUSIONS: Off-label use of fingolimod in patients younger than age 18 years may be a good therapeutic option for multiple sclerosis control. PMID- 26026898 TI - Pharmacological study of the light/dark preference test in zebrafish (Danio rerio): Waterborne administration. AB - Anxiety is a complex disorder; thus, its mechanisms remain unclear. Zebrafish (Danio rerio) are a promising pharmacological model for anxiety research. Light/dark preference test is a behaviorally validated measure of anxiety in zebrafish; however, it requires pharmacological validation. We sought to evaluate the sensitivity of the light/dark preference test in adult zebrafish by immersing them in drug solutions containing clonazepam, buspirone, imipramine, fluoxetine, paroxetine, haloperidol, risperidone, propranolol, or ethanol. The time spent in the dark environment, the latency time to first crossing, and the number of midline crossings were analyzed. Intermediate concentrations of clonazepam administered for 600s decreased the time spent in the dark and increased locomotor activity. Buspirone reduced motor activity. Imipramine and fluoxetine increased time spent in the dark and the first latency, and decreased the number of alternations. Paroxetine did not alter the time in the dark; however, it increased the first latency time and decreased locomotor activity. Haloperidol decreased the time spent in the dark at low concentrations. Risperidone and propranolol did not change any parameters. Ethanol reduced the time spent in the dark and increased the number of crossings at intermediate concentrations. These results corroborate the previous work using intraperitoneal drug administration in zebrafish and rodents, suggesting that water drug delivery in zebrafish can effectively be used as an animal anxiety model. PMID- 26026899 TI - Cigarette smoking may modify the association between cannabis use and adiposity in males. AB - INTRODUCTION: The few population-based studies that investigate the association between cannabis use and adiposity are inconclusive possibly because nicotine moderates the effect of cannabis on adiposity. The objective was to test the hypotheses that the association between cannabis use and adiposity in young men and women is modified by cigarette smoking. METHODS: Data were drawn from the Nicotine Dependence in Teens (NDIT) study, a 13-year prospective cohort investigation of the natural course of nicotine dependence. A total of 271 males and 319 females aged 12-13years at cohort inception provided data on past-year cannabis use and number of cigarettes smoked per day in the past three months, at age 20years. Outcomes included change in body mass index (BMI) and in waist circumference (WC) from ages 17 to 24years. The hypothesis was tested in multiple linear regression models that included interaction terms for cannabis use and cigarette smoking and controlled for physical activity, sedentary behavior, alcohol use, and level of the outcome at baseline. RESULTS: The association between cannabis use and change in adiposity was U-shaped in male non-smokers and in females, and an inverted U-shape in male smokers. In males, the interaction between cannabis use and cigarette smoking was significant in both the models for change in BMI (p=0.004; n=271) and change in WC (p=0.04; n=250). In females, the interaction between cannabis use and cigarette smoking was not significant. CONCLUSION: Smoking cigarettes appears to modify the association between cannabis use and adiposity in young men. PMID- 26026900 TI - Non-lethal sampling for mercury evaluation in crocodilians. AB - Mercury (Hg) is a ubiquitous environmental contaminant that poses potential threats to ecosystems due to its toxicity to humans and wildlife. The development of non-lethal sampling techniques is a critical step for evaluation of Hg in threatened species in tropical floodplain environments, where most of Hg found is the result of land use and gold mining activities, and more methylation sites are available. We evaluated the spatial and seasonal effectiveness of caudal scutes and claws to estimate Hg bioaccumulation in crocodilians (Caiman yacare), in the scarcely documented Pantanal. Hence, we investigated the potential for Hg bioaccumulation in top predators according to its proximity to mining sites, and in water bodies with different hydrological characteristics and connectivity with the main river during two phases of the flood pulse (dry and flood). The highest Hg concentrations were detected in caimans captured close to mining activities, in claws (2176 ng g(-1) ww) and caudal scutes (388 ng g(-1) ww). THg concentration in claws was related to the flood season and its mean concentration was thirteen fold higher than Hg concentration in scutes during whole year. Both tissues were found to be effective as non-lethal sampling techniques for measuring Hg bioaccumulation in reptiles over time. Nevertheless, claw tissue seems to have a more consistent result, since its constitutional chemical characteristics makes it a better indicator of spatial patterns that influence on Hg exposure. PMID- 26026901 TI - Modeling bioaccumulation and biomagnification of nonylphenol and its ethoxylates in estuarine-marine food chains. AB - There are several studies on bioaccumulation and biomagnification of nonylphenol (NP) and its ethoxylates (NPEOs), but their toxico-kinetic mechanisms remain unclear. In the present investigation, we explored the accumulation of NP and NPEOs in estuarine-marine food chains with a bioaccumulation model comprising five trophic levels. Using this model, we estimated uptake and elimination rate constants for NPEOs based on the organisms' weight and lipid content and the chemicals' Kow. Further, we calculated accumulation factors for NP and NPEOs, including biota-sediment accumulation factors (BSAF) and biomagnification factors (BMF), and compared these to independent field measurements collected in the Western Scheldt estuary in The Netherlands and field data reported in the literature. The estimated BSAF values for NP and total NPEOs were below 1 for all trophic levels. The estimated BMF values were around 1 for all trophic levels except for the highest level (carnivorous mammals and birds). For this trophic level, the estimated BMF value varied between 0.1 and 2.4, depending on the biotransformation capacity. For all trophic levels, except primary producers, the accumulation estimates that accounted for biotransformation of NPEOs into NP were closer to the field data than model estimates that did not include biotransformation, indicating that NP formation by biotransformation of NPEOs might occur in organisms. PMID- 26026902 TI - Enantiomeric fraction and isomeric composition to assess sources of DDT residues in soils. AB - Chiral pesticides such as o,p'-DDT can undergo enantioselective microbial degradation in soil. Hence, the enantiomeric fraction (EF) of o,p'-DDT was used as an approach to assess potential recent inputs of DDT in the lower part of the Ebro River basin (NE Spain), a region heavily impacted by agricultural and industrial activities, including a dicofol production and a chloro-alkali plants. The EFs of five out of nineteen soils were not different from the racemic value (0.505+/-0.010), confirming that the Ebro River and some of its tributaries, Segre and Cinca rivers, transported fresh DDT residues despite its ban in Spain during the 90 s. o,p'-DDT/p,p'-DDT ratios in soils suggest that recent use of technical DDT and/or DDT-contaminated dicofol may be responsible for the fresh DDT inputs in the Segre River, while in the Ebro River, they indicate a dominant contribution of technical DDT, likely related to the residues accumulated by the chloro-alkali plant discharges. PMID- 26026903 TI - Predictivity of in vitro non-clinical cardiac contractility assays for inotropic effects in humans--A literature search. AB - Adverse drug effects on the cardiovascular system are a major cause of compound attrition throughout compound discovery and development. There are many ways by which drugs can affect the cardiovascular system, including effects on the electrocardiogram, vascular resistance, heart rate and the force of contraction of the heart (inotropy). Compounds that increase the force of contraction of the heart can be harmful in patients with ischemic heart disease, whilst negative inotropes can induce symptoms of heart failure. There is a range of non-clinical in vitro and in vivo assays used to detect inotropic effects of drugs. We have conducted a literature review of the in vitro assays and compared the findings from these with known effects on cardiac contractility in man. There was a wide variety of assays used, ranging from perfuse whole hearts to isolated regions of the heart (papillary muscle, ventricle and atria), which were removed from a number of species (cat, guinea pig, rabbit and rat). We conducted two analyses. The first was investigating the concordance of the findings from the in vitro assays at any concentration with those observed in man (an assessment of hazard identification) and the second was the concordance of the in vitro findings at concentrations tested up to 10-fold higher than those tested in the clinic. We found that when used as a hazard identification tool, the available assays had good sensitivity (88%), although the specificity was not so good (60%), but when used as a risk management tool the sensitivity was considerably reduced (sensitivity 58-70% and specificity 60%). These data would suggest that the available in vitro assays can be used as hazard identification tools for adverse drug effects on cardiac contractility, but there is a need for new assays to better predict the exposures in man that may cause a change in cardiac contractility and therefore better predict the likely therapeutic index of compounds prior to nomination of compounds for clinical development. PMID- 26026904 TI - Are ta-siRNAs only originated from the cleavage site of miRNA on its target RNAs and phased in 21-nt increments? AB - Trans-acting siRNAs (ta-siRNAs) are a class of small RNAs playing crucial roles in the regulation of plant gene expression. According to the canonical model, specific miRNA-guided cleavage of a TAS transcript triggers and sets the registry for the subsequent production of ta-siRNAs at 21-nt increments from the cleavage site. However, a previously validated 22-nt ta-siR2140 indicated that ta-siRNAs might be initiated from other phase increments and registers, which resulted in massive ta-siRNAs missing in the canonical model. To test this hypothesis, we employed high-throughput sequencing data to thoroughly identify the miR173 triggered ta-siRNAs from TAS1/TAS2 transcripts. As a result, thousands of phased siRNAs not generated through the canonical pathway were identified and 110 novel siRNA-target interactions were further validated based on degradome sequencing data. Based on these results, we propose that the canonical biogenesis model of ta-siRNAs should be modified in order to recruit the previously unidentified ta siRNA candidates. PMID- 26026905 TI - A novel recombinant AzrC protein proposed by molecular docking and in silico analyses to improve azo dye's binding affinity. AB - Azo dyes are broadly used in different industries through their chemical stability and ease of synthesis. These dyes are usually identified as critical environmental pollutants and many attentions were performed to degradation of azo dyes using biological systems. In this study, the interactions of an azoreductase from mesophilic gram-positive Bacillus sp. B29, AzrC, with four common azo dyes (orange I, orange II, orange G and acid red 88) were investigated. Fifteen points, double, triple and quadruple mutant forms of AzrC were made using Molegro Virtual Docker 6.0 in order to improve the binding affinity of azo dyes to AzrC. The impact of 15 different mutations on azo dye affinity potency of AzrC was computationally analyzed using AzrC-azo dye molecular docking, and each interaction was scored based on AutoDock 4.2 free binding energy. Our results have indicated that Asn 104 (A), Asn 187 (B), and Tyr 151 (A) make stable hydrogen bond between AzrC and azo dyes. The hydrophobic amino acids like Phe105 (A), Phe 125 (B), and Phe 172 (B) in wild type form make hydrophobic interactions. In addition, the presence of more hydrophobic residues F60 (B), I119 (B), I121 (B) and F132 (B) in mutant forms made more powerful hydrophobic pocket in the active site. In conclusion, recombinant AzrC with quadruple mutations was suggested in order to increase the biodegradation capacity of AzrC through improving its affinity to four studied azo dyes. This study would be promising for future experimental analyses in order to produce recombinant form of AzrC. PMID- 26026906 TI - HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution. AB - 293 cell line (widely known as the Human Embryonic Kidney 293 cells) and its derivatives were the most used cells after HeLa in cell biology studies and after CHO in biotechnology as a vehicle for the production of adenoviral vaccines and recombinant proteins, for analysis of the neuronal synapse formation, in electrophysiology and neuropharmacology. Despite the historically long-term productive exploitation, the origin, phenotype, karyotype, and tumorigenicity of 293 cells are still debated. 293 cells were considered the kidney epithelial cells or even fibroblasts. However, 293 cells demonstrate no evident tissue specific gene expression signature and express the markers of renal progenitor cells, neuronal cells and adrenal gland. This complicates efforts to reveal the authentic cell type/tissue of origin. On the other hand, the potential to propagate the highly neurotropic viruses, inducible synaptogenesis, functionality of the endogenous neuron-specific voltage-gated channels, and response to the diverse agonists implicated in neuronal signaling give credibility to consider 293 cells of neuronal lineage phenotype. The compound phenotype of 293 cells can be due to heterogeneous, unstable karyotype. The mean chromosome number and chromosome aberrations differ between 293 cells and derivatives as well as between 293 cells from the different cell banks/labs. 293 cells are tumorigenic, whereas acute changes of expression of the cancer-associated genes aggravate tumorigenicity by promoting chromosome instability. Importantly, the procedure of a stable empty vector transfection can also impact karyotype and phenotype. The discussed issues caution against misinterpretations and pitfalls during the different experimental manipulations with 293 cells. PMID- 26026907 TI - Complete mammary necrosis due to acenocoumarol. PMID- 26026908 TI - Celiac artery stenosis due to median arcuate ligament compression: A risk factor in cephalic duodenopancreatectomy? PMID- 26026909 TI - [Inverted-3 sign of Frostberg forces to exclude malignancy]. PMID- 26026910 TI - In vivo studies of silk based gold nano-composite conduits for functional peripheral nerve regeneration. AB - We report a novel silk-gold nanocomposite based nerve conduit successfully tested in a neurotmesis grade sciatic nerve injury model in rats over a period of eighteen months. The conduit was fabricated by adsorbing gold nanoparticles onto silk fibres and transforming them into a nanocomposite sheet by electrospinning which is finally given a tubular structure by rolling on a stainless steel mandrel of chosen diameter. The conduits were found to promote adhesion and proliferation of Schwann cells in vitro and did not elicit any toxic or immunogenic responses in vivo. We also report for the first time, the monitoring of muscular regeneration post nerve conduit implantation by recording motor unit potentials (MUPs) through needle electromyogram. Pre-seeding the conduits with Schwann cells enhanced myelination of the regenerated tissue. Histo-morphometric and electrophysiological studies proved that the nanocomposite based conduits pre seeded with Schwann cells performed best in terms of structural and functional regeneration of severed sciatic nerves. The near normal values of nerve conduction velocity (50 m/sec), compound muscle action potential (29.7 mV) and motor unit potential (133 MUV) exhibited by the animals implanted with Schwann cell loaded nerve conduits in the present study are superior to those observed in previous reports with synthetic materials as well as collagen based nerve conduits. Animals in this group were also able to perform complex locomotory activities like stretching and jumping with excellent sciatic function index (SFI) and led a normal life. PMID- 26026911 TI - Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity. AB - Piperlongumine is a natural compound recently identified to be toxic selectively to tumor cells in vitro and in vivo. However, the molecular mechanism underlying its anti-tumor action still remains unclear. In this report, we describe another novel mechanism by which piperlongumine mediates its anti-tumor effects. We found that piperlongumine is a novel nuclear export inhibitor. Piperlongumine could induce nuclear retention of tumor suppressor proteins and inhibit the interactions between CRM1 and these proteins. Piperlongumine could directly bind to the conserved Cys528 of CRM1 but not to a Cys528 mutant peptide. More importantly, cancer cells expressing mutant CRM1 (C528S) are resistant to piperlongumine, demonstrating the nuclear export inhibition via direct interaction with Cys528 of CRM1. The inhibition of nuclear export by piperlongumine may account for its therapeutic properties in cancer diseases. Our findings provide a good starting point for development of novel CRM1 inhibitors. PMID- 26026912 TI - Aflatoxin B1 augments the synthesis of corticotropin releasing hormone in JEG-3 placental cells. AB - Aflatoxins pose a major threat to food safety. These toxins are classified as hepatocarcinogens; however, their effect on the other tissues is unclear. During pregnancy, the fetus and placental tissues are especially sensitive to toxin exposure. In the present study aflatoxin B1 was found to induce the mRNA expression of corticotrophin-releasing hormone (CRH) in placental cells. A corresponding increase in CRH peptide in the culture medium was also observed. Since signal transduction pathways have been described previously in the control of CRH transcription, the status of protein kinase Cs (PKCs) and mitogen activated protein kinases (MAPKs) were determined by Western analysis. In the aflatoxin B1-treated cultures, PKC alpha/betaII/delta and ERK-1/2 were activated. As the PKC inhibitor bisindolylmaleimide I and the ERK inhibitor PD98059 could revert the induced CRH expression, the pathways dictated by PKC and ERK were likely involved in the transcriptional regulation. Electrophoretic mobility shift assay showed that C/EBP could be the ultimate activated transcription factor. Taken together, this study demonstrated that aflatoxin B1 could increase the parturition-related placental hormone in vitro. These findings might have significant implications for public health. PMID- 26026913 TI - Dithiocarbamate fungicides increase intracellular Zn(2+) levels by increasing influx of Zn(2+) in rat thymic lymphocytes. AB - Dithiocarbamate fungicides are used as alternative antifouling agents to highly toxic organotin antifouling agents, such as tri-n-butyltin and triphenyltin. There are some concerns regarding their environmental and health risks. It has been shown that tri-n-butyltin increases intracellular Zn(2+) levels of mammalian lymphocytes. Therefore, we examined the effects of dithiocarbamate fungicides (Ziram, Thiram, and Zineb) on rat thymic lymphocytes using a flow-cytometric technique to elucidate how these fungicides affect intracellular Zn(2+) levels. We further determined whether the agents increase intracellular Zn(2+) and/or Ca(2+), because both Zn(2+) and Ca(2+) are intracellular signals in lymphocytes, and excessive increases in their intracellular concentrations can have adverse effects. Dithiocarbamate fungicides increased intracellular Zn(2+) levels, without affecting intracellular Ca(2+) levels. Ziram was the most potent compound, increasing intracellular Zn(2+) levels via Zn(2+) influx. Ziram (1MUM) greatly decreased the cellular nonprotein thiol content, and Zn(2+) chelators attenuated the Ziram-induced decrease. Ziram increased the population of annexin V-positive cells in a Zn(2+)-dependent manner. Therefore, we propose that dithiocarbamate fungicides induce Zn(2+) influx, resulting in an excessive elevation of intracellular Zn(2+) levels, leading to the induction of apoptosis. This study gives a basic insight into the mechanisms of dithiocarbamate fungicide induced adverse events. PMID- 26026914 TI - Stress lowers the threshold dose at which bisphenol A disrupts blastocyst implantation, in conjunction with decreased uterine closure and e-cadherin. AB - Exposure to stress can disrupt blastocyst implantation in inseminated female mice, and evidence implicates elevation of the female's estrogen:progesterone ratio. Exposure to the xenoestrogen, bisphenol A (BPA) can also disrupt implantation. Undisturbed control female CF-1 mice were compared to other females that were exposed to predators (rats) across a wire-mesh grid during gestation days (GD) 1-4, a procedure that elevates corticosterone but does not on its own disrupt implantation in this genetic strain. They were concurrently exposed to varied doses of BPA that on their own were below the threshold dose sufficient to disrupt implantation. On GD 6, we measured the number of intrauterine implantation sites and extracted their uteri, which subsequently were stained and analyzed for uterine luminal area and epithelial cadherin (e-cadherin), a molecule that causes uterine closure and adhesion of blastocysts to the uterine epithelium. The combination of rat-exposure stress and BPA significantly disrupted implantation and increased uterine luminal area, whereas either manipulation on its own did not. E-cadherin was significantly reduced by exposure to BPA, positively correlated with the number of implantation sites, and inversely correlated with luminal area. BPA exposure was also associated with nonmonotonic perturbation of urinary corticosterone concentrations and increased urinary estradiol concentrations on GD 6. These data are consistent with a potential summation of stress-induced estrogen and xenoestrogen activity. PMID- 26026915 TI - Effect of echolocation behavior-related constant frequency-frequency modulation sound on the frequency tuning of inferior collicular neurons in Hipposideros armiger. AB - In constant frequency-frequency modulation (CF-FM) bats, the CF-FM echolocation signals include both CF and FM components, yet the role of such complex acoustic signals in frequency resolution by bats remains unknown. Using CF and CF-FM echolocation signals as acoustic stimuli, the responses of inferior collicular (IC) neurons of Hipposideros armiger were obtained by extracellular recordings. We tested the effect of preceding CF or CF-FM sounds on the shape of the frequency tuning curves (FTCs) of IC neurons. Results showed that both CF-FM and CF sounds reduced the number of FTCs with tailed lower-frequency-side of IC neurons. However, more IC neurons experienced such conversion after adding CF-FM sound compared with CF sound. We also found that the Q 20 value of the FTC of IC neurons experienced the largest increase with the addition of CF-FM sound. Moreover, only CF-FM sound could cause an increase in the slope of the neurons' FTCs, and such increase occurred mainly in the lower-frequency edge. These results suggested that CF-FM sound could increase the accuracy of frequency analysis of echo and cut-off low-frequency elements from the habitat of bats more than CF sound. PMID- 26026916 TI - Syria: end sanctions and find a political solution to peace. PMID- 26026917 TI - Maternal and fetal morbidity associated with uterine rupture of the unscarred uterus. AB - OBJECTIVE: We sought to report obstetric and neonatal characteristics and outcomes following primary uterine rupture in a large contemporary obstetric cohort and to compare outcomes between those with primary uterine rupture vs those with uterine rupture of a scarred uterus. STUDY DESIGN: This was a retrospective case-control study. Cases were defined as women with uterine rupture of an unscarred uterus. Controls were women with uterine rupture of a scarred uterus. Demographics, labor characteristics, and obstetric, maternal, and neonatal outcomes were compared. Primary rupture case outcomes were also compared by mode of delivery. RESULTS: There were 126 controls and 20 primary uterine rupture cases. Primary uterine rupture cases had more previous live births than controls (3.6 vs 1.9; P < .001). Cases were more likely to have received oxytocin augmentation (80% vs 37%; P < .001). Vaginal delivery was more common among cases (45% vs 9%; P < .001). Composite maternal morbidity was higher among primary uterine rupture mothers (65% vs 20%; P < .001). Cases had a higher mean estimated blood loss (2644 vs 981 mL; P < .001) and higher rate of blood transfusion (68% vs 17%; P < .001). Women with primary uterine rupture were more likely to undergo hysterectomy (35% vs 2.4%; P < .001). Rates of major composite adverse neonatal neurologic outcomes including intraventricular hemorrhage, periventricular leukomalacia, seizures, and death were higher in cases (40% vs 12%; P = .001). Primary uterine rupture cases delivering vaginally were more likely to ultimately undergo hysterectomy than those delivering by cesarean (63% vs 9%; P = .017). CONCLUSION: Although rare, primary uterine rupture is particularly morbid. Clinicians must remain vigilant, particularly in the setting of heavy vaginal bleeding and severe pain. PMID- 26026919 TI - Does magnesium exposure affect neonatal resuscitation? AB - OBJECTIVE: Research on immediate neonatal resuscitation suggests that maternal magnesium exposure may be associated with increased risk of low Apgar scores, hypotonia, and neonatal intensive care unit admission. However, not all studies support these associations. Our objective was to determine whether exposure to magnesium at the time of delivery affects initial neonatal resuscitation. STUDY DESIGN: This is a secondary analysis of the Randomized Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy that evaluated whether the study drug (magnesium or placebo) that was administered at the time of delivery was associated with increased risk for a composite adverse neonatal resuscitation outcome (5-minute Apgar score <7, oxygen administration in the delivery room, intubation, chest compressions, hypotension, and hypotonicity). A subgroup analysis was performed among patients who delivered at >=30 weeks of gestation. Log-linear regression was used to control for possible confounders. RESULTS: Data for 1047 patients were analyzed, of whom 461 neonates (44%) were exposed to magnesium. There was no increased risk for the primary composite outcome associated with magnesium exposure. Individual adverse neonatal outcomes and other secondary short-term neonatal outcomes that were evaluated also did not demonstrate an association with magnesium exposure. CONCLUSION: Exposure to magnesium sulfate did not affect neonatal resuscitation or other short-term outcomes. These findings may be useful in planning neonatal care and patient counseling. PMID- 26026918 TI - Maternal marijuana use and neonatal morbidity. AB - OBJECTIVE: Marijuana use is becoming increasingly common in the obstetric population; however, it is unknown whether it is associated with poor neonatal outcomes. We sought to determine the prevalence and risk factors for marijuana use in pregnancy and to evaluate whether marijuana use is independently associated with poor neonatal outcomes. STUDY DESIGN: This was a retrospective cohort study of all consecutive, nonanomalous, term deliveries at 1 institution over a 4-year study period. Women with marijuana use during pregnancy, either by self-report or positive urine drug screen, were compared with women who did not use marijuana. The primary outcome was a composite neonatal morbidity including birthweight less than 2500 g, neonatal intensive care unit admission, 5-minute Apgar score less than 7, and umbilical artery pH less than 7.10. Univariate, bivariate, and multiple logistic regression analyses were performed. RESULTS: Among the 8138 women in the cohort, 680 (8.4%) used marijuana during pregnancy. Women who used marijuana were younger; more likely to be of African American race; have inadequate prenatal care; and use tobacco, alcohol, and other drugs. Medical comorbidities did not differ between groups. After adjusting for smoking, other drug use, and African American race, the composite and all individual markers of poor neonatal outcome were not significantly higher among women who used marijuana during pregnancy. CONCLUSION: Marijuana use is common in pregnancy but may not be an independent risk factor for poor neonatal outcomes in term pregnancies. PMID- 26026920 TI - Progress of induced labor in trial of labor after cesarean delivery. AB - OBJECTIVE: The purpose of this study was to compare the first stage of labor progress in women who undergo an induction of labor after cesarean delivery with women who have spontaneous labor after cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study of consecutive women who had been admitted for delivery with a vertex-presenting fetus who achieved vaginal delivery after cesarean delivery. We compared women who underwent an induction of labor after cesarean delivery with women with spontaneous labor after cesarean delivery. Labor curves were constructed with a repeated-measures analysis; interval censored regression was used to estimate the median time spent to dilate 1 cm, stratified by induction status, and adjusted by obesity, macrosomia, epidural, and previous vaginal delivery. RESULTS: Of 473 laboring women with a previous cesarean delivery, 234 women (49%) were induced. After adjustment for obesity, macrosomia, epidural, and previous vaginal delivery, women who underwent an induction had significantly longer labors than those women who experienced spontaneous labor. The median time to dilate from 4-10 cm took 5.6 hours (95% confidence interval, 1.8-18.0 hours) in the induction group and 3.2 hours (95% confidence interval, 1.0-10.3 hours) in the spontaneous labor group (P < .01). The time to progress 1 cm in dilation from 3-7 cm was different; however, after 7 cm, the time to progress 1 cm was not statistically different. CONCLUSION: Women who undergo an induction of labor after cesarean delivery have a longer latent labor phase, but a similar active phase than those women who experience spontaneous labor. When making the diagnosis of labor dystocia for women who undergo an induction of labor after cesarean delivery, clinicians should use the same normative standards for labor treatment of women without a previous cesarean delivery as has been shown in previous work. PMID- 26026921 TI - Do laborists improve delivery outcomes for laboring women in California community hospitals? AB - OBJECTIVE: We sought to determine the impact of the laborist staffing model on cesarean rates and maternal morbidity in California community hospitals. STUDY DESIGN: This is a cross-sectional study comparing cesarean rates, vaginal birth after cesarean rates, composite maternal morbidity, and severe maternal morbidity for laboring women in California community hospitals with and without laborists. We conducted interviews with nurse managers to obtain data regarding hospital policies, practices, and the presence of laborists, and linked this information with patient-level hospital discharge data for all deliveries in 2012. RESULTS: Of 248 childbirth hospitals, 239 (96.4%) participated; 182 community hospitals were studied, and these hospitals provided 221,247 deliveries for analysis. Hospitals with laborists (n = 43, 23.6%) were busier, had more clinical resources, and cared for higher-risk patients. There was no difference in the unadjusted primary cesarean rate for laborist vs nonlaborist hospitals (11.3% vs 11.7%; P = .382) but there was a higher maternal composite morbidity rate (14.4% vs 12.0%; P = .0006). After adjusting for patient and hospital characteristics, there were no differences in laborist vs nonlaborist hospitals for any of the specified outcomes. Hospitals with laborists had higher attempted trial of labor after cesarean rates, and lower repeat cesarean rates (90.9% vs 95.9%; P < .0001). However, among women attempting trial of labor after cesarean, there was no difference in the vaginal birth after cesarean success rate. CONCLUSION: We were unable to demonstrate differences in cesarean and maternal childbirth complication rates in community hospitals with and without laborists. Further efforts are needed to understand how the laborist staffing model contributes to neonatal outcomes, cost and efficiency of care, and patient and physician satisfaction. PMID- 26026922 TI - Usefulness of 99mTc-hydroxymethylene-diphosphonate single photon emission computed tomography/computed tomography hybrid imaging in the study of tarsal tunnel syndrome. PMID- 26026923 TI - Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. AB - Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress. PMID- 26026924 TI - Towards a new understanding of NCL pathogenesis. AB - The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders that have been traditionally grouped together on the basis of certain shared clinical and pathological features. However, as the number of genes that appear to cause new forms of NCL continues to grow, it is timely to reassess our understanding of the pathogenesis of these disorders and what groups them together. The various NCL subtypes do indeed share features of a build-up of autofluorescent storage material, progressive neuron loss and activation of the innate immune system. The characterisation of animal models has highlighted the selective nature of neuron loss and its intimate relationship with glial activation, rather than the generalised build-up of storage material. More recent data provide evidence for the pathway-dependent nature of pathology, the contribution of glial dysfunction, and the involvement of new brain regions previously thought to be unaffected, and it is becoming apparent that pathology extends beyond the brain. These data have important implications, not just for therapy, but also for our understanding of these disorders. However, looking beneath these broadly similar pathological themes evidence emerges for marked differences in the nature and extent of these events in different forms of NCL. Indeed, given the widely different nature of the mutated gene products it is perhaps more surprising that these disorders resemble each other as much as they do. Such data raise the question whether we should rethink the collective grouping of these gene deficiencies together, or whether it would be better to consider them as separate entities. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease). PMID- 26026925 TI - Genetics of the neuronal ceroid lipofuscinoses (Batten disease). AB - The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults and are grouped together by similar clinical features and the accumulation of autofluorescent storage material. More than a dozen genes containing over 430 mutations underlying human NCLs have been identified. These genes encode lysosomal enzymes (CLN1, CLN2, CLN10, CLN13), a soluble lysosomal protein (CLN5), a protein in the secretory pathway (CLN11), two cytoplasmic proteins that also peripherally associate with membranes (CLN4, CLN14), and many transmembrane proteins with different subcellular locations (CLN3, CLN6, CLN7, CLN8, CLN12). For most NCLs, the function of the causative gene has not been fully defined. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity, and progression, including distinct clinical phenotypes. There remain disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)." PMID- 26026926 TI - Meta-analysis of nocturia and risk of all-cause mortality in adult population. PMID- 26026927 TI - Diagnostic relevance of optical coherence tomography imaging in aborted acute myocardial infarction with a "Takotsubo component". PMID- 26026928 TI - Inappropriate shocks in the subcutaneous ICD: Incidence, predictors and management. AB - BACKGROUND: The entirely subcutaneous implantable cardioverter-defibrillator (S ICD) eliminates the need for transvenous leads, and therefore has the potential to improve lead-longevity and reduce lead-related complications. The S-ICD has a morphology-based sensing algorithm of which inappropriate shocks have been reported. METHODS: We analyzed the incidence, predictors and management of inappropriate shocks in the EFFORTLESS S-ICD Registry, which collects S-ICD implantation information and follow-up data from clinical centers in Europe and New Zealand. RESULTS: During a follow-up of 21 +/- 13 months, 48 out of 581 S-ICD patients (71% male, age 49 +/- 18 years) experienced 101 inappropriate shocks (8.3%). The most common cause was cardiac signal oversensing (73%), such as T wave oversensing. Eighteen shocks (18%) were due to supraventricular tachycardias (SVT), of which 15 occurred in the shock-only zone. Cox-proportional hazard modeling using time-dependent covariates demonstrated that patients with a history of atrial fibrillation (HR 2.4) and patients with hypertrophic cardiomyopathy (HR 4.6) had an increased risk for inappropriate shocks, while programming the primary vector for sensing (from xyphoid to V6) reduced the risk. Reprogramming or optimization of SVT treatment after the first clinical event of inappropriate shock was successful in preventing further inappropriate shocks for cardiac oversensing and SVT events. CONCLUSIONS: Inappropriate shocks, mainly due to cardiac oversensing, occurred in 8.3% of the S-ICD patients. Patients with hypertrophic cardiomyopathy or a history of atrial fibrillation were at increased risk, warranting specific attention for sensing and programming in this population. PMID- 26026929 TI - Seasonality in acute ischemic stroke related hospitalizations and case fatality rate in the United States. PMID- 26026930 TI - Sensitive and Selective Determination of Orotic Acid in Biological Specimens Using a Novel Fluorogenic Reaction. AB - Orotic acid is an intermediate in the synthesis pathway of uridine-5' monophosphate, and increases in body fluids of patients suffering from hereditary disorders such as orotic aciduria and hyperammonemia. In this study, we developed a spectrofluorometric method with or without high-performance liquid chromatography for the selective and sensitive quantification of orotic acid in human biological specimens, using 4-trifluoromethylbenzamidoxime (4-TFMBAO) as a fluorogenic reagent. This reagent provided intensive fluorescence for only orotic acid amongst 62 compounds including structurally related bio-substances such as nucleic acid bases, nucleosides, nucleotides, amino acids, vitamins, bilirubin, uric acid, urea, creatine, creatinine and sugars. Under optimized reaction conditions, orotic acid was reacted with 4-TFMBAO, K3[Fe(CN)6] and K2CO3 in an aqueous solution. The fluorescence produced from the orotic acid derivative was measured at an excitation of 340 nm and an emission of 460 nm. A concentration of 1.2 MUM orotic acid per 1.0 mM creatinine in normal urine and 0.64 nmol orotic acid per 5.0 * 10(5) HeLa cells were determined by this method. The present method permitted the facile quantification of orotic acid in healthy human urine and cultured HeLa cells by spectrofluorometry and/or high-performance liquid chromatography. PMID- 26026932 TI - Response to Letter to the Editor from SMJ Mortazavi. PMID- 26026931 TI - Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models. AB - The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation. PMID- 26026933 TI - Depth distribution of cesium-137 in paddy fields across the Fukushima pollution plume in 2013. AB - Large quantities of radiocesium were deposited across a 3000 km(2) area northwest of the Fukushima Dai-ichi nuclear power plant after the March 2011 accident. Although many studies have investigated the fate of (137)Cs in soil in the months following the accident, the depth distribution of this radioactive contaminant in rice paddy fields requires further examination after the typhoons that occurred in this region. Such investigations will help minimize potential human exposure in rice paddy fields. Radionuclide activity concentrations, organic content and particle size were analysed in 10 soil cores sampled from paddy fields in November 2013, 20 km north of the Fukushima power plant. Our results demonstrate limited depth migration of (137)Cs with the majority concentrated in the uppermost layers of soils (<5 cm). More than 30 months after the accident, between 46.8 and 98.7% of the total (137)Cs inventories was found within the top 5 cm of the soil surface, despite cumulative rainfall totalling 3300 mm. Furthermore, there were no significant correlations between (137)Cs depth distribution and the other parameters. We attributed the maximum depth penetration of (137)Cs to grass cutting (73.6-98.5% of (137)Cs in the upper 5 cm) and farming operations (tillage - 46.8-51.6% of (137)Cs in the upper 5 cm). As this area is exposed to erosive events, ongoing decontamination works may increase soil erodibility. We therefore recommend the rapid removal of the uppermost - contaminated - layer of the soil after removing the vegetation to avoid erosion of contaminated material during the subsequent rainfall events. Further analysis is required to thoroughly understand the impacts of erosion on the redistribution of radiocesium throughout the Fukushima Prefecture. PMID- 26026934 TI - Infliximab reverses progressive deafness. PMID- 26026935 TI - Comparison of epitheliotrophic factors in autologous serum eyedrops from sera of chronic renal failure patients vs. normal controls. AB - PURPOSE: To investigate the composition and biological activity of serum epitheliotrophic factors from chronic renal failure (CRF) patients vs. healthy controls. METHODS: Twenty, 50 and 100 % autologous serum eyedrops (ASEs) were prepared from 16 CRF patients and 16 normal subjects. Serum epithelial growth factor (EGF), platelet-derived growth factor-AB (PDGF-AB), transforming growth factor-beta1 (TGF-beta1) and fibronectin levels were quantified using enzyme linked immunosorbent assay kits. A 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazoliumbromide (MTT) assay was used to compare the proliferative effects of serum from CRF patients and healthy donors in a human corneal epithelial cell (HCEC) culture model. Migration assays were conducted via manual scraping of HCECs for migratory potential of ASEs. Morphologic changes were studied with transmission electron microscopy (TEM). RESULTS: EGF, PDGF-AB and TGF-beta1 levels in ASEs from healthy donors were significantly higher than in serum of CRF patients. Cellular proliferation was similar in the CRF patient and normal control groups. ASEs from the normal group had a significantly higher effect on cell migration. ASEs in both groups facilitated better proliferation and migration than the negative control. Furthermore, we observed an enhancement after incubation with diluted serum vs. undiluted serum. In TEM analysis, HCECs incubated with CRF patients' 50 % ASEs showed some loss of microvilli without alterations of cytoplasmic organelles. CONCLUSIONS: Epitheliotrophic factors concentrations and biologic activities from CRF patient sera differed from healthy controls. ASEs in CRF patients are also helpful in the corneal healing process, especially when applied at a 50 % concentration. PMID- 26026937 TI - Augmentation treatment for alpha1 antitrypsin deficiency. PMID- 26026936 TI - Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: The efficacy of alpha1 proteinase inhibitor (A1PI) augmentation treatment for alpha1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in alpha1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS: The RAPID study was a multicentre, double blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with alpha1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe alpha1 antitrypsin deficiency (serum concentration <11 MUM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1.50 g/L per year [SE 0.22]; placebo -2.12 g/L per year [0.24]; difference 0.62 g/L per year [95% CI 0.02 to 1.26], p=0.06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1.45 g/L per year [SE 0.23]) than in the placebo group (-2.19 g/L per year [0.25]; difference 0.74 g/L per year [95% CI 0.06-1.42], p=0.03), but was not at FRC alone (A1PI -1.54 g/L per year [0.24]; placebo -2.02 g/L per year [0.26]; difference 0.48 g/L per year [-0.22 to 1.18], p=0.18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe alpha1 antitrypsin deficiency. FUNDING: CSL Behring. PMID- 26026938 TI - Enhanced rifamycin SV production by submerged fermentation using Amycolatopsis mediterranei. AB - Rifamycin is a broad-spectrum antimicrobial drug produced commercially by submerged fermentation where the yields are far less in comparison to its demand in human drug therapy. Addressing the need, sequential mutational strain improvement was carried using UV and EtBr that resulted in improved strain yielding rifamycin SV up to 4.32 g/L. Further optimization of six important fermentation factors was followed which include temperature, agitation, inoculum level, period of fermentation, inorganic nitrogen source and amino acids. For the first time, we report a maximum yield of 5.32 g/L of rifamycin SV. Among the amino acids, proline known for its slowest assimilation by Amycolatopsis mediterranei produced the highest improvement in antibiotic yields. Following mutational strain improvement and process optimization, a total of 3.8-fold increase in antibiotic titre was achieved. Following a conventional procedure of mutational strain improvement, highest yield of rifamycin SV was reported by optimizing submerged fermentation process. PMID- 26026939 TI - A hydrolase-based reporter system to uncover the protein splicing performance of an archaeal intein. AB - Extein amino acid residues around the splice site junctions affect the functionality of inteins. To identify an optimal sequence context for efficient protein splicing of an intein from the thermoacidophilic archaeon Picrophilus torridus, single extein amino acid residues at the splice site junctions were continuously deleted. The construction of a set of different truncated extein variants showed that this intein tolerates multiple amino acid variations near the excision sites and exhibits full activity when -1 and +1 extein amino acid residues are conserved in an artificial GST-intein-HIS fusion construct. Moreover, splicing of the recombinant intein took place at temperatures between 4 and 42 degrees C with high efficiency, when produced in Escherichia coli. Therefore, structural model predictions were used to identify optimal insertion sites for the intein to be embedded within a hemicellulase from the psychrophilic bacterium Pseudoalteromonas arctica. The P. torridus intein inserted before amino acid residue Thr75 of the reporter enzyme retained catalytic activity. Moreover, the catalytic activity of the xylan-degrading hydrolase could be easily monitored in routine plate assays and in liquid test measurements at room temperature when produced in recombinant form in E. coli. This tool allows the indirect detection of the intein's catalytic activity to be used in screenings. PMID- 26026940 TI - Structural insights into methanol-stable variants of lipase T6 from Geobacillus stearothermophilus. AB - Enzymatic production of biodiesel by transesterification of triglycerides and alcohol, catalyzed by lipases, offers an environmentally friendly and efficient alternative to the chemically catalyzed process while using low-grade feedstocks. Methanol is utilized frequently as the alcohol in the reaction due to its reactivity and low cost. However, one of the major drawbacks of the enzymatic system is the presence of high methanol concentrations which leads to methanol induced unfolding and inactivation of the biocatalyst. Therefore, a methanol stable lipase is of great interest for the biodiesel industry. In this study, protein engineering was applied to substitute charged surface residues with hydrophobic ones to enhance the stability in methanol of a lipase from Geobacillus stearothermophilus T6. We identified a methanol-stable variant, R374W, and combined it with a variant found previously, H86Y/A269T. The triple mutant, H86Y/A269T/R374W, had a half-life value at 70 % methanol of 324 min which reflects an 87-fold enhanced stability compared to the wild type together with elevated thermostability in buffer and in 50 % methanol. This variant also exhibited an improved biodiesel yield from waste chicken oil compared to commercial Lipolase 100L(r) and Novozyme(r) CALB. Crystal structures of the wild type and the methanol-stable variants provided insights regarding structure stability correlations. The most prominent features were the extensive formation of new hydrogen bonds between surface residues directly or mediated by structural water molecules and the stabilization of Zn and Ca binding sites. Mutation sites were also characterized by lower B-factor values calculated from the X-ray structures indicating improved rigidity. PMID- 26026941 TI - Changing the paradigm from resuscitation to physiological support. PMID- 26026942 TI - Longitudinally extensive optic neuritis as an MRI biomarker distinguishes neuromyelitis optica from multiple sclerosis. AB - OBJECTIVE: To differentiate MRI characteristics of optic neuritis associated with neuromyelitis optica (NMO) and relapsing remitting multiple sclerosis (RRMS). BACKGROUND: Optic neuritis is a common presenting feature of both neuromyelitis optica and multiple sclerosis. Distinguishing between NMO and RRMS is important in guiding treatment, but biomarkers of NMO and MS can be absent early in the disease process. We looked for differences in MRI characteristics of optic neuritis associated with NMO and MS that provide an early clue in the diagnostic workup. DESIGN/METHODS: We conducted a retrospective analysis of 26 NMO and 26 RRMS patients presenting to the Johns Hopkins Hospital with MRI-confirmed acute optic neuritis. MRIs were assessed to identify the location and longitudinal extent of each contrast enhancing lesion. For the purposes of this study, the optic nerve was divided into intraorbital, canalicular, pre-chiasmal, chiasmal, and optic tract. RESULTS: There are distinct differences in MRI characteristics between NMO- and RRMS-associated optic neuritis. The majority of NMO lesions were longitudinally extensive measuring at least 17.6mm in length and involving at least three optic nerve segments. At a cutoff of 17.6mm lesion length, the specificity for NMO is 76.9% with a sensitivity of 80.8% and positive likelihood ratio of 3.50. Conversely, MS lesions were more commonly focal in one optic nerve segment localized anteriorly. CONCLUSIONS: Optic neuritis in NMO has a distinct pattern on MRI as compared with RRMS and can help differentiate these two neuroinflammatory diseases at presentation. PMID- 26026943 TI - Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population. AB - Although, rs75932628 in triggering receptor expressed on myeloid cells 2 (TREM2) was shown to increase the risk for Alzheimer's disease, there is no agreement on the association between this variant and the risk for amyotrophic lateral sclerosis (ALS). We conducted a large-sample study to investigate if this variant is associated with ALS in a Chinese population. A total of 868 sporadic ALS (SALS) and 869 healthy controls were included. All cases were genotyped for the single nucleotide polymorphisms (SNP) using Sequenom iPLEX Assay technology. The rs75932628-T variant of the TREM2 gene was not identified in SALS patients and controls. It is unlikely to play a role in the pathogenesis of ALS in Chinese patients with SALS. PMID- 26026944 TI - Predictive value of MRI parameters in severity and recovery of first-episode myelitis in aquaporin-4 antibody disease. AB - BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) associated with aquaporin-4 antibodies (AQP4-Ab) typically causes longitudinally-extensive transverse myelitis (LETM). Few data exist about the association of MRI features with LETM attack severity and recovery. METHODS: AQP4-Ab positive NMOSD patients with a first myelitis attack were retrospectively identified and spinal MRI scans reviewed. Association of MRI features with EDSS scores at attack nadir and recovery was evaluated. RESULTS: 22 patients were included. Median nadir EDSS score was 8 (range 1 to 8.5). Nadir EDSS scores correlated with total MRI lesion length (r=0.48, p=0.025), higher scores were seen in those with gadolinium enhancement (p=0.025) and there was a trend towards higher scores with central cord involvement. The median recovery EDSS was 6 (range 0 to 10). Total lesion length correlated with poor recovery (r=0.48, p=0.027) but this was confounded by correlation between nadir and recovery EDSS scores. CONCLUSION: We confirm that myelitis in AQP4-Ab disease is severe and show that the severity correlates with lesion length and residual disability. Spinal cord lesions in first myelitis attacks are similar to appearances reported later in the disease course, with propensity to involve the central grey matter and high frequency of cord oedema and T1 hypointensity. PMID- 26026946 TI - A new paradigm for waste management of organic materials. PMID- 26026945 TI - Radiographic conjugate horizontal eye deviation in patients with acute cerebellar infarction. AB - BACKGROUNDS: Conjugate eye deviation (CED) has not been fully investigated in patients with acute cerebellar infarction. We investigated the incidence of CED on neurological examination and head imaging with acute cerebellar infarction and associations of CED with the involved vascular territory, lesion site and other clinical factors. METHODS: We retrospectively reviewed clinical records and imaging in patients with acute cerebellar infarction within 12h after onset. We defined radiographic CED as deviation of each eye to the same side >10 degrees on head imaging. RESULTS: Thirty-five patients with acute cerebellar infarction were identified (22 men; age range, 37-85 years). No patients showed CED on neurological examination, but 13 (37%) had radiographic CED, mostly contralateral to the lesion. As for infract location, the posterior inferior cerebellar artery (PICA) territory (44% vs. 20%, p=0.18) and flocculonodular lobe and/or vermis (54% vs. 32%, p=0.20) tended to be more involved in patients with radiographic CED than in those without. CONCLUSIONS: Radiographic CED seems relatively common in patients with acute cerebellar infarction, particularly the PICA territory infarcts including the flocculonodular lobe and/or vermis. PMID- 26026947 TI - Effectiveness of oscillatory gutter brushes in removing street sweeping waste. AB - In this paper, the novel concept of oscillatory gutter brushes of road sweepers is studied experimentally. Their effectiveness in removing different debris types is studied by means of a brushing test rig. The debris types dealt with are medium-size gravel, small and fine particles, wet thin debris, and compacted debris. The performance of two types of brushes, cutting and F128, under diverse operating conditions is investigated. The purpose of the tests is to ascertain whether brush oscillations superimposed onto brush rotation improve sweeping effectiveness. According to the results, brush oscillations seem to be useful for increasing brushing effectiveness in the case of bonded particles and wet thin debris, especially for bonded debris, but they seem to be of no value for other loosed debris. Also, appropriate values of brush penetration, sweeper speed, brush angle of attack, rotational speed, and frequency of brush speed oscillations, for the debris types studied are provided. PMID- 26026948 TI - Phylogenetic Diversity of Sponge-Associated Fungi from the Caribbean and the Pacific of Panama and Their In Vitro Effect on Angiotensin and Endothelin Receptors. AB - Fungi occupy an important ecological niche in the marine environment, and marine fungi possess an immense biotechnological potential. This study documents the fungal diversity associated with 39 species of sponges and determines their potential to produce secondary metabolites capable of interacting with mammalian G-protein-coupled receptors involved in blood pressure regulation. Total genomic DNA was extracted from 563 representative fungal strains obtained from marine sponges collected by SCUBA from the Caribbean and the Pacific regions of Panama. A total of 194 operational taxonomic units were found with 58% represented by singletons based on the internal transcribed spacer (ITS) and partial large subunit (LSU) rDNA regions. Marine sponges were highly dominated by Ascomycota fungi (95.6%) and represented by two major classes, Sordariomycetes and Dothideomycetes. Rarefaction curves showed no saturation, indicating that further efforts are needed to reveal the entire diversity at this site. Several unique clades were found during phylogenetic analysis with the highest diversity of unique clades in the order Pleosporales. From the 65 cultures tested to determine their in vitro effect on angiotensin and endothelin receptors, the extracts of Fusarium sp. and Phoma sp. blocked the activation of these receptors by more than 50% of the control and seven others inhibited between 30 and 45%. Our results indicate that marine sponges from Panama are a "hot spot" of fungal diversity as well as a rich resource for capturing, cataloguing, and assessing the pharmacological potential of substances present in previously undiscovered fungi associated with marine sponges. PMID- 26026949 TI - Nasolacrimal Duct Probing under Topical Anesthesia for Congenital Nasolacrimal Duct Obstruction in Taiwan. AB - BACKGROUND: To report the success rates of office probing for congenital nasolacrimal duct obstruction (NLDO) among children of different age groups in Taiwan. METHODS: In this single-center, retrospective study, 564 eyes of 477 patients under the age of 5 years diagnosed with congenital NLDO were treated in a stepwise manner between 2001 and 2013. For infants aged < 6 months, treatment with massage and observation was suggested, followed by deferred probing under topical anesthesia if symptoms persisted. However, in cases of severe infection, immediate probing was suggested. In children aged > 6 months, office probing was usually highly recommended. Those with probing failures received either a second probing or silicone intubation. Treatment success was defined as anatomic patency by immediate irrigation after probing and absence of epiphora or mucous discharge at the follow-up visit. RESULTS: Primary probing was successful in 457 of 564 eyes (success rate: 81%). The success rate of primary probing was negatively correlated with increasing age: 90.1% (163/181), 79.6% (164/206), 76.8% (73/95), 73.5% (36/49), 75% (18/24), and 33% (3/9) for the age groups of 0 to <6 months, 6 to <12 months, 12 to <18 months, 18 to <24 months, 24 to <36 months, and 36-60 months, respectively (p < 0.001, Fisher's exact test). The second probing was successful in 52 of 81 eyes. In total, probing was successful in 509 of 564 eyes (success rate: 90.2%). CONCLUSION: Office probing is safe and effective for treating congenital NLDO. The success rate of primary probing decreases significantly with age. PMID- 26026950 TI - Masculinity and nursing care: A narrative analysis of male students' stories about care. AB - Nursing education programmes and the nursing curriculum have been criticised for presenting an outdated and feminised description of care, which has had the effect of marginalising men, as well as hindering a more modern outlook for the profession. This article uses interview-based data from a qualitative study on Norwegian students' experiences in the first year of training. Using a narrative analysis method, the paper explores how male nursing students use stories to describe care and shows how their storytelling illustrates a way for men to negotiate their role in a feminised profession. The paper aims to deepen our understanding of the ways in which male students can challenge this historically female profession to broaden itself by including male-based caregiving as part of nursing care. In addition, the paper highlights the potential of stories and storytelling as a teaching and learning strategy in nursing education. PMID- 26026951 TI - A fluorescent approach for identifying P2X1 ligands. AB - There are no commercially available, small, receptor-specific P2X1 ligands. There are several synthetic derivatives of the natural agonist ATP and some structurally-complex antagonists including compounds such as PPADS, NTP-ATP, suramin and its derivatives (e.g. NF279, NF449). NF449 is the most potent and selective ligand, but potencies of many others are not particularly high and they can also act at other P2X, P2Y and non-purinergic receptors. While there is clearly scope for further work on P2X1 receptor pharmacology, screening can be difficult owing to rapid receptor desensitisation. To reduce desensitisation substitutions can be made within the N-terminus of the P2X1 receptor, but these could also affect ligand properties. An alternative is the use of fluorescent voltage-sensitive dyes that respond to membrane potential changes resulting from channel opening. Here we utilised this approach in conjunction with fragment based drug-discovery. Using a single concentration (300 MUM) we identified 46 novel leads from a library of 1443 fragments (hit rate = 3.2%). These hits were independently validated by measuring concentration-dependence with the same voltage-sensitive dye, and by visualising the competition of hits with an Alexa 647-ATP fluorophore using confocal microscopy; confocal yielded kon (1.142 * 10(6) M(-1) s(-1)) and koff (0.136 s(-1)) for Alexa-647-ATP (Kd = 119 nM). The identified hit fragments had promising structural diversity. In summary, the measurement of functional responses using voltage-sensitive dyes was flexible and cost-effective because labelled competitors were not needed, effects were independent of a specific binding site, and both agonist and antagonist actions were probed in a single assay. The method is widely applicable and could be applied to all P2X family members, as well as other voltage-gated and ligand gated ion channels. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. PMID- 26026952 TI - Concussion in rugby: knowledge and attitudes of players. AB - BACKGROUND: Concussion is a traumatic brain injury, resulting in the alteration of mental status with or without loss of consciousness. There is increasing awareness that recurrent concussion may contribute to long-term neurological complication. AIMS: To determine player knowledge and attitudes regarding concussion. To identify sources of information and medical care, and to estimate the incidence of concussion in this group. To determine if player gender and grade of competition are associated with differences in knowledge, attitudes, medical care, and incidence. METHODS: Five rugby teams were recruited and players invited to complete a paper-based questionnaire. The questionnaire sought information on player demographics, knowledge level, attitudes and concussion experience. RESULTS: 90.8 % of players knew they should not continue playing when concussed. 75 % of players would continue an important game even if concussed. Of those concussed, 39.1 % have tried to influence medical assessment with 78.2 % stating it is possible or quite easy to do so. Males are less likely to worry about long-term effects of concussion (chi (2) = 9.23, p = 0.026). Club players are less likely to have medical care at training (chi (2) = 28.2, p < 0.001) or matches (chi (2) = 19.47 p < 0.001). CONCLUSION: Despite good knowledge of concussion complications, management players engage in unsafe behaviour with little difference between gender and competition grades. Information regarding symptoms and management should be available to all players, coaches, and parents. Provision of medical care should be mandatory at every level of competition. PMID- 26026953 TI - Demographic and clinical factors predicting retention in methadone maintenance: results from an Irish cohort. AB - BACKGROUND: Retention in Methadone Maintenance Treatment (MMT) is superior to that of other therapies for opioid addiction, but with international retention rates around 50 % after 1 year of treatment, there remains a need for improved retention rates. AIMS: This study aimed to explore the demographic and clinical factors predicting retention in MMT. METHODS: Face-to-face surveys with MMT patients in a Dublin methadone clinic were conducted. Retention was assessed by the presence and duration of breaks in treatment at any stage. RESULTS: 189 patients participated in the study. 46 % (n = 87) reported having at least one break in treatment, and the median duration of a break was 3 months. Age, current methadone dose and prescription of antipsychotic medication were significant predictors of retention. Patients who were older, single, living in their own home, on a higher dose of methadone, or taking antipsychotic medications had fewer breaks in treatment. Males tended to have significantly longer breaks. Patients reported that the main reasons for breaks were relapse into drug use (21.8 %, n = 19), incarceration (11.4 %, n = 10), weary of MMT (13.7 %, n = 12) or problems at the clinic (10.3 %, n = 9). Factors enabling regular attendance included wanting to get or stay clean (37.5 %, n = 51), avoidance of withdrawal symptoms (16.1 %, n = 22), methadone dependence (13.9 %, n = 19) and services provided (10.2 %, n = 14). CONCLUSION: Patients who were older, single, living in their own home, on a higher dose of methadone, or taking antipsychotic medications had fewer breaks in treatment. PMID- 26026954 TI - Effect of integrating HIV and addiction care for non-engaging HIV-infected opiate dependent patients. AB - BACKGROUND: HIV-positive substance dependent patients contribute disproportionally to HIV morbidity and mortality as a result of poor compliance with their HIV treatment. For HIV-positive opiate-dependent patients integrating HIV and addiction care improves HIV morbidity but the effect on addiction morbidity is not known. AIMS: This study aims to establish if integrating HIV and addiction care has a significant effect on addiction and HIV morbidity for non engaging HIV-positive opiate-dependent patients. METHODS: Patients attending the National Drug Treatment Centre who had disengaged from their HIV treatment in St James's Hospital were recruited to receive HIV care integrated into their methadone maintenance programme. Outcome was investigated in terms of urine toxicology (opiates, cocaine, cannabis and amphetamines); adherence to methadone; proportion receiving directly observed antiretroviral therapy; proportion HIV virally suppressed; and the CD4 cell count. RESULTS: No significant change in substance use or methadone adherence was demonstrated in the 19 recruited participants. There was a significant increase in the proportion receiving directly observed antiretroviral therapy, and in the CD4 cell count. CONCLUSION: Integration of HIV and addiction care optimises the physical health of non engaging HIV-positive opiate-dependent patients with no substantial effect on their methadone maintenance programme. PMID- 26026955 TI - Molecular characterization of infectious bursal disease virus (IBDV) isolated in Argentina indicates a regional lineage. AB - In Argentina, classical vaccines are used to control infectious bursal disease virus (IBDV); however, outbreaks of IBDV are frequently observed. This could be due to failures in the vaccination programs or to the emergence of new strains, which would be able to break through the protection given by vaccines. Hence, genetic characterization of the viruses responsible for the outbreaks that occurred in recent years is crucial for the evaluation of the control programs and the understanding of the epidemiology and evolution of IBDV. In this study, we characterized 51 field samples collected in Argentina (previously identified as IBDV positive) through the analysis of previously identified apomorphic sequences. Phylogenetic analysis of regVP2 showed that 42 samples formed a unique cluster (Argentinean lineage), seven samples were typical classical strains (one of them was a vaccine strain), and two belonged to the very virulent lineage (vvIBDV). Interestingly, when the analysis was performed on the regVP1 sequences, the field samples segregated similarly to regVP2; thus, we observed no evidence of a reassortment event in the Argentinean samples. Amino acid sequence analysis of regVP2 showed a particular pattern of residues in the Argentinean lineage, particularly the presence of T272, P289 and F296, which had not been reported before as signature sequences for any IBDV phenotype. Notably, the residue S254, characteristic of the antigenic variant, was not present in any of the Argentinean samples. PMID- 26026956 TI - Complete sequence of three different biotypes of tomato spotted wilt virus (wild type, tomato Sw-5 resistance-breaking and pepper Tsw resistance-breaking) from Spain. AB - Tomato spotted wilt virus (TSWV) occurs worldwide and causes production losses in many important horticultural crops such as tomato and pepper. Breeding resistant cultivars has been the most successful method so far for TSWV disease control, but only two genes have been found to confer resistance against a wide spectrum of TSWV isolates: Sw-5 in tomato and Tsw in pepper. However, TSWV resistance breaking isolates have emerged in different countries a few years after using resistant cultivars. In this paper, we report the first complete nucleotide sequences of three Spanish TSWV isolates with different biotypes according to their abilities to overcome resistance: LL-N.05 (wild type, WT), Pujol1TL3 (Sw-5 resistance breaking, SBR) and PVR (Tsw resistance-breaking, TBR). The genome of these TSWV isolates consisted of three segments: L (8913-8914 nt), M (4752-4825 nt) and (S 2924-2961 nt). Variations in nucleotide sequences and genomic RNA lengths among the different virus biotypes are reported here. Phylogenetic analysis of the five TSWV open reading frames showed evidence of reassortment between genomic segments of LL-N.05 and Pujol1TL3, which was supported by analysis with different recombination-detecting algorithms. PMID- 26026957 TI - Detection of rotavirus and other enteropathogens in children hospitalized with acute gastroenteritis in Havana, Cuba. AB - The aim of the study was to diagnose infections with rotavirus and other enteric pathogens in children under five years old with acute gastroenteritis and to identify the most common epidemiological and clinical characteristics of these pathogens. The study was conducted using 110 stool samples from the same number of children under five years old who were inpatients at three paediatric hospitals in Havana, Cuba, between October and December 2011. The samples were tested for rotavirus and other enteric pathogens using traditional and molecular microbiological methods. Pathogens were detected in 85 (77.3 %) of the children. Rotavirus was the most commonly found, appearing in 54.5 % of the children, followed by bacteria (29 %) and parasites (10.9 %). Other viral pathogens detected included adenovirus (6.4 %) and astrovirus (3.6 %). In rotavirus positives cases, at least one other pathogen was detected, usually a bacterium (26.6 %). More than three episodes of watery diarrhea in 24 hours were observed in 78.3 % of the cases. Dehydration was found in 30 (50 %) rotavirus-positive children, of whom seven (11.6 %) were transferred to an intensive care unit due to complications of metabolic acidosis. Rotavirus was most commonly observed among children under 12 months old (65 %). The highest incidence of infection occurred in children who were under the care of a relative at home (78.3 %), had not been breastfed (65 %), or had been breastfed for less than six months (28.3 %). The genotype combinations most frequently found were G9P8 (28.3 %) and G1P8 (10 %). This study demonstrates the presence of rotavirus and other enteric pathogens as causes of gastroenteritis in hospitalized infants and young children in Cuba. PMID- 26026958 TI - Complete genome characterization of porcine epidemic diarrhea virus in Vietnam. AB - Porcine epidemic diarrhea virus (PEDV) first emerged in Vietnam in 2009. In this study, the complete genomes of three Vietnamese PEDV isolates were characterized. These three isolates were isolated from 3-day-old pigs experiencing diarrhea. Two isolates were from swine farms in the south, and the other was from northern Vietnam. The whole genome sequences of these isolates are 28,035 nucleotides in length and have characteristics similar to those of other PEDV isolates. All three Vietnamese PEDV isolates share 99.8 % and 99.6 % sequence identity at the nucleotide and amino acid level, respectively, and have insertions of four amino acids (GENQ) and one amino acid (N) at positions 56-59 and 140, respectively, and one deletion of two amino acids (DG) at positions 160-161. Phylogenetic analysis based on the whole genome revealed that the three Vietnamese PEDV isolates are grouped together with new variants from China from 2011 to 2012 and are genetically distinct from US isolates and the classical PEDV variant. The results suggest that Vietnamese PEDV isolates are new variants, as evidenced by their genetic composition of insertions and a deletion in the spike gene, and they might have originated from the same ancestor as the Chinese PEDV strain. This study provides a better understanding of the molecular characteristics of PEDV in Vietnam. PMID- 26026959 TI - Cr(VI)-contaminated groundwater remediation with simulated permeable reactive barrier (PRB) filled with natural pyrite as reactive material: Environmental factors and effectiveness. AB - Permeable reactive barriers (PRBs) are efficient technologies for in situ remediation of contaminated groundwater, the effectiveness of which greatly depends on the reactive media filled. Natural pyrite is an iron sulfide material with a very low content of iron and sulfur, and a mining waste which is a potential material for Cr(VI) immobilization. In this study, we conducted a series of batch tests to research the effects of typical environmental factors on Cr(VI) removal and also simulated PRB filled with natural pyrite to investigate its effectiveness, in order to find a both environmentally and economically fine method for groundwater remediation. Batch tests showed that pH had the significant impact on Cr(VI) removal with an apparently higher efficiency under acidic conditions, and dissolved oxygen (DO) would inhibit Cr(VI) reduction; a relatively high initial Cr(VI) concentration would decrease the rate of Cr(VI) sorption; ionic strength and natural organic matter resulted in no significant effects on Cr(VI) removal. Column tests demonstrated that the simulated PRB with natural pyrite as the reactive media was considerably effective for removing Cr(VI) from groundwater, with a sorption capability of 0.6222 mg Cr per gram of natural pyrite at an initial Cr(VI) concentration of 10mg/L at pH 5.5 in an anoxic environment. PMID- 26026960 TI - Convergence of air pollutant-induced redox-sensitive signals in the dendritic cells contributes to asthma pathogenesis. AB - Exposure to airborne particulate matter (PM) is a major risk factor for allergic airway inflammation such as asthma. Many of the PM components (i.e., polycyclic aromatic hydrocarbons and metals) are redox-active and capable of inducing cellular oxidative stress and injuries including inflammation and cell death. Airway epithelial cells and antigen-presenting dendritic cells (DC) are the major and direct targets of inhaled PM. The epithelial cells can further enhance the DC response to allergen and PM through several immune regulatory cytokines including thymic stromal lymphopoietin (TSLP), IL-33, and IL-25. Among these cytokines TSLP is particularly relevant to the mechanisms by which particulate air pollutants contribute to asthma pathogenesis. Studies have found that TSLP released by PM exposed human airway epithelial cells could polarize the DC towards a T-helper 2 immune response, which is one of the key immunological mechanisms in asthma pathogenesis. The convergence of regulatory signals generated by PM-induced oxidative stress in DC and the interactions among them may be one of the major mechanisms that are specifically related to the contribution of PM towards asthma pathogenesis. PMID- 26026961 TI - Nickel may contribute to EGFR mutation and synergistically promotes tumor invasion in EGFR-mutated lung cancer via nickel-induced microRNA-21 expression. AB - We recently reported that nickel accumulation in lung tissues may be associated with an increased in p53 mutation risk via reduced DNA repair activity. Here, we hypothesized that nickel accumulation in lung tissues could contribute to EGFR mutations in never-smokers with lung cancer. We enrolled 76 never-smoking patients to evaluate nickel level in adjacent normal lung tissues by ICP-MS. The prevalence of EGFR mutations was significantly higher in the high-nickel subgroup than in the low-nickel subgroup. Intriguingly, the OR for the occurrence of EGFR mutations in female, adenocarcinoma, and female adenocarcinoma patients was higher than that of all patients. Mechanistically, SPRY2 and RECK expressions were decreased by nickel-induced miR-21 via activation of the EGFR/NF-kappaB signaling pathway, which promoted invasiveness in lung cancer cells, and particularly in the cells with EGFR L858R expression vector transfection. The patients' nickel levels were associated with miR-21 expression levels. Kaplan Meier analysis revealed poorer overall survival (OS) and shorter relapse free survival (RFS) in the high-nickel subgroup than in low-nickel subgroup. The high nickel/high-miR-21 subgroup had shorter OS and RFS periods when compared to the low-nickel/low-miR-21 subgroup. Our findings support previous epidemiological studies indicating that nickel exposure may not only contribute to cancer incidence but also promote tumor invasion in lung cancer. PMID- 26026962 TI - International drugs markets database to improve global drugs accessibility. PMID- 26026963 TI - Enzymatic hydrolysis of 7-xylosyltaxanes by an extracellular xylosidase from Cellulosimicrobium cellulans. AB - OBJECTIVES: To find extracellular biocatalysts that can specifically and efficiently remove the C-7 xylosyl group from 7-xylosyltaxanes. RESULTS: A Cellulosimicrobium cellulans strain F16 that can remove the C-7 xylosyl group from 7-xylosyltaxanes was isolated from the root soil of an old Taxus yunnanensis tree. Using corn cob as sole carbon source, the maximum 7-xylosyl-10 deacetylpaclitaxel beta-xylosidase activity of 9.6 U l(-1) was achieved. The beta xylosidase could be trapped by a ceramic tubular membrane (pore size 50 nm), and exhibited an apparent molecular weight much greater than 500 kDa. Under optimized conditions, 3.75 l cell-free culture medium transformed 2 grams 7-xylosyltaxane mixtures to their corresponding aglycones within 3 h, with a conversion >98%. CONCLUSION: This is the first report that C. cellulans can produce extracellular beta-xylosidases capable of removing the C-7 xylosyl group from 7-xylosyltaxanes. PMID- 26026964 TI - Butyric acid production from red algae by a newly isolated Clostridium sp. S1. AB - OBJECTIVE: To produce butyric acid from red algae such as Gelidium amansii in which galactose is a main carbohydrate, microorganisms utilizing galactose and tolerating inhibitors in hydrolysis including levulinic acid and 5 hydroxymethylfurfural (HMF) are required. RESULTS: A newly isolated bacterium, Clostridium sp. S1 produced butyric acid not only from galactose as the sole carbon source but also from a mixture of galactose and glucose through simultaneous utilization. Notably, Clostridium sp. S1 produced butyric acid and a small amount of acetic acid with the butyrate:acetate ratio of 45.4:1 and it even converted acetate to butyric acid. Clostridium sp. S1 tolerated 0.5-2 g levulinic acid/l and recovered from HMF inhibition at 0.6-2.5 g/l, resulting in 85-92% butyric acid concentration of the control culture. When acid-pretreated G. amansii hydrolysate was used, Clostridium sp. S1 produced 4.83 g butyric acid/l from 10 g galactose/l and 1 g glucose/l. CONCLUSION: Clostridium sp. S1 produces butyric acid from red algae due to its characteristics in sugar utilization and tolerance to inhibitors, demonstrating its advantage as a red algae-utilizing microorganism. PMID- 26026965 TI - Purification and characterization of a novel beta-carotene-9',10'-oxygenase from Saccharomyces cerevisiae ULI3. AB - OBJECTIVES: A novel beta-carotene-9,10'-oxygenase (ScBCO2) has been characterized from Saccharomyces cerevisiae ULI3 to convert beta-carotene to beta-apo-10' carotenal, which is a precursor of the plant hormone strigolactone. RESULTS: The ScBCO2 enzyme was purified to homogeneity by ammonium sulfate precipitation, Q sepharose and Superdex-200 chromatography. The molecular mass of the enzyme was ~50 kDa by SDS-PAGE. The purified ScBCO2 enzyme displayed optimal activity at 45 degrees C and pH 8. Tween 20 (1%, w/v), Trition X-100 (1%, w/v), Mg(2+) (5 mM), Zn(2+) (5 mM), Cu(2+) (5 mM), Ca(2+) (5 mM) or DTT (5 mM) increased in the activity by 3, 7, 14, 17, 23, 26 and 27%, respectively. ScBCO2 only exhibited cleavage activity towards carotenoid substrates containing two beta-ionone rings and its catalytic efficiency (kcat/Km) followed the order beta-carotene > alpha carotene > lutein. CONCLUSION: ScBCO2 could be used as a potential candidate for the enzymatic biotransformation of beta-carotene to beta-apo-10'-carotenal in biotechnological applications. PMID- 26026966 TI - The Three Rs of Animal Research: What they Mean for the Institutional Animal Care and Use Committee and Why. AB - The Institutional Animal Care and Use Committee (IACUC) is entrusted with assessing the ethics of proposed projects prior to approval of animal research. The role of the IACUC is detailed in legislation and binding rules, which are in turn inspired by the Three Rs: the principles of Replacement, Reduction, and Refinement. However, these principles are poorly defined. Although this provides the IACUC leeway in assessing a proposed project, it also affords little guidance. Our goal is to provide procedural and philosophical clarity to the IACUC without mandating a particular outcome. To do this, we analyze the underlying logic of the Three Rs and conclude that the Three Rs accord animals moral standing, though not necessarily "rights" in the philosophical sense. We suggest that the Rs are hierarchical, such that Replacement, which can totally eliminate harm, should be considered prior to Reduction, which decreases the number of animals harmed, with Refinement being considered last. We also identify the need for a hitherto implicit fourth R: Reject, which allows the IACUC to refuse permission for a project which does not promise sufficient benefit to offset the pain and distress likely to be caused by the proposed research. PMID- 26026967 TI - Teaching Ethics to Engineers: A Socratic Experience. AB - In this paper we present the authors' experience of teaching a course in Ethics for Engineers, which has been delivered four times in three different universities in Spain and Chile. We begin by presenting the material context of the course (its place within the university program, the number of students attending, its duration, etc.), and especially the intellectual background of the participating students, in terms of their previous understanding of philosophy in general, and of ethics in particular. Next we set out the objectives of the course and the main topics addressed, as well as the methodology and teaching resources employed to have students achieve a genuine philosophical reflection on the ethical aspects of the profession, starting from their own mindset as engineers. Finally we offer some results based on opinion surveys of the students, as well as a more personal assessment by the authors, recapitulating the most significant achievements of the course and indicating its underlying Socratic structure. PMID- 26026968 TI - Polemics on Ethical Aspects in the Compost Business. AB - This paper focuses on compost use in overpasses and underpasses for wild animals over roads and other similar linear structures. In this context, good quality of compost may result in faster and more resistant vegetation cover during the year. Inter alia, this can be interpreted also as reduction of damage and saving lives. There are millions of tones of plant residue produced every day worldwide. These represent prospective business for manufacturers of compost additives called "accelerators". The opinions of the sale representatives' with regards to other alternatives of biowaste utilization and their own products were reviewed. The robust analyzes of several "accelerated" composts revealed that the quality was generally low. Only two accelerated composts were somewhat similar in quality to the blank sample that was produced according to the traditional procedure. Overlaps between the interests of decision makers on future soil fertility were weighed against the preferences on short-term profit. Possible causes that allowed the boom of these underperforming products and the possible consequences are also discussed. Conclusions regarding the ethical concerns on how to run businesses with products whose profitability depends on weaknesses in the legal system and customer unawareness are to follow. PMID- 26026969 TI - Managing fatigue: It really is about sleep. AB - Biomathematical models of fatigue can assist organisations to estimate the fatigue consequences of a roster before operations commence. These estimates do not account for the diversity of sleep behaviours exhibited by employees. The purpose of this study was to develop sleep transfer functions describing the likely distributions of sleep around fatigue level estimates produced by a commercial biomathematical model of fatigue. Participants included 347 (18 females, 329 males) train drivers working commercial railway operations in Australia. They provided detailed information about their sleep behaviours using sleep diaries and wrist activity monitors. On average, drivers slept for 7.7 (+/ 1.7)h in the 24h before work and 15.1 (+/-2.5)h in the 48h before work. The amount of sleep obtained by drivers before shifts differed only marginally across morning, afternoon and night shifts. Shifts were also classified into one of seven ranked categories using estimated fatigue level scores. Higher fatigue score categories were associated with significant reductions in the amount of sleep obtained before shifts, but there was substantial within-category variation. The study findings demonstrate that biomathematical models of fatigue have utility for designing round-the-clock rosters that provide sufficient sleep opportunities for the average employee. Robust variability in the amount of sleep obtained by drivers indicate that models are relatively poor tools for ensuring that all employees obtain sufficient sleep. These findings demonstrate the importance of developing approaches for managing the sleep behaviour of individual employees. PMID- 26026970 TI - Factors affecting the ambulance response times of trauma incidents in Singapore. AB - OBJECTIVES: Time to definitive care is important for trauma outcomes, thus many emergency medical services (EMS) systems in the world adopt response times of ambulances as a key performance indicator. The objective of this study is to examine the underlying risk factors that can affect ambulance response times (ART) for trauma incidents, so as to derive interventional measures that can improve the ART. MATERIAL AND METHODS: This was a retrospective study based on two years of trauma data obtained from the national EMS operations centre of Singapore. Trauma patients served by the national EMS provider over the period from 1 January 2011 till 31 December 2012 were included. ART was categorized into "Short" (<4min), "Intermediate" (4-8min) and "Long" (>8min) response times. A modelling framework which leveraged on both multinomial logistic (MNL) regression models and Bayesian networks was proposed for the identification of main and interaction effects. RESULTS: Amongst the process-related risk factors, weather, traffic and place of incident were found to be significant. The traffic conditions on the roads were found to have the largest effect-the odds ratio (OR) of "Long" ART in heavy traffic condition was 12.98 (95% CI: 10.66-15.79) times higher than that under light traffic conditions. In addition, the ORs of "Long ART" under "Heavy Rain" condition were significantly higher (OR 1.58, 95% CI: 1.26-1.97) than calls responded under "Fine" weather. After accounting for confounders, the ORs of "Long" ART for trauma incidents at "Home" or "Commercial" locations were also significantly higher than that for "Road" incidents. CONCLUSION: Traffic, weather and the place of incident were found to be significant in affecting the ART. The evaluation of factors affecting the ART enables the development of effective interventions for reducing the ART. PMID- 26026971 TI - A statistical law in the perception of risks and physical quantities in traffic. AB - This paper suggests that a universal psychophysical law influences the perception of risks and physical quantities in traffic. This law states that there will be a tendency to overestimate low probabilities or small quantities, while high probabilities or large quantities may be underestimated. Studies of the perception of risk and physical quantities in traffic have found a highly consistent pattern, which shows that: 1. Pedestrians intending to cross the road overestimate the stopping distance of cars travelling at low speed and underestimate the stopping distance of cars travelling at high speed. 2. Car drivers intending to overtake overestimate the distance needed at low speed, but underestimate it at high speed. 3. Car drivers asked to accelerate from standstill to a given speed overshoot the target speed; when asked to slow down to a stated speed, drivers also overshoot the target speed. 4. When asked what speed to choose to save a given amount of time on a trip of given length, drivers overestimate target speed when initial speed is low and underestimate it when initial speed is high. 5. Drivers overestimate the increase in risk associated with a small increase in speed and underestimate the increase in risk associated with a larger increase in speed. 6. Drivers overestimate the risk of apprehension for traffic offences when it is low and underestimate it when it is high. 7. Road users overestimate the risk associated with comparatively safe modes of tr The paper gives examples of all these misperceptions of physical quantities and risk. PMID- 26026972 TI - Antimicrobial susceptibilities of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in health care-associated urinary tract infection: focus on susceptibility to fosfomycin. AB - PURPOSE: The appearance of extended-spectrum beta-lactamase (ESBL)-producing gram negative bacteria in urinary tract infection (UTI) constitutes an important therapeutic challenge. The aim of this study was to describe drug susceptibility profiles of ESBL-producing bacteria isolated from urine samples. We also determined the antimicrobial co-resistance to several agents, including fosfomycin. METHODS: The computerized database was used to identify ESBL-positive urine samples. We analyzed E. coli and Klebsiella isolates obtained from urine cultures, and duplicate isolates and isolates not tested against fosfomycin were excluded. The cases were further categorized according to UTI definition [community-acquired (CoA) UTI, community-onset health care-associated (HCA) UTI, and hospital-acquired (HA) UTI]. ESBL isolates were stratified according to their origin into two groups: urology and non-urology isolates. RESULTS: Antimicrobial susceptibilities of the strains to fosfomycin were tested in 277 ESBL-positive strains, 217 ESBL-EC strains, and 60 ESBL-KP strains. The most effective agents were carbapenems, such as imipenem and meropenem. The least active substances were ciprofloxacin (20.7 %), levofloxacin (22.7 %), trimethoprim-sulfamethoxazole (34.3 %), and ampicillin-clavulanate (42.9 %). Overall, 243 out of the 277 (87.7 %) isolates tested were susceptible to fosfomycin. Higher fosfomycin sensitivity was observed in E. coli (94.9 %) compared to Klebsiella (61.7 %) (p = 0.001). ESBL-positive isolates from urological (68 isolates) and non-urological patients (209 isolates) showed similar susceptibility profiles. Other than carbapenems, isolates from CoA-UTI showed higher sensitivity to fosfomycin (100 %) and nitrofurantoin (93.1 %), isolates from HCA-UTI showed higher sensitivity to amikacin (94.1 %), and isolates from HA-UTI showed overall poor sensitivity to antibiotics. CONCLUSIONS: Fosfomycin could be an alternative treatment option for UTIs related to ESBL-producing E. coli spp. and CoA-UTI, but not for UTIs related to ESBL-producing Klebsiella spp. Antimicrobial susceptibilities of ESBL producing strains were different according to the UTI classification. Fosfomycin showed decreased activity against isolates from HCA-UTI and HA-UTI. However, further clinical verification is required to assess the clinical efficacy of fosfomycin for the treatment of UTIs caused by ESBL-producing E. coli isolates. PMID- 26026973 TI - Deciphering discord: How Drosophila research has enhanced our understanding of the importance of FMRP in different spatial and temporal contexts. AB - Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. In addition to its canonical definition as a neurodevelopmental disease, recent findings in the clinic suggest that FXS is a systemic disorder that is characterized by a variety of heterogeneous phenotypes. Efforts to study FXS pathogenesis have been aided by the development and characterization of animal models of the disease. Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatially and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients. PMID- 26026975 TI - Polymer antidotes for toxin sequestration. AB - Toxins delivered by envenomation, secreted by microorganisms, or unintentionally ingested can pose an immediate threat to life. Rapid intervention coupled with the appropriate antidote is required to mitigate the threat. Many antidotes are biological products and their cost, methods of production, potential for eliciting immunogenic responses, the time needed to generate them, and stability issues contribute to their limited availability and effectiveness. These factors exacerbate a world-wide challenge for providing treatment. In this review we evaluate a number of polymer constructs that may serve as alternative antidotes. The range of toxins investigated includes those from sources such as plants, animals and bacteria. The development of polymeric heavy metal sequestrants for use as antidotes to heavy metal poisoning faces similar challenges, thus recent findings in this area have also been included. Two general strategies have emerged for the development of polymeric antidotes. In one, the polymer acts as a scaffold for the presentation of ligands with a known affinity for the toxin. A second strategy is to generate polymers with an intrinsic affinity, and in some cases selectivity, to a range of toxins. Importantly, in vivo efficacy has been demonstrated for each of these strategies, which suggests that these approaches hold promise as an alternative to biological or small molecule based treatments. PMID- 26026976 TI - Human engineered heart tissue as a model system for drug testing. AB - Drug development is time- and cost-intensive and, despite extensive efforts, still hampered by the limited value of current preclinical test systems to predict side effects, including proarrhythmic and cardiotoxic effects in clinical practice. Part of the problem may be related to species-dependent differences in cardiomyocyte biology. Therefore, the event of readily available human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) has raised hopes that this human test bed could improve preclinical safety pharmacology as well as drug discovery approaches. However, hiPSC-CM are immature and exhibit peculiarities in terms of ion channel function, gene expression, structural organization and functional responses to drugs that limit their present usefulness. Current efforts are thus directed towards improving hiPSC-CM maturity and high-content readouts. Culturing hiPSC-CM as 3-dimensional engineered heart tissue (EHT) improves CM maturity and anisotropy and, in a 24-well format using silicone racks, enables automated, multiplexed high content readout of contractile function. This review summarizes the principal technology and focuses on advantages and disadvantages of this technology and its potential for preclinical drug screening. PMID- 26026974 TI - BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. AB - Male breast cancer (MBC) is a rare disease that represents <1% of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7%), 95.9% with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations . PMID- 26026977 TI - Treatment complexity: a description of chemotherapy and supportive care treatment visits in patients with advanced-stage cancer diagnoses. AB - PURPOSE: Modern chemotherapy regimens are growing increasingly complex, involving lengthy outpatient infusions, and additional visits for supportive care. The treatment of advanced-stage patients is uniquely one of unremitting therapy and varying complexity. The study's purpose was to describe and quantify the dimensions of treatment complexity in terms of chemotherapy (CT) and supportive care (SC) visits. METHODS: Electronic medical records for 121 subjects with stages III and IV cancer were reviewed. Visits were classified as SC and CT types, and actual hours and visit numbers were calculated for a 3-month treatment period. Analysis included descriptive and generalized linear modeling statistics. RESULTS: Subjects >=65 years spent fewer total hours (M = 18.17 h, SD = 10.17 h, p = 0.04), but experienced more total visits (M = 10.96 visits, SD = 4.65 visits, p = 0.02) than younger subjects. More than 71% of younger patients spent two or more hours per chemotherapy visit, compared to 41.7% of older patients (p = 0.001). Older subjects were more likely to have a SC visit (p = 0.03), but did not differ from younger subjects in SC visit numbers (p = 0.3) or hours (p = 0.6). Females averaged 3.81 more total hours (M = 22. 61 h, SD = 11.06 h, p = 0.055) and had more total visits (M = 10.80 visits, SD = 3.71, p = 0.02) than males. By visit type, women spent twice the hours undergoing SC than males (M = 3.3 vs. 1.5 h, p = 0.051), but genders did not differ in CT visit hours or average length. By diagnosis, colon/esophageal subjects spent more hours in CT visits (M = 21.90 h, SD = 8.60 h, p < 0.01), and lung subjects trended toward spending more hours in SC visits (M = 4.80 h, SD = 8.23 h, p < 0.06). CONCLUSIONS: Advanced-stage cancer patients differed in visit types, hours, and treatment length undergoing CT and SC visits. Age, gender, and diagnosis explained the differences, and this study adds new understanding to the phenomenon of treatment complexity. PMID- 26026978 TI - Clinical predictors of aspiration after esophagectomy in esophageal cancer patients. AB - PURPOSE: The purposes of this study are to assess the usefulness of bedside swallowing tests and identify the clinical risk factors for subglottic aspiration after esophagectomy in esophageal cancer patients. METHODS: The study included patients who underwent esophagectomy for esophageal cancer between January and August 2013. Videofluoroscopic swallowing study (VFSS) was carried out 7 to 10 days post-surgery, and clinical bedside swallowing tests were conducted to determine the risk factors for subglottic aspiration. RESULTS: A total of 118 patients were evaluated, 38 of whom (32.2%) showed evidence of subglottic aspiration on VFSS. The clinical bedside swallowing test yielded positive results in 26 of the 38 patients with subglottic aspiration (sensitivity 68.4%). Prolonged operation time and vocal cord paralysis were risk factors predicting aspiration in multiple logistic regression analysis (odds ratio (OR), 0.651 per hour; P = 0.017 and OR, 9.1; P < 0.001). When operation times were divided into two groups, greater than or equal to 6 h (>=6 h) and less than 6 h (<6 h), the OR of operation time >=6 h to aspiration was increased to 3.22 (P = 0.007). CONCLUSIONS: We found that the clinical bedside swallowing test had a sensitivity of 68.4%, which, without VFSS, was insufficient to detect subglottic aspiration. Operation time greater than or equal to 6 h and vocal cord paralysis were risk factors for subglottic aspiration. Therefore, VFSS should be recommended in esophageal cancer patients who have operation time greater than or equal to 6 h or have vocal cord paralysis after esophagectomy. PMID- 26026979 TI - Solid cancer patients: intensive care unit admission and long-term outcome. PMID- 26026980 TI - Chemical and biological evaluation of Egyptian Nile Tilapia (Oreochromis niloticas) fish scale collagen. AB - Collagen is considered to be one of the most useful biomaterials with different medical applications. However, collagen properties differ from one source to another. The aim of this study was to extract, purify, characterize and perform preliminary biological evaluation of type I collagen from scales of Egyptian Nile Tilapia. Pepsin-solubilized collagen (PSC) was successfully prepared from Nile Tilapia fish scale waste. Lyophilized collagen was dissolved in dilute HCl to form acidic collagen solutions (ACS) which was neutralized to form gel. To confirm the biocompatibility of the produced gel, baby hamster kidney (BHK-21) fibroblast cells were seeded onto a 3D collagen gel (0.3% and 0.5%, w/v). The results of an SDS-PAGE test showed that the extracted collagens were type I collagen, with alpha chain composition of (alpha1)2alpha2. Thermal analysis showed that the denaturation temperature was 32 degrees C. X-ray diffraction (XRD) analysis and Fourier-transform infrared spectra (FTIR) showed that the extracted collagen had a triple helix structure. Active proliferation of BHK-21 cells with no signs of toxicity was evident with both collagen gel concentrations tested. The results show that Nile Tilapia scales can be an effective source of collagen extraction that could be used as a potential biomaterial in biomedical applications. PMID- 26026981 TI - Isolation, structure, and surfactant properties of polysaccharides from Ulva lactuca L. from South China Sea. AB - Two polysaccharides (ULP1 and ULP2) were isolated through ultrasonic-assisted extraction from green seaweed Ulva lactuca L. which was collected from the South China Sea. The highest yield of 17.57% was obtained under the conditions of 2% NaOH, 90 degrees C, material/water mass ratio 1:80, liquid extraction 5h and subsequent ultrasound-assisted extraction 1h. The structure of ULPs were characterized with periodate oxidation followed by Smith degradation, (1)H NMR, (13)C NMR spectroscopy, FTIR, and GPC. The molecular weights of ULP1 and ULP2 were 189 kDa and 230 kDa, respectively. The structural characteristics of ULP1 and ULP2 were quite similar. They were composed of rhamnose, xylose, glucose, and glucuronic acid. The content of rhamnose, xylose, glucose, glucuronic acid, sulfate was 51.2%, 12.3%, 20.1%, 16.4%, 12.0% for ULP1, respectively, and 60.8%, 14.2%, 8.2%, 16.8%, 26.8%, respectively, for ULP2. Both ULP1 and ULP2 showed good surface activity. 5 mg/mL ULP1 (2.62*10(-2) mmol/L) decreased the water surface tension to 51.63 mN/m. The critical micellar concentration of ULP1 and ULP2 was 1.01 mg/mL (5.3*10(-3) mmol/L) and 1.14 mg/mL (5.0*10(-3) mmol/L), respectively. PMID- 26026982 TI - Purification, characterization and biological activity of a novel polysaccharide from Inonotus obliquus. AB - A novel water-soluble polysaccharide IP3a was successfully isolated and purified from I. obliquus by DEAE-cellulose, Sepharose CL-6B and Sephadex G-200 column chromatography. Chemical characterization and antitumor and immunoregulatory activity of IP3a were investigated. IP3a consisted of rhamnose, arabinose, glucose and galactose in a molar ratio of 2.5:4.6:1.0:2.6 with an average molecular weight of 48,820 Da. IP3a exhibited no significant antitumor activities in vitro. However, IP3a could not only inhibit the growth of transplantable Jurkat tumor in mice significantly, but also could enhance the splenocyte proliferation and lymphocyte proliferation induced by ConA and LPS in a dose dependent manner. At the same time, IP3a could promote cytokine secretion (IL-2, IL-6, IL-12 and TNF-alpha) and macrophage phagocytosis in mice. In addition, IP3a could increase Bax expression and inhibit Bcl-2 expression significantly. These results suggested that antitumor mechanisms of IP3a might be associated with improving immune response in vivo and inducing apoptosis of tumor cells in vitro. IP3a might be utilized as a potential therapeutic agent against lymphoma cancer with immunomodulatory activity. PMID- 26026983 TI - Influence of the nonexchangeable potassium of mica on radiocesium uptake by paddy rice. AB - A pot cultivation experiment was conducted to elucidate the influence of the nonexchangeable potassium (K) of mica on radiocesium ((137)Cs) uptake by paddy rice (Oryza sativa L. cv. Koshihikari), and to evaluate the potential of mica application as a countermeasure to reduce radiocesium transfer from soil to paddy rice. The increase in the exchangeable K concentrations of soils, measured before planting, due to mica (muscovite, biotite, and phlogopite) application was negligible. However, in trioctahedral mica (biotite and phlogopite)-treated soil, the release of nonexchangeable K from the mica interlayer maintained the soil solution K at a higher level during the growing season in comparison to the control, and consequently decreased the (137)Cs transfer factor for brown rice (TF). The sodium tetraphenylboron (TPB)-extractable K concentration of the soils, measured before planting, was strongly negatively correlated with the TF, whereas the exchangeable K concentration of the soils, also measured before planting, was not correlated with the TF. Therefore, we conclude that TPB-extractable K is more reliable than exchangeable K as a basis of fertilizer recommendations for radiocesium-contaminated paddy fields. Phlogopite-treated soils exhibited higher TPB-extractable K concentrations and lower TF values than biotite-treated soils. We thus conclude that phlogopite application is an effective countermeasure to reduce radiocesium uptake in paddy rice. PMID- 26026984 TI - Maternal transfer of anthropogenic radionuclides to eggs in a small shark. AB - Maternal transfer of radionuclides to progeny is one of the least known sources of contamination in marine biota and more information is needed to assess its radiological significance. A radiotracer study on spotted dogfish, Scyliorhinus canicula, evaluated the hypothesis that four anthropogenic radionuclides (Cobalt 60, Zinc-65, Americium-241 and Cesium-134) could be maternally transferred to eggs and each of their major components during maternal ingestion of radiolabelled food. The linear regressions between cumulative radioactivity that had been maternally ingested and the level in subsequently laid eggs were used to derive maternal-to-egg transfer factors (mTFs). These maternal transfers varied over an order of magnitude and were ranked (134)Cs > (65)Zn > (60)Co > (241)Am. This ranking was the same as their relative assimilation efficiencies in radiolabelled food consumed by adults. Among these four radionuclides the potential radiological exposure of embryos is accentuated for (65)Zn and (134)Cs due to their predominant transfer to egg yolk where they are available for subsequent absorption by the embryo as it develops prior to hatching from the egg capsule. Thus, for cartilaginous fish like shark, the potential radioecological consequences of a pulsed release of these radionuclides into the marine environment may extend beyond the temporal duration of the release. PMID- 26026985 TI - Example of cost calculations for an operating room and a post-anaesthesia care unit. AB - OBJECTIVE: The aim of this study was to evaluate the cost of an operating room using data from our hospital. Using an accounting-based method helped us. METHODS: Over the year 2012, the sum of direct and indirect expenses with cost sharing expenses allowed us to calculate the cost of the operating room (OR) and of the post-anaesthesia care unit (PACU). RESULTS: The cost of the OR and PACU was ?10.8 per minute of time offered. Two thirds of the direct expenses were allocated to surgery and one third to anaesthesia. Indirect expenses were 25% of the direct expenses. The cost of medications and single use medical devises was ?111.45 per anaesthesia. The total cost of anaesthesia (taking into account wages and indirect expenses) was ?753.14 per anaesthesia as compared to the total cost of the anaesthesia. The part of medications and single use devices for anaesthesia was 14.8% of the total cost. CONCLUSION: Despite the difficulties facing cost evaluation, this model of calculation, assisted by the cost accounting controller, helped us to have a concrete financial vision. It also shows that a global reflexion is necessary during financial decision-making. PMID- 26026986 TI - Cue-Reactive Altered State of Consciousness Mediates the Relationship Between Problem-Gambling Severity and Cue-Reactive Urge in Poker-Machine Gamblers. AB - In order to enhance our understanding of the nature of poker-machine problem gambling, a community sample of 37 poker-machine gamblers (M age = 32 years, M PGSI = 5; PGSI = Problem Gambling Severity Index) were assessed for urge to gamble (responses on a visual analogue scale) and altered state of consciousness (assessed by the Altered State of Awareness dimension of the Phenomenology of Consciousness Inventory) at baseline, after a neutral cue, and after a gambling cue. It was found that (a) problem-gambling severity (PGSI score) predicted increase in urge (from neutral cue to gambling cue, controlling for baseline; sr (2) = .19, p = .006) and increase in altered state of consciousness (from neutral cue to gambling cue, controlling for baseline; sr (2) = .57, p < .001), and (b) increase in altered state of consciousness (from neutral cue to gambling cue) mediated the relationship between problem-gambling severity and increase in urge (from neutral cue to gambling cue; kappa(2) = .40, 99 % CI [.08, .71]). These findings suggest that cue-reactive altered state of consciousness is an important component of cue-reactive urge in poker-machine problem-gamblers. PMID- 26026987 TI - The Social and Psychological Impacts of Gambling in the Cree Communities of Northern Quebec. AB - A detailed survey of gambling, addiction and mental health was conducted with randomly selected respondents (n = 506) from four Cree communities of Northern Quebec. The study examined the current patterns of gambling in relation to demographic, social, and psychological factors. Instruments included the Canadian Problem Gambling Index, Addiction Severity Index, Beck Depression Inventory and the computerized Diagnostic Interview Schedule for psychiatric diagnoses. Overall, 69.2 % of the total sample participated in any gambling/gaming activities over the past year; 20.6 % of this group were classified as moderate/high risk gamblers, and 3.2 % were classified in the highest "problem gambling" category. Considering the entire sample, the overall prevalence of problem gambling was 2.2 %. Women were significantly more likely to play bingo (56.6 %) compared to men (35.1 %) and they played more frequently; 20.8 % of women versus 3.8 % of men played once/week or more often. Compared to the no/low risk gamblers, a greater proportion of moderate/high risk gamblers were cigarette smokers (44.8 vs. 56.3 %), they were more likely to meet DSM-IV diagnostic criteria for alcohol dependence (21.2 vs. 46.2 %), and they were more likely to report moderate to severe depressive symptoms in the past month. Risk factors for problem gambling included traumatic life events (physical and emotional abuse), anxiety and depression, as well as drug/alcohol abuse. The high rates of comorbidity between problem gambling, tobacco dependence, substance abuse and other psychological problems demonstrate that gambling among some Cree adults is part of a pattern of high-risk factors for negative long-term health consequences. The results also have implications for treatment, suggesting that interventions for gambling disorders should not focus on gambling alone but rather the constellation of high-risk behaviours that pose a risk to recovery and well-being. PMID- 26026988 TI - Clustering Finnish Gambler Profiles Based on the Money and Time Consumed in Gambling Activities. AB - Gambling involves consumption of gamblers' money and time. Gamblers are a heterogeneous group, and in addition to grouping gamblers based on personality factors, it is also important to find different gambler profiles with respect to their gambling behavior. Using the nationally representative survey 'Finnish Gambling 2011' (N = 4484), this article studies the subtypes of Finnish gamblers based on the frequency of gambling and the amounts of money and time used in different gambling forms. Cluster analysis reveals six profiles of gamblers, from infrequent gamblers to omnivorous gamblers. In the further analysis of the clusters, it was found that the highest problem gambling prevalence was in the groups of sport betting + electronic gaming machine gamblers and omnivorous gamblers, which were also both dominated by men. Certain gambling consumption patterns and risk factors for problem gambling are related to both socio demographic backgrounds of the gamblers as well as the structural and situational characteristics of the games. The results have implications for the prevention of problem gambling, as some consumption patterns may be connected with the probability of developing gambling problems. PMID- 26026989 TI - Noscapine recirculates enterohepatically and induces self-clearance. AB - Noscapine (Nos), an antitussive benzylisoquinoline opium alkaloid, is a non-toxic tubulin-binding agent currently in Phase II clinical trials for cancer chemotherapy. While preclinical studies have established its tumor-inhibitory properties in various cancers, poor absorptivity and rapid first-pass metabolism producing several uncharacterized metabolites for efficacy, present an impediment in translating its efficacy in humans. Here we report novel formulations of Nos in combination with dietary agents like capsaicin (Cap), piperine (Pip), eugenol (Eu) and curcumin (Cur) known for modulating Phase I and II drug metabolizing enzymes. In vivo pharmacokinetic (PK), organ toxicity evaluation of combinations, microsomal stability and in vitro cytochrome P450 (CYP) inhibition effects of Nos, Cap and Pip using human liver microsomes were performed. Single-dose PK screening of combinations revealed that the relative exposure of Nos (2 MUg h/mL) was enhanced by 2-fold (4 MUg h/mL) by Cap and Pip and their plasma concentration time profiles showed multiple peaking phenomena for Nos indicating enterohepatic recirculation or differential absorption from intestine. CYP inhibition studies confirmed that Nos, Cap and Pip are not potent CYP inhibitors (IC50>1 MUM). Repeated oral dosing of Nos, Nos+Cap and Nos+Pip showed lower exposure (Cmax and AUClast) of Nos on day 7 compared to day 1. Nos Cmax decreased from 3087 ng/mL to 684 ng/mL and AUClast from 1024 ng h/mL to 508 ng h/mL. In presence of Cap and Pip, the decrease in Cmax and AUClast of Nos was similar. This may be due to potential enzyme induction leading to rapid clearance of Nos as the trend was observed in Nos alone group also. The lack of effect on intrinsic clearance of Nos suggests that the potential drug biotransformation modulators employed in this study did not contribute toward increased exposure of Nos on repeated dosing. We envision that Nos-induced enzyme induction could alter the therapeutic efficacy of co-administered drugs, hence emphasizing the need for strategic evaluation of the metabolism of Nos to reap its maximum efficacy. PMID- 26026990 TI - Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA. AB - Glucagon-like peptide-1 (GLP-1) is thought to preserve neurons and glia following axonal injury and neurodegenerative disorders. We investigated the neurotrophic and neuroprotective properties of exendin (Ex)-4, a synthetic GLP-1 receptor (GLP 1R) agonist, on adult rat dorsal root ganglion (DRG) neurons and PC12 cells. GLP 1R was predominantly localized on large and small peptidergic neurons in vivo and in vitro, suggesting the involvement of GLP-1 in both the large and small sensory fiber functions. Ex-4 dose-dependently (1 <= 10 <= 100 nM) promoted neurite outgrowth and neuronal survival at 2 and 7 days in culture, respectively. Treatment with 100 nM Ex-4 restored the reduced neurite outgrowth and viability of DRG neurons caused by the insulin removal from the medium and suppressed the activity of RhoA, an inhibitory regulator for peripheral nerve regeneration, in PC12 cells. Furthermore, these effects were attenuated by co-treatment with phosphatidylinositol-3'-phosphate kinase (PI3K) inhibitor, LY294002. These findings imply that Ex-4 enhances neurite outgrowth and neuronal survival through the activation of PI3K signaling pathway, which negatively regulates RhoA activity. Ex-4 and other GLP-1R agonists may compensate for the reduced insulin effects on neurons, thereby being beneficial for the treatment of diabetic neuropathy. PMID- 26026991 TI - Prevalence of gastroesophageal reflux disease symptoms and effects of esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis. AB - BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) symptoms has not been investigated in patients on maintenance hemodialysis in Japan, and few studies have reported the effect of proton pump inhibitors (PPIs) in hemodialysis patients with GERD symptoms. Here, we investigated the prevalence of GERD symptoms and the effects of the PPI esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis. METHODS: This was a cross-sectional/cohort study of hemodialysis outpatients implemented in 10 Japanese medical facilities from October 2012 to March 2014. The trial was registered in the UMIN Clinical Trial Registry (UMIN000009124). RESULTS: Forty one of 385 patients (11%) reported GERD symptoms on the Global Overall Symptom (GOS) questionnaire. Multivariate logistic regression analysis identified the independent prognostic factors for GERD symptoms as a history of gastric ulcer and use of sevelamer hydrochloride or calcium polystyrene sulfonate. Participants with GERD symptoms completed the Quality of Life in Reflux and Dyspepsia, Japanese version (QOLRAD-J) questionnaire and were assigned to receive 4-week esomeprazole treatment (20 mg/day). This PPI therapy significantly improved all QOLRAD-J domains in the full analysis set (n = 28) and improved the GERD symptoms listed in the GOS questionnaire. Significantly impaired disease-specific quality of life (QOL) in the QOLRAD-J domains was observed in 44.4-74.1% of patients who had symptoms before treatment. The mean GOS and QOLRAD-J scores correlated significantly. CONCLUSION: Therapy with 20 mg/day esomeprazole appears to be efficacious for improving disease-specific QOL and GERD symptoms in Japanese patients on maintenance hemodialysis. PMID- 26026992 TI - Surface display of the thermophilic lipase Tm1350 on the spore of Bacillus subtilis by the CotB anchor protein. AB - Lipases expressed in microbial hosts have great commercial value, but their applications are restricted by the high costs of production and harsh conditions used in industrial processes, such as high temperature and alkaline environment. In this study, an Escherichia coli-Bacillus subtilis shuttle vector (pHS-cotB Tm1350) was constructed for the spore surface display of the lipase Tm1350 from hyperthermophilic bacterium Thermotoga maritima MSB8. Successful display of the CotB-Tm1350 fusion protein on spore surface was confirmed by Western blot analysis and activity measurements. The optimal catalytic temperature and pH of the spore surface-displayed Tm1350 were 80 degrees C and 9, respectively, which were higher than non-immobilized Tm1350 (70 degrees C and pH 7.5). Analysis of thermal and pH stability showed that spore surface-displayed Tm1350 retained 81 or 70 % of its original activity after 8 h of incubation at pH 8 or pH 9 (70 degrees C), which were 18 % higher than the retained activity of the non immobilized Tm1350 under the same conditions. Meanwhile, recycling experiments showed that the recombinant spores could be used for up to three reaction cycles without a significant decrease in the catalytic rate (84 %). These results suggested that enzyme display on the surface of the B. subtilis spore could serve as an effective approach for enzyme immobilization, which has potential applications in the harsh biochemical industry. PMID- 26026993 TI - Principles of Pharmacology and Toxicology Also Govern Effects of Chemicals on the Endocrine System. AB - The present debate on chemicals with Hormonal activity, often termed 'endocrine disruptors', is highly controversial and includes challenges of the present paradigms used in toxicology and in hazard identification and risk characterization. In our opinion, chemicals with hormonal activity can be subjected to the well-evaluated health risk characterization approach used for many years including adverse outcome pathways. Many of the points arguing for a specific approach for risk characterization of chemicals with hormonal activity are based on highly speculative conclusions. These conclusions are not well supported when evaluating the available information. PMID- 26026994 TI - Cardiotoxicity due to Chemotherapy: the Role of Biomarkers. AB - An ever-increasing array of chemotherapeutic agents is being used in the treatment of solid organ or hematologic malignancies. The success of many of these agents has led to an increasing survival of patients with cancer. However, many of these agents, particularly anthracyclines and trastuzumab, are associated with the development of cardiotoxicity. The current standard for the evaluation of chemotherapy-associated cardiotoxicity typically involves the use of serial measurements of left ventricular (LV) function by echocardiogram (Echo) and radionuclide ventriculogram (MUGA). Unfortunately, this time-honored method offers low sensitivity to the early prediction or detection of cardiac events. Frequently, by the time cardiotoxicity is detected, significant LV dysfunction has occurred and ultimately this may not respond to standard cardioprotective treatment. Cardiac biomarkers, troponin I and B-type natriuretic peptide, may allow a more accurate and timely monitoring strategy. The current data and a summarized understanding of how to utilize cardiac biomarkers for the prevention and early detection of cardiac dysfunction during chemotherapy are presented. PMID- 26026995 TI - Impact of sex and ethnicity on arrhythmic risk. AB - Substantial differences in the risk of common arrhythmia syndromes exist between men and women, as well as in varying ethnic/racial groups. For example, despite an overall lower risk of sudden death and atrial fibrillation in women compared with men, women have longer QT intervals and a higher risk of torsades de pointes due to antiarrhythmic drugs and worse outcomes associated with atrial fibrillation. An ethnicity-related paradox in atrial fibrillation epidemiology is apparent; despite a higher prevalence of medical comorbidities such as hypertension, diabetes, and prolonged PR interval, blacks, Hispanics, and Asians have a lower risk of atrial fibrillation than whites. In this promising era of genomic medicine, an improved understanding of epidemiology and phenotype holds the potential for revealing novel therapeutic targets and preventing disease. PMID- 26026996 TI - Safety of implanted cardiac devices in an MRI environment. AB - Magnetic resonance imaging (MRI) has evolved into an essential diagnostic modality for the evaluation of various conditions. In line with the increase in MRI applications, the use of cardiac implantable electronic devices (CIED) is growing and many of the CEID recipients of today may require MRI examinations in the future. Traditionally, MRI examination of CIED recipients has been considered a contraindication. However, recent studies have provided strong evidence that MRI can safely be performed in selected patients with specific precautions. This review highlights the interactions of MRI with CIEDs, summarizes the literature, and outlines the Johns Hopkins Safety Protocol. PMID- 26026997 TI - Genetics of sudden cardiac death. AB - Sudden cardiac death (SCD) is defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed). It affects more than 3 million people annually worldwide and affects approximately 1/1000 people each year in the USA. Familial studies of syndromes with Mendelian inheritance, candidate genes analyses, and genome-wide association studies (GWAS) have helped our understanding of the genetics of SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the general population and were identified from candidate gene analyses and GWAS. Our understanding of the genetics of SCD will improve by the use of next generation sequencing/whole-exome sequencing as well as whole-genome sequencing which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD. PMID- 26026999 TI - Probing the structure of framework materials by high pressure and the example of a magnetic, non-porous coordination polymer. PMID- 26027000 TI - Structures beyond superspace. PMID- 26027001 TI - Pressure-induced structural phase transformation in cobalt(II) dicyanamide. AB - In situ synchrotron powder diffraction has been used to probe the pressure dependent structural properties of the magnetic molecular framework material Co(dca)2 [dca = dicyanamide or N(CN)2(-)]. An orthorhombic (Pmnn) to monoclinic (P21/n) transformation to a high-pressure phase, namely gamma-Co(dca)2, occurs at 1.1 GPa. Structural determination of gamma-Co(dca)2 shows that the rutile-like topology of the pristine material is retained at high pressures, with the lower symmetry allowing a progression of volume-reducing structural distortions. gamma Co(dca)2 was stable at the maximum pressure measured of 4.2 GPa. Both phases were soft, with bulk moduli (B0) for alpha-Co(dca)2 and gamma-Co(dca)2 of 13.15 (18) and 9.0 (6) GPa, respectively. Modest uniaxial negative linear compressibility (K) of the order of -4 TPa(-1) was observed over the entire measured pressure range. PMID- 26027002 TI - Aperiodic crystals and beyond. AB - Crystals are paradigms of ordered structures. While order was once seen as synonymous with lattice periodic arrangements, the discoveries of incommensurate crystals and quasicrystals led to a more general perception of crystalline order, encompassing both periodic and aperiodic crystals. The current definition of crystals rests on their essentially point-like diffraction. Considering a number of recently investigated toy systems, with particular emphasis on non-crystalline ordered structures, the limits of the current definition are explored. PMID- 26026998 TI - Dyslipidemia and cardiovascular disease in women. AB - Cardiovascular disease is the major cause of death in women in developed countries. Dyslipidemia is highly prevalent in women, particularly after the menopause. Elevated low-density lipoprotein cholesterol (LDL-C) has been identified as the key lipid parameter in both genders whereas HDL-cholesterol and triglycerides have been more closely associated, in some studies, with cardiovascular risk in women. Menopause has been shown to be associated with an increase in total and LDL-cholesterol and a decrease in HDL-cholesterol (predominantly in the HDL2 subfraction). Despite its beneficial effects on the lipid profile, hormone replacement therapy is not recommended for primary or secondary prevention of cardiovascular disease in women. The latest meta-analysis of statin trials with gender-specific outcomes showed a similar benefit in women and men. The addition of ezetimibe to simvastatin in patients with acute coronary syndromes showed a further reduction of the primary endpoint in both genders. While there are no gender-related differences in drug treatment of dyslipidemia, current guidelines, to avoid overtreatment, strongly suggest risk estimation before initiating lipid-lowering treatment in women without manifest cardiovascular disease. PMID- 26027003 TI - Neutron diffraction structures of water in crystalline hydrates of metal salts. AB - Neutron diffraction structures of water molecules in crystalline hydrates of metal salts have been collected from the literature up to December 2011. Statistical methods were used to investigate the influence on the water structures of the position and nature of hydrogen bond acceptors and cations coordinated to the water oxygen. For statistical modelling the data were pruned so that only structures with oxygen as hydrogen acceptors, single hydrogen bonds, and no more than two metals or hydrogens coordinated to the water oxygen were included. Multiple linear regression models were fitted with the water OH bond length and bond angle as response variables. Other variables describing the position and nature of the acceptors and ions coordinated to the waters were taken as explanatory variables. These variables were sufficient to give good models for the bond lengths and angles. There were sufficient structures involving coordinated Mg(2+) or Cu(2+) for a separate statistical modelling to be done for these cases. PMID- 26027004 TI - Synthesis, growth, structure and characterization of molybdenum zinc thiourea complex crystals. AB - Single crystals of molybdenum-incorporated tris(thiourea)zinc(II) sulfate (MoZTS) are grown by the slow evaporation solution growth technique. Crystal composition as determined by single-crystal X-ray diffraction analysis reveals that it belongs to the orthorhombic system with space group Pca21 and cell parameters a = 11.153 (2), b = 7.7691 (14), c = 15.408 (3) A, V = 1335.14 (4) A(3) and Z = 4. The surface morphological changes are studied by scanning electron microscopy. The vibrational patterns in FT-IR are used to identify the functional group and TGA/DTA (thermogravimetric analysis/differential thermal analysis) indicates the stability of the material. The structure and the crystallinity of the material were confirmed by powder X-ray diffraction analysis and the simulated X-ray diffraction (XRD) closely matches the experimental one with varied intensity patterns. The band gap energy is estimated using diffuse reflectance data by the application of the Kubelka-Munk algorithm. The relative second harmonic generation (SHG) efficiency measurements reveal that MoZTS has an efficiency comparable to that of tris(thiourea)zinc(II) sulfate (ZTS). Hirshfeld surfaces were derived using single-crystal X-ray diffraction data. Investigation of the intermolecular interactions and crystal packing via Hirshfeld surface analysis reveal that the close contacts are associated with strong interactions. Intermolecular interactions as revealed by the fingerprint plot and close packing could be the possible reasons for facile charge transfer leading to SHG activity. PMID- 26027006 TI - Tilting structures in inverse perovskites, M3TtO (M = Ca, Sr, Ba, Eu; Tt = Si, Ge, Sn, Pb). AB - Single-crystal X-ray diffraction experiments were performed for a series of inverse perovskites, M3TtO (M = Ca, Sr, Ba, Eu; Tt = tetrel element: Si, Ge, Sn, Pb) in the temperature range 500-50 K. For Tt = Sn, Pb, they crystallize as an 'ideal' perovskite-type structure (Pm3m, cP5); however, all of them show distinct anisotropies of the displacement ellipsoids of the M atoms at room temperature. This behavior vanishes on cooling for M = Ca, Sr, Eu, and the structures can be regarded as 'ideal' cubic perovskites at 50 K. The anisotropies of the displacement ellipsoids are much more enhanced in the case of the Ba compounds. Finally, their structures undergo a phase transition at ~ 150 K. They change from cubic to orthorhombic (Ibmm, oI20) upon cooling, with slightly tilted OBa6 octahedra, and bonding angles O-Ba-O ? 174 degrees (100 K). For the larger Ba(2+) cations, the structural changes are in agreement with smaller tolerance factors (t) as defined by Goldschmidt. Similar structural behavior is observed for Ca3TtO. Smaller Tt(4-) anions (Si, Ge) introduce reduced tolerance factors. Both compounds Ca3SiO and Ca3GeO with cubic structures at 500 K, change into orthorhombic (Ibmm) at room temperature. Whereby, Ca3SiO is the only representative within the M3TtO family where three polymorphs can be found within the temperature range 500-50 K: Pm3m-Ibmm-Pbnm. They show tiny differences in the tilting of the OCa6 octahedra, expressed by O-Ca-O bond angles of 180 degrees (500 K), ~ 174 degrees (295 K) and 170 degrees (100 K). For larger M (Sr, Eu, Ba), together with smaller Tt (Si, Ge) atoms, pronounced tilting of the OM6 octahedra, and bonding angles of O-M-O ? 160 degrees (295 K) are observed. They crystallize in the anti-GdFeO3 type of structure (Pbnm, oP20), and no phase transitions occur between 500 and 50 K. The observed phase transitions are all accompanied by multiple twinning, in terms of pseudo-merohedry or reticular pseudo-merohedry. PMID- 26027005 TI - Neutron Laue and X-ray diffraction study of a new crystallographic superspace phase in n-nonadecane-urea. AB - Aperiodic composite crystals present long-range order without translational symmetry. These materials may be described as the intersection in three dimensions of a crystal which is periodic in a higher-dimensional space. In such materials, symmetry breaking must be described as structural changes within these crystallographic superspaces. The increase in the number of superspace groups with the increase in the dimension of the superspace allows many more structural solutions. This is illustrated in n-nonadecane-urea, revealing a fifth higher dimensional phase at low temperature. PMID- 26027007 TI - Structure of magnesium selenate enneahydrate, MgSeO4.9H2O, from 5 to 250 K using neutron time-of-flight Laue diffraction. AB - The complete structure of MgSeO4.9H2O has been refined from neutron single crystal diffraction data obtained at 5, 100, 175 and 250 K. It is monoclinic, space group P21/c, Z = 4, with unit-cell parameters a = 7.222 (2), b = 10.484 (3), c = 17.327 (4) A, beta = 109.57 (2) degrees , and V = 1236.1 (6) A(3) [rho(calc) = 1770 (1) kg m(-3)] at 5 K. The structure consists of isolated [Mg(H2O)6](2+) octahedra, [SeO4](2-) tetrahedra and three interstitial lattice water molecules, all on sites of symmetry 1. The positions of the H atoms agree well with those inferred on the basis of geometrical considerations in the prior X-ray powder diffraction structure determination: no evidence of orientational disorder of the water molecules is apparent in the temperature range studied. Six of the nine water molecules are hydrogen bonded to one another to form a unique centrosymmetric dodecamer, (H2O)12. Raman spectra have been acquired in the range 170-4000 cm(-1) at 259 and 78 K; ab initio calculations, using density functional theory, have been carried out in order to aid in the analysis of the Raman spectrum as well as providing additional insights into the geometry and thermodynamics of the hydrogen bonds. Complementary information concerning the thermal expansion, crystal morphology and the solubility are also presented. PMID- 26027008 TI - Optical anomaly in artificial cubic hieratite, K2[SiF6]. AB - Crystals of K2[SiF6] were grown in agar gel, silica gel and jelly. Crystals grown in agar gel or jelly exhibit birefringence and consist of six double refracting growth sectors, each having the shape of a tetragonal pyramid. Nevertheless, the structure of the crystals from agar gel could be refined as cubic (space group Fm3m) with a weighted R factor of 0.043. The amount of birefringence was estimated by the Senarmont compensation method and the rotating polarizer method. PMID- 26027009 TI - Crystal structure, atomic net charges and electric moments in pyroelectric LiNaSO4 at 296 K. AB - The crystal structure and electric charge distribution in LiNaSO4 have been studied at 296 K by X-ray diffraction using a spherical crystal. LiNaSO4 is pyroelectric, nonferroelectric and an optically uniaxial insulator which crystallizes in the space group P31c. Least-squares refinement (MOLLY) was based on 13,026 reflections. The asymmetric unit contains Li(+), Na(+) and three SO4(2 ) ions, where one O and S lie on a threefold axis about which three O atoms are related with a threefold symmetry in each sulfate ion. Two of the O-S-O groups suffer from disorder. The net charges of the atoms in three independent sulfate ions were determined under ionic charge constraints. The S atoms have positive net electric charges and O atoms are negative. The components of the significant electric multipole moments in the principal axis directions are determined from the distribution of net atomic charges in each sulfate ion. Electric moments in the unit cell generate macroscopic electric moments in the crystal which interact with light. This interaction results in two axial vectors of second rank associated with an optical indicatrix. The ratio of the calculated axial vector components in the principal axis directions originating from the asymmetric unit is 1.0061 (1), which compares well with the ratio of 1.006 for the corresponding optical refractive indices of LiNaSO4 for lambda(Na) = 589.29 nm. PMID- 26027010 TI - Octahedral tilting in the tungsten bronzes. AB - Possibilities for 'simple' octahedral tilting in the hexagonal and tetragonal tungsten bronzes (HTB and TTB) have been examined, making use of group theory as implemented in the computer program ISOTROPY. For HTB, there is one obvious tilting pattern, leading to a structure in space group P63/mmc. This differs from the space group P63/mcm frequently quoted from X-ray studies - these studies have in effect detected only displacements of the W cations from the centres of the WO6 octahedra. The correct space group, taking account of both W ion displacement and the octahedral tilting, is P6322 - structures in this space group and matching this description have been reported. A second acceptable tilting pattern has been found, leading to a structure in P6/mmm but on a larger '2 * 2 * 2' unit cell - however, no observations of this structure have been reported. For TTB, a search at the special points of the Brillouin zones revealed only one comparable tilting pattern, in a structure with space-group symmetry I4/m on a '2(1/2) * 2(1/2) by 2' unit cell. Given several literature reports of larger unit cells for TTB, we conducted a limited search along the lines of symmetry and found structures with acceptable tilt patterns in Bbmm on a '2(1/2)2 * 2(1/2) * 2' unit cell. A non-centrosymmetric version has been reported in niobates, in Bbm2 on the same unit cell. PMID- 26027011 TI - Structural insights into M2O-Al2O3-WO3 (M = Na, K) system by electron diffraction tomography. AB - The M2O-Al2O3-WO3 (M = alkaline metals) system has attracted the attention of the scientific community because some of its members showed potential applications as single crystalline media for tunable solid-state lasers. These materials behave as promising laser host materials due to their high and continuous transparency in the wide range of the near-IR region. A systematic investigation of these phases is nonetheless hampered because it is impossible to produce large crystals and only in a few cases a pure synthetic product can be achieved. Despite substantial advances in X-ray powder diffraction methods, structure investigation on nanoscale is still challenging, especially when the sample is polycrystalline and the structures are affected by pseudo-symmetry. Electron diffraction has the advantage of collecting data from single nanoscopic crystals, but it is frequently limited by incompleteness and dynamical effects. Automated diffraction tomography (ADT) recently emerged as an alternative approach able to collect more complete three-dimensional electron diffraction data and at the same time to significantly reduce dynamical scattering. ADT data have been shown to be suitable for ab initio structure solution of phases with large cell parameters, and for detecting pseudo-symmetry that was undetected in X-ray powder data. In this work we present the structure investigation of two hitherto undetermined compounds, K5Al(W3O11)2 and NaAl(WO4)2, by a combination of electron diffraction tomography and precession electron diffraction. We also stress how electron diffraction tomography can be used to obtain direct information about symmetry and pseudo-symmetry for nanocrystalline phases, even when available only in polyphasic mixtures. PMID- 26027012 TI - The modulated average structure of mullite. AB - Homogeneous and inclusion-free single crystals of 2:1 mullite (Al(4.8)Si(1.2)O(9.6)) grown by the Czochralski technique were examined by X-ray and neutron diffraction methods. The observed diffuse scattering together with the pattern of satellite reflections confirm previously published data and are thus inherent features of the mullite structure. The ideal composition was closely met as confirmed by microprobe analysis (Al(4.82 (3))Si(1.18 (1))O(9.59 (5))) and by average structure refinements. 8 (5) to 20 (13)% of the available Si was found in the T* position of the tetrahedra triclusters. The strong tendencey for disorder in mullite may be understood from considerations of hypothetical superstructures which would have to be n-fivefold with respect to the three dimensional average unit cell of 2:1 mullite and n-fourfold in case of 3:2 mullite. In any of these the possible arrangements of the vacancies and of the tetrahedral units would inevitably be unfavorable. Three directions of incommensurate modulations were determined: q1 = [0.3137 (2) 0 1/2], q2 = [0 0.4021 (5) 0.1834 (2)] and q3 = [0 0.4009 (5) -0.1834 (2)]. The one-dimensional incommensurately modulated crystal structure associated with q1 was refined for the first time using the superspace approach. The modulation is dominated by harmonic occupational modulations of the atoms in the di- and the triclusters of the tetrahedral units in mullite. The modulation amplitudes are small and the harmonic character implies that the modulated structure still represents an average structure in the overall disordered arrangement of the vacancies and of the tetrahedral structural units. In other words, when projecting the local assemblies at the scale of a few tens of average mullite cells into cells determined by either one of the modulation vectors q1, q2 or q3 a weak average modulation results with slightly varying average occupation factors for the tetrahedral units. As a result, the real structure of mullite is locally ordered (as previously known), but on the long-range its average is not completely disordered, the modulated structure of mullite may be denoted the true 'average structure of mullite'. PMID- 26027013 TI - Structural analysis of the coordination of dinitrogen to transition metal complexes. AB - Transition-metal complexes show a wide variety of coordination modes for the nitrogen molecule. A structural database study has been undertaken for dinitrogen complexes, and geometrical parameters around the L(n)M-N2 unit are retrieved from the Cambridge Structural Database. These data were classified in families of compounds, according to metal properties, to determine the degree of lengthening for the dinitrogen bonding. The importance of the nature of the metal center, such as coordination number and electronic configuration, is reported. Our study reveals poor activation by coordination of dinitrogen in mononuclear complexes, always having end-on coordination. However, partial weakening of nitrogen nitrogen bonding is found for end-on binuclear complexes, whereas side-on complexes can be completely activated. PMID- 26027015 TI - Separation of enantiomers using vancomycin in a countercurrent process by suppression of electroosmosis. AB - Excellent separations were achieved using a coated column to suppress electroosmotic flow and employing a countercurrent process between chiral selector and racemic solute. Using the macrocyclic antibiotic vancomycin as a chiral selector in capillary electrophoresis the resolution of nonsteroidal anti inflammatories and dansyl amino acids was achieved. Improvement in sensitivity due to the elimination of background absorbance and increased efficiency due to the removal of wall adsorption effects are both achieved using this technique. PMID- 26027014 TI - Primary neuroendocrine tumor (carcinoid tumor) of the testis: a case report with review of literature. AB - BACKGROUND: The term carcinoid (Karzinoide) was coined by German pathologist Oberndorfer in 1907. Primary testicular carcinoid tumors (TCT) are rare, constituting 0.23% of all testicular tumors. In this report we describe a case of primary TCT of the testis and present the results of an extensive literature review to cover all the aspects of carcinoid tumor, including the definition, classification, origin, presentation, diagnostic evaluation, management, prognosis, and follow-up. CASE REPORT: A 34-year-old male presented with chronic right scrotal swelling with recent onset of pain. Radical orchiectomy revealed a solid intratesticular tumor confined to the testis and epididymis, without lymphovascular invasion. Histology was consistent with neuroendocrine carcinoma. The tumor was staged as pT1 N0 M0 S2. Immunohistochemistry was positive for neuroendocrine markers. An extratesticular carcinoid tumor was ruled out. Urinary excretion of 5-hydroxyindoleacetic acid and Chromogranin A were within normal range. CONCLUSIONS: It is important to follow serotonin levels since the elevated levels of serotonin can cause carcinoid heart disease. If metastatic lesions are not accessible for resection, a trial of octreotide therapy can be given. This case also adds to the rare reports in the literature of primary carcinoid tumors of the testis having low malignant potential. The literature review highlights new diagnostic and therapeutic interventions and stresses the importance of long term follow-up due to evidence of delayed metastasis or recurrences and also due to emergence of new complications as a result of improved prognosis and prolonged survival. PMID- 26027016 TI - Meeting of the Strategic Advisory Group of Experts on immunization, April 2015: conclusions and recommendations. PMID- 26027017 TI - Monthly report on dracunculiasis cases, January-April 2015. PMID- 26027018 TI - Uncovering a hidden cause of stroke. Longer monitoring for irregular heart rhythms could be useful for people in danger of a brain attack. PMID- 26027019 TI - Ask the doctor. The results of my recent stress test indicated I may have blockages in my coronary arteries. However, when I followed up with a cardiac catheterization, my arteries looked clear. How can that be? PMID- 26027020 TI - Ask the doctor. I had radiation and chemotherapy treatments for breast cancer. My cancer doctor sent me to a cardiologist for an ultrasound. Are there cardiac risks to cancer treatments? PMID- 26027021 TI - Rethinking alcohol use and heart disease. New research explores how genes may affect your drinking habits and heart health. PMID- 26027022 TI - What's new with the LVAD? The left ventricular assist device continues to find new roles in the treatment of advanced heart failure. PMID- 26027023 TI - Blood pressure drugs with bonus benefits. Both ACE inhibitors and ARBs also help stave off complications from heart failure and kidney disease. PMID- 26027024 TI - Halt heart disease with a plant-based, oil-free diet. A new study suggests you can. But a more lenient eating pattern may be easier to follow and just as effective. PMID- 26027029 TI - Varicose veins. Simple treatments can help. PMID- 26027030 TI - Health tips. How to swallow pills. PMID- 26027031 TI - New colon cancer test to be available soon. PMID- 26027032 TI - Taking a multivitamin doesn't help with cognitive decline. PMID- 26027034 TI - Monoclonal antibodies. Immune system tinkering. PMID- 26027033 TI - Is sitting the new smoking? New science, old habit. PMID- 26027035 TI - FRAX. A tool to estimate fracture risk. PMID- 26027036 TI - I recently had an abscess on my leg. My doctor drained it but didn't prescribe any antibiotics. Was that an oversight? PMID- 26027037 TI - Is too little sleep a cause of weight gain? PMID- 26027039 TI - Health tips. Healthy travel habits. PMID- 26027038 TI - Irritable bowel syndrome. New approaches for relief. PMID- 26027040 TI - Dogs prove effective at sniffing out cancer. PMID- 26027042 TI - Lymphedema surgery. New solutions for swelling. PMID- 26027041 TI - Mayo research: new ways to get drugs to the brain. PMID- 26027043 TI - Vitamin E. Hero or villain? PMID- 26027044 TI - Vaginal atrophy. Treatment options. PMID- 26027045 TI - I recently had a colonoscopy, but the cleansing preparation didn't work so well. My doctor had a hard time visualizing the inside of my colon and recommended another colonoscopy in a year. Does that seem right? PMID- 26027046 TI - I was considering wearing some shapewear under my outfit for an upcoming class reunion. But I heard a recent report saying that these garments can be risky. Is this true? PMID- 26027047 TI - Contamination of commercially available dog foods with thyroid tissue. PMID- 26027048 TI - The authors respond. PMID- 26027049 TI - Management of dogs and cats overdue for rabies booster. PMID- 26027050 TI - Continued recognition of the AVMA Council on Education. PMID- 26027051 TI - The AVMA Council on Education responds. PMID- 26027052 TI - Past council decisions a continued source of debate. PMID- 26027053 TI - AVMA hears calls to end accreditation role. PMID- 26027054 TI - International joint statements address horse slaughter, rabies in dogs. PMID- 26027055 TI - FDA warns of nonsterile saline solution bags. PMID- 26027056 TI - Analysis finds decreasing veterinary prices. PMID- 26027057 TI - US may adopt stricter pathogen standards for poultry. PMID- 26027058 TI - Avian influenza viruses found in Northwestern states. PMID- 26027060 TI - Teller, Bishop elected to AVMA Board of Directors. PMID- 26027059 TI - Veterinary medicine represented on Forbes' '30 Under 30' list. PMID- 26027061 TI - Students' animal welfare knowledge tested. PMID- 26027062 TI - UPenn receives gift for canine mitral valve disease research. PMID- 26027063 TI - Sen. Moran wins AVMA Advocacy Award. PMID- 26027064 TI - [Sleep disorder]. PMID- 26027065 TI - [Utility of organotypic raphe slice cultures to investigate the effects of psychotropic drugs on the function of serotoninergic neurons]. AB - A number of behavioral, neurochemical and electrophysiological studies have emphasized the importance of the serotonergic neurons in the pathophysiology of psychiatric disorders and the therapeutic actions of psychotropics. However, no in vitro serotonergic culture systems have successfully analyzed the long-term effects of psychotropics or the neural interaction between serotonergic and excitatory/inhibitory neurons. Recently, we have established rat organotypic raphe slice cultures, which have functional serotonergic neurons with the ability to release 5-HT in response to stimulation and to reuptake 5-HT through serotonin transporter and retain neural and synaptic functions. Here, we show the following results in the raphe slice cultures: 1) acute and sustained treatments with 3,4 methylenedioxymethamphetamine induce the 5-HT efflux via serotonin transporter and AMPA receptor-mediated exocytotic 5-HT release, respectively; 2) sustained treatment with antidepressants enhances the exocytotic 5-HT release, which is dependent on AMPA receptor stimulation, but not on desensitization of 5-HT(1A/1B) autoreceptors; 3) the augmentation therapy of an atypical antipsychotic, olanzapine, with antidepressants is caused by the decrease in the raphe inhibitory GABAergic tone through 5-HT6 receptor antagonism. Our findings suggest that the raphe slice cultures are suitable for analyzing the neural and molecular mechanisms underlying the efficacy of psychotropics in vitro. PMID- 26027066 TI - [JSNP Excellent Presentation Award for CINP2014]. PMID- 26027067 TI - [JSNP Excellent Presentation Award for CINP2014: pathway-specific modulation of nucleus accumbens in reward and aversive learning behaviors and drug addiction via selective transmitter receptors]. PMID- 26027068 TI - [JSNP Excellent Presentation Award for CINP20 14]. PMID- 26027069 TI - [JSNP Excellent Presentation Award for CINP2014: Tsc2 haploinsufficiency is associated with more severe autism-related behavioral deficits in mouse models of tuberous sclerosis complex]. PMID- 26027070 TI - [JSNP Excellent Presentation Award for CINP2014]. PMID- 26027071 TI - [JSNP Excellent Presentation Award for CINP2014: PACAP]. PMID- 26027072 TI - [JSNP Excellent Presentation Award for CINP2014]. PMID- 26027073 TI - [JSNP Excellent Presentation Award for CINP2014]. PMID- 26027074 TI - [JSNP Excellent Presentation Award for CINP2014]. PMID- 26027075 TI - JSNP Excellent Presentation Award for CINP2014: reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice. PMID- 26027076 TI - ICD-10 testing reveals potential challenges. You are not exempt from using the new code set. PMID- 26027077 TI - Resilience is needed in the recovery journey. Jessie Close has learned to look toward the future. PMID- 26027079 TI - 5 building blocks drive toward centers of excellence. The National Council's framework helps centers build best practices. PMID- 26027078 TI - Top 3 growth areas. Discover new opportunities among populations, geographic areas and treatment modalities. PMID- 26027080 TI - National Council dives deeply into big picture healthcare trends. Hospitals need behavioral health partners in the era of accountable care. PMID- 26027081 TI - Walk-in behavioral health clinics emerge as potential trend. The increase is related to a variety of factors including heightened awareness. PMID- 26027082 TI - Medicare plan launches addiction screening services. SCAN Health Plan will reach seniors with risk factors. PMID- 26027083 TI - SAMHSA barometer shows 6% increase in treatment utilization. More than 1.25 million people were enrolled in SUD programs. PMID- 26027084 TI - Does it pay to be a health home? Primary and behavioral providers are tracking improved outcomes in Medicaid populations. PMID- 26027085 TI - Proposed policy could eliminate insurance denials. A sweeping access proposal could put an end to utilization management review in New Jersey. PMID- 26027086 TI - 5 ways to ensure clean claims. How to improve the process and get paid sooner. PMID- 26027087 TI - Teams must follow best practices in succession planning. Executive departures are inevitable, but your organization doesn't have to flounder during the transition. PMID- 26027088 TI - Tight budgets push centers to consider managed care contracts. Why three good meals a day costs significantly more than a latte. PMID- 26027089 TI - Concord's acquisition model reinforces small treatment centers. A Nashville startup is taking pressure off owners who want to focus more on their mission. PMID- 26027090 TI - What investors are looking for. More private equity is coming into the market, but what do investors want? PMID- 26027092 TI - Preferred family healthcare St. Louis, Missouri. PMID- 26027091 TI - AAC under fire as its portfolio grows. An investigation will examine allegations of inflated revenues. PMID- 26027093 TI - [Gynecological theories and prescriptions for andriatric diseases]. AB - Andrology and gynecology have a similar or the same theoretical basis in Traditional Chinese Medicine (TCM). Andrology has a history of less than 3 decades in China, while TCM gynecology has developed for over a thousand years. The development of andrology could be greatly promoted with the guidance of the theories and prescriptions of gynecology. PMID- 26027094 TI - [Bone marrow mesenchymal stem cells suppress E coli-induced bacterial prostatitis in rats]. AB - OBJECTIVE: To investigate the inhibitory effect of bone marrow mesenchymal stem cells (BMSCs) on E coliinduced prostatitis in rats. METHODS: BMSCs were isolated, cultured and amplified by the attached choice method. Fifty SD rats were randomized into five groups of equal number: normal control, acute bacterial prostatitis (ABP) , chronic bacterial prostatitis (CBP), ABP + BMSCs, and CBP + BMSCs, and the animals in the latter four groups were injected with E. coli into both sides of the prostate under ultrasound guidance for 1 - 14 days to induce ABP and for 4 - 12 weeks to induce CBP. The control rats were injected with the same amount of PBS. Two weeks after injection of BMSCs into the prostates, pathomorphological changes in the prostate were observed under the light microscope and the mRNA and protein levels of IL-1beta and TNF-alpha determined by RT-PCR and ELISA, respectively, followed by statistical analysis with SPSS 18.0. RESULTS: Histopathological evaluation showed typical pathological inflammatory changes in the prostates of the rats in the ABP and CBP groups, including glandular structural changes, interstitial edema, inflammatory cell infiltration, and fibrous hyperplasia, which were all remarkably relieved after treated with BMSCs. The mRNA and protein levels of IL-beta ([0.829 +/- 0.121] and [271.75 +/- 90.59] pg/ml) and TNF-alpha ([0.913 +/- 0. 094] and [105.78 +/- 19. 05] pg/ml) in the ABP and those of IL-1beta ([0. 975 +/- 0. 114] and [265. 31 +/- 71. 34] pg/ml) and TNF-alpha ([0. 886 +/- 0. 084] and [107. 45 +/- 26. 11 ] pg/ml) in the CBP groups were significantly higher than those in the control rats ([0. 342 +/- 0.087] and [45.76 17. 99] pg/ml, P <0. 05); ([0.247 +/- 0.054] and ([19.42 +/- 7. 75] pg/ml, P <0. 01) as well as than those in the ABP + BMSCs ([0. 433 +/- 0. 072] and [51. 34 +/- 22. 13] pg/ml, P < 0. 05 ) ; ( [0. 313 +/- 0. 076] and [28. 38 +/- 8. 78] pg/ml, P < 0. 01) and the CBP + BMSCs group ([0.396 +/- 0.064] and [56.37 +/- 21.22] pg/ml, P <0.05); ([0.417 +/- 0.068] and [29.21 +/- 10.22] pg/ml, P <0.01). CONCLUSION: Injection of BMSCs can reduce E coli induced prostatic inflammation reaction, which.may be associated with its reduction of inflammatory cell infiltration and the expressions of IL-1beta and TNF-alpha in the prostate tissue. PMID- 26027095 TI - [Expressions of aquaporins decrease in the prostate and seminal vesicles of castrated rats]. AB - OBJECTIVE: To investigate the levels of secretions from the prostate and seminal vesicles and their association with the expressions of aquaporins (AQP) in the prostatic tissue and seminal vesicles of castrated rats. METHODS: We randomly divided 18 eight-week-old male SD rats into a control, a castration, and a testosterone (T) replacement group. Four weeks after surgical castration, we detected the plasma T level and measured the volumes of the secretions and the expressions of AQPs 3, 7, and 10 - 12 in the prostate and seminal vesicles of the rats. RESULTS: The plasma T level was significantly lower in the castrated models ([30. 98 +/- 28. 84] ng/dl) than in the rats of the control ([700.78 +/- 123.8] ng/dl) and T replacement groups ([688.08 +/- 132. 47] ng/dl) (P <0. 05). The castration group, in comparison with the control and T replacement groups, showed remarkably reduced ratios of prostatic secretion volume / prostate weight ([11.1 +/- 0.30] vs [2.32 +/- 0.61] and [2.13 +/- 0.56] %, P <0. 05) and seminal vesicle secretion volume / seminal vesicle weight ( [4. 78 +/- 1. 97 ] vs [57. 36 +/- 11. 86] and [55. 74 +/- 7. 21] %, P < 0. 05). Immunohistochemistry revealed the expressions of AQPs 3 and 7 in the epithelial envelop and cytoplasm and that of AQP 11 the in endothelial envelop and cytoplasm of the prostate and seminal vesicles. Western blot exhibited significantly lower expressions of AQPs 3, 7, and 10 - 12 in the prostate and seminal vesicles of the castrated rats than in the animals of the control and T replacement groups (P <0. 05). CONCLUSION: Significant decreases of the secretions from the prostate and seminal vesicles may be related to the reduced expressions of AQPs 3, 7, and 10 - 12 in the prostatic tissue and seminal vesicles in castrated rats. PMID- 26027096 TI - [Diagnosis and treatment of prostatic malignant mesenchymal tumors: Analysis of 20 cases]. AB - OBJECTIVE: To explore the diagnosis, treatment, and prognosis of prostatic malignant mesenchymal tumors (PMMT). METHODS: We retrospectively analyzed the clinical and follow-up data about 20 cases of PMMT and reviewed the literature relevant to the diagnosis, treatment, and prognosis of the disease. RESULTS: Based on the results of pathology and immunohistochemistry, the 20 PMMT cases included leiomyosarcoma (n = 7), rhabdomyosarcoma (n = 5), prostatic stromal sarcoma (n = 3), chondrosarcoma (n = 1), and undifferentiated PMMT (n = 4). Twelve of the patients were treated by radical prostatectomy (3 concurrently by sigmoid colostomy and 1 by cystostomy), 2 by pelvic tumor resection following arterial embolization, 1 by total pelvic exenteration, 1 by colostomy with pelvic lymph node biopsy, and 4 by conservative therapy because of metastasis to the lung, pelvis and bone. Of the 20 patients, 9 died of systemic metastasis within 3 months after treatment, 3 died at 6, 7, and 14 months, respectively, 3 survived with tumor for 5, 11, and 12 months, respectively, 2 survived without tumor for 12 and 24 months so far, all subjected to periodic chemotherapy postoperatively, and 3 lost to follow-up. CONCLUSION: PMMT is a tumor of high malignancy and rapid progression, for which transrectal ultrasound-guided biopsy remains the main diagnostic method. The clinical stage of the tumor is an important factor influencing its prognosis and the survival rate of the patients can be improved by early diagnosis and combined therapy dominated by radical prostatectomy. PMID- 26027097 TI - [Expressions of TFF1 and TFF3 in prostate cancer and prostatic intraepithelial neoplasia and their clinical significance]. AB - OBJECTIVE: To explore the expressions of trefoil factor 1 (TFF1) and trefoil factor 3 (TFF3) in prostate cancer (PCa) and prostate intraepithelial neoplasia (PIN) and their clinical significance. METHODS: Using immunohistochemistry, we detected the expressions of TFF1 and TFF3 in the prostatic tissues of 89 cases of PCa, 50 cases of PIN, and 65 cases of benign prostate hyperplasia (BPH), and evaluated their clinical significance. RESULTS: The positive rates of TFF1 and TFF3 expressions were 77. 53% and 48. 31% in PCa and 66.00% and 30.00% in PIN, significantly higher than 49.23% and 13. 85% in BPH (P <0. 05). The expression of TFF1 was not correlated with Gleason score (P >0. 05), while that of TFF3 was significantly higher in the PCa cases with Gleason score <=7 than in those with Gleason score > 7 (70. 00% vs 42. 03%, P <0. 05). No significant correlation was observed between TFF1 and TFF3 expressions in PCa (P >0. 05). CONCLUSION: The expressions of TFF1 and TFF3 may contribute to the occurrence and progression of PCa, and therefore could be used as laboratory indexes in the diagnosis, differential diagnosis, and prognosis of PCa. PMID- 26027098 TI - [Expression of the epithelial cell adhesion molecule in prostate cancer and its clinical significance]. AB - OBJECTIVE: To explore the expression of the epithelial cell adhesion molecule (EpCAM) in prostate cancer (PCa) and its clinical significance. METHODS: We collected tissue samples from 63 cases of PCa, 46 cases of prostatic intraepithelial neoplasia (PIN), and 58 cases of benign prostatic hyperplasia (BPH) adjacent to PCa and determined the expression of EpCAM in the epithelial and stromal cells by immunohistochemistry. RESULTS: The positive expression rates of EpCAM in the epithelial cells were significantly higher in PCa and PIN than in PCa-adjacent BPH (98. 4 and 97. 8 vs 51.7%, P <0. 01), and so was that in the stromal cells of PCa than in those of PCa-adjacent PIN (89.5 vs 50.0%, P <0.01). The expression of EpCAM.was remarkably higher in the stromal cells of bone metastasis than in those of non-bone metastasis tissue (100. 0 vs 40. 0%, P <0. 01) but showed no statistically significant differences between the highly and poorly differentiated PCa tissues (88.5 vs 91.9%, P >0.05). CONCLUSION: The expression level of EpCAM in the stromal cells of PCa is related to the occurrence, progression, and bone metastasis of the tumor, and therefore may be used as a marker in the early diagnosis of PCa as well as a predictor of bone metastasis of the tumor. PMID- 26027099 TI - [Extracorporeal shock wave: An effective and safe therapy for the pain symptom of type IIIB prostatitis]. AB - OBJECTIVE: To investigate the effect and safety of extracorporeal shock wave (ESW) in the treatment of pain symptom of type III B prostatitis. METHODS: We treated 50 cases of type III B prostatitis by ESW once a week for 4 weeks. Then we evaluated the clinical effect and safety of the therapy based on the NIH-CPSI scores, visual analogue scale (VAS) scores, IIEF-5 scores, prostate volume and morphous, state of urination, color of urine, results of routine semen analysis, and changes of cytokines (IL-6, TNF-alpha and IL-1beta) in expressed prostatic secretion (EPS). RESULTS: All the patients successfully accomplished the treatment. Compared with the baseline, decreases were observed after 4 weeks of cytokine treatment in the pain scores (14. 61 +/- 1. 82 vs 9. 36 +/- 1. 47, P <0. 01), urination symptom scores (4. 59 +/- 1. 01 vs.4. 66 +/- 0. 89, P >0. 05) , quality of life scores (6. 51 +/- 1. 03 vs 4. 56 +/- 1. 02, P <0. 01), NIH-CPSI (25. 43 +/- 1. 72 vs 18. 28 +/- 2. 32, P <0. 01 ), and VAS (6. 59 +/- 1. 10 vs 3. 02 +/- 1. 07, P < 0. 01). The concentration of IL-6 in the EPS was significantly increased ([55.82 +/- 6. 28] vs [86.59 +/- 4. 55] ng/ml, P <0. 01) , while the level of TNF-alpha ([3.89 +/- 0. 12] vs [3. 19 +/- 0.22] ng/ml, P<0.01) and that of IL-1beta ([3.21 +/- 1.01] vs [1.48 +/- 0.95] ng/ml, P< 0. 01) remarkably reduced after treatment. However, there were no statistically significant differences in IIEF-5 scores (18. 58 +/- 2. 03 vs 18. 51 1. 89, P >0. 05) or various sperm parameters before and after treatment (P >0. 05). And no significant changes were observed in the prostate volume, morphous or internal echoes. CONCLUSION: The ESW therapy is effective and safe for the pain symptom of type III B prostatitis. PMID- 26027100 TI - [Clinical effect of circumcision stapler in the treatment of phimosis and redundant prepuce]. AB - OBJECTIVE: To observe the clinical effect and safety of circumcision stapler in the treatment of phimosis and redundant prepuce. METHODS: We treated 120 patients with redundant prepuce or phimosis using circumcision stapler and another 60 by conventional dorsal-incision circumcision. We observed intraoperative blood loss, operation time, postoperative pain, wound healing time, cosmetic appearance of the penis, and postoperative complications and compared them between the two groups of patients. RESULTS: Stapler circumcision showed obvious advantages over the conventional method in intraoperative blood loss ([2. 3 +/- 1. 3] vs [15.6 +/ 2.9] ml), operation time ([7.1 +/- 1.4] vs [22.6 +/- 4.6] min), wound healing time ([12.0 +/- 2.9] as [16.3 +/- 3. 1] d), postoperative pain score (1. 9 +/- 1. 3 vs 5. 2 +/- 1. 7), incision edema, and cosmetic appearance of the penis (all P <0. 05). Besides, stapler circumcision exempted the patients from stitch-removal pain. However, the incidence rate of postoperative local ecchymosis was significantly higher in the circumcision stapler group than in the conventional circumcision group (20. 8% vs 8. 3% , P <0. 05). CONCLUSION: Circumcision stapler, with its advantages of easier manipulation, shorter operation time, better cosmetic penile appearance, less pain, and fewer complications, is superior to conventional circumcision in the treatment of phimosis and redundant prepuce. PMID- 26027101 TI - [Clinical effects of the circumcision stapler, foreskin cerclage, and traditional circumcision: A comparative study]. AB - OBJECTIVE: To compare the clinical effects of the circumcision stapler, circumcision cerclage, and traditional circumcision in the treatment of phimosis and redundant prepuce. METHODS: Using the circumcision stapler (group A), foreskin cerclage (group B), and traditional circumcision (group C), we treated 276 patients with phimosis or redundant prepuce. We made comparisons among the three groups in the operation time, intraoperative blood loss, intraoperative and 24-hour postoperative pain scores, and incidence of postoperative complications. Results: The operation time, intraoperative blood loss, and intraoperative pain score were (6.52 +/- 2.45) min, (1.93 +/- 0.82) ml, and 1.37 +/- 0.68 in group A and (7.24 +/- 1.86) min, (1.51 +/- 0.72) ml, and 1.20 +/- 0.79 in group B, all significantly lower than (28. 36 +/- 4.22) min, (9.52 +/- 3.29) ml, and 3.06 +/- 0.75 in group C (P <0.05). The 24-hour postoperative pain score was remarkably higher in group B than in A and C (3. 18 +/- 0. 82 vs 1. 85 +/- 0. 63 and 1. 82 +/- 0. 75, P <0. 05). The incidence rate of postoperative complications was markedly lower in group A than in B (5. 43% vs 14. 13%, P < 0.05), but with no significant differences between either A and C or B and C (P >0.05). CONCLUSION: The circumcision stapler, with its advantages of simple operation, minimal invasiveness, fewer complications, and better cosmetic result, deserves a wider clinical application. PMID- 26027102 TI - [Application of calcium ionophore A23187 in ICSI for globozoospermia: A report of 2 cases and review of the literature]. AB - OBJECTIVE: To investigate the pathogenesis of globozoospermia, fertilization ability of round-headed sperm, and the application value of assisted oocyte activation in intracytoplasmic sperm injection (ICSI) for the wives of glohozoospermia men. METHODS: We collected oocytes from the wives of 2 globozoospermia patients and randomly divided them into two groups after ICSI to receive calcium ionophore A23187-activation and conventional treatment, respectively. We reviewed the relevant literature published at home and abroad, and discussed the etiology of globozoospermia, fertilization ability of round headed sperm, and treatment options for this disease. RESULTS: Quality embryos were obtained in the A23187-activation group while no fertilized oocytes, oocyte cleavage, quality embryos, or blastular formation were found in the conventional treatment group. Both women achieved pregnancy and gave birth to healthy neonates after transfer of the quality embryos from the A23187-activation group. CONCLUSION: Calcium ionophore A23187 can be applied to ICSI for the wives of globozoospermia men and bring about desirable clinical outcomes. Meanwhile, attention should be paid to its safety. PMID- 26027103 TI - [Professor Xu Fu-song's traditional Chinese medicine protocols for male diseases: A descriptive analysis]. AB - OBJECTIVE: To analyze the efficacy and medication principles of Professor Xu Fu songs traditional Chinese medicine (TCM) protocols for male diseases. METHODS: We reviewed and descriptively analyzed the unpublished complete medical records of 100 male cases treated by Professor Xu Fu-song with his TCM protocols from 1978 to 1992. RESULTS: The 100 cases involved 32 male diseases, most of which were difficult and complicated cases. The drug compliance was 95%. Each prescription was made up of 14 traditional Chinese drugs on average. The cure rate was 32% , and the effective rate was 85%. Professor Xu Fu-song advanced and proved some new theories and therapeutic methods. CONCLUSION: Professor Xu Fu-song's TCM protocols can be applied to a wide range of male diseases, mostly complicated, and are characterized by accurate differentiation of symptoms and signs, high drug compliance, and excellent therapeutic efficacy. PMID- 26027104 TI - [Association of DAZL A260G and A386G polymorphisms with oligozoospermia- or azoospermia-induced male infertility: A meta-analysis]. AB - OBJECTIVE: To investigate the association of A260G and A386G polymorphisms of the DAZL gene with male infertility caused by oligozoospermia or azoospermia. METHODS: We searched the PubMed, Science Direct, Wiley Online Library, CNKI, VIP, and CDDB databases up to November 30, 2013 for case-control studies evaluating the relationship of SNP260 and SNP386 polymorphisms of the DAZL gene with male infertility, and meanwhile conducted manual sourcing of the references in the identified studies and relevant articles. Two reviewers independently screened the title, abstract and keywords of each article retrieved. The StataSE12. 0 software was used for meta-analysis and other statistical analyses. RESULTS: Totally, 13 case-control studies were included (10 about A260G and 11 about A386G), involving 2 715 infertile patients (2 500 with oligozoospermia or azoospermia) and 1 835 normozoospermic men. DAZL A260G showed no statistical significance in the allele, dominant, recessive, co-dominant, or super-dominant gene model (P >0. 05). DAZL A386G exhibited a strong correlation with oligozoospermia or azoospermia in Asians in the allele gene model (OR = 0. 15, 95% CI 0.07 -0.34, P <0.05), dominant gene model (OR =0. 16, 95% CI 0.07 - 0. 35, P <0.05), co-dominant gene model (AA/AG) (OR = 0. 15, 95% CI 0. 06 - 0. 33, P < 0. 05), and super-dominant gene model (OR = 0. 15 (95% CI 0.06 - 0.33, P <0.05) , and so did it in Chinese in the four gene models ( OR = 0. 11, 95% CI 0.04 - 0. 28, P <0.05; OR =0. 11, 95% CI 0.04 - 0.28, P<0.05; OR = 0.09, 95% CI 0.03 - 0.26, P<0.05; OR = 0.09, 95% CI 0.03 - 0.26, P< 0.05). CONCLUSION: Our study manifested that the DAZL polymorphism A386G, but not A260G, was correlated with reduced sper- matogenesis or sperm count specifically in Chinese males. More high quality trials are required for a deeper insight into the exact relationship of DAZL A260G and A386G polymorphisms with oligozoospermia- or azoospermia-induced male infertility. PMID- 26027105 TI - [Progress in the studies of prostate cancer related molecules]. AB - Prostate cancer is one of the common malignant tumors of the urinary system and mostly found in elderly men. Like most tumors, prostate cancer involves a variety of molecules in its occurrence and progression. More studies on the development of prostate cancer focus on the tumor markers, DNA damage repair related genes, and tumor invasion and metastasis related factors. This article presents an overview on the research progress in these three aspects. PMID- 26027106 TI - [Updated genomics of testicular germ cell tumor]. AB - Testicular germ cell tumor (TGCT) is a most common testicular malignancy with an increasing incidence, and its pathogenesis and mechanisms are not yet clear. The next generation sequencing has become the main tool to uncover the underlying mechanisms of TGCT. The differential gene expressions, gene mutation, predisposing gene-dominated signaling pathways, and changes of the relevant genes in the sex chromosome are largely involved in the occurrence and development of TGCT. Studies on the genomics of TGCT contribute a lot to identifying the pivotal pathogenic genes and paving a theoretical ground for the early screening and targeted therapy of TGCT. This paper summarizes the advances in the studies of the genomics of TGCT so as to reveal thetmechanisms of the disease at the genetic level. PMID- 26027107 TI - [Selective breeding research on new cultivar "ChuanPeng 1" of Curcuma phaeocaulis]. AB - OBJECTIVE: To breed a new good cultivar of Curcuma phaeocaulis. METHODS: Three rounds of selection were systematically made for screening the new cultivar using biological technology. Firstly, individual plant selection. Promising individual plant selection was made based on the thousands of Curcuma phaeocaulis resources collected from all over the country. Secondly, strain selection. The promising strain was selected continually from the superior individuals on basis of specificities such as biological characteristics, yield, content of volatile oil and resistance. Thirdly, strain comparison test. The superior strain was selected through strain trial and regional trial. RESULTS: For the new cultivar "ChuanPeng 1" , its main rhizome was in ovoid or spindle shape, and it was fleshy and corpulent. Average amount of rhizome was 4, with 6. 27 cm in length and 3. 37 cm in diameter, while the secondary roots were cylindrical-like, with a yellow green cross section as the main rhizome. Slender root ends were inflated into the fleshy spindle shape, average amount of whose was 25, 3. 20 cm in length and 1. 33 cm in diameter with a yellow green or near white cross section. Average yield of rhizome is 5 314. 5 kg/hm2, while the root is 1 942. 5 kg/hm2, which was 32. 9% and 22. 7% higher than the local main cultivar respectively. The average extract content of rhizome was 15. 41% and content of volatile oil was 2. 82%, which was 15. 60% and 9. 30% higher than the local cultivar respectively. CONCLUSION: " ChuanPeng 1" has good stability and strong adaptability with high yield and superior internal quality. It can be cultivated and promoted in Jinma River Valley,Sichuan. PMID- 26027108 TI - [Determination and analyse of soil fertility of Pseudostellariae Radix planting base of Shibing County and Huangping County in Guizhou Province]. AB - OBJECTIVE: To determine soil fertility of the Pseudostellariac Radix planting base of Shibing County and Huangping County in Guizhou Province, and to provide experimental basis for soil improvement and balanced fertilization. METHODS: 12 soil samples from Shibing County and 10 soil samples from Huangping County were involved in the detection. RESULTS: In the soil samples from Shibing County, the contents of organic matter, total N, available N, total P, available P and available K were higher, while the content of total P was at middle level. In the soil samples from Huangping County, the contents of total N, available P, total K and available K were higher,the contents of organic matter, total K and available N were at middle level. CONCLUSION: The level of soil fertility of the Pseudostellariae Radix planting base in Guizhou Province is common. The soil fertility of Shibing County is superior to that of Huangping County. The soil pH value of Shibing and Huangping County is low. In Shibing County, lime, farmyard manure and neutral fertilizer can be used to increase the pH of soil. Potash fertilizer can be increased, while nitrogen fertilizer and phosphate fertilizer can be reduced in the soil of Shibing County. Potash fertilizer and phosphate fertilizer will be increased, while nitrogen fertilizer can be reduced in the soil of Huangping County. The soil fertility can be improved by these measures. PMID- 26027109 TI - [Study on mineral elements distribution in soil of Angelica sinensis producing regions and its relationship with altitude and soil types]. AB - OBJECTIVE: To investigate the distribution characteristics of mineral elements in the soil of Angelica sinensis producing regions and its relationship with altitude and soil types. METHODS: The contents of 15 mineral elements in 103 batches of soil from 13 counties were determined by ICP-MS or AAS. Pearson correlation analysis, partial correlation analysis and systematical cluster analysis were used to analyze the data. RESULTS: Pearson correlation analysis showed that the content of Mg in soil and altitude showed significant positive correlation(P <0. 01), the content of Cd in soil and altitude showed significant negative correlation(P <0. 05), and the con- tents of Pb, Cd, As, Cu, Cr as well as Ni in soil and altitude showed negative correlation. The result of systematic cluster analysis showed that 103 batches of soil were clustered into 5 groups. The main soil types of group I were black soil, haplic kastanozems and black sandy-soil, group II was loess, group III was cinnamon soil, group IV were red soil and grey cinnamon soil, and group V were black soil, haplic kastanozems, grey cinnamon soil and cinnamon soil. CONCLUSION: The distribution of mineral elements in soil is closely related to altitude and soil types. PMID- 26027110 TI - [Effects of acidic soil improvement on active-state Cd content in soil and Cd content in Ligusticum chuanxiong]. AB - OBJECTIVE: To explore the method to reduce the Cd content in Ligusticum chuanxiong, and to offer the reference for planting Ligusticum chuanxiong with low Cd content. METHODS: A field experiment was carried out to improve the acidic Cd-contaminated soils by different quicklime application, and the effect of quicklime on the percentage of active-state Cd in soil and Cd content in Ligusticum chuanxiong was examined. RESULTS: Quicklime could reduce the percentage of active-state Cd in soil by increase the acid soil pH value,and as a result, significantly reduce Cd content in Ligusticum chuanxiong. A highly significant negative correlation was found be- tween the Cd content in Ligusticum chuanxiong and quicklime application rate(P =0. 008). Compared with the blank group, Cd content in Ligusticum chuanxiong was reduced by 27. 66%, 24. 87% and 46. 20%, with 750, 1 125 and 1 500 kg/hm2 quicklime application, respectively; while with 1 500 kg/hm2 quicklime application, the soil pH value increased significantly and kept steadily, and the percentage of active-state Cd in soil showed a regular trend which was decreased firstly and increased subsequently. CONCLUSION: Cd content in Ligusticum chuanxiong can be reduced significantly by quicklime application,and the effect of high application of quicklime on Cd content in Ligusticum chuanxiong, soil pH values and percentage of active-state Cd in soil is more effective and steady. PMID- 26027111 TI - [Study on synergistic effect of sodium cantharidinate combined with chemotherapeutic drugs on hepatic carcinoma and its effective mechanism]. AB - OBJECTIVE: To study the synergistic effect on hepatoma cell(SMMC-7721) and the reduction killing effect on normal liver cells(LO-2) treated with sodium cantharidinate (SCA) in combination with fluorouracil(5-FU) or cisplatin(DDP) as well as the related mechanism. METHODS: MTT assay was used to select the best ratio of SCA with 5-FU or SCA with DDP which had less toxicity on LO-2 cell line and had synergistic effect on SMMC-7721 cell line; Flow cytometry assay was used to analyze the apoptosis-induction of the different ratio of drugs on both cell lines; Hoechst-33258 fluorescent staining assay was used to observe the nuclear morphological changes of cells; Immunoblotting assay was used to analyze the Ras/Raf/ERK1/2 signaling pathway and the apoptosis related signaling pathway in both cell lines. RESULTS: MTI assay indicated that the proliferation inhibition of SCA,5-FU and DDP on SMMC-7721 cell line was in a time-and dose-dependent manner respectively. Among them, SCA had a more significant inhibition on SMMC 7721 cell line than on LO-2 after 12 h or 24 h treatment (P <0. 01). Moreover, after a treatment of 48 h,the ratio of 2. 5 ug/mL SCA and 2 ug/mL DDP showed a more significant inhibition on SMMC-7721 cell line than on LO-2 cell line,which was then be considered as the optimal concentration ratio for the following experiment. Co-treatment of SCA (2. 5 ug/mL) with DDP (2 ug/mL) induced a more significant apoptosis on SMMC-7721 cell line compared with single treatment with SCA (2. 5 ug/mL) or DDP (2 ug/mL) respectively (P < 0. 01). After a 48 h treatment of the optimal ratio of drugs, the significant morphological apoptotic characteristics were observed both under inverted microscope and by Hoechst-33258 fluorescent staining assay in both cell lines. The results of Western blot assay showed that this ratio of drugs could significantly increase the protein expression of Bax,P53 and P21 and decreased the expression of BCL-2, Casepase-3, p-Erk, p-Ras and p-c-Raf in SMMC-7721 cells. Meanwhile,the effect on the proteins mentioned above was lesser in LO-2 cells. CONCLUSION: These results indicates that 2. 5 ug/mL SCA + 2 ug/mL DDP showed a higher inhibition on the hepatic carcinoma cells and a relatively lower cytotoxicity on normal liver cells. The major anti-cancer mechanism is related with the inhibition on Erk signaling pathway and the induction of apoptosis through the mitochondrial pathway. PMID- 26027112 TI - [Isolation and identification of an antimicrobial endophytic actinomycete from Macleaya cordata]. AB - OBJECTIVE: An antimicrobial endophytic actinomycete strain was isolated from the root of Macleaya cordata, and its phylogenetic position was also investigated. METHODS: Endophytic actinomycetes were isolated from the root of Macleaya cordata growing in Dabie Mountain by tablet coating method. Antimicrobial activities of endophytic actinomycetes were determined by the agar block method,and then a potential strain was identified by morphology, biochemical characterization and molecular methods. RESULTS: A total of 15 strains of endophytic actinomycetes were isolated from the samples, six of them had antimicrobial activity to the test strains which accounts for 40% of all strains. Among the six strains,the strain BL7 was found to produce antibiotic substances which showed significant inhibitory effects on Staphylococcus aureus and Bacillus subtilis,with a formed inhibition zone of 29 mm and 20 mm respectively. Based on the morphology, biochemical characterization and 16S rDNA sequence analysis,the strain BL7 was preliminary identified as Streptomyces mobaraensis. CONCLUSION: Some members of Streptomyces genus have a very wide application prospect in medicine. This is the first report that Streptomyces mobaraensis strain was isolated from Macleaya cordata, and this study provides basis for the further exploration of the strain. PMID- 26027113 TI - [Characteristics of inorganic elements in Panacis Majoris Rhizoma and relationship with its Daodi habitat]. AB - OBJECTIVE: To investigate the Daodi habitat of Panacis Majoris Rhizoma by analyzing the characteristics of inorganic elements in Panacis Majoris Rhizoma from different habitats. METHODS: The contents of inorganic elements in Panacis Majoris Rhizoma from different habitats were determined by ICP-AES. The characteristics of inorganic elements in Panacis Majoris Rhizoma were analyzed by correlation analysis, principal component analysis and cluster analysis. RESULTS: It was showed that there was a correlation between the contents of inorganic elements and the medicine quality of Panacis Majoris Rhizoma; Fe, Cr, Al, Mg, Cd, Ca and Zn were principal components of Panacis Majoris Rhizoma; and the contents of inorganic elements in Panacis Majoris Rhizoma existed regional differences. CONCLUSION: The contents of inorganic elements Ca, Fe and Zn,especially the content of the essential trace elements Fe and Zn, can be used as one of the key reference for medicinal quality evaluation of Panacis Majoris Rhizoma; as well, Shaanxi Province is probably the Daodi habitat of Panacis Majoris Rhizoma. PMID- 26027114 TI - [Comparative study of four alkaloids contents and antitussive activities of Stemona tuberosa from different habitats of Guangxi Province]. AB - OBJECTIVE: To compare the contents of four alkaloids and antitussive activities of Stemona tuberosa from different habitats of Guangxi Province. METHODS: The HPLC separation was performed on a Merck Purospher STAR RP18 (250 mm x 4. 6 mm, 5 um) column by gradient elution using 0. 05% ammonia-acetonitrile as the mobile phase. The flow rate was 1. 0 mL/min, the dectection wave-length was set at 210 nm,and the column temperature was 40 degrees C. The antitussive potency of total alkaloids of Stemonae Radix from different habitats was evaluated on guinea pigs with citric acid aerosol to induce cough. RESULTS: The range of recoveries of this mehtod was 98. 24% ~ 101. 21%, with all the constituents showing good linearity(the correlation coefficents above 0. 999). The major chemotype of Stemonae Radix in Guangxi was stemoninine, following by tuberostemonine and croomine, and finally neotuberostemonine. The antitussive activitiy of Stemona tuberosa was in a concentration-dependent manner. CONCLUSION: Stemonae Radix from Dongxing, Fangcheng can reduce cough times and prolong cough incubation period, and thus Dongxing, Fangcheng is the best habitat in Guangxi in the present experiments. PMID- 26027115 TI - [Effect of Codonopsis Radix maintained with sulfur fumigation on immune function in mice]. AB - OBJECTIVE: To investigate the immune function of mice being given the extract of Codonopsis Radix maintained with sulfur fumigation. METHODS: Mice were divided into five groups. Except the normal control group, the mice were fed with the extract of Codonopsis Radix maintained with sulfur fumigation at the high,medium and low doses, as well as medium dose of Codonopsis Radix maintained with low temperature vacuum method, respectively. Mice were treated once a day for 10 continuous days. Weight change,organ indexes, blood cell indices, macrophage phagocytic function, and IL-2 and IFN-gamma levels were measured. RESULTS: Compared with normal control group, Codonopsis Radix maintained with sulfur fumigation at medium and high doses inhibited body weight increase of mice; white blood cell count of high dose group was significantly increased; significant increase of macrophage phagocytosis were observed for all groups except the normal control group; and spleen index and IFN-gamma level of Codonopsis Radix maintained with sulfur fumigation medium dose group were increased significantly. CONCLUSION: Codonopsis Radix maintained with sulfur fumigation can promote mouse immune function to a certain degree. There was no difference in immune effect between Codonopsis Radix maintained with sulfur fumigation and low-temperature vacuum method during experimental period. However,taking the extract of Codonopsis Radix maintained with sulfur fumigation can exert negative effect on appetite and body weight in mice. PMID- 26027116 TI - [Study on UIPLC-DAD fingerprint of Disporum cantoniense]. AB - OBJECTIVE: To establish an UHPLC-DAD fingerprint of 30 batches of Miao medicine Disporum cantoniense from Guizhou, and to provide a theoretical evidence to evaluate its quality. METHODS: The analysis was carried out on an Agilent Eclipse ZOR-BAX Plus C18 (100 mm x 2. 1 mm, 1. 8 um) column with a mobile phase consisting of acetonitrile-water(containing 0. 1% formic acid) with gradient elution, and the flow rate was 0. 3 mL/min. The column temperature was set at 40 degrees C and UV detection wavelength was set at 290 nm. The sample injection volume was 3 uL. The similarity evaluation and principal component analysis(PCA) of these fingerprints were carried out. RESULTS: The UHPLC-DAD fingerprint was established and compared by 30 batches of samples similarity with 12 common peaks and 3 peaks were identified. The similarities of 30 batches of Disporum cantoniense were between 0. 766 and 0. 994. The principal component analysis showed that compounds 1 and 12 were representative for the fingerprint. CONCLUSION: The method is accurate and credible,which can be used for identification and quality control of Disporum cantoniense. PMID- 26027117 TI - [HPLC fingerprint analysis of flavonoids of phyllanthi fructus from different habitats]. AB - OBJECTIVE: To establish the HPLC fingerprint of flavonoids of Phyllanthi Fructus from different habitats. METHODS: HPLC method was adopted. The flavonoids composition of Phyllanthi Fructus from 10 different habitats was determined on an Agilent C, chromatographic column with 0. 5% formic acid water (A)-acetonitrile (B) as the mobile phase in gradient elution under the wavelength of 254 nm. The HPLC fingerprints of flavonoids composition of Phyllanthi Fructus were established to evaluate the qualitiy of them. RESULTS: The HPLC fingerprints of flavonoids composition of Phyllanthi Fructus from 10 different habitats were established. 18 common peaks were found and the similarities of them were more than 0. 90 except the ones from Guangxi and Guangdong. CONCLUSION: The method is simple, accurate and repeatable. It can be used for research and quality control of the effective components in Phyllanthi Fructus. PMID- 26027118 TI - [Probe excavations about using gene chip to identify original plants in Chinese pharmacopoeia based on NCBI sequence database]. AB - OBJECTIVE: Based on the DNA fragments of medicinal plants of NCBJ database, the DNA Probe,which can be used to identify original plants in the Chinese Pharmacopoeia (2010 edition), was got. METHODS: First of all, get the Latin name of the original plants by collating the Chinese Pharmacopoeia. Next,download the medicinal plants' DNA fragments from the NCBI database, including ITS, matK, rbcL, psbK-psbI and trnH-psbA, then design probe by using Array Designer 4. 2. Finally, analyze each probe's versatility in the same kind of original plant and conservatism in different kinds of original plants by using Matlab, then determine the specificity of the probe. RESULTS: Regarding the Latin name of 586 original plants in the Chinese Pharmacopoeia (2010 edition) and the above five gene fragments as retrieval condition, 7 613 sequences were downloaded from NCBI, then 315 436 probes were got in total by analyzing. What's more, after analyzing versatility and conservatism of the probes,13 814 specific probes were got. Furthermore,in theory, 376 kinds of original plants could be detected. Because there existed the lack of related gene fragments in the NCBI database,or the sequences were short of specificity,210 species of original plants which were involved in the Chinese Pharmacopoeia didn't receive the corresponding probe. CONCLUSION: The results of the study can provide the further development of medicinal plants' identification chip with vital information support,and the excavation methods of probe can be widely used. Furthermore,the results of the study indicate the original plants which need sequencing importantly in the future. PMID- 26027120 TI - [Study on chemical components of Tripterospermum chinense]. AB - OBJECTIVE: To investigate the chemical components of the whole herb of Tripterospermum chinense. METHODS: Various column chromatography methods were used in the isolation and purification. Physio-chemical constant determination and spectral analysis were adopted to determine the chemical structures. RESULTS: Ten compounds were isolated and identified as 1, 7-dihydroxy-3,8 dimethoxyxanthone(1),1,3-dihydroxy-7,8-dimethoxyxanthone (2) 1,3,6,7 tetrahydroxyxanthone (3),1,8-dihydroxyxanthone(4),2'-deoxythymidine(5), 4 hydroxyphthalide(6),2,4-dihydroxy benzyl alcohol (7),2,5-dihydroxyphenetole (8), saponarin (9) and 4'-methoxysaponarin(10). CONCLUSION: Compounds 2 - 8 and 10 are isolated from this plant for the first time. PMID- 26027119 TI - [Study on anti-tumor chemical constituents from pericarps of Juglans mandshurica]. AB - OBJECTIVE: To study the anti-tumor chemical components of the pericarps of Juglans mandshurica. METHODS: The chemical constituents were isolated and purified by AB-8 macroporous adsorption resin, silica gel, Sephadex LH-20 columns and recrystallization. The structures were elucidated on the basis of physicochemical properties and NMR spectral data analysis. RESULTS: From the pericarps of Juglans mandshurica, twelve compounds were separated and identified as 3-methoxy juglone(1), 3-ethoxy juglone(2), 1,8-di-hydroxy anthraquinone (3), juglone (4), 2alpha, 3alpha, 19alpha-trihydroxy ursolic acid (5), 1alpha, 3beta dihydroxy-olean-18-ene (6), methyl gallate (7), pterocarine(8), quercetin(9), kaempferol(10), daucosterol(11), and beta-sitosterol(12). CONCLUSION: Compounds 1 - 3 and 6 are isolated from the pericarps of Juglans mandshurica for the first time. Compounds 5 and 7 are isolated from Juglans genus for the first time. PMID- 26027121 TI - [Ethyl acetate-soluble chemical constituents from Callicarpa kwangtungensis]. AB - OBJECTIVE: To study the ethyl acetate-soluble chemical constituents of Callicarpa kwangtungensis. METHODS: The chemical constituents were isolated by column chromatography on silica gel, Sephadex LH-20 and MPLC. Their chemical structures were elucidated on the basis of special analysis. RESULTS: Seven compounds were isolated from ethyl acetate part, whose structures were elucidated as caffeic acid(1),2alpha,3alpha, 19alpha-trihyhydroxy-urs-12-en-28-O-beta-D-glucopyranoside (2),2alpha,3, 19alpha-trihyhydroxy-olean-12-en-28-O-beta-D-glucopyranoside (3), 2alpha, 3alpha, 19alpha-trihyhydroxy-olean-12-en-28-O-beta-D-glucopyranoside (4), ferulic acid (5), 2alpha, 3beta, 19alpha-trihyhydroxy-urs-12-en-28-O-beta-D glucopyranoside(6), and ( + )-isolariciresinol-9-O-beta-D-glucopyranoside(7). CONCLUSION: All these compounds are isolated from this plant for the first time. PMID- 26027122 TI - [Study on secondary metabolites of endophytic fungus Arthrinium sp. A092 from Uvaria microcarpa]. AB - OBJECTIVE: To study the secondary metabolites of the endophytic fungus Arthrinium sp. A092 from Uvaria microcarpa. METHODS: The compounds were isolated and purified by silica gel column chromatography, reverse silica gel column chromatography, Sephadex LH-20 column chromatography, HPLC, preparative TLC and recrystallization. Their structures were identified by extensive analysis of their spectroscopic data. RESULTS: Ten compounds were isolated from the fermentation broth extract of strain A092 and identified as flemingipanic acid(1), ( - )-gynuraone(2),2-(4-methoxy-phenyl)-ethanol(3),2-hexyl-methymaleic anhydride(4), {1-[(12E, 16E)]-12,16-eicosadienoyl]-2-[ (E, E)-7, 10 octadecadienoyl]-3-stearoylglycerol} (5), mycoediketoperazine (6), libertellenone C(7),4-hydroxymethyl-4, 6-octadiene-2, 3-diol (8), dimethyl phthalate (9), and di (2-ethyl)-hexylphthalate (10). CONCLUSION: Compounds 1,3 - 5 and 8 - 10 are isolated from the genus Arthrinium for the first time. PMID- 26027123 TI - [Chemical constituents from stems of Clausena excavata]. AB - OBJECTIVE: To study the chemical constituents from the stems of Clausena excavata. METHODS: The constituents were isolated by various chromatographic techniques(silica gel, RP-MPLC and PHPLC) and their structures were determined on the basis of their spectroscopic data, as well as literatures. RESULTS: Eleven compounds were separated and identified as adicardin(1),7-[O-alpha-L-rh amnopyranosyl-(1-->6)-O-beta-D-glucopyranosyloxy]coumarin(2), 6-methoxy-7-[O alpha-L-rhamnopyranosyl-(1-->6)-O-beta-D-glucopyranosyloxy] coumarin (3), alloisoimperatorin (4), isopentenoyloxypsoralen (5), nordentatin (6), xanthyletin (7), 7-hydroxycoumarin (8), 3-formylcarbazole(9), 3-formyl-6-methoxy carbazole(10), and murrayanine(11). CONCLUSION: compounds 2-4 and 10 are isolated from this plant for the first time, and compounds 1 and 5 are isolated from Clausena genus for the first time. PMID- 26027124 TI - [Chemical constituents from supercritical CO2 extraction of Schisandra chinensis]. AB - OBJECTIVE: To study the chemical constituents from the supercritical CO2 extraction of Schisandra chinensis. METHODS: The compounds were separated and purified by conventional column chromatography and their structures were identified by spectroscopic methods. RESULTS: Nine compounds were isolated from the supercritical CO2 extraction of Schisandra chinensis, and their structures were identified as chrysophanol(1),schisandrin B(2), beta-sitosterol(3), schisandrin C(4),schisandrol A(5), angeloylgomisin H(6), daucosterol(7) 1, 5 dimethyl citrate (8), and shikimic acid (9). CONCLUSION: Compounds 1, 8 and 9 are isolated from Schisandra chinensis for the first time,and compound 1 as an anthraquinone is isolated from this genus for the first time. PMID- 26027125 TI - [Studies on chemical constituents from seeds of Euryale ferox]. AB - OBJECTIVE: To study the chemical constituents from the seeds of Euryale ferox. METHODS: The chemical constituents were isolated by silica gel column, Sephadex LH-20 and their structures were identified by physico-chemical and spectral analysis. RESULTS: Seven compounds were purified from the 95% ethanol extract. These constituents were elucidated as protocatechuic acid (1), gallic acid (2), gallic acid ethyl ester(3),5 ,7-dihydroxychromone(4), beta-sitosterol(5), daucosterol(6), and 5,7-dihydroxy-6,4'-dimethoxyflavone(7), respectively. CONCLUSION: All compounds are isolated from this plant for the first time. PMID- 26027126 TI - [SPME-GC-MS combined with Kovat's retention index analysis for volatile components in Pistacia chinensis]. AB - OBJECTIVE: To analyze and compare the volatile components in fruits and leaves of Pistacia chinesis. METHODS: The volatile components were extracted from the fruits and leaves of Pistacia chinesis by solid-phrase microextration, and were analyzed and identified by gas chromatography-mass spectrometry(GC-MS) combined with Kovat's retention index. The relative content of each component was calculated by normalization method. RESULTS: 29 and 17 volatile components were identified from the fruits and leaves respectively, representing the relative content of 95. 30% and 96. 91% of the volatile components. 13 common components were identified in both the fruits and leaves. CONCLUSION: The volatile components in the fruits vary from that in the leaves in type and content, terpenoids are major components in the fruits and leaves of Pistacia chinesis in Shaanxi. Monoterpenes(76. 32%) are the major components of the fruits, while sesquiterpenes(65. 42%) are the major components of the leaves. PMID- 26027127 TI - [Study on antithrombotic activities and structure-activity relationships of Veratrum nigrum Alkaloids]. AB - OBJECTIVE: To explore antithrombotic effects and mechanisms of total alkaloids (VnA) and single alkaloids (Al - A6) from Veratrum nigrum. METHODS: The effects of VnA and Al - A6 on thrombosis and coagulation parameters (APTT, PT and TT) were examined in rat in vivo, while their effects on platelet aggregation induced by ADP and thrombin were determined in rabbit in vitro. RESULTS: VnA and Al ~ A5 decreased thrombus wet weight and platelet aggregation, increased TT, while they had no influence on APTT or PT. A6 had no obvious effect on thrombus wet weight, platelet aggregation or coagulation parameters. CONCLUSIONS: VnA and Al ~ A5 have antithrombotic activities on venous thrombosis. The effective component in VnA is A2 probably. The antithrombotic effects are possibly related to the inhibition of platelet aggregation and the extension of TT. The cevanine type skeleton of steroidal alkaloids is necessary for antithrombotic activities and the ester substitute at C3 can enhance antithrombotic activities. PMID- 26027128 TI - [Protective effects of Qizhen Jiangtang granules in diabetic nephropathy rats]. AB - OBJECTIVE: To study the curative and protective effects of Qizhen Jiangtang Granules in the diabetic nephropathy (DN) model rats. METHODS: Healthy SD rats were fed a high-sucrose and high-fat diet and intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) to establish the DN model. The rats were divided into six groups including normal control group,model group, positive control group, high-dosage group(200 mg/kg), medium-dosage group (100 mg/kg), and low dosage group(50 mg/kg). After oral administration of Qizhen Jiangtang Granules for eight weeks, FBG,TG,TC, LDL-c, HDL-c, SCr and BUN levels in rats serum were determined, while the pathological damage of kidney tissue with PAS and HE staining were observed under microscope. RESULTS: After treatment, TG, TC, LDL c,SCr and BUN levels were significantly decreased(P <0. 05), and HDL-c level was significantly increased(P <0. 05). The treatment also alleviated the pathological damage of kidney tissue. CONCLUSION: Qizhen Jiangtang Granules have a protective effect against kidney damage in DN model rats. The mechanism may be related to the regulation of lipid and sugar levels in serum. PMID- 26027129 TI - [Synergism inhibition of curcumin combined with cisplatin on T24 bladder carcinoma cells and its related mechanism]. AB - OBJECTIVE: To investigate the synergism inhibition of curcumin combined with cisplatin on T24 bladder carcinoma cells and the down-regulating effect of curcumin on the Keapl-Nrf2 pathway, a well recognized anti-drug pathway in almost drugged tumor cells. METHODS: T24 cells were cultured and treated with increasing concentrations of curcumin(5 ,10 and 20 umol/mL) combined with cisplatin(30 ug/mL) for 24 hours. The inhibitory effects on T24 cells were tested with MTI colorimetric assay. Nuclear Nrf2 and Keapl , cytoplasmic Keapl and two typical phase II enzymes (GSTP1 and NQOl) were checked with Western blotting. RESULTS: The proliferation of T24 cells was significantly inhibited by different concentrations of curcumin combined with cisplatin. After the treatment with different concentrations of curcumin, Nuclear Nrf2 was decreased but Keapl was increased, and GSTP1 and NQO1 were decreased. CONCLUSION: Synergism inhibition of curcumin combined with cisplatin on T24 bladder carcinoma cells is observed in this research. The Keapl-Nrf2 pathway in T24 cells is down-regulated by curcumin. The expression of typical phase I enzymes (GSTP1 and NQO1) mediated by Nrf2 are decreased by curcumin. The sensitivity of tumor cells to chemotherapeutic drugs is then enhanced. These may be the mechanism of synergism effect of curcumin combined with cisplatin. PMID- 26027130 TI - [Effect of Triptolide on expression of NMDAR1 and BSI-B4 binding sites in spinal dorsal horn and dorsal root ganglion in rats with adjuvant arthritis]. AB - OBJECTIVE: To study the analgesic effect of Triptolide(TP) in rats with adjuvant and the possible mechanism. METHODS: Fifty healthy SD rats were randomly divided into normal control group (group A), model group (group B), and low(group C), middle (group D) and high(group E) dose TP treatment groups. Except the group A, each group of rats were reared by toe intradermal injection of 0. 1 mL Freund's complete adjuvant. After 14 days,rats in the C, D and E groups were taken different doses (0. 1 mg/kg group C, 0. 2mg/kg group D, and 0. 4 mg/kg group E) by intraperitoneal injection of TP for 9 days, and then thermal withdrawal latency and the expression of NMDAR1 and BSI-B4 binding sites in lumbar5 (L5) spinal dorsal horn and DRG were detected. RESULTS: Thermal withdrawal latency of rats in group B was significantly lower than that of group A (P <0. 01), while those in group C, D and E were significantly higher than those in group B (P <0. 05 or P <0. 01). TP increased the thermal pain threshold by a quantity-effect relationship; NMDAR-1 and BSI-B4 binding sites expression levels were significantly increased in group B than those in group A (P <0. 01), while those in group C, D and E were lower than those in group B. CONCLUSION: Analgesic effect of TP is related to reducing levels of expression of NMDAR1 and BSI-B4 binding sites in spinal dorsal horn and DRG in rats with adjuvant arthritis. PMID- 26027131 TI - [Study on pharmacokinetics of demethoxycurcumin phospholipid complex in rats]. AB - OBJECTIVE: To study the pharmacokinetics of Demethoxycurcumin phospholipid complex in rats with oral administration. METHODS: Drawing blood from the SD rats after oral administration Demethoxycurcumin phospholipid complex and free demethoxycurcumin. The blood concentration were determined by HPLC. RESULTS: The pharmacokinetics parameter of Demethoxycurcumin phos- pholipid complex were calculated and the results were as follows: AUC0-t (693. 306 +/- 128. 55) ug/(L . h),1. 96-fold increase in the area under the plasma concentration versus time curve (AUC0-t) than that of free demethoxycurcumin, and AUC0-infinity (716. 174 +/- 123. 18) ug/(L - h), 1. 93-fold increase than that of free demethoxycurcumin. Cmax (95. 044 +/- 6. 95) ug/L, Tmax (0. 17 +/- 0) h. Conclusion:Demethoxycurcumin phospholipid complex have higher bioavailability than free demethoxycurcumin,and their preparations bioequivalence are unqualified. PMID- 26027132 TI - [Preparation and quality evaluation of tanshinone IIA microemulsion for parenteral injection]. AB - OBJECTIVE: To study the prescription and preparation technology of tanshinone IIA microemulsion for parenteral injection, and to evaluate its quality. METHODS: The prescription was selected and optimized through single-factor test, compatibility experiment and the pseudo-ternary phase diagram method. The preparation technology was investigated, and the droplet morphous, particle diameter, zeta potential, stability and haemolyticus were evaluated. RESULTS: The prescription composition of tanshinone IIA microemulsion was MCT:Solutol HS-15: fabaceous lecithin: absolute alcohol = 9:10:5:6(m/m), oil phase: aqueous phase = 1:10, with the drug-loaded of 1. 0 mg/g. The acquired microemulsion exhibited salmon pink,uniform and transparent, with the average particle diameter of 16. 04 nm, Zeta potential of -11. 57 mV, and the encapsulation efficiency of 98. 53%. The stability result showed that tanshinone IIA content in microemulsion was influenced by high temperature and illumination, indicating tanshinone IIA microemulsion should to be stored at low temperature and protected from light. The preparation was without hemolytic crisis. CONCLUSION: The preparation of tanshinone IIA micro- emulsion is simple,corresponding to the main index of parenteral injection and offering the basis for new dosage form development of tanshinone IIA. PMID- 26027133 TI - [Preparation and formulation investigation of gastric retention calcium alginate microspheres containing Brucea javanica oil]. AB - OBJECTIVE: To investigate the preparation technologies of gastric retention calcium alginate microsphere containing Brucea javanica oil, and to evaluate its formulations. METHODS: The formulations of gastric retention calcium alginate microspheres were optimized with G/M ration and concentration of sodium alginate,use level of iron calcium solution and pore-forming agent, cross-link time and pH value of cross-link solution, which had shown a great effect on microspheres morphology, drug release behavior, drug loaded and encapsulation efficiency. RESULTS: Brucea javanica oil alginate microspheres looked spherical, homogeneous and well distributive. And the drug loaded of Brucea javanica oil was over 40%, encapsulation efficiency was over 70%. CONCLUSION: The prepared gastric retention calcium alginate microspheres have a great sustained release and floating capability, which can provide a strong topical therapy for gastric diseases. PMID- 26027134 TI - [Optimization of process of icraiin be hydrolyzed to Baohuoside I by cellulase based on Plackett-Burman design combined with CCD response surface methodology]. AB - OBJECTIVE: To optimize the process of Icraiin be hydrolyzed to Baohuoside I by cellulase by Plackett-Burman design combined with Central Composite Design (CCD) response surface methodology. METHODS: To select the main influencing factors by Plackett-Burman design, using CCD response surface methodology to optimize the process of Icraiin be hydrolyzed to Baohuoside I by cellulase. Taking substrate concentration, the pH of buffer and reaction time as independent variables, with conversion rate of icariin as dependent variable,using regression fitting of completely quadratic response surface between independent variable and dependent variable,the optimum process of Icraiin be hydrolyzed to Baohuoside I by cellulase was intuitively analyzed by 3D surface chart, and taking verification tests and predictive analysis. RESULTS: The best enzymatic hydrolytic process was as following: substrate concentration 8. 23 mg/mL, pH 5. 12 of buffer,reaction time 35. 34 h. CONCLUSION: The optimum process of Icraiin be hydrolyzed to Baohuoside I by cellulase is determined by Plackett-Burman design combined with CCD response surface methodology. The optimized enzymatic hydrolytic process is simple, convenient, accurate, reproducible and predictable. PMID- 26027135 TI - [Clinical research on supplementing Qi and activating blood circulation herbs on lung protection in acute lung injury ventilation patients]. AB - OBJECTIVE: To study the supplementing Qi and activating blood circulation herbs on lung protection in acute lung injury (ALI) ventilation patients. METHODS: 67 cases of ALI patients were enrolled and randomly divided into two groups. Routine treatment was for 32 cases of control group while treatment with adding supplementing Qi and activating blood circulation herbs was for 35 cases of treatment group, by 60 mL per time for 14 consecutive days with each day three times. Hemodynamics, changes of arterial blood gas, assay of pdymorphonuclears (PMN) value and the image of bronchoscopes between two groups in T0, T3, T7 and T14 were compared. RESULTS: PMN, HR, SVR, PaO2 , PO2/FiO2 and pH of treatment group were significantly improved compared with control group during T0, T3, T7 and T14 (P <0. 05). The compared differences were remarkable on hemodynamics, changes of arterial blood gas and assay of PMN value between treatment group and control group. The image of bronchoscopes in treatment group was improved significantly. CONCLUSIONS: The intervention of supplementing Qi and activating blood circulation herbs can effectively protect the lung function from ALI patients who received ventilation. PMID- 26027136 TI - Introducing nonlinear thinking into the psychoanalytic conversation. PMID- 26027137 TI - Transformational processes and therapeutic action: what David knew. AB - The often neglected nonlinear dimension of the developmental process is described and its usefulness in the consulting room will be highlighted by a clinical example of the psychoanalytic treatment of an adolescent. The concept of transformation and its linkage with nonlinearity and discontinuity are also outlined. PMID- 26027138 TI - Fragmentation, fluidity, and transformation: nonlinear development in middle childhood. AB - The results of a small group of children studied through ages six through eleven suggest that latency is no longer an accurate term to describe middle childhood and preadolescence. This longitudinal research suggests a more nonlinear process than has previously been documented in psychoanalytic research and supports a dynamic systems approach to development. Self structures break down and remain in an ongoing state of non-linear development. Without stable structural organization, sexual and aggressive thoughts and feelings are less contained and less differentiated throughout this period of development. Gender role identity is in a continuous state of fluidity during middle childhood. While both boys and girls experience gender role fluidity, the meaning of male and female gender identifications and the expression of sexual and aggressive feelings differ for boys and girls. PMID- 26027139 TI - The story of Sam: continuities and discontinuities in development, transforming into and out of a perversion. AB - The aim of this paper is to suggest new ways of understanding development that offer new therapeutic possibilities. I use observational and interview data showing the development of one research subject over forty years to highlight that the concepts of continuity and discontinuity need to be considered together to grasp the full complexity of psychological development. In the subject an unanticipated transformation occurs at age 14, the emergence of a perversion, whichfades by age 28. I will show that the observations can be best understood by co-ordinating the influence of antecedents that exert a pull backward with the transformative potential arising from the pull forward into new structures, compromises, and organizations. PMID- 26027140 TI - Coherence, competence, and confusion in narratives of middle childhood. AB - Middle childhood is a pivotal time in character development during which enduring internal structures are formed. Fiction can offer insights into the cognitive and affective shifts of this developmental phase and how they are transformed in adulthood. While the success of beloved books for latency age children lies in the solutions they offer to the conflict between the pull toward independence and the pull back to the safety of childhood, the enduring stories for adults about children in their middle years can be seen as works of mourning for the relationship with the parents and the childhood self, but more importantly as attempts to transform their experience of middle childhood through the retrospective creation of a coherence that was initially absent. Thematic and structural elements distinguish two groups of stories for adults: the first appears to solve the conflicts of this period by importing adult knowledge and perspective into the narrative of childhood; the second describes the unconscious disorganizing aspects of this period, thereby offering readers a chance to reorganize their own memories, to make a coherent whole out of the fragmented, the confusing, and the unresolved. PMID- 26027141 TI - Historiography 101 for psychoanalysts. AB - I plant to propose an outline for a course for psychoanalytic clinicians called Historiography 101. My presentation is made up of three parts: an argument justifying the proposal, a clinical anecdote to anchor the argument, and a description of what the course might actually look like. PMID- 26027142 TI - Building emotional muscle in children and parents. AB - The concept of "emotional muscle" arose from clinical work in relation to therapeutic impasse and as a criterion for moving toward a "good goodbye. "It was applied to work at Allen Creek Preschool, a non-profit psychoanalytic school in Ann Arbor, Michigan, dedicated to the emotional and cognitive growth of families and their children from 0-6 years of age. The idea of building emotional muscle makes immediate intuitive sense to parents, children, teachers, therapists, and patients. It is a bridge between the abstract concepts and findings of developmental researchers and the everyday practicalities of family life, school, and the consulting room. The concept of "emotional muscle" promotes multidisciplinary understanding of personality structure and growth and contributes to the use of multi-modal therapeutic techniques. PMID- 26027143 TI - Interpretation and play: some aspects of the process of child analysis. AB - Taking a combination of Anna Freudian and Winnicottian approaches to play and playing, this paper considers the nonlinear relationship between interpretation and play in the process of child analysis. Using extensive clinical material from the analysis of a late latency girl who had been adopted, the author revisits the technique of using the displacement in play and the variety of modalities within which a child's unconscious concerns can be approached when disruption of the setting threatens because of the child's fragile ego. PMID- 26027144 TI - Discussion of "interpretation and play". AB - This discussion addresses the conflict in technique between play versus interpretation. It further considers how the nature of the interpretation may be affected by a consideration of what is being projected into the analyst. PMID- 26027145 TI - Latency-aged children with attachment disturbances: a conjoint treatment model. AB - Psychoanalytic theory and practice has increasingly accepted the importance of attachment relationships in psychic development. However, there have been only very limited efforts to develop psychoanalytically informed interventions for older adopted and foster children who show significant disturbances in attachment. This paper reviews theory and research that lays groundwork for a framework for conceptualizing treatment needs for attachment disordered children. Two cases of conjoint work with parents and their latency age sons are presented. The treatment cases highlight the importance of work to increase parents' reflective functioning capacities and the need to challenge children's defensively excluded early internal working models of self and caregivers. PMID- 26027146 TI - Five year olds with good conscience development. AB - Results from a longitudinal study on factors influencing conscience development contributed to our appreciation of the importance of moral internalization for a child's well-being. In this article we first present a summary of the research on moral development in children, including findings from infant research, with emphasis on the work of Robert N. Emde. Characteristics of classical psychoanalytic theory about superego development are compared with more recent insights. This is followed by a short description of two cheating games--as a measure of conscience development--played with 101 preschoolers. Some contrasts in our empirical data between the fair-play group and the children that cheated are presented and discussed in the light of the theoretical points of view. Finally some reflections on future research and the implications for parenting, prevention and clinical work are followed by suggestions for psychoanalytic theory. PMID- 26027147 TI - The aging of Anna Freud's diagnostic profile: a re-examination and re-application of the psychoanalytic assessment for older adults. AB - In 1962 Anna Freud published her pioneering paper on the Diagnostic Profile, proposing a framework for organizing relevant clinical material and observations for the assessment of a child's inner world. Since that time, the Profile has been applied, with modifications, to work with babies, adolescents, adults, blind children, and others. This paper strives to demonstrate the Profile's applicability to a group often neglected in the psychoanalytic literature, namely the older population, a vibrant group frequently seeking psychotherapy and even psychoanalysis. A case study of a woman in her 70s is used to illustrate the advantages for clinicians of the Profile for a clearer understanding, both diagnostically and intrapsychically, of the older adult. PMID- 26027148 TI - An artist's "motoric perception" and its influence upon the formal aspect of her art. AB - A young sculptor came to analysis because of depression and work block. Her depression began after she left her family to come to America. She had a childhood depression when she was three when her mother left her for several months. Her childhood depression was "treated" by her older brothers by throwing her from brother to brother until her cries turned to shrieks and finally exhausted sleep. This experience altered her ability to mourn and seemed a model for her use of physical actions at times of stress. The patient maintained that she had no visual memory of objects that she used in her art work. She looks at such objects with little visual awareness of them, feels sensations in her limbs and trunk which she then translates directly into the work of art. In analysis it was possible to demonstrate that she had a "motoric memory" of these objects. After this was demonstrated, a visual memory of the "forgotten" object became available to her. This impressed her and following this, she was better able to look at objects to be used in her art. Gradually, in the course of an eight-year analysis she could let herself experience loss without sinking into a helpless state of fear and depression. PMID- 26027149 TI - Oskar Kokoschka and Alma Mahler: art as diary and as therapy. AB - The Austrian artist, Oskar Kokoschka, had an affair with Alma Mahler, widow of the composer Gustav Mahler, 1912-1914. This affair profoundly influenced his life and art. His palette at first brightened, with thick brush strokes and flashes of light and dark, indicating his psychological and emotional lability. Painting what he did not or could not express in words, his art of this period can be understood as an intimate visual diary of the vicissitudes of his relationship with Alma Mahler. For Kokoschka his work became a form of art therapy, following the crushing loss of Alma Mahler and near fatal physical injuries sustained in World War I. His gradual recovery was associated with his extraordinary attachment to and destruction of a lifelike effigy of Alma Mahler, thereby working through childhood trauma. PMID- 26027150 TI - Psychoanalytic reflections through the prism of September 11, 2001. AB - An important area for psychoanalytic study is the significance for intrapsychic life of important events taking place in the community of which analyst and analysand are a part. September 11, 2001 provides a vantage point for examination of questions that arise from looking at the interrelationship between current environment and intrapsychic life. Two cases are presented as a focus for discussing the interaction of the memorialized past and occurrences in present reality, the significance for an analysis of analyst and patient sharing the same experience, instigations to progress that a current event may provide and the ways in which communal experience influences intrapsychic life. As a part of the discussion, we ask as well in what ways a common experience may be shared, and the significance of radically different meanings that the same event may have for analyst and analysand. We also pose the question whether the differences and similarities, each in their own way, may serve as progressive forces in the analysis. PMID- 26027151 TI - Against death's representability: Freud and the question of death's psychic presence. AB - What has been described as the psychoanalytic neglect and rejection of death is grounded in a set of claims made by Freud against the possible representation of death. Death is held to be absent from unconscious thought because death is negative, abstract, and involves time, because there is neither an instinctual correlative for it, nor a past precedent. In addition, when we ponder death, we discover that we are still there as spectators. These arguments have played a cardinal role in shaping analytic approaches to death, and it is crucial therefore to probe their value and function. Upon examination, some of these arguments turn out to be simply unconvincing. More importantly, whether convincing or not, Freud applied analytic principles to death much more eagerly and strictly than to other issues. These arguments have also not been sufficiently reevaluated with the advancement and development of psychoanalytic theory. Plausible solutions, even if partial, have been available, but not used. These considerations together give the impression that Freud's arguments are more of a way to justify a preexisting position. This paper also questions whether the idea of an isolated representation is indeed a suitable way to think about death's work and suggests a preliminary framework for conceptualizing death's psychic presence. PMID- 26027152 TI - Nutritional status, assessment, requirements and adequacy of traumatic brain injury patients. AB - Traumatic Brain Injury (TBI) has been considered as a serious public health problem. Each year, traumatic brain injuries are contributing to a substantial number of cases of permanent disability and deaths and it can be classified according to the severity into penetrating and closed head injury. Symptoms, beside to be unconscious can be defined as vomiting, nausea, headache, dizziness, lack of motor coordination, difficulty in balancing, blurred vision and lightheadedness, bad taste in the mouth, ringing in the ears, fatigue and lethargy as well as changes in sleep patterns. The brain is known to be the functional regulator for all the metabolic activities inside the body and TBI patients mostly have a complex metabolic alterations including aberrant cellular metabolism, abnormal metabolic processes, changes in hormones functions and inflammatory cascade. The TBI patient's status needed to be assessed medically and nutritionally since the medical status of the patients can affect the nutrition part. Data from the four assessment tools are needed to be correctly used and interpreted in order to make a proper nutritional diagnosis, clinical assessment, biochemistry as well as anthropometric measurements. Regardless the methods used for assessing TBI patients, having adequate intake and medical care can lead to a reduction in hospital costs, numbers of day hospitalized, numbers of hours of mechanical ventilation and in the overall infection rates. PMID- 26027153 TI - Nutritional status and cognitive impairment in elderly. AB - The elderly population is increasing worldwide and it has been suggested that senior citizens will continue to constitute the bulk of the population in many countries. Nutritional status of senior citizens are adversely affected by their frailty, chronic condition and declining cognitive functioning. Conversely, malnourished elderly further deteriorate their frailty, chronic disease and cognitive functioning. The aim of this review article is to recognize the importance of nutritional assessment of elderly population particularly those with cognitive impairment. First part is to highlight characteristic cognitive impairment among senior citizens and the second one highlight t he background in which malnutrition is a factor that leads to increased risk of morbidity and mortality in the elderly. This review also highlight salgorithms for safeguarding nutritional status among senior citizen and focuses on importance of nutritional screening, assessment and early intervention for safeguarding further deterioration of elderly who are likely to prone to cognitive impairment. PMID- 26027155 TI - Nutritional value of Kejeik: a dry fish product of the Sudan. AB - Kejeik product samples were collected from two different locations in Sudan including Singah city (Blue Nile) and Kusti city (White Nile). The contents of protein, moisture, ash, fat, crude fiber and carbohydrates varied considerably and ranged between 63.52-78.06, 5.37-6.69, 5.78-11.8, 9.04-16.13, 0.55-1.34 and 0.59-1.61% respectively, in the various Kejeik samples. However, the production area has a non-significant effect in most of the chemical components. All Kejeik samples contained appreciable amounts of macro-minerals and the calcium was the highest in all samples. In addition, Kejeik samples contained most of the micro minerals, however, Nawk and Ijl Kejeik collected from Singah contained the lowest concentrations of iron. The study concluded that Kejeik is a safe food with a highly nutritive value which is recommended to be utilized in Sudanese meals especially during shortage of protein and other nutrients sources. PMID- 26027154 TI - Evaluation of antioxidant and alpha-glucosidase inhibitory activities of some subtropical plants. AB - The antioxidant and alpha-glucosidase inhibitory activities of the methanolic leaf extracts of some subtropical plants were evaluated in the present study. Antioxidant activity was evaluated based on 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity, reducing power, hydrogen peroxide and beta-carotene bleaching assays. alpha-Glucosidase inhibitory activity and enzyme kinetics as well as the total phenolic content of the extracts were also investigated. Elaeocarpus sylvestris extract had the highest activities on all the antioxidant assays performed such as DPPH scavenging activity (IC50 12.7 +/- 0.5 MUg mL(-1)), reducing power (491.1 +/- 6.3 mg QE g(-1) dry extract), hydrogen peroxide (IC50 65.6 +/- 0.4 MUg mL(-1)) and beta-carotene bleaching assays (IC50 5.1 +/- 1.9 MUg mL(-1)). The total phenolic content of the E. sylvestris extract also had the highest values for gallic acid, quercetin and rutin equivalents (353.8 +/- 28.6 mg GAE g(-1) dry extract; 294.9 +/- 24.5 mg QE g(-1) dry extract; 663.0 +/- 52.3 mg RE g(-1) dry extract, respectively). alpha-Glucosidase inhibition assay revealed that Distylium racemosum had the highest activity with an IC50 value of 22.6 +/- 1.9 MUg mL(-1). The results of the present study revealed the potencies of E. sylvestris, D. racemosum, Acer mono Maxim and Liquidambar styraciflua as alternative sources for antioxidants and alpha-glucosidase inhibitors. PMID- 26027156 TI - Effect of 17alpha-hydroxyprogesterone and 17alpha-hydroxypregnenolone on sperm quality and sperm quantity in male mud spiny lobster (Panulirus polyphagus). AB - The present study aimed to determine the effect of 17alpha-hydroxyprogesterone (17alpha-OHP) and 17alpha-hydroxypregnenolone (17alpha-OHPL) on sperm quality and sperm quantity in male mud spiny lobster (Panulirus polyphagus). The mean of sperm quality was increased in 17alpha-OHP and 17alpha-OHPL treated hormones. In 17alpha-OHP injected animals, the mean of sperm quantity of dose 0.01 MUg g(-1) b.wt. was increased than 17alpha-OHPL. Meanwhile, 17alpha-OHP and 17alpha-OHPL concentrations were lower when injected with the hormones but 17alpha-OHP was higher at only day 15 (dose 0.01 and 0.1 MUg g(-1) b.wt.). For 17alpha-OHPL, the hormone was a prohormone in the body of P. polyphagus and only required smaller to increase the sperm quantity. Besides, when the higher dose of 17alpha-OHPL (0.1 MUg g(-1) b.wt.) was used in P. polyphagus, the development of P. polyphagus was inhibited and decreased the sperm quantity and 17alpha-OHPL concentration in hemolymph was lower. Injection of 17alpha-OHP in P. polyphagus has increased the sperm quality and quantity for both 17alpha-OHP dosage of 0.01 and 0.1 MUg g(-1) b.wt. However, injection of 17alpha-OHPL in P. polyphagus has decreased the sperm quantity only, also for both dosage of 0.01 and 0.1 MUg g(-1) b.wt. and lower on hormone concentration. PMID- 26027157 TI - Survival and growth rate of several climax species of tree in tropical rains forest Ulu Gadut West Sumatra Indonesia. AB - Long-term study of the growth of a forest stand is needed in order to conserve tropical forests. We have been monitoring the survival and growth of six species of climax (Cleistanthus glandulosus, Hopea dryobalanoides, Mastixia trichotoma, Microcos florida, Nephelium juglandifolium and Swintonia schwenkii) in Ulu Gadut tropical rain forest, West Sumatra, 32-year period (1981-2013). The average of Relative Diameter Growth Rate (RDGR) for six species ranged from 000 1-0028 cm year(-1) with a survival rate of 46.15-86.67%. There was a significant difference in the growth of each species (f = 2,613; p < 0.05, Scheffe post-hoc test). Growth of Trichotoma mastixia and Microcos florida were faster than other species. This indicated that the second species was the determinant of the sustainability of tropical rain forests in Ulu Gadut in the future. PMID- 26027158 TI - Trace elements in water, soil, earthworm and fishes from Otokutu end of Warri River, Delta State, Nigeria. AB - Selected environmental samples such as water, fishes (Tilapia mariae and Clarias gariepinus), earthworm (Libyodrillus violaceous) and soils were obtained from the Otokutu end of Warri River, digested with acid mixtures and analyzed for trace metal concentrations using the atomic absorption spectrophotometry. The trace metals measured include; zinc, lead, copper, arsenic, iron, cadmium and mercury. The results obtained showed variations in the concentrations of metals in the entire samples analyzed. Lowest metal concentrations were recorded in the water samples. Trace metal concentrations in Tilapia mariae, Clarias gariepinus and Libyodrillus violaceous were higher than levels recorded in water and soil samples, respectively. The elevated concentrations of lead, arsenic, iron, cadmium and mercury were traceable to anthropogenic wastes and activities of industries operating in Warri and its environs. PMID- 26027159 TI - Periodic variation of the water use efficiency in durum wheat. AB - Water Use Efficiency (WUF) of five durum wheat varieties (Khiar, Karim, Nasr, Razzak and Sobirano) cultivated in Tunisia was investigated. The experiment was conducted under rainfed field conditions, irrigated pots and test tubes at ESA Kef experiment station during the cropping season of 2010-2011. Under rainfed conditions, Khiar has the highest grain yield with 29.35 q ha(-1). Biological WUE ranged from 1.72-1.49 mg dry matter per g of water for Razzak and Nasr, respectively. The WUE of grain ranged.from 0.81-0.48 mg grain per g of water for Khiar and Sobirano, respectively. Biological WUE showed positive correlation to grain yield and stomatal density and negatively correlated with leaf area. Periodic water use efficiency in pot and test tube trials indicated variation of wheat genotypes according to stage periods and how the experiment was conducted. Test tubes trials showed high, accurate and maximum value of water use. Therefore, we can consider that Khiar has a high WUE in the first period; germination-early tillering (6.70 mg dry matter per g water). Nasr and Sobirano valorise well had got water use during the second period; tillering (9.16 and 10.20 mg dry matter per g of water). Razzak shows a high WUE for the third period; booting-early heading (9.06 mg dry matter per g of water). Finally, Karim cultivar has the highest WUE during for the fourth period; heading-physiological maturity (22.13 mg dry matter per g of water). Periods of high WUE can be targeted for appropriate time of wheat cultivar irrigation. PMID- 26027160 TI - Thymoquinone attenuates toxicity and oxidative stress induced by bisphenol A in liver of male rats. AB - Bisphenol A (BPA) is a fairly ubiquitous compound which has a great concern to human health. The current study was designed to (1) Assess the adverse effect of oral administration of BPA on liver of male rats and (2) Evaluate the role of thymoquinone (TQ), the major bioactive ingredient in the oil of Nigella sativa seed, in alleviating the possible detrimental effects of BPA on the liver. Rats were divided into control group administered olive oil, BPA group administered 10 mg BPA kg(-1) day(-1), TQ group administered 10 mg TQ kg(-1) day(-1) and BPA-TQ group administered the same previous doses of both BPA and TQ. After 24 h of the last dose, rats were decapitated and blood and liver were collected to determine some oxidative stress and biochemical parameters. Bisphenol A elicited a significant elevation in lipid peroxidation concomitant with depletion of antioxidant defense system in hepatic tissue. It also induced liver dysfunction as indicated by altered liver function markers and biochemical parameters. The administration of TQ attenuated the BPA-induced oxidative stress, alleviated the antioxidative system and improved to a large extent the liver functioning. This data clearly indicates that TQ has the potential to be a protective agent against oxidative stress and liver injury. PMID- 26027161 TI - Self care behaviors among elderly with chronic heart failure and related factors. AB - Self Care Behaviors (SCB) is one of the most important challenges in controlling readmission and improving the elderly patients outcomes. The aims of this study were to describe the SCB among elderly with heart failure and to assess relationships between SCB, demographic characteristics, age-related characteristics and clinical characteristics. In this cross sectional study, 184 elderly (age 60) with heart failure were selected with convenience sampling from 4 teaching hospitals. To assess SCB, the European Heart Failure Self Care Behavior Scale was used. Its validity and reliability were confirmed (CVI = 0.97 and alpha = 0.74). Data was collected from patients' medical record and by interviews. The highest percentage of behaviors not performing properly (score > 2), were related to self reported exercise (96.2%), receiving a flu shot (89.7%) and weight monitoring (80.5%), respectively. There was significant relationship between SCB and cognitive impairment (p < 0.001), serum sodium level (p < 0.001), charlson co-morbidity Index (p = 0.001), ejection fraction (p = 0.002), visual impairment (p = 0.002), sleep disorders (p = 0.003), poly-pharmacy (p = 0.004), hearing impairment (p = 0.012) and systolic blood pressure (p = 0.049). Significant relationship between SCB and age-related characteristics suggests the need to design both supportive and preventive programs among elderly with heart failure. PMID- 26027162 TI - Potent alpha-glucosidase inhibitors isolated from Ginkgo biloba leaves. AB - In vitro alpha-glucosidase inhibitory activity of Ginkgo biloba leaves was investigated. The inhibitory activity of methanol extracts from yellow and green leaves was 13.8 and 40.1 MUg mL(-1), respectively. Each methanol extract was separated into its respective fraction by solvent-solvent extraction with n hexane, chloroform, ethyl acetate and n-butanol. The n-hexane fractions (in both methanol extracts from green and yellow leaves) exhibited high alpha-glucosidase inhibitory activity with IC50 values of 13.6 and 13.4 MUg mL(-1), respectively. Further fractionation of the n-hexane fractions by silica gel column chromatography gave the most active fraction which was identified as ginkgolic acid (C13:0) and a mixture (C13:0, C15:0, C15: 1, C17:1 and C17:2). Ginkgolic acid (C13:0) exhibited the highest alpha-glucosidase inhibitory activity. This is the first study to successfully isolate ginkgolic acids as alpha-glucosidase inhibitors. PMID- 26027163 TI - Urate synthesis and oxidative stress in phenytoin hepatotoxicity: the role of antioxidant vitamins. AB - Phenytoin is known to induce microsomal enzymes including xanthine oxidase which catalyzes uric acid synthesis with superoxides as byproducts, thus contributing to the oxidative stress of phenytoin hepatotoxicity. To investigate the role of antioxidant vitamins in ameliorating phenytoin induced hepatic changes through possible actions on xanthine oxidase activities as measured by urate concentration. Growing albino rats of Wistar strain were randomly divided into 8 groups of 7 rats each. Group 2, 3, 4, 5, 6, 7 and 8 were treated with phenytoin alone, phenytoin + folic acid, phenytoin + vitamin E, phenytoin + vitamin E + vitamin C, phenytoin + vitamin C, phenytoin + folic acid + vitamin E and phenytoin + vitamin E + vitamin C + folic acid respectively while animals in group 1 were given normal saline to serve as control. Serum concentrations of uric acid, albumin, total protein and the activities of aspartate and alanine aminotransferases (AST and ALT) and catalase were measured spectrophotometrically using appropriate commercial reagent kits. Result showed that administration of phenytoin alone caused significant (p < 0.05) increase in serum levels of globulin, uric acid, AST and ALT activities while the levels of albumin and catalase were reduced significantly (p < 0.05). Supplementation of phenytoin treatment with vitamins resulted in various degrees of protection. However, the elevated level of uric acid in serum was not significantly (p < 0.05) affected by any of the vitamins used and there was no significant correlation between the activities of aminotransferases and uric acid concentration in the vitamin treated animals as was observed between aminotransferases and catalase. The findings in this study suggest that antioxidant vitamins were able to ameliorate phenytoin hepatotoxic effects by improving oxidant radicals removal in the animals but would not inhibit further generation of the superoxides by xanthine oxidase activity and that xanthine oxidase may contribute significantly to the oxidative stress of phenytoin therapy. PMID- 26027165 TI - Natural immunity against Haemophilus influenza type B in splenectomised Beta thalassaemia children. AB - Patients with beta-thalassaemia major and asplenia have an increased risk of encapsulated bacterial infections. The aim of this study was to determine the Haemophilus influenza type b (Hib) antibody concentrations in beta-thalassaemia patients with or without spleens. The Hib antibody concentrations were investigated in 850 patients with thalassaemia major, of whom 437 had undergone splenectomy. Hib antibody levels equal or greater than 1.0 MUg mL(-1) were classified as long-term protection, those between 0.15 and less than 1.0 MUg mL( 1) as short-term protection and those less than 0.15 MUg mL(-1) as no protection. The mean Hib antibody level was lower in asplenic subjects than in non splenectomised subjects (0.39 +/- 0.5 vs. 1.08 +/- 0.55 MUg mL(-1), p < 0.001). The protective antibody level prevalence in asplenic patients was significantly lower than that in patients with spleens (32.3% vs. 85.7%, p < 0.001). Protection against Hib decreased as the time interval after splenectomy increased from 57.2% at a less than 60 months interval to 10.8% at a greater than 120 months interval (p = 0.001). Nearly 30% of the 437 splenectomised subjects had long-term protection against Hib, whereas 64.4% of the 413 non splenectomised subjects had long-term protection (p < 0.001). Asplenic subjects had lower Hib antibody levels than non splenectomised subjects. Additionally, the antibody levels decreased as the time interval increased after splenectomy. A Hib vaccine recommendation for splenectomised thalassaemia major seems essential. PMID- 26027164 TI - Effect of berberine on nitric oxide production during oxygen-glucose deprivation/reperfusion in OLN-93 oligodendrocytes. AB - In this study, the effect of berberine, an isoquinoline alkaloid isolated from Coptidis rhizoma, on Nitric Oxide (NO) production, as a possible involved factor, during excitotoxic injury in oligodendroglial cells were evaluated. The overactivation of ionotropic glutamate receptors which is known as the excitotoxicity, is an important phenomenon because of the contribution in acute injury to the central nervous system, chronic neurodegenerative disorders, oligodendrocyte loss and demyelinating diseases as Multiple Sclerosis (MS). Intracellular Ca2+ overload, have a key role during excitotoxic injury and such increase in cytoplasmic Ca2+ triggers a series of events such as production of NO that end to cell death. Previous report showed the protective effects of berberine on ischemic-induced excitotoxic insult in oligodendrocytes. Hereby, we intended to know if the NO production could be associated with oxygen-glucose deprivation/reperfusion-induced excitotoxic damage in oligodendrocyte; moreover, the alteration of NO production could be considered as an involved mechanism for protective effect of berberine in such condition. Therefore, the effect of berberine (2 MUM) on NO production during oxygen-glucose deprivation/24 h reperfusion in oligodendrocytes were examined. The OLN-93 cell line (a permanent immature rat oligodendrocyte) was used as a model of oligodendrocyte. Thirty minutes-oxygen-glucose deprivation/24 h reperfusion was used to induce excitotoxicity. NO production was evaluated by Griess method. Our results demonstrated that berberine (2 MUM) significantly decreased NO production during 30 min oxygen-glucose deprivation/reperfusion. It seems that blockade of NO production by berberine may also participate in oligodendroglial cell protection against oxygen-glucose deprivation/reperfusion-induced insult. PMID- 26027166 TI - A review on omega-3 and omega-6 essential fatty acids: uses, benefits and their availability in pumpkins (Cucurbita maxima) seed and desert dates (Balanites aegyptiaca) seed kernel oils. PMID- 26027167 TI - Effect of potassium nitrate on antioxidants production of date palm (Phoenix dactylifera L.) in vitro. AB - Antioxidants present in dates are necessary for all physiological processes of humans and animals. In Saudi Arabia date palm is a national fruit tree, produces millions of tons of dates for consumption and is considered a major source of antioxidants. The main aim of this study was to determine the role of potassium nitrate (KNO3) in the formation of antioxidants from explants collected from date palm cultivars in Al-Ahsa Oasis, Kingdom of Saudi Arabia (KSA) and to monitor the extent of its effect on growth and development of cells during callus formation stage via somatic embryogenesis. The results showed that full concentration of KNO3 was the best for callus formation in general. While, the half concentration of KNO3 played an important role for stimulating the explants to form phenolic compounds and the browning emergence for all the cultivars under investigation. On the other hand, the chemical analysis for measuring the phenolic compounds in the explants showed that all the explants formed antioxidants but with varying degrees. The highest mean of phenolic contents was found in those explants cultured with the half concentration of KNO3 for Shishi cv 2.053 +/- 0.010a mg g( 1) and antioxidant activity by ABTS Inhibition and UM Trolox was 80.694 +/- 0.439 and 801.575 +/- 2.391, respectively. PMID- 26027168 TI - A decade of follow-up and therapeutic drug monitoring in HIV-2 immunocompromised patients at St Camille and General Lamizana Military Medical Centers, Burkina Faso, West Africa. AB - Although, HIV-2 is generally less pathogenic than HIV-1 and its progression towards AIDS occurs less frequently. HIV-2 remains an important cause of disease in West Africa. This study aimed to evaluate HIV-1 and HIV-2 prevalence among pregnant women and to describe the demographic and clinical profile of patients with HIV-2 infection from 2003-2013 at St Camille and General Lamizana Military Medical Centers. A retrospective investigation was conducted using 12,287 medical records from patients screened for HIV. To respond to the lack of data available regarding HIV-2 treatment and also to address the approach to clinical, biological as well as therapeutic monitoring, 62 HIV-2 infected patients' medical records were studied. Seroprevalence of 10.6 and 0.14% were obtained, respectively for HIV-1 and HIV-2 among 12,287 women screened during the study period. From the sixty two (62) HIV-2 patients, the average age was 49.2 years (sex ratio was 0.65). The weight loss and diarrhea were the major clinical manifestations observed, respectively 54.8 and 25.8%. Fungi and herpes zoster (shingles) infections were reported as major opportunistic infections. Also, nearly half of the patients had more than 60 kg, less than 2% were in WHO stage IV and about 2/3 had a CD4 count bellow 250 cells mm(-3). AZT-3TC-IDV/LPV/R was the most prescribed combination. The gain in weight gain the Body Mass Index (BMI) improvement and the non-significant increase of the rate of CD4 between 1st (M1) and 24th month (M24) were observed after treatment with antiviral. PMID- 26027169 TI - Response of some antioxidant parameters in post juveniles of Clarias gariepinus after exposure to Nigerian crude oil (Forcados, Bonny Light and Qua-Iboe). AB - The adverse effect of crude oil on aquatic ecosystem is a modern day peril. This study investigated the acute toxicities of some Nigerian crude oil (Forcados, Bonnylight and Qua-Iboe) against Clarias gariepinus and the antioxidant enzyme response of the fish to the pollutants. The toxicity assessment was based on LC50 at 96 h. Static renewal bioassays were used to determine the toxicological effects of the 3 crude oils on the antioxidant enzymes of post juveniles Clarias gariepinus using the liver. The 96 h LC50 value for Qua Iboe was 18.966 mL L(-1), Forcados, 2.776 mL L(-1) and Bonny light, 3.948 mL L(-1), indicating that Forcados is the most toxic of the crude oils. Induction of the Glutathione-S transferase (GST), Glutathione (GSH), Superoxide dismutase (SOD) and Catalase (CAT) in the liver of Clarias gariepinus exposed to Forcados and Bonny light for a period of 28 days was inhibited while it was enhanced in Qua-Iboe crude oil. Malondialdehyde (MDA) levels increased with increasing toxicity and exposure time. SOD, CAT, GSH, GST and MDA are reliable environmental biomarkers for crude oil induced oxidative stress in Clarias gariepinus and therefore useful biological indicators of environmental contamination in the aquatic ecosystem. PMID- 26027170 TI - Antimutagenic and anticancer activity of Al Madinah Alhasawy mint (Mentha longifolia) leaves extract. AB - Mentha is one of the genera of Lamiaceae family. The aim of the present study was to evaluate the antimutagenic and anticancer activity of the water and methanolic extract of Alhasawy mint (Mentha longifolia), that grown in Madina Province, western region, Saudi Arabia using three different bioassays namely; Brine shrimp bioassay, Ames mutagenicity bioassay using 3 Hist-Salmonella typhimurium strains of different mutations (TA98, TA97 and TA100) and 2 reference mutagenic drugs nitrosopiperidine (NP) and 2-amino-3-methylimidazo-quinolidine (IQ) and Mammalian cell lines bioassays using 2 different cell lines HepG2 and Vero cell lines. The plant extract showed an efficient antimutagenic activity against the studied bioassays in a directly proportional effect with concentration. PMID- 26027171 TI - Effects of local curcumin on oxidative stress and total antioxidant capacity in vivo study. AB - Plants have been one of the important sources of medicine even since the-dawn of human civilization. Curcumin has been found to possess tremendous therapeutic potency as antiinflammatory, antioxidant and antimicrobial agent. The present study was designed to examine possible potential therapeutic and protective effect of curcumin from oxidative stress and on total antioxidant capacity in liver damage. The study was conducted using H2O2 as inducing agent of oxidative stress in vivo. Rats were randomly divided into five groups, where n = 20 for each group. Group 1 (G1) rats served as control group. Group 2 (G2) rats subjected to experimentally induced oxidative stress by the ad libitum supply of drinking water containing 0.5% H2O2(v/v) was prepared daily over entire 60 days. Group 3 (G3) rats received H2O2 for sixty days followed by giving 200 mg kg(-1) of curcumin for 30 days. Group 4 (G4) was simultaneously given curcumin (200 mg kg(-1)) for 15 days then followed by receiving H2O2 with curcumin for sixty days. Group 5 (G5) rats was received H2O2 for sixty days followed by giving 200 mg kg( 1) of N-acetyl 1-cystine as standard drug for 30 days. Levels of marker enzymes (ALT, AST and ALP), uric acid, Total Protein (TP) and tumor necrosis factor (alpha-TNF) were assessed in serum for all studied groups. Malondialdehyde (MDA), 8-hydroxy-2-deoxyguinosine, Total Antioxidant Capacity (TAC), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) were assayed in liver homogenates for all studied groups. The results revealed significant increase (p < 0.05) in levels of ALT, AST, ALP, uric acid and alpha-TNF while there are significant decrease (p < 0.05) in levels of TP in G2 comparing to G1. Also there are significant differences (p < 0.05) between G3 and G4 comparing to G2 and between G3, G4 and G5 which curcumin elicited a significant hepatoprotective activity by lowering the levels of serum marker enzymes and lipid peroxidation. The results also revealed a significant increase (p < 0.05) in levels of MDA and 8-H-2-deoxy guinosine while there was significant reduction (p < 0.05) in TAC, GSH, SOD and catalase in G2 comparing to G1. Also there are significant differences (p < 0.05) between G3 and G4 comparing to G2 and between G3, G4 and G5. The conclusion could be drown from this study that the ability of curcumin as therapeutic agent and hepatoprotective against liver damage from oxidative damage and on TAC more than N-acetyl 1-cystine related to its antioxidant and free radical scavenger activity. PMID- 26027172 TI - [Disability and society for a civic integration]. PMID- 26027173 TI - [End of life, the recommendations of the Claeys-Leonetti report]. PMID- 26027174 TI - [The research nurse and paramedic, an opportunity for caregivers]. PMID- 26027175 TI - [Give nursing students their rightful place!]. PMID- 26027176 TI - [A decree on the validation of acquired experience]. PMID- 26027178 TI - [A supplement to the nursing diploma]. PMID- 26027177 TI - [Patches, attention to the risk of medication error]. PMID- 26027179 TI - [A public consultation on the self-administration of drugs]. PMID- 26027180 TI - [Fourth edition of GrippeNet device]. PMID- 26027181 TI - [Money and health, an issue of bioethics]. PMID- 26027182 TI - [Feedback, a pedagogical tool in the emergency department resuscitation room]. AB - The specific care provided in the emergency department resuscitation room requires a high level of knowledge, skill and competence. The lessons learned methodology is a dynamic approach and an educational tool which promotes the transfer of knowledge and the continuous improvement of the quality and safety of care. PMID- 26027183 TI - [Training peer supporters in the treatment of anxiety disorders]. AB - A study carried out in Quebec focused on the development of training for peer supporters in this area. Its results enable the necessary skills and the experience of these peer supporters to be assessed, in order to construct adapted training modules. PMID- 26027184 TI - [Specialized and personalized support]. PMID- 26027185 TI - [Wound care at the end of life]. AB - Wounds in end-of-life care are treated in a particular context as the healing of the wound and/or the recovery of the patient are no longer the main priority. These wounds very often have a significant impact on quality of life, both physically due to the pain or the functional incapacity, as well as psychologically. PMID- 26027186 TI - [Malignant wounds in palliative care]. AB - In the alsence of effective cancer treatment, malignant wounds evolve. The decisions taken by the multi-disciplinary team with regard to their care vary depending on whether the patient is in the initial, advanced or terminal phase of palliative care. Modern dressings can be used to control bleeding, odours and drainage. The aim is to control the symptoms and improve the quality of life, until its end. PMID- 26027187 TI - [Managing pressure ulcers in palliative care in geriatric units]. AB - Many elderly people at the end of life, in geriatric units, suffer from pressure ulcers despite preventive care. Measures are put in place in order to prevent the occurrence of new pressure ulcers and to define a local and general treatment strategy for those already occured . The priority remains to relieve the pain and improve the patient's comfort and quality of life. PMID- 26027188 TI - [Wound surgery in patients receiving palliative care]. AB - Surgery, normally considered inappropriate for patients receiving palliative care, can nevertheless be an option in the case of infection. Some procedures are carried out in these situations, such as emergency debridement or the amputation of the foot or lower limb. These techniques also aim to improve the comfort of the patient at the end of life. Discussion between the whole multi-disciplinary team ahead of the treatment is in some cases necessary. PMID- 26027189 TI - [Palliative care and telemedicine]. AB - Palliative care at home is a major challenge for health professionals. Teleconsultations constitute a solution for community caregivers and the patient's family, particularly in order to compensate for the lack of technical skills in the case of complexwounds. Experts from the Cicat-Languedoc-Roussillon network are thereby called upon to work remotely. PMID- 26027190 TI - [The contribution of telemedicine in the management of pressure ulcers in palliative care]. AB - The use of telemedicine in the treatment of pressure sores in palliative care. The benefit of telemedicine in nursing homes has been demonstrated notably in the case of pressure sores. It gives health professionals the possibility to establish valuable exchanges. A real support and trainingtool, it enables them to improve their skills and share good practices across geriatrics. PMID- 26027191 TI - [Critical limb ischemia in an elderly patient]. AB - Critical limb ischemia in an elderly patient. Peripheral arterial disease is a common condition in the elderly, often revealed by critical limb ischemia. The aim is to save the limb through revascularization, wherever possible. The patient must be hospitalized in a specialized unit for multidisciplinary assessment due to the complexity of the diagnosis and treatment. The decision to amputate is difficult and should be discussed with patient and family. PMID- 26027192 TI - [Caring for patients at the very end of life]. AB - During the death process, certain signs can be identified to help caregivers understand how the patient may be suffering and to provide adequate relief. As the end of life approaches, patients may be conscious and aware and comfort care is therefore continued and adapted. At the very end of life, the focus moves to supporting the patient's family. PMID- 26027193 TI - [The challenges of treating wounds in palliative care]. PMID- 26027194 TI - [Publication Notes]. PMID- 26027195 TI - [Phenomenography: a useful method in nursing research]. AB - Phenomenography is a qualitative research methodology the aim of which is to describe the variations in understanding of a phenomenon. This approach can be used to answer certain types of research questions, relating to different patient experiences, or as part of health professionals' learning processes. PMID- 26027196 TI - [1/10. Objectives and regulation of cooperation protocols]. PMID- 26027197 TI - [Weight loss maintenance]. PMID- 26027199 TI - [How to lose weight effectively and in a sustainable manner: a review of current topics]. AB - There is a lot of conflicting information regarding the best way to lose weight, especially regarding food diets. A recent study compared the different diets and ultimately revealed that there is no significant difference in their efficacy for weight loss. Furthermore, it is recommended to lose weight gradually because rapid weight loss was a risk factor for more rapid and important weight regain. This notion has been challenged by a study that compared the two approaches and demonstrated that the rate of weight loss has no influence on weight regain. Ultimately, the key is to develop strategies that are best suited to the patient, so that he can adhere more easily and maintain his efforts on the long run. PMID- 26027200 TI - [Food addiction]. AB - Food addiction is a common term used in everyday language by obese patients. Although the neurobiological evidence points to some similarities between addictive mechanisms and the consumption of certain foods, this diagnosis is not yet officially recognized. After a brief history of food addiction compared to other eating disorders, we review the neurobiological processes underlying this concept. A food addiction assessment tool is presented and discussed with the current literature and new classifications of the DSM-5. The concept of food addiction needs to be rethought and requires further research. PMID- 26027201 TI - [Physical activity adapted to the obese patients' needs: which assessments for what kind of prescription?]. AB - Physical activity is a key element for the obese patient willing to lose weight. The main aim of physical activity is to contribute to produce, and maintain, a negative energy balance. A recent approach suggests to focus on the intensity eliciting the maximal lipid oxidation rate. Physical activity prescription should however be adapted to the patient's physiological and metabolic profile. Determining the physical fitness of the patient during an incremental test and assessing body composition may be central elements determining physical activity prescription. Provided the activities are adapted to the patient's profile, numerous physical activities may be performed by the obese patient. A practical, clinical approach, based upon the metabolic profiling of the patient is proposed in this article. PMID- 26027202 TI - [The cure of type 2 diabetes and patient education]. AB - Type 2 diabetes is a potentially reversible disease. Patient education encompasses a deep investment of the health care providers, who with the aid of pedagogic tools, help the pa tient commit to this path. This facilitates the learning of uncommon knowledge and skills required. Whether or not it leads to a complete remission of the disease may not be the main purpose. The main goal lies in the patient's motivation to learn and change on a long term basis. PMID- 26027203 TI - [Bariatric surgery: what is the ideal length of the preoperative track?]. AB - Bariatric surgery not only has significant somatic implications but also imposes substantial behavioural and psychological changes. It is therefore essential to check previously that the potential candidate has not psychosomatic contraindications and its psychoocial context to allow adaptation to the changes requested by the intervention. After this preliminary phase the multidisciplinary support must provide a complete and adequate preparation for potential intervention, and ensure a follow-up to life in these patients. Bariatric support is therefore an ongoing process, which involves, in the preoperative phase, three steps: (1) to inform, (2) to assess and (3) prepare candidates. PMID- 26027204 TI - [Insulin therapy and parenteral nutrition in intensive care: practical aspects]. AB - Critically ill patients are hypercatabolic due to stress and inflammation. This condition induces hyperglycemia. Muscle wasting is intense during critical illness. Its prevention is essential. This is possible by early and appropriate nutritional support. Preserving the function of the gastrointestinal tract with enteral nutrition is the gold standard. However, when targeted protein-caloric intake is not met through enteral nutrition within the first three days in the intensive care unit (ICU), supplemental parenteral nutrition is administered to reduce morbidity and mortality. In addition, in order to limit metabolic imbalance and reduce mortality, glycemic control using insulin therapy is mandatory. This article reviews the current understanding of parenteral nutrition and insulin therapy in ICU patients, and provides the decision model applied in our institution. PMID- 26027205 TI - [Roma populations and health]. AB - The health status of the so-called "Roma" is usually much poorer than that of neighbouring non-Roma populations with a life expectancy gap of 5-15 years. This results from prolonged exposure to adverse determinants of health and to persistent exclusion from social and political arenas. Scientific and social research has only poorly addressed the health issues of Roma and evidences are scarce. Insufficient access to public services, including to health care and non optimal clinical practices are modifiable factors. If correctly addressed, this could contribute to reduce health disparities, including in Switzerland. PMID- 26027206 TI - [Incidental discovery of an immunoglobulin deficiency]. PMID- 26027207 TI - [To learn how to die, France will have to stop looking towards Switzerland]. PMID- 26027208 TI - [Without title]. PMID- 26027209 TI - [Penis transplantation in South Africa. Risk of suicide using varenicline?]. PMID- 26027210 TI - [Working too much is associated with higher alcohol consumption]. PMID- 26027211 TI - [Food withdrawal to help and let die?]. PMID- 26027212 TI - [Precisions on utilization of electronic medical records]. PMID- 26027213 TI - [To practice in Switzerland, physicians must master the local language]. PMID- 26027214 TI - ["We're all zombies, nobody is conscious". Or not?]. PMID- 26027215 TI - [Dexmedetomidine as a part of analgesic component of general anesthesia for laparoscopic operations]. AB - The article deals with a study of efficacy and safety of the dexmedetomidine as an analgesic adjuvant drug for anaesthesia during laparoscopic gynecological and abdominal surgeries. Patients and methods: 32 patients received intraoperative infusion of dexmedetomidine. We assessed an effects of dexmedetomidine on data of central circulation during surgeries. CONCLUSIONS: The use of dexmedetomidine allows to decrease an amount of opioid analgesics, inhalation anaesthetics and to avoid severe changes of circulation during traumatic phases of surgeries. PMID- 26027216 TI - [Comparison of sedation with dexmedetomidine and haloperidol in patients with delirium after femoral neck fractures]. AB - Delirium seriously complicates the recovery period after surgery, injury and increases mortality in elderly patients with femoral fractures. PATIENTS AND METHODS: We examined 80 geriatric patients admitted to the Institute of Traumatology and Orthopedics in Astana in the period from September 2012 to June 2014. We evaluated the efficacy of dexmedetomidine and haloperidol sedation according to RASS, communication ability and level of tolerance of procedures. The effect of dexmedetomidine was better and was expressed 30.3% decreasing of the duration of delirium in comparison with haloperidol (p < 0.05). Overall assessment of the ability of patients to the interaction, cooperation and tolerance of procedures evaluated by nurses, was higher in the dexmedetomidine group compared with haloperidol, as well as evaluating the effectiveness of individual communication and cooperation (8.3 +/- 2.3 points vs 4.5 +/- 1.9 points, p < 0.05). Despite the development of bradycardia in a small number of patients, as well as headaches and nausea after stopping the infusion, dexmedetomidine provided a more controlled and safe sedation compared with haloperidol. PMID- 26027217 TI - [Predicting of postoperative pain level and morphine consumption by preoperative pressure pain assessment in patients before elective surgery]. AB - The aim of this study was to predict a postoperative pain severity and morphine consumption by preoperative pressure pain assessment. DESIGN: 321 patients scheduled for elective surgery (lumbar discectomy, lumbar spinal fusion, hysterectomy, thoracotomy and total hip replacement) in 2009-2013 were enrolled in retrospective study. Pre-operatively, the pain threshold (PTH) and tolerance (PT) in Newton (N) were measured using the pressure algometry. Post-operatively, the pain scores at rest and during movement at 1st postoperative day (POD) using 10 cm VAS were also recorded Patients could get morphine by PCA device in addition to nonopioid analgesia post-operatively. RESULTS: PTH and PT were respectively 34 (24; 45.6) and 74 (54; 95) N, VAS at 1 POD 2 (1; 3.75) at rest and 4 (2,5; 6.25) cm during movement. Pre-operative PT correlated significantly with pain score during movement in patients at 1 POD (R = -0.124, p = 0.026, n = 320). Logit regression analysis found that pain control adequacy during movement at 1 POD could be predicted with PT (beta = 0.011, Std. Err = 0.004, chi2 = 8.536, p = 0.004, OR = 1.011, 95% CI = 1.004-1.018). Morphine consumption by PCA device in patients was 21.25 (7.5; 38) mg. We found a significant correlation between pre-operative PT and post-operative morphine consumption (R = -0.306, p = 0.0006, n = 122). CONCLUSIONS: Post-operative pain severity during movement at 1st postoperative day can be predicted with the pre-operative pain tolerance using the pressure algometry. There is significant moderate negative correlation between pre- operative pain tolerance and post-operative morphine consumption by PCA device in patients at 1st postoperative day. PMID- 26027218 TI - [Analgesia of labor in women with diabetes mellitus]. AB - The article deals with a study of duration of physiological labors in women with diabetes mellitus. PATIENTS AND METHODS: 120 women were devided into three groups according to method of analgesia. We assessed data of central haemodynamics, efficacy of analgesia, glucose level in blood, conditions of fetus and newborn. RESULTS: We found that epidural analgesia with bupivacaine hydrochloride was an optimal method of labor analgesia in women with diabetes mellitus. This method provided a stabilization of glucose level in blood, normalization of data of central haemodynamics and allowed to avoid anomalies of labor CONCLUSIONS: Analgesia with promedol and paracetamol is a preferable method in case of presence of epidural analgesia contraindications. PMID- 26027219 TI - [Background and perspectives of opioid analgesics for the treatment of chronic pain in cancer patients in Russia]. AB - The article deals with an analysis of availability of narcotic analgesics for the patients in the Russian Federation. The analysis was based on datafrom official sources on the scopes of opioids delivery in different regions of the Russian Federation and showed an extremely limited availability of narcotic analgesics for the patients in the Russian Federation. We found that availability of narcotic analgesics in Russia is hundreds times lower than the same indexes in European countries with various level of economic activity and in the USA. The analysis showed ten most progressive Russian regions where the use of opioids in the noninvasive forms has become part of systematic clinical practice according to WHO recommendations as well as 10 ten most backward regions where these drugs are hardly used despite of high figures of case death rates from cancer. We made a list of most needed modern Russian and internationally produced drugs according to international data and personal experience. Drugs from this list can be effectually used for the chronic pain therapy in oncology. The most advanced drugs that are soon will be produced are also named. The article describes high priority measures that have already been done to improve current situation and measures to be executed in the future. PMID- 26027220 TI - [Clinical aspects of the service of acute postoperative pain treatment]. AB - PURPOSE OF THE STUDY: To analyze work results of the service of acute postoperative pain treatment in the orthopedic hospital. DISIGN: Single-center retrospective observational cohort study. PATIENTS AND METHODS: We studied 1343 patients underwent total hip arthroplasty (64%), total knee arthroplasty (33%), and revision surgeries (3%). The average age of the patients was 59 +/- 12 years, and body mass index was 30 +/- 6. All patients received triple pain therapy in postoperative period which included pracetamol, NSA IDs or specific ciclooxygenase-2 inhibitor and epidural analgesia or peripheral blockade and patient controlled intravenous or epidural analgesia. The pain intensity was recorded four times a day--every 6 hours during 2 days after surgeries. RESULTS: All patients received oral or intravenous analgesics. 90% of patients received prolonged epidural infusion, 10%--prolonged block of the femoral nerve after total knee arthroplasty. Patient controlled analgesia was used in 6-10% of patients. Average pain intensity was 20 mm according to VAS. Pain intensity over 40 mm was observed in 8-13% of patients at 1st day after surgery and in 2-15% at 2nd day after surgery. Deep vein thrombosis was found in 5.7% of patients, and bleeding in 0.2%. Length of stay in a hospital after total hip arthroplasty and total knee arthroplasty was 6 +/- 2 days and 10 +/- 8 days after revision surgeries. CONCLUSIONS: The work of the service of acute postoperative pain treatment in the orthopedic hospital, the use of multimodal treatment protocols and mandatory clinical monitoring provide proper control of postoperative pain, patient satisfaction, and allow to accelerate early recovery and reduce the time of postoperative hospital stay after total replacement of large joints. PMID- 26027221 TI - [Effect of prolonged epidupal analgesia on respiratory function after major laparoscopic surgery]. AB - The article deals with a study of role of epidural analgesia, used as a part of intra- and postoperative analgesia in patients underwent major laparoscopic surgery (gastric resections, pancreas and duodenal resections, hemicolectomy, resections of colon). PATIENTS AND METHODS: The study included 127 patients aged 65 +/- 13 years. Main group--patients who had undergone extensive and prolonged laparoscopic surgery; comparison group--patients after traditional open surgery. Terms of laparoscopic and open surgeries was similar Postoperatively we assessed dynamics ofpostoperative pain and physical activity (using appropriate scales), dynamics of respiratory function (spirometry) in with and without use of epidural analgesia. CONCLUSION: major laparoscopic surgery accompanied with lower decreasing of speed and volume figures of spirometry if epidural analgesia is used as a part of intra- and postoperative analgesia. PMID- 26027222 TI - [Influence of remote ischemic preconditioning on brain injury markers dynamics during cardiopulmonary bypass]. AB - INTRODUCTION: Remote ischemic preconditioning has gained clinicians' attention as a technique to protect the heart in patients undergoing cardiac surgery under cardiopulmonary bypass. While experimental data report neuroprotective properties of remote ischemic preconditioning, we failed to find any clinical studies investigating its effects on neurologic outcome in cardiac surgery. PURPOSE OF THE STUDY: This prospective randomized placebo-controlled study was undertaken with the aim of elucidating the role of remote ischemic preconditioning for neuroprotection in cardiac surgery. PATIENTS AND METHODS: 88 patients with coronary heart disease scheduled for on-pump coronary bypass grafting surgery were randomized to receive either remote ischemic preconditioning or control. We studied S100B peptide and neuron-specific enolase to assess neurological damage. Psychophysiological tests were employed to investigate cognitive function after surgery. RESULTS: The perioperative dynamics of S100B and neuron-specific enolase followed similar patterns in both groups throughout the observation period. At the end of surgery, level of S100B was significantly higher in the preconditioning group as compared to controls--0.58 (0.33-0.65) vs. 0.34 (0.23 0.42) mcg/l, p= 60 CU. The investigation of blood serum was performed on 1-3, 7, 14, 21 and 28 day after burn injury. Malondialdehyde (MDA), total antioxidant status (TAS), the level of middle weight molecules, stable metabolites of nitric oxide (NOx) and angiotensin-converting enzyme (ACE) activity were determined in the serum. Significant increase of MDA level, decrease of TAS and NOx level were found in two groups of patients throughout the observation period. We also found a disturbance in coupled interaction of NO and ACE. These data point to the development of oxidative stress and imbalance in endogenous regulation of vascular tone. There was a trend toward more pronounced oxidative stress in group 2. Significant correlations between parameters of oxidative stress, endogenous intoxication, endogenous factors of vascular regulation, depth of burn injury and FI were obtained in two groups. MDA, TAS can serve as one of the prognostic markers of condition severity of burned patients and therapy adequacy. PMID- 26027226 TI - [Anaesthesia and intensive care during intraoperative intraperitoneal hyperthermic chemotherapy in patients with gastric cancer (literature review and own clinical experience)]. AB - Despite a steady decline in the incidence in recent decades, gastric cancer remains one of the most frequent causes of death from cancer in the world. By the time of diagnosis the tumor process is locally advanced or generalized in nearly 70% of patients that reduces the possibility of radical surgical treatment. Peritoneal carcinomatosis is a one of the main causes of treatment failure. There patients need complex treatment with cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) to improve the quality and duration of life. Today in Russia, surgeries with IHIC are performed in a very limited number of oncology hospitals, thus there is no unified approach to the perioperative management of these patients. DESIGN: Since November 2010 in our institution we started a prospective clinical study of the use of intraoperative hyperthermic intraperitoneal chemotherapy in patients with locally advanced or metastatic gastric cancer. MATERIALS AND METHODS: The study included 30 patients (18 men and 12 women) who underwent transabdominal gastrectomy with extended lymphadenectomy D2, supplemented principled cholecystectomy and oophorectomy (in women). Mean age was 48.5 +/- 5.3 years. Technique involved the use of regional anesthesia com- ponent and inhalation anesthetic sevoflurane. Preoperative preparation included enteral nutrition (based on 25-30 kcal/ kg/day), liver protection (intravenous remaxol infusion of 500 ml/day for 3 days prior to surgery), antisecretory and antifermental therapy (omeprazole 40 mg/day, 100 mg octreotide for 2 h before surgey, aprotinin sulfate 30000 after induction of anesthesia), antioxidant and immunomodulatory therapy (galavit, cytoflavin, ceruloplasmin vitamin C), anticoagulant prophylaxis (enoxaparin sodium 40 mg on the evening before surgery). RESULTS: Analysis of the world and our own clinical experience with intraoperative hyperthermic intraperitoneal chemotherapy in a comprehensive plan of treatment of patients with gastric cancer showed that the this aggressive, but highly effective technique can be requires not only careful patient selection according to the criteria, but also the use of special methods to protective therapy at all stages of the surgical treatment. Application of pathogenetic ways of protection from thermal injury, timely control and correction of homeostasis caused by the toxic effects of chemotherapy and burn peritoneum, early enteral nutrition and the use of organ-therapy reduce the risk of complications and achieve better results of treatment in cancer patients. PMID- 26027227 TI - [Optimization of infusion therapy in patients with ovarian cancer]. AB - We investigated the clinical observations and the results of a comprehensive survey of 70 patients with ovarian cancer stage III-IV aged 30 to 70 years with the presence of endotoxemia. Integral assessment of prognosis and severity of the condition was performed according to SAPS II and SOFA. Infusion program included a preliminary correction of hypovolemia prior to surgery on the operating table in equal parts, HES and balanced crystalloid solutions, with in- creased infusion of 15% of blood volume based on the method of anesthesia. In the early postoperative period, infusion programs were complemented by various embodiments of metabolic correction. Patients of group-1 (n = 35) received remaxol in a dose of 800 mI/day. Patients of group-2 (n = 35) received ademethionine (heptral) 800 mg/day. Analysis of the results revealed that premorbid background in patients with ovarian cancer stage III-IV was characterized by hypovolemia, phenomena hepatopathy, and endotoxemia, and mixed forms of hypoxia of varying severity. Differentiated approach to the choice of pathogenesis-based perioperative infusion according to premorbid condition, anesthesia and blood loss contributed to the elimination of hypovolemia, favored efficient oxygen delivery and consumption, the ade- quacy of tissue oxygenation. Remaxol inclusion in the perioperative infusion programs in patients with ovarian cancer enhanced their clinical efficiency, reduced cytolytic and cholestatic syndromes, recovered of protein and synthetic liver function, reduced the appearance of mixedforms of hypoxia and endogenous intoxication. PMID- 26027228 TI - [Comparison of pharmacological renal preconditioning with dalargin and lithium ions in the model of gentamycin-induced acute renal failure]. AB - PURPOSE: To examine the efficacy of renal preconditioning effect of dalargin and lithium ions by observing the model of gentamycin-induced acute renalfailure. MATERIALS AND METHODS: The experiments were performed on white rats, male. The influence of dalargin and lithium ions on the development of gentamycin-induced acute renalfailure was studied in vivo. On the first 24 hours after dalargin injections were terminated, the rats were euthanized humanly. After this we took the blood for a biochemistry study and a renal culture for biochemical test and also for the test of gsk-3beta activity. Concentrations of creatinine and urea were studied in serum. The culture samples of renal tubular epithelium before insertion of gentamycin were incubated in dalargin or lithium ions in different concentrations. After that the substratum was immediately changed to gentamycin in different concentrations also and the incubated for 24 hours. After all the standards MTT-test was performed (based on the ability of living cells to reduce the unpainted form by 3-4,5-dimethylthiazol-2-yl-2,5-difenilterarazola to blue crystalline farmazan). RESULTS: Lithium precondition leads to the 250% increase of gsk-3beta concentration (p = 0.035). The same results were observed after injection of dalargin in 50 mcg/kg concentration. Concentration of creatinine was 44% lower in the dalargin group than in the control group (p = 0.022). Concentration of creatinine was 32% lower in the lithium group than in the control group (p = 0.030). Concentration of urea was 27% lower in the lithium group than in the control group (p = 0.049). Morphological inflammatory changes in the control group were more significant also. In vitro studies showed the maximum efficacy in the lithium group. The most effective dalargin concentration was 5 mg/ml. CONCLUSION: Lithium and dalargine preconditioning lowers the signs of gentamycine induced acute renal failure and damage rate of renal parenchyma in vivo and in vitro. PMID- 26027229 TI - [Monitoring of haemodynamics and function of the aortic prosthesis during transcatheter aortic valve replacement]. AB - PURPOSE: To find an advisability of use of invasive monitoring of intracardiac haemodynamics during transfemoral transcatheter aortic valve replacement. PATIENTS AND METHODS: The study included 12 patients underwent transfemoral transcatheter aortic valve replacement (TTAVR). All patients were monitored according to Harvard standard. Additionally, we performed a catheterization of the right heart chambers, transesophageal or transthoracic echocardiography. Pressure in the left ventricle and aorta was measured directly after implantation ofthe aortic prosthesis. RESULTS: Cardiac output was increased authentically in comparison with baseline in all patients. There was cardiac index increasing, however the increasing was not reliable (p <= 0.07). In 9 cases, baseline pulmonary artery pressure (PAP) was not changed during surgery. In 3 patients, PAP and pulmonary artery wedge pressure (PAOP) before surgery were increased. In 2 of this 3 patients, PAP and PAOP were significantly decreased after surgery. In 1 case, the pressure in the pulmonary circulation stayed increased. Ejection fraction (EF) of the left ventricle was increased after surgeries in 2 patients from 30 to 40% and from 20 to 25%. The values of stroke volume and stroke index were similar in all patients before and after surgeries. Valvular regurgitation after successful implantation of the aortic prosthesis was found in 11 patients (91.6%). We calculated dia- stolic gradient of left ventricle and the aorta and aortic regurgitation index and compared this parameters with data of echocardiography. The index of aortic regurgitation was 36.5 (35; 46), and diastolic pressure gradient in the aorta and ventricle was 48.0 (40.5; 65.5) mmHg. Calculated systolic pressure gradient in the left ventricle and aorta was 5.5 (3.0; 11.5) mmHg., this data proved that there was no stenosis of aortic prosthesis. CONCLUSION: Invasive monitoring of intracardiac haemodynamics during transfemoral transcatheter aortic valve replace-ment allows to diagnose quality of prosthesis implantation accurately and provides data about valvular regurgitation. Invasive monitoring helps to provide haemodynamic stability in patients with critical aortic stenosis during anaesthesia. PMID- 26027230 TI - [Diagnostic opportunities of noninvasive brain thermomonitoring]. AB - Development of new means and methods of cerebral temperature monitoring is an actual problem due to the fact that severity and outcomes of diseases in patients with brain damages (strokes, a head trauma) in big degree depend on development of neurogenetic fever and a local cerebral hyperthermia. The temperature monitoring, which is carried out by the implanted sensors, is applied in neurosurgical patients and is practically not used in patients with disorders of cerebral bloodflow. In this regard, noninvasive techniques of brain temperature registration are developing: proton nuclear magnetic resonance spectroscopy and registration of own electromagnetic radiation (EMR) at the high range of frequencies (microwave). The main objective of the study was to define of diagnostic opportunities of noninvasive temperature measurement of brain by means of microwave radiothermometry. PMID- 26027231 TI - [Microdialysis--a new method of monitoring of the transplanted cadaveric kidneys function]. AB - PURPOSE: To assess ischemia-reperfusion injury of renal allograft by microdialysis. DESIGN: A pilot, single-center; prospective study. PATIENTS AND METHODS: The study included 7 patients (4 males and 3 females, average age was 46.71 +/- 6.53 years) after cadaveric kidney allograft transplantation (CKA) under general combined anaesthesia. CONCLUSIONS: Microdialysis provides an opportunity of continuous monitoring of metabolic changes in the tissue of transplanted kidney. The main advantage of the monitoring by microdialysis is an opportunity of early identifying of ischemia-reperfusion complications. Thus, early assessment of CKA by microdialysis can be for the improving of patient's treatment in the early post operative period. Further clinical studies must be done to define the role of microdialysis. PMID- 26027232 TI - [Intensive therapy of ovarian hyperstimulation syndrome (clinical guidelines)]. PMID- 26027233 TI - [Protracted pneumonia]. AB - The paper discusses the current characteristics of the etiology and clinical presentation of protracted pneumonia (PP), gives approaches to its differential diagnosis in detail, and considers risk factors for PP and approaches to treating patients with this pathology. PMID- 26027234 TI - [Clinical and laboratory parameters in assessing the risk of exacerbations in chronic obstructive pulmonary disease]. AB - AIM: To estimate the significance of measuring the concentrations of cytokines and immunoglobulins and the relative counts of lymphocyte subpopulations in peripheral blood, as well as clinical parameters in patients with chronic obstructive pulmonary disease (COPD) in order to assess the risk of exacerbations. SUBJECTS AND METHODS: Thirty-seven patients with COPD were examined. A study group consisted of 31 patients. Patients with rare exacerbations were assigned to those who had no or one case; patients with frequent exacerbations were those who had two or more cases a year after examination. A prognostic model was created using the binary logistic regression analysis. RESULTS: A significant statistical model was developed as a regression equation involving 4 indicators (vascular endothelial growth factor, C-reactive protein, CAT scores, and number of exacerbations in the previous year). This mathematical model can predict frequent exacerbations in next year with a sensitivity of 94.1% and a specificity of 80%. CONCLUSION: The mathematical model created to estimate the risk of frequent exacerbations may be used to elaborate adequate individual treatment regimens for both smoking and non-smoking patients with COPD. PMID- 26027235 TI - [New ideas on the therapeutic effect of a combination of vaccines against pneumococcal, Haemophilus influenzae type b infection, and influenza in patients with chronic obstructive pulmonary disease]. AB - AIM: To estimate the indicators of the therapeutic effect of combination vaccination against pneumococcal, Haemophilus influenzae type b infection, and influenza in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Clinical, bacteriological, and immunological studies, by determining the quality of life (QL), were conducted in COPD patients during a year after combination vaccination against pneumococcal, Haemophilus influenza type b infection, and influenza. RESULTS: One year after the vaccination, there were reductions in the number of COPD exacerbations by 3.7 times, in that of antibiotic therapy cycles by 3.4 times, in the levels of inflammatory mediators of interleukins 2 and 8 and interferon-gamma, and in the synthesis of IgG antibodies to Streptococcus pneumoniae, Haemophilus influenzae type b, and influenza virus strains as compared to the baseline values. CONCLUSION: Combination vaccination against bacterial and viral infections substantially improves the major clinical parameters of COPD, positively affecting LQ indicators that generally characterize the therapeutic effect of immunization. PMID- 26027236 TI - [The concept of risk factors in assessing the impact of smoking on an exacerbation of chronic obstructive pulmonary disease]. AB - AIM: By using the risk concept, to determine a quantitative relationship between smoking in patients with chronic obstructive pulmonary disease (COPD) and the development of an exacerbation. SUBJECTS AND METHODS: Case history data were studied in 166 patients admitted for a COPD exacerbation in 2009 to 2012. There were 2 exacerbations for a year or longer. The patients were divided into 2 groups: smokers (n=110) and nonsmokers (n=56). The concept for estimating the risks was based on the calculation of absolute risk in the exposed and unexposed groups, attributable risk, relative risk, and population attributable risk and on the determination of standard errors for each type of risk and confidence interval. RESULTS: The methodological aspects of determining the quantitative relationship between smoking in patients with COPD and the development of its exacerbations (twice or more per year) were considered on the basis of the statistical concept of risk factors. A risk factor concept-based analysis has shown that the impact of smoking is directly related to the worsening of COPD. The frequency of exacerbations is 71.8% in the group of smoking patients and 32.1 % in that of nonsmoking patients; the risk factor increases the likelihood of this event by 39.7%. CONCLUSION: Smoking leads to a 2.2-fold increase in the frequency of COPD exacerbations. The potential hazard index was 2.5. PMID- 26027237 TI - [Impact of tobacco smoking on the clinical and functional indicators and markers of systemic inflammation in patients with severe asthma]. AB - AIM: To study cytokine status and to reveal a possible relationship of clinical and functional indicators and systemic inflammation in patients with severe asthma to tobacco smoking. Subjects and methods. Examinations were made in 139 patients with severe asthma during its exacerbation and without the latter after 12 months. Groups 1 and 2 included 98 nonsmoking and 41 smoking patients with severe asthma, respectively. A control group consisted of 40 apparently healthy volunteers. External respiratory function, plasma TNF-alpha, IFN-gamma, IL-2, IL 4, IL-6, IL-8, IL-10, C-reactive protein, and neutrophil elastase levels, and integral cytokine index were studied. RESULTS: Systemic inflammation that was more marked on a disease exacerbation and mediated by elevated TNF-alpha, IL-2, and C-reactive protein levels was detected in severe asthma in both groups. The smoking patient group showed a statistically significant increase in IL-8 and neutrophil elastase levels, which may be indirectly indicative of the active participation of neutrophils in the development of chronic persistent inflammation. CONCLUSION: Tobacco smoking is a clinically significant risk factor that aggravates both the course of asthma and the magnitude of inflammation during a disease exacerbation. PMID- 26027238 TI - [An immune response and an alveolar macrophage phenotype in asthma, gastroesophageal reflux disease and their concurrence]. AB - AIM: To test the hypothesis that an impaired pulmonary immune response in asthma, gastroesophageal reflux disease (GERD) and their concurrence of these diseases is largely determined by disordered alveolar macrophage (AM) reprogramming and to assess the pulmonary immune response and an AM phenotype in patients with asthma, GERD and their concurrence. SUBJECTS AND METHODS: The levels of proinflammatory M1 cytokines, such as IL-1beta, IL-8, IL-12p70, IFN-gamma, TNF-alpha, and TNF beta, anti-inflammatory M2 cytokines, such as IL-4, IL-5, and IL-10, and bivalent M1/M2 cytokines, such as IL-2 and IL-6, were determined in bronchoalveolar lavage fluid (BALF) and AM culture medium. RESULTS: Serious deformations in the pulmonary immune response were first detected in patients with mixed pathology towards to an anti-inflammatory M2 phenotype. The change in the pulmonary immune response phenotype in GERD towards Ml and in comorbidity towards M2 was coincident with that of the AM phenotype. In asthma, the change in the pulmonary immune response phenotype occurred towards to M2 and that in the intrinsic AM phenotype did towards M1. This phenotype is likely to form a proinflammatory component and to cause an asthma exacerbation. CONCLUSION: Analysis of the spectrum of cytokines in BALF and produced by macrophages in asthma, GERD and their concurrence validated the hypothesis that impaired pulmonary immune responses in these diseases are associated with disordered AM reprogramming. The findings also suggest that therapy for the inflammatory component in these diseases should be performed by taking into account the specificity of the cytokine structure of an immune response and the phenotypic heterogeneity of immune cells. PMID- 26027239 TI - [Clinical value of surfactant protein D as a biomarker of pulmonary fibrosis in patients with scleroderma systematica in relation to the presence of gastroesophageal reflux]. AB - AIM: To study the role of serum surfactant protein D (SP-D) as a biomarker of lung injury in scleroderma systematica (SDS) in relation to the presence of gastroesophageal reflux (GER). SUBJECTS AND METHODS: Fifty-six patients (mean age 46+/-14 years) with diffuse and circumscribed SDS were examined and underwent pulmonary functional tests, X-ray and, if lung injury was present, high resolution computed tomography of the lung, echocardiography, gastroduodenoscopy, and barium X-ray of the esophagus; an enzyme-linked immunosorbent assay was used to determine serum SP-D levels. RESULTS: SP-D concentrations significantly correlate with the presence of lung injury in SDS and are significantly higher in the presence of pulmonary fibrosis and the signs of frosted glass and honeycomb lung patterns. SP-D levels were higher in the patients with lung injury and SDS in the group of those with pulmonary fibrosis and GER than in the group of pulmonary fibrosis patients without the latter. CONCLUSION: Serum SP-D may be considered in a number of biomarkers for the severity of lung injury in SDS, including GER-associated lung injury. PMID- 26027240 TI - [X-ray, laboratory, and functional parallels in intrathoracic sarcoidosis]. AB - AIM: to compare respiratory function and laboratory data with the radiographic stages of intrathoracic sarcoidosis. SUBJECTS AND METHODS: Three hundred and eleven patients (70.4% for women and 29.6% for men; mean age, 44.7+/-0.6 years) with histologically verified sarcoidosis underwent X-ray computed tomography, spirography, estimation of carbon monoxide diffusing capacity (DLCO), oxygen saturation, blood count and serum total calcium blood test. The patients were assigned according to sarcoidosis stages as follows: 3.9% with stage 0; 16.4% with stage I; 65.3% with stage II; 13.2% with stage III; 1.3% with stage IV, and 12.9% with Lofgren's syndrome. Results. DLCo decreased together with an increasing sarcoidosis stage (<80% of the due X2=8.69 for DLCO; p=0.057); the difference was significant between stages I (84.2+/-2.8%) and III (76.1+/-2.9%, p=0.05). According to the radiographic changes, there were decreases in forced vital capacity (FVC) from 99.0+/-2.5% in stage I to 76.1+/-3.5% in Stage IV and in forced instantaneous expiratory flow rate at 75% of lung volume (FEF75) from 64.4+/-3.1 to 44.0+/-5.9%, respectively. DLCO correlated with FVC, peak expiratory flow, and FEF, (p<0.01) and arterial oxygen saturation (SaO2) did only with FVC. There was a strong association between the decrease in DLCO and FVC below 80% of the due values (X2=28.23; d.f.=1; p<0.001). L6fgren's syndrome failed to affect functional data. In the patients with Lofgren's syndrome, the serum level of calcium was significantly lower (2.09+/-0.10 versus 2.35+/-0.02 mmol/l(p=0.023); however, this indicator did not significantly differ between the radiological stages of intrathoracic sarcoidosis. CONCLUSION: In sarcoidosis, the changes in DLCO and FVC vary with radiological stages. Decreased SaG2 was observed in Stage IV. The total level of total blood calcium is an indicator independent of the radiological stages of sarcoidosis. PMID- 26027241 TI - [Pulmonary paecilomycosis: Diagnosis and treatment]. AB - AIM: To represent the advances of Russia and Uzbekistan in studying the problem of paecilomycosis. The goal of the investigation was to develop the diagnosis and treatment of pulmonary paecilomycosis (PP). SUBJECTS AND METHODS: Two hundred and twenty-five people, including 200 patients with bronchopulmonary infection with fungi of the Paecilomyces genus and 25 clinically healthy individuals (a control group), were examined. Clinico-anamnestic, laboratory diagnostic, mycological, and immunological studies were conducted; a lymphocyte antigen-binding test was used for differential diagnosis. Paecilomyces infection was diagnosed by microscopically examining the morphology of the fungi in the pathological material (blood, sputum) and by isolating the cultured fungi in the media (Sabouraud's and Czapek's ones). The severe complication of PP - atypical paecilomycosis-associated myocarditis (APAM) - was studied in 112 patients with helminthiasis-complicated paecilomycosis. These patients underwent using the conventional echocardiography. RESULTS: Bronchopulmonary paecilomycosis resulting from primary and secondary infection with fungi of the Paecilomyces genus was clinically manifested as chronic obstructive bronchitis (11.5%), recurrent pneumonia (13.5%), exogenous allergic alveolitis (37%), and asthma (26%) complicated by helminthiasis (12%). Iodine deficiency promotes the prevalence of paecilomycosis and echinococcosis favors Paecilomycosis infection; moreover, the helminth capsule itself serves as a nutrient medium for the development of the mycelial form of the fungus. APAM is a severe complication of PP. Almost 50% of the patients with PP presented with carditis. The patients with APAM occasionally experienced fear and the most severe intermittent pain. The latter first occurred in the chest.and irradiated to the axilla, left hand, and its fingertips, paralyzing the arm. In some patients, the pain manifested itself in both arms with abdominal irradiation, by being accompanied by faints. Current analgesics (meloxicam, tizanidine, nimesulide, morphine, promedole) in combination with fluconazole provided a temporary positive effect. CONCLUSION: Further investigations that must also include neurologists and anesthetists are required to work out effective pain relief regimens for APAM in patients with PP. PMID- 26027242 TI - [Positive effect of low-activity thromboxane A synthase gene on prognosis in coronary heart disease]. AB - AIM: To analyze the influence of pharmacogenetic factors on the risk of clopidogrel resistance and cardiovascular events during 18-months follow-up. SUBJECTS AND METHODS: Two hundred and fifty patients taking clopidogrel were examined. Platelet function was determined by optical aggregometry. Thromboxane A synthase 1 (TBS1) gene polymorphism was investigated in all the patients. The impact of TBS1 gene polymorphism on the risk of clopidogrel resistance and cardiovascular events was analyzed during 18 months of follow-up. RESULTS: The carriage of TBS1 gene polymorphism AA was shown to affect the risk of clopidogrel resistance. Cardiovascular complications significantly less frequently occurred in TBSI gene polymorphism AA carriers during 18 months. CONCLUSION: The carriage of a slow AA allele of the'TBS1 gene is suggested to be a clinically significant protective factor in the secondary prevention of coronary heart disease PMID- 26027243 TI - [Optimization of treatment in hypertensive patients in real clinical practice: Role of a fixed-dose perindopril A and amlodipine combination (Results of the Russian observational CONSTANTA trial]. AB - AIM: To provide a detailed analysis of the efficacy and tolerability of Prestance (perindopril A/amlodipine) in a subgroup of 1936 people participating in the Russian observational CONSTANTA program, most cases of whom were given the drug as a substitute for earlier ineffective monotherapy and combination therapy, without using other antihyperterisive agents. SUBJECTS AND METHODS: The analysis included 1936 patients (aged 58.2+/-7.5 years; 35% men) with uncontrolled hypertension who received angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (AT II) receptor antagonists alone or in conjunction with free or fixed-dose combinations of two-three antihypertensive agents and who were given Prestance to correct antihypertensive therapy, as decided by their doctors. The goal blood pressure (BP) was <140/<90 mm Hg for all the patients. Their treatment lasted three months. RESULTS: At the end of trial, the patients received Prestance (perindopril A/amlodipine) in the following doses: 5/5 mg (15% of the patients), 10/5 mg (39.9%), 5/10 mg (9.8%), 10/10 mg (36.6%). In the analyzed group, the baseline BP was 163.4+/-13.7/94.6+10,1 mm Hg; heart rate (HR), 74.0+/ 10.9 beats/min; 3 months later, there were decreases in BP to 130.8+/-10.2/78.5+/ 7.2 mm Hg (as compared to the baseline values; p<0.001) and in HR to 67.9?5.4 beats/min (p<0.01). The mean BP reduction was 32.6+/-10.8/16.1+/-7.2 mm Hg. A total of 1607 (83.0%) patients achieved the goal BP while 1520 (78.5%) patients did this without having another antihypertensive therapy. CONCLUSION: To switch hypertensive patients receiving ineffective monotherapy or dual therapy using ACE inhibitors or AT II receptor blockers to fixed-dose perindopril A and amlodipine combination (Prestance) is a rational way of optimizing a therapy regimen in these patients with a wide range of baseline BP levels; moreover, four out of five patients did not need any additional antihypertensive drug. PMID- 26027244 TI - [Workplace stress and its impact on the 16-year risk of myocardial infarction and stroke in an open female population aged 25-64 years in Russia/Siberia (WHO MONICA-psychosocial program)]. AB - AIM: To determine the impact of workplace stress on the hazard ratio (HR) of myocardial infarction (M) and stroke in an open female population aged 25-64 years in Russia/Siberia (Novosibirsk) for 16 years. SUBJECTS AND METHODS: A random representative sample of 25-64-year-old women (n=870) residing in a Novosibirsk district was surveyed within the framework of the WHO <> program. Workplace stress was investigated using the Karasek scale; an attitude towards work and health prophylactic examinations was studied applying the Health Awareness and Attitude questionnaire of the WHO <> program. For 16 years (1994 to 2010), a cohort of all new cases of MI and stroke was examined employing the WHO <> program and all possible medical records. The Cox regression model was used to determine HR for MI and stroke in the open female population aged 25-64 years for 16 years. RESULTS: The prevalence of high-level stress in the open female population aged 25-64 years was 31.6%. The high level of job stress was associated with a high responsibility, impossibility to have a rest at the end of a working day, frequent professional dissatisfaction, and a reduced work capacity. During 16 years, the women having high-level job stress showed a 3.22- and 1.96-fold increases in the HR of MI (p<0.05) and stroke (p<0.05), respectively. The incidence of MI and stroke was higher in married women expressing job stress as managers or manual laborers and having high and low educational attainment. CONCLUSION: The prevalence of high-level workplace stress was substantial in the open population of 25-64-year-old women in Russia/Siberia (Novosibirsk). The stress-related HR of Ml and stroke was 3-2 times higher than in those without high-level stress. The HR of MI and stroke is affected by a social gradient. PMID- 26027245 TI - [Efficiency and safety of different etoricoxib regimens in patients with axial spondyloarthritis, including ankylosing spondylitis]. AB - AIM: To study the clinical and laboratory efficiency and safety of different etoricoxib (ET) regimens in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis. SUBJECTS AND METHODS: Forty patients with high axSpA activity (Bath Ankylosing Disease Activity Index (BASDAI 4) were examined and randomized to 2 groups: 1) 30 patients who received ET 90 mg continuously every day; 2) 10 patients who took the drug in the same dose intermittently 1-3 times weekly. The activity of axSpA (BASDAI, Ankylosing Spondylitis Disease Activity Score (ASDAS), erythrocyte sedimentation rate (ESR), and high sensitivity C-reactive protein (hs-CRP)) was evaluated at baseline, 2 and 12 weeks; adverse events were recorded at baseline, 2, 6, and 12 weeks. The number of patients who had achieved an ASAS40 response at 2 and 12 weeks were taken into consideration. RESULTS At 12 weeks, the continuous administration group displayed decreases in BASDAI from 8 to 4, in ASDAS from 3.8 to 2.6, and in hs-CRP levels from 9.5 to 3.9 mg/l; the intermittent administration group exhibited decreases in BASDAI from 7.6 to 6.0, in ASDAS from 3.5 to 3.1, and hs-CRP from 8.8 to 4.5 mg/l (p<0.05). At this time, an AS40 response was achieved by 22 (73.3%) and 2 (20%) patients in Groups 1 and 2, respectively (p<0.05 for all). No serious adverse events were recorded. CONCLUSION: The efficacy of ET given in a daily dose of 90 mg was much higher than that of the drug used thrice or less weekly in the patients with axSpA. PMID- 26027246 TI - [Familial partial lipodystrophy (Dunnigan syndrome) due to LMNA gene mutation: The first description of its clinical case in Russia]. AB - Hereditary lipodystrophies (HLD) are a heterogeneous group of rare diseases characterized by a complete or partial loss of subcutaneous fat and by the development of metabolic disturbances: diabetes mellitus with obvious insulin resistance and acanthosis nigricans, dyslipidemia, hepatic steatosis, hypertension, and polycystic ovary syndrome. The laminopathy variant familial partial lipodystrophy type 2 or Dunnigan syndrome (FPLD2) is the most common cause of partial LD. The paper describes a family (3 clinical cases) with FPLD2 caused by heterozygous R482W missense mutations in the gene encoding the protein lamin A/C (LMNA; 150330). This observation demonstrates that specialists should be more aware of this disease and make a timely diagnose in cases of concurrent severe metabolic disturbances at a young age, which contributes to more effective treatment of patients and to medical genetic counseling of their families. PMID- 26027247 TI - [Multicentric carpotarsal osteolysis in a rheumatologist's practice]. AB - Multicentric carpotarsal osteolysis (MCTO) syndrome is a rare skeletal dysplasia associated with missense mutation in the MAFB gene, usually manifesting in young childhood, and showing variative phenotypic signs and course. The clinical manifestations of the syndrome include aggressive osteolysis predominantly of carpal and tarsal bones, progressive nephropathy, and mild craniofacial anomalies. The similarity between the initial clinical manifestations of MCTO and the symptoms of childhood inflammatory joint diseases makes a diagnosis very difficult, in the early stages of the disease in particular, and frequently leads to the ungrounded use of long-term immunosuppressive therapy. The paper describes a familial case of MCTO without affecting the kidneys in the mother and daughter. PMID- 26027248 TI - [Choice of basic therapy for asthma in real clinical practice]. AB - According to the Global Initiative for Asthma, the treatment of asthma should be mainly based on its control that encompasses symptom control and exacerbation risk reduction. Control-based treatment contributes to decreases in the frequency of exacerbations, the incidence of drug side effects, the needs of asthmatic patients for emergency care, and the number of their visits to a doctor and hospitalizations, resulting in a reduction of direct health care costs of asthma. Drugs for the basic therapy of asthma are chosen on the basis of evidence for their efficacy and safety and the view of availability and cost of treatment. In case of poor asthma control it is important to reveal its causes and to change basic therapy according to the individual needs of the patient. A major role in the achievement of asthma control is assigned to a combination of inhaled glucocorticosteroids (ICS) and long-acting beta2-agonists. Combined medications are prescribed to asthma patients in accordance with the daily ICS dose required to achieve asthma control. PMID- 26027249 TI - [Impact of respiratory viruses on the course of chronic obstructive pulmonary disease: towards optimizing treatment]. AB - The paper analyzes the currently available data on the impact of respiratory viruses (RVs) on the exacerbations and clinical phenotype of chronic obstructive pulmonary disease (COPD), as well as on the molecular mechanisms of this impact. It emphasizes the role of acute respiratory viral infections (ARVI), primarily rhinovirus infections (RVI) as the most important triggers of COPD exacerbations and the causes of their severe and long-term course. Particular attention is given to ARVI-induced secondary bacterial infections that worsen COPD exacerbations. The mechanisms of how RVs potentiate chronic inflammation and remodeling of the airway, which are caused by tobacco smoke, are depicted. There are arguments that there is a much greater correlation of the acute episodes showing the more severe respiratory symptoms of COPD with ARVI than can be found by molecular methods for RV verification. The body's genetic and/or acquired excessive response to viral invasion does not reflect the efficacy of antiviral defense and is an endogenous damaging factor in this situation. The role of RVs in the formation of the clinical phenotypes of COPD with frequent exacerbations remains debatable. The need for a search and more active practical introduction of means to prevent virus-induced COPD exacerbations appears obvious. In this regard, the authors identify chemical and mechanical polyvalent bacterial lysates for oral and sublingual administration. In addition to nonspecific stimulation of antiviral defense, these medicines induce antigen-specific mucosal and systemic reactions against bacterial pathogens. The role of ARVI pathogens in COPD exacerbations deserves a greater practical attention focused towards optimizing the treatment of this social disease. PMID- 26027250 TI - [Alexander Grigorievich Chuchalin (on the occasion of the 75th anniversary of his birth]. PMID- 26027251 TI - [The inversion of concepts about biological role of system rennin-angiotensin II- aldosterone and functions of arterial tension as a metabolism regulator]. AB - The phylogenetic theory of general pathology postulates that in physiology and pathology the concepts of biological role of arterial tension had been subjected to inversion. The activation by nephron of synthesis of components rennin angiotensin II and increasing of aldosterone secretion are directed not to increase arterial tension but to preserve volume of piece of third world ocean privatized by each entity as pool of intercellular medium where all cells continue to live as billions years before. In phylogenetic sense, early organs can't regulate effect of physical factor of regulation of metabolism the late one in phylogenesis of arterial tension. The cause of increasing of arterial tension is the vasomotor center but not the kidneys. The vasomotor center increases arterial tension in the proximal section and further hydrodynamic tension in the distal section of arterial stream and tends to resuscitate function of nephrons, biological function of endoecology and biological reaction of excretion. The arterial tension, besides the main role in biological function of locomotion, is a physical factor of compensation of disorders of biological functions of homeostasis, trophology, endoecology and adaptation. In phylogenesis, three levels of metabolism regulation has been developed The specific regulation of biochemical reactions occurs on autocrine level. In paracrin regulated cell cenosises, at distal section of arterial stream, metabolism is regulated by billions of local peristaltic pumps through compensation of biological reaction of endothelium-depended vasodilatation, micro-circulation, effect of humoral mediators and hormonal principles. In vivo, from the level of vasomotor center, metabolism non-specifically and systemic regulates physical factor-arterial tension through sympathetic activation of heart. The arterial tension in proximal section of arterial stream overcomes resistance and physically "forces through" arterioles with disordered micro-circulation. The angiotensin II is a vasoconstrictor only in distal section of arterial stream. In the process of pathogenesis of essential metabolic arterial hypertension the paracrin cenosises of nephron and kidneys are secondary involved into realization of pathological compensation and very often are "guilty without guilt" as such another "target organs" as brain, lungs and heart as well. PMID- 26027252 TI - [The C3-aldehydes and disorder of cellular metabolism: possible modes of normalization of carbohydrate metabolism]. AB - The control of cellular metabolism is present in many organs and tissues and its loss means development of hypo- and hyperglycemia. The high level of glucose results in glycation of proteins and increase of concentration of ketoaldehyde and methyl glyoxal in cells. The increase of level of this ketoaldehyde and D lactate in organs and tissues also can be a result offormation of methyl glyoxal in particular enzymatic reactions including decomposition of one of substrates of glycolysis and conversion of aminoacetone catalyzed by semicarbazide-sensitive amine oxydase of endothelium cells. The methyl glyoxal attacks arginine residuals of proteins. This aldehyde is related to interruption in transmission of insulin signal, disorder of pro-antioxidant balance, inhibition of enzymes of glycolysis, etc. The model of cellular metabolism is proposed where methyl glyoxal plays a key role in development of resistance to insulin, hyperglycemia, hypokalemia and hypertension. The modes of increase of consumption of glucose in conditions of low activity of protein tyrosine kinase are considered. The possible involvement of tokopherol (its derivatives) in activation ofphosphodiesterase in liver and regulation of carbohydrate metabolism is considered too. The role of tokopherol carrier proteins and effect of tokopherol on functioning of OI-cells is discussed. It is still unclear if there is a direct relationship between low level of tokopherol-carrier proteins and diabetes or hypertension. Howeve, low level of tokopherol-carrier proteins results in "prolonged oxidative stress". PMID- 26027253 TI - [The dynamics of hormonal indicators in women of Arkhangelsk under stimulation of corticotropine]. AB - The test with pharmaceutical "Synachten Depot", a synthetic analogue of corticotropine was carried out. The sampling consisted of 30 clinically healthy women aged from 20 to 30 years and residents of Arkhangelsk. The scheme of blood sampling provided basal sample, 30 and 60 minutes, I and 4 days after administration of pharmaceutical. After 30 minutes of testing, increase of level of cortisol (F), progesterone (Delta4 = p), testosterone, triiodothyronine (T3) and decreasing of level of insulin and follitropin were established After 60 minutes of testing maximal level of cortisol, high concentration of progesterone and triiodothyronine, increasing of levels of testosterone, estradiol and insulin and decrease of concentration of thyrotropin and prolactin were observed. Up to the first day, the tests registered decrease of level of cortisol, progesterone, testosterone, thyrotropin, thyroxine and triiodothyronine under increasing of content of follitropin, estradiol and insulin in comparison with basal test. Up to the fourth day, tendency of increasing of the level of progesterone and estradiol and decreasing of lutropin and testosterone as compared with initial levels were observed. PMID- 26027254 TI - [The dynamics of indicators of selenium, glutathione and anti-oxidant defense of blood in patients with anemic cardiomyopathy against the background of treatment with preparations of iron and selenium]. AB - The study was carried out on samplings of 46 patients with asiderotic anemia of severe degree and complicated by cardiomyopathy and 16 healthy persons. The content of selenium was analyzed using I.I. Nazarenko technique of detection of mass concentration GOST 19413-89. The content of glutathione in blood was detected using the technique based on capacity of acid-soluble thiol aggregations at interaction with 5,5-dithio-bis(2-nitrobenzene) acid to form a colored compound--thio-2-nitrobenzene acid. The principle of technique of measurement of activity of glutathione peroxidase of blood ervthrocvtes is in capacity of peroxide hydrogen to form a resistant colored complex with molybdenum salts. The technique of detection of activity of glutathione peroxidase is based on its capacity to catalyze reaction of interaction of reduced glutathione with tretbutyl hydro peroxide and on capacity of glutathione reductase to catalyze NADFN-dependent reduction of oxidated glutathione. The principle of technique of detection of activity of superoxiddismutase is based on capacity of enzyme to suppress reaction of reduction of nitro blue tetrazolium with superoxide anion radical generated in vitro in the system xanthine-xanthineoxidase. The study established decreasing of content of selenium in blood of patients with anemic cardiomyopathy up to 1.8 times as compared with control group. The content of total glutathione in blood of patients was decreased up to 17.7% at the expense of decreasing of level of reduced glutathione up to 18.5%. The study established decreasing of activity of catalase in erythrocytes up to 1.3 times, glutathione peroxidase up to 2.5 times, glutathione reductase up to 2.1 times and superoxiddismutase up to 1.5 times as compared with control group. After the preparations of iron and selenium ware applied to patients with anemic cardiomyopathy the increase of level of selenium in blood up to 80.4% was established. The level of total glutathione increased up to 54.5% at the expense of increase of content of reduced glutathione up to 59.5%. The activity of blood erythrocytes in patients against the background of treatment increased up to 9.1%, the activity of glutathione peroxidase, glutathione reductase and superoxiddismutase of blood erythrocytes increased up to 3, 2.1 and 2 times respectively. PMID- 26027255 TI - [The hypoxic syndrome in children with cardiomyopathy]. AB - The children with inherited cardiopathy including hypersensitive (n = 85) and dilatation (n=10) cardiopathy as well as cardiopathy under Ehlers-Danlos Syndrome (n = 70) combined with different inherited heart disease were examined to establish signs of hematic and tissue hypoxia. The most typical signs turned out periodic decrease of blood pCO2 with increasing of content of lactate and pyruvate in blood and saliva, multiple caries of teeth and high rate of systemic hypoplasia of enamel of both temporary and permanent teeth. The study established decrease in blood of level of macro-ergic compounds (ATP, ADF AMP) with increasing of excretion calcium and phosphates with urine. The increase of rate of mutations of hypoxanthine guanine phosphoribosyltransferase in lymphocytes with increasing of content of uric acid in blood and/or in urine was detected. The study revealed increasing of processes of peroxide oxidation, alterations of morphology of cells of skeletal muscles (RRF) and accumulation ofcalcium, lipids and alteration of structure of mitochondria. PMID- 26027256 TI - [The characteristics of anemic syndrome in patients with prevalent phases of Hodgkin lymphoma before treatment]. AB - The study was carried out to analyze peripheral blood covering 23 patients with prevalent phases of Hodgkin lymphoma received no treatment previously. The clinical analysis of blood was implemented using hematologic analyzer Sysmex XE 2100. The content of ferritin, soluble receptors of transferrin and erythropoietin was estimated using enzyme-linked immunosorbent assay. The free hemoglobin was estimated using hemoglobin cyanide method. The direct Coombs test, counting of leukogram and analysis of morphology of erythrocytes were applied to all patients. The anemia is diagnosed in 19 patients (83%). In 18 out of them the anemic syndrome corresponded to anemia of chronic disease and in one patient asiderotic anemia was established. The rest of patients had no anemia. The anemia of chronic diseases characterized by microcytosis and hypochromia of erythrocytes, inadequate degree of anemia by production of erythropoietin and functional deficiency of iron in most of the patients. It should be emphasized that anemia of chronic diseases commonly is normocyte normochrome anemia whereas in patients with prevalent phases of Hodgkin Iymphoma the microcyte hypochrome anemia was detected before the treatment and it was followed by functional deficiency of iron. In patients without anemic syndrome microcytosis and hypochromia of erythrocytes were marked too. The techniques of laboratory diagnostic objectively reflecting iron metabolism (evaluation of level of soluble receptors of transferrin andferritin) and appropriate hormonal response to degree of anemia (production of erythropoietin) are to be included into algorithm of treatment of patients. The purpose is to timely detect type of anemia with the purpose of its appropriate correction prior to treatment onset. PMID- 26027257 TI - [The enzyme activity of neutrophils of blood in patients with chronic viral hepatitis C depending on gender characteristics]. AB - The study was carried out to analyze dynamics of diaphorase and esterase activity ofneutrophils of blood in patients with chronic viral hepatitis C of lower degree of activity depending on gender characteristics in dynamics of treatment. The examination and treatment were organized concerning sampling of 113 patients with chronic viral hepatitis C of lower degree of activity. The diaphorase and esterase activity of neutrophils in dynamics of treatment was detected The analysis of diaphorases was carried out according R.P. Nartsissov technique. The content of esterase was estimated by V.M. Wachstein-FG. Wolf technique. The count of results was implemented using Kaplow semiquantitative technique. In patients with chronic viral hepatitis C of lower degree of activity prior to treatment the activity of NAD-diaphorase was lowered both in males and females. The activity of NADF-diaphorase prior to treatment significantly exceeded standard in males and matched standard in females. The application of basic therapy resulted in qualitative redistribution of cellular composition of reacting cells. All of them reacted following medium degree of activity (b). At that, average cytochemical indicator of reaction was normal in males and in females increasing of activity was observed. The activity og both diaphorases after application of complex therapy (basic therapy and cycloferon) totally returned to normality both in males and females. The esterase activity prior to treatment was decreased in males and increased in females (alpha-naphthylacetate esterase) and vice versa (alpha-naphthylbutyrate esterase) was increased in males and decreased infemales. After application of basic therapy in males increasing of esterase activity was registered and total redistribution of qualitative composition of reacting neutrophils (from degree "a" to degree "b"). In females after treatment the activity of alpha-naphthylacetate esterase was decreased and alpha naphthylbutyrate esterase was increased. The redistribution of qualitative composition of cells was absent. The application of cycloferon brings to normality the activity of alpha-naphthylbutyrate esterase in males and activity of diaforaselpha- naphthylacetate esterase in females. In patients with chronic viral hepatitis C of lower degree of activity the differences in diaphorase and esterase activity ofneutrophils depending on gender characteristics in dynamics of treatment are observed. PMID- 26027258 TI - [The study of mechanisms of accumulation of daunorubicin and rodamin-123 in cells of human venous blood using cytometry technique]. AB - The article presents comparative data of cytometry estimation of accumulation of daunorubicin and rodamin-123 in cells of peripheralbloodofhealthypeople underincubation ofsubstances in vitro. It is demonstrated that maximal saturation of thrombocytes occurs during the first five minutes, of leukocytes during forty five minutes. The erythrocytes factually never accumulate these compounds. The maximal values of accumulation of substances in leukocytes are characterized by high inter-individual variation. The close correlation (Rs = 0.96-0.98) of parameters of accumulation of substances in lymphocytes and neutrophils testifies the presence ofsimilar mechanisms ofcontrol ofactivity transportation ofxenobiotics in nucleated cells of blood. However, the results of inhibitor analysis of input of Pgp-dependent mechanisms of accumulation of rodamin-123 by leukocytes differ the data received under application of daunorubicin that reflects differences of their intracellular binding sites. The expressed differences between parameters of accumulation ofdaunorubicin and rodamin-123 by leukocytes in various patients determine necessity of individual approach in monitoring of development of medicinal resistance. PMID- 26027259 TI - [The application of hemoreologic indicators in prognosis of complications of acute myocardium infarction]. AB - The sampling of 60 patients with acute myocardium infarction underwent a complex study of hemoreologic indicators with purpose to establish predictors of development of early complications of diseases to substantiate additions to algorithm of examination and to differentiate treatment regimens. It is established that under acute myocardium infarction the blood viscosity increases on low velocity of shifting and plasma. Also, the process of aggregation of erythrocytes increases and number of normocytes decreases without significant alterations of blood viscosity on high velocity of shift and capacity of erythrocytes to be distorted. At the same time, the mentioned above alterations in patients with acute myocardium infarction does not result in decreasing of effectiveness oftransportation of oxygen to tissues. Against the background of development the hemoreologic disorders have more apparent character and result in progressive decreasing of tissue perfusion. The most significant prognostic indicator concerning complications of acute myocardium infarction is a time parameter of increment of aggregation of erythrocytes surpassing 2.80 in 89% of patients with complications. The expedience of inclusion of detection of reologic blood indicators fir their subsequent correction in the complex of examination ofpatients with acute myocardium infarction. PMID- 26027260 TI - [The clinical informativeness of detection of antibodies to citrullinated proteins under rheumatoid arthritis]. AB - The main diagnostic laboratory markers of rheumatoid arthritis are IgM rheumatoid factor and antibodies to citrullinated proteins. The IgM rheumatoid factor is a sensitive but insufficiently specific marker of rheumatoid arthritis. The antibodies to citrullinated proteins have a higher specificity for diagnostic of rheumatoid arthritis. The antibodies to cyclic citrullinated peptide and modified citrullinated vimentin are the main representatives of family of antibodies to citrullinated proteins applying in clinical diagnostic practice. The study was carried out to deternine the role of antibodies to citrullinated proteins and modified citrullinated vimentin in diagnostic, evaluation of activity and severity of destructive alterations under rheumatoid arthritis. The samplings of 993 patients with reliable diagnosis of rheumatoid arthritis. 179 patients with other rheumatoid diseases and 30 healthy donors were examined. The measurement of serum concentration of IgM rheumatoid factor and C-reactive protein was implemented by immune nephelometric analysis and antibodies to citrullinated proteins were analyzed by enzymoimmunoassay The erythrocyte sedimentation rate was established using the Westergreen technique. It was established that antibodies to modified citrullinated vimentin had the highest diagnostic specificity (83%), antibodies to cyclic citrullinated peptide had the highest diagnostic specificity (87%). The diagnostic specificity of joint detection of IgM rheumatoid factor, antibodies to citrullinated proteins and antibodies to modified citrullinated vimentin made up to 87%. In patients negative to rheumatoid factor the rate ofdetection of antibodies to citrullinated proteins made up to 34% and antibodies to modified citrullinated vimentin made up to 48%. The diagnostic effectiveness of detection of antibodies to citrullinitted proteins (ratio of likelihood of positive and negative results of test was correspondingly 5.5 and 0.3; area under ROC curve 0.8) and antibodies to modified citrullinated vimentin (ratio of likelihood of positive and negative results of test was correspondingly 4.4 and 0.2; area under ROC curve 0.9) surpassed the same in analysis of IgM rheumatoid factor (ratio of likelihood of positive results--3.2, ratio of likelihood of negative results--0.4, area under ROC curve- 0.8). The weak positive correlation relationship was established between concentration of antibodies to cyclic citrillinatedpeptide/antibodies to modified citrullinated vimentin in blood serum and indicators of clinical laboratory activity of rheumatoid arthritis (ESR, CRP DAS 28, (r-0.2. p < 0.05). The high positive levels of antibodies to modified citrullinated vimentin associated with expressed destructive affection of joints (p < 0.02). The antibodies to cyclic citrullinated peptide are the most highly specific and clinically informative laboratory diagnostic marker of rheumatoid arthritis. The detection of antibodies to modified citrullinated vimentin is an important additional serological test to diagnose rheumatoid arthritis in IgM rheumatoid factor-negative and/or antibodies to cyclic citrullinated peptide-negative patients and to forecast severe destructive affection of joints under the given disease. The joint study of IgM rheumatoid factor, antibodies to cyclic citrullinated peptide and antibodies to modified citrullinated vimentin under rheumatoid arthritis has higher diagnostic sensitivity as compared with isolated antibodies to citrullinated proteins. PMID- 26027261 TI - [The development of biochip to detect anti-cholera antibodies in human blood serum]. AB - The full-scaled agglutinating immunoassay is commonly applied to detect content of antibodies to cholera agent Vibrio cholerae human in blood serum under application of serological diagnostic. The time of analysis implementation amounts to 18 hours. To shorten time of detection of antibodies a biological microchip (biochip) was developed. The biochip represents an activated slide with immobilized corpuscle and soluble antigen cholera agent (O-antigens, cholera toxin). The experimental work resulted in development of scheme of biochip and selection of optimal conditions of sorption and implementation of immunologic analysis using biochip. The application of biochip facilitated to detect specific antibodies to antigens of cholera agent in commercial experimental animal serums and blood serums of ill patients. The time of analysis implementation amounted to 2-3 hours. The results are substantiated by bacteriological and serological methods. PMID- 26027262 TI - [The characteristics of probiotic properties of strains of genus of bifidobacterium separated from gastrointestinal tract of residents of the central region of Russia]. AB - The 156 samples of feces separated from healthy residents of the Central region of Russia were used to compose collection of 87 strains of Bifidobacterium out of which 5 strains with wide antagonistic activity related to pathogenic and opportunistic microorganisms were selected. The selected strains are characterized by high probiotic potentials. They have adhesive properties and sensitivity to antibiotics and preparations corresponding to main requirements of common pharmacopoeia articles to strains of microorganisms used in production of probiotics for medicinal application. The given strains of Bifidobacterium can be recommended for development of effective probiotic pharmaceuticals directed to residents of the Central region of Russia. PMID- 26027263 TI - [The experience of application of test system "TB-Biochip" in the Tambov oblast]. AB - The analysis was implemented concerning application of biological chips technique developed by the V A. Engelgardt institute of molecular biology--"TB-Biochip" designed for detecting DNA agent of tuberculosis in diagnostic samples of human respiratory organs and establishing its medicinal sensitivity to rifampicin and isoniazid. It is demonstrated that "TB-Biochip" is a sensitive and highly specific method of detecting medicinal sensitivity to main anti-tuberculosis pharmaceuticals. At that, analysis time amount to less than 72 hours. The comparative analysis was carried out concerning results of detection of medicinal sensitivity of mycobacteria by two express techniques--TB-Biochip (Biochip-IMB) and BACTECTM MGITTM 960 ("Becton Dickonson"). The data obtained by two techniques matched in 97.6%for rifampicin and in 92.1% for isoniazid. PMID- 26027264 TI - [The structure of intestinal dysbioses in children of preschool age during long term period of monitoring]. AB - The study was organized to examine long-term (1990-2011) structure of intestinal dysbioses in children of preschool age residing in Irkutsk. The significant decrease of expression of micro-ecological shifts (IV and III degrees) to the end of period of monitoring and almost total lacking of cases of eubiosis and statistically reliable (p <= 0.05) increasing of rate of dysbioses of I and II degrees were established. The given circumstance can be related to ongoing on the territory ecological pressure on organism of negative factors of environment including factors of anthropogenic character. PMID- 26027265 TI - [The comparative analysis of various amyloid models]. AB - Considered natural and experimental amyloidosis models in the existing theories context and known amyloidogenesis mechanisms. Available clinical and experimental observations indicate that the opinion of a fatal incurable amyloidosis wrong. It is shown that there is a significant amount of experimental easily replicable amyloidosis models, which may be used for practicing the treatment methods of this pathology. We offer an amyloidosis models classification: natural (animal models with generic amyloidosis), cell clones, artificial (infectious, protein, etc.). Based on the analysis of amyloidosis existing models concluded--none of the accepted in the scientific the theories community for amyloid building does not combine or explains all known facts about the amyloidogenesis mechanisms. It is assumed that there is a proteins group, the beta-sheet structure, which are potentially capable of amyloid conformation building. It is assumed that beta sheets of these proteins have similar amino acid composition. The condition for the amyloid building conformation is getting too much protein in sufficient quantities in an uncharacteristic place where the ionic strength of the tissue fluid is such that it promotes the amyloid building conformation. It is assumed that an unfortunate amount of ionic strength environment amyloid protein is provided by polysaccharides, tubulins proteins and ionized silicon. PMID- 26027266 TI - [Glutathione-dependent enzymes and glutathione in infertility of men with different body mass]. AB - OBJECTIVE: Our aim was to investigate the glutathione-disulfide system of antioxidant defense in men with different body mass index and infertility. METHODS: 60 men with infertility were examined--30 with normal weight and 30 with overweight. 30fertile men were included in the control group. Hemolysate made from red blood cells was used as a materialfor study. The level of reduced (GSH) and oxidized glutathione (GSSG), and glutathione activity was determined by enzyme spectrofluorophotometer SHIMADZU-1501 (Japan). RESULTS: In infertile men with normal body weight decrease of GSH to 15.35% was combined with a decrease in the activity of enzymes--glutathione reductase (GR) to 53.41%, glutathione peroxidase (GPO) to 51.44%, and increased activity of glutathione-S-transferaze (GST) to 31.52% as compared with the controlgroup. In the group of infertile men with overweight a decrease in the activity of GR, 56.77% and 56.22% at the GPO on the background of a stable level of GST was detected in comparison with fertile men. The concentration of GSH in infertile group decreased by 20.08%, and the concentration of GSSG increased by 20.38%. CONCLUSION: It has been established that imbalance in the glutathione system is the most prominent feature in men with infertility and overweight as compared to infertile men with normal body weight. PMID- 26027267 TI - [Inflammation and brain aging]. AB - The review covers current concepts on cell and molecular mechanisms of neuroinflammation and aging with the special focus on the regulation of cytokine producing activity of astroglial cells and intercellular communication. The review reflects that a key component of the aging phenomenon as a result of ineffective implementation of anti-inflammatory response are processes of the dysregulated cytokine production, in particular, an increase in the secretion of proinflammatory cytokines and an imbalance in the expression of the receptors and receptor associated proteins. Interpretation of the molecular mechanisms of cell conjugating neuroinflammation and aging cells can give rise to new therapeutic strategies that are relevant to the treatment of a wide range of central nervous system diseases and the development of new experimental models of diseases of the central nervous system. PMID- 26027268 TI - [Roles of different macrophage phenotypes in the pathogenesis of some human diseases]. AB - Macrophages have recently been shown to play a key role in promoting of recovery after some diseases as well as in aggravation of inflammatory responses, all the functions being resulted from microenvironmental conditions and therefore phenotypes acquired by macrophages in these conditions. In this article some protective functions of macrophages during infectious and oncologic diseases as well as pathogenic roles in a number of inflammatory diseases are reviewed. Much attention is devoted to opportunities of macrophage reprogramming. PMID- 26027269 TI - [Obstructive sleep apnea syndrome in children as a risk of cardiovascular pathology development]. AB - OBJECTIVE: Our aim was to examine the predictors of cardiovascular disorders in children affected by obstructive sleep apnea syndrome (OSAS) based on the results of polysomnography and continuous monitoring of blood glycose. METHODS: Before the examination, parents filled in questionnaires concerning their children sleep quality. The procedure was followed by the study of the sleep by means of polysomnography (Embla s 7000, USA). A system of continuous monitoring of blood glucose was applied (Guardianreal-time, Medtronicminimed, USA) by means of which a glycemic profile tissue fluid was studied. RESULTS: A night sleep research of 120 children aged 3-16 y.o. is presented. There were 4 groups depending on the pathology: diseases of the nervous system (n = 31), ENT-pathology (n = 18), bronchial asthma (n = 24) and overweight and obesity (n = 34). The comparison group consisted of 13 apparently healthy children. The study has shown that the parents of every second child with sleep disorders did not know about the fact. The 60 % of the patients with high body mass index (BMI) had a snore, which was significantly higher the in children with normal body mass index--35% (p = 0.012). The index of apnea-hypopnea (AHI) was higher in the patients with ENT pathology 17 times (p < 0.001) and the patients with obesity 7 times (p < 0.001) in comparison to the comparison group. In the analysis of the overall sample (n = 120) was obtained significant negative correlation with heart rate variability and heart rate (r = 0.405; p < 0.001). It is also shown that among 14 investigated children with OSAS only 8 had episodes of hypoglycemia (less than 3.3 mmol/l) during night sleep. All of them were with a high body mass index and with above average stature (>1sd). CONCLUSION: Children with ENT-pathology and with high high body mass index have high risk of cardio-vascular diseases. Children with above average stature and with increased body mass index affected by OSAS have additional backgrounds for cardiovascular diseases develop- ment as a result of the latent periods of hypoglycemia at night. PMID- 26027270 TI - [Topical issues of food allergy diagnosis in pediatric practice]. AB - Food allergy (FA) in children, especially in infancy, is still a significant public health problem. The severity and prognosis of disease progression associated with FA considerably depends on the correct and early diagnostics of this pathology, as well as on the following management of a child. At the same time delayed elimination diet administration, unreasonable or overlong dietary intervention might have become abuse management of a patient and have a negative impact on the development of a child and reduce the quality of life. The article summarizes the current practical approaches to the diagnosis of FA based on evidence-based medicine and adopted European and Russian national consensus documents, as well as on our own experience of management of patients with this pathology. FA diagnosis in a child usually includes clinical laboratory tests and clarification of clinical and anamnestic data. Unfortunately, it is a fact that preference is given to laboratory methods for diagnosis based on specific IgE determination or skin samples. However, the basis for cause-significant allergen identifying is detecting detailed medical history and clinical picture of a disease which still appears to be the most reliable tool for FA diagnosis. PMID- 26027271 TI - [Rotavirus infection: epidemiology, pathology, vaccination]. AB - Diarrheal infections remain the major cause of morbidity and mortality among children under 5 years of age. The rotavirus holds the leading position among principal diarrheal pathogens that include also norovirus, enteropathogenic and enterotoxigenic Escherichia coli. Rotaviruses are transmitted by the fecal-oral route and are extremely contagious and stable in the environment. This facilitates viral transmission, particularly in daycare centers and hospitals. Rotavirus infection causes acute gastroenteritis with diarrhea and dehydration of various degrees resulting primarily from destruction of intestinal villus enterocytes with subsequent impairment of the ion transport and absorption. The incidence of rotavirus infection peaks during the winter and spring in countries with temperate climate. Many children have asymptomatic infection that supports rotavirus circulation in the popula- tion. Several vaccines have been developed for specific prophylaxis of rotavirus infections and demonstrated protection from severe acute rotavirus gastroenteritis and all-cause diarrheal mortality. PMID- 26027272 TI - [Surgical treatment of rare combination of intestinal malrotation with secondary lymphangiectasia]. AB - The rare combination of intestinal lymphangiectasia with malrotation of the duodenum in a child of three months of life is described. Basing on the literature review only 3 similar cases were described in the world practice. The boy with protein-losing enteropathy was examined at Moscow Scientific Centre of Children's Health. The child had vomiting, diarrhea, loss in body weight, hypoproteinemia, lymphopenia. The infectious nature of the disease was excluded. It had been suggested the Waldman desease (primary intestinal lymphangiectasia). The prognosis for such disease is unfavorable. An examination of the child was continued against the backdrop of ongoing symptomatic therapy. Complete physical examination included monitoring laboratory blood tests, X-ray examination with contrast, CT-scan, gastroduodenoscopy with biopsy of the mucosa of the small intestine. Malrotation duodenum with the recurrent mid-gut volvulus with the development of secondary intestinal lymphangiectasia was diagnosed. Modern methods of examination and multidisciplinary approach made it possible to diagnose the case. Operation to eliminate fixation duodenum resulted in the recovery of the patient. At the present time the child grows and develops according to age and does not require treatment. The prognosis for this disease is regarded as favorable. PMID- 26027273 TI - [Past and present of streptococcus pyogenes: some pathogenic factors and their genetic determination]. AB - In this review two aspects dealt with Streptococcus pyogenes--one of the leading agent responsible for infectious diseases and another related to their complications in humans worldwide--are given. In the first part of the review the comparative evaluation of laboratory diagnostic approaches and methods used in the second half of the twentieth century and molecular technologies developed during last twenty years are described. In the second part the role of the main microbial pathogenic factors as well as the data on intra- and interspecies genetic exchange with extrachromosomal genetic elements and their influence on biological properties of the pathogen are discussed. Essential for today possibilities for molecular epidemiology of streptococcal pathology approaches must be introduces in diagnostic laboratories within the country. PMID- 26027275 TI - [Risk management of a patient on the basis of remote health monitoring: current situation and prospects]. AB - Review is dedicated to the problem of remote monitoring of health status. Existing approaches to the organization of an outdoor monitoring of a patient using telemedicine technologies are reviewed and analyzed. A new approach to risk management of a patient which meets the requirements of pediatric hospital is provided. PMID- 26027274 TI - [Molecular-genetic characterization of shiga-toxin producing Escherichia coli isolated during a food-borne outbreak in St. Petersburg in 2013]. AB - Shiga toxin-producing Escherichia coli (STEC) food-borne infections are reported worldwide and represent a serious problem for public healthcare. In the Russian Federation there is little information on epidemiology and etiology of STEC infections as well as on molecular-genetic peculiarities of STEC pathogens. OBJECTIVE: Our aim was to describe a food-borne outbreak as hemorrhagic colitis (HC) along with hemolytic uremic syndrome (HUS), enterocolitis, and acute gastroenteritis in children in St. Petersburg in 2013. METHODS: Epidemiological, microbiological, molecular-genetic and bioinformatic methods were applied. RESULTS: Objects to study were clinical specimens, milk and food samples, as well as STEC strains isolated during the outbreak. The outbreak of food-borne infection was found to be caused by STEC-contaminated raw milk as confirmed by epidemiological analysis, detection of STEC DNA and isolation of relevant pathogens in milk and sick children fecal specimens. The whole-genome sequencing revealed two groups ofpathogens, E. coli O157:H7 and E. coli O101:H33 among collected strains. Group I strains were attributed to the previously known sequence type ST24, while group II strains belonged to the previously non described sequence type ST145. In strain genomes of both groups there were identified nucleotide sequences of VT2-like prophage carrying stx2c gene, plasmid enterohemolysin gene, and gene of the STEC main adhesion factor intimin. Gene of intimin gamma was identified in E. coli O157:H7 strains and intimin iota 2 in E. coli O101:H33 strains. The latter previously was identified only in enteropathogenic E. coli (EPEC) strains. CONCLUSION: The additional knowledge of epidemiology and biology of STEC pathogens would assist clinicians and epidemiologists in diagnosing, treating and preventing hemorrhagic colitis. PMID- 26027276 TI - [Diagnostic value of integral scoring systems in assessing the severity of acute pancreatitis and patient's condition]. AB - OBJECTIVE: The aim of the study was to evaluate the diagnostic value of specific and nonspecific scoring systems Tolstoy-Krasnogorov score, Ranson, BISAP, Glasgow, MODS 2, APACHE II and CTSI, which used at urgent pancreatology for estimation the severity of acute pancreatitis and status of patient. METHODS: 1550 case reports of patients which had inpatient surgical treatment at Road clinical hospital at the station Krasnoyarsk from 2009 till 2013 were analyzed. Diagnosis of severe acute pancreatitis and its complications were determined based on anamnestic data, physical exami- nation, clinical indexes, ultrasonic examination and computed tomography angiography. Specific and nonspecific scores (scoring system of estimation by Tolstoy-Krasnogorov, Ranson, Glasgow, BISAP, MODS 2, APACHE II, CTSI) were used for estimation the severity of acute pancreatitis and patient's general condition. Effectiveness of these scoring systems was determined based on some parameters: accuracy (Ac), sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Most valuables score for estimation of acute pancreatitis's severity is BISAP (Se--98.10%), for estimation of organ failure--MODS 2 (Sp- 100%, PPV--100%) and APACHE II (Sp--100%, PPV--100%), for detection of pancreatonecrosis sings--CTSI (Sp--100%, NPV--100%), for estimation of need for intensive care--MODS 2 (Sp--100%, PPV--100%, NPV--96.29%) and APACHE II (Sp- 100%, PPV--100%, NPV--97.21%), for prediction of lethality--MODS 2 (Se-- 100%, Sp -98.14%, NPV--100%) and APACHE II (Se--95.00%, NPV-.99.86%). CONCLUSION: Most effective scores for estimation of acute pancreatitis's severity are Score of estimation by Tolstoy-Krasnogorov, Ranson, Glasgow and BISAP Scoring systems MODS 2, APACHE I high specificity and positive predictive value allow using it at clinical practice. PMID- 26027277 TI - [Prostate cancer: papillomaviruses as a possible cause]. AB - Prostate cancer (PC) incidence and mortality are steadily increasing. Causation of PC is not clearly understood; in particular, role of human papillomaviruses (HPV) is still disputable. The review contains analysis of literature data on possible participation of HPV powerful biological carcinogens, in PC genesis. PC incidence increase in persons with immunodeficiency indicates involvement of some infectious agent in the disease etiology. Several research groups communicated HPV DNA finding including that of oncogenic types in PC specimens (transrectal biopsies). There are limited data on the occurrence of oncogenic HPV 16 oncoprotein E7 in such specimens and on its unfavorable effect on disease prognosis. The successful attempt is known to transfect normal human prostate cells with oncogenic HPVDNA in vitro. Epidemiological data on associations of PC with HPV are controversial. It may result from the considered in the present review certain technical peculiarities of these studies. Controlfor serum antibodies to HPV E6 and E7 oncoproteins recognized to indicate HPV-positive tumor growth in an organism has not been performed yet in PC patients. DNA of oncogenic HPV is rather commonly found in organs adjacent to prostate--urethra, rectum, urinary bladder. In the study held in Russia on a group of healthy men examined for sexually transmitted diseases genitourinary HPVinfection was found in every second person; 42% of them harbored oncogenic HPV. Possible participation of oncogenic HPV in PC genesis deserves close attention and further study. PMID- 26027278 TI - [Hypophysis-adrenal and thyroid secretion at law order staff depending on professional loading]. AB - BACKGROUND: A current etiological and pathogenic opinion about human health disturbance thereupon extreme factor effects is shown that this cause is principal mechanism of regulatory system (neuroimmunoendocrine complex) distress. In endocrine link occurs hormonal disbalance in hypothalamus-hypophysis axis, physiological interrelation disturbances in central-peripheral gland system (hypophysis-adrenal, hypophysis-thyroid) and metabolism abnormalities subsequently. OBJECTIVE: Our aim was to determine the particular content of adrenocorticotropic and thyrothrophin hormone, cortisol, thyroxin and triiodthyronine features at law order staff in dependence from professional loading. METHODS: It's provided two investigation series among law order staff groups--combatants, ordinary policemen and military school students. The investigation period for all people corresponds to combat mission beginning and its finish. In blood serum an adrenocorticotropic (ACTH) and thyrothrophin (TSH) hormone, cortisol, thyroxin (T) and triiodthyronine (T) levels were determined. RESULTS: A higher ACTH and TSH levels detected at combatants in both investigation series. A cortisol, T4 and T3 at combatants before military mission were least in comparative with other groups, but after mission it indexes were largest. CONCLUSION: Prolonged changes of endocrine secretory function that lead to hormonal disbalance can result to adaptation derangement. In connection with it in medical providing system for person that undergo extreme negative professional factors it's necessary create a special endocrine link with the view of organism resistance and life viability to extreme emergency factors and for prevention of pathological conditions. PMID- 26027279 TI - [Mechanisms of hypoxia development during pregnancy and the disorder of fetus blood supply at cytomegalovirus infection]. AB - OBJECTIVE: Our aim was to study the mechanisms of hypoxia development at pregnancy associated with cytomegalovirus infection (CMVI). METHODS: 30 parturient women with CMVI relapse at the 25-28 weeks of pregnancy and their newborns were examined. Cytochrome C, Hsp-70, p53, Bcl-2 and caspase-3 in placenta homogenate were found out with serologic methods, the morphology of erythrocytes with cytophotometry, erythrocytes membrane proteins with disc electrophoresis method, TBA-active products with V.B. Gavrilov's method, superoxide dismutase activity with spectrophotometry, 2.3-diphosphoglyceric acid (2.3 DPG) with I.S. Luganov's method, erythrocytes membrane microviscosity with fluorimethric method, oxyhemoglobin and methemoglobin with Evelyn and Malloy' method, and erythrocytes deformability with M. T. Lutsenko's method. RESULTS: In blood erythrocytes of CMV-seropositive parturient women there was the decrease of cytoskeleton proteins: alpha- and beta-spectrine was 1.14 times less, ankyrin was 1.62 times less, band 4. 1 protein was 1.29 times less; there was 1.87 times increase of antigen-binding glycophorin, 1.37 times growth of TBA-active products and 1.35 times drop of superoxide dismutase activity; the deformability index was 9.5 times less, 2.3 DPG was 1.22 times less and oxyhemoglobin was 1.06 times less. In placenta homogenate Bcl-2 was 1.5 times less, Hsp-70 was 2.5 times more, p53 was 6.1 times more, cytochrome C was 1.76 times more, caspase-3 was 3.86 times more. In umbilical cord blood erythrocytes 2.3 DPG was 1.3 times more and oxyhemoglobin was 1.06 times less. CONCLUSION: The obtained data proves that CMVI relapse at 25-28 weeks of pregnancy causes the disorder of morphofunctional state of mother's blood erythrocytes and their ability to oxygenation, the development offetoplacental barrier, the decrease offetus oxygen blood supply and the development of intrauterine hypoxia. PMID- 26027280 TI - [The influence of the thymus peptides on analgesia caused by acute and chronic immobilization]. AB - OBJECTIVE: Our aim was to investigate the influence of thymic polypeptides on pain sensitivity and to analyze a possible role of the opioid system in the implementation of the analgesia caused by immobilization stress. METHODS: The study was performed on male Wistar rats at the Moscow state University named after M. V. Lomonosov. We studied effects of thymus peptides: thymuline (0.15 mg/kg), fraction 5 thymosin (0.25 microgram/kg) and cattle thymus extracted product (CTEP) (0.5 mg/kg) on pain sensitivity in rats using test "tail flick" without stress, with acute (3 h) and sub acute (12 h) immobilization stress. The comparison groups were animals treated with saline and spleen polypeptides. RESULTS: It is shown that preparations of thymus increase the threshold of pain sensitivity in the intact animals. Immobilization stress duration 3 and 12 h in thymus peptides treated rats caused a less pronounced increase in pain threshold than in the control groups (immobilization stress 3 h: CTEP--p = 0.025, thymuline -p = 0.022, fraction 5 thymosin--p = 0.033; immobilization stress 12 h: CTEP--p = 0.034, thymuline--p = 0.027, fraction 5 thymosin--p = 0.036). The opioid receptor blocker naloxone (1 mg/kg) did not completely block the stress-induced analgesia, indicating the presence of both opioid and non -opioid components in this state. In thymus peptides treated rats, opioid component was less pronounced than in the control groups (CTEP--p = 0.031, thymuline--p = 0.026, fraction 5 thymosin--p = 0.029). CONCLUSION: Pre-activation of the opioid system by the thymus polypeptides leads to an increase in the share of non-opioid component of the stress-induced analgesia and prevents the depletion of the opioid system in immobilization stress. PMID- 26027282 TI - [Vadim Valentinovich Pokrovskii]. PMID- 26027281 TI - [Dynamics of pain tolerance thresholds and humoral immunity factors at dorsalgy]. AB - OBJECTIVE: Our aim was to study the possible markers of pain syndrome--indicators of pain sensitivity--pain pressure tolerance thresholds (PPTT), and immuno indicators--natural antibodies against pain processing mediators (eAb) for evaluation the possibility of its using for a objective pain assessment at chronic low back pain. METHODS: Pain sensitivity was assessed daily and nightly, by measuring the PPTT The natural antibody levels (eAb), were determined in serum by ELISA. Measurement of all parameters were performed at 1st, 10th and 21 days. RESULTS: 173 patients (93 women and 80 men) with chronic low back pain were included in the study. At 1st day most patients had lowered PPTT: 55% of men and 74% during the day, 72% of men and 89% of women at night. Dynamic study has shown a tendency of PPTT normalization in men. The study of diurnal PPTT variations have shown that night PPTT lower than day PPTT on 15-17%. We found gender PPTT differences: PPTT values in women 17-26% lower than in men. Analysis of individual eAb profiles has showed that elevated and high levels of eAb to beta endorphin, orphanin and histamine have 84%, 78%, 84% women and 82%, 85 and 95% men, respectively. These indicators higher than those for serotonin, dopamine and angiotensin (55%, 65%, 70% in women and 65%, 66%, 66% in men, respectively; p < 0.05). Dynamic study of eAb levels have shown a significant anti-histamine eAbs decrease (23%; p = 0.015) only. CONCLUSION: The pathological changes in pain sensitivity and levels of eAbs to pain-processing mediatos are evidenced. Further investigations are necessary to clarify to role of these variations in pain processing and for use these indicators for objective pain assessment. PMID- 26027283 TI - [Research and realization of signal processing algorithms based on FPGA in digital ophthalmic ultrasonography imaging]. AB - OBJECTIVE: To design and improve signal processing algorithms of ophthalmic ultrasonography based on FPGA. METHODS: Achieved three signal processing modules: full parallel distributed dynamic filter, digital quadrature demodulation, logarithmic compression, using Verilog HDL hardware language in Quartus II. RESULTS: Compared to the original system, the hardware cost is reduced, the whole image shows clearer and more information of the deep eyeball contained in the image, the depth of detection increases from 5 cm to 6 cm. CONCLUSION: The new algorithms meet the design requirements and achieve the system's optimization that they can effectively improve the image quality of existing equipment. PMID- 26027284 TI - [Study of motion artifacts correction algorithm in optical coherence tomography images]. AB - OBJECTIVE: Optical coherence tomography images may be distorted by motion artifacts in dynamic imaging, so it may lead to misdiagnosis in clinical diagnosis. Motion artifacts correction has become an urgent issue in optical coherence tomography imaging. METHODS: Firstly, using the improved complex nonlinear diffusion preprocessing filtering reduced the noise of the sequence images, then using the image mass center aligned the distortion data in the Y direction, finally, using the method of deviation average corrected motion artifacts along the Y direction. RESULTS: After correction, the motion artifacts in the longitudinal 2D images and the 3D image disappeared, the surface of the 2D and the 3D image became more smooth, the structure between layers of the images got clear and distinct, retinal en-face single slice image was sharp, and the fundus tissue structure could be observed. CONCLUSION: The algorithm of correction makes the physical structure of the retinal display truly after motion artifacts correction. PMID- 26027285 TI - [A method for bleeding detection in endoscopy images using SVM]. AB - Because the huge number of images of the digestive tract by Wireless Capsule Endoscopy (WCE) are left to the medical personnels detected by their eyes, huge burden leaves to doctors. This article provides a classification of method based on SVM (Support Vector Machine) for the capsule endoscopy bleeding intelligent recognition. We created a new kind of feature parameter, and the experiment result can reach 83% specificity and 94% sensitivity. PMID- 26027286 TI - [Simulation study on acoustic source reconstruction of magneto-acoustic tomography with magnetic induction (MAT-MI) based on transducer]. AB - OBJECTIVE: In order to accurately reconstruct the acoustic source image, the application of transducer's receiving characteristics in magneto-acoustic tomography with magnetic induction (MAT-MI) is studied. METHODS: The conductivity phantom model is built, and the magnetic acoustic signals are simulated and the acoustic sources are reconstructed according to the transducer's receiving characteristics. RESULTS: The reconstructed image of acoustic source is consistent with the topographic shape and size of the phantom model. CONCLUSION: MAT-MI based on the transducer's characteristics lays the foundation for further study. PMID- 26027287 TI - [Hemodynamic analysis of a centrifugal blood pump]. AB - This paper built the mathematical model of a centrifugal blood pump, which was designed by ourselves, combined it with that of the human cardiovascular system and simulated the coupling system using Matlab. Then we set up the experiment platform, linked the blood pump to mock human cardiovascular system in case of three-stage heart failure, and measured aortic pressure and flow under different speed. The comparison between experiment results and simulation results not only indicates the coupling model is correct and the blood pump works well, but also shows that with the increase of blood pump speed, the pulsation of aortic pressure and flow will be reduced, this situation will affect the structure and function of blood vessels. PMID- 26027288 TI - [Primary study of respiratory monitoring based on breath sounds]. AB - It is nonlinear relationship between breath sounds and respiratory flow rate, thus breath sounds might be a new solution for respiratory monitoring. The envelope of the breath sounds was created firstly. And the linear relationship between the logarithm of envelope and the respiratory flow rate was proved. Then model parameters were derived from every subject using regression analysis. Finally, using these parameters estimated respiratory flow rate was achieved by the logarithm of envelope with 14.9% error. Therefore, respiratory flow rate estimation and respiration monitoring based on breath sounds are feasible. PMID- 26027289 TI - [Web-based support system for medical device maintenance]. AB - A Web-based technology system was put forward aiming at the actual problems of the long maintenance cycle and the difficulties of the maintenance and repairing of medical equipments. Based on analysis of platform system structure and function, using the key technologies such as search engine, BBS, knowledge base and etc, a platform for medical equipment service technician to use by online or offline was designed. The platform provides users with knowledge services and interactive services, enabling users to get a more ideal solution. PMID- 26027290 TI - [The design of bionic left ventricular auxiliary pump]. AB - This paper reports a novel design of bionic left ventricular auxiliary pump, and the characteristic is that elastic diaphragm of pump driven by hydraulic, having smooth, reliable blood supply, can prevent blood clots, can use the flow sensor, pressure sensor detection showing the blood pressure and blood volume at the inlet and outlet of the pump. The pump can go with heart rate synchronization or asynchronous auxiliary by the R wave of human body's ECG. The design goal is realization of bionic throb. Through the animal experiment, the blood pressure waveforms are close to expectations, stable flow can stroke according to the set value, which prove that the pump can meet the requirement for heart disease patients for bionic left ventricular assistant. PMID- 26027291 TI - [Research progress of polyethylene inserts wear measurement and evaluation in total knee arthroplasty]. AB - Wear of polyethylene (PE) tibial inserts is a significant cause of implant failure of total knee arthroplasty (TKA). PE inserts wear measurement and evaluation is the key in TKA researches. There are many methods to measure insert wear. Qualitative methods such as observation are used to determine the wear and its type. Quantitative methods such as gravimetric analysis, coordinate measuring machines (CMM) and micro-computed tomography (micro-CT) are used to measure the mass, volume and geometry of wear. In this paper, the principle, characteristics and research progress of main insert wear evaluation method were introduced and the problems and disadvantages were analyzed. PMID- 26027292 TI - [The survey on modeling methods of soft-tissue deformation in virtual surgery]. AB - Soft-tissue deformation is one of the important research directions in virtual surgery. Mass-spring model and finite-element model are the two most important modeling technology of the soft tissue modeling. It is very important for the current soft-tissue deformation modelling to analysize, to summarize the main idea, the influence factors and the modeling route of the two kinds of modeling methods and then to give comprehensive review. PMID- 26027293 TI - [The research and expectation on wearable health monitoring system]. AB - Wearable health monitoring systems that use wearable biosensors capturing human motion and physiological parameters, to achieve the wearer's movement and health management needs. Wearable health monitoring system is a noninvasive continuous detection of human physiological information, data wireless transmission and real time processing capabilities of integrated system, can satisfy physiological condition monitoring under the condition of low physiological and psychological load. This paper first describes the wearable health monitoring system structure and the relevant technology applied to wearable health monitoring system, and focuses on the current research work what we have done associated with wearable monitoring that wearable respiration and ECG acquisition and construction of electric multi-parameter body area network. Finally, the wearable monitoring system for the future development direction is put forward a simple expectation. PMID- 26027294 TI - [Research development of surface hydrophilicity and lubrication modification of interventional guide wire]. AB - Surface lubricity is one of the important performance criteria for interventional guide wire. In this paper, a review of the methods of surface hydrophilicity and lubrication modification of interventional guide wire is presented, including their fundamental principles, effects and some relative applications. These methods all have their own advantages and disadvantages, therefore, limitations of experimental conditions need to be taken into account. PMID- 26027295 TI - [Software version and medical device software supervision]. AB - The importance of software version in the medical device software supervision does not cause enough attention at present. First of all, the effect of software version in the medical device software supervision is discussed, and then the necessity of software version in the medical device software supervision is analyzed based on the discussion of the misunderstanding of software version. Finally the concrete suggestions on software version naming rules, software version supervision for the software in medical devices, and software version supervision scheme are proposed. PMID- 26027296 TI - [Overview on the market, supervision and standardization of nanomaterial contained medical devices]. AB - In this paper, industry development and market tendency, supervision and standardization of nanomaterial-contained medical devices are overviewed comprehensively based on a large number of reference data including national and international information. Furthermore, the consideration about standardization of biological evaluation for nanomaterial-contained medical devices is discussed by combined some works performed in our laboratory. PMID- 26027297 TI - [Interpretation of YY/T 0841-2011 Medical electrical equipment--recurrent test and test after repair of medical electrical equipment standard]. AB - The paper introduces the background of YY/T 0841 standard, and interprets the main content of this standard. It is helpful to understand and applicate the standard. PMID- 26027298 TI - [Discussion on the application for standards of photobiological safety in the products of medical devices]. AB - This paper describes photobiological hazards and the standards of photobiological safety in the application of medical devices. It analyzes and discusses the current status of the international standardization and the national standardization. PMID- 26027299 TI - [Magnetic resonance compatibility research for coronary mental stents]. AB - The objective of this article is to research magnetic resonance compatibility for coronary mental stents, and to evaluate the magnetic resonance compatibility based on laboratory testing results. Coronary stents magnetic resonance compatibility test includes magnetically induced displacement force test, magnetically induced torque test, radio frequency induced heating and evaluation of MR image. By magnetic displacement force and torque values, temperature, and image distortion values to determine metal coronary stent demagnetization effect. The methods can be applied to test magnetic resonance compatibility for coronary mental stents and evaluate its demagnetization effect. PMID- 26027300 TI - [Study on the performance of piezoelectric micro pump for insulin injection]. AB - In terms of performance of piezoelectric micro pump, this paper explores the piezoelectric ceramic plate in different wave driven micro pump flow rate. The conclusion is that the square wave voltage gets the biggest micro pump velocity. The velocity and pressure of the micro pump is almost linear relationship, and having nothing to do with the different inner diameter pipes. The piezoelectric micro pump's stability is not good and exists attenuation. PMID- 26027301 TI - [Patient-specific dose verification method using ArcCHECK for total marrow irradiation with intensity modulated arc therapy]. AB - To investigate the patient-specific dose verification method using ArcCHECK for total marrow irradiation (TMI) with Volumetric Modulated Arc Therapy (VMAT) and Helical Tomotherapy (HT). The kVCT images collected from 8 patients were respectively designed for RapidArc and Tomotherapy plans in total marrow irradiation. ArcCHECK was used for dose verification for the head-neck, chest abdomen and pelvic. The merging function of ArcCHECK was used in VMAT and the method of double plans (reference and delivery plans) were used in HT. The gamma analysis passing rates for the head-neck, chest-abdomen, pelvic were 98.9% +/- 1.9%, 98.4% +/- 1.8%, 97.4% +/- 2.1% for VMAT plans and 94.3% +/- 1.5%, 96.5 +/- 1.2%, 94.1% +/- 1.9% for HT plans. The results show that using the merging function of ArcCHECK can achieve the dose verification well for VMAT plans with TMI. The method of double plans was done for the dose verification of HT plans with TMI as well as the plans with the targets keeping away from the set-up center. PMID- 26027302 TI - [The realization way and lean management about medical consumable material in clinical use]. AB - The medical consumable material management is an important part of logistic support in the management of hospital, but the hospital has many weak links in the management of supplies. This paper aims to explore the common problems (especially in clinical use) existing in the management of medical consumables and years of management experience in Changhai hospital's practice, then discusses lean management from the perspective of lean management PMID- 26027303 TI - [The digital information platform after-sale service of medical equipment]. AB - This paper describes the after-sale service of medical equipment information management platform, with large data sharing resources to further enhance customer service in the whole management process of medical service, to strengthen quality management, to control medical risk. PMID- 26027304 TI - [Application of fFN and CRP in the evaluation of therapeutic effect for preterm labor]. AB - Select 106 pregnant women with threatened preterm labor between 28 and 37 weeks of gestation. They have been treated continually by the preventing preterm labor therapy including antibiotics and magnesium sulfate. Cervicovaginal fetal fibronectin (fFN) and C-reactive protein (CRP) in serum were detected before treatment and after 3-day and 7-day treatment respectively. 100 normal pregnant women were included as control group. (1) The fFN and CRP had significant differences between study group and control group (P<0.05). (2) The fFN and CPR were different compared in the treatment period (P<0.05). Fetal fibronectin and CRP can be used can be used in therapeutic effect evaluation of threatened preterm labor. PMID- 26027305 TI - The two earths of Eratosthenes. AB - In the third century B.C.E., Eratosthenes of Cyrene made a famous measurement of the circumference of the Earth. This was not the first such measurement, but it is the earliest for which significant details are preserved. Cleomedes gives a short account of Eratosthenes' method, his numerical assumptions, and the final result of 250,000 stades. However, many ancient sources attribute to Eratosthenes a result of 252,000 stades. Historians have attempted to explain the second result by supposing that Eratosthenes later made better measurements and revised his estimate or that the original result was simply rounded to 252,000 to have a number conveniently divisible by 60 or by 360. These explanations are speculative and untestable. However, Eratosthenes' estimates of the distances of the Sun and Moon from the Earth are preserved in the doxographical literature. This essay shows that Eratosthenes' result of 252,000 stades for the Earth's circumference follows from a solar distance that is attributed to him. Thus it appears that Eratosthenes computed not only a lower limit for the size of the Earth, based on the assumption that the Sun is at infinity, but also an upper limit, based on the assumption that the Sun is at a finite distance. The essay discusses the consequences for our understanding of his program. PMID- 26027306 TI - From the archives of scientific diplomacy: science and the shared interests of Samuel Hartlib's London and Frederick Clodius's Gottorf. AB - Many historians have traced the accumulation of scientific archives via communication networks. Engines for communication in early modernity have included trade, the extrapolitical Republic of Letters, religious enthusiasm, and the centralization of large emerging information states. The communication between Samuel Hartlib, John Dury, Duke Friedrich III of Gottorf-Holstein, and his key agent in England, Frederick Clodius, points to a less obvious but no less important impetus--the international negotiations of smaller states. Smaller states shaped communication networks in an international (albeit politically and religiously slanted) direction. Their networks of negotiation contributed to the internationalization of emerging science through a political and religious concept of shared interest. While interest has been central to social studies of science, interest itself has not often been historicized within the history of science. This case study demonstrates the co-production of science and society by tracing how period concepts of interest made science international. PMID- 26027307 TI - The "wonderful properties of glass": Liebig's Kaliapparat and the practice of chemistry in glass. AB - Everybody knows that glass is and always has been an important presence in chemical laboratories. Yet the very self-evidence of this notion tends to obscure a supremely important change in chemical practice during the early decades of the nineteenth century. This essay uses manuals of specifically chemical glassblowing published between about 1825 and 1835 to show that early nineteenth-century chemists began using glass in distinctly new ways and that their appropriation of glassblowing skill had profoundly important effects on the emerging discipline of chemistry. The new practice of chemistry in glass-exemplified in this essay by Justus Liebig's introduction of a new item of chemical glassware for organic analysis, the Kaliapparat--transformed not merely the material culture of chemistry but also its geography, its pedagogy, and, ultimately, its institutions. Moving chemistry into glass--a change so important that it warrants the term "glassware revolution"--had far-reaching consequences. PMID- 26027308 TI - The gatekeepers of modern physics: periodicals and peer review in 1920s Britain. AB - This essay analyzes the processes behind the publication of physics papers in two British journals in the 1920s: the Proceedings of the Royal Society of London: Series A and the Philosophical Magazine. On the surface, it looked as though the Philosophical Magazine was managed very informally, while the Proceedings had in place a seemingly rigid system of committee approval and peer review. This essay shows, however, that in practice the two journals were both influenced by networks of expertise that afforded small groups of physicists considerable control over the content of these prestigious scientific publications. This study explores the nature of peer review, suggesting how a historical approach can contribute to contemporary debates. In studying these relationships, the essay also considers the interplay of "classical" and "modern" ideas and physicists in 1920s Britain and cautions against an anachronistic approach to this classification. PMID- 26027309 TI - Putting the military back into the history of the military-industrial complex: the management of technological innovation in the U.S. Army, 1945-1960. AB - In 1946 General Dwight Eisenhower, the Army Chief of Staff, established the Research and Development (R&D) Division on the War Department General Staff to expedite major technological breakthroughs in weapons technology. This goal, based on the separation of the management of R&D from procurement, captured the Army's preference for qualitative rather than quantitative superiority on the battlefield, but it threatened to upend entrenched methods of incremental product improvement under way in the Army's supply organizations, collectively called the technical services. The division's brief existence (it ceased operations in 1947) contrasted sharply with the longevity of the Ordnance Department's in-house manufacturing arsenals; for more than a century they had exploited synergies between R&D and production to turn out new weapons mass-produced in industry. The history of the R&D Division and the corresponding management of technological innovation in the technical services broadens an otherwise narrow historiographical interpretation of postwar knowledge production in the United States that is still focused heavily on the moral and political economy of military-funded academic research. PMID- 26027310 TI - Multispecies networks: visualizing the psychological research of the Committee for Research in Problems of Sex. AB - In our current moment, there is considerable interest in networks, in how people and things are connected. This essay outlines one approach that brings together insights from actor-network theory, social network analysis, and digital history to interpret past scientific activity. Multispecies network analysis (MNA) is a means of understanding the historical interactions among scientists, institutions, and preferred experimental animals. A reexamination of studies of sexual behavior funded by the Committee for Research in Problems of Sex between the 1920s and the 1940s demonstrates the applicability of MNA to clarifying the relations that sustained this area of psychology. The measures of weighted degree and betweenness can highlight which nodes (whether organisms or institutions) were particularly "central" to this network. Rats featured as the animals most widely studied during this period, but the analysis also reveals distinct institutional and disciplinary cultures where different species were favored as either surrogates for humans or representatives of more general biological groups. PMID- 26027311 TI - Eloge: Richard Adrian Jarrell (1946-2013). PMID- 26027312 TI - Eloge: John V. Pickstone (1944-2014). PMID- 26027313 TI - [Focus on the conceptual and technical changes of the facial and cervical reconstruction]. PMID- 26027314 TI - [Clinical guideline of the dermal filler of hyaluronic acid]. PMID- 26027315 TI - [Clinical application of prefabricated super-thin perforator flaps after expansion in the reconstruction of facial and cervical scar]. AB - OBJECTIVE: To explore a combined application of tissue expansion, perforator flaps and super-thin flaps in reconstruction of extensive face and neck scars. METHODS: In the first stage, the position and course of the perforators were confirmed with the multi-detector computed tomography ( MDCT) and color Doppler ultrasound. The expanders were implanted between subdermal vascular plexus and superficial fascia. In the second stage, the expanded super-thin perforator flaps were transferred to resurface the extensive defects and deformities in the face and neck. RESULTS: 26 cases with extensive facial and cervical scars were included in this study. Except for one case with necrosis at the distal end, the other 25 flaps survived completely. The maximum flap size was 35 cm x 10 cm with a pedicle of 8 cm x 4 cm. Long-term follow-up showed that this combined application provided thinner flap than the conventional pre-expanded flap, thus avoiding secondary flap debulking and revisions. All the patients got improvement in contours, facial features and emotional expression. CONCLUSIONS: The combined application of tissue expansion, perforator flaps and super-thin flaps is a practical method which has advantages in feature recontouring and recovery of delicate emotions in reconstruction of extensive face and neck scars. PMID- 26027316 TI - [Reconstruction of facial and cervical scar with the expanded supraclavicular island flaps]. AB - OBJECTIVE: To observe the therapeutic effect of expanded supraclavicular island flaps for facial and cervical scar. METHODS: From Oct. 2010 to Nov. 2013, a series of 16 patients with facial and cervical scars were treated by the expanded supraclavicular island flaps, pedicled by the supraclavicular cutaneous branch of transverse cervical artery. In the first stage, the soft tissue expanders (ranging from 400 ml to 600 ml in volume) were implanted in the anterior thoracic region. In the second stage, the facial and cervical scars were removed and the contructures were released, the expanded flap was transferred to cover the defects. The wounds at the donor sites were closed directly. RESULTS: The flaps size ranged from 12 cm x 7 cm to 22 cm x 11 cm. All flaps survived with no flap necrosis. Hematoma occurred in one case and healed by debridement. 16 patients were followed up for 3-12 months. The color and texture of all flaps matched well with the surrounding skin tissue, no bulky appearance or hypertrophic scar were noticed. CONCLUSIONS: The expanded supraclavicular island flap is a good choice for repairing facial and cervical scar. The appearance and function can be improved. PMID- 26027317 TI - [Application of microbublle-enhanced ultrasound in preoperative mapping of perforators in supraclavicular artery based flaps]. AB - OBJECTIVE: To investigate the effectiveness of microbubble-enhanced ultrasound (MEUS) for detecting perforators preoperatively in supraclavicular flap surgery. METHODS: From May 2009 to October 2013, there were 20 patients (26 flaps were involved) who planned to undergo supraclavicular artery based flap surgeries to recover the large-area defects in head and neck. The MEUS together with regular color Doppler ultrasound ( CDUS) were conducted preoperatively to determine the anatomical features of perforators branching from supraclavicular arteries (SCA). The perforator with wider caliber, faster flow speed, longer pedicles and closer pivot point was selected and the flap was designed according to the observed results. RESULTS: There were 37 perforators of SCA detected by CDUS, whose calibers were ranging from 0.5 to 0.8 mm [Mean: (0.6 +/- 0.1) mm]. There were 48 perforators of SCA detected by MEUS. Compared to CDUS, the caliber obtained from MEUS for same vessel is significantly increased [(0.7 +/- 0.3) mm vs (0.6 +/- 0.1) mm, P < 0.05]. According to the results of MEUS and three-dimensional reconstructive techniques, in at least 65.4% (17/26) of the flaps, thoracic branch of SCA (TBSA) has large caliber and good flow velocity which can be regarded as the predominant vessel and used as the pedicle of flap. The results of the operations confirmed the existences of all the marked vessels. 25 flaps were obtained according to the preoperative plans and one case used perforators of internal mammary artery as free flaps since the perforator of SCA was found improper. The contrast-related complication occurred in one patient which was manifested by gastrointestinal adverse effect like nausea and anorexia. The patient recovered 1 day later without treatment. All the patients have been followed up for 3 to 16 months (Mean: 8 months) with well-survived flaps. CONCLUSIONS: The perforators of SCA demonstrated significant variations and preoperative mapping was vital for the success of surgery. MEUS is a valuable imaging modality for the preoperative assessment of the vascular supply for supraclavicular artery based flap. PMID- 26027318 TI - [Correction of severe alar retraction with alar rotation flap]. AB - OBJECTIVE: To investigate the therapeutic effect of alar rotation flap for severe alar retraction. METHODS: Patients with severely retracted alar underwent ala reconstruction using alar rotation flaps and autogenous cartilage batten grafts. First, costal cartilage was used to reshape the nasal tip and nasal dorsum. Then cartilage patch was used to extend and thicken the retracted alar. Then the alar rotation flap was transferred to correct retracted alar. RESULTS: Fourteen patients with severe alar retraction underwent alar reconstruction with alar rotation flap and alar batten grafts. The alar retraction was corrected in all cases, with improvements functionally and aesthetically. No recurrence of alar retraction was noted. The incision healed with acceptable cosmetic results, with obvious scar in only one patient (one side). CONCLUSIONS: The alar rotation flap is an effective and reliable surgical option to correct severe alar retraction. Scar can be kept inconspicuous by precise placement of the incision within the junction of the ala and the nasal dorsum, following principles of the aesthetic nasal subunits. PMID- 26027319 TI - [Combining mastopexy and triple-plane breast augmentation in correction of breast atrophy and ptosis]. AB - OBJECTIVE: To investigate the application of combining mastopexy and triple-plane breast augmentation in correction of breast ptosis and atrophy. METHODS: Peri areolar incision was performed to finish the fascia and dermal suspension to correct the breast ptosis. The implant was inserted under the pectoralis major muscle through lateral lower border of the gland and a "X" shape full thickness incision was made on the pectoralis major muscle according to the new position of nipple-areolar complex. RESULTS: 14 patients received combined mastopexy and triple-plane breast augmentation to correct breast atrophy and mastopexy simultaneously. All the patients were regularly followed for 6-12 months. No patients suffered severe complication and the results were satisfied. CONCLUSIONS: "Triple-plane" breast augmentation could be safely performed with peri-areolar mastopexy with minor injury. The technique could help to ensure the balance between the gland, nipple-areolar complex and the implant. PMID- 26027320 TI - [The anatomy and clinical application of reverse saphenous nerve neurocutaneous flaps for reparing skin defects of forefoot]. AB - OBJECTIVE: To investigate the effect of reverse saphenous nerve neurocutaneous flaps for skin defects of forefoot. METHODS: In the anatomic study, 50 cadaveric feet were injected with red latex and the anastomosis, distribution and external diameters of medialtarsal artery, medial anterior malleolus artery, medial plantar artery, the superficial branch of the medial basal hallucal artery and saphenousnerve nutritional vessels were observed. Based on anatomic research results, we designed the reverse saphenous nerve neurocutaneous flaps for repairing skin defects of forefoot. RESULTS: The blood supply of reverse saphenous nerve neurocutaneous flaps were based on the vasoganglion, which consist of arterial arch at the superior border of abductor hallucis and arterial network on the surface of abductor hallucis around the saphenous nerve and medial pedis flap. From Oct. 2006 to Oct. 2011, the reverse saphenous nerve neurocutaneous flaps were used to repair skin defects of forefoot in 11 cases. The flap size ranged from 2.5 cm x 3.5 cm to 7.5 cm x 8.5 cm. The wounds at donor site were covered with full-thickness skin graft. All flaps survived completely with no ulcer at the donor site. 11 cases were followed up for 6 to 18 months( mean, 10 months). The skin color and texture were satisfactory. The patients could walk very well. CONCLUSIONS: It is reliable to repair the skin defects of forefoot with reverse saphenous nerve neurocutaneous flaps. It is easily performed with less morbidity. This flap should be considered as a preferential way to reconstruct skin defects of forefoot. PMID- 26027321 TI - [Vaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermal matrix]. AB - OBJECTIVE: To introduce and evaluate the technical feasibility and anatomical and functional outcomes of one-stage vaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermis. METHODS: We retrospectively reviewed our experiences with 17 patients with Mayer- Rokitansky-Kuster-Hauser syndrome treated with primary surgery from September 2010 to April 2013. All patients underwent vaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermis. We describe the details of this technique, observe the time of epithelization and evaluate the long- term anatomical, functional, and sexual outcomes. RESULTS: The time of epithelization was 13 d (range: 12-15 d). At a mean follow-up of 15 months (range: 12-24 months), the mean postoperative dependence on the vaginal stent was 11.7 +/- 1.64 months (range: 9-15 months), the mean depth of the neovagina was (9.0 +/- 0.94) cm (range: 7-11 cm), the mean circumference was (12.3 +/- 1.36) cm (range: 10.0-14.5 cm) and the mean volume was (105 +/- 10) ml (range 85-120 ml). The mean female sexual function index score of the 12 sexually active patients was 29.5 +/- 2.6. No spouse reported discomfort during intercourse. CONCLUSIONS: Vaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermis is an effective and feasible approach for patients with Mayer-Rokitansky-Kuster-Hauser syndrome. The procedure has satisfactory long-term anatomical and functional results. The use of the acellular allogenic dermis is limited by the high price and the potential infection. PMID- 26027322 TI - [Nylon fixation at the internal and external canthus combined with skin graft for recurrent lower eyelids ectropion]. AB - OBJECTIVE: To investigate the long-time effects of nylon fixation at the internal and external canthus combined with skin graft for recurrent lower eyelids ectropion. METHODS: Under local anesthesia, the cicatricial contraction was released to repostion the lower eyelid. Then nylon thread was implanted in the fascial tissue at the upper margin of tarsus and was fixed on the periosteum at the internal and external canthus. The skin graft was applied on the wound of lower eyelids. RESULTS: 12 patients with lower eyelids ectropion at 19 sides were treated with primary healing. The patients were followed up for 6-24 months. All cases were satisfied with functional and cosmetic results. No complication and no recurrence happened. CONCLUSIONS: The technique of nylon fixation at the internal and external canthus combined with skin graft is an effective method for recurrent lower eyelids ectropion. PMID- 26027323 TI - [Therapeutic effect of heating and bandage treatment for chronic lymphedema of extremities accompanied with erysipelas: a report of 80 cases]. AB - OBJECTIVE: To investigate the therapeutic effect of heating and bandage treatment for chronic lymphedema of extremities accompanied with erysipelas. METHODS: From March 2004 to March 2013, 80 patients with chronic lymphedema of extremities accompanied with erysipelas were analyzed retrospectively. The patients underwent heating treatment (42 degree centigrade) with infrared light machine made by Shanghai Ninth People's Hospital, 2 hours a day, 20 hours for a session. Bandage treatment was adopted after heating treatment. 1 or 2 sessions were performed for each patient every year. The erysipelas occurring frequency, patients subjective feeling, treatment sessions and elastic material usage was recorded during the follow-up period. The erysipelas occurring frequency was tested by the method of rank and inspection. SPSS 17. 0 was used for statistical analysis. RESULTS: After heating and bandage treatment, the occurrence frequency of erysipelas was obviously controlled (Z = 7.598, P = 0.000). Erysipelas was not occurred any more in 60 (75%)patients. Remarkable reduction of occurrence frequency of erysipelas caused by various reasons was showed after treatment. Primary and secondary lymphedema after treatment were compared with those before treatment respectively, showing statistical difference (Z = 3.417 and 5.009, P = 0.001 and 0.000). Most of patients felt better subjectively. The relapse rate of erysipelas and lymphedema was lower if keeping using elastic material to give more pressure on extremities after therapy. CONLUSIONS: Heating and bandage treatment can obviously reduce the occurrence frequency of erysipelas. It can improve the quality of patients' lives. Simultaneously, the subsequent elastic material pressure therapy is essential. PMID- 26027324 TI - [The immunological characteristics of tonsil mesenchymal stem cells]. AB - OBJECTIVE: To investigate the immunological characteristics of human tonsil mesenchymal stem cells (TMSCs). METHODS: Human tonsil tissues were obtained from the children patients with chronic tonsillitis. TMSCs were separated, cultured, and were detected the expression profiles of HLA-I, HLA-II, CD80, CD86 by flow cytometry. The measurement of immunogenicity, the effect on phytohemagglutinin (PHA) induced peripheral blood mononuclear cell (PBMCs) proliferation and mixed lymphocytes reaction (MLR) were performed to identify the immunological characteristics of TMSCs. The co-cultures of TMSCs + PBMCs + PHA and TMSCs + MLR were established, respectively, and the concentration of kynurenine, which is the metabolin of indoleamine 2, 3-dioxygenase, in the culture supernatant were examined. Then we added 1-methyl-L-tryptophan into the co-culture of TMSCs + PBMCs + PHA and TMSCs + MLR, respectively, and tested the proliferation of PBMCs. Each experiment was repeated three times, and there were six samples in each group. Statistical significance was assessed by analysis of variance (ANOVA), and a P value less than 0.05 was considered statistically significant. RESULTS: TMSCs expressed HLA-I, were negative for HLA-II and co-stimulatory molecules CD80 and CD86. The stimulation index in the group of TMSCs + allogeneic PBMCs was 1.38 +/- 0.26, whereas the stimulation index in the group of allogeneic PBMCs was 1.22 +/- 0.28, and there was no significant difference between the two groups (P > 0.05), indicating that TMSCs could not initiate the proliferation of allogeneic PBMCs. The stimulation indexes in the group of TMSCs + allogeneic PBMCs + PHA were 1.49 +/- 0.29 and 1.23 +/- 0.22, respectively, whereas the stimulation index in the group of allogeneic PBMCs + PHA was 4.60 +/- 0.81, and the difference between the two groups had a statistical significance (P < 0.05) suggesting that TMSCs could inhibit PHA-induced PBMCs proliferation. The stimulation indexes in the group of TMSCs + MLR were 1.29 +/- 0.23 and 1.26 +/- 0.27, respectively, however, the stimulation index in the group of MLR was 3.04 +/- 0.66, and the difference between the two groups had a statistical significance (P < 0.05), demonstrating that TMSCs could suppress MLR-induced PBMCs proliferation. The levels of kynurenine were (26.0 +/- 2.3) MUmol/L and (23.5 +/- 4.5) MUmol/L in the culture of TMSCs + PBMCs + PHA and TMSCs + MLR, respectively, thus elevating significantly. After adding of 1-methyl-L-tryptophan, TMSCs-mediated proliferation suppression of PBMCs restored to normal levels. CONCLUSION: TMSCs possess low immunogenecity and immunosuppressive function, may be used in allogeneic transplantation. PMID- 26027325 TI - [Effect of photodynamic therapy on the cell proliferation and collagen secretion of keloid fibroblasts]. AB - OBJECTIVE: To investigate the effect of 8-aminolevulinic acid (ALA) photodynamic therapy (PDT) on the cell proliferation, apoptosis and collagen secretion in keloid fibroblasts and to provide the theoretical base for ALA-PDT treatment of keloids. METHODS: Fibroblasts from keloid patients were cultured to the third generation in vitro and incubated in 0, 1, 3, 6, 9 mmol/L of delta-aminolevulinic acid for 3 h in the darkness. Then they were exposed to 635 nm wavelength red light ( 30 J/cm2 ) and continued incubation 24 h after irradiation. CCK-8 assay was used to detect proliferation inhibition rate of fibroblasts. The content of hydroxyproline was measured by colorimetric method. The expression of p-Akt and programmed cell death 4 ( PDCD4) were detected by Western blot. RESULTS: The inhibition rate of keloid fibroblasts were respectively 0, (8.30 +/- 1.01)%, (29.48 +/- 3.27)%, (52.01 +/- 5.34)%, (79.99 +/- 5.85)% with the presence of difference concentrations (0, 1, 3, 6, 9 mmol/L) of ALA. The content of hydroxyproline were respectively (9.540 0 +/- 0.352 42), (6.242 5 +/- 0.224 85 ), (5.107 5 +/- 0.534 88), (3.490 0 +/- 0.623 48), (2.945 0 +/- 0.514 10) MUg/mg. The relative expression of p-Akt were respectively 1, 0.75 +/- 0.12, 0.52 +/- 0.14, 0.41 +/- 0.18, 0.32 +/- 0.09. The relative expression of PDCD4 were respectively 1, 1.18 +/- 0.19, 1.51 +/- 0.22, 0.15 +/- 0.30, 2.44 +/- 0.22. The difference was statistically significant when compared the group of 1, 3, 6, 9 mmol/L with 0 mmol/L (P < 0.05). CONCLUSIONS: In concentration within the range of 1-9 mmol/L, ALA could inhibit the proliferation of fibroblasts significantly, promote fibroblasts apoptosis and reduce the content of hydroxyproline in a dose dependent manner, indicating that 8-aminolevulinic acid photodynamic therapy may be a potential treatment for keloid. PMID- 26027326 TI - [Effects of extracts of Dragon's blood on fibroblast proliferation and extracellular matrix hyaluronic acid]. AB - OBJECTIVE: To investigate the effects of Dragon' s blood extract on proliferation and secret extracellular matrix function of fibroblasts in vitro. METHODS: Dragon' s blood was extracted by chloroform, acetoacetic ester, alcohol. Human fibroblast were cultured in vitro in media containing gradient dilutions of Dragon' s blood extracts (0.002, 0.02, 0.2, 2, 20 mg/ml) , which was followed by cell proliferation assessed with MTT assay on 0, 12, 24, 36, 48, 60, 72 h. Under the optimal concentration, the cell growth curves were drawn and the flow cytometry (FCM) was used to determine the changes of cell cycle. On 0, 12, 24, 36, 48, 60, 72 h, the concentration of hyaluronic acid in the supernatant of fibroblast culture was measured by radioimmunoassay. RESULTS: 0.2-2 mg/ml Dragon' s blood extracts enhanced the proliferation of fibroblasts in a dose-dependent manner. 2 mg/ml was the optimal dilution of Dragon's blood extract, and it increased the ratio of S cells in cell cycle [(25.80 +/- 3.10)%] than control group [(7.50 +/- 0.70)%, P < 0.01]. From 12 h to 72 h, in 2 mg/ml Dragon's blood group, concentration of Hyaluronic acid secreted by fibroblasts gradually increased, but were less than control (P < 0.01). CONCLUSIONS: Dragon's blood acetoacetic ester extract improved the proliferation of cultured human fibroblasts in vitro, might be beneficial to promote wound healing. PMID- 26027327 TI - [Frequency thresholds for stereopsis in the case of alternative presenting the left and right images of stereopair in children with ophthalmopathology]. AB - In this paper, we report the results of estimating the minimum frequency of alternative left-right stereopair image presentation necessary to obtain stereopsis in children with ophthalmopathology including or not including binocular disorders. It was found that all subjects without binocular disorders had stereo-effect with linear as well as with random-dot images. However, for stereopsis with random-dot stereotests, all children needed higher frequency of alternation than for stereopsis with simple linear images. It appeared that about 90% of children with binocular disorders were capable to perceive depth when simple linear stereoscopic images were presented alternatively to the two eyes. However, these patients needed a higher frequency of alternation than children with normal binocular functions. Only a small part (about 30%) of children with binocular disorders was capable to stereopsis with complex random-dot images and they needed rather high frequency (more than 30 Hz) of alternation for success. PMID- 26027328 TI - [Sensitivity of the hearing system to the velocity of auditory motion: difference thresholds and mismatch negativity]. AB - The parallel psychophysical and MMN study focused at the sensitivity of human hearing system to variations in velocity of sound image movement. The motion of sound stimuli with various velocities in the 450 deg/s to 732 deg/s range in increments of 6 deg/s to the left or to the right from the head midline was simulated by introducing linear changes of interaural delay into dichotic stimuli. The psychophysical experiments were designed according to the 2 alternative forced choice paradigm. The subjects were presented by pairs of moving stimuli and were asked to decide which moved faster. The stimuli created for the present study ensured that the subjects performed the discrimination task without relying on associated cues of sound displacement or duration. The psychophysical measures were compared with electrophysiological indexes of sound processing (auditory evoked responses (ERPs) and mismatch negativity (MMN)). Significant MMN was elicited by the difference of 170 deg/s between the reference and test velocity, which corresponded to the relative velocity increase of 38%. At the same time, the difference thresholds for velocity were much higher and exceeded 50%. The results suggest that MMN magnitude depended on the velocity difference between standard and deviant stimuli and was more sensitive to velocity difference than psychophysical measure. PMID- 26027330 TI - [Heart rate variability of subjects when the instruction reading and their interrelations with the effectiveness of the follow-visual-motor activities]. AB - Investigation of the processes of studying human instructions relevant follow-up in terms of systemic mechanisms of learning and memory processes, and moreover affects such a fundamental issue as psychophysiology focused attention, understanding the meaning of the information provided and the formation of social motivation in human activities. Analysis of heart rate variability in reading the instructions compared to the initial state of operational rest showed that this stage of the activity causes pronounced emotional stress, which is manifested in increased heart rate, decrease in variability and pronounced changes in the spectral characteristics of heart rate. Besides, it was revealed that heart rate variability in a state of operational rest before testing, and in the process of reading instructions positively correlated with the duration of the instruction reading and inversely correlated with effectiveness and the level of resistance of the subjects to the error after error when follow-up activities. Showing pronounced gender differences in the relationships between changes in the variability of heart rate when reading the instructions and the subsequent execution indicators of visual-motor test. PMID- 26027329 TI - [Psychophysiological analysis of the reading and text understanding]. AB - Presented cognitive studies aimed to identifying the individual properties of macro saccades, one of the most important oculomotor functions during text, the fairy tales reading. We measure, in the form of abstracts, the reduced analogue of the "school essays", the capabilities of our subjects, the students of liberal arts colleges, to understand the presented text (morality of tales). Evaluation of this abstracts was conducted by independent experts using school 6 point scales. The preparing of the abstract wasn't limited in time. We found that there is not any relationship between reading speed and the quality of the interpretation of the text. No relationship of understanding the hidden morality with the number of characters being picked for the fixation and the mean duration of the macro saccades. Correlation analysis showed an inverse relationship between the number of returns and the understanding of the text, more macro saccades returns--the worse was the understanding of the text. There is an inverse relationship between the number of exciting characters and a number of macro saccades. Number of fixations (capture) increases the reading of the text. This means that the bandwidth of visual channel per time unit is determined by the number of captured characters. Less number of captured during fixation of signs--more time reading and less bandwidth of the eyes per time unit. PMID- 26027331 TI - [A delayed motor production of open chains of linear strokes presented visually in static and dynamic modes: a comparison between 9 to 11 years old children and adults]. AB - The production of drawing movements was studied in 29 right-handed children of 9 to-11 years old. The movements were the sequences of horizontal and vertical linear stokes conjoined at right angle (open polygonal chains) referred to throughout the paper as trajectories. The length of a trajectory varied from 4 to 6. The trajectories were presented visually to a subject in static (linedrawing) and dynamic (moving cursor that leaves no trace) modes. The subjects were asked to draw (copy) a trajectory in response to delayed go-signal (short click) as fast as possible without lifting the pen. The production latency time, the average movement duration along a trajectory segment, and overall number of errors committed by a subject during trajectory production were analyzed. A comparison of children's data with similar data in adults (16 subjects) shows the following. First, a substantial reduction in error rate is observed in the age range between 9 and 11 years old for both static and dynamic modes of trajectory presentation, with children of 11 still committing more error than adults. Second, the averaged movement duration shortens with age while the latency time tends to increase. Third, unlike the adults, the children of 9-11 do not show any difference in latency time between static and dynamic modes of visual presentation of trajectories. The difference in trajectory production between adult and children is attributed to the predominant involvement of on-line programming in children and pre-programming in adults. PMID- 26027332 TI - [Effects of mechanical stimulation of the soles' support zones on H-reflex characteristics under support unloading condition]. AB - The aim of the work was to study the effects of mechanical stimulation of the soles' support zones on state of m. soleus motoneurone pool in man under 7-days support unloading conditions, which was provided by "Dry Immersion" model. Before, during and after immersion exposure the excitability of m. soleus motoneurone pool was estimated by H-reflex amplitude normalized by the maximal amplitude of M-wave. The data registered in two groups of volunteers: "control" in which only immersion exposure was used and "experimental" in which stimulation of support zones of sole was carried out during Dry Immersion were compared. During immersion relative amplitude of H-reflex increased in the control group. These alterations were not revealed in the experimental group with daily application of the support stimulation in natural locomotion regimens during immersion. PMID- 26027333 TI - [Nonlinear dynamics of involuntary shaking of the human hand under motor dysfunction]. AB - Using nonlinear dynamic methods we examined wavelet and multifractal features of involuntary shaking (tremor) arising during the performance the motor task (sustaining effort of fingers under isometric conditions). The wavelet score (the maximum of the global wavelet spectrum) and multifractal parameters (the width and asymmetry of the singularity spectrum) significantly differ in tremor of healthy subjects and patients with akinetic-rigid form of Parkinson's disease. The relations between the change of the patient state connected with the drug relief of parkinsonian symptoms and the variations of the parameter values have been obtained. The suggested analytic approach for noninvasive study of integrative activity of the central nervous system, formed as the motor exit during realization of the motor task, enables not only to estimate quantitatively the degree of deviation of the motor function from the healthy one, but it can help to a clinician to choose the optimal treatment in every particular case. PMID- 26027334 TI - [Shift in vertical stance parameters in humans while viewing different images]. AB - The type of the image shown to the subject could be an important factor in traditional stabilometric tests or tests with biofeedback, which could affect the test results. There is important aspect for medical practice, sport and other. The obtained results in 9 healthy volunteers might indicate the preference of using simple visual picture for stance stabilizing, which is probably associated with basic mechanisms of visual information processing. PMID- 26027335 TI - [Individual-typological evaluation of cardiorespiratory responses to hypoxia and hypercapnia in young healthy men]. AB - The aim of the study was the approaches development to a substantiation of recommendations on the persons selection for different types of physical exercise on the basis of individual chemoreflex reactivity of cardiorespiratory system. That's for the ventilatory and cardial responses in tests with increasing inhalation hypoxia and hypercapnia on the group of young healthy man was performed. It was shown that hypoxia induce predominantly cardial response, but hypercapnia--ventilatory response. On that predominantly chemoreflex reactions (respiration system to hypercarbia and cardiac--to hypoxaemia) four types of in parts were defined: small reactions in both parts (type 1), small reaction of cardiac system and strong of respiratory system (type 2), strong for heart response and small for respiration (type 3), and strong for both parts (type 4). Statistical analysis has shown that each type of reactions is specific to certain kind of sports training: 1 type for swimmers, 2 and 3 types for skiers, 4 type for boxers, weight lifters and wrestlers. For skiers group the inverse regression dependence between the growth of heart reactivity to hypoxaemia and depression of the pulmonary ventilation reactivity to hypercarbia is revealed at joint rising of the oxygen consumption per unit body weight. High quality skiers are distinguished by relative balance of chemoreflex responses of respiration and heart. It was found that physically untrained persons have pronounced individual variability of cardiorespiratory system chemoreflex reactions, what can be used for personal recommendations for choosing the kind of sports to employment. PMID- 26027336 TI - [Circadian rhythm of skin temperature of children during puberty]. AB - Results of long-term research of becoming circadian rhythm of temperature (CRT) of human skin of shoulder during puberty are presented. For this purpose, 48-hour monitoring T at children, teenagers and mature young men and female from 8 till 22-th years with application of a method "Thermochron iButton" has been led. Age dynamics of mesor, reflecting process of becoming thermoregulation of organism during puberty, has wave character. The first wave with maximum T was observed at children of 10-11 years, second maximum T--at teenagers of 14-15 years. And at persons man's and female dynamics of mesor is synchronous, however, at girls from 8 till 17 years mesor authentically above. At adult people mesoris above at young men. Dynamics of amplitude CRT does not vary till 12-13 years, in 14-15 years at boys the size of amplitude decreases, and at girls increases. In 16-17 years at children amplitude sharply increases with the subsequent significant decrease by the period of a maturity (20-22 years). At boys, amplitude of CRT it is authentic more, than at girls, at adult people this parameter does not differ. At research of a cycle a dream-wakefulness periods in which changes daily thermoregulation are revealed: at boys in the age of 10-11 years, and at girls at 10-11 and in 16 17 years. During these periods T at night is above, than in the afternoon. PMID- 26027337 TI - [Ischemic resistance of motor axons in children with viral meningitis and Guillain-Barre syndrome]. AB - The effect of temporal local ischemia at the forearm on ulnar motor nerve conduction velocity in the control (n = 26 children), group of patients with acute period viral meningitis (VM) (n = 16 children), 14 days after the clinical manifestation of VM (n = 11 children) and children with Guillain-Barre syndrome (GBS) in catamnesis (n = 11 children) was evaluated. Less pronounced reactivity of neural conduction on ischemia for 10 minutes (by 50%, p < 0.00001), was seen in children with GBS in catamnesis, comparing to the controls. In the acute period VM also less pronounced reactivity of neural conduction by 29%, than in the controls, was registered. We propose, that ischemic resistance in immune mediated neuropathy and in the acute period of infection may happen due to cytokine-mediated channelopathy. PMID- 26027338 TI - [The influence of induced sympathectomy on human peripheral nerves regeneration after autoneuroplasty]. AB - 86 patients with posttraumatic defects of median and ulnar nerves were examined. Autoneuroplasty was performed at all of patients: in 42 cases--in combination with sympathectomy (thoracoscopic clipping of Th3-4 sympathetic ganglions), in 44 cases--without sympathectomy. Ultrasonography of nerve trunks, stimulation electroneuromyography, computer thermography, laser Doppler flowmetry with spectral wavelet-analysis of blood flow oscillations were used during checkup. For the first time was shown that induced sympathectomy has positive activating influence on restoring innervation and tissue trophics in the course of posttraumatic nerve regeneration. Combination of autoneuroplasty with induced sympathectomy contributes to a more complete restoration of motor and sensory nerve fibres, helps to normalize blood flow in microvascular bed and thermotopography of the damaged segment of the extremity including the previously denervated area. PMID- 26027339 TI - [ENMG-assessment of efficiency of temporal epidural electroneurostimulation in combined with robotic kinesotherapy in the treatment of patients with spinal cord injury consequences]. AB - The goal of this study was to ENMG-assess effectiveness of the short combined neurorehabilitation course (temporal epidural stimulation of the spinal cord combined with a robotic kinesotherapy) in the restorative treatment of patients with traumatic spinal cord disease. Before and after completion of the combined instrumental neurorehabilitation (course duration--2-3 weeks) were tested 75 patients with spinal cord injury consequences. The authors used global and stimulation (H-reflex, M-response) electromyography methods. On the ENMG-data basis were calculated indices of sensorimotor deficit (ISD) and their postrehabilitation trends. ENMG-signs of sensorimotor deficit regression in the lower extremities were observed in 46.6% of events, in the upper extremities (if damaged cervical spine)--in 78.6% of events. The stabilizing effect of the used neurorehabilitation technology was identified an average of 24.0% of events. In 18.8% of events, the using of the combined neurorehabilitation technology has been ineffective. As indications for the use of combined neurorehabilitation courses series may be employed ENMG-signs of the partial corticospinal tracts conduction safety and a positive ISD trend after the each course completion. PMID- 26027341 TI - [Effect of inert gas xenon on the functional state of nucleated cells of peripheral blood during freezing]. AB - A new method of preservation of nucleated cells in the electric refrigerator with xenon. After slow freezing and storage is even one day at -80 degrees C persists for more than 60% leukocytes. Cell membranes are resistant to the vital dye. In 85% of granulocytes stored baseline lysosomal-cationic protein, reduced lipid peroxidation and antioxidant activity. Cryopreservation of biological objects in inert gases is a promising direction in the practice of medicine and can be an alternative to the traditional method using liquid nitrogen. PMID- 26027340 TI - [Comparision of forced expiratory time, recorded by two spirometers with flow sensors of various types, and acoustic duration of tracheal forced expiratory noises]. AB - In the sample of 44 volunteers forced expiratory time values obtained in spirometers, equipped with flow sensor of Lilly type and turbine flow sensor, and acoustic duration of tracheal forced expiratory noises are compared. It is shown that spirometric forced expiratory time is dependent on flow sensor type. Therefore it can't be used in diagnostic aims. PMID- 26027342 TI - [Psychophysiological features of adolescents]. AB - Behavioral characteristics of adolescents as determined by brain neurophysiological and neurochemical processes during puberty are the focus of this article. PMID- 26027343 TI - [Hypoxic stress as a trigger of multipotent mesenchymal stromal cell activation]. AB - Multipotent mesenchymal stromal (stem) cells (MSCs) are a heterogeneous cell population of different commitment and is actively involved in the physiological and regenerative tissue remodeling. MSC mobilization from local tissue depots and their activation in the tissue damage foci are the key issues in the study of mechanisms of MSC features. Short-term (up to 72 h) hypoxic stress that is considered as a constitutive feature of the damage foci, may contribute to the activation of MSC potential. This review is analyzed the data on the impact of short hypoxic stress ex vivo on the viability, functional activity of MSCs and possible molecular mechanisms of these effects. PMID- 26027344 TI - [Scientific and practical contribution of G.M. Zarakovskiy to domestic psychophysiology development (to the 90th anniversary)]. AB - This article presents the main directions and outcomes of G.M. Zarakovskiy researches of psychophysiological characteristics and human capabilities for them accounting in designing and defining the conditions and organization of human operator activity in order to improve the performance and reliability of professional labour. The article contains the main dates of his life and work at the Military Medical Academy, Institute of Aviation and Space Medicine, and in the all-Russian Research Institute of Technical Aesthetics and conceptual views and approaches of G.M. Zarakovskiy to solving actual problems of psychology and psychophysiology of labour as a condition for improving the quality of life of the population and the innovative development of the economy of the country. PMID- 26027345 TI - [To the 50th anniversary of the Skryabin Institute of Biochemistry and Physiology of Microorganisms]. PMID- 26027346 TI - [Aerobic methylobacteria as promising objects of modern biotechnology]. AB - The experimental data of the past decade concerning the metabolic peculiarities of aerobic meth ylobacteria and the prospects for their use in different fields of modern biotechnology, including genetic engineering techniques, have been summarized. PMID- 26027347 TI - [Antistress systems of the yeast Yarrowia lipolitica (review)]. AB - The authors' and literature data on the adaptation response of the micromycetes Yarrowia lipolytica to various stress impacts are considered in the review. The uniformity of cellular response to all stress factors is discussed. PMID- 26027348 TI - [Physiological and biochemical properties of actinobacteria as the basis of their high biodegradative activity (review)]. AB - The review summarizes the authors' own data and reports by other researchers concerning the degradation of stable organic compounds by actinobacteria. Properties of these microorganisms are characterized. They include the ability to survive and to maintain metabolic activity during prolonged exposure to adverse environmental conditions, as well as the presence of enzymes with a broad substrate specificity, which enables these bacteria to decompose natural and synthetic substances. The transformation pathways of key intermediates and the ability of actinobacteria to develop novel pathways are discussed. Approaches to increasing the destructive activity of bacterial cultures are presented. PMID- 26027349 TI - [Biosynthesis of secondary metabolites in methanotrophs: biochemical and genetic aspects (review)]. AB - The review summarizes the data on the metabolic potential of methanotrophs as producers of biopolymers, alternative biofuel, bioprotectants, and other secondary metabolites. The work provides the examples of modern 'omic' technologies used for genetic engineering of efficient methanotrophic producers. PMID- 26027350 TI - [Comparative characteristics of free-living ultramicroscopical bacteria obtained from extremal biotopes]. AB - We isolated 50 strains of free-living ultrasmall bacteria with a cell volume that varies from 0.02 to 1.3 microm3 from a range of extremal natural biotopes, namely permafrost soils, oil slime, soils, lake silt, thermal swamp moss, and the skin integuments of the clawed frog, Xenopus laevis. Of them, 15 isolates, characterized by a cell size of less than 0.1 microm3 and a genome size from 1.5 to 2.4 Mb, were subsumed to ultramicrobacteria belonging to different philogenetic groups (Alphaproteobacteria, Bacteroidetes, Actinobacteria) and genera (Kaistia, Chryseobacterium, Microbacterium, Leucobacter, Leifsonia, and Agrococcus) of the Bacteria domain. They are free-living mesophilic heterotrophic aerobic bacteria. The representatives of Kaistia and Chryseobacterium genera were capable of facultative parasitism on other species of chemo-organotrophic bacteria and cyanobacteria. The ultramicrobacteria differed in their morpholgy, cell ultrastructural organization, and physiological and biochemical features. According to the fine structure of their cell walls, the isolates were subdivided into two groups, namely Gram-positive and Gram-negative forms. PMID- 26027351 TI - [11beta-Hydroxylation of 6alpha-Fluoro-16alpha-Methyl-Deoxycorticosterone 21 Acetate by filamentous fungi]. AB - Selected filamentous fungi--98 strains of 31 genera--were screened for the ability to catalyze 11beta-hydroxylation of 6alpha-fluoro-16alpha-methyl deoxycorticosterone 21-acetate (FM-DCA). It was established that representatives of the genera Gongronella, Scopulariopsis, Epicoccum, and Curvularia have the ability to activate 11beta-hydroxylase steroids. The strains of Curvularia lunata VKM F-644 and Gongronella butleri VKM F-1033 expressed maximal activity and formed 6lpha-fluoro-16alpha-methyl-corticosterone as a major bioconversion product from FM-DCA. The structures of the major products and intermediates of the bioconversion were confirmed by TLC, H PLC, MS and 1H NMR analyses. Different pathways of 6alpha-fluoro-16alpha-methyl-corticosterone formation by C. lunata and G. butleri strains were proposed based on intermediate identification. The constitutive character and membrane-binding localization were evidence of a 11beta-hydroxylating system in G. butleri, while an inducible character and microsomal localization was confirmed for 11beta-hydroxylase of C. lunata. Under optimized conditions, the molar yield of 6alpha-fluoro-16alpha-methyl corticosterone reached 65% at a FM-DCA substrate loading of 6 g/L. PMID- 26027352 TI - [Formation of hydroxylated steroid lactones from Dehydroepiandrosterone by Spicaria fumoso-rosea F-881]. AB - The transformation of dehydroepiandrosterone by Spicaria fumoso-rosea VKM F-881 produced 7alpha- and 7beta-hydroxy-dehydroepiandrosterone, 3beta,7alpha-dihydroxy 17a-oxa-D-homo-androst-5-en-17-one, and 3beta,7beta-dihydroxy- 17a-oxa-D-homo androst-5-en-17-one. The yield of the main product-3beta,7beta-dihydroxy-17a-oxa D-homo-androst-5-en-17-one-was 49.5-72 mol % at substrate loadings of 5-20 g/L. Lactone formation proceeded through 7alpha- and 7beta-hydroxy derivatives of dehydroepiandrosterone. The structure of the products was determined by mass spectrometry, 1H-NMR spectroscopy, and 13C-NMR spectroscopy. The proposed microbiological method for producing steroid lactones opens prospects for the syn thesis of novel steroid compounds. PMID- 26027353 TI - [Microbial degradation of glyphosate herbicides (review)]. AB - This review analyzes the issues associated with biodegradation of glyphosate (N (phosphonomethyl)glycine), one of the most widespread herbicides. Glyphosate can accumulate in natural environments and can be toxic not only for plants but also for animals and bacteria. Microbial transformation and mineralization ofglyphosate, as the only means of its rapid degradation, are discussed in detail. The different pathways of glyphosate catabolism employed by the known destructing bacteria representing different taxonomic groups are described. The potential existence of alternative glyphosate degradation pathways, apart from those mediated by C-P lyase and glyphosate oxidoreductase, is considered. Since the problem of purifying glyphosate-contaminated soils and water bodies is a topical issue, the possibilities of applying glyphosate-degrading bacteria for their bioremediation are discussed. PMID- 26027354 TI - [Oil biodegradation by microbial-plant associations]. AB - The degradation of petroleum hydrocarbons by plant-microbial associations, as well as the peculiarities of the interaction between microorganisms in consortium and the associated plants, have been studied. It was shown that degrader microorganisms that are part of the consortium Rhodococcus erythropolis S26, Acinetobacter baumannii 1 B, Acinetobacter baumannii 7, and Pseudomonas putida F701 were effective in the degradation of oil and were good colonizers of plant roots (barley). The efficiency of oil degradation increases when microorganisms and plants are used together. PMID- 26027355 TI - [The role of mineral phosphorus compounds in naphthalene biodegradation by Pseudomonas putida]. AB - The effect of phosphate concentration in the culture medium on the growth and naphthalene degradation by Pseudomonas putida BS 3701 was studied. The limiting concentration of phosphate was 0.4 mM and 0.1 mM under cultivation in media with naphthalene and glucose, respectively The phosphate deficiency correlated with a decrease in the activities of naphthalene dioxygenase and salicylate hydroxylase and with salicylate accumulation in the culture medium. We suggest that this fact indicates the impaired regulation of gene expression of "upper" and "lower" pathways of naphthalene oxidation. Under naphthalene degradation, the cells accumulated three times more inorganic polyphosphates as compared with the consumption of glucose. The involvement of polyphosphates in the regulation of naphthalene metabolism has been considered. PMID- 26027356 TI - [Anaerobic bacteria involved in the degradation of aromatic sulfonates to methane]. AB - An anaerobic microbial consortium that degrades benzene- and p-toluenesulfonate to form methane and fatty acids has been produced. Pure cultures of three strains of anaerobic spore-forming bacteria Clostridium spp., as well as the sulfate reducing bacteria Desulfovibrio sp., were isolated and characterized. Phylogenetic analysis of 16S rRNA gene sequences of strains showed that pure cultures of clostridia strains 14, 24, and 21 are close to Clostridium lituseburense DSM 797T, C. sartagoforme DSM 1292T, and C. pascui DSM 10365T, and the sulfate-reducing strain SR1 is genotypically closer to Desulfovibrio aminophilus ALA-3T. Preliminary characterization of isolated bacteria makes it possible to assume that these are new species of the genera Clostridium and Desulfovibrio, the distinctive feature of which is the ability to incorporate aromatic sulfonates in their metabolisms. PMID- 26027357 TI - [Properties of unrelated salicylate hydroxylases in bacteria of the genus pseudomon]. AB - The unrelated salicylate hydroxylases NahG and NahU of the strains Pseudomonasfluorescens 142 NF and P. Putida BS3701 were extracted and purified by ion-exchange and hydrophobic and gel permeation chromatography. The extracted enzymes differed in kinetic and catalyst performance during salicylate hydrolysis. For NahU salicylate hydroxylase, Km and Vmax were found to be higher (3.1 +/- 0.6 microM and 7.7 +/- 0.4 microM/min, respectively) than for NahG salicylate hydroxylase (1.3 +/- 0.1 microM and 4.7 +/- 0.1 microM/min, respectively). The activity of both enzymes toward substituted salicylates was higher in cases where the substituent groups were in para position than in cases with those in meta position. The activity toward substituted salicylates with substituent groups in meta position was different. The activity of salicylate hydroxylase NahG was higher toward salicylates with substituent groups in position 3; salicylate hydroxylase NahU activity was higher toward those with substituent groups in position 5. This suggests a difference in the spatial configuration of active sites in extracted unrelated salicylate hydroxylases. PMID- 26027358 TI - [Selective regulation of laccase isoform production by the Lentinus strigosus 1566 fungus]. AB - The effects of a number of culture medium components, such as peptone, yeast extract, mono- and disaccharides, copper ions, 2,6-dimethylphenol, and polycaproamide fiber, on the laccase activity dynamics in the culture liquid and laccase isoform production by the Lentinus strigosus 1566 fungus were studied. It was demonstrated that some saccharides selectively induced or inhibited the synthesis of different laccase isoforms. Similar action was exerted by copper ions, 2,6-dimethylphenol, and polycaproamide fiber, as well as by their combination. Selective in vivo regulation of the production of certain laccase isoforms by basidial fungi by means of altering the culturing medium composition can be utilised for various biotechnological purposes. PMID- 26027359 TI - [Cultivation of a novel cellulase/xylanase producer, Trichoderma longibrachiatum mutant TW 1-59-27: production of the enzyme preparation and the study of its properties]. AB - As a result of gamma-mutagenesis of Trichoderma longibrachiatum TW1 and the subsequent selection of improved producers, a novel mutant strain, TW1-59-27, capable of efficiently secreting cellulase and xylanase was obtained. In a fed batch cultivation, the new TW1-59-27 mutant was significantly more active compared with the original TW1 strain. For instance, the activities of cellulase (towards carboxymethylcellulose) and xylanase in the culture broth (CB) increased by 1.8 and two times, respectively, and the protein content increased by 1.47 times. The activity of these enzymes in the dry enzyme preparation derived from the CB of the TW1-59-27 mutant was 1.3-1.8 times higher than that in the preparation derived from the original TW1 strain. It was established that the cellulase from the enzyme preparation of the mutant strain demonstrated the maximum activity at 55-65 degrees C; it occurred in xylanase at 60 degrees C. The pH optima of these enzymes were pH 4.5-5.0 and pH 5.0-6.0, respectively. It was shown that the content of endoglucanases in the enzyme preparation increased from 7% to 13.5%; the effect is largely driven by the secretion of endoglucanase-1. An enzyme preparation with increased endoglucanase-1 content is promising for use as a feed additive in agriculture. PMID- 26027360 TI - [Biosynthesis of biologically active low-molecular weight compounds by fungi of the genus Penicillium (review)]. AB - The recent data on exometabolite biosynthesis in fungi of the genus Penicillium is summarized. The study of creative species, as well as those isolated from extreme ecotopes, resulted in the identification of a number of novel, biologically active compounds. Alkaloid biosynthesis has been shown to begin on.the first day of fungus cultivation and to proceed throughout the cultivation period. Idiophase kinetics was observed for the biosynthesis of polyketide metabolites. The mechanisms of regulation of biosynthesis of promising bioactive compounds are discussed. PMID- 26027361 TI - [The effect of pH, aeration, and temperature on arachidonic acid synthesis by Mortierella alpina]. AB - The effects of pH, aeration, and temperature on the growth of fungal strain Mortierella alpina LPM-301 and the synthesis of lipids and arachidonic acid in glycerol-containing medium were studied. Arachidonic acid production in the stationary growth phase was found to depend considerably on the pH value; it reached the optimum at pH 6.0 and was irreversibly inhibited at a pH of 3.0. The PO2 values in a range from 10 to 50% showed no marked effect on mycelium growth or the synthesis of lipids and arachidonic acid. The temperature optimum for arachidonic acid production was 20-22 degrees C. Under continuous cultivation, the amount of arachidonic acid reached 29.8% of lipids and 7.4% of biomass. The arachidonic acid yield from the glycerol consumed was 4.1% by mass and 8.8% by energy. It is suggested that arachidonic acid synthesis at an unfavorable pH and elevated temperatures was limited by the activity of A-12-desaturase and by the conversion of linoleic to arachidonic acid, respectively. PMID- 26027362 TI - [Biosynthesis of isocitric acid by the yeast yarrowia lipolytica and its regulation]. AB - We studied the biosynthesis of isocitric acid from rapeseed (canola) oil by the yeast Yarrowia lipolytica and its regulation. We determined a fundamental possibility for directed biosynthesis of isocitric acid by Y lipolytica yeast, with only minimal amounts of citric acid byproduct, when grown on a medium containing canola oil. Wild type strains of Y lipolytica were mutagenized by UV irradiation and treatment with N-methyl-N'-nitro-N-nitrosoguanidine (NG). Subsequent selection on media with acetate and isocitrate resulted in isolation of a UV/NG Y lipolytica UV/NG mutant that synthesized isocitrate and citrate at a ratio of 2.7:1. In the parent strain, this ratio is 1:1. Inhibition of isocitrate lyase, a key enzyme in the metabolism of isocitric acid, by the addition of itaconic acid resulted in increased synthesis of isocitrate with a ratio of isocitrate to citrate reaching 6:1. Culturing of the Y lipolytica UV/NG mutant in a pilot industrial fermenter in the presence of itaconic acid resulted in the production of 88.7 g/L of isocitric acid with a yield of 90%. PMID- 26027363 TI - [Effect of Bacillus cereus hemolysin II on hepatocyte cells]. AB - We investigated the efficiency of increasing the permeability (permeabilization) of cell membranes in primary liver cells by Bacillus cereus hemolysin II. An assessment of the degree of permeabilization was car ried out by measuring the fluorescence intensity of various low molecular weight dyes, which enter through pores into hepatocyte cells cultivated with hemolysin. We uncovered a high efficacy of hemolysin HlyII action on hepatocyte cell walls, which exceeded the effect of nonionic detergent, digitonin, which is commonly employed for pore formation in various cell membranes. Our results also point to the reversibility of membrane permeabilization in primary hepatocytes. The data obtained in this study can be utilized for assessments of pore-forming activity, in studies of hepatic mechanisms of action, and also the determination of the liver toxicity for different low molecular weight drugs. PMID- 26027364 TI - [Biosensors and biofuel cells: research focused on practical application (review)]. AB - Studies on the production of microbial and enzyme biosensor analyzers and microbial biofuel cells for potential practical application are discussed. PMID- 26027365 TI - [Computerized optical image analysis as a tool for microbiological studies (review)]. AB - Computerized optical image analysis is a variant of using computerized analysis of images of study objects recorded by optical methods. This review covers the literature and our own data on computer analysis of optical images of microbial origin. It is concluded that the use of this type of analysis in microbiology makes it possible to accelerate, objectify, and automate many conventional microbiological methods, as well as opens up new possibilities for studying single cells. PMID- 26027366 TI - [Genetic and environmental aspects of mathematical disabilities]. AB - Mathematics has become highly important in today's high-tech life. Success in everyday life requires the presence of mathematical knowledge, which, in turn, appears to be the basis for any innovative scientific activity. However, a large percentage of the population demonstrates mathematical disabilities. Mathematical abilities and disabilities represent a complex and multifactorial phenomenon caused by the influence of both genetic and environmental factors. The present review is focused on studies based on a candidate gene approach and on genome wide association studies previously reporting associations between gene polymorphisms and cognitive impairments, particularly mathematical disabilities. According to the first approach, learning and memory formation are influenced by variants in neurotransmitter system genes, genes involved in the working memory and synaptic plasticity. The results of the second approach demonstrates that the matrix metalloproteinase 7 gene (MMP7), the glutamate receptor ionotropic kainate 1 gene (GRIK1), and the dynein axonemal heavy chain 5 gene (DNA H5) are responsible for developing mathematical disabilities. PMID- 26027367 TI - [Sex inversion and epigenetic regulation in Vertebrates]. AB - This review discusses issues related to the regulation of sex determination and differentiation in various groups of Vertebrates. Special attention was paid to factors of external and internal control for various genetic systems of sex determination, as well as to the epigenetic control of this process. Opportunities for sex inversion in various animals were also discussed. PMID- 26027368 TI - [Analysis of diversity and identification of the genovariants of plague agent strains from Mongolian foci]. AB - The genetic diversity of Yersinia pestis strains from the Mongolian natural plague foci has been investigated. A total of 32 strains isolated from western, eastern, and central aimaks, as well as from the territory of the Gobi region, have been studied. Twenty-four strains belong to the main Y. pestis subspecies, while eight belong to other subspecies. There is only one strain of biovar medievalis (genovariant 2.MED1) among the strains of the main subspecies, while the rest of the subspecies belong to the biovar antiqua. Biovar antiqua strains are split into three groups. Strains from the eastern part of the country were classified as genovariant 2.ANT3, and those from the western and central regions were classified as genovariant 3.ANT2, which was endemic for Mongolia. One strain from the Bayan-Ulegeiskii aimak had the rare genovariant 4.ANT. None of the strains of the biovar antiqua belonged to its ancient 0.ANT branch, which is inconsistent with the commonly accepted idea that ancient marmot's plague agent race originates from Mongolia. Six out of eight strains of the minor subspecies belonged to the ulegeica subspecies, which are endemic to Mongolia, one strain belonged to the microtus group, and the last belonged to a previously uncharacterized variant of the minor subspecies. PMID- 26027369 TI - [Insertional mutation in the AZOBR_p60120 gene is accompanied by defects in the synthesis of lipopolysaccharide and calcofluor-binding polysaccharides in the bacterium Azospirillum brasilense Sp245]. AB - In the bacterium Azospirillum brasilense Sp245, extracellular calcofluor-binding polysaccharides (Cal+ phenotype) and two types of lipopolysaccharides, LPSI and LPSII, were previously identified. These lipopolysaccharides share the same repeating O-polysaccharide unit but have different antigenic structures and different charges of their O-polysaccharides and/or core oligosaccharides. Several dozens of predicted genes involved in the biosynthesis of polysaccharides have been localized in the AZOBR_p6 plasmid of strain Sp245 (GenBank accession no. HE577333). In the present work, it was demonstrated that an artificial transposon Omegon-Km had inserted into the central region of the AZOBR_p60120 gene in the A. brasilense Sp245 LPSI- Cal- KM252 mutant. In A. brasilense strain Sp245, this plasmid gene encodes a putative glycosyltransferase containing conserved domains characteristic of the enzymes participating in the synthesis of O-polysaccharides and capsular polysaccharides (accession no. YP004987664). In mutant KM252, a respective predicted protein is expected to be completely inactivated. As a result of the analysis of the EcoRI fragment of the AZOBR_p6 plasmid, encompassing the AZOBR_p60120 gene and a number of other loci, novel data on the structure of AZOBR_p6 were obtained: an approximately 5-kb gap (GenBank accession no. KM189439) was closed in the nucleotide sequence of this plasmid. PMID- 26027370 TI - [Inheritance of reversions to male fertility in male-sterile sorghum hybrids with 9E cytoplasm male sterility induced by environmental conditions]. AB - Heritable phenotypic alterations occurring during plant ontogenesis under the influence of environmental factors are among the most intriguing genetic phenomena. It was found that male-sterile sorghum hybrids in the 9E cytoplasm from the F1 and F2 generations, which were obtained by crossing CMS lines with different fertile lines grown in field conditions, were transferred to greenhouse produce fertile tillers. Lines created by the self-pollination of revertant tillers exhibit complete male fertility upon cultivation under various environments (in the field, Tdry plot,(y) Tirrigated plot(y)). In a number of test-crosses of revertants to CMS lines in the 9E cytoplasm, restoration of male fertility in F1 hybrids was found, indicating that revertants possess functional fertility-restoring genes. A high positive correlation was found between the fertility level of the test-cross hybrids and the hydrothermal coefficient (the ratio of the sum of precipitation to the sum of temperatures) during the booting stage and pollen maturation (r = 0.75...0.91; P<0.01), suggesting that a high level of plant water availability is needed for the expression of fertility restoring genes of revertants. These data show that the fertility-restoring genes for the 9E cytoplasm are dominant in conditions of high water availability and recessive in drought conditions; reversions to male fertility are due to up regulation of fertility-restoring genes by a high level of water availability. Comparative MSAP-analysis of DNA of male-sterile and male-fertile test-cross hybrids using HpaII/MspI restrictases and primers to polygalacturonase gene ADPG2, which is required for cell separation during reproductive development, and gene MYB46, the transcription factor regulating secondary wall biosynthesis, revealed differences in the number and the length of amplified fragments. Changes in the methylation of these genes in conditions of drought stress are apparently the reason for male sterility of sorghum hybrids in the 9E cytoplasm. These data demonstrate that methylation of nuclear genes in sterility-inducing cytoplasm may be one of mechanisms causing the CMS phenomenon. PMID- 26027371 TI - [Genetic diversity of common wheat varieties at the gliadin-coding loci]. AB - One hundred and fifty Russian and foreign winter common wheat varieties were examined by the PAGE method. A total of 70 alleles were identified at seven gliadin-coding loci. It was demonstrated that 42% of varieties were heterogeneous, i.e., were represented by a number of genotypes, while 52% of varieties were homogeneous. A unique combination of gliadin alleles was typical of 91.3% of examined varieties, while 8.7% of varieties had identical alleles of all gliadin-coding loci and were indistinguishable. Frequent and rare alleles were identified, with the former accounting for 18.6% of all alleles. It was demonstrated that allelic diversity at the Gli-2 loci (47 alleles) was almost twice that at the Gli-1 loci (23 loci) and was determined by the number of rare alleles. New alleles for the winter common wheat, including three alleles of the GliA2 locus and two alleles of the Gli-B2 locus, were determined. A tendency toward a reduction of the genetic diversity level in modern varieties, which was due to the use of identical parental varieties in breeding programs, was identified. PMID- 26027372 TI - [Analysis of wheat and rye semidwarfing gene distribution in spring hexaploid triticale (Triticosecale Wittm.) varieties and lines]. AB - A collection of spring hexaploid triticale varieties and promising breeding lines has been examined for the presence of wheat Rht-B1b, Rht-B1e, and Rht8c semidwarfing genes and the rye Hl semidwarfing gene. It was discovered in spring triticale that these semidwarfing genes are represented by only one, the Rht-B1b wheat gene. The presence of this gene is associated with shortening of spring triticale plants by 28 cm on average, which constituted 26% of their initial height. Rht-B1b was found in all of the studied commercial varieties of spring triticale, which rendered it possible to conclude that plant height reduction is a necessary condition for increasing the competitiveness of this crop culture. PMID- 26027373 TI - [Features of the B chromosome in Korean wood mice Apodemus peninsulae (Thomas, 1906) from Transbaikalia and the Far East identified by the FISH method]. AB - Korean field mice (Apodemus peninsulae) are widely distributed throughout northeastern Asia, including the Russian Far East, northern China, the Korean peninsula, Sakhalin, and Hokkaido. This mouse species is characterized by a high frequency of animals with B chromosomes differing in their number, morphology, and DNA composition in different geographical regions. For the first time a comparative analysis of DNA probes from B chromosomes with metaphase chromosomes of mice from Transbaikalia, the Far East (including the Russian Far East), Japan, and South Korea was conducted by in situ hybridization. B chromosomes in mice from the Russian Far East were shown to exhibit low variability in DNA content; however, the DNA composition of B chromosomes in species from Transbaikalia and Japan were highly variable. B chromosomes in A. peninsulae from the South Korean population demonstrate minor differences from those from the Russian Far East. We discuss the origin of B chromosomes in the studied region in comparison with previously obtained data for mice from Siberia and the Baikal region, as well as the dispersal routes of the Korean field mouse. PMID- 26027374 TI - [Identification of potentially invasive species of black flies [Diptera: Simuliidae] from Armenia based on an analysis of variability in the mtDNA barcode of the cox1 gene and chromosomal polymorphism]. AB - Black flies (Diptera, Simuliidae) are well known for their medical, environmental, and veterinary importance. The simuliid fauna of Armenia includes 53 species. A number of dominant species are of ecological importance. Complex analysis, which involved morphometric, cytogenetic, and molecular genetic approaches, was conducted to characterize the species status of black flies inhabiting the territory of Armenia. It was shown that the predominant simuliid species, Simulium paraequinum and Simulium kiritshenkoi, belong to a group of species with minimal variability of the cox1 gene. The recently discovered species, Simulium noellery and Simulium [B.] erythrocephalum, which are new to Armenia, can be considered as potentially invasive, which is supported by the low level of variability of the cox1 gene. PMID- 26027375 TI - [Length and structure of telomeric DNA in three species of Baikal gastropods (Caenogastropoda: Hydrobioidea: Benedictiidae)]. AB - The structure of telomeric repeat (TTAGGG)n was determined and the length of telomeric DNA (tDNA) was measured in three species of gastropods from the family Benedictiidae that are endemic to Lake Baikal. Fluorescence in situ hybridization (FISH) confirmed the localization of a telomeric repeat at the chromosome ends. The sizes of tDNA in "giant" eurybathic, psammo-pelobiontic species Benedictia fragilis and shallow water litho-psammobiontic species B. baicalensis with medium shell sizes were similar (16 +/- 2.9 and 15 +/- 2.1 kb, respectively), but they had a greater length than that of the shallow water spongio-litobiontic species Kobeltocochlea martensiana with small shells (10.5 +/- 1.5 kb). We discuss tendencies in age-related changes in tDNA length in snails and a possible mechanism for maintaining tDNA size in ontogeny. PMID- 26027376 TI - Genome-wide association study identifies QTLs for EBV of backfat thickness and average daily gain in Duroc pigs. AB - Backfat thickness (BFT) and average daily gain (ADG) are two important economic traits in commercial swine production. Identifying QTLs and uncovering the molecular mechanism for BFT and ADG would greatly help to speed up the breeding progress. In current breeding program, EBV for these two traits are calculated and formulated a comprehensive breeding index, which then be used to improve pig performance. Using Illumina PorcineSNP60 BeadChip, a pilot genomewide association studies (GWAS) for BFT and ADG in 83 Duroc pigs were performed. A total of 31 genome-wise significant SN Ps were detected to be associated with BFT on SSC 4, 9, 11, 12 and 14, ten of which were coincident with previously reported QTL regions. There are two genome-wise loci prominently associated with ADG on SSC2 and SSC13, respectively. The two loci on SSC2 are well overlapped with the QTL regions previously reported. All the 31 significant SNPs associated with BFT are verified on 219 outbreed pigs, six SN Ps reach an extreme significant level and seven SNP reaches a significant level, CACNA1E and ACBD6 are chosen as positional candidate genes. Our findings not only confirmed previously findings, but also revealed a number of novel SNPs associated with BFT and ADG. Two positional candidate genes CACNA1E and ACBD6 were identified for further study. These results would facilitate the identification of causative genes for BFT and ADG. PMID- 26027377 TI - Differential expression of porcine TAP1 gene in the populations of pigs. AB - Transporter associated with antigen processing (TAP) transports peptides from the cytosol into the endoplasmic reticulum (ER) for subsequent loading onto the major histocompatibility complex (MHC) class I molecules. TAP is consisted of two subunits: TAP and TAP2. Using Real-time PCR technology, this study detected tissue expression profile and analyzed the differential expression of TAP1 gene in Sutai Escherichia coli-resistant group, Yorkshire and Meishan pigs. Tissue expression profile revealed that TAP1 gene expressed in all tissues we detected, and the expression levels were high in lung, immune tissues and intestines. Through the comparation of gene expression differention in different populations, TAP1 expression level of Sutai E. coli-resistant group was significantly higher than that of Yorkshire and Meishan populations in liver, spleen, lung, kidney, thymus, lymph, duodenum and jejunum (P<0.05). Meanwhile TAP1 gene was more highly expressed in Sutai E. coli-resistant group than that of Meishan population in stomach (P<0.05). In conclusion, the upregulation of TAP1 expression level in E. coli-resistant group could be related to E. coli F18 infection. In addition, Chinese local pigs may have special immune response and genetic mechanism in resisting E. coli F18 infection which is differing from MHC I moleculars. PMID- 26027378 TI - [Genetic diversity of cyanophages of the Myoviridae family as a constituent of the associated community of the Baikal sponge Lubomirskia baicalensis]. AB - Molecular-genetic analysis of cyanophages of the family Myoviridae from the associated community of the endemic Baikal sponge Lubomirskia baicalensis was carried out based on the g20 gene fragment. A large cyanophage diversity according to the g20 marker gene was found in the sponge. The Baikal sponge cyanophages were shown to be similar to those inhabiting plankton. Moreover, specific cyanophage groups that are significantly different from all of the known groups inhabiting the Lake Baikal were revealed. PMID- 26027379 TI - CKM gene polymorphism in Russian and Polish rowers. AB - Muscle-specific creatine kinase (CKMM) plays a vital role in the energy homeostasis of muscle cells. The A/G variation (rs8111989) located in the 3' untranslated region of the CKM gene has been found to be the most relevant in terms of genetic testing in sport. The aim of the presented study was to test the hypothesis that the G allele might represent a genetic element that contributes to the improvement of endurance performance in Polish and Russian rowers. The distribution of the CKM genotypes was examined in a group of Polish and Russian athletes in comparison with non-athlete controls. There were no statistical differences between the rowers and the control groups across the CKM genotypes when Polish or Russian participants were analyzed. Based on the obtained results, it may be speculated that the CKM A/G polymorphism is not an important determinant of endurance performance level in Polish and Russian rowers. However, these results should be interpreted with caution as they can be limited by many factors. PMID- 26027380 TI - [Oxygen-dependent energy deficit as related to the problems of ontogenetic development disorders and human sociobiological adaptation (theoretical and applied aspects)]. AB - The review states and argues theoretical propositions on the pathogenetic role of pre- and perinatal hypoxic-ischemic brain damage in the formation of sustained oxygen-dependent energy deficit underlying in further ontogenesis the following neurobiological abnormalities: a) a decline in the level of health and compensatory-adaptive capacities of the organism, b) disorders of the psycho speech development and adaptive behavior in children, c) early development of neuropsychic diseases, g) addition of other types of brain energy metabolism (including glucose metabolism) disorders in chronic polyetiologic diseases young and middle-aged individuals. We highlight and theoretically substantiate the integrated physiological parameters of the oxygen-dependent energy deficit types. We address the features of abnormalities in neuroreflectory and neurohumora regulatory mechanisms of the wakefulness level and its vegetative and hemodynamic provision in different types of energy deficit in children with DSMD, ADHD and school maladjustment. The use of the state-of-the-art neuroimaging techniques significantly increased the possibility of the disintegration of regulatory processes and cognitive functions in children with psycho-speech delays and in a wide range of chronic polyetiologic diseases. PMID- 26027381 TI - [Antiapoptotic effect of gangliosides on PC12 cells exposed to bacterial lipopolysaccharide]. AB - Lipopolysaccharide (LPS) from Escherichia coli of the 0111:B4 serotype was shown to exert the apoptotic effect on PC12 neuronal cells at concentrations of 0.1 and 0.125 mg/ml in DMEM (serum free medium). GD1a and GM1 gangliosides at a concentration of 100 MUM were found to raise the PC12 cell viability and decrease the percentage of PC12 cells in the late apoptotic phase after exposure to LPS. PMID- 26027382 TI - [The effect of hypoxia on cholinesterase activity in rat sensorimotor cortex]. AB - This study reports the dynamics of changes in postnatal ontogenesis of the activity of soluble and membrane-bound forms of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in sensorimotor cortex of rats as well as the pattern of their changes after prenatal hypoxia (E14, 7% O2, 3 h) or acute hypoxia in adult animals (4 months, 7% O2, 3 h). In normally developing rats the activity of the membrane-bound AChE form in the sensorimotor cortex gradually increased up to the end of the first month after birth and remained at this high level during all further postnatal ontogenesis, while the activity of the soluble form of AChE reached its maximum on the 10th day after birth and decreased significantly by the end of the first month. In animals exposed to prenatal hypoxia the activity both of the soluble and membrane bound forms of AChE during the first two weeks after birth was 20-25% lower, as compared to controls but increased by the end of the first month and even exceeded the control values remaining increased up to old age (1.5 years). The activity of both BChE forms in rat sensorimotor cortex at all stages of postnatal ontogenesis was significantly lower than of AChE, although the dynamics of their changes was similar to that of AChE. Prenatal hypoxia led to a decrease in the activity of the membrane-bound form of BChE, as compared to controls, practically at all developmental stages studied, but was higher at the end of the first month after birth. At the same time, the activity of the soluble form of BChE was decreased only on the 20th day of development, as compared to the control, but increased from the end of the first month of life onwards. Acute hypoxia in adult rats also led to a decrease in the activity of both forms of AChE and BChE in the sensorimotor cortex but the dynamics of these changes was different for each enzyme. Thus, insufficient oxygen supply to the nervous tissue at different stages of ontogenesis has a significant effect on the activity and ratio of various forms of cholinesterases exhibiting either growth factor or signaling properties. This may lead to changes in brain development and formation of behavioural reactions, including learning and memory, and also increase the risk of development of the sporadic form of Alzheimer's disease (AD)--one of the most common neurodegenerative diseases of advanced age. This study expands our knowledge of the properties of brain cholinesterases under normal and pathological conditions and may be useful for developing new approaches towards prevention and treatment of AD. PMID- 26027383 TI - [Different properties of pyruvate kinase from rabbit and hare muscles]. AB - Some catalytic and kinetic properties of pyruvate kinase (PK, EC 2.7.1.40) isolated from the heart and skeletal muscles of rabbits and hares with a 9-16 fold purification were studied. The initial specific activity of the enzyme in hare heart homogenates was 66% and in skeletal muscles 25% as high as in respective rabbit tissues. Temperature optimums and thermostability of PK from hare tissues were higher as compared with those in rabbits. From the comparison of K(M) (S0.5) values it follows that hare skeletal muscle PK exhibits a highest affinity to phosphoenol pyruvate, but lowest to ADP, as compared with rabbit skeletal muscle PK. Moreover, PK from both hare tissues exhibits a positive kinetic cooperativity (Hill coefficient > 1.35) of the phosphoenol pyruvate and ADP binding sites. In contrast to PK from rabbit tissues, the enzyme from the hare heart and muscles PK is presented by its allosteric isoform which might by advantageous under extreme conditions of the hare's habitation. PMID- 26027384 TI - [Long-term changes in adaptive behavior of rats after neonatal inflammatory pain]. AB - In this study we addressed the tonic nociceptive system functional activity in the formalin test, anxiety- and depression-like behaviors and spatial learning in adolescent male rats exposed in the neonatal development to repeated inflammatory pain peripheral stimulation. The following groups of 25-day-old rats were used after being exposed on days 7 and 8 to: 1) formalin-induced inflammatory pain with maternal separation for 60 min (FS), 2) the same inflammatory pain stimulation without maternal separation (FWS), 3) physiological saline injection with maternal separation for 1 h (SS), 4) physiological saline injection without maternal separation (SWS) and 5) no stimulation (intact rats). The data obtained indicate that pain caused in 7-8-day-old rat pups by formalin injection into the plantar pad of the hind paw manifests by adolescence (day 25 as a strengthened inflammatory response under the analogous painful stimulation in the formalin test, adaptive behavior disorder in the forced swimming test and spatial learning disability. Our findings that a short-term repeated maternal deprivation of the 7 8-day-old rat pups without inflammatory pain increases the depression-like behavior are also of particular interest. Thus, a repeated inflammatory pain during the neonatal development brings about significant changes in the adaptive behaviors studied as well as in spatial learning in adolescent rats. PMID- 26027385 TI - [Prenatal hypoxia modifies working memory and the activity of hippocampal polyphosphoinositide system in rats]. AB - The present study was aimed at the analysis of spatial learning abilities in the Morris water maze (working memory) as well as hippocampal levels of phosphatidylinositol 4,5-diphosphates (TPI), phosphatidylinositol 4-phosphates (DPI), phosphotidylinositols (MPI), and expression of the type 1 inositol 1,4,5 trisphosphate receptor (IR3R1) in rats exposed to severe hypobaric hypoxia (ascent to 11 km, 3 h) on prenatal days 14-16 (group 1) or 17-19 (group 2). Exposure to severe hypoxia led to significant elevation of TP 1 and DPI hippocampal levels in juvenile and adult rats in the group 1, however these changes were more pronounced in juvenile rats than in adults. In the group 2, hypoxia up-regulated TPI and DPI hippocampal levels in juvenile rats, but in adult animals of this group just a small TPI level up-regulation was detected. Activation of IR3R1 expression was found to occur in the hippocampus both of juvenile and adult rats in the groups 1 and 2. These finding are consistent with the impaired spatial learning ability we revealed in the Morris water maze, indicative of a working memory deficit in the rat offspring exposed to hypobaric hypoxia during the first half of the last week of pregnancy. PMID- 26027386 TI - [Correlations of reproductive parameters of water vole females (Arvicola amphibius) with morphometric and hormonal characteristics]. AB - Fluctuations in water vole population size depend on abiotic and intra-population factors affecting the physiological condition of females. The relationship between variability in reproductive success and morpho-physiological characteristics of female during pregnancy is studied quite poorly. In standard vivarium conditions, the morphometric and hormonal characteristics of female were assessed at different stages of pregnancy (first trimester--days 4-7, second trimester--days 8-14, third semester--days 15-20), and their relationship with potential and actual fecundity and the level of embryonic lethality was elucidated. The general regression model was used in the data analysis. Positive correlations were found between potential fecundity and the female body mass at mating, body mass index and blood testosterone level. The reproductive parameters under study were independent of the blood thyroxin level. A positive correlation was established between the level of embryonic loss and the indices of liver and lung functions. Liver and spleen are essential for the maintenance of the female body mass homeostasis during the reproductive period. PMID- 26027387 TI - [Serotonin and neuropeptide FMRFamide in the nervous system of Opisthioglyphe ranae (Trematoda: Plagiorchiidae). an immunocytochemical study]. AB - The presence and localization of the serotoninergic and FMRFamidergic structures in the nervous system of the trematode Opisthioglyphe ranae, the marsh frog intestinal parasite, was studied using immunocytochemistry. The serotonin immunoreactive nerve cells and fibers were revealed in the head ganglia, circular commissure, longitudinal nerve cords and their connective commissures, as well as around the oral and ventral suckers, oesophagus and genital pore. FMRF-specific immunoreactivity was observed in the head ganglia, longitudinal nerve cords and terminal parts of the reproductive system. The results obtained are discussed in light of the available data on the presence and functional significance of the above-mentioned neurotransmitters in trematodes. PMID- 26027388 TI - [Hearing sensitivity to bandpass filtering of low-frequency noise spectrum in dolphin Tursiops truncatus]. PMID- 26027389 TI - [Relict forms of copper-binding sites in the human blood coagulation factor VIII]. PMID- 26027390 TI - [Octopamine, the insect stress hormone, modifies grooming pattern in the cockroach Periplaneta americana]. PMID- 26027391 TI - [Multipeaked neurons in the primary fields of auditory cortex in the house mouse (Mus musculus)]. PMID- 26027392 TI - [Non-small cell lung cancer: HER2 oncogene status]. AB - OBJECTIVE: to study HER2 protein and HER2 gene, their heterogeneity in non-small cell lung cancer. MATERIAL AND METHODS: 218 intraoperative non-small cell lung samples were examined using tissue matrix methods. HER2 protein was determined by immunohistochemistry (clone 4B5, <> and HER2 gene and CEP1 7 were evaluated by in situ hybridization (SISH, <>). RESULTS: Positive and indefinite statuses were found in 59 (27%) and 47 (22%) cases, respectively; intratumor heterogeneity was detected in 32 (30%) cases. Amplification of the HER 2 gene was found in 12 (6%) cases; that of the HER2 gene along with an increase in CEPI 7 was observed in 7 (3%) cases; elevated CEP1 7 levels were seen in 19 (9%) cases. Intratumor heterogeneity of HER2 gene amplification was not found; however, one case of adenocarcinoma showed high-level HER2 gene amplification in the gland-like areas and low-level HER2 gene amplification in the solid areas. HER2-positive status and amplification were more common in adenocarcinoma than in squamous cell carcinoma (p<0.001). There was a moderate correlation between HER2 immunohistochemical status and amplification (r=0.38; p<0.001). CONCLUSION: Thus, in non-small cell lung cancer, there is an elevated HER2 protein level and, well less frequently, altered activity in the HER2 gene (amplification) as a cause of enhanced protein synthesis. PMID- 26027393 TI - [Molecular mechanisms of lung cancer development at its different stages in nuclear industry workers]. AB - OBJECTIVE: to assess mutational events in exons 5, 7, and 8 of the p53 gene and to reveal mutant p53 protein in verified cases of morphologically altered (proliferative and precancerous changes, lung cancer) and histologically unaltered, lung tissues in workers exposed to occupational radiation. MATERIAL AND METHODS: The investigation used formalin-fixed paraffin-embedded unaltered and altered lung tissue blocks (FFPBs) obtained from the human radiobiological tissue repository. The shelf-life of FFPBs was 5-31 years. An immunohistochemical technique using mouse antibodies against p53 protein (<>, Denmark), stained with diaminobenzidine (DAB) chromogen, was employed to determine p53 protein. DNA was isolated from lung tissue FFPBs with QIAmp DNA FFPE Tissue Kit, (<>, USA). Polymerase chain reaction (PCR) was performed to amplify the p53 gene exons 5, 7, and 8 selected for examination, by applying the sequences of genes and primers, the specificity of which was checked using the online resource (http://www.ncbi.nlm.nih.gov/blast). PCR products were detected by temporal temperature gradient gel-electrophoresis and the Sanger sequencing method. The obtained DNA fragments were analyzed on a sequencer ABI Prism 3100 Genetic Analizer (<>, USA). Computer-aided DNA analysis was made using the BLAST program. A package of applied Statistica 6.0 programs was employed for statistical data processing. Results. Immunohistochemical analysis showed that mutant p53 protein was absent in the cells of unaltered lung tissue and the number of cells with mutant p53 protein increased in all the patients with proliferative and precancerous changes and lung cancer, suggesting p53 protein dysfunction. The total number of p53 gene mutations in exons 5, 7, and 8, if there were proliferative and precancerous lung tissue changes and lung cancer, were 25, 20, and 40%, respectively. All the found mutations were transversions (the substitution of purine for pyrimidine or, conversely), indicating the action of exogenous mutagens. CONCLUSION: The results of this investigation have confirmed other investigators' data showing that p53 gene mutations in lung cancer are observed in 40-70% of cases. The differences in the number of cases of altered lung tissue with mutations in the p53 gene (not more than 40%) and in those of p53 protein expression were found in 100%, suggesting the regulation of p53 gene function in the cell at multiple levels. PMID- 26027394 TI - [Expression of plasminogen activator system components in the gastric mucosa in portal hypertensive gastropathy]. AB - OBJECTIVE: to study the expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the gastric mucosal (GM) vascular endothelium and epithelial cells of patients with portal hypertensive gastropathy (PHG) and those with portal hypertension (PH) without signs of PHG as compared to a control group. MATERIAL AND METHODS: GM biopsy specimens from patients with PHG, those with PH without signs of PHG, and controls with the normal gastric mucosa were immunohistochemically examined. RESULTS: Comparison of the expression of uPA in the GM vascular endothelium and epithelial vessels revealed no significant differences in the patient groups. The level of PAI-1 in the GM vessels was statistically significantly higher in the control group than in the groups of patients with PHG and PH without PHG. PAI-1 expression in the GM epithelial cells was significantly more commonly absent in the PHG group than in the control group. An analysis of an uPA and PAI-1 expression ratio showed a statistically significant predominance of the expression of uPA over its inhibitor in the GM vascular endothelium of the patients with PHG and those with PH without PHG as compared to the controls. CONCLUSION: The predominance of uPA over PAI-1 in the GM vessels and epithelial cells can play a role in the development of GM bleeding. PMID- 26027395 TI - [Postmortem diagnosis of influenza during its epidemic and interepidemic periods]. AB - OBJECTIVE: to assess the potential role of influenza virus in fatal pneumonia during the epidemic and interepidemic periods. MATERIAL AND METHODS An immunohistochemical method was used to clinically and morphologically analyze 40 fatal outcomes of acute pneumonias in 2009-2013. Laboratory tests could not establish the diagnosis of influenza in 20 cases of the study group with clinical and/or morphological pattern of this illness. Seventeen cases occurred during the epidemic period (autopsies from November 2009 to January 2010) and the seasonal rise of morbidity; 3 cases were observed during the interepidemic period. A control group was additionally formed from 20 cases with neither clinical nor further morphological evidence of suspected influenza in the presence of pneumonia in both the epidemic and interepidemic periods. RESULTS: In the study group, influenza virus nucleoprotein was detected by immunohistochemistry (IHC) in the bronchial epithelial cells with the signs of cytopathic changes in half of the cases and that in the alveolocytes in 30%. Sporadic cases displayed a positive IHC response of blood vessel endothelial cells, which was attended by staining of the epithelium and macrophages. The maximum disease periods with the virus nucleoprotein being detected by IHC in the macrophages doubled those in the epithelial cells (40 versus 22 days). The control group showed a large number of cases with a positive macrophage response that was approximately similar to that in the study group. Despite the frequent detection and intensive staining of macrophages, they demonstrated no cytopathic changes, which can be explained by the low virulence persistence of influenza virus in the macrophages. CONCLUSION: These investigations showed the role of influenza virus in the occurrence of additional deaths in the epidemic period and a possible fatal outcome in the interepidemic period. PMID- 26027396 TI - [Structure of teeth in mature ovarian teratoma]. AB - MATERIAL AND METHODS: The authors investigated three mature ovarian dermoid cysts that were found to contain atypically developed teeth (one tooth in one cyst; 2 teeth in another cyst, and a set of 8 teeth with jawbone fragments in the third one). Their structure was examined using the epoxy resin plastination technique to obtain plastinated sections. RESULTS: Some of these teratomous teeth have obvious signs of alteration in both dentin and enamel, which may be referred to as fluorosis or macular enamel hypoplasia in one case whereas other sections indicate a caries lesion. CONCLUSION: These facts are contradictory to the concept of the exogenous nature of dental caries, which is accepted in dentistry. PMID- 26027397 TI - [Computer technologies in teaching pathological anatomy]. AB - The paper gives experience with personal computers used at the Academician A.L. Strukov Department of Pathological Anatomy for more than 20 years. It shows the objective necessity of introducing computer technologies at all stages of acquiring skills in anatomical pathology, including lectures, students' free work, test check, etc. PMID- 26027398 TI - [Experience in teaching a biopsy-section course in Belarus]. AB - The paper deals with the improvement of teaching a biopsy-section course (BSC). The authors have analyzed the most frequent errors in the interaction of clinicians with a pathology service and summed up the experience of the Pathological Anatomy Department in practical work and teaching the BSC. The differentiated approach to teaching the BSC to resident students of different specialties is proposed. PMID- 26027399 TI - [Skin morphology in congenital ichthyosis (Harlequin fetus)]. AB - The paper describes a skin morphological examination using an immunohistochemical study (Ki-67, cytokeratin (CK) 5/6, and CK LMW) in a dead 4-month-old girl with congenital ichthyosis (Harlequin ichthyosis (HI)). There is impaired proliferative activity, abnormalities in epidermal differentiation with abnormal CK LMW synthesis, and those in the differentiation of the skin appendages. There are also pronounced sclerotic changes with a predominance of reticulin fibers, derma, and its vessels. The patient with HI and trichoepithelioma is noted to have the similar immunohistochemical phenotype of hair bulbs. PMID- 26027400 TI - [Immunohistochemical examination of skin biopsy specimens with calculation of C fibers in the diagnosis of polyneuropathy]. AB - The paper discusses the anatomy of innervation of the skin, the epidermis and dermis in particular, which are related to pain, the markers of skin nerves and cells. It gives data on the diagnosis of fine unmyelinated fibers, by immunohistochemically examining skin biopsy specimens. The paper also describes the morphometry of skin nerves: intraepidermal nerve fibers, dermal nerve fibers, and autonomic nerve fibers. It discusses whether a skin biopsy specimen may be used to diagnose polyneuropathies of different etiology: diabetic, immune, HIV related, and hereditary ones. PMID- 26027401 TI - [Vascularization of hepatoceliular carcinoma]. AB - The paper gives the data available in the literature on vascularization of hepatocellular carcinoma (HCC). Sinusoidal capillarization and unpaired arteries are shown to play an important role in the development and progression of HCC. The density of microvessels detected by immunohistochemical techniques is a morphological indicator of the degree of angiogenic processes. Higher-grade HCC is followed by changes in its vascularization and concurrent with a progressive increase in the proportion of blood entering along the hepatic artery. The morphological indicators of microvessel density are recommended to use as addi- tional criteria for determining the prognosis of the disease, designing targeted anti-angiogenic drugs, and evaluating the efficiency of performed therapy. PMID- 26027402 TI - [Angiogenesis and its association with inflammation and fibrosis in course of the development of scleroderma systematica]. AB - Scleroderma systematica (SDS) is a chronic autoimmune disease characterized by severe fibrosis of the skin and visceral organs. Vascular disorders are an important component of the disease, but the mechanisms of vascular injury and their prevention are unknown. Angiogenesis in SDS is accompanied by the apparent expression of angiogenic factors, such as vascular endothelial growth factor and basal or fibroblast growth factor. Imbalance of these markers with endostatin expression is noted. This disease is characterized by inflammation and the intensity of neoangiogenesis correlates with its activity. The fact that there may be a pathogenic relationship between the processes of angiogenesis and the intensity of further fibrosis is shown. There is a vicious circle of the induction and maintenance of the processes of angiogenesis, inflammation, and fibrosis in SDS. PMID- 26027403 TI - [The role and place of pathology services in ensuring and improving the quality of medical care: Organizational and legal aspects]. AB - The paper considers the legal and organizational issues of the activity of pathology services in improving medical care. It shows the main (diagnostic and medico-organizational) areas of pathology work to improve the quality of medical care. PMID- 26027404 TI - [Aleksey Nikolaevich Chistovich (on the occasion of the 110th birth anniversary)]. PMID- 26027405 TI - [Pathologists in the Great Patriotic War years (on the occasion of the 70th anniversary of the Great Victory)]. PMID- 26027406 TI - [Natalia Mikhailovna Khmelnitskaya (on the occasion of the 70h birth anniversary)]. PMID- 26027407 TI - America's bitter pill. PMID- 26027408 TI - Do emergency medicine residents and faculty have similar learning styles when assessed with the Kolb learning style assessment tool? AB - Experiential learning theory and the Kolb Learning Style Inventory (Kolb LSI) have influenced educators worldwide for decades. Knowledge of learning styles can create efficient learning environments, increase information retention, and improve learner satisfaction. Learning styles have been examined in medicine previously, but not specifically with Emergency Medicine (EM) residents and attendings. Using the Kolb LSI, the learning styles of Emergency Medicine residents and attendings were assessed. The findings showed that the majority of EM residents and attendings shared the accommodating learning style. This result was different than prior studies that found the majority of medical professionals had a converging learning style and other studies that found attendings often have different learning styles than residents. The issue of learning styles among emergency medical residents and attendings is important because learning style knowledge may have an impact on how a residency program structures curriculum and how EM residents are successfully, efficiently, and creatively educated. PMID- 26027409 TI - Imaging of a gastrobronchial fistula after gastric bypass surgery and the contrast dilemma. AB - Obesity and bariatric procedures have become more common in the United States over the past 20 years. Therefore, the incidence of previously rare complications is also on the rise. One of the more ominous complications is a gastric leak with subsequent creation of a fistulous tract. A very rare subset of this complication is when the fistulous tract connects the gastric pouch to the bronchial tree. Several contrast agents can be utilized for imaging of the upper gastrointestinal tract, some of which may cause significant adverse effects if not properly tailored to the specific pathology in question. We present a case of a gastrobronchial fistula developing several years after a laparoscopic Roux-en-Y gastric bypass and discuss the ideal choice of contrast material when imaging this specific pathology. PMID- 26027411 TI - Effects of ethanol and acetaldehyde load on erythrocyte deformability in healthy subjects and patients with liver cirrhosis. AB - Alcohol intake leads to the distribution of alcohol and its metabolite, acetaldehyde throughout the blood and organs. Hepatic cirrhosis is associated with abnormal red blood cell morphology and function, particularly impaired red blood cell deformability. To investigate the effect of drinking on red blood cells in patients with hepatic cirrhosis, erythrocyte deformability was evaluated in response to alcohol and acetaldehyde tolerance. Erythrocyte deformability in 10 healthy and 15 cirrhotic subjects was examined by filterability of the red blood cells. Erythrocyte deformability decreased markedly in the cirrhosis group compared with the healthy group (p < 0.05). No significant change in erythrocyte deformability was observed in healthy or cirrhotic subjects due to ethanol 100 mM tolerance. Acetaldehyde tolerance elicited a significant decrease in erythrocyte deformability at 2 mM in the cirrhosis group (p < 0.05). Alcohol consumption in cirrhotic patients was suggested to worsen erythrocyte deformability and red blood cell function. Decreased erythrocyte deformability worsens microcirculation in the liver, resulting in more severe hepatic dysfunction. PMID- 26027410 TI - Utilizing digital breast tomosynthesis to improve accuracy of preoperative needle localization for surgical excisional biopsy. AB - We describe a case of an 88-year-old female who presented for needle localization to undergo excisional biopsy of a subtle asymmetry in the left breast, with successful localization achieved using digital breast tomosynthesis. Initial attempts at localization under 2D mammography were inaccurate. Subsequent digital breast tomosynthesis application for triangulation resulted in better visualization of the target, and successful localization. Specimen radiography confirmed the lesion was accurately targeted and pathology revealed ductal carcinoma in situ. Needle localization guided by mammography and inherent limitations of 2D mammography are discussed, along with a literature review of tomosynthesis guided needle localization. PMID- 26027412 TI - [A review about new approaches using the Internet and computer technology for people with drug use disorder]. AB - PURPOSE: Over the past two decades, computerized and Internet-based interventions for the treatment of various health problems, including substance abuse, have been developed and used to resolve treatment-related issues. The purpose of this study is to review selected studies that conducted computerized and Internet based psychosocial interventions for people with drug-use problems. METHODS: We used a PubMed search to identify relevant studies to our review based on the following inclusion criteria: 1) the study participants were drug users; 2) the Internet or computer technologies were used for the interventions; 3) the study used psychosocial interventions; and 4) meta-analysis and randomized controlled trial (RCT). In total, 12 studies (meta-analysis = 1, RCT = 11) were identified and included in this review. The RCTs extracted in this study were not included in the meta-analysis. RESULTS: The meta-analysis showed that studies targeting people with alcohol and/or drug-use disorders (n = 11) had a small effect size (d = 0.24). However, the effect size was considered heterogeneous. Most of the reviewed RCTs assessed either drug use or abstinence as primary outcome using such methods as self-report and urine test, and showed that intervention groups exhibited greater improvement in the drug use condition than the control groups. The effect sizes (d) ranged from 0.19 to 0.54. One study revealed that a computerized intervention was more cost effective if it was added to treatment as usual. Various interventions were designed to use behavioral therapy approaches, e.g., cognitive behavioral therapy, motivational interviewing, as well as face-to face interventions. Treatment retention, adverse events, relationship with therapists and engagement in the treatment were assessed as secondary outcomes. These outcomes were equivalent or more effective for the intervention groups compared with the control groups. CONCLUSIONS: Computerized and Internet-based psychosocial interventions for drug users have a small to medium effect on the reduction of drug use but are highly cost effectiveness. These types of interventions can contribute to the improvement of treatment environments where treatment resources are very limited or where there is a stigma attached to drug users, as is often the case in Japan. PMID- 26027414 TI - An update on strengths-based, solution-focused brief therapy. PMID- 26027415 TI - "There's no-fresh air there": narratives of smoke exposure among residents of extended-stay hotels. AB - Hotel environments have been identified as places where hospitality workers and patrons are at an increased risk for smoke exposure and associated health hazards. However, little research has been conducted to understand experiences of long-term hotel residents. This article presents narrative accounts of tobacco smoke exposure from 37 residents at extended-stay hotels in a large metropolitan Atlanta county. Residents' narratives included an awareness of smoking as an unhealthy habit but a shared activity that facilitates social engagement at the hotel. Secondhand smoke narratives included descriptions of exposure from roommates and hotel neighbors. Thirdhand smoke narratives included reports of persistent pollution and smoke residue in the hotel environment. These results suggest a need for further research to understand the extent and impact of tobacco smoke exposure among this understudied population. The implications of this research support the efforts of social workers to engage in clean air advocacy and policy making for a vulnerable population. PMID- 26027416 TI - The practice of solution-focused brief therapy in mainland China. AB - Solution-focused brief therapy (SFBT) is a strengths-based approach that was developed by American social workers and a team of interdisciplinary colleagues in the early 1980s. This article provides a review of SFBT in mainland China, showing the cross-cultural and transdisciplinary use of SFBT by diverse professionals within China. In particular, this article discusses how SFBT has spread from the United States to China and how the practice of SFBT has grown in mainland China. This is the first article in English to review the Chinese literature and further summarize the use of SFBT in mental health and health care fields within China. Practice implications for the future use of SFBT with Chinese people are also discussed. PMID- 26027417 TI - The other 23 hours: a qualitative study of fitness provider perspectives on social support for health promotion for adults with mental illness. AB - Current efforts to reduce the increased risk of premature death from preventable cardiovascular disease among adults with serious mental illness (SMI) through lifestyle change have had limited success. Engaging informal support systems to promote healthy behaviors in everyday life may increase the effectiveness of health promotion interventions targeting this at-risk population. In-depth semistructured interviews were conducted with 10 fitness trainers serving adults with SMI in a health promotion program at community mental health centers to explore their perspectives on the potential of enlisting support from significant others for health behavior change. Trainers reported that the majority of participants had a relative or significant other who influenced their health behaviors, and they saw potential value in involving them in efforts to improve health outcomes by extending support into participants' daily lives. They did not feel qualified to work with families of individuals with mental illness, but they were willing to partner with providers who had experience in this area. Social workers who practice with families could play a critical role on health promotion teams addressing cardiovascular risk in adults with SMI by using their skills and experiences to engage families in supporting a relative through the process of health behavior change. PMID- 26027418 TI - Caste- and ethnicity-based inequalities in HIV/AIDS-related knowledge gap: a case of Nepal. AB - Caste- and ethnicity-based inequalities are major obstacles to achieving health equity. The authors investigated whether there is any association between caste- and ethnicity-based inequalities and HIV-related knowledge within caste and ethnic populations. They used the 2011 Nepal Demographic and Health Survey, a nationally represented cross-sectional study data set. The study sample consisted of 11,273 women between 15 and 49 years of age. Univariate and logistic regression models were used to examine the relationship between caste- and ethnicity-based inequalities and HIV-related knowledge. The study sample was divided into high Hindu caste (47.9 percent), "untouchable" caste (18.4 percent), and indigenous populations (33.7 percent). Within the study sample, the high caste population was found to have the greatest knowledge of the means by which HIV is prevented and transmitted. After controlling for socioeconomic and demographic characteristics, untouchables were the least knowledgeable. The odds ratio for incomplete knowledge about transmission among indigenous populations was 1.27 times higher than that for high Hindu castes, but there was no significant difference in knowledge of preventive measures. The findings suggest the existence of a prevailing HIV knowledge gap. This in turn suggests that appropriate steps need to be implemented to convey complete knowledge to underprivileged populations. PMID- 26027419 TI - How does intimate partner violence differ depending on level of rurality of residential area in Spain? AB - Intimate partner violence (IPV) is recognized as a worldwide public health problem. Most theories ascribe IPV to individual, family, or cultural factors. Authors analyzed different residential areas in Spain in terms of IPV frequency as well as its impact on health and the use of services. A standardized self administered cross-sectional survey was administered to ever-partnered adult women ages 18 to 70 years receiving care at primary health care centers (N = 10,322). Logistic regression analyzed the association between the level of rurality and health indicators, IPV, and use of services. The lowest frequency of IPV among women is reflected in higher rurality. Women of medium and low rurality presented a poorer self-perceived health and more physical health problems. Women from medium and low rurality areas declared seeking health services more frequently. These results show the importance of the environment in health and indicate the need for research on urban-rural differences in health problems to develop specific public health programs for each country. PMID- 26027420 TI - Patient and staff perceptions of social worker counseling before surgical therapy for head and neck cancer. AB - Patients who undergo surgical therapy for head and neck cancer often face a tremendous challenge involving considerable psychological distress and impaired social functioning. These difficulties are often compounded by logistical difficulties such as transportation, financial assistance, and continuity of care after the acute hospitalization. Social workers have a unique opportunity to address the psychosocial and logistical issues facing these patients through preadmission counseling and coordination. The study reported in this article aimed to assess the effect of preadmission counseling for patients planning to undergo major surgical therapy for head and neck cancer. Ten patients who received preadmission counseling were surveyed to ascertain the utility of it in regard to multiple social and logistical factors. Comparisons were made with patients who did not receive such counseling. Staff perceptions were likewise obtained. The surveys indicated that preadmission counseling helped in regard to improving peri-admission support and access to financial and logistical resources, and lowered levels of anxiety during admission. Areas of potential improvement were identified, including addressing substance abuse issues in a timely manner. PMID- 26027421 TI - Lessons learned from a secret Facebook support group. AB - The National Association of Social Workers developed practice standards for social workers using technology in their practice. These standards were derived from the foundation of the social work code of ethics and are helpful as social workers explore the use of new tools for the benefit of their clients. Hospice caregivers, both active and bereaved, are in great need of support but are often unable to attend traditional support groups. Facebook secret groups offer social workers a potential tool, given the geographic barriers that exist for traditional face-to-face support groups. The authors' experience with a secret Facebook group indicates that the technology can be useful when managed by a social worker facilitator. As social workers continue to explore helpful ways to use technology with clients, it is critical that they evaluate that practice and assess the clinical outcomes to establish an evidence base behind this practice. PMID- 26027422 TI - Factors associated with health care discrimination experiences among a national sample of female-to-male transgender individuals. AB - Transgender individuals experience harassment, violence, and discrimination in a number of settings. Although health care discrimination against transgender people has been documented, this issue is understudied. Using a national cross sectional survey data set (N = 1,711), the authors sought to determine how gender identity and presentation predict health care discrimination experiences among female-to-male (FTM) transgender people after demographic and socioeconomic characteristics are controlled. Analyses were conducted using chi-square tests and a two-step logistic regression. The majority of participants were white (73.9 percent) and between 25 and 44 years old (65.2 percent). Overall, 41.8 percent of FTM participants reported verbal harassment, physical assault, or denial of equal treatment in a doctor's office or hospital. When other factors were controlled, being Native American or multiracial, identifying as queer or asexual/other, having a graduate degree, living full-time as nonbirth gender, using hormones or surgery for medical transition, and having identification documents that list one's preferred gender were associated with increased reporting of health care discrimination experiences; being 45 years or older and reporting an annual income of $60,000 or more were associated with decreased risk. The study's findings can be useful to social workers, who play a role in educating health care providers and advocating for policies that improve health care experiences for FTM and other transgender patients. PMID- 26027423 TI - Effect of enrollment length in migrant Head Start on children's weight outcomes. AB - The purpose of this study is to examine whether the length of children's enrollment in Migrant Head Start affects children's weight outcomes. Children in the Michigan Migrant Head Start program were classified depending on years of enrollments: one year (n = 638), two years (n = 293), and three or more years (n = 426). Logistic regression analyses were conducted to examine whether the probability of children having overweight or obesity differed depending on years of enrollment. There is a lower obesity rate among children who attended Head Start for multiple years than in those who attended for one year. Among children who attended for one year, those who enrolled for more weeks were more likely to be overweight than those who enrolled for fewer weeks. Children with special needs, those with more siblings, and those on the Supplemental Nutrition Assistance Program (SNAP) had a lower obesity rate. Although the primary goal of the Head Start Program is school readiness rather than health improvement, migrant and seasonal farmworkers' children might need more years of comprehensive intervention, such as Head Start, to prevent obesity by making full use of the beneficial nutrition programs. SNAP access and other culturally competent practices could also reduce the obesity rate. PMID- 26027424 TI - Addressing childhood obesity using a multidisciplinary approach with social workers. AB - Childhood obesity can be effectively addressed with behavioral interventions in programs such as CATCH and Planet Health using a multidisciplinary approach. Social workers and school nurses are in close contact with children and youths at risk of obesity and their families within the school setting and are prepared to lead a multidisciplinary team in program planning, implementation, and evaluation related to reducing childhood obesity. PMID- 26027425 TI - Social work expertise: an overlooked opportunity for cutting-edge system design under the Patient Protection and Affordable Care Act. PMID- 26027426 TI - Severe iron-deficiency anaemia and feeding practices in young children. AB - OBJECTIVES: Fe-deficiency anaemia (IDA) occurs in 1-2 % of infants in developed countries, peaks at 1-3 years of age and is associated with later cognitive deficits. The objectives of the present study were to describe the characteristics of young children with severe IDA and examine modifiable risk factors in a developed-country setting. DESIGN: Two prospective samples: a national surveillance programme sample and a regional longitudinal study sample. SETTING: Canada, 2009-2011. SUBJECTS: Two samples of young children recruited from community-based health-care practices: a national sample with severe anaemia (Hb<80 g/l) due to Fe deficiency and a regional sample with non-anaemic Fe sufficiency. RESULTS: Children with severe IDA (n 201, mean Hb 55.1 g/l) experienced substantial morbidity (including developmental delay, heart failure, cerebral thrombosis) and health-care utilization (including a 42 % hospitalization rate). Compared with children with Fe sufficiency (n 597, mean Hb 122.4 g/l), children with severe IDA consumed a larger volume of cow's milk daily (median 1065 ml v. 500 ml, P<0.001) and were more likely to be using a bottle during the day (78 % v. 43 %, OR=6.0; 95 % CI 4.0, 8.9) and also in bed (60 % v. 21 %, OR=6.5; 95 % CI 4.4, 9.5). CONCLUSIONS: Severe IDA is associated with substantial morbidity and may be preventable. Three potentially modifiable feeding practices are associated with IDA: (i) cow's milk consumption greater than 500 ml/d; (ii) daytime bottle use beyond 12 months of age; and (iii) bottle use in bed. These feeding practices should be highlighted in future recommendations for public health and primary-care practitioners. PMID- 26027427 TI - Experimental study of antitumour activity and effects on leukocyte count of intraperitoneal administration and hyperthermic intraperitoneal chemoperfusion (HIPEC) with dioxadet in a rat model of ovarian cancer. AB - Survival of rats with advanced ovarian cancer after intraperitoneal (i.p.) administration and hyperthermic intraperitoneal chemoperfusion (HIPEC) with dioxadet and effects of these treatment modalities on leukocyte count were evaluated in two independent series of experiments. Hyperthermic intraperitoneal chemoperfusion with dioxadet (15 mg/kg) provided median survival of rats of 49 days (95% CI 28-70), i.p. administration of dioxadet (1.5 mg/kg) of 28 days (95% CI 16-36; P = 0.020). Single i.p. injection of dioxadet caused a significant decrease in total number of leukocytes (17-52%), granulocytes (18-75%), lymphocytes (18-62%) and monocytes (12-46%) in the peripheral blood of tumour bearing rats compared to untreated animals. After HIPEC with dioxadet, the total number of leukocytes, granulocytes, lymphocytes and monocytes in peripheral blood of rats remained significantly higher than the corresponding values in the group with dioxadet. PMID- 26027429 TI - Zein-Based Nanoparticles Improve the Oral Bioavailability of Resveratrol and Its Anti-inflammatory Effects in a Mouse Model of Endotoxic Shock. AB - Resveratrol offers pleiotropic health benefits including a reported ability to inhibit lipopolysaccharide (LPS)-induced cytokine production. The aim of this work was to prepare, characterize, and evaluate a resveratrol nanoparticulate formulation based on zein. For this purpose, the oral bioavailability of the encapsulated polyphenol as well as its anti-inflammatory effects in a mouse model of endotoxic shock was studied. The resveratrol-loaded nanoparticles displayed a mean size of 307 +/- 3 nm, with a negative zeta potential (-51.1 +/- 1.55 mV), and a polyphenol loading of 80.2 +/- 3.26 MUg/mg. In vitro, the release of resveratrol from the nanoparticles was found to be pH independent and adjusted well to the Peppas-Sahlin kinetic model, suggesting a mechanism based on the combination of diffusion and erosion of the nanoparticle matrix. Pharmacokinetic studies demonstrated that zein-based nanoparticles provided high and prolonged plasma levels of the polyphenol for at least 48 h. The oral bioavailability of resveratrol when administered in these nanoparticles increased up to 50% (19.2 fold higher than for the control solution of the polyphenol). Furthermore, nanoparticles administered daily for 7 days at 15 mg/kg were able to diminish the endotoxic symptoms induced in mice by the intraperitoneal administration of LPS (i.e., hypothermia, piloerection, and stillness). In addition, serum tumor necrosis factor-alpha (TNF-alpha) levels were slightly lower (approximately 15%) than those observed in the control. PMID- 26027428 TI - Functional Characterization of a Dehydratase Domain from the Pikromycin Polyketide Synthase. AB - Metabolic engineering of polyketide synthase (PKS) pathways represents a promising approach to natural products discovery. The dehydratase (DH) domains of PKSs, which generate an alpha,beta-unsaturated bond through a dehydration reaction, have been poorly studied compared with other domains, likely because of the simple nature of the chemical reaction they catalyze and the lack of a convenient assay to measure substrate turnover. Herein we report the first steady state kinetic analysis of a PKS DH domain employing LC-MS/MS analysis for product quantitation. PikDH2 was selected as a model DH domain. Its substrate specificity and mechanism were interrogated with a systematic series of synthetic triketide substrates containing a nonhydrolyzable thioether linkage as well as by site directed mutagenesis, evaluation of the pH dependence of the catalytic efficiency (V(max)/K(M)), and kinetic characterization of a mechanism-based inhibitor. These studies revealed that PikDH2 converts d-alcohol substrates to trans-olefin products. The reaction is reversible with equilibrium constants ranging from 1.2 to 2. Moreover, the enzyme activity is robust, and PikDH2 was used on a preparative scale for the chemoenzymatic synthesis of unsaturated triketide products. PikDH2 was shown to possess remarkably strict substrate specificity and is unable to turn over substrates that are epimeric at the beta-, gamma-, or delta-position. We also demonstrated that PikDH2 has a key ionizable group with a pK(a) of 7.0 and can be irreversibly inactivated through covalent modification by a mechanism-based inhibitor, which provides a foundation for future structural studies to elucidate substrate-protein interactions. PMID- 26027430 TI - Tuning Open-Circuit Voltage in Organic Solar Cells with Molecular Orientation. AB - The role of molecular orientation of a polar conjugated polymer in polymer fullerene organic photovoltaic (OPV) cells is investigated. A planar heterojunction (PHJ) OPV cell composed of poly(3-hexylthiophene) (P3HT) and [6,6] phenyl C61-butyric acid methyl ester (PCBM) is used as a model system to isolate the effect of the interfacial orientation on the photovoltaic properties. The molecular orientation of the aggregate P3HT relative to the PCBM layer is varied from highly edge-on (conjugated ring plane perpendicular to the interface plane) to appreciably face-on (ring plane parallel to the interface). It is found that as the P3HT stacking becomes more face-on there is a positive correlation to the OPV open-circuit voltage (V(OC)), attributed to a shift in the highest occupied molecular orbital (HOMO) energy level of P3HT. In addition, the PHJ OPV cell with a broad P3HT stacking orientation distribution has a V(OC) comparable to an archetypal bulk heterojunction (BHJ) device. These results suggest that, in the BHJ OPV cell, the hole energy level in the charge transfer state is defined in part by the orientation distribution of the P3HT at the interface with PCBM. Finally, the photoresponses of the devices are also shown to have a dependence on P3HT stacking orientation. PMID- 26027431 TI - Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. AB - BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.). PMID- 26027432 TI - The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence. AB - Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse. PMID- 26027434 TI - Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers. AB - B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE. PMID- 26027433 TI - Primary Treatment Options for High-Risk/Medically Inoperable Early Stage NSCLC Patients. AB - Lung cancer is among the most common cancers worldwide and is the leading cause of cancer death in both men and women. For patients with early stage (American Joint Committee on Cancer T1-2, N0) non-small-cell lung cancer, the current standard of care is lobectomy with systematic lymph node evaluation. Unfortunately, patients with lung cancer often have medical comorbities, which may preclude the option of surgical resection. In such cases, a number of minimally invasive to noninvasive treatment options have gained popularity in the treatment of these high-risk patients. These modalities provide significant advantages, including patient convenience, treatment in an outpatient setting, and acceptable toxicities, including reduced impact on lung function and a modest risk of postprocedure chest wall pain. We provide a comprehensive review of the literature, including reported outcomes, complications, and limitations of sublobar resection with or without intraoperative brachytherapy, radiofrequency ablation, microwave ablation, percutaneous cryoablation, photodynamic therapy, and stereotactic body radiotherapy. PMID- 26027435 TI - Epidemiological characteristics and influential factors of hand, foot and mouth disease (HFMD) reinfection in children in Anhui province. AB - Hand, foot and mouth disease (HFMD) is an acute contagious condition caused by a spectrum of human enteroviruses. HFMD reinfection is common in the absence of cross-protection from other virus subtypes. This study focused on reinfection in children in Anhui province, China between 2008 and 2013 using surveillance system data. We classified 8960 cases as reinfected, corresponding to a rate of 2.02%. The reinfection rate was higher in boys than in girls [odds ratio (OR) 1.27, 95% confidence interval (CI) 1.21-1.32, P < 0.001], children aged < 3 years (OR 3.82, 95% CI 3.58-4.07, P < 0.001), and children living in rural areas (OR 1.09, 95% CI 1.04-1.14, P = 0.001). The reinfection rate in children who were originally infected with non-enterovirus A71 (non-EVA71) enteroviruses was higher than those infected with EVA71 (OR 1.36, 95% CI 1.02-1.80, P = 0.034). Influential factors of reinfection rate included annual incidence (beta coefficient = 0.715, P = 0.002) and the proportion of EVA71 in patients with mild HFMD (beta coefficient = -0.509, P = 0.018). These results demonstrate that boys aged <3 years, especially those in rural areas or regions with a lower EVA71 proportion are more prone to reinfection, and specific health education programmes should be developed to protect these susceptible populations. PMID- 26027437 TI - A highly selective and fast-response fluorescent probe for visualization of enzymatic H2S production in vitro and in living cells. AB - An o-fluorinated-azido-capped rhodamine probe can react with H2S efficiently and selectively to give large off-on fluorescence enhancement. The probe was used to develop an assay for cystathionine beta-synthase acitivity and for in situ visualization of endogenously produced H2S in living cells. PMID- 26027438 TI - Preface. PMID- 26027439 TI - Mood disorders are associated with a more severe hypovitaminosis D than schizophrenia. AB - Patients with psychiatric disorders display high levels of hypovitaminosis D (<50nmol/L). It remains unclear whether it is associated with specific diagnoses. To further explore vitamin D status in psychiatric inpatients, 82 individuals with mood disorders or schizophrenia/schizoaffective disorders were included. Hypovitaminosis D was significantly lower in patients with mood disorders than patients with schizophrenia (standardized beta coefficient=0.385, p=0.007). Further studies are warranted to determine specific causes of hypovitaminosis D and the interest of supplementation. PMID- 26027436 TI - Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions. AB - INTRODUCTION: Heart valve disease is an increasingly prevalent and clinically serious condition. There are no clinically effective biological diagnostics or treatment strategies. The only recourse available is replacement with a prosthetic valve, but the inability of these devices to grow or respond biologically to their environments necessitates multiple resizing surgeries and life-long coagulation treatment, especially in children. Tissue engineering has a unique opportunity to impact heart valve disease by providing a living valve conduit, capable of growth and biological integration. AREAS COVERED: This review will cover current tissue engineering strategies in fabricating heart valves and their progress towards the clinic, including molded scaffolds using naturally derived or synthetic polymers, decellularization, electrospinning, 3D bioprinting, hybrid techniques, and in vivo engineering. EXPERT OPINION: Whereas much progress has been made to create functional living heart valves, a clinically viable product is not yet realized. The next leap in engineered living heart valves will require a deeper understanding of how the natural multi-scale structural and biological heterogeneity of the tissue ensures its efficient function. Related, improved fabrication strategies must be developed that can replicate this de novo complexity, which is likely instructive for appropriate cell differentiation and remodeling whether seeded with autologous stem cells in vitro or endogenously recruited cells. PMID- 26027440 TI - Investigation of automatic avoidance in displaced individuals with chronic Posttraumatic Stress Disorder (PTSD). AB - Avoidance of trauma-related stimuli is a key feature of Posttraumatic Stress Disorder (PTSD). However, avoidance has almost exclusively been investigated with explicit measures targeting more strategic aspects of behavior. The aim of the present study was to examine automatic avoidance in older individuals displaced as children at the end of World War II with (n=22) and without PTSD (n=26) and in non-traumatized control participants (n=23) with an Approach-Avoidance Task (AAT). Participants were instructed to respond to the color (gray, brown) of trauma-related, neutral, and control pictures by pushing or pulling a joystick. Groups did not differ significantly as to their behavioral tendencies towards trauma-related pictures. Thus, there was no evidence for automatic avoidance in individuals with PTSD. However, high vigilance was associated with stronger implicit avoidance towards trauma-related pictures in the PTSD group. Several explanations for the non-significant results as well as implications and limitations of the present findings are discussed. PMID- 26027442 TI - Prevalence and construct validity of compulsive buying disorder in shopping mall visitors. AB - Compulsive buying is a relatively new psychopathological concept and very few data are currently available regarding the prevalence and validity of compulsive buying disorder. In this cross-sectional study, we establish the prevalence of compulsive buying disorder in shopping mall visitors and explore the construct validity of the concept using the revised version of the Edwards Compulsive Buying Scale in 1441 shopping mall visitors looking at shopping habits, current substance use (smoking, alcohol and illicit drug) and various psychological characteristics. Overall, 8.7% (95% CI: 7.3-10.3) of our sample was classified as having a compulsive buying disorder. Compulsive buyers were younger, less educated and more likely to be female than non-compulsive buyers. They were also more likely to have used licit and illicit substances. Compulsive buyers also reported higher levels of impulsivity and obsessive-compulsive symptoms, lower levels of well-being and self-esteem and more psychological distress. Finally, compulsive buyers were five times more likely to meet criteria for borderline personality disorder than non-compulsive buyers. Compulsive buying is a frequent disorder in shopping mall visitors and is associated with important and robust indicators of psychopathology thus supporting the validity of the construct. PMID- 26027441 TI - Beta-catenin in schizophrenia: Possibly deleterious novel mutation. AB - Schizophrenia is a debilitating psychiatric disorder, affecting approximately 1% of the human population. Mostly genetic factors contribute to schizophrenia, but the genetics are complex and various aspects of brain functioning and structure, from development to synapse plasticity, seem to be involved in the pathogenesis. The goal of the study was to look for novel mutations in genes, implicated in molecular networks, important in schizophrenia. In the study four candidate genes taking part in the WNT signaling pathway were analyzed by sequencing in a cohort of 87 schizophrenia patients from Saint Petersburg, Russia. The gene list included CTNNB1 (beta-catenin), GSK3B, WNT2B and WNT7B. The impact of discovered variants on the protein function was analyzed in silico. We found three variants in the genes CTNNB1 and WNT7B, absent in healthy controls, including 212 controls from the same geographic area. The novel mutation c.1943A>G (p.N648S) in CTNNB1 seems to be the best candidate for disease-associated mutation in this study, as it damages the protein product in silico. This is the first study reporting mutations in CTNNB1 in schizophrenia. PMID- 26027443 TI - Human papillomavirus prevalence to age 60 years among Australian women prevaccination. AB - Background The prevalence of human papillomavirus (HPV) at the cervix varies with age, peaking following sexual debut and declining thereafter in most populations. In some populations, a second peak is observed. Here we describe the prevalence of HPV at the cervix among Australian women before the commencement of the HPV vaccination program. METHODS: Women aged 15 to 60 years attending health services for cervical screening between 2005 and 2008 were invited to participate. Liquid based cervical specimens were tested for 37 types of HPV using linear array. The percentage and 95% confidence interval of women with any type of HPV, any of 13 high risk HPV types, and with vaccine-preventable HPV types (types 6, 11, 16 and 18) were estimated in 5-year age bands. RESULTS: Among 1929 women aged 15-60 years, HPV prevalence peaked at 64% at age 15-20 years, then declined gradually to 12% at age 41-45 years, whereafter it rose to 19% in women 51-55 years then returned to 14% in 56-60 year olds. Prevalence curves were similar for high-risk HPV types and vaccine-targeted HPV types 6, 11, 16 and 18 and when results were restricted to women with only normal cytology. CONCLUSIONS: The shape of the prevalence curve we observed is similar to those from other Western populations. Variation in prevalence curves is likely due to differences in sexual behaviour between populations and over time, reactivation of HPV during perimenopause, and possibly the presence of cervical screening programs. These data are the first such data from the Oceania region. PMID- 26027445 TI - Association of Adventitial Vasa Vasorum and Inflammation With Coronary Hyperconstriction After Drug-Eluting Stent Implantation in Pigs In Vivo. AB - BACKGROUND: The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined. METHODS AND RESULTS: Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52+/-7% vs. BES, 22+/-3%, P<0.01), which was equally prevented by a selective Rho-kinase inhibitor, hydroxyfasudil. A significant difference in vasoconstriction between SES and BES was sustained for 6 months. A micro-CT showed VV augmentation at the SES site, extending to the proximal and distal edges. Immunostainings demonstrated that VV formation, macrophage infiltration in the adventitia and Rho-kinase expressions/activation were significantly enhanced at the SES edges as compared with the BES edges. CONCLUSIONS: The DES with durable polymers enhances VV formation and inflammation in the adventitia, associating with the pathogenesis of DES-induced coronary hyperconstriction through Rho-kinase activation in pigs in vivo. PMID- 26027446 TI - Could Circulatory Syndecan-1 Be a Predictable Biomarker for Acute Kidney Injury in Patients With Acute Decompensated Heart Failure? PMID- 26027447 TI - Why Is Proteinuria an Independent Risk Factor for Contrast-Induced Nephropathy? PMID- 26027448 TI - Reprint of: Food reformulation and the (neo)-liberal state: new strategies for strengthening voluntary salt reduction programs in the UK and USA. AB - Globally, excess salt intake is a significant cause of preventable heart disease and stroke, given the established links between high salt intake, high blood pressure, and cardiovascular disease. This paper describes and evaluates the voluntary approaches to salt reduction that operate in the United Kingdom and the United States, and proposes a new strategy for improving their performance. Drawing on developments in the theory and practice of public health governance, as well as theoretical ideas from the field of regulatory studies, this paper proposes a responsive regulatory model for managing food reformulation initiatives, including salt reduction programs. This model provides a transparent framework for guiding industry behavior, making full use of industry's willingness to participate in efforts to create healthier products, but using 'legislative scaffolding' to escalate from self-regulation towards co-regulation if industry fails to play its part in achieving national goals and targets. PMID- 26027449 TI - Public health and the value of disobedience. AB - The writings of a sixteenth century French teenager may seem a stretch for a public health readership, but Etienne de la Boetie's treatise on Voluntary Servitude explains why unjust systems prevail and how they can be changed. They prevail, he shows, because we let them (the losers always vastly outnumber the winners); and they change when we retract our permission (as Ghandi demonstrated). These vital insights have inspired progress down the centuries- the enlightenment philosophers, the French Revolution, Tolstoy, the American civil rights movement as well as the Indian struggle against the British Empire. In an era when widening inequalities have become all too apparent, and the harm this does to the commonweal much better understood, this paper argues that La Boetie's analysis retains all its power and can inspire a new vision for public health. PMID- 26027450 TI - Aerobic and resistance exercise training program intervention for enhancing gait function in elderly and chronically ill Taiwanese patients. AB - OBJECTIVES: This study aimed to develop an effective exercise training program for enhancing the postural stability and gait function of chronically ill patients to avoid falls. STUDY DESIGN: Pre training-post-training. Analyses were limited to those randomized to the exercise intervention. METHODS: The participants were chronically ill patients over 45 years old (47-89 years), of whom 25 completed the 12-week training regimen and assessment in the exercise group, whereas 29 completed the assessment in the control group, suffering from cardiovascular disease, diabetes mellitus, or osteoporosis. The average age of the participants was 67.56 +/- 10.70 years in the intervention group. All patients in this study signed institutional review board (IRB) agreements before participating (IRB approval no: FEMH-IRB-101029-E, v. 02, date: 20120429). RESULTS: The results revealed the beneficial effects of regular aerobic and resistance training, which improved in elderly, chronically ill patients. According to our data, most of the gait function measurements exhibited significant differences between the exercise group and control group. The duration of the 'timed up-and-go' test decreased from 7.67 s to 6.76 s (P = 0.00013), and the 'the base of support area' increased from 392.0 cm(2) to 433.2 cm(2) (P = 0.0088). Women attained more significant differences than men in the exercise and control groups (P = 0.0008), and the participants aged 45-65 years had a more satisfactory outcome than those aged > 65 years (P = 0.0109). CONCLUSION: Regular exercise regimens, such as aerobic, resistance or combination exercise training, enhance the gait function and sense of postural stability in elderly, chronically ill patients. Younger patients attained more positive results than older patients, and women attained more positive results than men. Regular exercise is a means of preventing falls; thus, the government and hospitals should increase promotional measures in aging communities to encourage regular exercise among elderly, chronically ill outpatients. PMID- 26027451 TI - Optimizing national immunization program supply chain management in Thailand: an economic analysis. AB - OBJECTIVES: This study aimed to conduct an economic analysis of the transition of the conventional vaccine supply and logistics systems to the vendor managed inventory (VMI) system in Thailand. STUDY DESIGN: Cost analysis of health care program. METHODS: An ingredients based approach was used to design the survey and collect data for an economic analysis of the immunization supply and logistics systems covering procurement, storage and distribution of vaccines from the central level to the lowest level of vaccine administration facility. Costs were presented in 2010 US dollar. RESULTS: The total cost of the vaccination program including cost of vaccine procured and logistics under the conventional system was US$0.60 per packed volume procured (cm(3)) and US$1.35 per dose procured compared to US$0.66 per packed volume procured (cm(3)) and US$1.43 per dose procured under the VMI system. However, the findings revealed that the transition to the VMI system and outsourcing of the supply chain system reduced the cost of immunization program at US$6.6 million per year because of reduction of un-opened vaccine wastage. CONCLUSIONS: The findings demonstrated that the new supply chain system would result in efficiency improvement and potential savings to the immunization program compared to the conventional system. PMID- 26027452 TI - Health inequalities - why so little progress? AB - Studies of the health of the population of Scotland over many years have provided new insights to the basis of inequalities in life expectancy across the Scottish population. Conventional descriptions of health inequalities as being due predominantly to smoking, obesity and alcohol do not fully account for the situation in Scotland. The deeper insights obtained from comprehensive analysis have prompted new approaches to narrowing the gap. Opportunities for well-being are created within the complex system of a well functioning society and novel methods are required if the outcomes of such a complex system are to improve. PMID- 26027458 TI - Facile, Large-Quantity Synthesis of Stable, Tunable-Color Silicon Nanoparticles and Their Application for Long-Term Cellular Imaging. AB - We herein introduce a facile, low-cost photochemical method capable of rapid (<40 min) and large-quantity (~10 g) production of highly fluorescent (quantum yield: 25%) silicon nanoparticles (SiNPs) of tunable optical properties (peak emission wavelength in the range of 470-560 nm) under ambient air conditions, by introducing 1,8-naphthalimide as a reducing agent and surface ligands. The as prepared SiNPs feature robust storage stability and photostability preserving strong and stable fluorescent during long-term (>3 h) high-power UV irradiation, in contrast to the rapid fluorescence quenching within 2 h of conventional organic dyes and II-VI quantum dots under the same conditions. The as-prepared SiNPs serving as photostable nanoprobes are workable for cellular imaging in long term manners. Our findings provide a powerful method for mild-condition and low cost, large-quantity production of highly fluorescent and photostable SiNPs for various promising applications. PMID- 26027459 TI - The effects of three commonly used extraction methods on the redox properties of extracellular polymeric substances from activated sludge. AB - Recently, the redox properties of extracellular polymeric substances (EPS) have attracted the attention of scientists due to their associated environmental significance, such as organic pollutant (e.g. nitroaromatics and substituted nitrobenzenes) degradation and heavy metal (e.g. Cr(VI) and U(VI)) detoxification. Although the separation of EPS from bacterial cells is more often the first step in studies on EPS, and studies have demonstrated that extraction procedures can influence the sorption properties of EPS, few attempts have been made to investigate how separation methods affect the redox properties of the obtained EPS. In this study, three common extraction approaches, that is, centrifugation, formaldehyde+NaOH and ethylene diamine tetra-acetic acid (EDTA), were employed to extract EPS from activated sludge, and the obtained EPS were evaluated for their redox properties using electrochemical means, including cyclic voltammetry and chronoamperometry. In addition, spectroscopic techniques were utilized to explore the structural characteristics and composition of EPS. The results indicated that EPS extracted by EDTA clearly displayed reversible oxidation-reduction peaks in cyclic voltammograms and significantly higher electron-accepting capacity compared with EPS extracted using the other two approaches. Fourier transform infrared spectra and three-dimensional excitation emission matrix spectra suggested that the EPS extracted with EDTA presented better redox properties because of the effective and efficient extraction of the humic substances, which are important components of the EPS of activated sludge. Therefore, extraction method has an impact on the composition and redox properties of EPS and should be chosen according to research purpose and EPS source. PMID- 26027460 TI - (Hyper)tension release by N-terminal acetylation. AB - A recent study links N-terminal acetylation and N-end rule degradation to blood pressure regulation. N-terminal mutants of Rgs2, a key G-protein regulator, are differentially processed by N-terminal acetyltransferases and the two branches of the N-end rule pathway. This leads to an imbalance in the signaling governing blood pressure. PMID- 26027461 TI - Heterotic Haplotype Capture: precision breeding for hybrid performance. AB - The need to improve hybrid performance, abiotic stress tolerance, and disease resistance without compromising seed quality makes the targeted capture of untapped diversity a major objective for crop breeders. Here we introduce the concept of Heterotic Haplotype Capture (HHC), in which genome sequence imputation is used to trace novel heterozygous chromosome blocks contributing to hybrid performance in large, structured populations of interrelated F1 hybrids containing interesting new diversity for breeding. PMID- 26027462 TI - Feasibility of new breeding techniques for organic farming. AB - Organic farming is based on the concept of working 'with nature' instead of against it; however, compared with conventional farming, organic farming reportedly has lower productivity. Ideally, the goal should be to narrow this yield gap. In this review, we specifically discuss the feasibility of new breeding techniques (NBTs) for rewilding, a process involving the reintroduction of properties from the wild relatives of crops, as a method to close the productivity gap. The most efficient methods of rewilding are based on modern biotechnology techniques, which have yet to be embraced by the organic farming movement. Thus, the question arises of whether the adoption of such methods is feasible, not only from a technological perspective, but also from conceptual, socioeconomic, ethical, and regulatory perspectives. PMID- 26027463 TI - Development of Novel Cyclizations via Rhodacycle Intermediate and Its Application to Synthetic Organic Chemistry. AB - Novel Rh(I)-catalyzed cyclizations through a different type of rhodacycle intermediate which is formed by hydroacylation of 4,6-dienal or oxidative addition of diene and alkene are described. Hydroacylation of 4,6-dienal afforded various 7-membered rings in good to high yields, while cycloisomerization of diene and alkene provided 5- or 6-membered rings in good yields. On the basis of these studies, we have also succeeded in developing the sequential reaction of hydroacylation followed by cycloisomerization to produce bicyclic compounds in a stereoselective manner and thus this reaction was expanded to the synthesis of epiglobulol. Furthermore, both Rh(I)-catalyzed hydroacylation and cycloisomerization using ionic liquid (IL) as a solvent were investigated and it was found that the IL recovered after the reaction, which contains the Rh(I) catalyst, could be recycled several times without loss of catalytic activity. PMID- 26027464 TI - Development and Characterization of Solid Self-emulsifying Drug Delivery System of Cilnidipine. AB - The present investigations highlight the development of solid self-emulsifying drug delivery system (solid-SEDDS) for improved oral delivery of the poorly water soluble drug; cilnidipine. Liquid SEDDS of the drug were formulated using Capryol 90 as the oil phase, Tween 80 as the surfactant, and Transcutol HP as the co surfactant after screening various vehicles. The prepared systems were characterized for self-emulsification time, robustness to dilution, % transmittance, globule size, drug release, and thermodynamic stability. Ternary phase diagrams were plotted to identify the area of microemulsification. The optimized liquid SEDDS was transformed into a free-flowing powder using Neusilin US2 as the adsorbent. Solid self-emulsifying powder retained the self-emulsifying property of the liquid SEDDS. Differential scanning calorimetric, X-ray powder diffraction studies revealed the possibility of transformation of the crystalline form of the drug to the amorphous form in the SEDDS prepared with the carrier. The morphology of solid-SEDDS from scanning electron microscopy studies demonstrated the presence of spherical, granular particles indicating good flowing ability. Dissolution studies revealed enhanced dissolution of the drug from the solid system compared with the pure drug and its marketed formulation. Similarly, the in vitro absorption profile of the drug from the formulated SEDDS was significantly higher compared with pure drug. Thus it can be concluded that solid-SEDDS, amenable for development of solid dosage form, can be successfully developed using Neusilin US2 with the potential of enhancing the solubility, dissolution rate, and bioavailability of the drug. PMID- 26027465 TI - Characterization and Thermodynamic Stability of Polymorphs of Di(arylamino) Aryl Compound ASP3026. AB - ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N'-[2 (propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed in Astellas Pharma Inc. as a novel and selective inhibitor of the fusion protein EML4-ALK. We investigated the thermodynamic stability of five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) in detail. To determine the most stable form at ambient temperature, powder X-ray diffraction, differential scanning calorimetry, and solubility measurements were conducted. Of the five polymorphs, A04 was the most stable and A05 was the least stable. The relationship between A04 and A03 and A04 and A01 were mutually monotropic, while that between A01 and A02 was enantiotropic. The transition temperature from A02 to A01 was estimated as 325 K. A02 was more thermodynamically stable at ambient temperature than A01. Furthermore, the method to estimate polymorphic transition temperatures using solution calorimetry was found to be effective. The systematic characterization of ASP3026 polymorphs presented in this study enables the selective crystallization of the most stable form and design of solid formulations. PMID- 26027466 TI - Formulation and in Vitro Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe. AB - This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactant-to-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant-cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant-cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability. PMID- 26027467 TI - Synthesis and in vitro antiproliferative evaluation of novel hybrids from 1,3,4 thiadiazole and benzisoselenazolone. AB - Novel hybrids from 1,3,4-thiadiazole and benzisoselenazolone were designed, synthesized and evaluated for their in vitro antiproliferative activities by CCK 8 assay against three types of human cancer cell lines, SMMC-7721, MCF-7 and A549 cells. The preliminary bioassay results demonstrated that all tested compounds 4a p showed potent antiproliferative activities, and some compounds exhibited better effects than positive control ethaselen and 5-fluorouracil (5-FU) against various cancer cell lines. Furthermore, compound 4g showed significant antiproliferative activities against SMMC-7721 cells with an IC50 value of 2.08 uM. Compounds 4b and 4m displayed highly effective biological activities against MCF-7 cells with an IC50 values of 2.03 and 2.06 uM, respectively. Compound 4i exhibited the best inhibitory effect against A549 cells with an IC50 value of 1.03 uM. PMID- 26027468 TI - New Metabolites from the South China Sea Sponge Diacarnus megaspinorhabdosa. AB - Chemical investigation on CH2Cl2 extract of the marine sponge Diacarnus megaspinorhabdosa resulted in the isolation of two new farnesylacetone derivatives 1-2, a new gamma-lactone 3, a known dinorditerpenone 4 and four known norsesterterpene peroxides 5-8. Their structures were elucidated by using one and two dimensional (1D and 2D)-NMR, high resolution-electrospray ionization (HR-ESI) MS, and comparison with the literature. Compounds 1 and 2 were cis/trans-olefinic isomers and determined through nuclear Overhauser effect spectroscopy (NOESY) experiment. The absolute configuration of 3 was established by comparison of circular dichroism (CD) data with known lactones. The cytotoxic activities of the compounds were evaluated against five cancer cell lines, and compound 3 showed moderate cytotoxicity activities against cancer cell lines HeLa, H446, NCI-H460, SGC-7901 and MCF-7, with IC50 values in the range of 18.5 to 47.1 uM. PMID- 26027469 TI - Application of new spectrofluorometric techniques for determination of atorvastatin and ezetimibe in combined tablet dosage form. AB - Two accurate, reliable, and highly sensitive spectrofluorometric methods were developed for simultaneous determination of the binary mixture of Atorvastatin and Ezetimibe without prior separation steps. The first method is based on double scan synchronous fluorescence spectrometry. Each of Atorvastatin and Ezetimibe can be determined independent of the other when scanned at Deltalambda=100 nm and 40 nm, respectively. The relative fluorescence intensity-concentration plots at two wavelengths, 272 (Deltalambda=100 nm) and 266 nm (Deltalambda=40 nm) were rectilinear over the range of 0.4-8 ug/mL (for Atorvastatin) and 0.6-8 ug/mL (for Ezetimibe), respectively. The second method is based on the technique of simultaneous equations (Vierodt's method), in which two equations are solved simultaneously after using a single excitation wavelength of 273 nm and lambdaEm1=380 nm of Atorvastatin and lambdaEm2=301 nm of Ezetimibe. Under the optimum conditions, linear relationships were found between the relative fluorescence intensity and the concentrations of the investigated drugs in the range of 0.4-8 ug/mL (for Atorvastatin) 0.6-8 ug/mL (for Ezetimibe). The different experimental parameters affecting the fluorescence intensities of the two drugs were carefully studied and optimized. The proposed methods were successfully applied for the determination of the investigated drugs in pure form, dosage form and in synthetic mixtures with good recovery and the results obtained were favorably compared to those obtained with a reference method. PMID- 26027470 TI - Uses of 1-(3-Cyano-4,5,6,7-tetrahydrobenzo[b]-thiophen-2-yl)-3-dodecanoylthiourea as a Building Block in the Synthesis of Fused Pyrimidine and Thiazine Systems. AB - The reaction of lauroyl isothiocyanate and 2-amino-4,5,6,7 tetrahydrobenzo[b]thiophene-3-carbonitrile was used to synthesize the title compound 2. Compound 2 could serve as the main building block in the synthesis of many target heterocyclic systems. Various fused pyrimidines were synthesized in the reactions of compound 2 with sodium ethoxide, hydrazine hydrate, phenyl hydrazine, ethyl carbazate, thiourea, and/or 2-aminothiophenol. The structures of the synthesized compounds were confirmed by microanalytical and spectral data. PMID- 26027471 TI - Magnetic resonance imaging study on the physical stability of menthol and diphenhydramine cream for the treatment of chronic kidney disease-associated pruritus. AB - A cream that contains menthol and diphenhydramine is widely prepared in hospital pharmacies and prescribed to patients for the treatment of pruritus associated with chronic kidney disease. However, there is a serious concern regarding its physical stability; therefore, we investigated this issue using magnetic resonance imaging (MRI). For a sample preparation, a menthol-containing ethanol solution was mixed with a commercial diphenhydramine cream. After storage for 7 d at 40 degrees C, substantial phase separation into two distinct layers (upper and lower layers) was observed in the sample. This study further examined the components of the phase-separated layers using magnetic resonance (MR) spectroscopy and chemical shift selective images, and it was verified that the upper layer consisted of packed oil droplet layers, whereas the lower was an aqueous phase. Subsequently, the time-dependent phase separation of the sample at different temperatures was investigated. From the MR images, including a T2 relaxation time map and apparent diffusion coefficient maps, it was obvious that the phase separation developed further with increasing temperature; the most substantial phase separation was observed from the sample stored at 40 degrees C, while no phase separation was detected at 25 degrees C. In the final phase of this study, we conducted a formulation study and succeeded in improving the cream's physical stability by adding a hydrophilic surfactant to the preparation. PMID- 26027472 TI - Synthesis and Structure-Activity Relationship Study of NBRI16716B, an Antitumor Natural Product. AB - The total synthesis of NBRI16716B (2), a naturally occurring modulator of tumor stroma interactions, was successfully achieved. Using this synthetic route, a dehydroxy analogue (21) and a derivative lacking the 5-hydroxy-3-methylpentenoyl side chain (22) became accessible. A preliminary structure-activity relationship study to unveil the structural requirements for selective inhibition of tumor cells cocultured with stromal cells revealed that both of the hydroxamate structures of 2 are indispensable, whereas the 5-hydroxy-3-methylpentenoyl side chain is not essential. PMID- 26027473 TI - Determination of Miglitol by Column-Switching Ion-Pair HPLC with Tris(2,2' bipyridine)ruthenium(II)-Electrogenerated Chemiluminescence Detection. AB - We have developed a highly sensitive, simple method for the quantitative determination of miglitol in standard serum samples using column-switching ion pair HPLC with tris(2,2'-bipyridine)ruthenium(II)-electrogenerated chemiluminescence detection. The serum samples were directly injected into a column-switching HPLC system with a Shim-pack MAYI-SCX precolumn to remove the serum matrix. Chromatographic separation of miglitol was achieved on a TSKgel ODS 100-V column using a mobile phase containing sodium 1-octanesulfonate as an ion pair reagent. The detection and quantification limits of miglitol were 3 and 10 ng/mL, respectively. The calibration curve for miglitol in the serum samples showed good linearity (r(2)=0.9997) in the range of 10-2500 ng/mL. The recovery rate of miglitol from the serum samples was more than 94% as calculated from blank serum samples spiked with miglitol 50, 100, 500, 1000, and 2000 ng/mL. Therefore, this method can be applied to routine therapeutic monitoring of miglitol in serum samples. PMID- 26027474 TI - Anti-inflammatory Activity of Pyrrolizidine Alkaloids from the Leaves of Madhuca pasquieri (Dubard). AB - A novel pyrrolizidine alkaloids, madhumidine A (1), and two known alkaloids, lindelofidine benzoic acid ester (2) and minalobine B (3) were isolated from the leaves of Madhuca pasquieri (Dubard) H. J. LAM. The chemical structures of these alkaloids were established mainly by NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against lipopolysaccharide-induced nitric oxide production in macrophage RAW264.7 cell. In addition, the cytotoxic activity of all isolated compounds was tested against a panel of cancer cell lines. PMID- 26027475 TI - Electrogenerated Chemiluminescence Bioanalytic System Based on Biocleavage of Probes and Homogeneous Detection. AB - A novel electrogenerated chemiluminescence (ECL) bioanalytic system based on biocleavage of a ECL probe and homogeneous detection was designed and utilized for the first time for highly sensitive quantification of proteases to overcome drawbacks from probes directly immobilized on electrodes and commercial ECL biosystems, based on bioaffinity reactions. Prostate-specific antigen (PSA) was taken as a model analyte and ruthenium complex-tagged specific peptide (CHSSKLQK) was designed as an ECL probe (peptide-Ru1). ECL bioconjugated magnetic beads were synthesized through a simple solid-phase synthesis. When analyte PSA was introduced into the suspension of ECL bioconjugated magnetic beads, a biocleavage of the peptide occurred and the cleaved Ru1 part was released from the magnetic beads. ECL measurement was carried out in the presence of co-reactant tripropylamine, using two models. One is homogeneous ECL detection on a bare graphite pencil electrode (PGE), and the other is enriching ECL detection after the cleaved Ru1 part of the peptide was concentrated into the surface film of Nafion/gold nanoparticles modified PGE (AuNPs/Nafion/PGE). The extremely low detection limit of 80 fg/mL and high reproducibility (relative standard deviation (RSD) of 5.4% for six measurements of 0.5 pg/mL) for the detection of PSA were achieved at AuNPs/Nafion/PGE. This work demonstrates that the bioanalytic system designed can not only quantify proteases with high sensitivity and selectivity, but also diminish the complicated electrode process and improve the reproducibility by conducting the biocleavage and transduction steps at different surfaces. It can be easily extended for ECL analysis of other proteases in this system and other detection techniques, including optics and electrochemistry. PMID- 26027476 TI - Burden of serious fungal infections in the Dominican Republic. AB - The Dominican Republic (DR) is the second largest Caribbean nation and, with Haiti, the DR accounts for nearly three-quarters of the cases of human immunodeficiency virus (HIV) infection in the Caribbean region and the highest rates of TB in the Americas. The present study estimated the burden of serious fungal infections and some other mycoses in the DR. The data were extracted from the World Health Organization Stop Tuberculosis (WHO STOP TB) program, the Joint United Nations Program on HIV/AIDS (UNAIDS), and searches for relevant literature via MEDLINE, PubMed, MedFacts, and so on. The chronic pulmonary aspergillosis (CPA), allergic bronchopulmonary aspergillosis (ABPA), and severe asthma with fungal sensitization (SAFS) rates were derived from the asthma and TB rates. When no data regarding mycoses were available, we used specific populations at risk and the frequencies of fungal infection in each of these populations to estimate the national prevalence. Among its population of 10,090,000, we estimated that 221,027 (2.2%) have a serious fungal infection, including 158,134 women with recurrent vulvovaginal candidiasis. We estimated high numbers of 25,150 for ABPA and 34,000 for severe asthma fungal sensitization (SAFS) (250 and 529/100,000, respectively). CPA was common, with an estimated 2122 cases, of which 707 followed pulmonary TB. The annual prevalence of CPA was estimated to be 1374 cases. Four cases of histoplasmosis and several cases of chromoblastomycosis have also been reported. Pityriasis versicolor and tinea capitis are frequent in children, and 11% have kerion. Local epidemiological investigations are urgently required to validate or modify these estimates of serious fungal infections in the DR. PMID- 26027478 TI - Retraction of "Hydrophilic Prodrug Approach for Reduced Pigment Binding and Enhanced Transscleral Retinal Delivery of Celecoxib". PMID- 26027477 TI - Device-associated infection rates and bacterial resistance in six academic teaching hospitals of Iran: Findings from the International Nocosomial Infection Control Consortium (INICC). AB - Device-associated health care-acquired infections (DA-HAIs) pose a threat to patient safety, particularly in the intensive care unit (ICU). However, few data regarding DA-HAI rates and their associated bacterial resistance in ICUs from Iran are available. A DA-HAI surveillance study was conducted in six adult and pediatric ICUs in academic teaching hospitals in Tehran using CDC/NHSN definitions. We collected prospective data regarding device use, DA-HAI rates, and lengths of stay from 2584 patients, 16,796 bed-days from one adult ICU, and bacterial profiles and bacterial resistance from six ICUs. Among the DA-HAIs, there were 5.84 central line-associated bloodstream infections (CLABs) per 1000 central line-days, 7.88 ventilator-associated pneumonias (VAPs) per 1000 mechanical ventilator-days and 8.99 catheter-associated urinary tract infections (CAUTIs) per 1000 urinary catheter-days. The device utilization ratios were 0.44 for central lines, 0.42 for mechanical ventilators and 1.0 for urinary catheters. The device utilization ratios of mechanical ventilators and urinary catheters were higher than those reported in the ICUs of the INICC and the CDC's NHSN reports, but central line use was lower. The DA-HAI rates in this study were higher than the CDC's NHSN report. However, compared with the INICC report, the VAP rate in our study was lower, while the CLAB rate was similar and the CAUTI rate was higher. Nearly 83% of the samples showed a mixed-type infection. The most frequent pathogens were Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa, followed by Klebsiella pneumoniae and Enterococcus spp. In the S. aureus isolates, 100% were resistant to oxacillin. Overall resistances of A. baumannii and K. pneumonia to imipenem were 70.5% and 76.7%, respectively. A multiple drug resistance phenotype was detected in 68.15% of the isolates. The DA-HAI rates in Iran were shown to be higher than the CDC-NHSN rates and similar to the INICC rates. Resistance to oxacillin and imipenem was higher as well. Comparing device use, DA-HAI rates, and bacterial resistance for the primary isolated bacteria indicated a direct association between urinary catheter use and the rates of CAUTI. PMID- 26027479 TI - Forums on small-molecule activation: from biological principles to energy applications. PMID- 26027480 TI - Preface for small-molecule activation: carbon-containing fuels. PMID- 26027481 TI - Multinational outbreak of Salmonella Enteritidis infection during an international youth ice hockey competition in Riga, Latvia, preliminary report, March and April 2015. AB - A multinational outbreak of salmonellosis linked to the Riga Cup 2015 junior ice hockey competition was detected by the Finnish health authorities in mid-April and immediately notified at the European Union level. This prompted an international outbreak investigation supported by the European Centre for Disease Prevention and Control. As of 8 May 2015, seven countries have reported 214 confirmed and suspected cases, among which 122 from Finland. The search for the source of the outbreak is ongoing. PMID- 26027482 TI - Genome sequence analysis of Ebola virus in clinical samples from three British healthcare workers, August 2014 to March 2015. AB - We determined complete viral genome sequences from three British healthcare workers infected with Ebola virus (EBOV) in Sierra Leone, directly from clinical samples. These sequences closely resemble those previously observed in the current Ebola virus disease outbreak in West Africa, with glycoprotein and polymerase genes showing the most sequence variation. Our data indicate that current PCR diagnostic assays remain suitable for detection of EBOV in this epidemic and provide confidence for their continued use in diagnosis. PMID- 26027483 TI - Post-vaccine measles in a child with concomitant influenza, Sicily, Italy, March 2015. AB - We describe the occurrence of measles in an 18 month-old patient in Sicily, Italy, in March 2015, who received the first dose of a measles-containing vaccine seven days before onset of prodromal symptoms. Measles virus infection was confirmed by PCR and detection of specific immunoglobulin; viral genotyping permitted the confirmation of a vaccine-associated illness. The patient had a concurrent influenza virus infection, during a seasonal epidemic outbreak of influenza. PMID- 26027484 TI - Genetic diversity of highly pathogenic H5N8 avian influenza viruses at a single overwintering site of migratory birds in Japan, 2014/15. AB - We isolated eight highly pathogenic H5N8 avian influenza viruses (H5N8 HPAIVs) in the 2014/15 winter season at an overwintering site of migratory birds in Japan. Genetic analyses revealed that these isolates were divided into three groups, indicating the co-circulation of three genetic groups of H5N8 HPAIV among these migratory birds. These results also imply the possibility of global redistribution of the H5N8 HPAIVs via the migration of these birds next winter. PMID- 26027485 TI - The challenge of West Nile virus in Europe: knowledge gaps and research priorities. AB - West Nile virus (WNV) is continuously spreading across Europe, and other continents, i.e. North and South America and many other regions of the world. Despite the overall sporadic nature of outbreaks with cases of West Nile neuroinvasive disease (WNND) in Europe, the spillover events have increased and the virus has been introduced into new areas. The high genetic diversity of the virus, with remarkable phenotypic variation, and its endemic circulation in several countries, require an intensification of the integrated and multidisciplinary research efforts built under the 7th Framework Programme of the European Union (FP7). It is important to better clarify several aspects of WNV circulation in Europe, including its ecology, genomic diversity, pathogenicity, transmissibility, diagnosis and control options, under different environmental and socio-economic scenarios. Identifying WNV endemic as well as infection-free areas is becoming a need for the development of human vaccines and therapeutics and the application of blood and organs safety regulations. This review, produced as a joint initiative among European experts and based on analysis of 118 scientific papers published between 2004 and 2014, provides the state of knowledge on WNV and highlights the existing knowledge and research gaps that need to be addressed with high priority in Europe and neighbouring countries. PMID- 26027486 TI - West Nile virus circulation in South-Eastern Romania, 2011 to 2013. AB - Lineage 2 West Nile virus (WNV), previously found only in sub-Saharan Africa and Madagascar, was identified in Hungary in 2004 and has rapidly expanded in Europe in the past decade. Following a significant outbreak of West Nile fever with neurological cases caused by lineage 1 WNV in Romania in 1996, scattered cases have been recorded in the south-east of the country in each transmission season. Another outbreak, affecting a larger area and caused by lineage 2 WNV, was recorded in 2010. We analysed human sera from neuroinvasive West Nile fever cases and mosquitoes, sampled in south-eastern Romania between 2011 and 2013, for the presence of WNV genome, and obtained partial NS5 and envelope glycoprotein sequences. Human- and mosquito-derived WNV sequences were highly similar (99%) to Volgograd 2007 lineage 2 WNV and differed from isolates previously detected in central and southern Europe. WNV was detected in one pool of Culex pipiens s.l. males, documenting vertical transmission. Lineage 4 WNV, of unknown pathogenicity to mammals, was found in the amphibian-feeding mosquito Uranotaenia unguiculata from the Danube Delta. Our results present molecular evidence for the maintenance of the same isolates of Volgograd 2007-like lineage 2 WNV in south-eastern Romania between 2011 and 2013. PMID- 26027487 TI - High throughput screening using acoustic droplet ejection to combine protein crystals and chemical libraries on crystallization plates at high density. AB - We describe a high throughput method for screening up to 1728 distinct chemicals with protein crystals on a single microplate. Acoustic droplet ejection (ADE) was used to co-position 2.5nL of protein, precipitant, and chemicals on a MiTeGen in situ-1 crystallization plateTM for screening by co-crystallization or soaking. ADE-transferred droplets follow a precise trajectory which allows all components to be transferred through small apertures in the microplate lid. The apertures were large enough for 2.5nL droplets to pass through them, but small enough so that they did not disrupt the internal environment created by the mother liquor. Using this system, thermolysin and trypsin crystals were efficiently screened for binding to a heavy-metal mini-library. Fluorescence and X-ray diffraction were used to confirm that each chemical in the heavy-metal library was correctly paired with the intended protein crystal. A fragment mini-library was screened to observe two known lysozyme ligands using both co-crystallization and soaking. A similar approach was used to identify multiple, novel thaumatin binding sites for ascorbic acid. This technology pushes towards a faster, automated, and more flexible strategy for high throughput screening of chemical libraries (such as fragment libraries) using as little as 2.5nL of each component. PMID- 26027488 TI - Tolerability of hypertonic injectables. AB - Injectable drug products are ideally developed as isotonic solutions. Often, hypertonic injectables may have to be marketed for a variety of reasons such as product solubilization and stabilization. A key concern during product formulation development is the local and systemic tolerability of hypertonic products upon injection. This report reviews and discusses the tolerability in terms of local discomfort, irritation, sensation of heat and pain, along with other observed side effects of hypertonicity in both in-vitro systems and in-vivo animal and human models. These side effects clearly depend on the degree of hypertonicity. The sensation of pain among different injection routes seems to follow this order: intramuscular>subcutaneous>intravenous or intravascular. It is recommended that the upper osmolality limit should be generally controlled under 600 mOsm/kg for drug products intended for intramuscular or subcutaneous injection. For drug products intended for intravenous or intravascular injection, the recommended upper limit should be generally controlled under 1,000 mOsm/kg for small-volume injections (<= 100 mL) and 500 mOsm/kg for large-volume injections (>100mL). Several options are available for minimization of hypertonicity-induced pain upon product administration. PMID- 26027490 TI - Dynamic behavior of a spring-powered micronozzle needle-free injector. AB - Conventional injection is still the leading method to deliver macromolecular therapeutics. Needle injection is considered a low compliance administration strategy, principally due to pain and needle phobia. This has fostered the research on the development of alternative strategies to circumvent the skin barrier. Among needle-free drug delivery methods, jet injection is an old strategy with great potential not yet completely disclosed. Here, the design, engineering and dynamic behavior of a novel spring-powered micronozzle needle free injector is presented. Fluid mechanics was first studied in air to calculate jet force and speed as well as injection duration in different conditions. Polyacrylamide gel was used to simulate a soft tissue and to investigate the jet evolution over time of different injected doses. Finally, ex vivo characterization was carried out on pig skin. Results evidenced a direct dependence of the force, velocity, and duration with the injection volume. The model material allowed individuating the different steps of jet penetration and to attempt a mechanistic explanation. A different behavior has been recorded in the skin with interesting findings for subcutaneous and/or dermal delivery. Peculiar features with respect to existing jet injectors confers to this device good potentiality for a future clinical application. PMID- 26027489 TI - A novel drug-polyethylene glycol liquid compound method to prepare 10 hydroxycamptothecin loaded human serum albumin nanoparticle. AB - Drug loading strategies and the methods derived for implementing those strategies are crucially important to the preparation of drug loaded human serum albumin nanoparticles (HSA-NPs), because each of them is focused on wrapping up specific types of drugs via certain physical and chemical properties. However, poor adaptability still exists to load drugs like model substance 10 hydroxycamptothecin (HCPT) by conventional methods. Because it typically represents a large class of water-insoluble drugs, who also structurally possess a certain number of hydrophilic groups. So even though they majorly have lipophilicity but they are of low liposolubility. This article presents a new concept of a loading strategy that takes a drug polymer liquid compound as a loading medium. The drug polymer liquid compound was made from low weight polyethylene glycol (l-PEG) and HCPT. Consequently, this strategy has managed to fabricate HCPT-loaded HSA-NPs through an unconventional approach that overcomes drawbacks of current loading means and better results have been obtained, like high entrapment efficiency (over 99%) and less toxicity involvement. Afterward, in vitro and in vivo evaluations and characterizations were performed to help with the in-depth interpretation of the loading mechanism in order to reveal and further investigate the possible far-reaching applications of this method. PMID- 26027491 TI - An injectable thermosensitive polymeric hydrogel for sustained release of Avastin(r) to treat posterior segment disease. AB - Delivery of drugs, especially bioactive macromolecules such as proteins and nucleic acids, to the posterior segment is still a significant challenge for pharmaceutical scientists. In the present study, we developed an injectable thermosensitive polymeric hydrogel for sustained release of Avastin((r)) to treat posterior segment disorders. The payload of Avastin((r)) to poly(lactic acid-co glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG PLGA) hydrogel did not influence its inherent sol-gel transition behavior, but shifted the sol-gel transition to a lower temperature. The resulting Avastin((r))/PLGA-PEG-PLGA hydrogels had a porous structure (pore size, 100 ~ 150 MUm) as determined by scanning electron microcopy (SEM), facilitating sustained Avastin((r)) release over a period of up to 14 days in vitro. The PLGA-PEG-PLGA hydrogel was immediately formed in the vitreous humor after intravitreal injection, followed by slow clearance over an 8 week study period. The PLGA-PEG PLGA hydrogel exhibited no apparent toxicity against retinal tissue, as indicated by the absence of inflammation, retinal necrosis, and stress responses, using optical coherence tomography (OCT) and histological/immunochemical analyses. Electrophysiology (ERG) examination also showed that the PLGA-PEG-PLGA hydrogel did not affect retinal function. In vivo pharmacokinetic studies indicated that the use of the PLGA-PEG-PLGA hydrogel greatly extended the release of Avastin((r)) over time in the vitreous humor and retina after intravitreal injection. Together, these results demonstrated that the PLGA-PEG-PLGA hydrogel was a promising candidate for ocular drug delivery of Avastin((r))via intravitreal injection. PMID- 26027492 TI - Preparation and characterization of paclitaxel nanosuspension using novel emulsification method by combining high speed homogenizer and high pressure homogenization. AB - The aim of this study was to develop an alternative, more bio-available, better tolerated paclitaxel nanosuspension (PTXNS) for intravenous injection in comparison with commercially available Taxol((r)) formulation. In this study, PTXNS was prepared by emulsification method through combination of high speed homogenizer and high pressure homogenization, followed by lyophilization process for intravenous administration. The main production parameters including volume ratio of organic phase in water and organic phase (Vo:Vw+o), concentration of PTX, content of PTX and emulsification time (Et), homogenization pressure (HP) and passes (Ps) for high pressure homogenization were optimized and their effects on mean particle size (MPS) and particle size distribution (PSD) of PTXNS were investigated. The characteristics of PTXNS, such as, surface morphology, physical status of paclitaxel (PTX) in PTXNS, redispersibility of PTXNS in purified water, in vitro dissolution study and bioavailability in vivo were all investigated. The PTXNS obtained under optimum conditions had an MPS of 186.8 nm and a zeta potential (ZP) of -6.87 mV. The PTX content in PTXNS was approximately 3.42%. Moreover, the residual amount of chloroform was lower than the International Conference on Harmonization limit (60 ppm) for solvents. The dissolution study indicated PTXNS had merits including effect to fast at the side of raw PTX and sustained-dissolution character compared with Taxol((r)) formulation. Moreover, the bioavailability of PTXNS increased 14.38 and 3.51 times respectively compared with raw PTX and Taxol((r)) formulation. PMID- 26027493 TI - One-step scalable preparation method for non-cationic liposomes with high siRNA content. AB - Cationic liposomes (LPs) have been utilized for short interfering RNA (siRNA) delivery in vitro and in vivo owing to their high affinity for siRNA via electrostatic binding. However, both cytotoxicity and non-specific adsorption of cationic LPs in the body have prevented clinical siRNA applications. These situations have led to siRNA encapsulation in non-cationic LPs. We found that the instillation of neutral phospholipids dissolved in ethanol into aqueous solutions containing siRNA and CaCl2 resulted in high siRNA encapsulation (siRNA encapsulation efficiency: ~ 80%; siRNA weight ratio: ~ 10 wt% of LPs). The products were monodispersed, ~ 200 nm, and negatively charged. Furthermore, when phospholipids with a high-phase transition temperature or cholesterol were used, the encapsulation efficiency and siRNA content remained high. Although anionic LPs could not encapsulate siRNAs using this method, the use of cholesterol conjugated siRNA helped achieve substantial siRNA encapsulation in anionic LPs. These non-cationic siRNA-containing LPs did not show cytotoxicity in vitro, and could be formed with polyethylene glycol-conjugated phospholipids. When conjugated with targeting ligand, the non-cationic siRNA-containing LPs could suppress the expression of target gene in vitro. These data demonstrate that our preparation method would be suitable for large-scale LP production for systemic siRNA delivery. PMID- 26027494 TI - FDA pharmaceutical quality oversight. AB - The launch of the Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) is a milestone in FDA's efforts to assure that quality medicines are available to the American public. As a new super-office within CDER, OPQ is strategically organized to streamline regulatory processes, advance regulatory standards, align areas of expertise, and originate surveillance of drug quality. Supporting these objectives will be an innovative and systematic approach to product quality knowledge management and informatics. Concerted strategies will bring parity to the oversight of innovator and generic drugs as well as domestic and international facilities. OPQ will promote and encourage the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality and potentially reinvigorate the pharmaceutical manufacturing sector in the United States. With a motto of "One Quality Voice," OPQ embodies the closer integration of review, inspection, surveillance, policy, and research for the purpose of strengthening pharmaceutical quality on a global scale. PMID- 26027495 TI - Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment. AB - Epigenetic mechanisms such as DNA methylation are part of an emerging story on how early-life experiences can alter behavioral trajectories and lead to the development of disease and psychological disorders. Previous work from our laboratory has demonstrated alterations in methylation of DNA associated with the brain-derived neurotrophic factor (bdnf) gene within the amygdala and hippocampus of infant and adult rats that were repeatedly exposed to caregiver maltreatment outside the home cage during their first week of life. In the current study we examine changes in global levels of DNA methylation (5-mC) and hydroxymethylation (5-hmC), as well as gene-specific changes in methylation patterns of the candidate gene bdnf (at exons I and IV) within the adolescent amygdala and hippocampus resulting from exposure to maltreatment. While adolescent females exposed to maltreatment showed no significant alterations in global 5-mC or 5-hmC levels, examination of bdnf DNA methylation revealed that maltreated females had greater methylation of exon IV DNA in the amygdala and ventral hippocampus. While adolescent males exposed to maltreatment showed no significant alterations in bdnf DNA methylation, maltreated males had significantly higher 5-mC levels in the dorsal hippocampus and lower 5-hmC levels in the amygdala. These findings demonstrate that the effects of the early caregiving environment are detectable in the adolescent brain at the level of the epigenome, with brain-region specific and sexually-dimorphic epigenetic consequences that could have relevance to adolescent mental health and behavior. PMID- 26027496 TI - Homozygosity for frameshift mutations in XYLT2 result in a spondylo-ocular syndrome with bone fragility, cataracts, and hearing defects. AB - Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects. Whole exome sequence analyses showed that both individuals had a homozygous c.692dup mutation (GenBank: NM_022167.3) in the xylosyltransferase II locus (XYLT2) (MIM: 608125), causing reduced XYLT2 mRNA and low circulating xylosyltransferase (XylT) activity. In an unrelated boy (individual 3) from the second family, we noted low serum XylT activity. Sanger sequencing of XYLT2 in this individual revealed a c.520del mutation in exon 2 that resulted in a frameshift and premature stop codon (p.Ala174Profs(*)35). Fibroblasts from individuals 1 and 2 showed a range of defects including reduced XylT activity, GAG incorporation of (35)SO4, and heparan sulfate proteoglycan assembly. These studies demonstrate that human XylT2 deficiency results in vertebral compression fractures, sensorineural hearing loss, eye defects, and heart defects, a phenotype that is similar to the autosomal-recessive disorder spondylo-ocular syndrome of unknown cause. This phenotype is different from what has been reported in individuals with other linker enzyme deficiencies. These studies illustrate that the cells of the lens, retina, heart muscle, inner ear, and bone are dependent on XylT2 for proteoglycan assembly in humans. PMID- 26027497 TI - Improved ancestry estimation for both genotyping and sequencing data using projection procrustes analysis and genotype imputation. AB - Accurate estimation of individual ancestry is important in genetic association studies, especially when a large number of samples are collected from multiple sources. However, existing approaches developed for genome-wide SNP data do not work well with modest amounts of genetic data, such as in targeted sequencing or exome chip genotyping experiments. We propose a statistical framework to estimate individual ancestry in a principal component ancestry map generated by a reference set of individuals. This framework extends and improves upon our previous method for estimating ancestry using low-coverage sequence reads (LASER 1.0) to analyze either genotyping or sequencing data. In particular, we introduce a projection Procrustes analysis approach that uses high-dimensional principal components to estimate ancestry in a low-dimensional reference space. Using extensive simulations and empirical data examples, we show that our new method (LASER 2.0), combined with genotype imputation on the reference individuals, can substantially outperform LASER 1.0 in estimating fine-scale genetic ancestry. Specifically, LASER 2.0 can accurately estimate fine-scale ancestry within Europe using either exome chip genotypes or targeted sequencing data with off-target coverage as low as 0.05*. Under the framework of LASER 2.0, we can estimate individual ancestry in a shared reference space for samples assayed at different loci or by different techniques. Therefore, our ancestry estimation method will accelerate discovery in disease association studies not only by helping model ancestry within individual studies but also by facilitating combined analysis of genetic data from multiple sources. PMID- 26027498 TI - Recessive osteogenesis imperfecta caused by missense mutations in SPARC. AB - Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans. PMID- 26027499 TI - Tracing the route of modern humans out of Africa by using 225 human genome sequences from Ethiopians and Egyptians. AB - The predominantly African origin of all modern human populations is well established, but the route taken out of Africa is still unclear. Two alternative routes, via Egypt and Sinai or across the Bab el Mandeb strait into Arabia, have traditionally been proposed as feasible gateways in light of geographic, paleoclimatic, archaeological, and genetic evidence. Distinguishing among these alternatives has been difficult. We generated 225 whole-genome sequences (225 at 8* depth, of which 8 were increased to 30*; Illumina HiSeq 2000) from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 individuals). West Eurasian components were masked out, and the remaining African haplotypes were compared with a panel of sub-Saharan African and non-African genomes. We showed that masked Northeast African haplotypes overall were more similar to non-African haplotypes and more frequently present outside Africa than were any sets of haplotypes derived from a West African population. Furthermore, the masked Egyptian haplotypes showed these properties more markedly than the masked Ethiopian haplotypes, pointing to Egypt as the more likely gateway in the exodus to the rest of the world. Using five Ethiopian and three Egyptian high-coverage masked genomes and the multiple sequentially Markovian coalescent (MSMC) approach, we estimated the genetic split times of Egyptians and Ethiopians from non-African populations at 55,000 and 65,000 years ago, respectively, whereas that of West Africans was estimated to be 75,000 years ago. Both the haplotype and MSMC analyses thus suggest a predominant northern route out of Africa via Egypt. PMID- 26027501 TI - Milk proteins as a source of tryptophan-containing bioactive peptides. AB - Tryptophan (W) is an essential amino acid which is primarily required for protein synthesis. It also acts as a precursor of key biomolecules for human health (serotonin, melatonin, tryptamine, niacin, nicotinamide adenine dinucleotide (NAD), phosphorylated NAD (NADP), quinolinic acid, kynureric acid, etc.). Among dietary proteins, milk proteins are particularly rich in W. W residues within milk proteins may be released by proteolytic/peptidolytic enzymes either as a free amino acid or as part of peptide sequences. Different W-containing peptides originating from milk proteins have been shown in vitro to display a wide range of bioactivities such as angiotensin converting enzyme (ACE) inhibition along with antioxidant, antidiabetic and satiating related properties. Free W has been shown in certain instances to have an effect on cognition and the aforementioned bioactive properties. However, a higher bioactive potency has generally been observed with specific W-containing peptides compared to free W. Since W is thermolabile, the impact of processing on the stability of W-containing peptides needs to be considered. Milk protein-derived W-containing peptides may have significant potential as natural health promoting agents in humans. PMID- 26027500 TI - Accurate and fast multiple-testing correction in eQTL studies. AB - In studies of expression quantitative trait loci (eQTLs), it is of increasing interest to identify eGenes, the genes whose expression levels are associated with variation at a particular genetic variant. Detecting eGenes is important for follow-up analyses and prioritization because genes are the main entities in biological processes. To detect eGenes, one typically focuses on the genetic variant with the minimum p value among all variants in cis with a gene and corrects for multiple testing to obtain a gene-level p value. For performing multiple-testing correction, a permutation test is widely used. Because of growing sample sizes of eQTL studies, however, the permutation test has become a computational bottleneck in eQTL studies. In this paper, we propose an efficient approach for correcting for multiple testing and assess eGene p values by utilizing a multivariate normal distribution. Our approach properly takes into account the linkage-disequilibrium structure among variants, and its time complexity is independent of sample size. By applying our small-sample correction techniques, our method achieves high accuracy in both small and large studies. We have shown that our method consistently produces extremely accurate p values (accuracy > 98%) for three human eQTL datasets with different sample sizes and SNP densities: the Genotype-Tissue Expression pilot dataset, the multi-region brain dataset, and the HapMap 3 dataset. PMID- 26027502 TI - Long-Term Survival with Long-Acting Somatostatin Analogues Plus Aggressive Cytoreductive Surgery in Patients with Metastatic Neuroendocrine Carcinoma. AB - BACKGROUND: Long-acting somatostatin analogues (S-LAR) improve recurrence-free survival in patients with metastatic neuroendocrine tumor (NET) from gastrointestinal (GI) primary, but their impact on overall survival when combined with aggressive cytoreductive surgery is unclear. STUDY DESIGN: We reviewed our institutional cancer database to identify patients who underwent cytoreductive surgery for metastatic NET from GI primary between December 1997 and June 2013. Additionally, a cohort selected from 3,384 metastatic neuroendocrine cases in the SEER-Medicare database (January 2003 to December 2009) was used to verify and expand on our results. RESULTS: Most of the 49 patients from our institution had primary lesions in the small intestine (22 of 49 [44.9%]) or pancreas (14 of 49 [28.6%]); 37 patients (75.5%) had metastatic disease at initial diagnosis. These patients underwent 1 (32 of 49 [65.3%]), 2 (11 of 49 [22.4%]), or at least 3 (6 of 49 [12.3%]) surgical procedures; 33 patients (67.3%) underwent resection plus ablation, 19 (38.7%) underwent major hepatectomy, and 34 (69.4%) received S-LAR (29.4% administered preoperatively). Median follow-up was 112 months. Rates of 1 , 5-, 10-, and 15-year disease-specific survival (DSS) were 94%, 78%, 64%, and 31%, respectively, in the 34 patients undergoing aggressive cytoreductive surgery plus S-LAR. Of the SEER-Medicare population, 1,741 patients met inclusion criteria. The DSS for the 104 patients treated with combination therapy was 68.3% at 5 years and 60.6% at 10 years, as compared with 54.7% and 51.8%, respectively, for the 202 patients receiving surgery alone, and 50.0% and 36.0%, respectively, for the 342 patients receiving S-LAR alone (p < 0.0001). The group receiving neither treatment (n = 1,093) had 5-year and 10-year DSS of 34.3% and 26.3%, respectively. CONCLUSIONS: Long-acting somatostatin analogues combined with aggressive cytoreductive surgery improves the long-term survival of select patients with metastatic NET from GI primary. PMID- 26027503 TI - Composite Measurement of Outcomes in Medicare Inpatient Laparoscopic Cholecystectomy. AB - BACKGROUND: Objective measurement of outcomes in surgical care lack standard definitions, effective and consistent surveillance, and identification of significant postdischarge events. STUDY DESIGN: Using the Medicare Inpatient file (2009 to 2011), we designed logistic prediction models for inpatient mortality, prolonged length of stay (prLOS) as a measure of serious inpatient complications, and all-cause 90-day postdischarge (90-DPd) deaths and hospital readmissions for elective and nonelective laparoscopic cholecystectomy (LC). Qualifying hospitals had more than 20 cases for the study period and met rigorous present-on-admission coding standards. RESULTS: A total of 902 hospitals had 64,021 LCs. There were 509 inpatient deaths (0.8%) and 4,624 (7.2%) were prLOS. At 90-DPd, 729 patients died without readmission with a prediction model of 15 variables (C-statistic = 0.848), and 11,052 patients (17.4% of live discharges) were readmitted (1,165 died) with a prediction model of 36 variables (C-statistic = 0.674). Among significant (p < 0.0001) odds ratios (ORs), 90-DPd deaths were associated with age greater than 84 years (OR 3.7), prLOS (OR 7.8), operations performed on day 3 or thereafter in the index hospitalization (OR 1.6), and other chronic disease variables. Similar variables were associated with 90-DPd readmissions. A composite measure of all inpatient and 90-DPd deaths, prLOS for the index hospitalization, and 90-DPd readmissions resulted in an overall adverse outcome rate of 23.7% (15,195 of 64,021). CONCLUSIONS: Adverse outcomes of inpatient deaths, prLOS, and 90-DPd readmissions and deaths provide an objective target for care redesign and improvement. The postdischarge period is the greatest source of adverse outcomes in LC. Composite measurement of adverse outcomes becomes a meaningful tool for the design of surgical warranties for episode-based payment initiatives. PMID- 26027504 TI - Magnetism in Na-filled Fe-based skutterudites. AB - The interplay of superconductivity and magnetism is a subject of ongoing interest, stimulated most recently by the discovery of Fe-based superconductivity and the recognition that spin-fluctuations near a magnetic quantum critical point may provide an explanation for the superconductivity and the order parameter. Here we investigate magnetism in the Na filled Fe-based skutterudites using first principles calculations. NaFe4Sb12 is a known ferromagnet near a quantum critical point. We find a ferromagnetic metallic state for this compound driven by a Stoner type instability, consistent with prior work. In accord with prior work, the magnetization is overestimated, as expected for a material near an itinerant ferromagnetic quantum critical point. NaFe4P12 also shows a ferromagnetic instability at the density functional level, but this instability is much weaker than that of NaFe4Sb12, possibly placing it on the paramagnetic side of the quantum critical point. NaFe4As12 shows intermediate behavior. We also present results for skutterudite FeSb3, which is a metastable phase that has been reported in thin film form. PMID- 26027505 TI - Epidemiology of fractures in type 2 diabetes. AB - Type 2 diabetes affects an increasing proportion of older adults, the population that is also at elevated risk of fracture. Type 2 diabetes itself increases the risk of fracture, particularly in African-American and Latino populations. In Western countries, overweight and obesity, associated with reduced fracture risk, are highly prevalent in diabetic patients. Studies in East Asian countries that have a lower prevalence of obesity with diabetes may help to disentangle the effects of diabetes and obesity on the skeleton. Type 2 diabetes is also associated with higher bone density, and as a result standard tools for fracture prediction tend to underestimate fracture risk in this population, an important challenge for risk assessment in the clinical setting. Contributing factors to the increased fracture risk in type 2 diabetes include more frequent falls and deficits in diabetic bone, not captured by dual X-ray absorptiometry (DXA), that are as yet not clearly understood. Recent epidemiological studies indicate that poor glycemic control contributes to increased fracture risk although intensive lowering of A1C is not effective in preventing fracture. This article is part of a Special Issue entitled "Bone and diabetes". PMID- 26027506 TI - Inflammatory signaling induced bone loss. AB - A broad spectrum of inflammatory disorders have the capacity to target the skeleton and to de-regulate the processes of physiological bone remodeling. This review will focus on the systemic inflammatory rheumatologic disorders, which target articular and peri-articular bone tissues. Many of these disorders also affect extra-articular tissues and organs, and in addition, have the capacity to produce systemic bone loss and increased risk of osteoporotic fractures. Attention will focus on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the seronegative spondyloarthropathies (SpAs), which include ankylosing spondylitis (AS), reactive arthritis (formerly designated as Reiter's syndrome), the arthritis of inflammatory bowel disease, juvenile onset spondyloarthropathy and psoriatic arthritis. The discussion will principally focus on RA, which is a prototypical model of an inflammatory disorder that de-regulates bone remodeling, but also will review the other forms of inflammatory joint disease to highlight the differential effects of inflammation on bone remodeling in these conditions. This article is part of a Special Issue entitled "Muscle Bone Interactions". PMID- 26027508 TI - Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) mediates periarticular bone loss, but not joint destruction, in murine antigen-induced arthritis. AB - Osteoclastogenesis requires immunoreceptor tyrosine-based activation motif signaling. Multiple immunoreceptors associated with immunoreceptor tyrosine-based activation motif adaptor proteins, including DNAX-activating protein 12 kDa (DAP12) and Fc receptor common gamma (FcRgamma), have been identified in osteoclast lineage cells, and some are involved in arthritis-induced bone destruction. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with DAP12. Whether Siglec-15 is involved in arthritis-induced bone lesions, however, remains unknown. Here we used a murine antigen-induced arthritis model to examine the role of Siglec-15 in the development of bone lesions induced by joint inflammation. Arthritis was unilaterally induced in the knee joints of 8-week-old female wild-type (WT) and Siglec-15(-/-) mice, and the contralateral knees were used as a control. The degree of joint inflammation, and cartilage and subchondral bone destruction in Siglec-15(-/-) mice was comparable to that in WT mice, indicating that Siglec-15 is not involved in the development of arthritis and concomitant cartilage and subchondral bone destruction. On the other hand, the degree of periarticular bone loss in the proximal tibia of the arthritic knee was significantly lower in Siglec-15(-/-) mice compared to WT mice. Although osteoclast formation in the metaphysis was enhanced in both WT and Siglec-15(-/-) mice after arthritis induction, mature multinucleated osteoclast formation was impaired in Siglec-15(-/-) mice, indicating impaired osteoclast bone resorptive function in the periarticular regions of the arthritic joint in Siglec-15(-/-) mice. Confirming this result, Siglec-15(-/-) primary unfractionated bone marrow cells harvested from arthritic femurs and tibiae failed to develop into mature multinuclear osteoclasts. Our findings suggest that Siglec-15 is a therapeutic target for periarticular bone loss, but not for joint destruction, in inflammatory arthritis, such as rheumatoid arthritis. PMID- 26027509 TI - Association of dietary consumption and serum levels of vitamin A and beta carotene with bone mineral density in Chinese adults. AB - BACKGROUND: Former studies suggested an adverse effect of hypervitaminosis A on bone health, while the effects of retinol and its precursor (beta-carotene) remain uncertain in populations consuming vitamin A (VA) mainly from plant sources. OBJECTIVE: We investigated the association of serum, dietary retinol, and beta-carotene with bone mineral density (BMD) in Chinese adults. METHODS: We recruited 2101 women and 1053 men (aged 40-75 years) in Guangzhou, China. Dietary intake was assessed through face-to-face interviews with food-frequency questionnaires at baseline and 3 years later. Serum levels of retinol and beta carotene were determined by HPLC using a baseline specimen, and the BMD for the whole body (WB), lumbar spine (LS), total hip (TH), and femur neck (FN) were measured using dual energy X-ray absorptiometry at follow-up. RESULTS: In general, greater levels of serum retinol, beta-carotene, and the beta-carotene-to retinol ratio were associated with a higher BMD after adjustment for potential covariates in the total sample. BMD values in the top (vs. bottom) quartile were increased by 2.06% (TH) for retinol; 2.87% (WB), 2.51% (LS), 3.10% (FN) for beta carotene; 2.21% (WB) and 2.05% (FN) for the beta-carotene-to-retinol ratio in the total sample (all p<0.05). A significant positive association with BMD was observed for dietary intake of beta-carotene and total VA in retinol equivalents at the hip sites in the total sample. CONCLUSION: Higher circulating and dietary levels of VA and beta-carotene and higher serum beta-carotene-to-retinol ratios were positively associated with BMD in Chinese adults consuming relatively low levels of VA, mainly from plant foods. PMID- 26027507 TI - Differences in childhood adiposity influence upper limb fracture site. AB - INTRODUCTION: Although it has been suggested that overweight and obese children have an increased risk of fracture, recent studies in post-menopausal women have shown that the relationship between obesity and fracture risk varies by fracture site. We therefore assessed whether adiposity and overweight/obesity prevalence differed by upper limb fracture site in children. METHODS: Height, weight, BMI, triceps and subscapular skinfold thickness (SFT) were measured in children aged 3 18 years with an acute upper limb fracture. Data was compared across three fracture sites (hand, forearm and upper arm/shoulder [UA]), and to published reference data. RESULTS: 401 children (67.1% male, median age 11.71 years, range 3.54-17.27 years) participated. 34.2%, 50.6% and 15.2% had fractures of the hand, forearm and UA, respectively. Children with forearm fractures had higher weight, BMI, subscapular SFT and fat percentage z-scores than those with UA fractures (p<0.05 for all). SFT and fat percentage z-scores were also higher in children with forearm fractures compared to hand fractures, but children with hand and UA fractures did not differ. Overweight and obesity prevalence was higher in children with forearm fractures (37.6%) than those with UA fractures (19.0%, p=0.009). This prevalence was also higher than the published United Kingdom population prevalence (27.9%, p=0.003), whereas that of children with either UA (p=0.13) or hand fractures (29.1%, p=0.76) did not differ. These differences in anthropometry and overweight/obesity prevalence by fracture site were evident in boys, but not present in girls. CONCLUSION: Measurements of adiposity and the prevalence of overweight/obesity differ by fracture site in children, and in particular boys, with upper limb fractures. PMID- 26027510 TI - A planning comparison of 3-dimensional conformal multiple static field, conformal arc, and volumetric modulated arc therapy for the delivery of stereotactic body radiotherapy for early stage lung cancer. AB - The primary objective of this study was to compare dosimetric variables as well as treatment times of multiple static fields (MSFs), conformal arcs (CAs), and volumetric modulated arc therapy (VMAT) techniques for the treatment of early stage lung cancer using stereotactic body radiotherapy (SBRT). Treatments of 23 patients previously treated with MSF of 48Gy to 95% of the planning target volume (PTV) in 4 fractions were replanned using CA and VMAT techniques. Dosimetric parameters of the Radiation Therapy Oncology Group (RTOG) 0915 trial were evaluated, along with the van't Riet conformation number (CN), monitor units (MUs), and actual and calculated treatment times. Paired t-tests for noninferiority were used to compare the 3 techniques. CA had significant dosimetric improvements over MSF for the ratio of the prescription isodose volume to PTV (R100%, p < 0.0001), the maximum dose 2cm away from the PTV (D2cm, p = 0.005), and van't Riet CN (p < 0.0001). CA was not statistically inferior to MSF for the 50% prescription isodose volume to PTV (R50%, p = 0.05). VMAT was significantly better than CA for R100% (p < 0.0001), R50% (p < 0.0001), D2cm (p = 0.006), and CN (p < 0.0001). CA plans had significantly shorter treatment times than those of VMAT (p < 0.0001). Both CA and VMAT planning showed significant dosimetric improvements and shorter treatment times over those of MSF. VMAT showed the most favorable dosimetry of all 3 techniques; however, the dosimetric effect of tumor motion was not evaluated. CA plans were significantly faster to treat, and minimize the interplay of tumor motion and dynamic multileaf collimator (MLC) motion effects. Given these results, CA has become the treatment technique of choice at our facility. PMID- 26027511 TI - An approach to contouring the dorsal vagal complex for radiotherapy planning. AB - Multiple studies suggest that radiation dose to the area of the brainstem called the "dorsal vagal complex (DVC)" influences the frequency of nausea and vomiting during radiotherapy. The purpose of this didactic article is to describe the step by-step process that we use to contour the general area of the DVC on axial computed tomography (CT) images as would be done for radiotherapy planning. The contouring procedure that we describe for contouring the area of the DVC is useful to medical dosimetrists and radiation oncologists. PMID- 26027512 TI - Typical but less frequently recognized findings in laparoscopic adjustable gastric band slippage. PMID- 26027513 TI - [Whipple disease in a patient under anti-TNFalpha therapy]. PMID- 26027514 TI - Cytomegalovirus enterocolitis in a patient with common variable immunodeficiency: A capsule endoscopy-aided diagnosis. PMID- 26027515 TI - Cluster headache management and beyond. AB - The therapeutic management of cluster headache is based on a very stable triad of drugs. Acute treatment has, in subcutaneous sumatriptan, its gold standard if compared to pure oxygen or indomethacin. Preventative treatment is based on verapamil at high doses (>= 360 mg) and is a gold standard if compared to lithium carbonate or topiramate. Transitional treatments, based on the short-term use of corticosteroids with either systemic or local administration (GON), can be useful for the suppression of most resistant cluster periods, but with a well-known carry-over phenomenon related to the length of the cluster period itself. The role of invasive or noninvasive neuromodulation approaches must still be determined on a large scale; therefore, its use is not recommended as of yet. Lifestyle changes, including alcohol avoidance during the active phase of the disease, sleep hygiene and use of vasodilation drugs, should be carefully considered and the patients should be fully informed. PMID- 26027516 TI - Phosphorylation state-dependent interaction between AKAP7delta/gamma and phospholamban increases phospholamban phosphorylation. AB - Changes in heart rate and contractility in response to sympathetic stimulation occur via activation of cAMP dependent protein kinase A (PKA), leading to phosphorylation of numerous substrates that alter Ca(2+) cycling. Phosphorylation of these substrates is coordinated by A-kinase anchoring proteins (AKAPs), which recruit PKA to specific substrates [1]. Phosphorylation of the PKA substrate phospholamban (PLB) is a critical determinant of Ca(2+) re-entry into the sarcoplasmic reticulum and is coordinated by AKAP7delta/gamma [2,3]. Here, we further these findings by showing that phosphorylation of PLB requires interaction with AKAP7delta/gamma and that this interaction occurs only when PLB is unphosphorylated. Additionally, we find that two mutants of PLB (R9C and Delta14), which are associated with dilated cardiomyopathy in humans, prevent association with AKAP7delta/gamma and display reduced phosphorylation in vitro. This finding implicates the AKAP7delta/gamma-PLB interaction in the pathology of the disease phenotype. Further exploration of the AKAP7delta/gamma-PLB association demonstrated a phosphorylation state-dependence of the interaction. Computational modeling revealed that this mode of interaction allows for small amounts of AKAP and PKA (100-200nM) to regulate the phosphorylation of large quantities of PLB (50MUM). Our results confirm that AKAP7gamma/delta binding to PLB is important for phosphorylation of PLB, and describe a novel phosphorylation state-dependent binding mechanism that explains how phosphorylation of highly abundant PKA substrates can be regulated by AKAPs present at ~100-200 fold lower concentrations. PMID- 26027518 TI - Something Higher: Lessons from Beyond Physicalism. PMID- 26027517 TI - The autotaxin-LPA2 GPCR axis is modulated by gamma-irradiation and facilitates DNA damage repair. AB - In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to gamma-irradiation that was abolished by mutation of the NF-kappaB site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-kappaB. The resolution kinetics of the DNA damage marker gamma-H2AX in LPA-treated IEC-6 cells exposed to gamma-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of gamma-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of gamma-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 transcripts in Lin(-)Sca-1(+)c Kit(+) enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual gamma-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that gamma irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNFalpha. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair. PMID- 26027520 TI - Development of a highly sensitive fluorescent light-up probe for G-quadruplexes. AB - G-quadruplexes are higher-order nucleic acid structures that have attracted extensive attention because of their biological significance and potential applications in supramolecular chemistry. An ever-increasing interest in G quadruplexes has promoted the development of selective and sensitive fluorescent probes as research tools for these structures. However, most current studies primarily focus on the improved selectivity of probes for G-quadruplexes. Their detection limits or ways to improve their detection limits are rarely described. In this study, a new set of di-substituted triarylimidazole fluorescent probes were designed and synthesized, with the aim of upgrading the detection limit of a lead triarylimidazole IZCM-1 for G-quadruplexes. Among these compounds, IZCM-7 was the most promising candidate. The limit of detection (LOD) value of IZCM-7 for the G-quadruplex was up to 3 nM in solution and up to 5 ng in a gel matrix. These values were significantly improved in comparison with those of IZCM-1. Further biophysical studies revealed that the fluorescence quantum yield and binding affinity of IZCM-7 for G-quadruplexes were markedly increased, and these two factors might be responsible for the significantly improved detection limit of IZCM-7. In addition, the sensitive and selective fluorescence performance of IZCM-7 for G-quadruplexes remained the same even in the presence of large amounts of non-G-quadruplex competitors, suggesting its promising application prospect. PMID- 26027519 TI - Cooperative folding of intrinsically disordered domains drives assembly of a strong elongated protein. AB - Bacteria exploit surface proteins to adhere to other bacteria, surfaces and host cells. Such proteins need to project away from the bacterial surface and resist significant mechanical forces. SasG is a protein that forms extended fibrils on the surface of Staphylococcus aureus and promotes host adherence and biofilm formation. Here we show that although monomeric and lacking covalent cross-links, SasG maintains a highly extended conformation in solution. This extension is mediated through obligate folding cooperativity of the intrinsically disordered E domains that couple non-adjacent G5 domains thermodynamically, forming interfaces that are more stable than the domains themselves. Thus, counterintuitively, the elongation of the protein appears to be dependent on the inherent instability of its domains. The remarkable mechanical strength of SasG arises from tandemly arrayed 'clamp' motifs within the folded domains. Our findings reveal an elegant minimal solution for the assembly of monomeric mechano-resistant tethers of variable length. PMID- 26027521 TI - Visible room-temperature phosphorescence of pure organic crystals via a radical ion-pair mechanism. AB - The afterglow of phosphorescent compounds can be distinguished from background fluorescence and scattered light by a time-resolved observation, which is a beneficial property for bioimaging. Phosphorescence emission accompanies spin forbidden transitions from an excited singlet state through an excited triplet state to a ground singlet state. Since these intersystem crossings are facilitated usually by the heavy-atom effect, metal-free organic solids are seldom phosphorescent, although these solids have recently been refurbished as low-cost, eco-friendly phosphorescent materials. Here, we show that crystalline isophthalic acid exhibits room-temperature phosphorescence with an afterglow that lasts several seconds through a nuclear spin magnetism-assisted spin exchange of a radical ion pair. The obvious afterglow that facilitates a time-resolved detection and the unusual phosphorescence mechanism that enables emission intensification by nuclear spin managements are promising for exploiting the phosphorescence materials in novel applications such as bioimaging. PMID- 26027522 TI - Serum Metal Ions with a Titanium Modular Neck Total Hip Replacement System. AB - The goal of this study is to evaluate serum levels of chromium (Cr), cobalt (Co), and titanium (Ti) within the first two years following total hip arthroplasty using a Ti modular neck system. Twenty-five patients were randomized to a metal on-metal (MoM) bearing with an all CoCr shell, and the remaining 25 received a metal-on-polyethylene (MoP) with a Ti shell. Serum levels demonstrated increases for Cr, Co, and Ti at 1 year (P < .001). MoM had similar Ti levels to MoP hips at 1 year (P=0.11) but lower at 2 years (P=0.03). Results suggest that the passive corrosion (i.e., chemical, pitting, and crevice corrosion) of exposed non articular metal surfaces may be a greater source of ions than the neck-stem or head-neck interfaces. PMID- 26027523 TI - Corrosion and Adverse Local Tissue Reaction in One Type of Modular Neck Stem. AB - Modular neck stems allow for optimization of joint biomechanics by restoring anteversion, offset, and limb length. A potential disadvantage is the generation of metal ions from fretting and crevice corrosion. We identified 118 total hip arthroplasty implanted with one type of dual-modular femoral component. Thirty six required revision due to adverse local tissue reaction. Multivariate analysis isolated females and low offset necks as risk factors for failure. Kaplan-Meir analysis revealed small stem sizes failed at a higher rate during early follow-up period. Although the cobalt/chrome levels were higher in the failed group, these tests had low diagnostic accuracy for ALTR, while MRI scan was more sensitive. We conclude that the complications related to the use of dual modular stems of this design outweigh the potential benefits. PMID- 26027524 TI - Letter to the Editor on "Bilateral Total Hip Arthroplasty has Similar Complication Rates to Unilateral Total Hip Arthroplasty". PMID- 26027525 TI - Construct Validity and Test Re-Test Reliability of the Forgotten Joint Score. AB - Consecutive patients undergoing knee arthroplasty completed questionnaires: FJS, Knee Injury and Osteoarthritis Outcome Score (KOOS) and WOMAC Score (mean 39 months after surgery), and were mailed a repeat questionnaire after 4 to 6 weeks. The test-retest reliability was almost perfect for the FJS (ICC = 0.97), and the FJS subdomains (ICC > 0.8). Convergent construct validity of the FJS was correlated with the KOOS Subscores of Quality of Life (0.63, P = 0.001), Symptom (0.33, P = 0.001), Pain (0.68, P = 0.001) and ADL (0.66, P = 0.001) and the Total WOMAC (0.70, P = 0.001). The FJS demonstrates high test-retest reliability and construct validity compared to the Normalised WOMAC and KOOS Subscales. The FJS does not demonstrate the ceiling effect of the WOMAC or KOOS pain scores so may have greater discriminatory ability following TKR. PMID- 26027526 TI - Oncolytic viruses get a boost with first FDA-approval recommendation. PMID- 26027527 TI - Regulators and industry tackle dose-finding issues. PMID- 26027531 TI - Combinations with checkpoint inhibitors at wavefront of cancer immunotherapy. PMID- 26027532 TI - Stephane Bancel. PMID- 26027533 TI - Neurodegenerative diseases: Repurposing for remyelination. PMID- 26027534 TI - Antiviral drugs: Searching the store cupboard for low-cost HCV drugs. PMID- 26027535 TI - Viral infections: New options to fight Ebola. PMID- 26027536 TI - Drug discovery for the developing world: progress at the Novartis Institute for Tropical Diseases. PMID- 26027537 TI - Photo-cross-linking using trifluorothymidine and 3-cyanovinylcarbazole induced a large shifted (19)F MR signal. AB - Photo-cross-linking of trifluorothymidine ((TF)T) using 3-cyanovinylcarbazole ((CNV)K) clearly shifted its (19)F nuclear magnetic resonance (NMR) signal 8 ppm. This (CNV)K mediated ultrafast photo-cross-linking-induced shift can be utilized for miRNA detection by hybridization chain reaction (HCR) to detect 10 nM of a target in a sequence-specific manner. PMID- 26027538 TI - Boule gene expression underpins the meiotic arrest in spermatogenesis in male rainbow trout (Oncorhynchus mykiss) exposed to DEHP and butachlor. AB - Boule, the ancestor of the DAZ (Deleted in AZoospermia) gene family, in most organisms is mainly involved in male meiosis. The present study investigates the effects of the plasticizer DEHP (50mg/kg body weight) and herbicide butachlor (0.39mg/L) on male rainbow trout (Oncorhynchus mykiss) for a 10-day period in two independent experiments. The results showed that plasma testosterone (T) concentrations were significantly lower in fish exposed to either DEHP or butachlor compared to the control fish (P<0.05). Fish showed a significantly elevated hepatosomatic index (HSI) in the butachlor treatment (P<0.05). However, no significant difference was observed in HSI values in the DEHP treatment (P>0.05). In addition, no significant differences were found in the gonadosomatic index (GSI) in both DEHP and butachlor treatments (P>0.05). Histologically, testes of male trout in the control groups were well differentiated and filled with large numbers of cystic structures containing spermatozoa. In contrast, the testes of male trout contained mostly spermatocytes with few spermatozoa in both treated group, suggesting that DEHP and butachlor may inhibit the progression of meiosis. Also, boule gene expression was significantly lower in the testes of male trout affected by DEHP and butachlor in comparison with their control groups (P<0.05), which confirmed the meiotic arrest in affected trout. Based on the results, the present study demonstrated that DEHP and butachlor can inhibit the progression of spermatogenesis in male trout, potentially by causing an arrest of meiosis, maybe due to down-regulation of boule gene expression through T and/or IGF1 via ERK1/2 signaling in T-independent pathways. In addition, these results confirmed that boule can be considered as a predictive marker to assess meiotic efficiency. PMID- 26027539 TI - Increased prevalence and geographic spread of the cardiopulmonary nematode Angiostrongylus vasorum in fox populations in Great Britain. AB - The nematode Angiostrongylus vasorum is becoming more widely recorded globally, and is of increasing concern as a cause of disease in dogs. Apparent geographic spread is difficult to confirm due to a lack of standardized disease recording systems, increasing awareness among veterinary clinicians, and recent improvements in diagnostic technologies. This study examines the hypothesis that A. vasorum has spread in recent years by repeating the methods of a previous survey of the fox population. The hearts and lungs of 442 foxes from across Great Britain were collected and examined by dissection and flushing of the pulmonary circulation and microscopic inspection of tracheal scrapes. Sampling and parasite extraction methods were identical to an earlier survey in 2005 to ensure comparability. Prevalence of A. vasorum was 18.3% (exact binomial confidence bounds 14.9-22.3), compared with 7.3% previously (5.3-9.9, n = 546), and had increased significantly in most regions, e.g. 7.4% in the Northern UK (previously zero) and 50.8% in the south-east (previously 23.2%). Other nematodes identified were Crenosoma vulpis (prevalence 10.8%, CI 8.1-14.2) and Eucoleus aerophilus (31.6%, CI 27.3-36.2). These data support the proposal that A. vasorum has increased in prevalence and has spread geographically in Great Britain. PMID- 26027540 TI - Genomic and Clinicopathologic Features of Primary Myelofibrosis With Isolated 13q Deletion. AB - BACKGROUND: Primary myelofibrosis (PMF) is a rare myeloproliferative stem cell disorder. The genomic features in PMF are poorly understood. Characterization of genomic alternations in PMF helps to determine their association with clinicopathologic features for further therapeutic implications. PATIENTS AND METHODS: In this retrospective study, we investigated genomic changes using array based comparative genomic hybridization (aCGH) in 17 PMF patients with isolated del(13q) and confirmed our aCGH findings with quantitative polymerase chain reaction (PCR) assay. We also compared the clinicopathologic features of patients with del(13q) (n = 17) with those of patients with a normal karyotype (NK) (n = 26). RESULTS: Clinicopathologically, del(13q) PMF patients had significantly higher blast counts (P = .03) than did NK patients, who had significantly higher marrow cellularity (P = .02). The degree of bone marrow fibrosis of PMF-3 was higher in the del(13q) group than in the NK group. Splenomegaly was present significantly more often in the del(13q) PMF group than in the NK group (P = .03). Genomically, the Janus Kinase 2 V617F mutation was observed less often in del(13q) PMF patients (P = .07). The common deleted region in del(13q) was confined to 13q13-13q14.3 according to G-band karyotyping, demonstrating a minimal deleted region (MDR) of 15.323 Mb, identified using aCGH. The tumor suppressor genes, Retinoblastoma, Forkhead box protein O1, and Succinyl -CoA ligase [ADP-forming] subunit beta in the MDR were deleted, confirmed using real time PCR to confirm our aCGH findings. CONCLUSION: Accurate molecular characterization of del(13q) in PMF using aCGH and quantitative PCR provided further insight to define the MDR and analyze the genomic changes in del(13q) PMF patients. PMID- 26027541 TI - We thought we would be perfect: medication errors before and after the initiation of Computerized Physician Order Entry. AB - BACKGROUND: Because the Institute of Medicine demanded health care improvement, electronic medical records have been implemented with the hopes of eliminating iatrogenic injury caused by avoidable mistakes. Electronic orders and electronic medical records survived its initial slow adoption and have since had a myriad of identifiable flaws as it becomes incorporated nationally. MATERIALS AND METHODS: This retrospective study at a university teaching hospital analyzed all medication order errors (OEs) for the 26 wk of paper-order entries before computer physician order entry (CPOE) and 26 weeks after CPOE was initiated. All OEs were included and documented by month as well as severity using standard taxonomy. RESULTS: Results indicated that CPOE yielded a significant increase in overall medication OE with five of six severity categories remaining the same or increasing in OE. Severity categories A and E saw a significant increase once CPOE began (P < 0.01). Pre-CPOE OEs were 1741, whereas Post-CPOE OEs were 2226, showing an increase in overall medication errors (P < 0.01). After CPOE began, the cumulative successive errors recorded were 112, 290, 267, 307, 412, 399, and 439 with an R(2) value of 0.849 and a P value of 0.003 in the analysis of variance to test regression relation. CONCLUSIONS: As CPOE adapts for its real world applications, it may eventually prove useful in reducing errors; however, perfection and error free order entry will not be achieved unless objective data analysis guides its evolution. PMID- 26027542 TI - Co-extraction of DNA and PLFA from soil samples. AB - Lipid/DNA co-extraction from one sample is attractive in limiting biases associated with microbial community analysis from separate extractions. We sought to enhance established co-extraction methods and use high-throughput 16S rRNA sequencing to identify preferentially extracted taxa from co-extracted DNA. Co extraction results in low DNA yields and distinct community structure changes. PMID- 26027543 TI - FCMM: A comparative metagenomic approach for functional characterization of multiple metagenome samples. AB - Next-generation sequencing (NGS) technologies make it possible to obtain the entire genomic content of microorganisms in metagenome samples. Thus, many studies have developed methods for the processing and analysis of metagenomic NGS reads, including analyses for predicting functions and their enrichments in environmental metagenome samples. Especially, comparative functional studies by using multi-metagenome samples are essential for identifying and comparing different characteristics of multiple environmental samples. In this paper, we introduce a pipeline for functional characterization of multiple metagenome samples to infer major functions as well as their quantitative scores in a comparative metagenomics manner. The pipeline performs the annotation of functions related to expected proteins in the metagenome samples, calculates their enrichment scores based on the reads per kilobase per million reads (RPKM) measure, and predicts the relative abundance of associated functions by a statistical test. The results from single sample analysis are then used to find common and sample-specific major functions. By applying the pipeline to six different environmental metagenome samples, including two ocean (Antarctica aquatic and Baltic Sea) and four terrestrial (Acid mine drainage, human gut microbiome, Amazon River, and Wasca soil) samples, we were able to predict common functions as well as environment-specific functions. Our pipeline is available at http://bioinfo.konkuk.ac.kr/FCMM/. PMID- 26027544 TI - Non-fullerene acceptors: exciton dissociation with PTCDA versus C60. AB - Extensive development of new polymer and small molecule donors has helped produce a steady increase in the efficiency of organic photovoltaic (OPV) devices. However, OPV technology would also benefit from the introduction of non-fullerene acceptors. Unfortunately, efforts to replace fullerenes have typically led to significantly reduced efficiencies. A number of possible explanations for reduced efficiencies with non-fullerene acceptors compared to fullerene acceptors have been suggested, including the formation of unfavorable morphologies in non fullerene systems and/or favorable excitation/carrier delocalization in fullerenes. In addition, enhanced exciton dissociation associated with fundamental characteristics of the fullerene molecular electronic states has also been suggested. We used time-resolved two-photon photoemission (TR-2PPE) to directly compare exciton dissociation at interfaces between zinc phthalocyanine (ZnPc) interfaces and the non-fullerene acceptor, perylene tetracarboxylic dianhydride (PTCDA) versus dissociation measured at the analogous interface with C60, and thus help discriminate between these potential explanations. Exciton dissociation rates are comparable for phthalocyanine interfaces with both acceptors, allowing us to suggest a hierarchy for the importance of various effects producing higher efficiencies with fullerene acceptors. PMID- 26027545 TI - Vectorcardiographic diagnostic & prognostic information derived from the 12-lead electrocardiogram: Historical review and clinical perspective. AB - In the course of time, electrocardiography has assumed several modalities with varying electrode numbers, electrode positions and lead systems. 12-lead electrocardiography and 3-lead vectorcardiography have become particularly popular. These modalities developed in parallel through the mid-twentieth century. In the same time interval, the physical concepts underlying electrocardiography were defined and worked out. In particular, the vector concept (heart vector, lead vector, volume conductor) appeared to be essential to understanding the manifestations of electrical heart activity, both in the 12 lead electrocardiogram (ECG) and in the 3-lead vectorcardiogram (VCG). Not universally appreciated in the clinic, the vectorcardiogram, and with it the vector concept, went out of use. A revival of vectorcardiography started in the 90's, when VCGs were mathematically synthesized from standard 12-lead ECGs. This facilitated combined electrocardiography and vectorcardiography without the need for a special recording system. This paper gives an overview of these historical developments, elaborates on the vector concept and seeks to define where VCG analysis/interpretation can add diagnostic/prognostic value to conventional 12 lead ECG analysis. PMID- 26027546 TI - Risk of Upper and Lower Gastrointestinal Bleeding in Patients Taking Nonsteroidal Anti-Inflammatory Drugs, Antiplatelet Agents, or Anticoagulants. PMID- 26027547 TI - Infant's Age Influences the Accuracy of Rectal Suction Biopsies for Diagnosing of Hirschsprung's Disease. AB - BACKGROUND & AIMS: Hirschsprung's disease (HD) is a rare birth defect of the distal colon. Analysis of rectal suction biopsy (RSB) is considered to be the most reliable method for its diagnosis in infants. However, the diagnostic accuracy of RSB analysis could be affected by the patient's age, possibly because of rapid development of the enteric nervous system in the first weeks after birth. Because there is a trend toward testing for HD at early ages, we aimed to determine whether the diagnostic accuracy of RSB analysis is associated with the patient's age. METHODS: We performed a retrospective analysis of all patients from whom 1 or more RSBs were analyzed from 1975 through 2011 (529 RSBs from 441 patients). Outcomes of RSB analyses were categorized as positive, inconclusive, or negative for HD. Primary diagnoses, based only on RSB, were compared with final diagnoses made after at least 1 year of clinical follow-up. Age at time of RSB analysis was corrected for the gestational age. By using these criteria, we determined the diagnostic accuracy of RSB analysis for different age groups. RESULTS: RSB analysis identified HD in patients with sensitivity values of 46% (patients -45 to 7 days old), 47% (8-22 days old), and 62% (23-39 days old) (corrected for gestational age). The average sensitivity with which RSB analysis identified HD in patients older than 39 days was 88%. RSB identified HD in patients younger than 39 days old with significantly lower sensitivity than in older patients (50% vs 88%, P < .001). The specificity with which RSB identified infants without HD was not affected by age (average 95%). Of all RSBs, 11% were inconclusive for the diagnosis of HD. CONCLUSIONS: RSB analysis identifies HD in patients younger than 39 days old with only 50% sensitivity. Moreover, RSBs obtained from younger patients often lead to inconclusive outcomes and require additional biopsies. We propose that for infants suspected of HD at these ages, a noninvasive technique, such as anorectal manometry, should be used for a primary diagnosis. RSB should thereafter be used to confirm the diagnosis when the infant is older than 39 days. PMID- 26027548 TI - Student learning styles in anatomy and physiology courses: Meeting the needs of nursing students. AB - Anatomy and Physiology is a core course in pre-registration nursing programs, yet many students have difficulty successfully negotiating the large volume of content and the complex concepts in these bioscience courses. Typically students perform poorly in these 'threshold' courses', despite multiple interventions to support student engagement. Investigation of the shortcomings in these courses, based on feedback from students indicated several key areas of difficulty in the course, especially focused around a relative lack of hands-on 'concrete' activities in laboratories and tutorials. To attempt to address this, academic and technical staff developed activities for students that promoted discussion and allowed students to interact easily and repetitively with content. Interactive tables and posters that needed to be labelled or 'filled-in' using pre-prepared Velcro dots, as well as pre-prepared flash cards to promote group work, were some examples of the activities used to enhance student experiences and promote hands-on learning. Over the academic year of 2013 these activities were introduced into the laboratory and tutorial classes for first year Bachelor of Nursing anatomy and physiology students. Staff and student participants positively rated implementation of these new activities on surveys, as they allowed them to explore the difficult aspects of anatomy and physiology, utilising various learning styles that may have been neglected in the past. PMID- 26027549 TI - Reply to: The need to resume chest compressions immediately after defibrillation attempts: An analysis of post-shock rhythms and duration of pulselessness following out-of-hospital cardiac arrest. PMID- 26027550 TI - Glycocalyx injury in adults with nephrotic syndrome: Association with endothelial function. AB - BACKGROUND: Glomerulopathy is a group of diseases that affect mainly young adults. Endothelial dysfunction, atherosclerosis, and increased cardiac mortality can complicate the evolution of such patients. However, there is no study evaluating endothelial glycocalyx in this pathology. METHODS: This cross sectional study included 49 patients with untreated primary nephrotic syndrome that were otherwise healthy. In addition to routine laboratory measurements, syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and e-selectin were measured. Moreover, flow-mediated dilation (FMD) was used as the main endothelial function surrogate. RESULTS: Of the 49 patients with nephrotic syndrome, 25 (51.0%) were females. The mean age of patients was 39.0+/-12.1y. FMD was reduced in nephrotic patients in comparison with controls (3.7+/-1.7 vs. 6.6+/-1.1%, p<0.001). Nephrotic patients had higher levels of ICAM-1 (616.6+/-219.7 vs. 356.9+/-102.0ng/ml, p<0.001) and syndecan-1 (180.3+/-64.1 vs. 28.2+/-9.8ng/ml, p<0.001). No significant difference was observed regarding e-selectin (129.9+/ 54.2 vs. 120.2+/-61.5ng/ml, p=0.489). After adjusting for age and glomerular filtration rate, syndecan-1 was significantly associated with 24-h urinary protein excretion, LDL-cholesterol, HDL-cholesterol, and triglycerides. While age, LDL-cholesterol, and 24-h urinary protein excretion were associated with FMD in the multivariate analysis, when syndecan-1, ICAM-1, and e-selectin were added to the model, only syndecan-1 was independently associated with FMD. CONCLUSIONS: We demonstrated that syndecan-1, a marker of endothelial glycocalyx damage, is increased in patients with nephrotic syndrome and near-normal renal function. Moreover, we determined its association with nephrotic syndrome features and suggest it can have a role in the endothelial dysfunction of these patients. PMID- 26027551 TI - Selective formation of organo, organo-aqueous, and hydro gel-like materials from partially hydrolysed poly(vinyl acetate)s based on different boron-containing crosslinkers. AB - Viscoelastic, gel-like, polymeric dispersions (HVPDs) can be prepared by crosslinking polyols with borax or boric acid in water under alkaline conditions. Rheologically similar HVPDs have been prepared in organic liquids containing no water or hydroxylic groups through crosslinking partially or fully hydrolysed poly(vinyl acetate)s with trimethyl borate, boric acid, or borax. The organo HVPDs are water-sensitive and rheoreversible on exposure to water. They were characterised rheologically and by solution and solid-state (11)B NMR spectroscopy. Spectroscopic analyses show the presence of mono- and di-diol crosslinks, as well as non-crosslinked boron species in HVPDs prepared with trimethyl borate or boric acid. The number of crosslinks in organo-HVPDs prepared with borax increased over the course of several days. Results from solution and solid-state (11)B NMR spectroscopy are comparable; no solid-like component was detectable. We demonstrate that hydro, organo, or organo-aqueous HVPDs can be obtained from partially hydrolysed poly(vinyl acetate)s by 'tuning' the structure of the boron-based crosslinker. PMID- 26027552 TI - Interpretation of data from studies of effects of nintedanib on surfactant protein-D expression in human lung epithelial cells. PMID- 26027553 TI - Variant course of bilateral anterior cerebral artery in semilobar holoprosencephaly. AB - We report an unusual case of semilobar holoprosencephaly with variant course of bilateral anterior cerebral arteries (ACA) in a 1-year-old child. This is a very rare arterial variant, given that holoprosencephalic brains are usually associated with azygous ACAs. PMID- 26027554 TI - Diaper Dermatitis in Infants Admitted to Social Pediatrics Health Center: Role of Socio-demographic Factors and Infant Care. AB - OBJECTIVE: To determine infant diaper dermatitis (DD) at pediatrics health center; its relation to socio-demographic factors and infant care. METHODS: The study included 113 infants aged 0-24 mo. Data on infants' age, sex, weight, mothers' education, nutrition, diaper change frequency, cleaning methods and prophylactic cream use were recorded. Infants with minimum one time rash, were accepted to have DD. RESULTS: Seventy six (67.3 %) infants had DD [32 girls (42.1 %), 44 boys (57 %), mean age: 6.5 mo]. Infants with DD had significantly higher age than those without (p 0.001). DD frequency in infants >=4.5 mo-old was 5.8(2.4-13.7) times more than in infants <=4.5 mo. Cleaning material types did not affect DD frequency. No significant difference was observed in DD with diaper change of <=3 times and >=4 times. Significant difference in DD increase was observed with supplementary food intake vs. without it (p 0.000). DD frequency in infants with supplementary food intake was 6.4 times (2.4-17.1) more than in those without it. Human milk intake was statistically significant in causing less occurrence of DD as shown in univariate model (p < 0.05). Rash incidence was significantly lower with cream use compared to without its use (p < 0.001). DD prevalence was decreased 0.203 (0.087-0.477) times by cream usage. CONCLUSIONS: Age, supplementary food intake and lack of cream use seem to be accountable for DD whereas human milk intake lessened the occurrence of DD. Mothers should be informed on dermatitis care and encouraged for breastfeeding. PMID- 26027555 TI - Isotonic versus Hypotonic Parenteral Maintenance Fluids in Very Severe Pneumonia. AB - OBJECTIVE: To compare the risk of hyponatremia between hypotonic and isotonic parenteral maintenance solutions (PMS) administered to children with very severe pneumonia, admitted in the general pediatric ward. METHODS: A randomized controlled open label trial was conducted in the pediatrics department of a tertiary care medical college hospital including euvolemic children 2 mo to 5 y of age, fulfilling the WHO clinical definition of very severe pneumonia and requiring PMS. They were randomized to receive either isotonic PMS (0.9% saline in 5% dextrose and potassium chloride 20 meq/L) or hypotonic PMS (0.18% saline in 5% dextrose and potassium chloride 20 meq/L) at standard rates for next 24 h. RESULTS: A total of 119 children were randomized (59: Isotonic; 60: Hypototonic PMS). Nine (15%) children in the isotonic PMS group and 29 (48%) in the hypotonic PMS group developed hyponatremia during the study period, (p <0.001) with a relative risk being 3.16 (95% CI 1.64 to 6.09). Mean serum sodium was significantly lower in the hypotonic group compared to the isotonic group (p < 0.001 each at 6, 12 and 24 h). The difference in mean change in serum sodium from baseline was also significant at 12 and 24 h (5.4 and 5.8 meq/L respectively; p < 0.001 each). CONCLUSIONS: This study demonstrates the rationality of the use of isotonic PMS in children with respiratory infections, a condition regularly encountered by most pediatricians. PMID- 26027556 TI - Complicated Infective Endocarditis. PMID- 26027557 TI - Gross primary production of global forest ecosystems has been overestimated. AB - Coverage rate, a critical variable for gridded forest area, has been neglected by previous studies in estimating the annual gross primary production (GPP) of global forest ecosystems. In this study, we investigated to what extent the coverage rate could impact forest GPP estimates from 1982 to 2011. Here we show that the traditional calculation without considering the coverage rate globally overestimated the forest gross carbon dioxide uptake by approximately 8.7%, with a value of 5.12 +/- 0.23 Pg C yr(-1), which is equivalent to 48% of the annual emissions from anthropogenic activities in 2012. Actually, the global annual GPP of forest ecosystems is approximately 53.71 +/- 4.83 Pg C yr(-1) for the past 30 years by taking the coverage rate into account. Accordingly, we argue that forest annual GPP calculated by previous studies has been overestimated due to the exaggerated forest area, and therefore, coverage rate may be a required factor to further quantify the global carbon cycle. PMID- 26027558 TI - Combined friction force microscopy and quantum chemical investigation of the tribotronic response at the propylammonium nitrate-graphite interface. AB - The energetic origins of the variation in friction with potential at the propylammonium nitrate-graphite interface are revealed using friction force microscopy (FFM) in combination with quantum chemical simulations. For boundary layer lubrication, as the FFM tip slides energy is dissipated via (1) boundary layer ions and (2) expulsion of near-surface ion layers from the space between the surface and advancing tip. Simulations reveal how changing the surface potential changes the ion composition of the boundary and near surface layer, which controls energy dissipation through both pathways, and thus the friction. PMID- 26027559 TI - Evidence for an anomalous current-phase relation in topological insulator Josephson junctions. AB - Josephson junctions with topological insulator weak links can host low-energy Andreev-bound states giving rise to a current-phase relation that deviates from sinusoidal behaviour. Of particular interest are zero-energy Majorana-bound states that form at a phase difference of pi. Here we report on interferometry studies of Josephson junctions and superconducting quantum interference devices (SQUIDs) incorporating topological insulator weak links. We find that the nodes in single-junction diffraction patterns and SQUID oscillations are lifted and independent of chemical potential. At high temperatures, the SQUID oscillations revert to conventional behaviour, ruling out asymmetry. The node-lifting of the SQUID oscillations is consistent with low-energy Andreev-bound states exhibiting a nonsinusoidal current-phase relation, co-existing with states possessing a conventional sinusoidal current-phase relation. However, the finite nodal currents in the single-junction diffraction pattern suggest an anomalous contribution to the supercurrent possibly carried by Majorana-bound states, although we also consider the possibility of inhomogeneity. PMID- 26027560 TI - Contribution of Nanotechnology to Improved Treatment of Periodontal Disease. AB - Periodontal disease is chronic inflammation of periodontal tissues resulting in formation of periodontal pockets, periodontal attachment loss and progressive destruction of the ligament and alveolar bone. This review gives an update on periodontal disease pathogenesis, which is important for the development of novel methods and delivery systems for its treatment. The available treatment approaches, including removal of dental plaque, modulation of the host inflammatory response, and regeneration of periodontal tissue, are reviewed and their drawbacks discussed. Furthermore the latest achievements involving development of nanomedicines, which represent a new approach to better treatment of periodontal disease, are highlighted. They enable local drug delivery to particular tissues, cells, or subcellular compartments in periodontal pockets, either to biofilm pathogens or host cells, as well as control the release of incorporated drugs, usually antibiotic or anti-inflammatory. Specific examples of the nanocarriers or nanomaterials such as liposomes, lipid and polymeric nanoparticles, nanocrystals, dendrimers, and nanofibers under development for the treatment of periodontal disease are also clearly reviewed. Nanofibers are of special interest as nanodelivery systems and scaffolds for the regeneration of periodontal tissue. Finally, the future outlook of novel therapeutic approaches involving nanodelivery systems in the treatment of periodontal disease is provided. PMID- 26027561 TI - Generation of Targeted Adeno-Associated Virus (AAV) Vectors for Human Gene Therapy. AB - Adeno-associated virus (AAV) vectors are promising human gene delivery vehicles due to their ability to establish long-term gene expression in a wide variety of target tissues; however, the broad native viral tropism raises concerns over the feasibility and safety of their systemic administration. To overcome this issue, much effort has been made to redirect AAVs toward specific tissues. This review presents several design strategies that have been applied to generate AAVs that target specific tissues and cells while inhibiting the transduction of non-target tissues. Multiple methods of vector capsid engineering have shown promise in vitro, including indirect targeting by adaptor systems and direct targeting by the insertion of antibodies or receptor-specific small peptide motifs. Other strategies, including creating mosaic or chimeric capsids and directed evolution, have also been used to successfully retarget AAV vectors. This research will further expand the clinical applications of AAV vectors by enhancing the control over tissue-specific gene delivery. PMID- 26027562 TI - EHDA Spraying: A Multi-Material Nano-Engineering Route. AB - Electrohydrodynamic atomization (EHDA) enabling platform technologies have gathered significant momentum over the last two decades. Utilisation of the underpinning jetting process in tandem with desired materials (including polymers, ceramics, metals and even naturally occurring compounds such as peptides, DNA and cells) provides the basis for novel engineered therapies. Through EHDA processes, the generation of a variety of nano-meter and micro-meter scaled structures with control on surface and encapsulation features is attainable in a single step. While a host of adaptable EHDA techniques have evolved (e.g. printing and template patterning), there are two main processes that continue to dominate: electrospraying (ESy) and electrospinning (ESp). Although ESp has drawn considerable researcher interest for nanofibre applications, ESy is an important and timely process for nano- and micro-particle fabrication. Thus, an appropriate evaluation of ESy is vital. This short review focuses on key developments in the ESy field in relation to nanotechnologies with potential healthcare applications using metals, polymers and ceramics. An insight into the process of particle formation (during EHDA spraying or ESy), process parameters and materials specifications, is provided. Emerging biomedical and other healthcare research through nanotechnologies are highlighted. PMID- 26027563 TI - Multidimensional Ophthalmic Nanosystems for Molecular Detection and Therapy of Eye Disorders. AB - Symptomatic distresses associated with common ophthalmic infections and their persistence, have remained a tribulation with repeated occurrences. Although being a directly accessible organ, traditional therapeutic strategies exhibiting seemingly fruitful outcome in treatment and prognosis of eye disorders call for improvement in disease intervention. This is due to frequent challenges presented by the ophthalmic environment. Contemporary research has addressed these challenges by applying nanotechnology as a central concept in designing more proficient diagnostic and therapeutic systems for eye ailments. Within such nanosystems (dendrimers, aptamers, metal nanoparticles, etc.), bioactive agents, drugs and genetic materials can be entrapped and these form the key elements that act at the biomolecular stage and bestow a high level of efficacy towards eradication of disease causatives and specificity for recognition and capture aiding diagnostic processes. In the current review, we present researched and patented nanocentric technologies as promising tools in detection and treatment of ophthalmic ailments. PMID- 26027564 TI - Graphene Oxide-Based Nanocarriers for Cancer Imaging and Drug Delivery. AB - Nano graphene oxide (nGO) is a member of graphene family, which is a novel, one atom-thickness, two-dimensional carbon nanomaterial. In comparison with graphene, nGO contains much higher extent of reactive chemical functionalities such as hydroxyl, carbonyl, carboxyl, and epoxy group, so as to enable its easier biochemo-functionalization, higher biocompatibility, and greater potentials of applications in biomedicine fields. Up to now, nGO has attracted extensive research interests in nanomedicine and drug delivery systems for cancer imaging and therapy due to its unique biochemical and in vivo properties. This review generally describes the preparation, functionalization, and toxicity of nGO firstly, and then focuses on the studies of biomedical applications for cancer imaging and drug delivery. PMID- 26027565 TI - Intratumoral Pharmacokinetics: Challenges to Nanobiomaterials. AB - Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. Solid tumor tissue is characterized by high density of vascular bed however; the vast majority of these blood vessels are not functioning. The vast majority of solid tumors can be described as poorly perfused with blood; and anticancer agents need to penetrate/distribute avascularly within solid tumor micro-milieu. Classic pharmacokinetic parameters correlate drug status within central compartment (blood) to all perfused body tissues according to their degree of perfusion. Yet, these classic pharmacokinetic parameters cannot fully elucidate the intratumoral drug penetration/distribution status of anticancer drugs due to the great discrepancies in perfusion between normal and solid tumor tissues. Herein, we will discuss the recently proposed pharmacokinetic parameters that might accurately portray the distribution of anticancer agents within solid tumor micro milieu. In addition, we will present the new challenges attributed to these new pharmacokinetic parameters towards designing nanobiomaterial drug delivery system. PMID- 26027566 TI - Zein-Based Nanofibres for Drug Delivery: Classes and Current Applications. AB - Plant proteins have been drawing increasing attention owing to their safety, abundance and relatively low cost in comparison with animal proteins. The development of plant protein-based delivery vehicles may lead to the provision of novel pharmaceutical products to patients. Zein is a class of alcohol-soluble prolamine proteins present in maize endosperm that was approved as a generally recognised as safe excipient in 1985 by the US FDA for use in pharmaceutical film coatings. Over the past few decades, numerous studies have been carried out to illustrate zein's potential for novel applications in the biomedical field. This paper reviews the present status of zein-based nanofibres, with emphasis on their fabrication and biomedical applications, particularly for drug delivery. Their benefits and limitations are also discussed to provide further insight into zein's potential as a promising biomaterial. PMID- 26027567 TI - Application of Carbon Nanomaterials in Gene Delivery for Endogenous RNA Interference In Vitro and In Vivo. AB - Knocking down expression by small interfering RNA (siRNA) has shown high affinity, specificity and potency in silencing target gene sites. For effective endogenous RNA interference (RNAi), proper siRNA delivery vehicles are essential, to take the siRNA inside cells and protect them during the circulation. Carbon nanomaterials (CNMs) have been successfully applied in biomedicine and biosensor based on their ultra-high surface functionalization and nucleic acid molecular loading capacity. Recently, CNMs have drawn considerable research interest and expectation as potential non-viral vectors for siRNA delivery. Here we reviewed the recent application of CNMs in gene delivery for RNAi, mainly about fullerenes, carbon nanotubes (CNTs) and graphene. PMID- 26027568 TI - Recent Developments of New DNA Origami Nanostructures for Drug Delivery. AB - DNA origami technique was first introduced in 2006 by Rothemund, it has gained widespread research interest and led to explosive achievements, in which long single-stranded DNA (ssDNA) is folded into a designed nanostructure, in either two dimensions (2D) or three dimensions (3D), with the aid of many shorter staple strands. A series of methods for new design principles for DNA origami nanostructures have already been proposed, ranging from the preparation of scaffold to the folding mechanisms. After that, novel strategies in functionalizing DNA origami nanostructures and their practical applications are gradually becoming research hotspots. This review focuses on the development in the new scaffold design approaches, folding conditions, various nano objects functionalized on DNA origami nanostructures, and their applications as drug carriers in the recent five years. We anticipate more exploratory and extendible work developed based on the summary of progress obtained previously. PMID- 26027569 TI - Functionalized Nanocarriers for Enhanced Bioactive Delivery to Squamous Cell Carcinomas: Targeting Approaches and Related Biopharmaceutical Aspects. AB - Cancer has been described as one of the major and leading causes of death worldwide. By the year 2030, it has been postulated that over 21.4 million new cases of cancer could be expected, 17 million cancer deaths yearly and a total of 75 million people will be living with cancer within five years of diagnosis. Chemotherapy is the main therapeutic intervention for treating people living with SCC. However, drug resistance has rendered it inefficient and ineffective in combating the disease even after combination chemotherapy. Many peptides and proteins have been investigated to possess biological activities that mark them as potential anti-cancer agents. Targeting peptides are conjugated with other functional peptides or nanoparticles to augment drug delivery both in vitro and in vivo assays. The current identification of tumor-homing peptides through phage display technology has opened a new strategy for targeted therapy in SCC diseases. Despite the advances in cancer nanomedicine, targeted approaches in the delivery of therapeutics for the treatment of squamous cell carcinoma related tumours have not been well established. In this review, current drugs employed in cancer nanomedicine are highlighted, possible rate limiting factors for the application of polymeric materials in cancer nanomedicine are elucidated and functionalized nano-constructs using receptor ligands and homing peptides as targeted moieties are discussed. The combinatorial strategy of attaching both homing peptides and receptor ligands as dual moieties on nano cargos should further strengthen the advantages of each technology in cancer targeted therapy. PMID- 26027570 TI - Nanoparticle-Based Combination Therapy for Cancer Treatment. AB - In recent years, combination of different types of therapies using nanoparticles has emerged as an advanced strategy for cancer treatment. Most of all, combination of chemotherapeutic drug and siRNA in nanoformulation has shown a great potential, because siRNA-mediated specific gene silencing can compensate for the incomplete anti-cancer actions of chemotherapy. In this article, nanoparticle-based combination therapy for cancer treatment is introduced to be focused on the therapeutic chemical and siRNA combination. It is classified into 3 groups: 1) general chemotherapy combined with siRNA carrying nanoparticle, 2) co-delivery of chemical and siRNA therapeutics within a single nanoparticle, and 3) Use of multiple nanoparticles for chemical and siRNA therapeutics. The purpose of the combination and the mechanisms of anti-cancer action was described according to the categories. Examples of some recent developments of nanotechnology-based chemo- and siRNA- therapeutics combination therapy are summarized for better understanding of its practical application. PMID- 26027571 TI - Formulation and Stability Aspects of Nanosized Solid Drug Delivery Systems. AB - Nano drug delivery systems are considered as useful means to remedy the problems of drugs of poor solubility, permeability and bioavailability, which became one of the most troublesome questions of the pharmaceutical industry. Different types of nanosized drug delivery systems have been developed and investigated for oral administration, providing auspicious solutions for drug development. In this paper nanosized drug delivery systems intended for oral administration are discussed based on the chemical nature of the carrier of drug molecules. Lipid nanoparticles comprising solid lipid nanoparticles, improved nanostructured lipid carriers and nanostructured silica- lipid hybrid particles have become popular in the formulation of lipophilic drugs of poor oral bioavailability. Polymeric nanoparticles including nanospheres and nanocapsules and polymeric fibrous systems have also emerged as potential drug delivery systems owing to their unique structure. The feasibility of surface functionalization of mesoporous materials and gold nanoparticles enables high level of control over particle characteristics making inorganic nanoparticles an exceptional formulation approach. The authors paid particular attention to the functionality-related stability of the reviewed delivery systems. PMID- 26027573 TI - Crystallization Methods for Preparation of Nanocrystals for Drug Delivery System. AB - Low water solubility of drug products causes delivery problems such as low bioavailability. The reduced particle size and increased surface area of nanocrystals lead to the increasing of the dissolution rate. The formulation of drug nanocrystals is a robust approach and has been widely applied to drug delivery system (DDS) due to the significant development of nanoscience and nanotechnology. It can be used to improve drug efficacy, provide targeted delivery and minimize side-effects. Crystallization is the main and efficient unit operation to produce nanocrystals. Both traditional crystallization methods such as reactive crystallization, anti-solvent crystallization and new crystallization methods such as supercritical fluid crystallization, high-gravity controlled precipitation can be used to produce nanocrystals. The current mini review outlines the main crystallization methods addressed in literature. The advantages and disadvantages of each method were summarized and compared. PMID- 26027572 TI - Lipid-Based Nanocarriers for RNA Delivery. AB - RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. In recent years, several clinical trials of RNAi therapeutics especially siRNAs have been conducted with limited success so far. For systemic administration of these poorly permeable and easily degradable macromolecules, it is obvious that a safe and efficient delivery platform is highly desirable. Because of high biocompatibility, biodegradability and solid track record for clinical use, nanocarriers made of lipids and/or phospholipids have been commonly employed to facilitate RNA delivery. In this article, the key features of the major sub classes of lipid-based nanocarriers, e.g. liposomes, lipid nanoparticles and lipid nanoemulsions, will be reviewed. Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges. It is hoped that by understanding more about the pros and cons of these most frequently used RNA delivery systems, the pharmaceutical scientists, biomedical researchers and clinicians will be more successful in overcoming some of the obstacles that currently limit the clinical translation of RNAi therapy. PMID- 26027574 TI - Emerging Use of Nanotechnology in the Treatment of Neurological Disorders. AB - Neurological disorders represent one of the major health concerns worldwide. Yet currently employed treatment strategies have not been very successful in the treatment of many of these disorders. One of the root causes of this lack of success is that many pharmaceutically active compounds are unable to reach their target sites of action inside the body. The delivery of substances from systemic circulation to the desired site of action, namely central nervous system (CNS), is hindered by CNS extracellular and intracellular barriers. One promising approach to circumvent these barriers is the use of nanoscaled drug delivery systems. These nanosized drug carriers display various advantages over other conventional drug delivery methods such as high drug loading capacity, targeted action, reduced toxicity, and increased therapeutic effect. Nano-neuroscience is thereby emerging as an exciting field of study and a promising future direction for the delivery of therapeutics to their targeted site of action inside the CNS for the treatment of various neurological and psychiatric disorders. Here, we will first discuss the general pharmacokinetics of therapeutics depending on the route of administration, drawbacks of conventional drug delivery systems and challenges for CNS drug delivery, namely CNS barriers. Next, a short overview of the strategies to circumvent these barriers will be given. Finally, nanotechnology and its emerging use as drug delivery systems will be discussed. This includes the advantages of nanoparticles over other conventional drug delivery systems; production of nanoparticles and their designing as an effective drug carrier; various types of nanoparticles; and some examples of their efficient use in the delivery of bioactive substances, and in the treatment of neurological disorders mainly Alzheimer's disease, brain tumors and neuroAIDS. Lastly, a future perspective on the use of nanotechnology in CNS drug delivery will be highlighted. PMID- 26027575 TI - Multifunctional Delivery Systems for Advanced oral Uptake of Peptide/Protein Drugs. AB - In recent years, advances in biotechnology and protein engineering have enabled the production of large quantities of proteins and peptides as important therapeutic agents. Various researchers have used biocompatible functional polymers to prepare oral dosage forms of proteins and peptides for chronic use and for easier administration to enhance patient compliance. However, there is a need to enhance their safety and effectiveness further. Most macromolecules undergo severe denaturation at low pH and enzymatic degradation in the gastrointestinal tract. The macromolecules' large molecular size and low lipophilicity cause low permeation through the intestinal membrane. The major strategies that have been used to overcome these challenges (in oral drug carrier systems) can be classified as follows: enteric coating or encapsulation with pH sensitive polymers or mucoadhesive polymers, co-administration of protease inhibitors, incorporation of absorption enhancers, modification of the physicochemical properties of the macromolecules, and site-specific delivery to the colon. This review attempts to summarize the various advanced oral delivery carriers, including nanoparticles, lipid carriers, such as liposomes, nano aggregates using amphiphilic polymers, complex coacervation of oppositely charged polyelectrolytes, and inorganic porous particles. The particles were formulated and/or surface modified with functional polysaccharides or synthetic polymers to improve oral bioavailability of proteins and peptides. We also discuss formulation strategies to overcome barriers, therapeutic efficacies in vivo, and potential benefits and issues for successful oral dosage forms of the proteins and peptides. PMID- 26027576 TI - Hydrophilic Polymers for Modified-Release Nanoparticles: A Review of Mathematical Modelling for Pharmacokinetic Analysis. AB - Hydrophilic polymers are the most common group of polymers used in the preparation of modifiedrelease drug delivery systems. This is due to their versatility, low cost, high production yield, as well as easy manufacturing and adequate in vitro/in vivo correlation. In normal physiological conditions, the matrix controls the release of the loaded drug over time through a process of diffusion and/or erosion of the matrix, depending on its physicochemical composition. This is particularly relevant when describing the pharmacokinetic profile of nanosized drug delivery systems (nanoparticles). The use of mathematical models became an important tool to characterize the pharmacokinetics of drugs loaded in nanoparticles to improve the drug bioavailability and to establish bioequivalence. Therefore, the drug release profile can be predicted by a minimum number of experimental studies, since the mathematical equations reveal the dissolution rate of the drug loaded in the hydrophilic matrix. The present paper discusses the use of mathematical models when developing modified-release drug delivery systems of nanometer size composed of hydrophilic polymers. PMID- 26027577 TI - Current Nanotechnological Approaches for an Effective Delivery of Bioactive Drug Molecules to Overcome Drug Resistance Tuberculosis. AB - Tuberculosis (TB) is an airborne communicable disease, mainly caused by aerobic, non-motile, rodshaped, weakly gram-positive, acid-fast tubercular bacillus Mycobacterium tuberculosis (MTb). Mycobacterium has worsened the problem in humans by acquiring various types of resistances like Multi-drug resistance (MDR), Single-drug resistance (SDR), and Extensive drug resistance (XDR). Some clinical problems and challenges associated with conventional TB chemotherapy include poor patient compliance, longer duration of chemotherapy, lesser cell permeability, primary drug resistance, difficulty in maintaining higher drug concentrations at the infected site, and degradation of the drug before reaching the target site. Thus, newer micrometric or nanometric carriers drug delivery approaches are needed. Colloidal (vesicular and particulate) drug carriers offer numerous advantages over conventional therapy such as better systemic bioavailability, rapid onset of therapeutic action, avoidance of first-pass metabolism, providing sustained and controlled release, fewer dosing frequencies, desired pharmacokinetic prole and route of administration. This review article present updates and fabrication of drug delivery approaches for tuberculosis chemotherapy in order to improve patient compliance. PMID- 26027578 TI - Recent Advances and Strategies in Tumor Vasculature Targeted Nano-Drug Delivery Systems. AB - In recent decades, targeted nano-drug delivery systems have attracted extensive attention in cancer therapy for their efficient drug delivery and tumor site specificity. Tumor vasculature, including angiogenesis and vasculogenic mimicry is associated tightly with tumor growth, progression and metastasis. Therefore, nano-drug delivery systems targeting tumor vasculature are becoming a promising approach for tumor treatment. As complicated mechanisms and various factors are involved in the tumor vasculature, different ligands modified on the surface of nanocarriers acquire active targeting through binding to the receptors over expressed by cancer cells or angiogenic endothelial cells. In this review, the tumor vasculature characteristics are briefly described and the recent advances and potential strategies in tumor vasculature targeted nano-drug delivery systems are introduced. PMID- 26027579 TI - Facing down climate change: now or never. PMID- 26027580 TI - Approaches to Climate Change & Health in Cuba: Guillermo Mesa MD MPhil, Director, Disasters & Health, National School of Public Health. Paulo Ortiz MS PhD, Senior Researcher, Climate Center, Cuban Meteorology Institute. AB - The US National Institutes of Health predict climate change will cause an additional 250,000 deaths between 2030 and 2050, with damages to health costing US$2-$4 billion by 2030. Although much debate still surrounds climate change, island ecosystems-such as Cuba's-in the developing world are arguably among the most vulnerable contexts in which to confront climate variability. Beginning in the 1990s, Cuba launched research to develop the evidence base, set policy priorities, and design mitigation and adaptation actions specifically to address climate change and its effects on health. Two researchers at the forefront of this interdisciplinary, intersectoral effort are epidemiologist Dr Guillermo Mesa, who directed design and implementation of the nationwide strategy for disaster risk reduction in the Cuban public health system as founding director of the Latin American Center for Disaster Medicine (CLAMED) and now heads the Disasters and Health department at the National School of Public Health; and Dr Paulo Ortiz, a biostatistician and economist at the Cuban Meteorology Institute's Climate Center (CENCLIM), who leads the research on Cuba's Climate and Health project and is advisor on climate change and health for the UN Economic Commission for Latin America and the Caribbean (ECLAC). PMID- 26027581 TI - Cuba confronts climate change. AB - Among environmental problems, climate change presents the greatest challenges to developing countries, especially island nations. Changes in climate and the resulting effects on human health call for examination of the interactions between environmental and social factors. Important in Cuba's case are soil conditions, food availability, disease burden, ecological changes, extreme weather events, water quality and rising sea levels, all in conjunction with a range of social, cultural, economic and demographic conditions. PMID- 26027582 TI - Influence of climate variability on acute myocardial infarction mortality in Havana, 2001-2012. AB - INTRODUCTION: Death from acute myocardial infarction is due to many factors; influences on risk to the individual include habits, lifestyle and behavior, as well as weather, climate and other environmental components. Changing climate patterns make it especially important to understand how climatic variability may influence acute myocardial infarction mortality. OBJECTIVES: Describe the relationship between climate variability and acute myocardial infarction mortality during the period 2001-2012 in Havana. METHODS: An ecological time series study was conducted. The universe comprised 23,744 deaths from acute myocardial infarction (ICD-10: I21-I22) in Havana residents from 2001 to 2012. Climate variability and seasonal anomalies were described using the Bulto-1 bioclimatic index (comprising variables of temperature, humidity, precipitation, and atmospheric pressure), along with series analysis to determine different seasonal-to-interannual climate variation signals. The role played by climate variables in acute myocardial infarction mortality was determined using factor analysis. The Mann-Kendall and Pettitt statistical tests were used for trend analysis with a significance level of 5%. RESULTS: The strong association between climate variability conditions described using the Bulto-1 bioclimatic index and acute myocardial infarctions accounts for the marked seasonal pattern in AMI mortality. The highest mortality rate occurred during the dry season, i.e., the winter months in Cuba (November-April), with peak numbers in January, December and March. The lowest mortality coincided with the rainy season, i.e., the summer months (May-October). A downward trend in total number of deaths can be seen starting with the change point in April 2009. CONCLUSIONS: Climate variability is inversely associated with an increase in acute myocardial infarction mortality as is shown by the Bulto-1 index. This inverse relationship accounts for acute myocardial infarction mortality's seasonal pattern. PMID- 26027583 TI - Spatial Models for Prediction and Early Warning of Aedes aegypti Proliferation from Data on Climate Change and Variability in Cuba. AB - INTRODUCTION: Climate variability, the primary expression of climate change, is one of the most important environmental problems affecting human health, particularly vector-borne diseases. Despite research efforts worldwide, there are few studies addressing the use of information on climate variability for prevention and early warning of vector-borne infectious diseases. OBJECTIVE: Show the utility of climate information for vector surveillance by developing spatial models using an entomological indicator and information on predicted climate variability in Cuba to provide early warning of danger of increased risk of dengue transmission. METHOD: An ecological study was carried out using retrospective and prospective analyses of time series combined with spatial statistics. Several entomological and climatic indicators were considered using complex Bulto indices -1 and -2. Moran's I spatial autocorrelation coefficient specified for a matrix of neighbors with a radius of 20 km, was used to identify the spatial structure. Spatial structure simulation was based on simultaneous autoregressive and conditional autoregressive models; agreement between predicted and observed values for number of Aedes aegypti foci was determined by the concordance index Di and skill factor Bi. RESULTS: Spatial and temporal distributions of populations of Aedes aegypti were obtained. Models for describing, simulating and predicting spatial patterns of Aedes aegypti populations associated with climate variability patterns were put forward. The ranges of climate variability affecting Aedes aegypti populations were identified. Forecast maps were generated for the municipal level. CONCLUSIONS: Using the Bulto indices of climate variability, it is possible to construct spatial models for predicting increased Aedes aegypti populations in Cuba. At 20 x 20 km resolution, the models are able to provide warning of potential changes in vector populations in rainy and dry seasons and by month, thus demonstrating the usefulness of climate information for epidemiological surveillance. PMID- 26027584 TI - Use of Home Peritoneal Dialysis by Cuba's Nephrology Institute, 2007-2012. AB - INTRODUCTION: Peritoneal dialysis is a maintenance therapy option for patients with end-stage renal disease. Continuous ambulatory peritoneal dialysis in Cuba was introduced in December 2007, and automated peritoneal dialysis one year later. This paper presents the outcomes attained with this blood purification technique, enabling an assessment to decide on scaling up its use in Cuba. OBJECTIVE: Describe the clinical course of patients in the first five years of the Home Peritoneal Dialysis Program at Havana's Nephrology Institute. METHODS: An observational, descriptive study with a retrospective cohort was conducted. The universe comprised the 40 Nephrology Institute patients who underwent treatment with home peritoneal dialysis from December 20, 2007 to December 20, 2012. Relative and absolute frequencies were calculated for the study variables and the Kaplan-Meier method was used for survival curves for patients and for the peritoneum as dialysis membrane. RESULTS Of the 40 patients in the program, 23 were men and 17 were women, primarily aged 40 to 59 years. The most frequent causes of chronic kidney failure were hypertension (42.5%), glomerulopathies (22.5%), and diabetes mellitus (22.5%). A total of 103 complications occurred, both infectious (68, 66%) and non-infectious (35, 34%). The most common infectious complication was peritonitis (45, 66.2%); the most frequent non infectious complication was catheter displacement (13, 37.1%). Seven patients left the peritoneal dialysis program. Of these, three died, two lost function of the peritoneum as a dialysis membrane, one received a kidney transplant and one recovered kidney function. Survival was 100% at one year, 97% at 2 years, 93.2% at 3 and 4 years, and 92% at 5 years. However, the peritoneal membrane was functional in 100% of patients during the first 2 years, decreasing to 96% at 3 and 4 years and to 88.6% at 5 years. CONCLUSIONS: In our setting, peritoneal dialysis attained outcomes similar to those obtained internationally, which supports its usefulness as a renal replacement therapy method in Cuban patients with end-stage renal disease. PMID- 26027585 TI - Stress-rest myocardial perfusion scintigraphy and adverse cardiac events in heart failure patients. AB - INTRODUCTION: Heart failure, primarily in the elderly, is a growing epidemic in today's world. It leads to high rates of disability and mortality, as well as significant health care expenditures, making it important to assess possible predictors of adverse cardiac events. In Cuba, heart failure mortality is 19.1/100,000 population. OBJECTIVES: Assess the value of stress-rest protocol gated-SPECT for identifying patients with symptomatic heart failure likely to suffer adverse cardiac events. METHODS: A study was conducted of 52 patients (mean age 59 years, SD 9; 62% women) with functional capacity II/III (New York Heart Association scale) and left ventricular ejection fraction <40%. Patients were divided into two groups based on coronary heart disease diagnosis: those with coronary heart disease (41), labeled ischemic; and those without (11), labeled nonischemic. All underwent gated SPECT myocardial perfusion scintigraphy with technetium-99m-labeled methoxyisobutyl isonitrile, using a two-day stress rest protocol, including evaluation of intraventricular synchrony by phase analysis. Patients were followed over 36 months for adverse cardiac effects. RESULTS: No significant differences were observed between the two groups during the stress test with regard to exercise time, metabolic equivalents or percentage of maximal heart rate during maximal stress. Summed stress, rest and difference scores, however, were significantly different between the ischemic and nonischemic groups: 16.82 (SD 6.37) vs. 7.54 (SD 5.8), p <0.001; 14.43 (SD 6.28) vs. 6.45 (SD 3.77), p = 0.001; and 2.39 (SD 4.89) vs. 1.09 (SD 3.7), p = 0.034. No differences were found in ventricular function, although stress-minus-rest left ventricular ejection fraction was slightly lower in patients with ischemic heart disease (-1.29, SD 5.8) than in patients without ischemic heart disease (1.27, SD 4.31). Dyssynchrony was greater in patients with ischemic heart disease than in those without, primarily during stress (p <0.01). The only variable that showed a possible association with the occurrence of adverse events was <5 metabolic equivalents on the stress test (p = 0.03), while resting phase SD showed only a tendency toward association (p = 0.05). CONCLUSIONS: Information on myocardial perfusion, functional capacity and intraventricular synchrony obtained from stress-rest gated SPECT may help identify patients with symptomatic heart failure who are likely to develop adverse cardiac events, enabling better management of higher-risk cases and improved allocation of resources. PMID- 26027586 TI - Psychological the most common elder abuse in a Havana neighborhood. AB - INTRODUCTION: Globally, older adults are a population group that often suffers abuse by their caregivers. Along with women and children, they are among those most often reported as victims of abuse of any kind in Cuba. OBJECTIVE: Characterize presence of domestic abuse of older adults in family doctor-and nurse office No. 28 of the Carlos Manuel Portuondo University Polyclinic in Havana, Cuba, determining the main manifestations of abuse and help-seeking behavior by the older adults identified as victims. METHOD: This was a descriptive cross-sectional study of adults aged >= 60 years; all those not diagnosed with dementia and who agreed to participate were interviewed. In a universe of 268 older adults, 29 were living outside the area, 24 declined to participate, and 18 had a diagnosis of dementia, leaving a study population of 197 individuals. Variables included: personal experience of abuse, type of abuse, perpetrator, help sought, and reasons for not seeking help. Statistical analysis was based on percentages. RESULTS: Of 197 older adults interviewed, 88 (44.7%) reported that they were victims of domestic abuse; 50 of these were women. The most common types of abuse were psychological abuse and disrespect for personal space, reported by 69 (78.4%) and 54 (61.4%) individuals, respectively. Sons- and daughters-in-law were identified as the abusers by 68 participants and grandchildren by 65. Of the 88 victims, 67 (76.1%) stated that they did not seek help. CONCLUSIONS: The finding that substantial numbers of older adults are victims of domestic abuse brings to light a hitherto insufficiently addressed issue in the community studied. More research is needed to deepen understanding of the scope and causes of the problem to inform prevention and management strategies, not only at the level of the polyclinic catchment area, but in the health system in general. PMID- 26027587 TI - Poor management of low birth weight compounds obesity and chronic diseases in Cuba. AB - The Cuban population exhibits high prevalence of overweight and associated chronic non-communicable diseases, trends that begin in childhood. In addition to factors related to the mother's health, factors contributing to excess weight gain in Cuban children are: reduced prevalence of exclusive breastfeeding of infants up to six months of age, full-term low birth weight infants and nutritional mismanagement of this group, incorrect complementary feeding, obesogenic diet, family history and sedentary lifestyles. Thus, it is important to adopt comprehensive, multisectoral strategies that promote adequate nutrition and weight control. This is particularly important for full-term low birth weight infants, predisposed to body fat storage. PMID- 26027588 TI - Cuba-USA: Environmental Protection Knows No Borders. PMID- 26027589 TI - Climate Change Highlights a Potentially Dangerous Trade-off. PMID- 26027590 TI - [Ureteral endometriosis as the cause of septic shock and single-sided renal failure]. AB - Ureteral endometriosis is a rare variant of an otherwise common condition, which is primarily seen among premenopausal women. The symptoms and the clinical findings include silent loss of kidney function, gross haematuria, abdominal pain, hypertension and tumour suspicion. We present a rare case of intrinsic ureteral endometriosis resulting in a life-threatening infection and loss of a kidney. Involvement of gynaecologists for early diagnosis and medical treatment in combination with surgical intervention could be of importance in order to prevent the serious consequences as described in this case. PMID- 26027591 TI - [The first Danish paediatric ethical committee]. AB - We report the experiences from the first two years of a paediatric ethical committee at Rigshospitalet. The committee consists of five clinicians (nurses and doctors) and five non-clinicians. Themes of the sixteen reported case were: genetic testing, life-sustaining treatment ("when is enough enough?"), non consensus between the parents and health personal and between different health personal, controversies to different religious wishes and to optimizing resources of the department versus individual care of a critically ill child. Within paediatrics a need for ethical reflection seems obvious. PMID- 26027592 TI - [The influence of melatonin on the immune system and cancer]. AB - Melatonin has been shown to play a fundamental part in neuroimmunomodulation. Besides regulating the circadian rhythm it works as a natural antioxidant with immune stimulatory and anti-cancer properties. Melatonin is a regulator of haemopoiesis and modifies various cells and cytokines of the immune system. Also, melatonin elicits oncostatic properties in a variety of different tumour cell lines. A number of studies have documented that when given in combination with chemo-therapy to patients with disseminated disease, melatonin increases the overall one-year survival and reduces toxic side effects. PMID- 26027593 TI - [Metformin can reduce the risk of colorectal cancer]. AB - Diabetes mellitus (DM) is an established, independent risk factor for colorectal cancer (CRC). Metformin is the first drug of choice for type 2 DM. Several studies have shown a decreased risk of developing CRC in patients with metformin treated DM, compared with patients with diabetes not treated with metformin. An increased overall survival and CRC-specific survival in patients with CRC and metformin-treated DM has still not been substantially proven. Further studies are needed before a conclusion can be made whether metformin should be used in the treatment of CRC. PMID- 26027594 TI - [Anaesthesia for patients with chronic wounds]. AB - Perioperative management of chronic wounds demands a multidisciplinary approach. Severe co-morbidities leave these patients prone to post-operative complications. To optimize wound healing, minimally invasive methods, both surgical and anaesthesiological, are applied. Ultrasound-guided peripheral nerveblocks (PNB) are an ideal anaesthesia method for wound revisions, amputations and split skin transplantations. The implementation of PNB allows continued anticoagulant treatment, provides post-operative analgesia, lowers opioid consumption and facilitates mobilization. PMID- 26027595 TI - Application of the Nutrition Functional Diversity indicator to assess food system contributions to dietary diversity and sustainable diets of Malawian households. AB - OBJECTIVE: Dietary diversity is associated with nutrient adequacy and positive health outcomes but indicators to measure diversity have focused primarily on consumption, rather than sustainable provisioning of food. The Nutritional Functional Diversity score was developed by ecologists to describe the contribution of biodiversity to sustainable diets. We have employed this tool to estimate the relative contribution of home production and market purchases in providing nutritional diversity to agricultural households in Malawi and examine how food system provisioning varies by time, space and socio-economic conditions. DESIGN: A secondary analysis of nationally representative household consumption data to test the applicability of the Nutritional Functional Diversity score. SETTING: The data were collected between 2010 and 2011 across the country of Malawi. SUBJECTS: Households (n 11 814) from predominantly rural areas of Malawi. RESULTS: Nutritional Functional Diversity varied demographically, geographically and temporally. Nationally, purchased foods contributed more to household nutritional diversity than home produced foods (mean score=17.5 and 7.8, respectively). Households further from roads and population centres had lower overall diversity (P<0.01) and accessed relatively more of their diversity from home production than households closer to market centres (P<0.01). Nutritional diversity was lowest during the growing season when farmers plant and tend crops (P<0.01). CONCLUSIONS: The present analysis demonstrates that the Nutritional Functional Diversity score is an effective indicator for identifying populations with low nutritional diversity and the relative roles that markets, agricultural extension and home production play in achieving nutritional diversity. This information may be used by policy makers to plan agricultural and market-based interventions that support sustainable diets and local food systems. PMID- 26027596 TI - Prevalence of dysmenorrhea and its correlating lifestyle factors in Japanese female junior high school students. AB - Dysmenorrhea is a common menstrual disorder experienced by adolescents, and its major symptoms, including pain, adversely affect daily life and school performance. However, little epidemiologic evidence on dysmenorrhea in Japanese adolescents exists. This cross-sectional study aimed to determine the prevalence of and identify factors associated with dysmenorrhea in Japanese female junior high school students. Among 1,167 girls aged between 12 and 15 years, 1,018 participants completed a questionnaire that solicited information on age at menarche, menstruation, and lifestyle, as well as demographic characteristics. Dysmenorrhea was defined based on menstrual pain using a Visual Analog Scale (VAS), with moderate or severe (moderate-severe) dysmenorrhea, which adversely affects daily life, defined as VAS >= 4, and severe dysmenorrhea defined as VAS >= 7. The prevalence of moderate-severe dysmenorrhea was 476/1,018 (46.8%), and that of severe dysmenorrhea was 180/1,018 (17.7%). Higher chronological and gynecological ages (years after menarche) were significantly associated with a higher prevalence of dysmenorrhea regardless of severity (P for trend < 0.001). In addition, short sleeping hours (< 6/day) were associated with moderate-severe dysmenorrhea (OR = 3.05, 95%CI: 1.06-8.77), and sports activity levels were associated with severe dysmenorrhea (P for trend = 0.045). Our findings suggest that dysmenorrhea that adversely affects daily activities is highly prevalent, and may be associated with certain lifestyle factors in junior high school students. Health education teachers should be made aware of these facts, and appropriately care for those suffering from dysmenorrhea symptoms, absentees, and those experiencing difficulties in school life due to dysmenorrhea symptoms. PMID- 26027597 TI - Interactions between psychological stress and drinking status in relation to diet among middle-aged men and women: a large-scale cross-sectional study in Japan. AB - The aim of this study was to investigate the interaction between psychological stress (PS) and drinking status in relation to diet among middle-aged Japanese men and women in a large-scale cross-sectional study. The study population included 5,587 middle-aged Japanese men and 2,718 middle-aged Japanese women who underwent annual health checkups. The subjects were divided into 2 groups (non drinkers and drinkers) and classified as having low, moderate, or high self reported PS levels. Energy-adjusted food and nutrient consumption was assessed with a validated food frequency questionnaire. Using a general linear model, food and nutrient consumption was estimated for each self-reported PS level in the 2 groups (non-drinkers and drinkers) and the interactions between self-reported PS levels and drinking status were calculated. In men, pork and beef; squid, octopus, shrimp, and clams; eggs; mushrooms; Japanese-style sweets; ice cream; bread; Chinese noodles; coffee; and soda as foods and protein, animal protein, fat, animal fat, carbohydrate, monounsaturated fatty acid, polyunsaturated fatty acid (PUFA), n-3 PUFA, n-6 PUFA, cholesterol, vitamin D, vitamin B2, vitamin B6, vitamin B12, niacin, pantothenic acid, magnesium, phosphorus, and zinc as nutrients significantly interacted with self-reported PS levels and drinking status (p for interaction <0.05 for all). No specific interactions were found in women. These findings suggest interactions between PS levels and drinking status with consumption of some foods and nutrients, especially macronutrient intake, in men but not in women. PMID- 26027598 TI - Health-related quality-of-life as co-primary endpoint in randomized clinical trials in oncology. AB - Overall survival (OS) has been considered as the most relevant primary endpoint but trials using OS often require large numbers of patients and long-term follow up. Therefore composite endpoints, which are assessed earlier, are frequently used as primary endpoint but suffer from important limitations specially a lack of validation as surrogate of OS. Therefore, Health-related quality of life (HRQoL) could be considered as an outcome to judge efficacy of a treatment. An alternative approach would be to combine HRQoL with composite endpoints as co primary endpoint to ensure a clinical benefit for patients of a new therapy. The decision rules of such design, the procedure to control the Type I error and the determination of sample size remain questions to debate. Here, we discusses HRQoL as co-primary endpoints in randomized clinical trials in oncology and provide some solutions to promote such design. PMID- 26027599 TI - [Diagnosis and therapy for neurocognitive disorders in Parkinson's disease]. AB - In the present review the recent developments in the definitions of neurocognitive disorders associated with Parkinson's disease are summarized including the possibilities for screening and treating. For a long time, the recognition of neurocognitive disorders associated in patients with Parkinson's disease was unsatisfactory due to the heterogeneity of definitions. The recently developed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM 5) introduced the definitions of mild and major neurocognitive disorders instead of mild cognitive impairment and dementia. The new DSM-5 definitions are clinically well applicable; therefore, the validation of the most frequent screening tests (Mini-Mental State Examination; Addenbrooke's Cognitive Examination; Montreal Cognitive Assessment; Mattis Dementia Rating Scale) is warranted. Based on a Hungarian sample of 295 patients with Parkinson's disease, the cut-off scores having the best discriminative values are highly dependent on education years (Addenbrooke's Cognitive Examination: 0-8 years of education: 82.5 points, 9-12 years of education: 83.5 points, and >=13 years of education: 84.5 points; Mini-Mental State Examination: 26.5-27.5-28.5 points, Montreal Cognitive Assessment: 23.5-24.5-24.5 points, Mattis Dementia Rating Scale: 138.5 139.5-139.5 points, respectively). PMID- 26027600 TI - [Dietary and pharmacological aspects of eosinophilic esophagitis]. AB - Eosinophilic esophagitis is considered to be a chronic antigen-driven disease whereby food and/or aeroallergens induce a chronic inflammatory infiltrate in the esophagus leading to pathological hyperplasia of the epithelial and muscular layers, fibrosis of the lamina propria and symptoms of dysphagia and food impaction. Eosinophilic esophagitis is often associated with other allergic diseases such as asthma or atopic dermatitis. Current first line treatments of the disease include strict dietary modification and topical anti-inflammatory steroids. In this review the authors summarize currently available treatment strategies of eosinophilic esophagitis. PMID- 26027601 TI - [Comparison of symptoms, laboratory parameters and illness perception in patients with irritable bowel syndrome and inflammatory bowel disease]. AB - INTRODUCTION: Symptoms-based differential diagnosis of irritable bowel syndrome and inflammatory bowel disease is often difficult. AIMS: To determine the differential diagnostic ability of clinical activity indexes and psychological questionnaires in these conditions, which have never been simultaneously analyzed. METHOD: 37 irritable bowel syndrome, 54 Crohn's disease and 41 ulcerative colitis patients were enrolled in the study. The patients completed the Crohn's Disease Activity Index test, Illness Perception Questionnaire and Inflammatory Bowel Disease Questionnaire. Hematocrit and C-reactive protein level of patients were also analyzed. RESULTS: Patients with irritable bowel syndrome felt their abdominal pain more severe than the other two groups (p = 0.005), while the quality of life was the worst in Crohn's disease (p = 0.0000001). Significantly more patients with inflammatory bowel disease considered that their condition is lifelong (p = 0.000781). The knowledge about disease was more appropriate in patients with inflammatory bowel disease (p = 0.00629). No significant difference was found in hematocrit levels, but the C-reactive protein level was significantly lower in patients with irritable bowel syndrome (p = 0.001). CONCLUSIONS: Illness perception questionnaires and C-reactive protein can help in the differentiation of inflammatory bowel disease from irritable bowel syndrome. PMID- 26027603 TI - [Lajos Markusovszky memorial meeting - 2015]. PMID- 26027602 TI - [Individualized therapy of synchronous ovarian and colon cancers with lymph]. AB - A 71-year-old female patient underwent urgent laparotomy due to severe right lower quadrant abdominal pain and fever. Macroscopically duplex coecal and transverse colon cancer as well as a sigmoid or left ovarian cancer were suspected. Pathological findings revealed synchronous left ovarian and transverse colonic neoplasms. Both primaries metastatized to their regional lymph nodes. Furthermore, the ovarian cancer infiltrating the sigmoid colon gave distant metastasis in the coecum, too. Ovarian cancer histology showed papillary adenocarcinoma, and transverse colon cancer was a tubular adenocarcinoma. The affected lymph nodes were clearly distinguished by immunohistochemistry staining: ovarian metastases were CK7 positive, and colonic metastases were CK20 and CEA positive. The patient was treated with combinated chemotherapy: FOLFOX-4 two weekly and paclitaxel monotherapy every other week. The patient tolerated this combined treatment well. The authors conclude that multiple synchronous neoplasms can be treated with individualized chemotherapeutic protocol with good efficacy and few adverse reactions. PMID- 26027605 TI - Matrix Stiffness and Nanoscale Spatial Organization of Cell-Adhesive Ligands Direct Stem Cell Fate. AB - One of the breakthroughs in biomaterials and regenerative medicine in the latest decade is the finding that matrix stiffness affords a crucial physical cue of stem cell differentiation. This statement was recently challenged by another understanding that protein tethering on material surfaces instead of matrix stiffness was the essential cue to regulate stem cells. Herein, we employed nonfouling poly(ethylene glycol) (PEG) hydrogels as the matrix to prevent nonspecific protein adsorption, and meanwhile covalently bound cell-adhesive arginine-glycine-aspartate (RGD) peptides onto the hydrogel surfaces in the form of well-defined nanoarrays to control specific cell adhesion. This approach enables the decoupling of the effects of matrix stiffness and surface chemistry. Mesenchymal stem cells (MSCs) were cultured on four substrates (two compressive moduli of the PEG hydrogels multiplied by two RGD nanospacings) and incubated in the mixed osteogenic and adipogenic medium. The results illustrate unambiguously that matrix stiffness is a potent regulator of stem cell differentiation. Moreover, we reveal that RGD nanospacing affects spreading area and differentiation of rat MSCs, regardless of the hydrogel stiffness. Therefore, both matrix stiffness and nanoscale spatial organization of cell-adhesive ligands direct stem cell fate. PMID- 26027606 TI - Predicting the incidence of hand, foot and mouth disease in Sichuan province, China using the ARIMA model. AB - Hand, foot and mouth disease (HFMD) is an infectious disease caused by enteroviruses, which usually occurs in children aged <5 years. In China, the HFMD situation is worsening, with increasing number of cases nationwide. Therefore, monitoring and predicting HFMD incidence are urgently needed to make control measures more effective. In this study, we applied an autoregressive integrated moving average (ARIMA) model to forecast HFMD incidence in Sichuan province, China. HFMD infection data from January 2010 to June 2014 were used to fit the ARIMA model. The coefficient of determination (R 2), normalized Bayesian Information Criterion (BIC) and mean absolute percentage of error (MAPE) were used to evaluate the goodness-of-fit of the constructed models. The fitted ARIMA model was applied to forecast the incidence of HMFD from April to June 2014. The goodness-of-fit test generated the optimum general multiplicative seasonal ARIMA (1,0,1) * (0,1,0)12 model (R 2 = 0.692, MAPE = 15.982, BIC = 5.265), which also showed non-significant autocorrelations in the residuals of the model (P = 0.893). The forecast incidence values of the ARIMA (1,0,1) * (0,1,0)12 model from July to December 2014 were 4103-9987, which were proximate forecasts. The ARIMA model could be applied to forecast HMFD incidence trend and provide support for HMFD prevention and control. Further observations should be carried out continually into the time sequence, and the parameters of the models could be adjusted because HMFD incidence will not be absolutely stationary in the future. PMID- 26027607 TI - Bacopa monniera recombinant mevalonate diphosphate decarboxylase: Biochemical characterization. AB - Mevalonate diphosphate decarboxylase (MDD; EC 4.1.1.33) is an important enzyme in the mevalonic acid pathway catalyzing the Mg(2+)-ATP dependant decarboxylation of mevalonate 5-diphosphate (MVAPP) to isopentenyl diphosphate (IPP). Bacopa monniera recombinant MDD (BmMDD) protein was overexpressed in Escherichia coli BL21 (DE3) strain and purified to apparent homogeneity. Km and Vmax for MVAPP were 144 MUM and 52 U mg(-1) respectively. The values of turnover (kcat) and kcat/Km for mevalonate 5-diphosphate were determined to be 40s(-1) and 2.77*10(5) M(-1) s(-1) and kcat and kcat/Km values for ATP were found to be 30 s(-1) and 2.20*10(4) M(-1) s(-1), respectively. pH activity profile indicated the involvement of carboxylate ion, lysine and arginine for the activity of enzyme. The apparent activation energy for the BmMDD catalyzed reaction was 12.7 kJ mol( 1). Optimum pH and temperature for the forward reaction was found to be 8.0 and 45 degrees C. The enzyme was most stable at pH 7 at 20 degrees C with the deactivation rate constant (Kd(*)) of 1.69*10(-4) and half life (t1/2) of 68 h. The cation studies suggested that BmMDD is a cation dependant enzyme and optimum activity was achieved in the presence of Mg(2+). PMID- 26027608 TI - Zinc inhibits glycation induced structural, functional modifications in albumin and protects erythrocytes from glycated albumin toxicity. AB - The present work aims to investigate the concentration and time dependant effect of zinc on the in vitro non enzymatic modifications of albumin by diabetic levels of glucose. Further, preventive and curative effect of zinc was studied by adding zinc before and after initiation of glycation respectively. Glycation of albumin was done at different concentrations of zinc (125, 250 and 500 MUM) at different time intervals (21, 28 and 35 days) with appropriate controls. The antiglycation potential of zinc was assessed by estimating different markers of albumin glycation (fructosamines, carbonyls, bound sugar, AGEs), structural modifications (free amino, thiol group, beta amyloid, native PAGE, ANS binding, fluorescence lifetime decay and CD analysis) and functional properties (antioxidant activity, hemolysis). Zinc at highest concentration (500 MUM) significantly reduced modifications of albumin which was comparable to aminoguanidine and also protected secondary and tertiary structure of albumin after 28 days of incubation. Zinc exhibited significant protective effect on erythrocytes by inhibiting hemolysis. Thus the present study indicate preventive mode of albumin glycation inhibition by zinc. PMID- 26027609 TI - Effect of shear viscosity on the preparation of sphere-like silk fibroin microparticles by electrospraying. AB - Silk fibroin (SF) is known to be a biocompatible material, and different forms of SF are used for various applications. However, the application of SF in particle form is rarely reported, compared to other forms. In this study, SF microparticles with a diameter of approximately 250 MUm were prepared by the electrospray method, using 1 M LiCl/DMSO as a solvent. The dissolution time of SF in the CaCl2/CH3CH2OH/H2O solution and the concentration of the SF dope solution affected the final morphology of the microparticles. A long dissolution time and a low SF concentration led to the formation of irregular microparticles, but a short dissolution time and a high concentration produced sphere-like microparticles. The shear viscosity of the SF dope solution was the main parameter that affected the morphology of the SF microparticles. Regardless of the dissolution time in the CaCl2/CH3CH2OH/H2O solution and the concentration of the SF dope solution, the shear viscosity of the dope solution must be higher than 0.33 Pa s to produce sphere-like microparticles. Finally, cell adhesion experiments demonstrated that these SF microparticles show potential for use as cell carriers. PMID- 26027610 TI - The future of cardiovascular clinical research in North America and beyond addressing challenges and leveraging opportunities through unique academic and grassroots collaborations. AB - Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment. PMID- 26027611 TI - Novel oral anticoagulants and reversal agents: Considerations for clinical development. AB - This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non-life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies. PMID- 26027614 TI - Geographic variation in the use of catheter ablation for atrial fibrillation among Medicare beneficiaries. AB - BACKGROUND: Catheter ablation for atrial fibrillation is used increasingly in older patients, yet the risks and benefits are not completely understood. With such uncertainty, local medical opinion may influence catheter ablation use. METHODS: In a 100% sample of Medicare beneficiaries >=65 years who underwent catheter ablation for atrial fibrillation between January 1, 2007, and December 31, 2009, we investigated variation in use by hospital referral region (HRR) for 20,176 catheter ablation procedures. RESULTS: Across 274 HRRs, median age was 71.2 years (interquartile range 70.5-71.8), a median of 98% of patients were white, and a median of 39% of patients were women. The median age-standardized prevalence of atrial fibrillation was 77.1 (69.4-84.2) per 1,000 beneficiaries; the median rate of catheter ablation was 3.5 (2.4-4.9) per 1,000 beneficiaries. We found no significant associations between the rate of catheter ablation and prevalence of atrial fibrillation (P = .99), end-of-life Medicare expenditures per capita (P = .09), or concentration of cardiologists (P = .45) but a slight association with Medicare expenditures per capita (linear regression estimate 0.016; 95% CI 0.001-0.031; P = .04). Examined HRR characteristics explained only 2% of the variation in HRR-level rates of catheter ablation (model R(2) = 0.016). CONCLUSION: The rate of catheter ablation for atrial fibrillation in older patients was low, varied substantially by region, and was not associated with the prevalence of atrial fibrillation, the availability of cardiologists, or end-of life resource use and was only slightly associated with overall Medicare expenditures per capita. PMID- 26027612 TI - Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST elevation myocardial infarction patients (the CIRCUS trial). AB - BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow <=1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. RESULTS: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. CONCLUSIONS: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up. PMID- 26027613 TI - Rationale and design of a cluster-randomized multifaceted intervention trial to improve stroke care quality in China: The GOLDEN BRIDGE-Acute Ischemic Stroke. AB - BACKGROUND: Prior studies have demonstrated a significant gap between guideline based recommendations and clinical practice in the management of acute ischemic stroke (AIS) in China. AIMS: This study implements a targeted multifaceted quality improvement intervention in AIS patients and identifies the feasibility and efficacy of this intervention. DESIGN: This is a multicenter, 2-arm, open label, cluster-randomized trial involving 40 clusters (hospitals) from China National Network of Stroke Research. Hospitals are randomized to receive a targeted multifaceted quality improvement intervention (experimental group) or routine standard of care (control group). The multifaceted intervention includes an evidence-based clinical pathway, written care protocols, a quality coordinator, and a monitoring and feedback system of performance measures. The number of enrolled patients in the trial will be 4,800. Primary outcome is the measure of the adherence to AIS evidence-based performance measures including the composite measure (defined as the total number of interventions performed among eligible patients divided by the total number of possible interventions among eligible patients) and the all-or-none measure (defined as the proportion of eligible patients who receive all of the performance measure interventions for which they are eligible). Secondary patient outcomes include inhospital death; a new vascular event; disability; and all-cause death at 3, 6, and 12 months after initial symptom onset. All analyses will be performed according to the intention to-treatment principle and accounted for clustering using generalized estimating equations. CONCLUSIONS: If proven effective, this targeted multifaceted intervention model will be extended nationwide as a model to bridge the evidence based gap in the AIS management in China. PMID- 26027615 TI - Predictors of silent brain infarction on magnetic resonance imaging in patients with nonvalvular atrial fibrillation: A transesophageal echocardiographic study. AB - BACKGROUND: Silent brain infarction (SBI) is often found in patients with atrial fibrillation (AF) and may be related to cognitive decline. We investigated the predictors of SBI on brain magnetic resonance imaging (MRI) using transesophageal echocardiography (TEE) in patients with nonvalvular AF. METHODS: The study population consisted of 103 neurologically asymptomatic patients with nonvalvular AF who underwent TEE before transcatheter AF ablation (76 men; mean age 63 +/- 10 years). Left atrial (LA) abnormalities such as LA thrombus, spontaneous echo contrast, or abnormal LA appendage emptying velocity (<20 cm/s) and complex plaques in the aortic arch defined as large plaques >=4 mm thickness, ulcerated plaques, or mobile plaques were evaluated by TEE. All patients were screened for SBI by brain MRI. RESULTS: Of 103 patients, 31 (30%) showed SBI on brain MRI. Most lesions were multiple (61%) and small (<15 mm) in diameter (84%). Patients with SBI had a higher prevalence of LA abnormalities (45% vs 14%; P < .001) and complex arch plaques (45% vs 7%; P < .001) compared with those without SBI. In a multivariate logistic regression analysis including age and CHADS2 score >=2, LA abnormalities (odds ratio 4.13; 95% CI 1.34-12.72; P = .014) and complex arch plaques (odds ratio 4.82; 95% CI 1.23-18.92; P = .024) were independent predictors of SBI. CONCLUSIONS: Left atrial abnormalities and complex arch plaques detected by TEE were closely associated with the presence of SBI on brain MRI, suggesting that microembolization of small thrombi derived from the fibrillating LA or advanced aortic atherosclerotic lesions may be important causes of SBI in patients with nonvalvular AF. PMID- 26027616 TI - Recidivism to uncontrolled blood pressure in patients with previously controlled hypertension. AB - BACKGROUND: Control of hypertension has improved nationally with focus on identifying and treating elevated blood pressures (BPs) to guideline recommended levels. However, once BP control is achieved, the frequency in which BP falls out of control and the factors associated with BP recidivism is unknown. In this retrospective cohort study conducted at 2 large, integrated health care systems we sought to examine rates and predictors of BP recidivism in adults with controlled hypertension. No change for methods, results and conclusion. METHODS: Patients with a prior diagnosis of hypertension based on a combination of International Classification of Diseases, Ninth Revision, codes, receipt of antihypertensive medications, and/or elevated BP readings were eligible to be included. We defined controlled hypertension as normotensive BP readings (<140/90 mmHg or <130/80 mmHg in those with diabetes) at 2 consecutive primary care visits. We then followed up patients for BP recidivism defined by the date of the second of 2 consecutive BP readings >140/90 mmHg (>130/80 mmHg for diabetes or chronic kidney disease) during a median follow-up period of 16.6 months. Cox proportional hazards regression assessed the association between patient characteristics, comorbidities, medication adherence, and provider medication management with time to BP recidivism. RESULTS: A total of 23,321 patients with controlled hypertension were included in this study. The proportion of patients with hypertension recidivism was 24.1% over the 16.6-month study period. For those with BP recidivism, the median time to relapse was 7.3 months. In multivariate analysis, those with diabetes (hazard ratio [HR] 3.99, CI 3.67 4.33), high normal baseline BP (for systolic BP HR 1.03, CI 1.03-1.04), or low antihypertensive medication adherence (HR 1.20, CI 1.11-1.29) had significantly higher rates of hypertension recidivism. Limitations of this work include demographics of our patient sample, which may not reflect other communities in addition to the intrinsic limitations of office-based BP measurements. CONCLUSIONS: Hypertensive recidivism occurs in a significant portion of patients with previously well-controlled BP and accounts for a substantial fraction of patients with poorly controlled hypertension. Systematic identification of those most at risk for recidivism and implementation of strategies to minimize hypertension recidivism may improve overall levels of BP control and hypertension related quality measures. PMID- 26027617 TI - Centenarians and their hearts: A prospective registry with comprehensive geriatric assessment, electrocardiogram, echocardiography, and follow-up. AB - BACKGROUND: Data on the cardiac characteristics of centenarians are scarce. Our aim was to describe electrocardiogram (ECG) and echocardiography in a cohort of centenarians and to correlate them with clinical data. METHODS: We used prospective multicenter registry of 118 centenarians (28 men) with a mean age of 101.5+/-1.7 years. Electrocardiogram was performed in 103 subjects (87.3%) and echocardiography in 100 (84.7%). All subjects underwent a follow-up for at least 6 months. RESULTS: Centenarians with abnormal ECG were less frequently females (72% vs 93%), had higher rates of previous consumption of tobacco (14% vs 0) and alcohol (24% vs 12%), and scored lower in the perception of health status (6.8+/ 2.0 vs 8.3+/-6.8). Centenarians with significant abnormalities in echocardiography were less frequently able to walk 6 m (33% vs 54%). Atrial fibrillation/flutter was found in 27 subjects (26%). Mean left ventricular (LV) ejection fraction was 60.0+/-10.5%. Moderate or severe aortic valve stenosis was found in 16%, mitral valve regurgitation in 15%, and aortic valve regurgitation in 13%. Diastolic dysfunction was assessed in 79 subjects and was present in 55 (69.6%). Katz index and LV dilation were independently associated with the ability to walk 6 m. Age, Charlson and Katz indexes, and the presence of significant abnormalities in echocardiography were associated with mortality. CONCLUSIONS: Centenarians have frequent ECG alterations and abnormalities in echocardiography. More than one fifth has atrial fibrillation, and most have diastolic dysfunction. Left ventricular dilation was associated with the ability to walk 6 m. Significant abnormalities in echocardiography were associated with mortality. PMID- 26027618 TI - A disproportionate elevation in right ventricular filling pressure, in relation to left ventricular filling pressure, is associated with renal impairment and increased mortality in advanced decompensated heart failure. AB - BACKGROUND: Discordance between left- and right-sided filling pressures occurs in a subset of patients presenting with acute decompensated heart failure (ADHF). We hypothesized that a disproportionately increased right atrial pressure (RAP) relative to the pulmonary capillary wedge pressure (PCWP) would be associated with both renal dysfunction and mortality in ADHF. METHODS: A total of 367 patients admitted with ADHF with elevated intracardiac filling pressures were treated with intensive medical therapy guided by invasive hemodynamic monitoring. Baseline characteristics, hemodynamics, and renal function at admission were stratified by RAP/PCWP quartiles. The association of RAP/PCWP quartile with all cause mortality after a median follow-up of 2.4 years was assessed in univariable and multivariable models, which included adjustment for the RAP. RESULTS: The median RAP/PCWP was 0.58 (interquartile range 0.43-0.75). Increasing RAP/PCWP was inversely associated with estimated glomerular filtration rate at baseline and with treatment (P < .0001) independently of RAP. High RAP/PCWP was associated with increased mortality (quartile 4 vs 1: hazard ratio [95% CI] 2.1 [1.3-3.5], P = .002). The association of RAP/PCWP with mortality persisted after adjustment for age, gender, mean arterial pressure, RAP, cardiac index, pulmonary vascular resistance, and estimated glomerular filtration rate (hazard ratio 2.4 [1.4-3.9], P = .007). CONCLUSION: A disproportionate increase in right to left ventricular filling pressures is associated with renal dysfunction and mortality, independently of the right atrial pressure. PMID- 26027619 TI - PDE 5 inhibition with udenafil improves left ventricular systolic/diastolic functions and exercise capacity in patients with chronic heart failure with reduced ejection fraction; A 12-week, randomized, double-blind, placebo controlled trial. AB - BACKGROUND: Impaired nitric oxide-mediated pulmonary vascular tone is commonly found in heart failure with reduced ejection fraction (HFrEF), and is associated with derangement of left ventricular (LV) hemodynamics and decreased exercise capacity, which may be reversed by PDE5 inhibitor. This study investigated the effects of a new, long-acting PDE5 inhibitor on LV hemodynamics and exercise capacity in HFrEF. METHODS: Patients with chronic HFrEF on optimal medical therapy for >30 days before enrollment were randomly assigned to placebo or udenafil at a dose of 50mg 2x/day for the first 4 weeks followed by 100mg 2x/day for the next 8 weeks. All patients underwent cardiopulmonary exercise echocardiography before and after the 12-week treatment. RESULTS: Improvement of subjective functional capacity was more frequently reported in the udenafil group (P = 0.002). Also, a higher increase in peak VO2 (Deltapeak VO2, 21.6% (6.9 ~ 106.4%) vs 1.9% (-15.7 ~ 21.0%) in the placebo group, P = 0.04) and a larger decrease in ventilatory efficiency were observed in the udenafil group (Delta-6.4 +/- 9.7 vs Delta1.9 +/- 12.1 in the placebo group, P = 0.03). Regarding LV systolic function, the extent of increment in LV ejection fraction was significantly greater in the udenafil group (6.6 +/- 6.4% vs 2.3 +/- 4.8% in the placebo group, P = 0.02). In the udenafil group, an echocardiographic surrogate of LV filling pressure was more prominently decreased (P = 0.006) along with a significant reverse remodeling of left atrial volume index (57 +/- 25mL at baseline to 44 +/- 23 at 12th week, P = 0.04) and a progressive fall in B-type natriuretic peptide level (589 +/- 679pg/mL at baseline to 220 +/- 225pg/mL at 12th week, P < 0.001), indicating LV diastolic function improvement. Udenafil was well tolerated without excess of adverse events compared to placebo. CONCLUSIONS: Udenafil improves LV systolic/diastolic functions and exercise capacity in conjunction with established conventional pharmacotherapy, without significant adverse events in HFrEF. PMID- 26027620 TI - Effect of center catheterization volume on risk of catastrophic adverse event after cardiac catheterization in children. AB - BACKGROUND: Procedural volume has been shown to be associated with outcome in cardiac catheterization and intervention in adults. The impact of center-level factors (such as volume) and their interaction with subject- and procedure-level factors on outcome after cardiac catheterization in children is not well described. We hypothesized that higher center catheterization volume would be associated with lower risk of catastrophic adverse events. METHODS: We studied children and young adults 0 to 21 years of age undergoing one or more cardiac catheterizations at centers participating in the Pediatric Health Information Systems database between 2007 and 2012. Using mixed-effects multivariable regression, we assessed the association between center catheterization volumes and the risk of a composite outcome of death and/or initiation of mechanical circulatory support within 1 day of cardiac catheterization adjusting for patient and procedure-level factors. RESULTS: A total of 63,994 procedures performed on 40,612 individuals from 38 of 43 centers contributing data to the Pediatric Health Information Systems database were included. The adjusted risk of the composite outcome was 0.1%. Increasing annual catheterization laboratory volume was independently associated with reduced risk of the composite outcome (odds ratio per a 100-procedure/y increment 0.78 [95% CI 0.65-0.93], P < .006). Younger age at catheterization, previous cardiac operation in the same admission as the catheterization, preprocedural vasoactive medications, and hemodialysis were also independently associated with an increased risk of adverse outcomes. CONCLUSIONS: Higher cardiac catheterization laboratory volume was associated with reduced risk of catastrophic adverse outcome in the immediate postcatheterization period in children. The observed benefit of catheterization at a larger volume center may be attributable to transmissible best practices or inextricable benefits of larger systems. PMID- 26027621 TI - Symptomatic graft failure and impact on clinical outcome after coronary artery bypass grafting surgery: Results from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry. AB - BACKGROUND: In contemporary coronary artery bypass graft (CABG) surgery, the association between symptomatic graft failure (GF) and long-term clinical outcome remains unclear. We sought to identify the clinical characteristics and outcomes of GF in symptomatic patients requiring cardiac catheterization within 1 year of CABG surgery. METHODS: Using the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease registry, 5,276 patients undergoing CABG surgery from September 2002 to August 2011 were identified. Clinical outcomes in patients with symptomatic GF were observed. Predictors of GF were analyzed at a graft level, whereas long-term survival was assessed at a patient level. A propensity score matching technique was used to adjust for baseline characteristics. RESULTS: Of our CABG cohort, 5.3% (281 patients [285 arterial and 653 vein grafts]) required symptom based coronary angiography within 1 year of CABG surgery. Acute coronary syndrome was the most common presentation (64.4%). At angiography, 27.0% (77/285) of arterial and 34.5% (225/653) of vein grafts were occluded. Respectively, arterial and vein GFs were treated as follows: percutaneous coronary intervention 61.0% versus 41.8%, re-do CABG 9.1% versus 0%, and medically without intervention 29.9% versus 58.2%. A strong trend toward reduced patient survival was noted with "arterial graft failure" (arterial +/- vein GF) compared to "vein graft failure only" (no arterial GF) (adjusted hazard ratio 2.2, 95% CI 0.98-5.0, P = .056). CONCLUSION: Although the rate of cardiac catheterization within 1 year of CABG is infrequent, these patients exhibit high GF rates and commonly present with an acute coronary syndrome. In addition, "arterial graft failure" compared to "vein graft failure only" confers a higher risk of adverse long-term survival. PMID- 26027622 TI - Incremental value of normal adenosine perfusion cardiac magnetic resonance: Long term outcome. AB - BACKGROUND: The purpose of the study was to determine the long-term prognostic value of normal adenosine stress cardiac magnetic resonance imaging (CMR) in patients referred for evaluation of myocardial ischemia. METHODS: We reviewed 300 consecutive patients (age 65 +/- 11 years, 74% male) with suspected or known coronary disease and normal wall motion who had undergone adenosine stress CMR negative for ischemia and scar. Most patients were at intermediate risk of coronary artery disease. The end points studied were all causes of mortality and major adverse cardiac events, including cardiac death, myocardial infarction, revascularization, and hospitalization for unstable angina. RESULTS: During a mean follow-up of 5.5 years (mean = 5.4 +/- 1.1), 16 patients died because of various causes (cardiac death in 5 patients). Three patients had a nonfatal myocardial infarction, 7 patients were hospitalized for revascularization, and 11 were medically treated for unstable angina. The annual cardiac event rate was 1.3% (0.78% in the first 3 years and 1.9% between the fourth and sixth years). The predictors of major adverse cardiac events in a multivariate analysis model were as follows: advanced age (hazard ratio [HR] 1.15, 95% confidence interval [95% CI] 1.02-1.30), diabetes (HR 17.5, 95% CI 2.2-140), and the habit of smoking (HR 5.9, 95% CI 1.0-35.5). For all causes of mortality, the only predictor was diabetes (HR 11.4, 95% CI 1.76-74.2). Patients with normal stress CMR had an excellent outcome during the 3 years after the study. The cardiac event rate was higher between the fourth and sixth years. CONCLUSION: Over a 5.5-year period, a low event rate and excellent prognosis occurred in patients with normal adenosine stress CMR. Low- to intermediate-risk patients with a normal CMR are at low risk for subsequent cardiac events. PMID- 26027623 TI - Variation in performance measure criteria significantly affects cardiology practice rankings: Insights from the National Cardiovascular Data Registry's Practice Innovation and Clinical Excellence Registry. AB - BACKGROUND: Million Hearts is a national initiative to prevent 1 million heart attacks and strokes over 5 years by improving cardiovascular prevention. An important tool in the success of programs like Million Hearts is public ranking on the quality of practices, yet different measures may provide different rankings, so the true quality of practices is difficult to discern. We evaluated the quality of ambulatory cardiology care using performance measure metrics. METHODS: We compared rankings of practices participating in the National Cardiovascular Data Registry's Practice Innovation and Clinical Excellence Registry using measures from (1) the physician quality reporting system and (2) the American College of Cardiology/American Heart Association/Physician Consortium for Performance Improvement. We compared achievement rates for measures between the 2 frameworks and determined correlations in rankings using Spearman correlation coefficients. RESULTS: From January 1, 2008 to December 31, 2012, there were 1,711,326 patients enrolled from 111 US practices. Among eligible patients, the physician quality reporting system and American College of Cardiology/American Heart Association/Physician Consortium for Performance Improvement measures were achieved in 76.1% versus 77.4% for antiplatelet prescription (P < .001), 68.3% versus 90.8% for blood pressure control (P < .001), 26.9% versus 43.4% for cholesterol control (P < .001), and 37.4% versus 40.6% for smoking cessation (P = .383). Practice rankings were strongly correlated for antiplatelet prescription (correlation coefficient 0.98) and cholesterol control (0.92) but poorly correlated for blood pressure control (0.39) and smoking cessation (0.22). CONCLUSIONS: Evaluation of preventive care and individual practice rankings vary significantly depending on how measures are defined. Publicly reported measures need to be validly associated with outcomes to avoid incorrectly evaluating practice performance and failing to achieve public health goals. PMID- 26027624 TI - Tai Chi Chuan improves functional capacity after myocardial infarction: A randomized clinical trial. AB - BACKGROUND: Patients with a recent myocardial infarction (MI) present a reduction in functional capacity expressed as a decrease in peak oxygen consumption (Vo2 peak). The impact of a Tai Chi Chuan (TCC) cardiac rehabilitation program for patients recovering from recent MI has yet to be assessed. Our goal is to evaluate functional capacity after a TCC-based cardiac rehabilitation program in patients with recent MI. METHODS: A single-blind randomized clinical trial was conducted. The researchers who performed the tests were blinded to group allocation. Between the 14th and 21st days after hospital discharge, all patients performed a cardiopulmonary exercise testing and a laboratory blood workup. Mean age was similar (56+/-9 years in the TCC group and 60+/-9 years in the control group). Patients allocated to the intervention group performed 3 weekly sessions of TCC Beijin style for 12 weeks (n=31). The control group participated in 3 weekly sessions of full-body stretching exercises (n=30). RESULTS: After the 12 week study period, participants in the TCC group experienced a significant 14% increase in Vo2 peak from baseline (21.6 +/- 5.2 to 24.6 +/- 5.2 mL/kg per minute), whereas control participants had a nonsignificant 5% decline in Vo2 peak (20.4 +/- 5.1 to 19.4 +/- 4.4 mL/kg per minute). There was a significant difference between the 2 groups (P<.0001). CONCLUSIONS: Tai Chi Chuan practice was associated with an increase in Vo2 peak in patients with a recent MI and may constitute an effective form of cardiac rehabilitation in this patient population. PMID- 26027625 TI - Relationship between the seismic scale of the 2011 northeast Japan earthquake and the incidence of acute myocardial infarction: A population-based study. AB - BACKGROUND: Previous studies have reported a relationship between large earthquakes and acute coronary events, but have yielded conflicting results. On March 11, 2011, a massive magnitude 9.0 earthquake hit the northeastern coast of Japan and generated repeated aftershocks. The aim of this study is to clarify the influence of this earthquake on the risk of acute myocardial infarction (AMI) including sudden cardiac death based on the data from a population-based analysis. METHODS: The study subjects were residents in the northeast of Iwate prefecture, Japan. Cases corresponding to the definition of AMI according to the criteria of the World Health Organization MONICA project were registered from 4 weeks before to 8 weeks after the disaster and in the corresponding periods in 2009 and 2010. RESULTS: The relative risk of AMI was 2.03 (95% CI 1.55-2.66) for the 4-week period after the disaster compared with the corresponding periods in the preceding years. The number of events peaked within the first week after the earthquake decreased to levels seen in the preceding years and then increased again after high-magnitude aftershocks. The incidence of AMI was positively correlated with the seismic scale of the earthquake (r = 0.75, P < .01). CONCLUSIONS: This population-based study suggests that the increase in AMI events after a major earthquake varies depending on the seismic scale of the initial shock and each aftershock. PMID- 26027626 TI - Effectiveness of implantable cardioverter-defibrillators in survivors of inhospital cardiac arrest. AB - BACKGROUND: Although implantable cardioverter-defibrillators (ICDs) reduce mortality in patients with out-of-hospital cardiac arrest, their effectiveness in survivors of "inhospital" cardiac arrest-a population with different arrest etiologies and higher illness acuity than out-of-hospital cardiac arrest-is unknown. We therefore sought to conduct a comparative effectiveness study of ICD therapy in survivors of inhospital cardiac arrest. METHODS: We linked data from a national inpatient cardiac arrest registry with Medicare files and identified 1,200 adults from 267 hospitals between 2000 and 2008 who were discharged after surviving an inhospital cardiac arrest due to ventricular fibrillation or pulseless ventricular tachycardia and who otherwise met traditional inclusion and exclusion criteria for secondary prevention ICD trials. The association between ICD treatment and long-term mortality was evaluated using an optimal match (<=4 controls for each ICD patient) propensity-score analysis. RESULTS: Of 1,200 survivors, 343 (28.6%) received an ICD during the index hospitalization. Overall, 3-year mortality was 44.2%, with higher unadjusted mortality in the non-ICD versus the ICD group (46.9% vs 37.3%; log-rank; P < .001). After successfully matching 343 patients treated with ICDs with 823 untreated patients by propensity score, ICD treatment was associated with a 24% lower mortality rate (adjusted hazard ratio [HR] 0.76; 95% CI 0.60-0.97; P = .025). This lower mortality was mediated by lower rates of out-of-hospital deaths among ICD-treated patients (22.1% vs 30.8%; adjusted HR 0.71 [0.52-0.96]; P = .019), whereas deaths occurring during a readmission were similar (15.2% vs 16.1%; adjusted HR 0.89 [95% CI 0.60-1.32]; P = .56). CONCLUSIONS: Implantable cardioverter-defibrillator therapy in survivors of inhospital cardiac arrest due to a pulseless ventricular rhythm is used uncommonly but associated with lower long-term mortality. Given that fewer than 3 in 10 eligible survivors are treated with ICDs after surviving an inhospital cardiac arrest, our findings highlight a potentially modifiable process of care, which could improve long-term survival in this high-risk population. PMID- 26027627 TI - Biomarkers for risk stratification of patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: Insights from the Platelet Inhibition and Patient Outcomes trial. AB - BACKGROUND: The incremental prognostic value of admission measurements of biomarkers beyond clinical characteristics and extent of coronary artery disease (CAD) in patients treated with primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is unclear. METHODS: Centrally analyzed plasma for biomarker measurements was available in 5,385 of the STEMI patients treated with PPCI in the PLATO trial. Extent of CAD was graded by operators in association with PPCI. We evaluated the prognostic value of high sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide (NT proBNP), and growth differentiation factor 15 (GDF-15) beyond clinical characteristics and extent of CAD using Cox proportional hazards analyses, C index, and net reclassification improvement (NRI). Outcomes were cardiovascular death (CVD) and spontaneous myocardial infarction (MI). RESULTS: Angiographic data on extent of CAD improved the prediction of CVD compared to clinical risk factors alone, increasing the C-index from 0.760 to 0.778, total NRI of 0.31. Biomarker information provided additional prognostic value for CVD beyond clinical risk factors and extent of CAD, C-indices ranging from 0.792 to 0.795 for all biomarkers, but with a higher NRI for NT-proBNP. Extent of CAD and high sensitivity cardiac troponin T were not associated with spontaneous MI. The prediction of spontaneous MI beyond clinical characteristics and extent of CAD (C index 0.647) was improved by both NT-proBNP (C-index 0.663, NRI 0.22) and GDF-15 (C-index 0.652, NRI 0.05). CONCLUSIONS: Biomarker measurement on admission is feasible and provides incremental risk stratification in patients with STEMI treated with PPCI, with NT-proBNP and GDF-15 being most valuable due to the association with both CVD and spontaneous MI. PMID- 26027628 TI - Reduced dose tenecteplase and outcomes in elderly ST-segment elevation myocardial infarction patients: Insights from the STrategic Reperfusion Early After Myocardial infarction trial. AB - BACKGROUND: Elderly patients with ST-segment elevation myocardial infarction (STEMI) have worse outcomes and a greater risk of intracranial bleeding than nonelderly patients. Baseline characteristics, clinical outcomes, and the relationship of the tenecteplase (TNK) dose reduction to the efficacy, safety, and electrocardiographic indicators of reperfusion efficacy were evaluated in STEMI patients >=75 years. METHODS: The STREAM trial evaluated early presenting STEMI patients who could not undergo primary percutaneous coronary intervention within 1 hour of first medical contact. Because of excess intracranial hemorrhage (ICH) in patients >=75 years, the dose of TNK was reduced by 50%. RESULTS: Before dose amendment, there were 3 (7.1%) of 42 elderly patients with ICH; 2 of these were fatal, whereas no ICH occurred in the 93 elderly patients who received half dose TNK postamendment. The median extent of ST-segment elevation resolution (>=50%) and proportion of patients with >=2 mm in the electrocardiogram lead with greatest ST-segment elevation was comparable in elderly patients preamendment and postamendment (63.2% vs 56.0% and 43.6% vs 40.0%, respectively). Patients requiring rescue coronary intervention after TNK was also similar (42.9% vs 44.1%). The primary composite end point (30-day all-cause death, cardiogenic shock, congestive heart failure, and reinfarction) was 31.0% before versus 24.7% postamendment. CONCLUSIONS: Our data, from a modest-sized population of elderly STEMI patients, indicate that half-dose TNK reduces the likelihood of ICH without compromising reperfusion efficacy. These observations are hypothesis generating and warrant further confirmation in randomized clinical trials in the elderly. PMID- 26027629 TI - Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. AB - BACKGROUND: In the PLATO trial, ticagrelor was superior to clopidogrel in reducing cardiovascular events among patients with acute coronary syndrome (ACS) at the expense of increased nonfatal bleeding. Because Asian patients, when compared with non-Asian patients, are believed to be more susceptible to bleeding, we evaluated the effects of ticagrelor compared with clopidogrel in Asian (n=1,106) and non-Asian (n=17,515) patients with acute coronary syndrome enrolled in the PLATO study. METHODS AND RESULTS: Interaction between Asian/non Asian and primary efficacy end point (a composite of vascular death, myocardial infarction, and stroke) and net clinical benefit (composite of primary efficacy end point and coronary artery bypass graft [CABG] surgery or non-CABG-related major bleeding) were evaluated with a Cox proportional hazards model. Baseline demographics and comorbidities were different between Asians and non-Asians. The overall cardiovascular event rates were higher in Asians, but bleeding rates were similar. Despite these observed differences, the effects of ticagrelor versus clopidogrel were not significantly different between Asians and non-Asians with respect to the primary efficacy outcome (hazard ratio for Asians vs non-Asians, 0.84 [95% CI 0.61-1.17] vs 0.85 [95% CI 0.77-0.93], P=.974), net clinical benefit (0.85 [95% CI 0.65-1.11] vs 0.93 [95% CI 0.86-0.99], P=.521), or individual efficacy end points. There was no significant interaction for bleeding (PLATO major bleeding, 1.02 [95% CI 0.70-1.49] vs 1.04 [95% CI 0.95-1.14], P=.938) and other related adverse events with ticagrelor compared with clopidogrel between Asians and non-Asians. CONCLUSIONS: We observed consistency of effects in Asian patients receiving ticagrelor and clopidogrel in the PLATO study. The relatively modest number of Asian patients in this analysis supports further investigation of larger cohorts to confirm our observations. PMID- 26027630 TI - Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. AB - BACKGROUND: The ODYSSEY COMBO I study (http://clinicaltrials.gov/show/NCT01644175) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia. METHODS: This multicenter, phase 3, randomized (2:1 alirocumab vs placebo), double-blind, 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. Alirocumab (75 mg every 2 weeks [Q2W]) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen. The alirocumab dose was increased to 150 mg Q2W (also 1 mL) at week 12 if week 8 low density lipoprotein cholesterol (LDL-C) was >=70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 (intention-to-treat analysis). RESULTS: At week 24, estimated mean (95% CI) changes in LDL-C from baseline were -48.2% (-52.0% to -44.4%) and -2.3% (-7.6% to 3.1%) for alirocumab and placebo, respectively, an estimated mean (95% CI) difference of -45.9% ( 52.5% to -39.3%) (P < .0001). Low-density lipoprotein cholesterol <70 mg/dL was achieved by 75% alirocumab versus 9% placebo patients at week 24. At week 12, 83.2% of evaluable alirocumab-treated patients remained on 75-mg Q2W. Treatment emergent adverse events were comparable between groups. CONCLUSIONS: Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals, versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy. The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups. PMID- 26027631 TI - The association between cardiorespiratory fitness and cardiovascular risk may be modulated by known cardiovascular risk factors. AB - BACKGROUND: We aimed to evaluate whether reduced cardiovascular fitness has a direct or indirect effect for the development of cardiovascular disease. METHODS: We investigated 15,595 men and women who were annually screened in a tertiary medical center. All subjects were free of ischemic heart disease and had completed maximal exercise stress test according to the Bruce protocol at their first visit. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1 as lowest fitness. Subjects were categorized at baseline into 3 groups: low fitness (Q1), moderate fitness (Q2-Q4), and high fitness (Q5). The primary end point of the current analysis was the development of a first cardiovascular event during follow-up. RESULTS: Mean age of study patients was 48 +/- 10 years, and 73% were men. A total of 679 events occurred during 92,092 person-years of follow-up. Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was significantly higher among subjects with low fitness (P < .001). Low fitness was associated with known cardiovascular risk factors, including hypercholesterolemia (odds ratio [OR] 1.58, 95% CI 1.31-1.89), diabetes mellitus (OR 2.32, 95% CI 1.58-3.41), and obesity (OR 10.46, 95% CI 8.43-12.98). The effect of low fitness on cardiovascular events was no longer significant when including diabetes mellitus, hypercholesterolemia, and obesity as mediators (hazard ratio 0.99, 95% CI 0.82-1.19). CONCLUSIONS: The association between cardiovascular fitness and adverse cardiovascular outcomes may be modulated through traditional cardiovascular risk factors. These findings need to be further validated in prospective clinical trials. PMID- 26027632 TI - Supervised vs unsupervised exercise for intermittent claudication: A systematic review and meta-analysis. AB - BACKGROUND: Supervised exercise (SE) is widely accepted as an effective therapy for intermittent claudication (IC), but its use is limited by cost. Unsupervised exercise (UE) represents a less costly alternative. We assessed the comparative effectiveness of SE vs UE in patients with IC. METHODS AND RESULTS: We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews and identified 27 unique studies (24 randomized controlled trials, 4 observational studies) that evaluated the comparative effectiveness of SE vs UE in 2074 patients with IC. Compared with UE, SE was associated with a moderate improvement in maximal walking distance at 6 months (effect size 0.77, 95% CI 0.36-1.17, P < .001) and 12 months (effect size 0.56, 95% CI 0.34-0.77, P < .001). Supervised exercise also improved claudication distance to a moderate extent compared with UE at 6 months (effect size 0.63, 95% CI 0.40-0.85, P < .001) and 12 months (effect size 0.41, 95% CI 0.18-0.65, P = .001). There was no difference in the Short Form-36 quality of life at 6 months (effect size -0.05, 95% CI -0.50 to 0.41, P = .84) or walking impairment questionnaire distance (effect size 0.24, 95% CI -0.03 to 0.50, P = .08) or speed (effect size 0.26, 95% CI -0.06 to 0.59, P = .11). CONCLUSIONS: In claudication patients, SE is more effective than UE at improving maximal walking and claudication distances, yet there is no difference in general quality of life or patient-reported community-based walking. Further studies are needed to investigate the relationship between functional gain and disease specific quality of life. PMID- 26027633 TI - First evidence of treatment efficacy in metastatic carcinoma of the parotid gland with BRD4/NUT translocation. AB - BACKGROUND: Nuclear protein in testis (NUT) midline carcinomas (NMC) are characterized by rearrangements of the gene NUT. In the majority of NMCs, a translocation t(15;19), resulting in a BRD4/NUT fusion gene, is present. Nuclear protein in testis midline carcinomas is a rare, but probably underdiagnosed entity due to misdiagnosis. Most cases have been reported in the mediastinum and upper aero-digestive tract. The clinical course of a NMC is extremely aggressive, in spite of intensive chemotherapy and radiotherapy, with an average survival < 1 year. METHODS AND RESULTS: A 32-year-old man presented with a pre-auricular swelling on the left side. After partial parotidectomy, the diagnosis of a NMC was made based on the presence of t(15;19)(q14;p13.1) and BRD4/NUT fusion gene demonstrated by fluorescence in situ hybridization (FISH). During postoperative radiotherapy, the patient developed bone metastases for which chemotherapy consisting of cisplatine, doxorubicine and ifosfamide (PAI) was initiated with remarkable clinical and radiological improvement. Nevertheless, the response was not durable. CONCLUSION: This case illustrates that responses to chemotherapy in the palliative treatment of a t(15;19)-translocated salivary gland carcinoma are possible but not durable. PMID- 26027634 TI - SHH inhibitors for the treatment of medulloblastoma. AB - Medulloblastoma is the most common malignant brain tumor of childhood. It is currently stratified into four molecular variants through the advances in transcriptional profiling. They include: wingless, sonic hedgehog (SHH), Group III, and Group IV. The SHH group is characterized by constitutive activation of the SHH signaling pathway, and genetically characterized by mutations in patched homolog 1 (PTCH1) or other downstream pathway mutations. SHH inhibitors have become of great clinical interest in treating SHH-driven medulloblastoma. Many inhibitors are currently in different stages of development, some already approved for other SHH-driven cancers, such as basal cell carcinoma. In vitro and in vivo medulloblastoma studies have shown efficacy and these findings have been translated into Phase I and II clinical trials. In this review, we present an overview of SHH medulloblastoma, as well as a discussion of currently available SHH inhibitors, and the challenges associated with their use. PMID- 26027635 TI - Anterior opercular syndrome induced by Epstein-Barr virus encephalitis. AB - We report a 19-year-old female presenting with fever, drooling, anarthria, and voluntary facial movement disruption, characteristic of anterior opercular syndrome (AOS). Serological examination revealed Epstein-Barr virus (EBV) infection following acute encephalitis with severe ataxia. A single-photon emission computerized tomography (SPECT) examination indicated hypoperfusion in the left perisylvian region, bilateral thalamus, occipital lobe, and cerebellum. This is the first report of AOS related to EBV encephalitis. SPECT was a useful method for detecting the damaged region of the operculum. In addition, AOS is a clinically distinct entity that may help us understand the mechanisms of language circuits within the operculum. PMID- 26027636 TI - Determination Trial of Nondigestible Oligosaccharide in Processed Foods by Improved AOAC Method 2009.01 Using Porcine Small Intestinal Enzyme. AB - We have previously shown that the Association of Official Analytical Chemists' (AOAC) methods 2001.03 and 2009.01 were not able to measure accurately nondigestible oligosaccharide because they are incapable of hydrolyzing digestible oligosaccharide, leading to overestimation of nondigestible oligosaccharide. Subsequently, we have proposed improved AOAC methods 2001.03 and 2009.01 using porcine small intestinal disaccharidases instead of amyloglucosidase. In the present study, we tried to determine nondigestible oligosaccharide in marketed processed foods using the improved AOAC method (improved method), and the results were compared with those by AOAC method 2009.01. In the improved method, the percentages of recovery of fructooligosaccharide, galactooligosaccharide, and raffinose to the label of processed food were 103.0, 89.9, and 102.1%, respectively. However, the AOAC method 2009.01 overestimated >30% of the quantity of nondigestible oligosaccharide in processed foods, because the margin of error was accepted +/ 20% on the contents of nondigestible oligosaccharides in processed foods for Japanese nutrition labeling, the improved method thus provided accurate quantification of nondigestible oligosaccharides in processed food and allows a comprehensive determination of nondigestible oligosaccharides. PMID- 26027637 TI - Stretchable Heater Using Ligand-Exchanged Silver Nanowire Nanocomposite for Wearable Articular Thermotherapy. AB - Thermal therapy is one of the most popular physiotherapies and it is particularly useful for treating joint injuries. Conventional devices adapted for thermal therapy including heat packs and wraps have often caused discomfort to their wearers because of their rigidity and heavy weight. In our study, we developed a soft, thin, and stretchable heater by using a nanocomposite of silver nanowires and a thermoplastic elastomer. A ligand exchange reaction enabled the formation of a highly conductive and homogeneous nanocomposite. By patterning the nanocomposite with serpentine-mesh structures, conformal lamination of devices on curvilinear joints and effective heat transfer even during motion were achieved. The combination of homogeneous conductive elastomer, stretchable design, and a custom-designed electronic band created a novel wearable system for long-term, continuous articular thermotherapy. PMID- 26027639 TI - Genotypic Variation in the Concentration of beta-N-Oxalyl-L-alpha,beta diaminopropionic Acid (beta-ODAP) in Grass Pea (Lathyrus sativus L.) Seeds Is Associated with an Accumulation of Leaf and Pod beta-ODAP during Vegetative and Reproductive Stages at Three Levels of Water Stress. AB - Grass pea (Lathyrus sativus L.) cultivation is limited because of the presence in seeds and tissues of the nonprotein amino acid beta-N-oxalyl-L-alpha,beta diaminopropionic acid (beta-ODAP), a neurotoxin that can cause lathyrism in humans. Seven grass pea genotypes differing in seed beta-ODAP concentration were grown in pots at three levels of water availability to follow changes in the concentration and amount of beta-ODAP in leaves and pods and seeds. The concentration and amount of beta-ODAP decreased in leaves in early reproductive development and in pods as they matured, while water stress increased beta-ODAP concentration in leaves and pods at these stages. The net amount of beta-ODAP in leaves and pods at early podding was positively associated with seed beta-ODAP concentration at maturity. We conclude that variation among genotypes in seed beta-ODAP concentration results from variation in net accumulation of beta-ODAP in leaves and pods during vegetative and early reproductive development. PMID- 26027640 TI - n-Fe2O3 to N+-TiO2Heterojunction Photoanode for Photoelectrochemical Water Oxidation. AB - To improve the performance of the thin hematite photoanode for photoelectrochemical water oxidation, in this work, an nN(+) alpha-Fe2O3 (hematite)-TiO2 heterojunction photoanode is constructed on fluorine-doped tin oxide substrate to establish a built-in field in the space charge region for facilitating the charge separation in the hematite layer. Charge distribution in the hematite-TiO2 heterostructure is investigated using Kelvin probe force microscopy, which confirms the improvement of charge separation in hematite layer by the formation of energy-matched nN(+) alpha-Fe2O3-TiO2 heterojunction. Compared to the hematite photoanode, an eightfold enhancement of the photocurrent density at 1.23 V versus reversible hydrogen electrode is measured in the hematite-TiO2 heterojunction photoanode. By using hydrogen peroxide as a hole scavenger, it demonstrates that both charge separation and charge injection efficiencies in the hematite-TiO2 heterojunction photoanode are superior to those in the hematite photoanode. It results from the significant suppressions of the charge recombinations occurring within the hematite layer as well as at the interface of photoelectrode and electrolyte by the formation of the nN(+) alpha Fe2O3-TiO2 heterojunction. PMID- 26027641 TI - Use of nitrates in ischemic heart disease. AB - Short-acting nitrates are beneficial in acute myocardial ischemia. However, many unresolved questions remain about the use of long-acting nitrates in stable ischemic heart disease. The use of long-acting nitrates is weakened by the development of endothelial dysfunction and tolerance. Also, we currently ignore whether lower doses of transdermal nitroglycerin would be better than those presently used. Multivariate analysis data from large nonrandomized studies suggested that long-acting nitrates increase the incidence of acute coronary syndromes, while data from another multivariate study indicate that they have positive effects. Because of methodological differences and open questions, the two studies cannot be compared. A study in Japanese patients with vasospastic angina has shown that, when compared with calcium antagonists, long-acting nitrates do not improve long-term prognosis and that the risk for cardiac adverse events increases with the combined therapy. We have many unanswered questions. PMID- 26027638 TI - Drug discovery in prostate cancer mouse models. AB - INTRODUCTION: The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. AREAS COVERED: The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. EXPERT OPINION: With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction. PMID- 26027642 TI - Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A. AB - Nemorosone (Nem) and guttiferone A (GutA) are acyl phloroglucinol derivatives (APD) that are present in different natural products. For both compounds anti cancer and anti-microbial properties have been reported. In particular, an anti leishmanial activity of both compounds was demonstrated. The aim of this study was to explore the possible role of mitochondria in the anti-leishmanial activity of Nem and GutA in comparison with their action on mammalian mitochondria. Both APD inhibited the growth of promastigotes of Leishmania tarentolae (LtP) with half maximal inhibitory concentration (IC50) values of 0.67 +/- 0.17 and 6.2 +/- 2.6 MU m; while IC50 values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29.5 +/- 3.7 and 9.2 +/- 0.9 MU m, respectively. Nemorosone strongly inhibited LtP oxygen consumption, caused species-specific inhibition (P < 0.05) of succinate:ubiquinone oxidoreductase (complex II) from LtP-mitochondria and significantly increased (P < 0.05) the mitochondrial superoxide production. In contrast, GutA caused only a moderate reduction of respiration in LtP and triggered less superoxide radical production in LtP compared with Nem. In addition, GutA inhibited mitochondrial complex III in bovine heart submitochondrial particles, which is possibly involved in its mammalian toxicity. Both compounds demonstrated at low micromolar concentrations an effect on the mitochondrial membrane potential in LtP. The present study suggests that Nem caused its anti-leishmanial action due to specific inhibition of complexes II/III of mitochondrial respiratory chain of Leishmania parasites that could be responsible for increased production of reactive oxygen species that triggers parasite death. PMID- 26027643 TI - The longevity effect of echinacoside in Caenorhabditis elegans mediated through daf-16. AB - Echinacoside (ECH), a natural polyphenolic compound, has been reported to possess important pharmacological activities. However, very little is known about whether or how ECH affects longevity in vivo. We have examined the effects of ECH on the life span and stress tolerance in Caenorhabditis elegans. Our studies demonstrate that the life span of wild-type worms could be extended in the presence of ECH. Furthermore, ECH was found to increase tolerance of worms to heat shock and oxidative stress, while not exerting any influence on pharyngeal pumping rate and progeny production. Our mechanistic studies indicate that supplementation of ECH increases the transcript level of daf-16. ECH treatment also modulates the nuclear localization and transcriptional activities of daf-16, thus fine tunes the expression of daf-16 target genes to promote longevity and increases stress response in C. elegans. Overall, this work reveals the longevity effect of ECH and elucidates the underpinning mechanisms. PMID- 26027644 TI - Co-liquefaction of sewage sludge and oil-tea-cake in supercritical methanol: yield of bio-oil, immobilization and risk assessment of heavy metals. AB - In this study, attention was concentrated on the yields of bio-oil and toxicities of heavy metals (HMs) in liquefaction residues (LRs). Liquefaction of sewage sludge (SS) or oil-tea-cake (OTC) or mixtures of SS and OTC were carried out under the condition of supercritical methanol (SCM). Results showed that the addition of OTC extraordinarily increased the yields of oil from 37.9% (SS) to 86.2% (SS + OTC). Furthermore, with the liquefaction of SS and OTC mixture, the bioavailable fraction (F1 + F2) of Cd and Cu (F1 + F2) was decreased from 2.47 to 1.64 mg/kg and from 98.84 to 67.48 mg/kg, respectively. However, the bioavailable fraction of Zn (F1 + F2) increased from 122.03 to 204.69 mg/kg with the liquefaction of SS. The bioavailable fraction (F1 + F2) of Pb in LRs was 0%, which did not express any changes during the liquefaction process. Risk assessments of geo-accumulation index (I(geo)), risk assessment code (RAC) and modified potential ecological risk index (MRI) were applied to evaluate the bioavailabilities, the potential ecological risks and the pollution levels of HMs. The results show that the OTC in SS can decrease the risk of HMs in LRs. Cd attracted many concerns for the highest risk to the environment among all of the HMs. Here, the good results obtained means that SCM liquefaction of mixture of SS and OTC could be a preferable method for SS treatment. PMID- 26027646 TI - Covalently Linked Dimer of Mn3 Single-Molecule Magnets and Retention of Its Structure and Quantum Properties in Solution. AB - [Mn3O(O2CMe)3(dpd)3/2)]2(I3)2 has been obtained from the reaction of 1,3 di(pyridin-2-yl)propane-1,3-dione dioxime (dpdH2) with triangular [Mn(III)3O(O2CMe)(py)3](ClO4). It comprises two [Mn(III)3O](7+) triangular units linked covalently by three dioximate ligands into a [Mn3]2 dimer. Solid state dc and ac magnetic susceptibility measurements reveal that each Mn3 subunit of the dimer is a separate single-molecule magnet (SMM) with an S = 6 ground state and that the two SMM units are very weakly ferromagnetically exchange coupled. High frequency EPR spectroscopy on a single crystal displays signal splittings indicative of quantum superposition/entanglement of the two SMMs, and parallel studies on MeCN/toluene (1:1) frozen solutions reveal the same spectral features. The dimer thus retains its structure and inter-Mn3 coupling upon dissolution. This work establishes that covalently linked molecular oligomers of exchange coupled SMMs can be prepared that retain their oligomeric nature and attendant inter-SMM quantum mechanical coupling in solution, providing a second phase for their study and demonstrating the feasibility of using solution methods for their deposition on surfaces and related substrates for study. PMID- 26027647 TI - Retraction of "Hypoxia Alters Ocular Drug Transporter Expression and Activity in Rat and Calf Models: Implications for Drug Delivery". PMID- 26027648 TI - Target-Triggered Switching on and off the Luminescence of Lanthanide Coordination Polymer Nanoparticles for Selective and Sensitive Sensing of Copper Ions in Rat Brain. AB - Copper ions (Cu(2+)) in the central nervous system play a crucial role in the physiological and pathological events, so simple, selective, and sensitive detection of cerebral Cu(2+) is of great importance. In this work, we report a facile yet effective fluorescent method for sensing of Cu(2+) in rat brain using one kind of lanthanide coordination polymer nanoparticle, adenosine monophosphate (AMP) and terbium ion (Tb(3+)), i.e., AMP-Tb, as the sensing platform. Initially, a cofactor ligand, 5-sulfosalicylic acid (SSA), as the sensitizer, was introduced into the nonluminescent AMP-Tb suspension, resulting in switching on the luminescence of AMP-Tb by the removal of coordinating water molecules and concomitant energy transfer from SSA to Tb(3+). The subsequent addition of Cu(2+) into the resulting SSA/AMP-Tb can strongly quench the fluorescence because the specific coordination interaction between SSA and Cu(2+) rendered energy transfer from SSA to Tb(3+) inefficient. The decrease ratio of the fluorescence intensities of SSA/AMP-Tb at 550 nm show a linear relationship for Cu(2+) within the concentration range from 1.5 to 24 MUM with a detection limit of 300 nM. The method demonstrated here is highly selective and is free from the interference of metal ions, amino acids, and the biological species commonly existing in the brain such as dopamine, lactate, and glucose. Eventually, by combining the microdialysis technique, the present method has been successfully applied in the detection of cerebral Cu(2+) in rat brain with the basal dialysate level of 1.91 +/- 0.40 MUM (n = 3). This method is very promising to be used for investigating the physiological and pathological events that cerebral Cu(2+) participates in. PMID- 26027649 TI - Design strategies of fluorescent probes for selective detection among biothiols. AB - Simple thiol derivatives, such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play key roles in biological processes, and the fluorescent probes to detect such thiols in vivo selectively with high sensitivity and fast response times are critical for understanding their numerous functions. However, the similar structures and reactivities of these thiols pose considerable challenges to the development of such probes. This review focuses on various strategies for the design of fluorescent probes for the selective detection of biothiols. We classify the fluorescent probes for discrimination among biothiols according to reaction types between the probes and thiols such as cyclization with aldehydes, conjugate addition-cyclization with acrylates, native chemical ligation, and aromatic substitution-rearrangement. PMID- 26027650 TI - Porphyrinic supramolecular daisy chains incorporating pillar[5]arene-viologen host-guest interactions. AB - A porphyrin functionalised with pillar[5]arene and a viologen at its 5- and 15 meso positions assembles in a head-to-tail manner, producing linear supramolecular daisy chains in dichloromethane. At high concentrations, it forms an organogel which has been investigated by electron microscopy and rheological measurements, paving the way for the preparation of other functional supramolecular assemblies which harness viologen?pillararene host-guest interactions. PMID- 26027651 TI - Cu(OAc)2-Et3N mediated oxidative coupling of alpha-azido ketones with pyridinium ylides: utilizing in situ generated imines for regioselective synthesis of imidazo[1,2-a]pyridines. AB - Phenacyl azides were reacted with pyridinium ylides in the presence of Cu(OAc)2 (2 mol%) and Et3N utilizing molecular oxygen as a green oxidant to yield imidazo[1,2-a]pyridines in exclusive regioselectivity. Following the optimized protocol, 28 different fused heterocycles were synthesized in high yields (71 92%). In order to get mechanistic insight into the reaction, a few control experiments were carried out and the role of the copper salt was discussed. PMID- 26027652 TI - Protein dynamics: from rattling in a cage to structural relaxation. AB - We present an overview of protein dynamics based mostly on results of neutron scattering, dielectric relaxation spectroscopy and molecular dynamics simulations. We identify several major classes of protein motions on the time scale from faster than picoseconds to several microseconds, and discuss the coupling of these processes to solvent dynamics. Our analysis suggests that the microsecond backbone relaxation process might be the main structural relaxation of the protein that defines its glass transition temperature, while faster processes present some localized secondary relaxations. Based on the overview, we formulate a general picture of protein dynamics and discuss the challenges in this field. PMID- 26027653 TI - Multiple scale investigation of molecular diffusion inside functionalized porous hosts using a combination of magnetic resonance methods. AB - Mass transport of molecular compounds through porous solids is a decisive step in numerous, important applications like chromatography or heterogeneous catalysis. It is a multi-scale, hierarchical phenomenon: macrodiffusion (>MUm) is influenced, in addition to parameters like grain boundaries and particle packing, by meso-scale (>10 nm, 12.5 degrees C [excess risk (ER) for 1 degrees C increase: 1.06%, 95% confidence interval (CI) 0.63-1.49 on lag day 3] and for relative humidity >40% (ER for 1% increase: 0.18%, 95% CI 0.12-0.24 at lag day 4); and there were linear effects of rainfall (ER for 1-mm increase: 0.22%, 95% CI 0.12-0.32), negative effects for wind speed (ER: -2.91%, 95% CI -4.28 to -1.52 at lag day 3) and sunshine duration (ER: -0.25% 95% CI -0.43 to -0.07 at lag day 4). This study suggests that there are thresholds for the effects of temperature and relative humidity on bacillary dysentery, and these findings should be considered in its prevention and control programmes. PMID- 26027679 TI - Generation of Mesenchymal Stem Cells by Blood Cell Reprogramming. AB - Mesenchymal stem cells (MSCs) have been successfully used to treat multiple diseases in animal studies and clinical trials. Currently, the commonly used MSCs are derived from bone marrow and adipose tissue. Alternative approaches include differentiation of induced pluripotent stem cells (iPSCs) into MSCs, or direct reprogramming of blood cells into MSCs. This review summarizes recent progresses concerning how to generate MSCs by blood cell reprogramming and how studies in cellular reprogramming may help identify new factors to expand or even rejuvenate adult MSCs. PMID- 26027680 TI - Molecular Mechanisms of PPAR-gamma Governing MSC Osteogenic and Adipogenic Differentiation. AB - Sharing the same precursor cell lineage located in the bone marrow, mesenchymal stroma/stem cells (MSCs), osteoblasts and adipocytes have a reciprocal relationship in differentiation and function. The nuclear transcription factor peroxisome-proliferator- activated receptor-gamma (PPAR-gamma) has been found expressed in both osteoblasts and adipocytes, as well as in MSCs, suggesting its crucial role in regulating adipocyte formation and osteoblast development. It has been observed in animal models that upregulated PPAR-gamma activity results in bone loss where marrow adiposity is facilitated, while downregulated PPAR-gamma activity leads to bone mass elevation. Evidence suggests that the dual function of PPAR-gamma in either anti-osteoblastic or pro-adipocytic aspects is determined by its ligand. Furthermore, various cytokines and extracellular signaling pathways are involved in the transactivation of PPAR-gamma, which can trigger the adipogenesis/osteoblastogenesis switch. PPAR-gamma, therefore, shows tremendous potential in novel strategies for bone tissue engineering and clinical application. This review summarizes the regulatory function of PPAR-gamma in MSC differentiation, as well as the cytokine and extracellular signaling pathways participating in the cross-talk between adipogenesis and osteoblastogenesis. PMID- 26027681 TI - An Update on Human Stem Cell-Based Therapy in Parkinson's Disease. AB - CDATA[Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and it is characterized by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Current pharmacological treatments for PD are only symptomatic and unfortunately there is still no cure for this disorder. Stem cell technology has become an attractive option to investigate and treat PD. Indeed, transplantation of fetal ventral mesencephalic cells into PD brains have provided proof of concept that cell replacement therapy can be beneficial for some patients, greatly improving their motor symptoms. However, ethical and practical aspects of tissue availability limit its widespread clinical use. Hence, the need of alternative cell sources are based on the use of different types of stem cells. Stem cell based therapies can be beneficial by acting through several mechanisms such as cell replacement, trophic actions and modulation of inflammation. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for PD and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for PD treatment. PMID- 26027682 TI - Regulators of Stem Cells Proliferation in Tissue Regeneration. AB - This review summarizes recent breakthroughs in studies regarding proliferation of adult stem cells which complement and extend our knowledge to various aspects of cell biology and signal pathways. In recent years, many interesting results and discoveries were achieved regarding the proliferative properties of stem cells. In vitro expansion of stem cells may benefit from high proliferation rates, which can produce a large amount of cells to regenerate tissue defects. Meanwhile, optimizing the culture conditions for stem cell propagation is helpful in maintaining the pluripotency and differentiation potential of stem cells, which are critical for tissue engineering and regenerative medicine. Additionally, understanding the proliferation of stem cells may help us to uncover new mechanisms of drug resistance, since stem cells are believed to play an important role in drug resistance. In this review, we focus on signaling pathways regulating the proliferation of various stem cells isolated from adult tissues. We also emphasize the significance of stem cells proliferation in cell research, as well as rapid propagation of adult stem cells for regenerative medicine. PMID- 26027683 TI - Genetic lineages and antimicrobial resistance genotypes in Staphylococcus aureus from children with atopic dermatitis: detection of clonal complexes CC1, CC97 and CC398. AB - The objective was to analyse the genetic lineages of Staphylococcus aureus recovered from nasal and skin samples of atopic dermatitis (AD) paediatric patients, and to characterize the antimicrobial resistance phenotype-genotype and the immune-evasion-cluster (IEC) type of isolates. Forty S. aureus isolates from 35 patients (skin: 26; nasal samples: 14) were characterized. Isolates were submitted to spa-, agr- and multilocus sequence typing. All S. aureus strains analyzed were methicillin-susceptible (MSSA). High genetic diversity was detected among the 40 MSSA isolates (especially among skin isolates), with detection of 27 different spa-types, 20 sequence-types and 16 clonal complexes (CCs). Lineages CC30 and CC5 were predominant among nasal isolates (71% vs 23% skin). Thirteen different CCs were detected among skin isolates, with detection of clades CC1, CC9 and CC398. Antimicrobial resistance rates detected were higher in skin than in nasal isolates, especially for macrolides, aminoglycosides, lincosamides and mupirocin. MSSA strains were characterized into five IEC-types, being A, B and F the predominant ones. MSSA strains of lineages CC45 and CC5 were detected in almost all cases in AD patients with severe Scoring Atopic Dermatitis (SCORAD) and lineages CC8, and CC30 in those with mild or moderate one. As conclusion, high-clonal-diversity was detected among MSSA from AD patients, especially in skin-isolates. Colonization with S. aureus of some CCs seems more associated with AD severity than other lineages. PMID- 26027684 TI - Cell-free DNA versus intact fetal cells for prenatal genetic diagnostics: what does the future hold? AB - Prenatal screening and diagnosis is currently focused on the development of a noninvasive prenatal diagnostic test capable of detecting abnormalities similar to those attainable with an invasive test. One contender is cell-free fetal DNA circulating in maternal plasma and the other is intact fetal cells either from the maternal blood or the cervix. Once adequate fetal DNA is available, laboratory analytic techniques, such as sequencing and microarray, can be applied allowing detection of most cytogenetic and Mendelian fetal disorders. The question is: how close are we to achieving this feat, and what does the future hold? PMID- 26027685 TI - Relinquishing or taking control? Community perspectives on barriers and opportunities in advance care planning. AB - OBJECTIVE: This paper reports on the experiences and perspectives of community members in relation to advance healthcare directives and enduring power of attorney, including the factors that encourage or discourage engagement in advance care planning (ACP). METHODS; A qualitative methodology was used involving 26 in-depth telephone interviews with community members (mean age 66 years). The aims of the interview question were to gain an understanding of: (1) motivations for engaging in ACP; (2) barriers that prevent people from engaging in ACP; and (3) suggestions for promoting ACP. RESULTS: The findings suggest that: (1) community members lack knowledge about ACP; (2) forms appear inaccessible and complex; (3) community members avoid ACP due to fear, mistrust and concerns over control; and (4) there are misperceptions regarding the relevance of ACP based on age and health. CONCLUSIONS: There is unnecessary fear, avoidance and mistrust around ACP activities, largely resulting from misinformation. There is an undoubted need for greater education and support to be offered to individuals and their families regarding ACP, its benefits and its limitations. PMID- 26027686 TI - Thinking critically about client-centred practice and occupational possibilities across the life-span. AB - BACKGROUND: Client-centred occupational therapy practice is tacitly guided by prevailing social values and beliefs about what are "normal" occupational possibilities. These values and beliefs privilege some occupations and negate others. AIM: This study aims to identify and problematize assumptions regarding the value of approximating normal occupational possibilities, showing how these assumptions influence and may diminish client-centred practice. METHODS: Using empirical research examples it demonstrates how occupational therapists and clients are immersed in contexts that shape values and beliefs about what are considered "normal" occupations and how these taken-for-granted values structure occupational therapy practice. CONCLUSION: Critique of client-centred practice requires conscious reflexivity, interrogating our own and our clients' predispositions to value some occupations over others. Engaging in critical reflexivity can help therapists develop new perspectives of how client-centred practice can be applied that includes enabling possibilities for occupations that would be missed altogether in the pursuit of "normal'. PMID- 26027687 TI - Absolute Configurations and NO Inhibitory Activities of Terpenoids from Curcuma longa. AB - Curcuma longa L., belonging to the Zingiberaceae family, is a perennial herb and has been used as a spice and a pigment in the food industry. In the ongoing search for inhibitory reagents of NO production and survey of the chemical composition of natural vegetable foods, the chemical constituents of C. longa used as spice were investigated. This investigation resulted in the isolation of 2 new terpenoids and 14 known analogues. Their structures were established on the basis of the extensive analyses of 1D and 2D NMR spectroscopic data, and the absolute configurations of 1-4 were elucidated by comparison of the calculated and experimental ECD spectra. Among them, compound 1 is a rare norditerpene with an ent-labdane skeleton, and 2 is a skeletally novel sesquiterpene having an eight-membered ring. All of the compounds were found to possess NO inhibitory activities in murine microglial BV-2 cells. The discovery of two new compounds in this chemical investigation further disclosed the chemical composition of C. longa used a food spice, and the bioassay implied that the natural food spice C. longa, containing terpenoids with NO inhibitory activities, may be potentially promotive to human health. PMID- 26027688 TI - Structure-Dependent Thermal Defunctionalization of Single-Walled Carbon Nanotubes. AB - Covalent sidewall functionalization of single-walled carbon nanotubes (SWCNTs) is an important tool for tailoring their properties for research purposes and applications. In this study, SWCNT samples were first functionalized by reductive alkylation using metallic lithium and 1-iodododecane in liquid ammonia. Samples of the alkyl-functionalized SWCNTs were then pyrolyzed under an inert atmosphere at selected temperatures between 100 and 500 degrees C to remove the addends. The extent of defunctionalization was assessed using a combination of thermogravimetric analysis, Raman measurements of the D, G, and radial breathing bands, absorption spectroscopy of the first- and second-order van Hove peaks, and near-IR fluorescence spectroscopy of (n,m)-specific emission bands. These measurements all indicate a substantial dependence of defunctionalization rate on nanotube diameter, with larger diameter nanotubes showing more facile loss of addends. The effective activation energy for defunctionalization is estimated to be a factor of ~1.44 greater for 0.76 nm diameter nanotubes as compared to those with 1.24 nm diameter. The experimental findings also reveal the quantitative variation with functionalization density of the Raman D/G intensity ratio and the relative near-IR fluorescence intensity. Pyrolyzed samples show spectroscopic properties that are equivalent to those of SWCNTs prior to functionalization. The strong structure dependence of the defunctionalization rate suggests an approach for scalable diameter sorting of mixed SWCNT samples. PMID- 26027689 TI - Panic disorder and incident coronary heart disease: a systematic review and meta regression in 1131612 persons and 58111 cardiac events. AB - BACKGROUND: Substantial healthcare resources are devoted to panic disorder (PD) and coronary heart disease (CHD); however, the association between these conditions remains controversial. Our objective was to conduct a systematic review of studies assessing the association between PD, related syndromes, and incident CHD. METHOD: Relevant studies were retrieved from Medline, EMBASE, SCOPUS and PsycINFO without restrictions from inception to January 2015 supplemented with hand-searching. We included studies that reported hazard ratios (HR) or sufficient data to calculate the risk ratio and 95% confidence interval (CI) which were pooled using a random-effects model. Studies utilizing self reported CHD were ineligible. Twelve studies were included comprising 1 131 612 persons and 58 111 incident CHD cases. RESULTS: PD was associated with the primary incident CHD endpoint [adjusted HR (aHR) 1.47, 95% CI 1.24-1.74, p < 0.00001] even after excluding angina (aHR 1.49, 95% CI 1.22-1.81, p < 0.00001). High to moderate quality evidence suggested an association with incident major adverse cardiac events (MACE; aHR 1.40, 95% CI 1.16-1.69, p = 0.0004) and myocardial infarction (aHR 1.36, 95% CI 1.12-1.66, p = 0.002). The risk for CHD was significant after excluding depression (aHR 1.64, 95% CI 1.45-1.85) and after depression adjustment (aHR 1.38, 95% CI 1.03-1.87). Age, sex, length of follow up, socioeconomic status and diabetes were sources of heterogeneity in the primary endpoint. CONCLUSIONS: Meta-analysis showed that PD was independently associated with incident CHD, myocardial infarction and MACE; however, reverse causality cannot be ruled out and there was evidence of heterogeneity. PMID- 26027690 TI - Structural and Electrical Investigation of C60-Graphene Vertical Heterostructures. AB - Graphene, with its unique electronic and structural qualities, has become an important playground for studying adsorption and assembly of various materials including organic molecules. Moreover, organic/graphene vertical structures assembled by van der Waals interaction have potential for multifunctional device applications. Here, we investigate structural and electrical properties of vertical heterostructures composed of C60 thin film on graphene. The assembled film structure of C60 on graphene is investigated using transmission electron microscopy, which reveals a uniform morphology of C60 film on graphene with a grain size as large as 500 nm. The strong epitaxial relations between C60 crystal and graphene lattice directions are found, and van der Waals ab initio calculations support the observed phenomena. Moreover, using C60-graphene heterostructures, we fabricate vertical graphene transistors incorporating n-type organic semiconducting materials with an on/off ratio above 3 * 10(3). Our work demonstrates that graphene can serve as an excellent substrate for assembly of molecules, and attained organic/graphene heterostructures have great potential for electronics applications. PMID- 26027691 TI - Allyl isothiocyanate induces stomatal closure in Vicia faba. AB - Isothiocyanates are enzymatically produced from glucosinolates in plants, and allyl isothiocyanate (AITC) induces stomatal closure in Arabidopsis thaliana. In this study, we investigated stomatal responses to AITC in Vicia faba. AITC induced stomatal closure accompanied by reactive oxygen species (ROS) and NO production, cytosolic alkalization and glutathione (GSH) depletion in V. faba. GSH monoethyl ester induced stomatal reopening and suppressed AITC-induced GSH depletion in guard cells. Exogenous catalase and a peroxidase inhibitor, salicylhydroxamic acid, inhibited AITC-induced stomatal closure, unlike an NAD(P)H oxidase inhibitor, diphenylene iodonium chloride. The peroxidase inhibitor also abolished the AITC-induced ROS production, NO production, and cytosolic alkalization. AITC-induced stomatal closure was suppressed by an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and an agent to acidify cytosol, butyrate. These results indicate that AITC-induced stomatal closure in V. faba as well as in A. thaliana and suggest that AITC signaling in guard cells is conserved in both plants. PMID- 26027692 TI - Pharmacologic treatment options for advanced epithelial skin cancer. AB - INTRODUCTION: Epithelial skin cancers (ESCs), namely basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), are considered common skin malignancies, with rising incidence rates over the past few decades. A subgroup of patients with ESC present with advanced and 'difficult'-to-treat tumours, including locally advanced and metastatic tumours. Currently, there is no widely accepted staging system for locally advanced ESCs, while metastatic BCCs and SCCs share a staging system. Therefore, selecting an appropriate therapeutic regimen for these patients may be difficult. AREAS COVERED: The purpose of this review is to highlight the pharmacologic treatment options for advanced ESCs. These include 'conventional' chemotherapeutic regimens such as 5-fluorouracil, cisplatin, vincristine, bleomycin and doxorubicin and newer, more 'targeted' therapies. EXPERT OPINION: Vismodegib, a Hedgehog (Hh) inhibitor, was recently approved for the treatment of advanced BCC showing a good efficacy rate and a relatively well tolerated safety profile in clinical studies. In addition, a number of hedgehog inhibitors are now in Phase I and II trials of advanced BCC demonstrating encouraging results. Phase II studies with epithelial growth factor receptor inhibitors, such as cetuximab, gefitinib, panitimumab and erlotinib have been conducted in patients with advanced SCCs, used either as monotherapy or in combination with chemotherapy. However, there is still much knowledge to be gained about the treatment efficacies, optimal treatment durations, mechanisms of drug tolerance, adverse events and the ways in which these therapies influence patient outcomes and quality of life. PMID- 26027693 TI - Seeking a comprehensive approach to tobacco control for Aboriginal and Torres Strait Islander people. PMID- 26027696 TI - Antibody-Drug Conjugates (ADCs): Magic Bullets at Last! PMID- 26027697 TI - Smart Plasmonic Glucose Nanosensors as Generic Theranostic Agents for Targeting Free Cancer Cell Screening and Killing. AB - Fast and accurate identification of cancer cells from healthy normal cells in a simple, generic way is very crucial for early cancer detection and treatment. Although functional nanoparticles, like fluorescent quantum dots and plasmonic Au nanoparticles (NPs), have been successfully applied for cancer cell imaging and photothermal therapy, they suffer from the main drawback of needing time consuming targeting preparation for specific cancer cell detection and selective ablation. The lack of a generic and effective method therefore limits their potential high-throughput cancer cell preliminary screening and theranostic applications. We report herein a generic in vitro method for fast, targeting-free (avoiding time-consuming preparations of targeting moiety for specific cancer cells) visual screening and selective killing of cancer cells from normal cells, by using glucose-responsive/-sensitive glucose oxidase-modified Ag/Au nanoshells (Ag/Au-GOx NSs) as a smart plasmonic theranostic agent. The method is generic to some extent since it is based on the distinct localized surface plasmon resonance (LSPR) responses (and colors) of the smart nanoprobe with cancer cells (typically have a higher glucose uptake level) and normal cells. PMID- 26027698 TI - In situ observation of the sodiation process in CuO nanowires. AB - In situ transmission electron microscopy was used to observe the dynamic evolution of the morphology and phase transformations in CuO nanowires during the process of sodiation. Our results facilitate a fundamental understanding of the sodiation mechanism in CuO nanostructures used as electrode materials in sodium ion batteries. PMID- 26027699 TI - A sputtered CdS buffer layer for co-electrodeposited Cu2ZnSnS4 solar cells with 6.6% efficiency. AB - Cu2ZnSnS4 thin films with thicknesses ranging from 0.35 to 1.85 MUm and micron sized grains (0.5-1.5 MUm) were synthesized using co-electrodeposited Cu-Zn-Sn-S precursors with different deposition times. Here we have introduced a sputtered CdS buffer layer for the development of CZTS solar cells for the first time, which enables breakthrough efficiencies up to 6.6%. PMID- 26027700 TI - Anions make the difference: insights from the interaction of big cations and anions with poly(N-isopropylacrylamide) chains and microgels. AB - Minute concentrations of big hydrophobic ions have the ability to induce substantial effects in soft matter systems, including novel phases in lipid layers, giant charge inversion in colloids and nanostructuration in polymer surfaces in contact with water. The effects are so strong that the term "soft matter disruptors" was coined to describe their deep impact on interfaces, which goes far beyond that found by using the classical ions considered in lyotropic (Hofmeister) sequences. In these effects, solvation thermodynamics plays a fundamental role. Interestingly, it is possible to obtain big hydrophobic cations and anions with an almost identical size and structure (e.g. Ph4B(-), Ph4As(+)), which only differ in their central atom. Here we employ different techniques (Molecular Dynamics (MD) simulations, electrophoretic mobility and Atomic Force Microscopy (AFM)) to demonstrate the dramatic differences in the interaction of Ph4B(-) and Ph4As(+) with poly(N-isopropylacrylamide) (PNIPAM), a thermoresponsive polymer with expanded (well hydrated) and collapsed (poorly hydrated) states. Although both ions interact strongly with neutral PNIPAM chains and cationic or anionic PNIPAM microgels in the collapsed states, the effects of Ph4B(-) on PNIPAM are always substantially stronger than the effects of Ph4As(+). MD simulations predict that ion-PNIPAM free energy of interaction is four times larger for Ph4B(-) than for Ph4As(+). Electrokinetic and AFM experiments show that, acting as counter-ions, both ions are able to invert the charge of anionic or cationic PNIPAM microgels at minute concentrations, but the charge inversion due to Ph4B(-) is much larger than that obtained with Ph4As(+). Therefore, even for big ions of identical size, shape and valence, the affinity of anions and cations for interfaces is intrinsically different. PMID- 26027701 TI - The first Fe-based Na(+)-ion cathode with two distinct types of polyanions: Fe3P5SiO19. AB - Herein, we report the synthesis, structure, and electrochemistry of the first Na(+)-ion cathode with two distinct types of polyanions: Fe3P5SiO19. The Fe-based cathode has a reversible capacity of ca. 70 mA h g(-1); ca. 1.7 Na(+) ions per formula can be inserted/extracted at an average voltage of 2.5 V versus Na(+)/Na. PMID- 26027702 TI - Serine O-sulfation probed by IRMPD spectroscopy. AB - The sulfation of amino acids is a frequent post-translational modification. It is highly labile, though, and characterizing it by mass spectrometry, an otherwise powerful and widely exploited tool in analytical proteomics, is a challenge. The presently reported study is aimed at revealing the O-sulfation of l-serine and elucidating the effects of protonation and deprotonation on the structure and stability of the ensuing ionic species, [sSer + H](+) and [sSer - H](-). These ions are obtained as gaseous, isolated species by electrospray ionization, trapped in a Paul ion-trap, and sampled by IR multiple photon dissociation (IRMPD) spectroscopy in either the 750-1900 cm(-1) fingerprint range, or the 2900 and 3700 cm(-1) range encompassing the N-H and O-H stretching modes. The recorded IRMPD spectra present diagnostic signatures of the sulfate modification which are missing in the spectra of the native serine ions, [Ser + H](+) and [Ser - H](-). The experimental IRMPD features have been interpreted by comparison with the linear IR spectra of the lowest energy structures that are likely candidates for the sampled ions, calculated at the M06-2X/6-311+G(d,p) level of theory. Evidence is gathered that the most stable conformations of [sSer + H](+) are stabilized by hydrogen bonding interactions between the protonated amino group and both the carbonyl and sulfate oxygens. [sSer - H](-) ions possess a negatively charged sulfate group involved in either a S=O...HN or a S=O...HO hydrogen bond. The experimental IRMPD spectra are consistent with the presence of multiple low-lying structures in a thermally equilibrated population of several species particularly in the case of [sSer - H](-) ions, where the high structural flexibility combined with the presence of a negative charge favors the co-existence of several different H-bonding motifs. PMID- 26027703 TI - Ultraviolet photodissociation action spectroscopy of gas-phase protonated quinoline and isoquinoline cations. AB - The gas-phase photodissociation action spectroscopy of protonated quinoline and isoquinoline cations (quinolineH(+) and isoquinolineH(+)) is investigated at ambient temperature. Both isomers exhibit vibronic detail and wavelength dependent photoproduct partitioning across two broad bands in the ultraviolet. Photodissociation action spectra are reported spanning 370-285 nm and 250-220 nm and analysed with the aid of electronic structure calculations: TD-DFT (CAM B3LYP/aug-cc-pVDZ) is used for spectra simulations and CBS-QB3 for dissociation enthalpies. It is shown that the action spectra are afforded predominantly by two photon excitation. The first band is attributed to both the S1 <- S0 and S2 <- S0 electronic transitions in quinolineH(+), with a S1 <- S0 electronic origin assigned at 27,900 cm(-1). For isoquinolineH(+) the S1 <- S0 transition is observed with an assigned electronic origin at 27,500 cm(-1). A separate higher energy band is observed for both species, corresponding to the S3 <- S0 transition, with origins assigned at 42,100 cm(-1) and 42,500 cm(-1) for quinolineH(+) and isoquinolineH(+), respectively. Franck-Condon absorption simulations provide an explanation for some vibrational structure observed in both bands allowing several normal mode assignments. The nature of the electronic transitions is discussed and it is shown that the excited states active in the reported spectra should be of pipi* character with some degree of charge transfer from the homocycle to the heterocycle. PMID- 26027704 TI - Regional differences in birth size: a comparison between the Helsinki Birth Cohort Study and contemporaneous births on the Aland Islands - CORRIGENDUM. PMID- 26027705 TI - Deficits of learning and memory in Hemojuvelin knockout mice. AB - Iron is involved in various physiological processes of the human body to maintain normal functions. Abnormal iron accumulation in brain has been reported as a pathogenesis of several neurodegenerative disorders and cognitive impairments. Hemojuvelin (HVJ) is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis. Although iron accumulation in brain has been related to neurodegenerative diseases, it remains unknown the effect of mutation of HVJ gene on cognitive performance. In our studies, HJV(-/-) mice showed deficits in novel object recognition and Morris water maze tests. Furthermore, the expression ration of apoptotic marker Bax and anti-apoptotic marker Bcl-2 in the hippocampus and prefrontal cortex showed higher levels in HJV(-/-) mice. Our results suggested that deletion of HJV gene could increase apoptosis in brain which might contribute to learning and memory deficits in mutant mice. These results indicated that HJV(-/-) mice would be a useful model to study cognitive impairment induced by iron overload in brain. PMID- 26027706 TI - Workflow interruptions, social stressors from supervisor(s) and attention failure in surgery personnel. AB - Workflow interruptions and social stressors among surgery personnel may cause attention failure at work that may increase rumination about work issues during leisure time. The test of these assumptions should contribute to the understanding of exhaustion in surgery personnel and patient safety. Workflow interruptions and supervisor-related social stressors were tested to predict attention failure that predicts work-related rumination during leisure time. One hundred ninety-four theatre nurses, anaesthetists and surgeons from a Swiss University hospital participated in a cross-sectional survey. The participation rate was 58%. Structural equation modelling confirmed both indirect paths from workflow interruptions and social stressors via attention failure on rumination (both p<0.05). An alternative model, assuming the reversed indirect causation from attention failure via workflow interruptions and social stressors on rumination-could not be empirically supported. Workflow interruptions and social stressors at work are likely to trigger attention failure in surgery personnel. Work redesign and team intervention could help surgery personnel to maintain a high level of quality and patient safety and detach from work related issues to recover during leisure time. PMID- 26027707 TI - Analysis of labour accidents in tunnel construction and introduction of prevention measures. AB - At present, almost all mountain tunnels in Japan are excavated and constructed utilizing the New Austrian Tunneling Method (NATM), which was advocated by Prof. Rabcewicz of Austria in 1964. In Japan, this method has been applied to tunnel construction since around 1978, after which there has been a subsequent decrease in the number of casualties during tunnel construction. However, there is still a relatively high incidence of labour accidents during tunnel construction when compared to incidence rates in the construction industry in general. During tunnel construction, rock fall events at the cutting face are a particularly characteristic of the type of accident that occurs. In this study, we analysed labour accidents that possess the characteristics of a rock fall event at a work site. We also introduced accident prevention measures against rock fall events. PMID- 26027708 TI - Optimal multi-floor plant layout based on the mathematical programming and particle swarm optimization. AB - In the fields of researches associated with plant layout optimization, the main goal is to minimize the costs of pipelines and pumping between connecting equipment under various constraints. However, what is the lacking of considerations in previous researches is to transform various heuristics or safety regulations into mathematical equations. For example, proper safety distances between equipments have to be complied for preventing dangerous accidents on a complex plant. Moreover, most researches have handled single-floor plant. However, many multi-floor plants have been constructed for the last decade. Therefore, the proper algorithm handling various regulations and multi floor plant should be developed. In this study, the Mixed Integer Non-Linear Programming (MINLP) problem including safety distances, maintenance spaces, etc. is suggested based on mathematical equations. The objective function is a summation of pipeline and pumping costs. Also, various safety and maintenance issues are transformed into inequality or equality constraints. However, it is really hard to solve this problem due to complex nonlinear constraints. Thus, it is impossible to use conventional MINLP solvers using derivatives of equations. In this study, the Particle Swarm Optimization (PSO) technique is employed. The ethylene oxide plant is illustrated to verify the efficacy of this study. PMID- 26027709 TI - A work-life perspective on sleep and fatigue--looking beyond shift workers. AB - This study examines sleep and fatigue through a work-life lens. Whilst most often thought of as an issue for shift workers, this study observed that self-reported insufficient sleep and fatigue were prevalent for workers on standard daytime schedules. Using a representative sample of 573 daytime workers (51.3% men; 70.7% aged 25-54 yr) from one Australian state, it was observed that 26.4% of daytime workers never or rarely get the seven hours of sleep a night that is recommended for good health. Those with parenting responsibilites (29.4%) or working long (45+) hours (37.4%) were most likely to report insufficient sleep. Whereas mothers in full-time work were most likely to report frequent fatigue (42.5%). This study highlights the common experience of insufficient sleep and fatigue in a daytime workforce, with significant implications for health and safety at work and outside of work. Stronger and more effective legislation addressing safe and 'decent' working time is clearly needed, along with greater awareness and acceptance within workplace cultures of the need to support reasonable workloads and working hours. PMID- 26027710 TI - What do firefighters desire from the next generation of personal protective equipment? Outcomes from an international survey. AB - The purpose of this study was to investigate smart features required for the next generation of personal protective equipment (PPE) for firefighters in Australia, Korea, Japan, and the USA. Questionnaire responses were obtained from 167 Australian, 351 Japanese, 413 Korean, and 763 U.S. firefighters (1,611 males and 61 females). Preferences concerning smart features varied among countries, with 27% of Korean and 30% of U.S. firefighters identifying 'a location monitoring system' as the most important element. On the other hand, 43% of Japanese firefighters preferred 'an automatic body cooling system' while 21% of the Australian firefighters selected equally 'an automatic body cooling system' and 'a wireless communication system'. When asked to rank these elements in descending priority, responses across these countries were very similar with the following items ranked highest: 'a location monitoring system', 'an automatic body cooling system', 'a wireless communication system', and 'a vision support system'. The least preferred elements were 'an automatic body warming system' and 'a voice recording system'. No preferential relationship was apparent for age, work experience, gender or anthropometric characteristics. These results have implications for the development of the next generation of PPE along with the international standardisation of the smart PPE. PMID- 26027711 TI - Current treatment options for dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans (DFSP) is rare, infiltrating dermal neoplasm, characterized by indolent growth and low probability of metastases. The critical event in DFSP development is the rearrangement of chromosome 17 and 22, leading to transcriptional up-regulation of platelet-derived growth factor, providing an autocrine and/or paracrine stimulus. The cornerstone of treatment for localized DFSP is complete surgical resection with microscopically negative margins. Adjuvant radiotherapy is suggested in cases of positive margins when re-excision is not feasible. The first effective systemic therapy in DFSP introduced into clinical practice was imatinib, demonstrating dramatic activity in advanced cases. Current results indicate that some DFSP patient initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned resectable after imatinib therapy and this rational approach leading to complete remission maybe potentially curative. The clinical experience with other tyrosine kinase inhibitors is limited and imatinib remains the gold standard treatment of locally unresectable/metastatic DFSP. This review summarizes state of the art and perspectives on the DFSP management. PMID- 26027712 TI - The Union of Shortest Path Trees of Functional Brain Networks. AB - Communication between brain regions is still insufficiently understood. Applying concepts from network science has shown to be successful in gaining insight in the functioning of the brain. Recent work has implicated that especially shortest paths in the structural brain network seem to play a major role in the communication within the brain. So far, for the functional brain network, only the average length of the shortest paths has been analyzed. In this article, we propose to construct the union of shortest path trees (USPT) as a new topology for the functional brain network. The minimum spanning tree, which has been successful in a lot of recent studies to comprise important features of the functional brain network, is always included in the USPT. After interpreting the link weights of the functional brain network as communication probabilities, the USPT of this network can be uniquely defined. Using data from magnetoencephalography, we applied the USPT as a method to find differences in the network topology of multiple sclerosis patients and healthy controls. The new concept of the USPT of the functional brain network also allows interesting interpretations and may represent the highways of the brain. PMID- 26027713 TI - The case for a 'one health' approach to combating vector-borne diseases. PMID- 26027714 TI - Electrical Control of near-Field Energy Transfer between Quantum Dots and Two Dimensional Semiconductors. AB - We investigate near-field energy transfer between chemically synthesized quantum dots (QDs) and two-dimensional semiconductors. We fabricate devices in which electrostatically gated semiconducting monolayer molybdenum disulfide (MoS2) is placed atop a homogeneous self-assembled layer of core-shell CdSSe QDs. We demonstrate efficient nonradiative Forster resonant energy transfer (FRET) from QDs into MoS2 and prove that modest gate-induced variation in the excitonic absorption of MoS2 leads to large (~500%) changes in the FRET rate. This in turn allows for up to ~75% electrical modulation of QD photoluminescence intensity. The hybrid QD/MoS2 devices operate within a small voltage range, allow for continuous modification of the QD photoluminescence intensity, and can be used for selective tuning of QDs emitting in the visible-IR range. PMID- 26027715 TI - Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China. AB - PURPOSE: This study investigated correlations between polymorphisms in DNA mismatch repair (MMR) genes and the risk of primary hepatocellular carcinoma (PHC). METHODS: Single nucleotide polymorphisms (SNPs) in the DNA MMR genes MLH3 (rs175080), PMS1 (rs5742933), PMS2 (rs1059060), MSH3 (rs26279), MSH5 (rs1150793, rs2075789) and MSH6 (rs1042821) were detected using the SNaPshot method in 250 PHC cases and in 308 patients without PHC in the Han population in northern China. RESULTS: The AA genotype in MLH3 (rs175080) increased the risk of PHC (odds ratio [OR] = 3.424; 95% confidence interval [CI]: 1.097-10.689). The AG and GG genotypes in MSH3 (rs26279) increased the risk of PHC (OR: 1.644 and 3.300; 95% CI: 1.112-2.428 and 1.765-6.168, respectively). The AA genotype in MSH5 (rs2075789) increased the risk of PHC (OR: 9.229; 95% CI: 1.174-72.535). The CT genotype in MSH6 (rs1042821) reduced the risk of PHC (OR: 0.629; 95% CI: 0.428 0.924). CONCLUSIONS: Our study suggests that polymorphisms in MLH3 (rs175080), MSH3 (rs26279), MSH5 (rs2075789) and MSH6 (rs1042821) may be independent risk factors for PHC. PMID- 26027716 TI - Duration of syphilis symptoms at presentations in men who have sex with men in Australia: are current public health campaigns effective? AB - The rapid rise in syphilis cases has prompted a number of public health campaigns to assist men who have sex with men (MSM) recognize and present early with symptoms. This study aimed to investigate the temporal trend of the duration of self-report symptoms and titre of rapid plasma reagin (RPR) in MSM with infectious syphilis. Seven hundred and sixty-one syphilis cases in MSM diagnosed at the Melbourne Sexual Health Centre (MSHC) from 2007-2013 were reviewed. Median duration of symptoms and RPR titres in each year were calculated. The median durations of symptoms with primary and secondary syphilis were 9 [interquartile range (IQR) 6-14] days and 14 (IQR 7-30) days, respectively. The overall median titre of RPR in secondary syphilis (median 128, IQR 64-256) was higher than in primary syphilis (median 4, IQR 1-32) and in early latent syphilis (median 32, IQR 4-64). The median duration of symptoms for primary syphilis, secondary syphilis and titre of RPR level did not change over time. Public health campaigns were not associated with a significant shorter time from onset of symptoms to treatment. Alternative strategies such as more frequent testing of MSM should be promoted to control the syphilis epidemic in Australia. PMID- 26027718 TI - Effect of N2 and H2 plasma treatments on band edge emission of ZnO microrods. AB - ZnO microrods were grown by laser assisted flow deposition technique in order to study their luminescence behaviour in the near band edge spectral region. Transmission electron microscopy analysis put in evidence the high crystallinity degree and microrod's compositional homogeneity. Photoluminescence revealed a dominant 3.31 eV emission. The correlation between this emission and the presence of surface states was investigated by performing plasma treatments with hydrogen and nitrogen. The significant modifications in photoluminescence spectra after the plasma treatments suggest a connexion between the 3.31 eV luminescence and the surface related electronic levels. PMID- 26027719 TI - Geriatric Screening Tools to Select Older Adults Susceptible for Direct Transfer From the Emergency Department to Subacute Intermediate-Care Hospitalization. AB - OBJECTIVES: Early transfer to intermediate-care hospitals, low-tech but with geriatric expertise, represents an alternative to conventional acute hospitalization for selected older adults visiting emergency departments (EDs). We evaluated if simple screening tools predict discharge destination in patients included in this pathway. DESIGN, SETTING, AND PARTICIPANTS: Cohort study, including patients transferred from ED to the intermediate-care hospital Parc Sanitari Pere Virgili, Barcelona, during 14 months (2012-2013) for exacerbated chronic diseases. MEASUREMENTS: At admission, we collected demographics, comprehensive geriatric assessment, and 3 screening tools (Identification of Seniors at Risk [ISAR], SilverCode, and Walter indicator). OUTCOME: Discharge destination different from usual living situation (combined death and transfer to acute hospitals or long-term nursing care) versus return to previous situation (home or nursing home). RESULTS: Of 265 patients (mean age +/- SD = 85.3 +/- 7.5, 69% women, 58% with acute respiratory infections, 38% with dementia), 80.8% returned to previous living situation after 14.1 +/- 6.5 days (mean +/- SD). In multivariable Cox proportional hazard models, ISAR >3 points (hazard ratio [HR] 2.06, 95% confidence interval [95% CI] 1.16-3.66) and >1 pressure ulcers (HR 2.09, 95% CI 1.11-3.93), but also continuous ISAR, and, in subanalyses, Walter indicator, increased the risk of negative outcomes. Using ROC curves, ISAR showed the best prediction among other variables, although predictive value was poor (AUC = 0.62 (0.53-0.71) for ISAR >3 and AUC = 0.65 (0.57-0.74) for continuous ISAR). ISAR and SilverCode showed fair prediction of acute hospital readmissions. CONCLUSIONS: Among geriatric screening tools, ISAR was independently associated with discharge destination in older adults transferred from ED to intermediate care. Predictive validity was poor. Further research on selection of candidates for alternatives to conventional hospitalization is needed. PMID- 26027717 TI - Type I interferons in anticancer immunity. AB - Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells. PMID- 26027720 TI - From Evidence to Action: Promoting a Multidimensional Approach to Mild Cognitive Impairment. PMID- 26027721 TI - Are Staffing, Work Environment, Work Stressors, and Rationing of Care Related to Care Workers' Perception of Quality of Care? A Cross-Sectional Study. AB - OBJECTIVES: To describe care worker-reported quality of care and to examine its relationship with staffing variables, work environment, work stressors, and implicit rationing of nursing care. DESIGN: Cross-sectional study. SETTING: National, randomly selected sample of Swiss nursing homes, stratified according to language region and size. PARTICIPANTS: A total of 4311 care workers of all educational backgrounds (registered nurses, licensed practical nurses, nurse aides) from 402 units in 155 nursing homes completed a survey between May 2012 and April 2013. MEASUREMENTS: Care worker-reported quality of care was measured with a single item; predictors were assessed with established instruments (eg, Practice Environment Scale-Nurse Working Index) adapted for nursing home use. A multilevel logistic regression model was applied to assess predictors for quality of care. RESULTS: Overall, 7% of care workers rated the quality of care provided as rather low or very low. Important factors related to better quality of care were higher teamwork and safety climate (odds ratio [OR] 6.19, 95% confidence interval [CI] 4.36-8.79); better staffing and resources adequacy (OR 2.94, 95% CI 2.08-4.15); less stress due to workload (OR 0.71, 95% CI 0.55-0.93); less implicit rationing of caring, rehabilitation, and monitoring (OR 0.34, 95% CI 0.24-0.49); and less rationing of social care (OR 0.80, 95% CI 0.69-0.92). Neither leadership nor staffing levels, staff mix, or turnover was significantly related to quality of care. CONCLUSIONS: Work environment factors and organizational processes are vital to provide high quality of care. The improvement of work environment, support in handling work stressors, and reduction of rationing of nursing care might be intervention points to promote high quality of care in nursing homes. PMID- 26027722 TI - The "leap forward" in nursing home development in urban China: future policy directions. AB - In the past decade, the number of nursing beds in China has increased annually by an average of 10%, reaching 4.3 million in 2013. Although the State Council pushed for further increases to a ratio of 30 nursing home beds per 1000 persons by 2015, service utilization, quality assurance, and regulatory oversight are the inherent challenges in developing an equitable long-term care (LTC) system that can safeguard older persons' rights. We review and analyze both laws and policies in light of demographic and socioeconomic changes and advocate 3 policy directions for LTC development in China: allocating LTC resources with comprehensive eligibility criteria, with particular consideration of family needs; establishing viable quality standards for outcome-driven evaluation; and highlighting standardized monitoring mechanisms in both institutional and home LTC settings. PMID- 26027723 TI - Advance care planning in 21st century Australia: a systematic review and appraisal of online advance care directive templates against national framework criteria. AB - OBJECTIVES: A drive to promote advance care planning at a population level has led to a proliferation of online advance care directive (ACD) templates but little information to guide consumer choice. The current study aimed to appraise the quality of online ACD templates promoted for use in Australia. METHODS: A systematic review of online Australian ACD templates was conducted in February 2014. ACD templates were identified via Google searches, and quality was independently appraised by two reviewers against criteria from the 2011 report A National Frameworkfor Advance Care Directives. Bias either towards or against future medical treatment was assessed using criteria designed to limit subjectivity. RESULTS: Fourteen online ACD templates were included, all of which were available only in English. Templates developed by Southern Cross University best met the framework criteria. One ACD template was found to be biased against medical treatment--the Dying with Dignity Victoria Advance Healthcare Directive. CONCLUSIONS: More research is needed to understand how online resources can optimally elicit and record consumers' individual preferences for future care. Future iterations of the framework should address online availability and provide a simple rating system to inform choice and drive quality improvement. PMID- 26027724 TI - Parental knowledge in pediatric otolaryngology surgical consultations: A qualitative content analysis. AB - OBJECTIVE: To understand the source of parents' knowledge prior to and desire for further information following pediatric otolaryngology surgical consultations. METHODS: Mixed-methods approach using descriptive and qualitative content analysis of interviews with parents following otolaryngology consultations for children under the age of 6 years was performed. The children were being seen for either tonsillitis, obstructive sleep apnea, otitis media, and/or sinusitis/nasal obstruction. RESULTS: Forty-one parents completed a phone interview two weeks following their child's surgical consultation. The majority of parents indicated that their primary care physician referred their child for either: investigation of symptoms (50%), to have a specific discussion about surgery (27.5%), or because other treatment options were no longer working (20%). Many parents (56.5%) indicated that the Internet was their primary source of information prior to the appointment. Most parents (93%) wanted more information; majority of these parents noted that a technology-based mode of delivery of information available prior to the appointment would be most desirable. Desired information was most often regarding the surgical procedure, including risks and benefits, and symptoms of concern prior to surgery. CONCLUSION: This study provides a description of parental knowledge and information sources prior to their child's surgical consultation and continued desire for information. This information may lead to decreased knowledge barriers and increased communication to facilitate shared decision-making between the provider and parents. PMID- 26027725 TI - Open airway surgery for subglottic hemangioma in the era of propranolol: Is it still indicated? AB - OBJECTIVES: With the emergence of propranolol as the primary treatment for hemangiomas the indications for surgical intervention have been greatly reduced. There remains a role for surgical management in those patients who fail medical therapy, particularly for hemangiomas involving the airway. Detailed is our experience with subglottic hemangiomas, including three patients who failed propranolol treatment and were successfully treated with surgical excision and single stage laryngotracheoplasty (LTP) with thyroid ala graft. METHODS: Retrospective case series (level of evidence: 4). RESULTS: Six patients were treated with propranolol for subglottic hemangiomas over a 6 year period (2008 2014). Three patients responded to propranolol therapy and required no adjunctive surgical procedures. Three patients failed propranolol treatment, and required open resection of their subglottic hemangiomas and thyroid ala graft placement. Indications for resection were complete lack of response to propranolol in one patient, and initial response to propranolol with subsequent regrowth in the other two patients. All three patients were treated with submucosal extirpation of their hemangioma and single stage LTP; hemangioma was confirmed in all cases by positive GLUT-1 staining. All three surgical patients were successfully extubated post-operatively and none had hemangioma regrowth. CONCLUSIONS: Fifty percent of patients in our series did not have long-term response to propranolol for subglottic hemangioma, highlighting the importance of close follow-up. When identified early, subglottic hemangiomas refractory to propranolol treatment can be successfully addressed with single stage LTP and tracheotomy can be avoided. PMID- 26027726 TI - Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2. AB - The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling. PMID- 26027727 TI - Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2. AB - Successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus. Myeloid-derived suppressor cells (MDSCs), which are capable of inhibiting T-cell responses, are highly increased in the early stages of pregnancy. Although recent reports indicate a role for MDSCs in fetal-maternal tolerance, little is known about the expansion of MDSCs during pregnancy. In the present study, we demonstrated that the trophoblast cell line HTR8/SVneo could instruct peripheral CD14(+) myelomonocytic cells toward a novel subpopulation of MDSCs, denoted as CD14(+)HLA-DR(-/low) cells, with suppressive activity and increased expression of IDO1, ARG-1, and COX2. After interaction with HTR8/SVneo cells, CD14(+) myelomonocytic cells secrete high levels of CCL2, promoting the expression of signal transducer and activator of transcription 3. We utilized a neutralizing monoclonal antibody to reveal the prominent role of CCL2 in the induction of CD14(+)HLA-DR(-/low) MDSCs. In combination, the results of the present study support a novel role for the cross-talk between the trophoblast cell line HTR8/SVneo and maternal CD14(+) myelomonocytic cells in initiating MDSCs induction, prompting a tolerogenic immune response to ensure a successful pregnancy. PMID- 26027728 TI - Clinical and electromyographic assessment of facial nerve function after temporomandibular joint surgery. AB - The aim of this study was to evaluate the factors that may cause alterations in facial nerve function during temporomandibular joint (TMJ) surgeries. Forty-six patients were included (66 joints) between the years 2000 and 2007. Study patients were those undergoing various surgical procedures for the treatment of TMJ disorders. Patients who had made an incomplete recovery from a facial nerve injury resulting from a previous operation and patients who presented with facial palsy after a previous TMJ surgery were excluded. The facial nerve function of all patients was evaluated at different time intervals using a facial nerve grading system, motor unit action potentials of the frontalis and orbicularis oculi muscles, and a facial nerve latency test. Various degrees of facial nerve affliction were initially noticed in 71% of the study cases (47 of 66 joints). Statistical analyses (chi(2) goodness-of-fit) revealed that several factors could lead to facial nerve injury following TMJ surgery, including the design of the skin incision, prior surgeries, type of surgery, and duration of surgery. Facial nerve injury during TMJ surgery is multifactorial. Electromyographic studies are non-invasive and valuable diagnostic and prognostic tools for assessing facial nerve function. PMID- 26027729 TI - Validation of screening examinations of the ureteral orifices in dogs: Comparison of ultrasonography with dissection. AB - In dogs, ultrasonography is performed to locate the ureteral orifices in the urinary bladder, but reference values for their normal location using this technique are missing. In this study, the ureterovesical-vesicourethral and inter ureterovesical distances were determined in 20 freshly euthanized medium size dogs by detecting artificially produced ureteral jets in color-flow Doppler ultrasonography at two different bladder volumes, and comparing them to manual measurements in the dissected bladder. All distances determined by ultrasonography were in agreement with values found by dissection (P >= 0.100). With increasing bladder volume only the left ureterovesical-vesicourethral distance changed (P = 0.041). The right ureteral opening was more cranial than the left in 16 dogs. The inter-ureterovesical distances differed by gender (P = 0.016), but spay/neuter status had no influence (P >= 0.847). In conclusion, ultrasonography is a reliable modality for screening ureteral orifices in medium size dogs and agrees with anatomical findings. PMID- 26027730 TI - Action of an endo-beta-1,3(4)-glucanase on cellobiosyl unit structure in barley beta-1,3:1,4-glucan. AB - beta-1,3:1,4-Glucan is a major cell wall component accumulating in endosperm and young tissues in grasses. The mixed linkage glucan is a linear polysaccharide mainly consisting of cellotriosyl and cellotetraosyl units linked through single beta-1,3-glucosidic linkages, but it also contains minor structures such as cellobiosyl units. In this study, we examined the action of an endo-beta-1,3(4) glucanase from Trichoderma sp. on a minor structure in barley beta-1,3:1,4 glucan. To find the minor structure on which the endo-beta-1,3(4)-glucanase acts, we prepared oligosaccharides from barley beta-1,3:1,4-glucan by endo-beta-1,4 glucanase digestion followed by purification by gel permeation and paper chromatography. The endo-beta-1,3(4)-glucanase appeared to hydrolyze an oligosaccharide with degree of polymerization 5, designated C5-b. Based on matrix assisted laser desorption/ionization (MALDI) time-of-flight (ToF)/ToF-mass spectrometry (MS)/MS analysis, C5-b was identified as beta-Glc-1,3-beta-Glc-1,4 beta-Glc-1,3-beta-Glc-1,4-Glc including a cellobiosyl unit. The results indicate that a type of endo-beta-1,3(4)-glucanase acts on the cellobiosyl units of barley beta-1,3:1,4-glucan in an endo-manner. PMID- 26027731 TI - Conformational Plasticity of the POTRA 5 Domain in the Outer Membrane Protein Assembly Factor BamA. AB - BamA is the main component of the beta-barrel assembly machinery (BAM) that folds and inserts outer membrane proteins in Gram-negative bacteria. Crystal structures have suggested that this process involves conformational changes in the transmembrane beta-barrel of BamA that allow for lateral opening, as well as large overall rearrangements of its periplasmic POTRA domains. Here, we identify local dynamics of the BamA POTRA 5 domain by solution and solid-state nuclear magnetic resonance. The protein region undergoing conformational exchange is highly conserved and contains residues critical for interaction with BamD and correct beta-barrel assembly in vivo. We show that mutations known to affect the latter processes influence the conformational equilibrium, suggesting that the plasticity of POTRA 5 is related to its interaction with BamD and possibly to substrate binding. Taken together, a view emerges in which local protein plasticity may be critically involved in the different stages of outer membrane protein folding and insertion. PMID- 26027732 TI - Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor. AB - Discerning the structural building blocks of macromolecules is essential for understanding their folding and function. For a new generation of modified nucleic acid ligands (called slow off-rate modified aptamers or SOMAmers), we previously observed essential functions of hydrophobic aromatic side chains in the context of well-known nucleic acid motifs. Here we report a 2.45-A resolution crystal structure of a SOMAmer complexed with nerve growth factor that lacks any known nucleic acid motifs, instead adopting a configuration akin to a triangular prism. The SOMAmer utilizes extensive hydrophobic stacking interactions, non canonical base pairing and irregular purine glycosidic bond angles to adopt a completely non-helical, compact S-shaped structure. Aromatic side chains contribute to folding by creating an unprecedented intercalating zipper-like motif and a prominent hydrophobic core. The structure provides compelling rationale for potent inhibitory activity of the SOMAmer and adds entirely novel motifs to the repertoire of structural elements uniquely available to SOMAmers. PMID- 26027733 TI - Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin like Growth Factor Hybrid Receptors. AB - The homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor monomers also assemble as heterodimers, the primary ligand-binding sites of which each comprise the first leucine-rich repeat domain (L1) of one receptor type and an alpha-chain C-terminal segment (alphaCT) of the second receptor type. We present here crystal structures of IGF-I bound to such a hybrid primary binding site and of a ligand-free version of an IR alphaCT peptide bound to an IR L1 plus cysteine-rich domain construct (IR310.T). These structures, refined at 3.0-A resolution, prove congruent to respective existing structures of insulin-complexed IR310.T and the intact apo-IR ectodomain. As such, they provide key missing links in the emerging, but sparse, repertoire of structures defining the receptor family. PMID- 26027734 TI - Structural Basis for Modulation of Quality Control Fate in a Marginally Stable Protein. AB - The human von Hippel-Lindau (VHL) tumor suppressor is a marginally stable protein previously used as a model substrate of eukaryotic refolding and degradation pathways. When expressed in the absence of its cofactors, VHL cannot fold and is quickly degraded by the quality control machinery of the cell. We combined computational methods with in vivo experiments to examine the basis of the misfolding propensity of VHL. By expressing a set of randomly mutated VHL sequences in yeast, we discovered a more stable mutant form. Subsequent modeling suggested the mutation had caused a conformational change affecting cofactor and chaperone interaction, and this hypothesis was then confirmed by additional knockout and overexpression experiments targeting a yeast cofactor homolog. These findings offer a detailed structural basis for the modulation of quality control fate in a model misfolded protein and highlight burial mode modeling as a rapid means to detect functionally important conformational changes in marginally stable globular domains. PMID- 26027735 TI - Insights into Disease-Associated Mutations in the Human Proteome through Protein Structural Analysis. AB - Most known disease-associated mutations are missense mutations involving changes of amino acids of proteins encoded by their genes. Given the plethora of genetic studies, sequenced exomes, and new protein structures determined each year, it is appropriate to revisit the role that structure plays in providing insights into the molecular basis of disease-associated mutations. In that regard, a large scale structural analysis of 6,025 disease-associated mutations as well as 4,536 neutral variations for comparison was performed. While buried amino acids are common among the disease-associated mutations, as reported previously, more are statistically significantly enriched at observed or predicted functional sites. Interesting findings are that ligand-binding sites adjacent to protein-protein interfaces and residues involved in enzymatic function are especially vulnerable to disease-associated mutations. Finally, a compositional analysis of disease associated mutations in comparison with variants identified in the 1000 Genomes Project provides a structural rationalization of the most disease-associated residue types. PMID- 26027736 TI - A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling. AB - The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders. PMID- 26027737 TI - A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict. AB - A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto striosomal circuit is selectively active in and causally necessary for cost benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival. PMID- 26027738 TI - A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion. AB - Vertebrate cells have evolved elaborate cell-autonomous defense programs to monitor subcellular compartments for infection and to evoke counter-responses. These programs are activated by pathogen-associated pattern molecules and by various strategies intracellular pathogens employ to alter cellular microenvironments. Here, we show that, when uropathogenic E. coli (UPEC) infect bladder epithelial cells (BECs), they are targeted by autophagy but avoid degradation because of their capacity to neutralize lysosomal pH. This change is detected by mucolipin TRP channel 3 (TRPML3), a transient receptor potential cation channel localized to lysosomes. TRPML3 activation then spontaneously initiates lysosome exocytosis, resulting in expulsion of exosome-encased bacteria. These studies reveal a cellular default system for lysosome homeostasis that has been co-opted by the autonomous defense program to clear recalcitrant pathogens. PMID- 26027739 TI - Functional Anatomy of the Human Microprocessor. AB - MicroRNA (miRNA) maturation is initiated by Microprocessor composed of RNase III DROSHA and its cofactor DGCR8, whose fidelity is critical for generation of functional miRNAs. To understand how Microprocessor recognizes pri-miRNAs, we here reconstitute human Microprocessor with purified recombinant proteins. We find that Microprocessor is an ~364 kDa heterotrimeric complex of one DROSHA and two DGCR8 molecules. Together with a 23-amino acid peptide from DGCR8, DROSHA constitutes a minimal functional core. DROSHA serves as a "ruler" by measuring 11 bp from the basal ssRNA-dsRNA junction. DGCR8 interacts with the stem and apical elements through its dsRNA-binding domains and RNA-binding heme domain, respectively, allowing efficient and accurate processing. DROSHA and DGCR8, respectively, recognize the basal UG and apical UGU motifs, which ensure proper orientation of the complex. These findings clarify controversies over the action mechanism of DROSHA and allow us to build a general model for pri-miRNA processing. PMID- 26027740 TI - Emotion regulation before and after transcranial magnetic stimulation in obsessive compulsive disorder. AB - BACKGROUND: Impaired emotion regulation may underlie exaggerated emotional reactivity in patients with obsessive compulsive disorder (OCD), yet instructed emotion regulation has never been studied in the disorder. METHOD: This study aimed to assess the neural correlates of emotion processing and regulation in 43 medication-free OCD patients and 38 matched healthy controls, and additionally test if these can be modulated by stimulatory (patients) and inhibitory (controls) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (dlPFC). Participants performed an emotion regulation task during functional magnetic resonance imaging before and after a single session of randomly assigned real or sham rTMS. Effect of group and rTMS were assessed on self-reported distress ratings and brain activity in frontal limbic regions of interest. RESULTS: Patients had higher distress ratings than controls during emotion provocation, but similar rates of distress reduction after voluntary emotion regulation. OCD patients compared with controls showed altered amygdala responsiveness during symptom provocation and diminished left dlPFC activity and frontal-amygdala connectivity during emotion regulation. Real v. sham dlPFC stimulation differentially modulated frontal-amygdala connectivity during emotion regulation in OCD patients. CONCLUSIONS: We propose that the increased emotional reactivity in OCD may be due to a deficit in emotion regulation caused by a failure of cognitive control exerted by the dorsal frontal cortex. Modulatory rTMS over the left dlPFC may influence automatic emotion regulation capabilities by influencing frontal-limbic connectivity. PMID- 26027741 TI - Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: Toward targeted personalized therapy. AB - Colorectal cancer (CRC) represents one of the most common malignancies and is major cause of cancer-related deaths worldwide. A great improvement in response rate and patient's survival was recently achieved through the introduction of new targeted agents including the anti-EGFR monoclonal antibodies cetuximab and panitumumab, the anti-angiogenic drugs bevacizumab and aflibercept, as well as the multi-kinase inhibitor regorafenib, in combination with standard fluoropyrimidines-based chemotherapeutic regimens. Intrinsic and acquired chemoresistance continue to be a major hindrance toward curative therapy. To overcome the obstacle of the currently unpredictable inter-individual variability in the therapy outcome, concentrated research efforts have been focused on elucidating the contribution of genetic variants predictive of pharmacoresistance in CRC. The occurrence of tumor somatic mutations in the RAS/RAF/MAPK and PI3K/PTEN/AKT pathways remains the main challenge for CRC treatment with the new biological agents. It has been recently proposed to consider a quadruple negative profile for CRC, based on the status of KRAS exon 2, BRAF-p.V600E, PI3KCA-exon 9 and PTEN, as tumor markers of sensitivity to anti-EGFR treatment. However, in the last years, great efforts have been devoted to address germline genetic profiles of pharmacoresistance. Heritable genetic variants in the ABC and SLC transport pathways; in the CYP450, GST, and UGT-mediated phase I and II metabolism; in the folate metabolic pathway; as well as in the EGF and VEGF signaling pathways, have been associated with a distinct tumor sensitivity phenotype in CRC patients treated with fluoropyrimidines combined with either irinotecan, oxaliplatin or targeted biological agents. More recently, computation of clinical pharmacogenetic algorithms, combining multiple host polymorphisms with clinico demographic features, appeared to be a more reliable strategy to test a complex phenomenon as tumor response to therapy. The final goal of the pharmacogenomics research in the domain of pharmacoresistance in CRC should be the definition of integrated somatic and germline genetic profiles of both intrinsic and acquired resistance. The aim of the present review is to provide a comprehensive update on the most important findings regarding the research of pharmacogenomics markers in the field of CRC treatment that could be integrated in clinical practice in order to accomplish an efficacious personalized treatment. PMID- 26027743 TI - Design of immunoprobes for electrochemical multiplexed tumor marker detection. AB - Many approaches have been developed for simultaneous detection of multiple tumor markers. Among these approaches, the electrochemical immunoassay has the advantage of high sensitivity and specificity and could be easily expanded into multiplex detection platform. For the simultaneous multianalyte electrochemical immunosensor, performance is closely related with the characteristics of the immunoprobes and substrate. In order to construct a multilabeled immunoprobe platform, the most important issue is how to discriminate each signal for each analyte from the multiple antigen-antibody reactions. Currently, enzyme-based, noble metal nanomaterials, carbonmaterials and polymer-based nanomaterial immunoprobes have been used for dual- or three-analyte detections. However, there are still some challenges in developing sensitive method to detect three or more tumor markers owing to the lack of redox-active species that can produce three or more distinctive peaks. Additionally, for the immunosensing substrate, good conductivity, high specific surface area and good biocompatibility are further necessities. PMID- 26027742 TI - Nontoxic singlet oxygen generator as a therapeutic candidate for treating tauopathies. AB - Methylene blue (MB) inhibits the aggregation of tau, a main constituent of neurofibrillary tangles. However, MB's mode of action in vivo is not fully understood. MB treatment reduced the amount of sarkosyl-insoluble tau in Drosophila that express human wild-type tau. MB concurrently ameliorated the climbing deficits of transgenic tau flies to a limited extent and diminished the climbing activity of wild-type flies. MB also decreased the survival rate of wild type flies. Based on its photosensitive efficacies, we surmised that singlet oxygen generated through MB under light might contribute to both the beneficial and toxic effects of MB in vivo. We identified rose bengal (RB) that suppressed tau accumulation and ameliorated the behavioral deficits to a lesser extent than MB. Unlike MB, RB did not reduce the survival rate of flies. Our findings indicate that singlet oxygen generators with little toxicity may be suitable drug candidates for treating tauopathies. PMID- 26027744 TI - Emerging drugs for the treatment of pruritus. AB - INTRODUCTION: Chronic pruritus occurs in 13% of the general population without age limitation. There is a high unmet need here as effective treatment options are still missing. AREAS COVERED: Clinical and experimental research during the past decade identified new mechanisms in chronic pruritus allowing the definition of a broad range of specific treatment targets for the first time. This refers specifically to inflammatory pruritic dermatoses, uremic and cholestatic pruritus. Targets identified are, for example, receptors for substance P, IL-31 and nerve growth factor. Search was made for current studies addressing these diseases and targets in the available clinical registration databases. EXPERT OPINION: The current pharmacological development is very promising especially for patients suffering from chronic pruritus in inflammatory dermatoses, chronic kidney diseases and hepatobiliary diseases. However, there are still several pruritic diseases in which neither mediators nor specific target populations (e.g., children) nor stages of diseases, have been identified; however, it can be assumed that within the next 10 years, major changes in the possibilities of antipruritic treatment will take place. PMID- 26027745 TI - Avascular necrosis in a patient with hip pain. AB - The patient was a 64-year-old man who was referred to a physical therapist 3 weeks following a right L3 hemilaminectomy and an L3-4 facetectomy. At the time of the initial evaluation, the patient was ambulating with a rolling walker due to low back and anterolateral right hip pain, as well as a giving-way sensation of the right hip with weight bearing. The patient was referred to his surgeon, where radiographs revealed collapse/dissolution of the femoral head that was consistent with avascular necrosis. PMID- 26027748 TI - Kiwifruit Flower Odor Perception and Recognition by Honey Bees, Apis mellifera. AB - Volatile organic compounds (VOCs) from male and female kiwifruit (Actinidia deliciosa 'Hayward') flowers were collected by dynamic headspace sampling. Honey bee (Apis mellifera) perception of the flower VOCs was tested using gas chromatography coupled to electroantennogram detection. Honey bees consistently responded to six compounds present in the headspace of female kiwifruit flowers and five compounds in the headspace of male flowers. Analysis of the floral volatiles by gas chromatography-mass spectrometry and microscale chemical derivatization showed the compounds to be nonanal, 2-phenylethanol, 4 oxoisophorone, (3E,6E)-alpha-farnesene, (6Z,9Z)-heptadecadiene, and (8Z) heptadecene. Bees were then trained via olfactory conditioning of the proboscis extension response (PER) to synthetic mixtures of these compounds using the ratios present in each flower type. Honey bees trained to the synthetic mixtures showed a high response to the natural floral extracts, indicating that these may be the key compounds for honey bee perception of kiwifruit flower odor. PMID- 26027749 TI - The power of power wheelchairs: Mobility choices of community-dwelling, older adults. AB - BACKGROUND: Power wheelchairs are purported to have a positive effect on health, occupation, and quality of life. However, there is limited knowledge about what factors shape power wheelchair use decisions. AIMS/OBJECTIVES: A study was undertaken to understand the mobility choices of community-dwelling, power wheelchair users. METHODS: A series of semi-structured qualitative interviews was conducted with 13 older adult power wheelchair users. Participants were interviewed at enrollment and four months later. Data analysis was informed by Bourdieu's theoretical constructs of habitus, capital, and field. RESULTS: Three main styles of power wheelchair use were identified: reluctant use, strategic use, and essential use, and each type is illustrated using an aggregate case study. CONCLUSION/SIGNIFICANCE: These findings highlight the need to alter the power relationship that exists between prescribers and device users and to effect policy changes that enable people with physical impairments to make as wide a range of mobility choices as possible. PMID- 26027747 TI - Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone. AB - Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms. PMID- 26027750 TI - Resilient High Catalytic Performance of Platinum Nanocatalysts with Porous Graphene Envelope. AB - Despite the innumerable developments of nanosized and well dispersed noble metal catalysts, the degradation of metal nanoparticle catalysts has proven to be a significant obstacle for the commercialization of the hydrogen fuel cell. Here, the formation of Pt nanoparticle catalysts with a porous graphene envelope has been achieved using a single step low temperature vaporization process. While these Pt-Gr core-shell nanoparticles possess superior resilience to degradation, it comes at the cost of degraded overall catalyst efficacy. However, it is possible to combat this lower overall performance through inclusion of low concentrations of nitrogen precursor in the initial stage of single-step synthesis, inhibiting the formation of complete graphene shells, as verified by atomic resolution aberration-corrected transmission electron microscopy (AC-TEM) imaging. The resultant porous graphene encapsulated Pt catalysts are found to have both the high peak performance of the bare Pt nanoparticle catalysts and the increased resilience of the fully shielded Pt-Gr core-shells, with the optimal N doped Pt-Gr yielding a peak efficiency of 87% compared to bare Pt, and maintaining 90% of its catalytic activity after extended potential cycling. The nitrogen treated Pt-Gr core-shells thus act as an effective substitute catalyst for conventional bare Pt nanoparticles, maintaining their catalytic performance over prolonged use. PMID- 26027751 TI - Tuning Localized Surface Plasmon Resonance in Scanning Near-Field Optical Microscopy Probes. AB - A reproducible route for tuning localized surface plasmon resonance in scattering type near-field optical microscopy probes is presented. The method is based on the production of a focused-ion-beam milled single groove near the apex of electrochemically etched gold tips. Electron energy-loss spectroscopy and scanning transmission electron microscopy are employed to obtain highly spatially and spectroscopically resolved maps of the milled probes, revealing localized surface plasmon resonance at visible and near-infrared wavelengths. By changing the distance L between the groove and the probe apex, the localized surface plasmon resonance energy can be fine-tuned at a desired absorption channel. Tip enhanced Raman spectroscopy is applied as a test platform, and the results prove the reliability of the method to produce efficient scattering type near-field optical microscopy probes. PMID- 26027752 TI - Coefficients of impairment in deforming spastic paresis. AB - This position paper introduces an assessment method using staged calculation of coefficients of impairment in spastic paresis, with its rationale and proposed use. The syndrome of deforming spastic paresis superimposes two disorders around each joint: a neural disorder comprising stretch-sensitive paresis in agonists and antagonist muscle overactivity, and a muscle disorder ("spastic myopathy") combining shortening and loss of extensibility in antagonists. Antagonist muscle overactivity includes spastic cocontraction (misdirected descending command), spastic dystonia (tonic involuntary muscle activation, at rest) and spasticity (increased velocity-dependent reflexes to phasic stretch, at rest). This understanding of various types of antagonist resistance as the key limiting factors in paretic movements prompts a stepwise, quantified, clinical assessment of antagonist resistances, elaborating on the previously developed Tardieu Scale. Step 1 quantifies limb function (e.g. ambulation speed in lower limb, Modified Frenchay Scale in upper limb). The following four steps evaluate various angles X of antagonist resistance, in degrees all measured from 0 degrees , position of minimal stretch of the tested antagonist. Step 2 rates the functional muscle length, termed XV1 (V1, slowest stretch velocity possible), evaluated as the angle of arrest upon slow and strong passive muscle stretch. XV1 is appreciated with respect to the expected normal passive amplitude, XN, and reflects combined muscle contracture and residual spastic dystonia. Step 3 determines the angle of catch upon fast stretch, termed XV3 (V3, fastest stretch velocity possible), reflecting spasticity. Step 4 measures the maximal active range of motion against the antagonist, termed XA, reflecting agonist capacity to overcome passive (stiffness) and active (spastic cocontraction) antagonist resistances over a single movement. Finally, Step 5 rates the residual active amplitude after 15 seconds of maximal amplitude rapid alternating movements, XA15. Amplitude decrement from XA to XA15 reflects fatigability. Coefficients of shortening (XN XV1)/XN, spasticity (XV1-XV3)/XV1, weakness (XV1-XA)/XV1 and fatigability (XA XA15)/XA are derived. A high (e.g., >10%) coefficient of shortening prompts aggressive treatment of the muscle disorder--e.g., by stretch programs, such as prolonged stretch postures -, while high coefficients of weakness or fatigability prompt addressing the neural motor command disorder, e.g. using training programs such as repeated alternating movements of maximal amplitude. PMID- 26027753 TI - Climate phase drives canopy condition in a large semi-arid floodplain forest. AB - To maintain and restore the ecological integrity of floodplains, allocating water for environmental benefits (i.e. environmental water) is widely practised globally. To efficiently manage the always limited environmental water, there is pressing need to advance our understanding of the ecological response to long term climate cycles as evidence grows of intensification of extreme climatic events such as severe drought and heat waves. In this study, we assessed the alleviating effects of artificial flooding on drought impact using the canopy condition of the iconic river red gum forests in Australia's Murray Darling Basin (MDB). To achieve this, we jointly analysed spatial-temporal patterns of NDVI response and drought conditions for the period of 2000-2013, during which the MDB experienced an extreme dry-wet cycle. Our results indicated that while NDVI derived canopy condition was better at the sites receiving environmental water during the dry phases, both watered and unwatered sites displayed great similarity in seasonality and trends. Furthermore, we did not find any significant difference in NDVI response of the canopy between the sites to suggest significant differences in ecosystem stability and resilience, with watered and unwatered sites showing similar responses to the extreme wet conditions as the drought broke. The highly significant relationship between long term drought index and NDVI anomaly suggest that climate phase is the main forcing driving canopy condition in semi-arid floodplain forests. PMID- 26027754 TI - Re-establishing an ecological discourse in the policy debate over how to value ecosystems and biodiversity. AB - In this paper we explore the discourses of ecology, environmental economics, new environmental pragmatism and social ecological economics as they relate to the value of ecosystems and biodiversity. Conceptualizing biodiversity and ecosystems as goods and services that can be represented by monetary values in policy processes is an economic discourse being increasingly championed by ecologists and conservation biologists. The latter promote a new environmental pragmatism internationally as hardwiring biodiversity and ecosystems services into finance. The approach adopts a narrow instrumentalism, denies value pluralism and incommensurability, and downplays the role of scientific knowledge. Re establishing an ecological discourse in biodiversity policy implies a crucial role for biophysical indicators as independent policy targets, exemplified in this paper by the Nature Index for Norway. Yet, there is a recognisable need to go beyond a traditional ecological approach to one recognising the interconnections of social, ecological and economic problems. This requires reviving and relating to a range of alternative ecologically informed discourses, including an ecofeminist perspective, in order to transform the increasingly dominant and destructive relationship of humans separated from and domineering over Nature. PMID- 26027755 TI - Hunting and hallucinogens: The use psychoactive and other plants to improve the hunting ability of dogs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cultures throughout the world give plants to their dogs in order to improve hunting success. These practices are best developed in lowland Ecuador and Peru. There is no experimental evidence for the efficacy of these practices nor critical reviews that consider possible pharmacological effects on dogs based on the chemistry of the ethnoverterinary plants. AIM: This review has three specific aims: (1) determine what plants the Ecuadorian Shuar and Quichua give to dogs to improve their hunting abilities, (2) determine what plants other cultures give to dogs for the same purpose, and (3) assess the possible pharmacological basis for the use of these plants, particularly the psychoactive ones. METHODS: We gathered Shuar (Province of Morona-Santiago) and Quichua (Napo and Orellano Provinces) data from our previous publications and field notes. All specimens were vouchered and deposited in QCNE with duplicates sent to NY and MO. Data presented from other cultures derived from published studies on ethnoveterinary medicine. Species names were updated, when necessary, and family assignments follow APG III (Angiosperm Phylogeny Group, 2009. An update of the Angiosperm Phylogeny Group classification for the orders and families of flowering plants: APG III. Bot. J. Linn. Soc. 161, 105 121). Chemical data were found using PubMed and SciFinder. RESULTS: The Shuar and Quichua of Ecuador use at least 22 species for ethnoveterinary purposes, including all but one of their principal hallucinogens. Literature surveys identified 43 species used in other cultures to improve hunting ability. No published studies have examined the pharmacological active of these plant species in dogs. We, thus, combined phytochemical data with the ethnobotanical reports of each plant and then classified each species into a likely pharmacological category: depuratives/deodorant, olfactory sensitizer, ophthalmic, or psychoactive. CONCLUSIONS: The use of psychoactive substances to improve a dog's hunting ability seems counterintuitive, yet its prevalence suggests that it is both adaptive and that it has an underlying pharmacological explanation. We hypothesize that hallucinogenic plants alter perception in hunting dogs by diminishing extraneous signals and by enhancing sensory perception (most likely olfaction) that is directly involved in the detection and capture of game. If this is true, plant substances also might enhance the ability of dogs to detect explosives, drugs, human remains, or other targets for which they are valued. PMID- 26027756 TI - Pharmacovigilance of herbal medicines in Africa: Questionnaire study. AB - In order to describe and evaluate Herbal Medicine (HM) pharmacovigilance in African countries who are members of the WHO International Programme for Drug Monitoring a survey questionnaire was sent to the national centres and national drug regulatory agencies of these countries. Data collection was carried out from October 1st to 31st December, 2014. Among the total of 39 African countries, 34 (87.2%) answered the questionnaire and 25 (64.1%) accepted to share their data in this publication. Spontaneous adverse reaction reporting for HM is voluntary in 7 (43.7%) countries. HM pharmacovigilance programmes covered suspected adverse HM reactions in 14 (87.5%) countries; HM information in 7 (43.7%) countries; HM dependence or abuse in 6 (37.5%) countries; medication errors in 5 (31.2%) countries; falsification and adulteration in 2 (each 12.5%) countries and HM-drug interactions in 1 (6.3%) country. Groups in countries encouraged to submit herbal reports were pharmacists and physicians (both n=15); nurses (n=13); herbal therapists (n=12); patients (n=11) and local manufacturers (n=8). The number of herbal reports received by most countries was very low or even insignificant. VigiFlow is used by 10 countries. Information from pharmacovigilance activities is disseminated using many means. Only five countries have regulatory status and quality control of their HM products. The participants identified a need for HM regulation, technical and training assistance, and funding as being major challenges to HM pharmacovigilance in countries. Particular attention to the development of pharmacovigilance of HM is required in Africa. PMID- 26027757 TI - Protein tyrosine phosphatase 1B inhibitory activity of alkaloids from Rhizoma Coptidis and their molecular docking studies. AB - ETHNOPHARMACOLOGIC RELEVANCE: Rhizoma Coptidis (the rhizome of Coptis chinensis Franch) has commonly been used for treatment of diabetes mellitus in traditional Chinese medicine due to its blood sugar-lowering properties and therapeutic benefits which highly related to the alkaloids therein. However, a limited number of studies focused on the Coptis alkaloids other than berberine. MATERIALS AND METHODS: In the present study, we investigated the anti-diabetic potential of Coptis alkaloids, including berberine (1), epiberberine (2), magnoflorine (3), and coptisine (4), by evaluating the ability of these compounds to inhibit protein tyrosine phosphatase 1B (PTP1B), and ONOO(-)-mediated protein tyrosine nitration. We scrutinized the potentials of Coptis alkaloids as PTP1B inhibitors via enzyme kinetics and molecular docking simulation. RESULTS: The Coptis alkaloids 1-4 exhibited remarkable inhibitory activities against PTP1B with the IC50 values of 16.43, 24.19, 28.14, and 51.04 MUM, respectively, when compared to the positive control ursolic acid. These alkaloids also suppressed ONOO(-) mediated tyrosine nitration effectively in a dose dependent manner. In addition, our kinetic study using the Lineweaver-Burk and Dixon plots revealed that 1 and 2 showed a mixed-type inhibition against PTP1B, while 3 and 4 noncompetitively inhibited PTP1B. Moreover, molecular docking simulation of these compounds demonstrated negative binding energies (Autodock 4.0=-6.7 to -7.8 kcal/mol; Fred 2.0=-59.4 to -68.2 kcal/mol) and a high proximity to PTP1B residues, including Phe182 and Asp181 in the WPD loop, Cys215 in the active sites and Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221 and Gln262 in the pocket site, indicating a higher affinity and tighter binding capacity of these alkaloids for the active site of the enzyme. CONCLUSION: Our results clearly indicate the promising anti-diabetic potential of Coptis alkaloids as inhibitors on PTP1B as well as suppressors of ONOO(-)-mediated protein tyrosine nitration, and thus hold promise as therapeutic agents for the treatment of diabetes and related disease. PMID- 26027758 TI - Norwood Stage I Palliation in Patients Less Than or Equal to 2.5 kg: Outcomes and Risk Analysis. AB - BACKGROUND: Hospital mortality of stage I palliation in patients with hypoplastic left heart syndrome and weighing less than or equal to 2.5 kg remains high. We aimed to (1) assess outcomes in this specific population in a dedicated neonatal cardiac program and (2) determine factors associated with poor outcomes. METHODS: We retrospectively analyzed outcomes in patients weighing less than or equal to 2.5 kg who underwent a stage I palliation at our institution (2006 to 2014) and performed a risk analysis. Twenty-eight patients were included. Mean follow-up was 26.2 +/- 27 months. RESULTS: Median weight at surgery was 2.29 kg (range, 1.3 to 2.5 kg). A Sano conduit as opposed to a Blalock-Taussig shunt was placed in 22 patients (78.6%). Timing of surgery was delayed in 5 patients (18%) because of prematurity or extracardiac condition. Coronary fistulae, ventricular dysfunction, and greater than moderate atrioventricular valve regurgitation were present in 2 patients each. Hospital mortality rate was 10.7% (3 of 28 patients). One patient (3.7%) required an early, unplanned reintervention, and 1 patient underwent a late arch revision at the time of stage II. Late mortality or heart transplant rate was 8% (2 of 25 patients). Stage II and stage III procedures were performed in 19 (76%) and 8 (32%) survivors. Survival after stage 2 palliation was 100% (19 of 19 patients) and 87% after Fontan (7 of 8 patients). On univariate analysis, low birthweight (p = 0.03), delayed surgery (p = 0.05), preoperative comorbidities (p = 0.03), postoperative extracorporeal membrane oxygenation (p = 0.04), neurologic complications (p = 0.03), and dialysis (p = 0.04) were associated with higher hospital mortality. CONCLUSIONS: Stage-I palliation in patients with hypoplastic left heart syndrome weighing less than or equal to 2.5 kg can be achieved with good early and late outcomes. Very low birth weight, delayed surgery, comorbidities, and severe postoperative complications were associated with higher hospital mortality. PMID- 26027759 TI - Hemato-immunological and biochemical parameters of silver catfish Rhamdia quelen immunized with live theronts of Ichthyophthirius multifiliis. AB - This study investigated the immunization by intraperitoneal injection (i.p.) (assay I) and immersion bath (assay II) with live theronts of Ichthyophthirius multifillis in Rhamdia quelen and its influence on the hemato-immunological and biochemical parameters. Fish were divided in control (non immunized no challenged); non immunized and challenged with 12,000 theronts/fish; non immunized and challenged with 22,000 theronts/fish; immunized and challenged with 12,000 theronts/fish; immunized and challenged with 22,000 theronts/fish. Six days after challenge, either in the assay I or in the assay II the prevalence of I. multifillis in the gills was higher in non immunized fish (33.33% and 27.77%, respectively). In the assay I showed higher numbers of thrombocytes, leukocytes, lymphocytes, neutrophils and monocytes 20 days after injection and lower numbers after challenge. The immunoglobulin values were higher in fish non immunized. Fish immunized by immersion bath (assay II) showed greater values of catalase (CAT) in the liver (1245.49 U/mgprt) when compared to i.p. (198.79 U/mgprt). The levels of CAT in the liver of fish from the assay II were greater (1738.47 U/mgprt) 14 days after immunization than that observed 21 days after (1114.26 U/mgprt). The vaccination by i.p method showed influence on the hematological parameters. On the other hand, the immersion bath vaccination showed greater influence on the catalase activity in the liver. The results showed that new parameters like total protein, immunoglobulin and antioxidant enzymes could be considered in evaluating the host response to infection. PMID- 26027760 TI - [The medical empathy, is it born or is it made? Evolution of the empathy in medical students]. AB - OBJECTIVE: Empathy is one of the basic skills in medicine that promotes better doctor-patient relationship, best professional competition and less professional stress. We don't found studies in our area. This study aims to measure the degree of empathy in medical students in our area and associated factors. DESIGN: Cross sectional study. LOCATION: Faculty of Medicine, University of Lleida (Spain). PARTICIPANTS: Pass in class of 1st, 3rd and second cycle of Medicine, at 191 students. 173 students (90%) completed the questionnaire. MAIN MEASUREMENTS: TECA questionnaire to measure general empathy with 4 subscales (empathic understanding, perspective taking, empathic happiness and empathic stress), and a sociodemographic questionnaire. RESULTS: We found a progression in empathy during medical courses. Women have greater empathy but also increased empathic stress. Men have less general empathy, less progression of empathy and less emphatic stress. Students that show a preference to House TV movie have less empathy and those with family doctors. Voluntary students have greater empathy and those who have had a sick friend. We don't have found relationship between empathy and preferred specialty. CONCLUSIONS: There are several variables that are related to empathy in medical students: Women, advanced courses, experiences close to serious illnesses and those involved in voluntary activities. PMID- 26027761 TI - [Information needs of the health and diseases in users of healthcare services in Primary Care at Salamanca, Spain]. AB - OBJECTIVE: To learn, interpret and understand the information needs of health and disease in users of the healthcare services of the urban Primary Care of Salamanca. DESIGN: Qualitative research corresponding an exploratory qualitative/structural perspective. LOCATION: Primary Care. Urban area, Salamanca in 2007. PARTICIPANTS: Ten discussion groups, 2 composed of members of health related associations and 8 primary care users, involved a total of 83 people. The structural variables considered are: gender, age, educational level and membership or not associations. METHOD: Generate information to achieve information saturation in the discussion groups. Upon obtaining their informed consent, all subjects in the study participated in videotaped conversations, which were transcribed verbatim. Four researchers categorized the content, intentionality of discourse and developed the concept map. After categorization, triangulation and coding, content obtained was analysed with the NudistQ6 program. RESULTS: Informative content suggest four information needs: health and prevention, early diagnosis, first aid and disease. Different intentions (information needs, watching, claim and improvement) and needs profiles are detected as structural variables. Major information needs are relate to diagnosis, prognosis and therapeutic options. There is agreement between the groups that the information transmitted to the patient must be intelligible, updated and coordinated among the different professionals and care levels. CONCLUSIONS: Participants require information of a clinical nature to exercise their right to autonomy translating tendency to empower users as part of the social change. PMID- 26027762 TI - Multi-institutional external validation of urinary TWIST1 and NID2 methylation as a diagnostic test for bladder cancer. AB - OBJECTIVES: We previously reported a clinical trial in which we were unable to replicate the excellent diagnostic metrics produced in the developmental study of the TWIST1 and NID2 gene methylation assay. In this expanded trial with subjects enrolled from another institution, we reexamine the diagnostic capabilities of the test to externally validate our previous study. MATERIALS AND METHODS: TWIST1 and NID2 gene methylation was assessed in DNA isolated from the urine of subjects at risk of bladder cancer undergoing cystoscopy for hematuria or bladder cancer surveillance. The diagnostic gold standard was cystoscopy. Two thresholds of TWIST1 and NID2 gene methylation were used for determining test result positivity, those published by Renard et al. and Abern et al. The sensitivity, specificity, positive and negative predictive values, diagnostic likelihood ratios, and receiver operating characteristic curves were calculated for each gene, as well as their combination. In all, 3 methods were used to combine TWIST1 and NID2 into a single composite test: (1) believe-the-positive decision rule-if either gene is methylated the test result is positive, which maximizes test sensitivity; (2) believe-the-negative decision rule-if either gene is not methylated the test result is negative, which maximizes test specificity; and (3) a likelihood-based logistic regression model approach that balances sensitivity and specificity. Clinical utility was determined using a decision curve analysis. RESULTS: A total of 209 subjects were evaluated: 40% for hematuria and 60% for bladder cancer surveillance. Approximately 75% were male, most of the prior cancers being low-grade Ta. Using cystoscopy as the gold standard, areas under the curve were 0.67 for TWIST1, 0.64 for NID2, and 0.66 for combined TWIST1 and NID2. Decision rule results revealed optimization of sensitivity at 67% using Renard thresholds and specificity using the Abern thresholds at 69%. We found improved sensitivity (78%) in current smokers. Decision curve analyses revealed that the methylation assay provided only a modest benefit even at high probabilities of missed cancer. CONCLUSION: A urine DNA test measuring TWIST1 and NID2 methylation was externally examined with a larger cohort and its results continue to be poor. These 2 biomarkers are unlikely to replace cystoscopy, but they may be worthy of study in active smokers. PMID- 26027763 TI - Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer. AB - OBJECTIVES: Docetaxel is used as the first-line chemotherapy for castration resistant prostate cancer (CRPC), but docetaxel resistance occurs in part owing to induction of P-glycoprotein (P-gp) encoded by multidrug resistance protein 1 (MDR1) gene. A recently developed taxane-cabazitaxel-has poor affinity for P-gp and is thereby effective in docetaxel-resistant CRPC. It has been recently demonstrated that exosomes in the body fluids could serve as a diagnostic marker because they contain proteins and RNAs specific to the cells from which they are derived. In this study, we aimed to investigate if P-gp in blood exosomes could be a marker to diagnose docetaxel resistance and select a taxoid for patients with CRPC. METHODS AND MATERIALS: Exosomes were isolated by differential centrifugation from docetaxel-resistant prostate cancer (PC-3) cells (PC-3R) and their parental PC-3 cells and from the serum of patients. Silencing of P-gp was performed by small interfering RNA transfection. Protein expression was examined by Western blot analysis. Viability of cells treated with docetaxel or cabazitaxel was determined by water soluble tetrazolium salt (WST) assay. RESULTS: The level of P-gp was higher in exosomes as well as cell lysates from PC 3R cells than in those from PC-3 cells. Cabazitaxel effectively killed PC-3R cells, and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel. The P-gp level in blood exosomes was relatively higher in clinically docetaxel-resistant patients than in therapy-naive patients. CONCLUSIONS: Our results suggest that detection of P-gp in blood exosomes, which is involved in resistance to docetaxel but not to cabazitaxel, could be useful to diagnose docetaxel resistance and select an appropriate taxoid for patients with CRPC-docetaxel or cabazitaxel. PMID- 26027764 TI - Comparison of outcomes between ultrasonography and cystoscopy in the surveillance of patients with initially diagnosed TaG1-2 bladder cancers: A matched-pair analysis. AB - PURPOSE: To examine the clinical outcomes of regular use of ultrasonography when compared with those of cystoscopy in the follow-up of patients with TaG1-2 bladder tumors. PATIENTS AND METHODS: Between 1990 and 2012, 197 patients with TaG1-2 bladder tumors from a retrospective 2-institution cohort were included. We assessed clinical outcomes in 83 patients followed up by ultrasonography, matched for propensity score calculated from clinicopathological variables including age, gender, tumor multiplicity, size, grade, postoperative immediate chemoinstillation, and adjuvant intravesical treatment. RESULTS: Among the 166 patients identified using the one-to-one propensity score analysis, the 5- and 10 year recurrence-free survival rates were both 63.3% in the cystoscopy group and 69.1% and 58.4%, respectively, in the ultrasonography group (P = 0.762). A total of 54 patients experienced disease recurrence, and 18 patients acquired progressive disease such as tumor grade 3, pT1 tumors, and the appearance of concurrent carcinoma in situ. There were no significant differences in the characteristics of recurrent tumors between both the groups, whereas time to first recurrence in the cystoscopy group was significantly shorter than that in the ultrasonography group (P = 0.021). In a subgroup analysis using 111 patients without adjuvant intravesical treatments, the 5- and 10-year recurrence-free survival rates were both 56.9% in the cystoscopy group and 71.9% and 60.3%, respectively, in the ultrasonography group (P = 0.282). CONCLUSIONS: This retrospective study suggests that ultrasonography may be one of the follow-up substitutes when considering the management of low-risk bladder tumors such as TaG1-2 bladder tumors. PMID- 26027765 TI - Imaging patterns of fatty liver in pediatric patients. AB - Fatty liver can present as focal, diffuse, heterogeneous, and multinodular forms. Being familiar with various patterns of steatosis can enable correct diagnosis. In patients with equivocal findings on ultrasonography, magnetic resonance imaging can be used as a problem solving tool. New techniques are promising for diagnosis and follow-up. We review imaging patterns of steatosis and new quantitative methods such as proton density fat fraction and magnetic resonance elastography for diagnosis of nonalcoholic fatty liver disease in children. PMID- 26027767 TI - Using 3D printed models for planning and guidance during endovascular intervention: a technical advance. AB - Three-dimensional (3D) printing applications in medicine have been limited due to high cost and technical difficulty of creating 3D printed objects. It is not known whether patient-specific, hollow, small-caliber vascular models can be manufactured with 3D printing, and used for small vessel endoluminal testing of devices. Manufacture of anatomically accurate, patient-specific, small-caliber arterial models was attempted using data from a patient's CT scan, free open source software, and low-cost Internet 3D printing services. Prior to endovascular treatment of a patient with multiple splenic artery aneurysms, a 3D printed model was used preoperatively to test catheter equipment and practice the procedure. A second model was used intraoperatively as a reference. Full-scale plastic models were successfully produced. Testing determined the optimal puncture site for catheter positioning. A guide catheter, base catheter, and microcatheter combination selected during testing was used intraoperatively with success, and the need for repeat angiograms to optimize image orientation was minimized. A difficult and unconventional procedure was successful in treating the aneurysms while preserving splenic function. We conclude that creation of small-caliber vascular models with 3D printing is possible. Free software and low cost printing services make creation of these models affordable and practical. Models are useful in preoperative planning and intraoperative guidance. PMID- 26027766 TI - In vivo nephroprotective efficacy of propolis against contrast-induced nephropathy. AB - PURPOSE: Contrast agents administered in diagnostic imaging or interventional procedures of clinical radiology may cause contrast-induced nephropathy (CIN). Preventive measures against CIN involve pharmaceutical pretreatments, such as N acetylcystein (NAC) or calpain, but alternative medicines can also be helpful. This study aims to assess the prospects of a natural compound, propolis, as a potential nephroprotector against a specific contrast agent, diatrizoate. METHODS: In vivo experiments were performed on 35 male rats in five groups: control, diatrizoate alone, and pretreatments with propolis, NAC, or calpain one hour before diatrizoate administration. Three days later, blood and renal tissue samples were collected and quantitatively processed for determining induced changes in critical biomarkers malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), as well as serum creatinine and plasma urea. RESULTS: Diatrizoate increased creatinine (113%), urea (400%), and MDA (162%) levels and decreased GSH (-71%), SOD (-69%), GSH-Px (-77%), and CAT (-73%) levels. Evaluating the response of each pretreatment provided sufficient evidence that propolis was as effective as either NAC or calpain, but consistently more prominent in restoring the MDA, GSH, SOD, and GSH-Px levels close to their normal range. This outcome demonstrated the nephroprotective effect of propolis against CIN. CONCLUSION: Propolis protects renal tissue against toxicity, free radicals, and other adverse effects induced by diatrizoate. This function is most likely exerted through the antioxidant and antitoxic activities of propolis. PMID- 26027768 TI - Multiparametric MRI guidance in first-time prostate biopsies: what is the real benefit? AB - PURPOSE: With the increased recognition of the capabilities of prostate multiparametric (mp) magnetic resonance imaging (MRI), attempts are being made to incorporate MRI into routine prostate biopsies. In this study, we aimed to analyze the diagnostic yield via cognitive fusion, transrectal ultrasound (TRUS) guided, and in-bore MRI-guided biopsies in biopsy-naive patients with positive findings for prostate cancer screening. METHODS: Charts of 140 patients, who underwent transrectal prostate biopsy after the adaptation of mp-MRI into our routine clinical practice, were reviewed retrospectively. Patients with previous negative biopsies (n=24) and digital rectal examination findings suspicious for >=cT3 prostate cancer (n=16) were excluded. T2-weighted imaging, diffusion weighted imaging, and dynamic contrast-enhanced imaging were included in mp-MRI. Cognitive fusion biopsies were performed after a review of mp-MRI data, whereas TRUS-guided biopsies were performed blinded to MRI information. In-bore biopsies were conducted by means of real-time targeting under MRI guidance. RESULTS: Between January 2012 and February 2014, a total of 100 patients fulfilling the inclusion criteria underwent TRUS-guided (n=37), cognitive fusion (n=49), and in bore (n=14) biopsies. Mean age, serum prostate specific antigen level, and prostate size did not differ significantly among the study groups. In TRUS-guided biopsy group, 51.3% were diagnosed with prostate cancer, while the same ratio was 55.1% and 71.4% in cognitive fusion and in-bore biopsy groups, respectively (P = 0.429). Clinically significant prostate cancer detection rate was 69.1%, 70.3%, and 90% in TRUS-guided, cognitive fusion, and in-bore biopsy groups, respectively (P = 0.31). According to histopathologic variables in the prostatectomy specimen, significant prostate cancer was detected in 85.7%, 93.3%, and 100% of patients in TRUS-guided, cognitive fusion, and in-bore biopsy groups, respectively. CONCLUSION: In the first set of transrectal prostate biopsies, mp-MRI guidance did not increase the diagnostic yield significantly. PMID- 26027769 TI - Increased 99mTc MDP activity in the costovertebral and costotransverse joints on SPECT-CT: is it predictive of associated back pain or response to percutaneous treatment? AB - PURPOSE: Pain related to costovertebral and costotransverse joints is likely an underrecognized and potentially important cause of thoracic back pain. On combined single-photon emission computed tomography and computed tomography (SPECT-CT), increased technetium-99m methylene diphosphonate (99mTc MDP) activity at these articulations is not uncommon. We evaluated whether this activity corresponds with thoracic back pain and whether it predicts response to percutaneous injection. METHODS: All 99mTc MDP SPECT-CT spine examinations completed at our institution from March 2008 to March 2014 were retrospectively reviewed to identify those with increased 99mTc MDP activity in the costovertebral or costotransverse joints. The presence of corresponding thoracic back pain, percutaneous injection performed at the relevant joint(s), and response to injection were recorded. RESULTS: A total of 724 99mTc MDP SPECT-CT examinations were identified. Increased 99mTc MDP activity at costovertebral or costotransverse joints was reported in the examinations of 55 patients (8%). Of these, 25 (45%) had corresponding thoracic back pain, and nine of 25 patients (36%) underwent percutaneous injection of the joint(s) with increased activity. At clinical follow-up two days to 12 weeks after injection, one patient (11%) had complete pain relief, two (22%) had partial pain relief, and six (67%) had no pain relief. CONCLUSION: The findings suggest that increased activity in costovertebral and costotransverse joints on 99mTc MDP SPECT-CT is only variably associated with the presence and location of thoracic back pain; it does not predict pain response to percutaneous injection. PMID- 26027770 TI - Floatable, Self-Cleaning, and Carbon-Black-Based Superhydrophobic Gauze for the Solar Evaporation Enhancement at the Air-Water Interface. AB - Efficient solar evaporation plays an indispensable role in nature as well as the industry process. However, the traditional evaporation process depends on the total temperature increase of bulk water. Recently, localized heating at the air water interface has been demonstrated as a potential strategy for the improvement of solar evaporation. Here, we show that the carbon-black-based superhydrophobic gauze was able to float on the surface of water and selectively heat the surface water under irradiation, resulting in an enhanced evaporation rate. The fabrication process of the superhydrophobic black gauze was low-cost, scalable, and easy-to-prepare. Control experiments were conducted under different light intensities, and the results proved that the floating black gauze achieved an evaporation rate 2-3 times higher than that of the traditional process. A higher temperature of the surface water was observed in the floating gauze group, revealing a main reason for the evaporation enhancement. Furthermore, the self cleaning ability of the superhydrophobic black gauze enabled a convenient recycling and reusing process toward practical application. The present material may open a new avenue for application of the superhydrophobic substrate and meet extensive requirements in the fields related to solar evaporation. PMID- 26027771 TI - Editorial overview: Macromolecular machines and assemblies: Rise and fall at the molecular level. PMID- 26027772 TI - Primary Sarcomatoid Tumor of the Bladder: A Different Entity but the Same Approach? AB - Bladder cancer remains a frequent cancer worldwide, and most tumors are diagnosed at localized stages. Urothelial carcinoma (UC) accounts for 90% of bladder cancer cases. Sarcomatoid carcinoma (SaC) of the bladder is a rare variant (0.5% of total bladder cancers) characterized by 2 components based on histology; the epithelial and mesenchymal phenotypes, which can be easily differentiated by immunohistochemistry. SaC has similar epidemiologic features to UC but different behavior, aggressiveness, and prognosis. In this review, we summarize the main differences between UC bladder cancers and SaC subtypes. The therapeutic strategies used in SaC today do not differ much from those used for the urothelial variant. However, there is still no standard treatment--the result of a lack of clinical trials for the sarcomatoid variant. Further multicenter comparative studies are needed to devise a better treatment strategy for patients with this rare histologic tumor subtype. PMID- 26027773 TI - Biodiversity, community structure and function of biofilms in stream ecosystems. AB - Multi-species, surface-attached biofilms often dominate microbial life in streams and rivers, where they contribute substantially to biogeochemical processes. The microbial diversity of natural biofilms is huge, and may have important implications for the functioning of aquatic environments and the ecosystem services they provide. Yet the causes and consequences of biofilm biodiversity remain insufficiently understood. This review aims to give an overview of current knowledge on the distribution of stream biofilm biodiversity, the mechanisms generating biodiversity patterns and the relationship between biofilm biodiversity and ecosystem functioning. PMID- 26027774 TI - SlyA regulates motA and motB, virulence and stress-related genes under conditions induced by the PhoP-PhoQ system in Dickeya dadantii 3937. AB - We previously showed that SlyA of Dickeya dadantii 3937 plays an important role in virulence toward plants, and that the DeltaslyA mutant is hypermotile, whereas flagellum synthesis and flagellin production are indistinguishable from the wild type. Here we show that motility factors, including the distance of continuous directed movement, time for that movement and speed, were significantly higher in the DeltaslyA mutant than in the wild type. Remarkably, transcription levels of motA and motB, that are involved in flagellar rotation, were elevated in the DeltaslyA mutant, suggesting that the mutant's hypermotility was due to an increase in flagellar rotation. In low (10 MUM) magnesium medium that activates the PhoP-PhoQ system, growth and virulence of the DeltaslyA mutant were much lower than for the wild type; expression of motA, motB, mgtA, pelA, pelB, pelC, pelD, pelE, pelI, indA, tolC, sodC, acsA and hrpN were also reduced in the mutant. Interestingly, motA, motB, pelD, pelE, pelI, sodC and indA were also reduced in phoP and phoQ mutants. Because the SlyA protein directly binds to the promoter region of PhoP, SlyA regulates virulence by controlling multiple pathogenicity-related genes directly and/or at least by controlling PhoP in D. dadantii 3937 when magnesium is low. PMID- 26027775 TI - Liaisons dangereuses: sexual recombination among pathogenic trypanosomes. AB - Sexual recombination between pathogenic microbes has the potential to mobilise genes for harmful traits into new genetic backgrounds creating new pathogen strains. Since 1986 we have known that genetic exchange can occur in trypanosomes, but we are only now starting to unravel details of the process. In Trypanosoma brucei genetic exchange occurs in the tsetse vector, but is not an obligatory part of the life cycle. The process involves meiosis and production of haploid gametes, and thus appears to be true sexual reproduction. This review looks at the experimental evidence concerning genetic exchange and identifies current gaps in our knowledge. PMID- 26027776 TI - Acquired hemophilia, rheumatoid arthritis, and TNFalpha antagonists: Comment on the article "Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis" by Banse et al., Joint Bone Spine 2015;82:200-2. PMID- 26027777 TI - An integrated genotyping approach for HLA and other complex genetic systems. AB - Clinical immunogenetics laboratories performing routine sequencing of human leukocyte antigen (HLA) genes in support of hematopoietic cell transplantation are motivated to upgrade to next-generation sequencing (NGS) technology by its potential for cost savings as well as testing accuracy and flexibility. While NGS machines are available and simple to operate, there are few systems available that provide comprehensive sample preparation and data analysis workflows to complete the process. We report on the development and testing of the Integrated Genotyping System (IGS), which has been designed to specifically address the challenges associated with the adoption of NGS in clinical laboratories. To validate the system for a variety of sample DNA sources, we have tested 336 DNA specimens from whole blood, dried blood spots, buccal swabs, and lymphoblastoid cell lines. HLA class I and class II genotypes were derived from amplicon sequencing of HLA-A, -B, -C for exons 1-7 and HLA-DPA1, -DPB1, -DQA1, -DQB1, DRB1, -DRB3, -DRB4, -DRB5 for exons 1-4. Additionally, to demonstrate the extensibility of the IGS to other genetic loci, KIR haplotyping of 93 samples was carried out in parallel with HLA typing using a workflow based on the HLA system. These results are discussed with respect to their applications in the clinical setting and consequent potential for advancing precision medicine. PMID- 26027779 TI - Clinically integrated ultrasound for decreasing the number of chest x-rays in the intensive care unit: It is high time to move forward a "global" use of ultrasound. PMID- 26027778 TI - Development and validation of a sample sparing strategy for HLA typing utilizing next generation sequencing. AB - We report the development of a general methodology to genotype HLA class I and class II loci. A Whole Genome Amplification (WGA) step was used as a sample sparing methodology. HLA typing data could be obtained with as few as 300 cells, underlining the usefulness of the methodology for studies for which limited cells are available. The next generation sequencing platform was validated using a panel of cell lines from the International Histocompatibility Working Group (IHWG) for HLA-A, -B, and -C. Concordance with the known, previously determined HLA types was 99%. We next developed a panel of primers to allow HLA typing of alpha and beta chains of the HLA DQ and DP loci and the beta chain of the DRB1 locus. For the beta chain genes, we employed a novel strategy using primers in the intron regions surrounding exon 2, and the introns surrounding exons 3 through 4 (DRB1) or 5 (DQB1 and DPB1). Concordance with previously determined HLA Class II types was also 99%. To increase throughput and decrease cost, we developed strategies combining multiple loci from each donor. Multiplexing of 96 samples per run resulted in increases in throughput of approximately 8-fold. The pipeline developed for this analysis (HLATyphon) is available for download at https://github.com/LJI-Bioinformatics/HLATyphon. PMID- 26027780 TI - Illiteracy and diabetic foot complications. AB - BACKGROUND: Diabetes is especially common in the United Arab Emirates. Its complications in patients residing in the region have yet to be fully explored. This study reports on foot problems in our diabetic patients, with emphasis on the impact of illiteracy on foot care and complications due to diabetes. METHODS: Adults were randomly recruited from the Diabetes Center at Tawam-John Hopkins affiliated hospital. A questionnaire addressing foot care and problems was completed for all patients. In addition, an examination was performed by a trained nurse, an endocrinologist, and a podiatrist. RESULTS: Four hundred twenty two adults with type 2 (93%) or type 1 (7%) diabetes were enrolled; 67% were females. Patients' mean age was 52 +/- 13 years and duration of diabetes >= 1 year. Illiterate patients were 51% and were less likely to practice foot care (p=0.002), recognize foot risk factors (p=0.004), use proper footwear (p=0.010), and being physically active (p<0.001). In addition, they were more likely to have diabetic complications, such as neuropathy (p=0.027), eye disease (p=0.032), hypertension (p<0.001), obesity (p=0.003), increased body fat percentage (p<0.001), reduced capillary refill time (p=0.002), reduced monofilament (p=0.003), and reduced vibration (p<0.001). Logistic regression analysis revealed literates [OR=2.4, CI=1.1-5.4, p=0.031], female gender [OR=2.7, CI=1.1-6.2, p=0.023], and history of foot ulcer [OR=6.0, CI=2.1-17.2, p=0.001] were predictors of practicing foot care. CONCLUSION: Illiteracy invoked significant challenges to diabetic attentiveness and imposed increased foot complications. Physicians should realize that illiterate patients are vulnerable and require effective strategies to improve their education about the disease and reduce their diabetic complications. PMID- 26027782 TI - Emotional modulation of alpha asymmetry in dysphoria: results from an emotional imagery task. AB - Studies on electroencephalographic (EEG) alpha band asymmetry at rest have reported that, compared to healthy controls, dysphoric and clinically depressed individuals often display relatively less left- than right-sided cortical activity at anterior scalp sites, and the opposite pattern at posterior scalp sites. It has also been shown that depression-related differences in alpha lateralization at anterior and posterior sites are more likely to emerge during emotional tasks and during visuospatial tasks, respectively, rather than during resting conditions. However, although it is the well-established that posterior cortical activity plays a key role also in emotional processing in healthy individuals, the influence of dysphoria on posterior alpha asymmetry sites during an emotional task has yet to be examined. To this end, dysphoric (n=23) and nondysphoric (n=24) individuals performed an emotional imagery task including pleasant, neutral, and unpleasant narratives. The group with, but not without, dysphoria showed reduced left relative to right cortical activity at anterior sites, irrespective of emotional condition. By contrast, at posterior sites, individuals with dysphoria showed reduced right relative to left parietal activity during unpleasant, but not pleasant and neutral, imagery condition compared to nondysphoric individuals. Results at anterior scalp sites provide further evidence for the presence of a stable pattern of reduced approach motivation in dysphoric individuals. The association between dysphoria and right relative to left parietal hypoactivation in response to unpleasant imagery suggests that dysphoric individuals are more likely to use state-dependent dysfunctional strategies to regulate negative emotions compared to nondysphoric individuals. PMID- 26027781 TI - Subnormal sensory attenuation to self-generated speech in schizotypy: Electrophysiological evidence for a 'continuum of psychosis'. AB - BACKGROUND: A 'continuum of psychosis' refers to the concept that psychotic-like experiences occur to certain extents in the healthy population and to more severe extents in individuals with psychotic disorders. If this concept is valid, neurophysiological abnormalities exhibited by patients with schizophrenia should also be present, to some degree, in non-clinical individuals who score highly on the personality dimension of schizotypy. Patients with schizophrenia have consistently been shown to exhibit electrophysiological suppression abnormalities to self-generated speech. The present study aimed to investigate whether these electrophysiological suppression abnormalities were also present in non-clinical individuals who scored highly on schizotypy. METHODS: Thirty-seven non-clinical individuals scoring High (above median) and 37 individuals scoring Low (below median) on the Schizotypal Personality Questionnaire (SPQ; a commonly used schizotypy scale) underwent electroencephalographic (EEG) recording. The amplitude of the N1 component of the auditory-evoked potential was measured while participants (a) vocalized simple syllables (Talk condition), (b) passively listened to a recording of these vocalizations (Listen condition) and (c) listened to a recording of the vocalizations while simultaneously watching a video depicting the sound-wave of the forthcoming vocalizations, allowing them to be temporally predicted (Cued Listen condition). RESULTS: The Low Schizotypy group exhibited significantly reduced N1-amplitude in the Talk condition relative to both the Listen and Cued Listen conditions; that is, they exhibited significant N1-suppression. The High Schizotypy group exhibited significantly lower levels of N1-suppression compared to the Low Schizotypy group. Furthermore, while the Cued Listen condition induced significantly lower N1-amplitudes compared to the Listen condition in the Low Schizotypy group, this was not the case for the High Schizotypy group. CONCLUSIONS: The results suggest that non clinical, highly schizotypal individuals exhibit subnormal levels of N1 suppression to self-generated speech, similar to the N1-suppression abnormalities which have previously been reported in patients with schizophrenia. This finding provides empirical support for the existence of a neurophysiological 'continuum of psychosis'. PMID- 26027783 TI - Uterine cells-an immunoprivileged cell source for therapy-but are they for everyone? PMID- 26027784 TI - CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction. AB - Epidemiological studies indicate that methylglyoxal (MGO) plasma levels are closely linked to diabetes and the exacerbation of diabetic cardiovascular complications. Recently, it was established that endoplasmic reticulum (ER) stress importantly contributes to the pathogenesis of diabetes and its cardiovascular complications. The objective of this study was to explore the mechanism by which diabetes instigates cardiomyocyte apoptosis and cardiac dysfunction via MGO-mediated myocyte apoptosis. Intriguingly, the MGO activated unfolded protein response pathway accompanying apoptotic events, such as cleavages of PARP-1 and caspase-3. In addition, Western blot analysis revealed that MGO-induced myocyte apoptosis was inhibited by depletion of CHOP with siRNA against Ddit3, the gene name for rat CHOP. To investigate the physiologic roles of CHOP in vivo, glucose tolerance and cardiac dysfunction were assessed in CHOP deficient mice. No significant difference was observed between CHOP KO and littermate naive controls in terms of the MGO-induced impairment of glucose tolerance. In contrast, myocyte apoptosis, inflammation, and cardiac dysfunction were significantly diminished in CHOP KO compared with littermate naive controls. These results showed that CHOP is the key signal for myocyte apoptosis and cardiac dysfunction induced by MGO. These findings suggest a therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy. PMID- 26027785 TI - Expression of apoptosis-regulating miRNAs and target mRNAs in oral squamous cell carcinoma. AB - Aberrations in the apoptotic mechanisms that cause excessive or deficient programmed cell death have been linked to a wide array of pathological conditions. In this study, using real-time reverse transcriptase-PCR, we analyzed the expression of apoptosis-regulating miRNAs (miR-15a, miR-16, miR-17-5p, miR 20a, miR-21, miR-29a, and miR-34a) in 20 oral squamous cell carcinoma and 5 normal oral mucosa tissue samples. Bioinformatic algorithms were used to identify the target genes of these miRNAs (BCL2, CASP2, CASP7, CASP8, DIABLO). The expression transcript levels of the target genes were measured in 50 oral squamous cell carcinoma and 10 normal oral mucosa tissue samples. We observed downregulation of miR-15a, miR-29a, and miR-34a in 50, 75, and 70% of samples, respectively. miR-16, miR-17-5p, miR-20a, and miR-21 expression was normal in 80, 75, 90, and 60% of samples, respectively. BCL2 transcripts were downregulated in 60% of samples, and normal-like expression was observed for CASP2, CASP7, CASP8, and DIABLO transcripts in 66, 82, 68, and 60% of samples, respectively. BCL2 expression was negative to weak, and that of proteins CASP2, CASP7, CASP8, and DIABLO was moderate to strong. Our study provides evidence of alterations in the expression of apoptosis-regulating miRNAs and genes in the apoptotic pathway, demonstrating that regulation of apoptosis is a hallmark of oral squamous cell carcinoma pathogenesis. PMID- 26027786 TI - Longitudinal ultra-extensive transverse myelitis as a manifestation of neurosarcoidosis. AB - OBJECTIVE: To analyze the clinical characteristics and outcome of patients with neurosarcoidosis manifesting as longitudinal transverse myelitis spanning 6 or more spinal segments. METHOD: Retrospective analysis of 7 cases from a single institution. RESULTS: Four males and 5 African-American were included. The mean onset age for neurological symptoms was 49.1 years old. Only 1 patient had a prior diagnosis of sarcoidosis. In all patients, spinal MRI showed contiguous cervical and/or thoracic cord lesions predominantly in a central or centrodorsal location, associated with parenchymal or leptomeningeal gadolinium enhancement. Cerebral spinal fluid (CSF) pleocytosis was present in all and hypoglycorrhachia in 3 patients. Angiotensin-converting enzyme (ACE) level was elevated in the serum of 1 patient while being normal in the CSF of all 4 cases tested. Chest imaging facilitated the diagnosis of sarcoidosis in all cases. The use of corticosteroid and immunosuppressive agents including infliximab and methotrexate led to improved outcome. CONCLUSIONS: Neurosarcoidosis should be considered in the differential diagnosis of longitudinal ultra-extensive myelitis, even in the absence of previously diagnosed sarcoidosis. Timely usage of corticosteroid and immunosuppressive agents improves the clinical outcome of patients with ultra extensive spinal cord sarcoidosis. PMID- 26027787 TI - Sweetness characterization of recombinant human lysozyme. AB - Lysozyme, a bacteriolytic enzyme, is widely distributed in nature and is a component of the innate immune system. It is established that chicken egg lysozyme elicits sweetness. However, the sweetness of human milk lysozyme, which is vital for combating microbial infections of the gastrointestinal tract of breast-fed infants, has not been characterized. This study aimed to assess the elicitation of sweetness using recombinant mammalian lysozymes expressed in Pichia pastoris. Recombinant human lysozyme (h-LZ) and other mammalian lysozymes of mouse, dog, cat and bovine milk elicited similar sweetness as determined using a sensory test, whereas bovine stomach lysozyme (bs-LZ) did not. Assays of cell cultures showed that h-LZ activated the human sweet taste receptor hT1R2/hT1R3, whereas bs-LZ did not. Point mutations confirmed that the sweetness of h-LZ was independent of enzyme activity and substrate-binding sites, although acidic amino acid residues of bs-LZ played a significant role in diminishing sweetness. Therefore, we conclude that elicitation of sweetness is a ubiquitous function among all lysozymes including mammalian lysozymes. These findings may provide novel insights into the biological implications of T1R2/T1R3-activation by mammalian lysozyme in the oral cavity and gastrointestinal tract. However, the function of lysozyme within species lacking the functional sweet taste receptor gene, such as cat, is currently unknown. PMID- 26027788 TI - The use of unequal randomisation in clinical trials--An update. AB - OBJECTIVE: To update a 2005 review of the reasons researchers have given for the use of unequal randomisation in randomised controlled trials (RCTs). MAIN MEASURES: Intervention being tested; type of study; number of participants; randomisation ratio; sample size calculation and reason given for using unequal randomisation. METHODS: Review of trials using unequal randomisation. DATABASES AND SOURCES: Cochrane library, Medline and CINAHL. RESULTS: A total of 86 trials were identified. Of these 82 trials (95%) recruited patients in favour of the experimental group. Various reasons for the use of unequal randomisation were given including: gaining treatment experience; identification of adverse events; ethical; logistic and enhancing recruitment. No trial reported explicitly used it for cost-effectiveness. Most of the papers (i.e. 47, 55%) did not state why they had used unequal randomisation and only 38 trials (44%) appeared to have taken the unequal randomisation into account in their sample size calculation. CONCLUSION: Most studies did not mention the rationale for unequal allocation, and a significant proportion did not appear to account for it in the sample size calculations. Unlike the previous review economic considerations were not stated as a rationale for its use. A number of trials used it to enhance recruitment, although this has not been tested. PMID- 26027789 TI - Zebrafish swimming behavior as a biomarker for ototoxicity-induced hair cell damage: a high-throughput drug development platform targeting hearing loss. AB - Hearing loss is one of the most common human sensory disabilities, adversely affecting communication, socialization, mood, physical functioning, and quality of life. In addition to age and noise-induced damage, ototoxicity is a common cause of sensorineural hearing loss with chemotherapeutic agents, for example, cisplatin, being a major contributor. Zebrafish (Danio rerio) are an excellent model to study hearing loss as they have neurosensory hair cells on their body surface that are structurally similar to those within the human inner ear. Anatomic assays of toxin-mediated hair cell damage in zebrafish have been established; however, using fish swimming behavior--rheotaxis--as a biomarker for this anatomic damage was only recently described. We hypothesized that, in parallel, multilane measurements of rheotaxis could be used to create a high throughput platform for drug development assessing both ototoxic and potentially otoprotective compounds in real time. Such a device was created, and results demonstrated a clear dose response between cisplatin exposure, progressive hair cell damage, and reduced rheotaxis in zebrafish. Furthermore, pre-exposure to the otoprotective medication dexamethasone, before cisplatin exposure, partially rescued rheotaxis swimming behavior and hair cell integrity. These results provide the first evidence that rescued swimming behavior can serve as a biomarker for rescued hair cell function. Developing a drug against hearing loss represents an unmet clinical need with global implications. Because hearing loss from diverse etiologies may result from common end-effects at the hair cell level, lessons learned from the present study may be broadly used. PMID- 26027791 TI - Probing hematopoietic stem cell function using serial transplantation: Seeding characteristics and the impact of stem cell purification. AB - Appropriate regulation of hematopoietic stem cell (HSC) numbers and function is a requisite for life-long blood cell replenishment. Knowledge of factors that regulate HSC activity is derived largely from murine model systems, with serial transplantation often considered a "gold standard" to assess longevity and self renewal of HSCs. In the literature, we noted inconsistencies in how serial transplantations are conducted and decided to assess a set of parameters at play in such experiments. We found that HSCs distribute and expand unevenly among individual bones following transplantation, suggesting that isolation of a limited number of bone marrow cells for serial transplantation and/or analysis can influence experimental outcomes. Comparing donor cell output from transplanted unfractionated bone marrow cells, as opposed to fluorescence activated cell-sorted HSCs, revealed distinct differences in the output of mature blood cells. Specifically, we found that long-lived progenitor and/or mature co transplanted cells can severely affect the interpretation of ongoing HSC activity in secondary hosts. The implications of these data for the design and execution of serial transplantation experiments are discussed. PMID- 26027792 TI - Genomic insights into a contagious cancer in Tasmanian devils. AB - The Tasmanian devil faces extinction due to a contagious cancer. Genetic and genomic technologies revealed that the disease arose in a Schwann cell of a female devil. Instead of dying with the original host, the tumour was passed from animal to animal, slipping under the radar of the immune system. Studying the genomes of the devil and the cancer has driven our understanding of this unique disease. From characterising immune genes and immune responses to studying tumour evolution, we have begun to uncover how a cancer can be 'caught' and are using genomic data to manage an insurance population of disease-free devils for the long-term survival of the species. PMID- 26027790 TI - Targeting EZH2 and PRC2 dependence as novel anticancer therapy. AB - Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repressive high-degree methylation of histone H3 at lysine 27 (H3K27), plays crucial roles in regulation of normal and malignant hematopoiesis. Recently, increasing evidence has indicated that recurrent gain-of-function mutation and overexpression of EZH2, the catalytic subunit of PRC2, drive and promote malignant transformation such as B-cell lymphomagenesis, providing a rationale for PRC2 inhibition as a novel anticancer strategy. Here, we summarize the recently developed strategies for inhibition of PRC2, which include a series of highly specific, highly potent, small-molecule inhibitors of EZH2 and EZH1, an EZH2-related methyltransferase. PRC2 establishes functional crosstalk with numerous epigenetic machineries during dynamic regulation of gene transcription. Perturbation of such functional crosstalk caused by genetic events observed in various hematologic cancers, such as inactivation of SNF5 and somatic mutation of UTX, confers PRC2 dependence, thus rendering an increased sensitivity to PRC2 inhibition. We discuss our current understanding of EZH2 somatic mutations frequently found in B-cell lymphomas and recurrent mutations in various other epigenetic regulators as novel molecular predictors and determinants of PRC2 sensitivity. As recent advances have indicated a critical developmental or tumor suppressive role for PRC2 and EZH2 in various tissue types, we discuss concerns over potentially toxic or even adverse effects associated with EZH2/1 inhibition in certain biological contexts or on cancer genetic background. Collectively, inhibition of PRC2 catalytic activity has emerged as a promising therapeutic intervention for the precise treatment of a range of genetically defined hematologic malignancies and can be potentially applied to a broader spectrum of human cancers that bear similar genetic and epigenetic characteristics. PMID- 26027793 TI - Implementation of a standardised method for the production of allogeneic serum eye drops from regular blood donors in a Norwegian University Hospital: Some methodological aspects and clinical considerations. AB - The use of autologous serum eye drops has been shown to be effective for the treatment of many ocular diseases. For patients were repeated blood sampling is not possible, allogeneic serum eye drops have been shown to be an effective and safe alternative. In our institution, we have managed to produce allogeneic serum eye drops from regular blood donors using a standardised procedure. The effectiveness and safety of this product will be evaluated in a clinical trial. PMID- 26027794 TI - Recurrence quantification analysis and support vector machines for golf handicap and low back pain EMG classification. AB - The quantification of non-linear characteristics of electromyography (EMG) must contain information allowing to discriminate neuromuscular strategies during dynamic skills. There are a lack of studies about muscle coordination under motor constrains during dynamic contractions. In golf, both handicap (Hc) and low back pain (LBP) are the main factors associated with the occurrence of injuries. The aim of this study was to analyze the accuracy of support vector machines SVM on EMG-based classification to discriminate Hc (low and high handicap) and LBP (with and without LPB) in the main phases of golf swing. For this purpose recurrence quantification analysis (RQA) features of the trunk and the lower limb muscles were used to feed a SVM classifier. Recurrence rate (RR) and the ratio between determinism (DET) and RR showed a high discriminant power. The Hc accuracy for the swing, backswing, and downswing were 94.4+/-2.7%, 97.1+/-2.3%, and 95.3+/ 2.6%, respectively. For LBP, the accuracy was 96.9+/-3.8% for the swing, and 99.7+/-0.4% in the backswing. External oblique (EO), biceps femoris (BF), semitendinosus (ST) and rectus femoris (RF) showed high accuracy depending on the laterality within the phase. RQA features and SVM showed a high muscle discriminant capacity within swing phases by Hc and by LBP. Low back pain golfers showed different neuromuscular coordination strategies when compared with asymptomatic. PMID- 26027795 TI - KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. AB - KBP-042 is a synthetic peptide dual amylin- and calcitonin-receptor agonist (DACRA) developed to treat type 2 diabetes by inducing a significant weight loss while improving glucose homeostasis. In this study the aim was to compare two different formulations: An oral formulation (1mg/kg) to subcutaneous formulations of KBP-042 (2.5MUg/kg, 5.0MUg/kg and 7.5MUg/kg) with comparable pharmacokinetic profiles. Furthermore to examine if differences in mode of action between the two different routes of administration in high-fat fed Sprague-Dawley rats were present. It was established that the subcutaneous administrations of KBP-042 were able to dose-dependently cause a significant weight-loss, reduce food intake, and improve glucose homeostasis without increasing insulin secretion, effects comparable to those observed with oral administration. At the same time, s.c. KBP 042 suppressed the inappropriate glucagon response better than the oral formulation. Furthermore, KBP-042 was found to reduce incretins GLP-1 and GIP and considerably, improve gastric emptying, and to alleviate leptin resistance, as well as insulin resistance. In conclusion, the subcutaneous route of administration was found to have the same beneficial effects on blood glucose homeostasis and weight loss as well as resistance towards important insulin and leptin, albeit with a markedly lower variation in both exposure and biological responses. These data support the application of subcutaneously delivered peptide for mechanistic studies, and highlight the potential of developing s.c. KBP-042 as a therapy for T2D. PMID- 26027797 TI - Comprehensive identification and profiling of host miRNAs in response to Singapore grouper iridovirus (SGIV) infection in grouper (Epinephelus coioides). AB - microRNAs (miRNAs) are an evolutionarily conserved class of non-coding RNA molecules that participate in various biological processes. Employment of high throughput screening strategies greatly prompts the investigation and profiling of miRNAs in diverse species. In recent years, grouper (Epinephelus spp.) aquaculture was severely affected by iridoviral diseases. However, knowledge regarding the host immune responses to viral infection, especially the miRNA mediated immune regulatory roles, is rather limited. In this study, by employing Solexa deep sequencing approach, we identified 116 grouper miRNAs from grouper spleen-derived cells (GS). As expected, these miRNAs shared high sequence similarity with miRNAs identified in zebrafish (Danio rerio), pufferfish (Fugu rubripes), and other higher vertebrates. In the process of Singapore grouper iridovirus (SGIV) infection, 45 and 43 miRNAs with altered expression (>1.5-fold) were identified by miRNA microarray assays in grouper spleen tissues and GS cells, respectively. Furthermore, target prediction revealed 189 putative targets of these grouper miRNAs. PMID- 26027796 TI - Inhibition of monocarboxylate transporter by N-cyanosulphonamide S0859. AB - The synthetic compound N-cyanosulphonamide S0859 has been described as a selective inhibitor of sodium-bicarbonate cotransporters (NBC, SLC4) in mammalian heart (Ch'en et al., 2008). First, for comparison, the electrogenic human NBCe1 (SLC4A4) was heterologously expressed in Xenopus laevis oocytes, where its transport activity was inhibited by S0859 with an IC50 of 9uM. The activity of monocarboxylate transporter (MCT) isoforms 1, 2, and 4 (SLC16A1, SLC16A7, SLC16A3), which transport lactate, pyruvate and ketone bodies, were also heterologously expressed in Xenopus oocytes, and their transport activity was similarly and reversibly inhibited by S0859 with an IC50 of 4-10uM. Partial inhibition of lactate transport by S0859 (50uM) was also obtained in cultured astrocytes of mice. Thus, S0859 appears to be an inhibitor of anion transport with a broader spectrum than previously thought, and may also interfere with cellular metabolite uptake/release. PMID- 26027798 TI - Professional phagocytic granulocyte-derived PGD2 regulates the resolution of inflammation in fish. AB - Prostaglandins (PGs) play a key role in the development on the immune response through the regulation of both pro- and anti-inflammatory processes. PGD(2) can be either pro- or anti-inflammatory depending on the inflammatory milieu. Prostaglandin D synthase (PGDS) is the enzyme responsible for the conversion of PGH(2) to PGD(2). In mammals, two types of PGDS synthase have been described, the hematopoietic (H-PGDS) and the lipocalin (L-PGDS). In the present study we describe the existence of two orthologs of the mammalian L-PGDS (PGDS1 and PGDS2) in the gilthead seabream and characterize their gene expression profiles and biological activity. The results showed a dramatic induction of the gene coding for PGDS1 in acidophilic granulocytes (AGs), which are functionally equivalent to mammalian neutrophils, after a prolonged in vitro activation with different pathogen associated molecular patterns (PAMPs). In contrast PGDS2 was not expressed in these cells. The functional relevance of the induction of PGDS1 in AGs was confirmed by the ability of these cells to release PGD(2) upon PAMP stimulation. To gain further insight into the role of PGD(2) in the resolution of inflammation in fish, we examined the ability of PGD(2) or its cyclopentenone derivates (cyPGs) to modulate the main functional activities of AGs. It was found that both PGD(2) and cyPGs inhibited the production of reactive oxygen species and downregulated the transcript levels of the gene encoding interleukin-1beta. Taken together, these results demonstrate that the use of PGD(2) and its metabolites in the resolution of inflammation was established before the divergence of fish from tetrapods more than 450 million years ago and support a critical role for granulocytes in the resolution of inflammation in vertebrates. PMID- 26027799 TI - Patents and Recent Innovations in Topical Membrane Therapy of Refractory Rhinosinusitis. AB - Chronic Rhinosinusitis (CRS), one of the commonest chronic inflammatory disorders, is encountered daily in all healthcare settings. In its refractory form, CRS seems to prevail over most up-to-date surgical interventions and systemic medical remedies, owing to our poor understanding of its perplexing pathophysiology. Although several systemic influences impinge on the progression of inflammation, the true interplay between offensive and defensive factors takes place on-site, i.e. across the sinonasal epithelial coating. Therefore, current treatment strategies shift the weight of CRS management toward topical modalities, which combine the benefits of surgical approach with the healing effect of conventional medications. An explosive emergence of relevant patents is still in progress, emphasizing the need for classification and comparison. Novel delivery methods of medications into the sinus cavities include modifications of traditional rinses, state-of-the-art nebulizing devices, and the revolutionary concept of sustained drug application utilizing carrier gels or nasal implants. As far as the introduction of new medications is concerned, recent patents propose alterations to the physical and chemical properties of irrigating solutions, as well as the local use of antiseptics, hydragogues, and anti-biofilm agents. This review focuses on the local pathophysiologic events of CRS and the most exciting innovations regarding its topical management. PMID- 26027800 TI - Digital breast tomosynthesis (3D-mammography) screening: data and implications for population screening. AB - The evidence on digital breast tomosynthesis (DBT), or quasi-3D-mammography, for population breast screening has emerged rapidly: two prospective and several retrospective studies provide convincing evidence that mammography with DBT improves screening detection measures compared with standard mammography. Based on population screening studies (which have used various methodologies), adjunct DBT's incremental breast cancer detection is in the range of 0.5-2.7/1000 screens, and the absolute false recall reduction attributed to DBT is in the range of 0.8-3.6%. Randomized controlled trials assessing the impact of DBT on interval cancer rates as a surrogate for screening benefit would provide critical evidence to underpin population screening policy and practice, and could be designed to also address existing evidence gaps including cost-effectiveness of DBT. PMID- 26027801 TI - Domino Tunneling. AB - Matrix-isolation experiments near 3 K and state-of-the-art quantum chemical computations demonstrate that oxalic acid [1, (COOH)2] exhibits a sequential quantum mechanical tunneling phenomenon not previously observed. Intensities of numerous infrared (IR) bands were used to monitor the temporal evolution of the lowest-energy O-H rotamers (1cTc, 1cTt, 1tTt) of oxalic acid for up to 19 days following near-infrared irradiation of the matrix. The relative energies of these rotamers are 0.0 (1cTc), 2.6 (1cTt), and 4.0 (1tTt) kcal mol(-1). A 1tTt -> 1cTt > 1cTc isomerization cascade was observed with half-lives (t1/2) in different matrix sites ranging from 30 to 360 h, even though the sequential barriers of 9.7 and 10.4 kcal mol(-1) are much too high to be surmounted thermally under cryogenic conditions. A general mathematical model was developed for the complex kinetics of a reaction cascade with species in distinct matrix sites. With this model, a precise, global nonlinear least-squares fit was achieved simultaneously on the temporal profiles of nine IR bands of the 1cTc, 1cTt, and 1tTt rotamers. Classes of both fast (t(1/2) = 30-50 h) and slow (t(1/2) > 250 h) matrix sites were revealed, with the decay rate of the former in close agreement with first principles computations for the conformational tunneling rates of the corresponding isolated molecules. Rigorous kinetic and theoretical analyses thus show that a "domino" tunneling mechanism is at work in these oxalic acid transformations. PMID- 26027804 TI - Organogold oligomers: exploiting iClick and aurophilic cluster formation to prepare solution stable Au4 repeating units. AB - A novel synthetic method to create gold based metallo-oligomers/polymers via the combination of inorganic click (iClick) with intermolecular aurophilic interactions is demonstrated. Complexes [PEt3Au]4(MU-N3C2C6H5) (1) and [PPhMe2Au]4(MU-N3C2C6H5) (2) and {[PEt3Au]4[(MU-N3C2)2-9,9-dihexyl-9H-fluorene]}n (8) have been synthesized via iClick. The tetranuclear structures of 1 and 2, induced by aurophilic bonding, are confirmed in the solid state through single crystal X-ray diffraction experiments and in solution via variable temperature NMR spectroscopy. The extended 1D structure of 8 is constructed by aurophilic induced self-assembly. (1)H DOSY NMR analysis reveals that the aurophilic bonds in 1, 2, and 8 are retained in the solution phase. The degree of polymerization within complex 8 is temperature and concentration dependent, as determined by (1)H DOSY NMR. Complex 8 is a rare example of a solution stable higher ordered structure linked by aurophilic interactions. PMID- 26027805 TI - Spatially Resolved Probing of Electrochemical Reactions via Energy Discovery Platforms. AB - The electrochemical reactivity of solid surfaces underpins functionality of a broad spectrum of materials and devices ranging from energy storage and conversion, to sensors and catalytic devices. The surface electrochemistry is, however, a complex process, controlled by the interplay of charge generation, field-controlled and diffusion-controlled transport. Here we explore the fundamental mechanisms of electrochemical reactivity on nanocrystalline ceria, using the synergy of nanofabricated devices and time-resolved Kelvin probe force microscopy (tr-KPFM), an approach we refer to as energy discovery platform. Through tr-KPFM, the surface potential mapping in both the space and time domains and current variation over time are obtained, enabling analysis of local ionic and electronic transport and their dynamic behavior on the 10 ms to 10 s scale. Based on their different responses in the time domain, conduction mechanisms can be separated and identified in a variety of environmental conditions, such as humidity and temperature. The theoretical modeling of ion transport through finite element method allows for creation of a minimal model consistent with observed phenomena, and establishing of the dynamic characteristics of the process, including mobility and diffusivity of charged species. The future potential of the energy discovery platforms is also discussed. PMID- 26027806 TI - Homeotropic nano-particle assembly on degenerate planar nematic interfaces: films and droplets. AB - A continuum theory is used to study the effects of homeotropic nano-particles on degenerate planar liquid crystal interfaces. Particle self-assembly mechanisms are obtained from careful examination of particle configurations on a planar film and on a spherical droplet. The free energy functional that describes the system is minimized according to Ginzburg-Landau and stochastic relaxations. The interplay between elastic and surface distortions and the desire to minimize defect volumes (boojums and half-Saturn rings) is shown to be responsible for the formation of intriguing ordered structures. As a general trend, the particles prefer to localize at defects to minimize the overall free energy. However, multiple metastable configurations corresponding to local minima can be easily observed due to the high energy barriers that separate distinct particle arrangements. We also show that by controlling anchoring strength and temperature one can direct liquid-crystal mediated nanoparticle self-assembly along well defined pathways. PMID- 26027807 TI - Schizophrenia and Toxoplasma gondii: an undervalued association? AB - The existence of an association between schizophrenia and an infection by the protozoan parasite Toxoplasma gondii has been suspected since the 1950s. Two significant phenomena first garnered the attention of the psychiatric community toward toxoplasmosis, the illness precipitated by an infection of the parasite. Transient symptoms of acute toxoplasmosis sometimes resemble the clinical picture of paranoid schizophrenia. Many studies have also found an increased seroprevalence of toxoplasmosis in clients of mental health institutions in comparison with members of control populations. We have had to wait until the first decade of our millennium for several independent research teams to make discoveries that would shed light on the possible mechanisms that link the Toxoplasma parasite to schizophrenia. PMID- 26027809 TI - Editorial: Prevention Strategies Targeting Different Preclinical Stages of Alzheimer's Disease. AB - The incidence of dementia is rapidly increasing not only in developed countries but also in developing countries with rising aging populations. This trend is expected to worsen, with the number of cases possibly tripling in the coming decades. Over the last few decades, epidemiological studies have revealed that vascular-or lifestyle-related factors are associated with an increased risk of Alzheimer's disease (AD) and dementia. Researches into the pathophysiological processes of AD have revealed that the pathological brain lesions of AD begin decades before the onset of symptoms. Many prevention studies have indicated that physical activity and/or mental training can improve cognition and daily life in subjects with AD or mild cognitive impairment (MCI). However, issues with early detection and preclinical staging and effective preventive approaches that are based on these stages remain unresolved. Therefore, we propose different strategies for AD prevention based on its preclinical stages: one involves physical and mental training that targets the risk factors in subjects without pathophysiological changes, and the second approach combines nonpharmacological and pharmacological methods and aims to treat MCI in individuals with amyloid deposits and/or neurodegeneration with drugs that target the amyloid cascade. The results of several ongoing and promising trials are expected in the next few years. PMID- 26027808 TI - Structural MRI Predictors of Late-Life Cognition Differ Across African Americans, Hispanics, and Whites. AB - BACKGROUND: Structural magnetic resonance imaging (MRI) provides key biomarkers to predict onset and track progression of Alzheimer's disease (AD). However, most published reports of relationships between MRI variables and cognition in older adults include racially, ethnically, and socioeconomically homogenous samples. Racial/ethnic differences in MRI variables and cognitive performance, as well as health, socioeconomic status and psychological factors, raise the possibility that brain-behavior relationships may be stronger or weaker in different groups. The current study tested whether MRI predictors of cognition differ in African Americans and Hispanics, compared with non-Hispanic Whites. METHODS: Participants were 638 non-demented older adults (29% non-Hispanic White, 36% African American, 35% Hispanic) in the Washington Heights-Inwood Columbia Aging Project. Composite scores of memory, language, speed/executive functioning, and visuospatial function were derived from a neuropsychological battery. Hippocampal volume, regional cortical thickness, infarcts, and white matter hyperintensity (WMH) volumes were quantified with FreeSurfer and in-house developed procedures. Multiple-group regression analysis, in which each cognitive composite score was regressed onto MRI variables, demographics, and cardiovascular health, tested which paths differed across groups. RESULTS: Larger WMH volume was associated with worse language and speed/executive functioning among African Americans, but not among non-Hispanic Whites. Larger hippocampal volume was more strongly associated with better memory among non-Hispanic Whites compared with Hispanics. Cortical thickness and infarcts were similarly associated with cognition across groups. CONCLUSION: The main finding of this study was that certain MRI predictors of cognition differed across racial/ethnic groups. These results highlight the critical need for more diverse samples in the study of cognitive aging, as the type and relation of neurobiological substrates of cognitive functioning may be different for different groups. PMID- 26027810 TI - Auditory Verbal Learning Test is Superior to Rey-Osterrieth Complex Figure Memory for Predicting Mild Cognitive Impairment to Alzheimer's Disease. AB - OBJECTIVE: To carry out meaningful comparisons on results of different research studies on mild cognitive impairment (MCI), it is critical to select an appropriate objective memory test to examine memory deficit. We aim to refine the operational criteria of amnestic MCI (aMCI) on neuropsychological tests that optimally balance the sensitivity and specificity. METHODS: We focused on 206 non demented subjects from memory clinic. We then classified each individual as having MCI or subjective cognitive decline (SCD) according to different neuropsychological criteria. By following them longitudinally, clinical outcomes were compared to evaluate the stability of MCI diagnoses and prediction of progression. RESULTS: The delayed recall of auditory verbal learning test (AVLT_DR) identified 116 subjects as MCI, resulted in the conversion rate as 44% over the roughly 30-month time interval, missed 7.8% incipient Alzheimer's disease (AD) patients in SCD group who eventually converted to dementia. The delayed recall of complex figure test (CFT_DR) identified fewer MCI patients (n=95) and misdiagnosed more preclinical AD patients (15.3%), in comparison with AVLT criterion. Criterion requiring deficits in both tests produced higher conversion rate (54.3%), but resulted in higher misdiagnosis rate (14.7%) simultaneously. The AVLT criterion had the largest area under the curve (0.7248, p<0.05). CONCLUSION: AVLT is superior to CFT in the stability of diagnoses and prediction of progression. In the clinical setting, the "one test" criterion AVLT has similar sensitivity to both-deficits methods, and is optimal in balancing sensitivity and specificity. PMID- 26027811 TI - Mild Cognitive Impairment: At the Crossroad of Neurodegeneration and Vascular Dysfunction. AB - The concept of mild cognitive impairment (MCI) was first introduced for the purpose of identifying individuals in an intermediate state between no cognitive impairment and Alzheimer's disease (AD). Recently, the heterogeneity of MCI has attracted attention as it has become clear that other diseases, such as cerebrovascular disease and Parkinson disease can also cause mild cognitive deficits, prompting a redefinition of MCI. Heterogeneity of MCI has been confirmed by neuropathological examinations. Most MCI patients not only possess amyloid plaques and neurofibrillary tau tangles, but also cerebral vascular pathology such as arteriosclerosis and cerebral amyloid angiopathy (CAA). CAA induces cerebral infarcts or hemorrhage of varying size and type, attributing to further cognitive impairment. Sporadic AD and CAA has been suggested to be the consequence of Abeta elimination failure, mainly caused by disturbance of the perivascular drainage system. Since severe CAA is an independent risk factor for dementia, facilitation of Abeta clearance has been suggested as a potential treatment of AD and MCI. Many epidemiological studies have shown that vascular risk factors increase incidence of MCI and its progression to AD. Accordingly, control of such factors has been shown to reduce risk of conversion to AD and ameliorate cognitive impairment in AD patients. Neurovascular approaches may therefore hold promise for the treatment of dementia in an era of preventive neurology. PMID- 26027812 TI - Development of Computer-Aided Cognitive Training Program for Elderly and Its Effectiveness through a 6 Months Group Intervention Study. AB - Since the increasing population of aging, cognitive training is focused as one of the non-pharmacological preventive approach of cognitive decline. Although the accumulation of the knowledge, they hardly reflect to the programs for clinical use. We developed a task set named "Atama-no-dojo," designed to activate multiple cognitive functions and enhance motivational incentives. The objective of our study is to confirm the effect of our program through a 6 months group intervention program. The intervention program conducted in a day service center for 6 months in the duration of 45 minutes per day, 4 days per month for a total of 25 sessions. Participants worked to the tasks on the screen all together with filling in the answering sheet. Neuropsychological tests, SF36 and GDS were assessed at pre-/post-intervention periods. Participants filled in a questionnaire about impression to the program at the last training session. Fourteen women (82.2 +/- 2.9 years old) were analyzed and significant changes were found in the improvement of memory, attention, inhibition, GDS and some items of SF36. All participants recognized the program as fun and wanted to continue. Some of the participants' positive impressions to the program correlated to cognitive improvement. The improved cognitive functions by 6 months intervention of "Atama-no-dojo" were mainly related to prefrontal cortex and the motivational incentives seemed supported the effect of task contents. We recognized the importance of task difficulty setting and motivational incentives to reduce frustration from working on difficult tasks and enhance the effects of improvement from activating brain function. PMID- 26027813 TI - Amyloid Beta-Weighted Cortical Thickness: A New Imaging Biomarker in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder pathologically characterized by amyloid-beta (Abeta) plaques and neurofibrillary tangles. The aggregation of Abeta precedes tau pathologies in AD; however, the causal relation between the two pathologies and the mechanisms by which aggregated forms of Abeta contribute to cortical thinning are not fully understood. We proposed quantitative Abeta-weighted cortical thickness analysis to investigate the regional relationship between cortical thinning and amyloid plaque deposition using magnetic resonance (MR) and Pittsburg Compound B (PiB) positron emission tomography (PET) images in patients with AD, mild cognitive impairment (MCI), and subjects with normal cognition. We hypothesized that there are cortical areas that have prominent changes associated with Abeta deposition and there are areas that are relatively independent from Abeta deposition where pathologies other than Abeta (such as tau) are predominant. The study was performed using MRI and PiB PET data from the Alzheimer's Disease Neuroimaging Initiative. We measured accuracy of classification models in three different pairs of groups comparing AD, MCI, and normal cognition. Classification models that used Abeta-weighted cortical thickness were not inferior to classification models that used only cortical thickness or amyloid deposition. In addition, based on timing of changes in cortical thinning and Abeta deposition such as Abeta deposition after cortical thinning; cortical thinning after Abeta deposition, or concurrent Abeta deposition and cortical thinning, we identified three types of relationships between cortical thinning and Abeta deposition: (1) Abeta-associated cortical thinning; (2) Abeta-independent cortical thinning; and (3) Abeta deposition only without cortical thinning. Taken together, these findings suggest that Abeta-weighted cortical thickness values can be used as an objective biomarker of structural changes caused by amyloid pathology in the brain. PMID- 26027814 TI - Social Markers of Mild Cognitive Impairment: Proportion of Word Counts in Free Conversational Speech. AB - BACKGROUND: Detecting early signs of Alzheimer's disease (AD) and mild cognitive impairment (MCI) during the pre-symptomatic phase is becoming increasingly important for costeffective clinical trials and also for deriving maximum benefit from currently available treatment strategies. However, distinguishing early signs of MCI from normal cognitive aging is difficult. Biomarkers have been extensively examined as early indicators of the pathological process for AD, but assessing these biomarkers is expensive and challenging to apply widely among pre symptomatic community dwelling older adults. Here we propose assessment of social markers, which could provide an alternative or complementary and ecologically valid strategy for identifying the pre-symptomatic phase leading to MCI and AD. METHODS: The data came from a larger randomized controlled clinical trial (RCT), where we examined whether daily conversational interactions using remote video telecommunications software could improve cognitive functions of older adult participants. We assessed the proportion of words generated by participants out of total words produced by both participants and staff interviewers using transcribed conversations during the intervention trial as an indicator of how two people (participants and interviewers) interact with each other in one-on-one conversations. We examined whether the proportion differed between those with intact cognition and MCI, using first, generalized estimating equations with the proportion as outcome, and second, logistic regression models with cognitive status as outcome in order to estimate the area under ROC curve (ROC AUC). RESULTS: Compared to those with normal cognitive function, MCI participants generated a greater proportion of words out of the total number of words during the timed conversation sessions (p=0.01). This difference remained after controlling for participant age, gender, interviewer and time of assessment (p=0.03). The logistic regression models showed the ROC AUC of identifying MCI (vs. normals) was 0.71 (95% Confidence Interval: 0.54 - 0.89) when average proportion of word counts spoken by subjects was included univariately into the model. CONCLUSION: An ecologically valid social marker such as the proportion of spoken words produced during spontaneous conversations may be sensitive to transitions from normal cognition to MCI. PMID- 26027815 TI - The Efficacy of Cognitive Intervention Programs for Mild Cognitive Impairment: A Systematic Review. AB - Mild cognitive impairment (MCI) describes a transitional state in progression from normal aging to dementia, especially Alzheimer's disease (AD). Currently, there is no effective pharmacological treatment that offers a long-term beneficial effect to delay the progression to dementia. There is growing evidence that supports an important role of non-pharmacological cognitive interventions. Therefore, it is warranted to clarify the distinct forms of cognitive interventions and their effects based on previous clinical trials. We aimed to provide a review of clinical trials of non-pharmacological cognitive interventions for MCI and to address the characteristics of the study patients, cognitive intervention programs and short-term / long-term benefits of the interventions. A total of 32 articles were identified according to the inclusion criteria. The results showed positive effects for both objective and subjective outcome variables, and these effects persisted from 1 month up to 5 years. Although many of the positive effects were related to improvement in trained tasks, alterations in neuroimaging and the transfer effects shown by some studies are encouraging. Future research in this area requires a larger sample size with a wider spectrum of MCI, more instructive outcome measures and a longer follow up duration. PMID- 26027816 TI - Disrupted Structural Brain Network in AD and aMCI: A Finding of Long Fiber Degeneration. AB - Although recent evidence has emerged that Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients show both regional brain abnormalities and topological degeneration in brain networks, our understanding of the effects of white matter fiber aberrations on brain network topology in AD and aMCI is still rudimentary. In this study, we investigated the regional volumetric aberrations and the global topological abnormalities in AD and aMCI patients. The results showed a widely distributed atrophy in both gray and white matters in the AD and aMCI groups. In particular, AD patients had weaker connectivity with long fiber length than aMCI and normal control (NC) groups, as assessed by fractional anisotropy (FA). Furthermore, the brain networks of all three groups exhibited prominent economical small-world properties. Interestingly, the topological characteristics estimated from binary brain networks showed no significant group effect, indicating a tendency of preserving an optimal topological architecture in AD and aMCI during degeneration. However, significantly longer characteristic path length was observed in the FA weighted brain networks of AD and aMCI patients, suggesting dysfunctional global integration. Moreover, the abnormality of the characteristic path length was negatively correlated with the clinical ratings of cognitive impairment. Thus, the results therefore suggested that the topological alterations in weighted brain networks of AD are induced by the loss of connectivity with long fiber lengths. Our findings provide new insights into the alterations of the brain network in AD and may indicate the predictive value of the network metrics as biomarkers of disease development. PMID- 26027817 TI - (Fe,Co)@nitrogen-doped graphitic carbon nanocubes derived from polydopamine encapsulated metal-organic frameworks as a highly stable and selective non precious oxygen reduction electrocatalyst. AB - A facile approach is reported to synthesize (Fe,Co)@nitrogen-doped graphitic carbon (NGC) nanocubes (NCs) via the pyrolysis of polydopamine-encapsulated Fe3[Co(CN)6]2 NCs at 700 degrees C. Besides the comparable catalytic activity for oxygen reduction reaction (ORR) to the Pt/C catalyst, it showed much more outstanding catalytic selectivity and superior durability. PMID- 26027819 TI - Collective ordering of microscale matters in natural analogy. AB - Collective interaction occurs in many natural and artificial matters in broad scales. In a biological system, collective spatial organization of live individuals in a colony is important for their viability determination. Interactive motions between a single individual and an agglomerate are critical for whole procedure of the collective behaviors, but few has been clarified for these intermediate range behaviors. Here, collective interactions of microscale matters are investigated with human cells, plant seeds and artificial microspheres in terms of commonly occurring spatial arrangements. Human cancer cells are inherently attractive to form an agglomerate by cohesive motion, while plant chia seeds are repulsive by excreting mucilage. Microsphere model is employed to investigate the dynamic assembly equilibrated by an attraction and repulsion. There is a fundamental analogy in terms of an onset of regular pattern formation even without physical contact of individuals. The collective interactions are suggested to start before the individual components become physically agglomerated. This study contributes to fundamental understanding on the microscale particulate matters and natural pattern formation which are further useful for various applications both in academic and industrial areas. PMID- 26027820 TI - Common mechanisms of onset of cancer and neurodegenerative diseases. AB - Onset of cancer and neurodegenerative disease occurs by abnormal cell growth and neuronal cell death, respectively, and the number of patients with both diseases has been increasing in parallel with an increase in mean lifetime, especially in developed countries. Although both diseases are sporadic, about 10% of the diseases are genetically inherited, and analyses of such familial forms of gene products have contributed to an understanding of the molecular mechanisms underlying the onset and pathogenesis of these diseases. I have been working on c myc, a protooncogene, for a long time and identified various c-Myc-binding proteins that play roles in c-Myc-derived tumorigenesis. Among these proteins, some proteins have been found to be also responsible for the onset of neurodegenerative diseases, including Parkinson's disease, retinitis pigmentosa and cerebellar atrophy. In this review, I summarize our findings indicating the common mechanisms of onset between cancer and neurodegenerative diseases, with a focus on genes such as DJ-1 and Myc-Modulator 1 (MM-1) and signaling pathways that contribute to the onset and pathogenesis of cancer and neurodegenerative diseases. PMID- 26027821 TI - Role of sulfatide in influenza A virus replication. AB - Sulfatide is a 3-O-sulfated galactosylceramide that is abundantly expressed in the gastrointestinal tract, kidney, trachea, and particularly the central nervous system. Cellular sulfatide is mainly localized in the Golgi apparatus, cellular membrane, and lysosomes in cytosol. Since our earlier report showed that the influenza A virus specifically binds to sulfatide, we have investigated the roles of sulfatide in the influenza A virus lifecycle. The viral binding is independent of sialic acids, which function as virus receptors in virus attachment to the host cell surface. Sulfatide is recognized by the ectodomain of the viral envelope glycoprotein hemagglutinin (HA). Nascent HA is transported on the surface membrane of infected cells. The binding of HA with sulfatide on the cell surface induces apoptosis through potential loss of the mitochondrial membrane and nuclear translocation of apoptosis-inducing factor in mitochondria, where PB1 F2 peptide from the viral gene is accumulated. In the nucleus of infected cells, viral ribonucleoprotein (vRNP) complexes are formed from viral RNA genomes, viral nucleoprotein, and viral RNA polymerase subunits, and these complexes are selectively exported into cytosol through the nuclear membrane. The apoptosis significantly enhances the nuclear export of vRNP complexes, resulting in efficient formation of progeny viruses and facilitation of virus replication. At that time, activation of the Raf/mitogen-activated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway through sulfatide is associated with virus replication. Our studies have demonstrated that sulfatide is not a viral receptor for virus infection, and that the binding of HA with sulfatide functions as an initiation switch for the formation of progeny viruses. PMID- 26027822 TI - Low-pH Stability of Influenza A Virus Sialidase Contributing to Virus Replication and Pandemic. AB - The spike glycoprotein neuraminidase (NA) of influenza A virus (IAV) has sialidase activity that cleaves the terminal sialic acids (viral receptors) from oligosaccharide chains of glycoconjugates. A new antigenicity of viral surface glycoproteins for humans has pandemic potential. We found "low-pH stability of sialidase activity" in NA. The low-pH stability can maintain sialidase activity under acidic conditions of pH 4-5. For human IAVs, NAs of all pandemic viruses were low-pH-stable, whereas those of almost all human seasonal viruses were not. The low-pH stability was dependent on amino acid residues near the active site, the calcium ion-binding site, and the subunit interfaces of the NA homotetramer, suggesting effects of the active site and the homotetramer on structural stability. IAVs with the low-pH-stable NA showed much higher virus replication rates than those of IAVs with low-pH-unstable NA, which was correlated with maintenance of sialidase activity under an endocytic pathway of the viral cell entry mechanism, indicating contribution of low-pH stability to high replication rates of pandemic viruses. The low-pH-stable NA of the 1968 H3N2 pandemic virus was derived from the low-pH-stable NA of H2N2 human seasonal virus, one of two types classified by both low-pH stability in N2 NA and a phylogenetic tree of N2 NA genes. The 2009 H1N1 pandemic virus acquired low-pH-stable NA by two amino acid substitutions at the early stage of the 2009 pandemic. It is thought that low-pH stability contributes to infection spread in a pandemic through enhancement of virus replication. PMID- 26027823 TI - 3beta-Angeloyloxy-8beta,10beta-dihydroxyeremophila-7(11)-en-12,8alpha-lactone Inhibits Lipopolysaccharide-Induced Nitric Oxide Production in RAW264.7 Cells. AB - Farfugium japonicum (L.) KITAM, named "Lian-Peng-Cao" in China, has been traditionally used in Chinese folk medicine to treat sore throat, cold and cough due to its anti-inflammatory properties. In this study, the anti-inflammatory action of 3beta-angeloyloxy-8beta,10beta-dihydroxyeremophila-7(11)-en-12,8alpha lactone (FJ1) isolated from Farfugium japonicum and its molecular mechanism in RAW264.7 cells were investigated. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay showed that FJ1 with or without 3 ug/mL lipopolysaccharide (LPS) had no significant cytotoxicity in RAW264.7 cells. The production of nitric oxide (NO) was identified with a Griess reagent kit. The mRNA expression of inducible nitric oxide synthase (iNOS) and cytokines, including tumor necrosis factor alpha (TNF-alpha) and cyclooxygenase-2 (COX-2), was measured by real-time polymerase chain reaction (PCR). Reactive oxygen species (ROS) production was detected by flow cytometry analysis. Western blot was used to examine the protein expression of nuclear factor-kappa B (NF kappaB)/p65, inhibitor of kappa B (IkappaB)-alpha, phosphorylated IkappaB-alpha (p-IkappaB-alpha), mitogen-activated protein kinase (MAPK) molecules, iNOS, and TNF-alpha. We discovered that FJ1 possesses anti-inflammatory effects that inhibit the release of LPS-stimulated pro-inflammatory cytokines, including NO and ROS. The molecular mechanism of FJ1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules, including extracellular signal related kinase 1/2 (ERK1/2), p38 MAPK, and c-Jun NH2-terminal kinase (JNK), FJ1 also reverses IkappaB degradation and attenuates the mRNA and protein expression of NF-kappaB-related downstream inducible enzymes and cytokines, such as iNOS, TNF-alpha in RAW264.7 cells. The results suggest that FJ1 has anti-inflammatory properties, which indicates that F. japonicum can be utilized to treat inflammatory diseases. The potential mechanism is associated with the NF-kappaB and MAPK activation pathways in LPS-stimulated macrophages. PMID- 26027824 TI - Efficacy of 2-Hydroxypropyl-beta-cyclodextrin in Niemann-Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease. AB - Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-beta-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (Npc1(-/-)) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000-4000 mg/kg HPBCD improved the lifespan of Npc1(-/-) mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1(-/-) mice. Serum HPBCD concentrations, when treated at the effective dosages (1000-4000 mg/kg), were approximately 1200-2500 ug/mL at 0.5 h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in Npc1(-/-) mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000 mg (approximately 2500 mg/kg) in a patient with NPC. We observed that the effective concentration in the in vivo study using Npc1(-/-) mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients. PMID- 26027825 TI - Berberine Attenuates Vascular Remodeling and Inflammation in a Rat Model of Metabolic Syndrome. AB - Berberine is a natural product that shows benefits for metabolic syndrome (MS). However, the effects of berberine on the improvement of vascular inflammation and remodeling in MS remain unclear. This study aimed to investigate whether berberine could prevent vascular remodeling and inflammation in the MS condition. A rat model of MS was established, and MS rats were divided into two groups: MS group without berberine treatment, and MSB group with berberine treatment (each group n-10). Ten normal Wistar rats were used as controls (NC group). Vascular damage was examined by transmission electron microscopy and pathological staining. Compared to the NC group, the secretion of inflammatory factors was increased and the aortic wall thicker in the MS group. The MSB group exhibited decreased secretion of inflammatory factors and improved vascular remodeling, compared to the MS group. In addition, the levels of p38 mitogen-activated protein kinase (p38 MAPK), activating transcription factor 2 (ATF-2) and matrix metalloproteinase 2 (MMP-2) were significantly decreased in the MSB group compared to the MS group. In conclusion, our data show that berberine improves vascular inflammation and remodeling in the MS condition, and this is correlated with the ability of berberine to inhibit p38 MAPK activation, ATF-2 phosphorylation, and MMP-2 expression. PMID- 26027827 TI - Transcriptome Analysis of Nine Tissues to Discover Genes Involved in the Biosynthesis of Active Ingredients in Sophora flavescens. AB - Sophora flavescens AITON (kurara) has long been used to treat various diseases. Although several research findings revealed the biosynthetic pathways of its characteristic chemical components as represented by matrine, insufficient analysis of transcriptome data hampered in-depth analysis of the underlying putative genes responsible for the biosynthesis of pharmaceutical chemical components. In this study, more than 200 million fastq format reads were generated by Illumina's next-generation sequencing approach using nine types of tissue from S. flavescens, followed by CLC de novo assembly, ultimately yielding 83,325 contigs in total. By mapping the reads back to the contigs, reads per kilobase of the transcript per million mapped reads values were calculated to demonstrate gene expression levels, and overrepresented gene ontology terms were evaluated using Fisher's exact test. In search of the putative genes relevant to essential metabolic pathways, all 1350 unique enzyme commission numbers were used to map pathways against the Kyoto Encyclopedia of Genes and Genomes. By analyzing expression patterns, we proposed some candidate genes involved in the biosynthesis of isoflavonoids and quinolizidine alkaloids. Adopting RNA-Seq analysis, we obtained substantially credible contigs for downstream work. The preferential expression of the gene for putative lysine/ornithine decarboxylase committed in the initial step of matrine biosynthesis in leaves and stems was confirmed in semi-quantitative polymerase chain reaction (PCR) analysis. The findings in this report may serve as a stepping-stone for further research into this promising medicinal plant. PMID- 26027826 TI - Involvement of Renin-Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice. AB - This study was performed to investigate the effect of angiotensin-converting enzyme inhibitor, captopril, on bone metabolism and histology, and the action of captopril on the components of the skeletal renin-angiotensin system (RAS) and bradykinin receptor in normal male mice. The mice were orally administered captopril (10 mg/kg) for 4 weeks with vehicle-treated mice as normal control. The histology of trabecular bone at the distal femoral end was determined by hematoxylin & eosin, Safranin O and Masson-Trichrome staining. The captopril treated mice showed a decreased level of testosterone (p<0.05) and procollagen type I N-terminal propeptide (p<0.05) in serum as compared to those in the control group. Captopril has detrimental effects on trabecular bone as demonstrated by the loss of cancellous bone mass and network connections as well as changes to the chondrocytes zone. The expression of angiotensin-converting enzyme (p<0.05), renin receptor (p<0.01), angiotensin II (p<0.05) and bradykinin receptor 2 (p<0.05) was significantly up-regulated following the captopril treatment. Thus, the potential underlying mechanism of the damage of captopril on bone can be attributed the increased activity of local bone RAS and the activation of bradykinin receptor. PMID- 26027828 TI - Effects of the 5-HT(1A) Receptor Agonist Tandospirone on ACTH-Induced Sleep Disturbance in Rats. AB - The aim of this study was to compare the effect of the serotonin (5-HT)1A receptor agonist tandospirone versus that of the benzodiazepine hypnotic flunitrazepam in a rat model of long-term adrenocorticotropic hormone (ACTH) induced sleep disturbance. Rats implanted with electrodes for recording electroencephalogram and electromyogram were injected with ACTH once daily at a dose of 100 ug/rat. Administration of ACTH for 10 d caused a significant increase in sleep latency, decrease in non-rapid eye movement (non-REM) sleep time, and increase in wake time. Tandospirone caused a significant decrease in sleep latency and increase in non-REM sleep time in rats treated with ACTH. The effect of tandospirone on sleep patterns was antagonized by the 5-HT1A receptor antagonist WAY-100635. In contrast, flunitrazepam had no significant effect on sleep parameters in ACTH-treated rats. These results clearly indicate that long term administration of ACTH causes sleep disturbance, and stimulating the 5-HT1A receptor by tandospirone may be efficacious for improving sleep in cases in which benzodiazepine hypnotics are ineffective. PMID- 26027829 TI - A Compound Inhibits Biofilm Formation of Staphylococcus aureus from Streptomyces. AB - Biofilm is one virulence factor of bacteria. It contributes not only to bacterial adherence to many kinds of infection-establishing surfaces, but also to bacterial resistance against antimicrobial agents and antiseptic agents. Thus, inhibitors of bacterial biofilm formation should be useful in the prevention of infections. We found that a culture of Streptomyces sp. strain MC11024 showed inhibitory activity on biofilm formation by Staphylococcus aureus and isolated streptorubin B as an inhibitor of this formation in S. aureus. The biofilm formation of methicillin resistant S. aureus (MRSA) N315 was reduced to less than 30% at 1 ug/mL of streptorubin B, and at this concentration cell growth was not affected. Our study suggests that streptorubin B has the potential to be a leading compound of anti-infectious agents of S. aureus. PMID- 26027830 TI - Cyclosporine nanomicelle eye drop: a novel medication for corneal graft transplantation treatment. AB - Corneal transplantation has been used to treat severe eye disease for decades, but the therapeutic effect of the operation is highly compromised by immunological allograft rejection. To improve the success rate of corneal transplantation, we studied the protective effects of cyclosporine nanomicelle eye drops (CNED) on immune rejection after high-risk corneal transplantation and its underlying mechanisms. The therapeutic effects against immune rejection of both conventional cyclosporine eye drop (CCED) and CNED in different concentrations were assessed and compared using animal models of corneal transplantation. In addition, the expression of nuclear factor-kappa-gene binding (NF-kappaB) as well as its target intracellular adhesion molecule 1 (ICAM-1) in the corneal samples obtained from recipients treated with either CCED or CNED was also screened. The results showed that the CNED displayed significantly better effects at suppressing the immune response induced by corneal transplantation compared to CCED. CNED also significantly down-regulated the NF-kappaB and ICAM-1 expressions, indicating NF-kappaB might play an important role in the initiation of an immune response against the allograft. Our study demonstrates CNED may suppress the NF-kappaB pathway to attenuate the immune response, which highlights the possible therapeutic applications of cyclosporine nanomicelle eye drops in corneal transplantation. PMID- 26027831 TI - In Vitro Study of L-Glutamate and L-Glutamine Transport in Retinal Pericytes: Involvement of Excitatory Amino Acid Transporter 1 and Alanine-Serine-Cysteine Transporter 2. AB - L-Glutamate (L-Glu) is known to be a relaxant of pericytes and to induce changes in microcirculatory hemodynamics. Since the concentration of L-Glu which induces the dilation of retinal capillaries is reported to be high compared with the estimated concentration in the retinal interstitial fluid, it is hypothesized that some systems involving concentrative L-Glu release are present in retinal pericytes. The purpose of this study was to investigate the existence of L-Glu storing systems, which contribute to autocrine L-Glu release, in retinal pericytes using conditionally immortalized rat retinal pericytes (TR-rPCT1 cells), which express mRNAs of L-Glu-synthesizing enzymes from L-glutamine (L Gln). TR-rPCT1 cells express the mRNAs of vesicular L-Glu transporter 1 (VGLUT1), indicating that L-Glu in the cytoplasm is taken up into VGLUT1-expressing vesicles of retinal pericytes. L-Glu and L-Gln are taken up into TR-rPCT1 cells via Na(+)-dependent saturable process(es) with a Km value of 22.4 uM and 163 uM, respectively. The [(3)H]L-Glu uptake was inhibited by ca. 50% in the presence of D-aspartate, a substrate of excitatory amino acid transporter (EAAT) subtypes, whereas substrates of alanine-serine-cysteine transporter (ASCT) subtypes exhibited only a weak inhibitory effect on [(3)H]L-Glu uptake compared with D aspartate. Regarding the L-Gln uptake by TR-rPCT1 cells, the inhibitory effect of ASCT substrates on the [(3)H]L-Gln uptake was stronger than that of substrates of other neutral amino acid transport systems. Consequently, it was determined that EAAT1 and ASCT2 play a role in the transport of L-Glu and L-Gln, respectively, from retinal interstitial fluid to the cytoplasm of retinal pericytes. PMID- 26027833 TI - Anti-apoptotic and Beneficial Metabolic Activities of Resveratrol in Type II Gaucher Disease. AB - Gaucher disease (GD) is one of the most common lysosomal storage disorders and is caused by an inherited deficiency in glucocerebrosidase. Resveratrol is a phytoalexin that has many beneficial activities, including anti-oxidant, anti apoptotic, and neuroprotective effects. The aim of this study was to determine if resveratrol has a therapeutic effect on primary fibroblast cells derived from a patient with type II GD. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of resveratrol on cell viability. The expression patterns of apoptosis-inducing factor (AIF), Bcl-2 associated X protein (Bax), caspase-3, acetyl-coenzyme A acetyltransferase 1 (ACAT1), E3-binding protein (E3BP), and citrate synthase (CS) were evaluated by Western blotting to characterize the effect of resveratrol treatment on GD cells. TLC was performed to determine glucosylceramide levels in resveratrol-treated GD cells. Resveratrol increased GD cell viability compared to untreated control cells. Further, resveratrol treatment dose-dependently decreased the apoptotic factors AIF, Bax, and cleaved caspase-3 levels, whereas ACAT1, E3BP, and CS expression dose-dependently increased. TLC analysis showed reduced levels of intracellular glucosylceramides in resveratrol-treated GD cells. These findings demonstrate that resveratrol can reduce cellular stress resulting from glucosylceramide accumulation, and suggest that resveratrol should be studied further as a novel therapeutic agent for GD. PMID- 26027832 TI - In Vivo Anti-tumor Effects of the Ethanol Extract of Gleditsia sinensis Thorns and Its Active Constituent, Cytochalasin H. AB - Angiogenesis is the process of new vessel formation from pre-existing blood vasculature and is critical for continuous tumor growth. We previously reported that an ethanolic extract of Gleditsia sinensis thorns (EEGS) and its active constituent, cytochalasin H, have anti-angiogenic activity in vitro and in vivo via suppression of endothelial cell functions. In the present study, EEGS and cytochalasin H were observed to efficiently inhibit tumor growth in an in ovo xenograft model without significant toxicity. We repeatedly observed the anti tumor and anti-metastatic effects of EEGS in representative animal models. These results suggest that EEGS and its active constituent, cytochalasin H, are potential candidates for the development of anti-angiogenic cancer drugs. PMID- 26027834 TI - In vitro and in vivo evaluations of buccal tablet formulations of ritodrine hydrochloride. AB - Buccal tablets of ritodrine (RD) hydrochloride (HCl), called RD-HCl, were prepared using the direct compression method with alginate (AL), lactose (LC), magnesium stearate (ST), and microcrystalline cellulose (MC) as excipients. The tablets were evaluated based on hardness, and tablets weighing 80 mg and with hardness of greater than 30 N were chosen as appropriate ones. As a result, tablets composed of RD-HCl (4 mg)/LC (38.5 mg)/ST (0.5 mg)/MC (37 mg) and RD-HCl (4 mg)/AL(7 mg)/LC (28.5 mg)/ST (0.5 mg)/MC (37 mg), called D9 and D10, respectively, were selected. These tablets were further evaluated based on in vitro dissolution and in vivo absorption studies in rats. D9 rapidly released RD, achieved an effective plasma concentration from 15 min to 7 h after its buccal administration, and did not exceed the toxic plasma level of 80 ng/mL. D10 gradually released RD, and maintained an effective concentration from 1 h to 7 h after its buccal administration, without exceeding the toxic plasma level. The absorption was more prolonged in D10 than D9. Their in vivo release was considered to be caused gradually from the amount of RD remaining in the oral cavity at 7 h, in particular D10. The superior retention of D10 in plasma and oral cavity appeared to be related to its higher mucoadhesive properties. Although these results were obtained using rats, they suggest that the chosen tablets should have adequate characteristics from the viewpoints of plasma levels. PMID- 26027835 TI - Nifedipine prevents sodium caprate-induced barrier dysfunction in human epidermal keratinocyte cultures. AB - Tight junctions (TJs) of the epidermis play an important role in maintaining the epidermal barrier. TJ breakdown is associated with skin problems, such as wrinkles and transepidermal water loss (TEWL). Clinical studies have reported that topical nifedipine is effective in reducing the depth of wrinkles and improving TEWL. However, it remains unknown whether nifedipine influences the TJ function in the epidermis. In the present study, we investigated the effect of nifedipine on epidermal barrier dysfunction in normal human epidermal keratinocytes (NHEKs) treated with sodium caprate (C10), a TJ inhibitor. Nifedipine reversed the C10-decreased transepithelial electrical resistance values as a measure of disruption of the epidermal barrier. Immunocytochemical observations revealed that nifedipine improved the C10-induced irregular arrangement of claudin-1, a key protein in TJs. Taken together, these findings suggest that nifedipine prevents epidermal barrier dysfunction, at least in part, by reconstituting the irregular claudin-1 localization at TJs in C10-treated NHEKs. PMID- 26027836 TI - Quantitative structure-activity relationship model for the fetal-maternal blood concentration ratio of chemicals in humans. AB - A quantitative structure-activity relationship (QSAR) model of the fetal-maternal blood concentration ratio (F/M ratio) of chemicals was developed to predict the placental transfer in humans. Data on F/M ratio of 55 compounds found in the literature were separated into training (75%, 41 compounds) and testing sets (25%, 14 compounds). The training sets were then subjected to multiple linear regression analysis using the descriptors of molecular weight (MW), topological polar surface area (TopoPSA), and maximum E-state of hydrogen atom (Hmax). Multiple linear regression analysis and a cross-validation showed a relatively high adjusted coefficient of determination (Ra(2)) (0.73) and cross-validated coefficient of determination (Q(2)) (0.71), after removing three outliers. In the external validation, R(2) for external validation (R(2)pred) was calculated to be 0.51. These results suggested that the QSAR model developed in this study can be considered reliable in terms of its robustness and predictive performance. Since it is difficult to examine the F/M ratio in humans experimentally, this QSAR model for prediction of the placental transfer of chemicals in humans could be useful in risk assessment of chemicals in humans. PMID- 26027837 TI - Irciniastatin A induces potent and sustained activation of extracellular signal regulated kinase and thereby promotes ectodomain shedding of tumor necrosis factor receptor 1 in human lung carcinoma A549 cells. AB - Irciniastatin A is a pederin-type marine product that potently inhibits translation. We have recently shown that irciniastatin A induces ectodomain shedding of tumor necrosis factor (TNF) receptor 1 with slower kinetics than other translation inhibitors. In human lung carcinoma A549 cells, irciniastatin A induced a marked and sustained activation of extracellular signal-regulated kinase (ERK) and induced little activation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK). Moreover, the TNF receptor 1 shedding induced by irciniastatin A was blocked by the MAP kinase/ERK kinase inhibitor U0126, but not by the p38 MAP kinase inhibitor SB203580 or the JNK inhibitor SP600125. Thus unlike other translation inhibitors that trigger ribotoxic stress response, our results show that irciniastatin A is a unique translation inhibitor that induces a potent and sustained activation of the ERK pathway, and thereby promotes the ectodomain shedding of TNF receptor 1 in A549 cells. PMID- 26027838 TI - Impaired skin barrier function in mice with colon carcinoma induced by azoxymethane and dextran sodium sulfate. AB - We have previously reported that impaired skin barrier function was induced by small intestinal injury in mice. Therefore, we postulated that other intestinal diseases might also influence skin barrier function. In this study, we evaluated the skin barrier function of hairless mice with colon carcinoma that was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). In mice treated with these drugs, we observed elevated transepidermal water loss and reduced skin hydration levels, compared to those in the control mice. In addition, plasma nitrogen di/trioxide (NO2(-)/NO3(-)) levels were significantly elevated, and expression of type I collagen was significantly reduced in the treated mice, compared to those in control. These results suggest that impaired skin barrier function occurs in mice when colon carcinoma is present. PMID- 26027839 TI - The management of eosinophilic gastroenteritis. AB - Eosinophilic gastroenteritis (EG) is a rare disorder characterized by eosinophilic infiltration of the gastrointestinal tract. No medication at present is approved by the Food and drug administration of United States for the treatment of EG. The rarity of the disease limits our experience with the different management options. It also limits the ability to conduct randomized controlled trials that could clearly delineate the efficacy of new therapeutic agents. This review assesses the various management options that have been tried on patients with EG. PMID- 26027840 TI - Spontaneous portosystemic shunts in noncirrhotic patients presenting with encephalopathy. AB - Portosystemic shunts (PSS) are common in patients with chronic liver disease and portal hypertension, however, their occurrence in noncirrhotic individuals is likely under appreciated. Patients may present with symptoms of hepatic encephalopathy and/or gastrointestinal bleeding and undergo extensive work up for liver disease to no avail. Often, these patients suffer for years with accruing medical expenses and numerous hospitalizations related to repeated episodes of encephalopathy. The underlying cause may go undiagnosed or misdiagnosed as occult hepatic dysfunction or even a neuropsychological disorder. In many cases, abdominal CT imaging demonstrates the abnormal portosystemic connection well before it is recognized as the cause of symptoms. In this brief report, we discuss three cases presenting with symptoms of encephalopathy and report successful management with endovascular occlusion of the portosystemic shunts. PMID- 26027841 TI - Chylothorax after esophagectomy for esophageal cancer: risk factors and management. AB - BACKGROUND: Chylothorax is an uncommon complication of esophagectomy. It carries significant morbidity and mortality. The predisposing factors are ill-defined. METHODS: We retrospectively evaluated the data of 45 patients of carcinoma esophagus who underwent esophagectomy after neoadjuvant chemoradiotherapy (NACRT) from January 2010 to July 2012 in our tertiary health care center. RESULTS: Four patients (8.88 %) had chylothorax. On analysis of perioperative factors, it was found that patients with chylothorax had tumor in middle third of thoracic esophagus (100 %), shown partial response to neoadjuvant chemoradiation (NACRT) (100 %) and were associated with difficult mediastinal dissection (75 %) leading to higher blood loss requiring transfusion unlike those without chylothorax. There was no significant difference in the incidence of chylothorax following transhiatal, 3/35 = 8.57 % or transthoracic esophagectomy 1/10 = 10 % (p = 0.898). Three patients were managed by transabdominal en masse ligation of tissue between aorta and azygos vein while one patient was managed conservatively. Patients were discharged after a mean hospital stay of 15.5 days. The 30-day mortality rates in the two groups were similar (0 % vs. 4.8 %). CONCLUSION: Difficult mediastinal dissection during esophagectomy in middle esophageal cancer may lead to thoracic duct injury. Complete response to NACRT may reduce the risk of chylothorax. Early transabdominal en masse ligation carries excellent results. Low output fistula following thoracic duct injury can be managed conservatively. PMID- 26027842 TI - Electrochemical and spectroscopic study of Zn(ii) coordination and Zn electrodeposition in three ionic liquids with the trifluoromethylsulfonate anion, different imidazolium ions and their mixtures with water. AB - In this paper we report on the use of three ionic liquids, 1-methylimidazolium trifluoromethylsulfonate ([MIm]TfO), 1-ethyl-3-methylimidazolium trifluoromethylsulfonate ([EMIm]TfO) and 1-ethyl-2,3-dimethylimidazolium trifluoromethylsulfonate ([EMMIm]TfO) containing zinc trifluoromethylsulfonate as electrolytes for zinc electrodeposition. By varying the cations from [MIm](+)via [EMIm](+) to [EMMIm](+), the vibrational band in the Far-IR spectra below 200 cm( 1), characterizing the cation-anion interaction, is shifted to lower wavenumbers, which suggests that the interaction between cations and anions is arranged in order of [MIm]TfO > [EMIm]TfO > [EMMIm]TfO. The coordination of Zn(2+) ions in these electrolytes was investigated by Raman spectroscopy. The Raman spectra show obvious differences in terms of the solvation of Zn(2+) ions in the dried electrolytes. The average number of TfO(-) anions bound to each Zn(2+) ion is lower in [MIm]TfO than in [EMIm]TfO and in [EMMIm]TfO, respectively. In ionic liquid-water mixtures, aqueous zinc species were formed in all cases. The differences in zinc species present in the electrolytes should have an influence on their electrochemical behavior and on the morphology of the deposits. In dried ionic liquids, the cyclic voltammograms reveal that the potentials for the deposition of zinc were shifted to more negative values by varying the cations, while in ionic liquid-water mixtures, the deposition of zinc occurs at almost the same potential. The SEM and XRD results show that the surface morphology, crystal shape and size as well as crystallographic orientation of the deposits are markedly affected by varying the cations of the ionic liquids. PMID- 26027843 TI - Influence of pneumoperitoneum and postural change on the cardiovascular and respiratory systems in dogs. AB - We investigated the influence of pneumoperitoneum#(PP) and postural change under inhalation anesthesia with isoflurane, which is routinely used in dogs, on the cardiovascular and respiratory systems. As test animals, 6 adult beagles were used. To induce anesthesia, atropine, butorphanol and propofol were intravenously injected. Anesthesia was maintained with 1.3 MAC (1.7%) isoflurane. The following were the experiment conditions: I:E ratio, 1:1.9; tidal air exchange, 20 ml/kg; and ventilation frequency, 14 times/min. Respiration was regulated so that the PaCO2 was approximately 35 to 40 mmHg before the start of the experiment. PP with CO2 (intraperitoneal pressure 15 mmHg) and a postural change (15 degrees C) was performed during the experiment. As parameters of circulatory kinetics, heart rate (HR), mean aortic pressure (MAP), mean pulmonary arterial pressure (MPAP), central venous pressure (CVP), femoral venous pressure (FVP) and cardiac output (CO) were measured. As parameters of respiratory kinetics, airway pressure (PAW) and blood gas (BG) were measured. There were significant increases in HR, MAP, MPAP, CVP, FVP, CO, PAW and PaCO2 after PP in the horizontal position. There were significant increases in CVP, FVP, PAW and PaCO2 after PP in the Trendelenburg position. There were significant increases in the MPAP, CVP, FVP, PAW and PaCO2 after PP in the inverse Trendelenburg position. There was a significant difference in FVP after PP between the Trendelenburg position and inverse Trendelenburg position. The results of this experiment suggest that appropriate anesthesia control, such as changing the ventilation conditions after PP, is required for laparoscopic surgery under inhalation anesthesia with isoflurane. PMID- 26027845 TI - Metabolic remodeling of bacterial surfaces via tetrazine ligations. AB - Bioorthogonal click ligations are extensively used for the introduction of functional groups in biological systems. Tetrazine ligations are attractive in that they are catalyst-free and display favorable kinetics. We describe the efficient remodeling of bacterial cell surfaces using unnatural d-amino acids derivatized with tetrazine ligation handles. The metabolic incorporation of these unnatural d-amino acids onto bacterial cell surfaces resulted in a site-selective installation of fluorophores. PMID- 26027844 TI - In vitro host range of feline morbillivirus. AB - Feline morbillivirus (FmoPV) is an emerging virus in cats, which is associated with tubulointerstitial nephritis. To study the in vitro host range of FmoPV, we inoculated FmoPV strain SS1 to 32 cell lines originated from 13 species and cultured for 2 weeks, followed by RNA extraction and reverse-transcription polymerase chain reaction for FmoPV detection. As a result, only cell lines derived from cats and African green monkeys were susceptible to FmoPV. FmoPV infects diverse feline cell lines: epithelial, fibroblastic, lymphoid and glial cells. These results indicate that the receptor (s) for FmoPV are ubiquitously expressed in cats. No infectivity of FmoPV was observed in human cell lines, which suggests least threatening of cross-species transmission of FmoPV from cats to humans. PMID- 26027846 TI - Structural biology. Copying the bunyavirus genome. PMID- 26027847 TI - Effects of different manganese precursors as promoters on catalytic performance of CuO-MnOx/TiO2 catalysts for NO removal by CO. AB - Two different precursors, manganese nitrate (MN) and manganese acetate (MA), were employed to prepare two series of catalysts, i.e., xCuyMn(N)/TiO2 and xCuyMn(A)/TiO2, by a co-impregnation method. The catalysts were characterized by XRD, LRS, CO-TPR, XPS and EPR spectroscopy. The results suggest that: (1) both xCuyMn(N)/TiO2 and xCuyMn(A)/TiO2 catalysts exhibit much higher catalytic activities than an unmodified Cu/TiO2 catalyst in the NO + CO reaction. Furthermore, the activities of catalysts modified with the same amount of manganese are closely dependent on manganese precursors. (2) The enhancement of activities for Mn-modified catalysts should be attributed to the formation of the surface synergetic oxygen vacancy (SSOV) Cu(+)-?-Mn(y+) in the reaction process. Moreover, since the formation of the SSOV (Cu(+)-?-Mn(3+)) in the xCuyMn(N)/TiO2 catalyst is easier than that (Cu(+)-?-Mn(2+)) in the xCuyMn(A)/TiO2 catalyst, the activity of the xCuyMn(N)/TiO2 catalyst is higher than that of the xCuyMn(A)/TiO2 catalyst. This conclusion is well supported by the XPS and EPR results. PMID- 26027848 TI - The Management of Schizophrenia in Clinical Practice (MOSAIC) Registry: a focus on patients, caregivers, illness severity, functional status, disease burden and healthcare utilization. AB - BACKGROUND: The Management of Schizophrenia in Clinical Practice (MOSAIC), a disease-based registry of schizophrenia, was initiated in December 2012 to address important gaps in our understanding of the impact and burden of schizophrenia and to provide insight into the current status of schizophrenia care in the US. Recruitment began in December 2012 with ongoing assessment continuing through May 2014. METHODS: Participants were recruited from a network of 15 centralized Patient Assessment Centers supporting proximal care sites. Broad entry criteria included patients diagnosed with schizophrenia, schizophreniform or schizoaffective disorder, presenting within the normal course of care, in usual treatment settings, aged >=18years and able to read and speak English. RESULTS: By May 2014, 550 participants (65.8% male, 59.8% White, 64.4% single, mean age 42.9years), were enrolled. The majority had a diagnosis of schizophrenia (62.0%). Mean illness duration at entry was 15.0years. Common comorbidities at entry were high lipid levels (26.9%), hypertension (23.1%) and type II diabetes (13%). Participants were categorized by baseline overall Clinical Global Impression-Schizophrenia Severity Score as minimally (9.1%), mildly (25.3%), moderately (39.9%), markedly (22.3%) and severely (3.4%) ill. Most commonly used second generation antipsychotics at entry were risperidone (17.8%), clozapine (16.5%), olanzapine (14.0%), aripiprazole (13.6%) and quetiapine (5.6%). CONCLUSIONS: No large-scale patient registry has been conducted in the US to longitudinally follow patients with schizophrenia and describe symptom attributes, support network, care access and disease burden. These data provide important epidemiological, clinical and outcome insights into the burden of schizophrenia in the US. PMID- 26027849 TI - Biomarkers in Interstitial lung diseases. AB - Interstitial lung diseases (ILD)s represent a heterogeneous group of rare respiratory disorders, mostly chronic and associated with high morbidity and mortality. They are complex diseases that remain, in children, largely underdiagnosed and difficult to manage. Therefore, identification of biomarkers, which could be used for ILD diagnosis, measurements of disease severity and progression, and responsiveness to treatments, is a major challenge for clinical practice and for translational research. The present review focuses on blood biomarkers and provides an overview on the current information on molecular parameters of interest for ILD patient management. PMID- 26027850 TI - Can they recover? An assessment of adult adjustment problems among males in the abstainer, recovery, life-course persistent, and adolescence-limited pathways followed up to age 56 in the Cambridge Study in Delinquent Development. AB - Much research has examined Moffitt's developmental taxonomy, focusing almost exclusively on the distinction between life-course persistent and adolescence limited offenders. Of interest, a handful of studies have identified a group of individuals whose early childhood years were marked by extensive antisocial behavior but who seemed to recover and desist (at least from severe offending) in adolescence and early adulthood. We use data from the Cambridge Study in Delinquent Development to examine the adult adjustment outcomes of different groups of offenders, including a recoveries group, in late middle adulthood, offering the most comprehensive investigation of this particular group to date. Findings indicate that abstainers comprise the largest group of males followed by adolescence-limited offenders, recoveries, and life-course persistent offenders. Furthermore, the results reveal that a host of adult adjustment problems measured at ages 32 and 48 in a number of life-course domains are differentially distributed across these four offender groups. In addition, the recoveries and life-course persistent offenders often show the greatest number of adult adjustment problems relative to the adolescence-limited offenders and abstainers. PMID- 26027851 TI - Evaluation of long term (10-years+) dysphagia and trismus in patients treated with concurrent chemo-radiotherapy for advanced head and neck cancer. AB - OBJECTIVES: Assessment of long term (10-years+) swallowing function, mouth opening, and quality of life (QoL) in head and neck cancer (HNC) patients treated with chemo-radiotherapy (CRT) for advanced stage IV disease. MATERIALS AND METHODS: Twenty-two disease-free survivors, participating in a multicenter randomized clinical trial for inoperable HNC (1999-2004), were evaluated to assess long-term morbidity. The prospective assessment protocol consisted of videofluoroscopy (VFS) for obtaining Penetration Aspiration Scale (PAS) and presence of residue scores, Functional Oral Intake Scale (FOIS) scores, maximum mouth opening measurements, and (SWAL-QOL and study-specific) questionnaires. RESULTS: At a median follow-up of 11-years, 22 patients were evaluable for analysis. Ten patients (46%) were able to consume a normal oral diet without restrictions (FOIS score 7), whereas 12 patients (54%) had moderate to serious swallowing issues, of whom 3 (14%) were feeding tube dependent. VFS evaluation showed 15/22 patients (68%) with penetration and/or aspiration (PAS?3). Fifty five percent of patients (12/22) had developed trismus (mouth opening?35mm), which was significantly associated with aspiration (p=.011). Subjective swallowing function (SWAL-QOL score) was impaired across almost all QoL domains in the majority of patients. Patients treated with IMRT showed significantly less aspiration (p=.011), less trismus (p=.035), and less subjective swallowing problems than those treated with conventional radiotherapy. CONCLUSION: Functional swallowing and mouth opening problems are substantial in this patient cohort more than 10-years after organ-preservation CRT. Patients treated with IMRT had less impairment than those treated with conventional radiotherapy. PMID- 26027852 TI - Prognostic Value of the Tumour-Infiltrating Dendritic Cells in Colorectal Cancer: A Systematic Review. AB - Dendritic cells (DCs) either boost the immune system (enhancing immunity) or dampen it (leading to tolerance). This dual effect explains their vital role in cancer development and progression. DCs have been tested as a predictor of outcomes for cancer progression. Eight studies evaluated tumour-infiltrating DCs (TIDCs) as a predictor for colorectal cancer (CRC) outcomes. The detection of TIDCs has not kept pace with the increased knowledge about the identification of DC subsets and their maturation status. For that reason, it is difficult to draw a conclusion about the performance of DCs as a predictor of outcome for CRC. In this review, we comprehensively examine the evidence for the in situ immune response due to DC infiltration, in predicting outcome in primary CRC and how such information may be incorporated into routine clinical assessment. PMID- 26027853 TI - Associations between Australian clinical medical practitioner exposure to workplace aggression and workforce participation intentions. AB - OBJECTIVE: The aim of the present study was to determine the association between clinician exposure to workplace aggression from any source in the previous 12 months and workforce participation intentions. METHODS: A cross-sectional survey, in the third wave of the Medicine in Australia: Balancing Employment and Life (MABEL) study, was conducted between March 2010 and June 2011. Respondents were a representative sample of 9449 Australian general practitioners (GPs) and GP registrars (n = 3515), specialists (n = 3875), hospital non-specialists (n = 1171) and specialists in training (n = 888). Associations between aggression exposure and workforce participation intentions were determined using logistic regression modelling. RESULTS: In adjusted models, aggression exposure was positively associated with a greater likelihood of intending to reduce clinical workload in the next 5 years (odds ratio (OR) = 1.15, 95% confidence interval (CI) 1.02-1.29) and intending to leave patient care within 5 years (OR = 1.20, 95% CI 1.07-1.35). When also accounting for well being factors, aggression exposure remained positively associated with intending to leave patient care within 5 years (OR = 1.13, 95% CI 1.00-1.27). CONCLUSIONS: Exposure to workplace aggression presents a risk to the retention of medical practitioners in clinical practice and a potential risk to community access to quality medical care. More concerted efforts in preventing and minimising workplace aggression in clinical medical practice are required. PMID- 26027857 TI - Global Mental Health: concepts, conflicts and controversies. AB - This paper introduces, describes and analyses the emerging concept of Global Mental Health (GMH). The birth of GMH can be traced to London, 2007, with the publication of a series of high-profile papers in The Lancet. Since then, GMH has developed into a movement with proponents, adherents, opponents, an ideology and core activities. The stated aims of the Movement for GMH are 'to improve services for people living with mental health problems and psychosocial disabilities worldwide, especially in low- and middle-income countries where effective services are often scarce'. GMH could be considered an attempt to right a historic wrong. During the colonial and post-colonial eras, the mental health of subject populations was accorded a very low priority. This was fuelled by scientific racism, which alleged that mental illness was uncommon in places such as Africa. As developing nations have made the epidemiological transition, the burden of mental illness has proportionately increased, with research suggesting a massive 'treatment gap' between those in need and those actually receiving formal mental health care. As such, much GMH research and action has been devoted to: (i) the identification and scale-up of cost-effective evidence-supported interventions that could be made more widely available; (ii) task-shifting of such intervention delivery to mental-health trained non-specialist Lay Health Workers. GMH has come under sustained critique. Critics suggest that GMH is colonial medicine come full circle, involving the top-down imposition of Western psychiatric models and solutions by Western-educated elites. These critiques suggest that GMH ignores the various indigenous modalities of healing present in non-Western cultures, which may be psychologically adaptive and curative. Relatedly, critics argue that GMH could be an unwitting Trojan horse for the mass medicalisation of people in developing countries, paving the way for exploitation by Big Pharma, while ignoring social determinants of health. PMID- 26027856 TI - Optimization of methods for the genetic modification of human T cells. AB - CD4(+) T cells are not only critical in the fight against parasitic, bacterial and viral infections, but are also involved in many autoimmune and pathological disorders. Studies of protein function in human T cells are confined to techniques such as RNA interference (RNAi) owing to ethical reasons and relative simplicity of these methods. However, introduction of RNAi or genes into primary human T cells is often hampered by toxic effects from transfection or transduction methods that yield cell numbers inadequate for downstream assays. Additionally, the efficiency of recombinant DNA expression is frequently low because of multiple factors including efficacy of the method and strength of the targeting RNAs. Here, we describe detailed protocols that will aid in the study of primary human CD4(+) T cells. First, we describe a method for development of effective microRNA/shRNAs using available online algorithms. Second, we illustrate an optimized protocol for high efficacy retroviral or lentiviral transduction of human T-cell lines. Importantly, we demonstrate that activated primary human CD4(+) T cells can be transduced efficiently with lentiviruses, with a highly activated population of T cells receiving the largest number of copies of integrated DNA. We also illustrate a method for efficient lentiviral transduction of hard-to-transduce un-activated primary human CD4(+) T cells. These protocols will significantly assist in understanding the activation and function of human T cells and will ultimately aid in the development or improvement of current drugs that target human CD4(+) T cells. PMID- 26027855 TI - Nitric oxide in liver diseases. AB - Nitric oxide (NO) and its derivatives play important roles in the physiology and pathophysiology of the liver. Despite its diverse and complicated roles, certain patterns of the effect of NO on the pathogenesis and progression of liver diseases are observed. In general, NO derived from endothelial NO synthase (eNOS) in liver sinusoidal endothelial cells (LSECs) is protective against disease development, while inducible NOS (iNOS)-derived NO contributes to pathological processes. This review addresses the roles of NO in the development of various liver diseases with a focus on recently published articles. We present here two recent advances in understanding NO-mediated signaling - nitrated fatty acids (NO2-FAs) and S-guanylation - and conclude with suggestions for future directions in NO-related studies on the liver. PMID- 26027858 TI - Trained clinical nurse specialists proficiently obtain bone marrow aspirates and trephine biopsies in a nearly painless procedure--a prospective evaluation study. AB - Patients often experience bone marrow examinations (BMEs) as frightening and painful. Varying operators and uncertainty about who will perform the BME worsen their anxiety. In our study, clinical nurse specialists (CNSs) were trained to perform BMEs to ensure continuity and to test the feasibility, patient satisfaction, and biopsy quality. This exploratory evaluation assessed 574 BMEs at our tertiary center between January 2012 and February 2013, 398 BMEs performed by CNS and 176 by physicians. Our aims were to determine whether BMEs by CNS yield results similar to those of physicians, analyzing (1) patient satisfaction with the BME (a) consent and (b) performance, (2) induced pain, and (3) quality of aspirates and length of trephine biopsies. When performed by CNS, 100 % of the patients were satisfied with the consent procedure and 99 % with the BME performance (physicians 99 and 91 %, respectively). The median pain score was low when both CNS and physicians performed the BME, with no or only mild pain in 92 and 76 % of patients, respectively. Bone marrow (BM) aspirates by CNS and physicians were assessed as technically evaluable in ~70 %; moreover, the median length of trephine biopsies was similar when performed by CNS or physicians with 12 and 13 mm, respectively. In conclusion, BMEs conducted by motivated CNS and within a structured training program are feasible and yield equal outcomes compared to physicians. The use of adequate pain management during BMEs by trained and experienced operators results in an extremely rare use of sedatives, low pain scores, and high patient satisfaction. PMID- 26027859 TI - Is thrombin time too sensitive to dabigatran anticoagulation for clinical decision making in the setting of acute hemorrhage? PMID- 26027860 TI - Surgical treatment of mandibular condyle fractures using the retromandibular anterior transparotid approach and a triangular-positioned double miniplate osteosynthesis technique: A clinical and radiological evaluation of 124 fractures. AB - OBJECTIVE: Different modalities have been described regarding the treatment of mandibular condyle fractures. The most advantageous and safest one is still a topic of discussion. The present analysis describes the combination of a retromandibular, transparotideal approach combined to a triangular-positioned double-miniplate osteosynthesis, with a special regard for the patients' long term outcomes. MATERIAL AND METHODS: Clinical data of 102 patients with 124 condyle fractures treated with the mentioned surgical procedure were evaluated. Functional parameters such as the maximal interincisal distance, deviations/deflections, facial nerve function, occlusion as well as complications regarding the parotid gland, osteosynthesis, and esthetics were evaluated 1 week, 2 weeks, 3 months, and 6 months postoperatively. RESULTS: The mean maximal interincisal distance ranged from 38 mm after 1 week to 45 mm after 6 months. Deviations/deflections were seen in 22.5% of the cases 1 week postoperatively and decreased to 2% at 6 months postoperatively. A temporary facial palsy was diagnosed in 3.9% during the first follow-up, whereas no impairment was recorded after 3 or 6 months. At the same time, no patient had occlusional disturbances or complications regarding the parotid gland or the osteosynthesis 6 months postoperatively. CONCLUSIONS: Direct fracture visualization and a stable three dimensional fracture stabilization are the main advantages of the presented combination of a surgical approach and osteosynthesis technique. Additionally, the absence of long-term complications confirms the safety of the procedure. Therefore, it may be considered as a successful treatment option for mandibular condyle fractures. PMID- 26027861 TI - The antioxidant and anti-inflammatory efficiency of hyaluronic acid after third molar extraction. AB - PURPOSE: Hyaluronic acid (HA) has a number of clinical applications in current practice. Therefore, correlation of HA with free radicals and inflammatory cells is clinically important. The purpose of this study is to measure the efficacy of high molecular weight HA on the oxidative stress of oral wounds (glutathione (GSH) and lipid peroxidation (LPO) levels), the inflammatory reaction (leucocytes, collagen and angiogenesis content), pain (visual analogue scale (VAS) records) and trismus (maximum interincisal opening (MIO) records) after third molar (M3) extraction. PATIENTS AND METHODS: 40 patients were included in this study. 0.2 ml 0.8% HA was applied immediately after surgery within the HA group (n = 20). Nothing was applied to the control group (n = 20). The primary outcome variables were the changes in the inflammatory reaction (leucocyte, angiogenesis and collagen content), oxidative stress (GSH, LPO) and clinical parameters (VAS, MIO). Results were compared immediately after extraction (T0) and 1 week after surgery (T1). Bivariate analyses were used to assess the differences between the HA and control groups for each study variable. RESULTS: There was a statistically significant difference of leucocyte infiltration and angiogenesis between the groups at T1. The HA group showed less leucocyte infiltration and more angiogenesis than the control group. There was no statistically significant difference in oxidative stress, VAS or MIO levels between the groups. CONCLUSION: Our results confirm the hypothesis that HA has an anti-inflammatory effect following M3 extraction. However, the oxidative stress levels and clinical outcomes were similar after one week. Further studies examining these parameters at different times are necessary. PMID- 26027862 TI - MicroCT-based evaluation of the trabecular bone quality of different implant anchorage sites for masticatory rehabilitation of the maxilla. AB - In the severely atrophied maxilla, implant anchorage in the zygomatic bone is considered a viable alternative to conventional dental implants with preceding bone augmentation procedures. The present microCT-based study compared the trabecular bone quality of the maxilla and zygomatic bone. MicroCT scanning was conducted in 12 halves of cadaver heads (5 male, 7 female) with edentulous, atrophied maxillae. Relevant trabecular bone quality parameters were determined in the anterior and posterior maxilla and in the zygomatic bone and compared by region and sex. Any difference in mean values between the anterior maxilla and the zygomatic bone was insignificant. Comparison of both with the posterior maxilla presented significantly higher values for bone volume fraction, surface density, and trabecular thickness and number, and significantly lower values for specific bone surface, structure model index, and trabecular separation. A significant sex-specific difference was not detected. The present microCT-based analysis is, to the best of our knowledge, the first intra-individual comparison of different implant anchorage sites for masticatory rehabilitation of the maxilla. The trabecular compartment of the zygomatic bone offered bone quality and, thus, an implant bed comparable with those of the anterior maxilla, and both were superior to the posterior maxilla. PMID- 26027863 TI - Comparison of skeletal stability after sagittal split ramus osteotomy with and without extraction of the third molar in patients with mandibular prognathism. AB - PURPOSE: The purpose of this study was to evaluate, through cephalometric analysis, the skeletal stability following BSSRO performed with and without extraction of the third molar, and to examine the healing of the extraction sockets through computed tomography (CT). PATIENTS AND METHODS: Sixty Japanese patients (male: 14, female: 46) diagnosed with mandibular prognathism were included in this study. While 30 patients underwent BSSRO along with extraction of the third molar (extraction group), the other 30 patients underwent BSSRO alone (non-extraction group). Skeletal stability was assessed using axial, frontal, and lateral cephalograms. CT scans were obtained 1 week after surgery and at the 1-year follow-up for all the patients. CT value was measured at the point of the extraction socket on the horizontal plane parallel to the Frankfurt plane using computer software (SimPlant 2011; Materialise Dental, Leuven, Belgium). The region of interest (ROI) was approximately 4 mm(2) and the mean value was recorded. Healing of the extraction sockets was examined through CT 1 year postoperatively. RESULTS: There were no significant differences between the groups for any of the parameters at any observation interval. In the extraction group, there were significant differences between the values of CT obtained 1 week postoperatively and 1 year postoperatively in the extraction socket (P = 0.0003). CONCLUSION: The results of this study indicate that there is no significant difference in the skeletal stability between BSSRO performed with and without third molar extraction. PMID- 26027864 TI - Biomechanical analysis of a temporomandibular joint condylar prosthesis during various clenching tasks. AB - The objective of this study was to evaluate the effect of clenching tasks on the stress and stability of a temporomandibular joint (TMJ) condylar prosthesis, as well as on the stress and strain in the whole mandible and bone surrounding three screws. Three-dimensional finite element models of the mandible and a TMJ condylar prosthesis using three screws were established. Six static clenching tasks were simulated in this study: incisal clench (INC), intercuspal position (ICP), right unilateral molar clench (RMOL), left unilateral molar clench (LMOL), right group function (RGF), and left group function (LGF). Based on the simulation of the six clenching tasks, none of the inserted screws or the TMJ condylar prosthesis were broken. In addition, the stability of the TMJ condylar prosthesis was sufficiently high for bone ongrowth. For the whole mandibular bone, the maximum von Mises stress and von Mises strain observed in the cortical bone and cancellous bone were yielded by the ICP and RMOL, respectively. For the bone surrounding the inserted screws, the maximum von Mises stress and von Mises strain in both the cortical bone and cancellous bone were yielded by the LMOL. Clenching tasks had significant effects on the stress distribution of the TMJ condylar prosthesis, as well as on the stress and strain distribution of the whole mandible and the bone surrounding the inserted screws. PMID- 26027865 TI - Adipose-derived stem cells and platelet-rich plasma for preventive treatment of bisphosphonate-related osteonecrosis of the jaw in a murine model. AB - OBJECTIVES: The main challenge in treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the absence of an effective established treatment. We aimed to compare different potentially preventive treatments for BRONJ after dental extractions in zoledronic acid (ZA)-treated animals. We studied the local application of different combinations of adipose-derived stem cells (ASCs) with or without previous stimulation with bone morphogenetic protein 2 (BMP-2) and platelet-rich plasma (PRP) in rats. MATERIAL AND METHODS: Fifty-six male Wistar rats were treated with ZA for 9 weeks. Dental extractions were performed in the eighth week, and the animals were divided into 4 groups. In group 1 (n = 14), alveolar coverage with mucoperiosteal flap was performed. In group 2 (n = 14), PRP was applied over the sockets and covered with the flap. In group 3 (n = 15), allogeneic ASCs with PRP were applied and covered with the flap. In group 4 (n = 13), animals were treated with ASCs cultured with BMP-2, PRP, and flap coverage. Histologic, fluorescence, and radiologic studies of the maxillae were performed. RESULTS: ASC-treated animals showed lower frequency of osteonecrosis (14% vs 50%, p = 0.007) and greater bone turnover (p = 0.024) and osteoclast count (p = 0.045) than those not receiving the ASC treatment. CONCLUSIONS: In this high-risk model, ASC-based treatments seem to prevent BRONJ more effectively than mucosal flap with or without PRP. The combination of ASCs and PRP appears to be synergistic, and the addition of BMP-2 could further improve the results. PMID- 26027866 TI - Three-dimensional virtual planning in orthognathic surgery enhances the accuracy of soft tissue prediction. AB - INTRODUCTION: Throughout the history of computing, shortening the gap between the physical and digital world behind the screen has always been strived for. Recent advances in three-dimensional (3D) virtual surgery programs have reduced this gap significantly. Although 3D assisted surgery is now widely available for orthognathic surgery, one might still argue whether a 3D virtual planning approach is a better alternative to a conventional two-dimensional (2D) planning technique. The purpose of this study was to compare the accuracy of a traditional 2D technique and a 3D computer-aided prediction method. METHODS: A double blind randomised prospective study was performed to compare the prediction accuracy of a traditional 2D planning technique versus a 3D computer-aided planning approach. The accuracy of the hard and soft tissue profile predictions using both planning methods was investigated. RESULTS: There was a statistically significant difference between 2D and 3D soft tissue planning (p < 0.05). The statistically significant difference found between 2D and 3D planning and the actual soft tissue outcome was not confirmed by a statistically significant difference between methods. CONCLUSIONS: The 3D planning approach provides more accurate soft tissue planning. However, the 2D orthognathic planning is comparable to 3D planning when it comes to hard tissue planning. This study provides relevant results for choosing between 3D and 2D planning in clinical practice. PMID- 26027867 TI - Bisphosphonates enhance bacterial adhesion and biofilm formation on bone hydroxyapatite. AB - BACKGROUND: Because of the suspicion that bisphosphonates enhance bacterial colonization, this study evaluated adhesion and biofilm formation by Streptococcus mutans 25175, Staphylococcus aureus 6538, and Pseudomonas aeruginosa 14454 reference strains on hydroxyapatite coated with clodronate, pamidronate, or zoledronate. MATERIAL AND METHODS: Bacterial strains were cultured on bisphosphonate-coated and noncoated hydroxyapatite discs. After incubation, nonadhered bacteria were removed by centrifugation. Biofilm formation was confirmed by scanning electron microscopy. Bacterial colonization was estimated using quantitative cultures compared by means with Kruskal-Wallis and post-hoc Student-Newman-Keuls tests. Modeling of the interactions between bisphosphonates and hydroxyapatite was performed using the Density Functional Theory method. RESULTS: Bacterial colonization of the hydroxyapatite discs was significantly higher for all tested strains in the presence of bisphosphonates vs. CONTROLS: Adherence in the presence of pamidronate was higher than with other bisphosphonates. Density Functional Theory analysis showed that the protonated amine group of pamidronate, which are not present in clodronate or zoledronate, forms two additional hydrogen bonds with hydroxyapatite. Moreover, the reactive cationic amino group of pamidronate may attract bacteria by direct electrostatic interaction. CONCLUSION: Increased bacterial adhesion and biofilm formation can promote osteomyelitis, cause failure of dental implants or bisphosphonate-coated joint prostheses, and complicate bone surgery in patients on bisphosphonates. PMID- 26027868 TI - A concept for scaffold-based tissue engineering in alveolar cleft osteoplasty. AB - BACKGROUND: Alveolar cleft osteoplasty (ACO) using autologous bone grafts, is used worldwide as a standard treatment in the management of patients with clefts. Harvesting of the various autologous bone grafts is accompanied by considerable donor-site morbidity. Use of scaffold-based tissue engineering in ACO could potentially provide treatment options with decreased, or no donor-site morbidity. This study aims to demonstrate the technical and cell biological feasibility of using scaffold-based tissue engineering in ACO. MATERIAL AND METHODS: Pre existing cone-beam computed tomography scans were used for 3D printing of custom made scaffolds (tricalcium phosphate-polyhydroxybutyrate (TCP-PHB)) according to the individual geometry of the alveolar bone in patients with clefts. The scaffolds were seeded with commercially available human mesenchymal stem cells (hMSCs). Cell survival and cell proliferation was monitored by live-dead assay, scanning electron microscopy (SEM) and WST-1 assay. The osteogenic differentiation of hMSCs on the scaffolds was evaluated by alkaline phosphatase (ALP) assay. RESULTS: The custom-made scaffolds were nearly identical to the size and shape of the digital master. Approximately 91% of the subsequently applied mesenchymal stem cells could be seeded on the rails. We could demonstrate successful cell proliferation by a factor of 5-7 over the first 3 weeks. SEM showed a pore-border growth of the hMSCs on the scaffolds after 3 weeks of cell proliferation. The successful osteogenic differentiation of the scaffold-seeded cells could be demonstrated. CONCLUSION: The concept of scaffold-based tissue engineering provides great potential as an alternative for the present gold standard of autologous bone grafts in ACO. The treatment causes less morbidity and is less invasive for managing young patients with cleft alveolar bone defects. Further in vivo studies and clinical trials are needed to demonstrate the advantages of this novel treatment for ACO in the clinical setting. PMID- 26027869 TI - An institutional experience in the management of pediatric mandibular fractures: A study of 74 cases. AB - BACKGROUND: In maxillofacial surgery, children represent a special group of patients, as they have significant differences from adults as far as the facial skeleton is concerned. The etiology and epidemiology of pediatric trauma involving the facial skeleton has been reported in a large series of patients. Nevertheless, few of these reports review large numbers of pediatric patients, and little is known about treatment protocols for fractures in children. The aims of this study were to retrospectively analyze the treatment methods and outcomes of pediatric mandibular fractures in children and young adolescents up to the age of 15 years, to discuss the findings, and to propose treatment protocols for maxillofacial fractures in childhood. MATERIALS AND METHODS: The present study retrospectively analyzed the treatment methods and outcome of the pediatric mandibular fractures in children and young adolescents' up to the age of 15 years over a period of 5 years. All patients were followed up for an average period of 18 months, with a maximum follow-up of 2 years. A total of 74 patients were treated for mandibular and dentoalveolar fractures in children upto the age of 15 years at the Department of Oral and Maxillofacial Surgery at Nair Hospital Dental College, Mumbai from 2007 to 2012. RESULTS: AND CONCLUSIONS: The treatment methods used at our centre had satisfactory outcomes at the end of a follow-up period of 2 years. Reported complications were minimal. Our results confirm the usefulness of open reduction and plate fixation in older children (>12 years of age) and a conservative approach in younger children (<=12 years of age) in treating mandibular fractures. PMID- 26027870 TI - Extranodal extension and thickness of metastatic lymph node as a significant prognostic marker of recurrence and survival in head and neck squamous cell carcinoma. AB - PURPOSE: We examined the effect of extranodal extension (ENE) and its thickness (ENET) of metastatic lymph node (LN) on the disease course of patients with head and neck squamous cell carcinoma. METHODS: Data from 438 patients who were initially treated surgically at our center was retrospectively analyzed. ENE presence and ENET were examined in metastatic LN from each patient. Clinicopathologic characteristics, recurrence, and survival were then compared. RESULTS: Of 438 patients, 219 (50%) showed positive nodal status, and ENE was identified in 84 (19.6%). Forty-five of 219 (20.5%) node-positive patients were classified with ENET >= 2 mm, which was associated with an increase in both the size and number of positive LN, bilateral cervical involvement, and a higher LN ratio. ENE-positive patients had a higher risk of recurrence and a lower overall survival rate; however, multivariate analysis failed to identify a significant difference in cancer-specific survival (CSS) between those with and those without ENE. On the contrary, ENET >= 2 mm was significantly associated with a poor CSS, even in multivariate analysis. CONCLUSION: ENET >= 2 mm might be a complementary prognostic marker in CSS estimation for ENE positivity. PMID- 26027872 TI - Controlled Release of Dexamethasone from Organosilicone Constructs for Local Modulation of Inflammation in Islet Transplantation. AB - Inflammation is a significant detriment to the engraftment of cells and tissues, particularly for islet transplantation, where a low tolerance for the inflammatory milieu results in significant graft loss. Local treatment with anti inflammatories, such as glucocorticoids, provides the benefits of site-targeted delivery with minimization of the broad side effects associated with systemic delivery. Polydimethylsiloxane (PDMS) is a flexible platform that is capable of providing sustained delivery of hydrophobic drugs. Here, we evaluated the capacity of PDMS constructs loaded with the anti-inflammatory glucocorticoid dexamethasone (Dex) to locally mitigate inflammation in islet grafts. Dex-PDMS constructs, fabricated in rod or disk geometries, demonstrated prolonged and sustained release at therapeutically relevant levels. In vitro, Dex-PDMS constructs inhibited endotoxin-induced human monocyte and macrophage activation, but they did not impair islet viability or function. Dex-PDMS rods, co transplanted with islet-seeded scaffolds in a murine model, demonstrated suppression of host inflammatory responses during early- and late-phase engraftment, without significantly altering islet graft potency. The facile nature of these glucocorticoid-doped PDMS constructs allows for the optimization of targeted dose delivery with wide applicability in cell and tissue transplantation. PMID- 26027871 TI - Direct observation of TALE protein dynamics reveals a two-state search mechanism. AB - Transcription activator-like effector (TALE) proteins are a class of programmable DNA-binding proteins for which the fundamental mechanisms governing the search process are not fully understood. Here we use single-molecule techniques to directly observe TALE search dynamics along DNA templates. We find that TALE proteins are capable of rapid diffusion along DNA using a combination of sliding and hopping behaviour, which suggests that the TALE search process is governed in part by facilitated diffusion. We also observe that TALE proteins exhibit two distinct modes of action during the search process-a search state and a recognition state-facilitated by different subdomains in monomeric TALE proteins. Using TALE truncation mutants, we further demonstrate that the N-terminal region of TALEs is required for the initial non-specific binding and subsequent rapid search along DNA, whereas the central repeat domain is required for transitioning into the site-specific recognition state. PMID- 26027873 TI - Projection of corn production and stover-harvesting impacts on soil organic carbon dynamics in the U.S. Temperate Prairies. AB - Terrestrial carbon sequestration potential is widely considered as a realistic option for mitigating greenhouse gas emissions. However, this potential may be threatened by global changes including climate, land use, and management changes such as increased corn stover harvesting for rising production of cellulosic biofuel. Therefore, it is critical to investigate the dynamics of soil organic carbon (SOC) at regional or global scale. This study simulated the corn production and spatiotemporal changes of SOC in the U.S. Temperate Prairies, which covers over one-third of the U.S. corn acreage, using a biogeochemical model with multiple climate and land-use change projections. The corn production (either grain yield or stover biomass) could reach 88.7-104.7 TgC as of 2050, 70 101% increase when compared to the base year of 2010. A removal of 50% stover at the regional scale could be a reasonable cap in view of maintaining SOC content and soil fertility especially in the beginning years. The projected SOC dynamics indicated that the average carbon sequestration potential across the entire region may vary from 12.7 to 19.6 g C/m(2)/yr (i.e., 6.6-10.2 g TgC/yr). This study not only helps understand SOC dynamics but also provides decision support for sustainable biofuel development. PMID- 26027874 TI - Ethnicity and Pathways of Fear in Endodontics. AB - INTRODUCTION: Cultural competencies in multicultural societies with different ethnic perceptions pose a challenge during the management and treatment of patients with dental fear and anxiety. This study aimed to identify the most common and relevant pathways of fear and anxiety related to root canal treatment in different ethnic groups. METHODS: All participants visiting the Griffith University Dental Clinics, Gold Coast, Australia, were invited to participate if they had undergone primary root canal treatment or were scheduled to undergo the same. Patients with mental disabilities, those with no history of root canal treatment, those who only had surgical root canal treatment, and those below 20 years old were excluded. All participants completed the "My Endodontic Fear questionnaire." RESULTS: Eight hundred seventy-nine patients (20-90 years old) who had root canal treatment or were scheduled to have one consented to participate in this study. White (54.5%) and Arab/African respondents (30.9%) were more likely (P < .001) to use the conditioning pathway compared with East Asian (10.5%) or Aboriginal/Pacific Islander groups (3.9%). Age was a significant factor for all ethnicities (P < .05); 40-year-old and 65+-year-old groups showed less fear compared with the 20- to 39-year old groups. Female sex was significantly related to the use of the informative (P < .001) and parental (P = .002) pathways. CONCLUSIONS: The present study showed that different pathways appear to be adopted by different ethnic groups, indicating the importance of customizing strategies in a multicultural society to manage fear and anxiety related to root canal treatment. PMID- 26027875 TI - Evaluation of Cold Plasma Treatment and Safety in Disinfecting 3-week Root Canal Enterococcus faecalis Biofilm In Vitro. AB - INTRODUCTION: Although endodontic infection is caused by multi-bacteria species, Enterococcus faecalis is usually isolated in chronic apical periodontitis. The aim of this study was to evaluate the effectiveness and mechanical safety of cold plasma therapy in disinfecting 3-week E. faecalis biofilms. METHODS: Teeth with 3 week E. faecalis biofilm were treated with AC argon/oxygen (Ar/O2) cold plasma for various treatment times and compared with those treated with Ca(OH)2, 2% chlorhexidine gel, and Ca(OH)2/chlorhexidine for a week. Antimicrobial efficacy was assessed by colony-forming unit method. Scanning electron microscopy was used to assess the morphologic changes of E. faecalis biofilm by plasma. Confocal laser scanning microscopy was used to confirm the viability of the biofilm after the plasma treatment. Microhardness and roughness changes of root canal dentin caused by plasma were verified with Vickers Hardness Tester and 3D Profile Measurement Laser Microscope, respectively. RESULTS: There were no detectable live bacteria after 12 minutes of cold plasma treatment. This was further confirmed by scanning electron microscopy and confocal laser scanning microscopy results. Microhardness and roughness of root canal dentin showed no significant difference after plasma treatment. CONCLUSIONS: Atmospheric pressure cold plasma is an effective therapy in endodontics for its strong sterilization effect on fully matured biofilm within a few minutes. Meanwhile, it has an accepted mechanical safety for its low temperature and not affecting the microhardness and roughness of root canal dentin significantly. PMID- 26027876 TI - Periapical Lesions Decrease Insulin Signaling in Rat Skeletal Muscle. AB - INTRODUCTION: Serum inflammatory cytokines derived from oral inflammation are associated with decreased insulin signaling (IS) and insulin resistance, which is a major risk factor for type 2 diabetes mellitus. This study aimed to investigate IS in the liver and skeletal muscle (SM) and disorders related to the serum lipid profile and glucose and insulin levels of nondiabetic rats with induced chronic periapical lesions (PLs). METHODS: Twenty-eight Wistar rats were divided into control and PL groups. PLs were induced by exposing the pulpal tissue to the oral environment. Experiments were conducted in both groups 30 days after pulp exposure. Maxillae were processed for histopathological analysis. IS was evaluated according to insulin receptor substrate (pp185-insulin receptor substrate 1 [IRS-1]/insulin receptor substrate 2 [IRS-2]) tyrosine phosphorylation status, IRS-1 serine phosphorylation status, and IRS-1 and IRS-2 content in the liver and SM by Western blotting. Serum total cholesterol, triglyceride, glucose, and insulin levels were measured enzymatically using a commercial kit. RESULTS: PL rats showed reduced pp185 P-Tyr and increased IRS-1 serine phosphorylation status in the SM but no change in the liver after insulin stimulation. No significant changes in IRS-1 and IRS-2 content, serum total cholesterol, triglyceride, glucose or insulin levels were noted. CONCLUSIONS: PLs are associated with decreased insulin signaling in the SM of rats. Because a decrease in insulin signaling is associated with insulin resistance, our results emphasize the importance of preventing local inflammatory diseases such as PLs to prevent alterations in IS in muscle. PMID- 26027877 TI - Direct Visualization of Catalytically Active Sites at the FeO-Pt(111) Interface. AB - Within the area of surface science, one of the "holy grails" is to directly visualize a chemical reaction at the atomic scale. Whereas this goal has been reached by high-resolution scanning tunneling microscopy (STM) in a number of cases for reactions occurring at flat surfaces, such a direct view is often inhibited for reaction occurring at steps and interfaces. Here we have studied the CO oxidation reaction at the interface between ultrathin FeO islands and a Pt(111) support by in situ STM and density functional theory (DFT) calculations. Time-lapsed STM imaging on this inverse model catalyst in O2 and CO environments revealed catalytic activity occurring at the FeO-Pt(111) interface and directly showed that the Fe-edges host the catalytically most active sites for the CO oxidation reaction. This is an important result since previous evidence for the catalytic activity of the FeO-Pt(111) interface is essentially based on averaging techniques in conjunction with DFT calculations. The presented STM results are in accord with DFT+U calculations, in which we compare possible CO oxidation pathways on oxidized Fe-edges and O-edges. We found that the CO oxidation reaction is more favorable on the oxidized Fe-edges, both thermodynamically and kinetically. PMID- 26027878 TI - Medication overuse and chronic migraine: a critical review according to clinical pharmacology. AB - INTRODUCTION: Chronic migraine is often complicated by medication-overuse headache (MOH), a headache due to excessive intake of acute medications. Chronic migraine and MOH are serious and disabling disorders. Since chronic migraine derives from the progression of originally episodic migraine, the fundamental therapeutic strategy is prevention. This narrative review describes how to try to prevent the development of MOH and how to manage it once it has appeared. AREAS COVERED: A PubMed database search (from 1988 to January 2015) and a review of published studies on chronic migraine and MOH were conducted. EXPERT OPINION: In spite of progress in migraine treatment, the prevalence of chronic headaches and MOH has not changed in the course of time. Today, a large number of migraine patients have turned to numerous expert physicians and experienced all sorts of prophylactic treatments without decisive benefits. Their condition seems to have crystallized even more as chronic and intractable. This means that to prevent chronification and MOH, we need more effective drugs and better strategies to use them. In particular, we must detect disease biomarkers and predictive factors for drug response that allow for personalized treatment when migraine is still episodic and make analgesic overuse pointless. PMID- 26027879 TI - The cost-effectiveness of diagnostic cardiac imaging for stable coronary artery disease. AB - Early and accurate diagnosis of stable coronary artery disease (CAD) is crucial to reduce morbidity, mortality and healthcare costs. This critical appraisal of health-economic literature concerning non-invasive diagnostic cardiac imaging aims to summarize current approaches to economic evaluation of diagnostic cardiac imaging and associated procedural risks, inform cardiologists how to use economic analyses for decision-making, highlight areas where new information could strengthen the economic evaluation and shed light on cost-effective approaches to diagnose stable CAD. Economic analysis can support cardiologists' decision making. Current economic evidence in the field does not provide sufficient information to guide the choice among different imaging modalities or strategies for each patient. Available economic analyses suggest that computed tomography coronary angiography (CTCA) is a cost-effective approach to rule out CAD prior to invasive coronary angiography in patients with low to intermediate pre-test probability of disease and that stress imaging modalities may be cost-effective at variable pre-test probabilities. PMID- 26027880 TI - Children's abstraction and generalization of English lexical stress patterns. AB - The current study investigated school-aged children's internalization of the distributional patterns of English lexical stress as a function of vocabulary size. Sixty children (5;3 to 8;3) participated in the study. The children were asked to blend two individually presented, equally stressed syllables to produce disyllabic nonwords with different resulting structures in one of two frame sentences. The frame sentences were designed to elicit either a noun or verb interpretation of the nonword. Children's receptive vocabulary was also assessed. The results indicated that children more readily blended syllable pairs that resulted in trochaic-compatible word structures than in iambic-compatible structures. This effect was strongest in young children with large vocabularies. As for stress placement, all children were sensitive to the effect of word structure, but only children with the largest vocabularies were sensitive to the biasing effect of grammatical category (noun = trochee; verb = iamb). The study results are discussed with reference to the observation that speech motor skills develop in tandem with lexical acquisition and the hypothesis that phonological knowledge emerges in part from abstraction across lexical representations. PMID- 26027881 TI - Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. AB - BACKGROUND: Whether patients with early-stage oral cancers should be treated with elective neck dissection at the time of the primary surgery or with therapeutic neck dissection after nodal relapse has been a matter of debate. METHODS: In this prospective, randomized, controlled trial, we evaluated the effect on survival of elective node dissection (ipsilateral neck dissection at the time of the primary surgery) versus therapeutic node dissection (watchful waiting followed by neck dissection for nodal relapse) in patients with lateralized stage T1 or T2 oral squamous-cell carcinomas. Primary and secondary end points were overall survival and disease-free survival, respectively. RESULTS: Between 2004 and 2014, a total of 596 patients were enrolled. As prespecified by the data and safety monitoring committee, this report summarizes results for the first 500 patients (245 in the elective-surgery group and 255 in the therapeutic-surgery group), with a median follow-up of 39 months. There were 81 recurrences and 50 deaths in the elective surgery group and 146 recurrences and 79 deaths in the therapeutic-surgery group. At 3 years, elective node dissection resulted in an improved rate of overall survival (80.0%; 95% confidence interval [CI], 74.1 to 85.8), as compared with therapeutic dissection (67.5%; 95% CI, 61.0 to 73.9), for a hazard ratio for death of 0.64 in the elective-surgery group (95% CI, 0.45 to 0.92; P=0.01 by the log-rank test). At that time, patients in the elective-surgery group also had a higher rate of disease-free survival than those in the therapeutic-surgery group (69.5% vs. 45.9%, P<0.001). Elective node dissection was superior in most subgroups without significant interactions. Rates of adverse events were 6.6% and 3.6% in the elective-surgery group and the therapeutic-surgery group, respectively. CONCLUSIONS: Among patients with early-stage oral squamous-cell cancer, elective neck dissection resulted in higher rates of overall and disease free survival than did therapeutic neck dissection. (Funded by the Tata Memorial Centre; ClinicalTrials.gov number, NCT00193765.). PMID- 26027882 TI - iPSC-MSCs and islet allograft tolerance. PMID- 26027883 TI - Relationship between jaw movement and masticatory performance in adults with natural dentition. AB - OBJECTIVE: This study determines the relationship between several characteristics of jaw movement and masticatory performance determined by multiple regression analysis and adjusted for occlusal contact area and bite force. MATERIALS AND METHODS: Forty-two young adults with natural dentition participated in this cross sectional study. Occlusal contact area was determined at the maximum intercuspal position by scanning interocclusal records. Maximum unilateral force was measured by means of a gnathodynamometer. The height and amplitude of mastication, occlusal glide length, lateral guidance angle, anterior-posterior distance and cycle duration were recorded using the ARCUSdigma II system. Masticatory performance was determined by sieving the Optosil particles resulting from 20 chewing cycles. RESULTS: Median particle size was negatively associated with height of mastication, maximum bite force, occlusal contact area and amplitude of mastication. Stepwise multiple linear regression analysis revealed that the height of mastication and dental guidance angle are the characteristics of jaw movement most closely related to masticatory performance. CONCLUSIONS: In adults with natural dentition, a large vertical height of mastication and a small dental guidance angle are the characteristics of jaw movement most closely associated with good masticatory performance, determined by multiple regression analysis and adjusted for occlusal contact area and bite force. PMID- 26027884 TI - Randomized structural sparsity via constrained block subsampling for improved sensitivity of discriminative voxel identification. AB - In this paper, we consider voxel selection for functional Magnetic Resonance Imaging (fMRI) brain data with the aim of finding a more complete set of probably correlated discriminative voxels, thus improving interpretation of the discovered potential biomarkers. The main difficulty in doing this is an extremely high dimensional voxel space and few training samples, resulting in unreliable feature selection. In order to deal with the difficulty, stability selection has received a great deal of attention lately, especially due to its finite sample control of false discoveries and transparent principle for choosing a proper amount of regularization. However, it fails to make explicit use of the correlation property or structural information of these discriminative features and leads to large false negative rates. In other words, many relevant but probably correlated discriminative voxels are missed. Thus, we propose a new variant on stability selection "randomized structural sparsity", which incorporates the idea of structural sparsity. Numerical experiments demonstrate that our method can be superior in controlling for false negatives while also keeping the control of false positives inherited from stability selection. PMID- 26027885 TI - Impact of an antimicrobial stewardship intervention on urinary tract infection treatment in the ED. AB - STUDY OBJECTIVE: The study objective is to assess changes in treatment of uncomplicated urinary tract infections (UTIs) after implementation of recommendations based on national guidelines and local resistance rates. METHODS: This preintervention and postintervention study included patients discharged home from the emergency department (ED) with an uncomplicated UTI at a 439-bed teaching hospital. Emergency department prescribers were educated on how local antimicrobial resistance rates impact UTI practice guidelines. Empiric treatment according to recommendations was assessed as the primary outcome. Agreement between chosen therapy and isolated pathogen susceptibility was compared before and after education. Reevaluation in the ED or hospital admission within 30 days for a UTI was also evaluated. RESULTS: A total of 350 patients were studied (174 before and 176 after education). Of those, 255 had cystitis, and 95 had pyelonephritis. After education, choice of therapy consistent with recommendations increased from 44.8% to 83% (difference, 38.2%; 95% confidence interval [CI], 33%-43%; P < .001). The change was predominately driven by an increase in nitrofurantoin use for cystitis from 12% to 80% (difference, 68%; 95% CI, 62%-73%; P < .001). Agreement between empiric treatment and the isolated pathogen susceptibility improved for cystitis 74% to 89% (P = .05), and no change occurred in 30-day repeat ED visits for a UTI. CONCLUSIONS: After implementation of treatment recommendations for uncomplicated UTIs based on local resistance, empiric antibiotic selection improved in the ED. To further meet goals of antimicrobial stewardship, additional interventions are needed. PMID- 26027886 TI - Comparing biomarkers of traumatic shock: the utility of anion gap, base excess, and serum lactate in the ED. AB - BACKGROUND: Biomarkers such as serum lactate, anion gap (AG), and base excess (BE) have been shown to be of use in determining shock in patients with seemingly normal vital signs. We seek to determine if these biomarkers can be used interchangeably in patients with trauma in the emergency setting based on their test characteristics and correlation to each other. METHODS: A prospective observational cohort study was undertaken at an urban level 1 trauma center. Baseline vital signs, point-of-care BE, AG, and serum lactate were recorded in all patients who presented for trauma. Correlation was determined by linear regression model. Overall test characteristics and relative risk were calculated. RESULTS: One hundred patients were enrolled. The median age was 30 years (interquartile range, 24-42 years), and 89% were male. Fifty-three percent of injuries were blunt trauma. Pearson correlation of serum lactate to BE was -0.81 (r(2) = 0.66; 95% confidence interval [CI], 0.53-0.75; P < .001), that of BE to AG was -0.71 (r(2) = 0.5; 95% CI, -0.80 to -0.57; P < .01), and that for serum lactate to AG was 0.71 (r(2) = 0.5; 95% CI, 0.57-0.80; P < .01). CONCLUSIONS: This study demonstrates that the biomarkers have similar test characteristics which may make them interchangeable as indicators for the presence of occult shock in patients with trauma. Lactate and BE correlate well with each other; however, AG was not as strongly correlated with either. PMID- 26027887 TI - Intracranial toxoplasmosis presenting as panhypopituitarism in an immunocompromised patient. AB - A 37-year-old man presented with worsening headache, vomiting, and right-sided weakness over the last few weeks. A head computed tomography showed a left hemispheric posterior medial parietal lobe lesion with surrounding edema. Further imaging with magnetic resonance imaging showed multiple enhancing mass lesions. The largest lesion measured 2.4 cm within the left occipital parietal region (Figure A and B). Laboratory data showed reactive HIV antibodies, confirmed by Western blot. An absolute CD4 count was 22 cells/MUL. Other laboratory test results showed low sodium, thyrotropin, FT4, FT3, cortisol levels, corticotropin, luteinizing hormone, and testosterone. Based on these findings, the brain lesions were believed to be causing his panhypopituitarism. A brain biopsy confirmed the presence of Toxoplasma gondii by polymerase chain reaction. The patient was started on pyrimethamine and clindamycin for toxoplasmosis treatment, and azithromycin and sulfamethoxazole/trimethoprime for appropriate prophylaxis. He was also started on hormone supplementation. His symptoms were completely resolved at the time of discharge. PMID- 26027888 TI - Cocaine-induced right ventricular dysfunction: right ventricular infarction or afterload elevation? PMID- 26027889 TI - Valley polarization assisted spin polarization in two dimensions. AB - Valleytronics is rapidly emerging as an exciting area of basic and applied research. In two-dimensional systems, valley polarization can dramatically modify physical properties through electron-electron interactions as demonstrated by such phenomena as the fractional quantum Hall effect and the metal-insulator transition. Here, we address the electrons' spin alignment in a magnetic field in silicon-on-insulator quantum wells under valley polarization. In stark contrast to expectations from a non-interacting model, we show experimentally that less magnetic field can be required to fully spin polarize a valley-polarized system than a valley-degenerate one. Furthermore, we show that these observations are quantitatively described by parameter-free ab initio quantum Monte Carlo simulations. We interpret the results as a manifestation of the greater stability of the spin- and valley-degenerate system against ferromagnetic instability and Wigner crystalization, which in turn suggests the existence of a new strongly correlated electron liquid at low electron densities. PMID- 26027890 TI - Cultivation strategies to enhance productivity of Pichia pastoris: A review. AB - Pichia pastoris, a methylotrophic yeast, is an established system for the production of heterologous proteins, particularly biopharmaceuticals and industrial enzymes. To maximise and optimise the production of recombinant products, recent molecular research has focused on numerous issues including the design of expression vectors, optimisation of gene copy number, co-expression of secretory proteins such as chaperones, engineering of glycosylation and secretory pathways, etc. However, the physiological effects of different cultivation strategies are often difficult to separate from the molecular effects of the gene construct (e.g., cellular stress through over-expression or incorrect post translational processing). Hence, overall system optimisation is difficult, even though it is urgently required in order to describe and understand the behaviour of new molecular constructs. This review focuses on particular aspects of recombinant protein production related to variations in biomass growth and their implications for strain design and screening, as well as on the concept of rational comparisons between cultivation systems for the development of specific production processes in bioreactors. The relationship between specific formation rates of secreted recombinant proteins, qp, and specific growth rates, MU, has been analysed in a conceptual attempt to compare different systems, particularly those based on AOX1/methanol and GAP/glucose, and this has now evolved into a pivotal concept for bioprocess engineering of P. pastoris. PMID- 26027891 TI - Rapid and high-throughput construction of microbial cell-factories with regulatory noncoding RNAs. AB - Due to global crises such as pollution and depletion of fossil fuels, sustainable technologies based on microbial cell-factories have been garnering great interest as an alternative to chemical factories. The development of microbial cell factories is imperative in cutting down the overall manufacturing cost. Thus, diverse metabolic engineering strategies and engineering tools have been established to obtain a preferred genotype and phenotype displaying superior productivity. However, these tools are limited to only a handful of genes with permanent modification of a genome and significant labor costs, and this is one of the bottlenecks associated with biofactory construction. Therefore, a groundbreaking rapid and high-throughput engineering tool is needed for efficient construction of microbial cell-factories. During the last decade, copious small noncoding RNAs (ncRNAs) have been discovered in bacteria. These are involved in substantial regulatory roles like transcriptional and post-transcriptional gene regulation by modulating mRNA elongation, stability, or translational efficiency. Because of their vulnerability, ncRNAs can be used as another layer of conditional control over gene expression without modifying chromosomal sequences, and hence would be a promising high-throughput tool for metabolic engineering. Here, we review successful design principles and applications of ncRNAs for high throughput metabolic engineering or physiological studies of diverse industrially important microorganisms. PMID- 26027892 TI - The portal venous system in cirrhotic patients: value of the computed tomography. PMID- 26027893 TI - Exploratory laparoscopy for carcinomatosis: discard that quiver full of trocars and use just one! PMID- 26027895 TI - Use of lung ultrasound in detection of complications of respiratory distress syndrome. AB - Repeated chest radiography is required for the diagnosis and follow-up of neonates with respiratory distress syndrome (RDS) and carries the risk of radiation hazards. Lung ultrasound (LUS) is a non-invasive bedside diagnostic tool that has proven to be effective in the diagnosis of RDS. Our aim was to assess the role of LUS with respect to the standard chest X-ray (CXR) in the detection of complications of RDS in neonates. Ninety premature newborns of both genders with RDS (mean gestational age = 29.91 +/- 1.33 wk) and 40 premature babies as a control group were involved in this study. All patients underwent initial clinical assessment as well as CXR and LUS. Those who presented with respiratory distress and/or exhibited deterioration of oxygenation parameters were followed by CXR and, within 4 h, by LUS. Alveolo-interstitial syndrome and pleural line abnormalities were detected in all cases (100%) in the initial assessment, patchy consolidation was detected in 34 cases and white lung was detected in 80 cases. Alveolo-interstitial syndrome was detected in 19 controls. In follow-up of the patients, LUS was superior to CXR in detection of consolidation and sub-pleural atelectasis, but not in detection of pneumothorax. We concluded that bedside LUS is a good non-hazardous alternative tool in the early detection and follow-up of RDS in the neonatal intensive care unit; it could be of value in reducing exposure to unnecessary radiation. PMID- 26027894 TI - Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. AB - Exosomes are small vesicles that mediate cell-cell communication. They contain proteins, lipids and RNA, and evidence is accumulating that these molecules are specifically sorted for release via exosomes. We recently showed that endothelial cell-produced exosomes promote angiogenesis in vivo in a small RNA-dependent manner. Recent deep sequencing studies in exosomes from lymphocytic origin revealed a broad spectrum of small RNAs. However, selective depletion or incorporation of small RNA species into endothelial exosomes has not been studied extensively. With next generation sequencing, we identified all known non-coding RNA classes, including microRNAs (miRNAs), small nucleolar RNAs, yRNAs, vault RNAs, 5p and 3p fragments of miRNAs and miRNA-like fragments. In addition, we mapped many fragments of messenger RNAs (mRNAs) and mitochondrial RNAs (mtRNAs). The distribution of small RNAs in exosomes revealed a considerable overlap with the distribution in the producing cells. However, we identified a remarkable enrichment of yRNA fragments and mRNA degradation products in exosomes consistent with yRNAs having a role in degradation of structured and misfolded RNAs in close proximity to endosomes. We propose that endothelial endosomes selectively sequester cytoplasmic RNA-degrading machineries taking part in gene regulation. The release of these regulatory RNAs via exosomes may have implications for endothelial cell-cell communication. PMID- 26027896 TI - Application of ultrasonography in the assessment of skeletal muscles in children with and without neuromuscular disorders: a systematic review. AB - The purpose of this study was to systematically review published studies (2000 2014) carried out on the application of ultrasonography (US) to evaluation of skeletal muscle size in children with and without neuromuscular disorders. Different databases including PubMed, Science Direct, OVID, MEDLINE, CINAHL, EMBASE, ProQuest and Google Scholar were searched. The key words used were: "children," "ultrasound," "skeletal muscles," "neuromuscular disease," "neurogenic disorders," "spina bifida," "myelomeningocele" and "reliability." Eighteen articles were found to be relevant. Eight studies applied US in combination with additional methods of assessment. Four of the 18 studies did not have a control group. Ten studies applied only US in the assessment of skeletal muscles in children with and without neuromuscular diseases. In 9 studies, there were children ranging widely in age, and in 3 studies US was used to determine normal values for skeletal muscles. According to the results of these 18 reviewed articles, US is an appropriate, reliable and highly predictive method for assessment of skeletal muscles in children. PMID- 26027897 TI - Potential Interactions Between Genetic Polymorphisms of the Transforming Growth Factor-beta Pathway and Environmental Factors in Abdominal Aortic Aneurysms. AB - OBJECTIVE/BACKGROUND: Evidence has accumulated that multiple polymorphisms in the transforming growth factor (TGF)-beta pathway and renin-angiotensin system play important roles in determining susceptibility to abdominal aortic aneurysm (AAA). Few studies have considered interactions between these gene polymorphisms and environmental factors. The aim of this study was to evaluate the contribution of single nucleotide polymorphisms (SNPs) and complex gene-environment interactions in AAA. METHODS: Six SNPs located in TGFB, TGFBR1, TGFBR2 and AGTR1 were selected. Genotyping of blood samples and collection of lifestyle factors were performed in 155 unrelated participants with AAAs and 310 non-AAA controls. Unconditional logistic regression was performed to assess the effects of SNPs on the risk of AAA. Generalized multifactor dimensionality reduction (GMDR) was used to evaluate gene-gene and gene-environment interactions. RESULTS: Participants carrying TGFB1 rs1800469 TT (odds ratio [OR] 1.83, 95% confidence interval [CI] 1.18-2.85) or AGTR1 rs12695895 TT (OR 4.21, 95% CI 1.41-12.53) genotypes had a higher risk of AAA than those with the common CC genotype. The gene-gene interaction of AGTR1 rs5182, TGFBR1 rs1626340, and TGFB1 rs1800469 was found to be the best model according to the results of the GMDR analysis (cross validation consistency [CVC]) 10/10; p = .010). Smoking, dyslipidemia, and rs1800469 together contributed to the risk of AAA, which demonstrated a potential and complex gene-environment interaction among the three variants that might affect AAA risk (CVC 6/10; p = .001). CONCLUSION: In this study of the Chinese population, homozygosity of TGFB1 rs1800469-T and AGTR1 rs12695895-T might be associated with increased risk of AAA. The complex gene-gene and gene-environment interactions might contribute to the risk of AAA. As a small study, the preliminary results need extensive validation and replication in larger populations. PMID- 26027898 TI - Endovascular Treatment of Ruptured Abdominal Aortic Aneurysms with Hostile Aortic Neck Anatomy. AB - OBJECTIVE: To compare the mid-term results of endovascular aortic aneurysm repair (EVAR) for ruptured abdominal aortic aneurysms (RAAAs) in patients with favourable aortic neck anatomy (FNA) and hostile aortic neck anatomy (HNA). METHODS: Patients treated for a RAAA in a high volume endovascular centre in the Netherlands between February 2009 and January 2014 were identified retrospectively and divided into two groups based on aortic neck anatomy, FNA and HNA. HNA was defined as RAAA with a proximal neck of <10 mm, or a proximal neck of 10-15 mm with a suprarenal angulation (alpha) >45 degrees and/or an infrarenal angulation (beta) >60 degrees , or a proximal neck of >15 mm combined with alpha >60 degrees and/or beta >75 degrees . Patient demographics, procedure details, 30 day and 1 year outcomes were recorded. RESULTS: Of 39 included patients, 17 (44%) had HNA. Technical success was 100% for FNA and 88% for HNA (p = .184). There were no type IA endoleaks on completion angiography in either group; however, more adjunctive procedures were necessary for intra-operative type IA endoleaks in the HNA group (24% vs. 0%, p = .029). Thirty day mortality rates were comparable, FNA 14% vs. HNA 12% (p = 1.000). There were no statistically significant differences at 1 year follow up in type I endoleaks, secondary endovascular procedures, or all cause mortality. CONCLUSION: Emergency EVAR provides excellent results for treatment of RAAA patients with both FNA and HNA. EVAR in RAAAs with HNA is technically feasible and safe in experienced endovascular centres. Article history. PMID- 26027899 TI - Use of Commercial Dry Yeast Products Rich in Mannoproteins for White and Rose Sparkling Wine Elaboration. AB - In sparkling wines, mannoproteins released during yeast autolysis largely affect their final quality. This process is very slow and may take several months. The aim of this work was to study the effect of several commercial dry yeast autolysates on the chemical composition, foam, and sensory properties of white and rose sparkling wines aged on lees for 9 months during two consecutive vintages. The addition of these products in the tirage phase did not affect either the content of phenolic compounds, amino acids, and biogenic amines or the foam properties. The commercial product with the highest mannoprotein content and the highest purity caused significant changes in the volatile composition of the wines and enhanced the fruity aromas in both Verdejo and Godello sparkling wines. PMID- 26027900 TI - [The relevance of correct identification and interpretation of susceptibility testing of Aeromonas spp. bacteremia isolates]. AB - OBJECTIVE: To assess the relevance of correct identification and interpretation of susceptibility testing of Aeromonas spp. bacteremia isolates using newly developed molecular methods in comparison to previous conventional methods. MATERIAL AND METHODS: The study included 22 patients with bacteremia due to Aeromonas hydrophila group, microbiologically characterized using the MicroScan system. Further identification to species level was performed by mass spectrometry, and confirmed by sequencing the rpoB gene. The MIC of imipenem, cefotaxime, piperacillin-tazobactam, ciprofloxacin and cotrimoxazole was studied using a commercial broth microdilution and antibiotic gradient strips with low and high inocula. Detection of carbapenemase production was performed using the modified Hodge test, and was confirmed by amplifying the cphA gene by PCR. RESULTS: A total of 9 (40.9%) isolates were identified as Aeromonas hydrophila, 8 (36.4%) as Aeromonas veronii, and the remaining 5 (22.7%) isolates as Aeromonas caviae. Resistance to beta-lactams according to both the commercial microdilution and MIC gradient strips methods was: 36%-50% to imipenem; 4%-56% to cefotaxime, and 27%-56% to piperacillin/tazobactam. The agreement between results generated by the automated system and the diffusion antibiotic gradient strip was, for all 3 species, 68% for imipenem, 50% to cefotaxime, and 46% to piperacillin/tazobactam. No resistance to cotrimoxazole and ciprofloxacin was found by either of the two methods, although 22.7% of the strains were resistant to nalidixic acid. CONCLUSIONS: It is essential to identify the isolates of Aeromonas spp. at the species level, due to the fact that beta-lactam resistance is species- and method-dependent. The high rate of resistance to beta-lactam and quinolones reduce their application as empiric treatments for invasive infection by Aeromonas ssp. PMID- 26027902 TI - Effect of temperature on ammonium removal in Scenedesmus sp. AB - The effect of temperature on microalgal ammonium uptake was investigated by carrying out four batch experiments in which a mixed culture of microalgae, composed mainly of Scenedesmus sp., was cultivated under different temperatures within the usual temperature working range in Mediterranean climate (15-34 degrees C). Ammonium removal rates increased with temperature up to 26 degrees C and stabilized thereafter. Ratkowsky and Cardinal temperatures models successfully reproduced the experimental data. Optimum (31.3 degrees C), minimum (8.8 degrees C) and maximum (46.1 degrees C) temperatures for ammonium removal by Scenedesmus sp. under the studied conditions were obtained as model parameters. These temperature-related parameters constitute very useful information for designing and operating wastewater treatment systems using these microalgae. PMID- 26027901 TI - Hybrid Graphene Oxide Based Plasmonic-Magnetic Multifunctional Nanoplatform for Selective Separation and Label-Free Identification of Alzheimer's Disease Biomarkers. AB - Despite intense efforts, Alzheimer's disease (AD) is one of the top public health crisis for society even at 21st century. Since presently there is no cure for AD, early diagnosis of possible AD biomarkers is crucial for the society. Driven by the need, the current manuscript reports the development of magnetic core plasmonic shell nanoparticle attached hybrid graphene oxide based multifunctional nanoplatform which has the capability for highly selective separation of AD biomarkers from whole blood sample, followed by label-free surface enhanced Raman spectroscopy (SERS) identification in femto gram level. Experimental ELISA data show that antibody-conjugated nanoplatform has the capability to capture more than 98% AD biomarkers from the whole blood sample. Reported result shows that nanoplatform can be used for SERS "fingerprint" identification of beta-amyloid and tau protein after magnetic separation even at 100 fg/mL level. Experimental results indicate that very high sensitivity achieved is mainly due to the strong plasmon-coupling which generates huge amplified electromagnetic fields at the "hot spot". Experimental results with nontargeted HSA protein, which is one of the most abundant protein components in cerebrospinal fluid (CSF), show that multifunctional nanoplatform based AD biomarkers separation and identification is highly selective. PMID- 26027903 TI - Multi-system Nernst-Michaelis-Menten model applied to bioanodes formed from sewage sludge. AB - Bioanodes were formed under constant polarization at -0.2 V/SCE from fermented sewage sludge. Current densities reached were 9.3+/-1.2 A m(-2) with the whole fermented sludge and 6.2+/-0.9 A m(-2) with the fermented sludge supernatant. The bioanode kinetics was analysed by differentiating among the contributions of the three redox systems identified by voltammetry. Each system ensured reversible Nernstian electron transfer but around a different central potential. The global overpotential required to reach the maximum current plateau was not imposed by slow electron transfer rates but was due to the potential range covered by the different redox systems. The microbial communities of the three bioanodes were analysed by 16S rRNA gene pyrosequencing. They showed a significant microbial diversity around a core of Desulfuromonadales, the proportion of which was correlated with the electrochemical performance of the bioanodes. PMID- 26027904 TI - Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. NAFLD hallmark is the excessive hepatic accumulation of neutral lipids that result from an imbalance between lipid availability and lipid removal. Recent data suggest that disturbed hepatic cholesterol homeostasis and liver free cholesterol (FC) accumulation are relevant to the pathogenesis of NAFLD/NASH. Hepatic FC accumulation in NAFLD results from alterations in intracellular cholesterol transport and from unbalanced cellular cholesterol homeostasis characterized by activation of cholesterol biosynthetic pathways, increased cholesterol de-esterification and attenuation of cholesterol export and bile acid synthesis pathways. FC accumulation leads to liver injury through the activation of intracellular signaling pathways in Kupffer cells (KCs), Stellate cells (HSCs) and hepatocytes. The activation of KCs and HSCs promotes inflammation and fibrogenesis. In addition, FC accumulation in liver mitochondria induces mitochondrial dysfunction, which results in increasing production of reactive oxygen species, and triggers the unfolded protein response in the endoplasmic reticulum (ER) causing ER stress and apoptosis. These events create a vicious circle that contributes to the maintenance of steatosis and promotes ongoing hepatocyte death and liver damage, which in turn may translate into disease progression. In the present review we summarize the current knowledge on dysregulated cholesterol homeostasis in NAFLD and examine the cellular mechanisms of hepatic FC toxicity and its contribution to ongoing liver injury in this disease. The therapeutic implications of this knowledge are also discussed. PMID- 26027905 TI - A case of Candida albicans fungus balls in the urinary tract appeared during the course of antifungal treatment for Candida endophthalmitis. AB - Fungus balls have been rarely implicated as a cause of urinary tract obstruction. Here, we report a case of Candida albicans fungus balls in the urinary tract after the treatment of Candida endophthalmitis that has enough periods and adequate amount of antifungal agents. The patient completely recovered from this rare complication by irrigating through single-J stent and changing antifungal agents. Here we emphasize that we should take into account not only the susceptibility test results but also the difference in excretion route and tissue distribution of antifungal agents. PMID- 26027906 TI - Proinflammatory cytokine responses correspond with subjective side effects after influenza virus vaccination. AB - BACKGROUND: Though typically mild, side effects to the influenza virus vaccine are common and may contribute to negative perceptions including the belief that the vaccine can cause the flu. However, the extent to which subjective symptoms correspond with biological response indicators is poorly understood. METHODS: This study examined associations among subjective side effects (soreness at the site of injection and illness-like symptoms), serum proinflammatory cytokines and body temperature a baseline, 1, 2, and 3 days following receipt of trivalent inactivated influenza vaccine (IIV3) in a sample of 56 women 18-40 years in age. RESULTS: In relation to local reactions, women reporting being very sore at the injection site at 1 day post-vaccination exhibited greater increases in serum TNF alpha and MIF in the days following vaccination compared to those with no or mild soreness. In addition, higher basal body temperature was observed in this group compared to other groups (98.7 degrees F versus 98.0-98.1 degrees ). In relation to systemic reactions, women endorsing illness-like symptoms (headache, fatigue, nausea, sore throat, dizziness, achiness, or mild fever) exhibited marginally higher IL-6 at baseline (p=0.055) and greater increases in serum MIF at 2 days post-vaccination than those reporting no systemic symptoms. Associations of systemic symptoms with inflammatory responses were not accounted for by concomitant local reactions. As expected, antibody responses to the vaccine were highly similar in women regardless of local or systemic symptoms. CONCLUSIONS: These results are consistent with the notion that subjective reports of local and systemic reactions following vaccination may be predicted by and correspond with biological indicators of inflammatory status, but are not meaningful predictors of antibody responses. To improve adherence to vaccine recommendations, clinicians should provide assurance that such symptoms may be related to normal mild inflammatory responses to the vaccine and do not reflect immunogenicity. PMID- 26027907 TI - Construction and evaluation of DNA vaccine encoding Hantavirus glycoprotein N terminal fused with lysosome-associated membrane protein. AB - BACKGROUND: Hantaviral diseases can have a high case fatality rate within the absence of broadly effective antiviral treatments or vaccines. We developed a DNA vaccine targeting the Hantavirus glycoprotein N-terminal (Gn) to major histocompatibility complex class II compartment by fusing the antigen with lysosome-associated membrane protein 1 (LAMP1), which altered antigen presenting pathway and activated the CD4+ T cells. METHODS: The segments of Gn and LAMP1 were cloned into vector pVAX1, and recombinant plasmid was constructed by inserting Gn sequence into LAMP1, between luminal and the transmembrane/cytoplasmic domains. Subsequently, the protein expression was identified through immunoprecipitation, western blot and Immunofluorescent assay. Adaptive immune responses were assessed by the presence of specific and neutralizing antibodies, interferon (ELISpot results, and cytotoxic T-lymphocyte (CTL) cytotoxicity. Epitope mapping was performed to study the T-cell epitopes. Protective immunity in vivo was evaluated using a novel HTNV-challenging model, and safety evaluation was based on histological and behavioral observations. RESULTS: Native or LAMP1 targeting HTNV Gn was successfully identified. Humoral immune responses were enhanced, featuring with satisfying titers of specific and neutralizing antibody production. The boosted activities of IFN-gamma and CTL cytotoxicity witnessed enhanced cellular immune responses. Effective protection against HTNV in vivo was conferred in all three vaccine groups by the challenge model. Safety was confirmed and one dominant T-cell epitope screened from immunized mice overlapped the specific T-cell hot spot in HFRS patients. CONCLUSION: LAMP1 targeting strategy successfully enhanced the efficacy of HTNV Gn-based vaccine, which is highly immunogenic and safe, showing promise for immunoprophylaxis against HFRS. Further investigations are warranted in the future. PMID- 26027908 TI - Aspirin is associated with reduced cartilage loss in knee osteoarthritis: Data from a cohort study. AB - OBJECTIVES: Aspirin, widely used in the prevention of cardiovascular disease, in low dose, has anti-inflammatory and vasculoprotective effects: both of these processes contribute to the pathogenesis of osteoarthritis. We examined whether use of low dose aspirin affects change in knee cartilage volume in osteoarthritis. METHODS: Participants from the Melbourne osteoarthritis cohort were classified as users and non-users of aspirin, according to baseline use (<=300 mg/day). Their knees were imaged twice over 2 years. Tibial cartilage volumes were measured and change calculated. RESULTS: Twenty one (18%) of 117 eligible participants were aspirin users. Annual change in medial tibial cartilage volume was -43 mm(3) (95% confidence intervals (CI) -93, 10) in aspirin users and -101 mm(3) (95% CI -125, -77) in non-users (p=0.043 for difference) after adjusting for age, gender, BMI and radiographic severity. Similar results were seen for annual percentage loss (1.9% vs 5.4%, p=0.034). No difference was observed for lateral tibial cartilage change and annual change (p=0.98, 0.87 respectively) CONCLUSION: Low dose aspirin use was associated with reduced medial tibial cartilage loss over 2 years in people with knee osteoarthritis. This data is hypothesis generating and clinical trials are required to confirm efficacy. If this hypothesis is confirmed, low dose aspirin may be used to reduce the progression of knee osteoarthritis. PMID- 26027909 TI - Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms. AB - Friedreich's ataxia (FRDA) is the most common form of hereditary ataxia caused by recessive mutations in the FXN gene. Recent results have indicated the presence of different frataxin isoforms due to alternative gene expression mechanisms. Our previous studies demonstrated the advantages of using high-capacity herpes simplex virus type 1 (HSV-1) amplicon vectors containing the entire FXN genomic locus (iBAC-FXN) as a gene-delivery vehicle capable of ensuring physiologically regulated and long-term persistence. Here we describe how expression from the 135 kb human FXN genomic locus produces the three frataxin isoforms both in cultured neuronal cells and also in vivo. Moreover, we also observed the correct expression of these frataxin isoforms in patient-derived cells after delivery of the iBAC-FXN. These results lend further support to the potential use of HSV-1 vectors containing entire genomic loci whose expression is mediated by complex transcriptional and posttranscriptional mechanisms for gene therapy applications. PMID- 26027910 TI - Pronounced Size Dependence in Structure and Morphology of Gas-Phase Produced, Partially Oxidized Cobalt Nanoparticles under Catalytic Reaction Conditions. AB - It is generally accepted that optimal particle sizes are key for efficient nanocatalysis. Much less attention is paid to the role of morphology and atomic arrangement during catalytic reactions. Here, we unravel the structural, stoichiometric, and morphological evolution of gas-phase produced and partially oxidized cobalt nanoparticles in a broad size range. Particles with diameters between 1.4 and 22 nm generated in cluster sources are size selected and deposited on amorphous alumina (Al2O3) and ultrananocrystalline diamond (UNCD) films. A combination of different techniques is employed to monitor particle properties at the stages of production, exposure to ambient conditions, and catalytic reaction, in this case, the oxidative dehydrogenation of cyclohexane at elevated temperatures. A pronounced size dependence is found, naturally classifying the particles into three size regimes. While small and intermediate clusters essentially retain their compact morphology, large particles transform into hollow spheres due to the nanoscale Kirkendall effect. Depending on the substrate, an isotropic (Al2O3) or anisotropic (UNCD) Kirkendall effect is observed. The latter results in dramatic lateral size changes. Our results shed light on the interplay between chemical reactions and the catalyst's structure and provide an approach to tailor the cobalt oxide phase composition required for specific catalytic schemes. PMID- 26027911 TI - Inhibition of microRNA-199a-5p reduces the replication of HCV via regulating the pro-survival pathway. AB - MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that post transcriptionally regulate the pathological processes of various liver diseases including hepatitis C virus (HCV) infection. In the present study, we demonstrated that HCV infection enhanced the expression of miR-199a-5p in HCV infected human hepatocytes and Huh7.5.1cells, as well as liver biopsy specimens. Inhibition of miR-199a-5p decreased HCV replication not only in terms of HCV RNA, but also the protein levels of NS3 and NS5A. Furthermore, we discovered that miR 199a-5p knockdown in Huh7.5.1 cells infected with genotype 2a (JFH1) or genotype 1b (SN1a) resulted in the remarkable inhibition of pro-survival pathways, as observed by the down-regulation of p-Akt, p-ERK and beta-catenin protein levels. Moreover, pre-treatment with the pro-survival pathway specific activator prominently ablated the inhibition of HCV replication induced by miR-199a-5p knockdown. Collectively, our results highlight the up-regulation of miR-199a-5p expression with HCV infection and the promotion of HCV replication by miR-199a 5p. Moreover, miR-199a-5p may facilitate HCV replication by regulating pro survival pathways through PI3K/Akt, Ras/ERK and Wnt/beta-catenin. miR-199a-5p might be a potential drug target for developing a novel strategy to combat HCV infection. PMID- 26027912 TI - Cardiac critical care: Balancing educational goals with optimal patient care. PMID- 26027914 TI - Chimeric antigen receptor (CAR)-redirected T cells: is there a place for them in infectious diseases? PMID- 26027913 TI - Coronary artery bypass grafting in diabetics: A growing health care cost crisis. AB - OBJECTIVES: To determine 4-decade temporal trends in the prevalence of diabetes and cardiovascular risk factors among patients undergoing coronary artery bypass grafting (CABG) and to compare in-hospital outcomes, resource utilization, and long-term survival after CABG in diabetics versus nondiabetics. METHODS: From January 1972 to January 2011, 10,362 pharmacologically treated diabetics and 45,139 nondiabetics underwent first-time CABG. Median follow-up was 12 years. Direct technical cost data were available from 2003 onward (n = 4679). Propensity matching by diabetes status was used for outcome comparisons. Endpoints were in hospital adverse events, resource utilization, and long-term survival. RESULTS: Diabetics undergoing CABG increased from 7% in the 1970s to 37% in the 2000s. Their outcomes were worse, with more (P < .05) in-hospital deaths (2.0% vs 1.3%), deep sternal wound infections (2.3% vs 1.2%), strokes (2.2% vs 1.4%), renal failure (4.0% vs 1.3%), and prolonged postoperative hospital stay (9.6% vs 6.0%); and their hospital costs were 9% greater (95% confidence interval 7%-11%). Survival after CABG among diabetics versus nondiabetics at 1, 5, 10, and 20 years was also worse: 94% versus 94%, 80% versus 84%, 56% versus 66%, and 20% versus 32%, respectively. Propensity-matched patients incurred similar costs, but the prevalence of postoperative deep sternal wound infections and stroke, as well as long-term survival, remained worse in diabetics. CONCLUSIONS: Diabetes is both a marker for high-risk, resource-intensive, and expensive care after CABG and an independent risk factor for reduced long-term survival. These issues, coupled with the increasing proportion of patients needing CABG who have diabetes, are a growing challenge in reining in health care costs. PMID- 26027915 TI - Variable incidence of candidemia in patients admitted to ICUs or medical wards of large tertiary-care Italian hospitals. PMID- 26027916 TI - Contemporary resistance trends and mechanisms for the old antibiotics colistin, temocillin, fosfomycin, mecillinam and nitrofurantoin. AB - Recently there has been a renewed interest in reviving older antimicrobial agents, particularly those with activity against multidrug-resistant Gram negative bacilli. Because many such antimicrobials are not licensed in all countries, there is a paucity of international surveillance data, and none of these agents is part of any antimicrobial resistance surveillance on the level of the EU. Some of the agents are used in lower urinary tract infection, whereas most available supranational surveillance data pertain to severe infections such as bloodstream infections. Among old antimicrobial agents, the most interesting compounds from a clinical perspective are the two intravenous agents colistin and temocillin, the two oral agents pivmecillinam and nitrofurantoin, and fosfomycin, which is available both for intravenous and oral use. The most interesting target microorganisms are Enterobacteriaceae, although colistin also has good activity against Pseudomonas aeruginosa and Acinetobacter species. Recent European surveillance data point to approximately 5% resistance to colistin in general among Klebsiella pneumoniae, whereas resistance in carbapenemase-producing Enterobacteriaceae may be up to 15% to 20% in some settings. Temocillin is stable against many extended-spectrum beta-lactamase-producing Enterobacteriaceae and some carbapenemase producers, but low-level resistance is not uncommon in extended-spectrum beta-lactamase producers, and high-level resistance is always seen with OXA-48 group carbapenemases. Fosfomycin resistance is rare in areas with limited use but increasing is in countries with higher usage. Resistance levels to mecillinam and nitrofurantoin are generally low in EU countries, but clinical data supporting treatment efficacy of multidrug-resistant strains are few. Systematic surveillance of the above-mentioned agents will be important, particularly for those agents used in severe infections. PMID- 26027917 TI - Possible human-to-human transmission of toxigenic Corynebacterium ulcerans. AB - Toxigenic Corynebacterium ulcerans is an emerging cause of diphtheria. In contrast to the classical diphtheria pathogen C. diphtheriae, human-to-human transmission of this primarily zoonotic pathogen has not been clearly documented. Here we report on a two-person cluster suggesting an initial zoonotic and a subsequent human-to-human transmission event. PMID- 26027918 TI - Effect of hypothyroidism on the expression of nuclear receptors and their co regulators in mammary gland during lactation in the rat. AB - Thyroid hormones (TH) regulate mammary function. Hypothyroidism (HypoT) has deleterious effects on lactation, litter growth and survival. We analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT in the expression of nuclear receptors, co-regulators and oxytocin receptor (OTR) on lactation (L) days 2, 7 and 14. TH receptors (TRs) were increased on L7 at mRNA and protein levels, except TRalpha protein, that fell on L14. HypoT decreased TRalpha2 mRNA on L7 and TRalpha1 protein on L2, while TRbeta1 protein increased on L14. HypoT increased estrogen receptor beta (ERbeta) mRNA on L7 but decreased its protein levels on L14. Progesterone receptor A (PRA) mRNA decreased from L2 to L14 while PRB increased, and at protein levels PRA levels showed a nadir on L7, while PRB peaked. HypoT decreased PRA mRNA and protein and increased PRB mRNA at L14. Nuclear receptor co-activator (NCOA) 1 and RXRalpha mRNA showed an opposite pattern to the TRs, while NCOA2 increased at L14; HypoT blocked the variations in NCOA1 and NCOA2. HypoT increased NCOR1 on L2 and decreased OTR at L2 and circulating estradiol and NCOR2 at L14. In controls the most notable changes occurred on L7, suggesting it is a key inflection point in mammary metabolism. The low levels of TRalpha1, NCOA1 and OTR, and increased NCOR1 produced by HypoT on L2 may hinder the mammary ability to achieve normal milk synthesis and ejection, leading to defective lactation. Later on, altered ER and PR expression may impair further mammary function. PMID- 26027920 TI - Low concentrations of Bisphenol A and para-Nonylphenol affect extravillous pathway of human trophoblast cells. AB - Bisphenol A (BPA) and para-Nonylphenol (p-NP) are chemicals of industrial origin which may influence human reproductive health. The effects of these substances in the prenatal life is an important topic that is receiving greater attention in the developed countries. In this study, human trophoblast cells HTR-8/SVneo were exposed to BPA and p-NP (1 * 10(-15), 1 * 10(-13), 1 * 10(-11), 1 * 10(-9) and 1 * 10(-7) M) and incubated for 24, 48 and/or 72 h then, examined for the main physiological processes which characterize the extravillous trophoblast. Cell proliferation showed no changes while the processes of cell migration and invasion were both reduced by BPA and p-NP. For each chemical, the activity was higher at lower concentrations with a maximum activity between 1 * 10(-13) and 1 * 10(-11) M (p < 0.05 for 1 * 10(-9) and p < 0.001 for 1 * 10(-11) M). Co-culture studies with human umbilical cord endothelial cells (HUVEC) revealed that trophoblast/endothelial interaction was significantly reduced by p-NP at 1 * 10( 11) M. Moreover, both chemicals were inducing differentiation of HTR-8/SVneo toward polyploidy by the process of endoreduplication. The estrogen-receptor antagonist ICI significantly reduced p-NP action, while it had no effect on BPA treated cells. In conclusion, p-NP and BPA act on trophoblast cells altering key physiological processes in placenta development. The exact mechanism of action of the chemicals in human trophoblast still needs to be clarified. PMID- 26027921 TI - Growth tethering devices for idiopathic scoliosis. AB - Adolescent idiopathic scoliosis is a 3D spine deformity that worsens during the whole growth. The treatments available are bracing during the whole growth to avoid progression of the deformity and surgical fusion of the spine at skeletal maturity for the most severe curves. Recent advances in flexible spinal implants have given rise to new expectations in the management of progressive scoliosis with growth modulation without fusion. For the first time, treatment allows us to expect a correction of progressive curves without fusion. This review discusses the recent developments in the field of spinal growth modulation techniques and discusses the pros and cons of the medical devices used in this indication. PMID- 26027922 TI - Lipoproteins from Clostridium perfringens and their protective efficacy in mouse model. AB - Clostridium perfringens is an obligately anaerobic rod-shaped bacterium and etiological agent for several diseases in humans and animals. The pathogen has been listed as Validated Biological Agent and warrants development of medical countermeasures. The homologs of some of the lipoproteins identified from various fractions of C. perfringens in our previous studies were observed to be virulence determinants in other pathogenic bacteria. Three putative virulence associated lipoproteins; polysaccharide deacetylase family protein, probable ion-uptake ABC transporter, and a putative lipoprotein of no known function are reported here with respect to their immuno-protective potentials. The three proteins were over expressed and purified to near homogeneity. The lipoproteins were shown to be exposed on the C. perfringens surface and, hence, accessible to antibodies and potentially visible to the host immune system. Immunization of mice with purified recombinant proteins elicited protective immunity against challenge with C. perfringens in mouse gas gangrene model. Distribution and relationship of orthologous proteins across other bacterial select agents especially among the members of Firmicutes, was carried out to look for conserved antigenic determinants. PMID- 26027919 TI - GATA factors in endocrine neoplasia. AB - GATA transcription factors are structurally-related zinc finger proteins that recognize the consensus DNA sequence WGATAA (the GATA motif), an essential cis acting element in the promoters and enhancers of many genes. These transcription factors regulate cell fate specification and differentiation in a wide array of tissues. As demonstrated by genetic analyses of mice and humans, GATA factors play pivotal roles in the development, homeostasis, and function of several endocrine organs including the adrenal cortex, ovary, pancreas, parathyroid, pituitary, and testis. Additionally, GATA factors have been shown to be mutated, overexpressed, or underexpressed in a variety of endocrine tumors (e.g., adrenocortical neoplasms, parathyroid tumors, pituitary adenomas, and sex cord stromal tumors). Emerging evidence suggests that GATA factors play a direct role in the initiation, proliferation, or propagation of certain endocrine tumors via modulation of key developmental signaling pathways implicated in oncogenesis, such as the WNT/beta-catenin and TGFbeta pathways. Altered expression or function of GATA factors can also affect the metabolism, ploidy, and invasiveness of tumor cells. This article provides an overview of the role of GATA factors in endocrine neoplasms. Relevant animal models are highlighted. PMID- 26027923 TI - Fine-scale genetic structure of Triatoma infestans in the Argentine Chaco. AB - The patterns of genetic structure in natural populations provide essential information for the improvement of pest management strategies including those targeting arthropod vectors of human diseases. We analyzed the patterns of fine scale genetic structure in Triatoma infestans in a well-defined rural area close to Pampa del Indio, in the Argentine Arid-Humid Chaco transition, where a longitudinal study on house infestation and wing geometric morphometry is being conducted since 2007. A total of 228 insects collected in 16 domestic and peridomestic sites from two rural communities was genotyped for 10 microsatellite loci and analyzed. We did not find departures from Hardy-Weinberg expectations in collection sites, with three exceptions probably due to null alleles and substructuring. Domestic sites were more variable than peridomestic sites suggesting the presence of older bug populations in domestic sites or higher effective population sizes. Significant genetic structure was detected using F statistics, a discriminant analysis of principal components and Bayesian clustering algorithms in an area of only 6.32 km(2). Microsatellite markers detected population structuring at a finer geographic scale (180-6300 m) than a previous study based on wing geometric morphometry (>4000 m). The spatial distribution of genetic variability was more properly explained by a hierarchical island than by an isolation-by-distance model. This study illustrates that, despite more than a decade without vector control interventions enhancing differentiation, genetic structure can be detected in T. infestans populations, particularly applying spatial information. This supports the potential of genetic studies to provide key information for hypothesis testing of the origins of house reinfestation. PMID- 26027925 TI - The eIF4E-Binding Protein 4E-T Is a Component of the mRNA Decay Machinery that Bridges the 5' and 3' Termini of Target mRNAs. AB - Eukaryotic mRNA degradation often initiates with the recruitment of the CCR4-NOT deadenylase complex and decay factors to the mRNA 3' terminus. How the 3' proximal decay machinery interacts with the 5'-terminal cap structure in order to engender mRNA decapping and 5'-3' degradation is unclear. Human 4E-T is an eIF4E binding protein that has been reported to promote mRNA decay, albeit via an unknown mechanism. Here, we show that 4E-T is a component of the mRNA decay machinery and interacts with factors including DDX6, LSM14, and the LSM1-7-PAT1 complex. We also provide evidence that 4E-T associates with, and enhances the decay of, mRNAs targeted by the CCR4-NOT deadenylase complex, including microRNA targets. Importantly, we demonstrate that 4E-T must interact with eIF4E to engender mRNA decay. Taken together, our data support a model where 4E-T promotes mRNA turnover by physically linking the 3'-terminal mRNA decay machinery to the 5' cap via its interaction with eIF4E. PMID- 26027927 TI - Quantitative High-Resolution Cellular Map of the Organ of Corti. AB - The organ of Corti harbors highly specialized sensory hair cells and surrounding supporting cells that are essential for the sense of hearing. Here, we report a single cell gene expression data analysis and visualization strategy that allows for the construction of a quantitative spatial map of the neonatal organ of Corti along its major anatomical axes. The map displays gene expression levels of 192 genes for all organ of Corti cell types ordered along the apex-to-base axis of the cochlea. Statistical interrogation of cell-type-specific gene expression patterns along the longitudinal gradient revealed features of apical supporting cells indicative of a propensity for proliferative hair cell regeneration. This includes reduced expression of Notch effectors, receptivity for canonical Wnt signaling, and prominent expression of early cell-cycle genes. Cochlear hair cells displayed expression gradients of genes indicative of cellular differentiation and the establishment of the tonotopic axis. PMID- 26027926 TI - Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators. AB - Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment. PMID- 26027928 TI - Environmental Temperature Differentially Modulates C. elegans Longevity through a Thermosensitive TRP Channel. AB - Temperature profoundly affects aging in both poikilotherms and homeotherms. A general belief is that lower temperatures extend lifespan, whereas higher temperatures shorten it. Although this "temperature law" is widely accepted, it has not been extensively tested. Here, we systematically evaluated the role of temperature in lifespan regulation in C. elegans. We found that, although exposure to low temperatures at the adult stage prolongs lifespan, low temperature treatment at the larval stage surprisingly reduces lifespan. Interestingly, this differential effect of temperature on longevity in larvae and adults is mediated by the same thermosensitive TRP channel TRPA-1 that signals to the transcription factor DAF-16/FOXO. DAF-16/FOXO and TRPA-1 act in larva to shorten lifespan but extend lifespan in adulthood. DAF-16/FOXO differentially regulates gene expression in larva and adult in a temperature-dependent manner. Our results uncover complexity underlying temperature modulation of longevity, demonstrating that temperature differentially regulates lifespan at different stages of life. PMID- 26027929 TI - MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy. AB - Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle to the effective treatment of breast cancer. Here, we have identified a mechanism by which the PI3K/Akt pathway mediates resistance to doxorubicin. In addition to inducing DNA damage, doxorubicin triggers sustained activation of Akt signaling in breast cancer cells. We show that Akt contributes to chemotherapy resistance such that PI3K or Akt inhibitors sensitize cells to doxorubicin. We identify MERIT40, a component of the BRCA1-A DNA damage repair complex, as an Akt substrate that is phosphorylated following doxorubicin treatment. MERIT40 phosphorylation facilitates assembly of the BRCA1-A complex in response to DNA damage and contributes to DNA repair and cell survival following doxorubicin treatment. Finally, MERIT40 phosphorylation in human breast cancers is associated with estrogen receptor positivity. Our findings suggest that combination therapy with PI3K or Akt inhibitors and doxorubicin may constitute a successful strategy for overcoming chemotherapy resistance. PMID- 26027930 TI - ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation. AB - Despite the significance for fetal nourishment in mammals, mechanisms of umbilical cord vascular growth remain poorly understood. Here, the secreted metalloprotease ADAMTS9 is shown to be necessary for murine umbilical cord vascular development. Restricting it to the cell surface using a gene trap allele, Adamts9(Gt), impaired umbilical vessel elongation and radial growth via reduced versican proteolysis and accumulation of extracellular matrix (ECM). Both Adamts9(Gt) and conditional Adamts9 deletion revealed that ADAMTS9 produced by mesenchymal cells acted non-autonomously to regulate smooth muscle cell (SMC) proliferation, differentiation, and orthogonal reorientation during growth of the umbilical vasculature. In Adamts9(Gt/Gt), we observed interference with PDGFRbeta signaling via the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, which regulates cytoskeletal dynamics during SMC rotation. In addition, we observed disrupted Shh signaling and perturbed orientation of the mesenchymal primary cilium. Thus, ECM dynamics is a major influence on umbilical vascular SMC fate, with ADAMTS9 acting as its principal mediator. PMID- 26027931 TI - Bidirectional Interplay between Vimentin Intermediate Filaments and Contractile Actin Stress Fibers. AB - The actin cytoskeleton and cytoplasmic intermediate filaments contribute to cell migration and morphogenesis, but the interplay between these two central cytoskeletal elements has remained elusive. Here, we find that specific actin stress fiber structures, transverse arcs, interact with vimentin intermediate filaments and promote their retrograde flow. Consequently, myosin-II-containing arcs are important for perinuclear localization of the vimentin network in cells. The vimentin network reciprocally restricts retrograde movement of arcs and hence controls the width of flat lamellum at the leading edge of the cell. Depletion of plectin recapitulates the vimentin organization phenotype of arc-deficient cells without affecting the integrity of vimentin filaments or stress fibers, demonstrating that this cytoskeletal cross-linker is required for productive interactions between vimentin and arcs. Collectively, our results reveal that plectin-mediated interplay between contractile actomyosin arcs and vimentin intermediate filaments controls the localization and dynamics of these two cytoskeletal systems and is consequently important for cell morphogenesis. PMID- 26027932 TI - Individual Human Cytotoxic T Lymphocytes Exhibit Intraclonal Heterogeneity during Sustained Killing. AB - The killing of antigen-bearing cells by clonal populations of cytotoxic T lymphocytes (CTLs) is thought to be a rapid phenomenon executed uniformly by individual CTLs. We combined bulk and single-CTL killing assays over a prolonged time period to provide the killing statistics of clonal human CTLs against an excess of target cells. Our data reveal efficiency in sustained killing at the population level, which relied on a highly heterogeneous multiple killing performance at the individual level. Although intraclonal functional heterogeneity was a stable trait in clonal populations, it was reset in the progeny of individual CTLs. In-depth mathematical analysis of individual CTL killing data revealed a substantial proportion of high-rate killer CTLs with burst killing activity. Importantly, such activity was delayed and required activation with strong antigenic stimulation. Our study implies that functional heterogeneity allows CTL populations to calibrate prolonged cytotoxic activity to the size of target cell populations. PMID- 26027933 TI - Dietary Protein to Carbohydrate Ratio and Caloric Restriction: Comparing Metabolic Outcomes in Mice. AB - Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake. PMID- 26027935 TI - Diverse Activators of the NLRP3 Inflammasome Promote IL-1beta Secretion by Triggering Necrosis. AB - The NLRP3 inflammasome is involved in caspase-1-dependent maturation of IL-1beta in many contexts. A two-signal model has emerged for IL-1beta maturation, with LPS providing "signal I" and diverse agents such as ATP, Nigericin, streptolysin O, uric acid crystals, and alum salts capable of acting as "signal II." In the absence of signal II, pro-IL-1beta is upregulated but typically fails to be processed or released. What unites signal II stimuli has been debated, with the ability to promote K+ efflux suggested as a common factor, but the mechanism of IL-1beta release remains unclear. Here, we show that all examined inflammasome signal II agents triggered necrosis, which was highly correlated with their ability to promote IL-1beta release. IL-1beta secretion occurred in tandem with the release of many additional proteins and was confined to necrotic cells. Thus, signal II agents initiate inflammation by promoting necrosis-driven IL-1beta release, suggesting that IL-1beta represents an inducible danger signal. PMID- 26027934 TI - Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation. AB - Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression. PMID- 26027937 TI - Microwave Ablation Compared to Radiofrequency Ablation for Hepatic Lesions: A Meta-Analysis. AB - To evaluate the efficacy and safety of microwave (MW) ablation compared with radiofrequency (RF) ablation for hepatic lesions by using meta-analytic techniques. Overall, 16 studies involving 2,062 patients were included. MW ablation was found to have significantly better 6-year overall survival than RF ablation (odds ratio, 1.64, 95% confidence interval, 1.15-2.35), but this was based on a few articles (n = 3 of 16). MW ablation and RF ablation had similar 1 5-year overall survival, disease-free survival, local recurrence rate, and adverse events. Based on similar safety and efficacy outcomes, either MW ablation or RF ablation may be used for effective local hepatic therapy. PMID- 26027936 TI - mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling. AB - mtDNA mutagenesis in somatic stem cells leads to their dysfunction and to progeria in mouse. The mechanism was proposed to involve modification of reactive oxygen species (ROS)/redox signaling. We studied the effect of mtDNA mutagenesis on reprogramming and stemness of pluripotent stem cells (PSCs) and show that PSCs select against specific mtDNA mutations, mimicking germline and promoting mtDNA integrity despite their glycolytic metabolism. Furthermore, mtDNA mutagenesis is associated with an increase in mitochondrial H2O2, reduced PSC reprogramming efficiency, and self-renewal. Mitochondria-targeted ubiquinone, MitoQ, and N acetyl-L-cysteine efficiently rescued these defects, indicating that both reprogramming efficiency and stemness are modified by mitochondrial ROS. The redox sensitivity, however, rendered PSCs and especially neural stem cells sensitive to MitoQ toxicity. Our results imply that stem cell compartment warrants special attention when the safety of new antioxidants is assessed and point to an essential role for mitochondrial redox signaling in maintaining normal stem cell function. PMID- 26027938 TI - Green and Efficient: Iron-Catalyzed Selective Oxidation of Olefins to Carbonyls with O2. AB - A mild and operationally simple iron-catalyzed protocol for the selective aerobic oxidation of aromatic olefins to carbonyl compounds is described. Catalyzed by a Fe(III) species bearing a pyridine bisimidazoline ligand at 1 atm of O2, alpha- and beta-substituted styrenes were cleaved to afford benzaldehydes and aromatic ketones generally in high yields with excellent chemoselectivity and very good functional group tolerance, including those containing radical-sensitive groups. With alpha-halo-substituted styrenes, the oxidation took place with concomitant halide migration to afford alpha-halo acetophenones. Various observations have been made, pointing to a mechanism in which both molecular oxygen and the olefinic substrate coordinate to the iron center, leading to the formation of a dioxetane intermediate, which collapses to give the carbonyl product. PMID- 26027939 TI - Managing mass events and competitions with difficult-to-access locations using mobile electrocardiac monitoring. AB - OBJECTIVE: Using mobile wireless technology to monitor ECG in participants of mass events and sports taking place in difficult-to-access location could both prevent and easier detect arrhythmias as well as provide real-time monitoring for any type of injury. We assessed the effectiveness of mobile wireless monitoring technology and IT in detecting possible emergencies during a skyscraper race. METHODS: We attached specially designed wireless surveillance biopatches on 120 individuals participating to monitor their continuous ECG and location during a skyscraper run-up race at Taipei 101 building, Taiwan. The outcomes of interest were detection of abnormal heartbeats and QRS waves indicative of possible cardiac problems and the exact location of participants during the occurrence of emergencies. RESULTS: The devices accurately sent over 50 warnings to our monitoring platform when both, danger limits were reached by competitors (<60 or >195 beats per minute) or competitors stopped moving, proving very effective in quickly detecting abnormities and alerting staff of possible emergencies at exact locations. CONCLUSION: This efficient and inexpensive monitoring method can also prevent arrhythmias in unscreened competitors, the danger of collision among staff and competitors, and preserves oxygen by eliminating additional on-foot monitoring staff. Additionally, it could have multipurpose usage, especially during disasters and accidents occurring in difficult-to-access locations, in military exercises and personal monitoring. PMID- 26027940 TI - Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson's disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study. AB - BACKGROUND: High-frequency deep brain stimulation (DBS) with a single electrical source is effective for motor symptom relief in patients with Parkinson's disease. We postulated that a multiple-source, constant-current device that permits well defined distribution of current would lead to motor improvement in patients with Parkinson's disease. METHODS: We did a prospective, multicentre, non-randomised, open-label intervention study of an implantable DBS device (the VANTAGE study) at six specialist DBS centres at universities in six European countries. Patients were judged eligible if they were aged 21-75 years, had been diagnosed with bilateral idiopathic Parkinson's disease with motor symptoms for more than 5 years, had a Hoehn and Yahr score of 2 or greater, and had a Unified Parkinson's disease rating scale part III (UPDRS III) score in the medication-off state of more than 30, which improved by 33% or more after a levodopa challenge. Participants underwent bilateral implantation in the subthalamic nucleus of a multiple-source, constant-current, eight-contact, rechargeable DBS system, and were assessed 12, 26, and 52 weeks after implantation. The primary endpoint was the mean change in UPDRS III scores (assessed by site investigators who were aware of the treatment assignment) from baseline (medication-off state) to 26 weeks after first lead implantation (stimulation-on, medication-off state). This study is registered with ClinicalTrials.gov, number NCT01221948. FINDINGS: Of 53 patients enrolled in the study, 40 received a bilateral implant in the subthalamic nucleus and their data contributed to the primary endpoint analysis. Improvement was noted in the UPDRS III motor score 6 months after first lead implantation (mean 13.5 [SD 6.8], 95% CI 11.3-15.7) compared with baseline (37.4 [8.9], 34.5-40.2), with a mean difference of 23.8 (SD 10.6; 95% CI 20.3-27.3; p<0.0001). One patient died of pneumonia 24 weeks after implantation, which was judged to be unrelated to the procedure. 125 adverse events were reported, the most frequent of which were dystonia, speech disorder, and apathy. 18 serious adverse events were recorded, three of which were attributed to the device or procedure (one case each of infection, migration, and respiratory depression). All serious adverse events resolved without residual effects and stimulation remained on during the study. INTERPRETATION: The multiple-source, constant current, eight-contact DBS system suppressed motor symptoms effectively in patients with Parkinson's disease, with an acceptable safety profile. Future trials are needed to investigate systematically the potential benefits of this system on postoperative outcome and its side-effects. FUNDING: Boston Scientific. PMID- 26027941 TI - Assisted nutrition: a difficult decision in patients with amyotrophic lateral sclerosis. PMID- 26027942 TI - Multiple-source current steering: a new arrow in the DBS quiver. PMID- 26027943 TI - Gastrostomy in patients with amyotrophic lateral sclerosis (ProGas): a prospective cohort study. AB - BACKGROUND: Gastrostomy feeding is commonly used to support patients with amyotrophic lateral sclerosis who develop severe dysphagia. Although recommended by both the American Academy of Neurology and the European Federation of Neurological Societies, currently little evidence indicates the optimum method and timing for gastrostomy insertion. We aimed to compare gastrostomy insertion approaches in terms of safety and clinical outcomes. METHODS: In this large, longitudinal, prospective cohort study (ProGas), we enrolled patients with a diagnosis of definite, probable, laboratory supported, or possible amyotrophic lateral sclerosis who had agreed with their treating clinicians to undergo gastrostomy at 24 motor neuron disease care centres or clinics in the UK. The primary outcome was 30-day mortality after gastrostomy. This study was registered on the UK Clinical Research Network database, identification number 9923. FINDINGS: Between Nov 2, 2010, and Jan 31, 2014, 345 patients were recruited of whom 330 had gastrostomy. 163 (49%) patients underwent percutaneous endoscopic gastrostomy, 121 (37%) underwent radiologically inserted gastrostomy, 43 (13%) underwent per-oral image-guided gastrostomy, and three (1%) underwent surgical gastrostomy. 12 patients (4%, 95% CI 2.1-6.2) died within the first 30 days after gastrostomy: five (3%) of 163 after percutaneous endoscopic gastrostomy, four (3%) of 121 after radiologically inserted gastrostomy, and three (7%) of 43 after per-oral image-guided gastrostomy (p=0.46). Including repeat attempts in 14 patients, 21 (6%) of 344 gastrostomy procedures could not be completed: 11 (6%) of 171 percutaneous endoscopic gastrostomies, seven (6%) of 121 radiologically inserted gastrostomies, and three (6%) of 45 per-oral image-guided gastrostomies (p=0.947). INTERPRETATION: The three methods of gastrostomy seemed to be as safe as each other in relation to survival and procedural complications. In the absence of data from randomised trials, our findings could inform clinicians and patients in reaching decisions about gastrostomy and will stimulate further research into the nutritional management in patients with amyotrophic lateral sclerosis. FUNDING: Motor Neurone Disease Association of Great Britain and Northern Ireland (MNDA) and the Sheffield Institute for Translational Neuroscience (SITraN). PMID- 26027945 TI - Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity. AB - Knowledge of the effects of glucotoxic and lipotoxic environments on proglucagon producing intestinal L cells and pancreatic alpha cells is limited compared with pancreatic beta cells. This study compares the in vitro responses of these cell types to hyperglycaemia and hyperlipidaemia. Glucose (30 mM) and palmitate (0.5mM) reduced GLUTag and MIN6 cell viability while alpha TC1 cells were sensitive only to lipotoxicity. Consistent with this, Cat mRNA expression was substantially higher in GLUTag and alpha TC1 cells compared to MIN6 cells. Glucose and palmitate reduced GLUTag cell secretory function while hypersecretion of glucagon was apparent from alpha TC1 cells. Glucose exposure increased transcription of Cat and Sod2 in MIN6 and GLUTag cells respectively while it decreased transcription of Cat and Gpx1 in alpha TC1 cells. Palmitate increased transcription of Cat and Sod2 in all three cell lines. Upregulation of antioxidant enzyme expression by palmitate was accompanied by an increase in Nfkb1 transcription, indicative of activation of defence pathways. Lipotoxicity activated ER stress response, evident from increased Hspa4 mRNA level in GLUTag and MIN6 cells. Glucose and palmitate-induced DNA damage and apoptosis, with substantially smaller effects in alpha TC1 cells. Thus alpha cells are resistant to gluco- and lipotoxicity, partly reflecting higher expression of genes involved in antioxidant defence. In contrast, intestinal L cells, like beta cells, are prone to gluco- and lipotoxicity, possibly contributing to abnormalities of GLP-1 secretion in type 2 diabetes. PMID- 26027946 TI - Intravenous administration of bone marrow-derived multipotent mesenchymal stromal cells enhances the recruitment of CD11b(+) myeloid cells to the lungs and facilitates B16-F10 melanoma colonization. AB - The discovery that the regenerative properties of bone marrow multipotent mesenchymal stromal cells (BM-MSCs) could collaterally favor neoplastic progression has led to a great interest in the function of these cells in tumors. However, the effect of BM-MSCs on colonization, a rate-limiting step of the metastatic cascade, is unknown. In this study, we investigated the effect of BM MSCs on metastatic outgrowth of B16-F10 melanoma cells. In in vitro experiments, direct co-culture assays demonstrated that BM-MSCs stimulated the proliferation of B16-F10 cells in a dose-dependent manner. For in vivo experiments, luciferase expressing B16-F10 cells were injected through tail vein and mice were subsequently treated with four systemic injections of BM-MSCs. In vivo bioluminescent imaging during 16 days demonstrated that BM-MSCs enhanced the colonization of lungs by B16-F10 cells, which correlated with a 2-fold increase in the number of metastatic foci. Flow cytometry analysis of lungs demonstrated that although mice harboring B16-F10 metastases displayed more endothelial cells, CD4 T and CD8 T lymphocytes in the lungs in comparison to metastases-free mice, BM-MSCs did not alter the number of these cells. Interestingly, BM-MSCs inoculation resulted in a 2-fold increase in the number of CD11b(+) myeloid cells in the lungs of melanoma-bearing animals, a cell population previously described to organize "premetastatic niches" in experimental models. These findings indicate that BM-MSCs provide support to B16-F10 cells to overcome the constraints that limit metastatic outgrowth and that these effects might involve the interplay between BM-MSCs, CD11b(+) myeloid cells and tumor cells. PMID- 26027944 TI - Hyaluronan based hydrogels provide an improved model to study megakaryocyte matrix interactions. AB - Hyaluronan (HA) is a glycosamminoglican involved in cell biology as well as a relevant polymer for tissue engineering and regenerative medicine. Megakaryocytes (Mks) are immersed in a mesh of extracellular matrix (ECM) components that regulate their maturation in the bone marrow (BM) and the release of platelets into the bloodstream. While fibrous ECMs such as collagens and fibronectin have been demonstrated to differently regulate Mk function and platelet release, the role of HA, that fills the majority of the BM extracellular interstitial space, has not been investigated so far. Here we demonstrated that, although human Mks express HA receptors, they are not affected by HA in terms of in vitro differentiation, maturation and platelet formation. Importantly, chemical properties of HA were exploited to generate hydrogels with entrapped ECMs that represent a useful model to more closely mimic the tridimensional characteristics of the BM environment for studying Mk function. In conclusion, in this work we demonstrated that HA is an ideal candidate for a 3D ex vivo model of human BM ECM component environment. PMID- 26027947 TI - Podophyllotoxin derivatives: a patent review (2012 - 2014). AB - INTRODUCTION: Podophyllotoxin (PPT) is a naturally occurring antimitotic agent and an interesting lead in the development of anticancer agents. Its optimization led to the development of etoposide and teniposide used in combination chemotherapy with other anticancer drugs; unlike PPT these drugs act by inhibiting topoisomerases. Clinical success and toxicity issues at later stages of etoposide usage inclined researchers to develop structurally modified PPT derivatives. Some of the compounds obtained are under clinical investigations and are anticipated to reach the market. AREAS COVERED: The present review summarizes the attempts made by researchers across the globe to find out newer anticancer agents based on the PPT structure. It brings out the outline of the inventions filed in the form of patents during the years 2012 - 2014. EXPERT OPINION: After the successful development of etoposide and teniposide there has been considerable interest in the PPT skeleton to develop newer chemotherapeutic agents. In this regard, several PPT derivatives such as TOP53, GL331, NK611, F11782, and so on, have been developed and are undergoing clinical trials. However, its low natural abundance is a major problem in carrying out research on PPT skeleton. This issue is expected to be addressed with the development of newer synthetic strategies to access structurally modified PPTs. PMID- 26027948 TI - PDE5 inhibition improves acquisition processes after learning via a central mechanism. AB - In previous studies, we have shown that phosphodiesterase type 5 inhibitors (PDE5 Is) can improve early consolidation of object memory. These conclusions were based on the timing of drug administration relative to the learning trial (i.e. before or after). However, there are very little pharmacological data available about the pharmacokinetic profile of orally administered PDE5-Is in the rat. Furthermore, there is still debate whether these effects are achieved via central or peripheral mechanisms and if acquisition processes are improved. In the current study, we tested the effects of the PDE5-I vardenafil in a cholinergic deficit model and compared the effects after intracerebroventricular (ICV) versus oral (PO) administration. We found that PO vardenafil restored a scopolamine induced memory impairment when dosed within 2 min after the learning trial while ICV vardenafil was able to restore memory when injected within 4 min after learning. Because the test trial was within 10 min after the learning trial, this suggests that these effects on object memory are related to acquisition processes that may still be ongoing in a time window after the learning trial. To further elucidate the extent of this acquisition window, we investigated the pharmacokinetic profile of vardenafil after PO administration where it was detected within 4 min post-dose. Taken together, our data suggest that PDE5 is involved in acquisition processes, which may linger for at least 4-6 min after learning. Further studies are needed to exclude that these effects could also be explained on basis of an effect on early consolidation processes. Additionally, the effectiveness of ICV-administered vardenafil provides further experimental evidence that PDE5-Is improve memory via a central mechanism. PMID- 26027949 TI - mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits. AB - Autism spectrum disorder (ASD) is multifactorial, with both genetic as well as environmental factors working in concert to develop the autistic phenotype. Immunological disturbances in autistic individuals have been reported and a role for food allergy has been suggested in ASD. Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well. Therefore, the mTOR pathway may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD. In this study it was investigated whether the mTOR pathway plays a role in food allergy-induced behavioral and immunological deficits. Mice were orally sensitized and challenged with whey protein. Meanwhile, cow's milk allergic (CMA) mice received daily treatment of rapamycin. The validity of the CMA model was confirmed by showing increased allergic immune responses. CMA mice showed reduced social interaction and increased repetitive self-grooming behavior. Enhanced mTORC1 activity was found in the brain and ileum of CMA mice. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of CMA mice. This effect was associated with increase of Treg associated transcription factors in the ileum of CMA mice. These findings indicate that mTOR activation may be central to both the intestinal, immunological, and psychiatric ASD-like symptoms seen in CMA mice. It remains to be investigated whether mTOR can be seen as a therapeutic target in cow's milk allergic children suffering from ASD-like symptoms. PMID- 26027950 TI - Biocompatible Glycopolymer Nanocapsules via Inverse Miniemulsion Periphery RAFT Polymerization for the Delivery of Gemcitabine. AB - Encapsulation of hydrophilic cancer drugs in polymeric nanocapsules was achieved in a one-pot process via the inverse miniemulsion periphery RAFT polymerization (IMEPP) approach. The chosen guest molecule was gemcitabine hydrochloride, which is used as the first-line treatment of pancreatic cancer. The resulting nanocapsules were confirmed to be ~200 nm, with excellent encapsulation (~96%) and loading (~12%) efficiency. Postpolymerization reaction was successfully conducted to create glyocopolymer nanocapsules without any impact on the loads as well as the nanocapsules size or morphology. The loaded nanocapsules were specifically designed to be responsive in a reductive environment. This was confirmed by the successful disintegration of the nanocapsules in the presence of glutathione. The gemcitabine-loaded nanocapsules were tested in vitro against pancreatic cancer cells (AsPC-1), with the results showing an enhancement in the cytotoxicity by two fold due to selective accumulation and release of the nanocapsules within the cells. The results demonstrated the versatility of IMEPP as a tool to synthesize functionalized, loaded-polymeric nanocapsules suitable for drug-delivery application. PMID- 26027951 TI - Thickness-Dependent Coherent Phonon Frequency in Ultrathin FeSe/SrTiO3 Films. AB - Ultrathin FeSe films grown on SrTiO3 substrates are a recent milestone in atomic material engineering due to their important role in understanding unconventional superconductivity in Fe-based materials. By using femtosecond time- and angle resolved photoelectron spectroscopy, we study phonon frequencies in ultrathin FeSe/SrTiO3 films grown by molecular beam epitaxy. After optical excitation, we observe periodic modulations of the photoelectron spectrum as a function of pump probe delay for 1-unit-cell, 3-unit-cell, and 60-unit-cell thick FeSe films. The frequencies of the coherent intensity oscillations increase from 5.00 +/- 0.02 to 5.25 +/- 0.02 THz with increasing film thickness. By comparing with previous works, we attribute this mode to the Se A1g phonon. The dominant mechanism for the phonon softening in 1-unit-cell thick FeSe films is a substrate-induced lattice strain. Our results demonstrate an abrupt phonon renormalization due to a lattice mismatch between the ultrathin film and the substrate. PMID- 26027952 TI - Contractile cell forces deform macroscopic cantilevers and quantify biomaterial performance. AB - Cells require adhesion to survive, proliferate and migrate, as well as for wound healing and many other functions. The strength of contractile cell forces on an underlying surface is a highly relevant quantity to measure the affinity of cells to a rigid surface with and without coating. Here we show with experimental and theoretical studies that these forces create surface stresses that are sufficient to induce measurable bending of macroscopic cantilevers. Since contractile forces are linked to the formation of focal contacts, results give information on adhesion promoting qualities and allow a comparison of very diverse materials. In exemplary studies, in vitro fibroblast adhesion on the magnetic shape memory alloy Fe-Pd and on the l-lysine derived plasma-functionalized polymer PPLL was determined. We show that cells on Fe-Pd are able to induce surface stresses three times as high as on pure titanium cantilevers. A further increase was observed for PPLL, where the contractile forces are four times higher than on the titanium reference. In addition, we performed finite element simulations on the beam bending to back up the calculation of contractile forces from cantilever bending under non-homogenous surface stress. Our findings consolidate the role of contractile forces as a meaningful measure of biomaterial performance. PMID- 26027953 TI - Slow magnetic relaxation in mononuclear seven-coordinate cobalt(II) complexes with easy plane anisotropy. AB - Two mononuclear seven-coordinate cobalt(II) complexes [Co(L)3(NO3)2] (L = 4-tert butylpyridine, 1; L = isoquinoline, 2) were prepared and structurally analyzed by single-crystal X-ray crystallography. The coordination spheres of 1 and 2 exhibit distorted pentagonal bipyramid geometry. Analysis of their direct-current magnetic data reveals the existence of easy plane anisotropy (D > 0) with a small transverse anisotropy (E), which was further confirmed by high-field electron paramagnetic resonance (HFEPR) spectroscopy. Field-induced slow magnetic relaxations were observed under the applied dc field in complexes 1 and 2 by alternating-current magnetic susceptibility measurements. Importantly, these complexes are new instances of mononuclear high-coordinate cobalt(II)-based single-molecule magnets. PMID- 26027954 TI - Supramolecular hydrophobic guest transport system based on pillar[5]arene. AB - A pillar[5]arene-based bioactive guest loading system has been developed, which can increase the solubility of the drug norharmane in aqueous medium, and also enable its pH-stimulated release. Furthermore, this supramolecular transport system reduces the toxicity of loaded guest. PMID- 26027955 TI - Lymph node density as a prognostic variable in node-positive bladder cancer: a meta-analysis. AB - BACKGROUND: Although lymph node (LN) status and the LN burden determine the outcome of bladder cancer patients treated with cystectomy, compelling arguments have been made for the incorporation of LN density into the current staging system. Here, we investigate the relationship between LN density and clinical outcome in patients with LN-positive disease, following radical cystectomy for bladder cancer. METHODS: PubMed, SCOPUS, the Institute for Scientific Information Web of Science, and the Cochrane Library were searched to identify relevant published literature. RESULTS: Fourteen studies were included in the meta analysis, with a total number of 3311 patients. Of these 14 publications, 6 studies, (533 patients), 10 studies (2966 patients), and 5 studies (1108 patients) investigated the prognostic association of LN density with disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS), respectively. The pooled hazard ratio (HR) for DFS was 1.45 (95% confidence interval [CI], 1.10-1.91) without heterogeneity (I2=0%, p=0.52). Higher LN density was significantly associated with poor DSS (pooled HR, 1.53; 95% CI, 1.23 1.89). However, significant heterogeneity was found between studies (I2=66%, p=0.002). The pooled HR for OS was statistically significant (pooled HR, 1.45; 95% CI, 1.11-1.90) without heterogeneity (I2=42%, p=0.14). The results of the Begg and Egger tests suggested that publication bias was not evident in this meta analysis. CONCLUSIONS: The data from this meta-analysis indicate that LN density is an independent predictor of clinical outcome in LN-positive patients. LN density may be useful in future staging systems, thus allowing better prognostic classification of LN-positive bladder cancer. PMID- 26027956 TI - A multiplexed assay for determination of neurotoxicant effects on spontaneous network activity and viability from microelectrode arrays. AB - Microelectrode array (MEA) recordings are increasingly being used as an in vitro method to detect and characterize the ability of drugs, chemicals and particles to cause neurotoxicity. While compound effects on spontaneous network activity are easily determined by MEA recordings, compound cytotoxicity is not routinely assessed, particularly within the same network from which recordings are collected. With the advent of higher-throughput 48 and 96 well MEA systems, rapid and simple methods to measure compound effects on cell health are required to facilitate efficient compound screening using MEAs. The present experiments sought to develop a multiplexed approach that allows measurement of network activity and cell health in the same MEA well. Primary cultures from rat cortex were exposed to six different compounds (glyphosate, beta-cyfluthrin, domoic acid, tributyltin, lindane and fipronil). Effects of these compounds (0.03-100 MUM) on spontaneous network activity (mean firing rate; MFR), cellular metabolic activity (Cell Titer BlueTM (CTB) assay) and lactate dehydrogenase (LDH) release were determined in the same well following a 60-min exposure. Glyphosate elicited no effect on MFR, LDH release or CTB reduction. Tributyltin caused concomitant decreases in MFR and CTB reduction and increases LDH release, while domoic acid and beta-cyfluthrin decreased MFR in a concentration-dependent manner without altering either LDH release or CTB reduction. By contrast, lindane and fipronil did not alter LDH release or CTB reduction, but caused biphasic alterations in MFR, with increases in MFR at lower concentrations followed by decreases at higher concentrations. These results demonstrate a simple and rapid method for the simultaneous determination of test compound effects on spontaneous electrical activity and cell health from the same network, and will facilitate rapid screening of compounds for potential neurotoxicity. PMID- 26027959 TI - A biomimetic phenol substituent effect on the reaction of a dimethylplatinum(ii) complex with oxygen: proton coupled electron transfer and multiple proton relay. AB - The complex [PtMe2({kappa(2)-N,N-RN[double bond, length as m-dash]CH-2-C5H4N})] reacts with oxygen in acetone solution to give the platinum(iv) complex [Pt(OH)Me2{kappa(3)-N,N,O-RNH-CH(2-C5H4N)(CH[double bond, length as m dash]CMeO)}], when R = 2-C6H4OH, but not when R = Ph. It has been suggested that the phenol substituent plays two key biomimetic roles; firstly, in proton coupled electron transfer reactions in the activation of oxygen and hydroperoxide groups and, secondly, in proton relay from a methyl group of the coordinated acetone. PMID- 26027958 TI - Mechanical competence of ovariectomy-induced compromised bone after single or combined treatment with high-frequency loading and bisphosphonates. AB - Osteoporosis leads to increased bone fragility, thus effective approaches enhancing bone strength are needed. Hence, this study investigated the effect of single or combined application of high-frequency (HF) loading through whole body vibration (WBV) and alendronate (ALN) on the mechanical competence of ovariectomy induced osteoporotic bone. Thirty-four female Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and divided into five groups: shOVX, OVX-shWBV, OVX-WBV, ALN-shWBV and ALN-WBV. (Sham)WBV loading was applied for 10 min/day (130 to 150 Hz at 0.3g) for 14 days and ALN at 2 mg/kg/dose was administered 3x/week. Finite element analysis based on micro-CT was employed to assess bone biomechanical properties, relative to bone micro-structural parameters. HF loading application to OVX resulted in an enlarged cortex, but it was not able to improve the biomechanical properties. ALN prevented trabecular bone deterioration and increased bone stiffness and bone strength of OVX bone. Finally, the combination of ALN with HF resulted in an increased cortical thickness in OVX rats when compared to single treatments. Compared to HF loading, ALN treatment is preferred for improving the compromised mechanical competence of OVX bone. In addition, the association of ALN with HF loading results in an additive effect on the cortical thickness. PMID- 26027960 TI - ESV Peer-Reviewed Journal for the 24th International Technical Conference on the Enhanced Safety of Vehicles (ESV). Foreword. PMID- 26027961 TI - Lower Leg Injury Reference Values and Risk Curves from Survival Analysis for Male and Female Dummies: Meta-analysis of Postmortem Human Subject Tests. AB - OBJECTIVE: Derive lower leg injury risk functions using survival analysis and determine injury reference values (IRV) applicable to human mid-size male and small-size female anthropometries by conducting a meta-analysis of experimental data from different studies under axial impact loading to the foot-ankle-leg complex. METHODS: Specimen-specific dynamic peak force, age, total body mass, and injury data were obtained from tests conducted by applying the external load to the dorsal surface of the foot of postmortem human subject (PMHS) foot-ankle-leg preparations. Calcaneus and/or tibia injuries, alone or in combination and with/without involvement of adjacent articular complexes, were included in the injury group. Injury and noninjury tests were included. Maximum axial loads recorded by a load cell attached to the proximal end of the preparation were used. Data were analyzed by treating force as the primary variable. Age was considered as the covariate. Data were censored based on the number of tests conducted on each specimen and whether it remained intact or sustained injury; that is, right, left, and interval censoring. The best fits from different distributions were based on the Akaike information criterion; mean and plus and minus 95% confidence intervals were obtained; and normalized confidence interval sizes (quality indices) were determined at 5, 10, 25, and 50% risk levels. The normalization was based on the mean curve. Using human-equivalent age as 45 years, data were normalized and risk curves were developed for the 50th and 5th percentile human size of the dummies. RESULTS: Out of the available 114 tests (76 fracture and 38 no injury) from 5 groups of experiments, survival analysis was carried out using 3 groups consisting of 62 tests (35 fracture and 27 no injury). Peak forces associated with 4 specific risk levels at 25, 45, and 65 years of age are given along with probability curves (mean and plus and minus 95% confidence intervals) for PMHS and normalized data applicable to male and female dummies. Quality indices increased (less tightness-of-fit) with decreasing age and risk level for all age groups and these data are given for all chosen risk levels. CONCLUSIONS: These PMHS-based probability distributions at different ages using information from different groups of researchers constituting the largest body of data can be used as human tolerances to lower leg injury from axial loading. Decreasing quality indices (increasing index value) at lower probabilities suggest the need for additional tests. The anthropometry-specific mid-size male and small-size female mean human risk curves along with plus and minus 95% confidence intervals from survival analysis and associated IRV data can be used as a first step in studies aimed at advancing occupant safety in automotive and other environments. PMID- 26027962 TI - Estimated injury risk for specific injuries and body regions in frontal motor vehicle crashes. AB - OBJECTIVE: Injury risk curves estimate motor vehicle crash (MVC) occupant injury risk from vehicle, crash, and/or occupant factors. Many vehicles are equipped with event data recorders (EDRs) that collect data including the crash speed and restraint status during a MVC. This study's goal was to use regulation-required data elements for EDRs to compute occupant injury risk for (1) specific injuries and (2) specific body regions in frontal MVCs from weighted NASS-CDS data. METHODS: Logistic regression analysis of NASS-CDS single-impact frontal MVCs involving front seat occupants with frontal airbag deployment was used to produce 23 risk curves for specific injuries and 17 risk curves for Abbreviated Injury Scale (AIS) 2+ to 5+ body region injuries. Risk curves were produced for the following body regions: head and thorax (AIS 2+, 3+, 4+, 5+), face (AIS 2+), abdomen, spine, upper extremity, and lower extremity (AIS 2+, 3+). Injury risk with 95% confidence intervals was estimated for 15-105 km/h longitudinal delta-Vs and belt status was adjusted for as a covariate. RESULTS: Overall, belted occupants had lower estimated risks compared to unbelted occupants and the risk of injury increased as longitudinal delta-V increased. Belt status was a significant predictor for 13 specific injuries and all body region injuries with the exception of AIS 2+ and 3+ spine injuries. Specific injuries and body region injuries that occurred more frequently in NASS-CDS also tended to carry higher risks when evaluated at a 56 km/h longitudinal delta-V. In the belted population, injury risks that ranked in the top 33% included 4 upper extremity fractures (ulna, radius, clavicle, carpus/metacarpus), 2 lower extremity fractures (fibula, metatarsal/tarsal), and a knee sprain (2.4-4.6% risk). Unbelted injury risks ranked in the top 33% included 4 lower extremity fractures (femur, fibula, metatarsal/tarsal, patella), 2 head injuries with less than one hour or unspecified prior unconsciousness, and a lung contusion (4.6-9.9% risk). The 6 body region curves with the highest risks were for AIS 2+ lower extremity, upper extremity, thorax, and head injury and AIS 3+ lower extremity and thorax injury (15.9-43.8% risk). CONCLUSIONS: These injury risk curves can be implemented into advanced automatic crash notification (AACN) algorithms that utilize vehicle EDR measurements to predict occupant injury immediately following a MVC. Through integration with AACN, these injury risk curves can provide emergency medical services (EMS) and other patient care providers with information on suspected occupant injuries to improve injury detection and patient triage. PMID- 26027963 TI - Census study of real-life near-side crashes with modern side airbag-equipped vehicles in the United States. AB - OBJECTIVE: This study aimed to investigate the crash characteristics, injury distribution, and injury mechanisms for Maximum Abbreviated Injury Score (MAIS) 2+ injured belted, near-side occupants in airbag-equipped modern vehicles. Furthermore, differences in injury distribution for senior occupants compared to non-senior occupants was investigated, as well as whether the near-side occupant injury risk to the head and thorax increases or decreases with a neighboring occupant. METHOD: National Automotive Sampling System's Crashworthiness Data System (NASS-CDS) data from 2000 to 2012 were searched for all side impacts (GAD L&R, all principal direction of force) for belted occupants in modern vehicles (model year > 1999). Rollovers were excluded, and only front seat occupants over the age of 10 were included. Twelve thousand three hundred fifty-four MAIS 2+ injured occupants seated adjacent to the intruding structure (near-side) and protected by at least one deployed side airbag were studied. To evaluate the injury risk influenced by the neighboring occupant, odds ratio with an induced exposure approach was used. RESULT: The most typical crash occurred either at an intersection or in a left turn where the striking vehicle impacted the target vehicle at a 60 to 70 degrees angle, resulting in a moderate change of velocity (delta-V) and intrusion at the B-pillar. The head, thorax, and pelvis were the most frequent body regions with rib fracture the most frequent specific injury. A majority of the head injuries included brain injuries without skull fracture, and non-senior rather than senior occupants had a higher frequency of head injuries on the whole. In approximately 50% of the cases there was a neighboring occupant influencing injury outcome. CONCLUSION: Compared to non-senior occupants, the senior occupants sustained a considerably higher rate of thoracic and pelvis injuries, which should be addressed by improved thorax side airbag protection. The influence on near-side occupant injury risk by the neighboring occupant should also be further evaluated. Furthermore, side airbag performance and injury assessments in intersection crashes, especially those involving senior occupants in lower severities, should be further investigated and side impact dummy biofidelity and injury criteria must be determined for these crash scenarios. PMID- 26027964 TI - Creating pedestrian crash scenarios in a driving simulator environment. AB - OBJECTIVE: In 2012 in the United States, pedestrian injuries accounted for 3.3% of all traffic injuries but, disproportionately, pedestrian fatalities accounted for roughly 14% of traffic-related deaths (NHTSA 2014 ). In many other countries, pedestrians make up more than 50% of those injured and killed in crashes. This research project examined driver response to crash-imminent situations involving pedestrians in a high-fidelity, full-motion driving simulator. This article presents a scenario development method and discusses experimental design and control issues in conducting pedestrian crash research in a simulation environment. Driving simulators offer a safe environment in which to test driver response and offer the advantage of having virtual pedestrian models that move realistically, unlike test track studies, which by nature must use pedestrian dummies on some moving track. METHODS: An analysis of pedestrian crash trajectories, speeds, roadside features, and pedestrian behavior was used to create 18 unique crash scenarios representative of the most frequent and most costly crash types. For the study reported here, we only considered scenarios where the car is traveling straight because these represent the majority of fatalities. We manipulated driver expectation of a pedestrian both by presenting intersection and mid-block crossing as well as by using features in the scene to direct the driver's visual attention toward or away from the crossing pedestrian. Three visual environments for the scenarios were used to provide a variety of roadside environments and speed: a 20-30 mph residential area, a 55 mph rural undivided highway, and a 40 mph urban area. RESULTS: Many variables of crash situations were considered in selecting and developing the scenarios, including vehicle and pedestrian movements; roadway and roadside features; environmental conditions; and characteristics of the pedestrian, driver, and vehicle. The driving simulator scenarios were subjected to iterative testing to adjust time to arrival triggers for the pedestrian actions. This article discusses the rationale behind creating the simulator scenarios and some of the procedural considerations for conducting this type of research. CONCLUSIONS: Crash analyses can be used to construct test scenarios for driver behavior evaluations using driving simulators. By considering trajectories, roadway, and environmental conditions of real-world crashes, representative virtual scenarios can serve as safe test beds for advanced driver assistance systems. The results of such research can be used to inform pedestrian crash avoidance/mitigation systems by identifying driver error, driver response time, and driver response choice (i.e., steering vs. braking). PMID- 26027965 TI - Occurrence of serious injury in real-world side impacts of vehicles with good side-impact protection ratings. AB - OBJECTIVE: The Insurance Institute for Highway Safety (IIHS) introduced its side impact consumer information test program in 2003. Since that time, side airbags and structural improvements have been implemented across the fleet and the proportion of good ratings has increased to 93% of 2012-2014 model year vehicles. Research has shown that drivers of good-rated vehicles are 70% less likely to die in a left-side crash than drivers of poor-rated vehicles. Despite these improvements, side impact fatalities accounted for about one quarter of passenger vehicle occupant fatalities in 2012. This study is a detailed analysis of real world cases with serious injury resulting from side crashes of vehicles with good ratings in the IIHS side impact test. METHODS: NASS-CDS and Crash Injury Research and Engineering Network (CIREN) were queried for occupants of good-rated vehicles who sustained an Abbreviated Injury Scale (AIS) >= 3 injury in a side-impact crash. The resulting 110 cases were categorized by impact configuration and other factors that contributed to injury. Patterns of impact configuration, restraint performance, and occupant injury were identified and discussed in the context of potential upgrades to the current IIHS side impact test. RESULTS: Three quarters of the injured occupants were involved in near-side impacts. For these occupants, the most common factors contributing to injury were crash severities greater than the IIHS test, inadequate side-airbag performance, and lack of side-airbag coverage for the injured body region. In the cases where an airbag was present but did not prevent the injury, occupants were often exposed to loading centered farther forward on the vehicle than in the IIHS test. Around 40% of the far-side occupants were injured from contact with the struck-side interior structure, and almost all of these cases were more severe than the IIHS test. The remaining far side occupants were mostly elderly and sustained injury from the center console, instrument panel, or seat belt. In addition, many far-side occupants were likely out of position due to events preceding the side impact and/or being unbelted. CONCLUSION: Individual changes to the IIHS side impact test have the potential to reduce the number of serious injuries in real-world crashes. These include impacting the vehicle farther forward (relevant to 28% of all cases studied), greater test severity (17%), the inclusion of far-side occupants (9%), and more restrictive injury criteria (9%). Combinations of these changes could be more effective. PMID- 26027966 TI - Differences in long-term medical consequences depending on impact direction involving passenger cars. AB - OBJECTIVE: There is limited knowledge of the long-term medical consequences for occupants injured in car crashes in various impact directions. Thus, the objective was to evaluate whether injuries leading to permanent medical impairment differ depending on impact direction. METHODS: In total, 36,743 injured occupants in car crashes that occurred between 1995 and 2011 were included. All initial injuries (n = 61,440) were classified according to the Abbreviated Injury Scale (AIS) 2005. Injured car occupants were followed for at least 3 years to assess permanent medical impairment. The data were divided into different groups according to impact direction and levels of permanent impairment. The risk of permanent medical impairment was established for different body regions and injury severity levels, according to AIS. RESULTS: It was found that almost 12% of all car occupants sustained a permanent medical impairment. Given an injury, car occupants involved in rollover crashes had the highest overall risk to sustain a permanent medical impairment. Half of the head injuries leading to long-term consequences occurred in frontal impacts. Far-side occupants had almost the same risk as near-side occupants. Occupants who sustained a permanent medical impairment from cervical spine injuries had similar risk in all impact directions (13%) except from rollover (17%). However, these injuries occurred more often in rear crashes. Most of the injuries leading to long-term consequences were classified as minor injuries by AIS for all impact directions. CONCLUSIONS: Studying crash data from a perspective of medical impairment is important to identify injuries that might not be prioritized only considering the AIS but might lead to lower quality of life for the occupant and also costs for society. These results can be used for road transport system strategies and for making priority decisions in vehicle design. PMID- 26027967 TI - Sensitivity of head and cervical spine injury measures to impact factors relevant to rollover crashes. AB - OBJECTIVE: Serious head and cervical spine injuries have been shown to occur mostly independent of one another in pure rollover crashes. In an attempt to define a dynamic rollover crash test protocol that can replicate serious injuries to the head and cervical spine, it is important to understand the conditions that are likely to produce serious injuries to these 2 body regions. The objective of this research is to analyze the effect that impact factors relevant to a rollover crash have on the injury metrics of the head and cervical spine, with a specific interest in the differentiation between independent injuries and those that are predicted to occur concomitantly. METHODS: A series of head impacts was simulated using a detailed finite element model of the human body, the Total HUman Model for Safety (THUMS), in which the impactor velocity, displacement, and direction were varied. The performance of the model was assessed against available experimental tests performed under comparable conditions. Indirect, kinematic based, and direct, tissue-level, injury metrics were used to assess the likelihood of serious injuries to the head and cervical spine. RESULTS: The performance of the THUMS head and spine in reconstructed experimental impacts compared well to reported values. All impact factors were significantly associated with injury measures for both the head and cervical spine. Increases in impact velocity and displacement resulted in increases in nearly all injury measures, whereas impactor orientation had opposite effects on brain and cervical spine injury metrics. The greatest cervical spine injury measures were recorded in an impact with a 15 degrees anterior orientation. The greatest brain injury measures occurred when the impactor was at its maximum (45 degrees ) angle. CONCLUSIONS: The overall kinetic and kinematic response of the THUMS head and cervical spine in reconstructed experiment conditions compare well with reported values, although the occurrence of fractures was overpredicted. The trends in predicted head and cervical spine injury measures were analyzed for 90 simulated impact conditions. Impactor orientation was the only factor that could potentially explain the isolated nature of serious head and spine injuries under rollover crash conditions. The opposing trends of injury measures for the brain and cervical spine indicate that it is unlikely to reproduce the injuries simultaneously in a dynamic rollover test. PMID- 26027968 TI - Feasibility study of airbag concept applicable to motorcycles without sufficient reaction structure. AB - OBJECTIVES: An airbag system for motorcycle applications was developed and marketed in 2006 followed by many research projects on the system. In the airbag system, the bag should be supported during the kinetic energy-absorbing period of a rider in a collision. The previously developed system employed a configuration in which motorcycle structures support the airbag, such as a gauge unit and/or a steering structure. The supporting structure functions to receive the reaction force to hold the airbag during a crash to properly absorb the rider's kinetic energy. However, the previous system requires a larger area for this reaction structure and is applicable only to the motorcycles that can provide that area. To overcome this limitation, we propose an airbag system employing another concept. In this concept, the airbag does not use its vehicle structures as a reaction structure but uses the structures of an opposing vehicle, such as doors and/or pillars of an opposing vehicle. In this project, we aim to verify the effectiveness of the proposed system when installed in a motorcycle that cannot provide a larger area for the reaction structure. METHODS: In the system with this concept, it is assumed that the occupant protection performance is largely affected depending on impact configurations. Accordingly, full-scale motorcycle to-car crash tests using 125 cm3 scooter-type models with and without the proposed system were conducted in various impact configurations. The 7 impact configurations specified in ISO 13232 were selected as the test configurations. Injury variables and injury indices of head, neck, chest, and abdomen were evaluated with the motorcyclist dummy. RESULTS: Injury variables and indices obtained from the crash tests with the airbag were compared to those of the baseline tests. In 2 impact configurations, the airbags were supported by the side structures of the opposing vehicle and performed to reduce the injury variable of head and/or chest compared to that of the baseline test. CONCLUSION: Through the crash tests, beneficial protection effects of the airbag system were confirmed in particular impact configurations. No significant risk for the occupant due to the airbag was observed in the conducted crash tests. It was concluded that the proposed airbag system has feasibility to reduce rider injury in a collision of a motorcycle without sufficient reaction structure. PMID- 26027969 TI - Potential of a precrash lateral occupant movement in side collisions of (electric) minicars. AB - OBJECTIVE: In minicars, the survival space between the side structure and occupant is smaller than in conventional cars. This is an issue in side collisions. Therefore, in this article a solution is studied in which a lateral seat movement is imposed in the precrash phase. It generates a pre-acceleration and an initial velocity of the occupant, thus reducing the loads due to the side impact. METHODS: The assessment of the potential is done by numerical simulations and a full-vehicle crash test. The optimal parameters of the restraint system including the precrash movement, time-to-fire of head and side airbag, etc., are found using metamodel-based optimization methods by minimizing occupant loads according to European New Car Assessment Programme (Euro NCAP). RESULTS: The metamodel-based optimization approach is able to tune the restraint system parameters. The numerical simulations show a significant averaged reduction of 22.3% in occupant loads. CONCLUSION: The results show that the lateral precrash occupant movement offers better occupant protection in side collisions. PMID- 26027970 TI - Combining coordination of motion actuators with driver steering interaction. AB - OBJECTIVE: A new method is suggested for coordination of vehicle motion actuators; where driver feedback and capabilities become natural elements in the prioritization. METHODS: The method is using a weighted least squares control allocation formulation, where driver characteristics can be added as virtual force constraints. The approach is in particular suitable for heavy commercial vehicles that in general are over actuated. The method is applied, in a specific use case, by running a simulation of a truck applying automatic braking on a split friction surface. Here the required driver steering angle, to maintain the intended direction, is limited by a constant threshold. This constant is automatically accounted for when balancing actuator usage in the method. RESULTS: Simulation results show that the actual required driver steering angle can be expected to match the set constant well. Furthermore, the stopping distance is very much affected by this set capability of the driver to handle the lateral disturbance, as expected. CONCLUSION: In general the capability of the driver to handle disturbances should be estimated in real-time, considering driver mental state. By using the method it will then be possible to estimate e.g. stopping distance implied from this. The setup has the potential of even shortening the stopping distance, when the driver is estimated as active, this compared to currently available systems. The approach is feasible for real-time applications and requires only measurable vehicle quantities for parameterization. Examples of other suitable applications in scope of the method would be electronic stability control, lateral stability control at launch and optimal cornering arbitration. PMID- 26027971 TI - Assessment of Integrated Pedestrian Protection Systems with Autonomous Emergency Braking (AEB) and Passive Safety Components. AB - OBJECTIVE: Autonomous emergency braking (AEB) systems fitted to cars for pedestrians have been predicted to offer substantial benefit. On this basis, consumer rating programs-for example, the European New Car Assessment Programme (Euro NCAP)-are developing rating schemes to encourage fitment of these systems. One of the questions that needs to be answered to do this fully is how the assessment of the speed reduction offered by the AEB is integrated with the current assessment of the passive safety for mitigation of pedestrian injury. Ideally, this should be done on a benefit-related basis. The objective of this research was to develop a benefit-based methodology for assessment of integrated pedestrian protection systems with AEB and passive safety components. The method should include weighting procedures to ensure that it represents injury patterns from accident data and replicates an independently estimated benefit of AEB. METHODS: A methodology has been developed to calculate the expected societal cost of pedestrian injuries, assuming that all pedestrians in the target population (i.e., pedestrians impacted by the front of a passenger car) are impacted by the car being assessed, taking into account the impact speed reduction offered by the car's AEB (if fitted) and the passive safety protection offered by the car's frontal structure. For rating purposes, the cost for the assessed car is normalized by comparing it to the cost calculated for a reference car. The speed reductions measured in AEB tests are used to determine the speed at which each pedestrian in the target population will be impacted. Injury probabilities for each impact are then calculated using the results from Euro NCAP pedestrian impactor tests and injury risk curves. These injury probabilities are converted into cost using "harm"-type costs for the body regions tested. These costs are weighted and summed. Weighting factors were determined using accident data from Germany and Great Britain and an independently estimated AEB benefit. German and Great Britain versions of the methodology are available. The methodology was used to assess cars with good, average, and poor Euro NCAP pedestrian ratings, in combination with a current AEB system. The fitment of a hypothetical A-pillar airbag was also investigated. RESULTS: It was found that the decrease in casualty injury cost achieved by fitting an AEB system was approximately equivalent to that achieved by increasing the passive safety rating from poor to average. Because the assessment was influenced strongly by the level of head protection offered in the scuttle and windscreen area, a hypothetical A-pillar airbag showed high potential to reduce overall casualty cost. CONCLUSIONS: A benefit-based methodology for assessment of integrated pedestrian protection systems with AEB has been developed and tested. It uses input from AEB tests and Euro NCAP passive safety tests to give an integrated assessment of the system performance, which includes consideration of effects such as the change in head impact location caused by the impact speed reduction given by the AEB. PMID- 26027972 TI - Using Sound to Reduce Visual Distraction from In-vehicle Human-Machine Interfaces. AB - OBJECTIVE: Driver distraction and inattention are the main causes of accidents. The fact that devices such as navigation displays and media players are part of the distraction problem has led to the formulation of guidelines advocating various means for minimizing the visual distraction from such interfaces. However, although design guidelines and recommendations are followed, certain interface interactions, such as menu browsing, still require off-road visual attention that increases crash risk. In this article, we investigate whether adding sound to an in-vehicle user interface can provide the support necessary to create a significant reduction in glances toward a visual display when browsing menus. METHODS: Two sound concepts were developed and studied; spearcons (time compressed speech sounds) and earcons (musical sounds). A simulator study was conducted in which 14 participants between the ages of 36 and 59 took part. Participants performed 6 different interface tasks while driving along a highway route. A 3 * 6 within-group factorial design was employed with sound (no sound /earcons/spearcons) and task (6 different task types) as factors. Eye glances and corresponding measures were recorded using a head-mounted eye tracker. Participants' self-assessed driving performance was also collected after each task with a 10-point scale ranging from 1 = very bad to 10 = very good. Separate analyses of variance (ANOVAs) were conducted for different eye glance measures and self-rated driving performance. RESULTS: It was found that the added spearcon sounds significantly reduced total glance time as well as number of glances while retaining task time as compared to the baseline (= no sound) condition (total glance time M = 4.15 for spearcons vs. M = 7.56 for baseline, p =.03). The earcon sounds did not result in such distraction-reducing effects. Furthermore, participants ratings of their driving performance were statistically significantly higher in the spearcon conditions compared to the baseline and earcon conditions (M = 7.08 vs. M = 6.05 and M = 5.99 respectively, p =.035 and p =.002). CONCLUSIONS: The spearcon sounds seem to efficiently reduce visual distraction, whereas the earcon sounds did not reduce distraction measures or increase subjective driving performance. An aspect that must be further investigated is how well spearcons and other types of auditory displays are accepted by drivers in general and how they work in real traffic. PMID- 26027973 TI - The real-world safety potential of connected vehicle technology. AB - OBJECTIVE: This article estimates the safety potential of a current commercially available connected vehicle technology in real-world crashes. METHOD: Data from the Centre for Automotive Safety Research's at-scene in-depth crash investigations in South Australia were used to simulate the circumstances of real world crashes. A total of 89 crashes were selected for inclusion in the study. The crashes were selected as representative of the most prevalent crash types for injury or fatal crashes and had potential to be mitigated by connected vehicle technology. The trajectory, speeds, braking, and impact configuration of the selected in-depth cases were replicated in a software package and converted to a file format allowing "replay" of the scenario in real time as input to 2 Cohda Wireless MK2 onboard units. The Cohda Wireless onboard units are a mature connected vehicle technology that has been used in both the German simTD field trial and the U.S. Department of Transport's Safety Pilot project and have been tuned for low false alarm rates when used in the real world. The crash replay was achieved by replacing each of the onboard unit Global Positioning System (GPS) inputs with the simulated data of each of the involved vehicles. The time at which the Cohda Wireless threat detection software issued an elevated warning was used to calculate a new impact speed using 3 different reaction scenarios and 2 levels of braking. RESULTS: It was found that between 37 and 86% of the simulated crashes could be avoided, with highest percentage due a fully autonomous system braking at 0.7 g. The same system also reduced the impact speed relative to the actual crash in all cases. Even when a human reaction time of 1.2 s and moderate braking of 0.4 g was assumed, the impact speed was reduced in 78% of the crashes. Crash types that proved difficult for the threat detection engine were head-on crashes where the approach angle was low and right turn-opposite crashes. CONCLUSIONS: These results indicate that connected vehicle technology can be greatly beneficial in real-world crash scenarios and that this benefit would be maximized by having the vehicle intervene autonomously with heavy braking. The crash types that proved difficult for the connected vehicle technology could be better addressed if controller area network (CAN) information is available, such as steering wheel angle, so that driver intent can be inferred sooner. More accurate positioning in the real world (e.g., combining satellite positioning and accelerometer data) would allow the technology to be more effective for near collinear head-on and rear-end crashes, because the low approach angles that are common in such crashes are currently ignored in order to minimize false alarms due to positioning uncertainty. PMID- 26027974 TI - Development and Validation of the Total HUman Model for Safety (THUMS) Toward Further Understanding of Occupant Injury Mechanisms in Precrash and During Crash. AB - OBJECTIVE: Active safety devices such as automatic emergency brake (AEB) and precrash seat belt have the potential to accomplish further reduction in the number of the fatalities due to automotive accidents. However, their effectiveness should be investigated by more accurate estimations of their interaction with human bodies. Computational human body models are suitable for investigation, especially considering muscular tone effects on occupant motions and injury outcomes. However, the conventional modeling approaches such as multibody models and detailed finite element (FE) models have advantages and disadvantages in computational costs and injury predictions considering muscular tone effects. The objective of this study is to develop and validate a human body FE model with whole body muscles, which can be used for the detailed investigation of interaction between human bodies and vehicular structures including some safety devices precrash and during a crash with relatively low computational costs. METHODS: In this study, we developed a human body FE model called THUMS (Total HUman Model for Safety) with a body size of 50th percentile adult male (AM50) and a sitting posture. The model has anatomical structures of bones, ligaments, muscles, brain, and internal organs. The total number of elements is 281,260, which would realize relatively low computational costs. Deformable material models were assigned to all body parts. The muscle-tendon complexes were modeled by truss elements with Hill-type muscle material and seat belt elements with tension-only material. The THUMS was validated against 35 series of cadaver or volunteer test data on frontal, lateral, and rear impacts. Model validations for 15 series of cadaver test data associated with frontal impacts are presented in this article. The THUMS with a vehicle sled model was applied to investigate effects of muscle activations on occupant kinematics and injury outcomes in specific frontal impact situations with AEB. RESULTS AND CONCLUSIONS: In the validations using 5 series of cadaver test data, force-time curves predicted by the THUMS were quantitatively evaluated using correlation and analysis (CORA), which showed good or acceptable agreement with cadaver test data in most cases. The investigation of muscular effects showed that muscle activation levels and timing had significant effects on occupant kinematics and injury outcomes. Although further studies on accident injury reconstruction are needed, the THUMS has the potential for predictions of occupant kinematics and injury outcomes considering muscular tone effects with relatively low computational costs. PMID- 26027975 TI - Development of a computationally efficient full human body finite element model. AB - INTRODUCTION: A simplified and computationally efficient human body finite element model is presented. The model complements the Global Human Body Models Consortium (GHBMC) detailed 50th percentile occupant (M50-O) by providing kinematic and kinetic data with a significantly reduced run time using the same body habitus. METHODS: The simplified occupant model (M50-OS) was developed using the same source geometry as the M50-O. Though some meshed components were preserved, the total element count was reduced by remeshing, homogenizing, or in some cases omitting structures that are explicitly contained in the M50-O. Bones are included as rigid bodies, with the exception of the ribs, which are deformable but were remeshed to a coarser element density than the M50-O. Material models for all deformable components were drawn from the biomechanics literature. Kinematic joints were implemented at major articulations (shoulder, elbow, wrist, hip, knee, and ankle) with moment vs. angle relationships from the literature included for the knee and ankle. The brain of the detailed model was inserted within the skull of the simplified model, and kinematics and strain patterns are compared. RESULTS: The M50-OS model has 11 contacts and 354,000 elements; in contrast, the M50-O model has 447 contacts and 2.2 million elements. The model can be repositioned without requiring simulation. Thirteen validation and robustness simulations were completed. This included denuded rib compression at 7 discrete sites, 5 rigid body impacts, and one sled simulation. Denuded tests showed a good match to the experimental data of force vs. deflection slopes. The frontal rigid chest impact simulation produced a peak force and deflection within the corridor of 4.63 kN and 31.2%, respectively. Similar results vs. experimental data (peak forces of 5.19 and 8.71 kN) were found for an abdominal bar impact and lateral sled test, respectively. A lateral plate impact at 12 m/s exhibited a peak of roughly 20 kN (due to stiff foam used around the shoulder) but a more biofidelic response immediately afterward, plateauing at 9 kN at 12 ms. Results from a frontal sled simulation showed that reaction forces and kinematic trends matched experimental results well. The robustness test demonstrated that peak femur loads were nearly identical to the M50-O model. Use of the detailed model brain within the simplified model demonstrated a paradigm for using the M50-OS to leverage aspects of the M50-O. Strain patterns for the 2 models showed consistent patterns but greater strains in the detailed model, with deviations thought to be the result of slightly different kinematics between models. The M50-OS with the deformable skull and brain exhibited a run time 4.75 faster than the M50-O on the same hardware. CONCLUSIONS: The simplified GHBMC model is intended to complement rather than replace the detailed M50-O model. It exhibited, on average, a 35-fold reduction in run time for a set of rigid impacts. The model can be used in a modular fashion with the M50-O and more broadly can be used as a platform for parametric studies or studies focused on specific body regions. PMID- 26027976 TI - Age- and sex-specific thorax finite element model development and simulation. AB - OBJECTIVE: The shape, size, bone density, and cortical thickness of the thoracic skeleton vary significantly with age and sex, which can affect the injury tolerance, especially in at-risk populations such as the elderly. Computational modeling has emerged as a powerful and versatile tool to assess injury risk. However, current computational models only represent certain ages and sexes in the population. The purpose of this study was to morph an existing finite element (FE) model of the thorax to depict thorax morphology for males and females of ages 30 and 70 years old (YO) and to investigate the effect on injury risk. METHODS: Age- and sex-specific FE models were developed using thin-plate spline interpolation. In order to execute the thin-plate spline interpolation, homologous landmarks on the reference, target, and FE model are required. An image segmentation and registration algorithm was used to collect homologous rib and sternum landmark data from males and females aged 0-100 years. The Generalized Procrustes Analysis was applied to the homologous landmark data to quantify age- and sex-specific isolated shape changes in the thorax. The Global Human Body Models Consortium (GHBMC) 50th percentile male occupant model was morphed to create age- and sex-specific thoracic shape change models (scaled to a 50th percentile male size). To evaluate the thoracic response, 2 loading cases (frontal hub impact and lateral impact) were simulated to assess the importance of geometric and material property changes with age and sex. RESULTS: Due to the geometric and material property changes with age and sex, there were observed differences in the response of the thorax in both the frontal and lateral impacts. Material property changes alone had little to no effect on the maximum thoracic force or the maximum percent compression. With age, the thorax becomes stiffer due to superior rotation of the ribs, which can result in increased bone strain that can increase the risk of fracture. For the 70-YO models, the simulations predicted a higher number of rib fractures in comparison to the 30-YO models. The male models experienced more superior rotation of the ribs in comparison to the female models, which resulted in a higher number of rib fractures for the males. CONCLUSION: In this study, age- and sex-specific thoracic models were developed and the biomechanical response was studied using frontal and lateral impact simulations. The development of these age- and sex specific FE models of the thorax will lead to an improved understanding of the complex relationship between thoracic geometry, age, sex, and injury risk. PMID- 26027977 TI - Age-dependent factors affecting thoracic response: a finite element study focused on Japanese elderly occupants. AB - OBJECTIVES: The ultimate goal of this research is to reduce thoracic injuries due to traffic crashes, especially in the elderly. The specific objective is to develop and validate a full-body finite element model under 2 distinct settings that account for factors relevant for thoracic fragility of elderly: one setting representative of an average size male and one representative of an average size Japanese elderly male. METHODS: A new thorax finite element model was developed from medical images of a 71-year-old average Japanese male elderly size (161cm, 60 kg) postmortem human subject (PMHS). The model was validated at component and assembled levels against original series of published test data obtained from the same elderly specimen. The model was completed with extremities and head of a model previously developed. The rib cage and the thoracic flesh materials were assigned age-dependent properties and the model geometry was scaled up to simulate a 50th percentile male. Thereafter, the model was validated against existing biomechanical data for younger and elderly subjects, including hub-to thorax impacts and frontal impact sled PMHS test data. Finally, a parametric study was conducted with the new models to understand the effect of size and aging factors on thoracic response and risk of rib fractures. RESULTS: The model behaved in agreement with tabletop test experiments in intact, denuded, and eviscerated tissue conditions. In frontal impact sled conditions, the model showed good 3-dimensional head and spine kinematics, as well as rib cage multipoint deflections. When properties representative of an aging person were simulated, both the rib cage deformation and the predicted number of rib fractures increased. The effects of age factors such as rib cortical thickness, mechanical properties, and failure thresholds on the model responses were consistent with the literature. Aged and thereby softened flesh reduced load transfer between ribs; the coupling of the rib cage was reduced. Aged costal cartilage increased the severity of the diagonal belt loading sustained by the lower loaded rib cage. CONCLUSIONS: When age-specific parameters were implemented in a finite element (FE) model of the thorax, the rib cage kinematics and thorax injury risk increased. When the effect of size was isolated, 2 factors, in addition to rib material properties, were found to be important: flesh and costal cartilage properties. These 2 were identified to affect rib cage deformation mechanisms and may potentially increase the risk of rib fractures. PMID- 26027978 TI - A simulation study on the efficacy of advanced belt restraints to mitigate the effects of obesity for rear-seat occupant protection in frontal crashes. AB - OBJECTIVE: Recent field data analyses have shown that the safety advantages of rear seats relative to the front seats have decreased in newer vehicles. Separately, the risks of certain injuries have been found to be higher for obese occupants. The objective of this study is to investigate the effects of advanced belt features on the protection of rear-seat occupants with a range of body mass index (BMI) in frontal crashes. METHODS: Whole-body finite element human models with 4 BMI levels (25, 30, 35, and 40 kg/m2) developed previously were used in this study. A total of 52 frontal crash simulations were conducted, including 4 simulations with a standard rear-seat, 3-point belt and 48 simulations with advanced belt features. The parameters varied in the simulations included BMI, load limit, anchor pretensioner, and lap belt routing relative to the pelvis. The injury measurements analyzed in this study included head and hip excursions, normalized chest deflection, and torso angle (defined as the angle between the hip-shoulder line and the vertical direction). Analyses of covariance were used to test the significance (P <.05) of the results. RESULTS: Higher BMI was associated with greater head and hip excursions and larger normalized chest deflection. Higher belt routing increased the hip excursion and torso angle, which indicates a higher submarining risk, whereas the anchor pretensioner reduced hip excursion and torso angle. Lower load limits decreased the normalized chest deflection but increased the head excursion. Normalized chest deflection had a positive correlation with maximum torso angle. Occupants with higher BMI have to use higher load limits to reach head excursions similar to those in lower BMI occupants. DISCUSSION AND CONCLUSION: The simulation results suggest that optimizing load limiter and adding pretensioner(s) can reduce injury risks associated with obesity, but conflicting effects on head and chest injuries were observed. This study demonstrated the feasibility and importance of using human models to investigate protection for occupants with various BMI levels. A seat belt system capable of adapting to occupant size and body shape will improve protection for obese occupants in rear seats. PMID- 26027979 TI - Fast calculating surrogate models for leg and head impact in vehicle-pedestrian collision simulations. AB - OBJECTIVE: In previous research, a tool chain to simulate vehicle-pedestrian accidents from ordinary driving state to in-crash has been developed. This tool chain allows for injury criteria-based, vehicle-specific (geometry, stiffness, active safety systems, etc.) assessments. Due to the complex nature of the included finite element analysis (FEA) models, calculation times are very high. This is a major drawback for using FEA models in large-scale effectiveness assessment studies. Therefore, fast calculating surrogate models to approximate the relevant injury criteria as a function of pedestrian vehicle collision constellations have to be developed. METHOD: The development of surrogate models for head and leg injury criteria to overcome the problem of long calculation times while preserving high detail level of results for effectiveness analysis is shown in this article. These surrogate models are then used in the tool chain as time-efficient replacements for the FEA model to approximate the injury criteria values. The method consists of the following steps: Selection of suitable training data sets out of a large number of given collision constellations, detailed FEA calculations with the training data sets as input, and training of the surrogate models with the FEA model's input and output values. RESULTS: A separate surrogate model was created for each injury criterion, consisting of a response surface that maps the input parameters (i.e., leg impactor position and velocity) to the output value. In addition, a performance test comparing surrogate model predictions of additional collision constellations to the results of respective FEA calculations was carried out. The developed method allows for prediction of injury criteria based on impact constellation for a given vehicle. Because the surrogate models are specific to a certain vehicle, training has to be redone for a new vehicle. Still, there is a large benefit regarding calculation time when doing large-scale studies. CONCLUSION: The method can be used in prospective effectiveness assessment studies of new vehicle safety features and takes into account specific local features of a vehicle (geometry, stiffness, etc.) as well as external parameters (location and velocity of pedestrian impact). Furthermore, it can be easily extended to other injury criteria or accident scenarios; for example, cyclist accidents. PMID- 26027980 TI - Effect of aging on brain injury prediction in rotational head trauma--a parameter study with a rat finite element model. AB - OBJECTIVE: The aim of this study was to investigate the possible effects of age related intracranial changes on the potential outcome of diffuse axonal injuries and acute subdural hematoma under rotational head loading. METHODS: A simulation based parametric study was conducted using an updated and validated finite element model of a rat head. The validation included a comparison of predicted brain cortex sliding with respect to the skull. Further, model material properties were modified to account for aging; predicted tissue strains were compared with experimental data in which groups of rats in 2 different lifecycle stages, young adult and mature adult, were subjected to rotational trauma. For the parameter study, 2 age-dependent factors-brain volume and region-specific brain material properties-were implemented into the model. The models young adult and old age were subjected to several injurious and subinjurious sagittal plane rotational acceleration levels. RESULTS: Sequential analysis of the simulated trauma progression indicates that an increase in acute subdural hematoma injury risk indicator occurs at an early stage of the trauma, whereas an increase in diffuse axonal injury risk indicators occurs at a later stage. Tissue stiffening from young adult to mature adult rats produced an increase in strain-based thresholds accompanied by a wider spread of strain distribution toward the rear part of the brain, consistent with rotational trauma experiments with young adult and mature adult rats. Young adult to old age brain tissue softening and brain atrophy resulted in an increase in diffuse axonal injuries and acute subdural hematoma injury risk indicators, respectively. CONCLUSIONS: The findings presented in this study suggest that age-specific injury thresholds should be developed to enable the development of superior restraint systems for the elderly. The findings also motivate other further studies on age-dependency of head trauma. PMID- 26027981 TI - Autoimmune hepatitis: recent advances in the pathogenesis and new diagnostic guidelines in Japan. AB - Autoimmune hepatitis (AIH) is thought to be associated with various genetic and immunological abnormalities. Concerning the pathogenesis of AIH, increasing attention has been paid to genome-wide association studies, toll-like receptors and Treg/Th17 balance. For Japanese patients with AIH, novel diagnostic guidelines have been proposed in view of the differential clinical features between Japanese and Caucasian patients. However, the diagnosis of some patients in acute hepatitis phase is not easy. Histologically, centrilobular necrosis without portal inflammation is particularly characteristic in the acute hepatitis phase. Some patients become resistant to steroid therapy and have a very poor prognosis once they progress to acute hepatic failure. Therefore, additional revision of the current diagnostic criteria, including severity grading, will be needed in the future. PMID- 26027982 TI - Comparison of the acute effects of right ventricular apical pacing and biventricular pacing in patients with heart failure. AB - OBJECTIVE: Upgrading to biventricular (BiV) pacing benefits heart failure patients with right ventricular (RV) apical pacing. However, the impact of switching from RV apical pacing to BiV pacing on the left ventricular (LV) function accompanied by changes in the QRS duration remains unknown. We aimed to investigate the effects of BiV pacing in heart failure patients under RV apical pacing. METHODS: In 37 patients with heart failure (LV ejection fraction: 22+/ 9%), the maximum rate of LV pressure rise (LV dP/dtmax) and time constant of LV relaxation (tau) were determined in order to assess LV contractility and diastolic relaxation, respectively, under RV apical pacing and BiV pacing. Switching from RV pacing to BiV pacing, the QRS duration was shortened from 209+/ 42 to 162+/-28 ms (p<0.001) and the LV dP/dtmax values were increased in all patients (+18.4+/-11.3%, p<0.001), whereas the LV tau values varied (-1.5+/ 13.0%, p=0.723). Shortening of the QRS duration correlated with the increase in LV dP/dtmax (r=-0.689, p<0.001); however, it was not closely associated with the changes in LV tau. CONCLUSION: Switching from RV apical pacing to BiV pacing improves the LV contractile function in proportion to the degree of QRS shortening. BiV pacing is recommended in patients with systolic heart failure and a prolonged RV-paced QRS duration. PMID- 26027983 TI - Changes in the Distribution of Capsular Serotypes of Streptococcus pneumoniae Isolated from Adult Respiratory Specimens in Japan. AB - OBJECTIVE: The objective of this study was to assess whether the distribution of pneumococcal capsular types has been changed, while also providing basic data on changes in the distribution after the introduction of Pneumococcal conjugated vaccine (PCV)13 in adult medical practice. METHODS: We analyzed 431 Streptococcus pneumoniae strains (200 in 2006 and 231 in 2012) that had been isolated from respiratory infection specimens from adult patients. Capsular typing was performed by the Quellung reaction and multiplex polymerase chain reaction. RESULTS: A comparison of the 2006 and 2012 strains revealed that the number and proportion of strains by serotype increased from 30 (15%) to 46 (20%) for serotype 3, from 4 (2%) to 14 (6%) for serotype 6A, and from 4 (2%) to 13 (6%) for serotype 6C, whereas the number and proportion of strains by serotype decreased from 8 (4%) to 0 (0%) for serotype 4 and from 24 (12%) to 17 (7%) for serotype 6B. From 2006 to 2012, the coverage rate significantly decreased from 39 to 28.1% for PCV7 (p=0.017). CONCLUSION: Our study showed a decrease in the vaccine coverage of PCV7. However, PCV13 covered serotypes 3 and 6A, which are prevalent, as well as penicillin-resistant S. pneumoniae strains. At present, PCV13 in adult clinical practice seems to be highly significant. However, there is a possibility that the distribution has changed, and careful screening should be continued in the future. PMID- 26027984 TI - Usefulness of Small Intestinal Endoscopy in a Case of Adult-onset Familial Mediterranean Fever Associated with Jejunoileitis. AB - A 66-year-old Japanese man consulted our institution due to paroxysmal and repetitive bouts of fever and abdominal pain that had persisted for more than one week. Capsule and double-balloon endoscopy (DBE) showed petal-shaped mucosal redness with white hemming in the jejunum and ileum, and histopathology of the biopsy specimens revealed villous atrophy and cryptitis with extensive severe neutrophil infiltration. A genetic examination disclosed compound heterozygous MEFV mutations (E84K, P369S), and familial Mediterranean fever was diagnosed. Treatment with colchicine and infliximab was very effective in inducing the complete disappearance of symptoms and normalization of the endoscopic findings. To the best of our knowledge, this is the first report to describe the findings of small intestinal endoscopic images obtained using capsule and DBE. PMID- 26027985 TI - Solid pseudopapillary neoplasm of the pancreas associated with familial adenomatous polyposis. AB - A man in his thirties visited our hospital for an evaluation of a 12*10-mm pancreatic solid tumor that was accidentally detected on computed tomography performed for follow-up of familial adenomatous polyposis (FAP). We diagnosed the patient with a solid pseudopapillary neoplasm (SPN) based on endoscopic ultrasound-guided fine-needle aspiration, and he underwent pancreaticoduodenectomy. Small SPN tumors appear as solid tumors, without typical features of SPN, making the definitive diagnosis more difficult. The genetic background of FAP patients can predispose them to SPN, and imaging of the pancreas should be performed at prescribed intervals in FAP patients. PMID- 26027986 TI - Primary squamous cell carcinoma of the pancreas: a report of two cases and review of the literature. AB - Primary squamous cell carcinoma (SCC) of the pancreas is extremely rare. We herein report two such cases. Aside from various morphological characteristics, the clinical presentation of pancreatic SCC is the same as that of adenocarcinoma. The treatment is controversial, and the prognosis is poor. PMID- 26027987 TI - Acute Liver Failure Associated with Diffuse Hepatic Infiltration of Malignant Melanoma of Unknown Primary Origin. AB - An 83-year-old man admitted for left hand pain due to a large necrotic ulcer presented with many sites of erythema on his trunk. Computed tomography revealed multiple poorly marginated masses in the liver; however, no malignant cells were detected on a biopsy of several skin lesions. He died on the 47th hospital day, and autopsy was subsequently performed, showing multiple nodules in the liver. The histological findings revealed clusters of malignant melanoma cells that had diffusely infiltrated the liver parenchyma. No tumor cells were detected in the skin lesions or lymph nodes. Immunohistochemically, the patient was diagnosed to have metastasis from malignant melanoma of unknown origin. PMID- 26027988 TI - Esophageal ulcer of unknown origin complicated by left atrial myxoma. AB - Myxoma induces the onset of paraneoplastic syndromes by excreting various humoral mediators and is therefore known to present with diverse symptoms. A 40-year-old woman was admitted to our hospital for the treatment of an esophageal ulcer, the cause of which could not be identified on various examinations. Notably, a left atrial tumor was incidentally found on chest enhanced computed tomography. The esophageal ulcer, which was intractable to conventional therapy, improved with the administration of 5-aminosalicylate, a drug known to inhibit IL-1beta. This inhibitory action effectively suppressed the development of myxoma-induced paraneoplastic syndrome. PMID- 26027989 TI - Elevated Expression of Pentraxin 3 in Anti-neutrophil Cytoplasmic Antibody associated Glomerulonephritis with Normal Serum C-reactive Protein. AB - A 20-year-old woman was admitted to our hospital with an elevated serum creatinine level of 1.61 mg/dL and a normal C-reactive protein level of less than 0.1 mg/dL. Her myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA) titer was slightly increased at 9.2 U/mL; a kidney biopsy revealed that 23 of 32 glomeruli had crescents. The expression of pentraxin 3 was detected in her kidney and her plasma pentraxin 3 level was elevated at 63.53 ng/mL. Plasma pentraxin 3 levels may be an activity marker for ANCA-associated glomerulonephritis, particularly when serum C-reactive protein levels are within the normal limits. PMID- 26027990 TI - Two Cases of Hemodialysis-associated Chronic Portal-systemic Shunt Encephalopathy (CPSE) with Opposite Changes in the Blood Ammonia Concentrations during Hemodialysis: A Case Report and Literature Review. AB - The onset of hyperammonemia due to the flow of ammonia-rich portal vein blood through a portal-systemic shunt causes a type of encephalopathy known as chronic portal-systemic shunt encephalopathy (CPSE). We herein report two cases of CPSE that presented with opposite changes in the blood ammonia concentrations during hemodialysis. It is curious that the encephalopathy was ameliorated by hemodialysis in case 1, but not case 2. Therefore, it is necessary to recognize CPSE and assess the blood ammonia concentrations in dialysis patients who develop a disturbance of consciousness, even if the serum transaminase level is normal. PMID- 26027991 TI - Lung cancer associated with seronegative myasthenia gravis. AB - A 64-year-old man presented with diplopia, muscle weakness, a pulmonary nodule and mediastinal widening on a chest radiograph. He was diagnosed with clinical stage IIIA (T2aN2M0) lung cancer. His neurological symptoms worsened following the initiation of thoracic radiation therapy (60 Gy) and chemotherapy. A diagnosis of myasthenia gravis (MG) was confirmed with a repetitive nerve stimulation test that showed a waning pattern, and a positive edrophonium test, although neither anti-acetylcholine receptor antibodies nor anti-muscle-specific tyrosine kinase antibodies were detected. The ptosis and limb muscle weakness improved with prednisolone and acetylcholinesterase inhibitor treatment, and a partial response of the lung cancer to chemoradiotherapy was obtained. However, the ptosis and limb muscle weakness worsened again following a recurrence of the lung cancer. The herein described case, in which lung cancer and MG occurred and recurred simultaneously, suggests that MG can develop as a paraneoplastic syndrome of lung cancer. PMID- 26027992 TI - Combined atypical carcinoid tumour and squamous cell carcinoma of the lung. AB - A 71-year-old man diagnosed with lung cancer in the right lower lobe with invasion to the middle lobe underwent right lower and middle lobectomy with mediastinal lymph node dissection. The cancer was pathologically diagnosed as stage IIB (pT3N0M0) with combined squamous cell carcinoma and an atypical carcinoid tumour. To the best of our knowledge, this is the first report of a combined atypical carcinoid tumour and non-small cell lung cancer. This case further expands the histological spectrum of combined neuroendocrine tumours. PMID- 26027993 TI - Pulmonary Metastasis of Combined Hepatocellular and Cholangiocarcinoma: A Unique Radiographic Presentation with Air-space Consolidation Masquerading as Pneumonia and Primary Pulmonary Adenocarcinoma. AB - Lung metastasis showing radiographic findings of air-space consolidation is considered to be rare. This report describes the case of a man with progressive left lower lobe air-space consolidation with a history of hepatocellular carcinoma. The pulmonary lesion was initially suspected to be infection and later clinically diagnosed as primary adenocarcinoma of the lung. Although the patient was treated with systemic chemotherapy, the disease progressed very rapidly. A postmortem examination revealed that the alveolar spaces were filled with neoplastic cells subsequently proven to be metastases of combined hepatocellular and cholangiocarcinoma. PMID- 26027994 TI - HIV-negative Primary Bone Marrow Hodgkin Lymphoma Manifesting with a High Fever Associated with Hemophagocytosis as the Initial Symptom: A Case Report and Review of the Previous Literature. AB - A 68-year-old man was referred to our hospital due to a high fever and pancytopenia. Neither tumors nor infectious lesions were detected. Hemophagocytosis was observed on the bone marrow (BM) smear, although without abnormal cells. Prednisolone therapy was ineffective for the patient's high fever. Later on, we obtained the results of a BM biopsy indicating the presence of infiltration of atypical Reed-Sternberg cells, leading to a diagnosis of HIV negative primary bone marrow Hodgkin lymphoma (PBMHL). However, the patient died of multiple organ failure before receiving chemotherapy. As the clinical course of PBMHL is rapid, physicians must keep in mind its possibility in similar cases. PMID- 26027995 TI - Hairy Cell Leukemia with Systemic Lymphadenopathy: Detection of BRAF Mutations in Both Lymph Node and Peripheral Blood Specimens. AB - A 47-year-old woman with pancytopenia, excessive systemic lymphadenopathy and splenomegaly was referred to our hospital. The peripheral blood (PB) smear findings indicated neutropenia with lymphoid cells exhibiting hairy projections, while the histological findings of the cervical lymph node (LN) suggested hairy cell leukemia (HCL). In addition, the BRAF V600E mutation was detected, and the immunoglobulin gene rearrangement patterns were identical in both the cervical LN and PB specimens. Based on these findings, we diagnosed the patient with systemic lymphadenopathy due to HCL. This is the first report of a BRAF mutation detected in both the PB and LN at the onset of HCL. PMID- 26027996 TI - Useful Strategy of Pulmonary Microvascular Cytology in the Early Diagnosis of Intravascular Large B-cell Lymphoma in a Patient with Hypoxemia: A Case Report and Literature Review. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal lymphoma characterized by the presence of tumor cells within blood vessels, and it is considered to be a subtype of diffuse large B-cell lymphoma. We report a case of IVLBCL presenting as progressive hypoxemia. In this case, a definitive diagnosis could not be achieved by repeated transbronchial lung biopsy, a bone marrow biopsy, and a random skin biopsy, and the ultimate diagnosis was made on the basis of a pulmonary microvascular cytology (PMC) examination. Therefore, PMC is considered to be a useful strategy for the diagnosis of IVLBCL, particularly in this critically ill patient suffering from hypoxemia. PMID- 26027997 TI - Idiopathic granulomatous hypophysitis: a rare cystic lesion of the pituitary. AB - Idiopathic granulomatous hypophysitis (GH) is a rare inflammatory disease of the pituitary gland. A 48-year-old woman was admitted to the hospital with an irregular menstrual cycle. MRI showed pituitary cystic lesion with sellar enlargement. The patient underwent endoscopic endonasal transsphenoidal surgical excision. A histopathological assessment revealed non-necrotizing granulomatous lesions and a diagnosis of GH was made. The rarity of GH and cystic form of the disease make it difficult to confirm the diagnosis until surgery. We herein report this rare case and provide a discussion of the MRI findings and relevant literature of GH. PMID- 26027998 TI - Tumefactive Demyelinating Lesion Differentiated from a Brain Tumor Using a Combination of Magnetic Resonance Imaging and (11)C-methionine Positron Emission Tomography. AB - A 37-year-old woman gradually developed a gait disturbance due to sensory loss in the left lower extremity three years after being diagnosed with clinically isolated syndrome. Brain magnetic resonance imaging (MRI) demonstrated an incomplete ring-enhanced lesion with perifocal edema in the subcortex of the right parietal lobe. (11)C-methionine positron emission tomography (MET-PET) showed an insignificant uptake in the lesion. The patient was noninvasively diagnosed with tumefactive multiple sclerosis and treated with corticosteroids, and her neurological symptoms and MRI findings improved with treatment. The combination of MRI findings and insignificant uptake on MET-PET is useful for noninvasively differentiating tumefactive demyelinating lesions from brain tumors. PMID- 26027999 TI - Cauda equina involvement in post-radiation lower motor neuron syndrome. AB - Post-radiation lower motor neuron syndrome (PRLMNS) is a rare neurological complication of radiation therapy and its pathogenesis is unclear. We herein report a patient with PRLMNS who developed leg weakness 17 years after craniospinal radiation as a treatment for suprasellar germinoma. The electrophysiological evaluation, via a novel magnetic stimulation method, indicated a prolonged cauda equina conduction time, suggesting focal demyelination of the nerve roots in the cauda equina. The distribution of the denervated muscles detected by magnetic resonance imaging was consistent with patchy motor nerve root lesions. These results support the hypothesis that PRLMNS originates from ischemic radiculopathy in the cauda equina. PMID- 26028000 TI - Methotrexate-associated Lymphoproliferative Disease with Multiple Pulmonary Nodules in a Patient with Rheumatoid Arthritis. AB - Patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) sometimes develop lymphoproliferative disease (LPD). MTX-associated LPD can affect nodal or extranodal sites, including the gastrointestinal tract, skin, lungs, kidneys and soft tissues, at almost equal frequency. However, it is very rare for MTX associated LPD to manifest as multiple nodules in the lungs. We herein report the case of a RA patient who developed MTX-associated LPD with multiple pulmonary nodules during a 5-year course of MTX therapy. PMID- 26028001 TI - Synovitis in a Patient with IgG4-related Disease. AB - A 71-year-old man was admitted to our department due to arthralgia and renal dysfunction. A physical examination disclosed swelling of the right shoulder and left wrist joints. Laboratory tests showed elevated serum IgG4 and creatinine levels, and magnetic resonance imaging of the wrist revealed bone erosion and synovitis. In addition, fluorodeoxyglucose positron emission tomography showed uptake in the submandibular glands, pancreas, kidneys, and affected joints and a renal biopsy revealed tubulointerstitial nephritis with the infiltration of IgG4+ plasma cells. The patient was subsequently diagnosed with IgG4-related disease (IgG4-RD) and successfully treated with corticosteroid therapy. This case suggests that erosive arthritis may occur in patients with IgG4-RD. PMID- 26028002 TI - Cerebral toxoplasmosis in a patient on methotrexate and infliximab for rheumatoid arthritis. AB - Cerebral toxoplasmosis is a rare disease predominantly found in immunocompromised hosts. However, cerebral toxoplasmosis has not been frequently described in association with the use of immunosuppressive medications. We herein report a case of cerebral toxoplasmosis in a 76-year-old Caucasian woman on methotrexate and infliximab for rheumatoid arthritis. The patient presented with right facial droop, slurred speech and difficulty walking. In addition to receiving methotrexate and infliximab and owning a cat, she had no other obvious risk factors. Imaging studies were not conclusive; however, brain biopsy confirmed the diagnosis. Serology was positive for anti-toxoplasma immunoglobulin G. Cerebral toxoplasmosis should be included in the differential diagnosis of patients under immunosuppressive medication who present with neurological manifestations. PMID- 26028003 TI - Pararenal Lymphatic Cyst Infection Caused by Helicobacter cinaedi. AB - A 43-year-old man was referred to our hospital for an acute-onset fever and left flank pain. He had been previously diagnosed with lymphangioma, and abdominal computed tomography showed pararenal cysts with fat stranding around the left kidney, of which infection was subsequently confirmed on magnetic resonance imaging. Gram-negative spiral bacilli were isolated from two sets of blood cultures, and Helicobacter cinaedi was identified using 16S rRNA sequencing. The patient was successfully treated with ceftriaxone therapy without recurrence. A multilocus sequence typing analysis indicated the current H. cinaedi strain differed from previous strains isolated in Japan. PMID- 26028004 TI - Primary A (H1N1) pdm09 Influenza Pneumonia Diagnosed on Reverse Transcription polymerase Chain Reaction (RT-PCR) of Bronchoalveolar Lavage Fluid but not Rapid Tests with Nasopharyngeal Swabs. AB - A 47-year-old man with a fever was highly suspected of having influenza A infection since his wife and son who lived with him had been diagnosed with influenza A. Although repeated rapid tests with a nasopharyngeal swab showed negative findings, the patient developed bilateral pneumonia and reverse transcription polymerase chain reaction (PCR) for A (H1N1) pdm09 virus in the bronchoalveolar lavage fluid was positive. We therefore diagnosed him with primary influenza pneumonia and initiated treatment with peramivir plus corticosteroids, which rapidly improved his condition. During the influenza season, sample collection from the lower airway and PCR should be considered for the definitive diagnosis of primary influenza viral pneumonia. PMID- 26028005 TI - PURE-LAMP Procedure for the Diagnosis of Extrapulmonary Tuberculosis: A Case Series. AB - Although the polymerase chain reaction is effective for the diagnosis of extrapulmonary tuberculosis (EPTB), it is typically unavailable in resource limited situations. In contrast, the loop-mediated isothermal amplification (LAMP) assay is a relatively cost-effective and accessible method. Additionally, when combined with the procedure for ultra-rapid extraction (PURE) kit, which enables simple DNA extraction, LAMP can detect Mycobacterium tuberculosis in sputum within 1.5 hours using a simple procedure. In this study, we investigated the utility of the PURE-LAMP technique to diagnose three cases of EPTB and showed that it may potentially be a valuable tool for the diagnosis of EPTB. PMID- 26028006 TI - Calcified pelvic masses on radiographs: a case report and discussion. AB - Calcified pelvic masses are frequently detected on plain radiographs in the field of emergency radiology, particularly after trauma. While many of these findings are benign, a subset may be life-threatening if not accurately identified. The differential diagnosis depends on the location of the tumor and the patient's gender and history of trauma. Diagnostic possibilities include aneurysms, musculoskeletal and female pelvic malignancies and more benign entities, such as heterotopic ossification or phleboliths. Considering the possibility of these lesions will help to accurately identify relevant findings on radiographs and effectively select the appropriate treatment plan for patients presenting to the emergency room with pain. PMID- 26028007 TI - Nasopharyngeal carcinoma with bone marrow metastasis: positive response to weekly paclitaxel chemotherapy. AB - A 51-year-old man with nasopharyngeal carcinoma underwent chemoradiotherapy with cisplatin and 5-fluorouracil, followed by a left cervical lymphadenectomy. Distant metastatic disease was excluded using fluoro-deoxyglucose positron emission tomography. Seven months later, bone marrow metastasis and disseminated intravascular coagulation were diagnosed. The patient received weekly paclitaxel therapy and maintained a good performance status for seven months. During the treatment period, the patient developed no severe organ toxicity except for neutropenia. Weekly paclitaxel may therefore be considered as the treatment of choice in patients with advanced or recurrent nasopharyngeal carcinoma with bone marrow metastasis. PMID- 26028008 TI - Large Subdural Hematoma in Advanced Huntington's Disease. PMID- 26028010 TI - [Peer review]. PMID- 26028009 TI - Complexation induced fluorescence and acid-base properties of dapoxyl dye with gamma-cyclodextrin: a drug-binding application using displacement assays. AB - Host-guest complexation of dapoxyl sodium sulphonate (DSS), an intramolecular charge transfer dye with water-soluble and non-toxic macrocycle gamma cyclodextrin (gamma-CD), has been investigated in a wide pH range. Steady-state absorption, fluorescence and time-resolved fluorescence measurements confirm the positioning of DSS into the hydrophobic cavity of gamma-CD. A large fluorescence enhancement ca. 30 times, due to 1 : 2 complex formation and host-assisted guest protonation have been utilised for developing a method for the utilisation of CD based drug-delivery applications. A simple fluorescence-displacement based approach is implemented at physiological pH for the assessment of binding strength of pharmaceutically useful small drug molecules (ibuprofen, paracetamol, methyl salicylate, salicylic acid, aspirin, and piroxicam) and six important antibiotic drugs (resazurin, thiamphenicol, chloramphenicol, ampicillin, kanamycin, and sorbic acid) with gamma-CD. PMID- 26028011 TI - [Clinical decision making with regard to the granting of escorted leave for forensic patients detained by court order in a Dutch psychiatric clinic. Role of gender, disorder and the type of offence in the procedure]. AB - BACKGROUND: An increase in the length of time until the first escorted leave is granted to a patient detained by court order (tbs) results in a longer period of treatment. Physicians involved in the treatment and clinic managers are striving to reduce, in a responsible manner, the length of the period of treatment preceding the patient's first escorted leave.
AIM: Forensic Psychiatric Clinic (fpk) 'De Woenselse Poort' aims to find out to what extent gender, pathology and the type of offence committed by the detainee influence the length of time that elapses before the patient's first leave is granted. METHOD: We conducted a retrospective study based on patients' records. RESULTS: Although men use physical aggression more often than women, we found that gender, pathology and the type of offence had no influence on the length of the treatment period that preceded the granting of the patient's first escorted leave. CONCLUSION: Partly on the basis of risk management scales, clinicians judge whether the patient has adopted a more positive or a more negative attitude to risk factors relating to his or her offence. If the risk factors have become more positive, one would expect the application for leave to be made earlier. Surprisingly, this was not the case. In order to speed up the decision-making process regarding the application for leave, a clinical method for evaluating risk related treatment needs to be developed in which offence related risk factors are identified and the patient's positive or negative attitude to these risks are measured and monitored. At each treatment evaluation practitioners should be required to produce arguments that determine whether or not the patient is to be granted permission to go on leave at a particular moment. PMID- 26028012 TI - [Psychiatric applications at the emergency department of the Brussels University Hospital between 2003 and 2012]. AB - BACKGROUND: Although the emergency department in Belgian hospital is an important gateway to mental health care, there is lack of information about the way in which this population has evolved. Various studies have reported on the increasing numbers of patients with psychiatric problems, particularly in the younger age group. AIM: To focus on the psychiatric applications at the emergency department of the Brussels University Hospital over a period of 10 years. METHOD: All patients who arrived with a psychiatric problem were studied with regard to the following variables: age, gender, diagnosis, time of arrival, referral, destination and application for compulsory admission. The 10-year study involved a total of 6,519 patients. RESULTS: The largest group of patients were aged between 26 and 45. We noted that there were more depressive disorders in women than in men, but men had more psychotic and substance-related disorders. 60% of the applicants came on their own initiative. The number of patients who returned home after an emergency consultation declined over the period of time under study. About 25% of the patients arrived at the hospital after 8 p.m. and before 8 a.m. There was an increase in the number of persons requesting compulsory admission; about 60% of these actually resulted in a compulsory admission. CONCLUSION: The results demonstrate the importance of psychiatric care in an emergency department of a general hospital and are remarkably similar to the results of other studies. However, some of the comments on the Brussels situation are influenced specifically by the metropolitan area in which the hospital is situated. PMID- 26028013 TI - [Stabilisation in trauma treatment: necessity or myth?]. AB - BACKGROUND: With regard to the treatment of patients who have been traumatised in childhood by interpersonal trauma and have been diagnosed as having symptoms of complex ptsd, it is advisable that exposure of such patients to traumatic memories should be preceded by a stabilisation phase: during this phase patients can be taught various techniques including particularly those that enable them to regulate their emotions. AIM: To find out whether there is strong empirical evidence for the introduction of a phase-based treatment approach for this patient group. METHOD: We performed a critical evaluation of the available scientific literature and guidelines. We took as our starting point the studies that formed the basis of the Expert Consensus Guidelines for Complex ptsd. RESULTS: Our research shows that trauma-focused treatment, be it with or without a preparatory stabilisation phase, is also effective for patients with complex ptsd symptoms. However, there is certainly no compelling evidence to support the assumption that well-organised and carefully administered evidence-based treatment has to be preceded by a stabilisation phase. CONCLUSION: Among the experts there is uncertainty about the best form of treatment for patients with complex ptsd that has resulted from interpersonal trauma in childhood. For the time being, the severity and complexity of trauma-related problems are not valid reasons for denying patients a period of stabilisation as recommended in national treatment guidelines, nor are they valid reasons for preferring a phase-based treatment over a trauma-focused type of treatment. PMID- 26028014 TI - [Emotion regulation belongs in the therapeutic arsenal for complex PTSD: consensus and evidence]. PMID- 26028015 TI - [Measuring alexithymia in fibromyalgia: the need for a multimodal measurement method to replace the TAS-20]. AB - BACKGROUND: In an earlier publication that investigated alexithymia in fibromyalgia, we showed the Toronto Alexithymia Scale was the only instrument being used to measure alexithymia. AIM: To find out which instruments are currently available for measuring alexithymia, to compare the psychometric properties of these instruments and to decide whether some of the test methods involved should be used to give extra value to alexithymia research. METHOD: We conducted a systematic review of the literature in Medline/PubMed with a number of search terms. We selected articles relating to psychometric properties of the tests performed and decided whether they could be influenced by negative affect. RESULTS: We found that 14 different instruments were used to measure alexithymia. From our evaluation we excluded tests which had weak psychometric properties or had been inadequately assessed. There remained three observation scales and two self-report questionnaires, which had been adequately validated and whose relative strengths and weaknesses were compared. CONCLUSION: In view of these findings, we recommend that in studies of alexithymia in fibromyalgia a multimodal measurement method should be used rather than only the tas-20. PMID- 26028016 TI - [Shared decision-making in mental health care: a role model from youth mental health care]. AB - BACKGROUND: In the communication and interaction between doctor and patient in Western health care there has been a paradigm shift from the paternalistic approach to shared decision-making. AIM: To summarise the background situation, recent developments and the current level of shared decision-making in (youth) mental health care. METHOD: We conducted a critical review of the literature relating to the methodology development, research and the use of counselling and decision-making in mental health care. RESULTS: The majority of patients, professionals and other stakeholders consider shared decision-making to be desirable and important for improving the quality and efficiency of care. Up till recently most research and studies have concentrated on helping patients to develop decision-making skills and on showing patients how and where to access information. At the moment more attention is being given to the development of skills and circumstances that will increase patients' interaction with care professionals and patients' emotional involvement in shared decision-making. In mental health for children and adolescents, more often than in adult mental health care, it has been customary to give more attention to these aspects of shared decision-making, particularly during counselling sessions that mark the transition from diagnosis to treatment. This emphasis has been apparent for a long time in textbooks, daily practice, methodology development and research in youth mental health care. Currently, a number of similar developments are taking place in adult mental health care. CONCLUSION: Although most health professionals support the policy of shared decision-making, the implementation of the policy in mental health care is still at an early stage. In practice, a number of obstacles still have to be surmounted. However, the experience gained with counselling and decision-making in (youth) mental health care may serve as an example to other sections of mental health care and play an important role in the further development of shared decision-making. PMID- 26028017 TI - [Takotsubo cardiomyopathy as a complication of electroconvulsive therapy]. AB - Takotsubo cardiomyopathy is an acute, stress-induced, reversible cardiac syndrome and can occur as a rare complication in electroconvulsive therapy. We give further details of this complication by referring to the case of a 67-year-old female patient. In addition, we give a brief description of the background of the syndrome. If this syndrome is suspected, the patient should immediately be referred for cardiac diagnostic tests to rule out myocardial infarction. There is no absolute contra-indication to ECT for a patient who has experienced Takotsubo cardiomyopathy. However, to start ECT treatment again it is recommended that this should be performed in a general hospital and in combination with beta-blockers. PMID- 26028018 TI - [Brua as an explanatory model for diseases]. AB - A 26-year-old woman from the island of Aruba who had been living in the Netherlands for ten years felt she was misunderstood by the various health professionals she had consulted because of her fear that she was being poisoned and would soon die. Due to her background en her belief in brua, she attributed her symptoms and her illness to 'voodoo', allegedly practiced by members of her husband's family in connection with relationship problems. A culture-sensitive approach to the patient, along with thorough psychiatric and neurological tests, yielded a surprising result. Our findings emphasise how important it is for us as health professionals to acquaint ourselves with explanatory models of the diseases of our patients, and how vital it is for us to be aware of a patient's background, particularly if the patient is of foreign descent. PMID- 26028019 TI - [The end of schizophrenia in the Netherlands? not yet]. PMID- 26028020 TI - Characterization and tissue distribution of conjugated metabolites of pyrene in the rat. AB - Pyrene (PY) is a polycyclic aromatic hydrocarbon (PAH) that is often used as a biomarker for human and wildlife exposure to PAHs. As the metabolites of PAHs, similar to their parent compounds, pose public health risks, it is necessary to study their characteristics and tissue-specific distribution. The present study was performed to experimentally characterize PY metabolites and analyze the tissue-specific distribution of the conjugated metabolites after oral administration of PY to rats. PY metabolites, such as pyrenediol-disulfate (PYdiol-diS), pyrenediol-sulfate (PYdiol-S), pyrene-1-sulfate (PYOS), pyrene-1 glucuronide (PYOG) and 1-hydroxypyrene (PYOH), were detected in rat urine. Although glucuronide conjugate was the predominant metabolite, the metabolite composition varied among tissues. Interestingly, the proportion of PYOH was high in the large intestine. Furthermore, PYOH was the only PY metabolite detected in feces. PMID- 26028022 TI - An accidental fatal attack on domestic pigeons by honey bees in Bangladesh. AB - Fatalities among avian species due to multiple bee stings are rare. Sixteen pigeons on a farm in Bangladesh each suffered multiple bee stings. Ten of the pigeons died before treatment, 5 (4-11 stings) died within 12 hr after treatment, and 1 pigeon (only 3 stings) survived. Body temperature, heart rate, respiratory rate, hematocrit, hemoglobin, erythrocytes, thrombocytes, MCV, MCH and MCHC decreased significantly after the incident, but leucocytes, heterophils, basophils, eosinophils, monocytes, ALT, AST, LDH, CK, creatinine, BUN and UA increased markedly. Overall, the hematological and biochemical changes in the bee stung pigeons were similar to those of mammals; however, avian species may be more sensitive to bee stings than mammals. PMID- 26028021 TI - Molecular epidemiological and phylogenetic analyses of canine parvovirus in domestic dogs and cats in Beijing, 2010-2013. AB - Fifty-five samples (15.62%) collected from dogs and cats were identified as canine parvovirus (CPV) infection in Beijing during 2010-2013. The nucleotide identities and aa similarities were 98.2-100% and 97.7-100%, respectively, when compared with the reference isolates. Also, several synonymous and non-synonymous mutations were also recorded for the first time. New CPV-2a was dominant, accounting for 90.90% of the samples. Two of the 16 samples collected from cats were identified as new CPV-2a (12.5%), showing nucleotide identities of 100% with those from dogs. Twelve samples (15.78%) collected from completely immunized dogs were found to be new CPV-2a, which means CPV-2 vaccines may not provide sufficient protection for the epidemic strains. PMID- 26028023 TI - The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and is on the rise in the United States. Previous studies showed that the matricellular protein CCN1 (CYR61) is induced during hepatic injuries and functions to restrict and resolve liver fibrosis. Here, we show that CCN1 suppresses hepatocarcinogenesis by inhibiting carcinogen-induced compensatory hepatocyte proliferation, thus limiting the expansion of damaged and potentially oncogenic hepatocytes. Consistent with tumor suppression, CCN1 expression is downregulated in human HCC. Ccn1(DeltaHep) mice with hepatocyte specific deletion of Ccn1 suffer increased HCC tumor multiplicity induced by the hepatocarcinogen diethylnitrosamine (DEN). Knockin mice (Ccn1(dm/dm)) that express an integrin alpha6beta1-binding defective CCN1 phenocopied Ccn1(DeltaHep) mice, indicating that CCN1 acts through its alpha6beta1 binding sites in this context. CCN1 effectively inhibits epidermal growth factor receptor (EGFR) dependent hepatocyte proliferation through integrin alpha6-mediated accumulation of reactive oxygen species (ROS), thereby triggering p53 activation and cell cycle block. Consequently, Ccn1(dm/dm) mice exhibit diminished p53 activation and elevated compensatory hepatocyte proliferation, resulting in increased HCC. Furthermore, we show that a single dose of the EGFR inhibitor erlotinib delivered prior to DEN-induced injury was sufficient to block compensatory proliferation and annihilate development of HCC nodules observed 8 months later, suggesting potential chemoprevention by targeting CCN1-inhibitable EGFR-dependent hepatocyte proliferation. Together, these results show that CCN1 is an injury response protein that functions not only to restrict fibrosis in the liver, but also to suppress hepatocarcinogenesis by inhibiting EGFR-dependent hepatocyte compensatory proliferation. PMID- 26028024 TI - Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. AB - BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers. PMID- 26028025 TI - Mitotic phosphorylation of Bloom helicase at Thr182 is required for its proteasomal degradation and maintenance of chromosomal stability. AB - Mutations in Bloom helicase (BLM) lead to Bloom Syndrome (BS). BS is characterized by multiple clinical manifestations including predisposition to a wide spectrum of cancers. Studies have revealed the mechanism of BLM recruitment after stalled replication and its role during the repair of DNA damage. We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7alpha. Fbw7alpha carries out its function after GSK3beta- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. Consequently lack of Thr182 phosphorylation leads to multiple manifestations of chromosomal instability including increased levels of DNA damage, lagging chromatin, micronuclei formation, breaks and quadriradials. Hence Thr182 phosphorylation on BLM has two functions-it regulates BLM turnover during mitosis and also helps to maintain the chromosomal stability. PMID- 26028026 TI - Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. AB - An enhanced capacity for de novo lipid synthesis is a metabolic feature of most cancer cells that distinguishes them from their cells of origin. However, the mechanisms through which oncogenes alter lipid metabolism are poorly understood. We find that expression of oncogenic PI3K (H1047R) or K-Ras (G12V) in breast epithelial cells is sufficient to induce de novo lipogenesis, and this occurs through the convergent activation of the mechanistic target of rapamycin complex 1 (mTORC1) downstream of these common oncogenes. Oncogenic stimulation of mTORC1 signaling in this isogenic setting or a panel of eight breast cancer cell lines leads to activation of the sterol regulatory element-binding proteins (SREBP1 and SREBP2) that are required for oncogene-induced lipid synthesis. The SREBPs are also required for the growth factor-independent growth and proliferation of oncogene-expressing cells. Finally, we find that elevated mTORC1 signaling is associated with increased mRNA and protein levels of canonical SREBP targets in primary human breast cancer samples. These data suggest that the mTORC1/SREBP pathway is a major mechanism through which common oncogenic signaling events induce de novo lipid synthesis to promote aberrant growth and proliferation of cancer cells. PMID- 26028027 TI - MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B. AB - The histone variant, macroH2A1, has an important role in embryonic stem cell differentiation and tumor progression in various types of tumors. However, the regulatory roles of macroH2A1 on bladder cancer progression have not been fully elucidated. Here, we show that macroH2A1 knockdown promotes stem-like properties of bladder cancer cells. The knockdown of macroH2A1 in bladder cancer cells increased tumorigenicity, radioresistance, degeneration of reactive oxygen species, increased sphere formation capability and an increase in the proportion of side populations. We found that macroH2A1 is required for the suppression of Lin28B identified as a novel downstream target of macroH2A1 in bladder cancer. Loss of macroH2A1 expression significantly correlated with the elevated levels of Lin28B expression and subsequently inhibited the mature let-7 microRNA expression. Furthermore, the stable overexpression of Lin28B enhances the several phenotypes, including tumorigenicity and sphere-forming ability, which are induced by macroH2A1 depletion. Importantly, Lin28B expression was regulated by macroH2A1-mediated reciprocal binding of p300 and EZH2/SUV39H1. Our results suggest that Lin28B/let-7 pathway is tightly regulated by macroH2A1 and its cofactors, and have a pivotal role in the bladder tumor progression and the regulation of stem-like characteristics of bladder cancer cells. PMID- 26028028 TI - Targeting of nucleotide-binding proteins by HAMLET--a conserved tumor cell death mechanism. AB - HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills tumor cells broadly suggesting that conserved survival pathways are perturbed. We now identify nucleotide-binding proteins as HAMLET binding partners, accounting for about 35% of all HAMLET targets in a protein microarray comprising 8000 human proteins. Target kinases were present in all branches of the Kinome tree, including 26 tyrosine kinases, 10 tyrosine kinase-like kinases, 13 homologs of yeast sterile kinases, 4 casein kinase 1 kinases, 15 containing PKA, PKG, PKC family kinases, 15 calcium/calmodulin-dependent protein kinase kinases and 13 kinases from CDK, MAPK, GSK3, CLK families. HAMLET acted as a broad kinase inhibitor in vitro, as defined in a screen of 347 wild-type, 93 mutant, 19 atypical and 17 lipid kinases. Inhibition of phosphorylation was also detected in extracts from HAMLET-treated lung carcinoma cells. In addition, HAMLET recognized 24 Ras family proteins and bound to Ras, RasL11B and Rap1B on the cytoplasmic face of the plasma membrane. Direct cellular interactions between HAMLET and activated Ras family members including Braf were confirmed by co immunoprecipitation. As a consequence, oncogenic Ras and Braf activity was inhibited and HAMLET and Braf inhibitors synergistically increased tumor cell death in response to HAMLET. Unlike most small molecule kinase inhibitors, HAMLET showed selectivity for tumor cells in vitro and in vivo. The results identify nucleotide-binding proteins as HAMLET targets and suggest that dysregulation of the ATPase/kinase/GTPase machinery contributes to cell death, following the initial, selective recognition of HAMLET by tumor cells. The findings thus provide a molecular basis for the conserved tumoricidal effect of HAMLET, through dysregulation of kinases and oncogenic GTPases, to which tumor cells are addicted. PMID- 26028029 TI - Prostate-specific G-protein-coupled receptor collaborates with loss of PTEN to promote prostate cancer progression. AB - Among frequent events in prostate cancer are loss of the tumor-suppressor phosphatase and tensin homologue (PTEN) and overexpression of prostate-specific G protein-coupled receptor (PSGR), but the potential tumorigenic synergy between these lesions is unknown. Here, we report a new mouse model (PSGR Pten(Delta/Delta)) combining prostate-specific loss of Pten with probasin promoter-driven PSGR overexpression. By 12 months PSGR-Pten(Delta/Delta) mice developed invasive prostate tumors featuring Akt activation and extensive inflammatory cell infiltration. PSGR-Pten(Delta/Delta) tumors exhibited E cadherin loss and increased stromal androgen receptor (AR) expression. PSGR overexpression increased LNCaP proliferation, whereas PSGR short hairpin RNA knockdown inhibited proliferation and migration. In conclusion, we demonstrate that PSGR overexpression synergizes with loss of PTEN to accelerate prostate cancer development, and present a novel bigenic mouse model that mimics the human condition, where both PSGR overexpression and loss of PTEN occur concordantly in the majority of advanced prostate cancers, yielding an environment more relevant to studying human prostate cancer. PMID- 26028030 TI - Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. AB - Acquired therapeutic resistance is the major drawback to effective systemic therapies for cancers. Aggressive triple-negative breast cancers (TNBC) develop resistance to chemotherapies rapidly, whereas the underlying mechanisms are not completely understood. Here we show that genotoxic treatments significantly increased the expression of miR-181a in TNBC cells, which enhanced TNBC cell survival and metastasis upon Doxorubicin treatment. Consistently, high miR-181a level associated with poor disease free survival and overall survival after treatments in breast cancer patients. The upregulation of miR-181a was orchestrated by transcription factor STAT3 whose activation depended on NF-kappaB mediated IL-6 induction in TNBC cells upon genotoxic treatment. Intriguingly, activated STAT3 not only directly bound to MIR181A1 promoter to drive transcription but also facilitated the recruitment of MSK1 to the same region where MSK1 promoted a local active chromatin state by phosphorylating histone H3. We further identified BAX as a direct functional target of miR-181a, whose suppression decreased apoptosis and increased invasion of TNBC cells upon Dox treatment. These results were further confirmed by evidence that suppression of miR-181a significantly enhanced therapeutic response and reduced lung metastasis in a TNBC orthotopic model. Collectively, our data suggested that miR-181a induction had a critical role in promoting therapeutic resistance and aggressive behavior of TNBC cells upon genotoxic treatment. Antagonizing miR-181a may serve as a promising strategy to sensitize TNBC cells to chemotherapy and mitigate metastasis. PMID- 26028031 TI - Rethinking pheochromocytomas and paragangliomas from a genomic perspective. AB - Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors of neural crest origin. These tumors are caused by germline or somatic mutations in known susceptibility genes in up to 70% of cases. Over the past few years, the emergence of high-throughput technologies has enabled the unprecedented characterization of genomic alterations in PCC/PGL, and has improved our understanding of the molecular mechanisms that distinguish the different tumor subtypes. Integrated genomic analyses have shown that the mutation status of PCC/PGL susceptibility genes strongly correlates with multi-omics data. These observations not only emphasize the role of the long-standing susceptibility genes as the main drivers of PCC/PGL tumorigenesis, but also illustrate the functional interdependence between genomic and epigenomic alterations. In this review, we discuss the genomic landscape underlying PCC/PGL, its functional consequences for tumorigenesis and tumor progression, and the potential clinical relevance of this knowledge for the application of precision medicine for patients with PCC/PGL. PMID- 26028032 TI - LPP inhibits collective cell migration during lung cancer dissemination. AB - Lipoma preferred partner (LPP) is a LIM domain protein, which has multiple functions as an actin-binding protein and a transcriptional coactivator, and it has been suggested that LPP has some roles in cell migration or invasion, however, its role in cancer cells remains to be elucidated. Here, we showed that LPP degraded N-cadherin in lung cancer, PC14PE6 cells via regulating the expression of matrix metalloproteinase 15 (MMP-15), and loss-of-LPP increases collective cell migration (CCM) and dissemination consequently. Knockdown of LPP and its functional partner, Etv5, markedly restores the full-length N-cadherin and increases cell-cell adhesion. We investigated the common target of LPP and Etv5, and found that MMP-15 is transcribed as their direct transcriptional target. Furthermore, MMP-15 could directly digest the N-cadherin extracellular domain. LPP knockdown in PC14PE6 cells increases N-cadherin-dependent CCM in the three-dimensional collagen gel invasion assays, and promoted the dissemination of cancer cells when they were orthotopically implanted in nude mice. Immunohistochemistry of lung adenocarcinoma specimens revealed the heterogeneity of LPP intensity and complementary expression of LPP and N-cadherin in the primary tumors. These findings suggest that loss-of-LPP, Etv5 or MMP-15 can be a prognostic marker of increasing malignancy. PMID- 26028033 TI - Tumor progression and the different faces of the PERK kinase. AB - The serine/threonine endoplasmic reticulum (ER) kinase, protein kinase R (PKR) like ER kinase (PERK), is a pro-adaptive protein kinase whose activity is regulated indirectly by protein misfolding within the ER. As the oxidative folding environment in the ER is sensitive to a variety of cellular stresses, many of which occur during neoplastic transformation and in the tumor microenvironment, there has been considerable interest in defining whether PERK positively contributes to tumor progression and whether it represents a significant therapeutic target. Herein, we review the current knowledge of PERK dependent signaling pathways, the contribution of downstream substrates including recently characterized new PERK substrates transcription factors Forkhead box O protein and diacyglycerol a lipid signaling second messenger, and efforts to develop small molecule PERK inhibitors. PMID- 26028035 TI - Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF. AB - KRAS and BRAF are among the most commonly mutated oncogenes in human cancer that contribute to tumorigenesis in both distinct and overlapping tissues. However, KRAS and BRAF mutations are mutually exclusive; they never occur in the same tumor cell. The reason for the mutual exclusivity is unknown, but there are several possibilities. The two mutations could be functionally redundant and not create a selective advantage to tumor cells. Alternatively, they could be deleterious for the tumor cell and induce apoptosis or senescence. To distinguish between these possibilities, we activated the expression of BRAF(V600E) and KRAS(G12D) from their endogenous promoters in mouse lungs. Although the tumor forming ability of BRAF(V600E) was higher than KRAS(G12D), KRAS(G12D) tumors were larger and more advanced. Coactivation of BRAF(V600E) and KRAS(G12D) markedly reduced lung tumor numbers and overall tumor burden compared with activation of BRAF(V600E) alone. Moreover, several tumors expressed only one oncogene, suggesting negative selection against expression of both. Similarly, expression of both oncogenes in mouse embryonic fibroblasts essentially stopped proliferation. The expression of both oncogenes hyperactivated the MEK-ERK-cyclin D pathway but reduced proliferation by increasing the production of p15, p16 and p19 proteins encoded by the Ink4/Arf locus and thereby increased senescence associated beta-galactosidase-positive cells. The data suggest that coexpression of BRAF(V600E) and KRAS(G12D) in early tumorigenesis leads to negative selection due to oncogene-induced senescence. PMID- 26028037 TI - Exact helical polymer synthesis by a two-point-covalent-linking protocol between C2-chiral spirobifluorene and C2- or C(s)-symmetric anthraquinone monomers. AB - Two types of one-handed exact helical polymers, coil- and screw-shaped polymers, were synthesized by the two-point-covalent-linking protocol using C2-chiral spirobifluorene (SBF) and C2- or C(s)-symmetric anthraquinone spacers. Central to this protocol is a new aromatic ring-forming reaction based on the stepwise reductive cyclization of bis(aryloxy group)-substituted anthraquinone derivatives. The helical structures of the polymers annulated by aromatic skeletons exhibited high thermal stability attributed to the rigid C2-chiral SBF units and the covalently two-point-connected structure. PMID- 26028034 TI - Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets. AB - HOXA9 is a homeodomain-containing transcription factor that has an important role in hematopoietic stem cell expansion and is commonly deregulated in acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia lead to overexpression of HOXA9, which is a strong predictor of poor prognosis. In many cases, HOXA9 has been shown to be necessary for maintaining leukemic transformation; however, the molecular mechanisms through which it promotes leukemogenesis remain elusive. Recent work has established that HOXA9 regulates downstream gene expression through binding at promoter distal enhancers along with a subset of cell-specific cofactor and collaborator proteins. Increasing efforts are being made to identify both the critical cofactors and target genes required for maintaining transformation in HOXA9-overexpressing leukemias. With continued advances in understanding HOXA9-mediated transformation, there is a wealth of opportunity for developing novel therapeutics that would be applicable for greater than 50% of AML with overexpression of HOXA9. PMID- 26028036 TI - Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway. AB - Cyclin-dependent kinase 2 (CDK2) is a known regulator in the cell cycle control of the G1/S and S/G2 transitions. However, the role of CDK2 in tumorigenesis is controversial. Evidence from knockout mice as well as colon cancer cell lines indicated that CDK2 is dispensable for cell proliferation. In this study, we found that ectopic CDK2 enhances Ras (G12V)-induced foci formation and knocking down CDK2 expression markedly decreases epidermal growth factor (EGF)-induced cell transformation mediated through the downregulation of c-fos expression. Interestingly, CDK2 directly phosphorylates ELK4 at Thr194 and Ser387 and regulates the ELK4 transcriptional activity, which serves as a mechanism to regulate c-fos expression. In addition, ELK4 is overexpressed in melanoma and knocking down the ELK4 or CDK2 expression significantly attenuated the malignant phenotype of melanoma cells. Taken together, our study reveals a novel function of CDK2 in EGF-induced cell transformation and the associated signal transduction pathways. This indicates that CDK2 is a useful molecular target for the chemoprevention and therapy against skin cancer. PMID- 26028038 TI - Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: meta-analysis of absolute prefrontal neuro metabolic concentrations. AB - Proton magnetic resonance spectroscopy ((1)H MRS) measures glutamatergic metabolites namely glutamate and glutamine located in neurons and astrocytes respectively. In this meta-analysis the contribution of glutamatergic neurotransmission to depressive symptoms was evaluated together with other putative prefrontal metabolites described in the pathogenesis of mood disorders, and in relation to treatment effects. A comprehensive literature search up to 2014 identified 17 reports which measured absolute concentrations of neurometabolites in the prefrontal cortex with (1)H MRS meeting criteria for inclusion in this meta-analysis. Excess of heterogeneity was investigated with meta-regressions. The analyses showed an exclusive reduction in absolute values of the composite measure of Glutamine and Glutamate (Glx) in the prefrontal cortex in depression, correlating in meta-regression analyses with treatment severity. Glutamate measurements in isolation did not differ vs. healthy controls or in relation to treatment and/or clinical improvement. Similarly there were no significant changes in other neurometabolites at baseline and following treatment. The analysis supports a role for glutamatergic dysfunction in the pathogeneses of mood dysregulation. The reduction in the absolute Glx values in the absence of changes in glutamate levels, suggests a possible modulatory role of astrocytes in the pathophysiology of depression. PMID- 26028041 TI - Antioxidant and Antimicrobial Properties of Veronica spicata L. (Plantaginaceae). AB - Tea made from Veronica spicata L. (syn. Pseudolysimachion spicatum (L.) Opiz, family Plantaginaceae) herb is used in traditional medicine as expectorant for cough and throat rinsing. To get insight into chemical compounds of V. spicata, the essential oil content (analysed by GC-FID and GC-MS), the content of phenolic compounds (analysed by HPLC), the content of macroelements and trace elements (analysed by ICP-AES), quantity of total phenols and total flavonoids (analysed by UV/Vis spectrophotometer), and antioxidant and antimicrobial properties were investigated. The main compounds of the essential oil were phytol (21.13%), heptacosane (10.22%) and pentacosane (8.91%). The most abundant investigated macroelement was K (8261 mg/kg) while Fe was the most represented element (32.49 mg/kg) among investigated micronutrients. Ten phenolic compounds (chrysin, rutin, quercitrin, quercitrin, and cichoric, ferulic, protocatehuic, rosmarinic, syringic and tannic acid) were identified and quantified. Additionally, V. spicata extract demonstrated notable radical-scavenging and chelating properties. The bacterial and fungal strains used in study were found to be susceptible toward methanolic and ethyl-acetate extracts with MIC values between 1.25 and 5.00 mg/mL using microdilution method. Aquose extracts were found to be antimicrobial inactive. PMID- 26028039 TI - IL-17 Axis Driven Inflammation in Non-Alcoholic Fatty Liver Disease Progression. AB - Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common chronic liver disease in the world, represents a spectrum of disorders that range from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. It is anticipated that NAFLD will soon surpass chronic hepatitis C infection as the leading cause for needing liver transplantation. Despite its clinical and public health significance no specific therapies are available. Although the etiology of NAFLD is multifactorial and remains largely enigmatic, it is well accepted that inflammation is a central component of NAFLD pathogenesis. Despite the significance, critical immune mediators, loci of immune activation, the immune signaling pathways and the mechanism(s) underlying disease progression remain incompletely understood. Recent findings have focused on the role of Interleukin 17 (IL-17) family of proinflammatory cytokines in obesity and pathogenesis of obesity-associated sequelae. Notably, obesity favors a Th17 bias and is associated with increased IL 17A expression in both humans and mice. Further, in mice, IL-17 axis has been implicated in regulation of both obesity and NAFLD pathogenesis. However, despite these recent advances several important questions require further evaluation including: the relevant cellular source of IL-17A production; the critical IL- 17RA-expressing cell type; the critical liver infiltrating immune cells; and the underlying cellular effector mechanisms. Addressing these questions may aid in the identification and development of novel therapeutic targets for prevention of inflammation- driven NAFLD progression. PMID- 26028042 TI - Apolipoprotein A5: Extracellular and Intracellular Roles in Triglyceride Metabolism. AB - This review addresses two major functions of apolipoprotein (apo) A5 including (1) its role in maintaining normal plasma levels of circulating triglyceride (TG) and (2) its role as a component of hepatic lipid droplets. ApoA5 is synthesized solely in the liver and circulating concentrations are extremely low. In the plasma, ApoA5 associates with TG-rich lipoproteins and enhances TG hydrolysis and remnant lipoprotein clearance. ApoA5 loss-of-function single nucleotide polymorphisms are associated with reduced lipolysis, poor remnant clearance and concomitantly, hypertriglyceridemia. Although there have been substantial breakthroughs in understanding pathophysiology associated with secreted ApoA5, there is a paucity of knowledge on the functionality of intracellular ApoA5. However, recent studies indicate that overexpression of intracellular ApoA5 is positively associated with accumulation of TG-rich lipid droplets in hepatocytes. It is thought that ApoA5 may have a causal role in non-alcoholic fatty liver disease (NAFLD) and thus, may serve as a target for developing therapeutics for NAFLD. PMID- 26028043 TI - Microscopies at the Nanoscale for Nano-Scale Drug Delivery Systems. AB - One of the frontier of nanoscience is undoubtedly represented by the use of nanotechnologies in the pharmaceutical research. During the last decades a big family of nanostructures that have a surface-acting action, such as NanoParticles (NPs), lipid nanocarriers and many more, have been developed to be used as Drug Delivery Systems (DDSs). However, these nanocarriers opened also new frontiers in nanometrology, requiring an accurate morphological characterization, near atomic resolution, before they are really available to clinicians to ascertain their elemental composition, to exclude the presence of contaminants introduced during the synthesis procedure and to ensure biocompatibility. Classical Transmission (TEM) and Scanning Electron Microscopy (SEM) techniques frequently have to be adapted for an accurate analysis of formulation morphology, especially in case of hydrated colloidal systems. Specific techniques such as environmental scanning microscopy and/or cryo preparation are required for their investigation. Analytical Electron Microscopy (AEM) techniques such as Electron Energy-Loss Spectroscopy (EELS) or Energy-Dispersive X-ray Spectroscopy (EDXS) are additional assets to determine the elemental composition of the systems. Here we will discuss the importance of Electron Microscopy (EM) as a reliable tool in the pharmaceutical research of the 21(st) century, focalizing our attention on advantages and limitations of different kind of NPs (in particular silver and carbon NPs, cubosomes) and vesicles (liposomes and niosomes). PMID- 26028040 TI - HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions. AB - Despite the success of combined antiretroviral therapy, more than half of HIV-1 infected patients in the USA show HIV-associated neurological and neuropsychiatric deficits. This is accompanied by anatomical and functional alterations in vulnerable brain regions of the mesocorticolimbic and nigrostriatal systems that regulate cognition, mood and motivation-driven behaviors, and could occur at early stages of infection. Neurons are not infected by HIV, but HIV-1 proteins (including but not limited to the HIV-1 trans activator of transcription, Tat) induce Ca(2+) dysregulation, indicated by abnormal and excessive Ca(2+) influx and increased intracellular Ca(2+) release that consequentially elevate cytosolic free Ca(2+) levels ([Ca(2+)]in). Such alterations in intracellular Ca(2+) homeostasis significantly disturb normal functioning of neurons, and induce dysregulation, injury, and death of neurons or non-neuronal cells, and associated tissue loss in HIV-vulnerable brain regions. This review discusses certain unique mechanisms, particularly the over-activation and/or upregulation of the ligand-gated ionotropic glutamatergic NMDA receptor (NMDAR), the voltage-gated L-type Ca(2+) channel (L-channel) and the transient receptor potential canonical (TRPC) channel (a non-selective cation channel that is also permeable for Ca(2+)), which may underlie the deleterious effects of Tat on intracellular Ca(2+) homeostasis and neuronal hyper-excitation that could ultimately result in excitotoxicity. This review also seeks to provide summarized information for future studies focusing on comprehensive elucidation of molecular mechanisms underlying the pathophysiological effects of Tat (as well as some other HIV-1 proteins and immunoinflammatory molecules) on neuronal function, particularly in HIV-vulnerable brain regions. PMID- 26028044 TI - Natural Products on Nonalcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a chronic disorder of lipid and carbohydrate metabolism and is often associated with endoplasmic reticulum stress, energy homeostasis dysregulation, and inflammation at cellular and molecular levels. Use of currently available anti-hyperlipidemia, hypoglycemia, or anti-inflammation drugs to treat NAFLD has not achieved desirable outcomes. A growing attention thus has been paid towards natural products as an alternative means in treating NALFD. Some of the natural products apparently possess the properties of ameliorating symptoms of NAFLD through restoration of lipid and carbohydrate metabolism and energy homeostasis. Data from recent animal and human studies concerning the use of natural products in the treatment of NAFLD are analyzed, and the potential underlying mechanisms are discussed. PMID- 26028045 TI - Recent Advances in Molecular Image-Guided Cancer Radionuclide Therapy. AB - Cancer-targeted radionuclide therapy is a promising approach for the treatment of a wide variety of malignancies, especially those resistant to conventional therapies. However, to improve the use of targeted radionuclide therapy for the management of cancer patients, the in vivo behaviors, dosimetry, and efficacy of radiotherapeutic agents need to be well characterized and monitored. Molecular imaging, which is a powerful tool for the noninvasive characterization and quantification of biological processes in living subjects at the cellular and molecular levels, plays an important role in the guidance of cancer radionuclide therapy. In this review, we introduce the radiotherapeutics for cancer-targeted therapy and summarize the most recent evidence supporting the use of molecular imaging to guide cancer radionuclide therapy. PMID- 26028046 TI - Advances in Hyaluronic Acid-Based Drug Delivery Systems. AB - Hyaluronic acid (HA) is a relatively new polymer for the construction of drug delivery systems. CD44 and the receptor for HA-mediated motility play a key role in vivo for the receptor-mediated endocytosis of HA. Cellular uptake and the efficiency of tumor-targeted drug delivery are supposed to increase through utilizing HA as drug carriers. Currently, HA has provided a promising platform to physically encapsulate or chemically conjugate with various drugs. In this review, we presented the most latest advances in HA-based drug delivery systems and some forward-looking ideas are discussed. PMID- 26028047 TI - Eph Receptors as Drug Targets: Single-Chain Antibodies and Beyond. AB - The Eph receptors are the largest sub-family of Receptor Tyrosine Kinases (RTK). They, together with their ephrin ligands, play central roles in cell-cell communication during development, and also in the maintenance of a normal adult physiology. Their malfunction, therefore, can contribute to various human diseases. Since the structures of the Eph receptors and ephrins are by now well characterized, there has been extensive recent work to develop ways to manipulate their action in order to achieve therapeutic benefits. Although few reagents have progressed to clinical trials thus far, it is evident that the Eph receptors are valid targets for therapeutic drugs. In this review we first summarize studies on the three-dimensional structures of Eph receptors. We then give an overview on small molecule inhibitors and activators using Ephs as targets. We put a special focus on the latest developments in the field of monoclonal antibodies and antibody fragments for inhibiting or activating the Eph/ephrin signaling. PMID- 26028048 TI - Tuning T Cell Activation: The Function of CD6 At the Immunological Synapse and in T Cell Responses. AB - CD6 immunotherapy to treat psoriasis and rheumatoid arthritis has reached the clinical trial stage with apparent success, and targeting CD6 with mAbs is being used in several animal models of autoimmunity and neuroinflammation with promising indications. However, the mode of action of the therapeutic CD6 mAbs is far from being understood, reflecting the uncertainties and controversy surrounding the mechanistic and biological functions of CD6. Initially regarded as a co-stimulatory receptor of T lymphocytes, recent studies suggest that CD6 can instead modulate early as well as late T cell responses. Also, opposing the contribution of CD6 adhesiveness in the establishment and stabilization of immunological synapses, the actual triggering of CD6 might induce anti proliferative signals to the T lymphocyte. CD6 has an unusually long cytoplasmic tail and its gene undergoes peculiar patterns of activation-dependent alternative splicing that can on one hand determine whether or not the CD6 protein binds to its ligand, and on the other include or exclude intracellular sequences that may transduce positive or negative signaling. In this review we discuss the multiple aspects that determine the nature of the signals transmitted via CD6 and the context that may define a dual role for this important T cell surface molecule. PMID- 26028049 TI - SUMOylation Modulates CFTR Biogenesis: Is the Pathway Druggable? AB - The SUMOylation pathway is involved in the regulation of numerous and diverse cellular functions, nuclear as well as extra-nuclear. Thus, it is not surprising that SUMO pathway components are implicated in diseases as diverse as cystic fibrosis, cancer and neurodegenerative diseases. Therefore, the components of the SUMOylation pathway should provide valid therapeutic targets for manipulation. While the related ubiquitylation system encompasses a vast number of enzymes as potential drug targets, there are only a handful of components that comprise the SUMOylation cascade. Whereas this alleviates the problem of target redundancy, it may complicate the potential to achieve drug specificity. The development of small molecule inhibitors aimed at SUMO pathway components is in its early stages. This review provides an outline of the pathway and summarizes drug development efforts targeted at individual SUMOylation pathway components, with an emphasis on how CFTR protein processing may be affected. PMID- 26028050 TI - Updates on HCN Channels in the Heart: Function, Dysfunction and Pharmacology. AB - The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play an important role in the generation of pacemaker activity of cardiac sinoatrial node cells and immature cardiomyocytes. HCN channels are also present in adult atrial and ventricular cardiomyocytes, where the physiological role is currently under investigation. In different cardiac pathologies, dysfunctional HCN channels have been suggested to be a direct cause of rhythm disorders. While loss-of-function mutations of HCN channels are associated with sinus bradycardia, HCN channel gain of-function in atrial fibrillation, ventricular hypertrophy and failure might help enhance ectopic electrical activity and promote arrhythmogenesis. Blockade of HCN channels with ivabradine, a selective bradycardic agent currently available for clinical use, improves cardiac performance and counteracts functional remodeling in experimental hypertrophy. Accordingly, ivabradine ameliorates clinical outcome in patients with chronic heart failure. Novel compounds with enhanced selectivity for cardiac HCN channel isoforms are being studied as potential candidates for new drug development. PMID- 26028051 TI - Chronic Exposure to Low-Level Cadmium in Diabetes: Role of Oxidative Stress and Comparison with Polychlorinated Biphenyls. AB - Among the most important physiological functions, maintenance of the oxidation reduction equilibrium in cells stands out as a major homeostatic event. Many environmental contaminants efficiently trap cellular reducing compounds, but the actual importance of this mode of toxicity is far from being precisely known. This statement applies to cases of slowly developing chronic diseases, such as neurodegenerations, diabetes, and many others. The involvement of oxidative challenge in diabetes is considered in connection with chronic dietary exposure to low-level concentrations of cadmium. Comparison is made with polychlorobiphenyl molecules (PCB): they are structurally unrelated to cadmium, they preferentially distribute into different organs than cadmium, and they follow different metabolic pathways. Yet, they have also pro-oxidative properties, and they are associated with diabetes. Since neither cadmium nor PCB is a direct oxidant, they both follow indirect pathways to shift the redox equilibrium. Thus, a difference must be made between the adaptable response of the organism, i.e. the anti-oxidant response, and the irreversible damage generated by oxidizing species, i.e. oxidative damage, when exposure occurs at low concentrations. The approximate border between high and low levels of exposure is estimated in this review from the available relevant data, and the strengths and weaknesses of experimental models are delineated. Eventually, chronic low level exposure to these contaminants sparks cellular responses setting ground for dysfunction and disease, such as diabetes: oxidative damage is an accompanying phenomenon and not necessarily an early mechanism of toxicity. PMID- 26028052 TI - Molecular diffusion and dc conductivity perfectly correlated with molecular rotational dynamics in a plastic crystalline electrolyte. AB - We probe the ionic conduction and the molecular dynamics in a pure and lithium salt doped dinitrile molecular plastic crystal. While the diffusion of the Li(+) ions is decoupled from the molecular reorientational dynamics, in the undoped plastic crystal the temperature dependence of the mobility of dinitrile ions and thus of the conductivity is virtually identical to that of on-site molecular rotations. The undoped material is found to obey the Walden and Stokes-Einstein rules typical of ideal liquid electrolytes, implying that an effective viscosity against diffusion can be defined even for a plastic crystalline phase. These surprising results, never reported before in a translationally ordered solid, indicate that in this dinitrile plastic crystalline material the timescale of translational diffusion is perfectly correlated with that of the purely reorientational on-site dynamics. PMID- 26028053 TI - Environmental Adaptations Improve Everyday Action in Schizophrenia. AB - Cognitive functioning, particularly executive functioning, is a strong predictor of functional outcomes in people with schizophrenia. Cognitive remediation has been shown to improve specific cognitive processes, but adjunctive interventions are required for meaningful gains in adaptive functioning, particularly in people with chronic illness. This study examined whether (and how) environmental adaptations, used without training, may circumvent cognitive difficulties and facilitate everyday task performance in individuals with chronic schizophrenia. Forty-two individuals with chronic schizophrenia/schizoaffective disorder were administered cognitive measures and two versions of the Naturalistic Action Test (NAT)-a standard version (ST-NAT), and a user-centered version (UC-NAT) that incorporated environmental adaptations designed to facilitate task performance. The NAT conditions were counterbalanced across participants. Analyses compared performance between the NAT versions and examined the cognitive correlates of each NAT condition. Individuals with schizophrenia made fewer errors on the UC NAT as compared to the ST-NAT; this between-group difference was significant for all error types. Compared to the ST-NAT, the UC-NAT performance was not significantly associated with an executive function measure of planning. Environmental adaptations may be implemented without extensive training to improve everyday action in individuals with chronic schizophrenia. Environmental adaptations that reduce planning demands may be most effective in this population. PMID- 26028054 TI - Promoting theory of mind in older adults: does age play a role? AB - OBJECTIVES: Previous research on age-related changes in Theory of Mind (ToM) showed a decline in older adults, particularly pronounced over 75 years of age. Evidence that ToM may be enhanced in healthy aging people has been demonstrated, but no study has focused on the role of age on the effects of ToM training for elderly people. The present study was designed to examine the efficacy of a ToM training on practiced (ToM Strange Stories) and transfer tasks (ToM Animations) in both young and older adults. METHOD: The study involved 127 older adults belonging to two age groups: young-old (Mage = 64.41; SD = 2.49; range: 60-69 years) and old-old (Mage = 75.66; SD = 4.38; range: 70-85 years), randomly assigned to either a ToM group or a control group condition. All participants took part in two 2-hour testing sessions and four 2-hour training sessions. RESULTS: Results showed that both young-old and old-old adults in the ToM group condition improved their ability to reason on complex-mental states significantly more than participants in the control group condition. This positive effect of the training was evident on practiced and transfer ToM tasks. Crucially, age did not moderate the effect of the ToM training. CONCLUSION: These findings demonstrate that young-old and old-old adults equally benefit from the ToM training. Implications for the positive effect of the ToM training in old-old adults are discussed. PMID- 26028055 TI - Associations of the 24-h activity rhythm and sleep with cognition: a population based study of middle-aged and elderly persons. AB - BACKGROUND: Cognitive functioning changes with age, sleep, and the circadian rhythm. We investigated whether these factors are independently associated with different cognitive domains assessed in middle-aged and elderly persons. METHODS: In 1723 middle-aged and elderly persons (age 62 +/- 9.4 years, mean +/- standard deviation, SD) of the Rotterdam Study, we collected actigraphy recordings of on average 138 h. Actigraphy was used to quantify 24-h rhythms by calculating the stability of the rhythm over days and the fragmentation of the rhythm. Sleep parameters including total sleep time, sleep-onset latency, and wake after sleep onset were also estimated from actigraphy. Cognitive functioning was assessed with the word learning test (WLT), word fluency test (WFT), letter digit substitution task (LDST), and Stroop color word test (Stroop). RESULTS: Persons with less stable 24-h rhythms performed worse on the LDST (B = 0.42 per SD increase, p = 0.004) and the Stroop interference trial (B = -1.04 per SD increase, p = 0.003) after full adjustment. Similarly, persons with more fragmented rhythms performed worse on the LDST (B = -0.47 per SD increase, p = 0.002) and the Stroop (B = 1.47 per SD increase, p <0.001). By contrast, longer observed sleep-onset latencies were related to worse performance on the WLT delayed recall (B = -0.19 per SD increase, p = 0.027) and the WFT (B = -0.45 per SD increase, p = 0.007). CONCLUSIONS: Disturbances of sleep and the 24-h activity rhythm were independently related to cognition; while persons with longer sleep onset latencies had worse performance on memory and verbal tasks, persons with 24 h rhythm disturbances performed less on executive functioning and perceptual speed tasks. PMID- 26028056 TI - Obstructive sleep apnoea is common in adults with biopsy-proven non-alcoholic fatty liver disease. PMID- 26028057 TI - MicroRNA expression is dysregulated in narcolepsy: a new evidence? PMID- 26028058 TI - A pilot study examining the effects of consuming a high-protein vs normal-protein breakfast on free-living glycemic control in overweight/obese 'breakfast skipping' adolescents. AB - To examine whether the daily consumption of normal-protein (NP) vs higher-protein (HP) breakfasts improve free-living glycemic control in overweight/obese, 'breakfast skipping' adolescents. Twenty-eight healthy, but overweight, teens (age: 19+/-1 year; BMI: 29.9+/-0.8 kg m(-2)) completed a 12-week randomized parallel-arm study in which the adolescents consumed either a 350 kcal NP breakfast (13 g protein) or HP breakfast (35 g protein). Pre- and post-study 24-h blood glucose measures were assessed using continuous glucose monitoring. Although no main effects of time or group were detected, time by group interactions were observed. Post hoc pairwise comparisons assessing the post-pre changes revealed that the daily consumption of the HP breakfasts tended to reduce the 24-h glucose variability (s.d.) vs NP (-0.17+/-0.09 vs +0.09+/-0.10 s.d.; P=0.06) and tended to reduce the time spent above the high glucose limit (-292+/ 118 vs -24+/-80 min; P=0.09). The consumption of the HP breakfasts also reduced the 24-h maximal (peak) glucose response (-0.94+/-0.36 vs +0.30+/-0.18 mmol l( 1); P<0.01) and reduced postprandial glucose fluctuations (-0.88+/-0.44 vs +0.49+/-0.34 mmol l(-1); P<0.03) vs NP. These data suggest that the daily addition of a HP breakfast, containing 35 g of high-quality protein, has better efficacy at improving free-living glycemic control compared with a NP breakfast in overweight/obese, but otherwise healthy, 'breakfast skipping' adolescents. PMID- 26028061 TI - Nutritional status and dietary intake of institutionalized elderly in Turkey: a cross-sectional, multi-center, country representative study. AB - OBJECTIVE: To evaluate the nutritional status and dietary intake of institutionalized elderly in Turkey. DESIGN: Cross-sectional study. SETTING: 25 institutions in 19 cities throughout Turkey. PARTICIPANTS: Elderly residents aged 65 years and older (n=554). MEASUREMENTS: Nutritional status using Mini Nutritional Assessment (MNA), food consumption with 24-h dietary recall and anthropometric measurements (body weight, height, body mass index (BMI), waist circumference (WC), hip circumference, waist/hip ratio, mid-upper arm circumference (MUAC)). RESULTS: The mean age of the elderly was 76.1+/-7.3 years. BMI of elderly men and women were found to be 26.59+/-4.58kg/m(2) and 30.07+/ 6.32kg/m(2), respectively. WC of elderly men and women were found to be 98.90+/ 1.33cm and 100.62+/-1.34cm, respectively. Most of the elderly were overweight based on BMI and at risk of metabolic diseases based on WC. According to MNA, 44.2% had normal nutritional status, 49.1% were at risk of malnutrition, 6.7% had malnutrition. All nutrients intake was favorable according to requirements, except for calcium and magnesium. Energy, protein, carbohydrate, fat, vitamins A, E, B1, B2, B6, C folat, iron, zinc intake of elderly who had normal nutritional status, who were at risk of malnutrition and malnourished were significantly different. Energy and nutrients intake of elderly who had normal nutritional status was found to be better than the others. CONCLUSION: Nutritional status should be periodically screened in the institutionalized elderly to prevent malnutrition. Also, it was noted that adequate energy and nutrients intake of the elderly played a crucial role in maintaining nutritional status and preventing malnutrition within residential homes. PMID- 26028060 TI - Body fat distribution, metabolic and inflammatory markers and retinal microvasculature in school-age children. The Generation R Study. AB - OBJECTIVE: To examine the associations of body fatness, metabolic and inflammatory markers with retinal vessel calibers among children. DESIGN: We performed a population-based cohort study among 4145 school-age children. At the median age of 6.0 years (95% range 5.8, 8.0 years), we measured body mass index, total and abdominal fat mass, metabolic and inflammatory markers (blood levels of lipids, insulin and C-peptide and C-reactive protein) and retinal vascular calibers from retinal photographs. RESULTS: We observed that compared with normal weight children, obese children had narrower retinal arteriolar caliber (difference -0.21 s.d. score (SDS; 95% confidence interval (CI) -0.35, -0.06)), but not venular caliber. Continuous analyses showed that higher body mass index and total body fat mass, but not android/gynoid fat mass ratio and pre-peritoneal fat mass, were associated with narrower retinal arteriolar caliber (P<0.05 for body mass index and total body fat mass), but not with retinal venular caliber. Lipid and insulin levels were not associated with retinal vessel calibers. Higher C-reactive protein was associated with only wider retinal venular caliber (difference 0.10 SDS (95% CI 0.06, 0.14) per SDS increase in C-reactive protein). This latter association was not influenced by body mass index. CONCLUSIONS: Higher body fatness is associated with narrower retinal arteriolar caliber, whereas increased C-reactive protein levels are associated with wider retinal venular caliber. Increased fat mass and inflammation correlate with microvascular development from school-age onwards. PMID- 26028063 TI - APJCP Loss of SCI Expanded Listing and the Future of the Journal. PMID- 26028062 TI - Sexual behaviours, sex toy and sexual safety methods reported by women who have sex with women and men. AB - Background Relative to women who engage in sex with exclusively men or women, women who have sex with women and men (WSWM) are more likely to report a history of sexually transmissible infections. Knowledge of the diversity and specificity of the sexual behaviours in which they engage may provide insight into the behavioural modes of infection. The present study sought to document a range of behaviours including concurrent multi-person sexual activity (e.g. orgy, threesome), anal sexual activity and sex toy use. Barrier use methods during specific behaviours were also assessed. METHODS: Eighty women who reported recent genital contact with at least one man and one woman were recruited via targeted Internet, venue-based and snowball sampling methods. Consenting participants were directed to an online survey. During an in-person timeline follow-back interview (the SEQUENCE((c)) calendar method), a subset of participants (n=53) provided detailed sexual behaviour data for each sexual partner over the previous 12 months. RESULTS: Almost three-quarters of the sample reported at least one concurrent multi-person sexual activity. Nearly two-thirds of participants reported engaging in sexual behaviour that involved their own (66.7%) or their partner's (49.4%) anus in the past year. Barrier use for sexual behaviours other than penile-vaginal intercourse was uncommon. Behaviours and safety strategies were similar with men and women regardless of partner gender. CONCLUSIONS: The sexual repertoires reported by participants in this study were diverse. Understanding the range of diverse sexual behaviours of the participants may enable the construction of tailored recommendations for sexual health maintenance among WSWM. PMID- 26028059 TI - Obesity-related insulin resistance: implications for the surgical patient. AB - In healthy surgical patients, preoperative fasting and major surgery induce development of insulin resistance (IR). IR can be present in up to 41% of obese patients without diabetes and this can rise in the postoperative period, leading to an increased risk of postoperative complications. Inflammation is implicated in the aetiology of IR. This review examines obesity-associated IR and its implications for the surgical patient. Searches of the Medline and Science Citation Index databases were performed using various key words in combinations with the Boolean operators AND, OR and NOT. Key journals, nutrition and metabolism textbooks and the reference lists of key articles were also hand searched. Adipose tissue has been identified as an active endocrine organ and the chemokines secreted as a result of macrophage infiltration have a role in the pathogenesis of IR. Visceral adipose tissue appears to be the most metabolically active, although results across studies are not consistent. Results from animal and human studies often provide conflicting results, which has rendered the pursuit of a common mechanistic pathway challenging. Obesity-associated IR appears, in part, to be related to inflammatory changes associated with increased adiposity. Postoperatively, the surgical patient is in a proinflammatory state, so this finding has important implications for the obese surgical patient. PMID- 26028064 TI - Current drugs and drug targets in non-small cell lung cancer: limitations and opportunities. AB - Lung cancer is a serious health problem and leading cause of death worldwide due to its high incidence and mortality. More than 80% of lung cancers feature a non small cell histology. Over few decades, systemic chemotherapy and surgery are the only treatment options in this type of tumor but due to their limited efficacy and overall poor survival of patients, there is an urge to develop newer therapeutic strategies which circumvent the problems. Enhanced knowledge of translational science and molecular biology have revealed that lung tumors carry diverse driver gene mutations and adopt different intracellular pathways leading to carcinogenesis. Hence, the development of targeted agents against molecular subgroups harboring critical mutations is an attractive approach for therapeutic treatment. Targeted therapies are clearly more preferred nowadays over systemic therapies because they target tumor specific molecules resulting with enhanced activity and reduced toxicity to normal tissues. Thus, this review encompasses comprehensive updates on targeted therapies for the driver mutations in non-small cell lung cancer (NSCLC) and the potential challenges of acquired drug resistance faced in the field of targeted therapy along with the imminent newer treatment modalities against lung cancer. PMID- 26028065 TI - Novel directions in adjuvant chemotherapy for early stage epithelial ovarian cancer. AB - Treatment of early stage ovarian cancer remains controversial despite advances in chemotherapeutic options. Over the past 30 years, molecular and clinicopathologic studies accelerated and treatment of ovarian cancer has undoubtedly improved although there is a debate as to whether this impacts outcome or not. More recently, the introduction of targeted therapy started a new era. Probably it is because early stage disease comprises a small portion of the epithelial ovarian cancer, studies have mostly ignored this group and still there is no clear consensus regarding systemic treatment of early-stage lesions. However this group of patients has the best chance of cure. In this review, we focus on current developments in the treatment of early stage ovarian cancer and query the options. PMID- 26028066 TI - Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development. AB - Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-alpha (TNF-alpha). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression). PMID- 26028067 TI - Hesa-A Improves Clinical Outcome of Oral Carcinoma by Affecting p53 Gene Expression in vivo. AB - BACKGROUND: Oral carcinoma (OC) remains as one of the most difficult malignancies to cure. Hesa-A is an Iranian herbal-marine compound that has shown promising anti-tumor properties on various human cancer cells, although the mechanisms of action remain to be addressed. This study was conducted to evaluate the effect of two doses of Hesa-A on mRNA expression of p53 as a main prognosticator of OC. MATERIALS AND METHODS: 60 rats were randomly divided into 5 groups of 12 animals each. Rats in carcinoma groups received 0, 250 and 500 mg/kg body weight of Hesa A three times a day. The two other groups considered as treated and untreated healthy groups. At the end of experiment, animals were sacrificed and tongue tissues subjected to H and E staining and real time PCR. RESULTS: Our results indicated that compared to healthy group, p53 over expressed ~ 40% in untreated carcinoma group. After treatment with 250 mg/kg and 500 mg/kg body weights of Hesa-A , p53 level dropped by 53.4% and 13.6 %, respectively, compared to untreated carcinoma group (p<0.05, p<0.0001). Moreover, there was a significant relation between p53 mRNA content and observed pathological changes in studied groups (p<0.05). CONCLUSIONS: These data provide insights into the mechanism(s) by which Hesa-A improves clinical outcome of oral carcinoma by modulation of p53 expression. PMID- 26028068 TI - Prevalence and Risk Factors for Infection by Opisthorchis viverrini in an Urban Area of Mahasarakham Province, Northeast Thailand. AB - The aim of this cross-sectional analytic study was to investigate the prevalence and risk factors for Opisthorchis viverrini (OV) infection in an urban area of Northeastern Thailand. The participants were 254 household representatives aged 15 years or older living in the most urbanised part of Chiang Yuen municipality in Mahasarakham Province. All participants provided stool samples which were examined using the modified Kato-Katz procedure, and a structured interview questionnaire was used to collection demographic information, knowledge about OV infection, and the consumption of unsafely prepared freshwater fish. The data were analyzed using descriptive statistics and logistic regression. The overall prevalence of OV infection was 15.0%, and in the multivariate analysis male gender was found to be significantly and positively associated with OV infection (ORadj=9.75, 95%CI: 34.03-23.58) while education to secondary school level or above was a significant protective factor (ORadj=0.30, 95%CI: 0.12-0.74). The eating of unsafely prepared fish and knowledge about OV were not significantly related to infection status. The findings were discussed in terms of issues for future research, especially the need to consider the possibility of higher rates of OV infection in urban areas than might be expected and to investigate the sources of infected fish products which may well be different from those in rural villages. PMID- 26028069 TI - Aberrant Expression of Markers of Cancer Stem Cells in Gastric Adenocarcinoma and their Relationship to Vasculogenic Mimicry. AB - BACKGROUND: Gastric cancer is the second leading cause of cancer-related death in Asia, and the majority type is gastric adenocarcinoma (GAC). Most GAC patients die of recurrence and metastasis. Cancer stem cells (CSCs) have been thought to be responsible for the initiation, development, metastasis, and ultimately recurrence of cancer. In this study, we aimed to investigate expression and clinical significance of CSCs markers, CD133 and Lgr5, and vasculogenic mimicry (VM) in primary GAC. MATERIALS AND METHODS: Specimens from 261 Chinese patients with follow-up were analyzed for CD133, Lgr5 protein expression and VM by immunohistochemical and histochemical staining. The Pearson Chi's square test was used to assess the associations among the positive staining of these markers and clinicopathological characteristics. Postoperative overall survival time was were studied by univariate and multivariate analyses. RESULTS: In GAC tissues, positive rates of 49.0%, 38.7%, and 26.8% were obtained for CD133, Lgr5, and VM, respectively. The mean score of microvessel density (MVD) was 21.7+/-11.1 in GAC tissues. There was a significantly difference between the positive and negative groups. There was a positive relationship between the VM, the expression of CD133 and Lgr5, and the score of MVD and the grades of tumor, lymph node metastasis, TNM stages (all p<0.05). The overall mean survival time of the patients with CD133, Lgr5, VM, and MVD (>=22) positive expression was lower than that of patients with negative expression. The score of MVD, positive expression of CD133 and VM were independent prognostic factors of GAC (p<0.05). CONCLUSIONS: VM, and expression of CD133, Lgr5, and the score of MVD are related to grades of tumor, lymph node metastasis, TNM stages, and overall mean survival time. It is suggested that CSCs and VM could play an important role in the evolution of GAC. PMID- 26028070 TI - Dietary resistant starch contained foods and breast cancer risk: a case-control study in northwest of Iran. AB - BACKGROUND: A protective effect of resistant starch (RS) containing foods on carcinogenesis has been shown from several lines of experimental evidence for gastrointestinal cancers. Therefore, we aimed to investigate the association between RS contained foods and breast cancer (BC) risk in a hospital-based, age- and origin- matched, case-control study. MATERIALS AND METHODS: A validated, semi quantitative, food frequency questionnaire (FFQ) was completed by 306 women newly diagnosed with BC aged 25 to 65 years, and 309 healthy women as matched controls. Odds ratios (ORs) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression models. RESULTS: Reduced BC risk was associated with the highest tertile of whole-wheat bread and boiled potato consumption with adjusted ORs at 0.34 (95%CI: 0.19-0.59) and 0.61 (95%CI: 0.37- 0.99), respectively. Among consumers of whole-wheat bread consumers were considered, the protective role of cereals remained relatively apparent at higher intakes level of fiber rich breads at adjusted models (OR=0.53, 95%CI: 0.28-1.01). Moreover, high intake of legumes was found out to be a significant protective dietary factor against risk of BC development with an OR of 0.01 (95%CI: 0.03-0.13). However, consumption of white bread and biscuits was positively related to BC risk. CONCLUSIONS: Our results show that certain RS containing foods, in particular whole wheat bread, legumes and boiled potato may reduce BC risk, whereas higher intake of white bread and biscuits may be related to increased BC risk. PMID- 26028071 TI - Paediatric retinoblastoma in India: evidence from the National Cancer Registry Programme. AB - BACKGROUND: Globally, retinoblastoma is the most common primary intraocular malignancy occurring in children. This paper documents the recent incidence rates of retinoblastoma by age and sex groups from the Population Based Cancer Registries (PBCRs) of Bangalore, Mumbai, Chennai, Delhi and Kolkata using the data from the National Cancer Registry Programme. MATERIALS AND METHODS: Relative proportions, sex ratio, method of diagnosis, and incidence rates (crude and age standardized) for each PBCR and pooled rates of the five PBCRs were calculated for the years 2005/06 to 2009/10. Standard errors and 95% confidence limits of ASIRs by sex group in each PBCR were calculated using the Poisson distribution. Standardised rate ratios of ASIR by sex group and rate ratios at risk were also calculated. RESULTS: The maximum retinoblastoma cases were in the 0-4 age group, accounting for 78% (females) and 81% (males) of pooled cases from five PBCRs. The pooled crude incidence rate in the 0-14 age group was 3.5 and the pooled ASIR was 4.4 per million. The pooled ASIR in the 0-4, 5-9 and 10-14 age group were 9.6, 2.0 and 0.1 respectively. The M/F ratio in Chennai (1.9) and Bangalore PBCRs (2.0) was much higher than the other PBCRs. Among the PBCRs, the highest incidence rate in 0-4 age group was found in males in Chennai (21.7 per million), and females in Kolkata (18.9 per million). There was a distinct variation in incidence rates in the PBCRs in different geographic regions of India. PMID- 26028072 TI - Preventive effects of a major component of green tea, epigallocathechin-3 gallate, on hepatitis-B virus DNA replication. AB - BACKGROUND: Hepatitis B virus infection is one of the major world health problems. Epigallocatechin-3 gallate is the major component of the polyphenolic fraction of green tea and it has an anti-viral, anti-mutagenic, anti- tumorigenic, anti-angiogenic, anti-proliferative, and/or pro-apoptotic effects on mammalian cells. In this study, our aim was to investigate the inhibition of HBV replication by epigallocatechin-3 gallate in the Hep3B2.1-7 hepatocellular carcinoma cell line. MATERIALS AND METHODS: HBV-replicating Hep3B2.1-7 cells were used to investigate the preventive effects of epigallocatechin-3 gallate on HBV DNA replication. The expression levels of HBsAg and HBeAg were determined using ELISA. Quantitative real-time-PCR was applied for the determination of the expression level of HBV DNA. RESULTS: Cytotoxicity of epigallocathechin-3-gallate was not observed in the hepatic carcinoma cell line when the dose was lower than 100 MUM. The ELISA method demonstrated that epigallocatechin-3 gallate have strong effects on HBsAg and HBeAg levels. Also it was detected by real-time PCR that epigallocatechin-3 gallate could prevent HBV DNA replication. CONCLUSIONS: The obtained data pointed out that although the exact mechanism of HBV DNA replication and related diseases remains unclear, epigallocatechin-3 gallate has a potential as an effective anti-HBV agent with low toxicity. PMID- 26028073 TI - Macrophage-secreted Exosomes Delivering miRNA-21 Inhibitor can Regulate BGC-823 Cell Proliferation. AB - Exosomes, membranous nanovesicles, naturally carry bio-macromolecules or miRNA and play impoetant roles in tumor pathogenesis. Here, we showed that macrophages cell-derived exosomes can function as vehicles to deliver exogenous miR-21 inhibitor into BGC-823 gastric cancer cells. Exosomes loaded with miR-21 inhibitor significantly increased miR-21 levels in BGC-823, but miR-21 inhibitor loaded in exosomes exerted an opposite effect. miRNA transfected with exosomes had less cellular toxicity to host cells compared to conventional transfection methods. The miR-21 inhibitor loaded exosomes promoted the migration ability and reduced apoptosis of BGC-823 gastric cancer cells. These observations indicate that miR-21 acts as a tumor promoter by targeting the PDCD4 gene and preventing apoptosis of gastric cancer cells through inhibition of PDCD4 expression. Furthermore, exosome -mediated miR-21 inhibitor delivery resulted in functionally more efficient inhibition and less cellular toxicity compared to conventional transfection methods. Similar approaches could be useful in modification of target biomolecules in vitro and in vivo. These findings contribute to our understanding of the functions of miR-21 and exosomes as a carrier for therapy of gastric cancer. PMID- 26028074 TI - Prophylactic Level VII Nodal Dissection as a Prognostic Factor in Papillary Thyroid Carcinoma: a Pilot Study of 27 Patients. AB - BACKGROUND: Prognostic value of prophylactic level VII nodal dissection in papillary thyroid carcinoma has been highlighted. MATERIALS AND METHODS: A total of 27 patients with papillary thyroid carcinoma with N0 neck underwent total thyroidectomy with level VI and VII nodal dissection through same collar neck incision. Multicentricity, bilaterality, extrathyroidal extension, level VI and VII lymph nodes were studied as separate and independent prognostic factors for DFS at 24 months. RESULTS: 21 females and 6 males with a mean age of 34.6 years old, tumor size was 5-24 mm. (mean 12.4 mm.), multicentricity in 11 patients 2-4 foci (mean 2.7), bilaterality in 8 patients and extrathyroidal extension in 8 patients. Dissected level VI LNs 2-8 (mean 5 LNs) and level VII LNs 1-4 (mean 1.9). Metastatic level VI LNs 0-3 (mean 1) and level VII LNs 0-2 (mean 0.5). Follow-up from 6-51 months (mean 25.6) with 7 patients showed recurrence (3 local and 4 distant). Cumulative DFS at 24 months was 87.8% and was significantly affected in relation to bilaterality (p-value<0.001), extrathyroidal extension (p value<0.001), level VI positive ((p-value<0.001) and level VII positive ((p value<0.001) LNs. No recurrences were detected during the follow-up period in the absence of level VI and level VII nodal involvement. CONCLUSIONS: Level VII prophylactic nodal dissection is an important and integral prognostic factor in papillary thyroid carcinoma. A larger multicenter study is crucial to reach a satisfactory conclusion about the necessity and safety of this approach. PMID- 26028075 TI - Evaluation of insulin like growth facror-1 genetic polymorphism with gastric cancer susceptibility and clinicopathological features. AB - Gastric cancer (GC) is one of the most common malignancies in the world. It is the first cause of cancer deaths in both sexes In Iranian population. Circulating insulin-like growth factor-one (IGF-1) levels have been associated for gastric cancer. IGF-1 protein has central roles involved in the regulation of epithelial cell growth, proliferation, transformation, apoptosis and metastasis. Single nucleotide polymorphism in IGF-1 regulatory elements may lead to alter in IGF-1 expression level and GC susceptibility. The aim of this study was to investigate the influence of IGF-1 gene polymorphism (rs5742612) on risk of GC and clinicopathological features for the first time in Iranian population. In total, 241 subjects including 100 patients with GC and 141 healthy controls were recruited in our study. Genotypes were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay with DNA from peripheral blood. The polymorphism was statistically analyzed to investigate the relationship with the risk of GC and clinicopathological properties. Logistic regression analysis revealed that there was no significant association between rs5742612 and the risk of GC. In addition, no significant association between genotypes and clinicopathological features was observed (p value>0.05). The frequencies of the CC, CT, and TT genotypes were 97%, 3%, and 0%, respectively, among the cases, and 97.9%, 2.1%, and 0%, respectively, among the controls. CC genotype was more frequent in cases and controls. The frequencies of C and T alleles were 98.9% and 1.1% in controls and 98.5% and 1.5% in patient respectively. Our results provide the first evidence that this variant is rare in Iranian population and it may not be a powerful genetic predisposing biomarker for prediction GC clinicopathological features in an Iranian population. PMID- 26028076 TI - Effect of hydronephrosis on survival in advanced stage cervical cancer. AB - BACKGROUND: Hydronephrosis is frequently encountered in advanced stage cervical cancers, and may be associated with mortality. In the present study, we aimed to demonstrate the effect of hydronephrosis on survival in patients with inoperable advanced stage cervical cancer. MATERIALS AND METHODS: The study data were acquired by retrospective analysis of the patient records belonging to 165 women with FIGO (International Federation of Gynecology and Obstetrics) stage-IIIB or more advanced cervical cancer, which were not surgical candidates. Parameters including patient age, pathological diagnosis, disease stage, pelvic sidewall extension, presence of hydronephrosis and administration of chemoradiation were analyzed. Further, the effects of these variables on survival were assessed. P values less than 0.05 were considered statistically significant. RESULTS: The distribution of the study patients according to disease stage was as follows: 131 (79.4%) had stage-IIIB, 18 (10.9%) had stage-IVB and 16 (% 9.7) patients had stage-IVA disease. Hydronephrosis was not evident in 91 (55.2%) of these patients, whereas 41 (24.8%) had unilateral and 33 (20%) patients had bilateral hydronephrosis. When compared to mean survival in patients who did not have hydronephrosis, survival was significantly shortened in patients who had bilateral and unilateral hydronephrosis (p<0.05). There was no significant survival difference between patients with unilateral and bilateral hydronephrosis (p>0.05). Although patient age, pathological type, pelvic involvement, and chemotherapy treatment rates were similar (p>0.05), radiotherapy requirement rate and disease stage were significantly different among the study groups (p<0.05). CONCLUSIONS: Hydronephrosis was found to be a significant predictor of poor survival in patients with advanced stage cervical cancer, irrespective of unilateral or bilateral involvement.While waiting for future studies with larger sample sizes, we believe that the FIGO stages in advanced cervical cancer could further be stratified into subgroups according to presence or absence of hydronephrosis. PMID- 26028077 TI - Performance of the R-way Colposcopic Evaluation System in Cervical Cancer Screening. AB - OBJECTIVE: To investigate the diagnostic value of the R-way colposcopic evaluation system (R-way system) in cervical cancer screening. MATERIALS AND METHODS: Between August 2013 and August 2014, a total of 1,059 cases referred to colposcopy in Peking University First Hospital were studied using both the R-way system and conventional colposcopy. Our study evaluated and compared the diagnostic ability of the two methods in detecting high-grade lesions and cervical cancer (hereinafter called CIN2+). Evaluation indicators including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Youden index and the area under the curve (AUC) of the receiver operating characteristic (ROC) were calculated. RESULTS: The R-way system had a slightly lower specificity (94.5%) than conventional colposcopy (96.0%) for CIN2+ detection (P=0.181). However, the sensitivity (77.8%) was significantly higher than with the conventional colposcopic method (46.6%) (chi2=64.351, P<0.001). In addition, the AUC of the ROC for CIN2+ detection using the R-way system (0.839) was larger than that with conventional colposcopy (0.731) (Z=4.348, P<0.001). If preliminary result had been drawn from cervical exfoliated cytology before colposcopy referral, combination of the R-way system with cytology could increase the sensitivity to 93.9% for CIN2+ detection (excluding ASCUS?LSIL), confirmed by multipoint biopsy or ECC. CONCLUSIONS: The diagnostic value of the R-way evaluation system is higher than that of conventional colposcopic evaluation in cervical cancer screening. Moreover, taking the ease of use and standardized quality control management into account, the R-way system is highly preferable. PMID- 26028078 TI - Assessment of Jordanian Patient's Colorectal Cancer Awareness and Preferences towards CRC Screening: Are Jordanians Ready to Embrace CRC Screening? AB - BACKGROUND: Colorectal cancer (CRC is increasingly becoming a major cause of cancer morbidity and mortality in Jordan. However the population's level of awareness about CRC, CRC screening test preferences and willingness to embrace screening are not known. The aim of this study was to assess the level of CRC awareness and screening preferences among Jordanian patients. MATERIALS AND METHODS: A survey assessing the CRC knowledge levels was distributed among patients attending outpatient gastroenterology clinics in public hospitals throughout Jordan. A total of 800 surveys were distributed and of these 713 (89.1%) were returned. RESULTS: Only 22% of the participants correctly judged CRC among the choices provided as the commonest cause of cancer related deaths. The majority of participants (68.3%) underestimated their risk for CRC. Only 26.8% correctly judged their life time risk while 5% overestimated their risk. Two thirds of participants (66%) were willing to pay 500 Jordanian Dinars (equivalent to 706 US$) in order to get a prompt colonoscopy if recommended by their physician, while 25.5% reported that they would rather wait for 6 months in order to get a free colonoscopy. CONCLUSIONS: Although the participants tended to underestimate their risk for CRC, they were mostly aware of CRC as a major cause of mortality and were willing to embrace the concept of CRC screening and bear the related financial costs. These findings about CRC awareness and propensity for screening provide a good foundation as the Jordanian health system moves forward with initiatives to promote CRC screening and prevention. PMID- 26028079 TI - Breast cancer statistics and prediction methodology: a systematic review and analysis. AB - Breast cancer is a menacing cancer, primarily affecting women. Continuous research is going on for detecting breast cancer in the early stage as the possibility of cure in early stages is bright. There are two main objectives of this current study, first establish statistics for breast cancer and second to find methodologies which can be helpful in the early stage detection of the breast cancer based on previous studies. The breast cancer statistics for incidence and mortality of the UK, US, India and Egypt were considered for this study. The finding of this study proved that the overall mortality rates of the UK and US have been improved because of awareness, improved medical technology and screening, but in case of India and Egypt the condition is less positive because of lack of awareness. The methodological findings of this study suggest a combined framework based on data mining and evolutionary algorithms. It provides a strong bridge in improving the classification and detection accuracy of breast cancer data. PMID- 26028080 TI - Predicting lympho-vascular space invasion in endometrial cancers with mucinous carcinomatous components. AB - OBJECTIVE: To determine the predictors of lympho-vascular space invasion (LVSI) in endometrial cancers which contain mucinous carcinomatous histology. MATERIALS AND METHODS: Clinical and histopathological data of endometrial carcinomas with a mucinous carcinomatous component diagnosed between January 2007 and January 2014 at the Gynecologic Oncology Department of Zekai Tahir Burak Women's Health Education and Research Hospital were reviewed retrospectively. RESULTS: Twelve patients (25.5%) were positive for LVSI and 35 (74.5%) patients were negative. Patients with LVSI were mostly staged higher than 1A. Mean age, BMI and parity were not significantly different between patient groups. Larger tumor diameter (>=2 cm) (p=0.04) and elevated Ca125 and Ca-19.9 (p=0.01) levels were significant for predicting LVSI. We also found >1/2 myometrial invasion (p<0.001), cervical stromal involvement (p=0.002) and higher grade (2-3) (p=0.001) significant for predicting LVSI. In multivariate analysis we found only grade significant for predicting LVSI. CONCLUSIONS: Especially grade of tumor is a crucial factor for determining LVSI in endometrial cancers with mucinous carcinomatous components. PMID- 26028081 TI - Identification of specific gene modules in mouse lung tissue exposed to cigarette smoke. AB - BACKGROUND: Exposure to cigarette may affect human health and increase risk of a wide range of diseases including pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), asthma, lung fibrosis and lung cancer. However, the molecular mechanisms of pathogenesis induced by cigarettes still remain obscure even with extensive studies. With systemic view, we attempted to identify the specific gene modules that might relate to injury caused by cigarette smoke and identify hub genes for potential therapeutic targets or biomarkers from specific gene modules. MATERIALS AND METHODS: The dataset GSE18344 was downloaded from the Gene Expression Omnibus (GEO) and divided into mouse cigarette smoke exposure and control groups. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to construct a gene co-expression network for each group and detected specific gene modules of cigarette smoke exposure by comparison. RESULTS: A total of ten specific gene modules were identified only in the cigarette smoke exposure group but not in the control group. Seven hub genes were identified as well, including Fip1l1, Anp32a, Acsl4, Evl, Sdc1, Arap3 and Cd52. CONCLUSIONS: Specific gene modules may provide better understanding of molecular mechanisms, and hub genes are potential candidates of therapeutic targets that may possible improve development of novel treatment approaches. PMID- 26028082 TI - Lympho-vascular space invasion indicates advanced disease for uterine papillary serous tumors arising from polyps. AB - BACKGROUND: Uterine papillary serous tumors are rarely seen and behave aggressively. Our aim was to evaluate uterine papillary serous tumors arising from polyps. MATERIALS AND METHODS: Clinicopathological data of patients with uterine serous cancer arising from a polyp at the Gynecological Oncology Department of Zekai Tahir Burak Women's Health Education and Research Hospital were reviewed retrospectively. RESULTS: We analyzed patients according to FIGO 2009 staging system as stage 1A and higher than stage 1A (3 and 6, respectively). All the patients were postmenopausal. Mean CA-125, CA-19.9 and CA15.3 levels were elevated in higher than stage 1A group. However we did not find a statistical difference between age, parity, polyp size, CA-125, CA-15.3, CA-19.9 and CEA levels. Lympho-vascular space invasion (LVSI) showed predictivity for advanced disease (p=0.025). CONCLUSIONS: The histopathologic nature of uterine serous carcinoma is a unique entity. LVSI is a prognosticator for defining an advanced stage uterine papillary tumor. PMID- 26028083 TI - Anxiety and pain in surgically treated breast cancer patients. AB - The aim of the study was to evaluate the level of anxiety and pain in women with breast cancer. Patients who had been treated with modified radical mastectomy or breast conserving surgery were included. Data were gathered using the state-trait anxiety inventory and the visual analog scale. The pain levels and analgesic consumption of the patients were evaluated after surgery. The study sample consisted of 150 women. The mean age of the participants was 50.54+/-10.02. Most of the patients (58%) received breast conserving surgery. The mean state anxiety score was 44.74+/-11.91, and the mean trait anxiety score was 48.78+/-9.48 before surgery. The mean pain level on the first day following surgery was 3.26+/-1.91 and analgesic consumption was 2.98+/-1.08. There was no correlation between patient pain and anxiety levels. There was very slightly positive correlation between trait anxiety and total analgesic consumption. Assessing the levels of anxiety in breast cancer patients before surgery may contribute to the determination of postoperative pain. PMID- 26028084 TI - Eyelid tumors: clinical data from an eye center in Ankara, Turkey. AB - INTRODUCTION: The aim of the study was to explore the distribution of eyelid tumors in Ankara, the capital city of Turkey, from a histopathological point of view. MATERIALS AND METHODS: Medical records of 1,502 patients who had eyelid surgery because of tumoral lesions were retrospectively reviewed after obtaining institutional review board approval. A total of 1,541 lesions with histopathologic diagnosis were included. Inflammatory tumoral lesions were excluded. The lesions were categorized into three groups according to the origin: epidermal, adnexal tumors and 'others', including melanocytic, neural and vascular lesions. RESULTS: Of the total of 1,541, 908 lesions were epidermal in origin. Only 22 (1.5%) were malignant, and 6.0% was premalignant lesions such as actinic keratosis and Bowen's disease. Twenty-one of 22 malignant lesions were basal cell carcinoma. There was only one patient with squamous cell carcinoma and no sebaceous cell carcinoma. Among the benign tumors (92.5%), squamous papilloma was the most frequent (21.8% of all lesions). The other frequent lesions were nevus (17.6%), seborrheic keratosis (17.3%), hydrocystomas (10.6%), xanthelasma (7.6%) and epidermal cysts (7.2%). CONCLUSIONS: The results of this study are in accordance with published literature. The absence of sebaceous cell carcinomas needs to be stressed. PMID- 26028085 TI - Expression of Vimentin and Ki-67 Proteins in Cervical Squamous Cell Carcinoma and their Relationships with Clinicopathological Features. AB - OBJECTIVES: To investigate the expression of vimentin and Ki-67 proteins in cervical squamous cell carcinoma (CSCC) and their relationships with patient clinicopathological features. MATERIALS AND METHODS: Fifty-seven CSCC samples archived in Department of Pathology in the First Affiliated Hospital of Wenzhou Medical University were selected. The expression of vimentin and Ki-67 proteins in CSCC tissue were detected using immunohistochemical SP method, and correlations between them and their relationships with clinicopathological features were analyzed. RESULTS: Among 57 CSCC tissues, there were 43 with positive expression of Vimentin, and the positive rate was 75.4%; there were 57 cases with positive expression of Ki-67, and the positive rate came up to 100.0%. The results of Pearson correlation analysis displayed that the expression of vimentin had a significantly-positive correlation with Ki-67 in CSCC tissue (r=0.984, co0.000). The expression of both Ki-67 and vimentin was intimately associated with the presence or absence of local invasion and lymph node metastasis as well as differentiated degrees of the tumor (P=0.003, 0.017, 0.000; P=0.001, 0.008, 0.003) instead of the age, tumor size and clinical staging (P>0.05). CONCLUSIONS: Epithelial-mesenchymal transition (EMT) tends to appear in poorly-differentiated CSCC tissue, and the up-regulation of vimentin expression is accompanied by high expression of Ki-67, suggesting that invasion and metastasis readily occur in these tumor cells. PMID- 26028086 TI - Suppression of Inflammatory Responses by Black Rice Extract in RAW 264.7 Macrophage Cells via Downregulation of NF-kB and AP-1 Signaling Pathways. AB - Anthocyanin, a phenolic compound, has been reported to have an anti-inflammatory effect against lipopolysaccharide (LPS) induced changes in immune cells. However, little is known about the molecular mechanisms underlying its anti-inflammatory effects. Few research studies have concerned the anti-inflammation properties of colored rice extract as a functional material. Therefore, the purpose of this study was to examine anti-inflammatory effects of the polar fraction of black rice whole grain extracts (BR-WG-P) that features a high anthocyanin content. Our results showed that BR-WG-P significantly inhibited LPS-induced pro- inflammatory mediators, including production of NO and expression of iNOS and COX-2. In addition, secretion of pro-inflammatory cytokines including TNF-alpha and IL-6 was also significantly inhibited. Moreover, BR-WG-P and anthocyanin inhibited NF kB and AP-1 translocation into the nucleus. BR-WG-P also decreased the phosphorylation of ERK, p38 and JNK in a dose dependent manner. These results suggested that BR-WG-P might suppress LPS-induced inflammation via the inhibition of the MAPK signaling pathway leading to decrease of NF-kB and AP-1 translocation. All of these results indicate that BR-WG-P exhibits therapeutic potential associated with the anthocyanin content in the extract for treating inflammatory diseases associated with cancer. PMID- 26028087 TI - Comparison of Effects of Hemoglobin Levels Upon Tumor Response among Cervical Carcinoma Patients Undergoing Accelerated Hyperfractionated Radiotherapy versus Cisplatin Chemoradiotherapy. AB - PURPOSE: Blood hemoglobin levels are known to influence response to radiotherapy. This retrospective analysis compared the effect of hemoglobin levels upon response to radiation among patients treated with radiation alone (by accelerated hyperfractionated radiotherapy) versus those treated with concurrent cisplatin chemoradiotherapy. MATERIALS AND METHODS: Among patients treated for locally advanced carcinoma of the cervix (LACC) during 2009-10, a total of 60 fulfilled the eligibility criteria. In this time frame, external beam radiotherapy was delivered with either concurrent chemoradiotherapy (CRT, n=31) (45 Gy over 25 fractions, with weekly cisplatin at 40 mg/m2), or with accelerated hyperfractionated radiotherapy (AHRT, n=29) (20 Gy over 10 daily fractions over the first two weeks, followed by 30 Gy over 20 fractions over the next two weeks, with two fractions of 1.5 Gy per day, without the use of chemotherapy). Mean weekly hemoglobin (MWH) levels of all patients were calculated as the arithmetic means of weekly recorded blood hemoglobin levels. As per MWH, patients in both of the AHRT or the CRT groups were classified into two subgroups- those with MWH between 10-10.9 g/dL, or with MWH>11 g/dL. Complete response (CR) to external beam RT phase (prior to brachytherapy) was declared after clinical examinations and computed tomography. The CR rate was noted for both MWH sub-groups within each of the AHRT and CRT groups. RESULTS: Within the AHRT group, patients with MWH>11 g/dL had a much better CR rate in comparison to those with MWH:10-10.9 g/dL (80% vs. 21.1%) which was statistically significant (p 0.0045). Within the CRT group, there was no significant difference in the outcomes within the MWH>11 g/dL and MWH:10-10.9 g/dL sub-groups ( CR rates of 80% vs. 61.9%, p=0.4285). CONCLUSIONS: The importance of maintaining a minimum hemoglobin level of 11 g/dL during RT is much greater for patients treated with RT alone, than for patients treated with concurrent chemoradiotherapy. Enhanced haemoglobin levels during RT may to an extent negate the ill-effects that may otherwise arise due to non-use of concurrent chemotherapy. PMID- 26028088 TI - No Association between the CCR5Delta32 Polymorphism and Sporadic Esophageal Cancer in Punjab, North-West India. AB - BACKGROUND: Chemokines and their receptors influence carcinogenesis and cysteine cysteine chemokine receptor 5 (CCR5) directs spread of cancer to other tissues. A 32 base pair deletion in the coding region of CCR5 that might alter the expression or function of the protein has been implicated in a variety of immune mediated diseases. The action of antiviral drugs being proposed as adjuvant therapy in cancer is dependent on CCR5 wild type status. In the present study, distribution of CCR5Delta32 polymorphism was assessed in North Indian esophageal cancer patients to explore the potential of using chemokine receptors antagonists as adjuvant therapy. MATERIALS AND METHODS: DNA samples of 175 sporadic esophageal cancer patients (69 males and 106 females) and 175 unrelated healthy control individuals (69 males and 106 females) were screened for the CCR5Delta32 polymorphism by direct polymerase chain reaction (PCR). RESULTS: The frequencies of wild type homozygous (CCR5/CCR5), heterozygous (CCR5/Delta32) and homozygous mutant (Delta32/Delta32) genotypes were 96.0 vs 97.72%, 4.0 vs 1.71% and 0 vs 0.57% in patients and controls respectively. There was no difference in the genotype and allele frequencies of CCR5Delta32 polymorphism in esophageal cancer patients and control group. CONCLUSIONS: The CCR5Delta32 polymorphism is not associated with esophageal cancer in North Indians. As the majority of patients express the wild type allele, there is potential of using antiviral drug therapy as adjuvant therapy. PMID- 26028089 TI - Pap Smear Combined with HPV Testing: A Reasonable Tool for Women with High-grade Cervical Intraepithelial Neoplasia Treated by LEEP. AB - BACKGROUND: To evaluate HPV testing by Hybrid Capture II (HCII) in conjunction with cytology in detecting the residual/recurrence disease after treatment of high-grade cervical intraepithelial neoplasia (CIN II-III) with loop electrosurgical excision procedure (LEEP). MATERIALS AND METHODS: A retrospective review of 158 patients with histologically confirmed CIN II-III who underwent LEEP between January 2011 and October 2012 was conducted. Post-treatment control was scheduled at the 3rd, 6th, 12th and 18th month. All patients were followed up by Pap smear and HR-HPV genotype and viral load testing. RESULTS: Pre-treatment, HR-HPV DNA, was detected in all specimens of the patients. At follow-up, 25 patients were diagnosed as the residual/recurrent disease during the FU visit, among whom, 16 patients with positive margin: 13 patients (52%) with HR-HPV DNA+/cytology+, 2 patients (8%) with HR-HPV DNA+/cytology-, 1 patient (4%) with cytology+/ HR-HPV DNA-; 9 patients with clean margin--5 patients (55.6%) with HR HPV DNA+/cytology+; 2 patients (22.2%) with HR- HPV DNA+/cytology-, 2 patients (22.2%) with cytology+/HR-HPV DNA-. None of them persisting HR-HPV DNA-/cytology- with positive or negative margin was identified as the residual/recurrent disease. The majority of residual/recurrent disease was detected at the 12th and 18th month FU, and there was almost no difference in the sensitivity and negative predictive value (NPV) between at the 3rd month and the 6th month FU visits. 14 residual/recurrence disease (14/46:30.4%) had pre-treatment high viral load (>5,000 RUL/PC) and 11 (11/112, 9.8%) with pre-treatment low viral load, P<0.05. CONCLUSIONS: (1) The persistence HR-HPV DNA is the root cause of the residual/recurrent disease for the women treated for high-grade CIN; the pre treatment viral load and margin can be seen as the predictor. (2) The FU visit beginning at the 6th month post-treatment and lasting at least 24 months with the combination of cytology and HPV testing. (3) Patients with high pre-treatment HPV load, which is considered as one risk of developing the residual/recurrent disease, should be paid more attention (especially above 500 RUL/PC) to by clinicians. PMID- 26028090 TI - Significance of Rumex vesicarius as anticancer remedy against hepatocellular carcinoma: a proposal-based on experimental animal studies. AB - Rumex vesicarius is an edible herb distributed in Egypt and Saudi Arabia. The whole plant has significant value in folk medicine and it has been used to alleviate several diseases. Hepatocellular carcinoma (HCC), the major primary malignant tumor of the liver, is one of the most life-threatening human cancers. The goal of the current study was to explore the potent role of Rumex vesicarius extract against HCC induced in rats. Thirty adult male albino rats were divided into 3 groups: (I): Healthy animals received orally 0.9% normal saline and served as negative control group, (II): HCC group in which rats were orally administered N-nitrosodiethylamine NDEA, (III): HCC group treated orally with R. vesicarius extract in a dose of 400 mg/kg b.wt daily for two months. ALT and AST, ALP and gamma-GT activities were estimated. CEA, AFP, AFU, GPC-3, Gp-73 and VEGF levels were quantified. Histopathological examination of liver tissue sections was also carried out. The results of the current study showed that the treatment of the HCC group with R. vesicarius extract reversed the significant increase in liver enzymes activity, CEA, AFP, AFU, glypican 3, golgi 73 and VEGF levels in serum as compared to HCC-untreated counterparts. In addition, the favorable impact of R. vesicarius treatment was evidenced by the marked improvement in the histopathological features of the liver of the treated group. In conclusion, the present experimental setting provided evidence for the significance of R. vesicarius as anticancer candidate with a promising anticancer potential against HCC. The powerful hepatoprotective properties, the potent antiangiogenic activity and the effective antiproliferative capacity are responsible for the anticancer effect of this plant. PMID- 26028091 TI - Dentatin from Clausena excavata Induces Apoptosis in HepG2 Cells via Mitochondrial Mediated Signaling. AB - Hepatocellular carcinoma (HCC) is a primary liver cancer with high global incidence and mortality rates. Current candidate drugs to treat HCC remain lacking and those in use possess undesirable side effects. In this investigation, the antiproliferative effects of dentatin (DTN), a natural coumarin, were evaluated on HepG2 cells and DTN's probable preliminary molecular mechanisms in apoptosis induction were further investigated. DTN significantly (p<0.05) suppressed proliferation of HepG2 cells with an IC50 value of 12.0 MUg/mL, without affecting human normal liver cells, WRL-68 (IC50>50 MUg/mL) causing G0/G1 cell cycle arrest via apoptosis induction. Caspase colorimetric assays showed markedly increased levels of caspase-3 and caspase-9 activities throughout the treatment period. Western blotting of treated HepG2 cells revealed inhibition of NF-kappaB that triggers the mitochondrial-mediated apoptotic signaling pathway by up-regulating cytoplasmic cytochrome c and Bax, and down-regulating Bcl-2 and Bcl xL. The current findings suggest DTN has the potential to be developed further as an anticancer compound targeting human HCC. PMID- 26028092 TI - Could the Breast Prognostic Biomarker Status Change During Disease Progression? An Immunohistochemical Comparison between Primary Tumors and Synchronous Nodal Metastasis. AB - BACKGROUND: Prognostic biomarkers in breast cancer are routinely investigated in the primary tumors to guide further management. However, it is proposed that the expression may change during the disease progression, and may result in a different immune profile in the metastatic nodes. This work aimed to investigate the expression of breast prognostic biomarkers in primary tumors and in its axillary nodal metastasis, to estimate the possible discordant expression. MATERIALS AND METHODS: 60 paired primary and axillary nodal metastasis samples were collected from patients with primary breast cancer with positive nodal deposits, diagnosed at the Maadi Military Hospital, Cairo, Egypt, during the year 2013. ER, PR and HER2 expression was assessed by immunohistochemistry in all samples RESULTS: 48.3% of the included cases showed concordant results for both ER and PR receptors between the primary tumor and its nodal metastasis while 51.7% showed discordant results and the discordance level was statistically significant. On the other hand, 70% of the cases showed concordant Her2 results between the primary tumors and the nodal deposits, 30% showed discordant results and the difference was significant. CONCLUSIONS: The study indicated that the discordance in ER and PR receptor expression between the primary breast tumor and their nodal metastasis may be significant. The possible switch in the biomarker status during the disease progression is worth noting and may change the patient therapeutic planning. So, whether the treatment selection should be based on biomarkers in the lymph node is a topic for further studies and future clinical trials. PMID- 26028093 TI - Comparison between Radiological and Invasive Diagnostic Modalities in Diagnosis of Breast Cancer. AB - BACKGROUND: Breast cancer is the most common cause of deaths of cancer in women. Nowadays, following completion of imaging methods, mainly fine needle aspiration biopsy (FNAB) and core biopsy methods have been used for establishing cytopathological diagnosis although discussions regarding superiority continue. MATERIALS AND METHODS: Those with a complaint of "mass in breast" along with those diagnosed to have a mass as a result of routine physical examination among all patients applying to our clinic between 01.01.2009 and 31.12.2011 were retrospectively assessed. Totals of 146 and 64 patients with complete radiological observation who had undergone FNAB and core biopsies, respectively, were evaluated. Postoperative pathological results of patients of both groups receiving surgery were also taken into consideration. All results were compared in terms of false positivity/negativity, sensitivity/specifity, surgery types and distribution of postoperative results with regard to diagnoses along with those of malignant/benign masses with regard to quadrants determined. RESULTS: Diagnostic malignancy power of mammographic BIRADS classification was 87.3%. However, the value was 75% in the core biopsy group. Sensitivity and specifity following comparison of FNAB and postoperative pathology results of those receiving surgery were 85.4% and 92.9% while they were 93.5% and 100% in the core biopsy group. Diagnostic malignancy power, calculated by determining AUC in ROC analysis, of FNAB was 89.1% while that of core biopsy was 96.7%. CONCLUSIONS: It was shown that core biopsy is superior to FNAB in terms of sensitivity, specificity and accurate histopathological classification. However; quick, cheap and basic diagnosis by means of FNAB should not be ignored. Sensitivity of FNAB is rather high in experienced hands and furthermore it would be expected to be lower than with core biopsy. PMID- 26028094 TI - Effect of Cisplatin on the Frequency and Immuno-inhibitory Function of Myeloid derived Suppressor Cells in A375 Melanoma Model. AB - BACKGROUND: To investigate the change of frequency and immuno-inhibitory function of myeloid-derived suppressor cells (MDSCs) after treatment of cisplatin (DDP) in A375 human melanoma model. MATERIALS AND METHODS: BALB/c nude mice were inoculated with A375 cells to establish the human melanoma model and randomly divided into control group given normal saline (NS) and experimental group treated with DDP (5 mg/ kg). The percentages of MDSCs in the tumor tissue and peripheral blood after DDP treatment were detected by flow cytometry. The proliferation and interferon-gamma (IFN-gamma) secretion of T cells co-cultured with MDSCs were analyzed through carboxyfluorescein succinimidyl ester (CFSE) labeling assay and enzyme-linked immunospot (ELISPOT) assay, respectively. RESULTS: In A375 human melanoma model, DDP treatment could significantly decrease the percentage of MDSCs in the tumor tissue, but exerted no effect on the level of MDSCs in peripheral blood. Moreover, DDP treatment could attenuate the immuno inhibitory function of MDSCs. T cells co-cultured with DDP-treated MDSCs could dramatically elevate the proliferation and production of INF-gamma. CONCLUSIONS: DDP can decrease the frequency and attenuate immuno-inhibitory function of MDSCs in A375 melanoma model, suggesting a potential strategy to augment the efficacy of combined immunotherapy. PMID- 26028095 TI - Oral squamous cell carcinoma and associated risk factors in Jazan, Saudi Arabia: a hospital based case control study. AB - BACKGROUND: Oral cancer is the third most common malignancy in Saudi Arabia, the highest incidence of which is reported from Jazan province. The objective of this study was to evaluate the association of various locally used substances, especially shamma, with oral cancer in the Jazan region of Saudi Arabia. MATERIALS AND METHODS: A hospital-based case-control study was designed and patient records were scanned for histologically confirmed oral cancer cases. Forty eight patients who were recently diagnosed with oral cancer were selected as cases. Two healthy controls were selected for each observed case and they were matched with age (+/-5 years) gender and location. Use of different forms of tobacco such as cigarettes, pipe-smoking and shamma (smokeless- tobacco) was assessed. Khat, a commonly used chewing substance in the community was also included. Descriptive analysis was first performed followed by multiple logistic regression (with and without interaction) to derive odds ratios (ORs) and 95% confidence interval (CIs). RESULTS: Mean age of the study sample (56% males and 44% females) was 65.3 years. Multinomial regression analysis revealed that shamma use increased the odds of developing oral cancer by 29 times (OR=29.3; 10.3 83.1). Cigarette (OR=6.74; 2.18-20.8) was also seen to have an effect. With the interaction model the odds ratio increased significantly for shamma users (OR=37.2; 12.3-113.2) and cigarette smokers (OR=10.5; 2.88-3.11). Khat was observed to have negative effect on the disease occurrence when used along with shamma (OR=0.01; 0.00-0.65). CONCLUSIONS: We conclude that shamma, a moist form of smokeless tobacco is a major threat for oral cancer occurrence in the Jazan region of Saudi Arabia. This study gives a direction to conduct further longitudinal studies in the region with increased sample size representing the population in order to provide more substantial evidence. PMID- 26028096 TI - Semi-quantitative exposure assessment of occupational exposure to wood dust and nasopharyngeal cancer risk. AB - Occupational exposure to wood dust is one cause of nasopharyngeal cancer (NPC); however, assessing this exposure remains problematic. Therefore, the objective of this study was to develop a semi-quantitative exposure assessment method and then utilize it to evaluate the association between occupational exposure to wood dust and the development of NPC. In addition, variations in risk by histology were examined. A case-control study was conducted with 327 newly diagnosed cases of NPC at the National Cancer Institute and regional cancer centers in Thailand with 1:1 controls matched for age, gender and geographical residence. Occupational information was obtained through personal interviews. The potential probability, frequency and intensity of exposure to wood dust were assessed on a job-by-job basis by experienced experts. Analysis was performed by conditional logistic regression and presented in odds ratio (ORs) estimates and 95% confidence intervals (CI). Overall, a non significant relationship between occupational wood dust exposure and NPC risk for all subjects was observed (ORs=1.61, 95%CI 0.99 2.59); however, the risk became significant when analyses focused on types 2 and 3 of NPC (ORs=1.62, 95%CI 1.03-2.74). The significant association was stronger for those exposed to wood dust for >10 year (ORs=2.26, 95%CI 1.10-4.63), for those with first-time exposure at age>25 year (ORs=2.07, 95%CI 1.08-3.94), and for those who had a high cumulative exposure (ORs=2.17, 95%CI 1.03-4.58) when compared with those considered unexposed. In conclusion, wood dust is likely to be associated with an increased risk of type 2 or 3 NPC in the Thai population. The results of this study show that semi-quantitative exposure assessment is suitable for occupational exposure assessment in a case control study and complements the information from self-reporting. PMID- 26028097 TI - Association of GSTP1 and RRM1 Polymorphisms with the Response and Toxicity of Gemcitabine-cisplatin Combination Chemotherapy in Chinese Patients with Non-small Cell Lung Cancer. AB - BACKGROUND: Previous studies showed that genetic polymorphisms of glutathione S transferase P1 (GSTP1) were involved in glutathione metabolism and genetic polymorphisms of ribonucleotide reductase (RRM1) were correlated with DNA synthesis. Here we explored the effects of these polymorphisms on the chemosensitivity and clinical outcome in Chinese non-small cell lung cancer (NSCLC) patients treated with gemcitabine-cisplatin regimens. MATERIALS AND METHODS: DNA sequencing was used to evaluate genetic polymorphisms of GSTP1 Ile105Val and RRM1 C37A-T524C in 47 NSCLC patients treated with gemcitabine cisplatin regimens. Clinical response was evaluated according to RECIST criteria after 2 cycles of chemotherapy and toxicity was assessed by 1979 WHO criteria (acute and subacute toxicity graduation criteria in chemotherapeutic agents). RESULTS: There was no statistical significance between sensitive and non sensitive groups regarding the genotype frequency distribution of GSTP1 Ile105Val polymorphism (p>0.05). But for RRM1 C37A-T524C genotype, sensitive group had higher proportion of high effective genotype than non-sensitive group (p=0.009). And according to the joint detection of GSTP1 Ile105Val and RRM1 C37A-T524C polymorphisms, the proportion of type A (A/A+high effective genotype) was significantly higher in sensitive group than in non-sensitive group (p=0.009). Toxicity showed no correlation with the genotypes between two groups (p>0.05). CONCLUSIONS: Compared with single detection of genetic polymorphisms of GSTP1 Ile105Val or RRM1 C37A-T524C, joint detection of both may be more helpful for patients with NSCLC to receive gemcitabine-cisplatin regimens as the first-line chemotherapy. Especially, genetic polymorphism of RRM1 is more likely to be used as an important biomarker to predict the response and toxicity of gemcitabine cisplatin combination chemotherapy in NSCLC. PMID- 26028098 TI - High Efficacy of Levofloxacin-Dexlansoprazole-Based Quadruple Therapy as a First Line Treatment for Helicobacter pylori Eradication in Thailand. AB - BACKGROUND: Levofloxacin is an effective medication for second line Helicobacter pylori (H. pylori) eradication. However, limited studies have approved its use as an effective antibiotic in first line therapy. Dexlansoprazole is a new PPI and lacks of evidence in support of a role in H. pylori eradication. This study was designed to evaluate efficacy of levofloxacin-dexlansoprazole-based quadruple therapy for H. pylori eradication in Thailand. MATERIALS AND METHODS: This prospective randomized control study was performed during June 2014 to December 2014. H. pylori infected gastritis patients were randomized to receive 7- or 14 day levofloxacin-dexlansoprazole based on quadruple therapy (levofloxacin 500 mg OD, dexlansoprazole 60 mg bid, clarithromycin MR 1000 mg OD, bismuth subsalicylate 1048 mg bid). CYP2C19 genotyping and antibiotic susceptibility tests were conducted for all patients. A 13C urea breath test was performed to confirm H. pylori eradication at least 4 weeks after treatment. RESULTS: A total of 100 patients were enrolled, comprising 44 males and 56 females (mean age of 52.6 years). Eradication rate by PP analysis was 85.7% (42/49) with the 7-day regimen and 98% (48/49) with the 14-day regimen (85.7% vs 98%; p-value=0.059). ITT analysis was 84% and 96% with 7- and 14-day regimens, respectively (84% vs 96%; p-value=0.092). Antibiotic susceptibility testing demonstrated 35.1% resistance to metronidazole, 18.3% to clarithromycin, and 13.5% to levofloxacin. CYP2C19 genotyping revealed 54.1% RM, 34.7% IM and 11.2% PM. The 14-day regimen provided 100% eradication in patients with clarithromycin or dual clarithromycin and metronidazole H. pylori resistant strains. Moreover, the eradication rate was 96.6% in patients with CYP2C19 genotype RM. CONCLUSIONS: The 14-day levofloxacin dexlansoprazole based quadruple therapy provides high H. pylori eradication regardless of CYP2C19 genotype, clarithromycin or dual clarithromycin and metronidazole resistant strains. This regimen could be use as an alternative first line therapy for H. pylori eradication in Thailand. PMID- 26028099 TI - Radical intermediate generation and cell cycle arrest by an aqueous extract of Thunbergia Laurifolia Linn. In human breast cancer cells. AB - Thunbergia Laurifolia Linn. (TL) is one of the most familiar plants in Thai traditional medicine that is used to treat various conditions, including cancer. However, the antitumor activity of TL or its constituents has never been reported at the molecular level to support the folklore claim. The present study was designed to investigate the antitumor effect of an aqueous extract of TL in human breast cancer cells and the possible mechanism(s) of action. An aqueous crude extract was prepared from dried leaves of TL. Folin-Ciocalteu colorimetric assays were used to determine the total phenolic content. Antiproliferative and cell cycle effects were evaluated in human breast adenocarcinoma MCF-7 cells by MTT reduction assay, cell growth inhibition, clonogenic cell survival, and flow cytometric analysis. Free radical generation by the extracts was detected using electron paramagnetic resonance spectroscopy. The exposure of human breast adenocarcinoma MCF-7 cells to a TL aqueous extract resulted in decreases in cell growth, clonogenic cell survival, and cell viability in a concentration-dependent manner with an IC50 value of 843 MUg/ml. Treatments with extract for 24 h at 250 MUg/ml or higher induced cell cycle arrest as indicated by a significant increase of cell population in the G1 phase and a significant decrease in the S phase of the cell cycle. The capability of the aqueous extract to generate radical intermediates was observed at both high pH and near-neutral pH conditions. The findings suggest the antitumor bioactivities of TL against selected breast cancer cells may be due to induction of a G1 cell cycle arrest. Cytotoxicity and cell cycle perturbation that are associated with a high concentration of the extract could be in part explained by the total phenolic contents in the extract and the capacity to generate radical intermediates to modulate cellular proliferative signals. PMID- 26028100 TI - Prognostic evaluation of tumor-stroma ratio in patients with early stage cervical adenocarcinoma treated by surgery. AB - BACKGROUND: The tumor-stroma ratio (TSR) represents the percentage of neoplastic cell components compared to the combined area of neoplastic cells and the surrounding tumor-induced stroma. A low TSR (predomination of stromal component) has been demonstrated to be an independent adverse prognostic factor in cancers of several organs. In cervical carcinoma patients, TSR has been evaluated in only one previous study with different histological types. The present study aimed to assess the prognostic value of TSR in early stage cervical cancer patients with adenocarcinoma histology only. MATERIALS AND METHODS: Histological slides of patients with early stage (IB-IIA) cervical adenocarcinoma who underwent surgical treatment between January 2003 and December 2011 were reviewed. Patients who had received preoperative chemotherapy were excluded. TSR was categorized as low (<50%) and high (>=50%). Correlations between TSR and clinicopathological variables were evaluated. Prognostic values of TSR and other variables were estimated using Cox's regression. RESULTS: Of 131 patients; 38 (29.0%) had low TSR and 93 (71.0%) had high TSR. The patients with low TSR had significantly higher proportions of deep cervical stromal invasion (outer third of wall, p=0.011; residual stroma less than 3 mm, p=0.008) and parametrial involvement (p=0.026). Compared to the patients with high TSR, those with low TSR tended to have lower 5-year disease-free survival rate (83.8% versus 88.9%) and overall survival rate (85.6% versus 90.3%), although the differences were not statistically significant. Low TSR was significantly associated with decreased overall survival in univariate analysis (HR 2.7; 95% CI 1.0-7.0; p=0.041), but not in multivariate analysis. TSR was not significantly associated with decreased disease-free survival. CONCLUSIONS: Low TSR is associated with decreased overall survival in patients with early stage cervical adenocarcinoma treated by surgery. However, it was not found to be an independent prognostic predictor in this study. PMID- 26028101 TI - In vitro Study of the Antagonistic Effect of Low-dose Liquiritigenin on Gemcitabine-induced Capillary Leak Syndrome in Pancreatic Adenocarcinoma via Inhibiting ROS- Mediated Signalling Pathways. AB - BACKGROUND: To investigate in-vitro antagonistic effect of low-dose liquiritigenin on gemcitabine-induced capillary leak syndrome (CLS) in pancreatic adenocarcinoma via inhibiting reactive oxygen species (ROS)- mediated signalling pathways. MATERIALS AND METHODS: Human pancreatic adenocarcinoma Panc-1 cells and human umbilical vein endothelial cells (HUVECs) were pre-treated using low-dose liquiritigenin for 24 h, then added into gemcitabine and incubated for 48 h. Cell viability, apoptosis rate and ROS levels of Panc-1 cells and HUVECs were respectively detected through methylthiazolyldiphenyl-tetrazoliumbromide (MTT) and flow cytometry. For HUVECs, transendothelial electrical resistance (TEER) and transcellular and paracellular leak were measured using transwell assays, then poly (ADP-ribose) polymerase 1 (PARP-1) and metal matrix proteinase-9 (MMP9) activity were assayed via kits, mRNA expressions of p53 and Rac-1 were determined through quantitative polymerase chain reaction (qPCR); The expressions of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and PARP-1 were measured via western blotting. RESULTS: Low-dose liquiritigenin exerted no effect on gemcitabine-induced changes of cell viability, apoptosis rate and ROS levels in Panc-1 cells, but for HUVECs, liquiritigenin (3 MUM) could remarkably elevate gemcitabine- induced decrease of cell viability, transepithelial electrical resistance (TEER), pro-MMP9 level and expression of ICAM-1 and VCAM-1 (p<0.01). Meanwhile, it could also significantly decrease gemcitabine-induced increase of transcellular and paracellular leak, ROS level, PARP-1 activity, Act-MMP9 level, mRNA expressions of p53 and Rac-1, expression of PARP-1 and apoptosis rate (p<0.01). CONCLUSIONS: Low-dose liquiritigenin exerts an antagonistic effect on gemcitabine-induced leak across HUVECs via inhibiting ROS-mediated signalling pathways, but without affecting gemcitabine-induced Panc-1 cell apoptosis. Therefore, low-dose liquiritigenin might be beneficial to prevent the occurrence of gemcitabine-induced CLS in pancreatic adenocarcinoma. PMID- 26028102 TI - Somatostatin receptor 2 and 5 expressions in gastroenteropancreatic neuroendocrine tumors in Turkey. AB - BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GNs) are slow growing and although their incidence has increased in recent years, they are relatively rarely seen. Somatostatin analogues are used in the treatment of GNs that express somatostatin receptor (SR). We aimed to investigate the expression of SR2 and SR5 in GNs. MATERIALS AND METHODS: In this study the expression of SR2 and SR5 was investigated immunohistochemically in 49 cases (26 males, 23 females) diagnosed and graded with GN according to the World Health Organization classification 2010. RESULTS: The percentage of SR2 staining was 91.0% in grade 1, 82.8% in grade 2 and 100% in grade 3. On the other hand, the percentage of SR5 staining was 81.8% % in grade 1, 60.0% in grade 2 and 0% in grade 3. According to the tumor localization, the percentages of SR2 expression were as follows: pancreas 85.7%, stomach 100%, small bowel 70%, appendix 85.7% and rectum 100%. The percentages of SR5 expression were: pancreas 61,9%, stomach 37.5%, small bowel 70%, appendix 71.5% and rectum 66.6%. There was a significant negative correlation between ki67 percentage and SR5 expression (r=-0.341, p=0.016). CONCLUSIONS: In this study, GNs were found to highly express SR2 and SR5. Although the expression of SR2 and SR5 changed according to tumor localization, the expression of SR2 was higher than the expression of SR5 in GN. There was a significant negative correlation between ki67 and SR5. Accordingly, SR5 may be a prognostic indicator of GN. PMID- 26028103 TI - Genetic Variation in Glutamate Carboxypeptidase II and Interaction with Dietary Natural Vitamin C May Predict Risk for Adenomatous Polyp Occurrence. AB - BACKGROUND: The C1561T variant of the glutamate carboxypeptidase II (GCPII) gene is critical for natural methylfolylpolyglutamte (methylfolate) absorption, and has been associated with perturbations in folate metabolism and disease susceptibility. However, little is known on C1561T-GCPII as a risk factor for colorectal cancer. Therefore, this study examined whether C1561T-GCPII influences folate metabolism and adenomatous polyp occurrence. MATERIALS AND METHODS: 164 controls and 38 adenomatous polyp cases were analysed to determine blood folate and plasma homocysteine (Hcy) level, dietary intake of natural methylfolate, synthetic pteroylglutamic acid (PteGlu), vitamin C and C1561T-GCPII genotype. RESULTS: In controls and cases, 7.3 and 18.4 percent of subjects respectively, were found to have the CT genotype, increasing the risk for adenomatous polyp occurrence 2.86 times (95% CI:1.37-8.0, p=0.035). Total dietary folate, methylfolate and PteGlu intake and the level of erythrocyte folate and plasma Hcy did not predict the occurrence of an adenomatous polyp. However, dietary natural vitamin C intake was associated with adenomatous polyp risk within C1561T-GCPII CT genotype subjects (p=0.037). CONCLUSIONS: The findings suggest that C1561T GCPII variation may be associated with risk for adenomatous polyp, and vitamin C may modify risk by interacting with the variant gene, its expression product and/or folate substrates. PMID- 26028104 TI - Expression pattern and prognostic significance of claudin 1, 4 and 7 in pancreatic cancer. AB - BACKGROUND: Tight junctions (TJs) organise paracellular permeability and they have an important role in epithelial and endothelial cell polarity and permanence of barrier function. It has been demonstrated that the Claudin family constitutes an important component of them. In this study, we assessed expression patterns of of Claudin1, 4 and 7 and whether they have any relation with prognosis in patients with pancreatic cancer. MATERIALS AND METHODS: Expression patterns of Claudin 1,4 and 7 were examined by immunohistochemistry in 25 patients with a histopathological diagnosis of pancreatic cancer using a semiquantitative scoring of the extent and intensity of staining. After grouping the staining scores as low (final score 0-2) and high (final score 3-9) the relation between expression of Claudin 1,4 and 7 and survival was evaluated. RESULTS: There was no significant relation between expression of Claudin 1,4 and 7 and gender and stage. No statistically significant relation was found between Claudin 1 and 4 expression and survival whereas a statistically significant relation was found between decrease in Claudin 7 expression and decrease in survival. CONCLUSIONS: Claudins have important functions other than their popular function known as adhesion. Supporting this hypothesis, we found a statistically significant relationship between increased Claudin 7 expression and increased survival time, and this suggests that Claudin 7 may exert different tumorigenic effects in pancreatic cancer other than its well- known adhesion effect. PMID- 26028105 TI - Analysis on clinical characteristics and influencing factors of patients with locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: To explore the independent prognostic factors for the recurrence/metastasis of patients with locoregionally advanced nasopharyngeal carcinoma (LANPC). MATERIALS AND METHODS: A total of 604 patients initially diagnosed as LANPC by pathohistology in Fujian Provincial Cancer Hospital were selected to analyze the relationship between the clinical pathological patterns, therapeutic protocols and clinical stages with the recurrence/metastasis of LANPC. RESULTS: The 1-, 3- and 5-year locoregionally recurrent rates of LANPC patients were 2.0%, 9.5% and 12.9% respectively, with average recurrent period being 78 months. Univariate analysis results indicated that clinical stages had certain influence on the recurrent period of LANPC patients. However, COX regression models showed that ages, genders and clinical stages were not the independent prognostic factors influencing the recurrence. The 1-, 3- and 5-year metastatic rates of LANPC patients were 6.6%, 17.5% and 18.8% respectively, with average metastatic period of 73 months. Univariate analysis results demonstrated that ages, N stages, clinical stages, locations of lymph node, retropharyngeal lymph node and extracapsular invasion of lymph node had certain influence on the metastatic period of LANPC patients. Additionally, further COX regression analysis results suggested that T stages, reduction protocols and extracapsular invasion of lymph node were the independent prognostic factors influencing the metastasis of patients with LANPC, in which T stages and extracapsular invasion of lymph node were the pestilent factors while reduction protocols the protective factor. CONCLUSIONS: Induction chemotherapy is beneficial to LANPC patients with initial treatment, and the metastatic rate decreases greatly after the application of reduction chemotherapy. PMID- 26028106 TI - Village Voices: Lessons about Processes for Disease Prevention from a Qualitative Study of Family Health Leaders in a Community in Northeastern Thailand. AB - BACKGROUND: Cancer is a primary source of concern in Thailand and other countries around the world, including the Asian-Pacific region. Evidence supports that an important contributing cause of cancer and other chronic illnesses such as stroke, diabetes, and hypertension is excessive alcohol consumption. Studies conducted in Thailand reveal a worrisome rise in the number of new and regular drinkers in communities. Therefore, actions for primary, secondary and tertiary prevention of problem drinking are necessary. In recent years nurses in North East Thailand have been developing and implementing the Khon Kaen Family Health Nursing model to embed disease prevention in communities through the actions of family health nurses and local family health leaders. AIM: The aim of this qualitative research was to better understand the experiences of the local family health leaders using this model and to synthesize lessons learned. MATERIALS AND METHODS: As part of a participatory action research approach involving analysis of focus group discussions and individual interviews, the experiences of 45 family health leaders were synthesized. RESULTS: Four main themes were identified, namely: i) Family first: role modeling beginning at the personal and family level. ii) Local leverage: using village community forums to reduce alcohol drinking. iii) Gentle growth: making the first step and treading gently; and iv) Respect, Redemption, Rehabilitation: valuing the person to re-integrate them in the village society. CONCLUSIONS: As alcohol consumption in the village declined significantly following the prevention program, these findings illuminate how low-tech integrated prevention approaches may be very useful, particularly in rural communities. The lessons learned may have relevance not only in Thailand but in other countries seeking to prevent and mitigate behavior that conduces to diseases such as cancer. PMID- 26028107 TI - Increased micronucleus frequency in peripheral blood lymphocytes contributes to cancer risk in the methyl isocyanate-affected population of Bhopal. AB - The Bhopal gas tragedy involving methyl isocyanate (MIC) is one of the most horrific industrial accidents in recent decades. We investigated the genotoxic effects of MIC in long-term survivors and their offspring born after the 1984 occurrence. There are a few cytogenetic reports showing genetic damage in the MIC exposed survivors, but there is no information about the associated cancer risk. The same is true about offspring. For the first time, we here assessed the micronucleus (MN) frequency using cytokinesis-blocked micronucleus (CBMN) assay to predict cancer risk in the MIC-affected population of Bhopal. A total of 92 healthy volunteers (46 MIC- affected and 46 controls) from Bhopal and various regions of India were studied taking gender and age into consideration. Binucleated lymphocytes with micronuclei (BNMN), total number of micronuclei in lymphocytes (MNL), and nuclear division index (NDI) frequencies and their relationship to age, gender and several lifestyle variabilities (smoking, alcohol consumption and tobacco-chewing) were investigated. Our observations showed relatively higher BNMN and MNL (P<0.05) in the MIC-affected than in the controls. Exposed females (EF) exhibited significantly higher BNMN and MNL (P<0.01) than their unexposed counterparts. Similarly, female offspring of the exposed (FOE) also suffered higher BNMN and MNL (P<0.05) than in controls. A significant reduction in NDI (P<0.05) was found only in EF. The affected group of non-smokers and non-alcoholics featured a higher frequency of BNMN and MNL than the control group of non-smokers and non-alcoholics (P<0.01). Similarly, the affected group of tobacco chewers showed significantly higher BNMN and MNL (P<0.001) than the non-chewers. Amongst the affected, smoking and alcohol consumption were not associated with statistically significant differences in BNMN, MNL and NDI. Nevertheless, tobacco-chewing had a preponderant effect with respect to MNL. A reasonable correlation between MNL and lifestyle habits (smoking, alcohol consumption and tobacco-chewing) was observed only in the controls. Our results suggest that EF and FOE are more susceptible to cancer development, as compared to EM and MOE. The genotoxic outcome detected in FOE reflects their parental exposure to MIC. Briefly, the observed cytogenetic damage to the MIC-affected could contribute to cancer risk, especially in the EF and FOE. PMID- 26028108 TI - Prognostic Significance of Preoperative Serum Alpha- fetoprotein in Hepatocellular Carcinoma and Correlation with Clinicopathological Factors: a Single-center Experience from China. AB - OBJECTIVES: To investigate the prognosis significance of preoperative serum alpha fetoprotein (AFP) and the correlation with clinicopathological factors of hepatocellular carcinoma (HCC) patients who underwent hepatectomy. MATERIALS AND METHODS: Clinicopathological data of retrospective analysis were collected for 251 HCC patients undergoing hepatectomy in this study. According to preoperative AFP level, patients were categorized into AFP-negative (0-20 ng/mL) and AFP positive (>20 ng/mL) groups for Kaplan-Meier analysis and Cox proportional hazard regression modeling. RESULTS: The results demonstrated that increased AFP was associated with longer prothrombin time (PTs), liver capsule invasion, low grade differentiation, and late Barcelona Clinic Liver Center (BCLC) stage. Moreover, the female patients had a greater prevalence of increased preoperative AFP than male patients [284.8 (3.975-3167.5) vs (3.653-140.65); Z-2.895, p=0.004]. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 78.1, 57.5, and 40.6 % in the AFP-negative group and 61.8, 37.7, and 31.4 %, respectively, in the AFP positive group (log-rank test 8.312, p=0.004). The 1-, 3-, and 5-year overall survival (OS) rates were 94.4, 83.8, and 62.3% in the AFP-negative group and 87.2, 60.0, and 36.7%, respectively, in the AFP-positive group. The difference was statistically significant (log-rank test, 16.884, p=0.000). Cox proportional hazards model identified preoperative AFP to be an independent prognostic predictor of overall survival. CONCLUSIONS: Preoperative serum AFP is an independent predictor of prognosis among HCC patients following surgical resection. Female patients have a higher preoperative AFP than their male counterparts. PMID- 26028109 TI - Awareness and Knowledge of Oral Cancer and Potentially Malignant Oral Disorders among Dental Patients in Far North Queensland, Australia. AB - BACKGROUND: Public awareness/knowledge on oral and pharyngeal cancer (OPC), potentially malignant disorders (PMODs) and their risk factors is crucial for prevention and early detection of OPC and PMODs. Yet, there are no published data available on the awareness and knowledge of OPC and PMODs among people living in Far North Queensland, Australia. MATERIALS AND METHODS: This study was conducted as a cross sectional survey. A self-administered questionnaire was designed and consisted of relevant questions to ascertain socio-demographic information, awareness and knowledge of OPC, PMODs and risk factors and questions on participant's exposure to risk factors and dietary history were also included. Survey was carried out at the Dental Clinic of the James Cook University School of Dentistry (JCU Dental), Cairns, Australia. Subjects above the age of 20 years (n=366) were randomly selected during the period from 31st July to 6th September 2013 and questionnaire was distributed to complete while they are waiting for treatment. Data analysis was carried out using SPSS version 21 and the chi squared test was employed to compare groups. P<0.05 was considered statistically significant. RESULTS: The study revealed that 52.3% of the respondents were aware of the existence of OPC but only 19.0% were aware of PMODs. Of those who were aware of oral cancer, 92% agreed or strongly agreed that smoking is a strong risk factor for OPC. Similarly a relatively high proportion of the respondents agreed or strongly agreed that tobacco chewing (84%), tobacco chewing with areca nut (68%), chewing areca nut alone (51%) and exposure to actinic radiation (71%) as risk factors. However, the results for alcohol intake, age, and HPV infection were found to be relatively poor with proportions 33%, 34%, and 23% respectively. CONCLUSIONS: This study revealed an alarming lack of awareness and knowledge of OPC and PMODs. PMID- 26028110 TI - Quantitative Assessment the Relationship between p21 rs1059234 Polymorphism and Cancer Risk. AB - p21 is a cyclin-dependent kinase inhibitor, which can arrest cell proliferation and serve as a tumor suppressor. Though many studies were published to assess the relationship between p21 rs1059234 polymorphism and various cancer risks, there was no definite conclusion on this association. To derive a more precise quantitative assessment of the relationship, a large scale meta-analysis of 5,963 cases and 8,405 controls from 16 eligible published case-control studies was performed. Our analysis suggested that rs1059234 was not associated with the integral cancer risk for both dominant model [(T/T+C/T) vs C/C, OR=1.00, 95% CI: 0.84-1.18] and recessive model [T/T vs (C/C+C/T), OR=1.03, 95% CI: 0.93-1.15)]. However, further stratified analysis showed rs1059234 was greatly associated with the risk of squamous cell carcinoma of head and neck (SCCHN). Thus, larger scale primary studies are still required to further evaluate the interaction of p21 rs1059234 polymorphism and cancer risk in specific cancer subtypes. PMID- 26028111 TI - KRAS Mutation as a Biomarker for Survival in Patients with Non-Small Cell Lung Cancer, A Meta-Analysis of 12 Randomized Trials. AB - BACKGROUND: Because there is no clear consensus for the prognostic implication of KRAS mutations in patients with non-small cell lung cancer (NSCLC), we conducted a meta-analysis based on 12 randomized trials to draw a more accurate conclusion. MATERIALS AND METHODS: A systematic computer search of articles from inception to May 1, 2014 using the PubMed, EMBASE, and Cochrane databases was conducted. The enrollment of articles and extraction of data were independently performed by two authors. RESULTS: Our analysis was based on the endpoints overall survival (OS) and progression-free survival (PFS). Nine records (All for OS, 7 for PFS) comprising 12 randomized trials were identified with 3701 patients who underwent a test for KRAS mutations. In the analysis of the pooled hazard ratios (HRs) for OS (HR: 1.39; 95% confidence interval [CI] 1.23-1.56) and PFS (HR: 1.33; 95% CI 1.17-1.51), we found that KRAS mutations are related to poor survival benefit for NSCLC. According to a subgroup analysis stratified by disease stage and line of therapy, the combined HRs for OS and PFS coincided with the finding that the presence of a KRAS mutation is a dismal prognostic factor. However, the prognostic role of KRAS mutations are not statistically significant in a subgroup analysis of patients treated with chemotherapy in combination with cetuximab based on the endpoints OS (P=0.141) and PFS (P=0.643). CONCLUSIONS: Our results indicate that KRAS mutations are associated with inferior survival benefits for NSCLC but not for those treated with chemotherapies integrating cetuximab. PMID- 26028112 TI - Epidemiology of Nasopharyngeal Cancers in Iran: A 6-year Report. AB - BACKGROUND: Nasopharyngeal cancer is a disease with distinct ethnic and geographical distribution. The aim of this review was to describe the epidemiological characteristics of nasopharyngeal cancer in Iran from 2004 to 2009 because no systematic study has been performed to evaluate the trends of its incidence yet. MATERIALS AND METHODS: The data were derived from the databases of the National Cancer Data System Registry in the period of 2004-2009. Nasopharyngeal cancers were classified according to the International Classification of Diseases for Oncology. Incidence rates and trends were calculated and evaluated by gender, age decade, and histopathology types. RESULTS: A total of 1,637 nasopharyngeal cancers were registered in Iran from 2004 to 2009 giving an incidence of 0.38 per 100,000. The male-to-female ratio was 2.08:1. The trend of incidence was found to have increased, with a significant increase observed in males. Undifferentiated carcinoma was the most common histopathology type in all the age decades. CONCLUSIONS: Because the incidence of nasopharyngeal cancers in Iran has increased, especially in males, further studies are recommended for understanding of the etiological factors involved in the rise of the disease. PMID- 26028113 TI - Health-related quality of life of patients with intermediate hepatocellular carcinoma after liver resection or transcatheter arterial chemoembolization. AB - BACKGROUND: The aim of our present study was to compare quality of life (QoL) between intermediate-stage (BCLC-B) HCC patients who had undergone either liver resection or transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: A total of 102 intermediate-stage HCC patients participated in our study, including 58 who had undergone liver resection and 44 who had undergone TACE. Baseline demographic characteristics, tumor characteristics, and long-term outcomes, such as tumor recurrence, were compared and analyzed. QoL was assessed using the Short Form (SF)-36 health survey questionnaire with the mental and physical component scales (SF-36 MCS and PCS). This questionnaire was filled out at HCC diagnosis and 1, 3, 6, 12, 24 months after surgery. RESULTS: For the preoperative QoL evaluation, the 8 domains related to QoL were comparable between the two groups. The PCS and MCS scores were significantly decreased in both the TACE and resection groups at1 month after surgery, and this decrease was greater in the resection group. These scores were significantly lower in the resection group compared with the TACE group (P<0.05). However, these differences disappeared at 3 and 6 months following surgery. One year after surgery, the resection group showed much higher PCS scores than the TACE patients (P=0.018), and at 2 years after surgery, the PCS and MCS scores for the resection group were significantly higher than those for the TACE group (P<0.05). Eleven patients (19.0%) in the resection group and 17 (38.6%) in the TACE group suffered HCC recurrence (P<0.05). Univariate and multivariate analyses indicated that tumor recurrence (HR=1.211, 95%CI: 1.086-1.415, P=0.012) was a significant risk factor for poorpostoperative QoL in the HCC patients. CONCLUSIONS: Due to its effects on reducing HCC recurrence and improving long-term QoL, liver resection should be the first choice for the treatment of patients with intermediate-stage HCC. PMID- 26028114 TI - Paraoxonase 1 (PON1) Q192R Gene Polymorphism and Cancer Risk: A Meta-Analysis Based on 30 Publications. AB - Common genetic variation Q192R in the paraoxonase 1 (PON1) gene has been considered to be implicated in the development of many cancers. Nevertheless, results from the related studies were inconsistent. To elucidate the association, we performed a meta-analysis for 8,112 cases and 10,037 controls from 32 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association by STATA 12.0 software. Overall, we revealed that the PON1-192R allele was associated with a reduced risk of the overall cancers. Moreover, in the stratified analysis by cancer types (breast cancer, prostate cancer, brain cancer etc.), the results showed that PON1 192R allele was associated with a decreased risk in breast cancer (R vs Q: OR=0.605, 95% CI=0.378-0.967, Pheterogeneity=0.000; RR vs QQ: OR=0.494, 95% CI=0.275-0.888, Pheterogeneity=0.002; RQ vs QQ: OR=0.465, 95% CI=0.259-0.835, Pheterogeneity=0.000; and RR+RQ vs QQ: OR=0.485, 95% CI=0.274-0.857, Pheterogeneity=0.000), and associated with prostate cancer in homozygote (RR vs QQ: OR=0.475, 95% CI=0.251- 0.897, Pheterogeneity=0.001) and recessive models (RR vs RQ+QQ: OR=0.379, 95% CI=0.169-0.853, Pheterogeneity=0.000), while an increased risk was identified in lymphoma (R vs Q: OR=1.537, 95% CI=1.246-1.896, Pheterogeneity=0.944; RR vs QQ: OR=2.987, 95% CI=1.861-4.795, Pheterogeneity=0.350; RR+RQ vs QQ: OR=1.354, 95% CI=1.021-1.796, Pheterogeneity=0.824; and RR vs RQ+QQ: OR=2.934, 95% CI=1.869-4.605, Pheterogeneity=0.433), and an increased risk in prostate cancer under heterozygote comparison (RQ vs QQ: OR=1.782, 95% CI=1.077-2.950, Pheterogeneity=0.000) and dominant models (RR+RQ vs QQ: OR=1.281, 95% CI=1.044 1.573, Pheterogeneity=0.056). When subgroup analysis that performed by the control source (hospital based or population based), a decreased risk of the overall cancers was revealed by homozygote (RR vs QQ: OR=0.601, 95% CI=0.366 0.987, Pheterogeneity=0.000) and dominant models (RR vs RQ+QQ: OR=0.611, 95% CI=0.384-0.973, Pheterogeneity=0.000) in hospital based group. Stratifying by ethnicity, a significantly reduced risk of the overall cancers under allele contrast model (R vs Q: OR=0.788, 95% CI=0.626-0.993, Pheterogeneity=0.000) was uncovered in Caucasian. In summary, these findings suggested that PON1 Q192R polymorphism was associated with a reduced risk of the overall cancers, nevertheless, it might increase cancer susceptibility of prostate and lymphoma risk. Large well-designed epidemiological studies will be continued on this issue of interest. PMID- 26028115 TI - Effects of analgecine on oxaliplatin-induced neurotoxicity in patients with gastrointestinal cancer. AB - BACKGROUND: As the third generation of platinum-based antineoplastic agent aginst gastrointestinal cancer, oxaliplatin is considered to be associated with severe sensory neurotoxicity. Acorrding to previous studies, vitaminE, intravenous Ca/Mg and glutamine may partly reduce the incidence and severity of oxaliplatin-induced neurotoxicity. The aim of this study was to investigate the safety and efficacy of analgecine for preventing oxaliplatin-induced neurotoxicity in the patients with gastrointestinal tumors. METHOD: In this study, patients undergoing oxaliplatin-based chemotherapy were assigned to analgecine (experimental) group or control group. Analgecine 6ml was administered once a day for seven days from the day of oxaliplatin treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) was used to evaluate oxaliplatin-induced neurotoxicity. The incidence rates and grade of neurotoxicity of patients were assessed before and during (after four and eight cycles) treatment. RESULTS: Totally, 82 patients were enrolled in this study, 42 in experimental group and 40 in control group. The occurrence of each grade neurotoxicity in the experimental group was significantly lower than that in control group. The overall occurrence rate was 31% vs 55% (P=0.043) after 4 cycles and 52% vs 75% (P=0.050) after 8 cycles. CONCLUSION: Analgecine appears could be effective in reducing oxaliplatin-induced neurotoxicity and be applicated for patients with gastrointestinal tumors who would be treated with oxaliplatin-based chemotherapy. PMID- 26028116 TI - Inhibition of Transient Receptor Potential Melastain 7 Enhances Apoptosis Induced by TRAIL in PC-3 cells. AB - Transient receptor potential melastain 7 (TRPM7) is a bifunctional protein with dual structure of both ion channel and protein kinase, participating in a wide variety of diseases including cancer. Recent researches have reported the mechanism of TRPM7 in human cancers. However, the correlation between TRPM7 and prostate cancer (PCa) has not been well studied. The objective of this study was to investigate the potential the role of TRPM7 in the apoptosis of PC-3 cells, which is the key cell of advanced metastatic PCa. In this study, we demonstrated the influence and potential function of TRPM7 on the PC-3 cells apoptosis induced by TNF-related apoptosis inducing-ligand (TRAIL). The study also found a novel up regulated expression of TRPM7 in PC-3 cells after treating with TRAIL. Suppression of TRPM7 by TRPM7 non-specific inhibitors (Gd3+ or 2-aminoethoxy diphenylborate (2-APB) ) not only markedly eliminated TRPM7 expression level, but also increased the apoptosis of TRAIL-treated PC-3 cells, which may be regulated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway accompany with up-regulated expression of cleaved Caspase-3, (TRAIL receptor 1, death receptors 4) DR4, and (TRAIL-receptor 2, death receptors 5) DR5. Taken together, our findings strongly suggested that TRPM7 was involved in the apoptosis of PC-3 cells induced by TRAIL, indicating that TRPM7 may be applied as a therapeutic target for PCa. PMID- 26028117 TI - Effects of corneal irregular astigmatism on visual acuity after conventional and femtosecond laser-assisted Descemet's stripping automated endothelial keratoplasty. AB - PURPOSE: To compare short-term outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) using a graft prepared with either a femtosecond laser or a microkeratome. METHODS: Thirty-eight patients underwent DSAEK with grafts prepared with either a femtosecond laser (f-DSAEK; 21 eyes) or a microkeratome (m-DSAEK; 17 eyes). Visual acuity, endothelial cell density, regular astigmatism and irregular astigmatism were compared between the two groups preoperatively and at 1, 3, and 6 months post-operatively. Fourier analysis was conducted to calculate astigmatism of the anterior and posterior surfaces, and total cornea, using anterior segment optical coherence tomography (AS-OCT). RESULTS: Visual acuity (logMAR) improved from 1.20 +/- 0.60 to 0.43 +/- 0.25 after m-DSAEK (P < 0.001) and from 1.20 +/- 0.57 to 0.77 +/- 0.33 after f DSAEK (P = 0.0028) at 6 months following DSAEK. Visual acuity after m-DSAEK was significantly better than after f-DSAEK at 1, 3, and 6 months (P < 0.05). AS-OCT corneal images revealed greater irregularities on the posterior surfaces of f DSAEK grafts compared to m-DSAEK grafts. Irregular astigmatism of the total cornea and the posterior surface was significantly larger after f-DSAEK than after m-DSAEK, although there was no significant difference in irregular astigmatism of the anterior surface at 6 months. Postoperative visual acuity was significantly correlated with the postoperative irregular astigmatism of the total cornea (r = 0.6657 and P < 0.001) and the anterior (r = 0.416, P = 0.016) and posterior surfaces (r = 0.7046, P < 0.001). CONCLUSIONS: Visual outcomes after f-DSAEK were poor compared to conventional m-DSAEK due to an increase in irregular astigmatism caused by posterior surface irregularities. PMID- 26028118 TI - Switched photocurrent direction in Au/TiO2 bilayer thin films. AB - Switched photocurrent direction in photoelectrodes is a very interesting phenomenon and has demonstrated their potentials in important applications including photodiodes, phototransistors, light-driven sensors and biosensors. However, the design and mechanism understanding of such photoelectrodes remain challenging to date. Here we report a new phenomenon of sequence-driven the photocurrent direction on a simple bilayer structure of 5 nm thick Au and 10 nm TiO2 under visible-light irradiation. It is found that when Au layer are deposited as the outer layer on TiO2 coated fluorine doped tin oxide (FTO) substrate (designated as FTO/TiO2/Au), anodic photocurrent is obtained due to the band bending formed at the electrode-electrolyte interface. Interestingly, simply swapping the deposition sequence of Au and TiO2 leads to cathodic photocurrent on FTO/Au/TiO2 electrode. Characterization and calculations on the photoelectrode reveals that the photogenerated electrons can be easily trapped in the energy well formed between the band bending and the Schottky contact, which allows electronic tunnelling through the 1.6 nm thick space charge layer, resulting in a unique anodic to cathodic photocurrent conversion. The understanding of this new phenomenon can be important for designing new generation optoelectronic converting devices in a low-cost and facile manner. PMID- 26028119 TI - Coordination and fine motor control depend on Drosophila TRPgamma. AB - Motor coordination is broadly divided into gross and fine motor control, both of which depend on proprioceptive organs. However, the channels that function specifically in fine motor control are unknown. Here we show that mutations in trpgamma disrupt fine motor control while leaving gross motor proficiency intact. The mutants are unable to coordinate precise leg movements during walking, and are ineffective in traversing large gaps due to an inability in making subtle postural adaptations that are requisite for this task. TRPgamma is expressed in proprioceptive organs, and is required in both neurons and glia for gap crossing. We expressed TRPgamma in vitro, and found that its activity is promoted by membrane stretch. A mutation eliminating the Na(+)/Ca(2+) exchanger suppresses the gap-crossing phenotype of trpgamma flies. Our findings indicate that TRPgamma contributes to fine motor control through mechanical activation in proprioceptive organs, thereby promoting Ca(2+) influx, which is required for function. PMID- 26028121 TI - Purpura fulminans 10 years after contaminated cocaine use. PMID- 26028122 TI - Withdrawal from methadone in US prisons: cruel and unusual? PMID- 26028120 TI - Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial. AB - BACKGROUND: Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals' risk behaviours and engagement with post-release treatment programmes. METHODS: In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care--forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution's standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from incarceration and time to engagement with methadone maintenance treatment, by intention-to-treat and as treated analyses, which we established in a follow-up interview with the participants at 1 month after their release from incarceration. Our study paid for 10 weeks of methadone treatment after release if participants needed financial help. This trial is registered with ClinicalTrials.gov, number NCT01874964. FINDINGS: Between June 14, 2011, and April 3, 2013, we randomly assigned 283 prisoners to our study, 142 to continued methadone treatment, and 141 to forced withdrawal from methadone. Of these, 60 were excluded because they did not fit the eligibility criteria, leaving 114 in the continued-methadone group and 109 in the forced-withdrawal group (usual care). Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2.04, 95% CI 1.48 2.80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively. INTERPRETATION: Although our study had several limitations--eg, it only included participants incarcerated for fewer than 6 months, we showed that forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release. Continuation of methadone maintenance during incarceration could contribute to greater treatment engagement after release, which could in turn reduce the risk of death from overdose and risk behaviours. FUNDING: National Institute on Drug Abuse and the Lifespan/Tufts/Brown Center for AIDS Research from the National Institutes of Health. PMID- 26028123 TI - Mental disorder and long-term risk of mortality: 41 years of follow-up of a population sample in Stockholm, Sweden. AB - BACKGROUND: An increased mortality risk associated with mental disorder has been reported for patients, but there are few studies are based on random samples with interview-based psychiatric diagnoses. Part of the increased mortality for those with mental disorder may be attributable to worse somatic health or hazardous health behaviour - consequences of the disorder - but somatic health information is commonly lacking in psychiatric samples. This study aims to examine long-term mortality risk for psychiatric diagnoses in a general population sample and to assess mediation by somatic ill health and hazardous health behaviour. METHOD: We used a double-phase stratified random sample of individuals aged 18-65 in Stockholm County 1970-1971 linked to vital records. First phase sample was 32 186 individuals screened with postal questionnaire and second phase was 1896 individuals (920 men and 976 women) that participated in a full-day examination (participation rate 88%). Baseline examination included both a semi-structured interview with a psychiatrist, with mental disorders set according to the 8th version of the International Classification of Disease (ICD-8), and clinical somatic examination, including measures of body composition (BMI), hypertension, fasting blood glucose, pulmonary function and self-reported tobacco smoking. Information on vital status was obtained from the Total Population Register for the years 1970-2011. Associations with mortality were studied with Cox proportional hazard analyses. RESULTS: A total of 883 deaths occurred among the participants during the 41-year follow-up. Increased mortality rates were found for ICD-8 functional psychoses (hazard ratio, HR = 2.22, 95% confidence interval (95% CI): 1.15-4.30); psycho-organic symptoms (HR = 1.94, 95% CI: 1.31-2.87); depressive neuroses (HR = 1.71, 95% CI: 1.23-2.39); alcohol use disorder (HR = 1.91, 95% CI: 1.40-2.61); drug dependence (HR = 3.71, 95% CI: 1.80-7.65) and psychopathy (HR = 2.88, 95% CI: 1.02-8.16). Non-participants (n = 349) had mortality rates similar to participants (HR = 0.98, 95% CI: 0.81-1.18). In subgroup analyses of those with psychoses, depression or alcohol use disorder, adjusting for the potential mediators smoking and pulmonary function, showed only slight changes in the HRs. CONCLUSIONS: This study confirms the increased risk of mortality for several psychiatric diagnoses in follow-up studies on American, Finnish and Swedish population-based samples. Only a small part of the increased mortality hazard was attributable to differences in somatic health or hazardous health behaviour measured at baseline. PMID- 26028124 TI - In Vivo Collagen Remodeling in the Vascular Wall of Decellularized Stented Tissue Engineered Heart Valves. AB - BACKGROUND: Decellularized tissue-engineered heart valves (TEHVs) are under investigation as alternative for current heart valve prostheses with the potential to rapidly repopulate with cells within the body. Ideally, these valves are stented for transapical or minimally invasive delivery. It is unclear if and how the matrix of these valves remodels under in vivo hemodynamic loading conditions and in the presence of a stent. Here, we study the evolution of collagen orientation and tissue maturation in the wall of stented decellularized TEHVs with time after implantation. METHODS AND RESULTS: In a previous study, stented TEHVs based on rapidly degrading scaffolds were cultured in bioreactors, decellularized, and transapically implanted as pulmonary valve replacement in sheep. In the present study, collagen (re)orientation in the initially isotropic valvular wall was assessed using a fluorescent collagen probe combined with confocal imaging and image analysis of explanted tissue at 8, 16, and 24 weeks following implantation. Collagen tortuosity or waviness in the explants, as a measure of matrix maturity, was quantified using a Gabor wavelet method and compared with tortuosity in native sheep vascular wall tissue. Results indicate that on the luminal side of the valvular wall, fibers became aligned in circumferential direction, while tortuosity increased with implantation time, showing striking similarities with the native collagen structure after 24 weeks. On the outside of the wall, where the engineered tissue touches the stent, collagen fibers in the vicinity of the struts aligned along the struts, whereas collagen fibers in between struts were randomly oriented. Immunohistochemistry was performed to evaluate the presence of elastin and collagen type I and III. After 8 weeks, collagen types I and III were mostly present at the luminal side of the wall, whereas at 16 and 24 weeks, a homogenous distribution of collagen I and III was observed throughout the wall. Elastin was mostly expressed at the luminal side after 24 weeks. Biochemical assays showed that the amount of DNA (as a measure of cell number) increased significantly after 8 and 24 weeks, glycosaminoglycans increased significantly after 8, 16, and 24 weeks, and hydroxyproline, as a measure of collagen amount, increased significantly after 24 weeks compared to the controls. CONCLUSIONS: The collagen matrix in the wall of decellularized TEHVs shows clear structural remodeling and maturation with time. While collagen orientation rapidly remodels toward a native anisotropic architecture on the luminal side of the engineered valvular wall, it is dominated and guided by stent geometry on the outer side of the wall. Collagen tortuosity was increased with implantation time and was accompanied by an increase in elastin, especially on the luminal side of the vessel. PMID- 26028125 TI - Glassy Metal Alloy Nanofiber Anodes Employing Graphene Wrapping Layer: Toward Ultralong-Cycle-Life Lithium-Ion Batteries. AB - Amorphous silicon (a-Si) has been intensively explored as one of the most attractive candidates for high-capacity and long-cycle-life anode in Li-ion batteries (LIBs) primarily because of its reduced volume expansion characteristic (~280%) compared to crystalline Si anodes (~400%) after full Li(+) insertion. Here, we report one-dimensional (1-D) electrospun Si-based metallic glass alloy nanofibers (NFs) with an optimized composition of Si60Sn12Ce18Fe5Al3Ti2. On the basis of careful compositional tailoring of Si alloy NFs, we found that Ce plays the most important role as a glass former in the formation of the metallic glass alloy. Moreover, Si-based metallic glass alloy NFs were wrapped by reduced graphene oxide sheets (specifically Si60Sn12Ce18Fe5Al3Ti2 NFs@rGO), which can prevent the direct exposure of a-Si alloy NFs to the liquid electrolyte and stabilize the solid-electrolyte interphase (SEI) layers on the surfaces of rGO sheets while facilitating electron transport. The metallic glass nanofibers exhibited superior electrochemical cell performance as an anode: (i) Si60Sn12Ce18Fe5Al3Ti2 NFs show a high specific capacity of 1017 mAh g(-1) up to 400 cycles at 0.05C with negligible capacity loss as well as superior cycling performance (nearly 99.9% capacity retention even after 2000 cycles at 0.5C); (ii) Si60Sn12Ce18Fe5Al3Ti2 NFs@rGO reveals outstanding rate behavior (569.77 mAh g(-1) after 2000 cycles at 0.5C and a reversible capacity of around 370 mAh g(-1) at 4C). We demonstrate the potential suitability of multicomponent a-Si alloy NFs as a long-cycling anode material. PMID- 26028126 TI - Artificial photosynthesis based on ruthenium(II) tetrazole-dye-sensitized nanocrystalline TiO2 solar cells. AB - We have demonstrated the optical and morphological properties of a novel TiO2 nanoparticle as photoanode in order to apply in dye sensitized solar cells. The nanoparticles were synthesized through hydrothermal method in Tri-n-octyl amine (TOA) as capping agent. From the results it is concluded that the molar ratio of TiCl4 and TOA has remarkable influence on the size and homogeneity of the nanoparticles. The optimized nanoparticles structure for photoanode incorporated into dye-sensitized solar cell was obtained via the molar ratio of 1:10 for TiCl4:TOA. It has also studied the photovoltaic properties of different synthesized TiO2 nanocrystalline (1-4) anchored to ruthenium(II) complexes. 4-(1H tetrazole-5-yl) benzoic acid (TzBA) applied as an anchoring ligand and 2,2 bipyridine (bpy), 1,10-phenanthroline (phen) and pyridine tetrazole (pyTz) used as ancillary ligands. A solar energy to electricity conversion efficiency (eta) of 1.06% was obtained for [Ru(TzBA)(bpy)(pyTz)(NCS)] (5) under the standard AM 1.5 irradiation with a Jsc of 2.29 mA cm(-2), a Voc of 0.51 V, and FF of 55% which are the highest values among Ru(TzBA) complexes. DSSC study reveals that pyTz as an auxiliary ligand exhibits improved current generating capacity than the bpy and phen, which are introduced by dye (5). PMID- 26028127 TI - Method for the Synthesis of Phenothiazines via a Domino Iron-Catalyzed C-S/C-N Cross-Coupling Reaction. AB - An environmentally benign and efficient method has been developed for the synthesis of phenothiazines via a tandem iron-catalyzed C-S/C-N cross-coupling reaction. Some of the issues typically encountered during the synthesis of phenothiazines in the presence of palladium and copper catalysts, including poor substrate scope, long reaction times and poor regioselectivity, have been addressed using this newly developed iron-catalyzed method. PMID- 26028128 TI - Tissue-engineered blood vessels as promising tools for testing drug toxicity. AB - Drug-induced vascular injury (DIVI) is a serious problem in preclinical studies of vasoactive molecules and for survivors of pediatric cancers. DIVI is often observed in rodents and some larger animals, primarily with drugs affecting vascular tone, but not in humans; however, DIVI observed in animal studies often precludes a drug candidate from continuing along the development pipeline. Thus, there is great interest by the pharmaceutical industry to identify quantifiable human biomarkers of DIVI. Small-scale endothelialized tissue-engineered blood vessels using human cells represent a promising approach to screen drug candidates and develop alternatives to cancer therapeutics in vitro. We identify several technical challenges that remain to be addressed, including high throughput systems to screen large numbers of candidates, identification of suitable cell sources and establishing and maintaining a differentiated state of the vessel wall cells. Adequately addressing these challenges should yield novel platforms to screen drugs and develop new therapeutics to treat cardiovascular disease. PMID- 26028129 TI - Protecting newborns against pertussis: the value of vaccinating during pregnancy. AB - Resurgence of pertussis has recently been reported in several countries with long standing pertussis immunization and high vaccination coverage. This situation requires consideration of alternative immunization strategies to protect newborns. In the absence of a vaccine that confers long-lasting immunity, maternal vaccination for pertussis during pregnancy seems to be a safe, immunogenic, effective and accepted strategy to protect infants during the first weeks of life. The existing scientific evidence provides the grounds for pregnant women and healthcare workers to make informed decisions regarding this measure as well as for countries with high pertussis-related infant morbidity and mortality that should consider implementation. Furthermore, this could be a promising strategy to address other vaccine-preventable diseases of pregnancy and the neonatal period. PMID- 26028130 TI - Secular Trends in Central Line-Associated Bloodstream Infection: Microbiological Pattern of Pathogens after Preventive Measures. PMID- 26028131 TI - A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer. AB - BACKGROUND: Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer. METHODS: In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected. RESULTS: The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups. CONCLUSIONS: Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.). PMID- 26028132 TI - User adaptation in long-term, open-loop myoelectric training: implications for EMG pattern recognition in prosthesis control. AB - OBJECTIVE: Recent studies have reported that the classification performance of electromyographic (EMG) signals degrades over time without proper classification retraining. This problem is relevant for the applications of EMG pattern recognition in the control of active prostheses. APPROACH: In this study we investigated the changes in EMG classification performance over 11 consecutive days in eight able-bodied subjects and two amputees. MAIN RESULTS: It was observed that, when the classifier was trained on data from one day and tested on data from the following day, the classification error decreased exponentially but plateaued after four days for able-bodied subjects and six to nine days for amputees. The between-day performance became gradually closer to the corresponding within-day performance. SIGNIFICANCE: These results indicate that the relative changes in EMG signal features over time become progressively smaller when the number of days during which the subjects perform the pre-defined motions are increased. The performance of the motor tasks is thus more consistent over time, resulting in more repeatable EMG patterns, even if the subjects do not have any external feedback on their performance. The learning curves for both able-bodied subjects and subjects with limb deficiencies could be modeled as an exponential function. These results provide important insights into the user adaptation characteristics during practical long-term myoelectric control applications, with implications for the design of an adaptive pattern recognition system. PMID- 26028133 TI - Concordance of Direct and Indirect Measures of Medication Adherence in A Treatment Trial for Cannabis Dependence. AB - The current study compared adherence rates as measured by two indirect measurement methods (pill count and daily medication diary) to two direct measurement methods (urine riboflavin and serum 6-OH-buspirone level measurement) among participants (n = 109) in a medication treatment trial for cannabis dependence. Pill count and diary data showed high levels of percent agreement and strong kappa coefficients throughout the study. Riboflavin levels indicated lower level of percent in adherence during the study as compared to both pill count and self-report. In the subset of participants with 6-OH-buspirone levels (n = 58), the kappa coefficient also showed low to moderate agreement between the pill count and medication diaries with 6-OH-buspirone levels. In contrast to pill count and medication diaries, adherence as measured by riboflavin and 6-OH buspirone significantly decreased over time. The findings from this study support previous work demonstrating that pill count and patient self-report of medication taking likely overestimate rates of medication adherence, and may become less reliable as the duration of a clinical trial increases. PMID- 26028134 TI - Tensile strength of Ni-Cr copings subjected to inner surface sandblasting using different cementing agents: An in vitro study. AB - OBJECTIVES: To evaluate the effect of thermal cycling and inner surface treatment with aluminum oxide at different granulations on the tensile strength of Ni-Cr copings cemented with different cementing agents. MATERIALS AND METHODS: Ninety six metal copings were manufactured and divided into two groups: before and after thermal cycling (n = 48). The copings of both groups were internally treated by sandblasting with aluminum oxide particles of 100 (n = 24) and 320 (n = 24) mesh. The copings were cemented on previously manufactured metal cores using zinc phosphate (n = 8), conventional glass ionomer (CGIC) (n = 8) and resin-modified glass ionomer (RMGIC) (n = 8) cements. The tensile strength before and after thermal cycling was then determined (Newtons). RESULTS: The tensile strength before and after thermal cycling was significantly higher in copings cemented with RMGIC compared to CGIC (p < 0.05) and was similar to that for zinc phosphate (p > 0.05). Thermal cycling and sandblasting of the inner surface of the metal copings with different granulations did not influence retention (p > 0.05). CONCLUSIONS: Zinc phosphate cements and RMGIC showed similar retention. Additionally, the retention of the cements was not influenced by either thermal cycling or the particle size of the aluminum oxide. PMID- 26028135 TI - Joint distraction attenuates osteoarthritis by reducing secondary inflammation, cartilage degeneration and subchondral bone aberrant change. AB - OBJECTIVE: Osteoarthritis (OA) is a progressive joint disorder. To date, there is not effective medical therapy. Joint distraction has given us hope for slowing down the OA progression. In this study, we investigated the benefits of joint distraction in OA rat model and the probable underlying mechanisms. METHODS: OA was induced in the right knee joint of rats through anterior cruciate ligament transaction (ACLT) plus medial meniscus resection. The animals were randomized into three groups: two groups were treated with an external fixator for a subsequent 3 weeks, one with and one without joint distraction; and one group without external fixator as OA control. Serum interleukin-1beta level was evaluated by ELISA; cartilage quality was assessed by histology examinations (gross appearance, Safranin-O/Fast green stain) and immunohistochemistry examinations (MMP13, Col X); subchondral bone aberrant changes was analyzed by micro-CT and immunohistochemistry (Nestin, Osterix) examinations. RESULTS: Characters of OA were present in the OA group, contrary to in general less severe damage after distraction treatment: firstly, IL-1beta level was significantly decreased; secondly, cartilage degeneration was attenuated with lower histologic damage scores and the lower percentage of MMP13 or Col X positive chondrocytes; finally, subchondral bone abnormal change was attenuated, with reduced bone mineral density (BMD) and bone volume/total tissue volume (BV/TV) and the number of Nestin or Osterix positive cells in the subchondral bone. CONCLUSION: In the present study, we demonstrated that joint distraction reduced the level of secondary inflammation, cartilage degeneration and subchondral bone aberrant change, joint distraction may be a strategy for slowing OA progression. PMID- 26028136 TI - Multi-scalar mechanical testing of the calcified cartilage and subchondral bone comparing healthy vs early degenerative states. AB - OBJECTIVE: The calcified cartilage layer is thought to be integral to force transmission between the compliant articular cartilage (AC) above and underlying stiff bone. This study aims to determine how such a stiffness gradient across the calcified cartilage and bone changes with joint degeneration and how different scalar levels of testing are correlated. METHOD: Using a bovine model of early osteoarthritis (OA), multiple samples of calcified cartilage on subchondral bone (SB) from sixteen bovine patellae, displaying a range of cartilage states from intact (healthy) to moderately degenerate, were tested using macroscopic three point bending, microhardness indentation, and nanoindentation. Mechanical properties were correlated to cartilage health and microstructural morphometric measurements obtained from high resolution imaging using Differential Interference Contrast (DIC) Microscopy. RESULTS: There was a significant decrease in the moduli obtained from tests done at increasing scalar levels. The macroscale average modulus obtained from three-point bending showed that the SB was 10 times stiffer than the calcified cartilage in healthy tissue, 5 times in tissue displaying mildly degenerate AC and 8 times with moderate degeneration. Microhardness testing of multiple points from the calcified cartilage to the SB revealed that there was a monotonic gradual increase in the mean modulus. The moduli obtained from nanoindentation testing indicated that the SB was about twice the stiffness of the calcified cartilage. CONCLUSION: The mechanical transition from calcified cartilage to SB involves a graded continuum of increasing material stiffness. This stiffness gradient is altered in association with early degenerative change in the overlying AC, detectable only at the macro level. PMID- 26028137 TI - ADAMTS-5 takes centre stage in new developments for aggrecanase inhibitors. PMID- 26028138 TI - Comparison of load responsiveness of cartilage T1rho and T2 in porcine knee joints: an experimental loading MRI study. AB - OBJECTIVE: To compare changes in T1rho and T2 values of the femoral cartilage in porcine knee joints under staged loading and unloading conditions. DESIGN: Sixteen porcine knee joints with intact capsules and surrounding muscle were imaged using a custom-made pressure device and 3.0 T magnetic resonance imaging. Sagittal T1rho and T2 images were obtained for the lateral and medial condyles under the following compression loads: none (Load 0), 140 N (Load 140), 300 N (Load 300), and no compression after decompression (Post-load). The percentage changes of cartilage T1rho and T2 values under each loading condition from those at Load 0 were calculated for weight-bearing overall and eight subdivided regions of interest (ROIs) in both femoral condyles. The actual contact pressure under Load 140 and Load 300 was measured using pressure-sensitive film. RESULTS: For the overall ROI, the mean decreases of T1rho and T2 values were 4.4% and 5.1% under Load 140% and 10.9% and 10.6% under Load 300 in the medial condyle and were 5.2% and 4.0% under Load 140% and 10.6% and 6.0% under Load 300 in the lateral condyle. In the medial condyle, the actual contact pressure correlated highly with percentage changes in T1rho (r = -0.84, P < 0.01) and T2 (r = -0.79, P < 0.01), but those correlations were relatively low in the lateral condyle. CONCLUSION: Although there were side-dependent variations in the correlations with actual pressure, cartilage T1rho and T2 showed similarly sensitive responses to applied load. PMID- 26028139 TI - Bone marrow lesions, subchondral bone cysts and subchondral bone attrition are associated with histological synovitis in patients with end-stage knee osteoarthritis: a cross-sectional study. AB - OBJECTIVE: The aim of this study was to examine the osteoarthritis (OA)-related structural changes associated with histological synovitis in end-stage knee OA patients. METHODS: Forty end-stage knee OA patients (female: 88%, mean age: 71.8 y) were enrolled. All participants underwent 3.0-T MRI. The structural changes, such as cartilage morphology, subchondral bone marrow lesion (BML), subchondral bone cyst (SBC), subchondral bone attrition (SBA), osteophytes, meniscal lesion and synovitis, were scored using the whole-organ MRI scoring (WORMS) method. Synovial samples were obtained from five regions of interest (ROIs) of the knee joint during total joint replacement surgery. The associations between the histological synovitis score (HSS) and WORMS or the synovial expression levels of cyclooxygenase (COX)-2, interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF)-beta were examined using Spearman's correlation coefficient. RESULTS: Among the seven OA-related structural changes, the BML, SBC, SBA and synovitis were significantly associated with the HSS (r = 0.33, 0.35, 0.48 and 0.36, respectively), while other morphological changes were not. Although synovial COX-2, IL-1beta or IL-6 expression levels were not associated with the HSS, the synovial TGF-beta expression levels were associated with the HSS. CONCLUSION: The presence of BML, SBC and SBA was associated with histological synovitis in end-stage knee OA patients. PMID- 26028140 TI - Ropivacaine- and bupivacaine-induced death of rabbit annulus fibrosus cells in vitro: involvement of the mitochondrial apoptotic pathway. AB - OBJECTIVE: The purposes of this study were to assess whether local anesthetics (LAs), such as ropivacaine and bupivacaine, could induce apoptosis of rabbit annulus fibrosus (AF) cells in vitro and further to explore the possible underlying mechanism. METHODS: Rabbit AF cells at second passage were treated with saline solution and various concentrations of LAs. Apoptosis of AF cells were examined by cell counting kit-8 (CCK-8), Annexin V assays, Hoechst 33342 staining, and Caspase-3, -9 activity assays. The expression of apoptosis-related markers was detected by real-time PCR (RT-PCR) and Western Blot. The JC-1 staining was used to evaluate the change of mitochondrial membrane potential (MMP). Moreover, the levels of reactive oxygen species (ROS) were determined with fluorescent probe DCFH-DA. RESULTS: The results of flow cytometry indicated that LAs could induce apoptosis of rabbit AF cells in a dose-dependent manner. Apoptosis was confirmed by cell morphology, condensed nuclei and activation of Caspase-3 and -9. In addition, the molecular data showed that LAs could significantly up-regulate the expression of Bax, accompanied by a significant down-regulation of Bcl-2 expression. Furthermore, we also observed that LAs resulted in alteration of MMP and accumulation of intracellular ROS in AF cells. Blockade of ROS production by N-acetyl-l-cysteine (NAC) inhibited LAs-induced apoptosis. CONCLUSIONS: These findings suggest that LAs in clinically relevant concentrations could induce apoptosis of rabbit AF cells in vitro, and the mitochondrial pathway was, at least in part, involved in the LAs-mediated apoptosis. Further investigations focusing on the potential cytotoxicity of LAs on IVD cells are needed. PMID- 26028141 TI - Association between cartilage degeneration and subchondral bone remodeling in patients with knee osteoarthritis comparing MRI and (99m)Tc-DPD-SPECT/CT. AB - OBJECTIVE: The purpose of this retrospective cross-sectional study was to investigate the association between cartilage lesions assessed with 3T-MRI and remodeling of the subchondral bone detected by (99m)Tc-DPD-SPECT/CT. DESIGN: (99m)Tc-DPD-SPECT/CT and MRI of 27 knees of 25 patients with chronic knee pain and risk factors for osteoarthritis (OA) were evaluated by one nuclear physician and one radiologist. Six regions of the knee (in total 162 regions in 27 knees) were assessed according to structural joint lesions graded with a modified Whole Organ MR imaging score (WORMS) and according to subchondral (99m)Tc-DPD-SPECT uptake. Relationships between regional WORMS scores and uptake were quantified using general estimating equations. In a secondary analysis the uptake sum with the WORMS sum per joint was compared using Spearman correlations. RESULTS: Elevated subchondral uptake was significantly associated with the grade of cartilage lesions (P < 0.0001). Mean uptake was significantly higher subjacent to full thickness cartilage lesions compared to partial thickness lesions (P < 0.0001). A similar association was observed between bone marrow edema pattern (BMEP) and cartilage lesions. The sum of uptakes per joint was positively correlated to the WORMS sum (rs = 0.42) and to the sum of cartilage lesions per joint (rs = 0.50). CONCLUSION: Both functional and structural changes of the subchondral bone in terms of scintigraphic osseous activity and the presence and degree of BMEP were significantly associated with cartilage lesions in patients with OA of the knee. This association was pronounced with full thickness lesions, indicating a possible protective effect of the cartilage layer for the subjacent bone. PMID- 26028142 TI - Utilization rates of knee-arthroplasty in OECD countries. AB - BACKGROUND: The number of knee arthroplasties and the prevalence of obesity are increasing exponentially. To date there have been no published reviews on utilization rates of knee arthroplasty in OECD countries. METHODS: We analysed economic, medical and population data relating to knee arthroplasty surgeries performed in OECD countries. Gross domestic product (GDP), health expenditures, obesity prevalence, knee arthroplasty utilization rates and growth in knee arthroplasty rates per 100,000 population were assessed for total population, for patients aged 65 years and over, and patients aged 64 years and younger. RESULTS: Obesity prevalence and utilization of knee arthroplasty have increased significantly in the past. The mean utilization rate of knee arthroplasty was 150 (22-235) cases per 100,000 total population in 2011. The strongest annual increase (7%) occurred in patients 64 years and under. Differences between individual countries can be explained by economic and medical patterns, with countries with higher medical expenditures and obesity prevalence having significantly higher utilization rates. Countries with lower utilization rates have significantly higher growth in utilization rates. The future demand for knee prostheses will increase x-fold by 2030, with exact rates dependant upon economic, social and medical factors. CONCLUSION: We observed a 10-fold variation in the utilization of knee arthroplasty among OECD countries. A significant and strong correlation of GDP, health expenditures and obesity prevalence with utilization of knee arthroplasty was found. Patients aged 64 years and younger show a two-fold higher growth rate in knee arthroplasty compared to the older population. This trend could result in a four-fold demand for knee arthroplasty in OECD countries by 2030. PMID- 26028143 TI - Preoperative factors associated with postoperative gait kinematics and kinetics after total hip arthroplasty. AB - OBJECTIVE: To determine how patient factors: age, sex, body mass index (BMI), clinical scores and physical exam findings, are associated with gait recovery after total hip arthroplasty (THA). METHOD: 145 subjects, who were evaluated with standard gait analysis, the Harris Hip Score (HHS), and a physical exam including passive range of motion (ROM), hip abductor strength assessment, before and after primary unilateral THA, were identified from an IRB-approved repository. Sagittal plane dynamic ROM and 3D peak external moments were averaged from operated-side normal-speed trials at each visit. We used linear regression analysis to evaluate the association among preoperative clinical factors and postoperative gait, with and without controlling for the influence of preoperative gait variables. RESULTS: Sagittal and transverse plane moments, and the peak abduction moment seen in early stance, significantly improved after THA (p < 0.001, effect size d = 0.22-1.04). The peak adduction moment did not change significantly (p = 0.646), although the change ranged from -2.7 to + 4.0 %Body weight * height (-80% to +315%). Preoperative gait, clinical factors and patient characteristics predicted up to 33% of the variability in postoperative gait. Notably, greater preoperative abductor strength was associated with higher postoperative adduction and external rotation moments (R = 0.197-0.266, p < 0.05) after adjusting for age, sex, BMI and preoperative gait. CONCLUSION: Preoperative clinical factors predicted several specific aspects of objectively-characterized postoperative gait function. Physical exam findings can augment the predictive ability of clinical outcome measures, and potentially help guide rehabilitation plans. PMID- 26028145 TI - Optimized rinsing procedures for enhancing removal of residues of highly viscous and colored substances in the Bovine Corneal Opacity and Permeability (BCOP) assay. AB - Two modifications of the rinsing procedure within the BCOP assay were proposed. Their ability to enhance the removal efficiency of highly viscous and colored samples was compared with an unmodified BCOP procedure (TG OECD 437). The first modification consisted of three-step washing of the applied chemicals from the cornea using Eagle's Minimum Essential Medium (EMEM), olive oil and EMEM, while the classical OECD TG 437 procedure prescribes only EMEM. Within the second modification, mechanical removal of the tested sample from the cornea surface prior to the two step washing procedure was performed. The in vitro irritation score (IVIS) exceeded the value of 55 for 9 out of 20 samples when a non-modified rinsing procedure was used. The first modification with the olive oil resulted in a decrease in IVIS for numerous samples, while an IVIS score drop below the threshold value of 55 was only observed for two of them. Mechanical removal of sample residua resulted in a further decline in the measured IVIS. Only the three samples treated by means of this procedure revealed an IVIS above 55. The decreases in IVIS observed during both modifications were mainly related to the reduced opacity, whereas the permeability mostly remained unaffected. PMID- 26028144 TI - Platelet actin nodules are podosome-like structures dependent on Wiskott-Aldrich syndrome protein and ARP2/3 complex. AB - The actin nodule is a novel F-actin structure present in platelets during early spreading. However, only limited detail is known regarding nodule organization and function. Here we use electron microscopy, SIM and dSTORM super-resolution, and live-cell TIRF microscopy to characterize the structural organization and signalling pathways associated with nodule formation. Nodules are composed of up to four actin-rich structures linked together by actin bundles. They are enriched in the adhesion-related proteins talin and vinculin, have a central core of tyrosine phosphorylated proteins and are depleted of integrins at the plasma membrane. Nodule formation is dependent on Wiskott-Aldrich syndrome protein (WASp) and the ARP2/3 complex. WASp(-/-) mouse blood displays impaired platelet aggregate formation at arteriolar shear rates. We propose actin nodules are platelet podosome-related structures required for platelet-platelet interaction and their absence contributes to the bleeding diathesis of Wiskott-Aldrich syndrome. PMID- 26028146 TI - Optimization of the THP-1 activation assay to detect pharmaceuticals with potential to cause immune mediated drug reactions. AB - Despite important impacts of systemic hypersensitivity induced by pharmaceuticals, for such endpoint no reliable preclinical approaches are available. We previously established an in vitro test to identify contact and respiratory allergens based on interleukin-8 (IL-8) production in THP-1 cells. Here, we challenged it for identification of pharmaceuticals associated with systemic hypersensitivity reactions, with the idea that drug sensitizers share common mechanisms of cell activation. Cells were exposed to drugs associated with systemic hypersensitivity reactions (streptozotocin, sulfamethoxazole, neomycin, probenecid, clonidine, procainamide, ofloxacin, methyl salicylate), while metformin was used as negative drug. Differently to chemicals, drugs tested were well tolerated, except clonidine and probenecid, with no signs of cytotoxicity up to 1-2mg/ml. THP-1 activation assay was adjusted, and conditions, that allow identification of all sensitizing drugs tested, were established. Next, using streptozotocin and selective inhibitors of PKC-beta and p38 MAPK, two pathways involved in chemical allergen-induced cell activation, we tested the hypothesis that similar pathways were also involved in drug-induced IL-8 production and CD86 upregulation. Results indicated that drugs and chemical allergens share similar activation pathways. Finally, we made a structure-activity hypothesis related to hypersensitivity reactions, trying to individuate structural requisite that can be involved in immune mediated adverse reactions. PMID- 26028147 TI - Copper-based nanoparticles induce high toxicity in leukemic HL60 cells. AB - From the increasing societal use of nanoparticles (NPs) follows the necessity to understand their potential toxic effects. This requires an in-depth understanding of the relationship between their physicochemical properties and their toxicological behavior. The aim of the present work was to study the toxicity of Cu and CuO NPs toward the leukemic cell line HL60. The toxicity was explored in terms of mitochondrial damage, DNA damage, oxidative DNA damage, cell death and reactive oxygen species (ROS) formation. Particle characteristics and copper release were specifically investigated in order to gain an improved understanding of prevailing toxic mechanisms. The Cu NPs revealed higher toxicity compared with both CuO NPs and dissolved copper (CuCl2), as well as a more rapid copper release compared with CuO NPs. Mitochondrial damage was induced by Cu NPs already after 2 h exposure. Cu NPs induced oxidation at high levels in an acellular ROS assay, and a small increase of intracellular ROS was observed. The increase of DNA damage was limited. CuO NPs did not induce any mitochondrial damage up to 6 h of exposure. No acellular ROS was induced by the CuO NPs, and the levels of intracellular ROS and DNA damage were limited after 2 h exposure. Necrosis was the main type of cell death observed after 18 h exposure to CuO NP and dissolved copper. PMID- 26028148 TI - Cyto- and genotoxic effects of metallic nanoparticles in untransformed human fibroblast. AB - Metallic nanoparticles such as silver (Ag), cerium dioxide (CeO2) and titanium dioxide (TiO2) are produced at a large scale and included in many consumer products. It is well known that most metallic NPs are toxic to humans which raise concerns about these engineered particles. Various studies have already been published on the subject, however, almost all of these studies have been conducted in cancer or transformed cell lines. In this work we performed a comparative evaluation of these metallic NPs on normal untransformed human fibroblasts (GM07492) detecting cyto- and geno-toxic responses after exposure to these NPs. Our results showed that all three metallic NPs were able to cross the plasma membrane and were mainly found in endocytic vesicles. The Ag and TiO2 NPs affected mitochondrial enzymatic activity (XTT), increased DNA fragmentation, oxidative damage (Comet assay) and induced cell death mainly by the apoptotic pathway. Ag NPs increased GADD45alpha transcript levels and the phosphorylation of proteins gammaH2AX. Transient genotoxicity was also observed from exposure to CeO2 NPs while TiO2 NPs showed no increase in DNA damage at sub-cytotoxic concentrations. In comparison, Ag NPs were found to be the most cyto-genotoxic NPs to fibroblasts. Thus, these results support the use of normal fibroblast as a more informative tool to detect the mechanisms of action induced by metallic NPs. PMID- 26028149 TI - Bisphenol A and its analogs induce morphological and biochemical alterations in human peripheral blood mononuclear cells (in vitro study). AB - Few studies have addressed the cellular effects of bisphenol S (BPS) and bisphenol AF (BPAF) on cells, and no study has been conducted to analyze the mechanism of action of bisphenols in blood cells. In this study, the effect of bisphenol A (BPA), bisphenol F (BPF), BPS and BPAF on human peripheral blood mononuclear cells (PBMCs) was analyzed. It was shown that BPA, BPF and BPAF in particular, decreased cell viability, which was associated with depletion of intracellular ATP level and alterations in PBMCs size and granulation. Bisphenols enhanced ROS (including OH) formation, which led to damage to lipids and proteins in PBMCs. The most significant alterations in ROS level were induced by BPF, and particularly BPAF. Moreover, it was shown that BPAF most strongly provoked lipid peroxidation, while BPA and BPS caused the greatest damage to proteins. It may be concluded that BPA and its analogs were capable of inducing oxidative stress and damage in PBMCs in the concentrations ranging from 0.06 to 0.5 MUM (0.02-0.1 MUg/ml), which may be present in human blood as a result of environmental exposure. Although, most of bisphenols studied decreased cell viability, size and ATP level at higher concentrations, BPAF exhibited its cytotoxic potential at low concentrations ranging from 0.3 to 3 MUM (0.1-1.0 MUg/ml) that may correspond to concentrations in humans following occupational exposure. PMID- 26028150 TI - Future perspectives of a cardiac non-neuronal acetylcholine system targeting cardiovascular diseases as an adjunctive tool for metabolic intervention. AB - It has been several years since the function of the non-neuronal cholinergic system was independently reported in cardiomyocytes by several research groups. Although these findings initially seemed to be negligible and insignificant, extraordinary findings about cardiomyocytes were subsequently reported in studies involving the knockdown of the non-neuronal cholinergic system. These studies provide the evidence that this system may be indispensable for maintaining principal cardiac functions. Despite the absence of an appropriate and reliable technology to detect cellular ACh in real time in cardiomyocytes, studies of this system have progressed, albeit very slowly, to gradually consolidate the significance of this system. Based on the many significant findings regarding this system, these will be critical to develop adjunctive intervention therapy against cardiovascular diseases, including peripheral artery disease and heart failure. In this study, previous studies focusing on the non-neuronal cholinergic system are reviewed along with our studies, both indicating the biologically significant roles of the cardiac non-neuronal acetylcholine system from a clinical perspective. PMID- 26028151 TI - Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats. AB - Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-kappaB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-kappaB and their downstream pro-inflammatory cytokines in the cortex and by up regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption. PMID- 26028152 TI - Upcoming biological therapies in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with unpredictable course, intermingled with flares and periods of remission. Although the prognosis of the disease has improved in the past decades, current therapies are still associated with treatment-related complications. Recently, there has been major progress in the understanding of the pathogenesis of SLE, paving the way for the development of new biological agents, potentially revolutionizing the treatment of SLE. This review summarizes available data on novel biological therapies for SLE, focusing on recent results from clinical trials. As a result of treatment strategies based upon an individualized therapeutic approach, it is hoped that the clinical view of SLE will change from a severe autoimmune disease to a condition in which significant damage, mortality and treatment related complications can be prevented in the majority of SLE patients. PMID- 26028153 TI - Triacylglycerol Analysis in Human Milk and Other Mammalian Species: Small-Scale Sample Preparation, Characterization, and Statistical Classification Using HPLC ELSD Profiles. AB - In this work, a method for the separation of triacylglycerols (TAGs) present in human milk and from other mammalian species by reversed-phase high-performance liquid chromatography using a core-shell particle packed column with UV and evaporative light-scattering detectors is described. Under optimal conditions, a mobile phase containing acetonitrile/n-pentanol at 10 degrees C gave an excellent resolution among more than 50 TAG peaks. A small-scale method for fat extraction in these milks (particularly of interest for human milk samples) using minimal amounts of sample and reagents was also developed. The proposed extraction protocol and the traditional method were compared, giving similar results, with respect to the total fat and relative TAG contents. Finally, a statistical study based on linear discriminant analysis on the TAG composition of different types of milks (human, cow, sheep, and goat) was carried out to differentiate the samples according to their mammalian origin. PMID- 26028154 TI - Premenstrual Syndrome and Premenstrual Dysphoric Disorder in Japanese Collegiate Athletes. AB - STUDY OBJECTIVE: To determine the prevalence and impact of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) in Japanese collegiate athletes, with a focus on their disruption of athletic performance. DESIGN: Cross-sectional study. SETTING: A university in Osaka, the largest city in western Japan. PARTICIPANTS: 232 female collegiate athletes. MAIN OUTCOME MEASURES: Premenstrual symptoms and social activities. RESULTS: The prevalence of each premenstrual symptom was high. The prevalence of moderate to severe PMS and PMDD was 8.6% and 2.9%, respectively, the same as in general high school students. The athletic performance of 44.3% of athletes was found to suffer in a game or in practice. "Elite athletes" (OR 8.63, 95% CI: 1.22-120.0), "Difficulty concentrating" (OR 3.15, 95% CI: 1.05-10.6), and "Fatigue or lack of energy" (OR 5.92, 95% CI: 1.32 34.5) increased the risk of poor athletic performance. CONCLUSIONS: This study showed that premenstrual symptoms affect not only the daily activities but also the athletic performance of collegiate athletes. PMID- 26028155 TI - Estimated age and gender profile of individuals missed by a home-based HIV testing and counselling campaign in a Botswana community. AB - INTRODUCTION: It would be useful to understand which populations are not reached by home-based HIV-1 testing and counselling (HTC) to improve strategies aimed at linking these individuals to care and reducing rates of onward HIV transmission. METHODS: We present the results of a baseline home-based HTC (HBHTC) campaign aimed at counselling and testing residents aged 16 to 64 for HIV in the north eastern sector of Mochudi, a community in Botswana with about 44,000 inhabitants. Collected data were compared with population references for Botswana, the United Nations (UN) estimates based on the National Census data and the Botswana AIDS Impact Survey IV (BAIS-IV). Analyzed data and references were stratified by age and gender. RESULTS: A total of 6238 age-eligible residents were tested for HIV 1; 1247 (20.0%; 95% CI 19.0 to 21.0%) were found to be HIV positive (23.7% of women vs. 13.4% of men). HIV-1 prevalence peaked at 44% in 35- to 39-year-old women and 32% in 40- to 44-year-old men. A lower HIV prevalence rate, 10.9% (95% CI 9.5 to 12.5%), was found among individuals tested for the first time. A significant gender gap was evident in all analyzed subsets. The existing HIV transmission network was analyzed by combining phylogenetic mapping and household structure. Between 62.4 and 71.8% of all HIV-positive individuals had detectable virus. When compared with the UN and BAIS-IV estimates, the proportion of men missed by the testing campaign (48.5%; 95% CI 47.0 to 50.0%) was significantly higher than the proportion of missed women (14.2%; 95% CI 13.2 to 15.3%; p<0.0001). The estimated proportion of missed men peaked at about 60% in the age group 30 to 39 years old. The proportions of missed women were substantially smaller, at approximately 28% within the age groups 30 to 34 and 45 to 49 years old. CONCLUSIONS: The HBHTC campaign seems to be an efficient tool for reaching individuals who have never been tested previously in southern African communities. However, about half of men from 16 to 64 years old were not reached by the HBHTC, including about 60% of men between 30 and 40 years old. Alternative HTC strategies should be developed to bring these men to care, which will contribute to reduction of HIV incidence in communities. PMID- 26028157 TI - [Thrombin generation test]. AB - Thrombin is a key enzyme of the coagulation cascade, having both pro- and anticoagulant functions. Global haemostasis assay, the so-called thrombin generation test is appropriate for its assessment. Estimation of an individual's potential to generate thrombin may correlate more closely with a hyper- or hypo coagulable phenotype, compared to traditional coagulation tests. In patients at risk of venous thrombosis, thrombin generation analysis may be utilized to detect underlying thrombophilia. In patients with documented venous thromboembolism, increased thrombin generation values are seen in those patients at greatest risk for recurrence. In patients with arterial vascular disease, the data are limited. In case of haemophilia thrombin generation assays reflect bleeding severity. It is applicable for monitoring of both conventional haemophilia treatment and inhibitor-bypassing therapy, which is needed when inhibitors develop in patients. Standardization of thrombin generation methods and determination of cut off values are required before its application in clinical practice. PMID- 26028156 TI - Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi. AB - INTRODUCTION: HIV-associated Kaposi sarcoma (HIV-KS) is the most common cancer in Malawi. In 2008, the non-governmental organization, Partners In Health, and the Ministry of Health established the Neno Kaposi Sarcoma Clinic (NKSC) to treat HIV KS in rural Neno district. We aimed to evaluate 12-month clinical outcomes and retention in care for HIV-KS patients in the NKSC, and to describe our implementation model, which featured protocol-guided chemotherapy, integrated antiretroviral therapy (ART) and psychosocial support delivered by community health workers. METHODS: We conducted a retrospective cohort study using routine clinical data from 114 adult HIV-KS patients who received ART and >=1 chemotherapy cycle in the NKSC between March 2008 and February 2012. RESULTS: At enrolment 97% of patients (n/N=103/106) had advanced HIV-KS (stage T1). Most patients were male (n/N=85/114, 75%) with median age 36 years (interquartile range, IQR: 29-42). Patients started ART a median of 77 days prior to chemotherapy (IQR: 36-252), with 97% (n/N=105/108) receiving nevirapine/lamivudine/stavudine. Following standardized protocols, we treated 20 patients (18%) with first-line paclitaxel and 94 patients (82%) with bleomycin plus vincristine (BV). Of the 94 BV patients, 24 (26%) failed to respond to BV requiring change to second-line paclitaxel. A Division of AIDS grade 3/4 adverse event occurred in 29% of patients (n/N=30/102). Neutropenia was the most common grade 3/4 event (n/N=17/102, 17%). Twelve months after chemotherapy initiation, 83% of patients (95% CI: 74-89%) were alive, including 88 (77%) retained in care. Overall survival (OS) at 12 months did not differ by initial chemotherapy regimen (p=0.6). Among patients with T1 disease, low body mass index (BMI) (adjusted hazard ratio, aHR=4.10, 95% CI: 1.06-15.89) and 1 g/dL decrease in baseline haemoglobin (aHR=1.52, 95% CI: 1.03-2.25) were associated with increased death or loss to follow-up at 12 months. CONCLUSIONS: The NKSC model resulted in infrequent adverse events, low loss to follow-up and excellent OS. Our results suggest it is safe, effective and feasible to provide standard-of-care chemotherapy regimens from the developed world, integrated with ART, to treat HIV KS in rural Malawi. Baseline BMI and haemoglobin may represent important patient characteristics associated with HIV-KS survival in rural sub-Saharan Africa. PMID- 26028158 TI - Intracellular Degradable Hydrogel Cubes and Spheres for Anti-Cancer Drug Delivery. AB - Shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH- and redox-sensitivity for intracellular delivery of anticancer drugs. The cubical and spherical poly(methacrylic acid) (PMAA) networks with disulfide links are obtained by cross-linking PMAA with cystamine within hydrogen-bonded multilayers of PMAA/poly(vinylpyrrolidone) (PMAA/PVPON) on sacrificial mesoporous templates. The pH-triggered hydrogel swelling/shrinkage not only affords effective doxorubicin entrapment but also efficient endosomal/lysosomal escape, and redox-triggered degradation provides drug release into the cytosolic space. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione, which should ensure a rapid renal clearance in vivo. Particle shape is found to affect internalization at the initial step of cell-particle interactions. Drug-loaded spherical particles are found to be 12% more cytotoxic than the corresponding cubes within the first 10 h of cell incubation suggesting more rapid internalization of spheres. Both doxorubicin-loaded hydrogel cubes and spheres demonstrate 50% and 90% cytotoxicity when incubated with HeLa cancer cells for 24 and 48 h, respectively. The presented approach integrates the advantages of pH-sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for use in controlled delivery of therapeutics. PMID- 26028159 TI - Thiophene and benzodioxole appended thiazolyl-pyrazoline compounds: Microwave assisted synthesis, antimicrobial and molecular docking studies. AB - A novel series of thiophene and benzodioxole appended thiazolyl-pyrazoline derivatives have been designed, synthesized and evaluated against different bacteria and fungi. The antimicrobial activity of the synthesized compounds were screened using MIC method and were proved synthesized compounds 7o, 7r and 7t to show good antimicrobial activity against bacteria and fungi. In silico molecular docking studies revealed that all the synthesized molecules showed good binding energy toward the target receptor DNA topoisomerase IV, ranging from -10.42 to 11.66 kcal/mol. PMID- 26028160 TI - The interplay between the paracetamol polymorphism and its molecular structures dissolved in supercritical CO2 in contact with the solid phase: In situ vibration spectroscopy and molecular dynamics simulation analysis. AB - The aim of this paper is to characterize the distribution of paracetamol conformers which are dissolved in a supercritical CO2 phase being in equilibrium with their corresponding crystalline form. The quantum calculations and molecular dynamics simulations were used in order to characterize the structure and analyze the vibration spectra of the paracetamol conformers in vacuum and in a mixture with CO2 at various thermodynamic state parameters (p,T). The metadynamics approach was applied to efficiently sample the various conformers of paracetamol. Furthermore, using in situ IR spectroscopy, the conformers that are dissolved in supercritical CO2 were identified and the evolution of the probability of their presence as a functions of thermodynamic condition was quantified while the change in the crystalline form of paracetamol have been monitored by DSC, micro IR and Raman techniques. The DSC analysis as well as micro IR and Raman spectroscopic studies of the crystalline paracetamol show that the subsequent heating up above the melting temperature of the polymorph I of paracetamol and the cooling down to room temperature in the presence of supercritical CO2 induces the formation of polymorph II. The in situ IR investigation shows that two conformers (Conf. 1 and Conf. 2) are present in the phase of CO2 while conformer 3 (Conf. 3) has a high probability to be present after re-crystallization. PMID- 26028161 TI - Temperature based forensic death time estimation: The standard model in experimental test. AB - The determination of the time since death is essential to forensic homicide investigations since the time of death represents the presumed time of the offence. Erroneous death time estimates may lead to false acquittal or conviction of suspects. Since its introduction 30years back, the nomogram method by Henbetage has been established as the standard procedure of temperature-based death time determination in the early post-mortem period. The present study provides an independent investigation of the validity of its death time estimates and their corresponding 95%-confidence intervals. Comparison to post-mortem cooling curves recorded under controlled conditions of 84 suddenly deceased with known death times yielded the following results: Since in the light of our experiments the validity of the nomogram method seems to be problematic, death time estimates - and particularly their 95%-confidence interval limits - have to be interpreted carefully and should only be restrictively used as court evidence to support or refute alibis. Systematic overestimation of the post-mortem interval in bodies of high mass and large surface area must be taken into account. PMID- 26028162 TI - Helical and Dendritic Unzipping of Carbon Nanotubes: A Route to Nitrogen-Doped Graphene Nanoribbons. AB - Bamboo structured nitrogen-doped multiwalled carbon nanotubes (CN(x)-MWCNTs) have been successfully unzipped by a chemical oxidation route, resulting in nitrogen doped graphene nanoribbons (CN(x)-GNRs) with a multifaceted microstructure. The oxidation of CN(x)-MWCNTs was carried out using potassium permanganate in the presence of trifluoroacetic acid or phosphoric acid. On the basis of the high resolution transmission electron microscopy studies, the bamboo compartments were unzipped via helical or dendritic mechanisms, which are different from the longitudinal unzipping of open channel MWCNTs. The product graphene oxide nanoribbons were simultaneously reduced and doped with nitrogen by thermal annealing in an ammonia atmosphere. The effects of the annealing temperature, time, and atmosphere on the doping level and types of the nitrogen functional groups have been investigated. X-ray photoelectron spectroscopy results indicate that a wide range of doping levels can be achieved (4-9 at %) simply by changing the annealing conditions. Pyridinic and pyrrolic nitrogen functional groups were the dominant species that were attached to the edges of the CN(x)-GNRs. The GNRs, with a faceted structure and pyridinic and pyrrolic groups on their edges, have abundant nitrogen sites. These active sites could play a vital role in enhancing the electrocatalytic performance of GNRs. PMID- 26028163 TI - Blockade of nociceptin/orphanin FQ receptor signaling reverses LPS-induced depressive-like behavior in mice. AB - Nociceptin/orphanin FQ is the natural ligand of a Gi-protein coupled receptor named NOP. This peptidergic system is involved in the regulation of mood states and inflammatory responses. The present study aimed to investigate the consequences of blocking NOP signaling in lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors in mice. LPS 0.8mg/kg, ip, significantly induced sickness signs such as weight loss, decrease of water and food intake and depressive-like behavior in the tail suspension test. Nortriptyline (ip, 60min prior the test) reversed the LPS-induced depressive states. The NOP receptor antagonist SB-612111, 30min prior LPS, did not modify LPS-induced sickness signs and depressive-like behavior. However, when injected 24h after LPS, NOP antagonists (UFP-101, icv, and SB-612111, ip) significantly reversed the mood effects of LPS. LPS evoked similar sickness signs and significantly increased tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) plasma levels 6h post-injection in wild-type ((NOP(+/+)) and NOP knockout ((NOP(-/-)) mice. However, LPS treatment elicited depressive-like effects in NOP(+/+) but not in NOP(-/-) mice. In conclusion, the pharmacological and genetic blockade of NOP signaling does not affect LPS evoked sickness signs while reversing depressive like behavior. PMID- 26028165 TI - WITHDRAWN: Expression of concern from journal editors. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26028164 TI - Knockdown of central ghrelin O-acyltransferase by vivo-morpholino reduces body mass of rats fed a high-fat diet. AB - The enzyme ghrelin O-acyltransferase (GOAT) activates the orexigenic peptide ghrelin by transferring an acyl group from fatty acids to the serine-3 residue of the ghrelin molecule. This allows ghrelin to bind to its only known receptor, the growth hormone secretagogue receptor type 1a (GHSR1a). While studies have examined the hypothalamic transcriptional response of GOAT to metabolic challenge in mice, little has been examined in the rat hypothalamus. Furthermore, it has not been possible to identify the role of central GOAT separate from that of the periphery, since previous studies either knocked out GOAT system-wide or administered a GOAT inhibitor intraperitoneally. To determine if central GOAT expression is modulated by changes in energy state, we subjected rats to either forty-eight hours of food deprivation or three weeks of food restriction and found that GOAT mRNA increases significantly in both the hypothalamus and the stomach fundus in response to both metabolic challenges. We also found increases in hypothalamic ghrelin mRNA and stomach GHSR1a mRNA in response to food deprivation, as well as increases in hypothalamic GHSR1a mRNA in response to food restriction. We then conducted a second study where we continuously infused amorpholino antisense oligonucleotide into the lateral ventricles of rats to knock-down GOAT centrally while the animals were exposed to a high fat diet. Our results show that rats receiving the GOAT antisense gained less weight, and decreased their caloric efficiency when eating a high fat diet compared to control animals. These data suggest that central GOAT plays a role in modulating metabolism in rats. PMID- 26028166 TI - Mercury (Hg) speciation in coral reef systems of remote Oceania: Implications for the artisanal fisheries of Tutuila, Samoa Islands. AB - We investigated Hg in muscle tissue of fish species from three trophic levels on fringing reefs of Tutuila (14 degrees S, 171 degrees W), plus water, sediment and turf alga. Accumulation of total Hg in the herbivore Acanthurus lineatus (Acanthuridae, lined surgeonfish, (n=40)) was negligible at 1.05 (+/-0.04) ng g( 1) wet-weight, (~65% occurring as methyl Hg). The mid-level carnivore Parupeneus spp. (Mullidae, goatfishes (n=10)) had total Hg 29.8 (+/-4.5) ng g(-1) wet-weight (~99% as methyl Hg). Neither A. lineatus or Parupeneus spp. showed a propensity to accumulate Hg based on body size. Both groups were assigned a status of "un restricted" for monthly consumption limits for non-carcinogenic health endpoints for methyl Hg. The top-level carnivore Sphyraena qenie (Sphyraenidae, blackfin barracuda, n=3) had muscle tissue residues of 105, 650 and 741 ng g(-1) wet weight (100% methyl Hg, with increasing concentration with body mass, suggesting that S. qenie >15 kg would have a recommendation of "no consumption". PMID- 26028167 TI - The seagrass Posidonia oceanica: Ecosystem services identification and economic evaluation of goods and benefits. AB - Posidonia oceanica is a marine angiosperm endemic from the Mediterranean. Despite their protection, its meadows are regressing. The economic valuation of ecosystem services (ES) assesses the contribution of ecosystems to human well-being and may provide local policy makers help in territorial development. To estimate the economic value of P. oceanica seagrass and the meadows that it forms to better account its presence in coastal development, identification and assessment of ES provided are first performed. Then goods and benefits (GB) and their economical values are estimated. In total, 25ES are identified and 7GB are economically evaluated. The economic value of GB provided by P. oceanica ranges between 25.3 million and 45.9 million?/year which means 283-513?/ha/year. Because of the lack of existing available data, only 7GB linked to 11/25ES have been estimated. Despite this overall undervaluation, this study offers a value for coastal development policies to take into account. PMID- 26028168 TI - The risk assessment of heavy metals in Futian mangrove forest sediment in Shenzhen Bay (South China) based on SEM-AVS analysis. AB - The risks of heavy metal in Futian mangrove forest sediment were assessed using the acid-volatile sulfide (AVS) and simultaneously extracted metals (SEM) methods. The results indicated that AVS distributions were more variable than the SEM distributions at all 16 sampling sites. The positive correlation between AVS and SEM indicated that their similar formative and existing conditions and that AVS acted as an important carrier for SEM. The major SEM component was Zn (69.7.3 94.2%), whereas the Cd contribution (the most toxic metal present) to SEM was no more than 1%. The possible adverse effects caused by heavy metals at ten sampling sites may be due to higher levels of SEMs, rather than AVSs. The total organic carbon (TOC) was an important metal-binding phase in the sediments. Taking into account the TOC concentration, there were no adverse effects due to heavy metals in any of the Futian mangrove forest sediments. PMID- 26028169 TI - Environmental radionuclides in a coastal wetland of the Southern Laizhou Bay, China. AB - The radioactivity concentration of (238)U, (232)Th, (226)Ra, (40)K, and (137)Cs in soil samples collected in a coastal wetland of the Southern Laizhou Bay, China were measured. Mean activity concentrations were 54.4+/-11.7, 57.9+/-9.7, 28.6+/ 4.3, 542+/-21, and 10.2+/-2.9Bqkg(-1) dry weight for (238)U, (232)Th, (226)Ra, (40)K and (137)Cs, respectively. Statistical analyses suggested significant correlations between clay content and (40)K as well as (137)Cs. The radium equivalent activity, the absorbed dose rate in the air at 1m above the ground surface, and the external hazard index were calculated. The result showed that the radioactivity level in the wetland was in normal range. But sites along the river tended to have higher radiological hazard indexes. The vertical distributions of radionuclides in profiles illustrated some phenomena, such as vertical transport of (238)U, disequilibrium between (238)U and (226)Ra, and change in material sources. PMID- 26028170 TI - Spatial distribution and fate of perfluoroalkyl substances in sediments from the Pearl River Estuary, South China. AB - In this study, 54 sediment samples were collected from the Pearl River Estuary (PRE) in Southern China to study the spatial distribution and patterns of PFASs in this region. PFAS concentrations in the sediment samples ranged from nd (below detection limit) to 2.41 ng g(-1) dw (dry weight) with an average value of 0.79 ng g(-1) dw. PFAS concentrations were higher at the nearshore sampling sites than in the others. Perfluorobutanesulfonate (PFBS) and perfluorohexanesulfonate (PFHxS) were the two dominant compounds among the target PFASs, which may be due to their production and use as PFOS substitutes in the Pearl River Delta (PRD) areas. Significant linear relationships were found between total PFAS concentrations and total organic carbon (TOC) (R=0.30, p<0.05). The preliminary environmental risk assessment indicated that PFOS and PFOA in the regional sediments posed no significant ecological risk to the benthic organisms at present levels. PMID- 26028171 TI - Featuring the guest editors: Special issue tumor microenvironment. PMID- 26028172 TI - Identification of a novel synergistic induction of cell death by Smac mimetic and HDAC inhibitors in acute myeloid leukemia cells. AB - Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in acute myeloid leukemia (AML) and contribute to resistance to programmed cell death. Here, we report that inhibition of IAP proteins by the small-molecule Smac mimetic BV6 acts together with histone deacetylase (HDAC) inhibitors (HDACIs) such as MS275 or SAHA to trigger cell death in AML cell lines in a synergistic manner, as underscored by calculation of combination index (CI). Also, BV6 and HDACIs cooperate to trigger DNA fragmentation, a marker of apoptotic cell death, and to suppress long-term clonogenic survival of AML cells. In contrast, equimolar concentrations of BV6 and MS275 or SAHA do not synergize to elicit cell death in normal peripheral blood lymphocytes (PBLs), emphasizing some tumor cell selectivity of this combination treatment. Addition of the tumor necrosis factor (TNF)alpha-blocking antibody Enbrel significantly reduces BV6/MS275-induced cell death in the majority of AML cell lines, indicating that autocrine/paracrine TNFalpha signaling contributes to cell death. Remarkably, the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue MV4-11, Molm13 and OCI-AML3 cells and even enhances BV6/MS275-mediated cell death, whereas zVAD.fmk reduces BV6/MS275-induced cell death in NB4 cells. Annexin-V/propidium iodide (PI) double staining reveals that BV6/MS275 cotreatment predominately increases the percentage of double-positive cells. Of note, the Receptor-Interacting Protein (RIP)1 inhibitor necrostatin-1 (Nec-1) or the Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitor necrosulfonamide (NSA) significantly reduce BV6/MS275-induced cell death in the presence of zVAD.fmk, suggesting that BV6/MS275 cotreatment triggers necroptosis when caspases are inhibited. Thus, BV6 acts in concert with HDACIs to induce cell death in AML cells and can bypass apoptosis resistance, at least in several AML cell lines, by engaging necroptosis as an alternative route of regulated cell death. The identification of a novel synergism of BV6 and HDACIs has important implications for the development of new treatment strategies for AML. PMID- 26028173 TI - Natriuretic peptides for the treatment of acute heart failure: a focus on nesiritide in recent clinical trials. AB - Nesiritide, a recombinant form of B-type natriuretic peptide, is a vasodilator and currently recommended as an additive therapy for patients with acute decompensated heart failure (ADHF) who have been optimized on loop diuretics. With hospitalizations for ADHF rising, appropriate selection of therapy becomes even more important to optimize efficacy and reduce adverse events. Nesiritide has many properties that antagonize the pathophysiologic processes of heart failure and has demonstrated a comparative benefit in previous reports; however, controversy still remains with respect to its efficacy and safety. Based on results from recent clinical trials, nesiritide has been shown to be safe at currently approved doses and strongly considered for the treatment of ADHF in patients who remain symptomatic despite optimal doses of intravenous loop divertics. PMID- 26028174 TI - Urologic and male genital manifestations of granulomatosis with polyangiitis. AB - Granulomatosis with polyangiitis (GPA) is a systemic necrotizing granulomatous vasculitis, which predominantly affects small-sized blood vessels. Major organ involvement includes the upper/lower respiratory tract and kidneys. In contrast, genitourinary disease is rare in GPA patients, reported in <1% of cases in large cohorts. Manifestations at this level include prostatitis, destructive urethritis, genital ulcers, orchitis and renal masses. Also, high-dose cyclophosphamide, one of the main immunosuppressive drugs used for GPA treatment, is associated with bladder toxicity, i.e., hemorrhagic cystitis and cancer. Here, we review the main urogenital symptoms associated with this ANCA-associated vasculitis. In addition, cyclophosphamide-induced urologic complications are detailed. PMID- 26028175 TI - Fat Mass Is Associated With Cystatin C and Estimated Glomerular Filtration Rate in Adolescents With Type 1 Diabetes. PMID- 26028176 TI - Dietary Self-Monitoring in Weight Management: Current Evidence on Efficacy and Adherence. PMID- 26028177 TI - Seasonal biodiversity of black flies (Diptera: Simuliidae) and evaluation of ecological factors influencing species distribution at Doi Pha Hom Pok National Park, Thailand. AB - This is the first study on the seasonal biodiversity of black flies and evaluation of ecological factors influencing their distribution at Doi Pha Hom Pok National Park, northern Thailand. Larvae were collected from six fixed-stream sites in relation to altitude gradients from May 2011 to April 2013. The water temperature, water pH, conductivity, total dissolved solids (TDS), salt, water velocity, stream width and depth, streambed particle sizes, riparian vegetation, and canopy cover were recorded from each site. Monthly collections from the six sites yielded 5475 last-instar larvae, belonging to 29 black fly species. The most frequently found species from all sites were Simulium asakoae (100%) followed by Simulium yuphae (83.3%), and Simulium chiangdaoense, Simulium gombakense, Simulium phahompokense, Simulium fruticosum, Simulium maeaiense and Simulium fenestratum (66.6%). Of the 5475 last-instar larvae, S. maeaiense (19.3%), S. chiangdaoense (15.8%) and S. asakoae (14.8%), were the three most abundant species. The Shannon diversity index (H) at the six sites with different altitudes of 2100m, 2000m, 1500m, 1400m, 700m, and 500m above mean sea level, were 2.042, 1.832, 2.158, 2.123, 1.821 and 1.822, respectively. The Shannon index and number of taxa in the cold season were higher than those in the rainy and hot seasons. Principal component analysis (PCA) indicated that at least three principal components have eigen values >1.0 and accounted for 93.5% of the total variability of ecological factors among sampling sites. The Canonical correspondence analyses (CCA) showed that most species had a trend towards altitude, canopy cover, riparian vegetation and water velocity. PMID- 26028178 TI - Mass mortality in ornamental fish, Cyprinus carpio koi caused by a bacterial pathogen, Proteus hauseri. AB - Moribund koi carp, Cyprinus carpio koi, from a farm with 50% cumulative mortality were sampled with the aim of isolating and detecting the causative agent. Three bacterial species viz., Citrobacter freundii (NSCF-1), Klebsiella pneumoniae (NSKP-1) and Proteus hauseri [genomospecies 3 of Proteus vulgaris Bio group 3] (NSPH-1) were isolated, identified and characterized on the basis of biochemical tests and sequencing of the 16S rDNA gene using universal bacterial primers. Challenge experiments with these isolates using healthy koi carp showed that P. hauseri induced identical clinical and pathological states within 3 d of intramuscular injection. The results suggest P. hauseri (NSPH-1) was the causative agent. In phylogenetic analysis, strain NSPH-1 formed a distinct cluster with other P. hauseri reference strains with >=99% sequence similarity. P. hauseri isolates were found sensitive to Ampicillin, Cefalexin, Ciprofloxacin and Cefixime and resistant to Gentamycin, Oxytetracycline, Chloramphenicol, and Kanamycin. The affected fish recovered from the infection after ciprofloxacin treatment. PMID- 26028180 TI - Combination treatment for allergic conjunctivitis - Plant derived histidine decarboxylase inhibitor and H1 antihistaminic drug. AB - Aim of present investigation was to study the effect of catechin and the combination of catechin and cetirizine in ovalbumin induced animal model of allergic conjunctivitis. Guinea pigs were divided into 5 groups: normal control, disease control, disease treated with catechin 100 mg/kg, disease treated with cetirizine 10 mg/kg, disease treated with combination of catechin and cetirizine, 50 mg/kg & 5 mg/kg respectively. Sensitization was carried out by intraperitoneal injection of ovalbumin for the period of 14 day. Simultaneously, catechin was administered orally for 14 days while, cetirizine was administered at the day of experiment. Determination of clinical scoring, mast cell and blood histamine content, histidine decarboxylase activity from stomach was carried out. Vascular permeability was measured by dye leakage after secondary challenge of allergen and conjunctival tissues were subjected for histopathological examinations. Treatment with catechin, cetirizine and combination showed significant (P < 0.05) decrease in clinical scoring and vascular permeability. While, catechin 100 mg/kg and catechin 50 mg/kg showed significant (P < 0.05) decrease in histamine content in mast and blood. The treatment also showed significant (P < 0.05) decrease in the histidine decarboxylase enzyme activity. However, cetirizine group did not show any difference in enzyme activity as well as histamine content. Histopathological examination also showed improvement in ulceration and decrease in edema and inflammation in all treatment groups. From the present study, we can conclude that catechin exhibits potent anti-allergic activity by histidine decarboxylase enzyme inhibition and combination shown significant anti-allergic activity at reduced dose by both enzyme inhibition as well as inhibition of histamine receptors. PMID- 26028181 TI - Self-cathing experience journal: Enhancing the patient and family experience in clean intermittent catheterization. AB - OBJECTIVE: This pilot study evaluated the safety, feasibility, and usefulness of the Self-Cathing Experience Journal (SC-EJ), an online resource for patients and families to address issues and stigma surrounding clean intermittent catheterization (CIC). Modeled after previous assessments of the Cardiac and Depression Experience Journals (EJs), this project uniquely included patients and caregivers. We explored whether patients and caregivers would find the SC-EJ helpful in increasing their understanding of CIC, accepting the medical benefits of self-catheterization, improving hopefulness, and diminishing social isolation. METHODS: Patients seen in a tertiary urology clinic were asked to view the SC-EJ for 30 min and rate its safety and efficacy. The cross-sectional sample included 25 families: 17 surveys were completed by the patient and their caregiver, five by the patient only, and three by the caregiver only. Mean patient age was 15.7 +/- 5.8 years (range 7-29 years). The patients were 64% female, and 72% used CIC due to neurological diagnoses. RESULTS: Mean overall patient satisfaction with the SC-EJ was moderately high (mean = 5, out of a 7-point Likert scale from 1 = not at all to 7 = extremely). Mean overall caregiver satisfaction was high (mean = 5.55) and was similar to caregiver satisfaction scores recorded in caregivers with children with congenital heart disease and depression (mean = 5.7 and mean = 5.75, respectively). No significant differences were noted in satisfaction between CIC patients and CIC caregivers or among caregivers of the three populations surveyed (CIC, Cardiac, and Depression). CIC patients and caregivers reported that SC-EJ viewing gave them a strong sense that others are facing similar issues (patient mean = 6.15, caregiver mean = 6.21) and that it was helpful to read about other families' CIC experiences (patient mean = 6, caregiver mean = 5.89). DISCUSSION: The SC-EJ appears to be safe, feasible, and useful to patients and families using CIC. Ratings from caregivers of CIC patients were similar to other cohorts of caregivers facing chronic childhood conditions. Despite beliefs that the EJ format best targets adults, high satisfaction ratings among patients suggest that the SC-EJ is acceptable and beneficial to children and adolescents. This web-based intervention can be a helpful clinical supplement in promoting healthy coping skills and a decreased sense of isolation among patients and families facing CIC. The unique integration of real patient and family experiences with accurate and vetted medical knowledge has the potential to enhance resiliency among viewers who use CIC. PMID- 26028182 TI - Night diuresis stimulation increases efficiency of alarm intervention. AB - INTRODUCTION: The prevalence of primary monosymptomatic nocturnal enuresis (PMNE) varies from 1.6% to 15%. Although treatment with enuretic alarms has been used for a long period of time, there are many disadvantages, including the necessity for long-term use and the high percentage of children who are resistant to such therapy. We hypothesized that more intense use of the alarm system would accelerate the process of forming the conditioned response to awakening, caused by the desire to urinate and, probably, increase the percentage of patients with positive results. Increased fluid intake will cause more frequent awakenings, so the use of alarm system will be more intense (Figure). OBJECTIVE: To study the effect of increased fluid intake, prior to going to bed, on the efficacy of alarm therapy. STUDY DESIGN: The treatment group consisted of 294 children (178 boys) average age: 11.3 (9.1-11.9) years. All participants completed an overactive bladder questionnaire (OAB-q) and a bladder diary, and underwent uroflowmetry, blood and urine testing. Group A (n = 141, mean age 10.9 (9.1-11.6) years), used the alarm system traditionally (Wet Stop/BYE-WET, USA). Group V (n = 153, mean age 11.5 (9.3-11.9) years) drank either water or any other transparent non colored fluid (any table mineral water with mineralization of less than 1 g per dm3) once immediately prior to sleep at a volume of 4-5 ml/kg of body weight. The effectiveness of therapy was assessed by the change in frequency of urination episodes during sleep per week, episodes of spontaneous awakenings, caused by the desire to urinate per week. Data were analyzed using JMP SAS Statistical Discovery 8.0.2. Wilcoxon criterion was used for comparison of results between groups; correlation of changes in groups was analyzed using the Spearman coefficient. RESULTS: Complete resolution of NE, 2 weeks after the end of alarm therapy, was found in 34 patients (24%) in Group A and 59 (39%) in Group B. This difference was statistically significant with a confidence level of 95%. DISCUSSION: Having searched the publication databases, including PubMed and Scopus, we failed to find any publication presenting evidence or recommendations on the ideal management of fluid intake in patients with PMNE. Although a limitation of fluid intake is commonly recommended, there is no evidence showing an increase in dry night frequency when such fluid restriction is used as monotherapy. In contrast, our study has shown an improvement in outcome when an increased fluid intake is used in combination with enuretic alarm therapy. CONCLUSION: We were able to prove that increased fluid intake improved the efficiency of alarm therapy intervention during the treatment of PMNE in children. PMID- 26028183 TI - Tailor-Made Pore Surface Engineering in Covalent Organic Frameworks: Systematic Functionalization for Performance Screening. AB - Imine-linked covalent organic frameworks (COFs) were synthesized to bear content tunable, accessible, and reactive ethynyl groups on the walls of one-dimensional pores. These COFs offer an ideal platform for pore-wall surface engineering aimed at anchoring diverse functional groups ranging from hydrophobic to hydrophilic units and from basic to acidic moieties with controllable loading contents. This approach enables the development of various tailor-made COFs with systematically tuned porosities and functionalities while retaining the crystallinity. We demonstrate that this strategy can be used to efficiently screen for suitable pore structures for use as CO2 adsorbents. The pore-surface-engineered walls exhibit an enhanced affinity for CO2, resulting in COFs that can capture and separate CO2 with high performance. PMID- 26028184 TI - Structure and nanostructure in ionic liquids. PMID- 26028185 TI - Neural correlates of the reverse Simon effect in the Hedge and Marsh task. AB - The Simon effect is a typical paradigm for investigating cognitive control in which participants respond faster and more accurately when the stimulus position corresponds to the response position (congruent) than when it does not (incongruent). However, Hedge and Marsh (1975) reported that the effect depended on task rules. Interestingly, the effect can be reversed (i.e., faster reaction time in the incongruent condition than in the congruent condition) when participants respond to the stimulus color by pressing the key labeled with an alternate color. A classic Simon effect is present when responding with the key possessing the same color as the stimulus. In the present study, we investigated the neural correlates of the Hedge and Marsh effect using functional magnetic resonance imaging (fMRI). We manipulated the overlap between the stimulus and response at both the perceptual and conceptual levels using physical color and Chinese pinyin as response labels. The behavioral results showed a classic Simon effect in the same-Color Mapping but a reversed Simon effect in the alternate Color Mapping. The fMRI results revealed a main effect of Color Mapping: stronger activation in the dorsal frontoparietal regions (bilateral superior parietal lobule [SPL] and dorsal premotor cortex [dPMC]), pre-supplementary motor area (pre-SMA)/anterior midcingulate cortex (aMCC) and bilateral dorsolateral prefrontal cortex (DLPFC), as well as a stronger deactivation in the default mode network (bilateral inferior parietal lobule, posterior cingulate cortex and ventral medial prefrontal cortex) in the alternate-Color Mapping compared to the same-Color Mapping. More importantly, some of those areas, including the bilateral SPL/intraparietal sulcus and dPMC, pre-SMA/aMCC, bilateral DLPFC and bilateral temporoparietal junction, also showed an interaction between Color Mapping and Spatial Congruency: stronger activity in the incongruent than in the congruent condition in the same-Color Mapping but weaker activity in the alternate-Color Mapping, which was similar to the behavioral results. The brain activation pattern was similar in the color and pinyin sessions. The implications of these results for cognitive control are discussed. PMID- 26028186 TI - Nanoparticles for controlled release of anti-biofilm agents WO2014130994 (A1): a patent evaluation. AB - Nanoparticles based on poly(dimethylaminoethyl methacrylate)-b poly(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate) (p-DMAEMA-b-(DMAEMA-co-PAA-co-BMA)) were loaded with farnesol or apigenin for the controlled, pH-dependent release of the two agents to inhibit pathogenic bacteria producing biofilms. The inventions are mainly directed against Streptococcus mutans, the oral cavity bacterium responsible for dental caries. PMID- 26028187 TI - Orange-red silver emitters for sensing application and bio-imaging. AB - Highly fluorescent Au(I)@Ag particles (emission maximum at 635 nm) have been obtained from a mixture of AgNO3, HAuCl4 and glutathione. Au(I)@Ag particles containing Ag2 and Ag3 clusters are produced when the reaction mixture is subjected to a modified hydrothermolysis (MHT) reaction. The silver clusters make the solution intensely fluorescent and the Au(I) moiety provides long term stability to the silver clusters by withdrawing electron density from the silver clusters. The vacuum-dried aqueous fluorescent solution leaves a yellow solid that exhibits higher emissive properties when re-dispersed in non-aqueous solvents. Fluorescent Au(I)@Ag particles have been found to be cytocompatible and efficient candidates for live cell imaging. Addition of S(2-) ions selectively and successively quenches the fluorescence of Au(I)@Ag particles without any significant interference from common anions. Thus, sensitive detection of S(2-) is possible with the fluorescent Au(i)@Ag particles in water and water-miscible non-aqueous solvents. Furthermore, Pb(ii) induced fluorescence enhancement of the solution containing Au(I)@Ag particles has been used to enable S(2-) detection free from interference by S2O3(2-) and I(-). The possibility of naked eye detection of S(2-) is also an additional advantage of this method as an orange color solution is developed exclusively with the S(2-) ion. Fluorometric determination of S(2-) has been rationalized for real environmental samples. PMID- 26028188 TI - Timing of post 131I ablation diagnostic whole body scan in differentiated thyroid cancer patients. Less than four months post ablation may be too early. AB - AIM: to determine whether the first three months after 131I ablation is too early to perform radioiodine diagnostic whole body scintigraphy (dxWBS) in differentiated thyroid carcinoma patients. PATIENTS, MATERIAL, METHODS: The files of 462 patients who were treated for DTC in our hospital were reviewed. All patients underwent surgical thyroidectomy. 146 patients had data available on a. a dxWBS which was performed less than four months (max 120 days) after 131I ablation with concurrent stimulated TSH stimulated thyroglobulin (Tg) measurement without further therapeutic measures between ablation and dxWBS and b. a second dxWBS or 131I therapy (rxWBS) within 1.5 years after ablation. RESULTS: A discordance between the initial and follow-up scan was found in 25/129 (19%) patients: of 54 patients with a positive initial dxWBS, scan results of a second dxWBS or rxWBS obtained with a suitable distance to the initial scan contradicted the initial one in 15 patients (27%). New lesions were discovered in 10/74 negative first dxWBS cases (14%). A discordance between the initial and follow-up stimulated Tg was found in 5/129 (4%) patients: 2/90 (2%) of patients with a negative stimulated Tg at initial dxWBS subsequently showed a positive results whereas 3/29 (10%) patients with an initially positive Tg showed a negative Tg level at the second procedure. CONCLUSION: Less than four months after 131I ablation is too early to perform radioiodine diagnostic whole body scintigraphy with concurrent TSH stimulated Tg measurement. The identification of the right, later, timepoint however requires further research. PMID- 26028189 TI - A fluorescent probe for hypochlorite based on the modulation of the unique rotation of the N-N single bond in acetohydrazide. AB - Herein, a novel signaling mechanism for constructing fluorescent probes was demonstrated for the first time based on modulation of the unique rotation of the N-N single bond in the acetohydrazide group. According to the new signaling mechanism, a fluorescent probe for hypochlorite was then judiciously developed. PMID- 26028191 TI - Zinc disrupts central carbon metabolism and capsule biosynthesis in Streptococcus pyogenes. AB - Neutrophils release free zinc to eliminate the phagocytosed bacterial pathogen Streptococcus pyogenes (Group A Streptococcus; GAS). In this study, we investigated the mechanisms underpinning zinc toxicity towards this human pathogen, responsible for diseases ranging from pharyngitis and impetigo, to severe invasive infections. Using the globally-disseminated M1T1 GAS strain, we demonstrate that zinc stress impairs glucose metabolism through the inhibition of the glycolytic enzymes phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase. In the presence of zinc, a metabolic shift to the tagatose-6 phosphate pathway allows conversion of D-galactose to dihydroxyacetone phosphate and glyceraldehyde phosphate, partially bypassing impaired glycolytic enzymes to generate pyruvate. Additionally, zinc inhibition of phosphoglucomutase results in decreased capsule biosynthesis. These data indicate that zinc exerts it toxicity via mechanisms that inhibit both GAS central carbon metabolism and virulence pathways. PMID- 26028192 TI - Controlled proliferation and screening of mammalian cells on a hydrogel functionalized small molecule microarray. AB - A hydrogel-functionalized small molecule microarray has been developed, on which PC-3 cancer cells were selectively grown. Subsequent controlled release of immobilized bioactive compounds enabled cell-based screening to be directly carried out on this platform. PMID- 26028193 TI - The handkerchief guide: a simple and practical method to improve ataxic gait in cerebellar subjects. AB - OBJECTIVE: Ataxic gait can be remarkably improved by a simple method called the "handkerchief guide" involving the patient and caregiver holding opposite ends of a handkerchief and walking together. Our objective was to assess the effect of the handkerchief guide on gait in patients with cerebellar ataxia. METHODS: Gait analysis was carried out on seven patients with degenerative cerebellar disease (DCD), seven patients with unilateral cerebellar vascular disease (CVD), and seven healthy control (HC) subjects. All subjects performed two walking tasks: free walking (FW) and handkerchief-guided walking (HGW) on a 10 m pathway. In the HGW condition, each subject walked with the caregiver while maintaining slight tension on the handkerchief. The HCs and patients with DCD held the handkerchief with their right hand, while the patients with unilateral limb ataxia due to CVD grasped it with their affected and unaffected hands in different trials. We measured 10 gait parameters. RESULTS: The HGW attenuated body-sway, lengthened step, and increased gait velocity in patients with cerebellar ataxia. In DCD, the HGW significantly improved seven parameters. In CVD, HGW with the affected hand improved five parameters, and HGW with the unaffected hand improved seven parameters. CONCLUSIONS: The HGW stabilized upright posture in patients with cerebellar ataxia during level-ground walking, probably by enabling subconscious postural adjustments to minimize changes in the arm and hand position relative to trunk, and in arm configuration. This led to improvement of gait performance. The handkerchief guide may be useful for walk training in patients with cerebellar ataxia. PMID- 26028194 TI - [Constructive disturbance and low-level perfusion in parietal areas in amyotrophic lateral sclerosis with dementia]. AB - Although amyotrophic lateral sclerosis with dementia (ALS-D) has been characterized by symptoms of fronto-temporal dysfunction, we report two patients with ALS-D who showed constructive disturbance and low-level perfusion in the parietal areas. The first was a 69-year-old woman (Case 1) who had been diagnosed with the bulbar type of ALS. She showed fronto-temporal dementia as well as low scores and disturbance on block construction and copying; however, she showed a better score on the imitation of finger postures. The second was a 73-year-old woman (Case 2) who had been diagnosed with the leg onset type of ALS. She showed mild impairment of the frontal function as well as mild disturbance on block construction and copying, but no problem on the imitation of finger postures. Case 1 showed more severe symptoms of dementia and constructive disturbance than Case 2, whereas Case 2 showed lower levels of cerebral perfusion over more extensive areas than Case 1. Cases 1 and 2 were compatible with definite ALS according to the El Escorial Criteria, and they showed constructive disturbance with characteristics reported previously, such as both left and right hemisphere damage and constructive disturbance similar to those seen in Alzheimer's disease. In addition, they showed poorer scores on performing tasks requiring the use of objects (block construction and copying) rather than using their body (imitation of finger postures). PMID- 26028195 TI - [A case of corticosteroid-responsive Lemierre syndrome with clivus osteomyelitis and a mass in the cavernous sinus-suprasellar region]. AB - Lemierre syndrome is a clinical syndrome that presents with internal jugular thrombophlebitis, septicemia and systemic abscess formations. In general, the condition is preceded by oropharyngeal infections. We report a case of a 73-year old man with Lemierre syndrome, clivus osteomyelitis and a steroid-responsive mass in the cavernous sinus-suprasellar region. He complained of fever, occipital pain, diplopia and right ptosis. Administration of oral steroids ameliorated the ophthalmic symptoms for a period before he was admitted to our hospital. After admission, the severity of his headache advanced, and his ophthalmic symptoms progressed bilaterally. Brain magnetic resonance imaging showed contrast enhancement of the clivus and revealed a mass lesion contrast-enhancement effect in the cavernous sinus-suprasellar region. Fusobacterium nucleatum was detected by blood culture, and computed tomography revealed multiple bacterial emboli in both lung fields and thrombosis of the left internal jugular vein; thus, he was diagnosed with Lemierre syndrome. After venous administration of antibiotics, his fever and headache markedly improved, but the ophthalmic symptoms did not. We prescribed an oral steroid because the cavernous sinus-suprasellar lesion was probably an inflammatory granuloma caused by a para-infectious mechanism rather than by infection. After the series of treatments, his ophthalmic symptoms improved, and the cavernous sinus-suprasellar region mass lesion decreased. He was eventually discharged in a fully ambulatory state and had no ophthalmic difficulties. We thought that the osteomyelitis of clivus was caused by Lemierre syndrome and its inflammatory processes formed the granuloma in the cavernous sinus-suprasellar region. This was a case of Lemierre syndrome with a rare combination of clivus osteomyelitis and a steroid-responsive tumour in the cavernous sinus-suprasellar region that was successfully treated. PMID- 26028196 TI - [A case of neurolymphomatosis presenting extended involvement of spinal nerve roots]. AB - A 56-year-old man suffered from diffuse large B-cell lymphoma (DLBCL) originated from the stomach. He received R-CHOP therapy, and had a complete remission. However, at age 57, he experienced left shoulder pain and weakness of left arm, and his muscle weakness and sensory disturbance subacutely progressed to other limbs. Cervical and lumbosacral MRI showed enhanced extended lesions of cervical, thoracic, lumbar, and sacral nerve roots and cauda equina. Cerebrospinal fluid analysis revealed a sustained low glucose level. Nerve conduction study showed abnormalities of measurement parameters of F-waves in all limbs. A diagnosis of recurrent DLBCL presenting neurolymphomatosis could be established by repeated cytology of cerebrospinal fluid. He received high dose methotrexate therapy, but his symptoms were worsened to tetraplegia. It should be noticed that DLBCL can involve spinal nerve roots extensively. PMID- 26028197 TI - [Successful corticosteroid therapies in a case of acute motor, sensory, autonomic neuropathy after cytomegalovirus infection]. AB - We report a rare case of autonomic neuropathy associated with cytomegalovirus (CMV) infection. The patient, a 53-year-old male, was admitted to our hospital because of prolonged fever, headache and neck stiffness followed by urinary retention. Cerebrospinal fluid examination revealed pleocytosis (219/mm(3), predominantly lymphocytes) with a markedly increased protein level (217 mg/dl) and serum IgM anti-CMV antibody was detected. While his meningitic symptoms gradually improved after intravenous administration of ganciclovir, he complained of numbness in the extremities and difficulty in walking. Neurologically, marked orthostatic hypotension, glove and stocking type of paresthesia, severe muscle weakness in extremities, and neurogenic atonic bladder were noted. Nerve conduction studies showed normal except for F-waves, which were absent in the left tibial nerve. A sural nerve specimen appeared normal in both myelinated and unmyelinated fibers. He was given immunological therapies such as corticosteroid and intravenous high dose immunoglobulin therapies. After corticosteroid therapies, not only sensory and motor symptoms but also autonomic symptoms remarkably improved. Of the anti-ganglioside antibodies, IgM anti-GM1 antibody and IgM anti-GM2 antibody were detected. Although some cases with Guillain-Barre syndrome preceded by CMV infection have been reported, few cases with autonomic neuropathy have been described in association with successful corticosteroid therapies. PMID- 26028198 TI - [A case of cerebellar brainstem form of progressive multifocal leukoencephalopathy associated with idiopathic CD4+ lymphocytopenia]. AB - A 77-year-old woman presented with a 6-month history of slowly progressive cerebellar ataxia. T2-weighted MRI showed high signal intensity in the left upper dorsal pons and bilateral middle cerebellar peduncles. JC virus (JCV) DNA was detected in cerebrospinal fluid (CSF). The patient had no HIV infection, collagen disease, or a history of immunosuppressive treatment, but she was found to have CD4+ lymphocytopenia. We made a diagnosis of cerebellar brainstem form of progressive multifocal leukoencephalopathy (PML) presenting as cerebellar ataxia, which was presumably associated with idiopathic CD4+ lymphocytopenia. Following the treatment with mefloquine, the patient slightly improved clinically and JCV DNA became negative in CSF. PMID- 26028199 TI - [A case of sensory ataxic axonal polyneuropathy with IgGlambda monoclonal gammopathy successfully treated with intravenous immunoglobulin therapy]. AB - We report the case of an 84-year-old man with sensory ataxic polyneuropathy and IgGlambda monoclonal gammopathy of undetermined significance (MGUS), which was successfully treated with intravenous immunoglobulin (IVIG) therapy. He had developed progressive ataxic gait over the span of 2 years before he was admitted to our hospital. On admission, he was unable to walk without assistance because of severe sensory ataxia. He performed poorly on the finger-nose-finger and heel knee tests, and his vibration and position sense in the feet was remarkably diminished. However, motor involvement was not remarkable. Serum immunoelectrophoresis revealed IgGlambda monoclonal gammopathy, and MGUS was diagnosed. Nerve conduction studies revealed sensory-dominant axonal polyneuropathy. The patient was successfully treated with IVIG (400 mg/kg/day, for 5 days). He regained his capacity to walk independently after treatment, but his nerve conduction results remained unchanged. This sensory ataxia might be partially due to underlying cervical spondylotic myelopathy. To our knowledge, this is the first report in our country of the successful use of IVIG therapy to treat a patient with IgGlambda monoclonal gammopathy and related sensory ataxic axonal polyneuropathy. PMID- 26028200 TI - [Ultrasound findings of hamstring hematoma in a patient taking anticoagulants]. AB - A patient started anticoagulation for secondary prevention of stroke, achieving a prothrombin time-international normalized ratio within the optimal therapeutic range. The patient subsequently complained of pain in the left thigh on hospital day 25, and ultrasonography showed a large intramuscular hematoma in the left hamstring. The intramuscular hematoma gradually reduced without surgical intervention. Ultrasound examination plays an important role in precisely diagnosing intramuscular hematoma and monitoring changes in hematoma size. PMID- 26028201 TI - [Hemichorea improved by carotid artery stenting in a 73-year-old man with hypoperfusion of the basal ganglia]. AB - A 73-year-old man presented with continuous hemichoreic movement of right arm and leg and with dyskinesia in his tongue. Magnetic resonance image (MRI) showed no ischemic lesion within the basal ganglia, but magnetic resonance angiography (MRA) and carotid duplex ultrasonography showed the left internal carotid occlusion and 80% stenosis in the right common carotid artery. Tc-99m-ECD-SPECT showed hypoperfusion of the frontal lobe, temporal lobe, parietal lobe, basal ganglia and thalamus. A trial of haloperidol had no effect; therefore, the right carotid artery stenting was performed. Hypoperfusion in the left internal carotid artery area was improved by cross flow from the right side, and his hemichorea gradually improved. This result supports the notion that hypoperfusion-related hemichorea may occur, even in the absence of cerebral ischemia. PMID- 26028202 TI - [Pathological diagnosis of coexistence of ALS with Alzheimer's disease]. PMID- 26028203 TI - [An autopsy case of frontotemporal lobar degeneration with motor neuron disease associated with numerous diffuse plaques, pretangles and neuropil threads]. PMID- 26028208 TI - [Editor's Note]. PMID- 26028209 TI - Ab initio study of the O4H(+) novel species: spectroscopic fingerprints to aid its observation. AB - A detailed ab initio characterization of the structural, energetic and spectroscopic properties of the novel O4H(+) species is presented. The equilibrium structures and relative energies of all multiplet states have been determined systematically by analyzing static and dynamical correlation effects. The two and three body dissociation processes have been studied and indicate the presence of conical intersections in various states including the ground state. Comparison with available thermochemical data is very good, supporting the applied methodology. The reaction, H3(+) + O4-> O4H(+) + H2, was found to be exothermic DeltaH = -19.4 kcal mol(-1) and therefore, it is proposed that the product in the singlet state could be formed in the interstellar medium (ISM) via collision processes. To aid in its laboratory or radioastronomy detection in the interstellar medium we determined spectroscopic fingerprints. It is estimated for the most stable geometry of O4H(+) dipole allowed electronic transitions in the visible region at 429 nm and 666 nm, an intense band at 1745 cm(-1) in the infrared and signals at 40.6, 81.2 and 139.2 GHz in the microwave region at 10, 50 and 150 K respectively, relevant for detection in the ISM. PMID- 26028211 TI - [Current status of bacteriological studies at prefectural and municipal public health institutes in Japan]. AB - Prefectural and municipal public health institutes are located in prefectures and ordinance-designated cities in Japan, and play a vital role in the regional surveillance of infectious diseases and foodborne illnesses. These institutes, in close cooperation with national institutes such as the National Institute of Infectious Diseases and the National Institute of Health Sciences, construct the national surveillance network for infectious diseases and their causative agents. Bacteriological examinations and studies on a variety of infectious diseases and foodborne illnesses are core activities of prefectural and municipal public health institutes, through which novel and important bacteriological findings have been acquired. In this article, we report the latest findings regarding bacteriological examinations/studies and interesting cases at these institutes, especially concerning foodborne illnesses, tuberculosis, and antimicrobial resistances. PMID- 26028212 TI - [Molecular targets of bacterial effectors and toxins that underlie vulnerability to diseases]. AB - Pathogenic bacteria produce a variety of effectors and/or toxins, which subvert target cell/tissue functions in the infected hosts. Some of those effectors/toxins also perturb host defense mechanism, thereby making up more complicated pathophysiological conditions. Such bacterial effectors/toxins may have been positively selected during evolution because they directly strike vulnerable points in the host system. In turn, this indicates that systemic exploration of molecules and signaling pathways targeted by bacterial effectors/toxins provides a powerful tool in digging up an unexpected Achilles' heel(s), malfunctioning of which gives rise to disorders not restricted to infectious diseases. Based on this viewpoint, this review shows molecular basis underlying host susceptibility and vulnerability to diseases through the studies of host molecules targeted by bacterial effectors and toxins. PMID- 26028213 TI - [Infectious diseases in Asia/International collaboration in bacterial infectious diseases]. AB - Proactive approaches to collect precise information are necessary to control infectious diseases in the whole world. A collaborative research for infectious diseases with institute or university of countries that infectious diseases occur is one of the good approaches. In this paper, we introduce collaborative researches on infectious diseases with Asian countries, such as Vietnam, Philippines, Thailand, and India. PMID- 26028214 TI - [Recent advances in the field of oral bacteriology]. AB - The oral cavity is inhabited by more than 600 bacterial species; these species compete for nutrients or coexist in order to survive along with the indigenous population. Extreme conditions are prevalent in the oral cavity, and these conditions are influenced by our immunity and variations in nutrition, temperature, and pH. Pathogens that cause dental caries or periodontal disease can survive in these extreme environments; these pathogens are virulent and can cause several diseases. Therefore, research on oral bacteriology is warranted to analyze the virulence factors of these bacteria as well as to ascertain environmental stress responses, interactions between bacteria and human immunity, comparisons of bacterial genomes, and oral microflora. In this review, we provide new data in the fields of bacteriology, immunology, and genomics and describe recent advances in the field of oral bacteriology. PMID- 26028215 TI - Hazardous o-toluidine mineralization by photocatalytic bismuth doped ZnO slurries. AB - Photocatalytic mineralization of o-toluidine in aqueous media under UV/solar irradiation was achieved by bare and bismuth doped zinc oxide nanoparticles. By adopting different analytical approaches a reaction mechanism is proposed, explaining the differences in photodetoxification performances. PMID- 26028216 TI - Incubation temperature affects the immune function of hatchling soft-shelled turtles, Pelodiscus sinensis. AB - Identifying how developmental temperature affects the immune system is critical for understanding how ectothermic animals defend against pathogens and their fitness in the changing world. However, reptiles have received little attention regarding this issue. We incubated eggs at three ecologically relevant temperatures to determine how incubation temperature affects the immune function of hatchling soft-shelled turtles, Pelodiscus sinensis. When exposed to bacterial infections, hatchlings from 24 degrees C had lower cumulative mortalities (55%, therefore, higher immunocompetence) than those from 28 degrees C (85%) or 32 degrees C (100%). Consistent with higher immunocompetence, hatchlings from low incubation temperature had higher IgM, IgD, and CD3gamma expressions than their counterparts from the other two higher incubation temperatures. Conversely, the activity of immunity-related enzymes did not match the among-temperature difference in immune function. Specifically, enzyme activity was higher at intermediate temperatures (alkaline phosphatase) or was not affected by incubation temperature (acid phosphatase, lysozyme). Our study is the first to provide unequivocal evidence (at the molecular and organismal level) about the significant effect of incubation temperature on offspring immunity in reptiles. Our results also indicate that the reduced immunity induced by high developmental temperatures might increase the vulnerability of reptiles to the outbreak of diseases under global warming scenarios. PMID- 26028217 TI - Organizer-Derived WOX5 Signal Maintains Root Columella Stem Cells through Chromatin-Mediated Repression of CDF4 Expression. AB - Stem cells in plants and animals are maintained pluripotent by signals from adjacent niche cells. In plants, WUSCHEL HOMEOBOX (WOX) transcription factors are central regulators of stem cell maintenance in different meristem types, yet their molecular mode of action has remained elusive. Here we show that in the Arabidopsis root meristem, the WOX5 protein moves from the root niche organizer, the quiescent center, into the columella stem cells, where it directly represses the transcription factor gene CDF4. This creates a gradient of CDF4 transcription, which promotes differentiation opposite to the WOX5 gradient, allowing stem cell daughter cells to exit the stem cell state. We further show that WOX5 represses CDF4 transcription by recruiting TPL/TPR co-repressors and the histone deacetylase HDA19, which consequently induces histone deacetylation at the CDF4 regulatory region. Our results show that chromatin-mediated repression of differentiation programs is a common strategy in plant and animal stem cell niches. PMID- 26028219 TI - Inherent Instability of Correct Kinetochore-Microtubule Attachments during Meiosis I in Oocytes. AB - A model for mitosis suggests that correct kinetochore-microtubule (KT-MT) attachments are stabilized by spatial separation of the attachment sites from Aurora B kinase through sister KT stretching. However, the spatiotemporal regulation of attachment stability during meiosis I (MI) in oocytes remains unclear. Here, we found that in mouse oocytes, Aurora B and C (B/C) are located in close proximity to KT-MT attachment sites after bivalent stretching due to an intrinsic property of the MI chromosomes. The Aurora B/C activity destabilizes correct attachments while allowing a considerable amount of incorrect attachments to form. KT-MT attachments are eventually stabilized through KT dephosphorylation by PP2A-B56 phosphatase, which is progressively recruited to KTs depending on the BubR1 phosphorylation resulting from the timer Cdk1 and independent of bivalent stretching. Thus, oocytes lack a mechanism for coordinating bivalent stretching and KT phosphoregulation during MI, which may explain the high frequency of KT-MT attachment errors. PMID- 26028218 TI - Phosphatidylinositol-Phosphatidic Acid Exchange by Nir2 at ER-PM Contact Sites Maintains Phosphoinositide Signaling Competence. AB - Sustained agonist-induced production of the second messengers InsP3 and diacylglycerol requires steady delivery of phosphatidylinositol (PtdIns) from its site of synthesis in the ER to the plasma membrane (PM) to maintain PtdIns(4,5)P2 levels. Similarly, phosphatidic acid (PtdOH), generated from diacylglycerol in the PM, has to reach the ER for PtdIns resynthesis. Here, we show that the Drosophila RdgB homolog, Nir2, a presumed PtdIns transfer protein, not only transfers PtdIns from the ER to the PM but also transfers PtdOH to the opposite direction at ER-PM contact sites. PtdOH delivery to the ER is impaired in Nir2 depleted cells, leading to limited PtdIns synthesis and ultimately to loss of signaling from phospholipase C-coupled receptors. These studies reveal a unique feature of Nir2, namely its ability to serve as a highly localized lipid exchanger that ensures that PtdIns synthesis is matched with PtdIns(4,5)P2 utilization so that cells maintain their signaling competence. PMID- 26028221 TI - [Congenital myasthenic syndromes in childhood: Drug therapeutic strategies]. AB - Congenital myasthenia syndromes (CMS) are a group of genetic disorders responsible for neuromuscular junction dysfunction. Usually beginning before 2 years of age, they are revealed by fatigability and muscle weakness, especially after stress, and often prevent the child's normal development. Over recent years, major advances in therapeutic strategies have been made following the discovery of numerous mutations responsible for CMS and the understanding of their pathogenic role. Here we report a pediatric CMS case caused by a mutation of the E subunit of the acetylcholine receptor. The initial treatment with acetylcholinesterase inhibitor rapidly showed its limits in terms of both effectiveness and tolerance. The association with 3.4 diaminopyridine (DAP), a new drug available to treat such conditions, has transformed the motor outcome of our patient and allowed psychomotor development. In addition to 3.4 DAP, other molecules adapted to other types of CMS are now available. Three major groups of CMS can be distinguished depending on whether the deficit is at the presynaptic, synaptic, or postsynaptic level of the neuromuscular junction. Depending on the type of CMS, therapeutic management may include acetylcholinesterase inhibitors, 3.4 DAP, fluoxetine, quinidine sulfate, or ephedrine. With the case report, we provide a recent review of the literature on such new therapeutic options, their indications and restrictions, their mechanism of action, and prescription modalities. Knowing the precise CMS type and the appropriate therapeutic options available is essential for the proper management of such chronic and severe but relatively treatable childhood disorders. PMID- 26028222 TI - On the interaction of triarylmethane dye crystal violet with LAPONITE(r) clay: using mineral nanoparticles to control the dye photophysics. AB - The combination of an organic dye with clays leads to very interesting hybrid materials with original properties. It is found that LAPONITE(r) nanoparticles have an impact on the photophysical properties of the crystal violet dye inducing a kinetic stabilization of its excited emissive state, turning this nonemissive dye into a fluorescent compound. PMID- 26028220 TI - HIF1alpha Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes. AB - Transcriptional mediators of cell stress pathways, including HIF1alpha, ATF4, and p53, are key to normal development and play critical roles in disease, including ischemia and cancer. Despite their importance, mechanisms by which pathways mediated by these transcription factors interact with one another are not fully understood. In addressing the controversial role of HIF1alpha in cardiomyocytes (CMs) during heart development, we discovered a mid-gestational requirement for HIF1alpha for proliferation of hypoxic CMs, involving metabolic switching and a complex interplay among HIF1alpha, ATF4, and p53. Loss of HIF1alpha resulted in activation of ATF4 and p53, the latter inhibiting CM proliferation. Bioinformatic and biochemical analyses revealed unexpected mechanisms by which HIF1alpha intersects with ATF4 and p53 pathways. Our results highlight previously undescribed roles of HIF1alpha and interactions among major cell stress pathways that could be targeted to enhance proliferation of CMs in ischemia and may have relevance to other diseases, including cancer. PMID- 26028223 TI - Working Memory and Cognitive Flexibility Mediates Visuoconstructional Abilities in Older Adults with Heterogeneous Cognitive Ability. AB - Previous studies suggest that executive functions influence the performance on visuoconstructional tasks. This study aims to investigate whether the relationship between planning ability and the copy of complex figures is mediated by distinct components of executive functions (i.e., working memory, inhibitory control and cognitive flexibility). We included a 129 older adults with Alzheimer's disease (n=36, AD), mild cognitive impairment (MCI, n=67), and with no evidence of cognitive impairment (controls, n=26). We evaluated the mediation effect of planning abilities, working memory, cognitive flexibility and inhibitory control on visuoconstructional tasks using a multiple mediation models. We found a significant direct effect of planning on visuoconstructional abilities and a partial mediation effect of working memory and cognitive flexibility on visuoconstructional abilities. The present results indicate that the performance on visuoconstructional task is mediated by multiple interrelated executive functions components, in particular working memory and cognitive flexibility. PMID- 26028224 TI - Subjective age and perceived distance-to-death moderate the association between posttraumatic stress symptoms and posttraumatic growth among older adults. AB - OBJECTIVES: Little research has addressed the association between posttraumatic stress (PTS) symptoms and posttraumatic growth (PTG) in the second half of life. This study examined whether subjective age and perceived distance-to-death moderate this association. METHOD: 339 community-dwelling older adults (age range 50-90; M = 65.44, SD = 9.77) were sampled through random dialing to Jewish residents in the south of Israel. Participants completed a phone-questionnaire on PTS symptoms, level of PTG, subjective age, and perceived distance-to-death. RESULTS: Higher levels of PTS symptoms were both linearly and curvilinearly related to higher PTG. Additionally, subjective age and perceived distance-to death moderated this association in a linear way, so that the association was strongest in participants who reported younger subjective age and further distance-to-death. DISCUSSION: The findings emphasize the moderating effect of two time perspectives, one that focuses on time since birth and another that concerns the time that remains before death. These two perspectives affect the association between posttraumatic stress and posttraumatic growth within older individuals. PMID- 26028226 TI - Risk of cardiovascular disease in HIV-positive Queensland men receiving combined antiretroviral therapy. AB - Background Cardiovascular disease (CVD) is a major cause of death among HIV positive individuals receiving combination antiretroviral therapy (cART). The risk of CVD is estimated using a variety of risk calculations, however, currently there is no specific CVD risk calculator endorsed for Australians receiving cART. METHODS: A retrospective study of 210 Queensland men older than 35 years with cART-treated HIV was conducted to estimate the prevalence of CVD and the risk of a cardiovascular event occurring within 5 years. The weighted Cohen's kappa coefficient was used to estimate the agreement between the Australian Absolute CVD Risk Calculator and the Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) 5-year Estimated CVD Risk Equation. RESULTS: The prevalence of CVD was 31.9%. Hypertensive disease was the most prevalent CVD (25.2%). Queensland men with cART-treated HIV were at moderate risk (5%) of a cardiovascular event in the next 5 years. There was a substantial agreement (kappa=0.63) between the Australian Absolute CVD Risk Calculator and the D:A:D 5-year Estimated CVD Risk Equation. CONCLUSIONS: Queensland men with cART-treated HIV are experiencing high prevalence of CVD and are at moderate risk of a CVD event in the next 5 years. Primary care guidelines should emphasise CVD prevention as a keystone for the treatment of people living with HIV. PMID- 26028225 TI - Prmt5 is a regulator of muscle stem cell expansion in adult mice. AB - Skeletal muscle stem cells (MuSC), also called satellite cells, are indispensable for maintenance and regeneration of adult skeletal muscles. Yet, a comprehensive picture of the regulatory events controlling the fate of MuSC is missing. Here, we determine the proteome of MuSC to design a loss-of-function screen, and identify 120 genes important for MuSC function including the arginine methyltransferase Prmt5. MuSC-specific inactivation of Prmt5 in adult mice prevents expansion of MuSC, abolishes long-term MuSC maintenance and abrogates skeletal muscle regeneration. Interestingly, Prmt5 is dispensable for proliferation and differentiation of Pax7(+) myogenic progenitor cells during mouse embryonic development, indicating significant differences between embryonic and adult myogenesis. Mechanistic studies reveal that Prmt5 controls proliferation of adult MuSC by direct epigenetic silencing of the cell cycle inhibitor p21. We reason that Prmt5 generates a poised state that keeps MuSC in a standby mode, thus allowing rapid MuSC amplification under disease conditions. PMID- 26028227 TI - Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma. AB - PURPOSE: To describe efficacy and safety of stereotactic body radiation therapy (SBRT) for the treatment of inoperable hepatocellular carcinoma. METHODS: The records of 77 consecutive patients treated with SBRT for 97 liver-confined HCC were reviewed. A total dose of 45Gy in 3 fractions was prescribed to the 80% isodose line. Local control (LC), overall survival (OS), progression-free survival (PFS) and toxicity were studied. RESULTS: The median follow-up was 12months. The median tumor diameter was 2.4cm. The LC rate was 99% at 1 and 2years. The 1 and 2-year OS were 81.8% and 56.6% respectively. The median time to progression was 9months (0-38). The rate of hepatic toxicity was 7.7% [1.6-13.7], 14.9% [5.7-23.2] and 23.1% [9.9-34.3] at 6months, 1year and 2years respectively. In multivariate analysis, female gender (HR 7.87 [3.14-19.69]), a BCLC B-C stage (HR 3.71 [1.41-9.76]), a sum of all lesion diameters ?2cm (HR 7.48 [2.09-26.83]) and a previous treatment (HR 0.10 [0.01-0.79]) were independent prognostic factors of overall survival. CONCLUSION: SBRT allows high local control for inoperable hepatocellular carcinomas. It should be considered when an ablative treatment is indicated in Child A patients. PMID- 26028228 TI - Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage II-III inoperable non-small cell lung cancer. AB - PURPOSE: We report long-term disease control, survival, and toxicity for patients with locally advanced non-small cell lung cancer prospectively treated with concurrent proton therapy and chemotherapy on a nonrandomized case-only observational study. METHODS: All patients received passive-scatter proton therapy, planned with 4D-CT-based simulation; all received proton therapy concurrent with weekly chemotherapy. Endpoints were local and distant control, disease-free survival (DFS), and overall survival (OS). RESULTS: The 134 patients (21 stage II, 113 stage III; median age 69 years) had a median gross tumor volume (GTV) of 70 cm(3) (range, 5-753 cm(3)); 77 patients (57%) received 74 Gy(RBE), and 57 (42%) received 60-72 Gy(RBE) (range, 60-74.1 Gy(RBE)). At a median follow up time of 4.7 years, median OS times were 40.4 months (stage II) and 30.4 months (stage III). Five-year DFS rates were 17.3% (stage II) and 18.0% (stage III). OS, DFS, and local and distant control rates at 5 years did not differ by disease stage. Age and GTV were related to OS and DFS. Toxicity was tolerable, with 1 grade 4 esophagitis and 16 grade 3 events (2 pneumonitis, 6 esophagitis, 8 dermatitis). CONCLUSION: This report of outcomes after proton therapy for 134 patients indicated that this regimen produced excellent OS with tolerable toxicity. PMID- 26028229 TI - What is the ideal radiotherapy dose to treat prostate cancer? A meta-analysis of biologically equivalent dose escalation. AB - PURPOSE: To determine if increasing the biologically equivalent dose (BED) via various radiation fractionation regimens is correlated with clinical outcomes or toxicities for prostate cancer. METHODS AND MATERIALS: We performed a meta analysis that included 12,756 prostate cancer patients from 55 studies published from 2003 to 2013 who were treated with non-dose-escalated conventionally fractionated external beam radiation therapy (non-DE-CFRT), DE-CFRT, hypofractionated RT, and high dose rate brachytherapy (HDR-BT; either mono or boost) with ?5-year actuarial follow-up. BEDs were calculated based on the following formula: (nd[1+d/(alpha/beta)]), where n is the number of fractions, and d is dose per fraction; assuming an alpha/beta of 1.5 for prostate cancer and 3.0 for late toxicities. Mixed effects meta-regression models were used to estimate weighted linear relationships between BED and the observed percentages of patients experiencing late toxicities or 5-year freedom from biochemical failure (FFBF). RESULTS: Increases in 10 Gy increments in BED (at alpha/beta of 1.5) from 140 to 200 Gy were associated with 5-unit improvements in percent FFBF. Dose escalation of BED above 200 Gy was not correlated with FFBF. Increasing BED (at alpha/beta of 3.0) from 98 to 133 Gy was associated with increased gastrointestinal toxicity. Dose escalation above 133 Gy was not correlated with toxicity. CONCLUSIONS: An increase in the BED to 200 Gy (at alpha/beta of 1.5) was associated with increased disease control. Doses above 200 Gy did not result in additional clinical benefit. PMID- 26028230 TI - Association of Polymorphisms in Innate Immunity Genes TLR9 and DEFB1 with Human Longevity. AB - The distribution of polymorphic variants of innate immunity genes TLR9 (+2848G>A) and DEFB1(-20G>A; -44C>G; -52G>A) was evaluated in long-living individuals. No significant differences were found in the distribution of genotypes and alleles of the TLR9 gene. The following features were revealed: increase in the frequency of AA and GG genotypes and decrease in the frequency of the AG genotype of the DEFB1(-20G>A) gene; increase in the frequency of the CC genotype and C allele and decrease in the frequency of CG and GG genotypes and G allele of the DEFB1(44C>G) gene; and increase in the frequency of AA and AG genotypes and A allele and decrease in the frequency of the GG genotypes and G allele of the DEFB1(-52G>A) gene. Genotypes and alleles of the DEFB1 gene found in long-living individuals can be considered as the factors that increase the probability of longevity and favorable course of age-related diseases. PMID- 26028231 TI - Biocompatibility of Textile Titanium Nickel Implants with Fibroblast Culture. AB - The parameters of biocompatibility of titanium nickel implants of different design with fibroblast culture are studied. Colonization of textile and mesh implants with fibroblasts and tissue development depend on the size of mesh cells and thread diameter. Titanium nickel implants of different constructions do not inhibit the growth of fibroblast culture. PMID- 26028232 TI - Age-Related Features of Cardiomyocyte Ploidy in Patients with Hypertrophic Obstructive Cardiomyopathy. AB - Endomyocardial biopsy samples of the interventricular septum from patients with hypertrophic cardiomyopathy isolated during myectomy were examined. We revealed significant variability of cardiomyocyte ploidy (from 2.9c to 13.5c) that directly correlated with myocyte size; the maximum ploidy was found in young patients. Ultrastructural signs of increased contractile and synthetic activity of cells were observed in patients with high DNA content in cardiomyocytes. PMID- 26028233 TI - Method for Correction of Consequences of Radiation-Induced Heart Disease using Low-Intensity Electromagnetic Emission under Experimental Conditions. AB - Effects of successive exposure to ionizing irradiation and low-intensity broadband red light on electrical activity of the heart and myocardium microstructure were studied in rats. Lowintensity red light corrected some ECG parameters, in particular, it normalized QT and QTc intervals and voltage of R and T waves. Changes in ECG parameters were followed by alterations in microstructure of muscle fi laments in the myocardium of treatment group animals comparing to control group. PMID- 26028234 TI - Coherent Fluctuation Nephelometry: A Rapid Method for Urine Screening for Bacterial Contamination. AB - Express-test by the method of coherent fluctuation nephelometry for urine contamination was carried out on two prototype instruments with standard polystyrene photometric cuvettes. We analyzed 209 and 119 urine samples. Due to high sensitivity of the method, up to 50% negative samples were detected within 10 min by initial opacity and 90% negative samples were detected during 3.5 h by registration of the bacterial growth curves. PMID- 26028235 TI - Cuprizone Model as a Tool for Preclinical Studies of the Efficacy of Multiple Sclerosis Diagnosis and Therapy. AB - To study demyelination and remyelination processes and their response to different drugs, a protocol for modeling multiple sclerosis using the copper chelator cuprizone was developed. Magnetic resonance imaging confirmed the presence of demyelination lesions on week 4 of 0.6% cuprizone-containing diet. Immunohistochemical staining with polyclonal antibodies to glial fibrillary acidic protein (pAb GFAP) confirmed the increase in the number of reactive astrocytes on week 4 of diet and during remyelination (week 2 after diet). Analysis of neurophysiological functions in mice with cuprizone-induced demyelination revealed motor and behavioral deficits. This model can be used as a tool for preclinical studies of the efficiency of multiple sclerosis diagnostic and therapy. PMID- 26028237 TI - Chemical reaction mechanisms in solution from brute force computational Arrhenius plots. AB - Decomposition of activation free energies of chemical reactions, into enthalpic and entropic components, can provide invaluable signatures of mechanistic pathways both in solution and in enzymes. Owing to the large number of degrees of freedom involved in such condensed-phase reactions, the extensive configurational sampling needed for reliable entropy estimates is still beyond the scope of quantum chemical calculations. Here we show, for the hydrolytic deamination of cytidine and dihydrocytidine in water, how direct computer simulations of the temperature dependence of free energy profiles can be used to extract very accurate thermodynamic activation parameters. The simulations are based on empirical valence bond models, and we demonstrate that the energetics obtained is insensitive to whether these are calibrated by quantum mechanical calculations or experimental data. The thermodynamic activation parameters are in remarkable agreement with experiment results and allow discrimination among alternative mechanisms, as well as rationalization of their different activation enthalpies and entropies. PMID- 26028236 TI - The Serum Profile of Hypercytokinemia Factors Identified in H7N9-Infected Patients can Predict Fatal Outcomes. AB - The novel avian origin influenza A (H7N9) virus has caused severe diseases in humans in eastern China since the spring of 2013. Fatal outcomes of H7N9 infections are often attributed to the severe pneumonia and acute respiratory distress syndrome (ARDS). There is urgent need to discover biomarkers predicting the progression of disease and fatal outcome of potentially lethal flu infections, based on sound statistical analysis. We discovered that 34 of the 48 cytokines and chemokines examined in this study were significantly elevated in the plasma samples from patients infected with H7N9. We report for the first time that the levels of MIF, SCF, MCP-1, HGF, and SCGF-beta are highly positively linked to disease severity and the profile of mediators MIF, SCF, MCP-1, HGF, SCGF-beta, IP-10, IL-18, and IFN-gamma is an independent outcome predictor. PMID- 26028239 TI - Will Sodium Intake Reduction Improve Cardiovascular Outcomes in the General Population? A Critical Review of Current Evidence. AB - The data associating blood pressure to salt intake in humans comes from randomized clinical trials of interventions on dietary salt intake and population studies. Generally, estimates from meta-analyses are similar to those derived from prospective population studies (1.7 mm Hg change in systolic blood pressure per 100 mmol change in 24-hour urinary sodium). This observation, however, does not translate into a higher risk of incidence rate of hypertension in individuals consuming a highsalt diet. On the other hand, prospective studies relating cardiovascular outcomes to 24-h urinary sodium excretion produced inconsistent conclusions. Thus, available evidence does not support current recommendations of an indiscriminate and generalized reduction of salt intake in the general population. PMID- 26028238 TI - N-myc downstream-regulated gene 1 (NDRG1) mediates pomegranate juice protection from apoptosis in hypoxic BeWo cells but not in primary human trophoblasts. AB - INTRODUCTION: N-Myc downstream-regulated gene 1 (NDRG1) expression is increased in placentas of human pregnancies with intrauterine growth restriction and in hypoxic cultured primary trophoblasts. We previously showed that elevated NDRG1 decreases trophoblast apoptosis induced by hypoxia. Separately, we found that pomegranate juice (PJ) decreases cell death induced by hypoxia in trophoblasts. Here, we test the hypothesis that PJ protects trophoblasts from hypoxia-induced apoptosis by modulating NDRG1 expression. METHODS: Quantitative rtPCR was used to investigate the effects of PJ treatment on mRNA levels of 22 candidate genes involved in apoptosis, oxidative stress, and differentiation in trophoblasts. Western blotting and immunofluorescence were used to analyze NDRG1 protein levels. siRNA-mediated NDRG1 knockdown was used to investigate the role of NDRG1 in response to PJ in hypoxic BeWo choriocarcinoma cells and hypoxic cultured primary human trophoblasts. RESULTS: The mRNA levels of eight genes were altered, with NDRG1 showing the largest response to PJ and thus, we pursued the role of NDRG1 here. PJ significantly increased NDRG1 protein expression in primary trophoblasts and in BeWo cells. Knockdown of NDRG1 in hypoxic BeWo cells in the presence of PJ yielded increased apoptosis. In contrast, knockdown of NDRG1 in hypoxic primary trophoblasts in the presence of PJ did not increase apoptosis. DISCUSSION: We conclude that the PJ-mediated decrease in cell death in hypoxia is partially mediated by NDRG1 in BeWo cells but not in primary trophoblasts. The disparate effects of NDRG1 between BeWo cells and primary trophoblasts indicate caution is required when extrapolating from results obtained with cell lines to primary trophoblasts. PMID- 26028240 TI - Pro Atrial Natriuretic Peptide (1-30) and 6-keto PGF1alpha Activity Affects Na(+) Homeostasis in Non-modulating Hypertension. AB - Non-modulating hypertension (NMHT) is a high renin subtype of salt sensitive hypertension, which fails to achieve renal vasodilatation and a correct Na(+) handling during sodium load. We investigate, in MHT and NMHT, the role of ANP, the renin-angiotensin system and PgI2, in the renal sodium handling mechanisms. After 10 days of low (20mmol.L) or after 72hs of high (250mmol.L) sodium intake, 13 NMHT (34+/-5y; 9 male) and 13 MHT (32+/-4y; 10male) were studied. Pro-ANP (1 30) PgI2, PRA and total exchangeable Na(+)24 (ENa(+)) were measured. Under low sodium intake, PRA (4.2+/-0.5ng.ml.h; p<0.05) and Pro-ANP (78.6+/-2pg/ml, p<0.05) were higher than in NMHT under (3.1+/-0.4ng.ml.h and 69.8+/-3 pg/ml). After 72h of high Na(+) intake, Pro-ANP (1-30) increased significantly only in MHT (82.1+/ 3pg/ml, p<0.05). PgI2, under low sodium intake (1.83+/-0.2pg/24h), increased in MHT after 72h under high sodium (2.58+/-0.5pg/ 24h, p<0.02). Under low sodium diet, PgI2 (2.16+/-0.11pg/24h) was as higher in NMHT, as in MHT. After 72h under high Na+ intake, it failed to show any change (2.61+/-0.36 pg/24h; p=ns). A significant correlation between variations in ENa(+) and mean blood pressure (r=0.50, p<0.01), variations in Pro-ANP (1-30) values and ENa(+) in MHT (r=0.95; p<0.001) while a negative correlation between ENa(+) variations and ENa(+) (r=0.81, p<0.05) was observed in NMHT. ENa(+) variations were only significantly related to variations in FF in MHT. Thus, in NMHT, there is an unbalanced relationship between vasonstrictor and vasodilator mediators. From these, as an extrarenal homeostatic mediator, ANP seems to play an important role to compensate the altered renal sodium handling. PMID- 26028241 TI - Sodium Intake as a Modulator of Kidney Function. AB - Individual responses to alterations in salt intake vary widely. While salt has no effect on blood pressure in some people, it may substantially increase pressure in others. The reason why this difference exists is not very clear yet but many observations point towards the kidney as an important mediator. The adaptation in urinary output of sodium after a salt challenge (increase or decrease) also is not uniform. It is thought that the renin-angiotensin system may play an important role in determining how much sodium the body expels or retains after salt intake is suddenly reduced or augmented. Recent data suggest that the peptide Ang (1-7) and the endogenous nitric oxide inhibitor asymmetric dimethylarginine could be critically involved in the regulation of the renal response to altered salt intake. PMID- 26028242 TI - Sodium Intake Recommendations: A Subject that Needs to be Reconsidered. AB - Hypertension affects 1 billion people worldwide and is considered the leading cause of death, stroke, myocardial infarction and congestive heart failure. Sodium intake is reported to be a modifiable determinant of hypertension and reductions in its consumption have been widely recommended. Various strategies have been proposed to address the observed epidemic of cardiovascular diseases, particularly in medium and low-income countries. Among these strategies, reducing dietary sodium intake and increasing dietary potassium intake are commonly included in guidelines for the treatment of hypertension and the prevention of cardiovascular disease. In the present article, we review the results of recent studies that have raised questions about potential adverse effects associated with low sodium intake on important health outcomes, including cardiovascular diseases and death. It is clear from these studies, that there are contradictory and irreconcilable positions in the interpretation of the evidence, a situation that indicates that there is an urgent need for international randomized controlled trials that consistently demonstrate that the low levels of sodium intake recommended in the guidelines are safe and beneficial for different populations around the world. In the interim, and in accordance with a number of experts, we agree that the current evidence argues against the reduction of dietary sodium as an isolated public health recommendation and that an alternative approach of recommending high quality, potassium rich diets, might achieve greater health benefits, including blood-pressure reduction, than aggressive sodium reduction alone. PMID- 26028243 TI - Mechanisms of Salt-Sensitive Hypertension. AB - Hypertension and its consequences, including heart failure, stroke, and kidney disease, are responsible for substantial morbidity and mortality worldwide. Lifestyle changes, particularly sodium reduction, contribute to blood pressure control. However, not all individuals, whether normotensive or hypertensive, have the same susceptibility to the effects of salt. While a variety of approaches have been proposed to identify salt sensitive patients, there is no consensus for a definition of salt sensitivity and the precise mechanisms that explain their association are not yet fully understood. In this review we summarize the current understanding of the various pathophysiological mechanisms potentially involved in determining the salt sensitive phenotype. Genetic, neuronal, and immune alterations are reviewed. Additionally, we provide an update on the current knowledge of a new approach proposing the interstitium of the skin may act as a sodium reservoir. The role of dietary potassium on salt sensitive hypertension is also summarized. PMID- 26028246 TI - Prospective memory performance in traumatic brain injury patients: a study of implementation intentions. AB - Traumatic brain injury (TBI) patients often present with prospective memory (PM) dysfunction. Forgetting to complete tasks may result in a loss of independence, limited employment prospects and anxiety, therefore, it is important to develop programs to improve PM performance in TBI patients. A strategy which may improve PM performance is implementation intentions. It involves making explicit plans specifying when, where and how one will perform a task in the future. In the present study, a group of 36 TBI patients and a group of 34 controls performed Virtual Week using either implementation intentions or no strategy. The results showed that the PM performance of TBI patients was less accurate than controls, in particular when the PM cue was time-based. No effect of implementation intentions was observed for TBI patients, however, controls improved their PM performance when the task was time-based. The findings suggest that strategies to improve PM in this clinical group are likely to be more complex than those that benefit healthy adults and may involve targeting phases of the PM process other than, or in addition to, the intention formation phase. PMID- 26028244 TI - Salt-Sensitive Hypertension: Perspectives on Intrarenal Mechanisms. AB - Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity. Although researchers have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure in response to high salt intake are complex and only partially understood. Until now, scientists have been unable to explain why some individuals are salt sensitive and others are salt resistant. Although a central role for the kidneys in the development of salt sensitivity and hypertension has been generally accepted, it is also recognized that hypertension is of multifactorial origin and a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt intake. Excess salt intake in susceptible persons may also induce inappropriate central and sympathetic nervous system responses and increase the production of intrarenal angiotensin II, catecholamines and other factors such as oxidative stress and inflammatory cytokines. One key factor is the concomitant inappropriate or paradoxical activation of the intrarenal renin-angiotensin system, by high salt intake. This is reflected by the increases in urinary angiotensinogen during high salt intake in salt sensitive models. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for some individuals to retain salt and develop salt-dependent hypertension. In this review, we focus mainly on the renal contributions that provide the mechanistic links between chronic salt intake and the development of hypertension. PMID- 26028249 TI - Microencapsulated Pig Islet Xenotransplantation as an Alternative Treatment of Diabetes. AB - Islet transplantation is emerging as an attractive option for the treatment of type 1 diabetes mellitus (T1DM). However, some major obstacles are needed to be overcome, including shortage of islet supply and excessive immunosuppressive therapy. Xenotransplantation of bioartificial pancreas (BAP) made of microencapsulated pig islets will effectively solve these problems. Before widespread application of this therapy, several important issues should be addressed to further improve pig islet viability and functionality, such as pig islet source, optimization of microcapsule preparation, cryopreservation of implant, selection of biocompatible material, and implant site, as well as prevention of xenoreaction and biosafety concern. It is hoped that improvements in these critical aspects will lead to wider human application of microencapsulation of pig islets. PMID- 26028250 TI - Homogenous Phase Enrichment of Cysteine-Containing Peptides for Improved Proteome Coverage. AB - We describe a proteomic reactor-based homogeneous phase enrichment of cysteine containing peptides in a filter aided sample preparation (FASP) format. In this approach thiol-reduced proteins are derivatized with thiol-activated polyethylene glycol (TAPEG) before protein cleavage. Consecutive digestion with endoproteinase LysC and trypsin allows isolation of two fractions of nonderivatized peptides. After reduction of disulfide bonds between cysteine-containing peptides and the polyethylene glycol moieties, a third fraction of peptides is collected. LC-MS/MS analyses revealed that on average this fraction consists of 95% cysteine containing peptides. Since 85-93% of all peptides are unique to a single subfraction, the combination of TAPEG and FASP offers an efficient peptide separation strategy. Analysis of whole cell lysates of mouse brain, liver, red muscle fibers, and CaCo-2 cells using the TAPEG FASP approach allowed identification of 6,900, 5,800, 4,200 and 7,900 proteins, 10-30% more than were identified using two-step digestion without isolation of Cys-containing peptides. The fractionation also increased the protein sequence coverage by 10-30%. PMID- 26028245 TI - Genomics and Pharmacogenomics of Salt-sensitive Hypertension. AB - Salt sensitivity is estimated to be present in 51% of the hypertensive and 26% of the normotensive populations. The individual blood pressure response to salt is heterogeneous and possibly related to inherited susceptibility. Although the mechanisms underlying salt sensitivity are complex and not well understood, genetics can help to determine the blood response to salt intake. So far only a few genes have been found to be associated with salt-sensitive hypertension using candidate gene association studies. The kidney is critical to overall fluid and electrolyte balance and long-term regulation of blood pressure. Thus, the pathogenesis of salt sensitivity must involve a derangement in renal NaCl handling: an inability to decrease renal sodium transport and increase sodium excretion in the face of an increase in NaCl load that could be caused by aberrant counter-regulatory natriuretic/antinatriuretic pathways. We review here the literature regarding the gene variants associated with salt-sensitive hypertension and how the presence of these gene variants influences the response to antihypertensive therapy. PMID- 26028251 TI - Car-Parrinello Molecular Dynamics Simulations of Infrared Spectra of Crystalline Vitamin C with Analysis of Double Minimum Proton Potentials for Medium-Strong Hydrogen Bonds. AB - We studied proton dynamics of a hydrogen bonds of the crystalline l-ascorbic acid. Our approach was based on the Car-Parrinello molecular dynamics. The focal point of our study was simulation of the infrared spectra of l-ascorbic acid associated with the O-H stretching modes that are very sensitive to the strength of hydrogen bonding. In the l-ascorbic acid there are four kinds of hydrogen bonds. We calculated their spectra by using anharmonic approximation and the time course of the dipole moment function as obtained from the Car-Parrinello simulation. The quantization of the nuclear motion of the protons was made to perform detailed analysis of strength and properties of hydrogen bonds. We presented double minimum proton potentials with small value of barriers for medium-strong hydrogen bonds. We have also shown the difference character of medium-strong hydrogen bonds compared to weaker hydrogen bonds in the l-ascorbic acid. PMID- 26028252 TI - Bacillus subtilis comes of age as a vaccine production host and delivery vehicle. AB - Bacillus subtilis is a vaccine production host and delivery vector with several advantages such as a low production cost, straightforward administration as it is safe for human consumption and the production of spores exerting adjuvant effects. This review summarizes the expression approaches and provides an updated outlook of how a myriad of pathogens have been targeted under this technology. Furthermore, by reviewing the literature, several promising candidates in terms of immunogenic and immunoprotective potential have been identified. The immune profiles achieved comprise either humoral or cellular responses, which reflect versatility for application in the fight of distinct pathologies that demand specific polarization on the immune responses. Some perspectives for this field are also envisioned. PMID- 26028253 TI - Preclinical studies of dendrimer prodrugs. AB - INTRODUCTION: Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. AREAS COVERED: This article summarizes preclinical studies pertaining to the use of drug dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. EXPERT OPINION: Drug-dendrimer conjugates are preferable to drug dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.' PMID- 26028254 TI - A 16-year-old girl with anti-NMDA-receptor encephalitis and family history of psychotic disorders. AB - BACKGROUND: Autoimmune NMDA-R encephalitis (ANRE) shares clinical features with schizophrenia. Recent research also indicates that both disorders are associated with dysfunction of the N-Methyl-D-Aspartate glutamate receptors (NMDA-R) subunit 1. METHODS: We present the case of Ms A, 16 years old. Ms A presented with acute personality change, bizarre behaviour, delusional ideas and atypical seizures. She had a family history of psychotic disorders, and autistic traits diagnosed in childhood. She was initially diagnosed with a psychotic disorder. Delayed testing of CSF indicated ANRE. As the patient was a Jehovah's witness the treating team was unable to use gammaglobulin therapy; they instead relied on combined plasmapheresis and rituximab. To exclude the possibility that the affected members of this family shared a gene coding for an abnormal configuration of the NMDA receptor subunit 1 we sequenced the region of the GRIN1 gene in DNA extracted from blood in both Ms A and her grandmother. RESULTS: Ms A's condition improved dramatically, though her long-term memory is still demonstrably impaired. No genetic abnormality was detected. CONCLUSIONS: This case emphasizes how important it is, for a first episode psychosis, to exclude ANRE and other autoimmune synaptic encephalitides, even in the face of significant family history, and if seronegative, the importance of testing for CSF autoantibodies. PMID- 26028257 TI - Passive leg raising and compression stockings: a note of caution. PMID- 26028256 TI - Efficacy of conversion gastrectomy following docetaxel, cisplatin, and S-1 therapy in potentially resectable stage IV gastric cancer. AB - BACKGROUND: Recent advances in gastric cancer chemotherapy have made macroscopic complete resection possible in some patients with stage IV disease. METHODS: We retrospectively investigated the efficacy of multimodal therapy with combined docetaxel, cisplatin, and S-1 (DCS) and conversion gastrectomy in 57 patients with stage IV gastric cancer. RESULTS: Of the 57 patients, 15 patients were categorized into potentially resectable case, which is defined as patients with single incurable factor including the upper abdominal para-aortic lymph node metastasis (16a2b1 PAN metastasis) or fewer than three peripheral liver metastases. The other 42 were categorized as initially unresectable. All of patients underwent DCS therapy, and then 34 patients underwent conversion gastrectomy. The 3-year overall survival (OS) rate among the patients who underwent conversion gastrectomy was 50.1% with MST of 29.9 months. They had significantly longer OS than patients who underwent DCS therapy alone (p < 0.01). Univariate analysis among the patents with conversion gastrectomy identified 16a2b1PAN metastasis, peritoneal metastasis, potential resectable case, R0 resection as significant prognostic factors. A 3-year OS in potential resectable cases was 92.9%. Multivariate analysis identified potential resectability as the only independent prognostic factor contributing to OS (HR 0.133, 95%CI 0.024-0. 744, p = 0.021). In contrast, clinical response was selected as the only independent prognostic factor in the subgroup of initially unresectable cases (HR 0.354, 95%CI 0.151-0.783, p = 0.021). CONCLUSION: Patients with potentially resectable disease had a remarkably good prognosis among stage IV gastric cancer patients, and might be ideal candidates for conversion gastrectomy following DCS therapy. PMID- 26028255 TI - PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. AB - BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20 week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.). PMID- 26028258 TI - Adipose-derived Mesenchymal Stem Cells and Their Reparative Potential in Ischemic Heart Disease. AB - Adipose tissue has long been considered an energy storage and endocrine organ; however, in recent decades, this tissue has also been considered an abundant source of mesenchymal cells. Adipose-derived stem cells are easily obtained, show a strong capacity for ex vivo expansion and differentiation to other cell types, release a large variety of angiogenic factors, and have immunomodulatory properties. Thus, adipose tissue is currently the focus of considerable interest in the field of regenerative medicine. In the context of coronary heart disease, numerous experimental studies have supported the safety and efficacy of adipose derived stem cells in the setting of myocardial infarction. These results have encouraged the clinical use of these stem cells, possibly prematurely. Indeed, the presence of cardiovascular risk factors, such as hypertension, coronary disease, diabetes mellitus, and obesity, alter and reduce the functionality of adipose-derived stem cells, putting in doubt the efficacy of their autologous implantation. In the present article, white adipose tissue is described, the stem cells found in this tissue are characterized, and the use of these cells is discussed according to the preclinical and clinical trials performed so far. PMID- 26028259 TI - Enhancing performances of SSVEP-based brain-computer interfaces via exploiting inter-subject information. AB - OBJECTIVE: A new training-free framework was proposed for target detection in steady-state visual evoked potential (SSVEP)-based brain-computer interfaces (BCIs) using joint frequency-phase coding. APPROACH: The key idea is to transfer SSVEP templates from the existing subjects to a new subject to enhance the detection of SSVEPs. Under this framework, transfer template-based canonical correlation analysis (tt-CCA) methods were developed for single-channel and multi channel conditions respectively. In addition, an online transfer template-based CCA (ott-CCA) method was proposed to update EEG templates by online adaptation. MAIN RESULTS: The efficiency of the proposed framework was proved with a simulated BCI experiment. Compared with the standard CCA method, tt-CCA obtained an 18.78% increase of accuracy with a data length of 1.5 s. A simulated test of ott-CCA further received an accuracy increase of 2.99%. SIGNIFICANCE: The proposed simple yet efficient framework significantly facilitates the use of SSVEP BCIs using joint frequency-phase coding. This study also sheds light on the benefits from exploring and exploiting inter-subject information to the electroencephalogram (EEG)-based BCIs. PMID- 26028260 TI - Panton-Valentine leucocidin expression by Staphylococcus aureus exposed to common antibiotics. AB - OBJECTIVES: We set out to investigate the impact of common antibiotics on Panton Valentine Leucocidin (PVL) expression by methicillin-sensitive Staphylococcus aureus (MSSA). PVL expression by methicillin-resistant S. aureus (MRSA) is reportedly enhanced by beta-lactams, but inhibited by protein-synthesis inhibitors, a fact that has influenced management of infections associated with PVL. Although PVL is more frequently associated with MSSA than MRSA in the UK, the effect of antibiotics on PVL expression by MSSA has not been fully addressed. METHODS: MSSA was cultured in vitro with varying concentrations of flucloxacillin, clindamycin or linezolid and PVL expression measured by qRT-PCR and Western blotting. A murine MSSA abscess model was developed to measure leucocidin expression in vivo following antibiotic treatment. RESULTS: 9% (27/314) of MSSA isolates from patients with uncomplicated community skin/soft tissue infections were positive for PVL genes (lukFS-PV). PVL expression by MSSA in broth was unaffected by varying concentrations of flucloxacillin, clindamycin or linezolid. In a murine abscess model, treatment with flucloxacillin did, however, enhance in vivo MSSA lukF-PV transcription and this was sustained even when flucloxacillin was combined with clindamycin, or clindamycin plus linezolid. Notwithstanding increased leucocidin transcription, functional leucotoxin activity was not enhanced. Treatment with flucloxacillin plus clindamycin significantly decreased leucotoxin activity, but the addition of a second protein synthesis inhibitor, linezolid, did not confer benefit. CONCLUSIONS: Our results suggest flucloxacillin in combination with a single protein-synthesis inhibitor such as clindamycin would give the best treatment outcome. PMID- 26028262 TI - Closing the Sex Gap in Advanced Heart Failure: Reality or Illusion? PMID- 26028261 TI - Randomized clinical trial of an integrated self-care intervention for persons with heart failure and diabetes: quality of life and physical functioning outcomes. AB - OBJECTIVES: Persons with concomitant heart failure (HF) and diabetes mellitus (DM) have complicated, often competing, self-care expectations and treatment regimens that may reduce quality of life (QOL). This randomized controlled trial tested an integrated self-care intervention on outcomes of HF and DM QOL, physical function, and physical activity (PA). METHODS AND RESULTS: Participants with HF and DM (n = 134; mean age 57.4 +/- 11 years, 66% men, 69% minority) were randomized to usual care (control) or intervention. The control group received standard HF and DM educational brochures with follow-up telephone contact. The intervention group received education and counseling on combined HF and DM self care (diet, medications, self-monitoring, symptoms, and PA) with follow-up home visit and telephone counseling. Measures included questionnaires for HF- and DM specific and overall QOL, PA frequency, and physical function (6-min walk test [6MWT]) and were obtained at baseline and 3 and 6 months. Analysis included mixed models with a priori post hoc tests. Adjusting for age, body mass index, and comorbidity, the intervention group improved in HF total (P = .002) and physical (P < .001) QOL scores at 3 months with retention of improvements at 6 months, improved in emotional QOL scores compared with control at 3 months (P = .04), and improved in health status ratings (P = .04) at 6 months compared with baseline. The intervention group improved in 6MWT distance (924 ft to 952 ft; P = .03) whereas the control group declined (834 ft to 775 ft; F1,63 = 6.86; P = .01). The intervention group increased self-reported PA between baseline and 6 months (P = .01). CONCLUSIONS: An integrated HF and DM self-care intervention improved perceived HF and general QOL but not DM QOL. Improved physical functioning and self-reported PA were also observed with the integrated self-care intervention. Further study of the HF and DM integrated self-care intervention on other outcomes, such as hospitalization and cost, is warranted. PMID- 26028263 TI - Repletion of Iron Stores With the Use of Oral Iron Supplementation in Patients With Systolic Heart Failure. AB - BACKGROUND: Iron deficiency is associated with reduced functional capacity and increased mortality in patients with heart failure with reduced ejection fraction (HFrEF). Correction of iron deficiency in HFrEF patients with the use of intravenous iron improves symptoms, quality of life, and exercise performance. Whether oral iron improves iron stores in HFrEF patients is unknown. We conducted a retrospective study to assess the efficacy of oral iron supplementation in iron deficient HFrEF patients. METHODS AND RESULTS: Iron-deficient HFrEF patients with a record of oral iron supplementation and iron studies before and ~180 days after supplementation were identified. Iron deficiency was defined as ferritin <100 ng/mL or as ferritin 100-300 ng/mL with transferrin saturation (Tsat) <20%. Spearman correlation was performed to assess for treatment responsiveness. In 105 patients, ferritin (from median 39 ng/mL to 75 ng/mL), Tsat (from 10% to 21%), iron (from 34 MUg/dL to 69 MUg/dL), and hemoglobin (from 10.4 g/dL to 11.6 g/dL) values increased (P < .0001), whereas total iron-binding capacity decreased (from 343 to 313 MUg/dL; P = .0007) at 164 days after initiation of oral iron supplementation. CONCLUSIONS: In this retrospective study, oral iron supplementation improved iron stores similarly to previously reported results with the use of intravenous iron repletion in HFrEF patients, suggesting that oral iron merits prospective evaluation as an intervention strategy in HFrEF. PMID- 26028264 TI - A deep coverage Dictyostelium discoideum genomic DNA library replicates stably in Escherichia coli. AB - The natural history of the amoeba Dictyostelium discoideum has inspired scientific inquiry for seventy-five years. A genetically tractable haploid eukaryote, D. discoideum appeals as a laboratory model as well. However, certain rote molecular genetic tasks, such as PCR and cloning, are difficult due to the AT-richness and low complexity of its genome. Here we report on the construction of a ~20 fold coverage D. discoideum genomic library in Escherichia coli, cloning 4-10 kilobase partial restriction fragments into a linear vector. End-sequencing indicates that most clones map to the six chromosomes in an unbiased distribution. Over 70% of these clones contain at least one complete open reading frame. We demonstrate that individual clones and library composition are stable over multiple replication cycles. Our library will enable numerous molecular biological applications and the completion of additional species' genome sequences, and suggests a path towards the long-elusive goal of genetic complementation. PMID- 26028265 TI - Total ankle replacement. PMID- 26028267 TI - Asymmetrical Squaraines Bearing Fluorine-Substituted Indoline Moieties for High Performance Solution-Processed Small-Molecule Organic Solar Cells. AB - Two novel asymmetrical squaraines based on the indoline unit, ASQ-5-F and ASQ-5 DF, with one and two fluorine substituents, have been developed to investigate the effect of fluorine substituted on small-molecule bulk-heterojunction (BHJ) organic solar cells (OSCs). In comparison with non-fluorine-substituted ASQ-5, both fluorine-substituted ASQ-5-F and ASQ-5-DF possess analogous absorption band gaps but 0.05 and 0.10 eV lowered highest occupied molecular orbital (HOMO) energy levels, respectively. Single-crystal analysis exhibits that ASQ-5-DF shows more desirable intermolecular packing patterns for the hole-carrier collection than ASQ-5 does; hence, higher hole mobility could be acquired. Therefore, solution-processed small-molecule BHJ OSCs fabricated with ASQ-5-F/PC71BM and ASQ 5-DF/PC71BM blends exhibit extremely higher power conversion efficiency (PCE; 5.0% and 6.0%, respectively) than that of ASQ-5/PC71BM (4.5%). The much improved PCE could be attributed to the simultaneously enhanced Voc, Jsc, and FF relative to those of the ASQ-5-based device. To our knowledge, this is the highest PCE (6.0%) among squaraine-based solution-processed BHJ OSCs and the highest PCE in OSCs based on the fluorinated donor segment of small molecules. PMID- 26028266 TI - Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms. AB - Investigating genomic structural variants at basepair resolution is crucial for understanding their formation mechanisms. We identify and analyse 8,943 deletion breakpoints in 1,092 samples from the 1000 Genomes Project. We find breakpoints have more nearby SNPs and indels than the genomic average, likely a consequence of relaxed selection. By investigating the correlation of breakpoints with DNA methylation, Hi-C interactions, and histone marks and the substitution patterns of nucleotides near them, we find that breakpoints with the signature of non allelic homologous recombination (NAHR) are associated with open chromatin. We hypothesize that some NAHR deletions occur without DNA replication and cell division, in embryonic and germline cells. In contrast, breakpoints associated with non-homologous (NH) mechanisms often have sequence microinsertions, templated from later replicating genomic sites, spaced at two characteristic distances from the breakpoint. These microinsertions are consistent with template switching events and suggest a particular spatiotemporal configuration for DNA during the events. PMID- 26028268 TI - The influence of intimate partnerships on nurse student progression: An integrative literature review. AB - OBJECTIVE: To identify the best available evidence on the influence of intimate partnerships (marriage or de facto relationships) on nurse student progression. BACKGROUND: Projections of future nursing workforce shortages have provided renewed impetus to study pre-registration nurse student progression. Factors external to the university are highly influential for non-traditional student groups such as nursing. As the average age of nurse students' rise, the influence of intimate partnerships requires investigation. DATA SOURCES: An international integrative review was conducted in literature from 1990 to 2015 across a range of databases. REVIEW METHODS: A structured approach was used for data collection, analysis and evaluation, resulting in a selection of 17 international papers. RESULTS: There were few common definitions, and little agreement regarding measurement of key factors and variables across the literature. Research into partnership influences on nurse student progression was minimal however findings across a range of disciplines revealed partner support as a principal influence; enabling or hindering the student's social and academic university involvement. Given that nursing is a highly feminised profession, the finding that support was less forthcoming from female students' male partners than vice versa was a particular concern. Women students reported challenging their partners' traditional domestic gender role expectations, which sometimes led, to relationship conflict and breakdown, further impeding their ability to progress. CONCLUSION: Lesser support from their male partners may have unwelcome implications for the progression of the increasing population of mature-age women nurse students. The comparatively few studies and their diversity limit the applicability of the review findings to current nurse education. With workforce sustainability threatened, studies directly investigating the influence of partnerships on nurse student progression are required, employing standardised and transparent terms and measurements. PMID- 26028269 TI - Some unbeautiful aspects about 'The Game'. PMID- 26028270 TI - Identifying and Quantifying Adulterants in Extra Virgin Olive Oil of the Picual Varietal by Absorption Spectroscopy and Nonlinear Modeling. AB - In this research, the detection and quantification of adulterants in one of the most common varieties of extra virgin olive oil (EVOO) have been successfully carried out. Visible absorption information was collected from binary mixtures of Picual EVOO with one of four adulterants: refined olive oil, orujo olive oil, sunflower oil, and corn oil. The data gathered from the absorption spectra were used as input to create an artificial neural network (ANN) model. The designed mathematical tool was able to detect the type of adulterant with an identification rate of 96% and to quantify the volume percentage of EVOO in the samples with a low mean prediction error of 1.2%. These significant results make ANNs coupled with visible spectroscopy a reliable, inexpensive, user-friendly, and real-time method for difficult tasks, given that the matrices of the different adulterated oils are practically alike. PMID- 26028271 TI - Reduced plasma serotonin and 5-hydroxyindoleacetic acid levels in Parkinson's disease are associated with nonmotor symptoms. AB - BACKGROUND: Accumulating evidence suggests that serotonergic system may be implicated in the pathophysiology of Parkinson's disease (PD), and particularly in nonmotor symptoms such as depression, fatigue, sleep disorders, sensory and autonomic dysfunction. This study aimed to evaluate plasma levels of serotonin (5 HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in PD patients, and investigate their associations with nonmotor symptoms. METHODS: Eighty-two PD patients and sixty-four controls underwent a series of clinical assessments, including Hamilton Depression Scale, Fatigue Severity Scale, Pittsburgh Sleep Quality Index, Visual Analog Scale for Pain, and Scale for Outcomes in PD for Autonomic Symptoms. Plasma 5-HT and 5-HIAA levels were measured by HPLC-ECD. RESULTS: PD patients exhibited worse performance on nonmotor symptom scales (all P-values <0.001) and presented lower plasma levels of 5-HT (P < 0.001) and 5-HIAA (P < 0.001) than control individuals. Within the PD group, decreased concentrations of plasma 5-HT and 5-HIAA were correlated with more severe depression (r = -0.447, P < 0.001; r = -0.407, P < 0.001, respectively) and pain (r = -0.485, P < 0.001; r = -0.416, P < 0.001, respectively). After performing multiple linear regression, plasma 5-HT (P = 0.01) and 5-HIAA (P = 0.006) remained significantly associated with depression. CONCLUSIONS: Our results suggest that serotonergic dysfunction might exist in PD, and specifically correlated with depression and pain in PD. Plasma levels of 5-HT and 5-HIAA may be considered as peripheral markers for depression in PD. PMID- 26028272 TI - Classic PD-like rest tremor associated with the tau p.R406W mutation. PMID- 26028273 TI - Sustained prevention of biofilm formation on a novel silicone matrix suitable for medical devices. AB - Bacterial colonization and biofilm formation on medical devices constitute major challenges in clinical long-term use of e.g. catheters due to the risk of (re)infection of patients, which would result in additional use of antibiotics risking bacterial resistance development. The aim of the present project was to introduce a novel antibacterial approach involving an advanced composite material applicable for medical devices. The polymeric composites investigated consisted of a hydrogel network of cross-linked poly(2-hydroxyethyl methacrylate) (PHEMA) embedded in a poly(dimethylsiloxane) (PDMS) silicone elastomer produced using supercritical carbon dioxide (scCO2). In these materials, the hydrogel may contain an active pharmaceutical ingredient while the silicone elastomer provides the sufficient mechanical stability of the material. In these conceptual studies, the antimicrobial agent ciprofloxacin was loaded into the polymer matrix by a post-polymerization loading procedure. Sustained release of ciprofloxacin was demonstrated, and the release could be controlled by varying the hydrogel content in the range 13-38% (w/w) and by changing the concentration of ciprofloxacin during loading in the range of 1-20mg/mL. Devices containing 25% (w/w) hydrogel and loaded with ciprofloxacin displayed a strong antibacterial effect against Staphylococcus aureus bacterial colonization and subsequent biofilm formation on the device material was inhibited for 29days. In conclusion, the hydrogel/silicone composite represents a promising candidate material for medical devices that prevent bacterial colonization during long-term use. PMID- 26028274 TI - Myasthenia gravis with presynaptic neurophysiological signs: Two case reports and literature review. AB - The distinction between myasthenia gravis and Lambert-Eaton myasthenic syndrome is based on clinical, neurophysiological and immunological features. We hereby report two cases with a clinical diagnosis of myasthenia gravis and neurophysiological features consistent with a pre-synaptic neuromuscular transmission defect. Both patients had increased anti-acetylcholine receptor antibody titres and showed a good response to cholinesterase inhibitors, along with a >100% facilitation of the compound muscle action potential on electrophysiological studies. We provide a review of English literature studies on co-existing features of myasthenia gravis and Lambert-Eaton myasthenic syndrome, and discuss diagnostic controversies. PMID- 26028275 TI - The influence of somatosensory and muscular deficits on postural stabilization: Insights from an instrumented analysis of subjects affected by different types of Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder. CMT1 is primarily demyelinating, CMT2 is primarily axonal, and CMTX1 is characterized by both axonal and demyelinating abnormalities. We investigated the role of somatosensory and muscular deficits on quiet standing and postural stabilization in patients affected by different forms of CMT, comparing their performances with those of healthy subjects. Seventy-six CMT subjects (CMT1A, CMT2 and CMTX1) and 41 healthy controls were evaluated during a sit-to-stand transition and the subsequent quiet upright posture by means of a dynamometric platform. All CMT patients showed altered balance and postural stabilization compared to controls. Multivariate analysis showed that in CMT patients worsening of postural stabilization was related to vibration sense deficit and to dorsi flexor's weakness, while quiet standing instability was related to the reduction of pinprick sensibility and to plantar-flexor's weakness. Our results show that specific sensory and muscular deficits play different roles in balance impairment of CMT patients, both during postural stabilization and in static posture. An accurate evaluation of residual sensory and muscular functions is therefore necessary to plan for the appropriate balance rehabilitation treatment for each patient, besides the CMT type. PMID- 26028276 TI - X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C>T substitution in the UBA1 gene. AB - Infantile X-linked spinal muscular atrophy (SMAX2) is a rare form of spinal muscular atrophy manifesting as severe hypotonia, areflexia, arthrogryposis, facial weakness and cryptorchidism, and frequently accompanied by bone fractures. We present a male patient with SMAX2 who presented with typical symptoms at birth, preceded by reduced fetal movements in the second and third trimesters of pregnancy. Clinical examination revealed a myopathic face with a characteristic tent-shaped open mouth, tongue fibrillations, profound muscle weakness, areflexia, multiple contractures, mild skeletal abnormalities and cryptorchidism. In the first days of the patient's life, fractures of the right femur and right humerus were found; however, calcium-phosphate metabolism and densitometric examination were normal. Molecular analysis revealed a de novo c.1731C>T substitution in the UBA1 gene, which was localized in exon 15, the specific hot spot for mutation. PMID- 26028277 TI - Analysis of composition of microbiomes: a novel method for studying microbial composition. AB - BACKGROUND: Understanding the factors regulating our microbiota is important but requires appropriate statistical methodology. When comparing two or more populations most existing approaches either discount the underlying compositional structure in the microbiome data or use probability models such as the multinomial and Dirichlet-multinomial distributions, which may impose a correlation structure not suitable for microbiome data. OBJECTIVE: To develop a methodology that accounts for compositional constraints to reduce false discoveries in detecting differentially abundant taxa at an ecosystem level, while maintaining high statistical power. METHODS: We introduced a novel statistical framework called analysis of composition of microbiomes (ANCOM). ANCOM accounts for the underlying structure in the data and can be used for comparing the composition of microbiomes in two or more populations. ANCOM makes no distributional assumptions and can be implemented in a linear model framework to adjust for covariates as well as model longitudinal data. ANCOM also scales well to compare samples involving thousands of taxa. RESULTS: We compared the performance of ANCOM to the standard t-test and a recently published methodology called Zero Inflated Gaussian (ZIG) methodology (1) for drawing inferences on the mean taxa abundance in two or more populations. ANCOM controlled the false discovery rate (FDR) at the desired nominal level while also improving power, whereas the t-test and ZIG had inflated FDRs, in some instances as high as 68% for the t-test and 60% for ZIG. We illustrate the performance of ANCOM using two publicly available microbial datasets in the human gut, demonstrating its general applicability to testing hypotheses about compositional differences in microbial communities. CONCLUSION: Accounting for compositionality using log-ratio analysis results in significantly improved inference in microbiota survey data. PMID- 26028278 TI - A CT-scan database for the facial soft tissue thickness of Taiwan adults. AB - Facial reconstruction is a branch of forensic anthropology used to assist in the identification of skeletal remains. The majority of facial reconstruction techniques use facial soft tissue depth chart data to recreate facial tissue on a skull or a model of a skull through the use of modeling clay. This study relied on 193 subjects selected from the Taiwanese population on the basis of age and gender to determine the average values of 32 landmarks, include midline and bilateral measures, by means of CT scans. The mean age of the subjects was 46.9+/ 16.4 years, with a mean age of 43.8+/-16.6 for males and 49.9+/-15.8 for females respectively. There were 16 landmarks with statistically significant differences between male and female subjects, namely S, G, N, Na, Ph, Sd and Id in the midline portion, FE, LO, ZA and Sub M2 in the bilateral-right and left portion, and IM point in the bilateral-left portion (abbreviations adapted from Karen T. Taylor's work). The mean soft tissue depth was greater in males than in females, and there was significant difference between the right and left sides of the face in Za point. This study's findings were compared with those of Bulut et al. PMID- 26028279 TI - Risk of poor neonatal outcome at term after medically assisted reproduction: a propensity score-matched study. AB - OBJECTIVE: To study risk of birth asphyxia and related morbidity among term singletons born after medically assisted reproduction (MAR). DESIGN: Population cohort study. SETTING: Not applicable. PATIENT(S): A total of 1,953,932 term singleton pregnancies selected from a national registry for 1999-2011. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome Apgar score <4; secondary outcomes Apgar score <7, intrauterine fetal death, perinatal mortality, congenital anomalies, small for gestational age, asphyxia related morbidity, and cesarean delivery. RESULT(S): The risks of birth asphyxia and related morbidity were calculated in women who conceived either through MAR or spontaneously (SC), with a subgroup analysis for in vitro fertilization (IVF). An additional propensity score matching analysis was performed with matching on multiple maternal baseline covariates (maternal age, ethnicity, socioeconomic status, parity, year of birth, and preexistent diseases). Each MAR pregnancy was matched to three SC controls. Relative to SC, the MAR singletons had an increased risk of adverse neonatal outcomes including Apgar score <4 (adjusted odds ratio [OR] 1.29; 95% CI, 1.14-1.46) and intrauterine fetal death (adjusted OR 1.61; 95% CI, 1.35-1.91). After propensity score matching, the risk of an Apgar score <4 was comparable between MAR and SC singletons (OR 0.99; 95% CI, 0.87-1.14). Cesarean delivery for both fetal distress and nonprogressive labor occurred more among MAR pregnancies compared with SC pregnancies. CONCLUSION(S): Term singletons conceived after MAR have an increased risk of morbidity related to birth asphyxia. Because this is mainly due to maternal characteristics, obstetric caregivers should be aware that the increased rates of cesareans reflect the behavior of women and physicians rather than increased perinatal complications. PMID- 26028280 TI - High-Resolution Size-Discrimination of Single Nonionic Synthetic Polymers with a Highly Charged Biological Nanopore. AB - Electrophysiological studies of the interaction of polymers with pores formed by bacterial toxins (1) provide a window on single molecule interaction with proteins in real time, (2) report on the behavior of macromolecules in confinement, and (3) enable label-free single molecule sensing. Using pores formed by the staphylococcal toxin alpha-hemolysin (aHL), a particularly pertinent observation was that, under high salt conditions (3-4 M KCl), the current through the pore is blocked for periods of hundreds of microseconds to milliseconds by poly(ethylene glycol) (PEG) oligomers (degree of polymerization approximately 10-60). Notably, this block showed monomeric sensitivity on the degree of polymerization of individual oligomers, allowing the construction of size or mass spectra from the residual current values. Here, we show that the current through the pore formed by aerolysin (AeL) from Aeromonas hydrophila is also blocked by PEG but with drastic differences in the voltage-dependence of the interaction. In contrast to aHL, AeL strongly binds PEG at high transmembrane voltages. This fact, which is likely related to AeL's highly charged pore wall, allows discrimination of polymer sizes with particularly high resolution. Multiple applications are now conceivable with this pore to screen various nonionic or charged polymers. PMID- 26028281 TI - No assembly required: Full-length MHC class I allele discovery by PacBio circular consensus sequencing. AB - Single-molecule real-time (SMRT) sequencing technology with the Pacific Biosciences (PacBio) RS II platform offers the potential to obtain full-length coding regions (~1100-bp) from MHC class I cDNAs. Despite the relatively high error rate associated with SMRT technology, high quality sequences can be obtained by circular consensus sequencing (CCS) due to the random nature of the error profile. In the present study we first validated the ability of SMRT-CCS to accurately identify class I transcripts in Mauritian-origin cynomolgus macaques (Macaca fascicularis) that have been characterized previously by cloning and Sanger-based sequencing as well as pyrosequencing approaches. We then applied this SMRT-CCS method to characterize 60 novel full-length class I transcript sequences expressed by a cohort of cynomolgus macaques from China. The SMRT-CCS method described here provides a straightforward protocol for characterization of unfragmented single-molecule cDNA transcripts that will potentially revolutionize MHC class I allele discovery in nonhuman primates and other species. PMID- 26028282 TI - A qualitative study exploring how the aims, language and actions of yoga for pregnancy teachers may impact upon women's self-efficacy for labour and birth. AB - BACKGROUND: As women's anxiety and the rate of medical intervention in labour and birth continue to increase, it is important to identify how antenatal education can increase women's confidence and their ability to manage the intense sensations of labour. AIM: To report a grounded theory study of how the aims, language and actions of yoga for pregnancy teachers may impact upon women's self efficacy for labour and birth. METHODS: Yoga for pregnancy classes in three locations were filmed. Semi-structured interviews were undertaken with the teachers to explore what they were trying to achieve in their classes, and how. Interviews and classes were transcribed and analysed using grounded theory. FINDINGS: There was considerable consistency in the teachers' aims, the language they used in classes and in their thinking about class structure. Four main themes emerged: creating a sisterhood, modelling labour, building confidence and enhancing learning. Teachers see yoga for pregnancy as a multi-faceted, non prescriptive intervention that enhances women's physical, emotional and social readiness for labour and birth, and supports women to make their own decisions across the transition to parenthood. CONCLUSION: Women's self-efficacy for labour is complex and multi-factorial. This study offers insights into the factors which may be involved in increasing it. These include not only traditional elements of yoga such as postures, breathing and meditation, but also the creation of safe, women-only groups where anxieties, experiences and stories can be shared, and pain-coping techniques for labour learned and practised. PMID- 26028283 TI - Multipathway modulation of exercise and glucose stress effects upon GH secretion in healthy men. AB - OBJECTIVE: Exercise evokes pulsatile GH release followed by autonegative feedback, whereas glucose suppresses GH release followed by rebound-like GH release (feedforward escape). Here we test the hypothesis that age, sex steroids, insulin, body composition and physical power jointly determine these dynamic GH responses. METHODS: This was a prospectively randomized glucose-blinded study conducted in the Mayo Center for Advancing Translational Sciences in healthy men ages 19-77 years (N=23). Three conditions, fasting/rest/saline, fasting/exercise/saline and fasting/rest/iv glucose infusions, were used to drive GH dynamics during 10-min blood sampling for 6h. Linear correlation analysis was applied to relate peak/nadir GH dynamics to age, sex steroids, insulin, CT estimated abdominal fat and physical power (work per unit time). RESULTS: Compared with the fasting/rest/saline (control) day, fasting/exercise/saline infusion evoked peak GH within 1h, followed by negative feedback 3-5h later. The dynamic GH excursion was strongly (R(2)=0.634) influenced by (i) insulin negatively (P=0.011), (ii) power positively (P=0.0008), and (iii) E2 positively (P=0.001). Dynamic glucose-modulated GH release was determined by insulin negatively (P=0.0039) and power positively (P=0.0034) (R(2)=0.454). Under rest/saline, power (P=0.031) and total abdominal fat (P=0.012) (R(2)=0.267) were the dominant correlates of GH excursions. CONCLUSION: In healthy men, dynamic GH perturbations induced by exercise and glucose are strongly related to physical power, insulin, estradiol, and body composition, thus suggesting a network of regulatory pathways. PMID- 26028284 TI - Research Priorities in Pediatric Palliative Care. AB - OBJECTIVE: To synthesize the perspectives of a broad range of pediatric palliative care (PPC) clinicians and parents, to formulate a consensus on prioritization of the PPC research agenda. STUDY DESIGN: A 4-round modified Delphi online survey was administered to PPC experts and to parents of children who had received PPC. In round 1, research priorities were generated spontaneously. Rounds 2 and 3 then served as convergence rounds to synthesize priorities. In round 4, participants were asked to rank the research priorities that had reached at least 80% consensus. RESULTS: A total of 3093 concepts were spontaneously generated by 170 experts and 72 parents in round 1 (65.8% response rate [RR]). These concepts were thematically organized into 78 priorities and recirculated for round 2 ratings (n = 130; 53.7% RR). Round 3 achieved response stability, with 31 consensus priorities oscillating within 10% of the mode (n = 98; 75.4% RR). Round 4 resulted in consensus recognition of 20 research priorities, which were thematically grouped as decision making, care coordination, symptom management, quality improvement, and education. CONCLUSIONS: This modified Delphi survey used professional and parental consensus to identify preeminent PPC research priorities. Attentiveness to these priorities may help direct resources and efforts toward building a formative evidence base. Investigating PPC implementation approaches and outcomes can help improve the quality of care services for children and families. PMID- 26028285 TI - Ways to Identify Children with Medical Complexity and the Importance of Why. PMID- 26028286 TI - Health Care Utilization and Costs of Publicly-Insured Children with Diabetes in California. AB - OBJECTIVE: To examine diabetes-related health care utilization and costs for a population-based sample of children with presumed type 1 diabetes (T1D) enrolled in the California Children's Services program. STUDY DESIGN: Our data source was the California Children's Services claims data for the period July 1, 2009, to June 30, 2012. We studied a sample of 652 children aged 0-21 years who were continuously enrolled for at least 365 days, had an outpatient visit for T1D, and were taking insulin. RESULTS: Compared with the younger age groups, individuals in the 19-21 year age group had the highest rates of hospitalization, T1D specific bed-days, and emergency department visits. The overall median cost for this population was $7654. The overall median costs per year (and proportion of total costs) were $5603 (59%) for hospitalizations, $58 (0.4%) for emergency department visits, $144 (1.3%) for outpatient utilization, $2930 (23%) for insulin, and $1579 (13%) for blood glucose monitoring supplies. For those who used them, the median cost of pumps was an additional $2162. CONCLUSION: Further studies are needed to provide more insight into patterns of care and adverse health outcomes for children with T1D as they transition into young adulthood. The costs of insulin, glucose monitoring supplies, and pump therapy for children with T1D is substantial and may factor into future policy considerations regarding coverage and cost-sharing with families. PMID- 26028287 TI - Racial/Ethnic Differences in Pediatric Brain Tumor Diagnoses in Patients with Neurofibromatosis Type 1. AB - OBJECTIVE: To evaluate evidence for differences in pediatric brain tumor diagnoses by race and ethnicity using a cross-sectional study design in individuals with neurofibromatosis type 1 (NF1). STUDY DESIGN: Subjects with NF1 were ascertained from the NF1 Patient Registry Initiative and through a clinical record database of patients at a large academic medical center. Logistic regression was employed to calculate ORs and 95% CIs to analyze differences in the odds of brain tumor diagnosis by race (White, Black, Asian, other/unknown) and ethnic (Hispanic vs non-Hispanic) groups. RESULTS: Data from a total of 1546, 629, and 2038 individuals who were ascertained from the NF1 Patient Registry Initiative, clinical records, and pooled datasets were analyzed, respectively. After adjusting for birth year, we observed a significantly reduced odds of brain tumor diagnoses in individuals self-identified or clinically reported as Black (OR = 0.13, 95% CI 0.05-0.31), Asian (OR = 0.15, 95% CI 0.04-0.64), and other/unknown (OR = 0.61, 95% CI 0.41-0.93) race compared with those with reported as White race. There was no significant difference in the odds of pediatric brain tumor diagnosis by Hispanic ethnicity. CONCLUSIONS: Consistent with prior smaller studies, these data suggest that pediatric brain tumor diagnoses vary by race in individuals with NF1. Reasons underlying observed differences by race warrant further investigation. PMID- 26028288 TI - Executive Function and Adaptive Behavior in Muenke Syndrome. AB - OBJECTIVE: To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls. STUDY DESIGN: Participants in this cross sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]). RESULTS: Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite. CONCLUSION: Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings. PMID- 26028290 TI - Biological factors underlying sex differences in neurological disorders. AB - The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies. PMID- 26028289 TI - Sexual Dimorphism in Newborn Vertebrae and Its Potential Implications. AB - OBJECTIVE: To examine whether the sex-related differences in vertebral cross sectional area (CSA) found in children and at the timing of peak bone mass-a major determinant of osteoporosis and future fracture risk-are also present at birth. STUDY DESIGN: Vertebral CSA, vertebral height, and intervertebral disc height were measured using magnetic resonance imaging in 70 healthy full-term newborns (35 males and 35 females). The length and CSA of the humerus, musculature, and adiposity were measured as well. RESULTS: Weight, body length, and head and waist circumferences did not differ significantly between males and females (P >= .06 for all). Compared with newborn boys, girls had significantly smaller mean vertebral cross-sectional dimensions (1.47 +/- 0.11 vs 1.31 +/- 0.12; P < .0001). Multiple linear regression analysis identified sex as a predictor of vertebral CSA independent of gestational age, birth weight, and body length. In contrast, the sexes were monomorphic with regard to vertebral height, intervertebral disc height, and spinal length (P >= .11 for all). There were also no sex differences in the length or cross-sectional dimensions of the humerus or in measures of musculature and adiposity (P >= .10 for all). CONCLUSION: Factors related to sex influence fetal development of the axial skeleton. The smaller vertebral CSA in females is associated with greater flexibility of the spine, which could represent the human adaptation to fetal load. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities and increases the susceptibility to fragility fractures later in life. PMID- 26028291 TI - Nuclear redox imbalance affects circadian oscillation in HaCaT keratinocytes. AB - Circadian clock is regulated by a transcriptional/translational feedback loop (TTFL) lasting ~24 h. Circadian oscillation of peroxiredoxins (PRDX1-6) redox status has been shown in mature erythrocytes. We have recently reported that nuclear levels of PRDX2 are circadian regulated in the HaCaT keratinocytes. In this study, we addressed whether PRDX2 translocation could influence the TTFL. A reporter HaCaT cell line stably expressing the luciferase gene under control of Bmal1 promoter was lentivirally transduced either with an empty vector (EV), a vector carrying a myc-tagged wild type PRDX2 (PRDX2-Myc) or the same gene with a nuclear localization sequence (PRDX2-MycNuc). PRDX2 overexpressing cells were protected from H2O2-induced oxidative stress. The amplitude of the Bmal1 promoter activity was significantly dampened in PRDX2-MycNuc versus EV cells when synchronized either by dexamethasone treatment or temperature cycles. Clock synchronization was not affected in PRDX2 silenced cells. N-acetyl cysteine or melatonin treatments, significantly dampened the Bmal1 promoter activity suggesting that sustained scavenging of ROS impairs clock synchronization. Noteworthy, H2O2 treatment rescued proper oscillation of the clock in synchronized PRDX2-MycNuc HaCaT cells. Since the histone deacetylase Sirtuin 1 (Sirt1) modulates clock gene expression amplitude, the effect of Sirt1 activator resveratrol or Sirt1 inhibitor nicotinamide were also investigated. Interestingly, NAM enhanced the molecular clock synchronization in PRDX2-MycNuc cells. Our findings demonstrate that PRDX2 regulates the TTFL oscillation by finely tuning the cellular redox status of the nucleus likely influencing the deacetilase activity of SIRT1 enzyme. PMID- 26028292 TI - Podosomes: Multipurpose organelles? AB - Thirty years of research have accumulated ample evidence that podosome clusters qualify as genuine cellular organelles that are being found in more and more cell types. A podosome is a dynamic actin-based and membrane-bound microdomain and the organelle consists in an interconnected network of such basic units, forming a cytoskeletal superstructure linked to the plasma membrane. At this strategic location, podosomes are privileged sites of interactions with the pericellular environment that regulates their formation, density, lifetime, distribution, architecture and functioning. Actin polymerization is the driving force behind most podosome characteristics. In contrast to classical organelles, podosomes are not vital at the cell level but rather serve diverse and often intricate functions of which adhesion, matrix degradation and substrate sensing are the most established. These capabilities involve specific molecules, depend on podosome organization and may vary according to the cell type in which they form. Podosome-associated diseases manifest by loss or gain of podosome functions and include genetic diseases affecting podosome components and various cancers where tumor cells ectopically express podosome equivalents (invadopodia). PMID- 26028293 TI - Cartilage immunoprivilege depends on donor source and lesion location. AB - The ability to repair damaged cartilage is a major goal of musculoskeletal tissue engineering. Allogeneic (same species, different individual) or xenogeneic (different species) sources can provide an attractive source of chondrocytes for cartilage tissue engineering, since autologous (same individual) cells are scarce. Immune rejection of non-autologous hyaline articular cartilage has seldom been considered due to the popular notion of "cartilage immunoprivilege". The objective of this study was to determine the suitability of allogeneic and xenogeneic engineered neocartilage tissue for cartilage repair. To address this, scaffold-free tissue engineered articular cartilage of syngeneic (same genetic background), allogeneic, and xenogeneic origin were implanted into two different locations of the rabbit knee (n=3 per group/location). Xenogeneic engineered cartilage and control xenogeneic chondral explants provoked profound innate inflammatory and adaptive cellular responses, regardless of transplant location. Cytological quantification of immune cells showed that, while allogeneic neocartilage elicited an immune response in the patella, negligible responses were observed when implanted into the trochlea; instead the responses were comparable to microfracture-treated empty defect controls. Allogeneic neocartilage survived within the trochlea implant site and demonstrated graft integration into the underlying bone. In conclusion, the knee joint cartilage does not represent an immune privileged site, strongly rejecting xenogeneic but not allogeneic chondrocytes in a location-dependent fashion. This difference in location-dependent survival of allogeneic tissue may be associated with proximity to the synovium. STATEMENT OF SIGNIFICANCE: Through a series of in vivo studies this research demonstrates that articular cartilage is not fully immunoprivileged. In addition, we now show that anatomical location of the defect, even within the same joint compartment, strongly influences the degree of the resultant immune response. This is one of the first investigations to show that (1) immune tolerance to allogeneic tissue engineered cartilage and (2) subsequent implant survival are dependent on the implant location and proximity to the synovium. PMID- 26028294 TI - Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to alpha-synuclein aggregates. AB - BACKGROUND: Special diphenyl-pyrazole compounds and in particular anle138b were found to reduce the progression of prion and Parkinson's disease in animal models. The therapeutic impact of these compounds was attributed to the modulation of alpha-synuclein and prion-protein aggregation related to these diseases. METHODS: Photophysical and photochemical properties of the diphenyl pyrazole compounds anle138b, anle186b and sery313b and their interaction with monomeric and aggregated alpha-synuclein were studied by fluorescence techniques. RESULTS: The fluorescence emission of diphenyl-pyrazole is strongly increased upon incubation with alpha-synuclein fibrils, while no change in fluorescence emission is found when brought in contact with monomeric alpha-synuclein. This points to a distinct interaction between diphenyl-pyrazole and the fibrillar structure with a high binding affinity (Kd=190+/-120nM) for anle138b. Several alpha-synuclein proteins form a hydrophobic binding pocket for the diphenyl pyrazole compound. A UV-induced dehalogenation reaction was observed for anle138b which is modulated by the hydrophobic environment of the fibrils. CONCLUSION: Fluorescence of the investigated diphenyl-pyrazole compounds strongly increases upon binding to fibrillar alpha-synuclein structures. Binding at high affinity occurs to hydrophobic pockets in the fibrils. GENERAL SIGNIFICANCE: The observed particular fluorescence properties of the diphenyl-pyrazole molecules open new possibilities for the investigation of the mode of action of these compounds in neurodegenerative diseases. The high binding affinity to aggregates and the strong increase in fluorescence upon binding make the compounds promising fluorescence markers for the analysis of aggregation-dependent epitopes. PMID- 26028295 TI - A generic high-throughput assay to detect aquaporin functional mutants: Potential application to discovery of aquaporin inhibitors. AB - BACKGROUND: The discovery of stable, yet functional, protein mutants is a limiting factor in the development of biotechnological applications, structural studies or in drug discovery. Rapid detection of functional mutants is especially challenging for water channel aquaporins, as they do not have a directly measurable enzymatic or binding activity. Current methods available are time consuming and only applicable to specific aquaporins. METHODS: Herein we describe an assay based on the protective effect of aquaporins on yeast S. cerevisiae in response to rapid freezing. RESULTS: Yeast overexpressing a functional water permeable aquaporin of choice are rescued after the challenge, while inactive or blocked aquaporins confer no protection and lead to cell death. The potential of this assay is shown by screening a small number of E. coli aquaporin Z (AQPZ) mutants. Additionally, a library of ~10,000 drug-like compounds was tested against human AQP1 (hAQP1). CONCLUSIONS: Since rescue is only dependent on transmembrane water flux, the assay is applicable to water-permeable aquaporins of any origin. GENERAL SIGNIFICANCE: Mapping of permissive mutations on the aquaporin structure can help delineate the minimal requirements for effective water transport. Alternatively, the assay can be potentially used to discover compounds that inhibit aquaporin water transport. When additionally screened for thermostability, functional aquaporin mutants can be useful in the development of biomimetic membranes for water purification, or to improve the likelihood of producing well-diffracting crystals, enabling rational design of much needed aquaporin inhibitors. PMID- 26028296 TI - Role of receptor for advanced glycation end products in the complication and progression of various types of cancers. AB - BACKGROUND: Receptor for advanced glycation end-products popularly known as RAGE is a cell surface immunoglobulin class of molecule, binds with multiple ligands and therefore considered as a multi-ligand receptor. Use of RAGE deficient mice (RAGE(-/-)) as well as established mouse models pertaining to inflammation associated carcinogenesis such as that of chemically induced carcinogenesis and colitis associated cancer provides a direct genetic evidence for a likelihood novel role of RAGE in cancer, with respect to its ability to lead cancer cell proliferation and survival. Besides inflammation, interaction of RAGE with its various ligands enhances oxidative stress both in cancerous and noncancerous cells which further complicates the progression of cancers. SCOPE OF REVIEW: Till date, no single review article has discussed the mechanism of RAGE dependent complication of cancers, particularly the role of RAGE in cancer cell proliferation, angiogenesis, survival and anti-apoptosis needs to be discussed. MAJOR CONCLUSION: RAGE enhances the number of cancer cells by activating the cell cycle proteins (e.g., cyclin D1), anti-apoptotic proteins (e.g., BCl2), prosurvival (AKT) and autophagic proteins. Role of RAGE has also been detected in formation of new blood vessels (angiogenesis) in the cancer cells and activation of myeloid derived suppressor cells (MDSCs). GENERAL SIGNIFICANCE: This review article describes the role of RAGE in the complication of various types of cancers and the possible usefulness of RAGE dependent therapy to confront cancers in a stronger magnitude. PMID- 26028297 TI - Children and Adults With Frequent Hospitalizations for Asthma Exacerbation, 2012 2013: A Multicenter Observational Study. AB - BACKGROUND: Earlier studies reported that many patients were frequently hospitalized for asthma exacerbation. However, there have been no recent multicenter studies to characterize this patient population with high morbidity and health care utilization. OBJECTIVE: To examine the proportion and characteristics of children and adults with frequent hospitalizations for asthma exacerbation. METHODS: A multicenter chart review study of patients aged 2 to 54 years who were hospitalized for asthma exacerbation at 1 of 25 hospitals across 18 US states during the period 2012 to 2013 was carried out. The primary outcome was frequency of hospitalizations for asthma exacerbation in the past year (including the index hospitalization). RESULTS: The cohort included 369 children (aged 2-17 years) and 555 adults (aged 18-54 years) hospitalized for asthma exacerbation. Over the 12-month period, 36% of the children and 42% of the adults had 2 or more (frequent) hospitalizations for asthma exacerbation. Among patients with frequent hospitalizations, guideline-recommended outpatient management was suboptimal. For example, among adults, 32% were not on inhaled corticosteroids at the time of index hospitalization and 75% had no evidence of a previous evaluation by an asthma specialist. At hospital discharge, among adults with frequent hospitalizations who had used no controller medications previously, 37% were not prescribed inhaled corticosteroids. Likewise, during a 3-month postdischarge period, 64% of the adults with frequent hospitalizations were not referred to an asthma specialist. Although the proportion of patients who did not receive these guideline-recommended outpatient care appeared higher in adults, these preventive measures were still underutilized in children; for example, 38% of the children with frequent hospitalizations were not referred to asthma specialist after the index hospitalization. CONCLUSIONS: This multicenter study of US patients hospitalized with asthma exacerbation demonstrated a disturbingly high proportion of patients with frequent hospitalizations and ongoing evidence of suboptimal longitudinal asthma care. PMID- 26028298 TI - Exercise-induced anaphylaxis after consumption of red meat in a patient with IgE antibodies specific for galactose-alpha-1,3-galactose. PMID- 26028299 TI - The pathophysiologic basis of abdominal aortic aneurysm progression: a critical appraisal. AB - An aneurysm of the abdominal aorta is a common pathology and a major cause of sudden death in the elderly. Currently, abdominal aortic aneurysms (AAAs) can only be treated by surgery and an effective medical therapy is urgently missing. The pathophysiology of AAAs is complex and is believed to be best described as a comprehensive inflammatory response with an accompanying proteolytic imbalance; the latter being held responsible for the progressive weakening of the aortic wall. Remarkably, while interference in inflammatory and/or proteolytic cascades proves highly effective in preclinical studies, emerging clinical studies consistently fail to show a benefit. In fact, some anti-inflammatory interventions appear to adversely influence the disease process. Altogether, recent clinical observations not only challenge the prevailing concepts of AAA progression, but also raise doubt on the translatability of findings from rodent models for growing AAA. PMID- 26028300 TI - Validation of the DRAGON Score in a Chinese Population to Predict Functional Outcome of Intravenous Thrombolysis-Treated Stroke Patients. AB - BACKGROUND: The DRAGON score predicts functional outcome of ischemic stroke patients treated with intravenous thrombolysis. Our aim was to evaluate its utility in a Chinese stroke population. METHODS: Patients with acute ischemic stroke treated with intravenous thrombolysis were prospectively registered in the Thrombolysis Implementation and Monitor of acute ischemic Stroke in China. We excluded patients with basilar artery occlusion and missing data, leaving 970 eligible patients. We calculated the DRAGON score, and the clinical outcome was measured by the modified Rankin Scale at 3 months. Model discrimination was quantified by calculating the C statistic. Calibration was assessed using Pearson correlation coefficient. RESULTS: The C statistic was .73 (.70-.76) for good outcome and .75 (.70-.79) for miserable outcome. Proportions of patients with good outcome were 94%, 83%, 70%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 3%, 9%, and 50% for 0 to 1, 2, 3, and 8 to 10 points, respectively. There was high correlation between predicted and observed probability of 3-month favorable and miserable outcome in the external validation cohort (Pearson correlation coefficient, .98 and .98, respectively, both P < .0001). CONCLUSIONS: The DRAGON score showed good performance to predict functional outcome after tissue-type plasminogen activator treatment in the Chinese population. This study demonstrated the accuracy and usability of the DRAGON score in the Chinese population in daily practice. PMID- 26028301 TI - On the Mg(2+) binding site of the epsilon subunit from bacterial F-type ATP synthases. AB - F-type ATP synthases, central energy conversion machines of the cell synthesize adenosine triphosphate (ATP) using an electrochemical gradient across the membrane and, reversely, can also hydrolyze ATP to pump ions across the membrane, depending on cellular conditions such as ATP concentration. To prevent wasteful ATP hydrolysis, mammalian and bacterial ATP synthases possess different regulatory mechanisms. In bacteria, a low ATP concentration induces a conformational change in the epsilon subunit from the down- to up-states, which inhibits ATP hydrolysis. Moreover, the conformational change of the epsilon subunit depends on Mg(2+) concentration in some bacteria such as Bacillus subtilis, but not in others. This diversity makes the epsilon subunit a potential target for antibiotics. Here, performing molecular dynamics simulations, we identify the Mg(2+) binding site in the epsilon subunit from B. subtilis as E59 and E86. The free energy analysis shows that the first-sphere bi-dentate coordination of the Mg(2+) ion by the two glutamates is the most stable state. In comparison, we also clarify the reason for the absence of Mg(2+) dependency in the epsilon subunit from thermophilic Bacillus PS3, despite the high homology to that from B. subtilis. Sequence alignment suggests that this Mg(2+) binding motif is present in the epsilon subunits of some pathogenic bacteria. In addition we discuss strategies to stabilize an isolated epsilon subunit carrying the Mg(2+) binding motif by site directed mutagenesis, which also can be used to crystallize Mg(2+) dependent epsilon subunits in future. PMID- 26028302 TI - The mitochondrial-targeted antioxidant, MitoQ, increases liver mitochondrial cardiolipin content in obesogenic diet-fed rats. AB - Cardiolipin (CL), a unique mitochondrial phospholipid, plays a key role in several processes of mitochondrial bioenergetics as well as in mitochondrial membrane stability and dynamics. The present study was designed to determine the effect of MitoQ, a mitochondrial-targeted antioxidant, on the content of liver mitochondrial membrane phospholipids, in particular CL, and its fatty acid composition in obesogenic diet-fed rats. To do this, twenty-four 6week old male Sprague Dawley rats were randomized into three groups of 8 animals and fed for 8weeks with either a control diet, a high fat diet (HF), or a HF diet with MitoQ (HF+MitoQ). Phospholipid classes and fatty acid composition were assayed by chromatographic methods in liver and liver mitochondria. Mitochondrial bioenergetic function was also evaluated. While MitoQ had no or slight effects on total liver fatty acid composition and phospholipid classes and their fatty acid composition, it had major effects on liver mitochondrial phospholipids and mitochondrial function. Indeed, MitoQ both increased CL synthase gene expression and CL content of liver mitochondria and increased 18:2n-6 (linoleic acid) content of mitochondrial phospholipids by comparison to the HF diet. Moreover, mitochondrial CL content was positively correlated to mitochondrial membrane fluidity, membrane potential and respiration, as well as to ATP synthase activity, while it was negatively correlated to mitochondrial ROS production. These findings suggest that MitoQ may decrease pathogenic alterations to CL content and profiles, thereby preserving mitochondrial function and attenuating the development of some of the features of metabolic syndrome in obesogenic diet fed rats. PMID- 26028303 TI - Mitochondria: Are they causal players in cellular senescence? AB - Cellular senescence entails an irreversible cell-cycle arrest characterised by drastic cytomorphological and metabolic changes. In recent years, the implications of cellular senescence in physiological and pathological settings, such as ageing and cancer, have gained firm ground. It is, therefore, important to understand the mechanisms underpinning the establishment and maintenance of senescence. Age-dependent alterations in cellular metabolic processes are greatly driven by changes in mitochondrial function and homeostasis. Classically, mitochondrial dysfunction has been implicated in cellular senescence mainly by promoting oxidative damage-induced cell-cycle arrest; however, emerging data suggests that other mitochondrial-dependent factors play an important role in the induction of senescent phenotypes. Here we review the role of mitochondrial homeostatic mechanisms, mitochondrial metabolites and ROS generation in the signalling pathways leading to the induction and maintenance of cellular senescence and discuss how this may contribute to the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID- 26028304 TI - SABR for aggressive local therapy of metastatic cancer: A new paradigm for metastatic non-small cell lung cancer. AB - Metastectomy has been performed for many years in situations where the functional consequences allow it, for example in the liver, lung, adrenal glands, and ovaries. This history suggests that selected patients may benefit from aggressive treatment of metastases. Technological developments now allow for ablative treatment of other tumor sites and perhaps for larger volume and/or increasing multiplicity of disease using Stereotactic Ablative Radiation Therapy (SABR) with relatively lower risk of morbidity to patients. Here we further explore the concept of aggressive local treatment of metastatic disease in adult patients and review the rationale for use of SABR to treat metastases and highlight new data supporting this approach in metastatic Non-Small Cell Lung Cancer. PMID- 26028306 TI - Insights from unusual aspects of the 1918 influenza pandemic. AB - The 1918 influenza pandemic was the most lethal single event in modern history. Besides its mortality the 1918 pandemic was unusual for several reasons. It preferentially killed young adults from 20 to 40 y with a peak mortality at age 28 y. Mortality was highly variable with death rates varying by at least 10 fold within similar groups of citizens, soldiers, cities and islands. Secondary bacterial pneumonia following influenza was the overwhelming cause of death and not viral pneumonitis or acute lung injury. Clinical expressions of the 1918 pandemic were unusual with bleeding into the respiratory tree including epistaxis and dark blue cyanotic skin. The 1918 influenza virus apparently ceased circulation in the human population in the early 1920s but continued to evolve in pigs. Immunizations using viruses from 1918 and 2009 can cross-protect laboratory animals even though the human mortality outcomes were very different between the first pandemics of the 20th and 21st centuries. Unusual aspects of historical epidemics may help to reconstruct what actually occurred in 1918 and thus better prepare for the next pandemic. PMID- 26028307 TI - Australian Hajj pilgrims' infection control beliefs and practices: Insight with implications for public health approaches. AB - BACKGROUND: Hajj is one of the largest annual mass gatherings around the world. Although the Saudi Arabian health authority recommends vaccination and other infection control measures, studies identified variable uptake of these measures among pilgrims, and the reasons behind this variability remain unclear. This qualitative study aimed to addresses this knowledge gap. METHODS: In-depth interviews were conducted with pilgrims over 18 years of age. RESULTS: A total of 10 participants took part in the study. There was low perception of the potential severity of respiratory conditions and the need for influenza vaccination during Hajj. Different attitudes were found by age group with elderly participants believing that they were under Allah's protection, and were fatalistic about the risk of illness. While younger participants described the impact infections would have on their worship. Facemask use was infrequent with discomfort; difficulty in breathing and a feeling of isolation were commonly cited barriers to use of facemasks. Participants accepted and trusted preventative health advice from travel agents and friends who had previously undertaken the Hajj more so than primary care practitioners. CONCLUSIONS: This study extended our understanding of how health beliefs influence uptake of preventive measures during the Hajj, and the gaps in the provision of Hajj-specific health information to pilgrims. PMID- 26028308 TI - Synthesis, Structures, and Properties of pi-Extended Double Helicene: A Combination of Planar and Nonplanar pi-Systems. AB - The synthesis, structures, and properties of a pi-extended double helicene 1 are described. This double helicene 1 was synthesized by a four-fold oxidative C-H biphenylation of naphthalene followed by the Scholl reaction or via five steps including the Suzuki-Miyaura cross-coupling reaction and the Scholl reaction. Due to the two helical substructures, 1 has three isomers, i.e., two enantiomers in a twisted form [(P,P) and (M,M)] and one diastereoisomer in a meso form. X-ray crystallographic analysis of the twisted isomers (twisted-1) revealed a tightly offset packing pattern of (P,P)- and (M,M)-twisted isomers, affording a three dimensional lamellar stacking structure. A high isomerization barrier (43.5 kcal mol(-1)) and the relative thermal stability of twisted-1 isomer over meso-1 by 0.9 kcal mol(-1) were estimated by DFT calculations. The three isomers were successfully separated by chiral HPLC and characterized by circular dichroism spectroscopy as well as by TD-DFT studies. Electronic state variation resulting from the molecular geometry difference between the two diastereoisomers (twisted 1 and meso-1) was observed by UV-vis absorption and fluorescence spectra. PMID- 26028310 TI - The role of extracellular matrix in spinal cord development. AB - The development of the spinal cord represents one of the most complex structure developments of the central nervous system (CNS) as it has to unfold along the longitudinal axis and within segmental cues. There it has to cope with on the one hand connection to the periphery (skeletal muscle, dermomyotome, smooth muscles) and connect it to the higher midbrain and cortical regions of the CNS. Major studies have been performed to analyze the specific subset of transcription factors of the different types of cells within the different segments of the spinal cord. But transcription factor expression is always a result of cellular positioning as the environment defines the intracellular changes during differentiation and in adulthood. The surrounding composed of mainly extracellular matrix does not only provide a "glue" to attach cells to each other but also provides signals with special domains docking to cell surface receptors and presents soluble molecules such as basic fibroblast growth factors (bFGFs) or Wnt-proteins. The availability of these molecules depends on the matrix composition and influences the transcription factor code of each cell. Recent research has also provided strong evidence that depletion of single matrix molecules like Tenascin C (TnC) can lead to developmental changes within the progenitor pools. Therefore beyond the transcription factor code that defines cellular properties we want to focus on the role of the extracellular matrix in the development of the spinal cord. PMID- 26028311 TI - MDM4 regulation by the let-7 miRNA family in the DNA damage response of glioma cells. AB - Despite extensive investigation into the role of let-7 miRNAs in pathological tumor processes, their involvement in the DNA damage response remains unclear. Here we show that most let-7 family members down-regulate MDM4 expression via binding to MDM4 mRNA at a conserved DNA sequence. Expression of exogenous let-7 miRNA mimics decreased MDM4 protein but not mRNA levels. Several DNA damage reagents increased let-7 expression, thereby decreasing MDM4 protein levels in glioma cells. Inhibition of endogenous let-7 with antisense RNAs rescued MDM4 protein levels with or without MG132, a proteasome-dependent degradation inhibitor. An MDM4 mutation identified in a glioma patient was associated with loss of the putative MDM4 target site. Therefore, let-7 binding to MDM4 is implicated in the DNA damage response. PMID- 26028309 TI - Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain. AB - Traumatic brain injury (TBI) is one of the leading causes of death in children worldwide. Emerging evidence suggests that alterations in mitochondrial function are critical components of secondary injury cascade initiated by TBI that propogates neurodegeneration and limits neuroregeneration. Unfortunately, there is very little known about the cerebral mitochondrial bioenergetic response from the immature brain triggered by traumatic biomechanical forces. Therefore, the objective of this study was to perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a high-fidelity large animal model of focal controlled cortical impact injury (CCI) 24h post-injury. This novel approach is directed at analyzing dysfunction in electron transport, ADP phosphorylation and leak respiration to provide insight into potential mechanisms and possible interventions for mitochondrial dysfunction in the immature brain in focal TBI by delineating targets within the electron transport system (ETS). Development and application of these methodologies have several advantages, and adds to the interpretation of previously reported techniques, by having the added benefit that any toxins or neurometabolites present in the ex-vivo samples are not removed during the mitochondrial isolation process, and simulates the in situ tricarboxylic acid (TCA) cycle by maximizing key substrates for convergent flow of electrons through both complexes I and II. To investigate alterations in mitochondrial function after CCI, ipsilateral tissue near the focal impact site and tissue from the corresponding contralateral side were examined. Respiration per mg of tissue was also related to citrate synthase activity (CS) and calculated flux control ratios (FCR), as an attempt to control for variability in mitochondrial content. Our biochemical analysis of complex interdependent pathways of electron flow through the electron transport system, by most measures, reveals a bilateral decrease in complex I-driven respiration and an increase in complex II-driven respiration 24h after focal TBI. These alterations in convergent electron flow though both complex I and II-driven respiration resulted in significantly lower maximal coupled and uncoupled respiration in the ipsilateral tissue compared to the contralateral side, for all measures. Surprisingly, increases in complex II and complex IV activities were most pronounced in the contralateral side of the brain from the focal injury, and where oxidative phosphorylation was increased significantly compared to sham values. We conclude that 24h after focal TBI in the immature brain, there are significant alterations in cerebral mitochondrial bioenergetics, with pronounced increases in complex II and complex IV respiration in the contralateral hemisphere. These alterations in mitochondrial bioenergetics present multiple targets for therapeutic intervention to limit secondary brain injury and support recovery. PMID- 26028312 TI - Characterization of the interactions between beta-amyloid peptide and the membranes of human SK-N-SH cells. AB - Interaction of beta-amyloid peptide (Abeta) with cell membranes is thought to be an initial step in Alzheimer's disease (AD). However, some data are controversial and the underlying mechanisms remain unclear. In this report, two populations of Abeta were found in human SK-N-SH neuroblastoma cells. Notably, one of the Abeta populations was tightly inserted into the plasma membrane whilst the other was only peripherally associated with it. Here we show that reducing membrane cholesterol decreased the number of membrane-embedded Abetas and increased the number of membrane-attached Abetas. We also found that cholesterol depletion inhibited Abeta degradation and exacerbated Abeta-mediated cytotoxicity. Our detailed and direct observations provide specific insights into the mechanism of Abeta membrane-associated toxicity. PMID- 26028313 TI - nagnag: Identification and quantification of NAGNAG alternative splicing using RNA-Seq data. AB - Regulation of proteome diversity by alternative splicing has been widely demonstrated in plants and animals. NAGNAG splicing, which was recently defined as a tissue specific event, results in the production of two distinct isoforms that are distinguished by three nucleotides (NAG) as a consequence of the intron proximal or distal to the splice site. Since the NAGNAG mechanism is not well characterized, tools for the identification and quantification of NAGNAG splicing events remain under-developed. Here we report nagnag, an R-based NAGNAG splicing detection tool, which accurately identifies and quantifies NAGNAG splicing events using RNA-Seq. Overall, nagnag produces user-friendly visualization reports and highlights differences between the DNA/RNA/protein across the identified isoforms of the reported gene. The package is available on https://sourceforge.net/projects/nagnag/files/; or http://genome.sdau.edu.cn/research/software/nagnag.html. PMID- 26028314 TI - Genetic mutations in epigenetic modifiers as therapeutic targets in acute myeloid leukemia. AB - INTRODUCTION: Despite enormous insights into the molecular mechanisms of acute myeloid leukemia (AML) pathophysiology, this disease is still fatal in the majority of patients, highlighting the urgent need for novel biomarkers useful in AML prognosis and therapy. AREAS COVERED: The advent of modern sequencing technologies has allowed the identification of genetic mutations in genes encoding for specific enzymes involved in the epigenetic regulation of gene expression. The authors review recent data demonstrating the involvement of mutations in genes encoding for epigenetic players and their complex combination with somatic genetic mutations in the pathogenesis of AML. They also discuss the prognostic and therapeutic implications of these findings. EXPERT OPINION: Current clinical and preclinical studies are underscoring the importance of targeting epigenetic modifiers as new biomarkers for a better prognostic risk stratification and therapeutic evaluation of intermediate-risk patients. Combining data from traditional and modern methodologies will allow a definition of the complex networks of epigenetic changes and molecular interactions between candidate epitargets and key regulators of hematopoiesis. It will thus be possible to achieve an overview of potential aberrant mechanisms driving leukemogenesis in different classes of AML patients. Such an improved approach could pave the way towards 'personalized' therapies. PMID- 26028315 TI - Excellent catalytic activity of magnetically recoverable Fe3O4-graphene oxide nanocomposites prepared by a simple method. AB - An Fe3O4-graphene oxide nanocomposite has been synthesized via a chemical reaction with a magnetite particle size of 18-25 nm. The resulting nanocomposite can be easily manipulated by an external magnetic field, exhibits excellent catalytic activity and may be reused for several cycles with marginal loss of activity. This recyclable nanocomposite provides an efficient, economic, novel route for multi-component A(3) coupling reactions of aldehydes, amines and alkynes and gives the propargylamine in excellent yields. PMID- 26028316 TI - Experimental and theoretical study of the oxidation of ventilation air methane over Fe2O3 and CuO. AB - Coal mine ventilation air methane (VAM) is an important contributor to methane emissions from the energy sector. Although various technologies are under development, treatment of the VAM with an efficient and cost-effective approach has been an ongoing challenge due to massive flow rates of the ventilation air and low and variable methane concentrations. Recently a new concept based on the principle of chemical looping combustion (CLC) has been proposed for VAM abatement (Appl. Energy, 2014, 113, 1916), in which oxidation of low concentration CH4 balanced by N2 with Fe2O3 or CuO as the oxygen carrier was studied. Here, we thoroughly examined the feasibility of CLC of VAM based on experimental study and theoretical calculations. Reduction of Fe2O3 and CuO and evolution of gas products during CH4 oxidation were investigated using TGA-MS under two reaction atmospheres: 1 vol% CH4 balanced by N2 and the simulated VAM containing 1 vol% CH4, 20 vol% O2, 0.4 vol% CO2 and balance N2. It was found that the CLC of VAM is fundamentally infeasible because the reduced phase of Fe2O3 and CuO cannot be formed for chemical looping when reacting with the simulated VAM containing abundant oxygen. Theoretical calculations revealed that Fe2O3 and CuO remain stable without the transition to the reduced phase as the generated oxygen vacancy on the surface of metal oxides during CH4 oxidation can recover quickly with O2 adsorption and dissociation. Calculations confirmed that both Fe2O3 and CuO play a role of surface catalyst in VAM oxidation. More importantly, it was found that the low-coordinated metal atoms and oxygen vacancies can stabilize CHx radicals to promote the dissociation of CH4, which is generally the rate determining step for CH4 oxidation. Such findings are useful for new development and understanding of high-performance and low-cost metal oxide catalysts for CH4 oxidation. PMID- 26028318 TI - Ultraviolet photoconductive devices with an n-GaN nanorod-graphene hybrid structure synthesized by metal-organic chemical vapor deposition. AB - The superior photoconductive behavior of a simple, cost-effective n-GaN nanorod (NR)-graphene hybrid device structure is demonstrated for the first time. The proposed hybrid structure was synthesized on a Si (111) substrate using the high quality graphene transfer method and the relatively low-temperature metal-organic chemical vapor deposition (MOCVD) process with a high V/III ratio to protect the graphene layer from thermal damage during the growth of n-GaN nanorods. Defect free n-GaN NRs were grown on a highly ordered graphene monolayer on Si without forming any metal-catalyst or droplet seeds. The prominent existence of the undamaged monolayer graphene even after the growth of highly dense n-GaN NRs, as determined using Raman spectroscopy and high-resolution transmission electron microscopy (HR-TEM), facilitated the excellent transport of the generated charge carriers through the photoconductive channel. The highly matched n-GaN NR graphene hybrid structure exhibited enhancement in the photocurrent along with increased sensitivity and photoresponsivity, which were attributed to the extremely low carrier trap density in the photoconductive channel. PMID- 26028319 TI - Nanoparticle-sulphur "inverse vulcanisation" polymer composites. AB - Composites of sulphur polymers with nanoparticles such as PbS, with tunable optical properties are reported. A hydrothermal route incorporating pre-formed nanoparticles was used, and their physical and chemical properties evaluated by transmission and scanning electron microscopy, thermogravimetric and elemental analyses. These polymers are easily synthesised from an industrial waste material, elemental sulphur, can be cast into virtually any form and as such represent a new class of materials designed for a responsible energy future. PMID- 26028320 TI - Repolarization effects of multiple-cycle chemotherapy and predictors of QTc prolongation: a prospective female cohort study on >2000 ECGs. AB - PURPOSE: Oncological patients are at increasing risk of QT prolongation, a risk factor for ventricular arrhythmia. We assessed impact and risk factors for corrected QT (QTc) prolongation during multiple-cycle chemotherapy. METHODS: We enrolled 100 outpatients initiating chemotherapy in a university center specializing in female cancer. Clinical, drug, laboratory, and 12-lead ECG data collection at baseline and at each chemotherapy cycle was performed. RESULTS: Enrolled patients were followed for 992 chemotherapy cycles (median 7; interquartile range 6-13); 2438 ECGs were recorded (20; 18-31) 36.8% pre-therapy, 36.8% following chemotherapy, and 22.5% 7-10 days after chemotherapy. Maximum QTc (Max-QTc) was recorded after 4 chemotherapy administrations in >50% of the entire cohort and also within every subset of patients with prolonged QTc (57% 471-480 ms; 54% 481-500 ms; 66% >500 ms). No cumulative effect on QTc was shown. QTc prolongation was comparable among the various protocols. Prophylactic/supportive drugs were not associated with additional QTc prolongation. Variables independently associated with QTc prolongation >470 ms were age (OR 1.056 95% CI 1.006-1.108, p = 0.028) and the baseline-first chemotherapy averaged QTc (BC-QTc) (OR 1.092 95% CI 1.051-1.136), a novel parameter devised for this study. Only BC QTc maintained significance for QTc >480 ms. BC-QTc >435 ms identified 100 % of patients with Max-QTc >500 ms, 96% with Max-QTc 481-500 ms, and 66% with Max-QTc 471-480 ms. Only 29% of patients with Max-QTc <=470 ms presented a BC-QTc >435 ms. CONCLUSIONS: Our results confirm the high prevalence of QTc prolongation after chemotherapy. Most of the patients reached Max-QTc after several cycles. BC QTc may help in stratifying arrhythmic risk in real-world clinical practice. PMID- 26028321 TI - Assessment of the Anticoagulation Activity of Apixaban. PMID- 26028322 TI - Assessment of the Anticoagulation Activity of Apixaban--Reply. PMID- 26028323 TI - Use of Oral Anticoagulants According to the Degree of Renal Impairment in Japanese Patients With Atrial Fibrillation--Which Non-Vitamin K Antagonist Oral Anticoagulant to Select? PMID- 26028324 TI - Different Implications of Functional Tricuspid Regurgitation Between Heart Failure (HF) With Reduced Ejection Fraction (EF) and HF With Preserved EF. PMID- 26028325 TI - Effects of electronic structure on the hydration of PbNO3(+) and SrNO3(+) ion pairs. AB - Hydration of PbNO3(+) and SrNO3(+) with up to 30 water molecules was investigated with infrared photodissociation (IRPD) spectroscopy and with theory. These ions are the same size, yet the IRPD spectra of these ion pairs for n = 2-8 are significantly different. Bands in the bonded O-H region (~3000-3550 cm(-1)) indicate that the onset of a second hydration shell begins at n = 5 for PbNO3(+) and n = 6 for SrNO3(+). Spectra for [PbNO3](+)(H2O)2-5 and [SrNO3](+)(H2O)3-6 indicate that the structures of clusters with Pb(ii) are hemidirected with a void in the coordinate sphere. A natural bond orbital analysis of [PbNO3](+)(H2O)5 indicates that the anisotropic solvation of the ion is due to a region of asymmetric electron density on Pb(ii) that can be explained by charge transfer from the nitrate and water ligands into unoccupied p-orbitals on Pb(ii). There are differences in the IRPD spectra of PbNO3(+) and SrNO3(+) with up to 25 water molecules attached. IR intensity in the bonded O-H region is blue-shifted by ~50 cm(-1) in nanodrops containing SrNO3(+) compared to those containing PbNO3(+), indicative of a greater perturbation of the water H-bond network by strontium. The free O-H stretches of surface water molecules in nanodrops containing 10, 15, 20, and 25 water molecules are red-shifted by ~3-8 cm(-1) for PbNO3(+) compared to those for SrNO3(+), consistent with more charge transfer between water molecules and Pb(ii). These results demonstrate that the different electronic structure of these ions significantly influences how they are solvated. PMID- 26028326 TI - Variation of Lipids and Fatty Acids of the Japanese Freshwater Eel, Anguilla japonica, during Spawning Migration. AB - The lipid and fatty acid composition of the muscle of the wild Japanese freshwater eel, Anguilla japonica, was analyzed between the initial and terminal stages of spawning migration to clarify the relationship between lipid physiology and maturation. Triacylglycerols were the only major component in the initial phase eels, which contained high levels of lipids, while comparatively low triacylglycerol levels were observed in terminal-phase eels (Mariana silvers) at spawning area. Significant levels of plasmalogens were found in its phosphatidylethanolamine, different from other common fish species, which have their little levels. The major fatty acids in A. japonica depot triacylglycerols were 14:0, 16:0, 18:0, 16:1n-7, 18:1n-7, 18:1n-9, and 18:2n-6. Noticeable levels of 20:4n-6, EPA, 22:5n-3, and DHA were also found in initial-phase sample TAG at the yellow and initial silver stages. High 18:2n-6 levels in all A. japonica lipids were similar to those in other common freshwater fishes. In all A. japonica tissue phospholipids, high levels of n-6 and n-3 PUFA, such as 20:4n-6, EPA, 22:5n-3, and DHA, were observed except for the matured terminal female sample. High n-6 PUFA levels in terminal-phase samples caught at the spawning area suggest that A. japonica maintains and uses initial fatty acids from inland waters without feeding during long spawning migrations. The post-spawning sample, containing low levels of 20:4n-6 and DHA with unusually high levels of its degradation products (18:3n-6, 20:2n-6, and 18:4n-3), indicates that A. japonica may finally use its most important PUFA as energy for spawning before ending its life. PMID- 26028327 TI - Regiospecific Distribution of trans-Octadecenoic Acid Positional Isomers in Triacylglycerols of Partially Hydrogenated Vegetable Oil and Ruminant Fat. AB - It is revealed that binding position of fatty acid in triacylglycerol (TAG) deeply relates to the expression of its function. Therefore, we investigated the binding positions of individual trans-octadecenoic acid (trans-C18:1) positional isomers, known as unhealthy fatty acids, on TAG in partially hydrogenated canola oil (PHCO), milk fat (MF), and beef tallow (BT). The analysis was carried out by the sn-1(3)-selective transesterification of Candida antarctica Lipase B and by using a highly polar ionic liquid capillary column for gas chromatography-flame ionization detection. Trans-9-C18:1, the major trans-C18:1 positional isomer, was selectively located at the sn-2 position of TAG in PHCO, although considerable amounts of trans-9-C18:1 were also esterified at the sn-1(3) position. Meanwhile, trans-11-C18:1, the major isomer in MF and BT, was preferentially located at the sn-1(3) position. These results revealed that the binding position of trans-C18:1 positional isomer varies between various fats and oils. PMID- 26028328 TI - Synthesis of Silica Nanotube Using Myelin Figure as Template and their Formation Mechanism. AB - Silica nanotubes are synthesized through a sol-gel reaction of tetraethyl orthosilicate (TEOS) using myelin figures of Pluronic P123 as the structure directing agent. The simultaneous progression of the formation of molecular assemblies that act as templates and the formation of silica frameworks though a sol-gel reaction of the silica precursor is a characteristic of this reaction system. The synthesized silica nanotubes were characterized using transmission electron microscopy (TEM), nitrogen adsorption/desorption measurements, and Fourier-transform infrared spectroscopy (FT-IR). The silica nanotubes were unilamellar with diameters of approximately 30 nm, membrane thicknesses of approximately 10 nm, and lengths exceeding a few hundred nanometers. The Brunauer Emmett-Teller (BET) specific surface area was 589.46 m(2)/g. Silica nanotubes can also be obtained using other Pluronic surfactants that can form myelin figures. In this work, we also investigated the formation mechanism of the silica nanotubes. The typical diameter of a myelin figure is a few tens of micrometers. However, myelin figures with diameters of approximately 10 um can form in systems with TEOS because bifurcation is induced by minute silica nuclei that form during the initial reaction between TEOS and water. Freeze fracture TEM (FF-TEM) observations revealed the existence of myelin figures with diameters of 20 to 30 nm, which are the same size and shape as the synthesized silica nanotubes. These results indicate that bifurcation of the myelin figures is induced by the silica nuclei that form via the initial reaction of TEOS, which result in the formation of bifurcated myelin figures with diameters of ~10 um. Myelin figures with diameters of 20 to 30 nm form on the surface, and they become templates where the reaction of TEOS progresses to form silica nanotubes with diameters of approximately 30 nm. PMID- 26028329 TI - An enzyme-free and DNA-based Feynman gate for logically reversible operation. AB - A logically reversible Feynman gate was successfully realized under enzyme-free conditions by integrating graphene oxide and DNA for the first time. The gate has a one-to-one mapping function to identify inputs from the corresponding outputs. This type of reversible logic gate may have great potential applications in information processing and biosensing systems. PMID- 26028330 TI - Dysfunction of the Reciprocal Feedback Loop between GATA3- and ZEB2-Nucleated Repression Programs Contributes to Breast Cancer Metastasis. AB - How loss-of-function of GATA3 contributes to the development of breast cancer is poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes including ZEB2 that are critically involved in epithelial-to mesenchymal transition and cell invasion. We demonstrate that the GATA3/G9A/NuRD(MTA3) complex inhibits the invasive potential of breast cancer cells in vitro and suppresses breast cancer metastasis in vivo. Strikingly, the expression of GATA3, G9A, and MTA3 is concurrently downregulated during breast cancer progression, leading to an elevated expression of ZEB2, which, in turn, represses the expression of G9A and MTA3 through the recruitment of G9A/NuRD(MTA1). PMID- 26028331 TI - Bottom-up-then-up-down Route for Multi-level Construction of Hierarchical Bi2S3 Superstructures with Magnetism Alteration. AB - A bottom-up-then-up-down route was proposed to construct multi-level Bi2S3 hierarchical architectures assembled by two-dimensional (2D) Bi2S3 sheet-like networks. BiOCOOH hollow spheres and flower-like structures, which are both assembled by 2D BiOCOOH nanosheets, were prepared first by a "bottom-up" route through a "quasi-emulsion" mechanism. Then the BiOCOOH hierarchical structures were transferred to hierarchical Bi2S3 architectures through an "up-down" route by an ion exchange method. The obtained Bi2S3 nanostructures remain hollow spherical and flower-like structures of the precursors but the constructing blocks are changed to 2D sheet-like networks interweaving by Bi2S3 nanowires. The close matching of crystal lattices between Bi2S3 and BiOCOOH was believed to be the key reason for the topotactic transformation from BiOCOOH nanosheets to 2D Bi2S3 sheet-like nanowire networks. Magnetism studies reveal that unlike diamagnetism of comparative Bi2S3 nanostructures, the obtained multi-level Bi2S3 structures display S-type hysteresis and ferromagnetism at low field which might result from ordered structure of 2D networks. PMID- 26028332 TI - Estimation of the prevalence of asymptomatic pancreatic cysts in the population of San Marino. AB - BACKGROUND: There has been a dramatic increase in the number of pancreatic cystic lesions observed in the past two decades but data regarding the prevalence of cysts in the general population are lacking. METHODS: All the individuals who undergo CT at the San Marino State Hospital are residents of the Republic of San Marino; their demographic distribution is available and precise. CT scans carried out over 1 year at the State Hospital were reviewed for asymptomatic pancreatic cysts. RESULTS: 1061 relevant CT scans were carried out on 814 patients; 762 individuals were eligible for the study and 650 patients underwent contrast enhanced CT. Thirty-five patients had at least one cyst at contrast-enhanced CT (5.4%). The prevalence of cysts increased with increasing age up to 13.4% (95% CI 6.6-20) in individuals 80-89 years of age (p < .001). Cyst prevalence was significantly higher in patients who underwent CT for malignancy (p = .038) but this difference was no longer significant in multivariate analysis. The odds of a cyst being present increased by 1.05 (95% CI 1.02-1.09) for each increasing year of age (p = .002). Approximately a quarter of the patients with cysts died within 1 year after CT from non pancreas-related disease. The estimated standardized age adjusted cyst prevalence is 2194 per 100,000 people. CONCLUSIONS: The likelihood of having a pancreatic cyst correlates with increasing age, not with the presence of extra-pancreatic malignancies. The estimated prevalence of CT-detectable asymptomatic pancreatic cysts in the general population is 2.2%. PMID- 26028333 TI - Late infection of pancreatic necrosis: A separate entity in necrotizing pancreatitis with low mortality. AB - BACKGROUND: Several studies have examined on the timing of the onset of infected necrosis and organ failure. The duration of these two complications and the effects of different durations of these two complications have not been mentioned. Our aim was to investigate the durations of these two complications and the corresponding effects of the different durations. METHODS: A post-hoc analysis was performed on a prospective database containing 578 patients with necrotizing pancreatitis. The patients who received intervention were divided into subgroups based on different durations of the two complications, and the outcomes were compared. RESULTS: The mortality rate in patients with late infection (occurred after 30 days) was lower than in the early (infection occurred within 30 days) group (3% vs. 22%, P < 0.05). The mortality rate in patients with long duration (>7 days) of infection before intervention was similar with those patients with short duration (<=7 days) of infection (6/27 vs. 11/74; P = 0.38). The mortality rate in patients with long duration (>7 days) of organ failure before intervention was higher than in patients with short duration (<=7 days) of organ failure (31/99 vs. 18/184; P < 0.001). CONCLUSION: Patients with late developed infection of pancreatic necrosis showed significantly better prognosis than patients with early infection. The duration of organ failure before intervention was correlated with mortality of necrotizing pancreatitis. PMID- 26028334 TI - Origin of the enhanced Li(+) ionic conductivity in Gd(+3) substituted Li5+2xLa3Nb2-xGdxO12 lithium conducting garnets. AB - In the present study, we report the synthesis and the Li(+)-ion conductivity of new Gd(+3) substituted Li5+2xLa3Nb2-xGdxO12 (x = 0.0, 0.25, 0.4, 0.5, 0.6) garnets. The structural study by XRD showed that pure cubic garnet phases were obtained with upto x = 0.5 composition. With the further increase of the Gd(+3) content to x>= 0.6, secondary phases are observed. The ionic conductivity was studied by impedance spectroscopy. We found that the Li(+) ionic conductivity increased with increasing Gd(+3) content with a maximum value of 1.12 * 10(-4) S cm(-1) at RT, which was two orders of magnitude larger than the previously reported value of 10(-6) S cm(-1) for pure Li5La3Nb2O12. A slight drop in the conductivity value to 6.25 * 10(-5) S cm(-1) was observed for x = 0.6 composition. By a systematic analysis of the conductivity spectra at different temperatures of the investigated materials, we are able to estimate the true values of the concentration, nc, and mobility, MU, of mobile Li(+) that contribute to the conduction process; nc was found to increase by a factor of only ~2 with increasing Gd(+3) content from x = 0.0 to x = 0.5, whereas the mobility/diffusivity of Li(+) increased considerably with increasing Gd(+3) content. Therefore, the enhanced conductivity of the current materials is mainly due to the enhanced mobility of Li(+). Surprisingly, the fraction of mobile Li(+) represents only 3.44-6.96% of the total Li(+) density of the materials. PMID- 26028335 TI - Unemployment and household food hardship in the economic recession. AB - OBJECTIVE: The present study examined the association between unemployment and household food insecurity during the 2007-2009 economic recession in the USA. DESIGN: Longitudinal survey of the Survey of Income and Program Participation (SIPP; 2008-2011). Food insecurity was measured by five questions excerpted from an eighteen-item Food Security Scale. Unemployment was measured by a dichotomous indicator, the number of job losses and the total duration of all episodes in the observation period. SETTING: As nationally representative data, the SIPP interviewed respondents in multiple waves with a time interval of four months. SUBJECTS: The study created two analytic samples including working-age household heads employed at the beginning of the observation period. The size of the two samples was 14,417 and 13,080. RESULTS: Unemployment was positively associated with food insecurity (OR=1.55; 95% CI 1.32, 1.83; P<0.001). Similar results were obtained when the analysis controlled for food insecurity status measured before unemployment (OR=1.54; 95% CI 1.27, 1.88; P<0.001). For households with the same duration of unemployment, one more episode of unemployment increased the odds of food insecurity by 8% (OR=1.08; 95% CI 1.00, 1.18; P<0.001). CONCLUSIONS: More in depth understanding of the relationship between unemployment and food insecurity is useful to better identify and serve the at-risk population. Connecting unemployment assistance closely to nutrition assistance could lower the prevalence of food insecurity among unemployed households. Public policy should better account for both episodes and duration of unemployment to reduce food insecurity. PMID- 26028336 TI - Noise reduction in urban LRT networks by combining track based solutions. AB - The overall objective of the Quiet-Track project is to provide step-changing track based noise mitigation and maintenance schemes for railway rolling noise in LRT (Light Rail Transit) networks. WP 4 in particular focuses on the combination of existing track based solutions to yield a global performance of at least 6dB(A). The validation was carried out using a track section in the network of Athens Metro Line 1 with an existing outside concrete slab track (RHEDA track) where high airborne rolling noise was observed. The procedure for the selection of mitigation measures is based on numerical simulations, combining WRNOISE and IMMI software tools for noise prediction with experimental determination of the required track and vehicle parameters (e.g., rail and wheel roughness). The availability of a detailed rolling noise calculation procedure allows for detailed designing of measures and of ranking individual measures. It achieves this by including the modelling of the wheel/rail source intensity and of the noise propagation with the ability to evaluate the effect of modifications at source level (e.g., grinding, rail dampers, wheel dampers, change in resiliency of wheels and/or rail fixation) and of modifications in the propagation path (absorption at the track base, noise barriers, screening). A relevant combination of existing solutions was selected in the function of the simulation results. Three distinct existing solutions were designed in detail aiming at a high rolling noise attenuation and not affecting the normal operation of the metro system: Action 1: implementation of sound absorbing precast elements (panel type) on the track bed, Action 2: implementation of an absorbing noise barrier with a height of 1.10-1.20m above rail level, and Action 3: installation of rail dampers. The selected solutions were implemented on site and the global performance was measured step by step for comparison with simulations. PMID- 26028337 TI - Late glacial initiation of Holocene eastern Mediterranean sapropel formation. AB - Recurrent deposition of organic-rich sediment layers (sapropels) in the eastern Mediterranean Sea is caused by complex interactions between climatic and biogeochemical processes. Disentangling these influences is therefore important for Mediterranean palaeo-studies in particular, and for understanding ocean feedback processes in general. Crucially, sapropels are diagnostic of anoxic deep water phases, which have been attributed to deep-water stagnation, enhanced biological production or both. Here we use an ocean-biogeochemical model to test the effects of commonly proposed climatic and biogeochemical causes for sapropel S1. Our results indicate that deep-water anoxia requires a long prelude of deep water stagnation, with no particularly strong eutrophication. The model-derived time frame agrees with foraminiferal delta(13)C records that imply cessation of deep-water renewal from at least Heinrich event 1 to the early Holocene. The simulated low particulate organic carbon burial flux agrees with pre-sapropel reconstructions. Our results offer a mechanistic explanation of glacial interglacial influence on sapropel formation. PMID- 26028338 TI - Women's views on human papillomavirus self-sampling: focus groups to assess acceptability, invitation letters and a test kit in the Australian setting. AB - Background The study evaluated acceptability, invitation letters and the test kit for a trial of human papillomavirus (HPV) self-sampling among never- and under screened women in Australia. METHODS: Victorian women, 30-69 years, who had never had a Pap test or were overdue for one, participated. Four focus groups including eight to nine participants segmented by age (30-49 and 50-69 years) and screening history (never- and under-screened) were conducted in August 2013. Discussions were recorded and transcribed verbatim and data analysed using thematic content analysis. RESULTS: The response to the concept of HPV self-sampling was positive. Decision-making was largely influenced by the content of a pre-invitation letter. Appealing features of self-sampling were cost (free), convenience (home-based) and anticipated less discomfort (with a swab) than a Pap test. Small kits that fit in mailboxes were preferred over post office parcel collection. The perceived barriers include concerns about test accuracy and lack of confidence that a home based test would give the same results as a physician administered test. Women wanted information on the timing of receipt of the results and information about the organisation providing the test. CONCLUSION: HPV self-sampling is a possible alternative for Australian women who are reluctant to have a Pap test and may increase the likelihood of participation in cervical cancer screening if women's concerns about it can be addressed. The findings of this study are relevant for researchers, policymakers and practitioners implementing self-sampling for under screened women as part of cervical screening programs. PMID- 26028340 TI - The glioblastoma problem: targeting by combined medicinal chemistry approaches. AB - Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB - WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current status of clinical research on GB, a literature search was conducted in PubMed using the terms: "glioma AND trial" over a 500 day period elapsing from Jan 1, 2013 to May 15, 2014 and results of Phase I, II and III trials were reviewed. Results in the pediatric setting were included as well. It was concluded that, as in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field are not presently translated to improved patients' survival. In order to explore novel therapeutic avenues for this deadly tumour, two innovative medicinal chemistry approaches are proposed and discussed: a) Specific glioma initiating cell-radiosensitization by ATM inhibitors [1] and b) Specific glioma initiating cell-chemotherapeutic targeting by MYC inhibitors [2]. PMID- 26028339 TI - Early biomarkers of joint damage in rheumatoid and psoriatic arthritis. AB - Joint destruction, as evidenced by radiographic findings, is a significant problem for patients suffering from rheumatoid arthritis and psoriatic arthritis. Inherently irreversible and frequently progressive, the process of joint damage begins at and even before the clinical onset of disease. However, rheumatoid and psoriatic arthropathies are heterogeneous in nature and not all patients progress to joint damage. It is therefore important to identify patients susceptible to joint destruction in order to initiate more aggressive treatment as soon as possible and thereby potentially prevent irreversible joint damage. At the same time, the high cost and potential side effects associated with aggressive treatment mean it is also important not to over treat patients and especially those who, even if left untreated, would not progress to joint destruction. It is therefore clear that a protein biomarker signature that could predict joint damage at an early stage would support more informed clinical decisions on the most appropriate treatment regimens for individual patients. Although many candidate biomarkers for rheumatoid and psoriatic arthritis have been reported in the literature, relatively few have reached clinical use and as a consequence the number of prognostic biomarkers used in rheumatology has remained relatively static for several years. It has become evident that a significant challenge in the transition of biomarker candidates to clinical diagnostic assays lies in the development of suitably robust biomarker assays, especially multiplexed assays, and their clinical validation in appropriate patient sample cohorts. Recent developments in mass spectrometry-based targeted quantitative protein measurements have transformed our ability to rapidly develop multiplexed protein biomarker assays. These advances are likely to have a significant impact on the validation of biomarkers in the future. In this review, we have comprehensively compiled a list of candidate biomarkers in rheumatoid and psoriatic arthritis, evaluated the evidence for their potential as biomarkers of bone (joint) damage, and outlined how mass spectrometry-based targeted and multiplexed measurement of candidate biomarker proteins is likely to accelerate their clinical validation and the development of clinical diagnostic tests. PMID- 26028341 TI - Insights on antimicrobial resistance, biofilms and the use of phytochemicals as new antimicrobial agents. AB - Antimicrobial resistance is one of the most serious public health problems. This is of particular concern when bacteria become resistant to various antimicrobial agents simultaneously and when they form biofilms. Consequently, therapeutic options for the treatment of infections have become limited, leading frequently to recurrent infections, treatment failure and increase of morbidity and mortality. Both, persistence and spread of antibiotic resistance, in combination with decreased effectiveness and increased toxicity of current antibiotics have emphasized the urgent need to search alternative sources of antimicrobial substances. Plants are recognized as a source of unexplored chemical structures with high therapeutic potential, including antimicrobial activity against clinically important microorganisms. Additionally, phytochemicals (plant secondary metabolites) present several advantages over synthetic molecules, including green status and different mechanisms of action from antibiotics which could help to overcome the resistance problem. In this study, an overview of the main classes of phytochemicals with antimicrobial properties and their mode of action is presented. A revision about the application of phytochemicals for biofilm prevention and control is also done. Moreover, the use of phytochemicals as scaffolds of new functional molecules to expand the antibiotics pipeline is reviewed. PMID- 26028343 TI - Modulation of Mitochondrial Permeability Transition in Ischemia-Reperfusion Injury of the Heart. Advantages and Limitations. AB - In the last twenty years, numerous reports provided solid evidence on the involvement of the mitochondrial permeability transition pore (PTP) in myocardial injury caused by ischemia and reperfusion. Indeed, significant cardioprotection is obtained by reducing the open probability of the PTP. This goal has been achieved by pharmacological and genetic interventions aimed at inhibiting cyclophilin D (CyPD), a regulatory protein that favors PTP opening. On the other hand, CyPD inhibition or deletion has been shown to worsen remodeling of the hypertrophic heart, an adverse outcome that must find an explanation within PTP modulation by CyPD. In this review, recent advancements in defining the molecular identity of the PTP are analyzed in relation to its pathophysiological functions and pharmacological modulation. In this respect, advantages and limitations of compounds targeting CyPD are discussed with the analysis of novel PTP inhibitors that do not interact with CyPD. PMID- 26028344 TI - Gardasil 9 joins the fight against cervix cancer. AB - A trial of 14,215 women aged between 16 and 26 years comparing a new vaccine with nine human papilloma virus types - four from the licensed Gardasil vaccine (types 6, 11,16 and 18) and five new ones (types 31, 33, 45, 52 and 58) to Gardasil - has shown improved protection against cervical cancer precursor lesions. Antibody response for the four original Gardasil types was not inferior and a 96.3% reduction in high-grade cervical disease for the other five types not in Gardasil was seen in the per-protocol population. Six-month persistent infection was reduced by 96% for these types. There were no serious safety concerns, although injection site reactions were more common with the new vaccine. PMID- 26028345 TI - Influence of Fluorescein Angiography on the Diagnosis and Management of Retinopathy of Prematurity. AB - PURPOSE: To examine the influence of fluorescein angiography (FA) on the diagnosis and management of retinopathy of prematurity (ROP). DESIGN: Prospective cohort study. PARTICIPANTS: Nine recognized ROP experts (3 pediatric ophthalmologists and 6 retina specialists) interpreted 32 sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images from infants with ROP. METHODS: All experts independently reviewed the 32 image sets on a secure website and provided a diagnosis and management plan for the case presented, first based on color fundus photographs alone, and then based on color fundus photographs and corresponding FA images. MAIN OUTCOME MEASURES: Sensitivity and specificity of the ROP diagnosis (zone, stage, plus disease, and category, i.e., no ROP, mild ROP, type 2 ROP, and ROP requiring treatment) were calculated using a consensus reference standard diagnosis, determined from the diagnosis of the color fundus photographs by 3 experienced readers in combination with the clinical diagnosis based on ophthalmoscopic examination. The kappa statistic was used to analyze the average intergrader agreement among experts for the diagnosis of zone, stage, plus disease, and category. RESULTS: Addition of FA to color fundus photography resulted in a significant improvement in sensitivity for diagnosis of stage 3 or worse disease (39.8% vs. 74.1%; P = 0.008), type 2 or worse ROP (69.4% vs. 86.8%; P = 0.013), and pre-plus or worse disease (50.5 vs. 62.6%; P = 0.031). There was a nonsignificant trend toward improved sensitivity for diagnosis of ROP requiring treatment (22.2% vs. 40.3%; P = 0.063). Using the kappa statistic, addition of FA to color fundus photography significantly improved intergrader agreement for diagnosis of ROP requiring treatment. Addition of FA to color fundus photography did not affect intergrader agreement significantly for the diagnosis of stage, zone, or plus disease. CONCLUSIONS: Compared with color fundus photography alone, FA may improve the sensitivity of diagnosis of ROP by experts, particularly for stage 3 disease. In addition, intergrader agreement for diagnosis of ROP requiring treatment may improve with FA interpretation. PMID- 26028346 TI - VEGFR2 Gene Polymorphisms and Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration. AB - PURPOSE: A previously published study demonstrated a pharmacogenetic association between the minor alleles of 2 VEGFR2 single nucleotide polymorphisms (SNPs) and greater improvement in visual acuity (VA) to treatment with ranibizumab, an anti vascular endothelial growth factor (VEGF) drug, in patients with neovascular age related macular degeneration (AMD). We evaluated whether this association was replicated among patients who participated in the Comparison of AMD Treatments Trials (CATT) or the Alternative Treatments to Inhibit VEGF in Patients with Age Related Choroidal Neovascularisation (IVAN) trial. DESIGN: Cohort studies within randomized clinical trials. PARTICIPANTS: Eight hundred thirty-five patients participating in CATT and 512 patients participating in IVAN. METHODS: Each patient was genotyped for the SNPs rs4576072 and rs6828477 in the VEGFR2 gene. MAIN OUTCOMES MEASURES: Mean change in VA from baseline to 1 year after initiation of treatment with ranibizumab or bevacizumab. Differences in VA response between the patient group homozygous for the minor allele of each SNP and the other genotype groups were evaluated with analysis of variance. Differences in VA response by the number of minor alleles present for either SNP or both combined were evaluated with tests of linear trend. Analyses were conducted separately for CATT and IVAN participants and with both the studies combined. RESULTS: No statistically significant difference in mean change in VA was identified between genotypes of either SNP (P >= 0.05). Furthermore, a stepwise analysis failed to show a significant interaction for either SNP based on the number of minor alleles present. The lack of association was similar in both the CATT and IVAN cohorts and whether the analysis combined patients treated with either ranibizumab or bevacizumab or when restricted to patients treated with ranibizumab only. CONCLUSIONS: The CATT and IVAN data do not support a pharmacogenetic association between the 2 VEGFR2 SNPs, rs4576072 and rs6828477, and change in VA in response to anti-VEGF therapy in patients with neovascular AMD. PMID- 26028347 TI - HELPing older people with very severe chronic obstructive pulmonary disease (HELP COPD): mixed-method feasibility pilot randomised controlled trial of a novel intervention. AB - BACKGROUND: Extending palliative care to those with advanced non-malignant disease is advocated, but the implications in specific conditions are poorly understood. AIMS: We piloted a novel nurse-led intervention, HELPing older people with very severe chronic obstructive pulmonary disease (HELP-COPD), undertaken 4 weeks after discharge from hospital, which sought to identify and address the holistic care needs of people with severe COPD. METHODS: This 6-month mixed method feasibility pilot trial randomised (ratio 3:1) patients to HELP-COPD or usual care. We assessed the feasibility of using validated questionnaires as outcome measures and analysed the needs/actions recorded in the HELP-COPD records. Semi-structured interviews with a purposive sample of patients, carers and professionals explored the perceptions of HELP-COPD. Verbatim transcriptions and field notes were analysed using Normalisation Process Theory as a framework. RESULTS: We randomised 32 patients (24 to HELP-COPD); 19 completed the study (death=3, ill-health=4, declined=6). The HELP-COPD record noted a mean of 1.6 actions/assessment, mostly provision of information or self-help actions: only five referrals were made. Most patients were positive about HELP-COPD, discussing their concerns and coping strategies in all domains, but the questionnaires were burdensome for some patients. Adaptation to their slowly progressive disability and a strong preference to rely on family support was reflected in limited acceptance of formal services. Professionals perceived HELP-COPD as addressing an important aspect of care, although timing overlapped with discharge planning. CONCLUSIONS: The HELP-COPD intervention was well received by patients and the concept resonated with professionals, although delivery post discharge overlapped with existing services. Integration of brief holistic care assessments in the routine primary care management of COPD may be more appropriate. PMID- 26028348 TI - Endosulfan activates the extrinsic coagulation pathway by inducing endothelial cell injury in rats. AB - Endosulfan, a persistent organic pollutant, is widely used in agriculture as a pesticide. The aim of the present study was to evaluate the blood toxicity of different doses of endosulfan in Wistar rats. The experimental sample was composed of four groups, a control group that did not receive endosulfan and three endosulfan-exposed groups that respectively received 1, 5, or 10 mg/kg/day (doses below LD50), of endosulfan for 21 days. The results showed that endosulfan significantly decreased the prothrombin time (PT) and upregulated the activated coagulation factors VIIa, Xa, and XIIIa; thrombin-antithrombin complex (TAT); and P-selectin. Plasma levels of tissue factor (TF) and malondialdehyde (MDA) were increased in the endosulfan groups. The activated partial thromboplastin time (APTT) and the level of activated coagulation factor IXa showed no obvious changes. Immunohistochemical results showed increased expression of von Willebrand factor (vWF) and the inflammatory cytokine interleukin (IL)-1beta in the groups exposed to endosulfan. The pathology and electron microscopy results showed impaired vascular tissue accompanied by the exfoliation of endothelial cells and mitochondrial damage in the endosulfan-exposed groups. In summary, our results suggest that endosulfan damages endothelial cells via oxidative stress and the inflammatory response, leading to the release of TF and vWF into the blood. The TF and vWF in the blood may activate extrinsic coagulation factors and platelets, thus triggering the extrinsic coagulation pathway. There were no obvious effects on the intrinsic coagulation pathway. PMID- 26028349 TI - Factors influencing inapplicability of cosolvency-induced model on organic acid sorption onto humic substance from methanol mixture. AB - Applicability of cosolvency model for describing the sorption of organic acids to humic substance was investigated by analyzing dataset of sorption (K m) and solubility (S m) of selected solutes (benzoic acid, 1-naphthoic acid, 2,4 dichlorophenoxyacetic acid, and 2,4,6-trichlorophenol (2,4,6-TCP)) as a function of pH(appCME) (apparent pH of liquid phase) and f c (methanol volume fractions). For all solutes, the K m decreased with f c with the K m reduction being less than the S m-based prediction. The slope of log K m-f c plot in the three organic carboxylic acids was well correlated with their cosolvency power, whereas the data of organic phenolic acid (2,4,6-TCP) was placed above the trend, indicating the different actions of functional groups. The occurrence of Ca(2+) bridge between carboxylate and negatively charged humic surface may explain this phenomenon. Normalizing the K m to the corresponding S m (alpha' = K m/S m) was not in unity over the pH(app)-f c range but decreased with f c, indicating a possible structural modification of sorption domain favoring extra sorption. For a given solute, the alpha' of neutral species was always greater than that of anionic species, showing that extra interaction will be likely at pH(app) 12h (odds ratio, 3.36 [2.40-4.72] and 2.53 [1.74-3.67]). CONCLUSIONS: We found no difference in the rate of inadequate bowel preparation between hospitalized patients and outpatients. PMID- 26028363 TI - Antigen-Loaded Upconversion Nanoparticles for Dendritic Cell Stimulation, Tracking, and Vaccination in Dendritic Cell-Based Immunotherapy. AB - A dendritic cell (DC) vaccine, which is based on efficient antigen delivery into DCs and migration of antigen-pulsed DCs to draining lymph nodes after vaccination, is an effective strategy in initiating CD8(+) T cell immunity for immunotherapy. Herein, antigen-loaded upconversion nanoparticles (UCNPs) are used to label and stimulate DCs, which could be precisely tracked after being injected into animals and induce an antigen-specific immune response. It is discovered that a model antigen, ovalbumin (OVA), could be adsorbed on the surface of dual polymer-coated UCNPs via electrostatic interaction, forming nanoparticle-antigen complexes, which are efficiently engulfed by DCs and induce DC maturation and cytokine release. Highly sensitive in vivo upconversion luminescence (UCL) imaging of nanoparticle-labeled DCs is successfully carried out, observing the homing of DCs to draining lymph nodes after injection. In addition, strong antigen-specific immune responses including enhanced T cell proliferation, interferon gamma (IFN-gamma) production, and cytotoxic T lymphocyte (CTL) mediated responses are induced by a nanoparticle-pulsed DC vaccine, which is promising for DC-based immunotherapy potentially against cancer. PMID- 26028364 TI - Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma. AB - Cancer is fueled by deregulation of signaling pathways in control of cellular growth and proliferation. These pathways are also targeted by infectious pathogens en route to establishing infection. Gallbladder carcinoma (GBC) is frequent in the Indian subcontinent, with chronic Salmonella enterica serovar Typhi infection reported as a significant risk factor. However, direct association and causal mechanisms between Salmonella Typhi infection and GBC have not been established. Deconstructing the epidemiological association between GBC and Salmonella Typhi infection, we show that Salmonella enterica induces malignant transformation in predisposed mice, murine gallbladder organoids, and fibroblasts, with TP53 mutations and c-MYC amplification. Mechanistically, activation of MAPK and AKT pathways, mediated by Salmonella enterica effectors secreted during infection, is critical to both ignite and sustain transformation, consistent with observations in GBC patients from India. Collectively, our findings indicate that Salmonella enterica can promote transformation of genetically predisposed cells and is a causative agent of GBC. PMID- 26028366 TI - Classification of dermal sensitizers in pharmaceutical manufacturing. AB - Workers in development and manufacturing of pharmaceuticals are at risk for occupational contact dermatitis (OCD) of irritative (ICD) or allergic (ACD) origin, due to contacts with reactive intermediates (IM) and drug substances (DS). We examined, if alternative methods could replace presently used animal tests for identification of ACD in pharmaceutical development and manufacturing, without apparent loss of worker health, in line with regulations. The status of alternative methods for regulatory toxicology for consumer products has recently been reviewed by the Organisation for Economic Co-operation and Development (OECD) and the European Commission's Joint Research Center (JRC) for the European Chemicals Agency (ECHA). They concluded that prediction of skin sensitization potential, extent and quality by in vitro methods, for regulatory assessments, will depend on the regulatory purpose and level of confidence required. Some alternative methods are currently in validation. Current Globally Harmonized System (GHS) regulations on classification, labeling and packaging of substances and mixtures depend on human and animal data, whereas alternative methods may provide supportive evidence. Since the levels of workplace skin exposure to DS and IM in manufacturing of pharmaceuticals are usually not known, it is not possible to conduct quantitative risk assessments based on threshold calculations for contact sensitizers. PMID- 26028365 TI - The PAMP c-di-AMP Is Essential for Listeria monocytogenes Growth in Rich but Not Minimal Media due to a Toxic Increase in (p)ppGpp. [corrected]. AB - Cyclic di-adenosine monophosphate (c-di-AMP) is a widely distributed second messenger that appears to be essential in multiple bacterial species, including the Gram-positive facultative intracellular pathogen Listeria monocytogenes. In this study, the only L. monocytogenes diadenylate cyclase gene, dacA, was deleted using a Cre-lox system activated during infection of cultured macrophages. All DeltadacA strains recovered from infected cells harbored one or more suppressor mutations that allowed growth in the absence of c-di-AMP. Suppressor mutations in the synthase domain of the bi-functional (p)ppGpp synthase/hydrolase led to reduced (p)ppGpp levels. A genetic assay confirmed that dacA was essential in wild-type but not strains lacking all three (p)ppGpp synthases. Further genetic analysis suggested that c-di-AMP was essential because accumulated (p)ppGpp altered GTP concentrations, thereby inactivating the pleiotropic transcriptional regulator CodY. We propose that c-di-AMP is conditionally essential for metabolic changes that occur in growth in rich medium and host cells but not minimal medium. PMID- 26028367 TI - Clinical and anatomic pathology effects of serial blood sampling in rat toxicology studies, using conventional or microsampling methods. AB - As a general practice in rodent toxicology studies, satellite animals are used for toxicokinetic determinations, because of the potential impact of serial blood sampling on toxicological endpoints. Besides toxicological and toxicokinetic determinations, blood samples obtained longitudinally from a same animal may be used for the assessment of additional parameters (e.g., metabolism, pharmacodynamics, safety biomarkers) to maximize information that can be deduced from rodents. We investigated whether removal of up to 6 * 200 MUL of blood over 24h can be applied in GLP rat toxicology studies without affecting the scientific outcome. METHODS: 8 week-old female rats (200-300 g) were dosed for up to 1 month with a standard vehicle and subjected or not (controls) to serial blood sampling for sham toxicokinetic/ancillary determinations, using miniaturized methods allowing collection of 6 * 50, 100 or 200 MUL over 24h. In-life endpoints, clinical pathology parameters and histopathology of organs sensitive to blood volume reduction were evaluated at several time points after completion of sampling. RESULTS: In sampled rats, minimal and reversible changes in red blood cell mass (maximally 15%) and subtle variations in liver enzymes, fibrinogen and neutrophils were not associated with any organ/tissue macroscopic or microscopic correlate. CONCLUSION: Serial blood sampling (up to 6 * 200 MUL over 24h) is compatible with the assessment of standard toxicity endpoints in adult rats. PMID- 26028368 TI - Vocal Fold Vibratory Changes Following Surgical Intervention. AB - High-speed videoendoscopy (HSV) captures direct cycle-to-cycle visualization of vocal fold movement in real time. This ultrafast recording rate is capable of visualizing the vibratory motion of the vocal folds in severely disordered phonation and provides a direct method for examining vibratory changes after vocal fold surgery. The purpose of this study was to examine the vibratory motion before and after surgical intervention. HSV was captured from two subjects with identifiable midvocal fold benign lesions and six subjects with highly aperiodic vocal fold vibration before and after phonosurgery. Digital kymography (DKG) was used to extract high-speed kymographic vocal fold images sampled at the midmembranous, anterior 1/3, and posterior 1/3 region. Spectral analysis was subsequently applied to the DKG to quantify the cycle-to-cycle movements of the left and the right vocal fold, expressed as a spectrum. Before intervention, the vibratory spectrum consisted of decreased and flat-like spectral peaks with robust power asymmetry. After intervention, increases in spectral power and decreases in power symmetry were noted. Spectral power increases were most remarkable in the midmembranous region of the vocal fold. Surgical modification resulted in improved lateral excursion of the vocal folds, vibratory function, and perceptual measures of Voice Handicap Index-10. These changes in vibratory behavior trended toward normal vocal fold vibration. PMID- 26028370 TI - Vocal Effects in Military Students Submitted to an Intense Recruit Training: A Pilot Study. AB - OBJECTIVES: This study aims at evaluating the vocal parameters of military officers before and after an Intense Recruit Training (IRT), consisting of a 48 hour exercise protocol involving high vocal demand combined with physical effort, lower body hydration levels, and fewer hours of sleep. STUDY DESIGN: Eighty-three young male military officers (aged between 18 and 22 years) were recorded on three occasions: before, immediately after, and 2 weeks after the IRT. METHODS: Maximum phonation times (MPTs) using vocalization of the vowel /a/, the fricative consonants /s/ and /z/, and connected speech samples were collected. A number of acoustic parameters were analyzed: mean fundamental frequency, mean intensity, jitter, shimmer, harmonics-to-noise ratio, spectral emphasis (acoustic correlate of vocal effort), H1-H2 (difference between the amplitude of the first and the second harmonic), and the frequency and intensity ranges. For the immediate effects, statistical analyses were conducted using a paired sample t test (P = 0.05) to compare two moments: before and after the IRT. For the long-lasting effect, statistical analyses were conducted using a one-way analysis of variance (ANOVA) test (P = 0.05) to compare between all three moments (before, immediately after, and 2 weeks after the IRT). RESULTS: The MPTs of /a/, /s/, and /z/, the acoustic parameters as spectral emphasis, and the mean of intensity showed statistically significant changes between the data from before and immediately after training took place. The MPT of /a/ and the intensity range showed statistically significant changes between the measurements taken immediately after training and the ones taken 2 weeks after training; there were significant differences in the comparisons between the three groups of data acquired. CONCLUSIONS: Some of the acoustic parameters were able to identify changes in the vocal conditions of the military students as consequence of high intensity voice and physical military training. The changes in the vocal intensity and MPT parameters seem to be related to general fatigue and lower hydration. The absence of impact in some parameters, specially 2 weeks after the IRT, may reveal that the students' voice is getting used to the military activities. PMID- 26028369 TI - Effects of Adventitious Acute Vocal Trauma: Relative Fundamental Frequency and Listener Perception. AB - OBJECTIVE: High voice users (individuals who demonstrate excessive or loud vocal use) are at risk for developing voice disorders. The objective of this study was to examine, both acoustically and perceptually, vocal changes in healthy speakers after an acute period of high voice use. METHODS: Members of a university women's volleyball team (n = 12) were recorded a week before (pre) and week after (post) the 10-week spring season; n = 6 control speakers were recorded over the same time period for comparison. Speakers read four sentences, which were analyzed for relative fundamental frequency (RFF). Eight naive listeners participated in an auditory-perceptual visual sort and rate (VSR) task, in which they rated each voice sample's overall severity and strain. RESULTS: No significant differences were found as a function of time point in the VSR ratings for the volleyball group. Onset cycle 1 RFF values were significantly lower (P = 0.04) in the postrecordings of the volleyball participants compared with prerecordings, but there was no significant difference (P = 0.20) in offset cycle 10 RFF values. Receiver operating characteristic analyses indicated moderate sensitivity and specificity of onset cycle 1 RFF for discrimination between the volleyball and control participants. Changes were not apparent in the control group as a function of time for either, onset cycle 1 RFF, offset cycle 10 RFF, or either vocal attribute. CONCLUSIONS: Onset cycle 1 RFF may be an effective marker for detecting vocal changes over an acute high voice use period of time before perceptual changes are noted. PMID- 26028371 TI - Prognostic factors and outcome analysis of salivary duct carcinoma. AB - OBJECTIVE: Salivary duct carcinoma (SDC) is highly aggressive, with high rates of recurrence and nodal and distant metastases. The aim of the current study was to evaluate the clinical implication of EGFR and HER2 expression for predicting prognosis and to identify the factors associated with outcome. METHODS: The medical records of 28 patients with SDC underwent surgery and adjuvant RT. Expression of c-erbB-2 and EGFR was determined immunohistochemically on the 25 SDC specimens. Disease-free survival (DFS), overall survival (OS) and distant metastasis-free survival (DMFS) were analyzed. RESULTS: Three-year DFS, OS and DMFS rates were 38.3%, 78.1% and 45.7%, respectively. Expression of c-erbB-2 and EGFR was seen in 64% and 40%. c-erbB-2 and EGFR expression did not correlate with recurrence or metastasis. Advanced N classification and perineural invasion (PNI) were significant predictors of DFS and DMFS. CONCLUSION: c-erbB-2 and EGFR expression did not correlate with recurrence or metastasis. Despite aggressive surgery and RT, approximately 50% of SDCs failed systemically. More effective therapy to inhibit distant metastases in patients with advanced N classification and PNI should be considered. PMID- 26028372 TI - [Anton p. Chejov. Taganrog (Russia), 1860-Badenweiler (Germany), 1904]. PMID- 26028373 TI - ABCDEFG of postpartum care after GDM (gestational diabetes mellitus). PMID- 26028374 TI - Effect of endometrial thickness on pregnancy outcome after intracytoplasmic sperm injection. AB - OBJECTIVE: To identify cut-off value of endometrial thickness required for implantation of embryo after intracytoplasmic sperm injection. METHODS: The auasi experimental study was conducted from July 2011 to June 2012 at an assisted reproductive clinic in Islamabad. Down-regulation of ovaries, controlled ovarian stimulation, oocyte pick-up, in vitro fertilisation, blastocyst transfer and confirmation of pregnancy with beta human chorionic gonadotropin more than 5mIU/ml. Patients were categorised into two groups on the basis of endometrial thickness < 8mm and >8mm.On ovulation induction, before human chorionic gonadotropin injection, endometrial thickness was measured by trans-vaginal scan. Receiver operating curve was used to define groups on the basis of endometrial thickness cut-off value for pregnancy. The groups were compared in terms of the number of retrieved, mature and fertilised oocytes along with oocyte maturity, fertilisation and implantation rates by chi square test. RESULTS: There were 282 females; 116(41%) in Group A with endometrial thickness < 8mm, and 166(59%) in Group B with endometrial thickness >8mm. In group A, 6(5%) and in Group B, 95(57.2%) patients had a positive pregnancy test. The number of mature, fertilised oocytes and cleaved embryos was significantly high in Group B (p=0.01; p=0.001; p=0.001respectively). Increase in endometrial thickness enhanced chances of oocyte maturity, fertilisation, cleavage and implantation (p< 0.0001 each). CONCLUSIONS: Endometrial thickness of 8mm was associated with a positive pregnancy outcome after intracytoplasmic sperm injection. Implantation of embryo was facilitated by better oocyte parameters, oocyte maturity, fertilisation and its cleavage in females who exhibited endometrial thickness above the cut-off value. PMID- 26028375 TI - Unwanted pregnancy and traditional self-induced abortion methods known among women aged 15 to 49. AB - OBJECTIVE: To determine the traditional methods known and used to terminate an unwanted pregnancy and the fertility characteristics of married women. METHODS: The descriptive cross-sectional study was conducted in Turkey at Afyonkarahisar Zubeyde Hanim Child and Maternity Hospital's outpatient clinic between December 27, 2010 and January 7, 2011, and comprised married women aged 17 to 49 who presented for an examination. Questions related to socio-demographic and fertility characteristics as well as known and used traditional abortion methods were included in the questionnaire which was administered through face-to-face interviews. SPSS 18.0 was used for statistical analysis. RESULTS: The median age of the 600 women in the study was 29.5 (range: 17-49) years. Overall, 134 (22.3%) women had experienced an unwanted pregnancy. In 53 (39.6%) cases, the unwanted pregnancy had occurred between the ages of 30 and 39, and 116(86.6%) women had married when they were between 15 and 24 (p< 0.008) years old. Pregnancy had been concluded normally in 78(58.2%)women with an unwanted pregnancy and 34(35.8%)preferred the withdrawal method for contraception. Traditional abortion methods were known to 413(68.8%)women, but only 8(1.3%) had used any of them. The harms of using a traditional abortion method were known to 464(77.3%)women. CONCLUSIONS: Very few women used traditional abortion methods to terminate pregnancy. Knowing the characteristics of women and their need for family planning should be the first priority for the prevention of unwanted pregnancies. PMID- 26028376 TI - Nursing students' medication errors and their opinions on the reasons of errors: A cross-sectional survey. AB - OBJECTIVE: To determine number and type of medication administration errors made by nursing students, and to explore the rate of reportings, emotions after the errors and the causes of errors. METHODS: The cross-sectional study was conducted at the two schools of nursing, Akdeniz University, Antalya, Turkey, in February 2009, and comprised students having worked in hospital settings for a minimum of one semester and who had been involved in administering medications. SPSS 13 was used for statistical analysis. RESULTS: Of the 324 subjects in the study, 124(38.3%) had made an error in clinical/field applications. Overall, 402 medication administration errors had been reported of which 155 (38.6%) were detected and corrected by academic nurses. The most common error reported was deviation from aseptic technique in 96(23.8%) cases. Most common emotions resulting from errors were fear in 45(28.8%) and anxiety in 37(23.5%). Most common cause was performance deficit in 141(43.4%) cases and the most common contributing factor was workload declared by 179(55.2%). CONCLUSIONS: The error rate among nursing students was high whereas reporting of errors was low. PMID- 26028377 TI - Iatrogenic Cushing's syndrome in children presenting at Children's Hospital Lahore using nappy rash ointments. AB - OBJECTIVE: To study the characteristics of infants and children presenting with iatrogenic Cushing's Syndrome due to nappy rash ointments. METHODS: The descriptive study was conducted at the Children's Hospital, Lahore, from April to September 2013, and comprised patients presenting with cushingoid features and history of using nappy rash ointments. Patients having Cushing's Syndrome due to causes other than iatrogenic were excluded and so were those taking oral or parenteral steroids due to skin allergy, renal or respiratory disease. Demographic data, history and examination of all patients were recorded on a proforma and results were analysed using SPSS 16. RESULTS: Of the total 18 patients, 13(72%) were girls and 5(27%) were boys. Eight (44.4%) patients were younger than 6 months, 6(33.3%) were between 6 months to 1 year, while 4(22.2%) were between 12 and 18 months of age. Clobetasol alone was the most frequently used agent responsible in 13(72%) cases. Duration of use of steroid ointment was as short as 3 weeks to as much as 1 year. All the patients were using disposable diapers. Ointment was prescribed by a doctor in 5(27%) cases and self-prescribed (relative or neighbour) in 13(72%). CONCLUSIONS: Self-medication and prolonged use of potent steroid ointments are major contributors in development of iatrogenic Cushing's Syndrome in infants and children. Younger age, female gender and use of disposable diapers were other important predisposing factors. PMID- 26028378 TI - Tetralogy of Fallot with absent pulmonary valve syndrome; appropriate surgical strategies. AB - OBJECTIVE: To evaluate patients presenting with Tetralogy of Fallot with absent pulmonary valve syndrome to a tertiary care hospital and their surgical management. METHODS: The retrospective study was conducted at Congenital Cardiac Services, Aga Khan University Hospital, Karachi, Pakistan, and comprised data of Tetralogy of Fallot patients between April 2007 and June 2012. Data was analysed together with follow-up echocardiography. Variables assessed included demographics, imaging, operative technique, complications, post-operative recovery and follow-up echocardiography. SPSS 17 was used for statistical analysis. RESULTS: Of the 204 patients, 6 (3%) had undergone surgical correction for Tetralogy of Fallot with absent pulmonary valve syndrome. All 6(100%) patients underwent complete repair. Median age for surgery was 8.5 years (range: 0.5-29 years). Of the different surgical strategies used, Contegra and Bioprosthetic valve placement had satisfactory outcome with minimal gradient at Right Ventricular Outflow Tract, good ventricular function and mild valvular regurgitation. One (16.6%) patient with Trans Annular Patch developed post operative Right Ventricle Outflow Tract gradient of 80mmHg with moderate pulmonary regurgitation. One (16.6%) patient with monocusp valve developed free pulmonary regurgitation at 6 months. The other 4(66.6%) patients are currently free from any complications or re-intervention. CONCLUSIONS: Early surgery is preferred in symptomatic patients. The repair depends upon achieving integrity of pulmonary circulation which is best achieved by using right ventricle to pulmonary artery conduit or inserting a pulmonary valve. PMID- 26028379 TI - Determinants of depression and somatisation symptoms in low back pain patients and its treatment: global burden of diseases. AB - OBJECTIVE: To determine the prevalence of Low Back Pain in primary care setting population and to examine its association with symptoms of depression and somatisation. METHODS: The cross-sectional study was conducted at 13 Primary Healthcare Centres (throughout Qatar from March to December, 2012. A General Health Questionnaire was used to identify the probable cases. A specially designed questionnaire with three parts was used for data collection: socio demographic information of the studied subjects, modified version of the Roland Morris scale for evaluating back-related functional disability, and Symptom Cheklist-90-Revised for depression and somatisation subscales. RESULTS: A representative sample of 2,600 patients was approached and 1,829(70.0%) of them participated in the study. The prevalence of low back pain in the study sample was 56.5%. There were statistically significant differences between subjects with and without low back pain in terms of body mass index (p< 0.025), gender (p< 0.003) and housing condition (p< 0.001). There was a significant difference between subjects with and without the pain in terms of all aspects of functional disability. Somatisation disorder in low back pain was 203 (19.6%) and depression disorder was 265 (25.4%). Most of the patients with LBP reported pain in the arms and legs (p< 0.001); shortness of breath (p< 0.028) palpitations (p=0.004); gastrointestinal complaints such as abdominal pain (p< 0.001), diarrhoea (p< 0.001) and vomiting (p< 0.001); feeling tired (p< 0.001); trouble with sleeping (p< 0.001); headache (p< 0.001) and fainting (p=0.043). The mode of treatment taken by the patients for relief were bed rest 695 (67.2%) followed by warm compression 480 (47.6%), physiotherapy 491 (47.5%), regular exercise 414 (40%), and back plasters 346 (33.5%). CONCLUSIONS: The present study showed that the symptoms of depression and somatisation were prevalent among low back pain patients. Functional disability was higher in the patients. Recognising this problem may lead to better patient-treatment matching and improved clinical outcomes. PMID- 26028380 TI - Status of emergency obstetric care in four districts of Punjab, Pakistan - results of a baseline assessment. AB - OBJECTIVE: To assess the availability and quality of Emergency Obstetric and Newborn Care in four districts of Punjab. METHODS: The cross-sectional descriptive study was conducted in Attock, Gujranwala, Rahim Yar Khan and Khanewal districts of Pakistan's Punjab province. Data was collected in July 2012 from all District Headquarter Hospitals, Tehsil Headquarter Hospitals and selective Rural Health Centres (RHCs) using a pre-formatted questionnaire to assess availability of signal functions of Emergency Obstetric and Newborn Care, including staffing and equipment, number of births and women with complications, maternal case fatality rate and stillbirth rate. SPSS 20 was used for statistical analysis. RESULTS: In total, 32 health care facilities were surveyed: 14(43.75%) providing basic care and, 18(56.25) providing comprehensive obstetric care. All required signal functions were available at 4(22%) in the latter category, and 3(21%) facilities in the former category. Met need for Emergency Obstetric and Newborn Care was 17.8%. Besides, there were 26 maternal deaths among the 1,482 women with recognised obstetric complications, indicating an overall case fatality rate for all districts of 1.75%. CONCLUSIONS: Continued efforts are needed to improve the availability and quality of Emergency Obstetric and Newborn Care through targeted skill-based training and provision of adequate drugs and equipment. PMID- 26028381 TI - Surfactant use in premature neonates <37 weeks gestation: Experience and outcome at a tertiary care hospital. AB - OBJECTIVE: To assess a single-centre experience and outcome of premature neonates who received surfactant therapy. METHODS: The prospective cohort study was done at Shifa International Hospital, Islamabad, from December 2005 to May 2007 and comprised premature neonates (< 37 weeks gestation) who had clinical and radiologic evidence of respiratory distress syndrome and had received surfactant therapy. SPSS 21 was used for statistical analysis. RESULTS: A total of 52 premature neonates received surfactant. Mean gestational age was 29+/-2.8 weeks and mean birth weight was 1273+/-487gms. Only 16(31%) mothers had received antenatal dexamethasone. Surfactant was used as single dose in 41(78%) neonates at 6.1+/-6.6hours of life or two doses in 11(22%). Chest X-ray and respiratory distress syndrome category showed an overall improvement in 29 (56%) neonates. Complications were seen in 17(33%) neonates, and 21(40%) died. Mortality was significantly associated with gestation (p< 0.000) and weight (p< 0.008). CONCLUSIONS: Surfactant administration is an option for respiratory distress syndrome in Pakistan. PMID- 26028382 TI - Histological changes induced by tamoxifen versus tamoxifen plus 13-cis-retinoic acid on rabbit uterine glands. AB - OBJECTIVE: To study the effects of tamoxifen versus tamoxifen plus 13-cis retinoic acid on the histology of uterine glands in rabbits. METHODS: The experimental, randomised, controlled trial was conducted at the Army Medical College, Rawalpindi, from March 2009 to June 2009 and comprised rabbits acquired from the National Institute of Health, Islamabad. The animals were randomly divided into three equal groups: group A had controls, group B was treated with tamoxifen, and group C with tamoxifen plus retinoic acid. The uterine weight and cross-sectional diameter of uterine horns were measured after sacrifice. The uteri were processed for paraffin embedding. The sections were then assessed for stratification of glandular epithelium, changes in the glandular shape and glandular epithelial height. SPSS 13 was used for statistical analysis. RESULTS: Tamoxifen administration resulted in variation of glandular shape and increase in glandular epithelial height in group B as compared to control group, p < 0.001 and 0.005 respectively. The adjuvant administration of 13-cis-retinoic acid showed a suppressive effect only on glandular epithelial height, when compared with Group B (p=0.01). CONCLUSIONS: The 13-cis-retinoic acid has no significant inhibitory effect on uterine glandular proliferation induced by tamoxifen after a short-term administration of three months. PMID- 26028383 TI - Frequency and risk of metabolic syndrome in prediabetics versus normal glucose tolerant subjects -- a comparative study. AB - OBJECTIVE: To compare the frequency and risk of metabolic syndrome in pre diabetics against normal glucose-tolerant subjects attending diabetes screening camps in an urban centre. METHODS: The cross-sectional study was carried out at the Jinnah Postgraduate Medical Centre, Karachi, from January to August, 2008, and comprised subjects recruited through diabetes screening camps. They were >30 years of age, without prior history of diabetes and were screened through fasting plasma glucose and 2-hour oral glucose tolerance test. Demographic, anthropometric, clinical and biochemical measurements were done. Frequency of different components and their constellation as metabolic syndrome were determined according to the Adult Treatment Panel-III criteria. Relative risk was estimated to find the risk of metabolic syndrome in pre-diabetics versus normal glucose-tolerant subjects. RESULTS: The study sample comprised 80 subjects; 40(50%) normal glucose-tolerant in Group A and 40(50%) pre-diabetics in Group B. In Group A, there were 25(62.5%) men and 15(37.5%) women, while Group B had 22(55%) men and 18(45%) women. The mean age in Group A was 38.08+/-5.35 years, while in Group B it was 39.09+/-6.12 years. The frequency of various cardiovascular risk factors was higher in pre-diabetics (p< 0.05). Central obesity was the most prevalent risk factor (85%, CI: 75.74-96.06), followed by low levels of high density lipoprotein (82.5%, CI: 72.64-94.27), raised triglycerides (67.5%, CI: 55.35-82.01), hypertension (57.5%, CI: 44.68-72.82), and fasting plasma glucose >100mg/dl (42.5%, CI: 29.68-57.82). Metabolic syndrome was found in 23(57.5%) in Group B compared to 9(22.5%) Group B, according to Adult Treatment Panel-III criteria. Calculated relative risk indicated that Group B was 1.9 times more prone to be suffering from metabolic syndrome compared to Group A. CONCLUSIONS: Pre-diabetics were more prone to developing cardiovascular disorders than normal glucose-tolerant subjects. PMID- 26028384 TI - Lumbosacral dysraphism as cause of neurogenic bladder: Magnetic Resonance Imaging based study from SIUT Pakistan. AB - OBJECTIVE: To find the frequency and types of spinal dysraphism in patients presenting with neurogenic bladder dysfunction. METHODS: The cross-sectional study was conducted at the Sindh Institute of Urology and Transplantation, Karachi, from February to September 2011, and comprised patients of either gender 5-15 years of age with neurogenic bladder suspected to be due to lumbosacral dysraphism. They all had magnetic resonance imaging of lumbosacral spine. All images were reviewed by an experienced radiologist and patients were diagnosed as having spinal dysraphism and were categorised according to the radiological features. Data was analysed using SPSS 10. RESULTS: Of the 175 patients in the study, 96(55%) were males and 79(45%) were females with an overall mean age of 7.3+/-2.15 years (range: 5-15 years). Spinal bony defects were found in 110(62.8%) patients, and of these, 96(87%) had spinal dysraphism. Myelomeningocele, meningocele and sacral agenesis was found in 58(60.4%) of the 96 patient with spinal dysraphism. CONCLUSIONS: Spinal dysraphism is the most common cause of neurogenic bladder in children up to 15 years of age and myelomeningocele, meningocele and sacral agenesis comprised more than 60% of such cases. PMID- 26028386 TI - Choice of the pulse sequence and parameters for improved signal-to-noise ratio in T1-weighted study of MRI. AB - OBJECTIVE: To investigate the practical impact of alteration of imaging parameters on signal-to-noise ratio for the most commonly used T1-weighted magnetic resonance sequences. METHODS: The study was conducted in the Department of Medical Physics, Ninewells Hospital and Medical School, Dundee, UK, in 2007. Magnetic resonance images of a tissue-equivalent material were generated with a set of T1 and T2 values. Experimental variations in the imaging parameters were performed in echo time and repetition time. Quantitative analysis consisted of signal-to-noise ratio. RESULTS: Percentage inaccuracy in signal-to-noise ratio was the result of inappropriate choice of parameters. We have investigated conventional spin echo, fast spin echo and fast fluid attenuated inversion recovery with one of corresponding percentage errors 28.68%, -36.65% and -40.34%, respectively. Conventional spin echo presented moderately low percentage error with the choice of repetition time and echo time. Factual error in fast spin echo was slightly higher than conventional spin echo. Fast fluid attenuated inversion recovery could create outstanding signal-to-noise ratio of high T1/T2 value phantoms in T1-weighted images. CONCLUSIONS: The role of repetition time and echo time in T1-weighted images was crucial to sustain the image quality. PMID- 26028385 TI - The impact of self-efficacy education on self-care behaviours of low salt and weight setting diets in hypertensive women covered by health-care centers of Dehaghan in 2013. AB - OBJECTIVE: To examine the impact of self-efficacy-based education on promoting self-care behaviour in low-salt and weight-setting diets for hypertensive women. METHODS: The quasi-experimental study was conducted in 2013 and comprised hypertensive women registered with healthcare centres in Dehaghan, Iran. The subjects were divided into two equal groups; intervention group and comparison group. For the intervention group, four educative sessions were conducted based on self-efficacy leading to self-care behaviours, while the comparison group did not receive any education. Self-efficacy and self-care questionnaires data (obtained before intervention, immediately after intervention and 3 months after intervention) was analysed using SPSS 20. RESULTS: There were 64 subjects divided into two groups of 32(50%) each. The mean age in the intervention group was 51.2+/-6.86years and 49.1+/-7.99years in the comparison group. Self-care behaviours of low salt diet (p=0.002) and weight-setting diet (p=0.004) were more significantly seen in the intervention group. The means of systolic blood pressure (p=0.004) and diastolic blood pressure (p< 0.001) were significantly reduced in the intervention group. The mean value for body mass index was not the same in the intervention group (p< 0.001). CONCLUSIONS: Self-efficacy-based education had an impact on self-care behaviours in hypertensive patients. PMID- 26028387 TI - Anti inflammatory effect of thymoquinone in comparison with methotrexate on pristane induced arthritis in rats. AB - OBJECTIVE: To determine the anti-inflammatory effects of thymoquinone on body weight, clinical score of inflammation, total leukocyte count and differential leukocyte count in arthritic rats and compare it with that of methotrexate. METHODS: The study was conducted at the Post-Graduate Medical Institute, Lahore, from March to September 2013, and comprised female Sprague-Dawley rats randomised into four equal groups; group A (healthy control), group B (positive control), group C (thymoquinone treated) and group D (methotrexate treated). Arthritis developed in Group B, C and D within two weeks after a single intra-dermal injection of pristane. Body-weight measured on electronic balance in grams and clinical score of inflammation scored on macroscopic scoring system were monitored on every alternate day while total leukocyte count and differential leukocyte count were taken at day 0, 16 and 30. After day 15, groups A and B were given 0.5ml of distilled water by intra-peritoneal injection daily for 15 consecutive days; group C was given thymoquinone 2mg/kg by intra-peritoneal injection daily for 15 consecutive days, and group D received methotrexate 0.5mg/kg by intra-peritoneal injection, daily for 15 consecutive days. SPSS 20 was used for statistical analysis. RESULTS: The 32 rats in the study were randomised into four groups of 8(25%) each. In group A the body-weight continued to increase and reached a mean of 144.13+/-10.8% of the baseline at day 30. In group B the weight reduced to 93.13+/-4.19% at day 16 and to 88.3+/-6.97% at day 30. In groups C and D the weight reduced to 87.25+/-7.69% and 88.5+/-7.07% respectively at day 16; then the animals in the two groups regained their weight which increased to 108.63+/-10.89% and 103.38+/-6.25% respectively at day 30. The score was zero in group A throughout the study period. The score of group B, which was zero at day 0, reached a mean of 16+/-0 at day 16. In groups C and D, the mean score increased till day 16 and reached 16+/-1 and 16+/-0 respectively, and then reduced to 5+/-2 and 4+/-1 at day 30 respectively. CONCLUSIONS: Evaluation of data supported the anti-inflammatory activities of thymoquinone, so it may be investigated as an effective anti-inflammatory drug in rheumatoid arthritis. PMID- 26028388 TI - Determination of methods used by the neonatal care unit nurses for management of procedural pain in Turkey. AB - OBJECTIVE: To determine the pharmacological and non-pharmacological methods used by neonatal intensive care unit nurses to reduce procedural pain. METHODS: The cross-sectional study was conducted from September 2011 to June 2012 and comprised nurses employed in the paediatric departments, consisting of neonatal intensive care units and newborn units, of 15 hospitals in various cities of Turkey: 8 in Istanbul, 3 in Izmir and two each in Antalya and Edirne. Data was collected using a questionnaire and analysed using SPSS 15. RESULTS: The mean age of the 486 nurses was 28.19+/-5.14 years; 316(65%) had bachelor's degrees; 278(57.2%) had nursing experience greater than 6 years; and 322(72.5%) had newborn nursing experience greater than 6 years. Overall, 364(74.9%) nurses used non-pharmacological methods, and 145(29.8%) used pharmacological methods for pain relief. The most commonly used non-pharmacological methods were skin touch 364(75%) and giving a pacifier 269(55.3%). The most commonly used pharmacological methods were paracetamol and ibuprofen by 145(29.8%) nurses. A statistically significant difference was found between the level of education and use of pharmacological and non-pharmacological methods for pain relief (p< 0.05). CONCLUSIONS: Among the nurses in both groups, very little pain management was used for invasive procedures. Educational programmes for pain management in newborns should be arranged to develop an institutional culture. Guidelines for these patients' pain management should also be established. PMID- 26028390 TI - Conservative treatment preferences and the plausible mechanism of Neer's stage 1 of shoulder impingement in younger people. AB - The interaction of various factors in the vicious cycle (VC) of subacromial impingement syndrome (SIS) is complex and there are conservative treatment preferences for speedy rehabilitation. The mechanism of SIS is not fully understood and the inappropriate treatment priorities cause delay in rehabilitation. SIS is related to the reduction in the subacromial space (SS). Posterior capsular tightness (PCT) and rotator cuff (RC) dysfunction are the two basic mechanisms in this regard. PCT may cause anterosuperior translation of humeral head (HH) and anterior acromion tipping through scapular dyskinesis, thereby reducing the subacromial space. Alteration in the force couple of muscle secondary to scapular dyskinesis eventually causes injury to subacromial structures. The rotator cuff is important in centring the humeral head in the glenoid cavity and superior translation of humeral head occurs if their function is compromised. Posterior capsular tightness may affect the function of rotator cuff action which leads to early fatigue, dysfunction of these muscles and eventually impingement. Adhesive changes take place in various structures around the shoulder secondary to impingement pain and relative immobility, which further aggravates the problem. To reverse the vicious cycle, conservative intervention should therefore be directed to loosen posterior capsular tightness, restore rotator cuff function through appropriate exercise in a pain-free range through appropriate exercise, mobilisation of adhesion through teraservers friction or pain-free mobilisation or grade I and grade II manipulation. Depending on the level of irritability, pain control intervention could be considered alongside. PMID- 26028389 TI - Guidelines on gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is the most common acid-related disorder encountered during clinical practice in Pakistan and is associated with significant impairment of health-related quality of life. A number of guidelines and recommendations for the diagnosis and management of GERD have been published in different countries, but a Pakistani accepted directive by the standards of evidence-based medicine is still lacking. Our aim was to create an understanding of the natural history and presentations of reflux disease; evaluating possible treatment options available for the patients with complex and uncomplicated reflux ailments with the development of current and up to date evidence based endorsement, relevant to the needs of Pakistani health care providers in order to treat oesophageal manifestations of GERD. In order to make such guidelines, a comprehensive literature search was conducted with pertinent evidence reviewed, and quality of relevant data assessed. The resultant conclusions were based on the best available evidence and expert opinion of the authors of technical review panel. PMID- 26028391 TI - Epidemiology of Karachi road traffic crash mortality in 2013. AB - Road Traffic Crash (RTC) is the eighth leading cause of death globally. In a recent World Health Organization report, there were 5,192 RTC deaths reported from Pakistan in 2010. The Road Traffic Injury Research and Prevention Center (RTIRPC) is a unique public-private public health enterprise in Karachi, and collects data from five major public and private hospitals' emergency departments in the city. Cumulatively, 1130 deaths were recorded in the year 2013. Males accounted for 981 (86.8%) deaths. The most vulnerable decades of life were twenties and thirties; accounting for 307 (27.2%) of all deaths. In terms of involvement of vehicle type in fatalities; over half 577 (51.1%) of all fatalities involved motorbikes, while the second most common type of vehicle involved were buses/coasters which accounted for 108 (9.6%) fatalities. In the burgeoning cities of developing countries, road injury and fatality surveillance can fulfill a vital role in highlighting the human cost of rapid motorization. PMID- 26028392 TI - Prevalence, correlates, and changes in injury epidemiology between 2006 and 2010 among 13-15 year Moroccan school attending adolescents. AB - Injuries are the leading cause of mortality among 10-19 years old children and adolescents globally. This study reports on correlates of injuries using multivariate analysis and compares trends in injury from 2006 to 2010 in Morocco. For the prevalence of all cause injury, there was a statistically significant decrease between year 2006 and 2010, cumulatively, as well as for each sex. Within same years, boys reported having sustained more injuries than girls, and this difference was found to be statistically significant. Within same years, boys reported having sustained more fall injuries than girls; however this was statistically significant for year 2006 only. All cause injuries were also found to be statistically significantly more common in boys compared to girls in the year 2010, in the multiple logistic regression model. To further mitigate the burden of injury malady in Morocco among adolescents; all stakeholders i.e. health policymakers, paediatricians, psychiatrists, general practitioners, teachers, and parents need to choreograph their moves in concert. PMID- 26028393 TI - Osteoid Osteoma of acetabulum, a rare presentation. AB - The case of a relatively frequent benign osteoblastic tumour, osteoid osteoma at an atypical site is presented. It was in a 20 year old man who attended the outpatient department of Aga Khan University Hospital, Karachi with pain in left groin since last 6 months which often occurred at night and was relieved by taking NSAIDs. X-ray failed to reveal the cause. CT scan showed central radiolucent nidus with surrounding sclerosis suggestive of osteoid osteoma in the left acetabulum. Acetabulum is a rare site for osteoid osteoma, the usual sites are diaphysis of long bones. Hence, the diagnosis is often difficult and delayed in such cases. CT scan, Bone scan and MRI, helped in diagnosing the condition. Resection of the lesion by open technique under fluoroscopic control was performed and histopathology confirmed the diagnosis. PMID- 26028394 TI - Hypothyroidism simulating as polymyositis. AB - Polymyositis-like syndrome in hypothyroidism is a rare condition characterised by proximal muscle weakness and elevated muscle enzymes. Patients with this condition can initially be misdiagnosed as having polymyositis due to similar characteristics of both diseases; however a response to thyroxine is the main differentiating feature. This report highlights the case of a 30-year-old male who had severe myalgia and proximal muscle weakness. In addition to raised creatinine phosphokinase (CPK) levels, his biochemical profile showed hypothyroidism. Initially thought to be suffering from polymyositis, improvement in both clinical and biochemical profile with thyroxine led to the diagnosis of polymyositis-like syndrome associated with hypothyroidism. PMID- 26028395 TI - Baloon angioplasty for venous sinus stenosis in a idiopathic intracranial hypertension case. AB - The Idiopathic Intracranial Hypertension (IIH) is a well characterised condition with intractable headaches, visual obscurations, and papilloedema as dominant features, mainly affecting obese women. With the advent of magnetic resonance (MR) venography and increased use of cerebral angiography, there has been recent emphasis on the significant number of patients with IIH found to have associated non-thrombotic dural venous sinus stenosis. This has led to a renewed interest in endovascular stenting and angioplasty as a treatment for IIH in patients non responsive to medical treatment. We present a patient without known risk factors for IIH and non-responsive to treatment. The 19-year-old woman presented with headache and diplopia. She was diagnosed with IIH since she was five years of age and had been non-responsive to lumbar cerebrospinal fluid (CSF) drainage and acetazolamide treatment. MR venography revealed thin calibration of transverse sinus. Digital subtraction angiography (DSA) venous phase also revealed 50% stenosis of transverse sinus, 50% stenosis of left proximal sigmoid sinus and 90% stenosis of its distal part leading to obstruction of left transverse sinus outflow and forced directed drainage of left hemisphere to the anterior region. PMID- 26028396 TI - Laparoscopic cystgastrostomy: A Pakistani perspective. AB - Laparoscopic Pancreatic Pseudocyst (PP) surgery can be performed via anterior or posterior cystogastrostomy, endoscopy-assisted surgery and cystojejunostomy. We conducted a prospective analysis of our patients undergoing laparoscopic cystogastrostomy to analyse the merits and demerits of the procedure. In a period of 3 years from January 2010 to December 2012 all the patients who underwent laparoscopic drainage of pancreatic pseudocysts were prospectively analysed. A total of 12 patients underwent a transgastric anterior cystogastrostomy with a stoma size of 4.5cms. There was no intraoperative or postoperative bleeding or leakage on anastomotic lines. Post-op pain score on the first post-op day was 4 (2-5) on the Visual Analogue Scale (VAS). Average hospital stay was 4.1+/-2.3 days. All patients had complete resolution of symptoms on follow-up. Follow-up computed tomography (CT) scans on 8 patients showed complete resolution of the cysts. Laparoscopic cystogastrostomy is a safe and feasible method and provides efficient drainage of PP. PMID- 26028397 TI - Vitamin D deficiency: Diagnosis and patient centred management. AB - This comprehensive review addresses the issue of Vitamin D deficiency and its management in adults. Briefly describing the history of Vitamin D development and its role in human physiology, it discusses D deficiency in adults. Pragmatic suggestion for diagnosis, choice of therapy, and monitoring are presented from a patient-centred viewpoint, keeping socioeconomic realities in perspective. The review adds to current medical literature by collating evidence in a format that will be useful to practicing clinicians. PMID- 26028398 TI - Oral combination therapy in primary care. AB - Diabetes is a multifactorial disease, with multiple pathophysiologic abnormalities. This means that a combination of drugs, acting upon as many pathologic mechanisms as possible, is necessary for optimal management of the syndrome. This article discusses how a rational combination of oral anti-diabetic drugs can be chosen and used in primary care practice. PMID- 26028399 TI - Crimean-Congo Haemorrhagic Fever: Breaking the chain of transmission. PMID- 26028400 TI - Post poliomyelitis syndrome: A rare sequel of acute poliomyelitis. PMID- 26028401 TI - Post poliomyelitis syndrome: A rare sequel of acute poliomyelitis-(Author Reply). PMID- 26028402 TI - An early tracheo-innominate fistula: Lessons learnt from a clinical encounter. PMID- 26028403 TI - A hospital-based comparative study of the knowledge, attitudes and practices of family planning among women belonging to different socio-economic status. AB - OBJECTIVE: To assess the knowledge, attitudes and practices of family planning among women belonging to different socio-economic status. METHODS: A cross sectional study was conducted in the outpatient department of three hospitals of Ziauddin University based on the socioeconomic divide. Total 351 married females of reproductive age group with at least one child were selected after informed consent through non probability convenience sampling. Data was analyzed by using SPSS version 21. RESULTS: The preferred method of contraception in all three groups was a male condom30.9%. The upper socioeconomic group relied more on the modern methods of contraception 92% while the middle socioeconomic group relied on modern 71.7% as well as natural methods of contraception 28.3%. Use of contraceptives was comparatively lower in the low socioeconomic group 19.5%. Lower socioeconomic group also had the most children per family with mean and standard deviation of 3.6+/-2.3 and also had the highest number of desired children with mean and standard deviation of 4+/-1.4. The general reasons for avoiding contraceptives were difficulty in getting pregnant (11.1%), the want for more children (10.2%), infrequent sexual intercourse (10.0%) and fear of side effects (6.9%). CONCLUSIONS: Awareness of contraception was found lowest in the lower socioeconomic class, with the elite class using a high percentage of contraceptives. PMID- 26028405 TI - In vitro modulation of probiotic bacteria on the biofilm of Candida glabrata. AB - A conspicuous new concept of pathogens living as the microbial societies in the human host rather than free planktonic cells has raised considerable concerns among scientists and clinicians. Fungal biofilms are communities of cells that possess distinct characteristic such as increased resistance to the immune defence and antimycotic agents in comparison to their planktonic cells counterpart. Therefore, inhibition of the biofilm may represent a new paradigm for antifungal development. In this study, we aim to evaluate the in vitro modulation of vulvovaginal candidiasis (VVC)-causing Candida glabrata biofilms using probiotic lactobacilli strains. Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 were shown to have completely inhibited C. glabrata biofilms and the results were corroborated by scanning electron microscopy (SEM), which revealed scanty structures of the mixed biofilms of C. glabrata and probiotic lactobacilli strains. In addition, biofilm-related C. glabrata genes EPA6 and YAK1 were downregulated in response to the probiotic lactobacilli challenges. The present study suggested that probiotic L. rhamnosus GR-1 and L. reuteri RC-14 strains inhibited C. glabrata biofilm by partially impeding the adherence of yeast cells and the effect might be contributed by the secretory compounds produced by these probiotic lactobacilli strains. Further investigations are required to examine and identify the biofilm inhibitory compounds and the mechanism of probiotic actions of these lactobacilli strains. PMID- 26028404 TI - Current achievements and future perspectives in whole-organ bioengineering. AB - Irreversible end-stage organ failure represents one of the leading causes of death, and organ transplantation is currently the only curative solution. Donor organ shortage and adverse effects of immunosuppressive regimens are the major limiting factors for this definitive practice. Recent developments in bioengineering and regenerative medicine could provide a solid base for the future creation of implantable, bioengineered organs. Whole-organ detergent perfusion protocols permit clinicians to gently remove all the cells and at the same time preserve the natural three-dimensional framework of the native organ. Several decellularized organs, including liver, kidney, and pancreas, have been created as a platform for further successful seeding. These scaffolds are composed of organ-specific extracellular matrix that contains growth factors important for cellular growth and function. Macro- and microvascular tree is entirely maintained and can be incorporated in the recipient's vascular system after the implant. This review will emphasize recent achievements in the whole organ scaffolds and at the same time underline complications that the scientific community has to resolve before reaching a functional bioengineered organ. PMID- 26028406 TI - Synthesis, Anticonvulsant and Binding Interaction Study of Novel Piperamides with Bovine Serum Albumin by Fluorescence Spectroscopy. AB - A series of piperamides (PA) 8a-j were designed, synthesized and evaluated for their antimicrobial and anticonvulsant activity. Compounds 8a and 8h showed considerable antibacterial activity against B. subtilis with minimum inhibitory concentration (MIC) of 8 and 10 ug/mL, respectively. Compounds 8a and 8h showed advanced anticonvulsant activity as well as lower neurotoxicity than the reference drugs. The interaction between bovine serum albumin (BSA) and PA was investigated using fluorescence quenching and UV-vis absorption spectroscopy. Results showed that PA could strongly quinch the intrensic fluorescence of BSA through a static quencing procedure. The binding constant and number of binding sites of PA with BSA were obtained. The binding distance was calculated based on Forster non-radiative energy transfer theory. PMID- 26028407 TI - Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. AB - BACKGROUND: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS: We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS: The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.). PMID- 26028408 TI - The effects of training and detraining after an 8 month resistance and stretching training program on forward head and protracted shoulder postures in adolescents: Randomised controlled study. AB - PURPOSE: This study aimed to evaluate the effects of a 32-week resistance and stretching training program applied in Physical Education classes on forward head posture and protracted shoulder posture of Portuguese adolescents (15-17 years old). The detraining effects after a 16-week period were also measured. METHODS: This prospective, randomized and controlled study was conducted in two secondary schools in Portugal. One hundred and thirty adolescents with forward head and protracted shoulder posture were randomly assigned to a control or experimental group. The sagittal head, cervical and shoulder angle were measured before and after a 32-week time intervention period. The control group (n = 46) did only the Physical Education classes whereas the exercise group (n = 42) received a posture corrective exercise programme in addition to Physical Education classes. A 16 week detraining period followed the 32-week. RESULTS: Significant increase were observed in the cervical and shoulder angle in the experimental group following the 32 week-intervention period. After the 16-week detraining period no significant differences were observed in the three postural angles in the intervention group. CONCLUSIONS: The exercise intervention was successful at decreasing forward head and protracted shoulder in adolescents. Detraining period was not sufficient to reduce the overall training effects. This study supports the postural training and rehabilitation performed during Physical Education classes, with the aim of preventing and managing upper quadrant musculoskeletal pain. CLINICALTRIALS. GOV IDENTIFIER: NCT02190331. PMID- 26028410 TI - [Frontier of Gastrointestinal Taste and Nutrient Sensor Research: Search for Potential Drug Target]. PMID- 26028409 TI - Apoptosis and cell proliferation in the mouse model of embryonic death induced by Tritrichomonas foetus infection. AB - Bovine tritrichomonosis is a sexually transmitted disease caused by the protozoon Tritrichomonas foetus and characterised by embryonic-death and abortion. During pregnancy, the processes of cell proliferation and death play a crucial role for blastocyst implantation and the subsequent maintenance of early pregnancy, and their misbalance may lead to the abortion. In this study, we aimed to investigate whether cell proliferation and death may be altered during tritrichomonosis. For this purpose, we used pregnant BALB/c mice as an alternative experimental animal model that has successfully reproduced the infection. We analysed the immunohistochemical expression of active caspase-3 and proliferating cell nuclear (PCNA) antigens in the endometrium of infected mice. We found an increase in the number of caspase-3 positive cells in infected mice that were not pregnant at the necropsy. Besides, the number of positive proliferating cells increased in the uterine luminal epithelium of infected animals killed at 5-7 days post coitum (dpc). Pregnant infected mice killed at 8-11 dpc showed higher proliferation than control animals. We suggest that the cytopathic effect induced by T. foetus in the uteri of infected mice may induce the apoptosis of the epithelial cells and, as a result, promote a compensatory proliferative response. The information described here will be helpful to further study the pathogenesis of the bovine tritrichomonosis. PMID- 26028411 TI - [Role of the sweet taste receptor in glucose metabolism: no sweets for diabetes?]. AB - Type 2 diabetes is closely associated with our daily diets and has become a global health problem with increasing number of patients. Maintaining energy homeostasis is essentially required for the treatment of diabetes. Energy metabolism starts with taking in a meal. Nutrients including amino acids, fatty acids and glucose in the digest have been shown to act on the neuroendocrine cells in the gastrointestinal (GI) tract, and thereby play important roles in energy homeostasis. Therefore, the GI tract is now recognized as a sensor system for nutrient signals. Taste receptor type 1 member 2 (T1R2) is known to function as a co-receptor with T1R3 to detect sweet chemicals in the taste buds. It has been proposed that the T1R2/T1R3 receptor complex acts as sweet sensor in the intestine, and plays a pivotal role in sensing sugars and maintaining glucose homeostasis through incretin secretion. To clarify the physiological roles of T1R2 in glucose homeostasis, T1r2-lacZ knock-in/knock-out mice were generated. We found lacZ gene expression in the GI tract where T1r3 expression has been reported. Interestingly, the T1r2-lacZ knock-in mice showed impaired glucose tolerance on oral glucose challenge but not on intraperitoneal injection. However, the fasting glucose level in T1r2-lacZ knock-in mice was comparable to that in wild type mice. These results suggest an important role of the sweet taste receptor system in the intestine when stimulated by glucose. Therefore, the roles of T1R2 will be presented and the mechanism for metabolic homeostasis will be discussed. PMID- 26028412 TI - [Free Fatty Acid Receptor Family: A New Therapeutic Target for Metabolic Diseases]. AB - Free fatty acids (FFAs) are not only essential nutritional components but they also act as signaling molecules in various physiological processes. A strategy to deorphanize G-protein-coupled receptors (GPCRs) identified a series of receptors for FFAs that play significant roles in nutrition regulation. In this free fatty acid receptor family, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long chain FFAs. FFAR1 regulates insulin secretion in pancreatic beta-cells, whereas FFAR4 promotes the secretion of glucagon-like peptide-1 (GLP-1) in the intestine, and also acts as a lipid sensor in adipose tissue to sense dietary fat and control energy balance. In this review, we discuss recent advances in the pharmacological characterization of FFAR1 and FFAR4, and we present a summary of current understandings of their physiological roles and their potential as drug targets. PMID- 26028413 TI - [Glutamate as a potential protective drug in the gastrointestinal mucosa]. AB - Monosodium glutamate (MSG) is known to provide the umami taste in the food. We have recently reported that glutamate has the potential to protect the small intestine against non-steroidal anti-inflammatory drugs (NSAIDs)-induced lesions in rats. In this paper, we examined this protective effect using sodium loxoprofen, one of the NSAIDs frequently used in Asian countries, to determine whether MSG accelerates the healing of loxoprofen-induced small intestinal lesions in rats. Loxoprofen at 60 mg/kg caused hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum. These lesions spontaneously healed within 7 days, but this healing process was delayed by repeated administration of loxoprofen at low doses (10, 30 mg/kg) for 5 d after lesion induction. The healing-impairment action of loxoprofen was accompanied by the down-regulation of vascular endothelium-derived growth factor (VEGF) expression and an angiogenic response. The impaired healing caused by loxoprofen was significantly restored by co-treatment with a diet containing 5% MSG for 5 d, accompanied by the enhancement of VEGF expression and angiogenesis. We suggest that daily intake of MSG not only protects the small intestine against NSAIDs-induced damage but also exerts healing-promoting effects on these lesions. PMID- 26028414 TI - [New remedy for dry mouth using the gustatory-salivary reflex]. AB - Patients with dry mouth are increasing in Japan due to the country's super-aging society and stressful modern society. Dry mouth affects quality of life, including difficulty with speech or swallowing, and also causes aspiration pneumonia and, respiratory infection. Moreover, dry mouth closely relates to taste dysfunction, resulting in malnutrition, a common risk of nursing care in the elderly. Against these backgrounds, dry mouth has recently been a target of social concern. Drugs for dry mouth such as M3, a muscarinic agonist, have been widely used: however, these drugs have serious side effects, such as vomiting, sweating and/or digestive disorders. We examined the gustatory-salivary reflex to explore a remedy for dry mouth. We have demonstrated that umami stimulation increases saliva from both minor- and major salivary-glands, and that the effect is longer-lasting than with the other four basic tastes. Stimulating the umami response could therefore be a safe and useful remedy for dry mouth. PMID- 26028415 TI - [Impact of Taste Sensitivity on Lifestyle-related Diseases]. AB - Individual taste sensitivity affects one's eating habits, and could thus play a role in the development of lifestyle-related diseases, such as obesity, hypertension and dyslipidemia. However, only a handful of studies have been conducted to investigate these associations. Therefore, we performed taste sensitivity tests on approximately 250 patients with lifestyle-related diseases who were undergoing outpatient treatment at the Department of Internal Medicine, or received a health check-up in order to examine the associations of individual taste sensitivity with their eating habits and lifestyle-related diseases. Our findings showed that sensitivity to sweet or salt taste was significantly lower in patients with cardiovascular diseases, and sensitivity to umami taste was significantly lower in obese patients. These findings suggest that taste sensitivity disorders may be linked not only to eating habits and lifestyle related diseases, but also to the onset of cardiovascular diseases. Many of the drugs used in the treatment of lifestyle-related diseases and cardiovascular diseases, including antihypertensive agents, statins, fibrates, and allopurinol, are known to form zinc chelates and thereby possibly cause drug-induced taste disorders. Focusing on individual taste sensitivity to improve or maintain intake levels may become a new target for drug development in the areas of lifestyle related and cardiovascular diseases. PMID- 26028416 TI - [Bias and confounding: pharmacoepidemiological study using administrative database]. AB - The provision of health care frequently creates digitalized data such as hospital based electronic data, medication prescription records, and claims data collectively termed "administrative database research". The data source and analytical opportunities for study create risks that can lead to misinterpretation or bias the results. This review serves as an introduction to the concept of bias and confounding to help researchers conduct methodologically sound pharmacoepidemiologic research projects using administrative databases. Beyond general considerations for observational study, there are several unique issues related to database research that should be addressed. The risks of uninterpretable or biased results can be minimized by: providing a robust description of the data tables used; focusing on why and how they were created; measuring and reporting the accuracy of diagnostic and procedural codes used; and properly accounting for any time-dependent nature of variables. The hallmark of good research is rigorously careful analysis and interpretation. The promise for value of real world evidence using databases in medical decision making must be balanced against concerns related to observational inherited limitations for bias and confounding. Researchers should aim to avoid bias in the design of a study, adjust for confounding, and discuss the effects of residual bias on the results. PMID- 26028417 TI - [Plasma concentrations of anionic uremic toxins in hemodialysis patients and their effects on protein binding of pravastatin]. AB - Uremic toxins (UTs) accumulate in the body of hemodialysis patients. UTs often exert unfavorable effects on patients and cause significant interactions with clinically relevant drugs. In this study, we assayed plasma concentrations of three typical anionic UTs, indoxyl sulfate (IS), 3-indoleacetic acid (IA), and 3 carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), in 20 hemodialysis patients and 5 healthy volunteers. Moreover, the effects of these anionic UTs on the binding of pravastatin to human serum albumin (HSA) were also evaluated. CMPF concentrations in the plasma of patients were unchanged before and after dialysis (63.0 +/- 6.3 MUM and 65.1 +/- 6.7 MUM, respectively), and these values were about 5-fold greater compared with those in healthy volunteers. Although dialysis decreased the plasma IS concentration from 157.9 +/- 19.9 MUM to 103.8 +/- 13.3 MUM, the value after hemodialysis was still ca. 27-fold greater than that in healthy volunteers. IA concentrations before and after hemodialysis were almost identical to those in healthy volunteers. There were no significant differences in the plasma concentrations of the three anionic UTs between male and female patients. The magnitude of protein binding was in the order CMPF>IS>IA, indicating that hemodialysis clearance of these anionic UTs was dependent on their protein binding capacities. The ability of IS to reduce pravastatin binding to HSA was much greater than that of CMPF. The present results suggest that statins bind to site II on HSA, and that their binding is modulated by IS when elevated in hemodialysis patients. PMID- 26028418 TI - [Evaluation of Antibiotics for the Treatment of Bacteremia Due to Extended spectrum beta-Lactamase-producing Escherichia coli]. AB - Recently, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli has been more frequently isolated from blood specimens than in the past. In this study we investigated a panel of therapeutic agents used to treat 37 patients with ESBL-producing E. coli bacteremia. Antimicrobial agents administered as definitive therapy displayed higher efficacy rates than when empiric therapy was administered (efficacy rates, 95.7% vs. 62.5%). The success rate of carbapenem was 95.8% (23/24) in patients with ESBL-producing E. coli bacteremia. In addition, the success rate of cefmetazole against ESBL-producing E. coli sensitive to this drug was 87.5% (7/8). In conclusion, patients at high risk of infection due to ESBL-producing E. coli should be empirically treated with carbapenem antibiotics. In addition, cefmetazole may be a treatment option for patients with ESBL-producing E. coli bacteremia. PMID- 26028419 TI - [Effect of food thickener on disintegration and dissolution of magnesium oxide tablets]. AB - It has been reported that magnesium oxide tablets are excreted in a non disintegrated state in the stool of patients when the tablets are administered after being immersed in a food thickener. Therefore we examined whether immersion in a food thickener affects the pharmacological effect in patients taking magnesium oxide tablets, and whether immersion affects its disintegration and solubility. The mean dosage (1705 mg/d) was higher for patients who took tablets after immersion in a food thickener than for those who took non-immersed tablets (1380 mg/d). The disintegration time and dissolution rate of the immersed tablets were lower than those of non-immersed tablets in vitro. Furthermore, components that constitute the food thickener and differences in composition concentrations differentially affect the disintegration and solubility of magnesium oxide tablets. This suggests that commercially available food thickeners are likely to be associated with changes in the degradation of magnesium oxide tablets, and they therefore should be carefully used in certain clinical situations. PMID- 26028420 TI - Phase inversion of ionomer-stabilized emulsions to form high internal phase emulsions (HIPEs). AB - Herein, we report the phase inversion of ionomer-stabilized emulsions to form high internal phase emulsions (HIPEs) induced by salt concentration and pH changes. The ionomers are sulfonated polystyrenes (SPSs) with different sulfonation degrees. The emulsion types were determined by conductivity measurements, confocal microscopy and optical microscopy, and the formation of HIPE organogels was verified by the tube-inversion method and rheological measurements. SPSs with high sulfonation degrees (water-soluble) and low sulfonation degrees (water-insoluble) can stabilize oil-in-water emulsions; these emulsions were transformed into water-in-oil HIPEs by varying salt concentrations and/or changing the pH. SPS, with a sulfonation degree of 11.6%, is the most efficient, and as low as 0.2 (w/v)% of the organic phase is enough to stabilize the HIPEs. Phase inversion of the oil-in-water emulsions occurred to form water in-oil HIPEs by increasing the salt concentration in the aqueous phase. Two phase inversion points from oil-in-water emulsions to water-in-oil HIPEs were observed at pH 1 and 13. Moreover, synergetic effects between the salt concentration and pH changes occurred upon the inversion of the emulsion type. The organic phase can be a variety of organic solvents, including toluene, xylene, chloroform, dichloroethane, dichloromethane and anisole, as well as monomers such as styrene, butyl acrylate, methyl methacrylate and ethylene glycol dimethacrylate. Poly(HIPEs) were successfully prepared by the polymerization of monomers as the continuous phase in the ionomer-stabilized HIPEs. PMID- 26028421 TI - Myeloid-derived suppressor cells in immunity and autoimmunity. AB - Myeloid-derived suppressor cells (MDSCs) play a critical role in suppressing immune responses in patients with cancer or severe inflammation. Recent studies have focused on the strong relationship between MDSCs and autoimmune diseases, such as autoimmune hepatitis, inflammatory bowel disease and experimental autoimmune encephalomyelitis. Interestingly, MDSCs appear to serve multifaceted functions in autoimmunity, playing both protective and pathogenic roles. Therefore, although MDSCs may be a functional target for the therapy of autoimmune diseases, the disorders that accompany such treatments should be noted. In this manuscript, we summarize the functions and molecular regulation of MDSCs in immunity and autoimmune disease. PMID- 26028422 TI - Impact of Frozen Storage on the Anthocyanin and Polyphenol Contents of American Elderberry Fruit Juice. AB - The effects of frozen storage on the anthocyanin and polyphenol content of elderberry fruit juice are investigated. Juice from three genotypes of American elderberry (Adams II, Bob Gordon, and Wyldewood) was screened for total phenolic (TP) and total monomeric anthocyanin (TMA) contents with spectrophotometric methods. The individual anthocyanin content (IAC) of the juice was tested by coupling solid phase extraction with ultraperformance liquid chromatography tandem mass spectrometry. Juice samples were tested initially upon harvest and then again after 3, 6, and 9 months of frozen storage. Juice from the three different genotypes had significantly different TP, TMA, and IAC profiles initially (p < 0.05). The TP, TMA, and IAC contents of the juice from different genotypes were significantly affected (p < 0.05) by the frozen storage time, suggesting that both genotype and length of frozen storage time can affect the anthocyanin content of elderberry fruit juice. PMID- 26028423 TI - Na+-dependent and Na+-independent betaine transport across the apical membrane of rat renal epithelium. AB - The low renal excretion of betaine indicates that the kidney efficiently reabsorbs the betaine filtered by the glomeruli but the mechanisms involved in such a process have been scarcely investigated. We have detected concentrative and non-concentrative betaine transport activity in brush-border membrane vesicles (BBMV) from rat renal cortex and medulla. The concentrative system is the Sodium/Imino-acid Transporter 1 (SIT1) because it is Na+- and Cl--dependent, electrogenic and is inhibited by an anti-SIT1 antibody. Its apparent affinity constant for betaine, Kt, is 1.1+/-0.5 mM and its maximal transport velocity, Vmax, 0.5+/-0.1 nmol betaine/mg protein/s. Inhibitors of the Na+/Cl-/betaine uptake are L-proline (75%) and cold betaine, L-carnitine and choline (40-60%). Neither creatine, TEA, taurine, beta-alanine, GABA nor glycine significantly inhibited Na+/Cl-/betaine uptake. The non-concentrative betaine transport system is Na+- and H+-independent, electroneutral, with a Kt for betaine of 47+/-7 MUM and a Vmax of 7.8+/-1 pmol betaine/mg protein/s. Its transport activity is nearly abolished by betaine, followed by L-carnitine (70-80%) and proline (40-50%), but a difference from the Na+/Cl-/betaine transport is that it is inhibited by TEA (approx. 50%) and unaffected by choline. The underlying carrier functions as an antiporter linking betaine entry into the BBMV with the efflux of either L carnitine or betaine, an exchange unaffected by the anti-SIT1 antibody. As far as we know this is the first work reporting that betaine crosses the apical membrane of rat renal epithelium by SIT1 and by a Na+- and H+-independent transport system. PMID- 26028424 TI - Proton-dependent glutamine uptake by aphid bacteriocyte amino acid transporter ApGLNT1. AB - Aphids house large populations of the gammaproteobacterial symbiont Buchnera aphidicola in specialized bacteriocyte cells. The combined biosynthetic capability of the holobiont (Acyrthosiphon pisum and Buchnera) is sufficient for biosynthesis of all twenty protein coding amino acids, including amino acids that animals alone cannot synthesize; and that are present at low concentrations in A. pisum's plant phloem sap diet. Collaborative holobiont amino acid biosynthesis depends on glutamine import into bacteriocytes, which serves as a nitrogen-rich amino donor for biosynthesis of other amino acids. Recently, we characterized A. pisum glutamine transporter 1 (ApGLNT1), a member of the amino acid/auxin permease family, as the dominant bacteriocyte plasma membrane glutamine transporter. Here we show ApGLNT1 to be structurally and functionally related to mammalian proton-dependent amino acid transporters (PATs 1-4). Using functional expression in Xenopus laevis oocytes, combined with two-electrode voltage clamp electrophysiology we demonstrate that ApGLNT1 is electrogenic and that glutamine induces large inward currents. ApGLNT1 glutamine induced currents are dependent on external glutamine concentration, proton (H+) gradient across the membrane, and membrane potential. Based on these transport properties, ApGLNT1-mediated glutamine uptake into A. pisum bacteriocytes can be regulated by changes in either proton gradients across the plasma membrane or membrane potential. PMID- 26028425 TI - Finite element analysis of the stability of transverse acetabular fractures in standing and sitting positions by different fixation options. AB - BACKGROUND: Treatment of a transverse acetabular fracture type is possible from an anterior approach, a posterior approach or both. Different fixation methods have been described but whether one is superior to the other is still under debate. The aim of the current study was to test the different fixation alternatives of stabilization of transverse acetabular fractures under two basic physiological loading conditions: standing and sitting utilizing a finite element model. MATERIAL AND METHODS: A transtectal transverse fracture model was fixed in five different alternatives: an anterior column plate; a posterior column plate; an anterior column plate combined with a posterior column screw; a posterior column plate combined with an anterior column screw; and a posterior column plate and an anterior column plate. In these models, a load of 400N was applied at standing and sitting positions and the displacements were analyzed by using three dimensional finite element stress analysis method. RESULTS: In the model simulating standing human position, overall motion at the posterior column was minimum when two columns were plated (0.071mm). The second best fixation was posterior column plate with an anterior column screw (0.077mm). Overall motion at the anterior column was minimum by posterior column plate with an anterior column screw (0.0326mm). The plating of two columns was associated with motion of (0.0333mm). In the model that simulates sitting position, the motion at the posterior column was minimum when two columns were plated (0.0478mm), and (0.0517mm) when a posterior column plate with an anterior column screw was used. Overall motion in the anterior column was minimum when posterior column plate with an anterior column screw (0.0198mm) was used, whereas the motion was (0.0203mm) when plating of both columns was examined. CONCLUSION: Posterior column plating combined with an anterior column screw has quite comparable results to a both column plating in transverse fractures, suggesting that two column fixations might be unnecessary. This method is also very superior to anterior column plating combined with a posterior column screw in that type of fractures. PMID- 26028426 TI - Primary possum macrophage cultures support the growth of a nidovirus associated with wobbly possum disease. AB - The objective of the study was to establish a system for isolation of a recently described, thus far uncultured, marsupial nidovirus associated with a neurological disease of possums, termed wobbly possum disease (WPD). Primary cultures of possum macrophages were established from livers of adult Australian brushtail possums (Trichosurus vulpecula). High viral copy numbers (up to 6.9*10(8)/mL of cell lysate) were detected in infected cell culture lysates from up to the 5th passage of the virus, indicating that the putative WPD virus (WPDV) was replicating in cultured cells. A purified virus stock with a density of 1.09 g/mL was prepared using iodixanol density gradient ultracentrifugation. Virus like particles approximately 60 nm in diameter were observed using electron microscopy in negatively stained preparations of the purified virus. The one-step growth curve of WPDV in macrophage cultures showed the highest increase in intracellular viral RNA between 6 and 12h post-infection. Maximum levels of cell associated viral RNA were detected at 24h post-infection, followed by a decline. Levels of extracellular RNA increased starting at 9h post-infection, with maximum levels detected at 48 h post-infection. The establishment of the in vitro system to culture WPDV will facilitate further characterisation of this novel nidovirus. PMID- 26028427 TI - Array-in-well serodiagnostic assay utilizing upconverting phosphor label technology. AB - In this study, a multiplex serological array-in-well assay was constructed for simultaneous detection of serum IgG antibodies against parvovirus B19 and human adenovirus. The array was prepared in streptavidin-coated 96-well microtiter plates by spotting biotinylated parvovirus B19 virus-like-particles, adenovirus type 2 and 5 hexon antigens, negative control of human serum albumin and positive controls of human IgG and anti-human IgG antibodies on the bottom of each well in an array format with a printable area of 2 mm * 2 mm. The array-in-well assay was evaluated with serum samples (n=89) of different antibody status as determined by commercial enzyme immunoassay for parvovirus IgG, and by in-house enzyme immunoassay for adenovirus IgG. The bound serum anti-parvovirus IgG, anti adenovirus IgG, and total IgG antibodies were detected with anti-human IgG antibody coated photon upconverting nanoparticles and the assay was measured with an anti-Stokes photoluminescence imager. Detection of specific antibodies by the multiplex array-in-well assay was in good agreement (100% for parvovirus B19 and 96% for adenovirus) with the reference results. In conclusion, the array-in-well with upconverting phosphor reporter technology was able to detect antiviral antibodies in human sera, and represents an efficient serodiagnostic concept that is a promising new tool for multiplex serology. PMID- 26028428 TI - Development of a SYBR Green real-time PCR assay with melting curve analysis for simultaneous detection and differentiation of canine adenovirus type 1 and type 2. AB - Canine adenovirus type 1 (CAdV-1) and canine adenovirus type 2 (CAdV-2) cause infectious canine hepatitis (ICH) and infectious tracheobronchitis (ITB) in dogs, respectively. Cases of ICH have been documented in recent years and recent surveys have demonstrated a wide percentage of asymptomatic CAdV-1 infection in the canine population. Since both CAdV types are detectable in the same biological matrices, and viral coinfection with CAdV-1 and CAdV-2 are reported with high frequency, it is urgent to have available a rapid, highly sensitive and specific assay for the diagnosis of CAdV infection and distinction between CAdV-1 and CAdV-2. In order to detect canine adenovirus in biological samples and to rapidly distinguish the two viral types, a SYBR Green real-time PCR assay was optimized to discriminate CAdV-1 and CAdV-2 via a melting curve analysis. The developed assay showed high sensitivity and reproducibility and was highly efficient and specific in discriminating the two CAdV types. This reliable and rapid technique may represent a simple, useful and economic option for simultaneous CAdV types detection, which would be feasible and attractive for all diagnostic laboratories, both for clinical purposes and for epidemiological investigations. PMID- 26028429 TI - Reply: To PMID 25314329. PMID- 26028430 TI - Surface oxygen-vacancy induced photocatalytic activity of La(OH)3 nanorods prepared by a fast and scalable method. AB - Uniform one-dimensional defective La(OH)3 nanorods were synthesized by a facile, fast and scalable method. This simple method avoids treatment at high temperature, utility of surfactants or templates, and can be finished within a short time. The results indicate that oxygen-vacancies were formed in La(OH)3 nanorods, which could extend the photoresponse range. The XPS, PL, solid state ESR measurements and DFT calculations revealed the pivotal role of oxygen-vacancy in the formation of an impurity level in the band gap of La(OH)3. The as-prepared La(OH)3 nanorods exhibited efficient photocatalytic activity in the removal of NO at the ppb-level under ultraviolet illumination. The highly enhanced photocatalytic activity of La(OH)3 nanorods could be ascribed to the synergy of the lower impurity level below the conduction band and the high separation efficiency of photogenerated electron-hole pairs. DMPO-ESR spin trapping results imply that the hydroxyl radicals are the main reactive species that are responsible for NO photooxidation. On the basis of combined experimental and theoretical investigation, an oxygen vacancy-mediated photocatalysis mechanism of defective La(OH)3 nanorods was proposed. This work could not only provide a fast and environmentally friendly approach for the synthesis of nanostructured photocatalysts, but also new insights into the understanding of the role of vacancy in semiconductor photocatalysis. PMID- 26028431 TI - Prevalence and dynamics of antibodies against Toxoplasma gondii in kids born from naturally infected goats. AB - We investigated the presence of antibodies against Toxoplasma gondii in domesticated goats intended for human consumption in a rural suburb of Rajshahi, Bangladesh. Antibodies to T. gondii were found in 55.1% (80/145) of the goats tested in our sample. The seroprevalence among goats aged <1 year, 1-2 years, 2-3 years and >=3 years were 36.7%, 66.0%, 59.1% and 100%, respectively. Our results demonstrated that seroprevalence increased with age. Among the seropositive goats, a subsample of eight free-ranging female goats with access to male goats was placed under continuous observation. During the observation period, these seropositive female goats delivered 11 kids, all of which were found to be seronegative before suckling colostrum. This finding strongly suggested that trans-placental infection rarely occurs in female goats that have acquired an infection before pregnancy. Our results indicate that infection via ingestion of oocysts plays a more important role than endogenous trans-placental infection in maintaining the endemicity of T. gondii among goats in Bangladesh. PMID- 26028432 TI - Electrospun Carbon Nanofibers with in Situ Encapsulated Co3O4 Nanoparticles as Electrodes for High-Performance Supercapacitors. AB - A facile electrospinning method with subsequent heat treatments is employed to prepare carbon nanofibers (CNFs) containing uniformly dispersed Co3O4 nanoparticles as electrodes for supercapacitors. The Co3O4/CNF electrodes with ~68 wt % active particles deliver a remarkable capacitance of 586 F g(-1) at a current density of 1 A g(-1). When the current density is increased to 50 A g( 1), ~66% of the original capacitance is retained. The electrodes also present excellent cyclic stability of 74% capacity retention after 2000 cycles at 2 A g( 1). These superior electrochemical properties are attributed to the uniform dispersion of active particles in the CNF matrix, which functions as a conductive support. The onionlike graphitic layers formed around the Co3O4 nanoparticles not only improve the electrical conductivity of the electrode but also prevent the separation of the nanoparticles from the carbon matrix. PMID- 26028433 TI - Frontal top-down signals increase coupling of auditory low-frequency oscillations to continuous speech in human listeners. AB - Humans show a remarkable ability to understand continuous speech even under adverse listening conditions. This ability critically relies on dynamically updated predictions of incoming sensory information, but exactly how top-down predictions improve speech processing is still unclear. Brain oscillations are a likely mechanism for these top-down predictions [1, 2]. Quasi-rhythmic components in speech are known to entrain low-frequency oscillations in auditory areas [3, 4], and this entrainment increases with intelligibility [5]. We hypothesize that top-down signals from frontal brain areas causally modulate the phase of brain oscillations in auditory cortex. We use magnetoencephalography (MEG) to monitor brain oscillations in 22 participants during continuous speech perception. We characterize prominent spectral components of speech-brain coupling in auditory cortex and use causal connectivity analysis (transfer entropy) to identify the top-down signals driving this coupling more strongly during intelligible speech than during unintelligible speech. We report three main findings. First, frontal and motor cortices significantly modulate the phase of speech-coupled low frequency oscillations in auditory cortex, and this effect depends on intelligibility of speech. Second, top-down signals are significantly stronger for left auditory cortex than for right auditory cortex. Third, speech-auditory cortex coupling is enhanced as a function of stronger top-down signals. Together, our results suggest that low-frequency brain oscillations play a role in implementing predictive top-down control during continuous speech perception and that top-down control is largely directed at left auditory cortex. This suggests a close relationship between (left-lateralized) speech production areas and the implementation of top-down control in continuous speech perception. PMID- 26028434 TI - Flies remember the time of day. AB - The circadian clock enables organisms to anticipate daily environmental cycles and drives corresponding changes in behavior [1, 2]. Such endogenous oscillators also enable animals to display time-specific memory [1, 3-5]. For instance, mice and honeybees associate the location of a stimulus (like food or mate) with a certain time of day (time-place learning) [6, 7]. However, the mechanism underlying time-related learning and memory is not known. In the present study, we investigate time-specific odor learning. We use a genetically tractable animal, the fly Drosophila melanogaster. Starved flies are trained in the morning and afternoon to associate distinct odors with sucrose reward. The training is repeated the next day, and their time-dependent odor preference is tested on the third day. Our results indicate that Drosophila can express appetitive memory at the relevant time of day if the two conditioning events are separated by more than 4 hr. Flies can form time-odor associations in constant darkness (DD) as well as in a daily light-dark (LD) cycle, but not when kept under constant light (LL) conditions. Circadian clock mutants, period(01) (per(01)) and clock(AR) (clk(AR)), learned to associate sucrose reward with a certain odor but were unable to form time-odor associations. Our findings show that flies can utilize temporal information as an additional cue in appetitive learning. Time-odor learning in flies depends on a per- and clk-dependent endogenous mechanism that is independent of environmental light cues. PMID- 26028435 TI - Draper/CED-1 mediates an ancient damage response to control inflammatory blood cell migration in vivo. AB - Tissue damage leads to a robust and rapid inflammatory response whereby leukocytes are actively drawn toward the wound. Hydrogen peroxide (H2O2) has been shown to be an immediate damage signal essential for the recruitment of these inflammatory blood cells to wound sites in both Drosophila and vertebrates [1, 2]. Recent studies in zebrafish have shown that wound-induced H2O2 is detected by the redox-sensitive Src family kinase (SFK) Lyn within the responding blood cells [3]. Here, we show the same signaling occurs in Drosophila inflammatory cells in response to wound-induced H2O2 with mutants for the Lyn homolog Src42A displaying impaired inflammatory migration to wounds. We go on to show that activation of Src42A is necessary to trigger a signaling cascade within the inflammatory cells involving the ITAM domain-containing protein Draper-I (a member of the CED-1 family of apoptotic cell clearance receptors) and a downstream kinase, Shark, that is required for migration to wounds. The Src42A-Draper-Shark-mediated signaling axis is homologous to the well-established SFK-ITAM-Syk-signaling pathway used in vertebrate adaptive immune responses. Consequently, our results suggest that adaptive immunoreceptor-signaling pathways important in distinguishing self from non-self appear to have evolved from a more-ancient damage response. Furthermore, this changes the role of H2O2 from an inflammatory chemoattractant to an activator signal that primes immune cells to respond to damage cues via the activation of damage receptors such as Draper. PMID- 26028437 TI - RAD sequencing highlights polygenic discrimination of habitat ecotypes in the panmictic American eel. AB - The two primary ways that species respond to heterogeneous environments is through local adaptation and phenotypic plasticity. The American eel (Anguilla rostrata) presents a paradox; despite inhabiting drastically different environments [1], the species is panmictic [2, 3]. Spawning takes place only in the southern Sargasso Sea in the Atlantic Ocean [1]. Then, the planktonic larvae (leptocephali) disperse to rearing locations from Cuba to Greenland, and juveniles colonize either freshwater or brackish/saltwater habitats, where they spend 3-25 years before returning to the Sargasso Sea to spawn as a panmictic species. Depending on rearing habitat, individuals exhibit drastically different ecotypes [4-6]. In particular, individuals rearing in freshwater tend to grow slowly and mature older and are more likely to be female in comparison to individuals that rear in brackish/saltwater [4, 6]. The hypothesis that phenotypic plasticity alone can account for all of the differences was not supported by three independent controlled experiments [7-10]. Here, we present a genome-wide association study that demonstrates a polygenic basis that discriminates these habitat-specific ecotypes belonging to the same panmictic population. We found that 331 co-varying loci out of 42,424 initially considered were associated with the divergent ecotypes, allowing a reclassification of 89.6%. These 331 SNPs are associated with 101 genes that represent vascular and morphological development, calcium ion regulation, growth and transcription factors, and olfactory receptors. Our results are consistent with divergent natural selection of phenotypes and/or genotype-dependent habitat choice by individuals that results in these genetic differences between habitats, occurring every generation anew in this panmictic species. PMID- 26028436 TI - Arp2/3 complex and cofilin modulate binding of tropomyosin to branched actin networks. AB - Tropomyosins are coiled-coil proteins that bind actin filaments and regulate multiple cytoskeletal functions, including actin network dynamics near the leading edge of motile cells. Previous work demonstrated that tropomyosins inhibit actin nucleation by the Arp2/3 complex and prevent filament disassembly by cofilin. We find that the Arp2/3 complex and cofilin, in turn, regulate the binding of tropomyosin to actin filaments. Using fluorescence microscopy, we show that tropomyosin (non-muscle Drosophila Tm1A) polymerizes along actin filaments, starting from "nuclei" that appear preferentially on ADP-bound regions of the filament, near the pointed end. Tropomyosin fails to bind dendritic actin networks created in vitro by the Arp2/3 complex, in part because the Arp2/3 complex blocks pointed ends. Cofilin promotes phosphate dissociation and severs filaments, generating new pointed ends and rendering Arp2/3-generated networks competent to bind tropomyosin. Tropomyosin's attraction to pointed ends reflects a strong preference for conformations localized to that region of the filament and reveals a basic molecular mechanism by which lamellipodial actin networks are insulated from the effects of tropomyosin. PMID- 26028438 TI - Scolicidal activity of biosynthesized silver nanoparticles against Echinococcus granulosus protoscolices. AB - Cystic hydatid disease (CHD), a helminth infection with various clinical complications caused by the larval stage of the dog tapeworm Echinococcus granulosus is considered as a public health problem in different regions of the world. To date, scolicidal agents have been broadly applied for inactivation of the fertile cysts and these scolicidal agents have several side effects on patients. Therefore, the objective of this study was to evaluate the scolicidal efficacies of synthesized silver nanoparticles (AgNPs) derived from the aqueous aerial extract of Penicillium aculeatum against protoscolices of CHD in-vitro. Protoscolices were aseptically aspirated from infected livers of sheep with CHD. Various concentrations (0.025, 0.05, 0.1 and 0.15 mg/mL) of green synthesis of Ag NPs and different exposure times (10, 30, 60 and 120 min) were used against protoscolices of CHD. Viability of protoscolices was confirmed by 0.1% eosin staining. The findings showed that the Ag-NPs at all concentrations have high scolicidal effects. The concentrations 0.1 and 0.15 mg/mL after 120 min of exposure times showed 83% and 90% mortality rate, respectively. The least scolicidal activity of biosynthesized Ag-NPs was 40% (0.025 mg/mL and 10 min). The current investigation indicated that applying biogenic Ag-NPs may be considered as a potential scolicidal agent for CHD surgery due to being economical, safer and non-toxic compared to the used chemical materials. However, further studies are required to evaluate the efficacy of Ag-NPs in vivo. PMID- 26028439 TI - Hexagonal-structured epsilon-NbN: ultra-incompressibility, high shear rigidity, and a possible hard superconducting material. AB - Exploring the structural stability and elasticity of hexagonal epsilon-NbN helps discover correlations among its physical properties for scientific and technological applications. Here, for the first time, we measured the ultra incompressibility and high shear rigidity of polycrystalline hexagonal epsilon NbN using ultrasonic interferometry and in situ X-ray diffraction, complemented with first-principles density-functional theory calculations up to 30 GPa in pressure. Using a finite strain equation of state approach, the elastic bulk and shear moduli, as well as their pressure dependences are derived from the measured velocities and densities, yielding BS0 = 373.3(15) GPa, G0 = 200.5(8) GPa, ?BS/?P = 3.81(3) and ?G/?P = 1.67(1). The hexagonal epsilon-NbN possesses a very high bulk modulus, rivaling that of superhard material cBN (B0 = 381.1 GPa). The high shear rigidity is comparable to that for superhard gamma-B (G0 = 227.2 GPa). We found that the crystal structure of transition-metal nitrides and the outmost electrons of the corresponding metals may dominate their pressure dependences in bulk and shear moduli. In addition, the elastic moduli, Vickers hardness, Debye temperature, melting temperature and a possible superconductivity of hexagonal epsilon-NbN all increase with pressures, suggesting its exceptional suitability for applications under extreme conditions. PMID- 26028440 TI - Delayed biodiversity change: no time to waste. AB - Delayed biodiversity responses to environmental forcing mean that rates of contemporary biodiversity changes are underestimated, yet these delays are rarely addressed in conservation policies. Here, we identify mechanisms that lead to such time lags, discuss shifting human perceptions, and propose how these phenomena should be addressed in biodiversity management and science. PMID- 26028441 TI - Synergy between baicalein and penicillins against penicillinase-producing Staphylococcus aureus. AB - The combination of baicalein (the active constituent of Scutellaria baicalensis) with penicillin G/amoxicillin showed potent synergy against 20 clinical penicillinase-producing Staphylococcus aureus strains including 10 isolates that were additionally methicillin-resistant (MRSA). The fractional inhibitory concentration (FIC) indices of penicillins+baiclein ranged from 0.14 to 0.38. Baicalein protected penicillins (penicillin G and amoxicillin) from penicillinase and increased the susceptibility of penicillinase-supplemented S. aureus ATCC 29213 in a dose-dependent manner. The inhibition of penicillinase activity by baicalein should be responsible for the synergism and protective effect. These findings offer us good evidence that the penicillins combined with baicalein showed potent synergistic activity against penicillinase-producing S. aureus and penicillinase-producing MRSA in vitro and might provide promising implications for clinical treatment of these bacterial infections. PMID- 26028442 TI - Researchers identify a genetic signature for sepsis. PMID- 26028443 TI - Efficient Production of Single-Stranded Phage DNA as Scaffolds for DNA Origami. AB - Scaffolded DNA origami enables the fabrication of a variety of complex nanostructures that promise utility in diverse fields of application, ranging from biosensing over advanced therapeutics to metamaterials. The broad applicability of DNA origami as a material beyond the level of proof-of-concept studies critically depends, among other factors, on the availability of large amounts of pure single-stranded scaffold DNA. Here, we present a method for the efficient production of M13 bacteriophage-derived genomic DNA using high-cell density fermentation of Escherichia coli in stirred-tank bioreactors. We achieve phage titers of up to 1.6 * 10(14) plaque-forming units per mL. Downstream processing yields up to 410 mg of high-quality single-stranded DNA per one liter reaction volume, thus upgrading DNA origami-based nanotechnology from the milligram to the gram scale. PMID- 26028444 TI - Febrile seizures in children with familial Mediterranean fever: Coincidence or association? AB - BACKGROUND: Familial Mediterranean fever (FMF) is an inherited disease characterized by recurrent bouts of fever and polyserositis and caused by MEditerranean FeVer gene (MEFV) mutations. Given the febrile characteristics of the disease one would expect higher frequency of febrile seizure in this group of pediatric patients. OBJECTIVES: To evaluate the frequency of febrile seizure and related factors in patients with FMF. METHODS: The children with the diagnosis of FMF were enrolled in the study. Information including clinical features, type of mutation and the history of febrile seizure were all noted. RESULTS: A total of 97 patients, 43 (44.3%) girls with a median age of 7.93 +/- 4.05 years (2-16) and a median follow-up period of 20.65 +/- 24.33 months (6-135) were included in the study. The frequency of febrile seizure in children with FMF was found as 13.4%, which is higher than the general population [p = 0.04, OR: 2.9 (95% CI: 1.0 8.5)]. The allele frequency of exon 2 mutations in MEFV genes was higher in the patients with febrile seizure (p = 0.03). Frequency of FMF related clinical findings (fever, abdominal pain, arthralgia/myalgia, arthritis, chest pain and erysipelas-like erythema) was similar between the two groups. However, frequency of headache was higher in the patients with febrile seizure (p = 0.014). CONCLUSION: The frequency of febrile seizure in children with FMF was found to be higher than the general population. Although this finding may be related to high fever during FMF attacks in individuals with genetic propensity of febrile seizure, it may also be a neurologic complication of FMF. PMID- 26028445 TI - [Song of songs about implementation of proven health care interventions]. PMID- 26028446 TI - Implementation science in healthcare: Introduction and perspective. AB - Implementation science is the scientific study of the methods to promote the uptake of research findings into routine healthcare in clinical, organisational, or policy contexts. The presence of gaps between knowledge and practice is well documented and a range of strategies is available to overcome these gaps. To optimize their impact, it is recommended that implementation strategies are tailored to the target population, setting and goals for improvement. Themes for future research in the field are: implementation of personalized medicine, the economics of implementation, knowledge implementation in various health professions, patient involvement in implementation, and a better understanding of the determinants of implementation. Addressing these challenges requires dedicated training programs, research funding, and networks for effective collaboration with stakeholders in healthcare. PMID- 26028447 TI - Context and implementation: A concept analysis towards conceptual maturity. AB - Context and implementation of health interventions have received increasing attention over the past decade, in particular with respect to their influence on the effectiveness and reach of complex interventions. The underlying concepts are both considered partially mature, limiting their operationalization in research and practice. We conducted systematic literature searches and pragmatic utility (PU) concept analyses to provide a state-of-the-art assessment of the concepts of "context" and "implementation" in the health sciences to create a common understanding for their use within systematic reviews and HTA. We performed two separate searches, one for context (EMBASE, MEDLINE) and the other for implementation (Google Scholar) to identify relevant models, theories and frameworks. 17 publications on context and 35 articles on implementation met our inclusion criteria. PU concept analysis comprises three guiding principles: selection of the literature, organization and structuring of the literature, and asking analytic questions of the literature. Both concepts were analyzed according to four features of conceptual maturity, i.e., consensual definitions, clear characteristics, fully described preconditions and outcomes, and delineated boundaries. Context and implementation are highly intertwined, with both concepts influencing and interacting with each other. Context is defined as a set of characteristics and circumstances that surround the implementation effort. Implementation is conceptualized as a planned and deliberately initiated effort with the intention to put an intervention into practice. The concept of implementation presents largely consensual definitions and relatively well defined boundaries, while distinguishing features, preconditions and outcomes are not yet fully articulated. In contrast, definitions of context vary widely, and boundaries with neighbouring concepts, such as setting and environment, are blurred; characteristics, preconditions and outcomes are ill-defined. Therefore, the maturity of both concepts should be further improved to facilitate operationalization in systematic reviews and HTAs. PMID- 26028448 TI - [Fitness to drive in dementia - theoretical framing and design of a recommendation for German general practice]. AB - BACKGROUND: General practitioners (GPs) are among the first to be contacted by persons with dementia and their relatives. Fitness to drive in dementia is a subject of uncertainty and conflict for GPs. OBJECTIVE: Development of recommendations for German general practice on managing fitness to drive in dementia. METHODS: Specification of problem areas by using relevant parts of a metasynthesis of international qualitative dementia research with GPs; literature review on evidence regarding the pre-defined problem areas; deduction of a preliminary design for a recommendation in a multi-professional team. RESULTS: The difficulties include the assessment of fitness to drive in the office setting, concerns about damaging the patient-physician relationship by raising the issue of driving fitness, and uncertainties about the GP's own legal role. A diagnosis of dementia does not per se preclude driving. The majority of elderly people would accept discussing fitness to drive with their GP. In Germany, GPs are not obliged to assess fitness to drive, or to report unsafe drivers to the Licensing Agency, but under certain conditions they do have the right to report. Addressing the issue of driving and dementia early with the patient seems to be a prerequisite for a resource-oriented and patient-centred management. DISCUSSION: The distinction between medical, ethical-communicative, and legal aspects enabled us to break down this complex problem and thus provide the informative basis to draft tailored recommendations. In an ongoing project, this framework will be further developed and informed by the expertise of patients, family caregivers, and professionals from various fields. PMID- 26028450 TI - [How patient safety programmes can be successfully implemented - an example from Switzerland]. AB - Internationally, the implementation of patient safety programmes poses a major challenge. In the first part, we will demonstrate that various measures have been found to be effective in the literature but that they often do not reach the patient because their implementation proves difficult. Difficulties arise from both the complexity of the interventions themselves and from different organisational settings in individual hospitals. The second part specifically describes the implementation of patient safety improvement programmes in Switzerland and discusses measures intended to bridge the gap between the theory and practice of implementation in Switzerland. Then, the national pilot programme to improve patient safety in surgery is presented, which was launched by the federal Swiss government and has been implemented by the patient safety foundation. Procedures, challenges and highlights in implementing the programme in Switzerland on a national level are outlined. Finally, first (preliminary) results are presented and critically discussed. PMID- 26028449 TI - [Guideline implementation study on asthma: Results of a pragmatic implementation approach]. AB - OBJECTIVE: Knowledge transfer from theory to practice in healthcare systems poses a challenge worldwide. Typical examples include national disease management guidelines. The present study contributes towards improving implementation strategies for an asthma guideline. METHODS: A guideline implementation strategy was examined in a four-armed, non-randomised, controlled intervention study with an additional control group. The study participants were general practitioners and paediatricians recruited from primary care quality circles. All study participants attended an interactive seminar on the evidence-based recommendations for patients with asthma. In addition, the participants were asked to choose among the following options: no further intervention, additional e-learning, training of their practice nurses, or e-learning and training of their practice nurses. The success of the intervention was measured by questionnaire (and the success rate expressed as a percentage). RESULTS: About one third of all participants (n=313) opted for the combination of an interactive seminar and a training of practice nurses; two third preferred the classic way of continuing medical education with an interactive seminar without a further intervention. Just 10 % of the physicians participated in e-learning. Independently of their choice for continuing medical education, all participants demonstrated an increase in knowledge about asthma and an improvement in the management of asthma. The physicians exhibited an average increase in both categories of about 10 % of the percentage values, compared to an increase of about 28 % among the practice nurses without continuing medical education. CONCLUSIONS: The physicians' free choice of the educative modules might be an integral part of successful implementation strategies. However, this will require a change of focus from general continuing medical education packages to a more individualised culture of continuing professional development in Germany. PMID- 26028451 TI - The Indiana University Center for Healthcare Innovation and Implementation Science: Bridging healthcare research and delivery to build a learning healthcare system. AB - In the United States, it is estimated that 75,000 deaths every year could be averted if the healthcare system implemented high quality care more effectively and efficiently. Patient harm in the hospital occurs as a consequence of inadequate procedures, medications and other therapies, nosocomial infections, diagnostic evaluations and patient falls. Implementation science, a new emerging field in healthcare, is the development and study of methods and tools aimed at enhancing the implementation of new discoveries and evidence into daily healthcare delivery. The Indiana University Center for Healthcare Innovation and Implementation Science (IU-CHIIS) was launched in September 2013 with the mission to use implementation science and innovation to produce great-quality, patient centered and cost-efficient healthcare delivery solutions for the United States of America. Within the first 24 months of its initiation, the IU-CHIIS successfully scaled up an evidence-based collaborative care model for people with dementia and/or depression, successfully expanded the Accountable Care Unit model positively impacting the efficiency and quality of care, created the first Certificate in Innovation and Implementation Science in the US and secured funding from National Institutes of Health to investigate innovations in dementia care. This article summarizes the establishment of the IU-CHIIS, its impact and outcomes and the lessons learned during the journey. PMID- 26028452 TI - [Health information on the Internet: Who is searching for what, when and how?]. AB - INTRODUCTION: The Institute for Quality and Efficiency in Health Care (IQWiG, Germany) has a statutory mandate to provide patients and their family members as well as the wider public with evidence-based health information (www.informedhealthonline.org). Since 2006 IQWiG has maintained the publicly available website gesundheitsinformation.de. Currently, about 80 million people live in Germany, and the majority of them have internet access. The goal of this project was to evaluate published studies examining health information seeking behaviour (who, when and how) on the internet. METHODS: A systematic search was conducted in several databases (PubMed, MEDLINE [Ovid)], PsycInfo [Ovid] und CINAHL [Ebsco]) for studies on internet searches for health information. No study type restrictions were imposed. Data were extracted from the relevant studies, and then discussed in the project group and summarised qualitatively. RESULTS: Of the 1,150 abstracts identified, 169 publications were analysed in full. 74 studies were included, most of which were surveys (n=59). The data were extracted from these studies and then summarised qualitatively to obtain an overview of the current state of research in this field. The results suggest that the group most often searching for health-related information on the internet - either on their own behalf or on behalf of others - consists of middle-aged women with a higher level of education and income. The most common reason for initiating a search for health information is a visit to the doctor, and the most common starting point is a search engine. Page layout and user-friendliness are the main criteria for assessing the credibility of websites and the information they provide. Users are more likely to trust information that is consistent with their own experiences and opinions. DISCUSSION: There is a growing trend of using the internet as a source for health information. It seems that trust in the credibility of a given website or information mostly depends on factors that are hardly related to the quality of content. This may pose a particular challenge for the creation and dissemination of evidence-based health information. Further research is required to examine the needs of the individual groups using internet-based health information. PMID- 26028453 TI - [Short information leaflets for patients - a service offered to physicians: Early implementation experiences]. AB - Since 2010, the German Agency for Quality in Medicine has developed so-called short information leaflets for patients that are specifically designed for use in doctor-patient encounters. Physicians, patient representatives and communication specialists were involved in the development of this format. Their implementation aims at enhancing awareness and dissemination of these leaflets amongst the members of the self-governing bodies and other multipliers (like medical specialty societies, patient organisations, other bodies and institutions of the healthcare system). This paper describes the first implementation experiences on the basis of internally collected data on the involvement of multipliers, availability and assessment of their relevance. A first analysis shows that the short information leaflets are broadly available amongst the self-governing bodies and that they are considered to be of high relevance. Due to the direct involvement of the members of specialty societies and patient organisations and other experts, short information leaflets are also gaining acceptance outside the self-governing system. This is emphasised by the rising number of requests to reprint or cite or use the leaflets. Consistency with evidence-based treatment recommendations promotes acceptance of these leaflets among physicians. PMID- 26028454 TI - [Guideline for the Development of Evidence-based Patient Information: insights into the methods and implementation of evidence-based health information]. AB - The "Guideline for the Development of Evidence-based Patient Information" project is a novelty. The aim of this project is to enhance the quality of health information. The development and implementation process is guided by national and international standards. Involvement of health information developers plays an essential role. This article provides an insight into the guideline's underlying methodology, using graphics as an example. In addition, the results of a qualitative study exploring the competencies of health information developers are presented. These results will guide the implementation of the guideline. We conducted systematic literature searches (until June 2014), critical appraisal and descriptive analyses applying GRADE for two selected guideline questions. Out of 3,287 hits 11 RCTs were included in the analysis. The evidence has been rated to be of low to moderate quality. Additional graphics may have a positive effect on cognitive outcomes. However, the relevance of the results is questionable. For graphics, we found some indication that especially pictograms but also bar graphs have a positive effect on cognitive outcomes and meet patients' preferences. In order to prepare for the implementation of the guideline, we conducted a qualitative study to explore the competencies of health information developers using expert interviews. Four telephone interviews were conducted, audio recorded, transcribed and analysed according to Grounded Theory. Six categories were identified: literature search, development of health information, participation of target groups, continuing education and further training of health information developers, cooperation with different institutions, essential competencies. Levels of competencies regarding the methods of evidence-based medicine and evidence-based health information vary considerably and indicate a need for training. These results have informed the development of a training programme that will support the implementation. PMID- 26028455 TI - [A methodological approach to assessing the quality of medical health information on its way from science to the mass media]. AB - A current research project deals with the question of how the quality of medical health information changes on its way from the academic journal via press releases to the news media. In an exploratory study a sample of 30 news items has been selected stage-by-stage from an adjusted total sample of 1,695 journalistic news items on medical research in 2013. Using a multidimensional set of criteria the news items as well as the corresponding academic articles, abstracts and press releases are examined by science journalists and medical experts. Together with a content analysis of the expert assessments, it will be verified to what extent established quality standards for medical journalism can be applied to medical health communication and public relations or even to studies and abstracts as well. PMID- 26028456 TI - [Trans-sectoral care for patients with colorectal cancer: Design of a prospective randomized controlled multi-center trial (FKZ 01GY1143)]. AB - BACKGROUND: Health-related quality of life (HrQoL) is an increasingly focused aim in the care for patients with colorectal cancer that are treated with curative intent. Achieving this aim partly depends on the quality of the transsectoral management of these patients throughout the entire treatment course. However, recent population-based surveys have shown that HrQoL in patients with colorectal cancer is significantly impaired over a long time following initial diagnosis. This also applies to patients for whom adjuncant chemotherapy is not indicated according to the German medical S3 guideline. In addition, the patients' need for medical and psychosocial support has repeatedly been reported to persist at a significantly increased level - despite the extensive establishment of certified cancer centres which has apparently failed to solve this problem sufficiently. AIM: The SCAN intervention aims to increase the percentage of patients reaching an enhancement of their HrQoL by at least 12 points (range: 0-100 pts.) within eight weeks after hospital discharge by 15 percent compared to standard care. DESIGN AND METHODS: The SCAN intervention is carried out as a randomised controlled multicentre trial in seven large- and middle-sized hospitals all over Saxony-Anhalt. 370 patients have been enrolled, 185 of whom are offered additional nurse-led outpatient counselling. INTERVENTION: Patients in the intervention group are offered transitional guidance and support consisting of routine symptom assessment and patient counselling regarding self-management, informed therapy-related decision-making and psychosocial support. ENDPOINTS: The primary endpoint of the study is the patients' global health-related quality of life (HrQoL), assessed by the EORTC Quality of Life Questionnaire QLQ C-30 V3.0, item 30. Disease-free survival within eight months, the utilisation of indicated adjuvant chemotherapies as well as therapy-related side effects, e. g., anxiety and depression and the patients' symptom burden are monitored as secondary endpoints. EXPECTED RESULTS: We assume that the SCAN intervention will be effective in increasing the percentage of patients reaching a clinically relevant enhancement of their HrQoL within eight weeks after hospital discharge by 15 percent compared to standard care. PMID- 26028457 TI - Five novel SUCLG1 mutations in three Chinese patients with succinate-CoA ligase deficiency noticed by mild methylmalonic aciduria. AB - OBJECTIVE: Methylmalonic aciduria is the most common organic aciduria in mainland China. Succinate-CoA ligase deficiency causes encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Patients usually present with severe encephalomyopathy, infantile lactic acidosis, which can be fatal, and mild methylmalonic aciduria. PATIENTS AND METHODS: Three Chinese patients (two boys and one girl) were hospitalized because of severe encephalomyopathy between 7 and 9 months. They presented with severe psychomotor retardation, hypotonia, dystonia, athetoid movements, seizures, feeding problems and failure to thrive. Mild elevated urine methylmalonic acid and blood propionylcarnitine indicated methylmalonic aciduria. Gene capture and high throughput genomic sequencing was carried out. RESULTS: Five novel mutations in SUCLG1 were identified in these patients: c.550G>A (p.G184S) in exon 5, c.751C>T (p.G251S) in exon 7, c.809A>C (p.L270W) in exon 7, c.961C>G (p.A321P) in exon 8 and c.826-2A>G (Splicing) in exon 9. Significant depletion of mtDNA was not observed in the peripheral leukocytes of the three patients in spite of mild decreasing of mitochondrial respiratory chain complex I in two patients and complex V in one patient. After treatment with cobalamin, calcium folinate, L carnitine, vitamin B1, C, and coenzyme Q10, and nutrition intervention, the patients improved. CONCLUSIONS: Succinate-CoA ligase deficiency due to SUCLG1 mutations is a rare cause of methylmalonic aciduria. Biochemical and gene studies are keys for the differential diagnoses. Three Chinese patients with mild methylmalonic aciduria were genetically diagnosed using high-throughput genomic sequencing. Five novel pathogenic mutations in SUCLG1 were identified. PMID- 26028458 TI - ADHD-like behavior in a patient with hypothalamic hamartoma. AB - We report a male patient with hypothalamic hamartoma (HH) who manifested central precocious puberty (CPP) at 4 years of age. Gonadotropin-releasing hormone (GnRH) analogue treatment was started at 6 years of age and his pubertal signs were suppressed. At 9 years of age, the patient was emotionally unstable, aggressive, and antisocial. He had severe attention deficit hyperactivity disorder (ADHD) like behavior and conduct disorder. No seizure activity was observed. GnRH analogue treatment was discontinued for 8 months from 9 years and 4 months of age due to his mother's illness. During this period sexual urges were observed. Treatment with daily methylphenidate markedly improved his behavioral problems. However, his sexual urges were not suppressed until 3 months after the GnRH analogue treatment was restarted. The present case is unique because the patient's behavioral problems were observed despite the parahypothalamic type of HH and absence of seizures. This case is also rare because behavioral problems were observed without seizures, and no ADHD cases with hamartoma have been reported previously. Recently, clinical studies have described an association between psychiatric morbidity, including ADHD, and hyperandrogenism disorders. Our patient's ADHD-like symptoms might be due to hyperandrogenism. In such cases, GnRH analogue with methylphenidate could be effective for improving ADHD-like symptoms. PMID- 26028459 TI - Microsecond Molecular Simulations Reveal a Transient Proton Pathway in the Calcium Pump. AB - The calcium pump sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) counter-transports Ca(2+) and H(+) at the expense of ATP hydrolysis. SERCA uses separate proton and metal ion pathways during active transport to neutralize the highly charged transport site, thus preserving SERCA's structural stability during active Ca(2+) transport. Although separate metal ion and proton pathways have been identified during slow (millisecond) structural transitions of SERCA, the existence of simultaneous metal and proton pathways during fast (microsecond) structural transitions remains unknown. We have analyzed microsecond-long trajectories of E1.H(+)771, a protonated intermediate of the pump populated during SERCA regulation. We found a transiently established hydrophobic pore in the luminal side of the transmembrane helices 6, 8, and 9. This narrow (0.5-0.6 nm) pore connects the transport sites to the sarcoplasmic reticulum lumen through a chain of water molecules. Protein pKa calculations of the transport site residues and structural analysis of the water molecules showed that this pore is suitable for proton transport. This transient proton pathway ensures neutralization of the transport sites during the rapid structural transitions associated with regulation of the pump. We conclude that this transient proton pathway plays a central role in optimizing active Ca(2+) transport by SERCA. Our discovery provides insight into ion-exchange mechanisms through transient hydrophobic pores in P-type ATPases. PMID- 26028460 TI - Leriche syndrome in a patient with situs inversus totalis. AB - Situs inversus is a rare congenital defect defined by a mirror image anatomic variation of the thoracic and abdominal organs. In this situation, abdominal aortic surgery may become particularly challenging. This is the case of a 51-year old man, who presented with an incapacitating lower limb claudication. On his workup, a complete occlusion of the infrarenal aorta requiring surgical revascularization was found. Additionally, a situs inversus totalis was identified along with a single horseshoe kidney. The patient underwent uneventfully a surgical aortobifemoral interposition. The sole modification to the standard procedure regarded the graft limbs tunneling, which was performed in a prerenal pathway in the retroperitoneal space, thus avoiding iatrogenic injury to the anteriorly positioned iliac veins. Although challenging, conventional aortic surgery can be safely accomplished in patients with situs inversus totalis. PMID- 26028461 TI - Nonoperative management of pediatric aortic injury with seat belt syndrome. AB - "Seat belt syndrome" was first described by Garret and Braunstein in 1962. The syndrome involves skin and abdominal wall ecchymosis (seat belt sign) intra abdominal solid organ and visceral injuries, as well as Chance fractures (compression and/or wedging deformity of the anterior portion of the vertebral body with disruption or fracture of the posterior elements, generally at L1-L3). We present a case of a 12-year-old male involved in a high-speed motor vehicle collision wearing only a lap belt resulting in seat belt syndrome, with disruption of the abdominal wall, mesenteric avulsion with multiple intestinal perforations, abdominal aortic dissection, and an L2 Chance fracture with cord transection. Intraoperative decision making is outlined with this scenario of complex injuries, and the literature of seat belt syndrome associated with blunt aortic injuries and its management is reviewed. PMID- 26028462 TI - Open surgery with frozen elephant trunk for the treatment of proximal stent graft induced new entry in type B aortic dissection: a case report. AB - Stent graft-induced new entry (SINE) is an infrequent complication, but high mortality rates have been observed after thoracic endovascular aortic repair. New entry after a stent-graft implantation of 50 mm is rare. To our knowledge, this article is the first-reported case of the surgical management of SINE after a large stent-graft implantation. PMID- 26028463 TI - Free tissue transfer after targeted endovascular reperfusion for complex lower extremity reconstruction: setting the stage for success in the presence of mutlivessel disease. AB - Recent advances in both microsurgical and endovascular techniques have redefined our approach to complex lower extremity reconstruction in high-risk patients with multivessel disease. When used as an adjunct to free tissue transfer, targeted endovascular therapy has been suggested to optimize recipient-site hemodynamics and promote flap survival in regions of compromised distal blood flow. With a paucity of published outcomes to support this approach, however, the perceived benefits derived from adjunctive endovascular therapy remain largely anecdotal. In this report, we present the outcomes and complications for 3 patients in whom preoperative endovascular therapy was used to improve both direct and collateral distal perfusion and recipient-vessel caliber. Flap survival in this series was 100%, and all patients remained ambulatory at a mean final follow-up of 24.7 months. Minor flap necrosis, necessitating debridement and skin grafting, was seen in one patient, who ultimately required a contralateral below-knee amputation secondary to nonsalvageable arterial disease. All patients were satisfied with respect to pain, function, and cosmetic appearance. On the basis of our experience and previously reported cases, we advocate a role for prereconstructive endovascular therapy as part of a multidisciplinary approach to functional limb salvage in patients with advanced arterial disease. PMID- 26028464 TI - Exostoses and vascular complications in the lower limbs: two case reports and review of the literature. AB - Exostosis is a very common bone tumor. Complications occur in 4% of the cases (nerve compression, exostosis degeneration, orthopedic complication); however, vascular complications are rare. This is the report of 2 cases of vascular complications that occurred in 2 patients-one with a solitary form and the other with hereditary multiple exostoses. A review of the literature found 57 cases of lower limb vascular complication, secondary to an exostosis. The most common vascular complication was the popliteal aneurysm. Femoral exostosis topography was found in 89% of the cases. A triggering trauma was found in 36% of the cases and the most common form was the solitary exostosis (58%). The treatment of these complications is surgical, and it treats the vascular lesion and the bone tumor at the same time. Surgical treatment of exostosis vascular complications is recommended as an urgent procedure to prevent the occurrence of irreversible damages. PMID- 26028465 TI - Drug-eluting balloons to treat iliac in-stent restenosis. AB - BACKGROUND: To report our experience in the use of drug-eluting balloons (DEBs) for the treatment of symptomatic iliac in-stent restenosis (ISR). CASE REPORTS: Six patients underwent treatment using DEBs for iliac ISRs in our centers between September 2011 and May 2014. The patients were predominantly women (4 of 6, 66.7%) with a mean age of 67.2 years (range, 46-75 years). Technical success was achieved in all cases. During the follow-up (mean duration, 15.5 months; range, 3 30 months), healing of the lesions/relief of symptoms was obtained in 5 of 6 cases (83.3%). Estimated 2-year rates of overall patency and limb salvage were 100%. CONCLUSIONS: The use of DEBs in the treatment of iliac ISR is safe and effective. The early and 2-year outcomes are promising. However, further experience with larger patient groups is needed. PMID- 26028466 TI - The relationship between telomere length and beekeeping among Malaysians. AB - The belief that beekeepers live longer than anyone else is present since ages. However, no research has been done to explore the longevity of life in beekeepers. Here, we investigated the telomere length in 30 male beekeepers and 30 male non-beekeepers and associated them with the longevity of life using Southern analysis of terminal restriction fragments (TRFs) generated by Hinf I/Rsa I digestion of human genomic DNA using TeloTAGGG Telomere Length Assay. Interestingly, we found that the telomere length of male beekeepers was significantly longer than those of male non-beekeepers with a p value of less than 0.05, suggesting that beekeepers may have longer life compared to non beekeepers. We further found that the consumption of bee products for a long period and frequent consumption of bee products per day are associated with telomere length. An increase of year in consuming bee products is associated with a mean increase in telomere length of 0.258 kbp. In addition, an increase in frequency of eating bee products per day was also associated with a mean increase of 2.66 kbp in telomere length. These results suggested that bee products might play some roles in telomere length maintenance. PMID- 26028469 TI - The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's disease. AB - Activation of peroxisome proliferator-activated receptors (PPARs), namely PPARgamma and PPARdelta, has been shown to provide neuroprotection in a number of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease (PD). The observed neuroprotective effects in experimental models of PD have been linked to anti-oxidant and anti-inflammatory actions. This study aimed to analyze the full influence of these receptors in neuroprotection by generating a nerve cell-specific conditional knock-out of these receptors and subjecting these genetically modified mice to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to model dopaminergic degeneration. Mice null for both receptors show the lowest levels of tyrosine hydroxylase (TH)-positive cell bodies following MPTP administration. Presence of one or both these receptors show a trend toward protection against this degeneration, as higher dopaminergic cell immunoreactivity and striatal monoamine levels are evident. These data supplement recent studies that have elected to use agonists of the receptors to regulate immune responses. The results place further importance on the activation of PPARs and the neuroprotective roles these have in inflammatory processes linked to neurodegenerative processes. PMID- 26028470 TI - Etomidate uniquely modulates the desensitization of recombinant alpha1beta3delta GABA(A) receptors. AB - Central GABA(A) receptors mediate GABAergic phasic and tonic inhibition. While synaptic alphabetagamma GABA(A) receptors primarily mediate phasic inhibition, extrasynaptic alphabetadelta receptors play an important role in mediating tonic inhibition. Etomidate is a general anesthetic that produces its effects by enhancing GABA(A) receptor activity. We previously showed that etomidate modulates the gating of oocyte-expressed alphabetagamma and alphabetadelta receptors with similar overall allosteric impact, but different pharmacological patterns. In alphabetagamma receptors, etomidate enhances apparent GABA sensitivity (reduces GABA EC50), modestly increases maximal GABA efficacy, and slows current deactivation without affecting desensitization (Zhong et al., 2008). In alphabetadelta receptors characterized by low GABA efficacy, etomidate dramatically increases responses to both low and maximal GABA. The effects of etomidate on desensitization and deactivation of alphabetadelta receptors are unknown. To investigate the kinetic effects of etomidate on alpha1beta3delta receptors of defined subunit arrangement, we expressed concatenated trimer (beta3 alpha1-delta) and dimer (beta3-alpha1) GABA(A) receptor subunit assemblies in human embryonic kidney (HEK)293T cells and recorded whole-cell voltage-clamp currents during rapid external solution exchanges. As expected, etomidate substantially increased maximal GABA-induced currents and prolonged deactivation. Moreover, desensitization was significantly decreased by etomidate. During prolonged GABA applications, etomidate enhanced steady-state currents more than peak currents. Thus, etomidate enhances tonic GABAergic inhibition through extrasynaptic alphabetadelta receptors by both augmenting gating and reducing desensitization. PMID- 26028472 TI - Stimulation of nitric oxide production contributes to the antiplatelet and antithrombotic effect of new peptide pENW (pGlu-Asn-Trp). AB - INTRODUCTION: New peptide pGlu-Asn-Trp (pENW), initially extracted from snake venom, significantly attenuates the formation of arterial and venous thrombi in vivo, and has modest in-vitro antiplatelet activity. This study was designed to investigate the underlying mechanisms. METHODS: The rat carotid thrombosis model induced by FeCl3 was established to evaluate the antithrombotic activity of pENW. The effects of pENW on the production of nitric oxide (NO), as well as the expression and activity of endothelial nitric oxide synthase (eNOS), were determined. The vasorelaxant effect of pENW was evaluated using isolated rat aortic rings in the absence or presence of N(G)-nitro-L-arginine methyl ester (L NAME, eNOS inhibitor). Furthermore, the in-vitro antiplatelet activity of pENW was investigated with the addition of sodium nitroprusside (SNP, NO donor) and/or L-NAME to further prove the role of NO and eNOS in the inhibitory effect of pENW on platelet aggregation. RESULTS: In vivo, pENW inhibited thrombus formation induced by endothelial injury in a dose-dependent manner, with a significantly prolonged time to the occurrence of arterial occlusion. It was shown that pENW offered protection for blood vessels from oxidative injury. pENW significantly increased NO production in rats treated with pENW at 4 or 2mg/kg body weight. Furthermore, the production of NO from the cultured vascular endothelial cells was increased with the treatment of 10(-4)M and 10(-5)M pENW; pENW also enhanced eNOS expression and activity both in vivo and in vitro, and elicited a concentration-dependent vasorelaxation which was significantly inhibited by L NAME. Notably, pENW inhibited ADP-induced platelet aggregation, and the inhibition was more significant in the presence of NO. The inhibition of platelet aggregation by pENW was significantly abolished by L-NAME. CONCLUSIONS: The in vivo antiplatelet and antithrombotic effects of pENW are at least partly mediated by the increased production of endogenous NO via up-regulation and stimulation of eNOS. The findings suggest that pENW could potentially be developed as a novel therapeutic agent in the treatment of platelet-driven disorders. PMID- 26028474 TI - Regulatory perspectives of Japan. AB - In this article, the 2013 regenerative medicine laws and regulations in Japan are addressed. The Regenerative Medicine Promotion Law was promulgated in May 2013 to promote comprehensive measures from research and development to practical use of regenerative medicines. In line with this purpose, two acts have been passed by the National Diet in November 2013. One is the Act on the Safety of Regenerative Medicine, which classifies regenerative medicines based on risk. Additionally this Act stipulates the procedures for offering regenerative medicines, the measures for appropriate provision of the regenerative medicines, and authorization to manufacture designated cellular therapeutic products for therapeutic use. The other is the Act on Pharmaceuticals and Medical Devices, previously named the Pharmaceutical Affairs Act, which establishes regulations tailored to the characteristics of regenerative medicinal products, including an expedited approval system. PMID- 26028473 TI - MR imaging findings of trigger thumb. AB - Trigger finger (or trigger thumb), also known as sclerosing tenosynovitis, is a common clinical diagnosis that rarely presents for imaging. Because of this selection bias, many radiologists may not be familiar with the process. Furthermore, patients who do present for imaging frequently have misleading examination indications. To our knowledge, magnetic resonance (MR) imaging findings of trigger thumb have not been previously reported in the literature. In this article, we review the entity of trigger thumb, the anatomy involved, and associated imaging findings, which include flexor pollicis longus tendinosis with a distinct nodule, A1 pulley thickening, and tenosynovitis. In addition, in some cases, an abnormal Av pulley is apparent. In the rare cases of trigger finger that present for MR imaging, accurate diagnosis by the radiologist can allow initiation of treatment and avoid further unnecessary workup. PMID- 26028475 TI - Impact of Cu(2+) ions on the structure of colistin and cell-free system nucleic acid degradation. AB - Colistin and transition metal ions are commonly used as feed additives for livestock animals. This work presents the results of an analysis of combined potentiometric and spectroscopic (UV-vis, EPR, CD, NMR) data which lead to conclude that colistin is able to effectively chelate copper(II) ions. In cell free system the oxidative activity of the complex manifests itself in the plasmid DNA destruction with simultaneous generation of reactive OH species, when accompanied by hydrogen peroxide or ascorbic acid. The degradation of RNA occurs most likely via a hydrolytic mechanism not only for complexed compound but also colistin alone. Therefore, huge amounts of the used antibiotic for nontherapeutic purposes might have a potential influence on livestock health. PMID- 26028476 TI - Ovarian and oocyte targets for development of female contraceptives. AB - INTRODUCTION: Steroid hormone-based contraceptives have been used by women for long time since their introduction. Efforts have been made to make steroidal contraceptives cost-effective, safe and improve their users' compliance. In addition, attempts have been made to develop nonsteroidal contraceptives. Contraceptive vaccines have been investigated as an alternate strategy for contraception. AREAS COVERED: The currently used steroidal contraceptives are reviewed. In addition, status of emerging nonsteroidal contraceptives that inhibit folliculogenesis, oocyte maturation, ovulation and endometrium receptivity targeting phosphodiesterase 3, angiopoietins, gonadotropin-releasing hormone, COX-2, progesterone/estrogen receptor and follicle-stimulating hormone receptor are presented. Various approaches to develop contraceptive vaccines aiming to inhibit ovarian follicle development, ovulation, fertilization and implantation including their current applications and limitations are discussed. EXPERT OPINION: Development of new nonsteroidal contraceptives, in addition to long-acting steroidal contraceptives, is pertinent for offering wider choice to women. It is imperative that basic research to discover new targets in the ovaries must be undertaken to facilitate development of novel contraceptives. Further, efforts on studying the feasibility and safety of contraceptive vaccines may be continued to bring these within the realm of application as contraceptives for humans. PMID- 26028478 TI - Glucose data-mining study inconclusive. PMID- 26028477 TI - Continuous metabolic monitoring based on multi-analyte biomarkers to predict exhaustion. AB - This work introduces the concept of multi-analyte biomarkers for continuous metabolic monitoring. The importance of using more than one marker lies in the ability to obtain a holistic understanding of the metabolism. This is showcased for the detection and prediction of exhaustion during intense physical exercise. The findings presented here indicate that when glucose and lactate changes over time are combined into multi-analyte biomarkers, their monitoring trends are more sensitive in the subcutaneous tissue, an implantation-friendly peripheral tissue, compared to the blood. This unexpected observation was confirmed in normal as well as type 1 diabetic rats. This study was designed to be of direct value to continuous monitoring biosensor research, where single analytes are typically monitored. These findings can be implemented in new multi-analyte continuous monitoring technologies for more accurate insulin dosing, as well as for exhaustion prediction studies based on objective data rather than the subject's perception. PMID- 26028479 TI - Special section on the Challenges in Environmental Science and Engineering, CESE 2014: 12-16 Oct., Persada Johor International Convention Centre, Johor Bahru, Malaysia. PMID- 26028480 TI - PredcircRNA: computational classification of circular RNA from other long non coding RNA using hybrid features. AB - Recently circular RNA (circularRNA) has been discovered as an increasingly important type of long non-coding RNA (lncRNA), playing an important role in gene regulation, such as functioning as miRNA sponges. So it is very promising to identify circularRNA transcripts from de novo assembled transcripts obtained by high-throughput sequencing, such as RNA-seq data. In this study, we presented a machine learning approach, named as PredcircRNA, focused on distinguishing circularRNA from other lncRNAs using multiple kernel learning. Firstly we extracted different sources of discriminative features, including graph features, conservation information and sequence compositions, ALU and tandem repeats, SNP densities and open reading frames (ORFs) from transcripts. Secondly, to better integrate features from different sources, we proposed a computational approach based on a multiple kernel learning framework to fuse those heterogeneous features. Our preliminary 5-fold cross-validation result showed that our proposed method can classify circularRNA from other types of lncRNAs with an accuracy of 0.778, sensitivity of 0.781, specificity of 0.770, precision of 0.784 and MCC of 0.554 in our constructed gold-standard dataset, respectively. Our feature importance analysis based on Random Forest illustrated some discriminative features, such as conservation features and a GTAG sequence motif. Our PredcircRNA tool is available for download at . PMID- 26028481 TI - MUTZ-3 derived Langerhans cells in human skin equivalents show differential migration and phenotypic plasticity after allergen or irritant exposure. AB - After allergen or irritant exposure, Langerhans cells (LC) undergo phenotypic changes and exit the epidermis. In this study we describe the unique ability of MUTZ-3 derived Langerhans cells (MUTZ-LC) to display similar phenotypic plasticity as their primary counterparts when incorporated into a physiologically relevant full-thickness skin equivalent model (SE-LC). We describe differences and similarities in the mechanisms regulating LC migration and plasticity upon allergen or irritant exposure. The skin equivalent consisted of a reconstructed epidermis containing primary differentiated keratinocytes and CD1a(+) MUTZ-LC on a primary fibroblast-populated dermis. Skin equivalents were exposed to a panel of allergens and irritants. Topical exposure to sub-toxic concentrations of allergens (nickel sulfate, resorcinol, cinnamaldehyde) and irritants (Triton X 100, SDS, Tween 80) resulted in LC migration out of the epidermis and into the dermis. Neutralizing antibody to CXCL12 blocked allergen-induced migration, whereas anti-CCL5 blocked irritant-induced migration. In contrast to allergen exposure, irritant exposure resulted in cells within the dermis becoming CD1a( )/CD14(+)/CD68(+) which is characteristic of a phenotypic switch of MUTZ-LC to a macrophage-like cell in the dermis. This phenotypic switch was blocked with anti IL-10. Mechanisms previously identified as being involved in LC activation and migration in native human skin could thus be reproduced in the in vitro constructed skin equivalent model containing functional LC. This model therefore provides a unique and relevant research tool to study human LC biology in situ under controlled in vitro conditions, and will provide a powerful tool for hazard identification, testing novel therapeutics and identifying new drug targets. PMID- 26028483 TI - Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro. AB - Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis-Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte Km and Vmax values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and Cmax was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers. PMID- 26028482 TI - The chalcone compound isosalipurposide (ISPP) exerts a cytoprotective effect against oxidative injury via Nrf2 activation. AB - The chalcone compound isosalipurposide (ISPP) has been successfully isolated from the native Korean plant species Corylopsis coreana Uyeki (Korean winter hazel). However, the therapeutic efficacy of ISPP remains poorly understood. This study investigated whether ISPP has the capacity to activate NF-E2-related factor (Nrf2)-antioxidant response element (ARE) signaling and induce its target gene expression, and to determined the protective role of ISPP against oxidative injury of hepatocytes. In HepG2 cells, nuclear translocation of Nrf2 is augmented by ISPP treatment. Consistently, ISPP increased ARE reporter gene activity and the protein levels of glutamate cysteine ligase (GCL) and hemeoxygenase (HO-1), resulting in increased intracellular glutathione levels. Cells pretreated with ISPP were rescued from tert-butylhydroperoxide-induced reactive oxygen species (ROS) production and glutathione depletion and consequently, apoptotic cell death. Moreover, ISPP ameliorated the mitochondrial dysfunction and apoptosis induced by rotenone which is an inhibitor of complex 1 of the mitochondrial respiratory chain. The specific role of Nrf2 activation by ISPP was demonstrated using an ARE-deletion mutant plasmid and Nrf2-knockout cells. Finally, we observed that extracellular signal-regulated kinase (ERK) and AMP-activated protein kinase (AMPK), but not protein kinase C (PKC)-delta or other mitogen activated protein kinases (MAPKs), are involved in the activation of Nrf2 by ISPP. Taken together, our results demonstrate that ISPP has a cytoprotective effect against oxidative damage mediated through Nrf2 activation and induction of its target gene expression in hepatocytes. PMID- 26028484 TI - Diagnosis of biopsy verified usual interstitial pneumonia by computed tomography. AB - OBJECTIVE: To identify the combination of clinical data and high resolution computed tomography (HRCT) features that best identified biopsy verified usual interstitial pneumonia (UIP). METHODS: The study included 91 patients with a tentative diagnosis of interstitial lung disease. All underwent clinical investigation, surgical lung biopsy and HRCT. Two independent readers assessed the HRCT images for the extent and pattern of abnormality. On the basis of the biopsy result the patients were categorized in three groups: 1) Usual interstitial pneumonia, 2) Other idiopathic interstitial pneumonias (IIPs) and hypersensitivity pneumonitis and 3) Other interstitial lung diseases. The diagnostic value of HRCT was investigated using likelihood ratio to estimate the post-test probability of UIP. RESULTS: We found that UIP was associated with significantly higher scores for reticular pattern and for bronchiectasis than the remaining patients (p < 0.001). Moreover, these scores showed a steeper cranial caudal increase in patients with histologically verified UIP than in the remaining patients (p < 0.001). UIP was associated with lower scores for ground glass opacities (p < 0.001). Using Bayes theorem and likelihood ratio estimation we found that UIP could be diagnosed with 90% certainty in patients 60 years or older and restrictive pattern in spirometry provided that HRCT demonstrated at least 15% reticular pattern and no ground glass opacities. CONCLUSION: In older patients with a restrictive spirometry in whom HRCT demonstrates a reticular pattern without ground glass opacities surgical lung biopsy is not warranted for the diagnosis of UIP. PMID- 26028487 TI - Constant capacitance in nanopores of carbon monoliths. AB - The results obtained for binder-free electrodes made of carbon monoliths with narrow micropore size distributions confirm that the specific capacitance in the electrolyte (C2H5)4NBF4/acetonitrile does not depend significantly on the micropore size and support the foregoing constant result of 0.094 +/- 0.011 F m( 2). PMID- 26028485 TI - Possible familial case of Birt-Hogg-Dube syndrome complicated with lung cancer: A possible link between these two disease entities. AB - A 65-year-old Japanese woman was introduced to our hospital for an examination of multiple pulmonary cystic lesions and a pulmonary nodule in the left lower lobe. She had a smoking history of 25 pack-years, and her two younger brothers had suffered from pneumothorax; one of them additionally had lung cancer with pulmonary multiple cystic lesions. A surgical biopsy specimen obtained from her left lower lobe revealed adenocarcinoma surrounded by a single epithelial layer that was covered with collagen fibers. The pathological features were compatible with the findings of the cystic lesions in the patients with Birt-Hogg-Dube syndrome (BHDS). A diagnosis of BHDS was eventually made according to the detection of a folliculin gene mutation. This is the first report of a possible familial case of BHDS complicated with primary lung cancer. We herein reviewed the previously reported cases of BHDS with lung cancer and other tumors and discussed a potential mechanism of tumorigenesis and carcinogenesis in the lung in the patients with BHDS. PMID- 26028488 TI - Long-term prognosis of patients with Brugada syndrome and an implanted cardioverter-defibrillator. AB - INTRODUCTION: Risk stratification of Brugada syndrome (BrS) remains controversial and recommendations for an implantable cardioverter-defibrillator (ICD) are not well established. The objective of this study was to assess the long-term prognosis of BrS patients with an ICD. METHODS AND RESULTS: Of 55 consecutive patients with BrS assessed between April 2002 and October 2012, 36 (mean age 41.7 +/- 13.8 years; 81.8% male) underwent ICD implantation. Nineteen (52.8%) were asymptomatic, 11 (30.6%) had previous history of syncope (arrhythmic cause suspected in eight) and six (16.7%) had aborted sudden cardiac death (SCD). Spontaneous type 1 electrocardiographic (ECG) pattern was present in 25 (69.4%) patients and electrophysiological study (EPS), performed in 26 (72.2%), was positive in 22 (84.6%). During a mean follow-up of 74 +/- 40 months (>5 years in 72% of cases), seven (19.4%) patients had appropriate shocks (annual event rate 2.8%). These patients most frequently had aborted SCD (54.1% vs. 6.9%; p=0.008) and nonsustained ventricular tachycardia (57.1% vs. 10.3%; p=0.016) during follow up. Spontaneous type 1 ECG pattern, syncope and positive EPS were not significantly associated with appropriate shocks. Multivariate analysis revealed that aborted SCD was an independent predictor of appropriate shocks (HR 8.07, 95% CI 1.58-41.2; p=0.012). ROC curve analysis demonstrated that aborted SCD had moderate discriminatory power to predict appropriate shocks (AUC 0.751), with sensitivity of 57% and specificity of 93%. In terms of ICD-related complications, eight (22.2%) patients had inappropriate shocks during the follow-up period, mainly due to sinus tachycardia (five patients); one patient had lead infection and another had a lead fracture. CONCLUSION: In this population of BrS patients with ICD, the long-term rate of appropriate shocks was 2.8%/year. Aborted SCD was associated with a higher risk of appropriate shocks, whereas syncope and spontaneous type I ECG pattern did not predict this event. PMID- 26028486 TI - Identifying cases of undiagnosed, clinically significant COPD in primary care: qualitative insight from patients in the target population. AB - BACKGROUND: Many cases of chronic obstructive pulmonary disease (COPD) are diagnosed only after significant loss of lung function or during exacerbations. AIMS: This study is part of a multi-method approach to develop a new screening instrument for identifying undiagnosed, clinically significant COPD in primary care. METHODS: Subjects with varied histories of COPD diagnosis, risk factors and history of exacerbations were recruited through five US clinics (four pulmonary, one primary care). Phase I: Eight focus groups and six telephone interviews were conducted to elicit descriptions of risk factors for COPD, recent or historical acute respiratory events, and symptoms to inform the development of candidate items for the new questionnaire. Phase II: A new cohort of subjects participated in cognitive interviews to assess and modify candidate items. Two peak expiratory flow (PEF) devices (electronic, manual) were assessed for use in screening. RESULTS: Of 77 subjects, 50 participated in Phase I and 27 in Phase II. Six themes informed item development: exposure (smoking, second-hand smoke); health history (family history of lung problems, recurrent chest infections); recent history of respiratory events (clinic visits, hospitalisations); symptoms (respiratory, non-respiratory); impact (activity limitations); and attribution (age, obesity). PEF devices were rated easy to use; electronic values were significantly higher than manual (P<0.0001). Revisions were made to the draft items on the basis of cognitive interviews. CONCLUSIONS: Forty-eight candidate items are ready for quantitative testing to select the best, smallest set of questions that, together with PEF, can efficiently identify patients in need of diagnostic evaluation for clinically significant COPD. PMID- 26028490 TI - Direct synthesis of macrodiolides via hafnium(IV) catalysis. AB - Efficient direct synthesis of macrodiolides via catalysis using Hf(OTf)4 is possible in high yields, forming water as the sole by-product. The first protocol for the direct synthesis of macrodiolides from equimolar mixtures of diols and dicarboxylic acids was developed (58-96%). In addition, modification of the reaction concentration allows for the synthesis of head-to-tail macrodiolides from the corresponding seco acids. The catalytic preparation of the macrodiolides using a commercially available catalyst without the need for slow addition or azeotropic condition provides an operationally simple alternative to protocols which employ toxic tin catalysts or stoichiometric activation strategies. PMID- 26028489 TI - Impact of atrial fibrillation type during acute coronary syndromes: Clinical features and prognosis. AB - INTRODUCTION: Atrial fibrillation (AF) is widely recognized as an adverse prognostic factor during acute myocardial infarction, although the impact of AF type - new-onset (nAF) or pre-existing (pAF) - is still controversial. OBJECTIVES: To identify the clinical differences and prognosis of nAF and pAF during acute coronary syndromes (ACS). METHODS: We performed a retrospective observational cohort study including 1373 consecutive patients (mean age 64 years, 77.3% male) admitted to a single center over a three-year period, with a six-month follow-up. RESULTS: AF rhythm was identified in 14.5% patients, of whom 71.4% presented nAF and 28.6% pAF. When AF types were compared, patients with nAF more frequently presented with ST-elevation ACS (p=0.003). Patients with pAF, in turn, were older (p=0.032), had greater left atrial diameter (p=0.001) and were less likely to have significant coronary lesions (p=0.034). Regarding therapeutic strategy, nAF patients were more often treated by rhythm control during hospital stay (p<0.001) and were less often anticoagulated at discharge (p=0.001). Compared with the population without AF, nAF was a predictor of death during hospital stay in univariate (p<0.001) and multivariate analysis (OR 2.67, p=0.047), but pAF was not. During follow-up, pAF was associated with higher mortality (p=0.014), while nAF patients presented only a trend towards worse prognosis. CONCLUSIONS: AF during the acute phase of ACS appears to have a negative prognostic impact only in patients with nAF and not in those with pAF. PMID- 26028491 TI - [Specificities of sex-cord stromal tumors in children and adolescents]. AB - Sex-cord stromal tumors (SCT) are rare pediatric tumors accounting for less than 5% of gonadal tumors in children and adolescents. They differ from those diagnosed in adults by their presentation, histology, evolution and treatment modalities. Testicular SCT occur mostly in infants less than 6 months. Testicular swelling is often the only symptom, but signs of hormonal secretion with gynecomastia may be present. Juvenile granulosa SCT is the main histologic subtype. Sertoli SCTs are much less frequent while Leydig tumors occurred in older children and adolescents. Prognosis is excellent after inguinal orchiectomy. Testis sparing surgery could be performed but indications and modalities have to be strongly defined. Ovarian SCT are diagnosed in older children and adolescents and present with abdominal symptoms and/or signs of hormonal secretion: estrogenic manifestations (isosexual pseudoprecocity, menometrorrhagia) or virilization (hirsutism, amenorrhea). Main histologic subtype is juvenile granulosa (rarely Sertoli-Leydig). If oophorectomy (or salpingo-oophorectomy) may be curative for localized disease, adjuvant cisplatin containing chemotherapy is mandatory in case of tumor rupture or peritoneal dissemination to prevent recurrences. Because of the rarity of these pediatric tumors, concerted multidisciplinary cares are required to best adapt therapeutic strategy before any surgical intervention. PMID- 26028492 TI - [Initial management of advanced ovarian cancer: What radiological, pathological and surgical information are important for optimal therapeutic strategy?]. AB - Because the majority of patients present advanced disease at diagnosis, the management of epithelial ovarian cancer needs specialist multidisciplinary teamwork. Expertise in surgery, chemotherapy, imaging and histopathology is essential to achieve optimum outcomes. Computed tomography scans are routinely used to determine the extent of disease and to aid in surgical planning. The histologic classification is crucial to plan the best therapeutic strategy and to define the prognosis of disease. Pathological prognostic factors, such as degree of differentiation, FIGO-stage, and histological type have to be described. This report is fundamental to assessing prognosis and selection of appropriate treatment strategy. An adequate staging procedure is an extensive staging by an experienced gynecological oncologist, exploring the entire upper abdomen, and the pelvic and para-aortic lymph node regions to define the Peritoneal Cancer Index (PCI). The final assessment is the completeness of cytoreduction (CC) score, which is an assessment of residual disease after a maximal surgical effort. Initial management of advanced ovarian cancer is best provided by a specialist multidisciplinary team, including a radiologist, a pathologist, a gynecologic oncologist and a medical oncologist. PMID- 26028493 TI - [Molecular biology of castration-resistant prostate cancer]. AB - Castration-resistant prostate cancer was subjected to a paradigm switch from hormone resistance to androgen deprivation therapy resistance during the last decade. Indeed, new therapeutics targeting the androgen receptor showed clinical efficacy in patients with progressive disease under castration. Thus, it is a proof that the AR remains a dominant driver of oncogenesis in earlier-called hormone resistant prostate cancer. This review summarizes the molecular mechanisms involved in castration-resistant prostate cancer. PMID- 26028494 TI - [How to manage patients with CRPC?]. AB - Despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression. Since the approval of docetaxel, four additional agents that show a survival benefit have been registered on the basis of randomized phase 3 trials. These have included enzalutamide and abiraterone, two agents designed specifically to affect the androgen axis, sipuleucel-T, which stimulates the immune system and cabazitaxel, a chemotherapeutic agent. Denosumab was shown to significantly delay skeletal related events. Clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision making more complex. The induction of constitutively-active AR splice variants (AR-Vs) driving clonal proliferation of AR-negative and AR-independent metastases may be one major potential mechanism of resistance to new hormone therapies. PMID- 26028495 TI - Using peer-assisted learning to teach and evaluate residents' musculoskeletal skills. AB - Although direct observation and corrective feedback are established methods of increasing select aspects of residents' musculoskeletal (MSK) clinical skills, the evaluation and management of patients with MSK complaints remains an underemphasized part of internal medicine training. This paper reports on the development of an innovative peer-assisted learning (PAL) model to teach five MSK areas (back, knee, shoulder, neck, or hip pain). Based on data from 42 participating interns and 44 senior residents from an urban US academic medical center, results from an objective structured clinical exam (OSCE) demonstrate gains in both knowledge and self-reported confidence in MSK skills. Moreover, subsequent focus group results reveal a strong preference for the PAL model. In conclusion, an educational module that utilizes the OSCE format holds much promise for teaching MSK skills to both intern and senior residents. PMID- 26028497 TI - New organically templated thiocyanatocadmates and chlorocuprate(II): synthesis and structural characterization. AB - With various organic base molecules as the countercations, five new thiocyanatocadmates [H2(tmen)][Cd(SCN)4] (tmen = N,N,N',N' tetramethylethylenediamine) 1, [H2(tmba)][Cd2(SCN)6] (tmba = N,N,N',N' tetramethyl-1,4-butanediamine) 2, [H2(teen)][Cd2(SCN)6] (teen = N,N,N',N'-tetra ethylethylenediamine) 3, [H(amp)][Cd(SCN)2(CH3COO)] (amp = 2-amino-6 methylpyridine) 4 and [H(abp)]4[Cd(SCN)4]SO4.H2O (abp = 2-amino-6-bromopyridine) 5, and one new chlorocuprate(II) [H2(cha)][CuCl4] (cha = 1,4-cyclohexanediamine) 6 were obtained from a series of simple room-temperature self-assemblies at pH = 2 or 6.5. X-ray single-crystal diffraction analysis reveals that (i) templated by [(CH3)2NH(CH2)2NH(CH3)2](2+) (H2(tmen)(2+)), the anion [Cd(SCN)4](2-) in 1 shows a 1-D linear single-chain structure, whereas templated by [(CH3)2NH(CH2)4NH(CH3)2](2+) (H2(tmba)(2+)), the anion [Cd2(SCN)6](2-) in 2 shows a 1-D linear double-chain structure. The number of C atoms between the two N atoms in the templating agent controls the width of the anionic chain through the N(amino)-H...N(SCN) interactions; (ii) templated by [(C2H5)2NH(CH2)2NH(C2H5)2](2+) (H2(teen)(2+)), the anion [Cd2(SCN)6](2-) in 3 exhibits a 3-D open-framework structure, which is based on zigzag anionic chains. A direct change of the substituent group from -CH3 to -C2H5 alters indirectly the shape of the anionic chain from a linear shape to a zigzag shape; (iii) 4 shows a 3-D supramolecular network structure, which is built up from the 1-D zigzag anionic structures by the H(amp)(+) molecules via N-H...O interactions. The formation of the zigzag chain derives from the chelation of the CH3COO(-) groups to the Cd(2+) centers; (iv) 5 is indeed a double salt of [H(abp)]2[Cd(SCN)4] and [H(abp)]2SO4. SO4(2-) and H(abp)(+) form a supramolecular aggregation. Surrounded by the aggregations, the anion [Cd(SCN)4](2-) only shows a dinuclear structure; and (v) templated by H2(cha)(2+), the anion [CuCl4](2-) in 6 displays a 2-D perovskite layer structure. The photoluminescence analysis indicates that upon excitation (lambda(ex) = 335 nm for 4, lambda(ex) = 395 nm for 5), and emit light (lambda(em) = 365 nm for 4, lambda(em) = 470 nm for 5), which can be seen clearly under the UV lamp. PMID- 26028496 TI - Alterations in DNA-methylation of the dopamine-receptor 2 gene are associated with abstinence and health care utilization in individuals with a lifetime history of pathologic gambling. AB - BACKGROUND: Several studies point towards a role for dopaminergic circuits in the pathophysiology of problematic gambling behavior. The aim of the present study was to investigate alterations of DNA methylation in the dopamine D2 receptor (DRD2)-gene in participants with pathologic gambling behavior. RESULTS: The study was part of a large epidemiological study on pathologic gambling in Germany. DNA methylation of the DRD2-gene was analyzed from oral mucosa using next generation bisulfite sequencing. The final sample included 77 participants. The study showed significantly lower methylation levels of the DRD2-gene in abstinent patients over the last 12 or 30months compared to non-abstinent participants. Furthermore, participants without any treatment utilization regarding gambling behavior showed higher DRD2-gene methylation levels compared to treatment-seeking participants. CONCLUSIONS: DNA-methylation patterns in the DRD2-gene were altered in respect to abstinence over a 12-month or a 30-month period and to treatment utilization with higher methylation levels in non-abstinent and participants without treatment seeking behavior. These results point towards a pathophysiologic relevance of altered DRD2-expression due to changes of DNA methylation in pathologic gambling behavior. PMID- 26028498 TI - The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers. AB - The ubiquitin-dependent proteasomal degradation of proteins controls signaling and cellular survival. An increasing body of evidence suggests that the E3 ubiquitin ligases SIAH1 and SIAH2 are able to dictate the growth, development, and chemo-/radiosensitivity of breast and prostate cancer cells. Here we review the current knowledge on the impact of SIAHs on breast and prostate tumorigenesis. Furthermore, we summarize how stress, hormones, and cytokines regulate SIAH1 and SIAH2 in transformed mammalian cells. PMID- 26028499 TI - Regulation of cell fate by lymphotoxin (LT) receptor signalling: Functional differences and similarities of the LT system to other TNF superfamily (TNFSF) members. AB - The role of TNFR family members in regulating cell fate both in the immune system and in non-lymphoid tissues has been under extensive research for decades. Moreover, the ability of several family members (death receptors) to induce death (mainly via apoptosis) represents a promising target for cancer therapy. Many studies have focused mostly on death receptors such as TNFRI, Fas and TRAIL-R due to their strong pro-apoptotic potential. Yet, cell death can be triggered via non classical death receptors, and the lymphotoxin (LT) system represents a very good example of such a TNFR subfamily. Here we provide a comprehensive review of intracellular signalling pathways and cellular responses to LT-specific signalling, and compare for the first time the LT system to other TNFRs, such as CD40. Our aim is to highlight that non-classical TNFR-TNFL dyads such as the LT system demonstrate more complex, cell-type and context-specific capabilities. Understanding these complexities will permit a better understanding of the biological mechanisms via which non-death domain-containing TNFRs induce cell death, but may also allow the design of better therapeutic strategies. PMID- 26028500 TI - The directionality of processive enzymes acting on recalcitrant polysaccharides is reflected in the kinetic signatures of oligomer degradation. AB - The enzymatic degradation of the closely related insoluble polysaccharides; cellulose (beta(1-4)-linked glucose) by cellulases and chitin (beta(1-4)-linked N acetylglucosamine) by chitinases, is of large biological and economical importance. Processive enzymes with different inherent directionalities, i.e. attacking the polysaccharide chains from opposite ends, are crucial for the efficiency of this degradation process. While processive cellulases with complementary functions differ in structure and catalytic mechanism, processive chitinases belong to one single protein family with similar active site architectures. Using the unique model system of Serratia marcescens with two processive chitinases attacking opposite ends of the substrate, we here show that different directionalities of processivity are correlated to distinct differences in the kinetic signatures for hydrolysis of oligomeric tetra-N-acetyl chitotetraose. PMID- 26028501 TI - The 4D nucleome: Evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments. AB - Recent methodological advancements in microscopy and DNA sequencing-based methods provide unprecedented new insights into the spatio-temporal relationships between chromatin and nuclear machineries. We discuss a model of the underlying functional nuclear organization derived mostly from electron and super-resolved fluorescence microscopy studies. It is based on two spatially co-aligned, active and inactive nuclear compartments (ANC and INC). The INC comprises the compact, transcriptionally inactive core of chromatin domain clusters (CDCs). The ANC is formed by the transcriptionally active periphery of CDCs, called the perichromatin region (PR), and the interchromatin compartment (IC). The IC is connected to nuclear pores and serves nuclear import and export functions. The ANC is the major site of RNA synthesis. It is highly enriched in epigenetic marks for transcriptionally competent chromatin and RNA Polymerase II. Marks for silent chromatin are enriched in the INC. Multi-scale cross-correlation spectroscopy suggests that nuclear architecture resembles a random obstacle network for diffusing proteins. An increased dwell time of proteins and protein complexes within the ANC may help to limit genome scanning by factors or factor complexes to DNA exposed within the ANC. PMID- 26028502 TI - The DRBD13 RNA binding protein is involved in the insect-stage differentiation process of Trypanosoma brucei. AB - DRBD13 RNA-binding protein (RBP) regulates the abundance of AU-rich element (ARE) containing transcripts in trypanosomes. Here we show that DRBD13 regulates RBP6, the developmentally critical protein in trypanosomatids. We also show DRBD13 specific regulation of transcripts encoding cell surface coat proteins including GPEET2, variable surface glycoprotein (VSG) and invariant surface glycoprotein (ISG). Accordingly, alteration in DRBD13 levels leads to changes in the target mRNA abundance and parasite morphology. The high consistency of the observed phenotype with known cell membrane exchanges that occur during progression of T. brucei through the insect stage of its life cycle suggests that DRBD13 is an important regulator in this largely unknown developmental process. PMID- 26028503 TI - Implementation of an Advanced Practice Provider Service on an Allogeneic Stem Cell Transplant Unit: Impact on Patient Outcomes. AB - Allogeneic stem cell transplantation (ASCT) is a complex medical procedure for some patients with hematologic malignancies. Most ASCTs occur at academic centers where either medical residents (house staff [HS]) or advanced practice providers (APPs) provide daily care. As a result of increasing work-hour regulations, APPs have assumed greater responsibilities, including those traditionally held by HS. In this study we evaluate ASCT patient outcomes by inpatient provider service. A retrospective, single-center chart review of ASCT patients was performed. ASCT patients admitted to an HS service from May 2011 to May 2012 (N = 86) were compared with ASCT patients admitted to a newly formed APP service from October 2012 to October 2013 (N = 81). As part of a secondary sensitivity analysis, we compared ASCT patients on the APP service to a subset of ASCT patients admitted to the HS service also from October 2012 to October 2013 (n = 27). Our primary outcomes were 100-day survival and relapse-free survival rates. Additional outcomes included length of stay (LOS), inpatient complications, and ordering behavior. Our primary pre- and post-analyses found no differences in 100-day overall survival and 100-day relapse-free survival rate between the services. The rate of pneumonia was lower on the APP service (15% versus 28%, P = .04), with no significant differences in other infectious complications. HS ordered more blood cultures (6.7 versus 4.2, P = .03) per patient than the APP service. There was no difference in LOS, readmission rates, or inpatient mortality. With regards to our secondary sensitivity analysis, no differences were found in 100-day overall survival and 100-day relapse-free survival rates between the services. There was a decreased LOS on the APP service (29.4 versus 37.2 days, P = .01). HS ordered more blood cultures (9.3 versus 4.2, P < .01) and more radiological films (8.1 versus 5.2, P = .05) per patient than the APP service. This increased ordering and LOS was associated with an increase in mean hospital charges on the HS service (P = .04). ASCT patients on an APP service had similar 100-day outcomes as those on the HS service. In the setting of limited resources, APPs are potential alternative providers for complex transplant inpatients. PMID- 26028504 TI - Establishment of Definitions and Review Process for Consistent Adjudication of Cause-specific Mortality after Allogeneic Unrelated-donor Hematopoietic Cell Transplantation. AB - Clinical trials commonly use adjudication committees to refine endpoints, but observational research or genome-wide association studies rarely do. Our goals were to establish definitions of cause-specific death after unrelated-donor allogeneic hematopoietic cell transplantation (URD-HCT), to estimate discordance between reported and adjudicated cause-specific death, and to identify factors contributing to inconsistency in cause-specific death determination. A consensus panel adjudicated cause-specific death in 1484 patients who died within 1 year after HCT, derived from 3532 acute leukemia or myelodysplasia patients after URD HCT from 2000 to 2011 reported by 151 US transplant centers to the Center for International Blood and Marrow Transplant Research. Deaths were classified as disease-related or transplant-related. The panel agreed with >99% of deaths reported by centers as disease-related and 80% reported as transplant-related. Year of transplant (cohort effect) and disease status significantly influenced agreement between the panel and centers. Sensitivity analysis of deaths < 100 days post-transplant yielded the lowest agreement between the panel and centers for myelodysplastic syndrome patients. Standard predefined criteria for adjudicating cause-specific death led to consistent application to similar clinical scenarios and clearer delineation of cause-specific death categories. Other studies of competing events such as cancer-specific versus treatment related mortality would benefit from our results. Our detailed algorithm should result in more consistent reporting of cause-specific death by centers. PMID- 26028506 TI - The skin migratory stage of the schistosomulum of Schistosoma mansoni has a surface showing greater permeability and activity in membrane internalisation than other forms of skin or mechanical schistosomula. AB - Skin schistosomula can be prepared by collecting them after isolated mouse skin have been penetrated by cercariae in vitro. The schistosomula can also migrate out of isolated mouse skin penetrated by cercariae in vitro and from mouse skin penetrated by cercariae in vivo. Schistosomula can also be produced from cercariae applied through a syringe or in a vortex. When certain surface properties of the different forms of schistosomula were compared, those migrating from mouse skin penetrated by cercariae in vivo or in vitro had greatly increased permeability to membrane impermeant molecules such as Lucifer yellow and high molecular weight dextrans. These migrating forms also possessed surfaces which showed greatly enhanced uptake into internal membrane vesicles of the dye FM 143, a marker for endocytosis. This greatly enhanced activity and permeability of the surfaces of tissue migrating schistosomula is likely to be of great importance in the adaptation to the new host. PMID- 26028507 TI - Impact of high hydrostatic pressure processing on individual cellular resuscitation times and protein aggregates in Escherichia coli. AB - Live cell biology approaches can contribute to a more comprehensive understanding of heterogeneous injury and resuscitation phenomena in stressed populations of foodborne pathogens and spoilage microorganisms, and in turn lead to better insights in the mechanisms and dynamics of inactivation that can improve food safety and preservation measures. Especially in the context of designing minimal processing strategies, which depend on a synergistic combination of different mild stresses to ensure sufficient microbial reduction, a more profound understanding of the impact of each such stress or hurdle is mandatory. High hydrostatic pressure (HHP) stress is an interesting hurdle in this concept since cells that manage to survive this stress nevertheless tend to be injured and sensitized to subsequent stresses. In this study, populations of Escherichia coli were subjected to different HHP intensities and studied at the single-cell level with time-lapse fluorescence microscopy while monitoring resuscitation times and protein aggregate integrity at the single-cell level. This approach revealed that higher pressure intensities lead to longer and more variable resuscitation times of surviving cells as well as an increased dispersal of intracellular protein aggregates. Interestingly, at mild HHP exposure, cells within the population incurring less dispersion of protein aggregates appeared to have a higher probability of survival. PMID- 26028505 TI - Immunotherapy with Donor T Cells Sensitized with Overlapping Pentadecapeptides for Treatment of Persistent Cytomegalovirus Infection or Viremia. AB - We conducted a phase I trial of allogeneic T cells sensitized in vitro against a pool of pentadecapeptides (15-mer peptides) spanning the sequence of CMVpp65 for adoptive therapy of 17 allogeneic hematopoietic cell transplant recipients with cytomegalovirus (CMV) viremia or clinical infection persisting despite prolonged treatment with antiviral drugs. All but 3 of the patients had received T cell depleted transplants without graft-versus-host disease (GVHD) prophylaxis with immunosuppressive drugs after transplantation. The CMVpp65-specific T cells (CMVpp65CTLs) generated were oligoclonal and specific for only 1 to 3 epitopes, presented by a limited set of HLA class I or II alleles. T cell infusions were well tolerated without toxicity or GVHD. Of 17 patients treated with transplant donor (n = 16) or third-party (n = 1) CMVpp65CTLs, 15 cleared viremia, including 3 of 5 with overt disease. In responding patients, the CMVpp65CTLs infused consistently proliferated and could be detected by T cell receptor Vbeta usage in CMVpp65/HLA tetramer + populations for period of 120 days to up to 2 years after infusion. Thus, CMVpp65CTLs generated in response to synthetic 15-mer peptides of CMVpp65 are safe and can clear persistent CMV infections in the post transplantation period. PMID- 26028508 TI - Laser induced magnetization switching in a TbFeCo ferrimagnetic thin film: discerning the impact of dipolar fields, laser heating and laser helicity by XPEEM. AB - We investigate laser induced magnetic switching in a ferrimagnetic thin film of Tb22Fe69Co9 by PEEM. Using a small laser beam with a spot size of 3-5 um in diameter in combination with high resolution magnetic soft X-ray microscopy we are able to discriminate between different effects that govern the microscopic switching process, namely the influence of the laser heating, of the helicity dependent momentum transfer, and of the dipolar coupling. Applying a sequence of femtosecond laser pulses to a previously saturated TbFeCo film leads to the formation of ring shaped magnetic structures in which all three effects can be observed. Laser helicity assisted switching is only observed in a narrow region within the Gaussian profile of the laser spot. Whereas in the center of the laser spot we find clear evidence for thermal demagnetization and in the outermost areas magnetic switching is determined by dipolar coupling with the surrounding film. Our findings demonstrate that by reducing the laser spot size the influence of dipolar coupling on laser induced switching is becoming increasingly important. PMID- 26028509 TI - Polyaromatic molecular tubes with a subnanometer pore and the guest-induced emission enhancement behavior. AB - New polyaromatic molecular tubes with a subnanometer pore (0.8 nm) were prepared. The tube bearing six sulfonate groups on the periphery and twelve methoxy groups at the openings provides a cylindrical hydrophobic cavity with a length of ~1.3 nm. The aqueous tube can quantitatively bind one molecule of hydrocarbon guests in water with accompanying guest-induced emission enhancement (up to ~3 times) of the host framework. PMID- 26028510 TI - Adsorption equilibrium and kinetics of monomer-dimer monoclonal antibody mixtures on a cation exchange resin. AB - Adsorption equilibrium and kinetics are determined for a monoclonal antibody (mAb) monomer and dimer species, individually and in mixtures, on a macroporous cation exchange resin both under the dilute limit of salt gradient elution chromatography and at high protein loads and low salt based on batch adsorption equilibrium and confocal laser scanning microscopy (CLSM) experiments. In the dilute limit and weak binding conditions, the dimer/monomer selectivity in 10mM phosphate at pH 7 varies between 8.7 and 2.3 decreasing with salt concentration in the range of 170-230mM NaCl. At high protein loads and strong binding conditions (0-60mM NaCl), the selectivity in the same buffer is near unity with no NaCl added, but increases gradually with salt concentration reaching high values between 2 and 15 with 60mM added NaCl. For these conditions, the two component adsorption kinetics is controlled by pore diffusion and is predicted approximately by a dual shrinking core model using parameters based on single component equilibrium and kinetics measurements. PMID- 26028511 TI - Inlet backflushing device for the improvement of comprehensive two dimensional gas chromatographic separations. AB - Comprehensive two-dimensional gas chromatography (GC*GC) is recognised as a powerful tool for the separation of complex mixtures of volatile and semi volatile compounds. In the analysis of challenging samples containing highly concentrated, active analytes or those with complicated matrices, it is often the case that less than ideal chromatography is produced. GC*GC chromatograms of such samples typically contain broad, tailing analyte bands. This results in difficulties with quantitation and poor utilisation of the separation space. In this study we investigated the inlet and the modulator as the potential sources of these tailing bands. A simple inlet backflushing device was developed to isolate the inlet from the primary column after the injection, and a similar setup was used to isolate the modulator from the primary column. The device allowed us to divert carrier gas flow back through the inlet at a specified time after the injection, while allowing analytes to pass through the column for separation. Analytes retained within the inlet were prevented from entering the column, and were subsequently removed via the carrier gas split line. The study revealed that the inlet plays a significant role in the development of tailing chromatographic bands, while the modulator simply modulates the already elongated band. Inlet backflushing is a cheap, simple and effective tool that can be used to improve the chromatography of problematic GC*GC analyses of samples consisting of concentrated and active analytes, those derived from natural products and containing complicated matrices. PMID- 26028512 TI - Sub-2-MUm seeded growth mesoporous thin shell particles for high-performance liquid chromatography: Synthesis, functionalisation and characterisation. AB - Nanometer control over the porous shell thickness of sub-2-MUm-shell particles is investigated. Three seeded growth mesoporous thin shell particles for HPLC were prepared, with 0.05MUm (or 50nm) porous shell layers: particle sizes 1.5MUm (solid core diameters 1.4MUm), 1.7MUm (solid core diameter 1.6MUm), 1.9MUm (solid core diameter 1.8MUm) and compared with a fourth 1.7MUm particle (solid core diameter 1.4MUm) surrounded by 0.15MUm (or 150nm) porous shell thickness. The thin shell particles were functionalised using a mono-functional octadecyldimethylchlorosilane ligand (C20H43SiCl) under optimised reflux conditions and packed in-house in narrow bore columns (2.1 I.D.*50mm) denoted as TS1.5-50-C18, TS1.7-50-C18, and TS1.9-50-C18 respectively. The synthesised thin shell particles and bonded materials were comprehensively characterised using scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential, BET analysis, elemental analysis (CHN), thermogravimetric analysis (TGA) and diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy. Experimental data from inverse size exclusion chromatography (ISEC) was used to measure external, internal and total column porosities. Five probe analytes (uracil, naphthalene, acetophenone, benzene and toluene) were chosen for the chromatographic performance analysis of these columns. Column evaluation and measurements of height equivalent to a theoretical plate (HETP) data were performed on naphthalene using 55% acetonitile in water. The retention coefficients for the thin shell particles (TS1.9-50-C18, TS1.7-50 C18, TS1.5-50-C18) were in the range 1.26-1.35 and 5.6 for the core-shell particle (EiS1.7-150-C18). The minimum reduced plate heights range from 3.89 to 4.26 for the thin shell particles and 2.03 for the core-shell particle. PMID- 26028513 TI - Improvements in ion reflux: An electrodialytic eluent generation and suppression device for ion chromatography. AB - This work describes a membrane based electrodialytic ion reflux device (IRD), which uses water as the pumped phase and integrates isocratic and gradient eluent generation and suppression. The current design incorporates several ion exchange membranes to create discrete chambers for suppression and eluent generation, while isolating the electrodes from the analytical stream. A small volume of recycled water can be used as the pumped phase while continuously refluxing the eluent ions. This current design permits electronically controlled eluent generation of at least 16.4MUeq KOHmin(-1), while maintaining low suppressed background conductivity (<0.5MUS/cm). The device was operated in gradient or isocratic mode continuously for up to 6 weeks. During this period, over 500 gradient and isocratic injections were performed, showing peak retention time precision below 1.5% RSD. PMID- 26028514 TI - Scanning precession electron tomography for three-dimensional nanoscale orientation imaging and crystallographic analysis. AB - Three-dimensional (3D) reconstructions from electron tomography provide important morphological, compositional, optical and electro-magnetic information across a wide range of materials and devices. Precession electron diffraction, in combination with scanning transmission electron microscopy, can be used to elucidate the local orientation of crystalline materials. Here we show, using the example of a Ni-base superalloy, that combining these techniques and extending them to three dimensions, to produce scanning precession electron tomography, enables the 3D orientation of nanoscale sub-volumes to be determined and provides a one-to-one correspondence between 3D real space and 3D reciprocal space for almost any polycrystalline or multi-phase material. PMID- 26028515 TI - The common neural parasite Pseudoloma neurophilia is associated with altered startle response habituation in adult zebrafish (Danio rerio): Implications for the zebrafish as a model organism. AB - The zebrafish's potential as a model for human neurobehavioral research appears nearly limitless despite its relatively recent emergence as an experimental organism. Since the zebrafish has only been part of the research community for a handful of decades, pathogens from its commercial origins continue to plague laboratory stocks. One such pathogen is Pseudoloma neurophilia, a common microparasite in zebrafish laboratories world-wide that generally produces subclinical infections. Given its high prevalence, its predilection for the host's brain and spinal cord, and the delicate nature of neurobehavioral research, the behavioral consequences of subclinical P. neurophilia infection must be explored. Fish infected via cohabitation were tested for startle response habituation in parallel with controls in a device that administered ten taps over 10 min along with taps at 18 and 60 min to evaluate habituation extinction. After testing, fish were euthanized and evaluated for infection via histopathology. Infected fish had a significantly smaller reduction in startle velocity during habituation compared to uninfected tankmates and controls. Habituation was eliminated in infected and control fish at 18 min, whereas exposed negative fish retained partial habituation at 18 min. Infection was also associated with enhanced capture evasion: Despite the absence of external symptoms, infected fish tended to be caught later than uninfected fish netted from the same tank. The combination of decreased overall habituation, early extinction of habituation compared to uninfected cohorts, and enhanced netting evasion indicates that P. neurophilia infection is associated with a behavioral phenotype distinct from that of controls and uninfected cohorts. Because of its prevalence in zebrafish facilities, P. neurophilia has the potential to insidiously influence a wide range of neurobehavioral studies if these associations are causative. Rigorous health screening is therefore vital to the improvement of the zebrafish as a translational model for human behavior. PMID- 26028517 TI - Docetaxel for advanced prostate cancer: how early to start? PMID- 26028516 TI - Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences. AB - Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype. PMID- 26028519 TI - Contents of therapeutic metabolites in Swertia chirayita correlate with the expression profiles of multiple genes in corresponding biosynthesis pathways. AB - Swertia chirayita, an endangered medicinal herb, contains three major secondary metabolites swertiamarin, amarogentin and mangiferin, exhibiting valuable therapeutic traits. No information exists as of today on the biosynthesis of these metabolites in S. chirayita. The current study reports the expression profiling of swertiamarin, amarogentin and mangiferin biosynthesis pathway genes and their correlation with the respective metabolites content in different tissues of S. chirayita. Root tissues of greenhouse grown plants contained the maximum amount of secoiridoids (swertiamarin, 2.8% of fr. wt and amarogentin, 0.1% of fr. wt), whereas maximum accumulation of mangiferin (1.0% of fr. wt) was observed in floral organs. Differential gene expression analysis and their subsequent principal component analysis unveiled ten genes (encoding HMGR, PMK, MVK, ISPD, ISPE, GES, G10H, 8HGO, IS and 7DLGT) of the secoiridoids biosynthesis pathway and five genes (encoding EPSPS, PAL, ADT, CM and CS) of mangiferin biosynthesis with elevated transcript amounts in relation to corresponding metabolite contents. Three genes of the secoiridoids biosynthesis pathway (encoding PMK, ISPD and IS) showed elevated levels (~57-104 fold increase in roots), and EPSPS of mangiferin biosynthesis showed an about 117 fold increase in transcripts in leaf tissues of the greenhouse grown plants. The study does provide leads on potential candidate genes correlating with the metabolites biosynthesis in S. chirayita as an initiative towards its genetic improvement. PMID- 26028521 TI - Identification and enzymatic characterization of an endo-1,3-beta-glucanase from Euglena gracilis. AB - Euglena produces paramylon as a storage polysaccharide, and is thought to require beta-1,3-glucan degrading enzymes to release and utilize the accumulated carbohydrate. To investigate beta-1,3-glucan degradation in Euglena, endo-1,3 beta-glucanases were partially purified from Euglena gracilis by hydrophobic, gel filtration and anion-exchange chromatography. Tryptic digests and mass spectrometric analysis identified three proteins in the purified fraction as a member of glycoside hydrolase family (GH) 17 and two members of GH81. These genes were cloned from an Euglena cDNA pool by PCR. EgCel17A fused with a histidine-tag at the carboxy terminus was heterologously produced by Aspergillus oryzae and purified by immobilized metal affinity chromatography. Purified EgCel17A had a molecular weight of about 40kDa by SDS-PAGE, which was identical to that deduced from its amino acid sequence. The enzyme showed hydrolytic activity towards beta 1,3-glucans such as laminarin and paramylon. Maximum activity of laminarin degradation by EgCel17A was attained at pH 4.0-5.5 and 60 degrees C after 1h incubation or 50 degrees C after 20h incubation. The enzyme had a Km of 0.21mg/ml and a Vmax of 40.5units/mg protein for laminarin degradation at pH 5.0 and 50 degrees C. Furthermore, EgCel17A catalyzed a transglycosylation reaction by which reaction products with a higher molecular weight than the supplied substrates were initially generated; however, ultimately the substrates were degraded into glucose, laminaribiose and laminaritriose. EgCel17A effectively produced soluble beta-1,3-glucans from alkaline-treated Euglena freeze-dried powder containing paramylon. Thus, EgCel17 is the first functional endo-1,3-beta-glucanase to be identified from E. gracilis. PMID- 26028518 TI - Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. AB - BACKGROUND: Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. METHODS: We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of >=8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10.8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731. FINDINGS: We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8.8 years (IQR 8.1-9.7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0.71, 95% CI 0.54-0.94, p=0.017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0.61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0.57), and there were no treatment-related deaths. INTERPRETATION: Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. FUNDING: Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer. PMID- 26028520 TI - Oleanane-type triterpene saponins with collagen synthesis-promoting activity from the flowers of Bellis perennis. AB - The methanol extract from Bellis perennis (Asteraceae) flowers was found to promote collagen synthesis in normal human dermal fibroblasts (NHDFs). Seven oleanane-type triterpene saponins, perennisosides XIII-XIX, and two known saponins, bellissaponins BS5 and BS9, were isolated from the methanol extract. The structures were determined based on chemical and physicochemical data, and confirmed using previously isolated related compounds as references. Among the isolates, including 19 previously reported saponins, perennisosides XVIII, I, II, VII, IX, and XI, asterbatanoside D, bernardioside B2, and bellissaponins BS5 and BS9 significantly promoted collagen synthesis at 3-30MUM without cytotoxicity. PMID- 26028522 TI - Fostering the action of versatile peroxidase as a highly efficient biocatalyst for the removal of endocrine disrupting compounds. AB - Response surface methodology (RSM) was used to optimize the removal of five endocrine disrupting compounds (EDCs) by the enzyme versatile peroxidase (VP): bisphenol A (BPA), triclosan (TCS), estrone (E1), 17beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2). The optimal variables of enzyme activity (90-100 U L(-1)), sodium malonate (29-43 mM) and MnSO4 (0.8-1 mM) led to very high removal rates of the five pollutants (2.5-5.0 mg L(-1) min(-1)). The structural elucidation of transformation products arising from the enzymatic catalysis of the EDCs was investigated by Gas Chromatography coupled to Mass Spectrometry (GC MS) and Liquid Chromatography Electrospray Time-of-Flight Mass Spectrometry (LC ESI-TOF-MS). The presence of dimers and trimers, indicative of oxidative coupling, was demonstrated. PMID- 26028523 TI - Nail apparatus melanoma: A comparative, clinicoprognostic study of the initial clinical and morphological characteristics of 49 patients. AB - BACKGROUND: Although nail apparatus melanoma has been widely evaluated, only limited data are available concerning its clinical features, which depend on its initial clinical morphology, broadly defined as a melanonychia or nonmelanonychia lesion. OBJECTIVE: We sought to determine heterogeneity on the basis of the initial clinical morphology of nail apparatus melanoma. METHODS: We searched the Asan Medical Center database for cases of nail apparatus melanoma that were confirmed by skin biopsy specimen. Patients were classified with either nail apparatus melanoma that began as melanonychia (group A) or nail apparatus melanoma that began as nonmelanonychia lesions (group B). RESULTS: We identified 49 patients with nail apparatus melanoma. Of these, 29 and 20 patients were included in groups A or B, respectively. The prediagnosis duration was significantly longer in group A. At the time of diagnosis, advanced stage and deeper Breslow thickness were noted in group B. The median overall survival period of the whole cohort was 93.0 months, and the 5-year overall survival was 67%. Patients in group A demonstrated better survival outcomes. LIMITATIONS: This study is a retrospective, single-center design. CONCLUSION: Nail apparatus melanoma demonstrates different clinical features and survival outcomes depending on whether the lesion begins as melanonychia or nonmelanonychia. PMID- 26028525 TI - Long-term effectiveness of infection and antibiotic control programs on the transmission of carbapenem-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex in central Taiwan. AB - OBJECTIVES: A carbapenem-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex (CRA complex) infection is one of most the difficult infections to control worldwide. We evaluated the long-term effects of infection control interventions on the incidence densities of healthcare-associated infection (HAI) and CRA complex infection, and the rates of Acinetobacter calcoaceticus Acinetobacter baumannii complex bacteremia (AB). PATIENTS AND METHODS: We performed a cross-sectional analysis at the Changhua Christian Hospital from January 2002 to December 2013. Interventions for infection control were implemented from 2002 to 2009 (period 1). From 2010 to 2013 (period 2), infection control programs were improved by in-service education and a hand hygiene campaign to prepare for international and national hospital accreditation. The effectiveness of infection and antibiotic control programs was assessed according to the incidence densities of HAI and CRA complex, rates of CRA complex and of AB, chlorhexidine consumption density, and defined daily dose of antibiotics. RESULTS: The incidence density of HAI decreased from 4.560/00 to 1.520/00 from periods 1 to 2 (P<0.001). Likewise, the incidence of AB decreased from 177.79 to 137.76 per person-years per 100,000 admissions (P<0.001). The incidence density of CRA complex ranged from 3.17-7.380/00. The chlorhexidine consumption density increased from 5.5 to 45.5 L per 1000 patient-days (P<0.001). The consumption of piperacillin-tazobactam was lower in period 2 than in period 1 (P<0.001). CONCLUSION: Education for infection control programs, hand hygiene campaigns, and antibiotics control programs may decrease the incidence density of AB and HAI, and may help control CRA complex infection. PMID- 26028524 TI - Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy. AB - BACKGROUND: Immunosuppressed patients have higher rates of cutaneous squamous cell carcinoma of the head and neck. OBJECTIVE: This study reviews the effect of immune status on disease characteristics and treatment outcomes. METHODS: Patients with cutaneous squamous cell carcinoma of the head and neck treated with surgery and postoperative radiotherapy between 2000 and 2011 were included. Immunosuppressed patients underwent prior organ transplantation or chemotherapy. Baseline variables were compared using chi(2) and unpaired t tests. Overall survival and disease-free survival were calculated using the Kaplan-Meier method. RESULTS: In this study of 59 patients, 38 (64%) were immunocompetent and 21 (36%) were immunosuppressed. Most patients had recurrent tumors (63%) and node-positive disease (61%), which were well balanced between the groups. Poorly differentiated tumors (62% vs 21%; P = .009), lymphovascular invasion (29% vs 11%; P = .08), and extracapsular extension (57% vs 41%; P = .09) were more frequent in the immunosuppressed group. Two-year disease-free survival (45% vs 62%) and 2-year overall survival (36% vs 67%) were inferior for immunosuppressed patients. LIMITATIONS: Limitations include single institution, retrospective study with small sample size, and potential referral bias. CONCLUSIONS: Immunosuppressed patients with cutaneous squamous cell carcinoma of the head and neck more frequently present with high-risk pathologic features and inferior outcomes. Early multidisciplinary assessment and alternate management strategies merit prospective investigation. PMID- 26028526 TI - Attentional and sensory contributions to postural sway in children with autism spectrum disorder. AB - Postural control is known to depend on sensory and cognitive factors. Little is known about how children with autism spectrum disorder (ASD) regulate static balance, and to what extent vision and cognition contribute to the regulation of balance in this group. We compared a group of children with mild ASD and a group of age- and gender-matched controls on various postural tasks, standing on a Wii Balance Board. We tested a sensory disturbance (closing the eyes) and a cognitive disturbance (word memorization) on the control of quiet standing. Analysis of center-of-pressure excursions revealed moderate effects of cognitive load, but clear effects of vision. We found a greater destabilizing effect of closing the eyes (greater postural excursions in the medio-lateral direction) for the ASD group than for controls. No group differences were found on word recall and on a standardized balance test (Movement Assessment Battery for Children; M-ABC2). We suggest that the postural effects reflect tighter coupling between vision and motor adjustments in ASD than in controls, which is consistent with recent suggestions of greater reliance on vision in this group. PMID- 26028527 TI - Effects of temporal constraints on medio-lateral stability when negotiating obstacles. AB - If an obstacle suddenly appears during walking, either the crossing step can be lengthened or the precrossing step shortened to avoid the obstacle. We investigated the effects of temporal constraints on dynamic stability during step adjustments. Twelve healthy young adults avoided a virtual white planar obstacle by lengthening or shortening their steps under free or constrained conditions. When constrained, participants had only one step to avoid the obstacle. The results indicated that center of mass (COM) displacement in the mediolateral (ML) direction and the COM velocity toward the swing-leg side during the crossing step were significantly increased in the long-constraint compared with the long-free condition. Consequently, the extrapolated COM (XcoM) position at the swing foot contact was also located further toward the swing-leg side. However, the distances between the XcoM and base of support (BOS) at the swing foot contact in the ML direction was unchanged because of greater lateral foot placement. In the anteriorposterior (AP) direction, temporal constraints led to greater AP COM displacement. The XcoM-BOS distance in the AP direction was unchanged in the long constraint condition because of greater step length. However, the value became negative in the short-constraint condition, violating the conditions for dynamic stability, because step length adjustments were obstructed by the spatial constraints of the obstacles. These results suggest that temporal constraints affect postural stability in the AP and ML directions during step adjustments. AP and ML stability at swing foot contact are maintained through adjustments of step length and lateral foot placement, respectively. PMID- 26028528 TI - Bmi-1 Regulates Extensive Erythroid Self-Renewal. AB - Red blood cells (RBCs), responsible for oxygen delivery and carbon dioxide exchange, are essential for our well-being. Alternative RBC sources are needed to meet the increased demand for RBC transfusions projected to occur as our population ages. We previously have discovered that erythroblasts derived from the early mouse embryo can self-renew extensively ex vivo for many months. To better understand the mechanisms regulating extensive erythroid self-renewal, global gene expression data sets from self-renewing and differentiating erythroblasts were analyzed and revealed the differential expression of Bmi-1. Bmi-1 overexpression conferred extensive self-renewal capacity upon adult bone marrow-derived self-renewing erythroblasts, which normally have limited proliferative potential. Importantly, Bmi-1 transduction did not interfere with the ability of extensively self-renewing erythroblasts (ESREs) to terminally mature either in vitro or in vivo. Bmi-1-induced ESREs can serve to generate in vitro models of erythroid-intrinsic disorders and ultimately may serve as a source of cultured RBCs for transfusion therapy. PMID- 26028529 TI - Human Germline: A New Research Frontier. AB - We recently elucidated the mechanism of human primordial germ cell (hPGC) specification and resetting of the epigenome for totipotency. The regulators of hPGC specification also initiate resetting of the epigenome, leading to a comprehensive erasure of DNA methylation, erasure of imprints and X reactivation in early hPGCs in vivo. These studies reveal differences with the mouse model, which are probably due to differences in the regulation of human pluripotency, and in postimplantation development at gastrulation, which indicates the importance of non-rodent models for investigations. Within the extreme hypomethylated environment of the early human germline are loci that are resistant to DNA demethylation, with subsequent predominant expression in neural cells. These loci provide a model for studies on the mechanism of transgenerational epigenetic inheritance, and their response to environmental factors. Such epigenetic mechanism of inheritance could potentially provide greater phenotypic plasticity, with significant consequences for human development and disease. PMID- 26028530 TI - Expression of alpha-Smooth Muscle Actin Determines the Fate of Mesenchymal Stromal Cells. AB - Pro-fibrotic microenvironments of scars and tumors characterized by increased stiffness stimulate mesenchymal stromal cells (MSCs) to express alpha-smooth muscle actin (alpha-SMA). We investigated whether incorporation of alpha-SMA into contractile stress fibers regulates human MSC fate. Sorted alpha-SMA-positive MSCs exhibited high contractile activity, low clonogenicity, and differentiation potential limited to osteogenesis. Knockdown of alpha-SMA was sufficient to restore clonogenicity and adipogenesis in MSCs. Conversely, alpha-SMA overexpression induced YAP translocation to the nucleus and reduced the high clonogenicity and adipogenic potential of alpha-SMA-negative MSCs. Inhibition of YAP rescued the decreased adipogenic differentiation potential induced by alpha SMA, establishing a mechanistic link between matrix stiffness, alpha-SMA, YAP, and MSC differentiation. Consistent with in vitro findings, nuclear localization of YAP was positively correlated in alpha-SMA expressing stromal cells of adiposarcoma and osteosarcoma. We propose that alpha-SMA mediated contraction plays a critical role in mechanically regulating MSC fate by controlling YAP/TAZ activation. PMID- 26028531 TI - A CRISPR/Cas-Mediated Selection-free Knockin Strategy in Human Embryonic Stem Cells. AB - The development of new gene-editing tools, in particular the CRISPR/Cas system, has greatly facilitated site-specific mutagenesis in human embryonic stem cells (hESCs), including the introduction or correction of patient-specific mutations for disease modeling. However, integration of a reporter gene into an endogenous locus in hESCs still requires a lengthy and laborious two-step strategy that involves first drug selection to identify correctly targeted clones and then excision of the drug-resistance cassette. Through the use of iCRISPR, an efficient gene-editing platform we recently developed, this study demonstrates a knockin strategy without drug selection for both active and silent genes in hESCs. Lineage-specific hESC reporter lines are useful for real-time monitoring of cell-fate decisions and lineage tracing, as well as enrichment of specific cell populations during hESC differentiation. Thus, this selection-free knockin strategy is expected to greatly facilitate the use of hESCs for developmental studies, disease modeling, and cell-replacement therapy. PMID- 26028532 TI - KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas. AB - Differentiated derivatives of human pluripotent stem cells in culture are generally phenotypically immature compared to their adult counterparts. Their identity is often difficult to determine with certainty because little is known about their human fetal equivalents in vivo. Cellular identity and signaling pathways directing differentiation are usually determined by extrapolating information from either human adult tissue or model organisms, assuming conservation with humans. To resolve this, we generated a collection of human fetal transcriptional profiles at different developmental stages. Moreover, we developed an algorithm, KeyGenes, which uses this dataset to quantify the extent to which next-generation sequencing or microarray data resemble specific cell or tissue types in the human fetus. Using KeyGenes combined with the human fetal atlas, we identified multiple cell and tissue samples unambiguously on a limited set of features. We thus provide a flexible and expandable platform to monitor and evaluate the efficiency of differentiation in vitro. PMID- 26028533 TI - Efficient Generation of Cardiac Purkinje Cells from ESCs by Activating cAMP Signaling. AB - Dysfunction of the specialized cardiac conduction system (CCS) is associated with life-threatening arrhythmias. Strategies to derive CCS cells, including rare Purkinje cells (PCs), would facilitate models for mechanistic studies and drug discovery and also provide new cellular materials for regenerative therapies. A high-throughput chemical screen using CCS:lacz and Contactin2:egfp (Cntn2:egfp) reporter embryonic stem cell (ESC) lines was used to discover a small molecule, sodium nitroprusside (SN), that efficiently promotes the generation of cardiac cells that express gene profiles and generate action potentials of PC-like cells. Imaging and mechanistic studies suggest that SN promotes the generation of PCs from cardiac progenitors initially expressing cardiac myosin heavy chain and that it does so by activating cyclic AMP signaling. These findings provide a strategy to derive scalable PCs, along with insight into the ontogeny of CCS development. PMID- 26028534 TI - The Dynamic Duo: Niche/Stem Cell Interdependency. AB - Most tissues in our bodies undergo constant cellular turnover. This process requires a dynamic balance between cell production and elimination. Stem cells have been shown in many of these tissues to be the major source of new cells. However, despite the tremendous advances made, it still remains unclear how stem cell behavior and activity are regulated in vivo. Furthermore, we lack basic understanding for the mechanisms that coordinate niche/stem cell interactions to maintain normal tissue homeostasis. Our lab has established a novel imaging approach in live mice using the skin as a model system to investigate these fundamental processes in both physiological and pathological settings such as cancer, with the goal of understanding how tissues successfully orchestrate tissue regeneration throughout the lifetime of an organism. PMID- 26028535 TI - Remote p-type Doping in GaSb/InAs Core-shell Nanowires. AB - By performing first-principles calculation, we investigated the electronic properties of remotely p-type doping GaSb nanowire by a Zn-doped InAs shell. The results show that for bare zinc-blende (ZB) [111] GaSb/InAs core-shell nanowire the Zn p-type doped InAs shell donates free holes to the non-doped GaSb core nanowire without activation energy, significantly increasing the hole density and mobility of nanowire. For Zn doping in bare ZB [110] GaSb/InAs core-shell nanowire the hole states are compensated by surface states. We also studied the behaviors of remote p-type doing in two-dimensional (2D) GaSb/InAs heterogeneous slabs, and confirmed that the orientation of nanowire side facet is a key factor for achieving high efficient remote p-type doping. PMID- 26028536 TI - Oxidative Modification of miR-184 Enables It to Target Bcl-xL and Bcl-w. AB - MicroRNAs (miRNAs) are small non-coding RNAs, and they bind to complementary sequences in the three prime untranslated regions (3' UTRs) of target mRNA transcripts, thereby inhibiting mRNA translation or promoting mRNA degradation. Excessive reactive oxygen species (ROS) can cause cell-damaging effects through oxidative modification of macromolecules leading to their inappropriate functions. Such oxidative modification is related to cancers, aging, and neurodegenerative and cardiovascular diseases. Here we report that miRNAs can be oxidatively modified by ROS. We identified that miR-184 upon oxidative modification associates with the 3' UTRs of Bcl-xL and Bcl-w that are not its native targets. The mismatch of oxidized miR-184 with Bcl-xL and Bcl-w is involved in the initiation of apoptosis in the study with rat heart cell line H9c2 and mouse models. Our results reveal a model of ROS in regulating cellular events by oxidatively modifying miRNA. PMID- 26028537 TI - Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2. AB - Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression. PMID- 26028538 TI - Distinct tRNA Accommodation Intermediates Observed on the Ribosome with the Antibiotics Hygromycin A and A201A. AB - The increase in multi-drug-resistant bacteria is limiting the effectiveness of currently approved antibiotics, leading to a renewed interest in antibiotics with distinct chemical scaffolds. We have solved the structures of the Thermus thermophilus 70S ribosome with A-, P-, and E-site tRNAs bound and in complex with either the aminocyclitol-containing antibiotic hygromycin A (HygA) or the nucleoside antibiotic A201A. Both antibiotics bind at the peptidyl transferase center and sterically occlude the CCA-end of the A-tRNA from entering the A site of the peptidyl transferase center. Single-molecule Forster resonance energy transfer (smFRET) experiments reveal that HygA and A201A specifically interfere with full accommodation of the A-tRNA, leading to the presence of tRNA accommodation intermediates and thereby inhibiting peptide bond formation. Thus, our results provide not only insight into the mechanism of action of HygA and A201A, but also into the fundamental process of tRNA accommodation during protein synthesis. PMID- 26028539 TI - A Conserved Structural Chassis for Mounting Versatile CRISPR RNA-Guided Immune Responses. AB - Bacteria and archaea rely on CRISPR (clustered regularly interspaced short palindromic repeats) RNA-guided adaptive immune systems for targeted elimination of foreign nucleic acids. These immune systems have been divided into three main types, and the first atomic-resolution structure of a type III RNA-guided immune complex provides new insights into the mechanisms of nucleic acid degradation. Here we compare the crystal structure of a type III complex to recently determined structures of DNA-targeting type I CRISPR complexes. Structural comparisons support previous assertions that type I and type III systems share a common ancestor and reveal how a conserved structural chassis is used to support RNA-, DNA-, or both RNA- and DNA-targeting mechanisms. PMID- 26028540 TI - Bidirectional Transcription Arises from Two Distinct Hubs of Transcription Factor Binding and Active Chromatin. AB - Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNA genes. We find that coupled sense and anti sense TSSs precisely define the boundaries of a nucleosome-depleted region (NDR) that is highly enriched in transcription factor (TF) motifs. Notably, as the distance between sense and anti-sense TSSs increases, so does the size of the NDR, the level of signal-dependent TF binding, and gene activation. We further discover a group of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Interestingly, this signature identifies divergent promoters that are activated during immune challenge. We propose that anti-sense promoters serve as platforms for TF binding and establishment of active chromatin to further regulate or enhance sense-strand mRNA expression. PMID- 26028541 TI - Wendler glottoplasty and voice-therapy in male-to-female transsexuals: results in pre and post-surgery assessment. AB - INTRODUCTION: With the development of new ENT techniques, many male transsexuals who wish to become women usually request a surgical procedure to raise the fundamental frequency of the voice (feminization). The ENT specialist and the voice-therapist have to use an interdisciplinary approach to this growing social demand. The aim of this study was to show the results in a group of transsexual patients after Wendler's anterior synechiae, with additional voice-therapy treatment. METHODS: Ten male transexulas who wish to become women patients who had Wendler glottoplasty and voice-therapy were assessed. The surgical procedure consisted of a de-epithelialization of the anterior third of both vocal folds; this area was sutured and the surface of both vocal folds was vaporised with laser diode. Pre- and postsurgery voice assessment consisted of measuring fundamental frequency (Fo) and maximum phonation time, administering the transgender self-assessment questionnaire (TSEQ) and obtaining perceptual voice assessment by inter-rater agreement. RESULTS: All the male transsexuals who wish to become women patients significantly increased their Fo (106 Hz on average) after the treatment. Furthermore, significant improvements were shown in self reported satisfaction and in the degree of voice feminization. No improvements in the maximum phonation time were observed. CONCLUSIONS: Wendler glottoplasty is a surgical procedure to contribute to feminising the voice, with good medium-term results and without noteworthy medical complications. The increase in vocal tone was observed using several pre- and post-surgery control measures and voice therapy. PMID- 26028542 TI - Modified type IV thyroplasty (cricothyroid approximation) in a patient with androphonia. PMID- 26028544 TI - Proaporphine and aporphine alkaloids with acetylcholinesterase inhibitory activity from Stephania epigaea. AB - An unusual proaporphine alkaloid bearing an isopropanenitrile group at isoquinoline nitrogen, named epiganine A (1) and a new aporphine alkaloid, epiganine B (2), together with eight known alkaloids, pronuciferine (3), dehydrodicentrine (4), romerine (5), romeline (6), N-methylcalycinine (7), phanostenine (8), dicentrine (9), and N-methyllaurotetanine (10), were isolated from the roots of Stephania epigaea. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD) and comparing with experimental data. Compounds 2 and 4 showed strong acetylcholinesterase (AChE) inhibitory effects with the IC50 values of 4.36 and 2.98MUM, respectively. Compounds 5-9 also exhibited potent AChE inhibitory activities. PMID- 26028545 TI - COMT genotype, gambling activity, and cognition. AB - Neuropsychological studies of adults with problem gambling indicate impairments across multiple cognitive domains. Catechol-O-methyltransferase (COMT) plays a unique role in the regulation of dopamine in the prefrontal cortex, and has been implicated in the cognitive dysfunction evident in problem gambling. This study examined adults with varying levels of gambling behavior to determine whether COMT genotype was associated with differences in gambling symptoms and cognitive functioning. 260 non-treatment-seeking adults aged 18-29 years with varying degrees of gambling behavior provided saliva samples for genotyping COMT val158met (rs4680). All subjects underwent clinical evaluations and neurocognitive assessment of decision-making, working memory, and impulsivity. The Val/Val COMT genotype was associated with the largest percentage of subjects with gambling disorder (31.8%), a rate significantly different from the Val/Met (13.2%) group (p = 0.001). The Val/Val COMT group was also associated with significantly more gambling disorder diagnostic criteria being met, greater frequency of gambling behavior, and significantly worse cognitive performance on the Cambridge Gamble Task (risk adjustment and delay aversion) and the Spatial Working Memory task (total errors). This study adds to the growing literature on the role of COMT in impulsive behaviors by showing that the Val/Val genotype was associated with specific clinical and cognitive elements among young adults who gamble, in the absence of differences on demographic measures and other cognitive domains. Future work should consider using genotyping to explore whether certain polymorphisms predict subsequent development of impulsive behaviors including gambling disorder, and treatment outcomes. PMID- 26028543 TI - Early programing of uterine tissue by bisphenol A: Critical evaluation of evidence from animal exposure studies. AB - Exposure to Bisphenol A (BPA) during the critical window of uterine development has been proposed to program the uterus for increased disease susceptibility based on well-documented effects of the potent xenoestrogen diethylstilbestrol. To investigate this proposal, we reviewed 37 studies of prenatal and/or perinatal BPA exposure in animal models and evaluated evidence for: molecular signatures of early BPA exposure; the development of adverse uterine health effects; and epigenetic changes linked to long-term dysregulation of uterine gene expression and health effects. We found substantial evidence for adult uterine effects of early BPA exposure. In contrast, experimental support for epigenetic actions of early BPA exposure is very limited, and largely consists of effects on Hoxa gene DNA methylation. Critical knowledge gaps were identified, including the need to fully characterize short-term and long-term uterine gene responses, interactions with estrogens and other endogenous hormones, and any long-lasting epigenetic signatures that impact adult disease. PMID- 26028546 TI - Predicting placebo response in adolescents with major depressive disorder: The Adolescent Placebo Impact Composite Score (APICS). AB - OBJECTIVE: The aim of this study was to construct a composite scoring system to predict the probability of placebo response in adolescents with Major Depressive Disorder (MDD). METHOD: Participants of the current study were 151 adolescents (aged 12-17 years) who were randomized to the placebo arm (placebo transdermal patches) of a randomized controlled trial (RCT) comparing the selegiline transdermal patch with placebo (DelBello et al., 2014). The primary outcome of response was defined as a CGI-I score of 1 or 2 (very much or much improved) at week 12 (study-end) or exit. As a first step, a multiple logistic mixed model was used to estimate the odds of placebo response from each predictor in the model, including age, CDRS-R total at baseline (depressive symptom severity), history of recurrent depression (yes vs. no), sex (female vs. male), and race (non-Caucasian vs. Caucasian). On the basis of the initial logistic mixed model analysis, we then constructed an Adolescent Placebo Impact Composite Score (APICS) that became the sole predictor in a re-specified Bayesian logistic regression model to estimate the probability of placebo response. Finally, the AUC for the APICS was tested against a nominal area of 0.50 to evaluate how well the APICS discriminated placebo response status. RESULTS: Among the 151 adolescents, with a mean age of 14.6 years (SD = 1.6) and a mean baseline CDRS-R total of 60.6 (SD = 12.1), 68.2% were females, 50.3% was Caucasian, and 39.7% had a history of recurrent depression. Placebo response rate was 58.3%. Based on the logistic mixed model, the re-specified equation with the highest discriminatory ability to estimate the probability of placebo response was APICS = age + (0.32 * CDRS-R Total at baseline) + (-2.85 * if female) + (-5.50 * if history of recurrent depression) + (-5.85 * if non-Caucasian). The AUC for this model was 0.59 (p = .049). Within a Bayesian decision-theoretic framework, in 95.5% of the time, the 10,000 posterior Monte Carlo samples suggested that as APICS decreased the probability of placebo response increased. The observed APICS and related probability of responding to placebo in this adolescent sample ranged from 14.1 = 74.1% (in placebo responders) to 39.1 = 41.8% (in placebo non-responders). CONCLUSION: The APICS model estimates the probability of placebo response in adolescents with MDD with a modest degree of accuracy (AUC = 0.59) and with a reasonable degree of positive predictive value (74.5%), and is based on five previously identified patient characteristics of placebo response from prior meta analytic studies (Bridge et al., 2009; Cohen et al., 2010) of randomized placebo controlled trials of antidepressants in youth with MDD. Calculation of the APICS should be restricted to the range of the adolescent ages (12-17 years) and CDRS-R total scores (17-113); thus, the APICS can assume possible calculated values and related probability of responding to placebo ranging from about 3 (84%) to 53 (25%). The APICS Bayesian logistic model, based on a given aggregate patient profile, has a range of predicted probabilities of placebo response that is fairly wide, albeit truncated, but potentially meaningful for predicting the probability of placebo response among adolescent youth with MDD. The ability of the APICS to objectify the probability of placebo response in adolescents with MDD could be accounted for in the clinical research design of the trial itself and perhaps aid clinicians in treatment strategy for youth who are more likely to experience placebo response. PMID- 26028547 TI - Obsessive-compulsive disorder--A question of conscience? An fMRI study of behavioural and neurofunctional correlates of shame and guilt. AB - Shame and guilt can be described as 'self-conscious emotions' and are an essential part of the psychopathology in obsessive-compulsive disorder (OCD). Our primary aim was to explore whether individuals with OCD are processing shame and guilt differently from healthy individuals (N = 20 in both groups; 50% female; age: 20-40 years) on the behavioural and neurobiological level. For the experimental task, participants were scanned with functional magnetic resonance tomography (functional magnetic resonance imaging, 3 T) while imagining neutral, shame inducing and guilt inducing scenarios. In addition to clinical questionnaires, participants were asked to complete questionnaires measuring shame and guilt. The functional data indicate an increased activity in OCD patients in the shame condition in the limbic, temporal and sub-lobar (hypothalamus) areas, in the guilt condition inter alia in frontal, limbic and temporal areas. In summary we found activity in OCD patients in neural networks which are responsible for stimulus filtering, emotion regulation, impulse control and memory. The results from our study may contribute to a better understanding of the origins and maintenance of OCD in association with the pathological processing of shame and guilt on different functional levels. PMID- 26028549 TI - Psychiatric disturbances in radiologically isolated syndrome. AB - BACKGROUND: Radiologically isolated syndrome (RIS) is characterized by incidental lesions suggestive of multiple sclerosis (MS) on MRI without typical symptoms of MS. Clinically isolated syndrome (CIS) is characterized by a first episode of neurologic symptoms caused by demyelination in the central nervous system. To date, psychiatric disorders have not been systematically addressed in RIS subjects. We assessed emotional disturbances, personality features and health related quality of life (HRQoL) in a cohort of RIS patients as compared with clinically isolated syndrome (CIS). METHODS: Twenty-eight RIS patients, 25 clinically isolated syndrome (CIS) patients, and 22 healthy subjects were enrolled in the study. Participants were administered a mood scale (Hamilton Depression Rating Scale), behavioural measures (Personality Assessment Inventory), and fatigue measures (Fatigue Impact Scale for Daily Use). HRQoL was quantified using the EuroQol-5. RESULTS: 14 (50%) of RIS patients had clinically significant depression, with over one-third of these having moderate depression, scores virtually identical to those observed in CIS patients. 11 of 28 (39.3%) subjects with RIS had anxious depression, a figure three times higher than that found in CIS patients. RIS patients' HAMD-17 total score showed a very strong correlation with severity of fatigue. In addition, RIS patients reported lower HRQoL (p = 0.036) and a significantly higher symptoms load for somatisation compared to both CIS and control groups (p < 0.002). CONCLUSION: RIS patients had high rates of depression, particularly anxious depression and somatization. Future studies are warranted to clarify whether these psychiatric disturbances are causally associated with a distinct white matter psychopathologic process. PMID- 26028550 TI - Metabolic decoupling in daily life in patients with panic disorder and agoraphobia. AB - Various studies have assessed autonomic and respiratory underpinnings of panic attacks, yet the psychophysiological functioning of panic disorder (PD) patients has rarely been examined under naturalistic conditions at times when acute attacks were not reported. We hypothesized that emotional activation in daily life causes physiologically demonstrable deviations from efficient metabolic regulation in PD patients. Metabolic coupling was estimated as within-individual correlations between heart rate (HR) and indices of metabolic activity, i.e., physical activity (measured by 3-axial accelerometry, Acc), and minute ventilation (Vm, measured by calibrated inductive plethysmography, as proxy for oxygen consumption). A total of 565 daytime hours were recorded in 19 PD patients and 20 healthy controls (HC). Pairwise cross-correlations of minute-by-minute averages of these metabolic indices were calculated for each participant and then correlated with several indices of self-reported anxiety. Ambulatory HR was elevated in PD (p = .05, d = 0.67). Patients showed reduced HR-Acc (p < .006, d = 0.97) and HR-Vm coupling (p < .009, d = 0.91). Combining Vm and Acc to predict HR showed the strongest group separation (p < .002, d = 1.07). Discriminant analyses, based on the combination of Vm and Acc to predict HR, classified 77% of all participants correctly. In PD, HR-Acc coupling was inversely related to trait anxiety sensitivity, as well as tonic and phasic daytime anxiety. The novel method that was used demonstrates that anxiety in PD may reduce efficient long term metabolic coupling. Metabolic decoupling may serve as physiological characteristic of PD and might aid diagnostics for PD and other anxiety disorders. This measure deserves further study in research on health consequences of anxiety and psychosocial stress. PMID- 26028548 TI - Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. AB - Treatment-resistant depression affects up to 20% of individuals suffering from major depressive disorder (MDD). The medications currently available to treat depression, including serotonin re-uptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), fail to produce adequate remission of depressive symptoms for a large number of patients. The monoamine hypothesis upon which these medications are predicated should be expanded and revised as research elucidates alternative mechanisms of depression and effective methods to treat the underlying pathologic consequences. Research into the role of tryptophan degradation and the kynurenine pathway in the setting of inflammation has brought new insight into potential etiologies of MDD. Further investigation into the connection between inflammatory mediators, tryptophan degradation, and MDD can provide many targets for novel antidepressant therapies. Thus, this review will highlight the role of the kynurenine pathway in the pathophysiology of depression, as well as a novel therapeutic target to classic and new modulators to treat depression based on findings from preclinical and clinical studies. PMID- 26028551 TI - Can computer-assisted cognitive remediation improve employment and productivity outcomes of patients with severe mental illness? A meta-analysis of prospective controlled trials. AB - BACKGROUND: Computer-assisted cognitive remediation (CACR) has been demonstrated to enhance cognition of patients with severe mental illness (SMI). Patients with improved cognitive skills may find it easier to be employed, and the ability to maintain employment is an important sign of recovery. AIM: To assess whether CACR is an effective method to enhance work-related outcomes in patients with SMI. METHOD: Prospective controlled trials evaluating CACR on productivity outcomes were systematically identified from the OVID databases. Employment rates, total days of work in a year, and total annual earnings were defined as the productivity outcomes. RESULTS: Nine trials were published between 2005 and 2014 and were conducted in the United States, Germany, Italy, Singapore and Japan. A total of 740 patients with mean age of 36.4 years were included. The duration of CACR ranged from 2 months to 2 years, and the patients were followed-up from 1 year to 3 years. Patients receiving CACR showed 20% higher employment rate (95% CI = 5%-35%), worked 19.5 days longer in a year (95% CI = 2.5-36.6 days), and earned US$959 more in total annual earnings (95% CI = US$285 to US$1634) than those not receiving CACR. CONCLUSION: CACR can enhance productivity outcomes for patients with SMI, including higher employment rate, longer duration of work and higher income. The economic benefit of CACR can enhance the quality of life for patients with SMI, and may reduce financial burden on the health and welfare system. Therefore, CACR can be recommended and incorporated into regular vocational rehabilitation programs. PMID- 26028552 TI - Novel frontiers in calcium signaling: A possible target for chemotherapy. AB - Intracellular calcium (Ca(2+)) is largely known as a second messenger that is able to drive effects ranging from vesicle formation to muscle contraction, energy production and much more. In spite of its physiological regulation, Ca(2+) is a strategic tool for regulating apoptosis, especially during transmission between the endoplasmic reticulum and the mitochondria. Contact sites between these organelles are well-defined as signaling platforms where oncogenes and oncosuppressors can exert anti/pro-apoptotic activities. Recent advances from in vivo investigations into these regions highlight the role of the master oncosuppressor p53 in regulating Ca(2+) transmission and apoptosis, and we propose that Ca(2+) signals are relevant targets when developing new therapeutic approaches. PMID- 26028553 TI - Express penetration of hydrogen on Mg(10?13) along the close-packed-planes. AB - Metal atoms often locate in energetically favorite close-packed planes, leading to a relatively high penetration barrier for other atoms. Naturally, the penetration would be much easier through non-close-packed planes, i.e. high-index planes. Hydrogen penetration from surface to the bulk (or reversely) across the packed planes is the key step for hydrogen diffusion, thus influences significantly hydrogen sorption behaviors. In this paper, we report a successful synthesis of Mg films in preferential orientations with both close- and non-close packed planes, i.e. (0001) and a mix of (0001) and (10?13), by controlling the magnetron sputtering conditions. Experimental investigations confirmed a remarkable decrease in the hydrogen absorption temperature in the Mg (10?13), down to 392 K from 592 K of the Mg film (0001), determined by the pressure composition-isothermal (PCI) measurement. The ab initio calculations reveal that non-close-packed Mg(10?13) slab is advantageous for hydrogen sorption, attributing to the tilted close-packed-planes in the Mg(10?13) slab. PMID- 26028555 TI - Thyroid disorders during pregnancy and postpartum. AB - An awareness of the gestational changes to thyroid physiology and the impact of uncontrolled thyroid disease on pregnancy and infant outcome is essential for the successful management of hypothyroidism and hyperthyroidism. This review summarizes strategies for the management of thyroid disease in pregnancy and post partum, and it highlights areas where there is still a lack of consensus. PMID- 26028554 TI - SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. AB - Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders. PMID- 26028556 TI - A normative dataset on human global stereopsis using the quick Disparity Sensitivity Function (qDSF). AB - Global stereopsis results from the lateral displacement of distributed textured elements between the eyes. In this study, we investigate how the key parameters of the disparity sensitivity function such as its peak sensitivity and spatial bandwidth are distributed across a pool of normal observers and how large the individual differences are. For this purpose, we adapted the quick Contrast Sensitivity Function (qCSF, Lesmes et al., 2010) to the quick Disparity Sensitivity Function (qDSF). We show that this new method is accurate and allows a rapid measurement of disparity sensitivity for a range of different disparity spatial frequencies. Our results confirm that there is a greater variability in human disparity sensitivity tuning compared to other common visual features, for example, 1st or 2nd order contrast sensitivity. PMID- 26028557 TI - Partial oxidation of landfill leachate in supercritical water: Optimization by response surface methodology. AB - To achieve the maximum H2 yield (GYH2), TOC removal rate (TRE) and carbon recovery rate (CR), response surface methodology was applied to optimize the process parameters for supercritical water partial oxidation (SWPO) of landfill leachate in a batch reactor. Quadratic polynomial models for GYH2, CR and TRE were established with Box-Behnken design. GYH2, CR and TRE reached up to 14.32mmol.gTOC(-1), 82.54% and 94.56% under optimum conditions, respectively. TRE was invariably above 91.87%. In contrast, TC removal rate (TR) only changed from 8.76% to 32.98%. Furthermore, carbonate and bicarbonate were the most abundant carbonaceous substances in product, whereas CO2 and H2 were the most abundant gaseous products. As a product of nitrogen-containing organics, NH3 has an important effect on gas composition. The carbon balance cannot be reached duo to the formation of tar and char. CR increased with the increase of temperature and oxidation coefficient. PMID- 26028558 TI - Reuse of process water in a waste-to-energy plant: An Italian case of study. AB - The minimisation of water consumption in waste-to-energy (WtE) plants is an outstanding issue, especially in those regions where water supply is critical and withdrawals come from municipal waterworks. Among the various possible solutions, the most general, simple and effective one is the reuse of process water. This paper discusses the effectiveness of two different reuse options in an Italian WtE plant, starting from the analytical characterisation and the flow-rate measurement of fresh water and process water flows derived from each utility internal to the WtE plant (e.g. cooling, bottom ash quenching, flue gas wet scrubbing). This census allowed identifying the possible direct connections that optimise the reuse scheme, avoiding additional water treatments. The effluent of the physical-chemical wastewater treatment plant (WWTP), located in the WtE plant, was considered not adequate to be directly reused because of the possible deposition of mineral salts and clogging potential associated to residual suspended solids. Nevertheless, to obtain high reduction in water consumption, reverse osmosis should be installed to remove non-metallic ions (Cl(-), SO4(2-)) and residual organic and inorganic pollutants. Two efficient solutions were identified. The first, a simple reuse scheme based on a cascade configuration, allowed 45% reduction in water consumption (from 1.81 to 0.99m(3)tMSW(-1), MSW: Municipal Solid Waste) without specific water treatments. The second solution, a cascade configuration with a recycle based on a reverse osmosis process, allowed 74% reduction in water consumption (from 1.81 to 0.46m(3)tMSW(-1)). The results of the present work show that it is possible to reduce the water consumption, and in turn the wastewater production, reducing at the same time the operating cost of the WtE plant. PMID- 26028559 TI - Functional enrichment analysis of three Alzheimer's disease genome-wide association studies identities DAB1 as a novel candidate liability/protective gene. AB - To explore genetic contributions of Alzheimer's disease (AD) at the level of biological terms and pathways, we analyzed three Caucasian population-based genome-wide association study datasets (TGEN_ND, GeneADA and NIA_LOAD) using the Database for Annotation, Visualization and Integrated Discovery (DAVID). This analysis identified 4 annotation terms ("Fibronectin type III-like fold," "Cell adhesion," "Cell motion" and "Ig-like-C2-type 3") and 17 genes that associated with AD susceptibility in two or more of the GWAS datasets. Ten of these genes, have previously been identified as candidate AD liability genes in genetic association studies (AGT, COL11A1) or encode proteins that function in biological systems or pathways previously implicated in AD (BARHL2, CSF3R, DAB1, HMCN1, LEPR, PTPRF, PXDN, TNR). Among these, DAB1 (Dab, reelin signal transducer, homolog 1) was of particular interest, since it encodes a protein that functions downstream from reelin, a signaling pathway previously identified as protective in AD. Multiple linear regression analysis of correlations between brain DAB1 mRNA expression and SNP genotype using data from the "BrainCloud" database identified five SNPs within the DAB1 locus that correlated with mRNA expression in human dorsolateral prefrontal cortex. Analysis of predicted levels of DAB1 mRNA expression based on genotype combinations present in AD cases and controls vs. the log10-transformed odds ratios for AD diagnosis, revealed statistically significant correlations in one of the GWAS datasets (GenADA), with high DAB1 mRNA expression correlating with AD protection. Multidimensional scaling (MDS) analysis of cases and controls in the three GWAS, revealed genetic differences between GenADA and TGEN_ND/NIA_LOAD, which were similar to each other. To our knowledge, this study is the first to provide genetic evidence for DAB1 as a candidate AD liability/protection gene, although the strength of the contribution of DAB1 may differ among populations. PMID- 26028560 TI - HSP27 phosphorylation protects against endothelial barrier dysfunction under burn serum challenge. AB - F-actin rearrangement is an early event in burn-induced endothelial barrier dysfunction. HSP27, a target of p38 MAPK/MK2 pathway, plays an important role in actin dynamics through phosphorylation. The question of whether HSP27 participates in burn-related endothelial barrier dysfunction has not been identified yet. Here, we showed that burn serum induced a temporal appearance of central F-actin stress fibers followed by a formation of irregular dense peripheral F-actin in pulmonary endothelial monolayer, concomitant with a transient increase of HSP27 phosphorylation that conflicted with the persistent activation of p38 MAPK/MK2 unexpectedly. The appearance of F-actin stress fibers and transient increase of HSP27 phosphorylation occurred prior to the burn serum induced endothelial hyperpermeability. Overexpressing phospho-mimicking HSP27 (HSP27(Asp)) reversed the burn serum-induced peripheral F-actin rearrangement with the augmentation of central F-actin stress fibers, and more importantly, attenuated the burn serum-induced endothelial hyperpermeability; such effects were not observed by HSP27(Ala), a non-phosphorylated mutant of HSP27. HSP27(Asp) overexpression also rendered the monolayer more resistant to barrier disruption caused by Cytochalasin D, a chemical reagent that depolymerizes F-actin specifically. Further study showed that phosphatases and sumoylation-inhibited MK2 activity contributed to the blunting of HSP27 phosphorylation during the burn serum-induced endothelial hyperpermeability. Our study identifies HSP27 phosphorylation as a protective response against burn serum-induced endothelial barrier dysfunction, and suggests that targeting HSP27 wound be a promising therapeutic strategy in ameliorating burn-induced lung edema and shock development. PMID- 26028561 TI - Novel chimeric peptide with enhanced cell specificity and anti-inflammatory activity. AB - An antimicrobial peptide (AMP), Hn-Mc, was designed by combining the N-terminus of HPA3NT3 and the C-terminus of melittin. This chimeric AMP exhibited potent antibacterial activity with low minimal inhibitory concentrations (MICs), ranging from 1 to 2 MUM against four drug-susceptible bacteria and ten drug-resistant bacteria. Moreover, the hemolysis and cytotoxicity was reduced significantly compared to those of the parent peptides, highlighting its high cell selectivity. The morphological changes in the giant unilamellar vesicles and bacterial cell surfaces caused by the Hn-Mc peptide suggested that it killed the microbial cells by damaging the membrane envelope. An in vivo study also demonstrated the antibacterial activity of the Hn-Mc peptide in a mouse model infected with drug resistant bacteria. In addition, the chimeric peptide inhibited the expression of lipopolysaccharide (LPS)-induced cytokines in RAW 264.7 cells by preventing the interaction between LPS and Toll-like receptors. These results suggest that this chimeric peptide is an antimicrobial and anti-inflammatory candidate as a pharmaceutic agent. PMID- 26028562 TI - Physiological characterization of the human EndoC-betaH1 beta-cell line. AB - In the new human EndoC-betaH1 beta-cell line, a detailed analysis of the physiological characteristics was performed. This new human beta-cell line expressed all target structures on the gene and protein level, which are crucial for physiological function and insulin secretion induced by glucose and other secretagogues. Glucose influx measurements revealed an excellent uptake capacity of EndoC-betaH1 beta-cells by the Glut1 and Glut2 glucose transporters. A high expression level of glucokinase enabled efficient glucose phosphorylation, increasing the ATP/ADP ratio along with stimulation of insulin secretion in the physiological glucose concentration range. The EC50 value of glucose for insulin secretion was 10.3 mM. Mannoheptulose, a specific glucokinase inhibitor, blocked glucose-induced insulin secretion (GSIS). The nutrient insulin secretagogues l leucine and 2-ketoisocaproate also stimulated insulin secretion, with a potentiating effect of l-glutamine. The Kir 6.2 potassium channel blocker glibenclamide and Bay K 8644, an opener of the voltage-sensitive Ca(2+) channel significantly potentiated GSIS. Potentiation of GSIS by IBMX and forskolin went along with a strong stimulation of cAMP generation. In conclusion, the new human EndoC-betaH1 beta-cell line fully mirrors the analogous physiological characteristics of primary mouse, rat and human beta-cells. Thus, this new human EndoC-betaH1 beta-cell line is very well suited for physiological beta-cell studies. PMID- 26028563 TI - Joint Contribution of Left Dorsal Premotor Cortex and Supramarginal Gyrus to Rapid Action Reprogramming. AB - BACKGROUND: The rapid adaptation of actions to changes in the environment is crucial for survival. We previously demonstrated a joint contribution of left dorsal premotor cortex (PMd) and left supramarginal gyrus (SMG) to action reprogramming. However, we did not probe the contribution of PMd to the speed and accuracy of action reprogramming and how the functional relevance of PMd changes in the presence of a dysfunctional SMG. OBJECTIVE: This study further dissociated the unique contribution of left PMd and SMG to action reprogramming. Specifically, we tested whether the critical contribution of PMd during action reprogramming depends on the functional integrity of SMG. METHODS: Adopting a condition-and-perturb repetitive transcranial magnetic stimulation (rTMS) approach, we first transiently conditioned left SMG with 1 Hz offline rTMS and then perturbed PMd activity with online rTMS whilst human subjects performed a spatially-precued reaction time task. RESULTS: Relative to sham rTMS, effective online perturbation of left PMd significantly impaired both the response speed and accuracy in trials that were invalidly pre-cued and required the subject to reprogram the prepared action. Moreover, the disruptive effect of rTMS over left PMd on response speed became stronger after SMG had been conditioned with offline rTMS. CONCLUSIONS: These results corroborate the notion that left PMd and SMG jointly contribute to rapid action reprogramming. Moreover, the strong virtual lesion effect observed with rTMS over PMd suggest that this area represents a key node for both the suppression of activation based on the precue and response activation based on the response target. PMID- 26028564 TI - 'I still don't know diddly': a longitudinal qualitative study of patients' knowledge and distress while undergoing evaluation of incidental pulmonary nodules. AB - BACKGROUND: Hundreds of thousands of incidental pulmonary nodules are detected annually in the United States, and this number will increase with the implementation of lung cancer screening. The lengthy period for active pulmonary nodule surveillance, often several years, is unique among cancer regimens. The psychosocial impact of longitudinal incidental nodule follow-up, however, has not been described. AIMS: We sought to evaluate the psychosocial impact of longitudinal follow-up of incidental nodule detection on patients. METHODS: Veterans who participated in our previous study had yearly follow-up qualitative interviews coinciding with repeat chest imaging. We used conventional content analysis to explore their knowledge of nodules and the follow-up plan, and their distress. RESULTS: Seventeen and six veterans completed the year one and year two interviews, respectively. Over time, most patients continued to have inadequate knowledge of pulmonary nodules and the nodule follow-up plan. They desired and appreciated more information directly from their primary care provider, particularly about their lung cancer risk. Distress diminished over time for most patients, but it increased around the time of follow-up imaging for some, and a small number reported severe distress. CONCLUSIONS: In settings in which pulmonary nodules are commonly detected, including lung cancer screening programmes, resources to optimise patient-centred communication strategies that improve patients' knowledge and reduce distress should be developed. PMID- 26028565 TI - [Surfactant replacement therapy with a minimally invasive technique: Experience in a tertiary hospital]. AB - INTRODUCTION: Surfactant delivered using a minimally invasive technique, known as MIST (Minimally Invasive Surfactant Therapy) is a method which allows surfactant to be administered to a patient connected to non-invasive respiratory support. This is an increasingly used therapy in Neonatal Units that reduces the intubation rate and the pathology associated with intubation and allows the surfactant to be administered to the patients who clinically need it. PATIENTS AND METHODS: In years 2013 and 2014 in the Hospital General Universitario de Elche surfactant was delivered using this method to 19 patients, five of whom were 28 or less weeks of gestation age at birth. A comparison is made with a historical cohort consisting of 28 patients with Respiratory Distress Syndrome treated initially with non-invasive respiratory support. RESULTS: No incidents were recorded that caused the interruption of the administration. A reduction in the fraction of inspired oxygen was observed in all cases after surfactant administration. Fewer intubations in the first 72 hours of life were found in the treatment group compared to the control group (42% vs. 54%). DISCUSSION: The experience recorded in the Hospital General Universitario de Elche shows that the administration of surfactant using a MIST technique is a reproducible method of treatment, which allows the surfactant distribution during spontaneous breathing with non invasive respiratory support. PMID- 26028566 TI - [Evaluation of the usefulness of a standard multivitamin supplement designed for patients with cystic fibrosis]. PMID- 26028567 TI - Measuring Acuity and Patient Progress for Youth With Special Health Care Needs in Transition Care Utilizing Nursing Outcomes. AB - Implementation of a nursing outcomes classification system (NOC) for youth with special health care needs (YSHCN) to support a transition care program may help describe the acuity and measure effectiveness of outcomes. Legislation mandates that care for YSHCN demonstrates effective coordination of care that is patient centered and age appropriate. Transition programs are recommended by leading authorities. In order to provide fair and equable care a universal rating process needs to be implemented to describe the patients' functional status and progress. NOC has the potential to measure patient acuity and outcomes for YSHCN that potentially may guide care needs. PMID- 26028568 TI - Association analysis of TPH-1 and TPH-2 genes with suicidal behavior in patients with attempted suicide in Mexican population. AB - BACKGROUND: Suicidal behavior is a worldwide health problem. Tryptophan hydroxylase (TPH) is a rate limiting enzyme in the biosynthesis of serotonergic neurotransmission. TPH-1 and TPH-2 genes encode for TPH isoforms and have been implicated as candidate genes for suicidal behavior. The aim of this study was to evaluate the association between the genetic variants of the TPH-1 (rs21102 and 1607395) and TPH-2 (rs4290270, rs7305115 and rs1007023) genes and suicidal behavior in a Mexican population. METHODS: We conducted a case-control study including 200 cases with suicide attempt and 263 controls. Patients were evaluated by a trained psychiatrist or clinical psychologists. Five polymorphisms were genotyped and assessed for allele, genotype and haplotype association with suicide attempt. RESULTS: The rs7305115 polymorphism of the TPH-2 gene was associated with suicidal behavior in a Mexican population in genotype (chi(2)=6.02, df=2, p=0.04) and allele (OR=1.39, 95%IC=1.06-1.81, p=0.01) frequencies. The THP-2 haplotypes GTA (chi(2)=5.68, p=0.01) and ATT (chi(2)=5.0, p=0.02) were associated with risk for suicide attempt. CONCLUSION: Our results provide evidence for an association between the rs7305115 polymorphism of the TPH 2 gene and suicidal behavior in a Mexican population. However, more studies are necessary to replicate these results using larger samples. PMID- 26028570 TI - Effect of dietary nitrate supplementation on tolerance to supramaximal intensity intermittent exercise. AB - Dietary nitrate (NO3(-)) supplementation has been shown to increase exercise tolerance and improve oxidative efficiency during aerobic exercise in healthy subjects. We tested the hypothesis that a 3-day supplementation in beetroot juice (BJ) rich in NO3(-) would improve the tolerance to supramaximal intensity intermittent exercise consisting of 15-s exercise periods at 170% of the maximal aerobic power interspersed with 30-s passive recovery periods. The number of repetitions completed before reaching volitional exhaustion was significantly higher in the BJ than in the placebo condition (26.1 +/- 10.7 versus 21.8 +/- 8.0 respectively, P < 0.05). In contrast to previous findings during exercise performed at intensity below the peak oxygen uptake (VO2peak), oxygen uptake (VO2) was unaffected (BJ: 2735 +/- 345 mL kg(-1) min(-1) vs. placebo: 2787 +/- 346 mL kg(-1) min(-1), NS). However, the Area Under the Curve for microvascular total hemoglobin (AUC-THb) in the vastus lateralis muscle assessed by near infrared spectroscopy during 3 time-matched repetitions was significantly increased with NO3(-) supplementation (BJ: 9662 +/- 1228 a.u. vs. placebo:8178 +/ 1589 a.u.; P < 0.05). Thus, increased NO3(-) (BJ: 421.5 +/- 107.4 MUM vs placebo:39.4 +/- 18.0 MUM) and NO2(-) (BJ: 441 +/- 184 nM vs placebo: 212 +/- 119 nM) plasma levels (P < 0.001 for both) are associated with improved muscle microvascular Red Blood Cell (RBC) concentration and O2 delivery during intense exercise, despite no effect on resting femoral artery blood flow, and vascular conductance. Maximal voluntary force during an isometric leg extensor exercise, and blood lactate levels were also unaffected by NO3(-) supplementation. To conclude, dietary NO3(-) supplementation enhances tolerance to exercise at supramaximal intensity, with increased microvascular total RBC concentration in the working muscle, in the absence of effect on contractile function and resting hemodynamic parameters. PMID- 26028571 TI - A qualitative evaluation of DAFNE-HART: A psychoeducational programme to restore hypoglycaemia awareness. AB - AIMS: Impaired awareness of hypoglycaemia (IAH) in people with type 1 diabetes is a dangerous condition that is associated with a six-fold greater risk of severe hypoglycaemia than for people with awareness. A new psychoeducational programme, DAFNE-HART, has been specifically designed to address persistent IAH. The initial pilot showed promising outcomes including fewer hypoglycaemic episodes and improved hypoglycaemia awareness. This aim of this paper is to report the development and qualitative evaluation of DAFNE-HART from participant interviews. METHODS: DAFNE-HART incorporates diabetes education with two psychological approaches that have demonstrated efficacy in long-term health conditions: motivational interviewing and cognitive behaviour therapy. The course, delivered across two UK locations included both group and individual support over a 6-week period facilitated by DAFNE educators, trained and supervised by a clinical psychologist. Semi-structured interviews were conducted with 19 participants immediately after their courses and the interviews were analysed using grounded theory. RESULTS: Five main themes emerged which describe the behavioural changes people made to their diabetes management, the development of new attitudes and beliefs, their experiences of regaining hypoglycaemia cues, reactions to the course format and the significance of the relationship with their care provider. Participants provide insights into how the course changed their view of IAH and led to practical changes in minimising hypoglycaemia. CONCLUSIONS: Integration of psychological techniques into diabetes education can address the cognitive and motivational barriers to restoring awareness and optimal diabetes management. It is suggested that further research is needed to evaluate this programme in a larger sample, over a longer time frame. PMID- 26028569 TI - Compartmentalized nitric oxide signaling in the resistance vasculature. AB - Nitric oxide (NO) was first described as a bioactive molecule through its ability to stimulate soluble guanylate cyclase, but the revelation that NO was the endothelium derived relaxation factor drove the field to its modern state. The wealth of research conducted over the past 30 years has provided us with a picture of how diverse NO signaling can be within the vascular wall, going beyond simple vasodilation to include such roles as signaling through protein S nitrosation. This expanded view of NO's actions requires highly regulated and compartmentalized production. Importantly, resistance arteries house multiple proteins involved in the production and transduction of NO allowing for efficient movement of the molecule to regulate vascular tone and reactivity. In this review, we focus on the many mechanisms regulating NO production and signaling action in the vascular wall, with a focus on the control of endothelial nitric oxide synthase (eNOS), the enzyme responsible for synthesizing most of the NO within these confines. We also explore how cross talk between the endothelium and smooth muscle in the microcirculation can modulate NO signaling, illustrating that this one small molecule has the capability to produce a plethora of responses. PMID- 26028572 TI - Relationship between sleep disordered breathing and diabetic retinopathy: Analysis of 136 patients with diabetes. AB - AIMS: Sleep disordered breathing (SDB) is associated with poor glycemic control. However, whether SDB contributes to diabetic microangiopathies, especially diabetic retinopathy (DR), is unknown. The aim of this study was to assess the relationship between SDB and DR. METHODS: Between January 2010 and November 2012, 136 patients underwent a sleep test and were divided into two groups according to the presence or absence of DR. Sleep test results and known risk factors for DR were compared between groups. Optic fundi were examined using indirect ophthalmoscope or retinal photographs and diagnosed by experienced ophthalmologists. Multivariate stepwise (backward) logistic regression analysis was performed to assess factors associated with DR. RESULTS: Ninety-nine patients without DR (NDR) and 37 patients with DR were assessed. Patients in the DR group had significantly longer duration of diabetes, were more likely to have hypertension and cardiovascular disease (CVD), and were more likely to be taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers (p=0.000 for each). In the multivariate backward logistic regression analysis, minimum SO2 (odds ratio [OR], 0.89; p=0.001), HbA1c (OR, 1.40; p=0.021), duration of diabetes (OR, 1.23; p<0.001), and history of CVD (OR, 8.96; p=0.008) remained significant. CONCLUSIONS: Minimum SO2 values were associated with DR independent from glycemic control level, duration of diabetes, and history of CVD. This finding suggests that SDB may contribute to the development of DR not through frequency, but due to the degree of intermittent hypoxia. PMID- 26028573 TI - Estimates of pain prevalence and severity in adults: United States, 2012. AB - Using a simple approach for coding pain severity, the present study describes self-reported pain in U.S. adults. Data are included for 8,781 adults who completed the Functioning and Disability Supplement of the 2012 National Health Interview Survey. An internationally piloted pain severity coding system was used to group participants into 5 discrete ordered pain categories based on their pain persistence (days with pain in the last 3 months) and bothersomeness (little, a lot, somewhere in between): pain free and categories 1 (low) to 4 (high). It is estimated that 126.1 million adults reported some pain in the previous 3 months, with 25.3 million adults (11.2%) suffering from daily (chronic) pain and 23.4 million (10.3%) reporting a lot of pain. Based on the persistence and bothersomeness of their pain, 14.4 million adults (6.4%) were classified as having the highest level of pain, category 4, with an additional 25.4 million adults (11.3%) experiencing category 3 pain. Individuals with category 3 or 4 pain were likely to have worse health status, to use more health care, and to suffer from more disability than those with less severe pain. Associations were seen between pain severity and selected demographic variables including race, ethnicity, preferred language, sex, and age. PERSPECTIVE: U.S. estimates of pain prevalence are presented using a simple approach for assigning pain severity developed by the Washington Group on Disability Statistics. Concurrent validity is assessed. Although this approach is promising, additional work is required to determine the usefulness of the Washington Group pain categories for pain research or clinical practice. PMID- 26028575 TI - C. elegans Punctin Clusters GABA(A) Receptors via Neuroligin Binding and UNC 40/DCC Recruitment. AB - Positioning type A GABA receptors (GABA(A)Rs) in front of GABA release sites sets the strength of inhibitory synapses. The evolutionarily conserved Ce-Punctin/MADD 4 is an anterograde synaptic organizer that specifies GABAergic versus cholinergic identity of postsynaptic domains at the C. elegans neuromuscular junctions (NMJs). Here we show that the Ce-Punctin secreted by GABAergic motor neurons controls the clustering of GABA(A)Rs through the synaptic adhesion molecule neuroligin (NLG-1) and the netrin receptor UNC-40/DCC. The short isoform of Ce-Punctin binds and clusters NLG-1 postsynaptically at GABAergic NMJs. NLG-1 disruption causes a strong reduction of GABA(A)R content at GABAergic synapses. Ce-Punctin also binds and localizes UNC-40 receptors in the postsynaptic membrane of NMJs, which promotes the recruitment of GABA(A)Rs by NLG-1. Since the mammalian orthologs of these genes are expressed in the central nervous system and their mutations are implicated in neuropsychiatric diseases, this molecular pathway might have been evolutionarily conserved. PMID- 26028574 TI - MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin. AB - At synapses, the presynaptic release machinery is precisely juxtaposed to the postsynaptic neurotransmitter receptors. We studied the molecular mechanisms underlying this exquisite alignment at the C. elegans inhibitory synapses. We found that the sole C. elegans neuroligin homolog, NLG-1, localizes specifically at GABAergic postsynapses and is required for clustering the GABA(A) receptor UNC 49. Two presynaptic factors, Punctin/MADD-4, an ADAMTS-like extracellular protein, and neurexin/NRX-1, act partially redundantly to recruit NLG-1 to synapses. In the absence of both MADD-4 and NRX-1, NLG-1 and GABA(A) receptors fail to cluster, and GABAergic synaptic transmission is severely compromised. Biochemically, we detect an interaction between MADD-4 and NLG-1, as well as between MADD-4 and NRX-1. Interestingly, the presence of NRX-1 potentiates binding between Punctin/MADD-4 and NLG-1, suggestive of a tripartite receptor ligand complex. We propose that presynaptic terminals induce postsynaptic receptor clustering through the action of both secreted ECM proteins and trans synaptic adhesion complexes. PMID- 26028576 TI - Erythema multiforme contact dermatitis after accidental exposure to acrylate based printing inks. PMID- 26028577 TI - [Management of Epidermal Growth Factor Inhibitor-Induced Papulopustular Rash: The Dermatologist's Role]. PMID- 26028578 TI - Description of Patients Undergoing Mohs Surgery in Spain: Initial Report on Data From the Spanish Registry of Mohs Surgery (REGESMOHS). AB - INTRODUCTION: The Spanish registry of Mohs micrographic surgery started collecting data in July 2013. The aim of the registry is to report on the use of this technique in Spain and the outcomes achieved. In the present article, we describe the characteristics of patients and the tumors treated. MATERIAL AND METHODS: This is a prospective cohort study of patients treated with Mohs micrographic surgery. The participating centers are hospitals where at least one intervention of this type is performed each week. All patients considered for Mohs micrographic surgery in participating centers are included in the registry except those who have been declared legally incompetent. RESULTS: Between July 2013 and October 2014, data from 655 patients were included in the registry. The most common tumor involved was basal cell carcinoma, and the most common histological subtype was infiltrative basal cell carcinoma. Most of the tumors treated were located on the face or scalp, and the most common site was the nose. Almost 40% of the tumors treated were recurrent or persistent, and preoperative tumor size was similar to that reported in other European studies and in Australia. In total, 45.5% of patients had received previous surgical treatment. CONCLUSION: The findings are similar to those reported in other studies, and the data collected are useful for assessing whether the results of studies carried out elsewhere are applicable in Spain. PMID- 26028579 TI - Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the obesity pandemic. We analyzed the transcriptional profiles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and phenotypes and functional characteristics of adipocyte tissue macrophages (ATMs), in obese patients undergoing bariatric surgery. METHODS: We collected anthropometric data; plasma samples; and SAT, VAT, and liver tissues from 113 obese patients undergoing bariatric surgery at academic hospitals in Europe (Antwerp and Leuven) and South Africa. Based on clinical and histologic features, patients were assigned to the following groups: obese, NAFLD, nonalcoholic steatohepatitis (NASH), or NASH with fibrosis. Microarray analyses were performed to identify genes expressed differentially among groups. We measured levels of cytokines and chemokines in plasma samples and levels of RNAs in adipose tissues by quantitative reverse-transcription polymerase chain reaction. ATMs were isolated from patients and 13 lean individuals undergoing cholecystectomy (controls), analyzed by flow cytometry, and cultured; immunophenotypes and levels of cytokines and chemokines in supernatants were determined. RESULTS: We observed increased expression of genes that regulate inflammation in adipose tissues from patients with NAFLD and NASH; expression of these genes increased as disease progressed from NAFLD to NASH. We found 111 genes associated with inflammation that were expressed differentially between VAT and SAT. Serum levels of interleukin 8, chemokine (C-C motif) ligand 3, and tumor necrosis factor-alpha correlated with liver inflammation and NAFLD activity score. We developed 2 models that could be used to determine patients' liver histology based on gene expression in VAT and SAT. Flow cytometry showed increased proportions of CD11c+CD206+ and CCR2+ macrophages in VAT from patients with NASH, and supernatants of cultured macrophages had increased levels of cytokines and chemokines compared with controls. CONCLUSIONS: VAT and SAT from patients with NAFLD and NASH have an increased expression of genes that regulate inflammation, and ATM produce increased levels of inflammatory cytokines, compared with adipose tissues from controls. We identified an expression profile of 5 genes in SAT that accurately predict liver histology in these patients. Transcript profiling: accession numbers: GSE58979 and GSE59045. PMID- 26028580 TI - Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers. AB - BACKGROUND & AIMS: The ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize the fibroblast growth factor (FGF)-15 produced by mouse intestine. This results in up-regulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool. We investigated whether abnormal bile acid signaling affects the hepatostat in mice. METHODS: We crossed Fah(-/-), Rag2(-/ ), Il2r(-/-) mice with nonobese diabetic mice to create FRGN mice, whose livers can be fully repopulated with human hepatocytes. We inserted the gene for human FGF19 (ortholog to mouse Fgf15), including regulatory sequences, into the FRGN mice to create FRGN19(+) mice. Livers of FRGN19(+) mice and their FRGN littermates were fully repopulated with human hepatocytes. Liver tissues were collected and bile acid pool sizes and RNA sequences were analyzed and compared with those of mice without humanized livers (controls). RESULTS: Livers were larger in FRGN mice with humanized livers (13% of body weight), compared with control FRGN mice; they also had much larger bile acid pools and aberrant bile acid signaling. Livers from FRGN19(+) normalized to 7.8% of body weight, and their bile acid pool and signaling more closely resembled that of control FRGN19(+) mice. RNA sequence analysis showed activation of the Hippo pathway, and immunohistochemical and transcription analyses revealed increased hepatocyte proliferation, but not apoptosis, in the enlarged humanized livers of FRGN mice. Cell sorting experiments showed that although healthy human liver does not produce FGF19, nonparenchymal cells from cholestatic livers produce FGF19. CONCLUSIONS: In mice with humanized livers, expression of an FGF19 transgene corrects bile acid signaling defects, resulting in normalization of bile acid synthesis, the bile acid pool, and liver size. These findings indicate that liver size is, in part, regulated by the size of the bile acid pool that the liver must circulate. PMID- 26028581 TI - Preparation and toxicological evaluation of methyl pyranoanthocyanin. AB - Anthocyanins are increasingly valued in the food industry for their functional properties and as food colorants. The broadness of their applications has, however, been limited by the lack of stability of these natural pigment extracts in a number of food systems. The potential application of pyranoanthocyanins, anthocyanin derivatives with better stability conferred by the added pyran ring, as a food ingredient was determined. Methylpyranoanthocyanin (MPA) was prepared from reaction of acetone and anthocyanin extracts from red grapes. Reaction products were sequentially purified with polyamide resin, TSK gel resin and semi preparative HPLC to a purity level >98%. Cytoprotective influence tests of the purified MPA indicated its significant protective effect against H2O2 induced MRC 5 cell damage. Results of evaluations of possible acute toxicity effects on MPA fed mice, including macro and microscopic assessments, support the conclusion of a non-toxic effect of MPA, and its potential safe use as a food additive. PMID- 26028582 TI - Molecularly imprinted polymer cartridges coupled to liquid chromatography for simple and selective analysis of penicilloic acid and penilloic acid in milk by matrix solid-phase dispersion. AB - A simple, fast and sensitive method for determination of the degradation products of penicillin (penicilloic acid and penilloic acid) in milk samples has been developed by combining selective surface molecularly imprinted matrix solid-phase dispersion and high performance liquid chromatography (SMIPs-MSPD-HPLC). The selected dispersant SMIPs had high affinity for penicilloic acid and penilloic acid in milk matrix and the obtained extract was sufficiently clean for direct injection for HPLC analysis without any interference from the matrix. The proposed SMIPs-MSPD-HPLC method was validated for linearity, precision, accuracy, limit of detection and limit of quantitation. Linearity ranged from 0.04 to 4 MUg g(-1) (correlation coefficient r(2) > 0.999). Recoveries of penicilloic acid from milk samples at different spiked levels were between 79.8 and 90.3%, with RSD values within 5.2-7.4%, and the limit of detection and limit of quantitation values were 0.04 and 0.13 MUg g(-1), respectively. Recoveries of penilloic acid from milk samples at different spiked levels were between 77.4 and 86.2%, with RSD values within 3.1-6.4%, and the limit of detection and limit of quantitation values were 0.05 and 0.17 MUg g(-1), respectively. The developed SMIPs-MSPD-HPLC method was successfully applied to direct determination of penicilloic acid and penilloic acid in milk samples. PMID- 26028583 TI - [Comparison of intracranial meningioma outcome scales in operated patients older than 65 years old. Our experience between 2002-2012 and a literature review]. AB - OBJECTIVE: Meningioma is the most common intracranial tumor in the elderly. Its incidence rate increases with age; so as life expectancy increases, meningiomas are diagnosed more frequently. A comparison is made between 4 outcome scales in this study: Clinical-Radiological Grading System, Geriatric Scoring Scale, SKALE (Sex, Karnofsky, ASA, localization and edema), and the Charlson score, to analyze which patients could benefit from surgery. MATERIALS AND METHODS: A total of 52 patients of 65 years and older operated in our hospital between 2002 and 2012 were identified, and a retrospective analysis was performed. All individual variables were collected and applied the scales to see their relationship with 3 month and annual mortality. The critical values of each scale were applied and their positive and negative predictive values were calculated. RESULTS: From the four scales, only the Clinical-Radiological Grading System and the SKALE had a significant statistical result when annual mortality was analyzed. None of them were associated with 3 month mortality. There was no statistically significant association between mortality and sex, edema, previous clinical history, and tumor location. But there was an association with age, tumor size and previous Karnofsky. CONCLUSION: The SKALE and the Clinical-Radiological Grading System are easy tools that can give an insight as regards patients who can benefit from a surgical treatment. Nevertheless, individualized patient analysis and neurosurgeon experience still have great importance. PMID- 26028584 TI - [Chagas disease: Globalization and new hope for its cure]. PMID- 26028585 TI - [Natural ocurrence of entomopathogenic fungi in soils cultivated with Paraguay tea (Ilex paraguariensis St. Hil.) in Misiones, Argentina]. AB - This study aimed to morphologically isolate, identify and characterize entomopathogenic fungi present in soils cultivated with Paraguay tea (Ilex paraguariensis). A survey of native entomopathogenic fungi was conducted from 40 soil samples grown with Paraguay tea in the province of Misiones, Argentina, from May 2008 to June 2010. The soil dilution plate methodology on selective culture media was used to isolate microorganisms. Taxonomic identification was performed using macroscopic and microscopic characters and specific keys. Twenty nine strains, belonging to the species Beauveria bassiana (n = 17), Metarhizium anisopliae (n = 2) and Purpureocillium lilacinum (n = 10) were isolated and identified. PMID- 26028586 TI - Novel alternative splice variants of NFIX and their diverse mRNA expression patterns in dairy goat. AB - The nuclear factor I/X (NFIX) is a member of NFI family and contributes to muscle and brain development. Numerous genes coding for alternative splicing isoforms play potential but different roles in the biological process. To date, transcript variants of NFIX gene and their expression profiles have never been elucidated in dairy goat. Herein, we identified and verified the expression of two novel transcripts (NFIXa and NFIXb) of NFIX gene in dairy goat. Compared with the normal transcript (NFIX), the NFIXa variant lacked the first and ninth exons, while the NFIXb variant lacked the first, seventh and ninth exons; the NFIXa variant was 69 nt longer than the normal transcript in the 5' end site of the seventh exon, while the NFIXb variant was 66 nt longer in the 5' end site of the seventh exon. Quantitative real-time PCR results showed that the expression levels of the three variants were significantly different. The normal NFIX variant was abundantly expressed in the lungs, the NFIXa variant was highly expressed in the pancreas, and the NFIXb variant was abundantly expressed in both the lung and the pancreas. Additionally, the NFIXa variant showed a significantly higher expression level than those of the normal NFIX and the alternative NFIXb variants in the liver, spleen, adipose, intestine and the testis (P<0.01 or P<0.05), respectively. Expression of the NFIXa variant in the brain was significantly higher than that of the NFIXb variant (P<0.01). These findings suggest that the NFIXa isoform is the most abundant isoform in certain tissues of the dairy goat. This study represents the first report on alternative splicing variants of the goat NFIX gene and their expression profiles. It should help elucidate the function of NFIX gene in dairy goat. PMID- 26028587 TI - Tracking global gene expression responses in T cell differentiation. AB - Upon receiving antigens from the innate immune cells, CD4(+) T cells differentiate into distinct effector cells. To probe the global responses of distinct effector cells, we analyzed transcriptome-wide expressions of Th1, Th2, Treg and Th17 using Pearson correlation, entropy and principal component analyses, with Th0 as a control. Although the global response of Th0 was quite distinct from Th17, surprisingly, it was highly similar to Th1, Th2 and Treg. Moreover, 8 major temporal groups consisting of 5704 differentially expressed genes were revealed for both Th0 and Th17. Gene functional enrichment analysis showed immune responses and metabolic processes were mainly activated between Th0 and Th17, while genes related to cell cycle and replication were differentially regulated. Moreover, we found the upregulation of several novel genes for Th0 and Th17. Overall, we deduce that Th0 is globally similar to Th1, Th2 and Treg. Our results indicate that Th0 is a differentiated state and, therefore, may not be used as a control cell type. PMID- 26028588 TI - Variability of miRNA expression during the differentiation of human embryonic stem cells into retinal pigment epithelial cells. AB - Embryonic stem cells (ESCs) and induced pluripotent stem cells can be induced to differentiate into retinal pigment epithelium (RPE). MiRNAs have been characterized and found playing important roles in the differentiation process of ESCs, but their length and sequence heterogeneity (isomiRs), and their non canonical forms of miRNAs are underestimated or ignored. In this report, we found some non-canonical miRNAs (dominant isomiRs) in all differentiation stages, and 27 statistically significant editing sites were identified in 24 different miRNAs. Moreover, we found marked major-to-minor arm-switching events in 14 pre miRNAs during the hESC to RPE cell differentiation phases. Our study for the first time reports exploring the variability of miRNA expression during the differentiation of hESCs into RPE cells and the results show that miRNA variability is a ubiquitous phenomenon in the ESC differentiation. PMID- 26028589 TI - Applying ATP bioluminescence to design and evaluate a successful new intensive care unit cleaning programme. AB - This was a two-phase prospective intervention study in the cardiology intensive care unit (CICU) and medical intensive care unit (MICU) and of a public 1800-bed medical centre in Taiwan. In phase I, cleaning efficacy was monitored by ATP bioluminescence after daily morning cleaning, and only 43.9% of 221 tested surfaces passed. The baseline data were used to define an intervention consisting of a new cleaning protocol as well as a new education/training programme. In phase II, following the intervention, 88.1% of 270 surfaces were found to be clean. The combined infection rate in the CICU and MICU showed a statistically significant decrease of 49.7%. PMID- 26028591 TI - Crowding of receptors induces ring-like adhesions in model membranes. AB - The dynamics of formation of macromolecular structures in adherent membranes is a key to a number of cellular processes. However, the interplay between protein reaction kinetics, diffusion and the morphology of the growing domains, governed by membrane mediated interactions, is still poorly understood. Here we show, experimentally and in simulations, that a rich phase diagram emerges from the competition between binding, cooperativity, molecular crowding and membrane spreading. In the cellular context, the spontaneously-occurring organization of adhesion domains in ring-like morphologies is particularly interesting. These are stabilized by the crowding of bulky proteins, and the membrane-transmitted correlations between bonds. Depending on the density of the receptors, this phase may be circumvented, and instead, the adhesions may grow homogeneously in the contact zone between two membranes. If the development of adhesion occurs simultaneously with membrane spreading, much higher accumulation of binders can be achieved depending on the velocity of spreading. The mechanisms identified here, in the context of our mimetic model, may shed light on the structuring of adhesions in the contact zones between two living cells. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26028592 TI - Phenomenological approaches to collective behavior in epithelial cell migration. AB - Collective cell migration in epithelial tissues resembles fluid-like behavior in time-lapse recordings. In the last years, hydrodynamic velocity fields in living matter have been studied intensely. The emergent properties were remarkably similar to phenomena known from active soft matter systems. Here, we review migration experiments of large cellular ensembles as well as of mesoscopic cohorts in micro-structured environments. Concepts such as diffusion, velocity correlations, swirl strength and polarization are metrics to quantify the cellular dynamics both in experiments as well as in computational simulations. We discuss challenges relating collective migration to single cell and oligocellular behavior as well as linking the phenotypic parameters to the underlying cytoskeleton dynamics and signaling networks. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26028590 TI - The potential impact of coinfection on antimicrobial chemotherapy and drug resistance. AB - Across a range of pathogens, resistance to chemotherapy is a growing problem in both public health and animal health. Despite the ubiquity of coinfection, and its potential effects on within-host biology, the role played by coinfecting pathogens on the evolution of resistance and efficacy of antimicrobial chemotherapy is rarely considered. In this review, we provide an overview of the mechanisms of interaction of coinfecting pathogens, ranging from immune modulation and resource modulation, to drug interactions. We discuss their potential implications for the evolution of resistance, providing evidence in the rare cases where it is available. Overall, our review indicates that the impact of coinfection has the potential to be considerable, suggesting that this should be taken into account when designing antimicrobial drug treatments. PMID- 26028593 TI - Identification of new susceptibility loci for IgA nephropathy in Han Chinese. AB - IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 * 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 * 10(-9)) and ODF1 KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 * 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 * 10( 19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 * 10(-19); rs12716641, P=9.53 * 10(-9); rs9314614, P=4.25 * 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN. PMID- 26028595 TI - Humble kidneys predict mighty heart troubles. PMID- 26028596 TI - What Is the Magnitude and Long-term Economic Cost of Care of the British Military Afghanistan Amputee Cohort? AB - BACKGROUND: Personal protection equipment, improved early medical care, and rapid extraction of the casualty have resulted in more injured service members who served in Afghanistan surviving after severe military trauma. Many of those who survive the initial trauma are faced with complex wounds such as multiple amputations. Although costs of care can be high, they have not been well quantified before. This is required to budget for the needs of the injured beyond their service in the armed forces. QUESTION/PURPOSES: The purposes of this study were (1) to quantify and describe the extent and nature of traumatic amputations of British service personnel from Afghanistan; and (2) to calculate an estimate of the projected long-term cost of this cohort. METHODS: A four-stage methodology was used: (1) systematic literature search of previous studies of amputee care cost; (2) retrospective analysis of the UK Joint Theatre Trauma and prosthetic database; (3) Markov economic algorithm for healthcare cost and sensitivity analysis of results; and (4) statistical cost comparison between our cohort and the identified literature. RESULTS: From 2003 to 2014, 265 casualties sustained 416 amputations. The average number of limbs lost per casualty was 1.6. The most common type of amputation was a transfemoral amputation (153 patients); the next most common amputation type was unilateral transtibial (143 patients). Using a Markov model of healthcare economics, it is estimated that the total 40-year cost of the UK Afghanistan lower limb amputee cohort is L288 million (USD 444 million); this figure estimates cost of trauma care, rehabilitation, and prosthetic costs. A sensitivity analysis on our model demonstrated a potential +/ 6.19% variation in costs. CONCLUSIONS: The conflict in Afghanistan resulted in high numbers of complex injuries. Our findings suggest that a long-term facility to budget for veterans' health care is necessary. CLINICAL RELEVANCE: Estimates here should be taken as the start of a challenge to develop sustained rehabilitation and recovery funding and provision. PMID- 26028597 TI - Analyses of in vivo interactions between transcription factors and the archaeal RNA polymerase. AB - Transcription factors regulate the activities of RNA polymerase (RNAP) at each stage of the transcription cycle. Many basal transcription factors with common ancestry are employed in eukaryotic and archaeal systems that directly bind to RNAP and influence intramolecular movements of RNAP and modulate DNA or RNA interactions. We describe and employ a flexible methodology to directly probe and quantify the binding of transcription factors to RNAP in vivo. We demonstrate that binding of the conserved and essential archaeal transcription factor TFE to the archaeal RNAP is directed, in part, by interactions with the RpoE subunit of RNAP. As the surfaces involved are conserved in many eukaryotic and archaeal systems, the identified TFE-RNAP interactions are likely conserved in archaeal eukaryal systems and represent an important point of contact that can influence the efficiency of transcription initiation. PMID- 26028598 TI - Towards integrative structural mass spectrometry: Benefits from hybrid approaches. AB - Structural mass spectrometry encompasses an increasing range of methods aimed at collecting as much structural information as possible on a biomolecule or its related complexes. Originally limited to the analysis of the primary structures of proteins, mass spectrometry has evolved over the past 20 years to provide information on the secondary, tertiary and even quaternary structure of proteins. Furthermore, the systems investigated with these methods have become more and more complex, as many developments have progressively overcome the main challenges of the size, heterogeneity, and/or solubility of protein complexes. A decade ago, most of these techniques were still the playground of a handful of specialists. However, the potential of these methods and their complementarity to other classical biophysical methods have driven an increasing number of users to develop new techniques and, perhaps more crucially, manufacturers have developed improved instruments and solutions/kits that are now commercially available. Today, more and more groups are combining structural proteomics techniques in order to gain additional information, as we will see in this review. This article will particularly focus on the analysis of peptides and protein complexes. First, the main methods of structural proteomics will be described. Then different possible combinations will be described, including how complementary they are, what synergistic information can be obtained from them, and what their current limitations are. PMID- 26028594 TI - Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. AB - BACKGROUND: The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS: We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4.2-19.0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS: The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0.0139 [95% CI 0.0105-0.0174] for ACR and 0.0065 [0.0042-0.0088] for eGFR) and heart failure (0.0196 [0.0108-0.0284] and 0.0109 [0.0059-0.0159]) than for coronary disease (0.0048 [0.0029-0.0067] and 0.0036 [0.0019-0.0054]) and stroke (0.0105 [0.0058-0.0151] and 0.0036 [0.0004-0.0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0.0227 (0.0158-0.0296) after omission of eGFR and ACR compared with less than 0.007 for any single modifiable traditional predictor. INTERPRETATION: Creatinine based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING: US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 26028599 TI - Assessing Microneurosurgical Skill with Medico-Engineering Technology. AB - OBJECTIVES: Most methods currently used to assess surgical skill are rather subjective or not adequate for microneurosurgery. Objective and quantitative microneurosurgical skill assessment systems that are capable of accurate measurements are necessary for the further development of microneurosurgery. METHODS: Infrared optical motion tracking markers, an inertial measurement unit, and strain gauges were mounted on tweezers to measure many parameters related to instrument manipulation. We then recorded the activity of 23 neurosurgeons. The task completion time, tool path, and needle-gripping force were evaluated for three stitches made in an anastomosis of 0.7-mm artificial blood vessels. Videos of the activity were evaluated by three blinded expert surgeons. RESULTS: Surgeons who had recently done many bypass procedures demonstrated better skills. These skilled surgeons performed the anastomosis with in a shorter time, with a shorter tool path, and with a lesser force when extracting the needle. CONCLUSIONS: These results show the potential contribution of the system to microsurgical skill assessment. Quantitative and detailed analysis of surgical tasks helps surgeons better understand the key features of the required skills. PMID- 26028600 TI - Realignment Subtalar Joint Arthrodesis. AB - Subtalar joint arthrodesis is a commonly performed procedure for the correction of hindfoot deformity and/or the relief of pain related to osteoarthritis. The purpose of the present study was to provide preoperative and intraoperative objective radiographic parameters to improve the accuracy and long-term success of realignment arthrodesis of the subtalar joint. We retrospectively reviewed the data from 16 patients, 11 male (57.9%) and 8 female (42.1%) feet, who had undergone realignment subtalar joint arthrodesis. A total of 19 fusions were performed in 9 (47.4%) right and 10 (52.6%) left feet, with a mean follow-up period of 2 (range 1 to 4.8) years. The mean age at surgery was 54.5 (range 14 to 77) years. Statistically significant improvement in radiographic alignment was found in the anteroposterior talo-first metatarsal angle (p = .002), lateral talo first metatarsal angle (p < .001), tibial-calcaneal angle (p < .001), and tibial calcaneal distance (p < .001). A positive correlation was observed between the tibial-calcaneal angle and tibial-calcaneal distance (r = 0.825, p < .001). The statistically significant improvement in tibial-calcaneal alignment, in both angulation and distance, support our conclusions that proper realignment of the calcaneus to vertical and central under the tibia will lead to short-term success and, likely, long-term success of subtalar joint arthrodesis. PMID- 26028601 TI - Intramedullary Fixation System for the Treatment of Hammertoe Deformity. AB - Hammertoe is one of the most common foot deformities. Arthrodesis or arthroplasty of the proximal interphalangeal joint using temporary Kirschner wire fixation is the most widespread method of surgical stabilization. However, this type of fixation is associated with some potential complications that can be obviated if percutaneous fixation is avoided. The purpose of the present study was to prospectively collect clinical and radiographic outcomes of operative correction of hammertoe deformity using a permanently implanted 1-piece intramedullary device. A total of 29 patients with 60 painful, rigid hammertoes were prospectively enrolled, clinically and radiographically examined, operatively treated, then followed and re-examined. The outcomes were measured in terms of the American Orthopaedic Foot and Ankle Society lesser toe and visual analog pain scores. After >=18 months of follow-up, the incidence of fusion with satisfactory radiographic alignment was 85% (51 of 60 toes). One toe (1.67%) developed early postoperative implant failure because of dislocation of the device, there were no cases of infection, and the mean American Orthopaedic Foot and Ankle Society lesser toe score was 87.4 +/- 1.3 and the mean visual analog scale pain score was 1.78 +/- 0.94. Twenty-five patients (86.21%) stated that they had no symptoms in the involved toes after surgery, and 4 (13.8%) experienced occasional pain, 2 (6.9%) of whom reported limitations of recreational activities and 2 (6.9%) reported persistent swelling without activity limitations. All the patients stated that they would undergo the surgery again if they had the same preoperative condition. PMID- 26028602 TI - Evidence-Based Rationale for Ankle Cartilage Allograft Replacement: A Systematic Review of Clinical Outcomes. AB - The treatment of ankle arthritis remains controversial. Ankle cartilage allograft replacement is a novel and complex procedure. Many clinical studies have shown some level of promise, as well complications. We performed a systematic review of the clinical outcomes to describe and assess the different techniques and clinical outcomes for ankle cartilage allograft replacement. We performed a review of the published studies using MEDLINE((r)) by way of PubMed((r)) and Google Scholar((r)) from January 2000 through October 2014, ranging from case reports to clinical studies. The inclusion criteria consisted of ankle cartilage allograft procedures with objective findings and clinical outcome scoring and complication and fusion rates and excluded nonallograft synthetic graft techniques, bone substitutes or expanders, review reports, and technique instructional manuals. Evidence with the combination of objective findings and clinical outcomes for all 3 type of allograft replacement (osteochondral, unipolar, and bipolar) is lacking. Several techniques for cartilage fixation have been described, including absorbable and metallic fixation. Most of the studies reported many occurrences and a variety of complications. A myriad of techniques for ankle cartilage allograft replacement exists. The results from the present systematic review of the published studies appear promising; however, the lack of statistical power and inconsistent documentation made it difficult to determine the superiority of any one intervention compared with another for the treatment of ankle arthritis. PMID- 26028603 TI - Current Concepts in the Management of Ankle Osteoarthritis: A Systematic Review. AB - Ankle osteoarthritis is less common than hip or knee osteoarthritis; however, it is a relatively common presentation and is predominantly related to previous trauma. Treatments have traditionally consisted of temporizing measures such as analgesia, physiotherapy, and injections until operative treatment in the form of arthrodesis is required. More recently, interest has been increasing in both nonoperative and alternative operative options, including joint-sparing surgery, minimal access arthrodesis, and new arthroplasty designs. The present systematic instructional review has summarized the current evidence for the treatment options available for ankle osteoarthritis. PMID- 26028604 TI - Breastfeeding and language outcomes: A review of the literature. AB - Many researchers have investigated the potential impact of breastfeeding in infancy on a child's subsequent development, but only a small subset of these studies considers language development and impairment. This paper reviews that literature, discussing postnatal neurodevelopment, potential mechanisms for dietary influences on communication outcomes, studies of typically developing children, and studies of children with communication concerns. For population based studies of language development, a modest but statistically robust relationship is seen across large samples that account for breastfeeding exclusivity. A similar protective relationship is seen in studies that evaluate the relationship between breastfeeding and language disorders; effect sizes are typically larger in these papers. Implications for researchers and service providers are reviewed. LEARNING OUTCOMES: Readers will be able to describe possible mechanisms by which early diet might influence neurodevelopment. They will be able to describe the relationships observed between diet in infancy and language outcomes in large population-based studies, as well as the trends observed in studies of the relationship between infant diet and communication impairment. PMID- 26028605 TI - A community-based cross-sectional study of fatigue in middle-aged and elderly women. AB - BACKGROUND: Fatigue has been widely studied in the general population; however, limited studies have investigated it in the female population. The objectives of this community-based study were to (1) investigate the prevalence of fatigue, (2) explore the relationship between gynecological history and experiences of fatigue, and (3) identify risk factors for fatigue in middle-aged and elderly women. METHODS: Based on a cross-sectional health study that employed a multi instrument questionnaire, 1272 women aged 45years or older dwelling in the community were included. The Chinese version of Chalder Fatigue Scale (CFS) was used to assess fatigue, and socio-demographic, health-related, and gynecological data were also collected. Fatigue was defined as a total CFS score>=4. RESULTS: The prevalence of fatigue among women aged over 45years was 33.9%. Multivariate logistic regression analysis identified that older age, single marital status, lower education level, the presence of chronic diseases, underweight, hospitalization in the last year, postmenopause, and a higher number of live births were associated with an increased risk of fatigue (P<0.05). CONCLUSIONS: Our results indicated that fatigue was common in middle-aged and elderly females. Being postmenopausal and having more than three live births were the particular gynecological factors contributing to fatigue in the general population. PMID- 26028606 TI - Arterial stiffness is associated with adipokine dysregulation in non-hypertensive obese mice. AB - The aim of this study was to characterize alterations in vascular structure and mechanics in murine mesenteric arteries from obese non-hypertensive mice, as well as their relationship with adipokines. Four-week old C57BL/6J male mice were assigned either to a control (C, 10% kcal from fat) or a high-fat diet (HFD, 45% kcal from fat) for 32weeks. HFD animals weighed 30% more than controls (p<0.001), exhibited similar blood pressure, increased leptin, insulin and superoxide anion (O2(-)) levels, and reduced adiponectin levels and nitric oxide (NO) bioavailability. Arterial structure showed an outward remodeling with an increase in total number of both adventitial and smooth muscle cells in HFD. Moreover, HFD mice exhibited an increased arterial stiffness assessed by beta-values (C=2.4+/ 0.5 vs HFD=5.3+/-0.8; p<0.05) and aortic pulse wave velocity (PWV, C=3.4+/-0.1 vs HFD=3.9+/-0.1; p<0.05). beta-Values and PWV positively correlated with leptin, insulin or O2(-) levels, whereas they negatively correlated with adiponectin levels and NO bioavailability (p<0.01). A reduction in fenestrae number together with an increase in type-I collagen amount (p<0.05) were observed in HFD. These data demonstrate that HFD accounts for the development of vascular remodeling and arterial stiffness associated with adipokine dysregulation and oxidative stress, independently of hypertension development. PMID- 26028608 TI - Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis. AB - BACKGROUND: Seasonal/perennial allergic conjunctivitis is the most common allergic conjunctivitis, usually with acute manifestations when a person is exposed to allergens and with typical signs and symptoms including itching, redness, and tearing. The clinical signs and symptoms of allergic conjunctivitis are mediated by the release of histamine by mast cells. Histamine antagonists (also called antihistamines) inhibit the action of histamine by blocking histamine H1 receptors, antagonising the vasoconstrictor, and to a lesser extent, the vasodilator effects of histamine. Mast cell stabilisers inhibit degranulation and consequently the release of histamine by interrupting the normal chain of intracellular signals. Topical treatments include eye drops with antihistamines, mast cell stabilisers, non-steroidal anti-inflammatory drugs, combinations of the previous treatments, and corticosteroids. Standard treatment is based on topical antihistamines alone or topical mast cell stabilisers alone or a combination of treatments. There is clinical uncertainty about the relative efficacy and safety of topical treatment. OBJECTIVES: The objective of this review was to assess the effects of topical antihistamines and mast cell stabilisers, alone or in combination, for use in treating seasonal and perennial allergic conjunctivitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 July 2014. We also searched the reference lists of review articles and relevant trial reports for details of further relevant publications. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing topical antihistamine and mast cell stabilisers, alone or in combination, with placebo, no treatment or to any other antihistamine or mast cell stabiliser, or both, that examined people with seasonal or perennial allergic conjunctivitis, or both. The primary outcome was any participant reported evaluation (by questionnaire) of severity of four main ocular symptoms: itching, irritation, watering eye (tearing), and photophobia (dislike of light), both separately and, if possible, by an overall symptom score. We considered any follow-up time between one week and one year. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Disagreements were resolved by discussion among review authors and the involvement of a third review author. We followed standard methodological approaches used by Cochrane. MAIN RESULTS: We identified 30 trials with a total of 4344 participants randomised, with 17 different drugs or treatment comparisons. The following antihistamines and mast cell stabilisers were evaluated in at least one RCT: nedocromil sodium or sodium cromoglycate, olopatadine, ketotifen, azelastine, emedastine, levocabastine (or levocabastine), mequitazine, bepotastine besilate, combination of antazoline and tetryzoline, combination of levocabastine and pemirolast potassium. The most common comparison was azelastine versus placebo (nine studies).We observed a large variability in reporting outcomes. The quality of the studies and reporting was variable, but overall the risk of bias was low. Trials evaluated only short-term effects, with a range of treatment of one to eight weeks. Meta-analysis was only possible in one comparison (olopatadine versus ketotifen). There was some evidence to support that topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo. There were no reported serious adverse events related to the use of topical antihistamine and mast cell stabilisers treatment. AUTHORS' CONCLUSIONS: It seems that all reported topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo in the short term. However, there is no long-term data on their efficacy. Direct comparisons of different antihistamines and mast cell stabilisers need to be interpreted with caution. Overall, topical antihistamines and mast cell stabilisers appear to be safe and well tolerated. We observed a large variability in outcomes reported. Poor quality of reporting challenged the synthesis of evidence. PMID- 26028607 TI - Endothelial transcriptomic changes induced by oxidized low density lipoprotein disclose an up-regulation of Jak-Stat pathway. AB - Oxidized low density lipoproteins (oxLDLs) act as an etiological factor in the development of atherosclerosis by modifying the biological properties of endothelial cells through mechanisms of vascular inflammation. To deepen the oxLDL changes at cellular level, a transcriptomic analysis of human umbilical artery endothelial cells (HUAECs) treated with oxLDL was performed to identify the modified signaling pathways. Total RNA was isolated from HUAECs treated with oxLDL (100 MUg/ml). Gene expression analysis was carried out using Affymetrix oligonucleotide microarrays. Biological pathway analysis was performed using Ingenuity Pathway Analysis software. Microarray assay demonstrated that oxLDL strongly affected two metabolic and signaling transduction pathways: the biosynthesis of steroids, via modification of nine genes that act sequentially in this metabolic pathway, and the Jak-Stat signaling pathway acting through STAT1 and STAT2. By means of qPCR, immunoblot, RNA interference and inhibitors we demonstrate that the mechanism used by oxLDL to activate Jak-Stat signaling pathway in artery endothelial cells is mainly mediated by STAT1. These findings provide a new mechanistic framework to better understand the effects that oxLDLs exert in artery endothelial cell gene expression and provide a source of hypothesis to understand the involvement of oxLDL in diseases in which endothelial cells play a key role, such as atherosclerosis. PMID- 26028609 TI - To Receive or Not to Receive Analgesics in the Emergency Department: The Importance of the Pain Intensity Assessment and Initial Nursing Assessment. AB - Patients seeking emergency care for abdominal pain still experience poor pain management. Pain intensity is not always seen as a mandatory parameter in the initial nurse assessment. Despite the development of nurse-initiated analgesic protocols, many patients do not receive analgesics in the emergency department. The aim of this study was to describe initial nursing assessment related to pain management and to identify predictors for receiving or not receiving analgesics in the emergency department. The sample consists of 100 patients from an intervention group in a previously undertaken Swedish intervention study. The main findings were that the registered nurses assessed 62 patients as being in need of analgesics, and that 52 of these obtained analgesics. The majority of the patients assessed as not being in need of analgesics did not receive analgesics because they did not want medication. Median value for pain intensity at initial assessment was 6 on the numerical rating scale. The results for the logistic regression (n = 80) showed significant differences between receiving analgesics/not receiving analgesics and the predictor pain intensity (measured at initial nurse assessment). Nurses in emergency departments play a crucial role, in that their initial assessment is of specific importance for the patient's further care and whether the patient may or may not receive analgesics. However, more attention has to be paid to patients' experiences and their expectations regarding the pain management in the emergency department. These complex questions have to be studied further in a more systematic way. PMID- 26028610 TI - Pharmacological validation of the free-exploratory paradigm in male Wistar rats: A proposed test of trait anxiety. AB - The free-exploratory paradigm (FEP) has been proposed as a model of trait anxiety for both mice and rats. However, its pharmacological validation has only been carried out for the mice. Thus, the aim of the present study was to pharmacologically validate FEP for Wistar rats, by testing the effects of clinically established anxiolytic and anxiogenic drugs, in four different experiments. In all experiments, male Wistar rats were first tested in FEP to be categorized according to their levels of trait anxiety (high, medium and low). Then, only medium trait anxiety rats were selected to be tested again in FEP, two weeks later, after being pharmacologically treated, according to each experiment as follows: Experiment I: 0.5mg/kg of diazepam (DZP) or vehicle; Experiment II: 20mg/kg of pentylenetetrazole (PTZ) or vehicle; Experiment III: 5mg/kg of fluoxetine (FLX5) or vehicle: and Experiment IV: 0.5mg/kg of fluoxetine (FLX0.5) or vehicle. As a group, the results showed that PTZ and FLX5 increased levels of trait anxiety and reduced locomotor activity, whereas DZP and FLX0.5 decreased levels of trait anxiety, without impairing locomotor activity. These results demonstrate that FEP for rats is able to predict clinical anxiolytic and anxiogenic activities of different drugs, including fluoxetine, which is believed to present a dual effect on anxiety. Therefore, this paradigm can be proposed as an effective method for testing potential trait anxiety-reducing drugs, in rats. PMID- 26028611 TI - Role of trypsin in the replication of Avian metapneumovirus subtype C (strain MN 2a) and its entry into the Vero cells. AB - To understand the molecular mechanisms of Avian metapneumovirus (aMPV) and the requirements involved in the infection and fusion, trypsin treatment was done in the different stages of virus; before infection, during entry and after virus infection followed by aMPV infection. The growth kinetics of aMPV was compared in time dependent manner. The effect of trypsin was found in the later stage of aMPV infection increasing the numbers of infected cells with the significant higher titer of infectious virions to that of trypsin treated before infection, during entry and aMPV. A serine protease inhibitor reduced aMPV replication in a significant way, whereas cysteine peptidase (E-64), aspartic protease (pepstatin A), and metalloprotease (phosphoramidon) inhibitors had no effect on aMPV replication. Inoculation of aMPV on Vero cells expressing the membrane-associated protease TMPRSS2 resulted in higher virus titers than that inoculated on normal Vero cells and is statistically significant (p < 0.05). Also, an inhibitor of clathrin/caveolae-mediated endocytosis had no effect on virus progeny, indicating that aMPV does not use the endocytic pathway for entry but undergoes direct fusion. The effect of lysosomotropic agents was not significant, suggesting that aMPV does not require low-pH environment in endosomes to fuse its envelope with the plasma membrane. PMID- 26028612 TI - Toxicity of oxidized phosphatidylcholines in cultured human melanoma cells. AB - The oxidized phospholipids (oxPL) 1-palmitoyl-2-glutaroyl-sn-glycero-3 phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3 phosphocholine (POVPC) are generated from 1-palmitoyl-2-arachidonoyl phosphatidylcholine under conditions of oxidative stress. These oxPL are components of oxidized low density lipoprotein. They are cytotoxic in cells of the arterial wall thus playing an important role in the development and progression of atherosclerosis. The toxic lipid effects include inflammation and under sustained exposure apoptosis. The aim of this study was to find out whether such toxic effects, especially apoptosis, are also elicited by oxPL in melanocytic cells in order to assess their potential for therapeutic intervention. FACS analysis after staining with fluorescent markers was performed to identify the mode of lipid-induced cell death. Activation of sphingomyelinase which generates apoptotic ceramide was measured using an established fluorescence assay. Ceramide profiles were determined by mass spectrometry. We found that 50MUM POVPC induce cell death in human melanoma cells isolated from different stages of tumor progression but affect primary human melanocytes to a much lesser extent. In contrast, 50MUM PGPC was only apoptotic in two out of four cell lines used in this study. The toxicity of both compounds was associated with efficient lipid uptake into the tumor cells and activation of acid sphingomyelinase. In several but not all melanoma cell lines used in this study, activation of the sphingomyelin degrading enzyme correlated with an increase in the concentration of the apoptotic mediator ceramide. The individual patterns of the newly formed ceramide species were also cell line-specific. PGPC and POVPC may be considered potential drug candidates for topical skin cancer treatment. They are toxic in malignant cells. The respective oxidized phospholipids are naturally formed in the body and resistance to these compounds is not likely to occur. PMID- 26028613 TI - Club cells and CC16: another "smoking gun"? (With potential bullets against COPD). PMID- 26028614 TI - Primary immunodeficiencies: not just paediatric diseases. PMID- 26028615 TI - Prevention is better than cure: time to change the focus of community-acquired pneumonia management. PMID- 26028616 TI - Distilling the essence of breathlessness: the first vital symptom. PMID- 26028617 TI - Lung function, genetics and socioeconomic conditions. PMID- 26028618 TI - Unmet needs for the assessment of small airways dysfunction in asthma: introduction to the ATLANTIS study. PMID- 26028619 TI - Taking the "I" out of IPF. PMID- 26028621 TI - Higher mortality for weekend admissions: quality of care or selection bias? PMID- 26028622 TI - The emerging role of the contractile and vascular reserves in pulmonary arterial hypertension. PMID- 26028623 TI - The emerging role of the contractile and vascular reserves in pulmonary arterial hypertension. PMID- 26028624 TI - Supporting progress towards the post-2015 targets and regional tuberculosis elimination: a statement of intent from the third meeting of the Asian TB Experts Community. PMID- 26028625 TI - Erratum. Phenotype of asthmatics with increased airway S-nitrosoglutathione reductase activity. PMID- 26028626 TI - Author correction. Tiotropium and olodaterol fixed-dose combination versus mono components in COPD (GOLD 2-4). PMID- 26028629 TI - Chronic thromboembolic pulmonary hypertension: the evolving treatment landscape. PMID- 26028630 TI - Monitoring asthma in childhood. AB - The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. However, to date there is limited evidence on how to monitor patients with asthma. Childhood asthma introduces specific challenges in terms of deciding what, when, how often, by whom and in whom different assessments of asthma should be performed. The age of the child, the fluctuating course of asthma severity, variability in clinical presentation, exacerbations, comorbidities, socioeconomic and psychosocial factors, and environmental exposures may all influence disease activity and, hence, monitoring strategies. These factors will be addressed in herein. We identified large knowledge gaps in the effects of different monitoring strategies in children with asthma. Studies into monitoring strategies are urgently needed, preferably in collaborative paediatric studies across countries and healthcare systems. PMID- 26028628 TI - An official American Thoracic Society/European Respiratory Society statement: research questions in COPD. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes. PMID- 26028631 TI - Monitoring asthma in childhood: symptoms, exacerbations and quality of life. AB - Monitoring asthma in children in clinical practice is primarily performed by reviewing disease activity (daytime and night-time symptoms, use of reliever medication, exacerbations requiring frequent use of reliever medication and urgent visits to the healthcare professional) and the impact of the disease on children's daily activities, including sports and play, in a clinical interview. In such an interview, most task force members also discuss adherence to maintenance therapy and the patients' (and parents') views and beliefs on the goals of treatment and the amount of treatment required to achieve those goals. Composite asthma control and quality of life measures, although potentially useful in research, have limited value in clinical practice because they have a short recall window and do not cover the entire spectrum of asthma control. Telemonitoring of children with asthma cannot replace face-to-face follow-up and monitoring because there is no evidence that it is associated with improved health outcomes. PMID- 26028632 TI - Monitoring asthma in childhood: management-related issues. AB - Management-related issues are an important aspect of monitoring asthma in children in clinical practice. This review summarises the literature on practical aspects of monitoring including adherence to treatment, inhalation technique, ongoing exposure to allergens and irritants, comorbid conditions and side-effects of treatment, as agreed by the European Respiratory Society Task Force on Monitoring Asthma in Childhood. The evidence indicates that it is important to discuss adherence to treatment in a non-confrontational way at every clinic visit, and take into account a patient's illness and medication beliefs. All task force members teach inhalation techniques at least twice when introducing a new inhalation device and then at least annually. Exposure to second-hand tobacco smoke, combustion-derived air pollutants, house dust mites, fungal spores, pollens and pet dander deserve regular attention during follow-up according to most task force members. In addition, allergic rhinitis should be considered as a cause for poor asthma control. Task force members do not screen for gastro oesophageal reflux and food allergy. Height and weight are generally measured at least annually to identify individuals who are susceptible to adrenal suppression and to calculate body mass index, even though causality between obesity and asthma has not been established. In cases of poor asthma control, before stepping up treatment the above aspects of monitoring deserve closer attention. PMID- 26028633 TI - Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation. AB - This review focuses on the methods available for measuring reversible airways obstruction, bronchial hyperresponsiveness (BHR) and inflammation as hallmarks of asthma, and their role in monitoring children with asthma. Persistent bronchial obstruction may occur in asymptomatic children and is considered a risk factor for severe asthma episodes and is associated with poor asthma outcome. Annual measurement of forced expiratory volume in 1 s using office based spirometry is considered useful. Other lung function measurements including the assessment of BHR may be reserved for children with possible exercise limitations, poor symptom perception and those not responding to their current treatment or with atypical asthma symptoms, and performed on a higher specialty level. To date, for most methods of measuring lung function there are no proper randomised controlled or large longitudinal studies available to establish their role in asthma management in children. Noninvasive biomarkers for monitoring inflammation in children are available, for example the measurement of exhaled nitric oxide fraction, and the assessment of induced sputum cytology or inflammatory mediators in the exhaled breath condensate. However, their role and usefulness in routine clinical practice to monitor and guide therapy remains unclear, and therefore, their use should be reserved for selected cases. PMID- 26028634 TI - Idiopathic inflammatory myopathies and the lung. AB - Idiopathic inflammatory myositis (IIM) is a group of rare connective tissue diseases (CTDs) characterised by muscular and extramuscular signs, in which lung involvement is a challenging issue. Interstitial lung disease (ILD) is the hallmark of pulmonary involvement in IIM, and causes morbidity and mortality, resulting in an estimated excess mortality of 50% in some series. Except for inclusion body myositis, these extrapulmonary disorders are associated with the general and visceral involvement frequently found in other CTDs including fever, Raynaud's phenomenon, arthralgia, nonspecific cutaneous modifications and ILD, for which the prevalence is estimated to be up to 65%. Substantial heterogeneity exists within the spectrum of IIMs, and each condition is associated with various frequencies and subtypes of pulmonary involvement. This heterogeneity is partly related to the presence of various autoantibodies encompassing anti-synthetase, anti-MDA5 and anti-PM/Scl. ILD is present in all subsets of IIM including juvenile myositis, but is more frequent in dermatomyositis and overlap myositis. IIM can also be associated with other presentations of respiratory involvement, namely pulmonary arterial hypertension, pleural disease, infections, drug-induced toxicity, malignancy and respiratory muscle weakness. Here, we critically review the current knowledge about adult and juvenile myositis-associated lung disease with a detailed description of therapeutics for chronic and rapidly progressive ILD. PMID- 26028635 TI - Lung imaging. AB - Imaging of the lung is a mainstay of respiratory medicine. It provides local information about morphology and function of the lung parenchyma that is unchallenged by other noninvasive techniques. During the 2014 European Respiratory Society International Congress in Munich, Germany, a Clinical Year in Review session was held focusing on the latest developments in pulmonary imaging. This review summarises some of the main findings of peer-reviewed articles that were published in the 12-month period prior to the 2014 International Congress. PMID- 26028636 TI - Chronic thromboembolic pulmonary hypertension: a distinct disease entity. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct subtype of pulmonary hypertension (PH). One disease hypothesis is that CTEPH results from the non-resolution of venous thromboembolism. CTEPH is characterised by the presence of obstructive fibrotic thromboembolic material in the major pulmonary vessels, with concomitant microvascular arteriopathy, resulting in progressive PH. The clinical presentation of CTEPH is similar to pulmonary arterial hypertension with nonspecific symptoms, but it is distinguished from pulmonary arterial hypertension by the presence of mismatched segmental defects on the ventilation/perfusion scan. The exact prevalence and incidence of CTEPH are unknown, but are thought to have been underestimated in the past. CTEPH is unique among the subgroups of PH in that it is potentially curable with pulmonary endarterectomy, a surgical intervention intended to remove the occlusive material from the pulmonary vasculature. However, in some patients the obstructions are technically inaccessible or the risk/benefit ratios are unfavourable, making the condition inoperable. It is thought that the involvement of the smaller, more distal vessels is a target for medical treatment. Untreated, CTEPH may result in right heart failure and death. The pathophysiological mechanisms which cause CTEPH are complex and have not yet been fully elucidated. PMID- 26028637 TI - Diagnostic advances and opportunities in chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the presence of thromboembolic material in the pulmonary circulation, and patients have a poor prognosis without treatment. Patients present with nonspecific symptoms, such as breathlessness and syncope, which means that other more common conditions are sometimes suspected before CTEPH, leading to delayed diagnosis and treatment. This is problematic because CTEPH is potentially curable with surgical pulmonary endarterectomy (PEA); indeed, CTEPH should always be considered in any patient with unexplained pulmonary hypertension (PH). Several key evaluations are necessary and complementary to confirm a diagnosis of CTEPH and assess operability. Echocardiography is initially used to confirm a general diagnosis of PH. Ventilation/perfusion scanning is then essential in the first stage of CTEPH diagnosis, with a wedge-shaped perfusion deficit indicative of CTEPH. This should be followed by right heart catheterisation (RHC) which is mandatory in confirming the diagnosis and providing haemodynamic parameters that are key predictors of the risk associated with PEA and subsequent prognosis. RHC is ideally coupled with conventional pulmonary angiography, the gold-standard technique for confirming the location and extent of disease, and thus whether the obstruction is surgically accessible. Computed tomographic pulmonary angiography is also now routinely used as a complementary technique to aid diagnosis and operability assessment. Recent improvements in the resolution of other noninvasive techniques, such as cardiac magnetic resonance imaging, allow for detailed reconstructions of the vascular tree and imaging of vessel defects, and interest in their use is increasing. PMID- 26028638 TI - Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension. AB - Pulmonary endarterectomy (PEA) is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It is a complex surgical procedure with a simple principle: removal of obstructive thromboembolic material from the pulmonary arteries in order to reduce pulmonary vascular resistance, relieve pulmonary hypertension (PH) and alleviate right ventricular dysfunction. In the majority of patients there is symptomatic and prognostic benefit. However, not all patients with CTEPH are suitable for treatment with PEA. Operability assessment is not always easy, being largely subjective and based on experience. It is therefore important that all patients are referred to an experienced CTEPH centre for careful evaluation of suitability for surgery. The most common reason for inoperability is distal vasculopathy accounting for a high proportion of the vascular resistance. Surgery requires cardiopulmonary bypass and periods of deep hypothermic circulatory arrest. Complications include reperfusion lung injury and persistent PH. However, with careful patient selection, surgical technique and post-operative management, PEA is a highly effective treatment with mortality rates <5% at experienced centres. Patients who are unsuitable for surgery may be candidates for medical therapy. PMID- 26028639 TI - Pharmacological therapy for patients with chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life threatening disease resulting from unresolved thromboembolic obstructions. Pulmonary endarterectomy (PEA) surgery is the gold-standard treatment as it is potentially curative; however, not all patients are deemed operable and up to one third have persistent or recurrent CTEPH after the procedure. Pulmonary arterial hypertension (PAH) and CTEPH have similar clinical presentations and histopathological features, so agents shown to be effective in PAH have often been prescribed to patients with CTEPH in the absence of proven therapies. However, clinical evidence for this strategy is not compelling. A number of small uncontrolled trials have investigated endothelin receptor antagonists, prostacyclin analogues and phosphodiesterase type 5 inhibitors in CTEPH with mixed results, and a phase III study of the endothelin receptor antagonist bosentan met only one of its two co-primary end-points. Recently, however, the soluble guanylate cyclase stimulator, riociguat, was approved in the USA and Europe for the treatment of inoperable or persistent/recurrent CTEPH following positive results from the phase III CHEST study (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial). This article reviews the current evidence for the use of pharmacological therapies in CTEPH. PMID- 26028640 TI - Clinically relevant subgroups in COPD and asthma. AB - As knowledge of airways disease has grown, it has become apparent that neither chronic obstructive pulmonary disease (COPD) nor asthma is a simple, easily defined disease. In the past, treatment options for both diseases were limited; thus, there was less need to define subgroups. As treatment options have grown, so has our need to predict who will respond to new drugs. To date, identifying subgroups has been largely reported by detailed clinical characterisation or differences in pathobiology. These subgroups are commonly called "phenotypes"; however, the problem of defining what constitutes a phenotype, whether this should include comorbid diseases and how to handle changes over time has led to the term being used loosely. In this review, we describe subgroups of COPD and asthma patients whose clinical characteristics we believe have therapeutic or major prognostic implications specific to the lung, and whether these subgroups are constant over time. Finally, we will discuss whether the subgroups we describe are common to both asthma and COPD, and give some examples of how treatment might be tailored in patients where the subgroup is clear, but the label of asthma or COPD is not. PMID- 26028641 TI - Adverse childhood experience and asthma onset: a systematic review. AB - Adverse childhood experiences such as abuse and neglect are associated with subsequent immune dysregulation. Some studies show an association between adverse childhood experiences and asthma onset, although significant disparity in results exists in the published literature. We aimed to review available studies employing a prospective design that investigates associations between adverse childhood experience and asthma. A search protocol was developed and studies were drawn from four electronic journal databases. Studies were selected in accordance with pre-set inclusion criteria and relevant data were extracted. 12 studies, assessing data from a total of 31 524 individuals, were identified that investigate the impact of a range of adverse childhood experiences on the likelihood of developing asthma. Evidence suggests that chronic stress exposure and maternal distress in pregnancy operate synergistically with known triggers such as traffic-related air pollution to increase asthma risk. Chronic stress in early life is associated with an increased risk of asthma onset. There is evidence that adverse childhood experience increases the impact of traffic related air pollution and inconsistent evidence that adverse childhood experience has an independent effect on asthma onset. PMID- 26028642 TI - Occupational exposure to pesticides and respiratory health. AB - This article aims to review the available literature regarding the link between occupational exposure to pesticides and respiratory symptoms or diseases. Identification of epidemiological studies was performed using PubMed. 41 articles were included, 36 regarding agricultural workers and five regarding industry workers. Among the 15 cross-sectional studies focusing on respiratory symptoms and agricultural pesticide exposure, 12 found significant associations with chronic cough, wheeze, dyspnoea, breathlessness or chest tightness. All four studies on asthma found a relationship with occupational exposure, as did all three studies on chronic bronchitis. The four studies that performed spirometry reported impaired respiratory function linked to pesticide exposure, suggestive of either obstructive or restrictive syndrome according to the chemical class of pesticide. 12 papers reported results from cohort studies. Three out of nine found a significant relationship with increased risk of wheeze, five out of nine with asthma and three out of three with chronic bronchitis. In workers employed in pesticide production, elevated risks of chronic obstructive pulmonary disease (two studies out of three) and impaired respiratory function suggestive of an obstructive syndrome (two studies out of two) were reported. In conclusion, this article suggests that occupational exposure to pesticides is associated with an increased risk of respiratory symptoms, asthma and chronic bronchitis, but the causal relationship is still under debate. PMID- 26028643 TI - Development of a simple binary response questionnaire to identify airflow obstruction in a smoking population in Argentina. AB - The CODE questionnaire (COPD detection questionnaire), a simple, binary response scale (yes/no), screening questionnaire, was developed for the identification of patients with chronic obstructive pulmonary disease (COPD). We conducted a survey of 468 subjects with a smoking history in 10 public hospitals in Argentina. Patients with a previous diagnosis of COPD, asthma and other respiratory illness were excluded. Items that measured conceptual domains in terms of characteristics of symptoms, smoking history and demographics data were considered. 96 (20.5%) subjects had a diagnosis of COPD according to the 2010 Global Initiative for Chronic Obstructive Lung Disease strategy document. The variables selected for the final questionnaire were based on univariate and multivariate analyses and clinical criteria. Finally, we selected the presence or absence of six variables (age >=50 years, smoking history >=30 pack-years, male sex, chronic cough, chronic phlegm and dyspnoea). Of patients without any of these six variables (0 points), none had COPD. The ability of the CODE questionnaire to discriminate between subjects with and without COPD was good (the area under the receiver operating characteristic curve was 0.75). Higher scores were associated with a greater probability of COPD. The CODE questionnaire is a brief, accurate questionnaire that can identify smoking individuals likely to have COPD. PMID- 26028644 TI - Idiopathic pulmonary fibrosis and sleep disorders: no longer strangers in the night. AB - The prevalence of obstructive sleep apnoea (OSA) is continuously increasing in patients with idiopathic pulmonary fibrosis (IPF) and, for the first time, the recent IPF guidelines recognise OSA as an important associated comorbidity that can affect patient's survival. Thus, it becomes conceivable that clinicians should refer patients with newly diagnosed IPF to sleep centres for the diagnosis and treatment of OSA as well as for addressing issues regarding the reduced compliance of patients with continuous positive airway pressure therapy. The discovery of biomarkers common to both disorders may help early diagnosis, institution of the most appropriate treatment and follow-up of patients. Better understanding of epigenetic changes may provide useful information about pathogenesis and, possibly, development of new drugs for a dismal disease like IPF. PMID- 26028645 TI - Biomarkers for efficacy of adjuvant chemotherapy following complete resection in NSCLC stages I-IIIA. AB - Biomarkers may be useful when deciding which nonsmall cell lung cancer (NSCLC) patients may benefit from adjuvant chemotherapy following complete resection and which chemotherapeutic agents may be used preferably in individual patients in order to maximise survival. A literature search covering the period from 2003 to May, 2014 was conducted using PubMed and the following search terms: "non-small cell lung cancer", "NSCLC", "adjuvant chemotherapy", "randomized", "randomised", "biomarkers", "prognostic", "predictive". This review focuses on current knowledge of biomarkers for prognosis or efficacy of adjuvant treatment following complete resection in stage I-IIIA NSCLC patients. This review includes results on 18 different biomarkers and five gene profiles. A statistically significant prognostic impact was reported for: iNTR, TUBB3, RRM1, ERCC1, BRCA1, p53, MRP2, MSH2, TS, mucin, BAG-1, pERK1/2, pAkt-1, microRNA, TopIIA, 15-gene profile, 92 gene profile, 31-gene profile and 14-gene profile. A statistically significant predictive impact was reported for: ERCC1, p53, MSH2, p27, TUBB3, PARP1, ATM, 37 gene profile, 31-gene profile, 15-gene profile and 92-gene profile. Uncertainties regarding the optimal analysis method and cut-off levels for the individual markers may blur the prognostic or predictive signals. None of the possible predictive markers have been validated in prospective trials. Thus, there are no biomarkers ready to use in an adjuvant setting in NSCLC. PMID- 26028646 TI - Mucosal immunity and novel tuberculosis vaccine strategies: route of immunisation determined T-cell homing to restricted lung mucosal compartments. AB - Despite the use of bacille Calmette-Guerin (BCG) for almost a century, pulmonary tuberculosis (TB) continues to be a serious global health concern. Therefore, there has been a pressing need for the development of new booster vaccines to enhance existing BCG-induced immunity. Protection following mucosal intranasal immunisation with AdHu5Ag85A is associated with the localisation of antigen specific T-cells to the lung airway. However, parenteral intramuscular immunisation is unable to provide protection despite the apparent presence of antigen-specific T-cells in the lung interstitium. Recent advances in intravascular staining have allowed us to reassess the previously established T cell distribution profile and its relationship with the observed differential protection. Respiratory mucosal immunisation empowers T-cells to home to both the lung interstitium and the airway lumen, whereas intramuscular immunisation activated T-cells are largely trapped within the pulmonary vasculature, unable to populate the lung interstitium and airway. Given the mounting evidence supporting the safety and enhanced efficacy of respiratory mucosal immunisation over the traditional parenteral immunisation route, a greater effort should be made to clinically develop respiratory mucosal-deliverable TB vaccines. PMID- 26028647 TI - Control of asthma in real life: still a valuable goal? AB - Although studies show that control of asthma can be achieved in the majority of patients, surveys repeatedly show that this is not the case in real life. Important measures to implement in order to achieve asthma control are trained healthcare professionals, a good patient-doctor relationship, patient education, avoidance of exposure to triggers, personalised management and adherence to treatment. These measures help the majority of asthma patients but have not yet been widely implemented and there should be a concerted action for their implementation. Moreover, further and focused research is needed in severe/refractory asthma. PMID- 26028648 TI - Interstitial lung disease in an adult patient with dermatomyositis and anti-NXP2 autoantibody. PMID- 26028649 TI - Thioredoxin Activates MKK4-NFkappaB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells. AB - The mitogen-activated protein kinase kinase 4 (MKK4) is activated via phosphorylation of Ser-257 and Thr-261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress. We show that thioredoxin (Trx), a cellular redox protein, activates MKK4 via Cys-246 and Cys-266 residues as mutation of these residues renders MKK4 insensitive to phosphorylation by MAP3Ks, TNFalpha, or Trx. MKK4 is activated in vitro by reduced Trx but not oxidized Trx in the absence of an upstream kinase, suggesting that autophosphorylation of this protein occurs due to reduction of Cys-246 and Cys-266 by Trx. Additionally, mutation of Cys-246 and Cys-266 resulted in loss of kinase activity suggesting that the redox state of Cys-246 and Cys-266 is a critical determinant of MKK4 activation. Trx induces manganese superoxide dismutase (MnSOD) gene transcription by activating MKK4 via redox control of Cys-246 and Cys-266, as mutation of these residues abrogates MKK4 activation and MnSOD expression. We further show that MKK4 activates NFkappaB for its binding to the MnSOD promoter, which leads to AP 1 dissociation followed by MnSOD transcription. Taken together, our studies show that the redox status of Cys-246 and Cys-266 in MKK4 controls its activities independent of MAP3K, demonstrating integration of the endothelial redox environment to MAPK signaling. PMID- 26028650 TI - Transactivation Function-2 of Estrogen Receptor alpha Contains Transactivation Function-1-regulating Element. AB - ERalpha has a ligand-dependent transactivation function in the ligand binding domain of ERalpha C terminus (AF-2) and a ligand-independent activation function in the N terminus (AF-1). It is still not fully understood how AF-1 and AF-2 activities are regulated cooperatively by ligands. To evaluate the AF-1 involvement in the estrogenic activities of various compounds, we analyzed these transactivation functions using AF-1-truncated and AF-2-mutated ERalpha mutants. AF-2 is composed of two domains with flexible and static regions. We used an AF-2 flexible region mutant and an AF-2 static region mutant. Both mutants have been reported as non-E2 responsive due to disruption of E2-mediated coactivator recruitment to the AF-2. The AF-2 mutants were not activated by agonists, but surprisingly antagonists and selective estrogen receptor modulators (SERMs) activated the AF-2 mutants. This antagonist reversal activity was derived from AF 1. Furthermore, we demonstrated that the AF-2 contains an AF-1 suppression function using C-terminal-truncated ERalpha mutants. From these findings we hypothesized that the mutation of AF-2 disrupted its ability to suppress AF-1, causing the antagonist reversal. To assess the AF-2-mediated AF-1 suppression, we analyzed the transcription activity of physically separated AF-1 and AF-2 using a novel hybrid reporter assay. We observed that the AF-1 activity was not suppressed by the physically separated AF-2. Furthermore, SERMs did not induce the AF-1-mediated activity from the separated mutant AF-2, which differed from the intact protein. These results imply that SERM activity is dependent on a conformational change of the full-length ERalpha molecule, which allows for AF-1 activation. PMID- 26028651 TI - Systematic Review on Post-Traumatic Stress Disorder Among Survivors of the Wenchuan Earthquake. AB - Post-traumatic stress disorder (PTSD) widely occurs among victims or witness of disasters. With flashbacks, hyperarousal, and avoidance being the typical symptoms, PTSD became a focus of psychological research. The earthquake in Wenchuan, China, on May 12, 2008, was without precedent in magnitude and aftermath and caused huge damage, which drew scientists' attention to mental health of the survivors. We conducted a systematic overview by collecting published articles from the PubMed database and classifying them into five points: epidemiology, neuropathology, biochemistry, genetics and epigenetics, and treatment. The large body of research during the past 6 years showed that adolescents and adults were among the most studied populations with high prevalence rates for PTSD. Genomic and transcriptomic studies focusing on gene * environment studies as well as epigenetics are still rare, although a few available data showed great potential to better understand the pathophysiology of PTSD as multifactorial disease. Phytotherapy with Chinese herbs and acupuncture are rarely reported as of yet, although the first published data indicated promising therapy effects. Future studies should focus on the following points: (1) The affected populations under observation should be better defined concerning individual risk factor, time of observation, spatial movement, and individual disease courses of patients. (2) The role of social support for prevalence rates of PTSD should be observed in more detail. (3) Efficacy and safety of Chinese medicine should be studied to find potential interventions and effective treatments of PTSD. PMID- 26028652 TI - Clinical impact of second-generation everolimus-eluting stents compared with first-generation drug-eluting stents in diabetic patients undergoing multivessel percutaneous coronary intervention. AB - OBJECTIVES: This study aimed to evaluate the safety and efficacy of everolimus eluting stent (EES) use compared with first-generation drug-eluting stent (DES) use in diabetic patients undergoing multivessel percutaneous coronary intervention (PCI). BACKGROUND: Although the benefits of EES over first generation DES were demonstrated for the general population, there is a paucity of data in diabetic patients with multivessel disease. METHODS: The retrospective study cohort included 429 consecutive diabetic patients who underwent native multivessel PCI, defined as >=2 same-generation DESs in >=2 different native vessel territories during the index procedure. The primary safety endpoint was the combined incidence of death, non-fatal Q-wave myocardial infarction, and definite stent thrombosis (ST) at 1 year. RESULTS: At 1 year, the primary safety endpoint was reached in 2.9% of the patients in the EES group, which was significantly lower than the 9.3% noted with first-generation DES (P=.03). The occurrence of definite or probable ST was lower in the EES group (0% vs. 3.7%; P=.04). Similarly, there was a trend toward lower all-cause mortality (2.9% vs. 8.5%; P=.05) and cardiac death (1% vs. 4.9%; P=.08) in the EES group. However, there were no significant differences in the rates of target lesion revascularization (12.6% vs. 9.3%; P=.33) between groups. In a multivariate model, EES was independently associated with a lower risk of composite primary endpoint compared with first-generation DES (hazard ratio, 0.28; 95% confidence interval, 0.09-0.94). CONCLUSION: In diabetic patients undergoing native multivessel PCI, the use of EES was associated with superior 1-year safety as compared with use of first-generation DES. PMID- 26028653 TI - Systematic Review of the BridgePoint System for Crossing Coronary and Peripheral Chronic Total Occlusions. AB - BACKGROUND: The BridgePoint system consists of the CrossBoss coronary catheter and Stingray CTO system (Boston Scientific) for coronary chronic total occlusions (CTOs), and the Viance crossing catheter and Enteer re-entry system (Covidien) for peripheral CTOs. METHODS: We performed a systematic review of the literature on the BridgePoint system published between October 2008 and August 2014, in accordance with the standards set forth in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: We identified a total of 20 studies: 12 studies on coronary CTOs (10 retrospective with 2 prospective case series) and 8 studies on peripheral CTOs (all retrospective). Among 320 patients undergoing coronary CTO intervention, pooled technical success and major adverse cardiac event rates were 77.1% and 3.8%, respectively. Among 175 patients undergoing peripheral CTO intervention, pooled technical success and major adverse events were 82.2% and 4.6%, respectively. Only 1 study reported long-term outcomes after use of the coronary BridgePoint system, demonstrating similar incidence of major adverse cardiac events between BridgePoint-treated and non-BridgePoint treated patients; however, the study had low power. CONCLUSIONS: The BridgePoint system is associated with high procedural success rates and low complication rates when used for crossing both coronary and peripheral CTOs. PMID- 26028654 TI - Utility of transradial approach for peripheral vascular interventions. AB - This review demonstrates the feasibility of the transradial approach (TRA) to address different peripheral vascular lesions. The TRA has long been used to address practically all coronary artery lesion subsets. It has shown significant benefits when compared with transfemoral approach (TFA), particularly a reduction in puncture-site related bleeding complications. TRA can be utilized effectively to address peripheral vascular lesions, including the renal, iliac, subclavian, carotid, vertebrobasilar, and superficial femoral systems. Utility of TRA for addressing peripheral vascular lesions using different techniques has been discussed in detail. Advantages and limitations of the TRA are highlighted, and the results of different studies using TRA for peripheral interventions are discussed. The pros and cons of TRA versus TFA for peripheral procedures are also demonstrated. The TRA is an effective alternative for TFA to address most peripheral vascular lesion subsets. However, there is a need for the development of radial-specific hardware to track bulky devices. PMID- 26028655 TI - Percutaneous paravalvular leak closure for balloon-expandable transcatheter aortic valve replacement: a comparison with surgical aortic valve replacement paravalvular leak closure. AB - AIMS: Paravalvular leak (PVL) is frequently observed after transcatheter aortic valve replacement (TAVR) and is related to increased mortality. Percutaneous PVL closure, which is a viable option for this complication, has been performed following surgical aortic valve replacement (SAVR); however, the experience in TAVR remains limited. We sought to compare this technique between post-TAVR and post-SAVR cases. METHODS AND RESULTS: A single-center series of patients consecutively undergoing percutaneous PVL closure was reviewed. Each group had 10 cases and procedural/imaging variables were assessed. Although there was no severe complication during the procedures, procedural success rate was lower in the post-TAVR group (60% vs. 100%; P=.04). There was resistance in all 4 unsuccessful cases, and we were unable to advance the delivery sheath over the wire. Computed tomography revealed that unsuccessful cases had higher calcification volume in the corresponding leaflet (351.4 +/- 205.1 mm3 vs. 121.8 +/- 111.7 mm3; P=.049). This finding can explain the mechanism of difficulty; the higher volume of calcification increases the resistance while advancing the delivery sheath. CONCLUSION: This is the first study revealing the difficulty of percutaneous PVL closure following TAVR compared with SAVR. However, it is a preferred approach in TAVR patients given their high risk for a surgical procedure. Computed tomography assessment of calcification volume provides important information for preprocedural planning. PMID- 26028656 TI - A Comparative Study of Defibrillator Leads at a Large-Volume Implanting Hospital: Results From the Pacemaker and Implantable Defibrillator Leads Survival Study ("PAIDLESS"). AB - OBJECTIVES: The purpose of the study was to examine survival in the implantable defibrillator subset of implanted leads at a large-volume implanting hospital. BACKGROUND: Implantable lead survival has been the subject of many multicenter studies over the past decade. Fewer large implanting volume single-hospital studies have examined defibrillator lead failure as it relates to patient survival and lead construction. METHODS: This investigator-initiated retrospective study examined defibrillator lead failure in those who underwent implantation of a defibrillator between February 1, 1996 and December 31, 2011. Lead failure was defined as: failure to capture/sense, abnormal pacing and/or defibrillator impedance, visual insulation defect or lead fracture, extracardiac stimulation, cardiac perforation, tricuspid valve entrapment, lead tip fracture and/or lead dislodgment. Patient characteristics, implant approach, lead manufacturers, lead models, recalled status, patient mortality, and core lead design elements were compared using methods that include Kaplan Meier analysis, univariate and multivariable Cox regression models. RESULTS: A total of 4078 defibrillator leads were implanted in 3802 patients (74% male; n = 2812) with a mean age of 70 +/- 13 years at Winthrop University Hospital. Lead manufacturers included: Medtronic: [n = 1834; 801 recalled]; St. Jude Medical: [n = 1707; 703 recalled]; Boston Scientific: [n = 537; 0 recalled]. Kaplan-Meier analysis adjusted for multiple comparisons revealed that both Boston Scientific's and St. Jude Medical's leads had better survival than Medtronic's leads (P<.001 and P=.01, respectively). Lead survival was comparable between Boston Scientific and St. Jude Medical (P=.80). A total of 153 leads failed (3.5% of all leads) during the study. There were 99 lead failures from Medtronic (5.4% failure rate); 56 were recalled Sprint Fidelis leads. There were 36 lead failures from St. Jude (2.1% failure rate); 20 were recalled Riata or Riata ST leads. There were 18 lead failures from Boston Scientific (3.35% failure rate); none were recalled. Kaplan Meier analysis also showed lead failure occurred sooner in the recalled leads (P=.01). A total of 1493 patients died during the study (mechanism of death was largely unknown). There was a significant increase in mortality in the recalled lead group as compared with non-recalled leads (P=.01), but no significant difference in survival when comparing recalled leads from Medtronic with St. Jude Medical (P=.67). A multivariable Cox regression model revealed younger age, history of percutaneous coronary intervention, baseline rhythm other than atrial fibrillation or atrial flutter, combination polyurethane and silicone lead insulation, a second defibrillation coil, and recalled lead status all contributed to lead failure. CONCLUSION: This study demonstrated a significantly improved lead performance in the Boston Scientific and St. Jude leads as compared with Medtronic leads. Some lead construction variables (insulation and number of coils) also had a significant impact on lead failure, which was independent of the manufacturer. Recalled St. Jude leads performed better than recalled Medtronic leads in our study. Recalled St. Jude leads had no significant difference in lead failure when compared with the other manufacturer's non recalled leads. Defibrillator recalled lead status was associated with an increased mortality as compared with non-recalled leads. This correlation was independent of the lead manufacturer and clinically significant even when considering known mortality risk factors. These results must be tempered by the largely unknown mechanism of death in these patients. PMID- 26028657 TI - Arteria Lusoria in a Patient With ST-Segment Elevation Acute Myocardial Infarction: Implications for Primary PCI. AB - Arteria lusoria is a rare aortic arch anomaly, with 1%-2% incidence. This image series documents the discovery of this anatomic variant in a patient who presented for primary percutaneous coronary intervention due to myocardial infarction. Awareness of this anomaly and subsequent rapid conversion to femoral access can reduce door-to-balloon time during primary PCI. PMID- 26028658 TI - Suicide left ventricle due to conduction disturbance following transcatheter aortic valve replacement and reversal with restoration of sinus rhythm: is there life after death? AB - Dynamic left ventricular outflow tract obstruction and left ventricular mid cavity obliteration are phenomena that can complicate the postoperative course in patients who undergo surgical aortic valve replacement for aortic stenosis, and may be markers of increased morbidity and mortality. Recently, reports describing dynamic intraventricular obstruction following transcatheter aortic valve replacement (TAVR) have emerged. We report a case of dynamic left ventricular mid cavity obstruction due to disordered atrioventricular synchrony immediately following TAVR, and its reversal with restoration of atrioventricular synchrony. This case highlights the essential role of atrial contraction in the management of this phenomenon. PMID- 26028659 TI - Recurrent spontaneous coronary artery dissection in a woman with fibromuscular dysplasia. AB - We report a case of five recurrent myocardial infarctions due to repeat spontaneous coronary artery dissection (SCAD) in a woman with underlying fibromuscular dysplasia. Her angiographic SCADs were missed on two occasions. Patients with a history of SCAD are at risk for recurrent dissections. This case also highlights the angiographic variants of SCAD, and the utility of intracoronary imaging in diagnosing suspected SCAD. PMID- 26028660 TI - Radial Artery Occlusion: Size and More--How Small is Too Small? PMID- 26028661 TI - Incidence and predictors of radial artery occlusion. PMID- 26028662 TI - Coronary flow velocity reserve in donor artery and myocardial performance index after successful recanalization of chronic total coronary occlusions. AB - BACKGROUND: Percutaneous recanalization of chronic total coronary occlusion (CTO) tends to show a positive effect on left ventricular remodeling and ejection fraction (LVEF). Coronary flow velocity reserve (CFVR) is an important diagnostic index of the functional capacity of coronary arteries. The aim of this study was to evaluate, by non-invasive CFVR, whether the blood flow of donor artery reverts to normal after CTO percutaneous coronary intervention (PCI). Also, we assessed the effects of CTO recanalization on global cardiac functions by using myocardial performance index (MPI). METHODS: We evaluated 25 patients (mean age, 57.5 +/- 14.1 years) who underwent CTO-PCI of the right coronary artery, whose collaterals were provided by the left anterior descending (LAD) artery. The coronary flow velocities in the distal LAD were measured using transthoracic echocardiography (TTE) before, 24 hours after, and within 3 months of PCI. Both two-dimensional and tissue Doppler (tD) echocardiography were used to calculate MPI. RESULTS: CFVR at month 3 was significantly increased compared to the basal and early CFVR (1.8 +/- 0.3 vs. 2.3 +/- 0.3 [P<.001] and 1.8 +/- 0.2 vs. 2.3 +/- 0.3 [P<.001], respectively). MPI at month 3 was significantly decreased compared to the basal and early MPI (0.61 +/- 0.09 vs. 0.53 +/- 0.07 [P<.001] and 0.60 +/- 0.08 vs. 0.53 +/- 0.07 [P<.001], respectively). Also, tD-MPI within 3 months was significantly decreased (0.58 +/- 0.9 vs. 0.53 +/- 0.8 [P=.01] and 0.57 +/- 0.07 vs. 0.53 +/- 0.8 [P<.001], respectively, for tD-MPI septal and 0.59 +/- 0.08 vs. 0.51 +/- 0.07 [P<.001] and 0.58 +/- 0.08 vs. 0.51 +/- 0.07 [P<.001], respectively, for tD-MPI lateral). CONCLUSION: Successful recanalization of CTO results in increased CFVR-indicated blood flow in the donor artery and MPI indicated global cardiac functions. PMID- 26028663 TI - Transcatheter pulmonary valve implantation in patients with right ventricular outflow tract dysfunction: early and mid-term results. AB - OBJECTIVE: The aim of this study was to determine early and long-term results after transcatheter pulmonary valve implantation (TPVI) performed with the use of Medtronic Melody and Edwards Sapien valves in patients with full conduit or patched right ventricular outflow tract (RVOT) dysfunction. METHODS AND RESULTS: The study comprised 40 consecutive patients (full conduit, n = 25; RVOT patch, n = 15) who underwent TPVI between December 2008 and April 2012. TPVI was successfully performed in 37 patients (92.5%). The gradient across RVOT decreased from 82.96 +/- 37.90 mm Hg to 34.33 +/- 22.2 mm Hg on the day following TPVI (P<.001) and remained low at follow-up of 20.4 +/- 11.4 months. The competency of the pulmonary valve was restored and maintained during the follow-up. New York Heart Association class, right ventricle end-diastolic volume, and right ventricular ejection fraction all improved as soon as 1 month after the procedure. Infective endocarditis was observed in 4 patients (1 died). Four patients underwent surgeries due to endocarditis, homograft rupture, stent migration, and early valve compression. CONCLUSION: TPVI may be performed safely and effectively in patients with right ventricle-pulmonary artery conduit and in selected patients with patched RVOT. PMID- 26028664 TI - Comparison of the effectiveness and safety of single versus dual occluders for the closure of multiple atrial septal defects. AB - BACKGROUND: The purpose of this study was to compare the effectiveness and safety of a single vs dual occluders in the treatment of multiple atrial septal defects (ASDs). METHODS: We retrospectively reviewed the records of patients with multiple ASDs treated with single or dual Amplatzer septal occluders from January 2010 to March 2013. Data extracted from the medical records included patient demographic information, ASD sizes, distance between the defects, preprocedure and postprocedure echocardiographic parameters, and treatment-related complications. Treatment success was defined as the occluder stably fixed without shunting, and no effects to other heart structures. RESULTS: Sixty-four patients were included. There were no significant differences between the two groups with respect to age, weight, gender, larger ASD diameter, smaller ASD diameter, and echocardiographic parameters before treatment. Successful closure was achieved in all patients in the single-occluder group regardless of whether the distance between defects was >=7 mm or <7 mm, and in all patients in the dual-occluder group. Residual shunting after surgery and residual leakage after 1-year follow up were significantly more common in the dual-occluder group compared with the single-occluder group (residual shunting: 31% vs. 8%, respectively; P=.02 and residual leakage: 19% vs. 2%, respectively; P=.04). No procedure-related complications occurred in either group. CONCLUSIONS: Single and dual occluders are both safe and effective for the repair of multiple ASDs; however, the risk of residual shunt is greater with dual occluders. PMID- 26028665 TI - The interventional cardiologist as cath lab team leader. AB - Interventional cardiologists act as leaders every time they step into a catheterization laboratory (cath lab), but leadership training is rarely included in cardiology training programs. Cath lab physicians should cultivate and practice effective leadership skills. Specifically, (1) before each procedure assess whether the cath lab team is prepared; (2) delegate authority to trainees and team members when appropriate; (3) use every procedure to improve the performance of team members through teaching, coaching, and mentorship; (4) debrief the team after adverse events; (5) develop the traits, styles, and skills associated with successful leadership; and (6) provide team training for the cath lab team. PMID- 26028666 TI - Mutations of c-Cbl in myeloid malignancies. AB - Next generation sequencing has shown the frequent occurrence of point mutations in the ubiquitin E3 ligase c-Cbl in myeloid malignancies. Mouse models revealed a causal contribution of c-Cbl for the onset of such neoplasms. The point mutations typically cluster in the linker region and RING finger domain and affect both alleles by acquired uniparental disomy. The fast progress in the detection of c Cbl mutations is contrasted by our scarce knowledge on their functional consequences. The c-Cbl protein displays several enzymatic functions by promoting the attachment of differentially composed ubiquitin chains and of the ubiquitin like protein NEDD8 to its target proteins. In addition, c-Cbl functions as an adapter protein and undergoes phosphorylation-dependent inducible conformation changes. Studies on the impact of c-Cbl mutations on its functions as a dynamic and versatile adapter protein, its interactomes and on its various enzymatic activities are now important to allow the identification of druggable targets within the c-Cbl signaling network. PMID- 26028667 TI - Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa dependent apoptosis through the activation of the MEK/ERK pathway. AB - KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro survival pathways, but it also triggers the trans-activation of pro-apoptotic genes. In our work, we show that G13D mutations of KRAS activate the MAPK pathway, and ERK2, but not ERK1, up-regulates Noxa basal levels. Accordingly, premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa-dependent manner. In contrast to these findings, colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression. We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment, especially in presence of oncogenic KRAS. In conclusion, our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene-activated pro-apoptotic stimulation. On the contrary, the combination of chemotherapy to inhibitors of specific pro-survival pathways, such as the one controlled by AKT, could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation. PMID- 26028668 TI - High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. AB - Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup. PMID- 26028670 TI - The Use of Neutron Analysis Techniques for Detecting The Concentration And Distribution of Chloride Ions in Archaeological Iron. AB - Chloride (Cl) ions diffuse into iron objects during burial and drive corrosion after excavation. Located under corrosion layers, Cl is inaccessible to many analytical techniques. Neutron analysis offers non-destructive avenues for determining Cl content and distribution in objects. A pilot study used prompt gamma activation analysis (PGAA) and prompt gamma activation imaging (PGAI) to analyse the bulk concentration and longitudinal distribution of Cl in archaeological iron objects. This correlated with the object corrosion rate measured by oxygen consumption, and compared well with Cl measurement using a specific ion meter. High-Cl areas were linked with visible damage to the corrosion layers and attack of the iron core. Neutron techniques have significant advantages in the analysis of archaeological metals, including penetration depth and low detection limits. PMID- 26028669 TI - Social bonds in the dispersing sex: partner preferences among adult female chimpanzees. AB - In most primate societies, strong and enduring social bonds form preferentially among kin, who benefit from cooperation through direct and indirect fitness gains. Chimpanzees, Pan troglodytes, differ from most species by showing consistent female-biased dispersal and strict male philopatry. In most East African populations, females tend to forage alone in small core areas and were long thought to have weak social bonds of little biological significance. Recent work in some populations is challenging this view. However, challenges remain in quantifying the influence of shared space use on association patterns, and in identifying the drivers of partner preferences and social bonds. Here, we use the largest data set on wild chimpanzee behaviour currently available to assess potential determinants of female association patterns. We quantify pairwise similarities in ranging, dyadic association and grooming for 624 unique dyads over 38 years, including 17 adult female kin dyads. To search for social preferences that could not be explained by spatial overlap alone, we controlled for expected association based on pairwise kernel volume intersections of core areas. We found that association frequencies among females with above-average overlap correlated positively with grooming rates, suggesting that associations reflected social preferences in these dyads. Furthermore, when available, females preferred kin over nonkin partners for association and grooming, and variability was high among nonkin dyads. While variability in association above and below expected values was high, on average, nonkin associated more frequently if they had immature male offspring, while having female offspring had the opposite effect. Dominance rank, an important determinant of reproductive success at Gombe, influenced associations primarily for low-ranking females, who associated preferentially with each other. Our findings support the hypothesis that female chimpanzees form well-differentiated social relationships that are of potential adaptive value to females and their offspring. PMID- 26028671 TI - The microbiome--a major determinant of health? PMID- 26028672 TI - Ethical question of the month--June 2015. PMID- 26028673 TI - Erysipelothrix rhusiopathiae associated with recent widespread muskox mortalities in the Canadian Arctic. PMID- 26028674 TI - High mortality in laying hen pullets caused by crop and gizzard impactions associated with ingestion of bale net wrap. AB - High mortality was observed in young replacement layers. Balls of bale net wrap strings were found in the crop and/or gizzard of birds causing impaction and traumatic injury. Some birds experienced loss of portions or the entire tongue secondary to ischemic necrosis. Mortality stopped with the removal of strings from the environment. PMID- 26028675 TI - Hemorrhage in the central canal of the cervical spinal cord in a coonhound diagnosed with canine juvenile polyarteritis (steroid responsive meningitis arteritis). AB - Patchy meningeal and parenchymal contrast enhancement of the spinal cord with multifocal central canal dilations was noted in a computed tomography myelogram of the cervical spine of a 6-month-old intact female coonhound with a confirmed diagnosis of canine juvenile polyarteritis and associated hemorrhage within the central canal. PMID- 26028676 TI - Anthracycline-induced cardiomyopathy in a dog treated with epirubicin. AB - An 8-year-old American cocker spaniel dog was diagnosed with dilated cardiomyopathy. Four years earlier, the dog had been diagnosed with multicentric lymphoma and had received 4 cycles of multi-agent chemotherapy, including doxorubicin and epirubicin. The total cumulative dose of epirubicin was 168 mg/m(2). Dilated cardiomyopathy was considered a consequence of epirubicin toxicity. PMID- 26028678 TI - Patterns and durations of journeys by horses transported from the USA to Canada for slaughter. AB - Concern has been expressed over the welfare of horses transported from the USA for slaughter in Canada. United States Department of Agriculture owner/shipper certificates for the year 2009 were analyzed to provide quantitative information on the patterns and durations of these journeys. In 2009, horses from 16 states in the northern USA were transported to 6 equine slaughter plants in Canada. Thirty-two percent of loads were from auction centers, 33% from feedlots, and 35% from horse collection centers. The median duration of the journey was 19 h. Thirty-six percent of horses were transported for < 6 h, 11% for 6 to 18 h, 13% for 18 to 24 h, 25% for 24 to 36 h, 9% for 36 to 48 h, and apparently 6% > 48 h. Some journeys exceeded those specified in regulations and, based on other research, would put these horses at risk of negative welfare outcomes, such as dehydration, injury, and fatigue. PMID- 26028677 TI - Seroprevalence of equine granulocytic anaplasmosis and lyme borreliosis in Canada as determined by a point-of-care enzyme-linked immunosorbent assay (ELISA). AB - Equine granulocytic anaplasmosis (EGA) and Lyme borreliosis (LB) are an emerging concern in Canada. We estimated the seroprevalence of EGA and equine LB by testing 376 convenience serum samples from 3 provinces using a point-of-care SNAP((r)) 4Dx((r)) ELISA (IDEXX Laboratories, Westbrook, Maine, USA), and investigated the agreement between the point-of-care ELISA and laboratory-based serologic tests. The estimated seroprevalence for EGA was 0.53% overall (0.49% in Saskatchewan, 0.71% in Manitoba), while the estimated seroprevalence for LB was 1.6% overall (0.49% in Saskatchewan, 2.86% in Manitoba). There was limited agreement between the point-of-care ELISA and an indirect fluorescent antibody test for EGA (kappa 0.1, PABAK 0.47) and an ELISA/Western blot combination for LB (kappa 0.23, PABAK 0.71). While the SNAP((r)) 4Dx((r)) ELISA yielded expected seroprevalence estimates, further evaluation of serologic tests for the purposes of disease exposure recognition may be needed. PMID- 26028679 TI - Erratum. PMID- 26028680 TI - A retrospective study of canine strychnine poisonings from 1998 to 2013 in Western Canada. AB - This study describes observations related to 93 cases of strychnine poisoning in dogs over a 16-year period in Saskatchewan, Alberta, and Manitoba. Epidemiological information describing age, gender, breed, and size of the dogs, geographical distribution of poisonings, and strychnine concentrations in tissue matrices were tabulated. The mortality in dogs poisoned with strychnine was 60.2%. Strychnine poisoning cases varied by year (P = 0.0012) and by season (P = 0.0005). The highest number of confirmed cases occurred in years 2000 and 2001. Poisonings occurred most frequently during the spring. There were no statistical differences related to age or gender, but older, male dogs appeared to be more commonly affected. Large dog breeds were most commonly affected. Strychnine was detected in multiple tissue matrices, including stomach contents, liver, urine, vomitus, and gastric washings. The study indicates that strychnine poisoning in the dog remains a common toxicosis in western Canada. PMID- 26028681 TI - A retrospective analysis of 25% human serum albumin supplementation in hypoalbuminemic dogs with septic peritonitis. AB - This study describes the influence of 25% human serum albumin (HSA) supplementation on serum albumin level, total protein (TP), colloid osmotic pressure (COP), hospital stay, and survival in dogs with septic peritonitis. Records of 39 dogs with septic peritonitis were evaluated. In the HSA group, initial and post-transfusion TP, albumin, COP, and HSA dose were recorded. In the non-supplemented group, repeated values of TP, albumin, and COP were recorded over their hospitalization. Eighteen dogs survived (53.8% mortality). Repeat albumin values were higher in survivors (mean 23.9 g/L) and elevated repeat albumin values were associated with HSA supplementation. Repeat albumin and TP were higher in the HSA supplemented group (mean 24 g/L and 51.9 g/L, respectively) and their COP increased by 5.8 mmHg. Length of hospitalization was not affected. Twenty-five percent HSA increases albumin, TP, and COP in canine patients with septic peritonitis. Higher postoperative albumin levels are associated with survival. PMID- 26028682 TI - Factors associated with long-term survival in dogs undergoing liver lobectomy as treatment for liver tumors. AB - The objectives of the study were to describe clinicopathologic findings in dogs that underwent surgical treatment of liver tumors and to define outcome associated variables in this canine population. Medical records of 118 dogs that underwent liver lobectomy were reviewed. Variables were assessed via univariate and multivariate Cox regression analyses. Hazard ratios, median survival times (MSTs), and Kaplan-Meier Survival curves (KMSCs) were created for significant variables. Of the dogs with surgically addressed hepatic tumors, 93% survived to discharge. The MST was not reached. Lethargic dogs had a mortality risk 10.2 times that of non-lethargic dogs. Non-tachypneic dogs had a mortality risk 4.3 times that of tachypneic dogs. Dogs that experienced anesthetic complications had a mortality risk 100 times that of dogs that did not. We conclude that the prognosis associated with liver tumors is good. Lethargy, respiratory rate, and anesthetic complications were associated with outcome. PMID- 26028683 TI - Standing placement of transphyseal screw in the distal radius in 8 Thoroughbred yearlings. AB - This retrospective study describes placement of distal radial transphyseal screws in Thoroughbred yearlings with carpal varus deformities while standing, and identifes short- and long-term complications following the procedure. Data gathered from 2009 to 2013 identified 8 yearlings that met the inclusion criteria. Horses were sedated intravenously and a single 4.5-mm cortical screw was placed in the distal lateral radial physis following application of local anesthetic and surgical preparation of a pre-placed hole. All horses were evaluated weekly after surgery and screw removal was performed standing and under sedation when correction of the angular limb deformity was achieved. The mean time for screw removal was 46 days. No short- or long-term complications were identified. Findings indicate that placing a single transphyseal screw in the lateral aspect of the distal radial physis with the horse standing is a viable option to treat varus angular limb deformity of the carpus in horses. PMID- 26028684 TI - Comparison of tibial plateau angles in small and large breed dogs. AB - Cranial cruciate ligament (CCL) disease can affect dogs of all sizes. The literature describing tibial plateau angle (TPA) in small breed dogs is limited. A retrospective study was conducted in unselected dogs presented for stifle or tibial examination to compare TPA in small breed dogs (n = 146 dogs, 185 stifles) versus large breed dogs (n = 200 dogs, 265 stifles). Small breed dogs had a mean TPA 3.1 degrees +/- 0.6 degrees higher than large breed dogs. There were higher TPAs in spayed females and castrated males for all dogs compared with intact males (3.6 degrees +/- 1.0 degrees and 2.7 degrees +/- 1.0 degrees , respectively). Dogs with unilateral and bilateral CCL disease had higher TPAs compared to dogs with intact CCLs (2.0 degrees +/- 0.7 degrees and 2.5 degrees +/- 0.8 degrees , respectively). Tibial morphology differs between large and small breed dogs; however, the significance of the impact of TPA on CCL disease in small breed dogs is unknown. PMID- 26028685 TI - Comparison of limited-contact dynamic compression plate and locking compression plate constructs for proximal interphalangeal joint arthrodesis in the horse. AB - This study compared in vitro monotonic and cyclic mechanical properties of equine proximal interphalangeal joint arthrodeses stabilized using an open or closed technique combined with axial 4.5 mm narrow limited-contact dynamic compression plate (LC-DCP) or 4.5 mm narrow locking compression plate (LCP). Ten forelimb pairs were randomly assigned to LCP or LC-DCP groups. One limb in each pair was assigned to either open or closed technique. Limbs were tested for cyclic fatigue at 20 000 cycles and then single-cycle to failure under 3-point dorsopalmar bending. There was no significant difference in stiffness of constructs during cyclic fatigue testing or on force or stiffness at failure in single cycle to failure testing between open and closed techniques or between plate types. Both implants, surgical technique, or combinations thereof are suitable for clinical use. More work is necessary to define the interaction between implant type and surgical technique. PMID- 26028687 TI - Can veterinarians contribute to the doctor-assisted death issue? PMID- 26028686 TI - Chronic progressive polyarthritis in a domestic shorthair cat. AB - A 6-year-old, neutered male, domestic shorthair cat was presented with shifting leg lameness and palpable effusion of the carpal and tarsal joints. Blood work, arthrocentesis, and radiographs identified an immune-mediated erosive polyarthritis. The cat was positive for feline syncytia-forming virus, and with his signalment, was diagnosed with feline chronic progressive polyarthritis. PMID- 26028688 TI - Conceptualizing the ethical questions in the use of livestock protection dogs. PMID- 26028689 TI - Interfacial communication. PMID- 26028690 TI - Early childbearing, human capital attainment and mortality risk: Evidence from a longitudinal demographic surveillance area in rural-KwaZulu-Natal, South Africa. AB - Using a rich longitudinal dataset, we examine the relationship between teen fertility and both subsequent educational outcomes and HIV related mortality risk in rural South Africa. Human capital deficits among teen mothers are large and significant, with earlier births associated with greater deficits. In contrast to many other studies from developed countries, we find no clear evidence of selectivity into teen childbearing in either schooling trajectories or pre fertility household characteristics. Enrolment rates among teen mothers only begin to drop in the period immediately preceding the birth and future teen mothers are not behind in their schooling relative to other girls. Older teen mothers and those further ahead in school for their age pre-birth are more likely to continue schooling after the birth. In addition to adolescents' higher biological vulnerability to HIV infection, pregnancy also appears to increase the risk of contracting HIV. Following women over an extended period, we document a higher HIV related mortality risk for teen mothers that cannot be explained by household characteristics in early adulthood. Controlling for age at sexual debut, we find that teen mothers report lower condom use and older partners than other sexually active adolescents. PMID- 26028691 TI - Thanks to 70 years of Inter American Statistical cooperation, the world's largest integrated census microdata dissemination site www.ipums.org/international. AB - Seventy years of Inter American Statistical cooperation, symbolized by the 70th anniversary of Estadistica, made possible the construction of IPUMS International, the world's largest integrated census microdata dissemination site, www.ipums.org/international. Currently, the site offers access to 238 samples totaling over 540 million person records representing 74 countries. The Americas, which account for only about one-seventh of the world's population, amount to over one-third (36%) of the person records in the IPUMS-International database. Likewise, 35% of the citations in the IPUMS-International bibliography are for studies focused on Latin America, with about half of these analyzing a single Latin American country. This article discusses salient features of the IPUMS integration methods and system. National Statistical Institutes that have not yet entrusted 2010 census microdata to the initiative are invited to do so. Researchers and teachers are invited to use the data freely in analysis and teaching. Setenta anos de cooperacion estadistica inter-Americana, simbolizada por el 70 aniversario de la revista Estadistica, han hecho posible la construccion de IPUMS-internacional, la base en linea de microdatos censales harmonizados mas grande del mundo, www.ipums.org/international. Actualmente, IPUMS proporciona acceso a 238 muestras con mas de 540 millones de registros individuales de 74 paises. Las Americas, que albergan una septima parte de la poblacion mundial, representan mas de un tercio (36%) de todos los registros individuales en la base de datos IPUMS-internacional. Asimismo, el 35% de todas las referencias en la bibliografia de IPUMS son de estudios realizados sobre America Latina, la mitad de estas basadas en un solo pais de la region. Este articulo presenta las principales caracteristicas del sistema de integracion y difusion de datos de IPUMS. Los Institutos Nacionales de Estadisticas que todavia no ha entregado la muestra de microdatos de la ronda de 2010 son invitados a hacerlo. Los investigadores y profesores son invitados a utilizar los datos de forma gratuita para sus actividades de investigacion y docencia. PMID- 26028692 TI - Should Fallopian Tubes Be Removed During Hysterectomy Procedures? - A Statement by AGO Ovar. PMID- 26028693 TI - Diagnostic Value of Vaginal Discharge, Wet Mount and Vaginal pH - An Update on the Basics of Gynecologic Infectiology. AB - The majority of uncomplicated vulvovaginal complaints (e.g. bacterial vaginosis, vulvovaginal candidiasis, trichomoniasis) can be detected with uncomplicated basic infectiological tests and can usually be treated effectively without requiring further diagnostic procedures. Tests include measurement of vaginal pH, preparation and assessment of wet mount slides prepared from vaginal or cervical discharge, and the correct clinical and microbiological classification of findings. In Germany, at least in recent years, this has not been sufficiently taught or practiced. As new regulations on specialist gynecologic training in Germany are currently being drawn up, this overview provides basic information on gynecologic infectiology and summarizes clinically relevant aspects of recent microbiological findings on the physiology and pathology of vaginal flora. The clinical signs and symptoms of aerobic vaginitis, the pathogenesis of which is still not completely understood, are also reviewed. Finally, the symptoms, indications and risk factors for pelvic inflammatory disease (PID) are presented. In contrast to the above-listed infections, PID requires immediate culture of the pathogen from samples (e.g. obtained by laparoscopy) with microbiological diagnostic procedures carried out by specialist laboratories. A schematic summary of all pathologies discussed here is presented. PMID- 26028694 TI - Increasing Liability Premiums in Obstetrics - Analysis, Effects and Options. AB - Whenever people act, mistakes are made. In Germany, it is thought that a total of 40 000 cases of malpractice occur per year. In recent years, costs for liability insurance have risen significantly in almost all spheres of medicine as a whole. Liability in the health care sector is founded on the contractual relationship between doctor and patient. Most recently, case law developed over many years has been codified with the Patients' Rights Act. In obstetrics, the focus of liability law is on brain damage caused by hypoxia or ischemia as a result of management errors during birth. The costs per claim are made up of various components together with different shares of damage costs (increased needs, in particular therapy costs and nursing fees, acquisition damage, treatment costs, compensation). In obstetrics in particular, recent focus has been on massively increased liability payments, also accompanied by higher liability premiums. This causes considerable financial burdens on hospitals as well as on midwives and attending physicians. The premiums are so high, especially for midwives and attending physicians, that professional practice becomes uneconomical in some cases. In recent years, these circumstances have also been intensely debated in the public sphere and in politics. However, the focus here is on the occupation of midwife. In 2014, in the GKV-FQWG (Statutory Health Insurance - Quality and Further Development Act), a subsidy towards the occupational liability premium was defined for midwives who only attended a few deliveries. However, to date, a complete solution to the problem has not been found. A birth will never be a fully controllable risk, but in rare cases will always end with injury to the child. The goal must be to minimise this risk, through good education and continuous training, as well as constant critical analysis of one's own activities. Furthermore, it seems sensible, especially in non-clinical Obstetrics, to look at the current study data more closely. Among the many solutions which have been proposed, such as the development of quality management, risk management and prevention, better remuneration, a waiver on recourse claims by social insurance underwriters, a cap on damage costs of liability insurers, state liability, an indemnity fund, a system change to Medical Treatment Risk Insurance, as well as a discussion on whether or not it makes sense to use non-clinical obstetrics for the prevention of a further increase in premiums, not one stands out as being especially convincing. On the contrary, a meaningful coordination of various concepts should follow. What seems sensible is a higher remuneration per birth, taking into account the liability premiums as well as, in the medium term, the establishment of a liability fund which, from a certain limit upwards, steps in as liable third party. PMID- 26028695 TI - Development and Validation of a Standardized Questionnaire and Standardized Diary for Use in Integrative Medicine Consultations in Gynecologic Oncology. AB - Introduction: Use of complementary and alternative medicine (CAM) in diagnoses is not standardized and is very heterogeneous. There are few published standards on integrative medicine consultations or CAM-specific validated follow-up questionnaires. The aim of this study was to develop a standard for integrative medicine consultations, a patient questionnaire which could be used as a basis for medical decisions, and a diary to evaluate the course of the integrative therapy. Patients and Methods: Between June 2013 and September 2014 a standardized integrative medicine consultation in gynecologic oncology was developed and implemented at the Department of Gynecology and Obstetrics of Erlangen University Hospital. A standard operating procedure for consultations was developed; the necessary instruments were developed and validated. Results: Overall patient assessment of the integrative medicine questionnaire and the integrative medicine diary with regard to the time required for completion, comprehensibility, complexity and functionality was positive. Patients evaluated the standardized overall concept of the integrative medicine consultation and its instruments as suitable. Conclusion: Our team is one of the first study groups to develop, validate and publish a standard procedure for integrative medicine consultations. In future, the standard operating procedure for integrative medicine procedures of the Department of Gynecology and Obstetrics of Erlangen University Hospital could be introduced in other hospitals and certified breast cancer centers and gynecologic cancer centers. This would offer patients maximum security and a standardized quality of care in integrative medicine. PMID- 26028696 TI - Operative Therapy for Heterotopic Scar Pregnancy and Successful Birth of the Intrauterine Foetus - Case Report and Review of the Literature. AB - A heterotopic pregnancy in the vicinity of a previous Caesarean section scar (HSP) occurs frequently after fertility treatment. In spite of the low incidence to date, the increasing numbers of Caesarean sections as well as IVF treatment will probably lead to a higher prevalence in the future. Up to now the literature contains only isolated case reports on therapeutic options. These range from conservative management through selective termination of the HSP by injections of methotrexate or potassium chloride into the amniotic sac to invasive methods such as resectoscopic removal or laparoscopy. In the case presented here we describe the successful excision of the HSP by laparotomy with a subsequent uncomplicated Caesarean section and delivery of a healthy baby at the 37 + 0 week of pregnancy. PMID- 26028697 TI - Different Patterns of Drug Use and Barriers to Continuous HIV Care Post Incarceration. AB - Individuals with a drug use history often experience drug use relapse when they are released from incarceration. This article explores the processes by which a sample of adults experienced relapse post-incarceration and consequently experienced HIV treatment interruption. Data are from in-depth interviews with 25 formerly incarcerated HIV-positive adults who have a self-reported history of drug use. Findings reveal that each participant relapsed post-incarceration. Some participants relapsed immediately after release; others remained drug free until something "triggered" a relapse. Once a participant relapsed, factors that contributed to HIV treatment interruption included re-incarceration, a lack of concern for HIV care, and the overlap of symptoms between addiction and HIV infection. The relationship between drug use and HIV treatment interruption was exacerbated when the participant reported also having a mental health disorder. Cessation of drug use facilitated HIV treatment engagement for participants. The implications of these findings for policy and practice are discussed. PMID- 26028698 TI - Enzymatic polishing of cereal grains for improved nutrient retainment. AB - Consumer acceptance of food products is largely driven by the dietary and functional quality of their ingredients. Though whole cereal grains are well known for bioactive components, scientists are facing dire need for better technologies to prevent the nutritional losses incurred through the conventional food processing technologies. Application of enzyme for depolymerisation of carbohydrates present in bran layer of grain is becoming an efficient method for phenolic mobilization and dietary fiber solubilisation. The present article emphasizes deep insights about the application of enzyme as an alternative technology for cereal grain processing to improve the product quality while forbidding the nutritional losses in an eco-friendly manner. PMID- 26028699 TI - Efficient extraction strategies of tea (Camellia sinensis) biomolecules. AB - Tea is a popular daily beverage worldwide. Modulation and modifications of its basic components like catechins, alkaloids, proteins and carbohydrate during fermentation or extraction process changes organoleptic, gustatory and medicinal properties of tea. Through these processes increase or decrease in yield of desired components are evident. Considering the varied impacts of parameters in tea production, storage and processes that affect the yield, extraction of tea biomolecules at optimized condition is thought to be challenging. Implementation of technological advancements in green chemistry approaches can minimize the deviation retaining maximum qualitative properties in environment friendly way. Existed extraction processes with optimization parameters of tea have been discussed in this paper including its prospects and limitations. This exhaustive review of various extraction parameters, decaffeination process of tea and large scale cost effective isolation of tea components with aid of modern technology can assist people to choose extraction condition of tea according to necessity. PMID- 26028700 TI - Role of antioxidants and phytochemicals on acrylamide mitigation from food and reducing its toxicity. AB - Nowadays, the presence of acrylamide in lots of fried and baked foods raises concerns due to its potential to cause toxicity and cancer in animals and human. Consequently, a number of papers have focused on evaluation of various chemicals in reduction of acrylamide in various food sources, as well as decreasing its related toxicities. In addition, plants are important sources of diverse metabolites demonstrating either possible effectiveness in acrylamide toxicity or reduction of acrylamide content in food sources. In this paper, we have criticized all relevant studies in terms of acrylamide mitigation from food by phytochemicals and antioxidants, and the influence of herbal medicines and phyto pharmaceuticals on reduction of acrylamide toxicity in both animals and human. PMID- 26028701 TI - Review of methods for the detection and quantification of adulteration of rice: Basmati as a case study. AB - Rice is a staple and widely grown crop endowed with rich genetic diversity. As it is difficult to differentiate seeds of various rice varieties based on visual observation accurately, the harvested seeds and subsequent processed products are highly prone to adulteration with look-alike and low quality seeds by the dishonest traders. To protect the interests of importing countries and consumers, several methods have been employed over the last few decades for unambiguous discrimination of cultivars, accurate quantification of the adulterants, and for determination of cultivated geographical area. With recent advances in biotechnology, DNA based techniques evolved rapidly and proved successful over conventional non-DNA based methods to purge the problem of adulteration at commercial level. In the current review, we made an attempt to summarize the existing methods of adulteration detection and quantification in a comprehensive manner by providing Basmati as a case study to enable the traders to arrive at a quick resolution in choosing the apt method to eliminate the adulteration practice in the global rice industry. PMID- 26028702 TI - Statistically designed optimal process conditions for recuperation of protein from rapeseed meal. AB - This work proposes the exploitation of under-utilized, non-expensive rapeseed press-cake as a source for producing high yield of protein, having superior whiteness and emulsion properties, and reduced level of residual phytate content. The chosen response parameters are relevant to food, pharmaceutical and cosmetic industries. Improvement in functional properties (emulsion properties) along with reduction in dark colour and toxic phytic acid level is expected to make rapeseed protein safer and commercially more viable for various applications. A multi objective optimization technique based on Response surface methodology (RSM) has been presented. Using Derringer function, an optimum and feasible experimental condition was obtained with high composite desirability. The calculated regression model proved suitable for the evaluation of extraction process, whose adequacy was confirmed by Anderson-Darling Normality tests, Relative Standard Error of the Estimate (RSEE) and also by means of additional experiments performed at derived feasible experimental condition. The proposed simple alkaline protein extraction process, from defatted partially dephenolized rapeseed meal, under feasible optimal condition, was found to be suitable and potent for the recovery of high-quality vegetable protein. PMID- 26028703 TI - Reduction in phytic acid content and enhancement of antioxidant properties of nutricereals by processing for developing a fermented baby food. AB - Cereal blends containing pearl millet (Pennisetum glaucum), sorghum (Sorghum bicolor) and oat (Avena sativa) in different ratios were processed (roasted and germinated) and also used as unprocessed flours followed by fermentation with Lactobacillus sp. (Lactobacillus casei and Lactobacillus plantarum). They were screened for total phenolic content (TPC), phytic acid content (PAC) and free radical scavenging activity (FRSA). A formulation with the highest TPC, FRSA and the lowest PAC was selected to optimize a nutricereal based fermented baby food containing selected fermented cereal blends (FCB), rice-corn cooked flour (RCF), whole milk powder (WMP), whey protein concentrate (WPC) and sugar. The optimized baby food formulation contained 37.41 g 100 g(-1) FCB, 9.75 g 100 g(-1) RCF, 27.84 g 100 g(-1) WMP, 5 g 100 g(-1) WPC and 20 g 100 g(-1) sugar. It had high protein, vitamin, minerals, as well as good quantity of carbohydrates and fat, to fulfil the nutritional needs of preschool children of age 1-3 years. The nutricereal based fermented baby food showed high water absorption capacity, dispersibility, wettability and flowability indicating good reconstitution properties. PMID- 26028704 TI - Antioxidant activity of whey protein hydrolysates in milk beverage system. AB - The aim of the present study was to evaluate the antioxidant activity of flavoured milk enriched with antioxidative whey protein hydrolysates (WPHs) by radical scavenging method. Whey protein concentrate (WPC) was hydrolyzed by using three commercial proteases; flavouzyme, alcalase and corolase PP and these WPHs were analyzed for degree of hydrolysis and antioxidant activity. The antioxidant activities of these WPHs were evaluated using ABTS method. Trolox equivalent antioxidant activity of all the hydrolysates i.e. flavourzyme (0.81 +/- 0.04), alcalase (1.16 +/- 0.05) and corolase (1.42 +/- 0.12) was higher than the WPC (0.19 +/- 0.01). Among these, whey protein hydrolysates prepared using corolase showed maximum antioxidant activity. Total 15 beta-lactoglobulin, 1 alpha lactoalbumin, and 6 beta-casein derived peptide fragments were identified in the WPHs by LC-MS/MS. Due to their size and characteristic amino acid composition, all the identified peptides may contribute for the antioxidant activity. The strawberry and chocolate flavoured milk was supplemented with WPC and WPHs and 2 % addition has shown increase in antioxidant activity upto 42 %. The result suggests that WPH could be used as natural biofunctional ingredients in enhancing antioxidant properties of food products. PMID- 26028705 TI - Optimization of microwave assisted extraction (MAE) and soxhlet extraction of phenolic compound from licorice root. AB - In present study, response surface methodology was used to optimize extraction condition of phenolic compounds from licorice root by microwave application. Investigated factors were solvent (ethanol 80 %, methanol 80 % and water), liquid/solid ratio (10:1-25:1) and time (2-6 min). Experiments were designed according to the central composite rotatable design. The results showed that extraction conditions had significant effect on the extraction yield of phenolic compounds and antioxidant capacities. Optimal condition in microwave assisted method were ethanol 80 % as solvent, extraction time of 5-6 min and liquid/solid ratio of 12.7/1. Results were compared with those obtained by soxhlet extraction. In soxhlet extraction, Optimum conditions were extraction time of 6 h for ethanol 80 % as solvent. Value of phenolic compounds and extraction yield of licorice root in microwave assisted (MAE), and soxhlet were 47.47 mg/g and 16.38 %, 41.709 mg/g and 14.49 %, respectively. These results implied that MAE was more efficient extracting method than soxhlet. PMID- 26028706 TI - Effect of moisture on the physical properties of three varieties of kenaf seeds. AB - The physical properties of three kenaf varieties were evaluated as a function of moisture contents varying from 7.67 to 26.21, 7.35 to 25.96 and 7.27 to 25.53 % (dry basis) for cv. Everglades, Tainung and SF-459, respectively. The results showed that the increase in the moisture content of the kenaf seeds linearly decreased the bulk density, true density and rupture force, whereas it linearly increased the length, width, thickness, arithmetic mean diameter, geometric mean diameter, sphericity, surface area, seed volume, thousand seed mass, porosity, angle of repose and terminal velocity. Among the three varieties, maximum values for most selected physical properties of kenaf seeds were obtained for the Everglades seeds. At all moisture contents, the highest static coefficient of friction was found on the plywood surface followed by rubber, then galvanized iron, aluminum, glass and finally stainless steel. This study was conducted to investigate some moisture-dependent physical properties of kenaf seeds. These physical properties are necessary for the design of equipments for harvesting, processing, transportation, sorting, separating and packing. PMID- 26028707 TI - Lipid and fatty acid profile of the edible fungus Laetiporus sulphurous. Antifungal and antibacterial properties. AB - Laetiporus sulphureus is a saprophyte belonging to a specific group of wood decomposing Basidiomycetes growing on deciduous trees. This fungus has been characterized as a herbal medicine and is also known for its antimicrobial properties. In the present study, high energy extraction techniques using different solvents were compared to obtain maximum yield of the edible fungus Laetiporus sulphureus total lipids. The lipid classes and fatty acid composition of the fruiting bodies' total lipids has been studied using GC-FID and Iatroscan TLC-FID analysis. Among the lipids, the neutral lipids predominated followed by phospholipids and glycolipids. Triglycerides were the most abundant in the neutral lipid fraction, whereas phosphatidylcholine in phospholipids. The existence of relatively high amount of sterols may be correlated to fungus pharmaceutical properties. Total lipids were found to contain high unsaturated degree fatty acids (UFA/SFA>3.4) and dominated of C18:2omega-6, C18:1omega-9 and C16:0 fatty acids. Antibacterial and antifungal properties of mushrooms' lipid extracts from two different solvents were also examined. Results indicated that hexane extracts possessed better antifungal and slightly better antibacterial activity compared to chloroform extracts though both were less active than the commercial antimicrobial agents. PMID- 26028708 TI - Vitamin B12 biosynthesis over waste frying sunflower oil as a cost effective and renewable substrate. AB - Statistical experimental designs were used to develop a medium based on waste frying sunflower oil (WFO) and other nutrient sources for production of vitamin B12 (VB12) by Propionibacterium freudenreichii subsp. freudenreichii PTCC 1674. The production of acetic acid and propionic acid were also evaluated using the same microorganism. The amount of WFO in the media was initially optimized. The amount of 4 % w/v of oil found to be an appropriate amount for production of VB12. A Plackett Burman design was then employed to identify nutrients that have significant effect on the production of VB12 in the WFO media. Dimethylbenzimidazolyl (DMB), cobalt chloride, ferrous sulfate, and calcium chloride were the most important compounds. The level optimization of nutrients as the significant factors was finally performed using response surface methodology based on a central composite design. The model predicted that a medium containing 35.56 mg/L DMB, 14.69 mg/L CoCl2.6H2O, 5.82 mg/L FeSO4.7H2O, and 11.41 mg/L CaCl2.2H2O gives the maximum VB12 production of 2.60 mg/L. The optimized medium provides a final concentration of vitamin 170 % higher than that by the original medium. This study offers valuable insights on a cost-effective carbon source for industrial production of food-grade VB12. PMID- 26028709 TI - Process standardization for the manufacture of Thabdi Peda. AB - Traditional dairy products in India are manufactured using age old methods. Such methods varies from place to place. For industrial production of such products a standardized process is needed. Present study was designed to arrive at a method of manufacture for Thabdi Peda, a very popular sweet in Saurashtra region of Gujarat. Range of process parameters like fat percent of milk (4 to 8 %), rate of sugar addition (6 to 10 %) and duration of final heat desiccation (20 to 60 min) were studied and optimum values determined using Response Surface Methodology (RSM) with central composite rotatable design (CCRD). The samples obtained from trials were analyzed for sensory, physicochemical, compositional and textural attributes. The optimized process developed with 10 kg batch of milk having 6 % fat, 8.33 % rate of sugar addition and 34 min duration of heating produced most acceptable product. Standardized Thabdi Peda was found to contain on an average 16.80 % fat, 17.48 % moisture, 11.25 % protein, 20.95 % lactose, 29.99 % sucrose, 3.53 % ash and it gave 28.75 % yield. The pH, water activity and HMF (MU Mole/100 g) content were 6.42, 0.807 and 121.91 respectively. Standard plate count, Yeast and Mold counts were observed to be 3.68 log cfu/g, and 2.51 log cfu/g respectively. No coliforms were observed in Thabdi Peda. PMID- 26028710 TI - Oryzanol as natural antioxidant for improving sunflower oil stability. AB - Sunflower oil is being made shelf stable by the incorporation of synthetic antioxidants such as tertiary butyl hydroquinone (TBHQ), while natural antioxidants like oryzanol and tocopherols can also be used. The aim of the current investigation was to evaluate the antioxidant effect of natural oryzanol (Oz) concentrate (15.5 % oryzanol) and purified Oz (80 % oryzanol) on oxidative and thermal stability of sunflower oil. Sunflower oil was incorporated with Oz concentrate to provide 0, 0.12, 0.25, 0.50, 0.84, 1.0, 1.60, 2.0, 2.5 and 3.20 % oryzanol in the oil, stored for 5 weeks at 37 degrees C and oxidative stability was evaluated. It was found that the oryzanol concentrate showed good antioxidant effect with increase in concentration of oryzanol. In another set of experiments, sunflower oil containing purified Oz at 1 % level individually and in combination with 0.1 % alpha- tocopherol (alpha-T) was heated at 120 degrees C for 24 h to evaluate thermal stability. Sunflower oil containing 1 % Oz (80 % purity) showed 98.40 % and sunflower oil containing 1 % Oz and 0.1 % alpha-T showed 108.75 % antioxidant effect compared to TBHQ taken as 100 %. The study indicated that sunflower oil containing 1 % Oz (80 % purity) and 0.1 % alpha-T combination provides a synergistic effect in inhibiting primary and secondary products and showed highest thermal stability. SFO containing 1 % Oz added as concentrate also showed good antioxidant effect during storage. Hence, instead of using synthetic antioxidants like TBHQ, we can add natural oryzanol (purified or as concentrate) to sunflower oil to increase its oxidative and thermal stability. PMID- 26028711 TI - Effects of antioxidants on the stability of beta-Carotene in O/W emulsions stabilized by Gum Arabic. AB - The potential of oil-in-water emulsions as a beta-carotene delivery system was examined in this study. Oil-in-water (O/W) emulsions containing beta-carotene were formed by gum arabic with alpha-tocopherol, tertiary butyl hydroquinone (TBHQ) and ascorbyl palmitate, respectively. The influence of antioxidants on the chemical degradation of beta-carotene in gum arabic stabilized emulsions was investigated at 4, 25, 45 and 65 degrees C in the dark, respectively. An accelerated photo-oxidation test was carried out at 45 degrees C (450 W/m(2)). Moreover, beta-carotene degradation rate constants (k 1-value), activation energy (E a ) and decimal reduction time (D-value) were estimated to interpret the degradation kinetics. The impact of antioxidants on the thermal stability of beta carotene in diluted emulsions was generally in the following order: alpha tocopherol > TBHQ > ascorbyl palmitate. alpha-Tocopherol was found to be the most effective to the antioxidation of beta-carotene at the concentration of 0.10 wt% under light exposure. It was concluded that the stability of beta-carotene in oil in-water emulsions could be improved by the presence of different antioxidants. PMID- 26028712 TI - Biochemical, textural, microbiological and sensory attributes of gutted and ungutted sutchi catfish (Pangasianodon hypophthalmus) stored in ice. AB - Pangasianodon hypophthalmus (sutchi catfish) is a fresh water catfish extensively being cultured in the South East Asian countries in the recent years. The present study provides the first report on the effects of gutting on the quality characteristics of aquacultured sutchi catfish stored in ice. pH of whole ungutted and gutted catfish didn't show significant difference (p > 0.05) during ice storage period. Total Volatile Base Nitrogen (TVB-N), Alpha Amino Nitrogen (AAN), Free Fatty Acids (FFA) and Thio Barbituric Acid Reactive Substance (TBARS) were lower in gutted fish compared to whole ungutted fish at any particular day during ice storage. However, gutted fish expressed higher rate of primary lipid oxidation than ungutted fish. Textural degradation of the fish muscle as indicated by hardness, cohesiveness, springiness and chewiness was lower in gutted fish. Results of sensory evaluation revealed that gutting has significantly improved the sensory quality of the fish. However, microbiological analysis revealed higher Total Plate Count (TPC) and Enterobactereaceae count in gutted fish. The shelf life of gutted and whole ungutted sutchi cat fish as determined by microbiological analysis was 16-18 days and 18-20 days respectively while storage in ice. PMID- 26028713 TI - Production of date palm fruits free of acaricides residues by ozone technology as post-harvest treatment. AB - Distilled water and ozonated water as postharvest wash treatments for 15-60 min as dipping times were tested to remove two acaricides namely, dicofol and amitraz from different varieties of date fruits. Recovered amount of the acaricides was extracted using solid phase extraction (SPE) and then analyzed by gas chromatography-mass spectrometry (GC-MS). Dicofol removal percentages in the presence of ozone increased in the order of Nabtet Aly > Nabout Seif > Khalas > Sakay, while amitraz removal increased in the order of Nabtet Aly > Nabout Seif > Sakay > Khalas, respectively, and the percentages of residues on date fruits depended on the dipping time. Kinetic studies revealed that dicofol and amitraz were easily removable from date fruits treated with ozonated water. Ozone-treated date palm fruits were not associated with significant changes in antioxidant capacity, and phenolic and sugar contents. Due to the large amount of dates consumed by Saudi residents, a higher risk of exposure to pesticides, especially in children and other vulnerable individuals may occur and the search for safety methods to remove pesticides with negligible residual deposits has always been preferred. Therefore, the present study validated that ozone technology as wash treatments is safe and promising processes for the removal of acaricides from date fruits surface under domestic conditions to reduce the impact over consumer's health. PMID- 26028714 TI - Antioxidant and sensory properties of protein hydrolysate derived from Nile tilapia (Oreochromis niloticus) by one- and two-step hydrolysis. AB - Antioxidant and sensory properties of Nile tilapia protein hydrolysates prepared by one- and two-step hydrolysis using commercial proteases were investigated. Hydrolysates prepared using single protease including Alcalase (HA), Flavourzyme (HF), Protamex (HPr) and papain (HPa) had increases in antioxidant activities as the degree of hydrolysis (DH) increased up to 40 % (P < 0.05). Amongst all hydrolysates, HA having 40 % DH showed the highest antioxidant activities. When HA was further hydrolysed by papain, the resulting hydrolysate (HAPa) exhibited the highest antioxidant activities for all assays tested (P < 0.05). ABTS radical scavenging activity and metal chelating of HAPa generally remained constant in a wide pH range (1-11) and during heating at 30-100 degrees C. Both activities increased in the simulated gastrointestinal tract model system, especially in intestine condition. HAPa (100-1,000 ppm) could retard lipid oxidation in beta carotene-linoleate and lecithin-liposome model systems in a dose dependent manner. Peptides in both HA and HAPa with molecular weight of 513 Da and 1,484 Da possessed the strongest ABTS radical scavenging activity and metal chelating activity, respectively. The amino acid profile of both HA and HAPa contained a high amount of hydrophobic amino acids (38.26-38.85 %) and had glutamic acid/glutamine, lysine and aspartic acid/asparagine as the dominant amino acids. However, HAPa showed a higher acceptability than did HA, owing to the lower bitterness. Therefore, the use of Alcalase in combination with papain for hydrolysis of protein isolate rendered the hydrolysate with antioxidant properties and reduced bitterness, which could serve as the functional supplement. PMID- 26028715 TI - Effects of added sucrose and pectin on the rheological behavior and freezing kinetics of passion fruit pulp Studied by response surface methodology. AB - The effects of pectin and sucrose addition on the rheological parameters and freezing kinetic of passion fruit pulp were studied. The effect of the air-blast freezing of passion fruit at -20 degrees C on the rheological parameters before and after freezing was evaluated. The rheological analyses were carried out using a viscometer at 25 degrees C, and the readings were converted into rheological measurements using the Mitschka method and fitted to the Ostwald-de Waele model. The freezing kinetics was analyzed using a controlled-temperature cold-stage instrument, which was coupled to a microscope integrated with a video capture system. The concentrations of sucrose and pectin were established using a Composite Rotational Design. The pulps combined with the additives exhibited a pseudoplastic behavior, and the values for the index flow (n) and consistency index (k) before and after freezing differed and were dependent on the additive concentrations. The rates of increase for the frozen areas were evaluated in a microfreezer and were significantly influenced by the additive concentrations. These concentrations were those that presented a lower index flow and a higher consistency index. The results are discussed in terms of the solubility and interaction of the pectin added to the fruit pulp with low pH, the presence of sucrose and low temperature. PMID- 26028716 TI - Water resistance and mechanical property improvement of tilapia (Tilapia zillii) scale gelatin films by dehydrated thermal treatment. AB - The effect of dehydrated thermal treatment on the tilapia scale gelatin films was investigated to improve their water resistance and mechanical properties. The gelatin extracted from tilapia scales was mainly composed of beta-chain, alpha chain and their degraded products with imino acid content of 21.2 %. When the films prepared from tilapia scale gelatin were heated at 80 degrees C, no significant changes in the properties of films were observed. As heating temperature was increased to 100 or 120 degrees C, the tensile strength of films was increased gradually with increasing thermal treatment time, while film solubility and protein solubility were decreased. Based on the SDS-PAGE analysis and the protein solubility of the gelatin films in various protein denaturant solutions, it was found that the cross-linking in the gelatin film network between beta-chain and alpha-chain could be induced by heating at 120 degrees C. It was revealed that the main interactions involved in the gelatin film formation were changed from ionic bonds and hydrogen bonds to hydrophobic interactions and covalent bonds, leading to improve water resistance properties of films. PMID- 26028717 TI - Flavonoid rich extract of Murraya Koenigii alleviates in-vitro LDL oxidation and oxidized LDL induced apoptosis in raw 264.7 Murine macrophage cells. AB - Several lines of evidences have established a lineage between Oxidised LDL (Ox LDL) to apoptosis of macrophages in which the high level of intracellular cholesterol play a crucial role. This study assesses the potency of Murraya koenigii (MK) leaf extract in alleviating LDL oxidation and Ox-LDL induced lipotoxicity in murine macrophage (RAW 264.7) cells. Results indicated that presence of MK extract prevented oxidation of LDL as evidenced by its oxidation kinetics and formation of LDL oxidation products. Also, MK extract accounted for improvement in cell viability and mitochondrial membrane potential of Ox-LDL treated cells. The Ox-LDL induced increment in intracellular oxidative stress, nuclear condensation and apoptosis was effectively prevented by MK extract possibly due to their established anti-oxidant and free radical scavenging potentials which may be attributed to the presence of flavonoids present in the extract. Prevention of oxidative modification of LDL, free radical induced damage and Ox-LDL induced death of RAW 264.7 cells provide preliminary evidences of its anti-atherosclerotic potential and warrants further elucidation and validation for its use in-vivo and may be useful as a functional food supplement and an alternative medicine to prevent LDL oxidation and oxidized LDL induced toxicity. PMID- 26028718 TI - Effect of active packaging on low-sodium restructured chicken steaks. AB - Contributing for a healthier lifestyle, the technology of active and biodegradable packaging with antimicrobial and/or antioxidants compounds and reduced sodium intake have been increasingly applied in meat and meat products. Thus, the objective of this research was to assess the effectiveness of oregano essential oil (OEO) and potassium sorbate incorporated in packaging applied to the restructured chicken steaks with 40 % reduction in sodium chloride in frozen storage for 150 days. The composition of packaging did not influence moisture, crude protein, total lipids, ash, sodium and potassium content as well as pH evaluated on days 0 and 150. Salty taste was the only significant indication in the sensory analysis (p < 0.05). The use of 1 % and 0.5 % OEO incorporated in packaging reduced rancidity through lipid oxidation and can be regarded as an active antioxidant; the use of oregano or potassium sorbate in active films caused the development delay effect E. coli. Thus, the use of active packaging may maintain the product quality. PMID- 26028719 TI - A mixture design approach to optimizing low cholesterol mayonnaise formulation prepared with wheat germ protein isolate. AB - The aim of this study was to optimize the mixture proportion of low cholesterol mayonnaise containing wheat germ protein isolate (WGPI) and xanthan gum (XG), as emulsifying agents in mayonnaise preparation. The mayonnaise prepared with different combinations of WGPI, egg yolk (0-9 % of each component) and XG (0-0.5 %). The optimized mixture proportions of low cholesterol mayonnaise were determined by applying the optimal mixture design method to acquire the mayonnaise with proper stability, texture, rheological properties and sensory scores. Optimum values of WGPI, XG and egg yolk in the mixture were found to be 7.87 %, 0.2 % and 0.93 %, respectively (of 9 % egg yolk). The WGPI, due to unique functional properties, had the greatest effect on properties of mayonnaise samples. Moreover, combination of XG and WGPI, improved the stability, heat stability, viscosity, consistency coefficient and textural properties of product. However, the overall acceptance was maximum in a mixture contained high amount of WGPI and XG and low amount of egg yolk. The results of this research showed the feasibility of preparation a low cholesterol mayonnaise by application a desirable combination of WGPI, XG, and egg yolk, with comparable properties those of the conventional mayonnaise. PMID- 26028720 TI - Effect of 24-epibrassinolide treatment on the metabolism of eggplant fruits in relation to development of pulp browning under chilling stress. AB - This study aims to investigate the effect of 24-epibrassinolide (EBR) on the metabolism in relation to development of chilling injury-induced pulp browning of eggplant fruit. The fruits were dipped for 10 min in solutions containing 10 MUmM EBR and then stored at 1 degrees C for 15 days. Chilling injury index, weight loss, electrolyte leakage and malondialdehyde (MDA) content of control fruit increased during storage. Chilling injury improved phenylalanine ammonia-lyase (PAL), polyphenol oxidase (PPO), and peroxidase (POD) activities, which are correlated with the increase of total phenolic content and pulp browning of eggplant fruit. The inhibition of pulp browning by EBR treatment was possibly attributed to preserving the cell membrane integrity, reducing total phenolic content, and decreasing PAL, PPO, and POD activities. These results suggest that EBR may inhibit chilling injury and pulp browning in eggplant fruit during cold storage. PMID- 26028721 TI - Therapeutic effect of umbelliferon-alpha-D-glucopyranosyl-(2(I)->1(II))-alpha-D glucopyranoside on adjuvant-induced arthritic rats. AB - The aim and objective of the present investigation was to evaluate the antiarthritic and antioxidant effect of umbelliferon-alpha-D-glucopyranosyl-(2I >1II)-alpha-D-glucopyranoside (UFD) in chemically induced arthritic rats. The different doses of the UFD were tested against the turpentine oil (TO), formaldehyde induced acute arthritis and complete fruend's adjuvant (CFA) induced chronic arthritis in Wistar rats. Arthritic assessment and body weight was measured at regular interval till 28 days. On day 28, all the groups animals were anaesthetized, blood were collected from the puncturing the ratro orbital and estimated the hematological parameters. The animals were sacrificed; synovial tissue was extracted and estimated the malonaldehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD). The different doses of the UFD showed the protective effect against turpentine oil, formaldehyde induced acute arthritis and CFA induced chronic arthritis at dose dependent manner. Acute model of arthritis such as TOand formaldehyde induced inflammation due to releasing of the inflammatory mediators; significantly inhibited by the UFD at dose dependent manner. CFA induced arthritic rats treated with the different doses of the UFD showed the inhibitory effect on the delayed increase in joint diameter as seen in arthritic control group rats. UFD significantly improved the arthritic index, body weight and confirmed the antiarthritic effect. UFD showed the effect on the hematological parameter such as improved the level of the RBC, Hb and decline the level of the EBC, ESR and confirmed the immune suppressive effect. UFD significantly improved the level of the endogenous antioxidant and confirmed the antioxidant effect. This present investigation suggests that the UFD has prominent antiarthritic impact which can be endorsed to its antiarthritic and antioxidant effects. PMID- 26028722 TI - Functional properties and structure changes of soybean protein isolate after subcritical water treatment. AB - Subcritical water is an emerging method in food industry. In this study, soybean protein isolate (SPI) was treated by subcritical water (SBW) at various temperatures (0, 120, 160, 200 degrees C) for 20 min. The changes in the appearances, physicochemical properties and structural changes were investigated. After SBW treatment, the color of SPI solution modified turned to be yellow. The mean particle size and turbidity of SPI had similar behaviors. The mean particle size was decreased from 263.7 nm to 116.8 nm at 120 degrees C and then reached the maximum at 160 degrees C (1446.1 nm) due to the aggregation of protein. Then it was decreased to 722.9 nm at 200 degrees C caused by the protein degradation. SBW treatment could significantly enhance the solubility, emulsifying and foaming properties of SPI. With increasing temperature, the crystalline structure of protein was gradually collapsed. The degradation of the protein advanced structure occurred, especially at 200 degrees C revealed by ultra-high resolution mass spectrometry. Better functional properties exhibited in hydrolysis products indicating that SBW treatment could be used as a good method to modify the properties of soy proteins isolate for specific purposes under appropriate treatment condition. PMID- 26028723 TI - Optimization of processing conditions to improve antioxidant activities of apple juice and whey based novel beverage fermented by kefir grains. AB - A central composite design (CCD) was used to evaluate the effects of fermentation temperature (20-30 oC) and kefir grains amount (2-8%w/v) on total phenolic content and antioxidant activities of apple juice and whey based novel beverage fermented by kefir grains. The response surface methodology (RSM) showed that the significant second-order polynomial regression equation with high R(2) (>0.86) was successfully fitted for all response as function of independent variable. The overall optimum region was found to be at the combined level of 7.56%w/v kefir grains and temperature of 24.82 oC with the highest value for total phenolic content (TPC) and antioxidant activities. At this optimum point TPC, 1, 1 Diphenyl-2-picrylhydrazyl radical scavenging, metal chelating effect, reducing power, inhibition of linoleic acid autoxidation and inhibition of ascorbate autoxidation were 165.02 mgGA/l, 0.38 ml/1 ml, 0.757 (absorbance at 700 nm), 46.12 %, 65.33 % and 21 %, respectively. No significant difference (p < 0.05) was found between actual values and predicated values. PMID- 26028724 TI - Effect of pre-treatments and drying methods on quality attributes of sweet bell pepper (Capsicum annum) powder. AB - Pre-treatments and methods of drying for producing good quality dried bell pepper powder for use in the ready-to-eat (RTE) food products were optimized. Out of various pre-treatments used (blanching in boiling water, KMS, CA and combination of KMS + CA at different concentrations), soaking of bell pepper shreds in KMS@ 0.20 % + CA@ 0.50 % after blanching fasten the drying process (19.75 h) compared to control (22.60 h), when dried in mechanical dehydrator at 58 +/- 2 degrees C. Blanching prior to drying improved the rate of drying and produced product with lower acidity (1.25 %). The samples (T7) treated with KMS@ 0.20 % + CA@ 0.50 % significantly (p < 0.05) retained the ascorbic acid content (47.75 mg/100 g) and also attained highest score for colour (8.0), texture (7.5) and overall acceptability (7.5) compared to rest of the treatments. Among different methods of drying, pre-treated bell peppers dried in solar poly tunnel drier produced bright red coloured powder with relatively higher amounts of sugars and ascorbic acid content, hence was optimized. Visual lump formation was observed at 19.75 % and 18.50 % critical moisture contents, which equilibrated at 42 % and 45 % RH for bell pepper powders dried in a mechanical dehydrator and solar poly tunnel drier, respectively. PMID- 26028725 TI - Physical, functional, and pasting properties of flours from corms of two Cocoyam (Colocasia esculenta and Xanthosoma sagittifolium) cultivars. AB - Physical, functional and physicochemical properties of flours of five cocoyam (Colocasia spp and Xanthosoma spp) cultivars were evaluated. Colour (L*a*b*) parameters of corms and flours, pasting and functional properties of the flours were determined. Xanthosoma spp showed significantly higher length (95.16 151.46), width (75.29-78.03) and weight (179.20-605.94) than the Colocasia spp., but the parameters did not vary significantly within either Xanthosoma and Colocasia spp. Generally, colour of peeled corms [L* (72.08-78.93); a* (+1.06 - +3.5); b* (+17.65 - +35.80)] was lighter than the flours [L* (69.35-84.97); a* (+0.30 - + 4.76); b* (+4.44 - +23.48)]. The NXs001 showed significantly higher peak (201.71RVU), trough (186.75 RVU), final (289.75 RVU) and setback (103 RVU) viscosities that the other cultivars. Pasting profiles of the cocoyam flours showed similar trend with the NXs001 showing a steeper curve. Pasting temperature and peak time ranged from 87.33 to 92.53 degrees C and 5.17-6.34 min, respectively. Water absorption capacity, gelling point, pH, foam capacity, bulk density and swelling power varied from 32-69 %, 6.56-7.59, 58.5-72.5 degrees C, 7.19-14.72 %, 0.94-1.01 g/mL and 3.18-7.36, respectively. PMID- 26028726 TI - Effect of cold pre-fermentative maceration on the color and composition of young red wines cv. Tannat. AB - Cold Pre-fermentative Maceration (CPM) is an interesting winemaking technique to enhance the extraction of pigments, aroma and flavour compounds from grape skins to wine. This work aimed to evaluate the effect of Cold Pre-fermentative Maceration (CPM) on the composition of Tannat red wines produced in Uruguay in several vintages. For this purpose, wines elaborated by CPM were compared with control wines produced by Traditional Maceration (TM) in 4 years. Control wines (TM) were made with classical fermentation on skins. The CPM was carried out with additions of dry ice for 5 days to keep the must at 10 oC. Wines were analysed at devatting. The impact of CPM on composition and color of wines was different in each year. Color intensity was significantly higher in CPM than control wines in 2007 and 2009 whereas the anthocyanins levels were higher in control wines every year. However, CPM wines had the highest polyphenols contents in 2007, 2009 and 2010 principally due to their catechins and proanthocyanidins contents. Anthocyanin profile was similar in the wines of each vintage, according to the varietal fingerprint. The highest contents of higher alcohols were verified in CPM wines. The Cold Pre-fermentative Maceration could have an important effect on the characteristics of Tannat red wines, although it depends strongly on the composition of the grapes of origin. PMID- 26028727 TI - Effects of multiple freezing (-18 +/- 2 degrees C) and microwave thawing cycles on the quality changes of sea bass (Dicentrarchus labrax). AB - Sensory, chemical [pH, total volatile basic nitrogen (TVB-N), trimethylamine (TMA N), thiobarbituric acid (TBA)] and composition (crude protein and crude lipid) analyses were carried out on whole, gutted and fillets of seabass that were frozen (-18 +/- 2 degrees C) and thawed more than once in microwave. It was detected that the sensorial acceptability values decreased certainly for all fish samples (whole, gutted and fillets of sea bass) when compared with control group. While chemical (pH, TVB-N, TMA-N, TBA) values increased, crude protein and crude lipid values decreased after the multiple freezing and thawing cycles under microwave. The obtained results offered that thawing by microwave is not appropriate sea bass because of the undesirable cooking effect of microwave to the some parts of fish such as tail, eye and fins. Also skin dryness, moisture losses in eye fluids and textural deteriorations were observed. Significant differences (P < 0.05) were found in general acceptability values and pH, TVB-N, TBA and crude protein results among the sea bass groups thawed in microwave conditions. PMID- 26028728 TI - Effect of aqueous extracts of Mentha arvensis (mint) and Piper betle (betel) on growth and citrinin production from toxigenic Penicillium citrinum. AB - Due to growing concern of consumers about chemical residues in food products, the demand for safe and natural food is increasing greatly. The use of natural additives such as spices and herbal oil as seasoning agents for their antimicrobial activity has been extensively investigated. This paper discusses the efficacy of the aqueous extract of mint (Mentha arvensis) and betel (Piper betle) on the mycelial growth and citrinin production of Penicillium citrinum. The present investigation revealed that mint extract inhibited citrinin production up to 73 % without inhibiting the mycelium growth. The citrinin production decreased with increase in the concentration of mint extract as observed from the data obtained from High pressure liquid chromatography. The samples also showed reduced cytotoxicity on HeLa cells. On the other hand betel extract resulted in stimulatory effect on citrinin production and mycelial growth. The study showed that mint extract has the potential to be used safely for restraining citrinin contamination. PMID- 26028729 TI - Antioxidant effect of supercritical CO2 extracted Nigella sativa L. seed extract on deep fried oil quality parameters. AB - Effect of supercritical CO2 extracted Nigella sativa L. seed extract (NE) on frying performance of sunflower oil and refined, bleached and deodorized (RBD) palm olein was investigated at concentrations of 1.2 % and 1.0 % respectively. Two frying systems containing 0 % N. sativa L. extract (Control) and 0.02 % butylated hydroxytoluene (BHT) were used for comparison. Physicochemical properties such as fatty acid composition (FAC), Peroxide Value (PV), Anisidine Value (AV), Totox Value (TV), Total Polar Content (TPC), C18:2/C16:0 ratio and viscosity of frying oils were determined during five consecutive days of frying. Results have shown that N. sativa L. extract was able to improve the oxidative stability of both frying oils during the frying process compared to control. The stabilizing effect of antioxidants were in the order of BHT > NE. RBD palm olein was found to be more stable than sunflower oil based on the ratio of linoleic acid (C18:2) to palmitic acid (C16:0) and fatty acid composition. PMID- 26028730 TI - Characterization of the new biodegradable WPI/clay nanocomposite films based on kefiran exopolysaccharide. AB - Physico-mechanical, thermal and structural characteristics of nanocomposite film composed of kefiran-whey protein isolate (WPI)-montmorillonite (MMT; 1, 3 and 5 % w/w) were studied. Incorporation of MMT significantly affected the mechanical attributes of the kefiran-WPI films. The tensile strength and Young's modulus increased and the percentage of elongation at break decreased as the MMT content increased. Moisture content, moisture absorption and water solubility decreased as the MMT concentration increased. Differential scanning calorimetry indicated that the glass transition temperature for kefiran-WPI film was -12.5 degrees C and was noticeably affected by an increase in MMT. X-ray diffraction analysis showed formation of an exfoliated structure with the addition of small amounts of MMT to the kefiran-WPI matrix. Intercalation and some exfoliation occurred up to 5 % (wt) increase in MMT. Scanning electron microscopy demonstrated ideal dispersion for MMT nanoparticles into the structure of the bio-nanocomposite films. PMID- 26028731 TI - Characterization of digestive enzymes from de-oiled mackerel (Scomber japonicus) muscle obtained by supercritical carbon dioxide and n-hexane extraction as a comparative study. AB - The oil in mackerel muscle was extracted using an environmental friendly solvent, supercritical carbon dioxide (SC-CO2) at a semi-batch flow extraction process and an n-hexane. The SC-CO2 was carried out at temperature 45 degrees C and pressures ranging from 15 to 25 MPa. The flow rate of CO2 (27 g/min) was constant at the entire extraction period of 2 h. The highest oil extracted residues after SC-CO2 extraction was used for activity measurement of digestive enzymes. Four digestive enzymes were found in water soluble extracts after n-hexane and SC-CO2 treated samples. Amylase, lipase and trypsin activities were higher in water soluble extracts after SC-CO2 treated samples except protease. Among the four digestive enzymes, the activity of amylase was highest and the value was 44.57 uM/min/mg of protein. The water soluble extracts of SC-CO2 and n-hexane treated mackerel samples showed same alkaline optimum pH and pH stability for each of the digestive enzymes. Optimum temperature of amylase, lipase, protease and trypsin was 40, 50, 60 and 30 degrees C, respectively of both extracts. More than 80 % temperature stability of amylase, lipase, protease and trypsin were retained at mentioned optimum temperature in water soluble extracts of both treated samples. Based on protein patterns, prominent protein band showed in water soluble extracts after SC-CO2 treated samples indicates no denaturation of protein than untreated and n-hexane. PMID- 26028732 TI - Evaluating the antimicrobial activity of Nisin, Lysozyme and Ethylenediaminetetraacetate incorporated in starch based active food packaging film. AB - The pleothera of micro organisms obtained from contaminated food cultured in a starch broth was effectively tested against antibacterial agents, i.e. nisin, lysozyme and chelating agent EDTA. A variety of combination treatments of these antimicrobial agents and their incorporation in Starch based active packaging film according to their permissibility standards was done. 4 variables of Nisin concentration (ranging from 0 to 750 IU/ml), 3 variables of lysozyme concentration (ranging from 0 to 500 IU/ml) and 3 variables of EDTA concentration from (0 to 20 MUM) were chosen. Bacterial inhibition by combination of different levels of different factors without antimicrobial films was evaluated using a liquid incubation method. The samples were assayed for turbidity at interval of 2, 4 and 24 h to check effectiveness of combined effects of antimicrobial agents which proved a transitory bactericidal effect for short incubation times. Zone of Inhibition was observed in the antimicrobial films prepared by agar diffusion method. Statistical analysis of experimental data for their antimicrobial spectrum was carried out by multi regression analysis and ANOVA using Design Expert software to plot the final equation in terms of coded factors as antimicrobial agents. The experimental data indicated that the model was highly significant. Results were also evaluated graphically using response surface showing interactions between two factors, keeping other factor fixed at values at the center of domain. Synergy was also determined among antibacterial agents using the fractional inhibitory concentration (FIC) index which was observed to be 0.56 supporting the hypothesis that nisin and EDTA function as partial synergistically. The presented work aimed to screen in quick fashion the combinatorial effect of three antimicrobial agents and evaluating their efficacy in anti microbial film development. PMID- 26028733 TI - Folate fortification of skim milk by a probiotic Lactococcus lactis CM28 and evaluation of its stability in fermented milk on cold storage. AB - In order to enhance folate levels in fermented foods, a folate producing probiotic lactic acid bacterium isolated from cow's milk and identified as Lactococcus lactis CM28 by 16S rRNA sequencing was used to fortify skim milk. Optimization of medium additives such as folate precursors, prebiotics and reducing agents along with suitable culture conditions enhanced folate levels in skim milk. Optimization resulted in a four fold increase in the extracellular folate (61.02 +/- 1.3 MUg/L) and after deconjugation the total folate detected was 129.53 +/- 1.2 MUg/L. The effect of refrigerated storage on the viability of L. lactis, pH, titratable acidity (TA) in terms of percentage lactic acid and finally on the stability of folate was determined. Only a slight variation in pH (4.74 +/- 0.02 to 4.415 +/- 0.007) and acidity (0.28 +/- 0.028 to 0.48 +/- 0.014 %) was noted during folate fermentation. During storage, only less than a log unit reduction was noted in the viable count of the probiotic after 15 days and about 90 % of the produced folate was retained in an active state. PMID- 26028734 TI - Design and testing of small scale fish meat bone separator useful for fish processing. AB - The present study relates to the food processing machinery and, more specifically machine for producing boneless comminuted meat from raw fish fillet. This machine is of belt and drum type meat bone separator designed for small scale fish processing in a continuous mode. The basic principal involved in this machine is compression force. The electric geared motor consists of 1HP and the conveyor belt has a linear velocity of 19 to 22 m min(-1), which was sufficient to debone the fish effectively. During the meat bone separation trials an efficiency up to 75 % on dressed fish weight basis was observed and with a capacity to separate 70 kg h(-1) of meat from fish at the machine speed of 25 rpm. During the trials, it was demonstrated that there was no significant change in the proximate composition of comminuted fish meat when compared to unprocessed fish meat. This design has a greater emphasis on hygiene, provision for cleaning-in-place (CIP) and gives cost effective need and reliability for small scale industries to produce fish meat in turn used for their value added products. PMID- 26028735 TI - Influence of Button mushroom (Agaricus bisporus) on quality and refrigerated storage stability of patties prepared from sutchi catfish (Pangasius hypophthalmus). AB - The ability of button mushroom (Agaricus bisporus) in changing physical, chemical, microbial and sensory properties of fish patties prepared from sutchi catfish (Pangasius hypophthalmus) was investigated. Two batches of fresh patties were prepared, one batch was treated with 15 % button mushroom (TP) and other batch was a control (CP) without mushroom. The patties were packed in polythene bags and stored under refrigerated condition (6 +/- 2 oC) without adding any preservatives for the estimation of storage stability. The analyses of patties were conducted at regular intervals of 3 days. The results showed that, Peroxide value, Thiobarbituric acid value, Free fatty acids increased significantly in CP at the end of 12 days whereas the TP was within the acceptable limit up to 16 days. Total volatile base nitrogen and Trimethylamine nitrogen also showed a similar trend. The Total plate count and Aerobic spore formers showed an increasing trend in CP when compared to TP. The sensory scores showed that the overall acceptability of CP were lower than TP, which was acceptable even after 16 days of storage. The present study showed that, the quality and storage stability of TP were observed to be in good condition up to 16 days and started deteriorating 20th day onwards, whereas the CP were acceptable only up to 12 days. Therefore it can be recommended that, addition of 15 % of button mushroom to sutchi catfish patty not only increases the nutritional quality but also increases the shelf life of patties under refrigerated storage. PMID- 26028736 TI - Aqueous two phase partitioning of fish proteins: partitioning studies and ATPS evaluation. AB - A suitable Aqueous Two Phase System (ATPS) has been identified for the partitioning of crude fish proteins from fish processing industrial effluent. A detailed study has been performed to analyze the influence of various parameters on protein partitioning such as molecular weight of PEG, effect of different salts (MgSO4, K2HPO4, Na3C6H5O7, Na2SO4, (NH4) 2PO4, K3C6H5O7) and their concentrations, pH, temperature, Tie Line Length (TLL), effluent loading and volume ratio. PEG 2000 - sodium sulphate ATPS was found to be a most favourable system among the selected ATPS for higher partition coefficient of proteins. The binodal curve and equilibrium characteristics of PEG 2000 - sodium sulphate were established and fitted to empirical equations. The equilibrium compositions (tie line) were correlated using Othmer-Tobias and Bancroft equations. PMID- 26028737 TI - Potential assessment of Rumex vesicarius L. as a source of natural antioxidants and bioactive compounds. AB - The present work is designed to evaluate the antioxidant activities of hydroalcoholic extract (HAE) and its fractions (viz., hexane (HF), chloroform (CF), ethyl acetate (AF), n-butanol (BF) and water (WF)) obtained from aerial part of Rumex vesicarius L. by using different in vitro antioxidant assays. The content in pigments (carotenoids and chlorophylls), total phenolics, flavonoids and tannins were determined using spectrophotometric methods. Qualitative analyses of major phenolics by TLC analysis were also evaluated. Experimental results obtained show that R. vesicarius is a rich source of beta-carotene (116.83 +/- 1.60 MUg/g DW), lycopene (156.40 +/- 1.59 MUg/g DW) and chlorophyll a (271.45 +/- 3.46 MUg/g DW). The greatest antioxidant activity was found in AF (IC50.DPPH = 0.07 +/- 0.00 mg/ml) followed by BF and CF (0.15 +/- 0.00 and 0.16 +/- 0.00 mg/ml, respectively). These fractions were also better in their effect on reducing the oxidation of beta-carotene. Reducing power of crude methanol extract/fractions increased with increasing concentration of the extract. The amount of total phenolics varied from 0.37 +/- 0.01 to 43.28 +/- 0.28 mg GAE/g of dry weight, HAE had the higher content (43.28 +/- 0.28 mg GAE/g of DW). A negative correlation was found between phenolic compounds and the antioxidant efficiencies of the crude extract/fractions, suggesting that phenolic compounds are not the only contributors to the antioxidant activities of Rumex vesicarius. The present findings suggest that Rumex vesicarius L. can be used as natural antioxidant source to prevent damage associated with free radicals. PMID- 26028738 TI - Effect on oxidative stress, glucose uptake level and lipid droplet content by Apigenin 7, 4'-dimethyl ether isolated from Piper longum L. AB - Piper longum L. (Family: Piperaceae), is a widely used herb in several Ayurvedic formulations prescribed for various diseases. Potential of the plant material as an antidiabetic and cardio protective agent has not been evaluated so far. In the study, we designed experiments to evaluate antioxidant, glucose uptake potential and lipid content regulating potential of extracts and compound from P. longum fruits. Solvent extracts from Piper longum fruits using hexane, ethyl acetate, methanol, 70 % methanol-water were taken and apigenin 7, 4'-dimethyl ether (ADE) was isolated from ethyl acetate extract. Antioxidant activity, glucose uptake potential and adipocyte differentiation assay was performed with extract and pure compound. Antioxidant activity in terms of TRP (196.03 MUg/mg GAE), DPPH assay (IC50-173.09 MUg/mL), hydroxyl radical scavenging assay (IC50-20.42 MUg/mL), inhibiting LDL oxidation (IC50-51.99 MUg/mL) and to enhance SOD activity (25.3 %) was higher in ethyl acetate extract (EAP). Phenolic and flavonoid content was measured and showed a positive correlation with antioxidant activity. Presence of apigenin 7, 4'-dimethyl ether (ADE) and piperine (Pip) in EAP was determined by HPTLC analysis and was isolated. ADE inhibited alpha-glucosidase and alpha amylase enzymes and enhanced 2-NBDG uptake in L6 cells. Hypolipidemic effect of ADE on mouse pre-adipocyte (3T3L1) cell lines also showed a dose dependent reduction on lipid droplet content and effective concentration range was determined as 1-2.5 MUg/mL. The results suggested that Piper longum fruits can provide a natural source of antioxidants with antidiabetic and anti obesity potential. PMID- 26028739 TI - Production, optimization and characterization of lactic acid by Lactobacillus delbrueckii NCIM 2025 from utilizing agro-industrial byproduct (cane molasses). AB - In the present work Lactobacillus delbrueckii was used to utilize agro-industrial byproduct (cane molasses) for lactic acid production under submerged fermentation process. Screening of LAB was done by Fourier transform infra red spectroscopy (FTIR). Effect of different amino acids (DL-Phenylalanine, L-Lysine and DL Aspartic acid) on the fermentation process was done by high performance liquid chromatography (HPLC). Central composite rotatable design (CCRD) was used to optimize the levels of three parameters viz. tween 80, amino acid and cane molasses concentration during fermentative production of lactic acid. Under optimum condition lactic acid production was enhanced from 55.89 g/L to 84.50 g/L. Further, validation showed 81.50 g/L lactic acid production. Scale up was done on 7.5 L fermentor. Productivity was found to be 3.40 g/L/h which was higher than previous studies with reduced fermentation time from 24 h to 12 h. Further characterization of lactic acid was done by FTIR. PMID- 26028740 TI - Pectinase production by Aspergillus niger using banana (Musa balbisiana) peel as substrate and its effect on clarification of banana juice. AB - Optimization of substrate concentration, time of incubation and temperature for crude pectinase production from A. niger was carried out using Bhimkol banana (Musa balbisiana) peel as substrate. The crude pectinase produced was partially purified using ethanol and effectiveness of crude and partially purified pectinase was studied for banana juice clarification. The optimum substrate concentration, incubation time and temperature of incubation were 8.07 %, 65.82 h and 32.37 degrees C respectively, and the polygalacturonase (PG) activity achieved was 6.6 U/ml for crude pectinase. The partially purified enzyme showed more than 3 times of polygalacturonase activity as compared to the crude enzyme. The SDS-PAGE profile showed that the molecular weight of proteins present in the different pectinases varied from 34 to 42 kDa. The study further revealed that highest clarification was achieved when raw banana juice was incubated for 60 min with 2 % concentration of partially purified pectinase and the absorbance obtained was 0.10. PMID- 26028741 TI - Microencapsulation of wheat germ oil. AB - Wheat germ oil (WGO) is beneficial for health since it is a rich source of omega 3, omega-6 and tocopherol. However, as it contains polyunsaturated fatty acids, it is prone to oxidation. The aim of this study was to encapsulate wheat germ oil and determine the effects of core to coating ratio, coating materials ratio and ultrasonication time on particle size distribution of emulsions and encapsulation efficiency (EE) and surface morphology of capsules. Maltodextrin (MD) and whey protein concentrate (WPC) at different ratios (3:1, 2:2, 1:3) were used as coating materials. Total solid content of samples was 40 % (w/w). Five core to coating ratios (1:8, 1:4, 1:2, 3:4, 1:1) were tried. Ultrasound was used at 320 W and 20 kHz for 2, 5, 10 min to obtain emulsions. Then, emulsions were freeze dried to obtain microcapsules. It was observed that, increasing WPC ratio in the coating resulted in higher encapsulation efficiency and smaller particle size. Microcapsules prepared with MD:WPC ratio of 1:3 were found to have higher EE (74.35-89.62 %). Increase in oil load led to decrease in EE. Thus 1:8 core to coating ratio gave better results. Increasing ultrasonication time also had a positive effect on encapsulation efficiency. PMID- 26028742 TI - The process of producing tomato paste by ohmic heating method. AB - In this study, the effect of ohmic heating technique on electrical conductivity, water evaporation rate, heating rate, colour parameters, pH and energy consumption of tomato samples was investigated. Ohmic heating was accomplished till the moisture content of the tomato samples reduced from initial moisture content of as 9.33 (dry basis) to a safer level of 2.2. The results of the nonlinear mathematical model including the effects of voltage gradient level and the temperature on the electrical conductivity changes had good agreement (R >= 0.955) with the experimental data. Also, it was observed that the electrical conductivity increased along with concentration of tomato samples. The range of electrical conductivity during ohmic heating was 3.19-8.95 (S/m). It was found that processing time decreased from 28.32 to 4.3 min over the voltage gradient range studied (6 to 14 V/cm), which resulted in decreased specific energy consumption from 4.63 to 3.05 (MJ/kg water). Due to increasing of heating rate and water evaporation rate at high voltage gradient, the change of the pH was limited. Samples processed in high voltage gradient had higher L*, b* and hue angle (h), lower a* and Chroma (C) values as compared to low voltage gradient. The optimum value of processing time, pH, colour, specific energy consumption was obtained at 14 V/cm voltage gradient level. PMID- 26028743 TI - Preharvest salicylic acid treatments to improve quality and postharvest life of table grapes (Vitis vinifera L.) cv. Flame Seedless. AB - Significance of preharvest salicylic acid (SA) treatments on maturity, quality and postharvest life of grape cv. Flame Seedless were studied during two years. The experiment was performed on 12-year old own rooted, grapevines planted at 3 m * 3 m spacing trained on overhead system. Vines were treated with aqueous solutions of SA (0.0, 1.0, 1.5 and 2.0 mM) at pea stage and at veraison. After harvesting, clusters were divided into two lots in which one was subjected to initial quality evaluation, while the other was stored in cold room (3-4 degrees C, 90-95 % RH) for evaluation of postharvest quality. SA at the dose of 1.5 and 2.0 mM hastened berry maturity by 3 to 5 days, produced less compact bunches alongside larger berries in contrast to control and the lowest dose. The same doses effectively maintained peel colour, higher firmness, lower pectin methyl esterase activity and electrolyte leakage alongside suppressing degradation of TSS and TA during cold storage. These two doses also exhibited higher efficacy on maintaining anthocyanins, phenols and organoleptic properties while reducing weight loss, rachis browning and decay incidence. Correlation analysis demonstrated that many quality parameters are interdependent. In conclusion, preharvest spray of 1.5 mM SA proved to be an effective means of improving quality and extending postharvest life of grape cv. Flame Seedless. PMID- 26028744 TI - Extraction of natural anthocyanin and colors from pulp of jamun fruit. AB - In this present study, natural pigment and colors from pulp of jamun fruit were extracted under different extraction conditions such as extraction temperature (40-60 C), time (20-100 min) and solid-liquid ratio (1:10-1: 15 g/ml) by aqueous extraction method. Three factors with three levels Box-Behnken response surface design was employed to optimize and investigate the effect of process variables on the responses (total anthocyanin and color). The results were analyzed by Pareto analysis of variance (ANOVA) and second order polynomial models were developed to predict the responses. Optimum extraction conditions for maximizing the extraction yield of total anthocyanin (10.58 mg/100 g) and colors (10618.3 mg/l) were found to be: extraction temperature of 44 degrees C, extraction time of 93 min and solid-liquid ratio of 1:15 g/ml. Under these conditions, experimental values are closely agreed with predicted values. PMID- 26028745 TI - Supercritical CO2 extraction of functional compounds from Spirulina and their biological activity. AB - Supercritical carbon dioxide (SCCO2) extraction and fractionation of Spirulina platensis was carried out to obtain functional compounds with antioxidant, antimicrobial and enzyme inhibitory activities. Extraction of SCCO2 was carried out using 200 g of Spirulina powder at 40 oC under 120 bar pressure with CO2 flow rate of 1.2 kg h(-1). SCCO2 fraction obtained was further treated with hexane and ethyl acetate to identify its components. Individual components were identified by comparing mass spectra of samples with standard data and retention indices (RI) of C5-C20 n-alkanes mixture using the kovat index formula. The phenolic and flavonoid content of the SCCO2 extract was found to be 0.34 +/- 0.01 g/100 g and 0.12 +/- 0.01 g/100 g respectively. The SCCO2 extract had antioxidant activity with IC50 value of 109.6 +/- 3.0 MUg mL(-1) for DPPH (2,2-Diphenyl-1-picryl hydrazyl radical), IC50 value of 81.66 +/- 2.5 MUg mL(-1) for reducing power and IC50 value of 112.70 +/- 0.8 MUg mL(-1) for hydroxyl radical scavenging activity. Further, antioxidant activity study on oxidative induced DNA damage was analysed to elucidate the positive role of SCCO2 extract. SCCO2 extracts showed high antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus FRI 722 and Bacillus cereus F 4810) compared to that of Gram negative bacteria (Escherichia coli MTCC 108 and Yersinia enterocolitica MTCC 859). The SCCO2 extract exhibited inhibitory activity on both Angiotensin-1 converting enzyme and alpha-glucosidase with IC50 values of 274 +/- 1.0 MUg mL(-1) and 307 +/- 2.0 MUg mL(-1) respectively. PMID- 26028746 TI - Optimization of the degumming process for camellia oil by the use of phospholipase C in pilot-scale system. AB - In present study, phospholipase C (PLC) was applied in camellia oil degumming and the response surface method (RSM) was used to determine the optimum degumming conditions (reaction time, reaction temperature and enzyme dosage) for this enzyme. The optimum conditions for the minimum residual phosphorus content (15.14 mg/kg) and maximum yield of camellia oil (98.2 %) were obtained at reaction temperature 53 oC, reaction time 2.2 h, PLC dosage 400 mg/kg and pH 5.4. The application of phospholipase A (PLA) - assisted degumming process could further reduce the residual phosphorus content of camellia oil (6.84 mg/kg) to make the oil suitable for physical refining while maintaining the maximal oil yield (98.2 %). These results indicate that PLC degumming process in combination with PLA treatment can be a commercially viable alternative for traditional degumming process. Study on the quality changes of degummed oils showed that the oxidative stability of camellia oil was slightly deceased after the enzymatic treatment, thus more attention should be paid to the oxidative stability in the further application. PMID- 26028747 TI - Study of mechanical properties of soy protein based edible film as affected by its composition and process parameters by using RSM. AB - The effect of process parameters on mechanical properties of Soy protein Isolate based edible film was studied by using response surface methodology. The process variables selected were Soy Protein Isolate (SPI) concentration, plasticizer concentration and pH whereas responses under consideration were thickness of film, tensile strength, Young's modulus and elongation at break. It was observed that as amount of SPI concentration increases in formulation, the thickness and tensile strength increased while it decreased young's modulus and elongation at break. However increase in plasticizer amount decreased thickness and tensile strength but it increased young's modulus and elongation at break. The optimum formulation for meeting the set criteria of response functions was; SPI concentration 8.65%, plasticizer concentration 60%, and pH 8.99. PMID- 26028748 TI - Browning inhibition mechanisms by cysteine, ascorbic acid and citric acid, and identifying PPO-catechol-cysteine reaction products. AB - The titled compounds were examined as PPO inhibitors and antibrowning agents; their various mechanisms were investigated and discussed. All compounds reduced significantly both the browning process and PPO activity. Browning index gave strong correlation with PPO activity (r(2) = 0.96, n = 19) indicating that the browning process is mainly enzymatic. Ascorbic acid could reduce the formed quinone instantly to the original substrate (catechol) at high concentration (>1.5 %) while at lower concentrations acted as competitive inhibitor (KI = 0.256 +/- 0.067 mM). Cysteine, at higher concentrations (>=1.0 %), reacted with the resulted quinone to give a colorless products while at the low concentrations, cysteine worked as competitive inhibitor (KI = 1.113 +/- 0.176 mM). Citric acid acted only as PPO non-competitive inhibitor with KI = 2.074 +/- 0.363 mM. The products of PPO-catechole-cysteine reaction could be separation and identification by LC-ESI-MS. Results indicated that the product of the enzymatic oxidation of catechol, quinone, undergoes two successive nucleophilic attacks by cysteine thiol group. Cysteine was condensed with the resulted mono and dithiocatechols to form peptide side chains. PMID- 26028749 TI - Physicochemical analysis of Psophocarpus tetragonolobus (L.) DC seeds with fatty acids and total lipids compositions. AB - Psophocarpus tetragonolobus (L.) DC. is a tropical legume with potential nutritional properties. In present study, the physical properties and proximate composition of the seeds were evaluated. Besides, the physico-chemical properties of fatty oil from fully mature seeds were also studied. The fatty oil compositions of immature, mature and fully mature seeds were evaluated by GC-FID, GC/MS and (1)H-NMR. The study revealed that, fatty oil from fully mature seeds contained high proportion of unsaturated fatty acids (75.5 %), whereas immature seeds contained higher percentage of saturated fatty acid (61.3 %). In addition, unsaponification matter (0.25 %) of fatty oil was identified as stigmasterol (66.4 %) and beta-sitosterol (25.1 %). Total lipids of fully mature seeds were extracted and isolated as neutral, glyco- and phospholipids. Overall, the fatty oil of fully mature seeds was enriched with mono-unsaturated fatty acids (38.6 %) and poly-unsaturated fatty acids (36.9 %) without trans-fatty acids, thus meeting the edible oil standard. PMID- 26028750 TI - Effects of hydrocolloids as texture improver in coriander bread. AB - An attempt was made to study the effects of hydrocolloids on loaf weight, volume, crumb grain characteristics, crumb moisture, firmness and dough rheological properties on 3.0 % coriander leaf supplemented breads. Carrageenan (CA), carboxymethylcellulose (CMC), guar gum (GG) and xanthan gum (XG) were added in the proportions of 0.25, 0.5, 0.75 and 1.0 % w/w of 100 g wheat flour. Addition of hydrocolloid increased the loaf volume and decreased the average cell area. An inverse relationship was observed between specific volume and average cell area. XG showed uniform change in crumb moisture on storage at all levels of substitution. However highest loss of moisture occurred in bread samples supplemented with GG. Crumb firming kinetics using Avrami's model showed slower firming rates for GG and CMC. High complex modulus (G*) values were observed in breads with 0.75 and 1.0 % XG. PMID- 26028751 TI - Evaluation of functional properties of composite flours and sensorial attributes of composite flour biscuits. AB - The present study was undertaken to develop biscuits from the composite flours. Composite flours were prepared by blending wheat flour with rice flour, green gram flour and potato flour in ratios of 100:0:0:0 (W100), 85:5:5:5 (W85), 70:10:10:10 (W70) and 55:15:15:15 (W55), respectively. The functional properties of composite flours such as swelling capacity, water absorption capacity, oil absorption capacity, emulsion activity, emulsion stability, foam capacity, foam stability, gelatinization temperature, least gelation concentration and bulk density were increased with increase in the incorporation of other flours with wheat flour. Overall acceptability for composite flour biscuits was awarded highest score for W55 followed by W70 and W85 as compared to control biscuits. All biscuits coincided in the range of 'like moderately' to 'like very much' for composite flours biscuits while 'like slightly' to like moderately' for control biscuits. PMID- 26028752 TI - Influence of pectinolyttic and cellulotyc enzyme complexes on cashew bagasse maceration in order to obtain carotenoids. AB - Cashew apple bagasse is a byproduct of cashew peduncle juice processing. Such waste is a source of carotenoids, but it is usually discarded after the juice extraction. The objective of this work was to study the influence of pectinolytic and cellulolytic enzyme complexes on cashew bagasse maceration in order to obtain carotenoids. It was observed that maceration with the enzymatic complex Pectinex Batch AR showed a higher content of carotenoids, with an overall gain of 79 % over the control carried out without enzyme complex addition. PMID- 26028753 TI - Effect of shortening replacement with flaxseed oil on physical, sensory, fatty acid and storage characteristics of cookies. AB - Omega-3 fatty acid imparted good evidence of health benefits. Flaxseed oil, being the richest vegetarian source of alpha linolenic acid (omega-3 fatty acid), was incorporated in cookies by replacing shortening at level of 5 %, 10 %, 20 %, 30 %, 40 % and 50 %. Effect of shortening replacement with flaxseed oil on physical, textural and sensory attributes were investigated. Spread ratio and breaking strength of cookies increased as flaxseed oil level increased. Sensory score was not significantly affected up to 30 % shortening replacement with flaxseed oil as compared with the control cookies. Above 30 % flaxseed oil, sensory score was adversely affected. Fatty acid profile confirmed the enhancement of omega-3 fatty acid from 0 (control) to 14.14 % (30 % flaxseed oil cookies). The poly unsaturated to saturated fatty acid ratio (P/S) increased from 0.088 (control) to 0.57 while omega - 6 to omega -3 fatty acid ratio of flaxseed oil cookies decreased from 4.51 (control) to 0.65 in the optimized cookies. The data on storage characteristics of the control and 30 % flaxseed oil cookies showed that there was significant change in the moisture content, Peroxide value (PV) and overall acceptability (OAA) up to 28 days of storage at 45 degrees C packed in polyethylene bags. Flaxseed oil cookies were acceptable up to 21 days of storage and afterwards noticeable off flavour was perceived. PMID- 26028754 TI - Effect of feeding lipids recovered from fish processing waste by lactic acid fermentation and enzymatic hydrolysis on antioxidant and membrane bound enzymes in rats. AB - Fish oil recovered from fresh water fish visceral waste (FVW-FO) through lactic acid fermentation (FO-LAF) and enzymatic hydrolysis (FO-EH) were fed to rats to study their influence on lipid peroxidation and activities of antioxidant and membrane bound enzyme in liver, heart and brain. Feeding of FO-LAF and FO-EH resulted in increase (P < 0.05) in lipid peroxides level in serum, liver, brain and heart tissues compared to ground nut oil (control). Activity of catalase (40 235 %) and superoxide dismutase (17-143 %) also increased (P < 0.05) with incremental level of EPA + DHA in diet. The increase was similar to cod liver oil fed rats at same concentration of EPA + DHA. FO-LAF and FO-EH increased (P < 0.05) the Na(+)K(+) ATPase activity in liver and brain microsomes, Ca(+)Mg(+) ATPase in heart microsome and acetylcholine esterase in brain microsomes when fed with 5 % EPA + DHA. There was also significant change in fatty acid composition and cholesterol/phospholipid ratio in microsomes of rat fed with FVW-FO. Feeding FVW-FO recovered by biotechnological approaches enhanced the activity of antioxidant enzymes in tissues, modulates the activities of membrane bound enzymes and improved the fatty acid composition in microsomes of tissues similar to CLO. Utilization of these processing wastes for the production of valuable biofunctional products can reduce the mounting economic values of fish oil and minimize the environmental pollution problems. PMID- 26028755 TI - Characterization of pomegranate juice and whey based novel beverage fermented by kefir grains. AB - Mixture of pomegranate juice and whey was evaluated as a potential substrate for production of a novel probiotic beverage by kefir grains. Different fermentation conditions were used as viz: two fermentation temperature (19 oC and 25 oC) and two levels of kefir grains inoculum (5 % and 8%w/v). pH, acidity, lactose consumption as well as organic acids formation were determined during 32 hours of fermentation. Results showed that kefir grains were able to utilize lactose and decrease pH, increase acidity, produce lactic acid and acetic acid, while the level of citric acid decreased. It was observed these change depended on temperature and level of kefir grains with the highest changes at the temperature of 25 oC and kefir grains inoculum of 8%w/v. Pomegranate juice and whey mixture therefore may serve as a suitable substrate for the production of novel probiotic dairy-fruit juice beverage by kefir grains and the sensory characteristics of this beverage were shown desirable results. PMID- 26028756 TI - Optimization of meat level and processing conditions for development of chicken meat noodles using response surface methodology. AB - Response surface methodology (RSM) is a mathematical and statistical technique for testing multiple process variables and their interactive, linear and quadratic effects, and useful in solving multivariable equations obtained from experiments simultaneously. In present study optimum meat level and processing conditions for development of shelf stable chicken meat noodles was determined using central composite design of response surface methodology (RSM). Effects of meat level (110-130 g); processing conditions such as steaming time (12-18 min) and drying time (7-9 h) on the water activity, yield, water absorption index, water solubility index, hardness, overall acceptability and total colour change of chicken noodles were investigated. The aim of present study was to optimize meat level and processing conditions for development of chicken noodles. The coefficients of determination, R(2) of all the response variables were higher than 0.8. Based on the response surface and superimposed plots, the optimum conditions such as 60 % meat level, 12 min steaming time and 9 h drying time for development of chicken noodles with desired sensory quality was obtained. PMID- 26028757 TI - Effect of packaging methods and crude aloe vera gel (Aloe vera barbadensis miller) on the storage quality of enrobed goat meat bites. AB - The storage stability of enrobed goat meat bites (EGMB) incorporated with 3 % crude aloe vera (AV) gel was evaluated under aerobic (T-1; unenrobed control product, T-2; enrobed AV treated product) and modified atmospheric packaging (MAP, 50:50, CO2 and N2) (T-3; unenrobed control product, T-4; enrobed AV treated product) at 4 +/- 1 degrees C for 42 days on the basis of physico-chemical, microbiological and sensory attributes. The pH value was higher, whereas water activity (aW) was lower in enrobed and MAP product. Thiobarbituric acid reacting substances (TBARS) and free fatty acid (FFA) values were significantly (P < 0.05) lower in MAP packaged (T-3) and AV treated products (T-2 and T-4) products than aerobic packaged (T-1), however it followed an increasing trend in all the products throughout storage. Instrumental colour and textural profile attributes were better maintained in MAP products than others. The sensory panellists graded T-4 'good to very good' even on Day 42, whereas T-1 was acceptable only up to 28 days. Standard Plate Count (SPC) was significantly (P < 0.05) lower in MAP products than aerobic packaged products. Results concluded that EGMB treated with AV gel can be successfully stored more than 42 days under MAP conditions without affecting its physico-chemical, textural, microbiological and sensory attributes. PMID- 26028758 TI - Thin layer convective air drying of wild edible plant (Allium roseum) leaves: experimental kinetics, modeling and quality. AB - The present study deals with the valorization of an edible spontaneous plant of the Tunisian arid areas: Allium roseum. This plant is traditionally used for therapeutic and culinary uses. Thin-layer drying behavior of Allium roseum leaves was investigated at 40, 50 and 60 degrees C drying air temperatures and 1 and l.5 m/s air velocity, in a convective dryer. The increase in air temperature significantly affected the moisture loss and reduced the drying time while air velocity was an insignificant factor during drying of Allium roseum leaves. Five models selected from the literature were found to satisfactorily describe drying kinetics of Allium roseum leaves for all tested drying conditions. Drying data were analyzed to obtain moisture diffusivity values. During the falling rate drying period, moisture transfer from Allium roseum leaves was described by applying the Fick's diffusion model. Moisture diffusivity varied from 2.55 * 10( 12) to 8.83 * 10(-12) m(2)/s and increased with air temperature. Activation energy during convective drying was calculated using an exponential expression based on Arrhenius equation and ranged between 46.80 and 52.68 kJ/mol. All sulfur compounds detected in the fresh leaves were detected in the dried leaves. Convective air drying preserved the sulfur compounds potential formation. PMID- 26028759 TI - The neuroprotective and antioxidant activities of protein hydrolysates from grass carp (Ctenopharyngodon idella) skin. AB - To observe the neuroprotective and antioxidant activities of the grass carp protein hydrolysates (GPH) obtained from grass carp (Ctenopharyngodon idella) skin by enzymatic hydrolysis. GPH prepared using Protamex, at different (5, 10, 15, 20 and 30 %) degrees of hydrolysis (DH) were investigated. The DPPH radial scavenging, reducing power and inhibition of linoleic acid oxidation activities of GPH were significantly improved by a low DH (5 %) compared with those of GPH with a higher DH (p < 0.05). A low degree of enzymatic hydrolysis was appropriate to obtain GPH with improved neuroprotective activities. These results suggest that the control of the DH may be an effective strategy to modify specific neuroprotective and antioxidant activities of GPH, and GPH has potential as a functional food ingredient for related functional and health benefits. PMID- 26028760 TI - Effect of different packaging films on shelf life and quality of peach under super and ordinary market conditions. AB - Peach (Prunus persica L. Batsch) fruits of cultivar 'Shan-i-Punjab' were harvested at colour break stage and packed in paper moulded trays followed by wrapping with different packaging films viz. cryovac heat shrinkable RD-106, cling and low density polyethylene (LDPE) film. After packaging, the fruits were stored under two different conditions i.e. super-market conditions (18-20 degrees C; 90-95 % RH) and ordinary market conditions (28-30 degrees C; 60-65 % RH). The fruits were evaluated for various quality attributes periodically. The shrink film helped in reducing the loss in weight, firmness, decay incidence and maintained the various qualities attributes like total soluble solids, sugars, acidity and ascorbic acid content of the fruits during shelf-life better than unwrapped control fruits. The pectin methyl esterase enzyme activity was also found to be lower in shrink film packed fruits over the unwrapped control fruits. The in-package gaseous composition (O2 and CO2) in shrink film packed fruits was found to be at desired level which resulted in maintenance of pleasant flavour of the fruits. On the other hand LDPE film accumulated very high level of CO2, which led to formation of fermenting odour and decay of fruits in the package. The data revealed that RD-106 film proved quite effective in prolonging the shelf-life and maintaining the quality of peach fruits for 9 and 4 days under super market conditions (SMC) and ordinary market conditions (OMC), respectively as against 6 and 2 days only in case of unpacked control fruits under both the marketing conditions. The results suggest that shrink film could be used in packaging of peach without negative effects on quality. PMID- 26028761 TI - Effect of protein concentrates, emulsifiers on textural and sensory characteristics of gluten free cookies and its immunochemical validation. AB - The effect of 5, 7.5 and 10 % protein concentrates namely soya protein isolate (SPI), whey protein concentrate (WPC) and addition of 0.5 % emulsifiers such as glycerol monostearate (GMS), sodium stearoyl- 2- lactylate (SSL) and lecithin (LEC) on the rheological, sensory and textural characteristics of cookies with rice flour and its immunochemical validation was studied. The results showed that the use of 7.5 % SPI/WPC along with GMS significantly improved the quality characteristics of cookies with rice flour. Dot-Blot and Western-blot studies of cookies with 7.5 % of SPI or WPC confirmed that the anti-gliadin did not recognize these proteins. Carry- through process using ELISA kit confirmed that gluten was within the permissible limit in all the stages of processing and hence these cookies can be consumed by people suffering from celiac disease. PMID- 26028762 TI - Optimization studies for enhanced bacteriocin production by Pediococcus pentosaceus KC692718 using response surface methodology. AB - Bacteriocins have been produced by various Lactic acid bacteria (LAB) strains isolated from dairy and fermented vegetable sources. In the current study we have isolated a novel bacteriocin producing strain Pediococcus pentosaceus KC692718 from mixed vegetable pickles (India). A 2 step process optimization for enhancing production of bacteriocin from the isolates was carried out with One-factor-at-a time (OFAT) and Response Surface Methodology (RSM) methods. A 2.5 fold (AU/mL) increase of bacteriocin was observed for sucrose (2.4 %) as carbon source and 4.7 fold (AU/mL) increased bacteriocin was observed in the presence of soyatone (1.03 %) as nitrogen source in the OFAT experiments. In order to increase bacteriocin production RSM tool was performed with optimized chemical and physical sources using Design expert 8.0.7.1. Soyatone (1.03 %), sucrose (2.4 %), pH (5.5) and temperature (34.5 oC) condition yielded 25,600.34 AU/mL of bacteriocin from P. pentosaceus KC692718. This is the first report which has produced 20 fold increase of bacteriocin for Pediococcus pentosaceus KC692718 from that of MRS medium with 1 280 AU/mL. PMID- 26028763 TI - Effects of Rosemary extracts on oxidative stability of chikkis fortified with microalgae biomass. AB - The present study evaluates the oxidative stability in chikkis enriched with omega 3 fatty acids using natural antioxidant from Rosmarinus officinalis. The best condition for the extraction of phenolic compounds from Rosmarinus officinalis L. (rosemary) was established, and the antioxidant activity was demonstrated based on inhibition of DPPH free radical formation. Nannochloropsis oculata and Isochrysis galbana are rich sources of Eicosapentanoic acid (EPA) and Docosahexaenoic acid (DHA). Biomass of these microalgae were incorporated in chikkis as omega 3 fatty acid source. Effects of addition of natural and synthetic antioxidants (BHA) on oxidative stability of chikkis were analyzed for storage period of 2 months. Evaluation of peroxide value (PV) and fatty acid profile showed that the process of oxidation slowed down. Natural antioxidant was found to be more effective when compared to synthetic antioxidant (BHA). Omega-3 PUFA levels (EPA+DHA) of 75 and 240 mg/100 g chikkis were observed if enriched with 1 and 3 % Nannochloropsis oculata biomass respectively. Similarly, Omega-3 PUFA levels (EPA+DHA) of 102 and 320 mg/100 g chikkis were observed if enriched with 1 and 3 % Isochrysis galbana biomass respectively. The effects of microalgae and antioxidant incorporation on the chikkis showed that color values remained stable during storage period of 2 months with no significant change (P < 0.05) in texture. Sensory evaluation revealed that up to 3 % microalgal biomass incorporation was positively classified and accepted. PMID- 26028764 TI - Studies on Osmo-air dehydration of different Indian apricot (Prunus armeniaca L.) cultivars. AB - Suitability of seven cultivars of apricot viz. New Castle, Kaisha, Royal, Suffaida, Nari, Kullu (Local) and Chulli (wild apricot) was evaluated for dehydration. Osmotic dehydration of fruits consisting of dipping prepared fruits in 70 degrees Brix sucrose syrup containing 2,000 ppm potassium metabisulphite (KMS) for 24 h followed by cabinet air drying (55 degrees C) to desired moisture (20 +/- 0.5 %) gave better dried product with good colour and appeal. Dried whole or halved fruits after removal of stones were preferred over whole fruits with stones with respect to appearance, texture and overall acceptability. Among different cultivars of apricot; cv. Kaisha followed by New Castle were found better with respect to yield as well as quality of dried product. Further, the quality of the osmo-air dried wild apricot fruits was found statistically at par with the quality of the osmo-air dried product obtained from cultivated apricots. Therefore, wild apricot fruits can also be utilized for preparation of acceptable quality of dried product. PMID- 26028765 TI - Subcritical water extraction and antioxidant activity evaluation with on-line HPLC-ABTS(.+) assay of phenolic compounds from marigold (Tagetes erecta L.) flower residues. AB - Subcritical water extraction (SWE) of phenolics was investigated from marigold (Tagetes erecta L.) flower residues. The total phenolics content (TPC), total flavonoids content (TFC) and antioxidant capacities of extracts were determined, furthermore, antioxidant activities of individual compounds were evaluated with on-line HPLC-ABTS(*+) system. The optimum SWE time was 45 min, solid-to-liquid ratio was 1:50, and the highest TPC and TFC were obtained at 220 degrees C respectively. The effect of SWE temperature on TPC and TFC was significant (p < 0.05), and TPC was ranged from 28.42 +/- 0.94 to 124.27 +/- 1.94 (mg GAE/g), and TFC ranged from 34.21 +/- 0.36 to 133.22 +/- 1.57 (mg GAE/g) between 80 and 220 degrees C. On-line HPLC-ABTS(*+) profiles revealed that quercetagetin from SWE at 200 degrees C had nearly twofold radical scavenging activities than that by leaching extraction. PMID- 26028766 TI - Optimization of conditions for isolation of high quality chitin from shrimp processing raw byproducts using response surface methodology and its characterization. AB - Chitin is one of the most abundant bioactive biopolymer on earth. It is commercially extracted from seafood processing crustacean shell byproducts by harsh thermochemical treatments. The extraction conditions, the source and pretreatment of raw material significantly affect its quality and bioactivity. In this investigation response surface methodology (RSM) has been applied to optimize and evaluate the interaction of variables for extraction of high quality chitin from shrimp processing raw byproducts. Variables such as, concentration of HCl (%, v/v) 4.5 (for wet) and 4.9 (for dry), reaction time 3 h, solid liquid ratio of HCl (w/v) 1:5.5 (for wet) and 1:7.9 (for dry) with two treatments achieved >98 % demineralization of shrimp byproduct. Variables such as, concentration of NaOH 3.6 % (w/v), reaction time 2.5 h, temperature 69.0 +/- 1 degrees C, solid liquid ratio of NaOH 7.4 (w/v) and two treatments accomplished >98 % deproteinization of demineralized byproducts. Significant (p <= 0.05-0.001) interactive effects were observed between different variables. Chitin obtained in these conditions had residual content (%, w/w) of ash <0.4 and protein <0.8 and the degree of N-acetylation was >93 % with purity of >98 %. In conclusion, the optimized conditions by RSM can be applied for large scale preparation of high quality chitin from raw shrimp byproduct. PMID- 26028767 TI - Physicochemical changes of myosin and gelling properties of washed tilapia mince as influenced by oxidative stress and microbial transglutaminase. AB - Physicochemical properties of myosin from tilapia subjected to oxidation via Fenton's reaction using H2O2 (0, 0.05, 0.1, 1 and 5 mM) were determined. With increasing H2O2 concentrations and times (from 0 to 12 h), sulfhydryl group content and Ca(2+)-ATPase activity decreased, while carbonyl content and surface hydrophobicity increased to a higher extent. After being subjected to oxidation, cross-linking via disulfide bond along with increased storage modulus (G') was observed. Microbial transglutaminase (MTGase) induced polymerization of myosin in both non-oxidized and oxidized forms and increased gel G'. Gel properties of washed mince and oxidized washed mince were determined in the presence and absence of MTGase. A stronger gel was observed when 0.3 unit MTGase/g was added, regardless of oxidation process. Nevertheless, the gel strengthening effect of MTGase was hampered when mince was subjected to severe oxidation. Excessive protein aggregation of oxidized samples prior to gelation resulted in the reduction of gel strength and water-holding capacity. Negative effect of protein oxidation on gelation could therefore be alleviated to some degree by MTGase addition. PMID- 26028768 TI - Functional and textural properties of Indian nuggets assorted with mushroom for lysine enrichment. AB - Nuggets popularly known as warrian is the traditional household food item of India and prepared from black gram but deficit in essential amino acid, lysine. Present study conducted to prepare lysine enriched nuggets using white button mushrooms (WBM) that contain all the essential amino acids. Black gram paste was fortified with WBM 0 (T0) to 50 at 10 % increments (T1 to T5). Moisture, ash, crude protein and fat were increased in T0 to T5 ranged from 10.00 to 13.52 %, 4.00 to 4.18 %, 13.90 to 23.80 % and 0.37 to 1.00 %, respectively. The cooking weight, cooking losses and antioxidant activity (as DPPH) were increased with increase in WBM (lysine enrichment) in nuggets. In textural analysis, hardness decreased with increases fortification from 1.971 to 0.889 kg. Based on physico chemical, cooking and textural properties, black gram to WBM ratio of 80: 20 was recommended. PMID- 26028770 TI - Steady shear rheological characteristics of model system meat emulsions: Power law and exponential type models to describe effect of corn oil concentration. AB - The effect of oil concentration (57.50, 58.75, 60.00 and 61.25 %) and temperature (5, 10 and 15 oC) on steady shear rheological properties of O/W model system meat emulsions were investigated. The effect of temperature and oil concentration was modeled using power law and exponential type functions. The meat emulsions showed non-Newtonian flow behavior because flow behavior index was lower than unity. Consistency coefficient and flow behavior index values of O/W model system meat emulsions were calculated using Oswald de Waele model with higher coefficients of determination. Apparent viscosities of emulsions at a specified shear rate (50 s( 1)) were in the range of 0.652-0.941 Pa s. Increasing oil concentration provided an increase in apparent viscosity and increase in temperature levels resulted a decrease in consistency coefficient values. The exponential function performed better than the power-law function (R (2) > 0.922) in terms of describing the effect of oil concentration on the steady shear rheological properties of the model system meat emulsions. Higher coefficients of determination (R (2) = 0.979 0.999) were observed in exponential-type function compared to a power law function (R (2) = 0.880-0.946). PMID- 26028769 TI - Protein glycation inhibitory activity and antioxidant capacity of clove extract. AB - Syzygium aromaticum (L.) (clove) is one of the most widely cultivated spices in many tropical countries. The aim of this study was to determine the phytochemical content, the antioxidant properties and the antiglycation properties of aqueous extract of clove against fructose-mediated protein glycation and oxidation. The result showed that the content of total phenolics and flavonoids in clove extract was 239.58 +/- 0.70 mg gallic acid equivalents/g dried extract and 65.67 +/- 0.01 mg catechin equivalents/g dried extract, respectively. In addition, clove exhibited antioxidant properties including DPPH radical scavenging activity (IC50 = 0.29 +/- 0.01 mg/ml), Trolox equivalent antioxidant capacity (4.69 +/- 0.03 MUmol Trolox equivalents/mg dried extract), ferric reducing antioxidant power (20.55 +/- 0.11 MUmol ascorbic acid equivalents/mg dried extract), Oxygen radical absorbance capacity (31.12 +/- 0.21 MUmol Trolox equivalents/mg dried extract), hydroxyl radical scavenging activity (0.15 +/- 0.04 mg Trolox equivalents/mg dried extract), and superoxide radical scavenging activity (18.82 +/- 0.50 mg Trolox equivalents/mg dried extract). The aqueous extract of clove (0.25-1.00 mg/ml) significantly inhibited the formation of fluorescent advanced glycation end products (AGEs) and non-fluorescent AGEs (N(E)-(carboxymethyl) lysine (CML)) in glycated BSA during 4 weeks of incubation. The extract also markedly prevented oxidation-induced protein damage by decreasing protein carbonyl formation and protecting against the loss of protein thiol group. These results clearly demonstrated that a polyphenol enriched clove extract, owing to its antioxidant, was capable to inhibit the formation of AGEs and protein glycation. The findings might lead to the possibility of using the clove extract for targeting diabetic complications. PMID- 26028771 TI - Detection of poultry meat specific bacteria using FTIR spectroscopy and chemometrics. AB - FTIR spectra of poultry meat specific bacteria viz. Salmonella enteritidis, Pseudomonas ludensis, Listeria monocytogenes and Escherichia coli were collected and investigated for identification of spectral windows capable of bacterial classification and quantification. Two separate datasets obtained at different times were used in the study to check reproducibility of results. Multivariate data analysis techniques viz. principal component analysis (PCA), partial least squares discriminant analysis (PLSDA) and soft independent modelling of class analogy (SIMCA) were used in the analysis. Using full cross-validation and separate calibration and prediction datasets, the highest correct classification results for SIMCA and PLSDA were achieved in spectral window (1800-1200 cm-1) for both datasets. The window was also tested then for quantification of different bacteria and it had been observed that PLS models had better R values for classification (R = 0.984) than predicting various concentration levels (R = 0.939) of all four poultry specific bacteria inoculated in distilled water. The identified spectral window 1800-1200 cm-1 also demonstrated potential for 100% correct classification of chicken salami samples contaminated with S. enteritidis and P. ludensis from control using SIMCA. However, this wavenumber range yielded few misclassifications using PLS-DA approach. Thus FTIR spectroscopy in combination with chemometrics is a powerful technique that can be developed further to differentiate bacteria directly on poultry meat surface. PMID- 26028772 TI - Efficacy of reverse micellar extracted fruit bromelain in meat tenderization. AB - Reverse micellar extraction (RME) was used for the separation and purification of bromelain from pineapple core and efficacy of RME purified bromelain (RMEB) in tenderization of beef meat was compared with that of commercial stem bromelain (CSB). RME resulted in reasonably high bromelain activity recovery (85.0 %) and purification fold (4.0). Reduction in meat toughness was higher in RMEB treated meat (52.1 %) compared to raw (control) and CSB treated (26.7 %). Significant increase in water holding capacity (WHC) was observed in RMEB treated meat (91.1 %) as against CSB treated (55.6 %) and control (56.6 %). No change in cooking loss was observed in RMEB treated meat, whereas the loss increased by nearly 14.0 % in case of CSB treated. While the meat color was retained, trichloroacetic acid (TCA) soluble protein content increased due to hydrolysis of protein in RMEB treated meat. Scanning electron microscopy (SEM) analysis revealed that RMEB treatment completely ruptures myofibril tissues, indicating a higher degree of tenderization. PMID- 26028773 TI - The study of the antimicrobial activity of colloidal solutions of silver nanoparticles prepared using food stabilizers. AB - The bactericidal effect of colloidal solutions of silver nanoparticles based on food stabilizers, gum arabic and chitosan, against bacterial cultures of microorganisms in food production is described. The antibacterial activity of nanotechnology products containing different amounts of stabilizing additives when applied to solid pH-neutral substrates is studied. For its evaluation a method making it possible to take into account the capability of nanoparticles to diffuse in solid media was applied. Minimal inhibitory concentrations of nanoparticles used against Erwinia herbicola, Pseudomonas fluorescens, Bacillus subtilis, Sarcina flava were found. A suggestion was made concerning the influence of the spatial structure of bacteria on the antibacterial activity of colloidal solutions of silver nanoparticles. The data concerning the antibacterial activity and minimal inhibiting concentrations of nanoparticles may be used for development of products suppressing activity of microorganisms hazardous for food production. PMID- 26028774 TI - Implementation of multivariate techniques for the selection of volatile compounds as indicators of sensory quality of raw beef. AB - This study was performed in order to select volatile compounds to predict the off odour and overall assessment of raw beef's freshness Maronesa breed, using multivariate analysis. M. longissimus dorsi packed in vacuum and MAP (70 % O2/20 % CO2/10 % N2) stored at 4 oC were examined for off-odour perception as well as the overall assessment of freshness at 10 and 21 days post mortem. The results achieved in this study demonstrated that the selected volatile compounds could be considered as volatile indicators of beef spoilage, enclosing information for discrimination of Maronesa beef samples in sensory classes of odour corresponding to unspoiled and spoiled levels. Fifty-four volatile compounds were detected. A significant increase of aldehydes, ketones and alcohols were observed during storage in MAP. 2 and 3-methylbutanal, 2 and 3-methylbutanol, 1-pentanol, 1 hexanol, 2,3-octanedione, 3,5-octanedione, octanal and nonanal were suggested as indicators of beef spoilage. 3-methylpentane was considered as a marker in the first stages of spoilage in beef, decreasing during storage. Data were examined using PCR and PLSR models for different optimal subsets of volatile compounds. The simplicity and usefulness of the technique in using 0/1 data in preserving high levels of accuracy was also prevalent. The powerful analytical methodologies for reducing variables and the choice of optimal subsets could be advantageous in both basic research and the routine quality control of chilled beef. PMID- 26028775 TI - The effect of packaging material and storage period on microwave-dried potato (Solanum tuberosum L.) cubes. AB - The effect of three packaging materials (transparent biaxially oriented polypropylene laminate (BOPP); semi-transparent BOPP; polyethylene-polyamide (PE PA) laminate) in three packaging conditions (vacuum, N2, natural atmosphere) and in two temperature treatments (blanching in hot water; steam) on microwave-dried potato (Solanum tuberosum L.; Solanaceae) cubes was studied. After storage for 60 and 120 days, the amount of ascorbic acid (AA), shrinkage and rehydration were determined. Dried potato cubes packaged under N2 atmosphere had the highest rehydration value (3.142 %). Since there is a direct relationship between the amount of water loss and shrinkage, samples packaged in PE-PA laminate packages under vacuum showed 4.947 % less shrinkage than transparent BOPP or semi transparent BOPP due to low permeability of these packages. Potatoes stored for 120 days resulted in 7.89 % more shrinkage than those stored for 60 days. The least loss in AA occurred in PE-PA laminate packaging. The shelf-life of potato cubes can be increased and their quantitative and qualitative characteristics can be best preserved by package-drying in PE-PA laminate under vacuum conditions. PMID- 26028776 TI - Iron (II)-chelating activity of buffalo alphaS-casein hydrolysed by corolase PP, alcalase and flavourzyme. AB - Iron is a vital substance for human health which participates in many biochemical reactions. It also act as initiator for many harmful oxidative process. Buffalo alphaS-casein enriched fraction (80 %) was hydrolysed independently by corolase PP (H1), alcalase (H2), flavourzyme (H3) and sequentially by alcalase-flavourzyme (H4). After ultrafiltration (10 and 3 kDa) hydrolysates were analysed for their iron chelation activity using ferrozine. For H1 group of hydrolysates highest iron (II)-chelation activity (265.58 MUM Fe(2+/)mg protein) was found after 8 h of hydrolysis for H2 (267.56 MUM Fe(2+/)mg protein) and H3 group of hydrolysates (380.68 MUM Fe(2+/)mg protein) after 6 h of hydrolysis. Sequential hydrolysis was not effective for iron (II)-chelation activity. 3 kDa fractions show higher iron (II)-chelation activity than 10 kDa fraction. Flavourzyme was more effective for generation of iron (II)-chelating peptides from buffalo alphaS-casein. PMID- 26028777 TI - Influence of the composition of unripe genipap (Genipa americana L.) fruit on the formation of blue pigment. AB - The physical and chemical characteristics of unripe genipap fruits and the proximate and amino acid compositions of the endocarp and mesocarp of the unripe fruits were determined, placing special emphasis on the possible role of the protein-amino acid fraction on the formation of the typical blue pigment of the matrix. The two parts of the fruit analyzed have low energy (49.88 kcal/100 g for mesocarp and 43.48 kcal/100 g for endocarp) and high fiber content (7.88 % for mesocarp and 16.76 % for endocarp). The endocarp showed protein content (3.19 %) five times higher than the mesocarp (0.62 %), which may explain in part the greater amounts of blue pigment formed in the endocarp when compared to the mesocarp. Furthermore, the pH found in mesocarp (4.49) and endocarp (5.21) is within the optimum range for the formation of the blue pigment. A significant color change (DeltaE (*) = 26.45) was observed in endocarp during its exposure to the air for 2 h. Free aspartic and glutamic acids and cystine were the predominant amino acids in the mesocarp, while glutamic and aspartic acids and leucine were predominant in the endocarp. According to the results, the formation of blue pigment does not cause any change in the amino acid composition. PMID- 26028778 TI - Commentary on Making Sense of the Science of Sodium. AB - Sodium reduction is an important component of a healthy dietary pattern to reduce cardiovascular disease risk. Numerous authoritative scientific bodies and professional health organizations have issued population sodium intake recommendations, all of which are at least 1000 mg/d lower than the current average American sodium intake of nearly 3500 mg/d. Recent research has called these recommendations into question, but a number of methodological issues may account for the inconsistency of results in observational studies examining the relationship between sodium intake and health outcomes. Health and nutrition professionals must consider that public health recommendations are made after weighing all of the evidence, including studies of greater and lesser strength of design and some with conflicting results. PMID- 26028779 TI - Spatiotemporal relationships among Late Pennsylvanian plant assemblages: Palynological evidence from the Markley Formation, West Texas, U.S.A. AB - The Pennsylvanian lowlands of western Pangea are best known for their diverse wetland floras of arborescent and herbaceous ferns, and arborescent horsetails and clubmosses. In apparent juxtaposition, a very different kind of flora, dominated by a xerophilous assemblage of conifers, taeniopterids and peltasperms, is occasionally glimpsed. Once believed to represent upland or extrabasinal floras from well-drained portions of the landscape, these dryland floras more recently have been interpreted as lowland assemblages growing during drier phases of glacial/interglacial cycles. Whether Pennsylvanian dryland and wetland floras were separated spatially or temporally remains an unsettled question, due in large part to taphonomic bias toward preservation of wetland plants. Previous paleobotanical and sedimentological analysis of the Markley Formation of latest Pennsylvanian (Gzhelian) age, from north central Texas, U.S.A, indicates close correlation between lithofacies and distinct dryland and wetland megaflora assemblages. Here we present a detailed analysis one of those localities, a section unusual in containing abundant palynomorphs, from the lower Markley Formation. Paleobotanical, palynological and lithological data from a section thought to represent a single interglacial/glacial phase are integrated and analyzed to create a complex picture of an evolving landscape. Megafloral data from throughout the Markley Formation show that conifer-dominated dryland floras occur exclusively in highly leached kaolinite beds, likely eroded from underlying soils, whereas a mosaic of wetland floras occupy histosols, ultisols, and fluvial overbank deposits. Palynological data largely conform to this pattern but reveal a more complex picture. An assemblage of mixed wetland and dryland palynofloral taxa is interpolated between a dryland assemblage and an overlying histosol containing wetland taxa. In this section, as well as elsewhere in the Markley Formation, kaolinite and overlying organic beds appear to have formed as a single genetic unit, with the kaolinite forming an impermeable aquiclude upon which a poorly drained wetland subsequently formed. Within a single inferred glacial/interglacial cycle, lithological data indicate significant fluctuations in water availability tracked by changes in palynofloral and megafloral taxa. Palynology reveals that elements of the dryland floras appear at low abundance even within wetland deposits. The combined data indicate a complex pattern of succession and suggest a mosaic of dryland and wetland plant communities in the Late Pennsylvanian. Our data alone cannot show whether dryland and wetland assemblages succeed one another temporally, or coexisted on the landscape. However, the combined evidence suggests relatively close spatial proximity within a fragmenting and increasingly arid environment. PMID- 26028780 TI - Competition between classical and hexadehydro-Diels-Alder (HDDA) reactions of HDDA triynes with furan. AB - We report here thermal reactions between furan and one of three related triyne substrates. Each triyne is capable of reacting initially in two modes: (i) unimolecular hexadehydro-Diels-Alder (HDDA) reaction or (ii) bimolecular Diels Alder reaction between one of its alkynes with furan. The relative rates of these initial events are such that two of the substrates react essentially in only one of modes (i) or (ii). The third is intermediate in behavior; its bifurcation is dependent on the concentration of the furan reactant. These results teach, more generally, principles relevant to the design of efficient HDDA-based reaction cascades. PMID- 26028781 TI - Nickel-catalyzed reductive arylation of activated alkynes with aryl iodides. AB - The direct, regioselective, and stereoselective arylation of activated alkynes with aryl iodides using a nickel catalyst and manganese reductant is described. The reaction conditions are mild (40 degrees C in MeOH, no acid or base) and an intermediate organomanganese reagent is unlikely. Functional groups tolerated include halides and pseudohalides, free and protected anilines, and a benzyl alcohol. Other activated alkynes including an amide and a ketone also reacted to form arylated products in good yields. PMID- 26028782 TI - Diastereoselective Ni-catalyzed 1,4-hydroboration of chiral dienols. AB - The Ni-catalyzed hydroboration of dienols occurs in a 1,4 fashion and delivers a syn-propionate motif in high diastereoselectivity and with a stereodefined trisubstituted crotylboronic ester. The boronic ester can be further manipulated to provide carbon-carbon or carbon-oxygen bonds. PMID- 26028783 TI - Gram-scale, chemoselective synthesis of N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2 oxopiperidine-3-carboxamide (HIOC). AB - N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) is a potent activator of the TrkB receptor in mammalian neurons and of interest because of its potential therapeutic uses. In the absence of a commercial supply of HIOC, we sought to produce several grams of material. However, a synthesis of HIOC has never been published. Herein we report the preparation of HIOC by the chemoselective N-acylation of serotonin, without using blocking groups in the key acylation step. PMID- 26028784 TI - A Silver(I)-Catalyzed Intramolecular Ficini's [2 + 2] Cycloaddition Employing Ynamides. AB - An intramolecular [2 + 2] cycloaddition using N-sulfonyl substituted ynamides tethered to an enone motif is described here. This thermally driven [2 + 2] cycloaddition manifold can be catalyzed effectively using AgNTf2, and represents the first examples of an intramolecular Ficini reaction. PMID- 26028785 TI - Toward the ABCD Core of the Calyciphylline A-Type Daphniphyllum Alkaloids: Solvent non-Innocence in Neutral Aminyl Radical Cyclizations. AB - The Daphniphyllum alkaloids remain an attractive target in the synthetic community because of their unique framework and promising biological activities. We have shown that the ABC core of the calyciphylline A-type alkaloids can be rapidly accessed via the tandem cyclization of a neutral aminyl radical with a polarized cyclic olefin. Deuterium labeling experiments and reactions omitting a tin hydride reagent suggest that the solvent is the major source of the terminating hydrogen atom in the cyclization cascade. Incorporation of an internal alkyne in the radical pathway was tolerated in the reaction, and it provided the necessary atoms to enable completion of the D ring of the calyciphylline A-type alkaloids. PMID- 26028786 TI - A useful methoxyvinyl cation equivalent: alpha-t-butyldimethylsilyl-alpha methoxyacetaldehyde. AB - Described are the synthesis and application of alpha-t-butyldimethylsilyl-alpha methoxyacetaldehyde as a formal methoxyvinyl cation equivalent. Addition of Grignard reagents to the title aldehyde, followed by treatment of the intermediate beta-hydroxysilanes with KH, gives good yields of large Z methoxyvinylated products. Assuming a Peterson-like elimination mechanism, one can infer that the Grignard addition proceeds with high syn selectivity. These results are consistent with a chelation control model involving coordination to the alpha-methoxy group in the title aldehyde rather than an alternative stereoelectronic Felkin-Anh-type model. It must be noted that a steric Felkin-Anh model also accounts for the observed stereochemistry. All told, the title reagent can be employed to efficiently append a Z-configured methoxyvinyl group to an appropriate R-M species, in two steps. PMID- 26028787 TI - A Solvent-free Approach to Glycosyl Amides: Towards the Synthesis of alpha-N Galactosyl Ceramides. AB - A new, simple and efficient method for the synthesis of both alpha- and beta glycosyl amides using solvent-free conditions is described. This method involves the coupling of glycosyl amines with the p-nitrophenol esters of lipids as a key step. PMID- 26028788 TI - Synthesis of carbocyclic nucleoside analogs with five-membered heterocyclic nucleobases. AB - New carbocyclic nucleoside analogs with five-membered heterocyclic nucleobases were synthesized and evaluated as potential anti-HIV and anti-HCV agents. Among the synthesized carbocyclic nucleoside analogs, the pyrazole amide 15f exhibited modest selective anti-HIV-1 activity (EC50 = 24 uM). PMID- 26028789 TI - Atropurpuran - Missing Biosynthetic Link Leading to the Hetidine and Arcutine C20 Diterpenoid Alkaloids or an Oxidative Degradation Product? AB - A possible biosynthetic link between atropurpuran, the hetidine diterpenoid alkaloids and the alkaloid arcutine and congeners is proposed. The feasibility of aspects of this biosynthesis, especially key 1,2-rearrangements, have been examined computationally. PMID- 26028790 TI - Integrative correlation: Properties and relation to canonical correlations. AB - The integrative correlation coefficient was developed to facilitate the validation of expression microarray results in public datasets, by identifying genes that are reproducibly measured across studies and even across microarray platforms. In the current study, we develop a number of interesting and important mathematical and statistical properties of the integrative correlation coefficient, including a unique permutation-based null distribution with the unusual property that the variance does not shrink as the sample size increases, discussing how these findings impact its use and interpretation, and what they have to say about any method for identifying reproducible genes in a meta analysis. PMID- 26028791 TI - Rare Moss-Built Microterraces in a High-Altitude, Acid Mine Drainage-Polluted Stream (Cordillera Negra, Peru). AB - The Rio Santiago in the Cordillera Negra of Peru is severely contaminated by acid mine drainage in its headwaters. In a strongly acid stream, at about 3800 m above sea level (masl), microterraces were found with terrace walls built up of dead moss, with encrustations and interstitial fine, creamy sediment. The stream water was turbid due to the presence of similar suspended sediment, which also occurred as a thin basal layer in inter-rim basins. The moss was identified as the rare bryophyte Anomobryum prostratum (Mull. Hal.) Besch. Chemical and mineralogical analyses show that green, living parts of the moss are gradually coated by Al/Fe (hydr)oxides, inducing their senescence and death. The necromass is covered by creamy crusts through precipitation of schwertmannite-type material from the stream water and simultaneous 'capture' of fine sediment. The latter consists of a mixture of precipitate and fine detrital primary minerals. These processes are held responsible for the formation of the microterraces, which regarding their composition and environment seem to be unique. Remarkable is the high As content of the creamy crusts and sediment, attributed to strong sorption of As, whereas its solute concentration is relatively low. This calls for more attention to suspended fine sediment in the assessment of environmental risks of stream water use. Lastly, the results raise serious doubts about the use of aquatic bryophytes as bioindicator for chemical pollution in acid mine drainage-polluted streams. PMID- 26028792 TI - Unpleasant and Pleasant Referential Thinking: Relations with Self- Processing, Paranoia, and Other Schizotypal Traits. AB - Referential thinking is the tendency to view innocuous stimuli as having a specific meaning for the self and is associated with personality traits and disorders. In three studies, this research examined the relations among referential thinking, self-processing, and paranoia. In study 1, follow-up questions on the Referential Thinking Scale (Lenzenweger, Bennett, & Lilenfeld, 1997) revealed that referential thoughts are experienced as unpleasant and pleasant. In Study 2, unpleasant referential thinking was more strongly associated with paranoia and maladaptive self-processing and personality. CFAs in Study 1 and 2 found that unpleasant and pleasant referential thinking loaded on different factors. In Study 3, a group of participants with elevated schizotypal personality reported more unpleasant and pleasant referential thoughts than a control group. PMID- 26028793 TI - Tense and Aspect in Childhood Language Impairment: Contributions from Hungarian. AB - Previous studies of children with language impairment (LI) reveal an insensitivity to aspect that may constitute part of the children's deficit. In this study, we examine aspect as well as tense in Hungarian-speaking children with LI. Twenty-one children with LI, 21 typically developing children matched for age, and 21 typically developing children matched for receptive vocabulary scores were tested on their comprehension and production of both imperfective and perfective verb forms in past tense contexts. Although the groups did not differ in their comprehension performance, the children with LI were less accurate than both comparison groups in producing both imperfective and perfective forms. Based on these results, it appears that children with LI have difficulties selecting the appropriate aspectual marking in past tense contexts. PMID- 26028794 TI - The genetic and environmental relationship between Cloninger's dimensions of temperament and character. AB - The purpose of this study was to determine whether Cloninger's revised 7-factor model of personality showed incremental validity over his four dimensions of temperament. A sample of 2517 Australian twins aged over 50 between 1993 and 1995 returned completed self-reported measures of Self-directedness, Cooperativeness, and Self-transcendence from Cloninger's Temperament and Character Inventory. Many of these twins had participated in a 1988 study containing Cloninger's temperament measures of Harm Avoidance, Novelty Seeking, Reward Dependence and Persistence. Contrary to theoretical expectations, univariate analyses revealed that familial aggregation for the character dimensions could be entirely explained by additive gene action alone. Although temperament explained 26, 37 and 10% of additive genetic variance in Self-directedness, Cooperativeness and Self-transcendence, respectively, seven genetic factors were required to explain the genetic variance among the TPQ dimensions, and almost all of the non-shared environmental variance was unique to each dimension of character. Our results indicate that the inclusion of all seven dimensions in a taxonomy of personality is warranted. PMID- 26028795 TI - Overcoming Old in Age-Friendliness. AB - In this article, we explore views on an age-friendly space in the Netherlands by analysing the responses of older individuals (N = 54) in focus groups and by examining the perspectives around an age-friendly zone in the Netherlands, Parkstad Limburg. We found that a central issue in the wishes for living at a later age are adjustments to envisioned physical limitations that come with the ageing process; this includes adjustments to ensure safety, accessibility and mobility, in order to facilitate older individuals' efforts to stay engaged with the world around them. In their wishes, the older participants constructed ideal dwelling places that closely resembled a senior home, but at the same time they rejected wishing to live in a place that was identified as a senior home. We explain this paradox by the representation of such a space as being for old people, i.e. needy older individuals, which was not how the older participants wished to be identified. We conclude that the conception of age-friendly environments will have to face the difficult challenge of overcoming the association with old age, while simultaneously taking into account adjustments that signify and relate to the ageing process and that seem inescapably tied to oldness. PMID- 26028797 TI - Reconstruction of hemodynamics and sensitizer distributions during interstitial PDT using spectroscopy with linear light sources. AB - Light dosimetry for photodynamic therapy requires a knowledge of the optical absorption spectrum of the tissue being treated Here, we present a theoretical and experimental analysis of the capabilities of a system using interstitial linear light sources ranging in length from 2 to 5 cm to illuminate the tissue interstitially, and isotropic point-like detectors to measure the resulting diffusely transmitted light. The sources and detectors are translated in transparent plastic catheters under the control of a motorized positioning system designed for interstitial measurements in the prostate. The light source is a quartz-tungsten-halogen (QTH), and the spectrally resolved detection is accomplished using a CCD-based grating spectrometer. The data are analyzed using an approximation to the radiative transport equation, assuming homogeneous scattering and heterogeneous absorption spectra Absorption spectra are reconstructed independently for individual source-detector channel pairs. Sequential reconstruction can then be used to create a 3-dimensional reconstruction. The results of simulated data, measurements made in multi component phantoms, and synthetic data reconstructed from in vivo measurements made with point sources demonstrate the feasibility of this method. PMID- 26028796 TI - Maternal emotion and cognitive control capacities and parenting: A conceptual framework. AB - PURPOSE: Emerging evidence suggests that maternal emotion and cognitive control capacities are critical to the development and maintenance of parenting practices and may be related to parents' ability to seek and use parenting help. The purpose of this paper is to present a cohesive conceptual framework on the intersection of maternal emotion and cognitive control capacities and parenting based on a review of literature. METHODS: We conducted a comprehensive literature review of articles published between 2000 and February 2014 that addressed maternal emotion and cognitive control and parenting. The 35 articles identified were assigned a methodological quality score. RESULTS: Low maternal emotion and cognitive control capacity is associated with increased risk of engaging in child maltreatment, whereas higher maternal emotion and cognitive regulation is associated with sensitive, involved parenting. Contextual factors, such as SES and household organization, play a complex and not clearly understood role on the association between maternal cognitive control and parenting. A conceptual framework was developed based on the results of the literature review. CONCLUSIONS: The conceptual framework developed can be used to inform future research and practice. Longitudinal studies that assess the temporal relationship of maternal emotion and cognitive control and parenting are necessary to establish causality. Research that addresses how maternal emotion regulation and cognitive control capacities are related to mothers' enrollment and participation in parenting and early intervention programs is an important next step to strengthening policy and intervention work. PMID- 26028798 TI - Spectroscopic evaluation of photodynamic therapy of the intraperitoneal cavity. AB - We present the results of spectroscopic measurements of diffuse reflectance and fluorescence before and after photodynamic therapy of healthy canine peritoneal cavity. Animals were treated intra-operatively after iv injection of the benzoporphyrin derivative (BPD). The small bowel was treated using a uniform light field projected by a microlenstipped fiber. The cavity was then filled with scattering medium and the remaining organs were treated using a moving diffuser. Diffuse reflectance and fluorescence measurements were made using a multi-fiber optical probe positioned on the surface of various tissues within the cavity before and after illumination. The measured data were analyzed to quantify hemoglobin concentration and oxygenation and sensitizer concentration. PMID- 26028799 TI - Investigating the photosensitizer-potential of targeted gallium corrole using multimode optical imaging. AB - We recently developed a novel therapeutic particle, HerGa, for breast cancer treatment and detection. HerGa consists of a tumor-targeted cell penetration protein noncovalently assembled with a gallium-metallated corrole. The corrole is structurally similar to porphyrin, emits intense fluorescence, and has proven highly effective for breast tumor treatment preclinically, without light exposure. Here, we tested HerGa as a photosensitizer for photodynamic therapy and investigated its mechanism of action using multimode optical imaging. Using confocal fluorescence imaging, we observed that HerGa disrupts the mitochondrial membrane potential in situ, and this disruption is substantially augmented by light exposure. In addition, spectral and fluorescence lifetime imaging were utilized to both validate the mitochondrial membrane potential disruption and investigate HerGa internalization, allowing us to optimize the timing for light dosimetry. We observed, using advanced multimode optical imaging, that light at a specific wavelength promotes HerGa cytotoxicity, which is likely to cause disruption of mitochondrial function. Thus, we can identify for the first time the capacity of HerGa as a photosensitizer for photodynamic therapy and reveal its mechanism of action, opening possibilities for therapeutic intervention in human breast cancer management. PMID- 26028800 TI - Scalable Brain Network Construction on White Matter Fibers. AB - DTI offers a unique opportunity to characterize the structural connectivity of the human brain non-invasively by tracing white matter fiber tracts. Whole brain tractography studies routinely generate up to half million tracts per brain, which serves as edges in an extremely large 3D graph with up to half million edges. Currently there is no agreed-upon method for constructing the brain structural network graphs out of large number of white matter tracts. In this paper, we present a scalable iterative framework called the epsilon-neighbor method for building a network graph and apply it to testing abnormal connectivity in autism. PMID- 26028801 TI - Automatic Sulcal Curve Extraction on the Human Cortical Surface. AB - The recognition of sulcal regions on the cortical surface is an important task to shape analysis and landmark detection. However, it is challenging especially in a complex, rough human cortex. In this paper, we focus on the extraction of sulcal curves from the human cortical surface. The previous sulcal extraction methods are time-consuming in practice and often have a difficulty to delineate curves correctly along the sulcal regions in the presence of significant noise. Our pipeline is summarized in two main steps: 1) We extract candidate sulcal points spread over the sulcal regions. We further reduce the size of the candidate points by applying a line simplification method. 2) Since the candidate points are potentially located away from the exact valley regions, we propose a novel approach to connect candidate sulcal points so as to obtain a set of complete curves (line segments). We have shown in experiment that our method achieves high computational efficiency, improved robustness to noise, and high reliability in a test-retest situation as compared to a well-known existing method. PMID- 26028802 TI - LOGISMOS-B for Primates: Primate Cortical Surface Reconstruction and Thickness Measurement. AB - Cortical thickness and surface area are important morphological measures with implications for many psychiatric and neurological conditions. Automated segmentation and reconstruction of the cortical surface from 3D MRI scans is challenging due to the variable anatomy of the cortex and its highly complex geometry. While many methods exist for this task in the context of the human brain, these methods are typically not readily applicable to the primate brain. We propose an innovative approach based on our recently proposed human cortical reconstruction algorithm, LOGISMOS-B, and the Laplace-based thickness measurement method. Quantitative evaluation of our approach was performed based on a dataset of T1- and T2-weighted MRI scans from 12-month-old macaques where labeling by our anatomical experts was used as independent standard. In this dataset, LOGISMOS-B has an average signed surface error of 0.01 +/- 0.03mm and an unsigned surface error of 0.42 +/- 0.03mm over the whole brain. Excluding the rather problematic temporal pole region further improves unsigned surface distance to 0.34 +/- 0.03mm. This high level of accuracy reached by our algorithm even in this challenging developmental dataset illustrates its robustness and its potential for primate brain studies. PMID- 26028803 TI - Shape index distribution based local surface complexity applied to the human cortex. AB - The quantification of local surface complexity in the human cortex has shown to be of interest in investigating population differences as well as developmental changes in neurodegenerative or neurodevelopment diseases. We propose a novel assessment method that represents local complexity as the difference between the observed distributions of local surface topology to its best-fit basic topology model within a given local neighborhood. This distribution difference is estimated via Earth Move Distance (EMD) over the histogram within the local neighborhood of the surface topology quantified via the Shape Index (SI) measure. The EMD scores have a range from simple complexity (0.0), which indicates a consistent local surface topology, up to high complexity (1.0), which indicates a highly variable local surface topology. The basic topology models are categorized as 9 geometric situation modeling situations such as crowns, ridges and fundi of cortical gyro and sulci. We apply a geodesic kernel to calculate the local SI histrogram distribution within a given region. In our experiments, we obtained the results of local complexity that shows generally higher complexity in the gyral/sulcal wall regions and lower complexity in some gyral ridges and lowest complexity in sulcal fundus areas. In addition, we show expected, preliminary results of increased surface complexity across most of the cortical surface within the first years of postnatal life, hypothesized to be due to the changes such as development of sulcal pits. PMID- 26028804 TI - Skeletal shape correspondence via entropy minimization. AB - PURPOSE: Improving the shape statistics of medical image objects by generating correspondence of interior skeletal points. DATA: Synthetic objects and real world lateral ventricles segmented from MR images. METHODS: Each object's interior is modeled by a skeletal representation called the s-rep, which is a quadrilaterally sampled, folded 2-sided skeletal sheet with spoke vectors proceeding from the sheet to the boundary. The skeleton is divided into three parts: up-side, down-side and fold-curve. The spokes on each part are treated separately and, using spoke interpolation, are shifted along their skeletal parts in each training sample so as to tighten the probability distribution on those spokes' geometric properties while sampling the object interior regularly. As with the surface-based correspondence method of Cates et al., entropy is used to measure both the probability distribution tightness and sampling regularity. The spokes' geometric properties are skeletal position, spoke length and spoke direction. The properties used to measure the regularity are the volumetric subregions bounded by the spokes, their quadrilateral sub-area and edge lengths on the skeletal surface and on the boundary. RESULTS: Evaluation on synthetic and real world lateral ventricles demonstrated improvement in the performance of statistics using the resulting probability distributions, as compared to methods based on boundary models. The evaluation measures used were generalization, specificity, and compactness. CONCLUSIONS: S-rep models with the proposed improved correspondence provide significantly enhanced statistics as compared to standard boundary models. PMID- 26028805 TI - Known-Component 3D-2D Registration for Image Guidance and Quality Assurance in Spine Surgery Pedicle Screw Placement. AB - PURPOSE: To extend the functionality of radiographic/fluoroscopic imaging systems already within standard spine surgery workflow to: 1) provide guidance of surgical device analogous to an external tracking system; and 2) provide intraoperative quality assurance (QA) of the surgical product. METHODS: Using fast, robust 3D-2D registration in combination with 3D models of known components (surgical devices), the 3D pose determination was solved to relate known components to 2D projection images and 3D preoperative CT in near-real-time. Exact and parametric models of the components were used as input to the algorithm to evaluate the effects of model fidelity. The proposed algorithm employs the covariance matrix adaptation evolution strategy (CMA-ES) to maximize gradient correlation (GC) between measured projections and simulated forward projections of components. Geometric accuracy was evaluated in a spine phantom in terms of target registration error at the tool tip (TRE x ), and angular deviation (TRE phi ) from planned trajectory. RESULTS: Transpedicle surgical devices (probe tool and spine screws) were successfully guided with TRE x <2 mm and TRE phi <0.5 degrees given projection views separated by at least >30 degrees (easily accommodated on a mobile C-arm). QA of the surgical product based on 3D-2D registration demonstrated the detection of pedicle screw breach with TRE x <1 mm, demonstrating a trend of improved accuracy correlated to the fidelity of the component model employed. CONCLUSIONS: 3D-2D registration combined with 3D models of known surgical components provides a novel method for near-real-time guidance and quality assurance using a mobile C-arm without external trackers or fiducial markers. Ongoing work includes determination of optimal views based on component shape and trajectory, improved robustness to anatomical deformation, and expanded preclinical testing in spine and intracranial surgeries. PMID- 26028806 TI - Effects of experimental warming on survival, phenology and morphology of an aquatic insect (Odonata). AB - 1. Organisms can respond to changing climatic conditions in multiple ways including changes in phenology, body size or morphology, and range shifts. Understanding how developmental temperatures affect insect life-history timing and morphology is crucial because body size and morphology affect multiple aspects of life history, including dispersal ability, while phenology can shape population performance and community interactions. 2. We experimentally assessed how developmental temperatures experienced by aquatic larvae affected survival, phenology, and adult morphology of dragonflies (Pachydiplax longipennis). Larvae were reared under 3 environmental temperatures: ambient, +2.5 degrees C, and +5 degrees C, corresponding to temperature projections for our study area 50 and 100 years in the future, respectively. Experimental temperature treatments tracked naturally-occurring variation. 3. We found clear effects of temperature in the rearing environment on survival and phenology: dragonflies reared at the highest temperatures had the lowest survival rates, and emerged from the larval stage approximately 3 weeks earlier than animals reared at ambient temperatures. There was no effect of rearing temperature on overall body size. Although neither the relative wing nor thorax size was affected by warming, a non-significant trend towards an interaction between sex and warming in relative thorax size suggests that males may be more sensitive to warming than females, a pattern that should be investigated further. 4. Warming strongly affected survival in the larval stage and the phenology of adult emergence. Understanding how warming in the developmental environment affects later life-history stages is critical to interpreting the consequences of warming for organismal performance. PMID- 26028807 TI - Salivary and serum cortisol levels during recovery from intense exercise and prolonged, moderate exercise. AB - The aim of this study was to compare serum (SERc) and salivary cortisol (SALc) responses during recovery from two different exhaustive exercises to determine peak cortisol sampling time and the agreement between SERc and SALc levels. Twelve healthy men underwent a maximal treadmill graded exercise to exhaustion (MEx) and a prolonged, submaximal cycle exercise in the heat for 90 min (PEx) while SERc and SALc samples were taken in parallel at baseline, end of exercise, and 15 min intervals over one hour of recovery. MEx and PEx significantly increased SERc and SALc levels (p < 0.01) while absolute SERc levels were approximately 7-10 folds higher than SALc. SERc and SALc showed highly positive correlation (R = 0.667-0.910, p < 0.05) at most sampling times and only a few individual values were out of 95% limit of agreement when analyzed by Bland Altman plots. However, peak SERc levels (MEx: 784.0+/-147, PEx: 705.5+/-212.0 nmol . L(-1)) occurred at 15 min of recovery, whereas peak SALc levels (MEx: 102.7+/-46.4, PEx: 95.7+/-40.9 nmol . L(-1)) were achieved at the end of exercise in MEx and PEx. The recovery trend of SERc and SALc also differed following MEx and PEx. Activity of 11beta-hydroxysteroid dehydrogenase type 2 enzymes may be suppressed following MEx compared to PEx. In conclusion, sampling for peak SERc and SALc levels should take into account their evolution and clearance characteristics as well as type of exercise performed, whereas SALc appeared to be a more sensitive marker than SERc for the measurement of cortisol responses during exercise recovery. PMID- 26028808 TI - Reliability of the calculated maximal lactate steady state in amateur cyclists. AB - Complex performance diagnostics in sports medicine should contain maximal aerobic and maximal anaerobic performance. The requirements on appropriate stress protocols are high. To validate a test protocol quality criteria like objectivity and reliability are necessary. Therefore, the present study was performed in intention to analyze the reliability of maximal lactate production rate ([Formula: see text]Lamax) by using a sprint test, maximum oxygen consumption ([Formula: see text]O2max) by using a ramp test and, based on these data, resulting power in calculated maximum lactate-steady-state (PMLSS) especially for amateur cyclists. All subjects (n = 23, age 26 +/- 4 years) were leisure cyclists. At three different days they completed first a sprint test to approximate [Formula: see text]Lamax. After 60 min of recreation time a ramp test to assess [Formula: see text]O2max was performed. The results of [Formula: see text]Lamax-test and [Formula: see text]O2max-test and the body weight were used to calculate PMLSS for all subjects. The intra class correlation (ICC) for [Formula: see text]Lamax and [Formula: see text]O2max was 0.904 and 0.987, respectively, coefficient of variation (CV) was 6.3% and 2.1%, respectively. Between the measurements the reliable change index of 0.11 mmol.l (-1)s (-1) for [Formula: see text]Lamax and 3.3 mlkg (-1)min (-1) for [Formula: see text]O2max achieved significance. The mean of the calculated PMLSS was 237 +/- 72 W with an RCI of 9 W and reached with ICC = 0.985 a very high reliability. Both metabolic performance tests and the calculated PMLSS are reliable for leisure cyclists. PMID- 26028809 TI - Rating of perceived exertion as a tool for prescribing and self regulating interval training: a pilot study. AB - The aim of the present study was to analyse the usefulness of the 6-20 rating of perceived exertion (RPE) scale for prescribing and self-regulating high-intensity interval training (HIT) in young individuals. Eight healthy young subjects (age = 27.5+/-6.7 years) performed maximal graded exercise testing to determine their maximal and reserve heart rate (HR). Subjects then performed two HIT sessions (20 min on a treadmill) prescribed and regulated by their HR (HR: 1 min at 50% alternated with 1 min at 85% of reserve HR) or RPE (RPE: 1 minute at the 9-11 level [very light-fairly light] alternated with 1 minute at the 15-17 level [hard very hard]) in random order. HR response and walking/running speed during the 20 min of exercise were compared between sessions. No significant difference between sessions was observed in HR during low- (HR: 135+/-15 bpm; RPE: 138+/-20 bpm) and high-intensity intervals (HR: 168+/-15 bpm; RPE: 170+/-18 bpm). Walking/running speed during low- (HR: 5.7+/-1.2 km . h(-1); RPE: 5.7+/-1.3 km . h(-1)) and high intensity intervals (HR: 7.8+/-1.9 km . h(-1); RPE: 8.2+/-1.7 km . h(-1)) was also not different between sessions. No significant differences were observed in HR response and walking/running speed between HIT sessions prescribed and regulated by HR or RPE. This finding suggests that the 6-20 RPE scale may be a useful tool for prescribing and self-regulating HIT in young subjects. PMID- 26028810 TI - Weight loss is not mandatory for exercise-induced effects on health indices in females with metabolic syndrome. AB - The aim of this study was to investigate the impact of moderate aerobic training on functional, anthropometric, biochemical, and health-related quality of life (HRQOL) parameters on women with metabolic syndrome (MS). Fifteen untrained women with MS performed moderate aerobic training for 15 weeks, without modifications of dietary behaviours. Functional, anthropometric, biochemical, control diet record and HRQOL parameters were assessed before and after the training. Despite body weight maintenance, the patients presented decreases in waist circumference (P = 0.001), number of MS components (P = 0.014), total cholesterol (P = 0.049), HDL cholesterol (P = 0.004), LDL cholesterol (P = 0.027), myeloperoxidase activity (P = 0.002) and thiobarbituric acid-reactive substances levels (P = 0.006). There were no differences in total energy, carbohydrate, protein and lipid intake pre- and post-training. Furthermore, improvements in the HRQOL subscales of physical functioning (P = 0.03), role-physical (P = 0.039), bodily pain (P = 0.048), general health (P = 0.046) and social functioning scoring (P = 0.011) were reported. Despite the absence of weight loss, aerobic training induced beneficial effects on functional, anthropometric, biochemical and HRQOL parameters in women with MS. PMID- 26028811 TI - Fracture Modes in Curved Brittle Layers Subject to Concentrated Cyclic Loading in Liquid Environments. AB - Damage response of brittle curved structures subject to cyclic Hertzian indentation was investigated. Specimens were fabricated by bisecting cylindrical quartz glass hollow tubes. The resulting hemi-cylindrical glass shells were bonded internally and at the edges to polymeric supporting structures and loaded axially in water on the outer circumference with a spherical tungsten carbide indenter. Critical loads and number of cycles to initiate and propagate near contact cone cracks and far-field flexure radial cracks to failure were recorded. Flat quartz glass plates on polymer substrates were tested as a control group. Our findings showed that cone cracks form at lower loads, and can propagate through the quartz layer to the quartz/polymer interface at lower number of cycles, in the curved specimens relative to their flat counterparts. Flexural radial cracks require a higher load to initiate in the curved specimens relative to flat structures. These radial cracks can propagate rapidly to the margins, the flat edges of the bisecting plane, under cyclic loading at relatively low loads, owing to mechanical fatigue and a greater spatial range of tensile stresses in curved structures. PMID- 26028812 TI - Response-Outcome versus Outcome-Response Associations in Pavlovian-to Instrumental Transfer: Effects of Instrumental Training Context. AB - One experiment with rats used Pavlovian-to-instrumental transfer (PIT) tests to explore potential competitive interactions between Pavlovian and instrumental processes during instrumental learning. Two instrumental response-outcome relations (e.g., left lever - grain pellets, right lever - sucrose pellets) were first trained in distinct contexts for one group of rats (Group Differential) or in each of two contexts for a second group (Group Non-Differential). Both of these groups then received training with two Pavlovian stimulus-outcome relations in a third experimental context. Selective PIT tests conducted in both the Pavlovian and instrumental contexts revealed greater selective PIT in Group Non Differential than in Group Differential subjects. This result is discussed in terms of the roles played by context-outcome, response-outcome, and outcome response associations during instrumental learning. The results further help us understand the nature of Pavlovian-instrumental interactions in specific PIT tasks. PMID- 26028813 TI - Personality, communication, and depressive symptoms across the transition to parenthood: A dyadic longitudinal investigation. AB - This study adopted a person (actor) by partner perspective to examine how actor personality traits, partner personality traits, and specific actor by partner personality trait interactions predict actor's depressive symptoms across the first two years of the transition to parenthood. Data were collected from a large sample of new parents (both partners in each couple) 6 weeks before the birth of their first child, and then at 6, 12, 18, and 24 months postpartum. The results revealed that higher actor neuroticism and lower partner agreeableness predicted higher levels of depressive symptoms in actors. Moreover, the specific combination of high actor neuroticism and low partner agreeableness was a particularly problematic combination, which was intensified when prepartum dysfunctional problem-solving communication and aggression existed in the relationship. These results demonstrate the importance of considering certain actor by partner disposition pairings to better understand actors' emotional well being during major life transitions. PMID- 26028814 TI - Responses to the Standard for Exchange of Nonclinical Data (SEND) in non-US countries. AB - The Standard for the Exchange of Nonclinical Data (SEND), adopted by the US FDA, is part of a set of regulations and guidances requiring the submission of standardized electronic study data for nonclinical and clinical data submissions. SEND is the nonclinical implementation of SDTM (Study Data Tabulation Model), the standard electronic format for clinical regulatory submissions to FDA. SEND, SDTM, and the associated Controlled Terminology have been developed by CDISC (Clinical Data Interchange Standards Consortium). In order to successfully implement SEND, interdisciplinary contributions between sponsors and CROs, need a model for task allocation. This is being undertaken by the Pharmaceutical Users Software Exchange (PhUSE). Because SEND is currently the preferred submission format of the US FDA only and will become required by it starting in December 2016, only American academic societies and companies are actively involved. An exception to this is the INHAND initiative, which leads the way in standardizing terminology for toxicological pathology. On the other hand, international globalization of other clinical and nonclinical practices is not feasible because there are substantial differences between the US and non-US countries in CRO involvement in drug development. Thus, non-US countries must consider and develop approaches to SEND that meet their needs. This paper summarizes the activities of the major organizations involved in SEND development and implementation, discusses the effective use of SEND, and details a compliance scheme (research material of the Showa University School of Medicine) illustrating how pharmaceutical companies can complete a large amount of work up to an FDA application with the effective utilization of CROs and solution providers. PMID- 26028815 TI - Sodium bicarbonate protects uranium-induced acute nephrotoxicity through uranium decorporation by urinary alkalinization in rats. AB - To evaluate the effectiveness of sodium bicarbonate (SB) in removing uranium and protecting animals from uranium toxicity, we intramuscularly administered 1 mg/kg of uranyl nitrate to 8-wk-old male SD rats, and 20 min after administration of uranyl nitrate, the animals were given a single oral administration of SB at 0.1, 0.3 or 1 g/kg. The SB treatment at a dose of 0.3 g/kg or more raised the pH of the rats' urine until 4 h after treatment, and it significantly reduced the uranium amounts in the kidneys at 1 day after treatment. In another experiment, rats were intramuscularly administered 1 mg/kg of uranyl nitrate, and 20 min later, the animals were treated with sodium bicarbonate (0.1 or 1 g/kg). The rats were autopsied at 1, 3 and 7 days after uranium treatment. High-dose SB resulted in a significant increase in urinary uranium excretion in the first 24 h and a reduction of uranium deposition in the kidneys and femurs, and it also significantly suppressed uranium-induced renal toxicity, as shown by both histopathology and clinical chemistry at 3 days after uranium treatment. Low-dose SB did not show such marked effects. Our findings demonstrated that the uranium decorporation effect of sodium bicarbonate was observed at the dosage showing urine alkalinization in rats and that decorporation effect of sodium bicarbonate might be beneficial if it is administered immediately after incorporation of soluble uranium. PMID- 26028816 TI - Morphometric analysis of progressive changes in hereditary cerebellar cortical degenerative disease (abiotrophy) in rabbits caused by abnormal synaptogenesis. AB - We previously investigated rabbit hereditary cerebellar cortical degenerative disease, called cerebellar cortical abiotrophy in the veterinary field, and determined that the pathogenesis of this disease is the result of failed synaptogenesis between parallel fibers and Purkinje cells. In this study, longitudinal changes in the development and atrophy of the cerebellum of rabbits with hereditary abiotrophy after birth were morphometrically examined (postnatal day [PD] 15 and 42) using image analysis. Although development of the cerebellum in rabbits with abiotrophy was observed from PD 15 to PD 42, the growth rate of the cerebellum was less than that in normal rabbits. In rabbits with abiotrophy, the number of granular cells undergoing apoptosis was significantly higher at PD 15 and dramatically decreased at PD 42. The number of granular cells did not increase from PD 15 to 42. The synaptogenesis peak at PD 15 occurred when the largest number of apoptotic granular cells in rabbits with abiotrophy was observed. Although 26% to 36% of parallel fiber terminals formed synaptic junctions with Purkinje cell spines, the remainder did not at PD 15 and 42. The rate of failure of synaptogenesis in the present study might be specific to this case of abiotrophy. Morphometric analysis revealed detailed changes in development and atrophy in animals with postnatal cerebellar disease occurring soon after birth. PMID- 26028817 TI - Expression and activation of EGFR and STAT3 during the multistage carcinogenesis of intrahepatic cholangiocarcinoma induced by 3'-methyl-4 dimethylaminoazobenzene in rats. AB - The purpose of this study was to investigate whether the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription-3 (STAT3) signal pathway contributes to the carcinogenesis of intrahepatic cholangiocarcinoma (ICC) induced by 3'-methyl-4 dimethylaminoazobenzene (3'Me DAB) in rats. EGFR, TGFalpha, STAT3 and p-STAT3 in different stages of carcinogenesis were detected by immunohistochemistry (IHC). In situ hybridization (ISH) was applied to investigate the expression of STAT3 mRNA. Oval cells were verified by the immunohistochemical staining of alpha-fetoprotein (AFP), CD133 and epithelial cell adhesion molecules (EpCAM). Sequential development of necrosis, oval cell proliferation, cholangiofibrosis (CF) and ICC was observed in the liver of rats administered 3'Me-DAB. Oval cells showed positive expression of AFP, CD133 and EpCAM. The expression of EGFR was significantly higher in the ICC than in oval cells, CF or normal bile ducts (p<0.05), but there was no difference in EGFR expression between the other groups. The highest expression of p-STAT3 and TGFalpha was observed in CF. The expression of these two molecules in the ICC and oval cells was significantly higher than in normal bile ducts (p<0.05). Elevation of STAT3 mRNA was detected during carcinogenesis as shown by ISH, strong intensity was observed in the ICC and moderate intensity was observed in oval cells and CF. These observations suggest that the EGFR and STAT3 signal pathway contributes to the carcinogenesis of ICC. High activity of STAT3 during the carcinogenesis of ICC may be the result of high activity of EGFR triggered by TGFalpha. PMID- 26028818 TI - Obstructive nephropathy induced with DL-potassium hydrogen tartrate in F344 rats. AB - We experienced obstructive nephropathy in F344 rats treated with DL-potassium hydrogen tartrate (PHT) in a 13-week oral repeated dose toxicity study. Six-week old male and female F344/DuCrj rats were fed a diet containing up to 2.0% PHT for 13 weeks. Microscopical findings including irregular dilation of the distal tubule lumen, foreign body giant cells, inflammatory cell infiltration, and regeneration of renal tubules were observed focally or multifocally in the renal cortex and/or medulla in the 0.5% and higher dosage groups of both sexes. The severity of these lesions increased in a dose-dependent manner. In the urinalysis, an increase in protein and white blood cells or the concentration of tartaric acid was detected in the 0.5% PHT and higher dosage groups of both sexes or males, respectively, though conventional blood biochemical analysis did not indicate failure of renal function. These results indicate that the PHT induces obstructive nephropathy in rats. There were no other treatment-related changes in other organs. PMID- 26028819 TI - Modifications of azoxymethane-induced carcinogenesis and 90-day oral toxicities of 2-tetradecylcyclobutanone as a radiolytic product of stearic acid in F344 rats. AB - A 90-day oral toxicity test in rats was performed to evaluate the toxicity of 2 tetradecylcyclobutanone (2-tDCB), a unique radiolytic product of stearic acid. Six-week-old male and female F344 rats (n=15/group) were given 2-tDCB at concentrations of 0, 12, 60 and 300 ppm in a powder diet for 13 weeks. Slight dose-dependent increases in serum total protein and albumin in male rats were found, but these changes were not considered to be a toxic effect. The fasting, but not non-fasting, blood glucose levels of the male rats in the 300 ppm group and female rats in the 60 and 300 ppm groups were lower than those of the controls. Gas chromatography-mass spectrometry analysis showed dose-dependent accumulation of 2-tDCB in adipose tissue, notably in males. Next, we performed an azoxymethane (AOM)-induced two-stage carcinogenesis study. After injection of 6 week-old male F344 rats (n=30/group) once a week for 3 weeks, the animals received 2-tDCB at concentrations of 0, 10, 50 and 250 ppm in a powder diet for 25 weeks. The incidences of colon tumors for the 2-tDCB dosages were 34%, 45%, 40% and 37%, respectively, and were not statistically significant. These data suggest that 2-tDCB shows no toxic or tumor-modifying effects under the present conditions, and that the no-observed-adverse-effect level for 2-tDCB is 300 ppm in both sexes, equivalent to 15.5 mg/kg b.w./day in males and 16.5 mg/kg b.w./day in females. PMID- 26028820 TI - Time course of the incidence/multiplicity and histopathological features of murine colonic dysplasia, adenoma and adenocarcinoma induced by benzo[a]pyrene and dextran sulfate sodium. AB - Benzo[a]pyrene (BP) is mutagenic but noncarcinogenic in the murine colon. Recently, we reported rapid induction of colonic tumors by treatment of CD2F1 mice with BP (125 mg/kg for 5 days) followed by a colitis inducer, dextran sulfate sodium (DSS) (4% in drinking water for 1 or 2 weeks). However, there are no reports on detailed time course and histopathological features of colonic proliferative lesions in this model. Here, we show the detailed time course of colonic dysplasia, adenoma and adenocarcinoma induced by treatment with BP, DSS, and a combination of the two (BP/DSS). In the colon of mice exposed to BP/DSS, 14.6 dysplastic foci per mouse were present one week after DSS treatment (week 4). The number of dysplastic foci decreased with time to 3.1 at week 9 and thereafter remained almost constant. At week 4, 1.5 adenocarcinomas were also observed, with a marked increase in numbers with time, reaching 29.3 at week 14. In contrast, the number of dysplastic foci induced by DSS alone showed a time course similar to that following BP/DSS treatment; however, only a few tumors appeared. Neither dysplastic foci nor neoplastic lesions were induced by BP only. In mice exposed to BP/DSS, beta-catenin was demonstrated immunohistochemically in the nucleus and/or cytoplasm of the tumor cells, and this translocation from the cell membrane was evident in subsets of dysplastic foci. In dysplastic foci induced by DSS alone, beta-catenin was absent in the nucleus/cytoplasm. These finding suggest that aberrant beta-catenin accumulation in dysplastic foci is associated with tumor progression in this BP/DSS model. PMID- 26028821 TI - Spontaneous and bilateral necrosis of the femoral head in a young experimental beagle dog. AB - This report describes the pathological characterizations of a rare case of necrosis of the femoral head that was spontaneous, bilateral, avascular and nontraumatic. A 14-month-old beagle dog was presented with pain in the hind limbs. At necropsy, the articular surface in the bilateral femoral head was markedly irregular. There were no gross abnormalities other than in the hip joints. Microscopically, a wide range of trabecular bone necrosis localized in the subchondral area was observed in both femoral heads. In the right femoral head, fibrosis and proliferative vessels were noted in the subchondral area. The articular cartilage was thickened irregularly, but there was no evidence of cartilage necrosis. The bone marrow adjacent to the affected area showed severe depression. In the metaphysis, atrophic bone marrow, but not bone necrosis, was observed. This was a rare case of spontaneous necrosis of the femoral head in an experimental beagle dog. PMID- 26028822 TI - Motion sequence analysis in the presence of figural cues. AB - The perception of 3D structure in dynamic sequences is believed to be subserved primarily through the use of motion cues. However, real-world sequences contain many figural shape cues besides the dynamic ones. We hypothesize that if figural cues are perceptually significant during sequence analysis, then inconsistencies in these cues over time would lead to percepts of non-rigidity in sequences showing physically rigid objects in motion. We develop an experimental paradigm to test this hypothesis and present results with two patients with impairments in motion perception due to focal neurological damage, as well as two control subjects. Consistent with our hypothesis, the data suggest that figural cues strongly influence the perception of structure in motion sequences, even to the extent of inducing non-rigid percepts in sequences where motion information alone would yield rigid structures. Beyond helping to probe the issue of shape perception, our experimental paradigm might also serve as a possible perceptual assessment tool in a clinical setting. PMID- 26028823 TI - Distributed situation awareness in complex collaborative systems: A field study of bridge operations on platform supply vessels. AB - : This study provides empirical data about shipboard practices in bridge operations on board a selection of platform supply vessels (PSVs). Using the theoretical concept of distributed situation awareness, the study examines how situation awareness (SA)-related information is distributed and coordinated at the bridge. This study thus favours a systems approach to studying SA, viewing it not as a phenomenon that solely happens in each individual's mind but rather as something that happens between individuals and the tools that they use in a collaborative system. Thus, this study adds to our understanding of SA as a distributed phenomenon. Data were collected in four field studies that lasted between 8 and 14 days on PSVs that operate on the Norwegian continental shelf and UK continental shelf. The study revealed pronounced variations in shipboard practices regarding how the bridge team attended to operational planning, communication procedures, and distracting/interrupting factors during operations. These findings shed new light on how SA might decrease in bridge teams during platform supply operations. The findings from this study emphasize the need to assess and establish shipboard practices that support the bridge teams' SA needs in day-to-day operations. PRACTITIONER POINTS: Provides insights into how shipboard practices that are relevant to planning, communication and the occurrence of distracting/interrupting factors are realized in bridge operations.Notes possible areas for improvement to enhance distributed SA in bridge operations. PMID- 26028824 TI - Nutrients and water masses in the Gulf of Maine - Georges Bank region: Variability and importance to blooms of the toxic dinoflagellate Alexandrium fundyense. AB - We report here the results of ten oceanographic survey cruises carried out in the Gulf of Maine - Georges Bank region of the Northwest Atlantic during the late spring to summer period in 2007, 2008 and 2010, for which we examine and characterize relationships among dissolved inorganic nutrient fields, water mass dynamics and cell densities of the toxic dinoflagellate Alexandrium fundyense. Nutrients are supplied to continental shelf waters of the Gulf of Maine - Georges Bank region by inflows of deep offshore water masses; once in the Gulf they are transported with the residual circulation and mix with surface waters, both in the Gulf and on the Bank. Those fluxes of offshore water masses and their nutrient loads are the major source of nutrients for phytoplankton production in the region, including annual blooms of A. fundyense in the Gulf and on Georges Bank. This much is already known. We suggest here that the locations and magnitude of A. fundyense blooms are controlled in part by variable nutrient fluxes to the interior Gulf of Maine from offshore, and, those interior Gulf of Maine waters are, in turn, the main nutrient source to Georges Bank, which are brought onto the Bank by tidal pumping on the Northern Flank. We present evidence that nitrate is the initial form of nitrogenous nutrient for A. fundyense blooms, but it is quickly depleted to limiting concentrations of less than 0.5 MUM, at which time continued growth and maintenance of the population is likely fueled by recycled ammonium. We also show that phosphate may be the limiting nutrient over much of Georges Bank in summer, allowing recycled ammonium concentrations to increase. Our temperature-salinity analyses reveal spatial and temporal (seasonal and interannual) variability in the relative proportions of two deep source waters that enter the Gulf of Maine at depth through the Northeast Channel: Warm Slope Water (WSW) and Labrador Slope Water (LSW). Those two source waters are known to vary in their nutrient loads, with nitrate concentrations about 50% higher in WSW than LSW, for example, and as such the proportions of these two water masses to one another are important determinants of the overall nutrient loads in the interior Gulf. In addition to these deep slope water fluxes, we show evidence here of episodic fluxes of relatively fresh and low-nutrient shelf waters from the Nova Scotian Shelf, which enter the Gulf in pulses at depths between the surface and approximately 150 m, displacing deep slope waters, and consequently they significantly dilute the Gulf's interior waters, reducing nutrient concentrations and, in turn, affect the magnitude of A. fundyense blooms. PMID- 26028825 TI - On global certification of training. PMID- 26028826 TI - The Benefit of the Smartphone in Oral and Maxillofacial Surgery: Smartphone Use Among Maxillofacial Surgery Trainees and iPhone Apps for the Maxillofacial Surgeon. AB - The use of smartphones has soared among healthcare professionals in recent years, with estimated figures reporting that the majority of clinicians own and use smartphones in the workplace. Smartphones allow the clinician to carry textbooks in their pocket, write documents on the move and use email and internet to enhance productivity and clinical decision making. These advances in smartphone technology have enabled access to healthcare information for the clinician and transfer of data between team members, giving rise to the phenomenon of telemedicine. With the ability to instantly transfer clinical data to the off site surgeon, combined with purpose-built medical apps, the smartphone is rapidly becoming an invaluable tool for the modern surgeon. Many studies have linked the benefits of smartphones and apps in other surgical specialities, but no article to date has highlighted the merits and full scope of this technology to the Oral and Maxillofacial Surgeon. We report that 94 % of British maxillofacial surgery trainees own a smartphone, with 61 % owning an iPhone. 89 % of trainees questioned had downloaded medical apps and used them regularly during clinical activities. We discuss the clinical application of the smartphone in the field of oral and maxillofacial surgery and review a list of useful and relevant apps for the modern maxillofacial surgeon using the iPhone as an example platform. PMID- 26028827 TI - Patterns of maxillofacial fractures in goa. AB - BACKGROUND: The maxillofacial skeleton is commonly fractured due to its prominent position. The pattern of maxillofacial fractures varies from one country to another. The aim of this retrospective study was to analyze the patterns of maxillofacial injuries in the state of Goa and compare the results with similar studies in India and rest of the world. PATIENTS AND METHODS: The data were collected from the records of the patients who reported to the Department of Oral and Maxillofacial Surgery, Goa Dental College and Hospital between 2005 and 2010. The site of fracture, age of patient, etiology of trauma, daily and monthly variation of the fractures was analysed. RESULTS: Records of 2,731 patients sustaining maxillofacial injury were examined. The most commonly fractured facial bone was the mandible followed by zygomaticomaxillary complex. Most fractures occurred in the third and fourth decade of life with male and female ratio of 6:1. Main etiology was road traffic accidents. CONCLUSION: Despite strict traffic legislation, road traffic accidents are the main cause of maxillofacial injuries. PMID- 26028828 TI - Maxillofacial injuries due to animal bites. AB - INTRODUCTION: Animal bites are a significant public health problem, with the majority of bites coming from dogs, cats and humans. These may present as punctures, abrasions, tears, or avulsions. The force and relative bluntness of the teeth also increases the possibility of a crush injury with devitalized tissue .The clinical presentation and appropriate treatment of infected bite wounds vary according to the animal and causative organisms. These wounds have always been considered complex injuries contaminated with a unique polymicrobial inoculum. MATERIALS: This article reviews animal bite wound incidence, bacteriology, risk factors for complications, evaluation components, recommended treatment and prevention based on advanced PUBMED search of the English language literature from the years 1970 to present. CONCLUSION: As the bite wounds are frequently located on the face, an oral and maxillofacial surgeon needs to be familiar with the treatment of animal bites, pitfalls in management and to educate patients on ways to avoid future bite injuries. The management of animal bites is an evidence poor area and most recommendations are based on small case series, microbiological data and expert opinion. The main controversies include whether wounds should or should not undergo primary closure and the use of prophylactic antimicrobials. PMID- 26028829 TI - Fever after maxillofacial surgery: a critical review. AB - PURPOSE: The aim of this paper is to review the pathophysiology of thermoregulation mechanism, various causes of fever after maxillofacial surgery and the different treatment protocols advised in the literature. DISCUSSION: Fever is one of the most common complaints after major surgery and is also considered to be an important clinical sign which indicates developing pathology that may go unnoticed by the clinician during post operative period. Several factors are responsible for fever after the maxillofacial surgery, inflammation and infection being the commonest. However, other rare causes such as drug allergy, dehydration, malignancy and endocrinological disorders, etc. should be ruled out prior to any definite diagnosis and initiate the treatment. Proper history and clinical examination is an essential tool to predict the causative factors for fever. Common cooling methods like tepid sponging are usually effective alone or in conjunction with analgesics to reduce the temperature. CONCLUSION: Fever is a common postoperative complaint and should not be underestimated as it may indicate a more serious underlying pathology. A specific guideline towards the management of such patients is necessary in every hospital setting to ensure optimal care towards the patients during post operative period. PMID- 26028830 TI - Role of ultrasonography in oral and maxillofacial surgery: a review of literature. AB - Maxillofacial surgery, like any other surgical specialty is greatly dependent on the discipline of radiology. This poses a greater challenge because of the complex anatomy of this region. Various investigation modalities have been applied in diagnosing various diseases which are found in the maxillofacial region, including IOPA, PET, USG, CT, MRI and panoramic radiographs. Of these, USG can easily diagnose non invasive and soft tissue diseases. It is very useful in diagnosing the diseases which are not usually evident on a conventional radiograph. However; many of the dentists are not aware of the benefits of USG in diagnosis of oral diseases. In this article, the use of ultrasound in diagnosing the various pathologies of maxillofacial region is elaborated. PMID- 26028831 TI - Botulinum toxin in the treatment of muscle specific Oro-facial pain: a literature review. AB - Facial pain associated with temporomandibular joint (TMJ) and surrounding structures has been a challenge to clinicians as far as diagnosis and management is concerned. Complexity of anatomical structures within a small area, function of teeth and surrounding periodontal ligament, action of muscles, pathologies, lack of diagnostic investigations, all these complicate specific diagnosis of TMJ disorders. Various classifications have been designed and studied to help diagnose and treat TMJ related disorders, of which the simplest one is pain from TMJ proper and surrounding muscles. Many treatment modalities to treat pain arising from muscles around TMJ like splints, mouth restriction exercises, injection of sclerosing agents etc. have been used with various degrees of success. Botulinum toxin has been shown to be effective in the treatment of oro facial pain due to muscular disorders and the same is discussed in detail in this review literature. PMID- 26028832 TI - Osteo-cementum Producing Odontogenic Myxomas. A Literature Review of a Distinctive Variant. AB - INTRODUCTION: Odontogenic myxoma (OM) is a benign neoplasm of mesenchymal origin with growth characteristics, clinical behaviour and radiographic presentation similar to those of ameloblastoma. It is an intraosseous neoplasm characterized by stellate and spindleshaped cells embedded in loose myxoid or mucoid extracellular matrix. Although sometimes bony islands that represent residual trabeculae are found throughout the lesion, the formation of osteocement-like calcified spherules within the tumour is an extremely rare phenomenon. REVIEW: We report a very rare case of an OM of the left maxilla exhibiting osteo-cementous metaplasia within the substance of the tumour and beyond the facial skeleton, in the nasopharynx. A review of all four similar cases previously reported in the literature is also presented. CONCLUSION: Whether or not this property to produce significant amounts of bone can be associated with a different biological behavior for this specific variant of OM remains to be proved with the study of more similar cases. PMID- 26028833 TI - Changing guidelines of cardiopulmonary resuscitation and basic life support for general dental practitioners and oral and maxillofacial surgeons. AB - INTRODUCTION: Every general dental practitioner and oral and maxillofacial surgeon needs a thorough knowledge of the diagnosis and management of medical emergencies. Cardiopulmonary arrest is the most urgent of emergencies and diagnosis must be done as soon as possible. PURPOSE: This paper discusses the importance of the International Liaison Committee on Resuscitation which forms the guidelines for cardiopulmonary resuscitation (CPR), highlighting the important changes in the guidelines of CPR from the year 2000 to 2010, the basic sequence of performing CPR and also the role of defibrillation and the use of automated external defibrillators. Finally the five part chain of survival which is of utmost importance to dental health care professionals and oral and maxillofacial surgeons. CONCLUSION: All dental health care personnel and oral & maxillofacial surgeons should recognize the importance of the changes in the guidelines of CPR, be trained and allowed to use a properly maintained defibrillator, to respond to cardiac arrest victims. PMID- 26028835 TI - Management of Late Post-traumatic Facial Artery Pseudoaneurysmal Cyst: Review of Literature. AB - Pseudoaneurysms of the branches of the external carotid artery as a result of trauma are rare in oral and maxillofacial surgery practice. The most affected branches are the superficial temporal artery, internal maxillary artery and distal part of facial artery, usually where they pass over the bone. Very few cases of facial artery pseudoaneurysms of proximal parts (from external carotid artery up to the lower border of the mandible) are reported in the literature. We present a review of literature for management of late post-traumatic pseudoaneurysmal cyst and a case report involving proximal part of facial artery in the submandibular region following open reduction and rigid fixation of the condylar fracture in a 25-year-old male. To our knowledge this is the fourth reported case of proximal facial artery pseudoaneurysm. PMID- 26028834 TI - Diagnostic modalities for squamous cell carcinoma: an extensive review of literature-considering toluidine blue as a useful adjunct. AB - INTRODUCTION: Oral Squamous Cell Carcinomas have been considered as the most prevalent malignancies in the head and neck region and are frequently undiagnosed until symptomatic with an advanced stage of disease. So there is an urgent need to device methods for the detection of oral premalignant lesions and oral cancer at an early stage in order to improve the survival rate for patients. A number of tests have been done for the detection of oral cancer which include oral brush biopsy, the Vizilite, oral autofluorescence including chemiluscence, photodynamic detection, toluidine blue staining, methylene blue staining, incisional biopsy and many more. MATERIAL: The article reviews various diagnostic modalities available at present for detection of squamous cell carcinomas and oral epithelial dysplasias based on advanced PUBMED search of the English language literature from the year 1972 to present in order to help us select the most suitable among them fulfilling the desired criteria of being non-invasive, highly specific and sensitive, economically viable, having a scope to be used for mass screening, easy to process, having low inter examiner variability and possibly not requiring high expertise to conduct and interpret the results. CONCLUSION: After reviewing various diagnostic modalities, we conclude that toluidine blue staining emerges as a clear winner among all these and it can act as a valuable adjunct to incisional biopsy in detection of oral cancer and may not substitute it except in certain circumstances when its results are carefully correlated with the patient history and clinical characteristics of the mucosal disorder, considering the fact that incisional biopsy has been reported to cause dissemination of cancer cells in the circulation there by increasing the possibility of metastasis. We must emphasize that toludine blue is a screening modality and not a diagnostic procedure like biopsy and hence cannot replace a confirmatory biopsy as a whole. PMID- 26028836 TI - Promising Role of Exfoliative Cytology in the Evaluation of Glycaemic Status of Type II Diabetics: A Pilot Study. AB - BACKGROUND: The degree of metabolic control in diabetes mellitus influences the susceptibility of patients to oral diseases. It is mandatory to regularly monitor glycaemic status, however invasive methods may be contraindicated or intolerable to diabetic individuals. Thus, cytology, being a simple, non-invasive and rapid procedure, is a promising protocol for assessing diabetic status and assisting in management. AIM: To assess the number of PAS positive glycogen containing cells and associated cellular changes in buccal smears of type II diabetics and correlate the findings with their serum glucose levels. SETTINGS AND DESIGN: The study was conducted at the out patient Department of Oral and Maxillofacial Pathology, KLES Institute of Dental Sciences, Belgaum. MATERIALS AND METHODS: Fifty known cases of type II diabetes mellitus and 50 healthy individuals were included in the study. Fasting blood glucose levels were estimated and buccal smears stained with Periodic Acid Schiff stain. The observed cellular changes were correlated with the glycaemic status of each patient. STATISTICAL ANALYSIS: Statistical evaluations such as Student's t test (P < 0.01-very significant; P < 0.001-highly significant), correlation-coefficient and probability values were computed. RESULTS: Smears of diabetic patients depicted an increase in the number of PAS positive cells in significant correlation to their glycaemic status. Cellular and nuclear morphological alterations were also found in squames of diabetic individuals. CONCLUSION: Cytological findings and clinical observations, suggest a correlation between the extent of these changes and clinical parameters like glycaemic control. Further studies in this aspect can help in improving the reliability of oral cytology as a diagnostic tool in diabetes. PMID- 26028837 TI - Satisfaction audit of patients undergoing mandibular distraction osteogenesis with extra-oral distraction appliances. AB - INTRODUCTION: The aim of this research was to evaluate the level of satisfaction of patients who were undergoing distraction osteogenesis of mandible with extraoral distraction appliance. MATERIAL AND METHODS: The prospective study was performed on 13 patients with facio-mandibular deformity reporting to the Oral Health Sciences Center, PGIMER, Chandigarh, India, who required surgical and orthodontic intervention for correction. A standardized multiple choice questionnaire was provided to all patients at 3 stages of treatment i.e. during predistraction, distraction and post distraction period. RESULTS: Predistraction evaluation showed that the main reason for patients to seek treatment was lack of facial esthetics and all of them were sure that there would be a change in their lives after they underwent this treatment procedure. During distraction phase the most common complaint was pain. None of the patients felt that they were suffering during active distraction phase and all felt that they made the right decision. In post distraction phase, all patients were satisfied with the treatment and felt that the treatment was worth it. Twelve out of 13 patients would recommend treatment to others without any hesitation. CONCLUSION: Our study concludes that distraction osteogenesis of the mandible with extra-oral appliances is acceptable to patients, and improved facial appearance is a positive influence. The appliance and results of the procedure are socially accepted and appreciated. PMID- 26028838 TI - A prospective study to assess the levels of interleukin-6 following administration of diclofenac, ketorolac and tramadol after surgical removal of lower third molars. AB - INTRODUCTION: The surgical removal of impacted third molars involves, trauma to soft and bony tissue and can result in considerable pain, swelling, and trismus. The greater the amount of tissue injury the greater is the amount of inflammation in the perisurgical region. Interleukin-6 (IL-6) is both a pro inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate the immune response. IL-6 is also an early marker of tissue damage. In addition to NSAIDs, corticosteroids, opioids also have immunomodulatory effects. AIM: To evaluate the changes in serum IL-6 levels following surgical removal of third molars under local anaesthesia after administration of two NSAIDs diclofenac and ketorolac and opioid tramadol post operatively. METHODS: Patients undergoing surgical removal of impacted mandibular third molar teeth were randomly assigned to three groups. Each group received one of the three analgesics viz diclofenac 50 mg, ketorolac 10 mg and tramadol 50 mg. The mean levels of IL-6 was then estimated by ELISA. RESULTS: The results of our study showed that all three drugs i.e. diclofenac, ketorolac and tramadol have properties which can downregulate the production of IL-6 in response to surgical trauma. CONCLUSION: It is of clinical significance that the suppression of IL-6 values occurs in tramadol group closely following the diclofenac group. Even though the drug ketorolac suppresses the IL-6 levels similar to diclofenac initially but after 7 days tramadol and ketorolac showed similarities in suppression of IL-6 expression which is less compared to diclofenac group. PMID- 26028839 TI - Evaluation of intra ocular pressure in zygomatico maxillary complex fractures. AB - PURPOSE: To study effects of zygomatico maxillary fractures and fracture reduction on intra ocular pressure (IOP). MATERIALS AND METHODS: IOPs of 20 patients with unilateral zygomatico-maxillary complex (ZMC) fractures (divided into 2 groups of 10 undisplaced, 10 displaced) were measured at various time intervals. The relationship between IOPs between the two groups at various time intervals was recorded and evaluated using independent T-tests. RESULTS: 20 subjects were divided into two equal groups (10 each of displaced and undisplaced fractures). Mean age of patients was 33.8 years with 90 % males and 10 % females. The change in IOP at the time of reporting, after 24 h and 7 days for patients with undisplaced ZMC fractures (Group I) was recorded and was found to be significant. The change in IOP at the time of reporting, before and after surgery, after 24 h and 7 days for patients with displaced ZMC fractures (Group II) was recorded and was also found to be significant. The IOPs of the two groups was compared at various time intervals and was found to be significant. Also, a significant increase in IOP was noted just after fracture reduction, which could be attributed to oculocardiac reflex, which has been proven to cause bradycardia, and in some cases, even death. CONCLUSION: A cautious eye needs to be kept over IOP while reducing ZMC fractures at regular intervals and the anaesthetist has to be informed to look for any bradycardia that can occur. Tonometers should be a part of standard armamentarium while reducing and fixing ZMC fractures. PMID- 26028840 TI - Unilateral one stage nasolabial flap for reconstruction of the lips. AB - BACKGROUND: Nasolabial flap (NLF) is one of the oldest described soft tissue flaps. Despite the great advances in maxillofacial reconstruction it still has a stable location in the reconstructive ladder of the face and oral cavity. Reconstruction of the lips, which are important structures that connect the oral cavity to the facial skin, with this flap is the interest of the surgeons. PATIENTS AND METHODS: Experience of the authors for reconstruction of the upper lip philtrum, correction of lower lip contracture and subtotal reconstruction of the lower lip with emphasis on simultaneous correction of the red lip (volume and color) is explained in five cases. RESULTS: Satisfactory functional and aesthetic results were obtained. Iatrogenic epidermoid cyst occurred in one patient. CONCLUSION: One stage reconstruction of lateral lower lip defects with/without commissural involvement in full or partial thickness defects is possible by NLF. Supplementary flaps are needed when the vermilion needs simultaneous reconstruction. PMID- 26028841 TI - A comparison of skin graft success in the head & neck with and without the use of a pressure dressing. AB - BACKGROUND: The success of skin grafting is dependent on the interplay between many factors including nutrient uptake and vascular in-growth. To allow this, it is important that the graft is immobile and traditionally a 'pressure dressing' has been placed over the graft to improve outcome and graft 'take'. We present the findings of our comparative study of full-thickness skin grafts performed in the head, neck and face region over a period of 24 months. We felt that there was an unacceptably high infection rate and graft failure using pressure dressings. METHODS: Data was collected retrospectively from the case notes on 70 patients who had undergone full-thickness skin grafting to the head, neck and face over a 2 year period. Thirty-five patients underwent grafting with pressure dressing and 35 without. The group with the pressure dressing had the same 'bolster' specification-type dressing and those without had their graft 'quilted' in and chloramphenicol ointment applied topically. Success was determined by the percentage 'take' of the grafts and absence of infection i.e. purulence. RESULTS: Infection in those with a pressure dressing stood at 26 % in contrast to those without, at 9 %. Without a pressure dressing we observed no total graft failures, compared to 6 % in those with a pressure dressing. CONCLUSIONS: The results confirmed the perception that there was a higher infection and graft failure rate where a pressure dressing was applied; however, this was not a statistically significant difference and a randomised control trial with a larger sample size would be required to validate the results. PMID- 26028842 TI - Eruption status of third molar and its possible influence on the location of mandibular angle fracture: a retrospective analysis. AB - INTRODUCTION: This study was designed to evaluate the influence of eruption status of mandibular third molars on the location of mandibular angle fracture. We also aimed to evaluate the incidence of damage to mandibular third molar teeth (M3) and its roots. MATERIALS AND METHODS: Medical records and panoramic radiographs of 142 patient cohorts with mandibular angle fractures with third molars present were retrospectively reviewed. RESULTS: Revealed that incidence of angle fracture were high in patients with fully erupted M3 when compared to unerupted group. Out of 142 patients, 108 fractures were found involving the M3 socket and 14.1 % had damage to M3. CONCLUSION: The presence of erupted mandibular third molar increases the chances of angle fracture when compared to impacted M3. Involvement of the M3 socket often resulted in increased operative time and complexity of the surgical procedure with possible removal of the damaged M3. PMID- 26028843 TI - ANKH Polymorphisms and Clicking of the Temporomandibular Joint in Dental Residents. AB - AIM: This study aimed to carry out a case-control research study to assess occurrence of clicking of the temporomandibular joint (TMJ) in order to establish the relationship between TMJ clicking and the genotype of "ANKH inorganic pyrophosphate transport regulator" (ANKH) polymorphisms. MATERIALS AND METHOD: A sample of 41 first-year dental residents was selected. Each was examined using standard clinical procedures and genotyping techniques. RESULTS: The participation rate was 91.8 %. The prevalence of TMJ clicking was 51.2 % (95 % CI: 35.7-66.7 %). Occurrence of TMJ clicking was not related to age, gender and genotypes of ANKH-OR as well as ANKH-TR polymorphisms (p >= 0.165). CONCLUSION: A similar distribution of ANKH genotypes in TMJ clicking and asymptomatic individuals has been demonstrated by this study. A high percentage of TMJ clicking has been confirmed. Future investigations are indicated. PMID- 26028844 TI - Comparison of the effectiveness of lidocaine in permanent maxillary teeth removal performed with single buccal infiltration versus routine buccal and palatal injection. AB - PURPOSE: For many dental patients, palatal injection proves to be a very traumatic experience. Diverse methods have been suggested to reduce the discomfort of palatal injection. Nevertheless, the reliability of these methods is not obviously evident and they are not found to be universally effective. The desirable method to evade pain during palatal injection is just not to have one. Hence, the present study aims at investigating if lidocaine hydrochloride could provide palatal anesthesia in maxilla when only a buccal infiltration anesthesia is done for teeth extraction. PATIENTS AND METHODS: One hundred and fifty patients requiring extraction of maxillary teeth were included in the study. Patients were randomly allotted to two groups, study and control. Patients in study group received a single buccal infiltration of 1.5 mL of lidocaine with epinephrine for extraction of maxillary teeth. Patients in control group received 1.5 mL of buccal and 0.3 mL of palatal infiltration of lidocaine with epinephrine for the extraction. After achieving adequate palatal anesthesia the tooth was extracted with consistent technique. Pain level experienced by the patients during injection procedure and during tooth extraction was rated in an 11-point pain rating scale. Time taken to achieve palatal anesthesia following a single buccal infiltration of anesthetic solution was evaluated by regular pin-prick evaluation of palatal tissues. RESULTS: The overall success rate of palatal anesthesia achieved with a single buccal infiltration is 81.3 %. The success rate reduced as we proceed from anterior to posterior maxilla. Time taken to achieve successful palatal anesthesia by single buccal infiltration is 7-9 min. CONCLUSION: The extraction of permanent maxillary anterior teeth and premolars is possible by depositing local anesthesia to the buccal vestibule of the tooth without palatal supplementation. However, the extraction of permanent maxillary posterior teeth with similar technique would result in fewer success rates suggesting its avoidance. PMID- 26028845 TI - A 7-year study of 1,278 patients with maxillofacial trauma and cerebrospinal fluid leak. AB - BACKGROUND: A number of patients with facial fractures have cerebrospinal fluid (CSF) leak that may result in meningitis and other central nervous system complications. Commonly, CSF leak occurs following trauma, but the etiology and pattern of this disorder are different from region to region. This study aims to evaluate the distribution of CSF leak in patients with maxillofacial fractures in Isfahan province, Iran. PATIENTS AND METHODS: In this retrospective cross sectional study, 1,287 medical files of patients admitted to a medical center with head and face injuries were evaluated during a 7-year period (2004-2010). Data was obtained using descriptive analysis. RESULTS: Of the 1,278 patients with head and maxillofacial fractures, 16 (1.25 %) males and one (0.07 %) female had CSF leak; all these cases had skull base fracture. Of these, 52.9 % had maxillary fracture, 23.5 % nasal fracture, 41.1 % orbital fracture, 11.7 % mandibular fracture, 23.5 % frontal fracture, and 41.1 % had more than one site of fracture. 58.8 % had rhinorrhea and 41.2 % otorrhea. Of all these patients with CSF leak, 8 (47 %), 2 (11.8 %), and 7 (41.2 %) cases were treated spontaneously, using lumbar drain placement, and by surgical intervention, respectively. CONCLUSIONS: Cerebrospinal fluid leak was observed most frequently in patients with fracture in the zygomatic and maxillary bone, and mostly exhibited itself as rhinorrhea and/or otorrhea. All cases with CSF leak had skull base fracture as well. However, post-traumatic CSF leaks are uncommon and are generally treated without surgical intervention (59 %). Distribution of CSF leak varies from one region to another and knowing this fact helps to manage the injury and prevent the complications. PMID- 26028846 TI - Horizontal and vertical reconstruction of the severely resorbed maxillary jaw using subantral augmentation and a novel tenting technique with bone from the lateral buccal wall. AB - AIM: The aim of this study was to evaluate the effect of using the lateral wall bone in sinus lifting two-dimensional reconstruction on bone augmentation. PATIENTS AND METHODS: Ten patients affected by class V or VI maxillary atrophy with less than 3 mm of residual horizontal ridge were selected. Using a piezo ultrasonic surgery tip bony lateral wall was cut. To expose native bone to the bone graft, multiple perforations, made through the cortical plate of the recipient site with a round bur. Once the bony buccal wall was adjusted it was fixed away from the ridge with two 1.5 x 13 mm bone fixation screws. Deficiencies created between the bony buccal wall and the ridge was filled with a mineralized cortical bone. A pericardium membrane was then placed on the graft. A biopsy for histologic evaluation was made. RESULTS: The data analysis in bone volume changes reported significant differences between the anterior and posterior locations before and after grafting (p < 0.05). The biopsy shows mature cancellous bone with predominantly lamellar structure. CONCLUSION: The use of the lateral wall bone in sinus lift surgery showed significant increase in bone volume. PMID- 26028847 TI - "Are we similar to caucasians": orthognathic surgery for north indians. AB - PRIMARY AIM: To establish the cephalometric standards for hard and soft tissues of the facial skeleton for north Indian population. METHODS: The sample comprised of lateral cephalograms taken in natural head position of 100 participants (50 men, 50 women). The cephalograms were traced, analyzed and interpreted using the landmarks and values given by Burstone's analysis for hard tissue and Legan and Burstone analysis for soft tissue respectively. The Student's t test, standard deviation and mean deviation were calculated to compare between the groups. RESULTS: Statistically significant results were found in various parameters between intra and inter group comparison. CONCLUSION: The results obtained in the north Indian population can be used as cephalometric norms for orthognathic surgery. PMID- 26028848 TI - Therapeutic interventions in oral submucous fibrosis: an experimental and clinical study. AB - INTRODUCTION: Oral submucous fibrosis (OSF) is a chronic debilitating disease and premalignant condition of the oral cavity and is a serious public health issue in India and many parts of the world. The treatment is still elusive and empirical because of poorly understood etiopathogenesis, which is believed to be multifactorial including areca nut chewing, ingestion of chillies, genetic and immunologic processes, nutritional deficiencies, and many others. The present investigations was focused to understand the possible therapeutic interventions of anti-OSF agents in arecoline induced experimental in vitro model of OSF and clinical application of these anti-OSF agents in the restoration of various grade of the disease. MATERIALS AND METHODS: The 127 subjects were selected from patients who visited the OPD of Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, K.G. Medical University, Lucknow. Further the subjects were divided in two groups on the basis of clinical examination. Group-1 subjects showed presence of fibrosis bands in the labial and/or buccal mucosa, loss of elasticity, difficulty to open the mouth and had a habit chewing areca nut in some form. Group-2 subjects had no habit of chewing areca-nut, were apparently healthy with no mucosal disorder. The samples were collected and were immediately transported to Indian Institute of Toxicology Research, Lucknow, for isolation and cultivation of primary cultures of mucosal fibroblast cells. Then isolation and cultivation of oral mucosal fibroblast, identification of non cytotoxic doses of arecoline, real time PCR, immunocytochemistry, cytokine determination in culture cells, western blot analyses, functional activity of collagenase, lysyl oxidase enzyme activity, collagen beads assay, cyclooxygenase (COX-2) expression analysis was done. RESULTS AND CONCLUSIONS: This study, shows that the reduction of phagocytic cells was strongly related to the arecoline levels in fibroblast culture when we exposed arecoline to normal oral mucosal cells (NOMC) and cells from OSF patient. An enhancement of phagocytic cells was observed following the pre exposure of cells to 1 MUM dexamethasone, a glucocorticoids, In this study, histologic evidence is presented which supports the finding that COX-2 expression is upregulated in OSF specimens compared to normal oral submucosal cells. Strong immunostaining for COX-2 was detected in arecoline exposed NOMC and cells from OSF patient. Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes. The number of phagocytic cells and phagocytic activity in cultured human oral fibroblasts from OSF site was lower than the fibroblasts from the normal regions of the same person. PMID- 26028849 TI - Comparison of efficacy of mandible and iliac bone as autogenous bone graft for orbital floor reconstruction. AB - OBJECTIVE: This study evaluated and compared the efficacy of mandible and iliac bone as autogenous bone graft for correction of orbital floor fractures. PATIENTS AND METHODS: Twenty patients who suffered orbital floor fractures took part in the study. The subjects enrolled in the study sustained both isolated orbital floor fracture and orbital floor fracture associated with fracture of zygomatico maxillary complex. Each inferior orbital wall was reconstructed using either a mandible bone graft or an iliac graft. Mandibular symphysis was opted as a donor site for graft harvest from mandible and anterior iliac crest for the iliac group. CT scans were taken before the operation. Inclusion criteria consisted of at least 2 months postsurgical follow-up, pre- and post-surgical photographic documentation, and complete medical records regarding inpatient and outpatient data. To describe the distribution of complications and facilitate statistical analysis, we categorized our findings into diplopia, enophthalmos, and restriction of ocular movements before and after treatment. We also considered the time required for the harvest of the grafts and the donor site complications. A comparative study was carried out using Chi square test and student t test. We considered P value <0.05 to be statistically significant. RESULTS: Ten iliac crest grafts and ten mandible bone grafts were placed. The mean age of the patients was 33.1 years. 80 % of the patients were males. The most common complication of orbital floor fracture was diplopia, followed by enophthalmos and restriction of ocular movements. The post operative results were compared after 2 months of the surgery. In iliac crest group, diplopia got corrected in six out of seven patients (85 %), enophthalmos in four out of five patients (80 %) and restricted ocular movement showed 100 % correction. While in mandible group, diplopia and ocular movement showed 100 % correction and enophthalmos got corrected in five out of six patients (83 %). No statistically significant differences were found between the two groups on comparing these variables. On the other hand the mean time required for the harvest of iliac graft and mandible graft was 30.2 +/- 3.52 min and 16.8 +/- 1.75 min respectively. The difference was statistically significant. CONCLUSION: There is no difference in the ability of mandible and anterior iliac crest bone grafts to correct post-traumatic diplopia, enophthalmos and restricted ocular movements. But the time and ease of harvest of the graft from mandible was comparatively less and easy especially when the treating doctor was an oral and maxillofacial surgeon. Secondly the post operative morbidity was low and the quality and contour of the bone graft was very adaptable for the reconstruction of the orbital floor. PMID- 26028850 TI - Evaluation of Non-vascular Fibula Graft for Mandibular Reconstruction. AB - INTRODUCTION: Functional and cosmetic defects in maxillofacial region are caused by various ailments like trauma, neoplasm, developmental, infections and iatrogenic causes. Reconstruction of these defects with free flaps remains the gold standard but demerits like need for surgical expertise and equipment, prolonged duration of surgery, compliance of the patient and increased cost are associated with microvascular reconstruction. Hence reconstruction with nonvascular bone grafts can be considered when defect is nonirradiated and <9 cm and with sufficient soft tissue cover available. PURPOSE: To retrospectively evaluate clinical, radiological outcome and complications encountered with mandibular reconstruction using non vascular fibula graft. PATIENTS AND METHODS: This retrospective study included 7 patients who were treated in the Department of Oral and Maxillofacial Surgery, Narayana Dental College and Hospital, Nellore, AP between 2011 and 2013 with histologically proven benign osteolytic lesions of mandible that require a segmental mandibulectomy and primary reconstruction using autogenous non-vascularised fibular graft. The clinical case records of the patients and personal patient assessment forms (Quality of Life Assessment Forms) were analysed. They were recalled every 3rd, 6th and 9th month after surgery for evaluation of clinical, radiological outcome of the graft and complications occurring at recipient and donor sites. RESULTS: In all the 7 patients, the lower border continuity was maintained except in one where the graft was dislodged. Tongue movements in all the patients were unrestricted. Jaw movements were affected in cases of ramus defects with slight deviation to operated side and reduced mouth opening. Radiological observations revealed no significant changes in 3 months except for slight reduction in graft height. The radioopaque bridging with continuity of lower border of mandible was noticed in 6th month indicating the take of the graft. This was achieved in every case except in one where the graft was lost due to dislodged reconstruction plate. In 9th month the edges of the graft i.e., graft to native mandible junction showed more resorption (3 mm) especially where there is >2 mm of gap. Whereas increase in height of graft in other areas especially in graft to graft junction was seen. Significant graft resorption was seen in two cases. There were no major complications associated with the donor site. CONCLUSION: Avascular fibula graft although a second choice to vascularised fibula, is a favourable option for mandible defects of 6-10 cm under optimum conditions especially in developing countries where financial and/or surgical resources are limited. An attempt for primary reconstruction with this is never futile as it prevents aesthetic deformity even in the event of failure and thus makes secondary reconstruction easy. However in order to confirm the results a prospective study with large scale of patients is necessary. PMID- 26028851 TI - The study of antilingula and its relation to the lingula and mandibular foramen, the presence of mylohyoid bridging in dry mandibles of South Indian population. AB - BACKGROUND AND OBJECTIVES: The mandibular foramen and the lingula, because of their relation to the inferior alveolar nerve are of clinical significance for the orodental surgeons. Identification of the antilingula is important in mandibular ramus surgery in which the medial surface of the ramus is not visualized. METHODS: The present study includes adult dry 50 mandibles of unknown age and sex. The measurements were taken using vernier calipers. The points taken for measurements were most prominent point on antilingula, tip of lingula, most anterior, posterior and inferior points of mandibular foramen. The measurements were denoted as A, B, C and D which represent the anterior, posterior, superior and inferior distances. RESULTS: Antilingula was present on right side in 25 and on left side in 28 mandibles. There was a significant difference in distances in mean between the antilingula and mandibular foramen of both the sides (p < 0.001). Retromolar foramen was observed in 6 mandibles. Mylohyoid bridging was seen in 3 mandibles. CONCLUSION: The mandibular foramen was located posterosuperior to the antilingula on both the sides. There was no statistical significance in the distances between the lingula and the antilingula. Therefore antilingula can be used as an important surgical landmark for locating the mandibular foramen in mandibular ramus osteotomies. PMID- 26028852 TI - Comparision between neocone, alvogyl and zinc oxide eugenol packing for the treatment of dry socket: a double blind randomised control trial. AB - OBJECTIVES: To prospectively evaluate and compare the effectiveness of Neocone, Alvogyl and Zinc Oxide Eugenol (ZOE) intra alveolar dressings for the management of dry socket and to study the epidemiological factors associated with the condition. STUDY DESIGN: All the patients who underwent extraction of teeth and who fulfilled our inclusion and exclusion criteria from 1st January 2012 to February 28th 2013 were included in our study. Patients who were diagnosed to suffer from dry socket were randomly allocated to three groups namely Group A (Alvogyl), Group B (ZOE), Group C (Neocone). Pain relief and healing of the socket were compared between these groups. The collected data were subjected to statistical analysis by Chi Square test, Z test of proportionality. RESULTS AND CONCLUSION: Alvogyl is superior to the other two medications for providing initial pain relief. Neocone provides complete pain relief and the healing was fastest with Neocone. Neocone emerged as the most suitable dressing material for the management of dry socket by virtue of shorter time required for complete pain relief, fewer visits and faster clinical healing. PMID- 26028853 TI - Fate of Free Fat Dermis Graft in TMJ Interpositional Gap Arthroplasty: A Long Term MRI Study. AB - INTRODUCTION: Free fat dermis graft is a good interpositional material for TMJ gap arthroplasty. Analysing the fate of the graft by magnetic resonance imaging (MRI) images helps in excellent visualization of both bony and soft tissue anatomy of the operated TMJ joint as well as in assessing the changes in dermis graft which was previously placed. PURPOSE OF THIS STUDY: To investigate the radiological fate of the dermis-fat graft within the TMJ using MRI. MATERIALS AND METHODS: Five joints of five patients who had dermis-fat grafts placed in their TMJ following gap arthroplasty were recruited for this study. Each patient had undergone TMJ gap arthroplasty with immediate dermis-fat graft placement. All the patients are then subjected to MRI. RESULTS: Fat graft was identified in close proximity to the mandibular condyle in all cases, with only three joints demonstrating fat covering the entire articular surface of the mandibular condyle. In the remaining joints the interpositional material found in the MRI defined joint space with mainly grey appearance, suggesting tissue change to other than fat, i.e. scar or granulation tissue. CONCLUSION: When free fat dermis graft is placed as interpositional material the graft occupied the entire TM joint and prevented it from recurrent ankylosis. The graft placed aids in normal functioning of the temperomandibular joint without any complications. PMID- 26028854 TI - Schwannoma of the cheek: clinical case and literature review. AB - INTRODUCTION: Schwannoma is a relatively uncommon benign tumor that apparently originates from Schwann cells of peripheral nerves. The most common intraoral site is the tongue followed by the palate, floor of mouth, buccal mucosa, lips and the jaws. The preoperative diagnosis is often difficult, and in the majority of cases, the diagnosis can only be made during surgery and by histological study. The immunohistochemistry reveals that the schwannoma cells test positive for S-100 protein. CASE REPORT: The authors report here a case of an intraoral schwannoma situated in the cheek, treated by complete surgical excision. In the present case the schwannoma presented as a slow growing, circumscribed swelling without any particular features to distinguish it from other benign soft-tissue lesions. The final diagnosis was established based on the clinical, histopathologic and immunohistochemical findings. CONCLUSION: The presence of schwannoma calls for the careful search for nerve tumors in other parts of the body, although in most cases none may be found. The differentiation of schwannoma from neurofibroma is essential, because an apparently solitary neurofibroma may be a manifestation of neurofibromatosis. PMID- 26028855 TI - The use of sodium tetradecyl sulphate for the treatment of venous malformations of the head and neck. AB - INTRODUCTION: Vascular malformations have devastating cosmetic effects in addition to being associated with pain and bleeding. Sclerotherapy has been used as an effective therapeutic modality for the management of vascular malformations. The purpose of this case series is to describe our clinical experience of using sodium tetradecyl sulphate (STS) 3 % in the treatment of venous malformation lesions of head and neck. MATERIALS AND METHODS: Thirteen patients were included in this study (three male and ten female; age range between 8 months and 54 years; mean age 18.2 years, +/-SD 15.71). The patients were treated by 3 % STS intralesional injections. Of the thirteen patients treated, complete resolution occurred in four patients (28.57 %), a good response occurred in five patients (35.7 %), a moderate response in two patients (14.28 %), a mild response in two patients (14.28 %) and no response in one patient (7.14 %). The side effects encountered in all patients were pain and edema after injection which was controlled by oral analgesics and an intramuscular injection of dexamethasone. In addition, two patients developed a superficial ulceration (11.76 %) which healed uneventfully, and one patient developed ecchymosis after injection (5.88 %). CONCLUSION: Sclerotherapy with 3 % STS is a simple, safe, and effective modality for the treatment of venous malformations. PMID- 26028856 TI - Management of extra-capsular temporo-mandibular joint ankylosis: does conservative approach to treatment have a role? AB - BACKGROUND: The conventional management of fibrous extracapsular temporo mandibular joint (TMJ) ankylosis, a debilitating disease, is associated with surgical complications and financial burden on the patients. OBJECTIVE: To assess the outcome of conservative approach to the management of fibrous extracapsular TMJ ankylosis. PATIENTS AND METHODS: This is a prospective study of patients who presented at the Dental and Maxillofacial Surgery Clinic of the University of Calabar Teaching Hospital, Nigeria, during the period from January 1999 to December 2012 with a history of inability to open the mouth diagnosed as fibrous extracapsular TMJ ankylosis. RESULTS: Twenty-one subjects were treated and their ages ranged from 11 to 22 years with mean at 15.0 years. There were 13 (61.9 %) males and 8 (38.1 %) females with male: female ratio of 1.6:1. The aetiological factor that predisposed to formation of extracapsular TMJ ankylosis was facial trauma. There was no facial asymmetry and the side distribution of the affliction showed that 1 (4.8 %) was bilateral while 20 (95.2 %) were unilateral. Eight cases (38.1 %) were incomplete ankylosis while the rest (n = 13, 61.9 %) were complete. The shorter the duration of fibrous ankylosis and the greater the initial inter-incisal distance before treatment, the better the treatment outcome. CONCLUSION: The outcome of treatment suggests that the conservative approach to management of this condition was beneficial to these patients because they presented early. However, randomized controlled clinical trials are needed to validate this treatment option. PMID- 26028857 TI - The Local Effect of Alendronate with Intra-alveolar Collagen Sponges on Post Extraction Alveolar ridge Resorption: A Clinical Trial. AB - INTRODUCTION: Extraction of teeth is followed by resorption of the residual alveolar ridge that continues throughout life resulting in loss of alveolar height and width. Of the numerous techniques that have been used to arrest post extraction alveoloar ridge resorption, the placement of a graft material inside the socket immediately after extraction has been mostly followed. Type 1 collagen is one of the commonly used graft material that prevent resorption by providing dimensional stability to the socket. Bisphosphonates are an anti-osteoclastic drug that prevent resorption by disrupting the membrane ruffling of the osteoclasts. Alendronate a bisphosphonate, is primarily used in diseases with bone loss. It has been used to reduce active bone resorption significantly without interfering with bone mineralization and quality. The need for the study is to examine the inhibitory effect of alendronate on residual ridge resorption when applied locally in combination with type I collagen on alveolar bone immediately following tooth extraction. MATERIALS AND METHODS: Twenty patients with age between 30 and 65 years were selected from the out patient department of The Oxford Dental College and Hospital. The patients were divided into two groups. In the first group after extraction of teeth from premolar to midline the sockets were irrigated with saline and sutured. On the left side type I collagen sponge was placed and sutured. In the other group the right side was treated the same way after extraction as in first group where as in the left side sockets type I collagen soaked in 20 mg/ml of alendronate was placed and sutured. Patients were evaluated clinically for any local irritation as well as radiologically with orthopantomograph X-rays were taken immediately after the extraction, 1 month after extraction and 4 months after extraction to determine the amount of bone loss prevented. RESULTS: The statistically significant bone loss prevented by the collagen alone was 22.8 % and in collagen with alendronate group was 44.38 % at the end of 4 months. CONCLUSION: Type I collagen soaked with alendronate when placed in the socket immediately after extraction of teeth prevents post-extraction alveolar ridge resorption. PMID- 26028858 TI - Skeletal relapse following sagittal split ramus osteotomy advancement. AB - BACKGROUND: Sagittal split ramus osteotomy (SSRO) is an accepted and standard procedure to address mandibular corpus deficiency. The relapse following the mandibular advancement has a negative impact both on clinician and patient. PURPOSE: To analyse the hard tissue changes and to investigate relapse following SSRO advancement procedure. MATERIALS AND METHODS: A retrospective review of 21 patients treated by bilateral SSRO advancement at our institute was conducted. Lateral cephalograms obtained at pre-treatment (T1), pre-surgery (T2), 2 months (T3) and 2 years post-surgery (T4) were evaluated by an independent investigator. The data T2-T3 revealed immediate postoperative changes, and T3-T4 revealed skeletal relapse following surgery after 2 years. RESULTS: Twelve females and nine males with age ranging from 16 to 24 years underwent mandibular advancement. The mean follow-up period was 2 years 7 months +/- 4 months. The mean mandibular advancement at pogonion was 5.1 +/- 1.25 mm with significant improvement in SNB, ANB, CoGn, maxillo-mandibular differential and SN:GoPg ratio following surgery. Comparison of the outcomes following surgery revealed that the mean relapse at pogonion was 0.2 +/- 0.44 mm. B point, mandibular corpus length, anterior and posterior facial height remained stable with no significant relapse following mandibular advancement. CONCLUSION: Sagittal split ramus osteotomy within the range of mandibular advancement is a stable procedure. PMID- 26028859 TI - Comparison between two techniques for the treatment of mandibular subcondylar fractures: closed treatment technique and transoral endoscopic-assisted open reduction. AB - PURPOSE: The endoscopic-assisted technique for the treatment of subcondylar fractures has been used successfully and its acceptance develops as more surgeons gain experience. We present the short term results of this technique in a randomized prospective clinical trial. METHODS AND MATERIALS: A total of 40 patients with mandibular subcondylar fracture were included in our study in two groups randomly. Patients of first group were treated by closed treatment technique and patients of second group by transoral endoscopic-assisted open reduction. All patients were followed for minimum of 12 weeks and occlusion, Mandibular Anterior Opening (MAO), mandibular deviation, and posterior ramal height were assessed. RESULTS: In the endoscopic group the MAO was significantly greater and mandibular deviation was lesser at 2nd and 4th week of follow up. Posterior ramal height showed significant increase in the endoscopic group rather than closed treatment group. CONCLUSION: The transoral endoscopic-assisted technique is a reliable and successful technique to address subcondylar fractures. The patients who were treated by this technique showed better results in the fields of mandibular function and patient satisfaction and comfort, although it is time consuming and needs expensive instruments. PMID- 26028860 TI - Treatment of oral submucous fibrosis using split skin graft and a polyethylene stent: a prospective study. AB - AIM: Aim of this study was to evaluate the split skin graft held in place with a polyethylene stent for the treatment of oral submucous fibrosis. METHODS: Fifteen prospective patients diagnosed clinically with oral submucous fibrosis, from June 2011 to 12 December 2012, were recruited for this study. All patients were treated surgically using the same surgical technique of fibrotomy followed by split skin graft along with a polyethylene stent. Preoperative and postoperative mouth opening measurements at 1 week and after a minimum of 6 months were evaluated by measuring the inter incisal distance. RESULTS: Mean follow up was 9.8 months with a minimum of 6 months. Mean preoperative mouth opening was 12.9 mm (6-20 mm). Intraoperatively mean mouth opening was 37.9 mm (36-41 mm). After 1 week mean mouth opening was 35.8 mm (31-40 mm). At 6 months follow up, mean mouth opening was 33 mm (20-40 mm). CONCLUSION: Fibrotomy followed by split skin graft along with a polyethylene sheet stent and sufficient postoperative physiotherapy is a simple, cost effective and viable treatment modality for oral submucous fibrosis. PMID- 26028861 TI - The Versatility in the Use of Buccal Fat Pad in the Closure of Oro-antral Fistulas. AB - INTRODUCTION: Oroantral communications (OAC) are probable surgical complications of dentoalveolar procedures. OACs 2 mm in diameter or smaller are likely to close spontaneously without the need for any surgical intervention. However, OACs 3 mm in diameter or larger, or OACs associated with maxillary or periodontal inflammation, may persist, and surgical closure is recommended. Various surgical techniques have been suggested for the closure of oroantral defects. CASE DETAILS: We have found the technique of two layer closure with buccal fat pad (BFP) and buccal mucoperiosteum quite useful for closure of chronic Oroantral fistula (OAF) and this article reports a case of OAF in the left first molar region of a 50 year old male, which has been closed successfully with this technique. CONCLUSION: Buccal fat pad is a pedicled locally available flap which has its own blood supply and hence can be used with great efficacy in closure of OAF. This paper aims to elaborate the surgical details of this technique and its usefulness in closure of chronic OAF. PMID- 26028862 TI - Cranioplasty using presurgically fabricated presterilised polymethyl methacrylate plate by a simple, cost-effective technique on patients with and without original bone flap: study on 29 patients. AB - OBJECTIVES: The purpose of the study was to assess the clinical effectiveness of presurgically fabricated pre-sterilized polymethyl methacrylate (PMMA) plate as a cranioplasty material. MATERIALS AND METHODS: The study group consisted of 29 patients with skull defect following decompressive craniectomy. Some patients had their original bone flap preserved and some were without it. In either group pre sterilized prefabricated PMMA plate was used. On each visit, patients were clinically assessed; CT scans were taken in immediate follow up period but if needed more films were taken in subsequent follow ups. Post-op complications that include infection, post-op hematoma, chronic pain, aesthetic, biocompatibility, post-op dimensional changes of prosthesis were evaluated. RESULTS: Mean follow up was 7 1/2 months. Five patients developed swelling and pain in the subsequent follow ups. One patient was treated conservatively with antibiotics. Tapping was performed in couple of patients. Surgical evacuation of hematoma was performed in one patient. Of the five infected plates, one demanded removal from the patient. One complained of chronic pain. Post-op follow up assessed clinically and by CT scan confirmed good aesthetic result, biocompatibility and dimensional stability of prosthesis. CONCLUSION: The result of this study support the view that the use of prefabricated pre-sterilized PMMA plate as cranioplasty material is a simple, reliable, convenient way that brings acceptable function and aesthetics to patients who underwent decompressive craniectomy, in an inexpensive way. PMID- 26028863 TI - A Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Comparing the Efficacy of Anti-edema Drugs for Edema Control in Orthognathic Surgery Using Digitizer 3-D to Measure Facial Swelling. AB - INTRODUCTION: Orthognathic surgery involves making several osteotomies. Any osteotomies leads to varying degrees of post-operative swelling. The aim of this study was to evaluate the effectiveness of anti-edema drugs for the control of edema, using Digitizer 3DTM for measuring soft-tissue thickness, in patients who underwent bimaxillaryorthognathic surgery. MATERIALS AND METHODS: In this double blinded, randomized, control trial, 24 patients (study group: 12 patients, control group: 12 patients) in whom bimaxillary orthognathic surgery was indicated, were included in this study. All swelling measurements were expressed as total 3-D area of the landmarks (cm(2)) in T0 pre-operative, T1 first day after surgery, T2 fourth day after surgery, T3 4 months after surgery. For each patient we compared, by adding left and right area, the increase of swelling between T1-T0, T2-T0 and T1-T3. RESULTS: The differences T0-T1 are highly significant (p < 0.01) between group 1 or study group (treated with Venoplant((r))) and group 2 (control group); the differences T0-T2 are significant (p < 0.05) between group 1 (treated with Venoplant((r))) and group 2 (control group). The differences T1-T3 are significant (p < 0.05) between group 1 (treated with Venoplant((r))) and group 2 (control group). DISCUSSION: The present study suggests that Venoplant((r)) significantly decreases postoperative edema in orthognathic surgery, thus precluding long-term corticosteroid use. PMID- 26028864 TI - Adenomatoid Odontogenic Tumor (AOT) Arising from a Dentigerous Cyst: Literature Review and Report of a Case. AB - Adenomatoid odontogenic tumor (AOT) is an uncommon benign tumor of odontogenic origin composed of odontogenic epithelium in a variety of histopathological patterns. These lesions are usually solid but are occasionally cystic. AOT has been reported to occur in association with odontogenic cysts. Very few cases have been described that arise in association with a dentigerous cyst. A systematic search of the English-language medical literature in PubMed and Medline search (keywords adenomatoid odontogenic tumor, dentigerous cyst) data bases revealed only ten such cases. The present case is very unique, exceptional and first of this kind that occurred in the posterior mandible associated with an impacted lower first premolar in a 19-year old female patient. The intraosseous follicular AOT, as this case reported here, frequently resemble dentigerous cysts. There is an uncertainty whether the lining of an associated cyst represents a true dentigerous cyst, cystic change within an AOT or may represent a distinct entity. We believe that this case represents an odontogenic cyst with neoplastic change. Hence, in such cases, the final diagnosis should be made on the basis of histological examination of extensive tissue sampling of entire excised tissue specimen. Further studies to determine whether the AOT derived from an odontogenic cyst could represent a distinct variant are to be done. PMID- 26028865 TI - Nebulisation Versus Spray-as-You-Go Airway Topical Anaesthesia in Patients with Temporomandibular Joint Ankylosis using 2 % Lignocaine. AB - STUDY DESIGN: This randomized, comparative clinical study was designed to compare 2 % lignocaine nebulization and 2 % lignocaine via spray-as-you-go technique for topical airway anaesthesia during or awake flexible fiberoptic intubation (AFOI) in temporomandibular joint (TMJ) ankylosis patients. METHODS: Sixty adult patients with TMJ ankylosis were randomly assigned to the following study groups using a computer generated random number table 2 % lignocaine nebulised (group A) and 2 % lignocaine via spray-as-you-go technique (group B). After airway anaesthesia, awake flexible fiberoptic nasotracheal intubation was performed. An independent investigator who did not participate in the study scored patients' comfort during airway topical anaesthesia and patients' reaction during awake FOI. Changes in haemodynamics during the airway manipulation were also observed. RESULTS: There were no statistically significant differences in the observed variables between the two groups. CONCLUSIONS: Both 2 % lignocaine nebulization and 2 % lignocaine spray-as-you-go technique provided acceptable conditions for AFOI in TMJ patients. PMID- 26028866 TI - Comparison Between Betamethasone and Sodium Hyaluronate Combination with Betamethasone Alone After Arthrocentesis in the Treatment of Internal Derangement of TMJ-Using Single Puncture Technique: A Preliminary Study. AB - PURPOSE: This study was designed to compare the intra-articular injection of betamethasone and sodium hyaluronate (combination) with betamethasone alone after arthrocentesis using single puncture technique into the upper joint space in the treatment of temporomandibular joint internal derangements. MATERIALS AND METHODS: Fourteen patients with internal derangement were randomly selected and divided into 2 groups (7 in each group). Arthrocentesis with single puncture technique of the upper joint space was then performed using ringer lactate under local anesthesia, followed by injection of either betamethasone and sodium hyaluronate combination or betamethasone alone into the joint. Clinical data was collected in the form of pain (visual analog scale), maximum mouth opening, and clicking sound before and after treatment up to 6 months. RESULTS: At the follow up of 6 months, there was statistically significant decrease in intensity of pain and increase in mouth opening was seen in betamethasone and sodium hyaluronate combination group compared to betamethasone alone group. Although there was statistically significant difference between the two groups when clicking was evaluated in the initial time interval (2nd post op day), on follow up of up to 6 months there was no statistically significant difference in clicking. CONCLUSION: Although patients benefitted from both techniques, arthrocentesis with intra articular injection of betamethasone and sodium hyaluronate combination is superior to arthrocentesis with betamethasone injection alone. PMID- 26028867 TI - Role of platelet rich fibrin and platelet rich plasma in wound healing of extracted third molar sockets: a comparative study. AB - AIMS AND OBJECTIVES: This prospective study was done to evaluate and compare the utility and effectiveness of platelet rich fibrin (PRF) with that of platelet rich plasma (PRP) on soft tissue healing and bone tissue healing of extracted third molar sockets. MATERIALS AND METHODS: This study included split mouths of 20 patients who underwent bilateral extraction of impacted third molars. During the same appointment, following which PRF and PRP were prepared from patients' autologous blood and placed in right and left extracted sockets, respectively. The data for soft tissue healing were recorded at end of 1 week, using healing index of Landry et al. and the data for bone tissue healing were recorded at the end of 4 months using digitalized orthopantomogram images on Adobe Photoshop CS; which was then compared between the two sites of the same patient. RESULTS: The mean values of soft tissue healing collected at 1 week post-operative, for PRF group were significantly higher as compared to PRP group. And the mean values of bone density collected at the end of fourth month post-operative, for PRF group were also significantly higher as compared to PRP group. Both tests showed p value of 0.00. CONCLUSION: PRF is significantly better in promoting soft tissue healing and also faster regeneration of bone after third molar extraction, in comparison with PRP. This could be attributed to simpler preparation protocols of PRF over PRP and the ability of PRF to release growth factors in a controlled way. PMID- 26028868 TI - Comparative study of alveolar bone height and implant survival rate between autogenous bone mixed with platelet rich plasma versus venous blood for maxillary sinus lift augmentation procedure. AB - AIM AND OBJECTIVES: The aim of this study was to evaluate changes in alveolar bone height by means of radiographic examination and Straumann implant survival rate following maxillary sinus lift augmentation using autogenous bone in combination with platelet rich plasma (PRP) versus venous blood (VB). METHODS: Fifty patients requiring sinus lift augmentation procedure included in the study were divided into two groups (n = 25). During the procedure the sub antral sinus cavity was augmented using autogenous bone taken from mandibular ramus area and mixed with PRP in one group and autogenous bone mixed with VB in the other group. Orthopantomograms were taken preoperatively, immediate, at 6 months and 1 year postoperatively. Height of alveolar bone at the site of sinus augmentation was measured on the radiographs. One hundred and twenty-one Straumann dental implants were placed after healing period. RESULTS: Age of the patients in the study groups ranged from 36 to 69 years. Differences in mean values of bone height measurements recorded in the PRP series revealed significant differences among the three subgroups (P = 0.001). Significant differences were noted between immediate postop and 6 month (P < 0.01), immediate postop and year (P < 0.01). In the VB series also significant differences were revealed among the three subgroups (P = 0.0280). Significant differences were noted between immediate postop and 6 month (P < 0.05). Comparison of results of subgroups of the two series at the three intervals revealed significant differences at 'immediate postop' values (P = 0.0002) and 'sixmon' values (P = 0.0435). Differences between 'year' values were not significant. Two implants were lost in PRP group. CONCLUSION: The results of this limited study reveals that both groups recorded a good increase in the alveolar bone height after sinus augmentation and showed no significant differences between these groups when compared to each other at 1 year postoperatively. When both sub groups compared with immediate postop to year, PRP group showed significant difference and blood group showed no significant difference. PMID- 26028869 TI - Posterior superior alveolar nerve blocks: a randomised controlled, double blind trial. AB - BACKGROUND: Local anesthesia has been a boon for dentistry to allay the most common fear of pain among dental patients. Several techniques to achieve anesthesia for posterior maxillae have been advocated albeit with minor differences. We compared two techniques of posterior superior alveolar nerve block (PSANB), the one claimed to be "most accurate" to the one "most commonly used." AIM: This study was conducted to assess and compare the efficacy as well as complications of "the straight needle technique" to that of "the bent needle technique" for PSANB. PATIENTS AND METHODS: We conducted a prospective, randomised, double blind study on 120 patients divided into two groups, using a 26-gauge, 38 mm long needle with 2 ml of 2 % lignocaine hydrochloride with 1:200,000 adrenaline solution. Objective symptoms were evaluated by a single investigator. Cold test using ice was used to evaluate the status of pulpal anesthesia. Data thus obtained was subjected to statistical analysis. RESULTS: Out of the 120 blocks, 19 blocks failed. Statistical analysis found straight needle technique to be more successful than the bent needle technique (p = 0.002). Both the techniques were equally effective for the first molar region on both right and left side (p = 0.66 on right side and p = 0.20 on left side). However, in the second and third molar region technique A was more effective than B (p = 0.01) on right side only. On Left side, both techniques were equally effective (p = 0.08). Sensitivity of the cold test was 82 % which is quite high but the specificity was 68 % which seems to be falling in the above average range only. Positive predictive value of 75 and negative predictive value of 76 was observed. We did not encounter any complications in this study. CONCLUSION: To the best of our knowledge, this is the first randomised controlled clinical study on PSANB techniques. This study suggests that the PSANB using the straight needle technique as advocated by Malamed [1] can be routinely and safely used to achieve anesthesia in the maxillary molar region and to great efficacy, with normal precautions. PMID- 26028870 TI - Evaluation of two different methods of arch bar application: a comparative prospective study. AB - PURPOSE: To comparatively evaluate the efficacy of a pencil type wire twister and the normal wire twister in terms of various parameters during arch bars application. METHOD: The study involved residents of the department enrolled in MDS course. Two study groups of 60 patients each were made by randomly selecting the patients from the outpatient department of Oral and Maxillofacial surgery who required arch bar application. Group A included the patients who underwent upper and lower arch bar application with the use of a pencil type twister and group B included patients who underwent arch bar application with a normal wire twister. All respondents were given a questionnaire after the completion of procedure involving the use of medical sharps. The paired samples t test was used for statistical analysis. RESULT: Among group A, mean glove perforations, actual wire stick injuries, mean time taken to complete the procedure, mean wire breakage during the procedure was less than in group B. Comfort level of patients and Ease of operator while performing the procedure was more in group A than in group B. Frictional abrasion of the finger was not associated with the use of pencil type twister. Overall rating of the procedure was more in group A than group B. CONCLUSION: The use of pencil type wire twister outweighs normal wire twister in various ways. It increases the overall efficacy of the operator during the procedure. PMID- 26028871 TI - Evaluation of mechanical resistance after fixation of mandibular condylar fracture with single and double miniplates: a comparative in vitro study. AB - OBJECTIVES: To evaluate the efficacy of two plating system in comparison with single plating systemTo study the biomechanical behaviour of single and two plating system when compression load is applied. MATERIALS AND METHODS: Twenty hemimandibles were divided into two groups A and B of ten each. A subcondylar fracture was created. Group A was stabilized by single adaptation plating technique and group B by double adaptation plating technique and both the groups were tested for stability by using universal testing machine. RESULTS: Higher mean displacement was observed in Group A compared to Group B, but the difference in mean displacement between the two groups was not statistically significant (p > 0.05). Higher mean load was recorded in group B compared to group A and the difference in mean load between them was found to be statistically significant (p < 0.001). CONCLUSION: The present study demonstrated that double adaptation plating technique had greater resistance to compression load than single adaptation plating technique and it shows more favorable biomechanical behavior. PMID- 26028872 TI - A prospective clinical evaluation of the effects of chlorhexidine, warm saline mouth washes and microbial growth on intraoral sutures. AB - INTRODUCTION: Post operative care of sutured wound is important after surgery. Sutured wounds within the oral cavity are kept clean through frequent rinses with either normal saline, chlorhexidine mouth rinses, hydrogen peroxide diluted with saline, or fresh tap water. PATIENTS AND METHODS: The patients were randomised into 3 groups (A, B and C). The container used had 34 chlorhexidine, 34 warm saline and 32 warm water mouth rinses. The latter served as control. All selected patients had scaling and polishing done preoperatively when needed. All participants in each group did not receive antibiotics but received analgesics (paracetamol 1 g 8 h for 5 days,). RESULTS: There were 49 females and 51 males, in the age range between 18 and 50 years. Microorganisms were found to grow on sutures with streptococcus viridians predominating followed by staphylococcus epidermides. The effects of chlorhexidine, warm saline and warm tap water mouth washes were not statistically significant. CONCLUSION: Chlorhexidine, warm salt water and warm tap water averagely produced the same number of colony forming units of bacteria, which shows that the three different mouth washes are equally effective as post-operative mouth rinses after oral surgery. PMID- 26028873 TI - Temporomandibular joint arthrocentesis for internal derangement with disc displacement without reduction. AB - Temporomandibular joint (TMJ) disc derangement is defined as a malpositioning of the articular disc relative to the condyle and eminence. Arthrocentesis of the TMJ is a minimally invasive chair side procedure for the patients with TMJ internal derangement. This case report presents convincing results to keep arthrocentesis as an imperative procedure to relieve such patients of their acute symptoms. TMJ dynamics has also been discussed for an in-depth understanding of the pathology in cases with internal derangement. PMID- 26028874 TI - A giant osteoma of the mandible. AB - An osteoma is a benign, slow growing osteogenic tumor characterized by proliferation of either compact or cancellous bone. It can be central, peripheral or extraskeletal. Clinically osteomas are usually asymptomatic. These lesions often go undetected unless incidentally found on radiographic survey or until they have extended to such an extent that they cause facial asymmetry or functional impairment. The most common site of osteoma to develop in maxillofacial region is skull. Giant osteomas in mandible are rare. We present and discuss a case of giant osteoma of right mandible which was surgically excised. PMID- 26028875 TI - Traumatic bone cyst of mandible. AB - The traumatic bone cyst, an uncommon lesion of the jaws, belongs to the category of 'pseudocyst' owing to its lack of a lining epithelial membrane. It is an asymptomatic lesion, which is often diagnosed accidentally during routine radiological examination commonly present in the posterior mandible as a unilocular radiolucency with scalloping borders. The exact etiopathogenesis of the lesion is still debated, though the role of trauma is often associated. Here we report a rare case of traumatic bone cyst in the anterior mandible, in a 16 year-old female patient with a previous history of trauma to chin; diagnosed and treated successfully in our surgical unit. The case is discussed in relation to its clinical presentation, etiopathogenesis, diagnosis, management and prognosis. PMID- 26028876 TI - Use of cervical collar in temporomandibular dislocation. AB - Dislocation of the temporomandibular joint represents 3 % of all reported dislocated joints. In the last 3 decades many cases of TMJ dislocation have been reported with a wide variety of treatment options ranging from non-surgical conservative approaches to open joint procedures. The question remains whether one method is superior to the others. Conservative treatments are still the option in this part of the continent due to financial constraints and as well as due to availability of skilled manpower. A variety of conservative techniques have been described for reducing dislocations, all of which require 10-14 days of immobilization of the jaw post reduction so as to prevent further episodes of dislocation. Immobilization of the jaw can be done in the form of barrel bandage, barton bandage, head chin cap or maxillomandibular fixation using arch bars. We suggest the use of a cervical collar as a form of post reduction immobilization technique to overcome the inherent disadvantages of conventional forms of immobilization techniques. PMID- 26028877 TI - Use of a single miniplate to achieve intra operative intermaxillary fixation. AB - There are different treatment modalities mentioned in the literature for achieving intermaxillary fixation (IMF). Arch bars are time consuming, can cause damage to the periodontium, maintenance of oral hygiene is poor. Eyelets are not suitable for dentitions that carry extensive crown and bridge work. IMF screw causes root damage. To avoid all these complications we recommended the use of single miniplate for achieving IMF. PMID- 26028878 TI - Surgical Gown's Cuff Modification to Prevent Surgical Contamination. AB - The gown-glove interface is the weakest point in the barrier system of gown and glove protection for the surgeon. We are herein presenting an easy modification in the cuff of the gown that increases the security of the gown-glove interface. PMID- 26028879 TI - The posterosuperiorly based platysmal myocutaneous flap: the underutilized reconstructive option. AB - The platysmal myocutaneous flap has shown promising results for the reconstruction of defects in the head and neck region. It has been successfully used for the reconstruction of the defects over the cheek, floor of the mouth, buccal mucosa, tongue, lower lip, mandibular alveolus, hypopharnx and supraglotic larynx. The posteriorly and the superiorly based platysmal flaps have a wide range of applicability in the reconstruction of intraoral defects. In the present series we have used a posterosuperiorly based platysmal flap which has shown encouraging results. It was also found that leaving the base of the mandible intact helps in maintaining the periosteal blood supply which further contributes to the survival of the flap. The thinness, arc of rotation, pliability and ease of availability of the platysmal myocutaneous flap gives the reconstructive surgeon an additional option, especially when a microvascular flap is not feasible. PMID- 26028880 TI - A tecnique to maximise length of pectoralis major muscle myocutaneous flap pedicle in orofacial reconstruction. AB - Introduction Pectoralis muscle flap is one of the most common regional flap used in orofacial reconstruction. Mobilization of pedicle and reach of the skin paddle is a technical consideration. Method Based on the anatomical difference in blood supply to clavicular and sternal head, we elaborate a tecnique to maximise the length of pedicle in maxillofacial reconstruction. Conclusion The proposed technique is reproducible and reliable and possibly increase the indications of usage of the flap. PMID- 26028881 TI - Fiberscope Assisted Videolaryngoscope Intubation in the Surgical Treatment of TMJ Ankylosis. AB - Temporomandibular ankylosis is characterized by the formation of a bony mass which replaces normal temporomandibular joint (TMJ) articulation. Anaesthetic management in these patients requires expertise and dependable intubation technique that allows successful intubation due to anticipated difficulty in accessing the airway. A novel technique of endotracheal intubation is used for the successful airway management during the surgical treatment in patients with TMJ ankylosis with the assistance of fiberscope and GlideScope((r)) videolaryngoscope. GlideScope((r)) videolaryngoscope is a recently introduced system for tracheal intubation that has a dedicated video camera encased into a laryngoscope blade and provides better panoramic view than the conventional laryngoscopes. This technique avoids complications such as trauma to soft tissue structures surrounding the glottis during the passage of the tube over the fiberscope. It gives a clear view of the tube and its cuff position during intubation. It also abbreviates the time required for intubation which is a crucial determinant in this subset of patients owing to the difficult airway associated with paediatric age group. PMID- 26028882 TI - Surgical Guides for Modified Oblique Le Fort III Osteotomy. AB - INTRODUCTION: The present work consists of the specific design of a surgical guide for modified oblique Le fort III osteotomy (MOLFIIIO), developed previously in the Stereolithography model of the patient. The guides are designed to perform an osteotomy for the orbital floor, zygoma and pterygomaxillary fossa. The fundamental objective of the malar guides will be: symmetrical orbitozygomatic osteotomies bilaterally. Regarding the guide of the orbital floor, it is of primary importance to begin the osteotomy 5 mm ahead of the inferior orbital fissure (IOF) in orbital antero posterior direction, crossing the orbital floor. The pterygomaxillary fossa guide, will cover the internal face of the malar bone exactly in the posterior portion of the butres (hidden portion) toward the IOF. This guide will be useful, revolutionize and make it easier and secure to access the osteotomy of the area for a lot of surgeons who fear manipulating the pterigomaxillary fossa in its upper third, due to the fear of damaging the internal maxillary artery, that will be reduced to a minimum with the guides. MATERIALS AND METHODS: Initially requires a CT scan, for designed the model patient stereolithography. The guides are prepared from self-curing acrylic and monomer. CONCLUSION: Surgical guides are very useful for MOLFIIIO, as being custom, manage to make a stable symmetrical bilateral cut, decreasing the possibility of injury to vascular structures and shorten the surgical time. PMID- 26028883 TI - A soft, flexible stent/bung for marsupialisation. AB - A soft flexible stent or bung for marsupialisation using putty elastomeric impression material rather than an acrylic bung. PMID- 26028884 TI - A new simplified technique for intermaxillary fixation by loop-designed wire. AB - In the treatment of maxillofacial fractures, Inter-maxillary fixation (IMF) is an important. The upper and lower arch bars or Ivy eyelet wiring is secured by wires and IMF is done with the help of box wiring. Here, we present a new type of IMF technique, using 26-gauze stainless steel 'loop-design' wire, which is a simple, quick, economical and minimally invasive technique without using arch bars. Typical indications for its use are minimally displaced fractures, deep bite cases, stabilization of fracture during open reduction and internal fixation, orthognathic surgeries and in tumor resection surgeries. PMID- 26028885 TI - Intubation techniques: preferences of maxillofacial trauma surgeons. AB - OBJECTIVE: To evaluate the clinical outcomes of alternative techniques of intubation in patients sustaining maxillofacial injuries, where nasotracheal intubation (NTI) is best avoided. MATERIAL AND METHODS: Alternative techniques to standard naso-tracheal intubation like submental intubation, orotracheal intubation-retrotuberosity/retromolar and missing dentition were used and variables of clinical outcome recorded. RESULTS: Submental intubation provides an unobstructed intraoral surgical field, avoids intraoperative and postoperative complications of tracheostomy, and overcomes the disadvantages of NTI. In our experience with submental intubation (6 cases), we only had complication related to tube apparatus like damage to pilot balloon. With retrotuberosity intubation (5 cases) we did not encounter any complications and the only limitations were bulbous maxillary tuberosity. Retromolar intubation (4 cases) a safe noninvasive technique has disadvantages like tube interference within the surgical field and not feasible in case of limited retromolar space. Orotracheal-missing dentition intubation (4 cases) is of great advantage i.e. it can be used in cases where NTI is contraindicated, no specialized skill required, no added cost, avoids the need for tracheostomy, no extra-oral procedures required and does not interfere with occlusion/MMF; with disadvantage of occasional tube interference within the surgical field. CONCLUSION: Preferred techniques of securing an airway like orotracheal, nasotracheal may not always be applicable, thus a trauma surgeon anesthesist team should always have alternative techniques in their armamentarium to reduce the morbidity associated with these patients without interference with occlusion, which is prime goal in jaw fracture reduction. We have used these techniques in a country with limited resources and found them equally effective and convenient to use. PMID- 26028886 TI - Utility of trephine drills in implant dentistry. AB - INTRODUCTION: The aim of this technical note was to compare the primary stability and less bone drilling with the help of conventional and trephine drills. MATERIALS AND METHODS: 40 patients were divided into two groups (I & II) of 20 each and group I patients treated with conventional drills and group II with trephine drills. The patients who were reported to dental clinic and research centre between Jan 2011 to june 2011 and who required their teeth replacement with the help of dental implants were included in the study and patients with diabetes, Arthritis and smokers were excluded from the study. CONCLUSION: Trephine drills provide better primary stability and good long term results. PMID- 26028887 TI - Arched needle technique for inferior alveolar mandibular nerve block. PMID- 26028888 TI - Letter to editor. PMID- 26028889 TI - Which Laboratory Investigation Should be Ordered to Assess Haemostasis in Patients on Platelet Function Altering Medications? PMID- 26028890 TI - Subcutaneous emphysema. AB - Subcutaneous emphysema is a potential surgical complication arising due to introduction of air into the facial planes of the connective tissue. presence of air and accompanying inflammation and or infection could prove fatal in immediate post surgical scenario. This case report aims to prevent one such case of subcutaneous emphysema that was promptly diagnosis and effectively managed. PMID- 26028891 TI - Erratum to: Duration of Hospital Stay Following Orthognathic Surgery at the Jordan University Hospital. AB - [This corrects the article DOI: 10.1007/s12663-011-0327-5.]. PMID- 26028892 TI - Erratum to: Nasotracheal Fiberoptic Intubation: Patient Comfort, Intubating Conditions and Hemodynamic Stability During Conscious Sedation with Different Doses of Dexmedetomidine. AB - [This corrects the article DOI: 10.1007/s12663-012-0469-0.]. PMID- 26028893 TI - Effect of repeated sterilization cycles on the physical properties of scaling instruments: a scanning electron microscopy study. AB - BACKGROUND: Repeated sterilizations cycles cause undesirable alterations in the material properties of the instruments, such as corrosion, alterations in the hardness of the metal and the loss of the cutting sharpness of the instrument. This research examined the effect of repeated dry heat sterilization and autoclaves cycles on carbon steel (CS) and stainless steel (SS) curettes during the scaling and root planning. MATERIALS AND METHODS: A total of 77 Gracey curettes were used in this study. Of these, 35 were SS and 42 were CS curettes submitted in different process: Dry heat, autoclave, inhibition of corrosion and autoclave, scaling, root planning and dry heat, scaling, root planning, inhibition of corrosion and autoclave. The inhibition of corrosion used on the carbon curettes (prior to sterilization in the autoclave) was sodium nitrite at 2%. The curettes received 10 consecutive cycles of sterilization and after that the cutting edges were examined in the electronic microscope, at 60 and 100 magnification times. RESULTS: The images were evaluated by three independent examiners, who compared the photographs of each group with the control group. CONCLUSION: The surface corrosion products and a deterioration of the edges were observed and the results showed that the SS curettes suffered little alteration with sterilization, scaling, root planning whereas the CS curettes were visibly affected by sterilization in the autoclave, but when the inhibition of corrosion was used prior to the sterilization, the oxidation was considerably reduced. PMID- 26028894 TI - Implant Supported Distal Extension over Denture Retained by Two Types of Attachments. A Comparative Radiographic Study by Cone Beam Computed Tomography. AB - BACKGROUND: This study was conducted to compare and evaluate the effect of two different attachments (locator attachment and ball and socket [B&S] attachment) on implants and natural abutments supporting structures, in cases of limited inter-arch spaces in mandibular Kennedy Class I implant supported removable partial over dentures by measuring the bone height changes through the cone beam radiographic technology. MATERIALS AND METHODS: Two implants were positioned in the first or second molar area following the two-stage surgical protocol. Two equal groups were divided ten for each: Group I: Sides were the placed implants restored by the locator attachment. Group II: The other sides, implants were restored by B&S attachment. Evaluation of the implants and main abutments supporting structures of each group was done at the time of removable partial over denture insertion, 6, 12 and 18 months by measuring the bone height changes using cone beam computed tomography. RESULTS: Implants with locator attachment showed marginal bone height better effects on implants and main abutments supporting structures. CONCLUSION: Implants restored by locator attachment shows better effects on bone of both main natural abutments and implant than those restored with ball and socket. PMID- 26028895 TI - Comparison of periodontal ligament injection and inferior alveolar nerve block in mandibular primary molars pulpotomy: a randomized control trial. AB - BACKGROUND: Inferior alveolar nerve block is a common technique for anesthesia of the primary mandibular molars. A number of disadvantages have been shown to be associated with this technique. Periodontal ligament (PDL) injection could be considered as an alternative to inferior alveolar nerve block. The aim of this study was to evaluate the effectiveness of PDL injection in the anesthesia of primary molar pulpotomy with mandibular block. METHODS: This study was performed using a sequential double-blind randomized trial design. 80 children aged 3-7 years old who required pulpotomy in symmetrical mandibular primary molars were selected. The teeth of these children were anesthetized with periodontal injection on one side of the mandible and block on the other. Pulpotomy was performed on each patient during the same appointment. Signs of discomfort, including hand and body tension and eye movement, the verbal complaint and crying (SEM scale), were evaluated by a dental assistant who was blinded to the treatment allocation of the patients. Finally, the data were analyzed using the exact Fisher test and Pearson Chi-squared exact test. RESULTS: Success rate was 88/75 and 91/25 in the PDL injection and nerve block groups, respectively. There was no statistically significant difference between the two techniques (P = 0.250). CONCLUSION: Results showed that PDL injection can be used as an alternative to nerve block in pulpotomy of the mandibular primary molars. PMID- 26028896 TI - Knowledge, Attitudes, and Practice of Infection Control among Dental Students at Sana'a University, Yemen. AB - BACKGROUND: The aim of this study was to evaluate knowledge, attitudes, and practices regarding infection control procedures among senior dental students. MATERIALS AND METHODS: A questionnaire-based cross-sectional survey was conducted among 145 4(th)- and 5(th)-year dental students at the Faculty of Dentistry, Sana'a University, Yemen. The self-administered questionnaire was comprised of 20 open- and close-ended items regarding barrier techniques, vaccination status, infection control practices, and awareness. Data were analyzed with a Chi-square test. A P <= 0.05 was considered significant. RESULTS: The response rate was 72% (145 out of 204 potential respondents). Overall, 71.7% of the students had been vaccinated for hepatitis B and only 9.5% were tested for post-hepatitis B virus immunization serology. While the vast majority (96.6%) reported always wearing gloves for all dental procedures, the use of face masks and eyewear were reported by only 53.8% and 14.0% of students, respectively, with no significant difference between genders and year of study (P > 0.05). A significantly higher percentage of 5(th)-year students (58.9%) showed positive attitudes toward the treatment of patients with infectious diseases, as compared to only 31.0% of 4(th) year students (P < 0.01). A great number of students (62%) reported non-sterile occupational percutaneous and mucous injuries while treating their patients. CONCLUSIONS: These unsatisfactory findings highlight the necessity of continued infection control education in order to improve knowledge, attitudes, and practices regarding infection control among dental students at Sana'a University. PMID- 26028897 TI - Occlusal Status among 12-16 Year-Old School Children in Riyadh, Saudi Arabia. AB - BACKGROUND: Identifying occlusal status in a particular population will be valuable in planning the appropriate preventive and treatment programs. The purpose of this study was to assess the status of occlusion among school children in Riyadh, Saudi Arabia. MATERIALS AND METHODS: This study was conducted at Riyadh, Saudi Arabia from September 2012 to June 2013. A total of 1825 Saudis (1007 males and 818 females) of 12-16 years old were randomly selected from 20 schools in different areas of Riyadh city to determine the status of their occlusion. The examiners assessed molar and canine relationships, spacing and crowding, overjet, overbite, anterior and posterior cross bite. These occlusal parameters were examined by two experienced examiners using a mouth mirror, small light source and calibrated fiber ruler. RESULTS: About 60.11% of Saudis presented with Class I molar relationship while 7.12% and 10.13% of the subjects had Class II and III molar relationship, respectively. The most prevalent canine relationship was Class I (54.13%), followed by Class II (12.4%) and Class III (11.2). Normal overjet and overbite were observed in 76% and 67% of the sample, respectively. The prevalence of malocclusion traits were crowding (45.4%), Spacing (26.9%), excessive over jet (16.4%), posterior cross bite (8.9%), anterior open bite (8.4%) and excessive overbite (6.68%). No statistically significant differences were found between the genders about the prevalence of any occlusion traits (P > 0.05). CONCLUSION: Class I molar relationship, normal overbite, and normal overjet were dominant features among Saudis. Crowding was the most prevalent malocclusion trait, followed by spacing. These findings will help in understanding the occlusion status in order to plan for prevention and treatment of malocclusion in Riyadh city. PMID- 26028898 TI - Evaluation and comparison of resistance to compression of various interocclusal recording media: an in vitro study. AB - BACKGROUND: This in vitro study was conducted to compare the compression resistance of various interocclusal recording materials when subjected to a compressive load. MATERIALS AND METHODS: Each interocclusal recording material was manipulated according to the manufacturer instruction and placed into a metallic cylinder. A total of 20 specimens for each interocclusal recording material were made. A total 100 specimens were fabricated. Each specimen was placed in the Universal Testing Machine exerting pressure on it, and a force of 100 g/cm(2) was exerted on each sample. 30 s later the reading of the Universal Testing Machine was recorded using a vertical traveling micrometer microscope with an accuracy of +/- 0.001 mm. This value was marked as reading "A." 60 s after the application of the first force (100 g/cm(2)), a second force of 1000 g/cm(2) was applied gradually during an interval of 10 s. 30 s later the reading of the Universal Testing Machine exerting pressure on the specimen was recorded again. This value was marked as reading "B." The difference between readings "A" and "B" recorded the compression to resistance of each material. Comparisons within the groups and between the groups were done by using one-way ANOVA and Tukey's HSD test. RESULT: There was significant variation between all interocclusal bite registration materials. According to the mean valve of each interocclusal bite registration material, Polyvinylsiloxane Bite Registration Material have better resistance to compression followed by Polyether interocclusal bite registration material, Aluwax Bite, and Impression Wax, Modeling Wax and at last Zinc Oxide Eugenol Impression Paste. CONCLUSION: Polyvinylsiloxane interocclusal registration material had the greatest resistance to compression. The least resistance to compression was noticed with zinc oxide eugenol paste. PMID- 26028899 TI - A novel method of coating orthodontic archwires with nanoparticles. AB - BACKGROUND: The major hazard to the orthodontic tooth movement is the friction developing at the bracket wire interface. In the past, there have been various attempts to reduce this friction. We believe that coating the commercially available orthodontic wires with nanoparticles can result in a successful reduction of this friction. The objective of this study is to develop a novel method of coating orthodontic archwires with nanoparticles. MATERIALS AND METHODS: Stainless steel (Ormco, CA, USA), titanium molybdenum alloy (Ormco, CA, USA) and nickel-titanium (G and H Wire Company, USA) orthodontic wires with a rectangular cross-section dimension of 0.019"* 0.025", were selected. The wires were later coated with a uniform and smooth nanoparticle film using 100 ml nanocremics. The coating procedure described in this article is a sol-gel thin film dip coating method. RESULTS: The coating procedure was verified by comparing the surface topography of nanocoated archwires with the commercially available archwires in an environmental scanning electron microscope (ESEM). The ESEM images prove that the surface topography of the coated wires was found to be smoother with less surface deteriorations as compared to the commercially available wires. CONCLUSION: Commercially available orthodontic wires can be successfully coated using a novel method of sol-gel thin film dip coating method. PMID- 26028900 TI - Effects of different ligature materials on friction in sliding mechanics. AB - BACKGROUND: During orthodontic tooth movement friction occurs at the bracket wire interface. Out of the total force applied to the tooth movement, some of it is dissipated as friction, and the remainder is transferred to the supporting structures of the tooth to mediate tooth movement. However many factors affect friction, and method of arch wire ligation being an important contributing factor. Hence, this study was carried out to evaluate the effects of different ligature materials on friction in sliding mechanics and to compare the effect of environment (dry and wet) on friction produced in sliding mechanics. MATERIALS AND METHODS: The evaluation of friction between the bracket and the archwire consisted of a simulated half arch fixed appliance with archwire ligated in a vertical position. Four 0.022" maxillary stainless steel premolar brackets having a - 0 degrees torque and 0 degrees angulation were aligned with a 0.019" * 0.025" stainless steel arch wire onto a rigid Plexiglass sheet. The movable test bracket was fitted with a 10 mm long, 0.045" thick stainless steel power arm on the bonding surface. Testing was performed on a Hounsfield material testing machine. A total of 100 g weight was suspended from the power arm and the load needed to move the bracket over the distance of not <4 mm across the central span was recorded separately. Fifteen representative readings were taken with one reading per test sample. RESULTS: The results showed that the mean frictional force of different groups in dry and wet state was statistically significantly different. The mean frictional force in a dry state was statistically significantly higher than wet state in elastomeric group. CONCLUSION: The type of ligation material and environment significantly affected the degree of friction generated during sliding mechanics. Teflon coated stainless steel ligatures produced the least friction among the materials tested in both dry and wet conditions and there was no significant effect on friction in this group caused due to lubrication. PMID- 26028901 TI - In vitro Comparative Evaluation of Tensile Bond Strength of 6(th), 7(th) and 8(th) Generation Dentin Bonding Agents. AB - BACKGROUND: Newer dentin bonding agents were developed to improve the quality of composite restoration and to reduce time consumption in its application. The aim of the present study was to evaluate tensile bond strength of 6(th), 7(th) and 8(th) generation bonding agents by in vitro method. MATERIALS AND METHODS: Selected 60 permanent teeth were assigned into 20 in each group (Group I: 6(th) generation bonding agent-Adper SE plus 3M ESPE, Group II: 7(th) generation bonding agent-G-Bond GC Corp Japan and Group III: 8(th) generation dentin adhesives-FuturaBond, DC, Voco, Germany). With high-speed diamond disc, coronal dentin was exposed, and selected dentin bonding agents were applied, followed by composite restoration. All samples were saved in saline for 24 h and tensile bond strength testing was done using a universal testing machine. The obtained data were tabulated and statistically analyzed using ANOVA test. RESULTS: The tensile bond strength readings for 6(th) generation bonding agent was 32.2465, for 7(th) generation was 31.6734, and for 8(th)-generation dentine bonding agent was 34.74431. The highest tensile bond strength was seen in 8(th) generation bonding agent compared to 6(th) and 7(th) generation bonding agents. CONCLUSION: From the present study it can be conclude that 8(th) generation dentine adhesive (Futura DC, Voco, Germany) resulted in highest tensile bond strength compared to 6(th) (Adper SE plus, 3M ESPE) and 7(th) generation (G-Bond) dentin bonding agents. PMID- 26028902 TI - Evaluation of different dentin adhesive systems and its effect on apical microleakage: an in vitro study. AB - BACKGROUND: Regardless of the technique and the material used, the goal of obturation remained the same that is to seal every portal of exit in the root canal system. It's not only the apical openings that need to be sealed but also lateral openings, coronal access opening and perforations if they exist failure of the adhesive root canal sealer has led to the idea of usage of dentin bonding agents (DBAs) in endodontics, to make a three dimensional seal. In our study, we used traditional gutta-percha, time tested epoxy resin and DBA to make the root canal leak proof. MATERIALS AND METHODS: A total of 40 maxillary incisors teeth were decoronated at cemento-enamel junction. Instrumenting to size 40 they were randomly assigned to four groups (n = 10) according to the dentin adhesive system used for obturation in combination with AH Plus sealer and gutta-percha points. The hybrid layer formation was observed using scanning electron microscope and the extent of dye penetration was measured using a stereomicroscope. RESULTS: Group I: Control group, no hybrid layer formation. Group II: Uniform thin hybrid layer, with short multiple resin tags and lateral branchings. Group III: Uniform hybrid layer with short and thick resin tag formations. Group IV: Hybrid layer with numerous long discontinuous resin tags. CONCLUSIONS: Group I, (without adhesive) showed the highest apical microleakage highlighting the need for dental adhesive. PMID- 26028903 TI - Radiographic Estimation of Chronological Age using Mineralization of Third Molars in Coastal Andhra, India. AB - BACKGROUND: Age estimation is an important factor in establishing the identity of a person. Among various techniques, dental age estimation is helpful in estimating the age in children above 16 years of age. Determination of age using developmental stages of teeth is more useful than using tooth eruption. MATERIALS AND METHODS: A total of 550 orthopantomographs of 248 males and 302 females aged between 15 and 22 years were taken and evaluated by Demirjian's tooth mineralization stages. Statistical assessment was done using logistic regression analysis. RESULTS: Complete apical closure of third molars was observed at the age of 20.4 years in 50% of males. Gender is also thought to influence mineralization and males showed early apical closure than females. Mean value testing is also done but showed influence of high and lower end age groups on age estimation. CONCLUSION: Finally, we conclude that, though the exact age of a person cannot be determined, the Demirjian's stage at which 18 years of age is attained can be found out. PMID- 26028904 TI - An in vitro comparative evaluation of fracture resistance of custom made, metal, glass fiber reinforced and carbon reinforced posts in endodontically treated teeth. AB - BACKGROUND: Posts are used to enhance crown buildup in pulpless teeth with destructed crown portion. Different types of post are used in endodontically treated teeth. The aim of the present in vitro study was to evaluate fracture resistance of custom made, metal, glass fiber reinforced and carbon reinforced posts in endodontically treated teeth. MATERIALS AND METHODS: An in vitro study was carried out on extracted 40 human maxillary central incisor teeth, which was divided into four groups with 10 samples in each group with custom made, metal post, glass fiber reinforced, and carbon reinforced posts. The samples were decoronated at cemento-enamel junction and endodontically treated. Post space was prepared and selected posts were cemented. The composite cores were prepared at the height of 5 mm and samples mounted on acrylic blocks. Later fracture resistance to the compressive force of samples was measured using Universal Testing Machine. RESULTS: The maximum resistance to the compressive force was observed in carbon reinforced and glass fiber reinforced posts compared others which is statistically significant (P > 0.001) and least was seen in custom fabricated post. CONCLUSION: It is concluded that carbon reinforced fiber post and glass fiber posts showed good fracture resistance compared to custom made and metal posts. PMID- 26028905 TI - Supernumerary teeth: an investigating tool in forensic crime investigation. AB - BACKGROUND: Supernumerary tooth is an additional entity to the normal series and is seen in all the quadrants of the jaw. The prevalence rates of supernumerary teeth in the permanent dentition, reported in the literature, vary between 0.1% and 6.9%. The presence of supernumerary teeth may be part of developmental disorders. As supernumerary tooth is a rare condition, it can be used as identification tool for crime investigation. MATERIAL AND METHODS: A total of 30 volunteers with a supernumerary tooth were analyzed and casts were made after taking alginate impression. All the casts were coded and were given to five observers for correct identification of those volunteers with respective prepared cast. RESULT: Personal identification and the cast identification of volunteers were done (cast of the volunteers). The matching identification is followed as below: Of five observers 1(st) observer able to detect 25 (83%), 2(nd) observer 27 (90%), 3(rd) observer 26 (87%), 4(th) observer 25 (83%) and 5(th) observer 28 (91%). CONCLUSION: As positive matching identification was 87%, supernumerary tooth can be used for crime investigation and used as greatest weapon in criminal identification. PMID- 26028906 TI - A Forgotten Technique for Replacement of Maxillary Anteriors and an associated Bony Defect: A Case Report. AB - Fixed replacement of maxillary anterior teeth with an associated bony defect has challenged the restoring dentist with problems like weight of the prosthesis thereby leading to weakening of abutment teeth, difficulty in establishing smile line and mechanical stability. This article describes the management of a patient with such defect with a forgotten prosthesis - the Andrew bridge system, which has a fixed and a removable prosthetic component with retentive clips, which anchors on to a bar spanning the edentulous space. Andrew's bridge system has definite indications and offers immense advantages over the other prosthesis for rehabilitation of cases of such scenario. It addresses the problems aforementioned and provides the optimal retention, mechanical stability, esthetics and comfort to the patient. PMID- 26028907 TI - Buccal exostosis: a rare entity. AB - Buccal exostoses are broad-based, non-malignant surface growth occurring on the outer or facial surface of the maxilla and/or mandible, found usually in the premolar and molar region. Etiology is still not established, but it has been suggested that the bony overgrowth can be because of abnormally increased masticatory forces to the teeth. They tend to appear in early adolescence and may very slowly increase in size with time. They are painless, self-limiting and may increase patient concern about poor esthetics, inability to perform oral hygiene procedures, and compromised periodontal health by causing food lodgment. The following article presents a very rare case of bilateral buccal-sided maxillary exostoses and its management with surgical exploration. PMID- 26028908 TI - Space closure with loop mechanics for treatment of bimaxillary protrusion: a case report. AB - This case report intends to highlight the space closure with tear drop loop mechanics for bimaxillary protrusion. Loops can be fabricated in a sectional or full arch wire, and closing loops are usually used in loop mechanics for extraction space closure. The major advantage of loop mechanics is the lack of friction between the bracket and arch wire during space closure. An adult patient with bimaxillary protrusion reported to the clinic. The patient was treated successfully by maximum retraction of maxillary and mandibular anterior teeth after extraction of all first premolars. Space closure was begun using a moment differential between posterior and anterior segments created by a Tear drop loop. Anterior teeth were moved with bodily movement, and no anchorage loss of the posterior segments was seen using a Tear drop loop spring. A stable result with normal over jet and overbite was achieved with retraction of maxillary and mandibular anterior teeth. With a Tear drop loop, individual biomechanical responses can be achieved, and it is possible to calculate force magnitude for every patient. PMID- 26028909 TI - Agenesis of multiple primary and permanent teeth unilaterally and its possible management. AB - Oligodontia is the agenesis of numerous teeth (more than six teeth). Agenesis of teeth in primary and permanent dentition is a rare incidence and very few are reported in the dental literature. Although the etiology of congenital agenesis of teeth is unclear, several factors such as a tendency toward genetic predilection, metabolic disorders, trauma, infection, radiation or idiopathic reasons are found to be responsible. Available literature reports agenesis most often of third molars, maxillary lateral incisors, mandibular central and lateral incisors, and mandibular second premolars in decreasing order of frequency of occurrence. Males are more often affected than females. Maxillary primary teeth are more often found affected by agenesis than mandibular primary teeth. Available literature reports missing teeth to be found unilaterally or orbilaterally with a predisposition toward a similar phenomenon occurring in the permanent dentition. In congenital agenesis impaired growth of the alveolar process, reduced lower facial height, speech impairment, deep bite, restriction in the movement of the tongue due to ankyloglossia, asymmetry of the affected side of the face are clinical features evident. There has been no report of complete agenesis of primary and permanent teeth in a whole mandibular quadrant in conjunction with the absence of maxillary second and third molars on the affected side. Here, we report an incidence of a rare occurrence of complete agenesis of more than 10 primary and permanent teeth, unilaterally, in the right mandibular quadrant, in a child of 10 years presenting with a chief complaint of several missing primary teeth and difficulty in speech due to its complete absence. Treatment strategies included various orthodontic and restorative procedures to improve esthetics and function. The orthodontic procedures involved expansion of the narrow maxillary arch to obtain a functionally adapted occlusion and creation of space for future alignment, and uprighting and protecting maxillary right posteriors to accommodate the tongue and rectify speech. Restorative procedures involved fabrication of a removable partial denture as a temporary measure to restore missing teeth, improve esthetics, give lingual support to the lower lip, prevent further downward growth of the right maxillary ridge and to prevent supra eruption of these teeth. PMID- 26028910 TI - Apical Closure of Nonvital Permanent Teeth: 15 Months Follow-up Study of Four Cases. AB - Obtaining a complete seal of the root canal system is a major problem in performing root canal treatment in nonvital teeth with incomplete root development and wide open apices. The aim was to study apexification using mineral trioxide aggregate (MTA), clinically and radiographically over a period of 15 months. MTA was used in four cases of teeth with incomplete root development in order to achieve an apical seal and the remaining canal was obturated with gutta-percha. Clinical and radiographic assessments of teeth were done. The clinical and radiographic results indicated that apexification procedure was predictable by using MTA. The total number of patients' visits and the total time duration required to obtain an apical barrier using MTA was markedly less than that of conventional techniques using calcium hydroxide. PMID- 26028911 TI - Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. AB - Recurrent aphthous stomatitis (RAS) is a well-known oral disease with unclear etiopathogenesis for which symptomatic therapy is only available. This kind of study aimed to highlight the main points that the general practitioners should be taken in their consideration. We have collected our data from PubMed line from 1972 to 2011. Our criteria included the papers that refer to the general predisposing factors, and the general treatment of RAS. Some papers which indicated to the specific details related to RAS that needed a consultant or specialist in Oral Medicine have not included. There is no clear guideline of the etiology, diagnosis, and management of RAS; therefore, the majority of the general practitioners refer most of the cases to appropriate specialist. PMID- 26028913 TI - Dental Outreach Program - How Effective it is in Reaching Out to the Community. PMID- 26028912 TI - Oral and craniofacial clinical signs associated to genetic conditions in human identification part I: a review. AB - BACKGROUND: Forensic dentistry is one of the most reliable methods used in human identification when other technique as fingerprint, DNA, visual identification cannot be used. Genetic disorders have several manifestations that can target the intra-oral cavity, the cranio-facial area or any location in the human body. MATERIALS AND METHODS: A literature search of the scientific database (Medline and Science Direct) for the years 1990 to 2014 was carried out to find out all the available papers that indicate oral, cranio-facial signs, genetic and human identification. RESULTS: A table with 10 genetic conditions was described with oral and cranio-facial signs that can help forensic specialist in human identification. CONCLUSION: This review showed a correlation between genetics, facial and intra-oral signs that would help forensic ondontologist in the identification procedures. PMID- 26028914 TI - Facial transplantation surgery introduction. AB - Severely disfiguring facial injuries can have a devastating impact on the patient's quality of life. During the past decade, vascularized facial allotransplantation has progressed from an experimental possibility to a clinical reality in the fields of disease, trauma, and congenital malformations. This technique may now be considered a viable option for repairing complex craniofacial defects for which the results of autologous reconstruction remain suboptimal. Vascularized facial allotransplantation permits optimal anatomical reconstruction and provides desired functional, esthetic, and psychosocial benefits that are far superior to those achieved with conventional methods. Along with dramatic improvements in their functional statuses, patients regain the ability to make facial expressions such as smiling and to perform various functions such as smelling, eating, drinking, and speaking. The ideas in the 1997 movie "Face/Off" have now been realized in the clinical field. The objective of this article is to introduce this new surgical field, provide a basis for examining the status of the field of face transplantation, and stimulate and enhance facial transplantation studies in Korea. PMID- 26028915 TI - Reporting results of research involving human subjects: an ethical obligation. AB - Researchers have an ethical responsibility to report the results of research involving human subjects. Dissemination of results ensures that patient care is based on good science and that the field of medicine advances based on complete and accurate knowledge. However, current evidence suggests that publication is often neglected or substantially delayed, especially in the case of negative and inconclusive results. Researchers, editors and reviewers should value all high quality research regardless of the conclusiveness of the results and ensure that all research involving human subjects is registered in a publicly accessible database. PMID- 26028916 TI - Egalitarian health policy preference and its related factors in Korea: national representative sample survey. AB - Recently in Korea, the commercialization of health services has come to the fore, and the issue of egalitarianism/universal coverage in health is a matter for debate. This study explored the extent of Korean citizen's preference for egalitarian health policies focusing on the provision of health care service, financing and related factors. The data came from the 2011 Korean General Social Survey (KGSS) and the International Social Survey Program (ISSP). The preference for an egalitarian health policy (dependent variable) was divided into a preference for an egalitarian health services provision (ES) and a willingness to contribute (WC) to it. Each index was linearly regressed with demographic factors, socioeconomic status, ideology, and health-related factors. ES was significantly associated with an individual's egalitarianism and political liberalism, having illness/disability, having no additional private health insurance, and their perception of health insurance coverage. WC was associated with age, sex, household income, education, egalitarianism, and their perception of health insurance coverage. There were evidently different factors between ES and WC, mainly socioeconomic factors. WC was strongly influenced by socioeconomic status, whereas ES seemed to be linked more closely to economic affordability. Moreover, the results showed that Korean citizens prefer ES but do not like WC. These results deserve great attention, and the authorities should keep it in perspective. If the government wants to make a successful attempt to change the healthcare system through public policy, it will need to take public preferences into account. PMID- 26028917 TI - A 12-month single arm pilot study to evaluate the efficacy and safety of sirolimus in combination with tacrolimus in kidney transplant recipients at high immunologic risk. AB - The optimal immunosuppressive strategy for renal transplant recipients at high immunologic risk remains a topic of investigation. This prospective single arm pilot study was undertaken to evaluate the safety and efficacy of a combined tacrolimus and sirolimus regimen in recipients at immunological high risk and to compare outcomes with a contemporaneous control group received tacrolimus and mycophenolate mofetil. Patients that received a renal allograft between 2010 and 2011 at high risk (defined as panel reactive antibodies > 50%, 4 or more human leukocyte antigen mismatches, or retransplantation) were enrolled. All patients received basiliximab induction and corticosteroids. A total of 28 recipients treated with tacrolimus and sirolimus were enrolled in this study and 69 recipients were retrospectively reviewed as a control group. The sirolimus group showed a higher, but not statistically significant, incidence of biopsy proven acute rejection and a lower glomerular filtration rate than the control group. Furthermore, sirolimus group was associated with significant increases in BKV infection (P = 0.031), dyslipidemia (P = 0.004), and lymphocele (P = 0.020). The study was terminated prematurely due to a high incidence of adverse events. A de novo tacrolimus/sirolimus combination regimen may not be an ideal choice for recipients at high immunological risk. PMID- 26028918 TI - Comparison of Arbekacin and Vancomycin in Treatment of Chronic Suppurative Otitis Media by Methicillin Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of ear infections. We attempted to evaluate the clinical usefulness of arbekacin in treating chronic suppurative otitis media (CSOM) by comparing its clinical efficacy and toxicity with those of vancomycin. Efficacy was classified according to bacterial elimination or bacteriologic failure and improved or failed clinical efficacy response. Ninety-five subjects were diagnosed with CSOM caused by MRSA. Twenty of these subjects were treated with arbekacin, and 36 with vancomycin. The bacteriological efficacy (bacterial elimination, arbekacin vs. vancomycin: 85.0% vs. 97.2%) and improved clinical efficacy (arbekacin vs. vancomycin; 90.0% vs. 97.2%) were not different between the two groups. However, the rate of complications was higher in the vancomycin group (33.3%) than in the arbekacin group (5.0%) (P=0.020). In addition, a total of 12 adverse reactions were observed in the vancomycin group; two for hepatotoxicity, one for nephrotoxicity, eight for leukopenia, two for skin rash, and one for drug fever. It is suggested that arbekacin be a good alternative drug to vancomycin in treatment of CSOM caused by MRSA. PMID- 26028919 TI - Clinical features of seizures in patients with human immunodeficiency virus infection. AB - Patients with human immunodeficiency virus (HIV) infection have a higher burden of seizures, but few studies have examined seizures in HIV-infected individuals in Korea. A retrospective study was conducted to determine the epidemiology and clinical characteristics of seizures in patients with HIV infection. Among a total of 1,141 patients, 34 (3%) had seizures or epilepsy; 4 of these individuals had epilepsy before HIV infection, and the others showed new-onset seizures. Most patients exhibited moderate (200 to 500, n = 13) or low (below 200, n = 16) CD4 counts. The most common seizure etiology was progressive multifocal leukoencephalopathy (n = 14), followed by other HIV-associated central nervous system (CNS) complications (n = 6). Imaging studies revealed brain lesions in 21 patients. A total of 9 patients experienced only one seizure during the follow-up period, and 25 patients experienced multiple seizures or status epilepticus (n = 2). Multiple seizures were more common in patients with brain etiologies (P = 0.019) or epileptiform discharges on EEG (P = 0.032). Most seizures were controlled without anticonvulsants (n = 12) or with a single anticonvulsant (n = 12). Among patients with HIV infection, seizures are significantly more prevalent than in the general population. Most seizures, with the exception of status epilepticus, have a benign clinical course and few complications. PMID- 26028920 TI - Application of a Novel Diagnostic Rule in the Differential Diagnosis between Acute Gouty Arthritis and Septic Arthritis. AB - Septic arthritis and gout are major diseases that should be suspected in patients with acute monoarthritis. These two diseases are clinically similar and often indistinguishable without the help of synovial fluid analysis. Recently, a novel diagnostic rule for gout without synovial fluid analysis was developed and showed relevant performances. This study aimed to determine whether this diagnostic rule could perform well in distinguishing gout from septic arthritis. The diagnostic rule comprises 7 clinical and laboratory variables, each of which is given a specified score. The probability of gout is classified into 3 groups according to the sum of the scores: high (>= 8), intermediate (> 4 to < 8) and low probability (<= 4). In this retrospective study, we applied this diagnostic rule to 136 patients who presented as acute monoarthritis and were subsequently diagnosed as acute gout (n = 82) and septic arthritis (n = 54) based on synovial fluid analysis. The mean sum of scores of acute gout patients was significantly higher than that of those with septic arthritis (8.6 +/- 0.2 vs. 3.6 +/- 0.32, P < 0.001). Patients with acute gout had significantly more 'high', and less 'low' probabilities compared to those with septic arthritis (Eta[eta]: 0.776). The prevalence of acute gouty arthritis, as confirmed by the presence of monosodium crystal, was 95.5% (61/64), 57.5% (19/33), and 5.1% (2/39) in high, intermediate and low probability group, respectively. The recently introduced diagnostic rule properly discriminates acute gout from septic arthritis. It may help physicians diagnose gout in cases difficult to be differentiated from septic arthritis. PMID- 26028921 TI - Serum Specific IgE to Thyroid Peroxidase Activates Basophils in Aspirin Intolerant Urticaria. AB - Thyroid antibodies are frequently observed in urticaria patients, but their roles in urticaria are not clearly elucidated. We investigated the role of serum specific IgE to thyroid peroxidase (TPO) in patients with aspirin intolerant acute urticaria (AIAU) and aspirin intolerant chronic urticaria (AICU). We recruited 59 AIAU and 96 AICU patients with 69 normal controls (NC). Serum specific IgE to TPO was measured by manual direct ELISA, and CD203c expressions on basophil with additions of TPO were measured to prove a direct role of TPO in effector cells. The prevalences of serum specific IgE to TPO were significantly higher in AIAU (15.2%) and AICU groups (7.5%) compared to NC (0%, P=0.018: P=0.013, respectively). Flow cytometry showed CD203c induction in a dose dependent manner with serial additions of TPO in some AIAU and AICU patients having high specific IgE to TPO. Our findings show that the prevalence of serum specific IgE to TPO was significantly higher in both AIAU and AICU patients than in NC. It is suggested that specific IgE to TPO play a pathogenic role in AIAU and AICU. PMID- 26028922 TI - Stereotactic Body Radiation Therapy for Low- to Intermediate-risk Prostate Adenocarcinoma. AB - The aim of the present study was to evaluate the efficacy and toxicity of stereotactic body radiation therapy (SBRT) for low- to intermediate-risk prostate adenocarcinoma. Thirty-nine patients were retrospectively reviewed. The SBRT was delivered using the CyberKnife with the fiducial tracking method combined with In tempo imaging. The gross target volume, which included the prostate only, was delineated on the fused CT/MRI scans. The prescription dose was delivered every other day as 5 fractions of 7.5 Gy. Venous blood was obtained before and after SBRT to assess the prostate-specific antigen (PSA) level. Toxicity was evaluated using the CTCAE, v4.03. The median follow-up time was 30.0 months. The median initial PSA level was 7.7 ng/mL. PSA levels decreased in all patients treated with SBRT, and after 5 months, the median PSA was less than 2 ng/mL. The rate of overall 3-yr actuarial biochemical failure free survival was 93.9%. Acute side effects were generally comparable with those of previous studies. The PSA change and toxicity after SBRT for low- to intermediate-risk prostate adenocarcinoma indicates favorable biochemical responses and tolerable levels of toxicity. Additionally short course treatment may produce cost benefit and convenience to patients. PMID- 26028923 TI - Three dimensional quantitative coronary angiography can detect reliably ischemic coronary lesions based on fractional flow reserve. AB - Conventional coronary angiography (CAG) has limitations in evaluating lesions producing ischemia. Three dimensional quantitative coronary angiography (3D-QCA) shows reconstructed images of CAG using computer based algorithm, the Cardio-op B system (Paieon Medical, Rosh Ha'ayin, Israel). The aim of this study was to evaluate whether 3D-QCA can reliably predict ischemia assessed by myocardial fractional flow reserve (FFR) < 0.80. 3D-QCA images were reconstructed from CAG which also were evaluated with FFR to assess ischemia. Minimal luminal diameter (MLD), percent diameter stenosis (%DS), minimal luminal area (MLA), and percent area stenosis (%AS) were obtained. The results of 3D-QCA and FFR were compared. A total of 266 patients was enrolled for the present study. FFR for all lesions ranged from 0.57 to 1.00 (0.85 +/- 0.09). Measurement of MLD, %DS, MLA, and %AS all were significantly correlated with FFR (r = 0.569, 0609, 0.569, 0.670, respectively, all P < 0.001). In lesions with MLA < 4.0 mm(2), %AS of more than 65.5% had a 80% sensitivity and a 83% specificity to predict FFR < 0.80 (area under curve, AUC was 0.878). 3D-QCA can reliably predict coronary lesions producing ischemia and may be used to guide therapeutic approach for coronary artery disease. PMID- 26028924 TI - Prevalence of Spirometrically-defined Restrictive Ventilatory Defect in Korea: The Fourth-2, 3, and Fifth Korean National Health and Nutrition Examination Survey, 2008-2012. AB - The aim of the study was to evaluate the prevalence of restrictive ventilatory defect and to determine the risk factors in subjects with spirometrically-defined restrictive ventilatory defect. We used the population-based, fourth-2, 3 (2008, 2009) and fifth (2010-2012) Korea National Health and Nutrition Examination Survey (KNHANES) to analyze 15,073 subjects, aged >=40 yr who underwent spirometry. Chest radiographs were also analyzed to identify restrictive lung disease. Spirometrically-defined restrictive ventilatory defect (FEV1/FVC>=70% and FVC<80% of mean predicted value) was detected in 11.3% (n= 1,709) of subjects aged >=40 yr. The prevalence increased to 12.3% on using the lower limit of normal (LLN) criteria. Approximately 99.4% of subjects were classified as mild restrictive. Among these, 11.3% had inactive tuberculosis (TB) lesion, 2.2% cardiac disease, 2.0% previous operation scar or radiation injury and/or mediastinal disease, and 7.4% other pulmonary disease suggestive of restrictive lung diseases on chest radiograph. Evidence of previous TB history was independently associated with restrictive ventilatory defect (odds ratios [OR], 1.78; 95% confidence interval, 1.45-2.18) after adjustment for gender, age, smoking, area for residence and body mass index. The prevalence of restrictive ventilatory defect among the nationwide population in Korea was 11.3% with fixed ratio criterion and 12.3% with LLN criterion. Most cases were of the mild restrictive category and previous TB history is the independent risk factor for restrictive ventilatory defect. PMID- 26028925 TI - Acceptability of sputum specimens for diagnosing pulmonary tuberculosis. AB - The evaluation of the quality of a sputum specimen prior to bacterial culture has been an accepted practice. However, optimal sputum criteria for pulmonary tuberculosis (TB) are not well established. We investigated indicators for sputum acceptability in tuberculosis cultures and acid-fast bacilli (AFB) smear. A post hoc analysis of a randomized trial with 228 sputum specimens from 77 patients was conducted. In the trial, pulmonary TB suspects were requested for collecting three sputum specimens. We performed both TB study (AFB smear and M. tuberculosis culture) and Gram staining in each specimen. By using generalized estimating equations, the association between sputum characteristics and positive TB testings were analyzed. Although acceptable specimens for bacterial pneumonia showed higher TB-culture positive rates than unacceptable specimens (adjusted odds ratio [aOR]=1.66; 95% confidence interval [CI]=1.11-2.49), a specimen with >=25 white blood cells/low-power field was the better predictor for positive M. tuberculosis cultures (aOR=2.30; 95% CI=1.48-3.58) and acid-fast bacilli smears (aOR=1.85; 95% CI=1.05-3.25). Sputum leukocytosis could be an indicator of sputum acceptability for diagnosing pulmonary tuberculosis. PMID- 26028926 TI - Effect of airflow limitation on acute exacerbations in patients with destroyed lungs by tuberculosis. AB - History of treatment for tuberculosis (TB) is a risk factor for obstructive lung disease. However, it has been unclear whether the clinical characteristics of patients with destroyed lung by TB differ according to the presence or absence of airflow limitation. The objective of the study was to evaluate differences in acute exacerbations and forced expiratory volume in 1 second (FEV1) decline in patients with destroyed lung by TB according to the presence or absence of airflow limitation. We performed a retrospective cohort study and enrolled patients with destroyed lung by TB. The presence of airflow limitation was defined as FEV1/forced vital capacity (FVC) < 0.7. One hundred and fifty-nine patients were enrolled, and 128 (80.5%) had airflow limitation. The proportion of patients who experienced acute exacerbation was higher in patients with airflow limitation compared to those without (89.1 vs. 67.7%, respectively; P = 0.009). The rate of acute exacerbation was higher in patients with airflow limitation (IRR, 1.19; 95% CI, 1.11-1.27). Low body mass index (X vs. X + 1; HR, 0.944; 95% CI, 0.895-0.996) in addition to airflow limitation (HR, 1.634; 95% CI, 1.012 2.638), was an independent risk factor for acute exacerbation. The annual decline of FEV1 was 2 mL in patients with airflow limitation and 36 mL in those without (P < 0.001). In conclusion, the presence of airflow limitation is an independent risk factor for acute exacerbation in patients with the destroyed lung by TB. PMID- 26028927 TI - Organ Correlation in IgG4-Related Diseases. AB - IgG4-related disease (IgG4-RD) is a potentially multiorgan disorder. In this study, clinical and serological features from 132 IgG4-RD patients were compared about organ correlations. Underlying pathologies comprised autoimmune pancreatitis (AIP) in 85 cases, IgG4-related sclerosing cholangitis (IgG4-SC) in 12, IgG4-related sialadenitis (IgG4-SIA) in 56, IgG4-related dacryoadenitis (IgG4 DAC) in 38, IgG4-related lymphadenopathy (IgG4-LYM) in 20, IgG4-related retroperitoneal fibrosis (IgG4-RF) in 19, IgG4-related kidney disease (IgG4-KD) in 6, IgG4-related pseudotumor (IgG4-PT) in 3. Sixty-five patients (49%) had multiple IgG4-RD (two affected organs in 36 patients, three in 19, four in 8, five in 1, and six in 1). Serum IgG4 levels were significantly higher with multiple lesions than with a single lesion (P<0.001). The proportion of association with other IgG4-RD was 42% in AIP, the lowest of all IgG4-RDs. Serum IgG4 level was lower in AIP than in other IgG4-RDs. Frequently associated IgG4 RDs were SIA (25%) and DAC (12%) for AIP; AIP (75%) for IgG4-SC; DAC (57%), AIP (38%) and LYM (27%) for IgG4-SIA; AIP (26%) and LYM (26%) for IgG4-DAC; SIA (75%), DAC (50%) and AIP (45%) for IgG4-LYM; SIA (58%), AIP (42%) and LYM (32%) for IgG4-RF; AIP (100%) and SIA (67%) for IgG4-KID; and DAC (67%) and SIA (67%) for IgG4-PT. Most associated IgG4-RD lesions were diagnosed simultaneously, but IgG4-SIA and IgG4-DAC were sometimes identified before other lesions. About half of IgG4-RD patients had multiple IgG4-RD lesions, and some associations were seen between specific organs. PMID- 26028928 TI - Helicobacter pylori Eradication for Prevention of Metachronous Recurrence after Endoscopic Resection of Early Gastric Cancer. AB - Controversies persist regarding the effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer (EGC). The aim of this study was to assess the efficacy of Helicobacter pylori eradication after endoscopic resection of EGC for the prevention of metachronous gastric cancer. A systematic literature review and meta-analysis were conducted using the core databases PubMed, EMBASE, and the Cochrane Library. The rates of development of metachronous gastric cancer between the Helicobacter pylori eradication group vs. the non-eradication group were extracted and analyzed using risk ratios (RRs). A random effect model was applied. The methodological quality of the enrolled studies was assessed by the Risk of Bias table and by the Newcastle-Ottawa Scale. Publication bias was evaluated through the funnel plot with trim and fill method, Egger's test, and by the rank correlation test. Ten studies (2 randomized and 8 non-randomized/5,914 patients with EGC or dysplasia) were identified and analyzed. Overall, the Helicobacter pylori eradication group showed a RR of 0.467 (95% CI: 0.362-0.602, P < 0.001) for the development of metachronous gastric cancer after endoscopic resection of EGC. Subgroup analyses showed consistent results. Publication bias was not detected. Helicobacter pylori eradication after endoscopic resection of EGC reduces the occurrence of metachronous gastric cancer. PMID- 26028929 TI - Determination of rifaximin treatment period according to lactulose breath test values in nonconstipated irritable bowel syndrome subjects. AB - Small intestinal bacterial overgrowth (SIBO) can partly explain irritable bowel syndrome (IBS), and rifaximin has been observed to improve abdominal symptoms in nonconstipated IBS patients. However, there are few reports on the association of the rifaximin treatment periods with the results of a lactulose breath test (LBT). Therefore, we performed a retrospective review of patient charts to investigate the relation between the rifaximin treatment periods with LBT results in nonconstipated IBS patients. We also evaluated the time to achieve a symptomatic improvement in the IBS patients as compared to the changes in the LBT. We reviewed the charts for patients who showed IBS symptoms with documented positive results for LBT during their initial visit and who had a follow-up LBT after treatment with rifaximin. The LBT values were compared to the subjects' symptom scores. A total of 102 subjects had a follow-up LBT to assess LBT normalization. The subjects were divided into groups according to treatment periods of 4 weeks (n = 36), 8 weeks (n = 43), and 12 weeks (n = 23). The groups with a longer treatment exhibited an increase in the hydrogen gas value at 90 min and its sum during 90 min at the initial LBT. There were significant differences in hydrogen gas value at 90 min and in its sum during 90 min at the initial LBT between the groups treated for 4 and 12 weeks. The most significant treatment response was observed during the first 4 weeks for all treatment groups. Symptomatic improvement occurred earlier than LBT normalization in the treatment period over 4 weeks. The results indicate that different rifaximin treatment periods are needed in accordance with LBT levels to effectively eradicate SIBO. PMID- 26028930 TI - Relationship between the Clinical Characteristics and Intervention Scores of Infants with Apparent Life-threatening Events. AB - We investigated the clinical presentations, diagnostic and therapeutic modalities, and prognosis from follow-up of infants with apparent life threatening events (ALTE). In addition, the relationship between the clinical characteristics of patients and significant intervention scores was analyzed. We enrolled patients younger than 12 months who were diagnosed with ALTE from January 2005 to December 2012. There were 29 ALTE infants with a peak incidence of age younger than 1 month (48.3%). The most common symptoms for ALTE diagnosis were apnea (69.0%) and color change (58.6%). Eleven patients appeared normal upon arrival at hospital but 2 patients required cardiopulmonary resuscitation during the initial ALTE. The most common ALTE cause was respiratory disease, including respiratory infection and upper airway anomalies (44.8%). There were 20 cases of repeat ALTE and 2 cases of death during hospitalization. Four patients (15.4%) experienced recurrence of ALTE after discharge and 4 patients (15.4%) showed developmental abnormalities during the follow-up period. The patients with ALTE during sleep had lower significant intervention scores (P=0.015) compared to patients with ALTE during wakefulness and patients with previous respiratory symptoms had higher significant intervention scores (P=0.013) than those without previous respiratory symptoms. Although not statistically significant, there was a weak positive correlation between the patient's total ALTE criteria and total significant intervention score (Fig. 2, r=0.330, P=0.080). We recommend that all ALTE infants undergo inpatient observation and evaluations with at least 24 hr of cardiorespiratory monitoring, and should follow up at least within a month after discharge. PMID- 26028931 TI - The Proteomic Analysis of Human Placenta with Pre-eclampsia and Normal Pregnancy. AB - Preeclampsia is one of the most important and complexed disorders for women's health. Searching for novel proteins as biomarkers to reveal pathogenesis, proteomic approaches using 2DE has become a valuable tool to understanding of preeclampsia. To analyze the proteomic profiling of preclamptic placenta compared to that of normal pregnancy for better understanding of pathogenesis in preeclampsia, placentas from each group were handled by use of proteomics approach using 2DE combined with MALDI-TOF-MS. The 20 spots of showing differences were analysed and identified. Among differentially expressed protein spots Hsp 27 and Hsp 70 were selected for validation using Western blot analysis. In preeclamptic placenta 9 differentially expressed proteins were down-regulated with Hsp 70, serum albumin crystal structure chain A, lamin B2, cytokeratin 18, actin cytoplasmic, alpha fibrinogen precursor, septin 2, dihydrolipoamide branched chain transacylase E2 and firbrinogen beta chain. The 11 up-regulated proteins were fibrinogen gamma, cardiac muscle alpha actin proprotein, cytokeratin 8, calumenin, fibrinogen fragment D, F-actin capping protein alpha-1 subunit, Hsp 27, Hsp 40, annexin A4, enoyl-CoA delta isomerase and programmed cell death protein 6. The western blot analysis for validation also showed significant up-regulation of Hsp 27 and down-regulation of Hsp 70 in the placental tissues with preeclmaptic pregnancies. This proteomic profiling of placenta using 2DE in preeclampsia successfully identifies various proteins involved in apoptosis, mitochondrial dysfunction, as well as three Hsps with altered expression, which might play a important role for the understanding of pathogenesis in preeclampsia. PMID- 26028932 TI - Comparison of regional gray matter atrophy, white matter alteration, and glucose metabolism as a predictor of the conversion to Alzheimer's disease in mild cognitive impairment. AB - We compared the predictive ability of the various neuroimaging tools and determined the most cost-effective, non-invasive Alzheimer's disease (AD) prediction model in mild cognitive impairment (MCI) individuals. Thirty-two MCI subjects were evaluated at baseline with [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET), MRI, diffusion tensor imaging (DTI), and neuropsychological tests, and then followed up for 2 yr. After a follow up period, 12 MCI subjects converted to AD (MCIc) and 20 did not (MCInc). Of the voxel-based statistical comparisons of baseline neuroimaging data, the MCIc showed reduced cerebral glucose metabolism (CMgl) in the temporo-parietal, posterior cingulate, precuneus, and frontal regions, and gray matter (GM) density in multiple cortical areas including the frontal, temporal and parietal regions compared to the MCInc, whereas regional fractional anisotropy derived from DTI were not significantly different between the two groups. The MCIc also had lower Mini-Mental State Examination (MMSE) score than the MCInc. Through a series of model selection steps, the MMSE combined with CMgl model was selected as a final model (classification accuracy 93.8%). In conclusion, the combination of MMSE with regional CMgl measurement based on FDG-PET is probably the most efficient, non-invasive method to predict AD in MCI individuals after a two-year follow-up period. PMID- 26028933 TI - Seizure Frequencies and Number of Anti-epileptic Drugs as Risk Factors for Sudden Unexpected Death in Epilepsy. AB - The purpose of this study was to investigate the association between clinical variables and sudden unexpected death in epilepsy (SUDEP) and identify risk factors for SUDEP. SUDEP is one of the most frequent causes of death in patients with epilepsy. Previous studies have reported possible risk factors associated with SUDEP, but there need to be elucidated yet. The cases were 26 patients with SUDEP and three control patients were included for each case, matched for age, sex, and date of initial clinical visit. All demographic and clinical characteristics, including age, sex, disease duration, classification of epilepsy, age at seizure onset, kind and number of antiepileptic drugs, were compared between cases and controls. Seizure frequency was higher in SUDEP cases than in controls (P=0.035). Univariate analysis using conditional logistic regression showed that higher seizure frequency (odds ratio [OR]=3.1, P=0.021) and the number of antiepileptic drugs (AEDs) (OR=2.0, P=0.009) were significantly associated with SUDEP. Only the number of AEDs remained significant in multivariate analysis (OR=1.8, P=0.026). Frequent seizures and multi-drug therapy were associated with SUDEP. This may suggest that the severity of epilepsy is associated with SUDEP, regardless of the type of AED used. PMID- 26028934 TI - A U-shaped Association between Body Mass Index and Psychological Distress on the Multiphasic Personality Inventory: Retrospective Cross-sectional Analysis of 19 year-old Men in Korea. AB - Objective personality tests, such as the Minnesota Multiphasic Personality Inventory (MMPI), might be more sensitive to reflect subclinical personality and be more state-dependent in an individual's lifetime, so they are good scales to predict the psychological distress regarding certain states. The aim of this study was to identify the specific pattern between body mass index (BMI) and psychological distress using the objective personality test. For this study, we investigated BMI and the Korean Military Multiphasic Personality Inventory (MPI). A retrospective cross-sectional study was conducted with 19-yr-old examinees who were admitted to the Military Manpower Administration in Korea from February 2007 to January 2010. Of 1,088,107 examinees, we enrolled 771,408 subjects who were psychologically apparent healthy possible-military-service groups. Afterwards, we reviewed and analyzed directly measured BMI and MPI results. In terms of the validity scales, the faking-good subscale showed an inverted U-shaped association, and faking-bad and infrequency subscales showed a U-shaped association with BMI groups. In terms of the neurosis scales, all clinical subscales (anxiety, depression, somatization, and personality disorder) also showed a U-shaped association with BMI groups. For the psychopath scales, the schizophrenia subscale showed a U-shaped association, and the paranoia subscale showed a near-positive correlation with BMI. In conclusion, a specific U-shaped pattern was observed between BMI and the MPI in 19-yr-old men in Korea. Underweight and obesity are related to psychological distress, so supportive advice and education are needed to them. PMID- 26028935 TI - Shock duration after resuscitation is associated with occurrence of post-cardiac arrest acute kidney injury. AB - This retrospective observational study investigated the clinical course and predisposing factors of acute kidney injury (AKI) developed after cardiac arrest and resuscitation. Eighty-two patients aged over 18 yr who survived more than 24 hr after cardiac arrest were divided into AKI and non-AKI groups according to the diagnostic criteria of the Kidney Disease/Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI. Among 82 patients resuscitated from cardiac arrest, AKI was developed in 66 (80.5%) patients (AKI group) leaving 16 (19.5%) patients in the non-AKI group. Nineteen (28.8%) patients of the AKI group had stage 3 AKI and 7 (10.6%) patients received renal replacement therapy during admission. The duration of shock developed within 24 hr after resuscitation was shorter in the non-AKI group than in the AKI group (OR 1.02, 95% CI 1.01-1.04, P < 0.05). On Multiple logistic regression analysis, the only predisposing factor of post-cardiac arrest AKI was the duration of shock. In conclusion, occurrence and severity of post-cardiac arrest AKI is associated with the duration of shock after resuscitation. Renal replacement therapy is required for patients with severe degree (stage 3) post-cardiac arrest AKI. PMID- 26028936 TI - Treatment Response Evaluation of Breast Cancer after Neoadjuvant Chemotherapy and Usefulness of the Imaging Parameters of MRI and PET/CT. AB - This study was aimed to evaluate the ability of imaging parameters measured on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted MRI (DWI) and positron emission tomography/computed tomography (PET/CT) to serve as response markers in breast cancer after neoadjuvant chemotherapy (NAC). In 20 patients with breast cancer, DCE-MRI and DWI using a 3 T scanner and PET/CT were performed before and after NAC. DCE-MRI was analyzed using an automatic computer-aided detection program (MR-CAD). The response imaging parameters were compared with the pathologic response. The areas under the curve (AUCs) for DCE-MRI using MR-CAD analysis, DWI and PET/CT were 0.77, 0.59 and 0.76, respectively. The combination of all parameters measured by MR-CAD showed the highest diagnostic performance and accuracy (AUC = 0.77, accuracy = 90%). The combined use of the parameters of PET/CT with DCE-MRI or DWI showed a trend toward improved specificity and negative predictive value (100%, 100%, accuracy = 87.5%). The use of DCE-MRI using MR-CAD parameters indicated better diagnostic performance in predicting the final pathological response compared with DWI and PET/CT, although no statistically significant difference was observed. The combined use of PET/CT with DCE-MRI or DWI may improve the specificity for predicting a pathological response. PMID- 26028937 TI - Size Control of (99m)Tc-tin Colloid Using PVP and Buffer Solution for Sentinel Lymph Node Detection. AB - Colloidal particle size is an important characteristic that allows mapping sentinel nodes in lymphoscintigraphy. This investigation aimed to introduce different ways of making a (99m)Tc-tin colloid with a size of tens of nanometers. All agents, tin fluoride, sodium fluoride, poloxamer-188, and polyvinylpyrrolidone (PVP), were mixed and labeled with (99m)Tc. Either phosphate or sodium bicarbonate buffers were used to adjust the pH levels. When the buffers were added, the size of the colloids increased. However, as the PVP continued to increase, the size of the colloids was controlled to within tens of nanometers. In all samples, phosphate buffer added PVP (30 mg) stabilized tin colloid ((99m)Tc-PPTC-30) and sodium bicarbonate solution added PVP (50 mg) stabilized tin colloid ((99m)Tc-BPTC-50) were chosen for in vitro and in vivo studies. (99m)Tc-BPTC-50 (<20 nm) was primarily located in bone marrow and was then secreted through the kidneys, and (99m)Tc-PPTC-30 (>100 nm) mainly accumulated in the liver. When a rabbit was given a toe injection, the node uptake of (99m)Tc PPTC-30 decreased over time, while (99m)Tc-BPTC-50 increased. Therefore, (99m)Tc BPTC-50 could be a good candidate radiopharmaceutical for sentinel node detection. The significance of this study is that nano-sized tin colloid can be made very easily and quickly by PVP. PMID- 26028938 TI - Single center experience of five diffuse panbronchiolitis patients clinically presenting as severe asthma. AB - Diffuse panbronchiolitis (DPB) is a bronchiolitis affecting the whole lung fields which can be treated by macrolide. Especially East Asian patients are more susceptible to diffuse panbronchiolitis. As asthma and DPB both can cause airway obstruction, differential diagnosis is important for the 2 diseases. Here we report 5 patients with DPB clinically presenting as severe asthma in Korea, who were well treated by macrolide. Among the 5 patients, 2 could stop their asthma inhalers and the other 3 could reduce asthma medications after diagnosis and treatment of DPB. In conclusion, considering DPB as differential diagnosis for asthmatics in Asian ethnic groups is important. PMID- 26028939 TI - Scaling up Treatment for Co-morbid Mental Disorders. PMID- 26028940 TI - Financial Incentives to Reviewers: Double-edged Sword. PMID- 26028941 TI - Combined cataract extraction and vitrectomy for macula-sparing retinal detachment: visual outcomes and complications. AB - PURPOSE: To evaluate the visual outcome of combined phacoemulsification, intraocular lens implantation, and vitrectomy for macula-sparing rhegmatogenous retinal detachment. METHODS: The results of combined vitrectomy with cataract extraction were retrospectively analyzed in patients with preexisting cataracts and new-onset rhegmatogenous retinal detachment. To qualify, patients must also have had macular sparing in a region 6,000 um in diameter on optical coherence tomography. The anatomical success rate, visual outcomes, and postoperative complications relating to visual acuity were evaluated. RESULTS: In 56 patients followed postoperatively for more than 12 months, the initial and final surgical success rate was 96.4% and 100%, respectively. The mean preoperative logarithm of the minimum angle of resolution visual acuity was 0.05 and decreased to 0.11 postoperatively (p < 0.001). Of the 56 patients, 20 (35.7%) had worse visual acuity postoperatively, compared with preoperatively (0.06 vs. 0.27, p < 0.001); these cases were comprised of six patients with epiretinal membranes, 12 patients with a posterior capsule opacity, and two patients with cystoid macular edema. In the remaining 36 patients, there were no significant differences in visual acuity preoperatively and postoperatively (0.04 vs. 0.03, p = 0.324). CONCLUSIONS: In patients with cataracts who develop macula-sparing rhegmatogenous retinal detachment and whose visual prognosis is excellent assuming the retina can be reattached successfully, combined phacoemulsification, intraocular lens implantation, and vitrectomy might be an effective treatment. However, the visual prognosis is significantly affected by postoperative complications such as an epiretinal membranes, posterior capsule opacity, and cystoid macular edema. Therefore, further studies should examine methods to prevent these postoperative complications. PMID- 26028942 TI - Demographic features of idiopathic macular telangiectasia in Korean patients. AB - PURPOSE: To investigate the clinical and demographic features of idiopathic macular telangiectasia (MacTel) in Korean patients since the introduction of spectral domain optical coherence tomography (SD-OCT). METHODS: We reviewed medical records of patients who were diagnosed with MacTel from 2009 to 2013. All patients underwent fluorescein angiography and SD-OCT and were classified as type 1 or type 2 according to the classification system proposed by Yannuzzi. RESULTS: Over a period of 5 years, 4 (18.2%) patients were diagnosed with type 1 MacTel and 18 (81.8%) patients were diagnosed with type 2 MacTel. All patients with type1 MacTel were male, and their mean age was 51 +/- 8.6 years. Among patients with type 2 MacTel, 3 (16.7%) were male, 15 (83.3%) were female, and the mean age was 60 +/- 13.6 years. Whereas all type 1 MacTel patients had either metamorphopsia or mild scotoma, of the 18 patients with type 2 MacTel, only 4 (22.2%) had those symptoms, 10 (55.6%) complained of only mild visual impairment, and the other 4 (22.2%) had no symptoms. Intraretinal cystoid spaces were observed in 26 (72.2%) of 36 eyes with type 2 MacTel by SD-OCT. These cystoid spaces had irregular boundaries and did not correspond to angiographic leakages. CONCLUSIONS: Type 2 MacTel was most common in the present study. The wider availability of SD-OCT may have contributed to the diagnosis of type 2 MacTel. Type 2 MacTel may be more prevalent than type 1 in Koreans, which corresponds to the results of Western countries. PMID- 26028944 TI - Simplified correction of ischemic index in diabetic retinopathy evaluated by ultra-widefield fluorescein angiography. AB - PURPOSE: To develop a novel, simplified method for correcting the ischemic index of nonperfused areas in diabetic retinopathy (DR). METHODS: We performed a retrospective review of 103 eyes with naive DR that underwent ultra-widefield angiography (UWFA) over a year. UWFAs were graded according to the quantity of retinal non-perfusion, and uncorrected ischemic index (UII) and corrected ischemic index (CII) were calculated using a simplified, novel method. RESULTS: The average differences between UII and CII in the non-proliferative DR group and the proliferative DR group were 0.7 +/- 0.9% in the <25% CII group, 3.0 +/- 0.9% in the 25% to 49.9% CII group, and 3.6 +/- 0.6% in the >50% CII group, respectively. A CII >25% was critical for determining DR progression (p < 0.001). CONCLUSIONS: Distortion created by UWFA needs to be corrected because the difference between UII and CII in DR increases with the ischemic index. PMID- 26028943 TI - The association between choroidal thickness variations and response to intravitreal bevacizumab in central serous chorioretinopathy. AB - PURPOSE: To analyze differences in the subfoveal choroidal thickness (SFChT) between bevacizumab responders (BevRs) and nonresponders (BevNRs) in patients with idiopathic central serous chorioretinopathy (CSC). METHODS: The medical records of 30 unilateral chronic CSC patients who were treated with intravitreal bevacizumab (IVB) as a first line treatment were reviewed. Patients were categorized as BevNRs when CSC did not completely resolve after a minimum of 3 IVB treatments. Enhanced depth imaging-optical coherence tomography was used and SFChT was measured before and after treatment. Choroidal hyperpermeability was also evaluated using indocyanine angiography. RESULTS: Twenty and 10 eyes were classified as BevRs or BevNRs, respectively. The mean number of IVB treatments was 2.22 +/- 0.89 in BevRs, and 4.80 +/- 1.03 in BevNRs. Compared with BevNRs, BevRs demonstrated significantly greater pretreatment SFChT (441.25 +/- 88.09 vs. 364.10 +/- 61.97 um); SFChT reduction following IVB was significantly greater in BevRs than BevNRs. SFChT in the unaffected eyes was also greater in BevRs than BevNRs. Choroidal hyperpermeability was detected less frequently in BevNRs (hypofluorescence on late-phase, 0.0% and 33.3% in BevNRs and BevRs, respectively; p= 0.049). CONCLUSIONS: Compared with CSC eyes that did not respond well to IVB, BevRs demonstrated significantly thicker SFChT at baseline, greater reduction in SFChT after IVB treatment, and hyperfluorescence on late-phase indocyanine green angiography. We recommend IVB injection as the first-line therapy for CSC eyes with relatively high SFChT and hyperfluorescence on late phase indocyanine green angiography. PMID- 26028945 TI - Relationship between control grade, stereoacuity and surgical success in basic intermittent exotropia. AB - PURPOSE: This study was conducted to identify the relationship between control grade, stereoacuity and surgical success in basic intermittent exotropia. METHODS: This retrospective study involved 44 basic intermittent exotropia patients who underwent strabismus surgery and completed at least 6 months of follow-up. The 44 patients were divided into three subgroups according to their control grade: group 1 (good control group, n = 12), group 2 (fair control group, n = 18), and group 3 (poor control group, n = 14). Evaluation was done to identify the relationships between near and distance stereoacuity and control grade, and between surgical success and control grade. Surgical success was defined as ocular alignment between 5 prism diopters esodeviation and 10 prism diopters exodeviation in the primary position at the final visit. RESULTS: Mean near stereoacuity measured by the graded circle test was 57.50 seconds of arc (seconds) in group 1, 77.77 seconds in group 2, and 131.43 seconds in group 3 (p < 0.01). Mean distance steroacuity measured by Mentor B-VAT II BVS contour circle was 108.33 seconds in group 1, 148.33 seconds in group 2, and 262.82 seconds in group 3 (p < 0.01). Ten patients (83.33%) in group 1, 12 (66.67%) in group 2, and 9 (64.29%) in group 3 obtained surgical success (p = 0.28). CONCLUSIONS: In basic intermittent exotropia, better control grade was significantly accompanied by better stereoacuity. Better control grade was accompanied by higher surgical success rate but with no statistical significance. PMID- 26028946 TI - Comparison of the refractive measurements with hand-held autorefractometer, table mounted autorefractometer and cycloplegic retinoscopy in children. AB - PURPOSE: To evaluate the performance of the hand-held and table-top autorefractokeratometer in measuring refractive errors by comparing them with cycloplegic retinoscopy. METHODS: Included in the study were 112 eyes of 112 pediatric patients whose mean age was 6.78 +/- 2.61 years (range, 2 to 12 years). The refractive errors of all the eyes were measured with and without cycloplegia using a hand held autorefractokeratometer (Retinomax K-plus 3), table top autorefractokeratometer (Canon RK-F1) and performing cycloplegic retinoscopy. The spherical equivalent, cylindrical axis and keratometer values were statistically compared. RESULTS: The mean spherical equivalent obtained from the Retinomax K plus 3 was significantly less hyperopic than that of Canon RK-F1 (p = 0.004) before cycloplegia. When the Bland Altman analysis was performed in comparisons of spherical equivalent values measured with the Retinomax K-plus 3, Canon RK-F1 and cycloplegic retinoscopy, it was seen that almost all of the differences between the measurements remained within the range of +/-2 standard deviation. Good agreement was found between Retinomax K-plus 3 and Canon RK-F1 for the Jackson cross-cylinder values at axis 0 degrees and 45 degrees ; keratometer values respectively. CONCLUSIONS: The refractive error components were highly correlated between the two instruments and cycloplegic retinoscopy. PMID- 26028947 TI - The parameters of pattern visual evoked potential in the severe visual loss patients in Korean. AB - PURPOSE: To compare the characteristics of the pattern visual evoked potential (PVEP) in patients with severe visual loss and normal controls, and to demonstrate the range of PVEP parameters in normal Koreans. METHODS: The patients were divided into three groups according to visual acuity: group 1, ranging from no light perception to less than 0.02; group 2, ranging from 0.02 to 0.1; and group 3, ranging from 0.125 to 0.25. Group 4 was established as a healthy control group. The 95% confidence intervals (CIs) of the PVEP parameters were calculated for group 4. The PVEP parameters were compared among these four groups, and the amplitudes were evaluated with respect to the 95% CIs. We used the area under the curve to integrate the sensitivity and the specificity of the PVEP parameter quantitative values (7.01 to 9.57 uV and 6.75 to 10.11 uV). RESULTS: A total of 101 eyes were investigated. The 95% CIs of the P100 and N135 amplitudes of group 4 were 7.01 to 9.57 uV and 6.75 to 10.11 uV, respectively. The amplitudes of P100 and N135 were significantly higher in group 4 (p < 0.001). The P100 and N135 amplitude were below the 95% CI in all group 1 patients. The area under the curve of the P100 amplitude was the highest (0.789). CONCLUSIONS: No legally blind patient in the present study exhibited a value within the 95% CI of the controls. The P100 amplitude may be the best parameter for defining blindness in patients. PMID- 26028948 TI - Assessment of patient pain experience during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection. AB - PURPOSE: To compare pain scores of patients during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection procedures. METHODS: Seventy eyes of 70 patients who had not previously undergone intravitreal anti-vascular endothelial growth factor therapy were included in this study. Thirty-five patients received ranibizumab and 35 patients received bevacizumab. The diagnoses of the patients were: 27 age related macular degeneration, 15 diabetic macular edema, 9 diabetic vitreous hemorrhage, 6 central retinal vein occlusion, 11 branch retinal vein occlusion and 2 central serous chorioretinopathy. Bevacizumab (1.25 mg/0.05 mL) was injected into the vitreous cavity using a 27-gauge needle, and ranibizumab (0.5 mg/0.05 mL) was injected with 30-gauge needle. Patients were asked just after the injection to rate their perceived pain during the injection using the visual analogue scale (VAS) of 0 (no pain) to 10 (unbearable/worst pain). The average of these scores was used as the primary outcome. RESULTS: The VAS pain scores in the ranibizumab and bevacizumab groups were 1.06 +/- 0.91 (range, 0 to 3) and 1.94 +/- 1.55 (range, 0 to 7), respectively, a significant difference (p = 0.005). Patients <65 and >=65 years of age in both the ranibizumab and bevacizumab groups were then compared. For patients <65, there was a significant difference in the average VAS pain scores between groups (p = 0.003). However, for patients >=65 years, there was not a significant difference in the average VAS pain scores between groups (p = 0.238). Female and male patients in both ranibizumab and bevacizumab groups were also compared. For female patients, there was a significant difference in the average VAS pain scores between groups (p = 0.016), although not for male patients (p = 0.078). CONCLUSIONS: Thirty-gauge intravitreal injection is more comfortable than 27 gauge injection. Injection of bevacizumab with 30-gauge needle syringes may be more tolerable for patients. PMID- 26028950 TI - Pathophysiology of transient corneal edema and pseudophakic cystoid macular edema. PMID- 26028949 TI - Estimation of intraocular lens power calculation after myopic corneal refractive surgery: using corneal height in anterior segment optical coherence tomography. AB - PURPOSE: To investigate the feasibility of estimating effective lens position (ELP) and calculating intraocular lens power using corneal height (CH), as measured using anterior segment optical coherence tomography (AS-OCT), in patients who have undergone corneal refractive surgery. METHODS: This study included 23 patients (30 eyes) who have undergone myopic corneal refractive surgery and subsequent successful cataract surgery. The CH was measured with AS OCT, and the measured ELP (ELPm) was calculated. Intraocular lens power, which could achieve actual emmetropia (Preal), was determined with medical records. Estimated ELP (ELPest) was back-calculated using Preal, axial length, and keratometric value through the SRK/T formula. After searching the best-fit regression formula between ELPm and ELPest, converted ELP and intraocular lens power (ELPconv, Pconv) were obtained and then compared to ELPest and Preal, respectively. The proportion of eyes within a defined error was investigated. RESULTS: Mean CH, ELPest, and ELPm were 3.71 +/- 0.23, 7.74 +/- 1.09, 5.78 +/- 0.26 mm, respectively. The ELPm and ELPest were linearly correlated (ELPest = 1.841 * ELPm - 2.018, p = 0.023, R = 0.410) and ELPconv and Pconv agreed well with ELPest and Preal, respectively. Eyes within +/-0.5, +/-1.0, +/-1.5, and +/ 2.0 diopters of the calculated Pconv, were 23.3%, 66.6%, 83.3%, and 100.0%, respectively. CONCLUSIONS: Intraocular lens power calculation using CH measured with AS-OCT shows comparable accuracy to several conventional methods in eyes following corneal refractive surgery. PMID- 26028951 TI - A case of sympathetic ophthalmia after 23-gauge transconjunctival sutureless vitrectomy. PMID- 26028952 TI - Optic nerve head drusen mimicking optic nerve tumor. PMID- 26028953 TI - Delayed non-arteritic anterior ischemic optic neuropathy following acute primary angle closure. PMID- 26028954 TI - Design and Analysis of a Novel Centrifugal Braking Device for a Mechanical Antilock Braking System. AB - A new concept for a mechanical antilock braking system (ABS) with a centrifugal braking device (CBD), termed a centrifugal ABS (C-ABS), is presented and developed in this paper. This new CBD functions as a brake in which the output braking torque adjusts itself depending on the speed of the output rotation. First, the structure and mechanical models of the entire braking system are introduced and established. Second, a numerical computer program for simulating the operation of the system is developed. The characteristics of the system can be easily identified and can be designed with better performance by using this program to studying the effects of different design parameters. Finally, the difference in the braking performance between the C-ABS and the braking system with or without a traditional ABS is discussed. The simulation results indicate that the C-ABS can prevent the wheel from locking even if excessive operating force is provided while still maintaining acceptable braking performance. PMID- 26028955 TI - The Design of Hand Gestures for Human-Computer Interaction: Lessons from Sign Language Interpreters. AB - The design and selection of 3D modeled hand gestures for human-computer interaction should follow principles of natural language combined with the need to optimize gesture contrast and recognition. The selection should also consider the discomfort and fatigue associated with distinct hand postures and motions, especially for common commands. Sign language interpreters have extensive and unique experience forming hand gestures and many suffer from hand pain while gesturing. Professional sign language interpreters (N=24) rated discomfort for hand gestures associated with 47 characters and words and 33 hand postures. Clear associations of discomfort with hand postures were identified. In a nominal logistic regression model, high discomfort was associated with gestures requiring a flexed wrist, discordant adjacent fingers, or extended fingers. These and other findings should be considered in the design of hand gestures to optimize the relationship between human cognitive and physical processes and computer gesture recognition systems for human-computer input. PMID- 26028956 TI - Emerging Issues and Future Developments in Capsule Endoscopy. AB - Capsule endoscopy (CE) has transformed from a research venture into a widely used clinical tool and the primary means for diagnosing small bowel pathology. These orally administered capsules traverse passively through the gastrointestinal tract via peristalsis and are used in the esophagus, stomach, small bowel, and colon. The primary focus of CE research in recent years has been enabling active CE manipulation and extension of the technology to therapeutic functionality; thus, widening the scope of the procedure. This review outlines clinical standards of the technology as well as recent advances in CE research. Clinical capsule applications are discussed with respect to each portion of the gastrointestinal tract. Promising research efforts are presented with an emphasis on enabling active capsule locomotion. The presented studies suggest, in particular, that the most viable solution for active capsule manipulation is actuation of a capsule via exterior permanent magnet held by a robot. Developing capsule procedures adhering to current healthcare standards, such as enabling a tool channel or irrigation in a therapeutic device, is a vital phase in the adaptation of CE in the clinical setting. PMID- 26028957 TI - Vitrectomy and internal limiting membrane peeling for macular folds secondary to hypotony in myopes. AB - BACKGROUND: Hypotony maculopathy (HM) changes may persist, and visual acuity remains poor, despite normalization of intraocular pressure (IOP). The aim of this study was to evaluate the visual and anatomical results of pars plana vitrectomy (PPV), internal limiting membrane (ILM) peeling, and 20% SF6 gas tamponade in five myopic patients with HM. METHODS: This retrospective interventional study was conducted at the Barraquer Center of Ophthalmology, a tertiary care center in Barcelona, Spain, and included five eyes from five consecutive patients (aged 55.4+/-13.1 years) with HM caused by different conditions. All the patients were treated with 23-gauge PPV, ILM peeling, and 20% SF6 gas tamponade. Preoperative and postoperative evaluation was performed using anterior and posterior biomicroscopy and best corrected visual acuity (BCVA) by logMAR charts. RESULTS: Before surgery, median spherical equivalent was -13.1 (range -7, -19) diopters of myopia. Preoperatively, four cases presented IOP <6.5 mmHg for 3 (range 2-8) weeks. In three of these four cases, IOP >6.5 mmHg was achieved over 16 (range 16-28) weeks, without resolution of HM; increased IOP was not achieved in the remaining case treated 2 weeks after diagnosis of HM. One case presented IOP >6.5 mmHg with HM for 28 weeks before surgery. Preoperative BCVA was 0.7 (range 0.26-2.3) logMAR, and 0.6 (range 0.3-0.7) logMAR and 0.5 (range 0.2-1) logMAR, respectively, at 4 and 12 months after surgery. There was no statistically significant difference between preoperative and postoperative BCVA. Hyper-pigmentation lines in the macular area were observed in three cases with hypotony. These lines progressed after surgery despite resolution of the retinal folds in the three cases, and BCVA decreased in parallel in two of these cases. CONCLUSION: PPV with ILM peeling followed by gas tamponade is a good alternative for the treatment of HM in myopic patients. However, persistent choroidal folds may compromise BCVA. We therefore recommend initiating treatment as early as possible. PMID- 26028958 TI - Clinical utility of 3% diquafosol ophthalmic solution in the treatment of dry eyes. AB - Diquafosol is a drug used for dry eye treatment with a novel mechanism of action. It stimulates the secretion of tear fluid and mucin on the ocular surface, thus enabling us to selectively treat the tear film layer, playing an important role in the establishment of the concept of "Tear Film Oriented Therapy (TFOT)", an effective therapeutic approach to dry eye in Japan. The 3% diquafosol ophthalmic solution has been widely used for the treatment of dry eye in clinical practice, and it is currently available in Japan and South Korea. This review provides an overview of the clinical utility of 3% diquafosol ophthalmic solution, focusing on the results of clinical studies on various types of dry eye, including aqueous deficient dry eye, short tear film breakup time-type dry eye, and post dry eye after laser in situ keratomileusis. It also introduces the additive effect of diquafosol on sodium hyaluronate monotherapy for dry eye, and the effect of 3% diquafosol ophthalmic solution for dry eye-related conditions. Additionally, it summarizes the ocular effects of diquafosol in healthy human eyes. Lastly, the importance of improving tear film stability in dry eye treatment, as well as general advances in dry eye treatments, are described. PMID- 26028959 TI - Pharmacogenetics and nutritional supplementation in age-related macular degeneration. AB - The Age-Related Eye Disease Study (AREDS) recommended treatment with antioxidants plus zinc in patients with intermediate or advanced age-related macular degeneration in order to reduce progression risks. Recent pharmacogenetic studies have reported differences in treatment outcomes with respect to variants in genes for CFH and ARMS2, although the treatment recommendations based on these differences are controversial. Different retrospective analyses of subsets of patients from the same AREDS trial have drawn different conclusions. The practicing clinician, who is not an expert on genetics, clinical trial design, or statistical analysis, may be uncertain how to interpret these results. Based on the balance of the available literature, we suggest not changing established practice recommendations until additional evidence from clinical trials becomes available. PMID- 26028960 TI - Biologic monotherapy in the treatment of rheumatoid arthritis. AB - Biologics, possibly in combination with a conventional disease-modifying antirheumatic drug (DMARD) - preferably methotrexate (MTX), are used in accordance with the recommendations of the international rheumatological societies. However, in clinical practice, this recommendation is often problematic, as many rheumatologists know from personal experience. The quality of life of the patient is affected mainly by drug-induced intolerances (eg, MTX). Thus, the acceptance of the patient to treatment is often so inadequate that a discontinuation of the drug is necessary. In daily practice, approximately 30% of patients with biological therapy receive no concomitant DMARD according to the register data. PMID- 26028961 TI - Construction of interference vector targeting Ep-CAM gene and its effects on colorectal cancer cell proliferation. AB - BACKGROUND: Prior study indicates that abnormal protein expression and functional changes in the development and progression of colorectal cancer is related to gene expression. The aim of this study was to construct an interference plasmid targeting the Ep-CAM gene and to investigate its effects on the proliferation of colorectal cancer cells. METHODS: In this study, HT-29 and HCT-116 colorectal cancer cell lines were selected as cell models. The double-stranded micro (mi)RNA oligo was inserted into the pcDNATM6.2-GW/EmGFPmiR vector, which is an expression of miRNA. LipofectamineTM 2000 was used to transfer plasmid into the empty plasmid group (transfected pcDNATM6.2-GW/EmGFPmiR-neg) and the interference group (transfected pcDNATM6.2-GW/EmGFPmiR-Ep-CAM-1), respectively. Meanwhile, the nontransferred HT-29 and HCT-116 acts as the blank control group. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the transfection efficiency. Western blot was used to detect Ep-CAM protein expression. The cell proliferation in each group was detected by using 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The results indicated that the Ep-CAM messenger (m)RNA expression in the interference group was lower significantly compared with that of the empty plasmid group and control group (P<0.01). Western blot analysis results showed that Ep-CAM protein expression was significantly lower in interference group compared with that of the empty plasmid group and the control group (P<0.01). MTT assay results demonstrated that the proliferation ability of cells in the interference group was significantly inhibited compared with the two other groups (P<0.05). CONCLUSION: Silencing of Ep-CAM can significantly inhibit the proliferation of colorectal cancer cells. PMID- 26028962 TI - A thorough QT study to assess the effects of tbo-filgrastim on cardiac repolarization in healthy subjects. AB - Tbo-filgrastim is a recombinant human granulocyte colony-stimulating factor approved by the US Food and Drug Administration to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. We assessed the effect of tbo-filgrastim on cardiac conduction and repolarization in healthy subjects. A three-arm, parallel-group, active- and placebo-controlled, double-blind study randomized healthy adults to a single 5 MUg/kg intravenous tbo-filgrastim infusion, a single intravenous placebo infusion, or a single 400 mg moxifloxacin oral dose. The primary end point was placebo-corrected time-matched change from baseline in QT interval corrected using a QT individual correction (QTcI) method. Secondary end points included heart rate, PR interval, QRS duration, change in electrocardiogram patterns, correlation between QTcI change from baseline (milliseconds) and tbo-filgrastim serum concentrations, and safety variables. A total of 145 subjects were enrolled (50 tbo-filgrastim, 50 placebo, 45 moxifloxacin). Peak placebo-corrected change from baseline for QTcI with tbo-filgrastim was 3.5 milliseconds, with a two-sided 95% upper confidence interval of 7.2 milliseconds, demonstrating no signal for any tbo-filgrastim effect on QTc. Concentration-effect modeling showed no evidence of an effect of tbo-filgrastim on cardiac repolarization. Tbo-filgrastim produced no clinically significant changes in other electrocardiogram parameters. Tbo-filgrastim was well tolerated. PMID- 26028963 TI - DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers. AB - Currently available scientific evidence erroneously suggests that mutagenic weakness or loss of the BRCA1/2 genes may liberate the proliferative effects of estrogen signaling, which provokes DNA damage and genomic instability. Conversely, BRCA mutation seems to be an imbalanced defect, crudely inhibiting the upregulation of estrogen receptor expression and liganded transcriptional activity, whereas estrogen receptor-repressor functions become predominant. In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes. In turn, BRCA proteins promote estrogen signaling by proper estrogen synthesis via CYP19 gene regulation and by induction of the appropriate expression and transcriptional activity of estrogen receptors. In this exquisitely organized regulatory system, the dysfunction of each player may jeopardize genome stability and lead to severe chronic diseases, such as cancer development. Female organs, such as breast, endometrium, and ovary, exhibiting regular cyclic proliferative activity are particularly vulnerable in case of disturbances in either estrogen signaling or BRCA-mediated DNA repair. BRCA mutation carrier women may apparently be healthy or exhibit clinical signs of deficient estrogen signaling in spite of hyperestrogenism. Even women who enjoy sufficient compensatory DNA-defending activities are at risk of tumor development because many endogenous and environmental factors may jeopardize the mechanisms of extreme compensatory processes. Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers. There are no toxic effects even in sky high doses and all physiologic cellular functions are strongly upregulated, while malignant tumor cells are recognized and killed in a Janus-faced manner. PMID- 26028964 TI - The usefulness of ozone treatment in spinal pain. AB - OBJECTIVE: The aim of this review is to elucidate the biochemical, molecular, immunological, and pharmaceutical mechanisms of action of ozone dissolved in biological fluids. Studies performed during the last two decades allow the drawing of a comprehensive framework for understanding and recommending the integration of ozone therapy for spinal pain. METHODS: An in-depth screening of primary sources of information online - via SciFinder Scholar, Google Scholar, and Scopus databases as well as Embase, PubMed, and the Cochrane Database of Systemic Reviews - was performed. In this review, the most significant papers of the last 25 years are presented and their proposals critically evaluated, regardless of the bibliometric impact of the journals. RESULTS: The efficacy of standard treatments combined with the unique capacity of ozone therapy to reactivate the innate antioxidant system is the key to correcting the oxidative stress typical of chronic inflammatory diseases. Pain pathways and control systems of algesic signals after ozone administration are described. CONCLUSION: This paper finds favors the full insertion of ozone therapy into pharmaceutical sciences, rather than as either an alternative or an esoteric approach. PMID- 26028965 TI - Impact of JAK2(V617F) mutation status on treatment response to anagrelide in essential thrombocythemia: an observational, hypothesis-generating study. AB - A JAK2(V617F) mutation is found in approximately 55% of patients with essential thrombocythemia (ET), and represents a key World Health Organization diagnostic criterion. This hypothesis-generating study (NCT01352585) explored the impact of JAK2(V617F) mutation status on treatment response to anagrelide in patients with ET who were intolerant/refractory to their current cytoreductive therapy. The primary objective was to compare the proportion of JAK2-positive versus JAK2 negative patients who achieved at least a partial platelet response (<=600*10(9)/L) after anagrelide therapy. Of the 47 patients enrolled, 46 were included in the full analysis set (JAK2-positive, n=22; JAK2-negative, n=24). At 12 months, 35 patients (n=14 and n=21, respectively) had a suitable platelet sample; of these, 74.3% (n=26) achieved at least a partial response. The response rate was higher in JAK2-positive (85.7%, n=12) versus JAK2-negative patients (66.7%, n=14) (odds ratio [OR] 3.00; 95% confidence interval [CI] 0.44, 33.97). By using the last observation carried forward approach in the sensitivity analysis, which considered the imbalance in patients with suitable samples between groups, the overall response rate was 71.7% (n=33/46), with 77.3% (n=17/22) of JAK2-positive and 66.7% (n=16/24) of JAK2-negative patients achieving at least a partial response (OR 1.70; 95% CI 0.39, 8.02). There was no significant change in median allele burden over 12 months in the 12 patients who achieved a response. In conclusion, the overall platelet response rate was high in both JAK2-positive and JAK2-negative patients; however, a larger study would be required to confirm the differences observed according to JAK2(V617F) mutation status. PMID- 26028966 TI - Frailty syndrome and self-care ability in elderly patients with heart failure. AB - BACKGROUND: Chronic heart failure is a serious medical condition. Recently, there has been an increasing interest in frailty syndrome and self-care levels among patients with cardiovascular conditions. Demonstrating the influence of frailty syndrome on self-care could improve the quality of self-care and prevent the adverse effects of frailty syndrome. The purpose of this study was to assess the influence of frailty syndrome on the self-care capabilities of patients with chronic heart failure, and to identify factors associated with frailty. METHODS: The data were collected between January and July 2014. The study included 110 patients with chronic heart failure who were hospitalized in the cardiology clinic. Frailty syndrome was assessed using the Tilburg Frailty Indicator, a self report questionnaire, and self-care behavior was assessed using the European Heart Failure Self-Care Behavior Scale. RESULTS: Fifty-four percent of the study patients were male and 46% were female. The mean age was 66+/-11 years, the mean Tilburg Frailty Indicator score was 7.45+/-3.02 points, and the mean self-care level was 27.6+/-7.13 points. Correlation analyses showed that patients with higher scores in the social components of the frailty scale had better self-care capabilities. Frailty was associated with age, education, duration of heart failure, number of hospitalizations, and New York Heart Association class. The effects of these patient characteristics differed across components of frailty (physical, psychological, social). CONCLUSION: The social components of frailty syndrome adversely affect the ability to self-care in elderly patients with heart failure. It is relevant to use a multidimensional measurement of frailty. PMID- 26028967 TI - Clinical, physiological, and radiological features of asthma-chronic obstructive pulmonary disease overlap syndrome. AB - BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is associated with rapid decline in lung function, poorer health-related quality-of-life outcomes, and frequent exacerbations, compared to COPD alone. Although the numbers of patients with ACOS have increased, there is little established evidence regarding diagnostic criteria and treatment options. Thus, the aim of our study was to clarify the clinical, physiological, and radiological features of patients with ACOS. METHODS: We examined a total of 100 patients with COPD and 40 patients with ACOS, who were selected based on clinical criteria. All patients underwent baseline testing, including a COPD assessment test, pulmonary function tests, and multidetector row computed tomography imaging. Percentage of low attenuation volume, percentage of wall area, and percentage of total cross sectional area of pulmonary vessels less than 5 mm(2) (%CSA <5) were determined using multidetector row computed tomography. ACOS patients were administered a fixed dose of budesonide/formoterol (160/4.5 MUg, two inhalations; twice daily) for 12 weeks, after which the ACOS patients underwent multidetector row computed tomography to measure the same parameters. RESULTS: At baseline, the ACOS patients and COPD patients had a similar degree of airflow limitation, vital capacity, and residual volume. ACOS patients had higher COPD assessment test scores, percentage of wall area, and %CSA <5 than COPD patients. Compared to baseline, budesonide/formoterol treatment significantly increased the forced expiratory volume in 1 second and decreased the degree of airway wall thickness (percentage of wall area) as well as pulmonary microvascular density (%CSA <5) in ACOS patients. CONCLUSION: Our results suggest that ACOS is characterized by an airway lesion-dominant phenotype, in contrast to COPD. Higher %CSA <5 might be a characteristic feature of ACOS. PMID- 26028968 TI - Prevalence of colorectal adenomatous polyps in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Colorectal adenomatous polyps are precancerous lesions of colorectal cancer. The aim of this study was to assess the prevalence of colorectal adenomatous polyps in chronic obstructive pulmonary disease (COPD) patients and determine whether COPD is associated with colorectal malignant potential. METHODS: Subjects who had undergone post-bronchodilator spirometry and colonoscopy and were 40 years or older were selected from the hospital database. COPD was defined as a spirometry in which the ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) is <0.7 in post-bronchodilator spirometry. The non-COPD group was matched for both age and sex, and were defined as having an FEV1, FVC, and FEV1/FVC >=0.7 in spirometry. Finally, 333 patients were retrospectively reviewed; of this group, 82 patients had COPD. RESULTS: Among the subjects, 201 patients (60%) were nonsmokers, while 78 (23%) were current smokers. The prevalence of colorectal adenomatous polyps was 39% (98/251) in the non-COPD group and 66% (54/82) in the COPD group. Among 54 patients with adenomatous polyps in the COPD group, 47 had tubular adenoma and seven had villous adenoma. Multiple logistic regression analyses revealed that only COPD patients whom matched to the criteria of COPD by pulmonary function test (odds ratio 2.1, 95% confidence interval: 1.1-3.8; P=0.019) were independently associated with colorectal malignant potential. CONCLUSION: The risk of colorectal malignant potential in the COPD group was higher than in the non-COPD group. We may suggest that COPD patients should consider regular colonoscopic evaluation to screen for premalignant colon polyps regardless of smoking. PMID- 26028969 TI - Factors associated with inadequate diagnosis of COPD: On-Sint cohort analysis. AB - BACKGROUND: The purpose of this study was to evaluate the frequency of inadequate diagnosis and factors predictive of this in patients with chronic obstructive pulmonary disease (COPD) participating in the On-Sint study. METHODS: The On-Sint cohort was recruited for a multicenter observational study in which 356 physicians (71.6% from primary care) included adult patients who had been diagnosed with COPD. Patients' clinical and functional information since diagnosis and details for the recruiting physicians were collected from patient files and at the inclusion visit. We performed a multivariate analysis to evaluate the influence of these variables on diagnostic inadequacy (absence of postbronchodilator forced expiratory volume in one second/forced vital capacity [FEV1/FVC] <0.70 or, if this value was missing, prebronchodilator FEV1/FVC <0.70). RESULTS: In total, 1,214 patients were included in the study. The patients had a mean age of 66.4+/-9.7 years and 78.8% were male. In total, 51.3% of patients did not have an obstructive spirometry performed, and 21.4% had a normal or non-obstructive spirometry pattern. Patient-related factors associated with inadequate diagnosis were: years since diagnosis (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05), number of exacerbations in the previous year (OR 1.01, 95% CI 1.01-1.02), comorbidities (OR 1.05, 95% CI 1.01-1.015), and obesity (OR 1.06, 95% CI 1.02-1.10 per kg/m(2) of body mass index), while a longer smoking history (OR 0.98, 95% CI 0.97-0.99 for each pack/year) and short acting or long-acting bronchodilator therapy (OR 0.61, 95% CI 0.44-0.76 and OR 0.46, 95% CI 0.27-0.76, respectively) were inversely related. With regard to physician-related variables, being followed up by primary care physicians (OR 3.0, 95% CI 2.11-4.34) and in rural centers (OR 1.63, 95% CI 1.12-2.38) were positively associated with an inadequate diagnosis, while having regular follow ups in the most severe cases (OR 0.66, 95% CI 0.46-0.93) and use of quality of life questionnaires (OR 0.55, 95% CI 0.40-0.76) were negatively associated. CONCLUSION: Diagnosis of COPD was inadequate in half of the patients from the On Sint cohort. There were multiple factors, both patient-related and physician related, associated with this misdiagnosis. PMID- 26028970 TI - Enhanced pharmacological activity of vitamin B12 and penicillin as nanoparticles. AB - Sonochemistry has become a well-known technique for fabricating nanomaterials. Since one of the advantages of nanomaterials is that they have higher chemical activities compared with particles in the bulk form, efforts are being made to produce nano organic compounds with enhanced biological activities that could be exploited in the medical area. This study uses the sonication technique to prepare nano Vitamin B12 and nano Penicillin, and demonstrates their enhanced biological and pharmacological activity. The size and morphology of the nano Penicillin and nano Vitamin B12 were investigated using electron microscopy as well as dynamic light scattering techniques. The sizes of Penicillin and Vitamin B12 nanoparticles (NPs) were found to be 70 and 120-180 nm, respectively. The bactericidal effect of nano Penicillin was studied and found to be higher than that of the bulk form. Reducing the size of Vitamin B12 resulted in their enhanced antioxidative activity as observed using the electron paramagnetic spectroscopy technique. The penetration depth of these organic NPs can be detected by an optical iterative method. It is believed that nano organic drugs fabrication will have a great impact on the medical field. PMID- 26028971 TI - Development and molecular characterization of polymeric micro-nanofibrous scaffold of a defined 3-D niche for in vitro chemosensitivity analysis against acute myeloid leukemia cells. AB - Standard in vitro drug testing employs 2-D tissue culture plate systems to test anti-leukemic drugs against cell adhesion-mediated drug-resistant leukemic cells that harbor in 3-D bone marrow microenvironments. This drawback necessitates the fabrication of 3-D scaffolds that have cell adhesion-mediated drug-resistant properties similar to in vivo niches. We therefore aimed at exploiting the known property of polyurethane (PU)/poly-L-lactic acid (PLLA) in forming a micro nanofibrous structure to fabricate unique, not presented before, as far as we are aware, 3-D micro-nanofibrous scaffold composites using a thermally induced phase separation technique. Among the different combinations of PU/PLLA composites generated, the unique PU/PLLA 60:40 composite displayed micro-nanofibrous morphology similar to decellularized bone marrow with increased protein and fibronectin adsorption. Culturing of acute myeloid leukemia (AML) KG1a cells in FN-coated PU/PLLA 60:40 shows increased cell adhesion and cell adhesion-mediated drug resistance to the drugs cytarabine and daunorubicin without changing the original CD34(+)/CD38(-)/CD33(-) phenotype for 168 hours compared to fibronectin tissue culture plate systems. Molecularly, as seen in vivo, increased chemoresistance is associated with the upregulation of anti-apoptotic Bcl2 and the cell cycle regulatory protein p27(Kip1) leading to cell growth arrest. Abrogation of Bcl2 activity by the Bcl2-specific inhibitor ABT 737 led to cell death in the presence of both cytarabine and daunorubicin, demonstrating that the cell adhesion-mediated drug resistance induced by Bcl2 and p27(Kip1) in the scaffold was similar to that seen in vivo. These results thus show the utility of a platform technology, wherein drug testing can be performed before administering to patients without the necessity for stromal cells. PMID- 26028972 TI - Coping strategies, hope, and treatment efficacy in pharmacoresistant inpatients with neurotic spectrum disorders. AB - BACKGROUND: Approximately 30%-60% of patients with neurotic spectrum disorders remain symptomatic despite treatment. Identifying the predictors of good response to psychiatric and psychotherapeutic treatment may be useful for increasing treatment efficacy in neurotic patients. The objective of this study was to investigate the influence of hope, coping strategies, and dissociation on the treatment response of this group of patients. METHODS: Pharmacoresistant patients, who underwent a 6-week psychotherapeutic program, were enrolled in the study. All patients completed the Clinical Global Impression (CGI) - both objective and subjective forms, Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI)-II at baseline and after 6 weeks. The COPE Inventory, the Adult Dispositional Hope Scale (ADHS), and the Dissociative Experiences Scale (DES) were completed at the start of the treatment. RESULTS: Seventy-six patients completed the study. The mean scores for all scales measuring the severity of the disorders (BAI, BDI-II, subjective and objective CGI) significantly decreased during the treatment. Several subscores of the COPE Inventory, the overall score of ADHS, and the overall score of DES significantly correlated with the treatment outcome. Multiple regression was used to find out which factors were the most significant predictors of the therapeutic outcomes. The most important predictors of the treatment response were the overall levels of hope and dissociation. CONCLUSION: According to our results, a group of patients with a primary neurotic disorder, who prefer the use of maladaptive coping strategies, feel hopelessness, and have tendencies to dissociate, showed poor response to treatment. PMID- 26028973 TI - The relationship of psychological trauma with trichotillomania and skin picking. AB - OBJECTIVE: Interactions between psychological, biological and environmental factors are important in development of trichotillomania and skin picking. The aim of this study is to determine the relationship of traumatic life events, symptoms of post-traumatic stress disorder and dissociation in patients with diagnoses of trichotillomania and skin picking disorder. METHODS: The study included patients who was diagnosed with trichotillomania (n=23) or skin picking disorder (n=44), and healthy controls (n=37). Beck Depression Inventory, Traumatic Stress Symptoms Scale and Dissociative Experiences Scale were administered. All groups checked a list of traumatic life events to determine the exposed traumatic events. RESULTS: There was no statistical significance between three groups in terms of Dissociative Experiences Scale scores (P=0.07). But Beck Depression Inventory and Traumatic Stress Symptoms Scale scores of trichotillomania and skin picking groups were significantly higher than the control group. Subjects with a diagnosis of trichotillomania and skin picking reported statistically significantly higher numbers of traumatic and negative events in childhood compared to healthy subjects. CONCLUSION: We can conclude that trauma may play a role in development of both trichotillomania and skin picking. Increased duration of trichotillomania or skin picking was correlated with decreased presence of post-traumatic stress symptoms. The reason for the negatively correlation of severity of post-traumatic stress symptoms and self harming behavior may be speculated as developing trichotillomania or skin picking symptoms helps the patient to cope with intrusive thoughts related to trauma. Future longitudinal research must focus on whether trauma and post-traumatic stress or trichotillomania and skin picking precede the development of mental disorder. PMID- 26028975 TI - Circulating VEGF as a biomarker for diagnosis of ovarian cancer: a systematic review and a meta-analysis. AB - VEGF is a frequently studied angiogenic factor in ovarian cancer (OC), and is considered to have an important role in the progression of OC. However, its diagnostic value has not been widely accepted because the conclusions are inconsistent and even conflicting. Therefore, we performed a meta-analysis to evaluate the diagnostic value of VEGF in OC. A systematic literature search was conducted using the PubMed, Cochrane Library, EMBASE, Chinese National Knowledge Infrastructure, and WANFANG databases for relevant published articles (the last search update was November 18, 2014). The diagnosis sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the summary receiver operating characteristic curves were pooled by Meta DiSc 1.4 software. A total of ten studies with 1,131 subjects were finally included in this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and summary receiver operating characteristic curves were 0.67 (0.63-0.73), 0.78 (0.75-0.81), 3.08 (6.36-12.22), 0.39 (0.29-0.51), 9.10 (5.43-45.25), and 0.8175, respectively. Furthermore, to explore the sources of heterogeneity, we conducted subgroup analyses based on ethnicity and sample size. The diagnostic accuracy of VEGF was higher in an Asian population than in a Caucasian population. A similar finding was found in subgroups with the smaller sample size (<100 subjects). In conclusion, the present meta-analysis suggests that VEGF has moderate diagnostic accuracy for OC. Considering our limitations and the heterogeneity among our selected studies, larger, well-designed prospective and multicenter validation studies are needed to evaluate the diagnostic value of serum VEGF for OC. PMID- 26028974 TI - Optimal management of constipation associated with irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a common chronic functional disorder of the gastrointestinal tract, meanly characterized by recurrent abdominal pain or discomfort and altered bowel habit. It is a complex disorder involving biological, environmental, and psychosocial factors. The diagnosis is achieved according to the Rome III criteria provided that organic causes have been excluded. Although IBS does not constitute a life-threatening condition, it has a remarkable prevalence and profoundly reduces the quality of life with burdening socioeconomic costs. One of the principal concerns about IBS is the lack of effective therapeutic options. Up to 40% of patients are not satisfied with any available medications, especially those suffering from chronic constipation. A correct management of IBS with constipation should evolve through a global approach focused on the patient, starting with careful history taking in order to assess the presence of organic diseases that might trigger the disorder. Therefore, the second step is to examine lifestyle, dietary habits, and psychological status. On these bases, a step-up management of disease is recommended: from fiber and bulking agents, to osmotic laxative drugs, to new molecules like lubiprostone and linaclotide. Although new promising tools for relief of bowel-movement-related symptoms are being discovered, a dedicated doctor-patient relationship still seems to be the key for success. PMID- 26028976 TI - Bronchial thermoplasty in asthma: current perspectives. AB - Bronchial thermoplasty (BT) is a novel therapy for patients with severe asthma. Using radio frequency thermal energy, it aims to reduce the airway smooth muscle mass. Several clinical trials have demonstrated improvements in asthma-related quality of life and a reduction in the number of exacerbations following treatment with BT. In addition, recent data has demonstrated the long-term safety of the procedure as well as sustained improvements in rates of asthma exacerbations, reduction in health care utilization, and improved quality of life. Further study is needed to elucidate the underlying mechanisms that result in these improvements. In addition, improved characterization of the asthma subphenotypes likely to exhibit the largest clinical benefit is a critical step in determining the precise role of BT in the management of severe asthma. PMID- 26028977 TI - Chronic Lyme disease: misconceptions and challenges for patient management. AB - Lyme disease, infection with the tick-borne spirochete Borrelia burgdorferi, causes both specific and nonspecific symptoms. In untreated chronic infection, specific manifestations such as a relapsing large-joint oligoarthritis can persist for years, yet subside with appropriate antimicrobial therapy. Nervous system involvement occurs in 10%-15% of untreated patients and typically involves lymphocytic meningitis, cranial neuritis, and/or mononeuritis multiplex; in some rare cases, patients have parenchymal inflammation in the brain or spinal cord. Nervous system infection is similarly highly responsive to antimicrobial therapy, including oral doxycycline. Nonspecific symptoms such as fatigue, perceived cognitive slowing, headache, and others occur in patients with Lyme disease and are indistinguishable from comparable symptoms occurring in innumerable other inflammatory states. There is no evidence that these nonspecific symptoms reflect nervous system infection or damage, or that they are in any way specific to or diagnostic of this or other tick-borne infections. When these symptoms occur in patients with Lyme disease, they typically also subside after antimicrobial treatment, although this may take time. Chronic fatigue states have been reported to occur following any number of infections, including Lyme disease. The mechanism underlying this association is unclear, although there is no evidence in any of these infections that these chronic posttreatment symptoms are attributable to ongoing infection with B. burgdorferi or any other identified organism. Available appropriately controlled studies indicate that additional or prolonged courses of antimicrobial therapy do not benefit patients with a chronic fatigue-like state after appropriately treated Lyme disease. PMID- 26028979 TI - Factors affecting acceptance of provider-initiated HIV testing and counseling services among outpatient clients in selected health facilities in Harar Town, Eastern Ethiopia. AB - PURPOSE: To improve the slow uptake of HIV counseling and testing, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed draft guidelines on provider-initiated testing and counseling (PITC). Both in low- and high-income countries, mainly from outpatient clinics and tuberculosis settings, indicates that the direct offer of HIV testing by health providers can result in significant improvements in test uptake. In Ethiopia, there were limited numbers of studies conducted regarding PITC in outpatient clinics. Therefore, in this study, we have assessed the factors affecting the acceptance of PITC among outpatient clients in selected health facilities in Harar, Harari Region State, Ethiopia. MATERIALS AND METHODS: Institutional-based, cross-sectional quantitative and qualitative studies were conducted from February 12-30, 2011 in selected health facilities in Harar town, Harari Region State, Ethiopia. The study participants were recruited from the selected health facilities of Harar using a systematic random sampling technique. The collected data were double entered into a data entry file using Epi Info version 3.5.1. The data were transferred to SPSS software version 16 and analyzed according to the different variables. RESULTS: A total of 362 (70.6%) clients accepted PITC, and only 39.4% of clients had heard of PITC in the outpatient department service. Age, occupation, marital status, anyone who wanted to check their HIV status, and the importance of PITC were the variables that showed significant associations with the acceptance of PITC upon bivariate and multivariate analyses. The main reasons given for not accepting the tests were self-trust, not being at risk for HIV, not being ready, needing to consult their partners, a fear of the results, a shortage of staff, a busy work environment, a lack of private rooms, and a lack of refresher training, which were identified as the main barriers for PITC. CONCLUSION: There is evidence of the relatively increased acceptability of PITC services by outpatient department clients. A program needs to be strengthened to enhance the use of PITC; the Ministry of Health, Regional Health Bureau, and other responsible bodies - including health facilities - should design and strengthen information education and communication/behavioral change and communication interventions and promote activities related to PITC and HIV counseling and testing in both health facilities and the community at large. PMID- 26028978 TI - PI3K mutations in breast cancer: prognostic and therapeutic implications. AB - The PI3K pathway is the most frequently enhanced oncogenic pathway in breast cancer. Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (~30%) observed, along with protein loss of PTEN. Since the first discovery of PIK3CA mutations in solid malignancies in 2004, numerous studies have revealed the prognostic and therapeutic implications of these mutations. Although many issues remain unconfirmed, some have been carved in stone by the level of consistency they have shown among studies: 1) PIK3CA mutations are most likely to be observed in ER-positive/HER2-negative tumors, and are associated with other good prognostic characters; 2) PIK3CA mutations can coexist with other PI3K-enhancing mechanisms, such as HER2 amplification and PTEN protein loss; 3) PIK3CA mutations are potentially a good prognostic marker; 4) PIK3CA may predict a poorer tumor response to trastuzumab-based therapies, but its impact on disease free survival and overall survival is uncertain; and 5) based on reports of early clinical trials, PIK3CA mutations do not guarantee a dramatic response to PI3K inhibitors. Collectively, there is currently no sufficient evidence to recommend routine genotyping of PIK3CA in clinical practice. Given that PIK3CA-mutant breast cancer appears to have a distinct tumor biology, development of more individualized targeted therapies based on the PIK3CA genotype is awaited. PMID- 26028980 TI - Older people's perspectives on an elderly-friendly hospital environment: an exploratory study. AB - BACKGROUND: Many older people are vulnerable with multiple health problems and need of extensive care and support for quality of life. The main objective of this study was to explore the older people's perspectives on an "elderly friendly" hospital. METHODS: Hospital was stratified by four domains including government, semi-government, community, and private. We interviewed 33 hospitalized older patients and four hospital managers between June and December 2014 in Kathmandu, Nepal, using purposive sampling technique. We executed a qualitative content analysis step with extensive review of the interviews. Final name of the theme was given after the agreement between the research team and experts to improve trustworthiness. Elderly-friendly services, expectation from government and hospital, and health policy related to senior citizen were developed as main themes. RESULTS: Most of the participants were satisfied with the behavior of health personnel. However, none of the health personnel were trained with geriatric health care. Elderly-friendly hospital guidelines and policy were not developed by any hospitals. Older people health card, advocacy for older people's health and benefit, and hospital environment were the common expectations of older patients. Government policy and budget constraint were the main obstacles to promote elderly-friendly health care services. CONCLUSION: Elderly-related health policies, physical environments of hospital, elderly friendly health manpower, advocacy, and other facilities and benefits should be improved and developed. There are urgent needs to develop elderly-friendly hospital policies and guidelines that focus on older people's health benefits and friendly services. PMID- 26028981 TI - Understanding and perceptions of final-year Doctor of Pharmacy students about generic medicines in Karachi, Pakistan: a quantitative insight. AB - GENERAL OBJECTIVE: To evaluate the understanding and perceptions of generic medicines among final-year Doctor of Pharmacy students in Karachi, Pakistan. METHODS: A 23-item survey instrument that included a question on the bioequivalence limits and Likert-type scale questions regarding the understanding and perceptions of generic medicines among the students was executed. Cronbach's alpha was found to be 0.62. RESULTS: Responses were obtained from 236 final-year Doctor of Pharmacy students (n=85 from a publicly funded institute; n=151 from a privately funded institute). When comparing a brand-name medicine to a generic medicine, pharmacy students scored poorly on bioequivalence limits. More than 80% of the students incorrectly answered that all the products that are rated as generic equivalents are therapeutically equivalent to each other (P<0.04). Half of the students agreed that a generic medicine is bioequivalent to the brand-name medicine (P<0.001). With regard to quality, effectiveness, and safety, more than 75% of the students disagreed that generic medicines are of inferior quality and are less effective than brand-name medicines (P<0.001). More than 50% of the students disagreed that generic medicines produce more side effects than brand name medicines (P<0.001). CONCLUSION: The current study identified a positive perception toward generic medicines but also gaps in the understanding of generic medicines. Pharmacy students lacked a thorough understanding of the concepts of bioequivalence. Pharmacy academia should address these issues, which will help build confidence in generic medicines and increase the generic medicine use in Pakistan. PMID- 26028982 TI - Diversity of United States medical students by region compared to US census data. AB - PURPOSE: Increasing the diversity of the United States (US) physician workforce to better represent the general population has received considerable attention. The purpose of this study was to compare medical student race data to that of the US general population. We hypothesized that race demographics of medical school matriculants would reflect that of the general population. PATIENTS AND METHODS: Published race data from the United States Census Bureau (USCB) 2010 census and the 2011 Association of American Medical Colleges (AAMC) allopathic medical school application and enrollment by race and ethnicity survey were analyzed and compared. Race data of enrolled medical students was compared to race data of the general population within geographic regions and subregions. Additionally, race data of medical school applicants and matriculants were compared to race data of the overall general population. RESULTS: Race distribution within US medical schools was significantly different than race distribution for the overall, regional, and subregional populations of the US (P<0.001). Additionally, the overall race distribution of medical school applicants differed significantly to the race distribution of the general population (P<0.001). CONCLUSION: This study demonstrated that race demographics of US medical school applicants and matriculants are significantly different from that of the general population, and may be resultant of societal quandaries present early in formal education. Initiatives targeting underrepresented minorities at an early stage to enhance health care career interest and provide academic support and mentorship will be required to address the racial disparity that exists in US medical schools and ultimately the physician workforce. PMID- 26028983 TI - Exploratory ensemble designs for environmental models using k-extended Latin Hypercubes. AB - In this paper we present a novel, flexible, and multi-purpose class of designs for initial exploration of the parameter spaces of computer models, such as those used to study many features of the environment. The idea applies existing technology aimed at expanding a Latin Hypercube (LHC) in order to generate initial LHC designs that are composed of many smaller LHCs. The resulting design and its component parts are designed so that each is approximately orthogonal and maximises a measure of coverage of the parameter space. Designs of the type advocated for in this paper are particularly useful when we want to simultaneously quantify parametric uncertainty and any uncertainty due to the initial conditions, boundary conditions, or forcing functions required to run the model. This makes the class of designs particularly suited to environmental models, such as climate models that contain all of these features. The proposed designs are particularly suited to initial exploratory ensembles whose goal is to guide the design of further ensembles aimed at, for example, calibrating the model. We introduce a new emulator diagnostic that exploits the structure of the advocated ensemble designs and allows for the assessment of structural weaknesses in the statistical modelling. We provide illustrations of the method through a simple example and describe a 400 member ensemble of the Nucleus for European Modelling of the Ocean (NEMO) ocean model designed using the method. We build an emulator for NEMO using the created design to illustrate the use of our emulator diagnostic test. (c) 2015 The Authors. Environmetrics published by John Wiley & Sons Ltd. PMID- 26028984 TI - Visual perceptual learning by operant conditioning training follows rules of contingency. AB - Visual perceptual learning (VPL) can occur as a result of a repetitive stimulus reward pairing in the absence of any task. This suggests that rules that guide Conditioning, such as stimulus-reward contingency (e.g. that stimulus predicts the likelihood of reward), may also guide the formation of VPL. To address this question, we trained subjects with an operant conditioning task in which there were contingencies between the response to one of three orientations and the presence of reward. Results showed that VPL only occurred for positive contingencies, but not for neutral or negative contingencies. These results suggest that the formation of VPL is influenced by similar rules that guide the process of Conditioning. PMID- 26028985 TI - Economic correlates of violent death rates in forty countries, 1962-2008: A cross typological analysis. AB - OBJECTIVES: Our goal was to identify if there might be advantages to combining two major public health concerns, i.e., homicides and suicides, in an analysis with well-established macro-level economic determinants, i.e., unemployment and inequality. METHODS: Mortality data, unemployment statistics, and inequality measures were obtained for 40 countries for the years 1962-2008. Rates of combined homicide and suicide, ratio of suicide to combined violent death, and ratio between homicide and suicide were graphed and analyzed. A fixed effects regression model was then performed for unemployment rates and Gini coefficients on homicide, suicide, and combined death rates. RESULTS: For a majority of nation states, suicide comprised a substantial proportion (mean 75.51%; range 0-99%) of the combined rate of homicide and suicide. When combined, a small but significant relationship emerged between logged Gini coefficient and combined death rates (0.0066, p < 0.05), suggesting that the combined rate improves the ability to detect a significant relationship when compared to either rate measurement alone. Results were duplicated by age group, whereby combining death rates into a single measure improved statistical power, provided that the association was strong. CONCLUSIONS: Violent deaths, when combined, were associated with an increase in unemployment and an increase in Gini coefficient, creating a more robust variable. As the effects of macro-level factors (e.g., social and economic policies) on violent death rates in a population are shown to be more significant than those of micro-level influences (e.g., individual characteristics), these associations may be useful to discover. An expansion of socioeconomic variables and the inclusion of other forms of violence in future research could help elucidate long-term trends. PMID- 26028986 TI - Identification of quantitative trait loci underlying resistance to southern root knot and reniform nematodes in soybean accession PI 567516C. AB - Soybean cyst nematode (SCN, Heterodera glycine Ichinohe), southern root-knot nematode [SRKN, Meloidogyne incognita (Kofoid and White) Chitwood] and reniform nematode (RN, Rotylenchulus reniformis Linford and Oliveira) are three important plant-parasitic pests in soybean. Previous study showed that plant introduction (PI) 567516C harbored novel quantitative trait loci (QTL) conferring SCN resistance to soybean. However, QTL underlying resistance to SRKN and RN in PI 567516C remain unknown. The objectives of this study were to identify QTL for resistance to SRKN and RN in PI 567516C. Two hundred and forty-seven F6:9 recombinant inbred lines, derived from a cross between cultivar Magellan and PI 567516C, were evaluated for resistance to SRKN and RN. Two hundred and thirty eight simple sequence repeats and 687 single nucleotide polymorphism markers were used to construct a genetic linkage map. Three significant QTL associated with resistance to SRKN were mapped on chromosomes (Chrs.) 10, 13 and 17. Two significant QTL associated with resistance to RN were detected on Chrs. 11 and 18. Whole-genome resequencing revealed that there might be Peking-type Rhg1 in PI 567516C. Our study provides useful information to employ PI 567516C in soybean breeding in order to develop new cultivars with resistance to multiple nematodes. PMID- 26028987 TI - Assessing the genetic variation of Ty-1 and Ty-3 alleles conferring resistance to tomato yellow leaf curl virus in a broad tomato germplasm. AB - Tomato yellow leaf curl virus (TYLCV) hampers tomato production worldwide. Our previous studies have focussed on mapping and ultimately cloning of the TYLCV resistance genes Ty-1 and Ty-3. Both genes are derived from Solanum chilense and were shown to be allelic. They code for an RNA-dependent RNA polymerase (RDR) belonging to the RDRgamma type defined by a DFDGD catalytic domain. In this study, we first fine-mapped the TYLCV resistance in S. chilense LA1932, LA1960 and LA1971. Results showed that chromosomal intervals of the causal genes in these TYLCV-resistant accessions overlap and cover the region where Ty-1/Ty-3 is located. Further, virus-induced gene silencing was used to silence Ty-1/Ty-3 in tomato lines carrying TYLCV resistance introgressed from S. chilense LA1932, LA1938 and LA1971. Results showed that silencing Ty-1/Ty-3 compromised the resistance in lines derived from S. chilense LA1932 and LA1938. The LA1971 derived material remained resistant upon silencing Ty-1/Ty-3. Further, we studied the allelic variation of the Ty-1/Ty-3 gene by examining cDNA sequences from nine S. chilense-derived lines/accessions and more than 80 tomato cultivars, landraces and accessions of related wild species. The DFDGD catalytic domain of the Ty-1/Ty 3 gene is conserved among all tomato lines and species analysed. In addition, the 12 base pair insertion at the 5-prime part of the Ty-1/Ty-3 gene was found not to be specific for the TYLCV resistance allele. However, compared with the susceptible ty-1 allele, the Ty-1/Ty-3 allele is characterized by three specific amino acids shared by seven TYLCV-resistant S. chilense accessions or derived lines. Thus, Ty-1/Ty-3-specific markers can be developed based on these polymorphisms. Elevated transcript levels were observed for all tested S. chilenseRDR alleles (both Ty-1 and ty-1 alleles), demonstrating that elevated expression level is not a good selection criterion for a functional Ty-1/Ty-3 allele. PMID- 26028988 TI - Increasing Fragmentation of Disulfide-Bonded Proteins for Top-Down Mass Spectrometry by Supercharging. AB - The disulfide bond is an important post-translational modification to form and maintain the native structure and biological functions of proteins. Characterization of disulfide bond linkages is therefore of essential interest in the structural elucidation of proteins. Top-down mass spectrometry (MS) of disulfide-bonded proteins has been hindered by relatively low sequence coverage due to disulfide cross-linking. In this study, we employed top-down ESI-MS with Fourier-transform ion cyclotron resonance (FT-ICR) MS with electron capture dissociation (ECD) and collisionally activated dissociation (CAD) to study the fragmentation of supercharged proteins with multiple intramolecular disulfide bonds. With charge enhancement upon the addition of sulfolane to the analyte solution, improved protein fragmentation and disulfide bond cleavage efficiency was observed for proteins including bovine beta-lactoglobulin, soybean trypsin inhibitor, human proinsulin, and chicken lysozyme. Both the number and relative abundances of product ions representing disulfide cleavage increase with increasing charge states for the proteins studied. Our studies suggest supercharging ESI-MS is a promising tool to aid in the top-down MS analysis of disulfide-bonded proteins, providing potentially useful information for the determination of disulfide bond linkages. PMID- 26028989 TI - Bioavailability and biodistribution of differently charged polystyrene nanoparticles upon oral exposure in rats. AB - The likelihood of oral exposure to nanoparticles (NPs) is increasing, and it is necessary to evaluate the oral bioavailability of NPs. In vitro approaches could help reducing animal studies, but validation against in vivo studies is essential. Previously, we assessed the translocation of 50 nm polystyrene NPs of different charges (neutral, positive and negative) using a Caco-2/HT29-MTX in vitro intestinal translocation model. The NPs translocated in a surface charge dependent manner. The present study aimed to validate this in vitro intestinal model by an in vivo study. For this, rats were orally exposed to a single dose of these polystyrene NPs and the uptake in organs was determined. A negatively charged NP was taken up more than other NPs, with the highest amounts in kidney (37.4 ug/g tissue), heart (52.8 ug/g tissue), stomach wall (98.3 ug/g tissue) and small intestinal wall (94.4 ug/g tissue). This partly confirms our in vitro findings, where the same NPs translocated to the highest extent. The estimated bioavailability of different types of NPs ranged from 0.2 to 1.7 % in vivo, which was much lower than in vitro (1.6-12.3 %). Therefore, the integrated in vitro model cannot be used for a direct prediction of the bioavailability of orally administered NPs. However, the model can be used for prioritizing NPs before further in vivo testing for risk assessment. PMID- 26028990 TI - Influence of the filler on thermal properties of porous VP-TRIM copolymers. AB - In this paper, the synthesis and characterization of thermal properties of porous copolymers 1-vinyl-2-pyrrolidone with trimethylolpropane trimethacrylate are presented. They were obtained by suspension polymerization as a pure polymers or composite materials with different inorganic fillers. The influence of the type of filler on the textural and thermal properties was investigated in details. It was found that the value of the porous surface area of composites is much lower than in the case of pure copolymers. Thermal properties of the obtained materials were investigated by the means of thermogravimetry and differential scanning calorimetry. PMID- 26028991 TI - Biomineralisation by earthworms - an investigation into the stability and distribution of amorphous calcium carbonate. AB - BACKGROUND: Many biominerals form from amorphous calcium carbonate (ACC), but this phase is highly unstable when synthesised in its pure form inorganically. Several species of earthworm secrete calcium carbonate granules which contain highly stable ACC. We analysed the milky fluid from which granules form and solid granules for amino acid (by liquid chromatography) and functional group (by Fourier transform infrared (FTIR) spectroscopy) compositions. Granule elemental composition was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES) and electron microprobe analysis (EMPA). Mass of ACC present in solid granules was quantified using FTIR and compared to granule elemental and amino acid compositions. Bulk analysis of granules was of powdered bulk material. Spatially resolved analysis was of thin sections of granules using synchrotron-based MU-FTIR and EMPA electron microprobe analysis. RESULTS: The milky fluid from which granules form is amino acid-rich (<= 136 +/- 3 nmol mg-1 (n = 3; +/- std dev) per individual amino acid); the CaCO3 phase present is ACC. Even four years after production, granules contain ACC. No correlation exists between mass of ACC present and granule elemental composition. Granule amino acid concentrations correlate well with ACC content (r >= 0.7, p <= 0.05) consistent with a role for amino acids (or the proteins they make up) in ACC stabilisation. Intra-granule variation in ACC (RSD = 16%) and amino acid concentration (RSD = 22 35%) was high for granules produced by the same earthworm. Maps of ACC distribution produced using synchrotron-based MU-FTIR mapping of granule thin sections and the relative intensity of the nu2: nu4 peak ratio, cluster analysis and component regression using ACC and calcite standards showed similar spatial distributions of likely ACC-rich and calcite-rich areas. We could not identify organic peaks in the MU-FTIR spectra and thus could not determine whether ACC rich domains also had relatively high amino acid concentrations. No correlation exists between ACC distribution and elemental concentrations determined by EMPA. CONCLUSIONS: ACC present in earthworm CaCO3 granules is highly stable. Our results suggest a role for amino acids (or proteins) in this stability. We see no evidence for stabilisation of ACC by incorporation of inorganic components. Graphical abstractSynchrotron-based MU-FTIR mapping was used to determine the spatial distribution of amorphous calcium carbonate in earthworm-produced CaCO3 granules. PMID- 26028992 TI - Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma. AB - BACKGROUND: Adenocarcinoma of the periampullary region is associated with poor prognosis and new prognostic and treatment predictive biomarkers are needed for improved treatment. Membranous expression of podocalyxin-like 1(PODXL), which is a cell-adhesion glycoprotein and stem cell marker, has been found to correlate with an aggressive tumour phenotype and adverse outcome in several cancer types. The aim of the present study was to examine the clinicopathological correlates, prognostic and predictive significance of tumour-specific PODXL expression in a retrospective cohort of pancreatic and periampullary carcinoma, morphologically divided into intestinal type (I-type) and pancreatobiliary type (PB-type) tumours. METHODS: Immunohistochemical expression of PODXL was analysed in tissue microarrays with primary tumours and a subset of paired lymph node metastases from 175 patients operated with pancreaticoduodenectomy for periampullary adenocarcinoma. Chi square test was applied to analyse the relationship between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox regression models were applied to estimate differences in 5-year overall survival (OS) and recurrence-free survival (RFS) in strata according to membranous and non-membranous PODXL expression. RESULTS: Membranous PODXL expression was significantly higher in primary PB-type (49.5 %) as compared with I-type (17.5 %) tumours. In PB-type tumours, PODXL expression was significantly associated with female sex (p = 0.005), location to the pancreas (p = 0.005), and poor differentiation grade (p = 0.044). Membranous PODXL expression was significantly associated with a reduced RFS (HR = 2.44, 95 % CI 1.10-5.44) and OS (HR = 2.32, 95 % CI 1.05-5.12) in I-type tumours and with a reduced RFS (HR = 1.63, 95 % CI 1.07-2.49) but not OS in PB-type tumours. PODXL remained a significant independent prognostic factor only in I-type tumours (HR = 5.12, 95 % CI 1.43-18.31 for RFS and HR = 7.31, 95 % CI 2.12-25.16 for OS). Patients with I type tumours displaying membranous PODXL expression had a significant beneficial effect of adjuvant chemotherapy regarding 5-year OS. CONCLUSION: Membranous expression of PODXL is significantly higher in PB-type than in I-type periampullary adenocarcinomas and an independent factor of poor prognosis in the latter. The results further indicate a beneficial effect of adjuvant chemotherapy on I-type tumours with membranous PODXL expression, suggesting the potential utility of PODXL as a biomarker for improved treatment stratification of these patients. PMID- 26028993 TI - EXPLORING FUNCTIONAL CONNECTIVITY IN FMRI VIA CLUSTERING. AB - In this paper we investigate the use of data driven clustering methods for functional connectivity analysis in fMRI. In particular, we consider the K-Means and Spectral Clustering algorithms as alternatives to the commonly used Seed Based Analysis. To enable clustering of the entire brain volume, we use the Nystrom Method to approximate the necessary spectral decompositions. We apply K Means, Spectral Clustering and Seed-Based Analysis to resting-state fMRI data collected from 45 healthy young adults. Without placing any a priori constraints, both clustering methods yield partitions that are associated with brain systems previously identified via Seed-Based Analysis. Our empirical results suggest that clustering provides a valuable tool for functional connectivity analysis. PMID- 26028994 TI - Using the 4Kscore Test and Magnetic Resonance Imaging Results to Avoid Unnecessary Prostate Biopsy. PMID- 26028995 TI - Finding the Wolf in Sheep's Clothing: The 4Kscore Is a Novel Blood Test That Can Accurately Identify the Risk of Aggressive Prostate Cancer. AB - Better biomarkers that can discriminate between aggressive and indolent phenotypes of prostate cancer are urgently needed. In the first 20 years of the prostate-specific antigen (PSA) era, screening for prostate cancer has successfully reduced prostate cancer mortality, but has led to significant problems with overdiagnosis and overtreatment. As a result, many men are subjected to unnecessary prostate biopsies and overtreatment of indolent cancer in order to save one man from dying of prostate cancer. A novel blood test known as the 4Kscore(r) Test (OPKO Lab, Nashville, TN) incorporates a panel of four kallikrein protein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2) and other clinical information in an algorithm that provides a percent risk for a high-grade (Gleason score >= 7) cancer on biopsy. In 10 peer-reviewed publications, the four kallikrein biomarkers and algorithm of the 4Kscore Test have been shown to improve the prediction not only of biopsy histopathology, but also surgical pathology and occurrence of aggressive, metastatic disease. Recently, a blinded prospective trial of the 4Kscore Test was conducted across the United States among 1012 men. The 4Kscore Test replicated previous European results showing accuracy in predicting biopsy outcome of Gleason score >= 7. In a recent case-control study nested within a population-based cohort from Vasterbotten, Sweden, the four kallikrein biomarkers of the 4Kscore Test also predicted the risk for aggressive prostate cancer that metastasized within 20 years after the test was administered. These results indicate that men with an abnormal PSA or digital rectal examination result, and for whom an initial or repeat prostate biopsy is being considered, would benefit from a reflex 4Kscore Test to add important information to the clinical decision making process. A high-risk 4Kscore Test result may be used to select men with a high probability of aggressive prostate cancer who would benefit from a biopsy of the prostate to prevent an adverse and potentially lethal outcome from prostate cancer. Men with a low 4Kscore Test result may safely defer biopsy. PMID- 26028996 TI - Expectations of stress urinary incontinence surgery in patients with mixed urinary incontinence. AB - Mixed urinary incontinence is estimated to affect 30% of all women who have urinary incontinence, and it has been shown to be more bothersome to women than pure stress incontinence. Given the degree of bother, many women will undergo surgical correction for incontinence. Patients have high expectations about the success of these interventions. Understanding mixed incontinence and the effects of our interventions can help guide therapeutic choices and manage patients' expectations. PMID- 26028997 TI - 3D Printing and Its Urologic Applications. AB - 3D printing is the development of 3D objects via an additive process in which successive layers of material are applied under computer control. This article discusses 3D printing, with an emphasis on its historical context and its potential use in the field of urology. PMID- 26028999 TI - Thriving in the Independent Setting: Highlights From the 2014 LUGPA Annual Meeting. PMID- 26028998 TI - Hemostasis during urologic surgery: fibrin sealant compared with absorbable hemostat. AB - In the United States, fibrin sealants have been used to achieve hemostasis for nearly two decades. Although their clinical utility was first demonstrated in cardiac surgery, their effectiveness and safety have since been demonstrated to extend to a wide array of procedures. Fibrin sealants typically contain two components-fibrinogen and thrombin-that are combined and delivered simultaneously to a target bleeding site in order to achieve hemostasis. However, many commercial formulations contain other additional components, such as antifibrinolytic agents, that have been associated with adverse outcomes. This subanalysis compares the safety and effectiveness of a fibrin sealant versus an absorbable hemostat for achieving hemostasis during urologic procedures with mild to moderate bleeding. PMID- 26029000 TI - How best to use modifier 59. PMID- 26029001 TI - Best of the 2014 Pediatric Urology Fall Congress: Highlights From the 2014 Pediatric Urology Fall Congress, October 24-26, 2014, Miami, FL. PMID- 26029002 TI - Adenocarcinoma of the urethra with mucinous features. AB - Primary adenocarcinoma of the female urethra is a rare malignancy. Previous studies hypothesize multiple origins, including periurethral glands or intestinal metaplasia. We report a case of a 60-year-old white woman with adenocarcinoma of the urethra who initially presented with obstructive voiding complaints secondary to a urethral mass. Wide local excision revealed invasive adenocarcinoma of the urethra with mucinous features. There was intestinal metaplasia adjacent to the tumor, as well as separate identification of intestinal metaplasia along the urethra. Ultimately, the patient underwent radical cystectomy with ileal conduit urinary diversion with no evidence of recurrence, indicating the role of early identification and surgical intervention for such cases. PMID- 26029003 TI - Rare case of monozygotic twins diagnosed with klinefelter syndrome during evaluation for infertility. AB - Although neither Klinefelter syndrome nor monozygotic twins are particularly rare (1/667 male births and 3-4/1000 live births, respectively), the occurrence of both in the same pregnancy (ie, identical twins with Klinefelter syndrome) is exceedingly rare and has only been reported three times previously in the literature. This report describes the fourth ever reported case of monozygotic twins with Klinefelter syndrome (who presented to our male fertility clinic with failure to conceive) and sheds interesting light on the reproductive concordance observed with this rare clinical entity. To our knowledge, this is the first reported case of monozygotic twins with Klinefelter syndrome that describes the infertility workup and outcomes of microsurgical testicular sperm extraction. PMID- 26029004 TI - En Bloc Robot-assisted Laparoscopic Partial Cystectomy, Urachal Resection, and Pelvic Lymphadenectomy for Urachal Adenocarcinoma. AB - Primary adenocarcinomas of the bladder and urachus are extremely rare, accounting for 0.5% to 2.0% of all bladder malignancies. During fetal development, the urachus develops into the median umbilical ligament that stretches from the umbilicus to the bladder. Adenocarcinoma accounts for 90% of all cases of urachal carcinoma. There is no consensus regarding the management of urachal carcinoma. Although the preferred treatment is wide local excision with partial or radical cystectomy, bladder-sparing management is increasing. We report a case of robot assisted laparoscopic partial cystectomy with en bloc resection of the urachus and bilateral pelvic lymphadenectomy for urachal carcinoma. The robot-assisted laparoscopic approach allowed us to minimize surgical morbidity, postoperative pain, and convalescent time while maintaining the oncologic principle of wide local excision. PMID- 26029005 TI - Using mHealth Tools to Improve Rural Diabetes Care Guided by the Chronic Care Model. AB - BACKGROUND AND OBJECTIVE: Used as an integrated tool, mHealth may improve the ability of healthcare providers in rural areas to provide care, improve access to care for underserved populations, and improve biophysical outcomes of care for persons with diabetes in rural, underserved populations. Our objective in this paper is to present an integrated review of the impact of mHealth interventions for community dwelling individuals with type two diabetes. MATERIALS AND METHODS: A literature search was performed using keywords in PubMed to identify research studies which mHealth technology was used as the intervention. RESULTS AND DISCUSSION: Interventions using mHealth have been found to improve outcomes, be cost effective, and culturally relevant. mHealth technology that has been used to improve outcomes include: seeking out health information via the web, access to appointment scheduling and medication refills, secure messaging, computerized interventions to manage a chronic condition, use of a personal health record, use of remote monitoring devices, and seeking support from others with similar health concerns through social networks. CONCLUSION: Using the validated Chronic Care Model to translate what is known about mHealth technology to clinical practice has the potential to improve the ability of healthcare providers in rural areas to provide care, improve access to care for underserved populations, and improve biophysical outcomes of care for persons with diabetes in rural underserved populations. While these approaches were effective in improving some outcomes, they have not resulted in the establishment of the necessary electronic infrastructure for a sustainable mobile healthcare delivery model. PMID- 26029006 TI - A Person-Centered Approach to Clinical Practice. AB - Effective clinical practice depends on tools that facilitate nonstigmatizing personality assessment, rapid development of a therapeutic alliance, and the guided development of self-awareness so that people learn how to live well. As an expert in psychological medicine, the psychiatrist is uniquely qualified to develop a holistic treatment approach addressing the needs of the person's body, thoughts, and psyche for the promotion of health and well-being. Personality assessment can be integrated into psychiatric practice in a way that is practical and that has many benefits for the psychiatrist and his or her patients. Personal reflection on one's temperament and character profile promotes understanding without judging or blaming. The dialogue between psychiatrist and patient about personality promotes the rapid development of a therapeutic alliance based on mutual respect, positive regard, and shared goals. The expertise and empathy of the psychiatrist in knowing more about the person's strengths and vulnerabilities beyond even the person's own awareness builds respect, trust, and hope. In this way, the assessment of personality promotes recovery of well-being and reduces disease and stigma. Likewise, the psychiatrist is more effective and satisfied with practice, standing ready with expertise, patience, and compassion to assist patients to work and develop at their own chosen pace. PMID- 26029007 TI - Erratum to: The influence of a CYP1A2 polymorphism on the ergogenic effects of caffeine. AB - [This corrects the article DOI: 10.1186/1550-2783-9-7.]. PMID- 26029008 TI - Volumetric Semantic Segmentation using Pyramid Context Features. AB - We present an algorithm for the per-voxel semantic segmentation of a three dimensional volume. At the core of our algorithm is a novel "pyramid context" feature, a descriptive representation designed such that exact per-voxel linear classification can be made extremely efficient. This feature not only allows for efficient semantic segmentation but enables other aspects of our algorithm, such as novel learned features and a stacked architecture that can reason about self consistency. We demonstrate our technique on 3D fluorescence microscopy data of Drosophila embryos for which we are able to produce extremely accurate semantic segmentations in a matter of minutes, and for which other algorithms fail due to the size and high-dimensionality of the data, or due to the difficulty of the task. PMID- 26029009 TI - The cost of cancer-related physician services to Medicare. AB - Although physician services represent a substantial portion of cancer care costs, little is known about trends in the costs of physician cancer services in the fee for-service Medicare program. We analyzed aggregated data from all Part B Medicare claims for physician and supplier services attributed to cancer patients from 1999 to 2012 to characterize how billing and payments have changed over time for the most common cancer types. Billing and expenditure data are from the Medicare Statistical Supplement, and age-adjusted incidence data are from SEER. Physician services for cancer patients grew from $7.6 billion in 1999 to $12.3 billion in 2012 (60 percent increase). Reimbursements for physician and supplier services for cancer treatment in Medicare Part B beneficiaries steadily grew from 1999 to 2005 and then plateaued through 2012, led by a decrease in reimbursements for prostate cancer care. These trends may reflect shifts toward hospital-based care or changes in aggressiveness of care. PMID- 26029011 TI - Nuns, warts, viruses, and cancer. AB - It has been known for more than 150 years that the risk of carcinoma of the uterine cervix correlates with the number of sexual partners. Laboratory and epidemiological evidence demonstrated that infection with certain human papillomavirus (HPV) types initiates the vast majority of, if not all, cervical cancer, as well as a substantial fraction of other cancers, including other anogenital cancer and oropharyngeal cancer. Pap smear testing resulted in a dramatic reduction in the incidence of cervical cancer in the developed world, and HPV vaccination has the potential to eradicate HPV-associated cancer worldwide and represents a major public health breakthrough. The major current challenge is to ensure that HPV vaccines are widely administered. PMID- 26029010 TI - Gene-by-Environment Interactions in Pancreatic Cancer: Implications for Prevention. AB - Pancreatic cancer (PC) has been estimated to have higher incidence and correspondingly higher mortality rates in more developed regions worldwide. Overall, the age-adjusted incidence rate is 4.9/10(5) and age-adjusted mortality rate is at 4.8/10(5). We review here our current knowledge of modifiable risk factors (cigarette smoking, obesity, diet, and alcohol) for PC, genetic variants implicated by genome-wide association studies, possible genetic interactions with risk factors, and prevention strategies to provide future research directions that may further our understanding of this complex disease. Cigarette smoking is consistently associated with a two-fold increased PC risk. PC associations with dietary intake have been largely inconsistent, with the potential exception of certain unsaturated fatty acids decreasing risk and well-done red meat or meat mutagens increasing risk. There is strong evidence to support that obesity (and related measures) increase risk of PC. Only the heaviest alcohol drinkers seem to be at an increased risk of PC. Currently, key prevention strategies include avoiding tobacco and excessive alcohol consumption and adopting a healthy lifestyle. Screening technologies and PC chemoprevention are likely to become more sophisticated, but may only apply to those at high risk. Risk stratification may be improved by taking into account gene environment interactions. Research on these modifiable risk factors is key to reducing the incidence of PC and understanding who in the population can be considered high risk. PMID- 26029012 TI - Extracting knowledge from chemical imaging data using computational algorithms for digital cancer diagnosis. AB - Fourier transform infrared (FTIR) spectroscopic imaging is an emerging microscopy modality for clinical histopathologic diagnoses as well as for biomedical research. Spectral data recorded in this modality are indicative of the underlying, spatially resolved biochemical composition but need computerized algorithms to digitally recognize and transform this information to a diagnostic tool to identify cancer or other physiologic conditions. Statistical pattern recognition forms the backbone of these recognition protocols and can be used for highly accurate results. Aided by biochemical correlations with normal and diseased states and the power of modern computer-aided pattern recognition, this approach is capable of combating many standing questions of traditional histology based diagnosis models. For example, a simple diagnostic test can be developed to determine cell types in tissue. As a more advanced application, IR spectral data can be integrated with patient information to predict risk of cancer, providing a potential road to precision medicine and personalized care in cancer treatment. The IR imaging approach can be implemented to complement conventional diagnoses, as the samples remain unperturbed and are not destroyed. Despite high potential and utility of this approach, clinical implementation has not yet been achieved due to practical hurdles like speed of data acquisition and lack of optimized computational procedures for extracting clinically actionable information rapidly. The latter problem has been addressed by developing highly efficient ways to process IR imaging data but remains one that has considerable scope for progress. Here, we summarize the major issues and provide practical considerations in implementing a modified Bayesian classification protocol for digital molecular pathology. We hope to familiarize readers with analysis methods in IR imaging data and enable researchers to develop methods that can lead to the use of this promising technique for digital diagnosis of cancer. PMID- 26029013 TI - Approaches to identifying synthetic lethal interactions in cancer. AB - Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal interactions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use. PMID- 26029014 TI - Evolution of multidisciplinary brain metastasis management: case study and literature review. AB - Up to 40 percent of all cancer patients develop brain metastasis (BM) during the course of their disease. Despite advances in diagnosis and therapy, prognosis in patients with BM remains poor for many patients, but for some, survival can be of the order of several years in duration. Difficulty in predicting long-term survivors has created controversy in contemporary management of BM. Minimizing medical and neurocognitive side effects (disease borne or iatrogenic) to enhance functional independence and improving overall quality of life in these individuals requires a coordinated approach of first-line and salvage surgical, chemotherapeutic (cytotoxic, targeted, or immune based), and radiation (whole brain radiotherapy or stereotactic radiosurgery) modalities. This goal needs to be balanced against the more traditional targets of management such as symptom relief, reducing tumor burden, and local tumor control, thereby increasing progression-free survival. This case study and literature review demonstrates the role of various treatment modalities in the management of BM. PMID- 26029016 TI - The benefit and burden of cancer screening in Li-Fraumeni syndrome: a case report. AB - Li-Fraumeni syndrome is a rare cancer predisposition syndrome classically associated with remarkably early onset of cancer in families with a typical spectrum of malignancies, including sarcoma, breast cancer, brain tumors, and adrenocortical carcinoma. Because the risks of cancer development are strikingly high for Li-Fraumeni syndrome, aggressive cancer surveillance is often pursued in these individuals. However, optimal screening methods and intervals for Li Fraumeni syndrome have yet to be determined. In addition, there may be a significant psychosocial burden to intensive cancer surveillance and some prevention modalities. Here, we describe a case of a young woman with a de novo mutation in TP53 and multiple malignancies, with her most recent cancers found at early, curable stages due to aggressive cancer screening. The potential benefits and risks of intensive cancer surveillance in hereditary cancer syndromes is discussed. PMID- 26029017 TI - At the front line of combating cancer: an interview with Harriet Kluger, MD. PMID- 26029015 TI - Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. AB - Basal cell carcinoma (BCC) is the most common malignancy. Exposure to sunlight is the most important risk factor. Most, if not all, cases of BCC demonstrate overactive Hedgehog signaling. A variety of treatment modalities exist and are selected based on recurrence risk, importance of tissue preservation, patient preference, and extent of disease. The pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management of BCC will be discussed in this review. PMID- 26029018 TI - Ashley W. Oughterson, MD: Surgeon, Soldier, Leader. AB - Ashley W. Oughterson, MD, (1895-1956) was a longtime faculty surgeon at Yale University. He performed some of the earliest pancreatic resections in the United States. During World War II, Colonel Oughterson was the primary "Surgical Consultant" in the South Pacific and present at nearly every major battle. His meticulously kept diary is regarded as the foremost source detailing wartime surgical care. Colonel Oughterson led the initial Army team to survey Hiroshima and Nagasaki following the nuclear attacks. Thoughout his academic career at Yale, Oughterson was a key leader in several medical and surgical societies. As scientific director of the American Cancer Society, Oughterson lectured widely and guided research priorities in oncology following World War II. Oughterson also authored numerous benchmark papers in surgical oncology that continue to be cited today. These extensive contributions are examined here and demonstrate the wide-ranging impact Oughterson exerted during a formative period of American surgery. PMID- 26029019 TI - Plasticity of fibroblasts demonstrated by tissue-specific and function-related proteome profiling. AB - BACKGROUND: Fibroblasts are mesenchymal stromal cells which occur in all tissue types. While their main function is related to ECM production and physical support, they are also important players in wound healing, and have further been recognized to be able to modulate inflammatory processes and support tumor growth. Fibroblasts can display distinct phenotypes, depending on their tissue origin, as well as on their functional state. RESULTS: In order to contribute to the proteomic characterization of fibroblasts, we have isolated primary human fibroblasts from human skin, lung and bone marrow and generated proteome profiles of these cells by LC-MS/MS. Comparative proteome profiling revealed characteristic differences therein, which seemed to be related to the cell's tissue origin. Furthermore, the cells were treated in vitro with the pro inflammatory cytokine IL-1beta. While all fibroblasts induced the secretion of Interleukins IL-6 and IL-8 and the chemokine GRO-alpha, other inflammation related proteins were up-regulated in an apparently tissue-dependent manner. Investigating fibroblasts from tumorous tissues of skin, lung and bone marrow with respect to such inflammation-related proteins revealed hardly any conformity but rather individual and tumor type-related variations. However, apparent up regulation of IGF-II, PAI-1 and PLOD2 was observed in melanoma-, lung adenocarcinoma- and multiple myeloma-associated fibroblasts, as well as in hepatocellular carcinoma-associated fibroblasts. CONCLUSIONS: Inflammation related proteome alterations of primary human fibroblasts were determined by the analysis of IL-1beta treated cells. Tumor-associated fibroblasts from different tissue types hardly showed signs of acute inflammation but displayed characteristic functional aberrations potentially related to chronic inflammation. The present data suggest that the state of the tumor microenvironment is relevant for tumor progression and targeted treatment of tumor-associated fibroblasts may support anti-cancer strategies. PMID- 26029020 TI - Blood-brain barrier permeability imaging using perfusion computed tomography. AB - BACKGROUND: The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases. CONCLUSIONS: Blood-brain barrier permeability can be evaluated in vivo by perfusion computed tomography - an efficient diagnostic method that involves the sequential acquisition of tomographic images during the intravenous administration of iodinated contrast material. The major clinical applications of perfusion computed tomography are in acute stroke and in brain tumor imaging. PMID- 26029021 TI - Evaluation of radiographic and metabolic changes in bone metastases in response to systemic therapy with (18)FDG-PET/CT. AB - BACKGROUND: The aim of the study was to retrospectively evaluate radiographic and metabolic changes in bone metastases in response to systemic therapy with (18)FDG PET/CT and determine their roles on the evaluation of therapy response. PATIENTS AND METHODS: We retrospectively evaluated radiographic and metabolic characteristics of bone metastases in 30 patients who were referred for the evaluation of response to systemic therapy with (18)FDG-PET/CT. All patients underwent integrated (18)FDG-PET/CT before and after treatment. RESULTS: The baseline radiographic patterns of the target lesions in responders group were lytic, sclerotic, mixed and CT negative; after treatment the radiographic patterns of all target lesions changed to a sclerotic pattern and attenuation increased (p = 0.012) and metabolic activity decreased (p = 0.012). A correlation was found between decreasing metabolic activity and increasing attenuation of the target lesions (r = -0.55) (p = 0.026). However, in nonresponders group, the baseline radiologic patterns of the target lesions were lytic, blastic, mixed and CT negative; after treatment all lytic target lesions remained the same and one CT negative lesion turned to lytic pattern and the attenuation of the target lesions decreased (p +/- 0.12) and metabolic activity increased (p = 0.012). A correlation was found between increasing metabolic activity and decreasing attenuation (r = -0.65) (p = 0.032). An exception of this rule was seen in baseline blastic metastases which progressed with increasing in size, metabolic activity and attenuation. CONCLUSIONS: This study shows that the metabolic activity of lesions is a more reliable parameter than the radiographic patterns for the evaluation of therapy response. PMID- 26029022 TI - Thyroid lesions incidentally detected by (18)F-FDG PET-CT - a two centre retrospective study. AB - BACKGROUND: Incidental (18)F-FDG uptake in the thyroid on PET-CT examinations represents a diagnostic challenge. The maximal standardized uptake value (SUVmax) is one possible parameter that can help in distinguishing between benign and malignant thyroid PET lesions. PATIENTS AND METHODS: We retrospectively evaluated (18)F-FDG PET-CT examinations of 5,911 patients performed at two different medical centres from 2010 to 2011. If pathologically increased activity was accidentally detected in the thyroid, the SUVmax of the thyroid lesion was calculated. Patients with incidental (18)F-FDG uptake in the thyroid were instructed to visit a thyroidologist, who performed further investigation including fine needle aspiration cytology (FNAC) if needed. Lesions deemed suspicious after FNAC were referred for surgery. RESULTS: Incidental (18)F-FDG uptake in the thyroid was found in 3.89% - in 230 out of 5,911 patients investigated on PET-CT. Malignant thyroid lesions (represented with focal thyroid uptake) were detected in 10 of 66 patients (in 15.2%). In the first medical centre the SUVmax of 36 benign lesions was 5.6 +/- 2.8 compared to 15.8 +/- 9.2 of 5 malignant lesions (p < 0.001). In the second centre the SUVmax of 20 benign lesions was 3.7 +/- 2.2 compared to 5.1 +/- 2.3 of 5 malignant lesions (p = 0.217). All 29 further investigated diffuse thyroid lesions were benign. CONCLUSIONS: Incidental (18)F-FDG uptake in the thyroid was found in 3.89% of patients who had a PET-CT examination. Only focal thyroid uptake represented a malignant lesion in our study - in 15.2% of all focal thyroid lesions. SUVmax should only serve as one of several parameters that alert the clinician on the possibility of thyroid malignancy. PMID- 26029023 TI - Primary central nervous system lymphoma: is absence of intratumoral hemorrhage a characteristic finding on MRI? AB - BACKGROUND: Previous studies have shown that intratumoral hemorrhage is a common finding in glioblastoma multi-forme, but is rarely observed in primary central nervous system lymphoma. Our aim was to reevaluate whether intratumoral hemorrhage observed on T2-weighted imaging (T2WI) as gross intratumoral hemorrhage and on susceptibility-weighted imaging as intratumoral susceptibility signal can differentiate primary central nervous system lymphoma from glioblastoma multiforme. PATIENTS AND METHODS: A retrospective cohort of brain tumors from August 2008 to March 2013 was searched, and 58 patients (19 with primary central nervous system lymphoma, 39 with glioblastoma multiforme) satisfied the inclusion criteria. Absence of gross intratumoral hemorrhage was examined on T2WI, and an intratumoral susceptibility signal was graded using a 3 point scale on susceptibility-weighted imaging. Results were compared between primary central nervous system lymphoma and glioblastoma multiforme, and values of P < 0.05 were considered significant. RESULTS: Gross intratumoral hemorrhage on T2WI was absent in 15 patients (79%) with primary central nervous system lymphoma and 23 patients (59%) with glioblastoma multiforme. Absence of gross intratumoral hemorrhage could not differentiate between the two disorders (P = 0.20). However, intratumoral susceptibility signal grade 1 or 2 was diagnostic of primary central nervous system lymphoma with 78.9% sensitivity and 66.7% specificity (P < 0.001), irrespective of gross intratumoral hemorrhage. CONCLUSIONS: Low intratumoral susceptibility signal grades can differentiate primary central nervous system lymphoma from glioblastoma multiforme. However, specificity in this study was relatively low, and primary central nervous system lymphoma cannot be excluded based solely on the presence of an intratumoral susceptibility signal. PMID- 26029024 TI - Doppler ultrasound for diagnosis of soft tissue sarcoma: efficacy of ultrasound based screening score. AB - BACKGROUND: The utility of ultrasound imaging in the screening of soft-part tumours (SPTs) has been reported. We classified SPTs according to their blood flow pattern on Doppler ultrasound and re-evaluated the efficacy of this imaging modality as a screening method. Additionally, we combined Doppler ultrasound with several values to improve the diagnostic efficacy and to establish a new diagnostic tool. PATIENTS AND METHODS: This study included 189 cases of pathologically confirmed SPTs (122 cases of benign disease including SPTs and tumour-like lesions and 67 cases of malignant SPTs). Ultrasound imaging included evaluation of vascularity by colour Doppler. We established a scoring system to more effectively differentiate malignant from benign SPTs (ultrasound-based sarcoma screening [USS] score). RESULTS: The mean scores in the benign and malignant groups were 1.47 +/- 0.93 and 3.42 +/- 1.30, respectively. Patients with malignant masses showed significantly higher USS scores than did those with benign masses (p < 1 * 10(-10)). The area under the curve was 0.88 by receiver operating characteristic (ROC) analysis. Based on the cut-off value (3 points) calculated by ROC curve analysis, the sensitivity and specificity for a diagnosis of malignant SPT was 85.1% and 86.9%, respectively. CONCLUSIONS: Assessment of vascularity by Doppler ultrasound alone is insufficient for differentiation between benign and malignant SPTs. Preoperative diagnosis of most SPTs is possible by combining our USS score with characteristic clinical and magnetic resonance imaging findings. PMID- 26029025 TI - Artery of Percheron infarction: review of literature with a case report. AB - BACKGROUND: Clinical features indicating an ischemic infarction in the territory of posterior cerebral circulation require a comprehensive radiologic examination, which is best achieved by a multi-modality imaging approach (computed tomography [CT], CT-perfusion, computed tomography angiography [CTA], magnetic resonance imaging [MRI] and diffusion weighted imaging [DWI]). The diagnosis of an acute ischemic infarction, where the damage of brain tissue may still be reversible, enables selection of appropriate treatment and contributes to a more favourable outcome. For these reasons it is essential to recognize common neurovascular variants in the territory of the posterior cerebral circulation, one of which is the artery of Percheron. CASE REPORT: A 69 year-old woman, last seen awake 10 hours earlier, presented with two typical clinical features of the artery of Percheron infarction, which were vertical gaze palsy and coma. Brain CT and CTA of neck and intracranial arteries upon arrival were interpreted as normal. A new brain CT scan performed 24 hours later revealed hypodensity in the medial parts of thalami. Other imaging modalities were not performed, due to the presumption that the window for the application of effective therapy was over. The diagnosis of an artery of Percheron infarction was therefore made retrospectively with the re-examination of the CTA of neck and intracranial arteries. CONCLUSIONS: A multi modality imaging approach is necessary in every patient with suspicion of the posterior circulation infarction immediately after the onset of symptoms, especially in cases where primary imaging modalities are unremarkable and clinical features are severe, where follow-up examinations are indicated. PMID- 26029026 TI - Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre clinical investigation. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells' local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. MATERIALS AND METHODS: The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 MUs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. RESULTS: In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. CONCLUSIONS: Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma, but has a potentiating effect on cytotoxicity of bleomycin in pancreatic tumour cell lines. Therefore, ECT could be considered as a valid alternative for the local control of non-resectable pancreatic cancer. PMID- 26029027 TI - Efficacy of intensity-modulated radiotherapy with concurrent carboplatin in nasopharyngeal carcinoma. AB - BACKGROUND: The aim of the prospective phase II study was to evaluate the efficacy and toxicities of concurrent carboplatin with intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Between October 2005 and November 2011, 73 stage II-IVB NPC patients received IMRT 70 Gy concurrently with three cycles of carboplatin (AUC 5) every three weeks, followed by three cycles of adjuvant carboplatin (AUC 5) and 5-FU (1,000 mg/m(2)/day for four days) every four weeks. All patients were evaluated for tumour response using response evaluation criteria in solid tumour (RECIST) criteria, survival analysis using Kaplan-Meier methods, and toxicities according to common terminology criteria for adverse events (CTCAE) version 4.0. RESULTS: At three months after chemoradiation, 82.2% and 17.8% of patients achieved complete and partial response, respectively. With a median follow-up of 48.1 months (1.3-97.8 months), 9.6% and 17.8% had local recurrence and distant metastasis, respectively. The median survival was not reached. A three-year overall survival was 83.6% and a progression-free survival was 65.3%. Regarding treatment compliance, 97.2%, 68.5% and 69.8% completed radiation treatment, concurrent carboplatin and adjuvant chemotherapy, respectively. Grade 3-4 acute toxicities were oral mucositis (16.4%), dysphagia (16.4%), xerostomia (15.1%) and haematotoxicity (6.8%). CONCLUSIONS: Carboplatin concurrently with IMRT provided excellent tumour response, manageable toxicities and good compliance. This should be considered as an alternative treatment for NPC patients. PMID- 26029028 TI - Preoperative treatment with radiochemotherapy for locally advanced gastroesophageal junction cancer and unresectable locally advanced gastric cancer. AB - BACKGROUND: To purpose of the study was to analyze the results of preoperative radiochemotherapy in patients with unresectable gastric or locoregionally advanced gastroesophageal junction (GEJ) cancer treated at a single institution. PATIENTS AND METHODS: Between 1/2004 and 6/2012, 90 patients with locoregionally advanced GEJ or unresectable gastric cancer were treated with preoperative radiochemotherapy at the Institute of Oncology Ljubljana. Planned treatment schedule consisted of induction chemotherapy with 5-fluorouracil and cisplatin, followed by concomitant radiochemotherapy four weeks later. Three-dimensional conformal external beam radiotherapy was delivered by dual energy (6 and 15 MV) linear accelerator in 25 daily fractions of 1.8 Gy in 5 weeks with two additional cycles of chemotherapy repeated every 28 days. Surgery was performed 4-6 weeks after completing radiochemotherapy. Following the surgery, multidisciplinary advisory team reassessed patients for the need of adjuvant chemotherapy. The primary endpoints were histopathological R0 resection rate and pathological response rate. The secondary endpoints were toxicity of preoperative radiochemotherapy and survival. RESULTS: Treatment with preoperative radiochemotherapy was completed according to the protocol in 84 of 90 patients (93.3%). Twenty patients (22.2%) did not undergo the surgery because of the disease progression, serious comorbidity, poor performance status or still unresectable tumour. In 13 patients (14.4%) only exploration was performed because the tumour was assessed as unresectable or diffuse peritoneal carcinomatosis was established. Fifty-seven patients (63.4%) underwent surgery with the aim of complete removal of the tumour. Radical resection was achieved in 50 (55.6%) patients and the remaining seven (7.8%) patients underwent non-radical surgery (R1 in five and R2 in two patients). In this group of patients (n = 57), pathological complete response of tumour was achieved in five patients (5.6% of all treated patients or 8.8% of all operated patients). Down-staging was recorded in 49 patients (86%), in one patient (1.8%) the stage after radiochemotherapy was unchanged while in seven patients (12.3%) the pathological stage was higher than clinical, mainly due to higher pN stage. No death was recorded during preoperative radiochemotherapy. Most grade 3 and 4 toxicities were due to vomiting, nausea and bone marrow suppression (granulocytopenia). Twenty-six (45.6%) patients died due to GEJ or gastric carcinoma, one died because of septic shock following the surgery and a reason for two deaths was unknown. Twenty-eight patients (49.1%) were disease free at the time of analysis, while 29 patients (50.9%) developed the recurrence, mostly as distant metastases. At two years, locoregional control, disease-free survival, disease-specific survival and overall survival were 82.9%, 43.9%, 56.9% and 53.9%, respectively. CONCLUSIONS: Preoperative radiochemotherapy was feasible in our group of patients and had acceptable toxicity. Majority of patients achieved down-staging, allowing greater proportion of radical resections (R0), which are essential for patients' cure. PMID- 26029029 TI - Febrile neutropenia in chemotherapy treated small-cell lung cancer patients. AB - BACKGROUND: Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients. METHODS: The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored. RESULTS: Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia. CONCLUSIONS: Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation. PMID- 26029030 TI - Mesenteric ischemia after capecitabine treatment in rectal cancer and resultant short bowel syndrome is not an absolute contraindication for radical oncological treatment. AB - BACKGROUND: Thrombotic events, arterial or venous in origin, still remain a source of substantial morbidity and mortality in cancer patients. The propensity for their development in oncology patients is partially a consequence of the disease itself and partially a result of our attempts to treat it. One of the rarest and deadliest thromboembolic complications is arterial mesenteric ischemia. The high mortality rate is caused by its rarity and by its non-specific clinical presentation, both of which make early diagnosis and treatment difficult. Hence, most diagnoses and treatments occur late in the course of the disease. The issue survivors of arterial mesenteric ischemia may face is short bowel syndrome, which has become a chronic condition after the introduction of parenteral nutrition at home. CASE REPORT: We present a 73-year-old rectal cancer patient who developed acute arterial mesenteric thrombosis at the beginning of the pre-operative radiochemotherapy. Almost the entire length of his small intestine, except for the proximal 50 cm of it, and the ascending colon had to be resected. After multiorgan failure his condition improved, and he was able to successfully complete radical treatment (preoperative radiotherapy and surgery) for the rectal carcinoma, despite developing short bowel syndrome (SBS) and being dependent upon home-based parenteral nutrition to fully cover his nutritional needs. CONCLUSIONS: Mesenteric ischemia and resultant short bowel syndrome are not absolute contraindications for radical oncological treatment since such patients can still achieve long-term remission. PMID- 26029031 TI - Clinical applicability of biologically effective dose calculation for spinal cord in fractionated spine stereotactic body radiation therapy. AB - BACKGROUND: The aim of the study was to investigate whether biologically effective dose (BED) based on linear-quadratic model can be used to estimate spinal cord tolerance dose in spine stereotactic body radiation therapy (SBRT) delivered in 4 or more fractions. PATIENTS AND METHODS: Sixty-three metastatic spinal lesions in 47 patients were retrospectively evaluated. The most frequently prescribed dose was 36 Gy in 4 fractions. In planning, we tried to limit the maximum dose to the spinal cord or cauda equina less than 50% of prescription or 45 Gy2/2. BED was calculated using maximum point dose of spinal cord. RESULTS: Maximum spinal cord dose per fraction ranged from 2.6 to 6.0 Gy (median 4.3 Gy). Except 4 patients with 52.7, 56.4, 62.4, and 67.9 Gy2/2, equivalent total dose in 2-Gy fraction of the patients was not more than 50 Gy2/2 (12.1-67.9, median 32.0). The ratio of maximum spinal cord dose to prescription dose increased up to 82.2% of prescription dose as epidural spinal cord compression grade increased. No patient developed grade 2 or higher radiation-induced spinal cord toxicity during follow-up period of 0.5 to 53.9 months. CONCLUSIONS: In fractionated spine SBRT, BED can be used to estimate spinal cord tolerance dose, provided that the dose per fraction to the spinal cord is moderate, e.g. < 6.0 Gy. It appears that a maximum dose of up to 45-50 Gy2/2 to the spinal cord is tolerable in 4 or more fractionation regimen. PMID- 26029032 TI - Dynamic CT angiography for cyberknife radiosurgery planning of intracranial arteriovenous malformations: a technical/feasibility report. AB - BACKGROUND: Successful radiosurgery for arteriovenous malformations (AVMs) requires accurate nidus delineation in the 3D treatment planning system (TPS). The catheter biplane digital subtraction angiogram (DSA) has traditionally been the gold standard for evaluation of the AVM nidus, but its 2D nature limits its value for contouring and it cannot be imported into the Cyberknife TPS. We describe a technique for acquisition and integration of 3D dynamic CT angiograms (dCTA) into the Cyberknife TPS for intracranial AVMs and review the feasibility of using this technique in the first patient cohort. PATIENTS AND METHODS: Dynamic continuous whole brain CT images were acquired in a Toshiba 320 volume CT scanner with data reconstruction every 0.5 sec. This multi-time-point acquisition enabled us to choose the CT data-set with the clearest nidus without significant enhancement of surrounding blood vessels. This was imported to the Cyberknife TPS and co-registered with planning CT and T2 MRI (2D DSA adjacent for reference). The feasibility of using dCTA was evaluated in the first thirteen patients with outcome evaluation from patient records. RESULTS: dCTA data was accurately co registered in the Cyberknife TPS and appeared to assist in nidus contouring for all patients. Imaging modalities were complementary. 85% of patients had complete (6/13) or continuing partial nidus obliteration (5/13) at 37 months median follow up. CONCLUSIONS: dCTA is a promising imaging technique that can be successfully imported into the Cyberknife TPS and appears to assist in radiosurgery nidus definition. Further study to validate its role is warranted. PMID- 26029033 TI - The cost of systemic therapy for metastatic colorectal carcinoma in Slovenia: discrepancy analysis between cost and reimbursement. AB - BACKGROUND: The aim of the study was to estimate the direct medical costs of metastatic colorectal cancer (mCRC) treated at the Institute of Oncology Ljubljana and to question the healthcare payment system in Slovenia. METHODS: Using an internal patient database, the costs of mCRC patients were estimated in 2009 by examining (1) mCRC direct medical related costs, and (2) the cost difference between payment received by Slovenian health insurance and actual mCRC costs. Costs were analysed in the treatment phase of the disease by assessing the direct medical costs of hospital treatment with systemic therapy together with hospital treatment of side effects, without assessing radiotherapy or surgical treatment. Follow-up costs, indirect medical costs, and nonmedical costs were not included. RESULTS: A total of 209 mCRC patients met all eligibility criteria. The direct medical costs of mCRC hospitalization with systemic therapy in Slovenia for 2009 were estimated as the cost of medications (cost of systemic therapy + cost of drugs for premedication) + labor cost (the cost of carrying out systemic treatment) + cost of lab tests + cost of imaging tests + KRAS testing cost + cost of hospital treatment due to side effects of mCRC treatment, and amounted to ?3,914,697. The difference between the cost paid by health insurance and actual costs, estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009, was ?1,900,757.80. CONCLUSIONS: The costs paid to the Institute of Oncology Ljubljana by health insurance for treating mCRC with systemic therapy do not match the actual cost of treatment. In fact, the difference between the payment and the actual cost estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009 was ?1,900,757.80. The model Australian Refined Diagnosis Related Groups (AR-DRG) for cost assessment in oncology being currently used is probably one of the reasons for the discrepancy between pay-outs and actual costs. We propose new method for more precise cost assessment in oncology. PMID- 26029034 TI - Full Discretisations for Nonlinear Evolutionary Inequalities Based on Stiffly Accurate Runge-Kutta and hp-Finite Element Methods. AB - The convergence of full discretisations by implicit Runge-Kutta and nonconforming Galerkin methods applied to nonlinear evolutionary inequalities is studied. The scope of applications includes differential inclusions governed by a nonlinear operator that is monotone and fulfills a certain growth condition. A basic assumption on the considered class of stiffly accurate Runge-Kutta time discretisations is a stability criterion which is in particular satisfied by the Radau IIA and Lobatto IIIC methods. In order to allow nonconforming hp-finite element approximations of unilateral constraints, set convergence of convex subsets in the sense of Glowinski-Mosco-Stummel is utilised. An appropriate formulation of the fully discrete variational inequality is deduced on the basis of a characteristic example of use, a Signorini-type initial-boundary value problem. Under hypotheses close to the existence theory of nonlinear first-order evolutionary equations and inequalities involving a monotone main part, a convergence result for the piecewise constant in time interpolant is established. PMID- 26029035 TI - Hippocampal developmental vulnerability to methylmercury extends into prepubescence. AB - The developing brain is sensitive to environmental toxicants such as methylmercury (MeHg), to which humans are exposed via contaminated seafood. Prenatal exposure in children is associated with learning, memory and IQ deficits, which can result from hippocampal dysfunction. To explore underlying mechanisms, we have used the postnatal day (P7) rat to model the third trimester of human gestation. We previously showed that a single low exposure (0.6 MUg/gbw) that approaches human exposure reduced hippocampal neurogenesis in the dentate gyrus (DG) 24 h later, producing later proliferation and memory deficits in adolescence. Yet, the vulnerable stem cell population and period of developmental vulnerability remain undefined. In this study, we find that P7 exposure of stem cells has long-term consequences for adolescent neurogenesis. It reduced the number of mitotic S-phase cells (BrdU), especially those in the highly proliferative Tbr2+ population, and immature neurons (Doublecortin) in adolescence, suggesting partial depletion of the later stem cell pool. To define developmental vulnerability to MeHg in prepubescent (P14) and adolescent (P21) rats, we examined acute 24 h effects of MeHg exposure on mitosis and apoptosis. We found that low exposure did not adversely impact neurogenesis at either age, but that a higher exposure (5 MUg/gbw) at P14 reduced the total number of neural stem cells (Sox2+) by 23% and BrdU+ cells by 26% in the DG hilus, suggesting that vulnerability diminishes with age. To determine whether these effects reflect changes in MeHg transfer across the blood brain barrier (BBB), we assessed Hg content in the hippocampus after peripheral injection and found that similar levels (~800 ng/gm) were obtained at 24 h at both P14 and P21, declining in parallel, suggesting that changes in vulnerability depend more on local tissue and cellular mechanisms. Together, we show that MeHg vulnerability declines with age, and that early exposure impairs later neurogenesis in older juveniles. PMID- 26029036 TI - Post-training depletions of basolateral amygdala serotonin fail to disrupt discrimination, retention, or reversal learning. AB - In goal-directed pursuits, the basolateral amygdala (BLA) is critical in learning about changes in the value of rewards. BLA-lesioned rats show enhanced reversal learning, a task employed to measure the flexibility of response to changes in reward. Similarly, there is a trend for enhanced discrimination learning, suggesting that BLA may modulate formation of stimulus-reward associations. There is a parallel literature on the importance of serotonin (5HT) in new stimulus reward and reversal learning. Recent postulations implicate 5HT in learning from punishment. Whereas, dopaminergic involvement is critical in behavioral activation and reinforcement, 5HT may be most critical for aversive processing and behavioral inhibition, complementary cognitive processes. Given these findings, a 5HT-mediated mechanism in BLA may mediate the facilitated learning observed previously. The present study investigated the effects of selective 5HT lesions in BLA using 5,7-dihydroxytryptamine (5,7-DHT) vs. infusions of saline (Sham) on discrimination, retention, and deterministic reversal learning. Rats were required to reach an 85% correct pairwise discrimination and single reversal criterion prior to surgery. Postoperatively, rats were then tested on the (1) retention of the pretreatment discrimination pair, (2) discrimination of a novel pair, and (3) reversal learning performance. We found statistically comparable preoperative learning rates between groups, intact postoperative retention, and unaltered novel discrimination and reversal learning in 5,7-DHT rats. These findings suggest that 5HT in BLA is not required for formation and flexible adjustment of new stimulus-reward associations when the strategy to efficiently solve the task has already been learned. Given the complementary role of orbitofrontal cortex in reward learning and its interconnectivity with BLA, these findings add to the list of dissociable mechanisms for BLA and orbitofrontal cortex in reward learning. PMID- 26029037 TI - The neural processing of hierarchical structure in music and speech at different timescales. AB - Music, like speech, is a complex auditory signal that contains structures at multiple timescales, and as such is a potentially powerful entry point into the question of how the brain integrates complex streams of information. Using an experimental design modeled after previous studies that used scrambled versions of a spoken story (Lerner et al., 2011) and a silent movie (Hasson et al., 2008), we investigate whether listeners perceive hierarchical structure in music beyond short (~6 s) time windows and whether there is cortical overlap between music and language processing at multiple timescales. Experienced pianists were presented with an extended musical excerpt scrambled at multiple timescales-by measure, phrase, and section-while measuring brain activity with functional magnetic resonance imaging (fMRI). The reliability of evoked activity, as quantified by inter-subject correlation of the fMRI responses, was measured. We found that response reliability depended systematically on musical structure coherence, revealing a topographically organized hierarchy of processing timescales. Early auditory areas (at the bottom of the hierarchy) responded reliably in all conditions. For brain areas at the top of the hierarchy, the original (unscrambled) excerpt evoked more reliable responses than any of the scrambled excerpts, indicating that these brain areas process long-timescale musical structures, on the order of minutes. The topography of processing timescales was analogous with that reported previously for speech, but the timescale gradients for music and speech overlapped with one another only partially, suggesting that temporally analogous structures-words/measures, sentences/musical phrases, paragraph/sections-are processed separately. PMID- 26029039 TI - Egalitarian reward contingency in competitive games and primate prefrontal neuronal activity. AB - How people work to obtain a reward depends on the context of the reward delivery, such as the presence/absence of competition and the contingency of reward delivery. Since resources are limited, winning a competition is critically important for organisms' obtaining a reward. People usually expect ordinary performance-reward contingency, with better performers obtaining better rewards. Unordinary reward contingency, such as egalitarianism (equal rewards/no-rewards to both good and poor performers), dampens people's motivation. We previously reported that monkeys were more motivated, and neurons in the lateral prefrontal cortex (LPFC) showed higher outcome-related activity in a competitive than in a noncompetitive game (Hosokawa and Watanabe, 2012). However, monkey's behavior and LPFC neuronal activity have not been examined in a competitive situation with an unordinary performance-reward contingency. Also, the fixed performance-reward contingency in the previous study did not allow us to examine effects of win/loss separately from those of reward/no-reward on prefrontal neuronal activity. Here, we employed the egalitarian competitive situation in which both the winner and loser, or neither of them, got a reward as well as the normal competitive situation in which only the winner got a reward. Monkey's behavioral performance greatly deteriorated in trials with the egalitarian outcome conditions. LPFC neurons showed activities that reflected the normal or egalitarian outcome condition while very few neurons coded win/loss independent of reward/no-reward. Importantly, we found neurons that showed reward-related activity in the normal, but not in the egalitarian outcome conditions, even though the same reward was given to the animal. These results indicate that LPFC may play an important role in monitoring the current reward contingency and integrating it with the performance outcome (win-loss) for better performing the competitive game, and thus for better survival. PMID- 26029038 TI - A hypothesis for the evolution of the upper layers of the neocortex through co option of the olfactory cortex developmental program. AB - The neocortex is unique to mammals and its evolutionary origin is still highly debated. The neocortex is generated by the dorsal pallium ventricular zone, a germinative domain that in reptiles give rise to the dorsal cortex. Whether this latter allocortical structure contains homologs of all neocortical cell types it is unclear. Recently we described a population of DCX+/Tbr1+ cells that is specifically associated with the layer II of higher order areas of both the neocortex and of the more evolutionary conserved piriform cortex. In a reptile similar cells are present in the layer II of the olfactory cortex and the DVR but not in the dorsal cortex. These data are consistent with the proposal that the reptilian dorsal cortex is homologous only to the deep layers of the neocortex while the upper layers are a mammalian innovation. Based on our observations we extended these ideas by hypothesizing that this innovation was obtained by co opting a lateral and/or ventral pallium developmental program. Interestingly, an analysis in the Allen brain atlas revealed a striking similarity in gene expression between neocortical layers II/III and piriform cortex. We thus propose a model in which the early neocortical column originated by the superposition of the lateral olfactory and dorsal cortex. This model is consistent with the fossil record and may account not only for the topological position of the neocortex, but also for its basic cytoarchitectural and hodological features. This idea is also consistent with previous hypotheses that the peri-allocortex represents the more ancient neocortical part. The great advances in deciphering the molecular logic of the amniote pallium developmental programs will hopefully enable to directly test our hypotheses in the next future. PMID- 26029040 TI - Molecular cloning, sequencing and tissue expression of vasotocin and isotocin precursor genes from Ostariophysian catfishes: phylogeny and evolutionary considerations in teleosts. AB - Basic and neutral neurohypophyseal (NH) nonapeptides have evolved from vasotocin (VT) by a gene duplication at the base of the gnathostome lineage. In teleosts, VT and IT are the basic and neutral peptides, respectively. In the present study, VT and IT precursor genes of Heteropneustes fossilis and Clarias batrachus (Siluriformes, Ostariophysi) were cloned and sequenced. The channel catfish Icatalurus punctatus NH precursor sequences were obtained from EST database. The catfish NH sequences were used along with the available Acanthopterygii and other vertebrate NH precursor sequences to draw phylogenetic inference on the evolutionary history of the teleost NH peptides. Synteny analysis of the NH gene loci in various teleost species was done to complement the phylogenetic analysis. In H. fossilis, the NH transcripts were also sequenced from the ovary. The cloned genes and the deduced precursor proteins showed conserved characteristics of the NH nonapeptide precursors. The genes are expressed in brain and ovary (follicular envelope) of H. fossilis with higher transcript abundance in the brain. The addition of the catfish sequences in the phylogenetic analysis revealed that the VT and IT precursors of the species-rich superorders of teleosts have a distinct phylogenetic history with the Acanthopterygii VT and IT precursors sharing a less evolutionary distance and the Ostariophysi VT and IT having a greater evolutionary distance. The genomic location of VT and IT precursors, and synteny analysis of the NH loci lend support to the phylogenetic inference and suggest a footprint of fish- specific whole genome duplication (3R) and subsequent diploidization in the NH loci. The VT and IT precursor genes are most likely lineage-specific paralogs resulting from differential losses of the 3R NH paralogs in the two superorders. The independent yet consistent retention of VT and IT in the two superorders might be directed by a stringent ligand-receptor selectivity. PMID- 26029042 TI - Glycolysis at 75: is it time to tweak the first elucidated metabolic pathway in history? PMID- 26029041 TI - Objective Bayesian fMRI analysis-a pilot study in different clinical environments. AB - Functional MRI (fMRI) used for neurosurgical planning delineates functionally eloquent brain areas by time-series analysis of task-induced BOLD signal changes. Commonly used frequentist statistics protect against false positive results based on a p-value threshold. In surgical planning, false negative results are equally if not more harmful, potentially masking true brain activity leading to erroneous resection of eloquent regions. Bayesian statistics provides an alternative framework, categorizing areas as activated, deactivated, non-activated or with low statistical confidence. This approach has not yet found wide clinical application partly due to the lack of a method to objectively define an effect size threshold. We implemented a Bayesian analysis framework for neurosurgical planning fMRI. It entails an automated effect-size threshold selection method for posterior probability maps accounting for inter-individual BOLD response differences, which was calibrated based on the frequentist results maps thresholded by two clinical experts. We compared Bayesian and frequentist analysis of passive-motor fMRI data from 10 healthy volunteers measured on a pre operative 3T and an intra-operative 1.5T MRI scanner. As a clinical case study, we tested passive motor task activation in a brain tumor patient at 3T under clinical conditions. With our novel effect size threshold method, the Bayesian analysis revealed regions of all four categories in the 3T data. Activated region foci and extent were consistent with the frequentist analysis results. In the lower signal-to-noise ratio 1.5T intra-operative scanner data, Bayesian analysis provided improved brain-activation detection sensitivity compared with the frequentist analysis, albeit the spatial extents of the activations were smaller than at 3T. Bayesian analysis of fMRI data using operator-independent effect size threshold selection may improve the sensitivity and certainty of information available to guide neurosurgery. PMID- 26029043 TI - Parallel workflow tools to facilitate human brain MRI post-processing. AB - Multi-modal magnetic resonance imaging (MRI) techniques are widely applied in human brain studies. To obtain specific brain measures of interest from MRI datasets, a number of complex image post-processing steps are typically required. Parallel workflow tools have recently been developed, concatenating individual processing steps and enabling fully automated processing of raw MRI data to obtain the final results. These workflow tools are also designed to make optimal use of available computational resources and to support the parallel processing of different subjects or of independent processing steps for a single subject. Automated, parallel MRI post-processing tools can greatly facilitate relevant brain investigations and are being increasingly applied. In this review, we briefly summarize these parallel workflow tools and discuss relevant issues. PMID- 26029045 TI - Dynamic expression of Lgr6 in the developing and mature mouse cochlea. AB - The Wnt/beta-catenin signaling pathway plays important roles in mammalian inner ear development. Lgr5, one of the downstream target genes of the Wnt/beta-catenin signaling pathway, has been reported to be a marker for inner ear hair cell progenitors. Lgr6 shares approximately 50% sequence homology with Lgr5 and has been identified as a stem cell marker in several organs. However, the detailed expression profiles of Lgr6 have not yet been investigated in the mouse inner ear. Here, we first used Lgr6-EGFP-Ires-CreERT2 mice to examine the spatiotemporal expression of Lgr6 protein in the cochlear duct during embryonic and postnatal development. Lgr6-EGFP was first observed in one row of prosensory cells in the middle and basal turn at embryonic day 15.5 (E15.5). From E18.5 to postnatal day 3 (P3), the expression of Lgr6-EGFP was restricted to the inner pillar cells (IPCs). From P7 to P15, the Lgr6-EGFP expression level gradually decreased in the IPCs and gradually increased in the inner border cells (IBCs). At P20, Lgr6-EGFP was only expressed in the IBCs, and by P30 Lgr6-EGFP expression had completely disappeared. Next, we demonstrated that Wnt/beta-catenin signaling is required to maintain the Lgr6-EGFP expression in vitro. Finally, we demonstrated that the Lgr6-EGFP-positive cells isolated by flow cytometry could differentiate into myosin 7a-positive hair cells after 10 days in-culture, and this suggests that the Lgr6-positive cells might serve as the hair cell progenitor cells in the cochlea. PMID- 26029044 TI - Potential primary roles of glial cells in the mechanisms of psychiatric disorders. AB - While neurons have long been considered the major player in multiple brain functions such as perception, emotion, and memory, glial cells have been relegated to a far lesser position, acting as merely a "glue" to support neurons. Multiple lines of recent evidence, however, have revealed that glial cells such as oligodendrocytes, astrocytes, and microglia, substantially impact on neuronal function and activities and are significantly involved in the underlying pathobiology of psychiatric disorders. Indeed, a growing body of evidence indicates that glial cells interact extensively with neurons both chemically (e.g., through neurotransmitters, neurotrophic factors, and cytokines) and physically (e.g., through gap junctions), supporting a role for these cells as likely significant modifiers not only of neural function in brain development but also disease pathobiology. Since questions have lingered as to whether glial dysfunction plays a primary role in the biology of neuropsychiatric disorders or a role related solely to their support of neuronal physiology in these diseases, informative and predictive animal models have been developed over the last decade. In this article, we review recent findings uncovered using glia-specific genetically modified mice with which we can evaluate both the causation of glia dysfunction and its potential role in neuropsychiatric disorders such as autism and schizophrenia. PMID- 26029046 TI - Delirium from the gliocentric perspective. AB - Delirium is an acute state marked by disturbances in cognition, attention, memory, perception, and sleep-wake cycle which is common in elderly. Others have shown an association between delirium and increased mortality, length of hospitalization, cost, and discharge to extended stay facilities. Until recently it was not known that after an episode of delirium in elderly, there is a 63% probability of developing dementia at 48 months compared to 8% in patients without delirium. Currently there are no preventive therapies for delirium, thus elucidation of cellular and molecular underpinnings of this condition may lead to the development of early interventions and thus prevent permanent cognitive damage. In this article we make the case for the role of glia in the pathophysiology of delirium and describe an astrocyte-dependent central and peripheral cholinergic anti-inflammatory shield which may be disabled by astrocytic pathology, leading to neuroinflammation and delirium. We also touch on the role of glia in information processing and neuroimaging. PMID- 26029048 TI - SINEUPs are modular antisense long non-coding RNAs that increase synthesis of target proteins in cells. AB - Despite recent efforts in discovering novel long non-coding RNAs (lncRNAs) and unveiling their functions in a wide range of biological processes their applications as biotechnological or therapeutic tools are still at their infancy. We have recently shown that AS Uchl1, a natural lncRNA antisense to the Parkinson's disease-associated gene Ubiquitin carboxyl-terminal esterase L1 (Uchl1), is able to increase UchL1 protein synthesis at post-transcriptional level. Its activity requires two RNA elements: an embedded inverted SINEB2 sequence to increase translation and the overlapping region to target its sense mRNA. This functional organization is shared with several mouse lncRNAs antisense to protein coding genes. The potential use of AS Uchl1-derived lncRNAs as enhancers of target mRNA translation remains unexplored. Here we define AS Uchl1 as the representative member of a new functional class of natural and synthetic antisense lncRNAs that activate translation. We named this class of RNAs SINEUPs for their requirement of the inverted SINEB2 sequence to UP-regulate translation in a gene-specific manner. The overlapping region is indicated as the Binding Doman (BD) while the embedded inverted SINEB2 element is the Effector Domain (ED). By swapping BD, synthetic SINEUPs are designed targeting mRNAs of interest. SINEUPs function in an array of cell lines and can be efficiently directed toward N-terminally tagged proteins. Their biological activity is retained in a miniaturized version within the range of small RNAs length. Its modular structure was exploited to successfully design synthetic SINEUPs targeting endogenous Parkinson's disease-associated DJ-1 and proved to be active in different neuronal cell lines. In summary, SINEUPs represent the first scalable tool to increase synthesis of proteins of interest. We propose SINEUPs as reagents for molecular biology experiments, in protein manufacturing as well as in therapy of haploinsufficiencies. PMID- 26029047 TI - Age- and sex-dependent susceptibility to phenobarbital-resistant neonatal seizures: role of chloride co-transporters. AB - Ischemia in the immature brain is an important cause of neonatal seizures. Temporal evolution of acquired neonatal seizures and their response to anticonvulsants are of great interest, given the unreliability of the clinical correlates and poor efficacy of first-line anti-seizure drugs. The expression and function of the electroneutral chloride co-transporters KCC2 and NKCC1 influence the anti-seizure efficacy of GABAA-agonists. To investigate ischemia-induced seizure susceptibility and efficacy of the GABAA-agonist phenobarbital (PB), with NKCC1 antagonist bumetanide (BTN) as an adjunct treatment, we utilized permanent unilateral carotid-ligation to produce acute ischemic-seizures in post-natal day 7, 10, and 12 CD1 mice. Immediate post-ligation video-electroencephalograms (EEGs) quantitatively evaluated baseline and post-treatment seizure burdens. Brains were examined for stroke-injury and western blot analyses to evaluate the expression of KCC2 and NKCC1. Severity of acute ischemic seizures post-ligation was highest at P7. PB was an efficacious anti-seizure agent at P10 and P12, but not at P7. BTN failed as an adjunct, at all ages tested and significantly blunted PB-efficacy at P10. Significant acute post-ischemic downregulation of KCC2 was detected at all ages. At P7, males displayed higher age-dependent seizure susceptibility, associated with a significant developmental lag in their KCC2 expression. This study established a novel neonatal mouse model of PB-resistant seizures that demonstrates age/sex-dependent susceptibility. The age-dependent profile of KCC2 expression and its post-insult downregulation may underlie the PB resistance reported in this model. Blocking NKCC1 with low-dose BTN following PB treatment failed to improve PB-efficacy. PMID- 26029049 TI - A commentary on "Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient". PMID- 26029050 TI - Protection against neurodegeneration with low-dose methylene blue and near infrared light. PMID- 26029051 TI - MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia. AB - Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK 801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes, and oligodendrocytes are affected differently in schizophrenia. Employing in vitro models using neurotransmitter agonists and antagonists may provide new insights about the pathophysiology of schizophrenia which could lead to a novel system for drug discovery. PMID- 26029053 TI - Autism spectrum disorders: emerging mechanisms and mechanism-based treatment. PMID- 26029052 TI - The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies. AB - There has been an explosion of research using transcranial direct current stimulation (tDCS) for investigating and modulating human cognitive and motor function in healthy populations. It has also been used in many studies seeking to improve deficits in disease populations. With the slew of studies reporting "promising results" for everything from motor recovery after stroke to boosting memory function, one could be easily seduced by the idea of tDCS being the next panacea for all neurological ills. However, huge variability exists in the reported effects of tDCS, with great variability in the effect sizes and even contradictory results reported. In this review, we consider the interindividual factors that may contribute to this variability. In particular, we discuss the importance of baseline neuronal state and features, anatomy, age and the inherent variability in the injured brain. We additionally consider how interindividual variability affects the results of motor-evoked potential (MEP) testing with transcranial magnetic stimulation (TMS), which, in turn, can lead to apparent variability in response to tDCS in motor studies. PMID- 26029054 TI - Expression and contributions of the Kir2.1 inward-rectifier K(+) channel to proliferation, migration and chemotaxis of microglia in unstimulated and anti inflammatory states. AB - When microglia respond to CNS damage, they can range from pro-inflammatory (classical, M1) to anti-inflammatory, alternative (M2) and acquired deactivation states. It is important to determine how microglial functions are affected by these activation states, and to identify molecules that regulate their behavior. Microglial proliferation and migration are crucial during development and following damage in the adult, and both functions are Ca(2+)-dependent. In many cell types, the membrane potential and driving force for Ca(2+) influx are regulated by inward-rectifier K(+) channels, including Kir2.1, which is prevalent in microglia. However, it is not known whether Kir2.1 expression and contributions are altered in anti-inflammatory states. We tested the hypothesis that Kir2.1 contributes to Ca(2+) entry, proliferation and migration of rat microglia. Kir2.1 (KCNJ2) transcript expression, current amplitude, and proliferation were comparable in unstimulated microglia and following alternative activation (IL-4 stimulated) and acquired deactivation (IL-10 stimulated). To examine functional roles of Kir2.1 in microglia, we first determined that ML133 was more effective than the commonly used blocker, Ba(2+); i.e., ML133 was potent (IC50 = 3.5 MUM) and voltage independent. Both blockers slightly increased proliferation in unstimulated or IL-4 (but not IL-10)-stimulated microglia. Stimulation with IL-4 or IL-10 increased migration and ATP-induced chemotaxis, and blocking Kir2.1 greatly reduced both but ML133 was more effective. In all three activation states, blocking Kir2.1 with ML133 dramatically reduced Ca(2+) influx through Ca(2+)-release-activated Ca(2+) (CRAC) channels. Thus, Kir2.1 channel activity is necessary for microglial Ca(2+) signaling and migration under resting and anti-inflammatory states but the channel weakly inhibits proliferation. PMID- 26029055 TI - Downregulation of the endogenous opioid peptides in the dorsal striatum of human alcoholics. AB - The endogenous opioid peptides dynorphins and enkephalins may be involved in brain-area specific synaptic adaptations relevant for different stages of an addiction cycle. We compared the levels of prodynorphin (PDYN) and proenkephalin (PENK) mRNAs (by qRT-PCR), and dynorphins and enkephalins (by radioimmunoassay) in the caudate nucleus and putamen between alcoholics and control subjects. We also evaluated whether PDYN promoter variant rs1997794 associated with alcoholism affects PDYN expression. Postmortem specimens obtained from 24 alcoholics and 26 controls were included in final statistical analysis. PDYN mRNA and Met enkephalin-Arg-Phe, a marker of PENK were downregulated in the caudate of alcoholics, while PDYN mRNA and Leu-enkephalin-Arg, a marker of PDYN were decreased in the putamen of alcoholics carrying high risk rs1997794 C allele. Downregulation of opioid peptides in the dorsal striatum may contribute to development of alcoholism including changes in goal directed behavior and formation of a compulsive habit in alcoholics. PMID- 26029056 TI - The discovery of the growth cone and its influence on the study of axon guidance. AB - For over a century, there has been a great deal of interest in understanding how neural connectivity is established during development and regeneration. Interest in the latter arises from the possibility that knowledge of this process can be used to re-establish lost connections after lesion or neurodegeneration. At the end of the XIX century, Santiago Ramon y Cajal discovered that the distal tip of growing axons contained a structure that he called the growth cone. He proposed that this structure enabled the axon's oriented growth in response to attractants, now known as chemotropic molecules. He further proposed that the physical properties of the surrounding tissues could influence the growth cone and the direction of growth. This seminal discovery afforded a plausible explanation for directed axonal growth and has led to the discovery of axon guidance mechanisms that include diffusible attractants and repellants and guidance cues anchored to cell membranes or extracellular matrix. In this review the major events in the development of this field are discussed. PMID- 26029058 TI - Corrigendum: Single cell electroporation for longitudinal imaging of synaptic structure and function in the adult mouse neocortex in vivo. AB - [This corrects the article on p. 36 in vol. 9, PMID: 25904849.]. PMID- 26029057 TI - Cytoarchitectonic mapping of the human brain cerebellar nuclei in stereotaxic space and delineation of their co-activation patterns. AB - The cerebellar nuclei are involved in several brain functions, including the modulation of motor and cognitive performance. To differentiate their participation in these functions, and to analyze their changes in neurodegenerative and other diseases as revealed by neuroimaging, stereotaxic maps are necessary. These maps reflect the complex spatial structure of cerebellar nuclei with adequate spatial resolution and detail. Here we report on the cytoarchitecture of the dentate, interposed (emboliform and globose) and fastigial nuclei, and introduce 3D probability maps in stereotaxic MNI-Colin27 space as a prerequisite for subsequent meta-analysis of their functional involvement. Histological sections of 10 human post mortem brains were therefore examined. Differences in cell density were measured and used to distinguish a dorsal from a ventral part of the dentate nucleus. Probabilistic maps were calculated, which indicate the position and extent of the nuclei in 3D-space, while considering their intersubject variability. The maps of the interposed and the dentate nuclei differed with respect to their interaction patterns and functions based on meta-analytic connectivity modeling and quantitative functional decoding, respectively. For the dentate nucleus, significant (p < 0.05) co-activations were observed with thalamus, supplementary motor area (SMA), putamen, BA 44 of Broca's region, areas of superior and inferior parietal cortex, and the superior frontal gyrus (SFG). In contrast, the interposed nucleus showed more limited co-activations with SMA, area 44, putamen, and SFG. Thus, the new stereotaxic maps contribute to analyze structure and function of the cerebellum. These maps can be used for anatomically reliable and precise identification of degenerative alteration in MRI-data of patients who suffer from various cerebellar diseases. PMID- 26029059 TI - Single-shot T1 mapping of the corpus callosum: a rapid characterization of fiber bundle anatomy. AB - Using diffusion-tensor magnetic resonance imaging and fiber tractography the topographic organization of the human corpus callosum (CC) has been described to comprise five segments with fibers projecting into prefrontal (I), premotor and supplementary motor (II), primary motor (III), and primary sensory areas (IV), as well as into parietal, temporal, and occipital cortical areas (V). In order to more rapidly characterize the underlying anatomy of these segments, this study used a novel single-shot T1 mapping method to quantitatively determine T1 relaxation times in the human CC. A region-of-interest analysis revealed a tendency for the lowest T1 relaxation times in the genu and the highest T1 relaxation times in the somatomotor region of the CC. This observation separates regions dominated by myelinated fibers with large diameters (somatomotor area) from densely packed smaller axonal bundles (genu) with less myelin. The results indicate that characteristic T1 relaxation times in callosal profiles provide an additional means to monitor differences in fiber anatomy, fiber density, and gray matter in respective neocortical areas. In conclusion, rapid T1 mapping allows for a characterization of the axonal architecture in an individual CC in less than 10 s. The approach emerges as a valuable means for studying neocortical brain anatomy with possible implications for the diagnosis of neurodegenerative processes. PMID- 26029060 TI - Corrigendum: Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. PMID- 26029061 TI - A novel wireless recording and stimulating multichannel epicortical grid for supplementing or enhancing the sensory-motor functions in monkey (Macaca fascicularis). AB - Artificial brain-machine interfaces (BMIs) represent a prospective step forward supporting or replacing faulty brain functions. So far, several obstacles, such as the energy supply, the portability and the biocompatibility, have been limiting their effective translation in advanced experimental or clinical applications. In this work, a novel 16 channel chronically implantable epicortical grid has been proposed. It provides wireless transmission of cortical recordings and stimulations, with induction current recharge. The grid has been chronically implanted in a non-human primate (Macaca fascicularis) and placed over the somato-motor cortex such that 13 electrodes recorded or stimulated the primary motor cortex and three the primary somatosensory cortex, in the deeply anaesthetized animal. Cortical sensory and motor recordings and stimulations have been performed within 3 months from the implant. In detail, by delivering motor cortex epicortical single spot stimulations (1-8 V, 1-10 Hz, 500 ms, biphasic waves), we analyzed the motor topographic precision, evidenced by tunable finger or arm movements of the anesthetized animal. The responses to light mechanical peripheral sensory stimuli (blocks of 100 stimuli, each single stimulus being <1 ms and interblock intervals of 1.5-4 s) have been analyzed. We found 150-250 ms delayed cortical responses from fast finger touches, often spread to nearby motor stations. We also evaluated the grid electrical stimulus interference with somatotopic natural tactile sensory processing showing no suppressing interference with sensory stimulus detection. In conclusion, we propose a chronically implantable epicortical grid which can accommodate most of current technological restrictions, representing an acceptable candidate for BMI experimental and clinical uses. PMID- 26029062 TI - GABAergic circuits underpin valuative processing. PMID- 26029063 TI - "And the little brain said to the big brain..." Editorial: Distributed networks: new outlooks on cerebellar function. PMID- 26029064 TI - Elevated dopamine alters consummatory pattern generation and increases behavioral variability during learning. AB - The role of dopamine in controlling behavior remains poorly understood. In this study we examined licking behavior in an established hyperdopaminergic mouse model-dopamine transporter knockout (DAT KO) mice. DAT KO mice showed higher rates of licking, which is due to increased perseveration of licking in a bout. By contrast, they showed increased individual lick durations, and reduced inter lick intervals. During extinction, both KO and control mice transiently increased variability in lick pattern generation while reducing licking rate, yet they showed very different behavioral patterns. Control mice gradually increased lick duration as well as variability. By contrast, DAT KO mice exhibited more immediate (within 10 licks) adjustments-an immediate increase in lick duration variability, as well as more rapid extinction. These results suggest that the level of dopamine can modulate the persistence and pattern generation of a highly stereotyped consummatory behavior like licking, as well as new learning in response to changes in environmental feedback. Increased dopamine in DAT KO mice not only increased perseveration of bouts and individual lick duration, but also increased the behavioral variability in response to the extinction contingency and the rate of extinction. PMID- 26029065 TI - Mutation-related differences in exploratory, spatial, and depressive-like behavior in pcd and Lurcher cerebellar mutant mice. AB - The cerebellum is not only essential for motor coordination but is also involved in cognitive and affective processes. These functions of the cerebellum and mechanisms of their disorders in cerebellar injury are not completely understood. There is a wide spectrum of cerebellar mutant mice which are used as models of hereditary cerebellar degenerations. Nevertheless, they differ in pathogenesis of manifestation of the particular mutation and also in the strain background. The aim of this work was to compare spatial navigation, learning, and memory in pcd and Lurcher mice, two of the most frequently used cerebellar mutants. The mice were tested in the open field for exploration behavior, in the Morris water maze with visible as well as reversal hidden platform tasks and in the forced swimming test for motivation assessment. Lurcher mice showed different space exploration activity in the open field and a lower tendency to depressive-like behavior in the forced swimming test compared with pcd mice. Severe deficit of spatial navigation was shown in both cerebellar mutants. However, the overall performance of Lurcher mice was better than that of pcd mutants. Lurcher mice showed the ability of visual guidance despite difficulties with the direct swim toward a goal. In the probe trial test, Lurcher mice preferred the visible platform rather than the more recent localization of the hidden goal. PMID- 26029066 TI - Regulation of ethanol intake under chronic mild stress: roles of dopamine receptors and transporters. AB - Studies have shown that exposure to chronic mild stress decreases ethanol intake and preference in dopamine D2 receptor wild-type mice (Drd2 (+/+)), while it increases intake in heterozygous (Drd2 (+/-)) and knockout (Drd2 (-/-)) mice. Dopaminergic neurotransmission in the basal forebrain plays a major role in the reinforcing actions of ethanol as well as in brain responses to stress. In order to identify neurochemical changes associated with the regulation of ethanol intake, we used in vitro receptor autoradiography to measure the levels and distribution of dopamine D1 and D2 receptors and dopamine transporters (DAT). Receptor levels were measured in the basal forebrain of Drd2 (+/+), Drd2 (+/-), and Drd2 (-/-) mice belonging to one of four groups: control (C), ethanol intake (E), chronic mild stress exposure (S), and ethanol intake under chronic mild stress (ES). D2 receptor levels were higher in the lateral and medial striatum of Drd2 (+/+) ES mice, compared with Drd2 (+/+) E mice. Ethanol intake in Drd2 (+/+) mice was negatively correlated with striatal D2 receptor levels. D2 receptor levels in Drd2(+/-) mice were the same among the four treatment groups. DAT levels were lower in Drd2(+/-) C and Drd2 (-/-) C mice, compared with Drd2 (+/+) C mice. Among Drd2(+/-) mice, S and ES groups had higher DAT levels compared with C and E groups in most regions examined. In Drd2(-/-) mice, ethanol intake was positively correlated with DAT levels in all regions studied. D1 receptor levels were lower in Drd2(+/-) and Drd2(-/-) mice, compared with Drd2(+/+), in all regions examined and remained unaffected by all treatments. The results suggest that in normal mice, ethanol intake is associated with D2 receptor-mediated neurotransmission, which exerts a protective effect against ethanol overconsumption under stress. In mice with low Drd2 expression, where DRD2 levels are not further modulated, ethanol intake is associated with DAT function which is upregulated under stress leading to ethanol overconsumption. PMID- 26029067 TI - Pre-stress performance in an instrumental training predicts post-stress behavioral alterations in chronically stressed rats. AB - Stress is a major factor in the development of major depressive disorder (MDD), but few studies have assessed individual risk based on pre-stress behavioral and cognitive traits. To address this issue, we employed appetitive instrumental lever pressing with a progressive ratio (PR) schedule to assess these traits in experimentally naive Sprague-Dawley rats. Based on four distinct traits that were identified by hierarchical cluster analysis, the animals were classified into the corresponding four subgroups (Low Motivation, Quick Learner, Slow Learner, and Hypermotivation), and exposed to chronic unpredictable stress (CUS) before monitoring their post-stress responses for 4 weeks. The four subgroups represented the following distinct behavioral phenotypes after CUS: the Low Motivation subgroup demonstrated weight loss and a late-developing paradoxical enhancement in PR performance that may be related to inappropriate decision making in human MDD. The Quick Learner subgroup exhibited a transient loss of motivation and the habituation of serum corticosterone (CORT) response to repeated stress. The Slow Learner subgroup displayed resistance to demotivation and a suppressed CORT response to acute stress. Finally, the Hypermotivation subgroup exhibited resistance to weight loss, habituated CORT response to an acute stress, and a long-lasting amotivation. Overall, we identified causal relationships between pre-stress traits in the performance of the instrumental training and post-stress phenotypes in each subgroup. In addition, many of the CUS-induced phenotypes in rats corresponded to or had putative relationships with representative symptoms in human MDD. We concluded that the consequences of stress may be predictable before stress exposure by determining the pre-stress behavioral or cognitive traits of each individual in rats. PMID- 26029068 TI - Molecular epigenetic switches in neurodevelopment in health and disease. AB - Epigenetic mechanisms encode information above and beyond DNA sequence and play a critical role in brain development and the long-lived effects of environmental cues on the pre- and postnatal brain. Switch-like, rather than graded changes, illustrate par excellence how epigenetic events perpetuate altered activity states in the absence of the initial cue. They occur from early neural development to maturation and can give rise to distinct diseases upon deregulation. Many neurodevelopmental genes harbor bivalently marked chromatin domains, states of balanced inhibition, which guide dynamic "ON or OFF" decisions once the balance is tilted in response to developmental or environmental cues. Examples discussed in this review include neuronal differentiation of embryonic stem cells (ESC) into progenitors and beyond, activation of Kiss1 at puberty onset, and early experience-dependent programming of Avp, a major stress gene. At the genome-scale, genomic imprinting can be epigenetically switched on or off at select genes in a tightly controlled temporospatial manner and provides a versatile mechanism for dosage regulation of genes with important roles in stem cell quiescence or differentiation. Moreover, retrotransposition in neural progenitors provides an intriguing example of an epigenetic-like switch, which is stimulated by bivalently marked neurodevelopmental genes and possibly results in increased genomic flexibility regarding unprecedented challenge. Overall, we propose that molecular epigenetic switches illuminate the catalyzing function of epigenetic mechanisms in guiding dynamic changes in gene expression underpinning robust transitions in cellular and organismal phenotypes as well as in the mediation between dynamically changing environments and the static genetic blueprint. PMID- 26029070 TI - Corrigendum: Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with beta-adrenergic activity. AB - [This corrects the article on p. 51 in vol. 9, PMID: 25784866.]. PMID- 26029069 TI - Aggressive vocal expressions-an investigation of their underlying neural network. AB - Recent neural network models for the production of primate vocalizations are largely based on research in nonhuman primates. These models seem yet not fully capable of explaining the neural network dynamics especially underlying different types of human vocalizations. Unlike animal vocalizations, human affective vocalizations might involve higher levels of vocal control and monitoring demands, especially in case of more complex vocal expressions of emotions superimposed on speech. Here we therefore investigated the functional cortico subcortical network underlying different types (evoked vs. repetition) of producing human affective vocalizations in terms of affective prosody, especially examining the aggressive tone of a voice while producing meaningless speech-like utterances. Functional magnetic resonance imaging revealed, first, that bilateral auditory cortices showed a close functional interconnectivity during affective vocalizations pointing to a bilateral exchange of relevant acoustic information of produced vocalizations. Second, bilateral motor cortices (MC) that directly control vocal motor behavior showed functional connectivity to the right inferior frontal gyrus (IFG) and the right superior temporal gyrus (STG). Thus, vocal motor behavior during affective vocalizations seems to be controlled by a right lateralized network that provides vocal monitoring (IFG), probably based on auditory feedback processing (STG). Third, the basal ganglia (BG) showed both positive and negative modulatory connectivity with several frontal (ACC, IFG) and temporal brain regions (STG). Finally, the repetition of affective prosody compared to evoked vocalizations revealed a more extended neural network probably based on higher control and vocal monitoring demands. Taken together, the functional brain network underlying human affective vocalizations revealed several features that have been so far neglected in models of primate vocalizations. PMID- 26029071 TI - The time course of altered brain activity during 7-day simulated microgravity. AB - Microgravity causes multiple changes in physical and mental levels in humans, which can induce performance deficiency among astronauts. Studying the variations in brain activity that occur during microgravity would help astronauts to deal with these changes. In the current study, resting-state functional magnetic resonance imaging (rs-fMRI) was used to observe the variations in brain activity during a 7-day head down tilt (HDT) bed rest, which is a common and reliable model for simulated microgravity. The amplitudes of low frequency fluctuation (ALFF) of twenty subjects were recorded pre-head down tilt (pre-HDT), during a bed rest period (HDT0), and then each day in the HDT period (HDT1-HDT7). One-way analysis of variance (ANOVA) of the ALFF values over these 8 days was used to test the variation across time period (p < 0.05, corrected). Compared to HDT0, subjects presented lower ALFF values in the posterior cingulate cortex (PCC) and higher ALFF values in the anterior cingulate cortex (ACC) during the HDT period, which may partially account for the lack of cognitive flexibility and alterations in autonomic nervous system seen among astronauts in microgravity. Additionally, the observed improvement in function in CPL during the HDT period may play a compensatory role to the functional decline in the paracentral lobule to sustain normal levels of fine motor control for astronauts in a microgravity environment. Above all, those floating brain activities during 7 days of simulated microgravity may indicate that the brain self-adapts to help astronauts adjust to the multiple negative stressors encountered in a microgravity environment. PMID- 26029072 TI - Age-related processing strategies and go-nogo effects in task-switching: an ERP study. AB - We studied cognitive and age-related changes in three task-switching (TS) paradigms: (1) informatively cued TS with go stimuli, (2) informatively cued TS with go and nogo stimuli, (3) non-informatively cued TS with go and nogo stimuli. This design allowed a direct comparison, how informative and non-informative cues influenced preparatory processes, and how nogo stimuli changed the context of the paradigm and cognitive processing in different aging groups. Beside the behavioral measures [reaction time (RT), error rate], event-related potentials (ERPs) were registered to the cue and target stimuli in young (N = 39, mean age = 21.6 +/- 1.6 years) and older (N = 40, mean age = 65.7 +/- 3.2 years) adults. The results provide evidence for declining performance in the older group: they had slower RT, less hits, more erroneous responses, higher mixing costs and decreased amplitude of ERP components than the participants of the younger group. In the task without the nogo stimuli young adults kept the previous task-set active that could be seen in shorter RT and larger amplitude of cue-locked late positivity (P3b) in task repeat (TR) trials compared to task switch trials. If both go and nogo stimuli were presented, similar RTs and P3b amplitudes appeared in the TR and TS trials. In the complex task situations older adults did not evolve an appropriate task representation and task preparation, as indicated by the lack of cue-locked P3b, CNV, and target-locked P3b. We conclude that young participants developed explicit representation of task structures, but the presence of nogo stimuli had marked effects on such representation. On the other hand, older people used only implicit control strategy to solve the task, hence the basic difference between the age groups was their strategy of task execution. PMID- 26029073 TI - Factors that determine depth perception of trapezoids, windsurfers, runways. AB - We report here a windsurfer illusion, a naturally occurring trapezoidal illusion in which the small end of the sail viewed at a distance appears to be pointed away from the observer even when it is closer. This naturally occurring illusion is so compelling that observers are unaware of their gross perceptual misinterpretation of the scene. Four laboratory experiment of this kind of trapezoidal illusion investigated the joint effects of retinal orientation, head position, relative motion, and the relative direction of gravity on automatic depth perception. Observers viewed two adjacent white trapezoids outlined on a black background rotating back and forth +/- 20 degrees on a vertical axis much like the sails of two adjacent windsurfers. Observers reported which side of the trapezoids (long or short) appeared to be closer to them (i.e., in front). The longer edge of the trapezoid was reported in front 76 +/- 2% of trials ("windsurfer effect") whether it was on the left or on the right. When the display was rotated 90 degrees to produce a runway configuration, there was a striking asymmetry: the long edge was perceived to be in front 97% when it was on the bottom but only 43% when it was on top ("runway effect"). The runway effect persisted when the head was tilted 90 degrees or when displays on the ceiling were viewed from the floor. Ninety-five percent of the variance of the variance in the strikingly different 3D perceptions produced by the same 2D trapezoid image was quantitatively explained by a model that assumes there are just three additive bias factors that account for perceiving an edge as closer: Implicit linear perspective, lower position on the retina (based on an automatic assumption of viewing from above), and being lower in world coordinates. PMID- 26029074 TI - Patterns of preserved and impaired spatial memory in a case of developmental amnesia. AB - The hippocampus is believed to have evolved to support allocentric spatial representations of environments as well as the details of personal episodes that occur within them, whereas other brain structures are believed to support complementary egocentric spatial representations. Studies of patients with adult onset lesions lend support to these distinctions for newly encountered places but suggest that with time and/or experience, schematic aspects of environments can exist independent of the hippocampus. Less clear is the quality of spatial memories acquired in individuals with impaired episodic memory in the context of a hippocampal system that did not develop normally. Here we describe a detailed investigation of the integrity of spatial representations of environments navigated repeatedly over many years in the rare case of H.C., a person with congenital absence of the mammillary bodies and abnormal hippocampal and fornix development. H.C. and controls who had extensive experience navigating the residential and downtown areas known to H.C. were tested on mental navigation tasks that assess the identity, location, and spatial relations among landmarks, and the ability to represent routes. H.C. was able to represent distances and directions between familiar landmarks and provide accurate, though inefficient, route descriptions. However, difficulties producing detailed spatial features on maps and accurately ordering more than two landmarks that are in close proximity to one another along a route suggest a spatial representation that includes only coarse, schematic information that lacks coherence and that cannot be used flexibly. This pattern of performance is considered in the context of other areas of preservation and impairment exhibited by H.C. and suggests that the allocentric-egocentric dichotomy with respect to hippocampal and extended hippocampal system function may need to be reconsidered. PMID- 26029075 TI - A review on functional and structural brain connectivity in numerical cognition. AB - Only recently has the complex anatomo-functional system underlying numerical cognition become accessible to evaluation in the living brain. We identified 27 studies investigating brain connectivity in numerical cognition. Despite considerable heterogeneity regarding methodological approaches, populations investigated, and assessment procedures implemented, the results provided largely converging evidence regarding the underlying brain connectivity involved in numerical cognition. Analyses of both functional/effective as well as structural connectivity have consistently corroborated the assumption that numerical cognition is subserved by a fronto-parietal network including (intra)parietal as well as (pre)frontal cortex sites. Evaluation of structural connectivity has indicated the involvement of fronto-parietal association fibers encompassing the superior longitudinal fasciculus dorsally and the external capsule/extreme capsule system ventrally. Additionally, commissural fibers seem to connect the bilateral intraparietal sulci when number magnitude information is processed. Finally, the identification of projection fibers such as the superior corona radiata indicates connections between cortex and basal ganglia as well as the thalamus in numerical cognition. Studies on functional/effective connectivity further indicated a specific role of the hippocampus. These specifications of brain connectivity augment the triple-code model of number processing and calculation with respect to how gray matter areas associated with specific number related representations may work together. PMID- 26029076 TI - Innervation zones of fasciculating motor units: observations by a linear electrode array. AB - This study examines the innervation zone (IZ) in the biceps brachii muscle in healthy subjects and those with amyotrophic lateral sclerosis (ALS) using a 20 channel linear electromyogram (EMG) electrode array. Raster plots of individual waveform potentials were studied to estimate the motor unit IZ. While this work mainly focused on fasciculation potentials (FPs), a limited number of motor unit potentials (MUPs) from voluntary activity of 12 healthy and seven ALS subjects were also examined. Abnormal propagation of MUPs and scattered IZs were observed in fasciculating units, compared with voluntarily activated MUPs in healthy and ALS subjects. These findings can be related to muscle fiber reinnervation following motor neuron degeneration in ALS and the different origin sites of FPs compared with voluntary MUPs. PMID- 26029077 TI - Prefrontal, posterior parietal and sensorimotor network activity underlying speed control during walking. AB - Accumulating evidence suggests cortical circuits may contribute to control of human locomotion. Here, noninvasive electroencephalography (EEG) recorded from able-bodied volunteers during a novel treadmill walking paradigm was used to assess neural correlates of walking. A systematic processing method, including a recently developed subspace reconstruction algorithm, reduced movement-related EEG artifact prior to independent component analysis and dipole source localization. We quantified cortical activity while participants tracked slow and fast target speeds across two treadmill conditions: an active mode that adjusted belt speed based on user movements and a passive mode reflecting a typical treadmill. Our results reveal frequency specific, multi-focal task related changes in cortical oscillations elicited by active walking. Low gamma band power, localized to the prefrontal and posterior parietal cortices, was significantly increased during double support and early swing phases, critical points in the gait cycle since the active controller adjusted speed based on pelvis position and swing foot velocity. These phasic gamma band synchronizations provide evidence that prefrontal and posterior parietal networks, previously implicated in visuo-spatial and somotosensory integration, are engaged to enhance lower limb control during gait. Sustained MU and beta band desynchronization within sensorimotor cortex, a neural correlate for movement, was observed during walking thereby validating our methods for isolating cortical activity. Our results also demonstrate the utility of EEG recorded during locomotion for probing the multi-regional cortical networks which underpin its execution. For example, the cortical network engagement elicited by the active treadmill suggests that it may enhance neuroplasticity for more effective motor training. PMID- 26029078 TI - Integrating electrodermal biofeedback into pharmacologic treatment of grand mal seizures. AB - Electrodermal activity (EDA) and electrodermal biofeedback, when integrated with pharmacologic treatments, indicate promising methods for the treatment of grand mal seizures. They can be used to monitor patient arousal and help patients learn new strategies to better cope with stress and anxiety. Our proposed method can possibly reduce the number of crises for patients who are dependent on pharmacologic therapy and can improve their quality of life. This article describes the scientific background of electrodermal monitoring and electrodermal biofeedback for patients affected by grand mal seizures. In this study, we have reported a clinical case study. The patient was treated for 2 years with electrodermal biofeedback to augment pharmacologic treatments. The trial has been designed in accordance with "n = 1 case study research". Our results have shown that our methods could achieve a significant reduction in grand mal seizures and sympathetic arousal when applied. The patient under consideration was also relaxed and exhibited greater competency to cope with stress. Additionally, the patient's sense of mastery and self-efficacy was enhanced. PMID- 26029080 TI - A study of tapping by the unaffected finger of patients presenting with central and peripheral nerve damage. AB - AIM: Whether the unaffected function of the hand of patients presenting with nerve injury is affected remains inconclusive. We aimed to evaluate whether there are differences in finger tapping following central or peripheral nerve injury compared with the unaffected hand and the ipsilateral hand of a healthy subject. METHODS: Thirty right brain stroke patients with hemiplegia, 30 left arm peripheral nerve injury cases, and 60 healthy people were selected. We tested finger tapping of the right hands, and each subject performed the test twice. RESULTS: Finger tapping following peripheral nerve injury as compared with the unaffected hand and the dominant hand of a healthy person was markedly higher than was found for central nerve injury (P < 0.05). Finger tapping of the male peripheral group's unaffected hand and the control group's dominant hand was significantly higher than the central group (P < 0.001). However, finger tapping of the female control group's dominant hand was significantly higher than the central group's unaffected hand (P < 0.01, P = 0.002), the peripheral group's unaffected hand (P < 0.05, P = 0.034). CONCLUSION: The unaffected function of the hand of patients with central and peripheral nerve injury was different as compared with the ipsilateral hand of healthy individuals. The rehabilitation therapist should intensify the practice of normal upper limb fine activities and coordination of the patient. PMID- 26029079 TI - Evaluating the effect of aging on interference resolution with time-varying complex networks analysis. AB - In this study we used graph theory analysis to investigate age-related reorganization of functional networks during the active maintenance of information that is interrupted by external interference. Additionally, we sought to investigate network differences before and after averaging network parameters between both maintenance and interference windows. We compared young and older adults by measuring their magnetoencephalographic recordings during an interference-based working memory task restricted to successful recognitions. Data analysis focused on the topology/temporal evolution of functional networks during both the maintenance and interference windows. We observed that: (a) Older adults require higher synchronization between cortical brain sites in order to achieve a successful recognition, (b) The main differences between age groups arise during the interference window, PMID- 26029081 TI - The effect of transcranial direct current stimulation on the expression of the flexor synergy in the paretic arm in chronic stroke is dependent on shoulder abduction loading. AB - Reaching ability of the paretic upper extremity in individuals with stroke decreases with increased shoulder abduction (SABD) loads. Transcranial direct current stimulation (tDCS) has been implemented to improve movement ability following stroke. However, results from previous studies vary, perhaps due to the influence of impairment level and the type of motor tasks that were used to study the effects of tDCS. This study specifically examines the impact of SABD loading on the effects of tDCS in 9 individuals with moderate to severe chronic stroke. In 3 different sessions, participants repeated a reaching assessment with various SABD loads (supported on a haptic table, 25%, and 50% of maximum voluntary SABD torque) in random order, pre and post one of the following 15-min tDCS protocols: anodal stimulation of lesioned M1, cathodal stimulation of non-lesioned M1, or anodal stimulation of non-lesioned M1. Sham stimulation was also conducted preceding one of the tDCS sessions. The averaged maximum reaching distance over valid trials was calculated for each condition. We observed significant interactions between SABD load, tDCS protocol and time (i.e., pre or post-tDCS). Post hoc test showed that anodal stimulation of the lesioned M1 caused a clear trend (p = 0.058) of increasing the reaching ability at a medium level of SABD loading (25%), but not for higher loads (50%). This suggests that anodal stimulation increases residual corticospinal tract activity, which successfully increases reaching ability at moderate loads; however, is insufficient to make significant changes at higher SABD loads. We also found that cathodal stimulation of the non-lesioned M1 significantly (p = 0.018) decreased the reaching distance at a high level of SABD loading (50%). This study demonstrated, for the first time, that the effect of tDCS on the reaching ability is dependent on SABD loads in individuals with moderate to severe stroke. PMID- 26029082 TI - Autism spectrum traits in normal individuals: a preliminary VBM analysis. AB - In light of the new DSM-5 autism spectrum disorders diagnosis in which the autism spectrum reflects a group of neurodevelopmental disorders existing on a continuum from mild to severe expression of autistic traits, and recent empirical findings showing a continuous distribution of autistic traits in the general population, our voxel based morphometry study compares normal individuals with high autistic traits to normal individuals with low autistic traits. We hypothesize that normal individuals with high autistic traits in terms of empathizing and systemizing [high systemizing (HS)/low empathizing (LE)] share brain irregularities with individuals that fall within the clinical autism spectrum disorder. We find differences in several social brain network areas between our groups. Specifically, we find increased gray matter (GM) volume in the orbitofrontal cortex, the cuneus, the hippocampus and parahippocampus and reduced GM volume in the inferior temporal cortex, the insula, and the amygdala in our HS/LE individuals relative to our HE/LS (low autistic traits in terms of empathizing and systemizing) individuals. PMID- 26029084 TI - Conceptual art made simple for neuroaesthetics. PMID- 26029085 TI - Task representation in individual and joint settings. AB - This paper outlines a framework for task representation and discusses applications to interference tasks in individual and joint settings. The framework is derived from the Theory of Event Coding (TEC). This theory regards task sets as transient assemblies of event codes in which stimulus and response codes interact and shape each other in particular ways. On the one hand, stimulus and response codes compete with each other within their respective subsets (horizontal interactions). On the other hand, stimulus and response code cooperate with each other (vertical interactions). Code interactions instantiating competition and cooperation apply to two time scales: on-line performance (i.e., doing the task) and off-line implementation (i.e., setting the task). Interference arises when stimulus and response codes overlap in features that are irrelevant for stimulus identification, but relevant for response selection. To resolve this dilemma, the feature profiles of event codes may become restructured in various ways. The framework is applied to three kinds of interference paradigms. Special emphasis is given to joint settings where tasks are shared between two participants. Major conclusions derived from these applications include: (1) Response competition is the chief driver of interference. Likewise, different modes of response competition give rise to different patterns of interference; (2) The type of features in which stimulus and response codes overlap is also a crucial factor. Different types of such features give likewise rise to different patterns of interference; and (3) Task sets for joint settings conflate intraindividual conflicts between responses (what), with interindividual conflicts between responding agents (whom). Features of response codes may, therefore, not only address responses, but also responding agents (both physically and socially). PMID- 26029083 TI - Non-invasive brain stimulation: an interventional tool for enhancing behavioral training after stroke. AB - Stroke is the leading cause of disability among adults. Motor deficit is the most common impairment after stroke. Especially, deficits in fine motor skills impair numerous activities of daily life. Re-acquisition of motor skills resulting in improved or more accurate motor performance is paramount to regain function, and is the basis of behavioral motor therapy after stroke. Within the past years, there has been a rapid technological and methodological development in neuroimaging leading to a significant progress in the understanding of the neural substrates that underlie motor skill acquisition and functional recovery in stroke patients. Based on this and the development of novel non-invasive brain stimulation (NIBS) techniques, new adjuvant interventional approaches that augment the response to behavioral training have been proposed. Transcranial direct current, transcranial magnetic, and paired associative (PAS) stimulation are NIBS techniques that can modulate cortical excitability, neuronal plasticity and interact with learning and memory in both healthy individuals and stroke patients. These techniques can enhance the effect of practice and facilitate the retention of tasks that mimic daily life activities. The purpose of the present review is to provide a comprehensive overview of neuroplastic phenomena in the motor system during learning of a motor skill, recovery after brain injury, and of interventional strategies to enhance the beneficial effects of customarily used neurorehabilitation after stroke. PMID- 26029087 TI - Responsiveness in DoC and individual variability. PMID- 26029086 TI - Rumination in major depressive disorder is associated with impaired neural activation during conflict monitoring. AB - Individuals with major depressive disorder (MDD) often ruminate about past experiences, especially those with negative content. These repetitive thoughts may interfere with cognitive processes related to attention and conflict monitoring. However, the temporal nature of these processes as reflected in event related potentials (ERPs) has not been well-described. We examined behavioral and ERP indices of conflict monitoring during a modified flanker task and the allocation of attention during an attentional blink (AB) task in 33 individuals with MDD and 36 healthy controls, and whether their behavioral performance and ERPs varied with level of rumination. N2 amplitude elicited by the flanker task was significantly reduced in participants with MDD compared to healthy controls. Level of self-reported rumination was also correlated with N2 amplitude. In contrast, P3 amplitude during the AB task was not significantly different between groups, nor was it correlated with rumination. No significant differences were found in behavioral task performance measures between groups or by rumination levels. These findings suggest that rumination in MDD is associated with select deficits in cognitive control, particularly related to conflict monitoring. PMID- 26029088 TI - On drawing a line through the spectrogram: how do we understand deficits of vocal pitch imitation? AB - In recent years there has been a remarkable increase in research focusing on deficits of pitch production in singing. A critical concern has been the identification of "poor pitch singers," which we refer to more generally as individuals having a "vocal pitch imitation deficit." The present paper includes a critical assessment of the assumption that vocal pitch imitation abilities can be treated as a dichotomy. Though this practice may be useful for data analysis and may be necessary within educational practice, we argue that this approach is complicated by a series of problems. Moreover, we argue that a more informative (and less problematic) approach comes from analyzing vocal pitch imitation abilities on a continuum, referred to as effect magnitude regression, and offer examples concerning how researchers may analyze data using this approach. We also argue that the understanding of this deficit may be better served by focusing on the effects of experimental manipulations on different individuals, rather than attempt to treat values of individual measures, and isolated tasks, as absolute measures of ability. PMID- 26029089 TI - Syllogisms delivered in an angry voice lead to improved performance and engagement of a different neural system compared to neutral voice. AB - Despite the fact that most real-world reasoning occurs in some emotional context, very little is known about the underlying behavioral and neural implications of such context. To further understand the role of emotional context in logical reasoning we scanned 15 participants with fMRI while they engaged in logical reasoning about neutral syllogisms presented through the auditory channel in a sad, angry, or neutral tone of voice. Exposure to angry voice led to improved reasoning performance compared to exposure to sad and neutral voice. A likely explanation for this effect is that exposure to expressions of anger increases selective attention toward the relevant features of target stimuli, in this case the reasoning task. Supporting this interpretation, reasoning in the context of angry voice was accompanied by activation in the superior frontal gyrus-a region known to be associated with selective attention. Our findings contribute to a greater understanding of the neural processes that underlie reasoning in an emotional context by demonstrating that two emotional contexts, despite being of the same (negative) valence, have different effects on reasoning. PMID- 26029090 TI - Near-infrared spectroscopy (NIRS) in functional research of prefrontal cortex. PMID- 26029091 TI - Visuomotor learning by passive motor experience. AB - Humans can adapt to unfamiliar dynamic and/or kinematic transformations through the active motor experience. Recent studies of neurorehabilitation using robots or brain-computer interface (BCI) technology suggest that passive motor experience would play a measurable role in motor recovery, however our knowledge of passive motor learning is limited. To clarify the effects of passive motor experience on human motor learning, we performed arm reaching experiments guided by a robotic manipulandum. The results showed that the passive motor experience had an anterograde transfer effect on the subsequent motor execution, whereas no retrograde interference was confirmed in the ABA paradigm experiment. This suggests that the passive experience of the error between visual and proprioceptive sensations leads to the limited but actual compensation of behavior, although it is fragile and cannot be consolidated as a persistent motor memory. PMID- 26029092 TI - Aging and loss decision making: increased risk aversion and decreased use of maximizing information, with correlated rationality and value maximization. AB - We investigated how adult aging specifically alters economic decision-making, focusing on examining alterations in uncertainty preferences (willingness to gamble) and choice strategies (what gamble information influences choices) within both the gains and losses domains. Within each domain, participants chose between certain monetary outcomes and gambles with uncertain outcomes. We examined preferences by quantifying how uncertainty modulates choice behavior as if altering the subjective valuation of gambles. We explored age-related preferences for two types of uncertainty, risk, and ambiguity. Additionally, we explored how aging may alter what information participants utilize to make their choices by comparing the relative utilization of maximizing and satisficing information types through a choice strategy metric. Maximizing information was the ratio of the expected value of the two options, while satisficing information was the probability of winning. We found age-related alterations of economic preferences within the losses domain, but no alterations within the gains domain. Older adults (OA; 61-80 years old) were significantly more uncertainty averse for both risky and ambiguous choices. OA also exhibited choice strategies with decreased use of maximizing information. Within OA, we found a significant correlation between risk preferences and choice strategy. This linkage between preferences and strategy appears to derive from a convergence to risk neutrality driven by greater use of the effortful maximizing strategy. As utility maximization and value maximization intersect at risk neutrality, this result suggests that OA are exhibiting a relationship between enhanced rationality and enhanced value maximization. While there was variability in economic decision-making measures within OA, these individual differences were unrelated to variability within examined measures of cognitive ability. Our results demonstrate that aging alters economic decision-making for losses through changes in both individual preferences and the strategies individuals employ. PMID- 26029094 TI - Interactions between sleep habits and self-control. AB - Good sleep habits and effective self-control are important components of successful functioning. Unfortunately chronic sleep loss and impaired self control are common occurrences for many individuals which can lead to difficulty with daily self-control issues such as resisting impulses and maintaining attentive behavior. Understanding how self-control is depleted and how good sleep habits may help replenish and maintain the capacity for self-control is an important issue. A sleep-deprived individual who has expended the necessary resources for self-control is at an increased risk for succumbing to impulsive desires, poor attentional capacity, and compromised decision making. To date, few studies have investigated how sleep and self-control are inter-related. The goal of this mini-review is to explore the intersection between sleep habits and self control and encourage researchers to focus on a new area of research that integrates what are at present largely separate areas in psychology and human neurosciences. PMID- 26029093 TI - Neuroprotective effects of yoga practice: age-, experience-, and frequency dependent plasticity. AB - Yoga combines postures, breathing, and meditation. Despite reported health benefits, yoga's effects on the brain have received little study. We used magnetic resonance imaging to compare age-related gray matter (GM) decline in yogis and controls. We also examined the effect of increasing yoga experience and weekly practice on GM volume and assessed which aspects of weekly practice contributed most to brain size. Controls displayed the well documented age related global brain GM decline while yogis did not, suggesting that yoga contributes to protect the brain against age-related decline. Years of yoga experience correlated mostly with GM volume differences in the left hemisphere (insula, frontal operculum, and orbitofrontal cortex) suggesting that yoga tunes the brain toward a parasympatically driven mode and positive states. The number of hours of weekly practice correlated with GM volume in the primary somatosensory cortex/superior parietal lobule (S1/SPL), precuneus/posterior cingulate cortex (PCC), hippocampus, and primary visual cortex (V1). Commonality analyses indicated that the combination of postures and meditation contributed the most to the size of the hippocampus, precuneus/PCC, and S1/SPL while the combination of meditation and breathing exercises contributed the most to V1 volume. Yoga's potential neuroprotective effects may provide a neural basis for some of its beneficial effects. PMID- 26029095 TI - Can apparent resting state connectivity arise from systemic fluctuations? AB - It is widely accepted that the fluctuations in resting state blood oxygenation level dependent (BOLD) functional MRI (fMRI) reflect baseline neuronal activation through neurovascular coupling; this data is used to infer functional connectivity in the human brain during rest. Consistent activation patterns, i.e., resting state networks (RSN) are seen across groups, conditions, and even species. In this study, we show that some of these patterns can also be generated from the dynamic, systemic, non-neuronal physiological low frequency oscillations (sLFOs) in the BOLD signal alone. We have previously used multimodal imaging to demonstrate the wide presence of the same sLFOs in the brain (BOLD) and periphery with different time delays. This study shows that these sLFOs from BOLD signals alone can give rise to stable spatial patterns, which can be detected during resting state analyses. We generated synthetic resting state data for 11 subjects based only on subject-specific, dynamic sLFO information obtained from resting state data using concurrent peripheral optical imaging or a novel recursive procedure. We compared the results obtained by performing a group independent component analysis (ICA) on this synthetic data (i.e., the result from simulation) to the results obtained from analysis of the real data. ICA detected most of the eight well-known RSNs, including visual, motor, and default mode networks (DMNs), in both the real and the synthetic data sets. These findings suggest that RSNs may reflect, to some extent, vascular anatomy associated with systemic fluctuations, rather than neuronal connectivity. PMID- 26029096 TI - Nonlinear dynamics based digital logic and circuits. AB - We discuss the role and importance of dynamics in the brain and biological neural networks and argue that dynamics is one of the main missing elements in conventional Boolean logic and circuits. We summarize a simple dynamics based computing method, and categorize different techniques that we have introduced to realize logic, functionality, and programmability. We discuss the role and importance of coupled dynamics in networks of biological excitable cells, and then review our simple coupled dynamics based method for computing. In this paper, for the first time, we show how dynamics can be used and programmed to implement computation in any given base, including but not limited to base two. PMID- 26029097 TI - In vivo comparison of the charge densities required to evoke motor responses using novel annular penetrating microelectrodes. AB - Electrodes for cortical stimulation need to deliver current to neural tissue effectively and safely. We have developed electrodes with a novel annular geometry for use in cortical visual prostheses. Here, we explore a critical question on the ideal annulus height to ensure electrical stimulation will be safe and effective. We implanted single electrodes into the motor cortex of anesthetized rats and measured the current required to evoke a motor response to stimulation, and the charge injection capacity (CIC) of the electrodes. We compared platinum iridium (PtIr) electrodes with different annulus heights, with and without a coating of porous titanium nitride (TiN). Threshold charge densities to evoke a motor response ranged from 12 to 36 MUC.cm(-2).ph(-1). Electrodes with larger geometric surface areas (GSAs) required higher currents to evoke responses, but lower charge densities. The addition of a porous TiN coating did not significantly influence the current required to evoke a motor response. The CIC of both electrode types was significantly reduced in vivo compared with in vitro measurements. The measured CIC was 72 and 18 MUC.cm(-2).ph(-1) for electrodes with and without a TiN coating, respectively. These results support the use of PtIr annular electrodes with annulus heights greater than 100 MUm (GSA of 38, 000 MUm(2)). However, if the electrodes are coated with porous TiN the annulus height can be reduced to 40 MUm (GSA of 16,000 MUm(2)). PMID- 26029098 TI - Stochastic undersampling steepens auditory threshold/duration functions: implications for understanding auditory deafferentation and aging. AB - It has long been known that some listeners experience hearing difficulties out of proportion with their audiometric losses. Notably, some older adults as well as auditory neuropathy patients have temporal-processing and speech-in-noise intelligibility deficits not accountable for by elevated audiometric thresholds. The study of these hearing deficits has been revitalized by recent studies that show that auditory deafferentation comes with aging and can occur even in the absence of an audiometric loss. The present study builds on the stochastic undersampling principle proposed by Lopez-Poveda and Barrios (2013) to account for the perceptual effects of auditory deafferentation. Auditory threshold/duration functions were measured for broadband noises that were stochastically undersampled to various different degrees. Stimuli with and without undersampling were equated for overall energy in order to focus on the changes that undersampling elicited on the stimulus waveforms, and not on its effects on the overall stimulus energy. Stochastic undersampling impaired the detection of short sounds (<20 ms). The detection of long sounds (>50 ms) did not change or improved, depending on the degree of undersampling. The results for short sounds show that stochastic undersampling, and hence presumably deafferentation, can account for the steeper threshold/duration functions observed in auditory neuropathy patients and older adults with (near) normal audiometry. This suggests that deafferentation might be diagnosed using pure-tone audiometry with short tones. It further suggests that the auditory system of audiometrically normal older listeners might not be "slower than normal", as is commonly thought, but simply less well afferented. Finally, the results for both short and long sounds support the probabilistic theories of detectability that challenge the idea that auditory threshold occurs by integration of sound energy over time. PMID- 26029099 TI - Age-related changes in brain activity are specific for high order cognitive processes during successful encoding of information in working memory. AB - Memory capacity suffers an age-related decline, which is supposed to be due to a generalized slowing of processing speed and to a reduced availability of processing resources. Information encoding in memory has been demonstrated to be very sensitive to age-related changes, especially when carried out through self initiated strategies or under high cognitive demands. However, most event-related potentials (ERP) research on age-related changes in working memory (WM) has used tasks that preclude distinction between age-related changes in encoding and retrieval processes. Here, we used ERP recording and a delayed match to sample (DMS) task with two levels of memory load to assess age-related changes in electrical brain activity in young and old adults during successful information encoding in WM. Age-related decline was reflected in lower accuracy rates and longer reaction times in the DMS task. Beside, only old adults presented lower accuracy rates under high than low memory load conditions. However, effects of memory load on brain activity were independent of age and may indicate an increased need of processing after stimulus classification as reflected in larger mean voltages in high than low load conditions between 550 and 1000 ms post stimulus for young and old adults. Regarding age-related effects on brain activity, results also revealed smaller P2 and P300 amplitudes that may signal the existence of an age dependent reduction in the processing resources available for stimulus evaluation and categorization. Additionally, P2 and N2 latencies were longer in old than in young participants. Furthermore, longer N2 latencies were related to greater accuracy rates on the DMS task, especially in old adults. These results suggest that age-related slowing of processing speed may be specific for target stimulus analysis and evaluation processes. Thus, old adults seem to improve their performance the longer they take to evaluate the stimulus they encode in visual WM. PMID- 26029100 TI - Corrigendum to: Swept-sine noise-induced damage as a hearing loss model for preclinical assays. AB - [This corrects the article on p. 7 in vol. 7, PMID: 25762930.]. PMID- 26029101 TI - A succinct overview of virtual reality technology use in Alzheimer's disease. AB - We provide a brief review and appraisal of recent and current virtual reality (VR) technology for Alzheimer's disease (AD) applications. We categorize them according to their intended purpose (e.g., diagnosis, patient cognitive training, caregivers' education, etc.), focus feature (e.g., spatial impairment, memory deficit, etc.), methodology employed (e.g., tasks, games, etc.), immersion level, and passive or active interaction. Critical assessment indicates that most of them do not yet take full advantage of virtual environments with high levels of immersion and interaction. Many still rely on conventional 2D graphic displays to create non-immersive or semi-immersive VR scenarios. Important improvements are needed to make VR a better and more versatile assessment and training tool for AD. The use of the latest display technologies available, such as emerging head mounted displays and 3D smart TV technologies, together with realistic multi sensorial interaction devices, and neuro-physiological feedback capacity, are some of the most beneficial improvements this mini-review suggests. Additionally, it would be desirable that such VR applications for AD be easily and affordably transferable to in-home and nursing home environments. PMID- 26029102 TI - Fractional anisotropy shows differential reduction in frontal-subcortical fiber bundles-A longitudinal MRI study of 76 middle-aged and older adults. AB - Motivated by the frontal- and white matter (WM) retrogenesis hypotheses and the assumptions that fronto-striatal circuits are especially vulnerable in normal aging, the goal of the present study was to identify fiber bundles connecting subcortical nuclei and frontal areas and obtain site-specific information about age related fractional anisotropy (FA) changes. Multimodal magnetic resonance image acquisitions [3D T1-weighted and diffusion weighted imaging (DWI)] were obtained from healthy older adults (N = 76, range 49-80 years at inclusion) at two time points, 3 years apart. A subset of the participants (N = 24) was included at a third time-point. In addition to the frontal-subcortical fibers, the anterior callosal fiber (ACF) and the corticospinal tract (CST) was investigated by its mean FA together with tract parameterization analysis. Our results demonstrated fronto-striatal structural connectivity decline (reduced FA) in normal aging with substantial inter-individual differences. The tract parameterization analysis showed that the along tract FA profiles were characterized by piece-wise differential changes along their extension rather than being uniformly affected. To the best of our knowledge, this is the first longitudinal study detecting age-related changes in frontal-subcortical WM connections in normal aging. PMID- 26029103 TI - Synergistic effects of free radical scavengers and cochlear vasodilators: a new otoprotective strategy for age-related hearing loss. AB - The growing increase in age-related hearing loss (ARHL), with its dramatic reduction in quality of life and significant increase in health care costs, is a catalyst to develop new therapeutic strategies to prevent or reduce this aging associated condition. In this regard, there is extensive evidence that excessive free radical formation along with diminished cochlear blood flow are essential factors involved in mechanisms of other stress-related hearing loss, such as that associated with noise or ototoxic drug exposure. The emerging view is that both play key roles in ARHL pathogenesis. Therapeutic targeting of excessive free radical formation and cochlear blood flow regulation may be a useful strategy to prevent onset of ARHL. Supporting this idea, micronutrient-based therapies, in particular those combining antioxidants and vasodilators like magnesium (Mg(2+)), have proven effective in reducing the impact of noise and ototoxic drugs in the inner ear, therefore improving auditory function. In this review, the synergistic effects of combinations of antioxidant free radicals scavengers and cochlear vasodilators will be discussed as a feasible therapeutic approach for the treatment of ARHL. PMID- 26029104 TI - Editorial: structural plasticity induced by drugs of abuse. PMID- 26029105 TI - Alpha-bisabolol, not a matter for cancer therapy. Commentary: "Research on the immunosuppressive activity of ingredients contained in sunscreens". PMID- 26029106 TI - Editorial: the changing faces of glutathione, a cellular protagonist. PMID- 26029107 TI - The case for inhibiting p38 mitogen-activated protein kinase in heart failure. AB - This minireview discusses the evidence that the inhibition of p38 mitogen activated protein kinases (p38 MAPKs) maybe of therapeutic value in heart failure. Most previous experimental studies, as well as past and ongoing clinical trials, have focussed on the role of p38 MAPKs in myocardial infarction and acute coronary syndromes. There is now growing evidence that these kinases are activated within the myocardium of the failing human heart and in the heart and blood vessels of animal models of heart failure. Furthermore, from a philosophical viewpoint the chronic activation of the adaptive stress pathways that lead to the activation of p38 MAPKs in heart failure is analogous to the chronic activation of the sympathetic, renin-aldosterone-angiotensin and neprilysin systems. These have provided some of the most effective therapies for heart failure. This minireview questions whether similar and synergistic advantages would follow the inhibition of p38 MAPKs. PMID- 26029108 TI - Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites. AB - BACKGROUND: A recent comparison showed the extensive similarities between the structural properties of metabolites in the reconstructed human metabolic network ("endogenites") and those of successful, marketed drugs ("drugs"). RESULTS: Clustering indicated the related but differential population of chemical space by endogenites and drugs. Differences between the drug-endogenite similarities resulting from various encodings and judged by Tanimoto similarity could be related simply to the fraction of the bitstrings set to 1. By extracting drug/endogenite substructures, we develop a novel family of fingerprints, the Drug Endogenite Substructure (DES) encodings, based on the ranked frequency of the various substructures. These provide a natural assessment of drug-endogenite likeness, and may be used as descriptors with which to derive quantitative structure-activity relationships (QSARs). CONCLUSIONS: "Drug-endogenite likeness" seems to have utility, and leads to a simple, novel and interpretable substructure-based molecular encoding for cheminformatics. PMID- 26029109 TI - What are the macrophages and stellate cells doing in pancreatic adenocarcinoma? AB - Pancreatic ductal adenocarcinoma is a devastating disease characterized by a dense desmoplastic stroma. Chemo- and radio-therapeutic strategies based on targeting cancer cells have failed in improving the outcome of this cancer suggesting important roles for stroma in therapy resistance. Cells in the tumor stroma have been shown to regulate proliferation, resistance to apoptosis and treatments, epithelial to mesenchymal transition (EMT) and stemness of cancer cells. Stellate cells in their activated state have been thought over the past decade to only have tumor promoting roles. However, recent findings suggest that stellate cells may have protective roles as well. The present review highlights the latest findings on the role of two major components of tumor stroma, pancreatic stellate cells and macrophages, in promoting or inhibiting pancreatic cancer, focused on their effects on EMT and cancer stemness. PMID- 26029111 TI - Editorial: Frontiers in skeletal muscle wasting, regeneration and stem cells. PMID- 26029112 TI - Using local scale exponent to characterize heart rate variability in response to postural changes in people with spinal cord injury. AB - Heart rate variability (HRV) is a promising marker for evaluating the remaining autonomic function in people with spinal cord injury (SCI). HRV is commonly assessed by spectral analysis and detrended fluctuation analysis (DFA). This study aimed to investigate whether local scale exponent alpha(t) can reveal new features of HRV that cannot be reflected by spectral measures and DFA coefficients. We studied 12 participants with SCI and 15 healthy able-bodied controls. ECG signals were continually recorded during 10 min sitting and 10 min prone postures. alpha(t) was calculated for scales between 4 and 60 s. Because alpha(t) could be overestimated at small scales, we developed an approach for correcting alpha(t) based on previous studies. The simulation results on simulated monofractal time series with alpha between 0.5 and 1.3 showed that the proposed method can yield improved estimation of alpha(t). We applied the proposed method to raw RR interval series. The results showed that alpha(t) in healthy controls monotonically decreased with scale at scales between 4 and 12 s (0.083-0.25 Hz) in both the sitting and prone postures, whereas in participants with SCI, alpha(t) slowly decreased at almost all scales. The sharp decreasing trend in alpha(t) in controls suggests a more complex dynamics of HRV in controls. alpha(t) at scales between 4 (0.25 Hz) and around 7 s (0.143 Hz) was lower in subjects with SCI than in controls in the sitting posture; alpha(t) at a narrow range of scales around 12 s (0.083 Hz) was higher in participants with SCI than in controls in the prone posture. However, none of normalized low frequency (0.04-0.15 Hz) power, the ratio of low frequency power to high frequency (0.15 0.4 Hz) power and long-term (>11 beats) DFA coefficient showed significant difference between healthy controls and subjects with SCI in the prone posture. Our results suggest that alpha(t) can reveal more detailed information in comparison to spectral measures and the standard DFA parameters. PMID- 26029110 TI - Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects. AB - Currently, schizophrenia is considered a multifactorial disease. Over the past 50 years, many investigators have considered the role of toxic free radicals in the etiology of schizophrenia. This is an area of active research which is still evolving. Here, we review the recent data and current concepts on the roles of nitric oxide (NO) and related molecules in the pathogenesis of schizophrenia. NO is involved in storage, uptake and release of mediators and neurotransmitters, including glutamate, acetylcholine, noradrenaline, GABA, taurine and glycine. In addition, NO diffuses across cell membranes and activates its own extrasynaptic receptors. Further, NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum) and fluids of subjects with schizophrenia. Given the roles of NO in central nervous system development, these changes may result in neurodevelopmental changes associated with schizophrenia. We describe here the recent literature on NOS gene polymorphisms on schizophrenia, which all point to consistent results. We also discuss how NO may be a new target for the therapy of mental disorders. Currently there have been 2 randomized double-blind placebo-controlled trials of L-lysine as an NOS inhibitor in the CNS. PMID- 26029113 TI - Endogenous electric fields as guiding cue for cell migration. AB - This review covers two topics: (1) "membrane potential of low magnitude and related electric fields (bioelectricity)" and (2) "cell migration under the guiding cue of electric fields (EF)."Membrane potentials for this "bioelectricity" arise from the segregation of charges by special molecular machines (pumps, transporters, ion channels) situated within the plasma membrane of each cell type (including eukaryotic non-neural animal cells). The arising patterns of ion gradients direct many cell- and molecular biological processes such as embryogenesis, wound healing, regeneration. Furthermore, EF are important as guiding cues for cell migration and are often overriding chemical or topographic cues. In osteoblasts, for instance, the directional information of EF is captured by charged transporters on the cell membrane and transferred into signaling mechanisms that modulate the cytoskeleton and motor proteins. This results in a persistent directional migration along an EF guiding cue. As an outlook, we discuss questions concerning the fluctuation of EF and the frequencies and mapping of the "electric" interior of the cell. Another exciting topic for further research is the modeling of field concepts for such distant, non-chemical cellular interactions. PMID- 26029114 TI - Neuromuscular function and fatigue resistance of the plantar flexors following short-term cycling endurance training. AB - Previously published studies on the effect of short-term endurance training on neuromuscular function of the plantar flexors have shown that the H-reflex elicited at rest and during weak voluntary contractions was increased following the training regime. However, these studies did not test H-reflex modulation during isometric maximum voluntary contraction (iMVC) and did not incorporate a control group in their study design to compare the results of the endurance training group to individuals without the endurance training stimulus. Therefore, this randomized controlled study was directed to investigate the neuromuscular function of the plantar flexors at rest and during iMVC before and after 8 weeks of cycling endurance training. Twenty-two young adults were randomly assigned to an intervention group and a control group. During neuromuscular testing, rate of torque development, isometric maximum voluntary torque and muscle activation were measured. Triceps surae muscle activation and tibialis anterior muscle co activation were assessed by normalized root mean square of the EMG signal during the initial phase of contraction (0-100, 100-200 ms) and iMVC of the plantar flexors. Furthermore, evoked spinal reflex responses of the soleus muscle (H reflex evoked at rest and during iMVC, V-wave), peak twitch torques induced by electrical stimulation of the posterior tibial nerve at rest and fatigue resistance were evaluated. The results indicate that cycling endurance training did not lead to a significant change in any variable of interest. Data of the present study conflict with the outcome of previously published studies that have found an increase in H-reflex excitability after endurance training. However, these studies had not included a control group in their study design as was the case here. It is concluded that short-term cycling endurance training does not necessarily enhance H-reflex responses and fatigue resistance. PMID- 26029115 TI - Scale dependence of structure-function relationship in the emphysematous mouse lung. AB - The purpose of this study was to determine how the initial distribution of elastase in mouse lungs determines the time course of tissue destruction and how structural heterogeneity at different spatial scales influences lung function. We evaluated lung function and alveolar structure in normal and emphysematous C57BL/6 mice at 2 and 21 days following orotracheal treatment with porcine pancreatic elastase (PPE). Initial distribution of elastase 1 h after treatment was assessed using red fluorescently labeled PPE (f-PPE) by laser scanning confocal microscopy. From measured input impedance of the respiratory system, the global lung compliance, and the variability of regional compliance were obtained. Lungs were fixed and equivalent airspace diameters were measured in four lobes of the right lung and three regions of the left lung. At day 2 and day 21, the mean airspace diameter of each region was significantly enlarged which was accompanied by an increased inter-regional heterogeneity. The deposition of f-PPE on day 0 was much more heterogeneous than the inter-regional diameters at both day 2 and day 21 and, at day 21, this reached statistical significance (p < 0.05). Microscale heterogeneity characterized by the overall variability of airspace diameters correlated significantly better with compliance than macroscale or inter-regional heterogeneity. Furthermore, while the spatial distribution of the inflammatory response does not seem to follow that of the elastase deposition, it correlates with the strongest regional determinant of lung function. These results may help interpret lung function decline in terms of structural deterioration in human patients with emphysema. PMID- 26029116 TI - New techniques for motion-artifact-free in vivo cardiac microscopy. AB - Intravital imaging microscopy (i.e., imaging in live animals at microscopic resolution) has become an indispensable tool for studying the cellular micro dynamics in cancer, immunology and neurobiology. High spatial and temporal resolution, combined with large penetration depth and multi-reporter visualization capability make fluorescence intravital microscopy compelling for heart imaging. However, tissue motion caused by cardiac contraction and respiration critically limits its use. As a result, in vitro cell preparations or non-contracting explanted heart models are more commonly employed. Unfortunately, these approaches fall short of understanding the more complex host physiology that may be dynamic and occur over longer periods of time. In this review, we report on novel technologies, which have been recently developed by our group and others, aimed at overcoming motion-induced artifacts and capable of providing in vivo subcellular resolution imaging in the beating mouse heart. The methods are based on mechanical stabilization, image processing algorithms, gated/triggered acquisition schemes or a combination of both. We expect that in the immediate future all these methodologies will have considerable applications in expanding our understanding of the cardiac biology, elucidating cardiomyocyte function and interactions within the organism in vivo, and ultimately improving the treatment of cardiac diseases. PMID- 26029117 TI - Unexpected plant odor responses in a moth pheromone system. AB - Male moths rely on olfactory cues to find females for reproduction. Males also use volatile plant compounds (VPCs) to find food sources and might use host-plant odor cues to identify the habitat of calling females. Both the sex pheromone released by conspecific females and VPCs trigger well-described oriented flight behavior toward the odor source. Whereas detection and central processing of pheromones and VPCs have been thought for a long time to be highly separated from each other, recent studies have shown that interactions of both types of odors occur already early at the periphery of the olfactory pathway. Here we show that detection and early processing of VPCs and pheromone can overlap between the two sub-systems. Using complementary approaches, i.e., single-sensillum recording of olfactory receptor neurons, in vivo calcium imaging in the antennal lobe, intracellular recordings of neurons in the macroglomerular complex (MGC) and flight tracking in a wind tunnel, we show that some plant odorants alone, such as heptanal, activate the pheromone-specific pathway in male Agrotis ipsilon at peripheral and central levels. To our knowledge, this is the first report of a plant odorant with no chemical similarity to the molecular structure of the pheromone, acting as a partial agonist of a moth sex pheromone. PMID- 26029119 TI - Maternal nutritional manipulations program adipose tissue dysfunction in offspring. AB - Based on the concept of Developmental Origin of Health and Disease, both human and animal studies have demonstrated a close link between nutrient supply perturbations in the fetus or neonate (i.e., maternal undernutrition, obesity, gestational diabetes and/or rapid catch-up growth) and increased risk of adult onset obesity. Indeed, the adipose tissue has been recognized as a key target of developmental programming in a sex-and depot-specific manner. Despite different developmental time windows, similar mechanisms of adipose tissue programming have been described in rodents and in bigger mammals (sheep, primates). Maternal nutritional manipulations reprogram offspring's adipose tissue resulting in series of alterations: enhanced adipogenesis and lipogenesis, impaired sympathetic activity with reduced noradrenergic innervations and thermogenesis as well as low-grade inflammation. These changes affect adipose tissue development, distribution and composition predisposing offspring to fat accumulation. Modifications of hormonal tissue sensitivity (i.e., leptin, insulin, glucocorticoids) and/or epigenetic mechanisms leading to persistent changes in gene expression may account for long-lasting programming across generations. PMID- 26029120 TI - Auditory beat stimulation and its effects on cognition and mood States. AB - Auditory beat stimulation may be a promising new tool for the manipulation of cognitive processes and the modulation of mood states. Here, we aim to review the literature examining the most current applications of auditory beat stimulation and its targets. We give a brief overview of research on auditory steady-state responses and its relationship to auditory beat stimulation (ABS). We have summarized relevant studies investigating the neurophysiological changes related to ABS and how they impact upon the design of appropriate stimulation protocols. Focusing on binaural-beat stimulation, we then discuss the role of monaural- and binaural-beat frequencies in cognition and mood states, in addition to their efficacy in targeting disease symptoms. We aim to highlight important points concerning stimulation parameters and try to address why there are often contradictory findings with regard to the outcomes of ABS. PMID- 26029118 TI - Human cervicovaginal fluid biomarkers to predict term and preterm labor. AB - Preterm birth (PTB; birth before 37 completed weeks of gestation) remains the major cause of neonatal morbidity and mortality. The current generation of biomarkers predictive of PTB have limited utility. In pregnancy, the human cervicovaginal fluid (CVF) proteome is a reflection of the local biochemical milieu and is influenced by the physical changes occurring in the vagina, cervix and adjacent overlying fetal membranes. Term and preterm labor (PTL) share common pathways of cervical ripening, myometrial activation and fetal membranes rupture leading to birth. We therefore hypothesize that CVF biomarkers predictive of labor may be similar in both the term and preterm labor setting. In this review, we summarize some of the existing published literature as well as our team's breadth of work utilizing the CVF for the discovery and validation of putative CVF biomarkers predictive of human labor. Our team established an efficient method for collecting serial CVF samples for optimal 2-dimensional gel electrophoresis resolution and analysis. We first embarked on CVF biomarker discovery for the prediction of spontaneous onset of term labor using 2D electrophoresis and solution array multiple analyte profiling. 2D-electrophoretic analyses were subsequently performed on CVF samples associated with PTB. Several proteins have been successfully validated and demonstrate that these biomarkers are associated with term and PTL and may be predictive of both term and PTL. In addition, the measurement of these putative biomarkers was found to be robust to the influences of vaginal microflora and/or semen. The future development of a multiple biomarker bed-side test would help improve the prediction of PTB and the clinical management of patients. PMID- 26029122 TI - Cross-cultural influences on rhythm processing: reproduction, discrimination, and beat tapping. AB - The structures of musical rhythm differ between cultures, despite the fact that the ability to entrain movement to musical rhythm occurs in virtually all individuals across cultures. To measure the influence of culture on rhythm processing, we tested East African and North American adults on perception, production, and beat tapping for rhythms derived from East African and Western music. To assess rhythm perception, participants identified whether pairs of rhythms were the same or different. To assess rhythm production, participants reproduced rhythms after hearing them. To assess beat tapping, participants tapped the beat along with repeated rhythms. We expected that performance in all three tasks would be influenced by the culture of the participant and the culture of the rhythm. Specifically, we predicted that a participant's ability to discriminate, reproduce, and accurately tap the beat would be better for rhythms from their own culture than for rhythms from another culture. In the rhythm discrimination task, there were no differences in discriminating culturally familiar and unfamiliar rhythms. In the rhythm reproduction task, both groups reproduced East African rhythms more accurately than Western rhythms, but East African participants also showed an effect of cultural familiarity, leading to a significant interaction. In the beat tapping task, participants in both groups tapped the beat more accurately for culturally familiar than for unfamiliar rhythms. Moreover, there were differences between the two participant groups, and between the two types of rhythms, in the metrical level selected for beat tapping. The results demonstrate that culture does influence the processing of musical rhythm. In terms of the function of musical rhythm, our results are consistent with theories that musical rhythm enables synchronization. Musical rhythm may foster musical cultural identity by enabling within-group synchronization to music, perhaps supporting social cohesion. PMID- 26029121 TI - Sex differences in behavioral impulsivity in at-risk and non-risk drinkers. AB - INTRODUCTION: Mounting evidence from both animal and human studies suggests that females are more vulnerable to drug and alcohol abuse than males. Some of this increased risk may be related to behavioral traits, such as impulsivity. Here, we examined sex differences in two forms of behavioral impulsivity (inhibitory control and impulsive choice) in young men and women, in relation to their level of alcohol consumption and alcohol-related problems (at-risk or non-risk). METHODS: Participants performed a go/no-go task to assess inhibitory control and a measure of delay discounting to assess impulsive choice. RESULTS: On the measure of inhibitory control, at-risk women committed significantly more inhibitory errors than at-risk men, indicating poorer behavioral control among the women. By contrast, no sex differences were observed between at-risk men and women in delay discounting, or between the male and female non-risk drinkers on any measure. CONCLUSION: Heavy drinking women displayed poorer inhibitory control than heavy drinking men. It remains to be determined whether the sex differences in inhibitory control are the result of drinking, or whether they pre-dated the problematic drinking in these individuals. PMID- 26029123 TI - Emotionally excited eyeblink-rate variability predicts an experience of transportation into the narrative world. AB - Collective spectator communications such as oral presentations, movies, and storytelling performances are ubiquitous in human culture. This study investigated the effects of past viewing experiences and differences in expressive performance on an audience's transportive experience into a created world of a storytelling performance. In the experiment, 60 participants (mean age = 34.12 years, SD = 13.18 years, range 18-63 years) were assigned to watch one of two videotaped performances that were played (1) in an orthodox way for frequent viewers and (2) in a modified way aimed at easier comprehension for first-time viewers. Eyeblink synchronization among participants was quantified by employing distance-based measurements of spike trains, D (spike) and D (interval) (Victor and Purpura, 1997). The results indicated that even non-familiar participants' eyeblinks were synchronized as the story progressed and that the effect of the viewing experience on transportation was weak. Rather, the results of a multiple regression analysis demonstrated that the degrees of transportation could be predicted by a retrospectively reported humor experience and higher real-time variability (i.e., logarithmic transformed SD) of inter blink intervals during a performance viewing. The results are discussed from the viewpoint in which the extent of eyeblink synchronization and eyeblink-rate variability acts as an index of the inner experience of audience members. PMID- 26029124 TI - Soccer results affect subjective well-being, but only briefly: a smartphone study during the 2014 FIFA World Cup. AB - The current research examined the effects of soccer match results on spectators' subjective well-being. Across the group stage of the soccer World Cup 2014, German-speaking participants indicated their well-being three times per day through a smartphone-based science app. In line with proposed hypotheses, comparisons of data taken after the three matches of the German national team showed robust effects, revealing that well-being was higher among spectators than non-spectators, with effects increasing as a function of goal difference. Moreover, this gain in well-being was only found in spectators supporting the German soccer team, allowing us to rule out a general emotional contagion effect affecting all spectators. Although soccer results are associated with national identity and pride, their effects on subjective well-being were short-lived and only affected supporters. PMID- 26029125 TI - The effects of processing and sequence organization on the timing of turn taking: a corpus study. AB - The timing of turn taking in conversation is extremely rapid given the cognitive demands on speakers to comprehend, plan and execute turns in real time. Findings from psycholinguistics predict that the timing of turn taking is influenced by demands on processing, such as word frequency or syntactic complexity. An alternative view comes from the field of conversation analysis, which predicts that the rules of turn-taking and sequence organization may dictate the variation in gap durations (e.g., the functional role of each turn in communication). In this paper, we estimate the role of these two different kinds of factors in determining the speed of turn-taking in conversation. We use the Switchboard corpus of English telephone conversation, already richly annotated for syntactic structure speech act sequences, and segmental alignment. To this we add further information including Floor Transfer Offset (the amount of time between the end of one turn and the beginning of the next), word frequency, concreteness, and surprisal values. We then apply a novel statistical framework ("random forests") to show that these two dimensions are interwoven together with indexical properties of the speakers as explanatory factors determining the speed of response. We conclude that an explanation of the of the timing of turn taking will require insights from both processing and sequence organization. PMID- 26029126 TI - Assessing motivation and readiness to change for weight management and control: an in-depth evaluation of three sets of instruments. AB - It is highly recommended to promptly assess motivation and readiness to change (RTC) in individuals who wish to achieve significant lifestyle behavior changes in order to improve their health, overall quality of life, and well-being. In particular, motivation should be assessed for those who face the difficult task to maintain weight, which implies a double challenge: weight loss initially and its management subsequently. In fact, weight-control may be as problematic as smoking or drugs-taking cessation, since they all share the commonality of being highly refractory to change. This paper will examine three well-established tools following the Transtheoretical Model, specifically assessing RTC in weight management: the University of Rhode Island Change Assessment Scale, the S-Weight and the P-Weight and the Decisional Balance Inventory. Though their strengths and weaknesses may appear to be rather homogeneous and similar, the S-Weight and P Weight are more efficient in assessing RTC in weight management and control. Assessing motivation and RTC may be a crucial step in promptly identifying psychological obstacles or resistance toward weight-management in overweight or obese hospitalized individuals, and it may contribute to provide a more effective weight-control treatment intervention. PMID- 26029127 TI - Just entertainment: effects of TV series about intrigue on young adults. AB - The potential harmful effects of media violence have been studied systematically and extensively. However, very little attention has been devoted to the intrigue and struggles between people depicted in the mass media. A longitudinal randomized experimental group-control group, pretest-posttest design study was conducted to examine the potential effects of this type of TV series on young adults. A typical and popular TV series was select as a stimulus. By scrutinizing the outline of this TV series and inspired by studies of the effects of media violence, one behavioral observation and five scales were adopted as dependent measures. The study did not find any effect of the intrigue TV series on any of the six dependent variables. Finally, possible interference variables or moderators were discussed. PMID- 26029128 TI - Decision-making competence predicts domain-specific risk attitudes. AB - Decision-making competence (DMC) reflects individual differences in rational responding across several classic behavioral decision-making tasks. Although it has been associated with real-world risk behavior, less is known about the degree to which DMC contributes to specific components of risk attitudes. Utilizing a psychological risk-return framework, we examined the associations between risk attitudes and DMC. Italian community residents (n = 804) completed an online DMC measure, using a subset of the original Adult-DMC battery. Participants also completed a self-reported risk attitude measure for three components of risk attitudes (risk-taking, risk perceptions, and expected benefits) across six risk domains. Overall, greater performance on the DMC component scales were inversely, albeit modestly, associated with risk-taking tendencies. Structural equation modeling results revealed that DMC was associated with lower perceived expected benefits for all domains. In contrast, its association with perceived risks was more domain-specific. These analyses also revealed stronger indirect effects for the DMC -> expected benefits -> risk-taking path than the DMC -> perceived risk > risk-taking path, especially for behaviors that may be considered more maladaptive in nature. These results suggest that DMC performance differentially impacts specific components of risk attitudes, and may be more strongly related to the evaluation of expected value of a specific behavior. PMID- 26029129 TI - Repeat what after whom? Exploring variable selectivity in a cross-dialectal shadowing task. AB - Twenty women from Christchurch, New Zealand and 16 from Columbus Ohio (dialect region U.S. Midland) participated in a bimodal lexical naming task where they repeated monosyllabic words after four speakers from four regional dialects: New Zealand, Australia, U.S. Inland North and U.S. Midland. The resulting utterances were acoustically analyzed, and presented to listeners on Amazon Mechanical Turk in an AXB task. Convergence is observed, but differs depending on the dialect of the speaker, the dialect of the model, the particular word class being shadowed, and the order in which dialects are presented to participants. We argue that these patterns are generally consistent with findings that convergence is promoted by a large phonetic distance between shadower and model (Babel, 2010, contra Kim et al., 2011), and greater existing variability in a vowel class (Babel, 2012). The results also suggest that more comparisons of accommodation toward different dialects are warranted, and that the investigation of the socio indexical meaning of specific linguistic forms in context is a promising avenue for understanding variable selectivity in convergence. PMID- 26029130 TI - From incoherence to mirth: neuro-cognitive processing of garden-path jokes. AB - In so-called garden-path jokes, an initial semantic representation is violated, and semantic revision reestablishes a coherent representation. 48 jokes were manipulated in three conditions: (i) a coherent ending, (ii) a joke ending, and (iii) a discourse-incoherent ending. A reading times study (N = 24) and three studies with recordings of ERP and pupil changes (N = 21, 24, and 24, respectively) supported the hypothesized cognitive processes. Jokes showed increased reading times of the final word compared to coherent endings. ERP data mainly indicated semantic integration difficulties (N400). Larger pupil diameters to joke endings presumably reflect emotional responses. ERP evidence for increased discourse processing efforts and emotional responses, as assumed to be reflected in modulations of the late left anterior negativity (LLAN) and in an enhanced late frontal positivity (fP600), respectively, remains however incomplete. Processing of incoherent endings was also accompanied by increased reading times, a stronger and sustained N400, and context-sensitive P600 effects. Together, these findings provide evidence for a sequential, non-monotonic, and incremental discourse comprehension of garden-path jokes. PMID- 26029131 TI - Do semantic contextual cues facilitate transfer learning from video in toddlers? AB - Young children typically demonstrate a transfer deficit, learning less from video than live presentations. Semantically meaningful context has been demonstrated to enhance learning in young children. We examined the effect of a semantically meaningful context on toddlers' imitation performance. Two- and 2.5-year-olds participated in a puzzle imitation task to examine learning from either a live or televised model. The model demonstrated how to assemble a three-piece puzzle to make a fish or a boat, with the puzzle demonstration occurring against a semantically meaningful background context (ocean) or a yellow background (no context). Participants in the video condition performed significantly worse than participants in the live condition, demonstrating the typical transfer deficit effect. While the context helped improve overall levels of imitation, especially for the boat puzzle, only individual differences in the ability to self-generate a stimulus label were associated with a reduction in the transfer deficit. PMID- 26029132 TI - Imitation as a mechanism in cognitive development: a cross-cultural investigation of 4-year-old children's rule learning. AB - Children learn about the social and physical world by observing other people's acts. This experiment tests both Chinese and American children's learning of a rule. For theoretical reasons we chose the rule of categorizing objects by the weight. Children, age 4 years, saw an adult heft four visually-identical objects and sort them into two bins based on an invisible property-the object's weight. Children who saw this categorization behavior were more likely to sort those objects by weight than were children who saw control actions using the same objects and the same bins. Crucially, children also generalized to a novel set of objects with no further demonstration, suggesting rule learning. We also report that high-fidelity imitation of the adult's "hefting" acts may give children crucial experience with the objects' weights, which could then be used to infer the more abstract rule. The connection of perception, action, and cognition was found in children from both cultures, which leads to broad implications for how the imitation of adults' acts functions as a lever in cognitive development. PMID- 26029134 TI - A cultural look at moral purity: wiping the face clean. AB - Morality is associated with bodily purity in the custom of many societies. Does that imply moral purity is a universal psychological phenomenon? Empirically, it has never been examined, as all prior experimental data came from Western samples. Theoretically, we suggest the answer is not so straightforward-it depends on the kind of universality under consideration. Combining perspectives from cultural psychology and embodiment, we predict a culture-specific form of moral purification. Specifically, given East Asians' emphasis on the face as a representation of public self-image, we hypothesize that facial purification should have particularly potent moral effects in a face culture. Data show that face-cleaning (but not hands-cleaning) reduces guilt and regret most effectively against a salient East Asian cultural background. It frees East Asians from guilt driven prosocial behavior. In the wake of their immorality, they find a face cleaning product especially appealing and spontaneously choose to wipe their face clean. These patterns highlight both culturally variable and universal aspects of moral purification. They further suggest an organizing principle that informs the vigorous debate between embodied and amodal perspectives. PMID- 26029133 TI - Is it the real deal? Perception of virtual characters versus humans: an affective cognitive neuroscience perspective. AB - Recent developments in neuroimaging research support the increased use of naturalistic stimulus material such as film, avatars, or androids. These stimuli allow for a better understanding of how the brain processes information in complex situations while maintaining experimental control. While avatars and androids are well suited to study human cognition, they should not be equated to human stimuli. For example, the uncanny valley hypothesis theorizes that artificial agents with high human-likeness may evoke feelings of eeriness in the human observer. Here we review if, when, and how the perception of human-like avatars and androids differs from the perception of humans and consider how this influences their utilization as stimulus material in social and affective neuroimaging studies. First, we discuss how the appearance of virtual characters affects perception. When stimuli are morphed across categories from non-human to human, the most ambiguous stimuli, rather than the most human-like stimuli, show prolonged classification times and increased eeriness. Human-like to human stimuli show a positive linear relationship with familiarity. Secondly, we show that expressions of emotions in human-like avatars can be perceived similarly to human emotions, with corresponding behavioral, physiological and neuronal activations, with exception of physical dissimilarities. Subsequently, we consider if and when one perceives differences in action representation by artificial agents versus humans. Motor resonance and predictive coding models may account for empirical findings, such as an interference effect on action for observed human-like, natural moving characters. However, the expansion of these models to explain more complex behavior, such as empathy, still needs to be investigated in more detail. Finally, we broaden our outlook to social interaction, where virtual reality stimuli can be utilized to imitate complex social situations. PMID- 26029135 TI - From the eyes and the heart: a novel eye-gaze metric that predicts video preferences of a large audience. AB - Eye-tracking has been extensively used to quantify audience preferences in the context of marketing and advertising research, primarily in methodologies involving static images or stimuli (i.e., advertising, shelf testing, and website usability). However, these methodologies do not generalize to narrative-based video stimuli where a specific storyline is meant to be communicated to the audience. In this paper, a novel metric based on eye-gaze dispersion (both within and across viewings) that quantifies the impact of narrative-based video stimuli to the preferences of large audiences is presented. The metric is validated in predicting the performance of video advertisements aired during the 2014 Super Bowl final. In particular, the metric is shown to explain 70% of the variance in likeability scores of the 2014 Super Bowl ads as measured by the USA TODAY Ad Meter. In addition, by comparing the proposed metric with Heart Rate Variability (HRV) indices, we have associated the metric with biological processes relating to attention allocation. The underlying idea behind the proposed metric suggests a shift in perspective when it comes to evaluating narrative-based video stimuli. In particular, it suggests that audience preferences on video are modulated by the level of viewers lack of attention allocation. The proposed metric can be calculated on any narrative-based video stimuli (i.e., movie, narrative content, emotional content, etc.), and thus has the potential to facilitate the use of such stimuli in several contexts: prediction of audience preferences of movies, quantitative assessment of entertainment pieces, prediction of the impact of movie trailers, identification of group, and individual differences in the study of attention-deficit disorders, and the study of desensitization to media violence. PMID- 26029136 TI - What's in and what's out in branding? A novel articulation effect for brand names. AB - The present approach exploits the biomechanical connection between articulation and ingestion-related mouth movements to introduce a novel psychological principle of brand name design. We constructed brand names for diverse products with consonantal stricture spots either from the front to the rear of the mouth, thus inwards (e.g., BODIKA), or from the rear to the front, thus outwards (e.g., KODIBA). These muscle dynamics resemble the oral kinematics during either ingestion (inwards), which feels positive, or expectoration (outwards), which feels negative. In 7 experiments (total N = 1261), participants liked products with inward names more than products with outward names (Experiment 1), reported higher purchase intentions (Experiment 2), and higher willingness-to-pay (Experiments 3a-3c, 4, 5), with the price gain amounting to 4-13% of the average estimated product value. These effects occurred across English and German language, under silent reading, for both edible and non-edible products, and even in the presence of a much stronger price determinant, namely fair-trade production (Experiment 5). PMID- 26029137 TI - Emotional expression recognition and attribution bias among sexual and violent offenders: a signal detection analysis. AB - Research with violent offenders has consistently shown impaired recognition of other's facial expressions of emotion. However, the extent to which similar problems can be observed among sexual offenders remains unknown. Using a computerized task, we presented sexual and violent offenders, and non-offenders, with male and female expressions of anger, disgust, fear, happiness, sadness, and surprise, morphed with neutral expressions at varying levels of intensity (10, 55, and 90% expressive). Based on signal detection theory, we used hit rates and false alarms to calculate the sensitivity index d-prime (d') and criterion (c) for each emotional expression. Overall, sexual offenders showed reduced sensitivity to emotional expressions across intensity, sex, and type of expression, compared with non-offenders, while both sexual and violent offenders showed particular reduced sensitivity to fearful expressions. We also observed specific effects for high (90%) intensity female faces, with sexual offenders showing reduced sensitivity to anger compared with non-offenders and violent offenders, and reduced sensitivity to disgust compared with non-offenders. Furthermore, both sexual and violent offenders showed impaired sensitivity to high intensity female fearful expressions compared with non-offenders. Violent offenders also showed a higher criterion for classifying moderate and high intensity male expressions as fearful, indicative of a more conservative response style, compared with angry, happy, or sad. These results suggest that both types of offender show problems in emotion recognition, and may have implications for understanding the inhibition of violent and sexually violent behaviors. PMID- 26029138 TI - An eye movement pre-training fosters the comprehension of processes and functions in technical systems. AB - The main research goal of the present study was to investigate in how far pre training eye movements can facilitate knowledge acquisition in multimedia (pre training principle). We combined considerations from research on eye movement modeling and pre-training to design and test a non-verbal eye movement-based pre training. Participants in the experimental condition watched an animated circle moving in close spatial resemblance to a static visualization of a solar plant accompanied by a narration in a subsequently presented learning environment. This training was expected to foster top-down processes as reflected in gaze behavior during the learning process and enhance knowledge acquisition. We compared two groups (N = 45): participants in the experimental condition received pre-training in a first step and processed the learning material in a second step, whereas the control group underwent the second step without any pre-training. The pre training group outperformed the control group in their learning outcomes, particularly in knowledge about processes and functions of the solar plant. However, the superior learning outcomes in the pre-training group could not be explained by eye-movement patterns. Furthermore, the pre-training moderated the relationship between experienced stress and learning outcomes. In the control group, high stress levels hindered learning, which was not found for the pre training group. On a delayed posttest participants were requested to draw a picture of the learning content. Despite a non-significant effect of training on the quality of drawings, the pre-training showed associations between learning outcomes at the first testing time and process-related aspects in the quality of their drawings. Overall, non-verbal pre-training is a successful instructional intervention to promote learning processes in novices although these processes did not directly reflect in learners' eye movement behavior during learning. PMID- 26029139 TI - Individual differences in toddlers' social understanding and prosocial behavior: disposition or socialization? AB - We examined how individual differences in social understanding contribute to variability in early-appearing prosocial behavior. Moreover, potential sources of variability in social understanding were explored and examined as additional possible predictors of prosocial behavior. Using a multi-method approach with both observed and parent-report measures, 325 children aged 18-30 months were administered measures of social understanding (e.g., use of emotion words; self understanding), prosocial behavior (in separate tasks measuring instrumental helping, empathic helping, and sharing, as well as parent-reported prosociality at home), temperament (fearfulness, shyness, and social fear), and parental socialization of prosocial behavior in the family. Individual differences in social understanding predicted variability in empathic helping and parent reported prosociality, but not instrumental helping or sharing. Parental socialization of prosocial behavior was positively associated with toddlers' social understanding, prosocial behavior at home, and instrumental helping in the lab, and negatively associated with sharing (possibly reflecting parents' increased efforts to encourage children who were less likely to share). Further, socialization moderated the association between social understanding and prosocial behavior, such that social understanding was less predictive of prosocial behavior among children whose parents took a more active role in socializing their prosociality. None of the dimensions of temperament was associated with either social understanding or prosocial behavior. Parental socialization of prosocial behavior is thus an important source of variability in children's early prosociality, acting in concert with early differences in social understanding, with different patterns of influence for different subtypes of prosocial behavior. PMID- 26029140 TI - Novel mechanisms, treatments, and outcome measures in childhood sleep. AB - Sleep disorders and sleep of insufficient duration and quality are on the increase due to changes in our lifestyle, particularly in children and adolescents. Sleep disruption is also more common in children with medical conditions, compounding their difficulties. Recent studies have focused on new mechanisms that explain how learning and cognitive performance depend on a good night's sleep. Growing alongside this latest understanding is an innovative new field of non-drug interventions that improve sleep architecture, with resulting cognitive improvements. However, we need to rigorously evaluate such potentially popular and self-administered sleep interventions with equally state-of-the-art outcome measurement tools. Animated hand-held games, that incorporate embedded sleep-dependent learning tasks, promise to offer new robust methods of measuring changes in overnight learning. Portable computing technology has the potential to offer practical, inexpensive and reliable tools to indirectly assess the quality of sleep. They may be adopted in both clinical and educational settings, providing a unique way of monitoring the effect of sleep disruption on learning, leading also to a radical rethink of how we manage chronic diseases. PMID- 26029141 TI - Network-based characterization of brain functional connectivity in Zen practitioners. AB - In the last decade, a number of neuroimaging studies have investigated the neurophysiological effects associated with contemplative practices. Meditation related changes in resting state functional connectivity (rsFC) have been previously reported, particularly in the default mode network, frontoparietal attentional circuits, saliency-related regions, and primary sensory cortices. We collected functional magnetic resonance imaging data from a sample of 12 experienced Zen meditators and 12 meditation-naive matched controls during a basic attention-to-breathing protocol, together with behavioral performance outside the scanner on a set of computerized neuropsychological tests. We adopted a network system of 209 nodes, classified into nine functional modules, and a multi-stage approach to identify rsFC differences in meditators and controls. Between-group comparisons of modulewise FC, summarized by the first principal component of the relevant set of edges, revealed important connections of frontoparietal circuits with early visual and executive control areas. We also identified several group differences in positive and negative edgewise FC, often involving the visual, or frontoparietal regions. Multivariate pattern analysis of modulewise FC, using support vector machine (SVM), classified meditators, and controls with 79% accuracy and selected 10 modulewise connections that were jointly prominent in distinguishing meditators and controls; a similar SVM procedure based on the subjects' scores on the neuropsychological battery yielded a slightly weaker accuracy (75%). Finally, we observed a good correlation between the across-subject variation in strength of modulewise connections among frontoparietal, executive, and visual circuits, on the one hand, and in the performance on a rapid visual information processing test of sustained attention, on the other. Taken together, these findings highlight the usefulness of employing network analysis techniques in investigating the neural correlates of contemplative practices. PMID- 26029142 TI - Patients experiences of maintaining mental well-being and hope within motor neuron disease: a thematic synthesis. AB - Research is required that can synthesize the experiences of patients with Motor Neuron Disease (MND). One value of being able to do this is to understand the psychological experiences and processes involved in maintaining mental well-being and hope. A qualitative thematic synthesis of studies was undertaken. Studies were electronically searched from inception until June 2014. Twenty-nine studies with 342 (175 male) unique individuals with MND were identified. Five themes were identified: (1)The effects of the disease on interactions, relationships, roles and meaningful activities, (2) Responses that relate to the expression of hope, (3) Factors which disable hope, (4) Factors which enable hope, and (5) Cognitive and Practical adaptation that enabled hope, control and coping. Finally, a model of hope enablement was identified that considers the psychological pathways undertaken by a patient which influence mental well-being and hope. Within this review article evidence is provided which illustrates the central importance of relationships and social support for individuals with MND. Further, it has been identified that periods of coping are possible and are likely associated with greater mental well-being for patients with MND. PMID- 26029143 TI - Positive relationship between odor identification and affective responses of negatively valenced odors. AB - Hedonic ratings of odors and olfactory preferences are influenced by a number of modulating factors, such as prior experience and knowledge about an odor's identity. The present study addresses the relationship between knowledge about an odor's identity due to prior experience, assessed by means of a test of cued odor identification, and odor pleasantness ratings in children who exhibit ongoing olfactory learning. Ninety-one children aged 8-11 years rated the pleasantness of odors in the Sniffin' Sticks test and, subsequently, took the odor identification test. A positive association between odor identification and pleasantness was found for two unpleasant food odors (garlic and fish): higher pleasantness ratings were exhibited by those participants who correctly identified these odors compared to those who failed to correctly identify them. However, we did not find a similar effect for any of the more pleasant odors. The results of this study suggest that pleasantness ratings of some odors may be modulated by the knowledge of their identity due to prior experience and that this relationship might be more evident in unpleasant odors. PMID- 26029144 TI - Good character at school: positive classroom behavior mediates the link between character strengths and school achievement. AB - Character strengths have been found to be substantially related to children's and adolescents' well-being. Initial evidence suggests that they also matter for school success (e.g., Weber and Ruch, 2012). The present set of two studies aimed at replicating and extending these findings in two different age groups, primary school students (N = 179; mean age = 11.6 years) and secondary school students (N = 199; mean age = 14.4 years). The students completed the VIA-Youth (Values in Action Inventory of Strengths for Youth), a self-report measure of the 24 character strengths in the VIA classification. Their teachers rated the students' positive behavior in the classroom. Additionally, school achievement was assessed: For the primary school students (Study 1), teachers rated the students' overall school achievement and for the secondary school students (Study 2), we used their grades as a measure of school achievement. We found that several character strengths were associated with both positive classroom behavior and school achievement. Across both samples, school achievement was correlated with love of learning, perseverance, zest, gratitude, hope, and perspective. The strongest correlations with positive classroom behavior were found for perseverance, self-regulation, prudence, social intelligence, and hope. For both samples, there were indirect effects of some of the character strengths on school achievement through teacher-rated positive classroom behavior. The converging findings from the two samples support the notion that character strengths contribute to positive classroom behavior, which in turn enhances school achievement. Results are discussed in terms of their implications for future research and for school interventions based on character strengths. PMID- 26029145 TI - Two steps to space for numbers. PMID- 26029146 TI - Dynamics of auditory working memory. AB - Working memory denotes the ability to retain stimuli in mind that are no longer physically present and to perform mental operations on them. Electro- and magnetoencephalography allow investigating the short-term maintenance of acoustic stimuli at a high temporal resolution. Studies investigating working memory for non-spatial and spatial auditory information have suggested differential roles of regions along the putative auditory ventral and dorsal streams, respectively, in the processing of the different sound properties. Analyses of event-related potentials have shown sustained, memory load-dependent deflections over the retention periods. The topography of these waves suggested an involvement of modality-specific sensory storage regions. Spectral analysis has yielded information about the temporal dynamics of auditory working memory processing of individual stimuli, showing activation peaks during the delay phase whose timing was related to task performance. Coherence at different frequencies was enhanced between frontal and sensory cortex. In summary, auditory working memory seems to rely on the dynamic interplay between frontal executive systems and sensory representation regions. PMID- 26029147 TI - Pedagogical applications of cognitive research on musical improvisation. AB - This paper presents a model for the implementation of educational activities involving musical improvisation that is based on a review of the literature on the psychology of music. Psychology of music is a complex field of research in which quantitative and qualitative methods have been employed involving participants ranging from novices to expert performers. The cognitive research has been analyzed to propose a pedagogical approach to the development of processes rather than products that focus on an expert's use of improvisation. The intention is to delineate a reflective approach that goes beyond the mere instruction of some current practices of teaching improvisation in jazz pedagogy. The review highlights that improvisation is a complex, multidimensional act that involves creative and performance behaviors in real-time in addition to processes such as sensory and perceptual encoding, motor control, performance monitoring, and memory storage and recall. Educational applications for the following processes are outlined: anticipation, use of repertoire, emotive communication, feedback, and flow. These characteristics are discussed in relation to the design of a pedagogical approach to musical improvisation based on reflection and metacognition development. PMID- 26029148 TI - The benefits of looking at intraindividual dynamics in cognitive training data. PMID- 26029149 TI - Negative emotion provides cues for orienting auditory spatial attention. AB - The auditory stimuli provide information about the objects and events around us. They can also carry biologically significant emotional information (such as unseen dangers and conspecific vocalizations), which provides cues for allocation of attention and mental resources. Here, we investigated whether task-irrelevant auditory emotional information can provide cues for orientation of auditory spatial attention. We employed a covert spatial orienting task: the dot-probe task. In each trial, two task-irrelevant auditory cues were simultaneously presented at two separate locations (left-right or front-back). Environmental sounds were selected to form emotional vs. neutral, emotional vs. emotional, and neutral vs. neutral cue pairs. The participants' task was to detect the location of an acoustic target that was presented immediately after the task-irrelevant auditory cues. The target was presented at the same location as one of the auditory cues. The results indicated that participants were significantly faster to locate the target when it replaced the negative cue compared to when it replaced the neutral cue. The positive cues did not produce a clear attentional bias. Further, same valence pairs (emotional-emotional or neutral-neutral) did not modulate reaction times due to a lack of spatial attention capture by one cue in the pair. Taken together, the results indicate that negative affect can provide cues for the orientation of spatial attention in the auditory domain. PMID- 26029151 TI - The close proximity of threat: altered distance perception in the anticipation of pain. AB - Pain is an experience that powerfully influences the way we interact with our environment. What is less clear is the influence that pain has on the way we perceive our environment. We investigated the effect that the anticipation of experimental pain (THREAT) and its relief (RELIEF) has on the visual perception of space. Eighteen (11F) healthy volunteers estimated the distance to alternating THREAT and RELIEF stimuli that were placed within reachable space. The results determined that the estimated distance to the THREAT stimulus was significantly underestimated in comparison to the RELIEF stimulus. We conclude that pain evoking stimuli are perceived as closer to the body than otherwise identical pain relieving stimuli, an important consideration when applied to our decisions and behaviors in relation to the experience of pain. PMID- 26029150 TI - Sleep smart-optimizing sleep for declarative learning and memory. AB - The last decade has witnessed a spurt of new publications documenting sleep's essential contribution to the brains ability to form lasting memories. For the declarative memory domain, slow wave sleep (the deepest sleep stage) has the greatest beneficial effect on the consolidation of memories acquired during preceding wakefulness. The finding that newly encoded memories become reactivated during subsequent sleep fostered the idea that reactivation leads to the strengthening and transformation of the memory trace. According to the active system consolidation account, trace reactivation leads to the redistribution of the transient memory representations from the hippocampus to the long-lasting knowledge networks of the cortex. Apart from consolidating previously learned information, sleep also facilitates the encoding of new memories after sleep, which probably relies on the renormalization of synaptic weights during sleep as suggested by the synaptic homeostasis theory. During wakefulness overshooting potentiation causes an imbalance in synaptic weights that is countered by synaptic downscaling during subsequent sleep. This review briefly introduces the basic concepts and central findings of the research on sleep and memory, and discusses implications of this lab-based work for everyday applications to make the best possible use of sleep's beneficial effect on learning and memory. PMID- 26029152 TI - Longitudinal changes in young children's 0-100 to 0-1000 number-line error signatures. AB - We use a latent difference score (LDS) model to examine changes in young children's number-line (NL) error signatures (errors marking numbers on a NL) over 18 months. A LDS model (1) overcomes some of the inference limitations of analytic models used in previous research, and in particular (2) provides a more reliable test of hypotheses about the meaning and significance of changes in NL error signatures over time and task. The NL error signatures of 217 6-year-olds' (on test occasion one) were assessed three times over 18 months, along with their math ability on two occasions. On the first occasion (T1) children completed a 0 100 NL task; on the second (T2) a 0-100 NL and a 0-1000 NL task; on the third (T3) occasion a 0-1000 NL task. On the third and fourth occasions (T3 and T4), children completed mental calculation tasks. Although NL error signatures changed over time, these were predictable from other NL task error signatures, and predicted calculation accuracy at T3, as well as changes in calculation between T3 and T4. Multiple indirect effects (change parameters) showed that associations between initial NL error signatures (0-100 NL) and later mental calculation ability were mediated by error signatures on the 0-1000 NL task. The pattern of findings from the LDS model highlight the value of identifying direct and indirect effects in characterizing changing relationships in cognitive representations over task and time. Substantively, they support the claim that children's NL error signatures generalize over task and time and thus can be used to predict math ability. PMID- 26029154 TI - Human peripheral clocks: applications for studying circadian phenotypes in physiology and pathophysiology. AB - Most light-sensitive organisms on earth have acquired an internal system of circadian clocks allowing the anticipation of light or darkness. In humans, the circadian system governs nearly all aspects of physiology and behavior. Circadian phenotypes, including chronotype, vary dramatically among individuals and over individual lifespan. Recent studies have revealed that the characteristics of human skin fibroblast clocks correlate with donor chronotype. Given the complexity of circadian phenotype assessment in humans, the opportunity to study oscillator properties by using cultured primary cells has the potential to uncover molecular details difficult to assess directly in humans. Since altered properties of the circadian oscillator have been associated with many diseases including metabolic disorders and cancer, clock characteristics assessed in additional primary cell types using similar technologies might represent an important tool for exploring the connection between chronotype and disease, and for diagnostic purposes. Here, we review implications of this approach for gathering insights into human circadian rhythms and their function in health and disease. PMID- 26029153 TI - The potential of pathological protein fragmentation in blood-based biomarker development for dementia - with emphasis on Alzheimer's disease. AB - The diagnosis of dementia is challenging and early stages are rarely detected limiting the possibilities for early intervention. Another challenge is the overlap in the clinical features across the different dementia types leading to difficulties in the differential diagnosis. Identifying biomarkers that can detect the pre-dementia stage and allow differential diagnosis could provide an opportunity for timely and optimal intervention strategies. Also, such biomarkers could help in selection and inclusion of the right patients in clinical trials of both Alzheimer's disease and other dementia treatment candidates. The cerebrospinal fluid (CSF) has been the most investigated source of biomarkers and several candidate proteins have been identified. However, looking solely at protein levels is too simplistic to provide enough detailed information to differentiate between dementias, as there is a significant crossover between the proteins involved in the different types of dementia. Additionally, CSF sampling makes these biomarkers challenging for presymptomatic identification. We need to focus on disease-specific protein fragmentation to find a fragment pattern unique for each separate dementia type - a form of protein fragmentology. Targeting protein fragments generated by disease-specific combinations of proteins and proteases opposed to detecting the intact protein could reduce the overlap between diagnostic groups as the extent of processing as well as which proteins and proteases constitute the major hallmark of each dementia type differ. In addition, the fragments could be detectable in blood as they may be able to cross the blood-brain barrier due to their smaller size. In this review, the potential of the fragment-based biomarker discovery for dementia diagnosis and prognosis is discussed, especially highlighting how the knowledge from CSF protein biomarkers can be used to guide blood-based biomarker development. PMID- 26029155 TI - Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth. AB - Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer. PMID- 26029156 TI - Impact of natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remitting multiple sclerosis. AB - BACKGROUND/OBJECTIVE: Fatigue, cognitive, and affective disorders are relevant symptoms in multiple sclerosis (MS). The treatment with Natalizumab has a positive effect on physical disabilities in patients with relapsing-remitting MS (RRMS). Some studies describe improvements in cognition and fatigue over 1 year of treatment. Only little is known about longer treatment effects especially on fatigue, and also on cognition and mood. Therefore, the present retrospective open label observational study investigates the effect of Natalizumab on fatigue, attention, and depression over a treatment period of 2 years. METHODS: About 51 RRMS patients who were treated with Natalizumab (male = 11, female = 40; mean age: 33. 9 +/- 9. 1 years) were included. The neuropsychological assessment consisted of different tests of attention (TAP: alertness, divided attention, flexibility, SDMT, PASAT), fatigue (WEIMuS, FSMC), and depression (CES-D). The assessments occurred immediately before the first administration of Natalizumab, after 1 and 2 years of treatment. RESULTS: Significant improvements were found in aspects of attention and depression from baseline to follow-up 1 [alertness: reaction time (RT) cued, p < 0.05; divided attention: visual RT, p < 0.05; SDMT: p = 0.05; CES-D: p < 0.05] and from baseline to follow-up 2 (divided attention: visual RT: p < 0.001; errors: p < 0.01, omissions: p < 0.05; flexibility: RT, p < 0.05; SDMT: p < 0.01; CES-D: p < 0.05). No significant changes were detected in fatigue, probably because of the small sample size, especially in the second year of treatment (WEIMuS: N = 16, FSMC: N = 8). CONCLUSION: The results show a positive effect of Natalizumab on attention in patients with RRMS, and for the first time, also in depression after 2 years of observation, and support the efficacy of the treatment over 2 years. More research is needed for fatigue. PMID- 26029157 TI - Owls and larks in mice. AB - Humans come in different chronotypes and, particularly, the late chronotype (the so-called owl) has been shown to be associated with several health risks. A number of studies show that laboratory mice also display various chronotypes. In mice as well as in humans, the chronotype shows correlations with the period length and rhythm stability. In addition, some mouse models for human diseases show alterations in their chronotypic behavior, which are comparable to those humans. Thus, analysis of the behavior of mice is a powerful tool to unravel the molecular and genetic background of the chronotype and the prevalence of risks and diseases that are associated with it. In this review, we summarize the correlation of chronotype with free-running period length and rhythm stability in inbred mouse strains, in mice with a compromised molecular clockwork, and in a mouse model for neurodegeneration. PMID- 26029158 TI - Dynamic changes in DNA methylation in ischemic tolerance. AB - Epigenetic mediators of gene expression are hypothesized to regulate transcriptomic responses to preconditioning ischemia and ischemic tolerance. Here, we utilized a methyl-DNA enrichment protocol and sequencing (ChIP-seq) to identify patterns of DNA methylation in an established model of ischemic tolerance in neuronal cultures (oxygen and glucose deprivation: OGD). We observed an overall decrease in global DNA methylation at 4 h following preconditioning ischemia (30 min OGD), harmful ischemia (120 min OGD), and in ischemic tolerant neuronal cultures (30 min OGD, 24 h recovery, 120 min OGD). We detected a smaller cohort of hypermethylated regions following ischemic conditions, which were further analyzed revealing differential chromosomal localization of methylation, and a differential concentration of methylation on genomic regions. Together, these data show that the temporal profiles of DNA methylation with respect to chromatin hyper- and hypo-methylation following various ischemic conditions are highly dynamic, and may reveal novel targets for neuroprotection. PMID- 26029159 TI - Functional and structural correlates of memory in patients with mesial temporal lobe epilepsy. AB - Individuals with medial temporal lobe epilepsy (mTLE) often show material specific memory impairment (verbal for left, visuospatial for right hemisphere), which can be exacerbated following surgery aimed at the epileptogenic regions of medial and anterolateral temporal cortex. There is a growing body of evidence suggesting that characterization of structural and functional integrity of these regions using MRI can aid in prediction of post-surgical risk of further memory decline. We investigated the nature of the relationship between structural and functional indices of hippocampal integrity with pre-operative memory performance in a group of 26 patients with unilateral mTLE. Structural integrity was assessed using hippocampal volumes, while functional integrity was assessed using hippocampal activation during the encoding of novel scenes. We quantified structural and functional integrity in terms of asymmetry, calculated as (L - R)/(L + R). Factor scores for verbal and visual memory were calculated from a clinical database and an asymmetry score (verbal - visual) was used to characterize memory performance. We found, as expected, a significant difference between left and right mTLE (RTLE) groups for hippocampal volume asymmetry, with each group showing an asymmetry favoring the unaffected temporal lobe. Encoding activation asymmetry showed a similar pattern, with left mTLE patients showing activation preferential to the right hemisphere and RTLE patients showing the reverse. Finally, we demonstrated that functional integrity mediated the relationship between structural integrity and memory performance for memory asymmetry, suggesting that even if structural changes are evident, ultimately it is the functional integrity of the tissue that most closely explains behavioral performance. PMID- 26029160 TI - Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy. AB - Mutations of the voltage-gated sodium channel SCN8A have been identified in approximately 1% of nearly 1,500 children with early-infantile epileptic encephalopathies (EIEE) who have been tested by DNA sequencing. EIEE caused by mutation of SCN8A is designated EIEE13 (OMIM #614558). Affected children have seizure onset before 18 months of age as well as developmental and cognitive disabilities, movement disorders, and a high incidence of sudden death (SUDEP). EIEE13 is caused by de novo missense mutations of evolutionarily conserved residues in the Nav1.6 channel protein. One-third of the mutations are recurrent, and many occur at CpG dinucleotides. In this review, we discuss the effect of pathogenic mutations on the structure of the channel protein, the rate of recurrent mutation, and changes in channel function underlying this devastating disorder. PMID- 26029161 TI - Audiometric characteristics of hyperacusis patients. AB - Hyperacusis is a frequent auditory disorder where sounds of normal volume are perceived as too loud or even painfully loud. There is a high degree of co morbidity between hyperacusis and tinnitus, most hyperacusis patients also have tinnitus, but only about 30-40% of tinnitus patients also show symptoms of hyperacusis. In order to elucidate the mechanisms of hyperacusis, detailed measurements of loudness discomfort levels (LDLs) across the hearing range would be desirable. However, previous studies have only reported LDLs for a restricted frequency range, e.g., from 0.5 to 4 kHz or from 1 to 8 kHz. We have measured audiograms and LDLs in 381 patients with a primary complaint of hyperacusis for the full standard audiometric frequency range from 0.125 to 8 kHz. On average, patients had mild high-frequency hearing loss, but more than a third of the tested ears had normal hearing thresholds (HTs), i.e., <=20 dB HL. LDLs were found to be significantly decreased compared to a normal-hearing reference group, with average values around 85 dB HL across the frequency range. However, receiver operating characteristic analysis showed that LDL measurements are neither sensitive nor specific enough to serve as a single test for hyperacusis. There was a moderate positive correlation between HTs and LDLs (r = 0.36), i.e., LDLs tended to be higher at frequencies where hearing loss was present, suggesting that hyperacusis is unlikely to be caused by HT increase, in contrast to tinnitus for which hearing loss is a main trigger. Moreover, our finding that LDLs are decreased across the full range of audiometric frequencies, regardless of the pattern or degree of hearing loss, indicates that hyperacusis might be due to a generalized increase in auditory gain. Tinnitus on the other hand is thought to be caused by neuroplastic changes in a restricted frequency range, suggesting that tinnitus and hyperacusis might not share a common mechanism. PMID- 26029162 TI - Lewis, Fischer 344, and sprague-dawley rats display differences in lipid peroxidation, motor recovery, and rubrospinal tract preservation after spinal cord injury. AB - The rat is the most common animal model for the preclinical validation of neuroprotective therapies in spinal cord injury (SCI). Lipid peroxidation (LP) is a hallmark of the damage triggered after SCI. Free radicals react with fatty acids causing cellular and membrane disruption. LP accounts for a considerable amount of neuronal cell death after SCI. To better understand the implications of inbred and outbred rat strain selection on preclinical SCI research, we evaluated LP after laminectomy sham surgery and a severe contusion of the T9 spinal cord in female Sprague-Dawley (SPD), Lewis (LEW), and Fischer 344 (F344) rats. Further analysis included locomotor recovery using the Basso, Beattie, and Bresnahan (BBB) scale and retrograde rubrospinal tract tracing. LEW had the highest levels of LP products 72 h after sham surgery and SCI, significantly different from both F344 and SPD. SPD rats had the fastest functional recovery and highest BBB scores; these were not significantly different to F344. However, LEW rats achieved the lowest BBB scores throughout the 2-month follow-up, yielding significant differences when compared to SPD and F344. To see if the improvement in locomotion was secondary to an increase in axon survival, we evaluated rubrospinal neurons (RSNs) via retrograde labeling of the rubrospinal tract and quantified cells at the red nuclei. The highest numbers of RSNs were observed in SPD rats then F344; the lowest counts were seen in LEW rats. The BBB scores significantly correlated with the amount of positively stained RSN in the red nuclei. It is critical to identify interstrain variations as a potential confound in preclinical research. Multi-strain validation of neuroprotective therapies may increase chances of successful translation. PMID- 26029164 TI - Global Characteristics of CSIG-Associated Gene Expression Changes in Human HEK293 Cells and the Implications for CSIG Regulating Cell Proliferation and Senescence. AB - Cellular senescence-inhibited gene (CSIG), also named as ribosomal_L1 domain containing 1 (RSL1D1), is implicated in various processes including cell cycle regulation, cellular senescence, apoptosis, and tumor metastasis. However, little is known about the regulatory mechanism underlying its functions. To screen important targets and signaling pathways modulated by CSIG, we compared the gene expression profiles in CSIG-silencing and control HEK293 cells using Affymetrix microarray Human Genome U133 Plus 2.0 GeneChips. A total of 590 genes displayed statistically significant expression changes, with 279 genes up-regulated and 311 down-regulated, respectively. These genes are involved in a broad array of biological processes, mainly in transcriptional regulation, cell cycle, signal transduction, oxidation reduction, development, and cell adhesion. The differential expression of genes such as ZNF616, KPNA5, and MAP3K3 was further validated by real-time PCR and western blot analysis. Furthermore, we investigated the correlated expression patterns of Cdc14B, ESCO1, KPNA5, MAP3K3, and CSIG during cell cycle and senescence progression, which imply the important pathways CSIG regulating cell cycle and senescence. The mechanism study showed that CSIG modulated the mRNA half-life of Cdc14B, CASP7, and CREBL2. This study shows that expression profiling can be used to identify genes that are transcriptionally or post-transcriptionally modified following CSIG knockdown and to reveal the molecular mechanism of cell proliferation and senescence regulated by CSIG. PMID- 26029163 TI - Reporter Cell Lines for the Characterization of the Interactions between Human Nuclear Receptors and Endocrine Disruptors. AB - Endocrine-disrupting chemicals (EDCs) are exogenous substances interfering with hormone biosynthesis, metabolism, or action, and consequently causing disturbances in the endocrine system. Various pathways are activated by EDCs, including interactions with nuclear receptors (NRs), which are primary targets of numerous environmental contaminants. The main NRs targeted by environmental contaminants are the estrogen (ER alpha, beta) and the androgen (AR) receptors. ERs and AR have pleiotropic regulatory roles in a diverse range of tissues, notably in the mammary gland, the uterus, and the prostate. Thus, dysfunctional ERs and AR signaling due to inappropriate exposure to environmental pollutants may lead to hormonal cancers and infertility. The pregnane X receptor (PXR) is also recognized by many environmental molecules. PXR has a protective role of the body through its ability to regulate proteins involved in the metabolism, the conjugation, and the transport of many exogenous and endogenous compounds. However, the permanent activation of this receptor by xenobiotics may lead to premature drug metabolism, the formation, and accumulation of toxic metabolites and defects in hormones homeostasis. The activity of other NRs can also be affected by environmental molecules. Compounds capable of inhibiting or activating the estrogen related (ERRgamma), the thyroid hormone (TRalpha, beta), the retinoid X receptors (RXRalpha, beta, gamma), and peroxisome proliferator activated (PPAR alpha, gamma) receptors have been identified and are highly suspected to promote developmental, reproductive, neurological, or metabolic diseases in humans and wildlife. In this review, we provide an overview of reporter cell lines established to characterize the human NR activities of a large panel of EDCs including natural as well as industrial compounds such as pesticides, plasticizers, surfactants, flame retardants, and cosmetics. PMID- 26029165 TI - Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines. AB - Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Several studies have confirmed the involvement of the insulin-like growth factor (IGF) system in the regulation of OS cell proliferation and differentiation as well as in the protection of cells from chemotherapy. Insulin receptor substrate (IRS)-1 is a critical mediator of IGF-1R signaling, and we recently reported that its overexpression in OS cells increases proliferation, migration, and metastasis both in vitro and in vivo. In this study, we evaluated the efficacy of NT157, a selective inhibitor of IRS-1/2, in a panel of OS cells. A strong dose-dependent inhibition of growth was observed in the MG-63, OS-19, and U-2OS OS cell lines, displaying IC50 values at sub-micromolar doses after 72 h of treatment. Exposure to NT157 elicited dose- and time-dependent decreases in IRS-1 levels. Moreover, a protein analysis showed that the degradation of IRS-1 inhibited the activation of principal downstream mediators of the IGF pathway. NT157 significantly affected the cells' migratory ability, as confirmed by a wound-healing assay. The inhibitor induced cytostatic effects, as evidenced by G2/M cell cycle arrest, and did not affect apoptosis. Consequently, NT157 was combined with drugs used to treat OS in order to capitalize on its therapeutic potential. Simultaneous treatments were made in association with chemotherapeutic agents in a fixed ratio for 72 h and cell proliferation was determined by MTT assay. Synergistic or addictive effects with respect to single agents are expressed as the combination index. Significant synergistic effects were obtained with several targeted drugs, such as Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and NVP-BEZ235, a dual inhibitor of PI-3K/mTOR. Overall, these findings provide evidence for the effectiveness of a selected inhibitor of IRS 1/2 NT157 in OS cells, displaying a promising approach based on the targeting of IRS-1 combined with other therapies for the treatment of this pediatric solid tumor. PMID- 26029166 TI - Editorial: neurological and psychiatric disorders in endocrine diseases. PMID- 26029168 TI - Transcriptomic evidence for microbial sulfur cycling in the eastern tropical North Pacific oxygen minimum zone. AB - Microbial communities play central roles in ocean biogeochemical cycles, and are particularly important in in oceanic oxygen minimum zones (OMZs). However, the key carbon, nitrogen, and sulfur (S) cycling processes catalyzed by OMZ microbial communities are poorly constrained spatially, temporally, and with regard to the different microbial groups involved. Here we sample across dissolved oxygen (DO) gradients in the oceans' largest OMZ by volume-the eastern tropical North Pacific ocean, or ETNP-and quantify 16S rRNA and functional gene transcripts to detect and constrain the activity of different S-cycling groups. Based on gene expression profiles, putative dissimilatory sulfite reductase (dsrA) genes are actively expressed within the ETNP OMZ. dsrA expression was limited almost entirely to samples with elevated nitrite concentrations, consistent with previous observations in the Eastern Tropical South Pacific OMZ. dsrA and 'reverse' dissimilatory sulfite reductase (rdsrA) genes are related and the associated enzymes are known to operate in either direction-reducing or oxidizing different S compounds. We found that rdsrA genes and soxB genes were expressed in the same samples, suggestive of active S cycling in the ETNP OMZ. These data provide potential thresholds for S cycling in OMZs that closely mimic recent predictions, and indicate that S cycling may be broadly relevant in OMZs. PMID- 26029169 TI - Potent antagonistic activity of Egyptian Lactobacillus plantarum against multiresistant and virulent food-associated pathogens. AB - Recent years have shown a growing interest to replace the administration of antibiotics with the application of probiotics. The aim of our investigation was to screen for promising strains with broad antimicrobial activity and also more resistant to the challenges met in the gastrointestinal tract. In our study, only 32 out of 50 (64%) probiotic isolates showed antagonistic activity against certain major extensively and pandrug-resistant Gram-positive and -negative food borne pathogens. Fifteen L. plantarum isolates had a broad antibacterial spectrum. Among these isolates, only five presented potent antibacterial activity relative to previous studies. The recorded inhibition zone diameter ranged from 25 to 44 mm. Pronounced cell-free supernatant activities (6400-25,600 AU/ml) were commonly detected at the end of the logarithmic phase at 37 degrees C. A marked increase in the range of activity (12,800-51,200 AU/ml) was recorded after the addition of 0.9% Na Cl to the media. Moreover, subjecting these isolates to different stressors, including high temperature, low pH, and different concentrations of bile and Na Cl, revealed different responses, and only two out of the five L. plantarum isolates showed marked resistance to all of the stress factors. Accordingly, this study highlights the intense and broad antagonistic activity induced by L. plantarum against various food associated pathogens, and their ability to resist different stressors suggests that they can be used in the food and pharmaceutical industry. PMID- 26029167 TI - The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link. AB - Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted. PMID- 26029170 TI - Shifts in methanogenic community composition and methane fluxes along the degradation of discontinuous permafrost. AB - The response of methanogens to thawing permafrost is an important factor for the global greenhouse gas budget. We tracked methanogenic community structure, activity, and abundance along the degradation of sub-Arctic palsa peatland permafrost. We observed the development of pronounced methane production, release, and abundance of functional (mcrA) methanogenic gene numbers following the transitions from permafrost (palsa) to thaw pond structures. This was associated with the establishment of a methanogenic community consisting both of hydrogenotrophic (Methanobacterium, Methanocellales), and potential acetoclastic (Methanosarcina) members and their activity. While peat bog development was not reflected in significant changes of mcrA copy numbers, potential methane production, and rates of methane release decreased. This was primarily linked to a decline of potential acetoclastic in favor of hydrogenotrophic methanogens. Although palsa peatland succession offers similarities with typical transitions from fen to bog ecosystems, the observed dynamics in methane fluxes and methanogenic communities are primarily attributed to changes within the dominant Bryophyta and Cyperaceae taxa rather than to changes in peat moss and sedge coverage, pH and nutrient regime. Overall, the palsa peatland methanogenic community was characterized by a few dominant operational taxonomic units (OTUs). These OTUs seem to be indicative for methanogenic species that thrive in terrestrial organic rich environments. In summary, our study shows that after an initial stage of high methane emissions following permafrost thaw, methane fluxes, and methanogenic communities establish that are typical for northern peat bogs. PMID- 26029171 TI - Heat shock protein 90 inhibitors repurposed against Entamoeba histolytica. AB - Hsp90 is an essential chaperone responsible for trafficking a vast array of client proteins, which are substrates that Hsp90 regulates in eukaryotic cells under stress conditions. The ATP-binding N-terminal domain of Hsp90 (also known as a GHKL type ATPase domain) can serve as a specific drug target, because sufficient structural diversity in the ATP-binding pocket of Hsp90 allows for ortholog selectivity of Hsp90 inhibitors. The primary objective of this study is to identify inhibitors specific for the ATP-binding domain of Entamoeba histolytica Hsp90 (EhHsp90). An additional aim, using a combination of site directed mutagenesis and a protein in vitro assay, is to show that the antiparasitic activity of Hsp90 inhibitors is dependent on specific residues within the ATP-binding domain. Here, we tested the activity of 43 inhibitors of Hsp90 that we previously identified using a high-throughput screen. Of the 43 compounds tested, 19 competed for binding of the EhHsp90 ATP-binding domain. Five out of the 19 EhHsp90 protein hits demonstrated activity against E. histolytica in vitro culture: rifabutin, rutilantin, cetylpyridinium chloride, pararosaniline pamoate and gentian violet. These five top E. histolytica Hsp90 inhibitors showed 30-100% inhibition of E. histolytica in culture in the micromolar range. These data suggest that E. histolytica-specific Hsp90 inhibitors are possible to identify and provide important lead compounds for the development of novel antiamebic drugs. PMID- 26029172 TI - Enlightening the malaria parasite life cycle: bioluminescent Plasmodium in fundamental and applied research. AB - The unicellular protozoan parasites of the genus Plasmodium impose on human health worldwide the enormous burden of malaria. The possibility to genetically modify several species of malaria parasites represented a major advance in the possibility to elucidate their biology and is now turning laboratory lines of transgenic Plasmodium into precious weapons to fight malaria. Amongst the various genetically modified plasmodia, transgenic parasite lines expressing bioluminescent reporters have been essential to unveil mechanisms of parasite gene expression and to develop in vivo imaging approaches in mouse malaria models. Mainly the human malaria parasite Plasmodium falciparum and the rodent parasite P. berghei have been engineered to express bioluminescent reporters in almost all the developmental stages of the parasite along its complex life cycle between the insect and the vertebrate hosts. Plasmodium lines expressing conventional and improved luciferase reporters are now gaining a central role to develop cell based assays in the much needed search of new antimalarial drugs and to open innovative approaches for both fundamental and applied research in malaria. PMID- 26029173 TI - Growth of Rhodococcus sp. strain BCP1 on gaseous n-alkanes: new metabolic insights and transcriptional analysis of two soluble di-iron monooxygenase genes. AB - Rhodococcus sp. strain BCP1 was initially isolated for its ability to grow on gaseous n-alkanes, which act as inducers for the co-metabolic degradation of low chlorinated compounds. Here, both molecular and metabolic features of BCP1 cells grown on gaseous and short-chain n-alkanes (up to n-heptane) were examined in detail. We show that propane metabolism generated terminal and sub-terminal oxidation products such as 1- and 2-propanol, whereas 1-butanol was the only terminal oxidation product detected from n-butane metabolism. Two gene clusters, prmABCD and smoABCD-coding for Soluble Di-Iron Monooxgenases (SDIMOs) involved in gaseous n-alkanes oxidation-were detected in the BCP1 genome. By means of Reverse Transcriptase-quantitative PCR (RT-qPCR) analysis, a set of substrates inducing the expression of the sdimo genes in BCP1 were assessed as well as their transcriptional repression in the presence of sugars, organic acids, or during the cell growth on rich medium (Luria-Bertani broth). The transcriptional start sites of both the sdimo gene clusters were identified by means of primer extension experiments. Finally, proteomic studies revealed changes in the protein pattern induced by growth on gaseous- (n-butane) and/or liquid (n-hexane) short chain n-alkanes as compared to growth on succinate. Among the differently expressed protein spots, two chaperonins and an isocytrate lyase were identified along with oxidoreductases involved in oxidation reactions downstream of the initial monooxygenase reaction step. PMID- 26029174 TI - Comparative genomics reveals diversified CRISPR-Cas systems of globally distributed Microcystis aeruginosa, a freshwater bloom-forming cyanobacterium. AB - Microcystis aeruginosa is one of the most common and dominant bloom-forming cyanobacteria in freshwater lakes around the world. Microcystis cells can produce toxic secondary metabolites, such as microcystins, which are harmful to human health. Two M. aeruginosa strains were isolated from two highly eutrophic lakes in China and their genomes were sequenced. Comparative genomic analysis was performed with the 12 other available M. aeruginosa genomes and closely related unicellular cyanobacterium. Each genome of M. aeruginosa containing at least one clustered regularly interspaced short palindromic repeat (CRISPR) locus and total 71 loci were identified, suggesting it is ubiquitous in M. aeruginosa genomes. In addition to the previously reported subtype I-D cas gene sets, three CAS subtypes I-A, III-A and III-B were identified and characterized in this study. Seven types of CRISPR direct repeat have close association with CAS subtype, confirming that different and specific secondary structures of CRISPR repeats are important for the recognition, binding and process of corresponding cas gene sets. Homology search of the CRISPR spacer sequences provides a history of not only resistance to bacteriophages and plasmids known to be associated with M. aeruginosa, but also the ability to target much more exogenous genetic material in the natural environment. These adaptive and heritable defense mechanisms play a vital role in keeping genomic stability and self-maintenance by restriction of horizontal gene transfer. Maintaining genomic stability and modulating genomic plasticity are both important evolutionary strategies for M. aeruginosa in adaptation and survival in various habitats. PMID- 26029175 TI - Identification of metabolism pathways directly regulated by sigma(54) factor in Bacillus thuringiensis. AB - Sigma(54) (sigma(54)) regulates nitrogen and carbon utilization in bacteria. Promoters that are sigma(54)-dependent are highly conserved and contain short sequences located at the -24 and -12 positions upstream of the transcription initiation site. sigma(54) requires regulatory proteins known as bacterial enhancer-binding proteins (bEBPs) to activate gene transcription. We show that sigma(54) regulates the capacity to grow on various nitrogen sources using a Bacillus thuringiensis HD73 mutant lacking the sigL gene encoding sigma(54) (DeltasigL). A 2-fold-change cutoff and a false discovery rate cutoff of P < 0.05 were used to analyze the DNA microarray data, which revealed 255 genes that were downregulated and 121 that were upregulated in the DeltasigL mutant relative to the wild-type HD73 strain. The sigma(54) regulon (stationary phase) was characterized by DNA microarray, bioinformatics, and functional assay; 16 operons containing 47 genes were identified whose promoter regions contain the conserved 12/-24 element and whose transcriptional activities were abolished or reduced in the DeltasigL mutant. Eight sigma(54)-dependent transcriptional bEBPs were found in the Bt HD73 genome, and they regulated nine sigma(54)-dependent promoters. The metabolic pathways activated by sigma(54) in this process have yet to be identified in Bacillus thuringiensis; nonetheless, the present analysis of the sigma(54) regulon provides a better understanding of the physiological roles of sigma factors in bacteria. PMID- 26029176 TI - Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids. AB - Gastric cancer can be classified as cardia and non-cardia subtypes according to the anatomic site. Although the gastric cancer incidence has decreased steadily in several countries over the past 50 years, the incidence of cardia cancers and esophageal adenocarcinoma (EAC) continue to increase. The etiological factors involved in the development of both cardia cancers and EACs are associated with high animal fat intake, which causes severe obesity. Central obesity plays roles in cardiac-type mucosa lengthening and partial hiatus hernia development. There are two distinct etiologies of cardia cancer subtypes: one associated with gastroesophageal reflux (GER), which predominantly occurs in patients without Helicobacter pylori (H. pylori) infection and resembles EAC, and the other associated with H. pylori atrophic gastritis, which resembles non-cardia cancer. The former can be developed in the environment of high volume duodenal content reflux, including bile acids and a higher acid production in H. pylori-negative patients. N-nitroso compounds, which are generated from the refluxate that includes a large volume of bile acids and are stabilized in the stomach (which has high levels of gastric acid), play a pivotal role in this carcinogenesis. The latter can be associated with the changing colonization of H. pylori from the distal to the proximal stomach with atrophic gastritis because a high concentration of soluble bile acids in an environment of low acid production is likely to act as a bactericide or chemorepellent for H. pylori in the distal stomach. The manuscript introduces new insights in causative factors of adenocarcinoma of the cardia about the role of bile acids in gastro-esophageal refluxate based upon robust evidences supporting interactions among pH, H. pylori, and bile acids. PMID- 26029177 TI - Examining the impact of acetylene on N-fixation and the active sediment microbial community. AB - Here we examined the impact of a commonly employed method used to measure nitrogen fixation, the acetylene reduction assay (ARA), on a marine sediment community. Historically, the ARA technique has been broadly employed for its ease of use, in spite of numerous known artifacts. To gauge the severity of these effects in a natural environment, we employed high-throughput 16S rRNA gene sequencing to detect differences in acetylene-treated sediments vs. non-treated control sediments after a 7 h incubation. Within this short time period, significant differences were seen across all activity of microbes identified in the sediment, implying that the changes induced by acetylene occur quickly. The results have important implications for our understanding of marine nitrogen budgets. Moreover, because the ARA technique has been widely used in terrestrial and freshwater habitats, these results may be applicable to other ecosystems. PMID- 26029178 TI - Sub-MICs of Mentha piperita essential oil and menthol inhibits AHL mediated quorum sensing and biofilm of Gram-negative bacteria. AB - Bacterial quorum sensing (QS) is a density dependent communication system that regulates the expression of certain genes including production of virulence factors in many pathogens. Bioactive plant extract/compounds inhibiting QS regulated gene expression may be a potential candidate as antipathogenic drug. In this study anti-QS activity of peppermint (Mentha piperita) oil was first tested using the Chromobacterium violaceum CVO26 biosensor. Further, the findings of the present investigation revealed that peppermint oil (PMO) at sub-Minimum Inhibitory Concentrations (sub-MICs) strongly interfered with acyl homoserine lactone (AHL) regulated virulence factors and biofilm formation in Pseudomonas aeruginosa and Aeromonas hydrophila. The result of molecular docking analysis attributed the QS inhibitory activity exhibited by PMO to menthol. Assessment of ability of menthol to interfere with QS systems of various Gram-negative pathogens comprising diverse AHL molecules revealed that it reduced the AHL dependent production of violacein, virulence factors, and biofilm formation indicating broad-spectrum anti-QS activity. Using two Escherichia coli biosensors, MG4/pKDT17 and pEAL08-2, we also confirmed that menthol inhibited both the las and pqs QS systems. Further, findings of the in vivo studies with menthol on nematode model Caenorhabditis elegans showed significantly enhanced survival of the nematode. Our data identified menthol as a novel broad spectrum QS inhibitor. PMID- 26029179 TI - Cytokines induce effector T-helper cells during invasive aspergillosis; what we have learned about T-helper cells? AB - Invasive aspergillosis caused by Aspergillus species (Aspergillus fumigatus, A. flavus, and A. terreus) is life-threatening infections in immunocompromised patients. Understanding the innate and adaptive immune response particularly T helper cells (TH-cells) against these Aspergillus species and how the different sub-set of TH-cells are regulated by differentiating cytokines at primary target organ site like lung, kidney and brain is of great significance to human health. This review focuses on presentation of Aspergillus through Antigen presenting cells (APCs) to the naive CD4(+) T-cells in the host. The production of differentiating/effector cytokines that activate following TH-cells, e.g., TH1, TH2, TH9, and TH17 has been reported in association or alone in allergic or invasive aspergillosis. Chemokines (CXCL1, CXCL2, CCL1, and CCL20) and their receptors associated to these TH-cells have also been observed in invasive aspergillosis. Thus, further study of these TH-cells in invasive aspergillosis and other elements of adaptive immune response with Aspergillus species are required in order to have a better understanding of host response for safer and effective therapeutic outcome. PMID- 26029181 TI - Vitamin B1 in marine sediments: pore water concentration gradient drives benthic flux with potential biological implications. AB - Vitamin B1, or thiamin, can limit primary productivity in marine environments, however the major marine environmental sources of this essential coenzyme remain largely unknown. Vitamin B1 can only be produced by organisms that possess its complete synthesis pathway, while other organisms meet their cellular B1 quota by scavenging the coenzyme from exogenous sources. Due to high bacterial cell density and diversity, marine sediments could represent some of the highest concentrations of putative B1 producers, yet these environments have received little attention as a possible source of B1 to the overlying water column. Here we report the first dissolved pore water profiles of B1 measured in cores collected in two consecutive years from Santa Monica Basin, CA. Vitamin B1 concentrations were fairly consistent between the two years ranging from 30 pM up to 770 pM. A consistent maximum at ~5 cm sediment depth covaried with dissolved concentrations of iron. Pore water concentrations were higher than water column levels and represented some of the highest known environmental concentrations of B1 measured to date, (over two times higher than maximum water column concentrations) suggesting increased rates of cellular production and release within the sediments. A one dimensional diffusion-transport model applied to the B1 profile was used to estimate a diffusive benthic flux of ~0.7 nmol m(-2) d( 1). This is an estimated flux across the sediment-water interface in a deep sea basin; if similar magnitude B-vitamin fluxes occur in shallow coastal waters, benthic input could prove to be a significant B1-source to the water column and may play an important role in supplying this organic growth factor to auxotrophic primary producers. PMID- 26029180 TI - Genomic analysis of six new Geobacillus strains reveals highly conserved carbohydrate degradation architectures and strategies. AB - In this work we report the whole genome sequences of six new Geobacillus xylanolytic strains along with the genomic analysis of their capability to degrade carbohydrates. The six sequenced Geobacillus strains described here have a range of GC contents from 43.9% to 52.5% and clade with named Geobacillus species throughout the entire genus. We have identified a ~200 kb unique super cluster in all six strains, containing five to eight distinct carbohydrate degradation clusters in a single genomic region, a feature not seen in other genera. The Geobacillus strains rely on a small number of secreted enzymes located within distinct clusters for carbohydrate utilization, in contrast to most biomass-degrading organisms which contain numerous secreted enzymes located randomly throughout the genomes. All six strains are able to utilize fructose, arabinose, xylose, mannitol, gluconate, xylan, and alpha-1,6-glucosides. The gene clusters for utilization of these seven substrates have identical organization and the individual proteins have a high percent identity to their homologs. The strains show significant differences in their ability to utilize inositol, sucrose, lactose, alpha-mannosides, alpha-1,4-glucosides and arabinan. PMID- 26029182 TI - Trehalose promotes Rhodococcus sp. strain YYL colonization in activated sludge under tetrahydrofuran (THF) stress. AB - Few studies have focused on the role of compatible solutes in changing the microbial community structure in bioaugmentation systems. In this study, we investigated the influence of trehalose as a biostimulant on the microbial community in tetrahydrofuran (THF)-treated wastewater bioaugmentation systems with Rhodococcus sp. YYL. Functional gene profile changes were used to study the variation in the microbial community. Soluble di-iron monooxygenases (SDIMO), particularly group-5 SDIMOs (i.e., tetrahydrofuran and propane monooxygenases), play a significant role in the initiation of the ring cleavage of tetrahydrofuran. Group-5 SDIMOs genes are enriched upon trehalose addition, and exogenous tetrahydrofuran monooxygenase (thmA) genes can successfully colonize bioaugmentation systems. Cytochrome P450 monooxygenases (P450s) have a significant role in catalyzing the region- and stereospecific oxidation of non activated hydrocarbons, and THF was reported to inhibit P450s in the environment. The CYP153 family was chosen as a representative P450 to study the inhibitory effects of THF. The results demonstrated that CYP153 family genes exhibited significant changes upon THF treatment and that trehalose helped maintain a rich diversity and high abundance of CYP153 family genes. Biostimulation with trehalose could alleviate the negative effects of THF stress on microbial diversity in bioaugmentation systems. Our results indicated that trehalose as a compatible solute plays a significant role for environmental strains under extreme conditions. PMID- 26029185 TI - Differential expression of midgut proteins in Trypanosoma brucei gambiense stimulated vs. non-stimulated Glossina palpalis gambiensis flies. AB - The unicellular pathogenic protozoan Trypanosoma brucei gambiense is responsible for the chronic form of sleeping sickness. This vector-borne disease is transmitted to humans by the tsetse fly of the group Glossina palpalis, including the subspecies G. p. gambiensis, in which the parasite completes its developmental cycle. Sleeping sickness control strategies can therefore target either the human host or the fly vector. Indeed, suppression of one step in the parasite developmental cycle could abolish parasite transmission to humans, with consequences on the spreading of the disease. In order to develop this type of approach, we have identified, at the proteome level, events resulting from the tripartite interaction between the tsetse fly G. p. gambiensis, its microbiome, and the trypanosome. Proteomes were analyzed from four biological replicates of midguts from flies sampled 3 days post-feeding on either a trypanosome-infected (stimulated flies) or a non-infected (non-stimulated flies) bloodmeal. Over 500 proteins were identified in the midguts of flies from both feeding groups, 13 of which were shown to be differentially expressed in trypanosome-stimulated vs. non stimulated flies. Functional annotation revealed that several of these proteins have important functions that could be involved in modulating the fly infection process by trypanosomes (and thus fly vector competence), including anti-oxidant and anti-apoptotic, cellular detoxifying, trypanosome agglutination, and immune stimulating or depressive effects. The results show a strong potential for diminishing or even disrupting fly vector competence, and their application holds great promise for improving the control of sleeping sickness. PMID- 26029186 TI - Bacterial N2-fixation in mangrove ecosystems: insights from a diazotroph-mangrove interaction. AB - Mangrove forests are highly productive ecosystems but represent low nutrient environments. Nitrogen availability is one of the main factors limiting mangrove growth. Diazotrophs have been identified as key organisms that provide nitrogen to these environments. N2-fixation by such organisms was found to be higher in the mangrove roots than in surrounding rhizosphere. Moreover, previous studies showed that mangroves grew better in the presence of N2-fixers indicating a potentially mutualistic relationship. However, the molecular signals and mechanisms that govern these interactions are still poorly understood. Here we present novel insights in the interaction of a diazotroph with a mangrove species to improve our understanding of the molecular and ecophysiological relationship between these two organisms under controlled conditions. Our results showed that Marinobacterium mangrovicola is a versatile organism capable of competing with other organisms to survive for long periods in mangrove soils. N2-fixation by this bacterium was up-regulated in the presence of mangrove roots, indicating a possible beneficial interaction. The increase in N2-fixation was limited to cells of the exponential growth phase suggesting that N2-fixation differs over the bacterial growth cycle. Bacterial transformants harboring a transcriptional nifH::gusA fusion showed that M. mangrovicola successfully colonized mangrove roots and simultaneously conducted N2-fixation. The colonization process was stimulated by the lack of an external carbon source suggesting a possible mutualistic relationship. M. mangrovicola represents an interesting genetically accessible diazotroph, which colonize mangrove roots and exhibit higher N2 fixation in the presence of mangrove roots. Consequently, we propose this microorganism as a tool to study molecular interactions between N2-fixers and mangrove plants and to better understand how changes in the environment could impact these important and relatively unknown interactions. PMID- 26029183 TI - Cytochromes c in Archaea: distribution, maturation, cell architecture, and the special case of Ignicoccus hospitalis. AB - Cytochromes c (Cytc) are widespread electron transfer proteins and important enzymes in the global nitrogen and sulfur cycles. The distribution of Cytc in more than 300 archaeal proteomes deduced from sequence was analyzed with computational methods including pattern and similarity searches, secondary and tertiary structure prediction. Two hundred and fifty-eight predicted Cytc (with single, double, or multiple heme c attachment sites) were found in some but not all species of the Desulfurococcales, Thermoproteales, Archaeoglobales, Methanosarcinales, Halobacteriales, and in two single-cell genome sequences of the Thermoplasmatales, all of them Cren- or Euryarchaeota. Other archaeal phyla including the Thaumarchaeota are so far free of these proteins. The archaeal Cytc sequences were bundled into 54 clusters of mutual similarity, some of which were specific for Archaea while others had homologs in the Bacteria. The cytochrome c maturation system I (CCM) was the only one found. The highest number and variability of Cytc were present in those species with known or predicted metal oxidation and/or reduction capabilities. Paradoxical findings were made in the haloarchaea: several Cytc had been purified biochemically but corresponding proteins were not found in the proteomes. The results are discussed with emphasis on cell morphologies and envelopes and especially for double-membraned Archaea like Ignicoccus hospitalis. A comparison is made with compartmentalized bacteria such as the Planctomycetes of the Anammox group with a focus on the putative localization and roles of the Cytc and other electron transport proteins. PMID- 26029184 TI - The genomes of closely related Pantoea ananatis maize seed endophytes having different effects on the host plant differ in secretion system genes and mobile genetic elements. AB - The seed as a habitat for microorganisms is as yet under-explored and has quite distinct characteristics as compared to other vegetative plant tissues. In this study, we investigated three closely related P. ananatis strains (named S6, S7, and S8), which were isolated from maize seeds of healthy plants. Plant inoculation experiments revealed that each of these strains exhibited a different phenotype ranging from weak pathogenic (S7), commensal (S8), to a beneficial, growth-promoting effect (S6) in maize. We performed a comparative genomics analysis in order to find genetic determinants responsible for the differences observed. Recent studies provided exciting insight into the genetic drivers of niche adaption and functional diversification of the genus Pantoea. However, we report here for the first time on the analysis of P. ananatis strains colonizing the same ecological niche but showing distinct interaction strategies with the host plant. Our comparative analysis revealed that genomes of these three strains are highly similar. However, genomic differences in genes encoding protein secretion systems and putative effectors, and transposase/integrases/phage related genes could be observed. PMID- 26029187 TI - Editorial: Roles and mechanisms of parasitism in aquatic microbial communities. PMID- 26029188 TI - Segregation of chromosome arms in growing and non-growing Escherichia coli cells. AB - In slow-growing Escherichia coli cells the chromosome is organized with its left (L) and right (R) arms lying separated in opposite halves of the nucleoid and with the origin (O) in-between, giving the pattern L-O-R. During replication one of the arms has to pass the other to obtain the same organization in the daughter cells: L-O-R L-O-R. To determine the movement of arms during segregation six strains were constructed carrying three colored loci: the left and right arms were labeled with red and cyan fluorescent-proteins, respectively, on loci symmetrically positioned at different distances from the central origin, which was labeled with green-fluorescent protein. In non-replicating cells with the predominant spot pattern L-O-R, initiation of replication first resulted in a L-O O-R pattern, soon changing to O-L-R-O. After replication of the arms the predominant spot patterns were, L-O-R L-O-R, O-R-L R-O-L or O-L-R L-O-R indicating that one or both arms passed an origin and the other arm. To study the driving force for these movements cell growth was inhibited with rifampicin allowing run-off DNA synthesis. Similar spot patterns were obtained in growing and non-growing cells, indicating that the movement of arms is not a growth sustained process, but may result from DNA synthesis itself. The distances between loci on different arms (LR-distances) and between duplicated loci (LL- or RR-distances) as a function of their distance from the origin, indicate that in slow-growing cells DNA is organized according to the so-called sausage model and not according to the doughnut model. PMID- 26029189 TI - The two kinases, AbrC1 and AbrC2, of the atypical two-component system AbrC are needed to regulate antibiotic production and differentiation in Streptomyces coelicolor. AB - Two-component systems (TCSs) are the most important sensing mechanisms in bacteria. In Streptomyces, TCSs-mediated responses to environmental stimuli are involved in the regulation of antibiotic production. This study examines the individual role of two histidine kinases (HKs), AbrC1 and AbrC2, which form part of an atypical TCS in Streptomyces coelicolor. qRT-PCR analysis of the expression of both kinases demonstrated that both are expressed at similar levels in NB and NMMP media. Single deletion of abrC1 elicited a significant increase in antibiotic production, while deletion of abrC2 did not have any clear effect. The origin of this phenotype, probably related to the differential phosphorylation ability of the two kinases, was also explored indirectly, analyzing the toxic phenotypes associated with high levels of phosphorylated RR. The higher the AbrC3 regulator phosphorylation rate, the greater the cell toxicity. For the first time, the present work shows in Streptomyces the combined involvement of two different HKs in the response of a regulator to environmental signals. Regarding the possible applications of this research, the fact that an abrC1 deletion mutant overproduces three of the S. coelicolor antibiotics makes this strain an excellent candidate as a host for the heterologous production of secondary metabolites. PMID- 26029190 TI - Silver nanoparticles synthesis mediated by new isolates of Bacillus spp., nanoparticle characterization and their activity against Bean Yellow Mosaic Virus and human pathogens. AB - Extracellular agents produced by newly isolated bacterial strains were able to catalyze the synthesis of silver nanoparticles (AgNPs). The most effective isolates were identified as Bacillus pumilus, B. persicus, and Bacillus licheniformis using molecular identification. DLS analysis revealed that the AgNPs synthesized by the above strains were in the size range of 77-92 nm. TEM observations showed that the nanoparticles were coated with a capping agent, which was probably involved in nanoparticle stabilization allowing their perfect dispersion in aqueous solutions. FTIR analyses indicated the presence of proteins in the capping agent of the nanoparticles and suggested that the oxidation of hydroxyl groups of peptide hydrolysates (originated from the growth medium) is coupled to the reduction of silver ions. Energy Dispersive X-ray Spectroscopy confirmed the above results. The nanoparticles, especially those synthesized by B. licheniformis, were stable (zeta potential ranged from -16.6 to -21.3 mV) and showed an excellent in vitro antimicrobial activity against important human pathogens and a considerable antiviral activity against the Bean Yellow Mosaic Virus. The significance of the particular antiviral activity is highlighted, given the significant yield reduction in fava bean crops resulting from Bean Yellow Mosaic Virus infections, in many African countries. PMID- 26029191 TI - The stoichiometric divisome: a hypothesis. AB - Dividing Escherichia coli cells simultaneously constrict the inner membrane, peptidoglycan layer, and outer membrane to synthesize the new poles of the daughter cells. For this, more than 30 proteins localize to mid-cell where they form a large, ring-like assembly, the divisome, facilitating division. Although the precise function of most divisome proteins is unknown, it became apparent in recent years that dynamic protein-protein interactions are essential for divisome assembly and function. However, little is known about the nature of the interactions involved and the stoichiometry of the proteins within the divisome. A recent study (Li et al., 2014) used ribosome profiling to measure the absolute protein synthesis rates in E. coli. Interestingly, they observed that most proteins which participate in known multiprotein complexes are synthesized proportional to their stoichiometry. Based on this principle we present a hypothesis for the stoichiometry of the core of the divisome, taking into account known protein-protein interactions. From this hypothesis we infer a possible mechanism for peptidoglycan synthesis during division. PMID- 26029192 TI - Long-term monitoring reveals carbon-nitrogen metabolism key to microcystin production in eutrophic lakes. AB - The environmental drivers contributing to cyanobacterial dominance in aquatic systems have been extensively studied. However, understanding of toxic vs. non toxic cyanobacterial population dynamics and the mechanisms regulating cyanotoxin production remain elusive, both physiologically and ecologically. One reason is the disconnect between laboratory and field-based studies. Here, we combined 3 years of temporal data, including microcystin (MC) concentrations, 16 years of long-term ecological research, and 10 years of molecular data to investigate the potential factors leading to the selection of toxic Microcystis and MC production. Our analysis revealed that nitrogen (N) speciation and inorganic carbon (C) availability might be important drivers of Microcystis population dynamics and that an imbalance in cellular C: N ratios may trigger MC production. More specifically, precipitous declines in ammonium concentrations lead to a transitional period of N stress, even in the presence of high nitrate concentrations, that we call the "toxic phase." Following the toxic phase, temperature and cyanobacterial abundance remained elevated but MC concentrations drastically declined. Increases in ammonium due to lake turnover may have led to down regulation of MC synthesis or a shift in the community from toxic to non toxic species. While total phosphorus (P) to total N ratios were relatively low over the time-series, MC concentrations were highest when total N to total P ratios were also highest. Similarly, high C: N ratios were also strongly correlated to the toxic phase. We propose a metabolic model that corroborates molecular studies and reflects our ecological observations that C and N metabolism may regulate MC production physiologically and ecologically. In particular, we hypothesize that an imbalance between 2-oxoglutarate and ammonium in the cell regulates MC synthesis in the environment. PMID- 26029194 TI - Corrigendum: Malaria and the liver: immunological hide-and-seek or subversion of immunity from within? AB - [This corrects the article on p. 41 in vol. 6, PMID: 25741320.]. PMID- 26029193 TI - The paramyxovirus polymerase complex as a target for next-generation anti paramyxovirus therapeutics. AB - The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV), as well as the emerging zoonotic Hendra and Nipah viruses. In the U.S., RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp) complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path toward the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers. PMID- 26029195 TI - Toward a new focus in antibiotic and drug discovery from the Streptomyces arsenal. AB - Emergence of antibiotic resistant pathogens is changing the way scientists look for new antibiotic compounds. This race against the increased prevalence of multi resistant strains makes it necessary to expedite the search for new compounds with antibiotic activity and to increase the production of the known. Here, we review a variety of new scientific approaches aiming to enhance antibiotic production in Streptomyces. These include: (i) elucidation of the signals that trigger the antibiotic biosynthetic pathways to improve culture media, (ii) bacterial hormone studies aiming to reproduce intra and interspecific communications resulting in antibiotic burst, (iii) co-cultures to mimic competition-collaboration scenarios in nature, and (iv) the very recent in situ search for antibiotics that might be applied in Streptomyces natural habitats. These new research strategies combined with new analytical and molecular techniques should accelerate the discovery process when the urgency for new compounds is higher than ever. PMID- 26029196 TI - Genetic and phenotypic evidence of the Salmonella enterica serotype Enteritidis human-animal interface in Chile. AB - Salmonella enterica serotype Enteritidis is a worldwide zoonotic agent that has been recognized as a very important food-borne bacterial pathogen, mainly associated with consumption of poultry products. The aim of this work was to determine genotypic and phenotypic evidence of S. Enteritidis transmission among seabirds, poultry and humans in Chile. Genotyping was performed using PCR-based virulotyping, pulse-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Pathogenicity-associated phenotypes were determined with survival to free radicals, acidic pH, starvation, antimicrobial resistance, and survival within human dendritic cells. As result of PCR and PFGE assays, some isolates from the three hosts showed identical genotypic patterns, and through MLST it was determined that all of them belong to sequence type 11. Phenotypic assays show diversity of bacterial responses among isolates. When results were analyzed according to bacterial host, statistical differences were identified in starvation and dendritic cells survival assays. In addition, isolates from seabirds showed the highest rates of resistance to gentamycin, tetracycline, and ampicillin. Overall, the very close genetic and phenotypic traits shown by isolates from humans, poultry, and seabirds suggest the inter-species transmission of S. Enteritidis bacteria between hosts, likely through anthropogenic environmental contamination that determines infection of seabirds with bacteria that are potentially pathogenic for other susceptible organism, including humans. PMID- 26029197 TI - Maximizing efficiency of rumen microbial protein production. AB - Rumen microbes produce cellular protein inefficiently partly because they do not direct all ATP toward growth. They direct some ATP toward maintenance functions, as long-recognized, but they also direct ATP toward reserve carbohydrate synthesis and energy spilling (futile cycles that dissipate heat). Rumen microbes expend ATP by vacillating between (1) accumulation of reserve carbohydrate after feeding (during carbohydrate excess) and (2) mobilization of that carbohydrate thereafter (during carbohydrate limitation). Protozoa account for most accumulation of reserve carbohydrate, and in competition experiments, protozoa accumulated nearly 35-fold more reserve carbohydrate than bacteria. Some pure cultures of bacteria spill energy, but only recently have mixed rumen communities been recognized as capable of the same. When these communities were dosed glucose in vitro, energy spilling could account for nearly 40% of heat production. We suspect that cycling of glycogen (a major reserve carbohydrate) is a major mechanism of spilling; such cycling has already been observed in single-species cultures of protozoa and bacteria. Interconversions of short-chain fatty acids (SCFA) may also expend ATP and depress efficiency of microbial protein production. These interconversions may involve extensive cycling of intermediates, such as cycling of acetate during butyrate production in certain butyrivibrios. We speculate this cycling may expend ATP directly or indirectly. By further quantifying the impact of reserve carbohydrate accumulation, energy spilling, and SCFA interconversions on growth efficiency, we can improve prediction of microbial protein production and guide efforts to improve efficiency of microbial protein production in the rumen. PMID- 26029198 TI - Nuclear entry of DNA viruses. AB - DNA viruses undertake their replication within the cell nucleus, and therefore they must first deliver their genome into the nucleus of their host cells. Thus, trafficking across the nuclear envelope is at the basis of DNA virus infections. Nuclear transport of molecules with diameters up to 39 nm is a tightly regulated process that occurs through the nuclear pore complex (NPC). Due to the enormous diversity of virus size and structure, each virus has developed its own strategy for entering the nucleus of their host cells, with no two strategies alike. For example, baculoviruses target their DNA-containing capsid to the NPC and subsequently enter the nucleus intact, while the hepatitis B virus capsid crosses the NPC but disassembles at the nuclear side of the NPC. For other viruses such as herpes simplex virus and adenovirus, although both dock at the NPC, they have each developed a distinct mechanism for the subsequent delivery of their genome into the nucleus. Remarkably, other DNA viruses, such as parvoviruses and human papillomaviruses, access the nucleus through an NPC-independent mechanism. This review discusses our current understanding of the mechanisms used by DNA viruses to deliver their genome into the nucleus, and further presents the experimental evidence for such mechanisms. PMID- 26029199 TI - Simplifying microbial electrosynthesis reactor design. AB - Microbial electrosynthesis, an artificial form of photosynthesis, can efficiently convert carbon dioxide into organic commodities; however, this process has only previously been demonstrated in reactors that have features likely to be a barrier to scale-up. Therefore, the possibility of simplifying reactor design by both eliminating potentiostatic control of the cathode and removing the membrane separating the anode and cathode was investigated with biofilms of Sporomusa ovata. S. ovata reduces carbon dioxide to acetate and acts as the microbial catalyst for plain graphite stick cathodes as the electron donor. In traditional 'H-cell' reactors, where the anode and cathode chambers were separated with a proton-selective membrane, the rates and columbic efficiencies of microbial electrosynthesis remained high when electron delivery at the cathode was powered with a direct current power source rather than with a potentiostat-poised cathode utilized in previous studies. A membrane-less reactor with a direct-current power source with the cathode and anode positioned to avoid oxygen exposure at the cathode, retained high rates of acetate production as well as high columbic and energetic efficiencies. The finding that microbial electrosynthesis is feasible without a membrane separating the anode from the cathode, coupled with a direct current power source supplying the energy for electron delivery, is expected to greatly simplify future reactor design and lower construction costs. PMID- 26029201 TI - Microbial interspecies interactions: recent findings in syntrophic consortia. AB - Microbes are ubiquitous in our biosphere, and inevitably live in communities. They excrete a variety of metabolites and support the growth of other microbes in a community. According to the law of chemical equilibrium, the consumption of excreted metabolites by recipient microbes can accelerate the metabolism of donor microbes. This is the concept of syntrophy, which is a type of mutualism and governs the metabolism and growth of diverse microbes in natural and engineered ecosystems. A representative example of syntrophy is found in methanogenic communities, where reducing equivalents, e.g., hydrogen and formate, transfer between syntrophic partners. Studies have revealed that microbes involved in syntrophy have evolved molecular mechanisms to establish specific partnerships and interspecies communication, resulting in efficient metabolic cooperation. In addition, recent studies have provided evidence suggesting that microbial interspecies transfer of reducing equivalents also occurs as electric current via biotic (e.g., pili) and abiotic (e.g., conductive mineral and carbon particles) electric conduits. In this review, we describe these findings as examples of sophisticated cooperative behavior between different microbial species. We suggest that these interactions have fundamental roles in shaping the structure and activity of microbial communities. PMID- 26029200 TI - Enzymatic modifications of exopolysaccharides enhance bacterial persistence. AB - Biofilms are surface-attached communities of bacterial cells embedded in a self produced matrix that are found ubiquitously in nature. The biofilm matrix is composed of various extracellular polymeric substances, which confer advantages to the encapsulated bacteria by protecting them from eradication. The matrix composition varies between species and is dependent on the environmental niche that the bacteria inhabit. Exopolysaccharides (EPS) play a variety of important roles in biofilm formation in numerous bacterial species. The ability of bacteria to thrive in a broad range of environmental settings is reflected in part by the structural diversity of the EPS produced both within individual bacterial strains as well as by different species. This variability is achieved through polymerization of distinct sugar moieties into homo- or hetero-polymers, as well as post-polymerization modification of the polysaccharide. Specific enzymes that are unique to the production of each polymer can transfer or remove non carbohydrate moieties, or in other cases, epimerize the sugar units. These modifications alter the physicochemical properties of the polymer, which in turn can affect bacterial pathogenicity, virulence, and environmental adaptability. Herein, we review the diversity of modifications that the EPS alginate, the Pel polysaccharide, Vibrio polysaccharide, cepacian, glycosaminoglycans, and poly-N acetyl-glucosamine undergo during biosynthesis. These are EPS produced by human pathogenic bacteria for which studies have begun to unravel the effect modifications have on their physicochemical and biological properties. The biological advantages these polymer modifications confer to the bacteria that produce them will be discussed. The expanding list of identified modifications will allow future efforts to focus on linking these modifications to specific biosynthetic genes and biofilm phenotypes. PMID- 26029203 TI - Plant extracts from Cameroonian medicinal plants strongly inhibit hepatitis C virus infection in vitro. AB - According to some recent studies, Cameroon is one of the sub-Saharan African countries most affected by hepatitis C, with low access to the standard therapy based on the combination of pegylated interferon and ribavirin. A first ethnobotanical survey, conducted in the Western region of Cameroon, reported the use of several medicinal plants in traditional medicine for the healing of liver related disorders. Crude organic extracts of five plants surveyed were prepared and their effect against hepatitis C virus (HCV) infection investigated. The HCV JFH1 strain cell culture system HCVcc was used. The antiviral activity was quantified by immunofluorescent labeling of HCV E1 envelope protein at 30 h post infection in the presence of the plant extracts. Active compounds were then tested in time course infection experiments. Dose-response and cellular toxicity assays were also determined. Three extracts, methanol extracts from roots of Trichilia dregeana, stems of Detarium microcarpum and leaves of Phragmanthera capitata, showed anti-HCV activity, with half-maximal inhibitory concentration of 16.16, 1.42, and 13.17 MUg/mL, respectively. Huh-7 cells were incubated with the extracts for 72 h and it appears that T. dregeana extract is not toxic up to 200 MUg/mL, D. microcarpum up to 100 MUg/mL and P. capitata up to 800 MUg/mL. All the three extracts showed a strong inhibition of HCV entry and no effect on replication or secretion. Taken together, these results showed that extracts from Cameroonian medicinal plants are promising sources of anti-HCV agents. PMID- 26029202 TI - The Min system and other nucleoid-independent regulators of Z ring positioning. AB - Rod-shaped bacteria such as E. coli have mechanisms to position their cell division plane at the precise center of the cell, to ensure that the daughter cells are equal in size. The two main mechanisms are the Min system and nucleoid occlusion (NO), both of which work by inhibiting assembly of FtsZ, the tubulin like scaffold that forms the cytokinetic Z ring. Whereas NO prevents Z rings from constricting over unsegregated nucleoids, the Min system is nucleoid-independent and even functions in cells lacking nucleoids and thus NO. The Min proteins of E. coli and B. subtilis form bipolar gradients that inhibit Z ring formation most at the cell poles and least at the nascent division plane. This article will outline the molecular mechanisms behind Min function in E. coli and B. subtilis, and discuss distinct Z ring positioning systems in other bacterial species. PMID- 26029204 TI - Is there a (host) genetic predisposition to progressive multifocal leukoencephalopathy? AB - Progressive multifocal leukoencephalopathy (PML) has been described in association with a variety of predisposing risk factors, including HIV/AIDS, lymphoproliferative disorders and, most recently, treatment with a range of biologics, most notably natalizumab in multiple sclerosis (MS) (1). However, while these underlying disorders appear to be (usually) necessary, they are not sufficient to predict the development of PML, since only a small fraction of such individuals will succumb, raising the question of whether host genetic factors must also play a role. Evidence is mounting that this is, indeed, the case but more work needs to be done to fully delineate these underlying genetic factors. Finally, while it is possible that an underlying genetic susceptibility for PML in general will be uncovered in the future, the current evidence argues for a collection of multiple, individually rare underlying susceptibilities (with one predominant single genetic susceptibility in each individual), as described in this review. PMID- 26029206 TI - Development of the Brazilian Anti Schistosomiasis Vaccine Based on the Recombinant Fatty Acid Binding Protein Sm14 Plus GLA-SE Adjuvant. AB - Data herein reported and discussed refer to vaccination with the recombinant fatty acid binding protein (FABP) family member of the schistosomes, called Sm14. This antigen was discovered and developed under a Brazilian platform led by the Oswaldo Cruz Foundation, from the Health Ministry in Brazil, and was assessed for safety and immunogenicity in healthy volunteers. This paper reviews past and recent outcomes of developmental phases of the Sm14-based anti schistosomiasis vaccine addressed to, ultimately, impact transmission of the second most prevalent parasitic endemic disease worldwide. PMID- 26029207 TI - Autoantibodies in renal diseases - clinical significance and recent developments in serological detection. AB - Autoimmune dysfunctions are the "bete noire" in a range of debilitating nephropathies. Autoimmune-mediated damage to the kidneys can be triggered by autoantibodies directed against specific proteins or renal structures, for example, the phospholipase A2 receptor or the glomerular basement membrane, resulting in glomerular diseases such as primary membranous nephropathy or Goodpasture's disease. Moreover, secondary damage to the kidney can be part of the wide-reaching effects of systemic autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE) - the latter counts lupus nephritis among its most severe manifestations. Systemic autoimmune diseases are characterized by non organ-specific autoantibodies, directed for example against neutrophil cytoplasmic antigens in systemic vasculitis and against double-stranded DNA and nucleosomes in SLE. A large variety of innovative and highly specific and sensitive autoantibody tests have been developed in the last years that are available to identify autoimmune kidney diseases at an early stage. Thus, serological in vitro diagnostics allow for appropriate interventional therapy in order to prevent disease progression often resulting in need of dialysis and transplantation. PMID- 26029205 TI - Regulatory T-Cells at the Interface between Human Host and Pathogens in Infectious Diseases and Vaccination. AB - Regulatory T-cells (Tregs) act at the interface of host and pathogen interactions in human infectious diseases. Tregs are induced by a wide range of pathogens, but distinct effects of Tregs have been demonstrated for different pathogens and in different stages of infection. Moreover, Tregs that are induced by a specific pathogen may non-specifically suppress immunity against other microbes and parasites. Thus, Treg effects need to be assessed not only in homologous but also in heterologous infections and vaccinations. Though Tregs protect the human host against excessive inflammation, they probably also increase the risk of pathogen persistence and chronic disease, and the possibility of disease reactivation later in life. Mycobacterium leprae and Mycobacterium tuberculosis, causing leprosy and tuberculosis, respectively, are among the most ancient microbes known to mankind, and are master manipulators of the immune system toward tolerance and pathogen persistence. The majority of mycobacterial infections occur in settings co-endemic for viral, parasitic, and (other) bacterial coinfections. In this paper, we discuss recent insights in the activation and activity of Tregs in human infectious diseases, with emphasis on early, late, and non-specific effects in disease, coinfections, and vaccination. We highlight mycobacterial infections as important models of modulation of host responses and vaccine-induced immunity by Tregs. PMID- 26029208 TI - The importance of autoantibody detection in autoimmune hepatitis. PMID- 26029209 TI - Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. AB - Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation. Here, we hypothesize that stresses (defined as homeostatic disturbances) can induce low-grade inflammation by increasing the availability of water, sodium, and energy-rich substances to meet the increased metabolic demand induced by the stressor. One way of triggering low-grade inflammation is by increasing intestinal barrier permeability through activation of various components of the stress system. Although beneficial to meet the demands necessary during stress, increased intestinal barrier permeability also raises the possibility of the translocation of bacteria and their toxins across the intestinal lumen into the blood circulation. In combination with modern life style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a low-grade inflammatory state. We support this hypothesis with numerous studies finding associations with NCDs and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of low-grade inflammation and its related diseases. PMID- 26029210 TI - Selective Hyaluronan-CD44 Signaling Promotes miRNA-21 Expression and Interacts with Vitamin D Function during Cutaneous Squamous Cell Carcinomas Progression Following UV Irradiation. AB - Hyaluronan (HA), the major extracellular matrix component, is often anchored to CD44, a family of structurally/functionally important cell surface receptors. Recent results indicate that UV irradiation (UVR)-induced cutaneous squamous cell carcinomas (SCC) overexpress a variety of CD44 variant isoforms (CD44v), with different CD44v isoforms appear to confer malignant SCC properties. UVR also stimulates HA degradation in epidermal keratinocytes. Both large HA polymers and their UVR-induced catabolic products (small HA) selectively activate CD44 mediated cellular signaling in normal keratinocytes and SCC cells, with all of the downstream processes being mediated by RhoGTPases (e.g., Rac1 and Rho). Importantly, we found that the hormonally active form of vitamin D 1,25(OH)2D3 not only prevents the UVR-induced small HA activation of abnormal keratinocyte behavior and SCC progression, but also enhances large HA stimulation of normal keratinocyte activities and epidermal function(s). The aim of this hypothesis and theory article is to question whether matrix HA and its UVR-induced catabolic products (e.g., large and small HA) can selectively activate CD44-mediated cellular signaling such as GTPase (Rac and RhA) activation. We suggested that large HA-CD44 interaction promotes Rac-signaling and normal keratinocyte differentiation (lipid synthesis), DNA repair, and keratinocyte survival function. Conversely, small HA-CD44 interaction stimulates RhoA activation, NFkappaB/Stat-3 signaling, and miR-21 production, resulting in inflammation and proliferation as well as SCC progression. We also question whether vitamin D treatment displays any effect on small HA-CD44v-mediated RhoA signaling, inflammation, and SCC progression, as well as large HA-CD44-mediated differentiation, DNA repair, keratinocyte survival, and normal keratinocyte function. In addition, we discussed that the topical application of signaling perturbation agents (e.g., Y27623, a ROK inhibitor) may be used to treat certain skin diseases displaying upregulation of keratinocyte proliferation such as psoriasis and actinic keratoses in order to correct the imbalance between Rac and RhoA signaling during various UV irradiation-induced skin diseases in patients. Finally, we proposed that matrix HA/CD44-signaling strategies and matrix HA (HAS vs. HAL or HAS -> HAL)-based therapeutic approaches (together with vitamin D) may be used for the treatment of patients suffering a number of UV irradiation induced skin diseases (e.g., inflammation, skin cancer, and chronic non-healing wounds). PMID- 26029212 TI - Aerobic glycolysis: beyond proliferation. AB - Aerobic glycolysis has been generally associated with cancer cell proliferation, but fascinating and novel data show that it is also coupled to a series of further cellular functions. In this Mini Review, we will discuss some recent findings to illustrate newly defined roles for this process, in particular in non malignant cells, supporting the idea that metabolism can be considered as an integral part of cellular signaling. Consequently, metabolism should be regarded as a plastic and highly dynamic determinant of a wide range of cellular specific functions. PMID- 26029211 TI - The Response of CD1d-Restricted Invariant NKT Cells to Microbial Pathogens and Their Products. AB - Invariant natural killer T (iNKT) cells become activated during a wide variety of infections. This includes organisms lacking cognate CD1d-binding glycolipid antigens recognized by the semi-invariant T cell receptor of iNKT cells. Additional studies have shown that iNKT cells also become activated in vivo in response to microbial products such as bacterial lipopolysaccharide, a potent inducer of cytokine production in antigen-presenting cells (APCs). Other studies have shown that iNKT cells are highly responsive to stimulation by cytokines such as interleukin-12. These findings have led to the concept that microbial pathogens can activate iNKT cells either directly via glycolipids or indirectly by inducing cytokine production in APCs. iNKT cells activated in this manner produce multiple cytokines that can influence the outcome of infection, usually in favor of the host, although potent iNKT cell activation may contribute to an uncontrolled cytokine storm and sepsis. One aspect of the response of iNKT cells to microbial pathogens is that it is short-lived and followed by an extended time period of unresponsiveness to reactivation. This refractory period may represent a means to avoid chronic activation and cytokine production by iNKT cells, thus protecting the host against some of the negative effects of iNKT cell activation, but potentially putting the host at risk for secondary infections. These effects of microbial pathogens and their products on iNKT cells are not only important for understanding the role of these cells in immune responses against infections but also for the development of iNKT cell-based therapies. PMID- 26029213 TI - Mechanisms of autoantibody production in systemic lupus erythematosus. AB - Autoantibodies against a panoply of self-antigens are seen in systemic lupus erythematosus, but only a few (anti-Sm/RNP, anti-Ro/La, anti-dsDNA) are common. The common lupus autoantigens are nucleic acid complexes and levels of autoantibodies can be extraordinarily high. We explore why that is the case. Lupus is associated with impaired central or peripheral B-cell tolerance and increased circulating autoreactive B cells. However, terminal differentiation is necessary for autoantibody production. Nucleic acid components of the major lupus autoantigens are immunostimulatory ligands for toll-like receptor (TLR)7 or TLR9 that promote plasma cell differentiation. We show that the levels of autoantibodies against the U1A protein (part of a ribonucleoprotein) are markedly higher than autoantibodies against other antigens, including dsDNA and the non nucleic acid-associated autoantigens insulin and thyroglobulin. In addition to driving autoantibody production, TLR7 engagement is likely to contribute to the pathogenesis of inflammatory disease in lupus. PMID- 26029214 TI - Editorial: T cell regulation by the environment. PMID- 26029215 TI - Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies. AB - Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies. PMID- 26029217 TI - Dynamics of NKT-Cell Responses to Chlamydial Infection. AB - Natural killer T (NKT) cells have gained great attention owing to their critical functional roles in immunity to various pathogens. In this review, we provide an overview of the current knowledge on the role of NKT cells in host defense against and pathogenesis due to Chlamydia, which is an intracellular bacterial pathogen that poses a threat to the public health worldwide. Accumulating evidence has demonstrated that NKT cells, particularly invariant NKT (iNKT) cells, play a crucial role in host defense against chlamydial infections, especially in C. pneumoniae infection. iNKT cells can promote type-1 protective responses to C. pneumoniae by inducing enhanced production of IL-12 by dendritic cells (DCs), in particular CD8alpha+ DCs, which promote the differentiation of naive T cells into protective IFN-gamma-producing Th1/Tc1 type CD4+/CD8+ T cells. This iNKT-cell-mediated modulation of DC function is largely dependent upon CD40 CD40L interaction, IFN-gamma production, and cell-to-cell contact. In addition, iNKT cells modulate the function of natural killer cells. NKT cells may be also involved in the pathogenesis of some chlamydial diseases by inducing different patterns of cytokine production. A better understanding of NKT-cell biology will enable us to rationally design prophylactic and therapeutic tools to combat infectious diseases. PMID- 26029216 TI - Hyaluronan - a functional and structural sweet spot in the tissue microenvironment. AB - Transition from homeostatic to reactive matrix remodeling is a fundamental adaptive tissue response to injury, inflammatory disease, fibrosis, and cancer. Alterations in architecture, physical properties, and matrix composition result in changes in biomechanical and biochemical cellular signaling. The dynamics of pericellular and extracellular matrices, including matrix protein, proteoglycan, and glycosaminoglycan modification are continually emerging as essential regulatory mechanisms underlying cellular and tissue function. Nevertheless, the impact of matrix organization on inflammation and immunity in particular and the consequent effects on tissue healing and disease outcome are arguably under studied aspects of adaptive stress responses. Herein, we review how the predominant glycosaminoglycan hyaluronan (HA) contributes to the structure and function of the tissue microenvironment. Specifically, we examine the evidence of HA degradation and the generation of biologically active smaller HA fragments in pathological settings in vivo. We discuss how HA fragments versus nascent HA via alternate receptor-mediated signaling influence inflammatory cell recruitment and differentiation, resident cell activation, as well as tumor growth, survival, and metastasis. Finally, we discuss how HA fragmentation impacts restoration of normal tissue function and pathological outcomes in disease. PMID- 26029218 TI - Development of cross-protective influenza a vaccines based on cellular responses. AB - Seasonal influenza vaccines provide protection against matching influenza A virus (IAV) strains mainly through the induction of neutralizing serum IgG antibodies. However, these antibodies fail to confer a protective effect against mismatched IAV. This lack of efficacy against heterologous influenza strains has spurred the vaccine development community to look for other influenza vaccine concepts, which have the ability to elicit cross-protective immune responses. One of the concepts that is currently been worked on is that of influenza vaccines inducing influenza specific T cell responses. T cells are able to lyse infected host cells, thereby clearing the virus. More interestingly, these T cells can recognize highly conserved epitopes of internal influenza proteins, making cellular responses less vulnerable to antigenic variability. T cells are therefore cross-reactive against many influenza strains, and thus are a promising concept for future influenza vaccines. Despite their potential, there are currently no T cell-based IAV vaccines on the market. Selection of the proper antigen, appropriate vaccine formulation and evaluation of the efficacy of T cell vaccines remains challenging, both in preclinical and clinical settings. In this review, we will discuss the current developments in influenza T cell vaccines, focusing on existing protein-based and novel peptide-based vaccine formulations. Furthermore, we will discuss the feasibility of influenza T cell vaccines and their possible use in the future. PMID- 26029219 TI - Sequencing, de novo assembly and comparative analysis of Raphanus sativus transcriptome. AB - Raphanus sativus is an important Brassicaceae plant and also an edible vegetable with great economic value. However, currently there is not enough transcriptome information of R. sativus tissues, which impedes further functional genomics research on R. sativus. In this study, RNA-seq technology was employed to characterize the transcriptome of leaf tissues. Approximately 70 million clean pair-end reads were obtained and used for de novo assembly by Trinity program, which generated 68,086 unigenes with an average length of 576 bp. All the unigenes were annotated against GO and KEGG databases. In the meanwhile, we merged leaf sequencing data with existing root sequencing data and obtained better de novo assembly of R. sativus using Oases program. Accordingly, potential simple sequence repeats (SSRs), transcription factors (TFs) and enzyme codes were identified in R. sativus. Additionally, we detected a total of 3563 significantly differentially expressed genes (DEGs, P = 0.05) and tissue-specific biological processes between leaf and root tissues. Furthermore, a TFs-based regulation network was constructed using Cytoscape software. Taken together, these results not only provide a comprehensive genomic resource of R. sativus but also shed light on functional genomic and proteomic research on R. sativus in the future. PMID- 26029220 TI - Time course of biochemical, physiological, and molecular responses to field mimicked conditions of drought, salinity, and recovery in two maize lines. AB - Drought and salinity stresses will have a high impact on future crop productivity, due to climate change and the increased competition for land, water, and energy. The response to drought (WS), salinity (SS), and the combined stresses (WS+SS) was monitored in two maize lines: the inbred B73 and an F1 commercial stress-tolerant hybrid. A protocol mimicking field progressive stress conditions was developed and its effect on plant growth analyzed at different time points. The results indicated that the stresses limited growth in the hybrid and arrested it in the inbred line. In SS, the two genotypes had different ion accumulation and translocation capacity, particularly for Na(+) and Cl(-). Moreover, the hybrid perceived the stress, reduced all the analyzed physiological parameters, and kept them reduced until the recovery. B73 decreased all physiological parameters more gradually, being affected mainly by SS. Both lines recovered better from WS than the other stresses. Molecular analysis revealed a diverse modulation of some stress markers in the two genotypes, reflecting their different response to stresses. Combining biochemical and physiological data with expression analyses yielded insight into the mechanisms regulating the different stress tolerance of the two lines. PMID- 26029222 TI - Discovery of non-climacteric and suppressed climacteric bud sport mutations originating from a climacteric Japanese plum cultivar (Prunus salicina Lindl.). AB - Japanese plums are classified as climacteric; however, some economically important cultivars selected in California produce very little ethylene and require long ripening both "on" and "off" the tree to reach eating-ripe firmness. To unravel the ripening behavior of different Japanese plum cultivars, ripening was examined in the absence (air) or in the presence of ethylene or propylene (an ethylene analog) following a treatment or not with 1-methylcyclopropene (1-MCP, an ethylene action inhibitor). Detailed physiological studies revealed for the first time three distinct ripening types in plum fruit: climacteric, suppressed climacteric, and non-climacteric. Responding to exogenous ethylene or propylene, the slow-softening supressed-climacteric cultivars produced detectable amounts of ethylene, in contrast to the novel non-climacteric cultivar that produced no ethylene and softened extremely slowly. Genetic analysis using microsatellite markers produced identical DNA profiles for the climacteric cultivars "Santa Rosa" and "July Santa Rosa," the suppressed-climacteric cultivars "Late Santa Rosa," "Casselman," and "Roysum" and the novel non-climacteric "Sweet Miriam," as expected since historic records present most of these cultivars as bud-sport mutations derived initially from "Santa Rosa." This present study provides a novel fruit system to address the molecular basis of ripening and to develop markers that assist breeders in providing high-quality stone fruit cultivars that can remain "on-tree," increasing fruit flavor, saving harvesting costs, and potentially reducing the need for low-temperature storage during postharvest handling. PMID- 26029221 TI - Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: implications for the genetic engineering of bioenergy crops. AB - Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC MS/MS, bioinformatics and literature analyses. This has led to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, beta-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/alpha-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional alpha-l arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (beta galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. The implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed. PMID- 26029223 TI - Leaf mineral nutrient remobilization during leaf senescence and modulation by nutrient deficiency. AB - Higher plants have to cope with fluctuating mineral resource availability. However, strategies such as stimulation of root growth, increased transporter activities, and nutrient storage and remobilization have been mostly studied for only a few macronutrients. Leaves of cultivated crops (Zea mays, Brassica napus, Pisum sativum, Triticum aestivum, Hordeum vulgare) and tree species (Quercus robur, Populus nigra, Alnus glutinosa) grown under field conditions were harvested regularly during their life span and analyzed to evaluate the net mobilization of 13 nutrients during leaf senescence. While N was remobilized in all plant species with different efficiencies ranging from 40% (maize) to 90% (wheat), other macronutrients (K-P-S-Mg) were mobilized in most species. Ca and Mn, usually considered as having low phloem mobility were remobilized from leaves in wheat and barley. Leaf content of Cu-Mo-Ni-B-Fe-Zn decreased in some species, as a result of remobilization. Overall, wheat, barley and oak appeared to be the most efficient at remobilization while poplar and maize were the least efficient. Further experiments were performed with rapeseed plants subjected to individual nutrient deficiencies. Compared to field conditions, remobilization from leaves was similar (N-S-Cu) or increased by nutrient deficiency (K-P-Mg) while nutrient deficiency had no effect on Mo-Zn-B-Ca-Mn, which seemed to be non-mobile during leaf senescence under field conditions. However, Ca and Mn were largely mobilized from roots (-97 and -86% of their initial root contents, respectively) to shoots. Differences in remobilization between species and between nutrients are then discussed in relation to a range of putative mechanisms. PMID- 26029224 TI - Enhanced Arabidopsis pattern-triggered immunity by overexpression of cysteine rich receptor-like kinases. AB - Upon recognition of microbe-associated molecular patterns (MAMPs) such as the bacterial flagellin (or the derived peptide flg22) by pattern-recognition receptors (PRRs) such as the FLAGELLIN SENSING2 (FLS2), plants activate the pattern-triggered immunity (PTI) response. The L-type lectin receptor kinase-VI.2 (LecRK-VI.2) is a positive regulator of Arabidopsis thaliana PTI. Cysteine-rich receptor-like kinases (CRKs) possess two copies of the C-X8-C-X2-C (DUF26) motif in their extracellular domains and are thought to be involved in plant stress resistance, but data about CRK functions are scarce. Here, we show that Arabidopsis overexpressing the LecRK-VI.2-responsive CRK4, CRK6, and CRK36 demonstrated an enhanced PTI response and were resistant to virulent bacteria Pseudomonas syringae pv. tomato DC3000. Notably, the flg22-triggered oxidative burst was primed in CRK4, CRK6, and CRK36 transgenics and up-regulation of the PTI-responsive gene FLG22-INDUCED RECEPTOR-LIKE 1 (FRK1) was potentiated upon flg22 treatment in CRK4 and CRK6 overexpression lines or constitutively increased by CRK36 overexpression. PTI-mediated callose deposition was not affected by overexpression of CRK4 and CRK6, while CRK36 overexpression lines demonstrated constitutive accumulation of callose. In addition, Pst DC3000-mediated stomatal reopening was blocked in CRK4 and CRK36 overexpression lines, while overexpression of CRK6 induced constitutive stomatal closure suggesting a strengthening of stomatal immunity. Finally, bimolecular fluorescence complementation and co-immunoprecipitation analyses in Arabidopsis protoplasts suggested that the plasma membrane localized CRK4, CRK6, and CRK36 associate with the PRR FLS2. Association with FLS2 and the observation that overexpression of CRK4, CRK6, and CRK36 boosts specific PTI outputs and resistance to bacteria suggest a role for these CRKs in Arabidopsis innate immunity. PMID- 26029225 TI - Distribution of XTH, expansin, and secondary-wall-related CesA in floral and fruit abscission zones during fruit development in tomato (Solanum lycopersicum). AB - After fruit development is triggered by pollination, the abscission zone (AZ) in the fruit pedicel strengthens its adhesion to keep the fruit attached. We previously reported that xyloglucan and arabinan accumulation in the AZ accompanies the shedding of unpollinated flowers. After the fruit has developed and is fully ripened, shedding occurs easily in the AZ due to lignin accumulation. Regulation of cell wall metabolism may play an important role in these processes, but it is not well understood. In the present report, we used immunohistochemistry to visualize changes in the distributions of xyloglucan and arabinan metabolism-related enzymes in the AZs of pollinated and unpollinated flowers, and in ripened fruits. During floral abscission, we observed a gradual increase in polyclonal antibody labeling of expansin in the AZ. The intensities of LM6 and LM15 labeling of arabinan and xyloglucan, respectively, also increased. However, during floral abscission, we observed a large 1 day post anthesis (DPA) peak in the polyclonal antibody labeling of XTH in the AZ, which then decreased. These results suggest that expansin and XTH play important, but different roles in the floral abscission process. During fruit abscission, unlike during floral abscission, no AZ-specific expansin and XTH were observed. Although lignification was seen in the AZ of over-ripe fruit pedicels, secondary cell wall specific cellulose synthase signals were not observed. This suggests that cellulose metabolism-related enzymes do not play important roles in the AZ prior to fruit abscission. PMID- 26029227 TI - Iron partitioning at an early growth stage impacts iron deficiency responses in soybean plants (Glycine max L.). AB - Iron (Fe) deficiency chlorosis (IDC) leads to leaf yellowing, stunted growth and drastic yield losses. Plants have been differentiated into 'Fe-efficient' (EF) if they resist to IDC and 'Fe-inefficient' (IN) if they do not, but the reasons for this contrasting efficiency remain elusive. We grew EF and IN soybean plants under Fe deficient and Fe sufficient conditions and evaluated if gene expression and the ability to partition Fe could be related to IDC efficiency. At an early growth stage, Fe-efficiency was associated with higher chlorophyll content, but Fe reductase activity was low under Fe-deficiency for EF and IN plants. The removal of the unifoliate leaves alleviated IDC symptoms, increased shoot:root ratio, and trifoliate leaf area. EF plants were able to translocate Fe to the aboveground plant organs, whereas the IN plants accumulated more Fe in the roots. FRO2-like gene expression was low in the roots; IRT1-like expression was higher in the shoots; and ferritin was highly expressed in the roots of the IN plants. The efficiency trait is linked to Fe partitioning and the up-regulation of Fe storage related genes could interfere with this key process. This work provides new insights into the importance of mineral partitioning among different plant organs at an early growth stage. PMID- 26029226 TI - Cell walls as a stage for intercellular communication regulating shoot meristem development. AB - Aboveground organs of plants are ultimately derived/generated from the shoot apical meristem (SAM), which is a proliferative tissue located at the apex of the stem. The SAM contains a population of stem cells that provide new cells for organ/tissue formation. The SAM is composed of distinct cell layers and zones with different properties. Primordia of lateral organs develop at the periphery of the SAM. The shoot apex is a dynamic and complex tissue, and as such intercellular communications among cells, layers and zones play significant roles in the coordination of cell proliferation, growth and differentiation to achieve elaborate morphogenesis. Recent findings have highlighted the importance of a number of signaling molecules acting in the cell wall space for the intercellular communication, including classic phytohormones and secretory peptides. Moreover, accumulating evidence has revealed that cell wall properties and their modifying enzymes modulate hormone actions. In this review, we outline how behaviors of signaling molecules and changes of cell wall properties are integrated for the shoot meristem regulation. PMID- 26029228 TI - Epigenetic landscape of germline specific genes in the sporophyte cells of Arabidopsis thaliana. AB - In plants, the germline lineages arise in later stages of life cycle as opposed to animals where both male and female germlines are set aside early in development. This developmental divergence is associated with germline specific or preferential expression of a subset of genes that are normally repressed for the rest of plant life cycle. The gene regulatory mechanisms involved in such long-term suppression and short-term activation in plant germline remain vague. Thus, we explored the nature of epigenetic marks that are likely associated with long-term gene repression in the non-germline cells. We accessed available Arabidopsis genome-wide DNA methylation and histone modification data and queried it for epigenetic marks associated with germline genes: genes preferentially expressed in sperm cells, egg cells, synergid cells, central cells, antipodal cells or embryo sac or genes that are with enriched expression in two or more of female germline tissues. The vast majority of germline genes are associated with repression-related epigenetic histone modifications in one or more non-germline tissues, among which H3K9me2 and H3K27me3 are the most widespread repression related marks. Interestingly, we show here that the repressive epigenetic mechanisms differ between male and female germline genes. We also highlight the diverse states of epigenetic marks in different non-germline tissues. Some germline genes also have activation-related marks in non-germline tissues, and the proportion of such genes is higher for female germline genes. Germline genes include 30 transposable element (TE) loci, to which a large number of 24-nt long small interfering RNAs were mapped, suggesting that these small RNAs take a role in suppressing them in non-germline tissues. The data presented here suggest that the majority of Arabidopsis gamete-preferentially/-enriched genes bear repressive epigenetic modifications or regulated by small RNAs. PMID- 26029229 TI - Fructan metabolism and changes in fructan composition during cold acclimation in perennial ryegrass. AB - Perennial ryegrass (Lolium perenne L.) produces high levels of fructans as a mixture of oligosaccharides and polysaccharides with different degrees of polymerization (DP). The present study describes the analysis of the compositional changes in the full spectrum of fructans, fructan distribution between above ground biomass (top) and the roots, and the transcription of candidate genes involved in fructan metabolism during cold acclimation in perennial ryegrass variety "Veyo" and ecotype "Falster" from distinct geographical origins. We observed changes in fructan composition and induction of low-DP fructans, especially DP = 4, in both the top and the roots of "Veyo" and "Falster" in response to low-temperature stress. The accumulation of DP > 50 fructans was only apparent in the top tissues where the Lp1-FFT expression is higher compared to the roots in both "Veyo" and "Falster." Our results also show the accumulation and depolymerization of fructans with different DP, together with the induction of genes encoding fructosyltransferases and fructan exohydrolases in both "Veyo" and "Falster" during cold acclimation, supporting the hypothesis that fructan synthesis and depolymerization occurring simultaneously. The ecotype "Falster," adapted to cold climates, increased total fructan content and produced more DP > 7 fructans in the roots than the variety "Veyo," adapted to warmer climates. This indicates that high-DP fructan accumulation in roots may be an adaptive trait for plant recovery after abiotic stresses. PMID- 26029230 TI - PECTOPLATE: the simultaneous phenotyping of pectin methylesterases, pectinases, and oligogalacturonides in plants during biotic stresses. AB - Degradation of pectin, a major component of plant cell wall, is important for fungal necrotrophs to achieve a successful infection. The activities of pectin methylesterases (PMEs) from both plants and pathogens and the degree and pattern of pectin methylesterification are critical for the outcome of plant-pathogen interaction. Partial degradation of pectin by pectin degrading enzymes releases oligogalacturonides (OGs), elicitors of plant defense responses. Few analytical techniques are available to monitor pectin methylesterification-modulating machineries and OGs produced during plant pathogen interaction. In the present study, ruthenium red is presented as useful dye to monitor both Botrytis cinerea mycelium growth and the induction of PME activity in plant tissue during fungal infection. Moreover a simple, inexpensive and sensitive method, named PECTOPLATE, is proposed that allows a simultaneous phenotyping of PME and pectinase activities expressed during pathogen infection and of pectinase potential in generating OGs. The results in the manuscript also indicate that PME inhibitors can be used in PECTOPLATE as a tool to discriminate the activities of plant PMEs from those of pathogen PMEs expressed during pathogenesis. PMID- 26029231 TI - Low temperature conditioning of garlic (Allium sativum L.) "seed" cloves induces alterations in sprouts proteome. AB - Low-temperature conditioning of garlic "seed" cloves substitutes the initial climatic requirements of the crop and accelerates the cycle. We have reported that "seed" bulbs from "Coreano" variety conditioned at 5 degrees C for 5 weeks reduces growth and plant weight as well as the crop yields and increases the synthesis of phenolic compounds and anthocyanins. Therefore, this treatment suggests a cold stress. Plant acclimation to stress is associated with deep changes in proteome composition. Since proteins are directly involved in plant stress response, proteomics studies can significantly contribute to unravel the possible relationships between protein abundance and plant stress acclimation. The aim of this work was to study the changes in the protein profiles of garlic "seed" cloves subjected to conditioning at low-temperature using proteomics approach. Two sets of garlic bulbs were used, one set was stored at room temperature (23 degrees C), and the other was conditioned at low temperature (5 degrees C) for 5 weeks. Total soluble proteins were extracted from sprouts of cloves and separated by two-dimensional gel electrophoresis. Protein spots showing statistically significant changes in abundance were analyzed by LC-ESI MS/MS and identified by database search analysis using the Mascot search engine. The results revealed that low-temperature conditioning of garlic "seed" cloves causes alterations in the accumulation of proteins involved in different physiological processes such as cellular growth, antioxidative/oxidative state, macromolecules transport, protein folding and transcription regulation process. The metabolic pathways affected include protein biosynthesis and quality control system, photosynthesis, photorespiration, energy production, and carbohydrate and nucleotide metabolism. These processes can work cooperatively to establish a new cellular homeostasis that might be related with the physiological and biochemical changes observed in previous studies. PMID- 26029232 TI - Profiling the expression domains of a rice-specific microRNA under stress. AB - Plant microRNAs (miRs) have emerged as important regulators of gene expression under normal as well as stressful environments. Rice is an important cereal crop whose productivity is compromised due to various abiotic stress factors such as salt, heat and drought. In the present study, we have investigated the role of rice-specific Osa-miR820, in indica rice cultivars showing contrasting response to salt stress. The dissection of expression patterns indicated that the miR is present in all the tissues but is enriched in the anther tissues. In salinity, the miR levels are up-regulated in the leaf tissues but down-regulated in the root tissues. To map the deregulation under salt stress comprehensive time kinetics of expression was performed in the leaf and root tissues. The reproductive stages were also analyzed under salt stress. It emerged that a common regulatory scheme for Osa-miR820 expression is present in the salt susceptible Pusa Basmati 1 and salt-tolerant Pokkali varieties, although there is a variation in the levels of the miR and its target transcript, OsDRM2. The regulation of Osa-miR820 and its target were also studied under other abiotic stresses. This study thus captures the window for the miR-target correlation and the putative role of this regulation is discussed. This will help in gaining useful insights on the role of species specific miRs in plant development and abiotic stress response. PMID- 26029233 TI - Comparative conventional- and quantum dot-labeling strategies for LPS binding site detection in Arabidopsis thaliana mesophyll protoplasts. AB - Lipopolysaccharide (LPS) from Gram-negative bacteria is recognized as a microbe associated molecular pattern (MAMP) and not only induces an innate immune response in plants, but also stimulates the development of characteristic defense responses. However, identification and characterization of a cell surface LPS receptor/binding site, as described in mammals, remains elusive in plants. As an amphiphilic, macromolecular lipoglycan, intact LPS potentially contains three MAMP-active regions, represented by the O-polysaccharide chain, the core and the lipid A. Binding site studies with intact labeled LPS were conducted in Arabidopsis thaliana protoplasts and quantified using flow cytometry fluorescence changes. Quantum dots (Qdots), which allow non-covalent, hydrophobic labeling were used as a novel strategy in this study and compared to covalent, hydrophilic labeling with Alexa 488. Affinity for LPS-binding sites was clearly demonstrated by concentration-, temperature-, and time-dependent increases in protoplast fluorescence following treatment with the labeled LPS. Moreover, this induced fluorescence increase was convincingly reduced following pre-treatment with excess unlabeled LPS, thereby indicating reversibility of LPS binding. Inhibition of the binding process is also reported using endo- and exocytosis inhibitors. Here, we present evidence for the anticipated presence of LPS-specific binding sites in Arabidopsis protoplasts, and furthermore propose Qdots as a more sensitive LPS-labeling strategy in comparison to the conventional Alexa 488 hydrazide label for binding studies. PMID- 26029234 TI - Monitoring protein phosphorylation by acrylamide pendant Phos-TagTM in various plants. AB - The aim of the present study is to rationalize acrylamide pendant Phos-TagTM in gel discrimination of phosphorylated and non-phosphorylated plant protein species with standard immunoblot analysis, and optimize sample preparation, efficient electrophoretic separation and transfer. We tested variants of the method including extraction buffers suitable for preservation of phosphorylated protein species in crude extracts from plants and we addressed the importance of the cation (Mn(2+) or Zn(2+)) used in the gel recipe for efficient transfer to PVDF membranes for further immunoblot analysis. We demonstrate the monitoring of Medicago sativa stress-induced mitogen activated protein kinase (SIMK) in stress treated wild type plants and transgenic SIMKK RNAi line. We further show the hyperosmotically-induced phosphorylation of the previously uncharacterized HvMPK4 of barley. The method is validated using inducible phosphorylation of barley and wheat alpha-tubulin and of Arabidopsis MPK6. Acrylamide pendant Phos-TagTMoffers a flexible tool for studying protein phosphorylation in crops and Arabidopsis circumventing radioactive labeling and the use of phosphorylation specific antibodies. PMID- 26029235 TI - Carbon allocation during defoliation: testing a defense-growth trade-off in balsam fir. AB - During repetitive defoliation events, carbon can become limiting for trees. To maintain growth and survival, the resources have to be shared more efficiently, which could result in a trade-off between the different physiological processes of a plant. The objective of this study was to assess the effect of defoliation in carbon allocation of balsam fir [Abies balsamea (L.) Mill.] to test the presence of a trade-off between allocation to growth, carbon storage, and defense. Three defoliation intensities [control (C-trees, 0% defoliation), moderately (M-trees, 41-60%), and heavily (H-trees, 61-80%) defoliated] were selected in order to monitor several variables related to stem growth (wood formation in xylem), carbon storage in stem and needle (non-structural soluble sugars and starch), and defense components in needles (terpenoids compound) from May to October 2011. The concentration of starch was drastically reduced in both wood and leaves of H-trees with a quasi-absence of carbon partitioning to storage in early summer. Fewer kinds of monoterpenes and sesquiterpenes were formed with an increasing level of defoliation indicating a lower carbon allocation for the production of defense. The carbon allocation to wood formation gradually reduced at increasing defoliation intensities, with a lower growth rate and fewer tracheids resulting in a reduced carbon sequestration in cell walls. The hypothesis of a trade-off between the allocations to defense components and to non-structural (NCS) and structural (growth) carbon was rejected as most of the measured variables decreased with increasing defoliation. The starch amount was highly indicative of the tree carbon status at different defoliation intensity and future research should focus on the mechanism of starch utilization for survival and growth following an outbreak. PMID- 26029236 TI - Arbuscular mycorrhizal fungi and rhizobium facilitate nitrogen uptake and transfer in soybean/maize intercropping system. AB - The tripartite symbiosis between legumes, rhizobia and mycorrhizal fungi are generally considered to be beneficial for the nitrogen (N) uptake of legumes, but the facilitation of symbiosis in legume/non-legume intercropping systems is not clear. Therefore, the aims of the research are as follows: (1) to verify if the dual inoculation can facilitate the N uptake and N transfer in maize/soybean intercropping systems and (2) to calculate how much N will be transferred from soybean to maize. A pot experiment with different root separations [solid barrier, mesh (30 MUm) barrier and no barrier] was conducted, and the (15)N isotopic tracing method was used to calculate how much N transferred from soybean to maize inoculated with arbuscular mycorrhizal fungi (AMF) and rhizobium in a soybean (Glycine max L.cv. Dongnong No. 42)/maize (Zea mays L.cv. Dongnong No. 48) intercropping system. Compared with the Glomus mosseae inoculation (G.m.), Rhizobium SH212 inoculation (SH212), no inoculation (NI), the dual inoculation (SH212+G.m.) increased the N uptake of soybean by 28.69, 39.58, and 93.07% in a solid barrier system. N uptake of maize inoculated with both G. mosseae and rhizobium was 1.20, 1.28, and 1.68 times more than that of G.m., SH212 and NI, respectively, in solid barrier treatments. In addition, the amount of N transferred from soybean to maize in a dual inoculation system with a mesh barrier was 7.25, 7.01, and 11.45 mg more than that of G.m., SH212 and NI and similarly, 6.40, 7.58, and 12.46 mg increased in no barrier treatments. Inoculating with both AMF and rhizobium in the soybean/maize intercropping system improved the N fixation efficiency of soybean and promoted N transfer from soybean to maize, resulting in the improvement of yield advantages of legume/non legume intercropping. PMID- 26029237 TI - The conserved transcription factors, MYB115 and MYB118, control expression of the newly evolved benzoyloxy glucosinolate pathway in Arabidopsis thaliana. AB - The evolution of plant metabolic diversity is largely driven by gene duplication and ensuing sub-functionalization and/or neo-functionalization to generate new enzymatic activities. However, it is not clear whether the transcription factors (TFs) regulating these new enzyme encoding genes were required to co-evolve with these genes in a similar fashion or if these new genes can be captured by existing conserved TFs to provide the appropriate expression pattern. In this study, we found two conserved TFs, MYB115, and MYB118, co-expressed with the key enzyme encoding genes in the newly evolved benzoyloxy glucosinolate (GLS) pathway. These TFs interacted with the promoters of the GLS biosynthetic genes and negatively influenced their expression. Similarly, the GLS profiles of these two TFs knockouts showed that they influenced the aliphatic GLS accumulation within seed, leaf and flower, while they mainly expressed in seeds. Further studies indicated that they are functionally redundant and epistatically interact to control the transcription of GLS genes. Complementation study confirmed their roles in regulating the aliphatic GLS biosynthesis. These results suggest that the newly evolved enzyme encoding genes for novel metabolites can be regulated by conserved TFs, which helps to improve our model for newly evolved genes regulation. PMID- 26029238 TI - Hidden among the crowd: differential DNA methylation-expression correlations in cancer occur at important oncogenic pathways. AB - DNA methylation is a frequent epigenetic mechanism that participates in transcriptional repression. Variations in DNA methylation with respect to gene expression are constant, and, for unknown reasons, some genes with highly methylated promoters are sometimes overexpressed. In this study we have analyzed the expression and methylation patterns of thousands of genes in five groups of cancer and normal tissue samples in order to determine local and genome-wide differences. We observed significant changes in global methylation-expression correlation in all the neoplasms, which suggests that differential correlation events are frequent in cancer. A focused analysis in the breast cancer cohort identified 1662 genes whose correlation varies significantly between normal and cancerous breast, but whose DNA methylation and gene expression patterns do not change substantially. These genes were enriched in cancer-related pathways and repressive chromatin features across various model cell lines, such as PRC2 binding and H3K27me3 marks. Substantial changes in methylation-expression correlation indicate that these genes are subject to epigenetic remodeling, where the differential activity of other factors break the expected relationship between both variables. Our findings suggest a complex regulatory landscape where a redistribution of local and large-scale chromatin repressive domains at differentially correlated genes (DCGs) creates epigenetic hotspots that modulate cancer-specific gene expression. PMID- 26029240 TI - Cosplicing network analysis of mammalian brain RNA-Seq data utilizing WGCNA and Mantel correlations. AB - Across species and tissues and especially in the mammalian brain, production of gene isoforms is widespread. While gene expression coordination has been previously described as a scale-free coexpression network, the properties of transcriptome-wide isoform production coordination have been less studied. Here we evaluate the system-level properties of cosplicing in mouse, macaque, and human brain gene expression data using a novel network inference procedure. Genes are represented as vectors/lists of exon counts and distance measures sensitive to exon inclusion rates quantifies differences across samples. For all gene pairs, distance matrices are correlated across samples, resulting in cosplicing or cotranscriptional network matrices. We show that networks including cosplicing information are scale-free and distinct from coexpression. In the networks capturing cosplicing we find a set of novel hubs with unique characteristics distinguishing them from coexpression hubs: heavy representation in neurobiological functional pathways, strong overlap with markers of neurons and neuroglia, long coding lengths, and high number of both exons and annotated transcripts. Further, the cosplicing hubs are enriched in genes associated with autism spectrum disorders. Cosplicing hub homologs across eukaryotes show dramatically increasing intronic lengths but stable coding region lengths. Shared transcription factor binding sites increase coexpression but not cosplicing; the reverse is true for splicing-factor binding sites. Genes with protein-protein interactions have strong coexpression and cosplicing. Additional factors affecting the networks include shared microRNA binding sites, spatial colocalization within the striatum, and sharing a chromosomal folding domain. Cosplicing network patterns remain relatively stable across species. PMID- 26029239 TI - An interpretive review of selective sweep studies in Bos taurus cattle populations: identification of unique and shared selection signals across breeds. AB - This review compiles the results of 21 genomic studies of European Bos taurus breeds and thus provides a general picture of the selection signatures in taurine cattle identified by genome-wide selection-mapping scans. By performing a comprehensive summary of the results reported in the literature, we compiled a list of 1049 selection sweeps described across 37 cattle breeds (17 beef breeds, 14 dairy breeds, and 6 dual-purpose breeds), and four different beef-vs.-dairy comparisons, which we subsequently grouped into core selective sweep (CSS) regions, defined as consecutive signals within 1 Mb of each other. We defined a total of 409 CSSs across the 29 bovine autosomes, 232 (57%) of which were associated with a single-breed (Single-breed CSSs), 134 CSSs (33%) were associated with a limited number of breeds (Two-to-Four-breed CSSs) and 39 CSSs (9%) were associated with five or more breeds (Multi-breed CSSs). For each CSS, we performed a candidate gene survey that identified 291 genes within the CSS intervals (from the total list of 5183 BioMart-extracted genes) linked to dairy and meat production, stature, and coat color traits. A complementary functional enrichment analysis of the CSS positional candidates highlighted other genes related to pathways underlying behavior, immune response, and reproductive traits. The Single-breed CSSs revealed an over-representation of genes related to dairy and beef production, this was further supported by over-representation of production-related pathway terms in these regions based on a functional enrichment analysis. Overall, this review provides a comparative map of the selection sweeps reported in European cattle breeds and presents for the first time a characterization of the selection sweeps that are found in individual breeds. Based on their uniqueness, these breed-specific signals could be considered as "divergence signals," which may be useful in characterizing and protecting livestock genetic diversity. PMID- 26029241 TI - Sites of instability in the human TCF3 (E2A) gene adopt G-quadruplex DNA structures in vitro. AB - The formation of highly stable four-stranded DNA, called G-quadruplex (G4), promotes site-specific genome instability. G4 DNA structures fold from repetitive guanine sequences, and increasing experimental evidence connects G4 sequence motifs with specific gene rearrangements. The human transcription factor 3 (TCF3) gene (also termed E2A) is subject to genetic instability associated with severe disease, most notably a common translocation event t(1;19) associated with acute lymphoblastic leukemia. The sites of instability in TCF3 are not randomly distributed, but focused to certain sequences. We asked if G4 DNA formation could explain why TCF3 is prone to recombination and mutagenesis. Here we demonstrate that sequences surrounding the major t(1;19) break site and a region associated with copy number variations both contain G4 sequence motifs. The motifs identified readily adopt G4 DNA structures that are stable enough to interfere with DNA synthesis in physiological salt conditions in vitro. When introduced into the yeast genome, TCF3 G4 motifs promoted gross chromosomal rearrangements in a transcription-dependent manner. Our results provide a molecular rationale for the site-specific instability of human TCF3, suggesting that G4 DNA structures contribute to oncogenic DNA breaks and recombination. PMID- 26029242 TI - Phage display and targeting peptides: surface functionalization of nanocarriers for delivery of small non-coding RNAs. PMID- 26029243 TI - Marine systems biology. PMID- 26029244 TI - Diagnostics, correction and prophylaxis of prepathological states using the non invasive cell technology is one of the ways of longevity. PMID- 26029245 TI - New insights into the structural characteristics of irradiated crotamine. AB - BACKGROUND: Since ionizing radiation has the potential to alter the molecular structure and affect the biological properties of biomolecules, it has been successfully employed to attenuate animal toxins. The present study aimed to characterize the structural modifications on irradiated crotamine, a toxin from Crotalus durissus terrificus venom, using circular dichroism (CD), fluorescence, Fourier transformed infrared spectroscopy (FTIR), atomic force microscopy (AFM) and differential scanning calorimetry (DSC). METHODS: A combination of size exclusion and ion-exchange chromatography was used to purify the peptide using crude venom. The pure toxin was then submitted to 2 kGy gamma irradiation doses from a cobalt-60 source. Native and irradiated crotamine were analyzed using a fluorescence spectrophotometer. Wavelength was fixed at 295 nm and fluorescence emission scans were collected from 300 to 400 nm. CD and FTIR techniques were used to identify the secondary structure of both samples. DSC analyses were performed at a starting temperature of 20 degrees C up to a final temperature of 90 degrees C. AFM provided a 3D profile of the surfaces of both crotamine forms adsorbed on mica. RESULTS: Fluorescence spectroscopy showed that the quantum yield of the irradiated form decreased. CD spectra of native and irradiated crotamine solutions showed differences between the samples in wavelength, indicating that irradiation induced a transition of a small portion of the random coil regions towards an alpha-helical conformation. FTIR and CD showed that the native and irradiated crotamine spectra were different with regard to secondary structure. The thermodynamic analysis showed that irradiation caused changes in the calorimetric profile and CD showed that temperature-induced changes also occur in the secondary structure. Finally, AFM showed the possible formation of insoluble aggregates. CONCLUSIONS: Our results indicate that irradiation leads to progressive changes in the structure of the toxin, which could explain a decrease in myotoxic activity. PMID- 26029246 TI - Resilience of health-care workers in the UK; a cross-sectional survey. AB - BACKGROUND: Working for the UK National Health Service (NHS) requires working for organisations under financial pressures and frequent restructures, which can lead to anxiety over continuing employment and income. There are currently no studies to date that have examined the influence of personal resilience across all professions and demographics in the NHS. This study aims to quantify resilience within an NHS trust and explore the contribution of demographic variables of gender, age, years of service, pay grade, hours worked, job role, and division worked to the resilience response of employees. The study also explores the relationship between resilience levels and absence rates, as a marker for health and well-being amongst NHS staff. METHODS: This study consists of a cross sectional on-line survey of staff employed in an NHS Trust. All trust employees were asked to complete a Resilience Scale (RS-25), and demographic questions including age, sex, length of service, NHS pay grade (banding), division, job role and number of hours worked per week. Trust level sickness absence rates were also collected during this period. Results were analysed using descriptive statistics, bivariate comparisons and chi-squared tests. RESULTS: Data was gained from 845 employees; a significant association between gender and resilience found females scoring higher on the resilience scale; x (2)(5) =18.30, p < 0.05. A weak positive correlation between age and resilience found older employees displaying a higher level of resilience; r = 0.11, p <0.05. Results also suggest employees working between 18.75-37.5 hours a week have higher levels of resilience. Ancillary staff scored low on resilience compared to all other staff groups which showed moderate resilience. Clinical staff scored lower on resilience compared to both administrative staff and clinical staff with line management responsibilities. No correlations were found between absence rates and resilience. CONCLUSION: This study gives a snapshot of the resilience of employees in a NHS trust. It is the first of its kind to take into consideration all job roles, divisions and the banding system within a trust. The results also indicate that resilience levels may not be a mediating factor for the health and well-being of NHS staff. PMID- 26029247 TI - The impact of multi-site musculoskeletal pain on work ability among health care providers. AB - BACKGROUND: Epidemiologic studies have reported that multi-site musculoskeletal pain threatens work ability. However, no study has been conducted on this topic among health care providers. The aim of the present study was to determine the association between multi-site pain and poor work ability among health care providers. METHODS: A cross-sectional study was conducted. Participants completed a self-administered questionnaire including basic characteristics, job satisfaction, stress screening, musculoskeletal pain at neck, upper extremities, low back, and lower extremities within the last month, and work ability index. Pain intensity was dichotomized according to a numerical pain rating scale score: less than five (no) and at least five (yes). Musculoskeletal pain was divided in three groups: 1) no pain, 2) few pain sites (one to two sites), and 3) many pain sites (three to four sites). The association of the number of pain sites with poor work ability was explored through multivariable logistic regression analysis. RESULTS: A total of 254 health care providers participated in the present study. The majority of participants were female (73.2 %) with mean age of 33.9 (SD 9.5) years. Few pain sites and many pain sites were reported by 79 (31.1 %) and 39 participants (15.4 %), respectively. The adjusted odds ratio for poor work ability of participants who had few pain sites and many pain sites were 1.85 (95 % CI: 0.91 - 3.76) and 2.41 (95 % CI: 1.04 - 5.58), respectively. CONCLUSION: The present study showed that multi-site musculoskeletal pain had an association with poor work ability. The magnitude of association was likely to increase by a higher number of pain sites. PMID- 26029248 TI - Qing-Yi decoction in participants with severe acute pancreatitis: a randomized controlled trial. AB - BACKGROUND: Qing-Yi Decoction (QYD) has been used for severe acute pancreatitis (SAP) patients in China for many years. There were two kinds of QYD: Num 1. QYD (QYD1) which is used in the acute response stage of SAP and Num 2. QYD (QYD2) which is used in the second stage of SAP. This study aims to evaluate the therapeutic efficacy of QYD in participants with SAP. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, participants aged 18-70 years within the first 7 days after acute onset of typical abdominal pain (the definition of SAP was according to the 2007 Guidelines for Management of Severe Acute Pancreatitis in China) were selected. The disease severity was determined by the Ranson, Acute Physiology and Chronic Health Evaluation II, and Balthazar CT scores. The test group received Western medicine and Chinese medicine (Num.1 QYD and Num.2 QYD), while the control group received Western medicine and placebo. The primary end-points were length of hospital stay, total hospitalization expenses, operation rate, and mortality. The secondary end-points were organ complications (i.e., heart failure, respiratory failure, acute renal failure, and hepatic failure), duration of paralytic ileus, infection, intensive care unit stay, and respirator use. RESULTS: From March 2008 to July 2010, a total of 300 participants with severe acute pancreatitis were assessed for eligibility in West China Hospital, and 100 were eligible for randomized allocation. Eighty-five participants (46 in the test group; 39 in the control group) were included in the statistical analyses. The two groups were similar in their baseline clinical characteristics (age, sex, and etiology) and disease severity. After the interventions, there were no differences between the two groups for length of hospital stay (P = 0.323), total hospitalization expenses (P = 0.252), operation rate (P = 0.231), mortality (P = 0.462), organ complications (P > 0.05), intensive care unit stay (P = 0.209), and respirator use (P > 0.05). However, the duration [median (interquartile range)] of paralytic ileus, i.e., 4 (2-6) days vs. 6 (4-8) days (P = 0.014) and rate of infection, i.e., (13.0 % vs. 35.9 %) (P = 0.013) differed significantly. CONCLUSIONS: QYD could restore gastrointestinal motility to normal and reduce the infection rates in the SAP patients who completed a full course of QYD treatment according to per protocol analysis. PMID- 26029249 TI - Effects of harvest, fire, and pest/pathogen disturbances on the West Cascades ecoregion carbon balance. AB - BACKGROUND: Disturbance is a key influence on forest carbon dynamics, but the complexity of spatial and temporal patterns in forest disturbance makes it difficult to quantify their impacts on carbon flux over broad spatial domains. Here we used a time series of Landsat remote sensing images and a climate-driven carbon cycle process model to evaluate carbon fluxes at the ecoregion scale in western Oregon. RESULTS: Thirteen percent of total forest area in the West Cascades ecoregion was disturbed during the reference interval (1991-2010). The disturbance regime was dominated by harvesting (59 % of all area disturbed), with lower levels of fire (23 %), and pest/pathogen mortality (18 %). Ecoregion total Net Ecosystem Production was positive (a carbon sink) in all years, with greater carbon uptake in relatively cool years. Localized carbon source areas were associated with recent harvests and fire. Net Ecosystem Exchange (including direct fire emissions) showed greater interannual variation and became negative (a source) in the highest fire years. Net Ecosystem Carbon Balance (i.e. change in carbon stocks) was more positive on public that private forestland, because of a lower disturbance rate, and more positive in the decade of the 1990s than in the warmer and drier 2000s because of lower net ecosystem production and higher direct fire emissions in the 2000s. CONCLUSION: Despite recurrent disturbances, the West Cascades ecoregion has maintained a positive carbon balance in recent decades. The high degree of spatial and temporal resolution in these simulations permits improved attribution of regional carbon sources and sinks. PMID- 26029250 TI - Plasmodium knowlesi - an emerging pathogen. AB - Ten years have passed since the publication of a large focus of Plasmodium knowlesi infections in the human population. The discovery was made during a molecular investigation of atypical P. malariae cases in the Kapit Health Division, Sarawak, Malaysian Borneo. Patients were more symptomatic with higher parasite counts than expected in P. malariae infections. The investigation found only P. knowlesi DNA present in patient blood samples. Morphological similarity had allowed P. knowlesi to masquerade as P. malariae during routine diagnostic microscopy for malaria. P. knowlesi, a malaria parasite of macaque monkeys, had entered the human population. The subsequent development of P. knowlesi species specific PCR assays soon demonstrated that the entry was not confined to the Kapit Division but extended across island and mainland Southeast Asia. Relevant clinical descriptions and guidelines for the treatment and management of patents with P. knowlesi malaria were not available. Nor was it clear whether P. knowlesi had undergone a host switch event into the human population or if infections were zoonotic. The outputs of studies on P. knowlesi malaria during the past 10 years will be summarized, highlighting major findings within the context of pathophysiology, virulence, host switch events, treatment, control and importantly malaria elimination. PMID- 26029251 TI - Alternative cell polarity behaviours arise from changes in G-protein spatial dynamics. AB - Yeast cells form a single mating projection when exposed to mating pheromone, a classic example of cell polarity. Prolonged treatment with pheromone or specific mutations results in alternative cell polarity behaviours. The authors performed mathematical modelling to investigate these unusual cell morphologies from the perspective of balancing spatial amplification (i.e. positive feedback that localises components) with spatial tracking (i.e. negative feedback that allows sensing of gradient). First, they used generic models of cell polarity to explore different cell polarity behaviours that arose from changes in the model spatial dynamics. By exploring the positive and negative feedback loops in each stage of a two-stage model, they simulated a variety of cell morphologies including single bending projections, single straight projections, periodic multiple projections and simultaneous double projections. In the second half of the study, they used a two-stage mechanistic model of yeast cell polarity focusing on G-protein signalling to integrate the modelling results more closely with the authors' previously published experimental observations. In summary, the combination of modelling and experiments describes how yeast cells exhibit a diversity of cell morphologies arising from two-stage G-protein signalling dynamics modulated by positive and negative feedbacks. PMID- 26029252 TI - Crystal structures of increasingly large molecules: meeting the challenges with CRYSTALS software. AB - BACKGROUND: The size and complexity of molecules being studied by single crystal diffraction is growing year by year, resulting in an increase in the difficulties encountered during structure determination. From the crystallisation itself and sample handling, to structure solution and refinement, specific problems due to larger molecules are discussed. RESULTS: During refinement, several methods are available to deal with the problems encountered with large structures within the software Crystals. Hydrogens atoms can neither be found easily nor refined freely, but restraints can be applied automatically. Special scattering factors can be used to model complex disorder. Finally chemical information can be included in the form of restraints in order to help the determination of a good model. Multicollinearity problems are more likely in the refinement of large structures; to some extent more precise and accurate algorithms can help. Also, if the global minimum is less well defined, faster refinement enables more cycles to be carried out, a necessity for good convergence. The efficiency of the algorithms in Crystals have been increased to help address these issues. CONCLUSIONS: Thus, crystal structures are getting larger and their complexity is increasing. Recent developments in precision and speed during the least squares in Crystals is helping the structural scientist to deal with larger structures more efficiently. PMID- 26029253 TI - Mental health risks among nurses under abusive supervision: the moderating roles of job role ambiguity and patients' lack of reciprocity. AB - BACKGROUND: While the nursing profession has been associated with mental health problems and the research into the antecedents of mental health has steadily grown, the relationship between abusive supervision and mental health issues of anxiety and depression remains largely unknown. AIM: This study aims to examine the relationship between abusive supervision and mental health problems. And we also aim to investigate whether this relationship is moderated by role ambiguity and the patients' lack of reciprocity. METHODS: A total of 227 frontline nurses from two public hospitals completed the survey questionnaire. RESULTS: (1) Abusive supervision was positively associated with poor mental health; (2) the positive relationship was moderated by nurses' perceived role ambiguity in such a way that the relationship was stronger when the perceived role ambiguity is high; (3) the positive relationship was moderated by the patients' lack of reciprocity in such a way that the relationship was stronger when patients' lack of reciprocity was high. CONCLUSIONS: To conclude, the present study showed that abusive supervision was positively associated with mental health problems of anxiety and depression among samples of Chinese nurses. Findings of this study also highlighted that this relationship was contingent upon perceived role ambiguity and patients' reciprocity. PMID- 26029254 TI - Association between length of hospital stay and implementation of discharge planning in acute psychiatric inpatients in Japan. AB - BACKGROUND: Japan has introduced an acute psychiatric care unit to the public healthcare insurance program, but its requirement of a shorter length of stay could lead to discharges without proper discharge planning. The aim of this study was to examine the association between the implementation of discharge planning and the length of stay of acute psychiatric inpatients in Japan. METHODS: This retrospective cross-sectional study included 449 patients discharged from the 'psychiatric emergency ward' of 66 hospitals during a two-week period from March 7 to 20, 2011. The assigned nurse or nursing assistant for each patient provided information on the implementation of discharge planning in the hospital stay. RESULTS: Approximately one quarter of the 449 patients (n = 122) received no support for coordination with post-discharge community care resources. The 122 patients who had received no support for community care coordination had a significantly lower mean age at admission, a shorter length of stay, and a higher rate of either no follow-up or unidentified post-discharge outpatient service than the other 327 patients. Multilevel linear regression analysis demonstrated a significantly greater length of stay among patients who were older, those who had a primary diagnosis of schizophrenia, those who were admitted compulsorily, those who received hospital outpatient services, and those who received community care coordination support from the assigned nurse or nursing assistant. The implementation of support for community care coordination did not indicate a significant association with these factors, which have been related to an increased risk of psychiatric readmission. CONCLUSION: Patients to whom the assigned nurse or nursing assistant provided support on community care coordination experienced a significantly greater length of hospital stay. The implementation of support for community care coordination did not indicate a significant association with these factors, which have been related to an increased risk of psychiatric readmission. The mental health policy should increase focus on discharge planning in the acute psychiatric setting to enhance a link between psychiatric inpatient care and post-discharge community care resources. PMID- 26029255 TI - Research highlights for issue 5: disease spillover among natural and managed populations. PMID- 26029256 TI - Integrating evolution in the management of captive zoo populations. AB - Both natural animal populations and those in captivity are subject to evolutionary forces. Evolutionary changes to captive populations may be an important, but poorly understood, factor that can affect the sustainability of these populations. The importance of maintaining the evolutionary integrity of zoo populations, especially those that are used for conservation efforts including reintroductions, is critical for the conservation of biodiversity. Here, we propose that a greater appreciation for an evolutionary perspective may offer important insights that can enhance the reproductive success and health for the sustainability of captive populations. We provide four examples and associated strategies that highlight this approach, including minimizing domestication (i.e., genetic adaptation to captivity), integrating natural mating systems into captive breeding protocols, minimizing the effects of translocation on variation in photoperiodism, and understanding the interplay of parasites/pathogens and inflammation. There are a myriad of other issues that may be important for captive populations, and we conclude that these may often be species specific. Nonetheless, an evolutionary perspective may mitigate some of the challenges currently facing captive populations that are important from a conservation perspective, including their sustainability. PMID- 26029258 TI - Experimental evolution reveals high insecticide tolerance in Daphnia inhabiting farmland ponds. AB - Exposure of nontarget populations to agricultural chemicals is an important aspect of global change. We quantified the capacity of natural Daphnia magna populations to locally adapt to insecticide exposure through a selection experiment involving carbaryl exposure and a control. Carbaryl tolerance after selection under carbaryl exposure did not increase significantly compared to the tolerance of the original field populations. However, there was evolution of a decreased tolerance in the control experimental populations compared to the original field populations. The magnitude of this decrease was positively correlated with land use intensity in the neighbourhood of the ponds from which the original populations were sampled. The genetic change in carbaryl tolerance in the control rather than in the carbaryl treatment suggests widespread selection for insecticide tolerance in the field associated with land use intensity and suggests that this evolution comes at a cost. Our data suggest a strong impact of current agricultural land use on nontarget natural Daphnia populations. PMID- 26029257 TI - Identifying designatable units for intraspecific conservation prioritization: a hierarchical approach applied to the lake whitefish species complex (Coregonus spp.). AB - The concept of the designatable unit (DU) affords a practical approach to identifying diversity below the species level for conservation prioritization. However, its suitability for defining conservation units in ecologically diverse, geographically widespread and taxonomically challenging species complexes has not been broadly evaluated. The lake whitefish species complex (Coregonus spp.) is geographically widespread in the Northern Hemisphere, and it contains a great deal of variability in ecology and evolutionary legacy within and among populations, as well as a great deal of taxonomic ambiguity. Here, we employ a set of hierarchical criteria to identify DUs within the Canadian distribution of the lake whitefish species complex. We identified 36 DUs based on (i) reproductive isolation, (ii) phylogeographic groupings, (iii) local adaptation and (iv) biogeographic regions. The identification of DUs is required for clear discussion regarding the conservation prioritization of lake whitefish populations. We suggest conservation priorities among lake whitefish DUs based on biological consequences of extinction, risk of extinction and distinctiveness. Our results exemplify the need for extensive genetic and biogeographic analyses for any species with broad geographic distributions and the need for detailed evaluation of evolutionary history and adaptive ecological divergence when defining intraspecific conservation units. PMID- 26029259 TI - Habitat corridors facilitate genetic resilience irrespective of species dispersal abilities or population sizes. AB - Corridors are frequently proposed to connect patches of habitat that have become isolated due to human-mediated alterations to the landscape. While it is understood that corridors can facilitate dispersal between patches, it remains unknown whether corridors can mitigate the negative genetic effects for entire communities modified by habitat fragmentation. These negative genetic effects, which include reduced genetic diversity, limit the potential for populations to respond to selective agents such as disease epidemics and global climate change. We provide clear evidence from a forward-time, agent-based model (ABM) that corridors can facilitate genetic resilience in fragmented habitats across a broad range of species dispersal abilities and population sizes. Our results demonstrate that even modest increases in corridor width decreased the genetic differentiation between patches and increased the genetic diversity and effective population size within patches. Furthermore, we document a trade-off between corridor quality and corridor design whereby populations connected by high quality habitat (i.e., low corridor mortality) are more resilient to suboptimal corridor design (e.g., long and narrow corridors). The ABM also revealed that species interactions can play a greater role than corridor design in shaping the genetic responses of populations to corridors. These results demonstrate how corridors can provide long-term conservation benefits that extend beyond targeted taxa and scale up to entire communities irrespective of species dispersal abilities or population sizes. PMID- 26029260 TI - Patterns of domestication in the Ethiopian oil-seed crop noug (Guizotia abyssinica). AB - Noug (Guizotia abyssinica) is a semidomesticated oil-seed crop, which is primarily cultivated in Ethiopia. Unlike its closest crop relative, sunflower, noug has small seeds, small flowering heads, many branches, many flowering heads, and indeterminate flowering, and it shatters in the field. Here, we conducted common garden studies and microsatellite analyses of genetic variation to test whether high levels of crop-wild gene flow and/or unfavorable phenotypic correlations have hindered noug domestication. With the exception of one population, analyses of microsatellite variation failed to detect substantial recent admixture between noug and its wild progenitor. Likewise, only very weak correlations were found between seed mass and the number or size of flowering heads. Thus, noug's 'atypical' domestication syndrome does not seem to be a consequence of recent introgression or unfavorable phenotypic correlations. Nonetheless, our data do reveal evidence of local adaptation of noug cultivars to different precipitation regimes, as well as high levels of phenotypic plasticity, which may permit reasonable yields under diverse environmental conditions. Why noug has not been fully domesticated remains a mystery, but perhaps early farmers selected for resilience to episodic drought or untended environments rather than larger seeds. Domestication may also have been slowed by noug's outcrossing mating system. PMID- 26029261 TI - Genotyping-by-sequencing approach indicates geographic distance as the main factor affecting genetic structure and gene flow in Brazilian populations of Grapholita molesta (Lepidoptera, Tortricidae). AB - The oriental fruit moth Grapholita molesta is one of the major pests of stone and pome fruit species in Brazil. Here, we applied 1226 SNPs obtained by genotyping by-sequencing to test whether host species associations or other factors such as geographic distance structured populations of this pest. Populations from the main areas of occurrence of G. molesta were sampled principally from peach and apple orchards. Three main clusters were recovered by neighbor-joining analysis, all defined by geographic proximity between sampling localities. Overall genetic structure inferred by a nonhierarchical amova resulted in a significant PhiST value = 0.19109. Here, we demonstrate for the first time that SNPs gathered by genotyping-by-sequencing can be used to infer genetic structure of a pest insect in Brazil; moreover, our results indicate that those markers are very informative even over a restricted geographic scale. We also demonstrate that host plant association has little effect on genetic structure among Brazilian populations of G. molesta; on the other hand, reduced gene flow promoted by geographic isolation has a stronger impact on population differentiation. PMID- 26029262 TI - Oceanography and life history predict contrasting genetic population structure in two Antarctic fish species. AB - Understanding the key drivers of population connectivity in the marine environment is essential for the effective management of natural resources. Although several different approaches to evaluating connectivity have been used, they are rarely integrated quantitatively. Here, we use a 'seascape genetics' approach, by combining oceanographic modelling and microsatellite analyses, to understand the dominant influences on the population genetic structure of two Antarctic fishes with contrasting life histories, Champsocephalus gunnari and Notothenia rossii. The close accord between the model projections and empirical genetic structure demonstrated that passive dispersal during the planktonic early life stages is the dominant influence on patterns and extent of genetic structuring in both species. The shorter planktonic phase of C. gunnari restricts direct transport of larvae between distant populations, leading to stronger regional differentiation. By contrast, geographic distance did not affect differentiation in N. rossii, whose longer larval period promotes long-distance dispersal. Interannual variability in oceanographic flows strongly influenced the projected genetic structure, suggesting that shifts in circulation patterns due to climate change are likely to impact future genetic connectivity and opportunities for local adaptation, resilience and recovery from perturbations. Further development of realistic climate models is required to fully assess such potential impacts. PMID- 26029263 TI - Life history traits and phenotypic selection among sunflower crop-wild hybrids and their wild counterpart: implications for crop allele introgression. AB - Hybridization produces strong evolutionary forces. In hybrid zones, selection can differentially occur on traits and selection intensities may differ among hybrid generations. Understanding these dynamics in crop-wild hybrid zones can clarify crop-like traits likely to introgress into wild populations and the particular hybrid generations through which introgression proceeds. In a field experiment with four crop-wild hybrid Helianthus annuus (sunflower) cross types, we measured growth and life history traits and performed phenotypic selection analysis on early season traits to ascertain the likelihood, and routes, of crop allele introgression into wild sunflower populations. All cross types overwintered, emerged in the spring, and survived until flowering, indicating no early life history barriers to crop allele introgression. While selection indirectly favored earlier seedling emergence and taller early season seedlings, direct selection only favored greater early season leaf length. Further, there was cross type variation in the intensity of selection operating on leaf length. Thus, introgression of multiple early season crop-like traits, due to direct selection for greater early season leaf length, should not be impeded by any cross type and may proceed at different rates among generations. In sum, alleles underlying early season sunflower crop-like traits are likely to introgress into wild sunflower populations. PMID- 26029265 TI - Predicting linear B-cell epitopes using amino acid anchoring pair composition. AB - BACKGROUND: Accurate identification of linear B-cell epitopes plays an important role in peptide vaccine designs, immunodiagnosis, and antibody productions. Although several prediction methods have been reported, unsatisfied accuracy has limited the broad usages in linear B-cell epitope prediction. Therefore, developing a reliable model with significant improvement on prediction accuracy is highly desirable. RESULTS: In this study, we developed a novel model for prediction of linear B-cell epitopes, APCpred, which was derived from the combination of amino acid anchoring pair composition (APC) and Support Vector Machine (SVM) methods. Systematic comparisons with the existing prediction models demonstrated that APCpred method significantly improved the prediction accuracy both in fivefold cross-validation of training datasets and in independent blind datasets. In the fivefold cross-validation test with Chen872 dataset at window size of 20, APCpred achieved AUC of 0.809 and accuracy of 72.94%, which was much more accurate than the existing models, e.g., Bayesb, Chen's AAP methods and the enhanced combination method of AAP with five AP scales. For the fivefold cross validation test with ABC16 dataset, APCpred achieved an improved AUC of 0.794 and ACC of 73.00% at window size of 16, and attained an AUC of 0.748 and ACC of 67.96% on Blind387 dataset after being trained with ABC16 dataset. Trained with Lbtope_Confirm dataset, APCpred achieved an increased Acc of 55.09% on FBC934 dataset. Within sequence window sizes from 12 to 20, APCpred final model on homology-reduced dataset achieved an optimal AUC of 0.748 and ACC of 68.43% in fivefold cross-validation at the window size of 20. CONCLUSION: APCpred model demonstrated a significant improvement in predicting linear B-cell epitopes using the features of amino acid anchoring pair composition (APC). Based on our study, a webserver has been developed for on-line prediction of linear B-cell epitopes, which is a free access at: http:/ccb.bmi.ac.cn/APCpred/. PMID- 26029266 TI - Natural human knockouts and the era of genotype to phenotype. AB - Complete loss of gene function in humans by naturally occurring biallelic loss-of function mutations (human knockout) is not a new concept. However, the recent identification of human knockouts along the entire spectrum of health and disease by next-generation sequencing promises to unlock their full potential to accelerate the medical and functional annotation of the human genome. PMID- 26029267 TI - Comprehensive treatment of dementia with Lewy bodies. AB - Dementia with Lewy bodies is an under-recognized disease; it is responsible for up to 20 % of all dementia cases. Accurate diagnosis is essential because the management of dementia with Lewy bodies is more complex than many neurodegenerative diseases. This is because alpha-synuclein, the pathological protein responsible for dementia with Lewy bodies (and Parkinson's disease), produces symptoms in multiple domains. By dividing the symptoms into cognitive, neuropsychiatric, movement, autonomic, and sleep categories, a comprehensive treatment strategy can be achieved. Management decisions are complex, since the treatment of one set of symptoms can cause complications in other symptom domains. Nevertheless, a comprehensive treatment program can greatly improve the patient's quality of life, but does not alter the progression of disease. Cholinesterase inhibitors are effective for cognitive and neuropsychiatric symptoms; rivastigmine has the widest evidence base. Special care needs to be taken to avoid potentially fatal idiopathic reactions to neuroleptic medications; these should be used for short periods only when absolutely necessary and when alternative treatments have failed. Pimavanserin, a selective serotonin 5-HT2A inverse agonist, holds promise as an alternative therapy for synuclein-associated psychosis. Levodopa/carbidopa treatment of parkinsonism is often limited by dopa induced exacerbations of neuropsychiatric and cognitive symptoms. Autonomic symptoms are under-recognized complications of synucleinopathy. Constipation, urinary symptoms and postural hypotension respond to standard medications. Rapid eye movement sleep behavior disorder is highly specific (98 %) to the synucleinopathies. Nonpharmacological treatments, melatonin and clonazepam are all effective. PMID- 26029268 TI - Efficacy of action potential simulation and interferential therapy in the rehabilitation of patients with knee osteoarthritis. AB - OBJECTIVE: Knee osteoarthritis (OA) is the main cause of pain, physical impairment and chronic disability in older people. Electrotherapeutic modalities such as interferential therapy (IFT) and action potential simulation (APS) are used for the treatment of knee OA. In this study, we aim to evaluate the therapeutic effects of APS and IFT on knee OA. METHODS: In this randomized clinical trial, 67 patients (94% female and 6% male with mean age of 52.80 +/- 8.16 years) with mild and moderate knee OA were randomly assigned to be treated with APS (n = 34) or IFT (n = 33) for 10 sessions in 4 weeks. Baseline and post treatment Western Ontario and McMaster Universities Osteoarthritis (WOMAC) subscales, visual analogue scale (VAS) and timed up and go (TUG) test were measured in all patients. RESULTS: VAS and WOMAC subscales were significantly improved after treatment in APS and IFT groups (p < 0.001 for all). TUG was also significantly improved after treatment in APS group (p < 0.001), but TUG changes in IFT was not significant (p = 0.09). There was no significant difference in VAS, TUG and WOMAC subscales values before and after treatment as well as the mean improvement in VAS, TUG and WOMAC subscales during study between groups. CONCLUSION: Short-term treatment with both APS and IFT could significantly reduce pain and improve physical function in patients with knee OA. PMID- 26029269 TI - Cartilage regeneration for treatment of osteoarthritis: a paradigm for nonsurgical intervention. AB - Osteoarthritis (OA) is associated with articular cartilage abnormalities and affects people of older age: preventative or therapeutic treatment measures for OA and related articular cartilage disorders remain challenging. In this perspective review, we have integrated multiple biological, morphological, developmental, stem cell and homeostasis concepts of articular cartilage to develop a paradigm for cartilage regeneration. OA is conceptually defined as an injury of cartilage that initiates chondrocyte activation, expression of proteases and growth factor release from the matrix. This regenerative process results in the local activation of inflammatory response genes in cartilage without migration of inflammatory cells or angiogenesis. The end results are catabolic and anabolic responses, and it is the balance between these two outcomes that controls remodelling of the matrix and regeneration. A tantalizing clinical clue for cartilage regrowth in OA joints has been observed in surgically created joint distraction. We hypothesize that cartilage growth in these distracted joints may have a biological connection with the size of organs and regeneration. Therefore we propose a novel, practical and nonsurgical intervention to validate the role of distraction in cartilage regeneration in OA. The approach permits normal wake-up activity while during sleep; the index knee is subjected to distraction with a pull traction device. Comparison of follow-up magnetic resonance imaging (MRI) at 3 and 6 months of therapy to those taken before therapy will provide much-needed objective evidence for the use of this mode of therapy for OA. We suggest that the paradigm presented here merits investigation for treatment of OA in knee joints. PMID- 26029270 TI - Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis. AB - Denosumab is a human monoclonal antibody which specifically blocks receptor activator of nuclear factor kappaB ligand and is a very potent antiresorptive drug. Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has been proven in a large prospective, randomized multicenter study of 7808 postmenopausal women with osteoporosis [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes somewhat greater increases in bone mineral density (BMD) than the class of bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass and bone strength in the spine, ultradistal and diaphysis of the radius, proximal tibia and the hip. Recently long-term treatment with denosumab has been shown to cause a continued almost linear increase in total hip and femoral neck BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ from the bisphosphonate group in which the rate of improvement of BMD diminishes and for some drugs becomes negative after 3-4 years when the process of secondary mineralization flattens out. This unique property of an antiresorptive drug points towards mechanisms of action which differ from the bisphosphonate group. Both types of antiresorptives decrease cortical porosity but contrary to bisphosphonates the reduction in cortical porosity continues with denosumab which, in addition, also seems to cause a slight continuous modeling-based formation of new bone despite suppression of bone remodeling. The net effect is an increase in cortical thickening and bone mass, and increased strength of cortical bone. This may contribute substantially to the significant further reduction of the nonvertebral fracture risk which was found in the long-term denosumab arm of the FREEDOM extension trial during years 4-7. PMID- 26029271 TI - Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women. AB - Odanacatib is a cathepsin K inhibitor developed for the treatment of postmenopausal osteoporosis. It is a bone resorption inhibitor, but which preserves bone formation to some extent. It can be administered once a week, in tablets also containing vitamin D. In a large clinical development program, it has been shown that odanacatib reduces bone resorption, with a reduction of about 60-70% in biochemical markers of resorption, while bone formation decreases to a lesser magnitude. Odanacatib continuously increases bone mineral density (BMD) at the hip and lumbar spine over 5 years. Once it is stopped, a complete resolution of effect is observed, with declining BMD and increased bone turnover. Bone microarchitecture and bone strength have also been improved in clinical trials using quantitative computed tomography (QCT) at the lumbar spine and hip, and high resolution peripheral QCT at the distal radius and tibia. In a phase III trial involving 16,713 postmenopausal women ?65 years of age with low BMD, the risk of fragility fracture was significantly reduced at the spine, hip and other nonvertebral sites compared with the placebo group. Odanacatib has been generally well tolerated, with no observation of osteonecrosis of the jaw so far, but with exceptional observations of subtrochanteric atypical fracture and morphea-like lesions. Odanacatib appears a useful new option in the treatment of postmenopausal osteoporosis. PMID- 26029272 TI - Quality of life in adolescents with hearing deficiencies and visual impairments. AB - INTRODUCTION: The term quality of life (in Portuguese, Qualidade de Vida; QV) has been expanded and modified over the years and has come to signify social development in terms of education, health, and leisure as well as economic issues. OBJECTIVE: To analyze the perception of QV in adolescents with hearing and visual impairments and the effects of socio-demographic characteristics on the domains of QV. METHOD: This descriptive series study comprised 42 adolescents aged 10 to 19 years who were students at Recife's state schools. The World Health Organization Quality of Life-Abbreviated questionnaire was used to evaluate QV. The data were analyzed using descriptive statistics and the Mann Whitney and Kruskal-Wallis tests with a significance level of p < 0.05. RESULTS: The global perception of QV was higher among adolescents with visual impairments than among those with hearing impairments. Among the individual components of QV, the environment domain garnered the lowest scores independent of the type of impairment. The subjects with visual impairments reported higher scores for social relationships, while the psychological domain scored higher among those with hearing impairments. The students integrated into normal classrooms perceived better QV in the psychological and social relationships domains than did those who sat in special classrooms. CONCLUSION: The environmental domain was the worst component of the QV of handicapped adolescents, suggesting a need for greater investments in policies to improve the QV of this population. PMID- 26029274 TI - News from NIH: a center for translation research and implementation science. PMID- 26029275 TI - News from CDC: applying a life course approach to primary cancer prevention. PMID- 26029273 TI - A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis. AB - BACKGROUND: In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive. METHODS: Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry. RESULTS: Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53 mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age. CONCLUSIONS: Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field. PMID- 26029276 TI - Applying the behaviour change technique (BCT) taxonomy v1: a study of coder training. AB - Behaviour Change Technique Taxonomy v1 (BCTTv1) has been used to detect active ingredients of interventions. The purpose of this study was to evaluate effectiveness of user training in improving reliable, valid and confident application of BCTTv1 to code BCTs in intervention descriptions. One hundred sixty-one trainees (109 in workshops and 52 in group tutorials) were trained to code frequent BCTs. The following measures were taken before and after training: (i) inter-coder agreement, (ii) trainee agreement with expert consensus, (iii) confidence ratings and (iv) coding competence. Coding was assessed for 12 BCTs (workshops) and for 17 BCTs (tutorials). Trainees completed a course evaluation. Methods improved agreement with expert consensus (p < .05) but not inter-coder agreement (p = .08, p = .57, respectively) and increased confidence for BCTs assessed (both p < .05). Methods were as effective as one another at improving coding competence (p = .55). Training was evaluated positively. The training improved agreement with expert consensus, confidence for BCTs assessed, coding competence but not inter-coder agreement. This varied according to BCT. PMID- 26029277 TI - Theory-based approach for maintaining resistance training in older adults with prediabetes: adherence, barriers, self-regulation strategies, treatment fidelity, costs. AB - Effectively preventing and treating chronic diseases through health behavior changes often require intensive theory- and evidence-based intervention including long-term maintenance components. We assessed the efficacy of theory-based maintenance approaches varying by dose for persistently performing resistance training (RT) with the hypothesis that a higher-dose social cognitive theory (SCT) approach would produce greater RT adherence than lower-dose Standard. The Resist-Diabetes study first established 2*/week resistance training (RT) in a 3 month supervised intervention in older (50-69 years, N = 170), overweight to obese (BMI 25-39.9 kg/m(2)) previously inactive adults who fit prediabetes criteria (fasting glucose concentration = 95-125 mg/dl; oral glucose tolerance test 2-h glucose concentration = 140-199 mg/dl or both). After the supervised phase, participants (N = 159) were then randomly assigned to one of two conditions for transition (3 weeks) and then RT alone in community settings for extended contact, maintenance (6 months), and then no contact (6 months). SCT featured continued tailored, interactive personal, and web-based check-ups focused on RT, self-regulation, and a barrier/strategies approach. Standard involved low-dose, generic personal, and web-based check-ups within the same theoretical approach. SCT and Standard both resulted in similar RT, 2*/week adherence during maintenance (74.4 %) and no-contact phases (53.1 %). Cost analysis indicated the Standard intervention for transition and maintenance was inexpensive ($160). Standard can be translated into practice with the potential for continuous contact and persistence in RT beyond the typical program maintenance phase. PMID- 26029278 TI - Tweet for health: using an online social network to examine temporal trends in weight loss-related posts. AB - Few studies have used social networking sites to track temporal trends in health related posts, particularly around weight loss. To examine the temporal relationship of Twitter messages about weight loss over 1 year (2012). Temporal trends in #weightloss mentions and #fitness, #diet, and #health tweets which also had the word "weight" in them were examined using three a priori time periods: (1) holidays: pre-winter holidays, holidays, and post-holidays; (2) Season: winter and summer; and (3) New Year's: pre-New Year's and post-New Year's. Regarding #weightloss, there were 145 (95 % CI 79, 211) more posts/day during holidays and 143 (95 % CI 76, 209) more posts/day after holidays as compared to 480 pre-holiday posts/day; 232 (95 % CI 178, 286) more posts/day during the winter versus summer (441 posts/day); there was no difference in posts around New Year's. Examining social networks for trends in health-related posts may aid in timing interventions when individuals are more likely to be discussing weight loss. PMID- 26029279 TI - Engaging veterans with substance abuse disorders into a research trial: success with study branding, networking, and presence. AB - Recruiting and retaining clients in health interventions can be challenging especially when targeting multiple behavior change in high-risk populations. To inform the methods of trials working with similarly complex clinical populations, we describe multi-pronged efforts to recruit and retain a representative sample. In a two-group RCT, veterans were recruited from a Veteran Affairs Medical Center. The goal was to enroll 200 participants over a 25-month period, and to exceed 70 % follow-up for all treatment arms. To meet these goals, a four-pronged strategy was developed: branding, outreach/networking, onsite presence, and incentives. In month 1, 32 % of the proposed sample size was met (n = 64), and by month 2, 45 % (n = 90); the recruitment goal (n = 200) was achieved 13 months ahead of schedule. Retention exceeds 90 % at all time points out to 18 months. The multipronged recruitment and retention plan was efficient, cost effective, and may generalize to other health promotion initiatives. PMID- 26029280 TI - Recruitment and initial interest of men in yoga for smoking cessation: QuitStrong, a randomized control pilot study. AB - Innovative treatments like yoga for men's smoking cessation (SC) are lacking. To examine the feasibility and acceptability of yoga for men's SC. We randomly assigned eligible men (smoker, >=5 cigarettes/day, age 18-65) to receive cognitive behavioral therapy for SC, plus a yoga or wellness program. Measures included feasibility (recruitment, class attendance) and acceptability (customer satisfaction). We enrolled 38 of 49 eligible men of 167 screened in response to ads (mean age 39.9 years, +/-13.7) who smoked on average 18.6 cigarettes/day (+/ 8.3). Wellness (75.8 %) versus yoga (56 %) men attended more SC classes, p < 0.01. Sixty percent attended >=1 yoga class. Men reported greater satisfaction with in-house versus community yoga classes. Wellness appears to be the preferred intervention; results indicated that it may be more feasible and showed increased attendance at smoking classes. To be fully feasible, yoga + SC may need to be a unified program offering all classes tailored for men and in the same location. PMID- 26029281 TI - Decisional outcomes following use of an interactive web-based decision aid for prostate cancer screening. AB - Informed decision-making tools are recommended for men considering prostate cancer screening. We evaluated the extent to which use of an interactive, web based decision aid was associated with decisional and screening outcomes. Participants (N = 253) were 57 (7.0) years old and completed telephone interviews at baseline, 1 month, and 13 months post-baseline. Tracking software captured minutes spent on the website (median = 33.9), sections viewed (median = 4.0/5.0), testimonials viewed (median = 4.0/6.0), and values clarification tool (VCT) use (77.3 %). In multivariable analyses, all four website use variables were positively associated with increased knowledge (p's < 0.05). Complete VCT use and number of informational sections were positively associated with greater decisional satisfaction (p's < 0.05). Decisional conflict and screening behavior were not associated with measures of website use. Increased use of informational content and interactive elements were related to improved knowledge and satisfaction. Methods to increase utilization of interactive website components may improve informed decision-making outcomes. PMID- 26029282 TI - Implementing an evidence-based breast cancer support and communication tool to newly diagnosed patients as standard care in two institutions. AB - While many women turn to the Internet to obtain health information, it is unlikely that unstructured Internet use provides optimal benefit to women newly diagnosed with breast cancer, due to uneven quality, conflicting claims, redundancy, and search engine idiosyncrasies, which may make finding information and assessing its accuracy and applicability difficult. To answer the need for information and support, the Comprehensive Health Enhancement Support System (CHESS) was developed to provide access to integrated information for decision making, behavior change, and emotional support, and has been validated in randomized trials. This observational study of real-world implementation focuses on the process of integrating CHESS into standard care in two Denver healthcare systems. Results from this study provide guidance for implementation of other web based patient information and support programs in large healthcare organizations. PMID- 26029283 TI - Disseminating results: community response and input on Kisumu breastfeeding study. AB - Communicating findings to study participants and their communities is a practice that often gets overlooked or receives low prioritization by research investigators, but is crucially important. The purpose of this study was to describe the process and community response to the dissemination of results from the Kisumu Breastfeeding Study (KiBS), specifically in terms of (1) community research knowledge and expectations and (2) impressions of result dissemination efforts. A qualitative evaluation was completed for 10 result dissemination events using focus group discussions (FGDs) (n = 10; total number of participants = 98). An inductive, thematic qualitative data analysis was completed in NVivo 8.0. Overall, FGD participants expressed great appreciation for being given information on the study results. Participants had a good understanding of what research entails and had specific expectations for the process, including that the community receive information about the study, not only at the end of the study but also at regular intervals throughout the study's conduct. They also wanted to receive the communications from a credible source, the principal investigator preferably. Other expectations centered on better community and research interactions and development and the use of community collaborators. Impressions of KiBS result dissemination events were positive, but suggestions for the future included having the event in a larger area, inviting more people, having more written materials, and putting the information in an entertaining format such as skits or movies. Sharing study findings with local community members is essential and beneficial to the researchers' long-term engagement with communities and importantly, the successful implementation of study findings when appropriate. It is imperative that dissemination of results be embedded as an integral part of research project planning and development. PMID- 26029284 TI - Network analysis of RE-AIM framework: chronology of the field and the connectivity of its contributors. AB - The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework has been widely used for translational research. We used social network analysis (SNA) to explore how innovative research frameworks, such as RE-AIM, have diffused over time in academic literature. A structured literature review was conducted on RE-AIM between 1999 and 2012. SNA indices of degree score, betweenness, centrality, and authorship ties were used to examine use of RE-AIM. Use of RE-AIM has grown since its inception and spread from a few research centers to use internationally. Investigation of co-authorship revealed many have published on RE-AIM, but a much smaller core of RE-AIM researchers have published together two or more times. SNA revealed how the RE-AIM framework has been used over time and identified areas to further expand use of the framework. SNA can be useful to understand how research frameworks diffuse over time. PMID- 26029285 TI - Translating evidence-based interventions from research to practice: challenges and lessons learned. AB - Despite the increasing popularity of translation research, few studies have described the process and challenges involved in implementing a translation study. The main objective was to determine whether a multi-component group behavioral intervention could be successfully translated from an academic setting into the community health system of federally qualified health centers (FQHCs) funded by the Health Resources and Services Administration (HRSA) in Miami, NY, and NJ. Key challenges and "lessons learned" from the dissemination and implementation process for the SMART/EST (Stress Management And Relaxation Training/Emotional Supportive Therapy) Women's Project (SWP) III in low-resource primary care settings are described. The Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) model served as the theoretical framework for the translation of the study. This study outlines several essential factors related to Glasgow's RE-AIM model that need to be considered in order to accomplish successful translation of evidence-based interventions from traditional academia to "real-world" community health center settings. PMID- 26029286 TI - Actin and Keratin are Binding Partners of the 1,25D3-MARRS Receptor/PDIA3/ERp57. AB - We have shown that the 1,25D3-MARRS receptor is necessary for the rapid, pre genomic effects of 1,25(OH)2D3 on phosphate and/or calcium absorption in chick intestines. However, a clear understanding of the proteins involved in the signaling mechanisms by which the 1,25D3-MARRS receptor facilitates 1,25(OH)2D3 mediated phosphate or calcium uptake, as well as other cellular effects, is still under investigation. We used co-immunoprecipitation studies and mass spectroscopy to identify actin and keratin as proteins that interact with the 1,25D3-MARRS receptor. Using confocal microscopy, we visualized 1,25(OH)2D3- MARRS receptor localizations relative to actin and/or keratin distribution in chick enterocytes. Cells cultured in media containing phenol red had the 1,25D3-MARRS receptor and actin localized largely in the nucleus, which was dispersed upon addition of (OH)2 1,25(OH)2D3. In the absence of phenol red, staining was cytoplasmic. Addition of steroid caused diminished staining at 10 s and 30 s, with a return of intensity between 1 and 5 min. Nuclear staining was observed after 1 min. We found that F-actin concentrations are maximal when 1,25D3-MARRS receptor localizations within enterocytes are low suggesting that cyclical conversions of F-actin to G-actin are involved in the 1,25(OH)2D3-mediated redistribution of the 1,25D3-MARRS receptor within the cell. We also found that keratin distribution remains constant with 1,25(OH)2D3 exposure when Factin depolymerizes into G actin, which suggests that actin and keratin work in concert to facilitate hormonemediated redistribution of the 1,25D3-MARRS receptor. We subsequently investigated whether the cyclical redistribution was related to either 1,25(OH)2D3-stimulated phosphate or calcium uptake, but no congruent pattern was found. PMID- 26029287 TI - Patient experiences living with pancreatic cancer risk. AB - BACKGROUND: Pancreatic cancer (PancCa) is recognized as a component of many well described hereditary cancer syndromes. Minimal research has focused on patient needs and experiences living with this risk. PURPOSE: To understand the meaning and experience of living with familial PancCa risk and to explore experiences related to screening and prevention of PancCa. METHODS: Participants underwent semi-structured, in-depth interviews. Adults without PancCa and who met familial or hereditary risk criteria were eligible. Thematic analysis was completed on the transcripts in order to identify patterns, consistencies, and differences. Narrative review of existing literature related to women living with hereditary breast and ovarian cancer (HBOC) risk was completed to explore similarities and differences between published findings and our current findings. RESULTS: Nineteen individuals (9 male, 10 female) participated. Major themes addressed participants' family experiences with PancCa and PancCa death and the associated grief from the experiences. Family experiences impacted how participants interpreted and approached their own cancer risk and participated in the cancer screening program. Participants wanted to control their cancer risk and sought information and resources to prevent PancCa or PancCa related death. Distress related to risk was not described as constant but occurred around salient time points. CONCLUSION & FUTURE IMPLICATIONS: Study results begin to describe the lived experience of individuals with PancCa risk. Through this research we have uncovered important variables to further understand, measure, and intervene upon in future research. Distress related to risk was not described as ongoing, but occurred around specific and salient time points that brought risk to the forefront. Individuals with familial PancCa risk may have a unique experience compared to other hereditary cancer syndromes due to the high mortality of the disease and uncertainty related to prevention and early detection outcomes. PMID- 26029288 TI - Comparison of multidetector computed tomography findings with clinical and laboratory data in pulmonary thromboembolism. AB - BACKGROUND: Pulmonary thromboembolism (PTE) is a common disease with a high mortality rate that is difficult to diagnose and treat. Because of the variety of clinical symptoms and signs, it is difficult to diagnose. Therefore, the diagnosis of PTE is mainly confirmed by imaging techniques. The aim of this study was to evaluate whether there is any corelation of the Wells rule, D-dimer and LDH values with computerized tomography pulmonary angiography (CTPA) findings in PTE diagnosis. MATERIAL/METHODS: A consecutive series of 62 patients, which included 31 males and 31 females, with high/moderate/low risk of embolism according to Wells pulmonary embolism score, selected from the emergency service and/or outpatient clinic, enrolled in this prospective study. The patients with clinical or laboratory findings of elevated D-dimer level or elevated lactate dehydrogenase (LDH) level were suspected of embolism and underwent tomography. RESULTS: PTE was detected in 26 patients (42%). A significant difference was not detected between tomography finding positive and negative embolisms in the patient group in terms of age or gender distribution (P=0.221 and P=0.416, respectively). No significant difference was detected between tomography finding positive and negative embolisms in the patient group in terms of elevated LDH or/and D-dimer levels (P=0.263 and P=1.000, respectively). The distribution of low-risk-factor patients in the non-embolism group, and the distribution of high risk-factor patients in the embolism-positive group was statistically significantly high (P<0.001). There was no statistically significant difference between the groups (P=0.053). Correlation test showed no correlation between LDH and D-dimer levels. (r=0.214, P=0.180). CONCLUSIONS: In conclusion, when a patient presents with chest pain, our carrying out LDH and D-Dimer tests will not exclude PTE without CTPA. However, we suggest that LDH isoenzymes should be studied in further research. PMID- 26029289 TI - Volumetric assessment of lymph node metastases in patients with non-seminomatous germ cell tumours treated with chemotherapy. AB - INTRODUCTION: We evaluate volumetry and RECIST (Response Evaluation Criteria In Solid Tumors) as methodologies for response after chemotherapy for non seminomatous germ cell tumour with retroperitoneal lymph node metastases. METHODS: We performed a retrospective analysis of non-seminomatous testicular tumours and concurrent retroperitoneal lymph node metastases, which received chemotherapy and had computed tomography scans before and after treatment. Volumetric analysis and RECIST criteria were used to calculate response rates. We included a new category (favourable response) for patients with response rates between <100% and >70%. We calculated the correlation between volumetric and RECIST criteria with histological and clinical variables. RESULTS: In total, 18 patients met the inclusion criteria. Histopathologic analysis of orchiectomy showed teratoma in 55.5% of patients, and those without teratoma had predominantly embryonal carcinoma. The mean baseline volume of retroperitoneal metastases was 447 cc, the mean post-chemotherapy volume was 33.6 cc, and the response rate was 62.6%. According to RECIST criteria, the mean baseline diameter was 4.93 cm, the mean post-chemotherapy diameter was 2.39 cm, and the response rate was 42.4%. Large post-chemotherapy residual masses correlated in both classifications with teratoma. The response rate was associated with the need for surgical treatment and the volumetric classification correlated with the need for lymphadenectomy. CONCLUSIONS: This study evaluated volumetry as a way to measure clinical response in lymph node metastases of non-seminomatous germ cell tumours. Volumetric analysis is the next step in the evaluation of response rate; its accuracy remains to be determined. Teratoma had greater residual masses and our classification correlated with the need for lymphadenectomy. PMID- 26029290 TI - Does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer? AB - INTRODUCTION: The ability of perineural invasion (PNI) in radical prostatectomy (RP) specimens to predict biochemical recurrence (BCR) is unclear. This study investigates this controversial question in a large cohort. METHODS: A retrospective analysis was undertaken of prospectively collected data from 1497 men who underwent RP (no neoadjuvant therapy) for clinically localized prostate cancer. The association of PNI at RP with other clinicopathological parameters was evaluated. The correlation of clinicopathological factors and BCR (defined as prostate-specific antigen [PSA] >0.2 ng/mL) was investigated with univariable and multivariable Cox regression analysis in 1159 men. RESULTS: PNI-positive patients were significantly more likely to have a higher RP Gleason score, pT3 disease, positive surgical margins, and greater cancer volume (p < 0.0005). The presence of PNI significantly correlated with BCR on univariable (hazard ratio 2.30, 95% confidence interval 1.50-3.55, p < 0.0005), but not multivariable analysis (p = 0.602). On multivariable Cox regression analysis the only independent prognostic factors were preoperative PSA, RP Gleason score, pT-stage, and positive surgical margin status. These findings are limited by a relatively short follow-up time and retrospective study design. CONCLUSIONS: PNI at RP is not an independent predictor of BCR. Therefore, routine reporting of PNI is not indicated. Future research should be targeted at the biology of PNI to increase the understanding of its role in prostate cancer progression. PMID- 26029291 TI - Efficacy of percutaneous cryoablation of renal cell carcinoma in older patients with medical comorbidities: Outcome study in 70 patients. AB - INTRODUCTION: The aim of this study was to establish the efficacy of cryoablation for incidentally discovered small renal cell carcinomas in older patients with medical comorbidities. METHODS: We carried out a retrospective chart analysis of outcomes of 70 patients treated by cryoablation. The inclusion criteria were age >56 years, medical comorbidities (Charlson class I-III), and suitability for cryoablation established by urologists and interventional radiologists. In total, 43 patients were male, 27 female, and the age range was 56 to 89. The lesions measured 1.5 to 4 cm; 29 were high-grade Fuhrman and 41 were low grade. All lesions were treated by 2 10-minute freezing cycles separated by an 8-minute thawing period. One to seven cryoprobes were inserted according to a preoperative, 3D computed tomography (CT)-based plan. RESULTS: Results were assessed on follow-up CTs (at 8-9 months). Of the 70 patients, 68 were treated by cryoablations and surgical salvage procedures; these patients were free of disease for 23 to 72 months (mean 39). One patient experienced recurrence and the other was lost to follow-up. One or two cryoablations rendered 66 patients tumour free and additional surgery rendered another 2 patients tumour-free. The location and configuration of the lesion affected outcomes. Of the 27 posterior lesions, there was 1 failure; of the postero-lateral lesions, there were 4 failures; of the anterior lesions, there were 5 lesions; finally of the 32 central or deep seated lesions, there were 9 failures. Implants with one and two cryoprobes had a high recurrence rate. Three major complications were managed by minor interventions. The mean hospitalization was 1.3 days and the procedure times were variable. CONCLUSION: Percutaneous cryoablation is recommended as a minimally invasive nephron-sparing treatment for amenable lesions in older patients with medical comorbidities. PMID- 26029292 TI - The influence of membranous stretched urethral length and urethral circumference on postoperative recovery of continence after radical prostatectomy: A pilot study. AB - INTRODUCTION: We investigate the influence of stretched membranous urethral length (SUL) and urethral circumference (UC) on postoperative recovery of continence after radical prostatectomy (RP). METHODS: To evaluate the distal continence zone intraoperatively, we individually measured and recorded stretched membranous urethral length (distance between the urogenital diaphragm and the prostate apex with cephalad retraction, SUL) and urethral circumference (UC) after exposure of the urethra. We analyzed the association between magnetic resonance imaging-measured membranous urethral length (MRIL) and urethral diameter (MRID) and intraoperative SUL and UC and influence on return to continence. RESULTS: The mean patient age, SUL and UC were 66.5 +/- 6.0 years, 24.2 +/- 3.3 mm, and 27.5 +/- 4.4 mm, respectively. MRIL and MRID were 11.3 +/- 1.6 mm and 10.6 +/- 1.9mm, respectively. In the bivariate correlation analysis, there was no statistically significant correlation between SUL and MRIL (p = 0.201) and between UC and MRID (p = 0.124). In the Kaplan-Meier curve analysis, cumulative continence rates between the two groups dichotomized at the median value according to age (p = 0.0519), SUL (p = 0.6583), UC (p = 0.4031), MRIL (p = 0.4042), and MRID (p = 0.8191) were not significantly different. High SUL-to-MRIL ratio (>2.2) was the only significant predictor of lower cumulative continence rate (p = 0.0457). CONCLUSIONS: MRIL measured during surgery was not associated with postoperative continence recovery after RP. We observed that an excessively long membranous urethra compared to the urethral length on preoperative MRI is predictive of poorer postoperative continence recovery. However, small sample size and potential confounding surgical factors limit the significance of this study. PMID- 26029293 TI - Magnetic resonance imaging detected prostate evasive anterior tumours: Further insights. AB - INTRODUCTION: Clinical confusion continues to exist regarding the underestimation of cancers among patients on active surveillance and among men with repeated negative prostate biopsies despite worrisome prostate-specific antigen (PSA) levels. We have previously described our initial experience with magnetic resonance imaging (MRI)-based detection of tumours in the anterior prostate gland. In this report, we update and expand our experience with these tumours in terms of multiparametric-MRI findings, staging, and grading. Furthermore, we report early treatment outcomes with these unique cancers. METHODS: We reviewed our prostate MRI dataset of 1117 cases from January 2006 until December 2012 and identified 189 patients who fulfilled criteria for prostate evasive anterior tumors (PEATS). Descriptive analyses were performed on multiple covariates. Kaplan-Meier actuarial technique was used to plot the treatment-related outcomes from PEATS tumours. RESULTS: Among the 189 patients who had MRI-detectable anterior tumours, 148 had biopsy proven disease in the anterior zone. Among these tumours, the average PSA was 18.3 ng/mL and most cancers were Gleason 7. In total, 68 patients chose surgical therapy. Among these men, most of their cancers had extra prostatic extension and 46% had positive surgical margins. Interestingly, upgrading of tumours that were biopsy Gleason 6 in the anterior zone was common, with 59% exhibiting upgrading to Gleason 7 or higher. Biochemical-free survival among men who elected surgery was not ideal, with 20% failing by 20 months. CONCLUSION: PEATS tumours are found late and are disproportionally high grade tumours. Careful consideration to MRI testing should be given to men at risk for PEATS. PMID- 26029294 TI - Improved effectiveness and safety of flexible ureteroscopy for renal calculi (<2 cm): A retrospective study. AB - INTRODUCTION: We discuss the efficacy and safety of flexible ureteroscopy for renal calculi with a burden of <2 cm, as well as the prevention and treatment of complications. METHODS: A total of 108 renal calculi with flexible ureteroscopy and holmium laser treatment were retrospectively analyzed. The stone-free rate was evaluated. The effectiveness, safety, surgical technique, incidence of complications, and relevant treatments were analyzed. RESULTS: All patients underwent only one lithotripsy procedure. The success rate of flexible ureteroscopy was 97.2% (105/108). Among the 105 cases, the total lithotripsy success rate was 97.1% (101/105). The total stone-free rate after 8 weeks post operation was 94.3% (99/105), the stone-free rate of the lower calyx was 85.7% (30/35); it was 98.6% (69/70) in the middle-upper calyceal and renal pelvis. The incidence of complications was 12.9% (14/108). None of the patients had serious adverse outcomes. CONCLUSION: Flexible ureteroscopy represents an optimal treatment option for selected renal calculi with burden of <2 cm. The effectiveness and safety of flexible ureteroscopy can be further improved through reasonable preoperative evaluation and advances in surgical techniques, as well as a better understanding of the inducement and treatment of complications. PMID- 26029295 TI - Intravesical bacillus Calmette-Guerin versus chemohyperthermia for high-risk non muscle-invasive bladder cancer. AB - INTRODUCTION: Patients with high-risk non-muscle invasive bladder cancer (NMIBC) need adjuvant intravesical treatment after surgery. Although bacillus Calmette Guerin (BCG) is highly effective, new adjuvant treatments to decrease recurrences and toxicity have been studies. We performed a retrospective propensity score matched study to compare the efficacy of BCG and chemohyperthermia (C-HT). METHODS: We included 1937 patients diagnosed with bladder cancer between January 2004 and January 2014. The primary efficacy endpoint was recurrence-free interval. Patients treated with C-HT were matched with patients treated with BCG using propensity score-matched analysis. Cox-regression models were used to estimate the association between intravesical treatments and the presence of recurrence and progression. RESULTS: Of the 710 patients treated with intravesical treatments, 40 and 142 were eligible for inclusion in C-HT and BCG groups, respectively. Following case matching, there were no differences in patient or tumour characteristics between treatment groups. The 2-year recurrence free interval in C-HT and BCG groups were 76.2% and 93.9%, respectively (p = 0.020). C-HT treatment (hazard ratio [HR] 5.42; 95% confidence interval [CI] 1.11 26.43; p = 0.036) and high-grade tumour (HR 4.60; 95% CI 1.01-20.88; p = 0.048) are associated with an elevated odds of tumour recurrence. In multivariate Cox regression analysis, there was no significant difference between C-HT and BCG in the odds of recurrence (p = 0.054). There were no differences in progression between C-HT and BCG. CONCLUSION: C-HT is not as effective treatment as BCG in high-risk NMIBC patients who are BCG-naive. Although, there were no significant difference in the odds of recurrence, recurrence-free interval is significantly improved by the administration of BCG. PMID- 26029296 TI - Bricker versus Wallace anastomosis: A meta-analysis of ureteroenteric stricture rates after ileal conduit urinary diversion. AB - INTRODUCTION: Data comparing the incidence of ureteroenteric strictures for Bricker and Wallace anastomoses are limited. This study compares both anastomotic techniques in terms of ureteroenteric stricture rates after radical cystectomy and ileal conduit urinary diversion. METHODS: Electronic databases (Medline, EMBASE, and Cochrane database) were searched for studies comparing Bricker and Wallace ureteroeneteric anastomoses for ileal conduit urinary diversion after radical cystectomy. Meta-analyses were performed using the random effects method. The primary outcome measure was to determine differences in postoperative ureteroenteric stricture rates for both surgical techniques. Four studies describing 658 patients met the inclusion criteria. The total number of ureters used for ureteroeneteric anastomoses was 1217 (545 in the Bricker group and 672 in the Wallace group). RESULTS: There were no significant differences in age (p = 0.472), gender (p = 0.897), duration of follow-up (p = 0.168), and duration to stricture development between groups (p = 0.439). The overall stricture rate was 29 of 1217 (2.4%); 16 of 545 ureters (2.9%) in the Bricker group and 13 of 672 ureters (1.9%) in the Wallace group. The Bricker anastomosis was not associated with a significantly higher overall stricture rate compared to the Wallace ureteroenteric anastomosis (odds ratio: 1.393, 95% confidence interval: 0.441 4.394, p = 0.572). CONCLUSION: Accepting limitations in the available data, we found no significant difference in the incidence of ureteroenteric stricture for Bricker and Wallace anastomoses. PMID- 26029297 TI - Open adrenalectomy for medium sized adrenocortical tumour: How I do it? AB - INTRODUCTION: The aim of our work was to report our experience in managing cases with medium-sized adrenocortical carcinoma by the high retroperitoneal extra pleural approach. METHODS: During the past 2 years, 10 patients with suspected adrenocortical carcinoma were managed by our technique: the high supra 10th rib, retroperitoneal extra pleural approach. We included cases with 5 to 10 cm adrenal masses, suspected as adrenocortical carcinoma. RESULTS: The mean patient age was 38 years (range: 26-44), the median tumour volume was 7 cm (range: 5-8). Of the 10 patients, 7 were female. Of the patients, 6 had right- and 4 had left-sided tumours. Intraoperatively, all cases had proper surgical removal, with no apparent residual tumour tissue. No single patient required a chest tube or developed respiratory problems. There were no major vascular injuries during surgery. We did not compare our findings to the standard lateral or subcostal approaches, as in our institution we adopt this high lateral approach for medium sized tumours, while managing larger tumours with transperitoneal subcostal approach and smaller tumours laparoscopically. CONCLUSION: The high supra 10th lateral retroperitoneal, extra pleural approach is a safe, doable technique, allowing easy access to medium-sized suprarenal tumours and its vasculature, for cases suspected to be adrenocortical carcinoma. PMID- 26029298 TI - Multiple urethral anomalies: Parameatal urethral cyst, penile curvature, incomplete hypospadiac anterior duplication of the urethra and distal hipospadias. AB - The male genitourinary system is quite complex. There are numerous known anomalies of the male urethra either as isolated cases or in combination with other disorders. An improved understanding of the embryology and anatomy of the normal male urethral development might help explain the causes of the various urethral abnormalities. We contribute to the etiology of congenital anomalies with this multiple urethral anomalies case. PMID- 26029299 TI - Penile amputation and successful reattachment and the role of winter shunt in postoperative viability: A case report and literature review. AB - Traumatic self-amputation of the penis by a psychotic patient is rare. Microvascular replantation is the favored management approach. There are no known cases of self-amputation followed by ingestion of the stump and subsequent replantation. A 51-year-old patient with paranoid schizophrenia presented 2 hours following penile amputation. He had swallowed the excised portion, which was endoscopically retrieved from the stomach in the emergency department. Successful reattachment was achieved including microvascular repair of the dorsal penile arteries without cavernosal arterial anastamoses. A Winter's shunt was performed to improve venous circulation. The patient has been followed for 3 years from the date of repair. He has adequate erection for intercourse and good urinary function, but has experienced sensory loss over the dorsal aspect and glans and urethral stricture dilation. This is the first report of replantation following ingestion of an amputated penis. PMID- 26029300 TI - Ureteric foreign body following previous aorto-iliac graft. AB - Foreign bodies in the ureter are extremely rare. We report a case of an 82-year old man who, after an incidental presentation with asymptomatic hydroureteronephrosis, had an intraureteric foreign body. The patient was managed with atraumatic endoscopic extraction of the specimen. PMID- 26029301 TI - Angiosarcoma of the adrenal gland with concurrent contralateral advanced renal cell carcinoma: A diagnostic and management dilemma. AB - Angiosarcoma is a rare high-grade malignant neoplasm with poor clinical outcome and survival rates, occurring most commonly in the skin and soft tissue. It is composed of neoplastic cells that demonstrate endothelial differentiation. The diagnosis of angiosarcoma can be difficult due to its pathohistologic presentation as a poorly differentiated neoplasm with associated secondary changes. We report a case of angiosarcoma of the adrenal gland with concurrent contralateral renal cell carcinoma (RCC) and renal vein thrombus. The presumptive clinical diagnosis was metastatic renal cell carcinoma to the contralateral adrenal gland. Pathohistologic evaluation demonstrated massive hematoma associated with intravascular papillary endothelial hyperplasia (IPEH)-like features. We discuss the pathohistological features used to ascertain a diagnosis of angiosarcoma in the presence of IPEH-like changes and differentiate it from reactive vascular proliferation seen in IPEH (Masson's tumour). PMID- 26029302 TI - The role of steroid treatment in intractable cystitis glandularis: A case report and literature review. AB - Cystitis glandularis is a proliferative disease of the urinary bladder epithelium. It is rare in children. We report a case of a 23-year-old female with intractable macroscopic hematuria and severe irritative bladder symptoms persisting for 13 years. The patient, who had undergone open and endoscopic bladder surgery at various medical centres, is currently being followed up at our clinic. Cystoscopy revealed multiple edematous papillary tumours on the bladder neck, trigone, and lateral wall on both sides and she underwent transurethral resection of the bladder tumour. The pathological diagnosis was cystitis glandularis in accordance with the histopathological reports obtained from the other medical centres. Her condition was resistant to transurethral resection, partial cystectomy, intravesical mitomycin, and bacillus Calmette-Guerin (BCG) treatment; it eventually could have affected the upper urinary tract. Oral steroid treatment was given for 6 months; after treatment, her symptoms improved and the cystoscopy revealed a dramatic improvement in her condition. PMID- 26029303 TI - Renal calculus complicated with squamous cell carcinoma of renal pelvis: Report of two cases. AB - Longstanding renal calculus is a risk factor of squamous cell carcinoma (SCC) of the renal pelvis. It is highly aggressive and usually diagnosed at advanced stages with a poor prognosis. We present two cases of kidney stone complications with renal pelvic SCC. These two patients had a radical nephrectomy and the dissected tissues were renal pelvic SCC. Our cases further emphasize that renal pelvic SCC should be considered in patients with longstanding renal calculus. These cases contribute greatly to an early diagnosis and early treatment, both of which will significantly minimize the damage of, and markedly improve the prognosis of, renal pelvic SCC. PMID- 26029304 TI - Colon perforation during percutaneous nephrolithotomy and fistula closure with Spongostan following conservative therapy. AB - Percutaneous nephrolithotomy (PCNL) is the first-line treatment for kidney stones. Colon perforation is a rare, but dangerous, complication. Colonic perforation might be very serious if it is not found early. After an unsuccessful extracorporeal shockwave lithotripsy, a 45-year-old female underwent a left-sided PCNL for two 1-cm kidney stones in the left kidney upper pole calyx. During dilatation, a colon perforation was suspected. The procedure was finished by inserting a 14Fr re-entry catheter into the colon. On postoperative day 5, a fluoroscopy was performed by injecting contrast dye through the re-entry catheter, which showed a fistula formation between skin and colon. The catheter was removed completely. A 16Fr external drainage catheter was inserted over the guide-wire through the fistula tract. The fistula was closed by introducing prepared absorbable hemostatic gelatin powder (Spongostan) particles into the fistula tract through the catheter. Fistula tracks can be closed early by injecting absorbable Spongostan particles into the colonic fistula tract, thereby reducing inpatient time and increasing patient comfort. PMID- 26029305 TI - Renal cell carcinoma after neuroblastoma: A case study and review of the literature. AB - We present a case of renal cell carcinoma (RCC) arising in a 26-year-old patient with a history of neuroblastoma. RCC after a previous diagnosis of neuroblastoma is very uncommon, and there have only been 23 reported cases. Using the results of our patient workup, we hoped to determine whether there was a genetic predisposition or iatrogenic cause for the RCC. There is no clear explanation why neuroblastoma survivors are prone to developing RCC. However, genetic predisposition and previous treatment likely play a role. Since there have been few cases described, and few investigations into the genetics of this subtype of RCC, it remains important for individual cases to be added to the literature of this recently described and rare entity. PMID- 26029306 TI - Isolated epididymal injury after blunt scrotal trauma from high velocity paintball round. AB - Isolated epididymal injury without associated underlying scrotal or testicular injury in the setting of blunt trauma is exceedingly rare. We present a case of an isolated epididymal injury incurred after scrotal trauma from a high velocity paintball round. Ultrasound demonstrated an enlarged, hypoechoic left epididymis with no evidence of underlying testicular injury. This case highlights the importance of obtaining imaging to evaluate for signs of testicular rupture, potentially obviating the need for surgery. It also reinforces the need for appropriate protective gear when participating in activities with potential for high velocity scrotal trauma. PMID- 26029307 TI - Large diverticulum of the urinary bladder: A rare cause of deep vein thrombosis with consecutive pulmonary embolism. AB - A 73-year-old man was admitted with progressive dyspnea; he also had benign prostatic hyperplasia (BPH). An angio computed tomography scan showed pulmonary embolism with thrombi in both main pulmonary arteries. By duplex ultrasonography, we detected a thrombus in the right vena femoralis superficialis and vena femoralis communis. Simultaneously, we also noticed a large diverticulum on the right side of the urinary bladder and urinary stasis II of the left kidney. We consider the BPH as the trigger for a secondary diverticulum of the urinary bladder. As a result of its large dimensions, mechanical compression of the deep right pelvic veins resulted in thrombosis which finally caused the pulmonary embolism. With respect to the urinary stasis II, surgical excavation of the diverticulum with infravesical desobstruction was planned. The potentially lethal course of large diverticula may require surgery. PMID- 26029308 TI - Outpatient percutaneous nephrolithotomy in a renal transplant patient: World's first case. AB - Percutaneous nephrolithotomy (PCNL) is an established safe and effective surgical treatment option for renal calculi in renal allografts. The advent of tubeless PCNL has led to reports of ambulatory or outpatient PCNL. This case report describes the successful outpatient management of a 49-year-old female with a symptomatic renal pelvic calculus in her transplanted kidney. Tubeless PCNL successfully removed the stone, free of complication, and the patient was discharged 2 hours and 17 minutes after the procedure in stable condition with minimal pain. This is, to the best of our knowledge, the first successful case of outpatient tubeless PCNL in a transplanted kidney. PMID- 26029309 TI - Primary squamous cell carcinoma of the urethral diverticulum mimicking prostate cancer: Case report and review of the literature. AB - Primary urethral carcinomas are uncommon, with urothelial carcinoma as the most common subtype. Urethral diverticulum is also rarely seen in men. A 44-year-old male presented with voiding symptoms. Abdominoperineal resection, prostatectomy, bladder neck excision, and proximal urethral excision were performed. A pathological examination revealed a well-differentiated squamous cell carcinoma (SCC) located inside an urethral diverticulum. We report this unusual case because primary SCC of the male urethral diverticulum is extremely rare. To our knowledge, our patient is only the second reported case. PMID- 26029310 TI - Prepubertal diagnosis of Klinefelter syndrome due to penoscrotal malformations: Case report and review of literature. AB - We report a case of 4 months old infant diagnosed as Klinefelter syndrome associated with perineal hypospadias, severe ventral chordee and complete penoscrotal transposition. A review of previous reported cases was carried out. Penoscrotal malformations at birth are very rare in Klinefelter syndrome. Awareness of the current standard indications of Karyotyping can help early detection of these cases. PMID- 26029311 TI - Primitive neuroectodermal tumour of the kidney: An unusual case mimicking renal angiomyolipoma with minimal fat. AB - Primitive neuroectodermal tumour (PNET) is a highly aggressive neoplasm that develops classically in the central nervous system. PNET of the kidney (rPNET) is extremely rare. Recently, a 23-year-old woman complained of left flank pain and intermittent hematuria for 3 months and was admitted to our hospital. A computed tomography (CT) scan and magnetic resonance imaging demonstrated a 5.1 * 4.4-cm heterogenous mass with unconspicuous reinforcement in the upper pole of the left kidney. F18-FDG positron emission tomography CT (PET-CT) revealed the mass as a benign lesion with internal extensive bleeding. Renal angiomyolipoma with minimal fat was diagnosed. Three months later, a CT scan showed that the mass shrank to 3.1 * 2.6 cm and nephron-sparing surgery of the left kidney was performed at the patient's request. However, histologic features and immunohistochemical analysis confirmed the diagnosis of rPNET. Five cycles of combined chemotherapy were executed. At the 11-month follow-up, the patient showed no evidence of metastasis or recurrence. PMID- 26029312 TI - Renal cell carcinoma and amyopathic dermatomyositis. AB - Amyopathic dermatomyositis (dermatomyositis sine myositis) is a rare disorder with cutaneous lesions identical to those of classic dermatomyositis, but with no clinical evidence of myopathy. Association with malignancy has been suggested in a number of reports. We report the case of a 69-year-old man with a recent diagnosis of amyopathic dermatomyositis, who presented to the urology service with hematuria. Investigations revealed a 5.8-cm renal cell carcinoma and the patient underwent left radical nephrectomy without complication. To our knowledge, an association with renal cell carcinoma and amyopathic dermatomyositis has not been previously described. PMID- 26029314 TI - The prostatic utricle cyst with huge calculus and hypospadias: A case report and a review of the literature. AB - Prostatic utricle cysts with calculus and hypospadias are rare. There are a few reported cases. We present a case of a prostatic utricle cyst with huge calculus in a 25-year-old male. He had a history of left cryptorchidism and surgery for penoscrotal hypospadias in his infancy. He was referred for frequent micturition, urgency of urination, urine pain, terminal hematuria, and dysuria. A computed tomography (CT) revealed a retrovesical cystic lesion of low density, showing a 5 * 5-cm calcification. Retrograde urethrocystography showed a 5 * 5-cm high density shadow in the posterior urethra. The cyst was incised by transperineal approach and the stone was clearly observed and removed. Urethral stricture repair was performed simultaneously. The patient recovered smoothly after surgery. PMID- 26029313 TI - A rare entity in adults: Bilateral Hutch diverticulum with calculi. AB - Congenital bladder diverticulum (CBD) is a very uncommon entity in adults. CBD could be unilateral or bilateral and is caused by a congenital weakness in the bladder musculature. CBD is differentiated from the paraureteral or Hutch type of diverticula. A 42-year-old male presented with bilateral Hutch diverticulum and multiple diverticulum calculus on intravenous pyelography. Cystoscopy revealed bladder diverticulum just medial to the left ureteral orifice with multiple calculi; the patient successfully underwent endoscopic laser cystolithotripsy with resolution of his urinary tract infection. To the best of our knowledge, this is the first case report presenting stone formation of CBD in an adult. PMID- 26029315 TI - [Not Available]. PMID- 26029316 TI - Bayesian Polynomial Regression Models to Fit Multiple Genetic Models for Quantitative Traits. AB - We present a coherent Bayesian framework for selection of the most likely model from the five genetic models (genotypic, additive, dominant, co-dominant, and recessive) commonly used in genetic association studies. The approach uses a polynomial parameterization of genetic data to simultaneously fit the five models and save computations. We provide a closed-form expression of the marginal likelihood for normally distributed data, and evaluate the performance of the proposed method and existing method through simulated and real genome-wide data sets. PMID- 26029317 TI - Design of Bioimpedance Spectroscopy Instrument With Compensation Techniques for Soft Tissue Characterization. AB - Bioimpedance spectroscopy (BIS) has shown significant potential in many areas of medicine to provide new physiologic markers. Several acute and chronic diseases are accompanied by changes in intra- and extracellular fluid within various areas of the human body. The estimation of fluid in various body compartments is therefore a simple and convenient method to monitor certain disease states. In this work, the design and evaluation of a BIS instrument are presented and three key areas of the development process investigated facilitating the BIS measurement of tissue hydration state. First, the benefit of incorporating DC stabilizing circuitry to the standard modified Howland current pump (MHCP) is investigated to minimize the effect of DC offsets limiting the dynamic range of the system. Second, the influence of the distance between the bioimpedance probe and a high impedance material is investigated using finite element analysis (FEA). Third, an analytic compensation technique is presented to minimize the influence of parasitic capacitance. Finally, the overall experimental setup is evaluated through ex vivo BIS measurements of porcine spleen tissue and compared to published results. The DC-stabilizing circuit demonstrated its ability to maintain DC offsets at less than 650 MUV through 100 kHz while maintaining an output impedance of 1 MOmega from 100 Hz to 100 kHz. The proximity of a bioimpedance probe to a high impedance material such as acrylic was shown to increase measured impedance readings by a factor of 4x as the ratio of the distance between the sensing electrodes to the distance between the bioimpedance probe and acrylic reached 1:3. The average parasitic capacitance for the circuit presented was found to be 712 +/- 128 pF, and the analytic compensation method was shown to be able to minimize this effect on the BIS measurements. Measurements of porcine spleen tissue showed close correlation with experimental results reported in published articles. This research presents the successful design and evaluation of a BIS instrument. Specifically, robust measurements were obtained by implementing a DC-stabilized current source, investigating probe material proximity issues and compensating for parasitic capacitance. These strategies were shown to provide tissue measurements comparable with published literature. PMID- 26029318 TI - Sex Differences in the Excess Risk of Cardiovascular Diseases Associated with Type 2 Diabetes: Potential Explanations and Clinical Implications. AB - Strong evidence suggests that type 2 diabetes confers a stronger excess risk of cardiovascular diseases in women than in men; with women having a 27 % higher relative risk of stroke and a 44 % higher relative risk of coronary heart disease compared with men. The mechanisms that underpin these sex differences in the associations between diabetes and cardiovascular disease risk are not fully understood. Some of the excess risk may be the result of a sex disparity in the management and treatment of diabetes, to the detriment of women. However, accruing evidence suggests that real biological differences between men and women underpin the excess risk of diabetes-related cardiovascular risk in women such that there is a greater decline in risk factor status in women than in men in the transition from normoglycemia to overt diabetes. This greater risk factor decline appears to be associated with women having to put on more weight than men, and thus attain a higher body mass index, to develop diabetes. Further studies addressing the mechanisms responsible for sex differences in the excess risk of cardiovascular diseases associated with diabetes are needed to improve the prevention and management of diabetes in clinical practise. PMID- 26029319 TI - Fundament and Prerequisites for the Application of an Antifungal TDM Service. AB - Therapeutic drug monitoring (TDM) involves the measurement of plasma or serum drug concentration to adapt dosages to achieve predefined target concentrations that are associated with optimal clinical response while minimizing the chance of encountering toxicity. Many papers in the field of antifungal drugs have focused on the evidence that supports the use of TDM thereby emphasizing the breakpoints or target concentrations in general literature. This review focuses on the process of TDM to inform health care workers on the fundaments and prerequisites that safeguard the good application of TDM. Knowledge on the complete process of TDM including pharmacokinetics (and relevant covariates), pharmacodynamic aspects, trials that are necessary to provide us with evidence, translation of knowledge to other populations and pathogens, and implications for the pre analytical, analytical, and post-analytical phases (the process of TDM) are discussed in relevant detail. For each individual step, recommendations are made for the readers. We believe this will be a valuable resource and to be of added value to the many papers that focus on relations between exposure and efficacy or toxicity. It will help to achieve greater benefit of TDM. PMID- 26029320 TI - Pattern of adult intestinal obstruction at Tenwek hospital, in south-western Kenya. AB - INTRODUCTION: Acute mechanical intestinal obstruction (IO) is one of the leading causes of surgical admissions in most emergency departments worldwide. The causes of IO vary significantly depending on geographical location. The aim of this study was to identify the etiology, management and outcomes of patients with acute mechanical IO presenting in south-western Kenya. METHODS: A 4 year (November 2009-October 2013) retrospective review of all adult patients admitted with acute mechanical IO at Tenwek Hospital in Bomet, Kenya. RESULTS: A total of 303 male and 142 female patients, presented with acute mechanical IO during the study period. Mean patient age was 40.6 years (range 17-91), with peak incidence in those aged 31-40 years. The foremost signs and symptoms were abdominal pain (89.4%), abdominal tenderness (81.6%), vomiting (78%), abdominal distension (65.4%) and constipation (50.8%). Sigmoid volvulus (25.6%), adhesions (23.1%), small bowel volvulus (21.3%), and ileo-sigmoid knotting (8.5%) were the leading causes of IO. Laparotomy was undertaken in 361 (81.1%) cases, with bowel gangrene noted in 112 (30.4%). The overall morbidity and mortality rates were 15% and 4.5% respectively. Patients with gangrenous bowel at laparotomy had a higher morbidity rate (22.3% vs 9.6%, P=.001), a higher mortality rate (9.8% vs 3.2%, P=.02) and a longer duration of stay (9.9 days vs 7.6 days, P=.0001) compared to those with viable bowel. CONCLUSION: The most common causes of IO in this study were sigmoid volvulus, adhesions, small bowel volvulus and ileo-sigmoid knotting. Presence of bowel gangrene was associated with higher morbidity and mortality rates. PMID- 26029321 TI - A rare image phytobezoar in stomach. PMID- 26029323 TI - [chronic atrophic polychondritis]. PMID- 26029322 TI - Prevalence of stroke in three semi-urban communities in middle-belt region of Nigeria: a door to door survey. AB - INTRODUCTION: The burden of stroke has been projected to increase for developing countries, but data are limited, especially in sub-Saharan Africa. This necessitated this study to determine the stroke prevalence in a semi urban community in middle-belt region of Nigeria. METHODS: A two-phase door-to-door study was performed in three semi-urban communities of Kwara state; in the first phase 12,992 residents were screened and probable stroke cases were identified by trained health care workers. In the second phase individuals adjudged to be positive for stroke were screened with a stroke-specific questionnaire and made to undergo a complete neurological examination by a neurologist. Stroke diagnosis was based on clinical evaluation using WHO criteria. RESULTS: Out of the numbers that were screened, 18 probable stroke cases were identified in the first stage, and of these, 17 fulfilled WHO criteria for stroke, giving a crude prevalence rate of 1.31/1000 population. The prevalence of stroke was higher among the males than the females (1.54/1000 vs. 1.08/1000) with a ratio 1.4: 1. Sixteen subjects (94.1%) had one or more risk factors for stroke. Uncontrolled systemic hypertension (82.4%) was the commonest risk factors for stroke followed by transient ischaemic attack (TIA) (41.2%). CONCLUSION: Stroke is a condition that is prevalent in our environment; especially in older adults and men. Uncontrolled systemic hypertension and previous transient ischaemic attacks were the commonest risk factors for stroke in our community. PMID- 26029324 TI - [Posttraumatic fracture of pancreas]. PMID- 26029325 TI - A potentially fatal complication that may occur during dental treatment: "foreign body aspiration". AB - Numerous systemic emergency situations, such as hypotension or allergic reactions, may be encountered during dental treatment. In addition, rare but life threatening complications such as foreign body aspiration in the air passages may also be seen. Aspirated foreign bodies include teeth, implants, mechanical supports or materials used during procedures. We report two separate cases of aspiration risk developing during the course of dental treatment. PMID- 26029326 TI - [Intramedullary metastasis of lung adenocarcinoma: about a case]. PMID- 26029327 TI - Prevalence and associated factors of partially/non-immunization of under-five in Goma city, Democratic Republic of Congo: a community-based cross-sectional survey. AB - INTRODUCTION: At the East part of DRC, anecdotal reports are advancing several causes of unsuccessful campaigns of vaccination by the time going: rumors about use of vaccines for killing purpose, injection of vaccine to decrease the reproductive potential in coming generations, use of vaccines by some rebellions and neighboring countries to kill children indirectly, ineffectiveness of vaccines currently on the market. While those rumors seem to be less reliable, potential beneficiaries are taking them seriously and justifying a reluctance to bring their children or siblings for immunization. Against this above background, our community Primary Health Care team indicates that still, in Goma city in general and even in the referral hospital catchment area, there are children who have never been vaccinated. OBJECTIVES: To determine the prevalence and determinants of non-immunization of under-five children in Goma City. STUDY DESIGN: Cross-sectional community-based survey. METHODS: A sample size of 384 children aged under-five years from the target population was used for the study. The ratio of under-five years of age Goma city to the total population of Goma city for the year 2012 was considered as the study population frame. RESULTS: The prevalence of under-five non-immunized children was 25.7%. There was an association between immunization status of children and their gender, school characteristics, age, sibling, the level of literacy, the marital status of their parents and the age of their mothers. CONCLUSION: For improving the quality of under-five children immunization, the medical authorities must consider these different determinants. PMID- 26029328 TI - [Systemic lupus and kidney disease: contribution of anti-SSA]. PMID- 26029329 TI - Warning: This may be as dangerous as firearm injuries;"grease-gun injury": A case report. AB - High-pressure injection gun (Grease-gun) injuries mainly occur with industrial labourers. Injuries associated with high pressure grease guns are very rare and frequently involve the hand and chest. The non-dominant hand is generally injured since the grease gun is usually held in the dominant hand. Even if high-pressure injection injury causes only a small lesion in the skin, it is still characterized by severe damage to subcutaneous tissue. Since initial presentation may be deceptive, treatment is frequently delayed. The characteristics of the material injected need to be known as a priority, and systemic intoxication must be ruled out. The risk of amputation is 16-55%. With solvents it goes up to 50 80%. Surgical treatment must be performed immediately, under general anesthesia or plexus block. Foreign material and necrotic tissue must be early debrided with wide microsurgical exploration. Positive outcomes in reacquisition of hand functions can be obtained with long-term and early physiotherapy. PMID- 26029330 TI - Transcriptome profiling of the spl5 mutant reveals that SPL5 has a negative role in the biosynthesis of serotonin for rice disease resistance. AB - BACKGROUND: Rice mutant, spl5 (spotted leaf 5), has spontaneous hypersensitive like lesions on its leaves and shows enhanced resistance to pathogens, indicating that SPL5 plays a role in programmed cell death (PCD) and disease resistance. To understand the molecular mechanism of SPL5 gene, we investigated the transcriptome profiles of the spl5 mutant leaves with few lesions (FL) and leaves with many lesions (ML) compared to the wild-type (WT) leaves respectively by microarray. RESULTS: The data from microarray revealed that 243 and 896 candidate genes (Fold change >= 3.0) were up- or down-regulated in the spl5-FL and spl5-ML, respectively, and a large number of these genes involved in biotic defense responses or reactive oxygen species (ROS) metabolism. Interestingly, according to our microarray and real-time PCR assays, the expressions of a transcription factor OsWRKY14 and genes responsible for the biosynthesis of serotonin, anthranilate synthase (AS), indole-3-glycerolphosphate synthase (IGPS), tryptophan synthase (TS) and tryptophan decarboxylase (TDC) were significantly up regulated in the spl5 mutant. It has been reported previously that TS and TDC expressions are regulated by OsWRKY14 in rice, which raises the possibility that OsWRKY14 regulates serotonin production through the up-regulation of TS and TDC. Our HPLC analysis further confirmed that serotonin levels were higher in the leaves of spl5 mutant than that in WT. CONCLUSIONS: Since the serotonin plays a critical role in inducing disease-resistance, the increased serotonin level may contribute, at least partly, to the disease resistance in spl5. The SPL5 gene may act as a negative regulatory factor activating the serotonin metabolic pathway, and these results might provide a new insight into the spl5-induced defense response mechanisms in plants. PMID- 26029331 TI - Oral Doxycycline in the Management of Acne Vulgaris: Current Perspectives on Clinical Use and Recent Findings with a New Double-scored Small Tablet Formulation. AB - Oral antibiotics have been used for the treatment of acne vulgaris for six decades. Among dermatologists, tetracyclines represent at least three-fourths of the oral antibiotics prescribed in clinical practice. Unlike other specialties, antibiotic use in dermatology is predominantly for the treatment of noninfectious disorders, such as acne vulgaris and rosacea, which usually involves prolonged therapy over several weeks to months as compared to short courses used to treat cutaneous infections. At the present time, doxycycline and minocycline are the most commonly prescribed tetracyclines in dermatology, used primarily for treatment of acne vulgaris with a long overall favorable track record of effectiveness and safety. Although both are commonly used, doxycycline may be chosen by clinicians more readily as there is a lower risk of rare yet potentially serious adverse reactions, although doxycycline does warrant preventative measures to reduce the risks of esophagitis and phototoxicity reactions. This article reviews data with a new double-scored small 150mg tablet of doxycycline hyclate that has proven functional scoring, exhibits bioavailability similar to enteric-coated doxycycline, and has been shown to be associated with a low potential for gastrointestinal adverse reactions very comparable to what is achieved with enteric-coated tablets. PMID- 26029332 TI - Efficacy and tolerability of a fixed combination of clindamycin phosphate (1.2%) and benzoyl peroxide (3.75%) aqueous gel in moderate or severe adolescent acne vulgaris. AB - BACKGROUND: Acne is commonplace in adolescents and can be difficult to manage. Providing an effective and well-tolerated treatment may lead to improved adherence, increased patient satisfaction, and improved clinical outcomes. METHODS: A post hoc analysis of efficacy and cutaneous tolerability in 289 adolescents (age range, 12 to <18 years) with moderate-to-severe acne who had been enrolled in a multicenter study and were randomized to receive either clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel or vehicle once daily for 12 weeks. RESULTS: Significantly superior reductions in lesion counts were observed in the clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel group compared to vehicle from Week 4, with mean percent reductions in inflammatory and noninflammatory lesions from baseline of 59.9 percent and 50.5 percent, respectively (both P<0.001 versus vehicle). One-third of patients treated with clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel achieved >=2-grade improvement from baseline in their Evaluator's Global Severity Score (compared to 8.5% with vehicle, P<0.001) and 35 percent of patients reported clear or almost clear skin at Week 12 (compared to 12.8% with vehicle, P<0.001). Cutaneous tolerability was excellent with all mean scores <=0.2 at Week 12 (where 1=mild). CONCLUSIONS: Clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel is an effective, safe, well-tolerated treatment for adolescents with moderate-to-severe acne. PMID- 26029333 TI - Effective treatments of atrophic acne scars. AB - Atrophic scarring is often an unfortunate and permanent complication of acne vulgaris. It has high prevalence, significant impact on quality of life, and therapeutic challenge for dermatologists. The treatment of atrophic acne scars varies depending on the types of acne scars and the limitations of the treatment modalities in their ability to improve scars. Therefore, many options are available for the treatment of acne scarring, including chemical peeling, dermabrasion, laser treatment, punch techniques, fat transplantation, other tissue augmenting agents, needling, subcision, and combined therapy. Various modalities have been used to treat scars, but limited efficacy and problematic side effects have restricted their application. In order to optimally treat a patient's scar, we need to consider which treatment offers the most satisfactory result. There are also promising procedures in the future, such as stem cell therapy. In this article, the authors review the different treatment options of atrophic acne scars. This may be useful for selecting the best therapeutic strategy, whether it be single or combined therapy, in the treatment of atrophic acne scars while reducing or avoiding the side effects and complications. PMID- 26029334 TI - Recessive dystrophic epidermolysis bullosa: a review of disease pathogenesis and update on future therapies. AB - OBJECTIVE: Review the pathogenesis of recessive dystrophic epidermolysis bullosa and provide an update on research currently underway that is aimed at treating and potentially curing this severe skin disorder. DESIGN: Review article. SETTING: Private practice and large teaching hospital. PARTICIPANTS: None. MEASUREMENTS: N/A. RESULTS: Currently, patients with recessive dystrophic epidermolysis bullosa are managed with only supportive care. However, there are several promising new treatment avenues that may help patients in the future. These include gene therapy, cell therapy, and protein-based therapy. Each approach offers distinct advantages and disadvantages. CONCLUSIONS: The advances in understanding the molecular basis for epidermolysis bullosa over the last few decades has led to significant progress in devising new treatment options. Though many of these approaches remain several years away from regular implementation, it is an exciting time for research in the field. PMID- 26029335 TI - Dermabrasion: a novel treatment for diffuse silicone granuloma. AB - OBJECTIVE: Formation of a foreign body granuloma is one of the serious complications of silicone injection, which can be difficult to treat. In this paper, the authors report their successful experience with dermabrasion as an innovative treatment in a patient who presented with diffuse silicone granuloma. CASE REPORT: The patient was a 51-year-old woman, with areas of induration and hyperpigmentation on both her legs with intermittent fevers and generalized malaise. The patient had a history of numerous bilateral hip injections of liquid silicone five years ago for cosmetic purposes. A skin biopsy showed a foreign body granuloma consistent with a paraffinoma with "Swiss cheese" appearance. After unsuccessful medical therapy and liposuction, an extensive bilateral dermabrasion was performed on both legs. Postoperatively, her wounds exuded a collection of thick, yellow viscous fluid under the transparent semi-occlusive dressings, which showed a markedly elevated level of silicone after analysis. She experienced no complication related to dermabrasion. CONCLUSION: The findings of this case demonstrate that dermabrasion may be an effective treatment option for diffuse silicone granuloma, particularly when the material resides superficially in the dermis. PMID- 26029336 TI - Treatment of Pearly Penile Papules with Fractionated CO2 Laser. AB - OBJECTIVE: Pearly penile papules are asymptomatic, benign growths distributed around the corona of the penis that can frequently be a source of significant psychological distress for the patient. Various treatment options are limited mainly by their complications. DESIGN: Two case reports and a review of the literature. SETTING: University academic setting. PARTICIPANTS: Two subjects of skin types I and V. MEASUREMENTS: Visual inspection and photographs were used to determine clearance. RESULTS: Two cases of pearly penile papules that were successfully treated using a fractionated CO2 laser. CONCLUSION: The fractionated CO2 laser is a well-tolerated treatment for pearly penile papules. Importantly, this modality is useful even in darker skin types. PMID- 26029337 TI - V1-distributed Herpes Zoster and Meningitis in a Two-year Old. AB - Since the advent of the varicella vaccine, occurrence of herpes zoster in children has been rare. However, a subset of patients may develop herpes zoster after receiving the vaccine. Herein the authors report a case of a two-year-old boy who developed herpes zoster in the V1 distribution and meningitis following a single dose of varicella vaccine. PMID- 26029338 TI - Value of Hybrid Imaging with PET/CT to Guide Percutaneous Revascularization of Chronic Total Coronary Occlusion. AB - Chronic total coronary occlusions (CTO) are documented in approximately one fifth of diagnostic invasive coronary angiographies (ICA). Percutaneous coronary interventions (PCI) of CTO are challenging and are accompanied by higher complication and lower success rates in comparison with non-CTO PCI. Scrutinous evaluation of ischemia and viability to justify percutaneous revascularization is therefore of importance to select eligible patients for such a procedure. Furthermore, knowledge of the anatomical features of the occlusion may predict the chances of success of PCI CTO and could even guide the procedural strategy to augment the likelihood of recanalization. Positron emission tomography (PET) is unequivocally accepted as the reference standard for ischemia and viability testing, whereas coronary computed tomography angiography (CCTA) currently allows for non-invasive detailed three-dimensional imaging of the coronary anatomy that adds morphological information over two-dimensional ICA. Hybrid PET/CT could therefore be useful for optimal patient selection as well as procedural planning. This review discusses the potential value of PET/CT to guide PCI in CTOs. PMID- 26029339 TI - Spermatogonial stem cells: Current biotechnological advances in reproduction and regenerative medicine. AB - Spermatogonial stem cells (SSCs) are the germ stem cells of the seminiferous epithelium in the testis. Through the process of spermatogenesis, they produce sperm while concomitantly keeping their cellular pool constant through self renewal. SSC biology offers important applications for animal reproduction and overcoming human disease through regenerative therapies. To this end, several techniques involving SSCs have been developed and will be covered in this article. SSCs convey genetic information to the next generation, a property that can be exploited for gene targeting. Additionally, SSCs can be induced to become embryonic stem cell-like pluripotent cells in vitro. Updates on SSC transplantation techniques with related applications, such as fertility restoration and preservation of endangered species, are also covered on this article. SSC suspensions can be transplanted to the testis of an animal and this has given the basis for SSC functional assays. This procedure has proven technically demanding in large animals and men. In parallel, testis tissue xenografting, another transplantation technique, was developed and resulted in sperm production in testis explants grafted into ectopical locations in foreign species. Since SSC culture holds a pivotal role in SSC biotechnologies, current advances are overviewed. Finally, spermatogenesis in vitro, already demonstrated in mice, offers great promises to cope with reproductive issues in the farm animal industry and human clinical applications. PMID- 26029340 TI - Osteogenic differentiation of amniotic fluid mesenchymal stromal cells and their bone regeneration potential. AB - In orthopedics, tissue engineering approach using stem cells is a valid line of treatment for patients with bone defects. In this context, mesenchymal stromal cells of various origins have been extensively studied and continue to be a matter of debate. Although mesenchymal stromal cells from bone marrow are already clinically applied, recent evidence suggests that one may use mesenchymal stromal cells from extra-embryonic tissues, such as amniotic fluid, as an innovative and advantageous resource for bone regeneration. The use of cells from amniotic fluid does not raise ethical problems and provides a sufficient number of cells without invasive procedures. Furthermore, they do not develop into teratomas when transplanted, a consequence observed with pluripotent stem cells. In addition, their multipotent differentiation ability, low immunogenicity, and anti inflammatory properties make them ideal candidates for bone regenerative medicine. We here present an overview of the features of amniotic fluid mesenchymal stromal cells and their potential in the osteogenic differentiation process. We have examined the papers actually available on this regard, with particular interest in the strategies applied to improve in vitro osteogenesis. Importantly, a detailed understanding of the behavior of amniotic fluid mesenchymal stromal cells and their osteogenic ability is desirable considering a feasible application in bone regenerative medicine. PMID- 26029341 TI - Stem cell therapy in the management of shoulder rotator cuff disorders. AB - Rotator cuff tears are frequent shoulder problems that are usually dealt with surgical repair. Despite improved surgical techniques, the tendon-to-bone healing rate is unsatisfactory due to difficulties in restoring the delicate transitional tissue between bone and tendon. It is essential to understand the molecular mechanisms that determine this failure. The study of the molecular environment during embryogenesis and during normal healing after injury is key in devising strategies to get a successful repair. Mesenchymal stem cells (MSC) can differentiate into different mesodermal tissues and have a strong paracrine, anti inflammatory, immunoregulatory and angiogenic potential. Stem cell therapy is thus a potentially effective therapy to enhance rotator cuff healing. Promising results have been reported with the use of autologous MSC of different origins in animal studies: they have shown to have better healing properties, increasing the amount of fibrocartilage formation and improving the orientation of fibrocartilage fibers with less immunologic response and reduced lymphocyte infiltration. All these changes lead to an increase in biomechanical strength. However, animal research is still inconclusive and more experimental studies are needed before human application. Future directions include expanded stem cell therapy in combination with growth factors or different scaffolds as well as new stem cell types and gene therapy. PMID- 26029342 TI - Epigenetic regulation of stemness maintenance in the neurogenic niches. AB - In the adult mouse brain, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are two zones that contain neural stem cells (NSCs) with the capacity to give rise to neurons and glia during the entire life of the animal. Spatial and temporal regulation of gene expression in the NSCs population is established and maintained by the coordinated interaction between transcription factors and epigenetic regulators which control stem cell fate. Epigenetic mechanisms are heritable alterations in genome function that do not involve changes in DNA sequence itself but that modulate gene expression, acting as mediators between the environment and the genome. At the molecular level, those epigenetic mechanisms comprise chemical modifications of DNA such as methylation, hydroxymethylation and histone modifications needed for the maintenance of NSC identity. Genomic imprinting is another normal epigenetic process leading to parental-specific expression of a gene, known to be implicated in the control of gene dosage in the neurogenic niches. The generation of induced pluripotent stem cells from NSCs by expression of defined transcription factors, provide key insights into fundamental principles of stem cell biology. Epigenetic modifications can also occur during reprogramming of NSCs to pluripotency and a better understanding of this process will help to elucidate the mechanisms required for stem cell maintenance. This review takes advantage of recent studies from the epigenetic field to report knowledge regarding the mechanisms of stemness maintenance of neural stem cells in the neurogenic niches. PMID- 26029343 TI - Epidermal stem cells and skin tissue engineering in hair follicle regeneration. AB - The reconstitution of a fully organized and functional hair follicle from dissociated cells propagated under defined tissue culture conditions is a challenge still pending in tissue engineering. The loss of hair follicles caused by injuries or pathologies such as alopecia not only affects the patients' psychological well-being, but also endangers certain inherent functions of the skin. It is then of great interest to find different strategies aiming to regenerate or neogenerate the hair follicle under conditions proper of an adult individual. Based upon current knowledge on the epithelial and dermal cells and their interactions during the embryonic hair generation and adult hair cycling, many researchers have tried to obtain mature hair follicles using different strategies and approaches depending on the causes of hair loss. This review summarizes current advances in the different experimental strategies to regenerate or neogenerate hair follicles, with emphasis on those involving neogenesis of hair follicles in adult individuals using isolated cells and tissue engineering. Most of these experiments were performed using rodent cells, particularly from embryonic or newborn origin. However, no successful strategy to generate human hair follicles from adult cells has yet been reported. This review identifies several issues that should be considered to achieve this objective. Perhaps the most important challenge is to provide three-dimensional culture conditions mimicking the structure of living tissue. Improving culture conditions that allow the expansion of specific cells while protecting their inductive properties, as well as methods for selecting populations of epithelial stem cells, should give us the necessary tools to overcome the difficulties that constrain human hair follicle neogenesis. An analysis of patent trends shows that the number of patent applications aimed at hair follicle regeneration and neogenesis has been increasing during the last decade. This field is attractive not only to academic researchers but also to the companies that own almost half of the patents in this field. PMID- 26029344 TI - Structural properties of scaffolds: Crucial parameters towards stem cells differentiation. AB - Tissue engineering is a multidisciplinary field that applies the principles of engineering and life-sciences for regeneration of damaged tissues. Stem cells have attracted much interest in tissue engineering as a cell source due to their ability to proliferate in an undifferentiated state for prolonged time and capability of differentiating to different cell types after induction. Scaffolds play an important role in tissue engineering as a substrate that can mimic the native extracellular matrix and the properties of scaffolds have been shown to affect the cell behavior such as the cell attachment, proliferation and differentiation. Here, we focus on the recent reports that investigated the various aspects of scaffolds including the materials used for scaffold fabrication, surface modification of scaffolds, topography and mechanical properties of scaffolds towards stem cells differentiation effect. We will present a more detailed overview on the effect of mechanical properties of scaffolds on stem cells fate. PMID- 26029345 TI - Systems biology approach to developing S(2)RM-based "systems therapeutics" and naturally induced pluripotent stem cells. AB - The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell's power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely "systems therapeutic", can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called "systems therapeutics". A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S(2)RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S(2)RM technology, to develop a new class of therapeutics called "systems therapeutics." Given the ubiquitous and powerful nature of innate S(2)RM-based healing in the human body, this "systems therapeutic" approach using S(2)RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications. PMID- 26029346 TI - Ovarian stem cells: From basic to clinical applications. AB - The field of reproductive biology has undergone significant developments in the last decade. The notion that there is a fixed reserve pool of oocytes before birth was established by Zuckerman in 1951. However, in 2004, an article published in nature challenged this central dogma of mammalian reproductive biology. Tilly's group reported the existence of ovarian germline stem cells (GSCs) in postnatal ovaries of mice and suggested that the bone marrow could be an extragonadal source of ovarian GSCs. These findings were strongly criticized; however, several independent groups have since successfully isolated and characterized ovarian GSCs in postnatal mice. The ovarian GSCs are located in the ovarian surface epithelium and express markers of undifferentiated GSCs. When transplanted into mouse ovaries, mouse ovarian GSCs could differentiate and produce embryos and offspring. Similarly, in a recent study, ovarian GSCs were found to be present in the ovaries of women of reproductive age. Conversely, there is increasing evidence that stem cells responsible for maintaining a healthy state in normal tissue may be a source of some cancers, including ovarian cancer. Cancer stem cells (CSCs) have been found in many tissues, including ovaries. Some researchers have suggested that ovarian cancer may be a result of the transformation and dysfunction of ovarian GSCs with self-renewal properties. Drug resistant and metastasis-generating CSCs are responsible for many important problems affecting ovarian cancer patients. Therefore, the identification of CSCs will provide opportunities for the development of new therapeutic strategies for treatments for infertility and ovarian cancer. In this article, we summarize the current understanding of ovarian GSCs in adult mammals, and we also discuss whether there is a relationship between GSCs and CSCs. PMID- 26029347 TI - Placental-derived stem cells: Culture, differentiation and challenges. AB - Stem cell therapy is a promising approach to clinical healing in several diseases. A great variety of tissues (bone marrow, adipose tissue, and placenta) are potentially sources of stem cells. Placenta-derived stem cells (p-SCs) are in between embryonic and mesenchymal stem cells, sharing characteristics with both, such as non-carcinogenic status and property to differentiate in all embryonic germ layers. Moreover, their use is not ethically restricted as fetal membranes are considered medical waste after birth. In this context, the present review will be focused on the biological properties, culture and potential cell therapy uses of placental-derived stem cells. Immunophenotype characterization, mainly for surface marker expression, and basic principles of p-SC isolation and culture (mechanical separation or enzymatic digestion of the tissues, the most used culture media, cell plating conditions) will be presented. In addition, some preclinical studies that were performed in different medical areas will be cited, focusing on neurological, liver, pancreatic, heart, muscle, pulmonary, and bone diseases and also in tissue engineering field. Finally, some challenges for stem cell therapy applications will be highlighted. The understanding of the mechanisms involved in the p-SCs differentiation and the achievement of pure cell populations (after differentiation) are key points that must be clarified before bringing the preclinical studies, performed at the bench, to the medical practice. PMID- 26029348 TI - Fetal kidney stem cells ameliorate cisplatin induced acute renal failure and promote renal angiogenesis. AB - AIM: To investigate whether fetal kidney stem cells (fKSC) ameliorate cisplatin induced acute renal failure (ARF) in rats and promote renal angiogenesis. METHODS: The fKSC were isolated from rat fetuses of gestation day 16 and expanded in vitro up to 3(rd) passage. They were characterized for the expression of mesenchymal and renal progenitor markers by flow cytometry and immunocytochemistry, respectively. The in vitro differentiation of fKSC towards epithelial lineage was evaluated by the treatment with specific induction medium and their angiogenic potential by matrigel induced tube formation assay. To study the effect of fKSC in ARF, fKSC labeled with PKH26 were infused in rats with cisplatin induced ARF and, the blood and renal tissues of the rats were collected at different time points. Blood biochemical parameters were studied to evaluate renal function. Renal tissues were evaluated for renal architecture, renal cell proliferation and angiogenesis by immunohistochemistry, renal cell apoptosis by terminal deoxynucleotidyl transferase nick-end labeling assay and early expression of angiogenic molecules viz. vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1alpha and endothelial nitric oxide synthase (eNOS) by western blot. RESULTS: The fKSC expressed mesenchymal markers viz. CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz. Wt1, Pax2 and Six2. They exhibited a potential to form CD31 and Von Willebrand factor expressing capillary-like structures and could be differentiated into cytokeratin (CK)18 and CK19 positive epithelial cells. Administration of fKSC in rats with ARF as compared to administration of saline alone, resulted in a significant improvement in renal function and histology on day 3 (2.33 +/- 0.33 vs 3.50 +/- 0.34, P < 0.05) and on day 7 (0.83 +/- 0.16 vs 2.00 +/- 0.25, P < 0.05). The infused PKH26 labeled fKSC were observed to engraft in damaged renal tubules and showed increased proliferation and reduced apoptosis (P < 0.05) of renal cells. The kidneys of fKSC as compared to saline treated rats had a higher capillary density on day 3 [13.30 +/- 1.54 vs 7.10 +/- 1.29, capillaries/high power fields (HPF), P < 0.05], and on day 7 (21.10 +/- 1.46 vs 15.00 +/- 1.30, capillaries/HPF, P < 0.05). In addition, kidneys of fKSC treated rats had an up regulation of angiogenic proteins hypoxia-inducible factor-1alpha, VEGF and eNOS on day 3 (P < 0.05). CONCLUSION: Our study shows that fKSC ameliorate cisplatin induced ARF in rats and promote renal angiogenesis, which may be an important therapeutic mechanism of these stem cells in the disease. PMID- 26029350 TI - Dento-maxillofacial radiology as a specialty. AB - This editorial discusses a relatively new specialty in dental and medical field namely dentomaxillofacial radiology. As a relatively newborn specialty it is obvious that there is a long way to go before dentomaxillofacial radiology is commonly known and respected by the society. All over the world, assigned committees work on the development of the training curriculum, determination of scientific and physical standards for institutions offering specialty training and arrangement of dental codes for reimbursement issues. Furthermore, adjustment of educational, scientific and legal regulations and prospective benefits are expected to boost this specialty's attractiveness to colleagues' worldwide. PMID- 26029349 TI - Hyperpolarization of "Neat" Liquids by NMR Signal Amplification by Reversible Exchange. AB - We report NMR Signal Amplification by Reversible Exchange (SABRE) hyperpolarization of the rare isotopes in "neat" liquids, each composed only of an otherwise pure target compound with isotopic natural abundance (n.a.) and millimolar concentrations of dissolved catalyst. Pyridine (Py) or Py derivatives are studied at 0.4% isotopic natural abundance 15N, deuterated, 15N enriched, and in various combinations using the SABRE-SHEATH variant (microTesla magnetic fields to permit direct 15N polarization from parahydrogen via reversible binding and exchange with an Ir catalyst). We find that the dilute n.a. 15N spin bath in Py still channels spin order from parahydrogen to dilute 15N spins, without polarization losses due to the presence of 14N or 2H. We demonstrate P(15N) ~ 1% (a gain of 2900 fold relative to thermal polarization at 9.4 T) at high substrate concentrations. This fundamental finding has a significant practical benefit for screening potentially hyperpolarizable contrast agents without labeling. The capability of screening at n.a. level of 15N is demonstrated on examples of mono- and dimethyl-substituted Py (picolines and lutidines previously identified as promising pH sensors), showing that the presence of a methyl group in the ortho position significantly decreases SABRE hyperpolarization. PMID- 26029352 TI - Silver nitrate mimicking a foreign body in the pharyngeal mucosal space. AB - Silver nitrate is sometimes used as a means of chemical cauterization for control of minor bleeding and management of hypergranulation tissue following bedside head and neck procedures. There are only few reports available on the imaging appearance of silver nitrate and its potential to mimic a foreign body. We report a case of a patient presenting with dysphagia, odynophagia, and fever following dental work who had a peritonsillar incision and drainage for treatment of a deep neck space infection. During the procedure, silver nitrate was applied to halt the bleeding. Patient was subsequently transferred to another institution. Since the patient was not showing significant clinical improvement on antibiotic therapy, a computed tomography (CT) scan was performed demonstrating a hyperdense structure lodged in the pharyngeal mucosal space in the oropharynx and soft palate that was mistaken for a foreign body such as bone. Silver nitrate can have density similar to bone but does not have the normal architecture of bone with cortex and marrow on CT. Familiarity with the appearance of silver nitrate on CT, lack of bone architecture, and proper documentation and communication of the use of silver nitrate to the consultant radiologist and medical personnel could help avoid misdiagnosis and potentially unnecessary surgical exploration. PMID- 26029351 TI - "To-and-fro" waveform in the diagnosis of arterial pseudoaneurysms. AB - Medical ultrasound imaging with Doppler plays an essential role in the diagnosis of vascular disease. This study intended to review the clinical use of "to-and fro" waveform at duplex Doppler ultrasonography (DDU) in the diagnosis of pseudoaneurysms in the arterial vessels of upper and lower extremities, abdominal aorta, carotid and vertebral arteries as well as to review our personal experiences of "to-and-fro" waveform at DDU also. After receiving institutional review board approval, an inclusive literature review was carried out in order to review the scientific foundation of "to-and-fro" waveform at DDU and its clinical use in the diagnosis of pseudoaneurysms in various arterial vessels. Articles published in the English language between 2000 and 2013 were evaluated in this review study. Pseudoaneurysms in arterial vessels of the upper and lower extremities, abdominal aorta, carotid and vertebral arteries characterized by an extraluminal pattern of blood flow, which shows variable echogenicity, interval complexity, and "to-and-fro" flow pattern on color Doppler ultrasonography. In these arterial vessels, Duplex ultrasonography can demonstrate the degree of clotting, pseudoaneurysm communication, the blood flow patterns and velocities. Spectral Doppler applied to pseudoaneurysms lumen revealed systolic and diastolic turbulent blood flow with traditional "to-and-fro" waveform in the communicating channel. Accurate diagnosis of pseudoaneurysm by spectral Doppler is based on the documentation of the "to-and-fro" waveform. The size of pseudoaneurysm determines the appropriate treatment approach as surgical or conservative. PMID- 26029353 TI - Diagnosis of prostatic neuroendocrine carcinoma: Two cases report and literature review. AB - Two cases of prostatic neuroendocrine carcinoma (PNEC) imaged by computed tomography (CT) and magnetic resonance imaging (MRI), and literature review are presented. Early enhanced CT, MRI, especially diffusion-weighted image were emphasized, the complementary roles of ultrasound, CT, MRI, clinical and laboratory characteristic's features in achieving accurate diagnosis were valued in the preoperative diagnosis of PNEC. PMID- 26029354 TI - Homology-independent metrics for comparative genomics. AB - A mainstream procedure to analyze the wealth of genomic data available nowadays is the detection of homologous regions shared across genomes, followed by the extraction of biological information from the patterns of conservation and variation observed in such regions. Although of pivotal importance, comparative genomic procedures that rely on homology inference are obviously not applicable if no homologous regions are detectable. This fact excludes a considerable portion of "genomic dark matter" with no significant similarity - and, consequently, no inferred homology to any other known sequence - from several downstream comparative genomic methods. In this review we compile several sequence metrics that do not rely on homology inference and can be used to compare nucleotide sequences and extract biologically meaningful information from them. These metrics comprise several compositional parameters calculated from sequence data alone, such as GC content, dinucleotide odds ratio, and several codon bias metrics. They also share other interesting properties, such as pervasiveness (patterns persist on smaller scales) and phylogenetic signal. We also cite examples where these homology-independent metrics have been successfully applied to support several bioinformatics challenges, such as taxonomic classification of biological sequences without homology inference. They where also used to detect higher-order patterns of interactions in biological systems, ranging from detecting coevolutionary trends between the genomes of viruses and their hosts to characterization of gene pools of entire microbial communities. We argue that, if correctly understood and applied, homology independent metrics can add important layers of biological information in comparative genomic studies without prior homology inference. PMID- 26029355 TI - Enantioselective cis-beta-lactam synthesis by intramolecular C-H functionalization from enoldiazoacetamides and derivative donor-acceptor cyclopropenes. AB - beta-Lactam derivatives are produced through intermediate donor-acceptor cyclopropene intermediates in high yield, exclusive cis-diastereoselectivity, and high enantiocontrol in a chiral dirhodium carboxylate catalyzed intramolecular C H functionalization reaction of enoldiazoacetamides. PMID- 26029356 TI - Azasugar inhibitors as pharmacological chaperones for Krabbe disease. AB - Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme beta-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure-activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease. PMID- 26029357 TI - Recent advances in crosslinking chemistry of biomimetic poly(ethylene glycol) hydrogels. AB - The design and application of biomimetic hydrogels have become an important and integral part of modern tissue engineering and regenerative medicine. Many of these hydrogels are prepared from synthetic macromers (e.g., poly(ethylene glycol) or PEG) as they provide high degrees of tunability for matrix crosslinking, degradation, and modification. For a hydrogel to be considered biomimetic, it has to recapitulate key features that are found in the native extracellular matrix, such as the appropriate matrix mechanics and permeability, the ability to sequester and deliver drugs, proteins, and or nucleic acids, as well as the ability to provide receptor-mediated cell-matrix interactions and protease-mediated matrix cleavage. A variety of chemistries have been employed to impart these biomimetic features into hydrogel crosslinking. These chemistries, such as radical-mediated polymerizations, enzyme-mediated crosslinking, bio orthogonal click reactions, and supramolecular assembly, may be different in their crosslinking mechanisms but are required to be efficient for gel crosslinking and ligand bioconjugation under aqueous reaction conditions. The prepared biomimetic hydrogels should display a diverse array of functionalities and should also be cytocompatible for in vitro cell culture and/or in situ cell encapsulation. The focus of this article is to review recent progress in the crosslinking chemistries of biomimetic hydrogels with a special emphasis on hydrogels crosslinked from poly(ethylene glycol)-based macromers. PMID- 26029358 TI - The primary cilium functions as a mechanical and calcium signaling nexus. AB - BACKGROUND: The primary cilium is an antenna-like, nonmotile structure that extends from the surface of most mammalian cell types and is critical for chemosensing and mechanosensing in a variety of tissues including cartilage, bone, and kidney. Flow-induced intracellular calcium ion (Ca(2+)) increases in kidney epithelia depend on primary cilia and primary cilium-localized Ca(2+) permeable channels polycystin-2 (PC2) and transient receptor potential vanilloid 4 (TRPV4). While primary cilia have been implicated in osteocyte mechanotransduction, the molecular mechanism that mediates this process is not fully understood. We directed a fluorescence resonance energy transfer (FRET) based Ca(2+) biosensor to the cilium by fusing the biosensor sequence to the sequence of the primary cilium-specific protein Arl13b. Using this tool, we investigated the role of several Ca(2+)-permeable channels that may mediate flow induced Ca(2+) entry: PC2, TRPV4, and PIEZO1. RESULTS: Here, we report the first measurements of Ca(2+) signaling within osteocyte primary cilia using a FRET based biosensor fused to ARL13B. We show that fluid flow induces Ca(2+) increases in osteocyte primary cilia which depend on both intracellular Ca(2+) release and extracellular Ca(2+) entry. Using siRNA-mediated knockdowns, we demonstrate that TRPV4, but not PC2 or PIEZO1, mediates flow-induced ciliary Ca(2+) increases and loading-induced Cox-2 mRNA increases, an osteogenic response. CONCLUSIONS: In this study, we show that the primary cilium forms a Ca(2+) microdomain dependent on Ca(2+) entry through TRPV4. These results demonstrate that the mechanism of mechanotransduction mediated by primary cilia varies in different tissue contexts. Additionally, we anticipate that this work is a starting point for more studies investigating the role of TRPV4 in mechanotransduction. PMID- 26029359 TI - Surfaces Presenting alpha-Phenyl Mannoside Derivatives Enable Formation of Stable, High Coverage, Non-pathogenic Escherichia coli Biofilms against Pathogen Colonization. AB - Prevention of pathogenic colonization on medical devices over a long period of time remains a great challenge, especially in a high-nutrient environment that accelerates production of biomass leading to biofouling of the device. Since biofouling and the subsequent pathogen colonization is eventually inevitable, a new strategy using non-pathogenic bacteria as living guards against pathogenic colonization on medical devices has attracted increasing interest. Crucial to the success of this strategy is to pre-establish a high coverage and stable biofilm of benign bacteria on the surface. Silicone elastomers are one of the most widely used materials in biomedical devices. In this work, we modified silicone surfaces to promote formation of high coverage and stable biofilms by a non-pathogenic Escherichia coli strain 83972 with type 1 fimbriae (fim+) to interfere the colonization of an aggressive biofilm-forming, uropathogenic Enterococcus faecalis. Although it is well known that mannoside surfaces promote the initial adherence of fim+ E. coli through binding to the FimH receptor at the tip of the type 1 fimbriae, it is not clear whether the fast initial adherence could lead to a high coverage and stable protective biofilm. To explore the role of mannoside ligands, we synthesized a series of alkyl and aryl mannosides varied in structure and immobilized them on silicone surfaces pre-coated with poly(amidoamine) (PAMAM) dendrimer. We found that stable and densely packed benign E. coli biofilms were formed on the surfaces presenting biphenyl mannoside with the highest initial adherence of fim+ E. coli. These non-pathogenic biofilms prevented the colonization of E. faecalis for 11 days at a high concentration (108 CFU mL-1, 100,000 times above the diagnostic threshold for urinary tract infection) in the nutrient-rich Lysogeny Broth (LB) media. The result shows a correlation among the initial adherence of fim+ E. coli 83972, the coverage and long-term stability of the resultant biofilms, as well as their efficiency for preventing the pathogen colonization. PMID- 26029360 TI - Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors. AB - Bone marrow is a heterogeneous organ containing diverse cell types, and it is a preferred metastatic site for several solid tumors such as breast and prostate cancer. Recently, it has been shown that bone metastatic cancer cells interact with the bone marrow microenvironment to survive and grow, and thus this microenvironment is referred to as the 'metastatic niche'. Once cancer cells spread to distant organs such as bone, the prognosis for the patient is generally poor. There is an urgent need to establish a greater understanding of the mechanisms whereby the bone marrow niche influences bone metastasis. Here we discuss insights into the contribution of the bone marrow 'metastatic niche' to progression of bone metastatic disease, with a particular focus on cells of hematopoietic and mesenchymal origin. PMID- 26029361 TI - Cancer Treatment-Induced Bone Loss in women with breast cancer. AB - Osteoporosis is one of the most frequent diseases in postmenopausal women, leading to an increased fracture risk due to the physiologic loss of the bone protective effects of estrogen. Hereby, several risk factors for fracture such as prevalent fracture, low bone mineral density (BMD), age, low body mass index, family history, tendency to falls, smoking, use of SSRIs, glucocorticoid use etc. have been identified. In addition, the further reduction in endogenous estrogens with chemotherapy (CHT), GnRH analoga or aromatase inhibitors (AIs) continuously increases fracture risk. Breast cancer (BC) on the other hand is the most frequent cancer type in women. Recent reports indicate a continuous increased incidence, whereas mortality, due to early diagnosis and treatment improvements, is decreasing. Dependent on specific tumor characteristics, radiation, CHT, antibody treatment as well as endocrine treatment have been included into the adjuvant clinical treatment setting. Some but not all of these cancer-specific treatments interfere with bone turnover, leading to an accelerated bone loss referred to as cancer treatment-induced bone loss (CTIBL). Whereas CHT leads to an unspecific increase in bone resorption, AI reduces residual serum endogenous estrogen level and is associated with a decrease in BMD and increased fracture risk. Independent of the type of AI administered, bone loss is 2-3-fold increased compared with healthy, age-matched postmenopausal controls. Therefore, several guidelines have emerged to help managing CTIBL in women with BC including strategies to identify and treat those at highest risk for fractures. This review summarizes the current knowledge on CTIBL and fracturing risk and indicates preventative strategies. PMID- 26029362 TI - Posttranslational modifications of alpha-tubulin in alzheimer disease. AB - BACKGROUND: In Alzheimer disease (AD), hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities. Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls, however, this reduction did not coincide with the presence of paired helical filaments. The latter suggests the presence of compensatory mechanism(s) that stabilize microtubule dynamics despite the loss of tau binding and stabilization. Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules. METHODS: In this study, we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry. RESULTS: Consistent with our previous study, we found decreased levels of alpha-tubulin in AD brain. Levels of tubulin with various posttranslational modifications such as polyglutamylation, tyrosination, and detyrosination were also proportionally reduced in AD brain, but, interestingly, there was an increase in the proportion of the acetylated alpha tubulin in the remaining alpha-tubulin. Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body. The number of processes containing polyglutamylated tubulin was well preserved in AD neurons. While there was a cell autonomous detrimental effect of NFTs on tubulin, this is likely a gradual and slow process, and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons. CONCLUSIONS: Overall, we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response. PMID- 26029364 TI - Incorporating smartphones into clinical practice. PMID- 26029363 TI - Acid-sensing ion channels: potential therapeutic targets for neurologic diseases. AB - Maintaining the physiological pH of interstitial fluid is crucial for normal cellular functions. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acid-sensing ion channels (ASICs), which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms (i.e., pain, stroke, and psychiatric conditions). Thus, it has become increasingly clear that ASICs are critical in the progression of neurologic diseases. This review is focused on the importance of ASICs as potential therapeutic targets in combating neurologic diseases. PMID- 26029365 TI - Immune parameters of patients treated with laquinimod, a novel oral therapy for the treatment of multiple sclerosis: results from a double-blind placebo controlled study. AB - Laquinimod is a novel orally administered drug for the treatment of relapsing remitting multiple sclerosis (RRMS). In this immunological substudy of the phase III Assessment of Oral Laquinimod in Preventing Progression of MS (ALLEGRO) trial, we performed an ex vivo and in vitro analysis of effects exerted by laquinimod on peripheral blood immune cell populations from RRMS patients with a special focus on monocyte phenotype and function. Approximately 100 patients were enrolled following a standardized protocol. Half of the patients received laquinimod and the other half received placebo. Peripheral blood samples were collected prior to commencement of therapy and after 1, 3, 6, 12, and 24 months of continuous therapy. Main lymphocytic and antigen presenting cell fractions were analyzed in peripheral blood mononuclear cells (PBMCs) ex vivo by flow cytometry. The proliferative response of PBMCs to mitogen or recall antigen was assessed in culture experiments. Untouched monocytes were sorted magnetically and cultured under pro-inflammatory conditions. PBMC analysis showed no significant differences of investigated lymphocytic and antigen presenting cell populations over time within each group, or between the two groups. However, the detailed in vitro analysis of monocytes demonstrated a lower level of CD86 expression on monocytes stimulated with LPS in laquinimod patients beginning from the 1st month of treatment. Upon pro-inflammatory stimulation, monocytes obtained from laquinimod treated patients tended to secrete lower levels of the proinflammatory chemokines CCL2 or CCL5. Taken together, in this prospective study, we demonstrate immune modulation but no immunosuppressive biological activity of laquinimod in a large group of MS patients. PMID- 26029366 TI - Differences in immune responses between CMV-seronegative and -seropositive patients with myocardial ischemia and reperfusion. AB - CMV infection is responsible for acceleration of immune senescence and linked to systemic pathologies, including cardiovascular diseases. In this study, we investigated differences in the immune response between CMV-seropositive and seronegative patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (MI). Peripheral blood samples were taken at six different time points: pre-, 15, 30, 90 min, 24 h after PPCI and at 3 months after MI. Absolute counts of lymphocyte subpopulations, immune response to specific and nonspecific stimulation, serum cytokines and levels of CMV-IgG, cardiolipin-IgG, and anti-endothelial cell antibodies were assessed. CMV seropositive patients with MI showed a twofold higher IFN-gamma production to PHA stimulation, up to 2.5-fold higher levels of IP-10 in serum and up to 30% lower serum levels of IL-16 compared to CMV-seronegative individuals. CMV-seropositive patients could be divided into two subgroups with high (IL-10Hi) and low (IL 10Lo) IL-10 serum levels during the acute stage of MI. The IL-10Hi CMV seropositive subgroup showed an increased exit of late-differentiated T lymphocytes, NK and NKT-like cells from the circulation, which may potentially enhance cytotoxic damage in the ischemic myocardium. Finally, we did not observe an acceleration of autoimmunity by MI in CMV-seropositive individuals. The immune response during acute MI showed characteristic differences between CMV seronegative and seropositive patients, with a stronger pro-inflammatory response in seropositive patients. The effects of IP-10, IL-16, and IL-10 on characteristics of acute immune responses and formation of different immune profiles in CMV-seropositive individuals require further investigation. PMID- 26029367 TI - Depletion of alveolar macrophages in CD11c diphtheria toxin receptor mice produces an inflammatory response. AB - Alveolar macrophages play a critical role in initiating the immune response to inhaled pathogens and have been shown to be the first cell type infected following intranasal inoculation with several pathogens, including Francisella tularensis. In an attempt to further dissect the role of alveolar macrophages in the immune response to Francisella, we selectively depleted alveolar macrophages using CD11c.DOG mice. CD11c.DOG mice express the diphtheria toxin receptor (DTR) under control of the full CD11c promoter. Because mice do not express DTR, tissue restricted expression of the primate DTR followed by treatment with diphtheria toxin (DT) has been widely used as a tool in immunology to examine the effect of acute depletion of a specific immune subset following normal development. We successfully depleted alveolar macrophages via intranasal administration of DT. However, alveolar macrophage depletion was accompanied by many other changes to the cellular composition and cytokine/chemokine milieu in the lung that potentially impact innate and adaptive immune responses. Importantly, we observed a transient influx of neutrophils in the lung and spleen. Our experience serves as a cautionary note to other researchers using DTR mice given the complex changes that occur following DT treatment that must be taken into account when analyzing data. PMID- 26029368 TI - Humoral responses to HIVconsv induced by heterologous vaccine modalities in rhesus macaques. AB - Vaccines delivering T cell immunogen HIVconsv vectored by plasmid DNA, non replicating simian adenovirus and non-replicating modified vaccinia virus Ankara (MVA) are under clinical evaluation in phase I/IIa trials in UK, Europe, and Africa. While these vaccines aim to induce effector T cell responses specific for HIV-1, we here characterized the humoral responses induced by HIVconsv administration to macaques using six different vaccine modalities: plasmid DNA, human adenovirus serotype 5, simian adenovirus serotype 63, MVA, Semliki Forest virus replicons, and adjuvanted overlapping synthetic long peptides (SLP). We found that only the SLP formulation, but none of the genetic vaccine platforms induced antibodies recognizing linear HIVconsv epitopes, median 32/46 SLP.HIVconsv peptides. These antibodies bound to 15-mer and SLP peptides, recombinant gp120 and trimeric gp140 of HIV-1 Bal, YU2, JRFL, and UG037, but failed to react with HIV-1 Bal and IIIB virions and HIV-1 Bal- and IIIB-infected human cells, and consequently failed to induce neutralizing antibodies. The HIVconsv immunogen contains conserved regions derived from Gag, Pol, Vif, and Env proteins of HIV-1, and antibodies induced by the SLP.HIVconsv vaccination resulted in positive signals in routine HIV-1 tests. Thus, only HIVconsv delivered by SLP resulted in seroconversion, an observation that provides important guidance for recruiting volunteers into future clinical trials. Furthermore, our data confirms that vaccine delivery by SLP induces humoral as well as cellular immune responses and could be considered for inclusion in future vaccine regimens where this is required. PMID- 26029369 TI - The proportion of CD16(+)CD14(dim) monocytes increases with tumor cell load in bone marrow of patients with multiple myeloma. AB - Multiple myeloma is an incurable cancer with expansion of malignant plasma cells in the bone marrow. Previous studies have shown that monocytes and macrophages in the bone marrow milieu are important for tumor growth and may play a role in the drug response. We therefore characterized monocytes in bone marrow aspirates by flow cytometry. We found that there was significant correlation between the proportion of CX3CR1 (+), CD16(+)CD14(dim) non classical monocytes, and percent plasma cells (PC) in the bone marrow of myeloma patients. The bone marrow monocytes could be stimulated by TLR ligands to produce cytokines which promote myeloma cell growth. The proportion of the non-classical monocytes increased with the tumor load, particularly in patients with tumor loads in the range of 10-30% bone marrow PC. PMID- 26029373 TI - Fabrication and adhesion of a bio-inspired microarray: capillarity-induced casting using porous silicon mold. AB - Inspired by the setal microstructure found on the gecko's toe-pads, a highly dense array of high-aspect-ratio (HAR) artificial setae has been developed with a novel mold-casting technique using a porous silicon (PSi) template. To overcome the high fluid resistance in the HAR capillary pores, the PSi template surface is modified with a monolayer coating of dimethylsilane. The coating exhibits similar chemical composition and surface energy to the precursor of the poly(dimethylsiloxane) (PDMS) replica. The compatibility between the template and the replica addresses the major challenge of molding HAR microstructures, resulting in high-resolution replicas of artificial PDMS microsetae with complicated geometry resembling a real gecko's setae. The artificial setae are characterized by a mean radius of 1.3 MUm, an aspect ratio of 35.1, and a density of ~4.7 * 105 per mm2. Results from adhesion characterizations reveal that with increasing preload, the shear adhesion of micro-setae continually increases while the normal adhesion decreases. The unique adhesion performance is caused by both van der Waals forces and the elastic resistance of PDMS setae. With further structural optimizations and the addition of an actuation mechanism, artificial setal arrays might eventually demonstrate the fascinating adhesion performances of the gecko for mimetic devices such as wall-climbing devices. PMID- 26029371 TI - Identification of novel CD8+ T cell epitopes in human herpesvirus 6B U11 and U90. AB - Human herpesvirus 6B (HHV6B) infects over 90% of the population, and normally establishes a latent infection, where episodes of reactivation are asymptomatic. However, in immunocompromised patients HHV6B reactivation is associated with high morbidity and mortality. Cellular immunotherapy has been utilised against other herpesvirus in immunocompromised settings. However, limited information on the immune response against HHV6B has hampered the development of immunotherapy for HHV6B-driven disease. In this study, we have analysed the cellular immune response against four HHV6B antigens in a panel of 30 healthy donors. We show that the base-line level of T cell reactivity in peripheral blood is very low to undetectable. A short-term reactivation step enabled expansion of T cell responses, and all donors responded to at least 1 antigen, but more commonly 3 or 4. A hierarchy of immunogenicity was determined with antigens U90 and U54 being co-dominant, followed by U11 and U39. Putative CD8+ T cell epitopes were mapped to U90 and U11, predicted to be presented in the context of HLA-A1, A29, B39 and C6. T cells reactive against these novel epitopes were able to recognise virus infected cells. Our data is supportive of the application and on-going development of T cell immunotherapy against HHVB-driven disease in the immunocompromised host. PMID- 26029374 TI - Ca2+-induced self-assembly of Bombyx mori silk sericin into a nanofibrous network like protein matrix for directing controlled nucleation of hydroxylapatite nano needles. AB - Bone biomineralization is a well-regulated protein-mediated process where hydroxylapatite (HAP) crystals are nucleated with preferred orientation within self-assembled protein matrix. Mimicking this process is a promising approach to the production of bone-like protein/mineral nanocomposites for bone repair and regeneration. Towards the goal of fabricating such nanocomposites from sericin, a protein spun by Bombyx mori (B.mori) silkworm, and bone mineral HAP, for the first time we investigated the chemical mechanism underpinning the synergistic processes of the conformational change/self-assembly of B.mori sericin ( BS ) as well as the nucleation of HAP on the resultant self-assembled BS matrix. We found that BS , rich in anionic amino acid residues, could bind Ca2+ ions from the HAP precursor solution through electrostatic attraction. The Ca2+binding drove the conformational change of BS from random coils into beta-sheets and its concomitant self-assembly into interconnected nanofibrous network-like protein matrix, which initiated the nucleation and growth of HAP crystals. HAP crystals directed by the resultant self-assembled BS matrix grew preferentially along their crystallographic c-axis, leading to the formation of HAP nano-needles. The HAP nano-needles in the self-assembled BS matrix were subsequently aggregated into globules, probably driven by the hydrogen bonding between C=O groups of BS and O-H groups of HAP nano-needles. The present work sheds light on the chemical mechanisms of BS self-assembly and the controlled mineralization directed by the self-assembled matrix. We also found that the resultant nanocomposites could promote the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Thus our work also generates a biomimetic approach to bone-like silk protein/mineral nanocomposite scaffolds that can find potential applications in bone repair and regeneration. PMID- 26029370 TI - Cell extrinsic alterations in splenic B cell maturation in Flt3-ligand knockout mice. AB - B lymphopoiesis in bone marrow (BM) is critical for maintaining a diverse peripheral B cell pool to fight infection and establish lifelong immunity. The generation of immature B cells is reduced in Flt3-ligand (FL-/-) mice leading to deficiencies in splenic B cells. Here, we sought to understand the cellular basis of the spleen B cell deficiency in FL-/- mice. Significant reductions in transitional (TS) and follicular (FO) B cells were found in FL-/- mice, and increased frequencies, but not absolute numbers, of marginal zone (MZ) B cells. BAFF-R expression on splenic B cells and serum levels of B cell activating factor (BAFF) was comparable to wildtype (WT) mice. Mixed BM chimeras revealed that the reductions in TS and FO B cells were cell extrinsic. FL administration into FL-/- mice restored the deficiency in TS B cells and normalized the MZ compartment. Ki67 analysis revealed a significant decrease in the proliferative capacity of TS B cells in FL-/- mice. A Bcl2 transgene did not rescue TS cells in FL-/- mice, uncoupling FL-deficiency to Bcl2-dependent survival pathways. Upregulation of CD1d expression and adoptive transfer experiments suggested MZ skewing in FL-/- mice. These findings support an integral role for Flt3 signaling in peripheral B cell maturation. PMID- 26029376 TI - Biomonitoring of metal contamination in estuarine ecosystem using seagrass. AB - Metals concentrations (As, Cd, Cu, Hg and Pb) in seawater, sediment and the seagrass (Enhalus acoroides) were analysed at Pulai River estuary, Johor Straits, Malaysia. In this research, Enhalus acoroides was used in order to find it's efficiency in up taking metals with a role in phytoremediation. Seawater, sediment and Enhalus acoroides samples were collected, and data of Pearson's correlation coefficients were analysed using SPSS 16 software. Results show that lead levels were the highest metal content in Enhalus acoroides (202 +/- 102 MUg/gDW), seawater (268 +/- 190 MUg/L) and sediment (248 +/- 218 MUg/gDW), compared to other metals. There was a positive correlation for metal concentrations between Enhalus acoroides and sediment, but no correlation was found between Enhalus acoroides with seawater at estuarine area may be caused by inconsistent metal concentrations in seawater due to the influences of tidal changes and stormy waves. This indicates that Enhalus acoroides is a species possessing the capabilities to uptake metals from sediment, and suitable to act as both a phytoremediator and biomonitor in estuarine ecosystems due to sharp sensitivity to variation in the environment. PMID- 26029375 TI - The global threat of antimicrobial resistance: science for intervention. AB - In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance. PMID- 26029377 TI - A review of epidemiological parameters from Ebola outbreaks to inform early public health decision-making. AB - The unprecedented scale of the Ebola outbreak in West Africa has, as of 29 April 2015, resulted in more than 10,884 deaths among 26,277 cases. Prior to the ongoing outbreak, Ebola virus disease (EVD) caused relatively small outbreaks (maximum outbreak size 425 in Gulu, Uganda) in isolated populations in central Africa. Here, we have compiled a comprehensive database of estimates of epidemiological parameters based on data from past outbreaks, including the incubation period distribution, case fatality rate, basic reproduction number (R 0 ), effective reproduction number (R t ) and delay distributions. We have compared these to parameter estimates from the ongoing outbreak in West Africa. The ongoing outbreak, because of its size, provides a unique opportunity to better understand transmission patterns of EVD. We have not performed a meta analysis of the data, but rather summarize the estimates by virus from comprehensive investigations of EVD and Marburg outbreaks over the past 40 years. These estimates can be used to parameterize transmission models to improve understanding of initial spread of EVD outbreaks and to inform surveillance and control guidelines. PMID- 26029379 TI - A database for the monitoring of thermal anomalies over the Amazon forest and adjacent intertropical oceans. AB - Advances in information technologies and accessibility to climate and satellite data in recent years have favored the development of web-based tools with user friendly interfaces in order to facilitate the dissemination of geo/biophysical products. These products are useful for the analysis of the impact of global warming over different biomes. In particular, the study of the Amazon forest responses to drought have recently received attention by the scientific community due to the occurrence of two extreme droughts and sustained warming over the last decade. Thermal Amazoni@ is a web-based platform for the visualization and download of surface thermal anomalies products over the Amazon forest and adjacent intertropical oceans using Google Earth as a baseline graphical interface (http://ipl.uv.es/thamazon/web). This platform is currently operational at the servers of the University of Valencia (Spain), and it includes both satellite (MODIS) and climatic (ERA-Interim) datasets. Thermal Amazoni@ is composed of the viewer system and the web and ftp sites with ancillary information and access to product download. PMID- 26029378 TI - Open science resources for the discovery and analysis of Tara Oceans data. AB - The Tara Oceans expedition (2009-2013) sampled contrasting ecosystems of the world oceans, collecting environmental data and plankton, from viruses to metazoans, for later analysis using modern sequencing and state-of-the-art imaging technologies. It surveyed 210 ecosystems in 20 biogeographic provinces, collecting over 35,000 samples of seawater and plankton. The interpretation of such an extensive collection of samples in their ecological context requires means to explore, assess and access raw and validated data sets. To address this challenge, the Tara Oceans Consortium offers open science resources, including the use of open access archives for nucleotides (ENA) and for environmental, biogeochemical, taxonomic and morphological data (PANGAEA), and the development of on line discovery tools and collaborative annotation tools for sequences and images. Here, we present an overview of Tara Oceans Data, and we provide detailed registries (data sets) of all campaigns (from port-to-port), stations and sampling events. PMID- 26029380 TI - An archive of longitudinal recordings of the vocalizations of adult Gombe chimpanzees. AB - Studies of chimpanzee vocal communication provide valuable insights into the evolution of communication in complex societies, and also comparative data for understanding the evolution of human language. One particularly valuable dataset of recordings from free-living chimpanzees was collected by Frans X. Plooij and the late Hetty van de Rijt-Plooij at Gombe National Park, Tanzania (1971-73). These audio specimens, which have not yet been analysed, total over 10 h on 28 tapes, including 7 tapes focusing on adult individuals with a total of 605 recordings. In 2014 the first part of that collection of audio specimens covering the vocalizations of the immature Gombe chimpanzees was made available. The data package described here covers the vocalizations of the adult chimpanzees. We expect these recordings will prove useful for studies on topics including referential signalling and the emergence of dialects. The digitized sound recordings were stored in the Macaulay Library and the Dryad Repository. In addition, the original notes on the contexts of the calls were translated and transcribed from Dutch into English. PMID- 26029381 TI - CKD in disadvantaged populations. PMID- 26029382 TI - Crystal structures of the water and acetone monosolvates of bis-[4'-(pyridin-4 yl)-2,2':6',2''-terpyridine]-manganese(II) bis-(hexa-fluorido-phosphate). AB - The crystal structures of bis-[4'-(pyridin-4-yl)-2,2':6',2''-terpyridine]-man-gan ese(II) bis-(hexa-fluorido-phosphate) monohydrate, [Mn(C20H14N4)2](PF6)2.H2O, (1), and bis-[4'-(pyridin-4-yl)-2,2':6',2''-terpyridine]-manganese(II) bis(hexa fluorido-phosphate) acetone monosolvate, (2), [Mn(C20H14N4)2](PF6)2.CH3COCH3, are described. At 150 K, (1) and (2) have monoclinic (P21/c) and ortho-rhom-bic (C2221) symmetries, respectively. Both structures exhibit octahedrally coordinated Mn(II) atoms and disorder. They display weak inter-actions, such as C H?F, C-H?N, C-H?pi, F?pi and pi-pi. The twofold rotation axis in the molecule of (2) is coincident with a twofold rotation axis of the crystal. PMID- 26029383 TI - Crystal structure of 5-{4'-[(2-{2-[2-(2-ammonio-eth-oxy)eth-oxy]eth-oxy}eth yl)carbamo-yl]-4-meth-oxy-[1,1'-biphen-yl]-3-yl}-3-oxo-1,2,5-thia-diazo-lidin-2 ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B). AB - The title compound, C24H32N4O8S, (I), crystallizes as a zwitterion. The terminal amine N atom of the [(2-{2-[2-(2-ammonio-eth-oxy)eth-oxy]eth-oxy}eth-yl)carbamo yl] side chain is protonated, while the 1,2,5-thia-diazo-lidin-3-one 1,1-dioxide N atom is deprotonated. The side chain is turned over on itself with an intra molecular N-H?O hydrogen bond. The 1,2,5-thia-diazo-lidin-3-one 1,1-dioxide ring has an envelope conformation with the aryl-substituted N atom as the flap. Its mean plane is inclined by 62.87 (8) degrees to the aryl ring to which it is attached, while the aryl rings of the biphenyl unit are inclined to one another by 20.81 (8) degrees . In the crystal, mol-ecules are linked by N-H?O and N-H?N hydrogen bonds, forming slabs lying parallel to (010). Within the slabs there are C-H?O and C-H?N hydrogen bonds and C-H?pi inter-actions present. PMID- 26029384 TI - Crystal structure of catena-poly[[di-aqua-bis-(4-formyl-benzoato-kappaO (1))cobalt(II)]-MU-pyrazine-kappa(2) N:N']. AB - In the title polymeric compound, [Co(C8H5O3)2(C4H4N2)(H2O)2] n , the Co(II) atom is located on a twofold rotation axis and has a slightly distorted octa-hedral coordination sphere. In the equatorial plane, it is coordinated by two carboxyl ate O atoms of two symmetry-related monodentate formyl-benzoate anions and by two N atoms of two bridging pyrazine ligands. The latter are bis-ected by the twofold rotation axis. The axial positions are occupied by two O atoms of the coordinating water mol-ecules. In the formyl-benzoate anion, the carboxyl-ate group is twisted away from the attached benzene ring by 7.50 (8) degrees , while the benzene and pyrazine rings are oriented at a dihedral angle of 64.90 (4) degrees . The pyrazine ligands bridge the Co(II) cations, forming linear chains running along the b-axis direction. Strong intra-molecular O-H?O hydrogen bonds link the water mol-ecules to the carboxyl-ate O atoms. In the crystal, weak O Hwater?Owater hydrogen bonds link adjacent chains into layers parallel to the bc plane. The layers are linked via C-Hpyrazine?Oform-yl hydrogen bonds, forming a three-dimensional network. There are also weak C-H?pi inter-actions present. PMID- 26029385 TI - Crystal structure of bis-[(1-ammonio-1-phosphono-eth-yl)phospho-nato]tetra-aqua cadmium dihydrate: a powder X-ray diffraction study. AB - In the title compound, [CdL 2(H2O)4].2H2O [L = (1-ammonio-1-phosphono-eth yl)phospho-nate, C2H8NO6P2 (-)], the Cd(II) ion is situated on an inversion centre being coordinated by four aqua mol-ecules in the equatorial plane and two phosphonate O atoms from two deprotonated L ligands in the axial positions in a distorted octa-hedral geometry. The asymmetric unit contains one-half of the complex mol-ecule and one lattice water mol-ecule. The ligand L exists in a zwitterionic form, with a positive charge on the NH3 group and a negative charge on the O atom of the non-coordinating phospho-nate group, and with an intra molecular O-H?O inter-action forming an S(6) ring motif and two intra-molecular N H?O inter-actions each generating an S(5) ring motif. In the crystal, N-H?O and O H?O hydrogen bonds link the complex mol-ecules into a three-dimensional network in which the voids of 38 A(3) are filled with ordered lattice water mol-ecules, which are also involved in O-H?O hydrogen bonding. PMID- 26029386 TI - Crystal structure of tetra-aqua-[2-(pyridin-2-yl)-1H-imidazole-kappa(2) N (2),N (3)]iron(II) sulfate. AB - In the title compound, [Fe(C8H7N3)(H2O)4]SO4, the central Fe(II) ion is octa hedrally coordinated by two N atoms from the bidentate 2-(pyridin-2-yl)-1H imidazole ligand and by four O atoms of the aqua ligands. The largest deviation from the ideal octa-hedral geometry is reflected by the small N-Fe-N bite angle of 76.0 (1) degrees . The Fe-N coordination bonds have markedly different lengths [2.1361 (17) and 2.243 (2) A], with the shorter one to the pyrimidine N atom. The four Fe-O coordination bond lengths vary from 2.1191 (18) to 2.1340 (17) A. In the crystal, the cations and anions are arranged by means of medium-strength O H?O hydrogen bonds into layers parallel to the ab plane. Neighbouring layers further inter-connect by N-H?O hydrogen bonds involving the imidazole fragment as donor group to one sulfate O atom as an acceptor. The resulting three-dimensional network is consolidated by C-H?O, C-H?pi and pi-pi inter-actions. PMID- 26029387 TI - Crystal structure of bis-(2-{1-[(E)-(4-fluoro-benz-yl)imino]-eth-yl}phenolato kappa(2) N,O)palladium(II). AB - The asymmetric unit of the title complex, [Pd(C15H13FNO)2], contains one half of the mol-ecule with the Pd(II) cation lying on an inversion centre and is coordinated by the bidentate Schiff base anion. The geometry around the cationic Pd(II) centre is distorted square planar, chelated by the imine N- and phenolate O-donor atoms of the two Schiff base ligands. The N- and O-donor atoms of the two ligands are mutually trans, with Pd-N and Pd-O bond lengths of 2.028 (2) and 1.9770 (18) A, respectively. The fluoro-phenyl ring is tilted away from the coordination plane and makes a dihedral angle of 66.2 (2) degrees with the phenolate ring. In the crystal, mol-ecules are linked into chains along the [101] direction by weak C-H?O hydrogen bonds. Weak pi-pi inter-actions with centroid centroid distances of 4.079 (2) A stack the mol-ecules along c. PMID- 26029388 TI - Crystal structure of [2,6-di-fluoro-3-(pyridin-2-yl-kappaN)pyridin-4-yl-kappaC (4)](pentane-2,4-dionato-kappa(2) O,O')platinum(II). AB - The asymmetric unit of the title compound, [Pt(C10H5F2N2)(C5H7O2)], comprises one Pt(II) atom, one 2,6-di-fluoro-2,3-bi-pyridine ligand and one acetyl-acetonate anion. The Pt(II) atom adopts a distorted square-planar coordination geometry, being C,N-chelated by the 2,6-di-fluoro-3-(pyridin-2-yl)pyridin-4-yl ligand and O,O'-chelated by the pentane-2,4-dionate ligand. The two pyridine rings of the bi pyridine ligand are approximately coplanar, making a dihedral angle of 1.2 (2) degrees . A variety of intra- and inter-molecular C-H?O and C-H?F hydrogen bonds, as well as pi-pi inter-actions [centroid-centroid distances = 4.337 (3) and 3.774 (3) A] contribute to the stabilization of the mol-ecular and crystal structures, and result in the formation of a three-dimensional supra-molecular framework. PMID- 26029389 TI - Crystal structure of 9-methacryloylanthracene. AB - In the title compound, C18H14O, with systematic name 1-(anthracen-9-yl)-2-methyl prop-2-en-1-one, the ketonic C atom lies 0.2030 (16) A out of the anthryl-ring system plane. The dihedral angle between the planes of the anthryl and methacryloyl moieties is 88.30 (3) degrees and the stereochemistry about the Csp (2)-Csp (2) bond in the side chain is transoid. In the crystal, the end rings of the anthryl units in adjacent mol-ecules associate in parallel-planar orientations [shortest centroid-centroid distance = 3.6320 (7) A]. A weak hydrogen bond is observed between an aromatic H atom and the O atom of a mol ecule displaced by translation in the a-axis direction, forming sheets of parallel-planar anthryl groups packing in this direction. PMID- 26029390 TI - Crystal structure of di-MU-hydroxido-bis-[aqua-(1,10-phenanthroline-kappa(2) N,N')copper(II)] naphthalene-2,6-di-carboxyl-ate hexa-hydrate. AB - In the title compound, [Cu2(OH)2(C12H8N2)2(H2O)2](C12H6O4).6H2O, the two hydroxide groups bridge the two Cu(II) cations, forming a centrosymmetric binuclear complex cation, in which the Cu(II) cation is coordinated by a 1,10 phenanthroline (phen) mol-ecule, one water mol-ecule and two bridging hydroxide O atoms in a distorted N2O3 square-pyramidal coordination geometry. The naphthalene 2,6-di-carboxyl-ate anion is also located on an inversion centre. In the crystal, O-H?O hydrogen bonds link the cations, anions and lattice water mol-ecules into a three-dimensional supra-molecular architecture. Extensive pi-pi stacking is observed between the parallel or nearly parallel aromatic rings of adjacent phen ligands and naphthalenedi-carboxyl-ate anions, the centroid-to-centroid distances ranging from 3.4990 (16) to 3.8895 (16) A. PMID- 26029391 TI - Crystal structure of bis-(fluoro-sulfato-kappaO)xenon(II), Xe(SO3F)2. AB - Thermally unstable Xe(SO3F)2 has been prepared by the reaction of XeF2 with HSO3F. Single crystals were obtained from HSO3F by slow cooling in a sealed tube. The mol-ecular structure is characterized by the Xe atom covalently bonded to two O atoms of two fluoro-sulfate tetra-hedra in an almost linear fashion [O-Xe-O = 179.13 (4) degrees ]. The crystal packing is strongly influenced by inter molecular van der Waals forces. PMID- 26029392 TI - Crystal structure of cis-diamminebis(nitrito-kappaN)platinum(II). AB - Single crystals of cis-[Pt(NO2)2(NH3)2], were obtained by means of hyper saturation directly out of a plating electrolyte. The square-planar coordination environment of the divalent Pt(II) atom is formed by four N atoms belonging to two ammine and two monodentate nitrite ligands. The ligands adopt a cis configuration. The crystal structure contains stacks of close-packed mol-ecules which run parallel to [001]. There are nine crystallographically independent inter-molecular N-H?O hydrogen bonds, resulting in a hydrogen-bonded hxl-type framework in which each mol-ecule serves as an eight-connected node. Four of the nine distinct hydrogen bonds connect complexes which belong to the same close packed column parallel to [001]. In contrast to the previously reported crystal structure of the trans isomer, the title structure does not display intra molecular hydrogen bonding. PMID- 26029393 TI - Serendipitous preparation of fac-(aceto-nitrile-kappaN)tri-chlorido-[(1,2,5,6 eta)-cyclo-octa-1,5-diene]iridium(III). AB - A reaction between [(COD)IrCl]2 (COD is cyclo-octa-1,5-diene), HCl and indene failed to provide the hoped for chlorido-indenyliridium dimer, but instead produced the title compound, [IrCl3(CH3CN)(C8H12)], which is an octa-hedral complex of iridium(III) with a chelating cyclo-octa-1,5-diene ligand, three chloride ligands in a fac arrangement, and one aceto-nitrile ligand. Attempts to devise a rational synthesis for the title compound were unsuccessful. PMID- 26029394 TI - Crystal structure of the co-crystal fac-tri-aqua-tris(thio-cyanato kappaN)iron(III)-2,3-di-methyl-pyrazine (1/3). AB - In the crystal of the title compound, [Fe(NCS)3(H2O)3].3C6H8N2, the Fe(III) cation is located on a threefold rotation axis and is coordinated by three N atoms of the thiocyanate anions and three water mol-ecules in a fac arrangement, forming a slightly distorted N3O3 octa-hedron. Stabilization within the crystal structure is provided by O-H?N hydrogen bonds; the H atoms from coordinating water mol-ecules act as donors to the N atoms of guest 2,3-di-methyl-pyrazine mol ecules, leading to a three-dimensional supra-molecular framework. PMID- 26029395 TI - Crystal structure of (2E)-2-meth-oxy-imino-2-{2-[(2-methyl-phen-oxy)meth-yl]phen yl}-N'-(4-nitro-benzyl-idene)ethano-hydrazide. AB - The title compound, C24H22N4O5, crystallizes with two mol-ecules in the asymmetric unit (Z' = 2) oriented almost perpendicular to each other [dihedral angle between the central core of each mol-ecule = 77.95 (3) degrees ]. The two mol-ecules exhibit similar conformations with an extended structure. An intra molecular C-H?N hydrogen bond occurs in each mol-ecule. The two mol-ecules are linked by a bifurcated N-H?(O,N) hydrogen bond involving the NH group in mol ecule A as donor. They are further linked into a ribbon along the a-axis direction by further bifurcated N-H?(O,N) hydrogen bonds involving the NH group in mol-ecule B as donor. C-H?O inter-actions are also observed. PMID- 26029396 TI - Crystal structure of {2,2'-[N,N'-bis-(pyridin-2-yl-meth-yl)cyclo-hexane-trans-1,2 diyldi(nitrilo)]di-acetato}-cobalt(III) hexa-fluorido-phosphate. AB - The title compound [Co(C22H26N4O4)]PF6, commonly known as [Co(bpcd)]PF6, where bpcd(2-) is derived from the historical ligand name N,N'-bis-(2-pyridyl-meth-yl) trans-1,2-di-amino-cyclo-hexane-N,N'-di-acetate, crystallized by slow evaporation of a saturated aceto-nitrile solution in air. The cation of the hexa-fluorido phosphate salt has the Co(III) atom in a distorted octa-hedral coordination geometry provided by an N4O2 donor atom set. The acetate groups, which are oriented trans with respect to each other, exhibit monodentate coordination whereas the pyridyl N atoms are coordinating in a cis configuration. The geometry of the cation is compared to the geometries of other di-amino di-acetate complexes with Co(III). PMID- 26029397 TI - Crystal structure of (E)-2-{[(6-meth-oxy-1,3-benzo-thia-zol-2-yl)imino]-meth yl}phenol. AB - The title compound, C15H12N2O2S, crystallizes in the ortho-rhom-bic space group Pna21 , with two mol-ecules in the asymmetric unit (Z' = 2). Each mol-ecule consists of a 2-hy-droxy Schiff base moiety linked through a spacer to a 2-amino benzo-thia-zole moiety. Each mol-ecule contains an intra-molecular hydrogen bond between the -OH group and imine N atom, forming a six-membered ring. The two independent molecules are linked by a pair of C-H?O hydrogen bonds, forming dimers with an R (2) 2(20) ring motif. These dimers are further lined into sheets in the ab plane by weak inter-molecular C-H?N inter-actions. The structure was refined as an inversion twin. PMID- 26029398 TI - Structure cristalline de la triple molybdate Ag0.90Al1.06Co2.94(MoO4)5. AB - Silver(I) aluminiun tricobalt(II) penta-kis-[tetra-oxidomolybdate(VI)], Ag0.90Al1.06Co2.94(MoO4)5, was synthesized using a solid-state reaction at 845 K. The structure can be described as a three-dimensional framework formed from dimeric M 2O10 (M = Co/Al) and trimeric M 3O14 units linked to MoO4 tetra-hedra by sharing corners, with the cavities occupied by disordered Ag(+) cations. It is shown that the Co and Al atoms occupy common positions with different occupancies. The Ag(+) cations are located at two different sites with occupancies of 0.486 (1) and 0.408 (1). The title coumpond is isotypic with NaMg3Al(MoO4)5 and NaFe4(MoO4)5. Differences and similarities with other related structures are discussed. PMID- 26029399 TI - Crystal structures of {[Cu(Lpn)2][Fe(CN)5(NO)].H2O} n and {[Cu(Lpn)2]3[Cr(CN)6]2.5H2O} n [where Lpn = (R)-propane-1,2-di-amine]: two heterometallic chiral cyanide-bridged coordination polymers. AB - The title compounds, catena-poly[[[bis-[(R)-propane-1,2-di-amine-kappa(2) N,N']copper(II)]-MU-cyanido-kappa(2) N:C-[tris-(cyanido-kappaC)(nitroso kappaN)iron(III)]-MU-cyanido-kappa(2) C:N] monohydrate], {[Cu(Lpn)2][Fe(CN)5(NO)].H2O} n , (I), and poly[[hexa-MU-cyanido-kappa(12) C:N hexa-cyanido-kappa(6) C-hexa-kis-[(R)-propane-1,2-di-amine-kappa(2) N,N']dichromium(III)tricopper(II)] penta-hydrate], {[Cu(Lpn)2]3[Cr(CN)6]2.5H2O} n , (II) [where Lpn = (R)-propane-1,2-di-amine, C3H10N2], are new chiral cyanide bridged bimetallic coordination polymers. The asymmetric unit of compound (I) is composed of two independent cation-anion units of {[Cu(Lpn)2][Fe(CN)5)(NO)]} and two water mol-ecules. The Fe(III) atoms have distorted octa-hedral geometries, while the Cu(II) atoms can be considered to be penta-coordinate. In the crystal, however, the units align to form zigzag cyanide-bridged chains propagating along [101]. Hence, the Cu(II) atoms have distorted octa-hedral coordination spheres with extremely long semicoordination Cu-N(cyanido) bridging bonds. The chains are linked by O-H?N and N-H?N hydrogen bonds, forming two-dimensional networks parallel to (010), and the networks are linked via N-H?O and N-H?N hydrogen bonds, forming a three-dimensional framework. Compound (II) is a two-dimensional cyanide-bridged coordination polymer. The asymmetric unit is composed of two chiral {[Cu(Lpn)2][Cr(CN)6]}(-) anions bridged by a chiral [Cu(Lpn)2](2+) cation and five water mol-ecules of crystallization. Both the Cr(III) atoms and the central Cu(II) atom have distorted octa-hedral geometries. The coordination spheres of the outer Cu(II) atoms of the asymmetric unit can be considered to be penta-coordinate. In the crystal, these units are bridged by long semicoordination Cu-N(cyanide) bridging bonds forming a two-dimensional network, hence these Cu(II) atoms now have distorted octa-hedral geometries. The networks, which lie parallel to (10-1), are linked via O-H?O, O-H?N, N-H?O and N-H?N hydrogen bonds involving all five non-coordinating water mol-ecules, the cyanide N atoms and the NH2 groups of the Lpn ligands, forming a three-dimensional framework. PMID- 26029400 TI - Crystal structure of ruthenocenecarbo-nitrile. AB - The mol-ecular structure of ruthenocenecarbo-nitrile, [Ru(eta(5)-C5H4C N)(eta(5) C5H5)], exhibits point group symmetry m, with the mirror plane bis-ecting the mol ecule through the C N substituent. The Ru(II) atom is slightly shifted from the eta(5)-C5H4 centroid towards the C N substituent. In the crystal, mol-ecules are arranged in columns parallel to [100]. One-dimensional inter-molecular pi-pi inter-actions [3.363 (3) A] between the C N carbon atom and one carbon of the cyclo-penta-dienyl ring of the overlaying mol-ecule are present. PMID- 26029401 TI - Crystal structure of catena-poly[[aqua-bis-(4-formyl-benzoato)-kappa(2) O (1),O (1');kappaO (1)-zinc]-MU-pyrazine-kappa(2) N:N']. AB - The asymmetric unit of the title polymeric compound, [Zn(C8H5O3)2(C4H4N2)(H2O)] n , contains two mol-ecular units. Each unit comprises two 4-formyl-benzoate (FB) anions, one pyrazine mol-ecule and one coordinating water mol-ecule; the FB anions act either as bidentate or as monodentate ligands. The O atoms of the bidentately coordinating FB anions are disordered over two positions, and they were refined with fixed occupancy ratios of 0.75:0.25 and 0.70:0.30, respectively. In the ordered monodentately coordinating FB anions, the carboxyl ate groups are twisted away from the attached benzene rings (B and E) by 12.1 (2) and 9.2 (2) degrees , respectively. In the disordered FB anions, the corresponding angles are 14.1 (1) and 4.0 (2) degrees for benzene rings A and D, respectively. Benzene rings A and B are oriented at a dihedral angle of 45.7 (1) degrees , D and E at 23.2 (1) degrees . Pyrazine ring C makes dihedral angles of 85.6 (1) and 72.7 (1) degrees , respectively, with benzene rings A and B, and pyrazine ring F makes dihedral angles of 87.0 (1) and 81.3 (1) degrees with benzene rings D and E, respectively. The pyrazine ligands bridge the Zn(II) cations, forming polymeric chains running parallel to the b-axis direction. Medium-strength intra-molecular O-H?O hydrogen bonds link the water mol-ecules to the carboxyl-ate O atoms. In the crystal, water-carboxyl-ate O-H?O hydrogen bonds link adjacent chains into layers parallel to the bc plane. The layers are linked via weak pyrazine-formyl C-H?O and form-yl-carboxyl-ate C-H?O hydrogen bonds. pi pi contacts between the benzene rings, with centroid-to-centroid distances of 3.7765 (16), 3.7905 (15) and 3.8231 (16) A, may further stabilize the structure. There are also weak C-H?pi inter-actions present. PMID- 26029402 TI - The crystal structures of three clozapinium salts: different mol-ecular configurations, and supra-molecular assembly in one, two and three dimensions. AB - The structures of three salts derived from clozapine, 8-chloro-11-(4-methyl piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, are reported, namely, clo-za-pin ium 3,5-di-nitro-benzoate dimethyl sulfoxide monosolvate, C18H20ClN4 (+).C7H3N2O6 (-).C2H6OS, (I), where the dimethyl sulfoxide component is disordered over two sets of atomic sites having occupancies 0.627 (2) and 0.373 (2); clo-za-pin-ium hydrogen maleate 0.21-hydrate, C18H20ClN4 (+).C4H3O4 (-).0.21H2O, (II), and clozapinium 2-hy-droxy-benzoate, C18H20ClN4 (+).C7H5O3 (-), (III). In all three salts, the protonation site is the methyl-ated N atom of the piperazine ring, and the dimensions and conformations of the fused tricyclic system are very similar. However, differences are apparent in the piperazine component: in both compounds (II) and (III), the unprotonated N atom of this ring has a pyramidal geometry, but in compound (I) this atom has a planar geometry. In compound (III), both N substituents in this ring occupy equatorial sites, but in compound (II) the fused tricyclic system occupies an axial site of the piperazine ring. The independent components of compound (I) are linked within the selected asymmetric unit by a combination of N-H?O and C-H?O hydrogen bonds, and these hydrogen-bonded aggregates are linked into chains by an aromatic pi-pi stacking inter-action. In compound (II), the components are linked into sheets by a combination of O-H?O, N H?O and C-H?O hydrogen bonds, and in compound (III), a combination of N-H?O, C H?O and C-H?N hydrogen bonds links the components into a three-dimensional framework structure. Comparisons are made with some similar compounds. PMID- 26029403 TI - Crystal structures of 2-(4-nitro-phen-yl)-3-phenyl-2,3-di-hydro-4H-1,3-benzo-thia zin-4-one and 2-(2-nitro-phen-yl)-3-phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4 one. AB - The crystal structures are reported of the isomeric compounds 2-(4-nitro-phen-yl) 3-phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one, (I), and 2-(2-nitro-phen-yl)-3 phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one, (II), both C20H14N2O3S, being the para-nitro and ortho-nitro forms, respectively, the meta-form of which is known [Yennawar et al. (2013). Acta Cryst. E69, o1679]. The six-membered thia zone ring fused with a benzene ring displays a screw-boat conformation with a total puckering amplitude of 0.627 (1) A in (I), and a near screw-boat conformation with a total puckering amplitude of 0.600 (1) A in (II). The dihedral angles between the planes of the substituent nitrophenyl and phenyl and rings with the benzene ring of the parent benzo-thia-zone moiety are 75.93 (5) and 82.61 (5) degrees [in (I)], and 76.79 (6) and 71.66 (6) degrees [in (II)]. Weak inter-molecular C-H?O hydrogen-bonding inter-actions between aromatic H-atom donors and both a nitro-O atom and a thia-zone O-atom acceptor in (I) and a thia zone O atom in (II) are present, forming in (I) a centrosymmetric 22-membered cyclic dimer which is extended through a similar inversion-related 14-membered cyclic hydrogen-bonding association into a zigzag chain structure extending along c. In (II), a single inter-molecular C-H?O hydrogen bond gives a chain structure extending along b. In addition, weak C-H?pi inter-actions are present in both structures [minimum C?ring-centroid separations = 3.630 (2) and 3.581 (2) A, respectively]. PMID- 26029407 TI - Crystal structure of (E)-2-[(2-hy-droxy-4-meth-oxy-phen-yl)(phen-yl)methyl-idene] N-phenyl-hydrazine-1-carboxamide. AB - The title compound, C21H19N3O3, has an E conformation about the azomethine double bond. The central moiety of the hydrazinecarboxamide moiety [-N-N-C(=O)-N-] has an almost coplanar arrangement [maximum deviation for the C atom = 0.010 (2) A]. This central moiety is flanked by three aromatic rings and its mean plane makes dihedral angles of 24.7 (1), 72.91 (12) and 34.26 (11) A, respectively, with the phenolic ring, the phenyl ring attached to the same C atom as the phenolic ring, and the phenyl-hydrazine ring. The adjacent phenolic and phenyl rings are twisted away from each other to reduce steric hindrance and make a dihedral angle of 80.59 (12) degrees . The phenolic and phenyl-hydrazine rings are inclined to one another by 28.89 (11) degrees . The rigidity of the mol-ecule is increased by an intra-molecular O-H?N hydrogen bond involving the phenolic hydrogen and the azomethine N atom. In the crystal, the carbonyl O atom forms bifurcated hydrogen bonds with the two NH atoms of the hydrazinic group, leading to the formation of chains propagating along [001]. Within the chains there are also C-H?O hydrogen bonds present. The chains are linked via C=O?pi [3.4316 (18) A] and parallel slipped pi-pi inter-actions, involving inversion-related benzene rings [centroid centroid distance = 3.8850 (14) A; inter-planar distance = 3.3895 (10) A; slippage = 1.899 A], forming sheets lying parallel to (100). PMID- 26029410 TI - Crystal structure of bis-(di-methyl-ammonium) hexa-aqua-cobalt(II) bis-(sulfate) dihydrate. AB - The title salt, (C2H8N)2[Co(H2O)6)](SO4)2.2H2O, is isotypic with (C2H8N)2[Ni(H2O)6)](SO4)2.2H2O. The Co-O bond lengths in the [Co(H2O)6](2+) complex cation show very similar distances as in the related Tutton salt (NH4)2[Co(H2O)6)](SO4)2 [average 2.093 (17) A], but are significantly longer than in the isotypic Ni(II) compound (Deltad ? 0.04 A). The cobalt cation reaches an overall bond-valence sum of 1.97 valence units. The S-O distances are nearly equal, ranging from 1.454 (4) to 1.470 (3) A [mean 1.465 (12) A]; however, the O S-O angles vary clearly from 108.1 (2) to 110.2 (2) degrees [average bond angle 109.5 (9) degrees ]. The non-coordinating water mol-ecules and di-methyl-ammonium cations connect the sulfate tetrahedra and the [Co(H2O)6](2+) octa-hedron via O H?O and N-H?O hydrogen bonds of weak up to medium strength into a three dimensional framework whereby the complex metal cations and sulfate anions are arranged in sheets parallel to (001). PMID- 26029405 TI - Crystal structure of (E)-N-[(2-chloro-6-meth-oxy-quinolin-3-yl)methyl-idene]-9 ethyl-9H-carbazol-3-amine. AB - In the title compound, C25H20ClN3O, the C=N bond of the central imine group adopts an E conformation. The mean planes through the essentially planar carbazole [maximum deviation = 0.052 (2)A] and quinoline [maximum deviation = 0.050 (2) A] ring systems form a dihedral angle of 50.2 (1) degrees . In the crystal, mol-ecules are linked by C-H?pi and pi-pi inter-actions [centroid centroid distances ranging from 3.635 (2) to 3.739 (2) A], forming a three dimensional supra-molecular network. PMID- 26029404 TI - Crystal structure of (E)-N-(3,3-di-phenyl-allyl-idene)-9-ethyl-9H-carbazol-3 amine. AB - In the title compound, C29H24N2, the C=N bond of the central imine group adopts an E conformation. The dihedral angles between the mean plane of the essentially planar carbazole ring system [r.m.s. deviation = 0.039 (2) A] and the two phenyl rings of the 3,3-di-phenyl-allyl-idene unit are 75.9 (1) and 64.6 (1) degrees . In the crystal, mol-ecules are linked by C-H?pi inter-actions, forming a three dimensional supra-molecular network. PMID- 26029408 TI - Crystal structure of hepta-kis-(2,6-di-methyl-phenyl isocyanide kappaC)vanadium(I) iodide. AB - The title salt, [V(C9H9N)7](+)I(-) or [V(CNX-yl)7](+)I(-) (Xyl is 2,6-di-methyl phen-yl), crystallized from tetra-hydro-furan at low temperatures after reacting (Et4N)(+)[V(CO)6](-), excess of CNXyl and iodine. The complex cation and the two crystallographically different iodide anions, each located on a different glide plane, are well separated in the crystal structure. The V(CN)7 core of the cation has the form of a distorted monocapped trigonal prism. This compound is of inter est as the first isolable homoleptic seven-coordinate vanadium analog of the 18 electron [V(CO)7](+) monocation. PMID- 26029412 TI - Crystal structure of bis-(4-acetyl-pyridine-kappaN)bis-(ethanol-kappaO)bis-(thio cyanato-kappaN)manganese(II). AB - In the crystal structure of the title compound, [Mn(NCS)2(C7H7NO)2(C2H5OH)2], the Mn(II) atom is coordin-ated by two N-bonded thio-cyanate anions, two 4-acetyl pyridine ligands, and two ethanol mol-ecules within a slightly distorted octa hedron. The asymmetric unit consits of one manganese cation, located on a centre of inversion, one thio-cyanate anion, one 4-acetyl-pyridine ligand and one ethanol mol-ecule in general positions. The discrete complexes are connected by inter-molecular O-H?O hydrogen bonds between the alcohol OH group and the carbonyl O atom into chains parallel to [011]. PMID- 26029409 TI - Crystal structure of di-chlorido-{2,6-bis-[(3-phenyl-1H-pyrazol-1-yl)meth yl]pyridine}cobalt(II). AB - In the title complex, [CoCl2(C25H21N5)], the Co(II) atom is coordinated by two Cl atoms and two N atoms, provided by a tridentate pyrazolylpyridyl ligand, forming a slightly distorted tetra-hedral geometry [range of angles: 96.51 (10) (chelate ring) to 118.60 (9) degrees ]. The dihedral angle between Cl/Co/Cl and N/Co/N planes is 86.83 (7) degrees . The chelate ring has the conformation of a distorted boat. The dihedral angle between pyridyl ring and the coordinated pyrazolyl ring is 56.16 (12) degrees . The uncoordinated pyrazolyl ring is almost perpendicular to the pyridyl ring with the dihedral angle of 87.49 (10) degrees . In the crystal packing, inter-molecular phenyl-C-H ?pi(pyrid-yl) inter-actions generate dimeric aggregates. These are connected into a zigzag supra-molecular chain along the c-axis direction via pi-pi inter-actions [inter-centroid distance between pyridyl and phenyl rings = 3.664 (2) A]. PMID- 26029411 TI - Crystal structure of catena-poly[[silver(I)-{MU-2,6-bis-[(1H-pyrazol-1-yl)meth yl]pyridine-kappa(3) N (1),N (2):N (2')}] nitrate]. AB - In the title complex, {[Ag(C13H13N5)]NO3} n , the Ag(I) atom is coordinated by three N atoms from two bidentate/monodentate pyrazolylpyridyl ligands to form a distorted trigonal-planar geometry [range of angles: 83.34 (6) (chelate ring) to 139.15 (7) degrees ]. The chelate ring has a distorted boat conformation. The dihedral angle between the pyridyl ring and the coordinating pyrazolyl ring is 67.22 (6) degrees . The non-coordinating pyrazolyl ring is twisted by 62.97 (7) degrees from the pyridyl ring. In the crystal, the complex cations are arranged in polymeric chains along the c-axis direction, with the nitrate counter-anions situated in between. Weak C-H?O hydrogen bonds link the ions into a three dimensional network. PMID- 26029413 TI - Crystal structure of trans-dihydrido-bis[tris-(di-methyl-amino)-phosphane kappaP]platinum(II). AB - The mol-ecule of the title compound, [PtH2(C6H18N3P)2], has a centrosymmetric square-planar structure in which the Pt(II) atom is bonded to two H and two P atoms in a mutually trans configuration. The Pt(II) atom sits on an inversion center and thus the asymmetric unit contains only half the mol-ecule. The Pt-P and Pt-H distances are 2.2574 (10) and 1.49 (7) A, respectively. PMID- 26029414 TI - Crystal structure of aqua-bis-[2-(1H-benzimidazol-2-yl-kappaN (3))aniline kappaN]zinc dinitrate. AB - The cation of the complex title salt, [Zn(C13H11N3)2(H2O)](NO3)2, lies about a twofold rotation axis, which passes through the Zn(II) atom and the O atom of the aqua ligand. The Zn(II) atom adopts a distorted trigonal-bipyramidal geometry defined by two N atoms in axial positions [angle = 166.24 (7) degrees ], and two N and one O atom in the equatorial plane [range of angles: 115.17 (7)-122.42 (3) degrees ]. The dihedral angle between the imidazole and aniline rings is 23.86 (5) degrees . In the crystal, N-H?O and O-H?O hydrogen bonds link the components into a three-dimensional network. PMID- 26029406 TI - Crystal structure of (2E)-1-(4-hy-droxy-1-methyl-2-oxo-1,2-di-hydro-quinolin-3 yl)-3-(4-hy-droxy-3-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C20H17NO5, the dihedral angle between the mean plane of the di-hydro-quinoline ring system (r.m.s. deviation = 0.003 A) and the benzene ring is 1.83 (11) degrees . The almost planar conformation is a consequence of an intra-molecular O-H?O hydrogen bond and the E configuration about the central C=C bond. In the crystal structure, O-H?O hydrogen bonds generate chains of mol ecules along the [10-1] direction. These chains are linked via pi-pi inter actions [inter-centroid distances are in the range 3.6410 (16)-3.8663 (17) A]. PMID- 26029415 TI - Crystal structure of bromido-nitro-syl-bis(tri-phenyl-phosphane kappaP)nickel(II). AB - The asymmetric unit of the title complex, [NiBr(NO){P(C6H5)3}2], comprises two independent mol-ecules each with a similar configuration. The Ni(II) cation is coordinated by one bromide anion, one nitrosyl anion and two tri-phenyl-phosphane mol-ecules in a distorted BrNP2 tetra-hedral coordination geometry. The coordination of the nitrosyl group is non-linear, the Ni-N-O angles being 150.2 (5) and 151.2 (5) degrees in the two independent mol-ecules. In the crystal, mol ecules are linked by weak C-H?Br hydrogen bonds and weak C-H?pi inter-actions into a three-dimensional supra-molecular architecture. PMID- 26029416 TI - Crystal structure of tris-[MU2-bis-(di-phenyl-phosphan-yl)methane-kappa(2) P:P']di-MU3-bromido-tris-ilver(I) bromide-N,N'-phenyl-thio-urea (1/1). AB - The title complex, [Ag3Br2(C25H22P2)3]Br.C7H8N2S, comprises a trinuclear [Ag3Br2(C25H22P2)3](+) unit, a Br(-) anion and one N,N'-di-methyl-thio-urea mol ecule (ptu). Three Ag(I) ions are linked via two MU3-bridging Br atoms, leading to a distorted triangular bipyramid with an Ag?Ag separation range of 3.1046 (6) 3.3556 (6) A. The triangular Ag3 arrangement is stabilized by six P atoms from three chelating bis-(di-phenyl-phosphan-yl)methane (dppm) ligands. The Ag(I) ion presents a distorted tetra-hedral coordination geometry. In the crystal, the bromide anion is connected to the ptu mol-ecule through N-H?Br hydrogen bonds [graph-set motif R 2 (1)(6)]. Each bromide/ptu aggregate links the complex ion via C-H?S and C-H?Br hydrogen bonds, leading to the formation of a three dimensional network. Two phenyl rings from two dppm ligands were modelled as disordered over two sites. PMID- 26029417 TI - Crystal structure of catena-poly[[di-aqua-cadmium(II)]-MU-3,3'-(1,3-phenyl ene)diacrylato]. AB - In the crystal of the title polymeric complex, [Cd(C12H8O4)(H2O)2] n , the Cd(II) cation, located on a twofold rotation axis, is coordinated by two water mol ecules and chelated by two phenyl-enediacrylate anions (mpda) in a distorted octa hedral geometry. The mpda anions bridge the Cd(II) cations, forming helical chains propagating along the c-axis direction. The mpba anion has twofold symmetry with two benzene C atoms located on the twofold rotation axis. In the crystal, O-H?O hydrogen bonds link the polymeric helical chains into a three dimensional supra-molecular architecture. PMID- 26029418 TI - Crystal structure of bis-{(Z)-(benzyl-amino)[(5Z)-2-(benzyl-imino-kappaN)-5-(2 meth-oxy-2-oxo-ethyl-idene)-4-oxo-thio-lan-3-yl-idene]methane-thiol-ato kappaS}copper(II). AB - The title complex, [Cu(C22H19N2O3S2)2], was obtained from the reaction between (Z)-methyl 2-(5-benzyl-imino-4-benzyl-carbamo-thioyl-3-oxo-thio-lan-2-yl idene)acetate and Cu(NO3)2. The Cu(II) atom is tetra-coordinated by two N,S bidentate ligands, forming a highly distorted tetra-hedral environment. The structure displays two intra-molecular N-H?O hydrogen bonds. PMID- 26029419 TI - Crystal structure of a binuclear nickel(II) complex constructed of 1H-imidazo[4,5 f][1,10]phenanthroline and doubly deprotonated benzene-1,3,5-tri-carb-oxy-lic acid. AB - The title complex, [Ni2(C9H4O6)2(C13H8N4)2(H2O)4].2H2O, bis-(MU-5-carb-oxy benzene-1,3-di-carboxyl-ato-kappa(2) O (1):O (1'))bis-[di-aqua(1H-imidazo[4,5 f][1,10]phenanthroline-kappa(2) N (7),N (8))nickel(II)] di-hydrate, was obtained under solvothermal conditions by the reaction of benzene-1,3,5-tricarboxylic acid (H3BTC) with Ni(NO3)2 in the presence of 1H-imidazo[4,5-f][1,10]phenanthroline (IP). The crystal has triclinic (P-1) symmetry with a centrosymmetric binuclear nickel(II) cluster. The Ni(II) atom is coordinated by two N atoms from a chelating 1H-imidazo[4,5-f][1,10]phenanthroline ligand, two carboxyl-ate O atoms from two 5-carb-oxy-benzene-1,3-di-carboxyl-ate ligands and two water mol-ecules in a slightly distorted octa-hedral geometry. Two carboxyl-ate groups bridge two Ni(II) cations, forming the binuclear complex. Extensive N-H?O, O-H?O and O-H?N hydrogen bonding is present in the crystal structure, forming a three-dimensional supermolecular framework. Weak pi-pi stacking is observed between parallel HBTC(2 ) and IP ring systems, the face-to-face separation being 3.695 (2) A. PMID- 26029420 TI - Crystal structure of MU-oxido-1,1'kappa(2) O:O-bis{tetra-MU-oxido-1:2kappa(2) O:O;1:3kappa(2) O:O;2:3kappa(4) O:O-tris[1,2,3(eta(5))-penta-methyl-cyclo-penta dien-yl]-trianglo-trititanium(IV)}. AB - The title polynuclear organometallic titanium(IV) oxide, [{Ti3(eta(5)-C5Me5)3(MU O)4}2(MU-O)], exhibits two Ti3O4 cores bridged by an O atom located on a twofold axis. All metal centres present the typical three-legged piano-stool coordination environment, where one site is occupied by a penta-methyl-cyclo-penta-dienyl ligand linked in an eta(5)-coordination fashion, while three bridging O atoms fill the other three sites. PMID- 26029421 TI - Crystal structure of {bis-[2-(3,5-di-methyl-pyrazol-1-yl-kappaN (2))eth-yl]amine kappaN}chlorido-platinum(II) chloride dihydrate. AB - The title complex, [PtCl(C14H23N5)]Cl.2H2O, is isomorphous with the Pd(II) compound characterized previously [Mendoza, Bernes & Mendoza-Diaz (2006 ?). Acta Cryst. E62, m2934-m2936]. The angle between pyrazole mean planes in the main ligand is 88.3 (4) degrees , similar to that observed in the Pd(II) analogue [87.62 (11) degrees ]. This tridentate ligand adopts a conformation approximating a twofold symmetry, allowing its coordination to the metal atom, together with a chloride ligand, in an almost perfect square-planar geometry. A chloride anion and two water mol-ecules in the asymmetric unit form a hydrogen-bonded network connected to the complex mol-ecules in the crystal via the NH amine groups, forming chains along [100]. PMID- 26029422 TI - Crystal structure of 4-azido-methyl-6-tert-butyl-2H-chromen-2-one. AB - In the title compound, C14H15N3O2, one of the methyl C atoms of the tert-butyl group lies almost in the plane of the chromene ring system [deviation = -0.097 (2) A], one lies above and one lies below [deviations = 1.460 (3) and 1.006 (3) A, respectively]. The C-C-N-N torsion angle is 142.33 (17) degrees . In the crystal, moelcules are linked by weak C-H?O hydrogen bonds to generate C(6) chains propagating in the [010] direction. PMID- 26029424 TI - Crystal structure of 7-[(2E)-2-benzyl-idene-3-oxobut-oxy]-4-methyl-2H-chromen-2 one. AB - Two independent mol-ecules (A and B) comprise the asymmetric unit of the title compound, C21H18O4. There are significant conformational differences between the mol-ecules relating in particular to the relative orientation of the 3-oxo-2 (phenyl-methyl-idene)but-oxy substituent with respect to the superimposable chromen-2-one residues. To a first approximation, the substituents are mirror images; both are approximately perpendicular to the chromen-2-one fused ring system with dihedral angles of 88.50 (7) (A) and 81.96 (7) degrees (B). Another difference between the independent mol-ecules is noted in the dihedral angles between the adjacent phenyl and but-3-en-2-one groups of 8.72 (12) (A) and 27.70 (10) degrees (B). The conformation about the ethene bond in both mol-ecules is E. The crystal packing features C-H?O, C-H?pi(ar-yl) and pi-pi [Cg?Cg = 3.6657 (8) and 3.7778 (8) A] stacking inter-actions, which generate a three-dimensional network. PMID- 26029423 TI - Crystal structure of (S)-5,7-diphenyl-4,7-di-hydro-tetra-zolo[1,5-a]pyrimidine. AB - The title compound, C16H13N5, was synthesized by coupling amino-tetra-zole with chalcone in the presence of an amine organocatalyst derived from chincona alkaloid. There are two mol-ecules, A and B, in the asymmetric unit. In mol-ecule A, the dihedral angles between the partly hydrogenated pyrimidine ring system (r.m.s. deviation = 0.056 A) and the sp (2)- and sp (3)-bonded phenyl groups are 33.32 (11) and 86.53 (11) degrees , respectively. The equivalent data for mol ecule B are 0.049 A, and 27.05 (10) and 85.27 (11) degrees , respectively. In the crystal, A+B dimers linked by pairs of N-H?N hydrogen bonds generate R 2 (2)(8) loops. The dimers are linked by aromatic pi-pi stacking inter-actions [shortest centroid-centroid separation = 3.5367 (15) A], which results in a three dimensional network. PMID- 26029425 TI - Crystal structure of 3-mesityl-1-[(pyridin-2-yl)meth-yl]-3,4,5,6-tetra-hydro pyrim-idin-1-ium bromide monohydrate. AB - In the title hydrated salt, C19H24N3 (+).Br(-).H2O, the values of the N-C bond lengths within the tetra-hydro-pyrimidinium ring indicate delocalization of the N=C double bond. In the cation, the dihedral angle formed by the pyridine and benzene rings is 14.97 (12) degrees . In the crystal, ions and water mol-ecules are linked by O-H?Br, O-H?N, C-H?Br and C-H?O hydrogen bonds into chains running parallel to the b axis. PMID- 26029426 TI - Crystal structure of 4-meth-oxy-N-[(pyrrolidin-1-yl)carbo-thio-yl]benzamide. AB - In the title compound, C13H16N2O2S, the pyrrolidine ring has a twisted conformation on the central -CH2-CH2- bond. Its mean plane is inclined to the 4 meth-oxy-benzoyl ring by 72.79 (15) degrees . In the crystal, mol-ecules are linked by N-H?O and C-H?O hydrogen bonds to the same O-atom acceptor, forming chains along [001]. The chains are linked via slipped parallel pi-pi inter actions [inter-centroid distance = 3.7578 (13) A], forming undulating slabs parallel to (100). PMID- 26029427 TI - Crystal structure of 4-azido-methyl-6-isopropyl-2H-chromen-2-one. AB - In the title mol-ecule, C13H13N3O2, the benzo-pyran ring system is essentially planar, with a maximum deviation of 0.017 (1) A. In the crystal, weak C-H?O hydrogen bonds link mol-ecules into ladders along [010]. In addition, pi-pi inter actions between inversion-related mol-ecules, with centroid-centroid distances in the range 3.679 (2)-3.876 (2) A, complete a two-dimensional network parallel to (001). PMID- 26029428 TI - Crystal structure of 2-(4-fluoro-3-methyl-phen-yl)-5-{[(naphthalen-1-yl)-oxy]meth yl}-1,3,4-oxa-diazole. AB - The title compound, C20H15FN2O2, adopts an almost planar conformation. The oxa diazole ring makes dihedral angles of 13.90 (1) and 7.93 (1) degrees with the naphthalene ring system and benzene ring, respectively, while the naphthalene ring system and benzene ring are inclined to one another by 6.35 (1) degrees . In the crystal, adjacent mol-ecules are linked via C-H?N hydrogen bonds, forming chains propagating along [100]. There are also pi-pi inter-actions present [inter centroid distances = 3.5754 (9) and 3.7191 (12) A], linking the chains to form ribbons lying parallel to (011). PMID- 26029429 TI - Crystal structure of 2-{[1-(4-bromo-benz-yl)-1H-1,2,3-triazol-4-yl]meth-oxy}naph thalene-1,4-dione. AB - In the title compound, C20H14BrN3O3, the benzene ring makes dihedral angles of 71.30 (11) and 68.95 (14) degrees with the naphthalene ring system and the triazole ring, respectively. The latter two ring systems are coplanar, with a dihedral angle of 2.92 (12) degrees . The O atoms deviate from the naphthalene ring system by 0.029 (2) and -0.051 (2) A. In the crystal, mol-ecules are linked by C-H?O and C-H?N hydrogen bonds, forming ribbons parallel to (10-1). The ribbons are linked via C-H?O and pi-pi stacking inter-actions [centroid-centroid distance = 3.4451 (14) A], forming slabs parallel to the bc plane. PMID- 26029430 TI - Crystal structure of benzyl 3-(3-methyl-phen-yl)di-thio-carbazate. AB - In the title compound, C15H16N2S2, the central CN2S2 residue is almost planar (r.m.s. deviation = 0.0354 A) and forms dihedral angles of 56.02 (4) and 75.52 (4) degrees with the phenyl and tolyl rings, respectively; the dihedral angle between the aromatic rings is 81.72 (5) degrees . The conformation about the N-N bond is gauche [C-N-N-C = -117.48 (15) degrees ]. Overall, the mol-ecule has the shape of the letter L. In the crystal packing, supra-molecular chains along the a axis are formed by N-H?S(thione) hydrogen bonds whereby the thione S atom accepts two such bonds. The hydrogen bonding leads to alternating edge-shared eight membered {?HNCS}2 and 10-membered {?HNNH?S}2 synthons. The chains are connected into layers by phen-yl-tolyl C-H?pi inter-actions; the layers stack along the c axis with no specific inter-actions between them. PMID- 26029431 TI - Crystal structure of N-[(2-hy-droxy-naphthalen-1-yl)(4-methyl-phen-yl)meth yl]acetamide. AB - In the title mol-ecule, C20H19NO2, the naphthalene ring system subtends a dihedral angle of 82.50 (7) degrees with the benzene ring and an intra-molecular N-H?O hydrogen bond closes an S(6) ring. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, which generate C(8) chains propagating in the [010] direction. The crystal structure also features weak pi-pi inter-actions [centroid centroid separation = 3.7246 (10) A]. PMID- 26029433 TI - Crystal structure of (5'S,8'S)-3-(2,5-di-methyl-phen-yl)-8-meth-oxy-3-nitro-1-aza spiro-[4.5]decane-2,4-dione. AB - The title compound, C18H22N2O5, was synthesized by nitrification of its enol precursor. The pyrrolidine ring plane adopts a twisted conformation about the C-C bond linking the spiro centre and the C=O group remote from the N atom. It makes dihedral angles of 71.69 (9) and 88.92 (9) degrees , respectively, with the benzene ring plane and the plane defined by the four C atoms that form the seat of the of the cyclo-hexane chair. At the spiro centre, the NH group is axial and the C=O group is equatorial with respect to the cyclo-hexane ring. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R 2 (2)(8) loops. The dimers are linked by C-H?O inter-actions, generating a three dimensional network. PMID- 26029432 TI - Crystal structure of ethyl 2-(1H-benzimidazol-2-yl)-2-[2-(4-nitro-phen yl)hydrazinyl-idene]acetate. AB - The title compound, C17H15N5O4, was obtained via the condensation of 3-eth-oxy-2 [2-(4-nitro-phen-yl)hydrazono]-3-oxo-propanoic acid with 1,2-di-amino-benzene. In the mol-ecule, the dihedral angles between the acetate group and the two aromatic subunits (benzimidazole and nitro-phenyl-hydrazone) are 7.35 (9) and 18.23 (9) degrees , respectively. Intra-molecular N-H?O and N-H?N contacts occur. In the crystal, C-H?O and N-H?O hydrogen bonds link the mol-ecules into chains along the b-axis direction. PMID- 26029434 TI - The tripeptide N-Cbz-betaGly-Gly-Gly-Obz. AB - The title peptide, N-benzyl-oxycarbonyl-beta-glycylglycylglycine benzyl ester, C22H25N3O6, contains a non-proteinogenic amino acid residue, beta-glycine, which is a homologated analogue of glycine. In the mol-ecular structure, beta-glycine adopts an extended conformation with a trans conformation about its C(beta) C(alpha) bond. The second glycine residue adopts an extended conformation while the third glycine residue adopts a helical conformation. In the crystal, three N H?O hydrogen bonds, two involving the same carbonyl O atom as acceptor, results in an infinite two-dimensional network parallel to the bc plane. PMID- 26029435 TI - Crystal structure of 2-((1E)-{2-[bis-(2-methyl-benzyl-sulfan-yl)methyl idene]hydrazin-1-yl-idene}meth-yl)-6-meth-oxy-phenol. AB - In the title compound, C25H26N2O2S2, the central CN2S2 atoms are almost coplanar (r.m.s. deviation = 0.0058 A). One phenyl ring clearly lies to one side of the central plane, while the other is oriented in the plane but splayed. Despite the different relative orientations, the phenyl rings form similar dihedral angles of 64.90 (3) and 70.06 (3) degrees with the central plane, and 63.28 (4) degrees with each other. The benzene ring is twisted with respect to the central plane, forming a dihedral angle of 13.17 (7) degrees . The S2C=N, N-N and N-N=C bond lengths of 1.2919 (19), 1.4037 (17) and 1.2892 (19) A, respectively, suggest limited conjugation over these atoms; the configuration about the N-N=C bond is E. An intra-molecular O-H?N hydrogen bond is noted. In the crystal, phen-yl-meth oxy C-H?O and phen-yl-phenyl C-H?pi inter-actions lead to supra-molecular double chains parallel to the b axis. These are connected into a layer via meth-yl phenyl C-H?pi inter-actions, and layers stack along the a axis, being connected by weak pi-pi inter-actions between phenyl rings [inter-centroid distance = 3.9915 (9) A] so that a three-dimensional architecture ensues. PMID- 26029436 TI - Crystal structure of 2'-hy-droxy-aceto-phenone 4-methyl-thio-semicarbazide. AB - In the organic mol-ecule of the title hydrate, C11H15N3OS.H2O, {systematic name: 3-ethyl-1-{(E)-[1-(2-hy-droxy-phen-yl)ethyl-idene]amino}-thio-urea monohydrate}, a dihedral angle of 5.39 (2) degrees is formed between the hy-droxy-benzene ring and the non-H atoms comprising the side chain (r.m.s. deviation = 0.0625 A), with the major deviation from planarity noted for the terminal ethyl group [the C-N-C C torsion angle = -172.17 (13) degrees ]. The N-H H atoms are syn and an intra molecular hy-droxy-imine O-H?N hydrogen bond is noted. In the crystal, the N bonded H atoms form hydrogen bonds to symmetry-related water mol-ecules, and the latter form donor inter-actions with the hy-droxy O atom and with a hy-droxy benzene ring, forming a O-H?pi inter-action. The hydrogen bonding leads to supra molecular tubes aligned along the b axis. The tubes are connected into layers via C-H?O inter-actions, and these stack along the c axis with no directional inter actions between them. PMID- 26029437 TI - Crystal structure of 2,2-dimethyl-N-(pyridin-3-yl)propanamide. AB - In the title compound, C10H14N2O, the pyridine ring is inclined to the mean plane of the amide moiety [N-C(=O)C] by 17.60 (8) degrees . There is an intra-molecular C-H?O hydrogen bond present involving the carbonyl O atom. In the crystal, mol ecules are linked via N-H?N hydrogen bonds, forming chains propagating along [100]. The tert-butyl group is disordered over two sets of sites with a refined occupancy ratio of 0.758 (12):0.242 (12). PMID- 26029438 TI - Redetermination and absolute configuration of berkeleydione. AB - The crystal structure of the title compound, berkeleydione [systematic name; (5aS,7R,9S,11R,11aS)-methyl 9-hy-droxy-1,1,5,7,9,11a-hexa-methyl-14-methyl-idene 3,8,10-trioxo-1,3,4,5a,6,7,8,9,10,11,11a,12-dodeca-hydro-7,11-methano-cycloocta [4,5]cyclo-hepta-[1,2-c]pyran-11-carboxyl-ate], C26H32O7, has been reported previously [Stierle et al. (2004 ?). Org. Lett. 6, 1049-1052]. However, the absolute configuration could not be determined from the data collected with Mo Kalpha radiation and has now been determined by refinement of the Flack parameter with data collected using Cu Kalpha radiation. It is in agreement with the previous circular dichroism assignment, and the crystal packing is similar to that described previously. PMID- 26029439 TI - Crystal structure of 1-benzyl-sulfonyl-1,2,3,4-tetra-hydro-quinoline. AB - In the title compound, C16H17NO2S, the heterocyclic ring adopts a half-chair conformation and the bond-angle sum at the N atom is 354.6 degrees . The dihedral angle between the planes of the aromatic rings is 74.15 (10) degrees . In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, generating C(8) and C(4) chains propagating along [100] and [010], respectively, which together generate (001) sheets. PMID- 26029440 TI - Crystal structure of (2E,3E)-N (2),N (3)-bis-(3-ethyl-[1,1'-biphen-yl]-4 yl)butane-2,3-di-imine. AB - In the title compound, C32H32N2, synthesized by the con-densation reaction of 2 ethyl-4-phenyl-aniline and 2,3-butane-dione, the conformation about the C=N bonds is E and the substituted biphenyl units are trans to one another. In the two biphenyl ring systems, the planes of the two rings are inclined to one another by 25.25 (19) and 28.01 (19) degrees . The planes of the ethyl-substituted benzene rings are inclined to one another by 20.23 (19) degrees and to the mean plane of the butane-2,3-di-imine unit [maximum deviation = 0.014 (4) A] by 83.19 (19) and 63.38 (19) degrees . In the crystal, mol-ecules are linked by C-H?pi inter actions, forming sheets lying parallel to (101). PMID- 26029441 TI - Crystal structure of 3-methyl-pyridine-2-carbaldehyde 4-methyl-thio-semi-carba zone monohydrate. AB - In the title hydrate, C9H12N4S.H2O (systematic name: 3-methyl-1-{(E)-[(3-methyl pyridin-2-yl)methyl-idene]amino}-thio-urea monohydrate), a small twist is noted between the pyridine ring and the rest of the organic mol-ecule [dihedral angle = 6.96 (5) degrees ]. The imine and pyridine N atoms are syn, and the amine H atoms are anti. The latter arrangement allows for the formation of an intra-molecular N H?N(imine) hydrogen bond. Both the N-bonded H atoms form hydrogen bonds to symmetry-related water mol-ecules, and the latter forms O-H hydrogen bonds with the pyridine N and thione S atoms. These inter-actions lead to supra-molecular layers that stack along the a-axis direction with no specific inter-actions between them. PMID- 26029442 TI - Crystal structure of 3,3'-diisopropyl-1,1'-(pyridine-2,6-di-yl)bis-[1H-imidazole 2(3H)-thione]. AB - In the title compound, C17H21N5S2, the dihedral angles between the central pyridine ring and its pendant imidazole rings are 29.40 (9) and 40.77 (9) degrees ; the pendant rings are twisted in an opposite sense with respect to the central ring. In each case, the S atom is approximately anti to the N atom of the pyridine ring. For both substituents, the H atom attached to the central C atom of the isopropyl group is approximately syn to the S atom in the attached ring. In the crystal, mol-ecules are linked by weak C-H?S inter-actions, generating C(5) chains propagating along [001]. PMID- 26029443 TI - Crystal structure of ethyl 2-cyano-3-[(1-eth-oxy-ethyl-idene)amino]-5-(3-meth-oxy phen-yl)-7-methyl-5H-1,3-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate. AB - In the title compound, C22H24N4O4S, the central pyrimidine ring adopts a sofa conformation with the ring-junction N atom displaced by 0.2358 (6) A from the mean plane of the remaining ring atoms. The 3-meth-oxy-phenyl ring, at the chiral C atom opposite the other N atom, is positioned axially and is inclined to the thia-zolo-pyrimidine ring with a dihedral angle of 83.88 (7) degrees . The thia zole ring is essentially planar (r.m.s. deviation = 0.0034 A). In the crystal, pairs of weak C-H?O hydrogen bonds link mol-ecules related by twofold rotation axes to form R 2 (2)(8) rings, which in turn are linked by weak C-H?N inter actions, forming ribbons along [-110]. In addition, pi-pi stacking inter-actions [centroid-centroid distance = 3.5744 (15) A] connect the ribbons, forming slabs lying parallel to (001). PMID- 26029444 TI - Crystal structure of 2,3-bis-[(4-tert-butyl-2,6-di-methyl-phen-yl)imino]-butane. AB - The title compound, C28H40N2, was obtained from the condensation reaction of 4 tert-butyl-2,6-di-methyl-aniline and butane-2,3-dione. The mol-ecule lies on an inversion centre. The C=N bond has an E conformation. The plane of the benzene ring is almost perpendicular to the 1,4-di-aza-butadiene mean plane [dihedral angle = 89.8 (9) degrees ]. PMID- 26029445 TI - Crystal structure of diethyl 3,3'-{2,2'-(1E)-[1,4-phenyl-enebis(azan-1-yl-1-yl idene)]bis-(methan-1-yl-1-yl-idene)bis-(1H-pyrrole-2,1-di-yl)}di-propano-ate. AB - The complete mol-ecule of the title compound, C26H30N4O4, is generated by crystallographic inversion symmetry. The dihedral angle between the planes of the benzene and pyrrole rings is 45.20 (11) degrees ; the N atom bonded to the the benzene ring and the pyrrole N atom are in a syn conformation. The side chain adopts an extended conformation [N-C-C-C = 169.07 (17) degrees and C-O-C-C = 176.54 (17) degrees ]. No directional inter-actions could be identified in the crystal packing. PMID- 26029446 TI - Crystal structure of 8-hy-droxy-quinolin-ium 2-carboxy-6-nitro-benzoate mono hydrate. AB - In the title hydrated salt, C9H8NO(+).C8H4NO6 (-).H2O, the deprotonated carboxyl ate group is almost normal to its attached benzene ring [dihedral angle = 83.56 (8) degrees ], whereas the protonated carboxyl-ate group is close to parallel [dihedral angle = 24.56 (9) degrees ]. In the crystal, the components are linked by N-H?O and O-H?O hydrogen bonds, generating [001] chains. The packing is consolidated by C-H?O and pi-pi [centroid-to-centroid distances = 3.6408 (9) and 3.6507 (9) A] inter-actions, which result in a three-dimensional network. PMID- 26029447 TI - Crystal structure of (7-chloro-2-oxo-2H-chromen-4-yl)methyl N,N-di-methyl carbamodi-thio-ate. AB - In the title compound, C13H12Cl N O2S2, the 2H-chromene ring system is almost planar, with a maximum deviation of 0.005 (2) A. The packing features C-H?S hydrogen bonds and pi-pi inter-actions between fused benzene rings of chromene [shortest centroid-centroid distances = 3.6553 (13) and 3.5551 (13) A]. PMID- 26029448 TI - Crystal structure of S-octyl (E)-3-(4-meth-oxy-benzyl-idene)di-thio-carbazate. AB - As already observed in similar mol-ecules, the di-thio-carbazate group in the title compound, C17H26N2OS2, adopts an EE configuration with respect to the C=N bond of the benzyl-idene moiety. In the crystal, mol-ecules are connected into inversion dimers by pairs of N-H?S hydrogen bonds. The dimers are linked by weak pi-pi inter-actions, with centroid-to-centroid distances of 3.723 (11) A, forming chains parallel to [110]. PMID- 26029449 TI - Crystal structure of ethyl N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-di-hydro-1H-pyrazol 4-yl)carbamate. AB - In the title compound, C14H17N3O3, the dihedral angle between the benzene ring and the five-membered di-hydro-pyrazole ring is 52.26 (9) degrees . The ethyl ester group is approximately planar (r.m.s. deviation 0.0568 A) and subtends an angle 67.73 (8) degrees to the pyrazole ring. In the crystal, molecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(10) ring motif. Weaker C-H?O contacts link these dimers into a three dimensional network of mol-ecules stacked along the a-axis direction. Offset pi pi stacking inter-actions between the benzene rings [centroid-to-centroid distance = 3.8832 (12) A] further stabilize the crystal packing. PMID- 26029450 TI - Radiotherapy patterns of care in gastric adenocarcinoma: a single institution experience. AB - BACKGROUND: Gastric adenocarcinoma (GAC) is one of the most commonly diagnosed cancers worldwide. Two standard approaches for treatment of resectable GAC include adjuvant 5-fluorouracil-based chemoradiotherapy [per Intergroup 0116 (INT 0116) trial and perioperative epirubicin, cisplatin, fluorouracil (ECF) chemotherapy per Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial]. Controversy remains regarding the most appropriate treatment strategy to decrease recurrence rates and improve survival following surgery. The purpose of this study was to analyze how patterns of care for patients with GAC treated at Emory University Hospital changed following publication of the MAGIC trial in 2006. METHODS: We analyzed a prospectively maintained database of 150 patients who underwent resection for GAC between December 2000 and June 2013. Patients were divided into two cohorts, Early [2000 2006] and late [2007-2013]. The primary objective was to compare the number of patients assigned to adjuvant chemoradiotherapy (aCRT) vs. perioperative chemotherapy (PC) throughout the study period and secondarily assess for recurrence patterns and survival outcomes for patients assigned to those two strategies. RESULTS: Between 2000 and 2013, 124 patients received adjuvant therapy for GAC. Fifty-four patients were treated with PC and 70 patients with aCRT. The early cohort included 56 patients, and the late cohort included 94 patients. There was no statistical difference in the number of patients receiving aCRT between the Early and Late cohorts [n=23 (50%) vs. 35 (38%) respectively, P=0.21]. PC increased from 2 patients (3.6%) in the Early cohort to 32 patients (34%) in the Late cohort (P<0.001). Four-year overall survival (OS) was 32.6% for the Early cohort and 68.8% for the Late cohort (P=0.010). Overall recurrence rate was 25.3% with no significant difference in rates of recurrence seen between the Early and Late cohorts. CONCLUSIONS: PC has become more prevalent in patients treated at Emory following publication of the MAGIC trial in 2006. OS, but not recurrence rates, has also improved since publication. Although improved survival is suggestive of improved care, the question of optimal treatment regimen remains open. Further prospective comparisons of PC and aCRT are needed to identify patient and disease parameters that may guide therapy selection. PMID- 26029451 TI - Adjuvant intraoperative post-dissectional tumor bed chemotherapy-A novel approach in treating midgut neuroendocrine tumors. AB - BACKGROUND: Midgut neuroendocrine tumor (NET) patients are often diagnosed at an advanced stage with extensive mesenteric lymph node and liver metastasis. Even with skillful surgical dissection, macro and microscopic residual disease at the dissection site remains a possibility. We hypothesize these potential tumor residuals in mesenteric lymph node dissection beds can be eliminated safely by a local application of 5-fluorouracil (5-FU). We describe a novel technique invented by the author to treat these micro and macro residuals. METHODS: Retrospectively, charts of 62 consecutive midgut NET patients with boggy mesenteric lymphadenopathy who underwent cytoreductive debulking surgeries from 1/2007 to 12/2009 were reviewed. A total of 32 patients received an intraoperative application of 5-FU saturated gelfoam strips secured into the mesenteric defect following the extensive lymphadenectomy. A total of 30 untreated patients served as a control. RESULTS: The 5-year survival after cytoreductive surgeries was 22/32 (68.8%) for the treated group, vs. 20/30 (66.7%) for the control. Six patients (6/32, 18.8%) among the study group required additional debulking surgeries, vs. 16 patients (16/30, 53.3%) in the control group. Upon reoperation, loco-regional recurrence was noted in 9 of the 16 patients (56.3%) in the control group, vs. only 2/6 (33.3%) of treated patients. Overall, local recurrence rate is 6.25% (2/32) in the treated group vs. 30% (9/30) in the control group. Post-op complication rates are similar in the two arms. CONCLUSIONS: Intraoperative application of chemotherapy is a safe and effective adjuvant to reduce local recurrence and the need of reoperation by the tumoricidal or tumorstatic effects of 5-FU on any potential microscopic residual disease after extensive cytoreductive surgeries in advanced stage NET patients with mesenteric lymph node metastasis. It provides patients with sustained, slow releasing, high dose of 5-FU within the surgical bed with a negligible side effect profile. Further studies are required to evaluate its effect on long term survival. PMID- 26029452 TI - Comparative dosing and efficacy of sorafenib in hepatocellular cancer patients with varying liver dysfunction. AB - BACKGROUND: Sorafenib is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, dose reductions are often required, although there are limited efficacy data related to dose modifications. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib therapy in relation to dose and Child Pugh (CP) score. METHODS: A retrospective analysis was done of advanced HCC patients, starting sorafenib at 400 mg twice daily, or at physician discretion at 400 mg daily, with the goal of titrating to twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed. RESULTS: Among 107 patients, median OS (mOS) was 10.2 months; median PFS (mPFS) was 5.2 months. mOS for sorafenib 400 mg/day was 6.6 vs. 800 mg/day was 12.8 months [hazard ratio (HR), 0.59; P=0.04]; mPFS was 3.5 vs. 5.9 months, respectively (HR, 0.66; P=0.07). For Child Pugh A class (CP-A) patients, mOS was 15.8 months for 400 mg/day vs. 12.8 months for 800 mg/day (HR, 1.48; P=0.35); mPFS was 9.0 vs. 5.9 months, respectively (HR, 1.23; P=0.56). For Child Pugh B class (CP-B) patients, mOS was 5.0 months for 400 mg/day vs. 11.2 months for 800 mg/day (HR, 0.33; P=0.002); mPFS was 2.1 vs. 5.6 months, respectively (HR, 0.41; P=0.006). No differences in adverse events (AEs) were observed in CP-A vs. CP-B. CONCLUSIONS: Patients with CP-A or CP-B advanced HCC should be offered sorafenib at 400 mg twice daily with optimal management of AEs in order to improve survival. PMID- 26029453 TI - Surveillance for asymptomatic recurrence in resected stage III colon cancer: does it result in a more favorable outcome? AB - BACKGROUND: Evidence from dated and moderate quality trials supports a modest survival benefit for intensive surveillance in resected colon cancer (CC). This study evaluates surveillance in a modern population-based cohort of stage III CC patients (pts). METHODS: Records of pts who initiated oxaliplatin-based adjuvant chemotherapy (AC) for stage III CC between 2006-2011 at the British Columbia Cancer Agency (BCCA) were reviewed. Kaplan-Meier and log rank test were generated to investigate whether diagnosis of recurrence based on symptoms was associated with worse overall survival (OS). OS1 and OS2 were measured from date of recurrence or date of initial surgery, respectively. RESULTS: Of 635 pts who received AC for stage III CC, 175 pts (27.5%) recurred and 118 (18.6%) died at a median follow-up of 67.7 months. Recurrences were detected by surveillance in 149 pts (41% by CEA elevation and 44% by abnormal imaging), and symptoms in 26 pts (15%). Patients with surveillance-detected recurrences had a shorter median relapse-free survival (RFS) (18.5 vs. 25.3 months, HR 1.82, P<0.001), and longer median OS1 (28.5 vs. 6.5 months, HR 0.37, P<0.001). However, median OS2 was not significantly different (50.9 vs. 39.1 months, HR 0.66, P=0.091). Pts with surveillance-detected recurrence received more potentially curative metastasectomy (39% vs. 7%, P=0.002) and chemotherapy (70% vs. 50%, P=0.03). CONCLUSIONS: In this modern population-based cohort study, the OS impact of detecting asymptomatic recurrences in stage III CC is unclear. However, pts with asymptomatic recurrences were more likely to receive potentially curative metastasectomy and chemotherapy. PMID- 26029454 TI - Thrombotic events in metastatic colorectal cancer patients treated with leucovorin, fluorouracil and irinotican (FOLFIRI) plus bevacizumab. AB - OBJECTIVE: To determine the incidence and risk factors for thrombotic events (TEs) in patients with metastatic colorectal cancer (mCRC) who received bevacizumab (BV) and FOLFIRI (leucovorin, fluorouracil and irinotican) compared to FOLFIRI alone. METHODS: Single institution retrospective study of 450 mCRC patients who received either BV plus FOLFIRI or FOLFIRI alone between April 2004 and August 2012. Demographics, TE risk factors, and treatment data were abstracted from patients' records. Multivariate analysis was used to identify factors that contributed to thromboembolism. RESULTS: Two-hundred-sixty-one mCRC patients received BV plus FOLFIRI [64.8% males, mean body mass index (BMI) of 27.6] compared to 189 control patients who received FOLFIRI alone (61.9% males, BMI 27.2). The incidence of TEs was 14.9% in the BV plus FOLFIRI group, compared to 15.9% in the control group. Multivariate analysis controlling for age, BMI, gender, malignancy, metastatic sites, line of treatment, and risk factors did not suggest a significant increase in the risk of TE with the addition of BV (OR =0.83 95% CI: 0.40-1.70; P=0.602). No difference in the site of TEs was observed between the treatment groups. The only statistically significant risk factor for thrombosis in the FOLFIRI plus BV group was increased BMI (OR =1.05; 95% CI: 1.01 1.10; P=0.01). CONCLUSIONS: This study does not support a significant increase in the risk of TE in patients with mCRC who received BV in addition to FOLFIRI. Increased BMI may be a risk factor for thrombosis in patients treated with BV. PMID- 26029455 TI - Duodenojejunal flexure tumors: surgical difficulties with case series. AB - BACKGROUND: Distal duodenal and duodenojejunal flexure tumors are rare. They present late due to vague symptomatology and difficulties in establishing a diagnosis. Due to vague symptoms, these tumors would have had spread locally or metastasized to regional nodes or distant organs at presentation. Though the present standard is to achieve R0 resection for any tumor, it is quite difficult in these tumors because of their proximity to many important named vessels and viscera. Role of neoadjuvant and adjuvant therapy is not established yet. METHODS: Medical records of patients searched who were admitted and diagnosed to have duodenal tumors between January, 2011 and March, 2014. Patients with duodenal tumors arising from third or fourth part were analysed. Radiological, endoscopic findings were noted and compared with operative and histopathological report. RESULTS: Nine patients (seven males and two females) were found to have tumor in the third and fourth part of the duodenum. All had undergone laparotomy with curative intention in eight patients. R0 resection was feasible only in five (55%) patients. The most common histopathological type is adenocarcinoma in 66% patients. CONCLUSIONS: Segmental resection is feasible and may be curative in most of the patients with duodenojejunal flexure tumors, without the need for vascular resections and reconstructions. Adenocarcinomas are the most common variant. Lymph node involvement and microvascular invasion indicates poor prognosis. PMID- 26029456 TI - Human papillomavirus tumor infection in esophageal squamous cell carcinoma. AB - The association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) has been recognized for over three decades. Recently, multiple meta-analyses have drawn upon existing literature to assess the strength of the HPV-ESCC linkage. Here, we review these analyses and attempt to provide a clinically-relevant overview of HPV infection in ESCC. HPV-ESCC detection rates are highly variable across studies. Geographic location likely accounts for a majority of the variation in HPV prevalence, with high-incidence regions including Asia reporting significantly higher HPV-ESCC infection rates compared with low-incidence regions such as Europe, North America, and Oceania. Based on our examination of existing data, the current literature does not support the notion that HPV is a prominent carcinogen in ESCC. We conclude that there is no basis to change the current clinical approach to ESCC patients with respect to tumor HPV status. PMID- 26029457 TI - Local excision for early rectal cancer: transanal endoscopic microsurgery and beyond. AB - The goal of treatment for early stage rectal cancer is to optimize oncologic control while minimizing the long-term impact of treatment on quality of life. The standard of care treatment for most stage I and II rectal cancers is radical surgery alone, specifically total mesorectal excision (TME). For early rectal cancers, this procedure is usually curative but can have a substantial impact on quality of life, including the possibility of permanent colostomy and the potential for short and long-term bowel, bladder, and sexual dysfunction. Given the morbidity associated with radical surgery, alternative approaches to management of early rectal cancer have been explored, including local excision (LE) via transanal excision (TAE) or transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS). Compared to the gold standard of radical surgery, local procedures for strictly selected early rectal cancers should lead to identical oncological results and even better outcomes regarding morbidity, mortality, and quality of life. PMID- 26029458 TI - The functional and prognostic implications of regulatory T cells in colorectal carcinoma. AB - One of the cornerstones for the immune system is the discovery of T-regulatory cells (Treg), which play an essential role in maintaining self regulation of the immune response to foreign threats. However, they may also interfere with the immune response to tumoral cells, for which reason much effort has been put into characterizing the molecular makeup of this T cell population. It has been shown that Tregs are increased in the peripheral blood of patients with many cancer types, and also enriched in the tumor sites. However, the significance of this phenomenon on prognosis is controversial, especially in colorectal carcinoma, one of the most common cancers worldwide and a major cause of cancer-related death. This literature review focuses on characterization of the Treg cells in colorectal cancer patients and its implications on the prognosis of this disease. In the end, the potential therapeutic strategies aimed at Treg modification are discussed. PMID- 26029459 TI - Extended RAS testing in metastatic colorectal cancer-Refining the predictive molecular biomarkers. AB - Mutations of exon 2 of Kirsten rat sarcoma viral oncogene homologue (KRAS) (exon 2 codons 12/13) lead to constitutive activation of the EGFR (epidermal growth factor receptor) mediated signal transduction pathway and been shown to be a negative predictive biomarker for EGFR-directed monoclonal antibodies among patients with colorectal cancer (CRC). As selection of patients is very important for administration of anti-EGFR therapy, this lone biomarker has proved to be insufficient for selecting the appropriate patients as more patients lacking exon 2 KRAS mutation were resistant to anti-EGFR therapy. The results of various randomized clinical trials have confirmed the presence of other RAS mutation including additional RAS mutations (KRAS exons 3/4 and NRAS exon 1/2/3/4). Extended RAS analysis should be considered before initiating anti-EGFR therapy to patients of metastatic CRC. This can help in proper selection of patients leading to tailored individualistic treatment, decreasing cost of treatment and the adverse effects related to use of monoclonal antibody therapy. The new evidence is supporting the need to make 'Extended RAS' analysis essential before start of treatment with anti-EGFR monoclonal antibody therapy. Prior to this the Extended RAS testing should be standardized. PMID- 26029460 TI - Liver-directed conversion therapy in metastatic colon cancer. PMID- 26029461 TI - Irreversible electroporation of locally advanced pancreatic neck/body adenocarcinoma. AB - OBJECTIVE: Irreversible electroporation (IRE) of locally advanced pancreatic adenocarcinoma of the neck has been used to palliate appropriate stage 3 pancreatic cancers without evidence of metastasis and who have undergone appropriate induction therapy. Currently there has not been a standardized reported technique for pancreatic mid-body tumors for patient selection and intra operative technique. PATIENTS: Subjects are patients with locally advanced pancreatic adenocarcinoma of the body/neck who have undergone appropriate induction chemotherapy for a reasonable duration. MAIN OUTCOME MEASURES: Technique of open IRE of locally advanced pancreatic adenocarcinoma of the neck/body is described, with the emphasis on intra-operative ultrasound and intra operative electroporation management. RESULTS: The technique of open IRE of the pancreatic neck/body with bracketing of the celiac axis and superior mesenteric artery with continuous intraoperative ultrasound imaging and consideration of intraoperative navigational system is described. CONCLUSIONS: IRE of locally advanced pancreatic adenocarcinoma of the body/neck is feasible for appropriate patients with locally advanced unresectable pancreatic cancer. PMID- 26029462 TI - A phase II study of biweekly pralatrexate and docetaxel in patients with advanced esophageal and gastroesophageal carcinoma that have failed first-line platinum based therapy. AB - BACKGROUND: The appropriate second-line therapy for patients with advanced gastroesophageal (GE) or esophageal (E) cancer after failure of first-line platinum-based therapy is unclear. Pralatrexate and docetaxel have independently been shown to have efficacy in the treatment of these cancers. Thus, we performed a clinical trial examining the efficacy of the combination of these agents in the treatment of GE and E cancer. METHODS: A Fleming phase II design with a single stage of 32 patients was planned. Pralatrexate 120 mg/m(2) and docetaxel 35 mg/m(2) were administered on day 1 of 14-day cycles. The primary end-point was to evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and secondary end-points were to evaluate for progression-free survival (PFS) and overall survival (OS). RESULTS: The study was halted prematurely due to loss of funding after the accrual of six patients. Two patients had stable disease (SD) and four patients had disease progression per RECIST. When applying PERCIST criteria in four evaluable patients, two had a partial response (PR) and two had SD. Median PFS was 1.9 months (95% CI, 0.8-7.2) and median OS was 5.5 (0.8-11.7) months. CONCLUSIONS: Pralatrexate and docetaxel as therapy in refractory esophageal and GE adenocarcinoma did not demonstrate meaningful preliminary activity. PERCIST may prove to better assess the meaningfulness of anatomic SD. PMID- 26029463 TI - Optimal interval of surgery after neoadjuvant radiochemotherapy in T3-4/N0+ rectal cancer: population level evidence in addition to controlled trial. PMID- 26029464 TI - Capecitabine-induced leukocytoclastic vasculitis under neoadjuvant chemotherapy for locally advanced colorectal cancer. AB - We describe a case of capecitabine-induced leukocytoclastic vasculitis in a patient with locally advanced rectal cancer under curative neoadjuvant concurrent chemoradiation using capecitabine. After 5 days of the initiation of capecitabine the patient developed a pruritic maculopapular rash in her extremities consistent with vasculitis which was confirmed on skin biopsy without any signs of systemic involvement. Capecitabine was held and the rash was treated with topical steroids with complete resolution of both rash and pruritus. Due to a lack of other alternative chemotherapeutic options and the cutaneous-only involvement of vasculitis, the capecitabine was re-introduced. Two days later, the patient developed an identical maculopapular rash with a similar distribution. Prednisone was initiated while the capecitabine was continued with complete resolution of the rash. The patient successfully completed her curative neoadjuvant chemoradiation therapy treatment without the need to permanently discontinue the capecitabine. PMID- 26029465 TI - Functional imaging of radiation liver injury in a liver metastasis patient: imaging and pathologic correlation. AB - BACKGROUND: Radiation therapy (RT) is increasingly being utilized as a treatment modality for the treatment of primary and metastatic liver malignancies. Accurate assessment of liver function and prediction of radiation induced liver disease (RILD) remains a challenge with conventional laboratory tests and imaging. Imaging-pathology correlation of hepatic injury after RT has been described with computer tomography (CT) imaging that depicts perfusion changes. However, these imaging changes may not directly characterize the functional capacity of the liver. CASE PRESENTATION: This case report describes a patient that received preoperative chemoradiation and surgical resection for a liver metastasis from endometrial cancer. Sulfur colloid (SC) single photon emission computed tomography (SPECT/CT) was obtained post-chemoradiation and prior to surgery. Imaging-pathology correlation between radiation changes depicted on functional imaging using SC SPECT/CT and corresponding histopathology is described. DISCUSSION: Quantitative SC SPECT/CT may allow non-invasive assessment of global and spatial liver function before treatment and enable personalized treatment approaches for liver-directed therapies. PMID- 26029466 TI - Pulmonary metastases in pancreatic cancer, is there a survival influence? AB - Pancreatic cancer is known to be one of the most lethal cancers. The majority of patients present with advanced stage disease, making curative approach unachievable. In untreated patients, the median survival does not exceed 6 months in metastatic disease and 10 months in locally advanced disease. Furthermore, the 5-year survival rate remains poor even in patients with early stage disease who are surgical candidates. The detrimental outcome is related to the high potency of developing metastasis which can be detected at diagnosis, when the disease progresses or relapses after surgery. Although the liver is the most common site of pancreatic cancer metastases, the cancer can escape the liver in some cases and metastasize to the lung or other distant organs. The involvement of some sites not others might reflect subgroups of this cancer with different molecular backgrounds. Identifying these groups may have utility in determining prognosis and stratifying treatment for patients. PMID- 26029467 TI - Regression of hepatocellular carcinoma after treatment of hepatitis C: a case report. AB - Chronic hepatitis C induced cirrhosis predisposes to hepatocellular carcinoma (HCC). There is no data regarding the impact of hepatitis C treatment on HCC. We report a case of a 53-year-old man with chronic hepatitis C and HCC with lung metastasis who failed treatment with sorafenib but the tumor regressed after treatment of hepatitis C with ribavirin and sofosbuvir for 24 weeks. PMID- 26029468 TI - Surgical management of hepatocellular carcinoma after Fontan procedure. AB - The Fontan operation has successfully prolonged the lives of patients born with single-ventricle physiology. A long-term consequence of post-Fontan elevation in systemic venous pressure and low cardiac output is chronic liver inflammation and cirrhosis, which lead to an increased risk of hepatocellular carcinoma (HCC). Surgical management of patients with post-Fontan physiology and HCC is challenging, as the requirement for adequate preload in order to sustain cardiac output conflicts with the low central venous pressure (CVP) that minimizes blood loss during hepatectomy. Consequently, liver resection is rarely performed, and most reports describe nonsurgical treatments for locoregional control of the tumors in these patients. Here, we present a multidisciplinary approach to a successful surgical resection of a HCC in a patient with Fontan physiology. PMID- 26029469 TI - Paraneoplastic cutaneous lupus secondary to esophageal squamous cell carcinoma. AB - Sporadic subacute cutaneous lupus erythematosus (SCLE) in an elderly man does not fit a typical demographic for the disease process. Using the McLean's criteria we were able to establish a temporal relationship between the patient's diagnosis of esophageal squamous cell carcinoma (SCC) and his dermatosis, both of which responded to cytotoxic chemotherapy. The clinical presentation and progression of the clinical illness is supportive of a very unusual and not previously reported paraneoplastic SCLE secondary to esophageal SCC. PMID- 26029472 TI - Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma. AB - Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b+ Gr1hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b+ myeloid cells and CD4+ CD25+ T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease. PMID- 26029471 TI - Timing of radical cystectomy in Central Europe - multicenter study on factors influencing the time from diagnosis to radical treatment of bladder cancer patients. AB - INTRODUCTION: Time that passes between an unfavourable diagnosis to a radical cystectomy (RC) affects oncological outcomes in patients with bladder cancer. Unsatisfactory survival of patients after RC in Central Europe can potentially result from this factor. MATERIAL AND METHODS: The aim of this study was to assess the time interval between transurethral resection of the bladder tumor (TURBT) and RC in Central Europe and to identify clinical factors of possible delays. 941 consecutive patients who underwent RC in nine Central European urological centers were enrolled into the study. After the TURBT-RC time was calculated, selected clinical and pathological parameters were tested as potential factors influencing the timing of RC. RESULTS: On average, RCs were performed 73.8 days after TURBTs (median - 53, range 0-1587). In 238 patients (25.3%) the time exceeded 12 weeks. Patients with muscle-invasive cancer were operated earlier on than patients with nonmuscle-invasive cancer (67.6 vs.105.2 days, RR = 1.41, p = 0.00). In high volume centers (>30 RC per year) longer TURBT RC intervals were observed (97.6 vs. 66.3 days, RR = 2.49, p = 0.00). Simultaneously, factors such as female sex (RR = 1.21), more advanced age of patient (>65 years, RR = 1.23), presence of concomitant CIS (RR = 2.43), grade of cancer cells (RR = 1.67) and final post-RC stage (RR = 1.51) had no statistically significant effect on the results (p >0.05). CONCLUSIONS: The mean time interval between the diagnosis and radical treatment of patients with bladder cancer in Central Europe is adequate. However, there are still a relatively high number of patients waiting for radical cystectomy longer than 8 weeks. A lower stage of disease as well as a higher case load within of a hospital may delay the surgery. PMID- 26029473 TI - Affine Registration of label maps in Label Space. AB - Two key aspects of coupled multi-object shape analysis and atlas generation are the choice of representation and subsequent registration methods used to align the sample set. For example, a typical brain image can be labeled into three structures: grey matter, white matter and cerebrospinal fluid. Many manipulations such as interpolation, transformation, smoothing, or registration need to be performed on these images before they can be used in further analysis. Current techniques for such analysis tend to trade off performance between the two tasks, performing well for one task but developing problems when used for the other. This article proposes to use a representation that is both flexible and well suited for both tasks. We propose to map object labels to vertices of a regular simplex, e.g . the unit interval for two labels, a triangle for three labels, a tetrahedron for four labels, etc. This representation, which is routinely used in fuzzy classification, is ideally suited for representing and registering multiple shapes. On closer examination, this representation reveals several desirable properties: algebraic operations may be done directly, label uncertainty is expressed as a weighted mixture of labels (probabilistic interpretation), interpolation is unbiased toward any label or the background, and registration may be performed directly. We demonstrate these properties by using label space in a gradient descent based registration scheme to obtain a probabilistic atlas. While straightforward, this iterative method is very slow, could get stuck in local minima, and depends heavily on the initial conditions. To address these issues, two fast methods are proposed which serve as coarse registration schemes following which the iterative descent method can be used to refine the results. Further, we derive an analytical formulation for direct computation of the "group mean" from the parameters of pairwise registration of all the images in the sample set. We show results on richly labeled 2D and 3D data sets. PMID- 26029470 TI - Host Antimicrobial Peptides in Bacterial Homeostasis and Pathogenesis of Disease. AB - Innate immune responses function as a first line of host defense against the development of bacterial infection, and in some cases to preserve the sterility of privileged sites in the human host. Bacteria that enter these sites must counter host responses for colonization. From the host's perspective, the innate immune system works expeditiously to minimize the bacterial threat before colonization and subsequent dysbiosis. The multifactorial nature of disease further challenges predictions of how each independent variable influences bacterial pathogenesis. From bacterial colonization to infection and through disease, the microenvironments of the host are in constant flux as bacterial and host factors contribute to changes at the host-pathogen interface, with the host attempting to eradicate bacteria and the bacteria fighting to maintain residency. A key component of this innate host response towards bacterial infection is the production of antimicrobial peptides (AMPs). As an early component of the host response, AMPs modulate bacterial load and prevent establishment of infection. Under quiescent conditions, some AMPs are constitutively expressed by the epithelium. Bacterial infection can subsequently induce production of other AMPs in an effort to maintain sterility, or to restrict colonization. As demonstrated in various studies, the absence of a single AMP can influence pathogenesis, highlighting the importance of AMP concentration in maintaining homeostasis. Yet, AMPs can increase bacterial virulence through the co-opting of the peptides or alteration of bacterial virulence gene expression. Further, bacterial factors used to subvert AMPs can modify host microenvironments and alter colonization of the residential flora that principally maintain homeostasis. Thus, the dynamic interplay between host defense peptides and bacterial factors produced to quell peptide activity play a critical role in the progression and outcome of disease. PMID- 26029474 TI - Plasma epidermal growth factor decreased in the early stage of Parkinson's disease. AB - Epidermal growth factor (EGF) is a neurotrophic factor that plays an important role in Parkinson's disease (PD). We measured plasma EGF level in PD, essential tremor (ET) and normal controls to investigate whether it changes in PD and whether it is associated with motor and non-motor symptoms of PD. 100 patients with PD, 40 patients with ET as disease control and 76 healthy persons were enrolled in the present study. Motor and non-motor symptoms were assessed by different scales. Plasma EGF levels of three groups were measured by enzyme linked immunosorbent assay kit. Spearman test and linear logistics regression model were used to test the correlation of EGF with motor and non-motor symptoms of PD. Plasma EGF level was significantly decreased in early PD patients compared with normal control, but not in advanced PD patients. Interestingly, plasma EGF level was significantly increased in advanced PD and total PD patients compared with ET patients, but not in early PD patients. In addition, plasma EGF level was correlated with UPDRS-III scores in PD. Also plasma EGF level was correlated with UPDRS-III scores and NMS scores in early PD. Our results suggested that plasma EGF decreased in the early stage of PD and increased later on in the PD disease course. Also, plasma EGF level was increased significantly in PD compared with ET patients and correlated with motor and non-motor symptoms in early PD. PMID- 26029475 TI - Effects of Hospital-Based Physical Therapy on Hospital Discharge Outcomes among Hospitalized Older Adults with Community-Acquired Pneumonia and Declining Physical Function. AB - To examine whether hospital-based physical therapy is associated with functional changes and early hospital readmission among hospitalized older adults with community-acquired pneumonia and declining physical function. Study design was a retrospective observation study. Participants were community-dwelling older adults admitted to medicine floor for community-acquired pneumonia (n = 1,058). Their physical function using Katz activities of daily living (ADL) Index declined between hospital admission and 48 hours since hospital admission (Katz ADL Index 6->5). The intervention group was those receiving physical therapy for >= 0.5 hour/day. Outcomes were Katz ADL Index at hospital discharge and all-cause 30-day hospital readmission rate. The intervention and control groups did not differ in the Katz ADL Index at hospital discharge (p = 0.11). All-cause 30-day hospital readmission rate was lower in the intervention than in control groups (OR = 0.65, p = 0.02). Hospital-based physical therapy has the benefits toward reducing 30-day hospital readmission rate of acutely ill older adults with community-acquired pneumonia and declining physical function. PMID- 26029476 TI - Analysis of vertebral bone strength, fracture pattern, and fracture location: a validation study using a computed tomography-based nonlinear finite element analysis. AB - Finite element analysis (FEA) is an advanced computer technique of structural stress analysis developed in engineering mechanics. Because the compressive behavior of vertebral bone shows nonlinear behavior, a nonlinear FEA should be utilized to analyze the clinical vertebral fracture. In this article, a computed tomography-based nonlinear FEA (CT/FEA) to analyze the vertebral bone strength, fracture pattern, and fracture location is introduced. The accuracy of the CT/FEA was validated by performing experimental mechanical testing with human cadaveric specimens. Vertebral bone strength and the minimum principal strain at the vertebral surface were accurately analyzed using the CT/FEA. The experimental fracture pattern and fracture location were also accurately simulated. Optimization of the element size was performed by assessing the accuracy of the CT/FEA, and the optimum element size was assumed to be 2 mm. It is expected that the CT/FEA will be valuable in analyzing vertebral fracture risk and assessing therapeutic effects on osteoporosis. PMID- 26029477 TI - Patient-reported geriatric symptoms as risk factors for hospitalization and emergency department visits. AB - There is an urgent need to identify predictors of adverse outcomes and increased health care utilization in the elderly. The Mayo Ambulatory Geriatric Evaluation (MAGE) is a symptom questionnaire that was completed by patients aged 65 years and older during office visits to Primary Care Internal Medicine at Mayo Clinic in Rochester, MN. It was introduced to improve screening for geriatric conditions. We conducted this study to explore the relationship between self reported geriatric symptoms and hospitalization and emergency department (ED) visits within 1 year of completing the survey. This was a retrospective cohort study of patients who completed the MAGE from April 2008 to December 2010. The primary outcome was an ED visit or hospitalization within 1 year. Predictors included responses to individual questions in the MAGE. Data were obtained from the electronic medical record and administrative records. Logistic regression analyses were performed from significant univariate factors to determine predictors in a multivariable setting. A weighted scoring system was created based upon the odds ratios derived from a bootstrap process. The sensitivity, specificity, and AUC were calculated using this scoring system. The MAGE survey was completed by 7738 patients. The average age was 76.2 +/- 7.68 years and 57% were women. Advanced age, a self-report of worse health, history of 2 or more falls, weight loss, and depressed mood were significantly associated with hospitalization or ED visits within 1 year. A score equal to or greater than 2 had a sensitivity of 0.74 and specificity of 0.45. The calculated AUC was 0.60. The MAGE questionnaire, which was completed by patients at an outpatient visit to screen for common geriatric issues, could also be used to assess risk for ED visits and hospitalization within 1 year. PMID- 26029478 TI - Information theoretical analysis of aging as a risk factor for heart disease. AB - We estimate the weight of various risk factors in heart disease, and the particular weight of age as a risk factor, individually and combined with other factors. To establish the weights we use the information theoretical measure of normalized mutual information that permits determining both individual and combined correlation of diagnostic parameters with the disease status. The present information theoretical methodology takes into account the non-linear correlations between the diagnostic parameters, as well as their non-linear changes with age. Thus it may be better suited to analyze complex biological aging systems than statistical measures that only estimate linear relations. We show that individual parameters, including age, often show little correlation with heart disease. Yet in combination, the correlation improves dramatically. For diagnostic parameters specific for heart disease the increase in the correlative capacity thanks to the combination of diagnostic parameters, is less pronounced than for the less specific parameters. Age shows the highest influence on the presence of disease among the non-specific parameters and the combination of age with other diagnostic parameters substantially improves the correlation with the disease status. Hence age is considered as a primary "metamarker" of aging-related heart disease, whose addition can improve diagnostic capabilities. In the future, this methodology may contribute to the development of a system of biomarkers for the assessment of biological/physiological age, its influence on disease status, and its modifications by therapeutic interventions. PMID- 26029479 TI - Learning from Normal Aging: Preserved Emotional Functioning Facilitates Adaptation among Early Alzheimer's Disease Patients. AB - Alzheimer's disease (AD) has been largely characterized by severe deterioration of cognitive functioning. Only recently has more attention been shifted to identifying the preserved capacity and functioning of AD patients. By reviewing the AD literature, we observe that despite the various cognitive impairment and deficits, early Alzheimer's patients perform certain types of automatic emotion regulation and display a positivity effect in emotion recognition and emotional memory. Moreover, we argue that, like their healthy aged peers, the optimization of such preserved emotion-based capacities helps early AD patients increase positive emotions, which may counteract the negative effects of the disease, thus maintaining their socio-emotional functioning. Finally, we discuss the emotion based capacities strategies that AD patients may use to facilitate their adjustment to a life with Alzheimer's. PMID- 26029480 TI - Mechanisms of superoxide signaling in epigenetic processes: relation to aging and cancer. AB - Superoxide is a precursor of many free radicals and reactive oxygen species (ROS) in biological systems. It has been shown that superoxide regulates major epigenetic processes of DNA methylation, histone methylation, and histone acetylation. We suggested that superoxide, being a radical anion and a strong nucleophile, could participate in DNA methylation and histone methylation and acetylation through mechanism of nucleophilic substitution and free radical abstraction. In nucleophilic reactions superoxide is able to neutralize positive charges of methyl donors S-adenosyl-L-methionine (SAM) and acetyl-coenzyme A (AcCoA) enhancing their nucleophilic capacity or to deprotonate cytosine. In the reversed free radical reactions of demethylation and deacetylation superoxide is formed catalytically by the (Tet) family of dioxygenates and converted into the iron form of hydroxyl radical with subsequent oxidation and final eradication of methyl substituents. Double role of superoxide in these epigenetic processes might be of importance for understanding of ROS effects under physiological and pathological conditions including cancer and aging. PMID- 26029481 TI - Differentially expressed genes in adipocytokine signaling pathway of adipose tissue in pregnancy. AB - OBJECTIVE: To profile the differential gene expression of the KEGG Adipocytokine Signaling pathway in omental compared to subcutaneous tissue in normal pregnancy. STUDY DESIGN: Subjects included 14 nonobese, normal glucose tolerant, healthy pregnant women. Matched omental and subcutaneous tissue were obtained at elective cesarean delivery. Gene expression was evaluated using microarray and validated by RT-PCR. Differential gene expression was defined as >=1.5 fold increase at p < 0.05. RESULTS: Six genes were significantly downregulated with two upregulated genes in omental tissue. Downregulation of Adiponectin and Insulin Receptor substrate, key genes mediating insulin sensitivity, were observed with borderline upregulation of GLUT-1. There were downregulations of CD36 and acyl-CoA Synthetase Long-chain Family Member 1which are genes involved in fatty acid uptake and activation. There was a novel expression of Carnitine palmitoyltransferase 1C. CONCLUSION: Differential gene expression of Adipocytokine Signaling Pathway in omental relative to subcutaneous adipose tissue in normal pregnancy suggests a pattern of insulin resistance, hyperlipidemia, and inflammation. PMID- 26029482 TI - Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury. AB - Objective: Aberrant plasminogen activator inhibitor-1 (PAI-1) expression and activity have been implicated in bleeding disorders, multiorgan fibrosis, and wound healing anomalies. This study details the physiological consequences of targeted PAI-1 functional inhibition on cutaneous injury repair. Approach: Dorsal skin wounds from FVB/NJ mice, created with a 4 mm biopsy punch, were treated topically with the small-molecule PAI-1 antagonist tiplaxtinin (or vehicle control) for 5 days and then analyzed for markers of wound repair. Results: Compared to controls, tiplaxtinin-treated wounds displayed dramatic decreases in wound closure and re-epithelialization. PAI-1 immunoreactivity was evident at the migratory front in all injury sites indicating these effects were due to PAI-1 functional blockade and not PAI-1 expression changes. Stimulated HaCaT keratinocyte migration in response to recombinant PAI-1 in vitro was similarly attenuated by tiplaxtinin. While tiplaxtinin had no effect on keratinocyte proliferation, cell cycle progression, or apoptosis, it effectively reduced collagen deposition, the number of Ki-67+ fibroblasts, and incidence of differentiated myofibroblasts (i.e., smooth muscle alpha-actin immunoreactive cells), but not fibroblast apoptosis. Innovation: The role for PAI-1 in hemostasis and fibrinolysis is established; involvement of PAI-1 in cutaneous wound healing, however, remains unclear. This study tests the effect of a small molecule PAI-1 inhibitor in a murine model of skin wound repair. Conclusion: Loss of PAI-1 activity significantly impaired wound closure. Re-epithelialization and fibroblast recruitment/differentiation were both reduced in tiplaxtinin-treated mice. Therapies directed at manipulation of PAI-1 expression and/or activity may have applicability as a treatment option for chronic wounds and scarring disorders. PMID- 26029483 TI - Soluble Factors Released by Endogenous Viable Cells Enhance the Antioxidant and Chemoattractive Activities of Cryopreserved Amniotic Membrane. AB - Objective: Regulation of oxidative stress and recruitment of key cell types are activities of human amniotic membrane (hAM) that contribute to its benefits for wound treatment. Progress in tissue preservation has led to commercialization of hAM. The majority of hAM products are devitalized with various degrees of matrix alteration. Data show the importance of hAM matrix preservation, but little is known about the advantages of retaining viable endogenous cells. In this study, we compared the antioxidant and chemoattractive properties of viable intact cryopreserved hAM (int-hAM) and devitalized cryopreserved hAM (dev-hAM) to determine the benefits of cell preservation. Approach: We evaluated the ability of int-hAM and dev-hAM to protect fibroblasts from oxidant-induced cell damage, to suppress oxidants, and to recruit fibroblasts and keratinocytes in vitro. Results: Both the int-hAM-derived conditioned medium (CM) and the int-hAM tissue rescued significantly more fibroblasts from oxidant-induced damage than dev-hAM (844% and 93% more, respectively). The int-hAM CM showed a 202% greater antioxidant capacity than dev-hAM. The int-hAM CM enhanced the recruitment of fibroblasts and normal and diseased keratinocytes to a greater extent than dev hAM (1,555%, 315%, and 151% greater, respectively). Innovation and Conclusion: Int-hAM, in which all native components are preserved, including endogenous viable cells, demonstrated a significantly greater antioxidant and fibroblast and keratinocyte chemoattractive potential compared to dev-hAM, in which viable cells are destroyed. The release of soluble factors that protect fibroblasts from oxidative injury by hAM containing viable cells is a mechanism of hAM antioxidant activity, which is a novel finding of this study. PMID- 26029484 TI - NorLeu3-Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers. AB - Significance: Diabetes is a disorder that is well known to delay wound repair resulting in the formation of colonized chronic wounds. Over their lifetime, diabetic patients have a 25% incidence of foot ulcers (DFUs), which contribute to increased risk of morbidity, including osteomyelitis and amputations, and increased burden to the healthcare system. Recent Advances: The only active product approved for the treatment of diabetic ulcers, Regranex(r), is not widely used due to minimal proven efficacy and recent warnings added to the Instructions for Use. A novel topical agent that accelerates healing and increases the proportion of fully healed DFUs, DSC127 [aclerastide; active ingredient, NorLeu3 angiotensin (1-7) (NorLeu3-A(1-7))], is recruiting patients in Phase III clinical trials (NCT01830348 and NCT01849965). NorLeu3-A(1-7) is an analog of the naturally occurring peptide, angiotensin 1-7. The mechanisms of action include induction of progenitor proliferation, accelerated vascularization, collagen deposition, and re-epithelialization. Critical Issues: Current modalities for the treatment of DFUs include strict offloading, bandaging, debridement and, on a limited basis, application of Regranex. Novel potent therapies are needed to combat this significant burden to the diabetic patient and the healthcare system. Future Direction: Preclinical and clinical research shows that DSC127 is highly effective in the closure of diabetic wounds and is superior to Regranex in animal studies. Clinical development of DSC127 as a topical agent for the healing of DFU is underway. Further investigation into the mechanisms by which this product accelerates healing is warranted. PMID- 26029485 TI - Clinical Evaluation of a Novel Topical Negative Pressure Device in Promoting Healing in Chronic Wounds. AB - Aim: This observational study evaluated the use of a novel, ultraportable, mechanically powered topical negative pressure device in promoting healing in chronic wounds, including venous and mixed etiology leg ulcers and neuropathic foot ulcers. Materials and Methods: Evaluable patients (n=37) received treatment with the SNaP(r) Wound Care System for up to 6 weeks. The primary objective was percentage change in wound size, with secondary objectives of clinical assessment of wound parameters, ease of use, and impact on quality of life. Results: A 42.64% mean percentage decrease in wound area was observed, with an overall decrease for each wound etiology subgroup. Increased granulation tissue, decreased exudate levels, and decreased wound pain were reported. Quality-of-life scores increased overall, and the device was easy to use, comfortable, portable, and inconspicuous. Conclusion: The SNaP Wound Care System has the potential to promote healing in chronic wounds of different etiologies. PMID- 26029486 TI - EMLA and Lidocaine Spray: A Comparison for Surgical Debridement in Venous Leg Ulcers. AB - Objective: In this study the author proposes to compare eutectic mixture of local anesthetics (EMLA) and an odontoiatric spray solution of 10% Lidocaine (Ecocain) for surgical debridement in venous leg ulcers. Approach: Fifty patients were recruited and randomly assigned into two groups (A, B). All of them have venous leg ulcer in the medial and/or lateral malleolar region. Group A: topical anesthetic EMLA with film occlusion. Group B: topical anesthesia with Ecocain. The author proceeded to surgical debridement after local anesthesia. A questionnaire and a visual analog scale (VAS) were administered to assess the amount of pain felt during the debridement and during the following 6 h. Results: The analysis of the VAS revealed no major significant differences statistically. The analysis of the questionnaires showed patients treated with Ecocain took more analgesic drugs. Analysis of the timing and quality of procedure showed that Ecocain reduced the timing of debridement and dressing change, improving the outpatient management and patient compliance. Innovations: For rapid debridement, the most appropriate is to use Ecocain. Conclusion: Methods of local anesthesia are multiple and must be identified according to the needs of the patient and the surgeon trying to get the best anesthesia with minimal use of time and resources. PMID- 26029488 TI - Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition. AB - Current case definitions of Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS) have been based on consensus methods, but empirical methods could be used to identify core symptoms and thereby improve the reliability. In the present study, several methods (i.e., continuous scores of symptoms, theoretically and empirically derived cut off scores of symptoms) were used to identify core symptoms best differentiating patients from controls. In addition, data mining with decision trees was conducted. Our study found a small number of core symptoms that have good sensitivity and specificity, and these included fatigue, post-exertional malaise, a neurocognitive symptom, and unrefreshing sleep. Outcomes from these analyses suggest that using empirically selected symptoms can help guide the creation of a more reliable case definition. PMID- 26029489 TI - Cost efficient workup and management of patients with chronic rhinosinusitis - challenges and unmet needs. AB - Chronic rhinosinusitis (CRS) is a common disease, estimated to occur in 12-16% of the United States population. This prevalence creates a significant health burden with an estimated 15 million ambulatory visits for the condition annually. Consequently, practice guidelines have been designed to assist both the primary care provider and specialist in establishing a CRS diagnosis and prescribing effective treatment for CRS. The guidelines for CRS diagnosis have evolved since the United States Rhinosinusitis Task Force first published its symptom-based guidelines in 1997. Contemporary practice guidelines still require 12 weeks of appropriate symptoms, but now include corroboration of objective sinonasal inflammation demonstrated on physical exam, imaging, or endoscopy to arrive at a CRS diagnosis. While these diagnostic criteria are seemingly straightforward and are regarded as the gold standard for the diagnosis, the appropriate timing of imaging and endoscopy remain unspecified and continue to present challenges for both primary care and specialty providers. These considerations have to be measured by the direct and indirect costs of the diagnostic workup including office visits, CT scanning, endoscopy, as well as the potential for overuse of treatment modalities such as antibiotics and steroid medications. The goal of this review is to update the primary care provider and otolaryngologist on current evidence regarding the diagnosis and treatment of chronic rhinosinusitis, including the costs and timing of endoscopy and imaging. PMID- 26029487 TI - Gut Microbiome and Obesity: A Plausible Explanation for Obesity. AB - Obesity is a multifactorial disorder that results in excessive accumulation of adipose tissue. Although obesity is caused by alterations in the energy consumption/expenditure balance, the factors promoting this disequilibrium are incompletely understood. The rapid development of new technologies and analysis strategies to decode the gut microbiota composition and metabolic pathways has opened a door into the complexity of the guest-host interactions between the gut microbiota and its human host in health and in disease. Pivotal studies have demonstrated that manipulation of the gut microbiota and its metabolic pathways can affect host's adiposity and metabolism. These observations have paved the way for further assessment of the mechanisms underlying these changes. In this review we summarize the current evidence for possible mechanisms underlying gut microbiota induced obesity. The review addresses some well-known effects of the gut microbiota on energy harvesting and changes in metabolic machinery, on metabolic and immune interactions and on possible changes in brain function and behavior. Although there is limited understanding on the symbiotic relationship between us and our gut microbiome, and how disturbances of this relationship affects our health, there is compelling evidence for an important role of the gut microbiota in the development and perpetuation of obesity. PMID- 26029490 TI - Mental Health on the Go: Effects of a Gamified Attention Bias Modification Mobile Application in Trait Anxious Adults. AB - Interest in the use of mobile technology to deliver mental health services has grown in light of the economic and practical barriers to treatment. Yet, research on alternative delivery strategies that are more affordable, accessible, and engaging is in its infancy. Attention bias modification training (ABMT), has potential to reduce treatment barriers as a mobile intervention for stress and anxiety, but the degree to which ABMT can be embedded in a mobile gaming format and its potential for transfer of benefits is unknown. The present study examined effects of a gamified ABMT mobile application in highly trait anxious participants (N = 78). A single session of the active compared to placebo training reduced subjective anxiety and observed stress reactivity. Critically, the long (45 minutes) but not short (25 minutes) active training condition reduced the core cognitive process implicated in ABMT (threat bias) as measured by an untrained, gold-standard protocol. PMID- 26029491 TI - Statistical models for the analysis of skewed healthcare cost data: a simulation study. AB - Skewed data is the main issue in statistical models in healthcare costs. Data transformation is a conventional method to decrease skewness, but there are some disadvantages. Some recent studies have employed generalized linear models (GLMs) and Cox proportional hazard regression as alternative estimators. The aim of this study was to investigate how well these alternative estimators perform in terms of bias and precision when the data are skewed. The primary outcome was an estimation of population means of healthcare costs and the secondary outcome was the impact of a covariate on healthcare cost. Alternative estimators, such as ordinary least squares (OLS) for Ln(y) or Log(y), Gamma, Weibull and Cox proportional hazard regression models, were compared using Monte Carlo simulation under different situations, which were generated from skewed distributions. We found that there was not one best model across all generated conditions. However, GLMs, especially the Gamma regression model, behaved well in the estimation of population means of healthcare costs. The results showed that the Cox proportional hazard model exhibited a poor estimation of population means of healthcare costs and the beta1 even under proportional hazard data. Approximately results are consistent by increasing the sample size. However, increasing the sample size could improve the performance of the OLS-based model. PMID- 26029492 TI - Maggots as potential vector for pathogen transmission and consequences for infection control in waste management. AB - BACKGROUND AND AIMS: Debridement therapy with sterile bred larvae in non-healing wounds is a widely accepted safe and efficient treatment modality. However, during application in the contaminated wound bed microbial contamination with potential microbial pathogen spread after escape from the wound or after unreliable disposal procedure may happen, particularly in the case of not using bio-bags. The aims of this work were first to investigate the release of ingested bacteria into the environment by maggots and second to examine the common practice of freezing the maggots after use and/or disposal in trash-bags. Potential methods for hygienic safe disposal of used maggots should be deduced. METHODS: First, Maggots were contaminated with S. aureus by allowing them to crawl over an agar surface completely covered with bacterial growth over 24 h at 37 degrees C. After external disinfection maggots were transferred onto sterile Columbia agar plates and shedding of S. aureus was visualized. Second, maggots were frozen at -20 degrees C for 1, 2, 5, 10, 30, and 60 min. After exposure, the larvae were transferred onto Columbia blood agar with consecutive incubation at 37 degrees C over 48 h. The larvae were analyzed visually for mobility and eating activities. The frozen bodies of dead larvae were examined for viable bacteria. RESULTS: We could demonstrate that maggots release formerly ingested pathogens (S. aureus). Freezing at -20 degrees C for at least 60 min was able to kill all maggots, however the contaminant bacteria inside could survive. CONCLUSION: Since freezing is apparently able to kill maggots but not to reliabely inactivate the ingested bacterial pathogens, we recommend the disposal of free-range larvae in screw cap vials after use to achieve full hygienic control. PMID- 26029493 TI - Environmental Influences on Genomic Imprinting. AB - Genomic imprinting refers to the epigenetic mechanism that results in the mono allelic expression of a subset of genes in a parent-of-origin manner. These haploid genes are highly active in the placenta and are functionally implicated in the appropriate development of the fetus. Furthermore, the epigenetic marks regulating imprinted expression patterns are established early in development. These characteristics make genomic imprinting a potentially useful biomarker for environmental insults, especially during the in utero or early development stages, and for health outcomes later in life. Herein, we critically review the current literature regarding environmental influences on imprinted genes and summarize findings that suggest that imprinted loci are sensitive to known teratogenic agents, such as alcohol and tobacco, as well as less established factors with the potential to manipulate the in utero environment, including assisted reproductive technology. Finally, we discuss the potential of genomic imprinting to serve as an environmental sensor during early development. PMID- 26029494 TI - High ionic strength formation of DOPA-melanin coating for loading and release of cationic antimicrobial compounds. PMID- 26029496 TI - Genome Editing of the Blood: Opportunities and Challenges. AB - The ability to remove blood cells, including hematopoietic stem cells (HSCs), from a person and then re-transplant them (hematopoietic stem cell transplantation (HSCT) is a well-established treatment paradigm that can be used in both the autologous setting or in the allogeneic setting. Using allogeneic HSCT can cure different genetic diseases of the blood but has significant limitations. An alternative to allogeneic HSCT is to transplant genetically modified HSCs instead. A powerful approach to the precision modification of HSCs is to use genome editing whereby the genome is modified with spatial precision (at an exact location) in the genome and sometimes with nucleotide precision (the exact nucleotide changes are introduced). The progress and challenges of genome editing of blood are discussed. PMID- 26029495 TI - Manipulating miRNA Expression: A Novel Approach for Colon Cancer Prevention and Chemotherapy. AB - Small non-coding RNA has been implicated in the control of various cellular processes such as proliferation, apoptosis, and differentiation. About 50% of the miRNA genes are positioned in cancer-associated genomic regions. Several studies have shown that miRNA expression is deregulated in cancer and modulating their expression has reversed the cancer phenotype. Therefore, mechanisms to modulate microRNA (miRNA) activity have provided a novel opportunity for cancer prevention and therapy. In addition, a common cause for development of colorectal cancers is environmental and lifestyle factors. One such factor, diet has been shown to modulate miRNA expression in colorectal cancer patients. In this chapter, we will summarize the work demonstrating that miRNAs are novel promising drug targets for cancer chemoprevention and therapy. Improved delivery, increased stability and enhanced regulation of off-target effects will overcome the current challenges of this exciting approach in the field of cancer prevention and therapy. PMID- 26029498 TI - The dissociable effects of stereotype threat on older adults' memory encoding and retrieval. AB - The present study asks how subliminal exposure to negative stereotypes about age related memory deficits affects older adults' memory performance. Whereas prior research has focused on the effect of "stereotype threat" on older adults' memory for neutral material, the present study additionally examines the effect on memory for positive and negative words, as well as whether the subliminal "threat" has a larger impact on memory performance when it occurs prior to encoding or prior to retrieval (as compared to a control condition). Results revealed that older adults' memory impairments were most pronounced when the threat was placed prior to retrieval as compared to when the threat was placed prior to encoding or no threat occurred. Moreover, the threat specifically increased false memory rates, particularly for neutral items compared to positive and negative ones. These results emphasize that stereotype threat effects vary depending upon the phase of memory it impacts. PMID- 26029499 TI - Unsuspected pulmonary alveolar proteinosis in a patient with a slow resolving pneumonia: A case report. AB - Pulmonary Alveolar Proteinosis (PAP) is a rare condition with an incidence of one in two million and is classified as primary or secondary. This is the first reported case presenting as a slow resolving pneumonia. PMID- 26029497 TI - Obesity Hypoventilation Syndrome. AB - Obesity hypoventilation syndrome is a respiratory consequence of morbid obesity that is characterized by alveolar hypoventilation during sleep and wakefulness. The disorder involves a complex interaction between impaired respiratory mechanics, ventilatory drive and sleep-disordered breathing. Early diagnosis and treatment is important, because delay in treatment is associated with significant mortality and morbidity. Available treatment options include non-invasive positive airway pressure (PAP) therapies and weight loss. There is limited long term data regarding the effectiveness of such therapies. This review outlines the current concepts of clinical presentation, diagnostic and management strategies to help identify and treat patients with obesity-hypoventilation syndromes. PMID- 26029500 TI - The obstructive siblings: Relapsing polychondritis without chondritis? AB - Progressive narrowing of the central airways due to diffuse inflammation is a potential life-threatening condition. A number of diseases have been described as possible causes. We present two siblings with severe central airway obstruction. Despite considerable efforts we have not been able to match the clinical appearance of our patients with the diagnostic criteria of any of the disease entities known to cause this condition. PMID- 26029501 TI - Follicular bronchiolitis: A rare cause of persistent atelectasis in children. AB - Although atelectasis is common in children, its persistence or refractoriness to treatment should lead prompt evaluation to identify causal mechanism. We describe the case of a child presenting in first year of life with persistent left upper lobe atelectasis, recurrent wheezing and respiratory infections refractory to medical therapy, submitted to partial lobectomy when he was 3 years old age. Histopathological examination revealed follicular bronchiolitis. Systemic underlying diseases were excluded. Clinical improvement was initially achieved using inhaled corticosteroids, but oral therapy was needed due to clinical relapse, with favorable response. Follicular bronchiolitis, a rare pulmonary primary lymphoid lesion, consists of numerous reactive lymphoid follicles in a peribonchiolar distribution. Its precise cause is unknown, particularly in children, in which few cases have been reported. Treatment usually includes steroids and prognosis is generally good. PMID- 26029502 TI - Advanced lung adenocarcinoma in an EGFR-positive patient treated with Erlotinib for 52 months. AB - The authors present a case of a 53-years-old non-smoker Caucasian female who was diagnosed with lung adenocarcinoma (stage IA) and underwent surgical resection in 2002. Five years later, the tumor relapsed (stage IV disease) and she initiated chemotherapy with carboplatin, gemcitabine and bevacizumab as a first-line therapy. Despite partial remission after four cycles, this regimen was discontinued due to unacceptable toxicity. In 2008, the disease progressed and the patient was started on Erlotinib as second-line treatment. The patient had a sustained partial remission which she maintains at present - 52 months after initiation of Erlotinib. Molecular testing performed on the primary lung tumor revealed an Epidermal Growth Factor Receptor (EGFR) gene mutation (deletion in exon 19). PMID- 26029503 TI - Foreign body removed by the 'Fire and Ice Technique': A case report. AB - With the introduction of flexible bronchoscopies, several techniques and accessories have been available for the removal of foreign bodies (FB). However, in some cases, using conventional techniques are inappropriate and fail to remove the FB. Here we report a case of a 33-year-old male with 19 years foreign body aspiration history. A successfully removal of the ingrown FB was achieved by means of an argon plasma coagulation and a flexible cryoprobe. PMID- 26029504 TI - A case of idiopathic tracheal stenosis. AB - Acquired tracheal stenosis is a condition that often results from trauma, neoplasm, infection, vasculitis, inflammatory or infiltrative processes. Idiopathic tracheal stenosis is a rare entity and represents a diagnosis of exclusion. We report a case of severe localized extrathoracic tracheal stenosis in a 35 year old female who was initially suspected to have asthma as the cause of several months of chronic dyspnea. PMID- 26029505 TI - Catastrophic respiratory failure from tuberculosis pneumonia: Survival after prolonged extracorporeal membrane oxygenation support. AB - Tuberculosis (TB) is an uncommon cause of severe respiratory failure, even in highly endemic regions. Mortality in cases requiring mechanical ventilation (MV) varies between 60 and 90%. The use of extracorporeal membrane oxygenation (ECMO) is not frequently needed in TB. We report the case of a 24 year old woman diagnosed with bilateral pneumonia that required MV and intensive care, patient was managed with prone ventilation for 48 h, but persisted in refractory hypoxemia. Etiological study was only positive for mycobacterium tuberculosis. As a rescue therapy arterio-venous extracorporeal CO2 removal was started and lased for 4 days, but fails to support the patient due to greater impairment of oxygenation. Veno-venous ECMO was then initiated, thus normalizes gas exchanged and allows lungs to rest. ECMO was maintained for 36 days, with two episodes of serious complication treated successfully. Given the absence of clinical improvement and the lack of nosocomial infection, at 42-day of ICU stay methylprednisolone 250 mg daily for 4 days was started, since secondary organizing pneumonia associated with TB was suspected. Thereafter progressive improvement in pulmonary mechanics and reduction of pulmonary opacities was observed, allowing the final withdrawal of ECMO. Percutaneous tracheostomy was performed and the patient remained connected until her transfer to her base hospital at day 59 of admission to our unit. The tracheostomy was removed prior to hospital discharge, and the patient is today at home. Prolonged ECMO support is a useful and potentially successful tool in catastrophic respiratory failure caused by TB. PMID- 26029506 TI - The first patient recovered from avian influenza A H7N9 viral infection: A case report and review of the literature. AB - In March 2013, a novel avian-origin influenza A (H7N9) virus was isolated from throat swabs of 2 patients at the Fifth People's Hospital of Shanghai, China. Subsequently, 4 more patients infected by H7N9 were identified. Of the 6 patients, 4 died of acute respiratory distress syndrome. Here, we report the first case of a patient who recovered from pneumonia induced by H7N9 infection. The patient presented with fever, cough, and blood in sputum. Laboratory tests showed a low level of leukocytes, hypoxaemia, and increased levels of creatine kinase and lactate dehydrogenase. Imaging showed multiple areas of segmental ground-glass opacity in the right lung. Oseltamivir and antibiotics were administered. Supplemental oxygen helped relieve symptoms. Approximately 2 weeks after treatment, the patient finally recovered. A follow-up chest computed tomography scan taken 8 weeks later revealed that the ground-glass opacity was clearly absorbed. Therefore, timely intervention with oseltamivir and supplemental oxygen may be very important in the treatment of H7N9 infection. PMID- 26029507 TI - Pneumocystis pneumonia in everolimus therapy: An indistinguishable case from drug induced interstitial lung disease. AB - A 66-year-old male treated with everolimus for renal cell carcinoma developed exertional dyspnea. Chest computed tomography revealed diffuse interstitial shadows on both lungs. Bronchoalveolar lavage and the drug-induced lymphocyte stimulation test confirmed the diagnosis of drug-induced interstitial lung disease due to everolimus therapy. However, discontinuation of everolimus in combination with corticosteroid therapy did not prevent disease progression. On the basis of a PCR assay for Pneumocystis jirovecii and elevated beta-D-glucan levels, trimethoprim-sulfamethoxazole was administered immediately, resulting in a dramatic improvement. This case demonstrated that pneumocystis pneumonia should always be considered and treated during everolimus therapy, even when drug induced interstitial lung disease is suspected. PMID- 26029508 TI - A case report of tuberculous abscess of the chest wall accompanied with pulmonary carcinoma. AB - With the decreasing incidence of tuberculosis (TB), tuberculous abscess of the chest wall (TACW) is becoming rare. Pulmonary carcinoma coexisting with pulmonary TB has been reported in the past, but reports of pulmonary TB accompanied with TACW are scarce. We present the first case of a 66-year-old male with TACW accompanied with pulmonary carcinoma. PMID- 26029509 TI - Tumor lysis without syndrome in adenocarcinoma of the lung: Case report. AB - Tumor lysis syndrome TLS is commonly seen during the treatment of rapidly proliferating. However TLS is rarely reported in Non-small cell Lung Cancer. This may because of low proliferative rate and chemo-resistant nature of NSCLC. We are reporting a case of tumor lysis without concomitant syndrome in a patient with adenocarcinoma of Lung. PMID- 26029510 TI - Rheumatoid pleural effusion presenting as pseudochylothorax in a patient without previous diagnosis of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid pleurisy rarely occurs before a diagnosis of rheumatoid arthritis (RA). It is the second leading cause of pseudochylothorax, but there are few reports of RA-associated pseudochylothorax. CASE: A 50-year-old man presented to our hospital with an undiagnosed exudative pleural effusion. In order to obtain a definitive diagnosis, we performed medical thoracoscopy under local anesthesia. The pleural effusion was turbid and was identified as a pseudochylothorax. The parietal pleura was white and slightly thickened with numerous scattered small granules and the pleural biopsy showed an infiltration of inflammatory cells including lymphocytes and plasma cells with a lack of normal mesothelial cells, findings that were highly consistent with rheumatoid pleurisy. Additional laboratory data revealed elevated levels of CCP antibody and rheumatoid factor. During an outpatient visit about 30 days after discharge, the patient complained of polyarthralgia and was diagnosed with RA, resulting in a definitive diagnosis of the pleural effusion as rheumatoid pleurisy. CONCLUSION: We encountered a rare case of a rheumatoid pleural effusion without other symptoms of arthritis, which was identified as a pseudochylothorax by medical thoracoscopy. PMID- 26029511 TI - Human pulmonary dirofilariasis presenting as a solitary pulmonary nodule: A case report and a brief review of literature. AB - Human pulmonary dirofilariasis (HPD) is an uncommon disease in the United States. Dirofilaria is commonly known as "heartworm" based on the false belief that the worm resides in the heart which was based on findings from early necropsy reports. The first case was reported as an incidental autopsy finding in 1941. Since then only 87 more cases have been reported so far. We present an interesting case of this rare zoonotic disease affecting an elderly gentleman who presented with a rapidly growing lung nodule. We present a brief review of literature concerning the diagnosis and management of this disease. PMID- 26029512 TI - Idiopathic acute eosinophilic pneumonia: A retrospective case series and review of the literature. AB - INTRODUCTION: Idiopathic acute eosinophilic pneumonia (AEP) is characterized by hypoxemia, pulmonary infiltrates and pulmonary eosinophilia. Data is limited and the purpose of this study is to better understand this disorder. METHODS: A search of the computerized patient records from January 1, 1997 to October 15, 2010 for patients with suspicion of "eosinophilic pneumonia" was conducted. Included patients were 18 years or older with an acute febrile illness, hypoxemia, diffuse pulmonary infiltrates on imaging, and pulmonary eosinophilia. Patients were excluded with other known causes of pulmonary eosinophilia. RESULTS: Of 195 patients with pulmonary eosinophilia, 8 patients had "definite" or "probable" and 4 patients had "possible" idiopathic AEP. Three patients were categorized as "probable" idiopathic AEP due to exceeding expected maximal 30-day symptom duration and/or a maximal recorded temperature less than 38 degrees C. Four patients were defined as "possible" idiopathic AEP given histories of polymyalgia rheumatica, eczema or allergic rhinitis. Of the 8 included patients, 63% were male with a median age of 53. Median duration of symptoms was 21 days. Median nadir oxygen saturation was 83%. Median eosinophil count on bronchoalveolar lavage was 36%. Two patients required intubation. Two patients were current smokers, one of whom had reported a change in smoking habits. All patients were treated with steroids (median of two months). CONCLUSIONS: As diagnostic methods and pharmacologic knowledge improve, the number of patients meeting criteria for idiopathic AEP remains small. Much remains to be learned about this truly rare condition, and current criteria may exclude milder presentations of the disease. PMID- 26029513 TI - Primary nodal anthracosis identified by EBUS-TBNA as a cause of FDG PET/CT positive mediastinal lymphadenopathy. AB - Isolated mediastinal lymphadenopathy can result from a number of potentially serious aetiologies. Traditionally those presenting with mediastinal lymphadenopathy would undergo mediastinoscopy to elucidate a final diagnosis or receive empirical treatment. There is now increased utilization of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), in this setting. Five cases of mediastinal lymphadenopathy are presented here in which lymph node anthracosis was identified as the primary diagnosis using EBUS-TBNA. They were female, non-smokers presenting with non-specific symptoms, who retrospectively reported cooking over wood fires. Four were from South Asia. Three were investigated by F-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scanning and increased signal was identified in the anthracotic nodes sampled. With expansion of PET/CT and EBUS-TBNA services it is likely that primary nodal anthracosis will be encountered more frequently and should be considered in the differential diagnosis of those with PET/CT positive lymphadenopathy. It may mimic pathologies including tuberculosis and malignancy, thus accurate sampling and follow-up are essential. PMID- 26029514 TI - Adalimumab induced pulmonary sarcoid reaction. AB - Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology. There is evidence that Tumor Necrosis Factor alpha (TNF-alpha) antagonists are useful in the treatment of advanced or refractory disease. However, sarcoidosis-like reaction has been reported with TNF-alpha blockade in other inflammatory conditions. Here we report a case of sarcoid-like reaction in a patient with psoriatic arthritis shortly after initiation of adalimumab therapy. Stopping adalimumab and systemic anti-inflammatory therapy with corticosteroids resulted in resolution of pulmonary symptoms and chest radiographic findings. Though TNF-alpha plays a critical role in pathogenesis of sarcoidosis, the development of sarcoid reaction with TNF-alpha blockade is paradoxical and the mechanism of this response remains unknown. TNF-alpha induced sarcoid-reaction could involve multiple organs. Its development with one agent does not preclude therapy with other TNF-alpha blockers. PMID- 26029515 TI - Bilateral pneumothorax following a blunt trachea trauma. AB - A-13 year old boy had an accident with his bike with a blunt thorax trauma and presented shortly after with facial swelling. Due to respiratory insufficiency, intubation was done during the transport to the clinic. First, a chest radiograph was performed, which showed a unilateral pneumothorax. Later a CT scan revealed bilateral pneumothorax and pneumomediastinum. Bilateral chest tube insertions improved the respiratory situation. Bronchoscopy showed a tracheal lesion two cm posterior to the main carina. After good wound healing, the patient was dismissed after 21 days in good health. Conservative treatment can be recommended in selected patients with a tracheal lesion when having a stable respiratory situation. If the patient does not improve after 48 h or if the clinical condition worsens, surgical management should be considered. PMID- 26029516 TI - Interferon-alpha induced remission in three patients with eosinophilic granulomatosis and polyangiitis. A case study. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small vessel vasculitis associated with asthma and eosinophilia. Optimal therapy for maintenance of remission is yet to be defined. We present a case-series of three patients with EGPA in whom IFN-alpha, an immunomodulatory cytokine induced remission, which was maintained even after discontinuation of the drug. In all patients (ages 60, 51, and 50 years), remission was associated with normalisation of eosinophil counts and IgE-levels. Moreover, the patients remained in remission for one to four years. Two patients did not need further immunosuppression, one patient required low dose maintenance therapy. Although reversible side effects occur, IFN-alpha-therapy induces long-term remission of EGPA even after discontinuation of treatment. PMID- 26029517 TI - Case report: Biphasic presentation of multicystic haemorrhagic metastatic adenocarconoma of the lung. AB - Lung cancer is the one of the leading causes of death worldwide. Adenocarcinoma of the lung makes up over a quarter of all incidence of lung cancer. Multiple case reports describe haemorrhage resulting from primary or metastatic lesions affecting different organs. This case report describes an unusual presentation of a benign lung lesion that later progressed to multiple metastases with a characteristic radiological appearance. A review of prior similar reported cases is also included. PMID- 26029518 TI - Thoracic splenosis as a differential diagnosis of juxtapleural nodules. AB - Thoracic splenosis is rare and consists of ectopic implantation of splenic tissue into the chest after concomitant thoracic and abdominal trauma with diaphragm injury. It occurs in about 18% of cases of splenic ruptures. In almost all cases, diagnosis is given incidentally once patients are usually asymptomatic. Thoracic splenosis should be considered as a differential diagnosis in all patients with history of trauma presenting with juxtapleural nodules in chest computed tomography. However, malignant conditions should be ruled out firstly. Biopsy is not essential for the diagnosis once nuclear medicine can confirm splenosis in patients with pertinent history of trauma and suggestive tomographic image. We present a typical case of thoracic splenosis whose diagnosis was made by nuclear medicine and no invasive procedures were required. PMID- 26029519 TI - Granulomatous PJP presenting as a solitary lung nodule in an immune competent female. AB - Pneumocystis jiroveci pneumonia (PJP) opportunistically targets immunosuppressed patients, most notably those with advanced HIV/AIDS. Radiologically, PJP typically appears as bilateral diffuse pulmonary infiltrates. Herein an unusual case of an immunocompetent woman developing granulomatous PJP in the absence of evident risk factors is described. PJP may be an under-recognized cause of pulmonary nodules in immune competent individuals. PMID- 26029520 TI - Direct transbronchial administration of liposomal amphotericin B into a pulmonary aspergilloma. AB - Pulmonary aspergillomas usually occur in pre-existing lung cavities exhibiting local immunodeficiency. As pulmonary aspergillomas only partially touch the walls of the cavities containing them, they rarely come into contact with the bloodstream, which makes it difficult for antifungal agents to reach them. Although surgical treatment is the optimal strategy for curing the condition, most patients also have pulmonary complications such as tuberculosis and pulmonary fibrosis, which makes this strategy difficult. A 72-year-old male patient complained of recurrent hemoptysis and dyspnea, and a chest X-ray and CT scan demonstrated the existence of a fungus ball in a pulmonary cavity exhibiting fibrosis. Although an examination of the patient's sputum was inconclusive, his increased 1-3-beta-D-glucan level and Aspergillus galactomannan antigen index were suggestive of pulmonary aspergilloma. Since the systemic administration of voriconazole for two months followed by itraconazole for one month was ineffective and surgical treatment was not possible due to the patient's poor respiratory function, liposomal amphotericin B was transbronchially administered directly into the aspergilloma. The patient underwent fiberoptic bronchoscopy, and a yellow fungus ball was observed in the cavity connecting to the right B(2)bi-beta, a biopsy sample of which was found to contain Aspergillus fumigatus. Nine transbronchial administrations of liposomal amphotericin B were conducted using a transbronchial aspiration cytology needle, which resulted in the aspergilloma disappearing by seven and a half months after the first treatment. This strategy could be suitable for aspergilloma patients with complications because it is safe and rarely causes further complications. PMID- 26029521 TI - Pulmonary Strongyloides stercoralis infection. AB - The 17-year-old male patient presented with fever, weakness, dyspnea and weight loss. His chest radiography demonstrated diffuse reticulonodular density, and high-resolution lung tomography indicated diffuse micronodules and prevalent ground-glass pattern. The findings were consistent with miliary involvement. The patient underwent examinations for rheumatology, immunology, cytology and infectious conditions. His immune system was normal and had no comorbidities or any history of immunosuppressive treatment. Strongyloides stercoralis larvae were noted upon direct inspection of the feces. Clinical and radiological improvement was achieved with albendazole 400 mg/day. This case is being presented since miliary involvement in the lungs caused by S. stercoralis infection in an individual with intact immune system is rare and difficult to diagnosis. PMID- 26029522 TI - Lung physiology at play: Hemoptysis due to underwater hockey. AB - Hemoptysis can be a very concerning symptom, and the workup of a patient with hemoptysis may be expensive and invasive. Over the past decade, there has been increasing recognition of hemoptysis that occurs in highly trained athletes under conditions of extreme physical exertion and is explained by "pulmonary capillary stress failure". This report highlights the physiological mechanisms of pulmonary capillary stress failure in the highly trained athlete, with emphasis on the predisposition to develop this condition in underwater sports. We describe the case of an otherwise healthy 34 year-old competitive underwater hockey player who reported hemoptysis following particularly strenuous games. We postulate that the hemoptysis was a result of the pulmonary capillary stress failure caused by the cumulative hemodynamic effects of a markedly elevated cardiac output, the increased central blood volume caused by the hydrostatic effects of submersion in water, and the negative intrathoracic pressure produced by voluntary diaphragmatic contractions. PMID- 26029523 TI - Spontaneous pneumothorax in a teenager with prior congenital pulmonary airway malformation. AB - Congenital pulmonary airway malformation (CPAM), previously referred to as congenital cystic adenomatoid malformation (CCAM), is a developmental malformation of the lower respiratory tract and the most commonly reported congenital lung lesion. Affected patients typically present with respiratory distress in the neonatal period from expanding cysts and resulting compression of surrounding lung parenchyma. However, some patients also remain asymptomatic until later in life. In this report, we present a case of CPAM requiring emergent left lower lobectomy at the first day of life that remained asymptomatic until the patient developed a spontaneous pneumothorax 18 years later. Our patient's presentation with an isolated spontaneous pneumothorax at age 18 does not appear to have been previously reported. In addition, there are several aspects of this case that represent atypical features of CPAM. After an extensive literature search, few reports exist describing any long-term complications of CPAM following neonatal lobectomy. Chest imaging in our patient demonstrated residual left basilar bullae and there was a moderate fixed obstructive/restrictive defect on pulmonary function testing. His risk for recurrent pneumothorax or infectious complications is unknown based on minimal published information on long-term outcomes or complications in patients with resected CPAM lesions. We conclude that follow up of all CPAM patients should include an evaluation for evidence of residual lung disease both with spirometric testing and chest imaging. Furthermore, concern for infectious complications or symptomatic obstructive lung disease should likewise be considered. PMID- 26029524 TI - Pulmonary aspergilloma: A rare differential diagnosis to lung cancer after positive FDG PET scan. AB - Early diagnosis and treatment of lung cancer, one of the leading causes of cancer related death, is important to improve morbidity and mortality. Therefore any suspect solitary pulmonary nodule should prompt the pursuit for a definitive histological diagnosis. We describe the case of a 55-years-old male ex-smoker, who was admitted to our hospital due to recurrent hemoptysis and dry cough. A CT scan showed an irregular nodule of increasing size (28 mm in diameter) in the left lower lobe (LLL). A whole body PET-CT scan (643 MBq F-18 FDG i.v.) was performed and confirmed an avid FDG uptake of the nodule in the LLL, highly suspicious of lung cancer, without any evidence of lymphogenic or hematogenic metastasis. Bronchoscopy was not diagnostic and due to severe adhesions after prior chest trauma and the central location of the nodule, a lobectomy of the LLL was performed. Surprisingly, histology showed a simple aspergilloma located in a circumscribed bronchiectasis with no evidence of malignancy. This is a report of an informative example of an aspergilloma, which presented with symptoms and radiological features of malignant lung cancer. PMID- 26029525 TI - Rare coexistence of sarcoidosis and lung adenocarcinoma. AB - CASE: An eighty year old African-American female was evaluated for cough, chest pain, asymptomatic anemia and 21 pound weight loss over a six month period. Computerized tomography (CT) revealed a spiculated 2.8 cm right upper lobe lung nodule, other smaller nodules and lymphadenopathy. Gallium scan revealed abnormal uptake of radiotracer in lacrimal, hilar and mediastinal glands. Broncho-alveolar lavage showed CD4/CD8 ratio of 2:1 with 15% lymphocytes. Biopsy of right upper lobe lesion and mediastinoscopic lymph node biopsy showed numerous matured uniform non-caseating granulomatous inflammation, however stains and culture for Acid fast bacilli (AFB)/fungal organisms were negative. Patient improved on oral steroids. Six months later she returned with worsening dyspnea and chest X-ray showed bilateral pleural effusions. Thoracocentesis revealed Thyroid transcription factor 1 (TTF1) positive adenocarcinoma cells and Video assisted thoracic surgery (VATS) procedure revealed numerous pleural, pericardial, diaphragmatic metastasis. Biopsy also was positive for TTF1 adenocarcinoma and positive for Epidermal Growth Factor receptor (EGFR) mutation, however negative for Anaplastic Lymphoma Kinase (ALK). Talc pleurodesis was performed. She was treated with erlotinib while steroid was kept on hold. Initial tumor burden decreased but follow-up PET scan six months later showed progression of tumor with lymphadenopathy. After discussion with patient and family, patient opted for hospice care. DISCUSSION: Oncocentric theory postulates sarcoidosis as an immunological reaction to dispersal of tumor antigen. Sarcocentric theory postulates that cell-mediated immune abnormalities induced by sarcoidosis in CD4 and CD8 cells is involved in the onset of lung cancer. Thus considerable controversy exists regarding sarcoidosis and malignancy. In our case, TTF1 adenocarcinoma cells from thoracocentesis suggest peripheral nodules in right upper lobe and lingula were likely metastatic, presenting as malignant pleural effusions. However if noncaseating granulomatous inflammation is expected as an immunological reaction to tumor antigen, it is very interesting to observe that initial tissue biopsy of primary right upper lobe mass and mediastinal lymph nodes showed matured uniform non-caseating granulomatous inflammation and no evidence of adenocarcinoma. This being said, it would be highly unlikely for sarcoidosis to progress to lung adenocarcinoma within six months. This adds further controversy to whether granulomatous inflammation is a precursor to future malignancy or whether this elderly African-American female was predisposed to develop granulomatous inflammation in presence of a tumor antigen. One can also speculate whether repeat tissue sampling from right upper lobe mass would have shown granulomatous inflammation or TTF1 adenocarcinoma. CONCLUSION: While evidence is still lacking regarding association between sarcoidosis and lung adenocarcinoma, it is important for clinicians to exclude metastatic malignancy in patients exhibiting clinical and radiographic findings consistent with sarcoidosis. PMID- 26029526 TI - Idiopathic pleuroparenchymatous fibroelastosis: A case report and brief review of the literature. AB - We describe a patient with idiopathic pleuroparenchymal fibroelastosis (IPPFE). This rare clinicopathological syndrome is characterized by typical apical alterations op chest imaging, such as pleural thickening and subpleural fibrosis. Thickened visceral pleura and subpleural fibrosis consisting of dense collagen and elastin, are the main histopathological features. Etiology is unknown but a link between recurrent infections (in particular aspergillosis) and autoimmune diseases is suspected. At this time there is no standardized treatment regimen and the prognosis is variable. PMID- 26029527 TI - Pneumorachis after cocaine sniffing. AB - Air in the epidural space is called pneumorachis. The usual mechanism of pneumorachis is air diffusion from the mediastinal tissue layers through the inter-vertebral foramen. Alternatively, air can diffuse directly after spine traumas (e.g., blunt deceleration with vertebral dislocation) or medical procedures. Several mechanisms could explain pneumomediastinum and pneumorachis after cocaine sniffing. Passive apnea and/or cough that occur after sniffing can cause intra alveolar hyper-pressure, which is responsible for alveolar rupture and air diffusion. Another mechanism is alveolar wall fragility and rupture induced by repeated cocaine sniffing, in turn causing air diffusion to the mediastinum, sub-cutaneous tissues and the epidural space. The diagnosis is usually made on Chest tomography scan. Management consists in close monitoring in the intensive care unit to detect aggravation of pneumomediastinum and pneumorachis, which would require surgical management. Supplemental nasal oxygen can be given to accelerate nitrogen washout. We present a case of a 28 years old male who presented to the emergency department for chest pain directly after sniffing cocaine. A computed tomography scan of the chest showed pneumomediastinum, pneumorachis and sub-cutaneous emphysema. The patient was admitted for 24 h: after that delay, surveillance chest tomodensitometry showed stability, and he could be discharged without further treatment. PMID- 26029528 TI - Severe respiratory failure due to co-infection with human metapneumovirus and Streptococcus pneumoniae. AB - A 64-year-old male patient was admitted with respiratory failure, although chest X-rays revealed only mild bronchiolitis. Streptococcus pneumoniae, which usually presents as massive lobular pneumonia, was isolated from sputum, however, pan pathogen screening using a next-generation sequencer also detected human metapneumovirus genome fragments. PMID- 26029529 TI - Two patients with new granulomatous lung lesions during treatment of Crohn's disease. AB - Two patients with granulomatous lung lesions thought to be related to Crohn's disease (CD) are reported. Patient 1 was a 43-year-old man who was diagnosed with CD at age 11 years. He developed a fever in the 38 degrees C, and a chest X-ray and CT scan showed infiltrates with air bronchograms in the right upper lobe and left lingular segment. Transbronchial lung biopsy (TBLB) revealed granulomatous lesions. Patient 2 was a 76-year-old woman who was diagnosed with CD at age 44 years. Chest CT showed infiltrates and nodular shadows in both lung fields. Video assisted thoracoscopic surgery (VATS) in June 2012 revealed granulomatous lesions. Tuberculosis, fungal infections, drug-induced lung disorder, and sarcoidosis were ruled out as a cause of the granulomatous lesions in both patients. The aetiology was thought to be CD. PMID- 26029530 TI - Blizzard Sign as a specific endobronchial ultrasound image for ground glass opacity: A case report. AB - We report a case of lung adenocarcinoma presenting as pure ground glass opacity (GGO) and diagnosed by bronchoscopy with the use endobronchial ultrasound with a guide sheath (EBUS-GS). The lesion was indistinguishable by real-time fluoroscopy but simultaneous endobronchial ultrasound scanning of the involved lung segment showed a hyperechoic shadow that was subtly more intense than a typical snowstorm appearance when scanning normal alveolar tissue. Transbronchial biopsy from this area revealed adenocarcinoma with lepidic growth. On hindsight, it was the aforementioned ultrasound pattern that helped us decide the sampling site for EBUS-GS guided TBB when fluoroscopy was equivocal. We hypothesize that this pattern is specific for GGO and we name it the Blizzard Sign. PMID- 26029531 TI - Coinfection by Nocardia beijingensis and Nocardia arthritidis in an immunocompromised patient diagnosed by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). AB - 2 different strains of Nocardia were isolated from a lung mass in a post kidney pancreas transplant patient through convex endobronchial ultrasound transbronchial needle aspiration (EBUS-TNBA). TBNA cultures (16S rRNA gene targeted PCR sequencing) subsequently grew Nocardia beijingensis and Nocardia arthritidis. PMID- 26029532 TI - Progressing subglottic and tracheobronchial stenosis in a patient with CHARGE syndrome diagnosed in adulthood. AB - A 33-year-old woman was admitted for a pseudocroup-like cough and wheezing after general anesthesia. Several months ago, she had undergone cardiac re-operation and turbinectomy, both of which had involved difficult intubations. Bronchoscopy indicated a pin-hall-like subglottic stenosis; therefore, emergency tracheotomy was performed. Six years later, a computed tomography scan demonstrated progressive stenosis of the entire circumference of the trachea and main bronchi. She died at 40 years. Her autopsy revealed marked tracheobronchial stenosis. She had many medical histories that had gone undiagnosed and had been clinically ill with only heart defects. She did not have coloboma but had microphthalmos, atresia choanae, retarded growth development, and deafness; thus, we diagnosed CHARGE syndrome that refers to multiple congenital anomalies, including airway abnormalities, which can lead to secondary complications such as traumatic stenosis after intubation. Physicians should have knowledge of this rare disease and should pay special attention to potential airway problems. PMID- 26029533 TI - Hemomediastinum due to spontaneous rupture of a mediastinal bronchial artery aneurysm - A rare cause of thoracic pain. AB - Hemomediastinum is a rare pathological event. Multiple underlying causes and contributory factors can be identified, such as trauma, malignancy, iatrogenic, bleeding disorder or mediastinal organ hemorrhage. Also, a mediastinal bronchial artery aneurysm may be the source of a hemomediastinum. Hemoptysis is an important directive symptom, however occasionally, patients only present with thoracic pain or symptoms related to extrinsic compression of the airways or esophagus. Using contrast-enhanced computed tomography (CT) of the chest, hemomediastinum can be adequately diagnosed, and the involved vascular structures can be revealed. In case of a (ruptured) bronchial artery aneurysm, transcatheter embolization provides a minimally invasive procedure and is treatment of first choice. In this case report, a 76-year-old female is presented with spontaneous rupture of a mediastinal bronchial artery aneurysm resulting in hemomediastinum causing thoracic pain. Superselective embolization of the left bronchial artery was successfully performed. PMID- 26029534 TI - Community-acquired, hospital-acquired, and healthcare-associated pneumonia caused by Pseudomonas aeruginosa. AB - We describe three types of Pseudomonas aeruginosa pneumonia. Case 1. P. aeruginosa was isolated from the blood and sputum of a 29-year-old male non smoker who developed severe community-acquired pneumonia (CAP). Piperacillin was initially effective, but fever and lobular pneumonia with cavities developed seven days after discharge. Intravenous piperacillin/tazobactam and tobramycin were administered for four weeks, followed by oral ciprofloxacin for two weeks. He finally recovered, but developed recurrent CAP due to P. aeruginosa despite appropriate antibiotic therapy and immunocompetent status. Case 2. P. aeruginosa was isolated from the blood and sputum of a 57-year-old woman with renal cancer who developed hospital-acquired pneumonia (HAP) after surgical treatment. She recovered after meropenem administration for four weeks. Case 3. A 67-year-old woman with systemic sclerosis and malignant lymphoma who was followed up on an outpatient basis underwent immunosuppressive therapy. Thereafter, she developed pneumonia and was admitted to our institution where P aeruginosa was isolated from blood and sputum samples. Healthcare-associated pneumonia (HCAP) was diagnosed and effectively treated with tobramycin and ciprofloxacin. P. aeruginosa is not only a causative pathogen of HAP and HCAP, but possibly also of CAP. PMID- 26029535 TI - Continuous Positive Airway Pressure (CPAP) for prevention of recurrent pneumonia in the Neuromyelitis Optica patient. AB - INTRODUCTION: Traumatic spinal cord injury patients with quadriplegia associated respiratory compromise are at an immediately increased risk of developing pneumonia, but the onset of pneumonia risk and use of prevention strategies in the patient with quadriplegia due to Neuromyelitis Optica has not been described. CASE REPORT: This is a case of a Neuromyelitis Optica patient with quadriplegia, dysphagia and tracheostomy that suffered recurrent fevers due to respiratory infections. The non-specific presentation and test results led to extensive testing, while the frequent recurrence resulted in the patient residing in the acute care hospital 201 days and outside of this hospital only 118 days during the period of August 2011 to June 2012. The initiation of CPAP 10 cm while sleeping overnight for 8-10 h eliminated the recurrence of respiratory infections and thereby reduced both the frequency and duration of the patient's hospital stays. CONCLUSIONS: Patients with Neuromyelitis Optica differ from those with traumatic spinal cord injury as they have a chronic progressive systemic illness that causes continued deterioration of their nervous system resulting in the need for routine monitoring that ensures the timely addition of CPAP for the prevention of pneumonia and its associated medical expenses. PMID- 26029536 TI - A severe H7N9 pneumonia with syndrome of inappropriate antidiuresis and vitamin D deficiency. AB - OBJECTIVE: Some H7N9 patients presented with hyponatremia. But whether SIAD could be the etiology of hyponatremia in H7N9 pneumonia is still not known. DESIGN SETTING AND PARTICIPANTS: A H7N9 patient was enrolled. Clinical sign were evaluated. Effective osmolality, urinary osmolality, urinary sodium, thyroid function, adrenal function, 25(OH) Vitamin D and cellular immune function were measured. RESULTS: (1) The results showed low serum osmolality, inappropriately elevated urine osmolality, elevated urine sodium concentration, low serum uric acid concentration, relatively normal serum creatinine concentration, normal acid base and potassium balance, normal adrenal and thyroid function in our patient. (2) Our patient showed vitamin D deficiency and decline of cellular immune function. CONCLUSIONS: Some H7N9 pneumonia could cause SIAD. Early detection and appropriate treatment of SIAD in H7N9 pneumonia might be important. Our patient showed vitamin D deficiency and decline of cellular immune function. PMID- 26029537 TI - Cerebral air embolism following transbronchial lung biopsy during flexible bronchoscopy. AB - During a diagnostic flexible bronchoscopy an 84 year old patient suffered a sudden reduction in conscious level following a transbronchial lung biopsy. A subsequent computed tomography brain scan confirmed cerebral air emboli. The patient survived following a period of supportive treatment in the critical care unit. Transbronchial lung biopsy may cause disruption of vessels walls within the lung parenchyma. Increased airway pressure, caused by the patient exhaling against a bronchoscope wedged within a segmental bronchi, may subsequently force air bubbles through the vessel wall defects. This may explain the occurrence of air emboli. This is a rare report of air embolism complicating transbronchial lung biopsy and all bronchoscopists should aware of this potentially fatal complication. PMID- 26029538 TI - Two cases of culture proven Mycobacterium tuberculosis presenting with a broad complex tachycardia and non-caseating granulomas. AB - Tuberculosis is a leading cause of death worldwide. It affects pulmonary and extra-pulmonary sites with a multitude of differing presentations. In this report, we describe two cases in which TB causes myopericarditis and presents with a broad-complex tachycardia that did not respond typically to standard anti arrhythmic therapy; a very rare presentation with limited description in the literature. Both patients required extensive investigation culminating in identifying lymph nodes amenable to biopsy under endobronchial ultrasound guidance. It was not until both patients received anti-tuberculous chemotherapy alongside anti-arrhythmic management that any improvement to their condition was witnessed. Therefore, we recommend that the clinician should have a high index of suspicion for TB in any patient presenting with a broad-complex tachycardia that is not responding to standard first line management, especially if the patient is from a high risk background. We recommend an active diagnostic pursuit, and lymph node biopsy under endobronchial ultrasound guidance. PMID- 26029539 TI - Bullous emphysema - Not always nicotine-related!: Unusual distribution of emphysema in a patient with a rare hobby. AB - In a patient admitted for further investigation of haemoptysis and dyspnoea and known emphysema of the lung, a remarkable distribution of emphysematous bullae could be detected on CT-imaging. Further history, besides smoking, revealed apnoea diving-activity during younger adult age. The distinct appearance of partially septated pleura-based bullae lead to the suspicion of a positive pressure barotrauma of the lungs in the past, now complicated by infection and bleeding. This case highlights the importance of thorough questioning of the patient and underlines the consideration of differential diagnoses of emphysema. PMID- 26029540 TI - No effect of pirfenidone treatment in fulminant bleomycin-induced pneumonitis. AB - Bleomycin-induced pneumonitis (BIP) is a serious and potentially fatal adverse effect of bleomycin. Currently, BIP is treated on an empirical basis with high dose steroid. Pirfenidone is a new antifibrotic drug, which has been proven beneficial in idiopathic pulmonary fibrosis and is able to inhibit or reverse BIP in animal models. Here, the first two cases of human BIP treated with pirfenidone in addition to steroid therapy are presented. Unfortunately, both patients died, which may be explained by the initiation of therapy at a late stage. Therefore, studies of early or prophylactic treatment with pirfenidone in relation to bleomycin-containing chemotherapy regimens are needed. PMID- 26029541 TI - Emphysema and COPD in a young woman. AB - A 28-year old woman presented with a progressive cough and breathlessness. She had a family history of early onset COPD. Spirometry demonstrated airflow obstruction with no reversibility. An HRCT showed extensive centrolobular emphysema with an upper lobe predominance. Blood tests including an Alpha - 1 Antitrypsin level were normal. PMID- 26029542 TI - An unusual cause of an anterior mediastinal mass. AB - Mesothelioma is a rare tumour and its radiological growth pattern varies. We report the case of a biopsy proven Malignant Pleural Mesothelioma (MPM) presenting as an anterior mediastinal mass in a platinum miner. The prognosis for this aggressive tumour remains poor, despite combination treatment modalities. PMID- 26029543 TI - T-cell lymphoblastic lymphoma presenting with pleural effusion: A case report. AB - Adult lymphoblastic lymphoma (LBL) is an aggressive form of non-Hodgkin lymphoma occurring in predominantly adolescent and young adult men, accounting for 1% to 2% of all non-Hodgkin's lymphomas. In contrast to B-LBL, T-cell LBL is much more common, accounting for up to 90% of disease in adults. Mediastinal mass, pleural and/or pericardial effusions are the major characteristics of T-LBL. We report an 18-year-old male with a pleural effusion, mediastinal mass, a light pericardial effusion, and a normal hemogram. The cytology of the pleural effusion initially suggested malignancy, but definitive diagnosis was unclear. After a medical thoracoscopy, the partial pleura was picked and immunophenotypic study revealed the following: CD3(+), TdT(+), CD99(+), CD20(-). The patient was finally diagnosed with T-LBL and died only 6 months after that. The case highlight the point that medical thoracoscopy is a safe and accurate diagnostic procedure for pleural diseases, and partial pleura biopsy with immunophenotyping was essential for achieving the correct diagnosis of LBL. PMID- 26029544 TI - Bronchial leiomyoma, a case report and review of literature. AB - A 44 year old male former smoker from Ecuador presented with productive cough for 3 weeks, positive tuberculin skin test, 40 lbs weight loss and right lower lobe collapse. He denied wheezing or hemoptysis. He was treated with antibiotics and ruled out for tuberculosis with negative sputum smear. Bronchoscopy showed an endobronchial lesion at the distal end of bronchus intermedius as cause of the collapse. Endobronchial biopsy of the lesion revealed an endobronchial leiomyoma, a rare cause of endobronchial tumor. The patient underwent bilobectomy as definite therapy for the leiomyoma due to its large size and possible extra luminal extension, which made it not amenable to bronchoscopic resection or bronchoplasty. Differential diagnoses of endobronchial lesions are discussed along with clinical, radiographic, pathologic characteristics and various treatment modalities for endobronchial leiomyomas. PMID- 26029545 TI - Severe "sweet" pleural effusion in a continuous ambulatory peritoneal dialysis patient. AB - INTRODUCTION: Hydrothorax is a rare complication of continuous ambulatory peritoneal dialysis (CAPD) which can progress quickly to cause acute respiratory distress. CASE PRESENTATION: We present a 76 year-old female with a past medical history significant for end-stage renal disease (ESRD) on daily home peritoneal dialysis for 2 years presented to the hospital from home with shortness of breath at rest and cough for 2 days prior to admission. She developed severe respiratory distress and had emergent pleurocentesis that released 3.8 L of pleural fluid. The analysis showed significantly high sugar indicative of hydrothorax from CAPD. She underwent thoracotomy with pleurodesis and switched to hemodialysis for 6 weeks before resuming CAPD. CONCLUSION: A high glucose concentration in the pleural fluid is pathognomonic for hydrothorax from dialysis fluid after rule out other possible causes of pleural effusion. Patients who are on CAPD presenting with marked pleural effusion should prompt clinicians to consider the differential diagnosis of pleuroperitoneal communications. PMID- 26029546 TI - Chyloptysis causing plastic bronchitis. AB - Chyloptysis is a rare clinical problem that is associated with conditions affecting lymphatic channels in the thorax. Diagnosis is usually made when the patients present with expectoration of milky-white sputum or of thick tenacious mucus in the shape of smaller bronchi (bronchial cast). Typically the symptoms resolve after coughing up of the bronchial casts. Pleural, mediastinal, pulmonary or lymphatic abnormalities result in chyloptysis. Lymphangiography and detection of lipids (cholesterol or triglycerides) in sputum help to establish the diagnosis. However, lymphangiography may not be positive in all patients. We report 2 patients with chyloptysis and bronchial casts with different etiologies. Abnormal lymphatics were demonstrated in one of our cases, but the second patients lymphangiogram was normal. In this patient we suspect that high venous filling pressures due to congestive heart failure had a causative effect in the setting of compromised lymphatic drainage in the thorax due to a prior history of radiation therapy to the chest for lymphoma. PMID- 26029547 TI - Should patients be advised not to fly post thoracentesis? AB - Air travel poses a risk to patients with a pneumothorax due to in-flight pressure changes and guidance is available providing advice on air travel in patients with a pneumothorax. Pneumothorax is a recongnised complication of pleural thoracentesis, however chest radiographs have been shown to have limited sensitivity in diagnosing pneumothoraces and small pneumothoraces may not be recognised. There is, therefore a risk post thoracentesis, of exacerbating an unrecognised pneumothorax by air travel. This case outlines the presentation of a 55 year old lady, with a normal chest radiograph after an uncomplicated simple needle aspiration for a pleural effusion, who developed a large pneumothorax during air travel. PMID- 26029548 TI - Pneumomediastinum and (bilateral) pneumothorax after high energy trauma: Indications for emergency bronchoscopy. AB - High energy trauma may cause injury to tracheobronchial structures. This is sometimes difficult to diagnose immediately. Pneumomediastinum and (bilateral) pneumothorax seen on a CT-scan of the thorax may suggest possible damage to central airways. Emergency bronchoscopy should be performed to detect and locate a possible tracheobronchial injury. PMID- 26029549 TI - Complication of antiquated tuberculosis treatment. AB - In the early 20th century, the rapid spread of tuberculosis (TB) invited novel therapies for treatment. A surgical procedure known as plombage was one such method where lobes were forced to collapse by placing an inert object such as mineral oil, paraffin wax, gauze or Lucite (methyl methacylate) balls. The collapse would lead to isolation of TB infection and decrease aeration of the affected lung. Removal of these objects had initially been, usually after 24 months, however this fell out of favor after the patient had recovered without commonly seen late complications. Decades later, reports have been made illustrating complications such as migration and infection of the plombe as well as expanding oleothorax. PMID- 26029550 TI - Rapidly progressive pneumonia caused by Cryptococcus neoformans in the patient of granulomatosis with polyangiitis. AB - A 57-year-old male who had been treated for granulomatosis with polyangiitis (GPA) presented with cough and back pain that had persisted for three days. Mild infiltration shadows and nodules were found on computed tomography images at that time. Increase of GPA lesions and/or bacterial pneumonia was initially suspected. However, serum Cryptococcus neoformans antigen was positive and the chest X-ray findings had worsened by the following day despite of appropriate antibiotic treatment. Thus, pneumonia due to C. neoformans was diagnosed because C. neoformans was also isolated blood and lung tissues, and he was treated with antifungal agents: L-AMB and 5-FC, and followed up by chest radiography on a daily basis. PMID- 26029551 TI - Multiple distant metastases in a case of malignant pleural mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is a malignant of mesodermal neoplasm and arises from multipotential mesothelial or subserosal cells of the pleura, pericardium and peritoneum. CASE: A seventy five year-old male patient was admitted with chest and lower limb pain. He was a heavy smoker and exposed to environmental asbestos in his childhood. PET-CT scans showed multiple pathological FDG uptakes in lungs and other organs. Biopsies performed from lung and anterior thigh muscles were reported as epitheloid type malignant pleural mesothelioma. DISCUSSION: We emphasize that unexpected distant metastases can be observed in MPM and occasionally primary diagnosis can be determined by the biopsy of the metastatic regions. This case also points out the role of PET-CT in the staging of malign mesothelioma by determining different metastatic sites. PMID- 26029552 TI - Acute exacerbation of airspace enlargement with fibrosis. AB - In 2008, Kawabata et al. described a lesion which they termed "airspace enlargement with fibrosis" that could be included on the spectrum of smoking related interstitial lung diseases. This group also reported that patients with airspace enlargement with fibrosis but without coexisting interstitial pneumonia of another type had no acute exacerbations and favorable prognoses on clinical follow-up. Here we describe the first case, to our knowledge, of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of another type. An 82-year-old man was referred to our department for worsening dyspnea and new alveolar opacities on chest radiograph following left pulmonary segmentectomy (S6) for cancer. A diagnosis of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of other types was made, based on pathological evidence of airspace enlargement with fibrosis and organizing diffuse alveolar damage. Treatment with high-dose methylprednisolone followed by tapered oral prednisolone resulted in gradual improvement of the clinical condition and chest radiographic findings. Clinicians should be aware that patients with airspace enlargement with fibrosis may experience acute exacerbation. PMID- 26029553 TI - Malignant pleural effusion from prostate adenocarcinoma. AB - Prostate adenocarcinoma is the most common newly diagnosed cancer in males. Pulmonary and pleural metastasis are not uncommon on autopsy, but malignant effusions are not common clinical findings. There are no current recommendations to guide prostate specific antigen level assessment in pleural fluid. A 73 yo w/prostate cancer presented with complaints of subacute worsening of exertional dyspnea. He underwent a CT of the chest which excluded pulmonary emboli but did show moderate to large bilateral pleural effusions. The patient had a thoracentesis performed which confirmed an exudative effusion with atypical cells and elevated PSA levels. Metastatic visceral & parietal foci of prostate adenocarcinoma were found on medical pleuroscopy. The patient was symptomatically treated with bilateral tunneled chest tube catheters for intermittent drainage. Pulmonary metastasis secondary to prostate cancer is commonly found on autopsy, with pulmonary metastasis in 46% of patients and pleural metastasis in 21% of patients. Pleural effusions are not common, in one series, only 6/620 (1%) were found to have pleural masses/nodules or effusions. Diagnosis of pleural effusion secondary to metastatic prostate cancer can be achieved by direct cytology evaluation and/or PSA level elevation in the fluid. While specific, the sensitivity is not high enough to rule out disease if negative. Elevated pleural fluid PSA levels may aid in the diagnosis; however, there are no current recommendations as to what level may be considered diagnostic. Further studies are needed to define the sensitivity and specificity of PSA in pleural fluid. PMID- 26029554 TI - Benefit of a second opinion: From metastatic disease to resectable lung cancer with sarcoid-like reaction. AB - BACKGROUND: Mediastinal lymphadenopathy in combination with lung cancer is suggestive for lymph node metastases but can also have other origins. CASE REPORT: We describe a patient diagnosed with stage IV lung cancer presenting with parenchymal lesions and enlarged mediastinal lymph nodes. A second opinion including FDG-PET scan review and a mediastinoscopy followed by surgery revealed tumor specimens originating from a single primary tumor with a sarcoid-like reaction in the mediastinal lymph nodes, changing the diagnosis from metastasized to resectable lung cancer. DISCUSSION: PET positive lesions are not always synonymous with metastatic disease in the presence of a malignant tumor. Conscientious review of FDG-PET scans and tissue sampling are therefore mandatory to determine definitive staging and subsequent interventions. PMID- 26029555 TI - Endotracheal ectopic parathyroid adenoma mimicking asthma. AB - Primary benign tumors of the trachea are uncommon. These tumors may cause tracheal occlusion and lead to a misdiagnosis of asthma. Ectopic parathyroid adenoma (EPA) can be seen anywhere between the mandibular angle and the mediastinum. The distal part of the trachea is a rare location for EPA, and EPA obstructing the endotracheal lumen has not been reported in the literature. We herein describe a 52-year-old female with a several-year history of asthma treatment who presented with progressive dyspnea. Computed tomography revealed a mass that was obstructing the tracheal lumen. Total mass excision was performed via endobronchial treatment, and pathologic examination revealed EPA. PMID- 26029556 TI - Two cases of extrapulmonary onset granulomatosis with polyangiitis which caused diffuse alveolar haemorrhage. AB - Granulomatosis with polyangiitis (GPA) is a rare form of vasculitis. Multidisciplinary therapeutic approach and early diagnosis assume vital importance in management of patients with diffuse alveolar haemorrhage caused by GPA, which is a rare complication. The purpose of this study was to present the diagnostic and therapeutic challenges experienced by clinicians in management of two severe cases of GPA with insidious extrapulmonary manifestations which rapidly progressed into acute kidney injury, alveolar haemorrhage and acute respiratory failure. PMID- 26029557 TI - Argon plasma coagulation in the management of uncovered tracheal stent fracture. AB - Endotracheal and endobronchial stenting, particularly with uncovered stents, can be complicated by stent fracture, granulation tissue formation, direct airway injury, and airway obstruction. While stent removal is possible, it can result in significant complications and long-term benefit is not guaranteed. Argon plasma coagulation can be employed to trim fractured stent fragments and remove granulation tissue simultaneously. In this manuscript, we report a case and describe our experience with using this technique. PMID- 26029558 TI - Primary systemic amyloidosis: A rare cause for pleural effusion. AB - Pleural effusion is a common problem dealt by most of the practicing clinicians. Some causes for pleural effusion are less often considered as a differential diagnosis owing to its rarity. Here we report a case of renal amyloidosis on alternate day haemodialysis for about two months time presenting with left sided pleural effusion. On evaluation this turned out to be a case of amyloidosis on thoracoscopic pleural biopsy suggesting the possibility of Primary systemic amyloidosis. PMID- 26029559 TI - Disseminated tuberculosis infection and paradoxical reaction during antimycobacterial treatment related to TNF-alpha blocker agent Infliximab. AB - Tumor necrosis factor (TNF)-alpha inhibitors play an important role in the treatment of immun-mediated diseases such as Crohn's disease. But they also have been related to increased risk for disseminated Mycobacterium tuberculosis infections and paradoxical response to antimycobacterial treatment. Here we report a disseminated tuberculosis case and a paradoxical response to treatment after receiving TNF-inhibitor agent Infliximab for Crohn's disease. The patient had a severe clinical condition before the antimycobacterial treatment and although proper treatment was initiated his radiological findings were worsened one month after initiation of the treatment. All control microbologic tests for secondary infections were negative and this situation was accepted as a paradoxical response to antimycobacterial treatment and treatment was continued with the same regimen. At the end of the second month of the treatment, most of the symptoms disappeared and chest radiograph findings were better than the previous one. In conclusion, TNF-alpha inhibitor therapy increases risk of mycobacterial infections and patients should be examined carefully about tuberculosis before starting this therapy. Also, it is important for physicians to recognize and know how to manage paradoxical response related to TNF-alpha inhibitors during anti-tuberculosis treatment. PMID- 26029560 TI - A rare cause of hemoptysis. AB - Angiosarcomas are rare, malignant, endothelial-cell tumors of vascular origin that can arise at any body site. They frequently metastasize to the lung, heralded by dyspnea, hemoptysis, chest pain, pneumothoraces, and diffuse pulmonary hemorrhage. However, in most cases lung metastases are discovered after the diagnosis of a primary angiosarcoma has already been established. Very rarely will an undiagnosed metastatic angiosarcoma present as diffuse pulmonary hemorrhage. We describe the case of a 59-year-old male who presented to hospital with dyspnea and hemoptysis. CT chest revealed rapidly progressing nodular changes and broncho-alveolar lavage returns were progressively bloody. Open lung wedge biopsy ultimately revealed metastatic angiosarcoma and extensive pulmonary hemorrhage. Our case highlights the key clinical, radiological, and pathological features of this rare malignancy that frequently metastasizes to the lung and reminds clinicians to consider it as a cause of hemoptysis and pulmonary hemorrhage. PMID- 26029561 TI - Alkaline phosphatase flare phenomenon following epidermal growth factor receptor tyrosine kinase inhibitor treatment of non-small cell lung cancer: Report of a case and case review. AB - Alkaline phosphatase (ALP) flare phenomenon documented as scintigraphic flare phenomenon due to elevated serum ALP levels produced by osteoblasts reflects an osteoblastic reaction in response to the effective therapy of non-small cell lung cancer (NSCLC). Here, we report a case of ALP flare following gefitinib treatment for NSCLC. We also retrospectively analyzed the prevalence of ALP flare in lung cancer patients treated via epidermal growth factor receptor-tyrosine kinase inhibitor in our hospital. Recognition of this phenomenon is important for physicians treating NSCLC patients to avoid discontinuation of a potentially beneficial treatment because of misdiagnosis for refractory multiple bone metastasis or adverse effect. PMID- 26029562 TI - An interesting septic embolism. AB - Septic pulmonary embolism is a rare disease but mortality and morbidity of it is high. Septic pulmonary emboli comes from infected heart valves, thrombophlebitis, and pulmonary artery catheter or infected pacemaker wires as many sources [1,2]. In recent years, pacemaker is a common treatment of the bradiarrhythmia that is persisted in the etiology of septic embolism, its applications has started to pick up [3]. There is the growing number of patients with pacemaker, according to this the frequency of pacemaker lead infection and the number of patients at risk for right-sided endocarditis increase [4]. The patients don't have specific clinical and radiological features because of this it is very difficult to define, so the diagnosis is often delayed [5]. A detailed medical history, a detailed physical examination in diagnosis and evaluation of good additional imaging methods is very important. Early diagnosis and proper treatment, the implementation of the management, can provide good results. PMID- 26029563 TI - A rare tumor of trachea: Inflammatory myofibroblastic tumor diagnosis and endoscopic treatment. AB - Inflammatory myofibroblastic tumors (IMTs) are rare childhood neoplasms, with benign clinical course. Although etiology of IMTs are not clear, recent studies have reported that IMT is a true neoplasm rather than a reactive or inflammatory lesion. IMTs are rarely seen in adults and tracheal involvement is also rare both in adults and also in children. We describe a 16-year old female patient who was misdiagnosed and treated as asthma in another center for a few months and presented with acute respiratory distress due to upper airway obstruction. Computerized tomography (CT) of the chest and rigid bronchoscopy revealed a mass lesion that was nearly totally obliterating tracheal lumen. Bronchoscopic resection was performed under general anesthesia and the final pathological diagnosis was tracheal IMT. PMID- 26029564 TI - Disseminated tuberculosis in a non immun compromised patient with a complicated diagnosis. AB - Tuberculosis (TB) has become a global emergency worldwide. The long time period between the exposure to TB bacillus and the onset of symptoms cause a delay in diagnosis. Herein, we report a case of 64-year-old female patient suffering from dyspepsia, anorexia, weight loss and abdominal pain for the last 8 months. Physical examination, ascites fluid evaluation, chest radiography, ultrasonographic and tomographic scans, histopathological analysis of the lymphadenopathy (LAP) and endometrial tissue revealed TB. A fourfold antituberculous treatment with isoniazid, pyrazinamide, rifampicin and ethambutol was prescribed for two months and for four months maintenance therapy with isoniazid and rifampicin was given. On the fourth month of the medical treatment the patient clinically recovered. Since the diagnosis of TB is difficult, high grade suspicion, combination of the radiologic, microbiologic and histopathological examinations are needed to achieve a diagnosis. PMID- 26029565 TI - A rare benign intrathoracic mass in a patient with history of rocket explosion. AB - Thoracic splenosis is rare benign condition that follows trauma leading to diaphragmatic injury. Most of the patients including ours present with a clear traumatic event leading to autotransplantation of spleen in thoracic cavity. Mostly diagnosed incidentally and we need to avoid unnecessary workup including radiological and invasive. It is a very important case which signifies importance of good history taking and initial imaging for making diagnosis and making our pulmonogist and internist aware of this diagnosis. PMID- 26029566 TI - Improvement in idiopathic nonspecific interstitial pneumonia after smoking cessation. AB - Although cigarette smoking has been recognized as a risk factor for the development of several interstitial lung diseases, the relationship between smoking and nonspecific interstitial pneumonia (NSIP) has not yet been fully elucidated. We here present a case of fibrotic NSIP with mild emphysema in an elderly male with normal pulmonary function, whose symptoms, serum KL-6 level, and high-resolution computed tomography findings of interstitial changes markedly improved without medication following the cessation of smoking. Our case suggests that smoking may be an etiological factor in some patients with NSIP and that early smoking cessation before a clinically detectable decline in pulmonary function may be critical for smokers with idiopathic NSIP. PMID- 26029567 TI - Reexpansion pulmonary edema after chest drainage for pneumothorax: A case report and literature overview. AB - BACKGROUND: Reexpansion pulmonary edema (RPE) is a rare complication that may occur after treatment of lung collapse caused by pneumothorax, atelectasis or pleural effusion and can be fatal in 20% of cases. The pathogenesis of RPE is probably related to histological changes of the lung parenchyma and reperfusion damage by free radicals leading to an increased vascular permeability. RPE is often self-limiting and treatment is supportive. CASE REPORT: A 76-year-old patient was treated by intercostal drainage for a traumatic pneumothorax. Shortly afterwards he developed reexpansion pulmonary edema and was transferred to the intensive care unit for ventilatory support. Gradually, the edema and dyspnea diminished and the patient could be discharged in good clinical condition. CONCLUSION: RPE is characterized by rapidly progressive respiratory failure and tachycardia after intercostal chest drainage. Early recognition of signs and symptoms of RPE is important to initiate early management and allow for a favorable outcome. PMID- 26029568 TI - Dramatic and sustained responsiveness of pulmonary Langerhans cell histiocytosis associated pulmonary hypertension to vasodilator therapy. AB - Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized by the abnormal accumulation of Langerhans' cells around small airways and other distal lung compartments. Although pulmonary hypertension (PH) is a frequent complication of PLCH, the role of advanced PH therapies for PLCH-related PH is not well-established. We describe a PLCH patient with severe, disease-related PH that responded unexpectedly well to advanced PH therapy with sustained improvement over a 10 year follow-up period. This case indicates that PLCH-associated PH may, in certain instances, be highly responsive to advanced PH therapies and emphasizes the importance of trialing these therapies among patients with PLCH-related PH. PMID- 26029569 TI - Tension chylothorax following pneumonectomy. AB - Post-pneumonectomy chylothorax is an uncommon complication following surgery, with an estimated incidence of less than 0.7%. Post-pneumonectomy tension chylothorax, where rapid accumulation of chyle in the post-pneumonectomy space results in hemodynamic compromise, is exceedingly rare, with just 7 cases previously reported. All prior cases of tension chylothorax were managed operatively with decompressive chest tube placement followed by open thoracic duct repair. Our case is the first reported tension chylothorax to be managed conservatively by thoracostomy drainage coupled with a period of parenteral nutrition followed by a medium chain triglyceride-restricted diet. PMID- 26029570 TI - Bosentan for pulmonary hypertension secondary to idiopathic pulmonary fibrosis. AB - Pulmonary hypertension is a poor prognostic factor in patients with interstitial lung disease. No established treatment exists for pulmonary hypertension secondary to interstitial pneumonia. We describe the case of an 81-year-old woman with idiopathic pulmonary fibrosis (IPF), who was admitted to our hospital due to aggravation of dyspnea and decreased oxygen saturation, as well as onset of orthopnea and rapidly progressing edema. The transthoracic echocardiography and right heart catheterization showed the mean pulmonary artery pressure was 39 mmHg and the mean pulmonary capillary wedge pressure was 9 mmHg. After various examinations, the diagnoses of pulmonary hypertension (PH) due to IPF and of congestive heart failure secondary to PH were established. Diuretic therapy was started, but the patient's condition showed poor improvement. Subsequent initiation of oral bosentan therapy led to improvement in symptoms and findings. At the follow-up assessment one year later her pulmonary function showed no significant changes and no apparent worsening of arterial blood gases, with evident improvement of PH, WHO functional class, maximum exercise tolerance on treadmill exercise testing, right heart catheterization, and transthoracic echocardiography. This report describes a case of successful treatment with bosentan for severe pulmonary hypertension in a patient with idiopathic pulmonary fibrosis. We also present a review of the literature on treatment of pulmonary hypertension in patients with chronic lung disease. Bosentan appears to be efficacious in some patients with pulmonary hypertension secondary to idiopathic interstitial pneumonitis. PMID- 26029571 TI - Olanzapine-induced eosinophilic pleuritis. AB - An elderly patient, with a history of depression with psychosis, presented with breathlessness, a right exudative pleural effusion and a peripheral eosinophilia. The pleural fluid was eosinophil-rich (10% of leucocytes). Olanzapine therapy had been commenced 12 months previously. There was a family history of TB and the patient was of African origin. A full diagnostic work-up ensued including computed tomography of the thorax and local anaesthetic thoracoscopy. The pleura was unremarkable on CT and displayed bland smooth thickening at visual inspection during thoracoscopy. Pleural biopsies demonstrated chronic inflammation with eosinophils but no evidence of granulomatous inflammation or malignancy. Pleural tissue culture did not yield mycobacteria. A diagnosis of olanzapine-induced eosinophilic pleuritis was suspected and the pleural disease resolved with withdrawal of olanzapine. Eosinophilic pleural fluid is not a marker of non malignant aetiology and eosinophilic pleural effusions require a careful and systematic diagnostic work-up. This is the second case report to identify olanzapine as a causative agent in eosinophilic pleural effusion. PMID- 26029572 TI - Rescue therapy using an endobronchial valve and digital air leak monitoring in Invasive Pulmonary Aspergillosis. AB - In this case report, we describe the utilisation of two recently developed technologies for the successful management of a persistent air leak (PAL) in a critically ill patient in whom cardiothoracic surgical intervention was not possible. We report the case of a young leukaemic woman with a PAL complicating Invasive Pulmonary Aspergillosis (IPA), who was effectively managed using an Endobronchial Valve, supplemented by objective, digital air leak data provided by a Thopaz((r)) device (Medela, Switzerland). PMID- 26029573 TI - A breath from Houdini - A case of giant bullous emphysema. AB - We describe a case of a young man presenting with exertional dyspnea. His chest radiograph showed hyperlucency in his left lung, and he was subsequently diagnosed to have giant bullous emphysema. An approach to lesions of decreased attenuation on computed tomography of the chest, with a focus on cystic lung diseases is discussed. This is followed by a literature review of the clinical presentation, natural history, radiology and management of giant bullous emphysema. Although this is an uncommon condition, a clinician has to be cognizant of the fact that it may mimic other common respiratory diseases. This review highlights the importance of these caveats as misguided treatment options may lead to devastating consequences. PMID- 26029574 TI - Tracheal epithelial-myoepithelial carcinoma associated with sarcoid-like reaction: A case report. AB - Epithelial-myoepithelial carcinomas are rare tumors that primarily originate in the salivary glands but have also been found in the tracheobronchial tree. We report the first case of epithelial-myoepithelial carcinoma associated with sarcoidosis. A 61 year old Hispanic man presented with altered mental status and hypercalcemia. Imaging revealed diffuse intra-thoracic and intra-abdominal lymphadenopathy. A diagnostic bronchoscopy was performed where an incidental tracheal nodule was discovered and biopsied. Pathology was consistent with epithelial-myoepithelial carcinoma. Lymph node biopsy demonstrated non-caseating granulomas consistent with sarcoidosis. Patient underwent tracheal resection of the primary tumor with primary tracheal reconstruction. Hypercalcemia subsequently normalized with clinical improvement. Repeat CT imaging demonstrated complete resolution of lymphadenopathy. Our findings are suggestive of a possible paraneoplastic sarcoid-like reaction to the epithelial-myoepithelial carcinoma with associated lymphadenopathy and symptomatic hypercalcemia. PMID- 26029575 TI - Facioscapulohumeral muscular dystrophy and respiratory failure; what about the diaphragm? AB - INTRODUCTION: We present a case of facioscapulohumeral muscular dystrophy (FSHD) with a diaphragm paralysis as the primary cause of ventilatory failure. FSHD is an autosomal dominant inherited disorder with a restricted pattern of weakness. Although respiratory weakness is a relatively unknown in FSHD, it is not uncommon. METHODS: We report on the clinical findings of a 68-year old male who presented with severe dyspnea while supine. RESULTS: Supplementing our clinical findings with laboratory, electrophysiological and radiological performances led to the diagnosis of diaphragm paralysis. Arterial blood gas in sitting position without supplemental oxygen showed a mild hypercapnia. His sleep improved after starting non-invasive ventilation and his daytime sleepiness disappeared. DISCUSSION: We conclude that in patients with FSHD who have symptoms of nocturnal hypoventilation, an adequate assessment of the diaphragm is recommended. This is of great importance as we know that nocturnal hypoventilation can be treated effectively by non-invasive ventilation. PMID- 26029576 TI - Bullous emphysema as first presentation of Ehlers-Danlos syndrome in monozygotic twins. AB - Ehlers-Danlos syndrome, characterized by hyperextensible skin, hypermobile joints, and fragile vessels, is the most common heritable disorder of connective tissue and has an estimated prevalence of 1 in 5000. Pulmonary involvement with signs of lung destruction (bullous emphysema) as first presentation is unusual. We report a case of monozygotic twins 37 years old men with occasional evidence of bullous emphysema with previously undiagnosed Ehlers-Danlos syndrome type IV. We emphasize the importance of considering uncommon genetic causes of emphysema in young adults, discuss underlining pathophysiological mechanisms and propose a conservative management and follow-up. PMID- 26029577 TI - Melioidosis mycotic aneurysm: An uncommon complication of an uncommon disease. AB - Melioidosis is often considered an exotic and uncommon disease in most parts of the world. However it is an endemic disease in Southeast Asia and Northern Australia with an expanding distribution. Melioidosis can involve almost any organ and can deteriorate rapidly. In this report, we describe a rapidly fatal case of a mycotic aneurysm associated with melioidosis despite aggressive antibiotic therapy. The morbidity and mortality of this uncommon complication remains high despite prompt diagnosis and treatment. Especially when treating persistent/recurrent melioidosis, the physician's caution to the development of mycotic aneurysms is imperative so that early treatment and surgical intervention may be considered. PMID- 26029578 TI - Traumatic chylothorax: A case report and review. AB - Chylothorax is a rare entity characterised by leakage of lymphatic fluid into the pleural cavity from the thoracic duct. We present a case of traumatic chylothorax following a traumatic fracture of the L1 vertebra. An 84-year-old lady presented to the emergency department after being found collapsed at home. She gave a preceding history of one day of diarrhoea. Chest X-ray showed a rightsided effusion. Drainage of the effusion yielded a cloudy, off-white fluid that settled in layers in the drainage container. Pleural fluid examination revealed a lymphocyte-rich transudate with high levels of cholesterol and triglycerides. CT imaging of the chest, abdomen and pelvis revealed an acute left sided pulmonary embolus, and a multisegment burst fracture of the L1 vertebra. The patient was anticoagulated for the pulmonary embolus. Conservative fracture management was advised. Chylous drainage of 1l/24hr was observed. Due to ongoing chylous leak the patient was commenced on a medium-chain fatty acid diet and octreotide. Whilst chylous drainage ceased the patient died from infected pressure sores, malnutrition and acute kidney injury. Spinal trauma can rarely cause disruption of the thoracic duct and chylothorax. Diagnosis of chylothorax hinges on the typically high triglyceride content of chylous fluid and the detection of chylomicrons where the triglyceride concentration is equivocal. Management options for persistently draining chylothorax are varied and range from non invasive medical measures to radiological and surgical interventions (although the patient in the case we present was an unsuitable candidate for surgery). We discuss pertinent diagnostic testing and put forward possible medical management strategies for chylothorax. PMID- 26029579 TI - Recurrent nitrofurantoin-induced giant cell interstitial pneumonia: Case report and literature review. AB - Giant cell interstitial pneumonia (GIP) is a rare form of chronic interstitial pneumonia typically associated with hard metal exposure. Only two cases of GIP induced by nitrofurantoin have been reported in the medical literature. We are reporting a case of recurrent nitrofurantoin-induced GIP. Although extremely rare, GIP needs to be included in the differential diagnosis in patients with chronic nitrofurantoin use who present with respiratory illness. PMID- 26029580 TI - Clinico-pathological analysis referring hemeoxygenase-1 in acute fibrinous and organizing pneumonia patients. AB - Acute fibrinous and organizing pneumonia (AFOP) is a very rare pathological entity of lung injury characterized by intra-alveolar fibrin balls. Hemeoxygenase (HO) -1 is a cytoprotective enzyme against oxidative stress and inflammation. It is known to be expressed in the alveolar macrophages in the healthy adults and overexpressed in other various lung cells of the lung injury patients. We experienced two cases of subacute form AFOP for these 10 years and reviewed clinico-pathological characteristics. The average age was 62 years old and both were male. The etiology of both cases was idiopathic. The average PaO2/FIO2 ratio was 274.5 +/- 84.1. The average levels of C-reactive protein and surfactant protein - A of the serum were elevated to 19.8 +/- 6.3 mg/dL and 67.6 +/- 15.8 ng/mL, respectively. Serum sialylated carbohydrate antigen levels were normal in both cases. The characteristic radiographic findings were bilateral consolidations and ground glass opacities. Lung biopsy specimens revealed fibrin balls and alveolitis with abundant cellular HO-1 expression. Steroid response was excellent and the pulmonary involvements absolutely disappeared for about 3 months. PMID- 26029581 TI - Massive hemoptysis due to welding fumes. AB - Many pulmonary problems such as lung cancer, occupational asthma, and pneumoconiosis have been described due to welding in the literature until now. This is the first case report of alveolar hemorrhage due to welding fumes presented with massive hemoptysis. We report a rare case of massive hemopthisis associated with welder's lung, with a discussion based on a review of the literature. ESTABLISHED FACTS: Many pulmonary diseases such as lung cancer, occupational asthma, and pneumoconiosis have been attributed welding fumes in the literature. Alveolar hemorrhage due to welding fumes has never defined before. NOVEL INSIGHTS: We herein report a case of alveolar hemorrhage presented with massive hemoptysis due to welding fumes. Clinicians should be aware of such rare but serious clinical picture which can occur in welding workers. Palliative measures and bronchoscopic Ankaferd Blood Stopper((r)) application may help to stop bleeding. PMID- 26029582 TI - Survival in a case of diffuse alveolar hemorrhage due to Strongyloides stercoralis hyperinfection. AB - Strongyloides stercoralis is an intestinal nematode endemic to tropical and sub tropical regions. Although infection is typically asymptomatic or self-limited, immunocompromised individuals can develop a severe form of disease marked by hyperinfection. Pulmonary involvement accompanies hyperinfection in a majority of cases, though manifestations range from asymptomatic infiltrates to diffuse alveolar hemorrhage (DAH) and respiratory failure. When complicated by DAH, the hyperinfection syndrome is usually fatal. We report a case of a 65-year-old Guatemalan woman with chronic inflammatory demyelinating polyneuropathy (CIDP) treated with chronic steroids who presented with Escherichia coli urosepsis. She was initially treated with antibiotics and corticosteroids. She subsequently developed DAH due to disseminated strongyloidiasis. She was treated with oral and subcutaneous ivermectin and had complete recovery. PMID- 26029583 TI - Carbamazepine-induced interstitial pneumonitis associated with pan hypogammaglobulinemia. AB - Carbamazepine remains a first-line drug for treatment of epilepsy in children. A wide variety of side effects have been attributed to its use, including a mild involvement of the immune system, usually a transient decline in IgA. Pulmonary complications, including interstitial pneumonitis, were mainly described in adults, and are considered rare side effects. In this report we describe the first pediatric patient who developed a severe interstitial pneumonitis and a pan hypogammaglobulinemia 2 months after starting carbamazepine. A gradual resolution of symptoms and complete immune recovery was observed after the drug withdrawal, but 6 months later our patient still has a marked reduction in lung volumes and decreased exercise tolerance. We suggest that immunoglobulins should be carefully examined after carbamazepine initiation, particularly if the patient develops any sign of immunosuppression. PMID- 26029584 TI - Pneumonitis following diesel fuel siphonage. AB - Petroleum diesel is a complex mixture of liquid hydrocarbons and mainly used as fuel in transport vehicles. The practice of manual siphoning of diesel from fuel tanks is common in developing countries but hydrocarbon pneumonitis due to diesel siphonage is rarely reported. We report pneumonitis following diesel fuel siphonage in a 30-year-old driver. Initially patient had severe nausea and vomiting followed by chest pain and breathlessness after three days. In our case, induced sputum was diagnostic as against majority of cases where bronchoscopy was used as diagnostic tool. Recovery was complete with medical treatment. PMID- 26029585 TI - Lung cancer in idiopathic pulmonary fibrosis patients diagnosed during or after lung transplantation. AB - Lung transplantation is an accepted therapy for patients with end-stage lung disease and offers a major survival benefit in selected patients. The most important indications are chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis besides cystic fibrosis and pulmonary arterial hypertension. The incidence of lung cancer in patients after Ltx is 20-25 times higher than in the general population. Diagnosis is often difficult in IPF patients because of the diffuse lung abnormalities due to the underlying fibrosis. Moreover, the lung cancer may mimic a pulmonary infection. Symptoms are often aspecific, diagnosis is difficult, and prognosis is extremely poor. We describe three patients who were transplanted for idiopathic pulmonary fibrosis and who developed a primary lung cancer. PMID- 26029586 TI - Case of missing left lung. AB - Here we present a young female with missing left lung and history of upper respiratory infections in childhood. The lungs have ability to grow and regenerate in children. She has had no major complications into adulthood. It is important to know diagnosis in recurrent pulmonary infections and here bronchoscopy was diagnostic. PMID- 26029587 TI - Are all granulomatous lesions tuberculosis? AB - INTRODUCTION: Granulomatous reactions are seen in a wide variety of diseases. METHODS: We present 3 cases referred to our clinic with presumptive diagnosis of tuberculosis (TB) were diagnosed as nontuberculous granulomatous diseases. RESULTS: Three cases were diagnosed as Tularemia, Cat-Scratch Disease (CSD) and idiopathic granulomatous mastitis (IGM) respectively. CONCLUSION: In countries with high incidence of TB, TB is considered firstly in differential diagnosis of granulomatous diseases. Detailed anamnesis and physical examinations should be done in differential diagnosis of granulomatous diseases, and TB must be excluded. PMID- 26029588 TI - Cases non-specific interstitial pneumonia and hypersensitivity pneumonia: A new pathologic diagnosis or overlap syndrome. AB - ATS/ERS evaluation of ILD's has recently considered NSIP as a single entity and it has historically been considered a provisional diagnosis. As more cases are reviewed, pathologic characteristics may become more precise with less overlap and help in diagnosis of complex cases. Here, we present a series of cases of HP and NSIP recently admitted to Masih Daneshvari Hospital with hope to characterize them better and eventually have less ambiguity about nature of NSIP. PMID- 26029589 TI - Skinsarcoidosis: A trick for primary case physicians. AB - Sarcoidosis is a systemic disease of unknown etiology. Skin lesions occur in about a quarter of patients with sarcoidosis and specific manifestations include erythema nodosum, maculopapular eruption, plaques, lupus pernio and scar sarcoidosis. A 39-year old male presented with cutaneous involvement of sarcoidosis. The skin biopsy revealed non-caseating granuloma. Our patient had skin manifestation of makulopapular eruption form of skinsarcoidosis along with hilar and mediastinal lymphadenopathy. The 40 mg/day oral methylprednisolone was started and skin lesions were fully recovered. We report a case of skin involvement as a first sign of sarcoidosis. PMID- 26029590 TI - A not so simple effusion. AB - We describe the case of a patient with an empyema, how it forms and what the evidence behind the treatment options are with specific reference to intrapleural thrombolytic therapy. PMID- 26029591 TI - A case of empyema necessitatis caused by Mycobacterium abscessus. AB - Non-tuberculosis mycobacteria (NTM) have emerged as an important pathogen in lung infection. NTM infection is rarely accompanied by pleural involvement, and empyema necessitatis caused by NTM is very uncommon. We report a very rare case of Mycobacterium abscessus pulmonary disease with empyema accompanied by empyema necessitatis. The patient was successfully treated by percutaneous tube drainage of the empyema and empyema necessitatis with aggressive antibiotics treatment and surgical resection. PMID- 26029592 TI - A rare cause of hypoxia in a patient with liver cirrhosis. AB - Pulmonary syndromes in the setting of hepatic disease with portal hypertension include portopulmonary hypertension (POPH), hepatopulmonary syndrome (HPS) and hepatic hydrothorax. POPH is defined as pulmonary arterial hypertension with portal hypertension in the absence of other causes of pulmonary arterial hypertension. HPS is a defect in arterial oxygenation as a result of pulmonary micro vascular dilatation in the setting of liver disease. We discuss a case of 63-year-old female with liver cirrhosis, exertional dyspnea and hypoxia associated with coexistence of POPH and HPS. The coexistence of POPH and HPS is rare entity which can generate a renewal of interest in further understanding the intricate pathologies behind these diseases. PMID- 26029593 TI - Pseudoaneurysm of brachiocephalic artery mimicking the mediastinal tumor. AB - 58 year-old male admitted to the Hospital of Lithuanian University of Health Sciences due to suspicion of mediastinal tumor for diagnostic endobronchial ultrasound procedure (EBUS). The main patient's complain was progressive dyspnea. Objective investigation revealed no major findings: normal breath sounds, heart rate - 96 bpm, blood pressure - 120/80 mmHg. Chest CT scan showed the mediastinal tumor of 3.8 * 3.5 cm. During bronchoscopy smooth intratracheal nodule of 5 mm was found. Superficial biopsy showed normal airway mucosa. During EBUS procedure no clear lymph node structure or blood flow was detected. It was decided to observe the patient clinically. One month later massive hemoptysis started. Urgent bronchoscopy revealed large right-sided mass and intratracheal wall dislocation due to the possible mediastinal tumor in the same location as the polyp in the previous investigation. Repeated chest CT scan showed increasing tumor of size 4.0 * 3.2 * 4.0 cm in the mediastinum and pseudoaneurysm of brachiocephalic artery was suspected. The diagnosis was later confirmed by aortography. The patient underwent successful aneurysmectomy. PMID- 26029594 TI - A methemoglobinemia case who was previously diagnosed and treated as asthma. AB - Methemoglobinemia, one of the rare causes of cyanosis and hypoxemia, may occur in congenital and acquired forms. Coexistence of cyanosis and hypoxemia suggests an etiology associated with an underlying cardiac disease firstly, but if any cardiac pathology exists pulmonary diseases are investigated generally. Considering bronchial asthma in a young patient with shortness of breath is usual. On the other hand, evaluating all the signs and symptoms together with laboratory results is important in diagnosis of rare diseases such as methemoglobinemia. In this paper we present a congenital methemoglobinemia case who was treated with bronchodilator therapy for a period of nearly five years because of misdiagnosis of asthma. PMID- 26029595 TI - Anti-synthetase syndrome presenting as cryptogenic organizing pneumonia. AB - Interstitial lung disease (ILD) is a unique group of lung diseases that can be associated with inflammatory conditions, such as polymyositis-dermatomyositis (PM DM). Presentation of PM-DM with ILD is not uncommon but clinical and radiological features can be similar to other conditions (e.g. atypical pneumonia) and can be challenging to diagnose. Delayed diagnosis of PM-DM can be associated with progression of pulmonary involvement and potentially increase morbidity. We report a patient presenting with pulmonary symptoms who had positive anti-Jo-1 antibodies and cryptogenic organizing pneumonia features on biopsy, which is a rare reported finding. PMID- 26029596 TI - Sweet's syndrome with pulmonary involvement: Case report and literature review. AB - A 74 year old female presented with fever, associated with papules and plaque in her upper and lower extremities. Exams revealed blood leukocytosis and a positive urine culture. Antibiotic therapy was initiated with no clinical response. After 1 week, chest X-ray showed right upper lobe alveolar infiltrate. A skin biopsy of the lesion showed infiltration by neutrophils, consistent with Sweet's Syndrome. Patient's condition progressively worsened, requiring oxygentherapy. Bronchoscopy and bronchoalveolar lavage were normal, transbronchial biopsies suggested lung involvement of Sweet 's syndrome. Antibiotic therapy was stopped. Corticosteroid were started. Therapy resulted in rapid clinical and radiological improvement. PMID- 26029597 TI - Bronchial selective ventilation in a wide tracheocutaneous fistula. AB - We present the treatment and management of a wide tracheocutaneous fistula after tracheotomy correlated with excessive cuff pressure in a 36-year-old woman with cerebral palsy since infancy in which persistent type II respiratory failure required continuous ventilatory support. We discuss the surgical treatment adopted for the management of this particularly wide lesion. At the end of surgery, mechanical ventilation through a tracheal cannula was hindered by the reduced length of the residual trachea below the tracheotomy. The need to guarantee mechanical ventilation to the patient led to the implementation of a cuff securing system in the two main bronchi. We describe the approach that may be attempted under extreme conditions, when traditional ventilation methods cannot be applied for anatomical reasons. PMID- 26029598 TI - Clinical presentation of Churg-Strauss syndrome in children: A 12-year-old-boy with ANCA-negative Churg-Strauss syndrome. AB - Churg-Strauss syndrome is an uncommon multisystem disorder characterized by asthma, eosinophilia and vasculitis. We report on a 12-year-old boy with asthma and deterioration of his general condition, who was eventually diagnosed with an ANCA-negative Churg-Strauss syndrome. The propositus included, 50 cases of childhood Churg-Strauss syndrome have been reported. The patient characteristics and clinical characteristics of these children are summarized. The respiratory tract is most frequently involved with pulmonary infiltrates, asthma and sinusitis. Early recognition of childhood Churg-Strauss syndrome is important as delayed diagnosis can lead to severe organ involvement, and possible fatal outcome. PMID- 26029599 TI - Sirolimus induced granulomatous interstitial pneumonitis. AB - OBJECTIVES: Report a case of sirolimus induced granulomatous pneumonitis. BACKGROUND: Sirolimus is used in clinical transplantation as an immunosuppressive agent. Pulmonary toxicity does occur, but only a few cases of sirolimus associated granulomatous interstitial pneumonitis have been reported. METHODS: Case report and literature review. RESULTS: This 53-year-old woman with ESRD from polycystic kidney disease status post deceased donor kidney transplantation presented with fever, progressive dyspnea, and hypoxia for two weeks. She had been switched to sirolimus two months before admission. A CT scan of the chest revealed bilateral ill-defined patchy ground glass opacities. Extensive investigations were negative for infection. Video-assisted thoracoscopic biopsy showed granulomatous interstitial pneumonitis. Her symptoms and infiltrates resolved after sirolimus discontinuation and corticosteroid treatment. CONCLUSIONS: Drugs induced pneumonitis should always be considered in transplant patients after infectious or other etiologies have been excluded. Sirolimus can cause granulomatous infiltrates in the lung possibly secondary to T-cell mediated hypersensitivity. PMID- 26029600 TI - Pulmonary capillary haemangiomatosis - An unusual cause of hypoxia. AB - We describe the case of a 58-year-old man who presented with progressive dyspnoea on exertion and severe exertional hypoxia. There was a paucity of radiological findings, mild pulmonary hypertension, and no demonstrable anatomical shunt. Post mortem examination of lung tissue suggested a diagnosis of pulmonary capillary haemangiomatosis. The case is unusual in displaying few radiological findings. We postulate that the severe hypoxia was due to shunting through the abnormal capillary proliferations. PMID- 26029601 TI - Tuberculosis hiding a non-Hodgkin lymphoma "there may be more to this than meets the eye". AB - Tuberculosis and lymphoma can share common features. We report the case of a non HIV 60-year old man diagnosed with a severe form of disseminated tuberculosis in whom the atypical course of the disease under treatment led to investigations that unveiled the coexistence a non-Hodgkin lymphoma. This rare association has putative pathophysiological foundations. This justifies to raise the lymphoma hypothesis when a proved tuberculosis exhibits an atypical course. PMID- 26029602 TI - Metastatic Pulmonary Epithelioid Hemangioendothelioma: A case report and review of the literature. AB - Pulmonary Epithelioid Hemangioendothelioma is a rare and low grade tumor of endothelial origin found in the lungs. At onset patients are usually asymptomatic or present with non-specific symptoms. Chest imaging shows the presence of multiple, bilateral small nodules and diagnosis usually requires a lung biopsy. At this time there is no standardized treatment regimen and the prognosis is variable. PMID- 26029603 TI - Baron Munchhausen's lung function expertise. AB - A young anorectic woman suffering from asthma since her early childhood exacerbated without obvious cause and did not respond to treatment. Body plethysmography showed an isolated huge increase of the expiratory resistance. During inspiration, resistance was not elevated. However, in 1 out of 3 successive manoeuvres, expiratory resistance was completely normal. We believe this to be a Munchhausen's case coupled with a proven asthma. The pattern in lung function can be explained by putting the tongue forward into the spirometer's mouthpiece. In the assessment of asthma refractory to treatment, especially in workers in paramedical professions, Munchhausen's syndrome should be considered. PMID- 26029604 TI - Broncho pleuro subcutaneous fistula with subcutaneous emphysema: A rare presentation of pulmonary tuberculosis. AB - Subcutaneous tissue emphysema is observed in a several clinical settings but spontaneous subcutaneous emphysema in the absence of pneumothorax with broncho pleuro subcutaneous fistula is rare. We report a case of spontaneous subcutaneous emphysema secondary to cavitary pulmonary tuberculosis in the absence of pneumothorax. PMID- 26029605 TI - Sleep-disordered breathing in 15-year-old boy with arterial hypertension. AB - Obstructive sleep apnea/hypopnea syndrome (OSA/HS) is the basis of the spectrum of sleep-disordered breathing (SDB) and is a condition characterized by the presence of snoring, repetitive partial upper airway obstruction (hypopnea) and/or intermittent complete obstruction (apnea), long enough to cause reduce the level of oxygen in the blood (desaturation), fragmented sleep and excessive daytime sleepiness. It is known that OSA/HS in the middle and older age predisposes to arterial hypertension (AH). We discuss a case of 15-year-old boy with AH and OSA/HS. He was treated on nasal continuous positive pressure in the upper airway (nasal CPAP) with good results. PMID- 26029606 TI - A non-HIV case with disseminated Mycobacterium kansasii disease associated with strong neutralizing autoantibody to interferon-gamma. AB - Disseminated non-tuberculous mycobacterium (dNTM) infection is rare in humans without human immunodeficiency virus (HIV) infection. Previous reports have shown autoantibodies to human interferon-gamma (IFN-gamma), which play important roles in mycobacterium infection, in the sera of patients with non-HIV dNTM disease. Herein, we describe a 53-year-old male who was strongly suspected to have multicentric Castleman disease (MCD) based on bone marrow study and chest radiological findings. However, Mycobacterium kansasii was detected in respiratory samples including pleural effusion. We initiated anti-mycobacterial therapy under intensive care; he died on the 48(th) hospital day. We detected no hematological disorders, ruling out MCD postmortem. However, we detected M. kansasii in pulmonary, liver, spleen and bone marrow tissues. Moreover, anti-IFN gamma autoantibody was detected with strong neutralizing capacity for IFN-gamma. We consider our present report to contribute to understanding of the relationship between anti-IFN-gamma autoantibody and disease development. PMID- 26029607 TI - Roentgenological occult large-cell neuroendocrine carcinoma: Report of a long term survivor. AB - A 64-year-old male patient complained of a one-month history of bloody sputum. A polypoid tumor was almost obstructing the orifice of the subsegmental bronchus (B8b) of the anterior basal segment of the right lower lobe on bronchoscopy. Biopsy specimens of the tumor surface yielded a diagnosis of undifferentiated carcinoma. Clinical staging was T1aN0M0, stage IA. Surgical resection that comprised a right upper lobectomy with systematic mediastinal and hilar lymph node dissection was performed. Histopathologically, the tumor specimen was compatible with large-cell neuroendocrine carcinoma (LCNEC) of the subsegmental bronchus. Pathological staging was T1aN0M0, stage IA. To our knowledge, few cases of central-type LCNEC have been reported in the English literature, and ours is the first report of roentgenological occult LCNEC. PMID- 26029608 TI - Distinct immunologic and radiographic patterns in etanercept-induced lung injury. AB - Nonspecific clinical presentation of non-infectious, immune-mediated pulmonary complications of etanercept therapy makes the diagnosis difficult. While bronchoalveolar lavage fluid (BALF) cell analysis is frequently used in diagnosing drug-induced lung disease, BALF patterns in etanercept-induced lung injury (EILI) are not well established. Furthermore, previous reports of EILI diagnosis relied on transbronchial or surgical lung biopsies. Here, we report two patients who developed pulmonary toxicity after etanercept treatment. Both patients were diagnosed with EILI. While one patient presented with CD4(+) predominant lymphocytic alveolitis (consistent with a sarcoid-like pattern), the other patient exhibited a CD8(+)-predominant pattern (consistent with hypersensitivity pneumonitis-like reaction). The different BAL patterns were accompanied by distinct radiographic findings. Both patients significantly improved after etanercept discontinuation and corticosteroid initiation. We propose that EILI can present with distinct immunologic and radiographic phenotypes. In addition, early BALF analysis with lymphocyte immunophenotyping can further define the underlying immunologic abnormalities, and thereby, avoid more invasive procedures. PMID- 26029609 TI - Congenital broncho-oesophageal fistula: An unusual cause of persistent pneumonia in a young adult. AB - A 19-year-old female with a 3-day history of high temperature, productive cough and dyspnoea was admitted due to diabetic ketoacidosis and pneumonia of the right lower lobe. Antibiotics (amoxicillin-clavulanic acid), insulin, fluids and electrolytes were administered, as appropriate. The patient was doing well (normal temperature, normal glucose levels, normal acid-base balance) until the sixth day of hospitalization, when she reported bouts of cough when swallowing liquids. Barium oesophagography revealed the presence of a broncho-oesophageal fistula (BOF). Congenital BOFs are rare developmental malformations (only just over 100 reported cases in the literature), which are attributable to persistent attachments between the tracheobronchial tree and the oesophagus. When not combined with oesophageal atresia, symptoms may not appear until adult life. History of recurrent respiratory infections, bronchiectasis, haemoptysis and chronic cough associated with eating, may indicate investigation with conventional or multi-positional oesophagography. At the time that surgery was decided, our patient developed persistent pneumonia of both the middle and the lower right lobes. A fistulous tract between the medial segmental bronchus and the oesophagus was removed, along with right middle lobectomy. Post-operative clinical course was excellent. PMID- 26029610 TI - Diffuse alveolar damage associated with pulmonary thromboembolism. AB - In contrast to other internal organs, pulmonary arterial hypoperfusion does not always show ischemic changes in the lung parenchyma. Pulmonary thromboembolism (PTE)-related lung injury is extremely rare except in the case of pulmonary infarctions, in which PTE occasionally causes necrosis of the parenchyma. We describe the case of an 86-year-old woman who presented with respiratory failure and bilateral ground-glass opacity predominantly the upper lobes. Autopsy revealed a saddle-shaped old organized thrombi in the main pulmonary artery, relatively fresh thrombi in both pulmonary arteries, and localized diffuse alveolar damage (DAD) in the bilateral upper lung fields. The hypoperfused regions resulting from the thromboembolism anatomically coincided with the pulmonary lesion where DAD was identified. Although PTE is not regarded as a causal factor of DAD, it might induce DAD as a result of hypoperfusion in limited cases. PMID- 26029611 TI - Langerhans cell histiocytosis presenting with complicated pneumonia, a case report. AB - We describe a 2 1/2 year old boy presenting with fever, abdominal pain and splinter haemorrhages of the nails. On further examination there were signs of pneumonia with pleural effusion. This was treated with mini-thoracotomy, drainage and intravenous antibiotics. Further diagnostic workup for underlying causes showed diffuse cystic lung disease, suggestive of Langerhans cell histiocytosis. This was confirmed on pathology specimens, which showed Langerhans cells in lung tissue, nail bed and skin biopsy samples, indicating multisystem Langerhans cell histiocytosis. The patient was treated with Prednisone and Vinblastin according to the LCH-III guidelines. In this case report we give a brief description on cystic lung disease in children, Langerhans cell histiocytosis and associated nail abnormalities. PMID- 26029612 TI - A rare benign tumor of the lung: Inflammatory myofibroblastic tumor - Case report. AB - A fifty year old lady who was operated for thyroid cancer two years ago and completed adjuvant therapy, underwent a computer tomography (CT) of the chest during her follow up. The CT showed a mass lesion in the right lung, located to the lateral segment of the middle lobe. There were no intrabronchial lesions on bronchoscopy. Positron emission CT (PET CT) showed a dense hypermetabolic mass located in the right middle lobe lateral segment and having malignant characteristics. A videothorascopic wedge resection was performed and the specimen was sent for frozen section, which showed no evidence of malignancy. Pathology report revealed an inflammatory myofibroblastic tumor (IMT). Since IMT is a rare benign tumor of the lung, we herein report this patient along with a discussion of the relevant literature. PMID- 26029613 TI - Buried under gypsum powder - A rare respiratory complication. AB - Gypsum is a mineral dust consisting of calcium sulfate and is commonly used in building construction. We here report the first case of an acute calcium sulfate aspiration. An accidental avalanche of fine gypsum powder covered entirely a silo worker. He aspirated a large amount of gypsum powder without loosing consciousness. At admission to the emergency department the patient was breathing spontaneously and directly underwent emergency bronchoscopy. Acute tracheobronchitis was diagnosed. Remaining calcium sulfate was removed by aspiration without rinsing with additional water in order to avoid further exothermic damage to the bronchial mucosa from chemical reactions. He received steroid treatment and antibiotics, as well as bronchodilatative therapy in an attempt to increase mucociliary clearance. Within a month the patient was symptomfree without any residual radiological or functional impairment. This unusual aspiration accident is to our knowledge the first case report of an accidental calcium sulfate aspiration. Our treatment choice left the patient without residual pulmonary impairment. PMID- 26029614 TI - Pulmonary vasculitis as the first manifestation of rheumatoid arthritis. AB - In this report, we describe a 61-year-old man that presented with isolated pulmonary vasculitis and a positive anti-cyclic citrullinated peptide (CCP) antibody. Within a few months, the patient developed the symmetric polyarthritis consistent with rheumatoid arthritis (RA). Because the anti-CCP antibody is highly specific for RA and vasculitis is a known association of RA, we suspect the pulmonary vasculitis in this patient was the first manifestation of underlying RA. This case extends on previous reports that have shown that lung disease may predate the development of articular RA and that anti-CCP positivity and lung disease may represent a pre-RA phenotype. To our knowledge, this is the first case report of pulmonary vasculitis as the first manifestation of RA. PMID- 26029615 TI - A case of sarcoidosis with eosinophilia in peripheral blood and bronchoalveolar lavage fluid. AB - A 70-year-old woman, who has had a diagnosis of sarcoidosis since she was 38 years old, showed newly appearing diffuse ground-glass opacities in the bilateral lung field, and bilateral enlargement of the hilar and mediastinal lymph nodes. Based on findings from bronchoalveolar lavage fluid (BALF) and pathology analysis, eosinophilic pneumonia accompanied by sarcoidosis was suspected. Both disease conditions (sarcoidosis and BALF eosinophilia) worsened and improved simultaneously, and she showed two similar episodes during the follow-up. This case prompted us to conduct a retrospective investigation of eosinophil percentage in peripheral blood and BALF in 178 patients (excluding our patient) who had received a diagnosis of sarcoidosis between 2000 and 2009 in our department. Among the 178 patients, the highest eosinophil percentage in BALF was 2.6%; in contrast, peripheral blood eosinophilia was very common. Thus we concluded that, for subjects with sarcoidosis, marked eosinophilia in BALF, as observed in the case of this 70-year-old woman, was exceptional. PMID- 26029616 TI - Recurrent respiratory infections caused by a double aortic arch: The diagnostic role of spirometry. AB - A young woman with a clinical history characterized by recurrent respiratory infections, occurring since early infancy, was referred to our hospital. When the patient was a young girl, she underwent sweat chloride test, serum analysis of immunoglobulins, and evaluation of blood lymphocyte subsets; all these diagnostic tests were normal, as well as chest X ray aside from pneumonia episodes. Skin prick tests were positive for several different allergens, and a diagnosis of allergic rhinitis was made. At the age of 11 years, she started to complain of gastroesophageal reflux disease (GERD) symptoms, and a gastroscopy detected a hiatal hernia with esophagitis. Despite pharmacologic treatments for allergic rhinitis and GERD, the patient continued to complain of chronic cough, associated with choking and recurrent respiratory infections treated with antibiotic therapy. For the first time in her life, we performed a spirometry that showed a flow-volume curve characterized by a plateau in the expiratory phase, suggestive of an central airway obstruction. Bronchoscopy demonstrated a compression of the distal portion of trachea. Computed tomography (CT) angiogram revealed a double aortic arch. Barium enhancement evidenced an esophageal compression. A surgical division of the smaller of the two arches was then performed. Therefore, we strongly suggest to perform lung function tests in all cases of unexplained respiratory complaints. PMID- 26029618 TI - Swyer-James-MacLeod syndrome with an anomalous origin of coronary artery: Case report. AB - Swyer-James (Macleod) syndrome was first defined in the 1950s by Swyer, James and Macleod in patients with unilateral hyperlucent lungs. Coronary artery anomalies are congenital anomalies that affect a small part of the population. They constitute about 1-2% of congenital heart diseases. The incidence of a left coronary artery arising from the right coronary sinus Valsalva has been reported as 0.017%, and 1.3% among coronary artery anomalies. We hereby present this case since the case was diagnosed in adult age and was accompanied by a rare congenital heart disease. PMID- 26029619 TI - Four cases with group 3 out-of-proportion pulmonary hypertension with a favorable response to vasodilators. AB - Some patients with group 3 pulmonary hypertension (PH) (PH due to lung disease and/or hypoxia) exhibit disproportionately advanced or "out-of-proportion" PH. In the present case series, we document four consecutive patients with progressive out-of-proportion group 3 PH. All patients exhibited progressive dyspnea or peripheral edema and were treated by pulmonary artery hypertension (PAH)-specific vasodilator(s). At the follow-up assessment 3-4 months later, symptoms/signs and pulmonary hemodynamic measurements improved in all four patients (45 +/- 8% decrease in pulmonary vascular resistance). Pulmonary oxygenation deteriorated in one patient but improved or did not significantly change in the remaining three cases. Importantly, the background lung parenchymal disease (early-onset chronic obstructive pulmonary disease, rheumatoid arthritis-associated interstitial pneumonia, and combined pulmonary fibrosis and emphysema) was stable upon progression of the right heart failure symptoms/signs, and also during the 3-4 month follow-up period in all cases. We herein describe the clinical features of the four cases and discuss the potential benefits and risks of PAH-specific treatment in this emerging population. PMID- 26029620 TI - Use of a tyrosine kinase inhibitor as neoadjuvant therapy for non-small cell lung cancer: A case report. AB - We report here a 66-year-old woman diagnosed with bronchioloalveolar carcinoma of the right lung cT4N2M0. The patient was from the Philippines, had never smoked, and tested positive for an EGFR mutation. She received gefitinib as neoadjuvant therapy for two months and displayed a partial response. The tumour was resected by performing a right pneumonectomy. The residual viable tumour accounted for less than 10%. Adjuvant chemotherapy with carboplatin-taxol was administered for four cycles. Fifteen months post-surgery, two brain metastases were found. Gefitinib was prescribed, and one month later complete radiological response was assessed. The patient remains asymptomatic and without visible disease four months later. Controlled randomised trials are needed to clarify the role of these target therapies in the neoadjuvant setting. PMID- 26029621 TI - Sarcoidosis following Mycobacterium tuberculosis infection: Coincidence or consequence. AB - We describe the case of a 47-year-old Caucasian male patient who developed sarcoidosis 18 months after he was diagnosed with pulmonary tuberculosis for which he was treated according to guidelines. The presentation of sarcoidosis was very similar to his first presentation when he was diagnosed with tuberculosis. Mycobacterium tuberculosis as a possible aetiological agent in sarcoidosis has been point of debate since many years and has been studied thoroughly. Recent advances in immunologic and molecular techniques have strengthened the association between mycobacteria and sarcoidosis.(1) Sarcoidosis is a systemic inflammatory disorder of unknown aetiology, characterised by the presence of non caseating epitheloid cell granulomas. It is generally agreed that this is a tissue reaction to environmental agents in a genetically susceptible individual.(2) Tuberculosis is an infectious disease caused by M. tuberculosis and characterised by caseating granulomas. In both clinical and histopathological features sarcoidosis is remarkably similar to tuberculosis and therefore can be difficult to distinguish. First, this case report demonstrates the need of diagnostic testing when reactivation of tuberculosis is suspected. And second the role of M. tuberculosis in the aetiology of sarcoidosis will be discussed. PMID- 26029622 TI - Pulmonary mucormycosis presenting with vocal cord paralysis. AB - Pulmonary mucormycosis is a relatively uncommon infection. It can present in various forms. Very few cases of pulmonary mucormycosis presenting as vocal cord paralysis have been described in the literature. We report a case of pulmonary mucormycosis presenting as vocal cord paralysis in an uncontrolled diabetic patient. PMID- 26029623 TI - Primary salivary type lung tumor: Mucoepidermoid carcinoma. AB - Primary salivary type lung cancer are extremely rare intrathoracic malignancies. Mucoepidermoid tumor is one of the salivary gland tumor which originates from submucosal glands of tracheobronchial tree. These are very slow growing low grade malignant tumors. Surgery is the mainstay of treatment and rarely requires adjuvant therapy. In this case report, we describe a case of a young male who presented with cough and hemoptysis. On further investigation he was found to have mucoepidermoid tumor originating from the left bronchus. PMID- 26029624 TI - Multidetector computed tomography findings of central bronchopleural fistulas as sequelae of tuberculosis, chemo radiation and trauma: A report of three cases. AB - A bronchopleural fistula (BPF) is defined as a direct pathway between the bronchial tree or lung parenchyma and the pleural space. Herein, we describe the clinical findings and imaging results of BPFs in three cases. The patients' medical histories revealed that the first had recurrent pulmonary tuberculosis, the second had small-cell lung cancer (SCLC) and had previously undergone chemoradiotherapy, and the third had trauma. Multidetector computed tomography (MDCT) showed clear communication between the airways and pleural spaces which was sufficient for a proper diagnosis without performing a bronchoscopy. PMID- 26029625 TI - Rare case of idiopathic lymphocytic interstitial pneumonia exhibits good response to Mycophenolate Mofetil. AB - Lymphoid interstitial pneumonia (LIP) is a poorly understood lymphoproliferative disorder that can be idiopathic or associated with different conditions. LIP is considered to be steroid responsive. However, its response is mainly unpredictable with a high mortality rate. Here we describe a rare case of idiopathic LIP that shows clinical improvement to Mycophenolate Mofetil after intolerable side effects of high-dose steroids. PMID- 26029626 TI - Resolution of pancreatico-pleural fistula with endoscopic ultrasound-guided therapy. AB - Pancreatico-pleural fistula is an uncommon cause of recurrent pleural effusion. Delayed diagnosis may occur if fluid amylase level is not obtained early in the clinical course. As most cases of pancreatico-pleural effusion are due to chronic pancreatitis, endoscopic therapy may be effective if pancreatic fluid secretion can be diverted to a more physiologic pathway. However, when severe pancreatitis leads to disconnection of the pancreatic duct, it precludes conventional endoscopic treatment via transpapillary stenting of the pancreatic duct. We describe a patient with a chronic, refractory pancreatico-pleural fistula arising from chronic pancreatitis with a disconnected pancreatic duct syndrome, which resolved following endoscopic ultrasound-guided therapy. PMID- 26029627 TI - Cerebral tuberculomas - A clinical challenge. AB - Cerebral tuberculomas are a rare and serious form of tuberculosis (TB) due to the haematogenous spread of Mycobacterium Tuberculosis (MT). Symptoms and radiologic features are nonspecific, leading sometimes to misdiagnosis. Anti-TB drugs are essential for the successful treatment of cerebral tuberculomas but there is no agreement regarding the duration of therapy. The authors present a case of a 55 years old male, presented to the emergency room with sudden onset of diplopia. Cerebral computerized tomography revealed multiple brain lesions, with contrast enhancement and peri-lesional oedema. The patient was HIV negative and because of previous malignancy the first suspicion was metastatic disease. Cultural exam of the bronchial wash showed MT sensitive to all first-line drugs. The patient started antituberculosis treatment with 4 drugs (HRZE) for 2 months, followed by maintenance therapy (HR). Treatment was prolonged for 24 months because at 12th and 18th months of treatment one of the brain lesions, although significantly smaller, still showed contrast enhancement. Even though it is not clear if contrast enhancement lesions represent active lesions or just inflammation, continuing treatment until total resolution of the tuberculomas is probably prudent. PMID- 26029628 TI - Hermansky-Pudlak syndrome type 4 with interstitial pneumonia. AB - Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding tendency, and lysosomal accumulation of ceroid-like material, with occasional development of interstitial pneumonia (IP). Nine genetically distinct subtypes of HPS are known in humans; IP develops primarily in types 1 and 4. Most reported cases of HPS with IP are type 1, and there are no published reports of type 4 in Japanese individuals. A 58-year-old man with congenital oculocutaneous albinism and progressive dyspnea for 1 month was admitted to our hospital. We administered high-dose corticosteroids on the basis of a diagnosis of acute exacerbation of interstitial pneumonia. Respiratory symptoms and the findings of high-resolution computed tomography (CT) showed improvement. He was diagnosed with HPS type 4 with interstitial pneumonia on the basis of gene analysis. He has been receiving pirfenidone for 1 year and his condition is stable. This is the first report on the use of pirfenidone for HPS with IP caused by a novel mutation in the HPS4 gene. We conclude that HPS should be suspected in patients with albinism and interstitial pneumonia. High-dose corticosteroid treatment may be useful in cases of acute exacerbation of interstitial pneumonia due to HPS-4, and pirfenidone may be useful and well tolerated in patients with HPS-4. PMID- 26029631 TI - Oligometastatic prostate cancer to the navicular bone: case report. AB - This case of oligometastatic prostate cancer to the foot highlights the importance of: 1) metastasis remaining high in the differential for unexplained malady, in the setting of a primary cancer, despite an atypical presentation, and 2) comparing sequential imaging studies to baseline images, especially when remote, because subtle findings can declare themselves over time. PMID- 26029630 TI - Cardiac function in muscular dystrophy associates with abdominal muscle pathology. AB - BACKGROUND: The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. METHODS: Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. FINDINGS: The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients. PMID- 26029629 TI - Functional neuroanatomy of auditory scene analysis in Alzheimer's disease. AB - Auditory scene analysis is a demanding computational process that is performed automatically and efficiently by the healthy brain but vulnerable to the neurodegenerative pathology of Alzheimer's disease. Here we assessed the functional neuroanatomy of auditory scene analysis in Alzheimer's disease using the well-known 'cocktail party effect' as a model paradigm whereby stored templates for auditory objects (e.g., hearing one's spoken name) are used to segregate auditory 'foreground' and 'background'. Patients with typical amnestic Alzheimer's disease (n = 13) and age-matched healthy individuals (n = 17) underwent functional 3T-MRI using a sparse acquisition protocol with passive listening to auditory stimulus conditions comprising the participant's own name interleaved with or superimposed on multi-talker babble, and spectrally rotated (unrecognisable) analogues of these conditions. Name identification (conditions containing the participant's own name contrasted with spectrally rotated analogues) produced extensive bilateral activation involving superior temporal cortex in both the AD and healthy control groups, with no significant differences between groups. Auditory object segregation (conditions with interleaved name sounds contrasted with superimposed name sounds) produced activation of right posterior superior temporal cortex in both groups, again with no differences between groups. However, the cocktail party effect (interaction of own name identification with auditory object segregation processing) produced activation of right supramarginal gyrus in the AD group that was significantly enhanced compared with the healthy control group. The findings delineate an altered functional neuroanatomical profile of auditory scene analysis in Alzheimer's disease that may constitute a novel computational signature of this neurodegenerative pathology. PMID- 26029632 TI - Comparative Metal Oxide Nanoparticle Toxicity Using Embryonic Zebrafish. AB - Engineered metal oxide nanoparticles (MO NPs) are finding increasing utility in the medical field as anticancer agents. Before validation of in vivo anticancer efficacy can occur, a better understanding of whole-animal toxicity is required. We compared the toxicity of seven widely used semiconductor MO NPs made from zinc oxide (ZnO), titanium dioxide, cerium dioxide and tin dioxide prepared in pure water and in synthetic seawater using a five-day embryonic zebrafish assay. We hypothesized that the toxicity of these engineered MO NPs would depend on physicochemical properties. Significant agglomeration of MO NPs in aqueous solutions is common making it challenging to associate NP characteristics such as size and charge with toxicity. However, data from our agglomerated MO NPs suggests that the elemental composition and dissolution potential are major drivers of toxicity. Only ZnO caused significant adverse effects of all MO particles tested, and only when prepared in pure water (point estimate median lethal concentration = 3.5-9.1 mg/L). This toxicity was life stage dependent. The 24 h toxicity increased greatly (~22.7 fold) when zebrafish exposures started at the larval life stage compared to the 24 hour toxicity following embryonic exposure. Investigation into whether dissolution could account for ZnO toxicity revealed high levels of zinc ion (40-89% of total sample) were generated. Exposure to zinc ion equivalents revealed dissolved Zn2+ may be a major contributor to ZnO toxicity. PMID- 26029633 TI - Functional imaging of the musculoskeletal system. AB - Functional imaging, which provides information of how tissues function rather than structural information, is well established in neuro- and cardiac imaging. Many musculoskeletal structures, such as ligaments, fascia and mineralized bone, have by definition a mainly structural role and clearly don't have the same functional capacity as the brain, heart, liver or kidney. The main functionally responsive musculoskeletal tissues are the bone marrow, muscle and nerve and, as such, magnetic resonance (MR) functional imaging has primarily addressed these areas. Proton or phosphorus spectroscopy, other fat quantification techniques, perfusion imaging, BOLD imaging, diffusion and diffusion tensor imaging (DTI) are the main functional techniques applied. The application of these techniques in the musculoskeletal system has mainly been research orientated where they have already greatly enhanced our understanding of marrow physiology, muscle physiology and neural function. Going forwards, they will have a greater clinical impact helping to bridge the disconnect often seen between structural appearances and clinical symptoms, allowing a greater understanding of disease processes and earlier recognition of disease, improving prognostic prediction and optimizing the monitoring of treatment effect. PMID- 26029634 TI - Why China is currently underperforming in medical innovation and what China can do about it?-Part I. PMID- 26029635 TI - Why China is currently underperforming in medical innovation and what China can do about it?-Part II. PMID- 26029636 TI - The role of robotics in interventional radiology: current status. PMID- 26029637 TI - Evaluation of 2D spatially selective MR spectroscopy using parallel excitation at 7 T. AB - BACKGROUND: In this work, two-dimensional (2D) spatially selective magnetic resonance spectroscopy (MRS) was evaluated in both phantom and human brain using 8-channel parallel excitation (pTX) at 7 T and compared to standard STEAM. MATERIALS AND METHODS: A 2D spiral excitation k-space trajectory was segmented into multiple individual segments to increase the bandwidth. pTX was used to decrease the number of segments by accelerating the trajectory. Different radio frequency (RF) shim settings were used for refocusing, water suppression and fat saturation pulses. RESULTS: Phantom experiments demonstrate that, although segmented 2D excitation provided excellent spatial selectivity and spectral quality, STEAM outperformed it in terms of outer volume suppression with 0.6% RMSD compared to 1.7%, 2.5%, 3.9% and 5.5% RMSDs for acceleration factors of R=1, 2, 3 and 4, respectively. Seven major metabolites [choline (Cho), creatine (Cr), phosphocreatine (PCr), glutamate (Glu), glutamine (Gln), glutathione (GSH) and N acetylaspartate (NAA)] were detected with sufficient accuracy [Cramer-Rao lower bounds (CRLBs) <20%] from the in vivo spectra of both methods. Conservative RF power limits resulted in reduced SNR for 2D selective MR spectra (SNR 131 and 82 for R=1 and 2, respectively) compared to the reference STEAM spectrum (SNR 199). CONCLUSIONS: Single voxel spectra acquired using 2D selective MRS with and without pTX showed very good agreement with the reference STEAM spectrum. Efficient SAR management of the 2D selective MRS sequence would potentially improve the SNR of spectra. PMID- 26029638 TI - A theory of fine structure image models with an application to detection and classification of dementia. AB - BACKGROUND: Estimation of stochastic process models from data is a common application of time series analysis methods. Such system identification processes are often cast as hypothesis testing exercises whose intent is to estimate model parameters and test them for statistical significance. Ordinary least squares (OLS) regression and the Levenberg-Marquardt algorithm (LMA) have proven invaluable computational tools for models being described by non-homogeneous, linear, stationary, ordinary differential equations. METHODS: In this paper we extend stochastic model identification to linear, stationary, partial differential equations in two independent variables (2D) and show that OLS and LMA apply equally well to these systems. The method employs an original nonparametric statistic as a test for the significance of estimated parameters. RESULTS: We show gray scale and color images are special cases of 2D systems satisfying a particular autoregressive partial difference equation which estimates an analogous partial differential equation. Several applications to medical image modeling and classification illustrate the method by correctly classifying demented and normal OLS models of axial magnetic resonance brain scans according to subject Mini Mental State Exam (MMSE) scores. Comparison with 13 image classifiers from the literature indicates our classifier is at least 14 times faster than any of them and has a classification accuracy better than all but one. CONCLUSIONS: Our modeling method applies to any linear, stationary, partial differential equation and the method is readily extended to 3D whole organ systems. Further, in addition to being a robust image classifier, estimated image models offer insights into which parameters carry the most diagnostic image information and thereby suggest finer divisions could be made within a class. Image models can be estimated in milliseconds which translate to whole-organ models in seconds; such runtimes could make real-time medicine and surgery modeling possible. PMID- 26029639 TI - The effect of freeze-thawing on magnetic resonance imaging T2* of freshly harvested bovine patellar tendon. AB - BACKGROUND: Analysis of fresh specimens in research studies is ideal; however, it is often necessary to freeze samples for evaluation at a later time. Limited evaluation of the effect of freeze-thawing of tendon tissue samples on inherent magnetic resonance imaging (MRI) parameters, such as ultrashort echo time (UTE) T2* values, have been performed to date. METHODS: This study performed UTE MRI on 14 bovine patellar tendons at harvest and after four consecutive freeze-thaw cycles. RESULTS: Results demonstrated a small but significant reduction (12%) in tendon T2* values after the first freeze thaw cycle, but not after successive cycles. Tendons from juvenile animals with open physis had a significant reduction of T2* following a single freeze thaw cycle, P<0.0001. CONCLUSIONS: The results of this study emphasize the importance of using uniform tendon storage protocols when using UTE MRI in preclinical models. PMID- 26029640 TI - High-speed real-time magnetic resonance imaging of fast tongue movements in elite horn players. AB - This paper describes the use of high-speed real-time (RT) magnetic resonance imaging (MRI) in quantifying very rapid motor function within the oropharyngeal cavity of six elite horn players. Based on simultaneous sound recordings, the efficacy of RT-MRI films at 30 and 100 frames per second (fps) was assessed for tongue movements associated with double tonguing performance. Serial images with a nominal temporal resolution of 10.0 and 33.3 ms were obtained by highly undersampled radial fast low-angle shot (FLASH) sequences (5 and 17 spokes, respectively) using complementary sets of spokes for successive acquisitions (extending over 9 and 5 frames, respectively). Reconstructions of high-speed images were obtained by temporally regularized nonlinear inversion (NLINV) as previously described. A customized MATLAB toolkit was developed for the extraction of line profiles from MRI films to quantify temporal phenomena associated with task performance. The analyses reveal that for the present setting, which required the use of a temporal median filter to optimize image quality, acquisition rates of 30 fps are inadequate to accurately detect tongue movements during double tonguing, but that rates of 100 fps do allow for a precise quantification of movement. These data for the first time demonstrate the extreme performance of elite horn players. High-speed RT-MRI offers so far unavailable opportunities to study the oropharyngeal movements during brass playing with future potential for teaching and the treatment of patients suffering from dystonia. PMID- 26029641 TI - Evaluation of biocompatible alginate- and deferoxamine-coated ternary composites for magnetic resonance imaging and gene delivery into glioblastoma cells. AB - BACKGROUND: This paper describes comparative studies in cytotoxicities, magnetic resonance imaging (MRI), and gene delivery into glioblastoma U87MG or U138MG cells with ternary composites that are consist of superparamagnetic iron oxide (SPIO) nanoparticles (NPs) (size: 8-10 nm) with different surface coatings, circular plasmid DNA (pDNA) (~4 kb) equipped with fluorescent/luminescent probe, and branched polyethylenimine (25 kDa, PDI 2.5). METHODS: Three types of SPIO-NPs were used, including: (I) naked iron oxide NPs with Fe-OH surface group (Bare NP); (II) iron oxide NPs with a coating of alginate (Alg-NPs); and (III) iron oxide NPs with a coating of deferoxamine (Def-NPs). By tuning the polyethylenimine (PEI)/NP ratios and with a fixed DNA amount, different ternary composites were employed for NP/gene transfection into glioblastoma U87MG or U138MG cells, which were then characterized by Prussian blue staining, in vitro MRI, green fluorescence protein (GFP) fluorescence and luciferase assay. RESULTS: Among the composites prepared, 0.2 ng PEI/0.5 ug DNA/1.0 ug Bare-NP ternary composite possessed the best cellular uptake efficiency of NP to the cytoplasm, following the trend Bare-NP > Alg-NP > Def-NP. This observation was consistent to the MRI assessments with in vitro T 2 relaxivity (r 2) values of 46.0, 35.5, and 23.7 s(-1).uM(-1).Fe, respectively. For cellular uptake efficiency of the pDNA, all variations of PEI/NP ratios of the composites did not yield significant differences. However, cellular uptake efficiencies of pDNA in the ternary composites in U138MG cells were generally higher than that of U87MG cells by an order of magnitude. Exceptionally, the ternary composite 0.2 ng PEI/0.5 ug DNA/1.0 ug Bare-NP possessed a lowered luciferase activity RLU for gene expression in U138MG cells. A total of 0.2 ng PEI/0.5 ug DNA/0.1 ug Bare-NP would be uptaken to the cell nucleus with the highest luciferase activity. A working concentration range of PEI with at least 15% higher cell viabilities than lipofectamine was 0.1 to 0.2 ng/well. The cytotoxicities became significant when 0.5 ng/well PEI was present in the ternary composites. CONCLUSIONS: The as prepared composites offer potential biomedical applications in simultaneous gene delivery, imaging contrast enhancement, and metabolism study. PMID- 26029642 TI - Diffusion MRI on lymph node staging of gastric adenocarcinoma. AB - OBJECTIVE: The purpose of this study was to evaluate the accuracy of diffusion weighted magnetic resonance imaging (MRI) in preoperative assessment of metastatic lymph nodes of gastric cancer. METHODS: A total of 23 gastric cancer patients with a mean age of 59.4+/-10.9 years were analyzed. Lymph nodes were grouped as perigastric lesser curvature (Group Ia), perigastric greater curvature (Group Ib), D1+/D2 lymph nodes (Group II). Identification of histologically metastatic lymph nodes by diffusion weighted MRI was regarded as the main outcome. RESULTS: A total of 1,056 lymph nodes including 180 histologically proven metastatic lymph nodes were dissected. Although diffusion weighted MRI could identify the metastatic lymph nodes in 18 out of 23 patients (77.8%), only 69 of total 1,056 nodes (6.53%), either metastatic or non-metastatic, could be detected. There was no correlation between histopathology and diffusion weighted MRI with regard to lymph node groups (P>0.05 for all). Overall accuracy was calculated as 69.56, 65.21 and 52.17 for Groups II, Ib and Ia lymph nodes, respectively. Apparent diffusion coefficient (ADC) values could not be helpful to differentiate metastatic lymph nodes (P=0.673). CONCLUSIONS: Diffusion weighted MRI has low accuracy to detect or to differentiate metastatic and non-metastatic lymph nodes based on their ADC values in gastric cancer. PMID- 26029643 TI - The angle of pancreaticobiliary junction correlates with acute pancreatitis: a magnetic resonance cholangiopancreatography study. AB - OBJECTIVE: To study the correlation between the angle of the pancreaticobiliary junction (APJ) and the prevalence of acute pancreatitis using magnetic resonance cholangiopancreatography (MRCP). MATERIALS AND METHODS: From February 2014 to October 2014, thirty two subjects with normal pancreas (group A) and 40 patients with acute pancreatitis (group B) who underwent MRCP were enrolled into our study. The type of biliary duct and main pancreatic duct joining the duodenal wall was reviewed and divided into V, B-P and P-B type. The V type is the pancreatic duct and biliary duct joining the duodenal wall without a common channel; the B-P type is the biliary duct draining into the pancreatic duct and forming a common channel; and the P-B type is the pancreatic duct draining into the biliary duct and forming a common channel. APJ was measured on MRCP. The correlation between the APJ and the prevalence of acute pancreatitis was analyzed. RESULTS: The APJ in group A was smaller than in group B (51.45 degrees +/-13.51 degrees vs. 65.76 degrees +/-15.61 degrees , P<0.05). According to the type of biliary duct and main pancreatic duct joining the duodenal wall, the prevalence of acute pancreatitis in the V type and in the B-P type was higher than in the P-B type (12/17 vs. 10/29, or 18/26 vs. 10/29, respectively, all P<0.05), whereas there were no significant difference for the prevalence of acute pancreatitis between the V type and B-P type (P>0.05). The APJ were 59.32 degrees +/-20.04 degrees , 60.22 degrees +/-11.06 degrees , 57.13 degrees +/-17.27 degrees , respectively in V type, B-P type and P-B type joining of main pancreatic duct (P>0.05). CONCLUSIONS: A larger APJ is related to a higher prevalence of acute pancreatitis. PMID- 26029645 TI - Multi-detector CT assessment in pulmonary hypertension: techniques, systematic approach to interpretation and key findings. AB - Pulmonary arterial hypertension (PAH) may be suspected based on the clinical history, physical examination and electrocardiogram findings but imaging is usually central to confirming the diagnosis, establishing a cause and guiding therapy. The diagnostic pathway of PAH involves a variety of complimentary investigations of which computed tomography pulmonary angiography (CTPA) has established a central role both in helping identify an underlying cause for PAH and assessing resulting functional compromise. In particular CTPA is considered as the gold standard technique for the diagnosis of thromboembolic disease. This article reviews the CTPA evaluation in PAH, describing CTPA techniques, a systematic approach to interpretation and spectrum of key imaging findings. PMID- 26029644 TI - Diffusion weighted magnetic resonance imaging and its recent trend-a survey. AB - Since its inception in 1985, diffusion weighted magnetic resonance imaging has been evolving and is becoming instrumental in diagnosis and investigation of tissue functions in various organs including brain, cartilage, and liver. Even though brain related pathology and/or investigation remains as the main application, diffusion weighted magnetic resonance imaging (DWI) is becoming a standard in oncology and in several other applications. This review article provides a brief introduction of diffusion weighted magnetic resonance imaging, challenges involved and recent advancements. PMID- 26029646 TI - PET/SPECT molecular imaging in clinical neuroscience: recent advances in the investigation of CNS diseases. AB - Molecular imaging is an attractive technology widely used in clinical practice that greatly enhances our understanding of the pathophysiology and treatment in central nervous system (CNS) diseases. It is a novel multidisciplinary technique that can be defined as real-time visualization, in vivo characterization and qualification of biological processes at the molecular and cellular level. It involves the imaging modalities and the corresponding imaging agents. Nowadays, molecular imaging in neuroscience has provided tremendous insights into disturbed human brain function. Among all of the molecular imaging modalities, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have occupied a particular position that visualize and measure the physiological processes using high-affinity and high-specificity molecular radioactive tracers as imaging probes in intact living brain. In this review, we will put emphasis on the PET/SPECT applications in Alzheimer's disease (AD) and Parkinson's disease (PD) as major CNS disorders. We will first give an overview of the main classical molecular neuroimaging modalities. Then, the major clinical applications of PET and SPECT along with molecular probes in the fields of psychiatry and neurology will be discussed. PMID- 26029647 TI - New vistas in clinical practice: susceptibility-weighted imaging. AB - Susceptibility-weighted imaging (SWI) is a recently developed magnetic resonance imaging (MRI) technique where image contrast represents 'magnetic susceptibility effects'-a natural property of tissues. The applications of SWI are rapidly increasing, with much work being carried out to determine the usefulness of the technique in multiple disease states. Current clinical applications of the technique include detection of microbleeds, subarachnoid hemorrhage (SAH), ferromagnetic deposition in neurodegenerative disease, and characterization of cerebral tumors. PMID- 26029649 TI - Computer tomography imaging of an unusual cause of appendicitis: a case report. AB - Foreign body occlusion of appendices lumen is a quite rare cause of appendicitis due to foreign body. We present a case of a 63-year-old male who presented with right lower quadrant pain since 24 hours. Computed tomography (CT) demonstrated an acute appendicitis due to a metallic foreign body which was found to be a bullet. PMID- 26029648 TI - Top five medical innovations in China mainland since Xinhai revolution [1911]: results of AME survey-002. AB - OBJECTIVE: This survey aims to scrutinize important medical innovations in Chinese mainland since Xinhai (Hsin-hai) revolution in 1911, which marked the end of Manchurian imperial rule and the beginning of China's republican era. METHODS: An online cross-sectional survey was carried out during the period of Dec 29, 2014 to Feb 5, 2015, totaling 37 days. The survey was conducted on the platform provided by DXY (www.dxy.cn), which is the largest medical and paramedical related website in China. An email was sent to all DXY registered users to invite them to participate in a 5-minute survey. The participants were asked to nominate up to four important medical innovations in China mainland since Xinhai revolution. The participant could select 'zero' which means he/she felt there was no important medical innovations, or he/she did not know important medical innovations. It was noted that important medical innovations refer to (I) those with practical and almost immediate significance to improve healthcare; (II) should not only be introducing western technique to China, but those involve major improvement of existing western techniques count; (III) should not be those with important theoretical discovery but did not have almost immediate significance to improve healthcare. RESULTS: In total 1,513 DXY users participated in the voting. Totally 489 (32.3%), 441 (29.1%), 342 (22.6%), 150 (9.9%), 91 (6.0%) participants provided 0, 1, 2, 3, 4 nominations respectively. (I) Artemisine (Qinghaosu) for malaria treatment (Project 523 team, 1972); (II) arsenic Trioxide (As2O3) for acute promyelocytic leukemia (APL) treatment (ZHANG Ting-Dong and colleagues, 1970s); (III) limb re-plantation (CHEN Zhong-Wei and colleagues, 1963); (IV) all-trans retinoic acid (ATRA) for APL treatment (WANG Zhen-Yi and colleagues, 1988); and (V) Wu's mask for plague prevention (WU Lien The, 1910), were voted as the top five innovations in China mainland since Xinhai revolution, with 375, 96, 91, 53, and 8 votes respectively. CONCLUSIONS: In this voting exercise, five achievements were voted as top innovations in China mainland since Xinhai revolution. However, only ATRA for APL treatment was accomplished after the ending of Great Proletarian Cultural Revolution in year 1976 in China. PMID- 26029650 TI - Dyke-Davidoff-Masson syndrome: imaging features with illustration of two cases. AB - Dyke-Davidoff-Masson syndrome is a rare entity characterized by hemi cerebral atrophy/hypoplasia secondary to brain insult in fetal or early childhood period along with ipsilateral compensatory osseous hypertrophy and contralateral hemiparesis. We present two cases of this uncommon condition and discuss its imaging features, differential diagnosis, treatment options and prognosis. PMID- 26029651 TI - Atypical developmental venous anomaly associated with contrast enhancement and hyperperfusion in the surrounding basal ganglia. AB - Developmental venous anomalies (DVAs) are the most common type of cerebral vascular malformations. They are generally accepted as variants of venous development and frequently identified incidentally, particularly on contrast enhanced MR imaging. Most of the DVAs do not affect the integrity of the surrounding parenchyma. This article discusses an atypical DVA which is associated with contrast enhancement and increased perfusion within the drainage territory of the DVA, probably due to anomalous venous drainage. These unusual perfusion patterns of the DVAs should be differentiated from other entities such as hypervascular brain tumors or ischemia with hemodynamical changes which have different clinical management. PMID- 26029652 TI - Kenny Caffey syndrome with severe respiratory and gastrointestinal involvement: expanding the clinical phenotype. AB - Kenny Caffey syndrome (KCS) is a rare syndrome reported almost exclusively in Middle Eastern populations. It is characterized by severe growth retardation short stature, dysmorphic features, episodic hypocalcaemia, hypoparathyroidism, seizures, and medullary stenosis of long bones with thickened cortices. We report a 10-year-old boy with KCS with an unusually severe respiratory and gastrointestinal system involvement-features not previously described in the literature. He had severe psychomotor retardation and regressed developmentally from walking unaided to sitting with support. MRI brain showed bilateral hippocampal sclerosis, marked supra-tentorial volume loss and numerous calcifications. A 12 bp deletion of exon 2 of tubulin-specific chaperone E (TBCE) gene was identified and the diagnosis of KCS was confirmed. Hypercarbia following a sleep study warranted nocturnal continuous positive airway pressure (CPAP) when aged 6. When boy aged 8, persistent hypercarbia with increasing oxygen requirement and increased frequency and severity of lower respiratory tract infections led to progressive respiratory failure. He became fully dependent on non-invasive ventilation and by 9 years he had a tracheotomy and was established on long-term ventilation. He developed retching, vomiting and diarrhea. Chest CT showed changes consistent with chronic aspiration, but no interstitial pulmonary fibrosis. He died aged 10 from respiratory complications. PMID- 26029653 TI - Hemoptysis caused by ectopic lingual thyroid. AB - A 26-year-old man was referred to emergency department complaining of hemoptysis. Imaging studies showed ectopic lingual thyroid. PMID- 26029654 TI - Glow in the dark. AB - OBJECTIVE: To highlight the importance of radiation safety and handling of radioactive secretions following 131I-meta iodobenzylguanidine (131I-mIBG) use in the treatment of neuroblastoma. METHODS: We report a 4-year-old girl with stage 4 neuroblastoma, on whom's single-photon emission computer tomography (SPECT) scan we demonstrate four extra-corporal areas of radioactivity confirming radiation uptake in the four corners of her 'comfort blanket' that had been used to cover her during the scan. It transpired that she had been sucking on the four corners of this blanket. RESULTS: The patient's secretions remain radioactive for some time following scintigraphy, as evidence of radioactivity in the patient's comfort blanket. CONCLUSIONS: Radioactive uptake of 131I-mIBG in the salivary glands of patients has previously been reported. This illustrative case emphasizes that patient's secretions remain radioactive following treatment and highlights the importance of careful handling of radioactive secretions. PMID- 26029655 TI - A rare cyclic recurrent hematuria case; bladder endometriosis. AB - Endometriosis is a benign gynecological disease that is characterized by the presence of functional endometrial tissue outside the uterus. Although the ovaries and uterine ligaments are the most common locations, urinary tract involvement especially the bladder endometriosis is a rare entity in women of reproductive age with clinical symptoms of cyclical urgency, hematuria and suprapubic pain. We herein present magnetic resonance imaging (MRI) findings of spontaneous bladder endometriosis case with cyclical hematuria symptoms. PMID- 26029656 TI - Income of medical doctors in Germany. PMID- 26029657 TI - Why so many Chinese clinical doctors are competing for basic research grants? PMID- 26029658 TI - Editorial: Targeting MYCN in Pediatric Cancers. PMID- 26029659 TI - Cancer-associated fibroblasts from lung tumors maintain their immunosuppressive abilities after high-dose irradiation. AB - Accumulating evidence supports the notion that high-dose (>5 Gy) radiotherapy (RT) regimens are triggering stronger pro-immunogenic effects than standard low dose (2 Gy) regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study, we have investigated the effects of high-dose radiotherapy (HD-RT) on the immunomodulating functions of cancer-associated fibroblasts (CAFs). Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays, and T-cell cytokine production. Additionally, CAF-secreted immunoregulatory factors were studied by multiplex protein arrays, ELISAs, and by LC-MS/MS proteomics. In all functional assays, we observed a powerful immunosuppressive effect exerted by CAF-conditioned medium on activated T-cells (p > 0.001), and this effect was sustained after a single radiation dose of 18 Gy. Relevant immunosuppressive molecules such as prostaglandin E2, interleukin-6, and -10, or transforming growth factor-beta were found in CAF-conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immunosuppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT. PMID- 26029660 TI - Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma. AB - The treatment of melanoma by targeted inhibition of the mutated kinase BRAF with small molecules only temporarily suppresses metastatic disease. In the face of chemical inhibition tumor plasticity, both innate and adaptive, promotes survival through the biochemical and genetic reconfiguration of cellular pathways that can engage proliferative and migratory systems. To investigate this process, high resolution mass spectrometry was used to characterize the phosphoproteome of this transition in vitro. A simple and accurate, label-free quantitative method was used to localize and quantitate thousands of phosphorylation events. We also correlated changes in the phosphoproteome with the proteome to more accurately determine changes in the activity of regulatory kinases determined by kinase landscape profiling. The abundance of phosphopeptides with sites that function in cytoskeletal regulation, GTP/GDP exchange, protein kinase C, IGF signaling, and melanosome maturation were highly divergent after transition to a drug resistant phenotype. PMID- 26029661 TI - Editorial: "global challenges in radiation oncology". PMID- 26029662 TI - Editorial: multidrug resistance in cancer: pharmacological strategies from basic research to clinical issues. PMID- 26029663 TI - Salvage Fractionated Stereotactic Radiotherapy with or without Chemotherapy and Immunotherapy for Recurrent Glioblastoma Multiforme: A Single Institution Experience. AB - BACKGROUND: The current standard of care for salvage treatment of glioblastoma multiforme (GBM) is gross total resection and adjuvant chemoradiation for operable patients. Limited evidence exists to suggest that any particular treatment modality improves survival for recurrent GBM, especially if inoperable. We report our experience with fractionated stereotactic radiotherapy (fSRT) with and without chemo/immunotherapy, identifying prognostic factors associated with prolonged survival. METHODS: From 2007 to 2014, 19 patients between 29 and 78 years old (median 55) with recurrent GBM following resection and chemoradiation for their initial tumor, received 18-35 Gy (median 25) in three to five fractions via CyberKnife fSRT. Clinical target volume (CTV) ranged from 0.9 to 152 cc. Sixteen patients received adjuvant systemic therapy with bevacizumab (BEV), temozolomide (TMZ), anti-epidermal growth factor receptor (125)I-mAb 425, or some combination thereof. RESULTS: The median overall survival (OS) from date of recurrence was 8 months (2.5-61) and 5.3 months (0.6-58) from the end of fSRT. The OS at 6 and 12 months was 47 and 32%, respectively. Three of 19 patients were alive at the time of this review at 20, 49, and 58 months from completion of fSRT. Hazard ratios for survival indicated that patients with a frontal lobe tumor, adjuvant treatment with either BEV or TMZ, time to first recurrence >16 months, CTV <36 cc, recursive partitioning analysis <5, and Eastern Cooperative Oncology Group performance status <2 were all associated with improved survival (P < 0.05). There was no evidence of radionecrosis for any patient. CONCLUSION: Radiation Therapy Oncology Group (RTOG) 1205 will establish the role of re irradiation for recurrent GBM, however our study suggests that CyberKnife with chemotherapy can be safely delivered, and is most effective in patients with smaller frontal lobe tumors, good performance status, or long interval from diagnosis. PMID- 26029664 TI - Myeloid derived suppressor cells in chronic myeloid leukemia. AB - The suppression of the immune system creates a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells (MDSCs), immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression. Two different subpopulations have been identified and studied: granulocytic and monocytic MDSCs, with a different immunophenotype and immunosuppressive properties. Recently, an accumulation of both Gr-MDSCs and Mo MDSCs cells has been found in the peripheral blood of chronic myeloid leukemia (CML) patients. They are part of the tumor clone showing BCR/ABL expression. Imatinib therapy decreases both MDSCs and arginase 1 levels to normal ones. This review will focus on actual knowledge for human MDSCs and their immunosuppressive activity in CML patients, with a critical attention to comparison of Gr-MDSCs and polymorphonuclear cells (PMNs). We will then suggest the monitoring of MDSCs in patients who have discontinued tyrosine kinase inhibitors (TKIs) therapy to evaluate if their increase could correlate with disease relapse. PMID- 26029665 TI - Salvage stereotactic body radiotherapy for locally recurrent non-small cell lung cancer after sublobar resection and i(125) vicryl mesh brachytherapy. AB - PURPOSE: Locally recurrent non-small cell lung cancer (LR-NSCLC) remains challenging to treat, particularly in patients having received prior radiotherapy. Heterogeneous populations and varied treatment intent in existing literature result in significant limitations in evaluating efficacy of lung re irradiation. In order to better establish the impact of re-irradiation in patients with LR-NSCLC following high-dose radiotherapy, we report outcomes for patients treated with prior sublobar resection and brachytherapy that subsequently underwent stereotactic body radiotherapy (SBRT). METHODS: A retrospective review of patients initially treated with sublobar resection and I(125) vicryl mesh brachytherapy, who later developed LR-NSCLC along the suture line, was performed. Patients received salvage SBRT with curative intent. Dose and fractionation were based on tumor location and size, with a median prescription dose of 48 Gy in 4 fractions (range 20-60 Gy in 1-4 fractions). RESULTS: Thirteen consecutive patients were identified with median follow-up of 2.1 years (range 0.7-5.6 years). Two in-field local failures occurred at 7.5 and 11.1 months, resulting in 2-year local control of 83.9% (95% CI, 63.5-100.0%). Two-year disease-free survival and overall survival estimates were 38.5% (95% CI, 0.0-65.0%) and 65.8% (95% CI, 38.2-93.4%). Four patients (31%) remained disease free at last follow-up. All but one patient who experienced disease recurrence developed isolated or synchronous distant metastases. Only one patient (7.7%) developed grade >=3 toxicity, consisting of grade 3 esophageal stricture following a centrally located recurrence previously treated with radiofrequency ablation. CONCLUSION: Despite high-local radiation doses delivered to lung parenchyma previously with I(125) brachytherapy, re-irradiation with SBRT for LR NSCLC results in excellent local control with limited morbidity, allowing for potential disease cure in a subset of patients. PMID- 26029666 TI - Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases. AB - PURPOSE: To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. MATERIALS AND METHODS: Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1-4 brain metastases, Karnofsky performance status >=70, and life expectancy >=3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with >=1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses. RESULTS: Median survival for all patients was 11 months. Among patients with >=1-year WBRT-free survival, median survival was 33 months (12-107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p < 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (<=5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival. CONCLUSION: A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone. PMID- 26029667 TI - Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. AB - The MYCN proto-oncogene is associated with poor outcome across a broad range of pediatric tumors. While amplification of MYCN drives subsets of high-risk neuroblastoma and medulloblastoma, dysregulation of MYCN in medulloblastoma (in the absence of amplification) also contributes to pathogenesis. Since PI3K stabilizes MYCN, we have used inhibitors of PI3K to drive degradation. In this study, we show PI3K inhibitors by themselves induce cell cycle arrest, with modest induction of apoptosis. In screening inhibitors of PI3K against MYCN, we identified PIK-75 and its derivative, PW-12, inhibitors of both PI3K and of protein kinases, to be highly effective in destabilizing MYCN. To determine the effects of PW-12 treatment in vivo, we analyzed a genetically engineered mouse model for MYCN-driven neuroblastoma and a model of MYCN-driven medulloblastoma. PW-12 showed significant activity in both models, inducing vascular collapse and regression of medulloblastoma with prominent apoptosis in both models. These results demonstrate that inhibitors of lipid and protein kinases can drive apoptosis in MYCN-driven cancers and support the importance of MYCN as a therapeutic target. PMID- 26029668 TI - Pazopanib-induced alopecia, an underestimated toxicity? AB - Pazopanib and sunitinib are treatment options for metastatic renal cell cancer (mRCC), with similar efficacy, and minor differences in their toxicity profile. Our experience has suggested that pazopanib-induced alopecia may be a potentially significant but previously under-reported toxicity. For this reason, we performed a retrospective review of the clinical records of all patients with mRCC treated with pazopanib at the Royal Marsden Hospital from European licensing until June 2013, and all patients treated with sunitinib over the same period. We found that 36 patients with mRCC were treated with pazopanib and 85 patients with sunitinib. Four of the 36 (11%) patients treated with pazopanib developed alopecia severe enough to warrant a wig versus none of 85 patients treated with sunitinib (p = 0.007). In conclusion, grade 2 pazopanib-induced alopecia was reported at significantly higher rates when compared to sunitinib-induced alopecia. Hence, in our view, patients should be informed about this potential toxicity when discussing the treatment options for mRCC. PMID- 26029669 TI - Extracellular matrix-associated proteins form an integral and dynamic system during Pseudomonas aeruginosa biofilm development. AB - Though the essential role of extracellular matrix in biofilm development has been extensively documented, the function of matrix-associated proteins is elusive. Determining the dynamics of matrix-associated proteins would be a useful way to reveal their functions in biofilm development. Therefore, we applied iTRAQ-based quantitative proteomics to evaluate matrix-associated proteins isolated from different phases of Pseudomonas aeruginosa ATCC27853 biofilms. Among the identified 389 proteins, 54 changed their abundance significantly. The increased abundance of stress resistance and nutrient metabolism-related proteins over the period of biofilm development was consistent with the hypothesis that biofilm matrix forms micro-environments in which cells are optimally organized to resist stress and use available nutrients. Secreted proteins, including novel putative effectors of the type III secretion system were identified, suggesting that the dynamics of pathogenesis-related proteins in the matrix are associated with biofilm development. Interestingly, there was a good correlation between the abundance changes of matrix-associated proteins and their expression. Further analysis revealed complex interactions among these modulated proteins, and the mutation of selected proteins attenuated biofilm development. Collectively, this work presents the first dynamic picture of matrix-associated proteins during biofilm development, and provides evidences that the matrix-associated proteins may form an integral and well regulated system that contributes to stress resistance, nutrient acquisition, pathogenesis and the stability of the biofilm. PMID- 26029671 TI - Sertraline enhances the activity of antimicrobial agents against pathogens of clinical relevance. AB - BACKGROUND: Serotonin reuptake inhibitors were recently reported to possess antimicrobial potentials, potentiate activity of several antibiotics, reverse multidrug resistant phenotypes of bacteria and make them susceptible to previously resistant drugs. We investigated antimicrobial potentials of sertraline (SR) against ATCC strains, clinical isolates of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa alone and in-combination with seven antibiotics. Antifungal activity was investigated against four fungal strains including Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Fusarium solani. Intrinsic antibacterial action and Minimum Inhibitory Concentrations (MICs) were determined using well assay, nutrient broth and agar dilution techniques. Disk diffusion and nutrient broth methods were used to study bacterial susceptibility to SR. Minimum Fungicidal Concentrations (MFCs) of SR were determined using Sabouraud dextrose Agar (SDA). RESULTS: Sertraline possesses strong intrinsic antibacterial, antifungal activities and has augmented the antibacterial activities of antibiotics. For S. aureus ATCC 6538, E. coli ATCC 8739 and P. aeruginosa ATCC 9027, the MICs of SR were 20, 40 and 60 MUg ml( 1), respectively, whereas 55.5% clinical isolates of S. aureus and 50% of E. coli strains were inhibited at 20 and 60 MUg ml(-1) of SR, respectively. Among the tested fungi, 60% of A. niger and A. fumigatus were inhibited at 40 and 80 MUg ml(-1), respectively. MFCs were 60 and 80 MUg ml(-1) for A. flavus and F. solani, respectively. Antibacterial activities of all antibiotics were significantly increased (p < 0.001) with the addition of SR 100 MUg ml(-1) against all tested bacteria. CONCLUSION: Combination study revealed that SR had significantly increased the activity of antibiotics, and some previously resistant strains were made susceptible. Thus antidepressants are potential sources of resistance modifying agents when used in combination. PMID- 26029670 TI - Stenotrophomonas maltophilia responds to exogenous AHL signals through the LuxR solo SmoR (Smlt1839). AB - Quorum Sensing (QS) mediated by Acyl Homoserine Lactone (AHL) molecules are probably the most widespread and studied among Gram-negative bacteria. Canonical AHL systems are composed by a synthase (LuxI family) and a regulator element (LuxR family), whose genes are usually adjacent in the genome. However, incomplete AHL-QS machinery lacking the synthase LuxI is frequently observed in Proteobacteria, and the regulator element is then referred as LuxR solo. It has been shown that certain LuxR solos participate in interspecific communication by detecting signals produced by different organisms. In the case of Stenotrophomonas maltophilia, a preliminary genome sequence analysis revealed numerous putative luxR genes, none of them associated to a luxI gene. From these, the hypothetical LuxR solo Smlt1839, here designated SmoR, presents a conserved AHL binding domain and a helix-turn-helix DNA binding motif. Its genomic organization-adjacent to hchA gene-indicate that SmoR belongs to the new family "LuxR regulator chaperone HchA-associated." AHL-binding assays revealed that SmoR binds to AHLs in-vitro, at least to oxo-C8-homoserine lactone, and it regulates operon transcription, likely by recognizing a conserved palindromic regulatory box in the hchA upstream region. Supplementation with concentrated supernatants from Pseudomonas aeruginosa, which contain significant amounts of AHLs, promoted swarming motility in S. maltophilia. Contrarily, no swarming stimulation was observed when the P. aeruginosa supernatant was treated with the lactonase AiiA from Bacillus subtilis, confirming that AHL contributes to enhance the swarming ability of S. maltophilia. Finally, mutation of smoR resulted in a swarming alteration and an apparent insensitivity to the exogenous AHLs provided by P. aeruginosa. In conclusion, our results demonstrate that S. maltophilia senses AHLs produced by neighboring bacteria through the LuxR solo SmoR, regulating population behaviors such as swarming motility. PMID- 26029672 TI - Evaluation of oral mucosal epithelium in diabetic male patients by exfoliative cytology method. AB - BACKGROUND: The goal of present study is to examine comparatively the epithelium of oral mucosa in persons with diabetes types I and II and the healthy persons by cytomorphometric method. METHODS: Cytology smear was prepared from oral mucosa epithelium in 24 persons with diabetes and 30 healthy persons were stained by papanicolao method. Its before, from patients were requested acquiring written. The quantitative cytomorphometric characteristics were measured in each group by motic plus 2 software. Also, the qualitative evaluation of cytology slides are performed in three groups. RESULTS: There were decrease in the nuclear and cytoplasmic size, (P < 0.001) and increase in the ratio of nuclear to cytoplasm size in buccal mucosal areas (P = 0.001) and tongue (P = 0.011) of diabetic persons compared to the healthy persons. There was no significantly statistical difference in diabetic persons types I and II in buccal mucosal area (P = 0.15) and tongue (P = 0.86) in quantitative characteristics of cytomoerphometry. In nuclear and cytoplasm size, there was a significant statistical difference in persons with diabetes type I and persons of control I and persons with diabetes type II and persons of control II in buccal mucosa and the tongue (P < 0.001). Bilobed or multi-lobed nuleous, karyorrhexis and vacuolization of cytoplasm were more in diabetic persons compared to the healthy ones (P < 0.001). CONCLUSION: Diabetes are effective in creating some quantitative and qualitative cytometric alterations in the oral mucosa but the type of diabetes doesn't seem to be effective on these changes. PMID- 26029674 TI - A novel pancreaticogastrostomy method using only two transpancreatic sutures: early postoperative surgical results compared with conventional pancreaticojejunostomy. AB - PURPOSE: To evaluate the surgical outcomes of pancreaticogastrostomy (PG) using two transpancreatic sutures with a buttress method through an anterior gastrostomy (PGt), and compare these results with our previous experience with pancreaticojejunostomy (PJ) including the dunking and duct to mucosa methods after pancreaticoduodenectomy (PD). METHODS: In this study, 171 patients who had undergone PD between January 2005 and April 2013 were classified into three groups according to the method of the pancreaticoenteric anastomosis: dunking PJ (PJu group; n = 67, 39.1%), duct to mucosa PJ (PJm group; n = 41, 23.9%), and PGt (PGt group; n = 63, 36.8%). We retrospectively analyzed patient characteristics, perioperative outcomes, and surgical results. RESULTS: Both groups had comparable demographics and pathology, and there were no significant differences in operative time, estimated blood loss, or postoperative hospital stay. Within the two groups, morbidities occurred in 49 cases (10.7%), and were not significantly different between the two groups, excepting postoperative pancreatic fistula (POPF). The PGt group had a lower rate of POPF (18/63, 28.6%) than the PJu and PJm groups (21/67, 31.3% and 19/41, 46.3%; P = 0.048), especially in terms of grades B and C POPF (4/63 [6.3%] in the PGt group vs. 7/67 [10.4%] in the PJu group and 9/41 [22.0%] in the PJm group, P = 0.049). CONCLUSION: The PGt method showed feasible outcomes for POPF and had advantages over dunking PJ and duct to mucosa PJ with respect to immediate postoperative results. PGt may be a promising technique for pancreaticoenteric anastomosis after PD. PMID- 26029673 TI - Low parental support in late adolescence predicts obesity in young adulthood; Gender differences in a 12-year cohort of African Americans. AB - BACKGROUND: Most studies that have investigated the link between parenting behaviors and risk of obesity among offsprings have mostly used a cross-sectional design, enrolled Caucasian samples, focused on childhood obesity, and covered aspects of parenting behaviors that directly influence energy balance and food intake of the children. Thus, more longitudinal research is needed on how more general aspects of parenting influence obesity in young ethnic minority adults. The current longitudinal study aimed to test if baseline parental support predicts change in body mass index (BMI) of African Americans, and if this prediction varies based on gender of offspring. METHODS: The current study followed 227 young African American adults (109 male and 118 female) for 12 years from year 2000 (mean age 20) to year 2012 (mean age 32). All participants were enrolled from a disadvantaged urban area in the Midwest of the United States. Baseline demographics (age, gender), socio-economics (family structure, and parental employment), psychological symptoms (anxiety and depression), general parental support (maternal support, and paternal support) were measured. BMI was measured at baseline and at follow up. We used gender-specific linear regressions to test the predictive role of baseline paternal and maternal support (year 2000) on change in BMI (from 2000 to 2012). RESULTS: Regression analysis showed that among female African American young adults, high baseline maternal support was predictive of a lower increase in BMI from 2000 to 2012. The association remained significant while all covariates were in the model. We could not find such an association for male African American young adults. CONCLUSION: High maternal support appears to be protective against increases in BMI among African American female young adults. As parental support is a modifiable factor within available evidence-based interventions that enhance parenting, it should be included in obesity prevention programs for African American women. Policies and programs should support African American mothers in disadvantaged neighborhoods to enable them to provide high levels of parental support for their young adult daughters. Future research should test the efficacy of such programs and policies for reducing obesity among African American women. PMID- 26029675 TI - In vivo porcine training model for laparoscopic Roux-en-Y choledochojejunostomy. AB - PURPOSE: The purpose of this study was to develop a porcine training model for laparoscopic choledochojejunostomy (CJ) that can act as a bridge between simulation models and actual surgery for novice surgeons. The feasibility of this model was evaluated. METHODS: Laparoscopic CJ using intracorporeal sutures was performed on ten animals by a surgical fellow with no experience in human laparoscopic CJ. A single layer of running sutures was placed in the posterior and anterior layers. Jejunojejunostomy was performed using a linear stapler, and the jejunal opening was closed using absorbable unidirectional sutures (V-Loc 180). RESULTS: The average operation time was 131.3 +/- 36.4 minutes, and the CJ time was 57.5 +/- 18.4 minutes. Both the operation time and CJ time showed a steady decrease with an increasing number of cases. The average diameter of the CBD was 6.4 +/- 0.8 mm. Of a total of ten animals, eight were sacrificed after the procedure. In two animals, a survival model was evaluated. Both pigs recovered completely and survived for two weeks, after which both animals were sacrificed. None of the animals exhibited any signs of bile leakage or anastomosis site stricture. CONCLUSION: The porcine training model introduced in this paper is an adequate model for practicing laparoscopic CJ. Human tissue simulation is excellent. PMID- 26029676 TI - Analysis of patient-dropouts from the critical pathways for gastric cancer. AB - PURPOSE: This study was designed to determine the factors affecting completion of critical pathway for elective gastrectomy. METHODS: Since 2008, a critical pathway has been applied for elective gastrectomy at Chosun University Hospital. We retrospectively analyzed 252 patients who underwent elective gastrectomies from January 2009 to April 2013. The completion rate was determined, and risk factors for patient dropout were examined. RESULTS: The completion rate of the critical pathway was 45.6% (115/252). Mean length of stay was 11.7 +/- 8.6 days (8-59 days). Readmission rates were 4.4% (11/252). Causes of failure for clinical pathway were systemic complications (21/137, 15.3%), intra-abdominal complications (44/137, 32.8%), patient factors (41/137, 29.9%), and wound complications (30/137, 21.9%). There were no significant differences between the two groups in age, sex, American Society of Anesthesiologists (ASA) score, operation time, readmission, and underlying disease (P > 0.05). Body mass index (P = 0.008) and pathologic stage (P = 0.001) were significantly different between the two groups. In multivariate analysis, the conventional approach (odds ratio, 2.0), and total gastrectomy (odds ratio, 5.3) were determined to be independent risk factors to drop the critical pathway. But there were no significant differences between total and distal gastrectomy groups in age, gender, underlying diseases, ASA score, readmission, operation time, and cause of dropout (P > 0.05). CONCLUSION: We concluded that total gastrectomy may not be suitable for the critical pathway. We suggest that the critical pathway for elective distal gastrectomy is divided 2 subgroups, according to the surgical approach. PMID- 26029677 TI - Effect of visceral fat area on outcomes of laparoscopyassisted distal gastrectomy for gastric cancer: subgroup analysis by gender and parameters of obesity. AB - PURPOSE: The aim of this study was to investigate the impact of the visceral fat area (VFA) of patients with gastric cancer undergoing laparoscopic surgery on operative outcomes such as number of retrieved lymph nodes (LNs) and operative time. METHODS: We retrospectively reviewed the medical records and the CT scans of 597 patients with gastric cancer who underwent laparoscopy assisted distal gastrectomy (LADG) with partial omentectomy and LN dissection (>D1 plus beta). Patients were stratified by gender, VFA, and body mass index (BMI), and the clinicopathologic characteristics and operative outcomes were evaluated. Multiple linear regression analysis was used to assess the effects of VFA and BMI on the number of retrieved LNs and operative time in male and female patients. RESULTS: The mean number of retrieved LNs was significantly decreased for both male and female patients with high VFA. The operative time was significantly longer for both male and female patients with high VFA. The number of retrieved LNs had a statistically significant negative correlation with VFA in both men and women, but not with BMI. The operative time had a statistically significant positive correlation with VFA in men, whereas the operative time had a statistically significant positive correlation with BMI in women. CONCLUSION: The preoperative VFA of male patients with gastric cancer who undergo LADG may affect the number of retrieved LNs and operative time. VFA was more useful than BMI for predicting outcomes of LADG. PMID- 26029678 TI - Surgical indicators for the operative treatment of acute mechanical intestinal obstruction due to adhesions. AB - PURPOSE: Our aim was to investigate the predictive factors indicating strangulation, and the requirement for surgery in patients with acute mechanical intestinal obstruction due to adhesions. METHODS: This study retrospectively evaluated the records of patients with adhesive acute mechanical intestinal obstruction. The surgical treatment (group S), conservative treatment (group C), intraoperative bowel ischemia (group I), and intraoperative adhesion only (group A) groups were statistically evaluated according to the diagnostic and surgical parameters. RESULTS: The study group of 252 patients consisted of 113 women (44.8%), and 139 men (55.2%). The mean age was 62.79 +/- 18.08 years (range, 20 98 years). Group S consisted of 50 patients (19.8%), and 202 (80.2%) were in group C. Group I consisted of 19 patients (38%), where as 31 (62%) were in group A. In group S, the prehospital symptomatic period was longer, incidence of fever was increased, and elevated CRP levels were significant (P < 0.05). Plain abdominal radiography, and abdominal computerized tomography were significantly sensitive for strangulation (P < 0.05). The elderly were more prone to strangulation (P < 0.05). Fever, rebound tendernes, and urea & creatinine levels were significantly higher in the presence of strangulation (P < 0.05, P < 0.05, and P < 0.05, consecutively). CONCLUSION: Fever, rebound tenderness, urea & creatinine levels, plain abdominal radiography, and abdominal computerized tomography images were important indicators of bowel ischemia. Longer prehospital symptomatic period was related with a tendency for surgical treatment, and the elderly were more prone to strangulation. CRP detection was considered to be useful for the decision of surgery, but not significantly predictive for strangulation. PMID- 26029679 TI - Iliac anatomy and the incidence of adjunctive maneuvers during endovascular abdominal aortic aneurysm repair. AB - PURPOSE: Challenging iliac anatomy remains an important issue during endovascular aneurysm repair (EVAR), and it is known that the length of the common iliac artery (CIA) is shorter in Asians than in Western groups. We analyzed both the iliac anatomy and the incidence of adjunctive maneuvers to overcome iliac artery related difficulties during EVAR. METHODS: Seventy-four EVARs were performed for abdominal aortic aneurysm between January 2010 and March 2013. Patient demographic data, iliac anatomical characteristics (presence of iliac artery aneurysm, iliac artery diameter and length, and iliac tortuosity), and adjunctive iliac artery maneuvers were reviewed retrospectively. RESULTS: Mean CIA length was 52.8 mm (range, 6.6-98.0 mm) on the right and 56.3 mm (range, 0-94.8 mm) on the left. CIA length was >=20 mm, except in one patient with bilateral short CIAs. Forty patients (54%) had a CIA aneurysm, and 18 had aneurysms on both sides. Iliac adjunctive procedures were performed in 38 patients (51%) as follows: 23 internal iliac artery (IIA) embolizations or ligations, seven IIA revascularizations, 16 external iliac artery (EIA) balloon angioplasties or stenting, one EIA patch angioplasty, one EIA interposition, two femoral endarterectomies with patch angioplasty, and nine femoro-femoral bypasses after EVAR with an aorto-uni-iliac device. Technical success for the adjunctive iliac procedures was achieved in all patients. CONCLUSION: Short CIA length was uncommon. Although many patients had access-related difficulties, most were overcome by an endovascular or hybrid technique. Liberal use of iliac adjunctive procedures can facilitate EVAR. PMID- 26029680 TI - Drain insertion after appendectomy in children with perforated appendicitis based on a single-center experience. AB - PURPOSE: Management of appendicitis in children has always been an issue in pediatric surgery. Both diagnostic methods and treatment vary significantly among medical centers, and little consensus exists in many aspects of the care for patients with appendicitis. Here, we assessed the value of drain insertion after appendectomy in children. METHODS: This study is a retrospective review of pediatric patients who underwent appendectomy for perforated appendicitis at a tertiary medical center between 2003 and 2012. Patients who had a peritoneal drain inserted after appendectomy were compared with patients without drains regarding preoperative features and postoperative outcomes. Statistical analyses included a 2-tailed Student t-test and a chi-square or Fisher exact test. RESULTS: In total, 958 patients were reviewed. Of 342 patients with perforated appendicitis, 108 (31.6%) had Jackson-Pratt (JP) drains inserted. The JP group had a longer hospital stay compared with the non-JP group (6.38 +/- 3.59 days vs. 3.87 +/- 2.38 days, P < 0.001). The JP group also had higher complication rates (22.2% vs. 6.8%, P = 0.003), including the formation of intra-abdominal abscesses. CONCLUSION: According to our results, there seems to be little evidence to support peritoneal drain insertion after appendectomy, even in perforated appendicitis cases. PMID- 26029681 TI - Synchronous triple primary cancers occurring in the stomach, kidney, and thyroid. AB - We report an unusual case of synchronous triple primary cancer of the stomach, kidney, and thyroid in a 50-year-old male patient. Initial esophagogastroduodenoscopy with biopsy for the medical check-up revealed poorly differentiated adenocarcinoma. We performed an abdominal/pelvic computed tomography scan for staging and incidentally found a 1.7-cm exophytic hypervascular mass in the left kidney. Thyroid ultrasonography showed suspicious malignant nodules suspicious with multiple lymph nodes (LNs) metastasis in the right side of the neck. Subsequent fine needle aspiration biopsy of a nodule and a LN was performed. Cytologic report revealed papillary thyroid carcinoma with lateral LNs metastasis. Our integrate oncology team performed radical subtotal gastrectomy, partial nephrectomy, and total thyroidectomy with modified radical neck dissection. The postoperative pathologic finding was well-differentiated gastric adenocarcinoma (T1N0M0; stage 1A), renal cell carcinoma (T1aN0M0; stage 1), and papillary thyroid carcinoma (T4bN1bM0; stage 4B). He received postoperative a radio-active iodine ablation and is doing well with no recurrence. PMID- 26029682 TI - Alternative prosthetic vascular access creation using subscapular artery as inflow to prevent dialysis access related steal syndrome. AB - In patients highly suspected of developing steal syndrome, the subscapular artery may be a good supplier for functional prosthetic arteriovenous access, as well as a good solution for the prevention of steal syndrome. A 51-year-old woman was preparing to have a loop shaped polytetrafluoroethylene (PTFE) graft placed at the left upper extremity. The diameter of subscapular the artery was 3 mm. Arterial calcification was not evident. The diameter of the basilic vein was 6 mm. A 50-cm long 4-7 mm tapered PTFE graft was placed in a loop shape between both skin incisions. The patient was uneventfully discharged at postoperative day 4 without any remaining steal syndrome. The PTFE graft was well-functioning during the follow-up period. The patient did not experience symptoms of steal syndrome any longer. PMID- 26029684 TI - Individual and Social Predictors of Prosocial Behavior among Chinese Adolescents in Hong Kong. AB - Based on the human ecological model, this study hypothesized that individual competence in empathy, prosocial moral reasoning, and social influence from parents, peers, and school are the key determinants of prosocial behavior among Chinese adolescents in Hong Kong. We recruited a sample of high school students who engaged in volunteering activities regularly (N = 580). They completed a self administrated questionnaire designed to measure prosocial behavior and its hypothesized predictors using a number of standardized instruments. The results of multiple regression show that social influence factors, including peer, school, and parent influence, are strong predictors of helping intention and prosocial behavior, while individual competence factors like empathy and prosocial moral reasoning are not. Male participants had higher empathy scores and helping intention than females, perceived their parents as more helpful, and their schools as more supportive of prosocial behavior. However, the significant predictors of prosocial behavior and helping intention were similar across gender. The findings indicate that social influence is strongly linked to prosocial behavior. This implies that socialization and social support for prosocial norms and behavior can exert a powerful influence on the behavior of young people in a Chinese population. PMID- 26029683 TI - Orthognathic surgery and temporomandibular joint symptoms. AB - The aim of this article is to review temporomandibular joint symptoms as well as the effects of orthognathic surgery(OGS) on temporomandibular joint(TMJ). The causes of temporomandibular joint disease(TMD) are multifactorial, and the symptoms of TMD manifest as a limited range of motion of mandible, pain in masticatory muscles and TMJ, Joint noise (clicking, popping, or crepitus), myofascial pain, and other functional limitations. Treatment must be started based on the proper diagnosis, and almost symptoms could be subsided by reversible options. Minimally invasive options and open arthroplasty are also available following reversible treatment when indicated. TMD manifesting in a variety of symptoms, also can apply abnormal stress to mandibular condyles and affect its growth pattern of mandible. Thus, adaptive developmental changes on mandibular condyles and post-developmental degenerative changes of mandibular condyles can create alteration on facial skeleton and occlusion. The changes of facial skeleton in DFD patients following OGS have an impact on TMJ, masticatory musculature, and surrounding soft tissues, and the changes of TMJ symptoms. Maxillofacial surgeons must remind that any surgical procedures involving mandibular osteotomy can directly affect TMJ symptoms, thus pre-existing TMJ symptoms and diagnoses should be considered prior to treatment planning and OGS. PMID- 26029685 TI - Sleep in infancy predicts gender specific social-emotional problems in toddlers. AB - Despite strong evidence linking sleep to developmental outcomes, the longitudinal relationship between sleep and emotional well-being remains largely unknown. To address this gap in our knowledge, the current study examined sleep in infancy, measured via actigraphy, as a predictor of social-emotional problems in toddlers. A total of 47 children (29 males) were included in this longitudinal study. At time one, actigraphy measures of sleep were obtained from 3- to 4-month-old infants. At time two, parents rated their 18- to 24-month-old toddler's social emotional well-being using the Brief Infant Toddler Social Emotional Assessment. Results indicated that boys tended to have higher levels of externalizing behaviors than did girls. Additionally, boys with longer sleep durations also showed lower sleep efficiency. In girls, sleep duration in infancy was a significant predictor of autism spectrum disorder behaviors and approached significance as a predictor of externalizing problems in toddlerhood. Our findings are the first to show a relationship between sleep measured in infancy and autism spectrum disorder symptomatology measured in early childhood. They suggest that the etiology of social-emotional problems may differ between genders and raise the possibility that sleep/wake cycles may be differentially related to autism spectrum disorder symptoms in girls and boys. PMID- 26029686 TI - U.s. Undergraduate education in public health: hot or not? AB - OBJECTIVES: Undergraduate public health education has received growing attention in recent years. This includes a Washington Post article referring to undergraduate public health education as a "hot field" for a global generation, the Critical Component Elements of an Undergraduate Major in Public Health developed by the Association of School and Programs in Public Health (ASPPH), and a recent report from the de Beaumont Foundation and ASPPH. To evaluate the demand for the degree and assess the current state of undergraduate public health education, the researchers examined the number and characteristics of publicly reported U.S. baccalaureate public health programs. METHODS: The researchers reviewed three 2013 college directories and the ASPPH website and identified 112 institutions that used the term "public health" in their baccalaureate degree listings that guide prospective students in selecting an academic program. The researchers defined the undergraduate degree in public health as a major leading to a B.S., B.A., or other baccalaureate degree in public health or public health studies that provides students with a strong general background in areas of knowledge basic to public health, or a specialized training in at least one of the five core disciplines of public health. The researchers then compared the degree contents as listed in the directories to the institutions' websites to verify offering a public health curriculum. Carnegie Commission on Higher Education's classifications of colleges and universities were applied to assess the characteristics of institutions offering baccalaureate degrees in public health. RESULTS: Only 54 of the 2,968 U.S. institutions of higher education provided online information meeting the definition of an active undergraduate public health degree program. CONCLUSION: While public health may be a "hot" field in terms of the interest that it generates, the actual number of verified undergraduate programs presently available is relatively modest. PMID- 26029687 TI - My leadership engine. PMID- 26029688 TI - Nanostructured porous silicon: the winding road from photonics to cell scaffolds a review. AB - For over 20 years, nanostructured porous silicon (nanoPS) has found a vast number of applications in the broad fields of photonics and optoelectronics, triggered by the discovery of its photoluminescent behavior in 1990. Besides, its biocompatibility, biodegradability, and bioresorbability make porous silicon (PSi) an appealing biomaterial. These properties are largely a consequence of its particular susceptibility to oxidation, leading to the formation of silicon oxide, which is readily dissolved by body fluids. This paper reviews the evolution of the applications of PSi and nanoPS from photonics through biophotonics, to their use as cell scaffolds, whether as an implantable substitute biomaterial, mainly for bony and ophthalmological tissues, or as an in vitro cell conditioning support, especially for pluripotent cells. For any of these applications, PSi/nanoPS can be used directly after synthesis from Si wafers, upon appropriate surface modification processes, or as a composite biomaterial. Unedited studies of fluorescently active PSi structures for cell culture are brought to evidence the margin for new developments. PMID- 26029689 TI - Review of micro/nanotechnologies for microbial biosensors. AB - A microbial biosensor is an analytical device with a biologically integrated transducer that generates a measurable signal indicating the analyte concentration. This method is ideally suited for the analysis of extracellular chemicals and the environment, and for metabolic sensory regulation. Although microbial biosensors show promise for application in various detection fields, some limitations still remain such as poor selectivity, low sensitivity, and impractical portability. To overcome such limitations, microbial biosensors have been integrated with many recently developed micro/nanotechnologies and applied to a wide range of detection purposes. This review article discusses micro/nanotechnologies that have been integrated with microbial biosensors and summarizes recent advances and the applications achieved through such novel integration. Future perspectives on the combination of micro/nanotechnologies and microbial biosensors will be discussed, and the necessary developments and improvements will be strategically deliberated. PMID- 26029690 TI - Matrix-Immobilized BMP-2 on Microcontact Printed Fibronectin as an in vitro Tool to Study BMP-Mediated Signaling and Cell Migration. AB - During development, growth factors (GFs) such as bone morphogenetic proteins (BMPs) exert important functions in several tissues by regulating signaling for cell differentiation and migration. In vivo, the extracellular matrix (ECM) not only provides support for adherent cells, but also acts as reservoir of GFs. Several constituents of the ECM provide adhesive cues, which serve as binding sites for cell trans-membrane receptors, such as integrins. In conveying adhesion mediated signaling to the intracellular compartment, integrins do not function alone but rather crosstalk and cooperate with other receptors, such as GF receptors. Here, we present a strategy for the immobilization of BMP-2 onto cellular fibronectin (cFN), a key protein of the ECM, to investigate GF-mediated signaling and migration. Following biotinylation, BMP-2 was linked to biotinylated cFN using NeutrAvidin as cross-linker. Characterization with quartz crystal microbalance with dissipation monitoring and enzyme-linked immunosorbent assay confirmed the efficient immobilization of BMP-2 on cFN over a period of 24 h. To validate the bioactivity of matrix-immobilized BMP-2 (iBMP-2), we investigated short- and long-term responses of C2C12 myoblasts, which are an established in vitro model for BMP-2 signaling, in comparison to soluble BMP-2 (sBMP-2) or in absence of GFs. Similarly to sBMP-2, iBMP-2 triggered Smad 1/5 phosphorylation and translocation of the complex to the nucleus, corresponding to the activation of BMP-mediated Smad-dependent pathway. Additionally, successful suppression of myotube formation was observed after 6 days in sBMP-2 and iBMP-2. We next implemented this approach in the fabrication of cFN micropatterned stripes by soft lithography. These stripes allowed cell-surface interaction only on the patterned cFN, since the surface in between was passivated, thus serving as platform for studies on directed cell migration. During a 10-h observation time, the migratory behavior, especially the cells' net displacement, was increased in presence of BMP-2. As such, this versatile tool retains the bioactivity of GFs and allows the presentation of ECM adhesive cues. PMID- 26029691 TI - The use of collision detection to infer multi-camera calibration quality. AB - Optical motion capture systems are widely used in sports and medicine. The performance of these systems depends on, amongst other factors, the quality of the camera calibration process. This study proposes a technique to assess the accuracy of the extrinsic camera parameters, as estimated during calibration. This method relies on the fact that solid objects in the real world cannot possess a gap in between, nor interpenetrate, when in contact with each other. In our study, we used motion capture to track successive collisions of two solid moving objects. The motion of solid objects was simulated based on trajectories measured by a multi-camera system and geometric information acquired from computed tomography. The simulations were then used to determine the amount of overlap or gap between them. This technique also takes into account errors resulting from markers moving close to one another, and better replicates actual movements during motion capture. We propose that this technique of successively colliding two solid moving objects may provide a means of measuring calibration accuracy. PMID- 26029693 TI - Generation of skeletal muscle cells from pluripotent stem cells: advances and challenges. AB - Human pluripotent stem cells (hPSCs) possess unlimited proliferative potential while maintaining the ability to differentiate into any cell type including skeletal muscle cells (SMCs). hPSCs are amenable to genetic editing and can be derived from patient somatic cells, and thus represent a promising option for cell therapies for the treatment of degenerative diseases such as muscular dystrophies. There are unresolved challenges however associated with the derivation and scale-up of hPSCs and generation of differentiated cells in large quantity and high purity. Reported myogenic differentiation protocols are long, require cell sorting and/or rely on ectopic expression of myogenic master regulators. More recent advances have been made with the application of small molecules to enhance the myogenic differentiation efficiency and the identification of more selective markers for the enrichment of myogenic progenitors with enhanced regenerative potential. Here we review the field of myogenic differentiation and highlight areas requiring further research. PMID- 26029692 TI - Biomaterial-mediated modification of the local inflammatory environment. AB - Inflammation plays a major role in the rejection of biomaterial implants. In addition, despite playing an important role in the early stages of wound healing, dysregulated inflammation has a negative impact on the wound healing processes. Thus, strategies to modulate excessive inflammation are needed. Through the use of biomaterials to control the release of anti-inflammatory therapeutics, increased control over inflammation is possible in a range of pathological conditions. However, the choice of biomaterial (natural or synthetic), and the form it takes (solid, hydrogel, or micro/nanoparticle) is dependent on both the cause and tissue location of inflammation. These considerations also influence the nature of the anti-inflammatory therapeutic that is incorporated into the biomaterial to be delivered. In this report, the range of biomaterials and anti inflammatory therapeutics that have been combined will be discussed, as well as the functional benefit observed. Furthermore, we point toward future strategies in the field that will bring more efficacious anti-inflammatory therapeutics closer to realization. PMID- 26029694 TI - Oscillating Positive Airway Pressure Versus CPAP for the Treatment of Obstructive Sleep Apnea. AB - Although continuous positive airway pressure (CPAP) is the most effective therapy for obstructive sleep apnea (OSA), it is not always well tolerated by the patients. Previous physiological studies showed that pressure oscillations applied to the pharynx could activate upper airway muscles, but it is not clear whether these pressure oscillations could be tolerated during sleep in OSA patients. The aim of this study was to assess the tolerance of oscillating positive airway pressure (O-PAP) (a CPAP device delivering high-frequency pressure oscillations to the upper airway) compared to CPAP. Fourteen OSA patients currently on CPAP [age 59.9 +/- 10.1 years old, BMI 34.8 +/- 7.2 kg/m(2), initial apnea-hypopnea index (AHI): 58.7 +/- 25.2 events/h] used O-PAP or CPAP on two consecutive nights under polysomnography, in a single-blind randomized crossover design to assess sleep quality. A subtherapeutic pressure (70% of the optimal titrated pressure) was applied in both conditions and the residual AHI with each technique was also compared. There was no difference in measured or perceived sleep quality between the two treatment modalities (sleep efficiency 90.0% versus 88.1%, p = 0.54). Despite the small sample, we also found a trend toward a decrease in residual respiratory events with O-PAP compared to CPAP (median AHI 14.3 versus 20.5/h, p = 0.194). The good tolerance of O-PAP and the positive trend toward a reduction in residual AHI should stimulate further research on the effects of O-PAP in OSA patients. PMID- 26029695 TI - With a Little Help from my Enteric Microbial Friends. AB - Although the disciplines of bacteriology and virology frequently come together in the setting of a diagnostic medical microbiology laboratory, the two scientific fields are usually miles apart. The microbiologists basically form two non overlapping groups of scientists, the bacteriologists and virologists, which go to separate meetings and do not easily intermingle. Some recent research findings about elegant virus-bacterium interactions may change this situation. Obviously, interactions between these two microbes can occur only when they colocalize, which most likely occurs in the gut/intestines where 10(14) commensal bacteria reside (the microbiota). We review findings on the following enteric microbial tandems: norovirus - Enterobacter cloacae, mouse mammary tumor virus (MMTV) - bacterial lipopolysaccharide (LPS), poliovirus and reovirus - intestinal bacteria. The close bacterium-virus interplay may also present options to develop unique therapeutic strategies for those infected, and to prevent further virus spread, and thus minimize the risk for the community. PMID- 26029696 TI - Is there an interest to use deuteron beams to produce non-conventional radionuclides? AB - With the recent interest on the theranostic approach, there has been a renewed interest for alternative radionuclides in nuclear medicine. They can be produced using common production routes, i.e., using protons accelerated by biomedical cyclotrons or neutrons produced in research reactors. However, in some cases, it can be more valuable to use deuterons as projectiles. In the case of Cu-64, smaller quantities of the expensive target material, Ni-64, are used with deuterons as compared with protons for the same produced activity. For the Sc 44m/Sc-44g generator, deuterons afford a higher Sc-44m production yield than with protons. Finally, in the case of Re-186g, deuterons lead to a production yield five times higher than protons. These three examples show that it is of interest to consider not only protons or neutrons but also deuterons to produce alternative radionuclides. PMID- 26029697 TI - Is pooled data analysis of ventral and incisional hernia repair acceptable? AB - PURPOSE: In meta-analyses and systematic reviews comparing laparoscopic with open repair of ventral hernias, data on umbilical, epigastric, and incisional hernias are pooled. Based on data from the Herniamed Hernia Registry, we aimed to investigate whether the differences in the therapy and treatment results justified such an approach. METHODS: Between 1st September 2009 and 31st August 2013, 31,664 patients with a ventral hernia were enrolled in the Herniamed Hernia Registry. The implicated hernias included 16,206 umbilical hernias, 3,757 epigastric hernias, and 11,701 incisional hernias. Data on the surgical techniques, postoperative complication rates, and 1-year follow-up results were subjected to statistical analysis to identify any significant differences between the various hernia types. RESULTS: The laparoscopic IPOM technique was used significantly more often for incisional hernia than for epigastric hernia, 31.3 vs. 24.0%, respectively, and was used for 12.9% of umbilical hernias (p < 0.0001). Likewise, the open technique with suturing of defect was used significantly more often for umbilical hernia than for epigastric hernia, 56.1 vs. 35.4%, respectively, and was used for 12.5% of incisional hernias (p < 0.0001). The postoperative complication rates of 3.2% for umbilical hernia and 3.5% for epigastric hernia were significantly lower than for incisional hernia, at 9.2% (p < 0.0001). That was also true for the reoperation rates due to postoperative complications, of 1.0 vs. 1.2 vs. 4.2% (p < 0.0001). The 1-year follow-up revealed significantly higher recurrence rates as well as rates of chronic pain needing treatment of 6.3 and 7.9%, respectively, for incisional hernia, compared with 4.1 and 4.3%, respectively, for epigastric hernia, and 2 and 1.9%, respectively, for umbilical hernia (p < 0.0001). CONCLUSION: Since significant differences were identified in the therapy and treatment results between umbilical hernia, epigastric hernia, and incisional hernia, scientific studies should be conducted comparing the various surgical techniques only for a single hernia type. PMID- 26029698 TI - Vascular surgery trainees still need to learn how to sew: importance of learning surgical techniques in the era of endovascular surgery. AB - Vascular surgery represents one of the most rapidly evolving specialties in the field of surgery. It was merely 100 years ago when Dr. Alexis Carrel described vascular anastomosis. Over the course of next several decades, vascular surgeons distinguished themselves from general surgeons by horning the techniques of vascular surgery operations. In the era of minimally invasive interventions, the number of endovascular interventions performed by vascular surgeons has increased exponentially. Vascular surgery trainees in the current times spend considerable time in mastering the techniques of endovascular operations. Unfortunately, the reduction in number of open surgical operations has lead to concerns in regards to adequacy of learning open surgical techniques. In future, majority of vascular interventions will be done with minimally invasive techniques. Combination of poor training in open operations and increasing complexity of open surgical operations may lead to poor surgical outcomes. It is the need of the hour for vascular surgery trainees to realize the importance of learning and mastering open surgical techniques. One of the most distinguishing features of contemporary vascular surgeons is their ability to perform both endovascular and open vascular surgery operations, and we should strive to maintain our excellence in both of these arenas. PMID- 26029699 TI - A Commentary on: "A New Removable Uterine Compression by a Brace Suture in the Management of Severe Postpartum Hemorrhage". PMID- 26029701 TI - Perspectives on what is needed to implement genomic medicine. PMID- 26029700 TI - Developmental neurotoxicity of 3,3',4,4'-tetrachloroazobenzene with thyroxine deficit: Sensitivity of glia and dentate granule neurons in the absence of behavioral changes. AB - Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3',4,4' tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3'- triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND)4-21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations. PMID- 26029702 TI - Medical genetics and genomic medicine in India: current status and opportunities ahead. PMID- 26029703 TI - Distribution of fragile X mental retardation 1 CGG repeat and flanking haplotypes in a large Chinese population. AB - Fragile X syndrome is mainly caused by a CGG repeat expansion within the 5' UTR of the fragile X mental retardation 1 (FMR1) gene. Previous analyses of the FMR1 CGG repeat patterns and flanking haplotypes in Caucasians and African Americans have identified several factors that may influence repeat instability. However, the CGG repeat patterns and distribution for FRAXAC2 have not yet been investigated in mainland Chinese. We surveyed the CGG repeat lengths in 1113 Han Chinese (534 males and 579 females), and the CGG repeat patterns of 534 males were determined by sequence analysis. We also explored the flanking haplotypes (DXS548-FRAXAC1-FRAXAC2) in 566 unaffected and 28 unrelated fragile X Chinese males. The most frequent alleles for DXS548 and FRAXAC1 were identical between our Chinese population and other Asian populations. We identified several low abundance alleles for DXS548 and FRAXAC1 not found in previous studies in mainland Chinese and Taiwanese cohorts. The most frequent allele was (CGG)29 followed by (CGG)30, and the most frequent patterns were 9 + 9 + 9, 10 + 9 + 9, and 9 + 9 + 6 + 9, similar to those in Singaporeans. We identified only one premutation female carrier with 89 CGG repeats in the 1113 Han Chinese. A few associations between the CGG repeat patterns and flanking haplotypes were determined in this study. In general, the Chinese population had a smaller number of alleles and lower expected heterozygosity for all three STR markers and FRAXA locus when compared with Caucasians and African Americans. We identified a novel haplotype 7-3-5 + that is significantly associated with the full mutation. PMID- 26029704 TI - Quantifying the cumulative effect of low-penetrance genetic variants on breast cancer risk. AB - Many common diseases have a complex genetic basis in which large numbers of genetic variations combine with environmental factors to determine risk. However, quantifying such polygenic effects has been challenging. In order to address these difficulties we developed a global measure of the information content of an individual's genome relative to a reference population, which may be used to assess differences in global genome structure between cases and appropriate controls. Informally this measure, which we call relative genome information (RGI), quantifies the relative "disorder" of an individual's genome. In order to test its ability to predict disease risk we used RGI to compare single-nucleotide polymorphism genotypes from two independent samples of women with early-onset breast cancer with three independent sets of controls. We found that RGI was significantly elevated in both sets of breast cancer cases in comparison with all three sets of controls, with disease risk rising sharply with RGI. Furthermore, these differences are not due to associations with common variants at a small number of disease-associated loci, but rather are due to the combined associations of thousands of markers distributed throughout the genome. Our results indicate that the information content of an individual's genome may be used to measure the risk of a complex disease, and suggest that early-onset breast cancer has a strongly polygenic component. PMID- 26029705 TI - Diversity of the causal genes in hearing impaired Algerian individuals identified by whole exome sequencing. AB - The genetic heterogeneity of congenital hearing disorders makes molecular diagnosis expensive and time-consuming using conventional techniques such as Sanger sequencing of DNA. In order to design an appropriate strategy of molecular diagnosis in the Algerian population, we explored the diversity of the involved mutations by studying 65 families affected by autosomal recessive forms of nonsyndromic hearing impairment (DFNB forms), which are the most prevalent early onset forms. We first carried out a systematic screening for mutations in GJB2 and the recurrent p.(Arg34*) mutation in TMC1, which were found in 31 (47.7%) families and 1 (1.5%) family, respectively. We then performed whole exome sequencing in nine of the remaining families, and identified the causative mutations in all the patients analyzed, either in the homozygous state (eight families) or in the compound heterozygous state (one family): (c.709C>T: p.(Arg237*)) and (c.2122C>T: p.(Arg708*)) in OTOF, (c.1334T>G: p.(Leu445Trp)) in SLC26A4, (c.764T>A: p.(Met255Lys)) in GIPC3, (c.518T>A: p.(Cys173Ser)) in LHFPL5, (c.5336T>C: p.(Leu1779Pro)) in MYO15A, (c.1807G>T: p.(Val603Phe)) in OTOA, (c.6080dup: p.(Asn2027Lys*9)) in PTPRQ, and (c.6017del: p.(Gly2006Alafs*13); c.7188_7189ins14: p.(Val2397Leufs*2)) in GPR98. Notably, 7 of these 10 mutations affecting 8 different genes had not been reported previously. These results highlight for the first time the genetic heterogeneity of the early onset forms of nonsyndromic deafness in Algerian families. PMID- 26029706 TI - Identification of novel mutations in Mexican patients with Aarskog-Scott syndrome. AB - Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia (FGD, OMIM # 305400), is an X-linked disorder of recessive inheritance, characterized by short stature and facial, skeletal, and urogenital abnormalities. AAS is caused by mutations in the FGD1 gene (Xp11.22), with over 56 different mutations identified to date. We present the clinical and molecular analysis of four unrelated families of Mexican origin with an AAS phenotype, in whom FGD1 sequencing was performed. This analysis identified two stop mutations not previously reported in the literature: p.Gln664* and p.Glu380*. Phenotypically, every male patient met the clinical criteria of the syndrome, whereas discrepancies were found between phenotypes in female patients. Our results identify two novel mutations in FGD1, broadening the spectrum of reported mutations; and provide further delineation of the phenotypic variability previously described in AAS. PMID- 26029707 TI - Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. AB - The Aristaless-related homeobox (ARX) gene is implicated in intellectual disability with the most frequent pathogenic mutations leading to expansions of the first two polyalanine tracts. Here, we describe analysis of the ARX gene outlining the approaches in the Australian and Portuguese setting, using an integrated clinical and molecular strategy. We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non-pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX-related disorders is crucial for an adequate clinical follow-up and accurate genetic counseling of at-risk family members. PMID- 26029708 TI - Contiguous mutation syndrome in the era of high-throughput sequencing. AB - We investigated two siblings, born to consanguineous parents, with neurological features reminiscent of adaptor protein complex 4 (AP4) deficiency, an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity, severe intellectual disability speech delay, microcephaly, and growth retardation. Yet, both children also presented with early onset obesity. Whole-exome sequencing identified two homozygous substitutions in two genes 170 kb apart on 7q22.1: a c.1137+1G>T splice mutation in AP4M1 previously described in a familial case of AP4-deficiency syndrome and the AZGP1 c.595A>T missense variant. Haplotyping analysis indicated a founder effect of the AP4M1 mutation, whereas the AZGP1 mutation arose more recently in our family. AZGP1 encodes an adipokine that stimulate lipolysis in adipocytes and regulates body weight in mice. We propose that the siblings' phenotype results from the combined effects of mutations in both AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. Contiguous gene syndromes are the consequence of loss of two or more adjacent genes sensible to gene dosage and the phenotype reflects a combination of endophenotypes. We propose to broaden this concept to phenotypes resulting from independent mutations in two genetically linked genes causing a contiguous mutation syndrome. PMID- 26029709 TI - Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3. AB - Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload. PMID- 26029710 TI - Copy number variation in the ATP-binding cassette transporter ABCC6 gene and ABCC6 pseudogenes in patients with pseudoxanthoma elasticum. AB - Single mutations in the ATP-binding cassette transporter (ABCC6) gene (OMIM 603234) are known to cause the rare autosomal recessive disease pseudoxanthoma elasticum (PXE). Recently, we have found that copy number variations (CNVs) in pseudogenes of the ABCC6 gene are quite common. The aim of this study was to investigate the frequency and possible contribution of CNV in ABCC6 and its pseudogenes in PXE. Genomic DNA from 212 PXE individuals were examined for copy number by pyrosequencing and quantitative polymerase chain reaction (PCR) and compared with healthy individuals. The frequency of PXE individuals with any CNV was higher than in healthy individuals. The majority of variation comprised known and possibly new deletions in the ABCC6 gene and duplications of the ABCC6P1 and ABCC6P2 genes. ABCC6 deletions and ABCC6P2 duplications were not observed in 142 healthy individuals. In conclusion, by pyrosequencing and quantitative PCR, we were able to detect known and possibly new deletions in the ABCC6 gene that may have caused the PXE phenotype. Pyrosequencing may be used in PXE patients who have obtained incomplete genotype from conventional techniques. The frequency of ABCC6P2 pseudogene duplication was more common in PXE patients than healthy individuals and may affect the PXE phenotype. PMID- 26029712 TI - Efficacy of irreversible electroporation in human pancreatic adenocarcinoma: advanced murine model. AB - Irreversible electroporation (IRE) is a promising cell membrane ablative modality for pancreatic cancer. There have been recent concerns regarding local recurrence and the potential use of IRE as a debulking (partial ablation) modality. We hypothesize that incomplete ablation leads to early recurrence and a more aggressive biology. We created the first ever heterotopic murine model by inoculating BALB/c nude mice in the hindlimb with a subcutaneous injection of Panc-1 cells, an immortalized human pancreatic adenocarcinoma cell line. Tumors were allowed to grow from 0.75 to 1.5 cm and then treated with the goal of complete ablation or partial ablation using standard IRE settings. Animals were recovered and survived for 2 days (n = 6), 7 (n = 6), 14 (n = 6), 21 (n = 6), 30 (n = 8), and 60 (n = 8) days. All 40 animals/tumors underwent successful IRE under general anesthesia with muscle paralysis. The mean tumor volume of the animals undergoing ablation was 1,447.6 mm(3) +/- 884). Histologically, in the 14 , 21-, 30-, and 60-day survival groups the entire tumor was nonviable, with a persistent tumor nodule completely replaced fibrosis. In the group treated with partial ablation, incomplete electroporation/recurrences (N = 10 animals) were seen, of which 66% had confluent tumors and this was a significant predictor of recurrence (P < 0.001). Recurrent tumors were also significantly larger (mean 4,578 mm(3) +/- SD 877 versus completed electroporated tumors 925.8 +/- 277, P < 0.001). Recurrent tumors had a steeper growth curve (slope = 0.73) compared with primary tumors (0.60, P = 0.02). Recurrent tumors also had a significantly higher percentage of EpCAM expression, suggestive of stem cell activation. Tumors that recur after incomplete electroporation demonstrate a biologically aggressive tumor that could be more resistant to standard of care chemotherapy. Clinical correlation of this data is limited, but should be considered when IRE of pancreatic cancer is being considered. PMID- 26029713 TI - Corrigendum to "Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease". AB - [This corrects the article DOI: 10.1038/mtm.2014.18.]. PMID- 26029714 TI - Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. AB - Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome. PMID- 26029715 TI - High-level production of replication-defective human immunodeficiency type 1 virus vector particles using helper-dependent adenovirus vectors. AB - Gene transfer vectors based upon human immunodeficiency virus type 1 (HIV) are widely used in bench research applications and increasingly in clinical investigations, both to introduce novel genes but also to reduce expression of unwanted genes of the host and pathogen. At present, the vast majority of HIV based vector supernatants are produced in 293T cells by cotransfection of up to five DNA plasmids, which is subject to variability and difficult to scale. Here we report the development of a HIV-based vector production system that utilizes helper-dependent adenovirus (HDAd). All necessary HIV vector components were inserted into one or more HDAds, which were then amplified to very high titers of ~10(13) vp/ml. These were then used to transduce 293-based cells to produce HIV based vector supernatants, and resultant VSV G-pseudotyped lentiviral vector (LV) titers and total IU were 10- to 30-fold higher, compared to plasmid transfection. Optimization of HIV-based vector production depended upon maximizing expression of all HIV vector components from HDAd. Supernatants contained trace amounts of HDAd but were free of replication-competent lentivirus. This production method should be applicable to other retroviral vector systems. Scalable production of HIV-based vectors using this two-step procedure should facilitate their clinical advancement. PMID- 26029716 TI - Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin. AB - A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment. PMID- 26029717 TI - Clinical testing of a dendritic cell targeted therapeutic vaccine in patients with chronic hepatitis C virus infection. AB - The lack of antiviral cellular immune responses in patients with chronic hepatitis C virus (HCV) infection suggests that T-cell vaccines may provide therapeutic benefit. Due to the central role that dendritic cells (DC) play in the activation of T-cell responses, our aim was to carry out a therapeutic vaccination clinical trial in HCV patients using DC. Five patients with chronic HCV infection were vaccinated with three doses of 5 * 10(6) or 10(7) autologous DC transduced with a recombinant adenovirus encoding NS3 using the adapter protein CFh40L, which facilitates DC transduction and maturation. No significant adverse effects were recorded after vaccination. Treatment caused no changes in serum liver enzymes nor in viral load. Vaccination induced weak but consistent expansion of T-cell responses against NS3 and adenoviral antigens. Patients' DC, as opposed to murine DC or DC from healthy subjects, secreted high IL-10 levels after transduction, inducing the activation of IL-10-producing T cells. IL-10 blockade during vaccine preparation restored its ability to stimulate anti-NS3 Th1 responses. Thus, vaccination with adenovirus-transduced DC is safe and induces weak antiviral immune responses. IL-10 associated with vaccine preparation may be partly responsible for these effects, suggesting that future vaccines should consider concomitant inhibition of this cytokine. PMID- 26029718 TI - Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice. AB - Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid alpha-glucosidase (GAA)). Cardiac dysfunction and respiratory muscle weakness are primary features of this disorder. To attenuate the progressive and rapid accumulation of glycogen resulting in cardiorespiratory dysfunction, adult Gaa ( /-) mice were administered a single systemic injection of rAAV2/9-DES-hGAA (AAV9 DES) or bimonthly injections of recombinant human GAA (enzyme replacement therapy (ERT)). Assessment of cardiac function and morphology was measured 1 and 3 months after initiation of treatment while whole-body plethysmography and diaphragmatic contractile function was evaluated at 3 months post-treatment in all groups. Gaa (-/-) animals receiving either AAV9-DES or ERT demonstrated a significant improvement in cardiac function and diaphragmatic contractile function as compared to control animals. AAV9-DES treatment resulted in a significant reduction in cardiac dimension (end diastolic left ventricular mass/gram wet weight; EDMc) at 3 months postinjection. Neither AAV nor ERT therapy altered minute ventilation during quiet breathing (eupnea). However, breathing frequency and expiratory time were significantly improved in AAV9-DES animals. These results indicate systemic delivery of either strategy improves cardiac function but AAV9-DES alone improves respiratory parameters at 3 months post-treatment in a murine model of Pompe disease. PMID- 26029719 TI - Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction. AB - The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4 binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD) indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy. PMID- 26029720 TI - A comparison of AAV strategies distinguishes overlapping vectors for efficient systemic delivery of the 6.2 kb Dysferlin coding sequence. AB - Recombinant adeno-associated virus (rAAV) is currently the best vector for gene delivery into the skeletal muscle. However, the 5-kb packaging size of this virus is a major obstacle for large gene transfer. This past decade, many different strategies were developed to circumvent this issue (concatemerization-splicing, overlapping vectors, hybrid dual or fragmented AAV). Loss of function mutations in the DYSF gene whose coding sequence is 6.2kb lead to progressive muscular dystrophies (LGMD2B: OMIM_253601; MM: OMIM_254130; DMAT: OMIM_606768). In this study, we compared large gene transfer techniques to deliver the DYSF gene into the skeletal muscle. After rAAV8s intramuscular injection into dysferlin deficient mice, we showed that the overlap strategy is the most effective approach to reconstitute a full-length messenger. After systemic administration, the level of dysferlin obtained on different muscles corresponded to 0.5- to 2 fold compared to the normal level. We further demonstrated that the overlapping vector set was efficient to correct the histopathology, resistance to eccentric contractions and whole body force in the dysferlin deficient mice. Altogether, these data indicate that using overlapping vectors could be a promising approach for a potential clinical treatment of dysferlinopathies. PMID- 26029721 TI - Short-lived recombinant adeno-associated virus transgene expression in dystrophic muscle is associated with oxidative damage to transgene mRNA. AB - Preclinical gene therapy strategies using recombinant adeno-associated virus (AAV) vectors in animal models of Duchenne muscular dystrophy have shown dramatic phenotype improvements, but long-lasting efficacy remains questionable. It is believed that in dystrophic muscles, transgene persistence is hampered, notably by the progressive loss of therapeutic vector genomes resulting from muscle fibers degeneration. Intracellular metabolic perturbations resulting from dystrophin deficiency could also be additional factors impacting on rAAV genomes and transgene mRNA molecular fate. In this study, we showed that rAAV genome loss is not the only cause of reduced transgene mRNA level and we assessed the contribution of transcriptional and post-transcriptional factors. We ruled out the implication of transgene silencing by epigenetic mechanisms and demonstrated that rAAV inhibition occurred mostly at the post-transcriptional level. Since Duchenne muscular dystrophy (DMD) physiopathology involves an elevated oxidative stress, we hypothesized that in dystrophic muscles, transgene mRNA could be damaged by oxidative stress. In the mouse and dog dystrophic models, we found that rAAV-derived mRNA oxidation was increased. Interestingly, when a high expression level of a therapeutic transgene is achieved, oxidation is less pronounced. These findings provide new insights into rAAV transductions in dystrophic muscles, which ultimately may help in the design of more effective clinical trials. PMID- 26029722 TI - Reversal of diabetes following transplantation of an insulin-secreting human liver cell line: Melligen cells. AB - As an alternative to the transplantation of islets, a human liver cell line has been genetically engineered to reverse type 1 diabetes (TID). The initial liver cell line (Huh7ins) commenced secretion of insulin in response to a glucose concentration of 2.5 mmol/l. After transfection of the Huh7ins cells with human islet glucokinase, the resultant Melligen cells secreted insulin in response to glucose within the physiological range; commencing at 4.25 mmol/l. Melligen cells exhibited increased glucokinase enzymatic activity in response to physiological glucose concentrations, as compared with Huh7ins cells. When transplanted into diabetic immunoincompetent mice, Melligen cells restored normoglycemia. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that both cell lines expressed a range of beta-cell transcription factors and pancreatic hormones. Exposure of Melligen and Huh7ins cells to proinflammatory cytokines (TNF-alpha, IL-1beta, and IFN-gamma) affected neither their viability nor their ability to secrete insulin to glucose. Gene expression (microarray and qRT-PCR) analyses indicated the survival of Melligen cells in the presence of known beta cell cytotoxins was associated with the expression of NF-kappaB and antiapoptotic genes (such as BIRC3). This study describes the successful generation of an artificial beta-cell line, which, if encapsulated to avoid allograft rejection, may offer a clinically applicable cure for T1D. PMID- 26029723 TI - The human ankyrin 1 promoter insulator sustains gene expression in a beta-globin lentiviral vector in hematopoietic stem cells. AB - Lentiviral vectors designed for the treatment of the hemoglobinopathies require the inclusion of regulatory and strong enhancer elements to achieve sufficient expression of the beta-globin transgene. Despite the inclusion of these elements, the efficacy of these vectors may be limited by transgene silencing due to the genomic environment surrounding the integration site. Barrier insulators can be used to give more consistent expression and resist silencing even with lower vector copies. Here, the barrier activity of an insulator element from the human ankyrin-1 gene was analyzed in a lentiviral vector carrying an antisickling human beta-globin gene. Inclusion of a single copy of the Ankyrin insulator did not affect viral titer, and improved the consistency of expression from the vector in murine erythroleukemia cells. The presence of the Ankyrin insulator element did not change transgene expression in human hematopoietic cells in short-term erythroid culture or in vivo in primary murine transplants. However, analysis in secondary recipients showed that the lentiviral vector with the Ankyrin element preserved transgene expression, whereas expression from the vector lacking the Ankyrin insulator decreased in secondary recipients. These studies demonstrate that the Ankyrin insulator may improve long-term beta-globin expression in hematopoietic stem cells for gene therapy of hemoglobinopathies. PMID- 26029724 TI - Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina. AB - Accumulation of the nerve growth factor precursor (proNGF) and its receptor p75(NTR) have been associated with several neurodegenerative diseases in both brain and retina. However, whether proNGF contributes to microvascular degeneration remain unexplored. This study seeks to investigate the mechanism by which proNGF/p75(NTR) induce endothelial cell (EC) death and development of acellular capillaries, a surrogate marker of retinal ischemia. Stable overexpression of the cleavage-resistant proNGF and molecular silencing of p75(NTR) were utilized in human retinal EC and rat retinas in vivo. Stable overexpression of proNGF decreased NGF levels and induced retinal vascular cell death evident by 1.9-fold increase in acellular capillaries and activation of JNK and cleaved-PARP that were mitigated by p75(NTR)shRNA. In vitro, overexpression of proNGF did not alter TNF-alpha level, reduced NGF, however induced EC apoptosis evident by activation of JNK and p38 MAPK, cleaved-PARP. Silencing p75(NTR) using siRNA restored expression of NGF and TrkA activation and prevented EC apoptosis. Treatment of EC with human-mutant proNGF induced apoptosis that coincided with marked protein interaction and nuclear translocation of p75(NTR) and the neurotrophin receptor interacting factor. These effects were abolished by a selective p75(NTR) antagonist. Therefore, targeting p75(NTR) represents a potential therapeutic strategy for diseases associated with aberrant expression of proNGF. PMID- 26029725 TI - Lysophosphatidic acid induces YAP-promoted proliferation of human corneal endothelial cells via PI3K and ROCK pathways. AB - The first two authors contributed equally to this work.Silence of p120-catenin has shown promise in inducing proliferation in human corneal endothelial cells (HCECs), but there is concern regarding off-target effects in potential clinical applications. We aimed to develop ex vivo expansion of HCECs using natural compounds, and we hypothesized that lysophosphatidic acid (LPA) can unlock the mitotic block in contact-inhibited HCECs via enhancing nuclear translocation of yes-associated protein (YAP). Firstly, we verified that exogenous YAP could induce cell proliferation in contact-inhibited HCEC monolayers and postconfluent B4G12 cells. In B4G12 cells, enhanced cyclin D1 expression, reduced p27(KIP1)/p21(CIP1) levels, and the G1/S transition were detected upon transfection with YAP. Secondly, we confirmed that LPA induced nuclear expression of YAP and promoted cell proliferation. Moreover, PI3K and ROCK, but not ERK or p38, were required for LPA-induced YAP nuclear translocation. Finally, cells treated with LPA or transfected with YAP remained hexagonal in shape, in addition to unchanged expression of ZO-1, Na/K-ATPase, and smooth muscle actin (SMA), suggestive of a preserved phenotype, without endothelial-mesenchymal transition. Collectively, our findings indicate an innovative strategy for ex vivo cultivation of HCECs for transplantation and cell therapy. PMID- 26029726 TI - Coherence analysis discriminates between retroviral integration patterns in CD34(+) cells transduced under differing clinical trial conditions. AB - Unequivocal demonstration of the therapeutic utility of gamma-retroviral vectors for gene therapy applications targeting the hematopoietic system was accompanied by instances of insertional mutagenesis. These events stimulated the ongoing development of putatively safer integrating vector systems and analysis methods to characterize and compare integration site (IS) biosafety profiles. Continuing advances in next-generation sequencing technologies are driving the generation of ever-more complex IS datasets. Available bioinformatic tools to compare such datasets focus on the association of integration sites (ISs) with selected genomic and epigenetic features, and the choice of these features determines the ability to discriminate between datasets. We describe the scalable application of point-process coherence analysis (CA) to compare patterns produced by vector ISs across genomic intervals, uncoupled from association with genomic features. To explore the utility of CA in the context of an unresolved question, we asked whether the differing transduction conditions used in the initial Paris and London SCID-X1 gene therapy trials result in divergent genome-wide integration profiles. We tested a transduction carried out under each condition, and showed that CA could indeed resolve differences in IS distributions. Existence of these differences was confirmed by the application of established methods to compare integration datasets. PMID- 26029727 TI - Efficient gene delivery to photoreceptors using AAV2/rh10 and rescue of the Rho( /-) mouse. AB - As gene therapies for various forms of retinal degeneration progress toward human clinical trial, it will be essential to have a repertoire of safe and efficient vectors for gene delivery to the target cells. Recombinant adeno-associated virus (AAV) serotype 2/2 has been shown to be well tolerated in the human retina and has provided efficacy in human patients for some inherited retinal degenerations. In this study, the AAV2/8 and AAV2/rh10 serotypes have been compared as a means of gene delivery to mammalian photoreceptor cells using a photoreceptor specific promoter for transgene expression. Both AAV2/8 and AAV2/rh10 provided rescue of the retinal degeneration present in the rhodopsin knockout mouse, with similar levels of benefit as evaluated by molecular, histological, and functional readouts. Transgene expression levels were significantly higher (fivefold) 1 week postsubretinal injection when employing AAV2/8 for rhodopsin gene delivery compared to AAV2/rh10, and were indistinguishable by 6 weeks postadministration of vector. This study reports the use of the AAV2/rh10 serotype to provide rescue in a degenerating retina and provides a comparative evaluation of AAV2/rh10 with respect to AAV2/8, a serotype regarded as providing efficient delivery to photoreceptors. PMID- 26029728 TI - Development of a replication-competent lentivirus assay for dendritic cell targeting lentiviral vectors. AB - It is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (RCL) in lentiviral vector products prior to use in clinical trials. Immune Design previously described an HIV-1-based integration deficient lentiviral vector for use in cancer immunotherapy (VP02). VP02 is enveloped with E1001, a modified Sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) expressed on dendritic cells in vivo. Vector enveloped with E1001 does not transduce T-cell lines used in standard HIV-1-based RCL assays, making current RCL testing formats unsuitable for testing VP02. We therefore developed a novel assay to test for RCL in clinical lots of VP02. This assay, which utilizes a murine leukemia positive control virus and a 293F cell line expressing the E1001 receptor DC-SIGN, meets a series of evaluation criteria defined in collaboration with US regulatory authorities and demonstrates the ability of the assay format to amplify and detect a hypothetical RCL derived from VP02 vector components. This assay was qualified and used to test six independent GMP production lots of VP02, in which no RCL was detected. We propose that the evaluation criteria used to rationally design this novel method should be considered when developing an RCL assay for any lentiviral vector. PMID- 26029729 TI - Ototoxicity-induced loss of hearing and inner hair cells is attenuated by HSP70 gene transfer. AB - The most common reason for sensorineural deafness is death of hair cells (HCs). Heat shock proteins (HSPs) are molecular chaperones that participate in folding, targeting, and degrading proteins. HSP expression is increased in response to various environmental stresses to protect cells from damage. Here, we tested whether viral-mediated overexpression of HSP70 can protect HCs and hearing from severe ototoxicity (kanamycin and furosemide) in guinea pigs. Adenovirus-HSP70 mCherry (Ad.HSP70-mCherry) was injected to experimental animals and adenovirus mCherry to controls, 4 days before the ototoxic insult. Hearing thresholds were measured by auditory brainstem response before the insult and again before sacrificing the animals, 14 days after the insult. Epi-fluorescence immunocytochemistry showed that injection of Ad.HSP70-mCherry resulted in mCherry fluorescence in nonsensory cells of the organ of Corti. The ototoxic insult eliminated both outer HCs and inner HCs throughout most of the cochlea of control (adenovirus-mCherry-injected) ears and contralateral (uninjected) ears. Ad.HSP70 mCherry-injected ears exhibited a significant preservation of inner HCs compared to control and contralateral ears, but outer HCs were not protected. Auditory brainstem response thresholds were significantly better in Ad.HSP70-mCherry injected ears than in control and contralateral ears. Our data show that HSP70 augmentation may represent a potential therapy attenuating ototoxic inner HC loss. PMID- 26029730 TI - Optimization of energy window and evaluation of scatter compensation methods in myocardial perfusion SPECT using the ideal observer with and without model mismatch and an anthropomorphic model observer. AB - We used the ideal observer (IO) and IO with model mismatch (IO-MM) applied in the projection domain and an anthropomorphic channelized Hotelling observer (CHO) applied to reconstructed images to optimize the acquisition energy window width and to evaluate various scatter compensation methods in the context of a myocardial perfusion single-photon emission computed tomography (SPECT) defect detection task. The IO has perfect knowledge of the image formation process and thus reflects the performance with perfect compensation for image-degrading factors. Thus, using the IO to optimize imaging systems could lead to suboptimal parameters compared with those optimized for humans interpreting SPECT images reconstructed with imperfect or no compensation. The IO-MM allows incorporating imperfect system models into the IO optimization process. We found that with near perfect scatter compensation, the optimal energy window for the IO and CHO was similar; in its absence, the IO-MM gave a better prediction of the optimal energy window for the CHO using different scatter compensation methods. These data suggest that the IO-MM may be useful for projectiondomain optimization when MM is significant and that the IO is useful when followed by reconstruction with good models of the image formation process. PMID- 26029731 TI - The Postprandial Effects of a Moderately High-Fat Meal on Lipid Profiles and Vascular Inflammation in Alzheimer's Disease Patients: A Pilot Study. AB - OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease of aging with unknown causative factors. Accumulating evidence suggests that inflammation and neurovascular dysfunction play important roles in AD. The postprandial period following a moderately high-fat meal is associated with vascular inflammation in young, healthy individuals; however, this relationship has not been investigated in Alzheimer's patients despite their exaggerated inflammatory state. METHODS: Patients with AD and age-matched control subjects were recruited through the UC Davis Alzheimer's Disease Center. All subjects consumed a moderately high-fat breakfast meal. Fasting and postprandial blood samples were collected for lipid, lipoprotein, and oxylipin analyses, as well as assays for cytokine levels and monocyte activation. RESULTS: The plasma lipid analyses revealed similar levels of triglycerides and esterified oxylipins between groups, but there was an interaction between postprandial non-esterified fatty acid (NEFA) levels and body mass index in the AD group compared to the control subjects. The AD group also had increased behenic acid and decreased linoleic and oleic acids in the postprandial period; however, these were not significantly different. Inflammatory assays revealed elevated fasting levels of interleukin (IL)-10 and IL-12 p70, but no change in monocyte activation in the AD group. CONCLUSION: The postprandial period following a moderately high-fat meal is not associated with an exaggerated inflammatory state in Alzheimer's patients, and basal esterified oxylipin profiles do not indicate elevated oxidative stress. However, the baseline inflammatory state during fasting in AD patients includes elevated levels of plasma IL-10 and IL-12 p70, which may indicate a balance between immune responses mediated by these interleukins. PMID- 26029732 TI - Proteinase 3 and Serpin B1: a novel pathway in the regulation of caspase-3 activation, neutrophil spontaneous apoptosis, and inflammation. AB - Neutrophils are the first responders of the inflammatory response. They are characterized by their potent cytotoxic content but also by their limited lifetime. This short half-life is thought to be a self-protecting mechanism for the host, as highlighted by the numerous pathologies associated with imbalanced neutrophil survival. Neutrophil spontaneous death is the prototype of programmed cell death, harboring all the phenotypic hallmarks of apoptosis and dependent on the activation of the effector caspase-3. However, the pathways regulating neutrophil spontaneous death remain ill-defined. In a recent publication, we determined that in aging neutrophils, the cleavage and activation of caspase-3 was mediated by the serine protease Proteinase 3 (PR3), and was independent of the canonical extrinsic and intrinsic apoptosis pathways. In mature neutrophils, PR3 was stored in granules and progressively released to the cytosol during neutrophil aging. The release of PR3 was dependent on lysosomal membrane permeabilization (LMP). Once in the cytosol, PR3 cleaved procaspase-3 at a site upstream of the caspase-9 cleavage site, leading to caspase-3 activation. Inhibition, knockdown or knockout of PR3 delayed neutrophil apoptosis in vitro and in vivo. The adoptive transfer of both WT and PR3-deficient neutrophils to WT mice revealed that the delayed death of neutrophils lacking PR3 in vivo was due to an altered intrinsic apoptosis/survival pathway and not to difference in the inflammatory microenvironment. The cytosolic inhibitor of serine proteases serpin b1 counterbalanced the activity of PR3 in the cytosol of neutrophils, and the deletion of serpinb1 in neutrophils accelerated their spontaneous death. In summary, our results reveal that PR3 and serpinB1 are part of a newly characterized apoptosis pathway, regulating caspase-3 activation and neutrophil spontaneous death and the survival of neutrophils during inflammation. PMID- 26029733 TI - Tumor cell p38 MAPK: A trigger of cancer bone osteolysis. AB - Osteolytic bone destruction is a hallmark of bone-metastatic cancers. Current therapy is unable to completely cure or prevent this disease in patients. The p38 mitogen-activated protein kinase (MAPK) affects a diverse range of intracellular responses with well-known roles in development, cell-cycle and differentiation, inflammation, apoptosis, senescence, and tumorigenesis. This article is an overview of the contribution of tumor cell-expressed p38 MAPK to the regulation of osteoclastogenesis, osteoblastogenesis, and osteolyticbone lesions. PMID- 26029734 TI - Translating the human genome to manage pediatric postoperative pain. PMID- 26029735 TI - Stain-less staining for computed histopathology. AB - Dyes such as hematoxylin and eosin (H&E) and immunohistochemical stains have been increasingly used to visualize tissue composition in research and clinical practice. We present an alternative approach to obtain the same information using stain-free chemical imaging. Relying on Fourier transform infrared (FT-IR) spectroscopic imaging and computation, stainless computed histopathology can enable a rapid, digital, quantitative and non-perturbing visualization of morphology and multiple molecular epitopes simultaneously in a variety of research and clinical pathology applications. PMID- 26029736 TI - Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality. AB - Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstrated in vitro with endotoxin priming and tolerance in cultured monocytes. However, previous in vivo studies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre conditionings with super-low or low dose endotoxin lipopolysaccharide (LPS) cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP). This is in opposite to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET) in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a novel mechanism potentially responsible for the dynamic programming of innate immunity in vivo as it relates to sepsis risks. PMID- 26029737 TI - Quantitative Biomechanics of Healthy and Diseased Human Red Blood Cells using Dielectrophoresis in a Microfluidic System. AB - We present an experimental method to quantitatively characterize the mechanical properties of a large number of biological cells by introducing controlled deformation through dielectrophoresis in a microfluidic device. We demonstrate the capability of this technique by determining the force versus deformation characteristics of healthy human red blood cells (RBCs) and RBCs infected in vitro with Plasmodium falciparum malaria parasites. These experiments clearly distinguish uninfected and healthy RBCs from infected ones, and the mechanical signatures extracted from these tests are in agreement with data from other independent methods. The method developed here thus provides a potentially helpful tool to characterize quickly and effectively the isolated biomechanical response of cells in a large population, for probing the pathological states of cells, disease diagnostics, and drug efficacy assays. PMID- 26029738 TI - PHYSIOLOGIC AND QUANTITATIVE COMPUTED TOMOGRAPHY DIFFERENCES BETWEEN CENTRILOBULAR AND PANLOBULAR EMPHYSEMA IN COPD. AB - BACKGROUND: The purpose was to define the differences between centrilobular (CLE) and panlobular emphysema (PLE) phenotypes in cigarette smokers with COPD by a combined qualitative-quantitative computed tomography (CT) analysis. METHODS: Chest CT scans of 116 cigarette smokers were visually scored by 22 chest radiologists and 29 pulmonologists in a single setting for the predominant emphysema phenotype (e.g. CLE or PLE) and automatically quantified for emphysema{% low attenuation area (LAA) <= -950 HU - %LAAinsp-950, gas trapping extent and bronchial metrics{wall area % for segmental (%WAsegm) and subsegmental (%WAsubsegm) bronchi}. These quantitative CT indexes were compared and related to FEV1, FEV1/FVC, and smoking history as stratified for emphysema phenotype. RESULTS: Although more frequent than CLE in GOLD stages 3 and 4 (p = 0.01), PLE was also scored in 38.2% of combined GOLD stages 1 and 2. PLE was positively associated with %LAAinsp-950 (OR = 1.18, 95% CI: 1.12 to 1.27, beta coefficient = 0.17, p = <0.0001) and negatively associated with pack-years of smoking (OR = 0.97, 95% CI: 0.95 to 0.99, beta coefficient = -0.02, p = 0.03). Both %WAsegm and %WAsubsegm were more strongly associated with FEV1% (R2 = 0.6 for both measures, p< 0.001) in CLE as compared to PLE (R2= 0.15, p = 0.02; R2 = 0.26, p< 0.001). CONCLUSIONS: PLE likely represents a more advanced phase of emphysema, which may also occur in earlier COPD stages and show different interplay with airway disease as compared to CLE. PMID- 26029739 TI - Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. AB - The flavivirus nonstructural protein 3 (NS3) is a protease and helicase, and on the basis of its similarity to its homologue encoded by the hepatitis C virus (HCV), the flavivirus NS3 might be a promising drug target. Few flavivirus helicase inhibitors have been reported, in part, because few specific inhibitors have been identified when nucleic acid unwinding assays have been used to screen for helicase inhibitors. To explore the possibility that compounds inhibiting NS3 catalyzed ATP hydrolysis might function as antivirals even if they do not inhibit RNA unwinding in vitro, we designed a robust dengue virus (DENV) NS3 ATPase assay suitable for high-throughput screening. Members of two classes of inhibitory compounds were further tested in DENV helicase-catalyzed RNA unwinding assays, assays monitoring HCV helicase action, subgenomic DENV replicon assays, and cell viability assays and for their ability to inhibit West Nile virus (Kunjin subtype) replication in cells. The first class contained analogues of NIH molecular probe ML283, a benzothiazole oligomer derived from the dye primuline, and they also inhibited HCV helicase and DENV NS3-catalyzed RNA unwinding. The most intriguing ML283 analogue inhibited DENV NS3 with an IC50 value of 500 nM and was active against the DENV replicon. The second class contained specific DENV ATPase inhibitors that did not inhibit DENV RNA unwinding or reactions catalyzed by HCV helicase. Members of this class contained a 4-hydroxy-3-(5 methylfuran-2-carbonyl)-2H-pyrrol-5-one scaffold, and about 20 MUM of the most potent pyrrolone inhibited both DENV replicons and West Nile virus replication in cells by 50%. PMID- 26029740 TI - MiR-506: A Multitasker in Suppression of the Epithelial-to-Mesenchymal Transition. AB - MiRNAs emerge as important regulators of epithelial-to-mesenchymal transition (EMT). The Best known EMT regulatory miRNAs are targeting the transcriptional repressors of E-cadherin (E-cad). We identified miR-506 as a key EMT inhibitor through directly targeting the E-cad transcriptional repressor, SNAI2. Our recent studies showed that miR-506 simultaneously suppresses vimentin and N-cad. Thus, miR-506 possesses a multitasking property in the suppression of EMT and metastasis and thus may represent a promising tool in cancer therapeutics. PMID- 26029741 TI - Regulation of Aspartyl-(Asparaginyl)-beta-Hydroxylase Protein Expression and Function by Phosphorylation in Hepatocellular Carcinoma Cells. AB - BACKGROUND: Asparaginyl-beta-hydroxylase (AAH) promotes cell adhesion, migration, and invasion via Notch activation. AAH's expression is up-regulated by insulin/IGF signaling through PI3K-Akt, but its protein is independently regulated by GSK-3beta. The multiple predicted GSK-3beta phosphorylation sites suggest post-translational mechanisms may regulate AAH protein expression. METHODS: Human Huh7 hepatoma cells were transfected with recombinant plasmids that expressed full-length N-terminal Myc-tagged (N-Myc-AAH) or C-terminal HA tagged (C-HA-AAH) cDNA. Effects of IGF-1 on AAH protein were examined using cellular ELISAs, immunofluorescence, and Western blotting. Effects of kinase inhibitors relevant to AAH's predicted phosphorylation sites were studied. RESULTS: IGF-1 stimulation increased AAH protein expression and shifted AAH's localization from the perinuclear zone to the cell periphery, including podocytes. Subsequently, Notch-1 intracellular domain was translocated to the nucleus, which is critical for Notch- modulated gene expression. Besides GSK 3beta, inhibition of PKC, PKA, and CK2, which could potentially phosphorylate AAH, increased IGF-1 stimulated AAH protein. Finally, insulin and LiCl independently and additively increased long-term AAH protein expression. CONCLUSION: Insulin/IGF-1 stimulation of AAH and Notch are enhanced by inhibiting kinases that could phosphorylate AAH protein. Targeted manipulation of AAH's phosphorylation state may have therapeutic value for reducing AAH-Notch activation and attendant infiltrative growth of hepatocellular carcinomas. PMID- 26029742 TI - Interleukin-19 can enhance angiogenesis by Macrophage Polarization. AB - Hypoxia in ischemic limbs typically initiates angiogenic and inflammatory factors to promote angiogenesis in attempt to restore perfusion, and revascularization involves multiple cell types and systems. Macrophage display phenotype plasticity, and can polarize in response to local and systemic cytokine stimuli. M2 macrophage are known to play an important role in angiogenesis and wound healing. While accepted that many pro-inflammatory cytokines induce angiogenesis, the effects of anti-inflammatory interleukins on initiation of angiogenesis are less clear. Interleukin-19 [IL-19] is a presumed anti-inflammatory cytokine, with unknown effects on macrophage polarization. In our recent study, we used several experimental approaches and determined that IL-19 regulated neovascularization in the murine hind-limb ischemia model. In addition to endothelial cells, we found that IL-19 could target and polarize macrophage to the M2 phenotype. IL-19 could induce expression of angiogenic, and reduce expression of anti-angiogenic cytokines in these cells. This is the first study to demonstrate that IL-19 could polarize macrophage, and potentially identifies IL-19 as a therapy to induce angiogenesis in ischemic tissue. PMID- 26029743 TI - Bacterial Short Chain Fatty Acids Push All The Buttons Needed To Reactivate Latent Viruses. AB - The genomes of herpesviruses and HIV become silent during latency through multiple chromatin silencing mechanisms including: histone deacetylation, repressive histone methylation, and DNA methylation. Reactivation of the latent virus requires removal of the chromatin silencing marks and their replacement by activating modifications such as histone acetylation and activating histone methylation. In a complementary mechanism, RNA Polymerase II (RNAP II) elongation is regulated by the positive transcription elongation factor b (P-TEFb)-dependent phosphorylation of Ser2 residues on its C-terminal domain. In resting T-cells latently infected by HIV, expression of P-TEFb is restricted. We found that a group of short chain fatty acids (SCFAs) produced by oral bacteria not only promote histone acetylation but also change the histone methylation dynamics by decreasing repressive histone methylation while increasing activating histone methylation. SCFAs also block DNA methylation and activate P-TEFb to enable elongation of stalled RNA polymerase II. Thus these molecules do not simply act as histone deacetylase (HDAC) inhibitors as previously claimed. Instead, they impact multiple complementary epigenetic regulatory mechanisms to promote highly efficient reactivation of latent viruses. PMID- 26029744 TI - A NEW CLUSTERING METHOD AND ITS APPLICATION TO PROTEOMIC PROFILING FOR COLON CANCER. AB - In this paper, we introduce a new clustering method: quasi-clique merger, and its associated data pretreatment programs. This program constructs non-binary hierarchical trees with much smaller number of clusters in the outputs. And overlapping clusters are also allowed in the outputs. We applied this new method to cluster 60 human cancer cell lines (the NCI-60) using the previously identified proteomic determinants for chemosensitivity of 5-Fluorouracil (5-FU). All colon cancer cell lines were aggregated into a single cluster, indicating that the eight proteomic markers are potential diagnostic markers of colon cancer. The results based on the new clustering method have surpassed those based on previous methods on the same datasets. PMID- 26029746 TI - An Investigation Into Incorporating Visual Information in Audio Processing. AB - The number of persons with hearing and vision loss is on the rise as lifespans increase. Vision plays an important role in communication, especially in the presence of background noise or for persons with hearing loss. However, persons with vision loss cannot make use of this extra modality to overcome their hearing deficits. We propose automatically utilizing some visual information in hearing aids through the addition of a small wearable camera. Our initial results show potentially significant benefits to incorporating low level robust visual cues when the background noise is high. This technique can potentially benefit all persons with hearing loss, with substantial improvements possible for the speech perception performance of persons with dual sensory loss. PMID- 26029745 TI - Redesigning Organ Allocation Boundaries for Liver Transplantation in the United States. AB - Geographic disparities in access to and outcomes in transplantation have been a persistent problem widely discussed by transplant researchers and the transplant community. One of the alleged causes of disparities in the United States is administratively determined organ allocation boundaries that limit organ sharing across regions. This paper applies mathematical programming to construct alternative liver allocation boundaries that achieve more geographic equity in access to transplants than the current system. The performance of the optimal boundaries were evaluated and compared to that of current allocation system using discrete event simulation. PMID- 26029747 TI - Carrier concentration dependent optical and electrical properties of Ga doped ZnO hexagonal nanocrystals. AB - Colloidal trivalent gallium (Ga) doped zinc oxide (ZnO) hexagonal nanocrystals have been prepared to introduce more carrier concentration into the wide band gap of ZnO. The dopant (Ga) modifies the morphology and size of ZnO nanocrystals. Low content of Ga enhances the optical band gap of ZnO due to excess carrier concentration in the conduction band of ZnO. The interaction among free carriers arising from higher concentration of Ga gives rise to narrowing of the band gap. Surface plasmon resonance absorption appears in the infrared region due to excessive carrier concentration. A broad emission band consists of blue, yellow and green colors associated with different native defects of ZnO. Intrinsic defects and extrinsic dopant Ga control the defect related emission spectrum in the visible region. Replacement of Zn by Ga induces a room temperature metallic state in a degenerate semiconductor. Cationic disorder leads to metal semiconductor transition at low temperature strongly dependent on the concentration of Ga. Pure semiconducting behavior up to about 80 K is observed for the highest amount of Ga. Temperature dependent metal-semiconductor transition has been interpreted by localization of charge carriers due to disorder arising from random Ga substitution. PMID- 26029748 TI - Characterization of carotenoids in soil bacteria and investigation of their photodegradation by UVA radiation via resonance Raman spectroscopy. AB - A soil habitat consists of an enormous number of pigmented bacteria with the pigments mainly composed of diverse carotenoids. Most of the pigmented bacteria in the top layer of the soil are photoprotected from exposure to huge amounts of UVA radiation on a daily basis by these carotenoids. The photostability of these carotenoids depends heavily on the presence of specific features like a carbonyl group or an ionone ring system on its overall structure. Resonance Raman spectroscopy is one of the most sensitive and powerful techniques to detect and characterize these carotenoids and also monitor processes associated with them in their native system at a single cell resolution. However, most of the resonance Raman profiles of carotenoids have very minute differences, thereby making it extremely difficult to confirm if these differences are attributed to the presence of different carotenoids or if it is a consequence of their interaction with other cellular components. In this study, we devised a method to overcome this problem by monitoring also the photodegradation of the carotenoids in question by UVA radiation wherein a differential photodegradation response will confirm the presence of different carotenoids irrespective of the proximities in their resonance Raman profiles. Using this method, the detection and characterization of carotenoids in pure cultures of five species of pigmented coccoid soil bacteria is achieved. We also shed light on the influence of the structure of the carotenoid on its photodegradation which can be exploited for use in the characterization of carotenoids via resonance Raman spectroscopy. PMID- 26029749 TI - Gestation and birth of the European Journal of Neuroscience. PMID- 26029750 TI - A nanoliter self-priming compartmentalization chip for point-of-care digital PCR analysis. AB - A nanoliter self-priming compartmentalization (SPC) microfluidic chip suited for the digital polymerase chain reaction (dPCR) analysis in point-of-care testing (POCT) has been developed. This dPCR chip is fabricated of polydimethylsiloxane (PDMS). After the dPCR chip is evacuated, there will be a negative pressure environment in the chip because of the gas solubility of PDMS. The negative pressure environment can provide a self-priming power so that the sample solutions can be sucked into each reaction chamber sequentially. The whole sampling process requires no external power and is valve-free. Channels that contain water are designed around each sample panel to prevent the solvent (water) from evaporating during dPCR process. A glass coverslip is also used as a waterproof layer, which is more convenient and more efficient than other waterproof methods seen in literature. This dPCR chip allows three samples to be amplified at the same time. Each sample is distributed into 1040 reaction chambers, and each chamber is only 2.08 nL. Human beta-actin DNA solutions of known concentrations are used as the templates for the dPCR analyses to verify the sensitivity and accuracy of the method. Template DNA solutions diluted to concentrations of 300, 100 and 10 copies/MUL are tested and shown that this simple, portable and self-priming dPCR chip can be used at any clinic as a real POCT technique. PMID- 26029751 TI - Six healthy habits to reduce female mid-life cardiovascular disease. PMID- 26029752 TI - Endocrine disrupting chemicals associated with earlier menopause. PMID- 26029753 TI - Menopause through the crystal ball. PMID- 26029754 TI - HRT associated with modest risk increase in a relatively rare but serious cancer. PMID- 26029755 TI - Vasomotor symptoms typically last seven years: is a short-term approach appropriate? PMID- 26029756 TI - Analogy between glass rheology and crystal plasticity: yielding at high strain rate. AB - An abrupt increase of the yield stress at sufficiently high strain rate, seen in glassy as well as crystalline structures, signifies a transition from classical thermal fluctuation to stress activated processes. For crystals this behavior has been recently explained using transition-state-theory with a stress-dependent activation barrier for dislocation glide. An equivalent approach, developed independently for amorphous solids, suggests the physical basis of the upturn behavior of the yield stress is more general. Insights into the interplay between thermal and stress activation processes can contribute to the current efforts toward identifying materials science frontiers at the mesoscale. PMID- 26029757 TI - Rheology of polymer carbon nanotubes composites. AB - In this review paper the rheology of polymer nanocomposites with dispersed carbon nanotubes is presented. The major factors controlling the rheology of these nanocomposites are the overall concentration of the nanotubes and their state of dispersion. Percolation of anisotropic nanotubes and the transition from isotropic to nematic structures bound the range of concentrations over which the rheological properties of these nanocomposites is dominated by the meso-scale structure and dispersion and are of significance to the processing of nanotube based polymer nanocomposites. The percolation threshold and the concentration for the isotropic to nematic transition are strong functions of the inverse of the effective aspect ratio of the dispersed nanotubes and therefore restrict the range of concentrations over which such nanocomposites can be deployed. In this review we briefly describe the rheology in the dilute regime, where especially for the case of polymer nanocomposites the rheology is dominated by that of the polymer. Subsequently, the percolation phenomenon and rheological significances are presented. Finally, both linear and non-linear rheologies of semi-dilute dispersions with random orientation of nanotubes are discussed in detail. Where possible, the rheological responses are contextualized through the underlying structure of the nanocomposites and interplay of different forces. PMID- 26029758 TI - Prediction of polydisperse hard-sphere mixture behavior using tridisperse systems. AB - How many state-variables are needed to predict the equation of state and the jamming density of polydisperse mixtures in glassy, non-equilibrium compressed states? We propose to define equivalent and maximally equivalent systems as those that match three and five moments of a given polydisperse size distribution, respectively. Fluids can be represented well by an equivalent system with only s = 2 components (bidisperse). As little as s = 3 components (tridisperse) are enough to achieve a maximally equivalent system. Those match macroscopic properties in glassy states, but also the volume fraction of rattlers, suggesting strong microstructural equivalency too. For many soft and granular systems, tridisperse, maximally equivalent systems allow for a closed analytical treatment and well-controlled industrial applications, while our proposal waits for experimental validation. PMID- 26029759 TI - Room temperature water Leidenfrost droplets. AB - We experimentally investigate the Leidenfrost effect at pressures ranging from 1 to 0.05 atmospheric pressure. As a direct consequence of the Clausius-Clapeyron phase diagram of water, the droplet temperature can be at ambient temperature in a non-sophisticated lab environment. Furthermore, the lifetime of the Leidenfrost droplet is significantly increased in this low pressure environment. The temperature and pressure dependence of the evaporation rate is successfully tested against a recently proposed model. These results may pave the way for reaching efficient Leidenfrost micro-fluidic and milli-fluidic applications. PMID- 26029760 TI - Dynamical formation of lipid bilayer vesicles from lipid-coated droplets across a planar monolayer at an oil/water interface. AB - Recently, the transfer method has been shown to be useful for preparing cell sized phospholipid bilayer vesicles, within which desired substances at desired concentrations can be encapsulated, with a desired asymmetric lipid composition. Here, we investigated the transfer process of water-in-oil (W/O) droplets coated by phospholipid monolayers across an oil/water interface by both experimental observation and theoretical modeling. Real-time experimental observation of the transfer revealed that the transfer process is characterized by three kinetic regimes: a precontact process (approaching regime), an early fast process (entering regime), and a late slow process (relaxation regime). In addition, bigger droplets require much more time to transfer than smaller droplets. We propose a theoretical model to interpret this kinetic process. Our theoretical model reproduces the essential aspects of the transfer kinetics, including its size-dependence. PMID- 26029761 TI - Secondary structure and rigidity in model proteins. AB - There is tremendous interest in understanding the role that secondary structure plays in the rigidity and dynamics of proteins. In this work we analyze nanomechanical properties of proteins chosen to represent different secondary structures: alpha-helices (myoglobin and bovine serum albumin), beta-barrels (green fluorescent protein), and alpha + beta + loop structures (lysozyme). Our experimental results show that in these model proteins, the beta motif is a stiffer structural unit than the alpha-helix in both dry and hydrated states. This difference appears not only in the rigidity of the protein, but also in the amplitude of fast picosecond fluctuations. Moreover, we show that for these examples the secondary structure correlates with the temperature- and hydration induced changes in the protein dynamics and rigidity. Analysis also suggests a connection between the length of the secondary structure (alpha-helices) and the low-frequency vibrational mode, the so-called boson peak. The presented results suggest an intimate connection of dynamics and rigidity with the protein secondary structure. PMID- 26029762 TI - High-order jamming crossovers and density anomalies. AB - We demonstrate that particles interacting via core-softened potentials exhibit a series of successive density anomalies upon isothermal compression, leading to oscillations in the diffusivity and thermal expansion coefficient, with the latter reaching negative values. These finite-temperature density anomalies are then shown to correspond to zero-temperature high-order jamming crossovers. These occur when particles are forced to come into contact with neighbours in successive coordination shells upon increasing the density. The crossovers induce anomalous behavior of the bulk modulus, which oscillates with density. We rationalize the dependence of these crossovers on the softness of the interaction potential, and relate the jamming crossovers and the anomalous diffusivity via the properties of the vibrational spectrum. PMID- 26029763 TI - Tuning the aggregation behaviour of single-chain bolaamphiphiles in aqueous suspension by changes in headgroup asymmetry. AB - The self-assembly process in aqueous suspension of two new asymmetrical single chain bolaamphiphiles, namely 32-{[hydroxy(2 hydroxyethoxy)phosphinyl]oxy}dotriacontane-1-yl-{2-[N-(3-dimethylaminopropyl)-N,N dimethylammonio]ethylphosphate} (DMAPPC-C32-POH) and 32-hydroxydotriacontane-1-yl {2-[N-(3-dimethylaminopropyl)-N,N-dimethylammonio]ethylphosphate} (DMAPPC-C32 OH), was studied as a function of temperature using transmission electron microscopy, differential scanning calorimetry, FT-IR-spectroscopy, small angle neutron and small angle X-ray scattering to determine whether the asymmetry of the molecule induces the formation of types of aggregates other than the well characterized helical nanofibres of structurally similar symmetrical single-chain bolaamphiphiles with identical headgroups. DMAPPC-C32-POH in acetate buffer at pH 5 can still form nanofibres, i.e. the asymmetry does not induce the formation of other aggregate structures. However, the fibres display a tendency to break more easily and to form irregular, circular structures. This is also reflected by the rheological properties of the suspension that reveal decreased strain resistance at pH 5. In aqueous suspensions at pH 10, where the headgroups of the molecule are negatively charged, only short fibre segments are formed and no gel formation occurs. At higher temperature these fibres convert into micellar aggregates as observed before for symmetrical bolalipids with large headgroups. In contrast, in aqueous suspensions of DMAPPC-C32-OH, a bolalipid where the size difference of the headgroups is much larger, lamellar structures are formed at pH 10 where the headgroup of the molecule is zwitterionic. At low temperature, the molecules are packed in an orthorhombic lattice with interdigitated chains and a repeat distance between lamellae of 6.2 nm is observed. An increase in temperature leads to a lamellar phase with hexagonal packing of the chains. The chains become liquid-crystalline only at very high temperature above 90 degrees C. At low pH, when the headgroup of the molecule becomes positively charged, some short elongated micellar aggregates are seen besides sheet-like structures. A temperature increase leads to a similar sequence of transformations of the chain packing until formation of a liquid-crystalline lamellar phase at a temperature close to 90 degrees C. The results show that the aggregation behaviour of single chain bolaamphiphiles can not only be tuned by changes in chain length or size of both headgroups but also by the difference in headgroup size and charge in asymmetric bolaamphiphiles. PMID- 26029764 TI - Self-assembly of three bacterially-derived bioactive lipopeptides. AB - The self-assembly in aqueous solution of three lipopeptides obtained from Bacillus subtilis has been investigated. The lipopeptides surfactin, plipastatin and mycosubtilin contain distinct cyclic peptide headgroups as well as differences in alkyl chain length, branching and chain length distribution. Cryogenic transmission electron microscopy and X-ray scattering reveal that surfactin and plipastatin aggregate into 2 nm-radius spherical micelles, whereas in complete contrast mycosubtilin self-assembles into extended nanotapes based on bilayer ordering of the lipopeptides. Circular dichroism and FTIR spectroscopy indicate the presence of turn structures in the cyclic peptide headgroup. The unexpected distinct mode of self-assembly of mycosubtilin compared to the other two lipopeptides is ascribed to differences in the surfactant packing parameter. This in turn is due to specific features of the conformation of the peptide headgroup and alkyl chain branching. PMID- 26029765 TI - Non-linear surface dilatational rheology as a tool for understanding microstructures of air/water interfaces stabilized by oligofructose fatty acid esters. AB - In this paper, the rheological response of air/water interfaces, stabilized by various oligofructose fatty acid esters, to oscillatory dilatational deformations was studied and compared to the response of interfaces stabilized by sucrose esters. We have followed a traditional approach to surface rheology, where the development of the modulus as a function of time is studied as well as the frequency dependence of the modulus. We also adopted a different approach where we investigate in detail the amplitude dependence of the modulus. Finally, we studied the temperature dependence. We show that for an accurate characterization of the dilatational rheology of fluid-fluid interfaces with a complex microstructure, a protocol should be used that not only involves variations of surface pressure, frequency, and temperature, but also establishes amplitude dependence. We show that Lissajous plots of surface pressure versus deformation can be useful tools to help interpret surface dilatational behavior in terms of interfacial microstructure. The rheological response of interfaces stabilized by oligofructose esters differed significantly from the response of those stabilized by sucrose esters. Sucrose esters behaved like typical low molecular weight surfactants, and gave interfaces with relatively low moduli, a frequency scaling of the dilatational modulus with an exponent close to 0.5, and displayed no asymmetries in Lissajous plots. In contrast, the oligofructose esters gave, depending on the fatty acid tail, relatively high moduli, almost independent of frequency. Significant asymmetries were observed in the Lissajous plots, with strain hardening during compression and strain softening during extension. Our results suggest that the unusual rheological properties of interfaces stabilized by oligofructose esters may be the result of the formation of a two-dimensional soft glass phase by the oligofructose part of the ester. PMID- 26029766 TI - Effect of H-NS on the elongation and compaction of single DNA molecules in a nanospace. AB - The effect of the bacterial heat-stable nucleoid-structuring protein (H-NS) on the conformation of single DNA molecules confined in a nanochannel was investigated with fluorescence microscopy. With increasing concentration of H-NS, the DNA molecules either elongate or contract. The conformational response is related to filamentation of H-NS on DNA through oligomerization and H-NS mediated bridging of distal DNA segments and is controlled by the concentration and ionic composition of the buffer. Confinement in a nanochannel also facilitates compaction of DNA into a condensed form for over-threshold concentrations of H NS. Divalent ions such as magnesium facilitate but are not required for bridging nor condensation. The time scale of the collapse after exposure to H-NS was determined to be on the order of minutes, which is much shorter than the measured time required for filamentation of around one hour. We found that the effect of H NS is not only related to its binding properties but also the confinement is of paramount importance. The interplay between confinement, H-NS-mediated attraction, and filamentation controls the conformation and compaction of DNA. This finding might have implications for gene silencing and chromosome organisation, because the cross-sectional dimensions of the channels are comparable to those of the bacterial nucleoid. PMID- 26029767 TI - Plastic and viscous dissipations in foams: cross-over from low to high shear rates. AB - Soft glassy materials made of deformable cells, such as liquid foams, simultaneously display elastic, plastic and viscous behaviours. Bubble deformation is elastic until the material plastically yields and bubbles swap neighbours, then bubbles relax dissipatively towards a new energy minimum. This relaxation occurs in a finite time, and shearing a foam at a fast strain rate compared to that time leads to a viscous flow. To describe such an elastic, plastic and viscous behaviour we introduce a simplified scalar model of foam deformation and flow with a periodic pinning potential. The continuum mechanics behaviour of the foam emerges as an ensemble average over disordered units without requiring that they are coupled. Our model captures surprisingly well various features of the viscous dissipation during plastic deformation. At low shear rates, the time averaged stress is smaller than the static yield stress. A critical shear rate exists: any flow at fixed stress has a shear rate above this critical value. Moreover, the model only involves measurable parameters, which enables us to compare it with existing experiments and simulations. PMID- 26029768 TI - Bioinspired assembly of functional block-copolymer nanotemplates. AB - A new concept on bioinspired assembly of functional diblock copolymers, capable of forming different microstructures through nucleobase-induced supramolecular interactions, has been explored. In this paper, a new series of uracil functionalized poly(epsilon-caprolactone)-b-(4-vinylbenzyl uracil)s (PCL-b-PVBU) have been prepared which exhibit a high self-complementary ability in solution and solid states owing to the formation of uracil-uracil pairs by induced hierarchical self-assembly. The ordered morphologies of PCL-b-PVBU diblock copolymers changed from a lamellar, hexagonally packed cylinder to a sphere with respect to the content of the hydrogen bond segment. Moreover, we further show that the PCL segment could be easily extracted by enzymatic degradation, leading to a cylinder porous structure of long-range order, which gives a facile method for the fabrication of uracil-functionalized nanotemplates. In addition, bio complementary PCL-b-PVBU/9-hexadecyladenine (AC16) hierarchical supramolecular complexes formed through strong cooperative hydrogen bonding between the uracil group of PVBU and the adenine group of A-C16. When the mixing ratios of PCL-b PVBU/AC16 differ from the stoichiometric ratio, these complexes self-assemble into well-ordered lamellar and hexagonal structures; the changing morphology at different AC16 loadings reveals that the molecular structures of the PCL-b PVBU/AC16 complexes are readily tailored. PMID- 26029769 TI - International Journal of Prisoner Health. Editorial. PMID- 26029770 TI - Activated pathways for the directed insertion of patterned nanoparticles into polymer membranes. AB - We combine the string method with self-consistent field theory to compute the most probable transition pathway, i.e. the minimum free energy path, for the insertion of Janus and protein-like nanoparticles into a polymer membrane bilayer. The method makes no assumptions in the reaction coordinate and overcomes the long timescales challenge associated with simulating rare events. Our study suggests that one approach to building functional polymer-nanoparticle composite membranes with oriented nanoparticles is through electrostatic interactions. In particular, hydrophobic Janus nanoparticles with an asymmetric charge distribution can be made to directionally insert into charged membranes. This process is kinetically driven, and involves overcoming a thermally surmountable activation barrier, which requires favorable interactions between the nanoparticle and the hydrophilic block of the membrane. In contrast, the insertion of protein-like nanoparticles with alternating hydrophilic-hydrophobic hydrophilic domains into polymer membranes does not occur as a thermally activated event. PMID- 26029771 TI - Enabling efficient energy barrier computations of wetting transitions on geometrically patterned surfaces. AB - Proper roughness design is important in realizing surfaces with fully tunable wetting properties. Engineering surface roughness boils down to an energy barrier optimization problem, in which the geometric features of roughness serve as the optimization parameters. Computations of energy barriers, separating admissible equilibrium wetting states on patterned surfaces, have been demonstrated utilizing fine-scale simulators (e.g., lattice-Boltzmann for mesoscale and molecular dynamics for microscale simulations), however with substantial computational requirements. Here, by solving an augmented Young-Laplace equation with a disjoining pressure term, we demonstrate accurate and efficient computations of equilibrium shapes of entire millimeter sized droplets on patterned surfaces. In particular, by adopting a natural parameterization of the Young-Laplace equation along the liquid/air and liquid/solid interfaces, the tedious implementation of the Young's contact angle boundary condition at multiple three phase contact lines is bypassed. We, thus, enable the computation of wetting transition energy barriers, separating the well-known Cassie-Baxter and Wenzel states, as well as intermediate states, but with negligible computational cost. We demonstrate the method's efficiency by computing the equilibrium of droplets on stripe-patterned surfaces, and compare the results with mesoscopic lattice Boltzmann simulations. Our computationally efficient continuum-level analysis can be readily applied to patterned surfaces with increased and unstructured geometric complexity, and straightforwardly coupled with shape optimizers towards the design of surfaces with desirable wetting behavior. PMID- 26029772 TI - Crystallization, structural diversity and anisotropy effects in 2D arrays of icosahedral viruses. AB - We investigate two-dimensional (2D) assembly of the icosahedral turnip yellow mosaic virus (TYMV) under cationic lipid monolayers at the aqueous solution-vapor interface. The 2D crystallization of TYMV has been achieved by enhancing electrostatically induced interfacial adsorption, an approach recently demonstrated for another virus. In situ X-ray scattering reveals two close-packed 2D crystalline phases of TYMV that are distinct from the previously reported hexagonal and centered square (?2 * ?2) arrays of TYMV. One of the newly observed phases arises from either a dimeric double-square (2 * 1) or tetrameric square (2 * 2) unit cell. The other is a rhombic crystal with a lattice angle of 80 degrees . The two observed crystal phases are substantially less dense (by over 10%) than a 2D lattice of TYMV could be according to its known size and shape, indicating that local anisotropic interparticle interactions play a key role in stabilizing these crystals. TYMV's anisotropy attributes and numerical analysis of 2D arrays of virus-shaped particles are used to derive a model for the rhombic crystal in which the particle orientation is consistent with the electrostatic lipid-TYMV attraction and the interparticle contacts exhibit steric complementarity. The interplay between particle anisotropy and packing is contrasted between the rhombic crystal model and the square (?2 * ?2) crystal. This study highlights how the high symmetry and subtle asphericity of icosahedral particles enrich the variety and complexity of ordered 2D structures that can be generated through self-assembly. PMID- 26029773 TI - Iterative layer-by-layer assembly of polymer-tethered multi-bilayers using maleimide-thiol coupling chemistry. AB - The current study reports on the layer-by-layer assembly of a polymer-tethered lipid multi-bilayer stack using the iterative addition and roll out of giant unilamellar vesicles (GUVs) containing constituents with thiol and maleimide functional groups, respectively. Confocal microscopy and photobleaching experiments confirm stack integrity and stability over time, as well as the lateral fluidity of individual bilayers within the stacks. Complementary wide field single molecule fluorescence microscopy and atomic force microscopy experiments show that increasing bilayer-substrate distances are associated with changes in lipid lateral mobility and bilayer morphology. Importantly, the described iterative approach can be employed to assemble multi-bilayer stacks with more than two bilayers, thus further reducing the influence of the underlying solid substrate on membrane behavior. Furthermore, the presence of lipopolymers within the multi-bilayer stacks results in fascinating membrane dynamics and organization properties, with interesting parallels to those found in plasma membranes. In that sense, the described multi-bilayer architecture represents an attractive model membrane platform for a variety of different biophysical studies. PMID- 26029774 TI - Inertia-dependent dynamics of three-dimensional vesicles and red blood cells in shear flow. AB - A three-dimensional (3D) simulation study of the effect of inertia on the dynamics of vesicles and red blood cells (RBCs) has not been reported. Here, we developed a 3D model based on the front tracking method to investigate how inertia affects the dynamics of spherical/non-spherical vesicles and biconcave shaped RBCs with the Reynolds number ranging from 0.1 to 10. The results showed that inertia induced non-spherical vesicles transitioned from tumbling to swinging, which was not observed in previous 2D models. The critical viscosity ratio of inner/outer fluids for the tumbling-swinging transition remarkably increased with an increasing Reynolds number. The deformation of vesicles was greatly enhanced by inertia, and the frequency of tumbling and tank-treading was significantly decreased by inertia. We also found that RBCs can transit from tumbling to steady tank-treading through the swinging regime when the Reynolds number increased from 0.1 to 10. These results indicate that inertia needs to be considered at moderate Reynolds number (Re ~ 1) in the study of blood flow in the human body and the flow of deformable particle suspension in inertial microfluidic devices. The developed 3D model provided new insights into the dynamics of RBCs under shear flow, thus holding great potential to better understand blood flow behaviors under normal/disease conditions. PMID- 26029775 TI - Self-assembly of colloidal polymers via depletion-mediated lock and key binding. AB - We study the depletion-induced self-assembly of indented colloids. Using state-of the-art Monte Carlo simulation techniques that treat the depletant particles explicitly, we demonstrate that colloids assemble by a lock-and-key mechanism, leading to colloidal polymerization. The morphology of the chains that are formed depends sensitively on the size of the colloidal indentation, with smaller values additionally permitting chain branching. In contrast to the case of spheres with attractive patches, Wertheim's thermodynamic perturbation theory fails to provide a fully quantitative description of the polymerization transition. We trace this failure to a neglect of packing effects and we introduce a modified theory that accounts better for the shape of the colloids, yielding improved agreement with simulation. PMID- 26029776 TI - Wormlike micelles formed using Gemini surfactants with quaternary hydroxyethyl methylammonium headgroups. AB - The aggregation behavior of Gemini surfactants with hydroxyl groups in their headgroups, butane-1,4-bis(hydroxyethyl methylalkylammonium) bromides hereafter abbreviated as m-4-m MEA (m = 12, 14, 16), has been investigated in aqueous solution. Each formed a viscous fluid in water at low concentration in the absence of a salt. In solutions of 14-4-14 MEA, the formation of highly viscoelastic wormlike micelles could be detected using steady and dynamic rheological measurements. The existence of these long column micelles has also been confirmed using cryo-transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). Compared with conventional bis(dimethylalkylammonium) bromide Gemini molecules with the same spacer (14-4 14), 14-4-14 MEA demonstrated a better ability to fabricate wormlike micelles because of the change in the headgroup structure. As for 16-4-16 MEA, which has longer alkyl chains, its aqueous solutions behave more like elastic gels at a concentration of 80 mmol L(-1). The unique viscoelastic behavior of m-4-m MEA in water can be attributed to the synergistic interactions of hydrophobic attraction and hydrogen bonding. The obtained results are believed to be an important addition to the effect that the headgroups of Gemini surfactants have on their aggregation behavior in dilute solutions. PMID- 26029777 TI - Bubble nucleation in polymer-CO2 mixtures. AB - We combine density-functional theory with the string method to calculate the minimum free energy path of bubble nucleation in two polymer-CO2 mixture systems, poly(methyl methacrylate) (PMMA)-CO2 and polystyrene (PS)-CO2. Nucleation is initiated by saturating the polymer liquid with high pressure CO2 and subsequently reducing the pressure to ambient condition. Below a critical temperature (Tc), we find that there is a discontinuous drop in the nucleation barrier as a function of increased initial CO2 pressure (P0), as a result of an underlying metastable transition from a CO2-rich-vapor phase to a CO2-rich-liquid phase. The nucleation barrier is generally higher for PS-CO2 than for PMMA-CO2 under the same temperature and pressure conditions, and both higher temperature and higher initial pressure are required to lower the nucleation barrier for PS CO2 to experimentally relevant ranges. Classical nucleation theory completely fails to capture the structural features of the bubble nucleus and severely underestimates the nucleation barrier. PMID- 26029778 TI - The effect of concentration, temperature and stirring on hen egg white lysozyme amyloid formation. AB - Lysozyme is associated with hereditary systemic amyloidosis in humans. Hen egg white lysozyme (HEWL) has been extensively studied as an amyloid forming protein. In this study, we investigated HEWL amyloid formation over a range of temperatures at two stirring speeds and at low concentrations to avoid gel formation. The amyloid fibril formation was found to follow first order kinetics with the rate determining step being the unfolding of the lysozyme. Both the rate of formation and final amount of amyloid formed show maxima with temperature at approximately at 65 degrees C. CD measurements show that the lysozyme is unfolded by 55 degrees C. The decrease in amyloid formation at temperatures above 65 degrees C is attributed to competing amorphous aggregation. The majority of the non-fibrillar aggregates are small and uniform in size with a few larger amorphous aggregates observed in the AFM images. PMID- 26029779 TI - Charge-induced local dewetting on polymer electrets studied by atomic force microscopy. AB - Polymer electrets are one of the most important series of electrets, which are widely used both in academic research and industrial applications. The effect of trapped charges on dielectric properties of the polymer electret is critical for more intelligent utilization of these materials. Herein we report the charge induced polymer relaxation reflected by the local dewetting of the polymer electrets with charge patterns. Because the difference in charge-induced relaxation results in selective dewetting of thin polymer films, polymers in the charged areas are preferentially dewetted from the substrate compared with the neutral areas under heating or solvent annealing, leading to the appearance of hole arrays. Therefore, the effect of trapped charges on relaxation was also studied via monitoring the relaxation behaviours of homo-polymer and block copolymer films as well as measuring the mechanical properties of homo-polymers with charge patterns. These results demonstrate that the charge trapped in polymer electrets could accelerate relaxation and drive the dewetting process of thin polymer films. PMID- 26029780 TI - To the theory of rheological properties of magnetopolymer suspensions. AB - This paper deals with the theoretical study of the magnetorhelogical properties of dilute suspensions of polymer coils with ferromagnetic nanoparticles adsorbed on the macromolecules. The analysis shows that, under an applied magnetic field, these coils elongate in the field direction and swell. Both these factors lead to a significant increase in the effective viscosity of the system. Estimates show that in the magnetopolymer compositions, strong magnetoviscous effects are expected even though in standard ferrofluids these effects are negligible. PMID- 26029781 TI - Leveling effects of ammonium salts on thermal stabilities of polyethylene glycols. AB - In this work, the thermal stabilities of a series of polyethylene glycols (PEG 4000, 6000 and 10000) were investigated after compositing with different kinds of inorganic salts, such as ammonium molybdate tetrahydrate (AMT), NH4VO3, (NH4)2SO4, NH4NO3, Na2SO4, Na2MoO4. It was first observed that all the ammonium salts exerted leveling effects for the thermal stabilities of the PEGs. In other words, the presence of the ammonium salts caused the occurrence of the maximum decomposition rates of the PEGs with the same repeat sequence but different chain lengths at almost the same temperatures. Leveling effects were defined by three parameters: leveling spans, leveling degrees and dispersion degrees of leveling. Further experiments revealed that leveling effects also occur in similar types of polymers: polypropylene glycols (PPG 2000, 3000 and 4000). A series of independent experiments including Fourier transformation infrared spectroscopy, Raman spectroscopy, differential scanning calorimetry, time-of-flight mass spectrometry, conductivity and field-emission scanning electron microscopy were performed to explore the origin of leveling effects. We consider that the interaction between inorganic ions and polymer molecules and the Hofmeister effect of ions in solution are two important factors affecting the stability of salt-polymer composites, because they can contribute to decrease the interaction between the polymer chains, leading to changes in the conformation and pyrolysis mode of polymers. We believe that the finding of leveling effects would be significant for both basic and applied research of soft matter. PMID- 26029782 TI - Fluorofenidone attenuates oxidative stress and renal fibrosis in obstructive nephropathy via blocking NOX2 (gp91phox) expression and inhibiting ERK/MAPK signaling pathway. AB - BACKGROUND/AIMS: We evaluated the therapeutic effects of fluorofenidone (AKF-PD), a novel pyridone agent, targeting oxidative stress and fibrosis in obstructive nephropathy. METHODS: AKF-PD was used to treat renal interstitial fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of NOX2 (gp91phox), fibronectin and extracellular signal regulated kinase (ERK) were detected by western blot. A level of Malondialdehyde (MDA), an oxidative stress marker, was measured by ELISA. In addition, ROS and the expressions of NOX2, collagen I (a1), fibronectin and p-ERK were measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial cells (NRK-52E) in culture. RESULTS: In NRK-52E cells, AKF-PD reduced AngII induced expressions of ROS, NOX2, fibronectin, collagen I (a1) and p-ERK. In UUO kidney cortex, AKF PD attenuated the degree of renal interstitial fibrosis, which was associated with reduced the expressions of collagen I (a1) and fibronectin. Furthermore, AKF PD downregulated the expressions of NOX2, MDA and p-ERK. CONCLUSION: AKF-PD treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK/MAPK signaling pathway. PMID- 26029783 TI - A repertoire of leadership attributes: an international study of deans of nursing. AB - AIM: To determine which characteristics of academic leadership are perceived to be necessary for nursing deans to be successful. BACKGROUND: Effective leadership is essential for the continued growth of the discipline. METHOD: A qualitative study using semi-structured interviews with 30 deans (academics in universities who headed a nursing faculty and degree programmes) was conducted in three countries--Canada, England and Australia. The conversations were analysed for leadership attributes. RESULT: Sixty personal and positional attributes were nominated by the participants. Of these, the most frequent attribute was 'having vision'. Personal attributes included: passion, patience, courage, facilitating, sharing and being supportive. Positional attributes included: communication, faculty development, role modelling, good management and promoting nursing. CONCLUSION: Both positional and personal aspects of academic leadership are important to assist in developing a succession plan and education for new deans. IMPLICATIONS FOR NURSING MANAGEMENT: It is important that talented people are recognised as potential leaders of the future. These future leaders should be given every chance to grow and develop through exposure to opportunities to develop skills and the attributes necessary for effective deanship. Strategic mentoring could prove to be useful in developing and supporting the growth of future deans of nursing. PMID- 26029784 TI - Re: Renfree KJ. Percutaneous in situ versus open arthrodesis of the distal interphalangeal joint. J Hand Surg Eur. Epub ahead of print 18 March 2014. DOI: 10.1177/1753193414527387. Reply. PMID- 26029785 TI - Re: Tonkin, M. A. On the classification of congenital thumb hypoplasia. J Hand Surg Eur. 2014, 39: 948-55. Reply. PMID- 26029787 TI - Should psychiatry become social neuroscience? PMID- 26029786 TI - Re: Wong J. and McGrouther D. A. Minimizing trauma over 'no man's land' for flexor tendon retrieval. J Hand Surg Eur. 2014, 39: 1004-6. PMID- 26029789 TI - Visible-Light-Responsive Photocatalytic Flow Reactor Composed of Titania Film Photosensitized by Metal Complex-Clay Hybrid. AB - Synthetic saponite containing a photosensitizing metal complex, tris(2,2' bipyridine)ruthenium(II)), in the interlayer space was complexed with anatase nanoparticles to obtain transparent hybrid film photocatalyst. The catalyst film was mounted in a flow reactor device to catalyze such photocatalytic reactions as the decomposition of aqueous acetic acid and N-alkylation of benzylamine with ethanol. PMID- 26029790 TI - Two- and Three-Electron Oxidation of Single-Site Vanadium Centers at Surfaces by Ligand Design. AB - Rational, systematic tuning of single-site metal centers on surfaces offers a new approach to increase selectivity in heterogeneous catalysis reactions. Although such metal centers of uniform oxidation states have been achieved, the ability to control their oxidation states through the use of carefully designed ligands had not been shown. To this end, tetrazine ligands functionalized by two pyridinyl or pyrimidinyl substituents were deposited, along with vanadium metal, on the Au(100) surface. The greater oxidizing power of the bis-pyrimidinyltetrazine facilitates the on-surface redox formation of V(3+), compared to V(2+) when paired with the bis-pyridinyltetrazine, as determined by X-ray photoelectron spectroscopy. This demonstrates the ability to control metal oxidation states in surface coordination architectures by altering the redox properties of organic ligands. The metal-ligand complexes take the form of one-dimensional polymeric chains, resolved by scanning tunneling microscopy. The chain structures in the first layer are very uniform and are based on the same quasi-square-planar coordination geometry around single-site V with either ligand. Formation of a different, dimer structure is observed in the early stages of the second layer formation. These systems offer new opportunities in controlling the oxidation state of single-site transition metal atoms at a surface for new advances in heterogeneous catalysts. PMID- 26029791 TI - Enhanced Photoreduction of Nitro-aromatic Compounds by Hydrated Electrons Derived from Indole on Natural Montmorillonite. AB - A new photoreduction pathway for nitro-aromatic compounds (NACs) and the underlying degradation mechanism are described. 1,3-Dinitrobenzene was reduced to 3-nitroaniline by the widely distributed aromatic molecule indole; the reaction is facilitated by montmorillonite clay mineral under both simulated and natural sunlight irradiation. The novel chemical reaction is strongly affected by the type of exchangeable cation present on montmorillonite. The photoreduction reaction is initiated by the adsorption of 1,3-dinitrobenzene and indole in clay interlayers. Under light irradiation, the excited indole molecule generates a hydrated electron and the indole radical cation. The structural negative charge of montmorillonite plausibly stabilizes the radical cation hence preventing charge recombination. This promotes the release of reactive hydrated electrons for further reductive reactions. Similar results were observed for the photoreduction of nitrobenzene. In situ irradiation time-resolved electron paramagnetic resonance and Fourier transform infrared spectroscopies provided direct evidence for the generation of hydrated electrons and the indole radical cations, which supported the proposed degradation mechanism. In the photoreduction process, the role of clay mineral is to both enhance the generation of hydrated electrons and to provide a constrained reaction environment in the galley regions, which increases the probability of contact between NACs and hydrated electrons. PMID- 26029792 TI - Elevated Hb A2 Levels in a Patient with a Compound Heterozygosity for the (beta+) -31 (A > G) and (beta0) Codon 17 (A > T) Mutations Together with a Single alpha Globin Gene. AB - We report the molecular and hematological feature of a Thai woman who had clinical diagnosis of beta-thalassemia intermedia (beta-TI). Hemoglobin (Hb) high performance liquid chromatography (HPLC) analysis identified Hb A (64.4%), Hb F (12.3%) and Hb A2/E (15.9%) with small peaks of Hb Bart's (gamma4) and Hb H (beta4). She was initially diagnosed as EA Bart's disease, which occurs from combination of Hb H disease and Hb E (HBB: c.79G > A) trait. However, the Hb analysis using capillary electrophoresis (CE) demonstrated no Hb E, 68.5% Hb A, 15.5% Hb F and 16.0% Hb A2. DNA analysis showed a compound heterozygosity for (beta(+)) -31 (A > G) (HBB: c.-81A > G) and (beta(0)) codon 17 (A > T) (HBB: c.52A > T) mutations and deletional Hb H (- -(SEA)/-alpha(3.7)). Thus, she was finally diagnosed with a combination of Hb H disease and compound heterozygosity of beta(+)/beta(0)-thalassemia (beta(+)/beta(0)-thal). The beta-globin mutations could affect not only hematological parameters but also elevate the Hb A2 levels. These effects could not be ameliorated by the coinheritance of Hb H disease. Therefore, a better understanding of the effects of this combination on hematological analysis data will be useful for providing accurate diagnosis, genetic counseling, prevention and control programs of beta-thalassemia major (beta-TM). PMID- 26029793 TI - Heart Rate Variability for Early Detection of Iron Overload Cardiomyopathy in beta-Thalassemia Patients. AB - Iron overload cardiomyopathy remains the major cause of death in beta-thalassemia (beta-thal). Conventional routine screening parameters such as serum ferritin and echocardiogram (ECG) do not permit early detection of this condition. Although non-transferrin-bound iron (NTBI) is a reliable indicator for iron overload, it is still not universally available. Recently, heart rate variability (HRV), representing cardiac autonomic function, was found to be depressed in thalassemia patients. We hypothesized that HRV can be used for early detection of iron overload cardiomyopathy. Fifty patients (aged 29 +/- 11 years; 31 females and 19 males) with beta-thal were enrolled. The 24-hour Holter monitoring for HRV, serum ferritin, NTBI, hematological values and ECG were performed for each patient. Of the 50 patients, 29 carried beta-thal major (beta-TM). Non-transferrin-bound iron was weakly correlated to all time-domain HRV parameters. Low- and high-frequency domain HRV parameters were also inversely weakly correlated with NTBI. Neither HRV nor NTBI was correlated with serum ferritin. With its weak but significant correlation with NTBI, HRV may be considered to be used as a potential indicator of an iron overload condition and an early marker of cardiac involvement in patients with beta-thal. PMID- 26029794 TI - How Microsolvation Numbers at Li Control Aggregation Modes, sp(2) Stereoinversion, and NMR Coupling Constants (2)JH,H of H2C?C in alpha-(2,6 Dimethylphenyl)vinyllithium. AB - The title compound 4 is a trisolvated monomer 4&3THF in THF solution and dimerizes endothermically to form (4&THF)2 with a strongly positive (!) dimerization entropy in toluene as the solvent. In the absence of electron-pair donor ligands, 4 aggregates (>dimer) in hydrocarbon solutions. These results followed from the (13)C-alpha splitting patterns and the magnitudes of the one bond (13)C,(6)Li NMR coupling constants in combination with lithiation NMR shifts as secondary NMR criteria. The rate constants of cis/trans sp(2)-stereoinversion could be measured on the (1)H NMR time scale in THF, in which solvent the preinversion lifetime is 0.24 s at 25 degrees C. This inversion proceeds according to the pseudomonomolecular, ionic mechanism with the typical, strongly negative pseudoactivation entropy. In a different mechanism, the lifetimes are much longer at 25 degrees C for the dimer (4&t-BuOMe)2 in toluene (ca. 2.5 min) and for donor-free, aggregated 4 in hexane solution (roughly 1 min). The olefinic interproton two-bond coupling constants (2)JH,H of the H2C?CLi part are proposed as an indicator of microsolvation at Li, because they were found to increase linearly with the "explicit" solvation of alpha-arylvinyllithiums by 0, 1, 2, and 3 electron-pair donor ligands. PMID- 26029795 TI - Undulatory Locomotion of Magnetic Multilink Nanoswimmers. AB - Micro- and nanorobots operating in low Reynolds number fluid environments require specialized swimming strategies for efficient locomotion. Prior research has focused on designs mimicking the rotary corkscrew motion of bacterial flagella or the planar beating motion of eukaryotic flagella. These biologically inspired designs are typically of uniform construction along their flagellar axis. This work demonstrates for the first time planar undulations of composite multilink nanowire-based chains (diameter 200 nm) induced by a planar-oscillating magnetic field. Those chains comprise an elastic eukaryote-like polypyrrole tail and rigid magnetic nickel links connected by flexible polymer bilayer hinges. The multilink design exhibits a high swimming efficiency. Furthermore, the manufacturing process enables tuning the geometrical and material properties to specific applications. PMID- 26029796 TI - c-MYC Amplification in Acute Myelogenous Leukemia Evolving from Double Minutes (dmins) to Homogeneously Staining Region (hsr). AB - A bone marrow biopsy of a 68-year-old woman revealed 59% blasts and immature monocytes, consistent with acute myeloid leukemia (AML) with monocytic features. Occasional hypolobated megakaryocytes and decreased iron stores were also present. A peripheral blood sample showed 7% blasts in addition to monocytosis, macrocytic anemia and thrombocytopenia. Molecular testing was negative for FLT3 ITD, NPM1 and CEBPA. Fluorescence in situ hybridization (FISH) probes were negative for t(8;21), t(15;17), inversion 16 and 11q23 rearrangements. The karyotype was 46,XX,del(20)(q11.2q13.1),~50dmin[3]/47,idem,+4[13]/47,idem,+22[2]/46,XX[2]. FISH confirmed that the double minutes were c-MYC positive with cryptic deletion of the c-MYC FISH signal on one of the chromosome 8s. Two months post-diagnosis, 57% of our patient's cells were still positive for c-MYC amplification; however, by four months only 8% of cells were positive for c-MYC amplification. After seven months, the patient's karyotype had the 20q deletion, X chromosome loss and a ring chromosome that consisted of a homogeneously staining region (hsr) containing c-MYC amplification. This case demonstrates that gene amplification in the form of double minutes can transform into a more stable hsr. PMID- 26029797 TI - Base-Promoted beta-C(sp(3))-H Functionalization of Enaminones: An Approach to Polysubstituted Pyridines. AB - A convenient "one-pot" base-promoted synthesis of polysubstituted pyridines from 1-arylethylamines and ynones through the direct beta-C(sp(3))-H functionalization of enaminones under metal-free conditions has been developed. An intermolecular Michael addition reaction and an intramolecular condensation were involved in this procedure, which features high regioselectivity, high efficiency, and environmental friendliness. Various polysubstituted pyridines were provided in up to 92% yield for 34 examples. PMID- 26029798 TI - Gastrointestinal bleeding in a chronic myeloid leukaemia patient precipitated by dasatinib-induced platelet dysfunction: Case report. AB - Bleeding in patients with chronic myeloid leukaemia (CML) receiving the second line tyrosine kinase inhibitor (TKI) dasatinib is a well-documented side effect, occurring in up to 24% of patients. In most cases, it is attributed directly to a secondary grade 3 or 4 thrombocytopaenia. Platelet dysfunction precipitated by dasatinib has been demonstrated in multiple in vitro and in vivo studies; however, there is currently no correlative data that definitively associates this with clinically significant bleeding. In this case, we report a patient with chronic-phase CML receiving dasatinib who developed significant gastrointestinal bleeding secondary to angiodysplasia in the absence of a severe thrombocytopaenia or coagulopathy. Platelet function testing on the PFA-100 assay and formal platelet aggregometry demonstrated impaired platelet aggregation, however, upon cessation of dasatinib, platelet function normalised and the bleeding resolved without further intervention. This case demonstrates that dasatinib-induced platelet dysfunction can cause clinically significant bleeding and highlights the need for physicians to be aware of this adverse effect. PMID- 26029799 TI - Attention Must Be Paid: The Association of Plasma Clozapine/NDMC Ratio With Working Memory. PMID- 26029800 TI - The role of stimulants in late-life depression. PMID- 26029801 TI - Parents and genes and their effects on alcohol, drugs, and crime in triparental families. PMID- 26029802 TI - On being chronically ill. PMID- 26029803 TI - Psychiatric care during hepatitis C treatment: the changing role of psychiatrists in the era of direct-acting antivirals. PMID- 26029804 TI - The stone that mourns its victims: Haiti still recovering from its injuries and traumas 5 years after the 2010 earthquake. PMID- 26029805 TI - CBT for Adolescents With Anxiety: Mature Yet Still Developing. AB - Anxiety disorders are common in adolescents (ages 12 to 18) and contribute to a range of impairments. There has been speculation that adolescents with anxiety are at risk for being treatment nonresponders. In this review, the authors examine the efficacy of cognitive-behavioral therapy (CBT) for adolescents with anxiety. Outcomes from mixed child and adolescent samples and from adolescent only samples indicate that approximately two-thirds of youths respond favorably to CBT. CBT produces moderate to large effects and shows superiority over control/comparison conditions. The literature does not support differential outcomes by age: adolescents do not consistently manifest poorer outcomes relative to children. Although extinction paradigms find prolonged fear extinction in adolescent samples, basic research does not fully align with the processes and goals of real-life exposure. Furthermore, CBT is flexible and allows for tailored application in adolescents, and it may be delivered in alternative formats (i.e., brief, computer/Internet, school-based, and transdiagnostic CBT). PMID- 26029806 TI - Response to Ostacher et al. PMID- 26029807 TI - Monotherapy Antidepressant Treatment is Not Associated With Mania in Bipolar I Disorder. PMID- 26029808 TI - Evidence-based medicine and clinical expertise. PMID- 26029809 TI - Response to Saraga. PMID- 26029813 TI - Lipids beyond membranes; farnesylation targets Spindly to kinetochores. PMID- 26029815 TI - Facile Fabrication of Graphene Membranes with Readily Tunable Structures. AB - Advanced membranes that combine mechanical robustness with fast permeation are crucial to many applications such as water purification, ions selectivity, and gas separation. Graphene sheets offer a promising opportunity to fabricate thin, high-flux, and pressure-endurable membranes because of their unique 2D morphology, oxidizable surface, and electrical conductivity. We herein report a highly effective yet simple approach to the fabrication of graphene membranes featuring controllable oxidation degrees and thus tunable structures and properties. The graphene sheets comprise a single or a few layers with a lateral dimension of 50-100 nm; their C/O ratios can be manipulated from 4.1 for graphene with a low degree of oxidation (low-oxidation graphene) to 2.5 for medium oxidation graphene to 1.3 for high-oxidation graphene, by controlling the proportion of phosphoric acid during the 60 min fabrication. Fabricated by simple vacuum filtration, the membranes exhibited various water flux from 200.0 to 20.0 L/m(2).h.bar at 3 bar of pressure and mechanical robustness (Young's modulus can be up to 20 GPa and tensile strength to 100 MPa). When these membranes were used as electrodes for supercapacitors, specific capacitances of 58.8 F/g and 23.5 F/cm(3) were recorded for the low-oxidation graphene membrane at 1 A/g by a two electrode configuration; the capacity values retained ~95% after 800 cycles; the high capacitance would be caused by moderate wettability and high electrical conductivity. PMID- 26029817 TI - N-Trifluoromethylthiolated Sulfoximines. AB - Air- and moisture-stable N-trifluoromethylthio sulfoximines have been prepared from N-H-sulfoximines via the corresponding N-Br derivatives in excellent yields. The two-step process starts with an easy-to-perform bromination at the sulfoximine nitrogen, followed by a reaction with silver trifluoromethanethiolate. A one-pot reaction sequence allows difficult to prepare products to be obtained. PMID- 26029816 TI - A retrospective pooled analysis assessing the effect of age on the immunogenicity of HavrixTM in healthy adults. AB - Over recent decades, the global incidence of hepatitis A virus infection has been reduced by improvements in sanitation infrastructure and through immunization programs. The immunogenicity and field efficacy of the inactivated hepatitis A vaccine (HavrixTM, GSK, Belgium) has been demonstrated in clinical trials, population-impact studies as well as in several outbreak settings. However, immunological data in older populations are limited, with only few studies assessing the immune response of this vaccine in adults aged >= 40 years. This retrospective pooled analysis of 4 2-dose primary vaccination studies compared the immunogenicity and safety of the inactivated hepatitis A vaccine in adults aged >= 40 years with subjects aged 20-30 years (control group; N = 80 in each group). Fifteen days after the first vaccine dose, 79.7% (95% CI: 68.8-88.2) and 92.3% (95% CI: 84.0-97.1) of subjects were seropositive in the >= 40 years and control groups, respectively; 97.5% (95% CI: 91.2-99.7) and 97.4% (95% CI: 91.0 99.7), respectively, were seropositive one month after the first dose. All subjects in both groups (95% CIs: 95.4-100 and 95.3-100, respectively) were seropositive one month after the second dose. Safety profiles were similar in both groups. In conclusion, the inactivated hepatitis A vaccine induced similar immune responses in adults aged >= 40 and 20-30 years one month after the first and second dose whereas younger subjects may demonstrate a higher seroconversion rate 15 days after the first dose. PMID- 26029818 TI - Correlating Infrared and X-ray Absorption Energies for Molecular-Level Insight into Hydrogen Bond Making and Breaking in Solution. AB - While ubiquitous, the making and breaking of hydrogen bonds in solution is notoriously difficult to study due to the associated complex changes of nuclear and electronic structures. With the aim to reduce the according uncertainty in correlating experimental observables and hydrogen-bond configurations, we combine the information from proximate methods to study the N-H...O hydrogen bond in solution. We investigate hydrogen-bonding of the N-H group of N-methylaniline with oxygen from liquid DMSO and acetone with infrared spectra in the N-H stretching region and X-ray absorption spectra at the N K-edge. We experimentally observe blue shifts of the infrared stretching band and an X-ray absorption pre edge peak when going from DMSO to acetone. With ab initio molecular dynamics simulations and calculated spectra, we qualitatively reproduce the experimental observables but we do not reach quantitative agreement with experiment. The infrared spectra support the notion of weakening the N-H...O hydrogen bond from DMSO to acetone. However, we fail to theoretically reproduce the measured shift of the X-ray absorption pre-edge peak. We discuss possible shortcomings of the simulation models and spectrum calculations. Common features and distinct differences with the O-H...O hydrogen bond are highlighted, and the implications for monitoring hydrogen-bond breaking in solution are discussed. PMID- 26029819 TI - Distinct vortex-glass phases in Yb3Rh4Sn13 at high and low magnetic fields. AB - The vortex lattice (VL) in the mixed state of the stannide superconductor Yb3Rh4Sn13 has been studied using small-angle neutron scattering (SANS). The field dependences of the normalized longitudinal and transverse correlation lengths of the VL, xi(L)/a0 and xi(T)/a0, reveal two distinct anomalies that are associated with vortex-glass phases below MU0Hl ~ 700 G and above MU0Hh ~ 1.7 T (a0 is the intervortex distance). At high fields, around 1.7 T, the longitudinal correlation decreases abruptly with increasing fields indicating a weakening (but not a complete destruction) of the VL due to a phase transition into a glassy phase, below MU0Hc2 (1.8 K) ~2.5 T. xi(L)/a0 and xi(T)/a0, gradually decrease for decreasing fields of strengths less than 1 T and tend towards zero. The shear elastic modulus c66 and the tilting elastic modulus c44 vanish at a critical field MU0Hl ~ 700 G, providing evidence for a disorder-induced transition into a vortex-glass. A 'ring' of scattered intensity is observed for fields lower than 700 G, i.e. MU0Hc1 = 135 G < MU0H < 700 G. This low-field phenomenon is of different nature than the one observed at high fields, where xi(L)/a0 but not xi(T)/a0, decreases abruptly to an intermediate value. PMID- 26029820 TI - Randomizing bipartite networks: the case of the World Trade Web. AB - Within the last fifteen years, network theory has been successfully applied both to natural sciences and to socioeconomic disciplines. In particular, bipartite networks have been recognized to provide a particularly insightful representation of many systems, ranging from mutualistic networks in ecology to trade networks in economy, whence the need of a pattern detection-oriented analysis in order to identify statistically-significant structural properties. Such an analysis rests upon the definition of suitable null models, i.e. upon the choice of the portion of network structure to be preserved while randomizing everything else. However, quite surprisingly, little work has been done so far to define null models for real bipartite networks. The aim of the present work is to fill this gap, extending a recently-proposed method to randomize monopartite networks to bipartite networks. While the proposed formalism is perfectly general, we apply our method to the binary, undirected, bipartite representation of the World Trade Web, comparing the observed values of a number of structural quantities of interest with the expected ones, calculated via our randomization procedure. Interestingly, the behavior of the World Trade Web in this new representation is strongly different from the monopartite analogue, showing highly non-trivial patterns of self-organization. PMID- 26029821 TI - Development of early handwriting: Visual-motor control during letter copying. AB - Despite the importance of handwriting for school readiness and early academic progress, prior research on the development of handwriting has focused primarily on the product rather than the process by which young children write letters. In contrast, in the present work, early handwriting is viewed as involving a suite of perceptual, motor, and cognitive abilities, which must work in unison if children are to write letters efficiently. To study such coordination, head mounted eye-tracking technology was used to investigate the process of visual motor coordination while kindergarten children (N = 23) and adults (N = 11) copied individual letters and strings of letters that differed in terms of their phonemic properties. Results indicated that kindergarten children were able to copy single letters efficiently, as did adults. When the cognitive demands of the task increased and children were presented with strings of letters, however, their ability to copy letters efficiently was compromised: Children frequently interrupted their writing midletter, whereas they did not do so on single letter trials. Yet, with increasing age, children became more efficient in copying letter strings, in part by using vision more prospectively when writing. Taken together, the results illustrate how the coordination of perceptual, motor, and cognitive processes contributes to advances in the development of letter writing skill. PMID- 26029822 TI - Silver Ions Induce Lateral Etching of Gold Nanorods by K2PtCl4. AB - Selective etching is significant for fabrication of novel nanostructures. Here silver ions are introduced to control the lateral etching of gold nanorods by K2PtCl4 in a hot solution, producing a number of dumbbell-like PtAu-Au thin gold nanorods. Silver ions control the selective deposition of the reduced Pt(0) atoms, causing the selective etching of the unprotected Au. The middle diameter of the obtained dumbbell-like nanorods can be adjusted from 12 nm to <10 nm. It is believed that this is an effective method to reduce the diameter of gold nanorods. PMID- 26029823 TI - Catalytic subunits of the phosphatase calcineurin interact with NF-kappaB inducing kinase (NIK) and attenuate NIK-dependent gene expression. AB - Nuclear factor (NF)-kappaB-inducing kinase (NIK) is a serine/threonine kinase that activates NF-kappaB pathways, thereby regulating a wide variety of immune systems. Aberrant NIK activation causes tumor malignancy, suggesting a requirement for precise regulation of NIK activity. To explore novel interacting proteins of NIK, we performed in vitro virus screening and identified the catalytic subunit Aalpha isoform of serine/threonine phosphatase calcineurin (CnAalpha) as a novel NIK-interacting protein. The interaction of NIK with CnAalpha in living cells was confirmed by co-immunoprecipitation. Calcineurin catalytic subunit Abeta isoform (CnAbeta) also bound to NIK. Experiments using domain deletion mutants suggested that CnAalpha and CnAbeta interact with both the kinase domain and C-terminal region of NIK. Moreover, the phosphatase domain of CnAalpha is responsible for the interaction with NIK. Intriguingly, we found that TRAF3, a critical regulator of NIK activity, also binds to CnAalpha and CnAbeta. Depletion of CnAalpha and CnAbeta significantly enhanced lymphotoxin beta receptor (LtbetaR)-mediated expression of the NIK-dependent gene Spi-B and activation of RelA and RelB, suggesting that CnAalpha and CnAbeta attenuate NF kappaB activation mediated by LtbetaR-NIK signaling. Overall, these findings suggest a possible role of CnAalpha and CnAbeta in modifying NIK functions. PMID- 26029824 TI - Real-time and simultaneous monitoring of the phosphorylation and enhanced interaction of p53 and XPC acidic domains with the TFIIH p62 subunit. AB - Posttranslational modifications have critical roles in diverse biological processes through interactions. Tumor-suppressor protein p53 and nucleotide excision repair factor XPC each contain an acidic region, termed the acidic transactivation domain (TAD) and acidic fragment (AF), respectively, that binds to the pleckstrin homology (PH) domain of the p62 subunit of the transcription factor TFIIH. Human p53-TAD contains seven serine and two threonine residues, all of which can be phosphorylated. Similarly, XPC-AF contains six serine and two threonine residues, of which Thr117, Ser122 and Ser129 have been reported as phosphorylation sites in vivo, although their phosphorylation roles are unknown. Phosphorylation of Ser46 and Thr55 of p53-TAD increases its binding ability; however, the role of XPC-AF phosphorylation remains elusive. Here we describe a system for real-time and simultaneous monitoring of the phosphorylation and p62 PH affinity of p53-TAD and XPC-AF using nuclear magnetic resonance (NMR) spectroscopy. Unexpectedly, among seven reported kinases that presumably phosphorylate Ser46 and/or Thr55 of p53-TAD, only two specific and high efficiency enzymes were identified: JNK2alpha2 for Ser46 and GRK5 for Thr55. During interaction with p62-PH, four different affinity complexes resulting from various phosphorylation states of p53-TAD by the kinases were identified. The kinetics of the site-specific phosphorylation reaction of p53-TAD and its affinity for p62-PH were monitored in real-time using the NMR system. Isothermic calorimetry showed that phosphorylation of Ser129 of XPC-AF increases binding to p62-PH. Although CK2 was predicted to phosphorylate Ser122, Ser129 and Ser140 from its sequence context, it specifically and efficiently phosphorylated only Ser129. Simultaneous monitoring of the phosphorylation and augmentation in p62-PH binding identified a key residue of p62-PH for contacting phosphorylated Ser129. In summary, we have established an NMR system for real-time and simultaneous monitoring of site-specific phosphorylation and enhancement of affinity between phosphorylation domains and their target. The system is also applicable to other posttranslational modifications. PMID- 26029825 TI - Mutations of the functional ARH1 allele in tumors from ARH1 heterozygous mice and cells affect ARH1 catalytic activity, cell proliferation and tumorigenesis. AB - ADP-ribosylation results from transfer of the ADP-ribose moiety of nicotinamide adenine dinucleotide (NAD) to an acceptor with ADP-ribose-acceptor content determined by the activities of ADP-ribosyltransferases, which modify the acceptor, and ADP-ribose-acceptor hydrolase (ARH), which cleave the ADP-ribose acceptor bond. ARH1 was discovered as an ADP-ribose(arginine)protein hydrolase. Previously, we showed that ARH1-knockout and ARH1 heterozygous mice spontaneously developed tumors. Further, ARH1-knockout and ARH1 heterozygous mouse embryonic fibroblasts (MEFs) produced tumors when injected into nude mice. In tumors arising in ARH1 heterozygous mice and MEFs, we found both loss of heterozygosity (LOH) of the ARH1 gene and ARH1 gene mutations. In the present report, we found that these mutant ARH1 genes encode proteins with reduced ARH1 enzymatic activity. Moreover, MEFs transformed with ARH1 mutant genes exhibiting different levels of ARH1 activity showed altered rates of proliferation, anchorage independent colony growth in soft agar, and tumorigenesis in nude mice. MEFs transformed with the wild-type (WT) gene, but expressing low levels of hydrolase activity were also tumorigenic. However, transformation with the WT gene was less likely to yield tumors than transformation with a mutant gene exhibiting similar hydrolase activity. Thus, control of protein-ADP-ribosylation by ARH1 is critical for tumorigenesis. In the human cancer database, LOH and mutations of the ARH1 gene were observed. Further, ARH1 gene mutations were located in exons 3 and 4, comparable to exons 2 and 3 of the murine ARH1 gene, which comprise the catalytic site. Thus, human ARH1 gene mutations similar to their murine counterparts may be involved in human cancers. PMID- 26029826 TI - Nuclear accumulation of CDH1 mRNA in hepatocellular carcinoma cells. AB - Expression of E-cadherin has a central role in maintaining epithelial morphology. In solid tumors, reduction of E-cadherin results in disruption of intercellular contacts. Consequently, cells lose adhesive properties and gain more invasive mesenchymal properties. Nevertheless, the mechanism of E-cadherin regulation is not completely elucidated. Here we analyzed the distribution of E-cadherin expression at the cell level in human hepatocellular carcinoma, in which human liver paraffin blocks from 25 hepatocellular carcinoma patients were prepared from cancerous (CA) and noncancerous areas (NCA). In situ hybridization (ISH) was performed to detect E-cadherin and hypoxia-induced factor-1alpha (HIF1alpha) mRNAs and immunohistochemistry to stain E-cadherin protein. In parallel, RNA was extracted from CA and NCA, and E-cadherin and HIF1alpha were quantified by quantitative reverse transcription PCR. ISH revealed abundant E-cadherin mRNA in nuclei of hepatocellular carcinoma cells (HCCs), whereas immunohistochemistry showed depletion of E-cadherin protein from these areas. In sections of NCA, E cadherin mRNA was also found in the cytosol, and E-cadherin protein was detected on the membrane of cells. Experiments in cell lines confirmed E-cadherin mRNA in nuclei of cells negative for E-cadherin protein. HIF1alpha expression is elevated in CAs, which is associated with a clear cytosolic staining for this mRNA. Our results demonstrate that E-caderhin mRNA is selectively retained in nuclei of HCCs, whereas other mRNAs are still exported, suggesting that translocation of E cadherin mRNA from nuclei to cytoplasm has a role in regulating E-cadherin protein levels during epithelial mesenchymal transition. PMID- 26029827 TI - Compensatory angiogenesis and tumor refractoriness. AB - Since the establishment of tumor angiogenesis as a therapeutic target, an excitement in developing the anti-angiogenic agents was resulted in tailoring a humanized monoclonal antibody (Bevacizumab) against vascular endothelial growth factor (VEGF): a key factor in recruiting angiogenesis. The past three decades' research in the area of angiogenesis also invented a series of novel and effective anti-angiogenic agents targeting the VEGF signaling axis. Despite the demonstrable clinical benefits of anti-angiogenic therapy, the preclinical and clinical data of the current therapeutic settings clearly indicate the transient efficacy, restoration of tumor progression and aggressive recurrence of tumor invasion after the withdrawal of anti-angiogenic therapy. Therefore, the impact of this therapeutic regime on improving overall survival of patients has been disappointing in clinic. The recent advances in pathophysiology of tumor angiogenesis and related molecular and cellular underpinnings attributed the conspiracy of compensatory angiogenic pathways in conferring evasive and intrinsic tumor resistance to anti-angiogenic agents. The understandings of how these pathways functionally cross-talk for sustaining tumor angiogenesis during VEGF blockade is essential and perhaps may act as a basic prerequisite for designing novel therapeutic strategies to combat the growing arrogance of tumors toward anti-angiogenic agents. The present review offers a discourse on major compensatory angiogenic pathways operating at cellular and molecular levels and their attributes with resistance to anti-angiogenic agents along with strategic opinions on future setting in targeting tumor angiogenesis. PMID- 26029828 TI - Regulation of lipid synthesis by the RNA helicase Mov10 controls Wnt5a production. AB - Expression of the Wnt ligand Wnt5a is frequently elevated in melanoma and is thought to be a critical regulator of cell movement during metastasis. However, the mechanisms regulating its expression are unknown. We find that the level of secreted Wnt5a varies by as much as 10-fold between cell lines and correlates more strongly with invasion than total cellular levels. Our results indicate that the RNA helicase Mov10 plays a role in Wnt5a synthesis and secretion. Inhibition of Mov10 increases secreted Wnt5a levels in melanoma cells by increasing Wnt5a synthesis and acylation. This is achieved by increasing fatty acid synthase (FASN) and stearoyl-CoA desaturase expression, leading to elevated levels of palmitoleoyl-CoA, required for Wnt ligand lipid modification and secretion. Melanoma tumors exhibit reduced expression of Mov10 compared with benign nevi and Mov10 levels inversely correlate with FASN levels in primary tumors. These results reveal a previously unappreciated role for aberrant lipid metabolism in regulating Wnt5a signaling that may be a critical step in melanoma progression. PMID- 26029829 TI - Multifaceted Role for IL-17A in the Pathogenesis of Chronic Obstructive Pulmonary Disease. PMID- 26029830 TI - Is bronchiolitis obliterans after hematopoietic stem cell transplantation reversible? PMID- 26029831 TI - Macrolide-Resistant Pneumococcus in Community-acquired Pneumonia. Is There Still a Role for Macrolide Therapy? PMID- 26029832 TI - Elafin in pulmonary arterial hypertension. Beyond targeting elastases. PMID- 26029833 TI - A brief history of fluid and sleep. PMID- 26029834 TI - Adolescent obesity, adenotonsillar hypertrophy, and obstructive sleep apnea. PMID- 26029835 TI - Hit the Road, MAC, and Don't You Come Back No More. PMID- 26029836 TI - Rationale for a redundant formulary. The Hawthorne effect and the art of medicine. PMID- 26029837 TI - Update in sepsis and acute kidney injury 2014. AB - Sepsis and acute kidney injury (AKI) represent an important burden in intensive care unit clinical practices. The Journal published important contributions in sepsis for novel therapeutic approaches suggesting that combined molecular targets (e.g., dual inhibition of IL-1beta and IL-18, and coadministration of endothelial progenitor cells and stromal cell-derived factor-1alpha analog) could perform better. The clinical effectiveness of 1,25-dihydroxyvitamin D was reported in a double-blind, randomized, placebo-controlled trial. Although its experimental properties appeared favorable in the pro- and antiinflammatory cytokine balance, 1,25-dihydroxyvitamin D failed to improve survival. Strategies for decreasing antimicrobial resistances are of particular importance. Effective (aerosolized antibiotics for ventilator-associated pneumonia) and ineffective (procalcitonin algorithm for antibiotic deescalation) approaches were published. In 2014, several publications raised an important point shared by survivors from sepsis and/or AKI. The increased number of survivors over time brought out long term sequelae, leading to a poor outcome after hospital discharge. Among them, cardiovascular events and chronic kidney disease may explain the significant increase in the risk of death, which can persist up to 10 years and significantly increases the use of health care. Postdischarge survival represents a new target for future research in sepsis and AKI to find how we can prevent and manage long term sequelae. A milestone of the year was the Ebola outbreak. The Journal contributed to our better understanding of Ebola virus disease with a paper underlying the crucial role of a large implementation of pragmatic supportive care, including fluid infusion and correction of metabolic abnormalities, to save more lives. PMID- 26029838 TI - Fluid Protocol for Acute Respiratory Distress Syndrome, Catheter Thrombolysis for Intermediate Risk Pulmonary Embolism, and Steroids for Community-acquired Pneumonia. PMID- 26029839 TI - Pseudomyxoma pleuri. A rare manifestation of an uncommon disease. PMID- 26029840 TI - Coenzyme Q in asthma. PMID- 26029841 TI - Chronic ventilation in infants with surfactant protein C mutations: an alternative to lung transplantation. PMID- 26029842 TI - The workforce crisis: a functioning solution. PMID- 26029843 TI - Circulating fibrocytes as a biomarker of prognosis in Hermansky-Pudlak syndrome. PMID- 26029844 TI - Reply: circulating fibrocytes as a biomarker of prognosis in Hermansky-Pudlak syndrome. PMID- 26029845 TI - Erratum: epigenomics of idiopathic pulmonary fibrosis: evaluating the first steps. PMID- 26029846 TI - Comparing different gas chromatographic methods for the quantification of bisphenol A (BPA) trace levels in paper and cardboard products from the market. AB - Bisphenol A (BPA; 4,4'-(propane-2,2-diyl)diphenol), a suspected endocrine disruptor with weak estrogenic activity, is used in a variety of consumer products, including paper and cardboard products used as food contact materials. The present study compared four different gas chromatographic methods for the analysis of BPA in paper and cardboard food packages. Eighteen different food packages were extracted and BPA was determined using two different derivatisation reactions--trimethylsilylation with N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA) and halide alkylation with pentafluorobenzoyl chloride (PFBOCl)--and four different separation and detection techniques. The BSTFA derivatives were quantified with (1) GC-MS in single-ion monitoring (SIM) mode with electron ionisation (EI-GC-MS) and (2) GC-MS/MS in multiple reaction monitoring (MRM) mode using electron ionisation (EI-GC-MS/MS); while the PFBOCl derivatives were quantified with (3) GC-MS using electron ionisation (EI-GC-MS) as well as (4) GC MS with negative chemical ionisation (NCI-GC-MS). All developed methods showed good linearity (R(2) > 0.9938), precision (CV < 4.5% for reproducibility; CV < 2.2% for repeatability) and sensitivity, with limits of detection (LODs) between 0.02 ug kg(-1) for the pentafluorobenzoyl derivatives measured with the NCI-GC-MS method and 6 ug kg(-1) for the pentafluorobenzoyl derivatives determined with EI GC-MS. Levels of BPA in the samples were in agreement for all methods, ranging from values below the limit of quantitation (LOQ) to 11.9 mg kg(-1) paper. In a last step, the maximum potential migration into food products was calculated for all tested paper and cardboard samples, assuming a 'worst case' scenario of 100% migration. PMID- 26029847 TI - The PRKAA1/AMPKalpha1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML. AB - Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1 ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML. PMID- 26029848 TI - Preferential Acquisition and Activation of Plasminogen Glycoform II by PAM Positive Group A Streptococcal Isolates. AB - Plasminogen (Plg) circulates in the host as two predominant glycoforms. Glycoform I Plg (GI-Plg) contains glycosylation sites at Asn289 and Thr346, whereas glycoform II Plg (GII-Plg) is exclusively glycosylated at Thr346. Surface plasmon resonance experiments demonstrated that Plg binding group A streptococcal M protein (PAM) exhibits comparative equal affinity for GI- and GII-Plg in the "closed" conformation (for GII-Plg, KD = 27.4 nM; for GI-Plg, KD = 37.0 nM). When Plg was in the "open" conformation, PAM exhibited an 11-fold increase in affinity for GII-Plg (KD = 2.8 nM) compared with that for GI-Plg (KD = 33.2 nM). The interaction of PAM with Plg is believed to be mediated by lysine binding sites within kringle (KR) 2 of Plg. PAM-GI-Plg interactions were fully inhibited with 100 mM lysine analogue epsilon-aminocaproic acid (epsilonACA), whereas PAM-GII Plg interactions were shown to be weakened but not inhibited in the presence of 400 mM epsilonACA. In contrast, binding to the KR1-3 domains of GII-Plg (angiostatin) by PAM was completely inhibited in the presence 5 mM epsilonACA. Along with PAM, emm pattern D GAS isolates express a phenotypically distinct SK variant (type 2b SK) that requires Plg ligands such as PAM to activate Plg. Type 2b SK was able to generate an active site and activate GII-Plg at a rate significantly higher than that of GI-Plg when bound to PAM. Taken together, these data suggest that GAS selectively recruits and activates GII-Plg. Furthermore, we propose that the interaction between PAM and Plg may be partially mediated by a secondary binding site outside of KR2, affected by glycosylation at Asn289. PMID- 26029849 TI - Total Synthesis of (-)-Nodulisporic Acid D. AB - A convergent total synthesis of the architecturally complex indole diterpenoid ( )-nodulisporic acid D has been achieved. Key synthetic transformations include vicinal difunctionalization of an advanced alpha,beta-unsaturated aldehyde to form the E,F-trans-fused 5,6-ring system of the eastern hemisphere and a cascade cross-coupling/indolization protocol leading to the CDE multisubstituted indole core. PMID- 26029850 TI - Molecular basis of Streptococcus mutans sortase A inhibition by the flavonoid natural product trans-chalcone. AB - Sortase A (SrtA) from Gram positive pathogens is an attractive target for inhibitors due to its role in the attachment of surface proteins to the cell wall. We found that the plant natural product trans-chalcone inhibits Streptococcus mutans SrtA in vitro and also inhibited S. mutans biofilm formation. Mass spectrometry revealed that the trans-chalcone forms a Michael addition adduct with the active site cysteine. The X-ray crystal structure of the SrtA H139A mutant provided new insights into substrate recognition by the sortase family. Our study suggests that chalcone flavonoids have potential as sortase specific oral biofilm inhibitors. PMID- 26029851 TI - The Role of Baseline Cognitive Function in the Neurocognitive Effects of Electroconvulsive Therapy in Depressed Elderly Patients. AB - OBJECTIVE: Electroconvulsive therapy (ECT) is an effective biological treatment option for severely depressed elderly patients; however, it can cause cognitive side effects, including anterograde and retrograde amnesia. Elderly patients with "cognitive impairment no dementia" (CIND) are reported as being more vulnerable to the cognitive side effects of ECT compared with patients with "no cognitive impairment" (NCI). The few studies that have reached this conclusion can be criticized for using insensitive outcome measures. METHOD: The present study investigated cognitive side effects using standard neuropsychological tests before and after twice-weekly ECT. Patients were assessed at baseline (T1) and within one week after a course of ECT (consisting of a mean of 10 treatments) (T2), and were followed up for three months after T2 (T3). The sample included 54 patients with NCI (n = 36) or CIND (n = 18). For a control group, we recruited 17 healthy elderly persons. Tests of anterograde memory, information-processing speed, executive function, and retrograde memory were administered. We computed reliable change indices using simple regression methods. RESULTS: Short-term side effects were detected at T2 in a large minority of patients, with no significant differences between NCI and CIND patients. Considerable improvement in global cognitive function from T1 to T3 was observed in 44% of the CIND patients. At the group level, information-processing speed improved significantly in CIND vs. NCI patients. CONCLUSIONS: CIND patients were not more vulnerable to amnesia than were NCI patients. Long-term cognitive side effects of ECT were not detected. PMID- 26029853 TI - ALK FISH Assays for Non-small Cell Lung Cancer Treatment Selection: Scoring Issues and Probe Design. AB - Lung cancer is becoming more treatable with new pharmaceuticals. There is a growing interest in FISH testing to determine which drugs to use on lung cancer patients for the best results, with a concurrent need for laboratories to provide ALK FISH testing for nonsmall-cell lung cancer. However, the test has some unique difficulties and requires a great deal of experience to interpret in some cases. A three-color probe may help make the ALK FISH test more reliable. PMID- 26029852 TI - Comparing the Neuropsychological Test Performance of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans with and without Blast Exposure, Mild Traumatic Brain Injury, and Posttraumatic Stress Symptoms. AB - To compare neuropsychological test performance of Veterans with and without mild traumatic brain injury (MTBI), blast exposure, and posttraumatic stress disorder (PTSD) symptoms. We compared the neuropsychological test performance of 49 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans diagnosed with MTBI resulting from combat blast-exposure to that of 20 blast-exposed OEF/OIF Veterans without history of MTBI, 23 OEF/OIF Veterans with no blast exposure or MTBI history, and 40 matched civilian controls. Comparison of neuropsychological test performance across all four participant groups showed a complex pattern of mixed significant and mostly nonsignificant results, with omnibus tests significant for measures of attention, spatial abilities, and executive function. The most consistent pattern was the absence of significant differences between blast-exposed Veterans with MTBI history and blast-exposed Veterans without MTBI history. When blast-exposed Veteran groups with and without MTBI history were aggregated and compared to non-blast-exposed Veterans, there were significant differences for some measures of learning and memory, spatial abilities, and executive function. However, covariation for severity of PTSD symptoms eliminated all significant omnibus neuropsychological differences between Veteran groups. Our results suggest that, although some mild neurocognitive effects were associated with blast exposure, these neurocognitive effects might be better explained by PTSD symptom severity rather than blast exposure or MTBI history alone. PMID- 26029854 TI - Harvesting Low Molecular Weight Biomarkers Using Gold Nanoparticles. AB - We developed and characterized a platform based on gold (Au) nanoparticles (NPs) coated with poly(acrylic acid) (PAA) for harvesting positively charged, low molecular weight (LMW) proteins. The particles are synthesized using a layer by layer (LbL) procedure: first the gold NPs are coated with positively charged polyethylenimine (PEI) and subsequently with PAA. This simple procedure produces stable PAA-PEI-Au (PPAu) NPs with high selectivity and specificity. PPAu NPs successfully harvested, separated, and detected various LMW proteins and peptides from serum containing a complex mixture of abundant high molecular weight (HMW) proteins, including bovine serum albumin (BSA) and Immunoglobulin G (IgG). In addition, PPAu NPs selectively harvested and separated LMW proteins from serum in the presence of another positively charged competing protein. Furthermore, PPAu NPs successfully harvested a LMW biomarker in a mock diseased state. This system can be applied in various biomedical applications where selective harvesting and identifying of LMW proteins is required. A particularly useful application for this system can be found in early cancer diagnosis as described hereinafter. PMID- 26029855 TI - Effects of Nigella sativa oil with a low-calorie diet on cardiometabolic risk factors in obese women: a randomized controlled clinical trial. AB - Obesity is typically associated with increased risk factors of cardiovascular diseases (CVDs). Therefore, a therapeutic approach that aims to control body weight and metabolic profile might be effective in preventing CVDs. We aimed to determine the effects of Nigella Sativa (NS) oil with a low-calorie diet on cardiometabolic risk factors in obese women. In this double-blind randomized controlled clinical trial, 90 obese women were recruited. Participants were females aged 25-50 years old with body mass index (BMI) between 30 and 35 kg m( 2). They were randomly assigned to receive a low-calorie diet with 3 g per day (1 g before each meal) NS oil or placebo for 8 weeks. Anthropometric indices, dietary intake and biochemical parameters were measured at the baseline and after the intervention. Eighty-four females completed the trial (intervention n = 43, placebo n = 41). Two groups were similar in the baseline characteristics. After the intervention, dietary intake was changed in both groups compared to the baseline, but the differences were not significant between the two groups. In the NS group, weight (-6.0 vs. -3.6%; p < 0.01) and waist circumference (-6.9 vs. 3.4%; p < 0.01) decreased significantly compared with the placebo group at the end of the trial. Comparison of biochemical parameters presented a significant decline in triglyceride (-14.0 vs. 1.4%; p = 0.02) and very low density lipoprotein (-14.0 vs. 7%; p < 0.01) levels in the NS group compared to the placebo group. NS oil concurrent with a low-calorie diet can reduce cardiometabolic risk factors in obese women. However, more clinical trials are needed to elucidate efficacy of NS as a complementary therapy in obese subjects. PMID- 26029856 TI - Ultra-flexible nonvolatile memory based on donor-acceptor diketopyrrolopyrrole polymer blends. AB - Flexible memory cell array based on high mobility donor-acceptor diketopyrrolopyrrole polymer has been demonstrated. The memory cell exhibits low read voltage, high cell-to-cell uniformity and good mechanical flexibility, and has reliable retention and endurance memory performance. The electrical properties of the memory devices are systematically investigated and modeled. Our results suggest that the polymer blends provide an important step towards high density flexible nonvolatile memory devices. PMID- 26029857 TI - Cytotoxicity of the Urokinase-Plasminogen Activator Inhibitor Carbamimidothioic Acid (4-Boronophenyl) Methyl Ester Hydrobromide (BC-11) on Triple-Negative MDA MB231 Breast Cancer Cells. AB - BC-11 is an easily synthesized simple thiouronium-substituted phenylboronic acid, which has been shown to be cytotoxic on triple negative MDA-MB231 breast cancer cells by inducing a perturbation of cell cycle when administered at a concentration equal to its ED50 at 72 h (117 MUM). Exposure of cells to BC-11, either pre-absorbed with a soluble preparation of the N-terminal fragment of urokinase-plasminogen activator (uPa), or in co-treatment with two different EGFR inhibitors, indicated that: (i) BC-11 acts via binding to the N-terminus of the enzyme where uPa- and EGF receptor-recognizing sites are present, thereby abrogating the growth-sustaining effect resulting from receptor binding; and (ii) the co-presence of the EGFR inhibitor PD153035 potentiates BC-11's cytotoxicity. Exposure of cells to a higher concentration of BC-11 corresponding to its ED75 at 72 h (250 MUM) caused additional impairment of mitochondrial activity, the production of reactive oxygen species and promotion of apoptosis. Therefore, BC 11 treatment appears to show potential for the development of this class of compounds in the prevention and/or therapy of "aggressive" breast carcinoma. PMID- 26029858 TI - Chelation-assisted substrate-controlled asymmetric lithiation-allylboration of chiral carbamate 1,2,4-butanetriol acetonide. AB - The lithiation of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl diisopropylcarbamate (1) is achieved freely by sec-butyllithium in diethylether with high lk diastereoselectivity: the bicyclic chelate complexes 3a and 3b are reacted with electrophiles to form optically active precursors 4a and 4b with >95% diastereoselectivity. In addition, tertiary diamines can undergo an external complexation in contest with the internal oxygen ligand, leading to improved stereoselectivities. The further reactions of lithiated carbamates with trans alkenyl-9-BBN derivatives after 1,2 metallate rearrangements, gave the key intermediate alpha-substituted allylic boranes 7. Subsequent allylboration of aldehydes gave (Z)-anti-homoallylic alcohols 8 in good yield and excellent d.r. PMID- 26029859 TI - Reactivity of Aryl Halides for Reductive Dehalogenation in (Sea)water Using Polymer-Supported Terpyridine Palladium Catalyst. AB - A polymer-supported terpyridine palladium complex was prepared. The complex was found to promote hydrodechlorination of aryl chlorides with potassium formate in seawater. Generally, reductive cleavage of aryl chlorides using transition metal catalysts is more difficult than that of aryl bromides and iodides (reactivity: I > Br > Cl); however, the results obtained did not follow the general trend. Therefore, we investigated the reaction inhibition agents and found a method to remove these inhibitors. The polymeric catalysts showed high catalytic activity and high reusability for transfer reduction in seawater. PMID- 26029860 TI - Synthesis and characterization of two sulfonated resorcinarenes: a new example of a linear array of sodium centers and macrocycles. AB - Two sulfonated resorcinarenes were synthesized by reacting C-tetra(butyl) resorcinarene or C-tetra(2-(methylthio)ethyl)resorcinarene with formaldehyde in the presence of sodium sulfite. Their structures were determined via FT-IR, 1H NMR, 13C-NMR and mass spectrometry. Thermal gravimetric analyses of the derivatives were also carried out and revealed the presence of water molecules in the solid state. The sulfonated product of C-tetra(butyl)resorcinarene was characterized by an X-ray crystal structure determination. The asymmetric unit contains eight molecules of water and two of acetone, and analysis indicated that sulfonated resorcinarene prefers a cone configuration (rccc conformation) in the solid state. In the crystal array, classical hydrogen bond interactions O-H...O and intermolecular contacts were observed. In the crystal packing, a linear array of capsules of sulfonated resorcinarenes was generated for a chain of sodium atoms and sulfonate groups. PMID- 26029861 TI - Atmospheric interactions and cardiac arrhythmias. PMID- 26029862 TI - Assessment of ambient air quality in the port of Naples. AB - Two experimental monitoring campaigns were carried out in 2012 to investigate the air quality in the port of Naples, the most important in southern Italy for traffic of passengers and one of the most important for goods. Therefore, it represents an important air pollution source located close to the city of Naples. The concentrations of sulfur dioxide (SO2), nitrogen dioxide (NO2), and BTEX (benzene, toluene, ethylbenzene, and xylenes) in the air were measured at 15 points inside the Naples port area through the use of passive samplers. In addition, a mobile laboratory was positioned in a fixed point inside the port area to measure continuous concentration of pollutants together with particulate matter, ambient parameters, and wind direction and intensity. The pollution levels monitored were compared with those observed in the urban area of Naples and in other Mediterranean ports. Even though the observation time was limited, measured concentrations were also compared with limit values established by European legislation. All the measured pollutants were below the limits with the exception of nitrogen dioxide: its average concentration during the exposition time exceeded the yearly limit value. A spatial analysis of data, according to the measured wind direction and intensity, provided information about the effects that ship emissions have on ambient air quality in the port area. The main evidence indicates that ship emissions influence sulfur dioxide concentration more than any other pollutants analyzed. PMID- 26029863 TI - Electroretinographic assessment of rod- and cone-mediated bipolar cell pathways using flicker stimuli in mice. AB - Mouse full-field electroretinograms (ERGs) are dominated by responses of photoreceptors and depolarizing (ON-) bipolar cells, but not much of hyperpolarizing (OFF-) bipolar cells under conventional recording conditions. Here we investigate a novel ERG protocol in mice for functional assessment of the major ON- and OFF-bipolar cell pathways using flicker stimuli for a high luminance with varying frequency up to 30 Hz. Wild-type (WT) and functionally specific transgenic mice (Cnga3(-/-), no cone photoreceptor function; rho(-/-), no rod photoreceptor function; mGluR6(-/-), no ON-bipolar cell function) were examined. The Cnga3(-/-) flicker ERG was similar to the WT flicker ERG at very low stimulus frequencies, whereas ERGs were comparable between WT and rho(-/-) mice at 5 Hz and above. Between 5 and 15 Hz, ERGs in mGluR6(-/-) mice differed in configuration and amplitude from those in WT and rho(-/-) mice; in contrast, response amplitudes above 15 Hz were comparable among WT, rho(-/-) and mGluR6(-/ ) mice. In summary, we found three frequency ranges with these conditions that are dominated by activity in the rod pathways (below 5 Hz), cone ON-pathway (between 5 and 15 Hz), and cone OFF-pathway (above 15 Hz) that enables a quick overview of the functionality of the major bipolar cell pathways. PMID- 26029864 TI - Treatment, overall survival, and costs in patients with ALK-positive non-small cell lung cancer after crizotinib monotherapy. AB - BACKGROUND: Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden. OBJECTIVE: To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation. METHODS: This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population. RESULTS: A total of 119 ALK positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P = 0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P < 0.001). From claims data, 305 ALK-positive NSCLC patients discontinued crizotinib monotherapy. After discontinuation, 72% had no additional antineoplastic treatment. Among patients who continued antineoplastic treatment, monthly healthcare costs averaged $22,160, driven by pharmacy ($9202), inpatient ($6419), and outpatient radiotherapy ($2888) and imaging ($1179) costs. Among patients who discontinued any antineoplastic treatment, monthly healthcare costs averaged $3423, mostly driven by inpatient costs ($2074). CONCLUSIONS: After crizotinib monotherapy, most patients either received radiotherapy only or discontinued antineoplastic treatment altogether. OS after discontinuing crizotinib was poor and shorter among those with brain metastases than without, and among those without subsequent antineoplastic treatment than with. Patients who continued antineoplastic treatment incurred substantial healthcare costs. PMID- 26029866 TI - Prevalence, Natural History, and Outcome of Acute Fluid Collection and Pseudocyst in Children With Acute Pancreatitis. AB - OBJECTIVE: Recent years have witnessed an increase in acute pancreatitis (AP) in children; however, the natural history of acute fluid collection (AFC) and pseudocyst is largely unknown. We evaluated the frequency, clinical characteristics, and natural history of pseudocysts in children with AP. METHODS: Children with AP admitted at Sanjay Gandhi Postgraduate Institute of Medical Sciences from 2001 to 2011 were enrolled and studied until complete resolution. Subjects with inadequate follow-up, recurrent AP, and chronic pancreatitis were excluded. RESULTS: Of the 58 children (43 boys, median age 14 [1-18] years) with AP, 34 (58.6%) and 22 (38%) developed AFC and pseudocyst, respectively. No difference in age (12 [4-18] vs 13 [1-16] years), etiology (idiopathic 64% vs 47% and traumatic 27.2% vs 22.2%), and systemic complications (pulmonary [18% vs 11%], renal [22.7% vs 11%], and shock [13.6% vs 10%]) was observed between children with and without pseudocyst. A total of 11 of the 22 subjects with pseudocyst underwent drainage, the commonest symptom requiring drainage being gastric outlet obstruction [n = 5] and infection [n = 2]. The 11 of the 22 children with AP and pseudocyst (size 6.4 [3-14.4] cm) showed spontaneous resolution (disappearance [n = 9] and significant reduction in size [n = 2]) during 110 (25-425) days. Symptomatic pseudocysts requiring drainage were more often secondary to traumatic AP (6/6 vs 2/14 [idiopathic], P = 0.0007) than asymptomatic pseudocysts resolving spontaneously. Overall, only 26.4% (9/34) children with AFC required drainage because of symptomatic pseudocyst. CONCLUSIONS: Among children with AP, 58.6% developed AFC and 38% developed pseudocysts. Only patients with symptomatic pseudocyst need drainage, and asymptomatic pseudocyst can be safely observed irrespective of size and duration of collection. PMID- 26029865 TI - Placement of oppositely charged aminoacids at a polypeptide termini determines the voltage-controlled braking of polymer transport through nanometer-scale pores. AB - Protein and solid-state nanometer-scale pores are being developed for the detection, analysis, and manipulation of single molecules. In the simplest embodiment, the entry of a molecule into a nanopore causes a reduction in the latter's ionic conductance. The ionic current blockade depth and residence time have been shown to provide detailed information on the size, adsorbed charge, and other properties of molecules. Here we describe the use of the nanopore formed by Staphylococcus aureus alpha-hemolysin and polypeptides with oppositely charged segments at the N- and C-termini to increase both the polypeptide capture rate and mean residence time of them in the pore, regardless of the polarity of the applied electrostatic potential. The technique provides the means to improve the signal to noise of single molecule nanopore-based measurements. PMID- 26029867 TI - Synthesis and in vitro cytotoxicity of cross-conjugated prostaglandin A and J series and their hydroxy derivatives. AB - The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl] 4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 MUM. Moreover, the C7-hydroxy derivative of NEPP11 displayed high cytotoxic selectivity between cancer cell lines and normal human cells. On the other hand, the J-type prostaglandin analogue of NEPP11 and its C13-hydroxy derivatives were much less toxic or nontoxic against the cancer and normal cells at concentrations up to 1 mM. PMID- 26029868 TI - Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese. AB - To fine map association signals of human leukocyte antigen (HLA) variants in the major histocompatibility complex (MHC) region, we constructed a Japanese population-specific reference panel (n = 908). We conducted trans-ancestry comparisons of linkage disequilibrium (LD) and haplotype structure for HLA variants using an entropy-based LD measurement, E, and a visualization tool to capture high-dimensional variables. Our Japanese reference panel exhibited stronger LD between HLA genes than European or other East Asian populations, characterized by one population-specific common long-range HLA haplotype. We applied HLA imputation to genome-wide association study (GWAS) data for Graves' disease in Japanese (n = 9,003) and found that amino acid polymorphisms of multiple class I and class II HLA genes independently contribute to disease risk (HLA-DPB1, HLA-A, HLA-B and HLA-DRB1; P < 2.3 * 10(-6)), with the strongest impact at HLA-DPB1 (P = 1.6 * 10(-42)). Our study illustrates the value of population-specific HLA reference panels. PMID- 26029869 TI - Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. AB - Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype. PMID- 26029870 TI - Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma. AB - Pituitary adenoma is one of the most common intracranial neoplasms, and its genetic basis remains largely unknown. To identify genetic susceptibility loci for sporadic pituitary adenoma, we performed a three-stage genome-wide association study (GWAS) in the Han Chinese population. We first analyzed genome wide SNP data in 771 pituitary adenoma cases and 2,788 controls and then carried forward the promising variants for replication in another 2 independent sets (2,542 cases and 3,620 controls in total). We identified three new susceptibility loci below the genome-wide significance threshold (P < 5 * 10(-8)) in the combined analyses: 10p12.31 (rs2359536, P(meta) = 2.25 * 10(-10) and rs10828088, P(meta) = 6.27 * 10(-10)), 10q21.1 (rs10763170, P(meta) = 6.88 * 10(-10)) and 13q12.13 (rs17083838, P(meta) = 1.89 * 10(-8)). This study is the first GWAS to our knowledge on sporadic pituitary adenoma, and our results provide insight into the genetic basis of this disease. PMID- 26029871 TI - An allelic series of miR-17 ~ 92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron. AB - Polycistronic microRNA (miRNA) clusters are a common feature of vertebrate genomes. The coordinated expression of miRNAs belonging to different seed families from a single transcriptional unit suggests functional cooperation, but this hypothesis has not been experimentally tested. Here we report the characterization of an allelic series of genetically engineered mice harboring selective targeted deletions of individual components of the miR-17 ~ 92 cluster. Our results demonstrate the coexistence of functional cooperation and specialization among members of this cluster, identify a previously undescribed function for the miR-17 seed family in controlling axial patterning in vertebrates and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. By integrating phenotypic analysis and gene expression profiling, we provide a genome-wide view of how the components of a polycistronic miRNA cluster affect gene expression in vivo. The reagents and data sets reported here will accelerate exploration of the complex biological functions of this important miRNA cluster. PMID- 26029873 TI - Inhibitors of thermally induced burn incidents - characterization by microbiological procedure, electrophoresis, SEM, DSC and IR spectroscopy. AB - Differential scanning calorimetry (DSC) and thermogravimetric (TGA) investigations, acetate electrophoresis (CAE), Fourier-transform infrared spectrometry (FTIR), scanning electron microscopy (SEM) analysis and microbiological procedures were all carried out after heating the samples to a temperature sufficient for simulating a burn incident. In particular, the purpose of the present study was to analyze the effect of antioxidants, such as fucoidan from brown seaweed and flame-retardant cyclic organophosphates and phosphonates, on an organic chicken skin that gets changed by a burn incident. DSC was considered to be a useful tool in assessing in vitro temperature-mediated cross linking; an innovative analytical conclusion was obtained from the experimentation described in the paper. FTIR tests revealed that heating a dry organic chicken skin to the boiling point leads to the disappearance of a wide band in the 1650-1550 cm(-1) area or the conversion of a band, which may be attributed to the intermolecular beta-sheet aggregates. Fucoidan from brown seaweed and flame-retardant cyclic organophosphates and phosphonates probably bind with the collagen that is changed by the burn (in addition to the influence of antioxidant solutions on samples of a blank or not boiled organic chicken skin) incident forming a polymer film with the collagen of the chicken skin surface (SEM analysis), decreasing the aggregation process and native collagen recovery. Good bacteriostatic properties were determined for fucoidan samples from brown seaweed and flame-retardant cyclic organophosphates and phosphonates against the pathogenic bacteria Escherichia coli and Staphylococcus aureus. Thus, it was observed that the fucoidan incorporated into collagen films can be used as a therapeutically active biomaterial that speeds up the wound-healing process. PMID- 26029874 TI - Heritability of Amyotrophic Lateral Sclerosis: Insights From Disparate Numbers. PMID- 26029872 TI - Trbp regulates heart function through microRNA-mediated Sox6 repression. AB - Cardiomyopathy is associated with altered expression of genes encoding contractile proteins. Here we show that Trbp (Tarbp2), an RNA-binding protein, is required for normal heart function. Cardiac-specific inactivation in mice of Trbp (Trbp(cKO)) caused progressive cardiomyopathy and lethal heart failure. Loss of Trbp function resulted in upregulation of Sox6, repression of genes encoding normal cardiac slow-twitch myofiber proteins and pathologically increased expression of genes encoding skeletal fast-twitch myofiber proteins. Remarkably, knockdown of Sox6 fully rescued the Trbp-mutant phenotype, whereas mice overexpressing Sox6 phenocopied Trbp(cKO) mice. Trbp inactivation was mechanistically linked to Sox6 upregulation through altered processing of miR 208a, which is a direct inhibitor of Sox6. Transgenic overexpression of Mir208a sufficiently repressed Sox6, restored the balance in gene expression for fast- and slow-twitch myofiber proteins, and rescued cardiac function in Trbp(cKO) mice. Together, our studies identify a new Trbp-mediated microRNA-processing mechanism in the regulation of a linear genetic cascade essential for normal heart function. PMID- 26029875 TI - Sequence and organization of the complete mitochondrial genome of Hebius vibakari ruthveni from China. AB - The mitochondrial genome sequence of Hebius vibakari ruthveni is analyzed and presented for the public for the first time. The genome was 17,259 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and 2 control regions. The overall base composition is A (33.9%), C (26.5%), T (26.5%), and G (13.1%). Mitochondrial genomes analyses based on maximum parsimony (MP), neighbor-joining (NJ), and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the 24 Colubridae species. It shows that two major phyletic lineages were present in Colubridae: Hebius and Thamnophis. Hebius comprised 16 species and was supported by bootstrap values of 99%. A clade (H. craspedogaster, H. metusium, H. johannis, H. bitaeniatum and H. octolineatum) as the sister taxon to another clade (H. parallelum, H. khasiense, H. Boulengeri and H. popei) was supported by bootstrap values of 66%. This clade with the H. Atemporale is the sister taxon to H. optatum, H. sauteri, and H. v. ruthveni. PMID- 26029876 TI - Complete mitogenome of two moray eels of Gymnothorax formosus and Scuticaria tigrina (Anguilliformes: Muraenidae). AB - In this study, the complete mitogenome sequence of two moray eels of Gymnothorax formosus and Scuticaria tigrina (Anguilliformes: Muraenidae) has been sequenced by the next-generation sequencing method. The assembled mitogenome, with the length of 16,558 bp for G. formosus and 16,521 bp for S. tigrina, shows 78% identity to each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a non-coding control region of D-loop. The length of D-loop is 927 bp (G. formosus) and 850 bp (S. tigrina), which is located between tRNA-Pro and tRNA-Phe. The overall GC content is 45.5% for G. formosus and 47.9% for S. tigrina. Complete mitogenomes of G. formosus and S. tigrina provide essential and important DNA molecular data for further phylogenetic and evolutionary analysis for moray eel. PMID- 26029877 TI - The mitochondrial genome of Cethosia biblis (Drury) (Lepidoptera: Nymphalidae). AB - We present the complete mitogenome of Cethosia biblis (Drury) (Lepidoptera: Nymphalidae) in this article. The mitogenome was a circle molecular consisting of 15,286 nucleotides, 37 genes, and an A + T-rich region. The order of 37 genes was typical of insect mitochondrial DNA sequences described to date. The overall base composition of the genome is A (37.41%), T (42.80%), C (11.87%), and G (7.91%) with an A + T-rich hallmark as that of other invertebrate mitochondrial genomes. The start codon was mainly ATA in most of the mitochondrial protein-coding genes such as ND2, COI, ATP8, ND3, ND5, ND4, ND6, and ND1, but COII, ATP6, COIII, ND4L, and Cob genes employing ATG. The stop codon was TAA in all the protein-coding genes. The A + T region is located between 12S rRNA and tRNA(M)(et). The phylogenetic relationships of Lepidoptera species were constructed based on the nucleotides sequences of 13 PCGs of mitogenomes using the neighbor-joining method. The molecular-based phylogeny supported the traditional morphological classification on relationships within Lepidoptera species. PMID- 26029878 TI - Phylogenetic analysis of Dipus sagitta and Euchoreutes naso (Rodentia: Dipodidae) based on the mitochondrial genomes. AB - Dipus sagitta and Euchoreutes naso are both monotypic genus, both of them belong to the family of Dipodidae, and E. naso is an Endangered species (EN) defined by the World Conservation Union. The length of its complete mitochondrial sequence of D. sagitta and E. naso is 16,664 bp and 16,705 bp, respectively. Phylogenetic analysis displayed that D. sagitta, Jaculus jaculus, and E. naso were classified into the same cluster. This result was consistent with that of primary morphological taxonomy. The mitochondrial genome of D. sagitta and E. naso would be a key supplement for the gene pool of Rodentia and the conclusion of phylogenetic analysis was an important molecular evidence for the taxonomic status of the two species. PMID- 26029879 TI - The complete mitochondrial genome of the nematode endoparasitic fungus Hirsutella minnesotensis. AB - In this study, the complete mitochondrial genome of a nematode fungal pathogen, Hirsutella minnesotensis, is sequenced. The circular mitogenome of H. minnesotensis is 52,245 bp in length and consists of 2 rRNA, 25 tRNA and 14 standard protein-coding genes of the oxidative phosphorylation system as well as four additional free-standing ORFs encoding for an endonuclease or a hypothetical protein. Seven genes (rnl, cob, cox1, nad3, nad4, nad4L and nad5) are invaded by group I or unclassified introns, and these introns carry ORFs of ribosomal protein S3 and GIY-YIG/LAGLIDADG endonucleases or hypothetical proteins. Evidence of intron degeneration is significant for the nad4L intron and cox1-i1 due to unexpected stop codons and/or frame shifting. Phylogenetic analysis based on concatenated protein sequences confirms H. minnesotensis as a member of the fungal order Hypocreales. In this study, we present the complete mitogenome sequence of H. minnesotensis, which is the first complete mitogenome of the family Ophiocordycipitaceae. PMID- 26029880 TI - Sequencing and analysis of the complete mitochondrial genome of Amur minnow from China. AB - The complete mitogenome sequence of Amur minnow (Rhynchocypris lagowskii) was determined using long PCR. The genome was 16,594 bp in length and contained 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one control region. The overall base composition of the heavy strand is A (28.60%), C (26.32%), T (27.40%), and G (17.68%). The control region was 927 bp in length and the A + T content of the region was 63.32%. The extended termination-associated sequence domain, the central conserved domain, and the conserved sequence block domain are defined in the mitochondrial genome control region of Amur minnow. Mitochondrial genomes analyses based on maximum parsimony (MP), neighbor-joining (NJ), and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the 15 Cyprinidae species. It appeared that no less than two major phyletic lineages were present in Leuciscinae. The main clades within the Leuciscinae supported are: A clade is the Tribolodon. A clade (Rhynchocypris) with the Oreoleuciscus as the sister taxon to Tribolodon was supported by bootstrap values of 49%. The five different geographical populations of the R. lagowskii formed a paraphyletic group with the high bootstrap value (45%) in all examinations. PMID- 26029881 TI - A Decision Support Tool to Reduce Overtesting for Ceruloplasmin and Improve Adherence With Clinical Guidelines. PMID- 26029882 TI - Compliments of confinements: substitution and dimension induced magnetic origin and band-bending mediated photocatalytic enhancements in Bi(1-x)Dy(x)FeO3 particulate and fiber nanostructures. AB - The manifestation of substitution and dimension induced modifications in the magnetic origin and photocatalytic properties of Dy substituted bismuth ferrite (BDFOx) particulate and fiber nanostructures are reported herein. A gradual transformation from rhombohedral to orthorhombic structure is observed in BFO with the increasing concentration of Dy. Substitution induced size reduction in particulate and fiber nanostructures is evident from the scanning and transmission electron micrographs. Energy band structures of both particulate and fiber nanostructures are considerably influenced by the Dy substitution, which is ascribed to the formation of new energy states underneath the conduction band of host BFO. Field dependent and temperature dependent magnetic studies reveal that the origin of magnetism in pure BFO systems is due to the antiferromagnetic core/ferromagnetic-shell like structure. On the other hand, it gets completely switched into 'canted' spin structures due to the substitution induced suppression of cycloidal spins in BFO, which is found to be the origin of magnetism in BDFOx particulate and fiber nanostructures. The visible light driven photocatalytic activity of BDFOx nanostructures is found to be enhanced with increasing concentration of Dy. Substitution induced band gap modification, semiconductor band bending phenomenon mediated charge transfer and reduced recombination resistances are attributed to the observed photocatalytic enhancements in these nanostructures. PMID- 26029883 TI - Unraveling the effect of polymer dots doping in inverted low bandgap organic solar cells. AB - In this study, molecular doping with polymer dots was designed to unravel its effect on the photoconductivity in organic solar cells. The photocurrent in organic solar cells exhibited a considerable increase under optimal doping concentration, leading to an ultimate enhancement of power conversion efficiency from 2.30% to 3.64%. This can be attributed primarily to the improvement of the initial boost in charge carriers due to the background carriers induced by the polymer dots and increased tail absorption by the active layer. Based on single carrier device and impedance measurements, polymer dopant can efficiently decrease charge recombination and improve charge carriers mobilities. The obtained achievements pave an approach of molecular doping in affecting the operation of organic solar cells. PMID- 26029884 TI - Theory of Brushes Formed by Psi-Shaped Macromolecules at Solid-Liquid Interfaces. AB - We present a theoretical analysis targeted to describe the structural properties of brushes formed by Psi-shaped macromolecules tethered by terminal segment of stem to planar surface while exposing multiple free branches to the surrounding solution. We use an analytical self-consistent field approach based on the strong stretching approximation, and the assumption of Gaussian elasticity for linear chain fragments of the tethered macromolecules. The effect of weak and strong polydispersity of branches is analyzed. In the case of weakly polydisperse macromolecules, variations in length of branches lead to a more uniform polymer density distribution with slight increase in the brush thickness compared to the case of monodisperse chains with the same degree of polymerization. We demonstrate that in contrast to linear chains, strong polydispersity of Psi shaped macromolecules does not necessarily lead to strong perturbations in polymer density distribution. In particular, mixed brushes of the so-called "mirror" dendrons (in which number of stem monomers in one component coincides with number of monomers in a branch of the other component, and vice versa) give rise to a unified polymer density distribution with shape independent of the brush composition. The predictions of analytical theory are systematically compared to the results of numerical self-consistent field modeling based on the Scheutjens-Fleer approach. PMID- 26029885 TI - En face imaging of posterior precortical vitreous pockets using swept-source optical coherence tomography. AB - PURPOSE: To obtain sequential flat (en face) images of posterior precortical vitreous pockets (PPVPs) using swept-source optical coherence tomography (SS OCT). METHODS: We performed SS-OCT in the right eyes of 112 volunteers (mean age, 30.1 years; mean refraction, -2.5 diopters) while sitting using 12-mm horizontal, vertical scans of the 12- * 9-mm plane * 2.6-mm depth through the macula and optic disc. En face images of the posterior vitreous were obtained by En-View, a SS-OCT program. RESULTS: Swept-source OCT visualized the PPVPs and Cloquet's canals in all subjects; the PPVPs appeared as boat-shaped lacunae in the horizontal scan and extended superiorly as clefts in the vertical scan. En face imaging showed PPVPs and Cloquet's canals as two oval lacunae near the vitreoretinal interface and a septum between the nasal border of the PPVPs and Cloquet's canals. In all cases, the lacunas of the PPVPs were larger than those of Cloquet's canals. In 99 (88.4%) of 112 eyes, the PPVPs and Cloquet's canals were fused by connecting channels. The mean width of the connecting channels was 920.2 +/- 37.4 MUm, and the mean height was 288.6 +/- 20.0 MUm. On the anterior en face images, the PPVPs became crescent-shaped in all eyes. CONCLUSIONS: Using SS-OCT, we obtained en face images of PPVPs and Cloquet's canals in vivo. The en face images of the PPVPs near the retina showed oval shapes that changed to crescents, which corresponded to the superior edge of the PPVPs. The PPVPs were fused with Cloquet's canal by a flat-shaped connecting channel. PMID- 26029886 TI - Flicker adaptation desensitizes the magnocellular but not the parvocellular pathway. AB - PURPOSE: Anatomical and physiological studies show that in primates, visual information is conveyed through two parallel pathways, including the magnocellular (MC-) and parvocellular (PC-) pathways. However, the functional separation between the two pathways remains controversial and challenging. To resolve this, we show a psychophysical approach to desensitize the inferred MC pathway of human observers independently of the inferred PC-pathway. METHODS: The steady-pedestal and pulsed-pedestal paradigms that allow detection and discrimination to be mediated by only the inferred MC- or PC-pathway were used. Three observers (one male, aged 43 years, and two females, aged 33 and 62 years) adapted to either a steadily presented pedestal or a 2- or 10-Hz 50% contrast square-wave modulated luminance flicker. Contrast discrimination thresholds were measured following the flicker adaptation. RESULTS: Flicker adaptation reduces contrast detection and discrimination of the MC-pathway but not the PC-pathway, with larger MC losses from 10-Hz (~ 0.28 log unit loss, P < 0.05 for all observers) than 2-Hz flicker (~ 0.13 log unit loss, P < 0.05 for one or two observers depending on stimulus size). Further, our results show that the PC pathway does not mediate the contrast detection threshold at the background luminance following MC-pathway desensitization. CONCLUSIONS: This study demonstrates the feasibility of independently manipulating sensitivity of the MC pathway in human observers. Our paradigms provide powerful tools to independently investigate the perceptual functions in the MC- and PC-pathways. This could lead to a better understanding of the perceptual functions of these pathways. PMID- 26029887 TI - Development of congenital stromal corneal dystrophy is dependent on export and extracellular deposition of truncated decorin. AB - PURPOSE: Congenital stromal corneal dystrophy (CSCD) is an autosomal dominant condition with clouding of the cornea due to stromal opacities. It is caused by mutations in the decorin gene (DCN) leading to the expression of a truncated form of decorin. In an attempt to replicate this condition in mice, a knock-in mouse strain, 952delT Dcn, was created. METHODS: Mice were constructed by targeted mutation. Sequencing of genomic DNA confirmed correct genotype. Mouse and human corneas, including corneas from patients with CSCD, and primary keratocyte cultures were subjected to Western blot analysis, transmission electron microscopy, and immunofluorescence microscopy. RESULTS: Histologically, the mice did not show any organ pathology. Corneas were clear, and the electron-lucent deposits observed in CSCD were not present. Furthermore, while nearly equivalent amounts of normal and truncated decorin are present in CSCD corneas, truncated decorin was hardly detectable in the mouse corneas. By immunofluorescence analysis of corneas from 952delT Dcn homozygous mice, decorin was found only in keratocytes. In primary cultures of mouse corneal explants, truncated decorin was retained intracellularly in contrast with human corneal explants where truncated decorin was exported into the culture medium. Immunofluorescence analysis revealed that native mouse decorin localized to the Golgi complex, whereas the truncated decorin accumulated in the endoplasmic reticulum (ER). CONCLUSIONS: The ER retention of truncated decorin may explain why the mouse corneas remained clear. The consequences of the decorin mutation are different in mice and humans, and 952delT Dcn knock-in mice are therefore not a suitable model for CSCD. PMID- 26029889 TI - Salvage of a Live-Related Transplant Kidney Using an Interposition Polytetrafluoroethylene Vascular Graft: A Unique Case. AB - We describe a case of polytetrafluoroethylene vascular graft interposition between the internal iliac artery and the renal artery in a live-related kidney transplant. To the best of our knowledge, we present the first case in the literature that describes the salvage of a transplant kidney using this technique. PMID- 26029888 TI - Wnt/beta-Catenin Signaling Regulates the Expression of the Ammonium Permease Gene RHBG in Human Cancer Cells. AB - Ammonium is a metabolic waste product mainly detoxified by the liver. Hepatic dysfunction can lead to cytotoxic accumulation of circulating ammonium and to subsequent encephalopathy. Transmembrane ammonium transport is a widely spread process ensured by the highly conserved proteins of the Mep-Amt-Rh superfamily, including the mammalian Rhesus (Rh) factors. The regulatory mechanisms involved in the control of RH genes expression remain poorly studied. Here we addressed the expression regulation of one of these factors, RHBG. We identify HepG2 hepatocellular carcinoma cells and SW480 colon adenocarcinoma cells as expressing RHBG and show that its expression relies on beta-catenin signaling. siRNA mediated beta-catenin knockdown resulted in significant reduction of RHBG mRNA in both cell lines. Pharmaceutical inhibition of the TCF4/beta-catenin interaction or knockdown of the transcription factor TCF4 also downregulated RHBG expression. We identify a minimal RHBG regulatory sequence displaying a promoter activity and show that beta-catenin and TCF4 bind to this fragment in vivo. We finally characterize the role of potential TCF4 binding sites in RHBG regulation. Taken together, our results indicate RHBG expression as a direct target of beta-catenin regulation, a pathway frequently deregulated in many cancers and associated with tumorigenesis. PMID- 26029890 TI - Cost-Effective Large-Scale Occupancy-Abundance Monitoring of Invasive Brushtail Possums (Trichosurus Vulpecula) on New Zealand's Public Conservation Land. AB - There is interest in large-scale and unbiased monitoring of biodiversity status and trend, but there are few published examples of such monitoring being implemented. The New Zealand Department of Conservation is implementing a monitoring program that involves sampling selected biota at the vertices of an 8 km grid superimposed over the 8.6 million hectares of public conservation land that it manages. The introduced brushtail possum (Trichosurus Vulpecula) is a major threat to some biota and is one taxon that they wish to monitor and report on. A pilot study revealed that the traditional method of monitoring possums using leg-hold traps set for two nights, termed the Trap Catch Index, was a constraint on the cost and logistical feasibility of the monitoring program. A phased implementation of the monitoring program was therefore conducted to collect data for evaluating the trade-off between possum occupancy-abundance estimates and the costs of sampling for one night rather than two nights. Reducing trapping effort from two nights to one night along four trap-lines reduced the estimated costs of monitoring by 5.8% due to savings in labour, food and allowances; it had a negligible effect on estimated national possum occupancy but resulted in slightly higher and less precise estimates of relative possum abundance. Monitoring possums for one night rather than two nights would provide an annual saving of NZ$72,400, with 271 fewer field days required for sampling. Possums occupied 60% (95% credible interval; 53-68) of sampling locations on New Zealand's public conservation land, with a mean relative abundance (Trap Catch Index) of 2.7% (2.0-3.5). Possum occupancy and abundance were higher in forest than in non-forest habitats. Our case study illustrates the need to evaluate relationships between sampling design, cost, and occupancy-abundance estimates when designing and implementing large-scale occupancy-abundance monitoring programs. PMID- 26029891 TI - Relevance and Effectiveness of the WHO Global Code Practice on the International Recruitment of Health Personnel--Ethical and Systems Perspectives. AB - The relevance and effectiveness of the World Health Organization's (WHO's) Global Code of Practice on the International Recruitment of Health Personnel is being reviewed in 2015. The Code, which is a set of ethical norms and principles adopted by the World Health Assembly (WHA) in 2010, urges members states to train and retain the health personnel they need, thereby limiting demand for international migration, especially from the under-staffed health systems in low- and middle-income countries. Most countries failed to submit a first report in 2012 on implementation of the Code, including those source countries whose health systems are most under threat from the recruitment of their doctors and nurses, often to work in 4 major destination countries: the United States, United Kingdom, Canada and Australia. Political commitment by source country Ministers of Health needs to have been achieved at the May 2015 WHA to ensure better reporting by these countries on Code implementation for it to be effective. This paper uses ethics and health systems perspectives to analyse some of the drivers of international recruitment. The balance of competing ethics principles, which are contained in the Code's articles, reflects a tension that was evident during the drafting of the Code between 2007 and 2010. In 2007-2008, the right of health personnel to migrate was seen as a preeminent principle by US representatives on the Global Council which co-drafted the Code. Consensus on how to balance competing ethical principles--giving due recognition on the one hand to the obligations of health workers to the countries that trained them and the need for distributive justice given the global inequities of health workforce distribution in relation to need, and the right to migrate on the other hand--was only possible after President Obama took office in January 2009. It is in the interests of all countries to implement the Global Code and not just those that are losing their health personnel through international recruitment, given that it calls on all member states "to educate, retain and sustain a health workforce that is appropriate for their (need) ..." (Article 5.4), to ensure health systems' sustainability. However, in some wealthy destination countries, this means tackling national inequities and poorly designed health workforce strategies that result in foreign-trained doctors being recruited to work among disadvantaged populations and in primary care settings, allowing domestically trained doctors work in more attractive hospital settings. PMID- 26029892 TI - Global health diplomacy, national integration, and regional development through the monitoring and evaluation of HIV/AIDS programs in Papua New Guinea, Vanuatu, and Samoa. AB - The South Pacific countries of Vanuatu, Samoa, and Papua New Guinea have ascended rapidly up the development spectrum in recent years, refining an independent and post-colonial economic and political identity that enhances their recognition on the world stage. All three countries have overcome economic, political and public health challenges in order to stake their claim to sovereignty. In this regard, the contributions of national and international programs for the diagnosis, treatment and prevention of HIV/AIDS, with specific reference to their monitoring and evaluation (M&E) aspects, have contributed not just to public health, but also to broader political and diplomatic goals such as 'nation-building'. This perspective describes the specific contributions of global health programs to the pursuit of national integration, development, and regional international relations, in Vanuatu, Samoa and Papua New Guinea, respectively, based on in country M&E activities on behalf of the Global Fund to Fight AIDS, Tuberculosis (TB) and Malaria and the Australian Department of Foreign Affairs and Trade (DFAT) during 2014 and 2015. Key findings include: (1) that global health programs contribute to non-health goals; (2) that HIV/AIDS programs promote international relations, decentralized development, and internal unity; (3) that arguments in favour of the maintenance and augmentation of global health funding may be enhanced on this basis; and (4) that "smart" global health approaches have been successful in South Pacific countries. PMID- 26029893 TI - Oral hygiene status in a general population of Iran, 2011: a key lifestyle marker in relation to common risk factors of non-communicable diseases. AB - BACKGROUND: To estimate Oral Hygiene (OH) status in the Iranian population in 2011, and to determine the influence of socio-economic characteristics on OH, and its interrelation with common risk factors of Non-Communicable Diseases (NCDs). METHODS: Data including a total of 12,105 individuals aged 6-70 years were obtained from the sixth round of the surveys of NCDs risk factors in Iran. OH was recorded through a structured questionnaire measuring daily frequencies of tooth brushing and dental flossing. Descriptive analyses were performed on demographic characteristics in the complex sample survey setting. We also employed weighted binary logistic regression to compute Odds Ratio (OR) as a measure of association between the response and explanatory factors. Furthermore, to construct an asset index, we utilized Principal Component Analysis (PCA). RESULTS: The percentage with minimum recommended daily OH practices was 3.7% among men and 7.7% among women (OR= 2.3; P<0.001). Urban citizens were more likely to have their teeth cleaned compared to rural people (OR= 2.8; P<0.001). For both genders, a relatively better condition was observed in the 25-34 age group (male: 5.6%; female: 10.3%). In addition, OH status improved significantly by increase in both level of education (P<0.001) and economic status (P<0.001). There were also apparent associations between self-care practices and specific behavioral risk factors, though the correlation with dietary habits and tobacco use could be largely explained by socio-economic factors. CONCLUSION: OH situation in Iran calls for urgent need to assign proper interventions and strategies toward raising public awareness and reducing disparities in access to health facilities. PMID- 26029894 TI - Implementation of a health management mentoring program: year-1 evaluation of its impact on health system strengthening in Zambezia Province, Mozambique. AB - BACKGROUND: Avante Zambezia is an initiative of a Non-Governmental Organization (NGO), Friends in Global Health, LLC (FGH) and the Vanderbilt Institute for Global Health (VIGH) to provide technical assistance to the Mozambican Ministry of Health (MoH) in rural Zambezia Province. Avante Zambezia developed a district level Health Management Mentorship (HMM) program to strengthen health systems in ten of Zambezia's 17 districts. Our objective was to preliminarily analyze changes in four domains of health system capacity after the HMM's first year: accounting, Human Resources (HRs), Monitoring and Evaluation (M&E), and transportation management. METHODS: Quantitative metrics were developed in each domain. During district visits for weeklong, on-site mentoring, the health management mentoring teams documented each indicator as a success ratio percentage. We analyzed data using linear regressions of each indicator's mean success ratio across all districts submitting a report over time. RESULTS: Of the four domains, district performance in the accounting domain was the strongest and most sustained. Linear regressions of mean monthly compliance for HR objectives indicated improvement in three of six mean success ratios. The M&E capacity domain showed the least overall improvement. The one indicator analyzed for transportation management suggested progress. CONCLUSION: Our outcome evaluation demonstrates improvement in health system performance during a HMM initiative. Evaluating which elements of our mentoring program are succeeding in strengthening district level health systems is vital in preparing to transition fiscal and managerial responsibility to local authorities. PMID- 26029895 TI - Regional incentives and patient cross-border mobility: evidence from the Italian experience. AB - BACKGROUND: In recent years, accreditation of private hospitals followed by decentralisation of the Italian National Health Service (NHS) into 21 regional health systems has provided a good empirical ground for investigating the Tiebout principle of "voting with their feet". We examine the infra-regional trade-off between greater patient choice (due to an increase in hospital services supply) and financial equilibrium, and we relate it to the significant phenomenon of Cross-Border Mobility (CBM) between Italian regions. Focusing on the rules supervising the financial agreements between regional authorities and providers of hospital care, we find incentives for private accredited providers in attracting patient inflows. METHODS: The analysis is undertaken from an institutional, regulatory and empirical perspective. We select a sample of five regions with higher positive CBM balance and we examine regional regulations governing the contractual agreements between purchasers and providers of hospital care. According to this sample, we provide a statistical analysis of CBM and apply a Regional Attraction Ability Index (RAAI), aimed at testing patient preferences for private/public accredited providers. RESULTS: We find that this index is systematically higher for private providers, both in the case of distance/boundary patients and of excellence/general hospitals. CONCLUSION: Conclusions address both financial issues regarding the coverage of regional healthcare systems and equity issues on patient healthcare access. They also raise concerns on the new European Union (EU) directive inherent to patient mobility across Europe. PMID- 26029896 TI - Examining the potential role of a supervised injection facility in Saskatoon, Saskatchewan, to avert HIV among people who inject drugs. AB - BACKGROUND: Research predicting the public health and fiscal impact of Supervised Injection Facilities (SIFs), across different cities in Canada, has reported positive results on the reduction of HIV cases among People Who Inject Drugs (PWID). Most of the existing studies have focused on the outcomes of Insite, located in the Vancouver Downtown Eastside (DTES). Previous attention has not been afforded to other affected areas of Canada. The current study seeks to address this deficiency by assessing the cost-effectiveness of opening a SIF in Saskatoon, Saskatchewan. METHODS: We used two different mathematical models commonly used in the literature, including sensitivity analyses, to estimate the number of HIV infections averted due to the establishment of a SIF in the city of Saskatoon, Saskatchewan. RESULTS: Based on cumulative cost-effectiveness results, SIF establishment is cost-effective. The benefit to cost ratio was conservatively estimated to be 1.35 for the first two potential facilities. The study relied on 34% and 14% needle sharing rates for sensitivity analyses. The result for both sensitivity analyses and the base line estimates indicated positive prospects for the establishment of a SIF in Saskatoon. CONCLUSION: The opening of a SIF in Saskatoon, Saskatchewan is financially prudent in the reduction of tax payers' expenses and averting HIV infection rates among PWID. PMID- 26029897 TI - Strengthening core public health capacity based on the implementation of the International Health Regulations (IHR) (2005): Chinese lessons. AB - As an international legal instrument, the International Health Regulations (IHR) is internationally binding in 196 countries, especially in all the member states of the World Health Organization (WHO). The IHR aims to prevent, protect against, control, and respond to the international spread of disease and aims to cut out unnecessary interruptions to traffic and trade. To meet IHR requirements, countries need to improve capacity construction by developing, strengthening, and maintaining core response capacities for public health risk and Public Health Emergency of International Concern (PHEIC). In addition, all the related core capacity requirements should be met before June 15, 2012. If not, then the deadline can be extended until 2016 upon request by countries. China has promoted the implementation of the IHR comprehensively, continuingly strengthening the core public health capacity and advancing in core public health emergency capacity building, points of entry capacity building, as well as risk prevention and control of biological events (infectious diseases, zoonotic diseases, and food safety), radiological, nuclear, and chemical events, and other catastrophic events. With significant progress in core capacity building, China has dealt with many public health emergencies successfully, ensuring that its core public health capacity has met the IHR requirements, which was reported to WHO in June 2014. This article describes the steps, measures, and related experiences in the implementation of IHR in China. PMID- 26029898 TI - Diffusion of innovation in mental health policy adoption: what should we ask about the quality of policy and the role of stakeholders in this process? Comment on "Cross-national diffusion of mental health policy". AB - In his recent study, Gordon Shen analyses a pertinent question facing the global mental health research and practice community today; that of how and why mental health policy is or is not adopted by national governments. This study identifies becoming a World Health Organization (WHO) member nation, and being in regional proximity to countries which have adopted a mental health policy as supportive of mental health policy adoption, but no support for its hypothesis that country recipients of higher levels of aid would have adopted a mental health policy due to conditionalities imposed on aid recipients by donors. Asking further questions of each may help to understand more not only about how and why mental health policies may be adopted, but also about the relevance and quality of implementation of these policies and the role of specific actors in achieving adoption and implementation of high quality mental health policies. PMID- 26029899 TI - Health Policy and Management: in praise of political science. Comment on "On Health Policy and Management (HPAM): mind the theory-policy-practice gap". AB - Health systems have entered a third era embracing whole systems thinking and posing complex policy and management challenges. Understanding how such systems work and agreeing what needs to be put in place to enable them to undergo effective and sustainable change are more pressing issues than ever for policy makers. The theory-policy-practice-gap and its four dimensions, as articulated by Chinitz and Rodwin, is acknowledged. It is suggested that insights derived from political science can both enrich our understanding of the gap and suggest what changes are needed to tackle the complex challenges facing health systems. PMID- 26029900 TI - Your call could not be completed as dialled: why truth does not speak to power in global health. Comment on "Knowledge, moral claims and the exercise of power in global health". AB - This article contends that legitimacy in the exercise of power comes from the consent of those subject to it. In global health, this implies that the participation of poor country citizens is required for the legitimacy of major actors and institutions. But a review of institutions and processes suggests that this participation is limited or absent. Particularly because of the complex political economy of non-communicable diseases, this participation is essential to the future advancement of global health and the legitimacy of its institutions. More analysis of power and legitimacy provides one entry point for fostering progress. PMID- 26029901 TI - Morality and values in support of universal healthcare must be enshrined in law. Comment on "Morality and Markets in the NHS". AB - This is a commentary on Gilbert and colleagues' (1) paper on morality and markets in the National Health Service (NHS). Morality and values are not ephemeral qualities and universal healthcare is not simply an aspiration; it has to be enshrined in law. The creation of the UK NHS in 1948 was underpinned by core legal duties which required a system of public funding and delivery to follow. The moral values of the citizens in support of social solidarity were thus transformed into a political and legal contract for citizens. The NHS still survives in Scotland, Wales and Northern Ireland but the coalition government abolished it in England in 2012, reducing the NHS to a funding stream, a logo and a set of market regulators. This paper describes and explains the Health and Social Care (HSC) Act 2012 in England and how the NHS is withering away and health services are being remodeled along US Health Maintenance Organization (HMO) lines. There was nothing moral about this extraordinary act of savagery and violence against the public in England, and against common values and widely held beliefs in public ownership funding and provision of universal healthcare. The public health consequences will be catastrophic which is why after the election on May seventh a new Bill is required to Reinstate the NHS and the Secretary of State's legal duty to provide listed health services throughout England. PMID- 26029902 TI - Untimely applause was a distraction. Comment on "Shanghai rising: health improvements as measured by avoidable mortality since 2000". AB - The paper published in the January 2015 issue of this journal by Gusmano and colleagues entitled "Shanghai rising: health improvements as measured by avoidable mortality since 2000" has spurred this commentary. We discuss controversial issues surrounding the concept of avoidable mortality in health service research in general and Gusmano's study in particular. The impact of overall social development on mortality may be underappreciated in Gusmano's report; the innovative efforts of healthcare professionals to use cutting-edge technology and evidence-approved preventive strategies to reduce healthcare cost and improve the life quality of community members may not necessarily come to fruition in death reduction, and might be undervalued, too. More critically, the shape and magnitude of emerging health issues in Shanghai, such as accidents and injuries, pollution-related cancers, may be camouflaged in Gusmano's report. We conclude this commentary by suggesting the most urgent questions to be addressed in the future studies. PMID- 26029903 TI - NHS values, compassion and quality indicators for relationship based person centred healthcare. Comment on "Morality and markets in the NHS". AB - The paper by Gilbert et al. should be on the table of every politician and National Health Service (NHS) manager in the run up to the general election, when the NHS is at the hustings. They have raised profound moral dilemmas of the internal and external market in their present form, such as the practicalities of distributive justice and the enhancement of autonomy--to which are added the preservation of personhood, the values of listening, the maintenance of altruism and the origins of compassion. It is asserted that the quality of healthcare is dependent on the quality of the caring relationship between healthcare staff members, and between staff and patients. The nature of Compassionate Resilience is outlined with respect to Health Visitor training--and the contribution of faith communities to public health is also considered. The four Quality Indicators of an enabling environment first proposed by Cox and Gray are summarised, and the need for increased conceptual clarity of these key values recognised. PMID- 26029904 TI - Morality not markets: a manifesto for the NHS; Response to Pollock, Frith, and Cox. PMID- 26029905 TI - Contrast Enhancement of the Right Ventricle during Coronary CT Angiography--Is It Necessary? AB - PURPOSE: It is unclear if prolonged contrast media injection, to improve right ventricular visualization during coronary CT angiography, leads to increased detection of right ventricle pathology. The purpose of this study was to evaluate right ventricle enhancement and subsequent detection of right ventricle disease during coronary CT angiography. MATERIALS AND METHODS: 472 consecutive patients referred for screening coronary CT angiography were retrospectively evaluated. Every patient underwent multidetector-row CT of the coronary arteries: 128x 0.6mm coll., 100-120kV, rot. time 0.28s, ref. mAs 350 and received an individualized (P3T) contrast bolus injection of iodinated contrast medium (300 mgI/ml). Patient data were analyzed to assess right ventricle enhancement (HU) and right ventricle pathology. Image quality was defined good when right ventricle enhancement >200HU, moderate when 140-200HU and poor when <140HU. RESULTS: Good image quality was found in 372 patients, moderate in 80 patients and poor in 20 patients. Mean enhancement of the right ventricle cavity was 268HU+/-102. Patients received an average bolus of 108+/-24 ml at an average peak flow rate of 6.1+/-2.2 ml/s. In only three out of 472 patients (0.63%) pathology of the right ventricle was found (dilatation) No other right ventricle pathology was detected. CONCLUSION: Right ventricle pathology was detected in three out of 472 patients; the dilatation observed in these three cases may have been picked up even without dedicated enhancement of the right ventricle. Based on our findings, right ventricle enhancement can be omitted during screening coronary CT angiography. PMID- 26029907 TI - Carotid atherosclerotic disease predicts cardiovascular events in hemodialysis patients: a prospective study. AB - BACKGROUND: To evaluate the predictive value of carotid atherosclerotic disease (CAD) and intima-media thickness (IMT) on incident cardiovascular disease and mortality in hemodialysis patients. METHODS: Multicenter, observational, prospective study including 110 patients, followed-up to 6 years. Carotid doppler ultrasonographic findings were classified in 4 degrees of severity: 1) IMT <0.9 mm, 2) IMT >0.9 mm, 3) carotid plaque with stenosis <50% and 4) plaque with stenosis >50%. The associations between IMT and CAD and cardiovascular events, total and cardiovascular mortality were assessed. RESULTS: 83% of the patients had atherosclerotic plaques (CAD degrees 3-4). During follow-up, 29.1% of patients experienced cardiovascular events, and 28.2% died, 38.7% of cardiovascular origin. The presence of plaques was associated with cardiovascular events (p = 0.03) while calcified plaques were associated with both cardiovascular events (p = 0.01), cardiovascular mortality (p = 0.03) and non significantly with overall mortality (p = 0.08) in the survival analysis. Carotid IMT was not associated with outcomes. Cardiovascular events correlated with CAD severity (HR 2.27, 95% CI 1.13-4.54), age (HR 1.04, 1.01-1.06), previous cardiovascular disease (HR 1.75, 1.05-4.42), dyslipidemia (HR 2.25, 1.11-4.53), lipoprotein (a) (HR 1.01, 1.00-1.02), troponin I (HR 3.89, 1.07-14.18), fibrinogen levels (HR 1.38, 0.98-1.94) and antiplatelet therapy (HR 2.14, 1.04 4.4). In an age-adjusted multivariate model, cardiovascular events were independently associated with previous coronary artery disease (HR 3.29, 1.52 7.15) and lipoprotein (a) (HR 1.01, 1.00-1.02). CONCLUSIONS: The presence of carotid plaques and, especially, calcified plaques, are predictors of new cardiovascular events and cardiovascular mortality in hemodialysis patients, while IMT was not. The prognostic value of calcified plaques should be confirmed in future studies. PMID- 26029906 TI - Endogenous opioid antagonism in physiological experimental pain models: a systematic review. AB - Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using 'inhibitory' or 'sensitizing', physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized 'inhibitory' test paradigms (ITP) and 38 studies utilized 'sensitizing' test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), 'pain' models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 'pain' model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR antagonist demonstrated a consistent effect, presumably mediated by an EOS dependent mechanisms of analgesia and hyperalgesia. PMID- 26029908 TI - Anterior segment neovascularization in diabetic retinopathy: a masquerade. AB - PURPOSE: Anterior segment neovascularization (ASNV) could be a masquerade for ocular ischemic syndrome (OIS) in diabetic patients which misleads diagnosis and treatment. The purpose of our study is to find the relationship between blood flow velocity in carotid siphon and the development of ASNV in diabetic. METHODS: We reviewed 34 eyes of 17 diabetic patients who had Transcranial Color Doppler (TCD) examination with unilateral ASNV. The circulatory parameters of both eyes of each patient were compared and analyzed. In addition, 9 patients with more than 50% stenosis of extracranial internal carotid artery (ICA) and low velocity flow through TCD had been treated by carotid revascularization surgery. RESULTS: The maximal velocity in systole (Vmax) of carotid siphon (SCA) was lower in the eyes with ASNV than in the eyes without ASNV (P<0.05). ASNV of all the 9 patients regressed totally and BCVA improved significantly (P<0.05). Stenosis of ICA and arm-retina time (ART) decreased significantly (P<0.01) and SCA and ophthalmic artery (OA) increased significantly (P<0.01). CONCLUSIONS: Our study showed ASNV could be a masquerade for OIS in patients with diabetic retinopathy. The decreased blood flow velocity in carotid siphon is related to the development of ASNV. Circulatory parameters screening of SCA by TCD is important to help us to evaluate the blood flow in SCA, the possibility of development of ASNV, and the prognosis of the patient. Interference such as carotid endarterectomy (CEA) or carotid artery stenting (CAS) can be performed if necessary to improve the blood flow in SCA and make ASNV regression. PMID- 26029909 TI - Canonical discrimination of the effect of a new broiler production facility on soil chemical profiles as related to current management practices. AB - The effect dirt-floored broiler houses have on the underlying native soil, and the potential for contamination of the ground water by leaching under the foundation, is an understudied area. This study examines alterations in fifteen quantitative soil parameters (Ca, Cu, electrical conductivity, Fe, K, Mg, Mn, Na, NO3, organic matter, P, pH, S, soil moisture and Zn) in the underlayment of a newly constructed dirt-floored broiler house over the first two years of production (Native through Flock 11). The experiment was conducted near NW Robertson County, Texas, where the native soil is a fine, smectitic thermic Udertic Paleustalfs and the slopes range from zero to three percent. Multiple samples were collected from under each of three water and three feed lines the length of the house, in a longitudinal study during February 2008 through August 2010. To better define the relationship between the soil parameters and sampling times, a canonical discriminant analysis approach was used. The soil profiles assembled into five distinctive clusters corresponding to time and management practices. Results of this work revealed that the majority of parameters increased over time. The management practices of partial and total house clean outs markedly altered soil profiles the house underlayment, thus reducing the risk of infiltration into the ground water near the farm. This is important as most broiler farms consist of several houses within a small area, so the cumulative ecological impact could be substantial if not properly managed. PMID- 26029910 TI - Molecular characteristics of extended-spectrum cephalosporin-resistant Enterobacteriaceae from humans in the community. AB - OBJECTIVE: To investigate the molecular characteristics of extended-spectrum cephalosporin (ESC)-resistant Enterobacteriaceae collected during a cross sectional study examining the prevalence and risk factors for faecal carriage of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in humans living in areas with high or low broiler density. METHODS: ESC-resistant Enterobacteriaceae were identified by combination disc-diffusion test. ESBL/AmpC/carbapenemase genes were analysed using PCR and sequencing. For E. coli, phylogenetic groups and MLST were determined. Plasmids were characterized by transformation and PCR-based replicon typing. Subtyping of plasmids was done by plasmid multilocus sequence typing. RESULTS: 175 ESC-resistant Enterobacteriaceae were cultured from 165/1,033 individuals. The isolates were Escherichia coli(n=65), Citrobacter freundii (n=52), Enterobacter cloacae (n=38), Morganella morganii (n=5), Enterobacter aerogenes (n=4), Klebsiella pneumoniae (n=3), Hafnia alvei (n=2), Shigella spp. (n=2), Citrobacter amalonaticus (n=1), Escherichia hermannii (n=1), Kluyvera cryocrescens (n=1), and Pantoea agglomerans (n=1). The following ESBL genes were recovered in 55 isolates originating from 49 of 1,033 (4.7 %) persons: blaCTX-M-1 (n=17), blaCTX-M-15 (n=16), blaCTX-M-14 (n=9), blaCTX-M-2 (n=3), blaCTX-M-3 (n=2), blaCTX-M-24 (n=2), blaCTX-M-27 (n=1), blaCTX-M-32 (n=1), blaSHV-12 (n=2), blaSHV-65 (n=1) and blaTEM-52 (n=1). Plasmidic AmpC (pAmpC) genes were discovered in 6 out of 1,033 (0.6 %) persons. One person carried two different E. coli isolates, one with blaCTX-M-1 and the other with blaCMY-2 and therefore the prevalence of persons carrying Enterobacteriaceae harboring ESBL and/or pAmpC genes was 5.2 %. In eight E. coli isolates the AmpC phenotype was caused by mutations in the AmpC promoter region. No carbapenemase genes were identified. A large variety of E. coli genotypes was found, ST131 and ST10 being most common. CONCLUSIONS: ESBL/pAmpC genes resembled those from patients in Dutch hospitals, indicating that healthy humans form a reservoir for transmission of these determinants to vulnerable people. The role of poultry in the transmission to humans in the community remains to be elucidated. PMID- 26029911 TI - Depression among Asian-American Adults in the Community: Systematic Review and Meta-Analysis. AB - OBJECTIVES: In this systematic review, we provide an overview of the literature on depression among Asian-Americans and explore the possible variations in depression prevalence estimates by methodological and demographic factors. METHODS: Six databases were used to identify studies reporting a prevalence estimate for depression in Asian-American adults in non-clinical settings. Meta analysis was used to calculate pooled estimates of rates of depression by assessment type. Statistical heterogeneity was assessed for subgroup analyses by gender, age, ethnicity, and other participant characteristics. RESULTS: A total of 58 studies met the review criteria (n = 21.731 Asian-American adults). Heterogeneity across the studies was considerably high. The prevalence of major depression assessed via standardized clinical interviews ranged between 4.5% and 11.3%. Meta-analyses revealed comparable estimated prevalence rates of depression as measured by the Center for Epidemiologic Studies Depression Scale (35.6%, 95% CI 27.6%-43.7%) and the Geriatric Depression Scale (33.1%, 95% CI 14.9%-51.3%). Estimates varied by Asian racial/ethnic group and other participant characteristics. Estimates of depression among special populations, which included maternity, caregivers, and homosexuals, were significantly higher than estimates obtained from other samples (58.8% vs 29.3%, p = .003). Estimates of depression among Korean and Filipino-Americans were similar (33.3%-34.4%); however, the estimates were twice as high as those for Chinese-Americans (15.7%; p = .012 for Korean, p = .049 for Filipino). CONCLUSION: There appears to be wide variability in the prevalence rates of depression among Asian-Americans in the US. Practitioners and researchers who serve Asian-American adults need to be sensitive to the potential diversity of the expression of depression and treatment-seeking across Asian-American subgroups. Public health policies to increase Asian-American access to mental health care, including increased screening, are necessary. Further work is needed to determine whether strategies to reduce depression among specific Asian racial/ethnic groups is warranted. PMID- 26029912 TI - Breast tissue composition and its dependence on demographic risk factors for breast cancer: non-invasive assessment by time domain diffuse optical spectroscopy. AB - BACKGROUND: Breast tissue composition is recognized as a strong and independent risk factor for breast cancer. It is a heritable feature, but is also significantly affected by several other elements (e.g., age, menopause). Nowadays it is quantified by mammographic density, thus requiring the use of ionizing radiation. Optical techniques are absolutely non-invasive and have already proved effective in the investigation of biological tissues, as they are sensitive to tissue composition and structure. METHODS: Time domain diffuse optical spectroscopy was performed at 7 wavelengths (635-1060 nm) on 200 subjects to derive their breast tissue composition (in terms of water, lipid and collagen content), blood parameters (total hemoglobin content and oxygen saturation level), and information on the microscopic structure (scattering amplitude and power). The dependence of all optically-derived parameters on age, menopausal status, body mass index, and use of oral contraceptives, and the correlation with mammographic density were investigated. RESULTS: Younger age, premenopausal status, lower body mass index values, and use of oral contraceptives all correspond to significantly higher water, collagen and total hemoglobin content, and lower lipid content (always p < 0.05 and often p < 10-4), while oxygen saturation level and scattering parameters show significant dependence only on some conditions. Even when age-adjusted groups of subjects are compared, several optically derived parameters (and in particular always collagen and total hemoglobin content) remain significantly different. CONCLUSIONS: Time domain diffuse optical spectroscopy can probe non-invasively breast tissue composition and physiologic blood parameters, and provide information on tissue structure. The measurement is suitable for in vivo studies and monitoring of changes in breast tissue (e.g., with age, lifestyle, chemotherapy, etc.) and to gain insight into related processes, like the origin of cancer risk associated with breast density. PMID- 26029913 TI - An in vitro model of skeletal muscle volume regulation. AB - INTRODUCTION: Hypertonic media causes cells to shrink due to water loss through aquaporin channels. After acute shrinkage, cells either regulate their volume or, alternatively, undergo a number of metabolic changes which ultimately lead to cell death. In many cell types, hypertonic shrinkage is followed by apoptosis. Due to the complex 3D morphology of skeletal muscle and the difficulty in obtaining isolated human tissue, we have begun skeletal muscle volume regulation studies using the human skeletal muscle cell line TE671RD. In this study we investigated whether hypertonic challenge of the human skeletal muscle cell line TE671RD triggered cell death or evoked a cell volume recovery response. METHODS: The cellular volume of TE671RD cells was calculated from the 2D surface area. Cell death was assessed by both the trypan blue live/dead assay and the TUNEL assay. RESULTS: Medium osmolality was increased by addition of up to 200 mM sucrose. Addition of 200 mM sucrose resulted in mean cell shrinkage of 44+/-1% after 30 mins. At later time points (2 and 4 hrs) two separate cell subpopulations with differing mean cell volume became apparent. The first subpopulation (15+/-2% of the total cell number) continued to shrink whereas the second subpopulation had an increased cell volume. Cell death was observed in a small proportion of cells (approximately 6-8%). CONCLUSION: We have established that a substantial proportion of TE671RD cells respond to hypertonic challenge with RVI, but that these cells are resistant to hypertonicity triggered cell death. PMID- 26029914 TI - Uric Acid is independently associated with diabetic kidney disease: a cross sectional study in a Chinese population. AB - BACKGROUND: Association between hyperuricaemia and chronic kidney disease has been studied widely, but the influence of uric acid on the kidneys remains controversial. We aimed to summarize the association between uric acid and diabetic kidney disease (DKD), and to evaluate the role of uric acid in DKD. METHODS: We enrolled 3,212 type 2 diabetic patients in a cross-sectional study. The patients' basic characteristics (sex, age, BMI, duration of disease, and blood pressure) and chemical parameters (triglycerides, total cholesterol, low density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), microalbuminuria, creatinine, and uric acid) were recorded, and the association between uric acid and DKD was evaluated. RESULTS: In the 3,212 diabetic patients, the prevalence of diabetic kidney disease was higher in hyperuricaemic patients than in patients with normouricaemia (68.3% vs 41.5%). The prevalence of DKD increased with increasing uric acid (p < 0.0001). Logistic analysis identified uric acid as an independent predictor of DKD (p < 0.0001; adjusted OR (95%CI) = 1.005 (1.004-1.007), p < 0.0001). Uric acid was positively correlated with albuminuria and creatinine levels (p < 0.0001) but negatively correlated with eGFR (p < 0.0001) after adjusting for confounding factors. CONCLUSIONS: Hyperuricaemia is a risk factor for DKD. Serum uric acid levels within the high-normal range are independently associated with DKD. PMID- 26029915 TI - Population genetic structure of a centipede species with high levels of developmental instability. AB - European populations of the geophilomorph centipede Haplophilus subterraneus show a high proportion of individuals with morphological anomalies, suggesting high levels of developmental instability. The broad geographic distribution of this phenomenon seems to exclude local environmental causes, but the source of instability is still to be identified. The goal of the present study was to collect quantitative data on the occurrence of phenodeviants in different populations, along with data on the patterns of genetic variation within and between populations, in order to investigate possible association between developmental instability and genetic features. In a sample of 11 populations of H. subterraneus, distributed in western and central Europe, we looked for phenodeviants, in particular with respect to trunk morphology, and studied genetic variation through the genotyping of microsatellite loci. Overall, no support was found to the idea that developmental instability in H. subterraneus is related to a specific patterns of genetic variation, including inbreeding estimates. We identified a major genetic partition that subdivides French populations from the others, and a low divergence among northwestern areas, which are possibly related to the post-glacial recolonization from southern refugia and/or to recent anthropogenic soil displacements. A weak correlation between individual number of leg bearing segments and the occurrence of trunk anomalies seems to support a trade-off between these two developmental traits. These results, complemented by preliminary data on developmental stability in two related species, suggest that the phenomenon has not a simple taxonomic distribution, while it exhibits an apparent localization in central and eastern Europe. PMID- 26029916 TI - Novel hybrid adaptive controller for manipulation in complex perturbation environments. AB - In this paper we present a hybrid control scheme, combining the advantages of task-space and joint-space control. The controller is based on a human-like adaptive design, which minimises both control effort and tracking error. Our novel hybrid adaptive controller has been tested in extensive simulations, in a scenario where a Baxter robot manipulator is affected by external disturbances in the form of interaction with the environment and tool-like end-effector perturbations. The results demonstrated improved performance in the hybrid controller over both of its component parts. In addition, we introduce a novel method for online adaptation of learning parameters, using the fuzzy control formalism to utilise expert knowledge from the experimenter. This mechanism of meta-learning induces further improvement in performance and avoids the need for tuning through trial testing. PMID- 26029917 TI - Human mesenchymal stem cells are resistant to Paclitaxel by adopting a non proliferative fibroblastic state. AB - Human mesenchymal stem cell (hMSC) resistance to the apoptotic effects of chemotherapeutic drugs has been of major interest, as these cells can confer this resistance to tumor microenvironments. However, the effects of internalized chemotherapeutics upon hMSCs remain largely unexplored. In this study, cellular viability and proliferation assays, combined with different biochemical approaches, were used to investigate the effects of Paclitaxel exposure upon hMSCs. Our results indicate that hMSCs are highly resistant to the cytotoxic effects of Paclitaxel treatment, even though there was no detectable expression of the efflux pump P-glycoprotein, the usual means by which a cell resists Paclitaxel treatment. Moreover, Paclitaxel treatment induces hMSCs to adopt a non proliferative fibroblastic state, as evidenced by changes to morphology, cellular markers, and a reduction in differentiation potential that is not directly coupled to the cytoskeletal effects of Paclitaxel. Taken together, our results show that Paclitaxel treatment does not induce apoptosis in hMSCs, but does induce quiescence and phenotypic changes. PMID- 26029918 TI - Evaluation of Cardiovascular Risk Factors in the Wistar Audiogenic Rat (WAR) Strain. AB - INTRODUCTION: Risk factors for life-threatening cardiovascular events were evaluated in an experimental model of epilepsy, the Wistar Audiogenic Rat (WAR) strain. METHODS: We used long-term ECG recordings in conscious, one year old, WAR and Wistar control counterparts to evaluate spontaneous arrhythmias and heart rate variability, a tool to assess autonomic cardiac control. Ventricular function was also evaluated using the pressure-volume conductance system in anesthetized rats. RESULTS: Basal RR interval (RRi) was similar between WAR and Wistar rats (188 +/- 5 vs 199 +/- 6 ms). RRi variability strongly suggests that WAR present an autonomic imbalance with sympathetic overactivity, which is an isolated risk factor for cardiovascular events. Anesthetized WAR showed lower arterial pressure (92 +/- 3 vs 115 +/- 5 mmHg) and exhibited indices of systolic dysfunction, such as higher ventricle end-diastolic pressure (9.2 +/- 0.6 vs 5.6 +/- 1 mmHg) and volume (137 +/- 9 vs 68 +/- 9 MUL) as well as lower rate of increase in ventricular pressure (5266 +/- 602 vs 7320 +/- 538 mmHg.s-1). Indices of diastolic cardiac function, such as lower rate of decrease in ventricular pressure (-5014 +/- 780 vs -7766 +/- 998 mmHg.s-1) and a higher slope of the linear relationship between end-diastolic pressure and volume (0.078 +/- 0.011 vs 0.036 +/- 0.011 mmHg.MUL), were also found in WAR as compared to Wistar control rats. Moreover, Wistar rats had 3 to 6 ventricular ectopic beats, whereas WAR showed 15 to 30 ectopic beats out of the 20,000 beats analyzed in each rat. CONCLUSIONS: The autonomic imbalance observed previously at younger age is also present in aged WAR and, additionally, a cardiac dysfunction was also observed in the rats. These findings make this experimental model of epilepsy a valuable tool to study risk factors for cardiovascular events in epilepsy. PMID- 26029919 TI - Encoder-decoder optimization for brain-computer interfaces. AB - Neuroprosthetic brain-computer interfaces are systems that decode neural activity into useful control signals for effectors, such as a cursor on a computer screen. It has long been recognized that both the user and decoding system can adapt to increase the accuracy of the end effector. Co-adaptation is the process whereby a user learns to control the system in conjunction with the decoder adapting to learn the user's neural patterns. We provide a mathematical framework for co adaptation and relate co-adaptation to the joint optimization of the user's control scheme ("encoding model") and the decoding algorithm's parameters. When the assumptions of that framework are respected, co-adaptation cannot yield better performance than that obtainable by an optimal initial choice of fixed decoder, coupled with optimal user learning. For a specific case, we provide numerical methods to obtain such an optimized decoder. We demonstrate our approach in a model brain-computer interface system using an online prosthesis simulator, a simple human-in-the-loop pyschophysics setup which provides a non invasive simulation of the BCI setting. These experiments support two claims: that users can learn encoders matched to fixed, optimal decoders and that, once learned, our approach yields expected performance advantages. PMID- 26029920 TI - LUMOS--A Sensitive and Reliable Optode System for Measuring Dissolved Oxygen in the Nanomolar Range. AB - Most commercially available optical oxygen sensors target the measuring range of 300 to 2 MUmol L-1. However these are not suitable for investigating the nanomolar range which is relevant for many important environmental situations. We therefore developed a miniaturized phase fluorimeter based measurement system called the LUMOS (Luminescence Measuring Oxygen Sensor). It consists of a readout device and specialized "sensing chemistry" that relies on commercially available components. The sensor material is based on palladium(II)-5,10,15,20-tetrakis (2,3,4,5,6-pentafluorphenyl)-porphyrin embedded in a Hyflon AD 60 polymer matrix and has a KSV of 6.25 x 10-3 ppmv-1. The applicable measurement range is from 1000 nM down to a detection limit of 0.5 nM. A second sensor material based on the platinum(II) analogue of the porphyrin is spectrally compatible with the readout device and has a measurement range of 20 MUM down to 10 nM. The LUMOS device is a dedicated system optimized for a high signal to noise ratio, but in principle any phase flourimeter can be adapted to act as a readout device for the highly sensitive and robust sensing chemistry. Vise versa, the LUMOS fluorimeter can be used for read out of less sensitive optical oxygen sensors based on the same or similar indicator dyes, for example for monitoring oxygen at physiological conditions. The presented sensor system exhibits lower noise, higher resolution and higher sensitivity than the electrochemical STOX sensor previously used to measure nanomolar oxygen concentrations. Oxygen contamination in common sample containers has been investigated and microbial or enzymatic oxygen consumption at nanomolar concentrations is presented. PMID- 26029921 TI - Quality of Life after Diet or Exercise-Induced Weight Loss in Overweight to Obese Postmenopausal Women: The SHAPE-2 Randomised Controlled Trial. AB - INTRODUCTION: This study investigates the effect of a modest weight loss either by a calorie restricted diet or mainly by increased physical exercise on health related quality of life (HRQoL) in overweight-to-obese and inactive postmenopausal women. We hypothesize that HRQoL improves with weight loss, and that exercise-induced weight loss is more effective for this than diet-induced weight loss. METHODS: The SHAPE-2 trial was primarily designed to evaluate any additional effect of weight loss by exercise compared with a comparable amount of weight loss by diet on biomarkers relevant for breast cancer risk. In the present analysis we focus on HRQoL. We randomly assigned 243 eligible women to a diet (n = 97), exercise (n = 98), or control group (n = 48). Both interventions aimed for 5-6 kg weight loss. HRQoL was measured at baseline and after 16 weeks by the SF 36 questionnaire. RESULTS: Data of 214 women were available for analysis. Weight loss was 4.9 kg (6.1%) and 5.5 kg (6.9%) with diet and exercise, respectively. Scores of the SF-36 domain 'health change' increased significantly by 8.8 points (95% CI 1.6;16.1) with diet, and by 20.5 points (95% CI 13.2;27.7) with exercise when compared with control. Direct comparison of diet and exercise showed a statistically significantly stronger improvement with exercise. Both intervention groups showed a tendency towards improvements in most other domains, which were more pronounced in the exercise group, but not statistically different from control or each other. CONCLUSION: In a randomized trial in overweight-to-obese and inactive postmenopausal women a comparable 6%-7% weight loss was achieved by diet-only or mainly by exercise and showed improvements in physical and mental HRQoL domains, but results were not statistically significant in either the diet or exercise group. However, a modest weight loss does lead to a positive change in self-perceived health status. This effect was significantly larger with exercise-induced weight loss than with comparable diet-induced weight loss. TRIAL REGISTRATION: ClinicalTrials.gov NCT01511276. PMID- 26029922 TI - Autophagy-Regulated ROS from Xanthine Oxidase Acts as an Early Effector for Triggering Late Mitochondria-Dependent Apoptosis in Cathepsin S-Targeted Tumor Cells. AB - Cathepsin S (CTSS), which is highly expressed in various malignant tumor cells, has been proposed to promote tumor progression, migration, and invasion. CTSS inhibition not only blocks tumor cell invasion and endothelial tube formation but also induces cellular cytotoxicity. In our previous studies, we have observed that CTSS inhibition induces autophagy, which is responsible for up-regulating xanthine oxidase for early ROS generation and consequent cell death. However, whether the autophagy-regulated early ROS triggers apoptosis remains unclear. We conducted a long-term follow-up study to investigate the relationship between early autophagy and late mitochondria-dependent apoptosis. We demonstrated that early ROS generation is critical for mitochondria damage and the activation of intrinsic apoptotic pathway. Attenuating the early ROS level diminished later mitochondrial damage and downstream apoptotic signaling. Collectively, mitochondria-dependent apoptosis is regulated by autophagy-regulated early ROS, which serves as an early effector that triggers mitochondrial signaling for late apoptosis. The data emphasize the essential role of autophagy-regulated early ROS in triggering late apoptotic signaling. PMID- 26029923 TI - Exploring treatment by covariate interactions using subgroup analysis and meta regression in cochrane reviews: a review of recent practice. AB - BACKGROUND: Treatment by covariate interactions can be explored in reviews using interaction analyses (e.g., subgroup analysis). Such analyses can provide information on how the covariate modifies the treatment effect and is an important methodological approach for personalising medicine. Guidance exists regarding how to apply such analyses but little is known about whether authors follow the guidance. METHODS: Using published recommendations, we developed criteria to assess how well interaction analyses were designed, applied, interpreted, and reported. The Cochrane Database of Systematic Reviews was searched (8th August 2013). We applied the criteria to the most recently published review, with an accessible protocol, for each Cochrane Review Group. We excluded review updates, diagnostic test accuracy reviews, withdrawn reviews, and overviews of reviews. Data were summarised regarding reviews, covariates, and analyses. RESULTS: Each of the 52 included reviews planned or did interaction analyses; 51 reviews (98%) planned analyses and 33 reviews (63%) applied analyses. The type of analysis planned and the type subsequently applied (e.g., sensitivity or subgroup analysis) was discrepant in 24 reviews (46%). No review reported how or why each covariate had been chosen; 22 reviews (42%) did state each covariate a priori in the protocol but no review identified each post-hoc covariate as such. Eleven reviews (21%) mentioned five covariates or less. One review reported planning to use a method to detect interactions (i.e., interaction test) for each covariate; another review reported applying the method for each covariate. Regarding interpretation, only one review reported whether an interaction was detected for each covariate and no review discussed the importance, or plausibility, of the results, or the possibility of confounding for each covariate. CONCLUSIONS: Interaction analyses in Cochrane Reviews can be substantially improved. The proposed criteria can be used to help guide the reporting and conduct of analyses. PMID- 26029924 TI - Localized CCR2 Activation in the Bone Marrow Niche Mobilizes Monocytes by Desensitizing CXCR4. AB - Inflammatory (classical) monocytes residing in the bone marrow must enter the bloodstream in order to combat microbe infection. These monocytes express high levels of CCR2, a chemokine receptor whose activation is required for them to exit the bone marrow. How CCR2 is locally activated in the bone marrow and how their activation promotes monocyte egress is not understood. Here, we have used double transgenic lines that can visualize CCR2 activation in vivo and show that its chemokine ligand CCL2 is acutely released by stromal cells in the bone marrow, which make direct contact with CCR2-expressing monocytes. These monocytes also express CXCR4, whose activation immobilizes cells in the bone marrow, and are in contact with stromal cells expressing CXCL12, the CXCR4 ligand. During the inflammatory response, CCL2 is released and activates the CCR2 on neighboring monocytes. We demonstrate that acutely isolated bone marrow cells co-express CCR2 and CXCR4, and CCR2 activation desensitizes CXCR4. Inhibiting CXCR4 by a specific receptor antagonist in mice causes CCR2-expressing cells to exit the bone marrow in absence of inflammatory insults. Taken together, these results suggest a novel mechanism whereby the local activation of CCR2 on monocytes in the bone marrow attenuates an anchoring signalling provided by CXCR4 expressed by the same cell and mobilizes the bone marrow monocyte to the blood stream. Our results also provide a generalizable model that cross-desensitization of chemokine receptors fine-tunes cell mobility by integrating multiple chemokine signals. PMID- 26029925 TI - Coniferyl aldehyde attenuates radiation enteropathy by inhibiting cell death and promoting endothelial cell function. AB - Radiation enteropathy is a common complication in cancer patients. The aim of this study was to investigate whether radiation-induced intestinal injury could be alleviated by coniferyl aldehyde (CA), an HSF1-inducing agent that increases cellular HSP70 expression. We systemically administered CA to mice with radiation enteropathy following abdominal irradiation (IR) to demonstrate the protective effects of CA against radiation-induced gastrointestinal injury. CA clearly alleviated acute radiation-induced intestinal damage, as reflected by the histopathological data and it also attenuated sub-acute enteritis. CA prevented intestinal crypt cell death and protected the microvasculature in the lamina propria during the acute and sub-acute phases of damage. CA induced HSF1 and HSP70 expression in both intestinal epithelial cells and endothelial cells in vitro. Additionally, CA protected against not only the apoptotic cell death of both endothelial and epithelial cells but also the loss of endothelial cell function following IR, indicating that CA has beneficial effects on the intestine. Our results provide novel insight into the effects of CA and suggest its role as a therapeutic candidate for radiation-induced enteropathy due to its ability to promote rapid re-proliferation of the intestinal epithelium by the synergic effects of the inhibition of cell death and the promotion of endothelial cell function. PMID- 26029926 TI - The Remedial Efficacy of Spirulina platensis versus Chromium-Induced Nephrotoxicity in Male Sprague-Dawley Rats. AB - This study was conducted to investigate the possible protective effect of Spirulina platensis against chromium-induced nephrotoxicity. A total of 36 adult male Sprague-Dawley rats were divided into 4 equal groups (Gps). Gp1 served as control, rats of Gps 2, 3, and 4 were exposed to Spirulina platensis (300 mg/kg b.wt per os) and sodium dichromate dihydrate (SDD) via drinking water at concentration of 520 mg /l respectively. Chromium administration caused alterations in the renal function markers as evidenced by significant increase of blood urea and creatinine levels accompanied with significant increase in kidney's chromium residues and MDA level as well as decreased catalase activity and glutathion content in kidney tissue. Histologically, Cr provoked deleterious changes including: vascular congestion, wide spread tubular epithelium necrobiotic changes, atrophy of glomerular tuft and proliferative hyperplasia. The latter was accompanied with positive PCNA expression in kidney tissues as well as DNA ploidy interpretation of major cellular population of degenerated cells, appearance of tetraploid cells, high proliferation index and high DNA index. Morphometrical measurements revealed marked glomerular and tubular lumen alterations. On contrary, spirulina co-treatment with Cr significantly restored the histopathological changes, antioxidants and renal function markers and all the previously mentioned changes as well. PMID- 26029927 TI - The ACE2/Ang-(1-7)/Mas Axis Regulates the Development of Pancreatic Endocrine Cells in Mouse Embryos. AB - Angiotensin-converting enzyme 2 (ACE2), its product Angiotensin-(1-7) [Ang-(1 7)], and Ang-(1-7) receptor Mas, have been shown to regulate organogenesis during embryonic development in various species. However, it is not known whether a local ACE2/Ang-(1-7)/Mas axis is present in the fetal pancreas. It is hypothesized that there is a local ACE2/Ang-(1-7)/Mas axis in the embryonic pancreas in mice that is involved in regulating islet cell development. To address this issue, the endogenous expression profile of axis constituents in embryonic mouse pancreata was examined. Involvement of the ACE2 axis in the regulation of pancreatic development was also examined. The present experiments showed in an in vivo animal model that endogenous expression levels of ACE2 and the Mas receptor were upregulated in mouse pancreata in late embryogenesis, peaking on embryonic day E16.5, when it reached 3 folds compared to that seen at E12.5. Consistently, endogenous expression of Ang-(1-7) also peaked at E16.5. Treatment with the ACE2 inhibitor DX600 did not alter islet development. However, prenatal treatment with A779, a Mas receptor antagonist, reduced the beta-cell to alpha-cell ratio in neonatal islets, impaired islet insulin secretory function, and impaired the pups' glucose tolerance. In ex vivo pancreas explant cultures, A779 again decreased the beta-cell to alpha-cell ratio, apparently through its effects on beta-cell proliferation (reduced proliferation shown with Ki67 staining), and also decreased Insulin and Ngn3 mRNA expression. Furthermore, treatment of explant cultures with Ang-(1-7) increased mRNA levels of Insulin and pancreatic progenitor marker Ngn3, as well as Nox4, the ROS generation enzyme; these stimulatory effects were attenuated by co-treatment with A779, suggesting that Ang-(1-7), via Mas receptor signaling, may promote differentiation of pancreatic progenitors into insulin-producing cells via modulation of reactive oxygen species. These data together suggest that a Mas receptor-mediated mechanism may stimulate pancreatic cell development. PMID- 26029928 TI - Leprosy Reactions in Patients Coinfected with HIV: Clinical Aspects and Outcomes in Two Comparative Cohorts in the Amazon Region, Brazil. AB - BACKGROUND: Leprosy, caused by Mycobacterium leprae, can lead to scarring and deformities. Human immunodeficiency virus (HIV), a lymphotropic virus with high rates of replication, leads to cell death in various stages of infection. These diseases have major social and quality of life costs, and although the relevance of their comorbidity is recognized, several aspects are still not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: Two cohorts of patients with leprosy in an endemic region of the Amazon were observed. We compared 40 patients with leprosy and HIV (Group 1) and 107 leprosy patients with no comorbidity (Group 2) for a minimum of 2 years. Group 1 predominantly experienced the paucibacillary classification, accounting for 70% of cases, whereas Group 2 primarily experienced the multibacillary classification (80.4% of cases). There was no significant difference in the prevalence of leprosy reactions among the two groups (37.5% for Group 1 vs. 56.1% for Group 2), and the most frequent reaction was Type 1. The appearance of Group 1 patients' reversal reaction skin lesions was consistent with each clinical form: typically erythematous and infiltrated, with similar progression as those patients without HIV, which responded to prednisone. Patients in both groups primarily experienced a single episode (73.3% in Group 1 and 75% in Group 2), and Group 1 had shorter reaction periods (<=3 months; 93.3%), moderate severity (80%), with 93.3% of the patients in the state of acquired immune deficiency syndrome, and 46.7% presenting the reaction at the time of the immune reconstitution inflammatory syndrome. CONCLUSIONS/SIGNIFICANCE: This study used a large sample and makes a significant contribution to the clinical outcomes of patients in the reactive state with comorbid HIV and leprosy. The data indicate that these diseases, although concurrent, have independent courses. PMID- 26029929 TI - Structure Elucidation of the Metabolites of 2', 3', 5'-Tri-O-Acetyl-N6-(3 Hydroxyphenyl) Adenosine in Rat Urine by HPLC-DAD, ESI-MS and Off-Line Microprobe NMR. AB - 2', 3', 5'-Tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (also known as WS070117) is a new adenosine analog that displays anti-hyperlipidemic activity both in vitro and in vivo experiments as shown in many preliminary studies. Due to its new structure, little is known about the metabolism of WS070117. Hence, the in vivo metabolites of WS070117 in rat urine following oral administration were investigated. Identification of the metabolites was conducted using the combination of high-performance liquid chromatography (HPLC) coupled with diode array detector (DAD), ion trap electrospray ionization-mass spectrometry (ESI MS), and off-line microprobe nuclear magnetic resonance (NMR) measurements. Seven metabolites were obtained as pure compounds at the sub-milligram to milligram levels. Results of structure elucidation unambiguously revealed that the phase I metabolite, N6-(3-hydroxyphenyl) adenosine (M8), was a hydrolysate of WS070117 by hydrolysis on the three ester groups. N6-(3-hydr-oxyphenyl) adenine (M7), also one of the phase I metabolites, was the derivative of M8 by the loss of ribofuranose. In addition to two phase I metabolites, there were five phase II metabolites of WS070117 found in rat urine. 8-hydroxy-N6-(3-hydroxy-phenyl) adenosine (M6) was the product of M7 by hydrolysis at position 8. The other four were elucidated to be N6-(3-O-beta-D-glucuronyphenyl) adenine (M2), N8-hydroxy-N6 (3-O-sulfophenyl) adenine (M3), N6-(3-O-beta-D-glucuronyphenyl) adenosine (M4), and N6-(3-O- sulfophenyl) adenosine (M5). Phase II metabolic pathways were proven to consist of hydroxylation, glucuronidation and sulfation. This study provides new and valuable information on the metabolism of WS070117, and also demonstrates the HPLC/MS/off-line microprobe NMR approach as a robust means for rapid identification of metabolites. PMID- 26029930 TI - Interferon-gamma and nitric oxide synthase 2 mediate the aggregation of resident adherent peritoneal exudate cells: implications for the host response to pathogens. AB - Interferon-gamma (Ifngamma), a key macrophage activating cytokine, plays pleiotropic roles in host immunity. In this study, the ability of Ifngamma to induce the aggregation of resident mouse adherent peritoneal exudate cells (APECs), consisting primarily of macrophages, was investigated. Cell-cell interactions involve adhesion molecules and, upon addition of Ifngamma, CD11b re localizes preferentially to the sites of interaction on APECs. A functional role of CD11b in enhancing aggregation is demonstrated using Reopro, a blocking reagent, and siRNA to Cd11b. Studies with NG-methyl-L-arginine (LNMA), an inhibitor of Nitric oxide synthase (Nos), NO donors, e.g., S-nitroso-N-acetyl-DL penicillamine (SNAP) or Diethylenetriamine/nitric oxide adduct (DETA/NO), and Nos2-/- mice identified Nitric oxide (NO) induced by Ifngamma as a key regulator of aggregation of APECs. Further studies with Nos2-/- APECs revealed that some Ifngamma responses are independent of NO: induction of MHC class II and CD80. On the other hand, Nos2 derived NO is important for other functions: motility, phagocytosis, morphology and aggregation. Studies with cytoskeleton depolymerizing agents revealed that Ifngamma and NO mediate the cortical stabilization of Actin and Tubulin which contribute to aggregation of APECs. The biological relevance of aggregation of APECs was delineated using infection experiments with Salmonella Typhimurium (S. Typhimurium). APECs from orally infected, but not uninfected, mice produce high amounts of NO and aggregate upon ex vivo culture in a Nos2-dependent manner. Importantly, aggregated APECs induced by Ifngamma contain fewer intracellular S. Typhimurium compared to their single counterparts post infection. Further experiments with LNMA or Reopro revealed that both NO and CD11b are important for aggregation; in addition, NO is bactericidal. Overall, this study elucidates novel roles for Ifngamma and Nos2 in regulating Actin, Tubulin, CD11b, motility and morphology during the aggregation response of APECs. The implications of aggregation or "group behavior" of APECs are discussed in the context of host resistance to infectious organisms. PMID- 26029931 TI - Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways. AB - Since BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRalpha and TRbeta immunopositivity in BRCA1 associated (n = 38) and sporadic breast cancer (n = 86). Further, TRs were studied in MCF7 (BRCA1 wildtype) and HCC3153 (BRCA1 mutated) cells. TRbeta positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001). The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037). Regarding BRCA1 associated breast cancer cases TRbeta positivity turned out to be a positive prognostic factor for five-year (p = 0.007) and overall survival (p = 0.026) while TRalpha positivity predicted reduced five-year survival (p = 0.030). Activation of TRbeta resulted in down-modulation of CTNNB1 while TRalpha inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRalpha1 in response to T3 stimulation. Significantly, this study identified TRbeta to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients' prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when tumors are triple-negative. PMID- 26029932 TI - Limb ischemic preconditioning protects endothelium from oxidative stress by enhancing nrf2 translocation and upregulating expression of antioxidases. AB - Remote ischemic preconditioning is often performed by limb ischemic preconditioning (LIPC), which has been demonstrated to be beneficial to various cells, including endothelial cells. The mechanisms underlying the protection have not been well clarified. The present study was designed to observe the effects of sera derived from rats after LIPC on human umbilical vein endothelial cells (HUVECs) injured by hydrogen peroxide (H2O2) -induced oxidative stress and explore the involvement of redox state in the protection. Incubation with 1 mM H2O2 for 2 h induced a significant reduction in HUVECs' viability with increased production of malondialdehyde (MDA) and reactive oxygen species (ROS). Preincubation with early preconditioning serum (EPS) or delayed preconditioning serum (DPS) derived from rats subjected to LIPC alleviated these changes. Both EPS and DPS increased the nuclear translocation of transcription factor nuclear factor E2-related factor 2 (Nrf2) and the expression of antioxidases. The protective effects of EPS and DPS were blocked neither by MEK/ERK inhibitors U0126 nor by PI3K/Akt inhibitors LY294002. In conclusion, the present study provides the evidence that LIPC protects the HUVECs from H2O2-induced injury by, at least partially, enhancement of Nrf2 translocation and upregulation of antioxidases via signaling pathways independent of MEK/ERK and PI3K/Akt. PMID- 26029934 TI - Treatment of metastatic breast cancer with ??????-paclitaxel in the community practice setting: a US Oncology survey. AB - BACKGROUND: Different dosages-schedules of nab-paclitaxel have been assessed in trials of metastatic breast cancer (MBC). However, there is limited information on nab-paclitaxel dosing-scheduling in the community setting. OBJECTIVE: To report on experience with nab-paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative MBC and identify patient characteristics affecting nab paclitaxel treatment patterns in the community practice setting. METHODS: From September 6-October 21, 2013, a 35-question, web-based survey on nab-paclitaxel dosing, toxicities leading to dose modifications, management, and treatment duration was sent to US Oncology network oncologists. Respondents were categorized by percentage of their patients with HER2-negative MBC who received nab-paclitaxel. RESULTS: 104 of 428 oncologists responded; 84% were from large practices (>=16 oncologists), and 56% had a high level of experience using nab paclitaxel. For first- and second-line treatment, 100 mg/m2 weekly was the most common starting dosage-schedule, followed by 125 mg/m2 weekly and 260 mg/m2 every 3 weeks (q3w); 150 mg/m2 weekly was used least frequently. Several factors, including select aggressive disease characteristics, were found to affect nab paclitaxel dose selection. Weekly dosing was preferred in patients with select aggressive disease characteristics, whereas q3w dosing was commonly used in patients aged <=50 years and those with good performance status. Differences in management styles among oncologists with high compared with infrequent nab paclitaxel experience were also observed. Peripheral neuropathy and neutropenia were common dose-limiting toxicities. LIMITATIONS: Recall and response bias may be limitations of this study. CONCLUSIONS: In the community setting, nab paclitaxel 100 mg/m2 weekly was the most commonly used starting dose for patients with HER2-negative MBC, including those with aggressive disease characteristics. PMID- 26029933 TI - Gene transfer and genome-wide insertional mutagenesis by retroviral transduction in fish stem cells. AB - Retrovirus (RV) is efficient for gene transfer and integration in dividing cells of diverse organisms. RV provides a powerful tool for insertional mutagenesis (IM) to identify and functionally analyze genes essential for normal and pathological processes. Here we report RV-mediated gene transfer and genome-wide IM in fish stem cells from medaka and zebrafish. Three RVs were produced for fish cell transduction: rvLegfp and rvLcherry produce green fluorescent protein (GFP) and mCherry fluorescent protein respectively under control of human cytomegalovirus immediate early promoter upon any chromosomal integration, whereas rvGTgfp contains a splicing acceptor and expresses GFP only upon gene trapping (GT) via intronic in-frame integration and spliced to endogenous active genes. We show that rvLegfp and rvLcherry produce a transduction efficiency of 11~23% in medaka and zebrafish stem cell lines, which is as 30~67% efficient as the positive control in NIH/3T3. Upon co-infection with rvGTgfp and rvLcherry, GFP-positive cells were much fewer than Cherry-positive cells, consistent with rareness of productive gene trapping events versus random integration. Importantly, rvGTgfp infection in the medaka haploid embryonic stem (ES) cell line HX1 generated GTgfp insertion on all 24 chromosomes of the haploid genome. Similar to the mammalian haploid cells, these insertion events were presented predominantly in intergenic regions and introns but rarely in exons. RV transduced HX1 retained the ES cell properties such as stable growth, embryoid body formation and pluripotency gene expression. Therefore, RV is proficient for gene transfer and IM in fish stem cells. Our results open new avenue for genome wide IM in medaka haploid ES cells in culture. PMID- 26029935 TI - Health professionals' attitudes toward the detection and management of cancer related anorexia-cachexia syndrome, and a proposal for standardized assessment. AB - BACKGROUND: The identification and management of patients with cancer anorexia cachexia syndrome (CACS) can be a challenge despite recent international consensus on the definition of the condition. OBJECTIVES: To describe the current views and practice patterns of community oncologists and oncology nurses in regard to CACS and to propose a standardized, pragmatic assessment of CACS for oncological practice. METHODS AND MATERIALS: Responses from 151 community oncologists and nurses obtained across 5 surveys were analyzed. Questions addressed CACS in general and in patients with non-small-cell lung cancer (NSCLC). Surveys 1-3 were directed at physicians, and surveys 4 and 5 were directed at nurses. Surveys 1, 2, 4, and 5 focused on the recognition and monitoring of CACS, and Survey 3 on symptom management. RESULTS: 67% of medical oncologists in Survey 3 selected weight loss as the most important criterion for diagnosing CACS and cited declining appetite and performance status (PS) as the most bothersome effects for patients and families. Weight maintenance/gain was the primary treatment objective for oncologists. Respondents to surveys 1 and 2 acknowledged the risk for CACS is high (60%) in NSCLC but considered the risk much lower (4%) in patients completing a first course of therapy with good PS. 91% of oncologists in Survey 3 reported that symptoms that had an impact on calorie intake were important/very important, and 73% were willing to consider a symptom assessment instrument that included appetite. Nurses in surveys 4 and 5 reported weight loss and appetite were most commonly used to identify cachexia. They considered responsibility for the initial assessment of cachexia was the oncologist's (32%), followed by the nurse practitioner (28%), and the nurse (16%). CONCLUSION: Most oncologists and nurses recognize the core criteria for the CACS, although there may be under-recognition of the condition's prevalence, particularly earlier in the course of treatment. There is considerable interest in adopting a brief assessment tool for screening, management, and referral of patients who are affected by or at-risk of CACS. PMID- 26029937 TI - Significant response to lacosamide in a patient with severe chemotherapy-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity of potentially curative cancer therapy regimens. Cisplatin is the class of chemotherapy agent that has a broad spectrum of activity against several solid tumors, but it induces sensory neuropathy of upper and lower extremities. Cisplatin-induced peripheral neuropathy is usually in a "gloves and socks" distribution that can persist for months or years after completion of chemotherapy treatment. If the pain is severe, it affects the patient's long-term quality of life and can potentially result in chemotherapy dose reduction or treatment discontinuation. The mechanism of CIPN is not well understood, and a number of pathophysiological mechanisms have been proposed to explain the phenomenon. Although many therapies have been investigated for the prevention or treatment of CIPN, there is currently no accepted proven therapy. Here we report a case in which lacosamide alleviated painful CIPN symptoms. Lacosamide is an anticonvulsant drug that blocks the voltage-gated sodium channels in the neurons and may also be a promising novel candidate for the prevention and treatment of chemotherapy-induced peripheral neuropathy. Preclinical data support the role of lacosamide protective effect in a rat model of chemotherapy-induced neuropathy, randomized clinical trial is needed. PMID- 26029936 TI - Treatment differences between urban and rural women with hormone receptor positive early-stage breast cancer based on 21-gene assay recurrence score result. PMID- 26029938 TI - X-ray absorption spectroscopy on magnetic nanoscale systems for modern applications. AB - X-ray absorption spectroscopy facilitated by state-of-the-art synchrotron radiation technology is presented as a powerful tool to study nanoscale systems, in particular revealing their static element-specific magnetic and electronic properties on a microscopic level. A survey is given on the properties of nanoparticles, nanocomposites and thin films covering a broad range of possible applications. It ranges from the ageing effects of iron oxide nanoparticles in dispersion for biomedical applications to the characterisation on a microscopic level of nanoscale systems for data storage devices. In this respect, new concepts for electrically addressable magnetic data storage devices are highlighted by characterising the coupling in a BaTiO(3)/CoFe(2)O(4) nanocomposite as prototypical model system. But classical magnetically addressable devices are also discussed on the basis of tailoring the magnetic properties of self-assembled ensembles of FePt nanoparticles for data storage and the high-moment material Fe/Cr/Gd for write heads. For the latter cases, the importance is emphasised of combining experimental approaches in x-ray absorption spectroscopy with density functional theory to gain a more fundamental understanding. PMID- 26029939 TI - A Cryptic t(11;14) Translocation in Mantle Cell Lymphoma Highlights the Importance of FISH. AB - Mantle cell lymphoma (MCL) is a mature B-cell neoplasm composed of monomorphic small to medium-sized atypical lymphocytes arising from naive mantle zone B cells, with a generally aggressive and incurable clinical course. The t(11;14)(q13;q32) between IGH@ and CCND1 is present in almost all cases of MCL. Secondary cytogenetic abnormalities are common, and have been associated in some cases with clinical progression. Variant and cryptic t(11;14) translocations have been reported as well. Herein, we present the case of an 80-year old woman with classical MCL, and a cryptic t(11;14) translocation detected by fluorescence in situ hybridization (FISH), and not by conventional cytogenetics. FISH on previously G-banded metaphases showed a cryptic CCND1-IGH@ fusion signal on a derivative chromosome 10, and another fusion signal on one of the abnormal copies of chromosome 11. Cases such as this highlight the importance of FISH studies as part of an algorithmic and multidisciplinary approach to diagnosis. PMID- 26029941 TI - Dimensional structure of the Spanish version of the Positive and Negative Affect Schedule (PANAS) in adolescents and young adults. AB - The main purpose of this study was to examine the dimensional structure of the Spanish version of the PANAS, using a large sample of adolescents and young adults (N = 1103, age range 14 to 23). Furthermore, measurement invariance across gender and educational level was tested. Confirmatory factor analyses revealed that a bifactor model and a 3-factor model Positive Affect (PA), Negative Affect (NA) Upset, and NA Afraid (PA and NA uncorrelated) provided the best fit to the data. Multigroup confirmatory factor analyses showed that the 3-factor model of the PANAS had strong measurement invariance across gender and educational level. Results showed statistically significant differences in the latent mean scores. University students scored higher than adolescents in PA, NA Upset, and NA Afraid. Men scored higher than women in PA. The PANAS scores also showed acceptable internal consistency scores (range from .80 to .86). The results found support for the PANAS as a brief and useful tool for the screening PA and NA in adolescents and young adult's populations. These findings hold implications for the study and use of the PANAS in nonclinical populations. Future studies should test measurement invariance of the PANAS scores across cultures. (PsycINFO Database Record PMID- 26029940 TI - Short alleles, bigger smiles? The effect of 5-HTTLPR on positive emotional expressions. AB - The present research examined the effect of the 5-HTTLPR polymorphism in the serotonin transporter gene on objectively coded positive emotional expressions (i.e., laughing and smiling behavior objectively coded using the Facial Action Coding System). Three studies with independent samples of participants were conducted. Study 1 examined young adults watching still cartoons. Study 2 examined young, middle-aged, and older adults watching a thematically ambiguous yet subtly amusing film clip. Study 3 examined middle-aged and older spouses discussing an area of marital conflict (that typically produces both positive and negative emotion). Aggregating data across studies, results showed that the short allele of 5-HTTLPR predicted heightened positive emotional expressions. Results remained stable when controlling for age, gender, ethnicity, and depressive symptoms. These findings are consistent with the notion that the short allele of 5-HTTLPR functions as an emotion amplifier, which may confer heightened susceptibility to environmental conditions. PMID- 26029942 TI - A Brief Strengths Scale for individuals with mental health issues. AB - Using their strengths and virtues enables individuals to build resilience and alleviate mental health issues. However, most existing instruments for measuring strengths are too lengthy to provide effective assessment for clinical screening. A brief instrument with good factorial and ecological validity is needed to measure strengths, especially among individuals with mental health issues. In this study, the authors developed a brief inventory, the Brief Strengths Scale-12 (BSS-12), to assess 3 strengths: Temperance Strength, Intellectual Strength, and Interpersonal Strength. Two studies were conducted. Study 1 was conducted in Hong Kong. Service recipients (n = 149) from a psychiatric rehabilitation organization were recruited to establish the factor structure and construct validity of the BSS-12. In Study 2, 203 university undergraduates from mainland China were recruited to examine the factorial invariance of the BSS-12 in a different culture and population. Each factor demonstrated satisfactory internal consistency, content validity, and discriminant validity. The BSS-12 may be a useful tool for assessing strengths in clinical and nonclinical settings for service planning and the evaluation of intervention effectiveness. (PsycINFO Database Record PMID- 26029943 TI - Self-discrepancy: Long-term test-retest reliability and test-criterion predictive validity. AB - Long-term test-retest reliability and predictive test-criterion evidence of validity of scores on measures of the real-ideal self-discrepancy and of the real ought self-discrepancy were tested over periods of 1 year and 3 years. A sample of 184 undergraduates completed at 2 time points 1 year apart 3 instruments that each measure the 2 self-discrepancies: the idiographic Self-Concept Questionnaire Personal Constructs, the nonidiographic Self-Concept Questionnaire-Conventional Constructs, and the content-free Abstract Measures. A separate sample of 141 undergraduates completed the instruments 3 years apart. Both samples completed 3 depression instruments and 3 anxiety instruments at the second time point. Results of analyses using latent variables modeled with 3 observed variables showed substantial statistically significant test-retest reliabilities and significant test-criterion prediction of anxiety and depression on the real-ideal and real-ought discrepancy measures over both time periods. Results for the observed variables showed significant 1-year and 3-year reliabilities for scores on all self-discrepancy measures, as well as significant 1-year and 3-year predictive validity for scores on all self-discrepancy measures, except the abstract measure of real-ought discrepancy in predicting scores on all depression measures and on at least 1 anxiety measure. The findings support very strong long term stabilities of the self-discrepancy personality constructs and their long term associations with anxiety and depression. PMID- 26029944 TI - Clarifying the latent structure and correlates of somatic symptom distress: A bifactor model approach. AB - Distressing somatic symptoms are ubiquitous both in mental disorders and medical diseases. From a psychometric perspective, the structure of somatic symptom distress is unclear, and little is known about the strengths of associations to related constructs, such as health anxiety and somatosensory amplification. To clarify the structure of somatic symptom distress and to explore associations to health anxiety, somatosensory amplification, and functional somatic syndromes, data sets of 2 samples of college students from Germany (N = 1,520) and Switzerland (N = 3,053) were investigated with confirmatory factor analysis with robust estimation. A bifactor model (with 1 general and 4 orthogonal specific symptom factors-gastrointestinal, fatigue, cardio-pulmonary, and pain symptoms) revealed the best model fit. Medium-sized associations were found among latent factors of general somatic symptom distress, health anxiety, and depression. First evidence for the construct validity of the latent variables within the proposed bifactor structure was gained by observing (a) strong associations between the general somatic symptom distress factor and somatosensory amplification and (b) significant associations between both the general somatic symptom factor as well as the symptom-specific factors with functional somatic syndromes. The results offer a theoretically and psychometrically plausible model for the structure of somatic symptom distress and suggest a distinction between cognitive-affective and sensory aspects of symptom perception. The findings are compatible with current cognitive psychological and neuropsychological approaches to symptom perception and imply that somatic symptom distress is a multidimensional phenomenon that is both strongly linked to but also clearly separable from related constructs. PMID- 26029945 TI - Identifying an appropriate measurement modeling approach for the Mini-Mental State Examination. AB - The Mini-Mental State Examination (MMSE) is a 30-item, dichotomously scored test of general cognition. A number of benefits could be gained by modeling the MMSE in an item response theory (IRT) framework, as opposed to the currently used classical additive approach. However, the test, which is built from groups of items related to separate cognitive subdomains, may violate a key assumption of IRT: local item independence. This study aimed to identify the most appropriate measurement model for the MMSE: a unidimensional IRT model, a testlet response theory model, or a bifactor model. Local dependence analysis using nationally representative data showed a meaningful violation of the local item independence assumption, indicating multidimensionality. In addition, the testlet and bifactor models displayed superior fit indices over a unidimensional IRT model. Statistical comparisons showed that the bifactor model fit MMSE respondent data significantly better than the other models considered. These results suggest that application of a traditional unidimensional IRT model is inappropriate in this context. Instead, a bifactor model is suggested for future modeling of MMSE data as it more accurately represents the multidimensional nature of the scale. (PsycINFO Database Record PMID- 26029946 TI - Higher- and lower-order factor analyses of the Children's Behavior Questionnaire in early and middle childhood. AB - The Children's Behavior Questionnaire (CBQ; Rothbart, Ahadi, & Hershey, 1994), a 195-item parent-report questionnaire, is one of the most widely used measures of child temperament, with previous analyses of its scales suggesting that 3 broad factors account for the overarching structure of child temperament (Rothbart, Ahadi, Hershey, & Fisher, 2001). However, there are no published item-level factor analyses of the CBQ, meaning that it is currently unclear whether items clearly load onto CBQ scales as proposed by its developers. Additionally, although the CBQ is intended to cover a broad window of development (i.e., ages 3 7), little is known about whether the structure of the CBQ differs depending on child age. The present study used a bottom-up approach to examine the lower- and higher-order structure of the CBQ in a large community sample of children at ages 3 (N = 944) and 5/6 (N = 853). Item-level exploratory factor analyses (EFAs) identified 88 items at age 3 and 87 items at age 5/6 suitable (i.e., with loadings >=.40) for constructing lower-order factors. Of the lower-order factors derived at ages 3 and 5/6, fewer than half resembled original CBQ scales (Rothbart et al., 1994, 2001). Higher-order EFAs of the lower-order factors suggested that a 4-factor structure was the best fit at both ages 3 and 5/6. Thus, results indicate that a substantial number of CBQ items do not load well on a lower-order factor and that more than 3 factors are needed to account for its higher-order structure. PMID- 26029947 TI - Acute Myeloid Leukemia with a Masked Type of Three-Way t(8;11;21) Revealed by Fluorescence In Situ Hybridizations Using AML1-ETO Probe. AB - The translocation (8;21)(q22;q22) is associated with acute myeloblastic leukemia (AML) with M2 subtype. The accurate detection of this chromosomal rearrangement is vital due to its association with a favorable prognosis. Variants of t(8;21)(q22;q22) involving chromosomes 8, 21 and other chromosomes account for approximately 3% of all t(8;21)(q22;q22) in AML. Variants in some cases present as hidden translocations, and in such cases it is often difficult to confirm the presence of t(8;21)(q22;q22) by conventional cytogenetic analysis alone. The molecular detection of the AML1-ETO fusion gene is possible by reverse transcriptase polymerase chain reaction (RT-PCR) or dualcolor fluorescence in situ hybridization (FISH) using probes specific for AML1 and ETO. The mechanism described for variant formation is one step or two steps. We report a case of AML with a masked variant translocation. Conventional cytogenetics and FISH study was carried out on a bone marrow sample of the patient at diagnosis. Karyotype result at diagnosis revealed t(8;11)(q22;p15) by G-banding. FISH nalysis disclosed a 3 way translocation involving chromosomes 8, 11, and 21 and identified a masked variant t(8;21)(q22;q22) using AML1-ETO probe and whole chromosome paint probes (WCP) 8 and 11 with a one-step mechanism. FISH analysis with the AML1 and ETO probes is extremely valuable in cases of AML-M2 because of its ability to reveal masked t(8;21) (q22;q22) translocations and thus quickly confirm the diagnosis, allowing patients to be assigned to the correct risk group in terms of treatment. Simple variants of the t(8;21) translocation involving chromosome 8 and a chromosome other than number 21 are rare. Our case illustrates the challenge of recognizing complex aberrations that occur with variant t(8;21) and further reinforces the utility of FISH applications on metaphase for more accurate characterization of chromosome abnormalities which can lead to more precise therapeutic stratification. PMID- 26029948 TI - Peculiarities of the third natural frequency vibrations of a cantilever for the improvement of energy harvesting. AB - This paper focuses on several aspects extending the dynamical efficiency of a cantilever beam vibrating in the third mode. A few ways of producing this mode stimulation, namely vibro-impact or forced excitation, as well as its application for energy harvesting devices are proposed. The paper presents numerical and experimental analyses of novel structural dynamics effects along with an optimal configuration of the cantilever beam. The peculiarities of a cantilever beam vibrating in the third mode are related to the significant increase of the level of deformations capable of extracting significant additional amounts of energy compared to the conventional harvester vibrating in the first mode. Two types of a piezoelectric vibrating energy harvester (PVEH) prototype are analysed in this paper: the first one without electrode segmentation, while the second is segmented using electrode segmentation at the strain nodes of the third vibration mode to achieve effective operation at the third resonant frequency. The results of this research revealed that the voltage generated by any segment of the segmented PVEH prototype excited at the third resonant frequency demonstrated a 3.4-4.8-fold increase in comparison with the non-segmented prototype. Simultaneously, the efficiency of the energy harvester prototype also increased at lower resonant frequencies from 16% to 90%. The insights presented in the paper may serve for the development and fabrication of advanced piezoelectric energy harvesters which would be able to generate a considerably increased amount of electrical energy independently of the frequency of kinematical excitation. PMID- 26029949 TI - Design and implementation of an intrinsically safe liquid-level sensor using coaxial cable. AB - Real-time detection of liquid level in complex environments has always been a knotty issue. In this paper, an intrinsically safe liquid-level sensor system for flammable and explosive environments is designed and implemented. The poly vinyl chloride (PVC) coaxial cable is chosen as the sensing element and the measuring mechanism is analyzed. Then, the capacitance-to-voltage conversion circuit is designed and the expected output signal is achieved by adopting parameter optimization. Furthermore, the experimental platform of the liquid-level sensor system is constructed, which involves the entire process of measuring, converting, filtering, processing, visualizing and communicating. Additionally, the system is designed with characteristics of intrinsic safety by limiting the energy of the circuit to avoid or restrain the thermal effects and sparks. Finally, the approach of the piecewise linearization is adopted in order to improve the measuring accuracy by matching the appropriate calibration points. The test results demonstrate that over the measurement range of 1.0 m, the maximum nonlinearity error is 0.8% full-scale span (FSS), the maximum repeatability error is 0.5% FSS, and the maximum hysteresis error is reduced from 0.7% FSS to 0.5% FSS by applying software compensation algorithms. PMID- 26029950 TI - Cooperative energy harvesting-adaptive MAC protocol for WBANs. AB - In this paper, we introduce a cooperative medium access control (MAC) protocol, named cooperative energy harvesting (CEH)-MAC, that adapts its operation to the energy harvesting (EH) conditions in wireless body area networks (WBANs). In particular, the proposed protocol exploits the EH information in order to set an idle time that allows the relay nodes to charge their batteries and complete the cooperation phase successfully. Extensive simulations have shown that CEH-MAC significantly improves the network performance in terms of throughput, delay and energy efficiency compared to the cooperative operation of the baseline IEEE 802.15.6 standard. PMID- 26029951 TI - Low-cost impact detection and location for automated inspections of 3D metallic based structures. AB - This paper describes a new low-cost means to detect and locate mechanical impacts (collisions) on a 3D metal-based structure. We employ the simple and reasonably hypothesis that the use of a homogeneous material will allow certain details of the impact to be automatically determined by measuring the time delays of acoustic wave propagation throughout the 3D structure. The location of strategic piezoelectric sensors on the structure and an electronic-computerized system has allowed us to determine the instant and position at which the impact is produced. The proposed automatic system allows us to fully integrate impact point detection and the task of inspecting the point or zone at which this impact occurs. What is more, the proposed method can be easily integrated into a robot-based inspection system capable of moving over 3D metallic structures, thus avoiding (or minimizing) the need for direct human intervention. Experimental results are provided to show the effectiveness of the proposed approach. PMID- 26029952 TI - An optical biosensor from green fluorescent Escherichia coli for the evaluation of single and combined heavy metal toxicities. AB - A fluorescence-based fiber optic toxicity biosensor based on genetically modified Escherichia coli (E. coli) with green fluorescent protein (GFP) was developed for the evaluation of the toxicity of several hazardous heavy metal ions. The toxic metals include Cu(II), Cd(II), Pb(II), Zn(II), Cr(VI), Co(II), Ni(II), Ag(I) and Fe(III). The optimum fluorescence excitation and emission wavelengths of the optical biosensor were 400 +/- 2 nm and 485 +/- 2 nm, respectively. Based on the toxicity observed under optimal conditions, the detection limits of Cu(II), Cd(II), Pb(II), Zn(II), Cr(VI), Co(II), Ni(II), Ag(I) and Fe(III) that can be detected using the toxicity biosensor were at 0.04, 0.32, 0.46, 2.80, 100, 250, 400, 720 and 2600 MUg/L, respectively. The repeatability and reproducibility of the proposed biosensor were 3.5%-4.8% RSD (relative standard deviation) and 3.6% 5.1% RSD (n = 8), respectively. The biosensor response was stable for at least five weeks, and demonstrated higher sensitivity towards metal toxicity evaluation when compared to a conventional Microtox assay. PMID- 26029953 TI - Airborne relay-based regional positioning system. AB - Ground-based pseudolite systems have some limitations, such as low vertical accuracy, multipath effects and near-far problems. These problems are not significant in airborne-based pseudolite systems. However, the monitoring of pseudolite positions is required because of the mobility of the platforms on which the pseudolites are mounted, and this causes performance degradation. To address these pseudolite system limitations, we propose an airborne relay-based regional positioning system that consists of a master station, reference stations, airborne relays and a user. In the proposed system, navigation signals are generated from the reference stations located on the ground and are relayed via the airborne relays. Unlike in conventional airborne-based systems, the user in the proposed system sequentially estimates both the locations of airborne relays and his/her own position. Therefore, a delay due to monitoring does not occur, and the accuracy is not affected by the movement of airborne relays. We conducted several simulations to evaluate the performance of the proposed system. Based on the simulation results, we demonstrated that the proposed system guarantees a higher accuracy than airborne-based pseudolite systems, and it is feasible despite the existence of clock offsets among reference stations. PMID- 26029954 TI - A programmable high-voltage compliance neural stimulator for deep brain stimulation in vivo. AB - Deep brain stimulation (DBS) is one of the most effective therapies for movement and other disorders. The DBS neurosurgical procedure involves the implantation of a DBS device and a battery-operated neurotransmitter, which delivers electrical impulses to treatment targets through implanted electrodes. The DBS modulates the neuronal activities in the brain nucleus for improving physiological responses as long as an electric discharge above the stimulation threshold can be achieved. In an effort to improve the performance of an implanted DBS device, the device size, implementation cost, and power efficiency are among the most important DBS device design aspects. This study aims to present preliminary research results of an efficient stimulator, with emphasis on conversion efficiency. The prototype stimulator features high-voltage compliance, implemented with only a standard semiconductor process, without the use of extra masks in the foundry through our proposed circuit structure. The results of animal experiments, including evaluation of evoked responses induced by thalamic electrical stimuli with our fabricated chip, were shown to demonstrate the proof of concept of our design. PMID- 26029955 TI - An efficient and reliable geographic routing protocol based on partial network coding for underwater sensor networks. AB - Efficient routing protocols for data packet delivery are crucial to underwater sensor networks (UWSNs). However, communication in UWSNs is a challenging task because of the characteristics of the acoustic channel. Network coding is a promising technique for efficient data packet delivery thanks to the broadcast nature of acoustic channels and the relatively high computation capabilities of the sensor nodes. In this work, we present GPNC, a novel geographic routing protocol for UWSNs that incorporates partial network coding to encode data packets and uses sensor nodes' location information to greedily forward data packets to sink nodes. GPNC can effectively reduce network delays and retransmissions of redundant packets causing additional network energy consumption. Simulation results show that GPNC can significantly improve network throughput and packet delivery ratio, while reducing energy consumption and network latency when compared with other routing protocols. PMID- 26029956 TI - Atmospheric interactions and cardiac arrhythmias: Langrish et al. respond. PMID- 26029959 TI - Highly Stereoselective Synthesis of Saccharin-Substituted beta-Lactams via in Situ Generation of a Heterosubstituted Ketene and a Zwitterionic Intermediate as Potential Antibacterial Agents. AB - Highly stereoselective synthesis of saccharin derivatives containing functionalized 2-azetidinone moiety was achieved starting from saccharin as an available precursor. The approach to these valuable heterocyclic scaffolds involves a formal [2pi + 2pi] cycloaddition between Schiff bases and the saccharinylketene as a novel ketene which was generated in situ and an electrocyclic reaction of a zwitterionic intermediate. The identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TO*). Also, the antimicrobial activities of some new substituted saccharin against nine standard bacteria, four bacteria which were isolated from clinical samples and one yeast, were evaluated. PMID- 26029958 TI - Influences of Dilute Organic Adsorbates on the Hydration of Low-Surface-Area Silicates. AB - Competitive adsorption of dilute quantities of certain organic molecules and water at silicate surfaces strongly influence the rates of silicate dissolution, hydration, and crystallization. Here, we determine the molecular-level structures, compositions, and site-specific interactions of adsorbed organic molecules at low absolute bulk concentrations on heterogeneous silicate particle surfaces at early stages of hydration. Specifically, dilute quantities (~0.1% by weight of solids) of the disaccharide sucrose or industrially important phosphonic acid species slow dramatically the hydration of low-surface-area (~1 m(2)/g) silicate particles. Here, the physicochemically distinct adsorption interactions of these organic species are established by using dynamic nuclear polarization (DNP) surface-enhanced solid-state NMR techniques. These measurements provide significantly improved signal sensitivity for near-surface species that is crucial for the detection and analysis of dilute adsorbed organic molecules and silicate species on low-surface-area particles, which until now have been infeasible to characterize. DNP-enhanced 2D (29)Si{(1)H}, (13)C{(1)H}, and (31)P{(1)H} heteronuclear correlation and 1D (29)Si{(13)C} rotational-echo double-resonance NMR measurements establish hydrogen-bond-mediated adsorption of sucrose at distinct nonhydrated and hydrated silicate surface sites and electrostatic interactions with surface Ca(2+) cations. By comparison, phosphonic acid molecules are found to adsorb electrostatically at or near cationic calcium surface sites to form Ca(2+)-phosphonate complexes. Although dilute quantities of both types of organic molecules effectively inhibit hydration, they do so by adsorbing in distinct ways that depend on their specific architectures and physicochemical interactions. The results demonstrate the feasibility of using DNP-enhanced NMR techniques to measure and assess dilute adsorbed molecules and their molecular interactions on low-surface-area materials, notably for compositions that are industrially relevant. PMID- 26029960 TI - Graphene as a Massless Electrode for Ultrahigh-Frequency Piezoelectric Nanoelectromechanical Systems. AB - Designing "ideal electrodes" that simultaneously guarantee low mechanical damping and electrical loss as well as high electromechanical coupling in ultralow-volume piezoelectric nanomechanical structures can be considered to be a key challenge in the NEMS field. We show that mechanically transferred graphene, floating at van der Waals proximity, closely mimics "ideal electrodes" for ultrahigh frequency (0.2 GHz < f0 < 2.6 GHz) piezoelectric nanoelectromechanical resonators with negligible mechanical mass and interfacial strain and perfect radio frequency electric field confinement. These unique attributes enable graphene electrode-based piezoelectric nanoelectromechanical resonators to operate at their theoretically "unloaded" frequency-limits with significantly improved electromechanical performance compared to metal-electrode counterparts, despite their reduced volumes. This represents a spectacular trend inversion in the scaling of piezoelectric electromechanical resonators, opening up new possibilities for the implementation of nanoelectromechanical systems with unprecedented performance. PMID- 26029961 TI - Development and application of a dosimetry model (ExDoM2) for calculating internal dose of specific particle-bound metals in the human body. AB - The objective of the current study was to develop a dosimetry model (ExDoM2) for calculating internal dose of specific particle-bound metals (As, Pb, Cd, Cr and Mn) in the human body. The ExDoM2 is a revised version of a respiratory tract model (ExDoM) incorporating a new particle clearance mechanism in the respiratory tract model and a Physiologically-Based PharmacoKinetic (PBPK) model. The revised respiratory tract model was used to calculate the deposition, clearance and retention of particles in the human respiratory tract and the mass transferred to the oesophagus (gastrointestinal tract) and blood. The PBPK module was used to analyze the distribution of metals (As, Pb, Cd, Cr and Mn) from the blood circulation system to other organs or tissues like liver, kidneys, heart, brain, muscle and bone. The model was applied to calculate the internal human dose for an adult Caucasian male exposed to particulate mass matter (PM), PMPb, PMCd, PMMn and PMCr in an urban area (Athens, Greece). The analysis showed that at the end of the exposure (one day exposure scenario) to PMPb, the major accumulation occurs in the bone, blood and muscle, whereas as regards PMCd the major accumulation occurs in the other tissues, like kidney and liver. In addition, for PMMn, the major accumulation occurs in the other tissues and lungs, whereas as regards PMCr the major accumulation occurs in the gastrointestinal (GI) tract and lungs. Therefore, ExDoM2 is an important feature in studying deposition of particles in the human body. PMID- 26029962 TI - Orchestration of DSB repair: a novel BRCA2 connection. PMID- 26029963 TI - Significant Contributions of Isoprene to Summertime Secondary Organic Aerosol in Eastern United States. AB - A modified SAPRC-11 (S11) photochemical mechanism with more detailed treatment of isoprene oxidation chemistry and additional secondary organic aerosol (SOA) formation through surface-controlled reactive uptake of dicarbonyls, isoprene epoxydiol and methacrylic acid epoxide was incorporated in the Community Multiscale Air Quality Model (CMAQ) to quantitatively determine contributions of isoprene to summertime ambient SOA concentrations in the eastern United States. The modified model utilizes a precursor-origin resolved approach to determine secondary glyoxal and methylglyoxal produced by oxidation of isoprene and other major volatile organic compounds (VOCs). Predicted OC concentrations show good agreement with field measurements without significant bias (MFB ~ 0.07 and MFE ~ 0.50), and predicted SOA reproduces observed day-to-day and diurnal variation of Oxygenated Organic Aerosol (OOA) determined by an aerosol mass spectrometer (AMS) at two locations in Houston, Texas. On average, isoprene SOA accounts for 55.5% of total predicted near-surface SOA in the eastern U.S., followed by aromatic compounds (13.2%), sesquiterpenes (13.0%) and monoterpenes (10.9%). Aerosol surface uptake of isoprene-generated glyoxal, methylglyoxal and epoxydiol accounts for approximately 83% of total isoprene SOA or more than 45% of total SOA. A domain wide reduction of NOx emissions by 40% leads to a slight decrease of domain average SOA by 3.6% and isoprene SOA by approximately 2.6%. Although most of the isoprene SOA component concentrations are decreased, SOA from isoprene epoxydiol is increased by ~16%. PMID- 26029964 TI - AUTOMATED SYNTAX ANALYSES OF DRAWING TWO TANGENT PATTERNS IN CHILDREN WITH LOW AND AVERAGE HANDWRITING ABILITY (.). AB - Sequential strategies of digitized tablet drawings by 6-7-yr.-old children (N = 203) of average and below-average handwriting ability were analyzed. A Beery Visual Motor Integration (BVMI) and a Bender-Gestalt (BG) pattern, each composed of two tangential shapes, were predefined into area sectors for automatic analysis and adaptive mapping of the drawings. Girls more often began on the left side and used more strokes than boys. The below-average handwriting group showed more directional diversity and idiosyncratic strategies. PMID- 26029965 TI - EFFECT OF RESISTANCE TRAINING OF THE WRIST JOINT MUSCLES ON MULTI-DIGIT COORDINATION. AB - This study investigated the effects of a specific regimen of resistance training on coordinated actions of human hand digits during grasping. Participants were instructed to hold a rectangular object with all five digits and to maintain the orientation of the object against transient perturbation. Indices of co-varied actions (i.e., synergies) among multi-digit grasping and rotational actions were quantified. The index of anticipatory changes of co-varied actions among digit forces (i.e., anticipatory synergy adjustment) was also quantified, which represents the controller's ability to predict an upcoming perturbation. The synergies of both grasping force and moment stabilization increased with the training. No change in the index of anticipatory synergy adjustment with training was observed. The current results suggest that the resistance training on the wrist could be an effective way to enhance both voluntary muscle force/torque production capability and ability to stabilize task performances during multi digit prehensile tasks. PMID- 26029966 TI - EVALUATION OF BILATERAL ASYMMETRY BETWEEN UPPER LIMB MASSES IN RIGHT-HANDED YOUNG ADULTS OF BOTH SEXES. AB - The study introduced a novel precise method for measurement and calculation of upper arm mass and to assess the difference between masses of upper limbs on the dominant and non-dominant sides of the body of right-handed participants. Forty healthy untrained male (n = 20; M age = 20.8 yr., SD = 1.2) and female (n = 20; M age = 20.7 yr., SD = 1.3) participants without a history of upper-extremity pathology participated. Kinematic and kinetic data were collected during arm motion. The mass of each arm was calculated. Each participant performed 20 movements with each arm. Most often the dominant arm was more massive than the non-dominant in both sex groups; however, mass was more symmetric for female participants than for male participants. Regression equations related to total body mass were calculated for each arm independently. PMID- 26029967 TI - A BRIEF NOTE ON THE RELATIONSHIP BETWEEN ANXIETY AND PERFORMANCE IN SCUBA DIVING IN ADOLESCENTS: A FIELD STUDY. AB - This study explored the relationship between anxiety and scuba diving performance of young individuals (N = 44; 16.9 yr., SD = 1.2) participating in an introductory scuba diving activity. The question was whether the well-known negative correlation between anxiety and scuba diving performance found for experienced and middle-aged scuba divers will be observed in young participants in their first dive experience. Diving instructors rated standardized scuba diving skills that were correlated with individual state and trait anxiety. There was no relationship between anxiety and scuba diving performance, neither for state nor for trait anxiety. This non-significant correlation between anxiety and performance was in contrast to recent findings observed for experienced divers or those who participated at a scuba diving training program. Considering the differences in methodological design between this study and recent investigations, further research is needed to reveal possible relations between anxiety, scuba diving performance, and panic behavior in beginner-level youth or adults. PMID- 26029968 TI - EFFECT OF DELAYED AUDITORY FEEDBACK, SPEECH RATE, AND SEX ON SPEECH PRODUCTION. AB - Perturbations in Delayed Auditory Feedback (DAF) and speech rate were examined as sources of disruptions in speech between men and women. Fluent adult men (n = 16) and women (n = 16) spoke at a normal and an imposed fast rate of speech with 0, 25, 50, 100, and 200 msec. DAF. The syllable rate significantly increased when participants were instructed to speak at a fast rate, and the syllable rate decreased with increasing DAF delays. Men's speech rate was significantly faster during the fast speech rate condition with a 200 msec. DAF. Disfluencies increased with increasing DAF delay. Significantly more disfluency occurred at delays of 25 and 50 msec. at the fast rate condition, while more disfluency occurred at 100 and 200 msec. in normal rate conditions. Men and women did not display differences in the number of disfluencies. These findings demonstrate sex differences in susceptibility to perturbations in DAF and speech rate suggesting feedforward/feedback subsystems that monitor vocalizations may be different between sexes. PMID- 26029969 TI - THE WORKING MEMORY BENEFITS OF PROPRIOCEPTIVELY DEMANDING TRAINING: A PILOT STUDY (.). AB - The aim of this study was to investigate the effect of proprioception on working memory. It was also of interest whether an acute and highly intensive period of exercise would yield working memory gains. The training group completed a series of proprioceptively demanding exercises. There were also control classroom and yoga groups. Working memory was measured using a backward digit recall test. The data indicated that active, healthy adults who undertook acute, proprioceptively demanding training improved working memory scores compared to the classroom and yoga groups. One possible reason that the training yielded significant working memory gains could be that the training was proprioceptively dynamic, requiring proprioception and at least one other factor-such as locomotion or navigation-at the same time, which may have contributed to the improvements in working memory performance. PMID- 26029970 TI - ERRATUM. PMID- 26029971 TI - THE USE OF THE TRADITIONAL CHINESE VERSION OF THE UNIVERSITY OF PENNSYLVANIA SMELL IDENTIFICATION TEST AND THE SMELL THRESHOLD TEST FOR HEALTHY YOUNG AND OLD ADULTS IN TAIWAN. AB - This study investigated the use of the traditional Chinese version of the University of Pennsylvania Smell Identification Test and the Smell Threshold Test to assess olfactory function for healthy young and old adults in Taiwan. One hundred young adults (50 men; M = 24.34 yr., SD = 2.63; 50 women; M = 24.50 yr., SD = 2.96) and 49 old adults (20 men; M = 60.85 yr., SD = 4.21; 29 women; M = 59.93 yr., SD = 3.97) with normal olfaction completed the traditional Chinese versions of the University of Pennsylvania Smell Identification Test. Of these individuals, 40 young adults and 40 old adults also completed the Smell Threshold Test. The mean of the traditional Chinese versions of the University of Pennsylvania Smell Identification Test scores and Smell Threshold Test thresholds were significantly different between young and old adults. The threshold value for the Smell Threshold Test was lower in both young and old adults as compared to previously established American norms. Both tests require further modifications for clinical use in Taiwan. PMID- 26029972 TI - Antidepressants for the treatment of depression in people with cancer. AB - BACKGROUND: Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have been shown to have a negative impact in terms of quality of life, compliance with anti-cancer treatment, suicide risk and likely even the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy and tolerability of antidepressants in this population group are few and often report conflicting results. OBJECTIVES: To assess the effects and acceptability of antidepressants for treating depressive symptoms in adults (18 years or older) with cancer (any site and stage). SEARCH METHODS: We searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 3), MEDLINE Ovid (1946 to April week 3, 2014), EMBASE Ovid (1980 to 2014 week 17) and PsycINFO Ovid (1987 to April week 4, 2014). We additionally handsearched the trial databases of the most relevant national, international and pharmaceutical company trial registers and drug approving agencies for published, unpublished and ongoing controlled trials. SELECTION CRITERIA: We included RCTs allocating adults (18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis) comparing antidepressants versus placebo, or antidepressants versus other antidepressants. DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a form specifically designed for the aims of this review. The two authors compared the data extracted and then entered data into RevMan 5 with a double-entry procedure. Information extracted included study and participant characteristics, intervention details, outcome measures for each time point of interest, cost analysis and sponsorship by a drug company. We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We retrieved a total of nine studies (861 participants), with seven studies contributing to the meta-analysis for the primary outcome. Four of these compared antidepressants and placebo, two compared two antidepressants and one-three armed study compared two antidepressants and a placebo arm. For the acute phase treatment response (6 to 12 weeks), we found very low quality evidence for the effect of antidepressants as a class on symptoms of depression compared with placebo when measured as a continuous outcome (standardised mean difference (SMD) -0.45, 95% confidence interval (CI) -1.01 to 0.11, five RCTs, 266 participants) or as a proportion of people who had depression (risk ratio (RR) 0.82, 95% CI 0.62 to 1.08, five RCTs, 417 participants). No trials reported data on the follow-up response (more than 12 weeks). In head-to-head comparisons we only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, providing very low quality evidence for the difference between these two classes (SMD 0.08, 95% CI -0.34 to 0.18, three RCTs, 237 participants). No clear evidence of an effect of antidepressants versus either placebo or other antidepressants emerged from the analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low quality evidence). We found very low quality evidence for the effect of antidepressants as a class in terms of dropouts due to any cause compared with placebo (RR 0.87, 95% CI 0.49 to 1.53, six RCTs, 455 participants), as well as between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30, three RCTs, 237 participants). We downgraded the quality of the evidence because the included studies were at an unclear or high risk of bias due to poor reporting, imprecision arising from small sample sizes and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity. AUTHORS' CONCLUSIONS: Despite the impact of depression on people with cancer, available studies were very few and of low quality. This review found very low quality evidence for the effects of these drugs compared with placebo. On the basis of these results clear implications for practice cannot be made. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which agent should be prescribed may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggest a positive safety profile for the SSRIs. Large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer with depressive symptoms, with or without a formal diagnosis of a depressive disorder, are urgently needed to better inform clinical practice. PMID- 26029973 TI - Insight into the Interaction of Graphene Oxide with Serum Proteins and the Impact of the Degree of Reduction and Concentration. AB - As novel applied nanomaterials, both graphene oxide (GO) and its reduced form (rGO) have attracted global attention, because of their excellent properties. However, the lack of comprehensive understanding of their interactions with biomacromolecules highly limits their biomedical applications. This work aims to initiate a systematic study on the property changes of GO/rGO upon interaction with serum proteins and on how their degree of reduction and exposure concentration affect this interaction, as well as to analyze the possible biomedical impacts of the interaction. We found that the adsorption of proteins on GO/rGO occurred spontaneously and rapidly, leading to significant changes in size, zeta potential, and morphology. Compared to rGO, GO showed a higher ability in quenching intrinsic fluorescence of serum proteins in a concentration dependent manner. The protein adsorption efficiency and the types of associated proteins varied, depending on the degree of reduction and concentration of graphene. Our findings indicate the importance of evaluating the potential protein adsorption before making use of GO/rGO in drug delivery, because the changed physicochemical properties after protein adsorption will have significant impacts on safety and effectiveness of these delivery systems. On the other hand, this interaction can also be used for the separation, purification, or delivery of certain proteins. PMID- 26029974 TI - Directionality of Electron Transfer in Type I Reaction Center Proteins: High Frequency EPR Study of PS I with Removed Iron-Sulfur Centers. AB - A key step of photosynthetic solar energy conversion involves rapid light-induced sequential electron-transfer steps that result in the formation of a stabilized charge-separated state. These primary reactions take place in large integral membrane reaction center (RC) proteins, wherein a series of donor/acceptor cofactors are specifically positioned for efficient electron transfer. RCs can be divided in two classes, Type I and Type II and examples of both types, photosystem I (PS I) and photosystem II (PS II), are involved in the oxygenic photosynthesis of higher plants, cyanobacteria, and algae. High-resolution X-ray crystal structures reveal that PS I and PS II contain two nearly symmetric branches of redox cofactors, termed the A and B branches. While unidirectional ET along the A branch in Type II RCs is well established, there is still a debate of whether primary photochemistry in Type I RCs is unidirectional along the A branch or bidirectional proceeding down both of the A and B branches. Light-induced electron transfer through the B branch has been observed in genetically modified PS I and in native PS I pretreated with strong reducing conditions to reduce three [4Fe-4S] clusters, the terminal electron acceptors of PS I; however, the extent of asymmetry of ET along both cofactor branches remains an open question. To prove that bidirectional ET in PS I is not simply an artifact of a reducing environment or genetic modification and to determine the degree of PS I ET asymmetry, we have examined biochemically modified Synechococcus leopoliensis PS I RCs, wherein the [4Fe-4S] clusters FX, FA, and FB have been removed to prevent secondary ET from phylloquinones (A1A/A1B) to FX. For these Fe-removed proteins, we observe that ET along both the A and B branches occurs with a ratio close to 1. Together with previously reported data, the concomitant structural and kinetic information obtained with HF EPR unambiguously proves the bidirectional nature of ET in PS I over a broad temperature range. PMID- 26029976 TI - Magnetic-Assisted, Self-Healable, Yarn-Based Supercapacitor. AB - Yarn-based supercapacitors have received considerable attention recently, offering unprecedented opportunities for future wearable electronic devices (e.g., smart clothes). However, the reliability and lifespan of yarn-based supercapacitors can be seriously limited by accidental mechanical damage during practical applications. Therefore, a supercapacitor endowed with mechanically and electrically self-healing properties is a brilliant solution to the challenge. Compared with the conventional planar-like or large wire-like structure, the reconnection of the broken yarn electrode composed of multiple tiny fibers (diameter <20 MUm) is much more difficult and challenging, which directly affects the restoration of electrical conductivity after damage. Herein, a self-healable yarn-based supercapacitor that ensures the reconnection of broken electrodes has been successfully developed by wrapping magnetic electrodes around a self-healing polymer shell. The strong force from magnetic attraction between the broken yarn electrodes benefits reconnection of fibers in the yarn electrodes during self healing and thus offers an effective strategy for the restoration of electric conductivity, whereas the polymer shell recovers the configuration integrity and mechanical strength. With the design, the specific capacitance of our prototype can be restored up to 71.8% even after four breaking/healing cycles with great maintenance of the whole device's mechanical properties. This work may inspire the design and fabrication of other distinctive self-healable and wearable electronic devices. PMID- 26029975 TI - Safety assessment of adjuvanted vaccines: Methodological considerations. AB - Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID- 26029977 TI - Biomimetic Approach toward the Total Synthesis of rac-2 (Acylmethylene)pyrrolidine Alkaloids. AB - 2-(Acylmethylene)pyrrolidine derivatives were synthesized via intermolecular decarbonylative Mannich reaction from various methyl ketones and 1-alkyl-1 pyrroliniums, generated in situ from 1-alkylprolines. This approach mimics the biosynthetic pathway and provides a direct access to a series of 2 (acylmethylene)pyrrolidine alkaloids, including hygrine, N-methylruspolinone, dehydrodarlinine, and ruspolinone. PMID- 26029978 TI - Acute Effects of a Spinach Extract Rich in Thylakoids on Satiety: A Randomized Controlled Crossover Trial. AB - OBJECTIVE: By retarding fat digestion, thylakoids, the internal photosynthetic membrane system of green plants, promote the release of satiety hormones. This study examined the effect of consuming a single dose of concentrated extract of thylakoids from spinach on satiety, food intake, lipids, and glucose compared to a placebo. DESIGN: Sixty overweight and obese individuals enrolled in a double blind randomized crossover study consumed the spinach extract or placebo in random order at least a week apart. Blood was drawn for assessments of lipids and glucose before a standard breakfast meal, followed 4 hours later by a 5 g dose of the extract and a standard lunch. Visual analog scales were administered before lunch and at intervals until an ad libitum pizza dinner served 4 hours later. Two hours after lunch a second blood draw was conducted. Mixed models were used to analyze response changes. RESULTS: Compared to placebo, consuming the spinach extract reduced hunger (p < 0.01) and longing for food over 2 hours (p < 0.01) and increased postprandial plasma glucose concentrations (p < 0.01). There were no differences in plasma lipids and energy intake at dinner, but males showed a trend toward decreased energy intake (p = 0.08). CONCLUSIONS: At this dose, the spinach extract containing thylakoids increases satiety over a 2-hour period compared to a placebo. Thylakoid consumption may influence gender-specific food cravings. PMID- 26029979 TI - Evaluation of Histidylated Arginine-Grafted Bioreducible Polymer To Enhance Transfection Efficiency for Use as a Gene Carrier. AB - To increase cellular uptake and endosomal escape efficiency, various methods have been studied to efficiently deliver plasmid DNA (pDNA) into the cell. Here, we designed a histidylated arginine-grafted bioreducible polymer (HABP) as a nonviral gene carrier using different ratios of histidine and arginine-grafted bioreducible poly(cystaminebis(acrylamide)-diaminohexane) (poly(CBA-DAH)), known as ABP, to increase cellular uptake and endosomal escape efficiency. HABPs consist of arginine (cell penetrating functionality), histidine (endosome buffering functionality), and a disulfide bond backbone (bioreducible functionality in cytoplasm). These components result in the following: (1) polyplexes are easily taken up by cells, (2) polyplexes can easily escape from the endosome into the cytosol, and (3) pDNA can dissociate from polyplexes in reducing environments such as the cytoplasm. HABPs showed increased buffering capacity over histidine-ungrafted ABP, and HABPs formed nanosized polyplexes with pDNA. These polyplexes were about 90 nm in size and had positive charges of about of 30-40 mV. HABPs/pDNA polyplexes showed enhanced transfection efficiency and no significant cytotoxicity in comparison with polyethylenimine 25 kDa (PEI 25k), histidine-ungrafted ABP, and Lipofectamine (commercial reagent) in human cervical carcinoma (HeLa), rat cardiomyocytes (H9C2), and colon carcinoma (CT26) cells. PMID- 26029980 TI - Investigating the in Vitro Thermal Stability and Conformational Flexibility of Estrogen Receptors as Potential Key Factors of Their in Vivo Activity. AB - Among hormone-inducible transcription factors, estrogen receptors (ERs) play important roles in tissue growth and differentiation, via either direct or indirect binding, in the nucleus, to specific DNA targets called estrogen responsive elements (EREs), or through nongenomic pathways. In humans, two estrogen receptor isoforms (hERs), designated hERalpha and hERbeta, have been identified. These two hERs, encoded by genes located on distinct chromosomes, exhibit divergent tissue-specific functions and different subcellular distributions depending on their binding status, free or complexed to their cognate ligands. Because it is hypothesized that such distinct behaviors may arise from various conformational stabilities and flexibilities, the effect of salt concentration and temperature was studied on the free and estrogen-activated hERalpha and hERbeta. Our results show that the conformational stability of hERbeta is weakly modulated by salt concentration as opposed to hERalpha. In addition, we show that the estrogen-bound hERs exhibit a more constrained structure than the unliganded ones and that their conformational flexibility is more affected by diethylstilbestrol binding than that of estradiol, 4 hydroxytamoxifen, or raloxifen. In line with these results, conformational analysis and computational docking were performed on hERalpha and hERbeta, which confer molecular support of a diethylstilbestrol-induced restrained flexibility as compared to other ligands. We found that Trp383 in hERalpha and Trp335 in hERbeta can closely interact with the NR-box motif of the H12 helix and act as a gatekeeper of the agonist-bound versus antagonist-bound conformations. Altogether, our study contributes to an improved knowledge of the diverse physicochemical properties of full-length hERs, which will help in our understanding of their distinct cellular roles in various cellular contexts. PMID- 26029981 TI - A Huge Fetal Sacrococcygeal Teratoma with a Vascular Disruption Sequence. AB - Fetal sacrococcygeal teratomas (SCTs) occur in one to two per 20 000 pregnancies that cause high-output cardiac failure. High-output cardiac failure leads to polyhydramnios, hydrops, intrauterine fetal demise and preterm birth. Vascular disruption defects refer to those involving the interruption or destruction of some part of the fetal vasculature. We present a rare case of huge SCT causing multiple fetal disruption defects like cleft lip and palate and limb anomalies besides hydrops. PMID- 26029983 TI - Maladaptive Core Beliefs and their Relation to Generalized Anxiety Disorder. AB - Research has demonstrated that individuals with generalized anxiety disorder (GAD) hold unhelpful beliefs about worry, uncertainty, and the problem-solving process. Extant writings (e.g., treatment manuals) also suggest that other types of maladaptive beliefs may characterize those with GAD. However, these other beliefs have received limited empirical attention and are not an explicit component of cognitive theories of GAD. The present study examined the extent to which dysfunctional attitudes, early maladaptive schemas, and broad self-focused and other-focused beliefs explain significant variance in GAD symptoms, over and above negative and positive beliefs about worry, negative beliefs about uncertainty, and negative beliefs about problems. N = 138 participants classified into Probable GAD and Non-GAD groups completed self-report measures. After controlling for trait anxiety and depressive symptoms, only beliefs about worry, negative beliefs about uncertainty, and schemas reflecting unrelenting standards (e.g., "I must meet all my responsibilities all the time"), the need to self sacrifice (e.g., "I'm the one who takes care of others"), and less positive views of other people and their intentions (e.g., lower endorsement of views such as "other people are fair"), were unique correlates of Probable GAD versus Non-GAD or GAD severity. Theoretical and clinical implications are discussed. PMID- 26029982 TI - Mutant lamin A links prophase to a p53 independent senescence program. AB - Expression of oncogenes or short telomeres can trigger an anticancer response known as cellular senescence activating the p53 and RB tumor suppressor pathways. This mechanism is switched off in most tumor cells by mutations in p53 and RB signaling pathways. Surprisingly, p53 disabled tumor cells could be forced into senescence by expression of a mutant allele of the nuclear envelope protein lamin A. The pro-senescence lamin A mutant contains a deletion in the sequence required for processing by the protease ZMPSTE24 leading to accumulation of farnesylated lamin A in the nuclear envelope. In addition, the serine at position 22, a target for CDK1-dependent phosphorylation, was mutated to alanine, preventing CDK1 catalyzed nuclear envelope disassembly. The accumulation of this mutant lamin A compromised prophase to prometaphase transition leading to invaginations of the nuclear lamina, nuclear fragmentation and impaired chromosome condensation. Cells exited this impaired mitosis without cytokinesis and re-replicated their DNA ultimately arresting in interphase as polyploid cells with features of cellular senescence including increased expression of inflammatory gene products and a significant reduction of tumorigenicity in vivo. PMID- 26029984 TI - Resilience and related factors in urban, mid-aged Spanish women. AB - OBJECTIVE: To assess resilience and related factors among urban, mid-aged Spanish women. METHODS: This was a cross-sectional study performed in 227 women aged 40 65 years who filled out the 14-item Wagnild and Young Resilience Scale (WYRS-14), the Menopause Rating Scale (MRS) and a questionnaire containing personal sociodemographic data. RESULTS: For the whole sample, median (interquartile range) age and total WYRS-14 score were 52.4 (8.7) years and 79 (20.0) points, respectively. Resilience score was inversely related to non-working status, non university studies, depressed mood, perimenopausal status, and higher MRS total scores (>= 17). Using the 25th percentile of the obtained total WYRS-14 score as a cut-off value to define lower resilience (< 68.0 points), logistic regression analysis determined that low resilience was related to being unemployed, having depressed mood and being perimenopausal. Drinking less than 3 units/day of alcohol was significantly related to higher resilience. CONCLUSION: In this sample of urban, mid-aged Spanish women, low resilience (lower WYRS-14 scores) was related to unemployment status, depressed mood and severe menopausal symptoms. PMID- 26029985 TI - Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis. AB - OBJECTIVES: A history of prior fracture is one of the strongest predictors of a future fragility fracture. In FREEDOM, denosumab significantly reduced the risk of new vertebral, non-vertebral, and hip fractures. We carried out a post-hoc analysis of FREEDOM to characterize the efficacy of denosumab in preventing secondary fragility fractures in subjects with a prior fracture. METHODS: A total of 7808 women aged 60-90 years with a bone mineral density T-score of less than - 2.5 but not less than - 4.0 at either the lumbar spine or total hip were randomized to subcutaneous denosumab 60 mg or placebo every 6 months for 36 months. The anti-fracture efficacy of denosumab was analyzed by prior fracture status, to assess secondary fragility fracture, and by subject age, prior fracture site and history of prior osteoporosis medication use. RESULTS: A prior fragility fracture was reported for 45% of the overall study population. Compared with placebo, denosumab significantly reduced the risk of a secondary fragility fracture by 39% (incidence, 17.3% vs. 10.5%; p < 0.0001). Similar results were observed regardless of age or prior fracture site. In the overall population, denosumab significantly reduced the risk of a fragility fracture by 40% (13.3% vs. 8.0%; p < 0.0001), with similar results observed regardless of history of prior osteoporotic medication use. CONCLUSIONS: Denosumab reduced the risk of fragility fractures to a similar degree in all risk subgroups examined, including those with prior fragility fractures. Identifying and treating high-risk individuals could help to close the current care gap in secondary fracture prevention. PMID- 26029986 TI - Validation of the traditional Chinese version of the Menopausal Rating Scale with WHOQOL-BREF. AB - Objective To assess the criterion validity, construct validity and test-retest reliability of the traditional Chinese language version of the Menopause Rating Scale (MRS-TC version). Methods This was an observational, cross-sectional study covering hospital and community samples of 317 women aged 39-62 years. Two questionnaires were administered, namely, the MRS-TC version, made up of 11 items in three dimensions, and the World Health Organization Quality of Life-BREF (WHOQOL-BREF). The intraclass correlation coefficient was used to examine the test-retest reliability of the questionnaire on two separate occasions, 2 weeks apart. The internal consistency was assessed with Cronbach's alpha. To evaluate criterion validity, the relationship between the individual items and dimension scores of both instruments was estimated. Pearson's correlation was used to assess convergent and discriminant validity; construct validity was evaluated by comparing the mean scores of menopausal and non-menopausal women for each of the MRS dimensions. Results The final questionnaire comprised 11 items in three dimensions. The intra-class correlation (ICC) for the test-retest reliability ranged from 0.83 to 0.93; values of Cronbach's alpha for psychological, somatic, and urogenital symptom domains were 0.88, 0.68, and 0.59, respectively. For the convergent and discriminant validity, the correlations between the individual questionnaire and the WHOQOL-BREF were significant; those with the MRS dimensions were significantly negatively associated for the physical, psychological, social and environmental domains. Conclusion The MRS-TC version using the traditional Chinese language is a reliable and valid questionnaire for assessing menopausal symptoms and global quality of life in climacteric women. PMID- 26029987 TI - Vaginal erbium laser: the second-generation thermotherapy for the genitourinary syndrome of menopause. AB - Aim To evaluate the effects of the vaginal erbium laser (VEL) in the treatment of postmenopausal women suffering from genitourinary syndrome of menopause (GSM). Method GSM was assessed in postmenopausal women before and after VEL (one treatment every 30 days, for 3 months; n = 45); the results were compared with the effects of a standard treatment for GSM (1 g of vaginal gel containing 50 MUg of estriol, twice weekly for 3 months; n = 25). GSM was evaluated with subjective (visual analog scale, VAS) and objective (Vaginal Health Index Score, VHIS) measures. In addition, in 19 of these postmenopausal women suffering from stress urinary incontinence (SUI), the degree of incontinence was evaluated with the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) before and after VEL treatments. Results VEL treatment induced a significant decrease of VAS of both vaginal dryness and dyspareunia (p < 0.01), with a significant (p < 0.01) increase of VHIS. In postmenopausal women suffering from mild to moderate SUI, VEL treatment was associated with a significant (p < 0.01) improvement of ICIQ-SF scores. The effects were rapid and long lasting, up to the 24th week of the observation period. VEL was well tolerated with less than 3% of patients discontinuing treatment due to adverse events. Conclusion This pilot study demonstrates that VEL induces a significant improvement of GSM, including vaginal dryness, dyspareunia and mild to moderate SUI. Further studies are needed to explore the role of laser treatments in the management of GSM. PMID- 26029988 TI - Melatonin in aging women. AB - Melatonin is a neurohormone secreted mainly by the pineal gland that controls circadian rhythm, which is primarily regulated by light. Although melatonin levels are known to be altered in individuals with sleep disorders, melatonin also has modulatory effects on other body systems, including the skeletal and immune systems. In addition, melatonin has been shown to interfere with carbohydrate and lipid metabolism and to have significant antioxidant effects, both directly and via its metabolites. Melatonin levels vary throughout human life and are known to decrease with age but the effects of declining melatonin levels are poorly understood. In women, this age-related decrease in melatonin levels coincides with the menopause. This review aims to summarize the impact of altered melatonin levels in aging women and the outcomes of exogenous replacement therapies. PMID- 26029989 TI - Randomized clinical trial of a handheld cooling device (Menopod(r)) for relief of menopausal vasomotor symptoms. AB - OBJECTIVE: Anecdotal reports suggest that application of a cool device to the back of the neck at the onset of a hot flush can afford symptomatic relief. The effects of a novel handheld mechanical cooling device in a population of perimenopausal women with moderate-to-severe vasomotor symptoms were evaluated. METHODS: In this randomized, double-blind, sham-controlled pilot study, 40 perimenopausal women experiencing >= 7 moderate-to-severe hot flushes per day were recruited at a single university site. Women were randomized to the active (n = 20) or sham (n = 20) device, which was applied to the back of the neck with each hot flush over the 4-week treatment period. Hot flush scores were calculated based on frequency and severity of symptoms. The Carpenter Hot Flash Related Daily Interference Scale and Zung Anxiety Scale were used to evaluate impact on quality of life. At study end, participants completed an open-ended questionnaire to assess the degree of unblinding and overall subjective improvement in symptoms with use of the device. RESULTS: No statistically significant differences were observed between the effects of the active and sham device. However, thematic analysis of the open-ended questionnaire revealed that 12/17 women (70.6%) in the active group, compared to 4/18 (22.2%) women in the sham group felt the device provided some symptomatic relief. CONCLUSIONS: Although the majority of women using the active device acknowledged that its cooling effect afforded a degree of symptomatic relief, the symptom scores chosen for this pilot study did not reflect a beneficial effect. PMID- 26029991 TI - A Single-Site Technique of Multiple Lymphatic-Venous Anastomoses for the Treatment of Peripheral Lymphedema: Long-Term Clinical Outcome. AB - BACKGROUND: The authors' vast surgical experience in the treatment of primary and secondary peripheral lymphedemas using microsurgical procedures at the Centre of Lymphatic Surgery and Microsurgery of the University of Genoa, Italy, is reported. The objective is to describe the techniques and the long-lasting clinical outcomes based on 40 years' experience and research, with particular reference to advanced derivative and reconstructive lymphatic microsurgery at a single site. METHODS: More than 2,600 patients affected by upper and/or lower limb lymphedema, between 1973 and 2013, underwent lymphatic microsurgery. Derivative multiple lymphatic-venous anastomoses (MLVA) or lymphatic pathway reconstruction using interpositioned vein-grafted shunts multiple lymphatic venous lymphatic anastomoses (MLVLA) were performed at a single site, either the axillary or inguinal-crural region. Patients were followed up for a minimum of 5 years to over 20 years. Clinical outcomes included excess limb volume (ELV), frequency of dermatolymphangioadenitis (DLA) attacks, and use of conservative therapies. RESULTS: Compared with preoperative conditions, patients obtained significant reductions in ELV of over 84%, with an average follow-up of 10 years or more. Over 86% of patients with earlier stages of disease (stage IB or IIA) progressively stopped using conservative therapies and 42% of patients with later stages (stages IIB and III) decreased the frequency of physical therapies. DLA attacks considerably reduced by over 91%. CONCLUSION: MLVA or MLVLA techniques when performed at a single site produce excellent outcomes in the treatment of both primary and secondary lymphedemas, giving the possibility of a complete restoration of lymphatic flow in early stages of disease when tissue changes are minimal. PMID- 26029992 TI - 2D Hybrid Nanostructure of Reduced Graphene Oxide-CdS Nanosheet for Enhanced Photocatalysis. AB - Graphene-based hybrid nanostructures have recently emerged as a new class of functional materials for light-energy conversion and storage. Here, we have synthesized reduced graphene oxide (RGO)-semiconductor composites to improve the efficiency of photocatalysis. Zero-dimensional CdS nanoparticles (0D), one dimensional CdS nanorods (1D), and two-dimensional CdS nanosheets (2D) are grafted on the RGO sheet (2D) by a surface modification method using 4 aminothiophenol (4-ATP). Structural analysis confirms the attachment of CdS nanocrystals with RGO, and the strong electronic interaction is found in the case of a CdS nanosheet and RGO, which has an influence on photocatalytic properties. The degradation of dye under visible light varies with changing the dimension of nanocrystals, and the catalytic activity of the CdS NS/RGO composite is ~4 times higher than that of CdS nanoparticle/RGO and 3.4 times higher than that of CdS nanorod/RGO composite samples. The catalytic activity of the CdS nanosheet/RGO composite is also found to be ~2.5 times than that of pure CdS nanosheet samples. The unique 2D-2D nanoarchitecture would be effective to harvest photons from solar light and transport electrons to reaction sites with respect to other 0D-2D and 1D-2D hybrid systems. This observation can be extended to other graphene based inorganic semiconductor composites, which can provide a valuable opportunity to explore novel hybrid materials with superior visible-light-induced catalytic activity. PMID- 26029994 TI - Understanding the Mechanism of Enzyme-Induced Formation of Lyotropic Liquid Crystalline Nanoparticles. AB - Liquid crystalline nanoparticles have shown great potential for application in fields of drug delivery and agriculture. However, optimized approaches to generating these dispersions have long been sought after. This study focused on understanding the mechanism of formation of cubosomes during the recently reported enzymatic approach and extending the approach to alternative lipid types other than phytantriol. The chain length of digestible lipids was found to influence the effectiveness of triglycerides in disrupting the equilibrium cubic phase structure to form the emulsion precursor. In general, a greater hydrophobicity of the triglyceride required a lower concentration to inhibit liquid crystal structure formation. Selachyl alcohol was also examined due to its nondigestible trait and ability to form the inverted hexagonal phase. Digestion of its precursor emulsion formed hexosomes analogous to the phytantriol-based systems. Finally, the assumption that fatty acids liberated during digestion needed to partition out of the nondigestible lipids for the re-formation of the phase structure was found to be untrue. Their ionization state, however, did have an effect on the resulting nanostructure, and this unique property could potentially provide a useful attribute for oral drug delivery systems. PMID- 26029993 TI - Overexpression of the FoxO1 Ameliorates Mesangial Cell Dysfunction in Male Diabetic Rats. AB - The dysfunction of mesangial cells (MCs) in high-glucose (HG) conditions plays pivotal role in inducing glomerular sclerosis by causing the imbalance between generation and degradation of extracellular matrix (ECM) proteins, which ultimately leads to diabetic nephropathy. This study was designed to determine the function of forkhead box protein O1 (FoxO1), an important transcription factors in regulating cell metabolism and oxidative stress, in MCs in HG conditions. Up-regulation of fibronectin, collagen type IV, and plasminogen activator inhibitor (PAI-1) was observed under HG conditions in vivo and in vitro, accompanied with elevation of protein kinase B (Akt) phosphorylation and reduction of FoxO1 bioactivity. After overexpression of constitutively active (CA) FoxO1 in vivo and in vitro by using lentivirus vector, in vivo and in vitro, FoxO1 expression and activity was increased, in accordance with up-regulation of antioxidative genes (catalase and superoxide dismutase, leading to alleviated oxidative stress as well as attenuated Akt activity, whereas overexpression of wild type-FoxO1 only expressed partial effect. Moreover, CA-FoxO1 decreased the expression of fibronectin, collagen type IV, and PAI-1, causing amelioration of renal pathological changes and decrease of ECM protein deposition in glomerulus. Overexpression of CA-FoxO1 in renal cortex also decreased activin type-I receptor like kinase-5 levels and increased signaling mothers against decapentaplegic (Smad) 7 levels, and simultaneously inhibited Smad3 phosphorylation. Results from in vitro study indicated that increased combination of FoxO1 and Smad3 may interfere with the function of Smad3, including Smad3 phosphorylation and translocation, interaction with cAMP response element binding protein (CREB) binding protein, and binding with PAI-1 promoter. Together, our findings shed light on the novel function of FoxO1 in inhibiting ECM deposition, which is beneficial to ameliorate MC dysfunction. PMID- 26029995 TI - Liver Transplant for Fulminant Hepatic Failure: A Single-Center Experience. AB - OBJECTIVES: Acute liver failure is a life-threatening condition with sudden onset liver injury, decreased liver functions, hepatic encephalopathy, and coagulopathy in patients without preexisting liver disease. In this study, we sought to evaluate the results of liver transplant as a treatment for acute liver failure. MATERIALS AND METHODS: Between November 1988 and March 2015, we performed 482 liver transplants in 471 patients. We performed 36 liver transplants in 35 patients because of acute liver failure. Only 5 of these were from deceased donors. Thirty of those 34 patients were pediatric (85%) and 5 were adults (15%). RESULTS: Five patients died (4 in early postoperative period and 1 during the 18th month of living-donor liver transplant). We diagnosed 11 acute rejections (32%); 6 biliary leaks (17%); 6 intraabdominal hemorrhage (17%); 5 hepatic arterial thromboses (15%), and 1 venous complication (3%) during the early postoperative period. We have no morbidity or mortality in living-donor liver transplants. CONCLUSIONS: Living-donor liver transplants are an efficient and successful treatment for acute liver failure patients. In our center, we mostly consider and prefer living-donor liver transplants to deceased-donor liver transplant because of the paucity of organ donation, especially for pediatric patients. Considering acceptable postoperative complications, living-donor liver transplant is a lifesaving treatment for acute liver failure. PMID- 26029996 TI - Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors. AB - Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks. PMID- 26029998 TI - Dragon (repulsive guidance molecule b, RGMb) is a novel gene that promotes colorectal cancer growth. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer death. However, the molecular mechanisms underlying CRC initiation, growth and metastasis are poorly understood. Dragon (RGMb), a member of the repulsive guidance molecule (RGM) family, has been recently identified as a co-receptor for bone morphogenetic protein (BMP) signaling, but the role of Dragon in CRC development is undefined. Here, we show that Dragon expression was increased in colon cancer tissues compared to control tissues in CAC mouse model and in human patients. Dragon promoted proliferation of CT26.WT and CMT93 colon cancer cells and accelerated tumor growth in the xenograft mouse model. Dragon's action on colon cancer development was mediated via the BMP4-Smad1/5/8 and Erk1/2 pathways. Therefore, our results have revealed that Dragon is a novel gene that promotes CRC growth through the BMP pathway. Dragon may be exploited as a potential therapeutic target for CRC treatment. PMID- 26029997 TI - Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells. AB - Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in melanoma, yet it is inactive in the majority of cases due to dysregulation of upstream pathways. Thus, we screened for compounds that can activate p53 in melanoma cells. Here we describe effects of the small molecule MJ25 (2-{[2-(1,3 benzothiazol-2-ylsulfonyl)ethyl]thio}-1,3-benzoxazole), which increased the level of p53-dependent transactivation both as a single agent and in combination with nutlin-3. Furthermore, MJ25 showed potent cytotoxicity towards melanoma cell lines, whilst having weaker effects against human normal cells. MJ25 was also identified in an independent screen as an inhibitor of thioredoxin reductase 1 (TrxR1), an important selenoenzyme in the control of oxidative stress and redox regulation. The well-characterized TrxR inhibitor auranofin, which is FDA approved and currently in clinical trials against leukemia and a number of solid cancers, displayed effects comparable with MJ25 on cells and led to eradication of cultured melanoma cells at low micromolar concentrations. In conclusion, auranofin, MJ25 or other inhibitors of TrxR1 should be evaluated as candidate compounds or leads for targeted therapy of malignant melanoma. PMID- 26029999 TI - Mutation of N-linked glycosylation at Asn548 in CD133 decreases its ability to promote hepatoma cell growth. AB - The membrane glycoprotein CD133 is a popular marker for cancer stem cells and contributes to cancer initiation and invasion in a number of tumor types. CD133 promotes tumorigenesis partly through an interaction between its phosphorylated Y828 residue and the PI3K regulatory subunit p85, and the interaction with beta catenin. Although CD133 glycosylation is supposed to be associated with its function, the contribution of N-glycosylation to its functions remains unclear. Here we analyzed the exact site(s) of N-glycosylation in CD133 by mass spectrometry and found that all eight potential N-glycosylation sites of CD133 could be indeed occupied by N-glycans. Loss of individual N-glycosylation sites had no effect on the level of expression or membrane localization of CD133. However, mutation at glycosylation site Asn548 significantly decreased the ability of CD133 to promote hepatoma cell growth. Furthermore, mutation of Asn548 reduced the interaction between CD133 and beta-catenin and inhibited the activation of beta-catenin signaling by CD133 overexpression. Our results identified the characteristics and function of CD133 glycosylation sites. These data could potentially shed light on molecular regulation of CD133 by glycosylation and enhance our understanding of the utility of glycosylated CD133 as a target for cancer therapies. PMID- 26030000 TI - Estrogenic gper signaling regulates mir144 expression in cancer cells and cancer associated fibroblasts (cafs). AB - MicroRNAs (miRNAs) are small non coding RNA molecules that play a crucial role in several pathophysiological conditions, including cancer. The stimulation of hormone-sensitive tumors by estrogens are mediated by estrogen receptor (ER)alpha and G protein estrogen receptor (GPER). Previous studies have reported that ERalpha regulates miRNA expression, while this ability of GPER remains to be elucidated. Here, we demonstrate that in SkBr3 breast cancer and HepG2 hepatocarcinoma cells, 17beta-estradiol (E2) and the selective GPER ligand G-1 induce miR144 expression through GPER and the involvement of the PI3K/ERK1/2/Elk1 transduction pathway. Moreover, we show that E2 and G-1 down-regulate through miR144 the onco-suppressor Runx1 and increase cell cycle progression. The capability of E2 and G-1 in triggering the induction of miR144 and the down regulation of Runx1 was also confirmed in cancer-associated fibroblasts (CAFs) that are main components of the tumor microenvironment driving cancer progression. Further confirming these results, Runx1 protein levels were found decreased in tumor xenografts upon G-1 treatment. On the basis of our findings miR144 and Runx1 may be included among the oncotargets of GPER action. Moreover, the present data provide new insights regarding the ability of estrogens to trigger the GPER/miR144/Runx1 transduction pathway toward the stimulation of cancer progression. PMID- 26030001 TI - Demographically Corrected Normative Standards for the English Version of the NIH Toolbox Cognition Battery. AB - Demographic factors impact neuropsychological test performances and accounting for them may help to better elucidate current brain functioning. The NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neuropsychological tool, yet the original norms developed for the battery did not adequately account for important demographic/cultural factors known to impact test performances. We developed norms fully adjusting for all demographic variables within each language group (English and Spanish) separately. The current study describes the standards for individuals tested in English. Neurologically healthy adults (n=1038) and children (n=2917) who completed the NIH Toolbox norming project in English were included. We created uncorrected scores weighted to the 2010 Census demographics, and applied polynomial regression models to develop age-corrected and fully demographically adjusted (age, education, sex, race/ethnicity) scores for each NIHTB-CB test and composite (i.e., Fluid, Crystallized, and Total Composites). On uncorrected NIHTB-CB scores, age and education demonstrated significant, medium to-large associations, while sex showed smaller, but statistically significant effects. In terms of race/ethnicity, a significant stair-step effect on uncorrected NIHTB-CB scores was observed (African American 35% of the Exclusive Economic Zone) predicted in seven South Pacific countries and territories (Fiji, Matthew & Hunter, Nauru, New Caledonia, Tonga, Vanuatu and Wallis & Futuna). Predicted habitat also varied among species, with the proportion of predicted habitat highest for Aphareus and lowest for Etelis. Despite data paucity, the relationship between deep-sea snapper presence and their environments was sufficiently strong to predict their distribution across a large area of the Pacific Ocean. Our results therefore provide a strong baseline for designing monitoring programs that balance resource exploitation and conservation planning, and for predicting future distributions of deep-sea snappers. PMID- 26030068 TI - Concerns about direct potable reuse. PMID- 26030069 TI - Air quality and climate change: a delicate balance. PMID- 26030071 TI - Knowledge, Attitudes Toward, and Acceptability of Genetic Modification among Western Balkan University Students of Life Sciences (AGREE Study). AB - BACKGROUND: There are still no data on the attitudes and acceptance of genetic modification (GM) food in European developing countries, such as the Western Balkan countries. The aim of the study was to assess the knowledge, attitudes, and acceptance of GM but also to shed light on the multifactorial process leading to acceptance of genetic modifications among Western Balkan students of life sciences. METHODS: In this cross-sectional study, the final study population sample was composed of 1251 university students. The instrument for data collection was a questionnaire consisting of 49 items composed of 5 sections taken from the literature. Attitudes toward GM were analyzed by using Q-mode factor analysis and principal component analysis was run for the assessment of perception of personal health risks. The acceptability of GM was analyzed in binary probit models assessing the acceptability of GM products in different areas of application with Q models, sociodemographic variables, perception of personal health risks factors, respondents' knowledge about biotechnology, gender, and age as explanatory variables. RESULTS: This study demonstrated that students of life sciences supported the implementation of GM in industry and medicine production but not in food production. Their acceptance was most influenced by 3 out of 5 attitude models that were identified (p < 0.0001). Regarding the perception of personal health risks, the factor "credence risks" was seen as a negative predictor of acceptance of GM in industry and food production (p < 0.05). The main knowledge predictor of rejecting GM was misconception, whereas real knowledge had no impact (p < 0.0001). CONCLUSION: The AGREE study provided the first rough picture of the knowledge, attitudes, and acceptance of GM in this area. Given the target population, it could be expected that the general population's acceptance of all observed elements, especially knowledge, would be lower. PMID- 26030070 TI - Differentially Expressed Genes in Resistant and Susceptible Common Bean (Phaseolus vulgaris L.) Genotypes in Response to Fusarium oxysporum f. sp. phaseoli. AB - Fusarium wilt of common bean (Phaseolus vulgaris L.), caused by Fusarium oxysporum Schlechtend.:Fr. f.sp. phaseoli (Fop), is one of the most important diseases of common beans worldwide. Few natural sources of resistance to Fop exist and provide only moderate or partial levels of protection. Despite the economic importance of the disease across multiple crops, only a few of Fop induced genes have been analyzed in legumes. Therefore, our goal was to identify transcriptionally regulated genes during an incompatible interaction between common bean and the Fop pathogen using the cDNA amplified fragment length polymorphism (cDNA-AFLP) technique. We generated a total of 8,730 transcript derived fragments (TDFs) with 768 primer pairs based on the comparison of a moderately resistant and a susceptible genotype. In total, 423 TDFs (4.9%) displayed altered expression patterns after inoculation with Fop inoculum. We obtained full amplicon sequences for 122 selected TDFs, of which 98 were identified as annotated known genes in different functional categories based on their putative functions, 10 were predicted but non-annotated genes and 14 were not homologous to any known genes. The 98 TDFs encoding genes of known putative function were classified as related to metabolism (22), signal transduction (21), protein synthesis and processing (20), development and cytoskeletal organization (12), transport of proteins (7), gene expression and RNA metabolism (4), redox reactions (4), defense and stress responses (3), energy metabolism (3), and hormone responses (2). Based on the analyses of homology, 19 TDFs from different functional categories were chosen for expression analysis using quantitative RT PCR. The genes found to be important here were implicated at various steps of pathogen infection and will allow a better understanding of the mechanisms of defense and resistance to Fop and similar pathogens. The differential response genes discovered here could also be used as molecular markers in association mapping or QTL analysis. PMID- 26030072 TI - Defined nanoscale chemistry influences delivery of peptido-toxins for cancer therapy. AB - We present an in-silico-to-in-vitro approach to develop well-defined, self assembled, rigid-cored polymeric (Polybee) nano-architecture for controlled delivery of a key component of bee venom, melittin. A competitive formulation with lipid-encapsulated (Lipobee) rigid cored micelle is also synthesized. In a series of sequential experiments, we show how nanoscale chemistry influences the delivery of venom toxins for cancer regression and help evade systemic disintegrity and cellular noxiousness. A relatively weaker association of melittin in the case of lipid-based nanoparticles is compared to the polymeric particles revealed by energy minimization and docking studies, which are supported by biophysical studies. For the first time, the authors' experiment results indicate that melittin can play a significant role in DNA association dissociation processes, which may be a plausible route for their anticancer activity. PMID- 26030073 TI - Extension of Bolar exemption law: what will this mean for UK drug research? PMID- 26030074 TI - New changes in US patent term adjustment calculations after Novartis v. Lee. PMID- 26030075 TI - Generic product entry in EU markets. PMID- 26030076 TI - Intellectual property protection of molecules/proteins/genes/natural products: will recent case law change patent practice in the pharmaceutical industry? PMID- 26030078 TI - 10 years after implementation of TRIPS obligations in India. AB - The Patent (Amendment) Act of 2005 enforced after TRIPS raises many issues which hinder growth of Indian pharma companies. To tackle this, Indian pharma companies doubled their R&D expenditure and became significant players in global generic drug market. Indian pharmaceutical companies, which predominantly focused on import-oriented market, shifted to research-based approach by signing various agreements with MNCs that led to M&A and technology transfer. At the same time growth in R&D activities increased ANDA and DMF filing in the USA and Europe. Companies also kept their social responsibility by selling medicines at affordable price to patients. This paper highlights the changing business scenario of Indian pharmaceutical companies to counteract various issues evolved from new patent regime after TRIPS. PMID- 26030079 TI - Phosphodiesterase 10A inhibitors: analysis of US/EP patents granted since 2012. AB - Phosphodiesterases are enzymes that metabolically inactivate the intracellular second messengers 3',5'-cyclic adenosine and guanosine monophosphate contributing to the control of multiple biological processes. Among them, PDE10A has the most restricted distribution with high expression in striatal medium spiny neurons. Dysfunction of this key brain circuit has been associated with different psychiatric and neurodegenerative disorders. The unique role of PDE10A, together with its increased pharmacological characterization, have prompted enormous interest in investigating the potential of inhibitors of this enzyme as potential novel therapeutic agents This article reviews PDE10A related patents issued in the period 2012-2014 in the USA and Europe offering also a perspective on potential avenues for the future clinical development of phosphodiesterase 10A inhibitors. PMID- 26030080 TI - Novel drug therapies in myeloid leukemia. AB - Both acute myeloid leukemia and chronic myeloid leukemia are thought to arise from a subpopulation of primitive cells, termed leukemic stem cells that share properties with somatic stem cells. Leukemic stem cells are capable of continued self-renewal, and are resistant to conventional chemotherapy and are considered to be responsible for disease relapse. In recent years, improved understanding of the underlying mechanisms of myeloid leukemia biology has led to the development of novel and targeted therapies. This review focuses on clinically relevant patent applications and their relevance within the known literature in two areas of prevailing therapeutic interest, namely monoclonal antibody therapy and small molecule inhibitors in disease-relevant signaling pathways. PMID- 26030081 TI - TRPC channel modulators and their potential therapeutic applications. AB - The transient receptor potential canonical (TRPC) channels have gained interest as potential therapeutic targets for respiratory diseases, neurological disorders, cardiovascular disorders, pain, cancer and several other pathological conditions. The TRPC receptor family consists of seven isoforms (C1-C7) and has been divided into three subfamilies based on structural and functional similarities. Several pharmaceutical companies and academic institutes are currently exploring the potential of these nonselective cation channels as therapeutic targets using small molecule inhibitors or modulators. This review covers patents on TRPC receptor modulators published from 2002 to 2014. The review mainly focuses on TRPC receptor target biology, small and large molecule modulators and their therapeutic potential. PMID- 26030082 TI - Newer patents in antimycobacterial therapy. AB - Tuberculosis caused by Mycobacterium tuberculosis is a global health emergency. This deadly disease has far-reaching social and economic implications. Diseased individuals need prolonged polypharmacy which is not without ill effects. Treatment compliance is often compromised contributing to rising resistance. HIV co-infection has further worsened the scenario. On the other hand, no new anti-TB drug has hit the market in last 4-5 decades. After a long latency, only the last few years have witnessed growing research in this direction and a widening anti TB drug clinical pipeline. The compounds in preclinical stage of development have also shown a heartening increase. The present review is an attempt to discuss novel promising patents in this field. PMID- 26030083 TI - Detection of segmental chromosome copy number gains by improved fluorescence in situ hybridization techniques. AB - Fluorescence in situ hybridization (FISH) techniques are used for the targeted investigation of microduplication, microdeletion and structural rearrangements. More recently FISH techniques using probes specific to the region of interest have been applied to confirm genomic copy number variation (CNV). However, there are limitations in the assessment of FISH signal patterns. Tandem duplication of small CNVs appear as an increased signal size when standard FISH methods are applied. As such, interpretation of signal patterns is subjective and further complicated in the presence of mosaicism. Here we describe a pre-treatment that enhances the demonstration of tandem duplication. We assessed the sensitivity to CNVs of a minimum of 120 kb in size and determined that the lower limit of detection of mosaicism is 10 percent. In contrast to some methods of chromatin extension and elongation, this technique is done using fixed cell preparations from routine cytogenetic harvesting, and can be applied to freshly harvested or stored fixed cell suspensions. This modification to standard FISH preparations has the scope to be used as a screening tool for family and prenatal investigations. PMID- 26030084 TI - Decreasing Aerosol Water Is Consistent with OC Trends in the Southeast U.S. AB - Water is a ubiquitous and abundant component of atmospheric aerosols. It influences light scattering, the hydrological cycle, atmospheric chemistry, and secondary particulate matter (PM) formation. Despite the critical importance of aerosol liquid water, mass concentrations are not well-known. Using speciated ion and meteorological data from the Southeastern Aerosol Research and Characterization network, we employ the thermodynamic model ISORROPIAv2.1 to estimate water mass concentrations and evaluate trends from 2001 to 2012 in urban and rural locations. The purpose of this study is to better understand the historical trends of aerosol liquid water in the southeast U.S. in the context of improved air quality and recently noted reductions in particulate organic carbon (OC). Aerosol water mass concentrations decrease by ~79% from 2001 to 2012 in the region. Decreases are more prominent in rural than in urban areas. Fractional contribution of water to PM also decreases during the same time period, and this is consistent with recently noted improvements in visibility. These findings agree with the hypotheses that aerosol liquid water facilitates formation of biogenic secondary organic aerosol (SOA) and that biogenically derived SOA is modulated in the presence of anthropogenic perturbations. PMID- 26030085 TI - Giant enhancement in critical current density, up to a hundredfold, in superconducting NaFe0.97Co0.03 As single crystals under hydrostatic pressure. AB - Tremendous efforts towards improvement in the critical current density "Jc" of iron based superconductors (FeSCs), especially at relatively low temperatures and magnetic fields, have been made so far through different methods, resulting in real progress. Jc at high temperatures in high fields still needs to be further improved, however, in order to meet the requirements of practical applications. Here, we demonstrate a simple approach to achieve this. Hydrostatic pressure can significantly enhance Jc in NaFe0.97Co0.03As single crystals by at least tenfold at low field and more than a hundredfold at high fields. Significant enhancement in the in-field performance of NaFe0.97Co0.03As single crystal in terms of pinning force density (Fp) is found at high pressures. At high fields, the Fp is over 20 and 80 times higher than under ambient pressure at12 K and 14 K, respectively, at P = 1 GPa. We believe that the Co-doped NaFeAs compounds are very exciting and deserve to be more intensively investigated. Finally, it is worthwhile to say that by using hydrostatic pressure, we can achieve more milestones in terms of high Jc values in tapes, wires or films of other Fe-based superconductors. PMID- 26030086 TI - Associations of Physical Performance and Adiposity with Cognition in Children. AB - OBJECTIVES: To investigate the independent and combined associations of cardiorespiratory performance (CP), neuromuscular performance (NP; including motor performance [MP]) and body fat percentage (BF%) with cognition in children. METHODS: The participants were 202 boys and 201 girls age 6-8 yr. Cardiorespiratory performance was assessed using maximal cycle ergometer test and was expressed as maximal workload per lean body mass. Neuromuscular performance score included muscle strength, speed, agility, balance, manual dexterity, and flexibility; and MP included speed and agility, balance, and manual dexterity. Body fat percentage was assessed by dual-energy x-ray absorptiometry. Cognition was assessed using Raven Coloured Progressive Matrices (CPM). Linear regression and general linear models were used to analyze the independent and combined associations of CP, NP, MP, and BF% with Raven CPM score. RESULTS: Neuromuscular performance and MP were directly associated with the Raven CPM score (beta = 0.138-0.190; P < 0.01). Children in the lowest or the highest thirds of BF% and in the lowest third of MP had a lower Raven CPM score than other children (P < 0.05). Children in the lowest or highest third of BF% along with the poorest MP had a lower Raven CPM score than those in the middle third of BF% and higher MP (P < 0.05). These associations and differences were much stronger in boys than in girls. Cardiorespiratory performance was not related to the Raven CPM score. CONCLUSIONS: Poorer NP and MP were associated with a worse cognition in children and particularly in boys. Cognition was poorer especially among children with the lowest or highest BF% accompanied with a poorer MP. PMID- 26030087 TI - Nanoparticles Affect PCR Primarily via Surface Interactions with PCR Components: Using Amino-Modified Silica-Coated Magnetic Nanoparticles as a Main Model. AB - Nanomaterials have been widely reported to affect the polymerase chain reaction (PCR). However, many studies in which these effects were observed were not comprehensive, and many of the proposed mechanisms have been primarily speculative. In this work, we used amino-modified silica-coated magnetic nanoparticles (ASMNPs, which can be collected very easily using an external magnetic field) as a model and compared them with gold nanoparticles (AuNPs, which have been studied extensively) to reveal the mechanisms by which nanoparticles affect PCR. We found that nanoparticles affect PCR primarily by binding to PCR components: (1) inhibition, (2) specifity, and (3) efficiency and yield of PCR are impacted. (1) Excess nanomaterials inhibit PCR by adsorbing to DNA polymerase, Mg(2+), oligonucleotide primers, or DNA templates. Nanoparticle surface-active groups are particularly important to this effect. (2, a) Nanomaterials do not inhibit nonspecific amplification products caused by false priming as previously surmised. It was shown that relatively low concentrations of nanoparticles inhibited the amplification of long amplicons, and increasing the amount of nanoparticles inhibited the amplification of short amplicons. This concentration phenomenon appears to be the result of the formation of "joints" upon the adsorption of ASMNPs to DNA templates. (b) Nanomaterials are able to inhibit nonspecific amplification products due to incomplete amplification by preferably adsorbing single-stranded incomplete amplification products. (3) Some types of nanomaterials, such as AuNPs, enhance the efficiency and yield of PCR because these types of nanoparticles can adsorb to single-stranded DNA more strongly than to double-stranded DNA. This behavior assists in the rapid and thorough denaturation of double-stranded DNA templates. Therefore, the interaction between the surface of nanoparticles and PCR components is sufficient to explain most of the effects of nanoparticles on PCR. PMID- 26030089 TI - Effects of Hierarchical Surface Roughness on Droplet Contact Angle. AB - Superhydrophobic surfaces often incorporate roughness on both micron and nanometer length scales, although a satisfactory understanding of the role of this hierarchical roughness in causing superhydrophobicity remains elusive. We present a two-dimensional thermodynamic model to describe wetting on hierarchically grooved surfaces by droplets for which the influence of gravity is negligible. By creating wetting phase diagrams for droplets on surfaces with both single-scale and hierarchical roughness, we find that hierarchical roughness leads to greatly expanded superhydrophobic domains in phase space over those for a single scale of roughness. Our results indicate that an important role of the nanoscale roughness is to increase the effective Young's angle of the microscale features, leading to smaller required aspect ratios (height to width) for the surface structures. We then show how this idea may be used to design a hierarchically rough surface with optimally high contact angles. PMID- 26030088 TI - Comparison of Single-Point and Continuous Sampling Methods for Estimating Residential Indoor Temperature and Humidity. AB - Residential temperature and humidity are associated with multiple health effects. Studies commonly use single-point measures to estimate indoor temperature and humidity exposures, but there is little evidence to support this sampling strategy. This study evaluated the relationship between single-point and continuous monitoring of air temperature, apparent temperature, relative humidity, and absolute humidity over four exposure intervals (5-min, 30-min, 24 hr, and 12-days) in 9 northern Utah homes, from March-June 2012. Three homes were sampled twice, for a total of 12 observation periods. Continuous data-logged sampling was conducted in homes for 2-3 wks, and simultaneous single-point measures (n = 114) were collected using handheld thermo-hygrometers. Time centered single-point measures were moderately correlated with short-term (30 min) data logger mean air temperature (r = 0.76, beta = 0.74), apparent temperature (r = 0.79, beta = 0.79), relative humidity (r = 0.70, beta = 0.63), and absolute humidity (r = 0.80, beta = 0.80). Data logger 12-day means were also moderately correlated with single-point air temperature (r = 0.64, beta = 0.43) and apparent temperature (r = 0.64, beta = 0.44), but were weakly correlated with single-point relative humidity (r = 0.53, beta = 0.35) and absolute humidity (r = 0.52, beta = 0.39). Of the single-point RH measures, 59 (51.8%) deviated more than +/-5%, 21 (18.4%) deviated more than +/-10%, and 6 (5.3%) deviated more than +/-15% from data logger 12-day means. Where continuous indoor monitoring is not feasible, single-point sampling strategies should include multiple measures collected at prescribed time points based on local conditions. PMID- 26030090 TI - Log-normal diameter distribution of Pd-based metallic glass droplet and wire. AB - We have studied the formation of Pd42.5Cu30Ni7.5P20 metallic glass droplets and wires in the gas atomization process. We demonstrate that the sizes of droplets and wires can be distinguished by the Ohnesorge number (Oh), which is the proportion of the spinnability to the capillary instability, and the diameter distributions follow a log-normal distribution function, implying cascade fragmentation. For droplets, the number significantly increases at Oh < 1 but the diameter gradually decreases. For wires, the number greatly increases at Oh > 1 while the diameter steadies below 400 nm. Further, the wire diameter is quadrupled at Oh = 16 due to the high viscosity which suppresses both capillary breakup and ligament elongation. PMID- 26030091 TI - Case Report: Fetal Bilateral Diaphragmatic Agenesis, Ectopic Liver and Abnormal Pancreas. AB - Congenital bilateral diaphragm agenesis is a very rare condition. We describe limited (abdomen only) autopsy findings of a case of bilateral diaphragm agenesis in a 27-week male fetus with unusual findings of fibrosis of the pancreatic head and ectopic liver nodules in a mass at the upper abdomen that may represent a possible diaphragm anlage. We have correlated our observations with data from experimental and embryological studies to suggest possible mechanisms for the malformations that were present and their implications for our understanding of pancreas, liver and diaphragm development in the human fetus. PMID- 26030092 TI - Stathmin potentiates vinflunine and inhibits Paclitaxel activity. AB - Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs). In a previous study we showed that stathmin increases vinblastine (VLB) binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, vinflunine, using Isothermal Titration Calorimetry (ITC). These experiments revealed that stathmin binding to tubulin is increased in the presence of vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency. PMID- 26030093 TI - An HDAC-Targeted Imaging Probe LBH589-Cy5.5 for Tumor Detection and Therapy Evaluation. AB - Histone deacetylases (HDACs) are overexpressed in various cancers. In vivo imaging to measure the expression and functions of HDACs in tumor plays an important role for tumor diagnosis and HDAC-targeted therapy evaluation. The development of stable and highly sensitive HDAC targeting probe is highly desirable. Near-infrared (NIR) fluorescence optical imaging is a powerful technology for visualizing disease at the molecular level in vivo with high sensitivity and no ionizing radiation. We report here the design, synthesis, and bioactivity evaluation of LBH589-Cy5.5 for in vivo NIR fluorescence imaging of HDACs. The IC50 value of the resulting NIR probe to HDACs was determined to be 9.6 nM. In vitro fluorescence microscopic studies using a triple-negative breast cancer cell line, MDA-MB-231, established the binding specificity of LBH589-Cy5.5 to HDACs. An in vivo imaging study performed in MDA-MB-231 tumor xenografts demonstrated accumulation of the probe in tumor with good contrast from 2 h to 48 h postinjection. Furthermore, the fluorescent signal of LBH589-Cy5.5 in tumor was successfully blocked by coinjection of nonfluorescent LBH589 with the probe. In a following therapy evaluation study, the administration of SAHA, a clinically used HDAC inhibitor, decreased LBH589-Cy5.5 accumulation in tumor, demonstrating the potential application of LBH589-Cy5.5 for evaluating therapeutic response of HDAC inhibitors in cancer treatment. PMID- 26030094 TI - The influence of macrophytes on sediment resuspension and the effect of associated nutrients in a shallow and large lake (Lake Taihu, China). AB - A yearlong campaign to examine sediment resuspension was conducted in large, shallow and eutrophic Lake Taihu, China, to investigate the influence of vegetation on sediment resuspension and its nutrient effects. The study was conducted at 6 sites located in both phytoplankton-dominated zone and macrophyte dominated zone of the lake, lasting for a total of 13 months, with collections made at two-week intervals. Sediment resuspension in Taihu, with a two-week high average rate of 1771 g.m(-2).d(-1) and a yearly average rate of 377 g.m(-2).d( 1), is much stronger than in many other lakes worldwide, as Taihu is quite shallow and contains a long fetch. The occurrence of macrophytes, however, provided quite strong abatement of sediment resuspension, which may reduce the sediment resuspension rate up to 29-fold. The contribution of nitrogen and phosphorus to the water column from sediment resuspension was estimated as 0.34 mg.L(-1) and 0.051 mg.L(-1) in the phytoplankton-dominated zone. Sediment resuspension also largely reduced transparency and then stimulated phytoplankton growth. Therefore, sediment resuspension may be one of the most important factors delaying the recovery of eutrophic Lake Taihu, and the influence of sediment resuspension on water quality must also be taken into account by the lake managers when they determine the restoration target. PMID- 26030097 TI - The infection of turkeys and chickens by reassortants derived from pandemic H1N1 2009 and avian H9N2 influenza viruses. AB - Outbreaks of pandemic H1N1 2009 (pH1N1) in turkeys have been reported in several countries. Co-infection of pH1N1 and avian H9N2 influenza viruses in turkeys provide the opportunity for their reassortment, and novel reassortant viruses might further be transmitted to other avian species. However, virulence and transmission of those reassortant viruses in poultry remain unclear. In the present study, we generated 16 single-gene reassortant influenza viruses including eight reassortants on the pH1N1 background by individual replacement with a corresponding gene segment from H9N2 and eight reassortants on the H9N2 background replaced individually with corresponding gene from pH1N1, and characterized reassortants viruses in turkeys and chickens. We found that the pH1N1 virus dramatically increased its infectivity and transmissibility in turkeys and chickens after introducing any gene (except for PB2) from H9N2 virus, and H9N2 virus acquired single gene (except for HA) of pH1N1 almost did not influence its replication and transmission in turkeys and chickens. Additionally, 13 reassortant viruses transmitted from turkeys to chickens. Our results indicate that turkeys and chickens are susceptible to pH1N1-H9N2 reassortant viruses, and mixing breeding of different avian species would facilitate the transmission of these reassortant viruses. PMID- 26030098 TI - Free energy landscape and multiple folding pathways of an H-type RNA pseudoknot. AB - How RNA sequences fold to specific tertiary structures is one of the key problems for understanding their dynamics and functions. Here, we study the folding process of an H-type RNA pseudoknot by performing a large-scale all-atom MD simulation and bias-exchange metadynamics. The folding free energy landscapes are obtained and several folding intermediates are identified. It is suggested that the folding occurs via multiple mechanisms, including a step-wise mechanism starting either from the first helix or the second, and a cooperative mechanism with both helices forming simultaneously. Despite of the multiple mechanism nature, the ensemble folding kinetics estimated from a Markov state model is single-exponential. It is also found that the correlation between folding and binding of metal ions is significant, and the bound ions mediate long-range interactions in the intermediate structures. Non-native interactions are found to be dominant in the unfolded state and also present in some intermediates, possibly hinder the folding process of the RNA. PMID- 26030101 TI - High-Resolution Array CGH Analysis Identifies Regional Deletions and Amplifications of Chromosome 8 in Uveal Melanoma. AB - PURPOSE: Monosomy 3 (M3) and abnormalities of chromosome 8 associate with poor prognosis in uveal melanomas (UM). Although M3 has been the subject of more in depth studies, none have intensively focused on chromosome 8. To elucidate the potential role of chromosome 8 abnormalities, array comparative genomic hybridization (aCGH) was performed on primary UM. METHODS: A specifically designed custom high-resolution array was developed focusing on changes most implicated in UM. Probes for chromosome 8 had a mean spacing of 2.3 kb while chromosomes infrequently affected had a mean spacing of 36.6 kb. A series of 75 UM, including one formalin-fixed paraffin sample were analyzed, and where possible control DNA extracted from the patient's own peripheral blood was used. RESULTS: The most common copy number abnormalities were chromosome 8 (75%) and M3 (51%), with M3 and gain of the long arm of chromosome 8 (8q+) associated in 41% of cases. Also identified were partial deletions of chromosome 3 (3%) and regional 8q+ (23%), and the intensive coverage of chromosome 8 revealed small focal deletions and amplifications affecting both arms. The most significant predictor of prognosis was M3/8q+ having a hazard ratio of 10.1 (P < 0.0001). CONCLUSIONS: Neither 8p deletion nor focal changes affecting chromosome 8 were linked to outcome. The most significant indicator was M3/8q, and multiple 8q+ associated with shorter survival. Studying UM with this technology provides a powerful robust tool for predicting prognosis while considering other genetic changes, allowing the future incorporation of such data as it becomes clinically significant. PMID- 26030100 TI - Pericyte chemomechanics and the angiogenic switch: insights into the pathogenesis of proliferative diabetic retinopathy? AB - PURPOSE: To establish the regulatory roles that pericytes have in coordinating retinal endothelial cell (EC) growth and angiogenic potential. METHODS: Pericytes were derived from donor diabetic (DHuRP) or normal (NHuRP) human retinae, and characterized using vascular markers, coculture, contraction, morphogenesis, and proliferation assays. To investigate capillary "cross-talk," pericyte-endothelial coculture growth, and connexin-43 (Cx43) expression assays were performed. Paracrine effects were examined via treating EC with pericyte-derived conditioned media (CM) in proliferation, angiogenesis, and angiocrine assays. The effects of sphingosine 1-phosphate (S1P) were assessed using receptor antagonists. RESULTS: The DHuRP exhibit unique proliferative and morphologic properties, reflecting distinctive cytoskeletal and isoactin expression patterns. Unlike NHuRP, DHuRP are unable to sustain EC growth arrest in coculture and display reduced Cx43 expression. Further, CM from DHuRP (DPCM) markedly stimulates EC proliferation and tube formation. Treatment with S1P receptor antagonists mitigates DPCM growth promotion in EC and S1P-mediated pericyte contraction. Angiocrine assays on normal and diabetic pericyte secretomes reveal factors involved in angiogenic control, inflammation, and metabolism. CONCLUSIONS: Effects from the diabetic microenvironment appear sustainable in cell culture: pericytes derived from diabetic donor eyes seemingly possess a "metabolic memory" in vitro, which may be linked to original donor health status. Diabetes- and pericyte-dependent effects on EC growth and angiogenesis may reflect alterations in bioactive lipid, angiocrine, and chemomechanical signaling. Altogether, our results suggest that diabetes alters pericyte contractile phenotype and cytoskeletal signaling, which ultimately may serve as a key, initiating event required for retinal endothelial reproliferation, angiogenic activation, and the pathological neovascularization accompanying proliferative diabetic retinopathy. PMID- 26030099 TI - A chimeric Cfh transgene leads to increased retinal oxidative stress, inflammation, and accumulation of activated subretinal microglia in mice. AB - PURPOSE: Variants of complement factor H (Cfh) affecting short consensus repeats (SCRs) 6 to 8 increase the risk of age-related macular degeneration. Our aim was to explore the effect of expressing a Cfh variant on the in vivo susceptibility of the retina and RPE to oxidative stress and inflammation, using chimeric Cfh transgenic mice (chCfhTg). METHODS: The chCfhTg and age-matched C57BL/6J (B6) mice were subjected to oxidative stress by either normal aging, or by exposure to a combination of oral hydroquinone (0.8% HQ) and increased light. Eyes were collected for immunohistochemistry of RPE-choroid flat mounts and of retinal sections, ELISA, electron microscopy, and RPE/microglia gene expression analysis. RESULTS: Aging mice to 2 years led to an increased accumulation of basal laminar deposits, subretinal microglia/macrophages (MG/MPhi) staining for CD16 and for malondialdehyde (MDA), and MDA-modified proteins in the retina in chCfhTg compared to B6 mice. The chCfhTg mice maintained on HQ diet and increased light showed greater deposition of basal laminar deposits, more accumulation of fundus spots suggestive of MG/MPhi, and increased deposition of C3d in the sub-RPE space, compared to controls. In addition, chCfhTg mice demonstrated upregulation of NLRP3, IP-10, CD68, and TREM-2 in the RNA isolates from RPE/MG/MPhi. CONCLUSIONS: Expression of a Cfh transgene introducing a variant in SCRs 6 to 8 was sufficient to lead to increased retinal/RPE susceptibility to oxidative stress, a proinflammatory MG/MPhi phenotype, and a proinflammatory RPE/MG/MPhi gene expression profile in a transgenic mouse model. Our data suggest that altered interactions of Cfh with MDA-modified proteins may be relevant in explaining the effects of the Cfh variant. PMID- 26030102 TI - Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates. AB - PURPOSE: We evaluated promising new treatment options for strabismus. Neurotrophic factors have emerged as a potential treatment for oculomotor disorders because of diverse roles in signaling to muscles and motor neurons. Unilateral treatment with sustained release brain-derived neurotrophic factor (BDNF) to a single lateral rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop in correlation with extraocular muscle (EOM) changes during the critical period for development of binocularity. METHODS: The lateral rectus muscles of one eye in two infant macaques were treated with sustained delivery of BDNF for 3 months. Eye alignment was assessed using standard photographic methods. Muscle specimens were analyzed to examine the effects of BDNF on the density, morphology, and size of neuromuscular junctions, as well as myofiber size. Counts were compared to age-matched controls. RESULTS: No change in eye alignment occurred with BDNF treatment. Compared to control muscle, neuromuscular junctions on myofibers expressing slow myosins had a larger area. Myofibers expressing slow myosin had larger diameters, and the percentage of myofibers expressing slow myosins increased in the proximal end of the muscle. Expression of BDNF was examined in control EOM, and observed to have strongest immunoreactivity outside the endplate zone. CONCLUSIONS: We hypothesize that the oculomotor system adapted to sustained BDNF treatment to preserve normal alignment. Our results suggest that BDNF treatment preferentially altered myofibers expressing slow myosins. This implicates BDNF signaling as influencing the slow twitch properties of EOM. PMID- 26030103 TI - Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment. AB - PURPOSE: Unilateral treatment with sustained release IGF-1 to one medial rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop as a result of changes in extraocular muscles during the critical period of development of binocularity. METHODS: Sustained release IGF-1 pellets were implanted unilaterally on one medial rectus muscle in normal infant monkeys during the first 2 weeks of life. Eye position was monitored using standard photographic methods. After 3 months of treatment, myofiber and neuromuscular size, myosin composition, and innervation density were quantified in all rectus muscles and compared to those in age-matched controls. RESULTS: Sustained unilateral IGF-1 treatments resulted in strabismus for all treated subjects; 3 of the 4 subjects had a clinically significant strabismus of more than 10 degrees . Both the treated medial rectus and the untreated ipsilateral antagonist lateral rectus muscles had significantly larger myofibers. No adaptation in myofiber size occurred in the contralateral functionally yoked lateral rectus or in myosin composition, neuromuscular junction size, or nerve density. CONCLUSIONS: Sustained unilateral IGF-1 treatment to extraocular muscles during the sensitive period of development of orthotropic eye alignment and binocularity was sufficient to disturb ocular motor development, resulting in strabismus in infant monkeys. This could be due to altering fusion of gaze during the early sensitive period. Serial measurements of eye alignment suggested the IGF-1-treated infants received insufficient coordinated binocular experience, preventing the establishment of normal eye alignment. Our results uniquely suggest that abnormal signaling by the extraocular muscles may be a cause of strabismus. PMID- 26030104 TI - The PEDF Neuroprotective Domain Plus DHA Induces Corneal Nerve Regeneration After Experimental Surgery. AB - PURPOSE: To compare a 44-mer pigment epithelial-derived factor (PEDF) peptide with neurotrophic activity, and a 34-mer PEDF with antiangiogenic properties in association with docosahexaenoic acid (DHA) in corneal nerve regeneration after experimental surgery. METHODS: A corneal stromal dissection was performed in rabbits. Treatment groups received topical 44-mer, 34-mer, or full PEDF plus DHA. Corneal sensitivity and Schirmer's test were performed weekly. Rabbits were euthanized at 2 and 4 days and 8 weeks. Two- and 4-day samples were stained for neutrophils and CD11b+ cells. Corneal nerves were stained with betaIII tubulin and calcitonin gene-related peptide (CGRP) antibodies in specimens collected at 8 weeks. Subepithelial nerve plexus density was calculated. A PEDF-receptor (PEDF R) was analyzed in rabbit corneal epithelial cells (RCEC) by Western blot and immunofluorescence. RESULTS: Infiltration of CD11b+cells and neutrophils was reduced by treatment with 44-mer PEDF+DHA. A 3-fold increase in subepithelial corneal nerves and CGRP-positive nerves was found in the 44-mer PEDF+DHA-treated group compared with the 34-mer PEDF+DHA- and vehicle-treated groups. There was a 75% recovery of corneal sensitivity by week 7, and Schirmer's test reached control values in the 44-mer PEDF+DHA-treated corneas at 7 weeks. A PEDF-R protein with homology to calcium-independent phospholipase A2sigma was expressed in RCEC. CONCLUSIONS: The 44-mer PEDF+DHA, but not the 34-mer PEDF+DHA, promotes functional regeneration of damaged corneal nerves. Forty four-mer PEDF, by activating a corneal epithelial receptor, in conjunction with DHA could be a novel therapeutic agent for the treatment of neurotrophic keratitis and dry eye that develops as a result of corneal nerve damage. PMID- 26030105 TI - An N-Terminal ER Export Signal Facilitates the Plasma Membrane Targeting of HCN1 Channels in Photoreceptors. AB - PURPOSE: Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are widely expressed in the retina. In photoreceptors, the hyperpolarization activated current (Ih) carried by HCN1 is important for shaping the light response. It has been shown in multiple systems that trafficking HCN1 channels to specific compartments is key to their function. The localization of HCN1 in photoreceptors is concentrated in the plasma membrane of the inner segment (IS). The mechanisms controlling this localization are not understood. We previously identified a di-arginine endoplasmic reticulum (ER) retention motif that negatively regulates the surface targeting of HCN1. In this study, we sought to identify a forward trafficking signal that could counter the function of the ER retention signal. METHODS: We studied trafficking of HCN1 and several mutants by imaging their subcellular localization in transgenic X. laevis photoreceptors. Velocity sedimentation was used to assay the assembly state of HCN1 channels. RESULTS: We found the HCN1 N-terminus can redirect a membrane reporter from outer segments (OS) to the plasma membrane of the IS. The sequence necessary for this behavior was mapped to a 20 amino acid region containing a leucine-based ER export motif. The ER export signal is necessary for forward trafficking but not channel oligomerization. Moreover, this ER export signal alone counteracted the di-arginine ER retention signal. CONCLUSIONS: We identified an ER export signal in HCN1 that functions with the ER retention signal to maintain equilibrium of HCN1 between the endomembrane system and the plasma membrane. PMID- 26030106 TI - Age-related changes in the anterior segment biometry during accommodation. AB - PURPOSE: We investigated the dynamic response of human accommodative elements as a function of age during accommodation using synchronized spectral domain optical coherence tomography devices (SD-OCT). METHODS: We enrolled 33 left eyes from 33 healthy subjects (age range, 20-39 years, 17 males and 16 females). Two SD-OCT devices were synchronized to simultaneously image the anterior segment through pupil and the ciliary muscle during 6.00 diopter (D) accommodation for approximately 3.7 seconds in two repeated measurements. The anterior segment parameters included the lens thickness (LT), radius of curvature of the lens anterior surface (LAC), maximum thickness of ciliary muscle (CMTMAX), and anterior length of the ciliary muscle (CMAL). A first-order exponential equation was used to fit the dynamic changes during accommodation. The age-related changes in the dynamic response and their relationship were calculated and compared. RESULTS: The amplitude (r = -0.40 and 0.53 for LT and LAC, respectively) and peak velocity (r = -0.65 and 0.71 for LT and LAC, respectively) of the changes in LT and LAC significantly decreased with age (P < 0.05), whereas the parameters of the ciliary muscle remained unchanged (P > 0.05), except for the peak velocity of the CMAL (r = 0.44, P = 0.01). The difference in the time constant between the lens reshaping (LT and LAC) and CMTMAX increased with age (r = 0.46 and 0.57 for LT and LAC, respectively, P < 0.01). The changes in LT and LAC per millimeter of CMTMAX change decreased with age (r = -0.52 and -0.34, respectively, P < 0.05). The ciliary muscle forward movement correlated with the lens deformation (r = 0.35 and 0.40 for amplitude, while r = 0.36 and 0.58 for time constant, respectively, P < 0.05). CONCLUSIONS: Age-related changes in the lens reshaping and ciliary muscle forward movement were found. Lens reshaping was much slower than the contraction of the ciliary muscle, especially in aging eyes, and this process required the ciliary muscle to contract more to reach a given response. PMID- 26030107 TI - Functional limbal epithelial cells can be successfully isolated from organ culture rims following long-term storage. AB - PURPOSE: Because of a shortage of fresh corneal tissue for research, it was of interest to investigate the potential of successfully isolating human limbal epithelial cells (hLECs) from organ culture corneal-scleral (OCCS) rims. METHODS: Superficial segments of corneal limbus were dissected and digested using collagenase (0.5 mg/mL, 16 hours at 37 degrees C). Cell suspensions were separated into four different growth conditions: corneal epithelial cell medium (CM); CM + 3T3-Swiss albino cells; stromal stem cell medium (SM); and SM + 3T3 cells. Colony number, hLEC count, cell density, and colony forming efficiency (CFE) were quantified to assess different growth conditions. The expression profile associated with basal hLECs was assessed by immunofluorescence, and epithelial integrity was measured using our real architecture for 3D tissue (RAFT) corneal tissue equivalent. RESULTS: Human limbal epithelial cells can be successfully isolated from OCCS rims following 4 weeks in storage with an 80.55% success rate with 36 corneal rims. Stromal stem cell medium + 3T3s provided optimal growth conditions. Colony number, total cell number, and cell density were significantly higher at day 7 in cultures with SM than in CM. There were no significant differences between SM and CM when assessing CFE and the expression profile associated with basal hLECs. Cells maintained in SM were found to produce a higher quality epithelium than that cultured in CM. CONCLUSIONS: Organ culture corneal-scleral rims can be a valuable source for hLEC. Using a combination of collagenase-based isolation and medium designed for stromal stem cell isolation, a high number of good quality hLECs can be cultured from tissue that would have otherwise been ignored. PMID- 26030108 TI - Simultaneous increase in multiple proinflammatory cytokines in the aqueous humor in neovascular glaucoma with and without intravitreal bevacizumab injection. AB - PURPOSE: To investigate aqueous humor proinflammatory cytokine levels of patients with neovascular glaucoma (NVG), and to analyze the effects of background factors in the expression of these molecules. METHODS: This cross-sectional study enrolled 137 participants who were grouped into (1) primary open-angle glaucoma (POAG; n = 36) patients; (2) NVG patients (NVG; n = 33); and (3) cataract surgery patients as a comparative group (CG; n = 68). Aqueous humor samples were collected from the anterior chamber at the start of surgery, deposited in CryoTubes, registered, and stored at -80 degrees C until processing. Multiplex microparticle-based immunodetection was performed by using xMAP and the Human Cytokine/Chemokine Panel I. Bevacizumab was injected into the vitreous cavity 1 to 2 days before surgery in 22 NVG patients (IVB group), whereas 11 NVG patients received no antivascular endothelial growth factor (VEGF) therapy 3 months preoperatively (N group). The Wilcoxon rank sum test or Fisher's exact test for two variables and the Tukey-Kramer honestly significant difference test for multiple variables were used to compare the cytokine levels. RESULTS: The NVG patients had higher levels of interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tumor necrosis factor-alpha (TNF-alpha), and platelet-derived growth factor (PDGF)-AA compared to both the CG and POAG groups. The levels of IL 6, IL-8, MCP-1, and PDGF-AB/BB were higher in the IVB group than the N group, whereas the VEGF level was significantly lower in the IVB group (P < 0.01). CONCLUSIONS: Intravitreal bevacizumab injection decreased VEGF levels, but not those of the other cytokines. PMID- 26030109 TI - Vaccines: both sides of the same coin. PMID- 26030110 TI - Michael Smith, MD: Treat the Underlying Causes of Weight Gain to Facilitate Successful Weight Loss. Part 2: Examining the First 2 Pillars of Weight Gain. PMID- 26030111 TI - Terpenes and terpenoids in chemical sensitivity. AB - CONTEXT : Terpenes and terpenoids are a diverse class of organic compounds produced by a variety of plants, particularly conifers. Chemically sensitive patients can be targeted by terpenes and terpenoids, resulting in a triggering of symptoms and pathology. Often patients cannot clear their symptoms from exposure to chemicals unless terpenes and terpenoids are avoided and neutralized along with chemical avoidance and treatment. OBJECTIVE: This article evaluates the presence, diagnosis, and treatment of terpenes exposure in chemically sensitive patients. DESIGN: A double-blind, placebo-controlled, 2-part study was designed to establish the chemically sensitive state of the patients in part 1, followed by a second set of challenges to determine each patient's concurrent sensitivity to terpenes and terpenoids in part 2. In all of the challenges, normal saline was used as a control. A case report illustrates the history of 1 patient and describes the authors' treatment methods. SETTING: The study was developed and conducted at the Environmental Health Center of Dallas (EHC-D) because the environment within the center is 5 times less polluted than the surrounding environments, as determined by quantitative air analysis and particulate counts. PARTICIPANTS: A total of 45 chemically sensitive patients at EHC-D with odor sensitivity to terpenes. The cohort included 18 males and 27 females, aged 24-62 y.Intervention * Patients were deadapted (4 d) and evaluated in a 5-times-less polluted environment, which was evaluated using air analysis and particulate counts. After deadaptation, the patients were challenged by inhalation in a controlled, less-polluted glass steel booth inside an environmentally controlled room with an ambient air dose of the toxics in the order of parts per billion (PPB) and parts per million (PPM). These toxics included formaldehyde, pesticide, cigarette smoke, ethanol, phenol, chlorine, new sprint, perfume, and placebo. They were also challenged intradermally with extracts of volatile organic compounds (VOCs), including formaldehyde, orris root, ethanol, phenol, cigarette smoke, chlorine, newsprint, perfume, terpenes, terpenoids, and placebo. OUTCOME MEASURES: Inhaled challenges recorded pulse, blood pressure, peak bronchial flow, and other signs and symptoms 30 min before and at 15-min intervals for 2 h postchallenge. Intradermal challenges recorded wheal size and the provocation of signs and symptoms. RESULTS : Different numbers of patients were tested for each terpenes source because of time-related factors or the cumulative effect of testing, which made patients unable to continue. Of 45 chemically sensitive patients in the study, 43 demonstrated sensitivity to terpenes. CONCLUSIONS: This particular patient group was positive for a number of toxic and nontoxic chemicals provoking their symptoms. This study shows there was a connection between VOCs, other chemicals, and terpenes in chemically sensitive patients in a prospective cohort study. It has also shown the potential for terpenes to exacerbate symptoms of chemical sensitivity. Further research on this topic is recommended. PMID- 26030112 TI - Self-administered Acupressure for Persistent Cancer-related Fatigue: Fidelity Considerations. AB - CONTEXT: Complementary therapies are frequently used by breast cancer patients for symptom management; however, documentation of the components of intervention fidelity for studies is not widely available. OBJECTIVE: This report examines the components of intervention fidelity, as put forth by the Treatment Fidelity Workgroup of the Behavior Change Consortium at the National Institutes for Health (NIH-BCC Workgroup), within an ongoing acupressure study of breast cancer survivors with persistent cancer-related fatigue (PCRF). DESIGN: For the acupressure study, the research team designed a randomized, controlled trial (RCT) with 3 parallel groups: (1) stimulating acupressure (intervention group); (2) relaxing acupressure (intervention group); and (3) standard care (control group). SETTING: At baseline and at wk 3 and wk 6 of the study, women in the acupressure study attended sessions for training and data collection at clinics in the counties of Michigan where they lived. The self-administration of acupressure occurred in participants' homes. PARTICIPANTS: Targeted enrollment for the acupressure study is 300 breast cancer survivors who had experienced moderate-to-severe PCRF lasting longer than 1 y beyond treatment. The women are being recruited from 5 counties in Michigan, using the Michigan Tumor Registry to identify potential participants. The subsample report includes 183 participants who have completed all 10 wk of the acupressure study. Most participants in the acupressure study are Caucasian, are married, and have some college education. INTERVENTION: The acupressure study's educators teach participants in the intervention groups to self-administer either relaxing or stimulating acupressure for a 30-min period on a daily basis for 6 wk. All 3 groups receive the usual care for breast cancer survivors. OUTCOME MEASURES: For the acupressure study, the participants log the frequency of the self-administered acupressure sessions and their fatigue levels. Symptom assessments are made for all groups by telephone in the acupressure study at wk 2 through wk 5 to assess fatigue. A competency checklist is used at each session of training and retraining of both acupressure educators and participants. For this report, the 5 recommended fidelity components for interventions are (1) dose, (2) training, (3) intervention delivery, (4) intervention receipt, and (5) enactment of the intervention. RESULTS: The ongoing RCT incorporated all 5 components of fidelity and can serve as a model for future work in this area. CONCLUSIONS: Research protocols that address intervention fidelity can provide results that support internal and external validity. Clinicians should consider recommending complementary interventions that have incorporated fidelity components into their efficacy testing. PMID- 26030113 TI - Why does treatment fidelity matter? AB - Treatment fidelity is a relatively new concept in intervention research and has been discussed in scientific literature only in the last 25 y. Intervention fidelity improves power by reducing unintended variability in treatment effect, and it supports external validity by allowing for replication. As more self administered complementary and alternative medicine (CAM) treatments are being studied, the issue of fidelity concerns is becoming more of a burden to researchers. Despite the critical role of fidelity, no comprehensive, structured guide exists. PMID- 26030114 TI - Targeting NF-kappaBeta and TNF-alpha Activation by Electroacupuncture to Suppress Collagen-induced Rheumatoid Arthritis in Model Rats. AB - BACKGROUND: Rheumatoid arthritis is an autoimmune disease that can cause chronic inflammation of the joints and other areas of the body. Acupuncture is an emerging alternative therapy for rheumatoid arthritis; however, the molecular mechanism underlying the beneficial effect of acupuncture has not been elucidated. OBJECTIVE: The study aimed to determine the effects of electroacupuncture (EA) on the expression of nuclear factor kappa Beta (NF kappaBeta) and tumor necrosis factor alpha (TNF-alpha) in model rats and to elucidate its anti-inflammatory mechanism in rheumatoid arthritis. DESIGN: The research team conducted a randomized animal study evaluating the efficacies of acupuncture on rheumatoid arthritis. Setting * All processes for the study were conducted at the Hubei University of Chinese Medicine and the Tongji Medical College of the Huazhong University of Science and Technology. Intervention * Twenty rats were randomly selected from 80 male Wistar rats and designated as the normal control (NC) group. The remaining 60 rats were prepared as rheumatoid arthritis models by administering intradermal injections of bovine, type 2 collagen emulsified in incomplete Freund's adjuvant for 3 wk. The 60 rats were randomly divided into 3 groups: (1) a rheumatoid arthritis model (model group); (2) a real-acupuncture-plus model (RA group); and (3) a sham-acupuncture-plus model (SA group), with 20 rats randomly assigned to each group. Zusanli (ST-36), Xuanzhong (GB-39), and Shenshu (BL-23) were applied for treatment of the RA group, whereas sham acupoints were selected for the SA group. OUTCOME MEASURES: The study used ultrastructural observations, an arthritis index, the expression levels of TNF-alpha and NF-kappaBeta (p65) in synovial cells, and the content of serum inflammatory cytokines to measure results. RESULTS: The arthritis index, the expression levels of NF-kappaBeta (p65) and TNF-alpha in synovial tissues, and the contents of interleukin (IL) 1-beta (IL-1beta), IL-6, and IL-8 increased for the 3 model groups compared with measurements for the NC group (P < .01). Those parameters were lower for the RA group than for the model group (P < .05). However, no statistically significant difference was observed between the model and SA groups. CONCLUSIONS: Acupuncture mediates the anti-inflammatory NF-kB pathway to reduce disease severity in collagen-induced arthritis. PMID- 26030115 TI - Horticultural therapy: a pilot study on modulating cortisol levels and indices of substance craving, posttraumatic stress disorder, depression, and quality of life in veterans. AB - CONTEXT: Horticultural therapy (HT) is a subgroup of occupational therapy (OT). Both HT and OT have been successful as adjunctive treatment modalities in substance abuse treatment. Studies have indicated that gardening promotes neuroendocrine and affective restoration from stress. OBJECTIVES: The study intended to assess the effect of HT versus nonhorticultural OT on cortisol levels, depression, symptoms of posttraumatic stress disorder (PTSD), alcohol cravings, and quality of life. METHODS: The research team designed a randomized pilot study. SETTING: The study was open for participation from July 2012-October 2012. It took place during multiple occurrences of a 28-d treatment programs for substance use disorder at a Veterans Affairs medical center. Participants * Participants were 49 veterans, averaging 46.4 y old (SD = 11.9); the dropout rate was 37%. INTERVENTION: Participants were randomly assigned to the HT or the OT group. They attended supervised HT and OT groups 5 h/d for 3 wk. Outcome Measures * Pre- and posttreatment, participants completed the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), the Alcohol Craving Questionnaire (ACQ-NOW), the Posttraumatic Stress Disorder Checklist Civilian Version (PCLC), and the Center for Epidemiologic Studies Depression Scale (CES D). Salivary cortisol samples were taken at wk 1, 2, and 3. RESULTS: A repeated measures analysis of variance (ANOVA) (F2,20 = 0.878) revealed that the HT performed was associated with a 12% reduction in salivary cortisol levels from wk 1 to wk 3, but the difference was not statistically significant (P = .43). Separate 1-way analyses of covariance (ANCOVAs) revealed no statistically significant differences in the self-administered tests, although both the Q-LES-Q SF and CES-D showed a trend toward improving quality of life and depressive symptoms in the HT group compared with the OT group. Additional analysis of the nonbiologic tests suggests that most participants in the HT and OT had some benefit from the programmed activities. CONCLUSIONS: The trends suggest that HT may modulate stress in veterans, as evidenced by decreased cortisol levels and depressive symptoms, and may improve quality of life more than the programs in which the OT group participated. Further investigation with larger samples, including a nontreatment control group, is needed to determine whether the observed trends are treatment effects or due to abstinence. PMID- 26030116 TI - Food Intolerance: Immune Activation Through Diet-associated Stimuli in Chronic Disease. AB - The immune response is a very complex interplay of specific and nonspecific branches that have evolved to distinguish between nondangerous and dangerous or nontolerated factors. In the past, research has focused on the specific immune system much more than the host's innate defense. Studies have shown that a key component of the immune response involves activation of the inflammasome. A direct relationship between the presence of the inflammasome and the onset of disease has already been characterized for a variety of chronic and food-related diseases, including arthrosclerosis, metabolic syndrome, and chronic bowel diseases, such as Crohn's disease and ulcerative colitis. The leukocyte activation (ALCAT test), an immunological blood test for food intolerance reactions, is ideal to identify and eliminate individual food stimuli that may act as triggers for the cellular nonspecific immune response. Although the test is not diagnostic, studies have established that it can be a useful screening tool for the identification of foreign substances that may trigger immune cell activation, particularly of neutrophils, leading to inflammatory disorders. The ALCAT test, coupled with a targeted diet that is individually tailored according to the test's results, may support immune homeostasis and provide a valuable complementary approach for therapy and overall health. PMID- 26030117 TI - Efficacy of the wen dan decoction, a Chinese herbal formula, for metabolic syndrome. AB - CONTEXT: Metabolic syndrome (MS) refers to the clustering of metabolic derangements that include hyperglycemia, dyslipidemia, hypertension, and chronic kidney impairment. Those conditions are well known as being synergistically responsible for morbidity from cardiovascular disease as well as for driving the global epidemic of type 2 diabetes. It is still unknown whether an exact unifying pathogenesis of MS exists. OBJECTIVE: The meta-analysis intended to analyze the use of Chinese medicine (CM) as a therapeutic tool to explore indirectly the unifying pathogenesis of MS. METHODS: PubMed, the Chinese National Knowledge Infrastructure (CNKI), and the Wanfang databases were systematically searched from inception to November 2013 for randomized, controlled trials (RCTs) that compared treatment efficacy for MS patients using the Wen Dan decoction (WDD), a CM formula, versus Western conventional therapeutics. OUTCOME MEASURES: Measurements included tests of the overall therapeutic efficacy of WDD for hyperglycemia, hypertension, dyslipidemia, and renal functions, and the study also analyzed adverse events. Data were expressed as weighted mean differences (WMDs), with 95% confidence intervals (95% CIs) and the odds ratio (OR). RESULTS: A total of 31 RCTs were included for meta-analysis, involving 2512 patients and including 1282 participants in the intervention groups. The pooled data favored WDD over the control treatments as follows: (1) hyperglycemia, with a WMD of 0.95 mmol/L (95% CI: -1.19 to -0.71); (2) hypertension, with a WMD of -7.40 mm Hg (95% CI: -9.86 to -4.93); (3) dyslipidemia: (a) total cholesterol (TC), with a WMD of -0.62 mmol/L (95% CI: -0.90 to -0.33); (b) triglycerides (TGs), with a WMD of -0.32 mmol/L (95% CI: -0.52 to -0.13); (c) low-density lipoproteins (LDPs), with a WMD of -0.22 mmol/L (95% CI: -0.41 to -0.02); and (d) high-density lipoproteins (HDPs), with a WMD of 0.10 mmol/L (95% CI: 0.03 to 0.17); and (4) of renal functions: (a) urea, with a WMD of -3.41 mmol/L (95% CI: -5.50 to -1.32) and (b) creatinine, with a WMD of -68.81 MUmol/L (95% CI: -132.63 to -4.98). No statistical significance was documented in creatinine clearance between the 2 treatments with a WMD of 15.47 mL/min (95% CI: -7.71 to 38.64). The overall efficacy rate was 91.4% for WDD and 66.9% for the control treatments (OR: 5.33; 95% CI: 4.06 to 6.99). Adverse events were rare and minor. CONCLUSIONS: The consistent improvements found in metabolic profiles by use of the single herbal formula may indirectly imply a common pathogenesis in MS. PMID- 26030118 TI - Treatment of a medial collateral ligament sprain using prolotherapy: a case study. AB - Prolotherapy is effective in treating refractory tendinopathies, but inadequate clinical evidence exists to recommend its use as a treatment for acute or chronic, medial collateral ligament (MCL) injuries. The current case study documents an illustrative case of a rugby player who had a grade 2 sprain of the MCL and shows the clinical and radiological outcomes following injections of 15% dextrose combined with 0.2% lidocaine. In his case, the prolotherapy, together with an exercise therapy, lasted 3 wk. At the end of the 3 wk, the patient was pain free, with a full range of motion (ROM), and he was able to perform all rugby-specific movements. The mean duration for recovery with conservative treatment of isolated, complete tears of the MCL is normally 4-8 wk. PMID- 26030119 TI - High-Risk Cardiac Surgery in Patients with Intravenous Drug Abuse and/or Active Hepatitis C or HIV Infection: An Ethical Discussion of Six Cases. AB - OBJECTIVES: To discuss the dilemma of adequate decision making in patients with intravenous drug abuse and recurrent valve prosthesis infections or in patients with positive HIV or hepatitis C status. Ethical, social, and economic considerations, not only in terms of technical feasibility but also in terms of unpromising results and aspects of resources, are discussed. Thoughts are presented about the legitimation of cardiac surgery centers refusing to perform surgery in high-risk patients with HIV or hepatitis C infections. METHODS: Presentation of six cases for discussion. Three patients were addicted to intravenous drugs and had recurrent prosthetic valve endocarditis, and the other three patients had either paravalvular leakage of a mitral valve prosthesis or acute aortic dissection or coronary artery disease. Five of these patients suffered from HIV/AIDS and infective hepatitis C. Four of these patients were refused by other centers due to high risk or a lack of capacity. RESULTS: All six patients were operated during 2013. Mortality was 17%. CONCLUSION: Decision making in noncompliant drug addicts with recurrent prosthesis infection and in HIV-positive patients leads beyond surgical challenges to ethical and economic considerations. PMID- 26030120 TI - Transapical Transcatheter Aortic Valve Implantation Using the JenaValve: A One Year Follow-up. AB - OBJECTIVE: Since the first transcatheter aortic valve implantation (TAVI) in 2002, TAVI technique has gained an increasing popularity especially in high-risk patients. In this study, we present the first echocardiographic midterm outcome with the second-generation transapical JenaValve TAVI system (JenaValve Technology GmbH, Munich, Germany) in patients with aortic stenosis (AS). METHODS: Between November 2011 and November 2012, a total of 28 patients received transapical TAVI using the JenaValve. Primary endpoint was a combined efficacy endpoint after 1 year, which included all-cause mortality after more than 30 days, failure of current therapy for AS requiring hospitalization for symptoms of valve-related cardiac decompensation or prosthetic heart valve dysfunction. Moreover, we analyzed secondary endpoints after 3 and 12 months including cardiovascular mortality; major stroke; and life-threatening, disabling, or major bleeding. Mean echocardiographic follow-up was 471.35 +/- 102.72 days. RESULTS: Mean age was 80.43 +/- 6.03 years and EuroSCORE II was 8.80 +/- 7.21%. Successful implantation was accomplished in 100% (n = 28). Median transvalvular aortic mean pressure gradient was 44.5 mm Hg (interquartile range [IQR]: 34.5; 55.5) preoperatively, 12 mm Hg (IQR: 9; 16) postoperatively, and 11 mm Hg (IQR: 8; 16) after 1 year. After 12 months, no paravalvular leakage was seen in 52.38% of the patients and grade 1 paravalvular leakage was seen in 47.62% of the patients. There was no grade 2 or 3 leakage detected. Stroke, valve thrombosis or dislocation, myocardial infarction, or bleeding was also not observed. However, criteria for the combined efficacy endpoint after 1 year were met in five patients (17.86%). Thirty-day mortality was 14.29% (n = 4) and all-cause mortality after 1 year was 21.43% (n = 6). CONCLUSION: The JenaValve transapical TAVI system is a safe and feasible procedure with low peri- and postoperative complications and convincing midterm performance of the prosthesis. PMID- 26030121 TI - The Effects of Different Surgical Approaches on the Perioperative Level of Circulating Tumor Cells in Patients with Non-Small Cell Lung Cancer. AB - Background To observe and compare the effects of video-assisted thoracoscopic surgery (VATS) and conventional thoracotomy on the levels of circulating tumor cells (CTCs) in patients with non-small cell lung carcinoma (NSCLC). Methods Seventy-nine patients with a diagnosis of NSCLC were enrolled in the study. Forty three were treated with VATS and 36 were treated with conventional thoracotomy. Blood samples were collected 3 days prior to surgery (d-3), during surgery (d0), and 3 days after surgery (d3). After epithelial cell adhesion molecule (EpCAM) labeled immunomagnetic cell enrichment, anti-CK-PE and anti-CD45-FITC fluorescent labeled monoclonal antibodies were added to sort CTCs. Quantification of CTCs was performed using multiparameter flow cytometry. Results The number of CTCs on d0 was significantly higher than on d-3 (5.730 +/- 4.266 vs. 4.142 +/- 3.971, p = 0.033) in both groups. There was no significant difference in the change of CTCs from before surgery to during surgery in the VATS and conventional thoracotomy (open) groups (1.363 +/- 2.924 vs. 1.500 +/- 2.315, p = 0.329). However, the increase in number of CTCs from before surgery to after surgery was significantly lower in the VATS group than in the conventional thoracotomy (open) group (2.181 +/- 2.962 vs. 9.666 +/- 15.641, p = 0.015). Thirty of the 79 patients tested positive for CTCs before surgery (37.97%). All benign lung disease patients and volunteers tested negative for CTCs. Conclusion A smaller increase in CTCs was seen in patients treated with VATS lobectomy than in patients treated with conventional thoracotomy. This reduction in number of postoperative CTCs may improve long-term survival. PMID- 26030122 TI - Predictive power of a body shape index for development of diabetes, hypertension, and dyslipidemia in Japanese adults: a retrospective cohort study. AB - BACKGROUND/OBJECTIVES: Recently, a body shape index (ABSI) was reported to predict all-cause mortality independently of body mass index (BMI) in Americans. This study aimed to evaluate whether ABSI is applicable to Japanese adults as a predictor for development of diabetes, hypertension, and dyslipidemia. SUBJECTS/METHODS: We evaluated the predictive power of ABSI in a retrospective cohort study using annual health examination data from Chiba City Hall in Japan, for the period 2008 to 2012. Subjects included 37,581 without diabetes, 23,090 without hypertension, and 20,776 without dyslipidemia at baseline who were monitored for disease incidence for 4 years. We examined the associations of standardized ABSI, BMI, and waist circumference (WC) at baseline with disease incidence by logistic regression analyses. Furthermore, we conducted a case matched study using the propensity score matching method. RESULTS: Elevated BMI, WC, and ABSI increased the risks of diabetes and dyslipidemia [BMI-diabetes: odds ratio (OR) = 1.26, 95% confidence interval (95%CI) = 1.20-1.32; BMI-dyslipidemia: OR = 1.15, 95%CI = 1.12-1.19; WC-diabetes: OR = 1.24, 95%CI = 1.18-1.31; WC dyslipidemia: OR = 1.15, 95%CI = 1.11-1.19; ABSI-diabetes: OR = 1.06, 95%CI = 1.01-1.11; ABSI-dyslipidemia: OR = 1.04, 95%CI = 1.01-1.07]. Elevated BMI and WC, but not higher ABSI, also increased the risk of hypertension [BMI: OR = 1.32, 95%CI = 1.27-1.37; WC: OR = 1.22, 95%CI = 1.18-1.26; ABSI: OR = 1.00, 95%CI = 0.97-1.02]. Areas under the curve (AUCs) in regression models with ABSI were significantly smaller than in models with BMI or WC for all three diseases. In case-matched subgroups, the power of ABSI was weaker than that of BMI and WC for predicting the incidence of diabetes, hypertension, and dyslipidemia. CONCLUSIONS: Compared with BMI or WC, ABSI was not a better predictor of diabetes, hypertension, and dyslipidemia in Japanese adults. PMID- 26030123 TI - Effects of a Medical Home and Shared Savings Intervention on Quality and Utilization of Care. AB - IMPORTANCE: Published evaluations of medical home interventions have found limited effects on quality and utilization of care. OBJECTIVE: To measure associations between participation in the Northeastern Pennsylvania Chronic Care Initiative and changes in quality and utilization of care. DESIGN, SETTING, AND PARTICIPANTS: The northeast region of the Pennsylvania Chronic Care Initiative began in October 2009, included 2 commercial health plans and 27 volunteering small primary care practice sites, and was designed to run for 36 months. Both participating health plans provided medical claims and enrollment data spanning October 1, 2007, to September 30, 2012 (2 years prior to and 3 years after the pilot inception date). We analyzed medical claims for 17,363 patients attributed to 27 pilot and 29 comparison practices, using difference-in-difference methods to estimate changes in quality and utilization of care associated with pilot participation. EXPOSURES: The intervention included learning collaboratives, disease registries, practice coaching, payments to support care manager salaries and practice transformation, and shared savings incentives (bonuses of up to 50% of any savings generated, contingent on meeting quality targets). As a condition of participation, pilot practices were required to attain recognition by the National Committee for Quality Assurance as medical homes. MAIN OUTCOMES AND MEASURES: Performance on 6 quality measures for diabetes and preventive care; utilization of hospital, emergency department, and ambulatory care. RESULTS: All pilot practices received recognition as medical homes during the intervention. By intervention year 3, relative to comparison practices, pilot practices had statistically significantly better performance on 4 process measures of diabetes care and breast cancer screening; lower rates of all-cause hospitalization (8.5 vs 10.2 per 1000 patients per month; difference, -1.7 [95% CI, -3.2 to -0.03]), lower rates of all-cause emergency department visits (29.5 vs 34.2 per 1000 patients per month; difference, -4.7 [95% CI, -8.7 to -0.9]), lower rates of ambulatory care-sensitive emergency department visits (16.2 vs 19.4 per 1000 patients per month; difference, -3.2 [95% CI, -5.7 to -0.9]), lower rates of ambulatory visits to specialists (104.9 vs 122.2 per 1000 patients per month; difference, -17.3 [95% CI, -26.6 to -8.0]); and higher rates of ambulatory primary care visits (349.0 vs 271.5 per 1000 patients per month; difference, 77.5 [95% CI, 37.3 to 120.5]). CONCLUSIONS AND RELEVANCE: During a 3-year period, this medical home intervention, which included shared savings for participating practices, was associated with relative improvements in quality, increased primary care utilization, and lower use of emergency department, hospital, and specialty care. With further experimentation and evaluation, such interventions may continue to become more effective. PMID- 26030124 TI - The Lys-Specific Molecular Tweezer, CLR01, Modulates Aggregation of the Mutant p53 DNA Binding Domain and Inhibits Its Toxicity. AB - The tumor suppressor p53 plays a unique role as a central hub of numerous cell proliferation and apoptotic pathways, and its malfunction due to mutations is a major cause of various malignancies. Therefore, it serves as an attractive target for developing novel anticancer therapeutics. Because of its intrinsically unstable DNA binding domain, p53 unfolds rapidly at physiological temperature. Certain mutants shift the equilibrium toward the unfolded state and yield high molecular weight, nonfunctional, and cytotoxic beta-sheet-rich aggregates that share tinctorial and conformational similarities with amyloid deposits found in various protein misfolding diseases. Here, we examined the effect of a novel protein assembly modulator, the lysine (Lys)-specific molecular tweezer, CLR01, on different aggregation stages of misfolded mutant p53 in vitro and on the cytotoxicity of the resulting p53 aggregates in cell culture. We found that CLR01 induced rapid formation of beta-sheet-rich, intermediate-size p53 aggregates yet inhibited further p53 aggregation and reduced the cytotoxicity of the resulting aggregates. Our data suggest that aggregation modulators, such as CLR01, could prevent the formation of toxic p53 aggregates. PMID- 26030126 TI - Editorial: What's in a Name, or the Impact of Misnomers in Endocrine Research. PMID- 26030125 TI - Expression of glucose transporters in the prelaminar region of the optic-nerve head of the pig as determined by immunolabeling and tissue culture. AB - BACKGROUND: To develop the use of cultured tissue of the prelaminar optic nerve of the pig to explore possible alterations of the astrocyte-axon metabolic pathways in glaucoma, we map the distribution of the glucose transporters GLUT1 and GLUT3 in fresh and cultured tissue. METHODS: We monitor cell survival in cultures of the prelaminar optic-nerve tissue, measuring necrosis and apoptosis markers biochemically as well as morphologically, and establish the presence of the glucose transporters GLUT1 and GLUT3. We map the distribution of these transporters with immunolabeling in histological sections of the optic nerve using confocal and electronic transmission microscopy. RESULTS: We find that the main death type in prelaminar culture is apoptosis. Caspase 7 staining reveals an increment in apoptosis from day 1 to day 4 and a reduction from day 4 to day 8. Western blotting for GLUT1 shows stability with increased culture time. CLSM micrographs locate GLUT1 in the columnar astrocytes and in the area of axonal bundles. Anti-GLUT3 predominantly labels axonal bundles. TEM immunolabeling with colloidal gold displays a very specific distribution of GLUT-1 in the membranes of vascular endothelial cells and in periaxonal astrocyte expansions. The GLUT-3 isoform is observed with TEM only in axons in the axonal bundles. CONCLUSIONS: Tissue culture is suitable for apoptosis-induction experiments. The results suggest that glucose is transported to the axonal cleft intracytoplasmically and delivered to the cleft by GLUT1 transporters. As monocarboxylate transporters have been reported in the prelaminar region of the optic-nerve head, this area is likely to use both lactate and glucose as energy sources. PMID- 26030129 TI - Formation Mechanism for Stable Hybrid Clusters of Proteins and Nanoparticles. AB - Citrate-stabilized gold nanoparticles (AuNP) agglomerate in the presence of hemoglobin (Hb) at acidic pH. The extent of agglomeration strongly depends on the concentration ratio [Hb]/[AuNP]. Negligible agglomeration occurs at very low and very high [Hb]/[AuNP]. Full agglomeration and precipitation occur at [Hb]/[AuNP] corresponding to an Hb monolayer on the AuNP. Ratios above and below this value lead to the formation of an unexpected phase: stable, microscopic AuNP-Hb agglomerates. We investigated the kinetics of agglomeration with dynamic light scattering and the adsorption kinetics of Hb on planar gold with surface-acoustic wave-phase measurements. Comparing agglomeration and adsorption kinetics leads to an explanation of the complex behavior of this nanoparticle-protein mixture. Agglomeration is initiated either when Hb bridges AuNP or when the electrostatic repulsion between AuNP is neutralized by Hb. It is terminated when Hb has been depleted or when Hb forms multilayers on the agglomerates that stabilize microscopic clusters indefinitely. PMID- 26030131 TI - Bidirectional microfluidic pumping using an array of magnetic Janus microspheres rotating around magnetic disks. AB - We demonstrate a novel, flexible and programmable method to pump liquid through microchannels in lab-on-a-chip systems without the use of an external pump. The pumping principle is based on the rotation of ferromagnetic Janus microspheres around permalloy disks, driven by an external rotating magnetic field. By placing the disks close to the edge of the microchannel, a pumping rate of at least 0.3 nL min(-1) was measured using tracking microspheres. Geometric programming of the pumping direction is possible by positioning the magnetic disk close to the side wall. A second degree of freedom in the pumping direction is offered by the rotational direction of the external magnetic field. This method is especially suited for flow-controlled recirculation of chemical and biological species in microchannels - for example, medium recirculation in culture chambers - opening the way towards novel, portable, on-chip applications without the need for external fluidic or electrical connections. PMID- 26030130 TI - Circulating adiponectin and risk of endometrial cancer. AB - BACKGROUND: Adiponectin is an insulin-sensitizing hormone produced by adipocytes. It has been suggested to be involved in endometrial tumorigenesis. Published data have shown inconsistent results for the association between circulating adiponectin levels and endometrial cancer. In this study, we conducted a meta analysis to evaluate the predictive value of circulating adiponectin levels on the development of endometrial cancer. METHODS: PubMed, Embase, ISI web of knowledge, and Cochrane databases were searched for all eligible studies, and the summary relative risk (SRR) was calculated. Additionally, we performed dose response analysis with eight eligible studies. RESULTS: A total of 1,955 cases and 3,458 controls from 12 studies were included. The SRR for the 'highest' vs 'lowest' adiponectin levels indicated high adiponectin level reduced the risk of endometrial cancer [SRR = 0.40, 95% confidence interval (CI), 0.33-0.66]. Results from the subgroup analyses were consistent with the overall analysis. The SRR for each 1 ug/ml increase of adiponectin indicated a 3% reduction in endometrial cancer risk (95% CI: 2%-4%), and a 14% reduction for each increase of 5 ug/ml (95% CI: 9%-19%). No evidence of publication bias was found. CONCLUSIONS: This meta-analysis demonstrates that low level of circulating adiponectin is a risk factor for endometrial cancer. PMID- 26030132 TI - Dispersion Corrections Improve the Accuracy of Both Noncovalent and Covalent Interactions Energies Predicted by a Density-Functional Theory Approximation. AB - The use of pairwise dispersion corrections together with dispersion-correcting potentials (DCPs) offers a computationally low-cost approach to improving the performance of a density-functional theory based method with respect to the prediction of important chemical properties. In this work, we develop DCPs for the C, H, N, and O atoms for use with the BLYP generalized gradient approximation functional coupled with "D3" pairwise dispersion corrections and 6-31+G(2d,2p) basis sets. The combined approach, referred to as BLYP-D3-DCP, offers generally improved performance over both unadorned BLYP and BLYP with D3 corrections with respect to the prediction of noncovalent binding energies (BEs) and covalent bond dissociation enthalpies (BDEs). Predicted barrier heights for a set of pericyclic and Diels-Alder reactions are improved in some instances, as are organic bond separation reaction energies and radical stabilization energies. It is also shown that the BLYP-D3-DCP approach outperforms B3LYP-D3 in the prediction of many chemical properties, in particular noncovalent BEs and BDEs, suggesting that the addition of D3 and DCP corrections, which have negligible computational cost, to simple density functionals like BLYP may elevate their performance to that of more complex functionals such as B3LYP. PMID- 26030133 TI - Nanodiamond finding in the hyblean shallow mantle xenoliths. AB - Most of Earth's diamonds are connected with deep-seated mantle rocks; however, in recent years, MUm-sized diamonds have been found in shallower metamorphic rocks, and the process of shallow-seated diamond formation has become a hotly debated topic. Nanodiamonds occur mainly in chondrite meteorites associated with organic matter and water. They can be synthesized in the stability field of graphite from organic compounds under hydrothermal conditions. Similar physicochemical conditions occur in serpentinite-hosted hydrothermal systems. Herein, we report the first finding of nanodiamonds, primarily of 6 and 10 nm, in Hyblean asphaltene-bearing serpentinite xenoliths (Sicily, Italy). The discovery was made by electron microscopy observations coupled with Raman spectroscopy analyses. The finding reveals new aspects of carbon speciation and diamond formation in shallow crustal settings. Nanodiamonds can grow during the hydrothermal alteration of ultramafic rocks, as well as during the lithogenesis of sediments bearing organic matter. PMID- 26030134 TI - Consider the source: adolescents and adults similarly follow older adult advice more than peer advice. AB - Individuals learn which of their actions are likely to be rewarded through trial and error. This form of learning is critical for adapting to new situations, which adolescents frequently encounter. Adolescents are also greatly influenced by their peers. The current study tested the extent to which adolescents rely on peer advice to guide their actions. Adolescent and young adult participants completed a probabilistic learning task in which they chose between four pairs of stimuli with different reinforcement probabilities, with one stimulus in each pair more frequently rewarded. Participants received advice about two of these pairs, once from a similarly aged peer and once from an older adult. Crucially, this advice was inaccurate, enabling the dissociation between experience-based and instruction-based learning. Adolescents and adults learned equally well from experience and no age group difference was evident in the overall influence of advice on choices. Surprisingly, when considering the source of advice, there was no evident influence of peer advice on adolescent choices. However, both adolescents and adults were biased toward choosing the stimulus recommended by the older adult. Contrary to conventional wisdom, these data suggest that adolescents may prioritize the advice of older adults over that of peers in certain decision-making contexts. PMID- 26030136 TI - Identification of fleeting electrochemical reaction intermediates using desorption electrospray ionization mass spectrometry. AB - We report a new method for the mass spectrometric detection of fleeting reaction intermediates in electrochemical reactions utilizing a "waterwheel" working electrode setup. This setup takes inspiration from desorption electrospray ionization (DESI) mass spectrometry, where the sampling time is on the order of milliseconds, to sample directly from the surface of a working electrode for mass spectrometric analysis. We present data that show the formation of a diimine intermediate of the electrochemical oxidation of uric acid that has a lifetime in solution of 23 ms as well as data that provide evidence for the formation of a similar diimine species from the electrooxidation of xanthine, which has not been previously observed. PMID- 26030135 TI - The impact of stannous, fluoride ions and its combination on enamel pellicle proteome and dental erosion prevention. AB - OBJECTIVES: To compare the effects of stannous (Sn) and fluoride (F) ions and their combination on acquired enamel pellicle (AEP) protein composition (proteome experiment), and protection against dental erosion (functional experiment). METHODS: In the proteome experiment, bovine enamel specimens were incubated in whole saliva supernatant for 24h for AEP formation. They were randomly assigned to 4 groups (n=10), according to the rinse treatment: Sn (800ppm/6.7mM, SnCl2), F (225ppm/13mM, NaF), Sn and F combination (Sn+F) and deionized water (DIW, negative control). The specimens were immersed 3* in the test rinses for 2min, 2h apart. Pellicles were collected, digested, and analyzed for protein content using liquid chromatography electrospray ionization tandem mass spectrometry. In the functional experiment, bovine enamel specimens (n=10) were similarly treated for pellicle formation. Then, they were subjected to a five-day erosion cycling model, consisting of 5min erosive challenges (15.6 mM citric acid, pH 2.6, 6*/d) and 2min treatment with the rinses containing Sn, F or Sn+F (3*/d). Between the treatments, all specimens were incubated in whole saliva supernatant. Surface loss was determined by profilometry. RESULTS: Our proteome approach on bovine enamel identified 72 proteins that were common to all groups. AEP of enamel treated with Sn+F demonstrated higher abundance for most of the identified proteins than the other groups. The functional experiment showed reduction of enamel surface loss for Sn+F (89%), Sn (67%) and F (42%) compared to DIW (all significantly different, p<0.05). CONCLUSION: This study highlighted that anti erosion rinses (e.g. Sn+F) can modify quantitatively and qualitatively the AEP formed on bovine enamel. Moreover, our study demonstrated a combinatory effect that amplified the anti-erosive protection on tooth surface. PMID- 26030137 TI - Helmet-Wearing Practices and Barriers in Toronto Bike-Share Users: a Case-Control Study. AB - BACKGROUND: Helmet use among bike-share users is low. We sought to characterize helmet-use patterns, barriers to helmet use, and cycling safety practices among bike-share users in Toronto. METHODS: A standardized survey of public bike-share program (PBSP) users at semi-random distribution of PBSP stations was undertaken. By maintaining a ratio of one helmet-wearer (HW): two non-helmet-wearers (NHW) per survey period, we controlled for location, day, time, and weather. RESULTS: Surveys were completed on 545 (180 HW, 365 NHW) unique users at 48/80 PBSP locations, from November 2012 to August 2013. More females wore helmets (F: 41.1%, M: 30.9%, p=0.0423). NHWs were slightly younger than HWs (NHW mean age 34.4 years vs HW 37.3, p=0.0018). The groups did not differ by employment status, education, or income. Helmet ownership was lower among NHWs (NHW: 62.4% vs HW: 99.4%, p<0.0001), as was personal bike ownership (NHW: 65.8%, vs HW: 78.3%, p=0.0026). NHWs were less likely to always wear a helmet on personal bikes (NHW: 22.2% vs HW: 66.7%, p<0.0001), and less likely to wear a helmet always or most of the time on PBSP (NHW: 5.8% vs HW: 92.3%, p<0.0001). Both groups, but more HWs, had planned to use PBSP when leaving their houses (HW: 97.2% vs NHW: 85.2%, p<0.0001), primarily to get to work (HW: 88.3% vs NHW: 84.1%, p=0.19). NHWs were more likely to report that they would wear a helmet more (NHW: 61.4% vs HW: 13.9%, p<0.0001), and/or cycle less (NHW: 22.5% vs HW: 4.4%) if helmet use was mandatory. CONCLUSIONS: PBSP users surveyed appear to make deliberate decisions regarding helmet use. NHWs tended to be male, slightly younger, and less likely to use helmets on their personal bikes. As Toronto cyclists who do not wear helmets on PBSP generally do not wear helmets on their personal bikes, interventions to increase helmet use should target both personal and bike-share users. Legislating helmet use and provision of rental helmets could improve helmet use among bike-share users, but our results suggest some risk of reduced cycling with legislation. PMID- 26030139 TI - Nanoscale Probing of Local Electrical Characteristics on MBE-Grown Bi2Te3 Surfaces under Ambient Conditions. AB - The local electrical characteristics on the surface of MBE-grown Bi2Te3 are probed under ambient conditions by conductive atomic force microscopy. Nanoscale mapping reveals a 10-100* enhancement in current at step-edges compared to that on terraces. Analysis of the local current-voltage characteristics indicates that the transport mechanism is similar for step-edges and terraces. Comparison of the results with those for control samples shows that the current enhancement is not a measurement artifact but instead is due to local differences in electronic properties. The likelihood of various possible mechanisms is discussed. The absence of enhancement at the step-edges for graphite terraces is consistent with the intriguing possibility that spin-orbit coupling and topological effects play a significant role in the step-edge current enhancement in Bi2Te3. PMID- 26030138 TI - Identification of Novel Proteins Co-Purifying with Cockayne Syndrome Group B (CSB) Reveals Potential Roles for CSB in RNA Metabolism and Chromatin Dynamics. AB - The CSB protein, a member of the SWI/SNF ATP dependent chromatin remodeling family of proteins, plays a role in a sub-pathway of nucleotide excision repair (NER) known as transcription coupled repair (TCR). CSB is frequently mutated in Cockayne syndrome group B, a segmental progeroid human autosomal recessive disease characterized by growth failure and degeneration of multiple organs. Though initially classified as a DNA repair protein, recent studies have demonstrated that the loss of CSB results in pleiotropic effects. Identification of novel proteins belonging to the CSB interactome may be useful not only for predicting the molecular basis for diverse pathological symptoms of CS-B patients but also for unraveling the functions of CSB in addition to its authentic role in DNA repair. In this study, we performed tandem affinity purification (TAP) technology coupled with mass spectrometry and co-immunoprecipitation studies to identify and characterize the proteins that potentially interact with CSB-TAP. Our approach revealed 33 proteins that were not previously known to interact with CSB. These newly identified proteins indicate potential roles for CSB in RNA metabolism involving repression and activation of transcription process and in the maintenance of chromatin dynamics and integrity. PMID- 26030140 TI - Senescent cells talk frankly with their neighbors. PMID- 26030141 TI - Association between Personality Traits and Sleep Quality in Young Korean Women. AB - Personality is a trait that affects behavior and lifestyle, and sleep quality is an important component of a healthy life. We analyzed the association between personality traits and sleep quality in a cross-section of 1,406 young women (from 18 to 40 years of age) who were not reporting clinically meaningful depression symptoms. Surveys were carried out from December 2011 to February 2012, using the Revised NEO Personality Inventory and the Pittsburgh Sleep Quality Index (PSQI). All analyses were adjusted for demographic and behavioral variables. We considered beta weights, structure coefficients, unique effects, and common effects when evaluating the importance of sleep quality predictors in multiple linear regression models. Neuroticism was the most important contributor to PSQI global scores in the multiple regression models. By contrast, despite being strongly correlated with sleep quality, conscientiousness had a near-zero beta weight in linear regression models, because most variance was shared with other personality traits. However, conscientiousness was the most noteworthy predictor of poor sleep quality status (PSQI >= 6) in logistic regression models and individuals high in conscientiousness were least likely to have poor sleep quality, which is consistent with an OR of 0.813, with conscientiousness being protective against poor sleep quality. Personality may be a factor in poor sleep quality and should be considered in sleep interventions targeting young women. PMID- 26030142 TI - Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy. AB - Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, beta = -0.06, p = 1.1 x 10(-7)). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10(-7). Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury. PMID- 26030143 TI - The frequency of patient-initiated violence and its psychological impact on physicians in china: a cross-sectional study. AB - INTRODUCTION: In China, the severity of medical disputes has greatly increased during the past two decades, which has caused various adverse outcomes for health professionals. Previous research on violence in healthcare settings has primarily examined the occurrence of patient-initiated violence and its effects on physicians, but few studies have focused on the impact of the extent of physicians' exposure to violence. This study examined the different frequency levels of specific types of violence and their relationships to physicians' psychological wellbeing, including emotional exhaustion (EE), job satisfaction (JS), and intention to leave (IL). METHODS: Using a stratified random sampling method, the participants were drawn from 123 public hospitals in Shanghai, Hubei Province, and Gansu Province in China, and 1,656 completed questionnaires were collected. Chi-square test, analysis of variance, and mixed linear model were employed in the analysis. RESULTS: The results showed that the rate of exposure to verbal abuse (VA) was the highest (92.75%), followed by threats of assault (TA, 88.10%) and physical assaults (PA, 81.04%). Physicians' reported high frequency exposure to VA, TA, and PA was 35.14%, 27.72%, and 19.32%, respectively. The results indicated that exposure to violence significantly affected EE, JS, and IL, and the intensity of the harm of high-frequency exposure was several times stronger than that of low-frequency exposure. Interestingly, we found that VA produced a greater adverse impact on physicians' EE and satisfaction with work (JS-1) than did TA or PA. This finding may be attributed to the fact that physicians are more likely to be exposed to a high frequency of VA, and the effect of high-frequency exposure is much stronger. CONCLUSION: The results indicated that decreasing violent incidents and creating a safer work environment for physicians should be a top priority for both government and society. PMID- 26030144 TI - Skeletal muscle radio-density is an independent predictor of response and outcomes in follicular lymphoma treated with chemoimmunotherapy. AB - Skeletal muscle radio-density (SMD) measures muscle radiation attenuation (in Hounsfield Units, HU) on computed tomography (CT) scans. Low SMD is prognostic of poor survival in melanoma, however its significance is unknown for hematologic malignancies. We performed a single institution, retrospective review of all follicular lymphoma (FL) patients who received chemoimmunotherapy from 2004-2009. Patient demographics, FL International Prognostic Index 1 (FLIPI-1), progression free (PFS) and overall survival (OS) were collected as primary endpoints. Objective response rates (ORR) were secondary. SMD was calculated using pre treatment CT scans. In 145 patients reviewed, median values were age 59, FLIPI-1 of 2, stage III, and 8 chemoimmunotherapy cycles received. Median PFS for those with low SMD (<36.6 and <33.1 HU for patients with BMI <= 25 and > 25 kg/m2, respectively) compared to those with high SMD was profoundly worse, 69.6 vs. 106.7 months (hazard ratio [HR] 1.85; p = 0.01), respectively. Median OS was not reached in patients with high SMD vs. 92.7 months in low SMD patients (HR 4.02; p = 0.0002). Multivariate analysis supported lower SMD's OS detriment (HR = 3.40; p = 0.002) independent of FLIPI-1 (HR 1.46-2.76, p = 0.05) or gender. Low SMD predicted lower ORR, 83 vs. 96% (p = 0.01). SMD predicts survival independent of FLIPI-1 and potentially chemoimmunotherapy response. SMD is an inexpensive and powerful tool that can complement FLIPI-1. PMID- 26030145 TI - Effects of salmon-derived nutrients and habitat characteristics on population densities of stream-resident sculpins. AB - Movement of nutrients across ecosystem boundaries can have important effects on food webs and population dynamics. An example from the North Pacific Rim is the connection between productive marine ecosystems and freshwaters driven by annual spawning migrations of Pacific salmon (Oncorhynchus spp). While a growing body of research has highlighted the importance of both pulsed nutrient subsidies and disturbance by spawning salmon, their effects on population densities of vertebrate consumers have rarely been tested, especially across streams spanning a wide range of natural variation in salmon densities and habitat characteristics. We studied resident freshwater prickly (Cottus asper), and coastrange sculpins (C. aleuticus) in coastal salmon spawning streams to test whether their population densities are affected by spawning densities of pink and chum salmon (O. gorbuscha and O. keta), as well as habitat characteristics. Coastrange sculpins occurred in the highest densities in streams with high densities of spawning pink and chum salmon. They also were more dense in streams with high pH, large watersheds, less area covered by pools, and lower gradients. In contrast, prickly sculpin densities were higher in streams with more large wood and pools, and less canopy cover, but their densities were not correlated with salmon. These results for coastrange sculpins provide evidence of a numerical population response by freshwater fish to increased availability of salmon subsidies in streams. These results demonstrate complex and context dependent relationships between spawning Pacific salmon and coastal ecosystems and can inform an ecosystem-based approach to their management and conservation. PMID- 26030146 TI - Fine-tuning optical and electronic properties of graphene oxide for highly efficient perovskite solar cells. AB - Simplifying the process of fine-tuning the electronic and optical properties of graphene oxide (GO) is of importance in order to fully utilize it as the hole interfacial layer (HIL). We introduced silver trifluoromethanesulfonate (AgOTf), an inorganic chemical dopant, that tunes and controls the properties of single layered GO films synthesized by chemical vapor deposition. The morphology, work function, mobility, sheet resistance, and transmittance of the GO film were systematically tuned by various doping concentrations. We further developed a solution-processable low-temperature hole interfacial layer (HIL) poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS):AgOTf-doped GO HIL in highly efficient perovskite solar cells. The PEDOT: PSS:AgOTf-doped GO HIL grants the desirable charge-collection in the HIL allowing the entire device to be prepared at temperatures less than 120 degrees C. The fabricated perovskite solar cells utilize a rigid substrate and demonstrate compelling photovoltaic performance with a power conversion efficiency (PCE) of 11.90%. Moreover, flexible devices prepared using a polyethylene terephthalate (PET)/ITO demonstrate a PCE of 9.67%, while ITO-free flexible devices adopting PET/aluminum doped zinc oxide (AZO)/silver (Ag)/AZO demonstrate a PCE of 7.97%. This study shows that the PEDOT: PSS:AgOTf-doped GO HIL has significant potential to contribute to the development of low-cost solar cells. PMID- 26030147 TI - Reidentification of avian embryonic remains from the cretaceous of mongolia. AB - Embryonic remains within a small (4.75 by 2.23 cm) egg from the Late Cretaceous, Mongolia are here re-described. High-resolution X-ray computed tomography (HRCT) was used to digitally prepare and describe the enclosed embryonic bones. The egg, IGM (Mongolian Institute for Geology, Ulaanbaatar) 100/2010, with a three-part shell microstructure, was originally assigned to Neoceratopsia implying extensive homoplasy among eggshell characters across Dinosauria. Re-examination finds the forelimb significantly longer than the hindlimbs, proportions suggesting an avian identification. Additional, postcranial apomorphies (strut-like coracoid, cranially located humeral condyles, olecranon fossa, slender radius relative to the ulna, trochanteric crest on the femur, and ulna longer than the humerus) identify the embryo as avian. Presence of a dorsal coracoid fossa and a craniocaudally compressed distal humerus with a strongly angled distal margin support a diagnosis of IGM 100/2010 as an enantiornithine. Re-identification eliminates the implied homoplasy of this tri-laminate eggshell structure, and instead associates enantiornithine birds with eggshell microstructure composed of a mammillary, squamatic, and external zones. Posture of the embryo follows that of other theropods with fore- and hindlimbs folded parallel to the vertebral column and the elbow pointing caudally just dorsal to the knees. The size of the egg and embryo of IGM 100/2010 is similar to the two other Mongolian enantiornithine eggs. Well-ossified skeletons, as in this specimen, characterize all known enantiornithine embryos suggesting precocial hatchlings, comparing closely to late stage embryos of modern precocial birds that are both flight- and run-capable upon hatching. Extensive ossification in enantiornithine embryos may contribute to their relatively abundant representation in the fossil record. Neoceratopsian eggs remain unrecognized in the fossil record. PMID- 26030148 TI - Differential chromosome conformations as hallmarks of cellular identity revealed by mathematical polymer modeling. AB - Inherently dynamic, chromosomes adopt many different conformations in response to DNA metabolism. Models of chromosome organization in the yeast nucleus obtained from genome-wide chromosome conformation data or biophysical simulations provide important insights into the average behavior but fail to reveal features from dynamic or transient events that are only visible in a fraction of cells at any given moment. We developed a method to determine chromosome conformation from relative positions of three fluorescently tagged DNA in living cells imaged in 3D. Cell type specific chromosome folding properties could be assigned based on positional combinations between three loci on yeast chromosome 3. We determined that the shorter left arm of chromosome 3 is extended in MATalpha cells, but can be crumpled in MATa cells. Furthermore, we implemented a new mathematical model that provides for the first time an estimate of the relative physical constraint of three linked loci related to cellular identity. Variations in this estimate allowed us to predict functional consequences from chromatin structural alterations in asf1 and recombination enhancer deletion mutant cells. The computational method is applicable to identify and characterize dynamic chromosome conformations in any cell type. PMID- 26030149 TI - Additive regulation of adiponectin expression by the mediterranean diet olive oil components oleic Acid and hydroxytyrosol in human adipocytes. AB - Adiponectin, an adipocyte-derived insulin-sensitizing and anti-inflammatory hormone, is suppressed in obesity through mechanisms involving chronic inflammation and oxidative stress. Olive oil consumption is associated with beneficial cardiometabolic actions, with possible contributions from the antioxidant phenol hydroxytyrosol (HT) and the monounsaturated fatty acid oleic acid (OA, 18:1n-9 cis), both possessing anti-inflammatory and vasculo-protective properties. We determined the effects of HT and OA, alone and in combination, on adiponectin expression in human and murine adipocytes under pro-inflammatory conditions induced by the cytokine tumor necrosis factor(TNF)-alpha. We used human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes and murine 3T3-L1 adipocytes as cell model systems, and pretreated them with 1-100 MUmol/L OA, 0.1 20 MUmol/L HT or OA plus HT combination before stimulation with 10 ng/mL TNF alpha. OA or HT significantly (P<0.05) prevented TNF-alpha-induced suppression of total adiponectin secretion (by 42% compared with TNF-alpha alone) as well as mRNA levels (by 30% compared with TNF-alpha alone). HT and OA also prevented-by 35%-TNF-alpha-induced downregulation of peroxisome proliferator-activated receptor PPARgamma. Co-treatment with HT and OA restored adiponectin and PPARgamma expression in an additive manner compared with single treatments. Exploring the activation of JNK, which is crucial for both adiponectin and PPARgamma suppression by TNF-alpha, we found that HT and OA additively attenuated TNF-alpha-stimulated JNK phosphorylation (up to 55% inhibition). In conclusion, the virgin olive oil components OA and HT, at nutritionally relevant concentrations, have additive effects in preventing adiponectin downregulation in inflamed adipocytes through an attenuation of JNK-mediated PPARgamma suppression. PMID- 26030150 TI - Environmental Factors Influencing White-Tailed Deer (Odocoileus virginianus) Exposure to Livestock Pathogens in Wisconsin. AB - White-tailed deer (Odocoileus virginianus) are commonly exposed to disease agents that affect livestock but environmental factors that predispose deer to exposure are unknown for many pathogens. We trapped deer during winter months on two study areas (Northern Forest and Eastern Farmland) in Wisconsin from 2010 to 2013. Deer were tested for exposure to six serovars of Leptospira interrogans (grippotyphosa, icterohaemorrhagiae, canicola, bratislava, pomona, and hardjo), bovine viral diarrhea virus (BVDV-1 and BVDV-2), infectious bovine rhinotracheitis virus (IBR), and parainfluenza 3 virus (PI3). We used logistic regression to model potential intrinsic (e.g., age, sex) and extrinsic (e.g., land type, study site, year, exposure to multiple pathogens) variables we considered biologically meaningful to exposure of deer to livestock pathogens. Deer sampled in 2010-2011 did not demonstrate exposure to BVDV, so we did not test for BVDV in subsequent years. Deer had evidence of exposure to PI3 (24.7%), IBR (7.9%), Leptospira interrogans serovar pomona (11.7%), L. i. bratislava (1.0%), L. i. grippotyphosa (2.5%) and L. i. hardjo (0.3%). Deer did not demonstrate exposure to L. interrogans serovars canicola and icterohaemorrhagiae. For PI3, we found that capture site and year influenced exposure. Fawns (n = 119) were not exposed to L. i. pomona, but land type was an important predictor of exposure to L. i. pomona for older deer. Our results serve as baseline exposure levels of Wisconsin white-tailed deer to livestock pathogens, and helped to identify important factors that explain deer exposure to livestock pathogens. PMID- 26030151 TI - Identification of a Novel Mutation in the COL2A1 Gene in a Chinese Family with Spondyloepiphyseal Dysplasia Congenita. AB - Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short-trunk dwarfism, skeletal and vertebral deformities. Exome sequencing and Sanger sequencing were performed in a Chinese Han family with typical SEDC, and a novel mutation, c.620G>A (p.Gly207Glu), in the collagen type II alpha-1 gene (COL2A1) was identified. The mutation may impair protein stability, and lead to dysfunction of type II collagen. Family-based study suggested that the mutation is a de novo mutation. Our study extends the mutation spectrum of SEDC and confirms genotype-phenotype relationship between mutations at glycine in the triple helix of the alpha-1(II) chains of the COL2A1 and clinical findings of SEDC, which may be helpful in the genetic counseling of patients with SEDC. PMID- 26030153 TI - Carrier type inversion in quasi-free standing graphene: studies of local electronic and structural properties. AB - We investigate the local surface potential and Raman characteristics of as-grown and ex-situ hydrogen intercalated quasi-free standing graphene on 4H-SiC(0001) grown by chemical vapor deposition. Upon intercalation, transport measurements reveal a change in the carrier type from n- to p-type, accompanied by a more than three-fold increase in carrier mobility, up to MUh ~ 4540 cm(2) V(-1) s(-1). On a local scale, Kelvin probe force microscopy provides a complete and detailed map of the surface potential distribution of graphene domains of different thicknesses. Rearrangement of graphene layers upon intercalation to (n + 1)LG, where n is the number of graphene layers (LG) before intercalation, is demonstrated. This is accompanied by a significant increase in the work function of the graphene after the H2-intercalation, which confirms the change of majority carriers from electrons to holes. Raman spectroscopy and mapping corroborate surface potential studies. PMID- 26030152 TI - Neuropilin-2 Is a Newly Identified Target of PAX8 in Thyroid Cells. AB - PAX8 is a transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in the adult. In particular, PAX8 has been comprehensively shown to regulate genes that are considered markers of thyroid differentiation. However, a better knowledge of genes transcriptionally regulated by PAX8 is desirable to clarify its role in endocrine syndromes and cancer susceptibility. In order to further investigate PAX8 downstream targets, we recently performed a genome-wide expression analysis following PAX8 knockdown in FRTL-5 thyroid cells and Neuropilin-2 was identified as a potential transcriptional target of PAX8. In this study, we determined the role of the transcription factor PAX8 in the regulation of Neuropilin-2 expression. Indeed, in thyroid cells PAX8 directly binds the Neuropilin-2 promoter leading to its transcriptional repression. Interestingly, we observed an inverse correlation between the expression of PAX8 and Neuropilin-2 in thyroid carcinoma tissues and cell lines compared to non-tumor counterparts, suggesting a critical role of PAX8 in regulating Neuropilin-2 expression in vivo. Notably, ectopic overexpression of PAX8 in FB-2 thyroid cancer cells promotes Neuropilin-2 downregulation producing a significant reduction in cell proliferation, migration ability, and invasion activity and reverting the cell phenotype from mesenchymal to a more epithelial one. These findings uncover the novel interplay between PAX8 and Neuropilin-2, which is likely to be important in the pathogenesis of thyroid diseases. PMID- 26030154 TI - Telemedicine's Potential to Support Good Dying in Nigeria: A Qualitative Study. AB - OBJECTIVES: This qualitative study explores Nigerian health care professionals' concepts of good dying/a good death and how telemedicine technologies and services would fit the current Nigerian palliative care practice. MATERIALS AND METHODS: Supported by the Centre for Palliative Care Nigeria (CPCN) and the University College Hospital (UCH) in Ibadan, Nigeria, the authors organized three focus groups with Nigerian health care professionals interested in palliative care, unstructured interviews with key role players for palliative care and representatives of telecom companies, and field visits to primary, secondary and tertiary healthcare clinics that provided palliative care. Data analysis consisted of open coding, constant comparison, diagramming of categorizations and relations, and extensive member checks. RESULTS: The focus group participants classified good dying into 2 domains: a feeling of completion of the individual life and dying within the community. Reported barriers to palliative care provision were socio-economic consequences of being seriously ill, taboos on dying and being ill, restricted access to adequate medical-technical care, equation of religion with medicine, and the faulty implementation of palliative care policy by government. The addition of telemedicine to Nigeria's palliative care practice appears problematic, due to irregular bandwidth, poor network coverage, and unstable power supply obstructing interactivity and access to information. However, a tele-education 'lite' scenario seemed viable in Nigeria, wherein low-tech educational networks are central that build on non-synchronous online communication. DISCUSSION: Nigerian health care professionals' concepts on good dying/a good death and barriers and opportunities for palliative care provision were, for the greater part, similar to prior findings from other studies in Africa. Information for and education of patient, family, and community are essential to further improve palliative care in Africa. Telemedicine can only help if low-tech solutions are applied that work around network coverage problems by focusing on non-synchronous online communication. PMID- 26030155 TI - Tracking Visual Events in Time in the Absence of Time Perception: Implicit Processing at the ms Level. AB - Previous studies have suggested that even if subjects deem two visual stimuli less than 20 ms apart to be simultaneous, implicitly they are nonetheless distinguished in time. It is unclear, however, how information is encoded within this short timescale. We used a priming paradigm to demonstrate how successive visual stimuli are processed over time intervals of less than 20 ms. The primers were two empty square frames displayed either simultaneously or with a 17 ms asynchrony. The primers were followed by the target information after a delay of 25 ms to 100 ms. The two square frames were filled in one after another with a delay of 100 ms between them, and subjects had to decide on the location of the first of the frames to be filled in. In a second version of the paradigm, only one square frame was filled in, and subjects had to decide where it was positioned. The influence of the primers is revealed through faster response times depending on the location of the first and second primers. Experiment 1 replicates earlier results, with a bias towards the side of the second primer, but only when there is a delay of 75 to 100 ms between primers and targets. The following experiments suggest this effect to be relatively independent of the task context, except for a slight effect on the time course of the biases. For the temporal order judgment task, identical results were observed when subjects have to answer to the side of the second rather than the first target, showing the effect to be independent of the hand response, and suggesting it might be related to a displacement of attention. All in all the results suggest the flow of events is followed more efficiently than suggested by explicit asynchrony judgment studies. We discuss the possible impact of these results on our understanding of the sense of time continuity. PMID- 26030157 TI - Correction: changes to serum sample tube and processing methodology does not cause inter-individual variation in automated whole serum N-glycan profiling in health and disease. PMID- 26030156 TI - 3, 4-dihydroxyl-phenyl lactic acid restores NADH dehydrogenase 1 alpha subunit 10 to ameliorate cardiac reperfusion injury. AB - The present study aimed to detect the role of 3, 4-dihydroxyl-phenyl lactic acid (DLA) during ischemia/reperfusion (I/R) induced myocardial injury with emphasis on the underlying mechanism of DLA antioxidant. Male Spragu-Dawley (SD) rats were subjected to left descending artery occlusion followed by reperfusion. Treatment with DLA ameliorated myocardial structure and function disorder, blunted the impairment of Complex I activity and mitochondrial function after I/R. The results of 2-D fluorescence difference gel electrophoresis revealed that DLA prevented the decrease in NDUFA10 expression, one of the subunits of Complex I. To find the target of DLA, the binding affinity of Sirtuin 1 (SIRT1) to DLA and DLA derivatives with replaced two phenolic hydroxyls was detected using surface plasmon resonance and bilayer interferometry. The results showed that DLA could activate SIRT1 after I/R probably by binding to this protein, depending on phenolic hydroxyl. Moreover, the importance of SIRT1 to DLA effectiveness was confirmed through siRNA transfection in vitro. These results demonstrated that DLA was able to prevent I/R induced decrease in NDUFA10 expression, improve Complex I activity and mitochondrial function, eventually attenuate cardiac structure and function injury after I/R, which was possibly related to its ability of binding to and activating SIRT1. PMID- 26030158 TI - Real-time detection of hypochlorite in tap water and biological samples by a colorimetric, ratiometric and near-infrared fluorescent turn-on probe. AB - In this paper, we report a highly selective and sensitive ratiometric NIR fluorescent probe that can be used for real-time detection of the biologically important hypochlorite with colorimetric and significant NIR fluorescent turn-on signal changes at NIR excitation wavelength. In addition, experiments showed that this probe can be applied to detect hypochlorite in tap water, serum samples, and living cells with low cytotoxicity. PMID- 26030159 TI - Cerebral Lymphoma in a Kidney Transplant: A Case Report. AB - Posttransplant lymphoproliferative disorder is a serious complication during a solid-organ transplant. A 28-year-old Asiatic man developed a cerebral lesion that was considered an abscess, while undergoing a kidney transplant. The lesion diameter did not go down with antibiotic therapy, so he underwent a complete surgical mass excision. Pathology showed a B-cell lymphoma. The Epstein-Barr virus-DNA by polymerase chain reaction in plasma was negative. He began chemotherapy with methotrexate and rituximab, and radiation therapy. He had to be restarted on regular hemodialysis 1 year after surgery. Three years after receiving the diagnosis, he was alive and had not developed any other posttransplant lymphoproliferative disorder. This report presents case of a patient who developed primary central nervous system B-cell lymphoma, 2 years after undergoing a kidney transplant. A combination of chemotherapy and radiotherapy is the best option for treatment of brain posttransplant lymphoproliferative disorder. PMID- 26030160 TI - The Effectiveness of Crataegus orientalis M Bieber. (Hawthorn) Extract Administration in Preventing Alveolar Bone Loss in Rats with Experimental Periodontitis. AB - The purpose of this animal study was to evaluate the effects of hawthorn (Crataeus orientalis M Bieber.) extract on serum oxidative status and alveolar bone loss in experimental periodontitis. Twenty-seven Wistar rats were assigned to one of the following groups: non- ligated+placebo (saline) (NL, n = 9), ligature only+placebo (saline) (LO, n = 9), and ligature and treated with hawthorn extract in saline (H, n = 9) (100 mg/kg orogastrically, once a day for 11 days). Periodontitis was induced by submerging a 4/0 silk ligature in the sulcus of the mandibular right first molars of rats, and the animals were sacrificed after 11 days. Micro-CT examinations were performed for linear and volumetric parameter assessment of alveolar bone. Periodontal tissues were histopathologically examined to assess the differences among the study groups. Levels of serum total antioxidant status (TAS)/total oxidant status (TOS), and oxidative stress index (OSI) were also analyzed. Alveolar bone loss was significantly reduced by hawthorn administration compared to LO group (p<0.05). The number of inflammatory cells and osteoclasts in the LO group was significantly higher than that of the NL and H groups (p< 0.05). The number of osteoblasts in the LO and H groups was significantly higher than that of the NL group (p<0.05). TOS and OSI levels were significantly reduced in H group compared to LO group (P <0.05) and TAS levels were similar in H and NL group (p< 0.05). Hawthorn extract showed inhibitory effect on periodontal inflammation and alveolar bone loss by regulating TAS, TOS and OSI levels in periodontal disease in rats when administered systemically. PMID- 26030161 TI - Anti-tumor effects of metformin in animal models of hepatocellular carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: Several studies have reported that metformin can reduce the risk of hepatocellular carcinoma (HCC) in diabetes patients. However, the direct anti-HCC effects of metformin have hardly been studied in patients, but have been extensively investigated in animal models of HCC. We therefore performed a systematic review and meta-analysis of animal studies evaluating the effects of metformin on HCC. METHODS: We collected the relevant studies by searching EMBASE, Medline (OvidSP), Web of Science, Scopus, PubMed Publisher, and Google Scholar. Studies were included according to the following inclusion criteria: HCC, animal study, and metformin intervention. Study quality was assessed using SYRCLE's risk of bias tool. A meta-analysis was performed for the outcome measures: tumor growth (tumor volume, weight and size), tumor number and incidence. RESULTS: The search resulted in 573 references, of which 13 could be included in the review and 12 included in the meta-analysis. The study characteristics of the included studies varied considerably. Two studies used rats, while the others used mice. Only one study used female animals, nine used male, and three studies didn't mention the gender of animals in their experiments. The quality of the included studies was low to moderate based on the assessment of their risk of bias. The meta-analysis showed that metformin significantly inhibited the growth of HCC tumour (SMD -2.20[-2.96,-1.43]; n=16), but no significant effect on the number of tumors (SMD-1.05[-2.13,0.03]; n=5) or the incidence of HCC was observed (RR 0.62[0.33,1.16]; n=6). To investigate the potential sources of significant heterogeneities found in outcome of tumor growth (I2=81%), subgroup analyses of scales of growth measures and of types of animal models used were performed. CONCLUSION: Metformin appears to have a direct anti-HCC effect in animal models. Although the intrinsic limitations of animal studies, this systematic review could provide an important reference for future preclinical animal trials of good quality and clinical development. PMID- 26030163 TI - Investigating the Expression of Oncogenic and Tumor Suppressive MicroRNA in DLBCL. AB - Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of lymphoma, accounting for 40 percent of newly diagnosed cases each year. DLBCL is an aggressive abnormal growth of tissue characterized by the accumulation of abnormal B-lymphocytes in the lymphatics of affected individuals. The goal of this study was to analyze microRNA (miRNA) as an alternative method of diagnosis and treatment for patients affected with the observed cancer. MiRNAs are small, non-coding, endogenous RNA that control gene expression at the post transcriptional level. Emerging evidence suggests that miRNA-mediated gene regulation has a functional role in cancer and could prove to be crucial targets for therapeutic intervention. Here, we provide a quantitative study on the expression of a diverse class of oncogenic and tumor suppressive miRNA that have shown to regulate oncoproteins involved in differentiation, proliferation, and/or apoptosis. PMID- 26030162 TI - Spatio-temporal analysis of smear-positive tuberculosis in the Sidama Zone, southern Ethiopia. AB - BACKGROUND: Tuberculosis (TB) is a disease of public health concern, with a varying distribution across settings depending on socio-economic status, HIV burden, availability and performance of the health system. Ethiopia is a country with a high burden of TB, with regional variations in TB case notification rates (CNRs). However, TB program reports are often compiled and reported at higher administrative units that do not show the burden at lower units, so there is limited information about the spatial distribution of the disease. We therefore aim to assess the spatial distribution and presence of the spatio-temporal clustering of the disease in different geographic settings over 10 years in the Sidama Zone in southern Ethiopia. METHODS: A retrospective space-time and spatial analysis were carried out at the kebele level (the lowest administrative unit within a district) to identify spatial and space-time clusters of smear-positive pulmonary TB (PTB). Scan statistics, Global Moran's I, and Getis and Ordi (Gi*) statistics were all used to help analyze the spatial distribution and clusters of the disease across settings. RESULTS: A total of 22,545 smear-positive PTB cases notified over 10 years were used for spatial analysis. In a purely spatial analysis, we identified the most likely cluster of smear-positive PTB in 192 kebeles in eight districts (RR= 2, p<0.001), with 12,155 observed and 8,668 expected cases. The Gi* statistic also identified the clusters in the same areas, and the spatial clusters showed stability in most areas in each year during the study period. The space-time analysis also detected the most likely cluster in 193 kebeles in the same eight districts (RR= 1.92, p<0.001), with 7,584 observed and 4,738 expected cases in 2003-2012. CONCLUSION: The study found variations in CNRs and significant spatio-temporal clusters of smear-positive PTB in the Sidama Zone. The findings can be used to guide TB control programs to devise effective TB control strategies for the geographic areas characterized by the highest CNRs. Further studies are required to understand the factors associated with clustering based on individual level locations and investigation of cases. PMID- 26030164 TI - Rapid and scalable synthesis of innovative unnatural alpha,beta or gamma-amino acids functionalized with tertiary amines on their side-chains. AB - We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural alpha,beta or gamma-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity. PMID- 26030165 TI - Seizure Disorder in a Patient with a 5.09 Mb 7q11.23-q21.11 Microdeletion Including the MAGI2 Gene. AB - Infantile spasms (IS) are a severe form of epilepsy characterized by hysparrhythmia on EEG, spasms, and intellectual disability. Typically occurring before one year of age, 40-60% of patients diagnosed with IS eventually develop other seizure disorders later in life. The etiology of IS is broad, and only recently have IS-associated genes been identified. MAGI2, an implicated IS associated gene located within the 7q11.23-q21.11 chromosome region, encodes for a synaptic scaffolding protein involved in synaptic development and function. To date, several case reports of patients with 7q11.23-q21.11 microdeletions involving MAGI2 have been described, with the majority presenting with IS or other seizure disorders that are attributed to loss of heterozygosity of the MAGI2 gene. In addition, several other patients with 7q11.23 microdeletions not including MAGI2 have been described with clinical features that include IS, epilepsy, intellectual disabilities, and neurobehavioral problems, suggesting additional IS-associated candidate genes within the 7q11.23 region. Adding to the literature, we report on a 21-year-old female with a de novo 5.09 Mb 7q11.23 q21.11 microdeletion (aCGH analysis) involving the MAGI2 gene with a history of seizure disorder, intellectual disability, and dysmorphic features. Although we agree that MAGI2 is the most likely candidate gene for seizure disorder in our patient, other candidate genes must be considered in 7q11.23 deletion cases not spanning the MAGI2 gene. PMID- 26030166 TI - Which matters most? Demographic, neuropsychological, personality, and situational factors in long-term marijuana and alcohol trajectories for justice-involved male youth. AB - Justice-involved youth have high rates of alcohol and marijuana use. However, little is known about what may drive these rates over time. Using a large-scale (N = 1,056; 41.4% African American, 33.5% Hispanic) longitudinal study with strong retention (M retention = 90% over Years 1-7), we utilized random-effects regression to determine the comparative contribution of four sets of factors in justice-involved males' patterns of marijuana and heavy alcohol use (number of times drunk) over 7 years of follow-up: demographic, personality, situational, and neuropsychological factors. Across both marijuana and heavy alcohol use models, three factors were particularly strong contributors to lower rates of substance use: (a) Hispanic ethnicity, (b) less exposure (street) time, and (c) better impulse control. Similarly, two factors were strong contributors to increased rates of marijuana and heavy alcohol use: (a) delinquent peers and (b) family member arrest. Together, these findings indicate the relative superiority of these independent variables over other categories (i.e., neuropsychological factors) in predicting high-risk youths' long-term (7-year) rates of substance use. These findings also suggest the importance of evaluating the connection of these areas for high-risk, adjudicated youth. PMID- 26030167 TI - Gateway to curiosity: Medical marijuana ads and intention and use during middle school. AB - Over the past several years, medical marijuana has received increased attention in the media, and marijuana use has increased across the United States. Studies suggest that as marijuana has become more accessible and adults have become more tolerant regarding marijuana use, adolescents perceive marijuana as more beneficial and are more likely to use if they are living in an environment that is more tolerant of marijuana use. One factor that may influence adolescents' perceptions about marijuana and marijuana use is their exposure to advertising of this product. We surveyed sixth- to eighth-grade youth in 2010 and 2011 in 16 middle schools in Southern California (n = 8,214; 50% male; 52% Hispanic; mean age = 13 years) and assessed exposure to advertising for medical marijuana, marijuana intentions, and marijuana use. Cross-lagged regressions showed a reciprocal association of advertising exposure with marijuana use and intentions during middle school. Greater initial medical marijuana advertising exposure was significantly associated with a higher probability of marijuana use and stronger intentions to use 1 year later, and initial marijuana use and stronger intentions to use were associated with greater medical marijuana advertising exposure 1 year later. Prevention programs need to better explain medical marijuana to youth, providing information on the context for proper medical use of this drug and the potential harms from use during this developmental period. Furthermore, as this is a new frontier, it is important to consider regulating medical marijuana advertisements, as is currently done for alcohol and tobacco products. PMID- 26030168 TI - Prosocial behavior leads to happiness in a small-scale rural society. AB - Humans are extraordinarily prosocial, and research conducted primarily in North America indicates that giving to others is emotionally rewarding. To examine whether the hedonic benefits of giving represent a universal feature of human behavior, we extended upon previous cross-cultural examinations by investigating whether inhabitants of a small-scale, rural, and isolated village in Vanuatu, where villagers have little influence from urban, Western culture, survive on subsistence farming without electricity, and have minimal formal education, report or display emotional rewards from engaging in prosocial (vs. personally beneficial) behavior. In Study 1, adults were randomly assigned to purchase candy for either themselves or others and then reported their positive affect. Consistent with previous research, adults purchasing goods for others reported greater positive emotion than adults receiving resources for themselves. In Study 2, 2- to 5-year-old children received candy and were subsequently asked to engage in costly giving (sharing their own candy with a puppet) and non-costly giving (sharing the experimenter's candy with a puppet). Emotional expressions were video-recorded during the experiment and later coded for happiness. Consistent with previous research conducted in Canada, children displayed more happiness when giving treats away than when receiving treats themselves. Moreover, the emotional rewards of giving were largest when children engaged in costly (vs. non costly) giving. Taken together, these findings indicate that the emotional rewards of giving are detectable in people living in diverse societies and support the possibility that the hedonic benefits of generosity are universal. PMID- 26030169 TI - A self-serving bias in children's memories? AB - Although children's initial perceptions and judgments about sociomoral situations are being actively explored, little is known about what children remember about them. In four experiments testing over 400 children, we investigated children's memories for small acts of giving and taking. When asked to recall their own giving and taking, children were relatively accurate following a number of delays. In contrast, when asked to recall a child's giving or taking, children exaggerated the child's taking after a 1-day or 1-week delay. Notably, this pattern of misremembering occurred only when children recalled the actions of a child but not an adult. We consider the idea that children spontaneously engage in social comparison, which colors their memories of the social world. PMID- 26030170 TI - Changing visual perspective changes processing style: A distinct pathway by which imagery guides cognition. AB - Action images can be depicted either from the actor's first-person or an observer's third-person visual perspective. This research demonstrates that visual perspective of action imagery influences the extent to which people process actions abstractly. Two experiments presented photographs of everyday actions, manipulating their visual perspective (first-person vs. third-person), holding constant the scope and objects depicted. Subsequently, participants interpreted actions unrelated to the images. Across both experiments, viewing third-person (vs. first-person) photographs caused participants to construe the unrelated actions more abstractly. This carryover effect demonstrates a shift in processing style, sheds light on an underlying mechanism of perspective effects, and suggests that imagery is a more versatile cognitive tool than traditionally assumed. PMID- 26030171 TI - Speakers of different languages process the visual world differently. AB - Language and vision are highly interactive. Here we show that people activate language when they perceive the visual world, and that this language information impacts how speakers of different languages focus their attention. For example, when searching for an item (e.g., clock) in the same visual display, English and Spanish speakers look at different objects. Whereas English speakers searching for the clock also look at a cloud, Spanish speakers searching for the clock also look at a gift, because the Spanish names for gift (regalo) and clock (reloj) overlap phonologically. These different looking patterns emerge despite an absence of direct language input, showing that linguistic information is automatically activated by visual scene processing. We conclude that the varying linguistic information available to speakers of different languages affects visual perception, leading to differences in how the visual world is processed. PMID- 26030172 TI - Correction to McVay and Kane (2012). AB - Reports an error in "Why does working memory capacity predict variation in reading comprehension? On the influence of mind wandering and executive attention" by Jennifer C. McVay and Michael J. Kane (Journal of Experimental Psychology: General, 2012[May], Vol 141[2], 302-320). The values in Table 2 should be reversed between the F-K grade and F-K ease columns for the following five measures: SS1, SS2, JA1, JA2, and W&P. (The following abstract of the original article appeared in record 2011-19417-001.) Some people are better readers than others, and this variation in comprehension ability is predicted by measures of working memory capacity (WMC). The primary goal of this study was to investigate the mediating role of mind-wandering experiences in the association between WMC and normal individual differences in reading comprehension, as predicted by the executive-attention theory of WMC (e.g., Engle & Kane, 2004). We used a latent-variable, structural-equation-model approach, testing skilled adult readers on 3 WMC span tasks, 7 varied reading-comprehension tasks, and 3 attention-control tasks. Mind wandering was assessed using experimenter-scheduled thought probes during 4 different tasks (2 reading, 2 attention-control). The results support the executive-attention theory of WMC. Mind wandering across the 4 tasks loaded onto a single latent factor, reflecting a stable individual difference. Most important, mind wandering was a significant mediator in the relationship between WMC and reading comprehension, suggesting that the WMC comprehension correlation is driven, in part, by attention control over intruding thoughts. We discuss implications for theories of WMC, attention control, and reading comprehension. PMID- 26030173 TI - Interactivity fosters Bayesian reasoning without instruction. AB - Successful statistical reasoning emerges from a dynamic system including: a cognitive agent, material artifacts with their actions possibilities, and the thoughts and actions that are realized while reasoning takes place. Five experiments provide evidence that enabling the physical manipulation of the problem information (through the use of playing cards) substantially improves statistical reasoning, without training or instruction, not only with natural frequency statements (Experiment 1) but also with single-event probability statements (Experiment 2). Improved statistical reasoning was not simply a matter of making all sets and subsets explicit in the pack of cards (Experiment 3), it was not merely due to the discrete and countable layout resulting from the cards manipulation, and it was not mediated by participants' level of engagement with the task (Experiment 5). The positive effect of an increased manipulability of the problem information on participants' reasoning performance was generalizable both over problems whose numeric properties did not map perfectly onto the cards and over different types of cards (Experiment 4). A systematic analysis of participants' behaviors revealed that manipulating cards improved performance when reasoners spent more time actively changing the presentation layout "in the world" as opposed to when they spent more time passively pointing at cards, seemingly attempting to solve the problem "in their head." Although they often go unnoticed, the action possibilities of the material artifacts available and the actions that are realized on those artifacts are constitutive of successful statistical reasoning, even in adults who have ostensibly reached cognitive maturity. PMID- 26030174 TI - Mapping out past and future minds: The perceived trajectory of rationality versus emotionality over time. AB - Who do we see when envisioning our "past self" and "future self"? Extant research finds a motivation to perceive improvement over time, such that past selves are seen as worse versions, and future selves as better versions, of current selves. However, the broader components comprising "worse" or "better" beyond domain specific achievement (e.g., "Last year I failed at dieting, but next year I'll succeed") are less well understood. Are there more general qualities ascribed to the person we recall versus imagine being? Six studies suggest so, extending the 2-dimensional mind perception framework to the self: Past selves seem to possess highly emotional but not very rational minds, whereas future selves seem to possess highly rational but not very emotional minds (Studies 1a, 1b, 1c). Consistent with motivated improvement, this asymmetry does not emerge in evaluating others and applies uniquely to self-judgment (Study 2). Thus, our pervasive belief in changing for the "better" specifically means becoming more rational types of people. This observation has asymmetric consequences. Participants who brought to mind future selves sought intellectual enrichment (Study 3) and performed better on a self-control task (Study 4); however, participants who brought to mind past selves sought emotional enrichment and performed better on the same task when allegedly measuring enjoyment. These findings build a bridge between mind perception and intertemporal dynamics, raising novel implications for the present. Thinking about the future may not uniformly "improve" decisions and behaviors; rather, it mostly facilitates rational-related pursuits, whereas thinking about the past may enhance feeling related experiences. PMID- 26030175 TI - Correction to Yu et al (2015). AB - Reports an error in "Dynamics of postdecisional processing of confidence" by Shuli Yu, Timothy J. Pleskac and Matthew D. Zeigenfuse (Journal of Experimental Psychology: General, 2015[Apr], Vol 144[2], 489-510). The paragraph before the Conclusion section states: "To investigate when this occurs, we simulated Model 8 using the best fitting parameters for each participant in Study 2 and extended the IJT duration." "Model 8" should be "Model 1." (The following abstract of the original article appeared in record 2015-13746-006.) Most cognitive theories assume that confidence and choice happen simultaneously and are based on the same information. The 3 studies presented in this article instead show that confidence judgments can arise, at least in part, from a postdecisional evidence accumulation process. As a result of this process, increasing the time between making a choice and confidence judgment improves confidence resolution. This finding contradicts the notion that confidence judgments are biased by decision makers seeking confirmatory evidence. Further analysis reveals that the improved resolution is due to a reduction in confidence in incorrect responses, while confidence in correct responses remains relatively constant. These results are modeled with a sequential sampling process that allows evidence accumulation to continue after a choice is made and maps the amount of accumulated evidence onto a confidence rating. The cognitive modeling analysis reveals that the rate of evidence accumulation following a choice does slow relative to the rate preceding choice. The analysis also shows that the asymmetry between confidence in correct and incorrect choices is compatible with state-dependent decay in the accumulated evidence: Evidence consistent with the current state results in a deceleration of accumulated evidence and consequently evidence appears to have a decreasing impact on observed confidence. In contrast, evidence inconsistent with the current state results in an acceleration of accumulated evidence toward the opposite direction and consequently evidence appears to have an increasing impact on confidence. Taken together, this process-level understanding of confidence suggests a simple strategy for improving confidence accuracy: take a bit more time to make confidence judgments. PMID- 26030176 TI - Correction to Tuk, Zhang, and Sweldens (2015). AB - Reports an error in "The Propagation of Self-Control: Self-Control in One Domain Simultaneously Improves Self-Control in Other Domains" by Mirjam A. Tuk, Kuangjie Zhang and Steven Sweldens (Journal of Experimental Psychology: General, Advanced Online Publication, Mar 30, 2015, np). The affiliations for coauthors Kuangjie Zhang and Steven Sweldens were incorrect. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2015-13958-001.) A rich tradition in self-control research has documented the negative consequences of exerting self-control in 1 task for self-control performance in subsequent tasks. However, there is a dearth of research examining what happens when people exert self-control in multiple domains simultaneously. The current research aims to fill this gap. We integrate predictions from the most prominent models of self-control with recent neuropsychological insights in the human inhibition system to generate the novel hypothesis that exerting effortful self-control in 1 task can simultaneously improve self-control in completely unrelated domains. An internal meta-analysis on all 18 studies we conducted shows that exerting self-control in 1 domain (i.e., controlling attention, food consumption, emotions, or thoughts) simultaneously improves self control in a range of other domains, as demonstrated by, for example, reduced unhealthy food consumption, better Stroop task performance, and less impulsive decision making. A subset of 9 studies demonstrates the crucial nature of task timing-when the same tasks are executed sequentially, our results suggest the emergence of an ego depletion effect. We provide conservative estimates of the self-control facilitation (d = |0.22|) as well as the ego depletion effect size (d = |0.17|) free of data selection and publication biases. These results (a) shed new light on self-control theories, (b) confirm recent claims that previous estimates of the ego depletion effect size were inflated due to publication bias, and (c) provide a blueprint for how to handle the power issues and associated file drawer problems commonly encountered in multistudy research projects. PMID- 26030177 TI - Association of Parental Adverse Childhood Experiences and Current Child Adversity. PMID- 26030180 TI - Anion resonances and above-threshold dynamics of coenzyme Q0. AB - Temporary radical anions (resonances) of isolated co enzyme Q0 (CQ0) and their associated above-threshold dynamics have been studied using frequency-, angle-, and time-resolved photoelectron imaging (FAT-PI). Experimental energetics and dynamics are supported with ab initio calculations. All results support that CQ0 exhibits similar resonances and energetics compared with the smaller para benzoquinone subunit, which is commonly considered as a prototype electrophore for larger biological para-quinone species. However, the above-threshold dynamics in CQ0 relative to para-benzoquinone show significantly enhanced prompt detachment compared with internal conversion, particularly around the photoexcitation energy of 3.10 eV. The change in dynamics can be attributed to a combination of an increase in the shape character of the optically-accessible resonance at this energy, a decrease in the autodetachment lifetime due to the higher density of states in the neutral, and a decrease in the probability that the wavepacket formed in the Franck-Condon window can access the local conical intersection in CQ0 over the timescale of autodetachment. Overall, this study serves as a clear example in understanding the trends in spectroscopy and dynamics in relating a simple prototypical para-quinone electrophore to a more complex biochemical species. PMID- 26030178 TI - Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. AB - Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors. PMID- 26030181 TI - The influence of nonresident fathers on adolescent and young adult cigarette smoking. AB - INTRODUCTION: In this analysis we examine the relationship between nonresidential father involvement with their children and adolescent smoking behavior using a nationally representative longitudinal dataset. We attempt to determine what influence, if any, nonresident fathers have in the development of this health risk behavior in their adolescent children while accounting for aspects of parenting and family life that have been hypothesized to also influence adolescent cigarette smoking. METHOD: Data for this analysis come from the first 3 waves of the Longitudinal Study of Adolescent to Adult Health. Given the longitudinal nature of the data, we are able to ascertain whether nonresident father involvement affects adolescent cigarette smoking, an important advance in our understanding of the influence of fathers. RESULTS: We found that greater levels of nonresidential father involvement significantly decrease both the odds of participation in and the intensity of cigarette smoking, especially among girls. This influence is demonstrated not only in adolescence but persists into young adulthood. DISCUSSION: Our findings underscore the importance of adolescents' living arrangements and the role that nonresident fathers might play in influencing adolescent cigarette smoking, a health risk behavior of strong public health significance. Fathers make important contributions to the health and wellbeing of their children, and interventions focused on nonresident fathers in particular would likely be of significant help to the substance abuse prevention field. Interventions to support father involvement, particularly of nonresident fathers, with their children should be implemented as a preventive strategy to reduce the likelihood of adolescent cigarette smoking. PMID- 26030179 TI - Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. AB - Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade. PMID- 26030182 TI - Determination of the Action Spectrum of UVR-Induced Mitochondrial DNA Damage in Human Skin Cells. AB - Biological responses of human skin to UVR including cancer and aging are largely wavelength-dependent, as shown by the action spectra of UVR-induced erythema and nuclear DNA (nDNA) damage. A molecular dosimeter of UVR exposure is therefore required. Although mitochondrial DNA (mtDNA) damage has been shown to be a reliable and sensitive biomarker of UVR exposure in human skin, its wavelength dependency is unknown. The current study solves this problem by determining the action spectrum of UVR-induced mtDNA damage in human skin. Human neonatal dermal fibroblasts and primary human adult keratinocyte cells were irradiated with increasing doses of UVR. Dose-response curves of mtDNA damage were produced for each of the UVR sources and cell types, and an action spectrum for each cell type was determined by mathematical induction. Similarities between these mtDNA damage action spectra and previously determined nDNA damage were observed, with the most detrimental effects occurring over the shorter UVR wavelengths. Notably, a statistically significant (P<0.0001) greater sensitivity to mtDNA damage was observed in dermal fibroblasts compared with keratinocytes at wavelengths >300 nm, possibly indicating a wider picture of depth dependence in sensitivity. This finding has implications for disease/photodamage mechanisms and interventions. PMID- 26030183 TI - IL-27 Suppresses Antimicrobial Activity in Human Leprosy. AB - The mechanisms by which intracellular pathogens trigger immunosuppressive pathways are critical for understanding the pathogenesis of microbial infection. One pathway that inhibits host defense responses involves the induction of type I interferons and subsequently IL-10, yet the mechanism by which type I IFN induces IL-10 remains unclear. Our studies of gene expression profiles derived from leprosy skin lesions suggested a link between IL-27 and the IFN-beta induced IL 10 pathway. Here, we demonstrate that the IL-27p28 subunit is upregulated following treatment of monocytes with IFN-beta and Mycobacterium leprae, the intracellular bacterium that causes leprosy. The ability of IFN-beta and M. leprae to induce IL-10 was diminished by IL-27 knockdown. Additionally, treatment of monocytes with recombinant IL-27 was sufficient to induce the production of IL 10. Functionally, IL-27 inhibited the ability of IFN-gamma to trigger antimicrobial activity against M. leprae in infected monocytes. At the site of disease, IL-27 was more strongly expressed in skin lesions of patients with progressive lepromatous leprosy, correlating and colocalizing with IFN-beta and IL-10 in macrophages. Together, these data provide evidence that in the human cutaneous immune responses to microbial infection, IL-27 contributes to the suppression of host antimicrobial responses. PMID- 26030184 TI - Race and Melanocortin 1 Receptor Polymorphism R163Q Are Associated with Post-Burn Hypertrophic Scarring: A Prospective Cohort Study. AB - The genetic determinants of post-burn hypertrophic scarring (HTS) are unknown, and melanocortin 1 receptor (MC1R) loss-of-function leads to fibrogenesis in experimental models. To examine the associations between self-identified race and MC1R single-nucleotide polymorphisms (SNPs) with severity of post-burn HTS, we conducted a prospective cohort study of burned adults admitted to our institution over 7 years. Subjects were evaluated using the Vancouver Scar Scale (VSS), asked to rate their itching, and genotyped for 8 MC1R SNPs. Testing for association with severe HTS (VSS>7) and itch severity (0-10) was based on multivariate regression with adjustment for known risk factors. Of 425 subjects analyzed, 77% identified as White. The prevalence of severe HTS (VSS>7) was 49%, and the mean itch score was 3.9. In multivariate analysis, Asian (prevalence ratio (PR) 1.54; 95% CI: 1.13-2.10), Black/African American (PR 1.86; 95% CI: 1.42-2.45), and Native American (PR 1.87; 95% CI: 1.48-2.35) race were independently associated with severe HTS. MC1R SNP R163Q was also significantly (P<0.001) associated with severe HTS. Asian race (linear regression coefficient 1.32; 95% CI: 0.23-2.40) but not MC1R SNP genotype was associated with increased itch score. We conclude that MC1R genotype may influence post-burn scarring. PMID- 26030185 TI - Electrochemical water-splitting based on hypochlorite oxidation. AB - Effective catalytic water-splitting can be electrochemically triggered in an alkaline solution of sodium hypochlorite. Hypochlorite oxidation on polycrystalline platinum yields ClO. radicals, which initiate a radical-assisted water-splitting, yielding oxygen, hydrogen peroxide, and protons. The efficiency of the O2 production corresponds to about two electrons per molecule of the produced O2 and is controlled primarily by the hypochlorite concentration and pH. PMID- 26030188 TI - The adiponectin levels and asthma control in non-obese children with asthma. AB - OBJECTIVE: To determine the relationship between adiponectin levels and asthma control in non-obese asthmatic children. METHODS: Eighty-two children with asthma who had been followed up in a single center were included. The control group included 28 children with no evidence of allergic disease. Adiponectin levels were analyzed in all children. Additionally, skin prick tests and pulmonary function tests were also performed in patients. RESULTS: Three groups were designated with respect to asthma control as; well-controlled group (n = 28), partially controlled group (n = 34) and uncontrolled group (n = 20). There was no significant difference of gender, age, height, weight, BMI and adiponectin levels between study and control groups (p > 0.05). The duration of illness, presence of atopy and sensitivities to mite, pollens, dander and cockroaches were similar between the groups (p > 0.05). Adiponectin, FEV1, FVC, and FEV1/FVC levels were significantly lower in uncontrolled group (p < 0.05). Sensitivity to Alternaria alternata was significantly higher in the uncontrolled group (p < 0.05). In logistic regression analysis, as dependent parameter, adiponectin, FEV1, FVC and FEV1/FVC levels were found to be statistically significant for uncontrolled asthma. CONCLUSION: Adiponectin levels in non-obese asthmatics were not different from controls. Lower levels of adiponectin were associated with uncontrolled asthma. Low adiponectin level can therefore be used as an indicator of uncontrolled asthma. PMID- 26030187 TI - Mycobacteria-Specific Cytokine Responses Detect Tuberculosis Infection and Distinguish Latent from Active Tuberculosis. AB - RATIONALE: Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-gamma release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management. OBJECTIVES: To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB. METHODS: A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays. MEASUREMENTS AND MAIN RESULTS: IFN-gamma, interferon-inducible protein-10 (IP 10), tumor necrosis factor (TNF)-alpha, IL-1ra, IL-2, IL-13, and MIP-1beta (macrophage inflammatory protein-1beta) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF alpha, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-alpha, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-alpha/IL-1ra and TNF-alpha/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively. CONCLUSIONS: We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone. PMID- 26030186 TI - Structural similarities and differences between the human and the mouse pancreas. AB - Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand both similarities and differences between the 2 species. Beside the apparent difference in size and macroscopic organization of the organ in the 2 species, there are a number of less evident and only recently described differences in organization of the acinar and ductal exocrine tissue, as well as in the distribution, composition, and architecture of the endocrine islets of Langerhans. Furthermore, the differences in arterial, venous, and lymphatic vessels, as well as innervation are potentially important. In this article, the structure of the human and the mouse pancreas, together with the similarities and differences between them are reviewed in detail in the light of conceivable repercussions for basic research and clinical application. PMID- 26030189 TI - Kirkwood-Buff Approach Rescues Overcollapse of a Disordered Protein in Canonical Protein Force Fields. AB - Understanding the function of intrinsically disordered proteins is intimately related to our capacity to correctly sample their conformational dynamics. So far, a gap between experimentally and computationally derived ensembles exists, as simulations show overcompacted conformers. Increasing evidence suggests that the solvent plays a crucial role in shaping the ensembles of intrinsically disordered proteins and has led to several attempts to modify water parameters and thereby favor protein-water over protein-protein interactions. This study tackles the problem from a different perspective, which is the use of the Kirkwood-Buff theory of solutions to reproduce the correct conformational ensemble of intrinsically disordered proteins (IDPs). A protein force field recently developed on such a basis was found to be highly effective in reproducing ensembles for a fragment from the FG-rich nucleoporin 153, with dimensions matching experimental values obtained from small-angle X-ray scattering and single molecule FRET experiments. Kirkwood-Buff theory presents a complementary and fundamentally different approach to the recently developed four site TIP4P-D water model, both of which can rescue the overcollapse observed in IDPs with canonical protein force fields. As such, our study provides a new route for tackling the deficiencies of current protein force fields in describing protein solvation. PMID- 26030191 TI - Ligand Control of E/Z Selectivity in Nickel-Catalyzed Transfer Hydrogenative Alkyne Semireduction. AB - A nickel-catalyzed transfer hydrogenative alkyne semireduction protocol that can be applied to both internal and terminal alkynes using formic acid and Zn as the terminal reductants has been developed. In the case of internal alkynes, the (E)- or (Z)-olefin isomer can be accessed selectively under the same reaction conditions by judicious inclusion of a triphos ligand. PMID- 26030190 TI - Nuclear localized Akt enhances breast cancer stem-like cells through counter regulation of p21(Waf1/Cip1) and p27(kip1). AB - Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44(+High)/CD24(-Low) phenotype. This effect was completely reversed in the presence of Akt-specific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21(Waf1/Cip1) and exhibited increased clonogenicity and proliferation as assayed by colony forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. SUMMARY: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells. PMID- 26030192 TI - Neuronox versus BOTOX in the Treatment of Post-Stroke Upper Limb Spasticity: A Multicenter Randomized Controlled Trial. AB - BACKGROUND: Botulinum toxin type A is widely used for treating spasticity. Neuronox (Neu-BoNT/A), a newly manufactured botulinum toxin a, has not yet been investigated for its efficacy and safety in the treatment of post-stroke upper limb spasticity. OBJECTIVE: We evaluated the efficacy and safety of Neuronox (Neu BoNT/A) compared with BOTOX (onabotulinum toxin A) for treating post-stroke upper limb spasticity. METHODS: In total, 196 stroke patients with moderate to severe upper limb spasticity were randomly assigned to either Neuronox or BOTOX intervention. The wrist flexors were mandatory and elbow, finger, and thumb flexors were optional muscles to be injected. Assessments were performed at baseline and 4, 8, and 12 weeks after the intervention. The primary outcome measure was the change from baseline of the Modified Ashworth Scale (MAS) at the wrist flexors at week 4. Secondary outcome measures included the change of MAS at each visit, response rate, Disability Assessment Scale (DAS), Carer Burden Scale, and Global Assessment of treatment benefit. RESULTS: Primary outcome measures were -1.39+/-0.79 and -1.56+/-0.81 in the Neuronox and BOTOX groups, respectively. The difference was within the noninferiority margin of 0.45 (95% upper limit=0.40). There were no significant differences between the groups in the secondary outcome and safety measures, except the change of the MAS at the elbow flexors at week 12 (-0.88+/-0.75 in the Neuronox group, -0.65+/-0.74 in the BOTOX group; P=0.0429). Both groups showed significant improvements in the MAS, DAS, and Carer Burden Scale at weeks 4, 8, and 12. CONCLUSION: Neuronox showed equivalent efficacy and safety compared with BOTOX for treating post-stroke upper limb spasticity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01313767. PMID- 26030193 TI - Phenotypes of children with 20q13.3 microdeletion affecting KCNQ2 and CHRNA4. AB - In order to clarify the phenotypes of 20q13.33 microdeletion, clinical manifestations and genetic findings from four patients are discussed in relation to chromosomal microdeletions at 20q13.33. All patients had epileptic seizures mostly beginning within the neonatal period and disappearing by 4 months of age, similar to epilepsy phenotypes of benign familial neonatal seizures. We performed array comparative, genomic hybridization analysis in order to investigate the chromosomal aberration. Developmental outcome was good in two patients with deletion restricted to three genes (CHRNA4, KCNQ2, and COL20A1), whereas delay in developmental milestones was observed in the other two with a wider range of deletion. Information obtained from array comparative genomic hybridization may be useful to predict seizure and developmental outcome, however, there is no distinctive pattern of abnormalities that would arouse clinical suspicion of a 20q13.33 microdeletion. Deletion of KCNQ2 and CHRNA4 does not appear to affect seizure phenotype. Molecular cytogenetic techniques, such as array comparative genomic hybridization, will be necessary to clarify the relationship between phenotypes and individual genes within this region. PMID- 26030194 TI - Pediatric vaccines and neurodevelopment: primate study finds no adverse behavioral effects. PMID- 26030195 TI - Use of Loop Diuretics is Associated with Increased Mortality in Patients with Suspected Coronary Artery Disease, but without Systolic Heart Failure or Renal Impairment: An Observational Study Using Propensity Score Matching. AB - BACKGROUND: Loop diuretics are widely used in patients with heart and renal failure, as well as to treat hypertension and peripheral edema. However, there are no randomized, controlled trials (RCT) evaluating their long term safety, and several observational reports have indicated adverse effects. We sought to evaluate the impact of loop diuretics on long term survival in patients with suspected coronary artery disease, but without clinical heart failure, reduced left ventricular ejection fraction or impaired renal function. METHOD AND FINDINGS: From 3101 patients undergoing coronary angiography for suspected stable angina pectoris, subjects taking loop diuretics (n=109) were matched with controls (n=198) in an attempted 1:2 ratio, using propensity scores based on 59 baseline variables. During median follow-up of 10.1 years, 37.6% in the loop diuretics group and 23.7% in the control group died (log-rank p-value 0.005). Treatment with loop diuretics was associated with a hazard ratio (95% confidence interval) of 1.82 (1.20, 2.76), and the number needed to harm was 7.2 (4.1, 30.3). Inclusion of all 3101 patients using propensity score weighting and adjustment for numerous covariates provided similar estimates. The main limitation is the potential of confounding from unmeasured patient characteristics. CONCLUSIONS: The use of loop diuretics in patients with suspected coronary artery disease, but without systolic heart failure or renal impairment, is associated with increased risk of all-cause mortality. Considering the lack of randomized controlled trials to evaluate long term safety of loop diuretics, our data suggest caution when prescribing these drugs to patients without a clear indication. PMID- 26030196 TI - Characterization of Isolates of Streptococcus agalactiae from Diseased Farmed and Wild Marine Fish from the U.S. Gulf Coast, Latin America, and Thailand. AB - We examined Lancefield serogroup B Streptococcus isolates recovered from diseased, cultured hybrid Striped Bass (Striped Bass Morone saxatilis * White Bass M. chrysops) and wild and cultured Gulf Killifish Fundulus grandis from coastal waters of the U.S. Gulf of Mexico (Gulf coast) and compared those isolates to strains from tilapias Oreochromis spp. reared in Mississippi, Thailand, Ecuador, and Honduras and to the original Gulf coast strain identified by Plumb et al. ( 1974 ). The isolates were subjected to phylogenetic, biochemical, and antibiotic susceptibility analyses. Genetic analysis was performed using partial sequence comparison of (1) the 16S ribosomal RNA (rRNA) gene; (2) the sipA gene, which encodes a surface immunogenic protein; (3) the cspA gene, which encodes a cell surface-associated protein; and (4) the secY gene, which encodes components of a general protein secretion pathway. Phylogenies inferred from sipA, secY, and cspA gene sequence comparisons were more discriminating than that inferred from the 16S rRNA gene sequence comparison. The U.S. Gulf coast strains showed a high degree of similarity to strains from South America and Central America and belonged to a unique group that can be distinguished from other group B streptococci. In agreement with the molecular findings, biochemical and antimicrobial resistance analyses demonstrated that the isolates recovered from the U.S. Gulf coast and Latin America were more similar to each other than to isolates from Thailand. Three laboratory challenge methods for inducing streptococcosis in Gulf Killifish were evaluated-intraperitoneal (IP) injection, immersion (IMM), and immersion plus abrasion (IMMA)-using serial dilutions of S. agalactiae isolate LADL 97-151, a representative U.S. Gulf coast strain. The dose that was lethal to 50% of test fish by 14 d postchallenge was approximately 2 CFU/fish via IP injection. In contrast, the fish that were challenged via IMM or IMMA presented cumulative mortality less than 40% by 14 d postchallenge. PMID- 26030197 TI - Diagnostic Value of Transthoracic Echocardiography in Patients with Coarctation of Aorta: The Chinese Experience in 53 Patients Studied between 2008 and 2012 in One Major Medical Center. AB - Although aortography is well known as the "gold standard" for the diagnosis of coarctation of aorta (CoA), the method is invasive, expensive and not readily accepted by some patients. Ultrasound diagnosis for CoA is non-invasive, inexpensive, readily accepted by every patient, and can be repeated as frequently as necessary. The purpose of this presentation is to evaluate the applicability of transthoracic echocardiography for the diagnosis of CoA. The echocardiographic appearances of 53 patients with CoA who had undergone surgery during a 5-year period from January 2008 to October 2012 were analyzed retrospectively, and the results were compared with findings at surgery. Fifty-three patients with CoA include six with isolated CoA and 47 of CoA associated with other cardiac anomalies. Of the 53 operated patients, 48 were correctly diagnosed preoperatively by echocardiography, while two were misdiagnosed as interrupted aortic arch and the diagnosis were missed in three other patients. Thus the diagnostic accuracy rate was 90.6%, and the misdiagnosis rate was 9.4%. Preoperative echocardiographic evaluation offers very satisfactory anatomic assessment in most patients with CoA. It makes preoperative angiography unnecessary. Thus transthoracic echocardiography should be the first-line method for the diagnosis of coarctation of the aorta. PMID- 26030199 TI - Teachers' perceptions of Twitter for professional development. AB - PURPOSE: The aim of this study was to determine how school teachers in the United States (US) perceived using Twitter as a means for professional development, engagement in communities of practice, and any benefits or drawbacks to participating in Twitter. METHOD: This qualitative research utilized an embedded case design with three sources of data: (a) three consecutive months of tweet data from late 2011 archived on the host website, relating to #EdChat, a weekly online chat in Twitter about education issues; (b) interviews with 19 school teachers in the US who participated in the #EdChat online discussions in Twitter; and (c) Twitter bio and Tweet data of the 19 teachers interviewed. All data were entered into NVIVO (QSR International Pty. Ltd., Doncaster, Australia) for content thematic coding, and The Communities of Practice and Connectivist Conceptual Framework was used to inform this analysis. The researchers' interpretations were verified with participants, and data triangulated across all sources to strengthen confidence in the results. RESULTS: Five main themes and 17 subthemes emerged from the data across all sources. The main themes were teachers' perceptions of sharing knowledge and resources, Twitter promoting a sense of belonging, Twitter providing meaningful professional development, and teachers' views on the technical benefits and drawbacks of using Twitter. CONCLUSION: Regardless of years teaching, subject area, or age, educators perceived Twitter as providing an online forum to reflect upon practice, exchange knowledge and experience, and be in the presence of supportive colleagues. While participants experienced the pace and volume of information as being overwhelming at times, educators developed skills to managing this and perceived discussions to be learner-centered and supportive. Teachers valued the sense of community and learning that they reported were not otherwise available in their own physical workplace. Overall, participants perceived that the benefits of participation in online Twitter chats for learning outweighed any drawbacks experienced. This article includes implications for future research and how social network sites may be used as a supportive venue for educators, therapists, and students, including individuals with disabilities. PMID- 26030198 TI - Clade 8 and Clade 6 Strains of Escherichia coli O157:H7 from Cattle in Argentina have Hypervirulent-Like Phenotypes. AB - The hemolytic uremic syndrome (HUS) whose main causative agent is enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a disease that mainly affects children under 5 years of age. Argentina is the country with the highest incidence of HUS in the world. Cattle are a major reservoir and source of infection with E. coli O157:H7. To date, the epidemiological factors that contribute to its prevalence are poorly understood. Single nucleotide polymorphism (SNP) typing has helped to define nine E. coli O157:H7 clades and the clade 8 strains were associated with most of the cases of severe disease. In this study, eight randomly selected isolates of EHEC O157:H7 from cattle in Argentina were studied as well as two human isolates. Four of them were classified as clade 8 through the screening for 23 SNPs; the two human isolates grouped in this clade as well, while two strains were closely related to strains representing clade 6. To assess the pathogenicity of these strains, we assayed correlates of virulence. Shiga toxin production was determined by an ELISA kit. Four strains were high producers and one of these strains that belonged to a novel genotype showed high verocytotoxic activity in cultured cells. Also, these clade 8 and 6 strains showed high RBC lysis and adherence to epithelial cells. One of the clade 6 strains showed stronger inhibition of normal water absorption than E. coli O157:H7 EDL933 in human colonic explants. In addition, two of the strains showing high levels of Stx2 production and RBC lysis activity were associated with lethality and uremia in a mouse model. Consequently, circulation of such strains in cattle may partially contribute to the high incidence of HUS in Argentina. PMID- 26030200 TI - Sexual functioning and sexual well-being in people with a limb amputation: a cross-sectional study in the Netherlands. AB - PURPOSE: This study aimed to: (a) investigate whether, and if so which, sexual problems are present in people with a limb amputation; (b) analyze how they experience their sexuality; and (c) investigate whether sexuality was discussed with them during their rehabilitation process. METHOD: In total, 301 participants completed a survey consisting of a questionnaire on participant characteristics, the Hospital Anxiety and Depression Scale (HADS), the Maudsley Marital Questionnaire (MMQ), the Amputee Body Image Scale (ABIS), the Questionnaire about Sexual Counselling, the Questionnaire about Sexuality and the Short Sexual Functioning Scale (SSFS). RESULTS: Overall, 20% of the participants experienced one or more sexual dysfunction(s). Participants who had at least one sexual dysfunction were more likely to be male, had an amputation more recently, and had a more negative body image. Moreover, sexuality was only scantly discussed by rehabilitation professionals. CONCLUSIONS: Sexual problems and sexual dysfunctions do occur in people with a limb amputation, but these problems are not discussed during the rehabilitation process. Justice for a person's "whole body" can only be served when sexuality is taken seriously in rehabilitation care in order to avoid cutting sexuality out of an amputee's life. Implications for Rehabilitation People with a limb amputation may be confronted with sexual problems and/or sexual dysfunctions. It is therefore important that sexuality is taken seriously as a part of standard rehabilitation care and that professionals bring up the issue of sexuality during the rehabilitation process. PMID- 26030201 TI - SEEING YOU FALL VS TAKING YOU DOWN: THE ROLES OF AGENCY AND LIKING IN SCHADENFREUDE. AB - People are more likely to experience schadenfreude, i.e., take pleasure in the misfortunes of another, if they do not like the person experiencing the downfall. In the current study, the roles of liking and agency (being the cause of the downfall vs a passive observer) were investigated using a live (rather than hypothetical) situation for participants to react to. Participants were exposed to a rude, neutral, or nice confederate who won a coveted prize. Participants were then put into a position to either cause the confederate to lose her prize, or to only passively observe it happen. Feelings of schadenfreude were strongest when participants were the agent of a rude other's downfall. Implications for incorporating aspects of this study into future research were discussed. PMID- 26030202 TI - DEATH CONCERN AND DEATH OBSESSION IN IRANIAN NURSES. AB - The goal of the present study was to examine whether nurses had increased death concern and death obsession compared to non-nursing staff. A Death Concern Scale and a Death Obsession Scale, translated into Persian, were administered to 56 female Iranian nurses (55% in their 30s) and compared to 56 female hospital staff members (45% in their 30s). The two groups did not differ significantly in their scores on either scale. It is, therefore, recommended that death education programs in hospitals be given to all staff, nursing and non-nursing. PMID- 26030203 TI - Caregiving representations at work and the moderating role of job self-efficacy. Psychological Reports: Employment Psychology & Marketing, 116, 1, 60-73. DOI: 10.2466/01.PRO.116k12w2. PMID- 26030204 TI - THE CONTINUUM OF PSYCHOSIS PRONENESS AND SCHIZOTYPAL TRAITS: A COMMENT ON LOAS, ET AL. (2013 ). AB - Loas, Dimassi, Monestes, and Yon (2013 ) studied a version of the Cognitive Slippage Scale and the Schizotypal Ambivalence Scale in support of the view that thought disorder and withdrawal are highly correlated with schizotypy, a central concept in investigations of the vulnerability for schizophrenia. As a brief comment on Loas, et al., I will draw attention to the need for expanding studies of schizotypal traits and the possibility of using these scales with adolescents and young adults who are developing personality disorders as well as with individuals who have experienced prodromal phases of psychosis. Investigations of the Cognitive Slippage Scale and the Schizotypal Ambivalence Scale might be enhanced by conducting studies with individuals at different points on the psychosis continuum, including those who have developed schizophrenia and other psychotic disorders, as well as with their first-degree relatives. PMID- 26030205 TI - SELF-REPORTED RELIGIOSITY IN KUWAITI AND AMERICAN COLLEGE STUDENTS. AB - In previous research, Kuwaiti students obtained higher scores than American students on a religiosity scale. For the present study, the self-reported religiosity of Kuwaiti and American students was assessed using a single item. The respondents were 154 Kuwaiti students (M age = 20.8 yr., SD = 2.4) and 154 American college students (M age = 21.8 yr., SD = 5.0; 82% women in both samples). The Kuwaiti students responded in Arabic and the American students in English to the question: "What is your level of religiosity in general?" using an 11-point Likert format anchored by 0 and 10. The high score indicates high religiosity. The Kuwaiti students obtained a significantly higher mean score for religiosity than did their American counterparts (6.5 vs 4.5), indicating that religiosity is more important in the lives of the present sample of Kuwaiti students than in their American counterparts. A single-item self-rating scale may be useful in brief surveys such as epidemiological studies. PMID- 26030206 TI - MATERNAL RATINGS OF BULLYING AND VICTIMIZATION: DIFFERENCES IN FREQUENCIES BETWEEN PSYCHIATRIC DIAGNOSES IN A LARGE SAMPLE OF CHILDREN (.). AB - Little is known about psychiatric diagnoses that place children at risk for bullying and victimization. Mothers of 1,707 children 6-18 yr. rated their child as a bully and a victim (not at all, to very often a problem) on the Pediatric Behavior Scale. Children with psychiatric diagnoses were evaluated in an outpatient psychiatry clinic (M age = 9.2 yr., 68.4% male). Control children were community children not on psychotropic medication and with no neurodevelopmental disorder (M age = 8.7 yr., 43.5% male). Children with autism, intellectual disability, and ADHD-Combined type had higher victim and bully maternal ratings than children in the ADHD-Inattentive, depression, anxiety, eating disorder, and control groups. Eating disorder and controls were the only groups in which most children were not rated a victim or a bully. Comorbid oppositional defiant disorder accounted for the higher bully ratings for ADHD-Combined, autism, and intellectual disability. Victimization ratings did not differ between psychiatric groups. Except for eating disorders, victimization ratings were greater in all groups than in control children, suggesting that most psychiatric disorders place children at risk for victimization, as perceived by their mothers. PMID- 26030207 TI - CROSS-NATIONAL APPLICABILITY OF A PARSIMONIOUS MEASURE OF ACCULTURATION TO GLOBAL CONSUMER CULTURE. AB - Cleveland and Laroche presented a scale to measure Acculturation to Global Consumer Culture. This measure was the first attempt to gauge consumer mindsets regarding their adaptation to global consumerism. Because this scale consisted of 57 scale items, applying such a lengthy scale can lead to response fatigue. Past research has also suggested that as more items are added to a scale, the informational value of each additional item is marginal. As an alternative, a shorter version of the Acculturation to Global Consumer Culture Scale is presented. The psychometric properties of this scale were verified via multiple group confirmatory factor analysis. A four-country investigation of young adults in China (n = 126; M age = 22.24 yr., SD = 3.63), New Zealand (n = 196; M age = 20.12 yr., SD = 4.12), Nigeria (n = 146; M age = 23.09 yr., SD = 3.80), and the United States (n = 120; M age = 21.67 yr., SD = 4.26) provides support for the cross-national applicability of the proposed parsimonious measure. Limitations and extensions are discussed. PMID- 26030208 TI - THE EFFECT OF THE "EVOKING FREEDOM" TECHNIQUE ON AN UNUSUAL AND DISTURBING REQUEST. AB - The "evoking freedom" technique consists in soliciting someone to comply with a request by simply saying that she is free to accept or to refuse the request. However, previous studies used low cost requests. The present study examined the magnitude of this technique associated with a more disturbing and costly request. Sixty men and 60 women aged approximately 20-25 years walking in the street were asked by a male confederate to hold a closed transparent box containing a live trap-door spider while he went into the post office to pick up a package. In the evoking freedom condition, the confederate added in his request that the participant was "free to accept or to refuse." More compliance occurred in the "evoking freedom" condition (53.3%) than in the control condition (36.7%). These results confirm the robustness and the magnitude of the evoking freedom technique on compliance and show that this technique remained effective even when the request was psychologically costly to perform and was associated with fear. PMID- 26030209 TI - High Methylmercury in Arctic and Subarctic Ponds is Related to Nutrient Levels in the Warming Eastern Canadian Arctic. AB - Permafrost thaw ponds are ubiquitous in the eastern Canadian Arctic, yet little information exists on their potential as sources of methylmercury (MeHg) to freshwaters. They are microbially active and conducive to methylation of inorganic mercury, and are also affected by Arctic warming. This multiyear study investigated thaw ponds in a discontinuous permafrost region in the Subarctic taiga (Kuujjuarapik-Whapmagoostui, QC) and a continuous permafrost region in the Arctic tundra (Bylot Island, NU). MeHg concentrations in thaw ponds were well above levels measured in most freshwater ecosystems in the Canadian Arctic (>0.1 ng L(-1)). On Bylot, ice-wedge trough ponds showed significantly higher MeHg (0.3 2.2 ng L(-1)) than polygonal ponds (0.1-0.3 ng L(-1)) or lakes (<0.1 ng L(-1)). High MeHg was measured in the bottom waters of Subarctic thaw ponds near Kuujjuarapik (0.1-3.1 ng L(-1)). High water MeHg concentrations in thaw ponds were strongly correlated with variables associated with high inputs of organic matter (DOC, a320, Fe), nutrients (TP, TN), and microbial activity (dissolved CO2 and CH4). Thawing permafrost due to Arctic warming will continue to release nutrients and organic carbon into these systems and increase ponding in some regions, likely stimulating higher water concentrations of MeHg. Greater hydrological connectivity from permafrost thawing may potentially increase transport of MeHg from thaw ponds to neighboring aquatic ecosystems. PMID- 26030210 TI - Performance of the Plusoptix A09 photoscreener in detecting amblyopia risk factors in Chinese children attending an eye clinic. AB - PURPOSE: To assess the accuracy of the Plusoptix A09 photoscreener in detecting amblyopia risk factors in children and determine referral criteria when using Plusoptix A09 for a large-scale vision screening. METHODS: Pediatric patients attending our eye clinic underwent a comprehensive ophthalmic examination that included photorefraction, orthoptic examination, anterior segment assessment, fundus examination and cycloplegic retinoscopy. The measurements were collected for statistical analyses. RESULTS: One hundred and seventy-eight children (mean age +/- SD: 6.2+/-2.4 years, range: 2.2 to 14.1 years) were included in the study. The mean spherical equivalent (SE) obtained using Plusoptix A09 (PSE) was 0.57 D lower than that obtained from cycloplegic retinoscopy (CRSE) (P = 0.00). However, there was no statistically significant difference of Jackson cross cylinder J0 and J45 between Plusoptix A09 (PJ) and cycloplegic retinoscopy (CRJ) (P = 0.14, P = 0.26). The relationship of SE obtained from Plusoptix A09 and SE obtained from cycloplegic retinoscopy was presented as the equation: CRSE = 0.358 + 0.776 PSE + 0.064 PSE2 + 0.011 PSE3. Based on the Receiver Operating Characteristic (ROC) curve, the Plusoptix A09 had an overall sensitivity of 94.9% and specificity of 67.5% for detecting refractive amblyopia risk factors. The sensitivity and specificity of the Plusoptix A09 for detection of strabismus were 40.7% and 98.3%, respectively; detection of amblyopia and/or strabismus was 84.7% and 63.2%, respectively. CONCLUSIONS: The Plusoptix A09 photoscreener underestimated hyperopia and overestimated myopia according to SE when compared with cycloplegic retinoscopy. The accuracy of the Plusoptix A09 in detecting amblyopia risk factors in children could be improved by the regression equation and optimized criteria for refractive amblyopia risk factors developed in the present study. Moreover, the Plusoptix A09 photoscreener is not suitable for a large-scale strabismus screening when it is applied solely. PMID- 26030211 TI - Cellular uptake: lessons from supramolecular organic chemistry. AB - The objective of this Feature Article is to reflect on the importance of established and emerging principles of supramolecular organic chemistry to address one of the most persistent problems in life sciences. The main topic is dynamic covalent chemistry on cell surfaces, particularly disulfide exchange for thiol-mediated uptake. Examples of boronate and hydrazone exchange are added for contrast, comparison and completion. Of equal importance are the discussions of proximity effects in polyions and counterion hopping, and more recent highlights on ring tension and ion pair-pi interactions. These lessons from supramolecular organic chemistry apply to cell-penetrating peptides, particularly the origin of "arginine magic" and the "pyrenebutyrate trick," and the currently emerging complementary "disulfide magic" with cell-penetrating poly(disulfide)s. They further extend to the voltage gating of neuronal potassium channels, gene transfection, and the delivery of siRNA. The collected examples illustrate that the input from conceptually innovative chemistry is essential to address the true challenges in biology beyond incremental progress and random screening. PMID- 26030212 TI - Effects of CO2-induced pH reduction on the exoskeleton structure and biophotonic properties of the shrimp Lysmata californica. AB - The anticipated effects of CO2-induced ocean acidification on marine calcifiers are generally negative, and include dissolution of calcified elements and reduced calcification rates. Such negative effects are not typical of crustaceans for which comparatively little ocean acidification research has been conducted. Crustaceans, however, depend on their calcified exoskeleton for many critical functions. Here, we conducted a short-term study on a common caridean shrimp, Lysmata californica, to determine the effect of CO2-driven reduction in seawater pH on exoskeleton growth, structure, and mineralization and animal cryptic coloration. Shrimp exposed to ambient (7.99 +/- 0.04) and reduced pH (7.53 +/- 0.06) for 21 days showed no differences in exoskeleton growth (percent increase in carapace length), but the calcium weight percent of their cuticle increased significantly in reduced pH conditions, resulting in a greater Ca:Mg ratio. Cuticle thickness did not change, indicating an increase in the mineral to matrix ratio, which may have mechanical consequences for exoskeleton function. Furthermore, there was a 5-fold decrease in animal transparency, but no change in overall shrimp coloration (red). These results suggest that even short-term exposure to CO2-induced pH reduction can significantly affect exoskeleton mineralization and shrimp biophotonics, with potential impacts on crypsis, physical defense, and predator avoidance. PMID- 26030214 TI - Does aspirin administration increase perioperative morbidity in patients with cardiac stents undergoing spinal surgery? AB - STUDY DESIGN: Cohort. OBJECTIVE: To compare the perioperative morbidity of patients with cardiac stents after spine surgery who continue to take aspirin before and after the operation with a similar group of patients who preoperatively discontinued aspirin. SUMMARY OF BACKGROUND DATA: The preoperative discontinuation of anticoagulant therapy has been the standard of care for orthopedic surgical procedures. However, recent literature has demonstrated significant cardiac risk associated with aspirin withdrawal in patients with cardiac stents. Although it has recently been demonstrated that performing orthopedic surgery while continuing low-dose aspirin therapy seems to be safe, studies focused on spinal surgery have not yet been performed. Because of the risk of intraspinal bleeding and the serious consequences of subsequent epidural hematoma with associated spinal cord compression, spinal surgeons have been reluctant to operate on patients taking aspirin. METHODS: This institutional review board-approved study included 200 patients. Preoperative parameters and postoperative outcome measures were analyzed for 100 patients who underwent spinal surgery after the discontinuation of anticoagulation therapy and 100 patients who continued to take daily aspirin through the perioperative period. The primary outcome measure was serious bleeding-related postoperative complications such as spinal epidural hematoma. The operative time, intraoperative estimated blood loss, hospital length of stay, transfusion of blood products, and 30-day hospital readmission rates were also recorded and compared. RESULTS: The patients who continued taking aspirin in the perioperative period had a shorter hospital length of stay on average (4.1 +/- 2.7 vs. 6.2 +/- 5.8; P < 0.005), as well as a reduced operative time (210 +/- 136 vs. 266 +/- 143; P < 0.01), whereas there was no significant difference in the estimated blood loss (642 +/- 905 vs. 697 +/- 1187), the amount of blood products transfused, overall intra- and postoperative complication rate (8% vs. 11%), or 30-day hospital readmission rate (5% vs. 5%). No clinically significant spinal epidural hematomas were observed in either of the study groups. CONCLUSION: The current study has observed no appreciable increase in bleeding-related complication rates in patients with cardiac stents undergoing spine surgery while continuing to take aspirin compared with patients who discontinued aspirin prior to surgery. Although very large studies will be needed to determine whether aspirin administration results in a small complication rate increase, the current study provides evidence that perioperative aspirin therapy is relatively safe in patients undergoing spinal surgery. LEVEL OF EVIDENCE: 2. PMID- 26030215 TI - SRS-7: A Valid, Responsive, Linear, and Unidimensional Functional Outcome Measure for Operatively Treated Patients With AIS. AB - STUDY DESIGN: Comparison of the Scoliosis Research Society-22 (SRS-22) questionnaire with a 7-item Rasch-derived questionnaire (SRS-7). OBJECTIVE: To compare the construct and discriminant validity, internal consistency, responsiveness, and dimensionality of SRS-7 against SRS-22 in operatively treated children with adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: SRS-22 has not been shown to possess linearity or unidimensionality (internal validity). METHODS: A multicenter database was queried for children with adolescent idiopathic scoliosis who underwent spinal fusion and answered all preoperative and 1-year postoperative SRS-22 questions. SRS-7 scores for the 685 patients were calculated from SRS-22 item responses. Traditional psychometric properties were assessed for both instruments (significance, P < 0.01). RESULTS: SRS-7 and SRS-22 scores correlated preoperatively and postoperatively (r = 0.78, P < 0.001, and r = 0.78, P < 0.001, respectively). Both instruments showed good discriminant validity in segregating 4 groups of patients with adolescent idiopathic scoliosis by curve magnitudes (F = 8.36, P < 0.001, and F = 8.38, P < 0.001, respectively). Pre- and postoperative SRS-7 and SRS-22 had internal consistency Cronbach alpha values of 0.64 and 0.67, and 0.85 and 0.85, respectively. With SRS-7, mean postsurgical improvement was 18.7 points (46.6-65.3, P < 0.001), with effect size measures of Cohen d = 1.57, Hedge g = 1.57, and r = 0.62. With SRS-22, mean improvement was 11.6 points (84.5-96.1, P < 0.01), with effect size measures of Cohen d = 1.25, Hedge g = 1.25, and r = 0.53. Iterative principal factor analysis of pre- and postoperative SRS-7 and SRS-22 showed the presence of 1 dominant latent factor (unidimensionality) and 4 latent factors (multidimensionality), respectively. CONCLUSION: SRS-7 shows good concurrent and discriminative validity, reasonable internal consistency, and excellent responsiveness. It has the advantages over SRS-22 of being short, unidimensional, and an interval scale. LEVEL OF EVIDENCE: 4. PMID- 26030213 TI - Proteomic analysis of cerebrospinal fluid in canine cervical spondylomyelopathy. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To identify proteins with differential expression in the cerebrospinal fluid (CSF) from 15 clinically normal (control) dogs and 15 dogs with cervical spondylomyelopathy (CSM). SUMMARY OF BACKGROUND DATA: Canine CSM is a spontaneous, chronic, compressive cervical myelopathy similar to human cervical spondylotic myelopathy. There is a limited knowledge of the molecular mechanisms underlying these conditions. Differentially expressed CSF proteins may contribute with novel information about the disease pathogenesis in both dogs and humans. METHODS: Protein separation was performed with 2-dimensional electrophoresis. A Student t test was used to detect significant differences between groups (P < 0.05). Three comparisons were made: (1) control versus CSM-affected dogs, (2) control versus non-corticosteroid treated CSM-affected dogs, and (3) non-corticosteroid-treated CSM-affected versus corticosteroid-treated CSM-affected dogs. Protein spots exhibiting at least a statistically significant 1.25-fold change between groups were selected for subsequent identification with capillary-liquid chromatography tandem mass spectrometry. RESULTS: A total of 96 spots had a significant average change of at least 1.25-fold in 1 of the 3 comparisons. Compared with the CSF of control dogs, CSM-affected dogs demonstrated increased CSF expression of 8 proteins including vitamin D-binding protein, gelsolin, creatine kinase B-type, angiotensinogen, alpha-2-HS-glycoprotein, SPARC (secreted protein, acidic, rich in cysteine), calsyntenin-1, and complement C3, and decreased expression of pigment epithelium derived factor, prostaglandin-H2 D-isomerase, apolipoprotein E, and clusterin. In the CSF of CSM-affected dogs, corticosteroid treatment increased the expression of haptoglobin, transthyretin isoform 2, cystatin C-like, apolipoprotein E, and clusterin, and decreased the expression of angiotensinogen, alpha-2-HS glycoprotein, and gelsolin. CONCLUSION: Many of the differentially expressed proteins are associated with damaged neural tissue, bone turnover, and/or compromised blood-spinal cord barrier. The knowledge of the protein changes that occur in CSM and upon corticosteroid treatment of CSM-affected patients will aid in further understanding the pathomechanisms underlying this disease. LEVEL OF EVIDENCE: N/A. PMID- 26030216 TI - Spinal hemangiomas: results of surgical management for local recurrence and mortality in a multicenter study. AB - STUDY DESIGN: Multicenter, ambispective observational study. OBJECTIVE: To quantify local recurrence and mortality rates after surgical treatment of symptomatic spinal hemangiomas and identify prognostic variables for local disease control. SUMMARY OF BACKGROUND DATA: Spinal hemangiomas are the most common primary tumors of the spine and are generally benign and usually asymptomatic. Because of the rarity of symptomatic spinal hemangiomas, optimal surgical treatment remains unclear. METHODS: AOSpine Knowledge Forum Tumor Investigators created a multicenter database of primary spinal tumors including demographics, presentation, diagnosis, treatment, survival, and recurrence data. Tumors were classified according to Enneking and Weinstein-Boriani-Biagini. Descriptive statistics were summarized and time to mortality and recurrence was determined. RESULTS: Between 1996 and 2012, 68 patients (mean age = 51 yr, SD = 16) underwent surgical treatment of a spinal hemangioma. Epidural disease was present in 55% of patients (n = 33). Pain and neurological compromise were presenting symptoms in 82% (n = 54) and 37% (n = 24) of patients, respectively. Preoperative embolization was performed in 35% of patients (n = 23), 10% (n = 7) had adjuvant radiotherapy, and 81% (n = 55) underwent posterior-alone surgery. The local recurrence rate was 3% (n = 2). Mortality secondary to spinal hemangioma was not observed (mean follow-up = 3.9 yr, SD = 3.8). CONCLUSION: This is the largest multicenter surgical cohort of spinal hemangiomas. Symptomatic spinal hemangiomas are a benign tumor despite frequently presenting with epidural disease and neurological compromise. Thus, formal en bloc resection is not required, and excellent rates of local control and long-term survival can result from aggressive intralesional resection during index surgery. LEVEL OF EVIDENCE: 3. PMID- 26030217 TI - Letters. PMID- 26030218 TI - Letters. PMID- 26030219 TI - Letter. PMID- 26030220 TI - Validation of the simplified Chinese version of the functional rating index for patients with nonspecific neck pain in mainland China. AB - STUDY DESIGN: Validation of a self-report questionnaire, Functional Rating Index (FRI). OBJECTIVE: To evaluate the psychometric properties of the simplified Chinese (SC) version of FRI in patients with nonspecific neck pain (NP). SUMMARY OF BACKGROUND DATA: FRI has been cross-culturally validated in few languages with excellent reliability, validity, and clinical utility when it is applied in patients with low back pain. Recently, it has been pointed out that FRI can be employed to assess patients with NP. However, FRI has not been validated in patients with NP in China. METHODS: The cross-culturally adapted 10-item SC-FRI was completed by 122 patients with nonspecific NP, along with the Neck Disability Index, Neck Pain and Disability Scale, 36-Item Short Form Health Survey, and Pain Visual Analogue Scale. Psychometric evaluation included score distribution, internal consistency, test-retest reliability, and construct validity. RESULTS: SC-FRI attained a high completion rate (96.9%). Each item was scored with a normal distribution without any floor and ceiling effects. The internal consistency and test-retest reliability were good to excellent (Cronbach alpha coefficient = 0.86; intraclass r = 0.97). Construct validity was confirmed by a strong correlation with Neck Disability Index, Neck Pain and Disability Scale, and Visual Analogue Scale (r = 0.77, 0.78, and 0.86, respectively, all P < 0.0001), and with the physical functioning and bodily pain domains (r = -0.69 and -0.66, respectively, both P < 0.0001), and by a weak correlation with the vitality, role-emotional, and mental health domains of 36-Item Short Form Health Survey. CONCLUSION: SC-FRI showed satisfactory clinical utility, internal consistency, test-retest reliability, and construct validity in Chinese-speaking patients with nonspecific NP. LEVEL OF EVIDENCE: 3. PMID- 26030221 TI - Reference Values of the Pain Disability Index in Patients With Painful Musculoskeletal and Spinal Disorders: A Cross-national Study. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine reference data for the Pain Disability Index (PDI) in Dutch and Canadian patient samples with a variety of musculoskeletal pain disorders and to test which potential factors are independently associated with the PDI score. SUMMARY OF BACKGROUND DATA: The PDI is a widely used generic instrument for measuring disability related to pain. It is unknown whether patients with spinal and other musculoskeletal diagnoses have different levels of disability when scored on the PDI. METHODS: Patients were referred to secondary and tertiary care centers in the Netherlands and Alberta, Canada, between 2009 and 2013. All patients filled out a baseline questionnaire including demographics and the PDI. After first consultation with a medical doctor, diagnoses were set by the medical specialist. Univariate general linear models were used to examine correlations between PDI scores and age, sex, country of residence, diagnosis, and work status. RESULTS: In total 6997 patients were included in this study: 1302 Canadian and 5695 Dutch patients. Mean PDI score of the total group was 37.8 +/- 14.2. Reference values are presented and clustered into the following diagnostic groups: spinal nerve and intervertebral disc disorders; nonspecific back pain; rheumatic soft-tissue pain (widespread pain or fibromyalgia); spinal stenosis; and whiplash-associated disorder. The PDI score was significantly and relevantly associated with pain intensity (eta explained variance from 20% to 25%), but not relevantly associated with age, sex, country of residence, and diagnostic group (eta<3%). In the working subgroup, adding "current sick leave" as covariate increased the explained variance to 34%. CONCLUSION: Reference values of the PDI are presented. Patient ratings of disability on the PDI are relevantly associated with pain intensity and work status, but not with nationality or diagnostic group. Only minimal differences were identified between the various musculoskeletal diagnoses included. LEVEL OF EVIDENCE: N/A. PMID- 26030223 TI - Fundamental Study of Electrospun Pyrene-Polyethersulfone Nanofibers Using Mixed Solvents for Sensitive and Selective Explosives Detection in Aqueous Solution. AB - Fluorescent pyrene-polyethersulfone (Py-PES) nanofibers were prepared through electrospinning technique using mixed solvents. The effects of mixed solvent ratio and polymer/fluorophore concentrations on electrospun nanofiber's morphology and its sensing performance were systematically investigated and optimized. The Py-PES nanofibers prepared under optimized conditions were further applied for highly sensitive detection of explosives, such as picric acid (PA), 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), and 1,3,5-trinitroperhydro 1,3,5-triazine (RDX) in aqueous phase with limits of detection (S/N = 3) of 23, 160, 400, and 980 nM, respectively. The Stern-Volmer (S-V) plot for Py excimer fluorescence quenching by PA shows two linear regions at low (0-1 MUM) and high concentration range (>1 MUM) with a quenching constant of 1.263 * 10(6) M(-1) and 5.08 * 10(4) M(-1), respectively. On the contrary, S-V plots for Py excimer fluorescence quenching by TNT, DNT, and RDX display an overall linearity in the entire tested concentration range. The fluorescence quenching by PA can be attributed to the fact that both photoinduced electron transfer and energy transfer are involved in the quenching process. In addition, pyrene monomer fluorescence is also quenched and exhibits different trends for different explosives. Fluorescence lifetime studies have revealed a dominant static quenching mechanism of the current fluorescent sensors for explosives in aqueous solution. Selectivity study demonstrates that common interferents have an insignificant effect on the emission intensity of the fluorescent nanofibers in aqueous phase, while reusability study indicates that the fluorescent nanofibers can be regenerated. Spiked real river water sample was also tested, and negligible matrix effect on explosives detection was observed. This research provides new insights into the development of fluorescent explosive sensor with high performance. PMID- 26030224 TI - Interactions of Multimodal Ligands with Proteins: Insights into Selectivity Using Molecular Dynamics Simulations. AB - Fundamental understanding of protein-ligand interactions is important to the development of efficient bioseparations in multimodal chromatography. Here we employ molecular dynamics (MD) simulations to investigate the interactions of three different proteins--ubiquitin, cytochrome C, and alpha-chymotrypsinogen A, sampling a range of charge from +1e to +9e--with two multimodal chromatographic ligands containing similar chemical moieties--aromatic, carboxyl, and amide--in different structural arrangements. We use a spherical harmonic expansion to analyze ligand and individual moiety density profiles around the proteins. We find that the Capto MMC ligand, which contains an additional aliphatic group, displays stronger interactions than Nuvia CPrime ligand with all three proteins. Studying the ligand densities at the moiety level suggests that hydrophobic interactions play a major role in determining the locations of high ligand densities. Finally, the greater structural flexibility of the Capto MMC ligand compared to that of the Nuvia cPrime ligand allows for stronger structural complementarity and enables stronger hydrophobic interactions. These subtle and not-so-subtle differences in binding affinities and modalities for multimodal ligands can result in significantly different binding behavior towards proteins with important implications for bioprocessing. PMID- 26030225 TI - A conversation with Craig Thompson. PMID- 26030226 TI - Putting together the autoimmunity puzzle. AB - Autoimmune diseases classically present with a complex etiology in which different factors concur in the generation and maintenance of autoreactive immune responses. Some mechanisms and pathways that lead to the development of imbalanced immune homeostasis and loss of self-tolerance have been identified as common to multiple autoimmune disorders. This Review series focuses on the general concepts of development and progression to pathogenic autoimmune phenotypes. A mechanistic discussion of the most recent advances in the field, together with related considerations of possible therapies, make this series of particular interest to both the basic and translational science communities. PMID- 26030230 TI - Emerging mechanisms of molecular pathology in ALS. PMID- 26030229 TI - CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells. PMID- 26030227 TI - Genetic basis of autoimmunity. AB - Autoimmune diseases affect up to approximately 10% of the population. While rare Mendelian autoimmunity syndromes can result from monogenic mutations disrupting essential mechanisms of central and peripheral tolerance, more common human autoimmune diseases are complex disorders that arise from the interaction between polygenic risk factors and environmental factors. Although the risk attributable to most individual nucleotide variants is modest, genome-wide association studies (GWAS) have the potential to provide an unbiased view of biological pathways that drive human autoimmune diseases. Interpretation of GWAS requires integration of multiple genomic datasets including dense genotyping, cis-regulatory maps of primary immune cells, and genotyped studies of gene expression in relevant cell types and cellular conditions. Improved understanding of the genetic basis of autoimmunity may lead to a more sophisticated understanding of underlying cellular phenotypes and, eventually, novel diagnostics and targeted therapies. PMID- 26030228 TI - MicroRNA regulation of lymphocyte tolerance and autoimmunity. AB - Understanding the cell-intrinsic cues that permit self-reactivity in lymphocytes, and therefore autoimmunity, requires an understanding of the transcriptional and posttranscriptional regulation of gene expression in these cells. In this Review, we address seminal and recent research on microRNA (miRNA) regulation of central and peripheral tolerance. Human and mouse studies demonstrate that the PI3K pathway is a critical point of miRNA regulation of immune cell development and function that affects the development of autoimmunity. We also discuss how miRNA expression profiling in human autoimmune diseases has inspired mechanistic studies of miRNA function in the pathogenesis of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and asthma. PMID- 26030231 TI - Bacteria-Targeting Conjugates Based on Antimicrobial Peptide for Bacteria Diagnosis and Therapy. AB - Chloramphenicol (CAP) is one of the most effective antimicrobial agents, but its therapeutic efficacy is greatly limited by its nonspecific distribution and consequent side effects in neutrophils. Targeting to the infection sites, and thus restricting CAP nonselective delivery, provides an alternative way to overcome this limitation. The antibacterial peptide fragment UBI29-41 was identified to have a high bacterial affinity. However, no research so far has been carried out to utilize UBI29-41 as a ligand for bacteria-targeting therapies. In this Article, we first labeled a near-infrared fluorescent dye (ICG02) with UBI29-41 to investigate its targeting capability in different bacteria (S. aureus, E. coli, and P. auruginosa) and bacteria-infected mouse models. Subsequently, UBI29-41 was conjugated with the typical antibiotic (CAP) through the linker glutaric anhydride to form the conjugate CAP-UBI29-41 for the bacteria-targeting therapy. In vitro studies demonstrated the enhanced antibacterial effects of CAP-UBI29-41 on S. aureus and E.coil. Meanwhile, the toxicity of CAP-UBI29-41 on normal cells decreased distinctly in comparison with CAP. Most importantly, CAP-UBI29-41 exhibited more favorable antibacterial efficacy than CAP in bacteria-bearing mouse models. All these results demonstrated that UBI29-41 is an ideal targeting ligand to construct antibacterial agents for bacteria-targeting therapy. PMID- 26030232 TI - A new phase from compression of carbon nanotubes with anisotropic Dirac fermions. AB - Searching for novel functional carbon materials is an enduring topic of scientific investigations, due to its diversity of bonds, including sp-, sp(2)-, and sp(3)-hybridized bonds. Here we predict a new carbon allotrope, bct-C12 with the body-centered tetragonal I4/mcm symmetry, from the compression of carbon nanotubes. In particular, this structure behaviors as the Dirac fermions in the kz direction and the classic fermions in the kx and ky directions. This anisotropy originates from the interaction among zigzag chains, which is inherited from (n, n)-naotubes. PMID- 26030234 TI - In reply. PMID- 26030233 TI - gamma-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of gamma-Secretase and Signal Peptide Peptidase. AB - gamma-Secretase inhibitors (GSIs) and modulators (GSMs) are at the frontline of cancer and Alzheimer's disease research, respectively. While both are therapeutically promising, not much is known about their interactions with proteins other than gamma-secretase. Signal peptide peptidase (SPP), like gamma secretase, is a multispan transmembrane aspartyl protease that catalyzes regulated intramembrane proteolysis. We used active site-directed photophore walking probes to study the effects of different GSIs and GSMs on the active sites of gamma-secretase and SPP and found that nontransition state GSIs inhibit labeling of gamma-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of GSMs, which have little effect on the labeling of gamma secretase but diminish labeling of SPP. These results demonstrate that GSIs and GSMs are altering the structure of not only gamma-secretase but also SPP, leading to potential changes in enzyme activity and specificity that may impact the clinical outcomes of these molecules. PMID- 26030235 TI - Subspecialty in community pathology practice. PMID- 26030236 TI - The College of American Pathologists House of Delegates redefined. PMID- 26030237 TI - Limiting specimen rejection. PMID- 26030238 TI - Has diagnostic (analytic) accuracy improved in anatomic pathology? Are we better today than we were 20 years ago? PMID- 26030239 TI - In vivo microscopy: will the microscope move from our desk into the patient? PMID- 26030240 TI - The Houston Society of Clinical Pathologists 55th Annual Spring Symposium, April 2014. PMID- 26030241 TI - Esophagitis: old histologic concepts and new thoughts. AB - CONTEXT: Inflammatory lesions of the esophagus are a diverse group, often with nonspecific histologic findings. These benign changes can produce diagnostic difficulties for pathologists. OBJECTIVE: To discuss the typical histologic findings of a variety of the most common causes of esophagitis (reflux, eosinophilic esophagitis, infections, medications) along with less common issues such as sloughing esophagitis and skin disorders involving the squamous mucosa. DATA SOURCES: The literature has been reviewed to discuss histologic definitions of current and developing issues in the area of esophagitis. CONCLUSIONS: Histologic features are not entirely sensitive and specific for inflammatory esophageal disorders. Awareness of these problems is essential; clinical and endoscopic information can be very useful in distinguishing among the various lesions. PMID- 26030242 TI - Molecular and histologic considerations in the assessment of serrated polyps. AB - CONTEXT : Colorectal cancer is a heterogeneous disease resulting from different molecular pathways of carcinogenesis. Recent data evaluating the histologic features and molecular basis of the serrated polyp-carcinoma pathway have significantly contributed to more comprehensive classifications of and treatment recommendations for these tumors. OBJECTIVE: To integrate the most recent molecular findings in the context of histologic classifications of serrated lesions and their implications in diagnostic pathology and colorectal cancer surveillance. DATA SOURCES: Published literature focused on serrated polyps and their association with colorectal cancer. CONCLUSIONS: Three types of serrated polyps are currently recognized: hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas. The BRAF V600E mutation is one of the most frequent molecular abnormalities identified in hyperplastic polyps and sessile serrated adenomas. In contrast, in traditional serrated adenomas, either BRAF V600E or KRAS mutations can be frequently identified. CpG methylation has emerged as a critical molecular mechanism in the sessile serrated pathway. CpG methylation of MLH1 often leads to reduced or lost expression in dysplastic foci and carcinomas arising in sessile serrated adenomas/polyps. PMID- 26030243 TI - IgG4-Related Disease of the Gastrointestinal Tract: A 21st Century Chameleon. AB - CONTEXT: Immunoglobulin G4 (IgG4)-related disease is a systemic fibroinflammatory disease capable of affecting virtually any organ. Although the pancreas and hepatobiliary system are commonly affected, involvement of the tubular gut is unusual. The pancreatic manifestations of this disease (autoimmune pancreatitis) often mimic pancreatic carcinoma, whereas the hepatobiliary manifestations are mistaken for cholangiocarcinoma or primary sclerosing cholangitis. The characteristic histologic features include a dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis. An increase in IgG4(+) plasma cells and an IgG4 to IgG ratio of more than 40% are considered obligatory components of the diagnostic algorithm. OBJECTIVE: To review the challenges associated with the diagnosis of IgG4-related disease of the gastrointestinal tract. DATA SOURCES: A review of pertinent literature, along with the author's personal experience, based on institutional and consultation materials. CONCLUSION: The complete spectrum of histologic changes is seldom captured in a biopsy specimen, and thus, the histopathology findings are best interpreted within the overall clinical context. Increased IgG4(+) plasma cells are identified in a variety of benign and malignant diseases of the gastrointestinal tract. PMID- 26030244 TI - Neuroendocrine tumors of the luminal gastrointestinal tract. AB - CONTEXT: Neuroendocrine tumors (NETs) of the gastrointestinal tract have been recognized for more than a century. Despite histologic similarities between different sites in the tract, behavior varies between areas. All of these tumors have malignant potential, but determination of exact risk is difficult. OBJECTIVES: To review the diagnosis of luminal gastrointestinal NETs, including a discussion of grading. Grading by mitotic index/activity, in conjunction with tumor size/stage, has been found to be the strongest predictor of behavior. DATA SOURCES: Literature review of luminal gastrointestinal NETs was performed and the results summarized. CONCLUSIONS: Our understanding of these lesions is incomplete and continues to evolve. PMID- 26030245 TI - Seven Q-Tracks monitors of laboratory quality drive general performance improvement: experience from the College of American Pathologists Q-Tracks program 1999-2011. AB - CONTEXT: Many production systems employ standardized statistical monitors that measure defect rates and cycle times, as indices of performance quality. Clinical laboratory testing, a system that produces test results, is amenable to such monitoring. OBJECTIVE: To demonstrate patterns in clinical laboratory testing defect rates and cycle time using 7 College of American Pathologists Q-Tracks program monitors. DESIGN: Subscribers measured monthly rates of outpatient order entry errors, identification band defects, and specimen rejections; median troponin order-to-report cycle times and rates of STAT test receipt-to-report turnaround time outliers; and critical values reporting event defects, and corrected reports. From these submissions Q-Tracks program staff produced quarterly and annual reports. These charted each subscriber's performance relative to other participating laboratories and aggregate and subgroup performance over time, dividing participants into best and median performers and performers with the most room to improve. Each monitor's patterns of change present percentile distributions of subscribers' performance in relation to monitoring durations and numbers of participating subscribers. Changes over time in defect frequencies and the cycle duration quantify effects on performance of monitor participation. RESULTS: All monitors showed significant decreases in defect rates as the 7 monitors ran variously for 6, 6, 7, 11, 12, 13, and 13 years. The most striking decreases occurred among performers who initially had the most room to improve and among subscribers who participated the longest. All 7 monitors registered significant improvement. Participation effects improved between 0.85% and 5.1% per quarter of participation. CONCLUSIONS: Using statistical quality measures, collecting data monthly, and receiving reports quarterly and yearly, subscribers to a comparative monitoring program documented significant decreases in defect rates and shortening of a cycle time for 6 to 13 years in all 7 ongoing clinical laboratory quality monitors. PMID- 26030246 TI - Squamous cell carcinoma of the cervix: a cytology-histology-human papillomavirus correlation in clinical practice. AB - CONTEXT: Cervical cancer mortality has declined by 74% in the United States since the implementation of the Papanicolaou (Pap) test. Nevertheless, more than 12,000 US women annually develop cervical cancer, and squamous cell carcinoma (SqCa) remains the predominant cervical malignancy. OBJECTIVE: To evaluate screening techniques used in the detection of SqCa of the cervix and provide insights regarding which technique(s) is (are) most efficacious in our study population. DESIGN: We retrospectively reviewed all available cytologic, human papillomavirus (HPV), and histologic malignancy burden data from patients diagnosed with SqCa. The clinical data were collected from 2 geographically and socioeconomically diverse hospital systems. Cases in which identified patients had a Pap test with a negative result/unsatisfactory specimen within 5 years of SqCa tissue diagnosis were considered Pap test screening failures. Cases in which patients were diagnosed with HPV-negative SqCa were considered HPV screening failures. RESULTS: Eighty-eight cases (patients' ages ranging from 19 to 73 years) were identified. Of those, cytologic history was available for 64 cases present in our electronic medical history record. Three cases were cytology screening failures (one being an unsatisfactory specimen) and 3 cases were HPV screening failures (one being the cytologic unsatisfactory case). Although measuring sensitivity in practice has limitations, we calculated the SqCa detection sensitivity at 95.3% by Pap test alone and 97% when HPV DNA testing was incorporated. CONCLUSIONS: Our results highlight the necessity of combining Pap and HPV testing. Although the number of cases identified is relatively small, our data suggest detection failures will decrease as the practice of combining HPV and Pap testing increases. PMID- 26030247 TI - Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis. AB - CONTEXT: The prognosis of appendiceal goblet cell carcinoid tumors (GCTs) is believed to be intermediate between appendiceal adenocarcinomas and conventional carcinoid tumors. However, GCTs can have mixed morphologic patterns, with variable amount of adenocarcinoma. OBJECTIVE: To evaluate the behavior of GCTs and related entities with variable components of adenocarcinoma. DESIGN: We classified 74 cases of appendiceal tumors into 3 groups: group 1, GCTs or GCTs with less than 25% adenocarcinoma; group 2, GCTs with 25% to 50% adenocarcinoma; group 3, GCTs with more than 50% adenocarcinoma; and a comparison group of 68 adenocarcinomas without a GCT component (group 4). Well-differentiated mucinous adenocarcinomas were excluded. Clinicopathologic features and follow-up were obtained from computerized medical records and the US Social Security Death Index. RESULTS: Of the 142 tumors studied, 23 tumors (16%) were classified as group 1; 27 (19%) as group 2; 24 (17%) as group 3; and 68 (48%) as group 4. Staging and survival differed significantly among these groups. Among 140 patients (99%) with available staging data, stages II, III, and IV were present in 87%, 4%, and 4% of patients in group 1 patients; 67%, 7%, and 22% of patients in group 2; 29%, 4%, and 67% of patients in group 3; and 19%, 6%, and 75% of patients in group 4, respectively (P = .01). Mean (SD) overall survival was 83.8 (34.6), 60.6 (30.3), 45.6 (39.7), and 33.6 (27.6) months for groups 1, 2, 3, and 4, respectively (P = .01). By multivariate analysis, only stage and tumor category were independent predictors of overall survival. CONCLUSION: Our data highlight the importance of subclassifying the proportion of adenocarcinoma in appendiceal tumors with GCT morphology because that finding reflects disease stage and affects survival. PMID- 26030248 TI - HepPar-1 and Arginase-1 Immunohistochemistry in Adenocarcinoma of the Small Intestine and Ampullary Region. AB - CONTEXT :HepPar-1 and Arginase-1 are urea cycle enzymes used to distinguish hepatocellular carcinoma from other carcinomas. HepPar-1, but not Arginase-1, is known to be immunoreactive with normal human small intestine. OBJECTIVES: To better define and compare the immunohistochemical staining patterns of HepPar-1 and Arginase-1 in adenocarcinomas arising in the small intestine, including the ampullary region. DESIGN: Staining for HepPar-1 and Arginase-1 was performed on 20 nonampullary small intestinal adenocarcinomas and 32 adenocarcinomas from the ampullary region. Ampullary adenocarcinomas were divided into intestinal morphology (15), pancreatobiliary morphology (14), and unclassifiable (3). Nonneoplastic small intestinal mucosa and colorectal adenocarcinomas were used as control groups. RESULTS: HepPar-1 stained 12 of 20 nonampullary small intestinal adenocarcinomas, with a median of 63% of cells staining in positive cases. It also stained 11 of 15 ampullary carcinomas with intestinal morphology, with a median of 75% of cells staining in positive cases. Two of 14 ampullary carcinomas with pancreatobiliary morphology were positive for HepPar-1. Arginase-1 showed positivity in 2 ampullary region carcinomas and diffuse positivity in 1 duodenal adenocarcinoma. Two of 22 colorectal carcinomas stained for HepPar-1 with none positive for Arginase-1. CONCLUSIONS: HepPar-1, but not Arginase-1, usually shows positivity in small intestinal adenocarcinomas and ampullary adenocarcinomas with intestinal morphology, but only rarely shows positivity in ampullary adenocarcinomas with pancreatobiliary morphology. HepPar-1 positivity in metastatic adenocarcinoma with intestinal morphology is suggestive of an upper gastrointestinal primary site. PMID- 26030249 TI - Multiphoton microscopy: a potential intraoperative tool for the detection of carcinoma in situ in human bladder. AB - CONTEXT: Urothelial carcinoma in situ (CIS) is a precursor of invasive bladder cancer, which if left untreated, will likely progress to more aggressive disease. Approximately 50% of CIS lesions are missed on routine cystoscopy owing to their flat architecture. Furthermore, many benign but abnormal-appearing areas may be biopsied owing to lack of cellular resolution of cystoscopes. Multiphoton microscopy (MPM) is an optical imaging technique that generates subcellular resolution three-dimensional images from unfixed tissue without using exogenous dyes. OBJECTIVE: To assess the diagnostic potential of MPM in identifying and differentiating benign from malignant flat bladder lesions, especially CIS. DESIGN: Seventy-eight specimens (benign = 46, CIS = 23, invasive = 9, as diagnosed on histopathology) were obtained from flat bladder mucosa via transurethral resection of bladder, cold cup biopsy, or cystectomy, imaged fresh with a commercial benchtop MPM, and submitted for routine histopathology. Multiphoton microscopy and hematoxylin-eosin diagnoses were compared. RESULTS: In 77 of 78 specimens (99%), accurate MPM diagnoses (benign/malignant) were given on the basis of their architectural and cytologic features (nuclear to cytoplasmic ratio, pleomorphism, polarity/organization of urothelial layers, etc). The sensitivity and specificity were 97% and 100%, respectively, with positive (malignant) and negative (benign) predictive values of 100% and 98%, respectively. The interobserver agreement, kappa, was 0.93. CONCLUSIONS: Our study demonstrates the capability of MPM to identify and differentiate benign from malignant flat bladder lesions, especially CIS. With the advent of MPM endoscopes, we foresee their potential as a biopsy guidance tool for early detection and treatment of CIS, thus reducing the rate of biopsies with benign diagnoses and their associated complications. PMID- 26030250 TI - Determination of genotypes using a fully automated molecular detection system. AB - CONTEXT: Although the value of pharmacogenomics to improve patient outcomes has become increasingly clear, adoption in medical practice has been slow, which can be attributed to several factors, including complicated and expensive testing procedures and required equipment, lack of training by private practice physicians, and reluctance of both private and commercial payers to reimburse for such testing. OBJECTIVES: To evaluate a fully automated molecular detection system for human genotyping assays, starting with anticoagulated whole blood samples, and to perform all sample preparation, assay, and analysis steps automatically with actionable results reported by the system's software. DESIGN: The genotypes of 254 random individuals were determined by performing bidirectional DNA sequencing, and that information was used to statistically train the imaging software of the automated molecular detection system to distinguish the 3 possible genotypes (ie, homozygous wild type, heterozygous, and homozygous mutant) at each of 3 different loci (CYP2C9*2, CYP2C9*3, and VKORC1). RESULTS: The resulting software algorithm was able to correctly identify the genotypes of all 254 individuals (100%) evaluated without any further user analysis. CONCLUSIONS: The EncompassMDx workstation (Rheonix, Inc, Ithaca, New York) is a molecular detection system that can automatically determine the genotypes of individuals in an unattended manner. Considerably less technical expertise was required to achieve results identical to those obtained using more complex, time-consuming, and expensive bidirectional DNA sequencing. This optimized system may dramatically simplify and reduce the costs of pharmacogenomics testing, thus leading to more-widespread use. PMID- 26030252 TI - Metaplastic carcinoma of the breast. AB - Metaplastic carcinoma of the breast is a rare but aggressive type of breast cancer that has been recognized as a unique pathologic entity by the World Health Organization. Morphologically, it is characterized by the differentiation of neoplastic epithelium into squamous cells and/or mesenchymal-looking elements (squamous cells, spindle cells, cartilage or bone, etc). It shares many similarities with invasive ductal carcinoma and benign lesions on mammography, which further complicates the diagnosis. Treatment for metaplastic breast carcinoma is relatively unknown because of the rarity of the disease, but studies suggest that removal of the tumor and adjuvant radiation therapy has the greatest benefit. PMID- 26030251 TI - Biobanking in genomic medicine. AB - CONTEXT: Genomic medicine requires the identification of biomarkers and therapeutic targets, which in turn, requires high-quality biospecimens. Achieving high-quality biospecimens requires implementing standard operating procedures to control the variations of preanalytic variables in biobanking. Currently, most biobanks do not control the variations of preanalytic variables when collecting, processing, and storing their biospecimens. However, those variations have been shown to affect the quality of biospecimens and gene expression profiling. OBJECTIVE: To identify evidence-based preanalytic parameters that can be applied and those parameters that need further study. DATA SOURCES: We searched the Biospecimen Research and PubMed databases using defined key words. We retrieved and reviewed 212 articles obtained through those searches. We included 58 articles (27%) according to our inclusion and exclusion criteria for this review. CONCLUSION: -Preanalytic variables in biobanking can degrade the quality of biospecimens and alter gene expression profiling. Variables that require further study include the effect of surgical manipulation; the effect of warm ischemia; the allowable duration of delayed specimen processing; the optimal type, duration, and temperature of preservation and fixation; and the optimal storage duration of formalin-fixed, paraffin embedded specimens in a fit-for-purpose approach. PMID- 26030253 TI - Gastric pyloric gland adenoma. AB - Pyloric gland adenomas are rare neoplasms of the gastrointestinal tract. Gastric pyloric gland adenomas have been shown to arise in chronically damaged mucosa. The neoplastic glands have gastric pyloric gland differentiation and have a tightly packed organization with occasional cystic dilatation. The individual cells are cuboidal to columnar, with eosinophilic to amphophilic cytoplasm and either no apical mucin cap or a poorly formed apical mucin cap. The nuclei are round to oval, with occasional prominent nucleoli. Immunohistochemically, the neoplastic cells label with markers of gastric pyloric gland differentiation, including MUC6 and MUC5AC. There is limited information regarding the natural history of pyloric gland adenomas, but clinical series have described adenocarcinomas in association with gastric pyloric gland adenomas. The ideal clinical management is adequate sampling of the lesion to investigate for high grade dysplasia and/or invasive cancer and recommendation to clinical colleagues to investigate the background mucosa for the etiology of chronic gastritis as well as potential additional neoplastic lesions. This review will focus on gastric pyloric gland adenomas. PMID- 26030254 TI - Radiation esophagitis. AB - The esophagus is frequently exposed to radiation during treatment of advanced stages of common cancers such as lung, breast, and esophagus. However, symptomatic radiation esophagitis requiring endoscopic and histologic evaluation occurs quite rarely, affecting less than 1% of patients receiving radiation treatment. Symptoms occur acutely, generally within the first 2 months. Patients typically present with nonspecific symptoms such as dysphagia and odynophagia. Endoscopic changes such as erythema and ulceration are also nonspecific and nondiagnostic. Biopsies from affected areas show variable inflammatory changes and radiation-related atypia of endothelial and stromal cells. Such atypia mimics cytomegalovirus cytopathic changes, which are ruled out through absence of immunostaining. Radiation esophagitis is thus clinically unsuspected and endoscopically and histologically quite different from the more common and familiar radiation proctitis for which angioectasia is the predominant finding. PMID- 26030255 TI - Performance Boost in Industrial Multifilamentary Nb3Sn Wires due to Radiation Induced Pinning Centers. AB - We report non-Cu critical current densities of 4. 09 ? 10(9) A/m(2) at 12 T and 2.27 ? 10(9) A/m(2) at 15 T obtained from transport measurements on a Ti-alloyed RRP Nb3Sn wire after irradiation to a fast neutron fluence of 8.9 ? 10(21) m(-2). These values are to our knowledge unprecedented in multifilamentary Nb3Sn, and they correspond to a Jc enhancement of approximately 60% relative to the unirradiated state. Our magnetometry data obtained on short wire samples irradiated to fast neutron fluences of up to 2.5 ? 10(22) m(-2) indicate the possibility of an even better performance, whereas earlier irradiation studies on bronze-processed Nb3Sn wires with a Sn content further from stoichiometry attested a decline of the critical current density at such high fluences. We show that radiation induced point-pinning centers rather than an increase of the upper critical field are responsible for this Jc enhancement, and argue that these results call for further research on pinning landscape engineering. PMID- 26030256 TI - Outcomes of predialysis nephrology care in elderly patients beginning to undergo dialysis. AB - BACKGROUND: The proportion of elderly patients beginning to undergo dialysis is increasing globally. Whether early referral (ER) of elderly patients is associated with favorable outcomes remains under debate. We investigated the influence of referral timing on the mortality of elderly patients. METHODS: We retrospectively assessed mortality in 820 patients aged >=70 years with end-stage renal disease (ESRD) who initiated hemodialysis at a tertiary university hospital between 2000 and 2010. Mortality data was obtained from the time of dialysis initiation until December 2010. We assigned patients to one of two groups according to the time of their first encounters with nephrologists: ER (>= 3 months) and late referral (LR; < 3 months). RESULTS: During a mean follow-up period of 25.1 months, the ER group showed a 24% reduced risk of long-term mortality relative to the LR group (HR = 0.760, P = 0.009). Rate of reduction in 90-day mortality for ER patients was 58% (HR = 0.422, P=0.012). However, the statistical significance of the difference in mortality rates between ER and LR group was not observed across age groups after 90 days. Old age, LR, central venous catheter, high white blood cell count and corrected Ca level, and lower levels of albumin, creatinine, hemoglobin, and sodium were significantly associated with increased risk of mortality. CONCLUSIONS: Timely referral was also associated with reduced mortality in elderly ESRD patients who initiated hemodialysis. In particular, the initial 90-day mortality reduction in ER patients contributed to mortality differences during the follow-up period. PMID- 26030257 TI - Autocrine Regulation of UVA-Induced IL-6 Production via Release of ATP and Activation of P2Y Receptors. AB - Extracellular nucleotides, such as ATP, are released from cells in response to various stimuli and act as intercellular signaling molecules through activation of P2 receptors. Exposure to the ultraviolet radiation A (UVA) component of sunlight causes molecular and cellular damage, and in this study, we investigated the involvement of extracellular nucleotides and P2 receptors in the UVA-induced cellular response. Human keratinocyte-derived HaCaT cells were irradiated with a single dose of UVA (2.5 J/cm2), and ATP release and interleukin (IL)-6 production were measured. ATP was released from cells in response to UVA irradiation, and the release was blocked by pretreatment with inhibitors of gap junction hemichannels or P2X7 receptor antagonist. IL-6 production was increased after UVA irradiation, and this increase was inhibited by ecto-nucleotidase or by antagonists of P2Y11 or P2Y13 receptor. These results suggest that UVA-induced IL 6 production is mediated by release of ATP through hemichannels and P2X7 receptor, followed by activation of P2Y11 and P2Y13 receptors. Interestingly, P2Y11 and P2Y13 were associated with the same pattern of IL-6 production, though they trigger different intracellular signaling cascades: Ca2+-dependent and PI3K dependent, respectively. Thus, IL-6 production in response to UVA-induced ATP release involves at least two distinct pathways, mediated by activation of P2Y11 and P2Y13 receptors. PMID- 26030258 TI - Sulfide Intrusion and Detoxification in the Seagrass Zostera marina. AB - Gaseous sulfide intrusion into seagrasses growing in sulfidic sediments causes little or no harm to the plant, indicating the presence of an unknown sulfide tolerance or detoxification mechanism. We assessed such mechanism in the seagrass Zostera marina in the laboratory and in the field with scanning electron microscopy coupled to energy dispersive X-ray spectroscopy, chromatographic and spectrophotometric methods, and stable isotope tracing coupled with a mass balance of sulfur compounds. We found that Z. marina detoxified gaseous sediment derived sulfide through incorporation and that most of the detoxification occurred in underground tissues, where sulfide intrusion was greatest. Elemental sulfur was a major detoxification compound, precipitating on the inner wall of the aerenchyma of underground tissues. Sulfide was metabolized into thiols and entered the plant sulfur metabolism as well as being stored as sulfate throughout the plant. We conclude that avoidance of sulfide exposure by reoxidation of sulfide in the rhizosphere or aerenchyma and tolerance of sulfide intrusion by incorporation of sulfur in the plant are likely major survival strategies of seagrasses in sulfidic sediments. PMID- 26030259 TI - Atomistic spin dynamics and surface magnons. AB - Atomistic spin dynamics simulations have evolved to become a powerful and versatile tool for simulating dynamic properties of magnetic materials. It has a wide range of applications, for instance switching of magnetic states in bulk and nano-magnets, dynamics of topological magnets, such as skyrmions and vortices and domain wall motion. In this review, after a brief summary of the existing investigation tools for the study of magnons, we focus on calculations of spin wave excitations in low-dimensional magnets and the effect of relativistic and temperature effects in such structures. In general, we find a good agreement between our results and the experimental values. For material specific studies, the atomistic spin dynamics is combined with electronic structure calculations within the density functional theory from which the required parameters are calculated, such as magnetic exchange interactions, magnetocrystalline anisotropy, and Dzyaloshinskii-Moriya vectors. PMID- 26030262 TI - A Standardized Protocol for the Treatment of Early Postoperative Stiffness following Total Knee Arthroplasty. AB - Manipulation under anesthesia (MUA) and continuous passive motion (CPM) are commonly used to optimize range of motion (ROM) for the treatment of early stiffness following total knee arthroplasty (TKA). The addition of systemic glucocorticoid as an adjunct to a standardized protocol of MUA and aggressive CPM treatment is outlined. Results demonstrate an average postoperative increase in knee ROM of 45 degrees in 78 TKAs at 10 weeks from MUA procedure with no complications reported. PMID- 26030260 TI - Hypoxia Inducible Factors Modulate Mitochondrial Oxygen Consumption and Transcriptional Regulation of Nuclear-Encoded Electron Transport Chain Genes. AB - Hypoxia inducible factor-1 (HIF1) is a stress-responsive nuclear transcription factor that is activated with a decrease in oxygen availability. HIF1 regulates the expression of genes involved in a cell's adaptation to hypoxic stress, including those with mitochondrial specific function. To gain a more comprehensive understanding of the role of HIF1 in mitochondrial homeostasis, we studied the link between hypoxia, HIF1 transactivation, and electron transport chain (ETC) function. We established immortalized mouse embryonic fibroblasts (MEFs) for HIF1alpha wild-type (WT) and null cells and tested whether HIF1alpha regulates mitochondrial respiration by modulating gene expressions of nuclear encoded ETC components. High-throughput quantitative real-time polymerase chain reaction was performed to screen nuclear-encoded mitochondrial genes related to the ETC to identify those whose regulation was HIF1alpha-dependent. Our data suggest that HIF1alpha regulates transcription of cytochrome c oxidase (CcO) heart/muscle isoform 7a1 (Cox7a1) under hypoxia, where it is induced 1.5-2.5 fold, whereas Cox4i2 hypoxic induction was HIF1alpha-independent. We propose that adaptation to hypoxic stress of CcO as the main cellular oxygen consumer is mediated by induction of hypoxia-sensitive tissue-specific isoforms. We suggest that HIF1 plays a central role in maintaining homeostasis in cellular respiration during hypoxic stress via regulation of CcO activity. PMID- 26030263 TI - Polyethylene Wear in Knee Arthroplasty. AB - Polyethylene (PE) wear and osteolysis are common causes for late revisions of knee arthroplasties. Several implant and surgical factors have been implicated in contributing to the development of wear, such as type of bearing surface used, inaccurate articular geometry, and poor knee kinematics. In addition, patient related factors, such as younger age and higher activity levels, may also contribute to wear. Our purpose was to evaluate and compare the effect of these variables on wear rates following knee arthroplasty. Recently, technological advancements have been aimed at reducing the incidence of wear by improving the PE manufacturing process, creating implants that minimize contact stresses, and refining our surgical techniques. Furthermore, the development of newer highly cross-linked PEs (HXLPEs) and the introduction of additives, such as vitamin E, to the PEs may improve overall implant survivorship. As a result, with the advent of newer implant and PE designs, wear is no longer the most common cause of early failure, though it remains an important factor in limiting long-term implant survivorship. However, there are a few clinical studies evaluating the long-term outcomes of newer HXLPEs and implant designs, with further evaluations necessary to determine the best implant-PE combination for improved knee arthroplasty survivorship. PMID- 26030261 TI - Fever as an initial manifestation of enthesitis-related arthritis subtype of juvenile idiopathic arthritis: retrospective study. AB - OBJECTIVE: We wished to determine the prevalence of fever as one of the first symptoms of the enthesitis-related arthritis (ERA) subtype of juvenile idiopathic arthritis. Also, we wished to ascertain if ERA patients with fever at disease onset differed from those without fever. METHODS: Consecutive cases of ERA were diagnosed and followed in a retrospective observational study from 1998 to 2013. Information about clinical/laboratory data, medications, magnetic resonance imaging (MRI), and disease activity during the study period was also recorded. RESULTS: A total of 146 consecutive ERA patients were assessed. Among them, 52 patients (35.6%) had fever as one of the first symptoms at disease onset. Compared with ERA patients without fever at disease onset, patients with fever had significantly more painful joints (3.5 vs. 2.8), more swollen joints (1.1 vs. 0.8), and more enthesitis (1.0 vs. 0.4) (p<0.05 for all comparisons). Patients with fever had significantly higher mean values of erythrocyte sedimentation rate, C-reactive protein, platelet count, and child health assessment questionnaire (CHAQ) scores (40.8 vs. 26.4 mm/h; 20.7 vs. 9.7 mg/dL; 353.2*109/L vs. 275.6*109/L; 1.0 vs. 0.8, respectively; all p<0.05). During two-year follow up, CHAQ score, number of flares, as well as the number of patients treated with oral non-steroidal anti-inflammatory drugs, corticosteroids and combination therapy with disease-modifying anti-rheumatic drugs, were significantly higher in ERA patients with fever. CONCLUSIONS: Fever was a frequent manifestation of ERA. ERA patients with fever had more active disease at disease onset and poorer outcomes than ERA patients without fever. PMID- 26030264 TI - Oral Appliance Therapy in Patients With Daytime Sleepiness and Snoring or Mild to Moderate Sleep Apnea: A Randomized Clinical Trial. AB - IMPORTANCE: Oral appliances that move the mandible forward during sleep are suggested as treatment for mild to moderate obstructive sleep apnea. OBJECTIVE: To test whether an adjustable, custom-made oral appliance improves daytime sleepiness and quality of life in patients with daytime sleepiness and snoring or mild to moderate obstructive sleep apnea. DESIGN, SETTING, AND PARTICIPANTS: Ninety-six patients with daytime sleepiness and an apnea-hypopnea index (AHI) lower than 30 were included in a randomized, placebo-controlled, parallel trial in Umea, Sweden, from May 2007 through August 2011. INTERVENTIONS: Four months' intervention with an oral appliance or a placebo device. MAIN OUTCOMES AND MEASURES: Daytime sleepiness was measured with the Epworth Sleepiness Scale, the Karolinska Sleepiness Scale, and the Oxford Sleep Resistance (OSLER) test. Quality of life was assessed with the Short-Form 36-Item Health Survey (SF-36) and the Functional Outcomes of Sleep Questionnaire (FOSQ). Secondary outcomes included the apnea-hypopnea index, headaches, symptoms of restless legs, and insomnia. RESULTS: Oral appliance therapy was not associated with improvements in daytime sleepiness from baseline to 4-month follow-up when compared with the placebo device; Epworth score >10: 53% at baseline to 24% at follow-up for the oral appliance group vs 54% at baseline to 40% at follow-up for the placebo device group, P = .11; median (IQR) for Karolinska score >=7/wk: 10 (8 to 14) at baseline to 7 (4 to 9) at follow-up for the oral appliance group vs 12 (6 to 15) at baseline to 8 (5 to 12) at follow-up for the placebo device group, P = .11; mean between-group difference in OSLER test, -2.4 min (95% CI, -6.3 to 1.4). The mean between-group difference for the total FOSQ score was insignificant (-1.2 [95% CI, -2.5 to 0.1]). No domain of the SF-36 differed significantly between the groups. The AHI was below 5 in 49% of patients using the active appliance and in 11% using placebo, with an odds ratio of 7.8 (95% CI, 2.6-23.5) and a number needed to treat of 3. Snoring (P < .001) and symptoms of restless legs (P = .02) were less frequent when using the oral appliance vs placebo, but this did not apply to headache or insomnia. CONCLUSIONS AND RELEVANCE: A custom-made, adjustable oral appliance reduces obstructive sleep apnea, snoring, and possibly restless legs without effects on daytime sleepiness and quality of life among patients with daytime sleepiness and snoring or mild to moderate sleep apnea. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00477009. PMID- 26030265 TI - Burkholderia cenocepacia and Salmonella enterica ArnT proteins that transfer 4 amino-4-deoxy-l-arabinose to lipopolysaccharide share membrane topology and functional amino acids. AB - We recently demonstrated that incorporation of 4-amino-4-deoxy-l-arabinose (l Ara4N) to the lipid A moiety of lipopolysaccharide (LPS) is required for transport of LPS to the outer membrane and viability of the Gram-negative bacterium Burkholderia cenocepacia. ArnT is a membrane protein catalyzing the transfer of l-Ara4N to the LPS molecule at the periplasmic face of the inner membrane, but its topology and mechanism of action are not well characterized. Here, we elucidate the topology of ArnT and identify key amino acids that likely contribute to its enzymatic function. PEGylation assays using a cysteineless version of ArnT support a model of 13 transmembrane helices and a large C terminal region exposed to the periplasm. The same topological configuration is proposed for the Salmonella enterica serovar Typhimurium ArnT. Four highly conserved periplasmic residues in B. cenocepacia ArnT, tyrosine-43, lysine-69, arginine-254 and glutamic acid-493, were required for activity. Tyrosine-43 and lysine-69 span two highly conserved motifs, (42)RYA(44) and (66)YFEKP(70), that are found in ArnT homologues from other species. The same residues in S. enterica ArnT are also needed for function. We propose these aromatic and charged amino acids participate in either undecaprenyl phosphate-l-Ara4N substrate recognition or transfer of l-Ara4N to the LPS. PMID- 26030266 TI - The Evolution of Carbon Nanotube Network Structure in Unidirectional Nanocomposites Resolved by Quantitative Electron Tomography. AB - Carbon nanotube (CNT) reinforced polymers are next-generation, high-performance, multifunctional materials with a wide array of promising applications. The successful introduction of such materials is hampered by the lack of a quantitative understanding of process-structure-property relationships. These relationships can be developed only through the detailed characterization of the nanoscale reinforcement morphology within the embedding medium. Here, we reveal the three-dimensional (3D) nanoscale morphology of high volume fraction (V(f)) aligned CNT/epoxy-matrix nanocomposites using energy-filtered electron tomography. We present an automated phase-identification method for fast, accurate, representative rendering of the CNT spatial arrangement in these low contrast bimaterial systems. The resulting nanometer-scale visualizations provide quantitative information on the evolution of CNT morphology and dispersion state with increasing V(f), including network structure, CNT alignment, bundling and waviness. The CNTs are observed to exhibit a nonlinear increase in bundling and alignment and a decrease in waviness as a function of increasing V(f). Our findings explain previously observed discrepancies between the modeled and measured trends in bulk mechanical, electrical and thermal properties. The techniques we have developed for morphological quantitation are applicable to many low-contrast material systems. PMID- 26030267 TI - Feeding History Affects Intraguild Interactions between Harmonia axyridis (Coleoptera: Coccinellidae) and Episyrphus balteatus (Diptera: Syrphidae). AB - While the effect of several factors such as predator and prey size, morphology and developmental stage on intraguild predation (IGP) is widely investigated, little is known about the influence of diet on the occurrence and outcome of IGP. In the present study, the effect of the diet experienced during larval development on IGP between the ladybird Harmonia axyridis and the syrphid Episyrphus balteatus is investigated. Four diets were tested for H. axyridis: eggs of the Mediterranean flour moth Ephestia kuehniella, pea aphids, Acyrthosiphon pisum, in an ad libitum amount, pea aphids in a limited amount, and honey bee pollen. For E. balteatus only the two aphid diets were tested. First, experiments were performed to determine the quality of the various diets for development of both predators. Second, IGP experiments between H. axyridis and E. balteatus were performed both in Petri dishes and on potted pepper plants. The diet of both species influenced the incidence of IGP between H. axyridis and E. balteatus both in Petri dishes and on potted plants. In general, smaller larvae of H. axyridis (those fed on poor or restricted diet) fed more on hoverflies than large (well-nourished) ladybird larvae. Further, poorly nourished (smaller) larvae of E. balteatus were more susceptible to predation than well-fed (larger) hoverfly larvae. The observed effects were not only due to the lower fitness of larvae of both predators reared on an inferior quality diet but also to changes in predator behaviour. The results from this study show that IGP interactions are influenced by a multitude of factors, including feeding history of the organisms involved, and emphasize the importance of taking these factors into account in order to fully understand the ecological relevance of IGP. PMID- 26030268 TI - Dedicated time for deliberate practice: one emergency medicine program's approach to point-of-care ultrasound (PoCUS) training. AB - Point-of-care ultrasound (PoCUS) has become an essential skill in the practice of emergency medicine (EM). Various EM residency programs now require competency in basic PoCUS applications. The education literature suggests that deliberate practice is necessary for skill acquisition and mastery. We used an educational theory, Ericsson's model of deliberate practice, to create a PoCUS curriculum for our Royal College of Physicians and Surgeons of Canada EM residency. Although international recommendations around curriculum requirements exist, this will be one of the first papers to describe the implementation of a specific PoCUS training program. This paper details the features of the program and lessons learned during its initial 3 years. Sharing this experience may serve as a nidus for scholarly discussion around how to best approach medical education in this area. PMID- 26030269 TI - 1,2-Diphosphonium dication: a strong P-based Lewis acid in frustrated lewis pair (FLP)-activations of B-H, Si-H, C-H, and H-H bonds. AB - A highly Lewis acidic diphosphonium dication [(C10H6)(Ph2P)2](2+) (1), in combination with a Lewis basic phosphine, acts as a purely phosphorus-based frustrated Lewis pair (FLP) and abstracts hydride from [HB(C6F5)3](-) and Et3SiH demonstrating the remarkable hydridophilicity of 1. The P-based FLP is also shown to activate H2 and C-H bonds. PMID- 26030270 TI - Optimal Length of Low Reynolds Number Nanopropellers. AB - Locomotion in fluids at the nanoscale is dominated by viscous drag. One efficient propulsion scheme is to use a weak rotating magnetic field that drives a chiral object. From bacterial flagella to artificial drills, the corkscrew is a universally useful chiral shape for propulsion in viscous environments. Externally powered magnetic micro- and nanomotors have been recently developed that allow for precise fuel-free propulsion in complex media. Here, we combine analytical and numerical theory with experiments on nanostructured screw propellers to show that the optimal length is surprisingly short-only about one helical turn, which is shorter than most of the structures in use to date. The results have important implications for the design of artificial actuated nano- and micropropellers and can dramatically reduce fabrication times, while ensuring optimal performance. PMID- 26030271 TI - A metagenomic survey of viral abundance and diversity in mosquitoes from Hubei province. AB - Mosquitoes as one of the most common but important vectors have the potential to transmit or acquire a lot of viruses through biting, however viral flora in mosquitoes and its impact on mosquito-borne disease transmission has not been well investigated and evaluated. In this study, the metagenomic techniquehas been successfully employed in analyzing the abundance and diversity of viral community in three mosquito samples from Hubei, China. Among 92,304 reads produced through a run with 454 GS FLX system, 39% have high similarities with viral sequences belonging to identified bacterial, fungal, animal, plant and insect viruses, and 0.02% were classed into unidentified viral sequences, demonstrating high abundance and diversity of viruses in mosquitoes. Furthermore, two novel viruses in subfamily Densovirinae and family Dicistroviridae were identified, and six torque tenosus virus1 in family Anelloviridae, three porcine parvoviruses in subfamily Parvovirinae and a Culex tritaeniorhynchus rhabdovirus in Family Rhabdoviridae were preliminarily characterized. The viral metagenomic analysis offered us a deep insight into the viral population of mosquito which played an important role in viral initiative or passive transmission and evolution during the process. PMID- 26030273 TI - Ineffective degradation of immunogenic gluten epitopes by currently available digestive enzyme supplements. AB - BACKGROUND: Due to the high proline content of gluten molecules, gastrointestinal proteases are unable to fully degrade them leaving large proline-rich gluten fragments intact, including an immunogenic 33-mer from alpha-gliadin and a 26-mer from gamma-gliadin. These latter peptides can trigger pro-inflammatory T cell responses resulting in tissue remodeling, malnutrition and a variety of other complications. A strict lifelong gluten-free diet is currently the only available treatment to cope with gluten intolerance. Post-proline cutting enzymes have been shown to effectively degrade the immunogenic gluten peptides and have been proposed as oral supplements. Several existing digestive enzyme supplements also claim to aid in gluten degradation. Here we investigate the effectiveness of such existing enzyme supplements in comparison with a well characterized post-proline cutting enzyme, Prolyl EndoPeptidase from Aspergillus niger (AN-PEP). METHODS: Five commercially available digestive enzyme supplements along with purified digestive enzymes were subjected to 1) enzyme assays and 2) mass spectrometric identification. Gluten epitope degradation was monitored by 1) R5 ELISA, 2) mass spectrometric analysis of the degradation products and 3) T cell proliferation assays. FINDINGS: The digestive enzyme supplements showed comparable proteolytic activities with near neutral pH optima and modest gluten detoxification properties as determined by ELISA. Mass spectrometric analysis revealed the presence of many different enzymes including amylases and a variety of different proteases with aminopeptidase and carboxypeptidase activity. The enzyme supplements leave the nine immunogenic epitopes of the 26-mer and 33-mer gliadin fragments largely intact. In contrast, the pure enzyme AN-PEP effectively degraded all nine epitopes in the pH range of the stomach at much lower dose. T cell proliferation assays confirmed the mass spectrometric data. CONCLUSION: Currently available digestive enzyme supplements are ineffective in degrading immunogenic gluten epitopes. PMID- 26030272 TI - Mitochondrial ribosome assembly in health and disease. AB - The ribosome is a structurally and functionally conserved macromolecular machine universally responsible for catalyzing protein synthesis. Within eukaryotic cells, mitochondria contain their own ribosomes (mitoribosomes), which synthesize a handful of proteins, all essential for the biogenesis of the oxidative phosphorylation system. High-resolution cryo-EM structures of the yeast, porcine and human mitoribosomal subunits and of the entire human mitoribosome have uncovered a wealth of new information to illustrate their evolutionary divergence from their bacterial ancestors and their adaptation to synthesis of highly hydrophobic membrane proteins. With such structural data becoming available, one of the most important remaining questions is that of the mitoribosome assembly pathway and factors involved. The regulation of mitoribosome biogenesis is paramount to mitochondrial respiration, and thus to cell viability, growth and differentiation. Moreover, mutations affecting the rRNA and protein components produce severe human mitochondrial disorders. Despite its biological and biomedical significance, knowledge on mitoribosome biogenesis and its deviations from the much-studied bacterial ribosome assembly processes is scarce, especially the order of rRNA processing and assembly events and the regulatory factors required to achieve fully functional particles. This article focuses on summarizing the current available information on mitoribosome assembly pathway, factors that form the mitoribosome assembly machinery, and the effect of defective mitoribosome assembly on human health. PMID- 26030274 TI - Fitness Consequences of Advanced Ancestral Age over Three Generations in Humans. AB - A rapid rise in age at parenthood in contemporary societies has increased interest in reports of higher prevalence of de novo mutations and health problems in individuals with older fathers, but the fitness consequences of such age effects over several generations remain untested. Here, we use extensive pedigree data on seven pre-industrial Finnish populations to show how the ages of ancestors for up to three generations are associated with fitness traits. Individuals whose fathers, grandfathers and great-grandfathers fathered their lineage on average under age 30 were ~13% more likely to survive to adulthood than those whose ancestors fathered their lineage at over 40 years. In addition, females had a lower probability of marriage if their male ancestors were older. These findings are consistent with an increase of the number of accumulated de novo mutations with male age, suggesting that deleterious mutations acquired from recent ancestors may be a substantial burden to fitness in humans. However, possible non-mutational explanations for the observed associations are also discussed. PMID- 26030276 TI - Plasmonic polymers with strong chiroptical response for sensing molecular chirality. AB - We report on the chiroptical transfer and amplification effect observed in plasmonic polymers consisting of achiral gold nanorod monomers linked by cysteine chiral molecules in an end-to-end fashion. A new strategy for controlling the hot spots based circular dichroism (CD)-active sites in plasmonic polymers was developed to realize tailored and reproducible chiroptical activity in a controlled way. We showed that by regulating the bond angles between adjacent nanorods and the degree of polymerization in the linear plasmonic polymer, weak molecular chirality in the ultraviolet spectral region can be amplified by more than two orders of magnitude via the induced CD response in the visible/near infrared region. We demonstrate that this plasmonic polymer can be used to provide not only the Raman "fingerprint" information for identifying the molecular identity but also the CD signatures for (i) resolving the enantiomeric pairs of cysteine molecules at a small quantity level, and (ii) quantifying the enantiomeric purity of the chiral analytes. Chiral analyses by chiroptically responsive plasmonic polymers may find important applications in bioscience and biomedicine. PMID- 26030275 TI - Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model. AB - Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA. PMID- 26030277 TI - The Wnt5a-Ror2 axis promotes the signaling circuit between interleukin-12 and interferon-gamma in colitis. AB - Wnt5a, which regulates various cellular functions in Wnt signaling, is involved in inflammatory responses, however the mechanism is not well understood. We examined the role of Wnt5a signaling in intestinal immunity using conditional knockout mice for Wnt5a and its receptor Ror2. Removing Wnt5a or Ror2 in adult mice suppressed dextran sodium sulfate (DSS)-induced colitis. It also attenuated the DSS-dependent increase in inflammatory cytokine production and decreased interferon-gamma (IFN-gamma)-producing CD4(+) Th1 cell numbers in the colon. Wnt5a was highly expressed in stromal fibroblasts in ulcerative lesions in the DSS-treated mice and inflammatory bowel disease patients. Dendritic cells (DCs) isolated from the colon of Wnt5a and Ror2 deficient mice reduced the ability to differentiate naive CD4(+) T cells to IFN-gamma-producing CD4(+) Th1 cells. In vitro experiments demonstrated that the Wnt5a-Ror2 signaling axis augmented the DCs priming effect of IFN-gamma, leading to enhanced lipopolysaccharide (LPS) induced interleukin (IL)-12 expression. Taken together, these results suggest that Wnt5a promotes IFN-gamma signaling, leading to IL-12 expression in DCs, and thereby inducing Th1 differentiation in colitis. PMID- 26030279 TI - Correction: enhancing anti-tumor efficacy of Doxorubicin by non-covalent conjugation to gold nanoparticles - in vitro studies on feline fibrosarcoma cell lines. PMID- 26030278 TI - Pre-emergency-department care-seeking patterns are associated with the severity of presenting condition for emergency department visit and subsequent adverse events: a timeframe episode analysis. AB - BACKGROUND: Many patients treated in Emergency Department (ED) visits can be treated at primary or urgent care sectors, despite the fact that a number of ED visitors seek other forms of care prior to an ED visit. However, little is known regarding how the pre-ED activity episodes affect ED visits. OBJECTIVES: We investigated whether care-seeking patterns involve the use of health care services of various types prior to ED visits and examined the associations of these patterns with the severity of the presenting condition for the ED visit (EDVS) and subsequent events. METHODS: This retrospective observational study used administrative data on beneficiaries of the universal health care insurance program in Taiwan. The service type, treatment capacity, and relative diagnosis were used to classify pre-ED visits into 8 care types. Frequent pattern analysis was used to identify sequential care-seeking patterns and to classify 667,183 eligible pre-ED episodes into patterns. Generalized linear models were developed using generalized estimating equations to examine the associations of these patterns with EDVS and subsequent events. RESULTS: The results revealed 17 care seeking patterns. The EDVS and likelihood of subsequent events significantly differed among patterns. The ED severity index of patterns differ from patterns seeking directly ED care (coefficients ranged from -0.05 to 0.13), and the odds ratios for the likelihood of subsequent ED visits and hospitalization ranged from 1.18 to 1.86 and 1.16 to 2.84, respectively. CONCLUSIONS: The pre-ED care-seeking patterns differ in severity of presenting condition and subsequent events that may represent different causes of ED visit. Future health policy maker may adopt different intervention strategies for targeted population to reduce unnecessary ED visit effectively. PMID- 26030280 TI - Stable Isotope Models Predict Foraging Habitat of Northern Fur Seals (Callorhinus ursinus) in Alaska. AB - We developed models to predict foraging habitat of adult female northern fur seals (Callorhinus ursinus) using stable carbon (delta13C) and nitrogen (delta15N) isotope values from plasma and red blood cells. Binomial generalized linear mixed models were developed using blood isotope samples collected from 35 adult female fur seals on three breeding colonies in Alaska during July-October 2006. Satellite location and dive data were used to define habitat use in terms of the proportion of time spent or dives made in different oceanographic/bathymetric domains. For both plasma and red blood cells, the models accurately predicted habitat use for animals that foraged exclusively off or on the continental shelf. The models did not perform as well in predicting habitat use for animals that foraged in both on- and off-shelf habitat; however, sample sizes for these animals were small. Concurrently collected scat, fatty acid, and dive data confirmed that the foraging differences predicted by isotopes were associated with diet differences. Stable isotope samples, dive data, and GPS location data collected from an additional 15 females during August-October 2008 validated the effective use of the models across years. Little within year variation in habitat use was indicated from the comparison between stable isotope values from plasma (representing 1-2 weeks) and red blood cells (representing the prior few months). Constructing predictive models using stable isotopes provides an effective means to assess habitat use at the population level, is inexpensive, and can be applied to other marine predators. PMID- 26030282 TI - Study of displacement efficiency and flow behavior of foamed gel in non homogeneous porous media. AB - Field trials have demonstrated that foamed gel is a very cost-effective technology for profile modification and water shut-off. However, the mechanisms of profile modification and flow behavior of foamed gel in non-homogeneous porous media are not yet well understood. In order to investigate these mechanisms and the interactions between foamed gel and oil in porous media, coreflooding and pore-scale visualization waterflooding experiments were performed in the laboratory. The results of the coreflooding experiment in non-homogeneous porous media showed that the displacement efficiency improved by approximately 30% after injecting a 0.3 pore volume of foamed gel, and was proportional to the pore volumes of the injected foamed gel. Additionally, the mid-high permeability zone can be selectively plugged by foamed gel, and then oil located in the low permeability zone will be displaced. The visualization images demonstrated that the amoeba effect and Jamin effect are the main mechanisms for enhancing oil recovery by foamed gel. Compared with conventional gel, a unique benefit of foamed gel is that it can pass through micropores by transforming into arbitrary shapes without rupturing, this phenomenon has been named the amoeba effect. Additionally, the stability of foam in the presence of crude oil also was investigated. Image and statistical analysis showed that these foams boast excellent oil resistance and elasticity, which allows them to work deep within formations. PMID- 26030281 TI - A molecular smart surface for spatio-temporal studies of cell mobility. AB - Active migration in both healthy and malignant cells requires the integration of information derived from soluble signaling molecules with positional information gained from interactions with the extracellular matrix and with other cells. How a cell responds and moves involves complex signaling cascades that guide the directional functions of the cytoskeleton as well as the synthesis and release of proteases that facilitate movement through tissues. The biochemical events of the signaling cascades occur in a spatially and temporally coordinated manner then dynamically shape the cytoskeleton in specific subcellular regions. Therefore, cell migration and invasion involve a precise but constantly changing subcellular nano-architecture. A multidisciplinary effort that combines new surface chemistry and cell biological tools is required to understand the reorganization of cytoskeleton triggered by complex signaling during migration. Here we generate a class of model substrates that modulate the dynamic environment for a variety of cell adhesion and migration experiments. In particular, we use these dynamic substrates to probe in real-time how the interplay between the population of cells, the initial pattern geometry, ligand density, ligand affinity and integrin composition affects cell migration and growth. Whole genome microarray analysis indicates that several classes of genes ranging from signal transduction to cytoskeletal reorganization are differentially regulated depending on the nature of the surface conditions. PMID- 26030283 TI - Hepatitis C Virus Nonstructural 3/4A Protein Dampens Inflammation and Contributes to Slow Fibrosis Progression during Chronic Fibrosis In Vivo. AB - HCV infection typically induces liver injury and inflammation, which appears to be responsible for the associated fibrogenesis. To date, the mechanism underlying the different rates of disease progression remains unclear. The aim of the study is to understand the possible role of the HCV non-structural (NS) 3/4A protein in the fibrosis progression. We used NS3/4A-expressing transgenic mice (NS3/4A-Tg) to accomplish the goals of the study. Different stages of liver fibrosis were induced in wild-type and NS3/4A-Tg mice by single carbon tetrachloride (acute) or multiple injections for 4 (intermediate) or 8 (chronic) weeks. Fibrotic parameters, inflammatory responses and hepatocyte turnover were extensively examined. Hepatic expression of HCV NS3/4A did not induce spontaneous liver damage. However, NS3/4A expression exerted contrasting effects during acute and chronic liver damage. During early fibrogenesis and intermediate fibrosis (4 weeks), NS3/4A-Tg mice exhibited enhanced liver damage whereas reduced fibrosis was observed in NS3/4A-Tg during chronic liver fibrosis (8 weeks). Furthermore, attenuated inflammation was observed in NS3/4A-Tg during chronic fibrosis with increase in M2 macrophages, hepatocyte proliferation, decreased hepatocyte apoptosis and decreased ductular reaction. In conclusion, during early fibrogenesis, HCV NS3/4A contributes to liver damage. While, during chronic liver fibrosis, NS3/4A dampens inflammation and induces hepatocyte regeneration thereby contributing to slow fibrosis progression to promote its survival or persistence. PMID- 26030284 TI - Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion. AB - The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status. PMID- 26030285 TI - Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. AB - Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of alphabeta-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of beta tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability. PMID- 26030286 TI - An aberrant splice acceptor site due to a novel intronic nucleotide substitution in MSX1 gene is the cause of congenital tooth agenesis in a Japanese family. AB - Congenital tooth agenesis is caused by mutations in the MSX1, PAX9, WNT10A, or AXIN2 genes. Here, we report a Japanese family with nonsyndromic tooth agenesis caused by a novel nucleotide substitution in the intronic region between exons 1 and 2 of the MSX1 gene. Because the mutation is located 9 bp before exon 2 (c.452 9G>A), we speculated that the nucleotide substitution would generate an abnormal splice site. Using cDNA analysis of an immortalized patient blood cell, we confirmed that an additional 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). We then studied the subcellular localization of truncated MSX1 protein in COS cells, and observed that it had a whole cell distribution more than a nuclear localization, compared to that of wild-type protein. This result suggests a deletion of the nuclear localization signal, which is mapped to the MSX1 homeodomain. These results indicate that this novel intronic nucleotide substitution is the cause of tooth agenesis in this family. To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations. We here report a rare case of an intronic mutation of the MSX1 gene responsible for human tooth agenesis. In addition, the missing tooth patterns were slightly but significantly different between an affected monozygotic twin pair of this family, showing that epigenetic or environmental factors also affect the phenotypic variations of missing teeth among patients with nonsyndromic tooth agenesis caused by an MSX1 haploinsufficiency. PMID- 26030287 TI - Suitable environmental ranges for potential coral reef habitats in the tropical ocean. AB - Coral reefs are found within a limited range of environmental conditions or tolerance limits. Estimating these limits is a critical prerequisite for understanding the impacts of climate change on the biogeography of coral reefs. Here we used the diagnostic model ReefHab to determine the current environmental tolerance limits for coral reefs and the global distribution of potential coral reef habitats as a function of six factors: temperature, salinity, nitrate, phosphate, aragonite saturation state, and light. To determine these tolerance limits, we extracted maximum and minimum values of all environmental variables in corresponding locations where coral reefs are present. We found that the global, annually averaged tolerance limits for coral reefs are 21.7-29.6 degrees C for temperature, 28.7-40.4 psu for salinity, 4.51 MUmol L-1 for nitrate, 0.63 MUmol L 1 for phosphate, and 2.82 for aragonite saturation state. The averaged minimum light intensity in coral reefs is 450 MUmol photons m-2 s-1. The global area of potential reef habitats calculated by the model is 330.5 * 103 km2. Compared with previous studies, the tolerance limits for temperature, salinity, and nutrients have not changed much, whereas the minimum value of aragonite saturation in coral reef waters has decreased from 3.28 to 2.82. The potential reef habitat area calculated with ReefHab is about 121*103 km2 larger than the area estimated from the charted reefs, suggesting that the growth potential of coral reefs is higher than currently observed. PMID- 26030288 TI - Characterising cytotoxic agent action as a function of the cell cycle using Fourier transform infrared microspectroscopy. AB - Fourier Transform Infrared (FTIR) micro-spectroscopy measurements were acquired to study infrared signatures of chemotherapeutic response as a function of the cell cycle. Renal carcinoma Caki-2 cells were exposed to IC50 doses of 5 fluorouracil and Paclitaxel for a period of 24 hours. The inherent cell cycle infrared signatures from untreated and drug-treated cells were successfully retrieved by the construction of a robust SVM able to discriminate the cell cycle phases of this cell line with an average accuracy of 83.7%. The overriding infrared signature observed relates to an apoptotic biochemical response that does not appear to be correlated with the events affected by the drugs' mode of action or the cell cycle. Since apoptosis is a well conserved mechanism among living species, these results suggest that both the stages of proliferation as well as the absence/presence of apoptosis need to be taken into account in order to elucidate the fine biochemical details revealing the immediate cellular response to the drug in order to assign reliable spectral patterns of drug action. PMID- 26030289 TI - Sensorimotor control of tracking movements at various speeds for stroke patients as well as age-matched and young healthy subjects. AB - There are aging- and stroke-induced changes on sensorimotor control in daily activities, but their mechanisms have not been well investigated. This study explored speed-, aging-, and stroke-induced changes on sensorimotor control. Eleven stroke patients (affected sides and unaffected sides) and 20 control subjects (10 young and 10 age-matched individuals) were enrolled to perform elbow tracking tasks using sinusoidal trajectories, which included 6 target speeds (15.7, 31.4, 47.1, 62.8, 78.5, and 94.2 deg/s). The actual elbow angle was recorded and displayed on a screen as visual feedback, and three indicators, the root mean square error (RMSE), normalized integrated jerk (NIJ) and integral of the power spectrum density of normalized speed (IPNS), were used to investigate the strategy of sensorimotor control. Both NIJ and IPNS had significant differences among the four groups (P<0.01), and the values were ranked in the following order: young controls < age-matched controls = 20 and <= 30 weeks) born from 1993 onward to residents of Nova Scotia were evaluated by the IWK Health Centre's Perinatal Follow-Up Program, and were entered in a database. Infants born to residents of Nova Scotia from January 1, 1993, to December 31, 2012, were included in this study. The incidences of IVH, PHH, and shunt surgery were calculated, basic demographic information was described, and chi-square test for trends over time was determined. RESULTS Of 1334 successfully resuscitated very preterm infants who survived to their initial screening ultrasound, 407 (31%) had an IVH, and 149 (11%) had an IVH Grade 3 or 4. No patients with IVH Grade 1 or 2 developed PHH. The percentage of very preterm infants with IVH Grade 3 or 4 has significantly increased over time (p = 0.013), as have the incidence of PHH and shunt surgery (p = 0.001 and p = 0.011, respectively) in infants with Grade 3 or 4 IVH. The proportion of patients with PHH receiving a shunt has not changed over time (p = 0.813). CONCLUSIONS The increasing incidence of high-grade IVH-and PHH and shunt surgery in infants with high-grade IVH-over time is worrisome. This study identifies a number of associated factors, but further research to identify preventable and treatable causal factors is warranted. PMID- 26030329 TI - Outcomes of intraventricular hemorrhage and posthemorrhagic hydrocephalus in a population-based cohort of very preterm infants born to residents of Nova Scotia from 1993 to 2010. AB - OBJECT Intraventicular hemorrhage (IVH) is a common complication of preterm birth, and the prognosis of IVH is incompletely characterized. The objective of this study was to describe the outcomes of IVH in a population-based cohort with minimal selection bias. METHODS All very preterm (>= 30 completed weeks) patients born in the province of Nova Scotia were included in a comprehensive database. This database was screened for infants born to residents of Nova Scotia from January 1, 1993, to December 31, 2010. Among very preterm infants successfully resuscitated at birth, the numbers of infants who died, were disabled, developed cerebral palsy, developed hydrocephalus, were blind, were deaf, or had cognitive/language scores assessed were analyzed by IVH grade. The relative risk of each outcome was calculated (relative to the risk for infants without IVH). RESULTS Grades 2, 3, and 4 IVH were significantly associated with an increased overall mortality, primarily in the neonatal period, and the risk increased with increasing grade of IVH. Grade 4 IVH was significantly associated with an increased risk of disability (RR 2.00, p < 0.001), and the disability appeared to be primarily due to cerebral palsy (RR 6.07, p < 0.001) and cognitive impairment (difference in mean MDI scores between Grade 4 IVH and no IVH: -19.7, p < 0.001). No infants with Grade 1 or 2 IVH developed hydrocephalus, and hydrocephalus and CSF shunting were not associated with poorer outcomes when controlling for IVH grade. CONCLUSIONS Grades 1 and 2 IVH have much better outcomes than Grades 3 or 4, including a 0% risk of hydrocephalus in the Grade 1 and 2 IVH cohort. Given the low risk of selection bias, the results of this study may be helpful in discussing prognosis with families of very preterm infants diagnosed with IVH. PMID- 26030330 TI - The association between Chiari malformation Type I, spinal syrinx, and scoliosis. AB - OBJECT Chiari malformation Type I (CM-I) is often found in patients with scoliosis. Most previous reports of CM-I and scoliosis have focused on patients with CM-I and a spinal syrinx. The relationship between CM-I and scoliosis in the absence of a syrinx has never been defined clearly. The authors sought to determine if there is an independent association between CM-I and scoliosis when controlling for syrinx status. METHODS The medical records of 14,118 consecutive patients aged <= 18 years who underwent brain or cervical spine MRI at a single institution in an 11-year span were reviewed to identify patients with CM-I, scoliosis, and/or syrinx. The relationship between CM-I and scoliosis was analyzed by using multivariate regression analysis and controlling for age, sex, CM-I status, and syrinx status. RESULTS In this cohort, 509 patients had CM-I, 1740 patients had scoliosis, and 243 patients had a spinal syrinx. The presence of CM-I, the presence of syrinx, older age, and female sex were each significantly associated with scoliosis in the univariate analysis. In the multivariate regression analysis, older age (OR 1.02 [95% CI 1.01-1.03]; p < 0.0001), female sex (OR 1.71 [95% CI 1.54-1.90]; p < 0.0001), and syrinx (OR 9.08 [95% CI 6.82-12.10]; p < 0.0001) were each independently associated with scoliosis. CM-I was not independently associated with scoliosis when controlling for these other variables (OR 0.99 [95% CI 0.79-1.29]; p = 0.9). CONCLUSIONS A syrinx was independently associated with scoliosis in a large pediatric population undergoing MRI. CM-I was not independently associated with scoliosis when controlling for age, sex, and syrinx status. Because CM-I is not independently associated with scoliosis, scoliosis should not necessarily be considered a symptom of low cerebellar tonsil position in patients without a syrinx. PMID- 26030331 TI - An unusual presentation of pediatric osteoblastoma in a patient with Klippel Trenaunay-Weber syndrome: case report. AB - Osteoblastoma is an uncommon primary bone tumor that usually presents as a painful lesion in a long bone or in the spine. Osteoblastoma has been reported only twice in the literature in conjunction with systemic fibromatosis. The authors report the case of an 8-year-old girl with suspected Klippel-Trenaunay Weber syndrome, a rare syndrome of systemic fibromatosis, who presented with a painless thoracic rib lesion that was found to be an osteoblastoma. PMID- 26030332 TI - The influence of lesion volume, perilesion resection volume, and completeness of resection on seizure outcome after resective epilepsy surgery for cortical dysplasia in children. AB - OBJECT Focal cortical dysplasia (FCD) is one of the most common causes of intractable epilepsy leading to surgery in children. The predictors of seizure freedom after surgical management for FCD are still unclear. The objective of this study was to perform a volumetric analysis of factors shown on the preresection and postresection brain MRI scans of patients who had undergone resective epilepsy surgery for cortical dysplasia and to determine the influence of these factors on seizure outcome. METHODS The authors reviewed the medical records and brain images of 43 consecutive patients with focal MRI-documented abnormalities and a pathological diagnosis of FCD who had undergone surgical treatment for refractory epilepsy. Preoperative lesion volume and postoperative resection volume were calculated by manual segmentation using OsiriX PRO software. RESULTS Forty-three patients underwent first-time surgery for resection of an FCD. The age range of these patients at the time of surgery ranged from 2 months to 21.8 years (mean age 7.3 years). The median duration of follow-up was 20 months. The mean age at onset was 31.6 months (range 1 day to 168 months). Complete resection of the area of an FCD, as adjudged from the postoperative brain MR images, was significantly associated with seizure control (p = 0.0005). The odds of having good seizure control among those who underwent complete resection were about 6 times higher than those among the patients who did not undergo complete resection. Seizure control was not significantly associated with lesion volume (p = 0.46) or perilesion resection volume (p = 0.86). CONCLUSIONS The completeness of FCD resection in children is a significant predictor of seizure freedom. Neither lesion volume nor the further resection of perilesional tissue is predictive of seizure freedom. PMID- 26030333 TI - Congenital spinal dermal tract: how accurate is clinical and radiological evaluation? AB - OBJECT A dermal sinus tract is a common form of occult spinal dysraphism. The presumed etiology relates to a focal failure of disjunction resulting in a persistent adhesion between the neural and cutaneous ectoderm. Clinical and radiological features can appear innocuous, leading to delayed diagnosis and failure to appreciate the implications or extent of the abnormality. If it is left untreated, complications can include meningitis, spinal abscess, and inclusion cyst formation. The authors present their experience in 74 pediatric cases of spinal dermal tract in an attempt to identify which clinical and radiological factors are associated with an infective presentation and to assess the reliability of MRI in evaluating this entity. METHODS Consecutive cases of spinal dermal tract treated with resection between 1998 and 2010 were identified from the departmental surgical database. Demographics, clinical history, and radiological and operative findings were collected from the patient records. The presence or absence of active infection (abscess, meningitis) at the time of neurosurgical presentation and any history of local sinus discharge or infection was assessed. Magnetic resonance images were reviewed to evaluate the extent of the sinus tract and determine the presence of an inclusion cyst. Radiological and operative findings were compared. RESULTS The surgical course was uncomplicated in 90% of 74 cases eligible for analysis. Magnetic resonance imaging underreported the presence of both an intradural tract (MRI 46%, operative finding 86%) and an intraspinal inclusion cyst (MRI 15%, operative finding 24%). A history of sinus discharge (OR 12.8, p = 0.0003) and the intraoperative identification of intraspinal inclusion cysts (OR 5.6, p = 0.023) were associated with an infective presentation. There was no significant association between the presence of an intradural tract discovered at surgery and an infective presentation. CONCLUSIONS Surgery for the treatment of spinal dermal tract carries a low morbidity. While it seems intuitive that tracts without intradural extension carry a low risk of spinal cord tethering, it is not possible to reliably detect these cases using MRI. Similarly, intraspinal dermoid cannot be reliably excluded using MRI and carries an increased risk of infection. These points justify excision together with intradural exploration of all spinal dermal sinus tracts. PMID- 26030334 TI - Syringohydromyelia in association with syringobulbia and syringocephaly: case report. AB - The authors present the case of a 14-year-old boy with holocord syringohydromyelia extending into the brainstem, cerebral peduncle, internal capsule, and cerebral cortex. At the posterior fossa exploration, an opaque thickened arachnoid with occlusion of the foramen of Magendie was encountered. Careful documentation of postoperative regression of the syringocephaly, syringobulbia, and syringohydromyelia was made. The pathophysiology is discussed. PMID- 26030335 TI - Beyond User Acceptance: A Legitimacy Framework for Potable Water Reuse in California. AB - Water resource managers often tout the potential of potable water reuse to provide a reliable, local source of drinking water in water-scarce regions. Despite data documenting the ability of advanced treatment technologies to treat municipal wastewater effluent to meet existing drinking water quality standards, many utilities face skepticism from the public about potable water reuse. Prior research on this topic has mainly focused on marketing strategies for garnering public acceptance of the process. This study takes a broader perspective on the adoption of potable water reuse based on concepts of societal legitimacy, which is the generalized perception or assumption that a technology is desirable or appropriate within its social context. To assess why some potable reuse projects were successfully implemented while others faced fierce public opposition, we performed a series of 20 expert interviews and reviewed in-depth case studies from potable reuse projects in California. Results show that proponents of a legitimated potable water reuse project in Orange County, California engaged in a portfolio of strategies that addressed three main dimensions of legitimacy. In contrast, other proposed projects that faced extensive public opposition relied on a smaller set of legitimation strategies that focused near-exclusively on the development of robust water treatment technology. Widespread legitimation of potable water reuse projects, including direct potable water reuse, may require the establishment of a portfolio of standards, procedures, and possibly new institutions. PMID- 26030336 TI - Comment on "A Tensor-Free Method for the Structural and Dynamic Refinement of Proteins using Residual Dipolar Couplings". PMID- 26030337 TI - Precision oncology for patients with advanced cancer: the challenges of malignant snowflakes. AB - Precision oncology implies customizing treatment to the unique molecular and biologic characteristics of each individual and their cancer. Its implementation is being facilitated by remarkable technological advances in genomic sequencing, as well as the increasing availability of targeted and immunotherapeutic drugs. Yet, next generation sequencing may be a disruptive technology in that its results suggest that classic paradigms for clinical research and practice are a poor fit with the complex reality encountered in metastatic malignancies. Indeed, it is evident that advanced tumors have heterogeneous molecular landscapes that mostly differ between patients. Traditional modes of clinical research/practice are drug centered, with a strategy of finding commonalities between patients so that they can be grouped together and treated similarly. However, if each patient with metastatic cancer has a unique molecular portfolio, a new patient-centered, N-of-one approach that utilizes individually tailored treatment is needed. PMID- 26030338 TI - Cardiogenic syncope diagnosed as epileptic seizures: the importance of ECG during video-EEG recording. AB - We describefourpatientswith a previous diagnosis of epilepsy. After reviewing the ECG during the video-EEG recording, cardiogenic syncope, resulting from a cardiac arrhythmia, was identified as the cause of the seizures. Epileptic disorders and cardiogenic syncope may both manifest with convulsions, loss of consciousness, and loss of postural tone, leading to a high level of misdiagnosis. The one-lead ECG during video-EEG monitoring is a key component, which may allow correct diagnosis and treatment. PMID- 26030339 TI - "We definitely need an audience": experiences of Twitter, Twitter networks and tweet content in adults with severe communication disabilities who use augmentative and alternative communication (AAC). AB - PURPOSE: The aim of this study was to investigate the Twitter experiences of adults with severe communication disabilities who use augmentative and alternative communication (AAC) to inform Twitter training and further research on the use of Twitter in populations with communication disabilities. METHOD: This mixed methods research included five adults with severe communication disabilities who use AAC. It combined (a) quantitative analysis of Twitter networks and (b) manual coding of tweets with (c) narrative interviews with participants on their Twitter experiences and results. RESULTS: The five participants who used AAC and Twitter were diverse in their patterns and experiences of using Twitter. Twitter networks reflected interaction with a close knit network of people rather than with the broader publics on Twitter. Conversational, Broadcast and Pass Along tweets featured most prominently, with limited use of News or Social Presence tweets. Tweets appeared mostly within each participant's micro- or meso-structural layers of Twitter. CONCLUSIONS: People who use AAC report positive experiences in using Twitter. Obtaining help in Twitter, and engaging in hashtag communities facilitated higher frequency of tweets and establishment of Twitter networks. Results reflected an inter connection of participant Twitter networks that might form part of a larger as yet unexplored emergent community of people who use AAC in Twitter. PMID- 26030340 TI - A chemical and computational approach to comprehensive glycation characterization on antibodies. AB - Non-enzymatic glycation is a challenging post-translational modification to characterize due to the structural heterogeneity it generates in proteins. Glycation has become increasingly recognized as an important product quality attribute to monitor, particularly for the biotechnology sector, which produces recombinant proteins under conditions that are amenable to protein glycation. The elucidation of sites of glycation can be problematic using conventional collision induced dissociation (CID)-based mass spectrometry because of the predominance of neutral loss ions. A method to characterize glycation using an IgG1 monoclonal antibody (mAb) as a model is reported here. The sugars present on this mAb were derivatized using sodium borohydride chemistry to stabilize the linkage and identified using CID-based MS(2) mass spectrometry and spectral search engines. Quantification of specific glycation sites was then done using a targeted MS(1) based approach, which allowed the identification of a glycation hot spot in the heavy chain complementarity-determining region 3 of the mAb. This targeted approach provided a path forward to developing a structural understanding of the propensity of sites to become glycated on mAbs. Through structural analysis we propose a model in which the number and 3-dimensional distances of carboxylic acid amino acyl residues create a favorable environment for glycation to occur. PMID- 26030341 TI - Teachers' Perceptions of Bullying of Lesbian, Gay, Bisexual, Transgender, and Questioning (LGBTQ) Students in a Southwestern Pennsylvania Sample. AB - This study was designed to ascertain teachers' perceptions of bullying of Lesbian, Gay, Bisexual, Transgender, and Questioning (LGBTQ) youth. In a sample of 200 educators (61.0% female; 96.5% White) from a county in southwestern Pennsylvania, there was a significant positive relationship between the teachers' perceptions of the supportiveness of school staff towards students regardless of sexual orientation and those teachers' reports of the frequency of bullying victimization experienced by LGBTQ students. Teachers' perceptions of a higher level of staff and student support was associated with higher reported frequencies of students' use of derogatory language about LGBTQ individuals and various types of bullying of LGBTQ students. Teachers with a lesbian, gay, or bisexual orientation were found to rate the school staff and students as significantly less supportive of students regardless of their sexual orientation, gender identity, or gender expression in comparison to heterosexual teachers. Finally, teachers who either were unaware of or believed that their school lacked an anti-bullying policy reported significantly higher rates of physical bullying victimization of LGBTQ students when compared to the rates observed by teachers who reported knowledge of their schools' anti-bullying policies. PMID- 26030342 TI - Exploring the glass transition region: crowding effect, nonergodicity and thermorheological complexity. AB - Monte Carlo simulations performed on multiple polymer chains have produced accurate relaxation modulus Gs(t) curves which match the experimental G(t) curves of polystyrene reasonably well, over a wide temperature range around the glass transition region. The inter-segmental interactions, defined in terms of epsilon* (well depth) and sigma (monomer size), exert a strong influence on the modulus, the length scale and the relaxation time scale of the system. Judicious selection of these interaction parameters has enabled us to create the whole range of temperature dependence of the thermorheological complexity, from DeltaT = 40 degrees C to DeltaT = 0 degrees C. Near the glass transition temperature, the development of nonergodicity vis-a-vis a crowding effect in the system emerges naturally from the analysis of the G(t) line shapes. The entropic slow mode is well described by the Rouse theory and the energetic fast mode shifts to longer time scales, revealing the generic behavior of the thermorheological complexity. Typical Gs(t) curves, when partitioned into glassy and rubbery components, are shown to obey Inoue-Okamoto-Osaki's modified stress-optical rule, with different stress-optical coefficients for each component. Closer to the glass transition temperature, the distance of the closest monomer shows a considerable increase, suggesting a penetrable resistance to the approach of another monomer. The parameter sigma represents the characteristic length scale of the system in the glassy region. The thermorheological complexity incorporates the dynamic length scale of structural relaxation, increasing with the decrease of temperature towards the glass transition point. PMID- 26030343 TI - Direct Synthesis of Palladium Nanocrystals in Aqueous Solution with Systematic Shape Evolution. AB - Palladium octahedra, truncated octahedra, cuboctahedra, truncated cubes, and nanocubes with sizes of tens of nanometers have been synthesized in an aqueous mixture of H2PdCl4 solution, cetyltrimethylammonium chloride (CTAC) surfactant, KBr solution, dilute KI solution, and ascorbic acid solution at 35 degrees C for 30 min. By tuning the amount of dilute KBr solution introduced, particle shape control can be achieved. Adjusting the volumes of the Pd precursor and KBr solutions added, smaller and larger Pd nanocrystals were obtained with excellent shape control. Extensive structural and optical characterization of these nanocrystals has been performed. Two absorption bands in the ultraviolet region can be discerned for these Pd nanocrystals. Concave Pd cubes can also be prepared. Pd cubes were found to grow at a faster rate than that for the formation of octahedra. The concentrations of KBr and KI in the solution are so low that spectral shifts were not detected upon their addition to the solution. The Pd nanocrystals can readily be used for various applications after simple removal of surfactant. PMID- 26030345 TI - Conversion of Aldehyde to Alkane by a Peroxoiron(III) Complex: A Functional Model for the Cyanobacterial Aldehyde-Deformylating Oxygenase. AB - Cyanobacterial aldehyde-deformylating oxygenase (cADO) converts long-chain fatty aldehydes to alkanes via a proposed diferric-peroxo intermediate that carries out the oxidative deformylation of the substrate. Herein, we report that the synthetic iron(III)-peroxo complex [Fe(III)(eta(2)-O2)(TMC)](+) (TMC = tetramethylcyclam) causes a similar transformation in the presence of a suitable H atom donor, thus serving as a functional model for cADO. Mechanistic studies suggest that the H atom donor can intercept the incipient alkyl radical formed in the oxidative deformylation step in competition with the oxygen rebound step typically used by most oxygenases for forming C-O bonds. PMID- 26030344 TI - Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification. AB - RATIONALE: Most immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to tuberculosis (TB) reactivation. However, current diagnostic tools cannot reliably distinguish nonprogressing from progressing patients a priori, and thus LTBI therapy must be prescribed with suboptimal patient specificity. We hypothesized that LTBI diagnostics could be improved by generating immunomarker profiles capable of categorizing distinct patient subsets by a combinatorial immunoassay approach. OBJECTIVES: A combinatorial immunoassay analysis was applied to identify potential immunomarker combinations that distinguish among unexposed subjects, untreated patients with LTBI, and treated patients with LTBI and to differentiate risk of reactivation. METHODS: IFN-gamma release assay (IGRA) was combined with a flow cytometric assay that detects induction of CD25(+)CD134(+) coexpression on TB antigen-stimulated T cells from peripheral blood. The combinatorial immunoassay analysis was based on receiver operating characteristic curves, technical cut-offs, 95% bivariate normal density ellipse prediction, and statistical analysis. Risk of reactivation was estimated with a prediction formula. MEASUREMENTS AND MAIN RESULTS: Sixty five out of 150 subjects were included. The combinatorial immunoassay approach identified at least four different T-cell subsets. The representation of these immune phenotypes was more heterogeneous in untreated patients with LTBI than in treated patients with LTBI or unexposed groups. Patients with IGRA(+) CD4(+)CD25(+)CD134(+) T-cell phenotypes had the highest estimated reactivation risk (4.11 +/- 2.11%). CONCLUSIONS: These findings suggest that immune phenotypes defined by combinatorial assays may potentially have a role in identifying those at risk of developing TB; this potential role is supported by risk of reactivation modeling. Prospective studies will be needed to test this novel approach. PMID- 26030346 TI - Effects of long-term oral testosterone undecanoate therapy on urinary symptoms: data from a 1-year, placebo-controlled, dose-ranging trial in aging men with symptomatic hypogonadism. AB - BACKGROUND: There has been a longstanding question as to whether testosterone therapy could precipitate or worsen urinary symptoms in aging men. We investigated the effects of 1-year oral testosterone undecanoate (TU) therapy on urinary symptoms in aging, hypogonadal men. METHODS: A total of 322 men >=50 years with symptomatic testosterone deficiency participated in a 1-year, randomized, multicenter, double-blind trial. Patients received placebo or oral TU 80 mg/day, 160 mg/day, or 240 mg/day. RESULTS AND LIMITATIONS: Compared with placebo, treatment with oral TU at doses of 80 mg/day and 160 mg/day resulted in no significant change in IPSS urinary symptoms or quality of life (QoL) scores. Treatment with oral TU 240 mg/day led to a statistically significant, but clinically insignificant, improvement in IPSS total score and a significant improvement in IPSS QoL score. None of the TU doses tested had a significant effect on PSA or PV. CONCLUSIONS: Long-term oral TU therapy had no deleterious effects on IPSS total score and did not change PV and PSA in aging, hypogonadal men. Oral TU therapy at a dose of 240 mg/day may even improve IPSS QoL score. PMID- 26030347 TI - Six weeks of conditioning exercise increases total, but not free testosterone in lifelong sedentary aging men. AB - INTRODUCTION: Advancing age is associated with a gradual decline in circulating androgens, and the putative role of exercise training on systemic androgens remains to be adequately defined. METHODS: The present investigation examined the impact of 6 weeks of supervised exercise training on resting levels of systemic hormones in a cohort of lifelong sedentary men [SED (n = 28), 62.5 +/- 5.3 years], compared with a positive control group of age-matched lifelong exercisers [LE (n = 20), 60.4 +/- 4.7 years, >30 years training history]. Blood hormones were sampled pre- and post-intervention from an antecubital forearm vein and analysed using electrochemiluminescent immunoassay. Cardiorespiratory fitness ([Formula: see text]) was determined via indirect calorimetry during an incremental cycle test to volitional exhaustion. RESULTS: Analysis of variance (ANOVA) revealed a lack of significant change in any parameter amongst LE, whilst SED experienced a significant exercise-induced improvement in cardiorespiratory fitness and total testosterone (all p < 0.05). Concurrent increases in sex hormone-binding globulin (SHBG; p < 0.05) resulted in a lack of change to either bioavailable or calculated free testosterone (p > 0.05) amongst SED. CONCLUSIONS: Although resting levels of systemic total testosterone increased in response to 6 weeks of exercise training, increases in SHBG negated any potential relationship between calculated-free or bioavailable testosterone. These findings indicate that increases in bioavailable testosterone fraction are not required for cardiorespiratory fitness improvements in aging men. PMID- 26030348 TI - Association of auricular reflective points and the status of lower urinary tract symptoms in aging males. AB - OBJECTIVE: This study aimed to investigate the association between auricular reflective points and the status of lower urinary tract symptoms (LUTS) among Chinese aging males. METHODS: A total of 113 male participants, with 69 having LUTS (LUTS+ve) and 44 having no LUTS (LUTS-ve), were recruited for this case control study. Ear diagnosis was conducted in three ways: inspection, electrical skin resistance measurement, and tenderness testing. RESULTS: Quality of life was lower among the LUTS+ve cases than among the LUTS-ve cases. The tenderness and electrical conductivity of a number of auricular points, including the "angle of superior concha", the "urinary bladder", the "ureter", the "kidney", the "urethra", and the "internal genitals" were associated with LUTS in the Chinese aging males. In terms of electrical conductivity, the "angle of superior concha" on both ears exhibited the highest sensitivity among the other auricular points under testing. This auricular point also demonstrated considerable sensitivity, specificity, and positive/negative predictive values for both ears during the tenderness testing. CONCLUSIONS: Auricular diagnosis has a pre-diagnostic value and could be considered as a screening method for the aging population with relatively high LUTS risk. PMID- 26030349 TI - Benign prostatic hyperplasia and metabolic syndrome: the expanding evidences of a new disease of aging male. PMID- 26030350 TI - Erectile dysfunction is a prognostic indicator of comorbidities in men with late onset hypogonadism. AB - INTRODUCTION: The role of testosterone deficiency in erectile dysfunction (ED) is increasingly recognized; however, there is a need to clarify the nature of the relationship between ED and late onset hypogonadism (LOH). AIM: In this study, we sought to determine the correlators of ED severity amongst men with LOH. METHODS: 130 patients diagnosed with LOH fulfilling the criteria of total testosterone <=3.5 ng/ml (<12 nmol/l) and with an erectile function domain score <21 on the International Index of Erectile Function questionnaire (IIEF questions 1-5) were enrolled for a subsequent trial of Testosterone Undecanoate. Demographic data were recorded at baseline. MAIN OUTCOME MEASURES: Subjects completed three standardised questionnaires to assess sexual health including International Prostate Symptom Score (IPSS), Aging Males Symptoms (AMS) and IIEF Sexual Health Inventory for Men (SHIM). Patients were stratified by ED severity with SHIM scores of 1-7 considered severe ED, 8-11 moderate ED and 12-16 mild to moderate. Serum testosterone, sex hormone binding globulin (SHBG) and lipids (total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein) were assessed along with plasma fasting glucose and HbA1c. Weight, BMI and waist circumference were also recorded. RESULTS: A significant association was observed between severity of ED and mean weight (p = 0.000), waist circumference (p = 0.000), triglycerides (p = 0.009), total cholesterol (p = 0.027), HbA1c (p = 0.000), fasting glucose (p = 0.003) and AMS scores (p = 0.043). No significant differences were seen in testosterone fractions and SHBG levels between ED subgroups. A positive correlation existed between the prevalence of diabetes mellitus (type 1 and type 2) and ED severity in this cohort (p = 0.018). CONCLUSIONS: The descriptive data of our cohort show that increased severity of ED within LOH patients correlated with an increased waist circumference, hyperglycemia, hypertriglyceridemia, hyperlipidemia and a history of diabetes mellitus. Severe ED functions as a prognostic indicator of co-morbidities in men with LOH. PMID- 26030351 TI - Absence of Structural Impact of Noble Nanoparticles on P3HT:PCBM Blends for Plasmon-Enhanced Bulk-Heterojunction Organic Solar Cells Probed by Synchrotron GI XRD. AB - The incorporation of noble metal nanoparticles, displaying localized surface plasmon resonance, in the active area of donor-acceptor bulk-heterojunction organic photovoltaic devices is an industrially compatible light trapping strategy, able to guarantee better absorption of the incident photons and give an efficiency improvement between 12% and 38%. In the present work, we investigate the effect of Au and Ag nanoparticles blended with P3HT: PCBM on the P3HT crystallization dynamics by synchrotron grazing incidence X-ray diffraction. We conclude that the presence of (1) 80 nm Au, (2) mix of 5 nm, 50 nm, 80 nm Au, (3) 40 nm Ag, and (4) 10 nm, 40 nm, 60 nm Ag colloidal nanoparticles, at different concentrations below 0.3 wt% for Au and below 0.1% for Ag in P3HT: PCBM blends, does not affect the behaviour of the blends themselves. PMID- 26030352 TI - Global Microarray Analysis of Alkaliphilic Halotolerant Bacterium Bacillus sp. N16-5 Salt Stress Adaptation. AB - The alkaliphilic halotolerant bacterium Bacillus sp. N16-5 is often exposed to salt stress in its natural habitats. In this study, we used one-colour microarrays to investigate adaptive responses of Bacillus sp. N16-5 transcriptome to long-term growth at different salinity levels (0%, 2%, 8%, and 15% NaCl) and to a sudden salt increase from 0% to 8% NaCl. The common strategies used by bacteria to survive and grow at high salt conditions, such as K+ uptake, Na+ efflux, and the accumulation of organic compatible solutes (glycine betaine and ectoine), were observed in Bacillus sp. N16-5. The genes of SigB regulon involved in general stress responses and chaperone-encoding genes were also induced by high salt concentration. Moreover, the genes regulating swarming ability and the composition of the cytoplasmic membrane and cell wall were also differentially expressed. The genes involved in iron uptake were down-regulated, whereas the iron homeostasis regulator Fur was up-regulated, suggesting that Fur may play a role in the salt adaption of Bacillus sp. N16-5. In summary, we present a comprehensive gene expression profiling of alkaliphilic Bacillus sp. N16-5 cells exposed to high salt stress, which would help elucidate the mechanisms underlying alkaliphilic Bacillus spp. survival in and adaptation to salt stress. PMID- 26030353 TI - Maternal hypoxia decreases capillary supply and increases metabolic inefficiency leading to divergence in myocardial oxygen supply and demand. AB - Maternal hypoxia is associated with a decrease in left ventricular capillary density while cardiac performance is preserved, implying a mismatch between metabolism and diffusive exchange. We hypothesised this requires a switch in substrate metabolism to maximise efficiency of ATP production from limited oxygen availability. Rat pups from pregnant females exposed to hypoxia (FIO2=0.12) at days 10-20 of pregnancy were grown to adulthood and working hearts perfused ex vivo. 14C-labelled glucose and 3H-palmitate were provided as substrates and metabolism quantified from recovery of 14CO2 and 3H2O, respectively. Hearts of male offspring subjected to Maternal Hypoxia showed a 20% decrease in cardiac output (P<0.05), despite recording a 2-fold increase in glucose oxidation (P<0.01) and 2.5-fold increase (P<0.01) in palmitate oxidation. Addition of insulin to Maternal Hypoxic hearts, further increased glucose oxidation (P<0.01) and suppressed palmitate oxidation (P<0.05), suggesting preservation in insulin signalling in the heart. In vitro enzyme activity measurements showed that Maternal Hypoxia increased both total and the active component of cardiac pyruvate dehydrogenase (both P<0.01), although pyruvate dehydrogenase sensitivity to insulin was lost (NS), while citrate synthase activity declined by 30% (P<0.001) and acetyl-CoA carboxylase activity was unchanged by Maternal Hypoxia, indicating realignment of the metabolic machinery to optimise oxygen utilisation. Capillary density was quantified and oxygen diffusion characteristics examined, with calculated capillary domain area increased by 30% (P<0.001). Calculated metabolic efficiency decreased 4-fold (P<0.01) for Maternal Hypoxia hearts. Paradoxically, the decline in citrate synthase activity and increased metabolism suggest that the scope of individual mitochondria had declined, rendering the myocardium potentially more sensitive to metabolic stress. However, decreasing citrate synthase may be essential to preserve local PO2, minimising regions of hypoxia and hence maximising the area of myocardium able to preserve cardiac output following maternal hypoxia. PMID- 26030354 TI - Oral Vaccination of Channel Catfish against Enteric Septicemia of Catfish Using a Live Attenuated Edwardsiella ictaluri Isolate. AB - Enteric septicemia of catfish (ESC), caused by Edwardsiella ictaluri, is the most problematic bacterial disease affecting catfish aquaculture in the southeastern United States. Efforts to develop an effective ESC vaccine have had limited industrial success. In commercial settings, ESC vaccines are typically administered by immersion when fry are transferred from the hatchery to rearing ponds. While this approach is a practical method of mass delivery, this strategy administers vaccines to very young fish, which lack a fully developed immune system. To circumvent this limitation, an oral vaccination strategy was evaluated as a means of immunizing catfish at the fingerling stage of production, when fish possess a more complete immune arsenal. A virulent E. ictaluri isolate (S97-773) was attenuated by successive passage on media containing increasing concentrations of rifamycin. In laboratory trials, cultured vaccine was diluted and mixed with feed (100 mL diluted vaccine/454 g feed). This mixture was then fed to Channel Catfish Ictalurus punctatus fingerlings. Two separate dilutions of cultured vaccine (1:10 and 1:100) were used to create the vaccine-feed mixture, equating to estimated doses of 5 * 107 and 5 * 106 CFU/g of feed, respectively. After 30 d, catfish were exposed by immersion (1 * 106 CFU/mL) to the virulent parental strain of E. ictaluri. The target dose (1:100 dilution, ~5 * 106 CFU/g of feed) offered exceptional protection (relative percent survival = 82.6-100%). In addition, negligible deaths occurred in fish vaccinated at 10 times the target dose (1:10 dilution, ~5 * 107 CFU/g of feed). In pond trials, antibody production increased 18-fold in orally vaccinated fish. When compared with nonvaccinated controls, vaccination significantly improved survival, feed fed, feed conversion, biomass produced, and total harvest. This research demonstrates Channel Catfish can be successfully immunized in a commercial setting against E. ictaluri with a single dose of an orally delivered, live attenuated, E. ictaluri vaccine. PMID- 26030355 TI - Fluorous Analogue of Chloramine-T: Preparation, X-ray Structure Determination, and Use as an Oxidant for Radioiodination and s-Tetrazine Synthesis. AB - A fluorous oxidant that can be used to introduce radioiodine into small molecules and proteins and generate iodinated tetrazines for bioorthogonal chemistry has been developed. The oxidant was prepared in 87% overall yield by combining a fluorous amine with tosyl chloride, followed by chlorination using aqueous sodium hypochlorite. A crystal structure of the oxidant, which is a fluorous analogue of chloramine-T, was obtained. The compound was shown to be stable for 7 days in EtOH and for longer than three months as a solid. The oxidant was effective at promoting the labeling of arylstannanes using [(125)I]NaI, where products were isolated in high specific activity in yields ranging from 46% to 86%. Similarly, iodinated biologically active proteins (e.g., thrombin) were successfully produced, as well as a radioiodinated tetrazine, through a concomitant oxidation halodemetalation reaction. Because of its fluorous nature, unreacted oxidant and associated reaction byproducts can be removed quantitatively from reaction mixtures by passing solutions through fluorous solid phase extraction cartridges. This feature enables rapid and facile purification, which is critical when working with radionuclides and is similarly beneficial for general synthetic applications. PMID- 26030356 TI - Unraveling the molecular architecture of a G protein-coupled receptor/beta arrestin/Erk module complex. AB - beta-arrestins serve as signaling scaffolds downstream of G protein-coupled receptors, and thus play a crucial role in a plethora of cellular processes. Although it is largely accepted that the ability of beta-arrestins to interact simultaneously with many protein partners is key in G protein-independent signaling of GPCRs, only the precise knowledge of these multimeric arrangements will allow a full understanding of the dynamics of these interactions and their functional consequences. However, current experimental procedures for the determination of the three-dimensional structures of protein-protein complexes are not well adapted to analyze these short-lived, multi-component assemblies. We propose a model of the receptor/beta-arrestin/Erk1 signaling module, which is consistent with most of the available experimental data. Moreover, for the beta arrestin/Raf1 and the beta-arrestin/ERK interactions, we have used the model to design interfering peptides and shown that they compete with both partners, hereby demonstrating the validity of the predicted interaction regions. PMID- 26030357 TI - Cognitive alexithymia is associated with the degree of risk for psychosis. AB - Alexithymia is a personality construct denoting emotion processing problems. It has been suggested to encompass two dimensions: a cognitive and affective dimension. The cognitive dimension is characterized by difficulties in identifying, verbalizing and analyzing emotions, while the affective dimension reflects the level of emotional arousal and imagination. Alexithymia has been previously proposed as a risk factor for developing psychosis. More specifically, the two alexithymia dimensions might be differentially related to the vulnerability for psychosis. Therefore, we examined the two dimensions of alexithymia, measured with the BVAQ in 94 siblings of patients with schizophrenia, 52 subjects at ultra-high risk (UHR) for developing psychosis, 38 patients with schizophrenia and 109 healthy controls. The results revealed that siblings and patients had higher levels of cognitive alexithymia compared to controls. In addition, subjects at UHR for psychosis had even higher levels of cognitive alexithymia compared to the siblings. The levels of affective alexithymia in siblings and patients were equal to controls. However, UHR individuals had significantly lower levels of affective alexithymia (i.e. higher levels of emotional arousal and fantasizing) compared to controls. Alexithymia was further related to subclinical levels of negative and depressive symptoms. These findings indicate that alexithymia varies parametrically with the degree of risk for psychosis. More specifically, a type-II alexithymia pattern, with high levels of cognitive alexithymia and normal or low levels of affective alexithymia, might be a vulnerability factor for psychosis. PMID- 26030359 TI - 10th International Phytotechnology Conference1-4 October 2013 Syracuse, NY, USA. PMID- 26030358 TI - Combination Patterns of Major R Genes Determine the Level of Resistance to the M. oryzae in Rice (Oryza sativa L.). AB - Rice blast caused by Magnaporthe oryzae is the most devastating disease of rice and poses a serious threat to world food security. In this study, the distribution and effectiveness of 18 R genes in 277 accessions were investigated based on pathogenicity assays and molecular markers. The results showed that most of the accessions exhibited some degree of resistance (resistance frequency, RF >50%). Accordingly, most of the accessions were observed to harbor two or more R genes, and the number of R genes harbored in accessions was significantly positively correlated with RF. Some R genes were demonstrated to be specifically distributed in the genomes of rice sub-species, such as Pigm, Pi9, Pi5 and Pi1, which were only detected in indica-type accessions, and Pik and Piz, which were just harbored in japonica-type accessions. By analyzing the relationship between R genes and RF using a multiple stepwise regression model, the R genes Pid3, Pi5, Pi9, Pi54, Pigm and Pit were found to show the main effects against M. oryzae in indica-type accessions, while Pita, Pb1, Pik, Pizt and Pia were indicated to exhibit the main effects against M. oryzae in japonica-type accessions. Principal component analysis (PCA) and cluster analysis revealed that combination patterns of major R genes were the main factors determining the resistance of rice varieties to M. oryzae, such as 'Pi9+Pi54', 'Pid3+Pigm', 'Pi5+Pid3+Pigm', 'Pi5+Pi54+Pid3+Pigm', 'Pi5+Pid3' and 'Pi5+Pit+Pid3' in indica-type accessions and 'Pik+Pib', 'Pik+Pita', 'Pik+Pb1', 'Pizt+Pia' and 'Pizt+Pita' in japonica-type accessions, which were able to confer effective resistance against M. oryzae. The above results provide good theoretical support for the rational utilization of combinations of major R genes in developing rice cultivars with broad-spectrum resistance. PMID- 26030360 TI - Enhanced vadose zone nitrogen removal by poplar during dormancy. AB - A pilot-scale, engineered poplar tree vadose zone system was utilized to determine effluent nitrate (NO3(-)) and ammonium concentrations resulting from intermittent dosing of a synthetic wastewater onto sandy soils at 4.5 degrees C. The synthetic wastewater replicated that of an industrial food processor that irrigates onto sandy soils even during dormancy which can leave groundwater vulnerable to NO3(-) contamination. Data from a 21-day experiment was used to assess various Hydrus model parameterizations that simulated the impact of dormant roots. Bromide tracer data indicated that roots impacted the hydraulic properties of the packed sand by increasing effective dispersion, water content and residence time. The simulated effluent NO3(-) concentration on day 21 was 1.2 mg-N L(-1) in the rooted treatments compared to a measured value of 1.0 +/- 0.72 mg-N L(-1). For the non-rooted treatment, the simulated NO3(-) concentration was 4.7 mg-N L(-1) compared to 5.1 +/- 3.5 mg-N L(-1) measured on day 21. The model predicted a substantial "root benefit" toward protecting groundwater through increased denitrification in rooted treatments during a 21-day simulation with 8% of dosed nitrogen converted to N2 compared to 3.3% converted in the non-rooted test cells. Simulations at the 90-day timescale provided similar results, indicating increased denitrification in rooted treatments. PMID- 26030361 TI - A user-friendly phytoremediation database: creating the searchable database, the users, and the broader implications. AB - Designers, students, teachers, gardeners, farmers, landscape architects, architects, engineers, homeowners, and others have uses for the practice of phytoremediation. This research looks at the creation of a phytoremediation database which is designed for ease of use for a non-scientific user, as well as for students in an educational setting ( http://www.steviefamulari.net/phytoremediation ). During 2012, Environmental Artist & Professor of Landscape Architecture Stevie Famulari, with assistance from Kyla Witz, a landscape architecture student, created an online searchable database designed for high public accessibility. The database is a record of research of plant species that aid in the uptake of contaminants, including metals, organic materials, biodiesels & oils, and radionuclides. The database consists of multiple interconnected indexes categorized into common and scientific plant name, contaminant name, and contaminant type. It includes photographs, hardiness zones, specific plant qualities, full citations to the original research, and other relevant information intended to aid those designing with phytoremediation search for potential plants which may be used to address their site's need. The objective of the terminology section is to remove uncertainty for more inexperienced users, and to clarify terms for a more user friendly experience. Implications of the work, including education and ease of browsing, as well as use of the database in teaching, are discussed. PMID- 26030362 TI - Potential of selected Canadian plant species for phytoextraction of trace elements from selenium-rich soil contaminated by industrial activity. AB - In this preliminary screening study, we tested the phytoextraction potential of nine Canadian native/well-adapted plant species on a soil highly polluted by trace elements (TE) from a copper refinery. Plant physiological parameters and soil cover index were monitored for a 12-week period. At the end of the trial, biomass yield, bioconcentration (BFC) and translocation (TF) factors for the main TE as well as phytoextraction potential were determined. Most plants were severely injured by the high pollution levels, showing symptoms of toxicity including chlorosis, mortality and very low biomass yield. However, Indian mustard showed the highest selenium extraction potential (65 mg m(-2)), even under harsh growing conditions. Based on our results, tall fescue and ryegrass, which mainly stored As, Cu, Pb and Zn within roots, could be used effectively for phytostabilization. PMID- 26030363 TI - Do selenium hyperaccumulators affect selenium speciation in neighboring plants and soil? An X-Ray Microprobe Analysis. AB - Neighbors of Se hyperaccumulators Stanleya pinnata and Astragalus bisulcatus were found earlier to have elevated Se levels. Here we investigate whether Se hyperaccumulators affect Se localization and speciation in surrounding soil and neighboring plants. X-ray fluorescence mapping and X-ray absorption near-edge structure spectroscopy were used to analyze Se localization and speciation in leaves of Artemisia ludoviciana, Symphyotrichum ericoides and Chenopodium album growing next to Se hyperaccumulators or non-accumulators at a seleniferous site. Regardless of neighbors, A. ludoviciana, S. ericoides and C. album accumulated predominantly (73-92%) reduced selenocompounds with XANES spectra similar to the C-Se-C compounds selenomethionine and methyl-selenocysteine. Preliminary data indicate that the largest Se fraction (65-75%), both in soil next to hyperaccumulator S. pinnata and next to nonaccumulator species was reduced Se with spectra similar to C-Se-C standards. These same C-Se-C forms are found in hyperaccumulators. Thus, hyperaccumulator litter may be a source of organic soil Se, but soil microorganisms may also contribute. These findings are relevant for phytoremediation and biofortification since organic Se is more readily accumulated by plants, and more effective for dietary Se supplementation. PMID- 26030364 TI - Thermal Characteristics of Hyperaccumulator and Fate of Heavy Metals during Thermal Treatment of Sedum plumbizincicola. AB - Thermal treatment is one of the most promising disposal techniques for heavy metal- (HM)-enriched hyperaccumulators. However, the thermal characteristics and fate of HMs during thermal treatment of hyperaccumulator biomass need to be known in detail. A horizontal tube furnace was used to analyze the disposal process of hyperaccumulator biomass derived from a phyto-extracted field in which the soil was moderately contaminated with heavy metals. Different operational conditions regarding temperature and gas composition were tested. A thermo-dynamic analysis by advanced system for process engineering was performed to predict HM speciation during thermal disposal and SEM-EDS, XRD and sequential chemical extraction were used to characterize the heavy metals. The recovery of Zn, Pb and Cd in bottom ash decreased with increasing temperature but recovery increased in the fly ash. Recovery of Zn, Pb and Cd fluctuated with increasing air flow rate and the metal recovery rates were higher in the fly ash than the bottom ash. Most Cl, S, Fe, Al and SiO2 were found as alkali oxides, SO2, Fe2(SO4)3, iron oxide, Ca3Al2O6, K2SiO3 and SiO2 instead of reacting with HMs. Thus, the HMs were found to occur as the pure metals and their oxides during the combustion process and as the sulfides during the reducing process. PMID- 26030365 TI - Selenium-fortified wheat: potential of microbes for biofortification of selenium and other essential nutrients. AB - Selenium (Se) is an essential micronutrient for humans and animals, and Se deficiency is a worldwide problem. Plants are a main dietary source of Se for humans and livestock. In this study we investigated the effect of two selenium tolerant bacterial strains Bacillus cereus-YAP6 and Bacillus licheniformis-YAP7, on the growth and Se uptake by wheat plants. The bacteria-inoculated plants exhibited a significant increase in spike length, shoot length and dry biomass. Inoculated Se-treated plants also showed increased stem Se, S, Ca and Fe concentrations, by up to 375%, 40%, 55%, and 104%, respectively, and increased kernel Se, S, Ca and Fe concentrations by up to 154%, 85%, 60%, and 240%, respectively, compared to un-inoculated Se-treated plants. In conclusion, inoculation with strains YAP6 andYAP7 is a good Se biofortification strategy for wheat. Both strains showed resistance to other toxic elements, i.e., As, Cd, Co, Cr, Cu, Mn and Zn. Optimal growth temperature and pH for both strains were 37 degrees C and pH7, respectively, but both strains can grow very well at different temperatures (28-45 degrees C) and at alkaline pH. Both strains have high Se reduction potential: strains YAP6 and YAP7 converted 92% and 32% of selenite into elemental Se within 48 h, respectively. PMID- 26030366 TI - Editorial retraction. PMID- 26030367 TI - Sustained Circadian Rhythms in Continuous Light in Synechocystis sp. PCC6803 Growing in a Well-Controlled Photobioreactor. AB - The cyanobacterial circadian clock has been well-studied and shown to be both robust and a dominant factor in the control of gene expression in Synechococcus elongatus PCC7942. In Synechocystis sp. PCC6803, the circadian clock is assumed to function similarly, yet appears to control transcription to a far lesser extent and its circadian rhythm was reported to not be sustained, or at least rapidly damped, under continuous illumination. One of the feedback loops that governs the clock in S. elongatus in addition to the core oscillator, i.e., the transcriptional-translation regulation loop hinging on KaiC-dependent expression of kaiBC, appears to be missing in Synechocystis, which would account for this difference. Here, we show that the clock in Synechocystis fulfills all criteria of a circadian clock: 1) a free-running period of approximately 24 h, 2) temperature compensation, and 3) being able to be entrained. A remarkably stable rhythm is generated despite the fact that the organism grows with a doubling time of less than 24 h in a photobioreactor run in turbidostat mode. No damping of the free-running circadian oscillation was observed in 2 weeks, suggesting that the clock in individual cells stays synchronized within a culture despite the apparent lack of a transcriptional-translation regulation loop. Furthermore, the dependence of chlorophyll synthesis on the presence of O2 was demonstrated. PMID- 26030368 TI - Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin. AB - Cyclophilins are peptidyl cis-trans prolyl isomerases (PPIases), whose activity is typically inhibited by cyclosporine A (CsA), a potent immunosuppressor. Cyclophilins are also chaperones. Emerging evidence supports that cyclophilins present nonoverlapping PPIase and chaperone activities. The proteostasis of the disease-relevant substrates, signal transducer and activator of transcription 3 and 5 (STAT3/STAT5), heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), and M-opsin, is regulated by nonoverlapping chaperone and PPIase activities of the cyclophilin domain (CY) of Ranbp2, a multifunctional and modular scaffold that controls nucleocytoplasmic shuttling and proteostasis of selective substrates. Although highly homologous, CY and the archetypal cyclophilin A (CyPA) present distinct catalytic and CsA-binding activities owing to unique structural features between these cylophilins. We explored structural idiosyncrasies between CY and CyPA to screen in silico nearly 9 million small molecules (SM) against the CY PPIase pocket and identify SMs with selective bioactivity toward STAT3, hnRNPA2B1, or M-opsin proteostasis. We found three classes of SMs that enhance the cytokine-stimulated transcriptional activity of STAT3 without changing latent and activated STAT3 levels, down-regulate hnRNPA2B1 or M-opsin proteostasis, or a combination of these. Further, a SM that suppresses hnRNPA2B1 proteostasis also inhibits strongly and selectively the PPIase activity of CY. This study unravels chemical probes for multimodal regulation of CY of Ranbp2 and its substrates, and this regulation likely results in the allosterism stemming from the interconversion of conformational substates of cyclophilins. The results also demonstrate the feasibility of CY in drug discovery against disease-relevant substrates controlled by Ranbp2, and they open new opportunities for therapeutic interventions. PMID- 26030370 TI - Effect of aqueous and ambient atmospheric environments on plasmon-driven selective reduction reactions. AB - We successfully realised plasmon-driven selective reduction reactions of 2-amino 5-nitrobenzenethiol (2A-5-NBT) to 3,3'-dimercapto-4,4'-diaminoazobenzene , an azobenzene derivative, using surface-enhanced Raman scattering (SERS) spectroscopy, and supported by the theoretical calculations. The SERS spectra demonstrated that two 5-nitro groups of 2A-5-NBTs were selectively reduced to the -N=N- chemical bond of 3,3'-dimercapto-4,4'-diaminoazobenzene, whereas the 2 amine group of 2A-5-NBT remained unchanged. Our experimental results revealed that aqueous environments were preferable to ambient atmospheric environments for this selective reduction reaction. The product is very stable in aqueous environments. However, in ambient atmosphere environments, the product is not stable and can revert back to 2A-5-NBT, where the -N=N- chemical bond can be broken by plasmon scissors. The plasmon-induced catalytic reactions in aqueous environments could be used for the efficient synthesis of aromatic azobenzene derivative compounds, which are valuable chemicals that are widely used in the chemical industry as dyes, food additives and drugs. PMID- 26030369 TI - Transcriptional upregulation of HNF-1beta by NF-kappaB in ovarian clear cell carcinoma modulates susceptibility to apoptosis through alteration in bcl-2 expression. AB - Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcriptional factor that has an important role in endometriosis-ovarian clear cell carcinoma (OCCC) sequence by modulating cell kinetics and glucose metabolism. However, little is known about the detailed molecular mechanisms that govern its regulation and function. Herein, we focus on upstream and downstream regulatory factors of HNF-1beta in OCCCs. In clinical samples, HNF-1beta expression was positively correlated with the active form of NF-kappaB/p65 in OCCCs, and closely linked with a low nuclear grade and non-solid architecture. In cell lines, transfection of p65 resulted in increased HNF-1beta mRNA and protein expression in TOV-21G cells (OCCC cell line with endogenous HNF-1beta expression), in line with activation of the promoter, probably through interacting with the basic transcriptional machinery. Suppression of endogenous HNF-1beta expression by siRNA increased apoptosis in TOV-21G cells, while treatment of Hec251 cells (endometrial carcinoma cell line with extremely low endogenous HNF-1beta expression) stably overexpressing exogenous HNF-1beta with doxorubicin abrogated apoptosis of the cells, along with increased ratio of bcl-2 relative to bax. Moreover, overexpression of HNF-1beta led to upregulation of bcl-2 expression at the transcriptional level in TOV-21G cells, which provided evidence for a positive correlation between HNF-1beta and bcl-2 expression in OCCCs. These data, therefore, suggest that association between HNF-1beta and NF-kappaB signaling may participate in cell survival by alteration of apoptotic events, particularly in mitochondria-mediated pathways, through upregulation of bcl-2 expression in OCCCs. PMID- 26030371 TI - Face aftereffects involve local repulsion, not renormalization. AB - After looking at a photograph of someone for a protracted period (adaptation), a previously neutral-looking face can take on an opposite appearance in terms of gender, identity, and other attributes-but what happens to the appearance of other faces? Face aftereffects have repeatedly been ascribed to perceptual renormalization. Renormalization predicts that the adapting face and more extreme versions of it should appear more neutral after adaptation (e.g., if the adaptor was male, it and hyper-masculine faces should look more feminine). Other aftereffects, such as tilt and spatial frequency, are locally repulsive, exaggerating differences between adapting and test stimuli. This predicts that the adapting face should be little changed in appearance after adaptation, while more extreme versions of it should look even more extreme (e.g., if the adaptor was male, it should look unchanged, while hyper-masculine faces should look even more masculine). Existing reports do not provide clear evidence for either pattern. We overcame this by using a spatial comparison task to measure the appearance of stimuli presented in differently adapted retinal locations. In behaviorally matched experiments we compared aftereffect patterns after adapting to tilt, facial identity, and facial gender. In all three experiments data matched the predictions of a locally repulsive, but not a renormalizing, aftereffect. These data are consistent with the existence of similar encoding strategies for tilt, facial identity, and facial gender. PMID- 26030373 TI - Screening-induced carrier transport in silicene. AB - Based on the Boltzmann transport equation in the MRT approximation, we present a theory to investigate low-field carrier transport in dual-gated silicene FETs by taking into account screened charged impurity scattering, which is the most likely scattering mechanism limiting the conductivity. Static RPA dielectric screening is also included in the conductivity calculation to study temperature dependent silicene transport. It is found that both calculated conductivity and band gap not only depend strongly on carrier sheet density, but also depend strongly on effective offset density. More importantly, screening-induced metal insulator-transition phenomena in buckled silicene can be observed theoretically, which is similar to that obtained in monolayer graphene. PMID- 26030372 TI - Mapping the Hydrogen Bond Networks in the Catalytic Subunit of Protein Kinase A Using H/D Fractionation Factors. AB - Protein kinase A is a prototypical phosphoryl transferase, sharing its catalytic core (PKA-C) with the entire kinase family. PKA-C substrate recognition, active site organization, and product release depend on the enzyme's conformational transitions from the open to the closed state, which regulate its allosteric cooperativity. Here, we used equilibrium nuclear magnetic resonance hydrogen/deuterium (H/D) fractionation factors (phi) to probe the changes in the strength of hydrogen bonds within the kinase upon binding the nucleotide and a pseudosubstrate peptide (PKI5-24). We found that the phi values decrease upon binding both ligands, suggesting that the overall hydrogen bond networks in both the small and large lobes of PKA-C become stronger. However, we observed several important exceptions, with residues displaying higher phi values upon ligand binding. Notably, the changes in phi values are not localized near the ligand binding pockets; rather, they are radiated throughout the entire enzyme. We conclude that, upon ligand and pseudosubstrate binding, the hydrogen bond networks undergo extensive reorganization, revealing that the open-to-closed transitions require global rearrangements of the internal forces that stabilize the enzyme's fold. PMID- 26030374 TI - Endoscope-assisted Transorbital Keyhole Surgical Approach to Ruptured Supratentorial Aneurysms. AB - BACKGROUND: Many different surgical approaches have been described to treat intracranial aneurysms. A common feature of all the approaches has been relatively extensive brain exposure and brain retraction with increasing surgical morbidity. Transorbital keyhole is one of the minimally invasive approaches. Endoscope-assisted transorbital keyhole surgery (EATOKS) combines minimally invasive transorbital keyhole surgery with endoscope-assisted microneurosurgery. We describe our experience with this approach and its efficacy in treating ruptured supratentorial aneurysms. MATERIALS AND METHOD: We retrospectively reviewed 62 patients (18 men [29%] and 44 women [71%]) with a ruptured supratentorial aneurysm who underwent surgical clipping via the EATOKS approach from April 2003 to July 2012. In all our cases, we use a rigid endoscope of 0, 30, or 45 degrees to inspect the aneurysm and its surrounding anatomy before clipping and ultimately to verify the completeness of the aneurysm clipping and the patency of the adjacent neurovascular structures. RESULTS: All patients with ruptured supratentorial aneurysms were successfully clipped including three with multiple aneurysms. Surgically related major and minor as well as medically related complications were 10%, 15%, and 10%, respectively. Three patients (4.8%) died of massive cerebral infarction due to fulminant postoperative vasospasm, multiorgan failure, and adult respiratory distress syndrome. At 6-month follow up, 81% of patients achieved good outcomes with Glasgow Outcome Scales of 4 and 5. Patients' satisfaction with the cosmetic results was satisfactory to excellent in most cases. CONCLUSION: EATOKS is a viable and safe option in the neurosurgical armamentarium to treat ruptured supratentorial aneurysms. PMID- 26030375 TI - Exploring digital professionalism. AB - The widespread use of digital media (both computing devices and the services they access) has blurred the boundaries between our personal and professional lives. Contemporary students are the last to remember a time before the widespread use of the Internet and they will be the first to practice in a largely e-health environment. This article explores concepts of digital professionalism and their place in contemporary medical education, and proposes a series of principles of digital professionalism to guide teaching, learning and practice in the healthcare professions. Despite the many risks and fears surrounding their use, digital media are not an intrinsic threat to medical professionalism. Professionals should maintain the capacity for deliberate, ethical, and accountable practice when using digital media. The authors describe a digital professionalism framework structured around concepts of proficiency, reputation, and responsibility. Digital professionalism can be integrated into medical education using strategies based on awareness, alignment, assessment, and accountability. These principles of digital professionalism provide a way for medical students and medical practitioners to embrace the positive aspects of digital media use while being mindful and deliberate in its use to avoid or minimize any negative consequences. PMID- 26030376 TI - Is Japanese medical education ready for the Tokyo Olympic Games in 2020? PMID- 26030378 TI - Flipping the classroom with adaptive learning technology. PMID- 26030377 TI - Challenges to professionalism: Social accountability and global environmental change. AB - This article explores the concept of professionalism as it relates to social change and social accountability, and expands on them in the light of global environmental changes. Professionalism in medicine includes concepts of altruism, service, professional knowledge, self-regulation and autonomy. Current dialogues around social accountability suggest that medical schools should re-orientate their strategy and desired education, research and service outcomes to the health needs of the communities they serve.This article addresses the following questions: * How do we reconcile ideas of medical professionalism with the demands of creating a more equal, just, sustainable and socially inclusive society? * What new challenges do or will we face in relation to environmental degradation, biodiversity loss, ecosystem health and climate change? * How can medical schools best teach social and environmental responsiveness within a framework of professionalism? * How do medical schools ensure that tomorrow's doctors possess the knowledge, skills and attitude to adapt to the challenges they will face in future roles?We offer ideas about why and how medical educators can change, recommendations to strengthen the teaching of professionalism and social accountability and suggestions about the contribution of an emerging concept, that of "environmental accountability". PMID- 26030379 TI - Professionalism under fire: Conflict, war and epidemics. AB - Today's medical students (tomorrow's doctors) will be entering a world of conflict, war and regular outbreaks of infectious diseases. Despite numerous international declarations and treaties protecting human rights, the last few decades has been fraught with reports of "lapses" in medical professionalism involving torture and force-feeding of detainees (e.g. captured during the War on Terror) and health care professionals refusing to treat infected patients (e.g. HIV and Ebola). This paper provides some historical background to the changing status of a physician's duty to treat and how medical practitioners came to be involved in the inhumane treatment of detainees during the War on Terror, culminating in reports of "lapses" in professionalism. The Theory of Planned Behavior, which takes into account the individual, the environment and the social context, is used to explain the factors that might influence an individual's behavior in challenging situations. The paper concludes with some recommendations for medical and health professions education. The recommendations include selecting students who, as a minimum, can provide evidence of "basic" professionalism, engaging them in exploring the history of the medical profession, exposing them to contexts of uncertainty and moral dilemmas and challenging them to reflect on their responses. PMID- 26030380 TI - Reflections on feedback: Closing the loop. PMID- 26030381 TI - "Doctors on the move": Exploring professionalism in the light of cultural transitions. AB - As the world becomes "flattened" and travel is easier, doctors and other health professionals move and live around the world in large numbers: some for short periods (such as student electives) others on a longer-term or permanent basis. Similarly, as wider migration patterns play out, all doctors need to learn to work in multi-cultural environments, whether they move countries or work in their "home country". We consider cross-cultural aspects of "professionalism" in terms of medical students' and graduates' assimilation into different cultures and some of the aspects of professional practice that may be problematic where cultural expectations and practices may differ. Specifically we explore professional socialization, identity formation, acculturation and cultural competency as related concepts that help our understanding of challenges for individuals and strategies for curriculum development or support mechanisms. PMID- 26030382 TI - Teaching from junior doctors: The experience of medical students. PMID- 26030383 TI - Immune Reactions against Gene Gun Vaccines Are Differentially Modulated by Distinct Dendritic Cell Subsets in the Skin. AB - The skin accommodates multiple dendritic cell (DC) subsets with remarkable functional diversity. Immune reactions are initiated and modulated by the triggering of DC by pathogen-associated or endogenous danger signals. In contrast to these processes, the influence of intrinsic features of protein antigens on the strength and type of immune responses is much less understood. Therefore, we investigated the involvement of distinct DC subsets in immune reactions against two structurally different model antigens, E. coli beta-galactosidase (betaGal) and chicken ovalbumin (OVA) under otherwise identical conditions. After epicutaneous administration of the respective DNA vaccines with a gene gun, wild type mice induced robust immune responses against both antigens. However, ablation of langerin+ DC almost abolished IgG1 and cytotoxic T lymphocytes against betaGal but enhanced T cell and antibody responses against OVA. We identified epidermal Langerhans cells (LC) as the subset responsible for the suppression of anti-OVA reactions and found regulatory T cells critically involved in this process. In contrast, reactions against betaGal were not affected by the selective elimination of LC, indicating that this antigen required a different langerin+ DC subset. The opposing findings obtained with OVA and betaGal vaccines were not due to immune-modulating activities of either the plasmid DNA or the antigen gene products, nor did the differential cellular localization, size or dose of the two proteins account for the opposite effects. Thus, skin-borne protein antigens may be differentially handled by distinct DC subsets, and, in this way, intrinsic features of the antigen can participate in immune modulation. PMID- 26030384 TI - Determinants of unlawful file sharing: a scoping review. AB - We employ a scoping review methodology to consider and assess the existing evidence on the determinants of unlawful file sharing (UFS) transparently and systematically. Based on the evidence, we build a simple conceptual framework to model the psychological decision to engage in UFS, purchase legally or do nothing. We identify social, moral, experiential, technical, legal and financial utility sources of the decision to purchase or to file share. They interact in complex ways. We consider the strength of evidence within these areas and note patterns of results. There is good evidence for influences on UFS within each of the identified determinants, particularly for self-reported measures, with more behavioral research needed. There are also indications that the reasons for UFS differ across media; more studies exploring media other than music are required. PMID- 26030385 TI - Polymorphisms in autophagy genes are associated with paget disease of bone. AB - Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an "autophagosome." It has been reported that at least 18 ATG genes (autophagy related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series. PMID- 26030386 TI - The Effect of State Policies on Organ Donation and Transplantation in the United States. AB - IMPORTANCE: Shortages in transplantable solid organs remain a critical public health challenge in the United States. During the past 2 decades, all states have implemented policies to increase organ supply, although their effectiveness is unknown. OBJECTIVE: To determine the effects on organ donation and transplantation rates of state policies to provide incentives for volunteer donation. DESIGN, SETTING, AND PARTICIPANTS: Using a quasi-experimental design and difference-in-differences regression analyses, we estimated the effect of policies in all 50 states and the District of Columbia on organ donors per capita and the number of transplantations from January 1, 1988, to December 31, 2010. Analyses were also stratified by type of donor (living vs deceased). Data were derived from the United Network for Organ Sharing. All data collection occurred between July 7 and September 27, 2013. EXPOSURES: Policies of interest were the presence of first-person consent laws, donor registries, dedicated revenue streams for donor recruitment activities, population education programs, paid leave for donation, and tax incentives. Information on states' passage of various policies was obtained from primary legislative and legal sources. MAIN OUTCOMES AND MEASURES: The number of organ donors and transplantations per state, per year, during the study period. RESULTS: From 1988 to 2010, the number of states passing at least 1 donation-related policy increased from 7 (14%) to 50 (100%). First-person consent laws, donor registries, public education, paid leave, and tax incentives had no robust, significant association with either donation rates or number of transplants. The establishment of revenue policies, in which individuals contribute to a protected state fund for donation promotion activities, was associated with a 5.3% increase in the absolute number of transplants (95% CI, 0.57%-10.1%; P = .03). These associations were driven by a 4.9% increase in organ donations (95% CI, 0.97%-8.7%; P = .01) and an 8.0% increase in transplants (95% CI, 3.1%-12.9%; P = .001) from deceased donors as opposed to changes among living donors or transplants from living donors. CONCLUSIONS AND RELEVANCE: Nearly all state-level policies to encourage organ donation have had no observable effect on the rate of organ donation and transplantation in the United States. The one exception was the establishment of revenue policies to promote organ donation, which may have led to small increases in organ donations and transplantations from deceased donors. New policy designs are needed to increase donation rates and curtail the widening gap between organ supply and demand. PMID- 26030387 TI - Fragment Coupling and the Construction of Quaternary Carbons Using Tertiary Radicals Generated From tert-Alkyl N-Phthalimidoyl Oxalates By Visible-Light Photocatalysis. AB - The coupling of tertiary carbon radicals with alkene acceptors is an underdeveloped strategy for uniting complex carbon fragments and forming new quaternary carbons. The scope and limitations of a new approach for generating nucleophilic tertiary radicals from tertiary alcohols and utilizing these intermediates in fragment coupling reactions is described. In this method, the tertiary alcohol is first acylated to give the tert-alkyl N-phthalimidoyl oxalate, which in the presence of visible-light, catalytic Ru(bpy)3(PF6)2, and a reductant fragments to form the corresponding tertiary carbon radical. In addition to reductive coupling with alkenes, substitution reactions of tertiary radicals with allylic and vinylic halides is described. A mechanism for the generation of tertiary carbon radicals from tert-alkyl N-phthalimidoyl oxalates is proposed that is based on earlier pioneering investigations of Okada and Barton. Deuterium labeling and competition experiments reveal that the reductive radical coupling of tert-alkyl N-phthalimidoyl oxalates with electron-deficient alkenes is terminated by hydrogen-atom transfer. PMID- 26030389 TI - Factors influencing oral adherence: qualitative metasummary and triangulation with quantitative evidence. AB - BACKGROUND: Concern about adherence to oral agents among patients with cancer has grown as more oral agents are being used for cancer treatment. Knowledge of common factors that facilitate or inhibit adherence to oral medication regimens can be beneficial to clinicians in identifying patients at risk for nonadherence, in planning care to address barriers to adherence, and in educating patients about ways to improve adherence. OBJECTIVES: The focus of this review is to synthesize the evidence about factors that influence adherence and identify implications for practice. METHODS: Literature was searched via PubMed and CINAHL(r). Evidence regarding factors influencing adherence was synthesized using a metasummary of qualitative research and triangulated with findings from quantitative research. FINDINGS: Forty-four factors influencing adherence were identified from 159 research studies of patients with and without cancer. Factors associated with adherence in oncology and non-oncology cases included provider relations, side effects, forgetfulness, beliefs about medication necessity, establishing routines for taking medication, social support, ability to fit medications in lifestyle, cost, and medication knowledge. Among patients with cancer, depression and negative expectations of results also were shown to have a negative relationship to adherence. PMID- 26030388 TI - Why patients prescribed oral agents for cancer need training: a case study. AB - BACKGROUND: Oral agents for cancer (OACs) are a common form of treatment. However, with OACs, the responsibility shifts from supervised healthcare providers who work in a clinic to patients and caregivers who must manage treatment on their own at home. Consequently, patients and caregivers must be knowledgeable about all aspects of care. In addition, most patients with cancer are older and have multiple comorbid conditions treated by several providers who prescribe medications, further complicating care. OBJECTIVES: This purpose of this article is to present a patient perspective of managing treatment with OACs in the home setting. METHODS: A case study format was used to describe challenges faced by a patient newly prescribed OACs. FINDINGS: Data from the patient interviews support the urgent need for patient and caregiver training; the outcome of treatment for patients taking OACs depends significantly on the patient or caregiver managing treatment in the home setting. PMID- 26030390 TI - Theoretical foundations of adherence behaviors: synthesis and application in adherence to oral oncology agents. AB - BACKGROUND: The use of theory can provide structure for understanding the dynamics of adherence to oral agents for cancer (OACs) and facilitate the development of strategies for patient assessment and care planning related to oral adherence. OBJECTIVES: The focus of this article is to identify common theories pertinent to medication-taking behavior, as well as their applications toward assessment and care planning regarding adherence to OACs. Approaches to apply these theories and their concepts in clinical practice are identified. METHODS: Theories applied to adherence behaviors were reviewed, and their concepts were compared and synthesized. These concepts were then applied to medication adherence behavior. FINDINGS: Various theories can help healthcare providers to better understand the influences and determinants of patients' adherence decisions and behaviors. They can then be used to structure assessment and plan related aspects of care. PMID- 26030391 TI - Overview of the challenges related to oral agents for cancer and their impact on adherence. AB - BACKGROUND: The increasing number and complexity of oral agents for cancer (OACs) have created a paradigm shift in the process and outcomes in oncology care. With 25%-30% of new oncology medications in development being oral agents, and a steady increase in approvals in the past 5-10 years, the issues are relevant in clinical practice. OBJECTIVES: The purpose of this article is to provide an overview of the challenges related to OACs, including adherence, and to describe the consequences of adherence and resources for oncology nurses. METHODS: The literature was searched to determine challenges related to OACs and their impact on adherence, and an overview of the issues was compiled. FINDINGS: Oncology nurses are key stakeholders in recognizing the challenges and issues associated with the change in treatment regarding OACs. Oncology nurses are an integral part of managing the oral agent process, from access to adherence. Oncology nurses need to understand the issues surrounding OACs so that adherence practices can be improved. PMID- 26030392 TI - Oral agents for cancer: safety challenges and recommendations. AB - BACKGROUND: The lack of knowledge and standardization of safety practices related to prescribing, dispensing, administering, and monitoring oral agents for cancer (OACs) has created significant safety challenges for patients and healthcare providers. Problems identified with the use of OACs include possible medication errors, increased potential for toxicity, unintentional exposure of hazardous medications to healthcare providers and informal caregivers, and possible pollution of the environment. OBJECTIVES: The purpose of this review is to provide information about the current state of knowledge and recommendations in the literature regarding safety concerns with OACs and strategies for risk reduction. METHODS: Articles published from 2003-2014 were retrieved using PubMed, CINAHL(r), and the Cochrane Library. FINDINGS: As the number of OACs continues to increase, existing standards related to medication errors and safety will require ongoing revision to lessen the risks and hazards for patients, caregivers, and healthcare providers. PMID- 26030393 TI - Assessment and measurement of medication adherence: oral agents for cancer. AB - BACKGROUND: Clinicians are challenged to find ways to assess and measure adherence to oral agents for cancer (OACs). OBJECTIVES: The purpose of this article is to report on available ways to assess and measure medication adherence by patients with cancer. METHODS: Tools examined include the Morisky Medication Adherence Scale (MMAS) and the Adherence Estimator, which are able to predict risk of nonadherence. Adherence Starts With Knowledge (ASK(r))-12 and the Brief Adherence Rating Scale (BARS) are likely to be effective for predicting nonadherence and measuring adherence rates. FINDINGS: Additional research needs to focus on the testing of reliable and valid tools that are sensitive and specific to patients with cancer who are prescribed OACs. The authors found that the MMAS and Adherence Estimator tools may be useful at predicting risk of medication nonadherence, and the ASK-12 and BARS may be useful for measuring rates of adherence. Tools could be modified to a specific clinical setting and used in a standardized format so that nurses can assess risk of medication nonadherence and measure adherence rates of OACs. PMID- 26030394 TI - Putting evidence into practice: evidence-based interventions for oral agents for cancer. AB - BACKGROUND: The limited evidence available suggests that adherence to oral agents for cancer is a significant clinical problem and may have a substantial impact on treatment success or failure. Adherence is a difficult issue among patients who are very sick with a life-threatening disease who often must adhere to complex treatment protocols independently at home. OBJECTIVES: This article aims to identify effective interventions for the promotion, treatment, and management of adherence to oral agents for cancer and to synthesize the literature for use in clinical practice. METHODS: As part of the Oncology Nursing Society (ONS) Putting Evidence Into Practice (PEP) initiative, a comprehensive examination of the current literature was conducted to identify effective interventions for patients prescribed oral agents for cancer. The ONS PEP weight-of-evidence classification schema levels of evidence were used to categorize interventions to assist nurses in identifying strategies that are effective at improving adherence. FINDINGS: The majority of evidence found was conducted in conditions other than cancer; therefore, research is needed to identify whether these interventions are effective at promoting adherence in patients with cancer. PMID- 26030395 TI - Using tools and technology to promote education and adherence to oral agents for cancer. AB - BACKGROUND: The use of oral agents for cancer (OACs) is increasing, and oncology nurses are in an ideal position to educate patients about them and suggest methods to improve adherence. Once an OAC is ordered, the administration is the responsibility of the patient. Oncology nurses can use tools and technology to assist with education, which may promote adherence, and suggest reminder tools that can be used. Many electronic tools have been developed, such as smartphone applications, text messaging, electronic alarms, and glowing pill bottles. OBJECTIVES: The researchers reviewed electronic devices, as well as traditional methods such as calendars and pillboxes, that can assist patients in remembering to take the medication they are administering at home. METHODS: A literature search was compiled and websites were searched for patient education tools, reminder tools (electronic and manual), and smartphone applications. The project was part of the Oncology Nursing Society Putting Evidence Into Practice effort on oral adherence. FINDINGS: Education alone is insufficient to promote adherence to oral medication regimens. Multicomponent interventions have demonstrated improved adherence, and tools and technology directed at improving adherence to oral agents can be used. The researchers found multiple reminder aids to assist patients in adhering to an oral regimen. They are highlighted in this article. PMID- 26030396 TI - Circulating Hemocytes from Larvae of the Japanese Rhinoceros Beetle Allomyrina dichotoma (Linnaeus) (Coleoptera: Scarabaeidae) and the Cellular Immune Response to Microorganisms. AB - Hemocytes of the last larva of the Japanese rhinoceros beetle A. dichotoma (Linnaeus) (Coleoptera: Scarabaeidae) were classified as granulocytes, plasmatocytes, oenocytoids, spherulocytes, prohemocytes, and adipohemocytes. Among these cell types, only the granulocytes became immunologically activated with obvious morphological changes, displaying large amoeba-like, lobopodia-like, and fan-like structures. In addition, their cytoplasmic granules became larger and greatly increased in number. To explore whether these granules could be immunologically generated as phagosomes, total hemocytes were stained with LysoTracker. Greater than 90% of the granulocytes retained the LysoTracker dye at 4 h post-bacterial infection. In flow cytometry analysis, the red fluorescent signal was highly increased at 4 h post-bacterial infection (60.36%) compared to controls (5.08%), as was confirmed by fluorescent microscopy. After 12 h post infection, these signals returned to basal levels. The uptake of pathogens by granulocytes rapidly triggered the translocation of the microtubule-associated protein 1 light chain 3 alpha (LC3) to the phagosome, which may result in enhanced pathogen killing. PMID- 26030397 TI - Single-Crystal Atomic-Layered Molybdenum Disulfide Nanobelts with High Surface Activity. AB - Nanostructured molybdenum disulfide (MoS2) has emerged as a promising catalytic alternative to the widely used Pt in the hydrogen evolution reaction from water because it is inexpensive and earth-abundant. The central prerequisite in realizing its potential is to enhance the surface activities by increasing the concentration of metallic edge sites. However, MoS2 thermodynamics favors the presence of a two-dimensional basal plane, and therefore, the one-dimensional edge sites surrounding the basal plane are very limited. Herein, we report the first synthesis of single-crystal MoS2 nanobelts with the top surface fully covered by edge sites. The nanobelt structure comprises parallel stacked atomic layers with the basal plane vertical to the substrate, and these layer edges form the top surface of the nanobelt. The surface is highly active: it optically quenches all of the indirect band gap excitons and chemically leads to a high electrocatalytic hydrogen evolution efficiency (a low onset overpotential of 170 mV for an electrocatalytic current density of 20 mA/cm(2) and a Tafel slope of 70 mV/decade). PMID- 26030398 TI - p53 checkpoint ablation exacerbates the phenotype of Hinfp dependent histone H4 deficiency. AB - Histone Nuclear Factor P (HINFP) is essential for expression of histone H4 genes. Ablation of Hinfp and consequential depletion of histones alter nucleosome spacing and cause stalled replication and DNA damage that ultimately result in genomic instability. Faithful replication and packaging of newly replicated DNA are required for normal cell cycle control and proliferation. The tumor suppressor protein p53, the guardian of the genome, controls multiple cell cycle checkpoints and its loss leads to cellular transformation. Here we addressed whether the absence of p53 impacts the outcomes/consequences of Hinfp-mediated histone H4 deficiency. We examined mouse embryonic fibroblasts lacking both Hinfp and p53. Our data revealed that the reduced histone H4 expression caused by depletion of Hinfp persists when p53 is also inactivated. Loss of p53 enhanced the abnormalities in nuclear shape and size (i.e. multi-lobed irregularly shaped nuclei) caused by Hinfp depletion and also altered the sub-nuclear organization of Histone Locus Bodies (HLBs). In addition to the polyploid phenotype resulting from deletion of either p53 or Hinfp, inactivation of both p53 and Hinfp increased mitotic defects and generated chromosomal fragility and susceptibility to DNA damage. Thus, our study conclusively establishes that simultaneous loss of both Hinfp and the p53 checkpoint is detrimental to normal cell growth and may predispose to cellular transformation. PMID- 26030399 TI - Creation of Superheterojunction Polymers via Direct Polycondensation: Segregated and Bicontinuous Donor-Acceptor pi-Columnar Arrays in Covalent Organic Frameworks for Long-Lived Charge Separation. AB - By developing metallophthalocyanines and diimides as electron-donating and accepting building blocks, herein, we report the construction of new electron donor-acceptor covalent organic frameworks (COFs) with periodically ordered electron donor and acceptor pi-columnar arrays via direct polycondensation reactions. X-ray diffraction measurements in conjunction with structural simulations resolved that the resulting frameworks consist of metallophthalocyanine and diimide columns, which are ordered in a segregated yet bicontinuous manner to form built-in periodic pi-arrays. In the frameworks, each metallophthalocyanine donor and diimide acceptor units are exactly linked and interfaced, leading to the generation of superheterojunctions-a new type of heterojunction machinery, for photoinduced electron transfer and charge separation. We show that this polycondensation method is widely applicable to various metallophthalocyanines and diimides as demonstrated by the combination of copper, nickel, and zinc phthalocyanine donors with pyrommellitic diimide, naphthalene diimide, and perylene diimide acceptors. By using time-resolved transient absorption spectroscopy and electron spin resonance, we demonstrated that the COFs enable long-lived charge separation, whereas the metal species, the class of acceptors, and the local geometry between donor and acceptor units play roles in determining the photochemical dynamics. The results provide insights into photoelectric COFs and demonstrate their enormous potential for charge separation and photoenergy conversions. PMID- 26030400 TI - A Community-Led Medical Response Effort in the Wake of Hurricane Sandy. AB - On October 29, 2012, Hurricane Sandy made landfall in the neighborhood of Red Hook in Brooklyn, New York. The massive tidal surge generated by the storm submerged the coastal area, home to a population over 11,000 individuals, including the largest public housing development in Brooklyn. The infrastructure devastation was profound: the storm rendered electricity, heat, water, Internet, and phone services inoperative, whereas local ambulatory medical services including clinics, pharmacies, home health agencies, and other resources were damaged beyond functionality. Lacking these services or lines of communication, medically fragile individuals became isolated from the hospital and 911-emergency systems without a preexisting mechanism to identify or treat them. Medically fragile individuals primarily included those with chronic medical conditions dependent on frequent and consistent monitoring and treatments. In response, the Red Hook community established an ad hoc volunteer medical relief effort in the wake of the storm, filling a major gap that continues to exist in disaster medicine for low-income urban environments. Here we describe this effort, including an analysis of the medically vulnerable in this community, and recommend disaster risk reduction strategies and resilience measures for future disaster events. PMID- 26030401 TI - Developing fiber specific promoter-reporter transgenic lines to study the effect of abiotic stresses on fiber development in cotton. AB - Cotton is one of the most important cash crops in US agricultural industry. Environmental stresses, such as drought, high temperature and combination of both, not only reduce the overall growth of cotton plants, but also greatly decrease cotton lint yield and fiber quality. The impact of environmental stresses on fiber development is poorly understood due to technical difficulties associated with the study of developing fiber tissues and lack of genetic materials to study fiber development. To address this important question and provide the need for scientific community, we have generated transgenic cotton lines harboring cotton fiber specific promoter (CFSP)-reporter constructs from six cotton fiber specific genes (Expansin, E6, Rac13, CelA1, LTP, and Fb late), representing genes that are expressed at different stages of fiber development. Individual CFSP::GUS or CFSP::GFP construct was introduced into Coker 312 via Agrobacterium mediated transformation. Transgenic cotton lines were evaluated phenotypically and screened for the presence of selectable marker, reporter gene expression, and insertion numbers. Quantitative analysis showed that the patterns of GUS reporter gene activity during fiber development in transgenic cotton lines were similar to those of the native genes. Greenhouse drought and heat stress study showed a correlation between the decrease in promoter activities and decrease in fiber length, increase in micronaire and changes in other fiber quality traits in transgenic lines grown under stressed condition. These newly developed materials provide new molecular tools for studying the effects of abiotic stresses on fiber development and may be used in study of cotton fiber development genes and eventually in the genetic manipulation of fiber quality. PMID- 26030402 TI - Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. AB - It is widely accepted that drug discovery often requires a systems-level polypharmacology approach to tackle problems such as lack of efficacy and emerging resistance of single-targeted compounds. Network pharmacology approaches are increasingly being developed and applied to find new therapeutic opportunities and to re-purpose approved drugs. However, these recent advances have been relatively slow to be translated into the field of natural products. Here, we argue that a network pharmacology approach would enable an effective mapping of the yet unexplored target space of natural products, hence providing a systematic means to extend the druggable space of proteins implicated in various complex diseases. We give an overview of the key network pharmacology concepts and recent experimental-computational approaches that have been successfully applied to natural product research, including unbiased elucidation of mechanisms of action as well as systematic prediction of effective therapeutic combinations. We focus specifically on anticancer applications that use in vivo and in vitro functional phenotypic measurements, such as genome-wide transcriptomic response profiles, which enable a global modelling of the multi-target activity at the level of the biological pathways and interaction networks. We also provide representative examples of other disease applications, databases and tools as well as existing and emerging resources, which may prove useful for future natural product research. Finally, we offer our personal view of the current limitations, prospective developments and open questions in this exciting field. PMID- 26030403 TI - Catalytic Enantioselective Ring-Opening and Ring-Closing Reactions of 3 Isothiocyanato Oxindoles and N-(2-Picolinoyl)aziridines. AB - 3-Isothiocyanato oxindoles have been successfully applied to an asymmetric formal [3 + 3] cycloaddition reaction with aziridines for the first time. The reaction was efficiently mediated by an in situ generated magnesium catalyst employing (R) 3,3'-fluorous-BINOL as a simple chiral ligand. Serials of polycyclic frameworks could be obtained after a ring-closing step. The enantioenriched ring-opening product was also utilized to modified amino acids, peptides, and bifunctional organocatalyst. PMID- 26030404 TI - A Novel Transgenic Mouse Line for Tracing MicroRNA-155-5p Activity In Vivo. AB - MicroRNA-155 (miR-155) plays significant role in various physiological processes involving both innate and adaptive immunity. miR-155 expression level changes dynamically during various immune responses. However, current approaches for miR 155 detection at the RNA level do not precisely reflect the real-time activity. Herein, we generated a transgenic mouse line (R26-DTR-155T) for determination of miR-155-5p activity in vivo by inserting miR-155-5p target sequence downstream of a reporter transgene comprising Diphtheria Toxin Receptor and TagBlue fluorescence protein. Using this approach, R26-DTR-155T mice were able to measure variation in levels of miR-155-5p activity in specific cell types of interest. The DTR expression levels were inversely correlated with the endogenous miR-155 expression pattern as detected by quantitative RT-PCR. Our data demonstrate a novel transgenic mouse line which could be useful for tracing miR-155-5p activity in specific cell types through measurement of miR-155-5p activity at single cell level. PMID- 26030406 TI - Controlled thickness and morphology for highly efficient inverted planar heterojunction perovskite solar cells. AB - Recently, inverted planar heterojunction (PHJ) perovskite solar cells have been developed rapidly by numerous preparations and relative optimizations. Sequential solution deposition is easy to manipulate but it is difficult to control the thickness and morphology of perovskite films. In this article, we report an improved sequential deposition, named twice dipping-vapor solution deposition (TD VSD) technology, to accurately achieve superior perovskite films. It is demonstrated that the morphology of perovskite films depended on the substrate temperatures as well as the dipping times. The resulting solar cells showed the power conversion efficiency as high as 11.77% based on the ideal thickness and morphology. This work provides a simple but effective fabrication to well control the perovskite films and enhance the power conversion efficiency for inverted PHJ solar cells. PMID- 26030405 TI - Valproate Inhibits Methamphetamine Induced Hyperactivity via Glycogen Synthase Kinase 3beta Signaling in the Nucleus Accumbens Core. AB - Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3beta (GSK3beta) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA) dependent behaviors, there is less direct evidence that how VPA acts on the GSK3beta signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor GSK3beta at serine 9 and total GSK3beta levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3beta activity. We further investigated whether microinjection of VPA (300 MUg/0.5 MUl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3beta at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3beta activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity. PMID- 26030407 TI - Paracrine effects of haematopoietic cells on human mesenchymal stem cells. AB - Stem cell function decline during ageing can involve both cell intrinsic and extrinsic mechanisms. Bone and blood formation are intertwined in bone marrow, therefore haematopoietic cells and bone cells could be extrinsic factors for each other. In this study, we assessed the paracrine effects of extrinsic factors from haematopoietic cells on human mesenchymal stem cells (MSCs). Our data showed that haematopoietic cells stimulate proliferation, osteoblast differentiation and inhibit senescence of MSCs; TNF-alpha, PDGF-beta, Wnt1, 4, 6, 7a and 10a, sFRP-3 and sFRP-5 are dominantly expressed in haematopoietic cells; the age-related increase of TNF-alpha in haematopoietic cells may perform as a negative factor in the interactions of haematopoietic cells on MSCs via TNF-alpha receptors and then activating NF-kappaB signaling or Wnt/beta-catenin signaling to induce senescence and reduce osteoblast differentiation in MSCs. In conclusion, our data demonstrated that there are paracrine interactions of haematopoietic cells on human MSCs; immunosenescence may be one of the extrinsic mechanisms by which skeletal stem cell function decline during human skeletal ageing. PMID- 26030408 TI - Adaptive Molecular Evolution of PHYE in Primulina, a Karst Cave Plant. AB - Limestone Karst areas possess high levels of biodiversity and endemism. Primulina is a typical component of Karst endemic floras. The high species richness and wide distribution in various Karst microenvironments make the genus an idea model for studying speciation and local adaptation. In this study, we obtained 10 full length sequences of the phytochrome PHYE from available transcriptome resources of Primulina and amplified partial sequences of PHYE from the genomic DNA of 74 Primulina species. Then, we used maximum-likelihood approaches to explore molecular evolution of PHYE in this Karst cave plant. The results showed that PHYE was dominated by purifying selection in both data sets, and two sites were identified as potentially under positive selection. Furthermore, the omega ratio varies greatly among different functional domains of PHYE and among different species lineages. These results suggest that potential positive selection in PHYE might have played an important role in the adaption of Primulina to heterogeneous light environments in Karst regions, and different species lineages might have been subjected to different selective pressures. PMID- 26030410 TI - Correction: Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing. PMID- 26030409 TI - Cardiac metabolic pathways affected in the mouse model of barth syndrome. AB - Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS. PMID- 26030411 TI - Significance of plankton community structure and nutrient availability for the control of dinoflagellate blooms by parasites: a modeling approach. AB - Dinoflagellate blooms are frequently observed under temporary eutrophication of coastal waters after heavy rains. Growth of these opportunistic microalgae is believed to be promoted by sudden input of nutrients and the absence or inefficiency of their natural enemies, such as grazers and parasites. Here, numerical simulations indicate that increasing nutrient availability not only promotes the formation of dinoflagellate blooms but can also stimulate their control by protozoan parasites. Moreover, high abundance of phytoplankton other than dinoflagellate hosts might have a significant dilution effect on the control of dinoflagellate blooms by parasites, either by resource competition with dinoflagellates (thus limiting the number of hosts available for infection) or by affecting numerical-functional responses of grazers that consume free-living parasite stages. These outcomes indicate that although both dinoflagellates and their protozoan parasites are directly affected by nutrient availability, the efficacy of the parasitic control of dinoflagellate blooms under temporary eutrophication depends strongly on the structure of the plankton community as a whole. PMID- 26030412 TI - Some like it hot: Thermal tolerance and oxygen supply capacity in two eurythermal crustaceans. AB - Thermal sensitivity of the cardiorespiratory oxygen supply capacity has been proposed as the cardinal link underlying the upper boundary of the temperature niche in aquatic ectotherms. Here we examined the evidence for this link in two eurythermal decapods, the Giant tiger shrimp (Penaeus monodon) and the European crayfish (Astacus astacus). We found that both species have a temperature resistant cardiorespiratory system, capable of maintaining oxygen delivery up to their upper critical temperature (Tcrit). In neither species was Tcrit reduced in hypoxia (60% air saturation) and both species showed an exponential increase in heart and gill ventilation rates up to their Tcrit. Further, failure of action potential conduction in preparations of A. astacus motor neurons coincided with Tcrit, indicating that compromised nervous function may provide the underlying determinant for Tcrit rather than oxygen delivery. At high temperatures, absolute aerobic scope was maintained in P. monodon, but reduced in A. astacus. However, A. astacus also displayed reduced exercise intensity indicating that impaired muscle performance with resulting reduced tissue oxygen demand may explain the reduced scope rather than insufficient oxygen supply capacity. This interpretation agrees with early literature on aquatic ectotherms, correlating loss of nervous function with impaired locomotion as temperatures approach Tcrit. PMID- 26030413 TI - A highly sensitive fluorescence assay for methyltransferase activity by exonuclease-aided signal amplification. AB - DNA methylation, catalyzed by methyltransferases, plays critical roles in various biological processes in both prokaryotes and eukaryotes. Bacterial DNA adenine methyltransferases (DAM) are associated with bacterial pathogenesis and essential for bacterial virulence and viability. Since mammals do not methylate DNA at adenine, bacterial DAM is considered to be a great candidate target for developing new therapeutics for diseases. In the current study, we developed a simple, rapid and highly sensitive fluorescence method for the detection of DAM based on exonuclease-aided signal amplification. In the proposed strategy, a liberated amplifier upon DAM methylation and Dpn I digestion of the substrate can hybridize with a reporter (FT) that contains a quencher (TAMRA) at the second base of the 3' end and a fluorophore (FAM) at the fifth base. Upon hybridization, exonuclease III degrades the reporter in the formed duplex DNA from the 3' end successively, releasing the fluorophore from the quencher and resulting in an intensive appearance of the fluorescent signal. The amplifier will hybridize with another reporter and enter a new cycle, which therefore can amplify the signal and dramatically increase the detection sensitivity even with an extremely low amount of amplifier. Using this strategy, the detection limit down to 0.0025 U mL(-1) of DAM was achieved within a short assay time of 30 min. Furthermore, the assay was applied to evaluate endogenous DAM activity in E. coli cell at different growth stages as well as the effects of inhibitors on DAM activity. Given the attractive analytical performance, the sensing strategy may find many important applications in biomedical research and clinical diagnosis. PMID- 26030414 TI - TRAIL Is Decreased Before 20 Weeks Gestation in Women with Hypertensive Disorders of Pregnancy. AB - OBJECTIVE: The present study evaluated maternal plasma protein profiles before the onset of hypertensive disorders of pregnancy (HDP) to assess the relationship between maternal plasma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and HDP before 20 weeks gestation and to evaluate the discriminatory performance of plasma TRAIL levels for HDP. METHODS: A 2-phase discovery/validation study was designed. In the discovery phase, a nested case controlled study was performed using plasma sampled at 8 to 20 weeks gestation from 20 women who later developed HDP and from 20 age- and gestational week matched controls. Plasma was analyzed using a human protein microarray technology designed to simultaneously detect 507 proteins. The functional annotation and clustering of the differentially expressed proteins were performed using DAVID and the GO database. TRAIL levels were further validated in an independent study using plasma obtained at 8 to 20 weeks gestation from 53 women who later developed HDP and from 106 matched controls, and 62 clinical risk factors were investigated. RESULTS: In the protein microarray analysis, 23 proteins were differentially expressed between the two groups. The ELISA showed that women who later developed HDP had significantly lower TRAIL levels compared to women with uncomplicated pregnancies. The multivariable Cox regression analysis identified the following three factors that were entered into the final Cox regression model: gravidity (OR = 2.02, 95% CI 1.00-4.09), pre-pregnancy BMI (OR = 1.46, 95% CI 1.21-1.76) and TRAIL levels (OR = 0.97, 95% CI 0.94-0.99). The model had a significantly better discriminatory power (AUC = 0.83, 95% CI 0.75-0.88) compared to TRAIL alone as an independent predictor of HDP (AUC = 0.59, 95% CI 0.51-0.67). CONCLUSION: Twenty-three differentially expressed proteins before 20 weeks gestation might be associated with the pathogenesis of HDP. Plasma TRAIL levels were associated with the development of HDP, and the combination of plasma TRAIL levels with pre-pregnancy BMI and gravidity had a good discriminatory performance for HDP before 20 weeks gestation. PMID- 26030415 TI - Unintended consequences of management actions in salt pond restoration: cascading effects in trophic interactions. AB - Salt evaporation ponds have played an important role as habitat for migratory waterbirds across the world, however, efforts to restore and manage these habitats to maximize their conservation value has proven to be challenging. For example, salinity reduction has been a goal for restoring and managing former salt evaporation ponds to support waterbirds in the South Bay Salt Pond Restoration Project in San Francisco Bay, California, USA. Here, we describe a case study of unexpected consequences of a low-dissolved oxygen (DO) event on trophic interactions in a salt pond system following management actions to reduce salinity concentrations. We document the ramifications of an anoxic event in water quality including salinity, DO, and temperature, and in the response of the biota including prey fish biomass, numerical response by California Gulls (Larus californicus), and chick survival of Forster's Tern (Sterna forsteri). Management actions intended to protect receiving waters resulted in decreased DO concentrations that collapsed to zero for >= 4 consecutive days, resulting in an extensive fish kill. DO depletion likely resulted from an algal bloom that arose following transition of the pond system from high to low salinity as respiration and decomposition outpaced photosynthetic production. We measured a >= 6-fold increase in biomass of fish dropped on the levee by foraging avian predators compared with weeks prior to and following the low-DO event. California Gulls rapidly responded to the availability of aerobically-stressed and vulnerable fish and increased in abundance by two orders of magnitude. Mark-recapture analysis of 254 Forster's Tern chicks indicated that their survival declined substantially following the increase in gull abundance. Thus, management actions to reduce salinity concentrations resulted in cascading effects in trophic interactions that serves as a cautionary tale illustrating the importance of understanding the interaction of water quality and trophic structure when managing restoration of salt ponds. PMID- 26030416 TI - Bone Marrow Cultures Stimulated with IL-2/CpG Oligonucleotide Benefits Chromosomal Aberration Detection of CLL Patients when Compared with Standard Culture. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States. Metaphase-based cytogenetic tests, such as G-Band karyotyping, are among the most effective to detect CLL and provide significant prognostic information. However, the use of metaphase cytogenetics is currently problematic due to the low mitotic index of most CLL cells in vitro cultures. Even when metaphases can be generated in the presence of traditional B-cell mitogen LPS, the quality is often poor and aberrations escape detection. PURPOSE: We hypothesized that immuno-stimulatory interleukin-2(IL-2) plus cytosine phosphodiester-guanine oligodeoxynucleotide (CpG ODN) can work as a novel B-cell mitogen to stimulate bone marrow cultures which result in a higher mitotic index than regular standard bone marrow cultures stimulated with LPS. This will increase the clonal chromosomal aberration detection rate in patients with CLL. METHODS: Bone marrow samples from CLL patients were divided and parallel cultures were set up using LPS and CpG Oligonucleotide/ IL-2 (IL-2/CpG) as mitogens, respectively. Mitotic index was read under the microscope blindly by three different readers (SQ, LV, RM). G-banding, and Spectral Karyotyping (SKY) were performed to confirm and compare abnormalities. RESULTS: The readings showed that mitotic index in IL-2/CpG stimulated bone marrow cultures was seven times higher than that of standard LPS bone marrow cultures with an average standard deviation of "0.92'" and CI of 95%, p less than 0.05. G-Banding and Spectral Karyotyping (SKY) showed the same abnormalities in IL-2/CpG found in LPS Bone marrow cultures. CONCLUSION: According to the results, IL-2/CpG cultures should be used in the cytogenetic lab for chromosomal analysis instead of LPS due to the higher mitotic index that helps in reducing false negative results. Further research should be done in order to lower false negative CLL detection results. PMID- 26030418 TI - Maximizing the EMR's Educational Potential. PMID- 26030419 TI - Concurrent t(4;11) and t(1:19) in a Pediatric Patient with B-Lymphoblastic Leukemia/Lymphoma (B-ALL): A Case Report and Review of the Literature. AB - We herein present the case of a pediatric patient with B-lymphoblastic leukemia (B-ALL) with MLL gene rearrangement associated with the t(4;11)(q21;q23). Complete remission was achieved with standard B-ALL-directed chemotherapy and whole brain radiation. The patient subsequently relapsed and cytogenetic assessment revealed an additional acquired t(1;19)(q23;p13) associated with the TCF3-PBX1 fusion. After reinduction chemotherapy with a relapse B-ALL protocol the patient achieved disease remission; however, he developed respiratory complications and died. This represents a unique case as these two translocations have never been described concurrently in pediatric acute leukemia patients. PMID- 26030417 TI - Pain modulation in waking and hypnosis in women: event-related potentials and sources of cortical activity. AB - Using a strict subject selection procedure, we tested in High and Low Hypnotizable subjects (HHs and LHs) whether treatments of hypoalgesia and hyperalgesia, as compared to a relaxation-control, differentially affected subjective pain ratings and somatosensory event-related potentials (SERPs) during painful electric stimulation. Treatments were administered in waking and hypnosis conditions. LHs showed little differentiation in pain and distress ratings between hypoalgesia and hyperalgesia treatments, whereas HHs showed a greater spread in the instructed direction. HHs had larger prefrontal N140 and P200 waves of the SERPs during hypnotic hyperalgesia as compared to relaxation-control treatment. Importantly, HHs showed significant smaller frontocentral N140 and frontotemporal P200 waves during hypnotic hypoalgesia. LHs did not show significant differences for these SERP waves among treatments in both waking and hypnosis conditions. Source localization (sLORETA) method revealed significant activations of the bilateral primary somatosensory (BA3), middle frontal gyrus (BA6) and anterior cingulate cortices (BA24). Activity of these contralateral regions significantly correlated with subjective numerical pain scores for control treatment in waking condition. Moreover, multivariate regression analyses distinguished the contralateral BA3 as the only region reflecting a stable pattern of pain coding changes across all treatments in waking and hypnosis conditions. More direct testing showed that hypnosis reduced the strength of the association of pain modulation and brain activity changes at BA3. sLORETA in HHs revealed, for the N140 wave, that during hypnotic hyperalgesia, there was an increased activity within medial, supramarginal and superior frontal gyri, and cingulated gyrus (BA32), while for the P200 wave, activity was increased in the superior (BA22), middle (BA37), inferior temporal (BA19) gyri and superior parietal lobule (BA7). Hypnotic hypoalgesia in HHs, for N140 wave, showed reduced activity within medial and superior frontal gyri (BA9,8), paraippocampal gyrus (BA34), and postcentral gyrus (BA1), while for the P200, activity was reduced within middle and superior frontal gyri (BA9 and BA10), anterior cingulate (BA33), cuneus (BA19) and sub-lobar insula (BA13). These findings demonstrate that hypnotic suggestions can exert a top-down modulatory effect on attention/preconscious brain processes involved in pain perception. PMID- 26030420 TI - Functional assessment of disease-associated regulatory variants in vivo using a versatile dual colour transgenesis strategy in zebrafish. AB - Disruption of gene regulation by sequence variation in non-coding regions of the genome is now recognised as a significant cause of human disease and disease susceptibility. Sequence variants in cis-regulatory elements (CREs), the primary determinants of spatio-temporal gene regulation, can alter transcription factor binding sites. While technological advances have led to easy identification of disease-associated CRE variants, robust methods for discerning functional CRE variants from background variation are lacking. Here we describe an efficient dual-colour reporter transgenesis approach in zebrafish, simultaneously allowing detailed in vivo comparison of spatio-temporal differences in regulatory activity between putative CRE variants and assessment of altered transcription factor binding potential of the variant. We validate the method on known disease associated elements regulating SHH, PAX6 and IRF6 and subsequently characterise novel, ultra-long-range SOX9 enhancers implicated in the craniofacial abnormality Pierre Robin Sequence. The method provides a highly cost-effective, fast and robust approach for simultaneously unravelling in a single assay whether, where and when in embryonic development a disease-associated CRE-variant is affecting its regulatory function. PMID- 26030421 TI - Opioids contribute to fracture risk: a meta-analysis of 8 cohort studies. AB - OBJECTIVE: To evaluate the association between chronic opioid use for non-cancer pain and fracture risk by conducting a meta-analysis of cohort studies. METHODS: Cohort studies were identified by searching PubMed and EMBASE from their inception to July 2014. A fracture was considered an endpoint. The information was extracted by two authors independently. When the heterogeneity was significant, a random-effects model was used to calculate the overall pooled risk estimates. RESULTS: Eight cohort studies were included in the final meta analysis. On the basis of the Newcastle-Ottawa Scale (NOS), six studies were considered to be of high quality. The overall combined relative risk for the use of opioids and fractures was 1.88 (95% confidence interval [CI] 1.51-2.34). A subgroup analysis revealed the sources of heterogeneity. The sensitivity analysis indicated stable results, and no publication bias was observed. CONCLUSIONS: This meta-analysis of cohort studies demonstrates that opioids significantly increase the risk of fractures. PMID- 26030422 TI - Cortical Response Similarities Predict which Audiovisual Clips Individuals Viewed, but Are Unrelated to Clip Preference. AB - Cortical responses to complex natural stimuli can be isolated by examining the relationship between neural measures obtained while multiple individuals view the same stimuli. These inter-subject correlation's (ISC's) emerge from similarities in individual's cortical response to the shared audiovisual inputs, which may be related to their emergent cognitive and perceptual experience. Within the present study, our goal is to examine the utility of using ISC's for predicting which audiovisual clips individuals viewed, and to examine the relationship between neural responses to natural stimuli and subjective reports. The ability to predict which clips individuals viewed depends on the relationship of the EEG response across subjects and the nature in which this information is aggregated. We conceived of three approaches for aggregating responses, i.e. three assignment algorithms, which we evaluated in Experiment 1A. The aggregate correlations algorithm generated the highest assignment accuracy (70.83% chance = 33.33%) and was selected as the assignment algorithm for the larger sample of individuals and clips within Experiment 1B. The overall assignment accuracy was 33.46% within Experiment 1B (chance = 06.25%), with accuracies ranging from 52.9% (Silver Linings Playbook) to 11.75% (Seinfeld) within individual clips. ISC's were significantly greater than zero for 15 out of 16 clips, and fluctuations within the delta frequency band (i.e. 0-4 Hz) primarily contributed to response similarities across subjects. Interestingly, there was insufficient evidence to indicate that individuals with greater similarities in clip preference demonstrate greater similarities in cortical responses, suggesting a lack of association between ISC and clip preference. Overall these results demonstrate the utility of using ISC's for prediction, and further characterize the relationship between ISC magnitudes and subjective reports. PMID- 26030423 TI - Rugby-specific small-sided games training is an effective alternative to stationary cycling at reducing clinical risk factors associated with the development of type 2 diabetes: a randomized, controlled trial. AB - INTRODUCTION: The present study investigated whether rugby small-sided games (SSG) could be an effective alternative to continuous stationary cycling (CYC) training at reducing clinical risk factors associated with the development of type 2 diabetes mellitus (T2DM). METHODS: Thirty-three middle-aged (48.6+/-6.6y), inactive men were randomized into a CYC (n=11), SSG (n=11), or control (CON, n=11) group. Participants trained 3d.wk(-1) for 8 weeks, while control participants maintained normal activity and dietary patterns. Exercise duration was matched between groups, which involved CYC or SSG (four quarters, interspersed with 2-min passive recovery). Both training programs were designed to induce similar internal loads of maximal heart rate (~80-85%HRmax) and rating of perceived exertion. Pre- and post-intervention testing included dual-energy x ray absorptiometry scan, graded exercise test, fasting 2 h oral glucose tolerance test and resting muscle biopsy. Western blotting was used to assess the content of skeletal muscle proteins associated with mitochondrial biogenesis and glucose regulation. RESULTS: Both CYC and SSG increased VO2 at 80%HRmax, and reduced glycated haemoglobin, glucose area under the curve (AUC; SSG, -2.3+/-2.4; CYC 2.2+/-1.6 mmol.L(1)(120 min)(1); p<0.05), and total body fat-mass (SSG -2.6+/ 0.9%; CYC -2.9+/-1.1%), compared to no change in CON (p<0.05). SSG reduced insulin AUC (-30.4+/-40.7 ulU.mL(1)(120 min)(1); p<0.05) and increased total body fat-free mass (1.1+/-1.2 kg; p<0.05), with no change in CYC or CON (P>0.05). There were no differences within or between conditions for protein content of peroxisome proliferator-activated receptor gamma coactivator-1alpha, sirtuin-1, p53, glucose transporter-4, protein kinase AKT/PKB, myocyte enhancer factor 2A, mitochondrial transcription factor, nuclear respiratory factor (NRF)-1, NRF-2 or mitochondrial complexes I-V (p>0.05). CONCLUSION: Rugby small-sided games is an effective alternative to continuous cycling for improving metabolic risk-factors associated with the prevention of T2DM. Despite such positive adaptations in clinical risk factors, there were no changes in the content of skeletal muscle proteins associated with glucose regulation and mitochondrial biogenesis. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12613000874718. PMID- 26030425 TI - Perirhinal cortex lesions in rats: Novelty detection and sensitivity to interference. AB - Rats with perirhinal cortex lesions received multiple object recognition trials within a continuous session to examine whether they show false memories. Experiment 1 focused on exploration patterns during the first object recognition test postsurgery, in which each trial contained 1 novel and 1 familiar object. The perirhinal cortex lesions reduced time spent exploring novel objects, but did not affect overall time spent exploring the test objects (novel plus familiar). Replications with subsequent cohorts of rats (Experiments 2, 3, 4.1) repeated this pattern of results. When all recognition memory data were combined (Experiments 1-4), giving totals of 44 perirhinal lesion rats and 40 surgical sham controls, the perirhinal cortex lesions caused a marginal reduction in total exploration time. That decrease in time with novel objects was often compensated by increased exploration of familiar objects. Experiment 4 also assessed the impact of proactive interference on recognition memory. Evidence emerged that prior object experience could additionally impair recognition performance in rats with perirhinal cortex lesions. Experiment 5 examined exploration levels when rats were just given pairs of novel objects to explore. Despite their perirhinal cortex lesions, exploration levels were comparable with those of control rats. While the results of Experiment 4 support the notion that perirhinal lesions can increase sensitivity to proactive interference, the overall findings question whether rats lacking a perirhinal cortex typically behave as if novel objects are familiar, that is, show false recognition. Rather, the rats retain a signal of novelty but struggle to discriminate the identity of that signal. PMID- 26030424 TI - Outbreak of uncommon O4 non-agglutinating Salmonella typhimurium linked to minced pork, Saxony-Anhalt, Germany, January to April 2013. AB - INTRODUCTION: In January 2013, the National Reference Centre for Salmonella (NRC) detected a salmonellosis cluster in Saxony-Anhalt, Germany, caused by uncommon O4 non-agglutinating, monophasic Salmonella (S.) Typhimurium DT193. Circulating predominant monophasic S. Typhimurium DT193 clones typically display resistance phenotype ASSuT. We investigated common exposures to control the outbreak, and conducted microbiological investigations to assess the strains' phenotype. METHODS: We conducted a case-control study defining cases as persons living or working in Saxony-Anhalt diagnosed with the O4 non-agglutinating strain between January and March 2013. We selected two controls contemporarily reported with norovirus infection, frequency-matched on residence and age group, per case. We interviewed regarding food consumption, especially pork and its place of purchase. We calculated odds ratios (ORs) with 95% confidence intervals (95% CI) using logistic regression. The NRC investigated human and food isolates by PCR, SDS-PAGE, MLST, PFGE, MLVA and susceptibility testing. RESULTS: Altogether, 68 O4 non-agglutinating human isolates were confirmed between January and April 2013. Of those, 61 were assigned to the outbreak (median age 57 years, 44% female); 83% cases >= 60 years were hospitalized. Eating raw minced pork from butcheries within 3 days was associated with disease (31 cases, 28 controls; OR adjusted for sex: 3.6; 95% CI: 1.0-13). Phage type DT193 and MLST ST34 were assigned, and isolates' lipopolysaccharide (LPS) matched control strains. Isolates linked to Saxony-Anhalt exhibited PFGE type 5. ASSuT- and ACSSuT phenotype proportions were 34 and 39% respectively; 54% were resistant to chloramphenicol. Three pork isolates matched the outbreak strain. DISCUSSION: Raw minced pork was the most likely infection vehicle in this first reported outbreak caused by O4 non agglutinating, mostly chloramphenicol-resistant S. Typhimurium DT193. High hospitalization proportions demand awareness on the risk of consumption of raw pork among elderly. LPS analysis indicated O4 expression; therefore, testing with antisera from different lots is recommendable in unexpected agglutination reactions. PMID- 26030426 TI - Memory-enhancing amygdala stimulation elicits gamma synchrony in the hippocampus. AB - Activation of the amygdala either during emotional arousal or by direct stimulation is thought to enhance memory in part by modulating plasticity in the hippocampus. However, precisely how the amygdala influences hippocampal activity to improve memory remains unclear. In the present study, brief electrical stimulation delivered to the basolateral complex of the amygdala (BLA) following encounters with some novel objects led to better memory for those objects 1 day later. Stimulation also elicited field-field and spike-field CA3-CA1 synchrony in the hippocampus in the low gamma frequency range (30-55 Hz), a range previously associated with spike timing and good memory. In addition, the hippocampal spiking patterns observed during BLA stimulation reflected recent patterns of activity in the hippocampus. Thus, the results indicate that amygdala activation can prioritize memory consolidation of specific object encounters by coordinating the precise timing of CA1 membrane depolarization with incoming CA3 spikes to initiate long-lasting spike-timing dependent plasticity at putative synapses between recently active neurons. PMID- 26030427 TI - Stability of age-related deficits in the mnemonic similarity task across task variations. AB - Several studies in our lab and others have demonstrated age-related declines in mnemonic discrimination during a recognition memory paradigm using repeated items, similar lures, and novel foils. In particular, older adults exhibit a shift in lure discriminability, identifying similar lures as old items at a greater rate than young adults. This shift likely reflects deficits in pattern separation processing as a result of underlying changes in the dentate gyrus of the hippocampus. Here, we explored whether alterations in the task design could rescue the age-related impairment or whether it was ubiquitous as one might expect if the neurobiological mechanisms were truly disturbed by typical aging. Despite overt instructions to study item details during encoding, we replicated the age-related deficit in mnemonic discrimination. We established reliable effects with short lists of stimuli and with repeated testing. Altering the task design from a study/test to a continuous recognition paradigm replicated the age related shift in lure discrimination as well. Modifying the task to an old/new response (rather than old/similar/new) showed the same effect and a d' analysis showed that lure items were more akin to target items in older adults. Finally, we varied the test instructions in order to promote gist or veridical responses in the old/new task. Even these overt veridical test instructions did not ameliorate older adults' lure discrimination problems. Together, these findings demonstrate the robust nature of this age-related deficit and support the hypothesis that typical aging results in neurobiological changes that underlie this impairment. PMID- 26030428 TI - A novel strategy for dissecting goal-directed action and arousal components of motivated behavior with a progressive hold-down task. AB - Motivation serves 2 important functions: It guides actions to be goal-directed, and it provides the energy and vigor required to perform the work necessary to meet those goals. Dissociating these 2 processes with existing behavioral assays has been a challenge. In this article, we report a novel experimental strategy to distinguish the 2 processes in mice. First, we characterize a novel motivation assay in which animals must hold down a lever for progressively longer intervals to earn each subsequent reward; we call this the progressive hold-down (PHD) task. We find that performance on the PHD task is sensitive to both food deprivation level and reward value. Next, we use a dose of methamphetamine (METH) 1.0 mg/kg, to evaluate behavior in both the progressive ratio (PR) and PHD tasks. Treatment with METH leads to more persistent lever pressing for food rewards in the PR. In the PHD task, we found that METH increased arousal, which leads to numerous bouts of hyperactive responding but neither increases nor impairs goal directed action. The results demonstrate that these tools enable a more precise understanding of the underlying processes being altered in manipulations that alter motivated behavior. PMID- 26030429 TI - Early life stress produces compulsive-like, but not impulsive, behavior in females. AB - Adverse experiences during childhood are associated with the development of psychiatric disorders later in life. In particular, childhood abuse and neglect are risk factors for addictive disorders, such as substance misuse and pathological gambling. Impulsivity and compulsivity are key features of these disorders. Therefore, we investigated whether childhood adversity might increase vulnerability for addictive disorders through promotion of compulsive and impulsive behaviors. Rats were exposed to a brief, variable childhood or prepubertal stress protocol (Postnatal Days 25-27), and their behavior in a delay discounting task was compared with that of control animals in adulthood. Prepubertal stress produced compulsive-type behavior in females. Specifically, stressed females displayed inappropriate responses during a choice phase of the task, perseverating with nosepoke responding instead of choosing between 2 levers. Stressed females also showed learning impairments during task training. However, prepubertal stress was not associated with the development of impulsive behavior, as rates of delay discounting were not affected in either sex. Childhood adversity may contribute to the establishment and maintenance of addictive disorders by increasing perseveration in females. Perseverative behavior may therefore provide a viable therapeutic target for preventing the development of addictive disorders in individuals exposed to childhood adversity. These effects were not seen in males, highlighting sex differences in response to early life stress. PMID- 26030430 TI - Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats. AB - Attention-deficit hyperactivity disorder (ADHD) may be caused by genetic or environmental factors. Among environmental factors, perinatal complications are related, such as neonatal hypoxia-ischemia (HI). Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats, and to correlate the behavioral results with brain damage volume. Male Wistar rats were divided into 2 groups: HI and control. The HI procedure consisted of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O2 and 92% N2) on the 7th postnatal day. Two months later, animals were evaluated in the open field test during a single 5-min session, and in the 5-choice serial reaction time task (5 CSRTT), over 25 weeks. Our results demonstrated that animals submitted to HI manifest cognitive impairments in task acquisition, deficits in sustained attention, and increases in impulsivity and compulsivity in response to task manipulation in the 5-CSRTT. Locomotor activity observed in open field did not differ between groups. Moreover, brain volume loss in the total hemisphere, cerebral cortex, white matter, hippocampus, and striatum were observed in HI animals, especially on the side ipsilateral to the lesion. From these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD that are associated with general brain atrophy. PMID- 26030431 TI - Immune deficiency influences juvenile social behavior and maternal behavior. AB - Mice with severe combined immunodeficiency (SCID) lack functional T and B lymphocytes, and have impaired cognitive abilities. We assessed social behaviors in male SCID and C57BL/6 (B6) juvenile mice. In a social preference task, SCID mice spent more time than B6 mice investigating a novel adult male mouse. In a social recognition task, SCID mice habituated to a novel ovariectomized mouse, but failed to show dishabituation when presented with an unfamiliar individual. We hypothesized that partial immune restoration could normalize behaviors. SCID pups (postnatal Day 7) received either saline or splenocytes from normal donors. Splenocyte-replaced SCID mice spent less time interacting with a novel mouse than saline-injected SCID or B6 control mice. Again, control SCID mice failed to dishabituate to a novel mouse, but splenocyte-replaced SCID mice showed dishabituation. In both of these studies, B6 and SCID pairs were used to produce offspring that remained with their dams until weaning. There are no studies of maternal behavior in SCID dams; therefore to investigate the potential role for this factor, we quantified maternal behavior in SCID and B6 dams; several significant differences were found. To control for differences in maternal care, we mated heterozygous SCIDs to produce offspring. These homozygous SCID and wild type offspring reared by dams of the same genotypes displayed similar responses to a novel mouse; however, in the social recognition task, SCID males did not display dishabituation to a novel mouse. Taken together, our data indicate that Gene * Environment interactions influence social interactions in immune deficient mice. PMID- 26030432 TI - Adult social behavior with familiar partners following neonatal amygdala or hippocampus damage. AB - The social behavior in a cohort of adult animals who received ibotenic acid lesions of the amygdala (4 female, 3 male) or hippocampus (5 female, 3 male) as neonates, and sham-operated controls (4 female, 4 male) was evaluated in their home environments with the familiar opposite sex monkey (pair-mate) with whom they were housed. Amygdala-lesioned animals spent less time with their familiar partners and engaged in higher frequencies of stress-related behaviors than control animals. Hippocampus-lesioned animals spent significantly more time socially engaging their pair-mates than both control and amygdala-lesioned animals. These results suggest that early damage to the amygdala or hippocampus subtly alter patterns of adult social behavior in a familiar context and stand in sharp contrast to extant studies of early damage to the amygdala or hippocampus and to the more dramatically altered patterns of behavior observed after damage to the adult amygdala. PMID- 26030433 TI - A sex difference in circadian food-anticipatory rhythms in mice: Interaction with dopamine D1 receptor knockout. AB - Restricted daily feeding schedules induce circadian rhythms of food-anticipatory activity (FAA) in mice and other species. The entrainment pathway(s) and location(s) of circadian oscillators driving these rhythms have not been definitively established. An important role for dopamine signaling and the dorsal striatum is suggested by a confluence of observations, including shifting of FAA rhythms by dopamine receptor agonists and attenuation by antagonists and D1 receptor knockout (D1R KO). The dopamine reward system exhibits sexual dimorphisms in structure and function; if FAA rhythms are regulated by this system, then FAA may also be sexually dimorphic. To assess this prediction, disk running and general activity were recorded continuously in male and female C57BL/6J mice with food available ad libitum and then restricted to a 4-hr daily meal in the middle of the light period. Compared with male mice, FAA in female mice was significantly reduced in duration, total count, peak level, and ratio relative to nocturnal activity. To determine whether these differences were mediated by D1 receptors, male and female homozygous D1R KO mice were examined. Compared with wild type and heterozygous mice, female and male D1R KO mice exhibited a marked attenuation of FAA parameters. The magnitude of the attenuation was greater in female mice. These results confirm an important role for dopamine D1 receptors in the circadian mechanism by which mice anticipate a daily meal, and they reveal a previously unreported sexual dimorphism in the expression of food-anticipatory rhythms that is amplified by D1R KO. PMID- 26030435 TI - Synergy between cannabidiol, cannabidiolic acid, and Delta9-tetrahydrocannabinol in the regulation of emesis in the Suncus murinus (house musk shrew). AB - Smoked marijuana contains over 100 different cannabinoids, including the psychoactive compound Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC, CBD, and its acidic precursor, cannabidiolic acid (CBDA), have all been shown to have antiemetic properties in the Suncus murinus (S. murinus; house musk shrew). Here we show that when subthreshold antiemetic doses of CBD (2.5 mg/kg ip) or CBDA (0.05 mg/kg ip) are combined with a subthreshold antiemetic dose of THC (1 mg/kg ip) in the S. murinus, both lithium-chloride-induced vomiting and abdominal retching are dramatically suppressed. These results suggest that combined effects of these compounds may lead to better control of vomiting with fewer side effects. PMID- 26030434 TI - Physical exercise affects attentional orienting behavior through noradrenergic mechanisms. AB - Spontaneously hypertensive rats (SHRs), a commonly used animal model of attention deficit/hyperactivity disorder, exhibit little habituation of the orienting response to repeated presentations of a nonreinforced visual stimulus. However, SHRs that have access to a running wheel for 5, 10, or 21 days exhibit robust habituation that is indistinguishable from normo-active rats. Two days of exercise, in comparison, is not sufficient to affect habituation. Here we tested the hypothesis that the effect of exercise on orienting behavior in SHRs is mediated by changes in noradrenergic function. In Experiment 1, we found that 5, 10, or 21 days of access to a running wheel, but not 2 days, significantly reduced levels of the norepinephrine transporter in medial prefrontal cortex. In Experiment 2, we tested for a causal relationship between changes in noradrenergic function and orienting behavior by blocking noradrenergic receptors during exercise. Rats that received propranolol (beta adrenergic/noradrenergic receptor blocker) during 10 days of exercise failed to exhibit an exercise induced reduction in orienting behavior. The results inform a growing literature regarding the effects of exercise on behavior and the potential use of exercise as a treatment for mental disorders. PMID- 26030436 TI - A fibre-reinforced poroviscoelastic model accurately describes the biomechanical behaviour of the rat Achilles tendon. AB - BACKGROUND: Computational models of Achilles tendons can help understanding how healthy tendons are affected by repetitive loading and how the different tissue constituents contribute to the tendon's biomechanical response. However, available models of Achilles tendon are limited in their description of the hierarchical multi-structural composition of the tissue. This study hypothesised that a poroviscoelastic fibre-reinforced model, previously successful in capturing cartilage biomechanical behaviour, can depict the biomechanical behaviour of the rat Achilles tendon found experimentally. MATERIALS AND METHODS: We developed a new material model of the Achilles tendon, which considers the tendon's main constituents namely: water, proteoglycan matrix and collagen fibres. A hyperelastic formulation of the proteoglycan matrix enabled computations of large deformations of the tendon, and collagen fibres were modelled as viscoelastic. Specimen-specific finite element models were created of 9 rat Achilles tendons from an animal experiment and simulations were carried out following a repetitive tensile loading protocol. The material model parameters were calibrated against data from the rats by minimising the root mean squared error (RMS) between experimental force data and model output. RESULTS AND CONCLUSIONS: All specimen models were successfully fitted to experimental data with high accuracy (RMS 0.42-1.02). Additional simulations predicted more compliant and soft tendon behaviour at reduced strain-rates compared to higher strain-rates that produce a stiff and brittle tendon response. Stress-relaxation simulations exhibited strain-dependent stress-relaxation behaviour where larger strains produced slower relaxation rates compared to smaller strain levels. Our simulations showed that the collagen fibres in the Achilles tendon are the main load-bearing component during tensile loading, where the orientation of the collagen fibres plays an important role for the tendon's viscoelastic response. In conclusion, this model can capture the repetitive loading and unloading behaviour of intact and healthy Achilles tendons, which is a critical first step towards understanding tendon homeostasis and function as this biomechanical response changes in diseased tendons. PMID- 26030437 TI - Harmony from chaos? Perceptual-motor delays enhance behavioral anticipation in social interaction. AB - Effective interpersonal coordination is fundamental to robust social interaction, and the ability to anticipate a coactor's behavior is essential for achieving this coordination. However, coordination research has focused on the behavioral synchrony that occurs between the simple periodic movements of coactors and, thus, little is known about the anticipation that occurs during complex, everyday interaction. Research on the dynamics of coupled neurons, human motor control, electrical circuits, and laser semiconductors universally demonstrates that small temporal feedback delays are necessary for the anticipation of chaotic events. We therefore investigated whether similar feedback delays would promote anticipatory behavior during social interaction. Results revealed that coactors were not only able to anticipate others' chaotic movements when experiencing small perceptual motor delays, but also exhibited movement patterns of equivalent complexity. This suggests that such delays, including those within the human nervous system, may enhance, rather than hinder, the anticipatory processes that underlie successful social interaction. PMID- 26030438 TI - Unexpected abrupt onsets can override a top-down set for color. AB - A substantial literature supports the contention that the involuntary allocation of spatial attention to salient stimuli is contingent on the top-down goals of the observer. However, recent studies suggest that stimuli that violate expectations built up through experience can override top-down set, resulting in cognitively impenetrable, involuntary shifts of spatial attention. The present studies provide a strong test of this hypothesis by manipulating the frequency of presentation of salient, irrelevant, stimuli in spatial cuing and rapid serial visual presentation (RSVP) paradigms. Experiments 1, 2, and 3 found that for targets defined by color, infrequent, uninformative onset precues produce evidence of capture, but that for targets defined by onset, infrequent color singleton precues do not. Experiment 4 provides strong converging evidence for the ability of infrequent onsets to override a top-down set for color; when monitoring an RSVP stream for a colored target, an infrequent onset in the periphery produced a decrement in target report indicative of attentional capture. Together, the results suggest that infrequent onsets represent a special class of stimuli that can produce involuntary shifts of spatial attention that are cognitively impenetrable. PMID- 26030439 TI - Correction: Expanding our Understanding of Sequence-Function Relationships of Type II Polyketide Biosynthetic Gene Clusters: Bioinformatics-Guided Identification of Frankiamicin A from Frankia sp. EAN1pec. PMID- 26030440 TI - Evidence, Politics, and the Future of the Children's Health Insurance Program. PMID- 26030441 TI - The Effect of OSM on MC3T3-E1 Osteoblastic Cells in Simulated Microgravity with Radiation. AB - Bone deterioration is a challenge in long-term spaceflight with significant connections to patients experiencing disuse bone loss. Prolonged unloading and radiation exposure, defining characteristics of space travel, have both been associated with changes in inflammatory signaling via IL-6 class cytokines in bone. While there is also evidence for perturbed IL-6 class signaling in spaceflight, there has been scant examination of the connections between microgravity, radiation, and inflammatory stimuli in bone. Our lab and others have shown that the IL-6 class cytokine oncostatin M (OSM) is an important regulator of bone remodeling. We hypothesize that simulated microgravity alters osteoblast OSM signaling, contributing to the decoupling of osteolysis and osteogenesis in bone homeostasis. To test this hypothesis, we induced OSM signaling in murine MC3T3-E1 pre-osteoblast cells cultured in modeled microgravity using a rotating wall vessel bioreactor with and without exposure to radiation typical of a solar particle event. We measured effects on inflammatory signaling, osteoblast activity, and mineralization. Results indicated time dependent interactions among all conditions in the regulation of IL-6 production. Furthermore, OSM induced the transcription of OSM receptor beta, IL 6 receptor alpha subunits, collagen alpha1(I), osteocalcin, sclerostin, RANKL, and osteoprotegerin. Measurements of osteoid mineralization suggest that the spatial organization of the osteoblast environment is an important consideration in understanding bone formation. Taken together, these results support a role for altered OSM signaling in the mechanism of microgravity-induced bone loss. PMID- 26030442 TI - Differential CARM1 Isoform Expression in Subcellular Compartments and among Malignant and Benign Breast Tumors. AB - PURPOSE: Coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for ERalpha and cancer-relevant transcription factors, and can methylate diverse cellular targets including histones. CARM1 is expressed in one of two alternative splice isoforms, full-length CARM1 (CARM1FL) and truncated CARM1 (CARM1DeltaE15). CARM1FL and CARM1DeltaE15 function differently in transcriptional regulation, protein methylation, and mediation of pre-mRNA splicing in cellular models. METHODS: To investigate the functional roles and the prognosis potential of CARM1 alternative spliced isoforms in breast cancer, we used recently developed antibodies to detect differential CARM1 isoform expression in subcellular compartments and among malignant and benign breast tumors. RESULTS: Immunofluorescence in MDA-MB-231 and BG-1 cell lines demonstrated that CARM1DeltaE15 is the dominant isoform expressed in the cytoplasm, and CARM1FL is more nuclear localized. CARM1DeltaE15 was found to be more sensitive to Hsp90 inhibition than CARM1FL, indicating that the truncated isoform may be the oncogenic form. Clinical cancer samples did not have significantly higher expression of CARM1FL or CARM1DeltaE15 than benign breast samples at the level of mRNA or histology. Furthermore neither CARM1FL nor CARM1DeltaE15 expression correlated with breast cancer molecular subtypes, tumor size, or lymph node involvement. CONCLUSIONS: The analysis presented here lends new insights into the possible oncogenic role of CARM1DeltaE15. This study also demonstrates no obvious association of CARM1 isoform expression and clinical correlates in breast cancer. Recent studies, however, have shown that CARM1 expression correlates with poor prognosis, indicating a need for further studies of both CARM1 isoforms in a large cohort of breast cancer specimens. PMID- 26030443 TI - Gag-Pol Transframe Domain p6* Is Essential for HIV-1 Protease-Mediated Virus Maturation. AB - HIV-1 protease (PR) is encoded by pol, which is initially translated as a Pr160gag-pol polyprotein by a ribosomal frameshift event. Within Gag-Pol, truncated p6gag is replaced by a transframe domain (referred to as p6* or p6pol) located directly upstream of PR. p6* has been proposed as playing a role in modulating PR activation. Overlapping reading frames between p6* and p6gag present a challenge to researchers using genetic approaches to studying p6* biological functions. To determine the role of p6* in PR activation without affecting the gag reading frame, we constructed a series of Gag/Gag-Pol expression vectors by duplicating PR with or without p6* between PR pairs, and observed that PR duplication eliminated virus production due to significant Gag cleavage enhancement. This effect was mitigated when p6* was placed between the two PRs. Further, Gag cleavage enhancement was markedly reduced when either one of the two PRs was mutationally inactivated. Additional reduction in Gag cleavage efficiency was noted following the removal of p6* from between the two PRs. The insertion of a NC domain (wild-type or mutant) directly upstream of PR or p6*PR did not significantly improve Gag processing efficiency. With the exception of those containing p6* directly upstream of an active PR, all constructs were either noninfectious or weakly infectious. Our results suggest that (a) p6* is essential for triggering PR activation, (b) p6* has a role in preventing premature virus processing, and PMID- 26030444 TI - Multiplexable, locus-specific targeting of long RNAs with CRISPR-Display. AB - Noncoding RNAs play diverse roles throughout biology and exhibit broad functional capacity. To investigate and harness these capabilities, we developed clustered regularly interspaced short palindromic repeats (CRISPR)-Display (CRISP-Disp), a targeted localization method that uses Cas9 to deploy large RNA cargos to DNA loci. We demonstrate that functional RNA domains up to at least 4.8 kb long can be inserted in CRISPR guide RNA at multiple points, allowing the construction of Cas9 complexes with protein-binding cassettes, artificial aptamers, pools of random sequences and natural long noncoding RNAs. A unique feature of CRISP-Disp is the multiplexing of distinct functions at multiple targets, limited only by the availability of functional RNA motifs. We anticipate the use of CRISP-Disp for ectopically targeting functional RNAs and ribonucleoprotein (RNP) complexes to genomic loci. PMID- 26030445 TI - Functional differentiation of human pluripotent stem cells on a chip. AB - Microengineering human "organs-on-chips" remains an open challenge. Here, we describe a robust microfluidics-based approach for the differentiation of human pluripotent stem cells directly on a chip. Extrinsic signal modulation, achieved through optimal frequency of medium delivery, can be used as a parameter for improved germ layer specification and cell differentiation. Human cardiomyocytes and hepatocytes derived on chips showed functional phenotypes and responses to temporally defined drug treatments. PMID- 26030446 TI - Traction microscopy to identify force modulation in subresolution adhesions. AB - We present a reconstruction algorithm that resolves cellular tractions in diffraction-limited nascent adhesions (NAs). The enabling method is the introduction of sparsity regularization to the solution of the inverse problem, which suppresses noise without underestimating traction magnitude. We show that NAs transmit a distinguishable amount of traction and that NA maturation depends on traction growth rate. A software package implementing this numerical approach is provided. PMID- 26030447 TI - Plasmodium falciparum genetic crosses in a humanized mouse model. AB - Genetic crosses of phenotypically distinct strains of the human malaria parasite Plasmodium falciparum are a powerful tool for identifying genes controlling drug resistance and other key phenotypes. Previous studies relied on the isolation of recombinant parasites from splenectomized chimpanzees, a research avenue that is no longer available. Here we demonstrate that human-liver chimeric mice support recovery of recombinant progeny for the identification of genetic determinants of parasite traits and adaptations. PMID- 26030449 TI - Stereotype threat and racial differences in citizens' experiences of police encounters. AB - We conducted 2 studies to investigate how cultural stereotypes that depict Blacks as criminals affect the way Blacks experience encounters with police officers, expecting that such encounters induce Blacks to feel stereotype threat (i.e., concern about being judged and treated unfairly by police because of the stereotype). In Study 1, we asked Black and White participants to report how they feel when interacting with police officers in general. As predicted, Blacks, but not Whites, reported concern that police officers stereotype them as criminals simply because of their race. In addition, this effect was found for Black men but not Black women. In Study 2, we asked Black and White men to imagine a specific police encounter and assessed potential downstream consequences of stereotype threat. Consistent with Study 1, Black but not White men anticipated feeling stereotype threat in the hypothetical police encounter. Further, racial differences in anticipated threat translated into racial differences in anticipated anxiety, self-regulatory efforts, and behavior that is commonly perceived as suspicious by police officers. By demonstrating that Blacks might expect to be judged and treated unfairly by police because of the negative stereotype of Black criminality, this research extends stereotype threat theory to the new domain of criminal justice encounters. It also has practical implications for understanding how the stereotype could ironically contribute to bias-based policing and racial disparities in the justice system. PMID- 26030448 TI - Application of BRET to monitor ligand binding to GPCRs. AB - Bioluminescence resonance energy transfer (BRET) is a well-established method for investigating protein-protein interactions. Here we present a BRET approach to monitor ligand binding to G protein-coupled receptors (GPCRs) on the surface of living cells made possible by the use of fluorescent ligands in combination with a bioluminescent protein (NanoLuc) that can be readily expressed on the N terminus of GPCRs. PMID- 26030450 TI - The generalizability of gender bias: Testing the effects of contextual, explicit, and implicit sexism on labor arbitration decisions. AB - Decades of social-psychological research show that gender bias can result from features of the social context and from individual-level psychological predispositions. Do these sources of bias impact legal decisions, which are frequently made by people subject to factors that have been proposed to reduce bias (training and accountability)? To answer the question, we examined the potential for 3 major social-psychological theories of gender bias (role congruity theory, ambivalent sexism, and implicit bias) to predict outcomes of labor arbitration decisions. In the first study, undergraduate students and professional arbitrators made decisions about 2 mock arbitration cases in which the gender of the employee-grievants was experimentally manipulated. Student participants' decisions showed the predicted gender bias, whereas the decisions of experienced professionals did not. Individual-level attitudes did not predict the extent of the observed bias and accountability did not attenuate it. In the second study, arbitrators' explicit and implicit gender attitudes were significant predictors of their decisions in published cases. The laboratory and field results suggest that context, expertise, and implicit and explicit attitudes are relevant to legal decision-making, but that laboratory experiments alone may not fully capture the nature of their effect on legal professionals' decisions in real cases. PMID- 26030451 TI - Does the evidence support the case for mental health courts? A review of the literature. AB - Mental health courts divert offenders with mental illness away from incarceration in return for participation in monitored mental health treatment. Since their inception in the late 1990 s, the proliferation of these problem-solving courts has outpaced the research on their effectiveness. A review of the literature was conducted, yielding 20 articles from peer-reviewed journals. Mental health courts were evaluated for their ability to improve psychiatric symptoms, connect individuals with behavioral health services, improve overall quality of life, and reduce recidivism rates. A majority of articles reported favorable recidivism outcomes for participants, with few evaluating their impact on therapeutic outcomes. At the present time, mental health courts represent an emerging practice, but have not yet reached the level of an evidence-based model. Existing studies of mental health courts suffer from methodological limitations, specifically, a lack of experimental design, use of nonrepresentative samples, and assessment over short timeframes. Moreover, the inherently idiosyncratic nature of these courts and the variance in reporting of court-specific eligibility criteria make cross-article comparison more difficult. It is recommended that future mental health court research examine the impact of available community services, as well as consider the effect of criminogenic risk factors, on therapeutic and recidivism outcomes. PMID- 26030452 TI - Addressing depression in the workplace. PMID- 26030454 TI - A struggle to forgive: my long battle with dystonia. PMID- 26030455 TI - News & notes. PMID- 26030457 TI - Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors. AB - The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity. PMID- 26030456 TI - Modulation of Silica Nanoparticle Uptake into Human Osteoblast Cells by Variation of the Ratio of Amino and Sulfonate Surface Groups: Effects of Serum. AB - To study the importance of the surface charge for cellular uptake of silica nanoparticles (NPs), we synthesized five different single- or multifunctionalized fluorescent silica NPs (FFSNPs) by introducing various ratios of amino and sulfonate groups into their surface. The zeta potential values of these FFSNPs were customized from highly positive to highly negative, while other physicochemical properties remained almost constant. Irrespective of the original surface charge, serum proteins adsorbed onto the surface, neutralized the zeta potential values, and prevented the aggregation of the tailor-made FFSNPs. Depending on the surface charge and on the absence or presence of serum, two opposite trends were found concerning the cellular uptake of FFSNPs. In the absence of serum, positively charged NPs were more strongly accumulated by human osteoblast (HOB) cells than negatively charged NPs. In contrast, in serum containing medium, anionic FFSNPs were internalized by HOB cells more strongly, despite the similar size and surface charge of all types of protein-covered FFSNPs. Thus, at physiological condition, when the presence of proteins is inevitable, sulfonate-functionalized silica NPs are the favorite choice to achieve a desired high rate of NP internalization. PMID- 26030460 TI - Primary rotational stability of various megaprostheses in a biomechanical sawbone model with proximal femoral defects extending to the isthmus. AB - PURPOSE: Fixation of proximal femoral megaprostheses is achieved in the diaphyseal isthmus. We hypothesized that after extended bone resection including the proximal part of the isthmus a reduced length of fixation will affect the stability and fixation characteristics of these megaprostheses. The aim of this study was to analyze in a validated sawbone model with extended proximal femoral defects which types of implants have sufficient primary stability to allow osteointegration and to describe their fixation characteristics. METHODS: Four different cementless megaprostheses were implanted into 16 Sawbones with an AAOS type III defect after resection 11 cm below the lesser trochanter involving the proximal isthmus. To determine the primary implant stability relative micromotions between bone and implant were measured in relation to a cyclic torque of 7Nm applied on the longitudinal axis of the implant. We determined the fixation characteristics of the different implant designs by comparing these relative micromotions along the longitudinal stem axis. RESULTS: In the tested sawbones all studied implants showed sufficient primary stability to admit bone integration with relative micromotions below 150 um after adapting our results to physiologic hip joint loadings. Different fixation characteristics of the megaprostheses were determined, which could be explained by their differing design and fixation concepts. CONCLUSIONS: Cementless megaprostheses of different designs seem to provide sufficient primary stability to bridge proximal femoral defects if the diaphyseal isthmus is partially preserved. In our sawbone model the different implant fixation patterns can be related to their stem designs. No evidence can be provided to favor one of the studied implants in this setting. However, femoral morphology is variable and in different isthmus configurations specific implant designs might be appropriate to achieve the most favorable primary stability, which enables bone integration and consequently long term implant stability. PMID- 26030458 TI - Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways. AB - Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNgamma stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment. PMID- 26030461 TI - Exercising in polluted areas: study suggests benefits outweigh the health risks of NO2 exposure. PMID- 26030462 TI - Donor Postoperative Biliary Complications After Living-Donor Liver Transplant. AB - OBJECTIVES: Although the main factors responsible for donor deaths after living donor liver transplant are liver failure and sepsis, the most common donor complications are associated with the biliary tract. MATERIALS AND METHODS: Between April 2006 and May 2012, five hundred ninety-three donors underwent living-donor hepatectomy procedures for living-donor liver transplants. The mean age of donors was 31.0 +/- 9.9 years and the ratio of men to women was 341:252. Of all donors, 533 (89.9%) underwent a right lobe hepatectomy, 45 (7.6%) underwent a left lateral segmentectomy, and 15 (2.5%) underwent a left hepatectomy. RESULTS: Biliary complications were observed in 51 liver donors (8.6%). Based on the Clavien-Dindo classification, grade I and grade II complications were 3.2% and 0%, while grade IIIa and grade IIIb complications were observed in 3.5% and 1.85% of cases. Right lobe donor biliary complications occurred at the rate of 8.2% in 44 donors. Grade IV and grade V complications were not observed. Grade IIIa complications necessitating radiologic and endoscopic procedures were observed in 21 liver donors (3.5%). Bile leakage unresponsive to medical therapy was detected in 19 donors (3.2%). Nasobiliary catheters were placed in 3 of 19 donors and internal stents were placed in 1. Two sessions of balloon dilatation were performed in the 2 grade IIIb donors (0.33%). Biliary strictures observed in 2 right lobe donors and 1 left lobe donor was treated by hepaticojejunostomy an average of 14 months after surgery. CONCLUSIONS: Avoidance of intraoperative issues and early recognition of bile leakage are fundamental in preventing complications in living-donor liver transplant donors. PMID- 26030463 TI - Phytochemical, chromatographic and spectroscopic investigation of Carum copticum seeds and their potential as immunomodulatory agents. AB - CONTEXT: Carum copticum seeds have been prescribed in the traditional system of medicine for the treatment of immune disorders, such as asthma and rheumatism. OBJECTIVE: The objective of this study was to determine immunomodulatory effects of the alcoholic extract and isolated compounds in Swiss albino mice. MATERIALS AND METHODS: Seeds of C. copticum were extracted with 95% v/v alcohol. The immunomodulatory activity of the crude extract was evaluated at the doses of 100, 300, and 500 mg/kg body weight of mice, administered in mice once daily (orally) for 25 days. Volatile oil of C. copticum was isolated by steam distillation and was characterized by GLC and HPLC. Bio-assay-guided fractionation and isolation were carried out and the isolated compounds were characterized and subjected to immunomodulatory activity studies. RESULTS: The n-hexane fraction yielded p cymene, carvacrol, and alpha-pinene. The LD50 value of the crude extract was found to be 4500 mg/kg and the values reported for p-cymene, carvacrol, and alpha pinene in the literature were 4750, 810, and 3700 mg/kg, respectively. The oral administration of crude extract, n-hexane fraction (HEF), and isolated oils at the dose of 500, 150, and 50 mg/kg body weight, respectively, showed a significant increase in the HA titers, DTH-response, and phagocytosis. The stimulatory effect observed, on humoral and cellular immunity, was compared with the standard (levamisole treated) and control groups. DISCUSSION AND CONCLUSION: The results obtained in the study endorse the traditional use of the seeds of C. copticum and the isolated constituents act as immunostimulants. PMID- 26030464 TI - Regulation of apoptosis through bcl-2/bax proteins expression and DNA damage by Zanthoxylum alatum. AB - CONTEXT: Many of the major chemotherapeutic agents are secondary metabolites found in nature. Zanthoxylum alatum Roxb. (Rutaceae) is traditionally used in the treatment of various diseases. OBJECTIVE: The present study evaluates the apoptotic activity of methanol extract of Z. alatum (MEZA) on Ehrlich ascites tumor (EAT) in Swiss albino mice. MATERIALS AND METHODS: The presence of flavonoids in MEZA was standardized by HPLC. The in vitro cytotoxicity of MEZA was measured by the MTT assay. The in vivo antitumor activity of MEZA (100 and 200 mg/kg b.w., i.p. for 9 days) was also evaluated. On the 10th day, EAT tumor volume, cell viability, and hematological parameters were assayed. Apoptotic morphology was determined by acredine orange/ethedium bromide using fluorescence microscopy. Apoptosis percentage was measured by flow cytometric analysis using annexine-V-FITC. Also, DNA damage and bcl-2/bax were estimated by UV-method and western blot, respectively. RESULTS AND DISCUSSION: HPLC analysis revealed presence of three flavonoids, rutin, myricetin, and quercetin. MEZA showed satisfactory cytotoxicity in MTT assay (IC50 = 111.50 ug/ml). The extract significantly (p < 0.01) changed the tumor volume, viable, non-viable cell count, and hematological parameters towards the normal. Apoptotic activity of MEZA was confirmed by acridine orange/ethidium bromide staining, annexin-V-FITC staining, DNA fragmentation, and Bcl-2/Bax ratio. CONCLUSION: The study showed that MEZA has antitumor activity which may be due to the presence of flavonoids in the extract. PMID- 26030465 TI - Wound healing activity of extracts derived from Shorea robusta resin. AB - CONTEXT: Shorea robusta Gaertn.f. (Dipterocarpaceae) resin is used for treating infected wounds and burns by tribals in India. OBJECTIVES: The objective of this study was to investigate wound-healing activity of S. robusta resin extracts and essential oil in rats. MATERIALS AND METHODS: Methanol extract (SRME), petroleum ether, benzene insoluble fraction of methanol extract (SRPEBIME), and essential oil (SREO) of S. robusta resin were incorporated in soft yellow paraffin (10% w/w) and applied once daily on incision and excision wounds of Wistar rats. Framycetin ointment (1.0% w/w) was applied to the standard group. Tensile strength (on the 10th day), wound contraction, and scar area (on the 14th day) were recorded. On the 15th day, granulation tissues of excision wounds were analyzed for total protein, hydroxyproline, and hexosamine contents and activities of lipid peroxidation and super oxide dismutase (SOD). Histopathology of the wounds was also studied. RESULTS AND DISCUSSION: SRPEBIME and SREO healed incision and excision wounds faster than plain ointment base and framycetin. Tensile strength of SRPEBIME-treated incision wounds was 53% higher than that of control animals. In excision wounds, wound contraction and scar areas were found to be 99% and 7.7 mm(2) (SRPEBIME) and 71.7% and 21 mm(2) (control). Protein and hydroxyproline contents were higher in SRPEBIME (20.8 and 3.5% w/w) and SREO (17.4 and 2.8% w/w) groups as against 9.95 and 1.48% w/w in control groups. Histopathology revealed complete epithelization and new blood vessel formation in SRPEBIME groups. DISCUSSION AND CONCLUSION: SRPEBIME and SREO have significant wound-healing activities on incision and excision wounds. PMID- 26030466 TI - Reversibility in Reactions of Linker-Bridged Distannenes with Terminal Alkynes at Ambient Temperature. AB - The linker-bridged distannene [(2,6-Mes2)C6H3Sn]2C12H8 (1) featuring an acenaphthene linker and the sterically demanding terphenyl substituent Ar(Me) (= C6H3-2,6-Mes2; Mes = C6H2-2,4,6-Me3) was prepared and characterized by single crystal analysis, NMR spectroscopy, as well as elemental analysis. Furthermore, the reactivity of distannene 1 and previously reported distannenes 2 and 3, bearing either a naphthalene or a 9,9-dimethylxanthene backbone and the terphenyl substituent Ar(Me), as well as bis(stannylene) 4, featuring a 9,9 dimethylxanthene backbone and the terphenyl substituent Ar(iPr) (= C6H3-2,6 Trip2; Trip = C6H2-2,4,6-i-Pr3), toward terminal alkynes at ambient temperature was investigated, leading to the formal [2 + 2] cycloaddition products 5-9. The reactions of distannene 1 with trimethylsilylacetylene and phenylacetylene, the reaction of distannene 2 with trimethylsilyl-acetylene, as well as the reaction of bis(stannylene) 4 with phenylacetylene show reversibility, while distannenes 2 and 3 react irreversibly with phenylacetylene at room temperature. A van't Hoff analysis of variable-temperature (1)H NMR spectra of the cycloadduct of the reaction of distannene 1 with trimethylsilylacetylene afforded a dissociation enthalpy (DeltaHdiss) of 71.6 kJ.mol(-1), which is in surprisingly good agreement with the results of accompanying DFT calculations (DeltaHdiss = 70.9 kJ.mol(-1)). PMID- 26030467 TI - Household water quantity and health: a systematic review. AB - While the quantity of water used in the home is thought to be an important determinant of health, much of the evidence relies on using water access as a proxy for quantity. This review examines the health effects of household water quantity using studies that directly measured water quantity. We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science, and article reference lists. Eligible studies included experimental and observational studies that measured a difference in water quantity and quantified an association between water quantity and health outcomes. 21 studies, divided into six of the many possible water-quantity associated outcomes, met the eligibility criteria. Due to heterogeneity in designs, settings, methods, and outcomes, a meta-analysis was inappropriate. Overall results showed a positive association between water quantity and health outcomes, but the effect depended on how the water was used. Increased water usage for personal hygiene was generally associated with improved trachoma outcomes, while increased water consumption was generally associated with reduced gastrointestinal infection and diarrheal disease and improved growth outcomes. In high-income countries, increased water consumption was associated with higher rates of renal cell carcinoma and bladder cancer but not associated with type II diabetes, cardiac-related mortality, or all-cause mortality. PMID- 26030468 TI - Modelling Anopheles gambiae s.s. Population Dynamics with Temperature- and Age Dependent Survival. AB - Climate change and global warming are emerging as important threats to human health, particularly through the potential increase in vector- and water-borne diseases. Environmental variables are known to affect substantially the population dynamics and abundance of the poikilothermic vectors of disease, but the exact extent of this sensitivity is not well established. Focusing on malaria and its main vector in Africa, Anopheles gambiae sensu stricto, we present a set of novel mathematical models of climate-driven mosquito population dynamics motivated by experimental data suggesting that in An. gambiae, mortality is temperature and age dependent. We compared the performance of these models to that of a "standard" model ignoring age dependence. We used a longitudinal dataset of vector abundance over 36 months in sub-Saharan Africa for comparison between models that incorporate age dependence and one that does not, and observe that age-dependent models consistently fitted the data better than the reference model. This highlights that including age dependence in the vector component of mosquito-borne disease models may be important to predict more reliably disease transmission dynamics. Further data and studies are needed to enable improved fitting, leading to more accurate and informative model predictions for the An. gambiae malaria vector as well as for other disease vectors. PMID- 26030469 TI - Socioeconomic inequalities and occupational injury disability in china: a population-based survey. AB - OBJECTIVE: To estimate the prevalence of occupational injury disability (OID) and to examine the socioeconomic status of OID in China. METHODS: The data derived from the China National Sample Survey on Disability in 2006 involving people aged 16-59 years old. Descriptive statistics are used to measure OID's prevalence, and a binary logistic regression is used to identify the risk factors. RESULTS: The population-weighted prevalence of OID is 1.81 (95% confidence interval (CI): 1.67 1.94). Socioeconomic risk factors include male sex, older age, living in urban areas, junior high school education, income below the poverty line, a lack of occupational injury insurance, living in the western region and working in high risk occupations. CONCLUSIONS: OID is common among Chinese people aged 16-59 years old. Being male or older and having a lower income are risk factors for OID, similar to the results of previous research, but education is different. More training and education needs to be implemented to prevent OID. PMID- 26030470 TI - Review of HIV Testing Efforts in Historically Black Churches. AB - This paper aims to critically assess the state of HIV testing in African American churches. A comprehensive review of peer-reviewed publications on HIV testing in church-based settings was conducted by two independent coders. Twenty-six papers published between 1991 and 2015, representing 24 unique projects, were identified addressing at least one dimension of HIV testing. Thirteen faith-based projects have implemented HIV testing events or had clergy promote the importance of testing and knowing one's HIV status, but empirical data and rigorous study designs were limited. Only eight papers reported onsite HIV testing in churches. Less than 5% of the studies reported the percentage of congregants who returned for their test results. Finally, no study has examined at baseline or post intervention behavioral intentions to be screened for HIV. Future research is needed to evaluate the effectiveness of HIV testing in churches and to explore the possibilities of the role of the church and leadership structure in the promotion of HIV treatment and care. PMID- 26030471 TI - Organising a safe space for navigating social-ecological transformations to sustainability. AB - The need for developing socially just living conditions for the world's growing population whilst keeping human societies within a 'safe operating space' has become a modern imperative. This requires transformative changes in the dominant social norms, behaviours, governance and management regimes that guide human responses in areas such as urban ecology, public health, resource security (e.g., food, water, energy access), economic development and biodiversity conservation. However, such systemic transformations necessitate experimentation in public arenas of exchange and a deepening of processes that can widen multi-stakeholder learning. We argue that there is an emergent potential in bridging the sustainability transitions and resilience approaches to create new scientific capacity that can support large-scale social-ecological transformations (SETs) to sustainability globally, not just in the West. In this article, we elucidate a set of guiding principles for the design of a 'safe space' to encourage stronger interactions between these research areas and others that are relevant to the challenges faced. We envisage new opportunities for transdisciplinary collaboration that will develop an adaptive and evolving community of practice. In particular, we emphasise the great opportunity for engaging with the role of emerging economies in facilitating safe space experimentation. PMID- 26030472 TI - The Effect of Engagement in Everyday Occupations, Role Overload and Social Support on Health and Life Satisfaction among Mothers. AB - One of the founding assumptions underlying the health professions is the belief that there is a strong relationship between engagement in occupations, health, and wellbeing. The ability to perform everyday occupations (occupational performance) has a positive effect on health and wellbeing. However, there is also conflicting evidence indicating that participation in multiple roles or in certain occupations may lead to poorer health. Therefore, there is a need to better understand this relationship. The purpose of the present study was to examine three possible theoretical models to explain mothers' health and life satisfaction from the perspective of their occupational performance, their role load, and their social support. 150 married mothers, ages of 25-45, who had at least one child between the ages of one to ten years, participated in the study. Data were collected by using seven self-report questionnaires. The models were analyzed using Structural Equation Modeling. The results show that social support has a direct effect on mothers' physical health and life satisfaction and an indirect effect, mediated through the occupational performance variables, on mothers' mental health and life satisfaction. Role overload does not affect mothers' health and life satisfaction. These results suggest that mothers could benefit from health programs that help them manage their occupational routines. Such programs should focus on improving the mother's occupational performance and adapting her social environment to fit her occupational needs. PMID- 26030473 TI - Anomia produced by direct cortical stimulation of the pre-supplementary motor area in a patient undergoing preoperative language mapping. AB - There is sparse data on the analysis of supplementary motor area in language function using direct cortical stimulation of the supplementary motor area. Here, we report a patient who experienced isolated anomia during stimulation of the anterior supplementary motor area and discuss the role of the supplementary motor area in speech production. The role of the pre-supplementary motor. area in word selection, observed in fMRI studies, can be confirmed by direct cortical stimulation. PMID- 26030474 TI - High-Performing Thin-Film Transistors in Large Spherulites of Conjugated Polymer Formed by Epitaxial Growth on Removable Organic Crystalline Templates. AB - Diketopyrrolopyrrole (DPP)-based conjugated polymer PDTDPPQT was synthesized and was used to perform epitaxial polymer crystal growth on removable 1,3,5 trichlorobenzene crystallite templates. A thin-film transistor (TFT) was successfully fabricated in well-grown large spherulites of PDTDPPQT. The charge carrier mobility along the radial direction of the spherulites was measured to be 5.46-12.04 cm(2) V(-1) s(-1), which is significantly higher than that in the direction perpendicular to the radial direction. The dynamic response of charge transport was also investigated by applying a pulsed bias to TFTs loaded with a resistor (~20 MOmega). The charge-transport behaviors along the radial direction and perpendicular to the radial direction were investigated by static and dynamic experiments through a resistor-loaded (RL) inverter. The RL inverter made of PDTDPPQT-based TFT operates well, maintaining a fairly high switching voltage ratio (Vout(ON)/Vout(OFF)) at a relatively high frequency when the source-drain electrodes are aligned parallel to the radial direction. PMID- 26030475 TI - Structure-based view on [PSI(+)] prion properties. AB - Yeast [PSI(+)] prion is one of the most suitable and well characterized system for the investigation of the prion phenomenon. However, until recently, the lack of data on the 3D arrangement of Sup35p prion fibrils hindered progress in this area. The recent arrival in this field of new experimental techniques led to the parallel and in-register superpleated beta-structure as a consensus model for Sup35p fibrils. Here, we analyzed the effect of amino acid substitutions of the Sup35 protein through the prism of this structural model. Application of a newly developed computational approach, called ArchCandy, gives us a better understanding of the effect caused by mutations on the fibril forming potential of Sup35 protein. This bioinformatics tool can be used for the design of new mutations with desired modification of prion properties. Thus, we provide examples of how today, having progress toward elucidation of the structural arrangement of Sup35p fibrils, researchers can advance more efficiently to a better understanding of prion [PSI(+)] stability and propagation. PMID- 26030477 TI - Teleocortin: A Novel Member of the CRH Family in Teleost Fish. AB - The CRH family of neuropeptides, including CRH and urocortins, plays pivotal roles in the regulation of physiological and behavioral stress responses in vertebrates. In this study, we identified a previously undescribed member of the CRH family of peptides in a teleost fish species (medaka; Oryzias latipes) and named this peptide teleocortin (Tcn). Medaka Tcn is a 41-amino acid polypeptide derived from the C terminus of a larger precursor protein that is encoded by a 2 exon gene, thus sharing common structural features with known CRH family peptides. tcn was found exclusively in teleost fish. Phylogenetic analysis suggested that tcn probably has an ancient origin but was lost from the tetrapod lineage shortly after the divergence of the teleost and tetrapod lineages. In the medaka brain, tcn was expressed in nuclei of the telencephalon, preoptic area, hypothalamus, tegmentum, and isthmic region. Because none of these nuclei have been implicated in the control of ACTH secretion from the pituitary, Tcn may exert its effects centrally in the brain rather than via stimulation of the pituitary-adrenal/interrenal axis. Most, if not all, tcn-expressing neurons also expressed crh, suggesting that Tcn and Crh share common physiological functions. Moreover, Tcn activated Crh receptors 1 and 2 with equivalent or slightly higher potency than Crh, further suggesting that these peptides share common functions. Taken together, these data identified Tcn as a novel, teleost-specific member of the CRH family of peptides that may act centrally with Crh to regulate physiological and behavioral stress responses. PMID- 26030478 TI - NO reduction by CO over CuO supported on CeO2-doped TiO2: the effect of the amount of a few CeO2. AB - This work is mainly focused on the investigation of the influence of the amount of a few CeO2 on the physicochemical and catalytic properties of CeO2-doped TiO2 catalysts for NO reduction by a CO model reaction. The obtained samples were characterized by means of XRD, N2-physisorption (BET), LRS, UV-vis DRS, XPS, (O2, CO, and NO)-TPD, H2-TPR, in situ FT-IR, and a NO + CO model reaction. These results indicate that a small quantity of CeO2 doping into the TiO2 support will cause an obvious change in the properties of the catalyst and the TC-60 : 1 (the TiO2/CeO2 molar ratio is 60 : 1) support exhibits the most extent of lattice expansion, which indicates that the band lengths of Ce-O-Ti are longer than other TC (the solid solution of TiO2 and CeO2) samples, probably contributing to larger structural distortion and disorder, more defects and oxygen vacancies. Copper oxide species supported on TC supports are much easier to be reduced than those supported on the pure TiO2 and CeO2 surface-modified TiO2 supports. Furthermore, the Cu/TC-60 : 1 catalyst shows the highest activity and selectivity due to more oxygen vacancies, higher mobility of surface and lattice oxygen at lower temperature (which contributes to the regeneration of oxygen vacancies, and the best reducing ability), the most content of Cu(+), and the strongest synergistic effect between Ti(3+), Ce(3+) and Cu(+). On the other hand, the CeO2 doping into TiO2 promotes the formation of a Cu(+)/Cu(0) redox cycle at high temperatures, which has a crucial effect on N2O reduction. Finally, in order to further understand the nature of the catalytic performances of these samples, taking the Cu/TC-60 : 1 catalyst as an example, a possible reaction mechanism is tentatively proposed. PMID- 26030480 TI - The "next-generation" knowledge of papillary thyroid carcinoma. AB - The application of Next-Generation Sequencing for studying the genetics of papillary thyroid carcinomas (PTC) has recently revealed new somatic mutations and gene fusions as potential new tumor-initiating events in patients without any known driver lesion. Gene and miRNA expression analyses defined clinically relevant subclasses correlated to tumor progression. In addition, it has been shown that tumor driver mutations in BRAF, and RET rearrangements - altogether termed "BRAF-like" carcinomas - have a very similar expression pattern and constitute a distinct category. Conversely, "RAS-like" carcinomas have a different genomic, epigenomic, and proteomic profile. These findings justify the need to reconsider PTC classification schemes. PMID- 26030479 TI - RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function. OBJECTIVES: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts. METHODS: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse. MEASUREMENTS AND MAIN RESULTS: Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased beta-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. CONCLUSIONS: The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension. PMID- 26030481 TI - Genome-wide mining, characterization, and development of microsatellite markers in gossypium species. AB - Although much research has been conducted to characterize microsatellites and develop markers, the distribution of microsatellites remains ambiguous and the use of microsatellite markers in genomic studies and marker-assisted selection is limited. To identify microsatellites for cotton research, we mined 100,290, 83,160, and 56,937 microsatellites with frequencies of 41.2, 49.1, and 74.8 microsatellites per Mb in the recently sequenced Gossypium species: G. hirsutum, G. arboreum, and G. raimondii, respectively. The distributions of microsatellites in their genomes were non-random and were positively and negatively correlated with genes and transposable elements, respectively. Of the 77,996 developed microsatellite markers, 65,498 were physically anchored to the 26 chromosomes of G. hirsutum with an average marker density of 34 markers per Mb. We confirmed 67,880 (87%) universal and 7,705 (9.9%) new genic microsatellite markers. The polymorphism was estimated in above three species by in silico PCR and validated with 505 markers in G. hirsutum. We further predicted 8,825 polymorphic microsatellite markers within G. hirsutum acc. TM-1 and G. barbadense cv. Hai7124. In our study, genome-wide mining and characterization of microsatellites, and marker development were very useful for the saturation of the allotetraploid genetic linkage map, genome evolution studies and comparative genome mapping. PMID- 26030482 TI - Preparation and Gas Sensing Properties of In2O3/Au Nanorods for Detection of Volatile Organic Compounds in Exhaled Breath. AB - A series of In2O3/Au nanorods (NRs) were fabricated and characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS). The length to diameter ratios of In2O3/Au NRs was periodically modulated in the range of 2.9 4.5 through controlling the initial content of indium salt and reaction time. Their gas sensing properties to volatile organic compounds (VOCs) were carefully studied and then applied in exhaled breath detection. The results demonstrate that In2O3/Au NRs gas sensor can effectively detect acetone at 250 degrees C and ethanol at 400 degrees C. The corresponding actual detection limit is as low as 0.1 ppm to acetone and 0.05 ppm to ethanol, respectively. Moreover, by using humidity compensation method, In2O3/Au NRs gas sensor can clearly distinguish the acetone and ethanol biomarkers in human breath. The main reason of the enhanced gas sensing properties was attributed to the "spillover effects" between Au and In2O3 NRs. The excellent sensing performance indicates that In2O3/Au NRs is a promising functional material to actual application in monitoring and detecting diabetes and safe driving area in a noninvasive and more accurate way. PMID- 26030483 TI - Ruffling a few feathers. PMID- 26030484 TI - Imposing genetic diversity. AB - The idea that a world in which everyone was born "perfect" would be a world in which something valuable was missing often comes up in debates about the ethics of technologies of prenatal testing and preimplantation genetic diagnosis (PGD). This thought plays an important role in the "disability critique" of prenatal testing. However, the idea that human genetic variation is an important good with significant benefits for society at large is also embraced by a wide range of figures writing in the bioethics literature, including some who are notoriously hostile to the idea that we should not select against disability. By developing a number of thought experiments wherein we are to contemplate increasing genetic diversity from a lower baseline in order to secure this value, I argue that this powerful intuition is more problematic than is generally recognized, especially where the price of diversity is the well-being of particular individuals. PMID- 26030485 TI - Disability, diversity, and preference for the status quo: bias or justifiable preference? PMID- 26030486 TI - Human biodiversity conservation: a consensual ethical principle. PMID- 26030487 TI - Procreative beneficence, diversity, intersubjectivity, and imprecision. PMID- 26030488 TI - Genetic diversity as a value: imposing fairness. PMID- 26030489 TI - Is disability conservationism rooted in status quo bias? PMID- 26030490 TI - Mitochondrial diversity and the reversal test. PMID- 26030491 TI - Reproductive genetic testing and human genetic variation in the era of genomic medicine. PMID- 26030492 TI - Imposing genetic diversity: an imposition on reproductive freedom. PMID- 26030493 TI - The Disvalue of Genetic Diversity, or: How (Not) to Treat a Sandelian Ethos on Steroids. PMID- 26030494 TI - Genetic technology to prevent disabilities: how popular culture informs our understanding of the use of genetics to define and prevent undesirable traits. PMID- 26030495 TI - The diversity of genetic perfection. PMID- 26030496 TI - Promoting individual well-being, increasing social welfare, and securing genetic diversity simultaneously: it is a matter of degree. PMID- 26030497 TI - Valuable and valueless diversity. PMID- 26030498 TI - U.S. Complicity and Japan's Wartime Medical Atrocities: Time for a Response. AB - Shortly before and during the Second World War, Japanese doctors and medical researchers conducted large-scale human experiments in occupied China that were at least as gruesome as those conducted by Nazi doctors. Japan never officially acknowledged the occurrence of the experiments, never tried any of the perpetrators, and never provided compensation to the victims or issued an apology. Building on work by Jing-Bao Nie, this article argues that the U.S. government is heavily complicit in this grave injustice, and should respond in an appropriate way in order to reduce this complicity, as well as to avoid complicity in future unethical medical experiments. It also calls on other U.S. institutions, in particular the Presidential Commission for the Study of Bioethical Issues, to urge the government to respond, or to at least inform the public and initiate a debate about this dark page of American and Japanese history. PMID- 26030499 TI - The U.S. Complicity in Japan's Medical War Crimes: A Restatement on Why the U.S. Government Should Apologize and the U.S. Community of Bioethics Should Respond. PMID- 26030500 TI - The diptych: Nazi and Japanese bioscience war crimes. PMID- 26030501 TI - U.S. Complicity and Japan's Atrocities: How to Respond? PMID- 26030502 TI - When saying sorry is not enough: acknowledging past wrongs in human subjects research. PMID- 26030503 TI - Looking to the Future From the Past: Take Home Lessons From Japanese World War II Medical Atrocities. PMID- 26030504 TI - Rather than responding to the past, shape the future instead. PMID- 26030505 TI - Bendable Zeolite Membranes: Synthesis and Improved Gas Separation Performance. AB - Separation and sequestration of CO2 emitted from fossil energy fueled electric generating units and industrial facilities will help in reducing anthropogenic CO2, thereby mitigating its adverse climate change effects. Membrane-based gas separation has the potential to meet the technical challenges of CO2 separation if high selectivity and permeance with low costs for large-scale manufacture are realized. Inorganic zeolite membranes in principle can have selectivity and permeance considerably higher than polymers. This paper presents a strategy for zeolite growth within the pores of a polymer support, with crystallization time of an hour. With a thin coating of 200-300 nm polydimethylsiloxane (PDMS) on the zeolite-polymer composite, transport data for CO2/N2 separation indicate separation factors of 35-45, with CO2 permeance between 1600 and 2200 GPU (1 GPU = 3.35 * 10(-10) mol/(m(2) s Pa)) using dry synthetic mixtures of CO2 and N2 at 25 degrees C. The synthesis process results in membranes that are highly reproducible toward transport measurements and exhibit long-term stability (3 days). Most importantly, these membranes because of the zeolite growth within the polymer support, as contrasted to conventional zeolite growth on top of a support, are mechanically flexible. PMID- 26030506 TI - A Facile Multi-interface Transformation Approach to Monodisperse Multiple-Shelled Periodic Mesoporous Organosilica Hollow Spheres. AB - The synthesis of well-defined and complex hollow structures via a simple method is still a major challenge. In this work, a facile and controllable "multi interface transformation" approach for preparation of monodisperse multi-shelled periodic mesoporous organosilica (PMO) hollow spheres has been established by a one-step hydrothermal treatment of successively grown organosilica particles. The multi-shelled PMO hollow spheres have inorganic-organic hybrid frameworks, controllable number (1-4) of shells, high surface area (~805 m(2)/g), accessible ordered mesochannels (~3.2 nm), large pore volume (1.0 cm(3)/g), and uniform and tunable diameter (300-550 nm), chamber size (4-54 nm), and shell thickness (10-30 nm). In addition, various organic groups (alkyl, aromatic, and heteroelement fragments) are successfully incorporated into the multi-shelled PMO hollow spheres by successively adding different bridged organosilica precursors. Notably, the distribution of different kinds of organic groups in the multi shelled PMO hollow spheres can be precisely controlled, showing great potential for future applications. We propose that the formation of the multi-shelled PMO hollow structures is ascribed to the creation of multiple highly cross-linked organosilica interfaces, providing a new and interesting fundamental principle for PMO materials. Due to their unique structure and frameworks, triple-shelled ethane-bridged PMO hollow spheres were successfully loaded with an anti-cancer drug doxorubicin and perfluoropentane gas, which present excellent effects in the killing of cancer cells and ultrasound imaging. It is expected that the multi interface transformation strategy provides a simple, controllable, versatile, and template-free method for preparation of various multifunctional PMOs for different applications. PMID- 26030508 TI - Optimal learning paths in information networks. AB - Each sphere of knowledge and information could be depicted as a complex mesh of correlated items. By properly exploiting these connections, innovative and more efficient navigation strategies could be defined, possibly leading to a faster learning process and an enduring retention of information. In this work we investigate how the topological structure embedding the items to be learned can affect the efficiency of the learning dynamics. To this end we introduce a general class of algorithms that simulate the exploration of knowledge/information networks standing on well-established findings on educational scheduling, namely the spacing and lag effects. While constructing their learning schedules, individuals move along connections, periodically revisiting some concepts, and sometimes jumping on very distant ones. In order to investigate the effect of networked information structures on the proposed learning dynamics we focused both on synthetic and real-world graphs such as subsections of Wikipedia and word-association graphs. We highlight the existence of optimal topological structures for the simulated learning dynamics whose efficiency is affected by the balance between hubs and the least connected items. Interestingly, the real-world graphs we considered lead naturally to almost optimal learning performances. PMID- 26030507 TI - Enzymatically Active Microgels from Self-Assembling Protein Nanofibrils for Microflow Chemistry. AB - Amyloid fibrils represent a generic class of protein structure associated with both pathological states and with naturally occurring functional materials. This class of protein nanostructure has recently also emerged as an excellent foundation for sophisticated functional biocompatible materials including scaffolds and carriers for biologically active molecules. Protein-based materials offer the potential advantage that additional functions can be directly incorporated via gene fusion producing a single chimeric polypeptide that will both self-assemble and display the desired activity. To succeed, a chimeric protein system must self-assemble without the need for harsh triggering conditions which would damage the appended functional protein molecule. However, the micrometer to nanoscale patterning and morphological control of protein-based nanomaterials has remained challenging. This study demonstrates a general approach for overcoming these limitations through the microfluidic generation of enzymatically active microgels that are stabilized by amyloid nanofibrils. The use of scaffolds formed from biomaterials that self-assemble under mild conditions enables the formation of catalytic microgels while maintaining the integrity of the encapsulated enzyme. The enzymatically active microgel particles show robust material properties and their porous architecture allows diffusion in and out of reactants and products. In combination with microfluidic droplet trapping approaches, enzymatically active microgels illustrate the potential of self-assembling materials for enzyme immobilization and recycling, and for biological flow-chemistry. These design principles can be adopted to create countless other bioactive amyloid-based materials with diverse functions. PMID- 26030511 TI - Massive retroperitoneal cystic mass in an adolescent. PMID- 26030512 TI - Preeclampsia, placental insufficiency, autism, and antiphospholipid antibodies. PMID- 26030513 TI - Preeclampsia, placental insufficiency, autism, and antiphospholipid antibodies reply. PMID- 26030514 TI - Indoor tanning: no safe amount. PMID- 26030516 TI - Breastfeeding and Childhood Leukemia Incidence: A Meta-analysis and Systematic Review. AB - IMPORTANCE: Childhood cancer is a leading cause of mortality among children and adolescents in the developed world and the incidence increases by 0.9% each year. Leukemia accounts for about 30% of all childhood cancer but its etiology is still mostly unknown. OBJECTIVE: To conduct a meta-analysis of available scientific evidence on the association between breastfeeding and childhood leukemia. DATA SOURCES: A thorough search for articles published between January 1960 and December 2014 researching the association between breastfeeding and childhood leukemia was conducted on PubMed, the Cochrane Library, and Scopus (performed in July and December 2014), supplemented by manual searches of reference lists. STUDY SELECTION: To be included in the meta-analyses, studies had to be case control; include breastfeeding as a measured exposure and leukemia as a measured outcome; include data on breastfeeding duration in months; and be published in a peer-reviewed journal with full text available in English. DATA EXTRACTION AND SYNTHESIS: The search identified 25 relevant studies, 18 of which met all inclusion criteria. No publication bias or heterogeneity among these 18 studies were detected. The quality of each study that met the inclusion criteria was assessed using the Newcastle-Ottawa Scale. Multiple meta-analyses were conducted using the random effect model on raw data in the StatsDirect statistical program. MAIN OUTCOMES AND MEASURES: No or short duration of breastfeeding and the incidence of childhood leukemia. RESULTS: The meta-analysis of all 18 studies indicated that compared with no or shorter breastfeeding, any breastfeeding for 6 months or longer was associated with a 19% lower risk for childhood leukemia (odds ratio, 0.81; 95% CI, 0.73-0.89). A separate meta-analysis of 15 studies indicated that ever breastfed compared with never breastfed was associated with an 11% lower risk for childhood leukemia (odds ratio, 0.89; 95% CI, 0.84-0.94), although the definition of never breastfed differed between studies. All meta analyses of subgroups of the 18 studies showed similar associations. Based on current meta-analyses results, 14% to 19% of all childhood leukemia cases may be prevented by breastfeeding for 6 months or more. CONCLUSIONS AND RELEVANCE: Breastfeeding is a highly accessible, low-cost public health measure. This meta analysis that included studies not featured in previous meta-analyses on the subject indicates that promoting breastfeeding for 6 months or more may help lower childhood leukemia incidence, in addition to its other health benefits for children and mothers. PMID- 26030515 TI - Predictors of timing of transfer from pediatric- to adult-focused primary care. AB - IMPORTANCE: A timely, well-coordinated transfer from pediatric- to adult-focused primary care is an important component of high-quality health care, especially for youths with chronic health conditions. Current recommendations suggest that primary-care transfers for youths occur between 18 and 21 years of age. However, the current epidemiology of transfer timing is unknown. OBJECTIVE: To examine the timing of transfer to adult-focused primary care providers (PCPs), the time between last pediatric-focused and first adult-focused PCP visits, and the predictors of transfer timing. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of patients insured by Harvard Pilgrim Health Care (HPHC), a large not-for-profit health plan. Our sample included 60 233 adolescents who were continuously enrolled in HPHC from 16 to at least 18 years of age between January 2000 and December 2012. Pediatric-focused PCPs were identified by the following provider specialty types, but no others: pediatrics, adolescent medicine, or pediatric nurse practitioner. Adult-focused PCPs were identified by having any provider type that sees adult patients. Providers with any specialty provider designation (eg, gastroenterology or gynecology) were not considered PCPs. MAIN OUTCOMES AND MEASURES: We used multivariable Cox proportional hazards regression to model age at first adult-focused PCP visit and time from the last pediatric focused to the first adult-focused PCP visit (gap) for any type of office visit and for those that were preventive visits. RESULTS: Younger age at transfer was observed for female youths (hazard ratio [HR], 1.32 [95% CI, 1.29-1.36]) who had complex (HR, 1.06 [95% CI, 1.01-1.11]) or noncomplex (HR, 1.08 [95% CI, 1.05 1.12]) chronic conditions compared with those who had no chronic conditions. Transfer occurred at older ages for youths who lived in lower-income neighborhoods compared with those who lived in higher-income neighborhoods (HR, 0.89 [95% CI, 0.83-0.95]). The gap between last pediatric-focused to first adult focused PCP visit was shorter for female youths than male youths (HR, 1.57 [95% CI, 1.53-1.61]) and youths with complex (HR, 1.35 [95% CI, 1.28-1.41]) or noncomplex (HR, 1.24 [95% CI, 1.20-1.28]) chronic conditions. The gap was longer for youths living in lower-income neighborhoods than for those living in higher income neighborhoods (HR, 0.80 [95% CI, 0.75-0.85]). Multivariable models showed an adjusted median age at transfer of 21.8 years for office visits and 23.1 years for preventive visits and an adjusted median gap length of 20.5 months for office visits and 41.6 months for preventive visits. CONCLUSIONS AND RELEVANCE: Most youths are transferring care later than recommended and with gaps of more than a year. While youths with chronic conditions have shorter gaps, they may need even shorter transfer intervals to ensure continuous access to care. More work is needed to determine whether youths are experiencing clinically important lapses in care or other negative health effects due to the delayed timing of transfer. PMID- 26030517 TI - Probing the Impact of Acidification on Spider Silk Assembly Kinetics. AB - Spiders utilize fine adjustment of the physicochemical conditions within its silk spinning system to regulate spidroin assembly into solid silk fibers with outstanding mechanical properties. However, the exact mechanism about which this occurs remains elusive and is still hotly debated. In this study, the effect of acidification on spider silk assembly was investigated on native spidroins from the major ampullate (MA) gland fluid excised from Latrodectus hesperus (Black Widow) spiders. Incubating the protein-rich MA silk gland fluid at acidic pH conditions results in the formation of silk fibers that are 10-100 MUm in length and ~2 MUm in diameter as judged by optical and electron microscope methods. The in vitro spider silk assembly kinetics were monitored as a function of pH with a (13)C solid-state MAS NMR approach. The results confirm the importance of acidic pH in the spider silk self-assembly process with observation of a sigmoidal nucleation-elongation kinetic profile. The rates of nucleation and elongation as well as the percentage of beta-sheet structure in the grown fibers depend on the pH. These results confirm the importance of an acidic pH gradient along the spinning duct for spider silk formation and provide a powerful spectroscopic approach to probe the kinetics of spider silk formation under various biochemical conditions. PMID- 26030519 TI - Time-dependent exchange and tunneling: detection at the same place of two electrons emitted simultaneously from different sources. AB - Two-particle scattering probabilities in tunneling scenarios with exchange interaction are analyzed with quasi-particle wave packets. Two initial one particle wave packets (with opposite central momentums) are spatially localized at each side of a barrier. After impinging upon a tunneling barrier, each wave packet splits into transmitted and reflected components. When the initial two particle anti-symmetrical state is defined as a Slater determinant of any type of (normalizable) one-particle wave packet, it is shown that the probability of detecting two (identically injected) electrons at the same side of the barrier is different from zero in very common (single or double barrier) scenarios. In some particular scenarios, the transmitted and reflected components become orthogonal and the mentioned probabilities reproduce those values associated to distinguishable particles. These unexpected non-zero probabilities are still present when non-separable Coulomb interaction or non-symmetrical potentials are considered. On the other hand, for initial wave packets close to Hamiltonian eigenstates, the usual zero two-particle probability for electrons at the same side of the barrier found in the literature is recovered. The generalization to many-particle scattering probabilities with quasi-particle wave packets for low and high phase-space density are also analyzed. The far-reaching consequences of these non-zero probabilities in the accurate evaluation of quantum noise in mesoscopic systems are briefly indicated. PMID- 26030520 TI - Constructing Quaternary Carbons from N-(Acyloxy)phthalimide Precursors of Tertiary Radicals Using Visible-Light Photocatalysis. AB - Tertiary carbon radicals have notable utility for uniting complex carbon fragments with concomitant formation of new quaternary carbons. This article explores the scope, limitations, and certain mechanistic aspects of Okada's method for forming tertiary carbon radicals from N-(acyloxy)phthalimides by visible-light photocatalysis. Optimized conditions for generating tertiary radicals from N-(acyloxy)phthalimide derivatives of tertiary carboxylic acids by visible-light irradiation in the presence of 1 mol % of commercially available Ru(bpy)3(PF6)2, diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (8), and i-Pr2NEt and their coupling in dichloromethane at room temperature with alkene acceptors were developed. Four representative tertiary N (acyloxy)phthalimides and 15 alkene radical acceptors were examined. Both reductive couplings with electron-deficient alkenes and radical substitution reactions with allylic and vinylic bromides and chlorides were examined with many such reactions occurring in good yield using only a slight excess (typically 1.5 equiv) of the alkene. In general, the yields of these photocatalytic reactions were higher than the analogous transformations of the corresponding N phthalimidoyl oxalates. Deuterium labeling and competition experiments reveal that the reductive radical coupling of tertiary N-(acyloxy)phthalimides with electron-deficient alkenes can be terminated by both hydrogen-atom transfer and single-electron reduction followed by protonation, and that this mechanistic duality is controlled by the presence or absence of i-Pr2NEt. PMID- 26030521 TI - Crisis Awaiting Heart Transplantation: Sinking the Lifeboat. AB - The number of heart transplants performed in the United States was 2177 in 1994 and 2166 in 2014. However, the number of transplant centers has increased, and the criteria for transplants have broadened to include patients 65 years or older, those with a body mass index greater than 30, and more comorbid conditions, such as diabetes mellitus and a history of smoking. As the transplant waiting list has become longer and waiting times have increased, the major route to heart transplants has become deterioration to the most urgent priority status, which accounts for 10% of patients on the waiting list but two-thirds of transplants. Many heart transplant candidates develop life-threatening complications of a ventricular assist device implanted to avert death while waiting. Some affluent patients, however, can afford to temporarily relocate and obtain a transplant in regions where the waiting times are shorter without prior surgery to implant a ventricular assist device. The ethics of allocating hearts for transplant have always recalled the classic lifeboat dilemma of how many people can be allowed to board an already overcrowded lifeboat without sinking the ship and everyone on board. As transplant physicians, we advocate with the best intentions on behalf of our own patients rather than denying transplants to those less likely to benefit. In recognizing our responsibilities as stewards of scarce donor hearts, we should reduce new listings for heart transplants, thus restoring balance to the waiting list and keeping the lifeboat afloat. PMID- 26030518 TI - Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. AB - BACKGROUND: Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer. METHODS: This phase 3 study involved 521 patients with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred. RESULTS: The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. CONCLUSIONS: Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone. (Funded by Pfizer; PALOMA3 ClinicalTrials.gov number, NCT01942135.). PMID- 26030522 TI - Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. AB - Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5alpha dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3beta-hydroxysteroid dehydrogenase (3betaHSD), steroid-5alpha-reductase (SRD5A) and 17beta hydroxysteroid dehydrogenase (17betaHSD) isoenzymes. Abiraterone, a steroidal 17alpha-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Delta(4)-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3betaHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment. PMID- 26030523 TI - Human body epigenome maps reveal noncanonical DNA methylation variation. AB - Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues. PMID- 26030524 TI - Structural and functional features of central nervous system lymphatic vessels. AB - One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. PMID- 26030527 TI - Design and Synthesis of Water-Soluble Multifunctionalizable Thiol-Reactive Polymeric Supports for Cellular Targeting. AB - Design and synthesis of novel water-soluble polymers bearing reactive side chains are actively pursued due to their increasing demand in areas such as bioconjugation and drug delivery. This study reports the fabrication of poly(ethylene glycol) methacrylate based thiol-reactive water-soluble polymeric supports that can serve as targeted drug delivery vehicles. Thiol-reactive maleimide units were incorporated into polymers as side chains by use of a furan protected maleimide containing monomer. Atom transfer radical polymerization (ATRP) was employed to obtain a family of well-defined copolymers with narrow molecular weight distributions. After the polymerization, the maleimide groups were activated to their reactive form, ready for conjugation with thiol containing molecules. Efficient functionalization of the maleimide moieties was demonstrated by conjugation of a tripeptide glutathione under mild and reagent free aqueous conditions. Additionally, hydrophobic thiol-containing dye (Bodipy SH) and a cyclic peptide-based targeting group (cRGDfC) were sequentially appended onto the maleimide bearing polymers to demonstrate their efficient multifunctionalization. The conjugates were utilized for in vitro experiments over both cancerous and healthy breast cell lines. Obtained results demonstrate that the conjugates were nontoxic, and displayed efficient cellular uptake. The presence of the peptide based targeting group had a clear effect on increasing the uptake of the dye-conjugated polymers into cells when compared to the construct devoid of the peptide. Overall, the facile synthesis and highly efficient multifunctionalization of maleimide-containing thiol-reactive copolymers offer a novel and attractive class of polyethylene glycol-based water soluble supports for drug delivery. PMID- 26030528 TI - Experimental analysis of bidirectional reflectance distribution function cross section conversion term in direction cosine space. AB - Of the many classes of bidirectional reflectance distribution function (BRDF) models, two popular classes of models are the microfacet model and the linear systems diffraction model. The microfacet model has the benefit of speed and simplicity, as it uses geometric optics approximations, while linear systems theory uses a diffraction approach to compute the BRDF, at the expense of greater computational complexity. In this Letter, nongrazing BRDF measurements of rough and polished surface-reflecting materials at multiple incident angles are scaled by the microfacet cross section conversion term, but in the linear systems direction cosine space, resulting in great alignment of BRDF data at various incident angles in this space. This results in a predictive BRDF model for surface-reflecting materials at nongrazing angles, while avoiding some of the computational complexities in the linear systems diffraction model. PMID- 26030526 TI - Importance of simultaneous evaluation of multiple risk factors for hemodialysis patients' mortality and development of a novel index: dialysis outcomes and practice patterns study. AB - BACKGROUND: For hemodialysis (HD) patients, many risk factors for death are associated with each other intricately. However, they are often considered separately in clinical settings. We evaluated the maintenance HD patients' risk of death within one year from multiple risk factors simultaneously considering their interrelationships using a novel index (survival index, SI) for HD patients in the United States developed using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS: We analyzed data from 3899 and 3765 patients to develop and validate SI, respectively. To predict death within one year, candidate models were developed using logistic regression models. The final model was determined by comparing the accuracy among the models for the prediction of deaths. RESULTS: The model included age; body mass index; serum creatinine, albumin, total cholesterol and phosphorus levels; history of cardiovascular diseases; and arteriovenous fistula use. SI showed a higher accuracy in predicting death (c-statistic, 0.739) than geriatric nutritional risk index (0.647) and serum albumin level (0.637). The probability of death predicted on the basis of SI matched the observed number of deaths. Cox proportional hazard models for time-dependent SI showed that patients with low SI had a higher risk of death than patients with high SI [reference, Group 4 (26.1<=SI)]; Group 1 (SI<12.7), adjusted hazard ratio, 7.97 (95% CI, 5.02, 12.65); Group 2 (12.7<=SI<19.0), 3.18 (95% CI, 1.96, 5.16); Group 3 (19.0<=SI<26.1), 2.20 (95% CI, 1.33, 3.66). CONCLUSION: Results of this study suggest that the simultaneous evaluation of multiple risk factors can more accurately assess patients' prognosis and identify patients at an increased risk of death than single factors. PMID- 26030525 TI - Condensin-driven remodelling of X chromosome topology during dosage compensation. AB - The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (~1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide. PMID- 26030529 TI - Tunable all-optical plasmonic diode based on Fano resonance in nonlinear waveguide coupled with cavities. AB - Tunable all-optical plasmonic diode is proposed based on the Fano resonance in an asymmetric and nonlinear system, comprising metal-insulator-metal waveguides coupled with nanocavities. The spatial asymmetry of the system gives rise to the nonreciprocity of the field localizations at the nonlinear gap between the coupled cavities and to the nonreciprocal nonlinear response. Nonlinear Fano resonance, originating from the interference between the discrete cavity mode and the continuum traveling mode, is observed and effectively tuned by changing the input power. By combining the unidirectional nonlinear response with the steep dispersion of the Fano asymmetric line shape, a transmission contrast ratio up to 41.46 dB can be achieved between forward and backward transmission. Our all optical plasmonic diode with compact structure can find important applications in integrated optical nanocircuits. PMID- 26030530 TI - Composite dielectric metasurfaces for phase control of vector field. AB - We designed, fabricated, and characterized a dielectric metamaterial lens created by varying the density of subwavelength low refractive index nanoholes in a high refractive index substrate, resulting in a locally variable effective refraction index. It is shown that a constructed graded index lens can overcome diffraction effects even when the aperture/wavelength (D/lambda) ratio is smaller than 40. In addition to the conventional design of a polarization insensitive lens, we also show that a polarization diversity lens (f(o)?f(e)) can be realized by arranging nanoholes in patterns with variable density in different transverse directions. Such a anisotropic microlens demonstrates polarization dependent focal lengths of 32 and 22 MUm for linearly x- and y-polarized light, respectively, operating at a wavelength of lambda=1550 nm. We also show numerically and demonstrate experimentally achromatic performance of the devices operating in the wavelength range of 1500-1900 nm with full width at half-maximum (FWHM) of the focal spots of about 4 MUm. PMID- 26030531 TI - Scanning balanced-path homodyne I/Q-interferometer scheme and its applications. AB - The balanced-path scheme of a heterodyne interferometer proposed by Yoon et al. has been applied to the scanning homodyne I/Q-interferometer. This provides an 11 dB improvement on common vibration rejection over the heterodyne scheme and, thereby, allows high sensitivity and high stability phase and amplitude measurements for high-speed scanning interferometer applications. It is shown that our new scanning interferometer scheme is very useful for diagnosing a sample that requires complex analysis. As an example, our new scanning interferometer scheme has been applied for obtaining phase and amplitude images of the protein biochip samples prepared by using the sandwich ELISA. The amplitude images are used for diagnosing homogeneity of the sample, while the phase images are used for measuring the phase difference between samples treated with different concentrations of IL-5. PMID- 26030532 TI - Fiber-optic gas pressure sensing with a laser-heated silicon-based Fabry-Perot interferometer. AB - We report a novel fiber-optic sensor for measurement of static gas pressure based on the natural convection of a heated silicon pillar attached to a fiber tip functioning as a Fabry-Perot interferometer (FPI). A visible laser beam is guided by the fiber to efficiently heat the silicon pillar, while an infrared whitelight source, also guided by the fiber, is used to measure the temperature of the FPI, which is influenced both by the laser power and the pressure through natural convection. We theoretically and experimentally show that, by monitoring the fringe shift caused by the laser heating, air pressure sensing with little temperature cross-sensitivity can be achieved. The pressure sensitivity can be easily tuned by adjusting the heating laser power. In our experiment, the sensor performance within the temperature range from 20 degrees C to 50 degrees C and the pressure range from 0 to 1400 psi has been characterized, showing an average sensitivity of -0.52 pm/psi. Compared to the passive version of the sensor, the pressure sensitivity was ~15 times larger, and the temperature cross-sensitivity was ~100 times smaller. PMID- 26030533 TI - Broad spectral excitation of opsin for enhanced stimulation of cells. AB - Optical stimulation of cells expressing light-sensitive proteins (opsins) has allowed targeted activation with cellular specificity. However, since narrow-band light has been used for excitation of these optogenetic probes, only active stimulation strategies are being attempted for clinical applications such as restoration of vision. Here, we report use of broad spectral excitation (white light) for optogenetic stimulation of opsin-sensitized cells. We found that ReaChR is optimally excited with white light offering significantly higher photocurrents compared to spectrally filtered narrow-band light stimulation. Our findings open up the possibility of passive stimulation strategy by use of natural sunlight for retinal stimulation, which could have benefits for ambient light stimulated vision restoration. PMID- 26030534 TI - Stimulated Raman gas sensing by backward UV lasing from a femtosecond filament. AB - We perform a proof-of-principle demonstration of chemically specific standoff gas sensing, in which a coherent stimulated Raman signal is detected in the direction anticollinear to a two-color laser excitation beam traversing the target volume. The proposed geometry is intrinsically free space as it does not involve back scattering (reflection) of the signal or excitation beams at or behind the target. A beam carrying an intense mid-IR femtosecond (fs) pulse and a parametrically generated picosecond (ps) UV Stokes pulse is fired in the forward direction. A fs filament, produced by the intense mid-IR pulse, emits a backward propagating narrowband ps laser pulse at the 337 and 357 nm transitions of excited molecular nitrogen, thus supplying a counter-propagating Raman pump pulse. The scheme is linearly sensitive to species concentration and provides both transverse and longitudinal spatial resolution. PMID- 26030535 TI - Alternating series of cross-spectral densities. AB - We establish a sufficient condition under which the alternation series of cross spectral densities (CSD) constitutes a valid CSD. Using such a condition, we introduce a novel class of multi-sinc Schell-model sources with circular and Cartesian symmetries. It is demonstrated that far fields produced by the new sources carry interesting characteristics, being adjustable multi-rings and lattice patterns. PMID- 26030536 TI - W-band OFDM Radio-over-Fiber system with power detector for vector signal down conversion. AB - This Letter proposes a W-band OFDM RoF system at 103.5 GHz employing power detector to support vector signal down-conversion. Additional RF tone is generated and transmitted from central office to replace the local oscillator at a wireless receiver. With a proper frequency gap and power ratio between the RF tone and the OFDM-modulated signal, the impact from signal-to-signal beating interference can be minimized. The data rate can achieve a 40 Gbps 16 QAM OFDM signal over 25 km fiber and 2 m wireless transmission. PMID- 26030537 TI - Electro-optic millimeter-wave harmonic downconversion and vector demodulation using cascaded phase modulation and optical filtering. AB - We describe and demonstrate an electro-optic technique to simultaneously downconvert and demodulate vector-modulated millimeter-wave signals. The system uses electro-optic phase modulation and optical filtering to perform harmonic downconversion of the RF signal to an intermediate frequency (IF) or to baseband. We demonstrate downconversion of RF signals between 7 and 70-GHz to IFs below 20 GHz. Furthermore, we show harmonic downconversion and vector demodulation of 2.5 Gb/s QPSK and 5-Gb/s 16-QAM signals at carrier frequencies of 40-GHz to baseband. PMID- 26030538 TI - Achromatization of waveplate for broadband polarimetric system. AB - A broadband polarimetric system with enhanced performance is highly desired in many applications, such as remote sensing. To achromatize a waveplate by combining a stack of retardance plates made of same material with different azimuths, two merit functions are presented in this Letter. The first merit function based on the Jones theorem directly accounts for the equivalent retardance and azimuthal angles of the combined plates. The second one can search for the optimal equivalent azimuthal angles automatically by using the condition number kappa2 based on 2-norm or the equally weighted variance EWV, two figures of merit for the full-Stokes polarimeters, as the objective function. Our study within the framework of the simplest full-Stokes polarimeter shows that, for the super-achromatic 131.8 degrees waveplate consisting of seven quartz plates, the root-mean-square errors of the kappa2 and EWV are about 0.49% and 0.07%, and the maximum deviations of the equivalent retardance and azimuthal angle are approximately 0.42 degrees and 0.59 degrees , respectively, over the waveband of 0.4-0.7 MUm. For the super-achromatic quarter-wave plate comprising seven quartz plates, the maximum deviations of the equivalent retardance and azimuthal angle are only 0.18 degrees and 0.7 degrees , respectively. PMID- 26030539 TI - Enhancing the heralded single-photon rate from a silicon nanowire by time and wavelength division multiplexing pump pulses. AB - Heralded single photons produced on a silicon chip represent an integrated photon source solution for scalable photonic quantum technologies. The key limitation of such sources is their non-deterministic nature introduced by the stochastic spontaneous four-wave mixing (SFWM) process. Active spatial and temporal multiplexing can improve this by enhancing the single-photon rate without degrading the quantum signal-to-noise ratio. Here, taking advantage of the broad bandwidth of SFWM in a silicon nanowire, we experimentally demonstrate heralded single-photon generation from a silicon nanowire pumped by time and wavelength division multiplexed pulses. We show a 90+/-5% enhancement on the heralded photon rate at the cost of only 14+/-2% reduction to the signal-to-noise ratio, close to the performance found using only time division multiplexed pulses. As single photon events are distributed to multiple wavelength channels, this new scheme overcomes the saturation limit of avalanche single-photon detectors and will improve the ultimate performance of such photon sources. PMID- 26030540 TI - Degenerate band edge resonances in periodic silicon ridge waveguides. AB - We experimentally demonstrate degenerate band edge resonances in periodic Si ridge waveguides that are compatible with carrier injection modulation for active electro-optical devices. The resonant cavities are designed using a combination of the plane-wave expansion method and the finite difference time domain technique. Measured and simulated quality factors of the first band edge resonances scale to the fifth power of the number of periods. Quality factor scaling is determined to be limited by fabrication imperfections. Compared to resonators based on a regular transmission band edge, degenerate band edge devices can achieve significantly larger quality factors in the same number of periods. Applications include compact electro-optical switches, modulators, and sensors that benefit from high-quality factors and large distributed electric fields. PMID- 26030541 TI - Robust high-dynamic-range optical roll sensing. AB - We present a robust optical-roll sensor with a high-dynamic range and high throughput capabilities. The working principle relies on tracking the amplitude of an optical square wave-encoded light source. After encoding a square wave onto a polarization reference, quadrature demodulation of the polarized light allows us to cancel common-mode noise. Benefits of this sensor include its simplicity, low cost, high-throughput, insensitivity to source amplitude fluctuations, and no inherent drift. In this Letter, we present the working principle and experimentally validate a 43 degrees usable working range with 0.002 degrees resolution. This sensor has the highest reported dynamic range for optical roll sensing. PMID- 26030542 TI - Dual-function photonic integrated circuit for frequency octo-tupling or single side-band modulation. AB - A dual-function photonic integrated circuit for microwave photonic applications is proposed. The circuit consists of four linear electro-optic phase modulators connected optically in parallel within a generalized Mach-Zehnder interferometer architecture. The photonic circuit is arranged to have two separate output ports. A first port provides frequency up-conversion of a microwave signal from the electrical to the optical domain; equivalently single-side-band modulation. A second port provides tunable millimeter wave carriers by frequency octo-tupling of an appropriate amplitude RF carrier. The circuit exploits the intrinsic relative phases between the ports of multi-mode interference couplers to provide substantially all the static optical phases needed. The operation of the proposed dual-function photonic integrated circuit is verified by computer simulations. The performance of the frequency octo-tupling and up-conversion functions is analyzed in terms of the electrical signal to harmonic distortion ratio and the optical single side band to unwanted harmonics ratio, respectively. PMID- 26030543 TI - Fiber-based dual-focus time-demultiplexed second harmonic generation microscopy. AB - We present a dual-focus second harmonic generation (SHG) microscopy approach based on stable, compact, and inexpensive fiber technology. One-tenth of the fiber laser output is coupled into a 100 m (?500 ns) long single-mode fiber and further amplified to achieve two separately guided beams with time-alternating pulse trains. SHG detection is performed sequentially, generating two individual images in one scan. Thus, the configuration allows for imaging of distinct areas within the field of view at twice the repetition rate of the fiber laser but is readily extended to a multiple of the repetition rate with tens of foci. PMID- 26030544 TI - Hybrid single-beam reconstruction technique for slow and fast varying wave fields. AB - An iterative single-beam wave field reconstruction technique that employs both non-paraxial, wave propagation based and paraxial deterministic phase retrieval techniques is presented. This approach overcomes two major obstacles that exist in the current state of the art techniques: iterative methods do not reconstruct slowly varying wave fields due to slow convergence and stagnation, and deterministic methods have paraxial limits, making the reconstructions of quickly varying object features impossible. In this work, a hybrid approach is reported that uses paraxial wave field corrections within iterative phase retrieval solvers. This technique is suitable for cases ranging from slow to fast varying wave fields, and unlike the currently available methods, can also reconstruct measurement objects with different regions of both slowly and quickly varying object features. It is further shown that this technique gives a higher accuracy than current single-beam phase retrieval techniques, and in comparison to the iterative methods, has a higher convergence speed. PMID- 26030545 TI - Square lattices of quasi-perfect optical vortices generated by two-dimensional encoding continuous-phase gratings. AB - We propose a type of two-dimensional (2D) encoding continuous-phase gratings capable of simultaneously generating a square lattice of multiple quasi-perfect vortices. As an example, a symmetrical and an asymmetrical 5*5 lattice of quasi perfect vortices are experimentally demonstrated. It is shown that multiple quasi perfect vortices with different topological charges are generated at different diffraction orders. The ring-width of these vortices is nearly constant, while there is a shift in the average ring-diameter when the carried charges are large enough, or when the ring-diameter is small. Additional axicon phase has been embedded into these 2D encoding gratings for the compensation of such shift in the average ring-diameter, and experimental results show that the shift can be greatly minimized after this compensation. PMID- 26030546 TI - High-power Yb:YAG single-crystal fiber amplifiers for femtosecond lasers in cylindrical polarization. AB - We demonstrate a three-stage diode-pumped Yb:YAG single-crystal-fiber amplifier to generate femtosecond pulses at high average powers with linear or cylindrical (i.e., radial or azimuthal) polarization. At a repetition rate of 20 MHz, 750-fs pulses were obtained at an average power of 85 W in cylindrical polarization and at 100 W in linear polarization. The report includes investigations on the use of Yb:YAG single-crystal fibers with different length/doping ratio and the zero phonon pumping at a wavelength of 969 nm in order to optimize the performance. PMID- 26030547 TI - Transformation-optics-inspired anti-reflective coating design for gradient index lenses. AB - Recent developments in transformation optics have led to burgeoning research on gradient index lenses for novel optical systems. Such lenses hold great potential for the advancement of complex optics for a wide range of applications. Despite the plethora of literature on gradient index lenses, previous works have not yet considered the application of anti-reflective coatings to these systems. Reducing system reflections is crucial to the development of this technology for highly sensitive optical applications. Here, we present effective anti-reflective coating designs for gradient index lens systems. Conventional anti-reflective design methodologies are leveraged in conjunction with transformation optics to develop coatings that significantly reduce reflections of a flat gradient index lens. Finally, the resulting gradient-index anti-reflective coatings are compared and contrasted with conventional homogeneous anti-reflective coatings. PMID- 26030548 TI - Direct comparison of kilohertz- and megahertz-repetition-rate femtosecond damage threshold. AB - We performed femtosecond laser-induced damage threshold (fs LIDT) measurements with substantially different repetition rate Ti:sapphire laser systems: a 1 kHz regenerative amplifier and a 4.3 MHz long-cavity oscillator. All other pulse parameters are kept the same. Comparative measurements of a dielectric high reflector, a chirped mirror, and metallic mirrors show at least a factor of 2.7 lower fs LIDT at megahertz repetition rates. We attribute this to thermally assisted damage mechanisms supported by complex heat transfer simulations. PMID- 26030549 TI - High-power synchronously pumped femtosecond Raman fiber laser. AB - We report a high-power synchronously pumped femtosecond Raman fiber laser operating in the normal dispersion regime. The Raman laser is pumped by a picosecond Yb(3+)-doped fiber laser. It produces highly chirped pulses with energy up to 18 nJ, average power of 0.76 W and 88% efficiency. The pulse duration is measured to be 147 fs after external compression. We observed two different regimes of operation of the laser: coherent and noise-like regime. Both regimes were experimentally characterized. Numerical simulations are in a good agreement with experimental results. PMID- 26030550 TI - Spoof surface plasmon-based stripe antennas with extreme field enhancement in the terahertz regime. AB - Retardation-based stripe antennas due to the excitation of spoof surface plasmons on a corrugated metal stripe are proposed and numerically studied in the terahertz regime, revealing sharp Fabry-Perot resonances in scattering cross section spectra with strongly enhanced local fields. The order of the resonance exhibiting the sharpest scattering cross section and strongest field enhancements (FEs) is found to coincide with the number of grooves, due to the hybridization of the antenna resonance with the individual groove resonance. The proposed (spoof surface plasmon-based) antennas with narrow resonances and large FE open up new possibilities for metamaterial design and seem very promising for sensing applications in the terahertz frequencies. PMID- 26030551 TI - Deep-UV microsphere projection lithography. AB - In this Letter, we present a single-exposure deep-UV projection lithography at 254-nm wavelength that produces nanopatterns in a scalable area with a feature size of 80 nm. In this method, a macroscopic lens projects a pixelated optical mask on a monolayer of hexagonally arranged microspheres that reside on the Fourier plane and image the mask's pattern into a photoresist film. Our macroscopic lens shrinks the size of the mask by providing an imaging magnification of ~1.86*10(4), while enhancing the exposure power. On the other hand, microsphere lens produces a sub-diffraction limit focal point-a so-called photonic nanojet-based on the near-surface focusing effect, which ensures an excellent patterning accuracy against the presence of surface roughness. Ray optics simulation is utilized to design the bulk optics part of the lithography system, while a wave-optics simulation is implemented to simulate the optical properties of the exposed regions beneath the microspheres. We characterize the lithography performance in terms of the proximity effect, lens aberration, and interference effect due to refractive index mismatch between photoresist and substrate. PMID- 26030552 TI - Singular-value demodulation of phase-shifted holograms. AB - We report on phase-shifted holographic interferogram demodulation by singular value decomposition. Numerical processing of optically acquired interferograms over several modulation periods was performed in two steps: (1) rendering of off axis complex-valued holograms by Fresnel transformation of the interferograms; and (2) eigenvalue spectrum assessment of the lag-covariance matrix of hologram pixels. Experimental results in low-light recording conditions were compared with demodulation by Fourier analysis, in the presence of random phase drifts. PMID- 26030553 TI - Storage of orbital angular momenta of light via coherent population oscillation. AB - We report on the storage of orbital angular momenta (OAM) of light via the phenomenon of coherent population oscillation (CPO) in cold cesium atoms. The experiment is performed using a delayed four wave mixing configuration, where the transverse optical information of a probe field carrying OAM associated with its azimuthal phase dependence is stored in the CPO of Zeeman sublevels of the hyperfine transition F=3->F'=2 of the cesium D2 line. We also demonstrate experimentally the simultaneous storage and retrieval of different OAM states propagating along different directions in space, leading to algebraic operations with OAM and, therefore, opening the possibility of multiplexing OAM states. PMID- 26030554 TI - Waveguide lasers in ytterbium-doped tantalum pentoxide on silicon. AB - A waveguide laser in an ytterbium-doped tantalum pentoxide film is reported. The waveguide is formed of a rib of sputtered tantalum pentoxide on top of oxidized silicon with an over-cladding of silica. Emission at a wavelength of 1025 nm was achieved with an absorbed pump power threshold and slope efficiency of ~29 mW and 27%, respectively, for a cavity formed by a high reflector mirror and an estimated 12% Fresnel reflection from the bare end-face at the output. PMID- 26030556 TI - Magnetic field control of plasmon polaritons in graphene-covered gyrotropic planar waveguide. AB - In this Letter, we report about magnetic field switching of plasmon polaritons propagating into a planar gyrotropic waveguide covered by two graphene layers at a deeply subwavelength scale. It is shown that applying an external magnetic field may lead to energy redistribution between two waveguide surfaces. The effect value resonantly depends on the relation between waveguide size and exciting light wavelength. A change in chemical potential of graphene layers may be used for tuning the phase shift between plasmon polaritons at near-resonant wavelengths. Evident effect may be observed at low magnetic fields (less than one tesla) for wavelengths about microns on a scale of tens of nanometers. Such an effect may be used for plasmonics, photonics. and optoelectronics devices, as well as sensing applications. PMID- 26030557 TI - Optical stealth transmission based on super-continuum generation in highly nonlinear fiber over WDM network. AB - In this Letter, the optical stealth transmission carried by super-continuum spectrum optical pulses generated in highly nonlinear fiber is proposed and experimentally demonstrated. In the proposed transmission scheme, super-continuum signals are reshaped in the spectral domain through a wavelength-selective switch and are temporally spread by a chromatic dispersion device to achieve the same noise-like characteristic as the noise in optical networks, so that in both the time domain and the spectral domain, the stealth signals are hidden in public channel. Our experimental results show that compared with existing schemes where stealth channels are carried by amplified spontaneous emission noise, super continuum signal can increase the transmission performance and robustness. PMID- 26030558 TI - Whispering gallery mode lasing in optically isolated III-nitride nanorings. AB - III-nitride nanorings fabricated from a combination of hybrid-nanosphere lithography and laser lift-off processes is demonstrated. Being formed on an interfacial metallic layer optically coupling between the optical ring and its substrate is eliminated, maximizing optical confinement of whispering gallery resonant mode within the ring cavity. The tapered cross-sectional profile also promotes coupling of emitted light into resonant modes. Optically pumped lasing with a dominant peak at 421.5 nm is observed at room temperature, with threshold energy density of ~6.5 mJ/cm2. Etch-induced sidewall roughness causes scattering of light at the interface to diminish confinement, and is also responsible for the mode-splitting effect according to finite-difference time-domain simulations. PMID- 26030555 TI - Miniaturized fiber-coupled confocal fluorescence microscope with an electrowetting variable focus lens using no moving parts. AB - We report a miniature, lightweight fiber-coupled confocal fluorescence microscope that incorporates an electrowetting variable focus lens to provide axial scanning for full three-dimensional (3D) imaging. Lateral scanning is accomplished by coupling our device to a laser-scanning confocal microscope through a coherent imaging fiber-bundle. The optical components of the device are combined in a custom 3D-printed adapter with an assembled weight of <2 g that can be mounted onto the head of a mouse. Confocal sectioning provides an axial resolution of ~12 MUm and an axial scan range of ~80 MUm. The lateral field-of-view is 300 MUm, and the lateral resolution is 1.8 MUm. We determined these parameters by imaging fixed sections of mouse neuronal tissue labeled with green fluorescent protein (GFP) and fluorescent bead samples in agarose gel. To demonstrate viability for imaging intact tissue, we resolved multiple optical sections of ex vivo mouse olfactory nerve fibers expressing yellow fluorescent protein (YFP). PMID- 26030559 TI - Near-infrared open-path measurement of CO2 concentration in the urban atmosphere. AB - Average concentration of carbon dioxide (CO2) has been measured over a path length of 5.1 km in the lower troposphere by the method of differential optical absorption spectroscopy (DOAS) using a near-infrared light source based on amplified spontaneous emission. The analysis of CO2 absorption intensity around 1575 nm observed during 10 days over the Chiba city area has revealed that the CO2 concentration varied in the range of around 360-450 ppmv, with presumable influence of air mass advection from nearby industrial facilities. In addition, a good correlation has been found in relative humidity values between the DOAS and meteorological station data. As a whole, the present result indicates the usefulness of such a DOAS approach for measuring the concentration of CO2 averaged over an optical path of a few kilometers in the lower troposphere. PMID- 26030560 TI - Slow-light all-optical soliton diode based on tailored Bragg-grating structure. AB - All-optical soliton diode (AOSD) is proposed based on a sandwich nonlinear Bragg grating structure: a linearly chirped Bragg-grating linked to a uniform Bragg grating and again to a chirped Bragg-grating. The nonreciprocity is achieved by introducing two spatially asymmetric chirped Bragg-gratings with optical nonlinearity. High transmission ratio up to 150 is obtained when launching a picosecond Gaussian pulse into the setting. We find that such pulses in a form of solitons propagate at a rather small velocity (<0.03c) when pulse wavelength is selected in the vicinity of photonic bandgap. PMID- 26030561 TI - Compact rubidium-stabilized multi-frequency reference source in the 1.55-MUm region. AB - Combining light modulation and frequency conversion techniques, a compact and simple frequency-stabilized optical frequency comb spanning over 45 nm in the 1.56-MUm wavelength region is demonstrated. It benefits from the high-frequency stability achievable from rubidium atomic transitions at 780 nm probed in a saturation absorption scheme, which is transferred to the 1.56-MUm spectral region via a second-harmonic generation process. The optical frequency comb is generated by an electro-optic modulator enclosed in a Fabry-Perot cavity that is injected by the fundamental frequency stabilized laser. Frequency stability better than 2 kHz has been demonstrated on time scales between 1000 s and 2 days both at 1560 nm, twice the rubidium wavelength, and for a comb line at 1557 nm. PMID- 26030562 TI - Inherent photoluminescence Stokes shift in GaAs. AB - The intrinsic photoluminescence Stokes shift, i.e., the energy difference between optical band gap and emission peak, of 350 MUm thick semi-insulating GaAs wafers is found to be 4 meV at room temperature. The result is based on the determination of the optical bulk band gap from the transmission trend via modified Urbach rule whose result is confirmed with the transmission derivative method. The findings reveal the detailed balance of the optically evoked transitions and disclose the intrinsic link between Stokes shift and the Urbach tail slope parameter. PMID- 26030563 TI - Tunable slow light via stimulated Brillouin scattering at 2 MUm based on Tm-doped fiber amplifiers. AB - We present a slow light system based on stimulated Brillouin scattering (SBS) at 2 MUm. A single-frequency fiber laser with Tm-doped fiber amplifiers was used to generate the SBS signal laser and the Brillouin pump light at 1.971 MUm. The maximum delay time reaches 16 ns for pulses with 43-ns width, and the pulse width is broadened to 56.4 ns. The maximum delay time for 57-ns pulses reaches 33.4 ns, and the pulse width is broadened to 77.6 ns. The relative delays are 0.37 and 0.58 for 43 and 57 ns pulses, respectively. This is the first demonstration, as far as we know, on a slow light system at 2 MUm, which may be substantial for future optical communications and LIDAR systems employing laser sources near 2 MUm band. PMID- 26030564 TI - Phase-sensitive optical coherence elastography at 1.5 million A-Lines per second. AB - Shear-wave imaging optical coherence elastography (SWI-OCE) is an emerging method for 3D quantitative assessment of tissue local mechanical properties based on imaging and analysis of elastic wave propagation. Current methods for SWI-OCE involve multiple temporal optical coherence tomography scans (M-mode) at different spatial locations across tissue surface (B- and C-modes). This requires an excitation for each measurement position leading to clinically unacceptable long acquisition times up to tens of minutes. In this Letter, we demonstrate, for the first time, noncontact true kilohertz frame-rate OCE by combining a Fourier domain mode-locked swept source laser with an A-scan rate of ~1.5 MHz and a focused air-pulse as an elastic wave excitation source. The propagation of the elastic wave in the sample was imaged at a frame rate of ~7.3 kHz. Therefore, to quantify the elastic wave propagation velocity in a single direction, only a single excitation was needed. This method was validated by quantifying the elasticity of tissue-mimicking agar phantoms as well as of a porcine cornea ex vivo at different intraocular pressures. The results demonstrate that this method can reduce the acquisition time of an elastogram to milliseconds. PMID- 26030565 TI - Broadband perfect absorber based on one ultrathin layer of refractory metal. AB - Broadband perfect absorber based on one ultrathin layer of the refractory metal chromium without structure patterning is proposed and demonstrated. The ideal permittivity of the metal layer for achieving broadband perfect absorption is derived based on the impedance transformation method. Since the permittivity of the refractory metal chromium matches this ideal permittivity well in the visible and near-infrared range, a silica-chromium-silica three-layer absorber is fabricated to demonstrate the broadband perfect absorption. The experimental results under normal incidence show that the absorption is above 90% over the wavelength range of 0.4-1.4 MUm, and the measurements under angled incidence within 400-800 nm prove that the absorber is angle-insensitive and polarization independent. PMID- 26030566 TI - Extended ultrahigh-Q-cavity diode laser. AB - We report on a study of a 698 nm extended cavity semiconductor laser with intracavity narrowband optical feedback from a whispering gallery mode resonator. This laser comprises an ultrahigh-Q (>10(10)) resonator supporting stimulated Rayleigh scattering, a diffraction grating wavelength preselector, and a reflective semiconductor amplifier. Single longitudinal mode lasing is characterized with sub-kilohertz linewidth and a 9 nm coarse tuning range. The laser has a potential application for integration with the 1S0-3P0 strontium transition to create compact precision atomic clocks. PMID- 26030567 TI - Evidence of lasing on the Balmer-alpha line of OVIII in an ablative capillary discharge. AB - In a low-inductance ablative discharge through a capillary made of polyacetal (POM), lasing on the Balmer-alpha line of OVIII at 10.24 nm is identified. In line with previous studies of lasing on CVI ions, it is argued to be the consequence of charge exchange collisions after a m=0 instability. Lasing in both cases occurred at about the same time after beginning of the discharge, although lasing on the Balmer-alpha line of OVIII was less frequently observed, i.e., in approximately one out of ten discharges. Lasing on the CVI ion was seen in one out of three discharges. This is probably due to the need of reaching higher electron temperatures to completely strip oxygen ions simultaneously in the hot constrictions (necks) of the plasma instability. PMID- 26030568 TI - High-performance infrared light trapping in nano-needle structured p+ SnOx (x <= 1)/thin film n-Ge photodiodes on Si. AB - We report nano-needle structured conductive SnOx (x<=1) as a self-assembled electrode for high-efficiency light trapping in thin-film infrared (IR) photonic devices, benefiting from the high scattering efficiency, high density, and low IR loss of the nano-needles. We demonstrate a 2.2* responsivity enhancement for a 1.5-MUm-thick Ge absorber in a nano-needled p(+) SnOx/n-Ge photodiode on Si at lambda=1580 nm, in good agreement with theoretical calculation of 2.3* enhancement assuming no IR loss in the nano-needles. Such low-loss light trapping can potentially enable 15-30* absorption enhancement at lambda=1600-1650 nm in the Ge layer when integrated with a perfect rear reflector. PMID- 26030569 TI - Polarization-modulation setup for ultrafast infrared anisotropy experiments to study liquid dynamics. AB - An infrared pump-probe setup using rapid polarization modulation has been developed to perform time-resolved vibrational anisotropy measurements. A photo elastic modulator is used as a rapidly switchable half-wave plate, enabling the measurement of transient absorptions for parallel and perpendicular polarizations of the pump and probe pulses on a shot-to-shot basis. In this way, infrared intensity fluctuations are nearly completely canceled, significantly enhancing the accuracy of the transient-anisotropy measurement. The method is tested on the OD-stretch vibration of HDO in H2O, for which the signal-to-noise ratio is found to be 4 times better than with conventional methods. PMID- 26030570 TI - Cryogenic Yb:YAG composite-thin-disk for high energy and average power amplifiers. AB - A cryogenic composite-thin-disk amplifier with amplified spontaneous emission (ASE) rejection is implemented that overcomes traditional laser system problems in high-energy pulsed laser drivers of high average power. A small signal gain of 8 dB was compared to a 1.5 dB gain for an uncapped thin-disk without ASE mitigation under identical pumping conditions. A strict image relayed 12-pass architecture using an off-axis vacuum telescope and polarization switching extracted 100 mJ at 250 Hz in high beam quality stretched 700 ps pulses of 0.6-nm bandwidth. PMID- 26030571 TI - Frequency-doubling characteristics of high-power, ultrafast vortex beams. AB - We report on frequency-doubling characteristics of high-power, ultrafast optical vortex beams in a nonlinear medium. Based on single-pass second-harmonic generation (SHG) of optical vortices in 1.2 mm long bismuth triborate (BIBO) crystal, we studied the effect of different parameters influencing the SHG process in generating high-power and higher-order vortices. We observed a decrease in SHG efficiency with the order, which can be attributed to the increase of the vortex beam area with order. Like a Gaussian beam, optical vortices show focusing-dependent conversion efficiency. However, under similar experimental conditions, the optimum focusing condition for optical vortices is reached at tighter focusing with orders. We observed higher angular acceptance bandwidth in the case of optical vortices than that of a Gaussian beam; however, there is no substantial change in angular acceptance bandwidth with vortex order. We also observed that in the frequency-doubling process, the topological charge has negligible or no effect in temporal and spectral properties of the beams. We have generated ultrafast vortices at 532 nm with power as much as 900 mW and order as high as 12. In addition, we have devised a novel scheme based on linear optical elements to double the order of any optical vortex at the same wavelength. PMID- 26030572 TI - Photonic radio-frequency dissemination via optical fiber with high-phase stability. AB - We demonstrate a photonic radio-frequency transmission system via optical fiber. Optical radio-frequency signal is generated utilizing a Mach-Zehnder modulator based on double-side-band with carrier suppression modulation scheme. The phase error induced by optical fiber transmission is transferred to an intermediate frequency signal by the dual-heterodyne phase error transfer scheme, and then canceled by a phase locked loop. With precise phase compensation, a radio frequency with high-phase stability can be obtained at the remote end. We performed 20.07-GHz radio-frequency transfer over 100-km optical fiber, and achieved residual phase noise of -65 dBc/Hz at 1-Hz offset frequency, and the RMS timing jitter in the frequency range from 0.01 Hz to 1 MHz reaches 110 fs. The long-term frequency stability also achieves 8*10(-17) at 10,000 s averaging time. PMID- 26030573 TI - Quantitative polarized light microscopy using spectral multiplexing interferometry. AB - We propose an interferometric spectral multiplexing method for measuring birefringent specimens with simple configuration and high sensitivity. The retardation and orientation of sample birefringence are simultaneously encoded onto two spectral carrier waves, generated interferometrically by a birefringent crystal through polarization mixing. A single interference spectrum hence contains sufficient information for birefringence determination, eliminating the need for mechanical rotation or electrical modulation. The technique is analyzed theoretically and validated experimentally on cellulose film. System simplicity permits the possibility of mitigating system birefringence background. Further analysis demonstrates the technique's exquisite sensitivity as high as ~20 pm for retardation measurement. PMID- 26030574 TI - On a propagation-invariant, orthogonal modal expansion on the unit disk: going beyond Nijboer-Zernike theory of aberrations. AB - Nijboer-Zernike's circle polynomials are broadly used for the evaluation of aberrations of optical systems or, more generally, wavefront analysis. This is because they are orthogonal over a unit circle and are directly related to the balanced classical aberrations for imaging systems with circular pupils. However, such expansion and successive extensions of the original theory suffer from a key limitation: it does not preserve its form under propagation. This means that even if a Nijboer-Zernike expansion for a field is known on a given reference plane, as soon as another plane is considered, a new, different set of polynomials for the same field appears. The origin of this problem is to be ascribed to the fact that Nijboer-Zernike polynomials are a useful mathematical tool which, however, are not bound to the physics of the electromagnetic problem they are employed in. In this work, we show that a more appropriate modal expansion does exist that is not only orthogonal on the unit disk but is also invariant on propagation. Besides impacting the field of aberrations analysis and retrieval, the modal expansion introduced here holds an enormous potential for digital classical and quantum optical communications, optical metrology, and adaptive optics too. The practical implementation, physical interpretation, and visualization of this new modal expansion are all very straightforward. PMID- 26030575 TI - Plasmon enhanced near-infrared quantum cutting of KYF4: Tb3+, Yb3+ doped with Ag nanoparticles. AB - Novel quantum cutting (QC) phosphor KYF4: Tb3+, Yb3+ doped Ag nanoparticles (NPs) was prepared by using the sol-gel method. Plasmon enhanced near-infrared (NIR) QC involving Yb3+ ion at 975 nm (2F5/2->2F7/2) emission was achieved under the excitation of 374 nm (7F6->5D3) and 485 nm (7F6->5D4) of Tb3+ ions, respectively. The effect of Ag NPs on NIR QC luminescence was investigated, and the results show that QC luminescence intensity first increases, then decreases with the increase of the Ag NPs concentration. The maximum enhancement factor is about 1.9 when the concentration of Ag NPs is 0.5%. Our study may have potential application in the field of silicon-based solar cells. PMID- 26030576 TI - Highly efficient Er/Yb-codoped fiber amplifier with an Yb-band fiber Bragg grating. AB - In this Letter, a high-power Er/Yb-codoped fiber amplifier (EYDFA) with a high reflection Yb-band fiber Bragg grating (FBG) at the pump end is experimentally investigated. The FBG was inscribed on a piece of double-clad fiber with a center wavelength of 1032 nm. Due to the selective reflection of the backward Yb-band amplified spontaneous emission (Yb ASE) by the FBG, a co-pump-propagating Yb-band auxiliary signal was generated. Because of the stimulated amplification and reabsorption of the auxiliary signal, the Yb ASE was dramatically suppressed and the pump conversion efficiency (PCE) of the EYDFA was notably improved. An output power of 6.48 W was achieved at a pump power of 16.5 W, which is equivalent to a PCE of ~39%. The slope efficiency relative to applied pump power was ~40%. The maximum output power was improved ~20% because of the introduction of the FBG. PMID- 26030577 TI - Normal incidence narrowband transmission filtering capabilities using symmetry protected modes of a subwavelength, dielectric grating. AB - We computationally study a normal incidence narrowband transmission filter based on a subwavelength dielectric grating that operates through Fano interference between supported guided leaky modes of the system. We characterize the filtering capabilities as the cross section of the grating is manipulated and suggest techniques for experimental demonstration. Using group theory, we study the plane wave coupling to the supported modes that leads to broadband reflectance and narrowband transmittance responses for rectangular, pentagonal, rhomboidal, and right trapezoidal cross-sectional geometries. PMID- 26030578 TI - Toward athermal silicon-on-insulator (de)multiplexers in the O-band. AB - We report on the design, fabrication, and characterization of a 1*4 silicon-on insulator (SOI) demultiplexer exhibiting a significant reduction of its thermo optical sensitivity in the O-band. The optical filtering is achieved by cascading several Mach-Zehnder interferometers (MZIs) fabricated on a 300-nm-thick SOI platform. Owing to an asymmetric design of the confinement for each MZIs, we found an athermal criterium that satisfies the spectral requirements. The thermal sensitivity of the structure is analyzed by a semi-analytical model in order to create an athermal multiplexer. Fiber-to-fiber thermo-optical testing reveals a thermal sensitivity of around 17 pm/ degrees C reduced by 75% compared to the standard devices with promising performances for both the crosstalk (15 dB), the insertion losses (4 dB), and absolute lambda registration (<0.25 nm). PMID- 26030579 TI - A generalized Kerker condition for highly directive nanoantennas. AB - A nanoantenna with balanced electric and magnetic dipole moments, known as the first Kerker condition, exhibits a directive radiation pattern with zero backscattering. In principle, a nanoantenna can provide even better directionality if higher order moments are properly balanced. Here, we study a generalized Kerker condition in the example of a nanoring nanoantenna supporting electric dipole and electric quadrupole moments. Nanoring antennas are well suited since both multipole moments can be almost independently tuned to meet the generalized Kerker condition. PMID- 26030580 TI - Adaptive linearized microwave downconversion utilizing a single dual-electrode Mach-Zehnder modulator. AB - An adaptive postprocessing approach to improve the linearity of the down converted analog photonic link has been proposed and experimentally demonstrated. With the inverse transformation for the detected signal, the third-order intermodulation distortion (IMD3) can be significantly suppressed when only the frequency and bandwidth of the signal are known. Experimental results show that the spurious-free dynamic range (SFDR) of the link can reach ~126 dB.Hz(4/5) after the proposed compensation scheme. PMID- 26030581 TI - Dual-color three-dimensional STED microscopy with a single high-repetition-rate laser. AB - We describe a dual-color three-dimensional stimulated emission depletion (3D STED) microscopy employing a single laser source with a repetition rate of 80 MHz. Multiple excitation pulses synchronized with a STED pulse were generated by a photonic crystal fiber, and the desired wavelengths were selected by an acousto optic tunable filter with high spectral purity. Selective excitation at different wavelengths permits simultaneous imaging of two fluorescent markers at a nanoscale resolution in three dimensions. PMID- 26030582 TI - Single-order diffraction grating designed by trapezoidal transmission function. AB - Diffraction grating is a widely used dispersion element in spectral analysis from the infrared to the x-ray region. Traditionally, it has a square-wave transmission function, suffering from high-order diffraction contamination. Single-order diffraction can be achieved by sinusoidal amplitude transmission grating, but the fabrication is difficult. Here, we propose a novel idea to design a grating based on trapezoidal transmission function, which makes traditional grating a special case. Grating designed by this idea can not only suppress higher order diffraction by several orders of magnitude as sinusoidal amplitude grating does but also greatly reduce the fabrication difficulty to the level of processing for traditional grating. It offers a new opportunity for fabrication of grating with single-order diffraction and measurement of spectrum without contamination of high-order harmonic components. This idea can easily extend to varied-line-space grating, concave grating with single-order diffraction, or zone plates with single foci and will bring great changes in the field of grating applications. PMID- 26030583 TI - Discrete-mode ZnO microparticle random laser. AB - A random laser incorporating irregular-shaped ZnO microparticles exhibits a small number of lasing lines with stable lasing intensities and negligibly low background emission. This unique feature is in direct contrast to that observed for a conventional ZnO nanoparticle film random laser. Gain competition between the discrete laser modes also occurs in this microparticle random laser. These lasing characteristics are because of the intra-particle confinement of the laser cavity modes in each ZnO microparticle. PMID- 26030584 TI - Modulation instability in a highly nonlinear fiber for discrete-time pulsed random bit generation. AB - A simple yet high-speed scheme by utilizing modulation instability (MI) on the discrete-time generation of random bits is proposed and demonstrated experimentally. We develop MI pulses by pumping a highly nonlinear fiber in the anomalous dispersion regime using a mode-locked laser. MI pulses contain fluctuating pulse-to-pulse variations of peak intensities for extraction into random bits. At a repetition rate of 10 GHz, 5 bits are extracted from each pulse in generating random bits at 50 Gbps, as verified by the National Institute of Standards and Technology test suite. PMID- 26030585 TI - High-power mid-infrared high repetition-rate supercontinuum source based on a chalcogenide step-index fiber. AB - We demonstrate a tunable and robust femtosecond supercontinuum source with a maximum output power of 550 mW and a maximum spectral width of up to 2.0 MUm, which can cover the mid-infrared region from 2.3 MUm up to 4.9 MUm by tuning the pump wavelength. As2S3 chalcogenide step-index fibers with core diameters of 7 and 9 MUm are pumped at different wavelengths from 2.5 MUm up to 4.1 MUm with femtosecond pulses by means of a post-amplified optical parametric oscillator pumped by an Yb:KGW laser. The spectral behavior of the supercontinuum is investigated by changing the pump wavelength, core diameter, fiber length, and pump power. Self-phase modulation is identified as the main broadening mechanism in the normal dispersion regime. This source promises to be an excellent laboratory tool for infrared spectroscopy owing to its high brilliance as demonstrated for the CS2-absorption bands around 3.5 MUm. PMID- 26030586 TI - Optimized emission in nanorod arrays through quasi-aperiodic inverse design. AB - We investigate a new class of quasi-aperiodic nanorod structures for the enhancement of incoherent light emission. We identify one optimized structure using an inverse design algorithm and the finite-difference time-domain method. We carry out emission calculations on both the optimized structure as well as a simple periodic array. The optimized structure achieves nearly perfect light extraction while maintaining a high spontaneous emission rate. Overall, the optimized structure can achieve a 20%-42% increase in external quantum efficiency relative to a simple periodic design, depending on material quality. PMID- 26030587 TI - Redesign of article pages for Optics Letters: editorial. AB - Optics Letters announces the redesign of its journal article pages and new manuscript templates for authors. PMID- 26030588 TI - Usefulness of midregional proadrenomedullin to predict poor outcome in patients with community acquired pneumonia. AB - BACKGROUND: midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP). We sought to confirm whether MR-proADM added to Pneumonia Severity Index (PSI) improves the potential prognostic value of PSI alone, and tested to what extent this combination could be useful in predicting poor outcome of patients with CAP in an Emergency Department (ED). METHODS: Consecutive patients diagnosed with CAP were enrolled in this prospective, single-centre, observational study. We analyzed the ability of MR-proADM added to PSI to predict poor outcome using receiver operating characteristic (ROC) curves, logistic regression and risk reclassification and comparing it with the ability of PSI alone. The primary outcome was "poor outcome", defined as the incidence of an adverse event (ICU admission, hospital readmission, or mortality at 30 days after CAP diagnosis). RESULTS: 226 patients were included; 33 patients (14.6%) reached primary outcome. To predict primary outcome the highest area under curve (AUC) was found for PSI (0.74 [0.64-0.85]), which was not significantly higher than for MR-proADM (AUC 0.72 [0.63-0.81, p > 0.05]). The combination of PSI and MR-proADM failed to improve the predictive potential of PSI alone (AUC 0.75 [0.65-0.85, p=0.56]). Ten patients were appropriately reclassified when the combined PSI and MR-proADM model was used as compared with the model of PSI alone. Net reclassification improvement (NRI) index was statistically significant (7.69%, p = 0.03) with an improvement percentage of 3.03% (p = 0.32) for adverse event, and 4.66% (P = 0.02) for no adverse event. CONCLUSION: MR-proADM in combination with PSI may be helpful in individual risk stratification for short-term poor outcome of CAP patients, allowing a better reclassification of patients compared with PSI alone. PMID- 26030589 TI - Regulation of Adipogenesis and Key Adipogenic Gene Expression by 1, 25 Dihydroxyvitamin D in 3T3-L1 Cells. AB - The functions of 1, 25-dihydroxyvitamin D (1, 25-(OH)2D3) in regulating adipogenesis, adipocyte differentiation and key adipogenic gene expression were studied in 3T3-L1 preadipocytes. Five concentrations (0.01, 0.1, 1, 10, 100 nM) of 1, 25-(OH)2D3 were studied and lipid accumulation measured by Oil Red O staining and expression of adipogenic genes quantified using quantitative real time PCR. Adipogenic responses to 1, 25-(OH)2D3 were determined on 6, and 12 h, and days 1-10 after induction of adipogenesis by a hormonal cocktail with or without 1, 25-(OH)2D3. In response to 1, 25-(OH)2D3 (1, 10, and 100 nM), lipid accumulation and the expression of PPARgamma, C/EBPalpha, FABP4 and SCD-1 were inhibited through day 10, and vitamin D receptor expression was inhibited in the early time points. The greatest inhibitory effect was upon expression of FABP4. Expression of SREBP-1c was only affected on day 2. The lowest concentrations of 1, 25-(OH)2D3 tested did not affect adipocyte differentiation or adipogenic gene expression. The C/EBPalpha promoter activity response to 1, 25-(OH)2D3 was also tested, with no effect detected. These results indicate that 1, 25-(OH)2D3 inhibited adipogenesis via suppressing adipogenic-specific genes, and is invoked either during PPARgamma activation or immediately up-stream thereof. Gene expression down-stream of PPARgamma especially FABP4 was strongly inhibited, and we suggest that the role of 1, 25-(OH)2D3 in regulating adipogenesis will be informed by further studies of adipogenic-specific gene promoter activity. PMID- 26030590 TI - The ABC's of Suicide Risk Assessment: Applying a Tripartite Approach to Individual Evaluations. AB - There is considerable need for accurate suicide risk assessment for clinical, screening, and research purposes. This study applied the tripartite affect behavior-cognition theory, the suicidal barometer model, classical test theory, and item response theory (IRT), to develop a brief self-report measure of suicide risk that is theoretically-grounded, reliable and valid. An initial survey (n = 359) employed an iterative process to an item pool, resulting in the six-item Suicidal Affect-Behavior-Cognition Scale (SABCS). Three additional studies tested the SABCS and a highly endorsed comparison measure. Studies included two online surveys (Ns = 1007, and 713), and one prospective clinical survey (n = 72; Time 2, n = 54). Factor analyses demonstrated SABCS construct validity through unidimensionality. Internal reliability was high (alpha = .86-.93, split-half = .90-.94)). The scale was predictive of future suicidal behaviors and suicidality (r = .68, .73, respectively), showed convergent validity, and the SABCS-4 demonstrated clinically relevant sensitivity to change. IRT analyses revealed the SABCS captured more information than the comparison measure, and better defined participants at low, moderate, and high risk. The SABCS is the first suicide risk measure to demonstrate no differential item functioning by sex, age, or ethnicity. In all comparisons, the SABCS showed incremental improvements over a highly endorsed scale through stronger predictive ability, reliability, and other properties. The SABCS is in the public domain, with this publication, and is suitable for clinical evaluations, public screening, and research. PMID- 26030591 TI - Behavior of replication origins in Eukaryota - spatio-temporal dynamics of licensing and firing. AB - Although every organism shares some common features of replication, this process varies greatly among eukaryotic species. Current data show that mathematical models of the organization of origins based on possibility theory may be applied (and remain accurate) in every model organism i.e. from yeast to humans. The major differences lie within the dynamics of origin firing and the regulation mechanisms that have evolved to meet new challenges throughout the evolution of the organism. This article elaborates on the relations between chromatin structure, organization of origins, their firing times and the impact that these features can have on genome stability, showing both differences and parallels inside the eukaryotic domain. PMID- 26030592 TI - Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation. AB - The Src family of tyrosine kinases (SFKs) regulate numerous aspects of cell growth and differentiation and are under the principal control of the C-terminal Src Kinase (Csk). Although Csk and SFKs share conserved kinase, SH2 and SH3 domains, they differ considerably in three-dimensional structure, regulatory mechanism, and the intrinsic kinase activities. Although the SH2 and SH3 domains are known to up- or down-regulate tyrosine kinase function, little is known about the global motions in the full-length kinase that govern these catalytic variations. We use a combination of accelerated Molecular Dynamics (aMD) simulations and experimental methods to provide a new view of functional motions in the Csk scaffold. These computational studies suggest that high frequency vibrations in the SH2 domain are coupled through the N-terminal lobe of the kinase domain to motions in the SH3 domain. The effects of these reflexive movements on the kinase domain can be viewed using both Deuterium Exchange Mass Spectrometry (DXMS) and steady-state kinetic methods. Removal of several contacts, including a crystallographically unobserved N-terminal segment, between the SH3 and kinase domains short-circuit these coupled motions leading to reduced catalytic efficiency and stability of N-lobe motifs within the kinase domain. The data expands the model of Csk's activation whereby separate domains productively interact with two diametrically opposed surfaces of the kinase domain. Such reversible transitions may organize the active structure of the tyrosine kinase domain of Csk. PMID- 26030594 TI - SBGNViz: A Tool for Visualization and Complexity Management of SBGN Process Description Maps. AB - BACKGROUND: Information about cellular processes and pathways is becoming increasingly available in detailed, computable standard formats such as BioPAX and SBGN. Effective visualization of this information is a key recurring requirement for biological data analysis, especially for -omic data. Biological data analysis is rapidly migrating to web based platforms; thus there is a substantial need for sophisticated web based pathway viewers that support these platforms and other use cases. RESULTS: Towards this goal, we developed a web based viewer named SBGNViz for process description maps in SBGN (SBGN-PD). SBGNViz can visualize both BioPAX and SBGN formats. Unique features of SBGNViz include the ability to nest nodes to arbitrary depths to represent molecular complexes and cellular locations, automatic pathway layout, editing and highlighting facilities to enable focus on sub-maps, and the ability to inspect pathway members for detailed information from EntrezGene. SBGNViz can be used within a web browser without any installation and can be readily embedded into web pages. SBGNViz has two editions built with ActionScript and JavaScript. The JavaScript edition, which also works on touch enabled devices, introduces novel methods for managing and reducing complexity of large SBGN-PD maps for more effective analysis. CONCLUSION: SBGNViz fills an important gap by making the large and fast-growing corpus of rich pathway information accessible to web based platforms. SBGNViz can be used in a variety of contexts and in multiple scenarios ranging from visualization of the results of a single study in a web page to building data analysis platforms. PMID- 26030593 TI - Loss of RhoA Exacerbates, Rather Than Dampens, Oncogenic K-Ras Induced Lung Adenoma Formation in Mice. AB - Numerous cellular studies have indicated that RhoA signaling is required for oncogenic Ras-induced transformation, suggesting that RhoA is a useful target in Ras induced neoplasia. However, to date very limited data exist to genetically attribute RhoA function to Ras-mediated tumorigenesis in mammalian models. In order to assess whether RhoA is required for K-Ras-induced lung cancer initiation, we utilized the K-RasG12D Lox-Stop-Lox murine lung cancer model in combination with a conditional RhoAflox/flox and RhoC-/- knockout mouse models. Deletion of the floxed Rhoa gene and expression of K-RasG12D was achieved by either CCSP-Cre or adenoviral Cre, resulting in simultaneous expression of K RasG12D and deletion of RhoA from the murine lung. We found that deletion of RhoA, RhoC or both did not adversely affect normal lung development. Moreover, we found that deletion of either RhoA or RhoC alone did not suppress K-RasG12D induced lung adenoma initiation. Rather, deletion of RhoA alone exacerbated lung adenoma formation, whereas dual deletion of RhoA and RhoC together significantly reduced K-RasG12D induced adenoma formation. Deletion of RhoA appears to induce a compensatory mechanism that exacerbates adenoma formation. The compensatory mechanism is at least partly mediated by RhoC. This study suggests that targeting of RhoA alone may allow for compensation and a paradoxical exacerbation of neoplasia, while simultaneous targeting of both RhoA and RhoC is likely to lead to more favorable outcomes. PMID- 26030595 TI - Novel classification of the posterior auricular artery based on angiographical appearance. AB - PURPOSE: To investigate the length variation of the posterior auricular artery and propose a novel classification of the posterior auricular artery based on angiographical appearance. PATIENTS AND METHODS: A series of 234 consecutive patients who had undergone conventional cerebral angiography was analyzed. The posterior auricular artery was examined on the lateral projection of the external carotid or common carotid arteriography. The posterior auricular artery was classified into four groups by length, using the external auditory canal and the top of the helix as radiographical landmarks. Our proposed classification is as follows: Type A, posterior auricular artery terminates between its origin and the center of the external auditory canal; Type B, posterior auricular artery terminates between the center of the external auditory canal and the top of the helix; Type C, posterior auricular artery terminates between the top of the helix and the vertex; and Type D, posterior auricular artery reaches up to the vertex. RESULTS: A total of 424 (right, 214; left, 210) posterior auricular arteries were analyzed in 111 men and 123 women aged 11 to 91 years (mean, 61.0 years) examined for aneurysms in 78 cases, occlusive vascular diseases in 56, intracranial hemorrhages in 41, tumors in 35, and others in 24. Types A, B, C, and D were found in 15.1%, 34.9%, 48.8%, and 1.2% of the patients, respectively. CONCLUSION: A novel classification of the posterior auricular artery identifies four types based on its length on cerebral angiography. PMID- 26030596 TI - Acrylate metathesis via the second-generation Grubbs catalyst: unexpected pathways enabled by a PCy3-generated enolate. AB - The diverse applications of acrylate metathesis range from synthesis of high value alpha,beta-unsaturated esters to depolymerization of unsaturated polymers. Examined here are unexpected side reactions promoted by the important Grubbs catalyst GII. Evidence is presented for attack of PCy3 on the acrylate olefin to generate a reactive carbanion, which participates in multiple pathways, including further Michael addition, proton abstraction, and catalyst deactivation. Related chemistry may be anticipated whenever labile metal-phosphine complexes are used to catalyze reactions of substrates bearing an electron-deficient olefin. PMID- 26030597 TI - What do patients think about dental services in Quebec? Analysis of a dentist rating website. AB - BACKGROUND: Disparity exists between the public view of the "ideal" dentist and patient experiences of dental practice: dentists are expected to be altruistic and patient-centred, yet patient surveys suggest that the profession is overly motivated by profit. OBJECTIVE: To determine how the public views dental care in Quebec. METHODS: A random sample of comments about Quebec dentists made in 2011 was extracted from the public website RateMDs.com. Dentist characteristics and patient comments were analyzed using descriptive statistics and qualitative deductive and inductive thematic analysis. RESULTS: Eighty-six entries from a random sample of 47 of a possible 750 dentists were extracted and analyzed. Most dentists were men (66%) and worked in Montreal (51%). Patient comments were mainly positive (83%). Themes included overall impressions, communication and care, clinical competence, professionalism and office environment. Positive comments focused on patient-centred communication, in which the patient felt respected and involved in treatment planning; competence, seen as comprehensive, efficient and long-lasting treatment; and professionalism, which included ethical behaviour such as knowing professional limits. Negative comments focused on reticent communication styles that did not encourage patient input; incompetence, which included poor pain management and unnecessary treatment; and unprofessional conduct, such as lack of transparency in pricing. CONCLUSION: In contrast with the negative image of dentists reported from patient surveys, comments on one public website were primarily positive. Our findings reinforce the importance of patient-centred education and communication training for students and continuing education. PMID- 26030598 TI - Clinical manipulation of mineral trioxide aggregate: lessons from the construction industry and their relevance to clinical practice. AB - Mineral trioxide aggregate (MTA) is based on ordinary Portland cement (with added radiopaque agents) and, thus, shares many of its features. Although MTA is reported to be difficult to handle clinically, concrete materials made using Portland cement are the foundation of the construction industry. In this paper, we summarize important lessons from the construction literature that are relevant to the successful use of MTA in clinical practice, including behaviour during storage, susceptibility to acidic environments, the effects of exposure of the setting material to moisture and interactions with substances that may interfere with the speed of setting and the quality of the end product. PMID- 26030599 TI - How do I manage the fracture of an abutment tooth for a removable partial denture? PMID- 26030600 TI - The participation of Ontario oral and maxillofacial surgeons in oral, lip and oropharyngeal cancer. AB - BACKGROUND: Oral, lip and oropharyngeal cancer accounts for up to 75% of head and neck cancers. Dental professionals contribute to improved treatment outcomes through early detection of these cancers. Oral and maxillofacial surgeons (OMFS) are trained to participate in numerous phases of care for patients with oral, lip and oropharyngeal cancer. OBJECTIVE: To quantify the participation of Ontario OMFS in various phases of oral, lip and oropharyngeal cancer care. METHODS: A survey assessing participation of Ontario OMFS in screening, education, prevention, diagnosis, surgical oncology, reconstruction and rehabilitation of patients with oral, lip and oropharyngeal cancer was conducted in January and February 2013. RESULTS: Of the 210 OMFS registered with the Royal College of Dental Surgeons of Ontario, 191 were contacted, and 95 (49.7%) responded to the survey. Of the respondents, 98.9% were involved in cancer screening, 96.8% were involved in prevention and early intervention (monitoring and treatment) of premalignant lesions and 94.7% participated in diagnosis and staging. Early stage oral, lip and oropharyngeal cancer was managed surgically by 44.1% of the respondents, while 6.4% managed late-stage disease. Oral rehabilitation was managed by 77.7% of respondents. CONCLUSION: OMFS are an integral part of all phases of oral and oropharyngeal cancer care including primary surgical oncology in Ontario. Dental professionals can help improve outcomes of this care through early identification of cancer using surveillance examinations at all routine dental visits. This early detection contributes directly to disease-free survival and quality of life. PMID- 26030601 TI - Melanotic neuroectodermal tumour of infancy: a case report. AB - Melanotic neuroectodermal tumour of infancy is a rare benign pigmented tumour that typically appears in the first year of life. We report an atypical presentation of this tumour, associated with an erupted primary tooth in a 7 month-old boy. We discuss the clinical, radiographic and histologic features of this rare tumour, as well as its surgical management and the follow-up treatment plan. PMID- 26030602 TI - Tracking early visits to the dentist: a look at the first 3 years of the Manitoba Dental Association's Free First Visit program. AB - INTRODUCTION: In 2010, the Manitoba Dental Association launched its Free First Visit (FFV) program to provide dental screening for infants and toddlers. In this article, we review 3 years of FFV data submitted by participating dentists. METHODS: Data from tracking forms were reviewed for children<=36 months of age. These forms include the age of the child at the time of their FFV, their home postal code and caries status. Descriptive and bivariate analyses were carried out, and postal code geomapping was completed. RESULTS: Of the 8396 tracking forms submitted, 51.8% were for boys. The mean age at the time of the first visit was 24.2+/-7.8 months. Although only 8.5% had an FFV by 12 months, 26.7% had an FFV by 18 months. The average number of FFVs per month was 231.4+/-49.7. Postal code mapping revealed that participation was highest for children in the southern half of the province, including some high-needs neighbourhoods in Winnipeg. Pediatric dentists provided most FFVs and saw significantly younger children compared with general dentists (23.8+/-7.8 months of age vs. 25.2+/-7.7 months, p<0.001). CONCLUSIONS: Although many Manitoba children have had an FFV, few visit a dentist by 12 months, as recommended by the dental profession. There is a need to improve the proportion of children visiting a dentist by the recommended age, and general practitioners should assume a greater role in providing this service. PMID- 26030603 TI - Interdisciplinary approach to caries disparity: a workshop summary. PMID- 26030604 TI - Pentacyclic triterpenoids with nitrogen- and sulfur-containing heterocycles: synthesis and medicinal significance. AB - Triterpenoids are natural compounds with a variety of biological activities and are usually produced by plants as secondary metabolites. In recent decades, scientists focused on the properties of triterpenoids have discovered many activities, such as antitumor, antiviral, antimicrobial, anti-inflammatory and others. Thousands of new triterpenoids with various skeletal modifications have now been synthesized. One of the most important modifications is the formation of a new heterocyclic ring. The simple fact that the vast majority of currently used drugs are heterocyclic compounds has encouraged a lot of researches to synthesize analogous triterpenoid derivatives in order to find new molecules with higher activities and consequently optimize their pharmacological profile. The biological properties of triterpenoid heterocycles are very promising and many of them have been studied, especially as antitumor agents. This review is mainly focused on the synthesis of various types of nitrogen and occasionally sulfur containing heterocyclic triterpenoids for their potential use as future drugs in medicine and in addition discusses their overall biological activities. PMID- 26030605 TI - Synthesis of Multiple-Substituted Pyrroles via Gold(I)-Catalyzed Hydroamination/Cyclization Cascade. AB - A gold-catalyzed cascade hydroamination/cyclization reaction of alpha-amino ketones with alkynes to form substituted pyrroles has been developed. The method offers several advantages such as high regioselectivity with the tested cases, wide functional group tolerance, and easily accessible starting materials. The synthetic utility of the obtained pyrrole products was demonstrated by their efficient transformations to 2-vinylated pyrroles via gold-catalyzed intermolecular hydroarylation. PMID- 26030607 TI - Rational design and synthesis of excavated trioctahedral Au nanocrystals. AB - Excavated polyhedral nanostructures, possessing the features of high surface area and well-defined surface structure with a specific crystal facet and avoidance of aggregation, could be one of the best choices for the purpose of reducing consumption and improving performance of noble metals in many application fields. However, the formation of the excavated structures is thermodynamically unfavourable and its rational synthesis is far beyond our knowledge. In this work, taking overgrowth of Pd onto trioctahedral Au nanocrystals as a model, we present a deep insight study for synthesizing an excavated structure relying on the protection role of surfactants under suitable crystal growth kinetics. Based on the abovementioned understanding, we designed a simple and effective strategy to synthesize Au nanocrystals with excavated trioctahedral structure in one step. Due to the novel feature of the excavated structure and exposed high energy {110} facets, excavated trioctahedral Au NCs exhibited optical extinction at the near infrared region and showed high catalytic activity towards the reduction of p nitrophenol. Moreover, the synthetic strategy can be extended to the synthesis of excavated Au-Pd alloys. PMID- 26030606 TI - Targeted resequencing of the pericentromere of chromosome 2 linked to constitutional delay of growth and puberty. AB - Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP. PMID- 26030608 TI - Self-organized criticality in cortical assemblies occurs in concurrent scale-free and small-world networks. AB - The spontaneous activity of cortical networks is characterized by the emergence of different dynamic states. Although several attempts were accomplished to understand the origin of these dynamics, the underlying factors continue to be elusive. In this work, we specifically investigated the interplay between network topology and spontaneous dynamics within the framework of self-organized criticality (SOC). The obtained results support the hypothesis that the emergence of critical states occurs in specific complex network topologies. By combining multi-electrode recordings of spontaneous activity of in vitro cortical assemblies with theoretical models, we demonstrate that different 'connectivity rules' drive the network towards different dynamic states. In particular, scale free architectures with different degree of small-worldness account better for the variability observed in experimental data, giving rise to different dynamic states. Moreover, in relationship with the balance between excitation and inhibition and percentage of inhibitory hubs, the simulated cortical networks fall in a critical regime. PMID- 26030609 TI - Natural Variants of the KPC-2 Carbapenemase have Evolved Increased Catalytic Efficiency for Ceftazidime Hydrolysis at the Cost of Enzyme Stability. AB - The spread of beta-lactamases that hydrolyze penicillins, cephalosporins and carbapenems among Gram-negative bacteria has limited options for treating bacterial infections. Initially, Klebsiella pneumoniae carbapenemase-2 (KPC-2) emerged as a widespread carbapenem hydrolyzing beta-lactamase that also hydrolyzes penicillins and cephalosporins but not cephamycins and ceftazidime. In recent years, single and double amino acid substitution variants of KPC-2 have emerged among clinical isolates that show increased resistance to ceftazidime. Because it confers multi-drug resistance, KPC beta-lactamase is a threat to public health. In this study, the evolution of KPC-2 function was determined in nine clinically isolated variants by examining the effects of the substitutions on enzyme kinetic parameters, protein stability and antibiotic resistance profile. The results indicate that the amino acid substitutions associated with KPC-2 natural variants lead to increased catalytic efficiency for ceftazidime hydrolysis and a consequent increase in ceftazidime resistance. Single substitutions lead to modest increases in catalytic activity while the double mutants exhibit significantly increased ceftazidime hydrolysis and resistance levels. The P104R, V240G and H274Y substitutions in single and double mutant combinations lead to the largest increases in ceftazidime hydrolysis and resistance. Molecular modeling suggests that the P104R and H274Y mutations could facilitate ceftazidime hydrolysis through increased hydrogen bonding interactions with the substrate while the V240G substitution may enhance backbone flexibility so that larger substrates might be accommodated in the active site. Additionally, we observed a strong correlation between gain of catalytic function for ceftazidime hydrolysis and loss of enzyme stability, which is in agreement with the 'stability-function tradeoff' phenomenon. The high Tm of KPC-2 (66.5 degrees C) provides an evolutionary advantage as compared to other class A enzymes such as TEM (51.5 degrees C) and CTX-M (51 degrees C) in that it can acquire multiple destabilizing substitutions without losing the ability to fold into a functional enzyme. PMID- 26030610 TI - Comparison of Bloodmeal Digestion and the Peritrophic Matrix in Four Sand Fly Species Differing in Susceptibility to Leishmania donovani. AB - The early stage of Leishmania development in sand flies is closely connected with bloodmeal digestion. Here we compared various parameters of bloodmeal digestion in sand flies that are either susceptible (Phlebotomus argentipes and P. orientalis) or refractory (P. papatasi and Sergentomyia schwetzi) to Leishmania donovani, to study the effects on vector competence. The volume of the bloodmeal ingested, time of defecation of bloodmeal remnants, timing of formation and degradation of the peritrophic matrix (PM) and dynamics of proteolytic activities were compared in four sand fly species. Both proven vectors of L. donovani showed lower trypsin activity and slower PM formation than refractory species. Interestingly, the two natural L. donovani vectors strikingly differed from each other in secretion of the PM and midgut proteases, with P. argentipes possessing fast bloodmeal digestion with a very high peak of chymotrypsin activity and rapid degradation of the PM. Experimental infections of P. argentipes did not reveal any differences in vector competence in comparison with previously studied P. orientalis; even the very low initial dose (2*103 promastigotes/ml) led to fully developed late-stage infections with colonization of the stomodeal valve in about 40% of females. We hypothesise that the period between the breakdown of the PM and defecation of the bloodmeal remnants, i.e. the time frame when Leishmania attach to the midgut in order to prevent defecation, could be one of crucial parameters responsible for the establishment of Leishmania in the sand fly midgut. In both natural L. donovani vectors this period was significantly longer than in S. schwetzi. Both vectors are equally susceptible to L. donovani; as average bloodmeal volumes taken by females of P. argentipes and P. orientalis were 0.63 MUl and 0.59 MUl, respectively, an infective dose corresponding to 1-2 parasites was enough to initiate mature infections. PMID- 26030611 TI - School's Out: Seasonal Variation in the Movement Patterns of School Children. AB - School children are core groups in the transmission of many common infectious diseases, and are likely to play a key role in the spatial dispersal of disease across multiple scales. However, there is currently little detailed information about the spatial movements of this epidemiologically important age group. To address this knowledge gap, we collaborated with eight secondary schools to conduct a survey of movement patterns of school pupils in primary and secondary schools in the United Kingdom. We found evidence of a significant change in behaviour between term time and holidays, with term time weekdays characterised by predominately local movements, and holidays seeing much broader variation in travel patterns. Studies that use mathematical models to examine epidemic transmission and control often use adult commuting data as a proxy for population movements. We show that while these data share some features with the movement patterns reported by school children, there are some crucial differences between the movements of children and adult commuters during both term-time and holidays. PMID- 26030612 TI - Smoking on treatment outcomes among tuberculosis patients. AB - BACKGROUND: Smoking is a risk factor not only for the development of cancer and coronary heart disease but also for tuberculosis (TB). The aim of this study was to determine the prevalence of smoking in patients with TB, identify demographic and clinical characteristics associated with smoking and to evaluate TB treatment outcomes in the smokers. METHOD: A retrospective cohort study of patients with TB was conducted at Khyber Teaching Hospital, Peshawar, Pakistan. All patients with pulmonary and extrapulmonary TB and those coinfected with HIV, hepatitis or diabetes mellitus were included in the study. The patients were categorized into smokers and nonsmokers. Treatment outcomes were evaluated by smear testing at the end of the treatment. RESULTS: Of 472 enrolled subjects, 68 (14.4%) were smokers. The prevalence of smoking among male and female patients with TB was 11.8% and 2.5%, respectively. Univariate analysis indicated that the gender, age group and marital status of patients with TB were associated with smoking. The results indicated that patient gender (P = 0.05), age: 15 to 24 years (P = 0.05) and age >55 years (P = 0.004) were risk factors associated with smoking among TB patients. Of the 68 smokers with TB, the treatment outcomes among 54 patients (79.4%) were unsuccessful. The treatment outcomes was statistically significantly associated with smoking (odds ratio: 2.58, P = 0.004). CONCLUSIONS: Findings from the current study proved smoking to be one of the main factors associated with the occurrence of TB and significantly reducing the outcomes of TB therapy. PMID- 26030613 TI - Underprescription of renin-angiotensin system blockers in moderate to severe chronic kidney disease. AB - BACKGROUND: Renin-angiotensin system (RAS) blockers slow the progression of chronic kidney disease (CKD). Despite this, up to 40% of patients with CKD and an indication for RAS blockade do not receive these medications. The purpose of this study was to examine variables associated with the prescription of RAS blockers in patients with CKD and to identify opportunities to increase their use. METHODS: The electronic medical records of patients with moderate to severe CKD and an indication for RAS blockade were reviewed. For patients with an indication for RAS blockade who were not prescribed these medications, previous notes were reviewed to ascertain reasons why RAS blockade was not prescribed. RESULTS: Six hundred twenty-seven patients with moderate to severe CKD and an indication for RAS blockade were identified. Of these patients, 225 (36%) were not prescribed RAS blockade. This group was found to have significantly less diabetes, to be significantly older and to have significantly lower estimated glomerular filtration rate and blood pressure than the group on RAS blockade. For the majority (59%), no documented reason for not being prescribed RAS blockade was found. Among documented reasons, hyperkalemia and a history of acute kidney injury were the most common. CONCLUSIONS: The authors found that a large proportion of patients with CKD and an indication for RAS blockade were not prescribed these medications. For the majority, there was no provider-documented reason explaining why these medications were not prescribed, and the findings suggest that there may be opportunities to increase RAS blocker prescribing. PMID- 26030614 TI - Genetic Characterization of H1N1 and H1N2 Influenza A Viruses Circulating in Ontario Pigs in 2012. AB - The objective of this study was to characterize H1N1 and H1N2 influenza A virus isolates detected during outbreaks of respiratory disease in pig herds in Ontario (Canada) in 2012. Six influenza viruses were included in analysis using full genome sequencing based on the 454 platform. In five H1N1 isolates, all eight segments were genetically related to 2009 pandemic virus (A(H1N1)pdm09). One H1N2 isolate had hemagglutinin (HA), polymerase A (PA) and non-structural (NS) genes closely related to A(H1N1)pdm09, and neuraminidase (NA), matrix (M), polymerase B1 (PB1), polymerase B2 (PB2), and nucleoprotein (NP) genes originating from a triple-reassortant H3N2 virus (tr H3N2). The HA gene of five Ontario H1 isolates exhibited high identity of 99% with the human A(H1N1)pdm09 [A/Mexico/InDRE4487/09] from Mexico, while one Ontario H1N1 isolate had only 96.9% identity with this Mexican virus. Each of the five Ontario H1N1 viruses had between one and four amino acid (aa) changes within five antigenic sites, while one Ontario H1N2 virus had two aa changes within two antigenic sites. Such aa changes in antigenic sites could have an effect on antibody recognition and ultimately have implications for immunization practices. According to aa sequence analysis of the M2 protein, Ontario H1N1 and H1N2 viruses can be expected to offer resistance to adamantane derivatives, but not to neuraminidase inhibitors. PMID- 26030615 TI - Differential Expression and Release of Activin A and Follistatin in Chronic Rhinosinusitis with and without Nasal Polyps. AB - BACKGROUND: Chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) should be regarded as distinct clinical entities based on differential inflammatory mediator and remodeling profiles. Activin A, a member of the TGF beta superfamily, plays an important role in inflammation and remodeling in the lower airways, although its expression and release in the upper airways remain undescribed. OBJECTIVE: To investigate the expression of activin A and its inhibitor follistatin in nasal tissue samples from CRSsNP and CRSwNP patients, and to monitor the spontaneous release of these molecules in a human mucosal model. METHODS: Protein levels were determined using ELISA for activin A, follistatin, TGF-beta1 and indicator proteins (IL-5, ECP, IFNgamma) in 13 CRSsNP, 23 CRSwNP, and 10 control samples. The spontaneous release rate and the release ratios of activin A, follistatin and TGF-beta1 were determined in 9 CRSsNP and 7 CRSwNP tissue fragments cultured ex-vivo. The induction of activin A and TGF beta1 by one another was studied in 7 CRSsNP tissue fragments cultured ex-vivo. RESULTS: Significantly higher concentrations of activin A, follistatin, TGF beta1, and IFNgamma were observed in CRSsNP compared with CRSwNP samples, whereas the concentrations of IL-5 and ECP were significantly lower. Follistatin was positively and linearly correlated with activin A in CRSsNP and CRSwNP. Activin A, follistatin and TGF-beta1 were all spontaneously released by the samples, although the relative ratios released by tissue fragments from CRSsNP and CRSwNP samples were significantly different, with a higher follistatin/activin A-ratio and a follistatin/TGFbeta1-ratio (with less overall TGF-beta1) in CRSwNP than in CRSsNP. Furthermore, TGF-beta1 enhanced activin A secretion in CRSsNP tissue fragments cultured ex-vivo. CONCLUSION: The differences in tissue concentrations and spontaneous release rates for activin A and follistatin in different CRS samples support the hypothesis that CRSsNP and CRSwNP are two distinct disease entities with respect to remodeling patterns. PMID- 26030617 TI - Correction: Interaction between Neuroanatomical and Psychological Changes after Mindfulness-Based Training. PMID- 26030616 TI - Cumulative risk, cumulative outcome: a 20-year longitudinal study. AB - Cumulative risk (CR) models provide some of the most robust findings in the developmental literature, predicting numerous and varied outcomes. Typically, however, these outcomes are predicted one at a time, across different samples, using concurrent designs, longitudinal designs of short duration, or retrospective designs. We predicted that a single CR index, applied within a single sample, would prospectively predict diverse outcomes, i.e., depression, intelligence, school dropout, arrest, smoking, and physical disease from childhood to adulthood. Further, we predicted that number of risk factors would predict number of adverse outcomes (cumulative outcome; CO). We also predicted that early CR (assessed at age 5/6) explains variance in CO above and beyond that explained by subsequent risk (assessed at ages 12/13 and 19/20). The sample consisted of 284 individuals, 48% of whom were diagnosed with a speech/language disorder. Cumulative risk, assessed at 5/6-, 12/13-, and 19/20-years-old, predicted aforementioned outcomes at age 25/26 in every instance. Furthermore, number of risk factors was positively associated with number of negative outcomes. Finally, early risk accounted for variance beyond that explained by later risk in the prediction of CO. We discuss these findings in terms of five criteria posed by these data, positing a "mediated net of adversity" model, suggesting that CR may increase some central integrative factor, simultaneously augmenting risk across cognitive, quality of life, psychiatric and physical health outcomes. PMID- 26030620 TI - A Chronic Myelogenous Leukemia (CML) Case with a Cryptic Insertion of the ABL1 Gene of Chromosome 9 into 22 Resulting in a Fusion Signal on the Derivative 22: 46,XY.ish ins(22;9)(q11.2;q34q34)BCR+,ABL1. AB - Chronic myelogenous leukemia (CML) is characterized by the specific cytogenetic translocation t(9;22)(q34;q11.2), also called the Philadelphia (Ph) chromosome. We present a case of a cryptic BCR/ABL1 fusion, which was not originally detected by standard karyotyping. The patient is a forty-seven-year-old man who presented with leukocytosis. Bone marrow biopsy was consistent with CML in chronic phase with no increase in myeloblasts. Conventional cytogenetic studies revealed a 46,XY karyotype. Despite this finding, the patient was started on hydroxyurea therapy followed by Gleevec. At six-month follow-up, a repeat karyotype was again normal, though FISH analysis was positive for BCR/ABL1 fusion. FISH performed on previously G-banded metaphases showed a very rare cryptic insertion involving 22q11. While most genetic abnormalities in CML can be diagnosed using classical cytogenetics, molecular studies remain the gold standard in definitively identifying the characteristic BCR/ALB1 fusion. This case represents one of the variant cryptic rearrangements in CML where clinical correlation with morphologic, immunophenotypic, cytogenetics and FISH findings are indicated and highlights the importance of molecular testing at the time of primary diagnosis. PMID- 26030618 TI - Group B streptococcal infection and activation of human astrocytes. AB - BACKGROUND: Streptococcus agalactiae (Group B Streptococcus, GBS) is the leading cause of life-threatening meningitis in human newborns in industrialized countries. Meningitis results from neonatal infection that occurs when GBS leaves the bloodstream (bacteremia), crosses the blood-brain barrier (BBB), and enters the central nervous system (CNS), where the bacteria contact the meninges. Although GBS is known to invade the BBB, subsequent interaction with astrocytes that physically associate with brain endothelium has not been well studied. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesize that human astrocytes play a unique role in GBS infection and contribute to the development of meningitis. To address this, we used a well- characterized human fetal astrocyte cell line, SVG A, and examined GBS infection in vitro. We observed that all GBS strains of representative clinically dominant serotypes (Ia, Ib, III, and V) were able to adhere to and invade astrocytes. Cellular invasion was dependent on host actin cytoskeleton rearrangements, and was specific to GBS as Streptococcus gordonii failed to enter astrocytes. Analysis of isogenic mutant GBS strains deficient in various cell surface organelles showed that anchored LTA, serine-rich repeat protein (Srr1) and fibronectin binding (SfbA) proteins all contribute to host cell internalization. Wild-type GBS also displayed an ability to persist and survive within an intracellular compartment for at least 12 h following invasion. Moreover, GBS infection resulted in increased astrocyte transcription of interleukin (IL)-1beta, IL-6 and VEGF. CONCLUSIONS/SIGNIFICANCE: This study has further characterized the interaction of GBS with human astrocytes, and has identified the importance of specific virulence factors in these interactions. Understanding the role of astrocytes during GBS infection will provide important information regarding BBB disruption and the development of neonatal meningitis. PMID- 26030619 TI - A new target region for changing the substrate specificity of amine transaminases. AB - (R)-stereospecific amine transaminases (R-ATAs) are important biocatalysts for the production of (R)-amine compounds in a strict stereospecific manner. An improved R-ATA, ATA-117-Rd11, was successfully engineered for the manufacture of sitagliptin, a widely used therapeutic agent for type-2 diabetes. The effects of the individual mutations, however, have not yet been demonstrated due to the lack of experimentally determined structural information. Here we describe three crystal structures of the first isolated R-ATA, its G136F mutant and engineered ATA-117-Rd11, which indicated that the mutation introduced into the 136(th) residue altered the conformation of a loop next to the active site, resulting in a substrate-binding site with drastically modified volume, shape, and surface properties, to accommodate the large pro-sitagliptin ketone. Our findings provide a detailed explanation of the previously reported molecular engineering of ATA 117-Rd11 and propose that the loop near the active site is a new target for the rational design to change the substrate specificity of ATAs. PMID- 26030621 TI - Hyperdiploidy in CLL/SLL: A Rare Cytogenetic Event Associated with Poor Prognosis. AB - Hyperdiploidy has been described in a variety of malignancies including acute lymphoblastic leukemia and plasma cell myeloma, in which the abnormality is associated with a very good prognosis. Herein, we describe a 61-year-old female that was diagnosed with atypical chronic lymphocytic leukemia (CLL). Initial chromosome analysis of a lymph node specimen showed an abnormal karyotype described as 46-48,XX,add(3)(q12),+16,+mar[cp3]/46,XX[1]. Chromosome analysis of the bone marrow a week later showed a pseudodiploid and normal diploid clone described as: 46,X,-X,-3,-6,+7,+9,-14,-15,+16,+17,+17,+20,-22[1]/46,XX[19]. Concurrent FISH studies of peripheral blood samples using the CLL FISH panel showed nuclei with an extra copy of chromosome 13 and an extra copy of the short arm of chromosome 17. FISH for t(11;14) was negative. These results suggest the presence of an underlying complex hyperdiploid karyotype. Hyperdiploidy is a rare event in SLL/CLL and is usually associated with a poor prognosis. PMID- 26030622 TI - Mandibular Advancement Therapy for Obstructive Sleep Apnea: Answers and (More) Questions. PMID- 26030623 TI - Renal Impairment and Prognosis of Patients with Atrial Fibrillation Undergoing Coronary Intervention - The AFCAS Trial. AB - BACKGROUND: Renal impairment is a well-known risk factor for cardiovascular complications, but the effect of different stages of renal impairment on thrombotic/thromboembolic and bleeding complications in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains largely unknown. We sought to evaluate the incidence and clinical impact of four stages of renal impairment in patients with AF undergoing PCI. METHODS: We assessed renal function by estimated glomerular filtration rate (eGFR) and outcomes in 781 AF patients undergoing PCI by using the data from a prospective European multicenter registry. End-points included all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE) and bleeding events at 12 months. RESULTS: A total of 195 (25%) patients had normal renal function (eGFR >=90 mL/min), 290 (37%) mild renal impairment (eGFR 60-89), 263 (34%) moderate renal impairment (eGFR 30-59) and 33 (4%) severe renal impairment (eGFR <30). Degree of renal impairment remained an independent predictor of mortality and MACCE in an adjusted a Cox regression model. Even patients with mild renal impairment had a higher risk of all-cause mortality (HR 2.25, 95%CI 1.02-4.98, p=0.04) and borderline risk for MACCE (HR 1.56, 95%CI 0.98- 2.50, p=0.06) compared to those with normal renal function. CONCLUSIONS: Renal impairment is common in patients with AF undergoing PCI and even mild renal impairment has an adverse prognostic effect in these patients requiring multiple antithrombotic medications. PMID- 26030624 TI - The teratogenicity and the action mechanism of gallic acid relating with brain and cervical muscles. AB - Gallic acid (3,4,5-trihydroxybenzoic acid) (GA) and other flavanoids are extensively used in nutraceuticals because of their antioxidant and antiinflammatory properties. While examining whether GA is effective in alleviating valproic-acid-induced teratogenesis in a chicken embryo model (CEM), we observed embryo hemorrhage and liposis in the musculi longissimus cervicis. We conducted this study to determine whether GA is inherently teratogenic and the extent to which the risk can be transferred to fetuses. A CEM was used to administer GA at 2, 6, 10, and 14 MUM. GA at 2 MUM did not exhibit cytotoxicity. At 6, 10, and 14 MUM, GA caused severe decreases in body and liver weights, causing -5.6%, -21.3%, and -27.5% body weights and 4.0, 3.8, and 3.2-g, liver weights, respectively, in day-1 chicks. The optimal alive birth rate (or damaging rate) reached 33.3%, 39.4%, and 29.2% at 6, 10, and 14 MUM GA, respectively. The damaged tissue was primarily cervical muscle (musculi longissimus cervicis), as evidenced by liposis, Zenker's necrosis, and hemolysis. The erythrocyte, hemoglobin, eosinophil, lymphocyte, and monocyte counts were severely reduced and PPAR-alpha was downregulated, whereas the Ras/Raf/JAK/STAT pathway was upregulated. The GA dose required to induce teratogenesis was >= 6 MUM (1.02 mg/kg), which can be easily consumed by pregnant women in typical teas such as Chinese Pu-'Er and Chinese black teas, indicating a potential risk to human fetuses. GA at doses >= 1.02 mg/kg of body weight potentially causes characteristic cerebral hemolysis and liposis in the musculi longissimus cervicis. The mechanism of action of GA is multidisciplinary: The liposis can be ascribed to downregulation of PPAR-alpha; the erythrocyte hemolysis can be attributed to its unique autooxidative and prooxidant behavior and the inhibition of carbonic anhydrase; and the proliferation and differentiation deficits can be attributed to the upregulation of the Ras/Raf/JAK/STAT pathway. PMID- 26030625 TI - 9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice. AB - The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand. PMID- 26030626 TI - Socioeconomic Associations with ADHD: Findings from a Mediation Analysis. AB - BACKGROUND: Children from disadvantaged socioeconomic backgrounds are at greater risk of a range of negative outcomes throughout their life course than their peers; however the specific mechanisms by which socioeconomic status relates to different health outcomes in childhood are as yet unclear. AIMS: The current study investigates the relationship between socioeconomic disadvantage in childhood and attention deficit/hyperactivity disorder (ADHD), and investigates putative mediators of this association in a longitudinal population-based birth cohort in the UK. METHODS: Data from the Avon Longitudinal Study of Parents and Children was used (n = 8,132) to explore the relationship between different measures of socioeconomic status at birth-3 years and their association with a diagnosis of ADHD at age 7. A multiple mediation model was utilised to examine factors occurring between these ages that may mediate the association. RESULTS: Financial difficulties, housing tenure, maternal age at birth of child and marital status were significantly associated with an outcome of ADHD, such that families either living in financial difficulty, living in council housing, with younger or single mothers' were more likely to have a child with a research diagnosis of ADHD at age 7. Financial difficulties was the strongest predictor of ADHD (OR 2.23 95% CI 1.57-3.16). In the multiple mediation model, involvement in parenting at age 6 and presence of adversity at age 2-4 mediated 27.8% of the association. CONCLUSIONS: Socioeconomic disadvantage, conceptualised as reported difficulty in affording basic necessities (e.g. heating, food) has both direct and indirect impacts on a child's risk of ADHD. Lower levels of parent involvement mediates this association, as does presence of adversity; with children exposed to adversity and those with less involved parents being at an increased risk of having ADHD. This study highlights the importance of home and environmental factors as small but important contributors toward the aetiology of ADHD. PMID- 26030627 TI - Serum HE4: An Independent Prognostic Factor in Non-Small Cell Lung Cancer. AB - Human epididymis secretory protein 4 (HE4) is a secreted glycosylated protein encoded by the WAP four-disulfide core domain 2 (WFDC2) gene, located on a chromosome 20 segment that is frequently amplified in many cancers. This study aimed at determining serum HE4 prognostic value in non-small cell lung cancer (NSCLC), following the REMARK guidelines. Serum samples from 346 consecutive patients with histologically proven and previously untreated NSCLC and 41 patients with benign pulmonary disease were collected at the Montpellier-Nimes Academic Hospital. Work-up investigations performed to determine the disease characteristics and treatment algorithms were congruent with international guidelines. HE4 levels in serum were measured with an ELISA test (Fujirebio Diagnostics) that uses two monoclonal antibodies, 2H5 and 3D8, against the C-WFDC domain of HE4. The area under the ROC curve (i.e., overall ability of HE4 to discriminate between controls and patients) was 0.78 (95% confidence interval [CI], 0.738-0.821; z test P <0.0001). Serum HE4 levels were significantly higher in patients with worse performance status, advanced TNM stage and positive nodal status. In the Cox model, overall survival was shorter in patients with high pretreatment serum HE4 (above 140 pmol/L) than in patients with serum H4 level <= 140 pmol/L [median survival: 17.7 weeks (95% CI, 11.9 to 24.9) and 46.4 weeks (95% CI, 38.6 to 56.3), respectively; hazard ratio: 1.48 (95% CI, 1.12 to 1.95) for high HE4; adjusted P = 0.0057]. High serum HE4 level at diagnosis is an independent determinant of poor prognosis in NSCLC. PMID- 26030628 TI - New phonotactic constraints learned implicitly by producing syllable strings generalize to the production of new syllables. AB - Novel phonotactic constraints can be acquired by hearing or speaking syllables that follow a novel constraint. When learned from hearing syllables, these newly learned constraints generalize to syllables that were not experienced during training. However, generalization of phonotactic learning to novel syllables has never been persuasively demonstrated in production. The typical production experiment examines phonotactic learning through speech errors. After participants repeat syllable sequences embedded with a novel phonotactic constraint, such as /f/ appearing only in onset position, their speech errors come to adhere to the novel constraint. For example, when participants mistakenly move an /f/ to another syllable, it overwhelmingly moves to an onset rather than a coda position. We assessed whether constraints learned and measured in this manner generalize to unexperienced syllables and, at the same time, whether the slips tend to create previously experienced syllables (a syllable priming effect). We found evidence of generalization but not of syllable priming in participants' speech errors. The effect of phonotactic learning was as powerfully expressed during the production of unexperienced as experienced syllables. A connectionist model simulated the experimental results using a single learning mechanism and successfully reproduced the constraint learning, generalization, and lack of priming. PMID- 26030629 TI - Highly proficient bilinguals implement inhibition: Evidence from n-2 language repetition costs. AB - Several, but not all, models of language control assume that highly proficient bilinguals implement little to no inhibition during bilingual language production. In the current study, we tested this assumption with a less equivocal marker of inhibition (i.e., n-2 language repetition costs) than previous language switching studies have. N-2 language repetition costs denote worse performance when switching back to a recently abandoned language (i.e., worse performance in ABA language sequences than CBA sequences, where A, B, and C refer to different languages). Whereas this marker has solely been used to investigate second language learners in prior studies, we examined highly proficient bilinguals. The results showed that substantial n-2 language repetition costs can be observed with highly proficient bilinguals. Moreover, this inhibition effect was substantial for all 3 languages, but larger for the 2 dominant languages (Turkish and German) relative to the less proficient language (English). These findings indicate that even highly proficient bilinguals implement inhibition to restrict language production to the target language. PMID- 26030630 TI - Choosing the larger versus choosing the smaller: Asymmetries in the size congruity effect. AB - The size congruity effect (SiCE) shows that number and physical size interact as magnitudes. That is, response times are faster when number and size are congruent (e.g., 2 4) than when they are incongruent (e.g., 2 4). A shared representational system has been the most influential account for the SiCE. Recently, this account has been challenged by findings showing that the SiCE may be influenced by attention. The attentional contribution to the SiCE suggests that the effect is produced by an attention capture effect to the larger stimulus. Even though plausible, the attentional account overlooks 2 important factors in the study of magnitudes, namely, task (numerical vs. physical) and polarity of instructions (choose the larger vs. the smaller). We studied the influence of these factors using a size congruity task. Experiment 1 showed that the SiCE was modulated by task and instructions. In Experiment 2, we used a new set of numbers to examine a possible influence of the so-called end effect (i.e., responses to the smallest and to the largest numbers may not require number comparison). Experiment 2 successfully replicated the pattern of Experiment 1. We suggest that both feature saliency and long-term semantic processes modulate the SiCE. PMID- 26030631 TI - Selective inhibition and naming performance in semantic blocking, picture-word interference, and color-word Stroop tasks. AB - In 2 studies, we examined whether explicit distractors are necessary and sufficient to evoke selective inhibition in 3 naming tasks: the semantic blocking, picture-word interference, and color-word Stroop task. Delta plots were used to quantify the size of the interference effects as a function of reaction time (RT). Selective inhibition was operationalized as the decrease in the size of the interference effect as a function of naming RT. For all naming tasks, mean naming RTs were significantly longer in the interference condition than in the control condition. The slopes of the interference effects for the longest naming RTs correlated with the magnitude of the mean interference effect in both the semantic blocking task and the picture-word interference task, suggesting that selective inhibition was involved to reduce the interference from strong semantic competitors either invoked by a single explicit competitor or strong implicit competitors in picture naming. However, there was no correlation between the slopes and the mean interference effect in the Stroop task, suggesting less importance of selective inhibition in this task despite explicit distractors. Whereas the results of the semantic blocking task suggest that an explicit distractor is not necessary for triggering inhibition, the results of the Stroop task suggest that such a distractor is not sufficient for evoking inhibition either. PMID- 26030632 TI - Differences between early and late readmissions among patients: a cohort study. AB - BACKGROUND: Early and late readmissions may have different causal factors, requiring different prevention strategies. OBJECTIVE: To determine whether predictors of readmission change within 30 days after discharge. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PARTICIPANTS: Patients admitted between 1 January 2009 and 31 December 2010. MEASUREMENTS: Factors related to the index hospitalization (acute illness burden, inpatient care process factors, and clinical indicators of instability at discharge) and unrelated factors (chronic illness burden and social determinants of health) and how they affect early readmissions (0 to 7 days after discharge) and late readmissions (8 to 30 days after discharge). RESULTS: 13 334 admissions, representing 8078 patients, were included in the analysis. Early readmissions were associated with markers of acute illness burden, including length of hospital stay (odds ratio [OR], 1.02 [95% CI, 1.00 to 1.03]) and whether a rapid response team was called for assessment (OR, 1.48 [CI, 1.15 to 1.89]); markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.19 [CI, 1.02 to 1.40]); and social determinants of health, including barriers to learning (OR, 1.18 [CI, 1.01 to 1.38]). Early readmissions were less likely if a patient was discharged between 8:00 a.m. and 12:59 p.m. (OR, 0.76 [CI, 0.58 to 0.99]). Late readmissions were associated with markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.24 [CI, 1.08 to 1.41]) or hemodialysis (OR, 1.61 [CI, 1.12 to 2.17]), and social determinants of health, including barriers to learning (OR, 1.24 [CI, 1.09 to 1.42]) and having unsupplemented Medicare or Medicaid (OR, 1.16 [CI, 1.01 to 1.33]). LIMITATION: Readmissions were ascertained at 1 institution. CONCLUSION: The time frame of 30 days after hospital discharge may not be homogeneous. Causal factors and readmission prevention strategies may differ for the early versus late periods. PRIMARY FUNDING SOURCE: Health Resources and Services Administration, National Institute on Aging, National Institutes of Health, Harvard Catalyst, and Harvard University. PMID- 26030633 TI - Revisit rates and associated costs after an emergency department encounter: a multistate analysis. AB - BACKGROUND: Return visits to the emergency department (ED) or hospital after an index ED visit strain the health system, but information about rates and determinants of revisits is limited. OBJECTIVE: To describe revisit rates, variation in revisit rates by diagnosis and state, and associated costs. DESIGN: Observational study using the Healthcare Cost and Utilization Project databases. SETTING: 6 U.S. states. PATIENTS: Adults with ED visits between 2006 and 2010. MEASUREMENTS: Revisit rates and costs. RESULTS: Within 3 days of an index ED visit, 8.2% of patients had a revisit; 32% of those revisits occurred at a different institution. Revisit rates varied by diagnosis, with skin infections having the highest rate (23.1% [95% CI, 22.3% to 23.9%]). Revisit rates also varied by state. For skin infections, Florida had higher risk-adjusted revisit rates (24.8% [CI, 23.5% to 26.2%]) than Nebraska (10.6% [CI, 9.2% to 12.1%]). In Florida, the only state with complete cost data, total revisit costs for the 19.8% of patients with a revisit within 30 days were 118% of total index ED visit costs for all patients (including those with and without a revisit). LIMITATION: Whether a revisit reflects inadequate access to primary care, a planned revisit, the patient's nonadherence to ED recommendations, or poor-quality care at the initial ED visit remains unknown. CONCLUSION: Revisits after an index ED encounter are more frequent than previously reported, in part because many occur outside the index institution. Among ED patients in Florida, more resources are spent on revisits than on index ED visits. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 26030634 TI - The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. AB - The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32 item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers. PMID- 26030635 TI - Celebrating the ACP centennial: from the Annals archive--Ebola virus disease. PMID- 26030636 TI - Opportunities and challenges for reducing hospital revisits. PMID- 26030637 TI - The PRISMA extension for network meta-analysis: bringing clarity and guidance to the reporting of systematic reviews incorporating network meta-analyses. PMID- 26030638 TI - Dr. Afshar's Grid. PMID- 26030640 TI - Supplemental ultrasonography screening for women with dense breasts. PMID- 26030641 TI - Supplemental ultrasonography screening for women with dense breasts. PMID- 26030642 TI - Supplemental ultrasonography screening for women with dense breasts. PMID- 26030643 TI - Supplemental ultrasonography screening for women with dense breasts. PMID- 26030644 TI - Can the United States buy better advance care planning? PMID- 26030645 TI - The doctor: for life and at the end of life. PMID- 26030646 TI - The doctor: for life and at the end of life. PMID- 26030647 TI - Chronic kidney disease. AB - This issue provides a clinical overview of chronic kidney disease, focusing on prevention, diagnosis, treatment, and patient information. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://mksap.acponline.org, and other resources referenced in each issue of In the Clinic. PMID- 26030648 TI - Web Exclusives. Annals graphic medicine: Mr. S changes doctors. PMID- 26030649 TI - Oxidative stress induced by zearalenone in porcine granulosa cells and its rescue by curcumin in vitro. AB - Oxidative stress (OS), as a signal of aberrant intracellular mechanisms, plays key roles in maintaining homeostasis for organisms. The occurrence of OS due to the disorder of normal cellular redox balance indicates the overproduction of reactive oxygen species (ROS) and/or deficiency of antioxidants. Once the balance is broken down, repression of oxidative stress is one of the most effective ways to alleviate it. Ongoing studies provide remarkable evidence that oxidative stress is involved in reproductive toxicity induced by various stimuli, such as environmental toxicants and food toxicity. Zearalenone (ZEA), as a toxic compound existing in contaminated food products, is found to induce mycotoxicosis that has a significant impact on the reproduction of domestic animals, especially pigs. However, there is no information about how ROS and oxidative stress is involved in the influence of ZEA on porcine granulosa cells, or whether the stress can be rescued by curcumin. In this study, ZEA-induced effect on porcine granulosa cells was investigated at low concentrations (15 MUM, 30 MUM and 60 MUM). In vitro ROS levels, the mRNA level and activity of superoxide dismutase, glutathione peroxidase and catalase were obtained. The results showed that in comparison with negative control, ZEA increased oxidative stress with higher ROS levels, reduced the expression and activity of antioxidative enzymes, increased the intensity of fluorogenic probes 2', 7'-Dichlorodihydrofluorescin diacetate and dihydroethidium in flow cytometry assay and fluorescence microscopy. Meanwhile, the activity of glutathione (GSH) did not change obviously following 60 MUM ZEA treatment. Furthermore, the underlying protective mechanisms of curcumin on the ZEA-treated porcine granulosa cells were investigated. The data revealed that curcumin pre treatment significantly suppressed ZEA-induced oxidative stress. Collectively, porcine granulosa cells were sensitive to ZEA, which may induce oxidative stress. The findings from this study clearly demonstrate that curcumin is effective to reduce the dysregulation of cellular redox balance on porcine granulosa cells in vitro and should be further investigated for its protective role against ZEA in animals. PMID- 26030650 TI - Neuropsychological Correlates of Brain Perfusion SPECT in Patients with Macrophagic Myofasciitis. AB - BACKGROUND: Patients with aluminum hydroxide adjuvant-induced macrophagic myofasciitis (MMF) complain of arthromyalgias, chronic fatigue and cognitive deficits. This study aimed to characterize brain perfusion in these patients. METHODS: Brain perfusion SPECT was performed in 76 consecutive patients (aged 49+/-10 y) followed in the Garches-Necker-Mondor-Hendaye reference center for rare neuromuscular diseases. Images were acquired 30 min after intravenous injection of 925 MBq 99mTc-ethylcysteinate dimer (ECD) at rest. All patients also underwent a comprehensive battery of neuropsychological tests, within 1.3+/-5.5 mo from SPECT. Statistical parametric maps (SPM12) were obtained for each test using linear regressions between each performance score and brain perfusion, with adjustment for age, sex, socio-cultural level and time delay between brain SPECT and neuropsychological testing. RESULTS: SPM analysis revealed positive correlation between neuropsychological scores (mostly exploring executive functions) and brain perfusion in the posterior associative cortex, including cuneus/precuneus/occipital lingual areas, the periventricular white matter/corpus callosum, and the cerebellum, while negative correlation was found with amygdalo hippocampal/entorhinal complexes. A positive correlation was also observed between brain perfusion and the posterior associative cortex when the time elapsed since last vaccine injection was investigated. CONCLUSIONS: Brain perfusion SPECT showed a pattern of cortical and subcortical changes in accordance with the MMF-associated cognitive disorder previously described. These results provide a neurobiological substrate for brain dysfunction in aluminum hydroxide adjuvant-induced MMF patients. PMID- 26030652 TI - Rainfall runoff modelling of the Upper Ganga and Brahmaputra basins using PERSiST. AB - There are ongoing discussions about the appropriate level of complexity and sources of uncertainty in rainfall runoff models. Simulations for operational hydrology, flood forecasting or nutrient transport all warrant different levels of complexity in the modelling approach. More complex model structures are appropriate for simulations of land-cover dependent nutrient transport while more parsimonious model structures may be adequate for runoff simulation. The appropriate level of complexity is also dependent on data availability. Here, we use PERSiST; a simple, semi-distributed dynamic rainfall-runoff modelling toolkit to simulate flows in the Upper Ganges and Brahmaputra rivers. We present two sets of simulations driven by single time series of daily precipitation and temperature using simple (A) and complex (B) model structures based on uniform and hydrochemically relevant land covers respectively. Models were compared based on ensembles of Bayesian Information Criterion (BIC) statistics. Equifinality was observed for parameters but not for model structures. Model performance was better for the more complex (B) structural representations than for parsimonious model structures. The results show that structural uncertainty is more important than parameter uncertainty. The ensembles of BIC statistics suggested that neither structural representation was preferable in a statistical sense. Simulations presented here confirm that relatively simple models with limited data requirements can be used to credibly simulate flows and water balance components needed for nutrient flux modelling in large, data-poor basins. PMID- 26030651 TI - Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study). AB - BACKGROUND AND AIM: Little is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan. DESIGN: Randomized, double blind, placebo-controlled, one-year intervention trial. SETTING AND PARTICIPANTS: Eighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year. INTERVENTION: Irbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients. OUTCOMES AND MEASUREMENTS: Cardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension. RESULTS: At baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on baseline parameters. CONCLUSION: Use of the ARB irbesartan as an add-on to other antihypertensive therapy did not significantly affect intradialytic hemodynamics, neither in short nor long-term, and no significant increase in hypotensive episodes was seen. TRIAL REGISTRATION: Clinicaltrials.gov NCT00791830. PMID- 26030653 TI - Strain-induced coupling of electrical polarization and structural defects in SrMnO3 films. AB - Local perturbations in complex oxides, such as domain walls, strain and defects, are of interest because they can modify the conduction or the dielectric and magnetic response, and can even promote phase transitions. Here, we show that the interaction between different types of local perturbations in oxide thin films is an additional source of functionality. Taking SrMnO3 as a model system, we use nonlinear optics to verify the theoretical prediction that strain induces a polar phase, and apply density functional theory to show that strain simultaneously increases the concentration of oxygen vacancies. These vacancies couple to the polar domain walls, where they establish an electrostatic barrier to electron migration. The result is a state with locally structured room-temperature conductivity consisting of conducting nanosized polar domains encased by insulating domain boundaries, which we resolve using scanning probe microscopy. Our 'nanocapacitor' domains can be individually charged, suggesting stable capacitance nanobits with a potential for information storage technology. PMID- 26030654 TI - Large anisotropic deformation of skyrmions in strained crystal. AB - Mechanical control of magnetism is an important and promising approach in spintronics. To date, strain control has mostly been demonstrated in ferromagnetic structures by exploiting a change in magnetocrystalline anisotropy. It would be desirable to achieve large strain effects on magnetic nanostructures. Here, using in situ Lorentz transmission electron microscopy, we demonstrate that anisotropic strain as small as 0.3% in a chiral magnet of FeGe induces very large deformations in magnetic skyrmions, as well as distortions of the skyrmion crystal lattice on the order of 20%. Skyrmions are stabilized by the Dzyaloshinskii-Moriya interaction, originating from a chiral crystal structure. Our results show that the change in the modulation of the strength of this interaction is amplified by two orders of magnitude with respect to changes in the crystal lattice due to an applied strain. Our findings may provide a mechanism to achieve strain control of topological magnetic structures based on the Dzyaloshinskii-Moriya interaction. PMID- 26030655 TI - Polarization-sensitive broadband photodetector using a black phosphorus vertical p-n junction. AB - The ability to detect light over a broad spectral range is central to practical optoelectronic applications and has been successfully demonstrated with photodetectors of two-dimensional layered crystals such as graphene and MoS2. However, polarization sensitivity within such a photodetector remains elusive. Here, we demonstrate a broadband photodetector using a layered black phosphorus transistor that is polarization-sensitive over a bandwidth from ~400 nm to 3,750 nm. The polarization sensitivity is due to the strong intrinsic linear dichroism, which arises from the in-plane optical anisotropy of this material. In this transistor geometry, a perpendicular built-in electric field induced by gating can spatially separate the photogenerated electrons and holes in the channel, effectively reducing their recombination rate and thus enhancing the performance for linear dichroism photodetection. The use of anisotropic layered black phosphorus in polarization-sensitive photodetection might provide new functionalities in novel optical and optoelectronic device applications. PMID- 26030656 TI - Spectral mapping of thermal conductivity through nanoscale ballistic transport. AB - Controlling thermal properties is central to many applications, such as thermoelectric energy conversion and the thermal management of integrated circuits. Progress has been made over the past decade by structuring materials at different length scales, but a clear relationship between structure size and thermal properties remains to be established. The main challenge comes from the unknown intrinsic spectral distribution of energy among heat carriers. Here, we experimentally measure this spectral distribution by probing quasi-ballistic transport near nanostructured heaters down to 30 nm using ultrafast optical spectroscopy. Our approach allows us to quantify up to 95% of the total spectral contribution to thermal conductivity from all phonon modes. The measurement agrees well with multiscale and first-principles-based simulations. We further demonstrate the direct construction of mean free path distributions. Our results provide a new fundamental understanding of thermal transport and will enable materials design in a rational way to achieve high performance. PMID- 26030657 TI - Correction: Prediction of CD8+ Epitopes in Leishmania braziliensis Proteins Using EPIBOT: In Silico Search and In Vivo Validation. PMID- 26030658 TI - MR Imaging of Adverse Local Tissue Reactions around Rejuvenate Modular Dual-Taper Stems. AB - PURPOSE: To describe the magnetic resonance (MR) imaging characteristics associated with adverse local tissue reactions and tissue damage around hip arthroplasties in which the recalled Rejuvenate modular dual-taper stem was used. MATERIALS AND METHODS: The institutional review board of the Hospital for Special Surgery approved the study. All study patients provided informed consent. MR imaging studies were retrospectively reviewed in a cohort of 58 patients with 66 hip arthroplasties with Rejuvenate stems who had presented for imaging evaluation because of recall of the implant. Multiple regression analysis was used to examine MR imaging features, biomechanical factors, and metal ion levels as predictors of aseptic lymphocytic vasculitis-associated lesion (ALVAL) score at histologic assessment while adjusting for age and sex for 54 revised hips. RESULTS: Revision surgery was performed in 54 hips on the basis of clinical or imaging findings (24% of hips were completely asymptomatic). The median ALVAL score among the revised hips was 9 (range, 1-10). Imaging characteristics observed with high frequency in patients with ALVAL included synovitis, mixed- or solid-type synovitis, synovial thickening, and capsular dehiscence. CONCLUSION: MR imaging provides an effective noninvasive method for assessing the presence and severity of adverse local tissue reaction, as well as the degree of pre existing tissue damage, thereby facilitating early and accurate identification of candidates for revision surgery. PMID- 26030659 TI - New-Generation Laser-lithographed Dual-Axis Magnetically Assisted Remote controlled Endovascular Catheter for Interventional MR Imaging: In Vitro Multiplanar Navigation at 1.5 T and 3 T versus X-ray Fluoroscopy. AB - PURPOSE: To assess the feasibility of multiplanar vascular navigation with a new magnetically assisted remote-controlled (MARC) catheter with real-time magnetic resonance (MR) imaging at 1.5 T and 3 T and to compare it with standard x-ray guidance in simulated endovascular catheterization procedures. MATERIALS AND METHODS: A 1.6-mm-diameter custom clinical-grade microcatheter prototype with lithographed double-saddle coils at the distal tip was deflected with real-time MR imaging. Two inexperienced operators and two experienced operators catheterized anteroposterior (celiac, superior mesenteric, and inferior mesenteric arteries) and mediolateral (renal arteries) branch vessels in a cryogel abdominal aortic phantom. This was repeated with conventional x-ray fluoroscopy by using clinical catheters and guidewires. Mean procedure times and percentage success data were analyzed with linear mixed-effects regression. RESULTS: The MARC catheter tip was visible at 1.5 T and 3 T. Among inexperienced operators, MARC MR imaging guidance was not statistically different from x-ray guidance at 1.5 T (67% successful vessel selection turns with MR imaging vs 76% with x-ray guidance, P = .157) and at 3 T (75% successful turns with MR imaging vs 76% with x-ray guidance, P = .869). Experienced operators were more successful in catheterizing vessels with x-ray guidance (98% success within 60 seconds) than with 1.5-T (65%, P < .001) or 3-T (75%) MR imaging. Among inexperienced operators, mean procedure time was nearly equivalent by using MR imaging (31 seconds) and x-ray guidance (34 seconds, P = .436). Among experienced operators, catheterization was faster with x-ray guidance (20 seconds) compared with 1.5-T MR imaging (42 seconds, P < .001), but MARC guidance improved at 3 T (31 seconds). MARC MR imaging guidance at 3 T was not significantly different from x ray guidance for the celiac (P = .755), superior mesenteric (P = .358), and inferior mesenteric (P = .065) arteries. CONCLUSION: Multiplanar navigation with a new MARC catheter with real-time MR imaging at 1.5 T and 3 T is feasible and comparable to x-ray guidance for anteroposterior vessels at 3 T in a vascular phantom. PMID- 26030660 TI - Effect of Change in Portal Venous Blood Flow Rates on the Performance of a 2.45 GHz Microwave Ablation Device. AB - PURPOSE: To investigate the effect of change in portal venous blood flow rates on the size and shape of ablations created by a 2.45-GHz microwave ablation device. MATERIALS AND METHODS: This study was exempt from review by the institutional animal care and use committee. An in vitro bovine liver model perfused with autologous blood via the portal vein at five flow rates (60, 70, 80, 90, and 100 mL/min per 100 g of liver) was used to evaluate the effect of change in flow rates on the size and shape of coagulation created by a 2.45-GHz, 140-W microwave ablation device operated for 5 and 10 minutes. Three ablations per ablation time were conducted in each of 10 livers, with two livers perfused at each flow rate. Short- and long-axis diameters were measured from gross specimens, and volume and sphericity index were calculated. General linear mixed models that accounted for correlations within the liver were used to evaluate the effects of lobe, flow, and ablation time on size and sphericity index of ablations. RESULTS: Flow did not have a significant effect on the size or shape of coagulation created at 5 or 10 minutes (P > .05 for all tests). The mean short- and long-axis diameters and volume were 3.2 cm (95% confidence interval [CI]: 3.1, 3.3), 5.6 cm (95% CI: 5.4, 5.8), and 30.2 cm(3) (95% CI: 28.4, 32.1) for the 5-minute ablations and 3.8 cm (95% CI: 3.7, 3.9), 6.5 cm (95% CI: 6.3, 6.7), and 49.3 cm(3) (95% CI: 47.5, 51.2), for the 10-minute ablations, respectively. The mean sphericity index for both 5- and 10-minute ablations was 34.4% (95% CI: 32%, 36.7%). CONCLUSION: Change in portal venous blood flow rates did not have an effect on the size and shape of ablations created by a 2.45-GHz microwave ablation device. PMID- 26030661 TI - Convenient Fabrication of Electrospun Prolamin Protein Delivery System with Three Dimensional Shapeability and Resistance to Fouling. AB - It has been newly discovered that by simply altering the applied voltage, the resultant electrospun prolamin protein fabrics can rapidly (within 30 s) form either flat sheets or self-rolled tubes when immersed in water. This phenomenon opens up many potential biomedical applications for drug delivery. The morphology and structure of both dry and wet fibers were characterized in detail. The hordein/zein fibers fabricated at relatively lower voltage were stabilized by the preaggregated nanoscale hydrophobic domains and exhibited restricted swelling while maintaining a flat sheet shape with minimal changes to secondary structure when immersed in water. By applying a higher voltage, we triggered a greater bending instability during the electrospinning process, and the hordein/zein network structure generated could rapidly relax in an aqueous environment. This increased mobility of molecular chains allowed the uneven aggregation of hydrophobic dopants, which catalyzed the self-rolling of the aligned fibers. Sessile drop measurements even showed a reduction in the contact angle from 106 to 39 degrees for the fibers with 50% zein prepared at raised voltage, indicating the conversion of surface properties caused by the relaxation. All the fibers demonstrated low toxicity in human primary dermal fibroblast cell culture. Moreover, the electrospun fabrics exhibited a strong resistance to protein adsorption and cell attachment, and the release experiment indicated that both three-dimensional porous structures could serve as a carrier for controlled release of incorporated bioactive compounds into phosphate-buffered saline. Therefore, these electrospun prolamin protein fabrics represent an ideal and novel platform to develop nonadherent drug delivery systems for wound dressing and other biomedical applications. PMID- 26030662 TI - In Vitro Inhibitory Effects of 8-O-Demethylmaritidine and Undulatine on Acetylcholinesterase and Their Predicted Penetration across the Blood-Brain Barrier. AB - Alzheimer's disease is the most common cause of dementia. Currently, acetylcholinesterase (AChE) inhibition is the most widely used therapeutic treatment. A large number of naturally occurring compounds have been found to inhibit AChE. In this report the mechanism of AChE inhibition of two Amaryllidaceae alkaloids, 8-O-demethylmaritidine (1) and undulatine (2), and their possible penetration across the blood-brain barrier have been studied. Both compounds act via a mixed inhibition mechanism. Based on the parallel artificial permeation assay (PAMPA) for the prediction of blood-brain barrier (BBB) penetration, only 2 should be able to cross the BBB by passive permeation. PMID- 26030663 TI - The Sesquiterpenes(E)-beta-Farnesene and (E)-alpha-Bergamotene Quench Ozone but Fail to Protect the Wild Tobacco Nicotiana attenuata from Ozone, UVB, and Drought Stresses. AB - Among the terpenes, isoprene (C5) and monoterpene hydrocarbons (C10) have been shown to ameliorate abiotic stress in a number of plant species via two proposed mechanisms: membrane stabilization and direct antioxidant effects. Sesquiterpene hydrocarbons (C15) not only share the structural properties thought to lend protective qualities to isoprene and monoterpene hydrocarbons, but also react rapidly with ozone, suggesting that sesquiterpenes may similarly enhance tolerance of abiotic stresses. To test whether sesquiterpenes protect plants against ozone, UVB light, or drought, we used transgenic lines of the wild tobacco Nicotiana attenuata. The transgenic plants expressed a maize terpene synthase gene (ZmTPS10) which produced a blend of (E)-beta-farnesene and (E) alpha-bergamotene, or a point mutant of the same gene (ZmTPS10M) which produced (E)-beta-farnesene alone,. (E)-beta-farnesene exerted a local, external, and transient ozone-quenching effect in ozone-fumigated chambers, but we found no evidence that enhanced sesquiterpene production by the plant inhibited oxidative damage, or maintained photosynthetic function or plant fitness under acute or chronic stress. Although the sesquiterpenes (E)-beta-farnesene and (E)-alpha bergamotene might confer benefits under intermittent heat stress, which was not tested, any roles in relieving abiotic stress may be secondary to their previously demonstrated functions in biotic interactions. PMID- 26030664 TI - Rhythmic Firing of Pedunculopontine Tegmental Nucleus Neurons in Monkeys during Eye Movement Task. AB - The pedunculopontine tegmental nucleus (PPTN) has been thought to be involved in the control of behavioral state. Projections to the entire thalamus and reciprocal connections with the basal ganglia nuclei suggest a potential role for the PPTN in the control of various rhythmic behaviors, including waking/sleeping and locomotion. Recently, rhythmic activity in the local field potentials was recorded from the PPTN of patients with Parkinson's disease who were treated with levodopa, suggesting that rhythmic firing is a feature of the functioning PPTN and might change with the behaving conditions even within waking. However, it remains unclear whether and how single PPTN neurons exhibit rhythmic firing patterns during various behaving conditions, including executing conditioned eye movement behaviors, seeking reward, or during resting. We previously recorded from PPTN neurons in healthy monkeys during visually guided saccade tasks and reported task-related changes in firing rate, and in this paper, we reanalyzed these data and focused on their firing patterns. A population of PPTN neurons demonstrated a regular firing pattern in that the coefficient of variation of interspike intervals was lower than what would be expected of theoretical random and irregular spike trains. Furthermore, a group of PPTN neurons exhibited a clear periodic single spike firing that changed with the context of the behavioral task. Many of these neurons exhibited a periodic firing pattern during highly active conditions, either the fixation condition during the saccade task or the free-viewing condition during the intertrial interval. We speculate that these task context-related changes in rhythmic firing of PPTN neurons might regulate the monkey's attentional and vigilance state to perform the task. PMID- 26030665 TI - Constitutive or Inducible Protective Mechanisms against UV-B Radiation in the Brown Alga Fucus vesiculosus? A Study of Gene Expression and Phlorotannin Content Responses. AB - A role as UV sunscreens has been suggested for phlorotannins, the phenolic compounds that accumulate in brown algae in response to a number of external stimuli and take part in cell wall structure. After exposure of the intertidal brown alga Fucus vesiculosus to artificial UV-B radiation, we examined its physiological responses by following the transcript level of the pksIII gene encoding a phloroglucinol synthase, likely to be involved in the first step of phlorotannins biosynthesis. We also monitored the expression of three targeted genes, encoding a heat shock protein (hsp70), which is involved in global stress responses, an aryl sulfotransferase (ast), which could be involved in the sulfation of phlorotannins, and a vanadium bromoperoxidase (vbpo), which can potentially participate in the scavenging of Reactive Oxygen Species (ROS) and in the cross-linking and condensation of phlorotannins. We investigated whether transcriptional regulation of these genes is correlated with an induction of phlorotannin accumulation by establishing metabolite profiling of purified fractions of low molecular weight phlorotannins. Our findings demonstrated that a high dose of UV-B radiation induced a significant overexpression of hsp70 after 12 and 24 hours following the exposure to the UV-B treatment, compared to control treatment. The physiological performance of algae quantified by the photosynthetic efficiency (Fv/Fm) was slightly reduced. However UV-B treatment did not induce the accumulation of soluble phlorotannins in F. vesiculosus during the kinetics of four weeks, a result that may be related to the lack of induction of the pksIII gene expression. Taken together these results suggest a constitutive accumulation of phlorotannins occurring during the development of F.vesiculosus, rather than inducible processes. Gene expression studies and phlorotannin profiling provide here complementary approaches to global quantifications currently used in studies of phenolic compounds in brown algae. PMID- 26030667 TI - A responsive supramolecular metallogel constructed by coordination-driven self assembly of a crown ether-based [3]pseudorotaxane and a diplatinum(II) acceptor. AB - Herein, a stimuli-responsive supramolecular metallogel was prepared by orthogonal coordination-driven self-assembly of a crown ether-based [3]pseudorotaxane and a 180 degrees organic di-Pt(II) acceptor. PMID- 26030666 TI - Depletion of Essential Fatty Acids in the Food Source Affects Aerobic Capacities of the Golden Grey Mullet Liza aurata in a Warming Seawater Context. AB - The objective of this study was to evaluate the combined effects of thermal acclimation and n-3 highly unsaturated fatty acids (n-3 HUFA) content of the food source on the aerobic capacities of fish in a thermal changing environment. The model used was the golden grey mullet Liza aurata, a species of high ecological importance in temperate coastal areas. For four months, fish were exposed to two food sources with contrasting n-3 HUFA contents (4.8% ecosapentaenoic acid EPA + docosahexaenoic acid DHA on the dry matter DM basis vs. 0.2% EPA+DHA on DM) combined with two acclimation temperatures (12 degrees C vs. 20 degrees C). The four experimental conditions were LH12, LH20, HH12 and HH20. Each group was then submitted to a thermal challenge consisting of successive exposures to five temperatures (9 degrees C, 12 degrees C, 16 degrees C, 20 degrees C, 24 degrees C). At each temperature, the maximal and minimal metabolic rates, metabolic scope, and the maximum swimming speed were measured. Results showed that the cost of maintenance of basal metabolic activities was particularly higher when n-3 HUFA food content was low. Moreover, fish exposed to high acclimation temperature combined with a low n-3 HUFA dietary level (LH20) exhibited a higher aerobic scope, as well as a greater expenditure of energy to reach the same maximum swimming speed as other groups. This suggested a reduction of the amount of energy available to perform other physiological functions. This study is the first to show that the impact of lowering n-3 HUFA food content is exacerbated for fish previously acclimated to a warmer environment. It raises the question of the consequences of longer and warmer summers that have already been recorded and are still expected in temperate areas, as well as the pertinence of the lowering n-3 HUFA availability in the food web expected with global change, as a factor affecting marine organisms and communities. PMID- 26030668 TI - Examining mixtures of disinfection by-products: rat study shows no effects on reproduction. PMID- 26030669 TI - How men and women respond to hypothetical parental discovery: the importance of genetic relatedness. AB - Paternal uncertainty has shaped human behavior both in evolutionary and cultural terms. There has been much research investigating parenting as a function of genetic relatedness to the child, with a focus on male behavior, but the nature of these sex differences is hard to evaluate. We devised a hypothetical scenario that was as similar as possible for men and women to test whether, even in such a scenario, sex differences would remain strong. Participants were presented with the discovery that a child that s/he believed to be theirs was not carrying their own genes. Irrespective of sex, participants (n = 1007) were more upset when the baby was not genetically related to them than when the child was genetically related but the sex gamete was not from a chosen donor. Women were more upset than men in both scenarios, but were more likely to want to keep the baby. The results are discussed with reference to evolved and rational mechanisms affecting parenting. PMID- 26030670 TI - Enhanced Visible Photovoltaic Response of TiO2 Thin Film with an All-Inorganic Donor-Acceptor Type Polyoxometalate. AB - In the field of material chemistry, it is of great significance to develop abundant and sustainable materials for solar energy harvesting and management. Herein, after evaluating the energy band characteristics of 13 kinds of polyoxometalates (POMs), the trisubstituted POM compound K6H4[alpha SiW9O37Co3(H2O)3].17H2O (SiW9Co3) was first studied due to its relatively smaller band gap (2.23 eV) and higher lowest unoccupied molecular orbital (LUMO) level ( 0.63 V vs NHE). Additionally, the preliminary computational modeling indicated that SiW9Co3 exhibited the donor-acceptor (D-A) structure, in which the cobalt oxygen clusters and tungsten skeletons act as the electron donor and electron acceptor, respectively. By employing SiW9Co3 to modify the TiO2 film, the visible photovoltaic and photocurrent response were both enhanced, and the light-induced photocurrent at 420 nm was improved by 7.1 times. Moreover, the highly dispersive and small sized SiW9Co3 nanoclusters loading on TiO2 were successfully achieved by fabricating the nanocomposite film of {TiO2/SiW9Co3}3 with the layer-by-layer method, which can result in the photovoltaic performance enhancement of dye sensitized solar cells (DSSCs), of which the overall power conversion efficiency was improved by 25.6% from 6.79% to 8.53% through the synergistic effect of POMs and Ru-complex. PMID- 26030671 TI - A Pyridine-Based Ligand with Two Hydrazine Functions for Lanthanide Chelation: Remarkable Kinetic Inertness for a Linear, Bishydrated Complex. AB - To study the influence of hydrazine functions in the ligand skeleton, we designed the heptadentate HYD ligand (2,2',2",2'''-(2,2'-(pyridine-2,6-diyl)bis(2 methylhydrazine-2,1,1-triyl)) tetraacetic acid) and compared the thermodynamic, kinetic, and relaxation properties of its Ln(3+) complexes to those of the parent pyridine (Py) analogues without hydrazine (Py = 2,6-pyridinebis(methanamine) N,N,N',N'-tetraacetic acid). The protonation constants of HYD were determined by pH-potentiometric measurements, and assigned by a combination of UV-visible and NMR spectroscopies. The protonation sequence is rather unusual and illustrates that small structural changes can strongly influence ligand basicity. The first protonation step occurs on the pyridine nitrogen in the basic region, followed by two hydrazine nitrogens and the carboxylate groups at acidic pH. Contrary to Py, HYD self-aggregates through a pH-dependent process (from pH ca. 4). Thermodynamic stability constants have been obtained by pH-potentiometry and UV-visible spectrophotometry for various Ln(3+) and physiological cations (Zn(2+), Ca(2+), Cu(2+)). LnHYD stability constants show the same trend as those of LnDTPA complexes along the Ln(3+) series, with log K = 18.33 for Gd(3+), comparable to the Py analogue. CuHYD has a particularly high stability (log K > 19) preventing its determination from pH-potentiometric measurements. The stability constant of CuPy was also revisited and found to be underestimated in previous studies, highlighting that UV-visible spectrophotometry is often indispensable to obtain reliable stability constants for Cu(2+) chelates. The dissociation of GdL, assessed by studying the Cu(2+)-exchange reaction, occurs mainly via an acid catalyzed process, with limited contribution from direct Cu(2+) attack. The kinetic inertness of GdHYD is remarkable for a linear bishydrated chelate; the 25 fold increase in the dissociation half-life with respect to the monohydrated commercial contrast agent GdDTPA (t1/2 = 5298 h for GdHYD vs 202 h for GdDTPA) is related to the rigidity of the HYD ligand due to the pyridine and methylated hydrazine functions of the backbone. A combined analysis of variable-temperature (17)O NMR and NMRD data on GdHYD yielded the microscopic parameters influencing relaxation properties. The high relaxivity (r1 = 7.7 mM(-1) s(-1) at 20 MHz, 25 degrees C) results from the bishydrated character of the complex combined with an optimized water exchange rate (kex(298) = 7.8 * 10(6) s(-1)). The two inner sphere water molecules are not replaced through interaction with biological cations such as carbonate, citrate, and phosphate as monitored by (1)H relaxivity and luminescence lifetime measurements. PMID- 26030672 TI - Functional Analysis of the Maize C-Repeat/DRE Motif-Binding Transcription Factor CBF3 Promoter in Response to Abiotic Stress. AB - The ZmCBF3 gene is a member of AP2/ERF transcription factor family, which is a large family of plant-specific transcription factors that share a well-conserved DNA-binding domain. To understand the regulatory mechanism of ZmCBF3 gene expression, we isolated and characterized the ZmCBF3 promoter (PZmCBF3). Three deletion fragments of PZmCBF3 were generated, C1-C3, from the translation start codon at position -1079, -638, and -234, and fused to the GUS reporter gene. Each deletion construct was analyzed by Agrobacterium-mediated stable transformation and expression in Arabidopsis thaliana. GUS expression assays indicated that the PZmCBF3 exhibited root-specific expression activity. A 234-bp fragment upstream of the ZmCBF3 gene conferred a high level of GUS activity in Arabidopsis. Some cis-acting elements involved in the down-regulation of gene expression were detected in the promoter, encompassing positions -1079 to -234. PZmCBF3 was activated by cold stress. The MYCCONSENSUSAT elements (CANNTG) were responsible for the ability of PZmCBF3 to respond to cold stress. The results of the present study suggest that PZmCBF3 might play a role in cold tolerance in maize. PMID- 26030673 TI - Association between Serum Soluble CD154 Levels and Mortality in Patients with Malignant Middle Cerebral Artery Infarction. AB - BACKGROUND: CD154 and its soluble counterpart (sCD154) are proteins of the tumor necrosis factor (TNF) family and exhibit proinflamatory and procoagulant properties. Higher circulating sCD154 levels have been found in ischemic stroke patients than in controls. However, the association between circulating sCD154 levels and mortality in ischemic stroke patients has not been reported, and was the focus of this study. METHODS: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We measured serum sCD154 from 50 patients with severe malignant middle cerebral artery infarction (MMCAI), defined as Glasgow Coma Scale (GCS) lower than 9, at the moment of the severe MMCAI diagnosis and from 50 healthy controls. The end-point of the study was 30-day mortality. RESULTS: We found higher serum sCD154 levels in patients with severe MMCAI than in healthy controls (p < 0.001). We found higher serum sCD154 levels (p < 0.001) in non-surviving (n = 26) than in surviving MMCAI patients (n = 24). Multiple binomial logistic regression analysis showed that serum sCD154 levels >1.41 ng/mmL were associated with 30-day mortality (OR = 10.25; 95% CI = 2.34-44.95; p = 0.002). CONCLUSIONS: The new more important finding of our study was that serum sCD154 levels in MMCAI patients were associated with mortality. PMID- 26030674 TI - Conformational ensembles explored dynamically from disordered peptides targeting chemokine receptor CXCR4. AB - This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target. PMID- 26030675 TI - Acetic acid-catalyzed formation of N-phenylphthalimide from phthalanilic acid: a computational study of the mechanism. AB - In glacial acetic acid, phthalanilic acid and its monosubstituents are known to be converted to the corresponding phthalimides in relatively good yields. In this study, we computationally investigated the experimentally proposed two-step (addition-elimination or cyclization-dehydration) mechanism at the second-order Moller-Plesset perturbation (MP2) level of theory for the unsubstituted phthalanilic acid, with an explicit acetic acid molecule included in the calculations. In the first step, a gem-diol tetrahedral intermediate is formed by the nucleophilic attack of the amide nitrogen. The second step is dehydration of the intermediate to give N-phenylphthalimide. In agreement with experimental findings, the second step has been shown to be rate-determining. Most importantly, both of the steps are catalyzed by an acetic acid molecule, which acts both as proton donor and acceptor. The present findings, along with those from our previous studies, suggest that acetic acid and other carboxylic acids (in their undissociated forms) can catalyze intramolecular nucleophilic attacks by amide nitrogens and breakdown of the resulting tetrahedral intermediates, acting simultaneously as proton donor and acceptor. In other words, double proton transfers involving a carboxylic acid molecule can be part of an extensive bond reorganization process from cyclic hydrogen-bonded complexes. PMID- 26030676 TI - The neurocognitive profile of the cerebellum in multiple sclerosis. AB - In recent years, a high number of studies have demonstrated that neuropsychological functions are altered in multiple sclerosis (MS) patients with cerebellar lesions, mainly including attention, working memory and verbal fluency. Since the present literature is often elusive on this topic, we aim to provide a comprehensive report about the real impact of cerebellar damages (evaluated as volume, lesions or connectivity measures) on cognitive functions. In particular in this review, we report and discuss recent works from 2009 to 2015, which have demonstrated the key role of the cerebellum in cognitive impairment of MS patients. PMID- 26030678 TI - Predicting small for gestational age in the first trimester of pregnancy using maternal ophthalmic artery Doppler indices. AB - OBJECTIVE: To assess the capacity of maternal ophthalmic Doppler indices for predicting small for gestational age (SGA) newborns in the first trimester of pregnancy. METHODS: We performed a prospective observational cohort study involving 499 singleton pregnancies during the first trimester scan (11-14 weeks). The following maternal ophthalmic Doppler indices were assessed: pulsatility index (PI), first diastolic peak velocity (PD1) and peak ratio (PR) = PD1/peak systolic velocity. We considered SGA all newborns with weight below 10th percentile. We used chi-square test (chi(2)) to compare the groups. We used area under receiver operating characteristics (ROC) curves with 95% confidence intervals (CI) and detection rate of 5% of false positive of each maternal ophthalmic Doppler index and the mean uterine artery PI for prediction SGA. RESULTS: 27 (5.4%) patients delivered SGA newborns, 12 (2.4%) patients developed preeclampsia (PE) and delivered SGA newborns, and 460 had uneventful pregnancies (controls). We observed significant difference of PI and PR between SGA (SGA and SGA+PE) and control groups, p = 0.043 and p = 0.014, respectively. To 5% of false positive, the detection rate of SGA (SGA and SGA+PE groups) using PI, PD1 and PR were 14.8, 3.7, 14.8, 16.7, 16.7 and 16.7%, respectively. Mean uterine PI was significantly higher in the SGA+PE group (p = 0.003). CONCLUSION: The isolated use of maternal ophthalmic Doppler indices or in combination with uterine artery Doppler, in the first trimester of pregnancy, was not efficient to predict SGA newborns. PMID- 26030677 TI - Synergistic and Antagonistic Action of Phytochrome (Phy) A and PhyB during Seedling De-Etiolation in Arabidopsis thaliana. AB - It has been reported that Arabidopsis phytochrome (phy) A and phyB are crucial photoreceptors that display synergistic and antagonistic action during seedling de-etiolation in multiple light signaling pathways. However, the functional relationship between phyA and phyB is not fully understood under different kinds of light and in response to different intensities of such light. In this work, we compared hypocotyl elongation of the phyA-211 phyB-9 double mutant with the wild type, the phyA-211 and phyB-9 single mutants under different intensities of far red (FR), red (R), blue (B) and white (W) light. We confirmed that phyA and phyB synergistically promote seedling de-etiolation in B-, B plus R-, W- and high R light conditions. The correlation of endogenous ELONGATED HYPOCOTYL 5 (HY5) protein levels with the trend of hypocotyl elongation of all lines indicate that both phyA and phyB promote seedling photomorphogenesis in a synergistic manner in high-irradiance white light. Gene expression analyses of RBCS members and HY5 suggest that phyB and phyA act antagonistically on seedling development under FR light. PMID- 26030679 TI - Neonatal outcome of late preterm uncomplicated monochorionic twins: what is the optimal time for delivery? AB - OBJECTIVE: To determine the neonatal outcome at late prematurity of uncomplicated monochorionic (MC) twin pregnancies. METHODS: A retrospective cohort study of 166 patients with uncomplicated MC diamniotic twins delivered between 34 and 37 weeks of gestation at a single tertiary center. The study population was classified into four groups according to the gestational age at delivery: (1) 34 weeks, (2) 35 weeks, (3) 36 weeks and (4) 37 weeks. Neonatal outcome measures were compared between the groups. RESULTS: Neonatal morbidity was significantly higher at 34 weeks of gestation compared to the other three groups including respiratory distress syndrome, oxygen requirement, hypothermia and hyperbilirubinemia. Moreover, the rate of admission to the special care unit and need for phototherapy were significantly higher in newborns born at 36 weeks compared to 37 weeks of gestation (p = 0.02 and 0.03 respectively). Multiple regression analysis revealed that the risk for adverse neonatal outcome was significantly associated with gestational age at delivery. Of note, there were no fetal or neonatal deaths in our cohort. CONCLUSIONS: The risk of neonatal morbidity of uncomplicated MC twins delivered at 34-37 weeks of gestation significantly decreases with advanced gestation. Therefore, under close fetal surveillance, uncomplicated MC twin pregnancies should be delivered at 37 weeks of gestation. PMID- 26030680 TI - Fully automated simultaneous umbilical arteriovenous exchange transfusion in term and late preterm infants with neonatal hyperbilirubinemia. AB - OBJECTIVES: The purpose of this study was to compare the efficacy and safety of two different catheterization techniques of exchange transfusion (ET) used in the therapy of newborn jaundice: fully automated two-way ET technique and the classical one-way ET. PATIENTS AND METHODS: The study included babies at gestational age of >34 weeks. In total, 107 ETs were performed on 86 babies. Totally, the umbilical vein (UV) group included 54 babies having undergone 69 ETs and the UV/UA group included 32 babies having undergone 38 ETs. RESULTS: The declines in bilirubin levels right after ET (p = 0.018) and 8 h after ET (p = 0.014) were higher in the fully automated UV/UA technique than in the classical UV technique. Furthermore, the duration of intensive phototherapy following ET was shorter in the UV/UA method than in the UV method (p = 0.003). There was no difference between the two methods in terms of ET-associated complications (p = 0.927). CONCLUSIONS: In neonatal hyperbilirubinemia, ET with fully automated UV/UA technique is more efficient than the classical ET technique, causing no additional side-effects. It is also more physiological than the classical technique, since it minimizes the fluctuations in the blood volume and intravascular pressure during ET. PMID- 26030681 TI - Diagnostic performance of placental alpha-microglobulin-1 test in women with prolonged pre-labour rupture of membranes. AB - OBJECTIVES: To determine diagnostic performance of placental alpha-microglobulin 1 (PAMG-1) test compared to conventional clinical assessment (CCA) in women with prolonged pre-labour rupture of membranes (PROM). METHODS: A double-blind study of women with symptoms and signs of PROM in Nnamdi Azikiwe University Teaching Hospital, Nnewi and University of Nigeria Teaching Hospital, Enugu, in south-east Nigeria using CCA for PROM and PAMG-1 test was done. Women were included if their symptoms, signs or complaints suggestive of PROM was more than 24 h duration. PROM was diagnosed if two out of three methods from CCA (pooling, positive nitrazine test or ferning) were present. Confirmation of PROM was done after delivery using any two of these clinical criteria: delivery in 48 h to 7 days, evidence of chorioamnionitis, membranes obviously ruptured at delivery and adverse perinatal outcomes strongly correlated with prolonged PROM. RESULTS: Accuracy, specificity and sensitivity value for CCA were 72.5, 36.8 and 86.0% lower than for PAMG-1 test which were 95.7, 94.1 and 96.2%. In equivocal cases, PAMG-1 was significantly more accurate than CCA (92.3% versus 38.5%; p < 0.001). CONCLUSIONS: This study in women with prolonged PROM, confirms that PAMG-1 test has high diagnostic accuracy irrespective of the duration of PROM before clinical evaluation. PMID- 26030682 TI - Platelet-rich plasma stimulated by pulse electric fields: Platelet activation, procoagulant markers, growth factor release and cell proliferation. AB - Therapeutic use of activated platelet-rich plasma (PRP) has been explored for wound healing, hemostasis and antimicrobial wound applications. Pulse electric field (PEF) stimulation may provide more consistent platelet activation and avoid complications associated with the addition of bovine thrombin, the current state of the art ex vivo activator of therapeutic PRP. The aim of this study was to compare the ability of PEF, bovine thrombin and thrombin receptor activating peptide (TRAP) to activate human PRP, release growth factors and induce cell proliferation in vitro. Human PRP was prepared in the Harvest SmartPreP2 System and treated with vehicle, PEF, bovine thrombin, TRAP or Triton X-100. Platelet activation and procoagulant markers and microparticle generation were measured by flow cytometry. Released growth factors were measured by ELISA. The releasates were tested for their ability to stimulate proliferation of human epithelial cells in culture. PEF produced more platelet-derived microparticles, P-selectin positive particles and procoagulant annexin V-positive particles than bovine thrombin or TRAP. These differences were associated with higher levels of released epidermal growth factor after PEF than after bovine thrombin or TRAP but similar levels of platelet-derived, vascular-endothelial, and basic fibroblast growth factors, and platelet factor 4. Supernatant from PEF-treated platelets significantly increased cell proliferation compared to plasma. In conclusion, PEF treatment of fresh PRP results in generation of microparticles, exposure of prothrombotic platelet surfaces, differential release of growth factors compared to bovine thrombin and TRAP and significant cell proliferation. These results, together with PEF's inherent advantages, suggest that PEF may be a superior alternative to bovine thrombin activation of PRP for therapeutic applications. PMID- 26030683 TI - Applicability of integrated cell culture quantitative PCR (ICC-qPCR) for the detection of infectious adenovirus type 2 in UV disinfection studies. AB - Practical difficulties of the traditional adenovirus infectivity assay such as intensive labor requirements and longer turnaround period limit the direct use of adenovirus as a testing microorganism for systematic, comprehensive disinfection studies. In this study, we attempted to validate the applicability of integrated cell culture quantitative PCR (ICC-qPCR) as an alternative to the traditional cell culture method with human adenovirus type 2 (HAdV2) in a low-pressure UV disinfection study and to further optimize the procedures of ICC-qPCR for 24-well plate format. The relatively high stability of the hexon gene of HAdV2 was observed after exposure to UV radiation, resulting in a maximum gene copy reduction of 0.5 log10 at 280 mJ cm(-2). Two-day post-inoculation incubation period and a maximum spiking level of 10(5) MPN mL(-1) were selected as optimum conditions of ICC-qPCR with the tested HAdV2. An approximate 1:1 correlation of virus quantities by the traditional and ICC-qPCR cell culture based methods suggested that ICC-qPCR is a satisfactory alternative for practical application in HAdV2 disinfection studies. ICC-qPCR results, coupled with a first-order kinetic model (i.e., the inactivation rate constant of 0.0232 cm(2) mJ(-1)), showed that an UV dose of 172 mJ cm(-2) achieved a 4-log inactivation credit for HAdV2. This estimate is comparable to other studies with HAdV2 and other adenovirus respiratory types. The newly optimized ICC-qPCR shows much promise for further study on its applicability of other slow replicating viruses in disinfection studies. PMID- 26030684 TI - Removal of pain-relieving drugs from aqueous solutions using Octolig and selected metalloligs. AB - The possibility of removing certain pharmaceuticals (acetaminophen and naproxen) from water was tested using Octolig, a commercially available material with polyethylenediimine moieties covalently attached to high-surface area silica gel. In addition, the efficacy of two transition metals (cupric and ferric) derivatives of Octolig was tested. Previously amoxicillin had been successfully subjected to column chromatography for removal by means of ion encapsulation, the effectiveness of which would depend upon having appropriate anionic functional groups. Both pharmaceuticals were removed by passage over Octolig columns, though with less effectiveness than was achieved previously with xanthenylbenzenes or selected food dyes. Somewhat greater removal, ca 90%, was achieved using Cuprilig, the copper(II) derivative, but not with Ferrilig the iron(III) derivative, perhaps because the hydroxide counter ion was more closely associated with the transition metal ion and was not available to assist in proton removal. PMID- 26030685 TI - Toxicity of zero-valent iron nanoparticles to a trichloroethylene-degrading groundwater microbial community. AB - The microbiological impact of zero-valent iron used in the remediation of groundwater was investigated by exposing a trichloroethylene-degrading anaerobic microbial community to two types of iron nanoparticles. Changes in total bacterial and archaeal population numbers were analyzed using qPCR and were compared to results from a blank and negative control to assess for microbial toxicity. Additionally, the results were compared to those of samples exposed to silver nanoparticles and iron filings in an attempt to discern the source of toxicity. Statistical analysis revealed that the three different iron treatments were equally toxic to the total bacteria and archaea populations, as compared with the controls. Conversely, the silver nanoparticles had a limited statistical impact when compared to the controls and increased the microbial populations in some instances. Therefore, the findings suggest that zero-valent iron toxicity does not result from a unique nanoparticle-based effect. PMID- 26030686 TI - Aroclor 1254 inhibits cell viability and induces apoptosis of human A549 lung cancer cells by modulating the intracellular Ca(2+) level and ROS production through the mitochondrial pathway. AB - To study the acute toxic effects of PCBs on airway exposure, the cell viability, apoptosis and mitochondrial functions of human lung cancer cell line A549 were measured and compared after Aroclor 1254 exposure for different time. The results showed that Aroclor 1254 could inhibit cell viability and increase cell apoptosis in a concentration- and time-dependent manner. The mitochondrial apoptosis pathway was confirmed playing an important role. ROS elevation was an early response within 1h treatment of Aroclor 1254. Then after 4 h of Aroclor 1254 exposure, the intracellular calcium level increased and mitochondrial transmembrane potential (DeltaPsim) collapsed, accompanying with Cytochrome c (Cyt-c) leakage, boosting expression of Bax, Apaf-1 and miRNA155, which were involved in the mitochondrial apoptosis pathway. After 24 h of Aroclor 1254 exposure, ROS returned to normal level, but cell apoptosis rate was higher than that at 4 h with DeltaPsim continued collapsing and intracellular calcium increased. In conclusion, Aroclor 1254 could suppress cell viability and induce apoptosis in A549 cells, which was associated with ROS over-production and elevated cellular Ca(2+) level, which may result in mitochondrial dysfunction, inducing expression of Bax/Cyt-c/Apaf-1 and miRNA155. PMID- 26030687 TI - Optimization of the sublethal dose of silver nanoparticle through evaluating its effect on intestinal physiology of Nile tilapia (Oreochromis niloticus L.). AB - Silver nanoparticles (SNPs) are widely used in a variety of biomedical and consumer products as an antimicrobial additive. The present study was conducted to evaluate the impacts of low-dose SNPs on intestinal physiology of tilapia (Oreochromis niloticus L.) for assessing its apparent environmental risk due to extensive commercial use. SNPs were synthesized by a chemical reduction method yielding 1-27 nm oval shaped particles. Early fingerlings of tilapia were exposed with two sublethal concentrations (0.8 and 0.4 mg L(-1)) of SNPs for twenty one days period and its impact on the intestinal physiology was evaluated by histochemistry, catalase expression, glutamate dehydrogenase activity, SDS-PAGE and gut micro flora count. Histological analysis showed thinning of intestinal wall, swelling on mucosal layer and immunohistochemical assay exhibited an enhanced catalase expression in SNPs treated fishes. Gut microflora count elicited a dose-dependent depletion and a variable SDS-PAGE profile followed by significant (P < 0.05) elevations in glutamate dehydrogenase activity in SNPs treated fishes. This study was designed to provide a better understanding of environmentally acceptable, dose-dependent SNPs delivery in fishes and to formulate guidelines in aquatic toxicology. PMID- 26030688 TI - Cardiac and renal nitrosative-oxidative stress after acute poisoning by a nerve agent Tabun. AB - We hypothesized that Tabun poisoning, as well as other organophosphorous treatment, cause specific organs' oxidative changes that have not previously been substantiated investigated. In this regard, a marker for nitrosative-oxidative stress in the main haemodynamic organs (heart and kidney) could reveal the existence of such changes. In this study, for the first time we studied the nitrosative/oxidative stress in heart and kidney after acute Tabun (Ethyl N,N- Dimethylphosphoramidocyanidate) poisoning measuring by immunohistochemistry the expression of 3-nitrotyrosine--a marker for nitrosative-oxidative stress. We investigated nitrotyrozine expression in three different groups of animals (with at least 3 animals in each group): the first group was treated with 0.5 LD50 Tabun and organs were collected after 24 h; the second group received vehicle for the same period; in the third group a highly specific re-activator was applied immediately after Tabun application. Heart and kidney were collected after 24 h. The levels of nitrotyrozine production significantly increased (more than 3 times) in cardiomyocytes after Tabun. The application of re-activator slightly reduced these levels not reaching the basal heart levels. Nitrotyrozine expression in kidney increased more than 2 times after Tabun and application of re-activator did not change it significantly. In conclusion, our study evidently demonstrated that Tabun trigger oxidative-nitrosative stress in heart and kidney and these cellular effects should be protected by an additional anti-oxidant therapy, since acetylcholinesterase re-activator is not efficient in this manner. PMID- 26030689 TI - An in ovo investigation into the hepatotoxicity of cadmium and chromium evaluated with light- and transmission electron microscopy and electron energy-loss spectroscopy. AB - Excessive agriculture, transport and mining often lead to the contamination of valuable water resources. Communities using this water for drinking, washing, bathing and the irrigation of crops are continuously being exposed to these heavy metals. The most vulnerable is the developing fetus. Cadmium (Cd) and chrome (Cr) were identified as two of the most prevalent heavy metal water contaminants in South Africa. In this study, chicken embryos at the stage of early organogenesis were exposed to a single dosage of 0.430 MUM physiological dosage (PD) and 430 MUM (*1000 PD) CdCl2, as well as 0.476 MUM (PD) and 746 MUM (*1000 PD) K2Cr2O7. At day 14, when all organ systems were completely developed, the embryos were terminated and the effect of these metals on liver tissue and cellular morphology was determined with light- and transmission electron microscopy (TEM). The intracellular localization of these metals was determined using electron energy loss spectroscopy (EELS). With light microscopy, the PD of both Cd and Cr had no effect on liver tissue or cellular morphology. At *1000 PD both Cd and Cr caused sinusoid dilation and tissue necrosis. With TEM analysis, Cd exposed hepatocytes presented with irregular chromatin condensation, ruptured cellular membranes and damaged or absent organelles. In contrast Cr caused only slight mitochondrial damage. EELS revealed the bio-accumulation of Cd and Cr along the cristae of the mitochondria and chromatin of the nuclei. PMID- 26030690 TI - Effect of mercury on porcine ovarian granulosa cells in vitro. AB - The objective of this in vitro study was to examine dose-dependent changes in the secretion activity [progesterone (P4) and insulin-like growth factor-I (IGF-I)] of porcine ovarian granulosa cells after experimental mercury (Hg) administration, including its apoptotic potential so as to ascertain the possible involvement of Hg in steroidogenesis. Ovarian granulosa cells were incubated with mercuric chloride [mercury (II) chloride or HgCl2] at the doses 50-250 MUg mL(-1) for 18 h and compared with control group without Hg addition. Release of P4 and IGF-I by ovarian granulosa cells was assessed by RIA and apoptosis by TUNEL assay. Observations show that P4 release by granulosa cells was significantly (P < 0.05) inhibited at all the doses, while IGF-I release was not affected at any of the doses used, although a decreasing trend in the release of IGF-I was noted in comparison to control. An increasing trend of apoptosis of granulosa cells was noted, the difference being significant (P < 0.05) only at the dose 130 MUg mL( 1) HgCl2, in comparison to control. Obtained data suggest a direct effect of Hg on the release of steroid hormone progesterone but not growth factor IGF-I, and a dose-dependent effect on apoptosis of porcine ovarian granulosa cells. Results indicate the interference of Hg in the pathways of steroidogenesis and apoptosis of porcine ovarian granulosa cells. PMID- 26030691 TI - Destruction of 1,1,1-trichloroethane and 1,2-dichloroethane DNAPLs by catalyzed H2O2 propagations (CHP). AB - Catalyzed H2O2 propagations (CHP) was studied to treat 1,1,1-trichloroethane (TCA) and 1,1-dichloroethane (DCA) dense nonaqueous phase liquids (DNAPLs) and to elucidate the reactive oxygen species responsible for their destruction. A TCA DNAPL was rapidly destroyed by CHP at a rate 3.5 times greater than its maximum rate of dissolution. Using systems that generate a single reactive oxygen species, the species responsible for TCA DNAPL destruction was found to be superoxide. Both hydroxyl radical and superoxide were responsible for the destruction of the DCA DNAPL. Both compounds were destroyed at equal rates in a mixed TCA/DCA DNAPL, which suggests that the rate of treatment is limited by a surface phenomenon at the DNAPL-water interface. The optimum pH for the destruction of TCA and DCA DNAPLs was near the pKa of 4.8 for perhydroxyl radical superoxide systems. The results of this research demonsrate that TCA and DCA DNAPLs are effectively destroyed by CHP and that superoxide generation is necessary for effective TCA DNAPL destruction, while both hydroxyl radical and superoxide are necessary for effective DCA DNAPL destruction. PMID- 26030692 TI - Kinetics of thermal and photo-initiated release of tris (1,3-dichloro-2-propyl) phosphate (TDCP) flame retardant from polyurethane foam materials. AB - Kinetics of thermal and photo-initiated release of Tris (1.3-dichloro-2-propyl) phosphate (TDCP) from the polyurethane foam (PUF) materials were studied using a validated chromatographic method with linear calibration curve in the range of 0.03-400 MUg mL(-1). Time dependence of TDCP leaching from foam samples was found to follow first-order kinetics; with rate constants directly dependent on ageing temperatures and intensity of UV radiation, rate constants for the thermally and photo initiated were 3.6 * 10(-3), 1.03 * 10(-2), 3.6 * 10(-2) and 3.94 * 10(-2) day(-1), respectively. Migration of TDCP from foam samples simulating skin or oral exposure were observed from all samples regardless of their ageing history, the presence of biological fluids found to enhance the migration rate. Oral exposure to foam material contains TDCP, which was simulated using the Head-over Heels test, reveals that an average amount of ~ 1.7% wt./wt. of the total amount of TDCP was found to leach into biological fluids, and it significantly increased to ~ 6.0% wt./wt. due to ageing conditions. Direct contact between foam material and skin simulated by using the Contact Blotting test reveals that TDCP is transferred from both aged and un-aged samples at different rates, due to the presence of biological fluids; the transferred amount is increased with ageing conditions. PMID- 26030693 TI - Sorption of arsenic on manganese dioxide synthesized by solid state reaction. AB - Arsenic in groundwater is a major concern in many parts of the world and suitable sorbents are required for removal of arsenic from ground water. Removal of arsenic from groundwater has been studied using manganese dioxide, synthesized by solid state reaction of manganese acetate with potassium permanganate. Manganese dioxide was characterized by X-ray diffraction (XRD), zeta potential, surface area, particle size measurements and thermal analysis. XRD measurement showed that the manganese dioxide had alpha-MnO2 structure. Sorption of As(III) and As(V) on manganese dioxide was studied by radiotracer technique using (76)As radio isotope. Arsenic removal efficiency for both As(III) and As(V) at concentration of 2 mg L(-1) was ~99% in the pH range of 3-9. The sorption capacities for As(III) and As(V) were ~60 mg g(-1). Kinetic studies showed that the equilibrium was reached within 30 s. Arsenic sorbed on manganese dioxide was present as As(V) irrespective of initial oxidation state. The presence of Ca(2+), Mg(2+), Cl(-) and SO4(2-) up to a concentration of 1000 mg L(-1) had no significant effect on arsenic sorption. The sorption of arsenic decreased significantly in the presence of phosphate and bicarbonate anions above 10 mg L( 1). Arsenic sorbed on manganese dioxide was desorbed by 0.1M NaOH. Arsenic was effectively removed by manganese dioxide from groundwater samples collected from arsenic contaminated areas of West Bengal, India. PMID- 26030694 TI - Optimization of simultaneous electrochemical determination of Cd(II), Pb(II), Cu(II) and Hg(II) at carbon nanotube-modified graphite electrodes. AB - The health of the environment is worsening every day. Monitoring of potentially toxic elements and remediation of environmental pollution are necessary. Therefore, the research and development of simple, inexpensive, portable and effective sensors is important. Electrochemistry is a useful component of the field of environment monitoring. The present study focuses on evaluating and comparing three types of electrodes (PIGE, PIGE/MWCNT/HNO3 and PIGE/MWCNT/EDTA/HNO3) employed for the simultaneous electrochemical determination of four potentially toxic elements: Cd(II), Pb(II), Cu(II) and Hg(II). Cyclic voltammograms were measured in an acetate buffer. The LOD, LOQ, the standard and relative precisions of the method and a prediction intervals were calculated (according to the technical procedure DIN 32 645) for the three electrodes and for each measured element. The LOD for PIGE/CNT/HNO3 (the electrode with narrowest calculated prediction intervals) was 2.98 * 10(-7) mol L(-1) for Cd(II), 4.83 * 10(-7) mol L(-1) for Pb(II), 3.81 * 10(-7) mol L(-1) for Cu(II), 6.79 * 10(-7) mol L(-1) for Hg(II). One of the benefits of this study was the determination of the amount of Hg(II) in the mixture of other elements. PMID- 26030695 TI - Microwave oxidation treatment of sewage sludge. AB - Microwave-oxidation treatment of sewage sludge using various oxidants was studied. Two treatment schemes with a combination of hydrogen peroxide and ozone were examined: hydrogen peroxide and ozone were introduced into the sludge simultaneously, followed by microwave heating. The other involved the ozonation first, and then the resulting solution was subjected to microwave and hydrogen peroxide treatment. The set with ozonation followed by hydrogen peroxide plus microwave heating yielded higher soluble materials than those of the set with hydrogen peroxide plus ozone first and then microwave treatment. No settling was observed for all treatments in the batch operation, except ozone/microwave plus hydrogen peroxide set at 120 degrees C. The pilot-scale continuous-flow 915 MHz microwave study has demonstrated that microwave-oxidation process is feasible for real-time industrial application. It would help in providing key data for the design of a full-scale system for treating sewage sludge and the formulation of operational protocols. PMID- 26030697 TI - Introduction: Deep brain stimulation: current assessment, new applications, and future innovations. PMID- 26030698 TI - Neurostimulation to improve level of consciousness in patients with epilepsy. AB - When drug-resistant epilepsy is poorly localized or surgical resection is contraindicated, current neurostimulation strategies such as deep brain stimulation and vagal nerve stimulation can palliate the frequency or severity of seizures. However, despite medical and neuromodulatory therapy, a significant proportion of patients continue to experience disabling seizures that impair awareness, causing disability and risking injury or sudden unexplained death. We propose a novel strategy in which neuromodulation is used not only to reduce seizures but also to ameliorate impaired consciousness when the patient is in the ictal and postictal states. Improving or preventing alterations in level of consciousness may have an effect on morbidity (e.g., accidents, drownings, falls), risk for death, and quality of life. Recent studies may have elucidated underlying networks and mechanisms of impaired consciousness and yield potential novel targets for neuromodulation. The feasibility, benefits, and pitfalls of potential deep brain stimulation targets are illustrated in human and animal studies involving minimally conscious/vegetative states, movement disorders, depth of anesthesia, sleep-wake regulation, and epilepsy. We review evidence that viable therapeutic targets for impaired consciousness associated with seizures may be provided by key nodes of the consciousness system in the brainstem reticular activating system, hypothalamus, basal ganglia, thalamus, and basal forebrain. PMID- 26030699 TI - Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain. AB - Chronic neuropathic pain is estimated to affect 3%-4.5% of the worldwide population. It is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders such as depression and anxiety, and disruption of family and social life. Current medical therapeutics often fail to adequately treat chronic neuropathic pain. Deep brain stimulation (DBS) targeting subcortical structures such as the periaqueductal gray, the ventral posterior lateral and medial thalamic nuclei, and the internal capsule has been investigated for the relief of refractory neuropathic pain over the past 3 decades. Recent work has identified the dorsal anterior cingulate cortex (dACC) as a new potential neuromodulation target given its central role in cognitive and affective processing. In this review, the authors briefly discuss the history of DBS for chronic neuropathic pain in the United States and present evidence supporting dACC DBS for this indication. They review existent literature on dACC DBS and summarize important findings from imaging and neurophysiological studies supporting a central role for the dACC in the processing of chronic neuropathic pain. The available neurophysiological and empirical clinical evidence suggests that dACC DBS is a viable therapeutic option for the treatment of chronic neuropathic pain and warrants further investigation. PMID- 26030696 TI - A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes. OBJECTIVES: To identify genetic determinants of quantitative imaging phenotypes. METHODS: We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD. MEASUREMENTS AND MAIN RESULTS: The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes. CONCLUSIONS: Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD and also identify imaging features associated with previously identified lung function loci. PMID- 26030700 TI - Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome. AB - Deep brain stimulation (DBS) has been reported to have beneficial effects in severe, treatment-refractory cases of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). In this report, the authors present the first case in which DBS was used to treat the neuropsychiatric symptoms of Kleefstra syndrome, a rare genetic disorder characterized by childhood hypotonia, intellectual disability, distinctive facial features, and myriad psychiatric and behavioral disturbances. A 24-year-old female patient with childhood hypotonia, developmental delay, and diagnoses of autism spectrum disorder, OCD, and TS refractory to medical management underwent the placement of bilateral ventral capsule/ventral striatum (VC/VS) DBS leads, with clinical improvement. Medical providers and family observed gradual and progressive improvement in the patient's compulsive behaviors, coprolalia, speech, and social interaction. Symptoms recurred when both DBS electrodes failed because of lead fracture and dislodgement, although the clinical benefits were restored by lead replacement. The symptomatic and functional improvements observed in this case of VC/VS DBS for Kleefstra syndrome suggest a novel indication for DBS worthy of further investigation. PMID- 26030701 TI - Erratum: A practical review of prognostic correlations of molecular biomarkers in glioblastoma. PMID- 26030702 TI - Deep brain stimulation for psychiatric disorders: where we are now. AB - Fossil records showing trephination in the Stone Age provide evidence that humans have sought to influence the mind through physical means since before the historical record. Attempts to treat psychiatric disease via neurosurgical means in the 20th century provided some intriguing initial results. However, the indiscriminate application of these treatments, lack of rigorous evaluation of the results, and the side effects of ablative, irreversible procedures resulted in a backlash against brain surgery for psychiatric disorders that continues to this day. With the advent of psychotropic medications, interest in invasive procedures for organic brain disease waned. Diagnosis and classification of psychiatric diseases has improved, due to a better understanding of psychiatric patho-physiology and the development of disease and treatment biomarkers. Meanwhile, a significant percentage of patients remain refractory to multiple modes of treatment, and psychiatric disease remains the number one cause of disability in the world. These data, along with the safe and efficacious application of deep brain stimulation (DBS) for movement disorders, in principle a reversible process, is rekindling interest in the surgical treatment of psychiatric disorders with stimulation of deep brain sites involved in emotional and behavioral circuitry. This review presents a brief history of psychosurgery and summarizes the development of DBS for psychiatric disease, reviewing the available evidence for the current application of DBS for disorders of the mind. PMID- 26030703 TI - Deep brain stimulation for severe autism: from pathophysiology to procedure. AB - Autism is a heterogeneous neurodevelopmental disorder characterized by early onset impairment in social interaction and communication and by repetitive, restricted behaviors and interests. Because the degree of impairment may vary, a spectrum of clinical manifestations exists. Severe autism is characterized by complete lack of language development and potentially life-threatening self injurious behavior, the latter of which may be refractory to medical therapy and devastating for affected individuals and their caretakers. New treatment strategies are therefore needed. Here, the authors propose deep brain stimulation (DBS) of the basolateral nucleus of the amygdala (BLA) as a therapeutic intervention to treat severe autism. The authors review recent developments in the understanding of the pathophysiology of autism. Specifically, they describe the genetic and environmental alterations that affect neurodevelopment. The authors also highlight the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development, which create a pattern of dysfunctional neural networks involved in socioemotional processing. They then discuss how these findings implicate the BLA as a key node in the pathophysiology of autism and review a reported case of BLA DBS for treatment of severe autism. Much progress has been made in recent years in understanding the pathophysiology of autism. The BLA represents a logical neurosurgical target for treating severe autism. Further study is needed that considers mechanistic and operative challenges. PMID- 26030704 TI - Predictors of unfavorable outcomes following deep brain stimulation for movement disorders and the effect of hospital case volume on outcomes: an analysis of 33, 642 patients across 234 US hospitals using the National (Nationwide) Inpatient Sample from 2002 to 2011. AB - OBJECT: With limited data available on association of risk factors and effect of hospital case volume on outcomes following deep brain stimulation (DBS), the authors attempted to identify these associations using a large population-based database. METHODS: The authors performed a retrospective cohort study involving patients who underwent DBS for 3 primary movement disorders: Parkinson's disease, essential tremor, and dystonia from 2002 to 2011 using the National (Nationwide) Inpatient Sample (NIS) database. Using national estimates, the authors identified associations of patient demographics, clinical characteristics, and hospital characteristics on short-term postoperative outcomes following DBS. Additionally, effect of hospital volume on unfavorable outcomes was investigated. RESULTS: Overall, 33, 642 patients underwent DBS for 3 primary movement disorders across 234 hospitals in the US. The mean age of the cohort was 63.42 +/- 11.31 years and 36% of patients were female. The inpatients' postoperative risks were 5.9% for unfavorable discharge, 10.2% for prolonged length of stay, 14.6% for high-end hospital charges, 0.5% for wound complications, 0.4% for cardiac complications, 1.8% for venous thromboembolism, and 5.5% for neurological complications, including those arising from an implanted nervous system device. Compared with low-volume centers, odds of having an unfavorable discharge, prolonged LOS, high end hospital charges, wound, and cardiac complications were significantly lower in the high-volume and medium-volume centers. CONCLUSIONS: The authors' study provides individualized estimates of the risks of postoperative complications based on patient demographics and comorbidities and hospital characteristics, which could potentially be used as an adjunct for risk stratification for patients undergoing DBS. PMID- 26030705 TI - Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson's disease. AB - OBJECT: Cases of postoperative psychosis in Parkinson's disease patients receiving deep brain stimulation (DBS) treatment have previously been published. However, the magnitude of symptom incidence and the clinical risk factors are currently unknown. This retrospective study sheds light on these issues by investigating psychosis in a group of 128 Parkinson's disease patients who received DBS implants. METHODS: A retrospective chart review was performed to obtain surgery dates, follow-up clinic visit dates, and associated stimulation parameter settings (contacts in use and the polarity of each along with stimulation voltage, frequency, and pulse width) for each patient. Unified Parkinson's Disease Rating Scale II Thought Disorder scores, used as a clinical assessment tool to evaluate the presence of psychosis at each visit, were also collected. The data were compiled into a database and analyzed. RESULTS: The lifetime incidence of psychosis in this cohort of patients was 28.1%. The data suggest that risk of psychosis remains fairly constant throughout the first 5 years after implantation of a DBS system and that patients older at the time of receiving the first DBS implant are not only more likely to develop psychosis, but also to develop symptoms sooner than their younger counterparts. Further analysis provides evidence that psychosis is largely independent of the clinically used electrode contact and of stimulation parameters prior to psychosis onset. CONCLUSIONS: Although symptoms of psychosis are widely seen in patients with Parkinson's disease in the years following stimulator placement, results of the present suggest that most psychoses occurring postoperatively are likely independent of implantation and stimulation settings. PMID- 26030706 TI - Deep brain stimulation for vocal tremor: a comprehensive, multidisciplinary methodology. AB - Tremulous voice is a characteristic feature of a multitude of movement disorders, but when it occurs in individuals diagnosed with essential tremor, it is referred to as essential vocal tremor (EVT). For individuals with EVT, their tremulous voice is associated with significant social embarrassment and in severe cases may result in the discontinuation of employment and hobbies. Management of EVT is extremely difficult, and current behavioral and medical interventions for vocal tremor result in suboptimal outcomes. Deep brain stimulation (DBS) has been proposed as a potential therapeutic avenue for EVT, but few studies can be identified that have systematically examined improvements in EVT following DBS. The authors describe a case of awake bilateral DBS targeting the ventral intermediate nucleus for a patient suffering from severe voice and arm tremor. They also present their comprehensive, multidisciplinary methodology for definitive treatment of EVT via DBS. To the authors' knowledge, this is the first time comprehensive intraoperative voice evaluation has been used to guide microelectrode/stimulator placement, as well as the first time that standard pre- and post-DBS assessments have been conducted, demonstrating the efficacy of this tailored DBS approach. PMID- 26030707 TI - Deep brain stimulation for obesity: past, present, and future targets. AB - The authors review the history of deep brain stimulation (DBS) in patients for treating obesity, describe current DBS targets in the brain, and discuss potential DBS targets and nontraditional stimulation parameters that may improve the effectiveness of DBS for ameliorating obesity. Deep brain stimulation for treating obesity has been performed both in animals and in humans with intriguing preliminary results. The brain is an attractive target for addressing obesity because modulating brain activity may permit influencing both sides of the energy equation--caloric intake and energy expenditure. PMID- 26030708 TI - Deep brain stimulation for obesity: rationale and approach to trial design. AB - Obesity is one of the most serious public health concerns in the US. While bariatric surgery has been shown to be successful for treatment of morbid obesity for those who have undergone unsuccessful behavioral modification, its associated risks and rates of relapse are not insignificant. There exists a neurological basis for the binge-like feeding behavior observed in morbid obesity that is believed to be due to dysregulation of the reward circuitry. The authors present a review of the evidence of the neuroanatomical basis for obesity, the potential neural targets for deep brain stimulation (DBS), as well as a rationale for DBS and future trial design. Identification of an appropriate patient population that would most likely benefit from this type of therapy is essential. There are also significant cost and ethical considerations for such a neuromodulatory intervention designed to alter maladaptive behavior. Finally, the authors present a consolidated set of inclusion criteria and study end points that should serve as the basis for any trial of DBS for obesity. PMID- 26030709 TI - Anterior nuclear deep brain stimulation guided by concordant hippocampal recording. AB - OBJECT: Anterior nuclear (AN) stimulation has been reported to reduce the frequency of seizures, in some cases dramatically; however, it has not been approved by the US Food and Drug Administration. The anterior nucleus is difficult to target because of its sequestered location, partially surrounded by the ventricle. It has traditionally been targeted by using transventricular or lateral transcortical routes. Here, the authors report a novel approach to targeting the anterior nucleus and neurophysiologically confirming effective stimulation of the target, namely evoked potentials in the hippocampus. METHODS: Bilateral AN 3389 electrodes were placed in a novel trajectory followed by bilateral hippocampal 3391 electrodes from a posterior trajectory. Each patient was implanted bilaterally with a Medtronic Activa PC+S device under an investigational device exemption approval. Placement was confirmed with CT. AN stimulation-induced hippocampal evoked potentials were measured to functionally confirm placement in the anterior nucleus. RESULTS: Two patients had implantations by way of a novel AN trajectory with concomitant hippocampal electrodes. There were no lead misplacements. Postoperative stimulation of the anterior nucleus with a PC+S device elicited evoked potentials in the hippocampus. Thus far, both patients have reported a > 50% improvement in seizure frequency. CONCLUSIONS: Placing AN electrodes posteriorly may provide a safer trajectory than that used for traditionally placed AN electrodes. In addition, with a novel battery that is capable of electroencephalographic recording, evoked potentials can be used to functionally assess the Papez circuit. This treatment paradigm may offer increased AN stimulation efficacy for medically intractable epilepsy by assessing functional placement more effectively and thus far has proven safe. PMID- 26030710 TI - Drugging Plk1: An attractive approach to inhibit androgen receptor signaling. PMID- 26030711 TI - Thin-film 'Thermal Well' Emitters and Absorbers for High-Efficiency Thermophotovoltaics. AB - A new approach is introduced to significantly improve the performance of thermophotovoltaic (TPV) systems using low-dimensional thermal emitters and photovoltaic (PV) cells. By reducing the thickness of both the emitter and the PV cell, strong spectral selectivity in thermal emission and absorption can be achieved by confining photons in trapped waveguide modes inside the thin-films that act as thermal analogs to quantum wells. Simultaneously, photo-excited carriers travel shorter distances across the thin-films reducing bulk recombination losses resulting in a lower saturation current in the PV cell. We predict a TPV efficiency enhancement with near-field coupling between the thermal emitter and the PV cell up to 38.7% using a thin-film germanium (Ge) emitter at 1000 K and an ultra-thin gallium antimonide (GaSb) cell supported by perfect back reflectors separated by 100 nm. Even in the far-field limit, the efficiency is predicted to reach 31.5%, which is over an order of magnitude higher than the Shockley Queisser limit of 1.6% for a bulk GaSb cell and a blackbody emitter at 1000 K. The proposed design approach does not require nanoscale patterning of the emitter and PV cell surfaces, but instead offers a simple low-cost solution to improve the performance of thermophotovoltaic systems. PMID- 26030713 TI - Comparison study of landfill gas emissions from subtropical landfill with various phases: A case study in Wuhan, China. AB - The compositions and annual variations of landfill gas (LFG) were studied at two large-scale sites of Chen-Jia-Chong Landfill. Seventy-six wells were built and used for the collection and measurement of LFG. The investigation revealed the similarities and differences of LFG components and variations at two sites with different phases. It was found that ambient temperature and rainfall exhibited strong correlations with LFG components at both sites. Methane (CH4) contents showed excellent correlations with CO2at both sites. Notable correlations between hydrogen sulfide (H2S) and major components (CH4and carbon dioxide [CO2]) were only observed in unstable methane phase. Especially, the CH4/CO2volumetric ratio could act as an excellent indicator for anaerobic reaction stage by judging its phasic variations. The study is beneficial for the efficient operation of LFG collection system and could shed light on gas purification and utilization. PMID- 26030712 TI - Myo-inositol improves the host's ability to eliminate balofloxacin-resistant Escherichia coli. AB - Antibiotic-resistant mechanisms are associated with fitness costs. However, why antibiotic-resistant bacteria usually show increasing adaptation to hosts is largely unknown, especially from the host's perspective. The present study reveals the host's varied response to balofloxacin-resistant Escherichia coli (BLFX-R) using an integrated proteome and metabolome approach and identifies myo inositol and phagocytosis-related proteins as crucial biomarkers. Originally, macrophages have an optimal attractive preference to BLFX-S due to more polarization of BLFX-S than BLFX-R, which renders faster elimination to BLFX-S than BLFX-R. The slower elimination to BLFX-R may be reversed by exogenous myo inositol. Primarily, myo-inositol depolarizes macrophages, elevating adherence to both BLFX-S and BLFX-R. Since the altered adherence is equal to both strains, the myo-inositol-treated macrophages are free of the barrier to BLFX-R and thereby promote phagocytosis of BLFX-R. This work provides a novel strategy based on metabolic modulation for eliminating antibiotic-resistant bacteria with a high degree of host adaptation. PMID- 26030714 TI - Stability of the Metastable alpha-Polymorph in Solid Triglyceride Drug-Carrier Nanoparticles. AB - Colloidal dispersions of crystalline nonpolar lipids are under intensive investigation as carrier systems in pharmaceutics and nutrition. In this context, the controlled preparation of particles in a metastable polymorphic state is of some interest for the delivery of active substances. In the present study, tristearin particles stabilized with three alpha-polymorph-preserving emulsifier regimes ((I) sodium glycocholate/saturated long-chain phospholipids, (II) sodium glycocholate, and (III) poly(vinyl alcohol) (PVA)) were investigated concerning the stability of the metastable alpha-polymorph after controlled crystallization of the particles from the melt. Upon long-term storage, the alpha-polymorph was preserved best in PVA-stabilized dispersions, followed by those stabilized with the glycocholate/phospholipid mixture and finally those stabilized solely with the bile salt. In particular for rapidly crystallized nanoparticles, the formation of an alpha-polymorph with highly reduced lamellarity was observed. According to time-/temperature-resolved synchrotron X-ray diffraction analysis with simultaneous DSC (differential scanning calorimetry) studies, this less ordered alpha-polymorph transformed into the common, lamellar alpha-form upon heating. Although the presence of the less-ordered form is probably related to the extraordinarily high stability of the metastable alpha-polymorph observed in some of the dispersions, it could not completely prevent the transition into the stable beta-polymorph. The higher the transition temperature of the less-ordered alpha-form to the ordered one, the slower was the polymorphic transition to the stable beta-polymorph. To estimate the polymorphic stability of the differently stabilized particles upon isothermal long-term storage, standard DSC measurements on samples stored at 23 degrees C for 4 weeks seem to be of predictive value. PMID- 26030715 TI - Potential-Scanning Localized Surface Plasmon Resonance Sensor. AB - Localized surface plasmon resonance (LSPR) sensors based on plasmonic nanoparticles attract much attention recently. Here we propose a new class of LSPR sensor, that is, a potential-scanning LSPR sensor, in which electron density of the plasmonic nanoparticles is controlled by potential scanning. The sensor exhibits a resonance peak during the potential scan, which negatively shifts with increasing local refractive index. Therefore, the present sensor can be applied to affinity biosensors and chemical sensors based on potential scan instead of wavelength scan. The potential-scanning LSPR sensors do not require space and a mechanical device for wavelength scanning, so the sensors are advantageous for miniaturization and cost reduction, in comparison with the conventional LSPR sensors. We explain the principle and theoretical sensitivities of the potential scanning LSPR sensors, and refractometry is demonstrated using a sensor with an ITO electrode loaded with gold nanospheres (13 or 40 nm diameter) or nanorods. The smaller and larger nanospheres are suitable for sensing with a wider dynamic range and with a higher sensitivity, respectively. The use of nanorods further improves the sensitivity and figure of merit. PMID- 26030717 TI - Red Kidney: Kidney Transplant From a Deceased Donor Who Received Massive Blood Transfusion During Cardiopulmonary Bypass. AB - Here, we present a case of a deceased-donor kidney transplant. The brain-dead donor had received a massive blood transfusion during cardiopulmonary bypass, which lead to hemolysis, hemoglobinuria, acute kidney injury, and renal replacement therapy. The kidney appeared red after in situ flush. Postoperatively, the recipient developed delayed graft function. Protocol biopsy during the postoperative period revealed the widespread deposition of heme pigment in the renal tubules. Massive blood transfusion and cardiopulmonary bypass surgery are associated with hemolysis and heme pigment deposition in the renal tubules, which subsequently lead to acute kidney injury. Kidneys from such donors appear red and, while this does not preclude transplant, are likely to develop delayed graft function. PMID- 26030716 TI - Clinical impact of kidney function on presepsin levels. AB - OBJECTIVE: Presepsin is highlighted as a diagnostic and prognostic marker of sepsis. Little information is available regarding the accurate association between presepsin levels and the degree of kidney function. We analyzed presepsin levels in patients with a glomerular filtration rate (GFR) in the categories G1 to G5, evaluated via inulin renal clearance test, and receiving hemodialysis (HD). METHODS: Patients who were not receiving HD were included if they had undergone inulin renal clearance measurements for the accurate measurement of GFR (measured GFR), and patients who were receiving hemodialysis (HD) were included if they had anuria. Exclusion criteria were infection, cancer, liver disease, autoimmune disorders, or steroid or immunosuppressant use. GFR category was defined as follows; G1: GFR >= 90 ml/min/1.73 m2, G2: GFR = 60 to 90 ml/min/1.73 m2, G3: GFR = 30 to 60 ml/min/1.73 m2, G4: GFR = 15 to 30 ml/min/1.73 m2, G5: GFR <= 15 ml/min/1.73 m2. RESULTS: Seventy-one patients were included. The median (IQR) presepsin values of patients in each GFR category were as follows: G1 + G2: 69.8 (60.8-85.9) pg/ml; G3: 107.0 (68.7-150.0) pg/ml; G4: 171.0 (117.0-200.0) pg/ml; G5: 251.0 (213.0-297.5) pg/ml; and HD: 1160.0 (1070.0-1400.0) pg/ml. The log-transformed presepsin values, excluding patients receiving HD, inversely correlated with the measured GFR (Pearson's correlation coefficient = -0.687, P < 0.001). The multivariate analysis revealed that measured GFR and hemoglobin levels significantly correlated with elevated presepsin levels. CONCLUSION: Presepsin levels were markedly high in patients receiving HD, similar to values seen in patients with severe sepsis or septic shock. In patients who were not receiving HD, presepsin levels increased as GFR decreased. Thus, the evaluation of presepsin levels in patients with chronic kidney disease requires further consideration, and a different cutoff value is needed for diagnosing sepsis in such patients. PMID- 26030718 TI - Quantitatively mimicking wet colloidal suspensions with dry granular media. AB - Athermal two-dimensional granular systems are exposed to external mechanical noise leading to Brownian-like motion. Using tunable repulsive interparticle interaction, it is shown that the same microstructure as that observed in colloidal suspensions can be quantitatively recovered at a macroscopic scale. To that end, experiments on granular and colloidal systems made up of magnetized particles as well as computer simulations are performed and compared. Excellent agreement throughout the range of the magnetic coupling parameter is found for the pair distribution as well as the bond-orientational correlation functions. This finding opens new ways to efficiently and very conveniently explore phase transitions, crystallization, nucleation, etc in confined geometries. PMID- 26030719 TI - Evaluation of occupational health interventions using a randomized controlled trial: challenges and alternative research designs. AB - Occupational health researchers regularly conduct evaluative intervention research for which a randomized controlled trial (RCT) may not be the most appropriate design (eg, effects of policy measures, organizational interventions on work schedules). This article demonstrates the appropriateness of alternative designs for the evaluation of occupational health interventions, which permit causal inferences, formulated along two study design approaches: experimental (stepped-wedge) and observational (propensity scores, instrumental variables, multiple baseline design, interrupted time series, difference-in-difference, and regression discontinuity). For each design, the unique characteristics are presented including the advantages and disadvantages compared to the RCT, illustrated by empirical examples in occupational health. This overview shows that several appropriate alternatives for the RCT design are feasible and available, which may provide sufficiently strong evidence to guide decisions on implementation of interventions in workplaces. Researchers are encouraged to continue exploring these designs and thus contribute to evidence-based occupational health. PMID- 26030721 TI - Brief Report: Persistence of Ebola Virus in Ocular Fluid during Convalescence. PMID- 26030720 TI - Mechanisms of cardiac radiation injury and potential preventive approaches. AB - In addition to cytostatic treatment and surgery, the most common cancer treatment is gamma radiation. Despite sophisticated radiological techniques however, in addition to irradiation of the tumor, irradiation of the surrounding healthy tissue also takes place, which results in various side-effects, depending on the absorbed dose of radiation. Radiation either damages the cell DNA directly, or indirectly via the formation of oxygen radicals that in addition to the DNA damage, react with all cell organelles and interfere with their molecular mechanisms. The main features of radiation injury besides DNA damage is inflammation and increased expression of pro-inflammatory genes and cytokines. Endothelial damage and dysfunction of capillaries and small blood vessels plays a particularly important role in radiation injury. This review is focused on summarizing the currently available data concerning the mechanisms of radiation injury, as well as the effectiveness of various antioxidants, anti-inflammatory cytokines, and cytoprotective substances that may be utilized in preventing, mitigating, or treating the toxic effects of ionizing radiation on the heart. PMID- 26030722 TI - Stability, elastic properties, and electronic structure of germanane nanoribbons. AB - The stability, elastic properties, and electronic structure of germanane nanoribbons (GeNRs) are studied from first-principles calculations. When using atomic H as the hydrogen source, a germanane monolayer spontaneously breaks into ribbons. GeNRs can be easily stretched due to their small in-plane stiffness, suggesting that it is feasible to modulate their properties by strain. All GeNRs show direct band gaps at the Gamma point when external strain is zero, with the gap value decreasing with increasing ribbon width. When axial tensile strain is applied, the band gap decreases, and a direct-to-indirect gap transition occurs. The transition can be attributed to different deformation potentials of different states in the valence band. These results suggest potential applications of GeNRs in the fields of pressure sensors and tunable optical electronics. PMID- 26030723 TI - Copper-Catalyzed Electrophilic Amination of Organoaluminum Nucleophiles with O Benzoyl Hydroxylamines. AB - A copper-catalyzed electrophilic amination of aryl and heteroaryl aluminums with N,N-dialkyl-O-benzoyl hydroxylamines that affords the corresponding anilines in good yields has been developed. The catalytic reaction proceeds very smoothly under mild conditions and exhibits good substrate scope. Moreover, the developed catalytic system is also well suited for heteroaryl aluminum nucleophiles, providing facile access to heteroaryl amines. PMID- 26030724 TI - Incorrect ICD-10 Code and MACE Endpoint. PMID- 26030725 TI - Pharmacogenomic and pharmacogenetic-guided therapy as a tool in precision medicine: current state and factors impacting acceptance by stakeholders. AB - Pharmacogenetic/pharmacogenomic (PGx) testing is currently available for a wide range of health problems including cardiovascular disease, cancer, diabetes, autoimmune disorders, mental health disorders and infectious diseases. PGx contributes important information to the field of precision medicine by clarifying appropriate treatments for specific disease subtypes. Tangible benefits to patients including improved outcomes and reduced total health care costs have been observed. However, PGx-guided therapy faces many barriers to full integration into clinical practice and acceptance by stakeholders, whether practitioner, patient or payer. Each stakeholder has a unique perspective on the role of PGx testing, although all are similarly challenged with demonstrating or appraising its cost-to-benefit value. Coverage by insurers is a critical step in achieving widespread adoption of PGx testing. The acceleration of adoption of precision medicine in general and for PGx testing in particular will be determined by how quickly robust evidence can be accumulated that shows a return on investment for payers in terms of real dollars, for clinicians in terms of patient clinical responses, and for patients in terms of economic, health and quality of life outcomes. Trends in PGx testing utilization and uptake by payers in real-world practice are discussed; the role of pharmacoeconomics in assessing cost-effectiveness is highlighted using a case study in psychiatric care, and several issues that will affect adoption of PGx testing in the United States (US) over the next few years are reviewed. PMID- 26030726 TI - Immobilization of enzymes via microcontact printing and thiol-ene click chemistry. AB - This Communication describes a bioconjugation method for the generation of enzyme microarrays on surfaces using photochemical thiol-ene chemistry in combination with microcontact printing. Glucose oxidase and lactase were readily immobilized (i.e., printing time 2 min) on alkene terminated self-assembled monolayers on glass as demonstrated by X-ray photoelectron spectroscopy and fluorescence microscopy. Furthermore, the activity of both immobilized enzymes was confirmed in single enzyme as well as cascade transformations. PMID- 26030727 TI - Antifungal design: The toxicity-resistance yin-yang. PMID- 26030728 TI - SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. AB - Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases. PMID- 26030729 TI - Nontoxic antimicrobials that evade drug resistance. AB - Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies. PMID- 26030730 TI - Efficient genetic encoding of phosphoserine and its nonhydrolyzable analog. AB - Serine phosphorylation is a key post-translational modification that regulates diverse biological processes. Powerful analytical methods have identified thousands of phosphorylation sites, but many of their functions remain to be deciphered. A key to understanding the function of protein phosphorylation is access to phosphorylated proteins, but this is often challenging or impossible. Here we evolve an orthogonal aminoacyl-tRNA synthetase/tRNACUA pair that directs the efficient incorporation of phosphoserine (pSer (1)) into recombinant proteins in Escherichia coli. Moreover, combining the orthogonal pair with a metabolically engineered E. coli enables the site-specific incorporation of a nonhydrolyzable analog of pSer. Our approach enables quantitative decoding of the amber stop codon as pSer, and we purify, with yields of several milligrams per liter of culture, proteins bearing biologically relevant phosphorylations that were previously challenging or impossible to access--including phosphorylated ubiquitin and the kinase Nek7, which is synthetically activated by a genetically encoded phosphorylation in its activation loop. PMID- 26030732 TI - Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus. AB - Staphyloferrin B (SB) is a citrate-based polycarboxylate siderophore produced and utilized by the human pathogen Staphylococcus aureus for acquiring iron when colonizing the vertebrate host. The first chemical synthesis of SB is reported, which enables further molecular and biological characterization and provides access to structural analogues of the siderophore. Under conditions of iron limitation, addition of synthetic SB to bacterial growth medium recovered the growth of the antibiotic resistant community isolate S. aureus USA300 JE2. Two structural analogues of SB, epiSB and SBimide, were also synthesized and employed to investigate how epimerization of the citric acid moiety or imide formation influence its function as a siderophore. Epimerization of the citric acid stereocenter perturbed the iron-binding properties and siderophore function of SB as evidenced by experimental and computational modeling studies. Although epiSB provided growth recovery to S. aureus USA300 JE2 cultured in iron-deficient medium, the effect was attenuated relative to that of SB. Moreover, SB more effectively sequestered the Fe(III) bound to human holo-transferrin, an iron source of S. aureus, than epiSB. SBimide is an imide analogous to the imide forms of other citric acid siderophores that are often observed when these molecules are isolated from natural sources. Here, SBimide is shown to be unstable, converting to native SB at physiological pH. SB is considered to be a virulence factor of S. aureus, a pathogen that poses a particular threat to public health because of the number of drug-resistant strains emerging in hospital and community settings. Iron acquisition by S. aureus is important for its ability to colonize the human host and cause disease, and new chemical insights into the structure and function of SB will inform the search for new therapeutic strategies for combating S. aureus infections. PMID- 26030731 TI - Squamousness: Next-generation sequencing reveals shared molecular features across squamous tumor types. AB - In order to gain a better understanding of the underlying biology of squamous cell carcinoma (SCC), we tested the hypothesis that SCC originating from different organs may possess common molecular alterations. SCC samples (N = 361) were examined using clinical-grade targeted next-generation sequencing (NGS). The most frequent SCC tumor types were head and neck, lung, cutaneous, gastrointestinal and gynecologic cancers. The most common gene alterations were TP53 (64.5% of patients), PIK3CA (28.5%), CDKN2A (24.4%), SOX2 (17.7%), and CCND1 (15.8%). By comparing NGS results of our SCC cohort to a non-SCC cohort (N = 277), we found that CDKN2A, SOX2, NOTCH1, TP53, PIK3CA, CCND1, and FBXW7 were significantly more frequently altered, unlike KRAS, which was less frequently altered in SCC specimens (all P < 0.05; multivariable analysis). Therefore, we identified "squamousness" gene signatures (TP53, PIK3CA, CCND1, CDKN2A, SOX2, NOTCH 1, and FBXW7 aberrations, and absence of KRAS alterations) that were significantly more frequent in SCC versus non-SCC histologies. A multivariable co alteration analysis established 2 SCC subgroups: (i) patients in whom TP53 and cyclin pathway (CDKN2A and CCND1) alterations strongly correlated but in whom PIK3CA aberrations were less frequent; and (ii) patients with PIK3CA alterations in whom TP53 mutations were less frequent (all P <= 0 .001, multivariable analysis). In conclusion, we identified a set of 8 genes altered with significantly different frequencies when SCC and non-SCC were compared, suggesting the existence of patterns for "squamousness." Targeting the PI3K-AKT mTOR and/or cyclin pathway components in SCC may be warranted. PMID- 26030734 TI - Altruists Proliferate Even at a Selective Disadvantage within Their Own Niche. AB - The evolutionary origin of altruism is a long-standing puzzle. Numerous explanations have been proposed, most prominently based on inclusive fitness or group selection. One possibility that has not yet been considered is that new niches will be created disproportionately often when altruism appears, perhaps by chance, causing altruists to be over-represented in such new niches. This effect is a novel variant of group selection in which altruistic groups benefit by discovering unoccupied niches instead of by competing for the limited resources within a single niche. Both an analytical population genetics model and computational simulations support that altruism systematically arises due to this side effect of increased carrying capacity even when it is strongly selected against within any given niche. In fact, even when selection is very strongly negative and altruism does not develop in most populations, it can still be expected to be observed in a consistent fraction of species. The ecological structure provided by niches thereby may be sufficient for altruists to proliferate even if they are always at a disadvantage within each niche considered individually. PMID- 26030735 TI - Measuring Fisher information accurately in correlated neural populations. AB - Neural responses are known to be variable. In order to understand how this neural variability constrains behavioral performance, we need to be able to measure the reliability with which a sensory stimulus is encoded in a given population. However, such measures are challenging for two reasons: First, they must take into account noise correlations which can have a large influence on reliability. Second, they need to be as efficient as possible, since the number of trials available in a set of neural recording is usually limited by experimental constraints. Traditionally, cross-validated decoding has been used as a reliability measure, but it only provides a lower bound on reliability and underestimates reliability substantially in small datasets. We show that, if the number of trials per condition is larger than the number of neurons, there is an alternative, direct estimate of reliability which consistently leads to smaller errors and is much faster to compute. The superior performance of the direct estimator is evident both for simulated data and for neuronal population recordings from macaque primary visual cortex. Furthermore we propose generalizations of the direct estimator which measure changes in stimulus encoding across conditions and the impact of correlations on encoding and decoding, typically denoted by Ishuffle and Idiag respectively. PMID- 26030736 TI - Predicting Attitudes toward Press- and Speech Freedom across the U.S.A.: A Test of Climato-Economic, Parasite Stress, and Life History Theories. AB - National surveys reveal notable individual differences in U.S. citizens' attitudes toward freedom of expression, including freedom of the press and speech. Recent theoretical developments and empirical findings suggest that ecological factors impact censorship attitudes in addition to individual difference variables (e.g., education, conservatism), but no research has compared the explanatory power of prominent ecological theories. This study tested climato-economic, parasite stress, and life history theories using four measures of attitudes toward censoring the press and offensive speech obtained from two national surveys in the U.S.A. Neither climate demands nor its interaction with state wealth--two key variables for climato-economic theory- predicted any of the four outcome measures. Interstate parasite stress significantly predicted two, with a marginally significant effect on the third, but the effects became non-significant when the analyses were stratified for race (as a control for extrinsic risks). Teenage birth rates (a proxy of human life history) significantly predicted attitudes toward press freedom during wartime, but the effect was the opposite of what life history theory predicted. While none of the three theories provided a fully successful explanation of individual differences in attitudes toward freedom of expression, parasite stress and life history theories do show potentials. Future research should continue examining the impact of these ecological factors on human psychology by further specifying the mechanisms and developing better measures for those theories. PMID- 26030737 TI - A hyaluronic acid nanogel for photo-chemo theranostics of lung cancer with simultaneous light-responsive controlled release of doxorubicin. AB - The combined delivery of photo- and chemo-therapeutic agents is an emerging strategy to overcome drug resistance in treating cancer, and controlled light responsive drug release is a proven tactic to produce a continuous therapeutic effect for a prolonged duration. Here, a combination of light-responsive graphene, chemo-agent doxorubicin and pH-sensitive disulfide-bond linked hyaluronic acid form a nanogel (called a graphene-doxorubicin conjugate in a hyaluronic acid nanogel) that exerts an activity with multiple effects: thermo and chemotherapeutic, real-time noninvasive imaging, and light-glutathione responsive controlled drug release. The nanogel is mono-dispersed with an average diameter of 120 nm as observed by using TEM and a hydrodynamic size analyzer. It has excellent photo-luminescence properties and good stability in buffer and serum solutions. Graphene itself, being photoluminescent, can be considered an optical imaging contrast agent as well as a heat source when excited by laser irradiation. Thus the nanogel shows simultaneous thermo-chemotherapeutic effects on noninvasive optical imaging. We have also found that irradiation enhances the release of doxorubicin in a controlled manner. This release synergizes therapeutic activity of the nanogel in killing tumor cells. Our findings demonstrate that the graphene-doxorubicin conjugate in the hyaluronic acid nanogel is very effective in killing the human lung cancer cell line (A549) with limited toxicity in the non-cancerous cell line (MDCK). PMID- 26030738 TI - A cross-lingual similarity measure for detecting biomedical term translations. AB - Bilingual dictionaries for technical terms such as biomedical terms are an important resource for machine translation systems as well as for humans who would like to understand a concept described in a foreign language. Often a biomedical term is first proposed in English and later it is manually translated to other languages. Despite the fact that there are large monolingual lexicons of biomedical terms, only a fraction of those term lexicons are translated to other languages. Manually compiling large-scale bilingual dictionaries for technical domains is a challenging task because it is difficult to find a sufficiently large number of bilingual experts. We propose a cross-lingual similarity measure for detecting most similar translation candidates for a biomedical term specified in one language (source) from another language (target). Specifically, a biomedical term in a language is represented using two types of features: (a) intrinsic features that consist of character n-grams extracted from the term under consideration, and (b) extrinsic features that consist of unigrams and bigrams extracted from the contextual windows surrounding the term under consideration. We propose a cross-lingual similarity measure using each of those feature types. First, to reduce the dimensionality of the feature space in each language, we propose prototype vector projection (PVP)--a non-negative lower dimensional vector projection method. Second, we propose a method to learn a mapping between the feature spaces in the source and target language using partial least squares regression (PLSR). The proposed method requires only a small number of training instances to learn a cross-lingual similarity measure. The proposed PVP method outperforms popular dimensionality reduction methods such as the singular value decomposition (SVD) and non-negative matrix factorization (NMF) in a nearest neighbor prediction task. Moreover, our experimental results covering several language pairs such as English-French, English-Spanish, English Greek, and English-Japanese show that the proposed method outperforms several other feature projection methods in biomedical term translation prediction tasks. PMID- 26030739 TI - Monitoring beta-arrestin recruitment via beta-lactamase enzyme fragment complementation: purification of peptide E as a low-affinity ligand for mammalian bombesin receptors. AB - Identification of cognate ligands for G protein-coupled receptors (GPCRs) provides a starting point for understanding novel regulatory mechanisms. Although GPCR ligands have typically been evaluated through the activation of heterotrimeric G proteins, recent studies have shown that GPCRs signal not only through G proteins but also through beta-arrestins. As such, monitoring beta arrestin signaling instead of G protein signaling will increase the likelihood of identifying currently unknown ligands, including beta-arrestin-biased agonists. Here, we developed a cell-based assay for monitoring ligand-dependent GPCR-beta arrestin interaction via beta-lactamase enzyme fragment complementation. Inter alia, beta-lactamase is a superior reporter enzyme because of its cell-permeable fluorescent substrate. This substrate makes the assay non-destructive and compatible with fluorescence-activated cell sorting (FACS). In a reporter cell, complementary fragments of beta-lactamase (alpha and omega) were fused to beta arrestin 2 and GPCR, respectively. Ligand stimulation initiated the interaction of these chimeric proteins (beta-arrestin-alpha and GPCR-omega), and this inducible interaction was measured through reconstituted beta-lactamase activity. Utilizing this system, we screened various mammalian tissue extracts for agonistic activities on human bombesin receptor subtype 3 (hBRS3). We purified peptide E as a low-affinity ligand for hBRS3, which was also found to be an agonist for the other two mammalian bombesin receptors such as gastrin-releasing peptide receptor (GRPR) and neuromedin B receptor (NMBR). Successful purification of peptide E has validated the robustness of this assay. We conclude that our newly developed system will facilitate the discovery of GPCR ligands. PMID- 26030740 TI - Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton. AB - Melanodiol 4"-O-protocatechuate (1) and melanodiol (2) represent novel flavonoid derivatives isolated from a botanical dietary supplement ingredient, dried black chokeberry (Aronia melanocarpa) fruit juice. These noncrystalline compounds possess an unprecedented fused pentacyclic core with two contiguous hemiketals. Due to having significant hydrogen deficiency indices, their structures were determined using computer-assisted structure elucidation software. The in vitro hydroxyl radical-scavenging and quinone reductase-inducing activity of each compound are reported, and a plausible biogenetic scheme is proposed. PMID- 26030741 TI - Introduction of Syphilis Point-of-Care Tests, from Pilot Study to National Programme Implementation in Zambia: A Qualitative Study of Healthcare Workers' Perspectives on Testing, Training and Quality Assurance. AB - Syphilis affects 1.4 million pregnant women globally each year. Maternal syphilis causes congenital syphilis in over half of affected pregnancies, leading to early foetal loss, pregnancy complications, stillbirth and neonatal death. Syphilis is under-diagnosed in pregnant women. Point-of-care rapid syphilis tests (RST) allow for same-day treatment and address logistical barriers to testing encountered with standard Rapid Plasma Reagin testing. Recent literature emphasises successful introduction of new health technologies requires healthcare worker (HCW) acceptance, effective training, quality monitoring and robust health systems. Following a successful pilot, the Zambian Ministry of Health (MoH) adopted RST into policy, integrating them into prevention of mother-to-child transmission of HIV clinics in four underserved Zambian districts. We compare HCW experiences, including challenges encountered in scaling up from a highly supported NGO-led pilot to a large-scale MoH-led national programme. Questionnaires were administered through structured interviews of 16 HCWs in two pilot districts and 24 HCWs in two different rollout districts. Supplementary data were gathered via stakeholder interviews, clinic registers and supervisory visits. Using a conceptual framework adapted from health technology literature, we explored RST acceptance and usability. Quantitative data were analysed using descriptive statistics. Key themes in qualitative data were explored using template analysis. Overall, HCWs accepted RST as learnable, suitable, effective tools to improve antenatal services, which were usable in diverse clinical settings. Changes in training, supervision and quality monitoring models between pilot and rollout may have influenced rollout HCW acceptance and compromised testing quality. While quality monitoring was integrated into national policy and training, implementation was limited during rollout despite financial support and mentorship. We illustrate that new health technology pilot research can rapidly translate into policy change and scale-up. However, training, supervision and quality assurance models should be reviewed and strengthened as rollout of the Zambian RST programme continues. PMID- 26030742 TI - Sporotrichosis: The Story of an Endemic Region in Peru over 28 Years (1985 to 2012). AB - BACKGROUND: Abancay province is a long-standing geographical focus of sporotrichosis in the south central highlands of Peru. Therefore, we examined the features of 36 newly identified cases of sporotrichosis from two hospital centers in Abancay province. We also performed a literature review of studies conducted in this endemic geographical focus over a period of 28 years (1998 to 2012), and analyzed the demographic, clinical and epidemiological features of sporotrichosis in the cases reported in these studies. METHODOLOGY: We examined the features of 36 new cases of sporotrichosis identified from two hospital centers in Abancay. Furthermore, we searched for relevant studies of cases of sporotrichosis in the endemic region using healthcare databases and literature sources. We analyzed a detailed subset of data on cases collected in Abancay, neighboring provinces, and other regions of Peru. RESULTS: A total of nine studies were identified, with 1467 cases included in the final analysis. We also analyzed 36 new cases found in the two hospital centers. Therefore, the combined total of cases analyzed was 1503. Of this total, 58% were male, and approximately 62% were aged <=14 years. As expected, most cases were from Abancay province (88%), although 12% were from neighboring provinces and other regions of Peru. The lymphocutaneous form (939 cases) was the commonest. The face was the most commonly affected region (647 cases). A total of 1224 patients (81.4%) received treatment: 95.8% received potassium iodide, 2.6% ketoconazole and 1.6% itraconazole. The overall success rates were 60.7% with potassium iodide, 32.2% with ketoconazole and 85% with itraconazole. CONCLUSIONS: The epidemic of sporotrichosis has been occurring for three decades in the province of Abancay in Peru. This mycosis affects primarily the pediatric population, with predominantly the lymphocutaneous form in the facial region. Although treatment with potassium iodide is safe and effective, response and adherence to treatment are influenced by its duration, cost, accessibility, and side effects. PMID- 26030744 TI - Self-powered flexible Fe-doped RGO/PVDF nanocomposite: an excellent material for a piezoelectric energy harvester. AB - In this work, we report the superior piezoelectric energy harvester ability of a non-electrically poled Fe-doped reduced graphene oxide (Fe-RGO)/poly(vinylidene fluoride) (PVDF) nanocomposite film prepared through a simple solution casting technique that favors the nucleation and stabilization of ~99% relative proportion of polar gamma-phase. The piezoelectric energy harvester was made with non-electrically poled Fe-RGO/PVDF nanocomposite film that gives an open circuit output voltage and short circuit current up to 5.1 V and 0.254 MUA by repetitive human finger imparting. The improvement of the output performance is influenced by the generation of the electroactive polar gamma-phase in the PVDF, due to the electrostatic interactions among the -CH2-/-CF2- dipoles of PVDF and the delocalized pi-electrons and remaining oxygen functionalities of Fe-doped RGO via ion-dipole and/or hydrogen bonding interactions. Fourier transform infrared spectroscopy (FT-IR) confirmed the nucleation of the polar gamma-phase of PVDF by electrostatic interactions and Raman spectroscopy also supported the molecular interactions between the dipoles of PVDF and the Fe-doped RGO nanosheets. In addition, the nanocomposite shows a higher electrical energy density of ~0.84 J cm(-3) at an electric field of 537 kV cm(-1), which indicates that it is appropriate for energy storage capabilities. Moreover, the surface of the prepared nanocomposite film is electrically conducting and shows an electrical conductivity of ~3.30 * 10(-3) S cm(-1) at 2 wt% loading of Fe-RGO. PMID- 26030743 TI - Reference gene selection for quantitative real-time PCR normalization in larvae of three species of Grapholitini (Lepidoptera: Tortricidae). AB - Despite the agricultural importance of species in the Grapholitini (Lepidoptera: Tortricidae), and the value of gene expression analysis for improved population management, few gene expression studies based on quantitative real-time PCR (qPCR) have been conducted for this tribe. Part of the reason for this lack of information is that suitable reference genes, which are fundamental for accurate normalization of qPCR studies, have not been identified for the tribe. Thus, the expression stability of six potential reference genes (ACT, AK, COI, EF1, ENO and TUB) was assessed in three different tissues (whole body, midgut and cuticle) of Cryptophlebia peltastica (Meyrick), Cydia pomonella (L.) and Thaumatotibia leucotreta (Meyrick). Additionally, these reference genes were tested using T. leucotreta at different temperatures (15 degrees C, 25 degrees C and 35 degrees C) with and without baculovirus infection. Suitable reference genes were identified for the whole body and midgut tissue of all three species, and for cuticle tissue of Cy. pomonella and T. leucotreta. When T. leucotreta was infected with the virus at all temperature conditions ACT, AK and EF1 were found to be the most suitable reference genes for experimental normalization. In general, for all tissue types, species and stress conditions, AK and EF1 were the best-performing reference genes. However, even though the three species analysed were closely related and within the same tribe, each species required varying gene combinations for suitable normalization. This study provides the first reference gene evaluation for the Tortricidae, and paves the way for future qPCR analysis in Tortricidae. PMID- 26030745 TI - Molecular pathway of near-infrared laser phototoxicity involves ATF-4 orchestrated ER stress. AB - High power lasers are used extensively in medicine while lower power applications are popular for optical imaging, optogenetics, skin rejuvenation and a therapeutic modality termed photobiomodulation (PBM). This study addresses the therapeutic dose limits, biological safety and molecular pathway of near-infrared (NIR) laser phototoxicity. Increased erythema and tissue damage were noted in mice skin and cytotoxicity in cell cultures at phototoxic laser doses involving generation of reactive oxygen species (ROS) coupled with a rise in surface temperature (>45 degrees C). NIR laser phototoxicity results from Activating Transcription Factor-4 (ATF-4) mediated endoplasmic reticulum stress and autophagy. Neutralizations of heat or ROS and overexpressing ATF-4 were noted to rescue NIR laser phototoxicity. Further, NIR laser mediated phototoxicity was noted to be non-genotoxic and non-mutagenic. This study outlines the mechanism of NIR laser phototoxicity and the utility of monitoring surface temperature and ATF4 expression as potential biomarkers to develop safe and effective clinical applications. PMID- 26030746 TI - Cloning and Functional Characterization of the Maize (Zea mays L.) Carotenoid Epsilon Hydroxylase Gene. AB - The assignment of functions to genes in the carotenoid biosynthesis pathway is necessary to understand how the pathway is regulated and to obtain the basic information required for metabolic engineering. Few carotenoid epsilon hydroxylases have been functionally characterized in plants although this would provide insight into the hydroxylation steps in the pathway. We therefore isolated mRNA from the endosperm of maize (Zea mays L., inbred line B73) and cloned a full-length cDNA encoding CYP97C19, a putative heme-containing carotenoid epsilon hydroxylase and member of the cytochrome P450 family. The corresponding CYP97C19 genomic locus on chromosome 1 was found to comprise a single-copy gene with nine introns. We expressed CYP97C19 cDNA under the control of the constitutive CaMV 35S promoter in the Arabidopsis thaliana lut1 knockout mutant, which lacks a functional CYP97C1 (LUT1) gene. The analysis of carotenoid levels and composition showed that lutein accumulated to high levels in the rosette leaves of the transgenic lines but not in the untransformed lut1 mutants. These results allowed the unambiguous functional annotation of maize CYP97C19 as an enzyme with strong zeinoxanthin epsilon-ring hydroxylation activity. PMID- 26030747 TI - Biologic Commonalities between Mental Illness and Addiction. AB - Epidemiologic studies indicate that co-occurring substance use disorders and psychiatric disorders are frequently found in clinical practice. From a neurobiologic perspective, what do these two seemingly different groups of disorders have in common? Currently, several hypotheses are postulated to explain the high rates of comorbidity. Chronic alcohol and drug use may lead to neuroadaptation in the biologic systems mediating psychiatric disorders. Conversely, co-occurring psychiatric and substance use disorders (SUDs) may represent phenotypic expressions of common premorbid neurobiologic abnormalities. Similar alterations in the dopamine-mediated reward system and various neurotransmitter systems including glutamate, gamma-aminobutyric acid, and serotonin are found in both SUDs and numerous psychiatric disorders. Stress and chronic distress with the resultant activation of the hypothalamic-pituitary adrenal axis and stress system has also been implicated in the pathophysiology of both psychiatric disorders and SUDs. Better understanding the commonalities between the two groups of disorders should lead to more efficacious treatments and targeted prevention strategies. PMID- 26030748 TI - Loss of SOX9 Expression Is Associated with PSA Recurrence in ERG-Positive and PTEN Deleted Prostate Cancers. AB - The transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in luminal cells of normal prostate glands (50% SOX9 positive) and 3,671 cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive), but was markedly increased in 3,116 ERG-fusion positive cancers (81% SOX9 positive, p<0.0001). While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG positive cancers (p<0.0001 each). SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive tumors harboring PTEN deletions (p=0.001), but had no significant effect in ERG-negative cancers or in tumors with normal PTEN copy numbers. In summary, the results of our study argue against a tumor-promoting role of SOX9 in prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive cancers harboring PTEN deletions. PMID- 26030750 TI - Epigenesis in acute myeloid leukemia: an update. AB - Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells leading to the disruption of normal hematopoiesis and bone marrow failure. While about 45% of AML cases show a normal karyotype with mutations detectable only at the molecular level, 55% display chromosomal rearrangements including deletions, insertions, segmental and complete monosomy/trisomy, and gene fusions created by translocations. However, AML is not induced by cytogenetic abnormalities and gene mutations alone: the current body of literature implicates abnormal epigenetics specifically, abnormal levels of DNA methylation, chemical modification of histones, and non-coding RNA expression-in the flawed regulation of the fundamental genes of hematopoiesis. Those three mechanisms may deviate the myeloid lineage from a healthy hematopoiesis to, instead, leukemogenesis. PMID- 26030749 TI - Discovery of novel inhibitors of human S-adenosylmethionine decarboxylase based on in silico high-throughput screening and a non-radioactive enzymatic assay. AB - Natural polyamines are small polycationic molecules essential for cell growth and development, and elevated level of polyamines is positively correlated with various cancers. As a rate-limiting enzyme of the polyamine biosynthetic pathway, S-adenosylmethionine decarboxylase (AdoMetDC) has been an attractive drug target. In this report, we present the discovery of novel human AdoMetDC (hAdoMetDC) inhibitors by coupling computational and experimental tools. We constructed a reasonable computational structure model of hAdoMetDC that is compatible with general protocols for high-throughput drug screening, and used this model in in silico screening of hAdoMetDC inhibitors against a large compound library using a battery of computational tools. We also established and validated a simple, economic, and non-radioactive enzymatic assay, which can be adapted for experimental high-throughput screening of hAdoMetDC inhibitors. Finally, we obtained an hAdoMetDC inhibitor lead with a novel scaffold. This study provides both new tools and a new lead for the developing of novel hAdoMetDC inhibitors. PMID- 26030751 TI - Multiple Copies of BCR/ABL Fusion Signals and t(3;21) in a Chronic Myeloid Leukemia: Patient with Blast Crisis - A Rare Event with Imatinib Mesylate (Gleevec)-Resistance in an Indian Patient. AB - Chronic myeloid leukaemia (CML) is characterized by the expression of BCR/ABL fusion gene, a constitutively activated tyrosine kinase that commonly results from the formation of the Philadelphia (Ph) chromosome after a t(9;22)(q34;q11) or variant rearrangement. The duplication of Ph chromosome is a recurring abnormality acquired during disease progression, whereas intrachromosomal amplification of BCR/ABL is a rare phenomenon and has been associated with imatinib mesylate (IM) therapy resistance. In the present study, we used G banding to identify the presence of identical isochromosomes of the Ph chromosome and t(3;21)(q26;q22) resulted from clonal evolution in IM-resistant patient. Fluorescence in situ hybridization (FISH) using dual color dual fusion probe analysis on interphase and metaphase nuclei confirmed the amplification of the fused BCR/ABL gene. Our study indicated that the progenitor of CML was BCR/ABL dependent through the amplification of Ph chromosome as a mechanism of resistance to IM therapy. The coexistence of BCR/ABL and t(3;21)(q26;q22) with RUNX1 rearrangement might play a pivotal role in the CML blast transformation. PMID- 26030753 TI - Does PCMH "Work"?--The Need to Use Implementation Science to Make Sense of Conflicting Results. PMID- 26030752 TI - Dietary MicroRNA Database (DMD): An Archive Database and Analytic Tool for Food Borne microRNAs. AB - With the advent of high throughput technology, a huge amount of microRNA information has been added to the growing body of knowledge for non-coding RNAs. Here we present the Dietary MicroRNA Databases (DMD), the first repository for archiving and analyzing the published and novel microRNAs discovered in dietary resources. Currently there are fifteen types of dietary species, such as apple, grape, cow milk, and cow fat, included in the database originating from 9 plant and 5 animal species. Annotation for each entry, a mature microRNA indexed as DM0000*, covers information of the mature sequences, genome locations, hairpin structures of parental pre-microRNAs, cross-species sequence comparison, disease relevance, and the experimentally validated gene targets. Furthermore, a few functional analyses including target prediction, pathway enrichment and gene network construction have been integrated into the system, which enable users to generate functional insights through viewing the functional pathways and building protein-protein interaction networks associated with each microRNA. Another unique feature of DMD is that it provides a feature generator where a total of 411 descriptive attributes can be calculated for any given microRNAs based on their sequences and structures. DMD would be particularly useful for research groups studying microRNA regulation from a nutrition point of view. The database can be accessed at http://sbbi.unl.edu/dmd/. PMID- 26030754 TI - Candidate Gene Association Analysis of Neuroblastoma in Chinese Children Strengthens the Role of LMO1. AB - Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and the most frequently diagnosed cancer in the first year of life. Previous genome wide association studies (GWAS) of Caucasian and African populations have shown that common single nucleotide polymorphisms (SNPs) in several genes are associated with the risk of developing NB, while few studies have been performed on Chinese children. Herein, we examined the association between the genetic polymorphisms in candidate genes and the risk of NB in Chinese children. In total, 127 SNPs in nine target genes, revealed by GWAS studies of other ethnic groups and four related lincRNAs, were genotyped in 549 samples (244 NB patients and 305 healthy controls). After adjustment for gender and age, there were 21 SNPs associated with NB risk at the two-sided P < 0.05 level, 11 of which were located in LMO1. After correction for multiple comparisons, only rs204926 in LMO1 remained significantly different between cases and controls (OR = 0.45, 95% CI: 0.31-0.65, adjusted P = 0.003). In addition, 16 haplotypes in four separate genes were significantly different between case and control groups at an unadjusted P value < 0.05, 11 of which were located in LMO1. A major haplotype, ATC, containing rs204926, rs110420, and rs110419, conferred a significant increase in risk for NB (OR = 1.82, 95% CI: 1.41-2.36, adjusted P < 0.001). The major finding of our study was obtained for risk alleles within the LMO1 gene. Our data suggest that genetic variants in LMO1 are associated with increased NB risk in Chinese children. PMID- 26030755 TI - Impaired Fracture Healing Caused by Deficiency of the Immunoreceptor Adaptor Protein DAP12. AB - Osteoclasts play an important role in bone metabolism, but their exact role in fracture healing remains unclear. DAP12 is an immunoadaptor protein with associated immunoreceptors on myeloid lineage cells, including osteoclasts. Its deficiency causes osteopetrosis due to suppression of osteoclast development and activation. In this report, we assessed the impact of DAP12 on the fracture healing process using C57BL/6 (B6) and DAP12-/- mice. Healing was evaluated using radiography, micro-CT, histology, immunohistochemistry and real-time RT-PCR. Radiography showed lower callus volume and lower callus radiolucency in DAP12-/- mice during later stages. Micro-CT images and quantitative structural analysis indicated that DAP12-/- mice developed calluses of dense trabecular structures and experienced deteriorated cortical shell formation on the surface. Histologically, DAP12-/- mice showed less cartilaginous resorption and woven bone formation. In addition, prominent cortical shell formation was much less in DAP12 /- mice. Immunohistochemistry revealed lower invasion of F4/80 positive monocytes and macrophages into the fracture hematoma in DAP12-/- mice. The expression levels of Col1a1, Col2a1 and Col10a1 in DAP12-/- mice increased and subsequently became higher than those in B6 mice. There was a decrease in the gene expression of Tnf during the early stages in DAP12-/- mice. Our results indicate that DAP12 deficiency impairs fracture healing, suggesting a significant role of DAP12 in the initial inflammatory response, bone remodeling and regeneration. PMID- 26030756 TI - Recovering more than tree cover: herbivores and herbivory in a restored tropical dry forest. AB - Intense and chronic disturbance may arrest natural succession, reduce environmental quality and lead to ecological interaction losses. Where natural succession does not occur, ecological restoration aims to accelerate this process. While plant establishment and diversity is promoted by restoration, few studies have evaluated the effect of restoration activities on ecological processes and animal diversity. This study assessed herbivory and lepidopteran diversity associated with two pioneer tree species growing in 4-year-old experimental restoration plots in a tropical dry forest at Sierra de Huautla, in Morelos, Mexico. The study was carried out during the rainy season of 2010 (July October) in eleven 50 x 50 m plots in three different habitats: cattle-excluded, cattle-excluded with restoration plantings, and cattle grazing plots. At the beginning of the rainy season, 10 juveniles of Heliocarpus pallidus (Malvaceae) and Ipomoea pauciflora (Convolvulaceae) were selected in each plot (N = 110 trees). Herbivory was measured in 10 leaves per plant at the end of the rainy season. To evaluate richness and abundance of lepidopteran larvae, all plants were surveyed monthly. Herbivory was similar among habitats and I. pauciflora showed a higher percentage of herbivory. A total of 868 lepidopteran larvae from 65 morphospecies were recorded. The family with the highest number of morphospecies (9 sp.) was Geometridae, while the most abundant family was Saturnidae, with 427 individuals. Lepidopteran richness and abundance were significantly higher in H. pallidus than in I. pauciflora. Lepidopteran richness was significantly higher in the cattle-excluded plots, while abundance was significantly higher in the non-excluded plots. After four years of cattle exclusion and the establishment of plantings, lepidopteran richness increased 20 fold in the excluded plots compared to the disturbed areas, whereas herbivory levels were equally high in both restored and disturbed sites. Restoration with plantings and exclusion of cattle and plantings was shown to be a successful strategy for attracting lepidopterans and cattle exclusion was the main factor explaining lepidopteran diversity. PMID- 26030757 TI - DynamicRoots: A Software Platform for the Reconstruction and Analysis of Growing Plant Roots. AB - We present a software platform for reconstructing and analyzing the growth of a plant root system from a time-series of 3D voxelized shapes. It aligns the shapes with each other, constructs a geometric graph representation together with the function that records the time of growth, and organizes the branches into a hierarchy that reflects the order of creation. The software includes the automatic computation of structural and dynamic traits for each root in the system enabling the quantification of growth on fine-scale. These are important advances in plant phenotyping with applications to the study of genetic and environmental influences on growth. PMID- 26030759 TI - Correction: BANF1 Is Downregulated by IRF1-Regulated MicroRNA-203 in Cervical Cancer. PMID- 26030758 TI - MiR-335 Regulates Hif-1alpha to Reduce Cell Death in Both Mouse Cell Line and Rat Ischemic Models. AB - Hypoxia inducible factor-1alpha facilitates cellular adaptation to hypoxic conditions. Hence its tight regulation is crucial in hypoxia related diseases such as cerebral ischemia. Changes in hypoxia inducible factor-1alpha expression upon cerebral ischemia influence the expression of its downstream genes which eventually determines the extent of cellular damage. MicroRNAs are endogenous regulators of gene expression that have rapidly emerged as promising therapeutic targets in several diseases. In this study, we have identified miR-335 as a direct regulator of hypoxia inducible factor-1alpha and as a potential therapeutic target in cerebral ischemia. MiR-335 and hypoxia inducible factor 1alpha mRNA showed an inverse expression profile, both in vivo and in vitro ischemic conditions. Given the biphasic nature of hypoxia inducible factor-1alpha expression during cerebral ischemia, miR-335 mimic was found to reduce infarct volume in the early time (immediately after middle cerebral artery occlusion) of embolic stroke animal models while the miR-335 inhibitor appears to be beneficial at the late time of stroke (24 hrs after middle cerebral artery occlusion). Modulation of hypoxia inducible factor-1alpha expression by miR-335 also influenced the expression of crucial genes implicated in neurovascular permeability, cell death and maintenance of the blood brain barrier. These concerted effects, resulting in a reduction in infarct volume bring about a beneficial outcome in ischemic stroke. PMID- 26030760 TI - Using the theory of planned behavior to improve treatment adherence in Mexican Americans with schizophrenia. AB - OBJECTIVE: Failure to adhere to treatment with antipsychotic medication is the most common cause of relapse among patients with schizophrenia. A novel multifamily group (MFG) intervention, informed by the Theory of Planned Behavior (TPB), demonstrated efficacy in increasing medication adherence and decreasing rehospitalizations in schizophrenia patients. This report explores the hypothesis that the improved outcomes obtained through the MFG approach were mediated by changes in the patients' attitudes toward medications, subjective norms-social influences, and perceived behavioral control of resources. METHOD: Data from a recently completed, randomized controlled trial of MFG was used to test the hypothesis that the improvement in adherence was mediated by the 3 TPB factors. Subjects were 174 Mexican American adults with schizophrenia-spectrum disorder who had participated in a study of MFG focused on improving medication adherence. Assessments occurred at baseline and at 4, 8, 12, 18, and 24 months. RESULTS: Path analysis revealed that the increased adherence associated with MFG was mediated by improvements in subjective norms but not attitudes toward medications nor perceived behavioral control. CONCLUSION: An MFG treatment specifically tailored to increase medication adherence among Mexican Americans with schizophrenia achieved its benefits by leveraging social influences through teaching family members how to support medication adherence in their ill relatives. PMID- 26030761 TI - Building an evidence-informed service array: Considering evidence-based programs as well as their practice elements. AB - OBJECTIVE: This study empirically examined options for building an evidence informed service array, comparing strategies to maximize the application of evidence-based treatment literature in a clinical service system. The overall goal was to determine the smallest set of treatments that could serve the largest percentage of clients. Solutions to this problem differ depending on how one defines "treatment." METHOD: Treatments were conceptualized as (a) programs (integrated treatments produced by specific research laboratories or investigators), and (b) collections of their constituent common procedures, referred to as practice elements. Programs listed by 2 separate government sanctioned registries were selected to illustrate the effects of "program" conceptualizations, and all available clinical trials testing the programs were analyzed. Practice elements were identified from these same studies and from studies of other treatments that met a standard of evidence but had not been organized into programs on these lists. Relevance mapping methodology was used to identify optimal sets of programs and practice elements. RESULTS: Among a large, diverse clinical population, results identified 11%-22% of youths for whom practice elements provide an evidence-informed treatment option whereas no programs meeting the standard of evidence were available on the registries. Results for the practice elements were able to be matched by a hybrid combination: "best" programs, which were then extended by practice elements. CONCLUSIONS: These results demonstrated that there are multiple ways to conceptualize treatments when planning a service array, and these options have significant implications regarding who can be served by treatments supported by evidence. PMID- 26030762 TI - Are there subtypes of panic disorder? An interpersonal perspective. AB - OBJECTIVE: Panic disorder (PD) is associated with significant personal, social, and economic costs. However, little is known about specific interpersonal dysfunctions that characterize the PD population. The current study systematically examined these interpersonal dysfunctions. METHOD: The present analyses included 194 patients with PD out of a sample of 201 who were randomized to cognitive-behavioral therapy, panic-focused psychodynamic psychotherapy, or applied relaxation training. Interpersonal dysfunction was measured with the Inventory of Interpersonal Problems-Circumplex (Horowitz, Alden, Wiggins, & Pincus, 2000). RESULTS: Individuals with PD reported greater levels of interpersonal distress than that of a normative cohort (especially when PD was accompanied by agoraphobia), but lower than that of a cohort of patients with major depression. There was no single interpersonal profile that characterized PD patients. Symptom-based clusters (with vs. without agoraphobia) could not be discriminated on core or central interpersonal problems. Rather, as revealed by cluster analysis based on the pathoplasticity framework, there were 2 empirically derived interpersonal clusters among PD patients that were not accounted for by symptom severity and were opposite in nature: domineering-intrusive and nonassertive. The empirically derived interpersonal clusters appear to be of clinical utility in predicting alliance development throughout treatment: Although the domineering-intrusive cluster did not show any changes in the alliance throughout treatment, the nonassertive cluster showed a process of significant strengthening of the alliance. CONCLUSIONS: Empirically derived interpersonal clusters in PD provide clinically useful and nonredundant information about individuals with PD. PMID- 26030763 TI - Molecular dynamic simulations reveal the structural determinants of Fatty Acid binding to oxy-myoglobin. AB - The mechanism(s) by which fatty acids are sequestered and transported in muscle have not been fully elucidated. A potential key player in this process is the protein myoglobin (Mb). Indeed, there is a catalogue of empirical evidence supporting direct interaction of globins with fatty acid metabolites; however, the binding pocket and regulation of the interaction remains to be established. In this study, we employed a computational strategy to elucidate the structural determinants of fatty acids (palmitic & oleic acid) binding to Mb. Sequence analysis and docking simulations with a horse (Equus caballus) structural Mb reference reveals a fatty acid-binding site in the hydrophobic cleft near the heme region in Mb. Both palmitic acid and oleic acid attain a "U" shaped structure similar to their conformation in pockets of other fatty acid-binding proteins. Specifically, we found that the carboxyl head group of palmitic acid coordinates with the amino group of Lys45, whereas the carboxyl group of oleic acid coordinates with both the amino groups of Lys45 and Lys63. The alkyl tails of both fatty acids are supported by surrounding hydrophobic residues Leu29, Leu32, Phe33, Phe43, Phe46, Val67, Val68 and Ile107. In the saturated palmitic acid, the hydrophobic tail moves freely and occasionally penetrates deeper inside the hydrophobic cleft, making additional contacts with Val28, Leu69, Leu72 and Ile111. Our simulations reveal a dynamic and stable binding pocket in which the oxygen molecule and heme group in Mb are required for additional hydrophobic interactions. Taken together, these findings support a mechanism in which Mb acts as a muscle transporter for fatty acid when it is in the oxygenated state and releases fatty acid when Mb converts to deoxygenated state. PMID- 26030764 TI - Pain Associated with Wound Care Treatment among Buruli Ulcer Patients from Ghana and Benin. AB - Buruli ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans. People living in remote areas in tropical Sub Saharan Africa are mostly affected. Wound care is an important component of BU management; this often needs to be extended for months after the initial antibiotic treatment. BU is reported in the literature as being painless, however clinical observations revealed that some patients experienced pain during wound care. This was the first study on pain intensity during and after wound care in BU patients and factors associated with pain. In Ghana and Benin, 52 BU patients above 5 years of age and their relatives were included between December 2012 and May 2014. Information on pain intensity during and after wound care was obtained during two consecutive weeks using the Wong-Baker Pain Scale. Median pain intensity during wound care was in the lower range (Mdn = 2, CV = 1), but severe pain (score > 6) was reported in nearly 30% of the patients. Nevertheless, only one patient received pain medication. Pain declined over time to low scores 2 hours after treatment. Factors associated with higher self-reported pain scores were; male gender, fear prior to treatment, pain during the night prior to treatment, and pain caused by cleaning the wound. The general idea that BU is painless is incorrect for the wound care procedure. This procedural pain deserves attention and appropriate intervention. PMID- 26030765 TI - Canine spontaneous head and neck squamous cell carcinomas represent their human counterparts at the molecular level. AB - Spontaneous canine head and neck squamous cell carcinoma (HNSCC) represents an excellent model of human HNSCC but is greatly understudied. To better understand and utilize this valuable resource, we performed a pilot study that represents its first genome-wide characterization by investigating 12 canine HNSCC cases, of which 9 are oral, via high density array comparative genomic hybridization and RNA-seq. The analyses reveal that these canine cancers recapitulate many molecular features of human HNSCC. These include analogous genomic copy number abnormality landscapes and sequence mutation patterns, recurrent alteration of known HNSCC genes and pathways (e.g., cell cycle, PI3K/AKT signaling), and comparably extensive heterogeneity. Amplification or overexpression of protein kinase genes, matrix metalloproteinase genes, and epithelial-mesenchymal transition genes TWIST1 and SNAI1 are also prominent in these canine tumors. This pilot study, along with a rapidly growing body of literature on canine cancer, reemphasizes the potential value of spontaneous canine cancers in HNSCC basic and translational research. PMID- 26030766 TI - Epigenetic regulation of bovine spermatogenic cell-specific gene boule. AB - Non-primate mammals have two deleted azoospermia (DAZ) family genes, DAZL and Boule; genes in this family encode RNA-binding proteins essential for male fertility in diverse animals. Testicular DAZL transcription is regulated by epigenetic factors such as DNA methylation. However, nothing is known about the epigenetic regulation of Boule. Here, we explored the role of DNA methylation in the regulation of the bovine Boule (bBoule) gene. We found that a long CpG island (CGI) in the bBoule promoter was hypermethylated in the testes of cattle-yak hybrids with low bBoule expression, whereas cattle had relatively low methylation levels (P < 0.01), and there was no difference in the methylation level in the short CGI of the gene body between cattle and cattle-yak hybrids (P > 0.05). We identified a 107 bp proximal core promoter region of bBoule. Intriguingly, the differences in the methylation level between cattle and cattle-yak hybrids were larger in the core promoter than outside the core promoter. An in vitro methylation assay showed that the core promoter activity of bBoule decreased significantly after M.SssI methylase treatment (P < 0.01). We also observed dramatically increased bBoule transcription in bovine mammary epithelial cells (BMECs) after treatment with the methyltransferase inhibitor 5-Aza-dC. Taken together, our results establish that methylation status of the core promoter might be involved in testicular bBoule transcription, and may provide new insight into the epigenetic regulation of DAZ family genes and clinical insights regarding male infertility. PMID- 26030767 TI - Metabolic syndrome and breast cancer risk: a case-cohort study nested in a multicentre italian cohort. AB - BACKGROUND: Metabolic syndrome (defined as at least three among abdominal obesity, high blood triglycerides, low high-density lipoprotein cholesterol, high blood glucose, and high blood pressure) is emerging as a risk factor for breast cancer; however few studies - most confined to postmenopausal women - have investigated associations between breast cancer risk and metabolic syndrome. The purpose of this study was to examine the association between metabolic syndrome and its components, and risk of breast cancer in postmenopausal and premenopausal women. METHODS: We performed a case-cohort study on 22,494 women recruited in 1993-1998 to four Italian centres (Turin, Varese, Naples, Ragusa) of the European Prospective Investigation into Cancer and Nutrition (EPIC) and followed-up for up to 15 years. A random subcohort of 565 women was obtained and 593 breast cancer cases were diagnosed. Hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounders, were estimated by Prentice-weighted Cox proportional hazards models. RESULTS: Presence of metabolic syndrome was associated with significantly increased breast cancer risk in all women (HR 1.52, 95%CI 1.14-2.02). When the analyses were repeated separately for menopausal status, the association was limited to postmenopausal women (HR 1.80, 95%CI 1.22 2.65) and absent in premenopausal women (HR 0.71, 95%CI 0.43-1.16); P for interaction between metabolic syndrome and menopausal status was 0.001. Of metabolic syndrome components, only high blood glucose was significantly associated with increased breast cancer risk in all women (HR 1.47, 95%CI 1.13 1.91) and postmenopausal women (HR 1.89, 95%CI 1.29-2.77), but not premenopausal women (HR 0.80, 95%CI 0.52-1.22; P interaction=0.004). CONCLUSIONS: These findings support previous data indicating that metabolic syndrome is an important risk factor for breast cancer in postmenopausal women, but not in premenopausal women, and suggest that prevention of metabolic syndrome through lifestyle changes could confer protection against breast cancer. PMID- 26030768 TI - K2 and Spice use among a cohort of college students in southeast region of the USA. AB - BACKGROUND: K2 and Spice consist of an herbal blend of plant matter and chemical synthetic cannabinoids. These substances emerged in the early 2000s as a popular alternative to marijuana among youth and young adults. OBJECTIVES: This study sought to identify rates and correlates of K2 and Spice at college entry and first use during college. METHODS: In Fall 2010, 3146 students at 11 colleges in North Carolina and Virginia were recruited to participate in a longitudinal cohort survey. The cohort was invited to participate in a total of six surveys over their college career. Random-effects logistic regression models were used to identify factors associated with lifetime K2 and Spice use at college entry and first use during college, adjusting for clustering within schools and sample weights. RESULTS: Weighted lifetime prevalence of K2 and Spice use at college entry was 7.6%. An additional 6.6% of students reported first use during college. By the cohort's fourth year, 17.0% reported lifetime K2 and Spice use. While lifetime prevalence increased, past 6-month prevalence decreased substantially over time. K2 and Spice use at college entry was associated with sensation seeking; hookah, marijuana, and illicit drug use; and low religiosity. First use during college was associated with having a father with less than a four-year degree; alcohol and hookah use. CONCLUSION: Universities should ensure that prevention efforts address current substance use, including K2/Spice, and that treatment options are available for first year students who use substances. PMID- 26030769 TI - Spatial heterogeneity, host movement and mosquito-borne disease transmission. AB - Mosquito-borne diseases are a global health priority disproportionately affecting low-income populations in tropical and sub-tropical countries. These pathogens live in mosquitoes and hosts that interact in spatially heterogeneous environments where hosts move between regions of varying transmission intensity. Although there is increasing interest in the implications of spatial processes for mosquito-borne disease dynamics, most of our understanding derives from models that assume spatially homogeneous transmission. Spatial variation in contact rates can influence transmission and the risk of epidemics, yet the interaction between spatial heterogeneity and movement of hosts remains relatively unexplored. Here we explore, analytically and through numerical simulations, how human mobility connects spatially heterogeneous mosquito populations, thereby influencing disease persistence (determined by the basic reproduction number R0), prevalence and their relationship. We show that, when local transmission rates are highly heterogeneous, R0 declines asymptotically as human mobility increases, but infection prevalence peaks at low to intermediate rates of movement and decreases asymptotically after this peak. Movement can reduce heterogeneity in exposure to mosquito biting. As a result, if biting intensity is high but uneven, infection prevalence increases with mobility despite reductions in R0. This increase in prevalence decreases with further increase in mobility because individuals do not spend enough time in high transmission patches, hence decreasing the number of new infections and overall prevalence. These results provide a better basis for understanding the interplay between spatial transmission heterogeneity and human mobility, and their combined influence on prevalence and R0. PMID- 26030770 TI - An investigative study into psychological and fertility sequelae of gestational trophoblastic disease: the impact on patients' perceived fertility, anxiety and depression. AB - OBJECTIVES: Gestational Trophoblastic Disease (GTD) comprises a group of disorders that derive from the placenta. Even if full recovery is generally expected, women diagnosed with GTD have to confront: the loss of a pregnancy, a potentially life-threatening diagnosis and delays in future pregnancies. The aim of the study is to evaluate the psychological impact of GTD, focusing on perceived fertility, depression and anxiety. METHODS: 37 patients treated for GTD at San Raffaele Hospital, Milan, took part in the study. The STAI-Y (State-Trait Anxiety Inventory), the BDI-SF (Beck Depression Scale-Short Form) and the FPI (Fertility Problem Inventory) were used. Patients were grouped on the basis of presence of children (with or without), age (< or >=35) and type of diagnosis (Hydatidiform Mole, HM, or Gestational Trophoblastic Neoplasia, GTN). Differences in the values between variables were assessed by a t-type test statistic. Three way ANOVAs were also carried out considering the same block factors. RESULTS: The study highlights that women suffering from GTN had higher depression scores compared to women suffering from HM. A significant correlation was found between anxiety (state and trait) and depression. Younger women presented higher Global Stress scores on the FPI, especially tied to Need for Parenthood and Relationship Concern subscales. Need for Parenthood mean scores significantly varied between women with and without children too. CONCLUSIONS: We can conclude that fertility perception seems to be negatively affected by GTD diagnosis, particularly in younger women and in those without children. Patients should be followed by a multidisciplinary team so as to be supported in the disease's psychological aspects too. PMID- 26030771 TI - Relationship between the use of statins and patient survival in colorectal cancer: a systematic review and meta-analysis. AB - BACKGROUND: Studies have indicated that statins influence the risks and mortality rates of several types of solid tumors. However, the association between statin use and survival in patients with colorectal cancer (CRC) remains unclear. METHODS: We searched the PubMed and Embase databases for relevant studies published up to September 2014 that assessed statin use and CRC prognosis. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). The secondary outcomes were disease-free survival (DFS) and recurrence-free survival (RFS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled with Mantel-Haenszel random-effect modeling. All statistical tests were two-sided. RESULTS: Four studies on post-diagnosis statin therapy and five studies on pre-diagnosis statin use were included in our meta-analysis of 70,608 patients. Compared with the non-users, the patients with post-diagnosis statin use gained survival benefits for OS (HR 0.76; 95% CI: 0.68 to 0.85, P<0.001) and CSS (HR 0.70; 95% CI: 0.60 to 0.81, P<0.001). In addition, we observed that pre-diagnosis statin use prolonged the survival of patients with CRC for OS (HR 0.70; 95% CI: 0.54 to 0.91, P=0.007) and CSS (HR 0.80; 95% CI: 0.74 to 0.86, P<0.001). However, we did not observe a survival benefit for DFS (HR 1.13; 95% CI: 0.78 to 1.62, P=0.514) or RFS (HR 0.98; 95% CI: 0.36 to 2.70, P=0.975) in the CRC patients with post-diagnosis statin use. CONCLUSIONS: Statin use before or after cancer diagnosis is related to reductions in overall and cancer-specific mortality in colorectal cancer survivors. PMID- 26030773 TI - Walking through doorways causes forgetting: Younger and older adults. AB - Previous research on event cognition has found that walking through doorways can cause forgetting. The explanation for this finding is that there is a competition between event models, producing interference, and depressing performance. The current study explored the degree to which this might be affected by the natural aging process. This is of interest because there is some evidence that older adults have trouble coordinating sources of interference, which is what is thought to underlie this effect. This would suggest that older adults should do worse on this task. Alternatively, there is also evidence that older adults are typically not disrupted at the event level of processing per se. This would suggest that older adults should perform similarly to younger adults on this task. In the study reported here, younger and older participants navigated through a virtual environment, and memory was tested with probes either before or after a shift and for objects that were associated with the participant (i.e., just picked up). In general, both younger and older adults had memory disrupted after walking through a doorway. Importantly, the magnitude of this disruption was similar in the 2 age groups. This is consistent with the idea that processing at the event level is relatively unaffected by the natural aging process. (PsycINFO Database Record PMID- 26030772 TI - Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations. AB - T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3zeta and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with gamma irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-gamma and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1 specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire. PMID- 26030774 TI - The effects of varying contextual demands on age-related positive gaze preferences. AB - Despite many studies on the age-related positivity effect and its role in visual attention, discrepancies remain regarding whether full attention is required for age-related differences to emerge. The present study took a new approach to this question by varying the contextual demands of emotion processing. This was done by adding perceptual distractions, such as visual and auditory noise, that could disrupt attentional control. Younger and older participants viewed pairs of happy neutral and fearful-neutral faces while their eye movements were recorded. Facial stimuli were shown either without noise, embedded in a background of visual noise (low, medium, or high), or with simultaneous auditory babble. Older adults showed positive gaze preferences, looking toward happy faces and away from fearful faces; however, their gaze preferences tended to be influenced by the level of visual noise. Specifically, the tendency to look away from fearful faces was not present in conditions with low and medium levels of visual noise but was present when there were high levels of visual noise. It is important to note, however, that in the high-visual-noise condition, external cues were present to facilitate the processing of emotional information. In addition, older adults' positive gaze preferences disappeared or were reduced when they first viewed emotional faces within a distracting context. The current results indicate that positive gaze preferences may be less likely to occur in distracting contexts that disrupt control of visual attention. PMID- 26030775 TI - Caring more and knowing more reduces age-related differences in emotion perception. AB - Traditional emotion perception tasks show that older adults are less accurate than are young adults at recognizing facial expressions of emotion. Recently, we proposed that socioemotional factors might explain why older adults seem impaired in lab tasks but less so in everyday life (Isaacowitz & Stanley, 2011). Thus, in the present research we empirically tested whether socioemotional factors such as motivation and familiarity can alter this pattern of age effects. In 1 task, accountability instructions eliminated age differences in the traditional emotion perception task. Using a novel emotion perception paradigm featuring spontaneous dynamic facial expressions of a familiar romantic partner versus a same-age stranger, we found that age differences in emotion perception accuracy were attenuated in the familiar partner condition, relative to the stranger condition. Taken together, the results suggest that both overall accuracy as well as specific patterns of age effects differ appreciably between traditional emotion perception tasks and emotion perception within a socioemotional context. PMID- 26030776 TI - The double burden of age and major depressive disorder on the cognitive control network. AB - Poor cognitive control (CC) is common among older individuals with major depressive disorder (OMDD). At the same time, studies of CC in OMDD with fMRI are relatively limited and often have small samples. The present study was conducted to further examine poor CC in OMDD with early onset depression, as well as to investigate the interactive effects of MDD and aging on cognitive control. Twenty OMDD, 17 older never-depressed comparisons (ONDC), 16 younger adults with MDD (YMDD), and 18 younger never-depressed comparisons (YNDC) participated. All participants completed the Go level of the Parametric Go/No-Go Test, which requires sustained attention and inhibitory control while undergoing functional MRI (fMRI). YNDC were faster in reaction times (RTs) to go targets relative to the other 3 groups, and the YMDD group was faster than the OMDD group. fMRI effects of both age and diagnosis were present, with greater activation in MDD, and in aging. Additionally, the interaction of age and MDD was also significant, such that OMDD exhibited greater recruitment of fronto-subcortical regions relative to older comparisons. These results are consistent with prior research reporting that OMDD recruit more fronto-striatal regions in order to perform at the same level as their never-depressed peers, here on a task of sustained attention and inhibitory control. There may be an interaction of cognitive aging and depression to create a double burden on the CC network in OMDD, including possible fronto-striatal compensation during CC that is unique to OMDD, as younger MDD individuals do not show this pattern. PMID- 26030777 TI - Dual-Microstructured Porous, Anisotropic Film for Biomimicking of Endothelial Basement Membrane. AB - Human endothelial basement membrane (BM) plays a pivotal role in vascular development and homeostasis. Here, a bioresponsive film with dual-microstructured geometries was engineered to mimic the structural roles of the endothelial BM in developing vessels, for vascular tissue engineering (TE) application. Flexible poly(epsilon-caprolactone) (PCL) thin film was fabricated with microscale anisotropic ridges/grooves and through-holes using a combination of uniaxial thermal stretching and direct laser perforation, respectively. Through optimizing the interhole distance, human mesenchymal stem cells (MSCs) cultured on the PCL film's ridges/grooves obtained an intact cell alignment efficiency. With prolonged culturing for 8 days, these cells formed aligned cell multilayers as found in native tunica media. By coculturing human umbilical vein endothelial cells (HUVECs) on the opposite side of the film, HUVECs were observed to build up transmural interdigitation cell-cell contact with MSCs via the through-holes, leading to a rapid endothelialization on the PCL film surface. Furthermore, vascular tissue construction based on the PCL film showed enhanced bioactivity with an elevated total nitric oxide level as compared to single MSCs or HUVECs culturing and indirect MSCs/HUVECs coculturing systems. These results suggested that the dual-microstructured porous and anisotropic film could simulate the structural roles of endothelial BM for vascular reconstruction, with aligned stromal cell multilayers, rapid endothelialization, and direct cell-cell interaction between the engineered stromal and endothelial components. This study has implications of recapitulating endothelial BM architecture for the de novo design of vascular TE scaffolds. PMID- 26030779 TI - High-Performance Poly(ethylene oxide)/Molybdenum Disulfide Nanocomposite Films: Reinforcement of Properties Based on the Gradient Interface Effect. AB - Herein, the molybdenum disulfide (MoS2) was simultaneously exfoliated and noncovalently functionalized by ultrasonication in a Pluronic aqueous solution and then was used to prepare the poly(ethylene oxide) (PEO) based nanocomposite films. The homogeneous dispersion of MoS2 and strong nanosheets/matrix interfacial adhesion were confirmed by representative electron microscopes. The considerable barrier action of the effective MoS2 nanosheets obviously restricted the ordering of crystal lamellae and the motion of polymer chains and then resulted in the formation of the devastated spherocrystal structure and morphological alterations in the nanocomposites, which were confirmed by polarized optical microscopy and the high value of the glass transition temperature. Importantly, MoS2 nanosheets hold great promise in reinforcing the thermal stability and mechanical property of polymer by increasing the effective volume of MoS2 nanosheets. A substantial reinforcement effect of PEO/MoS2 composite films was achieved: even at a relatively low loading level (0.9 wt %), 88.1% increase in Young's modulus, 72.7% increase in stress-at-failure, and 62.1 degrees C increment of the temperature corresponding to half weight loss were obtained. These significant reinforcements can be attributed to the gradient interface region, which could effectively transfer the stress from the weak polymer chains to the robust nanosheets, thus endowing the PEO/MoS2 composite films with excellent properties. PMID- 26030778 TI - Selection of Reference Genes for RT-qPCR Analysis in the Monarch Butterfly, Danaus plexippus (L.), a Migrating Bio-Indicator. AB - Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a powerful technique to quantify gene expression. To facilitate gene expression study and obtain accurate results, normalization relative to stably expressed reference genes is crucial. The monarch butterfly, Danaus plexippus (L.), is one of the most recognized insect species for its spectacular annual migration across North America. Besides its great voyages, D. plexippus has drawn attention to its role as a bio-indicator, ranging from genetically modified organisms (GMOs) to natural ecosystems. In this study, nine reference genes from D. plexippus genome were selected as the candidate reference genes. The expression profiles of these candidates under various biotic and abiotic conditions were evaluated using the four readily available computational programs, BestKeeper, Normfinder, geNorm, and DeltaCt method, respectively. Moreover, RefFinder, a web-based computational platform integrating the four above mentioned algorisms, provided a comprehensive ranking of the stability of these reference genes. As a result, a suite of reference genes were recommended for each experimental condition. Specifically, elongation factor 1alpha (EF1A) and ribosomal protein 49 (RP49) were the most stable reference genes, respectively, under biotic (development, tissue, and sex) and abiotic (photoperiod, temperature, and dietary RNAi) conditions. With the recent release of a 273-million base pair draft genome, results from this study allow us to establish a standardized RT-qPCR analysis and lay a foundation for the subsequent genomic and functional genomic research in D. plexippus, a major bio-indicator and an emerging model for migratory animals. PMID- 26030780 TI - Technically assisted rehabilitation - approaches for the upper extremity. PMID- 26030781 TI - Clinical and molecular characterization of five Spanish kindreds with X-linked adrenal hypoplasia congenita: atypical findings and a novel mutation in NR0B1. AB - BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is caused by NR0B1 (DAX1) gene mutations. Affected male children suffer from adrenal insufficiency, leading to a salt-wasting crisis in early infancy and hypogonadotropic hypogonadism in adulthood. OBJECTIVE: To characterize clinically and at the molecular level a cohort of Spanish patients with AHC. PATIENTS AND METHODS: Nine boys (from five families) with AHC were screened for NR0B1 mutations. Clinical and endocrine evaluations were recorded. RESULTS: NR0B1 gene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants. CONCLUSIONS: AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for NR0B1 mutations is indicated if there is a suspicion of an X-linked adrenal insufficiency in order to proceed with the appropriate therapy and genetic counseling. PMID- 26030782 TI - Dyshormonogenesis seems to be more frequent in a group of Cameroonian children with congenital hypothyroidism. AB - Congenital hypothyroidism is a main congenital endocrine disorder, affecting 1 in 4000 births. It is not well described in sub-Saharan countries, and to draw attention to that issue, we decided to describe affected pediatric patients. We retrospectively analyzed the records of eight patients over a period of 6 years. We analyzed clinical sings of hypothyroidism and psychomotor development; hormonal assays and thyroid ultrasound were performed. We included four boys and four girls aged from 3 to 84 months at diagnosis with a median thyroid stimulating hormone (TSH) level of 156.5 mUI/L. All except one present with a moderate psychomotor delay. Other clinical signs were classical for hypothyroidism. Thyroid ultrasound performed showed a goiter in half of patients, a normal gland in three of them and a hypoplasic gland in the last one, consonant with dyshormonogenesis. We therefore concluded that dyshormonogenesis seems to be more frequent in our context, and this raised the issue of neonatal screening of hypothyroidism in Africa. PMID- 26030783 TI - The spectrum of 46XY disorders of sex development in a University centre in Saudi Arabia. AB - BACKGROUND: The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. The spectrum of the 46XY (DSD) is so broad. In this study, we reviewed the clinical spectrum of a cohort of patients with 46XY DSD in a tertiary institute in the Middle East over two decades. OBJECTIVE: To define the clinical spectrum of 46XY DSD in a major teaching hospital, Riyadh, Saudi Arabia. MATERIALS AND METHODS: This is a retrospective, case series hospital-based study. The case notes, laboratory investigations, and imaging studies were reviewed for patients with 46XY DSD over a 20 years period (1989-2010) at King Khalid University Hospital, Riyadh, Saudi Arabia. Molecular genetics were not available in all patients. RESULTS: During the period under review; a total of 56 patients were seen with 46XY DSD due to variable etiologies. Androgen insensitivity syndromes (AIS) and 5-alpha-reductase deficiency were among the commonest (44.6%), with multiple siblings involvement within the family. Of these, 16 patients were showing variable degrees of insensitivity ranging between complete (n=5, 31.2%) and partial (n=11, 68.8%) insensitivity, whereas in nine patients the diagnosis of 5-alpha-reductase deficiency was entertained based on hormonal studies. Of interest to see was a high number of patients (n=14, 25%) either with a localized congenital anomalies such as the cloacal anomalies or generalized congenital malformations following the pattern of certain syndromes. CONCLUSION: A wide spectrum of causes were noted. Androgen insensitivity syndrome was the commonest. In Saudi Arabia, where consanguineous mating is high, 5-alpha reductase is also a common cause of 46XY DSD. PMID- 26030784 TI - Anti-Mullerian hormone in children: a ten-year prospective longitudinal study (EarlyBird 39). AB - BACKGROUND: Anti-Mullerian hormone (AMH) is produced by Sertoli cells of the testes and granulosa cells of the ovary. There are limited prospective longitudinal data assessing AMH concentrations throughout childhood in both sexes. OBJECTIVE: This study aimed to examine AMH throughout childhood with particular reference to the relationship of AMH to pubertal development in both sexes. DESIGN: This is a prospective longitudinal non-intervention cohort study with annual sampling for participants aged 5-14 years. SETTING: Community cohort study. PARTICIPANTS: A total of 307 healthy children (170 boys) recruited at 5 years from randomly selected schools in Plymouth, UK, participated in this study. Data sets are complete in 76% of the children at 14 years of age. MAIN OUTCOME MEASURE(S): Annual measures of serum AMH, follicle stimulating hormone (FSH) and luteinising hormone (LH), Tanner stage (TS). RESULTS: Boys: AMH was stable from 5 to 7 years, increased slightly from 8 to 10 years, then declined at TS2. This decline was preceded by rising FSH and the appearance of LH. AMH correlated inversely with gonadotrophic hormones during puberty. Girls: AMH increased slightly between 6 and 10 years, peaking during the final prepubertal year before returning to near baseline levels at TS3. Inverse correlations between AMH and FSH were apparent during the prepubertal years. CONCLUSIONS: Our longitudinal data clarified the development of individual AMH levels over a 10-year period. We described modest late prepubertal peaks in both boys and girls, and confirmed the pubertal decline in boys. The inverse association of AMH with gonadotrophins in young females supports its role as a marker of ovarian function, while the precise role for AMH in relation to testicular function in young males remains unclear. PMID- 26030785 TI - Primary systemic carnitine deficiency: a Turkish case with a novel homozygous SLC22A5 mutation and 14 years follow-up. AB - Systemic primary carnitine deficiency is an autosomal recessive disorder caused by the deficiency of carnitine transporter. Main features are cardiomyopathy, myopathy and hypoglycemic encephalopathy. We report a Turkish case with a novel SLC22A5 gene mutation presented with a pure cardiac phenotype. During the 14-year follow-up study, cardiac functions were remained within a normal range with oral L-carnitine supplementation. PMID- 26030786 TI - Can school health check-ups serve as screening tool for growth anomalies and obesity in children? AB - OBJECTIVE: To evaluate the prevalence of growth disorders and obesity in schoolchildren and determine whether school health check-ups are effective in their screening. Subjects-methods: Analysis of anonymized growth and body mass index (BMI) data from 2887 children attending the 3rd grade from 2008 to 2009 after selection of 75 elementary schools in Paris. RESULTS: Linear growth velocity was abnormal in 198 children. Height and weight were above the French reference values (+ 0.9 +/- 1.2 SD and + 1 +/- 1.7 SD, respectively). BMI was higher, compared to reference values (+ 0.4 +/- 1.4 SD). At their last check-up, 20.9% of children had a BMI > + 2 SD. CONCLUSIONS: School health check-ups constitute a good screening tool for growth and obesity. However, further work is needed to determine the most effective modality. The reference values currently used in France are no longer suitable and new reference charts need to be established. The high prevalence of obesity in schoolchildren remains a public health challenge. PMID- 26030787 TI - Evaluation of the relationship between serum adropin levels and blood pressure in obese children. AB - BACKGROUND: The prevalence of obesity and related cardiovascular comorbodities is increasing rapidly. Adipokines play a major role in the pathogenesis of obesity related inflammation and hypertension. AIM: The aim of this study was to evaluate the serum adropin levels in obese children and to determine the relationship between adropin levels and blood pressure (BP) in the pediatric age group. METHODS: Forty obese children (mean age: 12.5 +/- 2.5 years; male/female ratio: 18/22) and 15 healthy controls (mean age: 15 +/- 3.14 years; male/female ratio: 5/15) were included in the study. Serum adropin levels, and a number of laboratory and clinical variables were compared. Ambulatory blood pressure monitoring was performed on obese subjects. Relationship between adropin levels and BP variables was examined. RESULTS: Serum adropin levels were significantly lower in obese subjects than in healthy controls (193.56 +/- 94 vs. 289 +/- 187 pg/mL, p = 0.03). Adropin levels were correlated negatively with body mass index z-score (r = -0.56; p = 0.034). There was no correlation between serum adropin levels and laboratory variables in obese subjects. Five of the patients (12.5%) were nondipper, and nine of the patients (22.5%) had hypertension. There was no significant correlation between serum adropin levels and BP variables. CONCLUSION: Serum adropin levels were significantly lower in obese children; however, there was no correlation between serum adropin levels and BP variables. Further studies are needed to determine the role of adipokines on BP. PMID- 26030788 TI - Response of vitamin D binding protein and free vitamin D concentrations to vitamin D supplementation in hospitalized premature infants. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between 25(OH)D, Vitamin D Binding Protein (DBP), and free vitamin D in premature infants. METHODS: Thirty-two infants <32 weeks' gestation were randomized to two different levels of vitamin D3 supplementation (400 vs. 800 IU/day). 25(OH)D levels were measured by LC-MS/MS; DBP was measured by validated ELISA. Free vitamin D was calculated using molar ratios of 25(OH)D and DBP. The Wilcoxon signed rank test was used to compare DBP, free D and 25(OH)D levels; Spearman's correlation coefficients were used to assess correlations. RESULTS: The mean gestational age at birth was 30.5 weeks; mean birth weight was 1405 g. Mean 25(OH)D levels at birth were 17.3 ng/mL; DBP levels were 297 mg/L, and estimated free vitamin D levels were 18.9. There was a statistically significant change in 25(OH)D levels after 8 weeks (24.6 vs. 39.1 ng/mL in the 400 vs. 800 group, respectively, p=0.02). DBP levels from birth to 8 weeks showed a statistically significant decrease (267 vs. 208, p=0.04). Estimated free 25(OH)D concentrations increased over the study period, from 18.9 at birth to 64.7 at 8 weeks of age (p=0.0001). Free vitamin D levels at birth were associated with global DEXA bone mineral content at discharge from the NICU (r=0.58, p=0.05). CONCLUSION: Supplementation with vitamin D3 increased the free portion of the vitamin D metabolite, providing increased bioavailable substrate. Improved free vitamin D levels may improve measurable outcomes such as bone mineral content and deserve further evaluation. PMID- 26030789 TI - Clinical characteristics of children referred for signs of early puberty before age 3. AB - BACKGROUND: Signs of puberty in very young children are often benign, but the evaluation needed and follow-up are controversial. OBJECTIVES: The study had three objectives: 1) to analyze the frequency of diagnoses in children <3 years referred for early puberty; 2) to examine the usefulness of lab testing; and 3) to identify red flags indicating a more serious diagnosis. METHODS: Charts of all children younger than age 3 referred for early puberty between 7/09 and 6/13 were reviewed. RESULTS: Of 275 patients, 156 (57%) were diagnosed with premature thelarche (PT), 69 (25%; 56 F/13M) with genital hair of infancy (GHI) and 37 (13%, all F) with both (GHI/PT). Six patients had axillary odor only. Four patients had more serious diagnoses, one each with congenital adrenal hyperplasia (CAH), non-classical CAH, McCune-Albright syndrome and central precocious puberty (CPP). Diagnoses did not change in those who returned for follow-up. Hormone tests revealed that none of the PT patients had elevation of both luteinizing hormone (LH) and estradiol, and half of the GHI patients tested had mildly elevated DHEA-S but normal testosterone and 17-OH progesterone. CONCLUSIONS: Very few children referred for puberty at <3 years appear to have a serious underlying diagnosis, and progression of PT to CPP was not identified in this series. Hormone testing is unlikely to be helpful in typical cases of PT, GHI or both, and many such cases may be followed in the primary care setting after initial clinical evaluation. PMID- 26030790 TI - Rett syndrome and precocious puberty association. PMID- 26030791 TI - Inhibition of metalloproteinase and proteasome activities in colon cancer cells by citrus peel extracts. AB - BACKGROUND: Citrus peels are consumed in the form of infusions, candy or wine, based on their well-documented nutritional and medicinal properties. This study sought to investigate the effect of some citrus peels' [grapefruit (Citrus paradisii), orange (Citrus sinensis) and shaddock (Citrus maxima)] extracts on matrix metalloproteinase (MMP) and proteasome activities in primary human colonic tumor (Caco-2) and the metastatic cell lines (LoVo and LoVo/ADR) in a bid to explain the possible mechanism by which the peels could manage/prevent colon cancer. METHODS: The inhibition of MMP and proteasome activities in the cells by the peel extracts, as well as the identification of phenolic compounds using high performance liquid chromatography with diode-array detection (HPLC-DAD), was determined. RESULTS: Orange peel extracts had the strongest inhibition of MMP in Caco-2 and LoVo cells, while shaddock had the least. Shaddock peel extracts also had the least MMP inhibition in LoVo/ADR lysates. Grapefruit had the least proteasome inhibition in Caco-2 and LoVo lysates, while there was no significant (p>0.05) difference in the proteasome inhibition of the peel extracts in LoVo/ADR lysates. The extracts inhibited proteasome activity in extract-treated cells, and HPLC fingerprinting of the extracts revealed the presence of some phenolic compounds such as quercetin, caffeic acid, kaempferol, catechin and naringin. CONCLUSIONS: The inhibition of MMP and proteasome activities in colon cancer cell lines suggests the potential use of citrus peels as functional food in the management and/or prevention of colon cancer. PMID- 26030792 TI - Theranos phenomenon: promises and fallacies. AB - Recently, spectacular advances in diagnostic technologies, genomics, etc. offer unprecedented opportunities for widespread testing of asymptomatic individuals, in the hope that this testing will unravel early disease signs which could lead to preventative or more effective therapeutic measures. In particular, one commercial organization, Theranos, promises to revolutionize diagnostics by offering multi-analyte testing at low prices in commercial outlets, thus challenging the current paradigm of targeted and centralized diagnostic testing. In this paper, I analyze the Theranos technology and their promises, and contrast this information with the currently used technologies, to show that most of the company's claims are exaggerated. While it remains to be seen if this technology will revolutionize diagnostics, in this Opinion Paper, I also draw attention of associated issues, such as self-testing and self-interpretation of results, over testing, over-diagnosis and over-treatment, along with their associated harms. As the public is bombarded daily with new and revolutionary health-related advances, it is time to balance the enthusiasm of the seemingly obvious huge gains, by also explaining the associated possible harms. PMID- 26030793 TI - Bayes factors based on robust TDT-type tests for family trio design. AB - Adaptive transmission disequilibrium test (aTDT) and MAX3 test are two robust efficient association tests for case-parent family trio data. Both tests incorporate information of common genetic models including recessive, additive and dominant models and are efficient in power and robust to genetic model specifications. The aTDT uses information of departure from Hardy-Weinberg disequilibrium to identify the potential genetic model underlying the data and then applies the corresponding TDT-type test, and the MAX3 test is defined as the maximum of the absolute value of three TDT-type tests under the three common genetic models. In this article, we propose three robust Bayes procedures, the aTDT based Bayes factor, MAX3 based Bayes factor and Bayes model averaging (BMA), for association analysis with case-parent trio design. The asymptotic distributions of aTDT under the null and alternative hypothesis are derived in order to calculate its Bayes factor. Extensive simulations show that the Bayes factors and the p-values of the corresponding tests are generally consistent and these Bayes factors are robust to genetic model specifications, especially so when the priors on the genetic models are equal. When equal priors are used for the underlying genetic models, the Bayes factor method based on aTDT is more powerful than those based on MAX3 and Bayes model averaging. When the prior placed a small (large) probability on the true model, the Bayes factor based on aTDT (BMA) is more powerful. Analysis of a simulation data about RA from GAW15 is presented to illustrate applications of the proposed methods. PMID- 26030794 TI - Weighted Kolmogorov Smirnov testing: an alternative for Gene Set Enrichment Analysis. AB - Gene Set Enrichment Analysis (GSEA) is a basic tool for genomic data treatment. Its test statistic is based on a cumulated weight function, and its distribution under the null hypothesis is evaluated by Monte-Carlo simulation. Here, it is proposed to subtract to the cumulated weight function its asymptotic expectation, then scale it. Under the null hypothesis, the convergence in distribution of the new test statistic is proved, using the theory of empirical processes. The limiting distribution needs to be computed only once, and can then be used for many different gene sets. This results in large savings in computing time. The test defined in this way has been called Weighted Kolmogorov Smirnov (WKS) test. Using expression data from the GEO repository, tested against the MSig Database C2, a comparison between the classical GSEA test and the new procedure has been conducted. Our conclusion is that, beyond its mathematical and algorithmic advantages, the WKS test could be more informative in many cases, than the classical GSEA test. PMID- 26030795 TI - Application of the fractional-stable distributions for approximation of the gene expression profiles. AB - Nowadays, there are reliable scientific data highlighting that the probability density function of the gene expression demonstrates a number of universal features commonly observed in the microarray experiments. First of all, these distributions demonstrate the power-law asymptotics and, secondly, the shape of these distributions is inherent for all organisms and tissues. This fact leads to appearance of a number of works where authors investigate various probability distributions for an approximation of the empirical distributions of the gene expression. Nevertheless, all these distributions are not a limit distribution and are not a solution of any equation. These facts, in our opinion, are essential shortcoming of these probability laws. Besides, the expression of the individual gene is not an accidental phenomenon and it depends on the expression of the other genes. This suggests an existence of the genic regulatory net in a cell. The present work describes the class of the fractional-stable distributions. This class of the distributions is a limit distribution of the sums of independent identically distributed random variables. Due to the power law asymptotics, these distributions are applicable for the approximation of the experimental densities of the gene expression for microarray experiments. The parameters of the fractional stable distributions are statistically estimated by experimental data and the functions of the empirical and theoretical densities are compared. Here we describe algorithms for simulation of the fractional-stable variables and estimation of the parameters of the the fractional stable densities. The results of such a comparison allow to conclude that the empirical densities of the gene expression can be approximated by the fractional-stable distributions. PMID- 26030796 TI - CSI: a nonparametric Bayesian approach to network inference from multiple perturbed time series gene expression data. AB - Here we introduce the causal structure identification (CSI) package, a Gaussian process based approach to inferring gene regulatory networks (GRNs) from multiple time series data. The standard CSI approach infers a single GRN via joint learning from multiple time series datasets; the hierarchical approach (HCSI) infers a separate GRN for each dataset, albeit with the networks constrained to favor similar structures, allowing for the identification of context specific networks. The software is implemented in MATLAB and includes a graphical user interface (GUI) for user friendly inference. Finally the GUI can be connected to high performance computer clusters to facilitate analysis of large genomic datasets. PMID- 26030797 TI - The ACACB gene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis. AB - To date, case-control studies on the association between a single-nucleotide polymorphism (SNP), rs2268388, in the acetyl-coenzyme A carboxylase beta (ACACB) gene and diabetic nephropathy have provided controversial results. To clarify the effect of rs2268388 on the risk of diabetic nephropathy, a meta-analysis of all case-control studies was performed. The fixed effects and random effects models showed that the C allele was associated with a decreased susceptibility risk of diabetic nephropathy compared with the T allele among Caucasian patients with diabetes. The contrast of the recessive model produced the same pattern of results as the allele contrast. Our pooled data suggest a significant association exists between rs2268388 and diabetic nephropathy among Caucasian patients with diabetes. PMID- 26030798 TI - Correlation between hypervolemia, left ventricular hypertrophy and fibroblast growth factor 23 in hemodialysis patients. AB - INTRODUCTION: Left ventricular hypertrophy (LVH) is a significant risk factor for cardiovascular complications in hemodialysis (HD) patients. Hypervolemia has been accepted as an independent risk factor for progressive LVH in HD patients. Additionally, high FGF23 levels have been a significant predictor of cardiovascular mortality and morbidity in chronic kidney disease and HD patients. The aim of our study is to investigate the correlation among LVH, interdialytic volume increase and FGF-23 in the patients on a chronic hemodialysis program. DESIGN AND METHODS: A total of 97 chronic hemodialysis patients (64.43 +/- 11.28 years old, M/F:47/50) were included in the study. Human FGF-23 ELISA kit was used for FGF-23 analysis of predialysis blood samples. Echocardiographic evaluation was performed in all of the patients after dialysis. Left Ventricular Mass Index (LVMI) was calculated by using the Devereux Formula. We collected the following data: LVMI, FGF-23 levels, interdialytic fluid gain, blood pressure changes, and the other biochemical and clinical parameters. RESULTS: Mean LVMI of the patients was 184.41 +/- 48.62 g/m(2). LVMI of the patients with daily urine output > 250 mL was found significantly lower. Statistically significant positive correlation was found between predialysis systolic blood pressure, predialysis diastolic blood pressure, predialysis mean arterial blood pressure and LVMI measurements (p < 0.01). Mean interdialytic volume excess was correlated with LVMI measurements of the patients (r = 0.459; p < 0.01). Increased FGF-23 levels (159.79 +/- 134.99 ng/L) predicted increased LVMI measurements of the patients (r = 0.322; p < 0.01). In addition, FGF-23 levels were also increased as the interdialytic fluid volume increased (r = 0.326; p < 0.05). A positive correlation was also found between FGF-23 levels and interventricular septum thickness (r = 0.238; p < 0.05). Predialysis mean arterial blood pressure, predialysis volume overload and presence of diabetes were determined to be independent risk factors on LVMI on multivariate regression analysis. CONCLUSION: Our study showed that interdialytic volume overload increased both LVMI and FGF-23 values. We can consider that interdialytic volume control exerts positive effects on increased FGF-23 levels which predict the negative cardiovascular outcomes. PMID- 26030799 TI - Crosstalk between platelets and PBMC: New evidence in wound healing. AB - Platelet-derived products have proven useful in accelerating healing processes and tissue regeneration. However, despite their widespread use in clinical practice, the cellular and molecular mechanisms involved have not yet been completely clarified. Recent studies show that interaction between platelet gel (PG) and peripheral blood mononuclear cells (PBMC) can result in activation of PBMC and production of several cytokines involved in wound healing and tissue repair. The aim of our study was to analyze whether crosstalk between platelets and PBMC can influence wound healing by modulating release of VEGF, bFGF and IL 10 by PBMC. Cultures of PBMC alone and co-cultures with autologous PG of 24 healthy volunteers were incubated under normoxia for 24 h. VEGF, bFGF and IL-10 concentration and expression were then analyzed in supernatants by ELISA and by real-time RT-PCR. We observed a down-regulation of VEGF and bFGF release and an up-regulation of IL-10 release in co-cultures of PBMC and PG. Platelets are not only important in the early stages of the healing process (clot formation, direct release of growth factors), but also can influence the whole process of tissue regeneration by modulating synthesis and release of VEGF, bFGF and IL-10 by PBMC. These effects could give platelets a new key role in the control of healing processes and provide insights into the clinical success of platelet-derived products in many medical fields. PMID- 26030800 TI - Perspectives of the Breast Cancer Survivorship Continuum: Diagnosis through 30 Months Post-Treatment. AB - This study explored breast cancer survivors' perspectives regarding their experiences of the survivorship continuum from diagnosis through 30 months post treatment. The sample included women (N = 379) with newly-diagnosed breast cancer undergoing treatment at a Midwestern university-affiliated cancer center. Semi structured interviews were conducted using the Lymphedema and Breast Cancer Questionnaire at time of diagnosis, post-operatively, quarterly during the first year, and then semi-annually thereafter through 30 months post-treatment. A mixed methodology was used to analyze participants' comments. Themes central to long term survivorship experiences included social support, positive worldviews, breast cancer and lymphedema health literacy, religious/spiritual beliefs, self empowerment, and recovery expectations. These themes were consistent with a psychoneuroimmunological model of health in which psychosocial variables mediate stress and influence health outcomes. Qualitative data showed that social support and positive worldviews were the two themes with the most significant impact on long-term breast cancer survivorship experiences. Survivors expressed a need to advance their health care literacy in order to share ownership of breast cancer and lymphedema treatment decisions. Since breast cancer is an immune-mediated disease, long-term survivorship planning should address psychosocial factors that influence the long-term psychological distress associated with immune dysfunction. PMID- 26030801 TI - Charge and Spin States in Schiff Base Metal Complexes with a Disiloxane Unit Exhibiting a Strong Noninnocent Ligand Character: Synthesis, Structure, Spectroelectrochemistry, and Theoretical Calculations. AB - Mononuclear nickel(II), copper(II), and manganese(III) complexes with a noninnocent tetradentate Schiff base ligand containing a disiloxane unit were prepared in situ by reaction of 3,5-di-tert-butyl-2-hydroxybenzaldehyde with 1,3 bis(3-aminopropyl)tetramethyldisiloxane followed by addition of the appropriate metal(II) salt. The ligand H2L resulting from these reactions is a 2:1 condensation product of 3,5-di-tert-butyl-2-hydroxybenzaldehyde with 1,3-bis(3 aminopropyl)tetramethyldisiloxane. The resulting metal complexes, NiL.0.5CH2Cl2, CuL.1.5H2O, and MnL(OAc).0.15H2O, were characterized by elemental analysis, spectroscopic methods (IR, UV-vis, X-band EPR, HFEPR, (1)H NMR), ESI mass spectrometry, and single crystal X-ray diffraction. Taking into account the well known strong stabilizing effects of tert-butyl groups in positions 3 and 5 of the aromatic ring on phenoxyl radicals, we studied the one-electron and two-electron oxidation of the compounds using both experimental (chiefly spectroelectrochemistry) and computational (DFT) techniques. The calculated spin density distribution and localized orbitals analysis revealed the oxidation locus and the effect of the electrochemical electron transfer on the molecular structure of the complexes, while time-dependent DFT calculations helped to explain the absorption spectra of the electrochemically generated species. Hyperfine coupling constants, g-tensors, and zero-field splitting parameters have been calculated at the DFT level of theory. Finally, the CASSCF approach has been employed to theoretically explore the zero-field splitting of the S = 2 MnL(OAc) complex for comparison purposes with the DFT and experimental HFEPR results. It is found that the D parameter sign strongly depends on the metal coordination geometry. PMID- 26030802 TI - Synthesis, structure, and spectral and electrochemical properties of chromium(III) tris-(8-hydroxyquinolinate). AB - The kinetically inert chromium(III) tris-(8-hydroxyquinolinate), Crq3, has been synthesized, crystallized from 90% methanol-water, and characterized by MALDI-TOF mass spectrometry, thermogravimetry, FTIR, NMR spectroscopy, and X-ray powder diffraction. It is formed as a methanol solvate, but the solvent can be removed by heating. Large paramagnetic shifts and spectral broadening in (1)H NMR spectra indicate electron delocalization between the metal and the ligand. DFT calculations show it is present as the meridional isomer, with the HOMO largely based on one of the metal 3d orbitals and the LUMO essentially localized on the ligands. Cyclic voltammetry (CV) in acetonitrile solutions shows four oxidation peaks and two, less intense reduction waves on the first scan. The HOMO energy determined from the first oxidation peak is fairly close to that obtained by DFT, in agreement with this being mainly metal based. Although the number of peaks decreases on subsequent CV scans, the complex shows markedly enhanced electrochemical stability compared with aluminium(III) tris-(8 hydroxyquinolinate). Solution UV/visible absorption and solid diffuse reflectance spectra have a weak, long wavelength band, assigned to the metal based d-d transition, in addition to the normal, ligand based bands seen in metal quinolates. The energy of the lowest energy band is identical to the HOMO-LUMO separation obtained by cyclic voltammetry, in agreement with the above description. The compound is only weakly luminescent, in contrast to many other metal quinolates, due to the lowest energy transition being metal rather than ligand based. The potential of this compound as an electron transporting/hole blocking layer in optoelectronic devices is indicated. PMID- 26030803 TI - Computational Docking Study of p7 Ion Channel from HCV Genotype 3 and Genotype 4 and Its Interaction with Natural Compounds. AB - BACKGROUND: The current standard care therapy for hepatitis C virus (HCV) infection consists of two regimes, namely interferon-based and interferon-free treatments. The treatment through the combination of ribavirin and pegylated interferon is expensive, only mildly effective, and is associated with severe side effects. In 2011, two direct-acting antiviral (DAA) drugs, boceprevir and telaprevir, were licensed that have shown enhanced sustained virologic response (SVR) in phase III clinical trial, however, these interferon-free treatments are more sensitive to HCV genotype 1 infection. The variable nature of HCV, and the limited number of inhibitors developed thus aim in expanding the repertoire of available drug targets, resulting in targeting the virus assembly therapeutically. AIM: We conducted this study to predict the 3D structure of the p7 protein from the HCV genotypes 3 and 4. Approximately 63 amino acid residues encoded in HCV render this channel sensitive to inhibitors, making p7 a promising target for novel therapies. HCV p7 protein forms a small membrane known as viroporin, and is essential for effective self-assembly of large channels that conduct cation assembly and discharge infectious virion particles. METHOD: In this study, we screened drugs and flavonoids known to disrupt translation and production of HCV proteins, targeted against the active site of p7 residues of HCV genotype 3 (GT3) (isolatek3a) and HCV genotype 4a (GT4) (isolateED43). Furthermore, we conducted a quantitative structure-activity relationship and docking interaction study. RESULTS: The drug NB-DNJ formed the highest number of hydrogen bond interactions with both modeled p7 proteins with high interaction energy, followed by BIT225. A flavonoid screen demonstrated that Epigallocatechin gallate (EGCG), nobiletin, and quercetin, have more binding modes in GT3 than in GT4. Thus, the predicted p7 protein molecule of HCV from GT3 and GT4 provides a general avenue to target structure-based antiviral compounds. CONCLUSIONS: We hypothesize that the inhibitors of viral p7 identified in this screen may be a new class of potent agents, but further confirmation in vitro and in vivo is essential. This structure-guided drug design for both GT3 and GT4 can lead to the identification of drug-like natural compounds, confirming p7 as a new target in the rapidly increasing era of HCV. PMID- 26030804 TI - GC-MS Based Plasma Metabolomics for Identification of Candidate Biomarkers for Hepatocellular Carcinoma in Egyptian Cohort. AB - This study evaluates changes in metabolite levels in hepatocellular carcinoma (HCC) cases vs. patients with liver cirrhosis by analysis of human blood plasma using gas chromatography coupled with mass spectrometry (GC-MS). Untargeted metabolomic analysis of plasma samples from participants recruited in Egypt was performed using two GC-MS platforms: a GC coupled to single quadruple mass spectrometer (GC-qMS) and a GC coupled to a time-of-flight mass spectrometer (GC TOFMS). Analytes that showed statistically significant changes in ion intensities were selected using ANOVA models. These analytes and other candidates selected from related studies were further evaluated by targeted analysis in plasma samples from the same participants as in the untargeted metabolomic analysis. The targeted analysis was performed using the GC-qMS in selected ion monitoring (SIM) mode. The method confirmed significant changes in the levels of glutamic acid, citric acid, lactic acid, valine, isoleucine, leucine, alpha tocopherol, cholesterol, and sorbose in HCC cases vs. patients with liver cirrhosis. Specifically, our findings indicate up-regulation of metabolites involved in branched-chain amino acid (BCAA) metabolism. Although BCAAs are increasingly used as a treatment for cancer cachexia, others have shown that BCAA supplementation caused significant enhancement of tumor growth via activation of mTOR/AKT pathway, which is consistent with our results that BCAAs are up-regulated in HCC. PMID- 26030807 TI - Separation of soybean saponins from soybean meal by a technology of foam fractionation and resin adsorption. AB - Foam fractionation and resin adsorption were used to recover soybean saponins from the industrial residue of soybean meal. First, a two-stage foam fractionation technology was studied for concentrating soybean saponins from the leaching liquor. Subsequently, resin adsorption was used to purify soybean saponins from the foamate in foam fractionation. The results showed that the enrichment ratio, the recovery percentage, and the purity of soybean saponins by using the two-stage foam fractionation technology could reach 4.45, 74%, and 67%, respectively. After resin adsorption and desorption, the purity of soybean saponins in the freeze-dried powder from the desorption solution was 88.4%. PMID- 26030806 TI - Capsiate supplementation reduces oxidative cost of contraction in exercising mouse skeletal muscle in vivo. AB - Chronic administration of capsiate is known to accelerate whole-body basal energy metabolism, but the consequences in exercising skeletal muscle remain very poorly documented. In order to clarify this issue, the effect of 2-week daily administration of either vehicle (control) or purified capsiate (at 10- or 100 mg/kg body weight) on skeletal muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in mice. Mechanical performance and energy metabolism were assessed strictly non-invasively in contracting gastrocnemius muscle using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Regardless of the dose, capsiate treatments markedly disturbed basal bioenergetics in vivo including intracellular pH alkalosis and decreased phosphocreatine content. Besides, capsiate administration did affect neither mitochondrial uncoupling protein-3 gene expression nor both basal and maximal oxygen consumption in isolated saponin-permeabilized fibers, but decreased by about twofold the Km of mitochondrial respiration for ADP. During a standardized in vivo fatiguing protocol (6-min of repeated maximal isometric contractions electrically induced at a frequency of 1.7 Hz), both capsiate treatments reduced oxidative cost of contraction by 30-40%, whereas force-generating capacity and fatigability were not changed. Moreover, the rate of phosphocreatine resynthesis during the post electrostimulation recovery period remained unaffected by capsiate. Both capsiate treatments further promoted muscle mass gain, and the higher dose also reduced body weight gain and abdominal fat content. These findings demonstrate that, in addition to its anti-obesity effect, capsiate supplementation improves oxidative metabolism in exercising muscle, which strengthen this compound as a natural compound for improving health. PMID- 26030810 TI - Lessons Learned From Review of a Single Center Experience With 500 Consecutive Liver Transplants in a Region With Insufficient Deceased-Donor Support. AB - OBJECTIVES: We present here the outcomes of our first 500 liver transplants and discuss the lessons learned during this time. MATERIALS AND METHODS: We retrospectively analyzed the first 500 consecutive transplants within the listing criteria of the United Network for Organ Sharing, with recipients and donors with minimum 1-year follow-up. Patient survival and donor complications were analyzed for 31 liver transplant recipients with hepatocellular carcinoma beyond the Milan criteria who had transplant performed during the same time. RESULTS: Between August 2006 and March 2013, there were 519 liver transplants performed in 500 patients (365 adult, 135 pediatric). There were 394 living-donor and 125 deceased donor liver transplants. In addition, 31 adult liver transplants were performed in patients with hepatocellular carcinoma beyond Milan criteria (22 living-donor and 9 deceased-donor transplants). The main cause of chronic liver failure was biliary atresia in pediatric patients (30.4%) and chronic hepatitis B infection in adults (35.6%). The complication rate for primary nonfunction was 3.8%, overall biliary complications 24.0% (significantly higher after adult living donor liver transplant, 30.3%), hepatic artery thrombosis 1.6%, portal vein thrombosis 3.0%, retransplant 3.8%, acute cellular rejection 29.6%, and bacterial infection 39.4%. Overall 1-, 3-, and 5-year patient survival rates in the first 500 consecutive transplants performed on recipients within United Network for Organ Sharing listing criteria were 87.8%, 85.0%, and 78.6%; for hepatocellular carcinoma patients beyond the Milan criteria, survival rates were 71.9%, 52.5%, and 38.2%. CONCLUSIONS: In regions without a sufficient number of deceased donors, living-donor liver transplant, with its associated problems, is the only alternative to deceased-donor liver transplant. Liver transplant requires teamwork, with all players working well together for a successful outcome. The important keys to success in liver transplant include decision-making, timing, surgical skills, experience, and close follow-up. PMID- 26030809 TI - Beyond Benford's Law: Distinguishing Noise from Chaos. AB - Determinism and randomness are two inherent aspects of all physical processes. Time series from chaotic systems share several features identical with those generated from stochastic processes, which makes them almost undistinguishable. In this paper, a new method based on Benford's law is designed in order to distinguish noise from chaos by only information from the first digit of considered series. By applying this method to discrete data, we confirm that chaotic data indeed can be distinguished from noise data, quantitatively and clearly. PMID- 26030808 TI - Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia. AB - RATIONALE: Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis. OBJECTIVES: Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease. METHODS: We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes. MEASUREMENTS AND MAIN RESULTS: We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD. CONCLUSIONS: Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology. PMID- 26030811 TI - LKB1 regulates germinal center formation and termination. PMID- 26030812 TI - Fock-exchange for periodic structures in the real-space formalism and the KLI approximation. AB - The calculation of Fock-exchange interaction is an important task in the computation of molecule and solid properties. In this work we describe how we implement the Fock exchange in the real-space formalism using the KLI approximation for the OEP equation for 3D periodic systems. The implementation is demonstrated within the PARSEC real-space pseudopotential code that uses a discrete uniform grid and norm conserving pseudopotentials for the ionic potentials. PMID- 26030813 TI - Authentication of yerba mate according to the country of origin by using Fourier transform infrared (FTIR) associated with chemometrics. AB - This study deals with the development of a method for classification of yerba mate (Ilex paraguariensis) using attenuated total-reflectance Fourier transform infrared (ATR-FTIR) and multivariate analysis. Fifty-four brands of yerba mate from southern South America were analysed in order to classify the commercialised yerba mate according to the respective country of yerba mate processing. The yerba mate was ground in a cryogenic mill, and the reflectance was directly measured in the region ranging from 4000 to 650 cm(-1). Different pre-processing algorithms and three methods of multivariate analysis were investigated, including principal component analysis (PCA), partial least square discriminant analysis (PLS-DA) and support vector machine discriminant analysis (SVM-DA). The yerba mate classification was 100% correct when the reflectance spectra were pre treated (derived at first order, normalised by standard normal variation, smoothed and mean centred) and analysed using the SVM-DA method. PMID- 26030814 TI - Aberrant methylation of promoter region of SPINT2/HAI-2 gene: an epigenetic mechanism in hepatitis C virus-induced hepatocarcinogenesis. AB - BACKGROUND: Epigenetic changes, including DNA methylation, are recognized as one of the potential mechanisms involved in the pathogenesis of hepatocellular carcinoma (HCC). AIMS: We aimed to study the methylation status of the promoter region of Serine peptidase inhibitor/hepatocyte growth factor activator inhibitor type 2 (SPINT2/HAI-2) tumor suppressor gene in hepatitis C virus (HCV)-infected cirrhotic patients with and without HCC. METHODS: Methyl-specific polymerase (MSP) chain reaction was used to detect CpG methylation of the SPINT2/HAI-2 gene promoter in peripheral blood samples of 30 HCC and 50 HCV cirrhotic cases, along with 50 normal individuals. RESULTS: Aberrant methylation showed a stepwise increase in frequency from 40% in controls to 64% in HCV cirrhotics, and 66.7% in HCC cases with a significant difference among the studied groups (p=0.021). The combined patient groups had an increased risk of aberrant methylation with an odds ratio (OR) of 2.52, a 95% confidence interval (CI) of 1.23-5.14, and a p value of 0.05 that became more statistically significant after adjusting for age (OR=2.4, 95% CI=1.13-5.26, p-value=0.012), thereby confirming the association between HCV infection and aberrant methylation. CONCLUSIONS: Our study highlights the role of promoter hypermethylation in the multistep process of hepatocarcinogenesis, providing potential clinical applications in diagnosis and prognosis. PMID- 26030815 TI - Promotion of acceptor formation in SnO2 nanowires by e-beam bombardment and impacts to sensor application. AB - We have realized a p-type-like conduction in initially n-type SnO2 nanowires grown using a vapor-liquid-solid method. The transition was achieved by irradiating n-type SnO2 nanowires with a high-energy electron beam, without intentional chemical doping. The nanowires were irradiated at doses of 50 and 150 kGy, and were then used to fabricate NO2 gas sensors, which exhibited n-type and p-type conductivities, respectively. The tuneability of the conduction behavior is assumed to be governed by the formation of tin vacancies (under high-energy electron beam irradiation), because it is the only possible acceptor, excluding all possible defects via density functional theory (DFT) calculations. The effect of external electric fields on the defect stability was studied using DFT calculations. The measured NO2 sensing dynamics, including response and recovery times, were well represented by the electron-hole compensation mechanism from standard electron-hole gas equilibrium statistics. This study elucidates the charge-transport characteristics of bipolar semiconductors that underlie surface chemical reactions. The principles derived will guide the development of future SnO2-based electronic and electrochemical devices. PMID- 26030817 TI - Hypertension-Management of Hypertensive Disorders of Pregnancy According to International Guidelines: A Panel Discussion (Case 4: HELLP Syndrome). PMID- 26030816 TI - Assessing the effects of trematode infection on invasive green crabs in eastern north america. AB - A common signature of marine invasions worldwide is a significant loss of parasites (= parasite escape) in non-native host populations, which may confer a release from some of the harmful effects of parasitism (e.g., castration, energy extraction, immune activation, behavioral manipulation) and possibly enhance the success of non-indigenous species. In eastern North America, the notorious invader Carcinus maenas (European green crab) has escaped more than two-thirds its native parasite load. However, one of its parasites, a trematode (Microphallus similis), can be highly prevalent in the non-native region; yet little is known about its potential impacts. We employed a series of laboratory experiments to determine whether and how M. similis infection intensity influences C. maenas, focusing on physiological assays of body mass index, energy storage, and immune activation, as well as behavioral analyses of foraging, shelter utilization, and conspicuousness. We found little evidence for enduring physiological or behavioral impacts four weeks after experimental infection, with the exception of mussel handling time which positively correlated with cyst intensity. However, we did find evidence for a short-term effect of M. similis infection during early stages of infection (soon after cercarial penetration) via a significant drop in circulating immune cells, and a significant increase in the crabs' righting response time. Considering M. similis is the only common parasite infecting C. maenas in eastern North America, our results for minimal lasting effects of the trematode on the crab's physiology and behavior may help explain the crab's continued prominence as a strong predator and competitor in the region. PMID- 26030818 TI - Moment feature based fast feature extraction algorithm for moving object detection using aerial images. AB - Fast and computationally less complex feature extraction for moving object detection using aerial images from unmanned aerial vehicles (UAVs) remains as an elusive goal in the field of computer vision research. The types of features used in current studies concerning moving object detection are typically chosen based on improving detection rate rather than on providing fast and computationally less complex feature extraction methods. Because moving object detection using aerial images from UAVs involves motion as seen from a certain altitude, effective and fast feature extraction is a vital issue for optimum detection performance. This research proposes a two-layer bucket approach based on a new feature extraction algorithm referred to as the moment-based feature extraction algorithm (MFEA). Because a moment represents the coherent intensity of pixels and motion estimation is a motion pixel intensity measurement, this research used this relation to develop the proposed algorithm. The experimental results reveal the successful performance of the proposed MFEA algorithm and the proposed methodology. PMID- 26030819 TI - Self-Assembly of Nanoclusters into Mono-, Few-, and Multilayered Sheets via Dipole-Induced Asymmetric van der Waals Attraction. AB - Two-dimensional (2D) nanomaterials possessing regular layered structures and versatile chemical composition are highly expected in many applications. Despite the importance of van der Waals (vdW) attraction in constructing and maintaining layered structures, the origin of 2D anisotropy is not fully understood, yet. Here, we report the 2D self-assembly of ligand-capped Au15 nanoclusters into mono , few-, and multilayered sheets in colloidal solution. Both the experimental results and computer simulation reveal that the 2D self-assembly is initiated by 1D dipolar attraction common in nanometer-sized objects. The dense 1D attachment of Au15 leads to a redistribution of the surface ligands, thus generating asymmetric vdW attraction. The deliberate control of the coordination of dipolar and vdW attraction further allows to manipulate the thickness and morphologies of 2D self-assembly architectures. PMID- 26030820 TI - Accurate encoding and decoding by single cells: amplitude versus frequency modulation. AB - Cells sense external concentrations and, via biochemical signaling, respond by regulating the expression of target proteins. Both in signaling networks and gene regulation there are two main mechanisms by which the concentration can be encoded internally: amplitude modulation (AM), where the absolute concentration of an internal signaling molecule encodes the stimulus, and frequency modulation (FM), where the period between successive bursts represents the stimulus. Although both mechanisms have been observed in biological systems, the question of when it is beneficial for cells to use either AM or FM is largely unanswered. Here, we first consider a simple model for a single receptor (or ion channel), which can either signal continuously whenever a ligand is bound, or produce a burst in signaling molecule upon receptor binding. We find that bursty signaling is more accurate than continuous signaling only for sufficiently fast dynamics. This suggests that modulation based on bursts may be more common in signaling networks than in gene regulation. We then extend our model to multiple receptors, where continuous and bursty signaling are equivalent to AM and FM respectively, finding that AM is always more accurate. This implies that the reason some cells use FM is related to factors other than accuracy, such as the ability to coordinate expression of multiple genes or to implement threshold crossing mechanisms. PMID- 26030821 TI - Quantitative comparison of commercial and non-commercial metal artifact reduction techniques in computed tomography. AB - OBJECTIVES: Typical streak artifacts known as metal artifacts occur in the presence of strongly attenuating materials in computed tomography (CT). Recently, vendors have started offering metal artifact reduction (MAR) techniques. In addition, a MAR technique called the metal deletion technique (MDT) is freely available and able to reduce metal artifacts using reconstructed images. Although a comparison of the MDT to other MAR techniques exists, a comparison of commercially available MAR techniques is lacking. The aim of this study was therefore to quantify the difference in effectiveness of the currently available MAR techniques of different scanners and the MDT technique. MATERIALS AND METHODS: Three vendors were asked to use their preferential CT scanner for applying their MAR techniques. The scans were performed on a Philips Brilliance ICT 256 (S1), a GE Discovery CT 750 HD (S2) and a Siemens Somatom Definition AS Open (S3). The scans were made using an anthropomorphic head and neck phantom (Kyoto Kagaku, Japan). Three amalgam dental implants were constructed and inserted between the phantom's teeth. The average absolute error (AAE) was calculated for all reconstructions in the proximity of the amalgam implants. RESULTS: The commercial techniques reduced the AAE by 22.0+/-1.6%, 16.2+/-2.6% and 3.3+/-0.7% for S1 to S3 respectively. After applying the MDT to uncorrected scans of each scanner the AAE was reduced by 26.1+/-2.3%, 27.9+/-1.0% and 28.8+/ 0.5% respectively. The difference in efficiency between the commercial techniques and the MDT was statistically significant for S2 (p=0.004) and S3 (p<0.001), but not for S1 (p=0.63). CONCLUSIONS: The effectiveness of MAR differs between vendors. S1 performed slightly better than S2 and both performed better than S3. Furthermore, for our phantom and outcome measure the MDT was more effective than the commercial MAR technique on all scanners. PMID- 26030822 TI - Patient expression of emotions and neurologist responses in first multiple sclerosis consultations. AB - BACKGROUND: Anxiety and depression are common in people with multiple sclerosis (MS), but data on emotional communication during MS consultations are lacking. We assessed patient expressions of emotion and neurologist responses during first ever MS consultations using the Verona Coding Definitions of Emotional Sequences (VR-CoDES). METHODS: We applied VR-CoDES to recordings/transcripts of 88 outpatient consultations (10 neurologists, four MS Italian centers). Before consultation, patients completed the Hospital Anxiety and Depression Scale (HADS). Multilevel sequential analysis was performed on the number of cues/concerns expressed by patients, and the proportion of reduce space responses by neurologists. RESULTS: Patients expressed 492 cues and 45 concerns (median 4 cues and 1 concern per consultation). The commonest cues were verbal hints of hidden worries (cue type b, 41%) and references to stressful life events (type d, 26%). Variables independently associated with number of cues/concerns were: anxiety (HADS-Anxiety score >8) (incidence risk ratio, IRR 1.08, 95% CI 1.06 1.09; p<0.001); patient age (IRR 0.98, 95% CI 0.98-0.99; p<0.001); neurologist age (IRR 0.94, 95% CI 0.92-0.96; p=0.03); and second opinion consultation (IRR 0.72, 95% CI 0.60-0.86; p=0.007). Neurologists reacted to patient emotions by reducing space (changing subject, taking no notice, giving medical advice) for 58% of cues and 76% of concerns. Anxiety was the only variable significantly associated with 'reduce space' responses (odds ratio 2.17, 95% CI 1.32-3.57; p=0.003). CONCLUSIONS: Patient emotional expressions varied widely, but VR-CoDES cues b and d were expressed most often. Patient anxiety was directly associated with emotional expressions; older age of patients and neurologists, and second opinion consultations were inversely associated with patient emotional expression. In over 50% of instances, neurologists responded to these expressions by reducing space, more so in anxious patients. These findings suggest that neurologists need to improve their skills in dealing with patient emotions. PMID- 26030823 TI - Boechera species exhibit species-specific responses to combined heat and high light stress. AB - As sessile organisms, plants must be able to complete their life cycle in place and therefore tolerance to abiotic stress has had a major role in shaping biogeographical patterns. However, much of what we know about plant tolerance to abiotic stresses is based on studies of just a few plant species, most notably the model species Arabidopsis thaliana. In this study we examine natural variation in the stress responses of five diverse Boechera (Brassicaceae) species. Boechera plants were exposed to basal and acquired combined heat and high light stress. Plant response to these stresses was evaluated based on chlorophyll fluorescence measurements, induction of leaf chlorosis, and gene expression. Many of the Boechera species were more tolerant to heat and high light stress than A. thaliana. Gene expression data indicates that two important marker genes for stress responses: APX2 (Ascorbate peroxidase 2) and HsfA2 (Heat shock transcription factor A2) have distinct species-specific expression patterns. The findings of species-specific responses and tolerance to stress indicate that stress pathways are evolutionarily labile even among closely related species. PMID- 26030824 TI - Individual consistency and phenotypic plasticity in rockhopper penguins: female but not male body mass links environmental conditions to reproductive investment. AB - In marine habitats, increasing ocean temperatures due to global climate change may distinctly reduce nutrient and consequently food availability for seabirds. Food availability is a known driver of body mass and reproductive investment in birds, but these traits may also depend on individual effects. Penguins show extreme intra-annual body mass variation and rely on accumulated body reserves for successful breeding. However, no study so far has tested individual consistency and phenotypic responses in body mass and reproductive investment in this taxon. Using a unique dataset on individually marked female and male southern rockhopper penguins (Eudyptes chrysocome chrysocome) across six years, we investigated 1) the individual consistency in body mass (measured at egg laying), body condition and reproductive investment across years, subsequently 2) identified the best-explanatory temperature-related environmental variables for female and male body mass, and 3) tested the effect of female and male body mass on reproductive investment. Body mass, body condition and reproductive investment were all highly repeatable. As body condition should control for the structural size of the birds, the similarly high repeatability estimates for body mass and body condition suggested that the consistent between-individual body mass differences were independent of structural size. This supported the use of body mass for the subsequent analyses. Body mass was higher under colder environmental conditions (positive Southern Annular Mode), but the overall phenotypic response appeared limited. Reproductive investment increased with female but not male body mass. While environmental effects on body mass in our study period were rather small, one can expect that ongoing global climate change will lead to a deterioration of food availability and we might therefore in the long-term expect a phenotypical decline in body mass and reproductive investment. PMID- 26030825 TI - Hydrologic variability governs population dynamics of a vulnerable amphibian in an arid environment. AB - Dynamics of many amphibian populations are governed by the distribution and availability of water. Therefore, understanding the hydrological mechanisms that explain spatial and temporal variation in occupancy and abundance will improve our ability to conserve and recover populations of vulnerable amphibians. We used 16 years of survey data from intermittent mountain streams in the Sonoran Desert to evaluate how availability of surface water affected survival and adult recruitment of a threatened amphibian, the lowland leopard frog (Lithobates yavapaiensis). Across the entire study period, monthly survival of adults ranged from 0.72 to 0.99 during summer and 0.59 to 0.94 during winter and increased with availability of surface water (Z = 7.66; P < 0.01). Recruitment of frogs into the adult age class occurred primarily during winter and ranged from 1.9 to 3.8 individuals/season/pool; like survival, recruitment increased with availability of surface water (Z = 3.67; P < 0.01). Although abundance of frogs varied across seasons and years, we found no evidence of a systematic trend during the 16-year study period. Given the strong influence of surface water on population dynamics of leopard frogs, conservation of many riparian obligates in this and similar arid regions likely depends critically on minimizing threats to structures and ecosystem processes that maintain surface waters. Understanding the influence of surface-water availability on riparian organisms is particularly important because climate change is likely to decrease precipitation and increase ambient temperatures in desert riparian systems, both of which have the potential to alter fundamentally the hydrology of these systems. PMID- 26030826 TI - Disruption of thermally-stable nanoscale grain structures by strain localization. AB - Nanocrystalline metals with average grain sizes of only a few nanometers have recently been observed to fail through the formation of shear bands. Here, we investigate this phenomenon in nanocrystalline Ni which has had its grain structure stabilized by doping with W, with a specific focus on understanding how strain localization drives evolution of the nanoscale grain structure. Shear banding was initiated with both microcompression and nanoindentation experiments, followed by site-specific transmission electron microscopy to characterize the microstructure. Grain growth and texture formation were observed inside the shear bands, which had a wide variety of thicknesses. These evolved regions have well defined edges, which rules out local temperature rise as a possible formation mechanism. No structural evolution was found in areas away from the shear bands, even in locations where significant plastic deformation had occurred, showing that plastic strain alone is not enough to cause evolution. Rather, intense strain localization is needed to induce mechanically-driven grain growth in a thermally-stable nanocrystalline alloy. PMID- 26030827 TI - Physicochemical factors and sources of particulate matter at residential urban environment in Kuala Lumpur. AB - Long-term measurements (2004-2011) of PM10 (particulate matter with an aerodynamic diameter <10 MUm) and trace gases (carbon monoxide [CO], ozone [O3], nitrogen oxide [NO], oxides of nitrogen [NO(x)], nitrogen dioxide [NO2], sulfur dioxide [SO2], methane [CH4], nonmethane hydrocarbon [NMHC]) have been conducted to study the effect of physicochemical factors on the PM10 concentration. In addition, this study includes source apportionment of PM10 in Kuala Lumpur urban environment. An advanced principal component analysis (PCA) technique coupled with absolute principal component scores (APCS) and multiple linear regression (MLR) has been applied. The average annual concentration of PM10 for 8 yr is 51.3 +/- 25.8 MUg m-3, which exceeds the Recommended Malaysian Air Quality Guideline (RMAQG) and international guideline values. Detail analysis shows the dependency of PM10 on the linear changes of the motor vehicles in use and the amount of biomass burning, particularly from Sumatra, Indonesia, during southwesterly monsoon. The main sources of PM10 identified by PCA-APCS-MLR are traffic combustion (28%), ozone coupled with meteorological factors (20%), and wind-blown particles (1%). However, the apportionment procedure left 28.0 MUg m-3, that is, 51% of PM10 undetermined. PMID- 26030828 TI - Both hepatic and body iron stores are increased in dysmetabolic iron overload syndrome. A case-control study. AB - BACKGROUND & AIMS: Hepatic iron is increased in dysmetabolic iron overload syndrome (DIOS). Whether this reflects elevated body iron stores is still debated. The study was aimed at assessing body iron stores in DIOS patients by calculating the amount of mobilized iron (AMI). METHODS: We conducted a prospective case-control study comparing AMI in 12 DIOS patients and 12 overweight normoferritinemic subjects matched on BMI and age. All participants were phlebotomized until serum ferritin dropped <= 50MUg/L. RESULTS: The two groups were comparable with respect to metabolic abnormalities and differed according to serum ferritin levels only. AMI was significantly (p<0.0001) higher in DIOS (2.5g+/-0.7) than in controls (0.8g+/-0.3). No side effects were related to phlebotomies. PMID- 26030830 TI - Structure and Dynamics of Ionic Liquids Confined in Amorphous Porous Chalcogenides. AB - Besides the abundant literature on ionic liquids in porous silica and carbon, the confinement of such intriguing liquids in porous chalcogenides has received very little attention. Here, molecular simulation is employed to study the structural and dynamical properties of a typical ionic liquid confined in a realistic molecular model of amorphous chalcogenide with various pore sizes and surface chemistries. Using molecular dynamics in the isobaric-isothermal (NPT) ensemble, we consider confinement conditions relevant to real samples. Both the structure and self-dynamics of the confined phase are found to depend on the surface-to volume ratio of the host confining material. Consequently, most properties of the confined ionic liquid can be written as a linear combination of surface and bulk like contributions, arising from the ions in contact with the surface and the ions in the pore center, respectively. On the other hand, collective dynamical properties such as the ionic conductivity remain close to their bulk counterpart and almost insensitive to pore size and surface chemistry. These results, which are in fair agreement with available experimental data, provide a basis for the development of novel applications using hybrid organic-inorganic solids consisting of ionic liquids confined in porous chalcogenides. PMID- 26030829 TI - Interleukin-10 promoter gene polymorphisms and susceptibility to tuberculosis: a meta-analysis. AB - OBJECTIVE: As an update to other recent meta-analyses, the purpose of this study was to explore whether interleukin-10 (IL-10) polymorphisms and their haplotypes contribute to tuberculosis (TB) susceptibility. METHODS: We searched for published case-control studies examining IL-10 polymorphisms and TB in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wanfang databases and the Chinese National Knowledge Infrastructure (CNKI). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strengths of the associations. RESULTS: A total of 28 studies comprising 8,242 TB patients and 9,666 controls were included in the present study. There were no significant associations between the -1082G/A, -819C/T, and -592A/C polymorphisms and TB in the pooled samples. Subgroup analyses revealed that the -819T allele was associated with an increased TB risk in Asians in all genetic models (T vs. C: OR=1.17, 95% CI=1.05-1.29, P=0.003; TT vs. CC: OR=1.37, 95% CI=1.09-1.72, P=0.006; CT+TT vs. CC: OR=1.33, 95% CI=1.09-1.63, P=0.006; TT vs. CT+CC: OR=1.17, 95% CI=1.02-1.35, P=0.03) and that the -592A/C polymorphism was significantly associated with TB in Europeans under two genetic models (A vs. C: OR=0.77, 95% CI=0.60-0.98, P=0.03; AA vs. CC: OR=0.53, 95% CI=0.30-0.95, P=0.03). Furthermore, the GCC IL-10 promoter haplotype was associated with an increased risk of TB (GCC vs. others: P=1.42, 95% CI=1.02-1.97, P=0.04). Subgroup analyses based on ethnicity revealed that the GCC haplotype was associated with a higher risk of TB in Europeans, whereas the ACC haplotype was associated with a lower TB risk in both Asians and Europeans. CONCLUSIONS: This meta-analysis suggests that the IL 10-819T/C polymorphism is associated with the risk of TB in Asians and that the IL-10-592A/C polymorphism may be a risk factor for TB in Europeans. Furthermore, these data indicate that IL-10 promoter haplotypes play a vital role in the susceptibility to or protection against the development of TB. PMID- 26030831 TI - Magnetic structure of the antiferromagnetic Kondo lattice compounds CeRhAl4Si2 and CeIrAl4Si2. AB - We have investigated the magnetic ground state of the antiferromagnetic Kondo lattice compounds CeMAl4Si2(M = Rh, Ir) using neutron powder diffraction. Although both of these compounds show two magnetic transitions T(N1) and T(N2) in the bulk properties measurements, evidence for magnetic long-range order was only found below the lower transition T(N2). Analysis of the diffraction profiles reveals a commensurate antiferromagnetic structure with a propagation vector k = (0, 0, 1/2). The magnetic moment in the ordered state of CeRhAl4Si2 and CeIrAl4Si2 were determined to be 1.14(2) and 1.41(3) MU(B) Ce(-1), respectively, and are parallel to the crystallographic c-axis in agreement with magnetic susceptibility measurements. PMID- 26030832 TI - Bidirectional Flux of Methyl Vinyl Ketone and Methacrolein in Trees with Different Isoprenoid Emission under Realistic Ambient Concentrations. AB - Methyl vinyl ketone (MVK) and methacrolein (MAC) are key oxidation products (iox) of isoprene, the most abundant volatile organic compound (VOC) emitted by vascular plants in the atmosphere. Increasing attention has been dedicated to iox, as they are involved in the photochemical cycles ultimately leading to ozone (O3) and particle formation. However, the capacity of plants to exchange iox under low and realistic ambient concentrations of iox needs to be assessed. We hypothesized that a foliar uptake of iox exists even under realistic concentrations of iox. We tested the capacity of iox exchange in trees constitutively emitting isoprene (Populus nigra) or monoterpenes (Quercus ilex), or that do not emit isoprenoids (Paulownia imperialis). Laboratory experiments were carried out at the leaf level using enclosures under controlled environmental factors and manipulating isoprene and reactive oxygen species (ROS) production by using the isoprene specific inhibitor fosmidomycin, acute O3 exposure (300 ppbv for 4 h), and dark conditions. We also tested whether stress conditions inducing accumulation of ROS significantly enhance iox formation in the leaf, and their emission. Our results show a negligible level of constitutive iox emission in unstressed plants, and in plants treated with high O3. The uptake of iox increased linearly with exposure to increasing concentrations of ambient iox (from 0 to 6 ppbv of a 1:1 = MVK/MAC mixture) in all the investigated species, indicating iox fast removal and low compensation point in unstressed and stressed conditions. Plant capacity to take up iox should be included in global models that integrate estimates of iox formation, emission, and photochemical reactions in the atmosphere. PMID- 26030833 TI - Mitochondrial miRNA (MitomiR): a new player in cardiovascular health. AB - Cardiovascular disease is one of the major causes of human morbidity and mortality in the world. MicroRNAs (miRNAs) are small RNAs that regulate gene expression and are known to be involved in the pathogenesis of heart diseases, but the translocation phenomenon and the mode of action in mitochondria are largely unknown. Recent mitochondrial proteome analysis unveiled at least 2000 proteins, of which only 13 are made by the mitochondrial genome. There are numerous studies demonstrating the translocation of proteins into the mitochondria and also translocation of ribosomal RNA (viz., 5S rRNA) into mitochondria. Recent studies have suggested that miRNAs contain sequence elements that affect their subcellular localization, particularly nuclear localization. If there are sequence elements that direct miRNAs to the nucleus, it is also possible that similar sequence elements exist to direct miRNAs to the mitochondria. In this review we have summarized most of the miRNAs that have been shown to play an important role in mitochondrial function, either by regulating mitochondrial genes or by regulating nuclear genes that are known to influence mitochondrial function. While the focus of this review is cardiovascular diseases, we also illustrate the role of mitochondrial miRNA (MitomiR) in the initiation and progression of various diseases, including cardiovascular diseases, metabolic diseases, and cancer. Our goal here is to summarize the miRNAs that are localized to the mitochondrial fraction of cells, and how these miRNAs modulate cardiovascular health. PMID- 26030834 TI - A facile strategy to synthesize three-dimensional Pd@Pt core-shell nanoflowers supported on graphene nanosheets as enhanced nanoelectrocatalysts for methanol oxidation. AB - Here we demonstrate for the first time a water-based surfactant-free synthesis of three-dimensional porous Pd@Pt core-shell nanoflowers on graphene. The obtained Pd@Pt-graphene hybrids exhibited substantially enhanced electrocatalytic activity and stability relative to the commercial Pt/C catalyst originating from this exquisite nanoarchitecture for three-dimensional molecular accessibility and graphene-metal interaction. PMID- 26030835 TI - Epitaxial growth of highly-crystalline spinel ferrite thin films on perovskite substrates for all-oxide devices. AB - The potential growth modes for epitaxial growth of Fe3O4 on SrTiO3 (001) are investigated through control of the energetics of the pulsed-laser deposition growth process (via substrate temperature and laser fluence). We find that Fe3O4 grows epitaxially in three distinct growth modes: 2D-like, island, and 3D-to-2D, the last of which is characterized by films that begin growth in an island growth mode before progressing to a 2D growth mode. Films grown in the 2D-like and 3D-to 2D growth modes are atomically flat and partially strained, while films grown in the island growth mode are terminated in islands and fully relaxed. We find that the optimal structural, transport, and magnetic properties are obtained for films grown on the 2D-like/3D-to-2D growth regime boundary. The viability for including such thin films in perovskite-based all-oxide devices is demonstrated by growing a Fe3O4/La0.7Sr0.3MnO3 spin valve epitaxially on SrTiO3. PMID- 26030836 TI - Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study. AB - IMPORTANCE: Although prior studies have suggested a role of cardiometabolic health on pathogenesis of amyotrophic lateral sclerosis (ALS), the association with diabetes mellitus has not been widely examined. Amyotrophic lateral sclerosis is the most common motor neuron disorder. Several vascular risk factors have been associated with decreased risk for ALS. Although diabetes is also a risk factor for vascular disease, the few studies of diabetes and ALS have been inconsistent. OBJECTIVE: To examine the association between diabetes and obesity, each identified through International Statistical Classification of Diseases, Eighth or Tenth Revision codes in a hospital registry, and ALS using data from the Danish National Registers. DESIGN, SETTING, AND PARTICIPANTS: Population based nested case-control study of 3650 Danish residents diagnosed as having ALS between January 1, 1982, and December 31, 2009, and 365,000 controls (100 for each ALS case) matched on age and sex. The analysis was conducted in September and October 2014. MAIN OUTCOMES AND MEASURES: Adjusted odds ratio for ALS associated with diabetes or obesity diagnoses at least 3 years prior to the ALS diagnosis date. RESULTS: When considering diabetes and our obesity indicator together, the estimated odds ratio for ALS was 0.61 (95% CI, 0.46-0.80) for diabetes and 0.81 (95% CI, 0.57-1.16) for obesity. We observed no effect modification on the association with diabetes by sex. We did find a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association was stronger with increasing age at ALS diagnosis (P = .01), and the odds ratio for first mention of diabetes was 1.66 (95% CI, 0.85-3.21) before age 40 years but 0.52 (95% CI, 0.39-0.70) for older ages. These results are consistent with different associations for type 1 vs type 2 diabetes. CONCLUSIONS AND RELEVANCE: In this Danish nationwide study to investigate the association between diabetes and ALS diagnosis, our findings are in agreement with previous reports of a protective association between vascular risk factors and ALS and suggest that type 2 diabetes, but not type 1, is protective for ALS. PMID- 26030837 TI - Time to Test Incentives to Increase Organ Donation. PMID- 26030838 TI - A Michael Equilibration Model To Control Site Selectivity in the Condensation toward Aminopyrazoles. AB - A Michael equilibration model is presented to provide for site-selective pyrazole condensations between alkoxyacrylonitriles and hydrazines. Both pyrazole isomers were accessed with high selectivity by employment of kinetically or thermodynamically controlled conditions. Substrate scope and identification of Michael intermediates, as well as competitive pathways, support the presented mechanistic proposal. Sandmeyer derivatization provided site-selective access to fully substituted pyrazoles. PMID- 26030839 TI - Nonsurgical deep uterine transfer of vitrified, in vivo-derived, porcine embryos is as effective as the default surgical approach. AB - Surgical procedures are prevalent in porcine embryo transfer (ET) programs, where the use of vitrified embryos is quasi non-existent. This study compared the effectiveness of surgical vs nonsurgical deep uterine (NsDU) ET using vitrified, in vivo-derived embryos (morulae and blastocysts) on the reproductive performance and welfare of the recipients. The recipient sows (n=122) were randomly assigned to one of the following groups: surgical ET with 30 vitrified-warmed embryos (S 30 group, control); NsDU-ET with 30 vitrified-warmed embryos (NsDU-30 group) and NsDU-ET with 40 vitrified-warmed embryos (NsDU-40 group). Regardless of embryo stage, the NsDU-ET with 40 embryos presented similar rates of farrowing (72.7%) and litter size (9.9 +/- 2.1 piglets) as the customary surgical procedure (75.0% and 9.6 +/- 2.7 piglets). Numbers of ET-embryos appeared relevant, since the NsDU ET with 30 embryos resulted in a decrease (P<0.05) in farrowing rates (38.9%) and litter sizes (5.7 +/- 2.4 piglets). In conclusion, we demonstrate for the first time that farrowing rate and litter size following a NsDU-ET procedure increase in function of a larger number of transferred vitrified embryos, with fertility equalizing that obtained with the invasive surgical approach. The results open new possibilities for the widespread use of non-invasive ET in pigs. PMID- 26030840 TI - Macrocyclization of Peptide Side Chains by the Ugi Reaction: Achieving Peptide Folding and Exocyclic N-Functionalization in One Shot. AB - The cyclization of peptide side chains has been traditionally used to either induce or stabilize secondary structures (beta-strands, helices, reverse turns) in short peptide sequences. So far, classic peptide coupling, nucleophilic substitution, olefin metathesis, and click reactions have been the methods of choice to fold synthetic peptides by means of macrocyclization. This article describes the utilization of the Ugi reaction for the side chain-to-side chain and side chain-to-termini macrocyclization of peptides, thus enabling not only access to stable folded structures but also the incorporation of exocyclic functionalities as N-substituents. Analysis of the NMR-derived structures revealed the formation of helical turns, beta-bulges, and alpha-turns in cyclic peptides cross-linked at i, i + 3 and i, i + 4 positions, proving the folding effect of the multicomponent Ugi macrocyclization. Molecular dynamics simulation provided further insights on the stability and molecular motion of the side chain cross-linked peptides. PMID- 26030841 TI - Cobalt-Catalyzed [2pi + 2pi] Cycloadditions of Alkenes: Scope, Mechanism, and Elucidation of Electronic Structure of Catalytic Intermediates. AB - Aryl-substituted bis(imino)pyridine cobalt dinitrogen compounds, ((R)PDI)CoN2, are effective precatalysts for the intramolecular [2pi + 2pi] cycloaddition of alpha,omega-dienes to yield the corresponding bicyclo[3.2.0]heptane derivatives. The reactions proceed under mild thermal conditions with unactivated alkenes, tolerating both amine and ether functional groups. The overall second order rate law for the reaction, first order with respect to both the cobalt precatalyst and the substrate, in combination with electron paramagnetic resonance (EPR) spectroscopic studies established the catalyst resting state as dependent on the identity of the precatalyst and diene substrate. Planar S = 1/2 kappa(3) bis(imino)pyridine cobalt alkene and tetrahedral kappa(2)-bis(imino)pyridine cobalt diene complexes were observed by EPR spectroscopy and in the latter case structurally characterized. The hemilabile chelate facilitates conversion of a principally ligand-based singly occupied molecular orbital (SOMO) in the cobalt dinitrogen and alkene compounds to a metal-based SOMO in the diene intermediates, promoting C-C bond-forming oxidative cyclization. Structure-activity relationships on bis(imino)pyridine substitution were also established with 2,4,6 tricyclopentyl-substituted aryl groups, resulting in optimized catalytic [2pi + 2pi] cycloaddition. The cyclopentyl groups provide a sufficiently open metal coordination sphere that encourages substrate coordination while remaining large enough to promote a challenging, turnover-limiting C(sp(3))-C(sp(3)) reductive elimination. PMID- 26030843 TI - Hemocompatibility improvement of perfusion-decellularized clinical-scale liver scaffold through heparin immobilization. AB - Whole-liver perfusion-decellularization is an attractive scaffold-preparation technique for producing clinical transplantable liver tissue. However, the scaffold's poor hemocompatibility poses a major obstacle. This study was intended to improve the hemocompatibility of perfusion-decellularized porcine liver scaffold via immobilization of heparin. Heparin was immobilized on decellularized liver scaffolds (DLSs) by electrostatic binding using a layer-by-layer self assembly technique (/h-LBL scaffold), covalent binding via multi-point attachment (/h-MPA scaffold), or end-point attachment (/h-EPA scaffold). The effect of heparinization on anticoagulant ability and cytocompatibility were investigated. The result of heparin content and release tests revealed EPA technique performed higher efficiency of heparin immobilization than other two methods. Then, systematic in vitro investigation of prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), platelet adhesion and human platelet factor 4 (PF4, indicates platelet activation) confirmed the heparinized scaffolds, especially the /h-EPA counterparts, exhibited ultralow blood component activations and excellent hemocompatibility. Furthermore, heparin treatments prevented thrombosis successfully in DLSs with blood perfusion after implanted in vivo. Meanwhile, after heparin processes, both primary hepatocyte and endothelial cell viability were also well-maintained, which indicated that heparin treatments with improved biocompatibility might extend to various hemoperfusable whole-organ scaffolds' preparation. PMID- 26030842 TI - A fluorescent bimolecular complementation screen reveals MAF1, RNF7 and SETD3 as PCNA-associated proteins in human cells. AB - The proliferating cell nuclear antigen (PCNA) is a conserved component of DNA replication factories, and interactions with PCNA mediate the recruitment of many essential DNA replication enzymes to these sites of DNA synthesis. A complete description of the structure and composition of these factories remains elusive, and a better knowledge of them will improve our understanding of how the maintenance of genome and epigenetic stability is achieved. To fully characterize the set of proteins that interact with PCNA we developed a bimolecular fluorescence complementation (BiFC) screen for PCNA-interactors in human cells. This 2-hybrid type screen for interactors from a human cDNA library is rapid and efficient. The fluorescent read-out for protein interaction enables facile selection of interacting clones, and we combined this with next generation sequencing to identify the cDNAs encoding the interacting proteins. This method was able to reproducibly identify previously characterized PCNA-interactors but importantly also identified RNF7, Maf1 and SetD3 as PCNA-interacting proteins. We validated these interactions by co-immunoprecipitation from human cell extracts and by interaction analyses using recombinant proteins. These results show that the BiFC screen is a valuable method for the identification of protein-protein interactions in living mammalian cells. This approach has potentially wide application as it is high throughput and readily automated. We suggest that, given this interaction with PCNA, Maf1, RNF7, and SetD3 are potentially involved in DNA replication, DNA repair, or associated processes. PMID- 26030845 TI - Exposure to sunlight reduces the risk of myopia in rhesus monkeys. AB - Exposure to sunlight has recently been postulated as responsible for the effect that more time spent outdoors protects children from myopia, while early life exposure to natural light was reported to be possibly related to onset of myopia during childhood. In this study, we had two aims: to determine whether increasing natural light exposure has a protective effect on hyperopic defocus-induced myopia, and to observe whether early postnatal exposure to natural light causes increased risk of refractive error in adolescence. Eight rhesus monkeys (aged 20 30 days) were treated monocularly with hyperopic-defocus (-3.0D lens) and divided randomly into two groups: AL group (n=4), reared under Artificial (indoor) Lighting (08:00-20:00); and NL group (n=4), exposed to Natural (outdoor) Light for 3 hours per day (11:00-14:00), and to indoor lighting for the rest of the light phase. After being reared with lenses for ca. 190 days, all monkeys were returned to unrestricted vision until the age of 3 years. Another eight age matched monkeys, reared with unrestricted vision under artificial lighting since birth, were employed as controls. The ocular refraction, corneal curvature and axial dimensions were measured before lens-wearing (at 23+/-3 days of age), monthly during the light phase, and at the age of puberty (at 1185+3 days of age). During the lens-wearing treatment, infant monkeys in the NL group were more hyperopic than those in the AL group (F=5.726, P=0.032). Furthermore, the two eyes of most NL monkeys remained isometropic, whereas 3 of 4 AL monkeys developed myopic anisometropia more than -2.0D. At adolescence, eyes of AL monkeys showed significant myopic anisometropia compared with eyes of NL monkeys (AL vs NL: 1.66+/-0.87D vs -0.22+/-0.44D; P=0.002) and controls (AL vs Control: -1.66+/ 0.87D vs -0.05+/-0.85D; P<0.0001). All differences in refraction were associated with parallel changes in axial dimensions. Our results suggest that exposure to natural outdoor light might have an effect to reduced hyperopic defocus-induced myopia. Also, the data imply that early life exposure to sunlight may help to maintain normal development of emmetropization later in life, and thus lower the risk of myopic anisometropia in adolescent monkey. PMID- 26030844 TI - Cry protein crystals: a novel platform for protein delivery. AB - Protein delivery platforms are important tools in the development of novel protein therapeutics and biotechnologies. We have developed a new class of protein delivery agent based on sub-micrometer-sized Cry3Aa protein crystals that naturally form within the bacterium Bacillus thuringiensis. We demonstrate that fusion of the cry3Aa gene to that of various reporter proteins allows for the facile production of Cry3Aa fusion protein crystals for use in subsequent applications. These Cry3Aa fusion protein crystals are efficiently taken up and retained by macrophages and other cell lines in vitro, and can be delivered to mice in vivo via multiple modes of administration. Oral delivery of Cry3Aa fusion protein crystals to C57BL/6 mice leads to their uptake by MHC class II cells, including macrophages in the Peyer's patches, supporting the notion that the Cry3Aa framework can be used to stabilize cargo protein against degradation for delivery to gastrointestinal lymphoid tissues. PMID- 26030846 TI - Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. AB - Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance. PMID- 26030847 TI - Hand use predicts the structure of representations in sensorimotor cortex. AB - Fine finger movements are controlled by the population activity of neurons in the hand area of primary motor cortex. Experiments using microstimulation and single neuron electrophysiology suggest that this area represents coordinated multi joint, rather than single-finger movements. However, the principle by which these representations are organized remains unclear. We analyzed activity patterns during individuated finger movements using functional magnetic resonance imaging (fMRI). Although the spatial layout of finger-specific activity patterns was variable across participants, the relative similarity between any pair of activity patterns was well preserved. This invariant organization was better explained by the correlation structure of everyday hand movements than by correlated muscle activity. This also generalized to an experiment using complex multi-finger movements. Finally, the organizational structure correlated with patterns of involuntary co-contracted finger movements for high-force presses. Together, our results suggest that hand use shapes the relative arrangement of finger-specific activity patterns in sensory-motor cortex. PMID- 26030848 TI - Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses. AB - alpha- and beta-neurexins are presynaptic cell-adhesion molecules whose general importance for synaptic transmission is well documented. The specific functions of neurexins, however, remain largely unknown because no conditional neurexin knockouts are available and targeting all alpha- and beta-neurexins produced by a particular gene is challenging. Using newly generated constitutive and conditional knockout mice that target all neurexin-3alpha and neurexin-3beta isoforms, we found that neurexin-3 was differentially required for distinct synaptic functions in different brain regions. Specifically, we found that, in cultured neurons and acute slices of the hippocampus, extracellular sequences of presynaptic neurexin-3 mediated trans-synaptic regulation of postsynaptic AMPA receptors. In cultured neurons and acute slices of the olfactory bulb, however, intracellular sequences of presynaptic neurexin-3 were selectively required for GABA release. Thus, our data indicate that neurexin-3 performs distinct essential pre- or postsynaptic functions in different brain regions by distinct mechanisms. PMID- 26030849 TI - Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity. AB - Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self administration. PMID- 26030850 TI - beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. AB - Independent evidence associates beta-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of beta-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that beta amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC beta amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking beta-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which beta amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly. PMID- 26030851 TI - Host microbiota constantly control maturation and function of microglia in the CNS. AB - As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota. PMID- 26030852 TI - ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion. AB - Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression. PMID- 26030854 TI - (n,m) Assignments and quantification for single-walled carbon nanotubes on SiO2/Si substrates by resonant Raman spectroscopy. AB - The single-walled carbon nanotubes (SWNTs) on silicon substrates are a promising candidate for the next generation of electronic and photoelectronic devices, therefore an easy, convenient, and nondestructive method for characterizing such samples is quite important and strongly needed. In this study, we provide in detail such a method to assign (n,m) indices with considerable accuracy through resonant Raman spectra analysis. We developed an equation of omegaRBM = 235.9/dt + 5.5 for SWNTs grown by Ni, Co, and Fe catalysts on SiO2/Si substrates in the dt range of 1.2-2.1 nm. This method was further utilized to make (n,m) assignments and quantification for our SWNTs catalyzed by W6Co7, which is highly enriched with (12,6). The less abundant chiralities in the samples were also assigned and the contents were analyzed using a counting-based method. Moreover, these chirality-specified samples allowed us to collect 1330 RBM data for the single chirality (12,6) and the RBM variation was found to be no larger than +/-2.5 cm( 1). A step-by-step procedure is also provided as a general guide for (n,m) assignments. PMID- 26030853 TI - Differential susceptibility to environmental influences: Interactions between child temperament and parenting in adolescent alcohol use. AB - Temperament and parental practices (PP) are important predictors of adolescent alcohol use (AU); however, less is known about how they combine to increase or decrease risk of AU. This study examined whether age 6 temperament (i.e., impulsivity and inhibitory control) interacted with age 6 coercive PP and/or age 14 parental monitoring to predict AU at 15 years among 209 adolescents. Results showed that low parental monitoring was associated with more frequent AU and that coercive PP interacted with impulsivity to predict AU. This interaction was examined as a function of two models that were not studied before in the prediction of AU: the diathesis-stress model (i.e., impulsive children are more "vulnerable" to adverse PP than those with an easy temperament); and the differential susceptibility model (i.e., impulsive children are also more likely to benefit from good PP). Results supported the differential susceptibility model by showing that impulsive children were not only at higher risk for AU when combined with high coercive PP but also benefit from the absence of coercive PP. This supports the suggestion that the conception of certain temperament characteristics, or in this case impulsivity, as a "vulnerability" for adolescent AU, may need revision because it misrepresents the malleability it may imply. PMID- 26030857 TI - Corrections regarding prostate-specific antigen editorial. PMID- 26030858 TI - Cervical cancer screening by human papillomavirus testing followed by cytology triage. PMID- 26030859 TI - Cervical cancer screening by human papillomavirus testing followed by cytology triage--reply. PMID- 26030860 TI - Blood pressure and serum parathyroid hormone level. PMID- 26030861 TI - Blood pressure and serum parathyroid hormone level--reply. PMID- 26030862 TI - Incorrect MACE End Point. PMID- 26030863 TI - Missing signature block and author affiliations for in reply letter. PMID- 26030864 TI - Copper Tolerance and Biosorption of Saccharomyces cerevisiae during Alcoholic Fermentation. AB - At high levels, copper in grape mash can inhibit yeast activity and cause stuck fermentations. Wine yeast has limited tolerance of copper and can reduce copper levels in wine during fermentation. This study aimed to understand copper tolerance of wine yeast and establish the mechanism by which yeast decreases copper in the must during fermentation. Three strains of Saccharomyces cerevisiae (lab selected strain BH8 and industrial strains AWRI R2 and Freddo) and a simple model fermentation system containing 0 to 1.50 mM Cu2+ were used. ICP-AES determined Cu ion concentration in the must decreasing differently by strains and initial copper levels during fermentation. Fermentation performance was heavily inhibited under copper stress, paralleled a decrease in viable cell numbers. Strain BH8 showed higher copper-tolerance than strain AWRI R2 and higher adsorption than Freddo. Yeast cell surface depression and intracellular structure deformation after copper treatment were observed by scanning electron microscopy and transmission electron microscopy; electronic differential system detected higher surface Cu and no intracellular Cu on 1.50 mM copper treated yeast cells. It is most probably that surface adsorption dominated the biosorption process of Cu2+ for strain BH8, with saturation being accomplished in 24 h. This study demonstrated that Saccharomyces cerevisiae strain BH8 has good tolerance and adsorption of Cu, and reduces Cu2+ concentrations during fermentation in simple model system mainly through surface adsorption. The results indicate that the strain selected from China's stress-tolerant wine grape is copper tolerant and can reduce copper in must when fermenting in a copper rich simple model system, and provided information for studies on mechanisms of heavy metal stress. PMID- 26030865 TI - A new sauropod dinosaur from the Middle Jurassic of the United Kingdom. AB - A new record of a sauropodomorph dinosaur is here described from the Middle Jurassic (Aalenian) Saltwick Formation of Whitby (Yorkshire), UK. A single caudal vertebra represents an early sauropodomorph and signifies the earliest recognised eusauropod dinosaur from the United Kingdom. The absence of pleurocoels and a narrow, dorsoventrally deep, but craniocaudally short centrum, suggests a primitive sauropodomorph. Distinct spinopostzygopophyseal laminae rise from the lateral margins of the postzygapophyses and pass caudally along what remains of the neural spine, a character unique to a subgroup of sauropods that includes Barapasaurus, Omeisaurus and other neosauropods and eusauropods. The lack of phylogenetically robust characters in sauropod caudal vertebrae usually makes it difficult to establish affinities, but the absence of mild procoely excludes this specimen from both Diplodocoidea and Lithostrotia. The vertebra cannot be further distinguished from those of a wide range of basal sauropods, cetiosaurids and basal macronarians. However, this plesiomorphic vertebra still signifies the earliest stratigraphic occurrence for a British sauropod dinosaur. PMID- 26030866 TI - Incongruent nuclear and mitochondrial genetic structure of new world screwworm fly populations due to positive selection of mutations associated with dimethyl- and diethyl-organophosphates resistance. AB - Livestock production is an important economic activity in Brazil, which has been suffering significant losses due to the impact of parasites. The New World screwworm (NWS) fly, Cochliomyia hominivorax, is an ectoparasite and one of the most important myiasis-causing flies endemic to the Americas. The geographic distribution of NWS has been reduced after the implementation of the Sterile Insect Technique (SIT), being eradicated in North America and part of Central America. In South America, C. hominivorax is controlled by chemical insecticides, although indiscriminate use can cause selection of resistant individuals. Previous studies have associated the Gly137Asp and Trp251Leu mutations in the active site of carboxylesterase E3 to resistance of diethyl and dimethyl organophosphates insecticides, respectively. Here, we have sequenced a fragment of the carboxylesterase E3 gene (ChalphaE7), comprising part of intron iII, exon eIII, intron iIII and part of exon eIV, and three mitochondrial gene sequences (CR, COI and COII), of NWS flies from 21 locations in South America. These markers were used for population structure analyses and the ChalphaE7 gene was also investigated to gain insight into the selective pressures that have shaped its evolution. Analysis of molecular variance (AMOVA) and pairwise FST analysis indicated an increased genetic structure between locations in the ChalphaE7 compared to the concatenated mitochondrial genes. Discriminant analysis of principal components (DAPC) and spatial analysis of molecular variance (SAMOVA) indicated different degrees of genetic structure for all markers, in agreement with the AMOVA results, but with low correlation to geographic data. The NWS fly is considered a panmitic species based on mitochondrial data, while it is structured into three groups considering the ChalphaE7 gene. A negative association between the two mutations related to organophosphate resistance and Fay & Wu's H significant negative values for the exons, suggest that these mutations evolved under positive selection. PMID- 26030867 TI - TLR4 Expression Is Associated with Left Ventricular Dysfunction in Patients Undergoing Coronary Artery Bypass Surgery. AB - INTRODUCTION: Toll-like receptor 4 (TLR4) is an innate immune receptor expressed in immune cells and the heart. Activation of the immune system following myocardial ischemia causes the release of proinflammatory mediators that may negatively influence heart function. AIM: The aim of this study is to determine whether TLR4 is activated in peripheral monocytes and heart tissue taken from patients with varying degrees of myocardial dysfunction caused by coronary artery diseases and scheduled for coronary artery bypass graft (CABG) surgery before 12 months following operation. METHODS AND RESULTS: Patients (n = 44) undergoing CABG surgery having left ventricular ejection fraction <= 45% ('reduced EF', n = 20) were compared to patients with preserved EF >45% ('preserved EF' group, n = 24). 'Reduced EF' patients exhibited increased TLR4 expression in monocytes (2.78+/-0.49 vs. 1.76+/-0.07 rMFI, p = 0.03). Plasma levels of C-reactive protein, microRNA miR-320a, brain natriuretic peptide (pro BNP) and NADPH oxidase (NOX4) were also significantly different between the 'preserved EF' and 'reduced EF'groups. Elevated TLR4 gene expression levels in the right auricle correlated with those of EF (p<0.008), NOX4 (p<0.008) and miR320, (p<0.04). In contrast, no differences were observed in peripheral monocyte TLR2 expression. After CABG surgery, monocyte TLR4 expression decreased in all patients, reaching statistical significance in the 'reduced EF' group. CONCLUSION: TLR4 is activated in peripheral monocytes and heart tissue obtained from patients with ischemic heart disease and reduced left ventricular function. Coronary revascularization decreases TLR4 expression. We therefore propose that TLR4 plays a pathogenic role and may serve as an additional marker of ischemic myocardial dysfunction. PMID- 26030868 TI - The Structural Variation Is Associated with the Embryonic Lethality of a Novel Red Egg Mutant Fuyin-lre of Silkworm, Bombyx mori. AB - Bombyx mori presents several types of egg color mutations, all of which have been extensively discussed in sericulture. While the red egg mutation has been previously observed, lethal red-egg mutants have not been reported. In the present work, the red egg mutant Fuyin-lre (Fuyin-lethal red egg) was discovered from the Fuyin germplasm resource of B. mori. This mutant features red-colored eggs and embryonic lethality. Genetic analysis showed that Fuyin-lre follows recessive inheritance, with the red egg gene re governing the egg color, and the embryonic lethality of Fuyin-lre may be caused by mutations of other genes closely linked to re. Digital gene expression (DGE) was employed to compare the transcription profiles of Fuyin and Fuyin-lre eggs after 24 and 48 h of incubation. A total of 48 differentially expressed genes followed the same expression patterns in both groups at both time points (FDR < 0.01 and log 2 Ratio >= 1). Further analyses indicated that 8 out of the 48 genes (including re) were closely linked to re. These 8 genes were highly expressed in wild-type Fuyin and the red egg mutant re but showed nearly absent expression in Fuyin-lre. Sequencing of the re gene confirmed that the re gene itself does not induce embryonic lethality, and structure analysis showed that the structural variation of the region where the 8 genes were located may be associated with the embryonic lethality of Fuyin-lre. The present work provides a good foundation for future studies on the mechanism of embryonic lethality and embryonic development in Fuyin-lre. PMID- 26030869 TI - Understanding the Low Level of Cervical Cancer Screening in Masaka Uganda Using the ASE Model: A Community-Based Survey. AB - Cervical cancer is one of the leading causes of cancer deaths among women globally and its impact is mostly felt in developing countries like Uganda where its prevalence is higher and utilization of cancer screening services is low. This study aimed to identify factors associated with intention to screen for cervical cancer among women of reproductive age in Masaka Uganda using the attitude, social influence and self efficacy (ASE) model. A descriptive community based survey was conducted among 416 women. A semi-structured interviewer administered questionnaire was used to collect data. Unadjusted and adjusted prevalence ratios (PR) were computed using a generalized linear model with Poisson family and a log link using STATA 12. Only 7% (29/416) of our study respondents had ever screened for cervical cancer although a higher proportion (63%, 262/416) reported intention to screen for cervical cancer. The intention to screen for cervical cancer was higher among those who said they were at risk of developing cervical cancer (Adjusted prevalence ratio [PR] 2.0, 95% CI 1.60 2.58), those who said they would refer other women for screening (Adjusted PR 1.4, 95% CI 1.06-1.88) and higher among those who were unafraid of being diagnosed with cervical cancer (Adjusted PR 1.6, 95% CI 1.36-1.93). Those who reported discussions on cervical cancer with health care providers (Adjusted PR 1.2, 95% CI 1.05-1.44), those living with a sexual partner (Adjusted PR 1.4, 95% CI 1.11-1.68), and those who were formally employed (Adjusted PR 1.2, 95% CI 1.03 1.35) more frequently reported intention to screen for cervical cancer. In conclusion, health education to increase risk perception, improve women's attitudes towards screening for cervical cancer and address the fears held by the women would increase intention to screen for cervical cancer. Interventions should also target increased discussions with health workers. PMID- 26030870 TI - Establishment of the tree shrew as an alcohol-induced Fatty liver model for the study of alcoholic liver diseases. AB - Currently, the pathogenesis of alcoholic liver diseases (ALDs) is not clear. As a result, there is no effective treatment for ALDs. One limitation is the lack of a suitable animal model for use in studying ALDs. The tree shrew is a lower primate animal, characterized by a high-alcohol diet. This work aimed to establish a fatty liver model using tree shrews and to assess the animals' suitability for the study of ALDs. Tree shrews were treated with alcohol solutions (10% and 20%) for two weeks. Hemophysiology, blood alcohol concentrations (BACs), oxidative stress factors, alcohol metabolic enzymes and hepatic pathology were checked and assayed with an automatic biochemical analyzer, enzyme-linked immunosorbent assay (ELISA), western blot, hematoxylin-eosin (HE) staining and oil red O staining, and magnetic resonance imaging (MRI). Compared with the normal group, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), total cholesterol (TC), triglyceride (TG), reactive oxygen species (ROS), and malondialdehyde (MDA) were significantly enhanced in alcohol-treated tree shrews. However, the activity of reduced glutathione hormone (GSH) and superoxide dismutase (SOD) declined. Notable changes in alcohol dehydrogenase(ADH1), aldehyde dehydrogenase(ALDH2), CYP2E1, UDP-glucuronosyl transferase 1A1 (UGT1A1) and nuclear factor erythroid-related factor 2 (Nrf2) were observed. HE and oil red O staining showed that hepatocyte swelling, hydropic degeneration, and adipohepatic syndrome occurred in the tree shrews. Alcohol can induce fatty liver-like pathological changes and result in alterations in liver function, oxidative stress factors, alcohol metabolism enzymes and Nrf2. Therefore, the established fatty liver model of tree shrews induced by alcohol should be a promising tool for the study of ALDs. PMID- 26030871 TI - The Divergent Effects of Fear and Disgust on Inhibitory Control: An ERP Study. AB - Negative emotional stimuli have been shown to attract attention and impair executive control. However, two different types of unpleasant stimuli, fearful and disgusting, are often inappropriately treated as a single category in the literature on inhibitory control. Therefore, the present study aimed to investigate the divergent effects of fearful and disgusting distracters on inhibitory control (both conscious and unconscious inhibition). Specifically, participants were engaged in a masked Go/No-Go task superimposed on fearful, disgusting, or neutral emotional contexts, while event-related potentials were measured concurrently. The results showed that for both conscious and unconscious conditions, disgusting stimuli elicited a larger P2 than fearful ones, and the difference waves of P3 amplitude under disgusting contexts were smaller than that under fearful contexts. These results suggest that disgusting distracters consume more attentional resources and therefore impair subsequent inhibitory control to a greater extent. This study is the first to provide electrophysiological evidence that fear and disgust differently affect inhibitory control. These results expand our understanding of the relationship between emotions and inhibitory control. PMID- 26030872 TI - Correction: Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis. PMID- 26030873 TI - Correction: New Insights on the Mechanism of the K+-Independent Activity of Crenarchaeota Pyruvate Kinases. PMID- 26030874 TI - Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. AB - Rapid neurotransmitter release depends on the Ca2+ sensor Synaptotagmin-1 (Syt1) and the SNARE complex formed by synaptobrevin, syntaxin-1 and SNAP-25. How Syt1 triggers release has been unclear, partly because elucidating high-resolution structures of Syt1-SNARE complexes has been challenging. An NMR approach based on lanthanide-induced pseudocontact shifts now reveals a dynamic binding mode in which basic residues in the concave side of the Syt1 C2B-domain beta-sandwich interact with a polyacidic region of the SNARE complex formed by syntaxin-1 and SNAP-25. The physiological relevance of this dynamic structural model is supported by mutations in basic residues of Syt1 that markedly impair SNARE complex binding in vitro and Syt1 function in neurons. Mutations with milder effects on binding have correspondingly milder effects on Syt1 function. Our results support a model whereby dynamic interaction facilitates cooperation between Syt1 and the SNAREs in inducing membrane fusion. PMID- 26030875 TI - Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic vesicle priming. AB - UNC-13-Munc13s have a central function in synaptic-vesicle priming through their MUN domains. However, it is unclear whether this function arises from the ability of the MUN domain to mediate the transition from the Munc18-1-closed syntaxin-1 complex to the SNARE complex in vitro. The crystal structure of the rat Munc13-1 MUN domain now reveals an elongated, arch-shaped architecture formed by alpha helical bundles, with a highly conserved hydrophobic pocket in the middle. Mutation of two residues (NF) in this pocket abolishes the stimulation caused by the Munc13-1 MUN domain on SNARE-complex assembly and on SNARE-dependent proteoliposome fusion in vitro. Moreover, the same mutation in UNC-13 abrogates synaptic-vesicle priming in Caenorhabditis elegans neuromuscular junctions. These results support the notion that orchestration of syntaxin-1 opening and SNARE complex assembly underlies the central role of UNC-13-Munc13s in synaptic-vesicle priming. PMID- 26030876 TI - Structure of the Atg101-Atg13 complex reveals essential roles of Atg101 in autophagy initiation. AB - Atg101 is an essential component of the autophagy-initiating ULK complex in higher eukaryotes, but it is absent from the functionally equivalent Atg1 complex in budding yeast. Here, we report the crystal structure of the fission yeast Atg101-Atg13 complex. Atg101 has a Hop1, Rev7 and Mad2 (HORMA) architecture similar to that of Atg13. Mad2 HORMA has two distinct conformations (O-Mad2 and C Mad2), and, intriguingly, Atg101 resembles O-Mad2 rather than the C-Mad2-like Atg13. Atg13 HORMA from higher eukaryotes possesses an inherently unstable fold, which is stabilized by Atg101 via interactions analogous to those between O-Mad2 and C-Mad2. Mutational studies revealed that Atg101 is responsible for recruiting downstream factors to the autophagosome-formation site in mammals via a newly identified WF finger. These data define the molecular functions of Atg101, providing a basis for elucidating the molecular mechanisms of mammalian autophagy initiation by the ULK complex. PMID- 26030877 TI - Spatial and Temporal Potato Intensification Drives Insecticide Resistance in the Specialist Herbivore, Leptinotarsa decemlineata. AB - Landscape-scale intensification of individual crops and pesticide use that is associated with this intensification is an emerging, environmental problem that is expected to have unequal effects on pests with different lifecycles, host ranges, and dispersal abilities. We investigate if intensification of a single crop in an agroecosystem has a direct effect on insecticide resistance in a specialist insect herbivore. Using a major potato pest, Leptinotarsa decemlineata, we measured imidacloprid (neonicotinoid) resistance in populations across a spatiotemporal crop production gradient where potato production has increased in Michigan and Wisconsin, USA. We found that concurrent estimates of area and temporal frequency of potato production better described patterns of imidacloprid resistance among L. decemlineata populations than general measures of agricultural production (% cropland, landscape diversity). This study defines the effects individual crop rotation patterns can have on specialist herbivore insecticide resistance in an agroecosystem context, and how impacts of intensive production can be estimated with general estimates of insecticide use. Our results provide empirical evidence that variation in the intensity of neonicotinoid-treated potato in an agricultural landscape can have unequal impacts on L. decemlineata insecticide insensitivity, a process that can lead to resistance and locally intensive insecticide use. Our study provides a novel approach applicable in other agricultural systems to estimate impacts of crop rotation, increased pesticide dependence, insecticide resistance, and external costs of pest management practices on ecosystem health. PMID- 26030878 TI - The Intra- or Extracellular Redox State Was Not Affected by a High vs. Low Glycemic Response Diet in Mice. AB - A low glycemic response (LGR) vs. high glycemic response (HGR) diet helps curtail the development of obesity and diabetes, though the mechanisms are unknown. We hypothesized that consumption of a HGR vs. a LGR diet would lead to a more oxidized circulating redox state and predicted that a HGR diet would increase fat accumulation, reduce insulin sensitivity, and impair metabolic acclimation to a high fat diet in a mouse model. Hence, male C57BL/6 mice consumed a HGR or LGR diet for 16 weeks and a subset of the mice subsequently consumed a high fat diet for 4 weeks. We found that body mass increased at a faster rate for those consuming the HGR diet. Percent body fat was greater and percent lean mass was lesser in the HGR group starting at 12 weeks. However, the groups did not differ in terms of glucose tolerance at week 14 and metabolic parameters (respiratory exchange ratio, heat production, activity) at weeks 4 or 15. Moreover, mice on either diet did not show differences in metabolic acclimation to the high fat leg of the study. At the termination of the study, the groups did not differ in terms of redox pairs (lactate/pyruvate and beta-hydroxybutyrate/acetoacetate) or thioredoxin reductase activity in blood. Also, total and oxidized glutathione levels and lipid peroxidation were similar in blood and liver. Correlations between baseline measures, longitudinal parameters, environmental conditions, and terminal metrics revealed that individual mice have innate propensities to metabolic regulation that may be difficult to perturb with diet alone; for example, starting mass correlated negatively with energy expenditure 4 weeks into the study and total hepatic glutathione at the end of the study. In conclusion, these data suggest that the mechanism by which HGR carbohydrates contributes to obesity is not via prolonged oxidation of the circulating redox state. PMID- 26030879 TI - Pre-Columbian floristic legacies in modern homegardens of Central Amazonia. AB - Historical ecologists have demonstrated legacy effects in apparently wild landscapes in Europe, North America, Mesoamerica, Amazonia, Africa and Oceania. People live and farm in archaeological sites today in many parts of the world, but nobody has looked for the legacies of past human occupations in the most dynamic areas in these sites: homegardens. Here we show that the useful flora of modern homegardens is partially a legacy of pre-Columbian occupations in Central Amazonia: the more complex the archaeological context, the more variable the floristic composition of useful native plants in homegardens cultivated there today. Species diversity was 10% higher in homegardens situated in multi occupational archaeological contexts compared with homegardens situated in single occupational ones. Species heterogeneity (beta-diversity) among archaeological contexts was similar for the whole set of species, but markedly different when only native Amazonian species were included, suggesting the influence of pre conquest indigenous occupations on current homegarden species composition. Our findings show that the legacy of pre-Columbian occupations is visible in the most dynamic of all agroecosystems, adding another dimension to the human footprint in the Amazonian landscape. PMID- 26030880 TI - Phosphorus-32, a clinically available drug, inhibits cancer growth by inducing DNA double-strand breakage. AB - Radioisotopes that emit electrons (beta particles), such as radioiodine, can effectively kill target cells, including cancer cells. Aqueous 32P[PO4] is a pure beta-emitter that has been used for several decades to treat non-malignant human myeloproliferative diseases. 32P[PO4] was directly compared to a more powerful pure beta-emitter, the clinically important 90Y isotope. In vitro, 32P[PO4] was more effective at killing cells than was the more powerful isotope 90Y (P <= 0.001) and also caused substantially more double-stranded DNA breaks than did 90Y. In vivo, a single low-dose intravenous dose of aqueous elemental 32P significantly inhibited tumor growth in the syngeneic murine cancer model (P <= 0.001). This effect is exerted by direct incorporation into nascent DNA chains, resulting in double-stranded breakage, a unique mechanism not duplicatable by other, more powerful electron-emitting radioisotopes. 32P[PO4] should be considered for human clinical trials as a potential novel anti-cancer drug. PMID- 26030881 TI - Free volume and gas permeation in anthracene maleimide-based polymers of intrinsic microporosity. AB - High free-volume copolymers were prepared via polycondensation with 2,3,5,6, tetrafluoroterephthalonitrile (TFTPN) in which a portion of the 3,3,3',3' tetramethyl-1,1'-spirobisindane (TTSBI) of PIM-1 was replaced with dibutyl anthracene maleimide (4bIII). An investigation of free volume using positron annihilation lifetime spectroscopy (PALS), and gas permeation measurements was carried out for the thin film composite copolymer membranes and compared to PIM 1. The average free volume hole size and the gas permeance of the copolymer membranes increased with decreasing TTSBI content in the copolymer. PMID- 26030882 TI - Derivatization of (quinolin-8-yl)phosphinimidic amides via ortho-lithiation revisited. AB - 5The direct ortho-lithiation of N-H containing (quinolin-8-yl)phosphinimidic amides by reaction with 1 equiv. of n-BuLi described by Wang and co-workers has been re-examined. The multinuclear magnetic resonance ((1)H, (2)H, (7)Li, (13)C, (15)N and (31)P) study of the species formed in the monolithiation of N-(tert butyl)-P,P-diphenyl-N'-(quinolin-8-yl)phosphinimidic amide 5 with n-BuLi in THF showed that proton abstraction occurred exclusively and quantitatively at the NH. The combination of the NMR results with a DFT study made it possible to describe the structure of the N-lithiated species 9 as a dimer consisting of an eight membered ring showing two lithium ions triply coordinated to nitrogen atoms corresponding to the deprotonated amine and aminoquinoline moieties of different monomers. The formation of a polymer featuring the same coordination mode couldn't be excluded. In addition, optimized conditions for the efficient derivatization of 5 via ortho-lithiation were realised. The reaction of 5 with 2.4 equiv. of t-BuLi in THF in the temperature range of -80 degrees C to 25 degrees C for 3 h afforded a N,C(ortho)-dilithiated species that was trapped with a series of electrophiles leading to new functionalized ortho derivatives of 5 in good yields. PMID- 26030883 TI - Shading and watering as a tool to mitigate the impacts of climate change in sea turtle nests. AB - Increasing sand temperatures resulting from climate change may negatively impact sea turtle nests by altering sex ratios and decreasing reproductive output. We analyzed the effect of nest shading and watering on sand temperatures as climate mitigation strategies in a beach hatchery at Playa Grande, Costa Rica. We set up plots and placed thermocouples at depths of 45 cm and 75 cm. Half of the plots were shaded and half were exposed to the sun. Within these exposure treatments, we applied three watering treatments over one month, replicating local climatic conditions experienced in this area. We also examined gravimetric water content of sand by collecting sand samples the day before watering began, the day after watering was complete, and one month after completion. Shading had the largest impact on sand temperature, followed by watering and depth. All watering treatments lowered sand temperature, but the effect varied with depth. Temperatures in plots that received water returned to control levels within 10 days after watering stopped. Water content increased at both depths in the two highest water treatments, and 30 days after the end of water application remained higher than plots with low water. While the impacts of watering on sand temperature dissipate rapidly after the end of application, the impacts on water content are much more lasting. Although less effective at lowering sand temperatures than shading, watering may benefit sea turtle clutches by offsetting negative impacts of low levels of rain in particularly dry areas. Prior to implementing such strategies, the natural conditions at the location of interest (e.g. clutch depth, environmental conditions, and beach characteristics) and natural hatchling sex ratios should be taken into consideration. These results provide insight into the effectiveness of nest shading and watering as climate mitigation techniques and illustrate important points of consideration in the crafting of such strategies. PMID- 26030884 TI - Phylogenetically Distant Viruses Use the Same BH3-Only Protein Puma to Trigger Bax/Bak-Dependent Apoptosis of Infected Mouse and Human Cells. AB - Viruses can trigger apoptosis of infected host cells if not counteracted by cellular or viral anti-apoptotic proteins. These protective proteins either inhibit the activation of caspases or they act as Bcl-2 homologs to prevent Bax/Bak-mediated outer mitochondrial membrane permeabilization (MOMP). The exact mechanism by which viruses trigger MOMP has however remained enigmatic. Here we use two distinct types of viruses, a double stranded DNA virus, herpes simplex virus-1 (HSV-1) and a positive sense, single stranded RNA virus, Semliki Forest virus (SFV) to show that the BH3-only protein Puma is the major mediator of virus induced Bax/Bak activation and MOMP induction. Indeed, when Puma was genetically deleted or downregulated by shRNA, mouse embryonic fibroblasts and IL-3-dependent monocytes as well as human colon carcinoma cells were as resistant to virus induced apoptosis as their Bax/Bak double deficient counterparts (Bax/Bak-/-). Puma protein expression started to augment after 2 h postinfection with both viruses. Puma mRNA levels increased as well, but this occurred after apoptosis initiation (MOMP) because it was blocked in cells lacking Bax/Bak or overexpressing Bcl-xL. Moreover, none of the classical Puma transcription factors such as p53, p73 or p65 NFkappaB were involved in HSV-1-induced apoptosis. Our data suggest that viruses use a Puma protein-dependent mechanism to trigger MOMP and apoptosis in host cells. PMID- 26030885 TI - Skin transcriptome profiles associated with skin color in chickens. AB - Nutritional and medicinal benefits have been attributed to the consumption of tissues from the black-boned chickens in oriental countries. Lueyang black-boned chicken is one of the native chicken breeds. However, some birds may instead have white or lighter skin, which directly causes economic losses every year. Previous studies of pigmentation have focused on a number of genes that may play important roles in coat color regulation. Illumina2000 sequencing technology was used to catalog the global gene expression profiles in the skin of the Lueyang chicken with white versus black skin. A total of 18,608 unigenes were assembled from the reads obtained from the skin of the white and black chickens. A total of 649 known genes were differentially expressed in the black versus white chickens, with 314 genes that were up regulated and 335 genes that were down-regulated, and a total of 162 novel genes were differentially expressed in the black versus white chickens, consisting of 73 genes that were up-regulated (including 4 highly expressed genes that were expressed exclusively in the skin of the black chickens) and 89 genes that were down-regulated. There were also a total of 8 known coat-color genes expressed in previous studies (ASIP, TYR, KIT, TYRP1, OCA2, KITLG, MITF and MC1R). In this study, 4 of which showed greater expression in the black chickens, and several were up-regulated, such as KIT, ASIP, TYR and OCA2. To our surprise, KITLG, MITF and MC1R showed no significant difference in expression between the black- and white-skinned chickens, and the expression of TYRP1 was not detected in either skin color. The expression of ASIP, TYR, KIT, TYRP1, OCA2, KITLG, MITF and MC1R was validated by real-time quantitative polymerase chain reaction (qPCR), and the results of the qPCR were consistent with the RNA-seq. This study provides several candidate genes that may be associated with the development of black versus white skin. More importantly, the fact that the MC1R gene showed no significant difference in expression between the black and white chickens is of particular interest for future studies that aim to elucidate its functional role in the regulation of skin color. PMID- 26030886 TI - The Origin, Development and Molecular Diversity of Rodent Olfactory Bulb Glutamatergic Neurons Distinguished by Expression of Transcription Factor NeuroD1. AB - Production of olfactory bulb neurons occurs continuously in the rodent brain. Little is known, however, about cellular diversity in the glutamatergic neuron subpopulation. In the central nervous system, the basic helix-loop-helix transcription factor NeuroD1 (ND1) is commonly associated with glutamatergic neuron development. In this study, we utilized ND1 to identify the different subpopulations of olfactory bulb glutamategic neurons and their progenitors, both in the embryo and postnatally. Using knock-in mice, transgenic mice and retroviral transgene delivery, we demonstrate the existence of several different populations of glutamatergic olfactory bulb neurons, the progenitors of which are ND1+ and ND1- lineage-restricted, and are temporally and regionally separated. We show that the first olfactory bulb glutamatergic neurons produced - the mitral cells - can be divided into molecularly diverse subpopulations. Our findings illustrate the complexity of neuronal diversity in the olfactory bulb and that seemingly homogenous neuronal populations can consist of multiple subpopulations with unique molecular signatures of transcription factors and expressing neuronal subtype-specific markers. PMID- 26030888 TI - Should we reconsider the use of self-expandable metal stents as a bridge to surgery in malignant colorectal obstruction? PMID- 26030887 TI - Rumen microbiome from steers differing in feed efficiency. AB - The cattle rumen has a diverse microbial ecosystem that is essential for the host to digest plant material. Extremes in body weight (BW) gain in mice and humans have been associated with different intestinal microbial populations. The objective of this study was to characterize the microbiome of the cattle rumen among steers differing in feed efficiency. Two contemporary groups of steers (n=148 and n=197) were fed a ration (dry matter basis) of 57.35% dry-rolled corn, 30% wet distillers grain with solubles, 8% alfalfa hay, 4.25% supplement, and 0.4% urea for 63 days. Individual feed intake (FI) and BW gain were determined. Within contemporary group, the four steers within each Cartesian quadrant were sampled (n=16/group) from the bivariate distribution of average daily BW gain and average daily FI. Bacterial 16S rRNA gene amplicons were sequenced from the harvested bovine rumen fluid samples using next-generation sequencing technology. No significant changes in diversity or richness were indicated, and UniFrac principal coordinate analysis did not show any separation of microbial communities within the rumen. However, the abundances of relative microbial populations and operational taxonomic units did reveal significant differences with reference to feed efficiency groups. Bacteroidetes and Firmicutes were the dominant phyla in all ruminal groups, with significant population shifts in relevant ruminal taxa, including phyla Firmicutes and Lentisphaerae, as well as genera Succiniclasticum, Lactobacillus, Ruminococcus, and Prevotella. This study suggests the involvement of the rumen microbiome as a component influencing the efficiency of weight gain at the 16S level, which can be utilized to better understand variations in microbial ecology as well as host factors that will improve feed efficiency. PMID- 26030889 TI - ERCP and reprocessing in focus: what can we do to prevent or manage infection outbreaks? PMID- 26030890 TI - Combined endobronchial and esophageal endosonography for the diagnosis and staging of lung cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). AB - This is an official guideline of the European Society of Gastrointestinal Endoscopy (ESGE), produced in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). It addresses the benefit and burden associated with combined endobronchial and esophageal mediastinal nodal staging of lung cancer. The Scottish Intercollegiate Guidelines Network (SIGN) approach was adopted to define the strength of recommendations and the quality of evidence.The article has been co-published with permission in the European Journal of Cardio-Thoracic Surgery and the European Respiratory Journal. Recommendations 1 For mediastinal nodal staging in patients with suspected or proven non-small-cell lung cancer (NSCLC) with abnormal mediastinal and/or hilar nodes at computed tomography (CT) and/or positron emission tomography (PET), endosonography is recommended over surgical staging as the initial procedure (Recommendation grade A). The combination of endobronchial ultrasound with real time guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic (esophageal) ultrasound with fine needle aspiration, with use of a gastrointestinal (EUS-FNA) or EBUS (EUS-B-FNA) scope, is preferred over either test alone (Recommendation grade C). If the combination of EBUS and EUS-(B) is not available, we suggest that EBUS alone is acceptable (Recommendation grade C).Subsequent surgical staging is recommended, when endosonography does not show malignant nodal involvement (Recommendation grade B). 2 For mediastinal nodal staging in patients with suspected or proven non-small-cell peripheral lung cancer without mediastinal involvement at CT or CT-PET, we suggest that EBUS-TBNA and/or EUS-(B)-FNA should be performed before therapy, provided that one or more of the following conditions is present: (i) enlarged or fluorodeoxyglucose (FDG) PET-avid ipsilateral hilar nodes; (ii) primary tumor without FDG uptake; (iii) tumor size >= 3 cm (Fig. 3a - c) (Recommendation grade C). If endosonography does not show malignant nodal involvement, we suggest that mediastinoscopy is considered, especially in suspected N1 disease (Recommendation grade C).If PET is not available and CT does not reveal enlarged hilar or mediastinal lymph nodes, we suggest performance of EBUS-TBNA and/or EUS-(B)-FNA and/or surgical staging (Recommendation grade C). 3 In patients with suspected or proven < 3 cm peripheral NSCLC with normal mediastinal and hilar nodes at CT and/or PET, we suggest initiation of therapy without further mediastinal staging (Recommendation grade C). 4 For mediastinal staging in patients with centrally located suspected or proven NSCLC without mediastinal or hilar involvement at CT and/or CT-PET, we suggest performance of EBUS-TBNA, with or without EUS-(B)-FNA, in preference to surgical staging (Fig. 4) (Recommendation grade D). If endosonography does not show malignant nodal involvement, mediastinoscopy may be considered (Recommendation grade D). 5 For mediastinal nodal restaging following neoadjuvant therapy, EBUS-TBNA and/or EUS-(B)-FNA is suggested for detection of persistent nodal disease, but, if this is negative, subsequent surgical staging is indicated (Recommendation grade C). 6 A complete assessment of mediastinal and hilar nodal stations, and sampling of at least three different mediastinal nodal stations (4 R, 4 L, 7) (Fig. 1, Fig. 5) is suggested in patients with NSCLC and an abnormal mediastinum by CT or CT-PET (Recommendation grade D). 7 For diagnostic purposes, in patients with a centrally located lung tumor that is not visible at conventional bronchoscopy, endosonography is suggested, provided the tumor is located immediately adjacent to the larger airways (EBUS) or esophagus (EUS-(B)) (Recommendation grade D). 8 In patients with a left adrenal gland suspected for distant metastasis we suggest performance of endoscopic ultrasound fine needle aspiration (EUS-FNA) (Recommendation grade C), while the use of EUS-B with a transgastric approach is at present experimental (Recommendation grade D). 9 For optimal endosonographic staging of lung cancer, we suggest that individual endoscopists should be trained in both EBUS and EUS-B in order to perform complete endoscopic staging in one session (Recommendation grade D). 10 We suggest that new trainees in endosonography should follow a structured training curriculum consisting of simulation-based training followed by supervised practice on patients (Recommendation grade D). 11 We suggest that competency in EBUS-TBNA and EUS-(B)-FNA for staging lung cancer be assessed using available validated assessment tools (Recommendation Grade D). PMID- 26030891 TI - Endoscopy-associated transmission of carbapenemase-producing Enterobacteriaceae: return of 5 years' experience. PMID- 26030892 TI - Pancreatic cystic lesions: the challenge of risk stratification for malignancy. PMID- 26030893 TI - Reply to Barresi et al. PMID- 26030894 TI - Cap, hood, cuff, and balloon - what next for colonoscopy? PMID- 26030895 TI - Reply to Mohammed & Rembacken. PMID- 26030898 TI - [In Process Citation]. PMID- 26030899 TI - [In Process Citation]. PMID- 26030900 TI - Video Comment on Verfaillie CJ et al. PMID- 26030901 TI - UVB Stimulates the Expression of Endothelin B Receptor in Human Melanocytes via a Sequential Activation of the p38/MSK1/CREB/MITF Pathway Which Can Be Interrupted by a French Maritime Pine Bark Extract through a Direct Inactivation of MSK1. AB - Melanogenesis is the physiological process by which melanin is synthesized to protect the skin from UV damage. While paracrine interactions between keratinocytes and melanocytes are crucial for regulating epidermal pigmentation, the endothelin (EDN)-endothelin B-receptor (EDNRB) interaction is one of the key linkages. In this study, we found that a single exposure of normal human melanocytes (NHMs) with UVB stimulates the expression of EDNRB and its upstream transcription factor microphthalmia-associated transcription factor (MITF) at the transcriptional and translational levels. That stimulation can be abrogated by post-irradiation treatment with a French maritime pine bark extract (PBE). UVB stimulated the phosphorylation of p38 and c-jun N-terminal kinase (JNK), but not ERK, followed by the increased phosphorylation of MSK1 and CREB. The post irradiation treatment with PBE did not affect the increased phosphorylation of p38 and JNK, but distinctly abrogated the phosphorylation of MSK1 and CREB. Post irradiation treatment with the MSK1 inhibitor H89 significantly down-regulated the increased gene expression of MITF and EDNRB in UVB-exposed NHMs. Our findings indicate for the first time that the increased expression of MITF that leads to the up-regulation of melanocyte-specific proteins in UVB-exposed NHMs is mediated via activation of the p38/MSK1/CREB pathway but not the ERK/RSK/CREB pathway. The mode of action by PBE demonstrates that interrupting MSK1 activation is a new target for antioxidants including PBE which can serve as anti-pigmenting agents in a reactive oxygen species-depletion-independent manner. PMID- 26030902 TI - Three dimensional imaging of paraffin embedded human lung tissue samples by micro computed tomography. AB - BACKGROUND: Understanding the three-dimensional (3-D) micro-architecture of lung tissue can provide insights into the pathology of lung disease. Micro computed tomography (uCT) has previously been used to elucidate lung 3D histology and morphometry in fixed samples that have been stained with contrast agents or air inflated and dried. However, non-destructive microstructural 3D imaging of formalin-fixed paraffin embedded (FFPE) tissues would facilitate retrospective analysis of extensive tissue archives of lung FFPE lung samples with linked clinical data. METHODS: FFPE human lung tissue samples (n = 4) were scanned using a Nikon metrology uCT scanner. Semi-automatic techniques were used to segment the 3D structure of airways and blood vessels. Airspace size (mean linear intercept, Lm) was measured on uCT images and on matched histological sections from the same FFPE samples imaged by light microscopy to validate uCT imaging. RESULTS: The uCT imaging protocol provided contrast between tissue and paraffin in FFPE samples (15 mm x 7 mm). Resolution (voxel size 6.7 um) in the reconstructed images was sufficient for semi-automatic image segmentation of airways and blood vessels as well as quantitative airspace analysis. The scans were also used to scout for regions of interest, enabling time-efficient preparation of conventional histological sections. The Lm measurements from uCT images were not significantly different to those from matched histological sections. CONCLUSION: We demonstrated how non-destructive imaging of routinely prepared FFPE samples by laboratory uCT can be used to visualize and assess the 3D morphology of the lung including by morphometric analysis. PMID- 26030903 TI - Fine Mapping and Candidate Gene Analysis of qSTL3, a Stigma Length-Conditioning Locus in Rice (Oryza sativa L.). AB - The efficiency of hybrid seed production can be improved by increasing the percentage of exserted stigma, which is closely related to the stigma length in rice. In the chromosome segment substitute line (CSSL) population derived from Nipponbare (recipient) and Kasalath (donor), a single CSSL (SSSL14) was found to show a longer stigma length than that of Nipponbare. The difference in stigma length between Nipponbare and SSSL14 was controlled by one locus (qSTL3). Using 7,917 individuals from the SSSL14/Nipponbare F2 population, the qSTL3 locus was delimited to a 19.8-kb region in the middle of the short arm of chromosome 3. Within the 19.8-kb chromosome region, three annotated genes (LOC_Os03g14850, LOC_Os03g14860 and LOC_Os03g14880) were found in the rice genome annotation database. According to gene sequence alignments in LOC_Os03g14850, a transition of G (Nipponbare) to A (Kasalath) was detected at the 474-bp site in CDS. The transition created a stop codon, leading to a deletion of 28 amino acids in the deduced peptide sequence in Kasalath. A T-DNA insertion mutant (05Z11CN28) of LOC_Os03g14850 showed a longer stigma length than that of wild type (Zhonghua 11), validating that LOC_Os03g14850 is the gene controlling stigma length. However, the Kasalath allele of LOC_Os03g14850 is unique because all of the alleles were the same as that of Nipponbare at the 474-bp site in the CDS of LOC_Os03g14850 among the investigated accessions with different stigma lengths. A gene-specific InDel marker LQ30 was developed for improving stigma length during rice hybrid breeding by marker-assisted selection. PMID- 26030904 TI - Multidrug-Resistant and Extended Spectrum Beta-Lactamase-Producing Escherichia coli in Dutch Surface Water and Wastewater. AB - OBJECTIVE: The goal of the current study was to gain insight into the prevalence and concentrations of antimicrobial resistant (AMR) Escherichia coli in Dutch surface water, and to explore the role of wastewater as AMR contamination source. METHODS: The prevalence of AMR E. coli was determined in 113 surface water samples obtained from 30 different water bodies, and in 33 wastewater samples obtained at five health care institutions (HCIs), seven municipal wastewater treatment plants (mWWTPs), and an airport WWTP. Overall, 846 surface water and 313 wastewater E. coli isolates were analysed with respect to susceptibility to eight antimicrobials (representing seven different classes): ampicillin, cefotaxime, tetracycline, ciprofloxacin, streptomycin, sulfamethoxazole, trimethoprim, and chloramphenicol. RESULTS: Among surface water isolates, 26% were resistant to at least one class of antimicrobials, and 11% were multidrug resistant (MDR). In wastewater, the proportions of AMR/MDR E. coli were 76%/62% at HCIs, 69%/19% at the airport WWTP, and 37%/27% and 31%/20% in mWWTP influents and effluents, respectively. Median concentrations of MDR E. coli were 2.2*10(2), 4.0*10(4), 1.8*10(7), and 4.1*10(7) cfu/l in surface water, WWTP effluents, WWTP influents and HCI wastewater, respectively. The different resistance types occurred with similar frequencies among E. coli from surface water and E. coli from municipal wastewater. By contrast, among E. coli from HCI wastewater, resistance to cefotaxime and resistance to ciprofloxacin were significantly overrepresented compared to E. coli from municipal wastewater and surface water. Most cefotaxime-resistant E. coliisolates produced ESBL. In two of the mWWTP, ESBL-producing variants were detected that were identical with respect to phylogenetic group, sequence type, AMR-profile, and ESBL-genotype to variants from HCI wastewater discharged onto the same sewer and sampled on the same day (A1/ST23/CTX-M-1, B23/ST131/CTX-M-15, D2/ST405/CTX-M-15). CONCLUSION: In conclusion, our data show that MDR E. coli are omnipresent in Dutch surface water, and indicate that municipal wastewater significantly contributes to this occurrence. PMID- 26030905 TI - Proteins Related to the Type I Secretion System Are Associated with Secondary SecA_DEAD Domain Proteins in Some Species of Planctomycetes, Verrucomicrobia, Proteobacteria, Nitrospirae and Chlorobi. AB - A number of bacteria belonging to the PVC (Planctomycetes-Verrucomicrobia Chlamydiae) super-phylum contain unusual ribosome-bearing intracellular membranes. The evolutionary origins and functions of these membranes are unknown. Some proteins putatively associated with the presence of intracellular membranes in PVC bacteria contain signal peptides. Signal peptides mark proteins for translocation across the cytoplasmic membrane in prokaryotes, and the membrane of the endoplasmic reticulum in eukaryotes, by highly conserved Sec machinery. This suggests that proteins might be targeted to intracellular membranes in PVC bacteria via the Sec pathway. Here, we show that canonical signal peptides are significantly over-represented in proteins preferentially present in PVC bacteria possessing intracellular membranes, indicating involvement of Sec translocase in their cellular targeting. We also characterized Sec proteins using comparative genomics approaches, focusing on the PVC super-phylum. While we were unable to detect unique changes in Sec proteins conserved among membrane-bearing PVC species, we identified (1) SecA ATPase domain re-arrangements in some Planctomycetes, and (2) secondary SecA_DEAD domain proteins in the genomes of some Planctomycetes, Verrucomicrobia, Proteobacteria, Nitrospirae and Chlorobi. This is the first report of potentially duplicated SecA in Gram-negative bacteria. The phylogenetic distribution of secondary SecA_DEAD domain proteins suggests that the presence of these proteins is not related to the occurrence of PVC endomembranes. Further genomic analysis showed that secondary SecA_DEAD domain proteins are located within genomic neighborhoods that also encode three proteins possessing domains specific for the Type I secretion system. PMID- 26030907 TI - Noise-driven causal inference in biomolecular networks. AB - Single-cell RNA and protein concentrations dynamically fluctuate because of stochastic ("noisy") regulation. Consequently, biological signaling and genetic networks not only translate stimuli with functional response but also random fluctuations. Intuitively, this feature manifests as the accumulation of fluctuations from the network source to the target. Taking advantage of the fact that noise propagates directionally, we developed a method for causation prediction that does not require time-lagged observations and therefore can be applied to data generated by destructive assays such as immunohistochemistry. Our method for causation prediction, "Inference of Network Directionality Using Covariance Elements (INDUCE)," exploits the theoretical relationship between a change in the strength of a causal interaction and the associated changes in the single cell measured entries of the covariance matrix of protein concentrations. We validated our method for causation prediction in two experimental systems where causation is well established: in an E. coli synthetic gene network, and in MEK to ERK signaling in mammalian cells. We report the first analysis of covariance elements documenting noise propagation from a kinase to a phosphorylated substrate in an endogenous mammalian signaling network. PMID- 26030906 TI - Religious involvement and mental disorders in mainland china. AB - PURPOSE: The present study aims to examine the association between religious involvement and mental disorder (anxiety disorder, mood disorder, alcohol use disorder) in a general Chinese population, and explore connections between religious belief and mental disorders in the Hui and Han ethnic groups. METHOD: Data were examined from a representative sample of 2,770 community-dwelling adults in the province of Ningxia located in western China. Self-reported religious attendance and the importance of religious in daily life were measured. The WHO Composite International Diagnostic Interview was used to diagnose mental disorders. RESULTS: In the overall sample, the importance of religious affiliation was positively associated with mental disorders (especially anxiety) (p<0.01). No association was found between any religious characteristic and mood disorders or alcohol use disorders. With regard to analyses within different ethnic groups, religious affiliation was positively associated with mental disorder in Han ethnicity (p<0.01), but not in Hui ethnicity. When stratified by age and ethnic group, religious affiliation was associated positively with mental disorder in younger Han (p<0.01); whereas high religiosity was associated positively with mental disorder in older Hui (p<0.05). Among older Hui, however, religious affiliation was inversely associated with mood disorder (p<0.05). CONCLUSIONS: In contrast to most previous studies in Western populations, religious involvement is less likely to be inversely related to mental disorder in Mainland China, although this association varies by age and ethnic group. PMID- 26030908 TI - Parametric modeling of visual search efficiency in real scenes. AB - How should the efficiency of searching for real objects in real scenes be measured? Traditionally, when searching for artificial targets, e.g., letters or rectangles, among distractors, efficiency is measured by a reaction time (RT) * Set Size function. However, it is not clear whether the set size of real scenes is as effective a parameter for measuring search efficiency as the set size of artificial scenes. The present study investigated search efficiency in real scenes based on a combination of low-level features, e.g., visible size and target-flanker separation factors, and high-level features, e.g., category effect and target template. Visible size refers to the pixel number of visible parts of an object in a scene, whereas separation is defined as the sum of the flank distances from a target to the nearest distractors. During the experiment, observers searched for targets in various urban scenes, using pictures as the target templates. The results indicated that the effect of the set size in real scenes decreased according to the variances of other factors, e.g., visible size and separation. Increasing visible size and separation factors increased search efficiency. Based on these results, an RT * Visible Size * Separation function was proposed. These results suggest that the proposed function is a practicable predictor of search efficiency in real scenes. PMID- 26030910 TI - Progress in Intravenous Thrombolytic Therapy for Acute Stroke. AB - IMPORTANCE: Intravenous recombinant tissue plasminogen activator (alteplase) was approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Nearly 20 years later, it remains the only approved treatment, despite limitations in both efficacy and safety. With a growing capacity for stroke treatment worldwide, physicians need to understand where we have come from and what the future of stroke treatment might be. OBJECTIVE: To present a historical prospective as well as current trends in thrombolytic therapy, focusing on characteristics of drugs that have worked and clinical trials that are moving the field forward. EVIDENCE REVIEW: Sources are published pivotal clinical trials; seminal articles on physiology, pharmacology, and neuroimanging; and listings from clinical trial registries. FINDINGS: The slow progress in thrombolysis for acute stroke has been multifactorial. A focus on extending the time window for alteplase beyond 4.5 hours has encumbered substantial resources in the field for many years, yet these efforts have been largely unsuccessful. New drug development has also been slow. Several drugs have failed in clinical trials and currently only tenecteplase remains to be tested as a potential alternative to alteplase. The parallel pursuit for catheter-based interventional revascularization in acute stroke, which appears to be successful, has shifted emphasis away from pharmacologically based studies. CONCLUSIONS AND RELEVANCE: Although the field of acute thrombolysis has been making progress slowly for many years, advances in neuroimaging and new clinical trials that combine thrombolytics with other pharmacological and interventional techniques are beginning to gain momentum once again. The emergence of new approaches based largely on combination therapy strategies has reset a course to advance thrombolytic treatment for acute stroke and promises to improve outcomes in acute stroke in the near future. PMID- 26030909 TI - Secreted frizzled-related protein 4 inhibits glioma stem-like cells by reversing epithelial to mesenchymal transition, inducing apoptosis and decreasing cancer stem cell properties. AB - The Wnt pathway is integrally involved in regulating self-renewal, proliferation, and maintenance of cancer stem cells (CSCs). We explored the effect of the Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), in modulating epithelial to mesenchymal transition (EMT) in CSCs from human glioblastoma cells lines, U87 and U373. sFRP4 chemo-sensitized CSC-enriched cells to the most commonly used anti-glioblastoma drug, temozolomide (TMZ), by the reversal of EMT. Cell movement, colony formation, and invasion in vitro were suppressed by sFRP4+TMZ treatment, which correlated with the switch of expression of markers from mesenchymal (Twist, Snail, N-cadherin) to epithelial (E-cadherin). sFRP4 treatment elicited activation of the Wnt-Ca2(+) pathway, which antagonizes the Wnt/beta-catenin pathway. Significantly, the chemo-sensitization effect of sFRP4 was correlated with the reduction in the expression of drug resistance markers ABCG2, ABCC2, and ABCC4. The efficacy of sFRP4+TMZ treatment was demonstrated in vivo using nude mice, which showed minimum tumor engraftment using CSCs pretreated with sFRP4+TMZ. These studies indicate that sFRP4 treatment would help to improve response to commonly used chemotherapeutics in gliomas by modulating EMT via the Wnt/beta-catenin pathway. These findings could be exploited for designing better targeted strategies to improve chemo-response and eventually eliminate glioblastoma CSCs. PMID- 26030911 TI - Eye tracking indices of attentional bias in children of depressed mothers: Polygenic influences help to clarify previous mixed findings. AB - Information-processing biases may contribute to the intergenerational transmission of depression. There is growing evidence that children of depressed mothers exhibit attentional biases for sad faces. However, findings are mixed as to whether this bias reflects preferential attention toward, versus attentional avoidance of, sad faces, suggesting the presence of unmeasured moderators. To address these mixed findings, we focused on the potential moderating role of genes associated with hypothalamic-pituitary-adrenal axis reactivity. Participants included children (8-14 years old) of mothers with (n = 81) and without (n = 81) a history of depression. Eye movements were recorded while children passively viewed arrays of angry, happy, sad, and neutral faces. DNA was obtained from buccal cells. Children of depressed mothers exhibited more sustained attention to sad faces than did children of nondepressed mothers. However, it is important that this relation was moderated by children's genotype. Specifically, children of depressed mothers who carried reactive genotypes across the corticotropin-releasing hormone type 1 receptor (CHRH1) TAT haplotype and FK506 binding protein 5 (FKBP5) rs1360780 (but not the solute carrier family C6 member 4 [SLC6A4] of the serotonin transporter linked polymorphic region [5 HTTLPR]) exhibited less sustained attention to sad faces and more sustained attention to happy faces. These findings highlight the role played by specific genetic influences and suggest that previous mixed findings may have been due to genetic heterogeneity across the samples. PMID- 26030912 TI - Interactions between Skeletal Muscle Myoblasts and their Extracellular Matrix Revealed by a Serum Free Culture System. AB - Decellularisation of skeletal muscle provides a system to study the interactions of myoblasts with muscle extracellular matrix (ECM). This study describes the efficient decellularisation of quadriceps muscle with the retention of matrix components and the use of this matrix for myoblast proliferation and differentiation under serum free culture conditions. Three decellularisation approaches were examined; the most effective was phospholipase A2 treatment, which removed cellular material while maximizing the retention of ECM components. Decellularised muscle matrices were then solubilized and used as substrates for C2C12 mouse myoblast serum free cultures. The muscle matrix supported myoblast proliferation and differentiation equally as well as collagen and fibronectin. Immunofluorescence analyses revealed that myoblasts seeded on muscle matrix and fibronectin differentiated to form long, well-aligned myotubes, while myoblasts seeded on collagen were less organized. qPCR analyses showed a time dependent increase in genes involved in skeletal muscle differentiation and suggested that muscle-derived matrix may stimulate an increased rate of differentiation compared to collagen and fibronectin. Decellularized whole muscle three-dimensional scaffolds also supported cell adhesion and spreading, with myoblasts aligning along specific tracts of matrix proteins within the scaffolds. Thus, under serum free conditions, intact acellular muscle matrices provided cues to direct myoblast adhesion and migration. In addition, myoblasts were shown to rapidly secrete and organise their own matrix glycoproteins to create a localized ECM microenvironment. This serum free culture system has revealed that the correct muscle ECM facilitates more rapid cell organisation and differentiation than single matrix glycoprotein substrates. PMID- 26030914 TI - Cancer stage, comorbidity, and socioeconomic differences in the effect of cancer on labour market participation: a danish register-based follow-up study. AB - PURPOSE: Socioeconomic inequality in return to work after cancer treatment and rehabilitation have been documented, but less is known about its causes. This paper investigates the role played by breast cancer stage at diagnosis and comorbidity. METHODS: We used the comprehensive Danish Cancer Registry to follow 7372 women aged 30-60, who were in the labour force when diagnosed with breast cancer in 2000-06 and survived at least three years. Controls were 213,276 women without breast cancer. Inequalities in employment outlook were estimated as interaction effects in linear regression between educational attainment and disease on employment. RESULTS: There is significant interaction between education and breast cancer, but it is only marginally affected by including stage and comorbidity in the regression models. Education, breast cancer stage, and comorbidity all have strong effects on later employment, and a considerable amount of the educational effect is mediated by comorbidity and pre-cancer labour market participation and income. CONCLUSION: The result of the study is negative in the sense that the stronger effect of breast cancer on employment among low educated compared to highly educated individuals is not explained by cancer stage or comorbidity. The fact that comorbidity has little impact on inequality may be due to a different social patterning of most comorbidity compared to breast cancer. PMID- 26030913 TI - MicroRNA-Mediated In Vitro and In Vivo Direct Conversion of Astrocytes to Neuroblasts. AB - BACKGROUND: The conversion of astrocytes to neuroblasts holds great promise for treatment of neurodegenerative and traumatic brain diseases. METHODOLOGY AND PRINCIPAL FINDINGS: Here we have shown that adult human astrocytes could be reprogrammed to neuroblasts by miR-302/367, both in vivo and in vitro. However, the reprogramming of adult mouse astrocytes to neuroblasts required valproic acid (VPA), a histone deacetylase inhibitor. Following induction of astrocytes toward neurons the expression of pluripotency markers were not detected, which suggested direct cell conversion. We did not observed tumor formation during two months follow up. CONCLUSIONS AND SIGNIFICANCE: These results show that neuroblasts can be generated directly from adult human and mouse astrocytes by miR-302/367-driven induction. This approach seems promising for converting glial scar cells into neuroblasts in a wide range of neurological diseases. PMID- 26030915 TI - Factors of force potentiation induced by stretch-shortening cycle in plantarflexors. AB - Muscle force is potentiated by countermovement; this phenomenon is called stretch shortening cycle (SSC) effect. In this study, we examined the factors strongly related to SSC effect in vivo, focusing on tendon elongation, preactivation, and residual force enhancement. Twelve healthy men participated in this study. Ankle joint angle was passively moved by a dynamometer, with a range of motion from 15 degrees dorsiflexion (DF) to 15 degrees plantarflexion (PF). Muscle contraction was evoked by electrical stimulation, with stimulation timing adjusted to elicit three types of contraction: (1) concentric contraction without preliminary contraction (CON), (2) concentric contraction after preliminary eccentric contraction (ECC), and (3) concentric contraction after preliminary isometric contraction (ISO). Joint torque was recorded at DF5 degrees , PF0 degrees , and PF5 degrees , respectively. SSC effect was calculated as the ratio of joint torque obtained in ECC or ISO with respect to that obtained in CON at the aforementioned three joint angles. SSC effect was prominent in the first half of movement in both ECC (DF5 degrees , 329.3 +/- 101.2%; PF0 degrees , 159.2 +/- 29.4%; PF5 degrees , 125.5 +/- 20.8%) and ISO (DF5 degrees , 276.4 +/- 87.0%; PF0 degrees , 134.5 +/- 24.5%; PF5 degrees , 106.8 +/- 18.0%) conditions. SSC effect was significantly larger in ECC than in ISO at all joint angles (P < 0.001). Even without preliminary eccentric contraction (i.e., ISO condition), SSC effect was clearly large, indicating that a significant part of SSC effect is derived from preactivation. However, the active lengthening-induced force potentiation mechanism (residual force enhancement) also contributes to SSC effect. PMID- 26030916 TI - Evidence that Altered Cis Element Spacing Affects PpsR Mediated Redox Control of Photosynthesis Gene Expression in Rubrivivax gelatinosus. AB - PpsR is a major regulator of photosynthesis gene expression among all characterized purple photosynthetic bacteria. This transcription regulator has been extensively characterized in Rhodobacter (Rba.) capsulatus and Rba. sphaeroides which are members of the alpha-proteobacteria lineage. In this study, we have investigated the biochemical properties and mutational effects of a ppsR deletion strain in the beta-proteobacterium Rubrivivax (Rvi.) gelatinosus in order to reveal phylogenetically conserved mechanisms and species-specific characteristics. A deletion of the ppsR gene resulted in de-repression of photosystem synthesis showing that PpsR functions as a repressor of photosynthesis genes in this species. We also constructed a Rvi. gelatinosus PpsR mutant in which a conserved cysteine at position 436 was changed to an alanine to examine whether or not this residue is important for sensing redox, as reported in Rhodobacter species. Surprisingly, the Cys436 Ala mutant retained the ability to repress photosynthesis gene expression under aerobic conditions, suggesting that PpsR from Rvi. gelatinosus has different redox-responding characteristics. Furthermore, biochemical analyses demonstrated that Rvi. gelatinosus PpsR only shows redox-dependent binding to promoters with 9-bp spacing, but not 8-bp spacing, between two PpsR-recognition sequences. These results indicate that redox-dependent binding of PpsR requires appropriate cis configuration of PpsR target sequences in Rvi. gelatinosus. These results also indicate that PpsR homologs from different species regulate photosynthesis genes with altered biochemical properties. PMID- 26030917 TI - A null model for Pearson coexpression networks. AB - Gene coexpression networks inferred by correlation from high-throughput profiling such as microarray data represent simple but effective structures for discovering and interpreting linear gene relationships. In recent years, several approaches have been proposed to tackle the problem of deciding when the resulting correlation values are statistically significant. This is most crucial when the number of samples is small, yielding a non-negligible chance that even high correlation values are due to random effects. Here we introduce a novel hard thresholding solution based on the assumption that a coexpression network inferred by randomly generated data is expected to be empty. The threshold is theoretically derived by means of an analytic approach and, as a deterministic independent null model, it depends only on the dimensions of the starting data matrix, with assumptions on the skewness of the data distribution compatible with the structure of gene expression levels data. We show, on synthetic and array datasets, that the proposed threshold is effective in eliminating all false positive links, with an offsetting cost in terms of false negative detected edges. PMID- 26030918 TI - The Effects of Lactobacillus acidophilus on the Intestinal Smooth Muscle Contraction through PKC/MLCK/MLC Signaling Pathway in TBI Mouse Model. AB - Clinical studies have shown that probiotics influence gastrointestinal motility. However, the molecular mechanisms by which probiotic Lactobacillus modulates intestinal motility in traumatic brain injury (TBI) mouse model have not been explored. In the present study, we provided evidence showing that treatment of TBI mice with Lactobacillus acidophilus significantly improved the terminal ileum villus morphology, restored the impaired interstitial cells of Cajal (ICC) and the disrupted ICC networks after TBI, and prevented TBI-mediated inhibition of contractile activity in intestinal smooth muscle. Mechanistically, the decreased concentration of MLCK, phospho-MLC20 and phospho-MYPT1 and increased concentration of MLCP and PKC were observed after TBI, and these events mediated by TBI were efficiently prevented by Lactobacillus acidophilus application. These findings may provide a novel mechanistic basis for the application of Lactobacillus acidophilus in the treatment of TBI. PMID- 26030919 TI - Lipoamide Acts as an Indirect Antioxidant by Simultaneously Stimulating Mitochondrial Biogenesis and Phase II Antioxidant Enzyme Systems in ARPE-19 Cells. AB - In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes. PMID- 26030921 TI - Correction: Development of SSR Markers and Genetic Diversity in White Birch (Betula platyphylla). PMID- 26030920 TI - Amino Acid Substitutions Improve the Immunogenicity of H7N7HA Protein and Protect Mice against Lethal H7N7 Viral Challenge. AB - Avian influenza A H7N7/NL/219/03 virus creates a serious pandemic threat to human health because it can transmit directly from domestic poultry to humans and from human to human. Our previous vaccine study reported that mice when immunized intranasally (i.n) with live Bac-HA were protected from lethal H7N7/NL/219/03 challenge, whereas incomplete protection was obtained when administered subcutaneously (s.c) due to the fact that H7N7 is a poor inducer of neutralizing antibodies. Interestingly, our recent vaccine studies reported that mice when vaccinated subcutaneously with Bac-HA (H7N9) was protected against both H7N9 (A/Sh2/2013) and H7N7 virus challenge. HA1 region of both H7N7 and H7N9 viruses are differ at 15 amino acid positions. Among those, we selected three amino acid positions (T143, T198 and I211) in HA1 region of H7N7. These amino acids are located within or near the receptor binding site. Following the selection, we substituted the amino acid at these three positions with amino acids found on H7N9HA wild-type. In this study, we evaluate the impact of amino acid substitutions in the H7N7 HA-protein on the immunogenicity. We generated six mutant constructs from wild-type influenza H7N7HA cDNA by site directed mutagenesis, and individually expressed mutant HA protein on the surface of baculovirus (Bac-HAm) and compared their protective efficacy of the vaccines with Bac-H7N7HA wild-type (Bac-HA) by lethal H7N7 viral challenge in a mouse model. We found that mice immunized subcutaneously with Bac-HAm constructs T143A or T198A I211V or I211V-T143A serum showed significantly higher hemagglutination inhibition and neutralization titer against H7N7 and H7N9 viruses when compared to Bac-HA vaccinated mice groups. We also observed low level of lung viral titer, negligible weight loss and complete protection against lethal H7N7 viral challenge. Our results indicated that amino acid substitution at position 143 or 211 improve immunogenicity of H7N7HA vaccine against H7N7/NL/219/03 virus. PMID- 26030922 TI - A Multi-country Study of the Household Willingness-to-Pay for Dengue Vaccines: Household Surveys in Vietnam, Thailand, and Colombia. AB - BACKGROUND: The rise in dengue fever cases and the absence of dengue vaccines will likely cause governments to consider various types of effective means for controlling the disease. Given strong public interests in potential dengue vaccines, it is essential to understand the private economic benefits of dengue vaccines for accelerated introduction of vaccines into the public sector program and private markets of high-risk countries. METHODOLOGY/PRINCIPAL FINDINGS: A contingent valuation study for a hypothetical dengue vaccine was administered to 400 households in a multi-country setting: Vietnam, Thailand, and Colombia. All respondents received a description of the hypothetical dengue vaccine scenarios of 70% or 95% effectiveness for 10 or 30 years with a three dose series. Five price points were determined after pilot tests in order to reflect different local situations such as household income levels and general perceptions towards dengue fever. We adopted either Poisson or negative binomial regression models to calculate average willingness-to-pay (WTP), as well as median WTP. We found that there is a significant demand for dengue vaccines. The parametric median WTP is $26.4 ($8.8 per dose) in Vietnam, $70.3 ($23.4 per dose) in Thailand, and $23 ($7.7 per dose) in Colombia. Our study also suggests that respondents place more value on vaccinating young children than school age children and adults. CONCLUSIONS/SIGNIFICANCE: Knowing that dengue vaccines are not yet available, our study provides critical information to both public and private sectors. The study results can be used to ensure broad coverage with an affordable price and incorporated into cost benefit analyses, which can inform prioritization of alternative health interventions at the national level. PMID- 26030923 TI - Maltose-Dependent Transcriptional Regulation of the mal Regulon by MalR in Streptococcus pneumoniae. AB - The maltose regulon (mal regulon) has previously been shown to consist of the mal gene cluster (malMP, malXCD and malAR operons) in Streptococcus pneumoniae. In this study, we have further elucidated the complete mal regulon in S. pneumoniae D39 using microarray analyses and beta-galactosidase assays. In addition to the mal gene cluster, the complete mal regulon of S. pneumoniae D39 consists of a pullulanase (PulA), a glucosidase (DexB), a glucokinase (RokB), a PTS component (PtsG) and an amylase (AmyA2). Our microarray studies and beta-galactosidase assays further showed that the LacI-family transcriptional regulator MalR represses the expression of the mal regulon in the absence of maltose. Furthermore, the role of the pleiotropic transcriptional regulator CcpA in the regulation of the mal regulon in the presence of maltose was explored. Our microarray analysis with a DeltaccpA strain showed that CcpA only represses the expression of the malXCD operon and the pulA gene in the presence of maltose. Hence, we extend the mal regulon now consisting of pulA, dexB, rokB, ptsG and amyA2 in addition to malMP, malXCD and malAR operons. PMID- 26030924 TI - A Linear Epitope in the N-Terminal Domain of CCR5 and Its Interaction with Antibody. AB - The CCR5 receptor plays a role in several key physiological and pathological processes and is an important therapeutic target. Inhibition of the CCR5 axis by passive or active immunisation offers one very selective strategy for intervention. In this study we define a new linear epitope within the extracellular domain of CCR5 recognised by two independently produced monoclonal antibodies. A short peptide encoding the linear epitope can induce antibodies which recognise the intact receptor when administered colinear with a tetanus toxoid helper T cell epitope. The monoclonal antibody RoAb 13 is shown to bind to both cells and peptide with moderate to high affinity (6x10^8 and 1.2x107 M-1 respectively), and binding to the peptide is enhanced by sulfation of tyrosines at positions 10 and 14. RoAb13, which has previously been shown to block HIV infection, also blocks migration of monocytes in response to CCR5 binding chemokines and to inflammatory macrophage conditioned medium. A Fab fragment of RoAb13 has been crystallised and a structure of the antibody is reported to 2.1 angstrom resolution. PMID- 26030925 TI - Ultrastructural Study on the Antibacterial Activity of Artonin E versus Streptomycin against Staphylococcus aureus Strains. AB - Staphylococci are facultative anaerobes, perfectly spherical un-encapsulated cocci, with a diameter not exceeding 1 micrometer in diameter. Staphylococcus aureus are generally harmless and remain confined to the skin unless they burrow deep into the body, causing life-threatening infections in bones, joints, bloodstream, heart valves and lungs. Among the 20 medically important staphylococci species, Staphylococcus aureus is one of the emerging human pathogens. Streptomycin had its highest potency against Staphylococcus infections despite the likelihood of getting a resistant type of staphylococcus strains. Methicillin-resistant S. aureus (MRSA) is the persister type of Staphylococcus aureus and was evolved after decades of antibiotic misuse. Inadequate penetration of the antibiotic is one of the principal factors related to success/failure of the therapy. The active drug needs to reach the bacteria at concentrations necessary to kill or suppress the pathogen's growth. In turn the effectiveness of the treatment relied on the physical properties of Staphylococcus aureus. Thus understanding the cell integrity, shape and roughness is crucial to the overall influence of the therapeutic agent on S. aureus of different origins. Hence our experiments were designed to clarify ultrastructural changes of S. aureus treated with streptomycin (synthetic compound) in comparison to artonin E (natural compound). In addition to the standard in vitro microbial techniques, we used transmission electron microscopy to study the disrupted cell architecture under antibacterial regimen and we correlate this with scanning electron microscopy (SEM) to compare results of both techniques. PMID- 26030926 TI - SDMdata: A Web-Based Software Tool for Collecting Species Occurrence Records. AB - It is important to easily and efficiently obtain high quality species distribution data for predicting the potential distribution of species using species distribution models (SDMs). There is a need for a powerful software tool to automatically or semi-automatically assist in identifying and correcting errors. Here, we use Python to develop a web-based software tool (SDMdata) to easily collect occurrence data from the Global Biodiversity Information Facility (GBIF) and check species names and the accuracy of coordinates (latitude and longitude). It is an open source software (GNU Affero General Public License/AGPL licensed) allowing anyone to access and manipulate the source code. SDMdata is available online free of charge from . PMID- 26030927 TI - Markets and morals: an experimental survey study. AB - Most societies prohibit some market transactions based on moral concerns, even when the exchanges would benefit the parties involved and would not create negative externalities. A prominent example is given by payments for human organs for transplantation, banned virtually everywhere despite long waiting lists and many deaths of patients who cannot find a donor. Recent research, however, has shown that individuals significantly increase their stated support for a regulated market for human organs when provided with information about the organ shortage and the potential beneficial effects a price mechanism. In this study we focused on payments for human organs and on another "repugnant" transaction, indoor prostitution, to address two questions: (A) Does providing general information on the welfare properties of prices and markets modify attitudes toward repugnant trades? (B) Does additional knowledge on the benefits of a price mechanism in a specific context affect attitudes toward price-based transactions in another context? By answering these questions, we can assess whether eliciting a market-oriented approach may lead to a relaxation of moral opposition to markets, and whether there is a cross-effect of information, in particular for morally controversial activities that, although different, share a reference to the "commercialization" of the human body. Relying on an online survey experiment with 5,324 U.S. residents, we found no effect of general information about market efficiency, consistent with morally controversial markets being accepted only when they are seen as a solution to a specific problem. We also found some cross effects of information about a transaction on the acceptance of the other; however, the responses were mediated by the gender and (to a lesser extent) religiosity of the respondent--in particular, women exposed to information about legalizing prostitution reduced their stated support for regulated organ payments. We relate these findings to prior research and discuss implications for public policy. PMID- 26030928 TI - In Vivo Administration of Scallop GnRH-Like Peptide Influences on Gonad Development in the Yesso Scallop, Patinopecten yessoensis. AB - Existing research on the role of gonadotropin-releasing hormone (GnRH) in bivalve reproduction is inadequate, even though a few bivalve GnRH orthologs have been cloned. The objective of this paper was to elucidate the in vivo effect of GnRH administration in Yesso scallop reproduction. We performed in vivo administration of scallop GnRH (py-GnRH) synthetic peptide into the developing gonad, and analyzed its effect on gonad development for 6 weeks during the reproductive season. The resulting sex ratio in the GnRH administered (GnRH(+)) group might be male biased, whereas the control (GnRH(-)) group had an equal sex ratio throughout the experiment. The gonad index (GI) of males in the GnRH(+) group increased from week 2 to 24.8% at week 6. By contrast the GI of the GnRH(-) group peaked in week 4 at 16.6%. No significant difference was seen in female GI between the GnRH(+) and GnRH(-) groups at any sampling point. Oocyte diameter in the GnRH(+) group remained constant (about 42-45 MUm) throughout the experiment, while in the GnRH(-) group it increased from 45 to 68 MUm i.e. normal oocyte growth. The number of spermatogonia in the germinal acini of males in the GnRH(+) group increased from week 4 to 6. Hermaphrodites appeared in the GnRH(+) group in weeks 2 and 4. Their gonads contained many apoptotic cells including oocytes. In conclusion, this study suggests that py-GnRH administration could have a potential to accelerate spermatogenesis and cause an inhibitory effect on oocyte growth in scallops. PMID- 26030929 TI - Childhood Environment and Mental Wellbeing at Age 60-64 Years: Prospective Evidence from the MRC National Survey of Health and Development. AB - BACKGROUND: Mental wellbeing, conceptualised as positive affect, life satisfaction and realisation of needs that contribute to psychological growth, captures more than the absence of mental ill health. Several nations now aim to monitor and improve mental wellbeing. Whilst many studies document associations between adverse childhood experiences and mental disorders in adulthood, possible links between childhood experiences and adult mental wellbeing have so far received less attention. METHODS: Using data from 1976 men and women in the MRC National Survey for Health and Development, we investigated prospective associations between childhood socioeconomic and psychosocial environments and the Warwick Edinburgh Mental Wellbeing Scale, designed to capture both hedonic and eudaimonic facets of wellbeing, at age 60-64. RESULTS: Whilst there was no evidence that childhood socioeconomic circumstances were related to later wellbeing independently of other childhood experiences, elements of childrearing and parenting, parental health and adjustment, and childhood illness were related. More advantaged socioeconomic position was associated with greater wellbeing but this did not explain the links between these childhood exposures and adult wellbeing, suggesting alternative explanatory pathways should be considered. CONCLUSIONS: Childhood illness and family psychosocial environment are associated with mental wellbeing in early older age, with effects sizes that are larger or comparable to socioeconomic circumstances in adulthood. Initiatives to improve the nation's mental wellbeing that include programmes targeted to supporting families and children may additionally have benefits that continue into older age. PMID- 26030932 TI - Correction: Correction: Cell-Penetrating Peptide Derived from Human Eosinophil Cationic Protein Inhibits Mite Allergen Der p 2 Induced Inflammasome Activation. PMID- 26030930 TI - Sequencing and De Novo Assembly of the Gonadal Transcriptome of the Endangered Chinese Sturgeon (Acipenser sinensis). AB - BACKGROUND: The Chinese sturgeon (Acipenser sinensis) is endangered through anthropogenic activities including over-fishing, damming, shipping, and pollution. Controlled reproduction has been adopted and successfully conducted for conservation. However, little information is available on the reproductive regulation of the species. In this study, we conducted de novo transcriptome assembly of the gonad tissue to create a comprehensive dataset for A. sinensis. RESULTS: The Illumina sequencing platform was adopted to obtain 47,333,701 and 47,229,705 high quality reads from testis and ovary cDNA libraries generated from three-year-old A. sinensis. We identified 86,027 unigenes of which 30,268 were annotated in the NCBI non-redundant protein database and 28,281 were annotated in the Swiss-prot database. Among the annotated unigenes, 26,152 and 7,734 unigenes, respectively, were assigned to gene ontology categories and clusters of orthologous groups. In addition, 12,557 unigenes were mapped to 231 pathways in the Kyoto Encyclopedia of Genes and Genomes Pathway database. A total of 1,896 unigenes, potentially differentially expressed between the two gonad types, were found, with 1,894 predicted to be up-regulated in ovary and only two in testis. Fifty-five potential gametogenesis-related genes were screened in the transcriptome and 34 genes with significant matches were found. Besides, more paralogs of 11 genes in three gene families (sox, apolipoprotein and cyclin) were found in A. sinensis compared to their orthologs in the diploid Danio rerio. In addition, 12,151 putative simple sequence repeats (SSRs) were detected. CONCLUSIONS: This study provides the first de novo transcriptome analysis currently available for A. sinensis. The transcriptomic data represents the fundamental resource for future research on the mechanism of early gametogenesis in sturgeons. The SSRs identified in this work will be valuable for assessment of genetic diversity of wild fish and genealogy management of cultured fish. PMID- 26030931 TI - Application of overall dynamic body acceleration as a proxy for estimating the energy expenditure of grazing farm animals: relationship with heart rate. AB - Estimating the energy expenditure of farm animals at pasture is important for efficient animal management. In recent years, an alternative technique for estimating energy expenditure by measuring body acceleration has been widely performed in wildlife and human studies, but the availability of the technique in farm animals has not yet been examined. In the present study, we tested the potential use of an acceleration index, overall dynamic body acceleration (ODBA), as a new proxy for estimating the energy expenditure of grazing farm animals (cattle, goats and sheep) at pasture with the simultaneous evaluation of a conventional proxy, heart rate. Body accelerations in three axes and heart rate for cows (n = 8, two breeds), goats (n = 6) and sheep (n = 5) were recorded, and the effect of ODBA calculated from the body accelerations on heart rate was analyzed. In addition, the effects of the two other activity indices, the number of steps and vectorial dynamic body acceleration (VeDBA), on heart rate were also investigated. The results of the comparison among three activity indices indicated that ODBA was the best predictor for heart rate. Although the relationship between ODBA and heart rate was different between the groups of species and breeds and between individuals (P<0.01), the difference could be explained by different body weights; a common equation could be established by correcting the body weights (M: kg): heart rate (beats/min) = 147.263?M-0.141 + 889.640?M-0.179?ODBA (g). Combining this equation with the previously reported energy expenditure per heartbeat, we estimated the energy expenditure of the tested animals, and the results indicated that ODBA is a good proxy for estimating the energy expenditure of grazing farm animals across species and breeds. The utility and simplicity of the procedure with acceleration loggers could make the accelerometry technique a worthwhile option in field research and commercial farm use. PMID- 26030933 TI - Surgically induced astigmatism: distinguishing between dioptric vectors and non vectors. PMID- 26030936 TI - Medical devices; immunology and microbiology devices; classification of multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures. Final order. AB - The Food and Drug Administration (FDA) is classifying multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures into class II (special controls). The special controls that will apply to this device are identified in this order and will be part of the codified language for the multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26030937 TI - The many faces of persistent orofacial muscle pain. PMID- 26030938 TI - The many faces of persistent orofacial muscle pain. PMID- 26030939 TI - Medical devices; gastroenterology-urology devices; classification of the vibrator for climax control of premature ejaculation. Final order. AB - The Food and Drug Administration (FDA) is classifying the vibrator for climax control of premature ejaculation into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the classification of the vibrator for climax control of premature ejaculation. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26030940 TI - Medical devices; gastroenterology-urology devices; classification of the rectal control system. Final order. AB - The Food and Drug Administration (FDA) is classifying the rectal control system into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the rectal control system's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26030941 TI - [Causality and chance in oncogenesis]. PMID- 26030942 TI - The problem of underinsurance and how rising deductibles will make it worse. Findings from the Commonwealth Fund Biennial Health Insurance Survey, 2014. AB - New estimates from the Commonwealth Fund Biennial Health Insurance Survey, 2014, indicate that 23 percent of 19-to-64-year-old adults who were insured all year- or 31 million people--had such high out-of-pocket costs or deductibles relative to their incomes that they were underinsured. These estimates are statistically unchanged from 2010 and 2012, but nearly double those found in 2003 when the measure was first introduced in the survey. The share of continuously insured adults with high deductibles has tripled, rising from 3 percent in 2003 to 11 percent in 2014. Half (51%) of underinsured adults reported problems with medical bills or debt and more than two of five (44%) reported not getting needed care because of cost. Among adults who were paying off medical bills, half of underinsured adults and 41 percent of privately insured adults with high deductibles had debt loads of $4,000 or more. PMID- 26030943 TI - Authors' response. PMID- 26030944 TI - Proving personal use: the admissibility of evidence negating intent to distribute marijuana. AB - Against the backdrop of escalating state efforts to decriminalize marijuana, U.S. Attorneys' Offices continue to bring drug-trafficking prosecutions against defendants carrying small amounts of marijuana that are permitted under state law. Federal district courts have repeatedly barred defendants from introducing evidence that they possessed this marijuana for their own personal use. This Note argues that district courts should not exclude three increasingly common kinds of "personal use evidence" under Federal Rules of Evidence 402 and 403 when that evidence is offered to negate intent to distribute marijuana. Three types of personal use evidence are discussed in this Note: (1) a defendant's possession of a state-issued medical marijuana license, (2) evidence that a state has legalized possession of marijuana for recreational purposes, and (3) evidence that a defendant suffers from a disease that marijuana arguably treats. Part I examines each of these three categories of personal use evidence and contends that district courts are likely to confront disputes over such evidence with increasing frequency. Part II analyzes objections to the admissibility of personal use evidence on direct examination, focusing primarily on Rules 402 and 403. Part III responds to those objections and argues that the evidence is probative of intent to distribute in federal marijuana-trafficking prosecutions. PMID- 26030945 TI - Authors' response. PMID- 26030946 TI - Diabetes mellitus and cognition in patients with metabolic syndrome. AB - OBJECTIVE: to assess the influence of diabetes mellitus (DM) on cognitive functions of metabolic syndrome (MS) patients. 305 patients aged 45-89 years with chronic cerebrovascular disease and MS were enrolled into the study. All patients were divided into two groups: without DM (n=148) and with DM (n=1 57), comparable for age and level of education. Metabolic syndrome and its individual components were assessed. All patients underwent neurological examinations and the application of neuropsychological tests to assess cognitive functions as well as laboratory tests and MRI. Their blood pressure was measured and the body mass index (BMI) was calculated. The carotid intima-media thickness (IMT), plaque and degree of stenosis were measured by a high resolution B-mode ultrasound examination. Patients with metabolic syndrome and DM had more pronounced cognitive impairment (CI) according to MMSE, compared with the patients without DM. According to the neuropsychological test results, metabolic syndrome and hyperglycaemia were more strongly associated with information processing speed and mental flexibility (both including perceptual speed) rather than with memory (immediate and delayed recall). Therefore, prompt and adequate treatment of the existing metabolic syndrome and its individual components, in particular diabetes mellitus, will reduce the risk of both moderate CI and vascular dementia and improve the patients'quality of life. PMID- 26030947 TI - [Assessment of the angle between puborectal muscles in women with and without stress urinary incontinence in three-dimensional sonograph]. AB - Contemporary care of the woman, especially in the postmenopausal period is based not only on gynaecological periodic inspections, but also on the routine evaluation of the pelvis minorwith the ultrasound examination. Based on this examination we can manytimes initially diversify causes of wrong manifestations, so like, e.g., urinary incontinence, of social pathologies coming into existence in the result rolling within the pelvis minor. Urinary incontinence is a complaint which is changing the quality of life. Three-dimensional sonography (3D USG) supplies us more information than traditional two-dimensional sonography. It let us to make dynamic representation of examining structures and let us to observe them in any angle we need. The best way for sonographic examination of lower pelvis minor is translabial sonography, because it doesn't change mutual relationship of any parts in lower pelvic area, just like transrectal ortransvaginal probes can make. For good treatment of symptoms of urinary incontinence we have to perform not only functional examination of lower urinary tract, but also make very accurate rate of the static of female genital organs and pelvic floor. BACKGROUND: The aim of study was to rate the angle between both puborectal muscles measurements using translabial three-dimensional sonography in women with stress urinary incontinence without descension of the female genital tract. MATERIAL AND METHODS: Studied group included 100 patients who were examined with GE Kretz Voluson 730 (GE, Austria) scaner equipped 6-9 MHztranslabial probe. First group with stress urinary incontinence comprised 50 women in the mean age 56.22 (+/- 10.43) years old and the second without symptoms -50 women in the mean age 49.0 (+/- 13.22) years old. All cases of urinary stress incontinence in first group was confirm with urodynamic examination. Women in both groups were in similar body mass index, means (+/-SD): 26.88 (+/- 2.02) and 26.20 (+/- 4.14), respectively. Menopausal status in both groups was not statistically significant and aggregate 7.21 (+/- 8.71) in group of women with stress urinary incontinence and 4.70 (+/- 6.32) in group of women without symptoms. Means (+/- SD) quantity of deliveries was significantly higher in group of women with stress urinary incontinence than in control group and amount to 2.40 (+/- 1.03) and 1.56 (+/- 1.34), respectively. In all cases 3D USG coronal view of pelvic diaphragm was obtained and the angle between both puborectal muscles were measured. All women had about 200 ml urine in the bladder. RESULTS: Means (+/-SD) of this angle in these groups were 65.48 +/- 9.22 and 58.64 +/- 9.17 degrees, respectively. The differences between both groups in all measurements were statistically significant (p<0.0015). CONCLUSION: Stated during translabial three-dimensional ultrasound examination considerably different values of the angle between puborectal muscles at women with and without the urinary incontinence can be more helpful in a accurate diagnosing of the type of the urinary incontinence. PMID- 26030948 TI - [Evaluate the efficacy of combination therapy of ultrasound and currents of TENS professionally active in patients with pain of the lumbar spine]. AB - INTRODUCTION: Back pain most often affects people whose work is related to the load while performing activities related to lifting and in addition to the method and type of work performed, as well as office workers. The aim of the study is to evaluate the efficacy of combination therapy of ultrasound and TENS in the analgesic effect in patients with disorders of the lumbar spine. MATERIAL AND METHODS: The study group consisted of 115 patients aged from 24 to 65 years (mean 45.22 +/- 10.38 years) with pain complaints in the lumbar degenerative against overload and, as a result of long-term work involved in taking a forced static position or sitting. Twice (before and after treatment) pain intensity was assessed using of the modified questionnaire of indicators according to Laitinen and scale VAS and physical fitness bythe Oswestry questionnaire (ODI--Oswestry Disability Index). RESULTS: It has been demonstrated greater analgesic efficacy of combination therapy than the monotherapy, which had a characterizing effect on the improvement of mobility of patients according to the Oswestry questionnaire. Afterthe completion of the combination therapy was observed the highly statistical higher than in the monotherapy groups, reducing the intensity and frequency of pain, increase physical activity and reduce quantities medications you are taking. CONCLUSIONS: Combination antiretroviral the action of ultrasound and currentsTENS has a more effective analgesic effect and improve the efficiency of patients with pain in the lumbar spine than monotherapy with ultrasound or TENS currents. Enables faster recovery professional and social activity and a reduction in sickness absence at work. PMID- 26030949 TI - [Significance of circulating immune complexes (CIC) in the diagnosis of infections with Borrelia burgdorferi]. AB - INTRODUCTION: The infection caused by Borrelia burgdorferi initiates a number of reactions in the human immunological system and particular behaviors of the infectious factor. The aim of work was to analyze the level of circulating immune complexes (CIC) due to infection with Borrelia burgdorferi in persons professionally exposed to tick bites. MATERIAL AND METHODS: The group of tested consisted of 275 persons, who are professionally exposed to tick bites, including 171 foresters and 104agriculturists. The controlled group consisted of 45 people, living permanently ortemporarily in Biata Podlaska, city in the South Podlasie Lowland, who have not been exposed professionally on tick bites.The screening test ELISA (Euroimmun) has been carried among all persons from the tested group towards the presence ofantibodies IgM/IgG anty-Borrelia. Among those who met positive or delimited results from screening test Elisa, another test of Western blot (Wb, Euroimmun, Virotech GmbH) has been carried in order to confirm the infection. The serum which has been taken from a group of persons being professionally exposed to infection of B. burgdorferi and persons from a controlled group, has been tested in terms of estimating levels of circulating immune complexes CIC C1q (Elisa, DRG). RESULTS AND CONCLUSION: The circulating immune complexes (CIC) are increasingly generated at persons with present IgM and/or IgG anty-Borrelia but their existence accompanied by the presence of strongly expressed humoral response does not affect the diagnostic effectiveness of infections with B. burgdorferi. PMID- 26030950 TI - [Analysis of actions taken by medical rescue teams in the Polish Emergency Medical Servies system. Is the model of division into specialistad basic teams reasonable?]. AB - BACKGROUND: The Polish Emergency Medical Services (EMS) system is based on two types of medical rescue teams (MRT): specialist (S)--with system doctors and basic (B)--only paramedics. AIM OF THE STUDY: The aim of this study is to assess the reasonability of dividing medical rescue teams into specialist and basic. MATERIAL AND METHODS: The retrospective analysis of medical cards of rescue activities performed during 21,896 interventions by medical rescue teams, 15,877 of which--by basic medical rescue teams (B MRT) and 6,019--by specialist medical rescue teams (S MRT). The procedures executed by both types of teams were compared. RESULTS: In the analysed group of dispatches, 56.4% were unrelated to medical emergencies. Simultaneously, 52.7% of code 1 interventions and 59.2% of code 2 interventions did not result in transporting the patient to the hospital. The qualification of S teams' dispatches is characterised by a higher number of assigned codes 1 (53.2% vs. 15.9%). It is worth emphasising that the procedures that can be applied exclusively by system doctors do not exceed 1% of interventions. Moreover, the number of the actions performed in medical emergencies in the secured region by the S team that is dispatched as the first one is comparable to that performed by B teams. The low need for usinq S teams'aid by B teams (0.92% of the interventions) was also indicated. CONCLUSIONS: This study points to the necessity to discuss the implementation of straightforward principles of call qualification and the optimisation of the system doctors' role in prehospital activities. PMID- 26030951 TI - [The influence of maintenance immunosuppression scheme on D4d urinary excretion in kidney graft recipients]. AB - INTRODUCTION: The C4d urinary excretion varies according to the risk of graft rejection or progression of chronic allograft nephropathy. The most common maintenance immunosuppression (IS) schemes includes cyclosporine (CSA) ortacrolimus (TAC with azathiopryne (AZA) or mycophenolane mophetil (MMF). The chosen IS may influence on the kidney transplant outcomes and possibly modify C4d urinary secretion. The aim of the study was to assess whether IS scheme may influence on C4d urinary excretion. MATERIAL AND METHODS: The study involved 185 patients who underwent kidney allograft transplantation (KTx).The urinary specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion (ng/mg Ucr). The study population was grouped according the IS scheme, i.e., CSA+AZA, CSA+MMF and TAC+MMF. RESULTS: The highest C4d urinary excretion was noticed in patients treated with CSA+AZA--210 +/- 229 ng/ml (5.1 +/- 7.9 ng/mg Ucr) and the lowest in those in whom tacrolimus and mycophenolane mophetil was administered -198?188 ng/ml (4.4 +/- 7.1 ng/mg Ucr). In CSA+MMF group C4d excretion was 207?256 ng/ml (4.7 +/- 7.7 ng/mg Ucr). The statistically significant differences were seen only between CSA+AZA and TAC+MMF groups--ANOVA p<0.05 (p<0.01 for excretion calculated per Ucr). CONCLUSIONS: C4d urinary excretion in kidney graft recipients depends on immunosuppression scheme and is the lowest in patients treated with tacrolimus and mycophenolane mophetil. PMID- 26030952 TI - [Progress assessment of rehabilitation in patients after hip replacement. Preliminary report]. AB - INTRODUCTION: Coxarthrosis is one of the most common diseases of the motor system. We distinguish primary and secondary coxarthrosis. The premises for total hip replacement include pain, damage to the surface of the acetabulum and the head of the hip, relative shortening of the limb, gluteal, femur and crus muscle atrophy and gait dysfunctions. The aim of this paper is to present the influence of rehabilitation on the improvement of physical ability, especially in respect to quality of gait and antianalgesic efficacy of the physical therapy in patients after total hip replacement. MATERIALS AND METHODS: The study was carried out in 37 patients aged 35-72 (mean of age--53.78 +/- 9.92). The group consisted'of 21 women and 16 men. After the total hip replacement, all the patients underwent physical therapy which involved application of laser radiation on the postoperative scar, whirpool and classic massage of the operated limb, exercises in non-weight bearing and weight-bearing exercises and gait reeducation. Modified Laitinen Pain Indicator Questionnaire, Visual Analogue Scale-VAS and the standardized mobility test--Timed-Up-And-Go test were used in the study. The statistical analysis was carried out with the use of the STATYSTIKA 5 PL computer program. RESULTS: The results reached point to the analgesic efficacy of the physical therapy and a better gait quality. CONCLUSIONS: Multifactor physical therapy after total hip replacement shows analgesic action. Appropriate selection of exercises and physical treatment have positive influence on gait reeducation in patients after total hip replacement. The Timed Up and Go test may be used in functional assessment of gait in patients with musculoskeletal disorders. PMID- 26030953 TI - [Magnetledtherapy in the treatment of postoperative pain caused anal fissure--a case report]. AB - Anal fissures occur most often as a result of mechanical damage or strenuous activity or cracks in structures lining the final stretch of the anal canal. They can also be the result of frequent constipation and anal intercourse. The consequence of these changes are creating cracks, sores and painful rectal spasms that cause very intense and uncomfortable pain. Initially conservative treatment is introduced. In the absence of satisfactory results, the only effective treatment is surgery. In this paper he results of treatment of a 63-year-old patient after surgery of anal fissures is introduced. The treatment included magnetledtherapy procedures. For several years, the patientfelt a persistent and very strong pain. Aftertreatment, there is significant pain relief occurring and significant improvement in quality oflife of the patient. The results of treatment show that in the complex process of treatment it is also essential to take into accountthe procedures of physical medicine. PMID- 26030954 TI - [Lithium carbonate-induced hyperparathyroidism in a patient after removal of a parathyroid adenoma]. AB - Lithium compounds are widely used and effective drugs in the treatment of mood disorders. However, despite their efficacy, the use of lithium salts is limited by their narrow therapeutic window. Treatment with lithium salts may be associated with the risk of development of numerous adverse effects. Endocrine complications include: thyroid dysfunction, nephrogenic diabetes insipidus and hyperparathyroidism. Because symptoms of lithium-induced hyperparathyroidism may resemble those of the underlying disorder, hyperparathyroidism sometimes remains undetected. The pathogenic mechanism for parathyroid dysfunction in lithium treated patients is still unclear. We report a patient who had undergone removal of a parathyroid adenoma and later developed lithium-induced hyperparathyroidism. Cessation of lithium treatment normalised parathyroid function.The described case suggests that patients with preexisting parathyroid disorders may be particularly susceptible to the development of lithium-induced hyperparathyroidism. PMID- 26030955 TI - [Acute idiopathic longitudinally extensive transverse myelitis with peripheral axonal motor neuropathy]. AB - Acute longitudinally extensive transverse myelitis (LETM) is a rare disease of autoimmune, connective tissue or infectious etiology (bacterial or viral) in which spinal cord lesion extends vertically over three or more vertebral segments. The most common cause of LETM is neuromyelitis optica (Devic's syndrome). It's typically clinically characterized by a tetraparesis or paraparesis of the lower extremities, superficial and deep sensation disturbances and sphincter dysfunction. Differential diagnosis is complex and based on immunological, serological, biochemical tests. Authors present 37-year-old healthy woman with sudden onset of flaccid tetraplegia preceded by upper limbs paresthesia. MRI examination of cervical and thoracic part of the spinal cord revealed extensive, multiple hyperintensive lesions extending from C3 up toTh9. In electroneurography examination coexistent severe peripheral axonal motor neuropathy was diagnosed. Despite performed profound tests the etiology of LETM in our patient remained unknown. PMID- 26030956 TI - [Recent methods of evaluation of quality of life in patients with chronic venous disease]. AB - Chronic diseases permanently influence on quality of life. One of them is chronic venous disease (CVD). According to The World Health Organisation (WHO) it concerns amlost 80-83.6% of adult population of the world. As most of chronic diseases CVD is not only a medical problem but also social and financial one. This paper is an overview about impact of CVD on Qol and methods of its evaluations. PMID- 26030957 TI - [Cognitive impairment in multiple sclerosis]. AB - Cognitive impairment affects 40-70% of multiple sclerosis patients. It occurs in all stages of the disease and reduces quality of life. Cognitive areas mainly involved are memory, information-processing speed, attention and executive functions. Cognitive performance can be affected by other factors, including depression, fatigue, disease course and medication. Advanced neuroimaging has helped to increase our knowledge about structural and functional mechanisms responsible for cognitive decline in multiple sclerosis. Early detection of cognitive impairment is essential to provide appropriate therapeutic intervention. PMID- 26030958 TI - [Psoriasis and comorbidity--literature review]. AB - Nowadays we know that psoriasis is more than "skin deep": it is considered a systemic disease. An increasing number of studies on the pathogenesis of psoriasis have shown that this disease is associated with metabolic disorders such as obesity, diabetes and cardiovascular diseases. Psoriasis appears to be a risk factor for the development of these diseases. That is why the concept of "psoriatic march" was proposed to demonstate that severe psoriasis may cause cardiovascular diseases. Many epidemiological studies have shown frequent coexistence of metabolic syndrome (insulin resistance, atherogenic dyslipidemia, obesity, hypertension and diseases of the cardiovascular system) in patients with severe course of psoriasis. Additionally, we observe a frequent coexistence of autoimmune disorders and cancers in patients with psoriasis. Suffering from psoriasis causes impaired self-esteem and depressive disorders. It is a source of stress for the patients, making them more likely to use alcohol or cigarettes. PMID- 26030959 TI - [Pathogenesis of Sjogren's syndrome]. AB - Sjogren's syndrome (SS--Sjogren's Syndrom) is an autoimmune systemic disease of connective tissue. The aim of this study was to present the contemporary literature on the basis of the pathophysiology of the Sjogren's syndrome, with particular reference to the pathogenesis of the damage to the salivary glands. It also discusses the criteria for classification, aetiology and pathogenesis of the SS, as well as the clinical symptoms of the disease in the oral cavity and its influence on the composition of the saliva. The knowledge of the Sjbgren's syndrome is important for the diagnosis and treatment of this disease. PMID- 26030960 TI - [Drug-induced thyroid dysfunctions]. AB - latrogenic disorders are an important cause of morbidity, mortality, and admission to hospital in developed countries. Similarly to many other organs, the thyroid gland may be affected by various drugs, often used for the treatment of non-thyroid disorders. Drugs may affect thyroid function via different mechanisms, including thyroid hormone production, storage, secretion and metabolism offering numerous targets for drug interventions. Usually, the effect of pharmacotherapy is observed more frequently and is stronger in case of the presence of the concomitant disorder of this gland. An understanding of the proposed mechanisms of these drug interactions and their evaluation and differential diagnosis is helpful in the interpretation of the findings associated thyroid disorders and in establishing the correct treatment. The purpose of this article is to review the present state of knowledge on the influence of various drugs on the hypothalamic-pituitary-adrenal axis. We discuss pros and cons of the use of these agents in patients with concomitant thyroid disease and provide the reader with recommendations concerning the diagnosis and treatment of iatrogenic thyroid disorders. PMID- 26030961 TI - [The impact of smoking on diseases of the genitourinary system]. AB - The fight against smoking is now one of the priorities of the health system. This habit is one of the most serious threats of the modern world, both for health as also socioeconomic reasons. Smoking has a harmful proven action on the human body, causing cardiovascular, digestive or neurological diseases. Tobacco smoke contains more than 40 carcinogenic substances, thus is considered to be one of the major risk factors for cancer diseases. The threat of tobacco, is even more alarming, when we look at the number of people affected by this addiction. In Poland is addicted 27.2% of the citizens and what more staggering also one third of young people age 19 is smoking. In the urological matter, smoking is a issue in the etiology of cancer diseases of the kidneys and bladder. New publications are showing thattabacoo smoking has a prolonged risk in developing bladder cancer. More data also suggests that it is a riskfactorfor developing cancer of the prostate gland. Smoking also affects negatively the sexuality and male fertility. PMID- 26030962 TI - [Usefulness of imaging examinations in preoperative diagnosis of acute appendicitis]. AB - Acute appendicitis (AA) is the cause one of most operations perform in department of general surgery on emergency ward. Frequency of acute appendicitis range from 6-8% of population. Clinical presentation is frequently unspecified and despite common occurence leads to many difficulties in diagnosis. Diagnosis of acute appendicitis includes clinical examination, laboratory tests, diagnostic scoring systems, computer programs as physisian aids and imaging examinations. About 30 45% patients suspected of acute appendicitis have untypical clinical presentation and here use of US or CT is very helpful. Longstanding use of US resulted in high AA evaluation accuracy with high sensitivity (75-90%) and specificity (84-100%). CT demonstrates above 95% ratio of correct diagnoses, reduces negative appendectomy rates and perforation rates as well as unnecessary observations. CT sensitivity and specificity CT is estimated between 83-100% among different authors. Expedited AA diagnosis, surgery and reduced hospitalization time are possible advantages of imaging tests. Additionally these tests can detect alternative deseases imitating acute appnedicitis. Use of imaging tests especially CT is beneficial in fertile women because of frequent genito-urinary disorders leading to the most diagnostic errors. However thera are contraindications in use of CT, for example it can not be performed in early pregnancy etc... PMID- 26030963 TI - [The association between oral diseases and stroke]. AB - In recent years there have been many studies concerning the effect of periodontal disease on the vascular system, including the development of stroke, either ischemic or hemorrhagic. The aim of this study was to present the relationship between periodontal disease and stroke based on the available literature. As it is evident from studies, patients with periodontal disease are predisposed to the formation of chronic systemic inflammation, which in turn is a risk facto for cardiovascular diseases, particularly diseases of the large vessels, including atherosclerosis, as well as chronic inflammation in the atherosclerotic plaque Atherosclerosis is a recognized risk factor for stroke. Current knowledge indicates the relationship between periodontal inflammation and stroke. Periodonta diseases are considered as an independent risk factor for vascular disease of the brain. Therefore, the prevention of periodontal disease is important, also early detection and treatment. Dental care should be an essential element of primary and secondary prevention of vascular events of central nervous system. PMID- 26030964 TI - [Contemporary view on physician-patient relationship]. AB - One of the most important conditions of successful treatment is adequate psychological contact between physician and patient. Culture of communicatio appearance of a physician, method of examination should not cause a negative reaction in patient. Contact between physician and patient may cause in patient fear or nervousness. Especially it is related to the use of invasive methods or selecting between different methods of treatment. Advances in the technologic area and its application in medicine should not replace direct contact between physician and patient. During the management of the patient physician shou remember that he treats not only the patient, but, above all, patient. PMID- 26030965 TI - [Safety of bariatric surgery in women of childbearing age and its future impact on their offspring]. AB - Obesity is the greatest epidemic of the 21st century. Unfortunately, it is more and more common among young people, including women in reproductive age who may suffer from difficulties with conceiving, pregnancy complications and increased maternal-fetal risk in the perinatal period. As a result of poor effectiveness of conservative treatment of obesity, a new trend has emerged to use surgical methods, which show positive effects on patients'fertility. It has been proved that pregnancy among women after bariatric surgery is safer than for other obese women who didn't undergo this procedure. Moreover, children of mothers who were operated were less likely to suffer from cardiovascular complications, obesity and other metabolic disorders in the future. However, it is vital to have in mind the likelihood of side effects, which include mainly serious vitamins, micro-, and macronutrient deficiencies that usually leads to constant and lifelong supplementation and the need of medical supervision of the patient and her child. PMID- 26030966 TI - [The conference, "rare diseases not only in the curriculum" in Szczecin]. AB - The conference 'Rare diseases not only in the curriculum', organised on 12th May, 2014 in Pomeranian Medical University in Szczecin, had a scientific and educational character. Representatives of patient organizations, medical students, junior doctors and physiotherapist were active participants of the meeting. There were rare diseases presented--from the medical curriculum, e.g., Wilson disease, Noonan syndrome and Diamond Blackfan anemia--and diseases that are not discussed in the course of medical studies in Poland, as Costello syndrome, Rabson-Mendenhall syndrome and cholestasis familiaris groenlandica- Byler-like disease.The importance of physiotherapy of children with spinal muscular atrophy was discussed.The place ofthe issue of rare diseases in the idea of personalized medicine was specified and difficulties in the care of patients with rare diseases, including muscle and metabolic diseases, in Poland were explained. PMID- 26030967 TI - The possible involvement of D-amino acids or their metabolites in Arabidopsis cysteine proteinase/cystatin N-dependent proteolytic pathway. AB - Cysteine proteinases and their inhibitors 'cystatins' play essential roles in plant growth and development. They are involved in various signaling pathways and in the response to wide ranges of biotic and abiotic environmental stresses. To investigate their possible influence from D-amino acids or their metabolism in vivo, Arabidopsis seedlings were allowed to grow under four physicochemically different D-amino acids including D-aspartate, D-serine, D-alanine and D phenylalanine containing media. The reverse transcription polymerase chain reaction (R T-PCR) analysis of cysteine proteinase and cystatin gene expressions showed that the addition of D-amino acid to the plant growth media considerably induce the expression of proteinase transcript while decrease the expression level of inhibitor gene in the leaf and root tissues of the test plant in overall. Based on the obtained results the potential impact of D-amino acids or their metabolism on the activity of cysteine proteinase/cystatin-dependent proteolytic apparatus as well as their possible cooperation were predicted and discussed in the plant system. PMID- 26030968 TI - [Allelic variants of the gene bamyl barley in Eastern European and central Asian areas]. AB - The collections of varieties of spring barley cultivars from the Eastern European and Central Asian areas were analyzed by exonpecific PCR (EPIC) for beta-amylase genes. The endosperm beta-amylase gene (bamyl) was differentiated by the presence of 126 bp MITE insertion into intron 3 that is associated with low activity beta amylase. The findings suggest that a low level of genetic variation for bamylgene within climatic zones is associated with individual breeding program for each climatic zone. PMID- 26030969 TI - Hydrogel nanoparticle encapsulated plasmid as a suitable gene delivery system. AB - To facilitate the delivery of genetic material, the use of appropriate carriers such as polymers is necessary. Nanoparticles comprising of chitosan-alginate polymers were formed through pregel preparation method. Chi/Alg nanoparticles had a mean Z-Average diameter of 161.8 nm and mean zeta 29.3 mV, respectively. The ability of plasmidcomplex in preventing DNA migration showed Chi/Alg nanoparticles have great capacity to maintain plasmid. The efficiency of nanoparticles for transfection of pEGFP-N1 plasmid in the cultured HEK 293 cells was measured by flow cytometry. Cell viability assays indicated that nanoparticles had no toxic effect on HEK 293 cells after 4 or 24 h. Our suitable candidate for gene delivery would be Alg/Chi nanoparticles. PMID- 26030970 TI - [Influence of tissue-specific superoxide dismutase genes expression in brain cells on Drosophila melanogaster sensitivity to oxidative stress and viability]. AB - The study has shown that both functional gene knockout Sodl and Sod2 and their overexpression in neurons and glial tissue increase the sensitivity of Drosophila melanogaster to oxidative stress (OS) conditions. The lowest survival rate was only 20.5% in insects with Sod2 knockout in neurons. Comparative analysis of the survival curves showed that adults with altered tissue-specific expression of the studied genes had reduced average and maximum life span. Under OS conditions induced by 5% hydrogen peroxide the life spans of wild type Oregon R and transgenic insects were significantly reduced. Altered Sod gene expression in glial tissue leads to degenerative changes in Drosophila brain at the young age. During the aging of insects and the action of pro-oxidants increasing of neurodegenerative phenotype is observed. PMID- 26030971 TI - [Genetic diversity and mating system Pinus brutia var. Stankewiczii sukacz. in small localities of Sudak (Crimea)]. AB - A comparative analysis of genetic variation at 12 polymorphic isozyme loci, and the mating system has been carried out in mature trees and their seed progeny in three small localities of Pinus brutia var. stankewiczii Sukacz. near the town of Sudak--settlement of Novyi Svet in the Crimea. We found that embryos maintain the same allelic diversity as mother plants but their observed heterozygosity is lower on the average by 37.4%. The significant deviation of genotype distribution from the theoretically expected ratios caused by the deficiency of heterozygotes was observed at 8 out of 12 loci. Multilocus estimate of outcrossing rate (t(m)) in populations varied from 68.9 to 94.9% making on the average 80.7%. PMID- 26030973 TI - [Role of transcription factors in transdifferentiation of the gastric mucosa]. AB - The analysis of intestinal differentiation transcription factor CDX2 in the gastric mucosa biopsies has been carried out. It was established that CDX2 by itself promoter activation pathway can obtain intestinal phenotype for gastric mucosa cells. The loss of CDX2 expression in the nuclei of metaplastic epithelium may serve as a predictor of gastric mucosa malignization. PMID- 26030974 TI - [Cytogenetic genome stabilization in secalotriticum (x Triticosecale derzhavinii secalotriticum rozenst., et Mittelst., s/RRAABB, 2n = 42)]. AB - The article presents the results of cytogenetic research of the genome stabilization in hexaploid secalotriticum F(1-9) (s/RRAABB, 2n = 6x = 42). Nucleo cytoplasmic specificity and cytogenetic factors of genome stabilization were established in secalotriticum: subspecies specificity of cytotype, genotype specificity of hybrids, origin, polar centromere orientation, division and segregation type of the chromosomes in meiosis. The necessity for developing independent trends in heteroplasmic triticales breeding was substantiated. PMID- 26030972 TI - ITPA gene variant may protect against anemia induced during pegylated interferon alfa and ribavirin combination treatment in Ukrainian patients with chronic hepatitis C. AB - The aim of this study was to clarify the association between the inosine triphosphate pyrophosphatase (ITPA) gene variants and PEG-IFNalpha/RBV combination treatment induced anemia in chronic hepatitis C (CHC) Ukrainian patients. The data were collected from 80 CHC patients with HCV genotype 1 infection. All study participants received standard doses of PEG-IFNalpha and RBV According to the Hb level changes patients were distributed into: case group--42 patients with combination treatment induced anemia, and control group--38 patients with no signs of anemia. Genotyping for ITPA gene rs1127354 and rs7270101 variants was performed using PCR followed by RFLP assay. Fisher's exact test was used to estimate the difference in genotype and allelic distribution. Distribution of rs 7270101 genotypes was not significantly different between groups of CHC patients with RB Vinduced anemia and without it. The frequency of rs1127354 A allele carriers was significantly higher (P < < 0,05) in group of CHC patients without anemia (23.7%) comparing to the group ofpatients with anemia (7.3%). The respective allele frequency in control group (13.2%) was almost 3 fold higher (P < 0,05) comparing to the case group (4.9%). Significant association of ITPA gene rs1127354 with protection against RB V-induced hemolytic anemia was found in Ukrainian patients with CHC infection. Rs1127354 variant may assist as a pharmacogenetic marker in HCV antiviral therapy correction for side effect avoidance.. PMID- 26030975 TI - A mutagenicity and cytotoxicity study of limonium effusum aqueous extracts by Allium, Ames and MTT tests. AB - Nowadays plants or plant extracts have become very important for alternative medicine. Plants and their extracts have many therapeutical advantages but some of them are potentially toxic, mutagenic, carcinogenic and teratogenic. Root, stem and leafparts of Limonium effusum were used in this study and this species is an endemic species for Turkey. Mutagenic and cytotoxic effects of root, stem and leaf aqueous extracts were observed with Allium, Ames and MTT tests. Allium root growth inhibition test and mitotic index studies showed that aqueous extracts have dose-dependent toxic effects. Chromosome aberration studies indicated that especially sticky chromosome, anaphase-telophase disorder and laggard chromosome anomalies were highly observed. Ames test performed with Limonium effusum root aqueous extracts, showed weak mutagenic effects in Salmonella typhimurium TA98 strain with S9. MTT test based on mitochondrial activity indicated that most of the aqueous extracts have cytotoxic effects. This study aimed to determine the possible mutagenic and cytotoxic effects of L. effusum aqueous extracts by using bacterial, plant and mammalian cells. This research showed that some low concentrations of the L. effusum extracts have inhibited cytotoxic effects but high concentrations have induced cytotoxicity. On the other hand only a weak mutagenic activity was identified by Ames test with TA98 S9(+). PMID- 26030976 TI - [The bipolarity of the genetic structure of communities of the crucian carp (Carassius linnaeus, 1758) as a reflection of paradoxal reproductive relationships]. AB - An analysis of 133 populations of Carasiius spp. from water bodies in Ukraine showed their polyspecific structure: 62% of individuals of the studied 3453 specimens. turned out to be bisexual goldfishes C. auratus, 25%. were unisexual Prissian carps C. gibelio, 6% accounted for the aboriginal species crucian carp C. carassius, and 6% were hybrids C. auratus x C. carassius. In this case a clear trend has been revealed towards the formation of homogeneous alternative populations, specifically: either C. auratus, or C. gibelio. Individuals of C. carassius and the hybrids C. auratus x C. carassius typically comprise an admixture in various populations. The cause of the bipolar distribution of individuals of C. auratus and C. gibelio between various water bodies is the instability of mixed populations as far as individuals of C. auratus very quickly replace females of C. gibelio due to their low reproductive potential. PMID- 26030977 TI - [The mechanisms of Antartic vascular plants adaptation to abiotic environmental factors]. PMID- 26030978 TI - Fostering connections, fostering change. PMID- 26030979 TI - The path from process to outcomes: a cross-site evaluation of 24 family connection grantee projects. AB - This paper presents process and outcome results from 24 federally-funded grants designed to reconnect family members with children in or at risk of entering foster care. Authors used local evaluation designs, data collection, analyses, and grantee reporting, along with site visits and interviews, to implement a cross-site evaluation. Target populations; service models; parent, child, and family-level outcomes; and organizational and system-level outcomes are summarized. Limitations of the evaluation and recommendations to the field are discussed. PMID- 26030980 TI - Measuring the impact of enhanced kinship navigator services for informal kinship caregivers using an experimental design. AB - While relative care may offer significant benefits to kin children as compared to non-relative foster care, informal kinship caregivers often experience various hardships and needs without the resources of the child welfare system to aid them. They may benefit from services provided by an expanded kinship navigator program. This study, using an experimental design, adds to knowledge about the characteristics and needs of kinship caregivers and the impact of enhanced navigator services. The relative effect of this more intensive intervention was mixed. Caregivers had many of their expressed needs met. Yet, the enhanced services group did not demonstrate: an increase in perceived social support; reduction in caregiver stress; or improvement in child behavior compared to the families receiving brief, traditional navigator services. Little difference was found in post intervention involvement in the child welfare system. Further enhancements to the model are suggested. PMID- 26030981 TI - Family team conferencing: results and implications from an experimental study in Florida. AB - This article reports the outcome evaluation findings of an experimental study conducted with families in the child welfare system in Florida. Families were randomly assigned to one of three Family Team Conferencing (FTC) models. In Pathway 1, the comparison model, FTCs were facilitated by case-workers. In Pathway 2, one of two experimental models, FTCs were cofacilitated by caseworkers and a designated/trained facilitator, and included expedited family engagement as well as the provision of FTCs throughout the life of a case. Pathway 3, also an experimental model, had the same components of Pathway 2 but also included family alone time. In approximately three years of the project period, 623 families agreed to participate in the study. Study findings showed no statistically significant change observed for families participating in Pathway 1 FTCs in terms of protective factors, achieving family-defined service and plan-of-care goals, and emotional and behavioral symptomology of children. Cases in Pathway 2 demonstrated significant improvement in family functioning and resiliency, nurturing and attachment, and increasing parents' knowledge about "what to do as a parent." Caregivers and teens in Pathway 3 reported significant improvement in expression of emotional symptomology/problems, conduct problems, hyperactivity, peer problems, and a measure of total difficulties. However, foster care re-entry rates were significantly higher for Pathway 3 than Pathway 2 (but not Pathway 1). Moreover, Pathway 2 and Pathway 3 FTCs had a significant effect on moving the family toward agreed upon service goals. Taken together, these findings suggest that the experimental FTC models in which facilitators were used and family engagement was expedited and sustained through subsequent FTCs demonstrated moderate, yet mixed benefits to children, youth, and families. PMID- 26030982 TI - All in the family: variations in the use of family meetings in child welfare. AB - The current state of family meeting practice within and across child welfare jurisdictions in the United States is widespread and varies greatly, presenting challenges for rigorous research and evaluation. Three illustrative jurisdiction level case studies are provided, which demonstrate not only commonalities and differences in practice across agencies but the underlying reasons for this variation. The associated challenges for evaluation of this practice are also discussed. PMID- 26030983 TI - Using multi-informed fidelity data to determine the impact of a neutral child welfare facilitator for permanency decision teams. AB - Few studies have included fidelity monitoring and critical approaches to the evaluation of family decision meetings. The current study uses a mixed-methods approach to examine the implementation and fidelity adherence of one state's family decision meeting model. Main findings indicate that while individuals facilitating the meetings perceive their fidelity to the model is strong, the observation data suggest that model adherence is inconsistent among those facilitating the meetings. Practice implications are discussed. PMID- 26030984 TI - Residential family treatment for parents with substance use disorders who are involved with child welfare: two perspectives on program design, collaboration, and sustainability. AB - This article discusses the service design, implementation, and evaluation findings of two residential family treatment programs: Wayside House (MN) and OnTrack (OR). Both programs specialize in family-centered services for adults with substance use disorders (SUD) who are involved with child welfare. Information on program design, services offered, and key collaborations are detailed. Implications for program sustainability are provided. PMID- 26030985 TI - What is child andadolescent well-being?: you are the sum total of everything. PMID- 26030986 TI - Mental health care of families affected by the child welfare system. AB - The primary aim of this paper is to introduce practitioners to the mental health needs of children and families who are under the care and supervision of the child welfare system because of substantiated child maltreatment. Emphasis is placed on children and families who are receiving foster care services. The paper draws attention to the most prevalent mental health conditions that affect foster care children and their families based on type of maltreatment. Given that young children under age 5 are more likely to be placed in out-of-home placements and to spend a significant portion of their lives in foster care, their unique mental health needs are highlighted. Treatment approaches that are informed by both practice wisdom and evidence-based practice--such as ego-supportive intervention and trauma-focused, cognitive-behavioral therapy--are stressed. A case study is presented as a way of illustrating how mental health care may be delivered to families affected by the child welfare system. PMID- 26030987 TI - The Scottish children's panels as a catalyst for civic engagement and child well being. AB - Scotland's child welfare system has developed as hybrid of both residual and universal approaches and incorporates local involvement through trained volunteers participating in children's panels and community-based interventions. Furthermore, Scotland's move toward independence from the United Kingdom, called devolution in Scotland, has resulted in a resurgence of new recommendations focused on child well-being from birth through adolescence for all Scottish children. This article will explore policy development of Scotland's unique child welfare approach through the children's panels and the commitment to civic participation. It will expand on how recent initiatives, policy, and practice guidelines may have implications for providing a promising, sustainable model focused on child well-being, and may be useful for consideration in other cultural contexts that view liberty and civic engagement as core values. PMID- 26030988 TI - Child maltreatment entrenched by poverty: how financial need is linked to poorer outcomes in family preservation. AB - This cross-sectional secondary data analysis examined the ecological factors influencing the outcomes of families receiving services from a local department of social services to address child maltreatment risk and incidence. The results indicated that families that experienced repeated maltreatment also experienced greater poverty and material need than families with more successful outcomes. This study highlights the responsibility of the child welfare system to address deep-seated poverty issues of families experiencing child maltreatment risk and incidence. PMID- 26030989 TI - Former foster youth's perspectives on independent living preparation six months after discharge. AB - Research findings have developed a troubling narrative of youth leaving foster care. Congress attempted to address the post-discharge difficulties of foster youth by passing the Independent Living Initiative in 1986, which mandated that the states develop services that would prepare youth for life after foster care. However, it is unclear what effect these programs have on post-foster care trajectories. This largely qualitative study examined the perceptions of a sample of discharged foster six months after leaving care. Most youth felt prepared for life and foster care. They were also for the most part were satisfied with their independent living program, but had significant dissatisfactions with elements of the program. These satisfactions and dissatisfactions are reported along with suggestions for improvement. The policy and practice implications of these suggestions are considered. PMID- 26030990 TI - Risk of early sexual initiation and pregnancy among youth reported to the child welfare system. AB - This study found that youth involved with the child welfare system have high rates of sexual risk behaviors and outcomes, including forced sex, early age at first sex, low contraceptive use, and pregnancy, which are more than double those of adolescents from the general population. Caseworkers may need training in how to address sexual risk factors and may need to support caregivers in addressing these issues with their children. Findings highlight the importance for case workers, caregivers, and others to address the sexual and reproductive health needs of maltreated youth. PMID- 26030991 TI - Differential effects of single and double parental death on child emotional functioning and daily life in South Africa. AB - There is a high level of orphaning in Africa due to war, violence, and more recently HIV and AIDS. This study examines parental death in South African children and examines the differential impact on child functioning of double, single and non-orphanhoods. Bereavement, depression, behavior problems, and violence were examined in a consecutive sample of 381 children/adolescents (51.2% girls) between 8 and 19 years of age (M = 12.8). Parental death experience was high; 70 (17.5%) reported the death of one parent, and a further 24 (6%) reported the death of both. Group comparisons showed double orphans had elevated depression, worse psychosocial functioning, were more likely to be kept home from school for household chores, and were more likely to be slapped. Single orphans were more similar to the non-orphans than the double orphans on most scores. Our study reveals that parental loss should be studied with more fine-grained definitions and that emotional sequelae should be addressed. PMID- 26030992 TI - In vitro evidence for association between hepatitis C virus infection and insulin signaling pathways: a review. AB - Hepatitis C virus infection, besides its substantial unfavorable impact on liver health, has several other manifestations, from which we have focused on its associations with insulin resistance and diabetes mellitus in an in vitro setting in this review of the literature. Several epidemiologic studies have already proven the strong association between chronic HCV infection and development of diabetes mellitus. However, attempts to clarifying molecular mechanisms for this association have not made up until recent years. We made a comprehensive review of the literature but we only found 6 studies investigating HCV impact on insulin signaling pathway in an in vitro era. We tried to review and compare the findings of these studies to show what we already know on the issue and what we still need to know. PMID- 26030993 TI - In vitro propagation and cryopreservation of Aerides odorata Lour. (Orchidaceae). AB - An efficient method for in vitro propagation and cryopreservation of Aerides odorata was established. Leaf segments were cultured on New Dogashima (ND) mediums supplemented with various concentrations of Benzyladenine (BA) (0-5 mg L( 1)) combined with Naphthaleneacetic Acid (NAA) (0-2 mg L(-1)). The optimal treatment for inducing Protocorm-like Bodies (PLBs) from leaf segments was obtained from the combination of 1 or 3 mg L(-1) BA and 0.5 or 1 mg L(-1) NAA; whereas, the addition of BA or NAA alone induced shoot and/or root initiation rather than PLB or callus formation. Shoots rapidly developed on ND mediums containing 5 mg L(-1) BA. Cryopreservation of leaf segment-derived PLBs was successful using the encapsulation-dehydration method. The maximum survival percentage of Cryopreserved (Cryp) PLBs was achieved by encapsulating PLBs with 2% Na-alginate combined with 2 M glycerol and 0.4 M sucrose. The encapsulated PLBs were then precultured in 0.75 M sucrose for 24 h and dehydrated for 6 h before plunging into liquid nitrogen. Genetic stability of Cryp PLBs after regrowth was assessed by flow cytometry. The findings showed no different patterns of ploidy levels and morphology between Cryp and non-cryopreserved (Ncryp) control plantlets. PMID- 26030994 TI - Overexpression of Arabidopsis Dehydration-Responsive Element-Binding protein 2A confers tolerance to salinity stress to transgenic canola. AB - Stress responsive transcriptional regulation is an adaptive strategy of plants that alleviates the adverse effects of environmental stresses. The ectopic overexpression of Dehydration-Responsive Element Binding transcription factors (DREBs) either in homologous or in heterologous plants are the classical transcriptional regulators involved in plant responses to drought, salt and cold stresses. To elucidate the transcriptional mechanism associated with the DREB2A gene after removing PEST sequence, which acts as a signal peptide for protein degradation, 34 transgenic T0 canola plants overexpressing DREB2A were developed. The quantitative Real time PCR of transgenic plants showed higher expression of downstream stress-responsive genes including COR14, HSF3, HSP70, PEROX and RD20. The transgenic plants exhibited enhanced tolerance to salt stress. At the high concentration of NaCl the growth of non-transformed plants had been clearly diminished, whereas transgenic line was survived. These results indicated that transformed DREB2A gene might improve the plant response to salinity in transgenic canola plants. PMID- 26030995 TI - Influence of wastewater application and fertilizer use on growth, photosynthesis, nutrient homeostatis, yield and heavy metal accumulation in okra (Abelmoschus esculentus L. Moench). AB - The scarceness of freshwater assets is a serious problem in semi-arid zones and marginal quality water is increasingly being used in agriculture. This study aimed at evaluating the physico-chemical and biological risks on irrigated soils of treated wastewater, the nutrient supply and the effect on okra plant. A pot experiment based on completely randomized block design was conducted with Treated Wastewater (TW) and inorganic fertilizers to observe a comparative effect on biochemical characters using Okra var. Nidhi. The physico-chemical analysis of the TW showed that it was rich in total suspended and dissolved solids with large amount of BOD and COD. The higher amount of Cl-, Ca++, Mg++ and K+ were also present in the effluent. The heavy metal (Cd, Cr, Ni and Pb) content in TW is comparatively more than groundwater (GW). The values of these heavy metals were slightly higher in the soil irrigated with TW. The effluent severely affects crop plants and soil properties when used for irrigation. The growth parameters, photosynthetic characteristics, chlorophyll content, yield and nutrient homeostatis were analyzed during different growth periods in all treatments. All the parameters were found to increase due to wastewater application. Among the fertilizer treatments, N120 proved optimum, N90 deficient and N150 proved as luxury dose. The seeds accumulated Cd and Ni but their level was under permissible limits. Thus, it may be concluded that wastewater may be used profitably for the cultivation of okra. PMID- 26030996 TI - Diversity of macrofauna from continental shelf off Singarayakonda (southeast coast of India). AB - The present study was undertaken to study the benthic productivity of shelf region off Krishna River mouth. Standing stock of macrobenthos and its distribution were studied. Sampling was done onboard FORV Sagar Sampada from depths as 30, 50, 75, 100, 150 and 200 m using Smith-McIntyre grab having a bite area of 0.2 m2. After identification, data were treated using statistical package PRIMER v6. The nature of the sediment was medium sand up to 150 m depth and fine silt at 200 m. The benthic biomass (0.2977-3.1091 mg 0.2 m(-2)), abundance (58 289 nos. 0.2 m(-2) and number of species (12-48) decreased with increase in depth. The total number of species recorded was 69. Species estimators showed the possibility of collecting 129 species (Chao1) with intense sampling. Polychaetes formed the largest group with 40 species followed by molluscs (15 species) and crustaceans (14 species). The Spearman rank correlation (Rho) value (0.513) which was significant at 1.1% showed gradual change in species composition with increase in depth. The Pi value (3.78) comparing the similarity of benthos at 200 m depth with those of other depths (30, 150, 100, 75 and 50 m) showed significant differences (0.6%). Matching of biotic variables with that of environment showed the influence of dissolved oxygen on the distribution of macrobenthos (Rho 0.757). Intense sampling should be done to record all the species as shown by species estimators besides studying shelf productivity off other rivers and relating it with nutrient discharge and other environmental factors including sediment nature. PMID- 26030997 TI - Comparative study of antioxidant power, polyphenols, flavonoids and betacyanins of peel and pulp of three Tunisian Opuntia forms. AB - The antioxidant activity and the chemical composition of methanol extracts from peel and pulp belonging to two species of Tunisian prickly pears Opuntia ficus indica (spiny and thornless forms) and Opuntia stricta has been studied. The antioxidant capacity was measured by DPPH radical scavenging activity. The Total Phenolic Compound (TPC) and the total flavonoid content were determined by the Folin-Ciocalteu method and colorimetric method, respectively. The phenolic compounds were identified and quantified by High Performance Liquid Chromatography (HPLC) coupled with an electrospray ionization mass spectrometry (ESI-MS). The results showed that O. stricta fruits present the best antioxidant activities than the two forms of O. ficus indica while the TPC was more important in O. ficus indica than in the O. stricta fruits. The peels have higher flavonoids than pulps and the thornless has more flavonoid than the spiny. The RP HPLC and ESI-MS analysis detected two classes of phenolic compounds and betalain pigments. Isorhamnetin derivatives are the dominant flavonol glycoside identified in O. ficus indica (spiny: 65.25 MUg g(-1); thornless: 77.03 MUg g(-1)) and O. stricta peels (19.22 MUg g(-1)). PMID- 26030998 TI - Correlation and path coefficient analysis of quantitative characters in spine gourd (Momordica dioica Roxb.). AB - Fifty genotypes of spine gourd (Momordica dioica Roxb.) were evaluated in a randomized block design with two replications at the Vegetable Research Station, Rajendranagar, Hyderabad, Andhra Pradesh, India during kharif, 2012. Correlation and path coefficient analysis were carried out to study the character association and contribution, respectively for twelve quantitative characters namely vine length (m), number of stems per plant, days to first female flower appearance, first female flowering node, days to first fruit harvest, days to last fruit harvest, fruiting period (days), fruit length (cm), fruit width (cm), fruit weight (g), number of fruits per plant and fruit yield per plant (kg) for identification of the potential selection indices. Correlation and path coefficient analyses revealed that fruiting period and number of fruits per plant not only had positively significant correlation with fruit yield but also had positively high direct effect on it and are regarded as the main determinants of fruit yield. Days to first fruit harvest had positively moderate direct effect on fruit yield and its association was negatively significant, days to last fruit harvest had negatively high direct effect on fruit yield and its association was significant positively, hence restricted simultaneous selection can be made for days to first fruit harvest and days to last fruit harvest. The improvement in fruit yield can be effective if selection is based on days to first fruit harvest, days to last fruit harvest, fruiting period and number of fruits per plant. PMID- 26030999 TI - Alkaloid (Meleagrine and Chrysogine) from endophytic fungi (Penicillium sp.) of Annona squamosa L. AB - Several endophytic fungal strains from Srikaya plants (Annona squamosa L.) have been isolated and one of them was identified as Penicillium sp. Penicillium has been proven as an established source for a wide array of unique bioactive secondary metabolites that exhibit a variety of biological activities. The aim of this study is isolation of secondary metabolite from Penicillium, an endophytic of A. squamosa L. Penicillium sp. from endophytic of A. squamosa L. was fermented in Wicherham media. The whole extract from both liquid media and mycelium was partitioned by ethyl acetate and evaporated to obtain crude ethyl acetate extract. The ethyl acetate extract was then brokedown using column chromatography with silica as stationary phase and mixture of ethyl acetate/methanol (98%:2%) as mobile phase and then was separated by sephadex column. Structure elucidation of isolated compounds were mainly done by analysis of one and two dimensional NMR (Nuclear Magnetic Resonance) data and supported by HPLC (High performance Liquid Chromatography) and MS-TOF (Mass Spectrometer-Time of Flight). Isolated secondary metabolites were tested using in vitro assays for anticancer and antimicrobial activity. For anticancer activity, the metabolites were tested against breast cancer cells (MCF-7) using MTT assay, while for antimicrobial activity was performed using disk diffusion assays. From these physical, chemical and spectral evidences that the secondary metabolites were confirmed as Chrysogine and Meleagrine. Chrysogine and Meleagrine have no activity as anticancer and antimicrobial. PMID- 26031000 TI - Industrial effluent induced chromosomal aberration in catfish from Ogun River, Lagos, Nigeria. AB - The aim of the study is to evaluate the cytotoxic effect of effluents at inducing chromosomal aberrations, using this as a biomarker tool in wild Clarias pachynema for assessing and monitoring pollution of the aquatic environment. A total of 60 live fish (30 each downstream and upstream) were obtained and subjected to chromosomal analysis. Chromosomal aberration in the fish samples from the downstream sector was recorded at a rate of 30%, while there were no aberrations in the samples collected upstream the effluent discharge point. Water sample analysis revealed a high concentration of Ammonia and Nitrates above permissible standards of Federal Environmental Protection Agency (FEPA) guidelines. Heavy metal analysis also revealed the presence of Cr (0.05), Cu (0.01), Pb (0.05), Zn (5.0) and Fe (0.3) above permissible standards from the downstream section of the river. This study shows clearly that the ever increasing discharge of effluents from the industry could increase chromosomal damage in the aquatic components. PMID- 26031001 TI - Reduced red blood cell membrane damage in streptozotocin-induced diabetic rats supplemented with roselle (UKMR-2) calyx extract. AB - The aim of this study was to evaluate the effects of aqueous extract of roselle on the membrane composition of red blood cells. A total of 32 male Sprague-Dawley rats (230-250 g) were divided randomly into four groups. Diabetic rats were induced streptozotocin (45 mg kg(-1), i.v). The normal and diabetes groups were administrated with distilled water. The other normal and diabetes group were administrated with roselle aqueous extracts (100 mg kg(-1)). After 28 days, the blood was drawn by sinus orbital for biochemical tests including membrane total protein, cholesterol and phosphatidylcholine and morphology of red blood cells was carried out through light microscope. In diabetic rats, the result showed the weight of rat, membrane total protein and Phosphatidylcholine (PCh) were significantly lower (p<0.05), while blood glucose and membrane cholesterol showed significantly higher (p<0.05) than control rats. In diabetic rats demonstrated with roselle, the result showed no significant difference (p>0.05) in weight and blood glucose compared to diabetic rats. The membrane total protein and PCh were significantly higher (p<0.05) than diabetic rats, whereas membrane cholesterol was significantly lower (p<0.05) compared to diabetic rats. The observation red blood cells morphology that showed echinocytes, schistocytes and Heinz body in diabetic rats was caused by oxidative stress damage. The morphology of red blood cells in diabetic rats supplemented with roselle is normal. Aqueous extract of roselle showed potential protective effects on membrane composition of damaged red blood cells. PMID- 26031002 TI - Reference values of six-limb-lead electrocardiogram in conscious Labrador retriever dogs. AB - Breed-wise standard electrocardiographic values in dogs have been reported as there is variation in body and chest conformation, which limits the application of data of one breed for other breed. Labrador retrievers being originated from hunting dogs, their electrocardiogram (ECG) values might be different from standard normal range of other dog breeds. So, the purpose of the present study was to determine the standard ECG of Labrador retrievers and to check effect of body weight, gender and breed upon different ECG parameters. Six-lead ECGs, three bipolar standard limb leads (I, II and III) and three augmented unipolar limb leads (aVR, aVL and aVF), were taken from 24 Labrador retrievers positioned in right lateral recumbency without any chemical restraint. Amplitude and duration of P wave and QRS complex, PR interval, QT interval and mean electrical axis and heart rate were measured in each recording. Non-significant effect of gender and body weight was seen on all the ECG waves. Deep Q waves in Leads I, II and aVF and variation in relation to QRS pattern were noted. It was concluded that retrievers had a specific shape of QRS complex which must be considered when evaluating a patient suspected of having cardiac disease. However, amplitude and durations of different ECG waves in all the six leads were statistically not affected by gender or body weight. PMID- 26031003 TI - Biosystematic studies on Enicostema axillare (Lam.) A. Raynal subsp. Axillare (Gentianaceae) in peninsular India. AB - The pantropical genus Enicostema (Gentianaceae) has three species and two sub species world over, namely, E. verticillatum (L.) Engl. (America), E. elizabethae Veldkamp (Madagascar) and E. axillare having 3 subsp. viz., subsp. axillare (Lam.) A. Raynal (India), subsp. latilobum (N.E. Br.) A. Raynal (East Africa) and subsp. littorale (Blume) A. Raynal (Indonesia). The present study aims to delimit the Indian taxa based on field and herbarium studies. Comparative morphology is studied using live as well as consulting wide range of specimens housed at various herbaria. The anatomy of leaf, stem, and root is studied using free hand sections and from epidermal peelings. The seed and pollen morphology are studied under SEM. Information on anatomy, palynology and seed micromorphology of E. axillare subsp. axillare is provided for the first time. PMID- 26031004 TI - Growth indices and cost implications of hybro broiler chicks fed with graded levels of fermented wild cocoyam Colocasia esculenta (L.) Schott corm meal as a replacement for maize. AB - Corms such as wild cocoyam [Colocasia esculenta] have potential to replace maize as a cheaper energy source in poultry rations. A feeding trial was conducted to evaluate the effects of graded levels of fermented wild cocoyam [Colocasia esculenta (L.) Schott] corm (FWCC), as substitutes for maize in the diets of broilers at the starter phase. One hundred and twenty unsexed day-old Hybro broiler chicks were randomly distributed to four dietary treatments in a Completely Randomized Design (CRD). There were 3 replicates per dietary treatment with 10 birds per replicate. Diet 1 without FWCC served as the control. Diets 2, 3 and 4 contained 10, 20 and 30% FWCC. Each of the diets represented a treatment. The experimental diets and clean drinking water were supplied ad libitum for 4 weeks (28 days) representing the starter phase of the broiler production. Result of the performance revealed significant (p<0.05) differences in feed intake, weight gain and feed conversion ratio. The economic analysis also showed that cost (Naira58.52) of a kilogram feed was highest (p<0.05) for the control and least (Naira53.10) for 30% FWCC. The least cost (Naira101.24) of feed per kilogram weight gain (p<0.05) was obtained for birds fed 30% FWCC compared to (Naira105.53) for the control. It was concluded that maize can economically be substituted with 30% FWCC in broiler starter diets. PMID- 26031005 TI - Therapeutic hypoglycemic potential of Pentapetes phoenicea L. in experimentally induced hyperglycemic rats. AB - Diabetes mellitus is a metabolic disorder of endocrine system. This dreadful disease is found all over the world and is becoming a serious threat to the mankind health. Alternative to synthetic agents, plants provide a potential source of hypoglycemic drugs. The aim of the present study was to evaluate the hypoglycemic effect of 70% alcoholic extract of Pentapetesphoenicea (PPE) on blood glucose level in glucose loaded, normal and experimentally induced diabetic rats. Based on the acute toxicity test, two variable doses (250, 500 mg kg(-1) b.wt.) of hydro-alcoholic extract of P. phoenicea leaves were compared with glibenclamide for the influence on fasting blood glucose in glucose loaded, normoglycemic and streptozotocin (STZ) (55 mg kg(-1), i.p.) induced hyperglycemic rats. All the statistical comparisons were made by one-way analysis of variance (ANOVA) followed by Newman-Keuls Multiple Comparison Test using Graph Pad Prism 4.01 v for windows (Graph Pad Software, San Diego, CA, USA). The difference showing a p level of 0.05 or lower was considered to be statistically significant. The administration of PPE in two doses and glibenclamide (5 mg kg( 1)) to STZ induced hyperglycemic animals significantly lowered the blood glucose levels with 18.84% (p<0.01) for PPE 250 mg kg and 38.89% (p<0.001) for PPE 500 mg kg(-1) in a dose dependant manner. Considering all the results obtained, the study concludes that the hydro-alcoholic extract of P. phoenicea leaves produced promising decrease in blood glucose levels in STZ induced hyperglycemic rats which might be related to tannins, terpenoids, sterols and flavonoid contents. PMID- 26031006 TI - Antioxidant and antimicrobial activity of Araucaria cookii and Brassaia actinophylla. AB - Araucaria cookii is an ornamental plant, which are evergreen conifer found in India and in many other European countries. Similarly Brassaia actinophylla is also an ornamental plant with its native from Java, Australia and in U.S. Though these plants are used for various purposes, the medicinal properties of the plants were not investigated. In our study, the two ornamental plants were chosen for screening both antioxidant and antimicrobial activity. The Leaves of the plants were used for preparing crude extract and was prepared by Soxhlet extraction method. For the extraction of the leave extracts, different solvents viz., methanol, chloroform and petroleum ether were used based on our preliminary data. The obtained extracts were condensed and stored. For the antioxidant and antimicrobial activity, the extractions were prepared into various concentrations. For the antioxidant activity DPPH was used as scavenger of the free radicals which showed the inhibition of percentage for Araucaria cookii was 63% and the inhibition percentage for Brassaia actinophylla 41%. For the antimicrobial activity the extracts were checked against two bacterial and two fungal pathogens. The phytochemical analysis assists in the study of the antioxidant and antimicrobial activity as to the probable compounds responsible for the activity. The result thus obtained provides a report of Brassaia actinophylla as a possible source of antioxidants and also the use of both extracts as a probable antimicrobial agent. PMID- 26031007 TI - Seroprevalence of infectious bovine rhinotracheitis in dairy animals with reproductive disorders in Uttar Pradesh, India. AB - Respiratory and reproductive disorders in dairy animals due to various etiological agents have led to significant economic losses to dairy industry. These losses are due to abortions, metritis, retention of placenta, repeat breeding, death of animals, loss of production and trade restrictions etc. The objectives of this cross-sectional study were to detect the seroprevalence of infectious bovine rhinotracheitis (IBR, BHV-1) in dairy animals of western parts of Uttar Pradesh, India. Anti BHV-1 antibodies were measured using a commercial ELISA kit (SYANOVIR(r) IBR-Ab). Blood samples were collected from a total of 134 animals of different age, gender from 8 districts. Overall individual seroprevalence was 32.84%. The study revealed that BHV-1 is comparatively more widespread in cattle (46.51%) than buffalo (35.28%). Comparison of different sex groups of animals revealed that the higher numbers of infected animals were identified in male (48.00%) than female (29.35%). The seropositivity of IBR increased with age of animals. The highest prevalence of IBR (66.67%) was observed in animals aged more than 8 years. As vaccination against IBR is not practiced in the region and higher percent positivity (>20%) in all age group of animals indicated the natural circulation of BHV-1 virus in the population. Because of less awareness on the vaccination of animals against this virus, the disease may spread rapidly. The results of present study also indicate that strict monitoring and surveillance of IBR is need of today to protect the animals from infection and further spread. PMID- 26031008 TI - Physical characteristic and palatability of biscuit bio-supplement for dairy goat. AB - The objective of this study was to apply the physical characteristic and palatability of biscuit bio-supplement for dairy goat. This research was conducted at Laboratory of Feed Industry, Faculty of Animal Science, Bogor Agricultural University, Indonesia and the palatability test was conducted on the dairy goat farm at Leuwiliang, Bogor, Indonesia on March-July 2012. Twenty heads of dairy goat were randomly assigned to five dietary treatments (four heads of goat/treatment). Experimental design used Completely Randomized Design (CRD). The treatments were biscuit bio-supplement composition i.e., R1 = biscuit bio supplement of Indigofera sp., R2 = biscuit bio-supplement of Sauropus androgynus L. Merr leaf, R3 biscuit bio-supplement of Carica papaya L. leaf, R4 = biscuit bio-supplement of Sauropus androgynus L. Merr leaf and Indigofera sp., R5 = biscuit bio-supplement of Carica papaya L. leaf and Indigofera sp. The variables measured were moisture, water activity, water absorption, density and palatability of dairy goat. The results of this research indicated that the treatments of biscuit bio-supplement gave significant effect (p<0.05) on water content, water absorption, density and palatability, but had not significant effect on water activity. Palatability of R1 was 76.38+/-7.92, R2 was 23.81+/ 6.08, R3 was 40.25+/-3.54, R4 was 29.56+/-4.77 and R5 was 95.63+/-7.36 g/head. Biscuit bio-supplement of Carica papaya L. leaf and Indigofera sp., (R5) had the best value of palatability for dairy goat and had the best crude protein (36.65%), also had lowest water activity, highest density than the other biscuits. PMID- 26031009 TI - Single measurement of salivary estriol as a predictor of preterm birth. AB - One of the major problems in obstetrics and pediatrics is preterm birth. A new method of prediction of preterm birth is by salivary estriol. This study aimed to determine the predictive value of single measurement of salivary estriol and its relationship with preterm birth. In this study, the salivary specimens of 466 pregnant women of 25-34 weeks gestational age were collected and kept in a freezer until delivery. Consequently, the salivary specimens were thawed and estriol levels were measured. The cut-off point for estriol was determined by a receiver operating characteristics curve. Salivary estriol levels equal to or higher than the cut-off point (2.6 ng m(-1)) were considered as the estriol (+) group and those lower than 2.6 ng mL(-1) were considered as the estriol (-) group. Our findings showed that 36 (18.3%) subjects in the estriol (+) group and 22 (8.2%) subjects in the estriol (-) group had preterm deliveries. There was a significant relationship between salivary estriol levels and preterm birth (chi2 = 10.636, p = 0.001). Sensitivity, specificity and predictive values (positive and negative) of estriol were 62, 60, 18.3 and 82%, respectively. Single measurement of salivary estriol at 25-34 weeks of gestation, with its high negative predictive values, could be beneficial to identify women who will not develop preterm labor. This outcome suggests that unnecessary interventions should be avoided to prevent preterm births. PMID- 26031010 TI - Production of cellulase enzyme by Trichoderma reesei Cefl9 and its application in the production of bio-ethanol. AB - The present study aimed at the production of cellulase enzyme from the cellulolytic fungi Trichoderma reesei CEF19 and subsequent application of the cellulase for the fermentation of ethanol. For the same, the cellulolytic fungi, Trichoderma reesei CEF19 was isolated and was allowed to produce cellulase enzyme using optimized conditions. The cellulase enzyme was extracted and purified with the help of ammonium sulphate precipitation, dialysis followed by ion exchange chromatography with DEAE-Sephadex column. The purified cellulase enzyme was characterized using SDS-PAGE analysis. The saccharification of the cellulosic substrates was done using the cellulase enzyme. The fermentation of saccharified cellulosic substrates into ethanol was carried out using Saccharomyces cerevisiae. From the results obtained, rice straw was found to be the better source for the ethanol production when compared to the other substrates. PMID- 26031011 TI - Effect of Ambrex (a herbal formulation) on hematological variables in hyperlipidemic rats. AB - Cardiovascular and related disorders are one of the most common disease prevailing all over the world. Hyperlipidemic condition have been largely considered in the treatment of cardiovascular diseases. The present study was carried out to investigate the effect of Ambrex on hematological factors in hyperlipidemic rats and untreated hyperlipidemic rats. In this study, eighteen rats were randomly divided into three groups of six animals each. The groups received normal diet (Control Group A) high fat diet (HFD group B) and Ambrex treatment (Group C). After the study period, White Blood Cell (WBC), Red Blood Cell (RBC), hematocrit (HCT), Hemoglobin, platelet (PLT), lymphocytes, monocytes, granulocytes, Mean Corpuscular Hemoglobin Concentration (MCHC), plateletcrit (PCT), Mean Corpuscular Volume (MCV), Platelet Distribution Width (PDW), red cell distribution-standard deviation (RDW-SD), red cell distribution-correlation variance (RDW-CV), micro red blood cell (pRBC), macroRBC were measured using digital cell counter (MS9-3s). Hyperlipidemia increases markedly the PLT count. Administration of Ambrex appeared to significantly increase WBC, Lymphocytes, granulocytes. However, erythrocyte indices does not show statistically significant variations among the test groups and control groups. The findings demonstrated that Ambrex does not cause any significant undesirable alterations in hematological factors in male rats. Ambrex also enhances white blood cell concentration and lymphocytes which probably stimulate the immune defense mechanism. PMID- 26031012 TI - Proximate and elemental analyses of Tinospora cordifolia stem. AB - Tinospora cordifolia also known as Giloy or Guduchi, is an indigenous climber plant indigenous to tropical areas of India, Myanmar and Sri Lanka. Its stem is used for treatment of fever, jaundice, emaciation, skin ailments, diabetes, anaemia and various infectious diseases. The study was undertaken to evaluate the proximate and elemental analysis of the stems of Tinospora cordifolia. The proximate analyses were carried out using standard methods, while mineral elements were analyzed using Atomic Absorption Spectrophotometer, equipped with air acetylene flame. The proximate analysis of the stems of Tinospora cordifolia showed that it contained moisture 34.39%, ether extract 0.912%, crude protein 7.74%, crude fibre 56.42%, total ash 7.96%, nitrogen free extract 26.97%, cellulose 23.02% and hemicellulose 3.70%. The mineral analysis of the stems showed that they contain the following essential minerals: Calcium (102.23 ppm), phosphorous (24.81 ppm), iron (26.058 ppm), copper (3.733 ppm), zinc (7.342 ppm) and manganese (12.242 ppm). The study revealed that Tinospora cordifolia stems to be a potential source of nutrition and minerals for man as well as animals. PMID- 26031013 TI - Antimicrobial and cytotoxic activities from Jatropha dioica roots. AB - The antimicrobial and cytotoxic activities of organic extracts obtained from roots of the medicinal plant Jatropha dioica (Euphorbiaceae) were investigated. In order to evaluate their antimicrobial activity, the organic extracts were tested against clinical isolates of the human pathogens Bacillus cereus, Escherichia coli, Salmonella typhi, Staphylococcus aureus, Enterobacter aerogenes, Enterobacter cloacae, Salmonella typhimurium, Cryptococcus neoformans, Candida albicans, Candida parapsilosis and Sporothrix schenckii. Results revealed that the hexane extract possess the stronger activity and a broader microbicide spectrum compared to the acetone and ethanol extracts. The activity of hexane extract may be attributed in part to the presence of beta-sitosterol, the major compound identified by bioautography. The hexane extract, as well as the bioactive fraction were not cytotoxic when assays were profiled against the normal cell lines Chang, OK and LLCPK-1 (IC50>1000 MUg mL(-1)). PMID- 26031014 TI - Termite digestomes as a potential source of symbiotic microbiota for lignocelluloses degradation: a review. AB - Termites thrive in great abundance in terrestrial ecosystems and the symbiotic gut microbiota play important roles in digestion of lignocelluloses and nitrogen metabolism. Termites are excellent models of biocatalysts as they inhabit dense microbes in their guts that produce digestive enzymes to decompose lignocelluloses and convert it to end products such as sugars, hydrogen, and acetate. Different of digestive system between lower and higher termites which lower termites dependent on their dual decomposing system, consisting of termite's own cellulases and gut's protists. Higher termites decompose cellulose using their own enzymes, because of the absence of symbiotic protists. Termite gut prokaryotes efficiently support lignocelluloses degradation. In this review, a brief overview of recent experimental works, development and commercialization is discussed. Significant progress has been made to isolate cellulolytic strains from termites and optimise the digestion efficiency of cellulose. Future perspective should emphasize the isolation of cellulolytic strains from termites, genetically modifying or immobilization of the microbes which produce the desired enzyme and thus benefits on the microbiology and biotechnology. PMID- 26031015 TI - Ameliorating role of rutin on oxidative stress induced by iron overload in hepatic tissue of rats. AB - Iron is an essential element that participates in several metabolic activities of cells; however, excess iron is a major cause of iron-induced oxidative stress and several human diseases. Natural flavonoids, as rutin, are well-known antioxidants and could be efficient protective agents. Therefore, the present study was undertaken to evaluate the protective influence of rutin supplementation to improve rat antioxidant systems against IOL-induced hepatic oxidative stress. Sixty male albino rats were randomly divided to three equal groups. The first group, the control, the second group, iron overload group, the third group was used as iron overload+rutin group. Rats received six doses of ferric hydroxide polymaltose (100 mg kg(-1) b.wt.) as one dose every two days, by intraperitoneal injections (IP) and administrated rutin (50 mg kg(-1) b.wt.) as one daily oral dose until the sacrificed day. Blood samples for serum separation and liver tissue specimens were collected three times, after three, four and five weeks from the onset of the experiment. Serum iron profiles total iron, Total Iron Binding Capacity (TIBC), Unsaturated Iron Binding Capacity (UIBC), transferrin (Tf) and Transferrin Saturation% (TS%)}, ferritin, albumin, total Protein, total cholesterol, triacylglycerols levels and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were determined. Moreover, total iron in the liver, L-malondialdehyde (L-MDA), glutathione (GSH), Nitric Oxide (NO) and Total Nucleic Acid (TNA) levels and glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) activities were also determined. The obtained results revealed that, iron overload (IOL) resulted in significant increase in serum iron, TIBC, Tf, TS% and ferritin levels and AST and ALT activities and also increased liver iron, L-MDA and NO levels. Meanwhile, it decreased serum UIBC, total cholesterol, triacylglycerols, albumin, total protein and liver GSH, TNA levels and Gpx, CAT and SOD activities when compared with the control group. Rutin administration to iron-overloaded rats resulted in significant decrease in serum total iron, TIBC, Tf, TS%, ferritin levels and AST and ALT activities and liver total iron, L-MDA and NO levels with significant increases in serum UIBC, albumin, total protein and total cholesterol levels and in liver GSH, CAT and SOD activities compared with the IOL group. This study provides in vivo evidence that rutin administration can improve the antioxidant defense systems against IOL induced hepatic oxidative stress in rats. This protective effect in liver of iron loaded rats may be due to both antioxidant and metal chelation activities. PMID- 26031016 TI - Gallic acid improves cognitive, hippocampal long-term potentiation deficits and brain damage induced by chronic cerebral hypoperfusion in rats. AB - Abstract: Cerebral Hypoperfusion Ischemia (CHI) has important role in neuronal damage and behavioral deficits, including memory and Long-term Potentiation (LTP) impairment. Protective effects of Gallic Acid (GA) on memory, hippocampus LTP and cell viability were examined in permanent bilateral common carotid artery occlusion in rats. Animals were divided into 9 groups: Control (Cont); sham operated (Sho); Cerebral Hypoperfusion Ischemia (CHI); CHI received normal saline (CHI +Veh); CHI treated with different doses gallic acid (50, 100, 200 mg kg(-1) for 5 days before and 5 days after CHI induction, orally); CHI treated with phenytoin (50 mg kg(-1), ip) (CHI+Phe); and sham operated received 100 mg kg(-1), orally (Sho+GA100). CHI was induced by bilateral common carotid artery occlusion (2VO). Behavioral, electrophysiological and histological evaluations were performed. Data were analyzed by one-way and repeated measures ANOVA followed by tukey's post-hoc test. GA improved passive avoidance memory, hippocampal LTP and cell. viability in hippocampus and cortex of ischemic rats significantly (p < 0.01). The results suggest that gallic acid via its antioxidative and free radicals scavenging properties attenuates CHI induced behavioral and electrophysiological deficits and has significant protective effect on brain cell viability. Dose of 100 mg kg(-1) GA has affected the ischemic but not intact rats and its effect was more potent significantly than phenytoin, a routine drug for ischemic subjects. PMID- 26031017 TI - Motor and cognitive deficits due to permanent cerebral hypoperfusion/ischemia improve by pomegranate seed extract in rats. AB - This study aimed to evaluate the effect of two weeks oral administration of Pomegranate Seed Extract (PGSE) on active avoidance memory and motor coordination activities after permanent bilateral common carotid arteries occlusion (2CCAO) in male adult rats. Adult male albino rats of Wistar strain (250 +/- 20 g, 3-4 months) were used. Animals were divided into eight groups with 10 in each: (1) Sham operated (Sh); (2) Ischemic (I); (3) Ischemic received 100 mg kg(-1) PGSE, orally (I+E100); (4) Ischemic received 200 mg kg(-1) PGSE, orally (I+E200); (5) Ischemic received 400 mg kg(-1) PGSE, orally (I+E400); (6) Ischemic received 800 mg kg(-1) PGSE, orally (I+ E800); (7) Ischemic received 2 mL kg(-1) normal saline, orally (I+Veh); (8) Sham operated received 400 mg kg(-1) PGSE, orally (Sh+E400). In order to make 2CCAO an animal Cerebral Hypoperfusion Ischemia (CHI) model, carotid arteries were ligatured and then bilaterally cut. To evaluate active avoidance task, Correct Response Percentages (CRP) was measured by Y-maze apparatus and motor coordination activity was evaluated using standard behavioral tests by rotarod apparatus in all the rats. It was found that memory. Memory and motor coordination activities were significantly impaired in the rats after CHI (p < 0.01). PGSE treatment significantly improved impairment of memory and motor coordination in the rats with 2CCAO (p < 0.001). PGSE exhibited therapeutic potential for memory and muscular coordination, which was most likely related at least in some part to its antioxidative and free radical scavenging actions. PMID- 26031018 TI - Isolation of hyperoside and isoquercitrin from Camellia sasanqua as antioxidant agents. AB - Two antioxidant active compounds were isolated from the methanol extract of Camellia sasanqua using various in vitro assays: 1,1-diphenyl-2-picrylhydrazyl (DPPH), beta-carotene bleaching and reducing power assays. The ethyl acetate (EtOAc) fraction of the methanol extract had the highest DPPH radical-scavenging activity with an Inhibition Concentration (IC50) value of 18.3 +/- 1.63 MUg mL( 1). Sephadex LH-20 column chromatography was used to separate the EtOAc fraction into eight fractions (F1-F8). Antioxidant activity was significantly higher in fraction 5 with an IC50 value 14.61 +/- 0.02 MUg mL(-1). Fraction 5 was further separated by HPLC preparative with Capcellpak C18 MG followed by the Cosmosil 5C18-AR-II column, using a guided DPPH radical-scavenging assay. The compounds isolated were identified as: Hyperoside (1) and isoquercitrin (2) after recrystallization from ethanol, based on Mass Spectrum (MS) and Nuclear Magnetic Resonance (NMR) analyses. Their DPPH radical-scavenging activities based on the 50% scavenging concentration decreased in the following order: Isoquercitrin (21.6 mM) > hyperoside (27.5 mM). The antioxidant activities of hyperoside and isoquercitrin were 67.52 +/- 0.64 and 64.33 +/- 0.51%, respectively, in the beta carotene bleaching assay. These compounds were found to have good reducing powers (OD value: 2.5-3.8) at concentrations of 50-140 MUg mL(-1), using the potassium ferricyanide reduction method. Although, these compounds are well-known, hyperoside (1) was isolated from this herb for the first time. PMID- 26031019 TI - Seaweed composition from Bintulu coast of Sarawak, Malaysia. AB - Species composition of seaweed and distribution were investigated in the coastal waters of Bintulu, Sarawak. The seaweed samples were collected during low tide between May 2011 and May 2012 from the six different stations. In total 54 species of seaweeds were identified from study areas of Bintulu coastal waters. Among them, 23 species were from Rhodophyta with 11 families, 15 species were from Phaeophyta with 2 families and 16 species were from Chlorophyta with 10 families: Seventeen species of seaweeds were recorded from the Tanjung Batu, while 23 species from Pantai Telekom, 14 species from Golden Beach, 26 species from Kuala Similajau, 12 species from Kuala Nyalau and 21 species from Batu Mandi. Seaweeds abundance was high in rocky substrate and Rhodophyta (11 families and 23 species) was the common and highest group of seaweeds in this coastal areas. Present study recorded high diversified seaweed species at the rocky shore area compare to reef area. PMID- 26031020 TI - Low cost medium for spore production of Bacillus KKU02 and KKU03 and the effects of the produced spores on growth of giant freshwater prawn (Macrobrachium rosenbergii de Man). AB - In order to extend the shelf life of 2 high potential Bacillus probiotic isolates which were Bacillus KKU02 and Bacillus KKU03, the spore forms of these 2 Bacillus isolates were studied for using as probiotic instead. The low cost medium for spore production of these 2 Bacillus isolates was examined in order to produce probiotic spores for feeding the shrimps. It was found that cassava at 100 g L( 1) and supplemented with 20.0 g L(-1) dextrose, 0.1 g L(-1) MgSO4 and 2.0 g L(-1) (NH4)2SO4 showed the highest spore concentration at about 1 x 10(8) CFU mL(-1). The effects of feeding these 2 Bacillus spores on the growth of giant freshwater prawns were further examined. The spores of Bacillus KKU02 and Bacillus KKU03 ( 10(7) spore mL(-1)) in pure and mixed culture forms were mixed with commercial prawn feed (200 mL kg(-1)) to give six feed treatments. Body length and weight of the prawns in mixed spore culture tanks after rearing for 90 days (13.5 cm and 59.8 g, respectively) were significantly higher (p = 0.05) than other treatments. The treated prawns were further challenged with Aeromonas hydrophila for 7 days. The percentages of survival after the challenge in the prawns fed with the mixed spores (46.8%) were also found significantly higher (p = 0.05) than others groups, except the mixed live cell treatment (60%). These results indicated that the spores of Bacillus KKU02 and Bacillus KKU03 had a high potential for using as commercial probiotics. PMID- 26031021 TI - The kinetics of methane production from co-digestion of cattle manure. AB - In this article, the kinetics of methane production from co-digestion of liquid manure from cattle with the addition of winemaking waste, food waste and biowaste was investigated in order to describe and evaluate methanogenesis in terms of growth curve of methanogenic bacteria. Experiments were carried out in "Hohenheim"n biogas yield testing system at the temperature of 37 degrees C. The cumulative methane yield was 0.330 +/- 0.038, 0.277 +/- 0.041, 0.1480 +/- 013 and 0.250 +/- 0.025 m3 CH4 per kg oDM in normal condition, respectively in mono digestion and co-digestion of liquid manure from cattle with winemaking, food and biowaste. The kinetic Gompertz parameters of methane production (P-potential yield of methane, R(m)-maximum methane production rate and lambda-duration of lag phase) were analyzed. The highest potential methane yield (P) showed co fermentation of liquid manure from cattle with biowaste 0.387 Nm3 (kg oDM)(-1), the highest methane production rate (R(m)) was 0.022 +/- 0.003 Nm3 (kg oDM)(-1) day(-1) for mono-digestion of cattle slurry, the lowest 0.006 Nm3 (kg oDM)(-1) day(-1) was obtained during co-digestion with food waste. Duration of lag phase (lambda) was within 10.17-14.60 days for all samples. Additional, the duration of digestion to produce 95% of the potential methane yield and efficient methane production was determined. PMID- 26031022 TI - Effect of diurnal temperature alternations on plant growth and mineral composition in cucumber, melon and watermelon. AB - This study investigated plant growth and mineral composition in three cucurbit crops of cucumber, melon and watermelon grown under four constant day and night temperatures (DIF) of 25/15, 22.5/17.5, 17.5/22.5 and 15/25 degrees C. As expected, the growth and development of the three cucurbits were strongly temperature dependent. Plant height and relative chlorophyll content of the three crops decreased linearly along with decreases in day temperature. Leaf and stem dry weight decreased significantly under negative DIFs and the lowest value was in DIF plot 15/25 degrees C. However, the negative DIF of 15/25 degrees C resulted in increased content of all mineral nutrients (N, P, K, Ca, Mg, Mn and Cu) in both the leaf and stem of the three cucurbit crops. The data suggest that a negative DIF as low as 15/25 degrees C may be beneficial to greenhouse-grown cucurbit crop producers, by controlling vegetative growth that facilitates crop management, with no negative effect on or enhancement of the uptake rates of mineral nutrients which are required to determine yield and fruit quality at the production stage. Effective utilization of diurnal temperature alternations is one strategy that can be used to reduce energy consumption in greenhouses. PMID- 26031023 TI - Mycobiota variation in stored rice straw and its cellulolytic profile. AB - Rice Straw (RS) one of most important agrowaste worldwide. Variation in mycobiota inhabiting long stored RS and its cellulolytic profile were studied. The highest number of fungi (23 species) was recovered from 1st storage period (1-3 year). Alternaria alternata, Aspergillus sp., Cladosporium herbarum, Fusarium incarnatum, Geotrichum candidum, Penicillium sp., Stemphylium lycopersici and Ulocladium atrum are the most frequent genera. Among 21 fungal species recovered in the 2nd period (3-5 year), Cladosporium herbarum, Fusarium incarnatum, Stemphylium lycopersici and Ulocladium atrum recorded 100% frequency, whereas Ulocladium atrum, Veticillium lecanii, Stemphylium lycopersici and Penicillium sp., were the most frequent species in the 3rd period (> 5 years). Regarding the pathogenic fungal isolates, Nigrospora oryzae was the most frequent with high intensity in all samples of the three storage periods, whereas Alternaria padwikii reached the highest frequency and intensity in the 1st period and absent the 2nd and 3rd ones. The isolated fungal species showed a high production of cellulases comparing to previous studies with positive and significant correlation between FPase from one side and CMCase (r = 0.634, p <= 0.05) and beta-glucosidase (r = 0.775, p <= 0.05) from the other side. PMID- 26031024 TI - Phytochemical characteristic and uterotonic effect of aqueous extract of Ficus deltoidea leaves in rats uterus. AB - Ficus deltoidea is traditionally consumed by Malay woman to augment labour and hastening parturition. This study was to investigate the phytochemical present and uterotonic activity of F. deltoidea var. Deltoidea (FDD) and F. deltoidea var. Angustifolia (FDA) leaves aqueous extract. FDD and FDA were qualitatively analysed. In uterine contraction activity, adult female Sprague Dawley rats were pretreated with 0.2 mg kg(-1) diethylstilbestrol 24 h to induce oestrus phase. The rats then killed and uterine horns were taken out, cut into two centimetres length and put into organ bath that connected to Powerlab instrument. The uterus separately tested with cumulative concentrations of FDD (10-1280 MUg mL(-1)), FDA (10-1280 MUg mL(-1)), oxytocin (0.02-0.64 MUg mL(-1)) and combination of oxytocin (0.08 MUg mL(-1)) with FDD and FDA (10-1280 MUg mL(-1)). FDD showed presence of flavonoid, saponin and tannin meanwhile FDA consist of flavonoid, tannin and terpenoid. Result showed FDD, FDA and oxytocin induced a dose-related increase in force of contraction of isolated rat uterus. The maximum uterine contraction (Emax) produced by FDD, FDA and oxytocin were at the concentration 640 MUg mL(-1) (EC50, 5.903 +/- 0.529 MUg mL), 20 MUg mL(-1) (EC50, 290.5 +/- 0.158 MUg mL(-1)) and 0.4 MUg mL(-1) (EC50, 0.060 +/- 0.011 MUg mL(-1)) respectively. Combination effects of oxytocin with FDD and FDA produced Emax at the concentration 80 MUg mL(-1) (EC50, 270.3 +/- 0.643 MUg mL(-1)) and 1280 MUg mL(-1) (EC50, 26.83 +/- 0.727 MUg mL(-1)), respectively. Study indicated F. deltoidea possess contractile effect on uterine contraction. This plant has great potential to develop as natural uterotonic agent in inducing labour and treatment for post-partum haemorrhage. PMID- 26031025 TI - Effect of altitude on some blood factors and its stability after leaving the altitude. AB - The underlying mechanisms of altitude training are still a matter of controversial discussion. The aim of this study was to compare the hemoglobin concentration, red blood cell count and volume between normal and high altitude situations and their persistence after returning back from higher altitudes. The study population included male students of Ardal Branch, Islamic Azad University. Twelve apparently healthy individual with high level of physical activity, mean age of 22.6 +/- 1.50 years were selected through purposive and available sampling method. In this study, blood samples were collected at different time and altitudes in order to compare the changes of Red Blood Cell (RBC), Mean Cell Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC) and Mean Cell Volume (MCV). The first blood sampling was conducted at the altitude of 1830 m. The subsequent blood samplings were conducted 48 and 72 h after reaching the altitude of 4000 m and 24, 48 and 72 h after returning back to the altitude of 1830 m. The statistical method used in this study was repeated measurement ANOVA. Red Blood Cell (RBC) changes between onset of climbing to 1830 m and 24, 48 and 2 h after sojourn at 1830 m height (after returning from 4000 m altitude) was significant. Mean Cell Hemoglobin (MCH) showed no significant change in any of the altitudes. MCHC changes between onset of moving toward altitude 1830 meters and 24, 48 and 72 h after sojourn at 1830 m height (after returning from 4000 m altitude) was also significant in addition, MCHC showed a significant difference between 24 h staying at 1830 m altitude with 48 and 72 h staying at 4000 m altitude. Mean Cell Volume (MCV) showed no significant difference between 48 and 72 h staying at 4000 m altitude and also between 24, 48 and 72 h staying at 1830 m altitude; however, there was a significant difference between onset of moving toward 1830 m altitude with 24, 48 and 72 h staying at 1830 m altitude and also 48 and 72 h staying at 4000 m altitude. The results showed that being in altitude has significant effect on RBC and MCHC. PMID- 26031026 TI - Prevalence of the genital tract bacterial infections after vaginal reconstructive surgery. AB - Due to frequent childbirth, heavy lifting and the structure of the lives of rural women in Shahrekord region, Iran, cystocele and rectocele are of the main medical problems of the women in this area and for its correction, vaginal reconstructive surgery is needed which causes infection. The purpose of this study was to identify the bacteria causing infection after vaginal reconstructive surgery and performing antibiogram to help these patients for faster recovery. Patients enrolled this study were 92 who had undergone previous vaginal reconstructive surgery and now had infection. After examination, the group of patients taking antibiotics (n = 26) were excluded and the remaining 66 completed the study questionnaire. A gynecologist performed sampling; related tests (aerobic and anaerobic culture using an anaerobic culture gas pack jar and type A which provides absolute anaerobic conditions) were performed; antimicrobial susceptibility testing using Disk Diffusion Method was carried out; and the results were recorded. All the positive samples were polymicrobial. Gardnerella vaginalis in 20 cases (31%), peptostreptococci and anaerobic cocci in 9 cases (13.6%), staphylococcus aureus in 8 cases (9.1%), bacteroides and fusobacterium in 7 cases (10.6%), streptococcus group B in 4 cases (6%), yeast cells in 11 cases (16.6%) and Trichomonas vaginalis in wet mount of 4 (6%) existed. Anaerobic bacteria showed 85% sensitivity to clindamycin, 82% to chloramphenicol, 85% sensitivity to ceftizoxime and 45% to penicillin. Facultative anaerobic bacteria showed a sensitivity rate of 90% to ceftizoxime, chloramphenicol and cephalothin. According to our findings, the rate of vaginal bacterial infection in women with vaginal reconstructive surgery has increased; from which, infections with anaerobic bacteria origins have increased dramatically. We recommend antibiotic prophylaxis prior to genital reconstructive surgeries. PMID- 26031027 TI - Effect of steaming process on new formulation and physical properties of earthworm-based fish pellets for African catfish (Clarias gariepinus). AB - Fish feed has been recognized as one of main part/unit in aquaculture industry. However, current fish feed faces few challenges in terms of health aspects and cost issues. Alternatively, new nutritional and economical/low cost formulation of fish pellets was designed by combination of earthworm powder and other economical ingredients such as fishmeal, soybean waste, rice bran and tapioca flour. The formulation was calculated using Pearson's square and optimized by One Factor-At-Time (OFAT) method. The effect of steaming processing on the water stability, soaking experiment, protein leaching test and breaking force of the earthworm-based fish pellets was investigated. Results indicate steam pellet at 80 degrees C for 40 min has higher water stability, less protein leaching and more durable than unsteam pellets. Introduction of this new formulation of fish meal is expected to provide essential nutrient, energy and improved the quality of pellets to fuel the growth of aquaculture industry. PMID- 26031028 TI - Sperm Viability Assessment over elapsing time maintained at 2 degrees C of orange mud crab, Scylla olivacea (Herbst, 1796). AB - The aim of this study was to evaluate how long the fresh sperm maintained at 2 degrees C would be utilized for fishery management. The study was conducted every 2 h to assess the sperm viability of orange mud crab Scylla olivacea. Evaluations were conducted as 3 treatments; T1, T2 and T3. In T1, the live specimens were sacrificed; for T2, only spermatophores were extracted and for T3 spermatophore extraction followed by homogenization to create a sperm suspension. All samples were stored with ice in an insulated box was keep fresh longer at 2 degrees C. The time '0' referred the immediate collection of sperm after the specimen was sacrificed. Spermatophore viability was determined using the sperm suspension by eosin-nigrosin staining method. Sperm viability for the fresh sample at time zero was 97.36 +/- 0.53%. Viability of the sperm significantly decreased in the 2nd h in all treatments, T1 was 44.66 +/- 0.54 to 4.2 +/- 0.22% at 16 and 18th h, T2 was 36.56 +/- 0.5 to 2.69 +/- 0.06% at the 12 and 14th h and T3 was 33.69 +/- 1.26 to 6.4 +/- 0.29% at 8 and 10th h. In comparison, T1 showed significantly higher than other treatments (p < 0.05). Extremely low viability percentages were recorded in T3. This study also proved that the time elapse had significant impact on the percentage of viable sperm count. PMID- 26031029 TI - Seroprevalence of latent Toxoplasma gondii infection among HIV-infected pregnant women in Bobo-Dioulasso, Burkina Faso. AB - The deficit of cellular immunity, as found in HIV infected individuals, may lead to the reactivation of latent Toxoplasma gondii cysts, with as consequence, the occurrence of toxoplasmosis and an eventual vertical transmission of the disease during pregnancy. The present study was designed for determining the occurrence of latent Toxoplasma gondii among HIV-infected pregnant women during the first trimester in Bobo-Dioulasso. Thus, 348 pregnant women aged from 17 to 47 years (average age of 6.64 +/- 4.75 yaers) were enrolled. The specific anti-Toxoplasma gondii IgG and IgM antibodies were quantified from whole blood specimens using the high-sensitivity direct agglutination and the enzyme linked fluorescent assays, respectively, the IgG avidity test being used for the dating of the primary infection. The results revealed that the seroprevalence of Toxoplasma gondii latent infection was 34.7%. It was significantly higher in HIV-infected women compared with uninfected ones (68,7%; CI 95%: 43,6%-88,9%) versus (33,1%; CI 95%: 28, 2%-38,3%). In addition, all the occurrences of the high IgG avidity were closely linked with the presence of IgM. These results underlined the need for the clinical follow-up of the maternal HIV diseases including the toxoplasmosis during the pregnancy since; the newborns are still exposed to vertical transmission of Toxoplasma infection in endemic areas like Burkina Faso. PMID- 26031030 TI - Antioxidant potential properties of mushroom extract (Agaricus bisporus) against aluminum-induced neurotoxicity in rat brain. AB - Aluminum (Al) is an environmental toxin that induces oxidative stress in neuronal cells. Mushroom cultivar extract (MCE) acted as a potent antioxidant agent and protects against cellular oxidative stress in human cultured neuronal cells. This study aimed to investigate the neuroprotective effect of MCE against Al-induced neurotoxicity in rat brain. Forty Sprague-Dawley rats were divided into 4 groups (10 rats per group), control group, MCE-fed group, Al-administered group and MCE/Al-treated group. Animals were continuously fed ad-libitum their specific diets for 4 weeks. At the end of the experiment, all rats were sacrificed and the brain tissues were homogenized and examined for biochemical measurements of neurocellular oxidative stress indices [glutathione (GSH), Total Antioxidant Capacity (TAC), antioxidant enzymes and oxidized dichlorofluorescein (DCF)]. Al administration caused inhibition of antioxidant enzymes and a significant decrease in GSH and TAC levels, meanwhile it positively increased cellular oxidized DCF level, as well as Al concentration in brain tissues. Feeding animals with MCE had completely offset the Al-induced oxidative stress and significantly restrict the Al accumulation in brain tissues of Al-administered rats. The results obtained suggest that MCE acted as a potent dietary antioxidant and protects against Al-mediated neurotoxicity, by abrogating neuronal oxidative stress. PMID- 26031031 TI - Chemical and phytochemical compositions of Voandzeia subterranea seeds. AB - The seeds of Voandzeia subterranean (L.) Thouars (Fabaceae), from Congo Brazzaville were studied for proximate, qualitative and quantitative compositions. Phytochemical screening of various solvent extracts showed the presence of alkaloids, flavonoids, glycosides, saponins, steroids, triterpenoids, phenols, anthocyanins and carotenoids. Tannins and anthraquinones were not found. Quantitative analysis showed a high amount of alkaloids (34.40 +/-0.2%), flavonoids (4.93 +/- 0.17%), saponins (2.20 +/- 0.11%) and anthocyanins (1.00 +/- 0.12%) in decreasing order. Phenols (0.60 +/- 0.12%) and carotenoids had low yields (0.26 +/- 0.07%). Proximate analysis of the seeds showed high moisture, carbohydrate and energy content values (49.14, 20.53% and 956.14 kJ 100 g(-1), respectively). The results showed low ash content (3.84%) and the relatively high fat (7.84%) and protein content (18.65%). The mineral analysis revealed that potassium (3.15%) and phosphorus (1.74%) were the most abundant minerals. Calcium (0.35) and magnesium (0.39%), were found in low amounts. Sodium, iron and aluminum were detected in trace quantities (0.01%). Manganese was not detected in the present study. The seeds were found to be important both for their nutrients and non-nutrients which determined the medicinal and nutritional value of the plant. PMID- 26031032 TI - [The organization of the preventive work in educational institutions: problems and solutions]. AB - Prevention measures are relevant for children and adolescents as among them there is the high prevalence of leading risk factors for chronic diseases. For the improvement of the preventive work it is necessary the introduction of amendments into the legislative documents and orders of the Ministry of Health, governing health care for children and adolescents in educational organizations. The consistent methodology for primary health care must be provided with the appropriate protocols. It is necessary to perform the systematic work on the reduction of the prevalence of risk factors for children's health and a healthy lifestyle. The number of doctors and nurses in the preschool and educational institutions is insufficient, and in organizations of primary and secondary vocational education is disastrous. Medical personnel departments of medical assistance to students due to the excessive load is not capable to fufill all of their functional responsibilities. Due to the low wages there is a constant reduction of health workers in schools and kindergartens. In the paper there are proposed measures aimed at improving the quality of preventive work in educational organizations. PMID- 26031033 TI - [Urbanization--a factor that increases the risk for health]. AB - The negative impact of urbanization on public health is obvious. However; due to the comprehensiveness and polymorphicity of its manifestations there are not established criteria for them. Health risk methodology allows, in principle, to obtain quantitative indices of the separate results of the impact on the health status of the citizens of metropolis that can be extremely effective in this area. The total cross-media riskfrom traffic pollution, drinking water quality, open ponds, noise, etc. permits to use of hygiene criteria in urban planning, insurance, taxation, etc. PMID- 26031034 TI - [Prevalence and routes of transmission of pyloric Helicobacter infection. II. Transmission infection from an external source (literature review)]. AB - AIM OF THE STUDY: On the available reports to assess the possibility of the infection with pyloric Helicobacter (H.pylori) from external sources--via contaminated food and water. BASIC CONCEPTS: H. pylori was established to be unable to multiply in dairy and other products, but under favorable conditions, can survive in the limited time. There are obtained epidemiological data about the feedback between the prevalence of H. pylori infection in the region and the availability of safe water. There was recorded ability of bacteria to survive for a short time in water in bacillary virulent form. In different water sources in different countries there was found H. pylori coccal form. CONCLUSION: H. pylori ability to survive in the commonly used product supports the hypothesis that contaminated food (tank-human) may serve as a conductor of infection. The literature data testify to the possibility and importance of the waterway for H. pylori infection transmission that changes the approaches to prophylaxis and the prevention of associated with it diseases. PMID- 26031036 TI - [Substantiation of a complex of radiation-hygienic approaches to the management of very low-level waste]. AB - In the article there are presented materials on radiation-hygienic approaches to the treatment of very low level radioactive waste (VLLW) and industrial waste containing radionuclides. There is done detailed information on radiation hygienic principles and criteria for the assurance ofradiation safety in the collection, transportation, storage and processing of VLLW as a category of radioactive waste.. Particular attention is paid to the problem of designing VLLW landfill site choice, system of radiation monitoring in operation and decommissioning of the landfill. There are presented data about the criteria for the release of VLLW buried at the site, from regulatory control. Also there are considered in detail the radiation-hygienic requirements for radiation safety of industrial waste containing radionuclides for which there is assumed unlimited and limited use of solid materials in economic activity, based on the requirements ofthe revised Basic Sanitary Rules for Radiation Safety - 99/2010. There are considered basic requirements for the organization of industrial waste landfill. As an example, there-are presented the hygiene requirements for industrial waste management and results of waste categorization in Northern Federal Enterprise for Radioactive Waste Management. PMID- 26031035 TI - [Disparity on the grade of exposure to ecological risks in the European region of WHO]. AB - Disparity in relation of ecological conditions and health concerns to the general differences in environmental conditions and in large extent is stipulated by socio-economic and demographic differences in the impact of its hazards. In addition to differences in the impact the inequality in relation of ecological conditions and health can also be caused by social or demographic differences in exposure to certain risks. This article offers an assessment of the evidence and data on differences in the impact of the environment in the European Region of the World Health Organization (WHO) received during the recent work of the European Regional Office of WHO. The obtained results testify that socio demographic disparity in the impact of the environment exists in all countries. Such inequality can be seen in respect of a variety offactors, such as age, gender income level, or on the contrary, poverty, education and employment, household type, location of the home. PMID- 26031037 TI - [Pollution hazard for water bodies at oil production]. AB - In the paper there have been summarizes the concepts of the danger of the pollution ofwater bodies in oil production (the most dangerous are reagents used in the drilling, drilling waste, oil and petrochemicals, oil biodestructors. There was shown the danger of the spread of oil pollution. New indices, presenting a hazard during drilling and oil production have been substantiated The tasks aimed to the improvement of the standards and methods of the control of the water pollution by oil, as well as of the documents regulating the conditions of environmental protection during the drilling have been conceived. PMID- 26031039 TI - [Hazard assessment of the impact of high temperature and air pollution on public health in Moscow]. AB - In the article there are considered the main problems of assessing public health risks of the combined effects of high temperatures and air pollution with the account taken of the consequences of abnormally hot weather observed in summer 2010 in Moscow and without equals in the history of meteorological measurements in the city. The daily average concentrations of fine suspended particles matter (PM10) in the city during peatland fires from 4 to 9 August are emphasized to be within the range of 431-906 MU/m3, being 7.2-15.1 times the Russian maximum permissible concentration (MPCs) (60 MU/m3). The anomalous heat and high levels of air pollution in this period were shown to cause a significant increase in excess mortality among the population of Moscow. There was established the relative gain in mortality from all natural causes per 10 MUg/m3 increase in daily average concentrations of PM10 and ozone, which was respectively: 0.47% (95%; CI: 0.31-0.63) and 0.41% (95%; CI: 0.31-1.13). On the base of the statistical analysis of daily mortality rates, meteorological indices, the concentrations of PM10 and ozone there was developed marking scale for the risk assessment of these indices accordingly to 4 gradings--low (permissible), warning, alert, and a hazard level. There has been substantiated the importance of the introduction of the system for the early alert for hazard weather events and the unified rating scale for the hazard of high air temperatures and high levels of air pollution with PM10 and ozone, which allows to take timely measures for the protection of the public health. PMID- 26031040 TI - [Lifetime of hydrobionts Daphnia magna in a noncontact-activated water]. AB - The article is devoted to the study of the influence of non-contact activated water on the lifetime and replicative function of aquatic organisms Daphnia magna, belonging to a highly organized animal organisms. There was established the proportional relationship between the concentration of hydrogen peroxide (in the anion-radical form) and the duration of aquatic lifetime of hydrobionts. In a non contact activated water media with values of redox -potential (Eh)~130mV (against Eh = 213mV--in the control) the lifetime of hydrobionts Daphnia magna is shown to increase in average up to 9 days and reaches 34 days (as 25 days in the control). Replicative junction activated in the aquatic environment does not change, but there was noted a delay in the time of dropping by 7 days in average. Noted regularities in the change in the lifetime of aquatic organisms Daphnia magna in aquatic activated environments are interpreted on the basis of the dependence of the proliferative activity of cells on the concentration of hydrogen peroxide in water. The obtained data on lifetime of Daphnia magna in activated electron-donor environments can serve as proof of the hygienic safety and biological activity of physically-activated (non-contact) drinking water. PMID- 26031038 TI - [The morphofunctional cellular evaluation of liver and kidney in rats in dynamics of 6-month consumption of water produced with the use of noncontact activation after electrochemical treatment]. AB - There were investigated morphofunctional indices of liver and kidney in male outbred rats in the dynamics of the 6-months consumption of water after its noncontact activation. There were studied 4 experimental groups of animals consumed waters named as "Anolyte" and in dependence on the activation time, 3 types of catholyte water ("Catholyte--5", "Catholyte--25", "Catholyte--40"). Moscow tap water settled for a week served as control. "Anolyte" water was found to increase in the kidney the number of hypertrophied gromeruli only in 6 months, while the consumption of "Catholyte--25" water and especially, "Catholyte--40" in 1 and 6 months caused the damage of liver and kidney, and for the index of alteration of renal glomeruli after 6 months of water consumption there was revealed the dependence on the activation time of "Catalytes". PMID- 26031041 TI - [Biological denoxation of chemical pathogens in aqueous medium]. AB - There are considered possibilities and perspectives of denoxation (decontamination) of chemical pathogens by means of biological methods for the environment sanitation and protection from contamination. There are presented numerous examples of successful practical application of the modern biotechnologies in industrial sewage denoxation from xenobiotics. PMID- 26031042 TI - [Ecological and hygienic condition urbanized area in the geographical center of New Moscow]. AB - The evaluation of ecological and hygienic condition of the environment was performed by ourselves in the geographical center of New Moscow--in the city of Troitsk. There was made an analysis as the published results of similar assessments in the times of the 1990s, data of Federal Service for Supervision of Consumer Rights Protection and Human Welfare concerning the control for soils quality (at a single point of the city) and drinking water for 2010-2011, and the author's materials on the chemical contamination of soils and grounds in July 2013. Local foci of moderately dangerous pollution of soil were found at lots close to the motorway and in the Worsted factory: Zc (SrBaCrVNiCoCuAgZnPbBeMoWB) = 17-20, benzo (a) pyrene to 218 mcg/kg and Zn up to 233.4 mg/kg. At the point of monitoring soils complied with the requirements according to toxicological, microbiological and parasitological characteristics.. In the drinking tap water there was observed, along with the increased total hardness, the presence up to 1.6 MAC of such natural pollutants as F and Li. In the undergrounds potable water the situation is worsening according to the content of Si, As, B, Br, U. There was no monitoring of surface water and air. However, pockets of soil contamination trace the possible occurrence in the air near the ground of hygienically dangerous anomalies of heavy metals and hydrocarbons. Modern ecological and sanitary situation in Troitsk, in general, can be considered to be quite safe if compared to the quality of the environment in industrialized cities. The thing that does cause concern is the quality of drinking water. PMID- 26031043 TI - [Effect of auto-road complex in the city of Surgut on air pollution and population health]. AB - Currently, due to the increase in motorization, the problem of environmental pollution by emissions of objects of auto-road complex is becoming more and more important not only for cities, butfor dynamically developing regional cities. The negative impact is characterized by the increase of the morbidity rate of environmentally-dependent diseases, primarily respiratory diseases, neoplasms. This exposure is most pronounced near the motorways, at the gas station, and also spreads to residential areas, which requires the optimization of protective and preventive measures. Presented article is devoted to the characterization of air pollution of various areas in the city of Surgut due to emission of sources of auto-road complex with the assessment of public health risks. PMID- 26031044 TI - [Hygienic characteristics of the population's morbidity rate associated with iodine deficiency in the Republic of Mordovia]. AB - In the article there are presented the results of research on naturally conditioned insufficiency of trace elements, particularly iodine, in the Republic of Mordovia. Iodine deficiency disorders are referred to the most common non infectious human pathology. According to WHO data, about two billion people on Earth live in conditions of in iodine deficiency. In the Russian Federation there are no areas in which the population would not be at risk for the development of iodine deficiency disorders. To these regions and the Republic of Mordovia is referred. The prevalence of diseases caused by iodine deficiency among the urban population accounted for 100-150, among rural--130-350. In some regions of endemic goiter rate reaches 800. Analysis of the morbidity rate of the population in the Republic of Mordovia, associated with the iodine deficiency, shows that in the structure of diseases related to micronutrient deficiency, by 2013 diffuse goiter plays a leading role, beingfollowed by a multi-node (endemic) goiter onward thyroiditis, subclinical hypothyroidism and hyperthyroidism. Thus, the analysis of indices of new cases of diseases associated with the iodine deficiency, allows to make the conclusion that diffuse goiter is the most significant pathology. In the structure of diseases related to the micronutrient deficiency, out of the most frequently detected iodine deficiency disorders, the greatest fraction are diffuse and multinodular goiter. The study was conducted with the support of the project, performed in the framework of the basic part of the State assignment (project 2859) and a RHSF grant. PMID- 26031045 TI - [Ambient air pollution in the city of Irkutsk by emissions from mobile sources (the use of the computational method)]. AB - In the article there are presented the results of calculations of a number of emissions of pollutants from motor vehicles in two districts of the city of Irkutsk. It was revealed that with the change in the structure and intensity of road traffic flows on highways of the city, there is altered the composition and quantity of pollutant emissions, tropic to the respiratory system of the human body. That is of great importance, because in the city of Irkutsk the rate of morbidity and mortality from respiratory diseases is higher than in average in Russia. PMID- 26031046 TI - [Health state of aluminum industry workers in the European North of Russia]. AB - Despite the constant performed improvement of technological processes, working conditions in the aluminum industry compose an increased risk of work-stipulated and occupational diseases. An examination of 1172 workers from aluminum facilities of European North of Russia showed that in the structure of their health state disorders and the pathology of the musculoskeletal system of dystrophic-degenerative character (29.8%) have the particular importance and the most commonly diagnosed disease is deforming osteoarthritis (8.6%). Conditions of the work in the professions "anode worker" and "electrolysis worker" (OR = 1.20; CI: 1.07-1.34), as well as the impact of aluminum production waste and the polluting the environment (OR = 1.62; CI 1.44-1.82) increase the risk of diseases of the musculoskeletal system. In the structure of occupational pathology diseases of the respiratory (39.6%) and musculoskeletal (38.5%) systems are of the most importance. There were made conclusions about the necessity of the optimization of working conditions in the aluminum industry, restoration of the state of the environment and the improvement of the medical methods of the prevention of health disorders in this contingent of workers. PMID- 26031047 TI - [The influence of ergonomic characteristics of the work place on the prevalence of pain syndrome in vocational drivers]. AB - The study of features of the working posture pattern of bus and trucks drivers showed the inconsistency to their optimal criteria. Deviations of goniometric indices of working posture pattern of drivers are noted for most brands of studied cars, that is caused by constructive disadvantages of the driving seat both of well buses and trucks. The study of the health state of drivers have shown the prevalence of dorsalgia in the group of bus and truck drivers reached 40.8 +/- 4.75, and in truckers drivers--15.6 +/- 2.96 cases per 100 employees. The largest share in the structure of the pathology in both groups is occupied by lumbodynia. Significantly more frequent pathology of musculoskeletal system in bus drivers is related with the long-term presence in the fixed uncomfortable position. There is emphasized the importance of design changes of the driver's seat, adapted with taken account of the individual anthropometric parameters, for the prevention of the disorders of the musculoskeletal system. PMID- 26031048 TI - [Character accentuations as a criterion for psychological risks in the professional activity of the builders of main gas pipelines in the conditions of arctic]. AB - The article is devoted to the study of character accentuations as a criterion for psychological risks in the professional activity of builders of main gas pipelines in the conditions of Arctic. OBJECTIVE: to study the severity of character accentuations in rotation-employed builders of main gas pipelines, stipulated by their professional activities, as well as personal resources to overcome these destructions. The study involved 70 rotation-employed builders of trunk pipelines, working in the Tyumen Region (duration of the shift-in--52 days), aged from 23 to 59 (mean age 34,9 +/- 8.1) years, with the experience of work from 0.5 years to 14 years (the average length of 4.42 +/- 3.1). Methods of the study: questionnaires, psychological testing, participant observation. STATISTICAL METHODS: One-Sample t-test of Student, multiple regression analysis, incremental analysis. In the work there were revealed differences of expression of character accentuations in builders of trunk pipelines with experience in work on rotation less and more than five years. There was determined that builders of the main gas pipelines, working on the rotation in Arctic, with more pronounced accentuation ofthe character use mainly psychological defenses of compensation, substitution and denial, and have an average level of expression of flexibility as the regulatory process. PMID- 26031049 TI - [Medical, educational and neurophysiological prerequisites to the formation of the motivation to exercises in students]. AB - A characteristic feature of the life activity of modern children and adolescents is the couch potato, mostly "sedentary" lifestyle. Biomedical and psychosocial significance of motor activity (MA) stipulates the necessity of the substantiation of scientific and methodological approaches to the formation of the motivation to exercises and sports in children. The purpose of the study was in the scientific substantiation and the delivery of medical, pedagogical and neurophysiological prerequisites for the formation of the motivation to increase MA in students in current conditions of their life activity. There were examined 189 students from 2-5th and 9th classes, out of them 65 students were observed in the dynamics of the school year; 585 students from the 1st-11th classes participated in the survey. Results of the study allowed to reveal the relation of students to the lessons of physical training, to evaluate the impact of a new educational program on the functional possibilities of the body of children from the special medical group "A" and to reveal the neurophysiological features of adolescents with different needs in motion. PMID- 26031050 TI - [Main trends in children's population health in the Republic of Tatarstan]. AB - There was performed a comparative analysis of the dynamics of newly diagnosed and the overall morbidity of children's population of the Republic of Tatarstan (RT) and the city of Kazan of main classes of diseases for 2004- 2012 according to the statistical reporting form N12. As an assessment of the possible impact of environmental factors on the formation of separate groups of diseases and changes in the systems of the body there was used health risk assessment according to annual average concentrations of chemicals in the ambient air Average annual indices of prevalence for the most of classes of diseases in children (0-14 years) of the population of the Republic of Tatarstan (RT) and the city of Kazan 2004-2012 (per 1000 children) showed significant differences for most classes of diseases and their rise in children of the city. Results of the assessment of the non-carcinogenic risk based on evolutionary models determined the magnitude of additional risks for the respiratory system. Non-carcinogenic health risk is assessed before the age of 19 years as negligible, until the age of 36 years as a moderate, until the age of 45 years as highfor persons over 46 years as very high. PMID- 26031051 TI - [Prevalence and medical and social importance of disorders and diseases of the musculoskeletal systems in children and adolescents (review of literature)]. AB - The urgency of the problem of the excess incidence of disorders and diseases of the musculoskeletal system (MSS) in contemporary children and adolescents is determined by its high medical and social significance. However, the poor quality of diagnosis of MSS disorders in children at the polyclinics level, especially at the initial stages, when timely commenced recreational and corrective-measures are most effective, do not allow to carry out remedial work timely, and this in turn is the cause of the high prevalence of violations of the MSS later With the aim of the improvement of the quality of diagnosis of early forms of musculoskeletal pathology in children and adolescents, as well as for the performance of the prevention during learning them in school there is developed an information system for health care workers "Identification, correction and prevention of disorders of the locomotor apparatus in students of educational institutions". The core of the system is formed by developed by authors a classification of functional disorders and initial forms of diseases of the MSS in students, as well as the organization of this work. PMID- 26031052 TI - [Monitoring and prognosis of psychophysiological status and educational performance of first/second-year female medical students]. AB - Monitoring of 28 indices in first/second-year female medical students during two years allowed to deliver the approximation of psychophysiological status and two patterns of educational performance during both session and examination period and according to them calculate the prognosis for these indices for two subsequent studying periods with high accuracy. Prognosis calculated upon the approximation and patterns would give the possibility to reveal negative impacts of stressor factors on students at the preliminary stage of the disease and to correct this condition with help of valeological programs. PMID- 26031053 TI - [Methodological approaches to the substantiation of a harmonized mean year maximum permissible nickel concentration in ambient air]. AB - In the article there are presented the results of the substantiation of a harmonized mean year maximum permissible nickel concentrations (MPNC) in ambient air according to the results of epidemiological studies and mathematical modeling of the evolution of risk Data of the analysis of hygienic standards of the nickel content in the air used both in Russia and abroad, as well as the results of the own research allow us to recommend as a harmonized mean year MPNC-0.00005 mg/m3, and as critical effects--disorders of the respiratory organs. PMID- 26031054 TI - [The content of protein regulators of apoptosis Bcl-2 and bad in regional lymph nodes of the liver under the influence of 50 Hz a magnetic field]. AB - There was investigated the expression of molecular and cellular regulators of apoptosis Bcl-2 and Bad in the regional lymph nodes of the liver in rats exposed to the magnetic field of 50 Hz during 14 days. There was revealed a reduction in the protein expression of regulators of apoptosis Bcl-2 in the cortical area of the regional lymph nodes of the liver in animals exposed to the magnetic field. PMID- 26031055 TI - [Toxicity assessment of sulpiride as the basis of its hygienic standardization]. AB - Toxic properties of sulpiride were studied with an aim of its hygienic standardization. LD50 of sulpiride in administration into the stomach of male rats and mice is 7200 and 3400 mg/kg, for female rats and mice - 6000 and 2300 mg/kg. It refers to substances of hazard Classes 3, 4. No significant differences were noted in the species and sex sensitivity of animals to a substance. In intraperitoneal administration LD50 for male rats is 220 mg/kg, for female rats- 150 mg/kg. It has a pronounced cumulation ability, cumulation coefficient: Kcum equals 2.9. It has not a local irritant effect on the skin. There were no identified skin-resorptive and sensitizing effects. It causes a slight irritant effect on the mucous membranes of the eyes. It has a toxic effect on the central nervous system, liver, kidneys. Threshold of acute inhalation action is--63.5 mg/m3. Occupational safety level of exposure to sulpiride in the working area air is 0.5 mg/m. PMID- 26031056 TI - [Scientific rationale for basic directions of the optimization of the population health in the development of municipal environmental programs]. AB - For the solution of ecological problems in the framework of the preparation of the municipal ecological program in the city of Verkhnyaya Pyshma (Sverdlovskaya Oblast) there was peiformed the assessment of the state of population health, the evaluation of carcinogenic and non-carcinogenic health risk from chemicals that pollute the air and drinking water Atmospheric air was established to be the main environment cause for carcinogenic and non-carcinogenic risks. The obtained results served as the basis for the development of technological, sanitary and hygienical measures of the program aimed at optimizing of the population health. PMID- 26031057 TI - [The informativeness of indices of the heart rate variability for the identification of the adverse effects of environmental factors on the health of adolescent girls]. AB - There was performed an investigation of informativeness of indices of the heart rate variability at rest and during orthostatic testing in the adolescent girls residing in the industrial town and in the village. The influence of unfa- vorable environmental factors was established to be reflected by the indices of the spectral analysis and cardioin- tervalography. In urban girls there was noted the marked increase of the centralization of heart rhythm control on the background of the increased activity of the sympathetic compartment and the reduction of the influence of the parasympathetic compartment of the autonomous nervous system on the sinus node. In rural adolescent girls the func- tional state of the autonomic nervous system being the optimal is characterized by an adequate response to the active orthostatic test of the parasympathetic and sympathetic compartments with the moderate involvement of mechanisms of the central control of the cardiac rhythm. Results of the study have an important significance for the diagnosis of the early disorders of health in adolescent girls. PMID- 26031058 TI - [Working conditions and morbidity rate in employers at the South-East railway transport]. AB - In the article there are presented the results of the examination of working conditions atfactories of the South-Eastern Railway, which has lost its effectiveness due to the action of certain laws. The situation on labor conditions was shown to be not entirely safe. There is given an analysis of the morbidity due to the temporary disability and occupational disease rates in foot plate staff workers. There was made an emphasis on working conditions and morbidity rate in foot-plate staff workers. There is posed a question about the inclusion of essential hypertension in foot-plate staff workers in the list of occupational diseases. PMID- 26031059 TI - [Size distribution characteristics of particulate mercury on haze and non-haze days]. AB - With the rapid economic development, China suffers from the severe haze and atmospheric mercury pollution. Particulate mercury transport has an important significance in its global cycle. In order to investigate the distribution characteristics of particulate mercury, 12 degrees Nano-moudi (6.2-9.9 MUm, 3.1 6.2 MUm, 1.8-3.1 MUm, 1.0-1.8 MUm, 0.56-1.0 MUm, 0.32-0.56 MUm, 0.18- 0.32 MUm, 0.10-0.18 MUm, 0.056-0.10 MUm, 0.032-0.056 MUm, 0.018-0.032 MUm, 0.010-0.018 MUm) impactor was used to measure the size distributions of atmospheric particulate mercury on both haze and non-haze days in Shanghai. The results indicated that particulate mercury levels were positively correlated with those of the particles. The average concentration of particulate mercury (0.31 ng x m (-3)) on haze days was 2-3 times than that on non-haze days (0.11 ng x m(-3)). The mass size distributions of aerosols and particulate mercury showed bimodal distributions. The peak shifted from 0.56-1.0 MUm and 3.1-6.2 MUm on haze days to 0.32-0.56 MUm and 3.1-6.2 MUm on non-haze days. The particles with aerodynamic diameter smaller than 1 MUm which could stay for a long time and transport for a long distance, had higher particulate mercury concentrations. The average contribution of particulate mercury to total PM aerosol were higher on haze days (0.029 ng x MUg(-1)) than on non-haze days (0.015 ng x MUg(-1)), indicating that secondary particles typically grew faster than mercury during the haze pollution events. The particulate mercury concentration in accumulation mode was 2.06 ng x m(-3) on haze days, while it was 0.55 ng x m(-3) on non-haze days. The large increase of the accumulation mode particles was a main reason for the formation of haze. Emissions from the coal burning as well as road surface dust and dust from long-range transport accounted for the serious pollution on haze days. PMID- 26031060 TI - [Impact of atmospheric pollutants transport pathways on aerosol optical properties at Shangdianzi background station]. AB - The impact of transport pathways on aerosol properties at Shangdianzi (SDZ) background station was analyzed using the back trajectory analysis method with the observation of PM2.5 concentration and aerosol scattering coefficients ( sigma(sp)) during 2005-2010. The results showed that the pollutant level at SDZ was influenced by both the direction and motion state of air masses. The southerly transport pathways of air masses had higher PM2.5 concentration and sigma(sp) than those of northerly pathways. The air masses with lower moving speed and altitude generally corresponded to higher PM2.5 concentration and sigma(sp). Air masses originated from the North China Plain in spring, summer and autumn, and air masses from the north of North China region in winter had a significant contribution to PM2.5 concentration and sigma (sp) at SDZ. Dust aerosol appeared frequently in spring, and the mean scattering efficiency (alpha(sp)) was 0.78 m2 x g(-1). The mean alpha(sp) of anthropogenic aerosol of four seasons was 4.00 m2 x g(-1) with the highest value in winter and the lowest in spring. The west-northwest, southerly pathways, and the northerly pathways with low moving speed in spring, summer and autumn correspond to higher alpha(sp) ( > 4.0 m2 x g(-1)). This indicated that these pathways were affected by the emissions form human activities. However, the alpha(sp) in winter kept at a high level among all pathways, which suggested that the emission effect was relatively uniform in surrounding regions in winter. The other northerly pathways in spring, summer and autumn were affected by anthropogenic pollutants mixed with dust. PMID- 26031061 TI - [Chemical characteristics of 3-year atmospheric precipitation in summer, Taiyuan]. AB - The chemical characteristics of the precipitation in Taiyuan in summer of 2011 2013 were investigated. The results showed that the pH of precipitation varied from 4.63 to 8.02 with a volume-weighted mean of 5.19. The frequency of acid rain was 37.0%, 31.2% and 17.4%, respectively, in 2011-2013. SO4(2-) and NO3(-) were dominant anions in the precipitation, which accounted for 67.2% and 22.0% of the total anions, respectively. While Ca2+ and NH4+ were dominant cations in the precipitation, which accounted for 55.1% and 29.0% of the total cations, respectively. There were evident declining trends in the concentration of SO4(2 ), NO3-, Ca2+ and NH4+ in the precipitation over the study period. The mean ratio of SO4(2-) to NO3(-) in summer precipitation was 3.02, indicating that the acid rain was of sulfuric-nitrous mixed type, however, NO3- was very important for the acidity of rain water. Neutralization factors (NF) were calculated to show that Ca2+ and NH4+ were the predominant neutralizers in rainwater samples, but Mg2+ could also not be negligible. The correlation analysis revealed that coal combustion was the dominant source of chemical composition of rainwater in summer of Taiyuan. The back trajectory analysis demonstrated that the air pollutants of Taiyuan were from the local plants and the coal coking plants in the southern Taiyuan basin. However, to improve the air quality in this city, both industrial emissions from thermal power plants and coal coking plants in Taiyuan basin need to be controlled. PMID- 26031062 TI - [Pollution characteristics of organic and elemental carbon in PM2.5 in Taiyuan]. AB - PM2.5 samples were collected at four sampling sites to study pollution characteristics of carbonaceous aerosols in Taiyuan during winter and summer. Organic carbon (OC) and elemental carbon (EC) in PM2.5 were analyzed by carbon analyzer, and the characteristics including pollution levels, temporal and spatial distributions of OC and EC, secondary organic carbon (SOC) and relationships of OC and EC were discussed in detail. The average concentrations of OC and EC in winter were 22.3 MUg x m(-3) and 18.3 MUg x m(-3), respectively, while in summer were 13.1 MUg x m(-3) and 9.8 MUg x m(-3), respectively. The concentrations of total carbon aerosol (TCA) accounted for 56.6% of PM2.5 in winter, and 36.5% in summer; the concentrations of OC and EC at four sites in winter were higher than those in summer, OC and EC levels showed a good uniformity in winter while in summer, the spatial distributions of OC and EC were obviously different; SOC levels were lighter than other cities; the correlation between OC and EC was stronger in winter than that in summer. PMID- 26031063 TI - [Levels and distribution of organochlorine pesticides and dioxin-like polychlorinated biphenyls in atmospheric particulates in Xining and Tianjun, Qinghai province, China]. AB - The levels of OCPs and DL-PCBs in the atmospheric particulates of Xining city and Tianjun county in Qinghai province were determined. DDTs and HCHs were the main component of OCPs in the atmospheric particulates. The average levels of DDTs and HCHs in the atmospheric particulates of Xining city were 35 pg x m(-3) and 5.9 pg x m(-3) in summer and 93 pg x m(-3) and 11 pg x m(-3) in winter, respectively. In Tianjun county, they were 83 pg x m(-3) and 6.4 pg x m(-3) in summer and 28 pg x m(-3) and 6.7 pg x m(-3) in winter, respectively. Compared with other Asian areas, the average levels of them in Qinghai province were lower. Meanwhile, the average levels of DL-PCBs in Xining city were 0.52 pg x m(-3) in summer and 0.99 pg x m(-3) in winter, respectively, and in Tianjun county were 0.58 pg x m(-3) in summer and 0.52 pg x m(-3) in winter, respectively. The average levels of OCPs in summer and winter of Xining city were higher than those in Tianjun county, but the average levels of DL-PCBs in two cities were similar. Compared with the polar region, the distribution principles of DL-PCBs in the plateau area were certainly similar, while HCHs and DDTs were different. PMID- 26031064 TI - [Particulate matter adsorption capacity of 10 evergreen species in Beijing]. AB - In the atmosphere, high concentrations of air particles PM (Particulate matter) cause not only environmental pollution, but also serious harm to human body. Green plants as an air filter, can effectively improve the air quality in urban and suburb, and protect human health. Therefore, it is necessary to understand the adsorption capacity of air particulate matter of different species. Based on aerosol generator (QRJZFSQ-I), the leaf surface of ten plants including six evergreen trees and four evergreen shrubs were measured to determine the atmosphere adsorption (TSP, PM10, PM2.5 and PM10) capacity in Beijing, the results showed that: (1) There was obvious difference in the PM adsorption capacity of the leaf surface of different species, the highest were Cedrus deodara and Pinus tabuliformis, which were (18.95 +/- 0.71) MUg x cm(-2) and (14.61 +/- 0.78) MUg x cm(-2) respectively, while Abiesfabri was the minimum, which was (8.02 +/- 0.4) MUg x cm(-2); (2) There was also difference in the per unit leaf area particulate adhesion ability among different tree species, the tree species with the strongest leaf PM10 adhesion ability were Pinus tabulformis and Cedrus deodara, those with the strongest leaf PM2.5 adhesion ability were Cedrus deodara, Juniperus procumbens , Juniperus chinensis cv. kaizuka and Pinus tabuliformis, while those with the strongest leaf PM10 adhesion ability were Cedrus deodara, Juniperus procumbens, Abies fabri and Pinus tabuliformis; (3) The proportions of particulate matters (PM10 and PM2.5) in TSP were different. PM10 had mainly two kinds of trends in April-June, one was firstly decreasing and then increasing, with the main tree type of the shrub species; and the other was increasing, with the main tree type of the tree species. But this change trend was not obvious in PM2.5. PMID- 26031065 TI - [Carbon sources metabolic characteristics of airborne microbial communities in constructed wetlands]. AB - Using BIOLOG-GN plates, this article describes the carbon sources metabolic characteristics of airborne microbial communities in a free surface-flow constructed wetland in different seasons and clarify the correlation between airborne microbial metabolic functions and environmental factors. The average well color development (AWCD), carbon metabolic profiles and McIntosh values of airborne microbial communities in different seasons were quite different. Analysis of the variations showed that AWCD in spring and summer differed significantly from that in autumn and winter (P < 0.01). In the same season, the degree of utilization of different types of carbon by airborne microbes was different. Summer had a significant difference from other seasons (P < 0.05). Dominant communities of airborne microbes in four seasons were carboxylic acids metabolic community, carbohydrates metabolic community, polymers metabolic community and carboxylic acids metabolic community respectively. Principal component analysis showed that the carbon metabolic characteristics of airborne microbial community in autumn were similar to those in winter but different from those in spring and summer. The characteristics of carbon metabolism revealed differences between summer and spring, autumn, or winter. These differences were mainly caused by amines or amides while the differences between spring and autumn or winter were mainly caused by carboxylic acids. Environmental factors, including changes in wind speed, temperature, and humidity acted to influence the carbon sources metabolic properties of airborne microbial community. The dominant environmental factors that acted to influence the carbon sources metabolic properties of airborne microbial community varied between different seasons. PMID- 26031066 TI - [Spatial distribution characteristics of the physical and chemical properties of water in the Kunes River after the supply of snowmelt during spring]. AB - Eight physical and chemical indicators related to water quality were monitored from nineteen sampling sites along the Kunes River at the end of snowmelt season in spring. To investigate the spatial distribution characteristics of water physical and chemical properties, cluster analysis (CA), discriminant analysis (DA) and principal component analysis (PCA) are employed. The result of cluster analysis showed that the Kunes River could be divided into three reaches according to the similarities of water physical and chemical properties among sampling sites, representing the upstream, midstream and downstream of the river, respectively; The result of discriminant analysis demonstrated that the reliability of such a classification was high, and DO, Cl- and BOD5 were the significant indexes leading to this classification; Three principal components were extracted on the basis of the principal component analysis, in which accumulative variance contribution could reach 86.90%. The result of principal component analysis also indicated that water physical and chemical properties were mostly affected by EC, ORP, NO3(-) -N, NH4(+) -N, Cl- and BOD5. The sorted results of principal component scores in each sampling sites showed that the water quality was mainly influenced by DO in upstream, by pH in midstream, and by the rest of indicators in downstream. The order of comprehensive scores for principal components revealed that the water quality degraded from the upstream to downstream, i.e., the upstream had the best water quality, followed by the midstream, while the water quality at downstream was the worst. This result corresponded exactly to the three reaches classified using cluster analysis. Anthropogenic activity and the accumulation of pollutants along the river were probably the main reasons leading to this spatial difference. PMID- 26031067 TI - [Composition characteristics and source analysis of major ions in four small lake watersheds on the Tibetan Plateau, China]. AB - To investigate the ionic compositions of small lake-watersheds on the Tibetan Plateau, water samples from the brackish lakes (Pung Co (lake), Angrenjin Co and Dajia Co), the freshwater lake (Daggyaima Co), their inflowing rivers and the hot spring (Dagejia Geothermal Field), were collected during July-August 2013. The results showed that the major anions and cations of the brackish lakes were HCO3 , SO4(2-) and Na+, respectively, and the hydrochemical types were HCO3-SO4-Na and HCO3-Na. The major anions and cations of the inflowing rivers and the freshwater lake were HCO3-, SO4(2-) and Ca2+, Mg2+, respectively, and the hydrochemical types were HCO3-Ca, HCO3-Ca-Mg, HCO3-Mg-Ca, HCO3-SO4-Ca and SO4-HCO3- Ca. The major anions and cations of the hot spring were HCO3- and Na+, respectively, and the hydrochemical type was HCO3-Na. Water chemistry in the brackish lakes was primarily dominated by evaporation-crystallization processes, while the inflowing rivers and the freshwater lake were mainly influenced by carbonate weathering, and the hot spring was mainly controlled by hot water-granite interaction. Ca2+ was preferentially removed over Mg2+ from the water when carbonate minerals precipitation occured, which resulted in the high Mg2+/Ca2+ molar ratios of the brackish lakes. In the contribution of cation compositions, the largest contribution was carbonate weathering (54% - 79%), followed by silicate weathering (13% -29%) and evaperite dissolution (4% -23%), and the smallest was atmospheric input (3% - 7%). PMID- 26031068 TI - [Seasonal stratification and eutrophication characteristics of a deep reservoir, Longtan Reservoir in subtropical area of China]. AB - In order to reveal the seasonal stratification and eutrophication characteristics of the subtropical large deep reservoir--Longtan Reservoir, the spatial and temporal distribution of environmental factors and eutrophic index were investigated during November (dry period) 2012, April (level period) and July (wet period) 2013. The results suggested that: (1) The stratification structure of Longtan Reservoir was meromictic lake, it had a single thermocline structure in the dry season, the surface layer to the 60 m was a mixomolimnion, 60-80 m was a thermocline, deeper more than 80 m was a monimolimnion. It had a double thermocline structure in flow period and wet period, the surface to 10 m was a mixed layer, 10-20 m was a thermocline, 20-40 m was a mixed layer, 40-60 m was a thermocline, deeper more than 60 m was a mixed layer. (2) The thermal stratification dominated the structure of other environmental factors, the stratification structure limited the water convection, especially the monimolimnion reduced the harm of the endogenous pollution. (3) The trophic level index (TLI) was 23.4-32.8 in the dry period, 27.1-38.6 in the flow period and 26.0-45.1 in the wet period, which were all Mesotropher. The trophic state index of total nitrogen was 60.3-72.5, which was eutropher to hyper eutropher, N: P was 107:1, which was phosphorus limited. PMID- 26031069 TI - [Phosphorus fractions, sorption characteristics and its release in the sediments of Yangtze Estuary Reservoir, China]. AB - To analyze the sediment phosphorus (P) fractions and sorption characteristics and P release from sediment of reservoir in Yangtze estuary, the sediment was investigated during April, 2011 to January, 2012. Results of chemical fractionation analysis showed that total P (TP) content in sediment ranged from 535.07 to 910.9 mg x kg(-1), inorganic P (IP) was a dominant component of TP and the content of organic P (OP) was low. IP presented in the form of P bounded to calcium ( HCl-P) and dominated 75.57% of TP. The batch experiments showed that sediments had the maximum P adsorption capacity from 9.78 to 39.84 mg x kg(-1), sorption data fitted the modified Langmuir isotherm model. However, EPC0 ( equilibrium phosphorus concentration) in all sampling sites was higher than the soluble-reactive P concentration in water column, which was from 0.024-0.12 mg x L(-1). Accordingly, the sediments from those sampling sites would release phosphorus into the overlying water as a P release source. The maximum released amount from sediment was 11.03 mg x kg(-1) about 6 hours. Correlation between P released amount and NaOH-P was found (P < 0.01), and sediment P release would mainly originate from the NaOH-P, OP and HCl-P fraction. It is evident that the inherent phosphorus present in sediments would be a major threat to the water quality in Yangtze River estuary reservoir. PMID- 26031070 TI - [Spatial-temporal distributions of dissolved inorganic carbon and its affecting factors in the Yellow River estuary]. AB - Estuary is an important area contributing to the global carbon cycle. In order to analyze the spatial-temporal distribution characteristics of the dissolved inorganic carbon (DIC) in the surface water of Yellow River estuary. Samples were collected in spring, summer, fall, winter of 2013, and discussed the correlation between the content of DIC and environmental factors. The results show that, the DIC concentration of the surface water in Yellow River estuary is in a range of 26.34-39.43 mg x L(-1), and the DIC concentration in freshwater side is higher than that in the sea side. In some areas where the salinity is less than 15 per thousand, the DIC concentration appears significant losses-the maximum loss is 20.46%. Seasonal distribution of performance in descending order is spring, fall, winter, summer. Through principal component analysis, it shows that water temperature, suspended solids, salinity and chlorophyll a are the main factors affecting the variation of the DIC concentration in surface water, their contribution rate is as high as 83% , and alkalinity, pH, dissolved organic carbon, dissolved oxygen and other factors can not be ignored. The loss of DIC in the low area is due to the calcium carbonate sedimentation. DIC presents a gradually increasing trend, which is mainly due to the effects of water retention time, temperature, outside input and environmental conditions. PMID- 26031071 TI - [Distributions of phosphorus fractions in suspended sediments and surface sediments of Tiaoxi mainstreams and cause analysis]. AB - Phosphorus is a primary nutrient showing the water quality status of river and inducing eutrophication, and a different phosphorus fraction can make diverse contributions to water quality. Four phosphorus forms of suspended sediments and surface sediments in Tiaoxi mainstreams were measured using a sequential extraction procedure, and the distributions of their forms were discussed. The results showed that the tropic status of Xitiaoxi River was inferior to that of Dongtiaoxi River as a whole, and the water quality in the middle reach of Dongtiaoxi River was better than that in the upper and lower reaches. The contents of nutrient elements in suspended sediments were significantly higher than those in surface sediment, which indicated an enrichment of nutrient in fine sediment. The percentages of the loosely absorbed phosphorus ( NH4Cl-P), the reductant phosphorus (BD-P) and the metal oxide bound phosphorus (NaOH-P) in the suspended sediment were higher than those in surface sediment, while the percentage of the calcium bound phosphorus (HCl-P) showed a reverse trend. Correlation analyses between phosphorus forms and chemical compositions of suspended sediments and surface sediments were performed. The results showed the phosphorus forms in suspended sediments and surface sediments of Xitiaoxi River had weak relationships with mineral components, while those in the Dongtiaoxi River had strong relationships with mineral, especially OM and clay mineral. The cause was associated with the geological setting and material sources in Tiaoxi watershed. PMID- 26031072 TI - [Characteristics of nitrogen pollution and the potential mineralization in surface sediments of Dianchi Lake]. AB - The nitrogen content, its different forms and their spatial distribution were studied by using the 53 sediment samples from different sites in Dianchi Lake. Thereafter, the potential nitrogen mineralization ability of the sediments and their pollution characteristics were also explored to understand the influencing factors of nitrogen pollution and its release risk from the sediment surface to the overlying water of Dianchi. The results showed: (1) the average total nitrogen content of surface sediment in Dianchi Lake was 3 515. 60 mg x kg(-1), which was at a high level from the inlets in Caohai Northeast thinning digging area, Panlong River and the Haikou into Dianchi Lake, but relatively low in Baoxiang River Estuary dredging area. The total organic nitrogen (TON) content, accounting for 85.86% of TN, was at a high level; on the other hand, the dissolved inorganic nitrogen ( DIN) content was lower, which accounted for 14.10% of TN. The spatial distribution of TON and TN kept the same trend, but not the DIN. Compared with other Lakes of China, the nitrogen content of sediment in Dianci was at a high level, and the extent of pollution was just below the serious polluted City Lakes. (2) The average potential mineralizable nitrogen (PMN) content of Lake Dianchi was 1 154.76 mg x kg(-1), accounting for 32.90% of TN, which raised the potential risk of its release into the overlying water. Higher PMN was found in the Caohai Lake area and the inlet of Panlong River in the North, the inlet of Luolong Rive in the Middle Lake, the inlet of Baiyukou Lake and Liangwang River in the South. Nowadays, the pH value of Dianchi Lake was favorable for its sediment nitrogen mineralization, and its nitrogen mineralization was affected by the release of NH4(+) -N from organic matter. In the heavy polluted area, the concentration of the overlying water nitrogen was seriously affected by nitrogen mineralization of sediment from Dianchi, while the light polluted area was less affected. PMID- 26031073 TI - [Influence of transient storage on solute transport and the parameter sensitivity analysis in a suburban drainage ditch]. AB - From September to October 2013, five in-stream tracer experiments involving slug additions of chloride were performed in Guanzhenhe Branch, a headwater stream in suburban Hefei. From the perspective of different transport mechanisms such as transient storage, lateral inflow and advection-dispersion, four scenarios were set to analyze the effects of transient storage on solute transport in the drainage ditch. And sensitivity analysis of parameters in OTIS model was conducted. The results showed that transient storage exerted a significant influence on the peak values of simulated chloride concentration breakthrough curves (BTCs) in the main channel, and the REs (relative errors) of peak values in the BTCs ranged from 24.23% to 117.26%, which were much higher than those of the peak times. Meanwhile, the effects on simulated BTCs of transient storage markedly exceeded those of lateral inflow. Correlation analysis results showed that A(s)/A were significantly correlated with the peak value REs and the peak time RE's, respectively. Moreover, the ranking of parameter sensitivity in OTIS model was A > A(s) > alpha > D. PMID- 26031074 TI - [Sources, pollution statue and potential ecological risk of heavy metals in surface sediments of Aibi Lake, Northwest China]. AB - In this paper, the surface sediment samples were harvested from Aibi Lake, and total contents of 8 heavy metals ( Cu, Pb, Zn, As, Hg, Cr, Ni and Cd) were determined. Then the sources, pollution statue, and potential ecological risk were analyzed by using multiple analysis methods. The results show that: (1) The order of the skewness for these 8 heavy metals is: Hg > Cd > Pb > Zn > As > Cu > Cr > Ni. (2) Multivariate statistical analysis shows that 8 heavy metals can be classified to 2 principle components, among which PC1 ( Cd, Pb, Hg and Zn) is man made source factor and mainly came from all kinds of waste of agriculture; PC2 ( Cu, Ni, Cr and As) is natural source and was mainly controlled by the background of the natural geography of this area. (3) Accumulation of index evaluation results show that the order of pollution degree values of 8 heavy metals in surface sediments of Aibi Lake is: Cd > Hg > Pb > Zn > As > Cu > Ni > Cr. In all samples, heavy metals Hg, Cd and Pb all belong to low and partial moderate pollution statue, while Zn, As, Cr, Ni and Cu belong to no pollution statue in majority samples. (4) Potential ecological risk assessment results show that the potential ecological risk of heavy metals in surface sediments of Aibi Lake mainly caused by Cd, Hg and Pb, and they accounting for 42.6%, 28.6% and 24.0% of the total amount, respectively, among which Cd is the main ecological risk factor, followed by Hg and Pb. In all samples, the potential ecological risk index values (RI) of 8 heavy metals are all lower than 150, and they are all at low ecological risk levels. However, this research also shows that there have high content of Cd and Pb in the sediment. Therefore, we should make long-term monitoring of the lake environment. PMID- 26031075 TI - [Speciation distribution and risk assessment of heavy metals in sediments in suburban outfall of industrial oasis region]. AB - The speciation distribution and potential environmental risk of Cu, Zn, Cd, Pb, Ni, Cr in sediments in suburban outfall of industrial oasis region, Baiyin City were studied by Tessier sequential extraction method, correlation analysis, enrichment factor (EF) and risk assessment code (RAC). The results indicated that, the average concentration of heavy metals in sediments samples of Dongdagou and Xidagou streams exceeded the background levels in Gansu Province, with Cr, as an exception. The enrichment factor suggested that the enrichment of Cd in sediments of Dongdagou and Xidagou streams were very serious, which posed a strong pollution level. Furthermore, the analysis of chemical speciation indicated that Zn, Ni, and Cr in sediments of Dongdagou stream were mainly dominated by the fraction of residual, the existence of Cu and Cd was mainly in organic forms, while Pb was composed mostly by its Fe-Mn oxides fraction; Pb in sediments of Xidagou stream existed by Fe-Mn oxides fraction, other metals mainly appeared with the residual fraction. The risk assessment code (RAC) showed that the risk level of heavy metals in sediments of Dongdagou stream descended in the order: Ni > Cd > Pb > Cu > Zn > Cr, Ni posed a highest risk level. The risk level of heavy metals in sediments of Xidagou stream decreased in the order: Pb > Cd > Ni > Cu > Zn > Cr, Cd, Pb and Ni posed a highest risk level. PMID- 26031076 TI - [Assessment of sources, spatial distribution and ecological risk of heavy metals in soils in a typical industry-based city of Shandong Province, Eastern China]. AB - A total of 106 samples were collected from surface soils in Gangcheng District, Laiwu city (a Typical industry-based city of Shandong Province, Eastern China), and the contents of 9 heavy metals including As, Cd, Co, Cr, Cu, Hg, Ni, Pb and Zn were determined. Multivariate analysis and geostatistics were,applied to examine the sources and spatial distributions of heavy metals in soils; and the assessment on ecological risk of heavy metals was carried out using Hakanson's method. The average concentrations of 9 heavy metals were higher than the background values of Shandong Province; in particular, the mean contents of Cd, Hg, Pb and Zn were 2.42, 4.69, 1.74 and 1.54 times of their respective background values, which indicated there were obvious accumulations of these heavy metals in surface soils. The results from multivariate analysis suggested that all the 9 heavy metals could be classified as 3 Principal Components (PCs). Cd, Pb and Zn, having high loads in PC1, were dominated by industrial, agricultural and traffic sources. PC2 including Co, Cr and Ni came from natural sources, and were controlled by parent materials. As and Hg with high loads in PC3, were originated from coal combustion and smelting. Cu had some loads on different PCs, and was affected by both natural and human sources. Assessment on ecological risk indicated that the study area suffered from a critical level between high and moderate risks. Hg was at the high ecological risk level, and Cd was at the moderate ecological risk level, while other metals had low ecological risk level. PMID- 26031077 TI - [Removal of triclosan with the method of UV/ClO2 and its degradation products]. AB - The UV/ClO2 process for triclosan ( TCS) removal was studied. The influences of several factors such as the initial pH, dose of ClO2, initial concentration of TCS and humic acid( HA) on TCS degradation in the UV/ClO2 combined process were discussed. The results showed that the UV/ClO2 process could effectively remove TCS and had a synergistic effect. When the light intensity was 6.5 MUW x Cm(-2), the dose of ClO2 was 0. 5 mg x L(-1) and the concentration of TCS was 300 MUg x L(-1), when UV and ClO2 were applied alone, the TCS removal rates within 1 min were only 5.23% and 84.93% respectively. The removal rate reached up to 99.13% after 1 min degradation using the UV/ClO2 combined process. In test conditions ( pH 6-9), the removal rate increased from 99.4% to 99. 63% with the increase of pH. Increasing dose of CIO2 could promote TCS removal. When the dose of ClO2 was 0.5-1.5 mg x L(-1), the removal rate was increased from 98.1% to 99.89%. The initial concentration of TCS was negatively correlated with the removal rate. When the initial concentration increased from 100 - 500 MUg x L(-1), the removal rate of TCS was decreased from 99.98% to 94.39%. Low concentration of humic acid was beneficial to the removal of TCS, and high concentration of it had the opposite effect. Degradation products of TCS were investigated by GC/MS. Degradation of TCS by the processes of UV, ClO2 and UV/ClO2 also indicated that the main degradation products of the TCS were 2, 4-dichlorophenol (2,4-DCP), 2,7 dichlorodibenzo-p-dioxin (2,7-DCDD), etc. PMID- 26031078 TI - [Mechanism of groundwater As(V) removal with ferric flocculation and direct filtration]. AB - The As removal process and mechanism from groundwater using ferric flocculation direct filtration system was investigated using batch, field pilot tests, extended X-ray absorption fine structure ( EXAFS) spectroscopy, and charge distribution multisite complexation (CD-MUSIC) model. The results showed that arsenate [As(V)] was the dominant As species in the groundwater with a concentration of 40 MUg x L(-1). The treatment system could supply 64 984 L As safe drinking water (< 10 MUg L(-1)) using Fe 1.5 mg x L(-1). Toxicity characteristic leaching procedure (TCLP) demonstrated that the leachate As was 3.4 MUg x L(-1), much lower than the EPA regulatory concentration (5 mg x L(-1)). EXAFS and CD-MUSIC model indicated that As(V) was adsorbed onto ferric hydroxide via bidentate binuclear complexes in the pH range of 3 to 9.5, while formation of precipitate with Ca or Mg dominated the As removal at pH > 9.5. PMID- 26031079 TI - [Preparation of nano zero-valent iron/Sargassum horneri based activated carbon for removal of Cr (VI) from aqueous solution]. AB - Nanoscale zero-valent iron supported on Sargassum horneri activated carbon (NZVI/SAC) was synthesized by zinc chloride activation and incipient wetness method, and characterized with X-ray diffraction (XRD), Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). XRD confirmed the existence of nano zero-valent iron, and SEM revealed that the material consisted of mainly 30-150 nm spherical particles aggregated into chains of individual units. The valence state of iron conformed with the nuclear-shell model. The effects of NZVI loading on AC, pH and the initial concentration of Cr(VI) on the removal of Cr(VI) were investigated. The final Cr(VI) removal percentage was up to 100% under the following conditions: 30 degrees C, pH = 2, NZVI/SAC dosage of 2 g x L(-1) and the amounts of NZVI loaded on SAC of 30%. And the equilibrium time was 10 minutes. These results showed that NZVI/SAC could be potentially applied for removal of high concentration Cr(VI). By analyzing the chemical change of NZVI/ SAC, we demonstrated that Cr(VI) was mainly reduced to insoluble Cr (III) compound in the reaction when pH was less than 4, and adsorbed by NZVI and SAC when pH was over 4. PMID- 26031080 TI - [Adsorption of Cr (VI) on magnetic graphene from aqueous solution]. AB - Chemical deposition method was applied to prepare magnetic graphene composites using graphite oxide and ferric salt (FeCl2 - 4H2O and FeCl3 x 6H2O) as starting materials. The static experiments were performed to study kinetics, thermodynamic, adsorption isotherm and effects of various parameters, such as pH, temperature and time on Cr(VI) adsorption. The results showed that adsorption kinetics followed the pseudo-second-order model. Compared with Freundlich isotherm, Langmuir isotherm could better describe the adsorption process. The parameters of thermodynamics were DeltaHtheta = 33.89 kJ x mol(-1), DeltaStheta = 120.15 J x (mol x K)(-1), DeltaGtheta = -2.51 kJ x mol(-1) (303 K), it demonstrated that the adsorption was a spontaneously endothermic process. It also indicated that the optimal pH was 2. Higher temperature and extension of time were in favor of adsorption. When used repeatedly for three times, the adsorption capacity decreased from 3.9 mg x g(-1) to 2.1 mg x g(-1) with an initial concentration of 5 mg x L(-1). By using a permanent magnet, the recycling process of adsorbent was easy to be operated and adsorbent could be regenerated by sodium hydrate solution. Hence, the composites is a promising adsorbent for efficient removal of Cr(VI) from wastewater. PMID- 26031081 TI - [Adsorption of the TiO2 @ yeast composite microspheres for adsorbing Fluorescent Whitening Agent-VBL in fixed bed]. AB - In this work, the adsorption potential of TiO2@ yeast composite microspheres to remove Fluorescent Whitening Agent-VBL (FWA-VBL) from aqueous solution was investigated using fixed-bed adsorption column. The effects of pH(2.0-8.0), bed height (1-3 cm), inlet concentration (20-80 mg x L(-1)) and feed flow rate (5-11 mL x min(-1)) on the breakthrough characteristics of the adsorption system were determined. The results showed that the highest bed capacity of 223.80 mg x g(-1) was obtained under the condition of pH 2.0, 80 mg x L(-1) inlet dye concentration, 1.0 cm bed height and 5 mL x min(-1) flow rate. The adsorption data were fitted to three well-established fixed-bed adsorption models, namely, BDST model, Thomas model and Yoon-Nelson model. The results fitted well to the three models with coefficients of correlation R2 > 0.980 in different conditions. The TiO2 @ yeast composite microspheres have desired regeneration ability and could be reused for four times. PMID- 26031082 TI - [Preparation and Pb2 electrosorption characteristics of MnO2/CFP composite electrode]. AB - The morphological structure and electrochemical properties of the electrode materials have direct impact on the electrosorption results. In this paper, Manganese dioxide ( MnO2) was composed on flexible carbon fiber paper ( CFP) via anodic electrodeposition technique to prepare the MnO2/CFP hybrid electrodes. The electrodes materials prepared showed stable electrochemical property, remarkable electrochemical capacitance, and the specific capacitance reached up to 360 F x g(-1). Electrosorption was conducted with this MnO2/CFP hybrid electrode to treat the waste water with an initial Pb2+ concentration of 6 mg x L(-1), and the effects of deposition time, initial pH, and voltage value on the electrosorption were investigated. It was shown that when the electrodeposition time was 500 s and the application of voltage value was 1.0 V, pH = 5.0, the best electroabsorption result was achieved. After 3 h electrosorption, the residual Pb2+ in the solution was lower than 0.01 mg x L(-1), and the removal efficiency could reach 99%. This study provides a new technology option for the removal of heavy metal ions in low concentrations in the waste water. PMID- 26031083 TI - [Preparation of weak light driven TiO2 multi composite photocatalysts via adsorption phase synthesis]. AB - Photodegradation of pollutions by TiO2 under irradiation of weak UV and visible lights was one of the key points to expand the application of heterogeneous photocatalysis. Based on the adsorption phase synthesis, N doping and co-doping with N and Fe2O3 were employed to prepare TiO2 multi composite photocatalysts. The activity of these photocatalyts was evaluated by photodegradation of methyl orange illuminated under weak UV and visible lights. Via UV-Vis diffuse reflectance spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and photoluminescence spectra, the effects on the light absorption and visible response expansion of catalysts caused by different conditions were explored, such as sintering temperature, doping content of N and co-doping. Followed that, the changes in the photocatalytic activities were studied under the irradiation of weak light. The results showed that, N doping could enhance the light absorption of the catalysts, thus significantly enhanced their photocatalytic activity illuminated under UV weak light. All N-doped photocatalysts had a higher activity than the commercial available P25 photocatalyst. The visible response of catalysts was expanded little caused by N doping, thereby most catalysts doped by single N element had no activity illuminated by weak visible light. Only the catalyst doped with 5% of N element showed a weak activity after calcined at 900 degrees C . Due to the synergy effects between N doping and Fe2O3 coupling, co doping did not only enhance the light absorption of the catalysts, but also significantly expanded the visible response of catalysts. So, co-doped catalysts showed a good catalytic activity when excited by weak visible light. PMID- 26031084 TI - [Photoelectrocatalytic degradation of bisphenol A in water by Fe doped-TiO2 nanotube arrays under simulated solar light irradiation]. AB - Seeking an efficient treatment method for bisphenol A ( BPA), a representative endocrine disrupting compound, is important for environmental remediation and human health. Herein, the degradation of BPA by means of photoelectrocatalysis was investigated. Fe doped-TiO2 nanotube arrays ( Fe/TNA ) served as the photoanode, and a xenon lamp simulated the solar light source. First, undoped TiO2 nanotube arrays (TNA) and a series of Fe/TNA were characterized by field emission scanning electron microscopy, X-ray diffraction and UV-Vis diffuse reflectance spectroscopy. The UV-Vis absorption spectra of Fe/TNA showed a red shift and an enhancement of the absorption in the visible-light region compared to TNA. Then, experimental conditions including Fe doping content, current intensity and aeration rate were varied to demonstrate their effects on the elimination of BPA. It was observed that the degradation of BPA could be fitted to the quasi-first-order equation. Under the following conditions: Fe/TNA prepared by 0.9 mol x L(-1) Fe(NO3)3 solution dip-coating as photoanode, titanium foil as cathode, current intensity of 1.15 mA x cm(-2) and initial BPA concentration of 10 mg x L(-1), 72.3% BPA was decomposed during 4 h reaction, with a rate constant of 5.32 x 10(-3) min(-1). Aeration enhanced the removal rate of BPA to 82.7% and 94.1% with an aerating rate of 1.0 L x min(-1) using titanium foil as cathode and an aerating rate of 0.2 L x min(-1) using carbon cloth as cathode, respectively, and the corresponding rate constants were 7.20 x 10(-3) min(-1) and 11.6 x 10(-3) min(-1), respectively. PMID- 26031085 TI - [Oxidation of cationic red 3R in water with H2O2 catalyzed by mineral loaded with Fe/Co]. AB - Catalyst supported on pyrite was prepared by the impregnation method to enhance the activity of catalyst and characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS) and X-ray diffraction (XRD). Some Fe2O3 and CoFe2O4 species were formed on the surface of pyrite. Synthetized catalyst was used to catalyze H2O2 oxidative discoloration of azo dye. Under the conditions of the catalyst adding dosage of 3 g x L (-1), H2O2 adding dosageof 0.3 mL x L(-1), and the oxidation reaction timeof 1 h, results showed that about 99.8% of color removal rate and 58.4% of TOC removal rate could be achieved. The active ingredients of catalyst were Fe2O3 and CoFe2O4. Hydroxyl radical was determined during the reaction by ESR technology, the chromophore of dyes could be destroyed with 1 min, and small molecular substances might be produced during the process according to the spectrum analysis. Reaction with wide pH ranges is beneficial to overcome the limitation of traditional Fenton reactions. This technology might be used as a potential alternative for treatment of recalcitrant wastewater. PMID- 26031086 TI - [Characteristics of acid red 3R wastewater treatment by ozone microbubbles]. AB - The application of microbubble technology for ozonation wastewater treatment could enhance ozone mass transfer, improve ozonation performance and increase ozone utilization efficiency. The ozone microbubbles were used to treat synthetic acid red 3R wastewater in the present study, and compared to ozone conventional bubbles. The ozone mass transfer and ozonation characteristics of acid red 3R were investigated when ozone microbubbles and ozone conventional bubbles were applied. The results confirmed the enhanced ozone mass transfer using microbubbles. The ozone mass transfer coefficient using microbubbles was 3.6 times higher than that using conventional bubbles under the same conditions. Simultaneously, the ozone decomposition coefficient using microbubbles was 6.2 times higher than that using conventional bubbles, which would be favorable for *OH generation. The ozonation rate and mineralization efficiency of acid red 3R could be improved significantly using ozone microbubbles. A TOC removal efficiency of 78.0% was achieved using ozone microbubbles, which was about 2 times higher than that using ozone conventional bubbles. The ozone utilization efficiency using microbubbles was much higher that using conventional bubbles during ozonation treatment of acid red 3R. The average ozone utilization efficiencies were 97.8% and 69.3% when microbubbles and conventional bubbles were used, respectively. The oxidative ability of ozone microbubbles could be increased by enhancing *OH generation, and as a result, the oxidative reaction of degradation intermediates was accelerated by ozone microbubbles. Especially, the mineralization ability of small organic acid intermediates using ozone microbubbles was about 1.6 times higher than that using ozone conventional bubbles. PMID- 26031087 TI - [Effects of carbon sources, temperature and electron acceptors on biological phosphorus removal]. AB - Effects of carbon sources, temperature and electron acceptors on phosphorus uptake and release were investigated in a pilot-scale oxidation ditch. Phosphorus uptake and release rates were measured with different carbon sources (domestic sewage, sodium acetate, glucose) at 25 degrees C. The results showed that the minimum phosphorus uptake and release rates of glucose were 5.12 mg x (g x h)(-1) and 6.43 mg x (g x h)(-1), respectively, and those of domestic sewage are similar to those of sodium acetate. Phosphorus uptake and release rates increased with the increase of temperature (12, 16, 20 and 25 degrees C) using sodium acetate as carbon sources. Anoxic phosphorus uptake rate decreased with added COD. Electron acceptors (oxygen, nitrate, nitrite) had significant effects on phosphorus uptake rate and their order was in accordance with oxygen > nitrate > nitrite. The mass ratio of anoxic P uptake and N consumption (P(uptake)/N (consumption)) of nitrate and nitrite were 0.96 and 0.65, respectively. PMID- 26031088 TI - [Startup, stable operation and process failure of EBPR system under the low temperature and low dissolved oxygen condition]. AB - A sequencing batch reactor (SBR) was started up and operated with alternating anaerobic/oxic (An/O) to perform enhanced biological phosphorus removal (EBPR) under the condition of 13-16 degrees C. The results showed that under the condition of low temperature, the EBPR system was successfully started up in a short time (<6 d). The reactor achieved a high and stable phosphorus removal performance with an influent phosphate concentration of 20 mg x L(-1) and the dissolved oxygen (DO) concentration of 2 mg x L(-1). The effluent phosphate concentration was lower than 0.5 mg x L(-1). It was found that decreasing DO had an influence on the steady operation of EBPR system. As DO concentration of aerobic phase decreased from 2 mg x L(-1) to 1 mg x L(-1), the system could still perform EBPR and the phosphorus removal efficiency was greater than 97.4%. However, the amount of phosphate released during anaerobic phase was observed to decrease slightly compared with that of 2 mg x L(-1) DO condition. Moreover, the phosphorus removal performance of the system deteriorated immediately and the effluent phosphate concentration couldn't meet the national integrated wastewater discharge standard when DO concentration was further lowered to 0.5 mg x L(-1). The experiments of increasing DO to recover phosphorus removal performance of the EBPR suggested the process failure resulted from low DO was not reversible in the short-term. It was also found that the batch tests of anoxic phosphorus uptake using nitrite and nitrate as electron acceptors had an impact on the stable operation of EBPR system, whereas the resulting negative influence could be recovered within 6 cycles. In addition, the mixed liquid suspended solids (MLSS) of the EBPR system remained stable and the sludge volume index (SVI) decreased to a certain extend in a long run, implying long-term low temperature and low DO condition favored the sludge sedimentation. PMID- 26031089 TI - [Effects of dissolved oxygen in the oxic parts of A/O reactor on degradation of organic pollutants and analysis of microbial community for treating petrochemical wastewater]. AB - Effects of dissolved oxygen (DO) on the biodegradation of organic pollutants were investigated using A/O reactors for the treatment of actual petrochemical wastewater. Two A/O reactors, DO were controlled at 2-3 mg x L(-1) in the oxic parts of reactor A and 5-6 mg x L(-1) of reactor B, were operated in parallel for comparison. The nearly a half of year operation results showed that the effluent COD in reactor A (72.5 +/- 14.8 mg x L(-1)) was slightly higher than that in reactor B (68.7 +/- 14.6 mg x L(-1)) at a HRT of 20 h. The average COD removal efficiencies were 67.0% and 68.8%, respectively. The effluent ammonium concentration was maintained at 0.8 mg x L(-1) and approximately 95% of ammonium removal was achieved. The effluent BOD, concentration was lower than 5 mg x L( 1). This indicated that the organic pollutants could be degraded thoroughly by the A/O processes, which were affected slightly by DO. Results of 454 pyrosequencing analysis of the sludge in oxic parts showed that at the phylum levels, sequences belonged to Proteobacteria, Planctomycetes and Bacteroidetes were abundant with 58.7% and 59.2%, 14.7% and 12.7%, 10.8% and 12.4% of total bacterial sequences in reactor A and B, respectively. Ammonium oxidation bacteria Nitrosomonas, nitrite oxidizing bacteria Nitrospira and obligate aerobic bacteria were highly enriched in reactor B with high DO levels, while the anaerobic denitrifiers Azospira and Acidovora were highly enriched in reactor A with low DO levels. The identified bacteria belonged to genera Novosphingobium, Comamonas, Sphingobium and Altererythrobacter were reported to degrade PAHs, chloronitrobenzene, pesticides and petroleum, which contributed to the degradation of petrochemical wastewater. PMID- 26031090 TI - [Isolation of filamentous fungi capable of enhancing sludge dewaterability and study of mechanisms responsible for the sludge dewaterability enhancement]. AB - To study the influence of filamentous fungi on the sludge dewaterability is very significant for the development of biological treatment methods for enhancing sludge dewaterability. In this study, filamentous fungi capable of enhancing sludge dewaterability were isolated from sewage sludge and the related mechanisms responsible for the sludge dewaterability enhancement were investigated. A filamentous fungus Mucor circinelloides ZG-3 was successfully isolated from sludge, and sludge dewaterability could be drastically improved by this fungus. Further study revealed that the enhancement of sludge dewaterability was influenced by inoculation method, inoculum size and solid content of sludge. The optimal inoculation method was mycelia inoculation, the optimal inoculum size was 10%, and the optimal solid content of sludge was about 4%. Under the optimized conditions, the specific resistance to filtration (SRF) of sludge could be decreased by 75.1% after being treated by M. circinelloides ZG-3. After the treatment, the COD value of sludge supernatant was only 310 mg x L(-1), and the treated sludge still exhibited good settleability. During the treatment of sewage sludge by M. circinelloides ZG-3, the mechanisms responsible for the sludge dewaterability enhancement included the degradation of sludge extracellular polymeric substances (EPS) and the decrease of sludge pH. Therefore, the treatment of sewage sludge using M. circinelloides ZG-3 is a useful and novel method for sludge conditioning. PMID- 26031091 TI - [Impacts of alkaline thermal treatment on characteristics of sludge from sewage treatment plant]. AB - Alkaline thermal treatment is an important pretreatment method for sewage sludge. In this paper, in order to optimize the alkaline thermal treatment conditions for sludge pretreatment, four pretreatment parameters ( sludge concentration, pH, temperature and treatment time) were investigated through orthogonal experiments to determine their effects on the sludge disintegration, sludge concentration and sludge morphology of sewage sludge. The experimental results showed that the significance of the four factors on sludge characteristics was in the order of pH > temperature > treatment time > sludge concentration. Additionally, the optimal conditions of the four factors for the release of soluble chemical oxygen demand (SCOD) of unit sludge and decrease of sludge concentration were as follows: 36.55 g x L(-1), pH 12.45, 175 degrees C and 60 min. While the optimal conditions for the decrease of particle size and fractal dimension were 36.55 g x L(-1), pH 12.5, 175 degrees C and 45 min. PMID- 26031092 TI - [Responses of ecosystem carbon budget to increasing nitrogen deposition in differently degraded Leymus chinensis steppes in Inner Mongolia, China]. AB - Based on a field manipulative nitrogen (N) addition experiment, the effects of atmospheric N deposition level change on the plant biomass and net primary productivity (NPP), soil respiration (Rs) and net ecosystem exchange (NEE) were investigated respectively in 2009 and 2010 in two differently degraded Leymus chinensis steppes in Inner Mongolia of China, and the difference in the response of NEE to equal amount of N addition [10 g x (M2 x a)(-1), MN] between the two steppes was also discussed. The results indicated that for the light degraded Leymus chinensis steppe (site A) , the average plant aboveground biomass (AGB) in MN treatment were 21.5% and 46.8% higher than those of CK in these two years. But for the moderate degraded Leymus chinensis steppe (site B), the N addition decreased the plant AGB and ANPP in 2009, while showed positive effects in 2010. N addition increased the belowground biomass (BGB) of the both sites and belowground NPP (BNPP) of site B in both years, but decreased the BNPP of site A in 2010. The increase of N input in the two steppes did not change the seasonal variation of Rs. The cumulative annual soil C emissions in MN treatment in site A showed an increase of about 14.6% and 25.7% of those in the CK respectively for these two years, while were decreased by about 10.4% and 11.3%, respectively in site B. The NEE of MN treatments, expressed by C, for the two steppes were 59.22 g x (m2 x a)(1) and 166.68 g x (m2 x a)(-1), as well as 83.27 g x (m2 x a)(-1) and 117.47 g x (m2 x a)(-1), respectively in these two years. The increments in NEE originated from N addition for these two years were 15.79 g x (M2 x a)(-1) and 82.94 g x (M2 x a)(-1) in site A and 74.54 g x (M2 x a)(-1) and 101.23 g x (M2 x a)(-1) in site B. The N input per unit could obtain greater C sink effect in the steppe with lower initial N level. PMID- 26031093 TI - [Impacts of elevated ozone concentration on N2O emission from arid farmland]. AB - To investigate the impact of elevated surface ozone (O3) concentration on nitrous oxide (N2O) emission from arid farmland, field experiments were carried out during winter-wheat and soybean growing seasons under the condition of simulating O3 concentrations, including free air (CK), 100 nL x L(-1) O3 concentration (T1), and 150 nL x L(-1) O3 concentration (T2). N2O emission fluxes were measured by static dark chamber-gas chromatograph method. The results showed that the accumulative amount of N2O (AAN) were decreased by 37.8% (P = 0.000 ) and 8.8% (P = 0.903 ) under T1 and T2 treatments, respectively, in the turning-green stage of winter wheat. In the elongation-booting stage, ANN were decreased by 15.0% (P = 0.217) and 39.1% (P = 0.000) under T1 and T2 treatments, respectively. ANN were decreased by 18.9% (P = 0.138) and 25.6% (P = 0.000) under T1 and T2 treatments, respectively, during the whole winter-wheat growing season. No significant impact of elevated O3 concentration on N2O emission from soil-soybean system was found due to the less rainfall during the soybean growing season, drought had a stronger stress on soybean than O3 concentration. The results of this study suggested that elevated O3 concentration could reduce N2O emission from arid farmland. PMID- 26031094 TI - [Multi-year measurement of soil respiration components in a subtropical secondary forest]. AB - A four-year field experiment was performed from March 2010 to February 2014 in order to investigate the contribution of different respiratory components to soil respiration and the temperature sensitivity of different respiratory components. Four blocks were arranged in field, and there were trenched and un-trenched plots in each block. Trenching, which can exclude roots, was performed around the trenched plots. A portable soil CO2 fluxes system ( Li-8100) was used to measure soil respiration rates. Soil temperature and soil moisture were simultaneously observed when measuring soil respiration rates. The results showed that the heterotrophic respiration rate in the trenched plots and the soil respiration rate in the un-trenched plots had the same seasonal pattern. Soil respiration rate in the un-trenched plots was significantly (P < 0.001) higher than that in the trenched plots. Mean soil respiration rates in untrenched plots and mean heterotrophic respiration rate in trenched plots were (2.59 +/- 0.48 ) and (1.74 +/- 0.28) MUmol x (M2 x s)(-1), respectively. There was no significant (P > 0.05) difference in the mean soil respiration rate or mean heterotrophic respiration rate between measurement years. The relationship between heterotrophic respiration and soil respiration could be fitted with a proportion function. Heterotrophic and autotrophic respiration contributed 65.9% and 34.1% to the soil respiration, respectively. The main contributor to soil respiration was heterotrophic respiration. The relationship between the ratio of heterotrophic respiration to soil respiration and measurement date could be fitted with a linear function. An exponential function could be used to fit the relationship between heterotrophic respiration and soil temperature, and between autotrophic respiration and soil temperature. The temperature sensitivity coefficient (Q10) for heterotrophic respiration was lower than that for autotrophic respiration. PMID- 26031095 TI - [Spatial variability of soil nitrogen and related affecting factors at a county scale in hilly area of Mid-Sichuan Basin]. AB - Spatial distribution characteristics of soil total nitrogen ( TN ) and available nitrogen ( AN ) were analyzed by using geostatistical methods and the effects of the influencing factors were quantified by regression analysis based on 555 soil samples collected in RenShou county. The results showed that the contents of soil TN ranged from 0.34-2.57 g x kg(-1) with a mean value of 1.12 g x kg(-1), which indicated the TN of the study area was at a medium level, and AN ranged from 25.86-184.17 mg x kg(-1) with a mean value of 74.35 mg x kg(-1), which indicated the AN of the study area was low. The values of the nugget to sill ratio were 0.608 and 0.790 respectively, which suggestd TN had moderate spatial dependence, which was determined by the co-effects of structural and random factors, while AN was mainly affected by random factors. The contents of TN and AN in north area were much higher than those of south area and distribution of Patchy. The soil parent materials were able to explain 6.3% and 1.0% of TN and AN spatial variability. Soil types explained 26.5% - 36.1% of TN variability and 27.7% - 28.7% of AN variability. Topographical factors explained 5.5% of TN variability and 6.1% of AN variability, the structural factors of soil types reflected spatial variability of nitrogen in the study area. The randomness factors of land use types explained 37.7% of TN variability and 40.0% of AN variability that were much larger than the other factors, which suggested land use had the higherst independent explaining capacity for nitrogen spatial variability among those influence factors and land use type was the main factor to accurately predict the spatial distribution of soil nitrogen in the hilly area of Middle Sichuan Basin. PMID- 26031096 TI - [Effects of land use change on soil active organic carbon in deep soils in Hilly Loess Plateau region of Northwest China]. AB - Response of soil active organic carbon to land-use change has become a hot topic in current soil carbon and nutrient cycling study. Soil active organic carbon distribution characteristics in soil profile under four land-use types were investigated in Ziwuling forest zone of the Hilly Loess Plateau region. The four types of land-use changes included natural woodland converted into artificial woodland, natural woodland converted into cropland, natural shrubland converted into cropland and natural shrubland converted into revegetated grassland. Effects of land-use changes on soil active organic carbon in deep soil layers (60-200 cm) were explored by comparison with the shallow soil layers (0-60 cm). The results showed that: (1) The labile organic carbon ( LOC) and microbial carbon (MBC) content were mainly concentrated in the shallow 0-60 cm soil, which accounted for 49%-66% and 71%-84% of soil active organic carbon in the profile (0-200 cm) under different land-use types. Soil active organic carbon content in shallow soil was significantly varied for the land-use changes types, while no obvious difference was observed in soil active organic carbon in deep soil layer. (2) Land-use changes exerted significant influence on soil active organic carbon, the active organic carbon in shallow soil was more sensitive than that in deep soil. The four types of land-use changes, including natural woodland to planted woodland, natural woodland to cropland, natural shrubland to revegetated grassland and natural shrubland to cropland, LOC in shallow soil was reduced by 10%, 60%, 29%, 40% and LOC in the deep layer was decreased by 9%, 21%, 12%, 1%, respectively. MBC in the shallow soil was reduced by 24% 73%, 23%, 56%, and that in the deep layer was decreased by 25%, 18%, 8% and 11%, respectively. (Land-use changes altered the distribution ratio of active organic carbon in soil profile. The ratio between LOC and SOC in shallow soil increased when natural woodland and shrubland were converted into farmland, but no obvious difference was observed in deep soil. The ratio of MBC/SOC in shallow soil decreased when natural shrubland was converted into farmland, also, no significant difference was detected in the ratio of MBC/SOC for other land-use change types. The results suggested that land use change exerted significant influence on soil active organic carbon content and distribution proportion in soil profile. Soil organic carbon in deep soil was more stable than that in shallow soil. PMID- 26031097 TI - [Carbon source metabolic diversity of soil microbial community under different climate types in the area affected by Wenchuan earthquake]. AB - The MS8.0 Wenchuan earthquake in 2008 led to huge damage to land covers in northwest Sichuan, one of the critical fragile eco-regions in China which can be divided into Semi-arid dry hot climate zone (SDHC) and Subtropical humid monsoon climate zone (SHMC). Using the method of Bilog-ECO-microplate technique, this paper aimed to determine the functional diversity of soil microbial community in the earthquake-affected areas which can be divided into undamaged area (U), recover area (R) and damaged area without recovery (D) under different climate types, in order to provide scientific basis for ecological recovery. The results indicated that the average-well-color-development (AWCD) in undamaged area and recovery area showed SDHC > SHMC, which was contrary to the AWCD in the damaged area without recovery. The AWCD of damaged area without recovery was the lowest in both climate zones. The number of carbon source utilization types of soil microbial in SHMC zone was significantly higher than that in SDHC zone. The carbon source utilization types in both climate zones presented a trend of recover area > undamaged area > damaged area without recovery. The carbon source metabolic diversity characteristic of soil microbial community was significantly different in different climate zones. The diversity index and evenness index both showed a ranking of undamaged area > recover area > damaged area without recovery. In addition, the recovery area had the highest richness index. The soil microbial carbon sources metabolism characteristic was affected by soil nutrient, aboveground vegetation biomass and vegetation coverage to some extent. In conclusion, earthquake and its secondary disasters influenced the carbon source metabolic diversity characteristic of soil microbial community mainly through the change of aboveground vegetation and soil environmental factors. PMID- 26031098 TI - [Optimization of electrode configuration in soil electrokinetic remediation]. AB - Electric field distributions of several different electrode configurations in non uniform electric field were simulated using MATLAB software, and the electrokinetic remediation device was constructed according to the best electrode configuration. The changes of soil pH and heavy metal residues in different parts of the device during the electrokinetic remediation were also studied. The results showed that, in terms of the effectiveness of the electric field strength, the square (1-D-1) and hexagonal (2-D-3) were the optimal electrode configurations for one-dimensional and two-dimensional respectively and the changes of soil pH, the removal of heavy metals and the distribution of electric field were closely related to one another. An acidic migration band, which could prevent premature precipitation of heavy metals to a certain extent and promote electrokinetic removal of heavy metals, was formed gradually along with the remediation in the whole hexagon device when the cathodic pH was controlled during the remediation of the four cationic metallic ions, Cd2+, Ni2+, Pb2+ and Cu2+. After 480-hour remediation, the total removals of Cd, Ni, Pb and Cu were 86.6%, 86.2%, 67.7% and 73.0%, respectively. Remediation duration and replacement frequency of the electrodes could be adjusted according to the repair target. PMID- 26031099 TI - [Distribution and health risk of HCHs and DDTs in a contaminated site with excavation]. AB - Air samples were collected to analyze the distribution of HCHs and DDTs around a contaminated site during its excavation. The carcinogenic risks and non carcinogenic risks through breath exposure were studied by health risk assessment modes. The results showed that, there was an obvious seasonal variation of HCHs and DDTs in air around the excavating area. The concentrations of HCHs and DDTs were higher in winter and autumn, lower in spring and summer. The Sigma HCHs concentration ranged from 5.65 ng x m(-3) to 133 ng x m(-3), and the average value was 28.6 ng x m(-3); Sigma DDTs concentration ranged from 4.48 ng x m(-3) to 2 800 ng x m(-3), and the average value was 457.3 ng x m(-3) in winter. However, the Sigma HCHs concentration was between 6.23 ng x m(-3) and 26.4 ng x m(-3), and the average value was 15.1 ng x m(-3) in spring; the Sigma DDTs concentration was between 3.17 ng x m(-3) and 8.1 ng x m(-3), and the average value was 6.1 ng x m(-3) in summer. So the pollution could be reduced by excavating in spring and summer. The concentrations of HCHs and DDTs in the residents area were negatively correlated to the height (P < 0.05, n = 33 ). The carcinogenic and non-carcinogenic risks of adult residents through respiration to residents near the excavating area were lower than the acceptable level, while the excavating process caused carcinogenic and non-carcinogenic risks to young residents to some extent. In order to decrease the risks, measures should be taken to restrain the pollutants in the excavation area diffusing into the air. PMID- 26031100 TI - [Transformation and mobility of arsenic in the rhizosphere and non-rhizosphere soils at different growth stages of rice]. AB - Speciation and bioavailability of arsenic in the rhizosphere and non-rhizosphere soils at different growth stages (tillering stage, jointing stage, booting stage, filling stage and maturing stage) of rice (Oryza sativa L.) were studied using toxicity characteristic leaching procedure (TCLP) and arsenic speciation analysis. Pot experiments were conducted and the soil samples were taken from a certain paddy soil in Hunan Province contaminated by mining industry. The results showed that: (1) With the extension of rice growth period, pH values and TCLP extractable arsenic levels in the rhizosphere and non-rhizosphere soils increased gradually. Soil pH and TCLP extractable arsenic levels in non-rhizosphere soils were higher than those in the rhizosphere soils at the same growth stage. (2) At the different growth stages of rice, contents of exchangeable arsenic (AE-As) in rhizosphere and non-rhizosphere soils were lower than those before the rice planting, and increased gradually with the extension of the rice growing period. Contents of Al-bound arsenic (Al-As), Fe-bound arsenic (Fe-As) and Ca-bound arsenic (Ca-As) increased gradually after rice planting, but not significantly. Residual arsenic (O-As) and total arsenic (T-As) decreased gradually after rice planting, by 37.30% and 14.69% in the rhizosphere soils and by 31.38% and 8.67% in the non-rhizosphere soils, respectively. (3) At the different growth stages of rice, contents of various forms of arsenic in the soils were in the following order: residual arsenic (O-As) > Fe-bound arsenic ( Fe-As) > Al-bound arsenic (Al As) > Ca-bound arsenic (Ca-As) > exchangeable arsenic (AE-As). In the pH range of 5.0- 5.8, significant positive linear correlations were found between most forms of arsenic or TCLP extractable arsenic levels and pH values, while the Ca-bound arsenic was poorly correlated with pH values in the rhizosphere soils. PMID- 26031101 TI - [Extraction of plant root apoplast solution: a case study with polycyclic aromatic hydrocarbons]. AB - It is of great importance to investigate the extraction of polycyclic aromatic hydrocarbons (PAHs) in plant root apoplast solution for elucidating the mechanisms underlying root absorption and translocation of PAHs and their control. However, little information is available on the extraction of plant root apoplast solution to date. In this study, wheat was employed and phenanthrene was used as the representative of PAHs. Phenanthrene extracted from wheat root apoplast solution increased with increasing vaccum degree, vacuum time, centrifugal speed and centrifugal time. Glucose- 6-phosphate dehydrogenase (G6PGH) activity in wheat root apoplast solution was enhanced with increasing vacuum degree, vacuum time, centrifugal speed and centrifugal time. For the vacuum infiltration centrifugation extraction, the optimal vacuum degree was 70 kPa, the optimal vacuum time was 10 min, the optimal centrifugal speed was 3 068 r x min(-1), and the optimal centrifugal time was 15 min. Our results provide a more convenient and effective method for investigation on pollutant transport in plant root apoplast. PMID- 26031102 TI - [Mechanism of manganese binding to leaf cell wall of Phytolacca americana L]. AB - Phytolacca americana L. (P. americana) is a manganese (Mn) hyperaccumulator and cell wall plays an important role in the accumulation and detoxicity of Mn. We studied the impact of pH and Mn initial concentration on the binding of Mn by the leaf cell wall of P. americana, and explored the binding mechanisms by Fourier Transform Infrared Spectroscopy (FTIR) and synchrotron-based X-ray Absorption Fine Structure (XAFS) Spectroscopy. The results show that the optimum pH of Mn bingding for the leaf cell wall is between 5 and 6. The adsorption behavior of leaf cell wall can be described by Langmuir equation (R2 = 0.978 5) and the maximum adsorption of Mn on the leaf cell wall is 62.50 MUmol x g(-1). Hydronyl and carbonyl groups are involved in the binding of Mn on the leaf cell wall. The Mn absorbed on the leaf cell wall is bonded by 6.3 oxygen around, and the bond length of Mn-O is 0.216 nm, which indicates the binding mechasnism of Mn to cell wall was inner-sphere complexation. PMID- 26031103 TI - [Degradation characteristics of naphthalene with a Pseudomonas aeruginosa strain isolated from soil contaminated by diesel]. AB - Abstract: A naphthalene-degrading bacterium (referred as HD-5) was isolated from the diesel-contaminated soil and was assigned to Pseudomonas aeruginosa according to 16S rDNA sequences analysis. Gene nah, which encodes naphthalene dioxygenase, was identified from strain HD-5 by PCR amplification. Different bioremediation approaches, including nature attenuation, bioaugmentation with strain Pseudomonas aeruginosa, biostimulation, and an integrated degradation by bioaugmentation and biostimulation, were evaluated for their effectiveness in the remediating soil containing 5% naphthalene. The degradation rates of naphthalene in the soil were compared among the different bioremediation approaches, the FDA and dehydrogenase activity in bioremediation process were measured, and the gene copy number of 16S rRNA and nah in soil were dynamically monitored using real-time PCR. It was shown that the naphthalene removal rate reached 71.94%, 62.22% and 83.14% in approaches of bioaugmentation (B), biostimulation(S) and integrated degradation composed of bioaugmentation and biostimulation (BS), respectively. The highest removal rate of naphthalene was achieved by using BS protocol, which also gives the highest FDA and dehydrogenase activity. The gene copy number of 16S rRNA and nah in soil increased by about 2.67 x 10(11) g(-1) and 8.67 x 10(8) g(-1) after 31 days treatment using BS protocol. Above-mentioned results also demonstrated that the screened bacterium, Pseudomonas aeruginosa, could grow well in naphthalene contaminated soil and effectively degrade naphthalene, which is of fundamental importance for bioremediation of naphthalene-contaminated soil. PMID- 26031104 TI - [Toxic effects of CdSe/ZnS QDs to zebrafish embryos]. AB - The toxic effects of CdSe/ZnS QDs on zebrafish (Danio rerio) embryos at different developmental stages were investigated in this study. The voluntary movement frequency, body length, hatching rate, mortality and malformation rate, SOD activities, MDA contents, mRNA expression of metallothionein (MT) and heat stress protein 70 (Hsp70) were used as indicators. The results showed that the EC50 was 316.994 nmol x L(-1) for zebrafish embryos (72 hpf) when exposed to CdSe/ZnS QDs. After the CdSe/ZnS QDs exposure, the embryos showed a significant increase in mortality and malformation rate, a decrease in hatching rate and body length, an advance in hatching time, and a changing in the spontaneous movement frequency, and many other toxic effects, such as the condensation of embryonic eggs, the formation of pericardial cysts and curvature of the spine. Moreover, it was found that the MDA contents in the embryos in CdSe/ZnS QDs groups were significantly increased, and the SOD activities were changed. In addition, the mRNA expression level of MT and Hsp70 were up-regulated. All the information suggests that exposure of CdSe/ZnS QDs can cause toxic effects on zebrafish embryos, and the effects may be related to the releasing of Cd2+, particle size and oxidative stress. PMID- 26031105 TI - [Physiological response of Neocaridina denticulate to the toxicity of Cu2+ and chlorpyrifos]. AB - In order to study the physiological response to heavy metals and organic phosphorus pesticide toxicity of aquatic organisms, Neocaridina denticulate was used as a test organism to investigate the impact of physiological indices of N. denticulate muscle tissues when they were exposed to Cu2+ and chlorpyrifos for 5 days respectively with the test methods of semi-static toxicity. The results showed that: when exposed to different concentrations of Cu2+ and chlorpyrifos solutions, the protein concentrations in muscle tissues were significantly lower with the extension of time to varying degrees. In the lower concentration groups of Cu2+ (0.086 mg x L(-1) and 0.172 mg-L-') and the higher concentration groups of chlorpyrifos (0. 006 0 [g-L-' and 0.012 0 MUg x L(-1)), the total SOD activity showed inhibitory effect; the trend of the higher concentration group of Cu2+ (0.344 mg x L(-1) and 0.688 mg x L(-1)) showed " inhibition-promotion inhibition", however, the lower concentration groups of chlorpyrifos (0.001 5 MUg x L(-1) and 0.003 0 MUg x L(-1)) showed the" inhibition-promotion" changes in trends; MDA contents changed similarly, and within a certain range of concentrations, MDA contents presented a gradually rising trend with increasing Cu2+ and chlorpyrifos concentration, which indicated that Cu2+ and chlorpyrifos accelerated lipid, peroxidation in muscle tissues of N. denticulate. In addition, AChE activity in Cu2+ and chlorpyrifos solutions showed inhibitory effect, and in the solutions with higher concentration of Cu2+ and chlorpyrifos, the activity was gradually decreased with the increase of concentration, indicating that Cu2+ and chlorpyrifoscs impacted the normal physiological functions of N. denticulate, and the higher the concentration, the greater the damage effect. Based on the analysis results, we confirmed that the total SOD, MDA and AChE played significant roles as physiological indicators in evaluating toxic effect of heavy metals and organic-phosphorus pesticide on N. denticulate. PMID- 26031106 TI - [Determination of anilines in environmental water samples by simultaneous derivatization and ultrasound assisted emulsification microextraction combined with gas chromatography-flame ionization detectors]. AB - This research demonstrated a new method, simultaneous derivatization and ultrasound assisted emulsification microextraction combined with gas chromatography-flame ionization detector (SD-USAEME-GC-FID), for the determination of anilines in environmental water samples. In this study, several factors, such as the volume of butylchloroformate (as derivatization agent/ extraction solvent), ultrasonication time, solution pH, salt addition, and centrifuging time and speed, were optimized in order to obtain good method performance. As a result, under the optimal conditions, the method showed good linearity in the concentration range of 6-60 000 MUg x L(-1) with correlation coefficients (R2) ranging from 0.999 7 to 0.999 9 for the five target anilines. The limit of detection ( LOD) , based on signal to noise ratio of 3 , ranged from 1.1-4.1 MUg x L(-1). The relative standard deviations (RSD) varied from 2.4% to 5.7% (n = 6) and the enrichment factors (EF) ranged from 317 to 846. The proposed method was also successfully applied to analyze seven environmental water samples, with the relative recoveries (RR) ranging from 86.8% to 105.5%. In a conclusion, this method was convenient, highly sensitive, inexpensive and environment-friendly, and therefore, the present method can be used as a preferred method for the determination of anilines in environmental water samples. PMID- 26031107 TI - [Adsorption of calcium ion from aqueous solution using Na(+)-conditioned clinoptilolite for hot-water softening]. AB - This work investigated adsorptive removal of calcium ion (Ca2+) by virtue of Na(+) -conditioned clinoptilolite simulating the process of softening for industrial hot-water system. Influential factors such as the activation/regeneration of sorbent and solution pH were tested. The kinetics/thermodynamics for adsorption of Ca2+ were analyzed and discussed. Results showed that: (1) The adsorption rate was in good agreement with the pseudo-second order kinetic models, and the process of adsorption better followed the Langmuir model; (2) Higher solution temperature allowed an enhanced efficiency on Ca2+ removal, albeit the maximum adsorption capacity of Na(+) conditioned clinoptilolite was hardly affected; (3) The process of adsorption was dominated by chemisorption, and also characterized by entropy increase with spontaneous/endothermic nature; (4) Solution temperature was suggested to be controlled within the range of 6 to 10, and more than 9 times of sorbent regeneration could be ensured for an effective adsorption towards Ca2+ with initial concentration less than 20 mg x L(-1). It was demonstrated that the activated clinoptilolite should be a promising alternative adsorbent for industrial hot-water softening. PMID- 26031108 TI - [Construction and application of economy-pollution-environment three-dimensional evaluation model for district]. AB - For deep analysis on the regional environmental economic system, the paper analyzes the mutual relation of regional economy development, environmental quality, environmental pollution, and builds the theoretical basis. Then, the economy-pollution-environment quality three-dimensional coupling evaluation model for district is constructed. It includes economic development level index, environmental pollution index, and environmental quality index. The model is a cube, which has spatialization and visualization characteristics. The model includes 8 sub cubes, which expresses 8 types of state, e. g. low pollution inferior quality-low level of economic development etc. The model can be used to evaluate the status of region, divide development phase, analyze evolution trend etc. It has two ways including relative meaning evaluation (RME) and absolute meaning evaluation (AME). Based on the model, Yinchuan City in the Ningxia Hui Autonomous Region is used as an example for the empirical study. Using RME, compared with Guangzhou city, The result shows that the Yinchuan City has been a high pollution-low quality-low level of economic development state for a long period during 1996-2010. After 2007, the state changed to a high pollution-high quality-low level of economic development. Now, the environmental quality of Yinchuan city gets better, but pollutant discharge pressure is high, and tends to be the break point of high environment quality and low environment. With AME, using national standard, the Yinchuan City remains a high pollution-low quality low level of economic development state during 1996-2010. Empirical research verifies that different target reference areas and relevant national standards have different main parameters, the evaluating result has an flexible range. The dimensionless data enhances the coupling of index. The data position in model increases the visibility to the environmental management decisions. The model improves mismatches of calculated data size, time asymmetry of spatial data, verification of the former multi-target coupling model. PMID- 26031109 TI - Focus on patient safety all day, every day. AB - Case managers may think their job doesn't involve patient safety, but they promote safety by ensuring a safe discharge and are in a position to see safety breaches and mistakes all over the hospital. CMS includes discharge planning in its worksheets for surveyors to use to assess a hospital's compliance with Medicare Conditions of Participation. Because they work with patients from admission to discharge, case managers know which clinicians are competent, those who are not, and may observe safety breaches like failure to wash hands and leaving the catheter in too long. Case managers should spend enough time with their patients to know their situations at home and their support systems and use the information to create workable and safe discharge plans. Hospitals should create an environment and a culture where case managers and other clinicians feel comfortable speaking up when they see safety breaches. PMID- 26031110 TI - Part of patient advocacy is reporting errors. PMID- 26031111 TI - Safety First initiative helps hospital cut safety events by 50%. AB - Virginia Commonwealth University Medical Center's Safety First Every Day initiative has resulted in a 50% reduction in serious safety events, declines in falls with injuries and infections in intensive care units, and an increase is safety occurrence reporting. All employees go through a four-hour safety training program that focuses on creating safety awarenees all day, every day. Employees who report safety breaches and work to correct them receive a gold pin awarded by the hospital's chief executive officer, who presents the pin at the employee's work site. The hospital has developed an Early Warning System which combines clinical expertise and technology to identify patients whose condition is deteriorating before they become worse. PMID- 26031112 TI - Case Management insider. The top ten mistakes you may be making in your case management department!: Part 1. AB - This month we have begun reviewing the top mistakes hospitals make within their case management department's infrastructure. As discussed, the biggest mistake is to not clearly and prospectively define the roles of the RN case manager and the social worker to optimize each discipline's skill sets. Associated with this mistake is to have inadequate patient ratios assigned to each discipline. These mistakes are related and when roles are not clearly defined, it becomes almost impossible to understand or advocate for appropriate staffing ratios. If it appears that nurses and social workers can all do the same things equally well, then the organization will likely choose to go with the professional group that will cost the organization the least amount of money. In the end, this logic is penny-wise and pound foolish. We do both disciplines a disservice when we don't apply their skill sets adequately and don't have each group functioning at the "top of their license!" Next month, we will continue to discuss the top mistakes hospitals make in their acute care management departments' design. We will discuss the use of clerical support staff, assessments, and days of coverage. PMID- 26031113 TI - System alerts clinicians when patients need interventions. PMID- 26031114 TI - Clinic visits, CM interventions fill gaps in care after discharge. AB - At-risk patients who are being discharged from Torrance (CA) Memorial Medical Center are referred to the Care Coordination Clinic for follow-up care and/or receive care coordination services from an ambulatory care-manager. At the Care Coordination Clinic, a physician or nurse practitioner reviews the discharge plan, reinforces discharge education, conducts medication reconciliation, and communicates with the patient's primary care physician. Patients are usually seen at the clinic only once, then followed by an ambulatory care manager unless they are having home health services. Then the care manager picks up after the patient is discharged from home health. The Care Coordination Clinic also sees patients who have not been hospitalized, but who have been referred by the emergency department staff or community physicians because their chronic conditions are deteriorating or they need palliative care. PMID- 26031115 TI - Electronic system, anonymity improve reporting. PMID- 26031116 TI - Hospital meets Triple Aim goal, improves safety. PMID- 26031117 TI - Looking forward. History of surgical education at Cook County Hospital. PMID- 26031118 TI - Strategies for sustainability: going green in the OR. PMID- 26031119 TI - PreOp program: can we achieve a "trickle-up" effect? PMID- 26031120 TI - Surgeons develop visionary plan to bring corneal transplants to developing countries. PMID- 26031121 TI - Statement in support of motorcycle helmet laws. PMID- 26031122 TI - Statement on physician tiering and narrow network programs. PMID- 26031123 TI - One surgeon's principles. PMID- 26031124 TI - Limited resection as a cure for early lung cancer: time to challenge the gold standard? PMID- 26031126 TI - Monitoring OR fires to improve patient safety. PMID- 26031125 TI - ACS Archives houses practice records of Franklin H. Martin. PMID- 26031127 TI - NTDB(r) data points: What's cookin'? Who's lookin'? PMID- 26031128 TI - ACS NSQIP hospitals significantly improve outcomes over time. PMID- 26031129 TI - 2014 IGS reports on experience from the perspective of a woman surgeon. PMID- 26031130 TI - [Consejo Mexicano de Ortopedia y Traumatologia, A.C]. PMID- 26031131 TI - [Treatment and reconstruction of bone tumors of the with a RIMAG unconventional prosthesis]. AB - INTRODUCTION: Conservative surgery and reconstruction with an unconventional prosthesis are indicated for tumors of the humerus without neurovascular compromise, as they help preserve shoulder, elbow and hand function. The humerus is the third most frequent site of benign, aggressive, malignant and metastatic tumors that cause functional limitation or limb loss. MATERIAL: Patients with a bone tumor of the humerus without neurovascular involvement that met the inclusion criteria. Unconventional, uncemented RIMAG prosthesis with diaphyseal fit and locking bolts. METHODS: 39 patients with intraarticular type I tumors according to the Malawer and Enneking classification were treated with tumor resection and reconstruction with an unconventional prosthesis and soft tissues. RESULTS: Patients enrolled included 18 females and 21 males ages 12-72 years with tumors such as: giant cell tumors (14), osteosarcomas (7), metastasis (7), chondrosarcomas (6), Ewing's sarcomas (2), chondroblastoma (2) and aneurysmatic bone cyst (1). Twelve patients died due to systemic disease and the remaining patients survived. Surgical margins were broad, with humeral resection between 100 and 230 mm. Functional results were assessed according to the Muscoloskeletal Tumor Society score as 13 excellent, 16 good, 5 failures and 5 poor. DISCUSSION: The resection level does not restrict the placement of this prosthesis, which permits future revisions. An appropriate result depends on the resection size and the preserved shoulder musculature and it is not limited by the size of resection, thus improving patients' disability. PMID- 26031132 TI - [Intradiscal temperature variation resulting from radiofrequency thermal therapy. Cadaver study]. AB - INTRODUCTION: Disc disease is one of the most common causes of lumbar pain. The new era of treatments for degenerative disc disease involves the use of minimally invasive thermal technologies allowing for collagen remodeling and destruction of nociceptors in the annulus. However, a better understanding of the treatment pathophysiology is needed. The purpose of this study was to measure intradiscal temperature variation after thermodiscoplasty. MATERIAL AND METHODS: A human cadaver spine specimen was obtained and divided into blocks, each composed of two intervertebral plates and an intact disc. Radio frequency was applied at five spots with three different time intervals. Temperature was measured in each of the combinations. Units were weighed before and after treatment. Finally, the disc was exposed and the tightening achieved with each radio frequency application was measured. Data were analyzed with the SPSS software. RESULTS: The mean weight reduction obtained was 1.4 g on average (SD 0.599), with values between 0.5 and 2.6 grams. Mean temperature in the posterior rim of the annulus was 37.6 degrees C and mean temperature variation was 3.0 degrees C (SD 6.407). Mean tightening achieved in all blocks overall was 1.4 mm. DISCUSSION: The results obtained show the effectiveness of radio frequency thermodiscoplasty when performed within the safety parameters. Temperature values with radio frequency were lower than those found in comparable studies. The weight and the tightening show the effect of disc shrinking and dehydration. This report is an effective tool to define time parameters for the application of this technology. PMID- 26031133 TI - [Achilles tendon plasty in inveterate lesions. Perez Teuffer modified technique]. AB - The purpose of this paper is to convey our experience with the technique used to treat chronic Achilles tendon lesions at ISSSTE "1 de Octubre" Regional Hospital. A prospective study with descriptive longitudinal follow-up was conducted in 30 patients with Achilles tendon rupture that occurred more than 10 days earlier. They were treated with the modified Perez-Teuffer technique at the Orthopedics and Trauma Service from March 2004 to March 2008. Plasty with transposition of the lateral peroneus brevis to the tendon stump was performed. The right side was affected in 70% of patients, mean age was 31.1 years, and males were predominant and accounted for 90%. Time elapsed since the lesion was 10-62 days with a mean of 26 days. We obtained excellent results in 90%, and good results in 10% of patients. One case had skin necrosis and limited mobility and two had pain. They were not considered as poor results as this did not interfere with the final functional results. PMID- 26031134 TI - [Opening of the first web space in patients with multiple congenital arthrogryposis and adducted thumb with a dorsoradial index finger flap]. AB - INTRODUCTION: Arthrogryposis multiplex congenita is a progressive syndrome characterized by deformed and stiff joints, atrophy or absence of muscles, contracture and thickening of the capsular articular and periarticular tissue, and normal psychic status. MATERIAL AND METHODS: A retrospective, descriptive, evidence level HI study was conducted on the surgical management of patients with Arthrogryposis multiplex congenita and congenital adducted thumb between January 2005 and December 2010. Twenty-seven opening procedures were performed in 16 patients with a dorsoradial index finger flap technique. In 80% of patients the dominant hand was operated first; patients included nine males and seven females; the operated hands included 15 right and 12 left hands. RESULTS: Flap design permits better advancement and space deepening, and cosmetic improvement. The mean preoperative first and second intermetacarpal angle was 20.5 degrees on average, with a minimum of 14 degrees and a maximum of 27 degrees. The mean postoperative first and second intermetacarpal angle was 50 degrees, with a minimum of 36 degrees and a maximum of 65 degrees. This was observed at the clinic with active thumb extension as well as proper thumb apposition. CONCLUSIONS: Flap design permits better advancement and space deepening, with a better balance between flexors and extensors. All patients had better limb function and cosmetic improvement. PMID- 26031135 TI - [Descriptive analysis of pelvic asymmetry in an asymptomatic population]. AB - INTRODUCTION: Pelvic tilt is clinically assessed based on its relationship with spinal conditions, but there is little evidence from the asymptomatic-population for comparison purposes. OBJECTIVE: To analyze an asymptomatic population focusing,on pelvic asymmetries using photogrammetry. MATERIAL AND METHODS: 92 subjects (18-35 years old) underwent marking of the anterior and posterior iliac spines and were photographed. Alcimage software was used to measure the pelvic tilt angle. Other tests included: the Kolmogorov normality test, t test, Wilcoxon test, and Pearson coefficient to measure the correlation. RESULTS: 11.96% of males had anteversion and 34.78% normality; 38.04% of females had anteversion and 15.22% normality. Angles between iliacs for bilateral tilt showed no difference, but a difference was seen with the predominance of one side. For unilateral tilt a difference between illacs was seen. Good correlation of predominance versus anteversion was observed, and correlation was poor for side angles. The rest showed a weak or non-significant correlation. CONCLUSION: Tilt cannot be used individually to characterize pelvic dysfunction or pathology. PMID- 26031136 TI - [Functional repercussions of meniscal injuries on the postoperative physical athletic performance of athletes]. AB - The practice of sports has experienced a huge boom in societies worldwide. It often involves knee injuries, specifically meniscal tears that warrant surgical treatment which may include: fragment remodeling and resection, meniscal repair or, in extreme cases, the use of a meniscal graft. In this prospective study we performed fragment resection and meniscal remodeling in athletes and we measured their postoperative physical-athletic performance. METHODS: Inclusion criteria: Patients of both sexes who practice a sport either as amateurs or at a recreational competitive level, who sustained a meniscal injury. Exclusion criteria: Patients with associated total anterior cruciate ligament tear, patients lost to follow-up, and patients eligible for meniscal repair. 23-patient cohort including 10 females and 13 males who presented at our hospital. A diagnostic protocol to certify the injury was applied. Patients underwent surgery to perform meniscal fragment resection and remodeling. They later underwent rehabilitation at the physiatrics service and finally received approval to return to sports. The Tegner Lysholm Knee Scoring Scale was used to assess postoperative results. CONCLUSION: All patients were able to return to practice their pre injury sport, but their performance was 20 to 30% lower than before. Recovery took longer in females. PMID- 26031137 TI - [Results of surgical management in proximal partial tibia fractures]. AB - INTRODUCTION: Proximal partial articular tibia fractures represent a great challenge for orthopedic surgeons due to their symptoms and complex management. OBJECTIVE: To describe the results of surgical treatment of proximal articular fractures of the tibia. MATERIAL AND METHODS: Descriptive study conducted at a tertiary care hospital. We included patients with proximal partial articular tibia fracture (Mueller AO/ASIF 41-B), of both sexes, with a six-month postoperative follow-up and a complete clinical record. Postoperative assessment was conducted with the Orfaly & Keating scale. We used descriptive statistics with central trend and scatter measurements, Fischer test for the relative risk and logistic regression. RESULTS: The total number of patients was 25. Mean age was 41.6 (16-81), SD was 17.03 years; 15 patients were males (60%) and 10 females (40%); 1 (4%) had type-2 diabetes mellitus; the left side was affected in 17 (68%) patients; all patients underwent surgery with osteosynthesis; there was 100% match between the preoperative and postoperative diagnoses (Kappa 1.0); patient course was appropriate in 76% and acceptable in 24% (Orfaly & Keating); 16% had angular valgus deformity and 12% had joint stiffness. Females with RR 1.33 (CI 0.869-2.045) had angular valgus deformity; those with RR 0.22 (CI 0.27 1.846) had joint stiffness, RR was 2.68 for hockey stick plate osteosynthesis, and RR was 1.088 (CI 95%, 0.7-3.1) for the unsatisfactory course according to the Orfaly & Keating scale. CONCLUSION: A positive relative risk was found among females for angular valgus deformity, and in hockey stick plate osteosynthesis and minimal osteosynthesis for an unsatisfactory course, according to the Orfaly & Keating scale, six months after surgical treatment. PMID- 26031138 TI - [Gas embolism after the use of the CarboJet lavage system during hip hemiarthroplasty. Clinical case and literature review]. AB - Case report of an 89-year-old patient who had cardiorespiratory arrest during cemented hip hemiarthroplasty and required cardiopulmonary resuscitation. This complication occurred immediately after using the carbon dioxide-based lavage system known as CarboJet and was attributed to gas embolism once other entities were ruled out. The possible factors that may contribute to this surgical complication are discussed. PMID- 26031139 TI - [Forestier syndrome: case report and literature review]. AB - INTRODUCTION: Forestier syndrome, also known as diffuse idiopathic skeletal hyperostosis, is a disease of unknown etiology, characterized by an increase in the bone mass in different parts of the body, which results in chronic cervical and back pain. METHODS: We report the case of a male 40-year-old patient with a diagnosis of Forestier syndrome in 2006 based on imaging studies. The clinical picture began with lumbar pain of progressive intensity irradiating to the right pelvic limb and associated with morning spine stiffness. Lumbar spine surgery was performed in June 2005 (laminotomy and L4-L5 diskectomy, interbody spaces filled with bone, and a dynamic interspinous spacer in L4-L5), but there was little postoperative improvement. We instituted antiinflammatory medical treatment as described in the literature and the patient did fine. DISCUSSION: This condition is reported as an infrequent entity leading to physicians not considering it within their initial differential diagnoses. It presents with dysphagia as the main symptom, together with neck or lumbar pain due to ligament hypertrophy and ossification, and increased bone mass leading to the formation of bone bridges. Lumbar or cervical pain is a frequent cause for visiting the neurosurgeon. CONCLUSIONS: The purpose of this paper is to present an unusual case of lumbar pain, which increases the diagnostic sensitivity of this disease, and may contribute to avoid unnecessary surgery. This was complemented with literature review. PMID- 26031140 TI - [Multiple fracture of the upper limb. Case report]. AB - Multifocal fractures of the upper limb are infrequent. We report a case of ipsilateral proximal humerus fracture, proximal and distal forearm fractures, and their surgical management. PMID- 26031141 TI - [Anterior cruciate ligament lesions]. AB - A bibliographic review was conducted on the current status of ACL ligamentoplasties including their anatomical and functional bases and surgical treatment. PMID- 26031142 TI - [The medical creed]. AB - In this review article the author discusses peculiarities of medical practice, requirements to medical profession, medicine as a vocation, and the role of these factors in the choice of health profession. Special attention is given to diagnostics and classifcation of internal diseases, problems of medical practice and science, significance of practical experience, medical intuition and judgment for diagnostics of pathological conditions. The role of medical deontology and ethics as a doctrine of commitment to speciality medicine is emphasized. The comprehensive examination of therapeutic problems include prescription of medication on an individual basis, the danger of polypragmasia and passivity in therapy. The critical attitude toward fashionable trends in medicine and the ability to think informally are encouraged. The article is concluded with the discussion of the relationship between medical science and practice. PMID- 26031143 TI - [Subclinical hypothyroidism as a cause of dyslipidemia]. AB - Subclinical hypothyroidism (SHT) is a clinical-laboratory syndrome characterized by an elevated thyrotropin level and normal levels of T3 and T4. Lipid metabolism disorders in patients with SHT and the influence of substitution therapy with L thyroxin on the lipid profile are considered in many publications, but the results of these studies are contradictory. This paper was aimed to discuss the relevant literature and search for the most effective treatment strategy. PMID- 26031145 TI - [The therapeutic potential of inhalation glucocorticoids in patients with bronchial asthma]. AB - The author considers the mechanism of action, peculiarities of clinical pharmacology, efficacy of inhalation glucocorticoids and their use for the treatment of patients with bronchial asthma with reference to their safety, possible side effects, and their prevention. PMID- 26031144 TI - [Polyneuropathy of thin fibers]. AB - Polyneuropathy of thin fibers (PTF) is a disorder with selective damage of Adelta and C-fibers. Having a skin biopsy the SFN became visible. In the article there are data on the pathogenesis, clinics and diagnostics of the PTF. The skin biopsy, the quantitative sensory testing, the corneal confocal microscopy, nociceptive evoked potentials, the microneurography and the autonomic testing are described in detail. New diagnostic criteria ofthe PTF are given. Main directions in the management of the PTF are the treatment of systemic diseases and the neuropathic pain relief. PMID- 26031146 TI - [Do we need new approaches to evaluate obesity?]. AB - The data on the influence of BMI on life expectancy are still contradictory despite the proved relationship between obesity and a number of chronic diseases. Many publications are devoted to an obesity paradox, i.e. improved survival of patients with elevated BMI and mild obesity compared with that of the patients having normal or reduced BMI. In 2013, the American Association of Endocrinologists proposed a new paradigm of assessment of BMI and obesity. A consensus of Russian specialists is needed as regards the desirability of acception and application of the proposed approaches in clinical practice. PMID- 26031147 TI - [Metabolic disorder and polymorphism of the genes encoding for beta-2-adrenergic receptor and apolipoproteins B in chronic hepatitis C and non-alcoholic fatty liver diseases]. AB - The aim of the study was to evaluate the relationship between metabolic disorders and polymorphic variants of the genes encoding for beta-2-adrenergic receptor (ADRB2 (rs1042713) and apolipoproteins B (ApoB(rs5742904) in patients with chronic hepatitis C (CHC) depending on virus genotype and in patients with non alcoholic fatty liver diseases (NAFLD) and concomitant metabolic syndrome (MS). MATERIALS AND METHODS: The study included 96 patients with CHC (51 with genotype 1 or 2 of hepatitis virus and 45 with genotype 3), 70 patients with NAFLD and MS, 51 healthy donors (controls). Gene polymorphism was studied by PCR (Sintol, Moscow) with a Real-time CFX-96 amplifier (Bio-Rad Lab. Inc., USA). RESULTS: CHC patients regardless of genotype had hypertriglyceridemia with increased atherogenicity index and C-peptide level. Hyperleptinemia was most frequently associated with genotype 3, hyperinsulinemia and insulin resistance with genotypes 1 and 2. The viremia level positively correlated with leptin level (p 0.021) and HOMA-IR index (p=0.022) which suggests virus-induced inactivation of mechanisms of steatogenesis and insulin resistance. Leptin production in CHC was associate with activation of liver fibrosis as appears from elasticity index measured by fibroelastography (p-0.22). Almost all patients with NAFLD had disturbances of lipid and carbohydrate metabolism. Hepatic lesions in 30% of the patients with MS were accompanied by laboratory signs of steatohepatitis. Patients with CHC showed an increased frequency of minor A allele of the ADRB2 (rs1042713) gene (up to 40%; p=0.04) and pathological A/A homozygote (22%; p=0.04). The occurrence of A allele was associated with hyperleptinemia (p=0.019). In NAFLD patients, the occurrence of A allele was higher than in controls (41%; p=0.02) with 55% of the case being A/G heterozygotes (p=0.005). The occurrence of A allele was related to hyperinsilinism (p=0.036), BMI (p=0.0330, and C-peptide production (p=0.038). No difference between the frequency of genotypes and ApoB(rs5742904) gene alleles in the patients of both groups and controls was documented. It is concluded that ADRB2 (rs1042713) gene polymorphism is associated with an increased risk of metabolic disorders in CHC and especially NAFLD with MS that aggravates liver disturbances. Dyslipidemia and insulin resistance in CHC patients is stimulated by viral infection. PMID- 26031148 TI - [The use of methotrexate for the treatment of sarcoidosis (data from a controlled prospective study)]. AB - We estimated the effectiveness and safety of methotrexate monotherapy of sarcoidosis in 63 patients refractory to the previous treatment. Methotrexate was given weekly at a dose of 5-20 mg. 54% of the patients reported improvement of their condition. Parameters of spirogram and the ray picture improved in 63.2 and 54% of the cases respectively. Methotrexate proved safe and had to be discontinued only in 12.6% of the patients. It is concluded that methotrexate can be used at least in half of the cases as a safe alternative to systemic steroid therapy. PMID- 26031149 TI - [Detection of cytochrome P4502C19 gene polymorphism to optimize therapy of acid dependent diseases]. AB - Therapeutic efficacy of proton pump inhibitors (PPI) used in therapy of acid dependent diseases largely depends on cytochrome CYP2C9 activity. The rate of washout of medications metabolized by this enzyme varies 5-20-fold in different patients and ethnic groups, in the first place due to genetic polymorphism. The natural metabolic status of CYP2C19 can be evaluated by genotyping and non invasive 13C-pantoprazole breath test. The aim of the study was to assess the frequency of fast, intermediate, and slow types of metabolism in Crimeans suffering gastroesophageal reflux disease by the latter method. MATERIAL AND METHODS: The study included 32 patients (21 women, 11 men) aged 18-60 (mean 42.25+/-3.02) years. They underwent the 13C-pantoprazole breath test prior to the onset of therapy. RESULTS: The patients were divided into 3 groups based on the results of the test. 12 (37.5%) of them had fast-type metabolism (mean delta over base (DOB) 4.725%+-0.3), 14 (43.75%) had intermediate metabolism (mean DOB 2.44+/ 0.162%) and 6 (18,75%) had slow metabolism (mean DOB 0.85+/-0.22%). The study showed the prevalence of fast and intermediate type metabolism in the inhabitants of Crimea which suggests the necessity of correction of standard PPI doses. PMID- 26031150 TI - [Clinical parameters and the level of certain cytokines in blood and cerebrospinal fluid of patients with Parkinson's disease]. AB - In the past decade, much attention has been given to immunological mechanisms of development of Parkinson's disease with special reference to the role of pro- and anti-inflammatory cytokines. The study was aimed at elucidating the cytokine status of PD patients taking account of the stage, duration, and clinical manifestations of the disease. It was shown that PD patients regardless of severity of the disease had elevated serum and liquor IL-1beta and IL-6 levels compared with controls while the I-IRA level was decreased. Patients with predominantly left-side localization of PD had an elevated blood TNFalpha level. It was shown for the first time that the cytokine profile in PD patients varies with progression of disease. The high rate of progression was associated with the high liquor TNFalpha level and blood IL-1beta level compared to the patients with moderate and slow progression. The blood IL-10 level was found to be related to the degree of anxiety and depression whereas the TNFalpha level correlated with the severity of cognitive deficit. PMID- 26031151 TI - [The influence of psychological factors on the integral health characteristic (data from a prospective population study)]. AB - AIM: To develop integral assessment of the health status based on the examination of representative samples from different regions of Russia (Veliky Novgorod, Nizhni-Novgorod, Vologda, Omsk and Nalchik) with the use of special questionnaires and simple anthropometric and functional methods in the framework of a prospective 3-year population study of organized groups. METHODS: The above questionnaires allowed to elucidate the socio-economic status of the patients, their somatic and psychological conditions (lifestyle index or psychological protection mechanisms (PPM), social adaptation, sanogenic reflexia; also used were Eysenck's psychotism scale, hospital anxiety and depression scale, the perceived stress scale (PSS), and moral potential of personality development scale. RESULTS: It was shown that the profile of psychological protection mechanisms is dominated by primitive reactions, such as projection, protection, and negation. Most subjects from the sample formed the pathogenic type of reflexia (inability to resolve a problem situation based on the cognitive components of the patient's mental state). Mathematical treatment of the so called "simple cross-tabulation" with unification of all negative PPM revealed the highly significant relationship of LSI (not norm) with most previous somatic diseases (p<0.001), i.e. the history of myocardial infarction, angina of effort, cardiovascular syndromes, diabetes, hypertension, chronic broncho-pulmonary, hepatic, gastrointestinal, urogynecological, oncological, and psychic diseases. (p<0.007). CONCLUSION: Pyschological changes have greater influence than somatic ones on physiological parameters determining the population health status which suggests the necessity of taking them into account when planning health promotion measures. PMID- 26031152 TI - [Association between depression and metabolic syndrome--a two-way street]. AB - The study with the use of the CES-D scale revealed the combination of depression and metabolic syndrome in 24% of the examined patients. The HADS scale showed depression in 16% of the interviewed patients. Based on the two scales, depression was documented in 32% of the patients. The chance of development of metabolic disorders in case of depression was estimated as 2.4 (95%); CI--1.3 4.6. Urinary 6-COMT level at 4.00 correlated with its total nocturnal and daytime concentrations and with sleep disorders (r = -0.41; r = -0.48; r = -0.43 respectively). Daytime sleepiness correlated with the daytime 6-COMT level (r = 0.32). The score values by the CES-D scale correlated with daytime 6-COMT level (r = -0.23). Multiple regression analysis showed that reduced melatonin level deteriorates quality of nocturnal sleep and increases the risk of depression (R = 0.4. coefficient beta = -0.413 (p<0.04) and F = 4.5). PMID- 26031153 TI - [The aggregation capacity of neutrophils in patients with arterial hypertension and dyslipidemia treated with fluvastatin]. AB - AIM: To elucidate the aggregation capacity of neutrophils in patients with arterial hypertension and dyslipidemia treated with fluvastatin. MATERIALS AND METHODS: 32 middle-aged patients with grade 1-2 AH and dyslipidemia (risk 3). Control group included 26 age-matched healthy subjects. We estimated lipid composition, antioxidant protection, lipid peroxidation in plasma and neutrophils and their aggregation. All patients were given 40 mg fluvastatin at bedtime. Clinical and laboratory characteristics were evaluated before and 4, 16, 52 weeks after treatment. The results were treated by the Student's t-test. RESULTS: The patients showed enhanced neutrophil aggregation due to lipid imbalance in cell membranes, intense lipid peroxidation, and marked changes in carbohydrate composition of membrane glycoprotein receptors. Fluvastatin significantly improved lipid composition and peroxidation in plasma and neutrophils and caused positive dynamics in their aggregation due to optimization of glycoprotein receptors. PMID- 26031154 TI - [Gender-specific features of chronic heart failure]. AB - AIM: To estimate the prevalence of chronic heart failure (CHF) in Azerbajan and analyse its gender-specific features in hospital patients based on retrospective observations. MATERIALS AND METHODS: Retrospective analysis included 3614 case histories of the patients admitted to D.M.Abdullaev Research Institute of Cardiology. RESULTS: Overall prevalence of CHF was estimated at 51.4%, lethality at 6%. The main causative factors of CHF were coronary heart disease and arterial hypertension. Marked differences in CHF etiology between men and women of different age were revealed. The prevalence of CHF in men was 56.8% or 1.3 times that in women. 41% of the patients with CHF were above 60 years of age. CHF with left ventricular ejection fraction of less than 45% and with the preserved one was found in 84% and 16% of the patients respectively. The number of women with this variant of CHF amounted to 22% and was 2 times that of men. PMID- 26031155 TI - [A rare variant of enterocele entrapment in the abdominal cavity of a woman]. AB - Abdominal enterocele is a result of entering abdominal organs into peritoneal pockets and folds through the holes in mesenterium or into the adjoining cavities through defects in their walls. Enteroceles are localized at the sites where one segment of the gastrointestinal tract passes into another, in a pocket behind the cecum and sigmoid, between mesenteric layers of small intestine and colon, in the holes of mesenterium of vermiform appendage, gastrocolic and falciform ligaments, pockets and holes of broad ligament of the uterine, omental foramen, rectouterine excavation, and diaphragmal defects. We observed a 26 year old woman with enterocele entrapment in the abdominal cavity complicated by necrosis of part of the small intestine. PMID- 26031156 TI - [Traumatic myocardial infarction]. AB - The paper reports development of acute myocardial infarction as a result of blunt chest injury in a woman having no signs of atherosclerosis. Coronary bleeding was caused by dissection of intima of the interior interventricular artery. Transdermal coronary intervention included balloon angioplasty and stenting of the anterior interventricular artery. PMID- 26031157 TI - [Obesity as pathology of adipocytes: number of cells, volume of arterial bloodstream,local pools of circulation in vivo, natriuretic peptides and arterial hypertension]. AB - The non-specific systemic biological reaction of arterial pressure from the level of organism. vasomotor center and proximal section of arterial bloodstream is appealed to compensate disorders of metabolism and microcirculation in distal section of arteries. This phenomenon occurs in several cases. The primarily local disorders of metabolism at autocrine level, physiological (aphysiological) death of cells, "littering" of intercellular medium become the cause of disorder of microcirculation in paracrin cenosises and deteriorate realization of biological functions of homeostasis, trophology, endoecology and adaptation. The local compensation of affected perfusion in paracrin cenosises at the expense of function of peripheral peristaltic pumps, redistribution of local bloodflow in biological reaction of endothelium-depended vaso-dilation has no possibility to eliminate disorders in realization of biological functions. The systemic increase of arterial pressure under absence of specific symptoms of symptomatic arterial hypertension is a test to detect disorder of biological functions of homeostasis, trophology, biological function of endoecology and adaptation. Allforms of arterial hypertension develop by common algorithm independently from causes of disorders of blood flow, microcirculation in distal section of arteries. The non specific systemic compensation ofdisorders of metabolism from level of organism, in proximal section of arterial bloodstream always is the same one and results in aphysiological alterations in organs-targets. To comprehend etiological characteristics of common pathogenesis of arterial hypertension is possible in case of application of such technically complicated and still unclear in differential diagnostic of deranged functions modes of metabolomics. PMID- 26031158 TI - [The proteomic profiling of blood serum of children with gastroesophageal reflux disease]. AB - The mass-spectra of proteome of blood serum from healthy children and children with gastroesophageal reflux disease were received. The technology platform including direct proteome mass-spectrometer profiling after pre-fractional rectification using magnetic particles MB WCX was applied. The significant differences in mass-spectra were established manifesting in detection of more mass-spectrometer peaks and higher indicators of their intensity and area in group of healthy children. The study detected 39 particular peptides and low molecular proteins predominantly intrinsic to healthy or ill children. It was established that two peptides with molecular mass 925 and 909 Da. are registered only in healthy patients and have no traces in group ofpatients with gastroesophageal reflux disease. The peptide 1564 Da is detected only in blood of children with gastroesophageal reflux disease and totally is absent in healthy children. The research data permitted to reveal specific patterns (signatures) of low-molecular proteins and peptides specific for blood serum of healthy children and patients with gastroesophageal reflux disease. The results testify the availability of singularities in metabolism of low-molecular proteins and can be used as a basis for development of minimally invasive mass-spectrometer system for its diagnostic. PMID- 26031159 TI - [The noninvasive evaluation of degree of expression of fibrosis of liver and significance of polymorphism of gene of hyaluronic acid under chronic hepatitis C]. AB - The study was carries out to evaluate degree of expression of fibrosis, reparation processes in liver and value of polymorphism of gene of hyaluronic acid HASI (rs11084111) in progression of affection of liver in patients with chronic hepatitis C. The sampling included 100 patients with chronic hepatitis C. The control group included 83 healthy donors. The blood serum was tested to detect concentration of hyaluronic acid and alpha-fetoprotein. The stage of liver fibrosis (F) was evaluated by using ultrasound fibroflexography The polymorphism of gene (rs11084111) was analysed by polymerase chain reaction technique. In the group of patients with F1 the average concentration of hyaluronic acid in blood serum in 1.8 times surpassed this indicator in group with F0. The concentration of hyaluronic acid was almost 2 times higher under F3 as compared with F1-F2. This indicator permitted differentiating F3 and F4 which followed by activation of cytolysis and cholestasis in F1 and F3 and by increasing of level of alpha fetoprotein at stages F1 and F4. The study detected no statistically significant difference between rates of genotypes and alleles of gene HASI (rs11084111) in groups of healthy patients and patients with chronic hepatitis C. The direct relationships are established between hyaluronic acid and markers of cytolysis, cholestasis, alpha-fetoprotein (p = 0.001), viral load (p = 0.003) liver elasticity index according fibroflexography data (p < 0.001) and fibrosis index (p < 0.001). The established relationships indicate association of hepatofibrosis with cytolysis, cholestasis, hepatocytes regeneration and virus activity. The hyaluronic acid permits to stratify minimal expressed fibrosis and also the transition of disease to the stage of cirrhosis. PMID- 26031160 TI - [The endogenous intoxication in pathogenesis of nephropathies]. AB - The endogenous intoxication of organism can be a primary cause of changing in content of protein molecules with enhancement of their capacity to adsorb microelements fastening conformation of proteins. Such an alteration add them antigen characteristics conditioning autoimmune damage of tissues, kidneys included. The most frequent syndromes (cases?) ofendogenous intoxication effecting kidneys pathology are presented. PMID- 26031161 TI - [The indicators of alteration of functional activity of vessel wall as new diagnostic criteria of development of initial stages of chronic lymphatic leukemia]. AB - The role of endothelium dysfunction in pathogenesis of B-cell mode of chronic lymphatic leukemia is still uncovered. However, detection of disorders of functional activity of vessel wall at early stages of development of this disease permits to widen actual diagnostic criteria of its initiation and thereafter to make more objective diagnostic itself. The study was targeted to establish the role of endothelium dysfunction in pathogenesis of initial stages (0-1 stages according classification Rai K. et al. 1975) of B-cell mode of chronic lymphatic leukemia. The article presents results of clinical laboratory examination of 30 patients with initial stages of B-cell mode of chronic lymphatic leukemia. The content of classic markers of endothelium dysfunction in blood serum were detected using one time solid-phase enzymoimmunoassay at the moment of admission to hospital before initiation of treatment. In patients with chronic lymphatic leukemia blood serum characterized by increasing of level of E-selectin. ICAM-1, endothelin-1, metabolites of nitrogen nitrite, angiotensin II. At the same time, content of protein C decreased at the stage 0-1 of mentioned pathology. Hence, it is recommended to apply determining in blood serum the content of markers of endothelium dysfunction as additional diagnostic criteria of development of paraneoplastic disorders at initial stages of chronic lymphatic leukemia. These markers include molecules of adhesion (E-selectin, ICAM-I), metabolites of nitrogen nitrite, endothelin-1, protein C. angiotensin II and homocysteine. PMID- 26031162 TI - [The automated analysis of anti-nuclear antibodies using technique of indirect reaction of immunofluorescence with application of HEP-2-cells]. AB - The identification of antinuclear antibodies in blood serum based on indirect reaction of immunofluorescence using cells of line HEp-2 (IRIF HEp-2)--a "golden standard" and key screening technique of laboratory diagnostic of autoimmune rheumatic diseases. The automated systems of interpretation of samples offluorescence promote standardization and increase effectiveness of detection of content of antinuclear antibodies with IRIF HEp-2 technique. The study was organized to comparatively analyze automated and visual interpretation of results of IRIF HEp-2 in detection of content antinuclear antibodies in patients with rheumatic diseases. The level of antinuclear antibodies in blood serums of 1178 patients with rheumatic diseases was detected using IRIF HEp-2 technique. The results of IRIF HEp-2 were evaluated by visual microscopy and using automated platform "AKLIDES". The degree of consistency of positive/negative results of detection (k = 0.5), types (k = 0.7) and titers/intensity of fluorescence (k = 0.45) of antinuclear antibodies under automated and traditional interpretation of IRIF HEp-2 was "good". The discordance of positive/negative results of analysis of content of IRIF HEp-2 was established in 18.5% of patients. The automated technique more often detected homogeneous (37.6%) and speckled (32.3%) fluorescence of nucleus. At the same time, there were no differentiation of type of fluorescence in 21.4% of patients. The visual technique detected mixed type of fluorescence in blood serums of most of the patients (72.8%). The mixed fluorescence was identified by system "AKLIDES" as homogeneous (40.5%), speckled (32.7%), nucleolar (2.4%), centromeric (0.9%), undifferentiated (23.5%). Under visual analysis of samples of fluorescence with undifferentiated type of fluorescence was identified as mixed (79.8%), homogeneous (5.9%) and speckled (14.3%). The titers of antinuclear antibodies less than 1:160 associated with intensity of fluorescence 0/B+/-; 1:160-0, B+/-, +, ++; more than 1:1280--+++, ++++. In common practice the automated system "AKLIDES" permits identifying positive/negative results of detection of content of antinuclear antibodies comparably with "classic" visual technique of interpretation of IRIF HEp-2 and prognosticate maximal finite titer of antinuclear antibodies in serums in patients with rheumatic diseases according intensity of fluorescence. To confirm results of automated evaluation of types of nuclear fluorescence and to specify titers of antinuclear antibodies it is recommended to apply additional expert visual analysis of positive samples of fluorescence. PMID- 26031163 TI - [The comparative characteristic of cytokine production in serum and whole blood in patients with chronic autoimmune nettle rash]. AB - The sampling of 100 patients with chronic autoimmune nettle rash and control group of 30 healthy donors was analyzed for identification of level of interleukin (IL)-4, IL-10, IL-17, IL-18 and gamma-interferon (IFN) in serum of patients. The same sampling was examined using method ex vivo for spontaneous and induced production by cells of immune system. In patients with chronic autoimmune nettle rash increasing of spontaneous production of IL-4 and spontaneous and induced production of IL-17 and IFN was identified. The decreasing of spontaneous and induced production of IL-18 was detected too. These occurrences indicate to simultaneous activation of Th1, Th2 and Th17-population of T-lymphocytes. The analysis of level of cytokines in blood serum established only decreasing of level of IL-4 in patients with chronic autoimmune nettle rash as compared with healthy individuals. The level of other analyzed cytokines had no reliable differences that demonstrate both low informativeness of detection ofcontent of cytokines in blood serum and advantage of application of method ex vivo with detection of level of cytokines in whole blood. PMID- 26031164 TI - [The comparative study of specificity of test-systems in diagnostic of HIV infection on categories of samples of blood serum of pregnant women]. AB - The detection of false positive serological reactions (FPSR) on HIV-infection under screening examination of pregnant women is an actual problem of practical health care. The original observations testify that under analysis of the same samples of blood serum of pregnant women using screening immune enzyme test systems of various manufacturers the unmatched data concerning FPSR can be obtained. The purpose of this study was to implement comparative evaluation of specificity of immune enzyme test-systems of three different manufacturers: "DS IFA-HIV-AGAT-SCREEN" ("Diagnostic Systems"), "Genscreen Ultra HIV Ag-Ab" "Bio Rad" France) and "The CombiBest HIV-1,2 AG/AT" ("Vector-Best" Novosibirsk). The sampling of 440 samples of blood serums of pregnant women from various medical institutions of Nizhnii Novgorod was analyzed. The results of the study demonstrated that FPSR were detected in all test-systems and at that spectrum of samples differed. The identical specificity of compared test-systems amounted to 98.64%. The alternative approach to FPSR to HIV issue under screening examinations of pregnant women was proposed. The proposed mode consisted of consistent application of two test-systems of fourth generation with different format of setup of reaction. PMID- 26031165 TI - [The level of interleukin-101, tumor a necrosis factor and their dissolving receptors in women with ischemic heart disease comorbide with osteoporosis]. AB - The sampling consisted of 98 women (average age 71.2 +/- 8.6 years) with ischemic heart disease. The combination of ischemic heart disease and severe osteoporosis was diagnosed in 48 out of them. All female patients were analyzed for level of IL-1beta, TNF-alpha and their soluble receptors in blood serum. The technique of immune enzyme analysis was applied. It was revealed that in women with associated pathology the level of TNF-alpha was higher and concentration of soluble receptors reliably lower than in women with isolated ischemic heart disease. It was established that direct correlation relationship exists between occurrence of bone fractures, coronary atherosclerosis and level of TNF-alpha. The occurrence of bone fractures was inversely correlated with level of soluble receptors of TNF (gamma = 0.3; p = 0.0029), and occurrence of ischemic heart disease with soluble receptors of IL-1. PMID- 26031166 TI - [The experience of implementation of REP-u RAPD-polymerase chain reaction in epidemiologic characteristic of nosocomial isolates Pseudomonas aeruginosa]. AB - The article presents comparative evaluation of diagnostic value of technique REP- u RAPD-polymerase chain reaction applied under genetic typing of clinical isolates of Pseudomonas Aeruginosa. The strains are isolated in different hospital departments of medical institutions in adult (8 medical institutions; n = 145) and children (5 medical institutions; n = 151) medical networks. The results of study demonstrated different boundary capacity of three reactions. The Simpson discrimination index made up to 0.993, 0.875 and 0.639 for RAPD-, ERIC- and BOX-polymerase chain reaction correspondingly. The RAPD-polymerase chain reaction makes it possible to detect individual characteristics of strains. Out of two alternatives the REP-polymerase chain reaction demonstrated its advantage, besides only with one primer ERIC2. The BOX-polymerase chain reaction has a least discriminating capacity under typing of isolates P. aeruginosa, detecting only species' characteristics. The clinical strains P. aeruginosa are distributed on 24 genome groups and 52 isolates had individual genotypes. The evaluation of results of genetic typing permitted to point out both similarity of tendencies in propagation of strains of P. aeruginosa among hospitalized adults and adolescents and specificity of detection in neonatal clinics. It is obvious that hospitals of different profiles, including departments of reanimation and intensive therapy represent specific ecological environment significantly different in its level of endogenous and exogenous infection. PMID- 26031167 TI - [The laboratory diagnostic of herpes viral infections under nosocomial pneumonia in oncologic hematologic patients]. AB - The study was organized to discover diagnostically valuable clinical material for detection of etiologic agent of pneumonia in oncological hematological patients, rate of association of nosocomial pneumonia with herpes viruses and evaluation of viral load in patients with depressed immunity. In oncological hematological patients, half of nosocomial pneumonia cases is associated with herpes virus. In every third patient DNA of Epstein-Barr virus and DNA of type I and II are detected. The most informative material in this case is broncho-alveolar lavage fluid and the most convenient diagnostic technique is polymerase chain reaction in real-time. The low viral load in broncho-alveolar lavage fluid is specfic for Epstein-Barr virus, cytomegalovirus and human herpes virus type VI. The concentration of DNA ofsimple herpes virus type I and type II is located in both high and low values. The paradox phenomena is established concerning more benevolent course of nosocomial pneumonia associated with simple herpes virus type I and II in patients with higher viral load in broncho-alveolar lavage fluid. The further research in this direction is needed. PMID- 26031168 TI - [The microbiological aspects of orthodontic treatment of children with dental maxillary anomalies]. AB - The issues of pre-nosologic diagnostic and effectiveness of treatment of diseases of oral cavity is an actual issue in dentistry. The long- duration orthodontic treatment of patients with dentoalveolar anomalies using non-removable devices is followed by such negative consequences as development demineralization of enamel and caries registered during treatment and after remove ofdevices. The level of quantitative content of oral streptococci was analyzed and dental status in children with dentoalveolar anomalies was evaluated during treatment with non removable devices was evaluated. The caries and inflammation of periodontium of oral cavity were most often detected in children with high level of content of streptococci. In different periods of study the firm tendency of increasing of concentration of Streptococcus mutans and S. sanguis of dental plaque of oral cavity is established. The established index indicators of dental status of patients testify intensity of caries damage, level of poor hygiene of oral cavity, development of average degree of severity of inflammation process of periodontium. The obtained results substantiate involvement ofstreptococci, associates of microbiota of dental plaque of oral cavity in children, in process of development of caries. The characteristics of micro-ecology of dental plaque to evaluate cariesgenic situation that can be used as a basis for constructing diagnostic algorithm under monitoring of patients with dentoalveolar anomalies with purpose of forthcoming planning and implementation of effective orthodontic treatment. PMID- 26031169 TI - [The species variety of microflora in samples from urogenital tract of female patients of large network laboratory and its dependence of content of lactobaccilli]. AB - The evaluation of content of DNA of lactobaccilli and particular types of aerobic anaerobic opportunistic bacteria in sampling of scrapes from urogenital tract offemale patients of the network laboratory INVITRO was implemented. The technique of polymerase chain reaction in real-time was implemented. It is demonstrated that decreasing of content of lactobaccilli in total bacterial mass isfollowed by increasing of occurrence, concentration and relative content of all types of opportunistic pathogens except ureaplasmna. These changes are expressed in different degree for different types of opportunistic pathogens. The increasing of varieties of types of microflora of urogenital tract under decreasing of content of lactobaccilli is noted. PMID- 26031170 TI - Nature, environment and quality of life. PMID- 26031171 TI - Nature or environment? PMID- 26031172 TI - [Quality of life. An intellectual history]. PMID- 26031173 TI - Created natures. PMID- 26031174 TI - Health: human and planetary. PMID- 26031175 TI - Human nature in the contemporary world. PMID- 26031176 TI - Planetary quality. PMID- 26031178 TI - Arithmetical periodicals in late eighteenth-century Germany: "mathematics for the use and the pleasure of civic life". PMID- 26031177 TI - [The contribution of Francois Viete to the contact angle debate]. PMID- 26031179 TI - Sharing discoveries. Boscovich's network and the discovery of Uranus. PMID- 26031180 TI - [A breviary for astronomers and sailors: time knowledge and calculators of Bureau des longitudes, from Lalande a Loewry (1772-1907)]. PMID- 26031181 TI - [The program of Genetics and radiobiology of the National Commission of Nuclear Energy in Mexico, and the work of Alfonso Leon de Garay]. PMID- 26031182 TI - Beyond disciplinary borders. H. A. Lorentz and S. Ramon y Cajal. AB - Science is a multidisciplinary enterprise. Mathematics, physics, chemistry, biology, geology, and many other, perhaps not so " basic ", but not less interesting disciplines form what we call " science ". The task of history of science is to recover and put order in the past of such disciplines. Although, on most the occasions, those histories are limited by the territories of the different sciences, we know that their frontiers are not impermeable, that there are relationships between them. However, it is not frequent to find studies dealing with those relationships, especially dealing with relations among scientists belonging to different fields. In the present paper, we study a case in which two outstanding scientists, a physicist and a histologist (or neuroscientist, as we would say today), the Dutchman Hendrik A. Lorentz and the Spanish Santiago Ramon y Cajal, maintained a, albeit brief, relation. Both being such prominent scientific figures, of worldwide stature, the relation they maintained deserves to be known. PMID- 26031183 TI - [Essay reviews]. PMID- 26031184 TI - Involvement of PAPP-A and IGFR1 in Cystic Ovarian Disease in Cattle. AB - Cystic ovarian disease (COD) is one of the main causes of infertility in dairy cattle. It has been shown that intra-ovarian factors, such as members of the insulin-like growth factor (IGF) system, may contribute to follicular persistence. The bioavailability of IGF to initiate its response by binding to specific receptors (IGFRs) depends on interactions with related compounds, such as pregnancy-associated plasma protein A (PAPP-A). The aim of this study was to determine IGFR1 and PAPP-A expression both in follicles at different stages of development and in cysts, to evaluate the roles in the etiopathogenesis of COD in cattle. The mRNA expression of PAPP-A was higher in granulosa cells of large tertiary follicles than in cysts, whereas the protein PAPP-A present in the follicular fluid from these follicles showed no differences. Although no PAPP-A mRNA expression was detected in smaller tertiary follicles, in their follicular fluid, this protease was detected in lesser concentration than in cysts. The mRNA expression of IGFR1 was lower in granulosa cells from cystic follicles than in those from tertiary ones. However, the protein expression of this receptor presented the highest levels in cystic structures, probably to increase the possibility of IGF response. The data obtained would indicate that animals with COD have an altered regulation of the IGF system in the ovary, which could be involved in the pathogenesis of this disease in cattle. PMID- 26031185 TI - Voluntary exercise protects against ulcerative colitis by up-regulating glucocorticoid-mediated PPAR-gamma activity in the colon in mice. AB - AIM: Voluntary exercise has been shown to protect against the development of ulcerative colitis, but the mechanism is not fully understood. We hypothesized that prior voluntary exercise would attenuate colonic inflammation and ameliorate clinical symptoms in dextran sulphate sodium (DSS)-induced ulcerative colitis by increasing glucocorticoid production and up-regulating PPAR-gamma activity in the colon. METHODS: Male C57Bl/6J mice were assigned to sedentary, exercise, exercise with PPAR-gamma antagonist GW9662 or glucocorticoid synthesis inhibitor metyrapone. Following the completion of the 30 days' exercise training programme, they were treated with or without 2% DSS in drinking water for 5 days, followed by 5 days of regular water. RESULTS: Compared with sedentary mice, exercise mice exhibited improved clinical symptoms (weight loss and diarrhoea) and less inflammation (expression of pro-inflammatory cytokines and histological injury) in response to DSS, whereas these beneficial effects were abolished by both GW9662 and metyrapone treatment. Molecular studies revealed that exercise significantly increased the expression of PPAR-gamma, augmented the expression of steroidogenic enzymes (CYP11A1 and CYP11B1) and elevated corticosterone levels in the colon. GW9662 treatment reversed the expression of PPAR-gamma without altering the expression of steroidogenic enzymes and corticosterone secretion in the colon, while metyrapone treatment blocked glucocorticoid secretion and abrogated the increase in PPAR-gamma expression in the colon. CONCLUSION: These findings suggest that prior voluntary exercise suppresses the expression of pro inflammatory cytokines in the colon in response to inflammatory challenge by up regulating glucocorticoid-mediated PPAR-gamma activity, contributing to protection against the development of ulcerative colitis. PMID- 26031186 TI - Cystic well-differentiated squamous cell carcinoma of the thymus: a clinicopathological and immunohistochemical study of six cases. AB - AIMS: To present six cases of cystic well-differentiated squamous cell carcinoma of the thymus. METHODS AND RESULTS: The patients were six men aged between 48 and 75 years (average: 61.5 years) who were symptomatic with chest pain, shortness of breath, and dyspnoea. Diagnostic imaging showed anterior mediastinal masses, and surgical resection was accomplished in all cases. Grossly, the tumours measured 40-90 mm in greatest diameter (average: 65 mm), and were described as ill-defined lesions with a prominent cystic component and focal areas of haemorrhage and necrosis. Histologically, they were characterized predominantly by their cystic architecture. The cyst walls were lined by squamous epithelium showing different degrees of cellular atypia. In focal, more solid areas, the tumours showed evidence of keratinization. By immunohistochemistry, tumour cells were positive for cytokeratin 5/6, p40, and Pax8. All tumours were staged as T1N0M0 according to the Weissferdt-Moran staging system. Clinical follow-up showed that four patients have remained alive and well after a period ranging from 1 to 2 years. Two patients were lost to follow-up. CONCLUSIONS: The current cases highlight an uncommon growth pattern of well-differentiated squamous cell carcinoma of the thymus that may cause diagnostic difficulty with mediastinoscopic biopsies. PMID- 26031188 TI - Introduction to Special Issue: Disruption of thyroid, sex steroid, and adrenal hormone systems and their crosstalk in aquatic wildlife. PMID- 26031187 TI - Subgroup Identification in Personalized Treatment of Alcohol Dependence. AB - BACKGROUND: Identification of patient subgroups to enhance treatment effects is an important topic in personalized (or tailored) alcohol treatment. Recently, several recursive partitioning methods have been proposed to identify subgroups benefiting from treatment. These novel data mining methods help to address the limitations of traditional regression-based methods that focus on interactions. METHODS: We propose an exploratory approach, using recursive partitioning methods, for example, interaction trees (IT) and virtual twins (VT), to flexibly identify subgroups in which the treatment effect is likely to be large. We apply these tree-based methods to a pharmacogenetic trial of ondansetron. RESULTS: Our methods identified several subgroups based on patients' genetic and other prognostic covariates. Among the 251 subjects with complete genotype information, the IT method identified 118 with specific genetic and other prognostic factors, resulting in a 17.2% decrease in the percentage of heavy drinking days (PHDD). The VT method identified 88 subjects with a 21.8% decrease in PHDD. Overall, the VT subgroup achieved a good balance between the treatment effect and the group size. CONCLUSIONS: A data mining approach is proposed as a valid exploratory method to identify a sufficiently large subgroup of subjects that is likely to receive benefit from treatment in an alcohol dependence pharmacotherapy trial. Our results provide new insights into the heterogeneous nature of alcohol dependence and could help clinicians to tailor treatment to the biological profile of individual patients, thereby achieving better treatment outcomes. PMID- 26031189 TI - The significance of Ciona intestinalis as a stem organism in integrative studies of functional evolution of the chordate endocrine, neuroendocrine, and nervous systems. AB - Ascidians are the closest phylogenetic neighbors to vertebrates and are believed to conserve the evolutionary origin in chordates of the endocrine, neuroendocrine, and nervous systems involving neuropeptides and peptide hormones. Ciona intestinalis harbors various homologs or prototypes of vertebrate neuropeptides and peptide hormones including gonadotropin-releasing hormones (GnRHs), tachykinins (TKs), and calcitonin, as well as Ciona-specific neuropeptides such as Ciona vasopressin, LF, and YFV/L peptides. Moreover, molecular and functional studies on Ciona tachykinin (Ci-TK) have revealed the novel molecular mechanism of inducing oocyte growth via up-regulation of vitellogenesis-associated protease activity, which is expected to be conserved in vertebrates. Furthermore, a series of studies on Ciona GnRH receptor paralogs have verified the species-specific regulation of GnRHergic signaling including unique signaling control via heterodimerization among multiple GnRH receptors. These findings confirm the remarkable significance of ascidians in investigations of the evolutionary processes of the peptidergic systems in chordates, leading to the promising advance in the research on Ciona peptides in the next stage based on the recent development of emerging technologies including genome-editing techniques, peptidomics-based multi-color staining, machine-learning prediction, and next-generation sequencing. These technologies and bioinformatic integration of the resultant "multi-omics" data will provide unprecedented insights into the comprehensive understanding of molecular and functional regulatory mechanisms of the Ciona peptides, and will eventually enable the exploration of both conserved and diversified endocrine, neuroendocrine, and nervous systems in the evolutionary lineage of chordates. PMID- 26031190 TI - Fish faunal provinces of the conterminous United States of America reflect historical geography and familial composition. AB - Although the conterminous USA has a long history of ichthyological exploration, the description of biogeographical provinces has been ad hoc. In this study we quantitatively determined fish faunal provinces and interpreted them in the context of the geological history of North America. We also evaluated influences of major river basin occupancy and contemporary environmental factors on provincial patterns. Our data set comprised 794 native fishes, which we used to generate a presence and absence matrix for U.S. Geological Survey (USGS) four digit hydrologic units. Three nested data sets were analysed separately: primary freshwater families, continental freshwater families (including primary and secondary families) and all freshwater families (including primary, secondary and peripheral families). We used clustering analysis to delimit faunal breaks and one-way analysis of similarity (ANOSIM) to determine significance among clusters (i.e. provinces). We used an indicator-species analysis to identify species that contributed most to province delineations and a similarity-percentage (SIMPER) analysis to describe the relative influence of representatives from each category (i.e. primary, secondary, peripheral) on provincial boundaries. Lastly, we used a parsimony redundancy analysis to determine the roles of historical (i.e. major river basin) and contemporary environmental factors in shaping provinces. Analysis of the nested data sets revealed lessening provincial structure with inclusion of more families. There were 10 primary freshwater provinces, 9 continental freshwater provinces and 7 all freshwater provinces. Major basin occupancy, but not contemporary environmental factors, explained substantial variance in faunal similarities among provinces. However, provincial boundaries did not conform strictly to modern river basins, but reflected river-drainage connections of the Quaternary. Provinces represent broad-scale patterns of endemism and provide a starting point for future studies. Relative malleability of province boundaries in the continental interior highlights this region as biogeographically diverse and dynamic. Interior-core provinces of this region (Central Gulf Coastal Plains, Northern Interior) have not been recognized previously and warrant further study. PMID- 26031191 TI - Reoperation for rhegmatogenous retinal detachment as quality indicator for disease management: a register study. AB - PURPOSE: To establish a quality indicator that could be used in optimizing treatment for rhegmatogenous retinal detachment (RRD). METHODS: The Danish National Patient Registry was used to identify surgery conducted in Denmark for RRD in the period 01 January 2001-31 December 2009. Cases were identified by diagnosis and surgical codes. RESULTS: A total of 6522 cases were operated for a primary RRD in the study period, and 22% (1434 patients) were reoperated for a redetachment. A Cox regression analysis showed that the risk of redetachment was equal to or less than detachment on the fellow eye 1 year after primary surgery with techniques not using silicone oil. The same was true 1.5 years after surgery for techniques using silicone oil. Based on this, we established a quality indicator defining failure as the need for operation for redetachment within 1 year from initial surgery when using techniques without oil and after 1.5 years for techniques using oil. Also the lack of oil removal within 1 year from initial surgery should be noted as an operational failure. We applied the quality indicators on the cohort of 6522 RRDs and found that in Denmark the need for redetachment surgery has decreased over time and also that high-volume departments have better outcome compared to smaller ones. CONCLUSIONS: The risk of reoperation for redetachment after initial surgery fulfils the criteria for a good quality indicator and can be used in RRD surgery. This indicator could aid in optimizing the management of RRD patients to minimize morbidity. PMID- 26031192 TI - Anxiety as a Moderator of the Relationship Between Body Image and Restrained Eating. AB - PURPOSE: To examine three indicators of psychopathology (stress, anxiety, and depression) as potential moderators of the relationship between body image dissatisfaction (BID) and restrained, emotional, and external eating, while controlling for family-related variables (i.e., household income, living situation, and psychopathology in the family) and individual variables (i.e., body mass index, physical activity, and major life events). DESIGN AND METHODS: A descriptive, correlational cross-sectional design was used. A sample of 894 female undergraduates aged between 18 and 25 completed a self-reported questionnaire. FINDINGS: Moderation analyses indicated that anxiety significantly moderated the relationship between BID and restrained eating, whereas depression and stress did not. PRACTICE IMPLICATIONS: Findings may be used in the development and implementation of education and prevention programs for disordered eating in college campuses. The usefulness of these findings for nursing practice is discussed. PMID- 26031193 TI - Visceral hypersensitivity in irritable bowel syndrome: evidence for involvement of serotonin metabolism--a preliminary study. AB - BACKGROUND: Altered serotonergic (5-HT) metabolism and visceral perception have been associated with the pathogenesis of irritable bowel syndrome (IBS). Aim of this preliminary study was to assess the effect of the direct precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on systemic 5-HT metabolites and visceral perception and to assess potential differential responses between IBS and controls. METHODS: 15 IBS patients and 15 healthy volunteers participated in this randomized double blind placebo controlled study. Visceroperception was measured by rectal barostat. The 100 mg 5-HTP or placebo was ingested orally. Serotonergic metabolites were assessed in platelet poor plasma. KEY RESULTS: 5-HTP induces rectal allodynia in a significant number of healthy controls; IBS patients exhibit lowered pain thresholds in both placebo and 5-HTP conditions. 5-HTP induces rectal hyperalgesia in hypersensitive but not in non-hypersensitive IBS patients. Administration of 5-HTP significantly increased plasma 5-HTP levels (p < 0.001), did not affect 5-HT levels (p > 0.05), while levels of the main metabolite of 5-HT, 5-hydroxyindoleacetic acid, increased significantly (p < 0.05) in both groups. The magnitude of these changes observed in 5-HT metabolites was significantly greater in IBS patients. CONCLUSIONS & INFERENCES: Oral administration of 5-HTP induced significant alterations in systemic 5-HT metabolites that were accompanied by increased visceroperception of pain in controls and hypersensitive IBS patients. Changes in 5-HT metabolism appear to be important factors involved in visceral hypersensitivity as the 5-HTP-induced pro nociceptive response was observed in all hypersensitive IBS patients and to a lesser magnitude in a significant number of healthy controls but in none of the non-hypersensitive IBS patients. PMID- 26031194 TI - Two new forms of hematoidin in the skin. PMID- 26031195 TI - Novel process for producing 6-deoxy monosaccharides from l-fucose by coupling and sequential enzymatic method. AB - We biosynthesized 6-deoxy-L-talose, 6-deoxy-L-sorbose, 6-deoxy-L-gulose, and 6 deoxy-L-idose, which rarely exist in nature, from L-fucose by coupling and sequential enzymatic reactions. The first product, 6-deoxy-L-talose, was directly produced from L-fucose by the coupling reactions of immobilized D-arabinose isomerase and immobilized L-rhamnose isomerase. In one-pot reactions, the equilibrium ratio of L-fucose, L-fuculose, and 6-deoxy-L-talose was 80:9:11. In contrast, 6-deoxy-L-sorbose, 6-deoxy-L-gulose, and 6-deoxy-L-idose were produced from L-fucose by sequential enzymatic reactions. D-Arabinose isomerase converted L-fucose into L-fuculose with a ratio of 88:12. Purified L-fuculose was further epimerized into 6-deoxy-L-sorbose by D-allulose 3-epimerase with a ratio of 40:60. Finally, purified 6-deoxy-L-sorbose was isomerized into both 6-deoxy-L gulose with an equilibrium ratio of 40:60 by L-ribose isomerase, and 6-deoxy-L idose with an equilibrium ratio of 73:27 by D-glucose isomerase. Based on the amount of L-fucose used, the production yields of 6-deoxy-L-talose, 6-deoxy-L sorbose, 6-deoxy-L-gulose, and 6-deoxy-L-idose were 7.1%, 14%, 2%, and 2.4%, respectively. PMID- 26031196 TI - More than one way to evolve a weed: parallel evolution of US weedy rice through independent genetic mechanisms. AB - Many different crop species were selected for a common suite of 'domestication traits', which facilitates their use for studies of parallel evolution. Within domesticated rice (Oryza sativa), there has also been independent evolution of weedy strains from different cultivated varieties. This makes it possible to examine the genetic basis of parallel weed evolution and the extent to which this process occurs through shared genetic mechanisms. We performed comparative QTL mapping of weediness traits using two recombinant inbred line populations derived from crosses between an indica crop variety and representatives of each of the two independently evolved weed strains found in US rice fields, strawhull (S) and blackhull awned (B). Genotyping-by-sequencing provided dense marker coverage for linkage map construction (average marker interval <0.25 cM), with 6016 and 13 730 SNPs mapped in F5 lines of the S and B populations, respectively. For some weediness traits (awn length, hull pigmentation and pericarp pigmentation), QTL mapping and sequencing of underlying candidate genes confirmed that trait variation was largely attributable to individual loci. However, for more complex quantitative traits (including heading date, panicle length and seed shattering), we found multiple QTL, with little evidence of shared genetic bases between the S and B populations or across previous studies of weedy rice. Candidate gene sequencing revealed causal genetic bases for 8 of 27 total mapped QTL. Together these findings suggest that despite the genetic bottleneck that occurred during rice domestication, there is ample genetic variation in this crop to allow agricultural weed evolution through multiple genetic mechanisms. PMID- 26031197 TI - Quinazoline-4-piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells. AB - BACKGROUND AND PURPOSE: Ectonucleotide pyrophosphatase/PDE1 (NPP1) is an ectoenzyme, which plays a role in several disorders including calcific aortic valve disease (CAVD). So far, compounds that have been developed as inhibitors of NPP1 lack potency and specificity. Quinazoline-4-piperidine sulfamides (QPS) have been described as potent inhibitors of NPP1. However, their mode of inhibition as well as their selectivity and capacity to modify biological processes have not been investigated. EXPERIMENTAL APPROACH: In the present series of experiments, we have evaluated the efficacy of two derivatives, QPS1-2, in inhibiting human NPP1, and we have evaluated the effect of the most potent derivative (QPS1) on other ectonucleotidases as well as on the ability of this compound to prevent phosphate-induced mineralization of human primary aortic valve interstitial cells (VICs). KEY RESULTS: The QPS1 derivative is a potent (Ki 59.3 +/- 5.4 nM) and selective non-competitive inhibitor of human NPP1. Moreover, QPS1 also significantly inhibited the K121Q NPP1 gene variant (Ki 59.2 +/- 14.5 nM), which is prevalent in the general population. QPS1 did not significantly alter the activity of other nucleotide metabolizing ectoenzymes expressed at the cell surface, namely NPP3, NTPDases (1-3), ecto-5'-nucleotidase and ALP. Importantly, QPS1 in the low micromolar range (<=10 MUM) prevented phosphate-induced mineralization of VICs and lowered the rise of osteogenic genes as expected for NPP1 inhibition. CONCLUSIONS AND IMPLICATIONS: We have provided evidence that QPS1 is a potent and selective non-competitive inhibitor of NPP1 and that it prevented pathological mineralization in a cellular model. PMID- 26031198 TI - Expert Review of Evidence Bases for Managing Monkey Bites in Travelers. PMID- 26031199 TI - Eligible Death Statistic: Not a True Measure of OPO Performance nor the Potential to Increase Transplantation. PMID- 26031200 TI - Can a combination of ultrasonographic parameters accurately evaluate concussion and guide return-to-play decisions? AB - Mild traumatic brain injury, often referred to as concussion, is a common, potentially debilitating, and costly condition. One of the main challenges in diagnosing and managing concussion is that there is not currently an objective test to determine the presence of a concussion and to guide return-to-play decisions for athletes. Traditional neuroimaging tests, such as brain magnetic resonance imaging, are normal in concussion, and therefore diagnosis and management are guided by reported symptoms. Some athletes will under-report symptoms to accelerate their return-to-play and others will over-report symptoms out of fear of further injury or misinterpretation of underlying conditions, such as migraine headache. Therefore, an objective measure is needed to assist in several facets of concussion management. Limited data in animal and human testing indicates that intracranial pressure increases slightly and cerebrovascular reactivity (the ability of the cerebral arteries to auto-regulate in response to changes in carbon dioxide) decreases slightly following mild traumatic brain injury. We hypothesize that a combination of ultrasonographic measurements (optic nerve sheath diameter and transcranial Doppler assessment of cerebrovascular reactivity) into a single index will allow for an accurate and non-invasive measurement of intracranial pressure and cerebrovascular reactivity, and this index will be clinically relevant and useful for guiding concussion diagnosis and management. Ultrasound is an ideal modality for the evaluation of concussion because it is portable (allowing for evaluation in many settings, such as on the playing field or in a combat zone), radiation-free (making repeat scans safe), and relatively inexpensive (resulting in nearly universal availability). This paper reviews the literature supporting our hypothesis that an ultrasonographic index can assist in the diagnosis and management of concussion, and it also presents limited data regarding the initial use of this index in healthy controls. PMID- 26031201 TI - Distinct domains in Bub1 localize RZZ and BubR1 to kinetochores to regulate the checkpoint. AB - The spindle assembly checkpoint (SAC) ensures proper chromosome segregation by delaying anaphase onset in response to unattached kinetochores. Checkpoint signalling requires the kinetochore localization of the Mad1-Mad2 complex that in more complex eukaryotes depends on the Rod-Zwilch-ZW10 (RZZ) complex. The kinetochore protein Zwint has been proposed to be the kinetochore receptor for RZZ, but here we show that Bub1 and not Zwint is required for RZZ recruitment. We find that the middle region of Bub1 encompassing a domain essential for SAC signalling contributes to RZZ localization. In addition, we show that a distinct region in Bub1 mediates kinetochore localization of BubR1 through direct binding, but surprisingly removal of this region increases checkpoint strength. Our work thus uncovers how Bub1 coordinates checkpoint signalling by distinct domains for RZZ and BubR1 recruitment and suggests that Bub1 localizes antagonistic checkpoint activities. PMID- 26031203 TI - New C13 lipids from the marine-derived fungus Trichoderma harzianum. AB - Chemical examination of the fermentation broth of a sponge-associated fungus Trichoderma harzinum HMS-15-3 led to the isolation of four pairs of new C13 lipid enantiomers namely harzianumols A-H (1a-4b). Their structures were elucidated on the basis of extensive spectroscopic (IR, MS, 1D, and 2D NMR) data analysis, including the modified Mosher's method for the assignment of their absolute configurations. The new compounds were evaluated for antihyperlipidemic effects in HepG2 cells. PMID- 26031202 TI - A novel technique for simultaneous whole-body and multi-organ decellularization: umbilical artery catheterization as a perfusion-based method in a sheep foetus model. AB - The aim of this study was to develop a method to generate multi-organ acellular matrices. Using a foetal sheep model have developed a method of systemic pulsatile perfusion via the umbilical artery which allows for simultaneous multi organ decellularization. Twenty sheep foetuses were systemically perfused with Triton X-100 and sodium dodecyl sulphate. Following completion of the whole-body decellularization, multiple biopsy samples were taken from different parts of 21 organs to ascertain complete cell component removal in the preserved extracellular matrices. Both the natural and decellularized organs were subjected to several examinations. The samples were obtained from the skin, eye, ear, nose, throat, cardiovascular, respiratory, gastrointestinal, urinary, musculoskeletal, central nervous and peripheral nervous systems. The histological results depicted well-preserved extracellular matrix (ECM) integrity and intact vascular structures, without any evidence of residual cellular materials, in all decellularized bioscaffolds. Scanning electron microscope (SEM) and biochemical properties remained intact, similar to their age-matched native counterparts. Preservation of the collagen structure was evaluated by a hydroxyproline assay. Dense organs such as bone and muscle were also completely decellularized, with a preserved ECM structure. Thus, as shown in this study, several organs and different tissues were decellularized using a perfusion-based method, which has not been previously accomplished. Given the technical challenges that exist for the efficient generation of biological scaffolds, the current results may pave the way for obtaining a variety of decellularized scaffolds from a single donor. In this study, there have been unique responses to the single acellularization protocol in foetuses, which may reflect the homogeneity of tissues and organs in the developing foetal body. PMID- 26031204 TI - Effects of Eyelid Warming Devices on Tear Film Parameters in Normal Subjects and Patients with Meibomian Gland Dysfunction. AB - PURPOSE: To evaluate the effects of commercially available eyelid warming devices on ocular temperatures, tear film function, and meibomian glands in normal subjects and patients with meibomian gland dysfunction (MGD). METHODS: Ten healthy volunteers were enrolled to evaluate the effects of a single warming and of repeated warming for 2 weeks. Ten MGD patients were enrolled for evaluation of repeated warming over 1 month. Two non-wet (Azuki no Chikara, Eye Hot R) and three wet (hot towel, Hot Eye Mask, Memoto Este) devices were compared in a masked manner. Visual analog scale (VAS) score for ocular symptoms, tear film breakup time (TFBUT), meibum grade, temperatures (eyelid skin, tarsal conjunctiva, central cornea), Schirmer test value, and meibomian gland area were measured before and after warming application. RESULTS: The single application of the five warming devices improved the VAS score, TFBUT, and ocular temperatures. In the repeated warming application, Azuki no Chikara as a representative non-wet warming device induced a stable and significant improvement in TFBUT and increased the tarsal conjunctival temperature and meibomian gland area in both normal subjects and MGD patients. It also improved meibum grade in MGD patients. CONCLUSION: Our results suggest that repeated eyelid warming with a non-wet device improves tear film function in normal individuals and may have beneficial effects on both tear film and meibomian gland function in MGD patients. PMID- 26031205 TI - Test of memory malingering with children: The utility of Trial 1 and TOMMe10 as screeners of test validity. AB - There is a growing body of research suggesting that the shorter versions of the Test of Memory Malingering (TOMM) may provide an accurate assessment of effort in children. During neuropsychological evaluations, some circumstances result in only one completed trial of the TOMM or partial completion of a trial. Research suggests that a cut-score of 40 or 41 on Trial1 is highly predictive of passing the TOMM overall. In the current study, 194 school-age children with academic and/or behavioral problems were used to compare the accuracy of TOMM1 and TOMMe10 (errors on the first 10 items of TOMM1) in predicting passing/failing of TOMM2. For the children in this sample, a score of < 40 items correct (>= 10 errors) on TOMM1 was highly accurate in predicting a passing performance on the TOMM2 (sensitivity = .80, specificity = .91) with a Negative Predictive Value = .98 at the malingering base rate of 7% (TOMM2 failure in our sample). A score of 2 errors (8 items correct) on the TOMMe10 was slightly less sensitive than that of the TOMM1 (specificity = .96, sensitivity = .53) but with a similar Negative Predictive Value (.96). Consistent with the research from adult populations, TOMM1 and TOMMe10 appear to be quite accurate in predicting performance on the standard administration of the TOMM and may be useful screeners. However, compared to that found in adult samples, slight differences in suggested cutoffs for TOMM1 and TOMMe10 may be warranted for children. PMID- 26031206 TI - Risk factors for bronchiolitis, recurrent wheezing, and related hospitalization in preterm infants during the first year of life. AB - BACKGROUND: Airway diseases are highly prevalent in infants and cause significant morbidity. We aimed to determine the incidence and risk factors for respiratory morbidity in a Spanish cohort of moderate-to-late preterm (MLP) infants prospectively followed during their first year of life. METHODS: SAREPREM is a multicenter, prospective, longitudinal study. Preterm infants born at 32-35 weeks of gestation with no comorbidities were enrolled within 2 weeks of life and followed at 2-4 weeks, 6, and 12 months of age. Multivariate mixed-models were performed to identify independent risk factors associated with (i) development of bronchiolitis, (ii) recurrent wheezing, or (iii) related hospital admissions. RESULTS: Overall, 977 preterm infants were included, and 766 (78.4%) completed follow-up. Of those, 365 (47.7%) developed bronchiolitis during the first year, 144 (18.8%) recurrent wheezing, and 48 (6.3%) were hospitalized. While low birthweight, day care attendance (DCA) and school-age siblings were significantly and independently associated with both the development of bronchiolitis and recurrent wheezing, lower maternal age increased the risk for bronchiolitis and respiratory-related hospitalizations. Lastly, mechanical ventilation was associated with a higher risk of bronchiolitis and history of asthma in any parent increased the likelihood of developing recurrent wheezing. CONCLUSIONS: In this study, several non-modifiable parameters (family history of asthma, low birthweight, need for mechanical ventilation) and modifiable parameters (young maternal age, DCA, or exposure to school-age siblings) were identified as significant risk factors for the development of bronchiolitis and recurrent wheezing during the first year of life in MLP infants. PMID- 26031207 TI - Cell-penetrating and endoplasmic reticulum-locating TAT-IL-24-KDEL fusion protein induces tumor apoptosis. AB - Interleukin-24 (IL-24) is a unique IL-10 family cytokine that could selectively induce apoptosis in cancer cells without harming normal cells. Previous research demonstrated that intracellular IL-24 protein induces an endoplasmic reticulum (ER) stress response only in cancer cells, culminating in apoptosis. In this study, we developed a novel recombinant fusion protein to penetrate into cancer cells and locate on ER. It is composed of three distinct functional domains, IL 24, and the targeting domain of transactivator of transcription (TAT) and an ER retention four-peptide sequence KDEL (Lys-Asp-Glu-Leu) that link at its NH2 and COOH terminal, respectively. The in vitro results indicated that TAT-IL-24-KDEL inhibited growth in bladder cancer cells, as well as in non-small cell lung cancer cell line and breast cancer cell line, but the normal human lung fibroblast cell line was not affected, indicating the cancer specificity of TAT IL-24-KDEL. Western blot analysis showed that apoptosis activation was induced by TAT-IL-24-KDEL through the ER stress-mediated cell death pathway. Treatment with TAT-IL-24-KDEL significantly inhibited the growth of human H460 xenografts in nude mice, and the tumor growth inhibition was correlated with increased hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. These findings suggest that the artificially designed recombinant fusion protein TAT-IL-24-KDEL may be highly effective in cancer therapy and worthy of further evaluation and development. PMID- 26031209 TI - Biological Insights from a Simulation Model of the Critical FtsZ Accumulation Required for Prokaryotic Cell Division. AB - A simulation model of prokaryotic Z-ring assembly, based on the observed behavior of FtsZ in vitro as well as on in vivo parameters, is used to integrate critical processes in cell division. According to the model, the cell's ability to divide depends on a "contraction parameter" (chi) that links the force of contraction to the dynamics of FtsZ. This parameter accurately predicts the outcome of division. Evaluating the GTP binding strength, the FtsZ polymerization rate, and the intrinsic GTP hydrolysis/dissociation activity, we find that inhibition of GTP FtsZ binding is an inefficient antibacterial target. Furthermore, simulations indicate that the temperature sensitivity of the ftsZ84 mutation arises from the conversion of FtsZ to a dual-specificity NTPase. Finally, the sensitivity to temperature of the rate of ATP hydrolysis, over the critical temperature range, leads us to conclude that the ftsZ84 mutation affects the turnover rate of the Z ring much less strongly than previously reported. PMID- 26031210 TI - The effects of antidepressants appear to be rapid and at environmentally relevant concentrations. AB - The effects of antidepressants on wildlife are currently raising some concern because of an increased number of publications indicating biological effects at environmentally relevant concentrations (<100 ng/L). These results have been met with some scepticism because of the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Because their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. The authors highlight studies on the effects of antidepressants, particularly on crustacean and molluskan groups, showing that they are susceptible to a wide variety of neuroendocrine disruptions at environmentally relevant concentrations. Interestingly, some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors can invoke changes in swimming behavior within hours. In mollusks, exposure to selective serotonin reuptake inhibitors can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain from selective serotonin reuptake inhibitors using magnetic resonance imaging scans, the authors discuss possible reasons for the discrepancy in former results in relation to the read across hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors. PMID- 26031211 TI - Antenatal dietary education and supplementation to increase energy and protein intake. AB - BACKGROUND: Gestational weight gain is positively associated with fetal growth, and observational studies of food supplementation in pregnancy have reported increases in gestational weight gain and fetal growth. OBJECTIVES: To assess the effects of education during pregnancy to increase energy and protein intake, or of actual energy and protein supplementation, on energy and protein intake, and the effect on maternal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015), reference lists of retrieved studies and contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials of dietary education to increase energy and protein intake, or of actual energy and protein supplementation, during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and checked for accuracy. Extracted data were supplemented by additional information from the trialists we contacted. MAIN RESULTS: We examined 149 reports corresponding to 65 trials. Of these trials, 17 were included, 46 were excluded, and two are ongoing. Overall, 17 trials involving 9030 women were included. For this update, we assessed methodological quality of the included trials using the standard Cochrane criteria (risk of bias) and the GRADE approach. The overall risk of bias was unclear. Nutritional education (five trials, 1090 women) Women given nutritional education had a lower relative risk of having a preterm birth (two trials, 449 women) (risk ratio (RR) 0.46, 95% CI 0.21 to 0.98, low-quality evidence), and low birthweight (one trial, 300 women) (RR 0.04, 95% CI 0.01 to 0.14). Head circumference at birth was increased in one trial (389 women) (mean difference (MD) 0.99 cm, 95% CI 0.43 to 1.55), while birthweight was significantly increased among undernourished women in two trials (320 women) (MD 489.76 g, 95% CI 427.93 to 551.59, low-quality evidence), but did not significantly increase for adequately nourished women (MD 15.00, 95% CI -76.30 to 106.30, one trial, 406 women). Protein intake increased significantly (three trials, 632 women) (protein intake: MD +6.99 g/day, 95% CI 3.02 to 10.97). No significant differences were observed on any other outcomes such as neonatal death (RR 1.28, 95% CI 0.35 to 4.72, one trial, 448 women, low quality evidence), stillbirth (RR 0.37, 95% CI 0.07 to 1.90, one trial, 431 women, low-quality evidence), small-for-gestational age (RR 0.97, 95% CI 0.45 to 2.11, one trial, 404 women, low-quality evidence) and total gestational weight gain (MD -0.41, 95% CI -4.41 to 3.59, two trials, 233 women). There were no data on perinatal death. Balanced energy and protein supplementation (12 trials, 6705 women)Risk of stillbirth was significantly reduced for women given balanced energy and protein supplementation (RR 0.60, 95% CI 0.39 to 0.94, five trials, 3408 women, moderate-quality evidence), and the mean birthweight was significantly increased (random-effects MD +40.96 g, 95% CI 4.66 to 77.26, Tau2 = 1744, I2 = 44%, 11 trials, 5385 women, moderate-quality evidence). There was also a significant reduction in the risk of small-for-gestational age (RR 0.79, 95% CI 0.69 to 0.90, I2 = 16%, seven trials, 4408 women, moderate-quality evidence). No significant effect was detected for preterm birth (RR 0.96, 95% CI 0.80 to 1.16, five trials, 3384 women, moderate-quality evidence) or neonatal death (RR 0.68, 95% CI 0.43 to 1.07, five trials, 3381 women, low-quality evidence). Weekly gestational weight gain was not significantly increased (MD 18.63, 95% CI -1.81 to 39.07, nine trials, 2391 women, very low quality evidence). There were no data reported on perinatal death and low birthweight. High-protein supplementation (one trial, 1051 women)High-protein supplementation (one trial, 505 women), was associated with a significantly increased risk of small-for-gestational age babies (RR 1.58, 95% CI 1.03 to 2.41, moderate-quality evidence). There was no significant effect for stillbirth (RR 0.81, 95% CI 0.31 to 2.15, one trial, 529 women), neonatal death (RR 2.78, 95% CI 0.75 to 10.36, one trial, 529 women), preterm birth (RR 1.14, 95% CI 0.83 to 1.56, one trial, 505 women), birthweight (MD -73.00, 95% CI -171.26 to 25.26, one trial, 504 women) and weekly gestational weight gain (MD 4.50, 95% CI -33.55 to 42.55, one trial, 486 women, low-quality evidence). No data were reported on perinatal death. Isocaloric protein supplementation (two trials, 184 women)Isocaloric protein supplementation (two trials, 184 women) had no significant effect on birthweight (MD 108.25, 95% CI 220.89 to 437.40) and weekly gestational weight gain (MD 110.45, 95% CI -82.87 to 303.76, very low-quality evidence). No data reported on perinatal mortality, stillbirth, neonatal death, small-for-gestational age, and preterm birth. AUTHORS' CONCLUSIONS: This review provides encouraging evidence that antenatal nutritional education with the aim of increasing energy and protein intake in the general obstetric population appears to be effective in reducing the risk of preterm birth, low birthweight, increasing head circumference at birth, increasing birthweight among undernourished women, and increasing protein intake. There was no evidence of benefit or adverse effect for any other outcome reported.Balanced energy and protein supplementation seems to improve fetal growth, and may reduce the risk of stillbirth and infants born small-for gestational age. High-protein supplementation does not seem to be beneficial and may be harmful to the fetus. Balanced-protein supplementation alone had no significant effects on perinatal outcomes.The results of this review should be interpreted with caution. The risk of bias was either unclear or high for at least one category examined in several of the included trials, and the quality of the evidence was low for several important outcomes. Also, as the anthropometric characteristics of the general obstetric population is changing, those developing interventions aimed at altering energy and protein intake should ensure that only those women likely to benefit are included. Large, well-designed randomised trials are needed to assess the effects of increasing energy and protein intake during pregnancy in women whose intake is below recommended levels. PMID- 26031212 TI - Self-Alignment of Beads and Cell Trapping in Precipitate Tubes. AB - Propagating reaction fronts allow the formation of materials in self-sustained, steep concentration gradients, which would otherwise rapidly decay. These conditions can result in macroscopic, noncrystallographic structures, such as tubes with large aspect ratios. For hollow silica/Zn(OH)2 tubes, we report the inclusion of diverse mesoscopic building blocks ranging from polymer beads to biological cells. For agarose beads, we observe spontaneous alignment along vertical tracks; the nearly periodic spacing of the beads along these tracks follows a log-normal distribution. We interpret this patterning in terms of hydrodynamic recruitment and discuss similarities to the adhesion dynamics of leukocytes in blood vessels. For diatoms and other cells, we observe novel surface textures, and yeast tagged with a green fluorescent protein shows strong fluorescence activity after trapping. The inclusion of these guest units should improve the possibilities for the application of these tubes in microfluidics and biotechnology. PMID- 26031213 TI - Effects of technological processes on enniatin levels in pasta. AB - BACKGROUND: Potential human health risks posed by enniatins (ENs) require their control primarily from cereal products, creating a demand for harvesting, food processing and storage techniques capable to prevent, reduce and/or eliminate the contamination. In this study, different methodologies to pasta processing simulating traditional and industrial processes were developed in order to know the fate of the mycotoxin ENs. The levels of ENs were studied at different steps of pasta processing. The effect of the temperature during processing was evaluated in two types of pasta (white and whole-grain pasta). Mycotoxin analysis was performed by LC-MS/MS. RESULTS: High reductions (up to 50% and 80%) were achieved during drying pasta at 45-55 degrees C and 70-90 degrees C, respectively. The treatments at low temperature (25 degrees C) did not change EN levels. The effect of pasta composition did not cause a significant effect on the stability of ENs. The effect of the temperature allowed a marked mycotoxin reduction during pasta processing. Generally, ENA1 and ENB showed higher thermal stability than did ENA and ENB1 . CONCLUSIONS: The findings from the present study suggested that pasta processing at medium-high temperatures is a potential tool to remove an important fraction of ENs from the initial durum wheat semolina. PMID- 26031214 TI - Rapid cycling bipolar disorder is associated with a higher lifetime prevalence of migraine. PMID- 26031215 TI - Evaluation of the levator veli palatini muscle thickness in patients with velocardiofacial syndrome using magnetic resonance imaging. AB - Velocardiofacial syndrome (VCFS) is associated with velopharyngeal insufficiency, which occurs in approximately 75% of VCFS patients. Surgical management of velopharyngeal insufficiency in VCFS patients is difficult with a high revision rate due to the anatomic and physiological abnormalities of the velopharynx. The aims of this study were to evaluate the thickness and symmetry of the levator veli palatini (LVP) muscle using magnetic resonance imaging (MRI), and to compare the findings in VCFS patients to those in patients with nonsyndromic submucous cleft palate. We conducted a prospective analysis of 17 VCFS patients (nine boys, eight girls; age range, 4-9 years) and nine patients with submucous cleft palate without VCFS (eight boys, one girl; age range, 4-13 years) who had undergone MRI between March 2009 and August 2013. The thickness of the LVP muscle was measured at six locations in both groups. The symmetry was determined by comparing the values between the average of the left three points and the right three points. The mean LVP muscle thickness was significantly thinner in VCFS patients (2.14 +/ 0.73 mm) than in patients without VCFS (3.70 +/- 1.08 mm) (p < 0.001). In addition, the difference between the left and right sides of muscle thickness in the VCFS group was larger than that in the nonsyndromic submucous cleft palate group (0.25 and 0.09 mm, respectively). The thinness and asymmetry of the LVP muscle should be considered when determining the surgical management of velopharyngeal insufficiency in VCFS patients. PMID- 26031216 TI - Chronic methamphetamine regulates the expression of MicroRNAs and putative target genes in the nucleus accumbens of mice. AB - MicroRNAs (miRNAs) are modulators of gene expression that play key regulatory roles in distinct cellular processes. Methamphetamine (METH) induces various aberrant changes in the limbic system by affecting a complex gene regulatory mechanism, yet the involvement of miRNAs in the effects of METH exposure remains unclear. This study identifies METH-responsive miRNAs and their potential effects in the nucleus accumbens (NAc) of mice. Using miRNA sequencing, we examined the expression of miRNAs in the NAc of saline- and METH-treated mice and identified 45 known miRNAs to be METH responsive. Additionally, we identified two novel miRNA candidates that were METH responsive (novel-m002C and novel-m009C). Our target prediction analysis suggested that the known METH-regulated miRNAs might target genes that are involved in cellular autophagy, cellular metabolism, and immune responses and that the novel METH-regulated miRNA candidates might target genes that are related to drug addiction. We also matched the predicted targets of METH-regulated miRNAs with the NAc messenger RNA expression profile, revealing eight putative METH-regulated target genes (Arc, Capn9, Gbp5, Lefty1, Patl2, Pde4c, Strc, and Vmn1r58). Thus, METH triggers an alteration in NAc miRNA expression, which could contribute to METH-induced changes in neuron autophagy, metabolism, and immune responses. The differential expression of putative target genes suggests their involvement following exposure to METH. PMID- 26031218 TI - Lateral Foot Pain. PMID- 26031217 TI - Ultrasound guided intra-articular ketorolac versus corticosteroid injection in osteoarthritis of the hip: a retrospective comparative study. AB - OBJECTIVE: Intra-articular steroid injection has been widely used in the management of symptomatic osteoarthritis; however, its frequent use is avoided since there is an increase in the incidence of articular infection and several mechanical side effects such as cartilage breakdown and loss of elasticity of the articular cartilage. For these reasons, nonsteroidal anti-inflammatory drugs instead of corticosteroids can be considered for intra-articular injection. On this basis, we investigated the effects and safety of ultrasound-guided intra articular ketorolac versus corticosteroid injection for patients with osteoarthritis of the hip. MATERIALS AND METHODS: This retrospective study included 98 patients with diagnoses of hip osteoarthritis who underwent ultrasound-guided intra-articular ketorolac or corticosteroid injection. Fifty patients who received ultrasound-guided intra-articular corticosteroid injection were administered a mixture of 0.5% lidocaine and triamcinolone. Forty-eight patients who received ultrasound-guided intra-articular ketorolac injection were administered 0.5% lidocaine and ketorolac. Outcome measurement was assessed using the Harris hip score and verbal numeric pain scale, which were evaluated before the injections and at 1, 3 and 6 months following the injection. Univariate analysis (using the x (2) test) and multiple logistic regression analysis were performed to evaluate the relationship between the possible outcome predictors (injected medications, patients' age, gender, pain duration and Kellgren-Lawrence classification) and the therapeutic effects. RESULTS: The Harris hip score and verbal numeric pain scale were improved at 1, 3 and 6 months after the injection in both groups. No statistical differences in the Harris hip score and verbal numeric pain scale were observed between the groups. The success rate was also not significantly different among the time periods of 1, 3 and 6 months. Multiple logistic regression and univariate analysis showed that injected medications patients' age, gender, pain duration and Kellgren-Lawrence classification were not independent predictors of successful outcome at midterm follow-up. CONCLUSION: The treatment of osteoarthritis of the hip with intra-articular ketorolac injection is as effective as that with intra-articular corticosteroid injection. Intra-articular ketorolac injection can be considered useful for patients with contraindications to using corticosteroids. PMID- 26031219 TI - Comparative pharmacokinetics of catalpol and acteoside in normal and chronic kidney disease rats after oral administration of Rehmannia glutinosa extract. AB - In this study, a sensitive and robust ultra-performance liquid chromatography mass spectrometry method with multiple-reaction monitoring mode was developed, validated, and applied to determine pharmacokinetics of catalpol and acteoside in normal and doxorubicin-induced chronic kidney disease rats after oral administration of Rehmannia glutinosa extract. The lower limits of quantification for catalpol and acteoside in rat plasma were 2.62 and 0.61 ng/mL, with a signal to-noise ratio of >=10. Precision and accuracy studies showed that catalpol and acteoside plasma concentrations were within the 10% range in all studies. The extraction recoveries of catalpol and acteoside were both >68.24% and the matrix effects ranged from 96.59 to 101.62%. The method was successfully applied to the pharmacokinetic study of catalpol and acteoside after oral administration of RG extract to normal and model rats, respectively. This study might further support the traditional use of RG to treat kidney diseases clinically. PMID- 26031220 TI - Teaching a Machine to Feel Postoperative Pain: Combining High-Dimensional Clinical Data with Machine Learning Algorithms to Forecast Acute Postoperative Pain. AB - BACKGROUND: Given their ability to process highly dimensional datasets with hundreds of variables, machine learning algorithms may offer one solution to the vexing challenge of predicting postoperative pain. METHODS: Here, we report on the application of machine learning algorithms to predict postoperative pain outcomes in a retrospective cohort of 8,071 surgical patients using 796 clinical variables. Five algorithms were compared in terms of their ability to forecast moderate to severe postoperative pain: Least Absolute Shrinkage and Selection Operator (LASSO), gradient-boosted decision tree, support vector machine, neural network, and k-nearest neighbor (k-NN), with logistic regression included for baseline comparison. RESULTS: In forecasting moderate to severe postoperative pain for postoperative day (POD) 1, the LASSO algorithm, using all 796 variables, had the highest accuracy with an area under the receiver-operating curve (ROC) of 0.704. Next, the gradient-boosted decision tree had an ROC of 0.665 and the k-NN algorithm had an ROC of 0.643. For POD 3, the LASSO algorithm, using all variables, again had the highest accuracy, with an ROC of 0.727. Logistic regression had a lower ROC of 0.5 for predicting pain outcomes on POD 1 and 3. CONCLUSIONS: Machine learning algorithms, when combined with complex and heterogeneous data from electronic medical record systems, can forecast acute postoperative pain outcomes with accuracies similar to methods that rely only on variables specifically collected for pain outcome prediction. PMID- 26031221 TI - Suppressing the Neurospora crassa circadian clock while maintaining light responsiveness in continuous stirred tank reactors. AB - Neurospora crassa has been utilized as a model organism for studying biological, regulatory, and circadian rhythms for over 50 years. These circadian cycles are driven at the molecular level by gene transcription events to prepare for environmental changes. N. crassa is typically found on woody biomass and is commonly studied on agar-containing medium which mimics its natural environment. We report a novel method for disrupting circadian gene transcription while maintaining light responsiveness in N. crassa when held in a steady metabolic state using bioreactors. The arrhythmic transcription of core circadian genes and downstream clock-controlled genes was observed in constant darkness (DD) as determined by reverse transcription-quantitative PCR (RT-qPCR). Nearly all core circadian clock genes were up-regulated upon exposure to light during 11hr light/dark cycle experiments under identical conditions. Our results demonstrate that the natural timing of the robust circadian clock in N. crassa can be disrupted in the dark when maintained in a consistent metabolic state. Thus, these data lead to a path for the production of industrial scale enzymes in the model system, N. crassa, by removing the endogenous negative feedback regulation by the circadian oscillator. PMID- 26031222 TI - Divergent Synthesis of Aeruginosins Based on a C(sp(3))-H Activation Strategy. AB - A general and scalable access to the aeruginosin family of marine natural products, exhibiting potent inhibitory activity against serine proteases, is reported. This was enabled by the strategic use of two recently implemented Pd catalyzed C(sp(3))-H activation reactions. The first method allowed us to obtain the common 2-carboxy-6-hydroxyoctahydroindole (Choi) core of the target molecules on a large scale, whereas the second method provided a rapid and divergent access to various hydroxyphenyllactic (Hpla) subunits, including halogenated ones. This unique strategy, together with an optimization of the fragment coupling sequence allowed the synthesis of four aeruginosins, that is, 98A-C and 298A from the chiral pool. Among them, aeruginosin 298A was synthesized on an unprecedentedly large scale. In addition, halogenated aeruginosins 98A and 98C were synthesized for the first time, thanks to a fine-tuning of the final hydrogenation step. PMID- 26031223 TI - Flow induced dispersion analysis rapidly quantifies proteins in human plasma samples. AB - Rapid and sensitive quantification of protein based biomarkers and drugs is a substantial challenge in diagnostics and biopharmaceutical drug development. Current technologies, such as ELISA, are characterized by being slow (hours), requiring relatively large amounts of sample and being subject to cumbersome and expensive assay development. In this work a new approach for quantification based on changes in diffusivity is presented. The apparent diffusivity of an indicator molecule interacting with the protein of interest is determined by Taylor Dispersion Analysis (TDA) in a hydrodynamic flow system. In the presence of the analyte the apparent diffusivity of the indicator changes due to complexation. This change in diffusivity is used to quantify the analyte. This approach, termed Flow Induced Dispersion Analysis (FIDA), is characterized by being fast (minutes), selective (quantification is possible in a blood plasma matrix), fully automated, and being subject to a simple assay development. FIDA is demonstrated for quantification of the protein Human Serum Albumin (HSA) in human plasma as well as for quantification of an antibody against HSA. The sensitivity of the FIDA assay depends on the indicator-analyte dissociation constant which in favourable cases is in the sub-nanomolar to picomolar range for antibody-antigen interactions. PMID- 26031224 TI - Hydroaminomethylation Beyond Carbonylation: Allene-Imine Reductive Coupling by Ruthenium-Catalyzed Transfer Hydrogenation. AB - Ruthenium(II)-catalyzed hydrogen transfer from 2-propanol mediates reductive coupling of 1,1-disubstituted allenes with formaldimines with complete branch regioselectivity, thus representing a new method for hydroaminomethylation beyond classical hydroformylation/reductive amination. PMID- 26031225 TI - Development and evaluation of two truncated recombinant NP antigen-based indirect ELISAs for detection of bovine parainfluenza virus type 3 antibodies in cattle. AB - Bovine parainfluenza virus type 3 (BPIV3) is one of the most important viral respiratory pathogens in both young and adult cattle. Nucleocapsid protein (NP) is the most abundant viral protein and the main regulator of virus replication and transcription. In this study, amino acid sequence data of BPIV3 NP was used to identify potential linear epitopic regions, which were subsequently used to design truncated recombinant NP antigens. The amino-terminal region (aa 9-157, NP N) and the carboxy-terminal region (aa 391-500, NP-C) were selected, and these two truncated recombinant BPIV3 NP proteins were expressed in Escherichia coli based on the results of prediction studies. Furthermore, Enzyme-Linked Immunosorbent Assays (ELISAs) were established using the truncated recombinant BPIV3-N proteins as antigens, and 154 clinical samples were used to evaluate the newly established ELISA systems in comparison with a virus neutralisation test (VNT) as a reference. The results showed that a high coincidence rate was observed for the data that were obtained by the two methods. The sensitivity of NP-N ELISA and NP-C ELISA were 98.4% and 94.6%, respectively, and the specificity of both ELISAs was 100% with reference to the VNTs. Our data indicated that both ends of NP have high immunogenicity during BPIV3 infection and that they were good targets for serodiagnosis. The ELISAs based on the two truncated proteins were especially suitable for use in large-scale epidemiological investigations. PMID- 26031226 TI - Brief Report: Human Mesenchymal Stem-Like Cells Facilitate Floating Tumorigenic Cell Growth via Glutamine-Ammonium Cycle. AB - How mesenchymal stem cells (MSCs) promote tumor growth remains incompletely understood. Here, we show that mesenchymal stem-like cells (MSLCs) are commonly present in malignant pleural effusion or ascites of cancer patients, where they directly interact with tumor cells. Chemokines and chemokine receptors, especially the CCL2/CCR2 pathway, are involved in this interaction. As a result, MSLCs exert tumor-promoting effects by enhancing the proliferation and colony formation of tumor-repopulating cells. The underlying molecular basis involves MSLC release of glutamine to tumorigenic cells. Inhibition of glutamine uptake impedes MSC-mediated tumor-promoting effects. More intriguingly, MSLCs take up tumor cell-released ammonium that, in turn, favors MSLC growth. Thus, glutamine and ammonium form a vicious cycle between MSLCs and tumorigenic cells. These findings suggest a potential clinical application by targeting MSLCs in patients with malignant pleural effusions or ascites. PMID- 26031227 TI - MRP1 expression in bronchoalveolar lavage cells in subjects with lung cancer who were chronically exposed to arsenic. AB - Alteration of multidrug resistance-associated protein-1 (MRP1) expression has been associated with certain lung diseases, and this protein may be pivotal in protecting the lungs against endogenous or exogenous toxic compounds. The aim of this study was to evaluate and compare the expression of MRP1 in bronchoalveolar cells from subjects with and without lung cancer who had been chronically exposed to arsenic through drinking water. MRP1 expression was assessed in bronchoalveolar cells in a total of 102 participants. MRP1 expression was significantly decreased in those with arsenic urinary levels >50 MUg/L when compared with the controls. In conclusion, chronic arsenic exposure negatively correlates with the expression of MRP1 in BAL cells in patients with lung cancer. PMID- 26031228 TI - Angiomyolipoma with minimal fat: differentiation from clear cell renal cell carcinoma and papillary renal cell carcinoma by texture analysis on CT images. AB - RATIONALE AND OBJECTIVES: To retrospectively evaluate the diagnostic performance of texture analysis (TA) for the discrimination of angiomyolipoma (AML) with minimal fat, clear cell renal cell cancer (ccRCC), and papillary renal cell cancer (pRCC) on computed tomography (CT) images and to determine the scanning phase, which contains the strongest discriminative power. MATERIALS AND METHODS: Patients with pathologically proved AMLs (n = 18) lacking visible macroscopic fat at CT and patients with pathologically proved ccRCCs (n = 18) and pRCCs (n = 14) were included. All patients underwent CT scan with three phases (precontrast phase [PCP], corticomedullary phase [CMP], and nephrographic phase [NP]). The selected images were analyzed and classified with TA software (MaZda). Texture classification was performed for 1) minimal fat AML versus ccRCC, 2) minimal fat AML versus pRCC, and 3) ccRCC versus pRCC. The classification results were arbitrarily divided into several levels according to the misclassification rates: excellent (misclassification rates <=10%), good (10%< misclassification rates <=20%), moderate (20%< misclassification rates <=30%), fair (30%< misclassification rates <=40%), and poor (misclassification rates >=40%). RESULTS: Excellent classification results (error of 0.00%-9.30%) were obtained with nonlinear discriminant analysis for all the three groups, no matter which phase was used. On comparison of the three scanning phases, we observed a trend toward better lesion classification with PCP for minimal fat AML versus ccRCC, CMP, and NP images for ccRCC versus pRCC and found similar discriminative power for minimal fat AML versus pRCC. CONCLUSIONS: TA might be a reliable quantitative method for the discrimination of minimal fat AML, ccRCC, and pRCC. PMID- 26031230 TI - The aggressive peripheral T-cell lymphomas: 2015. AB - BACKGROUND: T-cell lymphomas make up approximately 10%-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. DIAGNOSIS: The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the World Health Organization classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than that for aggressive B-cell lymphomas, with a range of 72%-97% for the aggressive PTCLs. RISK STRATIFICATION: Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography scans seem to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large-cell lymphoma-particularly young patients with the anaplastic lymphoma kinase positive subtype. RISK-ADAPTED THERAPY: Anaplastic large-cell lymphoma is the only subgroup to have a good response to a CHOP-like regimen. Angioimmunoblastic T cell lymphoma has a prolonged disease-free survival in only ~20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL not otherwise specified is not one disease. Anthracycline-containing regimens have disappointing results, and a new approach is needed. Natural killer/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy-containing regimens. Enteropathy-associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy-associated PTCL seem to benefit from intensive therapy. PMID- 26031229 TI - Breast density evaluation using spectral mammography, radiologist reader assessment, and segmentation techniques: a retrospective study based on left and right breast comparison. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to compare the precision of mammographic breast density measurement using radiologist reader assessment, histogram threshold segmentation, fuzzy C-mean segmentation, and spectral material decomposition. MATERIALS AND METHODS: Spectral mammography images from a total of 92 consecutive asymptomatic women (aged 50-69 years) who presented for annual screening mammography were retrospectively analyzed for this study. Breast density was estimated using 10 radiologist reader assessment, standard histogram thresholding, fuzzy C-mean algorithm, and spectral material decomposition. The breast density correlation between left and right breasts was used to assess the precision of these techniques to measure breast composition relative to dual energy material decomposition. RESULTS: In comparison to the other techniques, the results of breast density measurements using dual-energy material decomposition showed the highest correlation. The relative standard error of estimate for breast density measurements from left and right breasts using radiologist reader assessment, standard histogram thresholding, fuzzy C-mean algorithm, and dual-energy material decomposition was calculated to be 1.95, 2.87, 2.07, and 1.00, respectively. CONCLUSIONS: The results indicate that the precision of dual-energy material decomposition was approximately factor of two higher than the other techniques with regard to better correlation of breast density measurements from right and left breasts. PMID- 26031231 TI - Predictive accuracy of second-trimester uterine artery Doppler indices for stillbirth: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the predictive accuracy for stillbirth of second-trimester uterine artery Doppler. METHODS: We searched MEDLINE, EMBASE and The Cochrane Library databases from inception until March 2015 without language restrictions. The included studies were those that assessed the association of abnormal uterine artery Doppler parameters and stillbirth. Two independent reviewers selected the studies, extracted data and assessed quality. Results for studies that were performed in the second trimester were pooled and summary estimates of sensitivity, specificity, likelihood ratios and their 95% confidence intervals were obtained. An overall summary of test accuracy was provided by the diagnostic odds ratio. Subgroup analysis was performed according to whether the study population was high risk or unselected. RESULTS: Literature searches returned 338 relevant citations with 32 considered in full. Thirteen studies met our search criteria (85 845 women, 508 stillbirths) and were included in the review. Bivariate pooled estimate for sensitivity was 65% (95% CI, 38-85%) and for specificity 82% (95% CI, 72-88%). The positive likelihood ratio was 3.5 (95% CI, 2.3-5.5) and negative likelihood ratio 0.43 (95% CI, 0.22-0.85). The diagnostic odds ratio was 8.3 (95% CI, 3.0-22.4). Heterogeneity was high in the studies of high-risk women. CONCLUSIONS: Abnormal uterine artery Doppler indices are associated with a three- to four-fold increase in the risk of stillbirth. The heterogeneity was particularly high in the high-risk group rendering it impossible to draw firm conclusions. In view of this, there is a role for individual patient data meta-analysis to define which Doppler parameter and threshold value should be measured. PMID- 26031232 TI - Comparison of the substituent effects on the (13) C NMR with the (1) H NMR chemical shifts of CH=N in substituted benzylideneanilines. AB - Fifty-two samples of substituted benzylideneanilines XPhCH=NPhYs (XBAYs) were synthesized, and their NMR spectra were determined in this paper. Together with the NMR data of other 77 samples of XBAYs quoted from literatures, the (1) H NMR chemical shifts (deltaH (CH=N)) and (13) C NMR chemical shifts (deltaC (CH=N)) of the CH=N bridging group were investigated for total of 129 samples of XBAYs. The result shows that the deltaH (CH=N) and deltaC (CH=N) have no distinctive linear relationship, which is contrary to the theoretical thought that declared the deltaH (CH=N) values would increase as the deltaC (CH=N) values increase. With the in-depth analysis, we found that the effects of sigmaF and sigmaR of X/Y group on the deltaH (CH=N) and the deltaC (CH=N) are opposite; the effects of the substituent specific cross-interaction effect between X and Y (Deltasigma(2) ) on the deltaH (CH=N) and the deltaC (CH=N) are different; the contributions of parameters in the regression equations of the deltaH (CH=N) and the deltaC (CH=N) [Eqns and 7), respectively] also have an obvious difference. PMID- 26031233 TI - Transumbilical cord access (TUCA) for laparoscopy in infants and children: simple, safe and fast. AB - PURPOSE: We herein report a case series evaluating the safety and complication rate of transumbilical cord access (TUCA) for pediatric laparoscopic surgery. METHODS: Data were collected for 556 infants and children. Access into the abdominal cavity was gained via a transverse infraumbilical stab incision passing the fibrotic umbilical cord remnant. Ninety-two infants underwent laparoscopic pyloromyotomy (LPM), 159 female infants underwent herniorrhaphy (LHR) and 309 infants underwent appendectomy (LAP). Of the total operations, 70 % were performed by board-certified surgeons and 30 % were performed by non-board certified surgeons. The median time of follow-up was 24 months. RESULTS: No cases of acute severe bleeding or organ laceration were noted. TUCA-related complications were observed in nine patients (1.6 %). Omphalitis and persistent wound secretion were detected in eight children and foreign bodies consisting of cyanoacrylate were removed from three of these patients. Meanwhile, umbilical pain leading to surgical revision was observed in one child, and eight umbilical hernias were repaired during the TUCA procedures. No signs of postoperative incisional hernia were recorded. CONCLUSIONS: TUCA is a safe and comfortable access method for pediatric laparoscopic surgery in various age groups. This method is easy to learn and can be quickly and safely performed in the vast majority of children. PMID- 26031235 TI - The mitochondrial genome of the peach fruit fly, Bactrocera zonata (Saunders) (Diptera: Tephritidae): Complete DNA sequence, genome organization, and phylogenetic analysis with other tephritids using next generation DNA sequencing. AB - Mitochondrial genome can provide information for genomic structure as well as for phylogenetic analysis and evolutionary biology. The complete 15,935 bp mitochondrial genome of Bactrocera zonata (Diptera: Tephritidae), is assembled from Illumina MiSeq read data. The mitogenome information for B. zonata was compared to the homologous sequences of other tephritids. Annotation indicated that the structure and orientation of 13 protein coding genes (PCGs), 22 tRNA and 2 rRNA sequences were typical of, and similar to, the ten closely related tephritid species. The nucleotide composition shows heavily biased toward As and Ts accounting 73.34% and exhibits a slightly positive AT skew, which is similar to other known tephritid species. All PCGs are initiated by ATN codons, except for cox1 with TCG and atp8 with GTG. Nine PCGs use a common stop codon of TAA or TAG, whereas the remaining four use an incomplete termination codon T or TA likely to be completed by adenylation. All tRNAs have the typical clover-leaf structure, with an exception for trnS((AGN)). Four short intergenic spacers showed high degree of conservation among B. zonata and other ten tephritids. A poly(T) stretch at the 5' end followed by [TA(A)]n-like stretch and a tandem repeats of 39 bp has been observed in CR. The analysis of gene evolutionary rate revealed that the cox1 and atp6 exhibits lowest and highest gene substitution rates, respectively than other genes. The phylogenetic relationships based on Maximum Likelihood method using all protein-coding genes and two ribosomal RNA genes confirmed that B. zonata is closely related to Bactrocera correcta, Bactrocera carambolae, Bactrocera papayae, and Bactrocera philippinensis and Bactrocera dorsalis belonging to B. dorsalis species complex forms a monophyletic clade, which is in accordance with the traditional morphological classification and recent molecular works. PMID- 26031234 TI - Smoking behavior among adult childhood cancer survivors: what are we missing? AB - PURPOSE: Childhood cancer survivors are a growing population at increased risk for smoking-related health complications. This study compared smoking prevalence, age at smoking initiation, and time trend of smoking prevalence from 1997 to 2010 between adult survivors of childhood cancer and adults without a cancer history (controls) and identified predictors of smoking among these survivors. METHODS: Data were pooled from the 1997-2010 National Health Interview Survey (survivors, n = 1438; controls, n = 383,805). Smoking prevalence by age group was calculated using weighted least square regression analysis and weighted linear regression of prevalence on year for trend analysis. Logistic regression analyses adjusting for sample weights and design effects were performed to identify predictors of smoking among survivors. RESULTS: Compared to controls, survivors were significantly more likely to be younger, female, non-Hispanic White, unemployed, with lower income, and to weigh less and smoke more. Survivors initiated smoking earlier than controls. Smoking prevalence among survivors peaked at age 30 and 40 years old, compared to age 25 years in controls. Smoking prevalence decreased consistently from 1997 to 2010 among controls, with larger significant declines in survivors that were subject to more year-to-year variability. Compared to nonsmoking survivors, those who smoke were significantly more likely to be non Hispanic White, young, uninsured, poor, to have a high school education or less, and to report drinking alcohol. CONCLUSION: Smoking in adult survivors of childhood cancer continues as a persistent risk factor across socioeconomic groups. IMPLICATIONS FOR CANCER SURVIVORS: Targeted and tailored smoking cessation/prevention interventions for these survivors are needed. PMID- 26031236 TI - Wilson's disease caused by alternative splicing and Alu exonization due to a homozygous 3039-bp deletion spanning from intron 1 to exon 2 of the ATP7B gene. AB - We describe a case of Wilson's disease (WD) diagnosed at 5 years after routine biochemical test showed increased aminotransferases. Mutation analysis of the ATP7B gene revealed a 3039-bp deletion in the homozygous state spanning from the terminal part of intron 1 to nt position 368 of exon 2. This deletion results in the activation of 3 cryptic splice sites: an AG acceptor splice site in nt positions 578-579 producing a different breakpoint and removing the first 577 nts of exon 2, an acceptor and a donor splice site in nt positions 20363-4 and 20456 7, respectively, in intron 1, resulting in the activation of a 94-bp cryptic Alu exon being incorporated into the mature transcript. The resulting alternative transcript contains a TAG stop codon in the first amino acid position of the cryptic exon, likely producing a truncated, non-functional protein. This study shows that intron exonization can also occur in humans through naturally occurring gross deletions. The results suggest that the combination of DNA and RNA analyses can be used for molecular characterization of gross ATP7B deletions, thus improving genetic counseling and diagnosis of WD. Moreover these studies help to better establish new molecular mechanisms producing Wilson's disease. PMID- 26031237 TI - Assessing Reactive and Proactive Aggression in Detained Adolescents Outside of a Research Context. AB - The Reactive Proactive Aggression Questionnaire (RPQ) is a self-report tool for assessing reactive aggression (RA) and proactive aggression (PA). This study contributes to the literature by testing the psychometric properties of the RPQ across detained boys from various ethnicities whilst using data that were gathered during clinical assessments. The factorial, convergent, and criterion validity, and the internal consistency of the RPQ scores received strong support in the total sample and across four ethnicity groups. Also, three groups of boys were identified, with the group including boys with high levels of both RA and PA including the most severe boys in terms of anger, delinquency, alcohol/drug use, and psychopathic traits, and having the highest prevalence rate of conduct disorder and substance use disorder. Together, these findings suggest that the RPQ may hold promise for assessing RA and PA in detained boys, even when confidentiality and anonymity of the information is not guaranteed. PMID- 26031238 TI - Bleed-to-read disposable microsystems for the genetic and serological analysis of celiac disease markers with amperometric detection. AB - Celiac disease is an auto-immune disorder induced by ingestion of gluten in genetically predisposed individuals. Its diagnostics is more accurate using a combination of immunologic and genetic tests to detect of high levels of certain auto-antibodies and the presence human leukocyte antigen HLA-DQ2 or HLA-DQ8 genetic markers. In this work, we report the design and testing of automated microsystems combining sample treatment, storage, fluidic transport, and detection in a single platform able to carry out genetic or serologic analysis for detection of celiac disease markers. These microsystems share a common footprint and many fluidic features and are thus able to perform a complete assay. The microsystem for the genetic assay extracts and amplifies the DNA prior to detection, while the serology microsystem contains a filter and chamber for the generation and subsequent dilution of plasma. The performance of both platforms is demonstrated and compared with reference methods with an excellent correlation, which makes the developed platform amenable for clinical studies. PMID- 26031240 TI - Deficiency of monoclonal non-specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice. AB - Maternal immune tolerance to the semi-allogenic fetus is required for successful pregnancy in mammals. Monoclonal nonspecific suppressor factor beta (MNSFB) is an immunosuppressive factor present in uterine epithelial and stromal cells, as well as in macrophages and T cells. Although the functional neutralization of MNSFB using specific antibodies against it lead to failed embryo implantation in mice, the exact role of MNSFB at the fetal-maternal interface remains unclear. The present study generated conditional heterozygous Mnsfb-deficient (Mnsfb(+/) (-) ) mice using the LoxP/Cre system. Western-blot analyses showed that uterine MNSFB protein in Mnsfb(+/-) mice was remarkably down-regulated compared to that in the wild-type (Mnsfb(+/+) ) mice. The litter size of female Mnsfb(+/-) mice was significantly reduced, which corresponded to developmental failure of embryos beyond Day 11 of pregnancy. The expression level of MNSFB protein was also lower in the failing compared to the normal embryos. An aberrant interaction between the embryos of Day-4 pregnant wild-type mice and endometrial stromal cells of female Mnsfb(+/-) mice was observed in vitro. The uterine Day-5 abundance of P53, BAX, and BCL-G in pregnant Mnsfb(+/-) mice was significantly decreased compared to that of wild-type mice, whereas the expression of P27 and tumor necrosis factor alpha (TNFA) was elevated. By comparison, the levels of MNSFB and BAX proteins in human decidual tissues obtained from recurrent spontaneous miscarriage patients were significantly reduced compared to those obtained from legal medial abortion, highlighting the involvement of MNSFB in the pathogenesis of recurrent spontaneous miscarriage. Together, these results demonstrated that a deficiency in MNSFb is associated with pregnancy loss, probably through reduced P53 and/or increased TNFA production at the fetal-maternal interface. PMID- 26031242 TI - Comparison of echocardiographic results of CoreValve versus Edwards Sapien valves in patients with bicuspid aortic valve. PMID- 26031241 TI - Impact of aggressive management and palliative care on cancer costs in the final month of life. AB - BACKGROUND: A significant share of the cost of cancer care is concentrated in the end-of-life period. Although quality measures of aggressive treatment may guide optimal care during this timeframe, little is known about whether these metrics affect costs of care. METHODS: This study used population data to identify a cohort of patients who died of cancer in Ontario, Canada (2005-2009). Individuals were categorized as having received or having not received aggressive end-of-life care according to quality measures related to acute institutional care or chemotherapy administration in the end-of-life period. Costs (2009 Canadian dollars) were collected over the last month of life through the linkage of health system administrative databases. Multivariate quantile regression was used to identify predictors of increased costs. RESULTS: Among 107,253 patients, the mean per-patient cost over the final month was $18,131 for patients receiving aggressive care and $12,678 for patients receiving nonaggressive care (P < .0001). Patients who received chemotherapy in the last 2 weeks of life also sustained higher costs than those who did not (P < .0001). For individuals receiving end-of-life care in the highest cost quintile, early and repeated palliative care consultation was associated with reduced mean per-patient costs. In a multivariate analysis, chemotherapy in the 2 weeks of life remained predictive of increased costs (median increase, $536; P < .0001), whereas access to palliation remained predictive for lower costs (median decrease, $418; P < .0001). CONCLUSIONS: Cancer patients who receive aggressive end-of-life care incur 43% higher costs than those managed nonaggressively. Palliative consultation may partially offset these costs and offer resultant savings. PMID- 26031243 TI - Understanding Left Main Disease: Will the Right SYNTAX Help Us EXCEL in (PRE)COMBAT? PMID- 26031244 TI - Dyes in Liquid Crystals: Experimental and Computational Studies of a Guest-Host System Based on a Combined DFT and MD Approach. AB - Practical applications of guest-host liquid crystal systems are critically dependent on the alignment of the guest species within the liquid crystal host. UV/Vis absorption spectroscopy shows that the 1,5-dihydroxy-2,6-bis-(4 propylphenyl)-9,10-anthraquinone dye aligns within the E7 nematic host, giving an experimental dichroic ratio of 9.40 and dye order parameter of 0.74. This alignment was modelled by using a combination of density functional theory (DFT) and molecular dynamics (MD) computational approaches that do not require the input of experimental data. Time-dependent DFT calculations show that the electronic transition dipole moment is highly aligned with the long molecular axis of the dye. Fully atomistic MD simulations show that the long axis of the dye is less highly aligned within the E7 host, indicating that this contribution limits the overall dye alignment and, thereby, the potential practical applications of this particular system. Importantly, this study demonstrates an experimental and combined DFT and MD computational approach that may be applied generally to guest-host systems, providing a potential route to their rational design. PMID- 26031245 TI - Density patterns in metal films produced by laser interference. AB - Fringed periodic patterns have been produced by laser interference at 193 nm in an almost continuous 9.5 nm-thick Ag film that exhibits a number density of ~189 MUm(-2) holes. Patterns with four periods in the range of 1.8-10.2 MUm were produced by changing the projection optics. At high fluences, the film breaks up into nanostructures around the regions exposed to intensity maxima due to laser induced melting. At low fluences, a new process is observed that is triggered at the initial holes of the film by solid-state dewetting. Once the fluence is high enough to prevent the temperature balance across the pattern, mass transport from cold to hot regions is observed, leading to film densification in regions around intensity maxima sites. The novel patterns are thus formed by fringes of material that is more/less dense than the as-grown film, each of which is located at intensity maxima/minima sites, and have negligible topography. Comparing the present results to earlier reports in the literature shows that the thermal gradient across the pattern is influenced by the initial film microstructure, rather than by the thickness. The existence of a minimum period, which is achievable depending on the thermal continuity of the film, is also discussed. PMID- 26031250 TI - Repair of isolated hepatic artery injury from a samurai sword. PMID- 26031248 TI - Disappearing polymorphs revisited. AB - Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law. PMID- 26031251 TI - Hepatobiliary mucinous cystadenoma resulting in biliary obstruction. PMID- 26031252 TI - Splenic abscess and infarct concealing pancreatic cancer. PMID- 26031253 TI - Surgical treatment of cervical schwannomas arising from the vagus. PMID- 26031254 TI - Anterior chest wall disassociation: a pattern associated with serious underlying injury. PMID- 26031255 TI - Can prenatal ultrasound predict secondary gastrointestinal complications in neonates with gastroschisis? PMID- 26031256 TI - Intra-operative acoustic enhancement. PMID- 26031257 TI - Colonic adenocarcinoma recurrence in a biologic mesh after ventral hernia repair: what now? PMID- 26031258 TI - Scedosporium: an unlikely cause of fungal necrotizing fasciitis. PMID- 26031259 TI - Actinomycotic appendicitis presenting as biliary track disease treated with surgery alone. PMID- 26031260 TI - The Appleby maneuver: a safe approach for adrenal tumors involving the celiax axis. PMID- 26031261 TI - Angiodysplasia: an unusual case of gastrointestinal bleeding. PMID- 26031262 TI - Successful Rescue Therapy for Severe Acute Anemia: Managing the Critically Ill Jehovah's Witness. PMID- 26031263 TI - Sarcoidosis presenting as chronic sinusitis with orbital and intracranial extension. PMID- 26031264 TI - Alton Ochsner, MD (1896-1981): surgical pioneer and legacy linking smoking and disease. AB - Edward William Alton Ochsner kept a plain, metal card file in which he recorded close to 50 years worth of medical experiences, research, and insights. The most populated topics were filed as "Cancer, Lung" and "Cancer, Bronchogenic." These reflected his areas of greatest interest, for which he would go on to produce groundbreaking work. Of his many lifetime accomplishments, he is perhaps best known for being the first to report a link between cigarette smoking and lung cancer. This was just one of the many ways in which Ochsner worked to effect social change. The establishment of the Ochsner Health System in New Orleans was born from this similar passion. Ochsner went on to become one of the giants of his generation as a result of this tireless work as a leader, educator, and mentor. PMID- 26031265 TI - Machine perfusion: not just for marginal kidney donors. AB - Interest in machine perfusion (MP) for donated kidneys has markedly increased in the past decade as a means to improve graft function, although the donor populations in which it should be applied have not yet been resolved. All adults undergoing de-novo isolated kidney transplantation from standard-criteria donors in the UNOS database 2005 to 2011 were reviewed with the primary endpoint of delayed graft function (DGF), defined as dialysis within seven days of transplantation, in those who received kidneys that underwent MP versus cold storage (CS) alone. Three methods were used to control for differences between groups. Multivariable logistic regression was performed, adjusting for donor and recipient characteristics significantly associated with DGF. Rates were also compared in a cohort of propensity-matched MP vs CS recipients. Finally, a paired kidney study was performed, where one kidney underwent MP and the contralateral underwent CS. There were 36,323 patients, with unadjusted DGF rates of 18.6 per cent (n = 1830/9882) and 22.4 per cent (n = 5931/26,441; P < 0.001) in the MP vs CS groups, respectively. After multivariable analysis, the odds ratio for DGF in the MP group was 0.59 (P < 0.001) versus CS. In the propensity-matched cohort, there were 8929 patients each in the MP and CS groups. DGF occurred in 16.8 per cent of the MP group vs 25.3 per cent with CS (P < 0.001, OR 0.59). In the paired kidney study, rates of DGF were 16.7 per cent vs 24.3 per cent (P < 0.001) in the 1665 recipients each in the MP versus CS groups (OR 0.6). In conclusion, machine perfusion is beneficial in reducing DGF even when standard donors are utilized, and thus should not be limited to marginal kidneys. PMID- 26031266 TI - GHOST Protocol: Greatest Healing Opportunity for Soft Tissue, a Treatment Paradigm for Complex Sarcoma Reconstruction. AB - Modern sarcoma treatment has created new challenges for plastic surgeons. This study was designed to review the recent experience and practice patterns following complex sarcoma resection at a large sarcoma center. All cases from October 2013 to October 2014 involving rare nonepithelial tumors, a multidisciplinary surgical team, radiation and/or chemotherapy treatments, and plastic surgical reconstruction were included in the analysis. In addition to evaluating clinical outcomes, cases were reviewed to identify factors associated with excellent or poor patient care. Review of these cases formed the basis of the greatest healing opportunity for soft tissue (GHOST) protocol. Our patient population included seven males (64%) and four females (36%). All except one patient was exposed to radiotherapy, chemotherapy, or some combination. Diverse procedures were used for reconstruction. Early complications occurred in two patients (18%), and late complications in four patients (36%). Sarcoma resection was found to be highly morbid in our series. Patients with poor preoperative nutritional status were more likely to experience complications postoperatively. The decision to stage a reconstruction was complex and influenced by several factors. Multimodal sarcoma treatments may involve highly morbid procedures and create complex wounds. The GHOST protocol is a useful reference for plastic surgeons. PMID- 26031267 TI - Early versus delayed amputation in the setting of severe lower extremity trauma. AB - Leg-threatening injuries present patients and clinicians with the difficult decision to pursue primary amputation or attempt limb salvage. The effects of delayed amputation after failed limb salvage on outcomes, such as prosthetic use and hospital deposition, are unclear. We evaluated the timing of amputations and its effects on outcomes. We retrospectively reviewed all trauma patients undergoing lower extremity amputation from January 1, 2000 through December 31, 2010 at a Level 2 trauma center. Patients undergoing early amputation (amputation within 48 hours of admission) were compared with patients undergoing late amputation (amputations >48 hours after admission). Patient demographics, injury specifics, operative characteristics, and outcomes were documented. During the 11 year study period, 43 patients had a lower extremity amputation and 21 had early amputations. The two groups were similar except for a slightly higher Mangled Extremity Severity Score in the early amputation group. Total hospital length of stay significantly differed between groups, with the late amputation group length of stay being nearly twice as long. The late amputation group had significantly more ipsilateral leg complications than the early group (77% vs 15%). There was a trend toward more prosthetic use in the early group (93%vs 57%, P = 0.07). Traumatic lower extremity injuries requiring amputation are rare at our institution (0.3% incidence). Regardless of the amputation timing, most patients were able to obtain a prosthetic. Although the late group had a longer length of hospital stay and more local limb complications, attempted limb salvage still appears to be a viable option for appropriately selected trauma patients. PMID- 26031268 TI - Transsacrococcygeal approach for resection of retrorectal tumors. AB - Retrorectal tumors, are a rare and interesting entity, traditionally managed with surgery. The surgical approach is a key to get an easy and safe access. The purpose of this study was to evaluate the results of resection by a transsacrococcygeal approach. Thirty-six patients had retrorectal tumors resected by a transsacrococcygeal approach in our department. All the tumors were en bloc resected, irrespective of size and anatomical depth. The clinic data were retrospectively reviewed. Tumor mean size was 10 +/- 4.4 cm. In 16 cases, tumors were 10 cm or more in size. The largest tumor measured 20 cm. The estimated mean blood loss was 130 ml. No mortality and severe postoperative complications were observed. The most significant issues were wound infection and delayed healing. Pathology showed 15 cases of epidermal cysts, two cases of enterogenous cyst, one case of bronchogenic cyst, 12 cases of teratoma, two cases of schwannoma, two cases of low-grade malignant fibrous myxoma, one case of aggressive angiomyxoma, one case of desmoid tumor. The transsacrococcygeal approach gives an easy access and good visualization with fewer complications. This surgical approach shows to be safe and effective for resection of retrorectal tumors. PMID- 26031269 TI - Feasibility of subcutaneous gentamicin and pressurized irrigation as adjuvant strategies to reduce surgical site infection in colorectal surgery: results of a pilot study. AB - Surgical site infections (SSIs) remain a common and costly morbidity after colorectal surgery. This rate remains high even in the setting of strict adherence to Surgical Care Improvement Project Protocols. The aim of our pilot study was to determine the feasibility and safety of subcutaneous gentamicin injection or pressurized irrigation as adjuncts to reduce SSI. A total of 132 patients who underwent colorectal surgery at the VA North Texas Health Care System were prospectively assigned to a pressurized irrigation group (n = 44), a preincision gentamicin injection group (n = 48), or control (n = 40). The primary objective was to assess safety and feasibility of these strategies. Patient demographics were matched among groups. Univariate and multivariate analyses were performed to identify possible predictions of SSI in this cohort. The rate of SSI in the control group was 25 per cent, 13.5 per cent in the pressurized irrigation group, and 12.5 per cent in the gentamicin group (P = 0.26). Combined, the intervention groups had a 13 per cent SSI versus 25 per cent control (P = 0.09). Operative time was not increased by the interventions and no intraoperative complications specifically related to the interventions were noted. Postoperative complications were not different between groups. Both albumin and body mass index were associated with SSI. Body mass index was and independent predictor of SSI (P = 0.006). In conclusion, this pilot study demonstrates the feasibility of the interventions described. There was no detrimental effect of either intervention. There was trend toward a reduction in SSI in the intervention group, which warrants further investigation. PMID- 26031270 TI - Intraoperative indocyanine green fluorescence angiography--an objective evaluation of anastomotic perfusion in colorectal surgery. AB - The essentials for any bowel anastomosis are: adequate perfusion, tension free, accurate tissue apposition, and minimal local spillage. Traditionally, perfusion is measured by assessing palpable pulses in the mesentery, active bleeding at cut edges, and lack of tissue discoloration. However, subjective methods lack predictive accuracy for an anastomotic leak. We used intraoperative indocyanine green (ICG) fluorescence angiography to objectively assess colon perfusion before a bowel anastomosis. Seventy-seven laparoscopic colorectal operations, between June 2013 and June 2014, were retrospectively reviewed. The perfusion to the colon and ileum was clinically assessed, and then measured using the SPY Elite Imaging System. The absolute value provided an objective number on a 0-256 gray scale to represent differences in ICG fluorescence intensity. The lowest absolute value was used in data analysis for each anastomosis (including small bowel) to represent the theoretical least perfused/weakest anastomotic area. The lowest absolute value recorded was 20 in a patient who underwent a laparoscopic right hemicolectomy for an adenoma, with no postoperative complications. Four low anterior resection patients had additional segments of descending colon resected. There was one mortality in a patient who underwent a laparoscopic right hemicolectomy. This study illustrates an initial experience with the SPY system in colorectal surgery. The SPY provides an objective, numerical value of bowel perfusion. However, evidence is scant as to the significance of these numbers. Large-scale randomized controlled trials are required to determine specific cutoff values correlated with surgical outcomes, specifically anastomotic leak rates. PMID- 26031271 TI - Operative failure rate and documentation of family history in young patients undergoing focused parathyroidectomy for primary hyperparathyroidism. AB - Primary hyperparathyroidism in multiple endocrine neoplasia type I usually affects all parathyroid glands, making focused parathyroidectomy (FP) inappropriate. The risk of previously undiagnosed multiple endocrine neoplasia type I in a younger patient with primary hyperparathyroidism is higher than in an older patient. We hypothesized that FP may lead to a higher failure rate in younger versus older patients. A retrospective review was performed of a single institution database of patients who underwent parathyroidectomy for primary hyperparathyroidism. Routine statistical analysis was performed, including Fisher's exact test. A total of 635 patients were included. Operative failure occurred in 7/55 (13%) younger patients and 21/580 (4%) older patients (P = 0.007). In conclusion, operative failure occurred in a statistically significantly higher percentage of younger versus older patients undergoing FP. This is partly explained by undiagnosed multiple endocrine neoplasia syndrome type I in the younger patient group. Endocrine surgeons must make every effort to preoperatively identify multiple endocrine neoplasia syndrome type I in the younger patient population. PMID- 26031272 TI - The rationality of resectional surgery and palliative interventions in the management of patients with gallbladder cancer. AB - The aim of the present study was to evaluate in a retrospective manner, the survival period and survival rate according to stages and groups after R0, R1, R2 resections and palliative interventions. Between 2003 and 2012, 67 patients diagnosed with gallbladder carcinoma were retrospectively analyzed. Patient demographics, the survival period, and survival rate according to stages and groups after R0, R1, R2 resections and palliative interventions were retrospectively analyzed. Sixty-seven patients were diagnosed with gallbladder carcinoma. Thirty-eight patients (56.7%) were female and 29 patients (43.3%) were male. The median survival period was significantly longer in stage II and III diseases than in stage IV disease (P < 0.001). The R0, R1, and R2 resection rates in patients who underwent surgery with curative intent were 67.7, 19.4, and 12.9 per cent, respectively. The R0 resection rate according to the tumor stages was 100 per cent for stage I, 87.5 per cent for stage II, 66.7 per cent for stage III, and 42.8 per cent for stage IV disease. The median follow-up period was six months (eight days to 36 months). During this follow-up period, 53 patients (79.1%) died. In conclusion, R0 resection rate decreases when tumor stage increases. The highest survival rates after R0 resection are achieved in patients with stage I, II, and III diseases. Radical surgery has no benefit over palliative surgery for stage IV disease in terms of survival. PMID- 26031273 TI - Diverticulitis Outcomes are Equivalent Between Level 1 Trauma Centers and Community Hospitals in New Jersey. AB - Traditionally, general surgeons provide emergency general surgery (EGS) coverage by assigned call. The acute care surgery (ACS) model is new and remains confined mostly to academic centers. Some argue that in busy trauma centers, on-call trauma surgeons may be unable to also care for EGS patients. In New Jersey, all three Level 1 Trauma Centers (L1TC) have provided ACS services for many years. Analyzing NJ state inpatient data, we sought to determine whether outcomes in one common surgical illness, diverticulitis, have been different between L1TC and nontrauma centers (NTC) over a 10-year period. The NJ Medical Database was queried for patients aged 18 to 90 hospitalized from 2001 to 2010 for acute diverticulitis. Demographics, comorbidities, operative rates, and mortality were compiled and analyzed comparing L1TC to NTC. For additional comparison between L1TC and NTC, 1:1 propensity score matching with replacement was accomplished. chi(2), t test, and Cochran-Armitage trend test were used. From 2001 to 2010, 88794 patients were treated in NJ for diverticulitis. 2621 patients (2.95%) were treated at L1TCs. Operative rates were similar between hospital types. Patients treated at L1TCs were more often younger (63.1 +/- 0.3 vs 64.7 +/- 0.1; P < 0.001), nonwhite (43.1% vs 23.1%; P < 0.0001), and uninsured (11.0% vs 5.5%; P < 0.0001). After propensity matching, neither operative mortality (9.7% vs 7.9% P = 0.45), nor nonoperative mortality (1.2% vs 1.3% P = 0.60) were different between groups. Mortality and operative rates for patients with acute diverticulitis are equivalent between LT1C and NTC in NJ. Trauma centers in NJ more commonly provide care to minority and uninsured patients. PMID- 26031274 TI - Prospective Evaluation of Weight-Based Prophylactic Enoxaparin Dosing in Critically Ill Trauma Patients: Adequacy of AntiXa Levels Is Improved. AB - Venous thromboembolism (VTE) is a leading cause of death in multisystem trauma patients; the importance of VTE prevention is well recognized. Presently, standard dose enoxaparin (30 mg BID) is used as chemical prophylaxis, regardless of weight or physiologic status. However, evidence suggests decreased bioavailability of enoxaparin in critically ill patients. Therefore, we hypothesized that a weight-based enoxaparin dosing regimen would provide more adequate prophylaxis (as indicated by antifactor Xa levels) for patients in our trauma intensive care unit (TICU).These data were prospectively collected in TICU patients admitted over a 5-month period given twice daily 0.6 mg/kg enoxaparin (actual body weight). Patients were compared with a historical cohort receiving standard dosing. Anti-Xa levels were collected at 11.5 hours (trough, goal >= 0.1 IU/mL) after each evening administration. Patient demographics, admission weight, dose, and daily anti-Xa levels were recorded. Patients with renal insufficiency or brain, spine, or spinal cord injury were excluded. Data were collected from 26 patients in the standard-dose group and 37 in the weight-based group. Sixty-four trough anti-Xa measurements were taken in the standard dose group and 74 collected in the weight-based group. Evaluating only levels measured after the third dose, the change in dosing of enoxaparin from 30 to 0.6 mg/kg resulted in an increased percentage of patients with goal antifactor Xa levels from 8 per cent to 61 per cent (P < 0.0001). Examining all troughs, the change in dose resulted in an increase in patients with a goal anti-Xa level from 19 to 59 per cent (P < 0.0001). Weight-based dosing of enoxaparin in trauma ICU patients yields superior results with respect to adequate anti-Xa levels when compared with standard dosing. These findings suggest that weight-based dosing may provide superior VTE prophylaxis in TICU patients. Evaluation of the effects of this dosing paradigm on actual VTE rate is ongoing at our institution. PMID- 26031275 TI - The effects of the addition of a pediatric surgery fellow on the operative experience of the general surgery resident. AB - Adding fellows to surgical departments with residency programs can affect resident education. Our specific aim was to evaluate the effect of adding a pediatric surgery (PS) fellow on the number of index PS cases logged by the general surgery (GS) residents. At a single institution with both PS and GS programs, we examined the number of logged cases for the fellows and residents over 10 years [5 years before (Time 1) and 5 years after (Time 2) the addition of a PS fellow]. Additionally, the procedure related relative value units (RVUs) recorded by the faculty were evaluated. The fellows averaged 752 and 703 cases during Times 1 and 2, respectively, decreasing by 49 (P = 0.2303). The residents averaged 172 and 161 cases annually during Time 1 and Time 2, respectively, decreasing by 11 (P = 0.7340). The total number of procedure related RVUs was 4627 and 6000 during Times 1 and 2, respectively. The number of cases logged by the PS fellows and GS residents decreased after the addition of a PS fellow; however, the decrease was not significant. Programs can reasonably add an additional PS fellow, but care should be taken especially in programs that are otherwise static in size. PMID- 26031276 TI - Adhesive Small Bowel Obstruction: Early Operative versus Observational Management. AB - We assessed the nonoperative and operative management of adhesive small bowel obstruction (ASBO) and compared complication rates and surgical outcomes. ASBO is a common complication of abdominopelvic surgery. Although patients may respond to nonoperative management, many require surgery. We retrospectively studied patients admitted to Mount Sinai Hospital with a diagnosis of complete ASBO to determine outcomes of nonoperative management. Patients admitted with complete ASBO from 2001 to 2011 were included. Patients with no previous abdominopelvic surgery, surgery within the six weeks preceding admission and obstruction due to other identifiable causes, such as incarcerated hernia, were excluded. Complication rates and outcomes were compared between patients managed with immediate surgery and those managed initially with nonoperative strategies. Of 460 patients admitted with complete ASBO, 106 (23.0%) had surgery within 24 hours of admission. At surgery, 20 (18.9%) had ischemic bowel and 8 (7.5%) had perforations. The remaining 354 patients had a trial of nonoperative management lasting at least 24 hours. Of 354 patients managed initially without surgery, 100 (28.2%) patients were discharged without operative intervention during their index admissions. Among the patients having surgery more than 24 hours after admission, indications for surgery were generally failure to resolve, worsening clinical status, and change in imaging findings. Of those patients observed for at least 24 hours, 40 (15.7%) were found to have ischemic bowel and 5 (2.0%) had perforation at surgery. Rates of bowel resection, stoma creation and postoperative complications were similar for the immediate and delayed surgery groups. Among the delayed surgery group, 71 (28.0%) required a bowel resection and 11 (4.3%) stoma creation. Twenty one per cent had postoperative complications, most commonly ileus. There were no statistically significant differences in the outcomes between immediate and delayed groups regardless of duration of delay. Among patients observed with complete ASBO, 24.6 per cent of patients with adhesive obstruction resolved without surgery or readmission. Delaying operative management did not affect surgical findings or complication rates. PMID- 26031277 TI - Dynamic multiplanar real time ultrasound guided infraclavicular subclavian vein catheterization. AB - Ultrasound guided vascular access has been well-characterized as a safe and effective technique for internal jugular and femoral vein catheterization. However, there is limited experience with the use of ultrasound to access the infraclavicular subclavian vein. Multiple ultrasound techniques do exist to identify the subclavian vein, but real time access is limited by vessel identification in a single planar view. To overcome this limitation, a novel technique of ultrasound guided infraclavicular subclavian vein catheterization using a real time multiplanar approach has been developed. The initial experience with this approach is described. A single surgeon used combined oblique, transverse, and longitudinal views along with Doppler color flow images to both define the infraclavicular anatomy and to obtain subclavian vein access in 42 adult patients (20 M/22 F and 22 L/20 R) with a mean body mass index of 29.2 (range = 18.9-55.4). Chest x-ray was obtained to confirm position and to rule out pneumothorax. Subclavian vein cannulation was achieved in 100 per cent of patients; subsequent catheterization was successful in 92.9 per cent. The number of attempts required for cannulation averaged 1.3 (range = 1-5), and decreased after a five patient learning curve. No patient developed a pneumothorax, hematoma, or cannula malposition. Ultrasound guided multiplanar infraclavicular subclavian vein access appears to be a safe and effective adjunct for central line placement. PMID- 26031278 TI - Diagnostic Accuracy of Noncontrast CT in Detecting Acute Appendicitis: A Meta analysis of Prospective Studies. AB - The aim of the study is to evaluate the diagnostic accuracy of noncontrast CT in detecting acute appendicitis. Prospective studies in which noncontrast CT was performed to evaluate acute appendicitis were found on PubMed, EMBASE, and Cochrane Library. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were assessed. The summary receiver-operating characteristic curve was conducted and the area under the curve was calculated. Seven original studies investigating a total of 845 patients were included in this meta-analysis. The pooled sensitivity and specificity were 0.90 (95% CI: 0.86-0.92) and 0.94 (95% CI: 0.92-0.97), respectively. The pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio was 12.90 (95% CI: 4.80-34.67), 0.09 (95% CI: 0.04 0.20), and 162.76 (95% CI: 31.05-853.26), respectively. The summary receiver operating characteristic curve was symmetrical and the area under the curve was 0.97 (95% CI: 0.95-0.99). In conclusion, noncontrast CT has high diagnostic accuracy in detecting acute appendicitis, which is adequate for clinical decision making. PMID- 26031279 TI - The aging of America: a comprehensive look at over 25,000 geriatric trauma admissions to United States hospitals. AB - A 2001 study on geriatric trauma by trauma center (TC) status was based on 1989 Medicare data. The purpose of this study was to compare 1989 findings with a 2009 sample, and to examine patient characteristics and outcomes by TC status. From 2009 Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP NIS) data, we examined a geographically representative sample (n = 25,512) of injured older adults (>/= age 65) admitted to 127 TCs and non-TCs in 24 states. Data analysis included descriptive statistics for eight patient characteristics and four outcome variables (mortality, discharge disposition, length of stay, and total charges). chi(2) tests were conducted to examine differences between 1989 and 2009 for age groups, gender, and mortality. Higher percentages of patients were in older age groups in 2009, however mortality declined overall (4.8% vs 3.4%, P < .001). Consistent incremental patterns of differences were observed among TC levels for all patient characteristics and outcomes. Level I TCs admitted highest percentages of: lower age groups, males, nonwhite race, motor vehicle related trauma, and intracranial injuries. Non-TCs admitted highest percentages of oldest age groups, comorbidities, falls, femur neck fractures, and patients requiring OR procedures. Although Level I TCs had higher lengths of stay and total charges, a higher percentage of patients were discharged home. Despite a growing number of patients in older age groups, inpatient mortality declined over two decades. Level I TCs are managing patients at highest risk for decompensation and mortality; a significant percentage of patients are going to non-TCs. PMID- 26031280 TI - Reoperative Heller myotomy: more pain, less gain. AB - Heller myotomy provides durable and effective treatment of achalasia. Due to recurrence or persistence of symptoms, a small subset of patients seeks reoperation. This study was undertaken to determine if reoperative Heller myotomy provides salutary amelioration of symptoms. 609 patients undergoing laparoscopic Heller myotomy between 1992 to 2013 were prospectively followed; 38 underwent reoperative myotomy. Patients graded their symptom frequency and severity before and after myotomy on a Likert scale. Median data are reported. Patients undergoing reoperative myotomy, when compared to those undergoing their first myotomy, experienced a higher conversion rate to an "open" myotomy (8% vs 1%, P < 0.05) and a longer length of stay (3 vs 1 day, P < 0.05). Reoperative myotomy led to improvement in symptoms, but the magnitude of improvement in symptoms (e.g., dysphagia, choking, and coughing) was less than for patients undergoing their first myotomy (all P < 0.05). Patients undergoing reoperative Heller myotomy were less likely to report symptoms occurring once per month or less (83% vs 56%, P < 0.01). Patients undergoing reoperative myotomy note improvement in symptoms, although to a lesser extent than patients undergoing their first myotomy. Patients undergoing reoperative Heller myotomy can expect to experience less improvement of symptoms, denoting the importance of the first myotomy. PMID- 26031281 TI - Less Is More: Low-dose Prothrombin Complex Concentrate Effective in Acute Care Surgery Patients. AB - Optimal dosing of prothrombin complex concentrate (PCC) has yet to be defined and varies widely due to concerns of efficacy and thrombosis. We hypothesized a dose of 15 IU/kg actual body weight of a three-factor PCC would effectively correct coagulopathy in acute care surgery patients. Retrospective review of 41 acute care surgery patients who received 15 IU/kg (+/- 10%) actual body weight PCC for correction of coagulopathy. Demographics, laboratory results, PCC dose, blood and plasma transfusions, and thrombotic complications were analyzed. We performed subset analyses of trauma patients and those taking warfarin. Mean age was 69 years (18-94 years). Thirty (73%) trauma patients, 8 (20%) emergency surgery patients, 2 (5%) burns, and 1 (2%) nontrauma neurosurgical patient were included. Mean PCC dose was 1305.4 IU (14.2 IU/kg actual body weight). Mean change in INR was 2.52 to 1.42 (p 0.00004). Successful correction (INR <1.5) was seen in 78 per cent. Treatment failures had a higher initial INR (4.3 vs 2.03, p 0.01). Mean plasma transfusion was 1.46 units. Mean blood transfusion was 1.61 units. Patients taking prehospital warfarin (n = 29, 71%) had higher initial INR (2.78 vs 1.92, p 0.05) and received more units of plasma (1.93 vs 0.33, p 0.01) than those not taking warfarin. No statistical differences were seen between trauma and nontrauma patients. One thrombotic event occurred. Administration of low-dose PCC, 15 IU/kg actual body weight, effectively corrects coagulopathy in acute care surgery patients regardless of warfarin use, diagnosis or plasma transfusion. PMID- 26031282 TI - Activated prothrombin complex and the treatment of hypocoagulable trauma patients. PMID- 26031283 TI - Pediatric unintentional firearm injuries: a Northwestern Louisiana trauma center analysis. PMID- 26031284 TI - [Treatment strategies for ANCA-associated vasculitides]. AB - BACKGROUND: Recent data from randomized controlled clinical trials have allowed the development of recommendations for treatment of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV). METHODS: A selective literature search was carried out for studies and recommendations for treatment of AAV. RESULTS: In active severe AAV a combination of prednisolone and cyclophosphamide or rituximab leads to a therapeutic response in approximately 90 % of cases. Once remission is attained the administration of azathioprine or methotrexate for 2-4 years is required for maintenance of remission. Relapse occurs in more than 30 % of patients despite maintenance treatment. In cases of persistence or progression of disease activity during standard therapy, referral to an expert center should be considered. Despite improvement in the prognosis in recent years early mortality is increased, particularly due to infections. CONCLUSION: Stage and activity adapted treatment strategies have improved the outcome of AAV in the past three decades. The elevated early mortality and the risk of relapse show the need for further improvement of current treatment protocols with respect to substance selection, dosage of glucocorticoids and immunosuppressants and the duration of therapy. PMID- 26031285 TI - [Switching within the active ingredient group or changing the mechanism of action. Data situation by failure of the first line biologic]. AB - Despite the use of biologics many patients do not achieve remission or reduced disease activity, which raises the question of the optimal therapy when these therapy targets are not achieved. Most data from clinical studies and registry data refer to the approach following the unsuccessful use of one or more tumor necrosis factor (TNF) inhibitors. Randomized controlled studies investigating the effectiveness of a further biologic or TNF inhibitor in patients who received abatacept, tocilizumab or rituximab in the first line therapy are currently lacking, with the exception of the German MIRAI study. The majority of registry data and observational studies suggest that when the use of a TNF inhibitor is unsuccessful it is advantageous to change to a non-TNF biologic. This does not exclude that a change within the group of TNF inhibitors can represent an appropriate option, e.g. by injection or infusion reactions or secondary therapy failure. Whether determination of serum levels and neutralizing antibodies aids decision-making for individual patients, must currently remain open. The option to change within an active ingredient group of biologics only currently applies to the group of TNF inhibitors; however, with the development of further antibodies inhibiting interleukin 6, this question will also apply to this group of substances. The question of the optimal strategy after failure of the first and second line biologics will be asked more frequently when the therapy targets of remission and low disease activity are more stringently strived for. Predictive markers for an optimal approach to the sequential administration of biologics are lacking. In order to answer this question clinical studies which investigate the therapeutic approach in a randomized and controlled manner will be necessary in the future. PMID- 26031286 TI - [Immunogerontology - Research into aging]. PMID- 26031287 TI - [As valuable as an organ donation. Enrollment in a clinical study requires patient willingness to make sacrifices]. AB - Patients are by far the most important partners within the complete ensemble involved in clinical studies. Their participation involves a number of additional inconveniencies. Not infrequently, the consent discussion is followed by complementary diagnostic procedures. Besides the objective pressure of expectation there are also subjective fears, which increase in weight the longer the study progresses. During the post-observational period, participants are periodically requested to undertake further control examinations at varying time intervals. By means of their consent, study patients volunteer as supporters in favor of the anonymous successors in the study suffering from the same disease. Obviously, the sacrifices which the enrolled patients make for medical research can be placed on a par with organ donations. PMID- 26031290 TI - Floral volatiles interfere with plant attraction of parasitoids: ontogeny dependent infochemical dynamics in Brassica rapa. AB - BACKGROUND: The role of plant ontogeny on investment in direct defense against herbivores is well accepted, but the transition from the vegetative to the reproductive stage can also affect indirect resistance traits (i.e. attraction of the natural enemies of plant attackers). Here, we conducted behavioral bioassays in olfactometers to determine whether the developmental stage (vegetative, pre flowering, and flowering) of Brassica rapa plants affects attraction of Cotesia glomerata, a parasitoid of the herbivore Pieris brassicae, and examined the blends of volatile compounds emitted by plants at each developmental stage. RESULTS: Pieris-infested plants were always more attractive to parasitoids than control plants and plants infested by a non-host herbivore, independently of plant developmental stage. On the other hand, the relative attractiveness of Pieris-infested plants was ontogeny dependent: Pieris-infested plants were more attractive at the pre-flowering stage than at the vegetative stage, and more attractive at the vegetative stage than at the flowering stage. Chemical analyses revealed that the induction of leaf volatiles after herbivory is strongly reduced in flowering plants. The addition of synthetic floral volatiles to infested vegetative plants decreased their attractiveness to parasitoids, suggesting a trade-off between signaling to pollinators and parasitoids. CONCLUSION: Our results show that putative indirect resistance traits are affected by plant development, and are reduced during B. rapa reproductive stage. The effects of ontogenetic shifts in resource allocation on the behavior of members of the third trophic level may have important implications for the evolution of plant defense strategies against herbivores. PMID- 26031289 TI - Telephone-based goal management training for adults with mild traumatic brain injury: study protocol for a randomized controlled trial. AB - BACKGROUND: Approximately 1 million individuals experience a mild traumatic brain injury (TBI) and cost the United States nearly $17 billion each year. Many trauma survivors with mild TBI have debilitating and long-term physical, emotional, and cognitive impairments that are unrecognized at trauma centers. Early intervention studies are needed to address these impairments, especially cognitive deficits in executive functioning. Goal management training (GMT) is a structured cognitive rehabilitation program that has been found to improve executive functioning in patients with moderate to severe TBI. The current study adapted the GMT program for telephone delivery in order to improve the accessibility of rehabilitation services in a patient population with multiple barriers to care and significant yet unrecognized cognitive impairment. The primary objective of this study is to examine the efficacy of telephone-based GMT for improving executive functioning, functional status, and psychological health in trauma survivors with mild TBI. METHODS/DESIGN: This study is a three-group randomized controlled trial being conducted at a Level I trauma center. Ninety trauma survivors with mild TBI and cognitive deficits in executive functioning will be randomized to receive telephone-based GMT, telephone-based education, or usual care. GMT and education programs will be delivered by a physical therapist. The first in-person session is 1 h and the remaining six telephone sessions are 30 min. A battery of well established cognitive tests will be conducted and validated questionnaires will be collected that measure executive functioning, functional status, and depressive and posttraumatic stress disorder symptoms at 6 weeks, 4 months, and 7 months following hospital discharge. DISCUSSION: This study supports a telephone delivery approach to rehabilitation services in order to broaden the availability of evidence-based cognitive strategies. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov on 10 October 2012, registration number: NCT01714531. PMID- 26031291 TI - Single-incision assisted laparoscopic surgery (SILS) in the treatment of an intussusception induced by a solitary hamartomatous polyp: a case report and review of the literature. AB - INTRODUCTION: In this case report, we describe the successful treatment of a small-bowel intussusception, which was caused by a 3 cm solitary hamartomatous polyp, with single-incision laparoscopic surgery. Single-incision laparoscopic surgery is a minimally invasive surgical procedure with important advantages that allows the reduction of the intussusception and the resection of the polyp. This case report contributes to the medical literature by describing the advantages of this surgical technique that warrant its consideration as a treatment of choice in similar cases. CASE PRESENTATION: We report a case of a 19-year-old Greek woman who complained about intermittent, non-specific abdominal pain in her left lateral abdomen. She had been admitted to the hospital because of incomplete obstructive ileus. Ultrasound and computed tomography were carried out, which revealed an intussusception of the small bowel. This pathogenic situation was treated by single-incision laparoscopic surgery. Her pathology report revealed a benign, hamartomatous excised polyp of the Peutz-Jeghers type. The patient had a quick recovery without any post-operative complications. CONCLUSION: We recommend single-incision laparoscopic surgery for the safe excision of solitary hamartomatous polyps and the management of their complications, as it represents a potential advance in minimally invasive approaches. PMID- 26031293 TI - A genetic screen reveals a periplasmic copper chaperone required for nitrite reductase activity in pathogenic Neisseria. AB - Under conditions of low oxygen availability, Neisseria meningitidis and Neisseria gonorrhoeae are able to respire via a partial denitrification pathway in which nitrite is converted to nitrous oxide. In this process, nitrite reductase (AniA), a copper (Cu)-containing protein converts nitrite to NO, and this product is converted to nitrous oxide by nitric oxide reductase (NorB). NorB also confers protection against toxic NO, and so we devised a conditional lethal screen, using a norB mutant, to identify mutants that were resistant to nitrite-dependent killing. After random-deletion mutagenesis of N. meningitidis, this genetic screen identified a gene encoding a Cu chaperone that is essential for AniA function, AccA. Purified AccA binds one Cu (I) ion and also possesses a second binding site for Cu (II). This novel periplasmic Cu chaperone (AccA) appears to be essential for provision of Cu ions to AniA of pathogenic Neisseria to generate an active nitrite reductase. Apart from the Neisseria genus, AccA is distributed across a wide range of environmental Proteobacteria species. PMID- 26031294 TI - Burkholderia humisilvae sp. nov., Burkholderia solisilvae sp. nov. and Burkholderia rhizosphaerae sp. nov., isolated from forest soil and rhizosphere soil. AB - Strains Y-12(T) and Y-47(T) were isolated from mountain forest soil and strain WR43(T) was isolated from rhizosphere soil, at Daejeon, Korea. The three strains grew at 10-55 degrees C (optimal growth at 28-30 degrees C), at pH 3.0-8.0 (optimal growth at pH 6.0) and in the presence of 0-4.0% (w/v) NaCl, growing optimally in the absence of added NaCl. On the basis of 16S rRNA gene sequence analysis, the three strains were found to belong to the genus Burkholderia, showing the closest phylogenetic similarity to Burkholderia diazotrophica JPY461(T) (97.2-97.7%); the similarity between the three sequences ranged from 98.3 to 98.7%. Additionally, the three strains formed a distinct group in phylogenetic trees based on the housekeeping genes recA and gyrB. The predominant ubiquinone was Q-8, the major fatty acids were C16 : 0 and C17 : 0 cyclo and the DNA G+C content of the novel isolates was 61.6-64.4 mol%. DNA-DNA relatedness among the three strains and the type strains of the closest species of the genus Burkholderia was less than 50%. On the basis of 16S rRNA, recA and gyrB gene sequence similarities, chemotaxonomic and phenotypic data, the three strains represent three novel species within the genus Burkholderia, for which the names Burkholderia humisilvae sp. nov. (type strain Y-12(T)= KACC 17601(T) = NBRC 109933(T) = NCAIM B 02543(T)), Burkholderia solisilvae sp. nov. (type strain Y 47(T) = KACC 17602(T)= NBRC 109934(T) = NCAIM B 02539(T)) and Burkholderia rhizosphaerae sp. nov. (type strain WR43(T) = KACC 17603(T) = NBRC 109935(T) = NCAIM B 02541(T)) are proposed. PMID- 26031292 TI - Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin. AB - The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers. PMID- 26031295 TI - Cephalothrix gen. nov. (Cyanobacteria): towards an intraspecific phylogenetic evaluation by multilocus analyses. AB - For more than a decade, the taxonomy of the Phormidiaceae has been problematic, since morphologically similar organisms represent phylogenetically distinct entities. Based on 16S rRNA gene sequence analyses, the polyphyletic genus Phormidium and other gas-vacuolated oscillatorioids appear scattered throughout the cyanobacterial tree of life. Recently, several studies have focused on understanding the oscillatorioid taxa at the generic level. At the specific level, few studies have characterized cyanobacterial strains using combined datasets (morphology, ultrastructure and molecular multilocus analyses). Using a multifaceted approach, we propose a new, well-defined genus, Cephalothrix gen. nov., by analysing seven filamentous strains that are morphologically 'intermediate' between gas-vacuolated taxa and Phormidium. Furthermore, we characterize two novel species: Cephalothrix komarekiana sp. nov. (strains CCIBt 3277, CCIBt 3279, CCIBt 3523, CCALA 155, SAG 75.79 and UTEX 1580) and Cephalothrix lacustris sp. nov. (strain CCIBt 3261). The generic name and specific epithets are proposed under the provisions of the International Code of Nomenclature for Algae, Fungi, and Plants. PMID- 26031296 TI - Cold Hemodiafiltration for Exertional Heat Stroke Resulting in Multiple Organ Failure. PMID- 26031297 TI - Consequences of Circadian and Sleep Disturbances for the Cardiovascular System. AB - Circadian rhythms play a crucial role in our cardiovascular system. Importantly, there has been a recent flurry of clinical and experimental studies revealing the profound adverse consequences of disturbing these rhythms on the cardiovascular system. For example, circadian disturbance worsens outcome after myocardial infarction with implications for patients in acute care settings. Moreover, disturbing rhythms exacerbates cardiac remodelling in heart disease models. Also, circadian dyssynchrony is a causal factor in the pathogenesis of heart disease. These discoveries have profound implications for the cardiovascular health of shift workers, individuals with circadian and sleep disorders, or anyone subjected to the 24/7 demands of society. Moreover, these studies give rise to 2 new frontiers for translational research: (1) circadian rhythms and the cardiac sarcomere, which sheds new light on our understanding of myofilament structure, signalling, and electrophysiology; and (2) knowledge translation, which includes biomarker discovery (chronobiomarkers), timing of therapies (chronotherapy), and other new promising approaches to improve the management and treatment of cardiovascular disease. Reconsidering circadian rhythms in the clinical setting benefits repair mechanisms, and offers new promise for patients. PMID- 26031298 TI - Overnight Effects of Obstructive Sleep Apnea and Its Treatment on Stroke Volume in Patients With Heart Failure. AB - BACKGROUND: We previously showed in heart failure (HF) patients that obstructive respiratory events during sleep and generation of negative intrathoracic pressure during Mueller manoeuvres, mimicking obstructive apneas, acutely reduced stroke volume (SV). We also showed that treating obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) increased left ventricular ejection fraction over a 1-month period. We therefore hypothesized that, in HF patients, those with OSA would have greater overnight declines in SV and cardiac output (CO) than in those without sleep apnea, and that therapy of OSA using CPAP would prevent these declines. METHODS: We examined overnight percent change in SV and CO in 32 HF patients with and 28 without OSA using digital photoplethysmography. Among patients with OSA, we also examined changes in SV and CO during a CPAP titration study. RESULTS: During the baseline polysomnogram SV and CO decreased more overnight in those with OSA than in those without sleep apnea (-12.6 +/- 7.7% vs -3.2 +/- 6.8%; P < 0.001 and -16.2 +/- 9.9% vs -3.7 +/- 8.3%; P < 0.001, respectively). Overnight changes in SV and CO correlated inversely with total apnea-hypopnea index (r = -0.551; P < 0.001 and r = -0.522; P < 0.001, respectively). In 21 patients with OSA, CPAP reduced the total apnea-hypopnea index from 37.7 +/- 21.4 to 15.0 +/- 16.0 (P < 0.001) in association with attenuation of the overnight reduction of SV (from -14.0 +/- 7.9% to -3.4 +/- 9.8%; P = 0.002) and CO (from -17.2 +/- 9.0% to -9.7 +/- 10.7%; P = 0.042). CONCLUSIONS: In patients with HF, coexisting OSA causes overnight declines in SV and CO that are prevented through reversal of OSA by CPAP. PMID- 26031299 TI - Angiosarcoma: A rare malignancy with protean clinical presentations. AB - Angiosarcoma is a rare form of soft tissue sarcoma. Primary small intestinal angiosarcomas are especially uncommon. The clinical presentations of small intestinal angiosarcomas vary but gastrointestinal (GI) bleeding is a frequent finding. We present a case of persistent GI bleeding of unknown etiology culminating in operative exploration demonstrating a primary small intestinal angiosarcoma. A discussion of the diagnosis, pathology, and management of angiosarcoma with a review of the current literature is provided including molecular genetics, difficult cases, and current treatment options. PMID- 26031300 TI - [Consultations in oncological supportive care mono-, multi-, ou interdisciplinary: What should we favour?]. AB - According to the point 7.6 and 7.7 of the Cancer Plan 2014, all cancer patients should have access to supportive care. Indeed, the supportive care consultation in oncology is an important tool for the symptom management of cancer patients at all times of treatment. This consultation can be mono-disciplinary or multi disciplinary (with different professions: physician, nurse, psychologist, social service assistant...) with or without integration (multidisciplinary or interdisciplinary). There are few studies focusing on the types of consultations (mono- or multidisciplinary) to promote based on their expected outcomes. After describing the different types of consultations (initial, follow-up, unscheduled, discharge) and having highlighted the main issues of these consultations, we will present the possible configurations. Our discussion will concern then the advantages and disadvantages of monodisciplinarity and different types of multidisciplinary highlighting the possible improvements. At the end of this work, after a brief synthesis of the different outcomes associated with each type of consultation, we would like to discuss the type of consultation to choose according to the outcomes. PMID- 26031301 TI - Tomographic Evaluation of Reparative Dentin Formation after Direct Pulp Capping with Ca(OH)2, MTA, Biodentine, and Dentin Bonding System in Human Teeth. AB - INTRODUCTION: New materials can increase the efficiency of pulp capping through the formation of a complete reparative dentin bridge with no toxic effects. The present study involved tomographic evaluations of reparative dentin bridge formation after direct pulp capping with calcium hydroxide, mineral trioxide aggregate (MTA), Biodentine (Septodont, Saint Maur des Fosses, France), and Single Bond Universal (3M ESPE, Seefeld, Germany) in human teeth. METHODS: Forty four caries-free, intact, human third molars scheduled for extraction were subjected to mechanical pulp exposure and assigned to 1 of 4 experimental groups depending on the pulp capping agent used: calcium hydroxide, MTA, Biodentine, or Single Bond Universal. After 6 weeks, the teeth were extracted and processed for cone-beam computed tomographic imaging and histologic examination. Tomographic data, including the density and volume of formed reparative dentin bridges, were evaluated using a scoring system. RESULTS: The reparative dentin formed in the calcium hydroxide, MTA, and Biodentine groups was significantly superior to that formed in the Single Bond Universal group in terms of thickness and volume. The dentin bridges in the Biodentine group showed the highest average and maximum volumes. The mean density of dentin bridges was the highest in the MTA group and the lowest in the Single Bond Universal group. CONCLUSIONS: The volume of reparative dentin bridges formed after direct pulp capping is dependent on the material used. Biodentine and MTA resulted in the formation of bridges with a significantly higher average volume compared with Single Bond Universal, and cone beam computed tomographic imaging allowed for the identification of the location of dentin bridges. PMID- 26031302 TI - A cautionary note on fecal sampling and molecular epidemiology in predatory wild great apes. AB - Fecal samples are an important source of information on parasites (viruses, prokaryotes, or eukaryotes) infecting wild great apes. Molecular analysis of fecal samples has already been used for deciphering the origins of major human pathogens such as HIV-1 or Plasmodium falciparum. However, for apes that hunt (chimpanzees and bonobos), detection of parasite nucleic acids may reflect either true infection of the host of interest or ingestion of an infected prey, for example, another non-human primate. To determine the potential magnitude of this issue, we estimated the prevalence of prey DNA in fecal samples obtained from two wild chimpanzee communities. We observed values >15%, which are higher than or close to the fecal detection rates of many great ape parasites. Contamination of fecal samples with parasite DNA from dietary origin may therefore occasionally impact non-invasive epidemiological studies. This problem can be addressed (at least partially) by monitoring the presence of prey DNA. PMID- 26031303 TI - Bioreactor microbial ecosystems for thiocyanate and cyanide degradation unravelled with genome-resolved metagenomics. AB - Gold ore processing uses cyanide (CN(-) ), which often results in large volumes of thiocyanate- (SCN(-) ) contaminated wastewater requiring treatment. Microbial communities can degrade SCN(-) and CN(-) , but little is known about their membership and metabolic potential. Microbial-based remediation strategies will benefit from an ecological understanding of organisms involved in the breakdown of SCN(-) and CN(-) into sulfur, carbon and nitrogen compounds. We performed metagenomic analysis of samples from two laboratory-scale bioreactors used to study SCN(-) and CN(-) degradation. Community analysis revealed the dominance of Thiobacillus spp., whose genomes harbour a previously unreported operon for SCN( ) degradation. Genome-based metabolic predictions suggest that a large portion of each bioreactor community is autotrophic, relying not on molasses in reactor feed but using energy gained from oxidation of sulfur compounds produced during SCN(-) degradation. Heterotrophs, including a bacterium from a previously uncharacterized phylum, compose a smaller portion of the reactor community. Predation by phage and eukaryotes is predicted to affect community dynamics. Genes for ammonium oxidation and denitrification were detected, indicating the potential for nitrogen removal, as required for complete remediation of wastewater. These findings suggest optimization strategies for reactor design, such as improved aerobic/anaerobic partitioning and elimination of organic carbon from reactor feed. PMID- 26031304 TI - Effects of Cancer Therapy Targeting Vascular Endothelial Growth Factor Receptor on Central Blood Pressure and Cardiovascular System. AB - BACKGROUND: In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs. METHODS: Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment. RESULTS: Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13+/-15.5mm Hg, diastolic BP +7.1+/-9.3mm Hg, P < 0.001) and central BP (systolic BP +14+/-14.2mm Hg, diastolic BP +7.3+/-10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3+/-1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9+/-3.8% at T0, -17.8+/-2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped. CONCLUSIONS: All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti VEGFR drugs. PMID- 26031305 TI - Sex Differences in the Associations of Hemodynamic Load With Left Ventricular Hypertrophy and Concentric Remodeling. AB - BACKGROUND: Left ventricular hypertrophy (LVH) and concentric remodeling are associated with adverse cardiovascular outcomes. We hypothesized that measures of arterial load are associated with LVH and concentric remodeling, and that associations differ by sex. METHODS: We studied 600 non-Hispanic whites (59% women) belonging to hypertensive sibships. By integrating arterial tonometry with echocardiography, we obtained the following hemodynamic measures: aortic characteristic impedance (Z c), proximal aortic compliance (PAC), systemic vascular resistance, augmentation index, and carotid-femoral pulse wave velocity (cfPWV). LVH and concentric remodeling were assessed by left ventricular mass indexed to body surface area (LVMI) and relative wall thickness (RWT), respectively. LVMI was log-transformed to reduce skewness. Hemodynamic measures were indexed to body size. Sex-specific multivariable linear regression analyses adjusting for confounders were performed to assess the associations of measures of arterial load with log LVMI and RWT. RESULTS: None of the hemodynamic measures were associated with LVMI in either sex, or with RWT in men. However, in women, measures of aortic stiffness and early, pulsatile hemodynamic load were independently associated with increased RWT: beta +/- SE = 0.008 +/- 0.004 for Z c; 0.003 +/- 0.001 for cfPWV, and -0.009 +/- 0.003 for PAC (P <= 0.05 for each). Female sex was a significant effect modifier of the associations of Z c, cfPWV, and PAC with RWT (P <= 0.03 for each of the interaction terms). CONCLUSIONS: Greater Z c and cfPWV and lower PAC are independently associated with increased RWT in women but not in men. Our findings suggest that aortic stiffness and greater early, pulsatile hemodynamic load affect left ventricular concentric remodeling in a sex-specific manner. PMID- 26031307 TI - The sactibiotic subclass of bacteriocins: an update. AB - The sactibiotics are a recently designated subclass of bacteriocins that contain characteristic cysteine sulphur to alpha -carbon linkages mediated through post translational modifications. They are a relatively small subclass of bacteriocins compared to the most thoroughly studied lantibiotics. The sactibiotics that have been extensively studied thus far are thuricin CD, subtilosin A, thurincin H, and propionicin F. Despite their recent discovery, there have already been significant advances made in the study of sactibiotics, most notably the discovery of the narrow spectrum anti-Clostridium difficile sactibiotic, thuricin CD. In addition, scientists have gained insights into the mechanisms of action of the sactibiotic subtilosin A, which targets Listeria monocytogenes,Gardnerella vaginalis, and other pathogens. Also, the development of heterologous host systems and homologous expression and site-directed mutagenesis systems for the sactibiotic thurincin H have opened up many opportunities for further studies on this sactibiotic. These and other recent studies concerning the molecular biology, 3D structural elucidation, mode of action, self-protection mechanisms, and antimicrobial spectrum of the sactibiotic subgroup of bacteriocins are discussed in this review. PMID- 26031308 TI - Cardiac safety of tiotropium in patients with cardiac events: a retrospective analysis of the UPLIFT(r) trial. AB - BACKGROUND: Tiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT(r)) study, we re-evaluated the safety of tiotropium HandiHaler(r) in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study. METHODS: A post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT(r) and who completed the study. Descriptive analyses were performed. RESULTS: Most patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler(r) versus placebo. Patients who experienced a cardiac event and continued in UPLIFT(r) were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo. CONCLUSIONS: Risk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler(r) in patients with COPD. PMID- 26031309 TI - Systematic review of physical activity and exercise interventions on body mass indices, subsequent physical activity and psychological symptoms in overweight and obese adolescents. AB - AIMS: To examine the effects of physical activity and exercise interventions on body mass index, subsequent physical activity and psychological symptoms for overweight and obese adolescents (12-18 years). BACKGROUND: Overweight and obesity have increased among adolescents globally and physical activity has decreased. Healthcare systems face challenges promoting physical activity and in treating obesity. Promotion of physical activity must be effective and school nurses should be equipped with the information and resources required to implement counselling for overweight and obese adolescents. DESIGN: A systematic review of randomized controlled trials was conducted according to procedures by the Centre for Reviews and Dissemination and the Joanna Briggs Institute. DATA SOURCES: Research studies published between 1950-2013 were identified from the following databases. CINAHL, MEDLINE (Ovid) and PsycINFO. REVIEW METHODS: Selected studies were reviewed for quality and a risk-of-bias assessment was conducted for the included studies. A narrative synthesis was used to report results, while a fixed-effect meta-analysis was used to analyse the interventions effects on physical activity and body mass index. RESULTS: Fourteen published studies were included to this review. Supervised exercise interventions most affected adolescents' body mass index. The interventions effect on adolescents' physical activity was small and heterogeneous. Two interventions positively affected psychological symptoms. CONCLUSION: Interventions were complex, with more than one component and the aspect that effectively promotes physical activity in obese adolescents was not clear. However, it seems that exercise interventions affect the body mass index of overweight or obese adolescents. Interventions that include a component for promoting physical activity with or without supervised exercise can affect subsequent physical activity and body mass index. PMID- 26031306 TI - Disintegrins from snake venoms and their applications in cancer research and therapy. AB - Integrins regulate diverse functions in cancer pathology and in tumor cell development and contribute to important processes such as cell shape, survival, proliferation, transcription, angiogenesis, migration, and invasion. A number of snake venom proteins have the ability to interact with integrins. Among these are the disintegrins, a family of small, non-enzymatic, and cysteine-rich proteins found in the venom of numerous snake families. The venom proteins may have a potential role in terms of novel therapeutic leads for cancer treatment. Disintegrin can target specific integrins and as such it is conceivable that they could interfere in important processes involved in carcinogenesis, tumor growth, invasion and migration. Herein we present a survey of studies involving the use of snake venom disintegrins for cancer detection and treatment. The aim of this review is to highlight the relationship of integrins with cancer and to present examples as to how certain disintegrins can detect and affect biological processes related to cancer. This in turn will illustrate the great potential of these molecules for cancer research. Furthermore, we also outline several new approaches being created to address problems commonly associated with the clinical application of peptide-based drugs such as instability, immunogenicity, and availability. PMID- 26031310 TI - Unusual serological response to hepatitis E virus in plasma donors consistent with re-infection. AB - Hepatitis E virus (HEV)-positive plasma donations, identified by a plasma mini pool screening approach, were analysed using serological methods for the presence of anti-HEV IgM and IgG. Avidity testing was performed on the IgG-reactive donations. Anti-HEV IgG with high avidity was observed in two donors together with high viral loads, but with the absence of anti-HEV IgM. These data are suggestive of re-infection in a small proportion of plasma donors, which has not previously been reported. PMID- 26031311 TI - Quality-of-life and functional outcomes following pharyngolaryngectomy: a systematic review of literature. AB - BACKGROUND: The long-term prognosis of hypopharyngeal cancer is poor. Surgery necessitates pharyngolaryngectomy with flap reconstruction. For such patients, it is important that functional outcomes are preserved to maintain a respectable quality of life. OBJECTIVE OF REVIEW: To identify the functional outcomes following pharyngolaryngectomy with respect to quality of life, speech and swallow through a systematic review of literature. SEARCH STRATEGY: Searches of EBM databases and literature databases using key words: pharyngolaryngectomy, laryngopharyngectomy, swallow, dysphagia, speech and dysphonia from 1970 to August 2014. Articles were screened for relevance using pre-determined inclusion and exclusion criteria. EVALUATION METHOD: Articles reviewed by authors and data compiled in tables for analysis. RESULTS: No previous systematic reviews assessing functional outcomes were identified. Seventeen studies reported speech outcomes (576 patients) and fifteen reported swallow outcomes (1076 patients). The data suggests that patients who underwent trachea-oesophageal puncture developed more favourable speech outcomes than those rehabilitated using other measures. Overall stricture incidence was 11.4% and 6.5% of patients required long-term enteral nutrition. Four studies used validated speech measures, and three used validated swallow measures. They suggest an overall level of perceived impairment in quality of life. Speech and swallow outcomes were significantly poorer than patients who underwent total laryngectomy. CONCLUSIONS: Overall, there is an impairment in speech and swallow outcomes following pharyngolaryngectomy; however, the exact extent is unclear. There is a need for a general consensus on assessment measures and prospective multicentre studies to be conducted. This study compiles the available data to improve caregiver and patient awareness of functional outcomes. PMID- 26031312 TI - Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia mediated inflammation. AB - Recent studies have shown that sigma-1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl] 2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 agonist, has been recently identified as a potent allosteric modulator of sigma-1 receptor. Here, we investigated the anti-inflammatory effects of SKF83959 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL 1beta), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma-1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c17 to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma-1 receptors, and enhanced the inhibitory effects of DHEA on LPS-induced microglia activation in a synergic manner. Furthermore, in a microglia-conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS-activated microglia toward HT 22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia mediated inflammation. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Our results indicated that SKF83959 enhanced the activity of endogenous dehydroepiandrosterone (DHEA) in a synergic manner, and inhibited the activation of BV2 microglia and the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), inducible nitric oxide synthase (iNOS). PMID- 26031313 TI - Randomized Controlled Trial of Mailed Personalized Feedback for Risky Drinkers in the Emergency Department: The Impact on Alcohol Consumption, Alcohol-Related Injuries, and Repeat Emergency Department Presentations. AB - BACKGROUND: Due to the difficulty encountered in disseminating resource-intensive emergency department (ED)-based brief alcohol interventions into real-world settings, this study evaluated the effect of a mailed personalized feedback intervention for problem drinking ED patients. At 6-week follow-up, this intervention was associated with a statistically significant reduction in alcohol consumption among patients with alcohol-involved ED presentations. This study aimed to evaluate the effects of this intervention over time. METHODS: A randomized controlled trial was conducted among problem drinking ED patients, defined as those scoring 8 or more on the Alcohol Use Disorders Identification Test. Participants in the intervention group received mailed personalized feedback regarding their alcohol consumption. The control group received no feedback. Follow-up interviews were conducted over the phone, postal survey, or email survey 6 weeks and 6 months after baseline screening, and repeat ED presentations over 12-month follow-up were ascertained via linked ED records. RESULTS: Six-month follow-up interviews were completed with 210 participants (69%), and linked ED records were obtained for 286 participants (94%). The intervention had no effect on alcohol consumption, while findings regarding alcohol-related injuries and repeat ED presentations remain inconclusive. CONCLUSIONS: Further research in which the receipt of feedback is improved and a booster intervention is provided is recommended. PMID- 26031314 TI - Sleep in amphibians and reptiles: a review and a preliminary analysis of evolutionary patterns. AB - Despite the ubiquitous nature of sleep, its functions remain a mystery. In an attempt to address this, many researchers have studied behavioural and electrophysiological phenomena associated with sleep in a diversity of animals. The great majority of vertebrates and invertebrates display a phase of immobility that could be considered as a sort of sleep. Terrestrial mammals and birds, both homeotherms, show two sleep states with distinct behavioural and electrophysiological features. However, whether these features have evolved independently in each clade or were inherited from a common ancestor remains unknown. Unfortunately, amphibians and reptiles, key taxa in understanding the evolution of sleep given their position at the base of the tetrapod and amniote tree, respectively, remain poorly studied in the context of sleep. This review presents an overview of what is known about sleep in amphibians and reptiles and uses the existing data to provide a preliminary analysis of the evolution of behavioural and electrophysiological features of sleep in amphibians and reptiles. We also discuss the problems associated with analysing existing data, as well as the difficulty in inferring homologies of sleep stages based on limited data in the context of an essentially mammalian-centric definition of sleep. Finally, we highlight the importance of developing comparative approaches to sleep research that may benefit from the great diversity of species with different ecologies and morphologies in order to understand the evolution and functions of sleep. PMID- 26031315 TI - Correlates of Disability in Asian Patients With Major Depressive Disorder. AB - PURPOSE: To examine correlates of disability in Asian patients with major depressive disorder (MDD). DESIGN AND METHODS: Participants were outpatients with DSM-IV MDD. Global disability and three disability domains (i.e., work/school, social life/leisure, and family/home life) were key outcomes. Several socio demographic and clinical characteristics were determined for their associations with disability. FINDINGS: The sample was 493 MDD patients. Apart from the number of hospitalizations, the global disability was significantly associated with depression severity, fatigue, physical health, and mental health. Several clinical but only few socio-demographic characteristics associated with the other three disability domains were similar. PRACTICE IMPLICATIONS: Disability among Asian patients with MDD correlates with the severity of psychiatric symptoms and the hospitalizations due to depression. Socio-demographic characteristics have little impact on the overall disability. PMID- 26031316 TI - Cleaved PARP-1, an Apoptotic Marker, can be Detected in Ram Spermatozoa. AB - The presence of apoptotic features in spermatozoa has been related to lower quality and functional impairment. Members of the poly-ADP-ribose polymerases (PARP) familyare involved in both DNA repair and apoptosis, playing important roles in spermatogenesis. Poly-ADP-ribose polymerase can be cleaved by caspases, and the presence of its cleavage product (cPARP) in spermatozoa has been related to chromatin remodelling during spermatogenesis and to the activation of apoptotic pathways. There are no reports on immunodetection of cPARP in ram spermatozoa; thus, we have tested a commercially available antibody for this purpose. cPARP was microscopically detected in the acrosomal ridge of some spermatozoa (indirect immunofluorescence). A preliminary study was carried out by flow cytometry (direct immunofluorescence, FITC). Ram semen was extended in TALP and incubated for 4 h with apoptosis inducers staurosporine (10 MUm) or betulinic acid (200 MUm). Both inducers and incubation caused a significant increase in cPARP spermatozoa (0 h, control: 21.4+/-3.3%, inducers: 44.3+/-1.4%; 4 h, control: 44.3+/-2.4%, inducers: 53.3+/-1.4%). In a second experiment, we compared the sperm fractions after density gradient separation (pellet and interface). The pellet yielded a slightly lower proportion of cPARP spermatozoa (28.5+/-1.2% vs 36.2+/-2.0% in the interface; p < 0.001), and a 12-h incubation increased cPARP similarly in both fractions (p < 0.001). cPARP seems to be an early marker of apoptosis in ram semen, although its presence in untreated samples was weakly related to worse quality (pellet/interface). We suggest to study the relationship of PARP and cPARP levels with between-male differences on sperm fertility. PMID- 26031317 TI - Best-corrected visual acuity and retinal thickness are associated with improved cortical visual processing in treated wet AMD patients. AB - PURPOSE: In response to anti-VEGF treatment for wet AMD retinal anatomy and visual acuity is often remedied. In our previous study, we showed that visual evoked potentials (VEP) improve following successful anti-VEGF treatment. The aim of this study was to investigate, how visual acuity and retinal thickness changes are reflected in VEP parameters. Moreover, we wanted to assess the feasibility of VEP as a novel monitoring tool for wet AMD patients. METHODS: A total of 16 patients and six control subjects were enrolled in this study. Patients received three bevacizumab intravitreal injections. At the beginning of the study and four to 6 weeks after the last injection, the best-corrected visual acuity (BCVA) test, full biomicroscope examination, OCT analysis and VEP were performed. RESULTS: In treated eyes, logMAR visual acuity improved on average 0.18 +/- 0.32 units, OCT retinal thickness decreased 170 +/- 200 micrometres and VEP amplitude increased 1.0 +/- 1.4 microvolts. All changes were significant at p < 0.05. There was a significant correlation between the relative changes of VEP amplitude and retinal thickness r = -0.630 (p < 0.05), and between visual acuity (logMAR) and retinal thickness r = 0.576 (p < 0.05). CONCLUSION: We showed that both the increase in VEP amplitude and the improvement in visual acuity are associated with the decrease in retinal thickness in treated wet AMD patients. The results do not indicate additional usefulness of VEP in the diagnosis or monitoring of wet AMD. PMID- 26031318 TI - MeCP2 in the enteric nervous system. AB - BACKGROUND: Rett syndrome (RTT) is an intellectual deficit and movement disorder that develops during early childhood in girls. Affected children are normal until 6-18 months of age, after which symptoms begin to appear. Most cases of RTT are due to mutations in the MeCP2 gene leading to disruption of neuronal communication in the central nervous system. In addition, RTT patients show peripheral ailments such as gastrointestinal (GI), respiratory, and cardiac dysfunction. The etiology of intestinal dysfunction in RTT is not well understood. Reports on the presence of MeCP2 in the peripheral nervous system are scant. As such we examined the levels of MeCP2 in human and murine GI tissue and assessed MeCP2 expression at various developmental stages. METHODS: Immunohistochemistry for MeCP2, HuC/D, juvenile beta tubulin, and GFAP was performed on human and murine intestine. Western blots of these same tissues were probed with MeCP2, vAChT, nNOS, and beta-actin antibodies. KEY RESULTS: MeCP2 is expressed throughout the GI tract. MeCP2 is expressed specifically in the enteric nervous system of the GI tract. MeCP2 is expressed in the GI tract throughout development with appearance beginning at or before E11.5 in the murine intestine. CONCLUSIONS & INFERENCES: The proof of MeCP2 expression in enteric neurons suggests that the GI dysmotility in Rett may arise from enteric network dysfunction secondary to MeCP2 mutation. PMID- 26031320 TI - Women with an HbA1c of 41-49 mmol/mol (5.9-6.6%): a higher risk subgroup that may benefit from early pregnancy intervention. AB - AIMS: To examine whether women with an HbA1c of 41-49 mmol/mol (5.9-6.6%) at diagnosis of gestational diabetes are higher risk than women with an HbA1c of < 41 mmol/mol (5.9%) and whether pregnancy outcomes are improved if treated at < 24 weeks' gestation. METHODS: This was an observational study of women with gestational diabetes diagnosed by early HbA1c screening or subsequent oral glucose tolerance test at < 34 weeks' gestation who delivered at National Women's Health, Auckland, from July 2012 to June 2014. Data were extracted from the hospital database. Women with HbA1c 41-49 mmol/mol (5.9-6.6%) were divided into those seen < 24 weeks (Early, n = 134) and those seen >= 24 weeks (Later, n = 151). Those with HbA1c < 41 mmol/mol (5.9%) were labelled Other GDM (n = 661). RESULTS: The Early and Later groups, compared with Other GDM, had more Polynesian and fewer (non-Indian) Asian women, higher BMI and more required medication (P < 0.001). More were smokers (P = 0.007, 0.02) and more had chronic hypertension (P < 0.001, 0.02). There were higher rates of adverse outcomes in the Later group than the Other GDM group (pre-eclampsia 8.0% vs. 2.4%, P = 0.001, preterm birth 16.6% vs. 8.2%, P = 0.002, neonatal admission 15.5% vs. 9.2%, P = 0.02). Outcomes were similar between the Early group and Other GDM group (pre-eclampsia 1.5% vs. 2.4%, P = 0.5, preterm birth 10.5% vs. 8.2% P = 0.4, neonatal admission 13.6% vs. 9.2%, P = 0.12). Comparing the Early and Later groups, the Early group had less pre-eclampsia, 1.5% vs. 8.0%, adjusted P = 0.03. Other outcomes were not statistically different. CONCLUSIONS: An HbA1c of 41-49 mmol/mol (5.9-6.7%) identifies a higher-risk group of women with gestational diabetes. Overall, our data support early treatment of women with an HbA1c >= 41 mmol/mol (5.9%). PMID- 26031321 TI - Differential degradation of polycyclic aromatic hydrocarbon mixtures by indigenous microbial assemblages in soil. AB - Environmental contamination by polycyclic aromatic hydrocarbons (PAHs) typically occurs as mixtures of compounds. In this study, the response of indigenous soil bacterial and fungal communities to mixtures containing phenanthrene, fluoranthene and benzo(a)pyrene in various combinations was examined using molecular fingerprinting techniques and quantification of a key PAH degradative gene. Results were compared to a parallel study by Sawulski et al. (2014) which examined the effect of these PAHs on soil microbial communities when added as single contaminants. The rate of degradation of individual PAHs varied depending on whether the PAH was present as a single contaminant or in a mixture; phenanthrene was degraded most rapidly when present as a sole contaminant, fluoranthene was removed faster in the presence of the lower molecular weight phenanthrene and the rate of benzo(a)pyrene degradation was reduced in the presence of the 4-ring PAH, fluoranthene. Bacterial and fungal assemblages differed significantly between treatments regardless of which PAH was added to soil. Although less abundant than the Gram-negative PAH-RHDalpha gene, the gene associated with Gram-positive bacteria responded to a greater extent to the presence of PAHs, either as single compounds or as mixtures and this increase was significantly correlated with PAH degradation. SIGNIFICANCE AND IMPACT OF THE STUDY: Contaminated sites generally contain complex mixtures of pollutants. Development of effective bioremediation strategies for contaminated soils requires knowledge of the response of soil microbial communities to such mixtures. This study provides information on the degradation of different mixtures of three priority pollutants in soil with a history of polycyclic aromatic hydrocarbon contamination and examines the response of soil bacterial and fungal communities to the presence of these pollutants as sole contaminants or as part of a mixture. This is one of few studies to-date to compare the effects of single compounds and pollutant mixtures on more than one soil microbial community. PMID- 26031322 TI - Influenza Outbreaks Among Passengers and Crew on Two Cruise Ships: A Recent Account of Preparedness and Response to an Ever-Present Challenge. AB - BACKGROUND: During spring 2014, two large influenza outbreaks occurred among cruise ship passengers and crew on trans-hemispheric itineraries. METHODS: Passenger and crew information for both ships was obtained from components of the ship medical records. Data included demographics, diagnosis of influenza-like illness (ILI) or acute respiratory illness (ARI), illness onset date, passenger cabin number, crew occupation, influenza vaccination history, and rapid influenza diagnostic test (RIDT) result, if performed. RESULTS: In total, 3.7% of passengers and 3.1% of crew on Ship A had medically attended acute respiratory illness (MAARI). On Ship B, 6.2% of passengers and 4.7% of crew had MAARI. In both outbreaks, passengers reported illness prior to the ship's departure. Influenza activity was low in the places of origin of the majority of passengers and both ships' ports of call. The median age of affected passengers on both ships was 70 years. Diagnostic testing revealed three different co-circulating influenza viruses [influenza A(H1N1)pdm09, influenza A(H3N2), and influenza B] on Ship A and one circulating influenza virus (influenza B) on Ship B. Both ships voluntarily reported the outbreaks to the Centers for Disease Control and Prevention (CDC) and implemented outbreak response plans including isolation of sick individuals and antiviral treatment and prophylaxis. CONCLUSIONS: Influenza activity can become widespread during cruise ship outbreaks and can occur outside of traditional influenza seasons. Comprehensive outbreak prevention and control plans, including prompt antiviral treatment and prophylaxis, may mitigate the impact of influenza outbreaks on cruise ships. PMID- 26031323 TI - Increasing the Number of Organ Transplants in the United States by Optimizing Donor Authorization Rates. AB - While recent policies have focused on allocating organs to patients most in need and lessening geographic disparities, the only mechanism to increase the actual number of transplants is to maximize the potential organ supply. We conducted a retrospective cohort study using OPTN data on all "eligible deaths" from 1/1/08 to 11/1/13 to evaluate variability in donor service area (DSA)-level donor authorization rates, and to quantify the potential gains associated with increasing authorization rates. Despite adjustments for donor demographics (age, race/ethnicity, cause of death) and geographic factors (rural/urban status of donor hospital, statewide participation in deceased-donor registries) among 52 571 eligible deaths, there was significant variability (p < 0.001) in donor authorization rates across the 58 DSAs. Overall DSA-level adjusted authorization rates ranged from 63.5% to 89.5% (median: 72.7%). An additional 773-1623 eligible deaths could have been authorized, yielding 2679-5710 total organs, if the DSAs with authorization rates below the median and 75th percentile, respectively, implemented interventions to perform at the level of the corresponding reference DSA. Opportunities exist within the current organ acquisition framework to markedly improve DSA-level donor authorization rates. Such initiatives would mitigate waitlist mortality while increasing the number of transplants. PMID- 26031324 TI - Skeletal muscle mass assessed by computed tomography correlates to muscle strength and physical performance at a liver-related hospital experience. AB - AIM: We aimed to evaluate whether skeletal muscle mass measured by computed tomography (CT) or bioelectrical impedance analysis (BIA) correlated to muscle strength and physical performance in liver-related hospital cases. METHODS: We prospectively conducted this study in 120 liver-related hospital cases. Skeletal muscle mass was measured by CT scan and BIA. Muscle strength was determined by hand grip strength and physical performance by usual gait speed. RESULTS: Skeletal muscle mass measured using CT significantly correlated to usual gait speed (r(2) = 0.17, P < 0.0001) and hand grip strength (r(2) = 0.66, P < 0.0001), but the correlations were lower using BIA (r(2) = 0.1, P = 0.0005; r(2) = 0.54, P < 0.0001). With regard to liver function, the relationship between skeletal muscle mass measured by CT and BIA and two muscle function parameters in the Child-Pugh A group were significant. In contrast, skeletal muscle mass measured by BIA in the Child-Pugh B or C group was not significantly related to usual gait speed. CONCLUSION: Skeletal muscle mass measured by CT was significantly correlated to hand grip strength and usual gait speed, with higher correlations compared with BIA. Moreover, skeletal muscle mass measured by CT significantly correlated with two muscle functions, even in patients with Child Pugh B or C. PMID- 26031319 TI - Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes. AB - Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium-derived factors, that is, relaxing factors (endothelium-derived relaxing factors; EDRFs) and contracting factors (endothelium-derived contracting factors; EDCFs), which mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, COX-derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4 A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4 A in hypertension- and diabetes associated vascular dysfunction is unclear. In the present review, we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4 A) in vascular dysfunction associated with hypertension and diabetes. PMID- 26031325 TI - Validation of a Comprehensive Early Childhood Allergy Questionnaire. AB - BACKGROUND: Parental questionnaires to assess incidence of pediatric allergic disease have been validated for use in school-aged children. Currently, there is no validated questionnaire-based assessment of food allergy, atopic dermatitis (AD), and asthma for infants and young children. METHODS: The Comprehensive Early Childhood Allergy Questionnaire was designed for detecting AD, asthma, and IgE mediated food allergies in children aged 1-5 years. A nested case-control design was applied. Parents of 150 children attending pediatric outpatient clinics completed the questionnaire before being clinically assessed by a pediatrician for allergies. Sensitivity, specificity, and reproducibility of the questionnaire were assessed. RESULTS: Seventy-seven children were diagnosed with one or more current allergic diseases. The questionnaire demonstrated high overall sensitivity of 0.93 (95% CI 0.86-0.98) with a specificity of 0.79 (95% CI 0.68 0.88). Questionnaire reproducibility was good with a kappa agreement rate for symptom-related questions of 0.45-0.90. CONCLUSIONS: Comprehensive Early Childhood Allergy Questionnaire accurately and reliably reflects the presence of allergies in children aged 1-5 years. Its use is warranted as a tool for determining prevalence of allergies in this pediatric age group. PMID- 26031326 TI - Living Well with Pain: Development and Preliminary Evaluation of the Valued Living Scale. AB - OBJECTIVES: Encouraging individuals with chronic pain to focus on nonpain-related goals that are consistent with personal values is a goal of most psychosocial pain interventions. A valid and reliable measure of goal-related variables would be useful to evaluate the importance of these to patient quality of life and as factors that may explain treatment outcome. DESIGN: We developed items for a measure (the Valued Living Scale, VLS) to assess goal importance, success, and confidence with respect to eight value domains and 26 specific values-related goals, and administered these items to individuals with three chronic pain conditions (low back pain, N = 58; fibromyalgia, N = 55; headache, N = 61). RESULTS: Analyses supported: 1) a two-factor model of the VLS items assessing goal-related variables associated with a) health and productivity and b) social relations; 2) VLS scale score reliability, with Cronbach's alphas greater than 0.70; and 3) VLS scale score validity, as indicated by significant associations with pain intensity, depression, and pain interference in the expected directions. CONCLUSIONS: The VLS items can be administered and scored to assess: 1) the importance of as well as 2) confidence in and 3) success in achieving values-consistent goals. The measure can be used by clinicians to monitor and track changes in patient's perceptions about their goals with treatment. Researchers can use the VLS to test theoretical models of the roles that patient perceptions about goal importance, confidence, and success play in chronic pain treatment outcome. PMID- 26031327 TI - Reply: To PMID 23465084. PMID- 26031328 TI - Agro-industrial waste to solid biofuel through hydrothermal carbonization. AB - In this paper, the use of grape marc for energy purposes was investigated. Grape marc is a residual lignocellulosic by-product from the winery industry, which is present in every world region where vine-making is addressed. Among the others, hydrothermal carbonization was chosen as a promising alternative thermochemical process, suitable for the treatment of this high moisture substrate. Through a 50 mL experimental apparatus, hydrothermal carbonization tests were performed at several temperatures (namely: 180, 220 and 250 degrees C) and residence times (1, 3, 8 h). Analyses on both the solid and the gaseous phases obtained downstream of the process were performed. In particular, solid and gas yields versus the process operational conditions were studied and the obtained hydrochar was evaluated in terms of calorific value, elemental analysis, and thermal stability. Data testify that hydrochar form grape marc presents interesting values of HHV (in the range 19.8-24.1 MJ/kg) and physical-chemical characteristics which make hydrochar exploitable as a solid biofuel. In the meanwhile, the amount of gases produced is very small, if compared to other thermochemical processes. This represents an interesting result when considering environmental issues. Statistical analysis of data allows to affirm that, in the chosen range of operational conditions, the process is influenced more by temperature than residence time. These preliminary results support the option of upgrading grape marc toward its energetic valorisation through hydrothermal carbonization. PMID- 26031329 TI - Comparative evaluation of anaerobic digestion for sewage sludge and various organic wastes with simple modeling. AB - Anaerobic co-digestion of sewage sludge and other organic wastes, such as kitchen garbage, food waste, and agricultural waste, at a wastewater treatment plant (WWTP) is a promising method for both energy and material recovery. Substrate characteristics and the anaerobic digestion performance of sewage sludge and various organic wastes were compared using experiments and modeling. Co-digestion improved the value of digested sewage sludge as a fertilizer. The relationship between total and soluble elemental concentrations was correlated with the periodic table: most Na and K (alkali metals) were soluble, and around 20-40% of Mg and around 10-20% of Ca (alkaline earth metals) were soluble. The ratio of biodegradable chemical oxygen demand of organic wastes was 65-90%. The methane conversion ratio and methane production rate under mesophilic conditions were evaluated using a simplified mathematical model. There was reasonably close agreement between the model simulations and the experimental results in terms of methane production and nitrogen concentration. These results provide valuable information and indicate that the model can be used as a pre-evaluation tool to facilitate the introduction of co-digestion at WWTPs. PMID- 26031330 TI - Construction and demolition waste: Comparison of standard up-flow column and down flow lysimeter leaching tests. AB - Five samples of construction and demolition waste (C&DW) were investigated in order to quantify leaching of inorganic elements under percolation conditions according to two different experimental setups: standardised up-flow saturated columns (<4mm particle size) and unsaturated, intermittent down-flow lysimeters (<40mm particle size). While standardised column tests are meant primarily to provide basic information on characteristic leaching properties and mechanisms and not to reproduce field conditions, the lysimeters were intended to mimic the actual leaching conditions when C&DW is used in unbound geotechnical layers. In practice, results from standardised percolation tests are often interpreted as estimations of actual release from solid materials in percolation scenarios. In general, the two tests yielded fairly similar results in terms of cumulative release at liquid-to-solid ratio (L/S) 10l.kgTS; however, significant differences were observed for P, Pb, Ba, Mg and Zn. Further differences emerged in terms of concentration in the early eluates (L/S<5l.kg(-1)TS) for Al, As, Ba, Cd, Cu, DOC, Mg, Mn, Ni, P, Pb, Sb, Se, Si, Zn. Observed differences between tests are likely to be due to differences in pH related to crushing and exposure of fresh particle surfaces, as well as in equilibrium conditions. In the case of C&DW, the standardised column tests, which are more practical, are considered to acceptably describe cumulative releases at L/S 10l.kg(-1)TS in percolation scenarios. However, when the focus is on estimation of initial concentrations for (for example) risk assessment, data from standardised column tests may not be fully applicable, and data from lysimeters may be used for validation purposes. Se, Cr and, to a lesser extent, SO4 and Sb were leaching from C&DW in critical amounts compared with existing limit values. PMID- 26031331 TI - Tat/HA2 Peptides Conjugated AuNR@pNIPAAm as a Photosensitizer Carrier for Near Infrared Triggered Photodynamic Therapy. AB - To achieve an efficiency of intracellular photosensitizers (PSs) delivery and efficacy of photodynamic therapy, we have developed a novel class of PS formulation for encapsulating sulfonated aluminum phthalocyanine (AlPcS4) by taking advantage of the membrane-disruptive peptides Tat/HA2 and the photothermally triggered delivery system using AuNR@pNIPAAm. The coordinated effects of cell penetrating peptide Tat and fusogenic peptide HA2 could enhance the efficient cellular internalization and endo/lysosome escape of PSs delivery systems. Singlet oxygen generation was inhibited due to the reaction between loaded AlPcS4 and Au nanorods, which indicated that the AlPcS4-loaded, AuNR@pNIPAAm delivery system might be nonphototoxic in the circulatory system. However, this PSs-loaded nanosystem became highly phototoxic as it underwent the near-infrared irradiation by using the combined lights of 808 and 680 nm. Upon irradiation, the Tat/HA2 conjugated AuNR@pNIPAAm-Pc elicited an active photodynamic response against the cancer cells, leading to effective cells killing via mitochondria-associated apoptotic pathway. This study also demonstrated improved PDT therapeutic efficacy after intravenous administration of Tat/HA2-AuNR@pNIPAAm-Pc and the subsequent lights irradiations in tumor bearing mice. We describe here a strategy for enhanced photodynamic eradication of solid tumors by endo/lysosomal escape and highlight the great promise of peptide-based nanocarriers used for cancer therapy. PMID- 26031332 TI - Sestrin2 Protects Dopaminergic Cells against Rotenone Toxicity through AMPK Dependent Autophagy Activation. AB - Dysfunction of the autophagy-lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS) was thought to be an important pathogenic mechanism in synuclein pathology and Parkinson's disease (PD). In the present study, we investigated the role of sestrin2 in autophagic degradation of alpha-synuclein and preservation of cell viability in a rotenone-induced cellular model of PD. We speculated that AMP activated protein kinase (AMPK) was involved in regulation of autophagy and protection of dopaminergic cells against rotenone toxicity by sestrin2. The results showed that both the mRNA and protein levels of sestrin2 were increased in a TP53-dependent manner in Mes 23.5 cells after treatment with rotenone. Genetic knockdown of sestrin2 compromised the autophagy induction in response to rotenone, while overexpression of sestrin2 increased the basal autophagy activity. Sestrin2 presumably enhanced autophagy in an AMPK-dependent fashion, as sestrin2 overexpression activated AMPK, and genetic knockdown of AMPK abrogated autophagy induction by rotenone. Restoration of AMPK activity by metformin after sestrin2 knockdown recovered the autophagy activity. Sestrin2 overexpression ameliorated alpha-synuclein accumulation, inhibited caspase 3 activation, and reduced the cytotoxicity of rotenone. These results suggest that sestrin2 upregulation attempts to maintain autophagy activity and suppress rotenone cytotoxicity through activation of AMPK, and that sestrin2 exerts a protective effect on dopaminergic cells. PMID- 26031333 TI - The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin. AB - Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. In Pde3b knockout (KO) adipocytes, insulin was unable to suppress beta adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis. PMID- 26031334 TI - Lighting Up the Force: Investigating Mechanisms of Mechanotransduction Using Fluorescent Tension Probes. AB - The ability of cells to sense the physical nature of their surroundings is critical to the survival of multicellular organisms. Cellular response to physical cues from adjacent cells and the extracellular matrix leads to a dynamic cycle in which cells respond by remodeling their local microenvironment, fine tuning cell stiffness, polarity, and shape. Mechanical regulation is important in cellular development, normal morphogenesis, and wound healing. The mechanisms by which these finely balanced mechanotransduction events occur, however, are not well understood. In large part, this is due to the limited availability of tools to study molecular mechanotransduction events in live cells. Several classes of molecular tension probes have been recently developed which are rapidly transforming the study of mechanotransduction. Molecular tension probes are primarily based on fluorescence resonance energy transfer (FRET) and report on piconewton scale tension events in live cells. In this minireview, we describe the two main classes of tension probes, genetically encoded tension sensors and immobilized tension sensors, and discuss the advantages and limitations of each type. We discuss future opportunities to address major biological questions and outline the challenges facing the next generation of molecular tension probes. PMID- 26031335 TI - Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Calpha Signaling. AB - Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca(2+) homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1(-/-) mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca(2+) entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca(2+) entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cgamma (PLC-gamma), TRPC1 mediated Ca(2+) entry and triggered protein kinase Calpha (PKCalpha) activity to facilitate nuclear translocation of NF-kappaB/Jun N terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1 PKCalpha signaling circuit. PMID- 26031338 TI - SiGe quantum dot crystals with periods down to 35 nm. AB - By combining extreme ultraviolet interference lithography with Si/Ge molecular beam epitaxy, densely packed quantum dot (QD) arrays with lateral periodicities down to 35 nm are realized. The QD arrays are featured by perfect alignment and remarkably narrow size distribution. Also, such small periodicities allow the creation of three-dimensional QD crystals by vertical stacking of Si/Ge layers using very thin Si spacer layers. Simulations show that the distances between adjacent QDs are small enough for coupling of the electron states in lateral as well as vertical directions. PMID- 26031337 TI - IRE1alpha-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2alpha Phosphorylation and Suppresses Protein Synthesis. AB - The unfolded protein response (UPR) regulates endoplasmic reticulum (ER) homeostasis and protects cells from ER stress. IRE1alpha is a central regulator of the UPR that activates the transcription factor XBP1s through an unconventional splicing mechanism using its endoribonuclease activity. IRE1alpha also cleaves certain mRNAs containing XBP1-like secondary structures to promote the degradation of these mRNAs, a process known as regulated IRE1alpha-dependent decay (RIDD). We show here that the mRNA of CReP/Ppp1r15b, a regulatory subunit of eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphatase, is a RIDD substrate. eIF2alpha plays a central role in the integrated stress response by mediating the translational attenuation to decrease the stress level in the cell. CReP expression was markedly suppressed in XBP1-deficient mice livers due to hyperactivated IRE1alpha. Decreased CReP expression caused the induction of eIF2alpha phosphorylation and the attenuation of protein synthesis in XBP1 deficient livers. ER stress also suppressed CReP expression in an IRE1alpha dependent manner, which increased eIF2alpha phosphorylation and consequently attenuated protein synthesis. Taken together, the results of our study reveal a novel function of IRE1alpha in the regulation of eIF2alpha phosphorylation and the translational control. PMID- 26031336 TI - Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation. AB - Embryonic stem cells (ESCs) are characterized by their ability to self-renew and to differentiate into all cell types of a given organism. Understanding the molecular mechanisms that govern the ESC state is of great interest not only for basic research-for instance, ESCs represent a perfect system to study cellular differentiation in vitro-but also for their potential implications in human health, as these mechanisms are likewise involved in cancer progression and could be exploited in regenerative medicine. In this minireview, we focus on the latest insights into the molecular mechanisms mediated by the pluripotency factors as well as their roles during differentiation. We also discuss recent advances in understanding the function of the epigenetic regulators, Polycomb and MLL complexes, in ESC biology. PMID- 26031339 TI - Relationships Between Malnutrition, Inflammation, Sleep Quality, and Restless Legs Syndrome in Hemodialysis Patients. AB - Restless legs syndrome (RLS) is a common neurologic sensorimotor disorder. It is also seen in hemodialysis patients in whom the mechanism is not thoroughly understood. The aim of this study was to evaluate the association between malnutrition-inflammation score (MIS), sleep quality, and RLS in chronic hemodialysis patients. This cross-sectional study included 232 adult stable chronic hemodialysis patients (mean age 60.9 +/- 14.1 years, 56.5% male). RLS frequency, MIS, Pittsburgh Sleep Quality Index (PSQI), laboratory data of patients as well as severity of RLS were evaluated. Thirty-seven patients (15.9%) were diagnosed with RLS. Mean MIS of patients with or without RLS were similar. PSQI of patients with RLS was significantly higher than patients without RLS (P = 0.002). There was a significant positive correlation between RLS severity and PSQI (r = 0.445, P = 0.006). A significant positive correlation was also found between PSQI and MIS in patients with RLS (r = 0.419, P = 0.010). RLS severity was positively correlated with some inflammatory parameters such as white blood cell count and C-reactive protein (r = 0.427, P = 0.008 and r = 0.418 P = 0.010). PSQI was found as an independent significant predictor of RLS (odds ratio [OR] = 1.15 (1.06-1.25), P = 0.001) in multivariate logistic regression analysis. Our study revealed that there was no significant relationship between RLS and MIS in chronic hemodialysis patients. However, RLS severity is correlated with inflammatory parameters. Also, sleep quality in chronic hemodialysis patients with RLS is negatively associated with MIS. PMID- 26031341 TI - Intervertebral reaction force prediction using an enhanced assembly of OpenSim models. AB - OpenSim offers a valuable approach to investigating otherwise difficult to assess yet important biomechanical parameters such as joint reaction forces. Although the range of available models in the public repository is continually increasing, there currently exists no OpenSim model for the computation of intervertebral joint reactions during flexion and lifting tasks. The current work combines and improves elements of existing models to develop an enhanced model of the upper body and lumbar spine. Models of the upper body with extremities, neck and head were combined with an improved version of a lumbar spine from the model repository. Translational motion was enabled for each lumbar vertebrae with six controllable degrees of freedom. Motion segment stiffness was implemented at lumbar levels and mass properties were assigned throughout the model. Moreover, body coordinate frames of the spine were modified to allow straightforward variation of sagittal alignment and to simplify interpretation of results. Evaluation of model predictions for level L1-L2, L3-L4 and L4-L5 in various postures of forward flexion and moderate lifting (8 kg) revealed an agreement within 10% to experimental studies and model-based computational analyses. However, in an extended posture or during lifting of heavier loads (20 kg), computed joint reactions differed substantially from reported in vivo measures using instrumented implants. We conclude that agreement between the model and available experimental data was good in view of limitations of both the model and the validation datasets. The presented model is useful in that it permits computation of realistic lumbar spine joint reaction forces during flexion and moderate lifting tasks. The model and corresponding documentation are now available in the online OpenSim repository. PMID- 26031340 TI - Dengue Virus Uses a Non-Canonical Function of the Host GBF1-Arf-COPI System for Capsid Protein Accumulation on Lipid Droplets. AB - Dengue viruses cause the most important human viral disease transmitted by mosquitoes. In recent years, a great deal has been learned about molecular details of dengue virus genome replication; however, little is known about genome encapsidation and the functions of the viral capsid protein. During infection, dengue virus capsid progressively accumulates around lipid droplets (LDs) by an unknown mechanism. Here, we examined the process by which the viral capsid is transported from the endoplasmic reticulum (ER) membrane, where the protein is synthesized, to LDs. Using different methods of intervention, we found that the GBF1-Arf1/Arf4-COPI pathway is necessary for capsid transport to LDs, while the process is independent of both COPII components and Golgi integrity. The transport was sensitive to Brefeldin A, while a drug resistant form of GBF1 was sufficient to restore capsid subcellular distribution in infected cells. The mechanism by which LDs gain or lose proteins is still an open question. Our results support a model in which the virus uses a non-canonical function of the COPI system for capsid accumulation on LDs, providing new ideas for antiviral strategies. PMID- 26031342 TI - Early language processing efficiency predicts later receptive vocabulary outcomes in children born preterm. AB - As rates of prematurity continue to rise, identifying which preterm children are at increased risk for learning disabilities is a public health imperative. Identifying continuities between early and later skills in this vulnerable population can also illuminate fundamental neuropsychological processes that support learning in all children. At 18 months adjusted age, we used socioeconomic status (SES), medical variables, parent-reported vocabulary, scores on the Bayley Scales of Infant and Toddler Development (third edition) language composite, and children's lexical processing speed in the looking-while-listening (LWL) task as predictor variables in a sample of 30 preterm children. Receptive vocabulary as measured by the Peabody Picture Vocabulary Test (fourth edition) at 36 months was the outcome. Receptive vocabulary was correlated with SES, but uncorrelated with degree of prematurity or a composite of medical risk. Importantly, lexical processing speed was the strongest predictor of receptive vocabulary (r = -.81), accounting for 30% unique variance. Individual differences in lexical processing efficiency may be able to serve as a marker for information processing skills that are critical for language learning. PMID- 26031343 TI - Melatonin inhibits granulocyte adhesion to ICAM via MT3/QR2 and MT2 receptors. AB - Neutrophils are cells of the innate immune system that first respond and arrive to the site of infection. Melatonin modulates acute inflammatory responses by interfering with leukocyte recruitment. It is known that melatonin modulates granulocyte migration though the endothelial layer thereby acting on the endothelial cell. Here we investigated whether melatonin could modulate granulocyte infiltration by acting directly on granulocytes. Granulocyte infiltration into the peritoneal cavity was investigated in mice kept at normal light/dark conditions and mice kept under constant lighting. To induce migration of neutrophils from the blood into the injury site via the endothelial layer, a bacterial product N-formyl-l-methionyl- l-leucyl- l-phenylalanine (fMLP) was injected into the peritoneal cavity. We found that the number of infiltrated granulocytes during the dark time was lower than that during the light time. It did not depend on circadian time. Moreover, the expression of an adhesion molecule, CD18, on granulocytes, was also lower during the dark time as compared with the light time. We have found that melatonin inhibited fMLP-induced CD18 up regulation. Importantly, melatonin also inhibited the integrin-mediated granulocyte adhesion to intercellular adhesion molecule-coated plates. This study additionally showed that melatonin receptors MT2 and MT3/quinone reductase 2 (QR2) are expressed on granulocytes. Interestingly, melatonin increases the expression of its MT3/QR2 receptor. The fMLP-mediated CD18 up-regulation was inhibited by melatonin via MT2 receptor and the integrin-mediated granulocyte adhesion was inhibited by melatonin via MT3/QR2 and MT2 receptors. In conclusion, we show that melatonin suppresses granulocyte migration via endothelium by acting directly on granulocytes. PMID- 26031345 TI - Bone density in apheresis donors and whole blood donors. AB - Apheresis donation using citrate causes acute decrease in serum calcium and increase in serum parathyroid hormone. Long-term consequences, such as decrease in bone mineral density (BMD), are not known. In this study, we compared the BMD of 20 postmenopausal apheresis donors (mean donation number 115 times in up to 15 years) with that of 20 whole blood donors (for 15 years or more) aged 55-70. BMD in the lumbar spine was not lower in apheresis donors than in blood donors (mean +/- SD 1.00 +/- 0.18 vs. 0.92 +/- 0.12, P = 0.09). In the hip, BMD was not different between the groups. PMID- 26031344 TI - A cluster randomized trial on improving nurses' detection and management of elder abuse and neglect (I-NEED): study protocol. AB - AIM: The aim of this study was to describe a trial protocol of an educational intervention for nurses to improve their awareness and practice in detecting and managing elder abuse and neglect. BACKGROUND: Knowledgeable and skilful nurses are crucial amidst the growing numbers of maltreated older patients. DESIGN: This trial is a multi-site, three-armed, community-based cluster randomized controlled trial with 6-months follow-up. METHODS: This study will involve 390 community and registered nurses from government health clinics in Negeri Sembilan, Malaysia (protocol approved in October 2013). This three-phased study, premised on the Precede-Proceed Model, comprises baseline focus group discussion and survey (Phase 1), development of training module (Phase 2) and implementation and evaluation of the training (Phase 3). Eligible participants will be randomized to the control group (continuous nursing education), intervention group A (face-to face intensive training programme) or group B (face-to-face intensive training programme and an educational video). Outcome measures include improvement in knowledge and awareness on elder abuse and neglect and the number of cases identified and managed during follow-up. Data will be collected at baseline, immediate postintervention, 3- and 6-month follow-up. CONCLUSION: Findings from this study will provide empirical support for the development of a training module for nurses on the detection and management of elder abuse and neglect, towards improving healthcare delivery and the well-being of vulnerable older adults. This study is funded by the University of Malaya Research Grant (RP001C 13HTM), (FL002-13SBS) and University of Malaya Grand Challenge (PEACE) Grant (GC001C-14HTM) awarded in May 2013, July 2013 and September 2014. PMID- 26031347 TI - Anatomical reposition of incus after transmastoid facial nerve decompression using bone cement: preliminary results in 17 patients. PMID- 26031346 TI - Interactive and Indirect Effects of Anxiety and Negative Urgency on Alcohol Related Problems. AB - BACKGROUND: Although drinking for tension reduction has long been posited as a risk factor for alcohol-related problems, studies investigating anxiety in relation to risk for alcohol problems have returned inconsistent results, leading researchers to search for potential moderators. Negative urgency (the tendency to become behaviorally dysregulated when experiencing negative affect) is a potential moderator of theoretical interest because it may increase risk for alcohol problems among those high in negative affect. This study tested a cross sectional mediated moderation hypothesis whereby an interactive effect of anxiety and negative urgency on alcohol problems is mediated through coping-related drinking motives. METHODS: The study utilized baseline data from a hazardously drinking sample of young adults (N = 193) evaluated for participation in a randomized controlled trial of naltrexone and motivational interviewing for drinking reduction. RESULTS: The direct effect of anxiety on physiological dependence symptoms was moderated by negative urgency such that the positive association between anxiety and physiological dependence symptoms became stronger as negative urgency increased. Indirect effects of anxiety and negative urgency on alcohol problems (operating through coping motives) were also observed. CONCLUSIONS: Although results of the current cross-sectional study require replication using longitudinal data, the findings suggest that the simultaneous presence of anxiety and negative urgency may be an important indicator of risk for alcohol use disorders via both direct interactive effects and indirect additive effects operating through coping motives. These findings have potentially important implications for prevention/intervention efforts for individuals who become disinhibited in the context of negative emotional states. PMID- 26031349 TI - Indexing cardiovascular and respiratory variables: allometric scaling principles. AB - OBJECTIVES: To describe the allometric scaling principles underlying appropriate indexing of cardiovascular and respiratory measurements obtained in adult mammals, and to propose guidelines for indexing experimental cardiovascular and respiratory data. DATABASE USED: PubMed, using the terms 'allometry', 'allometric', 'indexing', 'cardiovascular' and 'respiratory'. CONCLUSIONS: Indexing of cardiopulmonary variables is commonly used in attempts to account for the effects of body size on measurements and to standardize them. Some cardiopulmonary variables have been indexed using various functions of body mass in a process that often ignores the underlying relationship between the variable of interest and body size, as described in the allometry literature. This can result in a failure to ideally reduce the effect of body size on measurements in a manner that highlights differences. We review how commonly measured cardiopulmonary variables are related to body mass in mammalian species according to the allometry literature, and offer suggestions on how this information can be used to appropriately index cardiopulmonary variables in a simple and informative manner. PMID- 26031348 TI - N-acetyl-l-tryptophan, but not N-acetyl-d-tryptophan, rescues neuronal cell death in models of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss. Evidence suggests that mitochondrial dysfunction, apoptosis, oxidative stress, inflammation, glutamate excitotoxicity, and proteasomal dysfunction are all responsible for ALS pathogenesis. N-acetyl tryptophan has been identified as an inhibitor of mitochondrial cytochrome c release and therefore is a potential neuroprotective agent. By quantifying cell death, we demonstrate that N-acetyl-l-tryptophan (L-NAT) and N-acetyl-DL tryptophan are neuroprotective in NSC-34 motor neuron-like cells and/or primary motor neurons, while their isomer N-acetyl-d-tryptophan has no protective effect. These findings are consistent with energy minimization and molecular modeling analysis, confirming that L-NAT generates the most stable complex with the neurokinin-1 receptor (NK-1R). L-NAT inhibits the secretion of Substance P and IL 1beta (Enzyme-Linked Immunosorbent Assay and/or dot blots) and mitochondrial dysfunction by effectively inhibiting the release of cytochrome c/Smac/AIF from mitochondria into the cytoplasm and activation of apoptotic pathways, including the activation of caspase-1, -9, and -3, as well as proteasomal dysfunction through restoring chymotrypsin-like, trypsin-like, and caspase-like proteasome activity. These data provide insight into the molecular mechanisms by which L-NAT offers neuroprotection in models of ALS and suggest its potential as a novel therapeutic strategy for ALS. We demonstrate that L-NAT (N-acetyl-l-tryptophan), but not D-NAT, rescues NSC-34 cells and primary motor neurons from cell death. L NAT inhibits the secretion of Substance P and IL-1beta, and caspase-1 activation, the release of cytochrome c/Smac/AIF, and the activation of caspase -9, and -3, as well as proteasomal dysfunction. The data suggest the potential of L-NAT as a novel therapeutic strategy for amyotrophic lateral sclerosis (ALS). AIF, apoptosis-inducing factor. PMID- 26031350 TI - Photophysics and Rotational Dynamics of a Hydrophilic Molecule in a Room Temperature Ionic Liquid. AB - We have studied the photophysics and rotational diffusion of hydrophilic solute 7 (N, N'-diethylamino)coumarin-3-carboxylic acid (7-DCCA) in a room temperature ionic liquid methyltrioctylammonium bis(trifluoromethylsulfonyl) imide ([N1888 ][NTf2 ]). Comparison of activation energies of viscous flow and nonradiative decay shows that the photophysical properties of 7-DCCA are not guided by the bulk viscosity of the medium but are dependent on the specific solute solvent interaction and structural heterogeneity of the medium. The rotational relaxation behaviour of 7-DCCA in [N1888 ][NTf2] shows significant deviation from the Stokes Einstein Debye hydrodynamic model of rotational diffusion. This is indicative of the influence of specific solute solvent interaction on the rotational relaxation behaviour of 7-DCCA. Comparison of activation energy of rotational relaxation with activation energy of viscous flow clearly reinforces our assumption that the structural heterogeneity of the medium and specific solute solvent interaction plays a dominant role on the rotational diffusion instead of bulk viscosity. PMID- 26031351 TI - The Impact of Reproductive Technologies on Stallion Mitochondrial Function. AB - The traditional assessment of stallion sperm comprises evaluation of sperm motility and membrane integrity and identification of abnormal morphology of the spermatozoa. More recently, the progressive introduction of flow cytometry is increasing the number of tests available. However, compared with other sperm structures and functions, the evaluation of mitochondria has received less attention in stallion andrology. Recent research indicates that sperm mitochondria are key structures in sperm function suffering major changes during biotechnological procedures such as cryopreservation. In this paper, mitochondrial structure and function will be reviewed in the stallion, when possible specific stallion studies will be discussed, and general findings on mammalian mitochondrial function will be argued when relevant. Especial emphasis will be put on their role as source of reactive oxygen species and in their role regulating sperm lifespan, a possible target to investigate with the aim to improve the quality of frozen-thawed stallion sperm. Later on, the impact of current sperm technologies, principally cryopreservation, on mitochondrial function will be discussed pointing out novel areas of research interest with high potential to improve current sperm technologies. PMID- 26031352 TI - Inverse relationship between sleep duration and myopia. AB - PURPOSES: To investigate the association between sleep duration and myopia. METHODS: This population-based, cross-sectional study using a nationwide, systemic, stratified, multistage, clustered sampling method included a total of 3625 subjects aged 12-19 years who participated in the Korean National Health and Nutrition Examination Survey 2008-2012. All participants underwent ophthalmic examination and a standardized interview including average sleep duration (hr/day), education, physical activity and economic status (annual household income). Refractive error was measured by autorefraction without cycloplegia. Myopia and high myopia were defined as <=-0.50 dioptres (D) and <=-6.0 D, respectively. Sleep durations were classified into 5 categories: <5, 6, 7, 8 and >9 hr. RESULTS: The overall prevalence of myopia and high myopia were 77.8% and 9.4%, respectively, and the overall sleep duration was 7.1 hr/day. The refractive error increased by 0.10 D per 1 hr increase in sleep after adjusting for potential confounders including sex, age, height, education level, economic status and physical activity. The adjusted odds ratio (OR) for refractive error was 0.90 (95% confidence interval [CI], 0.83-0.97) per 1 hr increase in sleep. The adjusted OR for myopia was decreased in those with >9 hr of sleep (OR, 0.59; 95% CI, 0.38-0.93; p for trend = 0.006) than in those with <5 hr of sleep. However, high myopia was not associated with sleep duration. CONCLUSIONS: This study provides the population-based, epidemiologic evidence for an inverse relationship between sleep duration and myopia in a representative population of Korean adolescents. PMID- 26031353 TI - Coffee: A Selected Overview of Beneficial or Harmful Effects on the Cardiovascular System? AB - With a history that began in 800 A.D., coffee is the most popular drink known and as a result, the issues regarding its physiologic effects deserve attention. Maintaining alertness is a well-known benefit and in addition, the cardiovascular (CV) effects of the active compounds, which include polyphenols and caffeine, must be considered. Genetics are relevant and where slow caffeine metabolism is inherent, the risk of nonfatal myocardial (MI) has been shown to be increased. Overall risk for coronary heart disease (CHD) is not supported and unless there is excessive intake, congestive heart failure (CHF) is not adversely affected; in moderation, there may be some benefit for CHF. There is no apparent increased risk of sudden cardiac death (SCD). Overall, there also appears to be a beneficial inverse association with all-cause mortality, although this is not absolute for extra heavy intake. Benefit in reducing stroke also has supportive evidence. Hypertension is not increased by coffee. Boiled and unfiltered coffee appears to increase plasma cholesterol and triglycerides but for the overall metabolic syndrome, there appears to be benefit. There is also some evidence that paper-filtered coffee results in an increase in some markers of inflammation. Association of coffee with arrhythmias has been a major concern though in moderation it is not a significant overall problem. Therefore, only if a patient were to associate major arrhythmic symptoms with coffee would cessation have to be advised. Where coffee clearly shines from a CV standpoint is in the established decrease in onset of type 2 diabetes mellitus (DM). Any benefit or harm has always been attributed to caffeine as the apparent major component. However, coffee contains a myriad of compounds, including polyphenols. These other substances may be most relevant for potential benefit or harm and some of these may be partially removed or altered by coffee preparation methods such as paper filtration. Multiple studies support this by what appears to be no CV advantage or disadvantage for decaffeinated coffee. The bottom line on coffee, for those who enjoy the brew, is that it is a wonderful beverage with rare associated CV disadvantage and with much to recommend it from an overall CV standpoint. PMID- 26031354 TI - The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. AB - Following their activation in response to inflammatory signals, innate immune cells secrete T-cell-polarizing cytokines that promote the differentiation of naive CD4 T cells into T helper (Th) cell subsets. Among these, Th17 cells play a prominent role in the development of a number of autoimmune diseases. Although regarded primarily as an immunosuppressant signal, cAMP has been found to mediate pro-inflammatory effects of macrophage-derived prostaglandin E2 (PGE2) on Th17 cells. Here we show that PGE2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2. Following its dephosphorylation, CRTC2 stimulates the expression of the cytokines IL-17A and IL-17F by binding to CREB over both promoters. CRTC2-mutant mice have decreased Th17 cell numbers, and they are protected from experimental autoimmune encephalitis, a model for multiple sclerosis. Our results suggest that small molecule inhibitors of CRTC2 may provide therapeutic benefit to individuals with autoimmune disease. PMID- 26031357 TI - Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease. AB - This article is part of a Special Issue "SBN 2014". Alzheimer's disease is one of the most prevalent and costly neurological diseases in the world. Although decades of research have focused on understanding Alzheimer's disease pathology and progression, there is still a great lack of clinical treatments for those who suffer from it. One of the factors most commonly associated with the onset of Alzheimer's disease is a decrease in levels of gonadal hormones, such as estrogens and androgens. Despite the correlational and experimental data which support the role of these hormones in the etiology of Alzheimer's disease, clinical trials involving their reintroduction through hormone therapy have had varied results and these gonadal hormones often have accompanying health risks. More recently, investigation has turned toward other hormones in the hypothalamic pituitary-gonadal axis that are disrupted by age-related decreases in gonadal hormones. Specifically, luteinizing hormone, which is increased with age in both men and women (in response to removal of negative feedback), has surfaced as a potentially powerful player in the risk and onset of Alzheimer's disease. Mounting evidence in basic research and epidemiological studies supports the role of elevated luteinizing hormone in exacerbating age-related cognitive decline in both males and females. This review summarizes the recent developments involving luteinizing hormone in increasing the cognitive deficits and molecular pathology characteristic of Alzheimer's disease. PMID- 26031356 TI - Sex hormones regulate cerebral drug metabolism via brain miRNAs: down-regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol. AB - BACKGROUND AND PURPOSE: Brain cytochrome P450 2D (CYP2D) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP2D can be regulated in an organ-specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNAs in the selective regulation of brain CYP2D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone. EXPERIMENTAL APPROACH: The regulation of CYP2D and brain-enriched miRNAs by testosterone was investigated using SH-SY5Y cells, U251 cells, and HepG2 cells as well as orchiectomized growth hormone receptor knockout (GHR-KO) mice and rats. Concentration-time curves of tramadol in rat brain were determined using a microdialysis technique. The analgesic action of tramadol was assessed by the tail-flick test in rats. KEY RESULTS: miR-101 and miR-128-2 bound the 3'-untranslated region of the CYP2D6 mRNA and decreased its level. Testosterone decreased CYP2D6 catalytic function via the up-regulation of miR-101 and miR-128-2 in SH-SY5Y and U251 cells, but not in HepG2 cells. Orchiectomy decreased the levels of miR-101 and miR-128-2 in the hippocampus of male GHR-KO mice, indicating that androgens regulate miRNAs directly, not via the alteration of growth hormone secretion patterns. Changes in the pharmacokinetic and pharmacodynamic profiles of tramadol by orchiectomy was attenuated by either testosterone supplementation or a specific brain CYP2D inhibitor. CONCLUSIONS AND IMPLICATIONS: The selective regulation of brain CYP2D via brain-enriched miRNAs, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances. PMID- 26031358 TI - A review of statistical designs for improving the efficiency of phase II studies in oncology. AB - Phase II oncology trials are carried out to assess whether an experimental anti cancer treatment shows sufficient signs of effectiveness to justify being tested in a phase III trial. Traditionally such trials are conducted as single-arm studies using a binary response rate as the primary endpoint. In this article, we review and contrast alternative approaches for such studies. Each approach uses only data that are necessary for the traditional analysis. We consider two broad classes of methods: ones that aim to improve the efficiency using novel design ideas, such as multi-stage and multi-arm multi-stage designs; and ones that aim to improve the analysis, by making better use of the richness of the data that is ignored in the traditional analysis. The former class of methods provides considerable gains in efficiency but also increases the administrative and logistical issues in running the trial. The second class consists of viable alternatives to the standard analysis that come with little additional requirements and provide considerable gains in efficiency. PMID- 26031359 TI - Approaches for dealing with various sources of overdispersion in modeling count data: Scale adjustment versus modeling. AB - Overdispersion is a common problem in count data. It can occur due to extra population-heterogeneity, omission of key predictors, and outliers. Unless properly handled, this can lead to invalid inference. Our goal is to assess the differential performance of methods for dealing with overdispersion from several sources. We considered six different approaches: unadjusted Poisson regression (Poisson), deviance-scale-adjusted Poisson regression (DS-Poisson), Pearson-scale adjusted Poisson regression (PS-Poisson), negative-binomial regression (NB), and two generalized linear mixed models (GLMM) with random intercept, log-link and Poisson (Poisson-GLMM) and negative-binomial (NB-GLMM) distributions. To rank order the preference of the models, we used Akaike's information criteria/Bayesian information criteria values, standard error, and 95% confidence interval coverage of the parameter values. To compare these methods, we used simulated count data with overdispersion of different magnitude from three different sources. Mean of the count response was associated with three predictors. Data from two real-case studies are also analyzed. The simulation results showed that NB and NB-GLMM were preferred for dealing with overdispersion resulting from any of the sources we considered. Poisson and DS-Poisson often produced smaller standard-error estimates than expected, while PS-Poisson conversely produced larger standard-error estimates. Thus, it is good practice to compare several model options to determine the best method of modeling count data. PMID- 26031360 TI - Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans. AB - Aging is a highly controlled biological process characterized by a progressive deterioration of various cellular activities. One of several hallmarks of aging describes a link to transcriptional alteration, suggesting that it may impact the steady-state mRNA levels. We analyzed the mRNA steady-state levels of polyCAG encoding transgenes and endogenous genes under the control of well-characterized promoters for intestinal (vha-6), muscular (unc-54, unc-15) and pan-neuronal (rgef-1, unc-119) expression in the nematode Caenorhabditis elegans. We find that there is not a uniform change in transcriptional profile in aging, but rather a tissue-specific difference in the mRNA levels of these genes. While levels of mRNA in the intestine (vha-6) and muscular (unc-54, unc-15) cells decline with age, pan-neuronal tissue shows more stable mRNA expression (rgef-1, unc-119) which even slightly increases with the age of the animals. Our data on the variations in the mRNA abundance from exemplary cases of endogenous and transgenic gene expression contribute to the emerging evidence for tissue specific variations in the aging process. PMID- 26031361 TI - Inter-rater reliability and validity of automated impedance manometry analysis and fluoroscopy in dysphagic patients after head and neck cancer radiotherapy. AB - BACKGROUND: Pharyngeal automated impedance manometry (AIM) analysis is a novel non-radiological method to analyze swallowing function based on impedance pressure recordings. In dysphagic head and neck cancer patients, we evaluated the reliability and validity of the AIM-derived swallow risk index (SRI) and a novel measure of postswallow residue (iZn/Z) by comparing it against videofluoroscopy as the gold standard. METHODS: Three blinded experts classified 88 videofluoroscopic swallows from 16 patients for aspiration and degree of postswallow residue. Pressure-impedance recordings of the patient and age-matched control swallows were analyzed using AIM by three observers who derived the SRI and iZn/Z. Intra-class correlation coefficients (ICC) were calculated for videofluoroscopic and AIM measures. Patient pressure/impedance measurements were compared with videofluoroscopy scores and control subjects to determine validity for detecting clinically relevant swallowing dysfunction. KEY RESULTS: Agreement among observers assessing presence of penetration and aspiration was modest (ICC 0.57) for videofluoroscopy and good (ICC 0.71, 0.82) for AIM-derived SRI and iZn/Z. When compared with age-matched controls, the SRI was higher in patients with aspiration (mean diff. 28.6, 95% CI [55.85, 1.355], p < 0.05). The iZn/Z had moderate positive correlation with bolus residue on fluoroscopy (BRS score) (rs (86) = 0.4120, p < 0.0001) and was increased in both patients with aspiration (?244 [419.7, 69.52; p < 0.05]) and penetration (?240 [394.3, 85.77]; p < 0.05) compared to controls. CONCLUSIONS & INFERENCES: AIM-based measures of swallowing function have better inter-rater reliability than comparable fluoroscopically derived measures. These measures are easily determined and objective markers of clinically relevant features of disordered swallowing following radiotherapy. PMID- 26031362 TI - Partial tearing of the interventricular septum after blunt chest trauma. AB - Cardiac trauma after blunt chest trauma is a rare complication of patients arriving alive to an emergency department. We here present the case of patient who had a partial rupture of the interventricular septum after having had a blunt chest trauma in a traffic accident. As there was no ventricular septal defect, conservative management was deemed appropriate. At 3-year follow-up, the patient was free of right heart failure symptoms suggestive of the septal defect progression. PMID- 26031363 TI - Right ventricle apical diverticulum associated with a congenital cardiopathy and a mid line abdominal malformation. A case report. PMID- 26031364 TI - In-hospital mortality risk factors for patients with cerebral vascular events in infectious endocarditis. A correlative study of clinical, echocardiographic, microbiologic and neuroimaging findings. AB - OBJECTIVE: Cardiac complications in infectious endocarditis (IE) are seen in nearly 50% of cases, and systemic complications may occur. The aim of the present study was to determine the characteristics of inpatients with IE who suffered acute neurologic complications and the factors associated with early mortality. METHODS: From January 2004 to May 2010, we reviewed clinical and imaging charts of all of the patients diagnosed with IE who presented a deficit suggesting a neurologic complication evaluated with Computed Tomography or Magnetic Resonance within the first week. This was a descriptive and retrolective study. RESULTS: Among 325 cases with IE, we included 35 patients (10.7%) [19 males (54%), mean age 44-years-old]. The most common underlying cardiac disease was rheumatic valvulopathy (n=8, 22.8%). Twenty patients survived (57.2%, group A) and 15 patients died (42.8%, group B) during hospitalization. The main cause of death was septic shock (n=7, 20%). There was no statistical difference among groups concerning clinical presentation, vegetation size, infectious agent and vascular territory. The overall number of lesions was significantly higher in group B (3.1 vs. 1.6, p=0.005) and moderate to severe cerebral edema were more frequent (p=0.09). Sixteen patients (45.7%) (12 in group A and 4 in group B, p=0.05) were treated by cardiac surgery. Only two patients had a favorable outcome with conservative treatment (5.7%). CONCLUSIONS: In patients with IE complicated with stroke, the number of lesions observed in neuroimaging examinations and conservative treatment were associated with higher in-hospital mortality. PMID- 26031365 TI - Serum Proteome Signature of Radiation Response: Upregulation of Inflammation Related Factors and Downregulation of Apolipoproteins and Coagulation Factors in Cancer Patients Treated With Radiation Therapy--A Pilot Study. AB - PURPOSE: Ionizing radiation affects the proteome of irradiated cells and tissue, yet data concerning changes induced during radiation therapy (RT) in human blood are fragmentary and inconclusive. We aimed to identify features of serum proteome and associated processes involved in response to partial body irradiation during cancer treatment. METHODS AND MATERIALS: Twenty patients with head and neck squamous cell cancer (HNSCC) and 20 patients with prostate cancer received definitive intensity modulated RT. Blood samples were collected before RT, just after RT, and 1 month after the end of RT. Complete serum proteome was analyzed in individual samples, using a shotgun liquid chromatography-tandem mass spectrometry approach which allowed identification of approximately 450 proteins. Approximately 100 unique proteins were quantified in all samples after exclusion of immunoglobulins, and statistical significance of differences among consecutive samples was assessed. Processes associated with quantified proteins and their functional interactions were predicted using gene ontology tools. RESULTS: RT induced changes were marked in the HNSCC patient group: 22 upregulated and 33 downregulated proteins were detected in post-RT sera. Most of the changes reversed during follow-up, yet levels of some proteins remained affected 1 month after the end of RT. RT-upregulated proteins were associated with acute phase, inflammatory response, and complement activation. RT-downregulated proteins were associated with transport and metabolism of lipids (plasma apolipoproteins) and blood coagulation. RT-induced changes were much weaker in prostate cancer patients, which corresponded to differences in acute radiation toxicity observed in both groups. Nevertheless, general patterns of RT-induced sera proteome changes were similar in both of the groups of cancer patients. CONCLUSIONS: In this pilot study, we proposed to identify a molecular signature of radiation response, based on specific features of serum proteome. The signature included upregulation of factors involved in acute or inflammatory response but also downregulation of plasma apolipoproteins and factors involved in blood coagulation. PMID- 26031366 TI - MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma. AB - PURPOSE: To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment. METHODS AND MATERIALS: The expression of miR-20a and PTEN were detected in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Akt pathway. RESULTS: MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a-induced radioresistance. CONCLUSION: MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR 20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC. PMID- 26031367 TI - Interim PET After Two ABVD Cycles in Early-Stage Hodgkin Lymphoma: Outcomes Following the Continuation of Chemotherapy Plus Radiotherapy. AB - PURPOSE: This multicenter retrospective study was designed to evaluate the prognostic role of interim fluorodeoxyglucose-labeled positron emission tomography (i-FDG-PET) in a cohort of patients affected with early-stage Hodgkin lymphoma (HL) treated initially with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by radiation therapy, and to assess the role of chemotherapy continuation plus radiation therapy for i-FDG-PET-positive patients. METHODS AND MATERIALS: Data from 257 patients were retrieved from 4 hematology and radiation oncology departments. Inclusion criteria were stage I to IIAB HL, "intention-to-treat" AVBD plus radiation therapy, and FDG-PET at diagnosis and after the first 2 ABVD cycles. All i-FDG-PET scans underwent blinded local review by using the Deauville 5-point scoring system; patients were stratified as negative or positive using 2 Deauville score cutoff values, >=3 or >=4. RESULTS: Median follow-up time was 56 months (range: 9-163 months); 5-year overall survival (OS) and disease-specific survival (DSS) for the whole cohort were 97.5% and 98.3%, respectively. Five-year progression-free survival (PFS) was 95.6%. After i-FDG-PET revision, 43 of 257 patients (16.7%) had a positive i-FDG PET (Deauville scores: 3-5). Five-year PFS rates for i-FDG-PET-negative and i-FDG PET-positive patients were 98.1% and 83.7%, respectively, if using a Deauville score cutoff of 3, and 97.7% and 78.6%, respectively, if using a cutoff of 4 (P=.0001). Five-year OS for i-FDG-PET-negative and i-FDG-PET-positive patients was 98.5% and 93.0%, respectively, if using a cutoff of 3, and 98.6% and 89.3%, respectively, if using a cutoff of 4 (P=.029 and P=.002). At univariate regression analysis, i-FDG-PET positivity was associated with worse OS and PFS. At multivariate analysis, performed only for PFS, i-FDG-PET positivity confirmed its negative impact (P=.002). CONCLUSIONS: i-FDG-PET is prognostic for PFS and OS in early-stage HL patients treated with combined modality therapy; the continuation of chemotherapy followed by radiation therapy is able to obtain durable, complete remission in most i-FDG-PET-positive patients. PMID- 26031368 TI - Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial. AB - OBJECTIVE: Intensified preoperative treatments have been increasingly investigated in locally advanced rectal cancer (LARC), but limited data are available for the impact of these regimens on quality of life (QoL) and bowel function (BF). We assessed these outcome measures in EXPERT-C, a randomized phase 2 trial of neoadjuvant capecitabine combined with oxaliplatin (CAPOX), followed by chemoradiation therapy (CRT), total mesorectal excision, and adjuvant CAPOX with or without cetuximab in magnetic resonance imaging-defined, high-risk LARC. METHODS AND MATERIALS: QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. Bowel incontinence was assessed using the modified Fecal Incontinence Severity Index questionnaire. RESULTS: Compared to baseline, QoL scores during preoperative treatment were better for symptoms associated with the primary tumor in the rectum (blood and mucus in stool, constipation, diarrhea, stool frequency, buttock pain) but worse for global health status, role functioning, and symptoms related to the specific safety profile of each treatment modality. During follow up, improved emotional functioning and lessened anxiety and insomnia were observed, but deterioration of body image, increased urinary incontinence, less sexual interest (men), and increased impotence and dyspareunia were observed. Cetuximab was associated with a deterioration of global health status during neoadjuvant chemotherapy but did not have any long-term detrimental effect. An improvement in bowel continence was observed after preoperative treatment and 3 years after sphincter-sparing surgery. CONCLUSIONS: Intensifying neoadjuvant treatment by administering induction systemic chemotherapy before chemoradiation therapy improves tumor-related symptoms and does not appear to have a significantly detrimental effect on QoL and BF, in both the short and the long term. PMID- 26031369 TI - [Right coronary artery compression in the postoperatory of an aortic intramural haematoma tipe A. Another mechanism of myocardial ischemia]. PMID- 26031370 TI - [Crystalloids in critical patient resuscitation]. PMID- 26031371 TI - Evaluation of current surveillance guidelines following radical cystectomy and proposal of a novel risk-based approach. AB - BACKGROUND: Evidence supporting surveillance guidelines after radical cystectomy (RC) are lacking. Herein, we evaluate the ability of the National Comprehensive Cancer Network (NCCN) guidelines and the European Association of Urology (EAU) guidelines to capture recurrences and provide an alternative approach that balances risks of recurrence with non-bladder cancer death. METHODS: We identified 1,797 patients who had M0 urothelial carcinoma who underwent RC at our institution between 1980 and 2007. The success of current guidelines to capture recurrences was assessed by calculating the percentage of recurrences detected during the recommended follow-up time: the NCCN--2 years and the EAU--5 years. An alternative protocol was created using Weibull distributions, which estimate when a patient's risk of non-bladder cancer death exceeds their risk of recurrence. RESULTS: At a median follow-up of 10.6 years (interquartile range : 6.8-15.2), a total of 714 patients recurred. Of these, 491 (68.7%) would have been detected by the NCCN guidelines and 642 (89.8%) by the EAU guidelines. Using a risk-adapted approach, vastly different surveillance durations were appreciated. For example, for patients older than 80 years with pT0Nx-0 or pTa/CIS/1Nx-0 disease, recurrence risk to any location never exceeded their risk of non-bladder cancer death, whereas for patients aged 60 years and younger with pT3/4Nx-0 or pTanyN+disease, risk of abdominal/pelvis recurrence remained greater than their risk of non-bladder cancer death for>20 years. CONCLUSIONS: The duration of post RC follow-up recommended by the NCCN and the EAU does not comprehensively capture recurrences. A surveillance algorithm based on the interaction between recurrence risk and competing health factors individualizes recommendations and may improve capture of recurrences and resource allocation. PMID- 26031372 TI - Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome. AB - BACKGROUND: Mutations in SCN5A, which encodes the cardiac voltage-gated sodium channels, can be associated with multiple electrophysiological phenotypes. A novel SCN5A R1632C mutation, located in the domain IV-segment 4 voltage sensor, was identified in a young male patient who had a syncopal episode during exercise and presented with atrial tachycardia, sinus node dysfunction, and Brugada syndrome. OBJECTIVE: We sought to elucidate the functional consequences of the R1632C mutation. METHODS: The wild-type (WT) or R1632C SCN5A mutation was coexpressed with beta1 subunit in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp methods. RESULTS: INa density, measured at 20 mV from a holding potential of -120 mV, for R1632C was significantly lower than that for WT (R1632C: -433 +/- 52 pA/pF, n = 14; WT: -672 +/- 90 pA/pF, n = 15; P < .05); however, no significant changes were observed in the steady-state activation and fast inactivation rate. The steady-state inactivation curve for R1632C was remarkably shifted to hyperpolarizing potentials compared with that for WT (R1632C: V1/2 = -110.7 +/- 0.8 mV, n = 16; WT: V1/2 = -85.9 +/- 2.5 mV, n = 17; P < .01). The steady-state fast inactivation curve for R1632C was also shifted to the same degree. Recovery from fast inactivation after a 20-ms depolarizing pulse for R1632C was remarkably delayed compared with that for WT (R1632C: tau = 246.7 +/- 14.3 ms, n = 8; WT: tau = 3.7 +/- 0.3 ms, n = 8; P < .01). Repetitive depolarizing pulses at various cycle lengths greatly attenuated INa for R1632C than that for WT. CONCLUSION: R1632C showed a loss of function of INa by an enhanced fast-inactivated state stability because of a pronounced impairment of recovery from fast inactivation, which may explain the phenotypic manifestation observed in our patient. PMID- 26031373 TI - Cryoablation of typical AVNRT: Younger age and administration of bonus ablation favor long-term success. AB - BACKGROUND: Cryoablation (CA) is an emerging tool for the treatment of supraventricular tachyarrhythmias. Determinants of long-term success still need clarification. OBJECTIVE: The purpose of this study was to assess which patients' and procedural features affect the long-term efficacy of CA for typical atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: Eighty-five consecutive patients undergoing CA for typical AVNRT were divided into 3 groups of age: group A, <=20 years, n = 20 (23.5%); group B, 21-50 years, n = 30 (35.3%); group C, >=51 years, n = 35 (41.2%). CA was performed for 5 minutes at 75 degrees C in all; 4-minute bonus CA was delivered if not contraindicated (ie, transient PR interval lengthening during the first application and narrow triangle of Koch). The efficacy end point was the absence of recurrences at 12 month follow-up. RESULTS: CA was acutely successful in all 85 patients (100%). Bonus ablation was performed in 69 (81.2%). No permanent complications were observed. At follow-up, AVNRT recurrences occurred in 9 patients (10.6%): group A, 0 (0%); group B, 2 (6.7%), group C, 7 (20%). Incidence of recurrences was significantly different between age groups (P = .047) and between patients receiving (7.2%) and not receiving (25.0%) bonus CA (P = .038). In multivariable analysis, age groups (odds ratio [OR] 5.917; 95% confidence interval [CI] 1.372 25.518; P = .017) and bonus CA (OR 0.115; 95% CI 0.018-0.724; P = .021) were the only independent predictors of recurrences. Furthermore, age as a continuous variable remained statistically associated with recurrences (OR 1.046; 95% CI 1.002-1.091; P = .038). CONCLUSION: CA is effective and safe for typical AVNRT ablation. Younger age and bonus CA administration are independent predictors of success at 12 months. Incidence of recurrences is low in patients younger than 21 years. PMID- 26031374 TI - Cryotherapy of cardiac arrhythmia: From basic science to the bedside. AB - This review focuses on the basic science of cellular destruction by tissue freezing and application of transvenous cryocatheter technology to treat cardiac arrhythmia. Ideally, foci for arrhythmias are selectively ablated, arrhythmogenic tissues are destroyed, and reentry circuits are bisected in order to silence adverse electrical activity, with the goal of restoring normal sinus rhythm. The mechanism of ablation using cryotherapy results in distinct lesion qualities advantageous to radiofrequency (Khairy P, Chauvet M, Lehman J, et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation 2003;107:2045-2050). This review is devoted to the mechanism of cryoablation, postablation histopathological changes, and how this information should be used by the clinicians to improve safety and maximize ablation success. PMID- 26031375 TI - Finding the optimal ablation site in ventricular tachycardia through a single electrogram: Is it too good to be true? PMID- 26031378 TI - Noninvasive scalp recording of cortical auditory evoked potentials in the alert macaque monkey. AB - Scalp-recorded evoked potentials (EP) provide researchers and clinicians with irreplaceable means for recording stimulus-related neural activities in the human brain, due to its high temporal resolution, handiness, and, perhaps more importantly, non-invasiveness. This work recorded the scalp cortical auditory EP (CAEP) in unanesthetized monkeys by using methods that are essentially identical to those applied to humans. Young adult rhesus monkeys (Macaca mulatta, 5-7 years old) were seated in a monkey chair, and their head movements were partially restricted by polystyrene blocks and tension poles placed around their head. Individual electrodes were fixated on their scalp using collodion according to the 10-20 system. Pure tone stimuli were presented while electroencephalograms were recorded from up to nineteen channels, including an electrooculogram channel. In all monkeys (n = 3), the recorded CAEP comprised a series of positive and negative deflections, labeled here as macaque P1 (mP1), macaque N1 (mN1), macaque P2 (mP2), and macaque N2 (mN2), and these transient responses to sound onset were followed by a sustained potential that continued for the duration of the sound, labeled the macaque sustained potential (mSP). mP1, mN2 and mSP were the prominent responses, and they had maximal amplitudes over frontal/central midline electrode sites, consistent with generators in auditory cortices. The study represents the first noninvasive scalp recording of CAEP in alert rhesus monkeys, to our knowledge. PMID- 26031376 TI - Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: An International VT Ablation Center Collaborative Group study. AB - BACKGROUND: The impact of catheter ablation of ventricular tachycardia (VT) on all-cause mortality remains unknown. OBJECTIVE: The purpose of this study was to examine the association between VT recurrence after ablation and survival in patients with scar-related VT. METHODS: Analysis of 2061 patients with structural heart disease referred for catheter ablation of scar-related VT from 12 international centers was performed. Data on clinical and procedural variables, VT recurrence, and mortality were analyzed. Kaplan-Meier analysis was used to estimate freedom from recurrent VT, transplant, and death. Cox proportional hazards frailty models were used to analyze the effect of risk factors on VT recurrence and mortality. RESULTS: One-year freedom from VT recurrence was 70% (72% in ischemic and 68% in nonischemic cardiomyopathy). Fifty-seven patients (3%) underwent cardiac transplantation, and 216 (10%) died during follow-up. At 1 year, the estimated rate of transplant and/or mortality was 15% (same for ischemic and nonischemic cardiomyopathy). Transplant-free survival was significantly higher in patients without VT recurrence than in those with recurrence (90% vs 71%, P<.001). In multivariable analysis, recurrence of VT after ablation showed the highest risk for transplant and/or mortality [hazard ratio 6.9 (95% CI 5.3-9.0), P<.001]. In patients with ejection fraction <30% and across all New York Heart Association functional classes, improved transplant free survival was seen in those without VT recurrence. CONCLUSION: Catheter ablation of VT in patients with structural heart disease results in 70% freedom from VT recurrence, with an overall transplant and/or mortality rate of 15% at 1 year. Freedom from VT recurrence is associated with improved transplant-free survival, independent of heart failure severity. PMID- 26031379 TI - A novel cognitive impairment mechanism that astrocytic p-connexin 43 promotes neuronic autophagy via activation of P2X7R and down-regulation of GLT-1 expression in the hippocampus following traumatic brain injury in rats. AB - Connexin 43 (Cx43) is one of the major gap junction proteins in astrocytes. Our previous studies reported that astrocytic phosphorylated Cx43 (p-CX43) regulated neuronic autophagy levels in the rat hippocampus after traumatic brain injury (TBI). In this study, we explored the underlying molecular mechanism by which gap junctional intercellular communication influenced neuronic autophagy and therefore initiated cognitive and memory impairments after TBI. The gap junctional blocker carbenoxolone (CBX) or autophagy inhibitor 3-methyladenine (3 MA) reduced latencies, as compared to TBI rats. Similarly, CBX or 3-MA restored long-term potentiation (LTP), relative to TBI hippocampal slices. Immunoblotting analysis showed that the expression of autophagy-related gene Beclin-1 in the hippocampus post-TBI were decreased in response to treatment with CBX, the P2X7 receptor (P2X7R) antagonist Oxidized ATP (OxATP) or ceftriaxone (Cef) which increased the expression and activity of the glutamate transporter (GLT-1) in the central nervous system (CNS). Moreover, CBX or OxATP pretreatment increased GLT-1 level in the rat hippocampus after TBI. However, CBX pretreatment suppressed P2X7R expression whereas maintained P2X7 level post-TBI. Confocal images revealed that p-CX43, P2X7 and GLT-1 strongly colocalized with glial fibrillary acidic protein (GFAP). Taken together, these results implied that Cx43, might induce neuronic autophagy by activation of P2X7R and reduce the expression of GLT-1 in the hippocampus, promoting TBI-induced cognitive deficits repair. Therefore, control of this communication may be serve as therapeutic strategies for intervention against TBI. PMID- 26031380 TI - Local brain gyrification as a marker of neurological soft signs in schizophrenia. AB - Patients with psychiatric disorders of significant neurodevelopmental origin, such as schizophrenia and autism frequently experience genuine motor abnormalities, such as neurological soft signs (NSS). Previous MRI studies in patients with schizophrenia have shown that NSS are associated with abnormal cortical, thalamic and cerebellar structure and function. So far, however, no neuroimaging study focused on the role of the local gyrification index (LGI) in the pathophysiology of NSS. This study sought to explore the relationship between NSS and folding patterns of the cerebral cortex that are thought to be established during early brain development. In this study, whole brain high resolution magnetic resonance imaging (MRI) at 3 Tesla was used to investigate the LGI in 33 patients with recent-onset schizophrenia. Cortical reconstruction was performed with the Freesurfer image analysis suite. NSS were examined on the Heidelberg Scale and related to LGI. Age, gender, years of education and medication were considered as potential confounding variables. In summary, higher NSS scores were positively associated with morphological changes of LGI predominantly in parietal and occipital areas. Our results confirm the hypothesis of a significant relationship between LGI changes and the NSS expression in schizophrenia. Investigation of LGI may help to explain subtle motor symptoms such as NSS in schizophrenia. PMID- 26031381 TI - Lithium chloride administration prevents spatial learning and memory impairment in repeated cerebral ischemia-reperfusion mice by depressing apoptosis and increasing BDNF expression in hippocampus. AB - Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression. PMID- 26031382 TI - Molluscan subfossil assemblages reveal the long-term deterioration of coral reef environments in Caribbean Panama. AB - Caribbean reef corals have declined sharply since the 1980s, but the lack of prior baseline data has hindered identification of drivers of change. To assess anthropogenic change in reef environments over the past century, we tracked the composition of subfossil assemblages of bivalve and gastropod mollusks excavated from pits below lagoonal and offshore reefs in Bocas del Toro, Panama. The higher prevalence of (a) infaunal suspension-feeding bivalves and herbivorous and omnivorous gastropods in lagoons and (b) epifaunal and suspension-feeding bivalves and carnivorous and suspension-feeding gastropods offshore reflected the greater influence of land-based nutrients/sediments within lagoons. Temporal changes indicated deteriorating environmental conditions pre-1960 in lagoons and post-1960 offshore, with offshore communities becoming more similar to lagoonal ones since 1960. Relative abundances of dominant bivalve species tracked those of their coral hosts, revealing broader ecosystem effects of coral community change. The nature and timing of changes implicate land-based runoff in reef deterioration. PMID- 26031383 TI - Optical coherence tomography-guided V-stenting in the distal left main. PMID- 26031384 TI - Unexpected subthreshold autism spectrum in a 25-year-old male stalker hospitalized for delusional disorder: a case report. AB - This paper highlights the clinical challenges faced when assessing patients with stalking behaviors with psychotic disorders, suggesting the need for an accurate assessment of adult autism spectrum symptoms. A 25-year-old man with a diagnosis of delusional disorder, erotomanic type, was hospitalized for acute psychotic symptoms occurred in the framework of a repeated stalking behavior towards his ex girlfriend. When assessed for adult autism spectrum symptoms upon an accurate clinical evaluation, he reported elevated scores in the mentalizing deficit and social anxiety domains by means of the 14 item Ritvo Autism and Asperger Diagnostic Scale (RAADS-14). Authors discuss a possible role of adult (subthreshold) autism spectrum symptoms, generally disregarded in adult psychiatry, on the type of psychotic features and stalking behavior developed that may help for appropriate diagnosis and treatment. PMID- 26031385 TI - An overview of recent developments in the analytical detection of new psychoactive substances (NPSs). AB - New psychoactive substances (NPSs), sometimes referred to as "legal highs" in more colloquial environments/the media, are a class of compounds that have been recently made available for abuse (not necessarily recently discovered) which provide similar effects to the traditional well studied illegal drugs but are not always controlled under existing local, regional or international drug legislation. Following an unprecedented increase in the number of NPSs in the last 5 years (with 101 substances discovered for the first time in 2014 alone) its, occasionally fatal, consequences have been extensively reported in the media. Such NPSs are typically marketed as 'not for human consumption' and are instead labelled and sold as plant food, bath salts as well as a whole host of other equally nondescript aliases in order to bypass legislative controls. NPSs are a new multi-disciplinary research field with the main emphasis in terms of forensic identification due to their adverse health effects, which can range from minimal to life threatening and even fatalities. In this mini-review we overview this recent emerging research area of NPSs and the analytical approaches reported to provide detection strategies as well as detailing recent reports towards providing point-of-care/in-the-field NPS ("legal high") sensors. PMID- 26031386 TI - Prenatal ethanol exposure and placental hCG and IGF2 expression. AB - INTRODUCTION: Fetal alcohol spectrum disorder (FASD) is the main cause of preventable non-genetic mental retardation. Diagnosis of prenatal exposure to ethanol (PEE) is based on questionnaires and biomarkers in perinatal matrices. Early diagnosis of FASD is important to mitigate secondary disabilities that will arise later in life. It is important to identify biomarkers related to cellular damage caused by PEE. The main objective was to identify novel candidate biomarkers from placental tissue using an in vitro model of exposure to ethanol and to support it in placental tissue obtained from pregnancies with PEE assessed by fatty acid esters in meconium samples. METHODS: First, hormone production was examined using two different human trophoblast cell lines, JEG3 and BeWo. Viable cell count by exclusion method was analyzed and human chorionic gonadotrophin (hCG) and insulin-like growth factor 2 (IGF2) were quantified by Western blot and ELISA. Second, these techniques were used in protein lysates from human placentas from pregnancies with and without exposure to ethanol. RESULTS: Both trophoblast cell lines showed a decrease in cell viability accompanied with apoptosis activation after a chronic ethanol treatment. Moreover, we showed an increase in the secretion of hCG and IGF2 in a dose-dependent manner. Interestingly, this increase was also observed in a set of human placenta tissue from fetuses exposed prenatally to ethanol. DISCUSSION: Ethanol exposure during pregnancy causes placenta cell damage, so altering its normal function. The specific hCG and IGF2 release pattern is a candidate surrogated biomarker of the damage due to PEE. PMID- 26031387 TI - Undiagnosed severe sleep apnoea and diabetic foot ulceration - a case series based hypothesis: a hitherto under emphasized factor in failure to heal. AB - BACKGROUND: Although great progress has been made in managing diabetic foot disease, it continues to carry significant morbidity and mortality. Obstructive sleep apnoea (OSA) and diabetes frequently coexist and recent studies suggest significant under-recognition of OSA in those with diabetes. There are no current reports on the direct clinical impact of OSA on acute or chronic diabetic foot ulcer healing. CASE REPORT: We describe three cases with Type 2 diabetes and a mean BMI of 50 kg/m(2) in whom we believe undiagnosed severe OSA may have impeded the rate of recovery of acutely infected foot ulcers. Despite standard care whilst in hospital with optimization of glycaemia, daily wound care, ulcer offloading techniques including casting, it was difficult to achieve satisfactory granulation in the first two cases with previously unrecognized and hence untreated severe OSA (Apnoea-Hypopnea Index > 30) until correction had been achieved through continuous positive airway pressure therapy (CPAP). In the third case, despite all optimization techniques, healing has not been achieved and individuals' reluctance to consider CPAP may be one possible factor. DISCUSSION: We observe in three severely obese individuals with diabetes that untreated severe OSA may have contributed to delayed wound healing. We also observed an improvement in two individuals after institution of CPAP therapy. Clinicians managing the diabetic foot should consider investigating the presence of OSA in non-healing or slowly progressive foot ulcers when all other factors have been fully optimized. PMID- 26031388 TI - Gold nanoparticle-based colorimetric aptasensor for rapid detection of six organophosphorous pesticides. AB - Fast immunoassay-based screening methods are unavailable for most small-molecule pesticides because of a lack of immunogenicity and the difficulty in obtaining antibodies by animal immunization. Aptamers are single-stranded DNA molecules selected through an in vitro process, which can bind to any target including nonimmunogenic small molecules with high affinity and specificity. Although various aptamer-based sensing methods have been developed for antibiotics, microorganisms, heavy metal ions, and biotoxins, there are few reports on aptamer based methods for quick detection of organophosphorous pesticides. The gold (Au) nanoparticle (AuNP) colorimetric assay is a widely utilized rapid detection method because of properties such as easy operation and visualized results. In the present study, organophosphorous pesticide aptamers were adsorbed on the surface of AuNPs to stabilize the AuNP solution against high concentrations of salt to prevent AuNP aggregation. After the addition of targets, the aptamers binding to the targets are detached from the AuNPs, resulting in aggregation of AuNPs and a color change from red to purple-blue. The proposed method can detect 6 organophosphorous pesticides with good recoveries from 72% to 135% in environmental river water samples. The present study provides a new way for simple, rapid, and multiplex detection of organophosphorous pesticides. PMID- 26031390 TI - Physiological changes and sHSPs genes relative transcription in relation to the acquisition of seed germination during maturation of hybrid rice seed. AB - BACKGROUND: During the production of early hybrid rice seed, the seeds dehydrated slowly and retained high moisture levels when rainy weather lasted for a couple of days, and the rice seeds easily occurred pre-harvest sprouting (PHS) along with high temperature. Therefore it is necessary to harvest the seeds before the PHS occurred. RESULTS: The seeds of hybrid rice (Oryza sativa L. subsp. indica) cv. Qianyou No1 that harvests from 19 to 28 days after pollination (DAP) all had high seed vigour. The seed moisture content at 10 DAP was 36.1%, and declined to 28.6% at 19 DAP; the contents of soluble sugar and total starch increased significantly with the development of seeds. The soluble protein content, the level of abscisic acid (ABA) and gibberellin (GA3 ), and ascorbate peroxidase (APX) activity continued to decrease from 10 DAP to 19 DAP. The seeds at 19 DAP had the highest peroxidase (POD) activity and lowest catalase (CAT) activity while the superoxide dismutase (SOD) activity had no significant difference among the different developing periods. The relative expressions of genes 64S Hsp18.0 and Os03g0267200 transcripts increased significantly from 10 to 19 DAP, and then decreased. However, no significant change was recorded in soluble protein, sugar and GA3 after 16 DAP, and they all significantly correlated with seed viability and vigour during the process of seed maturity. CONCLUSION: The seeds of hybrid rice Qianyou No1 had a higher viability and vigour when harvested from 19 DAP to 28 DAP, the transcription levels of 64S Hsp18.0 and Os03g0267200 increased significantly from 10 DAP to 19 DAP and the highest value was recorded at 19 DAP. The seeds could be harvested as early as 19 DAP without negative influence on seed vigour and viability. PMID- 26031389 TI - Endotoxin-stimulated Rat Hepatic Stellate Cells Induce Autophagy in Hepatocytes as a Survival Mechanism. AB - Bacterial lipopolysaccharide (LPS)-stimulated hepatic stellate cells (HSCs) produce many cytokines including IFNbeta, TNFalpha, and IL6, strongly inhibit DNA synthesis, but induce apoptosis of a small number of hepatocytes. In vivo administration of LPS (up to 10 mg/mL) causes modest inflammation and weight loss in rats but not mortality. We determined whether LPS-stimulated HSCs instigate mechanisms of hepatocyte survival. Rats received 10 mg/kg LPS (i.p.) and determinations were made at 6 h. In vitro, HSCs were treated with 100 ng/mL LPS till 24 h. The medium was transferred to hepatocytes, and determinations were made at 0-12 h. Controls were HSC-conditioned medium or medium-containing LPS. LPS treatment of rats caused autophagy in hepatocytes, a physiological process for clearance of undesirable material including injured or damaged organelles. This was accompanied by activation of c-Jun NH2 terminal kinase (JNK) and apoptosis of ~4-5% of hepatocytes. In vitro, LPS-conditioned HSC medium (LPS/HSC) induced autophagy in hepatocytes but apoptosis of only ~10% of hepatocytes. While LPS/HSC stimulated activation of JNK (associated with cell death), it also activated NFkB and ERK1/2 (associated with cell survival). LPS-stimulated HSCs produced IFNbeta, and LPS/HSC-induced autophagy in hepatocytes and their apoptosis were significantly inhibited by anti-IFNbeta antibody. Blockade of autophagy, on the other hand, strongly augmented hepatocyte apoptosis. While LPS stimulated HSCs cause apoptosis of a subpopulation of hepatocytes by producing IFNbeta, they also induce cell survival mechanisms, which may be of critical importance in resistance to liver injury during endotoxemia. PMID- 26031391 TI - Perinatal exposure to androgen excess and the effects on the rat uterine estradiol responsiveness. AB - Androgen exposure during sexual development induces alterations in steroidal target tissues. The objective of this study was to evaluate the uterine responsiveness to estradiol after perinatal androgenization. Pregnant Wistar rats were exposed to corn oil or testosterone propionate at 0.05, 0.1, or 0.2 mg/kg from gestational day 12 until postnatal day 21. Female offspring was challenged with estradiol (E2 ) after weaning (0.4 mg/kg) and at adulthood (10 or 100 ug/day), when the pituitary response was also evaluated. At adulthood, control and 0.05 mg/kg groups presented a uterine weight increment when exposed to 100 ug/day of E2 , 0.1 mg/kg group only responded to 10 ug/day of E2 , and the 0.2 mg/kg group showed increased uterine weight at both doses. The pituitary weight was similarly increased after estradiol stimulation in all experimental groups. In conclusion, testosterone propionate exposure induced an abnormal stimulation of uterine tissue growth by estrogen stimulus without affecting pituitary response. More studies are needed to clarify whether these alterations are capable of impairing the reproductive capacity of the female tract. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1460-1468, 2016. PMID- 26031392 TI - Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma. AB - BACKGROUND: Poorly controlled asthma and preventable exacerbations place a significant strain on healthcare, often requiring additional medications, hospital stays or treatment in the emergency department.Long-acting beta2 agonists (LABA) are the preferred add-on treatment for adults with asthma whose symptoms are not well controlled on inhaled corticosteroids (ICS), but have important safety concerns in asthma. Long-acting muscarinic antagonists (LAMA) have confirmed efficacy in chronic obstructive pulmonary disease and are now being considered as an alternative add-on therapy for people with uncontrolled asthma. OBJECTIVES: To assess the efficacy and safety of adding a LAMA to ICS compared with adding a LABA for adults whose asthma is not well controlled on ICS alone. SEARCH METHODS: We searched the Cochrane Airways Group's Specialised Register (CAGR) from inception to April 2015, and imposed no restriction on language of publication. We searched additional resources to pick up unpublished studies, including ClinicalTrials.gov, World Health Organization trials portal, reference lists of primary studies and existing reviews, and manufacturers' trial registries. The most recent search was conducted in April 2015. SELECTION CRITERIA: We searched for parallel and cross-over RCTs in which adults whose asthma was not well controlled with ICS alone were randomised to receive LAMA add on or LABA add-on for at least 12 weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the electronic and additional searches and extracted data from study reports. We used Covidence for duplicate screening, extraction of study characteristics and numerical data, and risk of bias ratings.The pre-specified primary outcomes were exacerbations requiring oral corticosteroids (OCS), quality of life and serious adverse events. MAIN RESULTS: We included eight studies meeting the inclusion criteria, but four double-blind, double-dummy studies of around 2000 people dominated the analyses. These four trials were between 14 and 24 weeks long, all comparing tiotropium (usually Respimat) with salmeterol on top of medium doses of ICS.Studies reporting exacerbations requiring OCS showed no difference between the two add-ons, but our confidence in the effect was low due to inconsistency between studies and because the confidence intervals (CI) included significant benefit of either treatment (odds ratio (OR) 1.05, 95% CI 0.50 to 2.18; 1753 participants; 3 studies); three more people per 1000 might have an exacerbation on LAMA, but the CIs ranged from 29 fewer to 61 more. Imprecision was also an issue for serious adverse events and exacerbations requiring hospital admission, rated low (serious adverse events) and very low quality (exacerbations requiring hospital admission), because there were so few events in the analyses.People taking LAMA scored slightly worse on two scales measuring quality of life (Asthma Quality of Life Questionnaire; AQLQ) and asthma control (Asthma Control Questionnaire; ACQ); the evidence was rated high quality but the effects were small and unlikely to be clinically significant (AQLQ: mean difference (MD) -0.12, 95% CI -0.18 to -0.05; 1745 participants; 1745; 4 studies; ACQ: MD 0.06, 95% CI 0.00 to 0.13; 1483 participants; 3 studies).There was some evidence to support small benefits of LAMA over LABA on lung function, including on our pre-specified preferred measure trough forced expiratory volume in one second (FEV1) (MD 0.05 L, 95% CI 0.01 to 0.09; 1745 participants, 4 studies). However, the effects on other measures varied, and it is not clear whether the magnitude of the differences were clinically significant.More people had adverse events on LAMA but the difference with LABA was not statistically significant. AUTHORS' CONCLUSIONS: Direct evidence of LAMA versus LABA as add-on therapy is currently limited to studies of less than six months comparing tiotropium (Respimat) to salmeterol, and we do not know how they compare in terms of exacerbations and serious adverse events. There was moderate quality evidence that LAMAs show small benefits over LABA on some measures of lung function, and high quality evidence that LABAs are slightly better for quality of life, but the differences were all small. Given the much larger evidence base for LABA versus placebo for people whose asthma is not well controlled on ICS, the current evidence is not strong enough to say that LAMA can be substituted for LABA as add-on therapy.The results of this review, alongside pending results from related reviews assessing the use of LAMA in other clinical scenarios, will help to define the role of these drugs in asthma and it is important that they be updated as results from ongoing and planned trials emerge. PMID- 26031393 TI - Ultrastructure of male reproductive system of Eurydema ventrale Kolenati 1846 (Heteroptera: Pentatomidae). AB - The male reproductive system of Eurydema ventrale Kolenati 1846 is studied morphologically and histologically by using light, scanning and transmission electron microscopes. The reproductive system of the male E.ventrale consists of a pair of testis, a pair of vas deferens, a pair of seminal vesicles, accessory glands, a bulbus ejaculatorius, a pair of ectodermal sacs, and a ductus ejaculatorius. The testicular follicles have three different development zones (growth zone, maturation zone, and differentiation zone). The testes are connected to the seminal vesicles by the vas deferens that is a specialized in sperm storage. Sperm have an elongated head and a tail (flagellum) with an axonema and two mitochondrial derivatives. Vas deferens and seminal vesicles are fine, long, and cylindrical. The seminal vesicle is connected with bulbus ejaculatorius, which is balloon shaped and surrounded with accessory glands. The bulbus ejaculatorius is continuous with ductus ejaculatorius which is connected to the aedeagus. PMID- 26031394 TI - Travel Medicine Encounters of Australian General Practice Trainees-A Cross Sectional Study. AB - BACKGROUND: Travel medicine is a common and challenging area of clinical practice and practitioners need up-to-date knowledge and experience in a range of areas. Australian general practitioners (GPs) play a significant role in the delivery of travel medicine advice. We aimed to describe the rate and nature of travel medicine consultations, including both the clinical and educational aspects of the consultations. METHODS: A cross-sectional analysis from an ongoing cohort study of GP trainees' clinical consultations was performed. Trainees contemporaneously recorded demographic, clinical, and educational details of consecutive patient consultations. Proportions of all problems/diagnoses managed in these consultations that were coded "travel-related" and "travel advice" were both calculated with 95% confidence intervals (CIs). Associations of a problem/diagnosis being "travel-related" or "travel advice" were tested using simple logistic regression within the generalized estimating equations (GEE) framework. RESULTS: A total of 856 trainees contributed data on 169,307 problems from 108,759 consultations (2010-2014). Travel-related and travel advice problems were managed at a rate of 1.1 and 0.5 problems per 100 encounters, respectively. Significant positive associations of travel-related problems were younger trainee and patient age; new patient to the trainee and practice; privately billing, larger, urban, and higher socioeconomic status practices; and involvement of the practice nurse. Trainees sought in-consultation information and generated learning goals in 34.7 and 20.8% of travel advice problems, respectively, significantly more than in non-travel advice problems. Significant positive associations of travel advice problems were seeking in-consultation information, generation of learning goals, longer consultation duration, and more problems managed. CONCLUSIONS: Our findings reinforce the importance of focused training in travel medicine for GP trainees and adequate exposure to patients in the practice setting. In addition, our findings have implications more broadly for the delivery of travel medicine in general practice. PMID- 26031395 TI - Routinised and compulsive-like behaviours in individuals with Down syndrome. AB - BACKGROUND: Increased intensities of routinised and compulsive-like behaviours are seen in those with intellectual disabilities and have sometimes been shown to be associated with worries. We used the Childhood Routines Inventory (CRI, Evans et al., 1997) with two samples of children and adults with Down syndrome: (1) to determine whether routinised and compulsive-like behaviours were associated with mental health problems and (2) to determine the factor structure of the CRI. METHOD: Parents or carers completed the CRI for (1) 125 adults with Down syndrome (aged 18-43 years) who had been assessed for mental health problems; worries and fears were also rated by parents/carers and (2) 206 individuals with Down syndrome (aged 4.5-43 years, with verbal mental ages of 2 years and above). RESULTS: (1) People with a psychiatric diagnosis had significantly more worries and fears than those without such a diagnosis, but there was no significant difference in CRI scores. Logistic regression indicated that the fear rating was the only significant predictor of a diagnosis. (2) Exploratory and confirmatory analyses showed a three-factor model (Just right, Repetitive behaviour and Clothes sensitivity) to be the best solution. Those with psychiatric diagnoses had significantly higher ratings on the Repetitive behaviour factor. CONCLUSION: Increased levels of routinised and compulsive-like behaviours were shown by individuals with Down syndrome of all ages, were not associated with mental health problems, but were associated with worries and fears. Factor analysis found three factors, two of which (Just right and Repetitive behaviours), were similar to those identified in typically developing samples. This suggests that the behaviours have similar adaptive functions in individuals with developmental delays. PMID- 26031396 TI - Co-expression of recombinant human prolyl with human collagen alpha1 (III) chains in two yeast systems. AB - In this study, we co-expressed the human prolyl 4-hydroxylases (P4H) with human collagen alpha1 (III) (COL3A1) in an inducible system: Pichia pastoris (pPICZB), and one constitutive system: P. pastoris (pGAPZalphaB). The P4H catalyses the post-translational hydroxylation of proline residues in collagen strands. Conventional protein expression system such as bacteria and yeasts, which lack endogenous P4H, are not efficient for the production of recombinant collagen. In this study, the P4H gene was constructed in pGAPZalphaB plasmid and pPICZB plasmid respectively. These two plasmids were transformed in P. pastoris #1 that carrying COL3A1. Colony PCR analysis and sequencing after electroporation P. pastoris GS115 showed that the target gene had inserted successfully. The results of reverse transcript-qPCR, SDS-PAGE, Western blotting and LC-MS/MS analysis of the rhCOL3A1 demonstrated that the P4H was expressed successfully. Besides, it is noted that low copy number, constitutive system was suitable for hydroxylated rhCOL3A1. SIGNIFICANCE AND IMPACT OF THE STUDY: Successful co-expression of recombinant human collagen alpha1 (III) (rhCOL3A1) and human prolyl 4 hydroxylases (P4H) in Picha pastoris GS115, simultaneously results in the acquisition of rhCOL3A1 with hydroxylation of proline (Hyp). Further, this experiment also discusses that the high or low copy numbers and different promoters affect the Hyp degree of rhCOL3A1. Selecting more appropriate strains can express high degree Hyp of rhCOL3A1. This work will be helpful to the collagen structure study. PMID- 26031397 TI - The effect of different mouth rinse products on intra-oral halitosis. AB - AIM: To evaluate the effect of different mouth rinses 12 h after rinsing on genuine intra-oral halitosis. MATERIALS AND METHODS: Twenty-four adults with halitosis were included in a double-blind, crossover, randomized clinical trial. Halitosis was evaluated 12 h after rinsing with placebo and five mouth rinse products containing zinc acetate and chlorhexidine diacetate; zinc lactate, chlorhexidine and cetylpyridinium chloride; zinc acetate and chlorhexidine diacetate with reduced amounts of mint and menthol; zinc chloride and essential oil; and chlorine dioxide using the organoleptic method and a gas chromatograph. Test periods were separated by 1 week. RESULTS: Hydrogen sulphide (H2 S), methyl mercaptan (MM) and the organoleptic scores (OLS) were significantly reduced 12 h following rinsing with all substances compared to placebo (P < 0.05). H2 S was more effectively reduced after rinsing with zinc acetate and chlorhexidine diacetate and zinc acetate and chlorhexidine diacetate with reduced amounts of mint and menthol compared to rinsing with zinc chloride and essential oil (P < 0.05), and significantly lower values of MM were obtained after rinsing with zinc acetate and chlorhexidine diacetate compared to zinc lactate, chlorhexidine and cetylpyridinium chloride (P < 0.05). The percentage effectively treated individuals (H2 S (<112 ppb), MM (<26 ppb) and OLS score <2) varied from 58% percentage (zinc acetate and chlorhexidine diacetate) to 26% (zinc chloride and essential oil). CONCLUSION: All treatments resulted in reduction in halitosis 12 h after rinsing compared to placebo. H2 S and MM were most effectively reduced by zinc acetate and chlorhexidine diacetate. PMID- 26031398 TI - 1H and 13C NMR assignments of two new piperazine-trione from the fungus Penicillium crustosum YN-HT-15. PMID- 26031399 TI - Ultrasound screening for fetal growth restriction at 36 vs 32 weeks' gestation: a randomized trial (ROUTE). AB - OBJECTIVE: To compare the utility of routine third-trimester ultrasound examination at 36 weeks' gestation with that at 32 weeks in detecting fetal growth restriction (FGR). METHODS: This was an open-label parallel randomized trial (ROUTE study) conducted at a single general hospital serving a geographically well-defined catchment area in Barcelona, Spain, between May 2011 and April 2014. Women with no adverse medical or obstetric history and a singleton pregnancy without fetal abnormalities at routine second-trimester scan were assigned randomly to undergo a scan at 32 weeks' gestation (n = 1272) or at 36 weeks' gestation (n = 1314). Primary outcome measures were detection rates of FGR (customized birth weight < 10(th) centile) and severe FGR (customized birth weight < 3(rd) centile). RESULTS: There were no significant differences in perinatal outcome between those who underwent a scan at 32 weeks' gestation and those who underwent a scan at 36 weeks' gestation. Severe FGR at birth was associated significantly with emergency Cesarean delivery for fetal distress (odds ratio (OR), 3.4 (95% CI, 1.8-6.7)), neonatal admission (OR, 2.23 (95% CI, 1.23-4.05)), hypoglycemia (OR, 9.5 (95% CI, 1.8-49.8)) and hyperbilirubinemia (OR, 9.0 (95% CI, 4.6-17.6)). Despite similar false-positive rates (FPRs) (6.4% vs 8.2%), FGR detection rates were superior at 36 vs 32 weeks' gestation (sensitivity, 38.8% vs 22.5%; P = 0.006), with positive and negative likelihood ratios of 6.1 vs 2.7 and 0.65 vs 0.84, respectively. In cases of severe FGR, FPRs for both scans were also similar (8.5% vs 8.7%), but detection rates were superior at 36 vs 32 weeks' gestation (61.4% vs 32.5%; P = 0.008). Positive and negative likelihood ratios were 7.2 vs 3.7 and 0.4 vs 0.74, respectively. CONCLUSION: In low-risk pregnancies, routine ultrasound examination at 36 weeks' gestation was more effective than that at 32 weeks' gestation in detecting FGR and related adverse perinatal and neonatal outcomes. PMID- 26031400 TI - Catalytic and non-catalytic roles of DNA polymerase kappa in the protection of human cells against genotoxic stresses. AB - DNA polymerase kappa (Pol kappa) is a specialized DNA polymerase involved in translesion DNA synthesis. Although its bypass activities across lesions are well characterized in biochemistry, its cellular protective roles against genotoxic insults are still elusive. To better understand the in vivo protective roles, we have established a human cell line deficient in the expression of Pol kappa (KO) and another expressing catalytically dead Pol kappa (CD), to examine the cytotoxic sensitivity to 11 genotoxins including ultraviolet C light (UV). These cell lines were established in a genetic background of Nalm-6-MSH+, a human lymphoblastic cell line that has high efficiency for gene targeting, and functional p53 and mismatch repair activities. We classified the genotoxins into four groups. Group 1 includes benzo[a]pyrene diolepoxide, mitomycin C, and bleomycin, where the sensitivity was equally higher in KO and CD than in the cell line expressing wild-type Pol kappa (WT). Group 2 includes hydrogen peroxide and menadione, where hypersensitivity was observed only in KO. Group 3 includes methyl methanesulfonate and ethyl methanesulfonate, where hypersensitivity was observed only in CD. Group 4 includes UV and three chemicals, where the chemicals exhibited similar cytotoxicity to all three cell lines. The results suggest that Pol kappa not only protects cells from genotoxic DNA lesions via DNA polymerase activities, but also contributes to genome integrity by acting as a non-catalytic protein against oxidative damage caused by hydrogen peroxide and menadione. The non-catalytic roles of Pol kappa in protection against oxidative damage by hydrogen peroxide are discussed. PMID- 26031401 TI - Simple preparation of new [(18) F]F-labeled synthetic amino acid derivatives with two click reactions in one-pot and SPE purification. AB - New [(18) F]fluorinated 1,2,3-triazolyl amino acid derivatives were efficiently prepared from Huisgen 1,3-dipolar cycloaddition reactions, well known as click reaction. We developed two simultaneous click reactions in one-pot with a simple solid-phase extraction (SPE) purification method. [(18) F]fluoro-1-propyne was obtained at a 45% non-decay corrected radiochemical yield based on the [(18) F]fluoride ion. The one-pot and simultaneous two click reactions were performed with unprotected azido-alkyl amino acid, [(18) F]fluoro-1-propyne, and lipophilic additive alkyne to produce three synthetic amino acid derivatives, AMC-101 ([(18) F]-6a), AMC-102 ([(18) F]-6b), and AMC-103 ([(18) F]-6c) with 29%, 28%, and 24% of non-decay corrected radiochemical yields, respectively. All radiotracers indicated that radiochemical purities were >95% without any residual organic solvent. Our new method involving two click reactions in one-pot showed high radiochemical and chemical purity by easy removal of the residual precursor from the simultaneous two click reactions. PMID- 26031402 TI - Comparative proteome analysis of human testis from newborn, young adult, and aged men identified spermatogenesis-associated proteins. AB - Human testis begins to produce spermatozoa in the young adult. However, with ageing, the capacity of spermatogenesis gradually decreases including reduction in semen volume and sperm motility and changes in sperm morphology. Spermatogenesis is strictly controlled by complex protein pathways, and changes in protein expression might cause abnormal sperm functions. Here, human testicular proteomes from newborn, young adult, and aged men were compared by 2D fluorescence difference gel electrophoresis analysis to discover spermatogenesis associated proteins. Forty-seven proteins were found increased, and 18 decreased, from newborn to young adult. Sixteen proteins were dramatically increased, and 21 decreased from young to aged organ. Proteins involved in general metabolism and structure1 functions were significantly increased from newborn to young adult testes, whereas proteins related to anti-oxidative function were dramatically downexpressed in the aged organs. All the differential proteins were confirmed by immunoblot and characterized by immunohistochemical analysis. Among these, vimentin and CCT5 located in the Sertoli cell may be related to germ cell maturation. Of the 24 sperm-associated proteins, more than 70% proteins are located in acrosome, neck, and postequatorial region, and thus might help the sperm to bind to, and fuse with, the egg. These spermatogenesis-associated proteins might serve as markers to evaluate sperm quality and deepen the knowledge of the physiological function of the human testis, which is to play an important role in male reproduction regulation. PMID- 26031404 TI - Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior. AB - Microvesicles (MVs) are membrane-enclosed cytoplasmic fragments released by normal and activated cells that have been described as important mediators of cell-to-cell communication. Although the ability of human induced pluripotent stem cells (hiPSCs) to participate in tissue repair is being increasingly recognized, the use of hiPSC-derived MVs (hiPSC-MVs) in this regard remains unknown. Accordingly, we investigated the ability of hiPSC-MVs to transfer bioactive molecules including mRNA, microRNA (miRNA), and proteins to mature target cells such as cardiac mesenchymal stromal cells (cMSCs), and we next analyzed effects of hiPSC-MVs on fate and behavior of such target cells. The results show that hiPSC-MVs derived from integration-free hiPSCs cultured under serum-free and feeder-free conditions are rich in mRNA, miRNA, and proteins originated from parent cells; however, the levels of expression vary between donor cells and MVs. Importantly, we found that transfer of hiPSC components by hiPSC-MVs impacted on transcriptome and proteomic profiles of target cells as well as exerted proliferative and protective effects on cMSCs, and enhanced their cardiac and endothelial differentiation potential. hiPSC-MVs also transferred exogenous transcripts from genetically modified hiPSCs that opens new perspectives for future strategies to enhance MV content. We conclude that hiPSC MVs are effective vehicles for transferring iPSC attributes to adult somatic cells, and hiPSC-MV-mediated horizontal transfer of RNAs and proteins to injured tissues may be used for therapeutic tissue repair. In this study, for the first time, we propose a new concept of use of hiPSCs as a source of safe acellular bioactive derivatives for tissue regeneration. PMID- 26031405 TI - Reversible Doping of a Dithienothiophene-Based Conjugated Microporous Polymer. AB - Dithienothiophene (DTT) based conjugated microporous polymers (CMPs) were synthesized by bulk and electrochemical oxidative polymerizations. Spectroelectrochemical measurements showed that DTT-CMP can be reversibly oxidized and reduced, accompanied by a significant change of the absorption properties making the material interesting for electrochromic devices. Reversible doping and dedoping of the bulk polymer network was also observed using iodine and ammonia, respectively. Nitrogen gas sorption measurements of the neutral, doped, and dedoped polymer networks indicated the presence of iodide species within the pores, and the conductivity of the networks is highly increased upon doping with iodine. The introduction of the strong electron donor DTT into a conjugated porous network, and the ability for redox switching, make DTT-CMPs interesting materials for organo(opto)electronic devices and sensors. PMID- 26031403 TI - Gold(I)-Catalyzed Desymmetrization of 1,4-Dienes by an Enantioselective Tandem Alkoxylation/Claisen Rearrangement. AB - An enantioselective alkoxylation/Claisen rearrangement reaction was achieved by a strategic desymmetrization of 1,4-dienes under the catalysis of (S)-DTBM Segphos(AuCl)2/AgBF4. This reaction system was highly selective for the formation of 3,3-rearrangement products, providing cycloheptenes with various substitutions in good yield and good to excellent enantioselectivity. This transformation was further extended to bicyclic ring substrates, providing the opportunity to easily assemble 5,6- and 6,7-fused ring systems. PMID- 26031407 TI - In Situ Formation of Dual-Phase Thermosensitive Ultrasmall Gold Nanoparticles. AB - A novel method for the in situ synthesis of dual-phase thermosensitive ultrasmall gold nanoparticles (USGNPs) with diameters in the range of 1-3 nm was developed by using poly(N-isopropylacrylamide)-block-poly(N-phenylethylenediamine methacrylamide) (PNIPAM-b-PNPEDMA) amphiphilic diblock copolymers as ligands. The PNPEDMA block promotes the in situ reduction of gold precursors to zero-valent gold and subsequently binds to the surface of gold nanoparticles, while PNIPAM acts as a stabilizing and thermosensitive block. The as-synthesized USGNPs stabilized by a thermosensitive PNIPAM layer exhibit a sharp, reversible, clear opaque transition in aqueous solution between 30 and 38 degrees C. An unprecedented finding is that these USGNPs also show a reversible soluble precipitate transition in nonpolar organic solvents such as chloroform at around 0 degrees C under acidic conditions. PMID- 26031406 TI - High prevalence of cannabis use among Aka foragers of the Congo Basin and its possible relationship to helminthiasis. AB - OBJECTIVES: Little is known about cannabis use in hunter-gatherers. Therefore, we investigated cannabis use in the Aka, a population of foragers of the Congo Basin. Because cannabis contains anthelminthic compounds, and the Aka have a high prevalence of helminthiasis, we also tested the hypothesis that cannabis use might be an unconscious form of self-medication against helminths. METHODS: We collected self- and peer-reports of cannabis use from all adult Aka in the Lobaye district of the Central African Republic (n = 379). Because female cannabis use was low, we restricted sample collection to men. Using an immunoassay for Delta9 tetrahydrocannabinol-11-oic acid (THCA), a urinary biomarker of recent cannabis consumption, we validated cannabis use in men currently residing in camps near a logging road (n = 62). We also collected stool samples to assay worm burden. A longitudinal reinfection study was conducted among a subsample of the male participants (n = 23) who had been treated with a commercial anthelmintic 1 year ago. RESULTS: The prevalence of self- and peer-reported cannabis use was 70.9% among men and 6.1% among women, for a total prevalence of 38.6%. Using a 50 ng/ml threshold for THCA, 67.7% of men used cannabis. Cannabis users were significantly younger and had less material wealth than the non-cannabis users. There were significant negative associations between THCA levels and worm burden, and reinfection with helminths 1 year after treatment with a commercial anthelmintic. CONCLUSIONS: The prevalence of cannabis use among adult Aka men was high when compared to most global populations. THCA levels were negatively correlated with parasite infection and reinfection, supporting the self-medication hypothesis. PMID- 26031408 TI - Robotic gastrectomy for gastric cancer. AB - Robotic surgery for gastric cancer overcomes technical difficulties with laparoscopic gastrectomy. Its benefits include reduced intraoperative bleeding and shorter hospital stays; it is also easier to learn. Because accuracy increases during lymphadenectomy, a larger number of lymph nodes is likely to be retrieved using robotic gastrectomy. Higher costs and longer operation times have hindered the widespread adaptation and use of robotic surgery. In this review, we summarize the current status and issues regarding robotic gastrectomy. PMID- 26031409 TI - Discovery, Structure Elucidation, and Biological Characterization of Nannocystin A, a Macrocyclic Myxobacterial Metabolite with Potent Antiproliferative Properties. AB - Microbial natural products are a rich source of bioactive molecules to serve as drug leads and/or biological tools. We investigated a little-explored myxobacterial genus, Nannocystis sp., and discovered a novel 21-membered macrocyclic scaffold that is composed of a tripeptide and a polyketide part with an epoxyamide moiety. The relative and absolute configurations of the nine stereocenters was determined by NMR spectroscopy, molecular dynamics calculations, chemical degradation, and X-ray crystallography. The compound, named nannocystin A (1), was found to inhibit cell proliferation at low nanomolar concentrations through the early induction of apoptosis. The mode of action of 1 could not be matched to that of standard drugs by transcriptional profiling and biochemical experiments. An initial investigation of the structure-activity relationship based on seven analogues demonstrated the importance of the epoxide moiety for high activity. PMID- 26031410 TI - Physiologically based and population PK modeling in optimizing drug development: A predict-learn-confirm analysis. AB - Physiologically based pharmacokinetic (PBPK) modeling and classical population pharmacokinetic (PK) model-based simulations are increasingly used to answer various drug development questions. In this study, we propose a methodology to optimize the development of drugs, primarily cleared by the kidney, using model based approaches to determine the need for a dedicated renal impairment (RI) study. First, the impact of RI on drug exposure is simulated via PBPK modeling and then confirmed using classical population PK modeling of phase 2/3 data. This methodology was successfully evaluated and applied to an investigational agent, orteronel (nonsteroidal, reversible, selective 17,20-lyase inhibitor). A phase 1 RI study confirmed the accuracy of model-based predictions. Hence, for drugs eliminated primarily via renal clearance, this modeling approach can enable inclusion of patients with RI in phase 3 trials at appropriate doses, which may be an alternative to a dedicated RI study, or suggest that only a reduced-size study in severe RI may be sufficient. PMID- 26031412 TI - Binding studies of the anti-retroviral drug, efavirenz to calf thymus DNA using spectroscopic and voltammetric techniques. AB - Interactions between efavirenz (EFZ) with calf thymus DNA (CT-DNA) were investigated in vitro under stimulated physiological conditions using multispectroscopic techniques, cyclic voltammetry viscosity measurement, and gel electrophoresis. Methylene blue and acridine orange dyes were used as spectral probes by fluorescence spectroscopy. Hypochromicity was observed in ultra-violet (UV) absorption band of EFZ. Considerable fluorescence enhancement of EFZ was observed in the presence of increasing amounts of DNA solution and the binding constants (Kf ) and corresponding numbers of binding sites (n) were calculated at different temperatures. Thermodynamic parameters including enthalpy change (DeltaH) and entropy change (DeltaS) were calculated to be -304.78 kJ mol(-1) and -924.52 J mol(-1) K(-1) according to the van 't Hoff equation, which indicated that reaction is predominantly enthalpically driven. In addition, UV/vis absorption titration of DNA bases confirmed that EFZ interacted with guanine and cytosine preferentially. Gel electrophoresis of DNA with EFZ demonstrated that EFZ also has the ability to cleave supercoiled plasmid DNA. Circular dichroism study showed stabilization of the right-handed B form of CT-DNA. All results suggest that EFZ interacts with CT-DNA via an intercalative mode of binding. PMID- 26031411 TI - Geographic comparison of plant genera used in frugivory among the pitheciids Cacajao, Callicebus, Chiropotes, and Pithecia. AB - Pitheciids are known for their frugivorous diets, but there has been no broad scale comparison of fruit genera used by these primates that range across five geographic regions in South America. We compiled 31 fruit lists from data collected from 18 species (three Cacajao, six Callicebus, five Chiropotes, and four Pithecia) at 26 study sites in six countries. Together, these lists contained 455 plant genera from 96 families. We predicted that 1) closely related Chiropotes and Cacajao would demonstrate the greatest similarity in fruit lists; 2) pitheciids living in closer geographic proximity would have greater similarities in fruit lists; and 3) fruit genus richness would be lower in lists from forest fragments than continuous forests. Fruit genus richness was greatest for the composite Chiropotes list, even though Pithecia had the greatest overall sampling effort. We also found that the Callicebus composite fruit list had lower similarity scores in comparison with the composite food lists of the other three genera (both within and between geographic areas). Chiropotes and Pithecia showed strongest similarities in fruit lists, followed by sister taxa Chiropotes and Cacajao. Overall, pitheciids in closer proximity had more similarities in their fruit list, and this pattern was evident in the fruit lists for both Callicebus and Chiropotes. There was no difference in the number of fruit genera used by pitheciids in habitat fragments and continuous forest. Our findings demonstrate that pitheciids use a variety of fruit genera, but phylogenetic and geographic patterns in fruit use are not consistent across all pitheciid genera. This study represents the most extensive examination of pitheciid fruit consumption to date, but future research is needed to investigate the extent to which the trends in fruit genus richness noted here are attributable to habitat differences among study sites, differences in feeding ecology, or a combination of both. PMID- 26031413 TI - Emodin ameliorates hepatic steatosis through endoplasmic reticulum-stress sterol regulatory element-binding protein 1c pathway in liquid fructose-feeding rats. AB - AIM: To investigate the effects of emodin on the treatment of non-alcoholic fatty liver in rats induced by liquid fructose-feeding in rats and the possible underlying mechanisms. METHODS: Sprague-Dawley rats were divided into the control, fructose-feeding group, and three fructose-feeding groups treated with 40, 80 and 160 mg/kg emodin, respectively. After 4 weeks of feeding, liquid consumption, food intake, bodyweight, liver index, serum triglyceride (TG), glucose and aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), liver TG contents and histology features were examined. The hepatic expression of lipogenic and fatty acid oxidation key enzymes, and an upstream transcriptional factor, sterol regulatory element-binding protein 1c (SREBP1c) were determined. Glucose regulated protein 78 (GRP78), a liver endoplasmic reticulum stress (ERS) marker and the unfolded protein response (UPR) related proteins were also measured. RESULTS: Emodin reduced bodyweight, liver index, serum TG levels of fructose-feeding rats with no significant difference in serum glucose, AST and ALT levels. Emodin improved hepatic steatosis by inhibiting SREBP1c activation and its target genes, and enhancing carnitine palmitoyltransferase 1 expression in fructose-feeding rats. Emodin resolved hepatic ERS and the UPR induced by liquid fructose in rats. CONCLUSION: Emodin is capable of improving the lipid accumulation through the ERS-SREBP1c pathway in fructose-induced non-alcoholic fatty liver disease. PMID- 26031414 TI - Dynamics of soft tissue healing at implants and teeth: a study in a dog model. AB - OBJECTIVE: The aim of this study was to describe and to compare some characteristics of the soft tissue healing process around teeth and implants after flap surgery. MATERIAL AND METHODS: Five adult beagle dogs had their third and fourth lower premolars extracted. After 3 months, four implants per dog were placed on the healed alveolar ridge and allowed to heal non-submerged during 3 months. After 3 months, four regions characterized by one implant and one adjacent tooth were identified in each dog. One region was randomly selected and soft tissue ressective flap surgery was performed at its buccal aspect. The remaining three regions were randomly treated in an identical manner, and the dogs were sacrificed to provide biopsies representing healing intervals of 1, 2, 4, and 12 weeks. The biopsies were prepared for histological and morphological analyses. RESULTS: Morphometric and histometric analyses have shown that the gingival tissues surrounding teeth were completely healed after a 4-week interval. However, it took from 4 to 12 weeks for the peri-implant mucosa to heal completely. CONCLUSION: The healing process around teeth and implants follows a similar sequence of events. Nevertheless, the complete process of healing and maturation of the peri-implant tissues takes longer than around teeth. PMID- 26031415 TI - Effect of stereotactic dosimetric end points on overall survival for Stage I non small cell lung cancer: a critical review. AB - Stereotactic body radiation therapy (SBRT) delivers a high biologically effective dose while minimizing toxicities to surrounding tissues. Within the scope of clinical trials and local practice, there are inconsistencies in dosimetrics used to evaluate plan quality. The purpose of this critical review was to determine if dosimetric parameters used in SBRT plans have an effect on local control (LC), overall survival (OS), and toxicities. A database of relevant trials investigating SBRT for patients with early-stage non-small cell lung cancer was compiled, and a table of dosimetric variables used was created. These parameters were compared and contrasted for LC, OS, and toxicities. Dosimetric end points appear to have no effect on OS or LC. Incidences of rib fractures correlate with a lack of dose-volume constraints (DVCs) reported. This review highlights the great disparity present in clinical trials reporting dosimetrics, DVCs, and toxicities for lung SBRT. Further evidence is required before standard DVCs guidelines can be introduced. Dosimetric end points specific to stereotactic treatment planning have been proposed but require further investigation before clinical implementation. PMID- 26031416 TI - Colloidal CdSe(1-x)S(x) Nanoplatelets with Narrow and Continuously-Tunable Electroluminescence. AB - Colloidal nanoplatelets, quasi-two-dimensional quantum wells, have recently been introduced as colloidal semiconductor materials with the narrowest known photoluminescence line width (~10 nm). Unfortunately, these materials have not been shown to have continuously tunable emission but rather emit at discrete wavelengths that depend strictly on atomic-layer thickness. Herein, we report a new synthesis approach that overcomes this issue: by alloying CdSe colloidal nanoplatelets with CdS, we finely tune the emission spectrum while still leveraging atomic-scale thickness control. We proceed to demonstrate light emitting diodes with sub-bandgap turn-on voltages (2.1 V for a device emitting at 2.4 eV) and the narrowest electroluminescence spectrum (FWHM ~12.5 nm) reported for colloidal semiconductor LEDs. PMID- 26031417 TI - Is there a risk profile for the vulnerable junior doctor? AB - BACKGROUND: Mental ill health is prevalent among doctors, especially those in the early stages of postgraduate training. However, a paucity of research has examined factors predictive of psychological distress in this population. AIMS: To report the findings from a multi-centre survey of mental health among junior doctors in Ireland, and assess the extent to which moderator variables (e.g., age, academic performance, nationality, etc.) alter the levels of psychological distress caused by internship. METHOD: An online, anonymous, questionnaire was distributed to all interns in the Republic of Ireland in January 2012. RESULTS: A total of 270 interns responded to the survey (45.0 % response rate), with 48.5 % of the respondents having a score indicative of psychological distress. A regression model found that nationality, academic performance, intern training network, rating of work stressors, home stressors, and work-life balance were associated with differing levels of mental health as measured by the General Health Questionnaire-12. CONCLUSIONS: There is a need to consider moderator variables when examining mental health in healthcare populations to avoid drawing overly simplistic conclusions. Interns in Ireland reported particularly high levels of psychological distress compared to other studies of mental health among healthcare populations. PMID- 26031418 TI - Enhanced photocurrent from Photosystem I upon in vitro truncation of the antennae chlorophyll. AB - Current effects on climate change and dwindling fossil fuel reserves require new materials and methods to convert solar energy into a viable clean energy source. Recent progress in the direct conversion of light into photocurrent has been well documented using Photosystem I. In plants, PSI consists of a core complex and multiple light-harvesting complexes, denoted LHCI and LHCII. Most of the methods for isolating PSI from plants involve a selective, detergent solubilization from thylakoids followed by sucrose gradient density centrifugation. These processes isolate one variant of PSI with a specific ratio of Chl:P700. In this study, we have developed a simple and potentially scalable method for isolating multiple PSI variants using Hydroxyapatite chromatography, which has been well documented in other Photosystem I isolation protocols. By varying the wash conditions, we show that it is possible to change the Chl:P700 ratios. These different PSI complexes were cast into a PSI-Nafion-osmium polymer film that enabled their photoactivity to be measured. Photocurrent increases nearly 400% between highly washed and untreated solutions based on equal chlorophyll content. Importantly, the mild washing conditions remove peripheral Chl and some LHCI without inhibiting the photochemical activity of PSI as suggested by SDS-PAGE analysis. This result could indicate that more P700 could be loaded per surface area for biohybrid devices. Compared with other PSI isolations, this protocol also allows isolation of multiple PSI variants without loss of photochemical activity. PMID- 26031419 TI - A novel mutation of the hGR gene causing Chrousos syndrome. AB - BACKGROUND: Natural mutations in the human glucocorticoid receptor (hGR, NR3C1) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. OBJECTIVE: To present a new case of Chrousos syndrome caused by a novel mutation in the hGR gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction. DESIGN AND RESULTS: The index case presented with hirsutism, acne, alopecia, anxiety, fatigue and irregular menstrual cycles, but no clinical manifestations suggestive of Cushing's syndrome. Endocrinologic evaluation revealed elevated 08:00 h plasma adrenocorticotropic hormone, serum cortisol and androstenedione concentrations and increased urinary free cortisol excretion. The patient harbored a novel A > G transition at nucleotide position 2177, which resulted in histidine (H) to arginine (R) substitution at amino acid position 726 of the receptor (c.2177A > G, p.H726R). Compared with the wild-type receptor, the mutant receptor hGRalphaH726R demonstrated decreased ability to transactivate glucocorticoid responsive genes and to transrepress the nuclear factor-kappaB signalling pathway, displayed 55% lower affinity for the ligand and a four-fold delay in nuclear translocation, and interacted with the glucocorticoid receptor interacting protein 1 coactivator mostly through its activation function-1 domain. Finally, a 3-dimensional molecular modelling study of the H726R mutation revealed a significant structural shift in the rigidity of helix 10 of the receptor, which resulted in reduced flexibility and decreased affinity of the mutant receptor for binding to the ligand. CONCLUSIONS: The natural mutant receptor hGRalphaH726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids. PMID- 26031420 TI - Intraprocedural Cleansing for Screening Colonoscopy: Avoiding Brownouts. PMID- 26031422 TI - Ischemia/Reperfusion Injury and Hepatocellular Carcinoma Recurrence After Liver Transplantation: Cancer at WIT's End? PMID- 26031421 TI - Vitamin D Deficiency Associated with Disease Activity in Patients with Inflammatory Bowel Diseases. AB - BACKGROUND: Evidence exists on the association between vitamin D deficiency and inflammatory bowel diseases (IBD). AIMS: To investigate whether vitamin D level is associated with disease activity and quality of life in IBD patients. METHODS: This cross-sectional study was conducted on known adult IBD patients referred to an outpatient clinic of gastroenterology in Isfahan city, Iran. Disease activity was evaluated using the Simplified Crohn's Disease Activity Index and Simple Clinical Colitis Activity Index. Quality of life was assessed with the Short Inflammatory Bowel Disease Questionnaire. Serum 25[OH]D was measured using the radioimmunoassay method. Vitamin D deficiency and insufficiency were defined as concentration of <50 and 50-75 nmol/L, respectively. RESULTS: Studied subjects were 85 ulcerative colitis and 48 Crohn's disease patients (54.1% females) with mean age of 42.0 +/- 14.0 years. Vitamin D deficiency and insufficiency were present in 52 (39.0%) and 24 (18.0%) patients, respectively. Thirty patients (22.5%) had active disease who, compared with patients in remission, had more frequent low vitamin D levels (80 vs. 50.4%, P = 0.005). Quality of life was not different between patients with low and those with normal vitamin D levels (P = 0.693). In the logistic regression model, low vitamin D was independently associated with active disease status, OR (95% CI) = 5.959 (1.695-20.952). CONCLUSIONS: We found an association between vitamin D deficiency/insufficiency and disease activity in IBD patients. Prospective cohorts and clinical trials are required to clarify the role of vitamin D deficiency and its treatment in clinical course of IBD. PMID- 26031423 TI - Percutaneous Microwave Ablation in the Spleen for Treatment of Hypersplenism in Cirrhosis Patients. AB - AIM: The aim of this study was to estimate the feasibility and therapeutic effectiveness of percutaneous microwave ablation in the treatment of hypersplenism in cirrhosis. METHODS: Forty-one cirrhosis patients with hypersplenism were treated with ultrasonography-guided percutaneous microwave ablation between February 2007 and August 2011. Peripheral blood cell counts, portal vein diameter, splenic vein diameter, and blood flow of splenic vein were evaluated before and after the operation, and complications of the treatment were also investigated. All patients were followed up for 24 months. RESULTS: The levels of platelets and white blood cells were increased, while the splenic vein diameter narrowed gradually after the therapy and 24 months later. Moreover, patients received percutaneous microwave ablation had much lower splenic venous flow velocity. The portal vein diameter did not change significantly 6 months after the treatment, although it narrowed gradually within 3 months after the treatment. Furthermore, no complications such as uncontrollable bleeding, splenic abscess, spleen rupture, and damage in surrounding organ happened after the therapy. CONCLUSIONS: Graded percutaneous microwave ablation, as a minimally invasive therapy, could damage the spleen, increase the levels of platelets and white blood cells, and reduce portal hypertension effectively without serious complications. Percutaneous microwave ablation is an effective, safe, and feasible method for cirrhosis patients with hypersplenism. PMID- 26031425 TI - Hydroalumination of Ketenimines and Subsequent Reactions with Heterocumulenes: Synthesis of Unsaturated Amide Derivatives and 1,3-Diimines. AB - The series of differently substituted ketenimines 1 was hydroluminated using di iso-butyl aluminum hydride. For the sterically congested ketenimine 1a, preferred hydroalumination of the C?N-bond was proven by X-ray crystallography (compound 5a). In situ treatment of the hydroaluminated ketenimines 5 with various heterocumulenes like carbodiimides, isocycanates, isothiocyanates and ketenimines as electrophiles and subsequent hydrolytic workup resulted in novel enamine derived amide species in case of N-attack (sterically less hindered ketenimines) under formation of a new C-N-bond or in 1,3-diimines by C-C-bond-formation in case of bulky substituents at the ketenimine-nitrogen atom. Furthermore, domino reactions with more than 1 equiv of the electrophile or by subsequent addition of two different electrophiles are possible and lead to polyfunctional amide derivatives of the biuret type which are otherwise not easily accessible. PMID- 26031424 TI - Relationship Between Cytomegalovirus Infection and Steroid Resistance in Inflammatory Bowel Disease: A Meta-Analysis. AB - BACKGROUND AND AIMS: Steroid resistance presents an administration difficulty in inflammatory bowel disease (IBD). The reason of steroid resistance is still unclear, but cytomegalovirus (CMV) infection may be a potential cause in some IBD patients. We carried out a meta-analysis to investigate the relationship between CMV infection and steroid-resistant IBD. METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched up to June 2014, with no language restrictions, for observational studies. Additional references were obtained from reviewed articles. RESULTS: Eleven studies involving 867 IBD patients were included in the meta-analysis. Steroid resistance rate was 70.0% in CMV-positive IBD patients, which was significantly higher than that in CMV-negative IBD patients (RR = 2.12, 95% CI = 1.72-2.61). There was significant heterogeneity in the included eleven studies (I (2) = 57.6%). When the only one study with a few patients was excluded, sensitivity analysis suggested a similar outcome (RR = 2.07, 95% CI = 1.80-2.39, 10 studies). Based on the funnel plot and Egger's test, we considered that there was a probable publication bias. CONCLUSION: Our meta analysis suggests that CMV-positive IBD patients have a nearly double risk of steroid resistance compared with CMV-negative IBD patients, indicating that CMV infection is a probable cause of steroid-resistant IBD. PMID- 26031426 TI - The pH-dependent photoluminescence of colloidal CdSe/ZnS quantum dots with different organic coatings. AB - The photoluminescence (PL) of colloidal quantum dots (QDs) is known to be sensitive to the solution pH. In this work we investigate the role played by the organic coating in determining the pH-dependent PL. We compare two types of CdSe/ZnS QDs equipped with different organic coatings, namely dihydrolipoic acid (DHLA)-capped QDs and phospholipid micelle-encapsulated QDs. Both QD types have their PL intensity quenched at acidic pH values, but they differ in terms of the reversibility of the quenching process. For DHLA-capped QDs, the quenching is nearly irreversible, with a small reversible component visible only on short time scales. For phospholipid micelle-encapsulated QDs the quenching is notably almost fully reversible. We suggest that the surface passivation by the organic ligands is reversible for the micelle-encapsulated QDs. Additionally, both coatings display pH-dependent spectral shifts. These shifts can be explained by a combination of irreversible processes, such as photo-oxidation and acid etching, and reversible charging of the QD surface, leading to the quantum-confined Stark effect (QCSE), the extent of each effect being coating-dependent. At high ionic strengths, the aggregation of QDs also leads to a spectral (red) shift, which is attributable to the QCSE and/or electronic energy transfer. PMID- 26031427 TI - Metformin: Potential analgesic? AB - OBJECTIVE: To determine the association of self-report use of metformin and pain intensity. DESIGN: Survey-based cross sectional. SETTING: Primary care in an academic medical center. SUBJECTS: Three hundred and twenty nine participants with diabetes. METHODS: A total of 329 men and women, aged 18-65, completed a phone-based survey. We utilized the Brief Pain Inventory to assess for pain intensity ratings; Leeds Assessment of Neuropathic Symptoms and Signs to screen for neuropathy; and the Personal Health Questionnaire (PHQ8) Depression Scale to assess for depression. RESULTS: Three hundred and twenty nine diabetics (mean age 54- +/- 8-year old) completed the study (162 metformin users, 167 nonusers). Compared with non-users, metformin users were used more often [38% vs 20%, P = 0.001]; had lower mean depression scores [6.8 vs 8.3; P = 0.026] and fewer comorbidities [1.5 vs 1.8, P = 0.022]. Adjusting for those three variables, pain scores were not significantly different between groups. In a subset analyses of those with neuropathic pain (n = 156), there were no differences in pain scores found between groups. CONCLUSIONS: In a clinic sample of patients with diabetes, the use of metformin at an average dose of 1,432 mg (SD = 596 mg) was not associated with lower pain scores. Given the anti-nociceptive effects of metformin in the animal models of pain, and the relative safety of metformin, future research should evaluate the effect of the higher dose of metformin as a potential analgesic. PMID- 26031428 TI - Effectiveness of an Adapted Diabetes Prevention Program Lifestyle Intervention in Older and Younger Adults. AB - OBJECTIVES: To compare participation, self-monitoring behaviors, and weight loss outcomes in older and younger participants in an adapted Diabetes Prevention Program (DPP) lifestyle intervention. DESIGN: Pre- and postevaluation of outcomes in participants enrolled in the Montana Cardiovascular Disease (CVD) and DPP lifestyle intervention from 2008 through 2012. SETTING: Community. PARTICIPANTS: Adults at high risk for CVD and type 2 diabetes mellitus (N = 3,804). MEASUREMENTS: Number of core (16 weekly sessions) and postcore (6 monthly sessions) intervention sessions attended, weekly self-monitoring of fat intake and minutes of physical activity, weight loss outcomes and achievement of the weight loss goal, and improvements in CVD-related risk factors. RESULTS: Participants aged 65 and older were significantly more likely to attend more intervention sessions, self-monitor their fat intake, and achieve the physical activity and weight loss goals than those younger than 65. Older and younger participants experienced significant improvements in CVD-related risk factors. CONCLUSION: Older adults at high risk of CVD and diabetes mellitus participating in an adapted DPP lifestyle intervention had higher participation and self monitoring rates than younger participants, were more likely to achieve physical activity and weight loss goals, and achieved similar CVD risk reduction. PMID- 26031429 TI - Differential Diagnosis of Acute Myelopathies: An Update. AB - Appropriate description may lead to adequate diagnostic and therapeutic measures, and therefore, a simple scheme to categorize and term the imaging findings of acute myelopathy is suggested based on current literature. Assigning imaging findings to five groups, that is (a) "segmental with rash," (b) "poliolike," (c) "granulomatous-nodular," (d) "longitudinally extensive transverse myelitis," (e) "short-segment ovoid or peripherally located," provides a rationale to lessen differential diagnoses. The key for understanding, proper description and differential diagnosis is the correlation of two time points: When did the first symptoms appear and when did imaging take place? Early infarction within the first 24 h will show neither swelling nor enhancement. PMID- 26031430 TI - The Past, Present and Future of Endovascular Aneurysm Treatment. AB - The technology available for the endovascular treatment of intracranial aneurysms is rapidly evolving. Both current and future devices are described. This includes, among others, UNO for parent vessel occlusion, the Medina device for saccular filling, the Comaneci device for remodeling, pCONus for assisted coil occlusion, and WEB and pCANvas for intrasaccular flow disruption. Perspectives of further development such as surface coating for increased radioopacity and decreased thrombogenicity are explained. PMID- 26031431 TI - Etiology of Corpus Callosum Lesions with Restricted Diffusion. AB - PURPOSE: Infarction of the corpus callosum is rare, and other conditions can cause magnetic resonance imaging (MRI) restricted diffusion in the callosum, leading to diagnostic uncertainty. We sought to characterize the etiology of lesions with diffusion restriction in the corpus callosum. METHODS: Callosal lesions with restricted diffusion were identified at our institution between January 2000 and December 2010. Radiographic and clinical data were reviewed to determine whether the lesion was vascular and if so, to identify the underlying mechanism. RESULTS: A total of 174 cases were reviewed in depth; 47 % were vascular and 53 % were nonvascular. Among vascular cases, atypical mechanisms of stroke (e.g., vasculitis/vasculopathy, hypercoagulable state) were most common (37 %), followed by cardioembolism (28 %). Vascular splenial lesions in particular were likely due to atypical causes of stroke. The most common nonvascular etiologies were trauma (44 %), tumor (22 %), and demyelination (15 %). Vascular lesions were more common in older, non-Caucasian patients with vascular risk factors. Nonvascular lesions were more likely to be found in association with T2-hyperintense cortical lesions, focal intraparenchymal enhancement, or edema/mass effect on MRI. CONCLUSIONS: More than half of lesions with diffusion restriction in the corpus callosum are due to a nonvascular cause. Clinical and radiographic characteristics can help distinguish vascular from nonvascular lesions in the corpus callosum. Nonvascular lesions are more likely to be seen in younger patients without vascular risk factors and are more often accompanied by enhancement and edema. Vascular lesions are most commonly due to atypical stroke etiologies, and these patients may require additional diagnostic testing. PMID- 26031432 TI - Assessment of pain, acceptance of illness, adjustment to life with cancer and coping strategies in breast cancer patients. AB - INTRODUCTION: Breast cancer is the most common malignant neoplasm in women. Over the past 40 years, the number of patients diagnosed with breast cancer quadrupled. Breast cancer is one of the most frequent causes of death in women aged 65 and more in Poland. PURPOSE: The purpose of the study was to evaluate coping strategies, pain management, disease acceptance and adjustment to cancer in patients diagnosed with breast cancer and to assess the effect of socioeconomic variables on the above mentioned issues. METHODS: The study included 193 patients diagnosed with breast cancer during outpatient chemotherapy (classical chemotherapy, hormone therapy, molecularly targeted therapies) at the Center of Oncology, Maria Sklodowska-Curie Institute in Warsaw. We applied the Paper and Pencil Interview (PAPI) technique. The questionnaire interview consisted of demographic questions (socioeconomic variables) and the following four psychometric tests: BPCQ (Beliefs about Pain Control Questionnaire), measuring the influence of factors affecting pain management in patients, CSQ (Coping Strategies Questionnaire), designed to evaluate pain coping strategies, AIS (Acceptance of Illness Scale) questionnaire, measuring disease acceptance, and the mini-MAC (Mental Adjustment to Cancer) scale. RESULTS: The results of BPCQ show that breast cancer patients mostly believe that doctors control pain; the mean result for the group was 17.09 and test values were differentiated by education and professional status. The top average score in the pain coping strategies questionnaire was recorded in the positive coping self-statement subscale (mean score = 21.81), whereas the lowest, in the catastrophizing subscale (mean score = 10.60). Here, education and income proved most significant in accounting for the differences recorded. The mean score on the AIS was 28.45, and the key factor differentiating the results was income. As far as the mini-MAC is concerned, we reported the highest score in the fighting spirit subscale (23.43). The average results in the scale were slightly differentiated by socioeconomic variables. CONCLUSIONS: Breast cancer patients mostly believe that those who control pain are doctors. Amongst the strategies of coping with pain, the top average score was recorded in the positive coping self-statement subscale. We found out that the level of disease acceptance depends on respondent's income. The higher the income, the greater the acceptance of illness. PMID- 26031434 TI - Examination of iodine status in the German population: an example for methodological pitfalls of the current approach of iodine status assessment. AB - PURPOSE: Preliminary iodine concentration (UIC) measurements in spot urines of the representative German adult study DEGS indicated a severe worsening of iodine status compared to previous results in German children (KiGGS study). Therefore, we aimed to evaluate adult iodine status in detail and to investigate the impact of hydration status on UIC. METHODS: UIC and creatinine concentrations were measured in 6978 spot urines from the German nationwide DEGS study (2008-2011). Twenty-four-hour iodine excretions (24-h UIE) were estimated by relating iodine/creatinine ratios to age- and sex-specific 24-h creatinine reference values. Urine osmolality was measured in two subsamples of spot urines (n = 100 each) to determine the impact of hydration status on UIC. RESULTS: In DEGS, median UIC was 69 ug/L in men and 54 ug/L in women, lying clearly below the WHO cutoff for iodine sufficiency (100 ug/L). Estimated median 24-h UIE was 113 ug/day, accompanied by 32 % of DEGS adults, lying below the estimated average requirement (EAR) for iodine. Comparative analysis with the KiGGS data (>14,000 spot urines of children; median UIC 117 ug/L) revealed a comparable percentage =24 hr/wk occupational sitting time was compared to <24 hr/wk for the 1990-2005 waves. CONCLUSIONS: Occupational sitting time increased by 18% in the Danish workforce, which seemed to be limited to people with high socio-economic status. If this increase is accompanied by increases in total sitting time, this development has serious public health implications, given the detrimental associations between total sitting time and mortality. The current study was inconclusive on the specific role that occupational sitting might play in the increased all-cause mortality risk associated with the total volume of sitting. PMID- 26031454 TI - Regulation of transcription factors on sexual dimorphism of fig wasps. AB - Fig wasps exhibit extreme intraspecific morphological divergence in the wings, compound eyes, antennae, body color, and size. Corresponding to this, behaviors and lifestyles between two sexes are also different: females can emerge from fig and fly to other fig tree to oviposit and pollinate, while males live inside fig for all their lifetime. Genetic regulation may drive these extreme intraspecific morphological and behavioral divergence. Transcription factors (TFs) involved in morphological development and physiological activity may exhibit sex-specific expressions. Herein, we detect 865 TFs by using genomic and transcriptomic data of the fig wasp Ceratosolen solmsi. Analyses of transcriptomic data indicated that up-regulated TFs in females show significant enrichment in development of the wing, eye and antenna in all stages, from larva to adult. Meanwhile, TFs related to the development of a variety of organs display sex-specific patterns of expression in the adults and these may contribute significantly to their sexual dimorphism. In addition, up-regulated TFs in adult males exhibit enrichment in genitalia development and circadian rhythm, which correspond with mating and protandry. This finding is consistent with their sex-specific behaviors. In conclusion, our results strongly indicate that TFs play important roles in the sexual dimorphism of fig wasps. PMID- 26031455 TI - Reactivation of hepatitis B (reverse seroconversion) after melphalan/dexamethasone therapy for primary amyloidosis: a case report. AB - INTRODUCTION: Hepatitis B virus (HBV) reactivation (so-called reverse seroconversion) is a rare but known complication of hematopoietic stem cell transplantation, immunosuppressive therapy, or high-dose chemotherapy plus rituximab. This event is linked to a treatment-related fall in titers of antibodies to hepatitis B surface antigen (HBsAb) below the protective threshold level. CASE PRESENTATION: A 77-year-old Korean man diagnosed with primary amyloidosis was started on melphalan/dexamethasone combination therapy. During treatment, laboratory indices of hepatic function suddenly deteriorated, and he developed acute hepatitis through reverse HBV seroconversion, becoming positive for hepatitis B surface antigen (HBsAg) and negative for HBsAb. HBV DNA was also detectable in serum to a profound extent. Normal liver function was gradually restored during the course of antiviral therapy (entecavir). CONCLUSIONS: HBV reactivation may lead to fatal liver disease in a significant percentage of patients. As a result, physicians often screen for HBsAg and HBsAb prior to initiating chemotherapy, advising antiviral treatment in patients seropositive for HBsAg, even in the absence of hepatitis B e antigen. Here, a case of HBV reactivation is described, involving a patient given relatively low-dose chemotherapy (melphalan/dexamethasone) for primary amyloidosis. PMID- 26031456 TI - Type I Chiari malformation presenting with laryngomalacia and dysphagia. AB - We describe clinical features of an infant with laryngomalacia and dysphagia caused by type I Chiari malformation (CM-I). A 12-month-old child presented with a 6 month history of progressive stridor, dysphagia, and gastroesophageal reflux. Examination of the airway and swallowing function indicated mild laryngomalacia and aspiration with all consistencies. Magnetic resonance imaging of the brain indicated CM-I. Symptoms were resolved after posterior fossa decompression. CM-I, typically diagnosed later in life, should be considered in the differential diagnosis of laryngomalacia and dysphagia. High clinical suspicion and thorough search for abnormalities ensure early diagnosis and proper management of children with neurologic variant laryngomalacia. PMID- 26031457 TI - Mental health nurse prescribing: the emerging impact. AB - Some mental health nurses have now been prescribing for their clients for several years. When suitably qualified they can prescribe the same range of medication as medical staff. Concern was expressed that nurse prescribers might become more like doctors and as a result would sacrifice their nursing skills. The views of those who have their medication prescribed by mental health nurses as well as views of nurse prescribers, pharmacist prescribers, nurse managers and doctors were explored by using interviews and focus groups. Most participants saw the inclusion of prescribing in the nursing role as a benefit to clients. Rather than detracting from the nurse patient relationship, results from this study suggest that the nurse patient relationship was improved and more holistic care was provided. Nurse prescribing is well received by those who have experienced it. As nurse prescribing effects a change of power dynamics this could result in the need for less involvement of the medical profession in clients' care. As clients found nurses easier to talk to about their medication than doctors, medication concordance could be increased. Medication reconciliation could also be increased as medications no longer required by clients were more likely to be reduced or stopped by nurse prescribers. Discontinuing medication may indicate a new culture around mental health nurse prescribing. It may be that this trend has an impact on future service provision to clients. Results suggest that clients prefer to have their medication prescribed by nurses. Mental health nurse prescribing has been established in some areas in the UK for quite some time. Other than speculation that nurse prescribing would have a detrimental effect on the nurse patient relationship, little has been written about the impact of nurse prescribing to date. Bradley and Nolan found that prescribing allowed nurses to overcome difficulties in the health-care system which would have previously delayed clients' access to medicines. Prescribing was believed to compliment many aspects of nursing and integrated previously diffuse aspects of the nursing role. Latter and Courtenay found that clients were generally satisfied with nurse prescribing. The aim of this study was to explore the impact mental health nurse prescribing has had on those involved. The views of clients, nurse prescribers, pharmacist prescribers, nurse managers and doctors were investigated. Questionnaires were used to gather demographic data and basic qualitative data. Focus groups and interviews were undertaken with 57 participants. The study was undertaken within one National Health Service Foundation Trust in England. Data analysis was guided by a framework approach. The majority of participants believed that the inclusion of prescribing in mental health nurses' roles improved the nurse-patient relationship, and five themes including the relationship, concordance, power, treatment approach and 'unprescribing' emerged. Trust was highly valued, and clients found nurses easier to talk to about their medication than doctors. Rather than detracting from the nurse-patient relationship, results from this study suggest that nurse prescribing enables mental health nurse prescribers to provide more holistic care than previously. PMID- 26031458 TI - [Diabetes mellitus and cardiovascular risk: Working group recommendations of Diabetes and Cardiovascular Disease of the Spanish Society of Diabetes (SED, 2015)]. AB - The present paper updates the Clinical Practice Recommendations for the management of cardiovascular risk factors (CVRF) in diabetes mellitus. This is a medical consensus agreed by an independent panel of experts from the Spanish Society of Diabetes (SED). Several consensuses have been proposed by scientific and medical Societies to achieve clinical goals. However, the risk score for general population may lack sensitivity for individual assessment or for particular groups at risk, such as diabetics. Traditional risk factors together with non-traditional factors are reviewed throughout this paper. Intervention strategies for managing CVRF in the diabetic patient are reviewed in detail: balanced food intake, weight reduction, physical exercise, smoking cessation, reduction in HbA1c, therapy for high blood pressure, obesity, lipid disorders, and platelet anti-aggregation. It is hoped that these guidelines can help clinicians in the decisions of their clinical activity. This regular update by the SED Cardiovascular Disease Group of the most relevant concepts, and of greater practical and realistic clinical interest, is presented in order to reduce CVR of diabetics. PMID- 26031459 TI - Design of clinical trials with failure-time endpoints and interim analyses: An update after fifteen years. AB - Time to event is the clinically definitive endpoint in Phase III trials of new treatments of cancer, cardiovascular and many other diseases. Because these trials involve relatively long follow-up, their protocols usually incorporate periodic interim analyses of the data by a Data and Safety Monitoring Board/Committee. This paper gives a review of the major developments in the design of these trials in the 21st century, spurred by the need for better clinical trial designs to cope with the remarkable advances in cancer biology, genomics and imaging that can help predict patients' sensitivity or resistance to certain treatments. In addition to this overview and discussion of related issues and challenges, we also introduce a new approach to address some of these issues. PMID- 26031460 TI - Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans. AB - MLN3897 is a small molecule antagonist of the C-C chemokine receptor-1. Since preclinical studies showed that the molecule was metabolized into two halves, the metabolism, excretion, and pharmacokinetics of MLN3897 were investigated in humans using MLN3897 14C-radiolabeled either on the chlorophenyl (CP) or the tricyclic (TC) half of MLN3897 after an oral dose. OBJECTIVE: To evaluate the mass balance, metabolism and pharmacokinetics of MLN3897 in two cohorts of six randomized healthy subjects. METHOD: After receiving informed consent, subjects were dosed after an overnight fast of 10-hours followed by at least 4- hours after dosing on day-1. Each cohort received a single 29 mg oral dose of either the CP or the TC as an oral solution in water. Serial blood samples, urine and feces were collected over a 10-day period post-dose. RESULTS: For both radiolabeled moieties, 55-59% of the dose was recovered in feces and 32% recovered in urine. MLN3897 was metabolized extensively in humans, with minor amounts of intact MLN3897 detected in the urine and feces. N-oxidation of the tricyclic moiety (M28) and N-dealkylation of the piperidinyl moiety were the primary metabolic pathways leading to further formation of the carboxylic acid metabolite (M19) and the (4-(4-chlorophenyl)-3,3- dimethylpiperidin-4-ol) metabolite (M40). Oxidative metabolites M11, M19, M28, M44 were present at >10% of the total circulating radioactivity and also at >25% of MLN3897 exposure. Metabolites resulting from the chlorophenyl-labeled moiety (M40) had significantly more systemic exposure compared to the tricyclic-labeled moiety (M19). PMID- 26031461 TI - Non-Clinical Disposition and Metabolism of DM1, a Component of Trastuzumab Emtansine (T-DM1), in Sprague Dawley Rats. AB - DM1, a derivative of maytansine, is the cytotoxic component of the antibody-drug conjugate trastuzumab emtansine (T-DM1). Understanding the disposition and metabolism of DM1 would help to assess (1) any tissue-specific distribution and risk for potential drug-drug interactions and (2) the need for special patient population studies. To this end, the current study determined the disposition and metabolism of DM1 following single intravenous administration of [(3)H]-DM1 in Sprague Dawley rats. Blood, tissues, urine, bile, and feces were collected up to 5 days after dose administration and analyzed for total radioactivity and metabolites. Results showed that radioactivity cleared rapidly from the blood and quickly distributed to the lungs, liver, kidneys, spleen, heart, gastrointestinal tract, adrenal glands, and other tissues without significant accumulation or persistence. The majority of dosed radioactivity was recovered in feces (~100% of the injected dose over 5 days) with biliary elimination being the predominant route (~46% of the injected dose over 3 days). Excretion in urine was minimal (~5% of the injected dose over 5 days). Mass balance was achieved over 5 days. An analysis of bile samples revealed a small fraction of intact DM1 and a predominance of DM1 metabolites formed through oxidation, hydrolysis, S methylation, and glutathione and its related conjugates. Collectively, these data demonstrate that DM1 is extensively distributed and quickly cleared from blood, and undergoes extensive metabolism to form multiple metabolites, which are mainly eliminated through the hepatic-biliary route, suggesting that hepatic function (but not renal function) plays an important role in DM1 elimination. PMID- 26031462 TI - Predicting Pediatric Drug Disposition-Present and Future Directions of Pediatric Physiologically-Based Pharmacokinetics. AB - This mini-review examines the current state of pediatric physiologically-based pharmacokinetic (PBPK) modeling, including methodologies, approaches, and recent developments. Also discussed are United States regulations that have helped to shape the pediatric PBPK landscape and the ongoing urgent need for pediatric clinical studies. Finally, current pediatric PBPK software as well as the areas of focus for future studies will be reviewed. PMID- 26031463 TI - Ontogeny of Human Conjugating Enzymes. AB - Understanding the detailed ontogeny of xenobiotic metabolizing enzymes is important if we are to be able to predict the risk of toxicity to the developing fetus or the fate of drugs in neonates and children. This review summarizes current knowledge of the development of the major families of conjugating enzymes in humans: the UDP-glucuronosyltransferases, sulfotransferases, glutathione S transferases, arylamine N-acetyltransferases and methyltransferases; little is known of the last three. Based on the available information, sulfation appears to be the most highly developed pathway during fetal development where glucuronidation in particular is lacking. Following birth, glucuronidation capacity develops rapidly and for many of the enzymes adult capacity occurs in mid-late childhood. The importance of developing pharmacokinetic and physiology based pharmacokinetic models to support the more informed use of drugs in children is highlighted. PMID- 26031464 TI - Upregulation of Leucine Zipper Protein mRNA in Hepatocellular Carcinoma Associated With Poor Prognosis. AB - BACKGROUND: Leucine zipper protein (LUZP) plays key roles in development. Overexpression of LUZP was documented in several types of solid tumors. In this study, expression of LUZP messenger RNA (LUZP mRNA) in human hepatocellular carcinoma (HCC) was examined, and the correlations of LUZP mRNA level with patients' characteristics and prognosis were also investigated. METHODS: Total RNA was extracted from HCC and paired noncancerous liver tissues of 77 patients. Expression of LUZP mRNA in the tissues was determined by real-time quantitative reverse transcriptase polymerase chain reaction. Using average LUZP mRNA level in noncancerous liver tissues as the cutoff, patients with HCC were categorized into high-expression group and low-expression group. Correlations of LUZP mRNA with clinical parameters were analyzed. Overall survival of the patients in the 2 groups was analyzed by Kaplan-Meier method. RESULTS: The LUZP mRNA level was significantly higher in HCC samples than in the noncancerous liver tissues (1.87 +/- 0.11 vs 0.58 +/- 0.05, P < .01). Significant differences were found between the 2 groups in terms of portal vein invasion, Tumor Lymph Node Metastasis (TNM) stage, and recurrence of HCC. The current study failed to find significant differences between the 2 groups in clinical characteristics such as age, gender, lymph node metastasis, hepatitis B virus infection, family HCC history, and alcohol intake. Overall survival in high-expression group was 12 months while that in the low-expression group was 34 months (P = .03). CONCLUSION: The LUZP mRNA is a prognostic indicator in HCC, and overexpression is associated with poor prognosis in patients with HCC. PMID- 26031465 TI - Insights into the evolutionary trajectories of fluoroquinolone resistance in Streptococcus pneumoniae. AB - OBJECTIVES: Fluoroquinolone resistance in Streptococcus pneumoniae typically arises through specific site mutations, but dynamic variation of mutations in the resistance evolution and interaction among these mutations have not been clearly demonstrated. The objectives of this study were to investigate the dynamics of allele frequency in populations evolved under fluoroquinolone pressure and pervasive interactions among mutations present in the evolutionary trajectories. METHODS: Thirty-three evolved populations were obtained by serial passages in the presence of antibiotic pressure and these populations were sequenced by using the Paired-End Illumina method. Mutants that occurred in the evolutionary trajectories were constructed by transforming the parental strain with PCR fragments containing corresponding mutations. RESULTS: The number of target mutations increased progressively, consistent with phenotypic adaptation to moxifloxacin and levofloxacin. However, more mutations are required for high level resistance to moxifloxacin than levofloxacin. Pervasive interactions, including positive epistasis between mutations, play a role in the evolutionary trajectories of resistance to the two drugs. Two mutations (R447C and P454S) in gyrB were identified to confer 2-fold increases in resistance to moxifloxacin and levofloxacin based on the background of the double mutant S81F/S79F in parC. Moreover, the dynamics of allele frequency in evolved populations was revealed and found to be directly correlated with the resistance levels of evolved populations. Clonal interference among alleles of mutations contributed to the molecular dynamics of resistance evolution. CONCLUSIONS: Our results provide novel insights into the evolutionary trajectories of resistance to fluoroquinolones and may serve as a theoretical basis for predicting resistance development and provide references for the clinical use of these drugs. PMID- 26031466 TI - Multiple hospital outbreaks of vanA Enterococcus faecium in Denmark, 2012-13, investigated by WGS, MLST and PFGE. AB - OBJECTIVES: In Denmark, the incidence of vancomycin-resistant Enterococcus faecium (VREfm) has increased since 2012. The aim of this study was to investigate the epidemiology and clonal relatedness of VREfm isolates in Danish hospitals in 2012-13 using WGS. The second aim was to evaluate if WGS-based typing could replace PFGE for typing of VREfm. METHODS: A population-based study was conducted including all VREfm isolates submitted for national surveillance from January 2012 to April 2013. All isolates were investigated by WGS, MLST and PFGE. RESULTS: One-hundred and thirty-two isolates were included. The majority of the isolates were from clinical samples (77%). Gastroenterology/abdominal surgery (29%) and ICUs (29%) were the predominant departments with VREfm. Genomics revealed a polyclonal structure of the VREfm outbreak. Seven subgroups of 3-44 genetically closely related isolates (separated by <17 SNPs) were identified using WGS. Direct or indirect transmission of VREfm between patients and intra- and inter-regional spreading clones was observed. We identified 10 STs. PFGE identified four major clusters (13-43 isolates) and seven minor clusters (two to three isolates). The results from the typing methods were highly concordant. However, WGS-based typing had the highest discriminatory power. CONCLUSIONS: This study emphasizes the importance of infection control measures to limit transmission of VREfm between patients. However, the diversity of the VREfm isolates points to the fact that other important factors may also affect the VREfm increase in Denmark. Finally, WGS is suitable for typing of VREfm and has replaced PFGE for typing of VREfm in Denmark. PMID- 26031468 TI - Is this a clinical trial? And should it be registered? PMID- 26031469 TI - Clijsen R, Fuchs J, Taeymans J. Effectiveness of exercise therapy in treatment of patients with patellofemoral pain syndrome: systematic review and meta-analysis. Phys Ther. 2014;94:1697-1708. PMID- 26031470 TI - A PCR-based method to quantify fungal growth during pretreatment of lignocellulosic biomass. AB - Filamentous fungi have shown great potential in the pretreatment of lignocellulosic biomass and their use in bio-processes based on Solid State Fermentation (SSF) opens promising perspectives for plant biomass valorization. Obviously, quantification of the fungal biomass throughout the fermentation is a crucial parameter for SSF evaluation and control, both at the laboratory and industrial scale. Here we provide a qPCR-based method as a reliable alternative to conventional methods to estimate mycelial growth during plant biomass treatment. For the three strains analyzed, the lowest detection limit ranged from 58 to 272 MUg mycelium dry weight per gram biomass (dry weight). We show that the qPCR-based method allows fungal growth monitoring during fermentation and provides relevant information for selection of the most appropriate fungal strains in specific SSF/reactor conditions. PMID- 26031471 TI - Atomic force microscopy and cells: Indentation profiles around the AFM tip, cell shape changes, and other examples of experimental factors affecting modeling. AB - We use atomic force microscopy in conjunction with a fluorescence microscope capable of optical sectioning to acquire images of white blood cells while force is applied with the AFM tip. The indentation profile within the cell is compared to the profile of the AFM tip: examples are shown for indentations at the center of the cell which are reasonable matches to the tip profile, and an additional example is shown for an indentation that is on the tilted side of a highly rounded cell and that differs from the tip shape. We also demonstrate that the AFM tip can interact with internal cell structures, we show that the contact area between the cell and the substrate can increase under applied pressure, that the main body of the cell can fuse with the extended lamellipodium, and that the cell can be displaced laterally by the AFM tip. The features illustrated here are relevant to the interpretation of indentation experiments that measure cell elasticity properties, as is discussed briefly. PMID- 26031472 TI - Modified olfactory training in patients with postinfectious olfactory loss. AB - OBJECTIVES/HYPOTHESIS: Patients with olfactory dysfunction benefit from repeated exposure to odors, so-called olfactory training (OT). This does not mean occasional smelling but the structured sniffing of a defined set of odors, twice daily, for a period of 4 months or longer. In this prospective study, we investigated whether the effect of OT might increase through the use of more odors and extension of the training period. STUDY DESIGN AND METHODS: This study shows OT results when performed with four or 12 odors for 36 weeks in patients with postinfectious olfactory dysfunction. A total of 85 subjects participated (mean age 45.6 +/- 10.5 years, range 24-68 years). Three groups were formed: 1) In the modified olfactory training (MOT) group, patients used three sets of four different odors sequentially. 2) Participants in the classical odor training (COT) group used four odors. 3) Participants in the control group did not perform OT. All groups were matched for age and sex distribution of participants. RESULTS: Both participants in the COT and MOT groups reached better scores than controls in terms of odor discrimination and odor identification. Continuing OT with four different odors after the 12th and 24th weeks produced better results in terms of odor discrimination and odor identification scores as compared to using the same four odors throughout the entire study. CONCLUSION: This study confirmed the effectiveness of OT. Increasing the duration of OT and changing the odors enhances the success rate of this therapy. LEVEL OF EVIDENCE: 2b. Laryngoscope, 125:1763-1766, 2015. PMID- 26031473 TI - Plants, people and traditions: ethnobotanical survey in the Lombard Stelvio National Park and neighbouring areas (Central Alps, Italy). AB - ETHNOPHARMACOLOGICAL RELEVANCE: The value of ethnobotanical information is now increasingly acknowledged. Our investigation added new data to the traditional knowledge on the plant uses in Italian alpine areas, where only in recent years the awareness of losing such valuable heritage stimulated interest of the scientific community and land managers in its recovery and enhancement. To this end, the present study aimed to collect and analyse information on plant species employed in Northern Italy (Lombardy Region), particularly in Alta Valtellina, an area of high naturalistic interest, where ethnobotanical knowledge is at the risk of passing covering a secondary role compared to other aspects of the local culture. MATERIALS AND METHODS: A total of 328 people from six municipalities were interviewed using semi-structured questionnaires. Data were evaluated by quantitative parameters such as ethnobotanicity and ethnophytonomic indices, factor informant consensus (Fic), fidelity level (Fl). Abandoned and current uses were compared. Herbarium materials were prepared and conserved. RESULTS: Inhabitants of Alta Valtellina used 212 plant species, including 19 mushrooms and 1 lichen for medicinal, food and cosmetic purposes. Despite half of medicinal uses has fallen into disuse, the plant species of this category were still collected in largest number. Digestive, respiratory and skin systems were the most frequently treated. Fic and Fl values, in addition to simple percentage data confirmed this finding. Although 40% of the known uses is now abandoned, a considerable number of them was recorded for the first time in an alpine area. CONCLUSIONS: The study revealed that the popular knowledge of plant species is still alive in the Alta Valtellina. The prerogatives of some species are now outdated, but they leave room for other uses of the plant resources that may provide new opportunities from the scientific, cultural and economic points of view. PMID- 26031474 TI - Serum levels of nitric oxide and protein oxidation in goats seropositive for Toxoplasma gondii and Neospora caninum. AB - The aim of this study was to assess and analyze the levels of nitric oxide (NO) and advanced oxidation protein products (AOPP) in serum of goats naturally infected by Toxoplasma gondii, Neospora caninum, or concomitantly infected by these two parasites. Thus, it was measured NOx and AOPP levels in twenty (n=20) sera samples of goats seronegative for T. gondii and N. caninum [negative control group (A)]; while the positive groups were composed by sera of infected animals, twelve (n=12) seropositive for N. caninum [group B]; eighteen (n=18) positive for T. gondii [group C]; and thirteen (n=13) seropositive for N. caninum and T. gondii [group D]. As results, it was observed that animals seropositive for N. caninum and T. gondii (Groups B to D) showed higher serum levels of NOx (P<0.001; F=9.5), when compared with seronegative animals. Additionally, it was observed a positive correlation between NOx levels and antibodies titrations for N. caninum (P<0.01; r=0.68) and T. gondii (P<0.05; r=0.56). AOPP levels were increase in groups C and D (P>0.05). Interestingly, group B did not show increase in AOPP, what led us to hypothesize that the major protein damage is linked to T. gondii infection. Therefore, our results showed an increased in NOx levels, which was probably related to the immune response, since it is an important inflammatory mediator; and AOPP were increased in groups where there was seropositivity for T. gondii, but not for the group composed only by animals seropositive for N. caninum, allowing us to suggest higher protein damage in toxoplasmosis. PMID- 26031475 TI - Descriptions and presentations of sepsis - A qualitative content analysis of emergency calls. AB - BACKGROUND: Sepsis is a serious condition which requires early treatment. We often fail to recognize sepsis patients in the chain of prehospital care. Knowledge of how sepsis is expressed in calls to the emergency medical communication centre (EMCC) is limited. An increased understanding could lead to earlier identification of patients with sepsis. OBJECTIVE: The aim of this study was to describe the descriptions of sepsis used during communication between the caller and the emergency medical dispatcher (EMD). METHODS: To achieve the aim of the study, an inductive approach of qualitative content analysis was used. In total, 29 consecutive patients, who arrived at the emergency department by ambulance and received a diagnosis of sepsis according to the International Classification of Diseases (ICD)-10, were included in the study. For each case, the corresponding emergency call recording from the EMCC was transcribed verbatim. Main categories and subcategories from the text were abstracted. RESULTS: From fifteen subcategories, three main categories were abstracted: "Deterioration", "Physical signs and symptoms" and "Difficulties establishing satisfactory contact with the patient." The way laymen and professionals expressed themselves seemed to differ. CONCLUSIONS: Sepsis was described in terms of the physical symptoms, changes of condition and communication abilities of the patient. This knowledge could lead to the identification of keywords which could be incorporated in the decision tool used by the EMD to increase sepsis identification, but further research is required. PMID- 26031476 TI - Sunlight-Driven Decarboxylative Alkynylation of alpha-Keto Acids with Bromoacetylenes by Hypervalent Iodine Reagent Catalysis: A Facile Approach to Ynones. AB - A novel and practical decarboxylative alkynylation of alpha-keto acids with bromoacetylenes is catalyzed by hypervalent iodine(III) reagents when irradiation by sunlight at room temperature. The product ynones are generated in good yields. Experiments show that results obtained with blue light (lambda=450-455 nm) are comparable to those obtained when using sunlight. Mechanistic studies demonstrate that the sunlight-driven decarboxylation undergoes a radical process. PMID- 26031477 TI - Unpredictable environments, opportunistic responses: Reproduction and population turnover in two wild mouse lemur species (Microcebus rufus and M. griseorufus) from eastern and western Madagascar. AB - Small-bodied, nocturnal mouse lemurs (Microcebus) are widespread across diverse forest habitats in Madagascar. They are strict seasonal breeders and can, depending on the habitat and species, undergo daily or prolonged torpor to minimize energy expenditure during periods of food and water scarcity. Duration of reproduction, number of litters per season and timing of births vary across individuals and species. The "polyestry-seasonality" hypothesis proposes that the duration of reproduction and number of litters per year are positively correlated with rainfall but negatively correlated with longevity, whereas the "hypervariability" hypothesis suggests that the duration of reproduction is negatively correlated with the degree of predictability of food resources. We test these hypotheses in two mouse lemur species inhabiting contrasting habitats, the brown mouse lemurs, Microcebus rufus, from Ranomafana (a less seasonal and more climatically predictable habitat) and the gray-brown mouse lemurs, M. griseorufus, from Beza Mahafaly (a more seasonal and less climatically predictable environment). We use capture/mark/recapture techniques and records of female reproductive status. We found evidence of polyestry at both study sites but faster population turnover and longer duration of the reproductive season at Beza Mahafaly. The "polyestry-seasonality" hypothesis is not supported but the "hypervariability" hypothesis could not be rejected. We conclude that reproductive output cannot be tied to climatic factors in a simple manner. Paradoxically, polyestry can be expressed in contrasting habitats: less seasonal forests where females can sustain multiple reproductive events, but also highly seasonal environments where females may not fatten sufficiently to sustain prolonged torpor but instead remain active throughout the year by relying on fallback resources. Am. J. Primatol. 77:936-947, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26031478 TI - Tungiasis Outbreak in Travelers From Madagascar. AB - Seven patients from a group of 16 travelers were diagnosed at our institution with one or more sand fleas on their toes, 1 day to 3 weeks after returning from Madagascar. A questionnaire was sent to the whole group to collect clinical and epidemiological information, which showed that 9 of 13 (69%) had received pre travel medical advice, but none were aware of sand flea; thus prevention measures were rarely applied. Five of seven (71%) patients wore open sandals throughout the trip. Overall, 10 sand fleas were extracted. PMID- 26031479 TI - Putative classification of clades of enterohemorrhagic Escherichia coli O157 using an IS-printing system. AB - Enterohemorrhagic Escherichia coli O157 (O157) strains can be classified in clades by single nucleotide polymorphisms (SNPs), but this analysis requires significant laboratory effort. As the distribution of insertion sequence (IS) 629 insertions has been reported to be biased among different clades, O157 isolates can be putatively classified in clades by comparison with an IS629 distribution database. A database of the IS629 distribution in O157 strains isolated in Chiba Prefecture and their classification in clades was determined by SNP analysis and IS-printing, an easy and quick analytical tool for IS629 in the O157 genome. The IS629 distribution in O157 strains isolated in Fukuoka and Yamagata Prefectures was determined by IS-printing. These strains were putatively classified in clades by Relative Likelihood calculations that compared the IS-printing data and the IS629 distribution database. Concordance Ratios were calculated, which compared the number of strains putatively classified in a clade by Relative Likelihood to the number of strains classified in that clade by SNP analysis. For the Fukuoka and Yamagata strains, the Concordance Ratios for clades 3, 6 and 8 were 97-100%, for clade 7 about 88%, and for clades 2 and 12 over 90%. In conclusion, O157 clade 2, 3, 6, 7, 8 and 12 strains could be putatively classified by IS-printing. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated that enterohemorrhagic E. coli O157 (O157) strains could be putatively classified in clades using an IS-printing system. IS-printing was previously developed as a relatively quick and easy tool for analysis of insertion sequence 629 in the O157 genome. Since most local government public health institutes in Japan carry out IS-printing for early detection of O157 outbreaks, these data should be useful for putative classification of O157 strains in each area. PMID- 26031480 TI - Technetium-99 m labeling and evaluation of olsalazine: a novel agent for ulcerative colitis imaging. AB - Ulcerative colitis is a chronic disease having a regressive nature. Commonly used diagnostic methods have the disadvantage to be invasive, time-consuming, and expensive. Therefore, a new sensitive method for the detection and monitoring of disease activity is urgently needed in clinical practice. In the current investigation, radio complexation of olsalazine with technetium-99m, its characterization, and optimization of the labeling conditions were explored. Optimum radiochemical yield of (99m) Tc-olsalazine (97.6% +/- 1.8%) was obtained via direct complexation with technetium-99m (~200 MBq) in the presence of stannous chloride dihydrate (100 ug) as reducing agent at pH 6. It was observed that the complex showed significant in vitro stability in serum at 37 degrees C for more than 11 h. The computer-generated optimized geometries of the (99m) Tc olsalazine were reported, and biodistribution studies were carried out using chemically and microbiologically mice-induced ulcerative colitis models. The tracer showed a good localization in both models and was excreted mainly via liver and to some extent via kidney. Imaging can be performed at 1-2 h post injection; at that time, the background activity has cleared, and the activity is concentrated in the target site. All the gathered biological data supported the usefulness of (99m) Tc-olsalazine as a potential imaging agent for ulcerative colitis. PMID- 26031481 TI - LC-MS untargeted metabolomic analysis of drug-induced hepatotoxicity in HepG2 cells. AB - Hepatotoxicity is the number one cause for agencies not approving and withdrawing drugs for the market. Drug-induced human hepatotoxicity frequently goes undetected in preclinical safety evaluations using animal models. Human-derived in vitro models represent a common alternative to in vivo tests to detect toxic effects during preclinical testing. Most current in vitro toxicity assays rely on the measurement of nonspecific or low sensitive endpoints, which result in poor concordance with human liver toxicity. Therefore, making more accurate predictions of the potential hepatotoxicity of new drugs remains a challenge. Metabolomics, whose aim is to globally assess all the metabolites present in a biological sample, may represent an alternative in the search for sensitive sublethal markers of drug-induced hepatotoxicity. To this end, a comprehensive LC MS-based untargeted metabolite profiling analysis of HepG2 cells, exposed to a set of well-described model hepatotoxins and innocuous compounds, was performed. It allowed to determine meaningful metabolic changes triggered by a toxic insult and gave a first estimation of the main toxicity-related pathways. Based on these metabolic patterns, a partial least squares-discriminant analysis model, able to discriminate between nontoxic and hepatotoxic compounds, was constructed. The approach described herein may provide an alternative for animal testing in preclinical stages of drug development and a controlled experimental approach to gain a better understanding of the underlying causes of hepatotoxicity. PMID- 26031482 TI - Hamstrings functional properties in athletes with high musculo-skeletal flexibility. AB - The purpose of this study was to examine whether athletes with highly flexible hamstring muscle-tendon units display different passive and contractile mechanical properties compared with controls. Flexibility, passive, and active torque-angle properties were assessed in 21 female elite rhythmic gymnasts and 16 female age-matched athletes. Passive resistance to stretch was measured during knee extension with the hip fixed at 100 degrees of flexion. Concentric isokinetic maximal voluntary knee flexion and extension torques were measured at 60 degrees /s in the same position. Tests of flexibility and passive resistance to stretch indicated a greater flexibility in the gymnasts. Despite no differences between groups in knee flexion and extension peak torque, gymnasts reached knee flexion peak torque at more extended positions (longer muscle lengths) and displayed significantly different torque-angle relations. When active torque was corrected for passive resistance to stretch, differences increased, gymnasts producing more work, and maintaining >= 70% of peak torque over a larger range of joint excursion. In conclusion, individuals with a higher flexibility of the hamstrings MTU present a different torque-angle profile, favoring the production of flexion torque toward extended knee positions, displaying larger functional range of motion and a higher mechanical work output during knee flexion. PMID- 26031483 TI - Spatially Controlled Out-of-Equilibrium Host-Guest System under Electrochemical Control. AB - Self-assembly to create molecular and nanostructures is typically performed at the thermodynamic minimum. To achieve dynamic functionalities, such as adaptability, internal feedback, and self-replication, there is a growing focus on out-of-equilibrium systems. This report presents the dynamic self-assembly of an artificial host-guest system at an interface, under control by a dissipative electrochemical process using (electrical) energy, resulting in an out-of equilibrium system exhibiting a supramolecular surface gradient. The gradient, its steepness, rate of formation, and complex surface composition after backfilling, as well as the surface compositions after switching between the different states of the system, are assessed and supported by modelling. Our method shows for the first time an artificial surface-confined out-of-equilibrium system. The electrochemical process parameters provide not only control over the system in time, but also in space. PMID- 26031484 TI - Insulin pump therapy before conception improves metabolic control in early pregnancy in women with type 1 diabetes. PMID- 26031485 TI - Management of gastronenteropancreatic neuroendocrine neoplasms: an ongoing challenge. PMID- 26031486 TI - Assessing the risk to green sturgeon from application of imidacloprid to control burrowing shrimp in Willapa Bay, Washington-Part I: exposure characterization. AB - Willapa Bay and Grays Harbor (WA, USA) comprise the largest region of commercial oyster cultivation on the Pacific Coast. The activities of 2 species of burrowing shrimp impair growth and survival of oysters reared on the intertidal mudflats. To maintain viable harvests, the oyster growers have proposed controlling the shrimp by applying the insecticide imidacloprid onto harvested beds. Green sturgeon (listed in the Endangered Species Act) forage on burrowing shrimp and could be exposed to imidacloprid in the sediment porewater and through consumed prey. Studies were conducted to evaluate the likelihood that green sturgeon would be exposed to imidacloprid and to characterize the subsequent environmental exposure. Comparisons between treated and untreated control beds following test application of the insecticide suggested that green sturgeon fed opportunistically on imidacloprid-impaired shrimp. The highest interpolated imidacloprid residue concentrations in field samples following chemical application were 27.8 ug kg(-1) and 31.4 ug kg(-1) in porewater and shrimp, respectively. Results from modeled branchial and dietary uptake, based on conservative assumptions, indicated that the porewater exposure route had the greatest contribution to systemic absorption of imidacloprid. The highest average daily uptake from porewater (177.9 ug kg(-1) body wt) was 9.5-fold greater than total dietary uptake (18.8 ug kg(-1) body wt). Concentrations and durations of exposure would be lower than the levels expected to elicit direct acute or chronic toxic effects. PMID- 26031487 TI - Eliminating mirror responses by instructions. AB - The observation of an action leads to the activation of the corresponding motor plan in the observer. This phenomenon of motor resonance has an important role in social interaction, promoting imitation, learning and action understanding. However, mirror responses not always have a positive impact on our behavior. An automatic tendency to imitate others can introduce interference in action execution and non-imitative or opposite responses have an advantage in some contexts. Previous studies suggest that mirror tendencies can be suppressed after extensive practice or in complementary joint action situations revealing that mirror responses are more flexible than previously thought. The aim of the present study was to gain insight into the mechanisms that allow response flexibility of motor mirroring. Here we show that the mere instruction of a counter-imitative mapping changes mirror responses as indexed by motor evoked potentials (MEPs) enhancement induced by transcranial magnetic stimulation (TMS). Importantly, mirror activation was measured while participants were passively watching finger movements, without having the opportunity to execute the task. This result suggests that the implementation of task instructions activates stimulus-response association that can overwrite the mirror representations. Our outcome reveals one of the crucial mechanisms that might allow flexible adjustments of mirror responses in different contexts. The implications of this outcome are discussed. PMID- 26031488 TI - Draft genome sequence of Parvularcula oceani JLT2013(T), a rhodopsin-containing bacterium isolated from deep-sea water of the Southeastern Pacific. AB - Parvularcula oceani JLT2013(T) is a novel member of the genus Parvularcula within the order 'Parvularculales'. Here, we present the draft genome sequence of a deep sea bacterium P. oceani JLT2013(T). The genome comprises 3,354,504bp with a G+C content of 67.44% and includes 3141 protein-coding genes and 42 tRNA genes. The genome contains three genes encoding rhodopsin protein. PMID- 26031489 TI - Editorial: NFAT signaling: no FAT as new weapon to fight shock. PMID- 26031490 TI - Editorial: CCR7 is required for leukocyte egression in an experimental model of Crohn's disease-like ileitis. PMID- 26031491 TI - Comparison of quality of facial scars after single low-level laser therapy and combined low-level with high-level (PDL 595 nm) laser therapy. AB - The main goal of our study was to compare the quality of resulting facials scar 12 weeks after single and combined laser therapy. Forty-one children from age 1.5 to 5 years with facial scars after injury participated in the study. Thirty-one underwent laser therapy, 14 were treated using single low-level laser therapy (670 nm, fluence 3-5 J/cm(-2) ), and 17 underwent combined high-level laser therapy with non-ablative pulsed dye laser (PDL; 595 nm, spot size 7 mm, delay 0.45 ms or 1.5 ms, fluence 9-11 J/cm(-2) , cryogen spray/delay 20/30 ms) and low level laser therapy. The control group consisted of 10 untreated children. Before treatment and at week 4, 8, and, 12 the scars were evaluated using the POSAS questionnaire. A statistically significant improvement in scars (between ratings before treatment and 4 weeks after therapy, before treatment and 8 weeks after therapy and before treatment and 12 weeks after therapy) was observed in all parameters in both treatment groups (p < 0.0001). For the HLLT+LLLT group the most significant enhancement in the quality of scars was found for all items and at all evaluations, except pigmentation and pliability. There was no improvement observed in quality of facial scars in the control group. PMID- 26031492 TI - Catalytic Conia-ene and related reactions. AB - Since its initial inception, the Conia-ene reaction, known as the intramolecular addition of enols to alkynes or alkenes, has experienced a tremendous development and appealing catalytic protocols have emerged. This review fathoms the underlying mechanistic principles rationalizing how substrate design, substrate activation, and the nature of the catalyst work hand in hand for the efficient synthesis of carbocycles and heterocycles at mild reaction conditions. Nowadays, Conia-ene reactions can be found as part of tandem reactions, and the road for asymmetric versions has already been paved. Based on their broad applicability, Conia-ene reactions have turned into a highly appreciated synthetic tool with impressive examples in natural product synthesis reported in recent years. PMID- 26031493 TI - MicroRNA as Biomarkers and Diagnostics. AB - MicroRNAs (miRNAs) are a group of small non-coding RNAs that are involved in regulating a range of developmental and physiological processes; their dysregulation has been associated with development of diseases including cancer. Circulating miRNAs and exosomal miRNAs have also been proposed as being useful in diagnostics as biomarkers for diseases and different types of cancer. In this review, miRNAs are discussed as biomarkers for cancer and other diseases, including viral infections, nervous system disorders, cardiovascular disorders, and diabetes. We summarize some of the clinical evidence for the use of miRNAs as biomarkers in diagnostics and provide some general perspectives on their use in clinical situations. The analytical challenges in using miRNAs in cancer and disease diagnostics are evaluated and discussed. Validation of specific miRNA signatures as biomarkers is a critical milestone in diagnostics. PMID- 26031494 TI - Review: Morphofunctional and biochemical markers of stress in sea urchin life stages exposed to engineered nanoparticles. AB - We describe the use of different life stages of the Mediterranean sea urchin Paracentrotus lividus for the assessment of the possible risk posed by nanoparticles (NPs) in the coastal water. A first screening for the presence of NPs in sea water may be obtained by checking their presence inside tissues of organisms taken from the wild. The ability of NPs to pass from gut to the coelomic fluid is demonstrated by accumulation in sea urchin coelomocytes; the toxicity on sperms can be measured by embryotoxicity markers after sperm exposure, whereas the transfer through the food chain can be observed by developmental anomalies in larvae fed with microalgae exposed to NPs. The most used spermiotoxicity and embryotoxicity tests are described, as well as the biochemical and histochemical analyses of cholinesterase (ChE) activities, which are used to verify toxicity parameters such as inflammation, neurotoxicity, and interference in cell-to-cell communication. Morphological markers of toxicity, in particular skeletal anomalies, are described and classified. In addition, NPs may impair viability of the immune cells of adult specimens. Molecular similarity between echinoderm and human immune cells is shown and discussed. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1552-1562, 2016. PMID- 26031495 TI - Approaches to measuring ejection fraction: Many tools, but how to decide which one? PMID- 26031496 TI - Analysis of the 17-segment left ventricle model using generalized estimating equations. PMID- 26031497 TI - Kimura disease associated with severe visual dysfunction due to remarkable periorbital involvement. PMID- 26031498 TI - Workings of the human spirit in palliative care situations: a consensus model from the Chaplaincy Research Consortium. AB - BACKGROUND: Chaplaincy is a relatively new discipline in medicine that provides for care of the human spirit in healthcare contexts for people of all worldviews. Studies indicate wide appreciation for its importance, yet empirical research is limited. Our purpose is to create a model of human spiritual processes and needs in palliative care situations so that researchers can locate their hypotheses in a common model which will evolve with relevant findings. METHODS: The Model Building Subgroup worked with the Chaplaincy Research Consortium as part of a larger Templeton Foundation funded project to enhance research in the area. It met with members for an hour on three successive occasions over three years and exchanged drafts for open comment between meetings. All members of the Subgroup agreed on the final draft. RESULTS: The model uses modestly adapted existing definitions and models. It describes the human experience of spirituality during serious illness in three renditions: visual, mathematical, and verbal so that researchers can use whichever is applicable. The visual rendition has four domains: spiritual, psychological, physical and social with process arrows and permeable boundaries between all areas. The mathematical rendition has the same four factors and is rendered as an integral equation, corresponding to an integrative function postulated for the human spirit. In both renditions, the model is notable in its allowance for direct spiritual experience and a domain or factor in its own right, not only experience that is created through the others. The model does not describe anything beyond the human experience. The verbal rendition builds on existing work to describe the processes of the human spirit, relating it to the four domains or factors. CONCLUSIONS: A consensus model of the human spirit to generate hypotheses and evolve based on data has been delineated. Implications of the model for how the human spirit functions and how the chaplain can care for the patient or family caregiver's spiritual coping and well-being are discussed. The next step is to generate researchable hypotheses, results of research from which will give insight into the human spirit and guidance to chaplains caring for it. PMID- 26031499 TI - Background Story of the Invention of Efficient InGaN Blue-Light-Emitting Diodes (Nobel Lecture). PMID- 26031500 TI - Optimizing agent-based transmission models for infectious diseases. AB - BACKGROUND: Infectious disease modeling and computational power have evolved such that large-scale agent-based models (ABMs) have become feasible. However, the increasing hardware complexity requires adapted software designs to achieve the full potential of current high-performance workstations. RESULTS: We have found large performance differences with a discrete-time ABM for close-contact disease transmission due to data locality. Sorting the population according to the social contact clusters reduced simulation time by a factor of two. Data locality and model performance can also be improved by storing person attributes separately instead of using person objects. Next, decreasing the number of operations by sorting people by health status before processing disease transmission has also a large impact on model performance. Depending of the clinical attack rate, target population and computer hardware, the introduction of the sort phase decreased the run time from 26% up to more than 70%. We have investigated the application of parallel programming techniques and found that the speedup is significant but it drops quickly with the number of cores. We observed that the effect of scheduling and workload chunk size is model specific and can make a large difference. CONCLUSIONS: Investment in performance optimization of ABM simulator code can lead to significant run time reductions. The key steps are straightforward: the data structure for the population and sorting people on health status before effecting disease propagation. We believe these conclusions to be valid for a wide range of infectious disease ABMs. We recommend that future studies evaluate the impact of data management, algorithmic procedures and parallelization on model performance. PMID- 26031501 TI - The impact of genomic testing on the recommendation for radiation therapy in patients with ductal carcinoma in situ: A prospective clinical utility assessment of the 12-gene DCIS scoreTM result. AB - BACKGROUND AND OBJECTIVES: Twenty percent of breast cancers are ductal carcinoma in situ (DCIS), with 15-60% having a local recurrence (LR) after surgery. Radiotherapy reduces LR by 50% but has not impacted survival. The validated Oncotype DX((r)) 12-gene assay (DCIS Score) provides individualized 10-year LR estimates. This is the first study to assess whether DCIS Score impacts physicians' recommendations for radiation. METHODS: Ten sites enrolled women (9/2012-2/2014) with DCIS eligible for breast-conserving therapy, excluding patients with invasive carcinoma and planned mastectomy. Prospective data collected included clinicopathologic factors, DCIS Score assay, and treatment recommendation before and after the assay result was known. RESULTS: In 115 patients (median age: 61 years; 74.8% postmenopausal), median DCIS size was 8 mm; 20% were nuclear grade 1, 46.1% grade 2; 64.4% reported necrosis. 86.1% were ER+, 79.1% PR+ (immunohistochemistry assay). Median DCIS Score: 29 (range: 0-85). Pre assay, 73% (95%CI: 64.0-80.9%) had radiotherapy recommendations vs. 59.1% (95%CI: 49.6-68.2%) post-assay (P= 0.008). Physicians rated DCIS Score as the most impactful factor in planning treatment. CONCLUSIONS: The radiotherapy recommendation changed from pre-assay to post-assay 31.3% (95%CI: 23.0-40.6%) of the time--a clinically significant change. This study supports the clinical utility of the DCIS Score and indicates that the test provides additional, individualized information on LR risk. PMID- 26031502 TI - New mutation leading to the full variety of typical features of the Netherton syndrome. PMID- 26031503 TI - A purely synthetic and biodegradable material for repair of cerebrospinal fluid rhinorrhoea. PMID- 26031504 TI - Trajectories of maternal sleep problems before and after childbirth: a longitudinal population-based study. AB - BACKGROUND: Sleep problems are common during pregnancy and in the postnatal period, but there is still a lack of longitudinal population-based studies assessing the quantity and quality of sleep in these women. The aim of the current study was to examine the natural development and stability of insomnia and short sleep duration in women from pregnancy to two years postpartum. METHODS: This was a longitudinal cohort study (the Akershus Birth Cohort Study) of 1480 healthy women, who completed three comprehensive health surveys, at week 32 of pregnancy, week 8 postpartum and year 2 postpartum. The survey was composed of the following validated questionnaires: the Bergen Insomnia Scale, the Pittsburgh Sleep Quality Index and the Edinburgh Postnatal Depression Scale. Differences in sleep characteristics between the three assessment points were compared using Analyses of Variance with repeated measures, and logistic regression analyses were used to examine the stability of sleep variables. RESULTS: One thousand four hundred and eighty women completed all three surveys, and the mean age at birth was 30.7 (+/-4.9). The prevalence of insomnia remained stable at 60 % at the first two time periods, and remained high at 41 % at year 2 postpartum. The mean sleep duration at the three time periods was 7 h 16 min, 6 h 31 min, and 6 h 52 min, respectively. Concurrent maternal depression could not explain the stability of sleep problems from during and immediately after pregnancy, to sleep problems 2 years postpartum. CONCLUSION: Both insomnia and short sleep duration were found to be very common both before and after pregnancy. PMID- 26031506 TI - Body composition in the Study of Women Entering and in Endocrine Transition (SWEET): A perspective of African women who have a high prevalence of obesity and HIV infection. AB - OBJECTIVES: Little data are available for sub-Saharan African women on changes in body composition in menopause transition (MT). The study aimed to determine whether there are differences in body adiposity, lean muscle mass, and bone mineral density (BMD) across MT groups in urban African women, who have a high prevalence of obesity and HIV infection, and if this is related to an altered hormonal milieu. DESIGN: Participants were 702 black urban women. Menopause stage was defined using STRAW+10 criteria. Levels of follicle stimulating hormone (FSH), estradiol (E2), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone (T) and sex hormone blinding globulin (SHBG) were measured. Body composition was measured with dual-energy X-ray absorptiometry (DXA) and ultrasound scans. RESULTS: Whole body lean mass (p=0.002) and BMD (p<0.0005) were significantly lower in postmenopausal compared to premenopausal groups. Estradiol (p<0.0005), SHBG (p<0.0005) and DHEAS (p=0007) were significantly lower in post- than premenopausal groups, while FSH was higher (p<0.0005). FSH correlated negatively (beta=-2.06, p<0.0005) with total lean mass while E2 correlated positively (beta=20.0, p=0.002) with BMD. Use of antiretroviral therapy (ART) correlated negatively with total fat mass (beta= 2.92, p=0.008) and total bone mineral content (BMC; beta=-78.8, p=0.003). CONCLUSIONS: The MT in this population is characterized by lower whole body lean mass and BMD in post- compared to premenopausal subjects but there are minimal differences in fat mass. Lower lean mass and BMD were associated with higher FSH and lower E2 serum levels, respectively. Use of ART was associated with lower fat mass and BMC. PMID- 26031505 TI - Circulating microRNA-320a and microRNA-486 predict thiazolidinedione response: Moving towards precision health for diabetes prevention. AB - INTRODUCTION: The aims of this study were to compare microRNA (miR) expression between individuals with and without insulin resistance and to determine whether miRs predict response to thiazolidinedione treatment. MATERIALS AND METHODS: In a sample of 93 healthy adults, insulin resistance was defined as steady state plasma glucose (SSPG)>=180 mg/dL and insulin sensitive as <120 mg/dL. Response to thiazolidinedione therapy was defined as >=10% decrease in SSPG. We selected a panel of microRNAs based on prior evidence for a role in insulin or glucose metabolism. Fold change and Wilcoxon rank sum tests were calculated for the 25 miRs measured. RESULTS: At baseline, 81% (n=75) of participants were insulin resistant. Five miRs were differentially expressed between the insulin resistant and sensitive groups: miR-193b (1.45 fold change (FC)), miR-22-3p (1.15 FC), miR 320a (1.36 FC), miR-375 (0.59 FC), and miR-486 (1.21 FC) (all p<0.05). In the subset who were insulin resistant at baseline and received thiazolidinediones (n=47), 77% (n=36) showed improved insulin sensitivity. Six miRs were differentially expressed between responders compared to non-responders: miR-20b 5p (1.20 FC), miR-21-5p, (0.92 FC), miR-214-3p (1.13 FC), miR-22-3p (1.14 FC), miR-320a (0.98 FC), and miR-486-5p (1.25 FC) (all p<0.05). DISCUSSION: This study is the first to report miRs associated with response to a pharmacologic intervention for insulin resistance. MiR-320a and miR-486-5p identified responders to thiazolidinedione therapy among the insulin resistant group. PMID- 26031507 TI - The Effect of Testosterone and Fenofibrate, Administered Alone or in Combination, on Cardiometabolic Risk Factors in Men with Late-Onset Hypogonadism and Atherogenic Dyslipidemia. AB - INTRODUCTION: Oral testosterone was found to reduce plasma levels of HDL cholesterol. No previous study has examined the effect of fibrates, known to increase HDL cholesterol, in patients with low testosterone levels requiring testosterone replacement. AIMS: The study included three age-, weight-, and lipid matched groups of older men with atherogenic dyslipidemia and late-onset hypogonadism, treated with oral testosterone undecanoate (120 mg daily, n = 15), micronized fenofibrate (200 mg daily, n = 15), or testosterone plus fenofibrate (n = 18). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were assessed before and after 16 weeks of therapy. RESULTS: Apart from an increase in plasma testosterone and a reduction in HDL cholesterol, testosterone undecanoate tended to decrease hsCRP and to improve insulin sensitivity. Fenofibrate administered alone increased HDL cholesterol, reduced triglycerides, decreased insulin resistance, reduced circulating levels of uric acid, hsCRP, and fibrinogen, as well as increased plasma levels of homocysteine. The strongest effect on testosterone, HOMA1-IR, uric acid, hsCRP, and fibrinogen was observed if fenofibrate was administered together with testosterone. Testosterone-fenofibrate combination therapy was also devoid of unfavorable effect on HDL cholesterol and homocysteine. CONCLUSIONS: Our study shows that fenofibrate produces a stronger effect on cardiometabolic risk factors in men with late-onset hypogonadism and atherogenic dyslipidemia than oral testosterone undecanoate. The obtained results suggest that this group of patients may benefit the most from the combined treatment with oral testosterone undecanoate and micronized fenofibrate. PMID- 26031508 TI - Encapsulating Ionic Liquid and Fe3O4 Nanoparticles in Gelatin Microcapsules as Microwave Susceptible Agent for MR Imaging-guided Tumor Thermotherapy. AB - The combination of therapies and monitoring the treatment process has become a new concept in cancer therapy. Herein, gelatin-based microcapsules have been first reported to be used as microwave (MW) susceptible agent and magnetic resonance (MR) imaging contrast agent for cancer MW thermotherapy. Using the simple coacervation methods, ionic liquid (IL) and Fe3O4 nanoparticles (NPs) were wrapped in microcapsules, and these microcapsules showed good heating efficacy in vitro under MW irradiation. The results of cell tests indicated that gelatin/IL@Fe3O4 microcapsules possessed excellent compatibility in physiological environments, and they could effectively kill cancer cells with exposure to MW. The ICR mice bearing H22 tumors treated with gelatin/IL@Fe3O4 microcapsules were obtained an outstanding MW thermotherapy efficacy with 100% tumor elimination under ultralow density irradiation (1.8 W/cm(2), 450 MHz). In addition, the applicability of the microcapsules as an efficient contrast agent for MR imaging in vivo was evident. Therefore, these multifunctional microcapsules have a great potential for MR imaging-guided MW thermotherapy. PMID- 26031509 TI - Dual-signal amplification strategy for ultrasensitive chemiluminescence detection of PDGF-BB in capillary electrophoresis. AB - Many efforts have been made toward the achievement of high sensitivity in capillary electrophoresis coupled with chemiluminescence detection (CE-CL). This work describes a novel dual-signal amplification strategy for highly specific and ultrasensitive CL detection of human platelet-derived growth factor-BB (PDGF-BB) using both aptamer and horseradish peroxidase (HRP) modified gold nanoparticles (HRP-AuNPs-aptamer) as nanoprobes in CE. Both AuNPs and HRP in the nanoprobes could amplify the CL signals in the luminol-H2 O2 CL system, owing to the excellent catalytic behavior of AuNPs and HRP in the CL system. Meanwhile, the high affinity of aptamer modified on the AuNPs allows detection with high specificity. As proof-of-concept, the proposed method was employed to quantify the concentration of PDGF-BB from 0.50 to 250 fm with a detection limit of 0.21 fm. The applicability of the assay was further demonstrated in the analysis of PDGF-BB in human serum samples with acceptable accuracy and reliability. The result of this study exhibits distinct advantages, such as high sensitivity, good specificity, simplicity, and very small sample consumption. The good performances of the proposed strategy provide a powerful avenue for ultrasensitive detection of rare proteins in biological sample, showing great promise in biochemical analysis. PMID- 26031511 TI - Reductive Alkylation of Arenes by a Thiol-Based Multicomponent Reaction. AB - A simple and highly chemo- and regioselective method for introducing primary alkyl substituents into aromatic compounds was developed. The method is based on an electrophilic aromatic substitution of an aldehyde, promoted by a thiol, to afford 1-(alkylthio)alkylarenes, which can either be reduced in situ with triethylsilane or reacted further. This multicomponent reaction enables the direct introduction of both aromatic and linear and branched aliphatic alkyl groups into arenes. The above one-pot protocol may be performed in air and in the presence of water and is compatible with various functional groups. PMID- 26031510 TI - Metabolic responses of the Antarctic fishes Notothenia rossii and Notothenia coriiceps to sewage pollution. AB - The present study aimed to assess the sewage effects of the Brazilian Antarctic Station Comandante Ferraz, Admiralty Bay, King George Island, on the hepatic metabolism (energetic, antioxidant, and arginase levels) and levels of plasma constituents of two Antarctic fish species Notothenia rossii and N. coriiceps. The bioassays were conducted under controlled temperature (0 degrees C) and salinity (35 psu), exposing the fish for 96 h, to sewage effluent diluted in seawater to 0.5 % (v/v). Liver homogenates were tested for the specific activities of the enzymes glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GPase), hexokinase, citrate synthase, lactate dehydrogenase, malate dehydrogenase, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutathione reductase, catalase, and arginase. Plasma levels of glucose, triacylglycerides, cholesterol, total protein, albumin, chloride, magnesium, calcium, and inorganic phosphate were also determined. In N. rossii, the decrease in citrate synthase and the increase in G6Pase and GPase suggested that the sewage effluent activated glycogenolysis and hepatic gluconeogenesis, whereas is N. coriiceps, only G6Pase levels were increased. In N. rossii, sewage effluent induced hypertriglyceridemia without modulating glucose plasma levels, in contrast to N. coriiceps, which developed hypoglycemia without elevating plasma triglyceride levels. The decrease in glutathione reductase levels in N. coriiceps and in superoxide dismutase and catalase in N. rossii suggest that these two species are susceptible to oxidative stress stemming from the production of reactive oxygen species. An increase in magnesium in N. rossii and a decrease in N. coriiceps showed that sewage effluent compromised the control of plasma levels of this cation. Although phylogenetically close, both species of Antarctic fish exhibited different metabolic responses to the sewage effluent, with N. coriiceps showing greater susceptibility to the toxic effects of the pollutants. The present study suggests that the biochemical responses of these two species are potential indicators of metabolic changes caused by sewage effluents. PMID- 26031512 TI - Ventricular tachycardias in patients with pulmonary hypertension: an underestimated prevalence? A prospective clinical study. AB - BACKGROUND: Sudden cardiac death (SCD) accounts for approximately 30 % in patients with pulmonary arterial hypertension (PAH). The exact circumference for SCD in this patient population is still unclear. Malignant cardiac arrhythmias are reported to be rarely present. There are no systematic data concerning long term electrocardiographic (ECG) recording in patients with PAH. OBJECTIVES: We sought to investigate the rate of potentially relevant arrhythmias in patients with pulmonary hypertension (PH). METHODS: Consecutive patients without diagnosis of known cardiac arrhythmias followed in our outpatient clinic for PH were enrolled in the study. All patients underwent a 72-h Holter ECG. Clinical data, 6 min walk distance, laboratory values, and echocardiography were collected/performed. RESULTS: Ninety-two consecutive patients (New York Heart Association class (NYHA) III/IV: 65.2 %/5.4 %, PH Group 1: 35.9 %, Group 3: 10.9 %, Group 4: 28.3 %, Group 5: 2.2 %) were investigated. Relevant arrhythmias were newly detected in 17 patients: non-sustained ventricular tachycardia (n = 12), intermittent second-degree heart block (n = 1), intermittent third-degree heart block (n= 3), and atrial flutter (n = 1). Echocardiographic systolic pulmonary pressure and diameter of the right heart were elevated in patients with relevant arrhythmias. Right heart catheterization revealed higher pulmonary vascular resistance (672 vs. 542 dyn . s . cm(-5), p = 0.247) and lower cardiac index (2.46 vs. 2.82 l/min/m(2), p = 0.184). CONCLUSIONS: Ventricular tachycardias occur more often in PH patients than previously reported. However, the prognostic relevance of non-sustained ventricular tachycardias in this cohort remains unclear. As a large number of PH patients die from SCD, closer monitoring, e.g., using implantable event recorders, might be useful to identify patients at high risk. PMID- 26031513 TI - [How to approach the patient with supraventricular tachycardia in the EP lab: A systematic overview]. AB - The term supraventricular tachycardia (SVT) summarizes those tachycardias involving the atrial myocardium along with the atrioventricular (AV) node. The prevalence is about 2.25 per 1000 (without atrial fibrillation and atrial flutter) and, therefore, SVT represents one of the most common group of arrhythmias besides atrial fibrillation encountered in the emergency department especially since they tend to recur until definite therapy. The clinical symptoms may include palpitations, anxiety, presyncope, angina, and dyspnea. Pharmacological therapy of these arrhythmias often fails. The present article deals with the differential diagnosis of SVT and also introduces a series of manuscripts that provide detailed insight into the differential diagnosis and treatment of these arrhythmias. PMID- 26031514 TI - [35 year ICD therapy: Where does it come from and where does it go?]. PMID- 26031515 TI - Mask-Like Symmetrical Microclusters through a Diffusion-Limited Assembly Approach. AB - A diffusion-limited assembly approach was explored to fabricate symmetrical [Cu(Succinate)]n microclusters with a different shape and size for the first time. The molecular structure of succinate and its coordination reaction capability towards copper(II) ions governed the one-dimensional growth of the nanofibers and the concomitant formation of the microclusters. In detail, a symmetrical concentration gradient was formed around the endpoints of the nanofibers caused by the diffusion-limited process at high reactant concentrations. The concentration gradient forced the nanofibers to grow divergently and further aggregate into open microcluster structure. The shape and size of the microclusters could be tuned by altering the concentration of the reactants. Particularly, mask-like double-hole symmetrical microclusters (MDHSMs) were obtained when the concentration of both reactants was as high as 140 mM. The resultant MDHSMs showed high selectivity in adsorption of dyes and proteins, and may find potential applications in water treatment, bioseparation, and immobilization of biomacromolecules. PMID- 26031516 TI - Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjogren's syndrome. AB - BACKGROUND: Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. METHODS: The DNA of eight patients affected by MAS [all of whom presenting with Sjogren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. RESULTS: Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes. CONCLUSIONS: Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity. PMID- 26031518 TI - [The precise diagnosis of myelodysplastic syndromes]. PMID- 26031517 TI - Extreme hypernatremic dehydration due to potential sodium intoxication: consequences and management for an infant with diarrhea at an urban intensive care unit in Bangladesh: a case report. AB - INTRODUCTION: Hypernatremia (serum sodium >= 150 mmol/L) is one of the most life threatening complications of childhood diarrhea, and its management remains challenging, even in a highly advanced critical care setting. This case report describes the acute clinical course and 3-month neurological follow-up after discharge of an infant with extreme hypernatremia in an intensive care unit in Dhaka, Bangladesh. CASE PRESENTATION: A 6-month-old Asian Bangladeshi girl of middle-class socioeconomic status was admitted to the intensive care unit of our institution in 2012 with acute watery diarrhea, lethargy and hypernatremia (208 mmol/L serum sodium). She had a history of taking excess oral rehydration salt: five packets each, inappropriately prepared, rice-based, properly diluted, glucose-based oral rehydration salt. Her hypernatremia was treated exclusively with oral rehydration salt solution. She experienced seizures on the third day of her hospitalization and was treated with anticonvulsant drugs. Later in the course of her hospitalization, Enterobacter spp bacteremia was detected and successfully treated with ciprofloxacin. Although magnetic resonance imaging of her brain at discharge showed cerebral edema, brain magnetic resonance imaging appeared normal at a follow-up examination 3 months after discharge. Electroencephalograms taken at discharge and at her 3-month follow-up examination also appeared normal. CONCLUSIONS: Successful management of extreme hypernatremia with only oral rehydration salt did not result in observable neurological consequences, which emphasizes the importance of the use of oral rehydration salt for the clinical management of childhood hypernatremia. PMID- 26031519 TI - [Chinese expert consensus on the treatment and diagnosis of acquired pure red cell aplasia (2015)]. PMID- 26031520 TI - [A retrospective analysis of autologous peripheral blood hematopoietic stem cell mobilizations and collections in 149 multiple myeloma patients]. AB - OBJECTIVE: To analyze the results and influential factors of mobilization and harvesting of autologous peripheral blood stem cell in patients with multiple myeloma (MM). METHODS: Retrospective analysis of peripheral blood stem cell collection data [CD34+ cells collected, successful mobilization rate (CD34+ cells>=2*106/kg body weight), good mobilization rate (CD34+ cells>=5*106/kg body weight)] of 149 multiple myeloma patients who were treated with cyclophosphamide (CTX) or E-CHOP (etoposide+ CTX+epirubicin+vindesine+prednisone) chemotherapy combined with G-CSF mobilization from January 1998 to March 2014. The relevance between gender, age, subtype, DS staging, ISS staging, treatment before mobilization, disease status at mobilization, regiment of mobilizationand the collection results was analyzed. RESULTS: A total of 177 stem cell mobilizations were performed in 149 MM patients, the median CD34+ cells harvested were 3.20 (0.13-22.34)*106/kg body weight (BW), successful mobilization rate and good mobilization rate were 74.5% and 27.5%, respectively. The single logistic regression analysis showed that gender, age (>60 ys vs <=60 ys), subtype, DS staging (III vs II+I), ISS staging (III vs II+I) and regiment of mobilization (E CHOP+G-CSF vs ID-CTX+G-CSF) were not correlated with the cell collection or successful mobilization rate (P>0.05). However, successful collection rate of single harvest in old patients (age>60 ys) was lower (P<0.05), andthe good mobilization rate in patients at ISS stage III was lower (P<0.05). The collection results of patients with fewer cycles of treatment (treatment before mobilization <=6 cycles) and optimal disease status (disease status at mobilization >=partial remission) were much better. Analysis of logistic factors revealed that treatment efficacy before mobilization affected success rate of collection (P=0.006). Risk of collection failure in patients who received more than 6 cycles of treatment before mobilization was high (OR 3.57, 95% CI 1.45-8.78). CONCLUSION: Gender, age, subtype, DS staging, ISS staging and mobilization regimen did not influence MM patients peripheral blood stem cell collection; but old patients may need twice mobilizations to collect sufficiently. Few cycles of treatment and stable disease status before mobilization is favorable to the mobilization and collection of peripheral blood stem cells. PMID- 26031521 TI - [The clinical efficacy of all-trans retinoic acid plus arsenic trioxide in 177 newly diagnosed acute promyelocytic leukemia patients]. AB - OBJECTIVE: To investigate the clinical efficacy of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia (APL). METHODS: A retrospective analysis of 298 newly diagnosed APL patients from the department of hematology, First Affiliated Hospital of Zhejiang University since September 2004 to December 2013, including 177 cases with ATRA plus ATO and 116 ATRA plus chemotherapy (CT), was performed to investigate the clinical efficacy between the low-intermediate (WBC<=10*109/L) and high (WBC>10*109/L) risk APL patients, respectively. RESULTS: For the low-intermediate risk patients, the relapse rate in ATRA plus CT and ATRA plus ATO are 22.0% and 6.1% (P=0.004), respectively; the 3 years estimated relapse-free survival (RFS) are 78.0% and 92.9% (P=0.021), respectively. For the high risk patients, the relapse rate in ATRA plus CT and ATRA plus ATO are 25.0% and 5.2% (P=0.035), respectively; the 3 years estimated RFS rate were 80.8% and 93.0% (P=0.021), respectively. But the rate of early death (ED), complete remission (CR) and overall survival (OS) between the two therapy protocols had no statistical difference (P>0.05). CONCLUSION: ATRA plus ATO in induction and maintenance therapy might prolong the RFS time of the low-intermediate risk APL patients and decrease the relapse rate of the low, intermediate and high risk APL patients. PMID- 26031522 TI - [CALR gene mutation detection and clinical observation of 150 essential thrombocythemia patients]. AB - OBJECTIVE: To explore the prevalence of CARL gene mutations and the mutation types in patients with essential thrombocythemia (ET), and to compare the patients clinical characteristics of CALR mutation with JAK2 V617F, MPL W515K mutation patients and triple negative group. METHODS: The mutations of CALR gene at extron 9 and MPL W515K in 150 ET patients were detected by PCR amplification followed by direct sequencing of genomic DNA, the JAK2 V617F mutation by using allele specific PCR. RESULTS: (1)The CALR mutations were found in 38 patients (25.3%) of 150 ET patients. A total of 4 types of CALR mutations were identified (type Ic.1092_1143del52bp, n=17; type II c.1154_1155insTTGTC, n=16; type III c.1094_1139del46bp, n=4; type IV c.1103_1136del34bp, n=1). (2)The incidence of JAK2 V617F and MPL W515K was 61.3% (92/150) and 2.7% (4/150), respectively. The frequency of CALR mutation was 70.4% (38/54) in 54 ET patients without JAK2 V617F and MPL W515K mutations. The co-occurrence of any two kinds of gene mutations was not detected. (3)The hemoglobin level and leukocyte counts of patients with CARL mutations were significantly lower than that in patients with JAK2 V617F mutations (P<0.05). The median age of patients with CALR mutation was significantly higher than that of triple negative patients (59 years vs 29.5 years, P<0.01). Cytogenetic analysis was performed in 147 patients, and there were 4 abnormal karyotype cases. CALR mutation incidence was significantly higher in abnormal karyotype cases than that in normal ones (75% vs 24.5%, P=0.019). CONCLUSION: The incidence of CALR mutations is high in ET patients without JAK2 V617F and MPL W515K mutations, and is associated with abnormal karyotype. CARL mutated cases showed a significantly lower leucocyte and hemoglobin levels compared with JAK2 V617F mutated cases. PMID- 26031523 TI - [Effect of ADAR1 on the development of MLL-AF9 induced murine AML]. AB - OBJECTIVE: To establish the ADAR1 (adenosine deaminase that act on RNA 1) knockout MLL-AF9 acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the effects of ADAR1 deletion on the development of AML. METHODS: The lineage- (Lin-) cells of ER-CreADAR1(lox/lox) mice and their ADAR1(lox/lox) counterparts were enriched by magnetic activated cell sorting (MACS) and then transduced with retrovirus carrying MSCV- MLL/AF9-IRES-GFP fusion gene. The efficiency of transduction was detected by flow cytometry, and equal number of GFP+ cells were transplanted into lethally irradiated recipient mice. The recipient mice were treated with tamoxifen at 48 hours after transplantation to induce ADAR1 knockout and divided into following groups: experimental group (ER Cre;ADAR1(lox/lox)+tamoxifen), control groups ((1)ER-Cre;ADAR1(lox/lox)+vechile, (2)ADAR1(lox/lox)+tamoxifen, (3)ADAR1(lox/lox)+vechile). The percentage of GFP+ cells in peripheral blood was examined at 10, 15 and 20 days respectively after transplantation and the survival of the recipient mice was observed. In vitro study, ER-Cre;ADAR1(lox/lox) and ADAR1(lox/lox) AML cells were cultured and the apoptosis rates of these cells 48 hours after 4-hydroxytamoxifen treatment were examined. RESULTS: The ADAR1 deletion MLL-AF9 AML mouse model was successfully established. Deletion of ADAR1 could decrease the percentage of GFP+ cells in the peripheral blood and significantly prolong the survival rate of recipient mice(P<0.05). In vitro study showed that the cultured total cell number, percentage of GFP+ cells decreased and the apoptosis rate of AML cells increased. CONCLUSION: Ablation of ADAR1 could delay the progression of AML in recipient mice. ADAR1 plays a critical role in the development and maintenance of murine MLL-AF9 AML. PMID- 26031524 TI - [Study on the correlation between CMV reactivation and bronchiolitis obliteans after allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the correlation between CMV reactivation and obliterative bronchiolitis (BO) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: From January 2011 to December 2013, 769 patients underwent allo-HSCT. The CMV infection was diagnosed by fluorescence quantitative PCR method for detecting the level of CMV-DNA and immunofluorescence staining of PP65 antigen in white blood cell. The frequency of BO in patients with and without CMV infection was compared, and the correlation between CMV infection and BO was analyzed. The clinical data of CMV infection patients with and without BO were analyzed and compared. RESULTS: Of 259 diagnosed CMV infection patients, BO occurred in 32 cases, the incidence rate was 12.35%, while in 510 cases without CMV infection, BO occurred in 8 cases, the incidence was 1.56%. The incidence rate of BO is significantly higher in patients with CMV infection than that in patients without CMV infection (P<0.001). The CMV related clinical data between the 32 cases with BO and 227 cases without BO were analyzed among the 259 cases of diagnosed CMV infection patients. BO incidence is higher in patients with more than 105 copies/ml CMV-DNA than that in patients with less than 102 copies/ml CMV-DNA. CONCLUSION: Among the risk factors related to BO post allo-HSCT, CMV infection is one of them to be worthy of attention. CMV reactivation with high virus titer, multiple CMV reactivations and CMV pneumonia are the risk factors. PMID- 26031525 TI - [The impact of renal function on prognostic value of beta2-microglobulin of ISS stage system in multiple myeloma patients--Clinical data analysis of 666 patients in a single center]. AB - OBJECTIVE: To investigate the influence of renal function on the level of beta2 microglobulin (beta2-MG) as prognostic factor in newly diagnosed multiple myeloma (MM) patients, and to analyze the overall survival (OS) in different level of beta2-MG with relatively normal or abnormal renal function in MM patients. METHODS: According to the level of beta2-MG, 666 newly diagnosed MM patients were divided into three groups as beta2-MG<3.5, 3.5-<5.5, >=5.5 mg/L. According to the level of serum creatinine, these patients were divided into two groups:serum creatinine <177 MUmol/L as relatively normal group, serum creatinine >=177 MUmol/L as abnormal group. RESULTS: Among 666 patients, there were 416 male and 250 female, the median age was 58 (25-86) years old. Comparison of OS among beta2 MG<3.5, 3.5-<5.5, >=5.5 mg/L groups indicated that the median OS of the three groups were 85.75 (95% CI 70.99-100.50), 47.25 (95% CI 40.98-53.53) and 35.05 (95% CI 30.75-39.35) months, respectively (P<0.01). Comparison of OS between serum creatinine <177 and >=177 mmol/L groups, the median OS of the two groups were 64.67 (95% CI 56.57-72.77) and 32.74 (95% CI 27.74-37.73) months, respectively (P<0.01). In beta2-MG>=5.5 mg/L, the median OS of relatively normal and abnormal groups were 37.25 (95% CI 31.45-43.06) and 32.55 (95% CI 26.26 38.83) months, respectively (P=0.142). CONCLUSION: High level of beta2-MG and renal function correlated with shorter survival of MM patients. Higher level of beta2-MG with abnormal renal function can't change the prognostic value of beta2 microglobulin on MM. PMID- 26031526 TI - [Rectal infiltration secondary to multiple myeloma:a case report]. PMID- 26031527 TI - [Clinical and laboratory characteristics of 12 Ph/BCR-ABL positive acute myeloid leukemia patients]. AB - OBJECTIVE: To explore the clinical and laboratory characteristics in favor of the diagnosis of Ph/BCR-ABL positive acute myeloid leukemia (Ph/BCR-ABL+ AML). METHODS: Retrospectively analyzed the clinical and laboratory characteristics of 12 Ph/BCR-ABL+ AML cases from Feb, 2006 to Dec, 2013, with classic myeloid blast crisis of chronic myeloid leukemia (CML-MBC) as control, and followed-up the survival in these two cohorts of patients. RESULTS: The median age of 12 Ph/BCR ABL+ AML was 27.5 years, 10 cases (83.3%) showed non/mild splenomegaly, and mainly comprised of M2 and M4 subtypes according to FAB classification. The median number of basophils and megakaryocytes in peripheral blood and bone marrow was lower than that of CML-CBC patients. All the cases expressed myeloid antigens, 8 cases (66.7%) expressed CD34, 11 cases were detected with t(9;22), 5 cases (45.5%) with additional chromosomal abnormalities, including 1 case of inv(16). All the cases had BCR-ABL transcripts at diagnosis:3(25.0%) cases were e1a2 type and the remaining was b2a2/b3a2type, among which 1 case coexpressed CBFbeta-MYH11. Two out of 6 cases existed AML-like mutations:1 case of CEBPA and the other of FLT3-TKD. For all the patients, 7 cases achieved complete remission (CR), including 6 out of 7 cases receiving induction chemotherapy combined with tyrosine kinase inhibitor (TKI) achieved CR, and 1 out of 3 cases receiving chemotherapy alone achieved CR. The median overall survival was 16.5 months, that of allo-HSCT group was 33.5 months, which was higher than that of non-HSCT group (5.5 months). CONCLUSION: The expression of e1a2 type BCR-ABL, the coexpression of fusion genes which were more common in AML, the existence of AML-like mutations were all indications of a de novo Ph/BCR-ABL+ AML. Low induction CR rate and short survival of Ph/BCR-ABL+ AML implied that chemotherapy combined with TKI and followed by allo-HSCT in CR was the only effective way to improve their survival. PMID- 26031528 TI - [Effect of shRNA-mediated silencing of BDNF gene on VEGF expression of RPMI8226 cells]. AB - OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF) of human multiple myeloma (MM) cell line RPMI8226 regulated by brain derived neurotrophic factor (BDNF), and preliminarily approach the close relationship between BDNF and angiogenesis of MM. METHODS: The recombinant eukaryotic BDNF siRNA expression vector was designed and constructed. The empty vector pGenesil-1, and the recombinant plasmid, pGenesil-shRNA-BDNF were transfected into RPMI8226 cells using LipofectamineTM 2000 (groups P0 and P1, respectively). BDNF mRNA and protein level in RPMI8226 cells were detected by RT PCR and Western blotting, respectively; the cellular proliferation activity was determined by MTT assay, while the cell apoptosis was measured by flow cytometry; the variation of VEGF mRNA level in RPMI8226 cells via transfection was determined by RT-PCR, the secretion of VEGF was detected by ELISA. RESULTS: (1)The recombinant eukaryotic BDNF siRNA expression vectors were successfully constructed. BDNF mRNA expression and protein level in P1 group were significantly inhibited compared to those in non-transfected group (Pn) and P0 groups (P<0.05); (2)MTT tests demonstrated that the cellular proliferation activities were obviously decreased in Pn (0.42 +/- 0.06) vs P0 (0.56 +/- 0.06) and P1 (0.50 +/- 0.04) groups (P<0.05); (3)The early cell apoptosis rates were statistically increased in P1 [(53.84 +/- 9.95)%] vs Pn [(5.23 +/- 2.46)%] and P0 [(9.10 +/- 3.46)%] groups (P<0.01); (4)The silence of endogenous BDNF significantly decreased the expression of VEGF in RPMI8226 cells:the relative expression level of VEGF121, VEGF145 and VEGF165 in P1 group were (0.62 +/- 0.07), (0.47 +/- 0.09) and (0.57 +/- 0.02) folds compared to Pn group (P<0.05); (5)ELISA demonstrated that secretion of VEGF in P1 group were (0.36 +/- 0.05) and (0.44 +/- 0.06) folds compared to Pn and P0 group, respectively (P<0.05). CONCLUSION: BDNF gene silence can obviously increase apoptosis of RPMI8226 cells, inhibit their proliferation and decrease the expression of VEGF. BDNF might mediate the expression of VEGF in MM cells, which may be involved in MM angiogenesis. PMID- 26031529 TI - [Functional study of hENT1 on SKM-1 cell resistance to decitabine]. AB - OBJECTIVE: To investigate the effect of human equilibrative nucleoside transporters 1 (hENT1) silencing on proliferation, apoptosis and demethylation of human myelodysplastic syndrome (MDS) derived cell line SKM-1 treated with 5-aza 2'-deoxycytidine (decitabine, DAC). METHODS: hENT1 was silenced in SKM-1 cells mediated by lentivirus transfection. The infection efficiency was detected by flow cytometry, and the mRNA expression level of hENT1 was confirmed by qRT-PCR. The proliferation ratio of SKM-1 cells treated with different concentrations (0.5, 1, 5 mmol/L) of DAC for 24, 48 and 72 h was detected by CCK-8 method after hENT1 silencing. The apoptosis of SKM-1 cells was detected by Western blot for cleaved level of caspase-3 and evaluated by flow cytometry after staining with anti-Annexin V-PE and 7-AAD. The p15(INK4B) DNA methylation status was measured by methylation specific PCR using EZ DNA Methylation-GoldTM Kit. RESULTS: The expression level of hENT1 silenced group (0.253+/-0.030) was statistically decreased compared with that in control group (1.000+/-0.091) (P<0.01). Compared with control, the proliferation inhibition rate of hENT1 silenced group was significantly decreased by different concentrations of DAC (0.5, 1, 5 MUmol/L) treatment for 24, 48, 72 h (P<0.05), which was (49.41+/-4.02)% and (33.03+/ 2.47)%, respectively (P=0.007) at 5 MUmol/L DAC treatment for 72 h in hENT1 silenced group and the control group. Western blot showed that cleaved caspase3 of hENT1 silenced group was also significantly inhibited. The percentage of Annexin V+ cells and demethylation status of p15(INK4B) were significantly decreased. CONCLUSION: Apoptosis of hENT1 silenced SKM-1 cells induced by DAC was decreased, and the susceptibility of these cells to demethylation treatment was also decreased. PMID- 26031530 TI - [Effects of SDF-1/CXCR4 signal pathway blockade by AMD3100 on the adhesion of leukemia cells to osteoblast niche and the drug resistance of leukemia cells]. AB - OBJECTIVE: To study the blocking effect of CXCR4 inhibitor AMD3100 on the adhesion of leukemia cells to osteoblast niche, and the reversal of multidrug resistance in leukemia cells. METHODS: Mesenchymal stem cells (MSCs) from leukemia patients were planted on the bio-derived bone scaffolds and then induced into osteoblasts to establish the bio-osteoblast niche. The levels of SDF-1were tested with ELISA. The leukemia cell line MV4-11 cells with FLT3-ITD mutation were inoculated into the bio-osteoblast niche to build a three-dimensional co- culture system. The expression level of CXCR4, adhesion and apoptosis rates of leukemia cells were observed by flow cytometry after incubation with AMD3100 and Ara-C for 24 h and 48 h. RESULTS: (1)The supernatant levels of SDF-1 in cultured osteoblast were (304 +/- 18), (410 +/- 28) and (396 +/- 16) pg/ml on 7 th, 14 th and 21 th day, respectively. It reached the highest on 14 th day. The expression level of CXCR4 in cultured MV4-11 cells was (72 +/- 16)%. (2)Adhesion rate of MV4 11 cells to osteoblast niche was (40.1 +/- 8.1)% after AMD3100 treatment for 24 h, while that of control group was (65.6 +/- 12.1)% (P<0.05). (3)The apoptosis rate of MV4-11 cells incubated with AMD3100 for 24 h was (5.6 +/- 0.8)%, while that of control group was (2.5 +/- 0.5)%. The apoptosis rates of AMD3100-induced MV4-11 cells were (10.0 +/- 2.4)%, (17.8 +/- 2.3)% and (25.1 +/- 2.4)% after treatment with Ara-C at 0.02, 0.20, 2.00 mg/ml respectively and they were (6.7 +/ 1.0)%, (10.3 +/- 1.5)%, (16.2 +/- 3.1)% respectively in AMD3100-noninduced control group, the difference was significant (P<0.05). CONCLUSION: AMD3100 can block the interaction between osteoblasts niches and leukemia cells, and play an important role in the reversal of multidrug resistance in leukemia cells. PMID- 26031531 TI - [Changes of angiopoietin 1 expression in G-CSF induced hematopoietic stem progenitor cells mobilization]. AB - OBJECTIVE: To investigate the changes and mechanism of angiopoietin1 (Ang1) in murine bone marrow during G-CSF induced mobilization of hematopoietic stem/progenitor cell. METHODS: The proportion of Lin-Sca1+cKit+ (LSK) cells in peripheral blood of C57BL/6 mice before and after G-CSF mobilization was detected by flow cytometry. Expression changes of Ang1 and osteocalcin (OCN) during HSC mobilization were determined by immunohistochemistry, enzyme linked immunosorbent assay (ELISA) and real-time fluorescence quantitative PCR. The number of osteoblasts in the bone marrow was counted under the microscope. RESULTS: After treated with G-CSF, the proportion of LSK cells in peripheral blood significantly increased from the controls (0.04 +/- 0.01)% to (0.61 +/- 0.05)% at day 5 (P<0.05). Before G-CSF mobilization, the endosteum cells expressed higher level of OCN and Ang1 than that of bone marrow nucleated cells. The mRNA expression level of OCN was significantly reduced from 28.64 +/- 8.61 in the controls to 12.55 +/- 7.06 on day 3 and 4.75 +/- 1.62 on day 5, and the expression level of Ang1 also declined from 2.84 +/- 0.95 in the controls to 0.93 +/- 0.30 on day 3 and to 0.92 +/- 0.22 on day 5 after G-CSF mobilization. The number of endosteum osteoblasts was significantly decreased after mobilization (P<0.05). The Ang1 expression was decreased in the BM after mobilization. The serum OCN was significantly reduced from (24.11 +/- 3.17) ng/ml in the controls to (9.96 +/- 2.16) ng/ml on day 3 and (8.43 +/- 2.62) ng/ml on day 5, and the Ang1 also declined from (2.24 +/- 0.52) ng/ml in the controls to (1.21+/-0.38) ng/ml on day 3 and (0.90+/-0.24) ng/ml on day 5. CONCLUSION: In G-CSFinduced HSPC mobilization, the bone marrow osteoblasts retraction causes reduction of Ang1, and the reduction of Ang1 may contribute to HSPC mobilization. PMID- 26031532 TI - [Growth inhibition effect of matrine on K562 cells mediated by IL-6/JAK/STAT3 signaling pathway]. AB - OBJECTIVE: To investigate the molecular mechanism of the growth inhibitory effect of matrine on K562 cells in JAK/STAT3 mediated signal pathway. METHODS: Western blot analyses were performed to investigate the differential expression of JAK2, STAT3, phosphor-STAT3 (Tyr705 & Ser727) and phosphor-JAK2 proteins after matrine treatment in K562 cells with or without human recombinant interleukin 6 (IL-6) pretreatment. The expression of STAT3 response gene products such as Bcl-xL, Cyclin D1 and c-Myc, were investigated by Western blot and quantitative real time RT-PCR (qRT-PCR). Expression of IL-6, a potent upstream activating factor of JAK/STAT3 pathway, was analyzed by both real time qRT-PCR and ELISA. RESUTLS: Western blot revealed that matrine treatment resulted in a strong down-regulation of phosphor-STAT3 both in Tyr705 and Ser727 sites or phosphor-JAK2 proteins expression without significant effects on the total STAT3 and JAK2 proteins. The expression of phosphor-Tyr705 STAT3 and phosphor-Ser727 STAT3 was decreased to 0.370 +/- 0.172 in K562 cells treated with 0.5 mg/ml matrine for 48 h, respectively, from 0.690 +/- 0.119 and 1.150 +/- 0.263 in control cells, accompanied with a dramatical down-regulation of phosphor-JAK2 from 0.670 +/- 0.137 to 0.049 +/- 0.057 (P<0.05). In addition, it was found that the expression of Bcl-xL, Cyclin D1, c-Myc was decreased both at the transcription and protein level in K562 cells after matrine treatment. Matrine treatment resulted in a significant decrease in the expression level of IL-6 in K562 cells from (35.1 +/- 1.93) to (10.74 +/- 1.83) and (8.66 +/- 1.24) pg/ml at the dose of 0.5 and 0.8 mg/ml, respectively (p<0.05). Matrine treatment could diminish the up-regulation of STAT3, JAK2, phosphor-STAT3 and phosphor-JAK2 protein following pretreatment with IL-6 in K562 cells. CONCLUSION: Matrine exerts its anti-leukemia effect by interfering with the JAK2/STAT3 signaling pathway. The inhibition of IL-6 expression may play a pivotal role in the disruption of JAK/STAT pathway by matrine. PMID- 26031533 TI - [Analysis of clinical features and genotype in an inherited coagulation factor VII deficiency pedigree]. PMID- 26031534 TI - [CD20-negative primary intestinal diffuse large B-cell lymphoma:a case report and literature review]. PMID- 26031535 TI - [Study on the effect and mechanism of HL-60 cell apoptosis induced by matrine combined with homoharringtonine]. PMID- 26031536 TI - [Clinical analysis of 8 cases therapy related leukemia]. PMID- 26031537 TI - [Myeloid sarcoma with acute promyelocytic leukemia:two cases report]. PMID- 26031538 TI - [Intermittent fever, dyspnea]. PMID- 26031539 TI - [One case of rhabdomyosarcoma with acute leukemia as the first symptom]. PMID- 26031540 TI - [Research progress of alloantibodies against von Willebrand factor]. PMID- 26031541 TI - Social support, social conflict, and immigrant women's mental health in a Canadian context: a scoping review. AB - ACCESSIBLE SUMMARY: Social support has positive and negative dimensions, each of which has been associated with mental health outcomes. Social networks can also serve as sources of distress and conflict. This paper reviews journal articles published during the last 24 years to provide a consolidated summary of the role of social support and social conflict on immigrant women's mental health. The review reveals that social support can help immigrant women adjust to the new country, prevent depression and psychological distress, and access care and services. When social support is lacking or social networks act as a source of conflict, it can have negative effects on immigrant women's mental health. It is crucial that interventions, programmes, and services incorporate strategies to both enhance social support as well as reduce social conflict, in order to improve mental health and well-being of immigrant women. ABSTRACT: Researchers have documented the protective role of social support and the harmful consequences of social conflict on physical and mental health. However, consolidated information about social support, social conflict, and mental health of immigrant women in Canada is not available. This scoping review examined literature from the last 24 years to understand how social support and social conflict affect the mental health of immigrant women in Canada. We searched MEDLINE, PsycINFO, CINAHL, Healthstar, and EMBASE for peer-reviewed publications focusing on mental health among immigrant women in Canada. Thirty-four articles that met our inclusion criteria were reviewed, and are summarized under the following four headings: settlement challenges and the need for social support; social support and mental health outcomes; social conflict and reciprocity; and social support, social conflict, and mental health service use. The results revealed that social support can have a positive effect on immigrant women's mental health and well-being, and facilitate social inclusion and the use of health services. When social support is lacking or social networks act as a source of conflict, it can have negative effects on immigrant women's mental health. The results also highlighted the need for health services to be linguistically-appropriate and culturally-safe, and provide appropriate types of care and support in a timely manner in order to be helpful to immigrant women. PMID- 26031542 TI - Reduced Sexual Risk Behaviors Among Young Men of Color Who Have Sex with Men: Findings from the Community-Based Organization Behavioral Outcomes of Many Men, Many Voices (CBOP-3MV) Project. AB - In 2006, the Centers for Disease Control and Prevention (CDC) funded community based organizations (CBOs) to deliver Many Men, Many Voices (3MV) to young men of color who have sex with men. Although 3MV, a group-level behavioral intervention designed to reduce human immunodeficiency virus (HIV) risk behaviors of black men who have sex with men (MSM), has shown effectiveness when delivered in a controlled research environment, there is limited evidence that the intervention is associated with similar outcomes in "real world" settings. For the current project, CDC funded three CBOs to conduct outcome monitoring of the 3MV intervention to determine if young MSM of color report changes in HIV risk behaviors postintervention. Using a repeated measures design, risk behaviors were collected at baseline and again at 3 and 6 months postintervention. Changes in risk behaviors were assessed using generalized estimating equations. Participants (n = 337) reported decreases in sexual risk behaviors at both follow-up time points, such as sex without a condom, sex without a condom and multiple partners, and sex without a condom with serodiscordant or status unknown partners. Results suggest that 3MV may be an effective tool for reducing HIV risk behaviors in this critical target population. PMID- 26031543 TI - The Association of (Effective and Ineffective) Analgesic Intake, Pain Interference and Heart Rate Variability in a Cross-Sectional Occupational Sample. AB - OBJECTIVE: Persistent pain is associated with dysfunction of the autonomic nervous system, in particular a loss of vagal inhibitory control, that can be indexed by decreased vagally mediated heart rate variability (vmHRV). Effective treatment (e.g., analgesic self-medication) may lead to a restoration of vmHRV. The objective of this article was to further explore the relationship of pain and vagal control and to investigate the effect of analgesic self-medication on the association of vmHRV and pain. METHODS: We used a large cross-sectional data set on pain ratings and analgesic intake from the Mannheim Industrial Cohort Study for secondary analysis. The root mean square of successive differences, a measure of vmHRV corresponding to the parasympathetic regulation of the heart, was derived from 24-hour electrocardiogram recordings. RESULTS: The frequency of analgesic intake and interference of pain are significantly associated. Individuals that report greater pain interference with their normal work routine (including both work outside the home and housework) and frequent analgesic intake have significantly lower vmHRV. Subjects with ineffective analgesic intake (reporting great pain interference and high frequent analgesic intake) had the lowest vmHRV. Individuals effectively taking analgesics (reporting no or low pain interference and high frequent analgesic intake) showed greater vmHRV compared to those ineffectively taking. Analysis revealed significant differences and linear trends on vmHRV between all groups. CONCLUSION: In line with previous research, vmHRV is inversely associated with pain interference. Analgesic intake mediates the association of vmHRV and pain. Effective analgesic self-medication may lead to a restoration in vmHRV. These results further support the vagus nerve as an objective indication of pain severity and treatment efficacy in patients with persistent pain. PMID- 26031544 TI - Microsatellite instability testing and its role in the management of colorectal cancer. AB - Opinion statement: TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12-15 % have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU) based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX. PMID- 26031545 TI - The UZ Leuven Policy for Extended Adjuvant Anti-estrogen Therapy in Women With Early Estrogen Receptor-Positive Breast Cancer. AB - Opinion statement: Five years after adjuvant endocrine treatment for estrogen receptor (ER)-positive breast cancer, patients have a 2 to 20 % risk of metastatic relapse during the next 5 years. Extended adjuvant endocrine therapy seems to further lower this. In UZ Leuven, extended endocrine therapy is now discussed unless the tumor was a grade 1-2, pT1N0, ER-positive, progesterone receptor (PR)-positive, HER2-negative lesion. After 5 years of adjuvant tamoxifen treatment for ER-positive breast cancer, we encourage women to take another 5 years of tamoxifen. If the tumor was lymph node-positive at diagnosis and patients are menopausal after the first 5 years of tamoxifen, we advise to take prolonged treatment with an oral aromatase inhibitor (AI). For this particular group, available data for extending endocrine therapy with an AI after 5 years of tamoxifen are strongest and more convincing for letrozole than for anastrozole or exemestane. Under these conditions, letrozole is reimbursed for 3 years in Belgium. If women are postmenopausal at diagnosis and already used an oral AI at any time during the first 5 years, we discuss an extra 5 years of tamoxifen. Results from ongoing clinical trials will tell us whether in these cases prolonged AI use is better than tamoxifen so that therapy can be adapted. Benefit from extended adjuvant endocrine therapy is likely larger with better compliance and potential side effects of extended endocrine therapy need to be discussed. Therefore, when advising extended adjuvant endocrine treatment, a balance should always be made between relapse risk and treatment tolerance/compliance. PMID- 26031546 TI - Follicular lymphoma: first-line treatment without chemotherapy for follicular lymphoma. AB - Opinion statement: The optimal initial treatment of follicular lymphoma (FL) is not known, and initial management of patients varies considerably between providers and institutions. The assertion that patients with low tumor burden can be observed for a period of time is being challenged owing to the safety and tolerability of novel therapeutics and the movement of the field away from traditional chemotherapy agents. Single agent rituximab has become increasingly popular as initial management of patients with low tumor burden disease, and there is evidence that prolonged treatment with rituximab can improve progression free survival (PFS) when compared to induction with rituximab or observation. Radioimmunotherapy (RIT) has similarly shown efficacy in low tumor burden disease. Novel agents such as lenalidomide, idelalisib, and ibrutinib are being studied in the first-line setting. Importantly, none of these strategies have demonstrated an improved overall survival in a randomized study versus observation. It is the opinion of the authors that endpoints such as PFS alone, while important, should not drive changes in management with limited resources. Composite endpoints including quality of life are more informative on the true impact of treatments on patients with follicular lymphoma. Providers should encourage all patients to be treated in the context of an appropriate clinical trial when possible. If a patient is not a clinical trial candidate, we typically treat patients with advanced stage and high tumor burden with chemoimmunotherapy. The decision to give maintenance rituximab is individualized to the patient, as there is no overall survival benefit. In patients with early stage disease, we favor consideration of radiation therapy if the patient is a candidate. Our initial recommendation to patients with advanced stage, low tumor burden disease, is close observation or "watch and wait." We have observed that most patients become comfortable over time with an observation approach. If a patient is not comfortable with this recommendation, we will use single agent rituximab. If the patient responds to therapy, we do not recommend maintenance rituximab in low tumor burden disease but rather prefer a retreatment strategy or an extended schedule of four additional doses of rituximab. PMID- 26031547 TI - A simple method for expression and purification of Shiga toxin 1 (Stx1) with biological activities by using a single-promoter vector and native signal peptide. AB - The entire stx1 region from Escherichia coli O157:H7, containing two open reading frames (stx1a and stx1b), was cloned into pET-32a with a single promoter. This region was transformed into E. coli TransB (DE3), which is a trxB and gor mutation strain. After expression in the E. coli periplasm in a completely soluble form, the rStx1 was purified and verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA, and Western blot analysis. Our rStx1 have Vero cell median cytotoxic dose (CD50 ) and median lethal dose (LD50 ) values of approximately 30 ng and 1.5 ug, respectively. The final yield of the purified rStx1 ranged from 2 to 3 mg/L by one-step nickel affinity gel column chromatography. This method is an easy approach to the large-scale preparation of Stx1 at a reasonable cost. PMID- 26031548 TI - Shade-Matching Performance Using a New Light-Correcting Device. AB - PURPOSE: To evaluate the shade-matching performance of dental students when using a new light-correcting device with polarization filter. MATERIALS AND METHODS: A total of 21 observers assessed the shade of the upper frontal teeth in one patient under three lighting conditions: daylight (A), daylight and a light correcting device (Smile Lite, Switzerland) (B), daylight and a light-correcting device with a polarization filter attached (C) by using two shade guides: VITA Classical and 3D Master. Matching scores were calculated as a sum of the color differences between the reference shades and the selected shades (DeltaEab *). Data were analyzed using analysis of variance (ANOVA) test (alpha = 0.05). RESULTS: A significant difference was found between the shade-matching scores under the three lighting conditions (p < 0.001). However, pairwise comparisons showed that between A (DeltaEab *A = 1,873.6) and C (DeltaEab *C = 2,019.1), there was no significant difference (p > 0.05). The best matching scores were calculated for B (DeltaEab *B = 1,652.5). Significant differences were found in respect to the observer's gender (p < 0.05) and color competency (p < 0.05), as well as with the shade guide used (p < 0.05). CONCLUSIONS: Dental students' shade matching ability was better when the light-correcting device was used, but the addition of the filter to it did not prove beneficial. The shade guides used, the observer's gender, and color competency influenced the shade matching. CLINICAL SIGNIFICANCE: The light-correcting device influenced the shade-matching performance; however, the attached polarization filter did not improve the results of the shade matching. PMID- 26031549 TI - Diel trends in stomatal response to ozone and water deficit: a unique relationship of midday values to growth and allometry in Pima cotton? AB - Plant responses to ozone (O3 ) and water deficit (WD) are commonly observed, although less is known about their interaction. Stomatal conductance (gs ) is both an impact of these stressors and a protective response to them. Stomatal closure reduces inward flux of O3 and outward flux of water. Stomatal measurements are generally obtained at midday when gas exchange is maximal, but these may not be adequate surrogates for stomatal responses observed at other times of day, nor for non-stomatal responses. Here, we find in Pima cotton that stomatal responses to O3 observed at midday do not reflect responses at other times. Stomata were more responsive to O3 and WD near midday, despite being at quasi-steady state, than during periods of active opening or closing in morning or evening. Stomatal responsivity to O3 was not coincident with maximum gas exchange or with periods of active regulation, but coincident with plant sensitivity to O3 previously determined in this cultivar. Responses of pigmentation and shoot productivity were more closely related to stomatal responses at midday than to responses at other times of day under well-watered (WW) conditions, reflecting higher stomatal responsivity, sensitivity to O3 , and magnitude of midday gs . Under WD conditions, shoot responses were more closely related to early morning gs. Root responses were more closely related to early morning gs under both WW and WD. Responses of stomata to O3 at midday were not good surrogates for stomatal responses early or late in the day, and may not adequately predicting O3 flux under WD or when maximum ambient concentrations do not occur near midday. PMID- 26031550 TI - Rapid assessment of cognitive function in down syndrome across intellectual level and dementia status. AB - BACKGROUND: Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population. METHODS: In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT). RESULTS: The RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs (114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment. CONCLUSION: Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia. PMID- 26031551 TI - Acute Cardiovascular Response during Resistance Exercise with Whole-body Vibration in Sedentary Subjects: A Randomized Cross-over Trial. AB - This study aimed to compare the acute cardiovascular responses during and after resistance exercise with and without whole-body vibration. Nineteen sedentary adults randomly performed one session of isometric squats without vibration and the same exercise with vibration. Systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) were measured. SBP, DBP and HR were also measured for 20 min after the sessions. The exercise with vibration demonstrated significant values (P < 0.05) for SBP (second to sixth sets), DBP (third to sixth sets) and SVR (second to sixth sets) compared with the exercise without vibration. After the sessions, the values of SBP for both exercises were significantly lower than the respective resting values; with no difference between the sessions. In conclusion, exercise with vibration caused increases in SBP, DBP and SVR compared with exercise with no vibration in sedentary adults. PMID- 26031552 TI - Long-term quality of life after oesophagectomy with gastric conduit interposition for cancer. AB - BACKGROUND: Gaining insight in long-term health-related quality of life more than 1year after oesophagectomy will assist clinical decision-making and inform patients about the long-term consequences of surgery. METHODS: In this cross sectional study, all consecutive patients who underwent oesophageal resection with gastric interposition for cancer at a tertiary referral centre between January 2007 and July 2012 were included. European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and QLQ-OES18 were sent to all patients alive without recurrence more than 1year after surgery. RESULTS: The questionnaires were completed by 92 of 100 patients. Median duration of follow-up after surgery at completing the questionnaire was 36months (range: 12-75). Global quality of life scores were similar to a general population reference group (76+/-19 versus 78+/-17; p=0.26). However, patients scored significantly worse compared to the general population reference group on physical-, role-, cognitive- and social functioning (p<0.001). Neoadjuvant therapy and minimally invasive oesophagectomy were associated with significantly better health-related quality of life (HRQL) and symptom scores (p<0.05). CONCLUSION: Global HRQL more than 1year after oesophagectomy with gastric tube reconstruction is comparable to the general Dutch background population, while specific functional and symptom scores are significantly worse. Neoadjuvant therapy and minimally invasive surgery are associated with quality of life benefits in long-term survivors. PMID- 26031553 TI - Associations between frailty and serum N-terminal propeptide of type I procollagen and 25-hydroxyvitamin D in older Spanish women: The Toledo Study for Healthy Aging. AB - Frail older people are at high risk for fractures and falls increasing the rates of institutionalization and mortality. Bone markers have been related to both aging and fractures. However, no previous reports have shown a potential relationship between serum bone markers such as N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (beta-CTX) and parathyroid hormone (PTH) with frailty in elderly female populations. This study is aimed at examining the associations of bone metabolism markers and frailty in older Spanish women through a descriptive cross-sectional analysis based on a cohort of the Toledo Study for Healthy Aging (TSHA). The levels of serum PINP, beta-CTX, PTH and 25-hydroxyvitamin D (25(OH)D) were assessed in 592 participants (median age 74years) who were defined as robust, prefrail and frail according to Fried's approach. Frail subjects had significantly high levels of PINP, beta-CTX and PTH and low production of 25(OH)D. After adjustment for confounders, high PINP levels (defined by the upper quartile) and low levels of 25(OH)D (lower quartile) remained significantly associated to frailty [OR for PINP: 2.19 (95% CI, 1.15-4.18; P=0.017); OR for 25(OH)D: 1.65 (95% CI, 1.02-2.67; P=0.042)]. Women with both high PINP levels and low 25(OH)D levels presented a 5.85-fold increased frailty risk (95% CI, 1.64-20.93; P=0.007). The main contribution of this paper is the novel definition of PINP and 25(OH)D markers as potential biomarkers of frailty and targets for intervention. PMID- 26031554 TI - [Pylephlebitis due to Aeromonas caviae secondary to acute cholecystitis]. PMID- 26031555 TI - A rare presentation of ruptured infected popliteal artery aneurysm with massive local emphysema. PMID- 26031556 TI - Effects of polysaccharides from selenium-enriched Pyracantha fortuneana on mice liver injury. AB - We have previously reported that polysaccharides extracted from Pyracantha fortuneana (Maxim.) Li (P. fortuneana) lowered the oxidative stress and inhibited the inflammatory responses in mice. Our present study aims to determine the effects of Selenium enriched P. fortuneana polysaccharides (Se-PFPs) against carbon tetrachloride (CCl4)-induced liver injury in a mouse model. Our results displayed that CCl4 remarkably elevated the levels of alanine transferase (ALT), aspartate transaminase (AST), lactic dehydrogenase (LDH), cholesterol, triglycerides in serum. However, similar to BP treatment, supplementation of mice with Se-PFPs resulted in reversal of ALT, AST, LDH, cholesterol, triglycerides in serum. Contrary to CCl4, supplementation of mice with Se-PFPs elevated the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and levels of glutathione (GSH) in liver. Furthermore, Se-PFPs treatment increased the expression of GPx and catalase (CAT) at mRNA and protein levels in liver which were decreased in CCl4 group. Contrary to CCl4, Se-PFPs supplement decreased the levels of thiobarbituric acid reactive substances (TBAR) and H2O2, which served as lipid peroxidation biomarker. Our study indicates that Se-PFPs administration is effective in attenuating CCl4-induced liver injury. The mechanism underlying this effect may be attributed to the reduction of oxidative stress and inflammation in the liver by Se-PFPs through up-regulation of the antioxidant system. Our study suggests that Se-PFPs might be a potential dietary agent in the prevention of hepatic damage. PMID- 26031557 TI - Loss of kinesin-14 results in aneuploidy via kinesin-5-dependent microtubule protrusions leading to chromosome cut. AB - Aneuploidy-chromosome instability leading to incorrect chromosome number in dividing cells-can arise from defects in centrosome duplication, bipolar spindle formation, kinetochore-microtubule attachment, chromatid cohesion, mitotic checkpoint monitoring or cytokinesis. As most tumours show some degree of aneuploidy, mechanistic understanding of these pathways has been an intense area of research, to provide potential therapeutics. Here we present a mechanism for aneuploidy in fission yeast based on spindle pole microtubule defocusing by loss of kinesin-14 Pkl1, leading to kinesin-5 Cut7-dependent aberrant long spindle microtubule minus-end protrusions that push the properly segregated chromosomes to the site of cell division, resulting in chromosome cut at cytokinesis. Pkl1 localization and function at the spindle pole is mutually dependent on spindle pole-associated protein Msd1. This mechanism of aneuploidy bypasses the known spindle assembly checkpoint that monitors chromosome segregation. PMID- 26031558 TI - Burkitt lymphoma with unusual presentation: Acute pancreatitis. AB - Pancreatitis due to malignant infiltration is an uncommon condition in childhood. Pancreatic lymphomas constitute <2% of all non-Hodgkin lymphomas. Only six reported cases with various clinical presentation have been documented in the literature. Described herein is the case of a nine-year-old boy with abdominal pain, jaundice, emesis, weight loss, diarrhea, who developed hyperlipidemia and cholestasis. Pancreatitis was suspected due to high amylase and lipase. Computed tomography and magnetic resonance cholangiopancreatography showed diffuse enlargement of the pancreas. This sausage pancreas imaging was suggestive of autoimmune pancreatitis, but the patient was diagnosed with Burkitt lymphoma on bone marrow aspiration, and rapidly improved with chemotherapy. Burkitt lymphoma should be kept in mind when patients present with pancreatitis, especially with diffuse enlarged pancreas. PMID- 26031559 TI - What's your excuse for Foley use? PMID- 26031560 TI - Estimating the Diurnal Cycle and Daily Insolation of Ultraviolet and Photosynthetically Active Radiation at the Sea Surface. AB - Accurate determination of the diurnal variability and daily insolation of surface (0(+) ) and subsurface (0(-) ) irradiance are essential to estimate several physical, chemical and biological processes occurring at the surface layer of marine environments. Natural downwelling PAR and spectral UVR were examined on eight occasions at 0(+) and 0(-) to refine empirical models, particularly in the UVR spectrum. The diurnal variability in UVR and PAR were wavelength dependent and were modeled by a sinusoidal equation. The best fit for PAR at 0(+) and 0(-) was the sinusoid power of n = 2 and n = 2.5, respectively. In the UVR spectrum, sinusoids increased as wavelengths decreased ranging from n = 2-5. Higher n values in the UV-B spectrum suggest sharper increase/decrease near sunrise and sunset hours, ultimately reducing the final value of daily insolation at specified wavelengths. Calculated daily insolation of UV-B/(UV-A + PAR) ratio suggests that photoinhibition from exposure to UV-B occurs within a shorter biologically effective day length than PAR, and is high during summer and low during winter. These results suggest that biogeochemical calculations based on diurnal models of irradiance measurements would benefit from accurate solar noon references and wavelength specificity, particularly in the UVR spectrum. PMID- 26031561 TI - [Sudden cardiac death during a city marathon run]. AB - Sudden cardiac death (SCD) in young athletes during physical stress is a rare event with an incidence of 1-3 deaths per 100,000 athletes per year. A coronary anomaly is the second most common cause of death following hypertrophic cardiomyopathy. Symptomatic prodromes occur in 20% of cases prior to the SCD event. This case report describes a 35-year-old male who collapsed near the finishing line of a half marathon run. Despite immediate resuscitation attempts and initial return of spontaneous circulation (ROSC), a pulseless electrical activity (PEA) followed and the patient died 1 h after arrival in the resuscitation unit. The autopsy revealed an anomalous left coronary artery (ALCA), which can lead to ischemia of the respective heart muscles under severe stress. PMID- 26031562 TI - Constructing three-dimensional (3D) nanocrystalline models of Li4SiO4 for numerical modeling and simulation. AB - The three-dimensional (3D) nanocrystalline models of lithium silicates with the log-normal grain size distribution are constructed by constrained Voronoi tessellation. During evolution process, the algorithm is improved. We proposed a new algorithm idea by combining Genetic Algorithm (GA) with Least Square (LS) method to make up for the disadvantages of traditional genetic algorithm which may be easily trapped in local optimal solution. In the process of modeling, it is the first time, to the best of our knowledge, that we keep the whole sample showing the charge neutrality by deleting the excess atoms on the polyhedron boundary during the modeling. By using the molecular-dynamics method, the relaxation procedure of nanostructured Li4SiO4 is carried out. The results show that the average mass density of the sample is slightly lower than the experimental data of the perfect crystal after relaxation process. In addition, boundary component proportion (BCP) and density reduction proportion (DRP) of the sample is obtained, respectively. The present results display a significantly reduced BCP but an increased DRP when increasing the mean grain size of the sample. PMID- 26031563 TI - Transmission of a pathogenic virus (Iridoviridae) of Culex pipiens larvae mediated by the mermithid Strelkovimermis spiculatus (Nematoda). AB - Little progress been made in elucidating the transmission pathway of the invertebrate iridescent virus (MIV). It has been proposed that the MIV has no active means to enter the mosquito larva. We have previously found that the presence of the mermithid nematode Strelkovimermis spiculatus is associated with MIV infection in Culex pipiens under field conditions. In the present study, we evaluated the transmission of MIV to C. pipiens larvae mediated by S. spiculatus and several factors involved in this pathway (mosquito instars, nematode:mosquito larva ratio, amount of viral inoculum). Our results indicate that S. spiculatus functions as an MIV vector to C. pipiens larvae and seems to be an important pathway of virus entry into this system. Moreover, TEM images of S. spiculatus exposed to the viral suspension showed no infections inside the nematode but showed that viral particles are carried over the cuticle of this mermithid. This explains the correspondence between MIV infection and the factors that affect the parasitism of S. spiculatus in C. pipiens larvae. PMID- 26031564 TI - Bee pathogens found in Bombus atratus from Colombia: A case study. AB - Bombus atratus bumblebees from Colombia that were caught in the wild and from breeding programs were screened for a broad set of bee pathogens. We discovered for the first time Lake Sinai Virus and confirmed the infection by other common viruses. The prevalence of Apicystis bombi, Crithidia bombi and Nosema ceranae was remarkably high. According to other studies the former two could have been co introduced in South America with exotic bumble bees as Bombus terrestris or Bombus ruderatus. Given the fact that none of these species occur in Colombia, our data puts a new light on the spread of these pathogens over the South American continent. PMID- 26031565 TI - Myrmecomorba nylanderiae gen. et sp. nov., a microsporidian parasite of the tawny crazy ant Nylanderia fulva. AB - A new microsporidian genus and species, Myrmecomorba nylanderiae, is described from North American populations of the tawny crazy ant, Nylanderia fulva. This new species was found to be heterosporous producing several types of binucleate spores in both larval and adult stages and an abortive octosporoblastic sporogony in adult ants. While microsporidia are widespread arthropod parasites, this description represents only the fifth species described from an ant host. Molecular analysis indicated that this new taxon is phylogenetically closely allied to the microsporidian family Caudosporidae, a group known to parasitize aquatic black fly larvae. We report the presence of 3 spore types (Type 1 DK, Type 2 DK, and octospores) with infections found in all stages of host development and reproductive castes. This report documents the first pathogen infecting N. fulva, an invasive ant of considerable economic and ecological consequence. PMID- 26031566 TI - Empagliflozin as add-on to metformin in people with Type 2 diabetes. AB - AIMS: To investigate the long-term efficacy and safety of empagliflozin as add-on to metformin in people with Type 2 diabetes. METHODS: Of 637 participants treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks, 463 (72.7%) were treated in a double-blind extension trial for >= 52 weeks. Prespecified exploratory endpoints included changes from baseline in HbA1c , weight and blood pressure at week 76. RESULTS: Compared with placebo, adjusted mean changes from baseline in HbA1c (overall baseline mean +/- sd 63 +/- 9 mmol/mol [7.9 +/- 0.9%]) were -7 mmol/mol [(-0.6%) 95% CI -8, -5 mmol/mol (-0.8, 0.5%); P < 0.001] and -8 mmol/mol [(-0.7%) 95% CI -10, -6 mmol/mol (-0.9, -0.6%); P < 0.001], for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, adjusted mean changes from baseline in weight were -1.9 kg (95% CI -2.5, -1.3; P < 0.001) and -2.2 kg (95% CI -2.8, -1.6; P < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Empagliflozin led to sustained reductions in systolic blood pressure vs. placebo. Adverse events were reported in 77.7, 80.2 and 72.0% of participants on placebo, empagliflozin 10 mg and empagliflozin 25 mg, respectively. Confirmed hypoglycaemic adverse events (glucose <= 3.9 mmol/l and/or event requiring assistance) were reported in 3.4, 4.1 and 4.2% of participants in these groups, respectively. CONCLUSIONS: In people with Type 2 diabetes, empagliflozin 10 mg and 25 mg given as add-on to metformin for 76 weeks were well tolerated and led to sustained reductions in HbA1c , weight and systolic blood pressure. PMID- 26031567 TI - Cognitive Status According to Homocysteine and B-Group Vitamins in Elderly Adults. AB - OBJECTIVES: To determine the association between hyperhomocysteinemia and cognitive function, taking into account the effect of B group vitamin (BGV) deficiency. DESIGN: Cross-sectional. SETTING: Memory Clinic, S. Anna University Hospital, Ferrara, Italy. PARTICIPANTS: Elderly individuals (>=65) (N = 318; 44 normal cognition, 127 with cognitive impairment, 147 with dementia) divided into four groups according to plasma homocysteine (high vs normal) and BGV (normal vs deficit) levels. MEASUREMENTS: Cognitive, clinical, biochemical, functional, and neuroimaging parameters were evaluated. RESULTS: Hyperhomocysteinemia (>15 MUmol/L) was associated with a higher prevalence of cognitive and functional impairment and dementia (odds ratio (OR) = 1.98, 95% confidence interval (CI) = 1.13-3.48), independent of BGV status and other confounders. Participants with hyperhomocysteinemia with normal BGV status had the worst functional status and the highest prevalence of dementia (high homocysteine/normal BGV vs normal homocysteine/normal BGV: OR = 3.20, 95% CI = 1.65-6.21). Homocysteine levels were correlated negatively with folate and vitamin B12 levels and glomerular filtration rate and positively with free thyroxine and uric acid levels (model coefficient of determination = 0.43). CONCLUSION: Hyperhomocysteinemia was associated with worse cognitive and functional status and dementia independently of BGV levels. Approximately half of participants with hyperhomocysteinemia had normal BGV levels, suggesting that other unmeasured factors might be associated with high homocysteine levels. PMID- 26031568 TI - Reproductive isolation with a learned trait in a structured population. AB - Assortative mating displays and/or preferences can be affected by learning across a wide range of animal taxa, but the specifics of how this learning affects speciation with gene flow are not well understood. We use population genetic models with trait learning to investigate how the identity of the tutor affects the divergence of a self-referent phenotype-matching trait. We find that oblique learning (learning from unrelated individual of the previous generation) and maternal learning mask sexual selection and therefore do not allow the maintenance of divergence. In contrast, by enhancing positive frequency-dependent sexual selection, paternal learning can maintain more divergence than genetic inheritance, but leads to the loss of polymorphism more easily. Furthermore, paternal learning inhibits the invasion of a novel self-referent phenotype matching trait, especially in a large population. PMID- 26031569 TI - Canine parvoviruses in New Zealand form a monophyletic group distinct from the viruses circulating in other parts of the world. AB - Canine parvovirus 2 (CPV-2) is a well-recognized cause of acute haemorrhagic enteritis in dogs worldwide. The aim of the current study was to identify which CPV-2 subtypes circulate among dogs in New Zealand, and to investigate the evolutionary patterns of contemporary CPV-2 viruses. Faecal samples were collected from 79 dogs with suspected CPV-2 infection over the period of 13 months, and tested for the presence of CPV-2 DNA by PCR. Of 70 positive samples, 69 were subtyped as CPV-2a and one as CPV-2. A majority of CPV-2 positive samples were collected from unvaccinated or not-fully vaccinated puppies <=6 months of age. The haplotype network produced from New Zealand CPV-2 sequences showed no structure when assessed based on location, vaccination status or age of the animals sampled. International haplotype network indicated that, unlike CPV-2 from other countries, the population of CPV-2 in New Zealand appeared to be monophyletic. PMID- 26031570 TI - Admission Glycaemia and Acute Insulin Resistance in Heart Failure Complicating Acute Coronary Syndrome. AB - BACKGROUND: Few data are so far available on the relation between increased glucose values and insulin resistance and mortality at short-term in patients with acute heart failure (AHF). METHODS: The present investigation, performed in 409 consecutive patients with AHF complicating acute coronary syndrome (ACS), was aimed at assessing the prognostic role of admission glycaemia and acute insulin resistance (as indicated by the Homeostatic Model Assessment - HOMA index) for death during Intensive Cardiac Care (ICCU) stay. Admission glucose tertiles were considered. RESULTS: In our series, diabetic patients accounted for the 33%. Patients in the third glucose tertiles exhibited the lowest LVEF (both on admission and at discharge), a higher use of mechanical ventilation, intra-aortic balloon pump and inotropic drugs and the highest in-ICCU mortality rate. In the overall population, hyperglycaemic patients (both diabetic and non diabetic) were 227 (227/409, 55.5%). Admission glycaemia was an independent predictor of in-ICCU mortality, together with admission LVEF and eGFR, while acute insulin resistance (as indicated by HOMA-index) was not associated with early death. The presence of admission hyperglycaemia in non-diabetic patients was independently associated with in-ICCU death while hyperglycaemia in diabetic patients was not. CONCLUSIONS: According to our results, hyperglycaemia is a common finding in patients with ACS complicated by AHF and it is an independent predictor of early death. Non-diabetic patients with hyperglycaemia are the subgroup with the highest risk of early death. PMID- 26031571 TI - Punishment in public goods games leads to meta-stable phase transitions and hysteresis. AB - The evolution of cooperation has been a perennial problem in evolutionary biology because cooperation can be undermined by selfish cheaters who gain an advantage in the short run, while compromising the long-term viability of the population. Evolutionary game theory has shown that under certain conditions, cooperation nonetheless evolves stably, for example if players have the opportunity to punish cheaters that benefit from a public good yet refuse to pay into the common pool. However, punishment has remained enigmatic because it is costly and difficult to maintain. On the other hand, cooperation emerges naturally in the public goods game if the synergy of the public good (the factor multiplying the public good investment) is sufficiently high. In terms of this synergy parameter, the transition from defection to cooperation can be viewed as a phase transition with the synergy as the critical parameter. We show here that punishment reduces the critical value at which cooperation occurs, but also creates the possibility of meta-stable phase transitions, where populations can 'tunnel' into the cooperating phase below the critical value. At the same time, cooperating populations are unstable even above the critical value, because a group of defectors that are large enough can 'nucleate' such a transition. We study the mean-field theoretical predictions via agent-based simulations of finite populations using an evolutionary approach where the decisions to cooperate or to punish are encoded genetically in terms of evolvable probabilities. We recover the theoretical predictions and demonstrate that the population shows hysteresis, as expected in systems that exhibit super-heating and super-cooling. We conclude that punishment can stabilize populations of cooperators below the critical point, but it is a two-edged sword: it can also stabilize defectors above the critical point. PMID- 26031572 TI - Uptake of community-based, self-collected HPV testing vs. visual inspection with acetic acid for cervical cancer screening in Kampala, Uganda: preliminary results of a randomised controlled trial. AB - OBJECTIVES: To compare two cervical cancer screening methods: community-based self-collection of high-risk human papillomavirus (HR-HPV) testing and visual inspection with acetic acid (VIA). METHODS: Pilot randomised controlled trial of 500 women aged 30-65 in the community of Kisenyi, Uganda. Women randomised to self-collection-based HR-HPV testing provided a cervico-vaginal swab for HR-HPV, and results were provided by phone after laboratory testing. Women who tested HPV positive were referred for VIA at the local health unit. Women randomised to VIA underwent screening at the local health unit, where women who tested positive with VIA were provided cryotherapy at time of screening, as per local standard of care. Women were referred for colposcopy when indicated. Outcome measures were uptake of screening, HR-HPV prevalence, VIA result and treatment rates. RESULTS: In the HR-HPV arm, 248 of 250 (p < 0.01) women provided samples, while in the VIA arm, 121 of 250 (48.4%) women attended screening. Among the 73 of 248 HR-HPV positive women, 45.2% (N = 33) attended VIA screening for follow-up, 21.2% (N = 7) of whom screened positive; five received treatment and two were missing clinical follow-up records. Of the 121 women in the VIA arm who attended screening, 13.2% (N = 16) screened positive; seven received cryotherapy, three refused treatment, five were referred to colposcopy; and one woman had suspected cervical cancer and received treatment after confirmatory testing. CONCLUSIONS: This pilot study demonstrated trial feasibility and willingness of the women to participate and be randomised successfully into the two arms. Self-collection based cervical cancer screening had a higher uptake than VIA. PMID- 26031573 TI - Response of bacteria and meiofauna to iron oxide colloids in sediments of freshwater microcosms. AB - The use of colloidal iron oxide (FeOx) in the bioremediation of groundwater contamination implies its increasing release into the environment and requires an assessment of its ecotoxicological risk. Therefore, microcosm experiments were carried out to investigate the impact of ferrihydrite colloids on the bacterial and meiofaunal communities of pristine freshwater sediments. The effects of ferrihydrite colloids were compared with those of ferrihydrite macroaggregates to discriminate between colloid-specific and general FeOx impacts. The influence of ferrihydrite colloids on the toxicity of sediment-bound fluoranthene was also considered. At high concentrations (496 mg Fe kg(-1) sediment dry wt), ferrihydrite colloids had a significant, but transient impact on bacterial and meiofaunal communities. Although bacterial community composition specifically responded to ferrihydrite colloids, a more general FeOx effect was observed for meiofauna. Bacterial activity responded most sensitively (already at 55 mg Fe kg( 1) dry wt) without the potential of recovery. Ferrihydrite colloids did not influence the toxicity of sediment-bound fluoranthene. Significant correlations between bacterial activity and meiofaunal abundances were indicative of trophic interactions between bacteria and meiofauna and therefore of the contribution of indirect food web effects to the observed impacts. The results suggest that the application of ferrihydrite colloids for remediation purposes in the field poses no risk for benthic communities, given that, with the exception of generic bacterial activity, any negative effects on communities were reversible. PMID- 26031574 TI - Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients. AB - Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG <= 1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28 months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials. PMID- 26031575 TI - Modulating the innate immune activity in murine tumor microenvironment by a combination of inducer molecules attached to microparticles. AB - Targeted cancer immunotherapy is challenging due to the cellular diversity and imposed immune tolerance in the tumor microenvironment (TME). A promising route to overcome those drawbacks may be by activating innate immune cells (IIC) in the TME, toward tumor destruction. Studies have shown the ability to "re-educate" pro tumor-activated IIC toward antitumor responses. The current research aims to stimulate such activation using a combination of innate activators loaded onto microparticles (MP). Four inducers of Toll-like receptors 4 and 7, complement C5a receptor (C5aR) and gamma Fc receptor and their combinations were loaded on MP, and their influence on immune cell activation evaluated. MP stimulation of immune cell activation was tested in vitro and in vivo using a subcutaneous B16-F10 melanoma model induced in C57BL6 mice. Exposure to the TLR4 ligand lipopolysaccharide (LPS) bound to MP-induced acute inflammatory cytokine and chemokine activity in vitro and in vivo, with the elevation of CD45(+) leukocytes in particular GR-1(+) neutrophils and F4/80 macrophages in the TME. Nevertheless, LPS alone on MP was insufficient to significantly delay tumor progression. LPS combined with the C5aR ligand C5a-pep on the same MP resulted in a similar inflammation activation pattern. However, interleukin-10 levels were lower, and tumor growth was significantly delayed. Mixtures of these two ligands on separate MP did not yield the same cytokine activation pattern, demonstrating the importance of the cells' dual activation. The results suggest that combining inducers of distinct innate immune activation pathways holds promise for successful redirection of TME-residing IIC toward anti-tumoral activation. PMID- 26031576 TI - Genetic susceptibility to cervical squamous cell carcinoma is associated with HLA DPB1 polymorphisms in Taiwanese women. AB - Cervical cancer is a multifactorial disease, and increasing evidence suggests that host immunogenetic background may contribute to its pathogenesis. Genetic variations in human leukocyte antigen (HLA) genes may alter the efficiency of immune response to human papillomavirus (HPV) antigens and have been implicated in the risk of cervical cancer. We investigated whether polymorphisms in the HLA DPB1 gene were associated with cervical cancer risk in a Taiwanese population. HLA-DPB1 alleles and +550 G/A polymorphism were genotyped in a case-control study of 473 women with cervical squamous cell carcinoma (CSCC) and 676 healthy controls. The presence and genotypes of HPV in CSCC were determined. We found that the DPB1*05:01 and +550 A alleles were associated with decreased and increased risk of CSCC, respectively [odds ratio (OR) = 0.72, Pc = 0.001; OR = 1.25, Pc = 0.03]. In subgroup analysis based on HPV type 16 positivity, significant associations were shown in the DPB1*05:01 and *13:01 alleles (OR = 0.65, Pc = 0.0007; OR = 1.83, Pc = 0.004). Furthermore, the DPB1*05:01-G and *13:01-G haplotypes conferred decreased and increased risk of both CSCC and HPV 16 positive CSCC women, respectively (OR = 0.72, Pc = 0.0009; OR = 0.63, Pc = 0.0004 for DPB1*05:01-G; OR = 1.55, Pc = 0.03; OR = 1.84, Pc = 0.004 for DPB1*13:01-G). A risk haplotype DPB1*02:01-A was also observed in the HPV-16 positive CSCC women (OR = 1.51, Pc = 0.05). These findings suggest that HLA-DPB1 gene is involved in the CSCC development. PMID- 26031577 TI - Introduction. PMID- 26031578 TI - Banff 2013 update: Pearls and pitfalls in transplant renal pathology. AB - The pathological classification of rejection in renal allografts (Banff classification) has undergone substantial evolution for more than 20 years, and has been the diagnostic gold standard in clinical practice. The 2013 updated Banff classification encompasses a revised scheme of antibody-mediated rejection (ABMR) that consists of donor-specific antibody (DSA) positivity, characteristic histological manifestations for both acute and chronic ABMR, and DSA-induced endothelial cell injury which is represented by either C4d positivity, microvascular inflammation or expression of activated endothelial gene transcripts. Other modified criteria include a C4d positivity threshold, and histological definition of transplant glomerulitis and transplant glomerulopathy. Morphologically, glomerulonephritis, either recurrent or de novo, can be challenging to differentiate from ABMR-mediated transplant glomerulitis. Endothelial arteritis by itself does not warrant the diagnosis of acute T-cell mediated rejection; ABMR should also be considered based on the DSA test results. With regard to polyomavirus BK-associated nephropathy, immunohistochemical examination using anti-simian virus (SV) 40 antibody can be a promising method to assess the quantitative viral load of polyomavirus BK and graft survival. In summary, the 2013 updated Banff classification strictly defines ABMR with histopathological and serological criteria irrespective of C4d positivity. Inclusion of gene expression data relevant to ABMR highlights that the Banff criteria have entered the era of 'Seeing the Unseen' schemes, reflecting recent advances in understanding the molecular events in allograft injury. PMID- 26031579 TI - Currently available useful immunohistochemical markers of renal pathology for the diagnosis of renal allograft rejection. AB - Renal allograft dysfunction may be induced by various causes, including alloimmune rejection, viral infection, urinary tract obstruction, calcineurin inhibitor nephrotoxicity and/or recurrent renal disease. In order to determine the underlying cause, a renal biopsy is performed and the renal transplant pathology is diagnosed using the internationally consensus Banff classification. Although a progressive understanding of allograft rejection has provided numerous immunohistochemical markers, only the C4d is regarded to be a sufficiently useful marker for antibody-mediated allograft rejection according to the Banff classification. This review summarizes currently available useful immunohistochemical markers of renal transplant pathology, including C4d, with diagnostic implications for human renal allograft rejection. In particular, we discuss immunohistochemical markers in the following three categories: immunohistochemical markers of renal pathology used to (i) analyze the mechanisms of alloimmune rejection, (ii) monitor cell injury and/or inflammation associated with rejection and (iii) identify renal components in order to improve the diagnosis of rejection. In addition, recent progress in the field of renal transplant pathology includes the development of a new method for assessing molecular pathology using OMICS analyses. As the recent findings of various studies in patients undergoing renal transplantation are very encouraging, novel immunohistochemical markers must be also developed and combined with new technologies for the diagnosis of human renal allograft rejection. PMID- 26031580 TI - The impact of C4d-negative acute antibody-mediated rejection on short-term prognosis among kidney transplant recipients. AB - AIM: We aimed to investigate the clinical and pathological features of C4d negative acute antibody-mediated rejection (aAMR), and examined the impact of C4d negative aAMR on short-term prognosis. METHODS: From 2005 to 2011, 626 kidney transplantations were performed in our institution and related hospitals. We excluded 174 ABO-incompatible transplantations, and analysed clinical and pathological data from the remaining 452 until December 2013. RESULTS: During the follow-up period, 39 patients underwent aAMR. We divided them into two groups. According to C4d positivity in each patient's first AMR, we divided the cohort into a C4d-positive aAMR group and a C4d-negative aAMR group, using the new Banff 2013 classification. We compared each aAMR patient's features to controls. Clinical and pathological characteristics were similar in both groups and the short-term outcomes of the two groups were similar, but both were worse than control. CONCLUSION: C4d-negative aAMR resembles C4d-positive aAMR in terms of clinical and pathological features, and that C4d positivity has no influence on short-term outcome. PMID- 26031581 TI - Clinical and pathological analyses of chronic vascular rejection after kidney transplantation. AB - AIM: We discuss the clinicopathological analysis of cases of chronic vascular rejection (CVR) cases after renal transplantation and clarify the mechanisms underlying the development and prognostic significance of CVR. PATIENTS: CVR was diagnosed in 46 renal allograft biopsy specimens (BS) obtained from 34 renal transplant patients being followed up at the Department of Urology, Tokyo Women's Medical University, between January 2009 and December 2013. RESULTS: CVR was diagnosed at a median of 47.4 months post-transplant. Among the 36 patients, 23 had a history of acute rejection. Among the 46 BS showing evidence of CVR, the CVR was mild (cv1 in Banff's classification) in 23, moderate (cv2) in 17, and severe (cv3) in 6. Of the 40 samples obtained at the time of the biopsy and assayed with plastic beads coated with HLA antigen, 31 (78%) showed circulating ant-HLA alloantibody, and 15 (38%) showed donor-specific antibodies. We then classified the 46 BS showing evidence of CVR by their overall histopathological features, as follows; cv alone was seen in 16 (35%) BS, cv + antibody-mediated rejection (AMR) in 26 (56%), and cv + T-cell-mediated rejection in 9 (19%). Loss of the renal allograft occurred during the observation period in nine of the patients (26%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 11 patients (32%). CONCLUSION: The results of our study suggest that AMR may underlie CVR in many cases, while T cell-mediated rejection may play an important role in some cases. PMID- 26031582 TI - Microvascular inflammation in early protocol biopsies of renal allografts in cases of chronic active antibody-mediated rejection. AB - AIM: Chronic active antibody-mediated rejection (chronic ABMR) is one important cause of late-stage renal allograft loss. However, few reports have used protocol biopsy to observe changes over time in cases that develop chronic ABMR. The aim of this study was to use protocol biopsy to clarify the histological features of cases that develop chronic ABMR. METHODS: We recruited 379 ABO compatible patients who underwent protocol biopsy at our hospital from 2010 to 2014. Seventeen of these patients were diagnosed with chronic ABMR (chronic ABMR group), and 12 patients were class 2 donor-specific antibody (DSA) positive and were not diagnosed with chronic ABMR (class 2 DSA-positive group). With the addition of a control group consisting of 30 DSA negative patients, these three groups were compared for Banff factors in protocol biopsies taken 3 months, 6 months, 1 year, 3 years, and 5 years after the transplant. RESULTS: Three months post transplant, the chronic ABMR group had a significantly higher number of patients exhibiting g + ptc > 0 than that in the control group (P = 0.01). At 1, 3, and 5 years post transplant, significantly more subjects in the chronic ABMR and class 2 DSA-positive groups compared with the control group exhibited g + ptc > 0 (P < 0.03). Five years post transplant, the chronic ABMR group exhibited a significantly higher mean c4d score than that in the control group (P = 0.02). The only significant difference observed between the chronic ABMR group and the class 2 DSA-positive group was in cg scores at 5 years post transplant, which were significantly higher in the chronic ABMR group (P = 0.03). CONCLUSIONS: These results suggest that cases exhibiting microvascular inflammation in the early post-transplant period may develop chronic ABMR, and it would be highly beneficial to perform focused electron microscope surveillance of these cases. PMID- 26031583 TI - Change in glomerular volume and its clinicopathological impact after kidney transplantation. AB - BACKGROUND: Both immunological and non-immunological etiologies affect graft function after kidney transplantation, including acute rejection, calcineurin inhibitor toxicity, and a recurrence of glomerulonephritis. Glomerular enlargement or glomerular sclerosis due to glomerular hyperfiltration related to increased renal blood flow is another cause. Although the glomerular volume in baseline biopsies predicts late allograft function, the relationship between allograft function and the annual changes in glomerular volume after kidney transplantation are unclear. AIM: We investigated changes in glomerular volume after kidney transplantation and their clinicopathological relationship. METHODS: We enrolled 23 patients with stable kidney function without an episode of rejection or any complication resulting in a functional decrease in the graft. We measured glomerular volume (GV) using the Weibel-Gomez method and glomerular density (GD) using 0,1 h biopsy samples as baseline controls and 1 yr biopsy samples and investigated the association between the changes in them and clinical parameters, including graft function, proteinuria, and renal hemodynamic markers, including effective renal plasma flow (ERPF) and filtration fraction (FF). The ERPF was calculated from a 99mTc-mercaptoacetyltriglycine (MAG3) renogram. RESULTS: The GV and ERPF increased significantly 1 yr after kidney transplantation. In contrast, proteinuria decreased significantly and Deltaproteinuria (1 yr - 1 month after transplantation) was correlated with DeltaGV (P < 0.05, rs = -0.467). CONCLUSION: Glomerular enlargement 1 yr after transplantation may be related to improved proteinuria. It is possible that glomerular enlargement serves as a renal adaptation after kidney transplantation. PMID- 26031584 TI - Clinical and pathological features of donor/recipient body weight mismatch after kidney transplantation. AB - BACKGROUND: Previous studies have shown that a donor/recipient body weight mismatch affects long-term graft survival and graft function after kidney transplantation. However, the mechanisms are not fully understood. AIM: To address the mechanisms, we compared the pathological and physiological features between patients with a donor/recipient body weight mismatch and those without a mismatch 1 yr after kidney transplantation. Furthermore, we investigated the correlation with the donor/recipient body weight ratio. METHODS: We examined allograft biopsy specimens from 10 recipients with stable kidney function, with body weight mismatch (donor/recipient body weight ratio [D/R BWR] < 0.9), and compared them with samples from 13 patients without mismatch. We measured glomerular volume (GV) using the Weibel-Gomez method and glomerular density (GD) defined by nonsclerotic glomerular number/renal cortical area as pathological findings. The physiological parameters included estimated glomerular filtration rate and proteinuria (mg/day). These data were evaluated to identify a correlation with D/R BWR. RESULTS: The pathological features showed that GV and GD were identical in the two groups. However, when glomerular enlargement was defined by DeltaGV (GV at the 1-yr biopsy minus GV at baseline biopsy), DeltaGV was higher in mismatch cases compared with that in cases without a mismatch (10.6 +/- 4.6 vs. 5.5 +/- 7.1 * 10(5) MUm(3) ; P = 0.049). Furthermore, D/R BWR was significantly correlated with DeltaGV (P = 0.03, r = -0.436). eGFR values were physiologically identical between the two groups, but the mismatch cases had significantly higher proteinuria levels than that of the cases without a mismatch at 1 yr after kidney transplantation. CONCLUSION: A donor/recipient body weight mismatch could affect glomerular enlargement and increased proteinuria 1 yr after kidney transplantation. How these two features affect long-term graft survival and function must be addressed in the future. PMID- 26031585 TI - Histological reversibility of diabetic nephropathy after kidney transplantation from diabetic donor to non-diabetic recipient. AB - AIM: Given the recent increase in the prevalence of diabetes mellitus, it is not uncommon for kidney transplantation donors to have diabetes. We perform kidney transplantation in our hospital if the diabetic donors are receiving oral hypoglycaemic agents, but not insulin, and their haemoglobin A1C (HbA1C) is below 6.5%. There are few reports about histological changes to diabetic nephropathy after transplantation of kidney grafts from donors with diabetes mellitus to non diabetic recipients. Therefore, we studied the histological diabetic changes in grafts from diabetic donors at protocol biopsies (1 hour, 1 month, 1 year), and evaluated whether they improved under the recipient's good glycaemic control. METHODS: Three cases of kidney transplantation from donors with diabetes mellitus to non-diabetic recipients were selected. We used a pathological classification established by the Renal Pathology Society for evaluating histological improvements in diabetic nephropathy. RESULTS: The results revealed that early diabetic changes found at the 1-hour and 1-month protocol biopsies were reversed and improved at the 1-year biopsy. CONCLUSION: We concluded that early diabetic changes in grafts from diabetic donors may improve if the graft recipient has good glycaemic control after kidney transplantation. PMID- 26031586 TI - Temporal serum creatinine increase and exacerbation of tubulointerstitial inflammation during the first two months in resolving polyomavirus BK nephropathy. AB - AIM: Polyomavirus BK nephropathy (BKVN) is an important complication in kidney transplantation. After immunosuppressive agents are reduced, some patients experience a temporal increase in serum creatinine (sCr) before viral clearance. The histological characteristics of re-biopsies were therefore investigated to evaluate the time course of remission. METHODS: sCr was measured and urinary cytology evaluated periodically in 14 patients with biopsy-proven BKVN. Remission of BKVN was defined as re-biopsies negative for SV40 large T antigen (SV40-TAg) or for decoy cells on at least three consecutive cytology tests. Early changes in sCr were correlated with re-biopsy findings. RESULTS: Mean sCr was 1.6 +/- 0.6 mg/dL at diagnosis, increasing during the first 2 months to 2.6 +/- 2.0 mg/dL, and decreasing thereafter, to 2.3 +/- 1.2 mg/dL at 3-4 months. Two patients who experienced further increases in sCr at 3 months showed early graft loss, while the others showed clinical or histological remission. Nineteen re-biopsies were obtained from eight patients over 4 months. Banff i-scores were higher in re biopsies obtained during the first 2 months than the index biopsies and re biopsies at 2-4 months (P = 0.02). SV40-TAg positivity was common in re-biopsies during the first 2 months (10/11 biopsies), but rarer at 2-4 months (2/8 biopsies, P = 0.001). CONCLUSIONS: Temporal graft dysfunction and increased inflammation, called immune reconstitution, were observed at 2 months. Later sCr reversal is associated with remission. PMID- 26031587 TI - Arteriosclerosis in zero-time biopsy is a risk factor for tacrolimus-induced chronic nephrotoxicity. AB - AIM: Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens. METHODS: Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score. RESULTS: Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P < 0.01) and acute rejection episodes (OR: 1.58, 95%CI: 1.00-2.47, P = 0.04) were independent risk factors for tacrolimus-induced chronic nephrotoxicity. However, tacrolimus-induced chronic nephrotoxicity did not affect long-term graft survival. CONCLUSION: This is the first report showing that arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity. PMID- 26031588 TI - Tacrolimus reduction with everolimus addition for calcineurin inhibitor-induced arteriolopathy in kidney allografts. AB - AIM: The aim of this study was to evaluate the effect of tacrolimus (TAC) reduction with everolimus (EVR) addition on the maintenance immunosuppression for the recipients with calcineurin inhibitor arteriolopathy (CNIA). METHODS: This retrospective study consisted of 13 kidney allograft recipients who were found to have CNIA on protocol biopsy specimens. The time of intervention was 9-89 months. All the patients were on TAC, mycophenolate mofetil (MMF). 9 of 13 were on steroid. EVR was added and TAC dose was reduced. MMF dose was not changed. Revaluation biopsy was taken 12 months after the intervention. TAC trough levels (TACC0 , ng/mL), EVR trough levels (EVRC0 , ng/mL), estimated glomerular filtration rate (eGFR, mL/min), and urine protein per creatinine (uP/Cr, g/g creatinine) were compared before and 1 year after intervention. Changes in pathological findings and adverse events were also reviewed. RESULTS: Aah scores improved in 5 patients. Aah scores did not change in the rest of the patients. No deterioration was observed. No improvement was seen in those with aah3. TACC0 reduced from 3.3 to 2.3. EVRC0 at revaluation was 4.1. eGFR improved from 44.3 to 49.8. uP/Cr slightly increased from 0.20 to 0.26. EVR was discontinued in 1 patient due to an adverse event. EVR dose was reduced in 5 patients due to adverse events. CONCLUSION: TAC reduction with EVR addition improves CNIA histologically in selected cases. PMID- 26031589 TI - Atypical hemolytic uremic syndrome diagnosed four years after ABO-incompatible kidney transplantation. AB - Atypical hemolytic uremic syndrome (aHUS) in allograft kidney transplantation is caused by various factors including rejection, infection, and immunosuppressive drugs. We present a case of a 32 year old woman with aHUS four years after an ABO incompatible kidney transplantation from a living relative. The primary cause of end-stage renal disease was unknown; however, IgA nephropathy (IgAN) was suspected from her clinical course. She underwent pre-emptive kidney transplantation from her 60 year old mother. The allograft preserved good renal function [serum creatinine (sCr) level 110-130 MUmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 MUmol/L), decreasing platelet count, and hemolytic anemia with schizocytes. On allograft biopsy, there was thrombotic microangiopathy in the glomeruli, with a cellular crescent formation and mesangial IgA and C3 deposition. Microvascular inflammation, such as glomerulitis, peritubular capillaritis, and arteriole endarteritis were also detected. A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) did not decrease and Shiga toxin was not detected. Donor-specific antibodies or autoantibodies, including anti neutrophil cytoplasmic antibody and anti-glomerular basement membrane (anti-GBM) antibody, were negative. The patient was diagnosed with aHUS and received three sessions of plasmapheresis and methylprednisolone pulse therapy, followed by oral methylprednisolone (0.25-0.5 mg/kg) instead of tacrolimus. She temporarily required hemodialysis (sCr level, 658.3 MUmol/L). Thereafter, her sCr level improved to 284.5 MUmol/L without dialysis therapy. This case is clinically considered as aHUS after kidney transplantation, associated with various factors, including rejection, glomerulonephritis, and toxicity from drugs such as tacrolimus. PMID- 26031590 TI - A suspected case of plasma cell-rich acute renal transplant rejection associated with de novo donor-specific antibody. AB - A kidney transplant case with de novo donor-specific antibody showed monoclonal plasma cell infiltration into the graft with ABO incompatibility. Three years after transplantation, the patient's graft function suddenly deteriorated. Interstitial edema and the predominant infiltration of inflammatory plasma cells with kappa chain monoclonality were observed in biopsy specimens. The in situ hybridization of Epstein-Barr virus was negative and post-transplant lymphoproliferative disorder was not evident from radiological examinations. On laboratory examination, the patient had de novo donor-specific antibody for HLA DQ. We suspected plasma cell-rich acute rejection for which methylprednisolone pulse therapy, plasma exchange, rituximab, and 15-deoxyspergualin were given. In the ensuing biopsy, the degree of plasma cell infiltration was similar to the first biopsy; however, kappa chain monoclonality relatively weakened. Owing to resistance to these treatments, intravenous immunoglobulin (IVIG) (0.5 g/kg/day) was added. The serum creatinine level gradually declined to 3.1 mg/dL; however, it increased up to 3.6 mg/dL again. In the final biopsy, the infiltrated plasma cells disappeared but severe interstitial fibrosis developed. This case showed difficulty in the diagnosis and treatment of plasma cell-rich acute rejection. A detailed consideration of this case may be helpful in understanding the clinical features and pathogenesis of this condition. PMID- 26031591 TI - Acute T cell-mediated rejection accompanied by C4d-negative acute antibody mediated rejection and cell debris in tubulus: A case report. AB - Herein, we report a complicated case of acute T-cell-mediated rejection (ACR) accompanied by C4d-negative acute antibody-mediated rejection (AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine (S-Cr) level of 1.83 mg/dL and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection (UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S-Cr level decreased to ~1.5 mg/dL following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI. PMID- 26031592 TI - Probable C4d-negative accelerated acute antibody-mediated rejection due to non HLA antibodies. AB - We report a case of probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies. A 44 year-old male was admitted to our hospital for a kidney transplant. The donor, his wife, was an ABO minor mismatch (blood type O to A) and had Gitelman syndrome. Graft function was delayed; his serum creatinine level was 10.1 mg/dL at 3 days after transplantation. Open biopsy was performed immediately; no venous thrombosis was observed during surgery. Histology revealed moderate peritubular capillaritis and mild glomerulitis without C4d immunoreactivity. Flow cytometric crossmatching was positive, but no panel-reactive antibodies against HLA or donor-specific antibodies (DSAbs) to major histocompatibility complex class I-related chain A (MICA) were detected. Taken together, we diagnosed him with probable C4d-negative accelerated antibody-mediated rejection due to non-HLA, non-MICA antibodies, the patient was treated with steroid pulse therapy (methylprednisolone 500 mg/day for 3 days), plasma exchange, intravenous immunoglobulin (40 g/body), and rituximab (200 mg/body) were performed. Biopsy at 58 days after transplantation, at which time S-Cr levels were 1.56 mg/dL, found no evidence of rejection. This case, presented with a review of relevant literature, demonstrates that probable C4d negative accelerated acute AMR can result from non-HLA antibodies. PMID- 26031593 TI - Biopsy findings on a stable recipient after secondary donor specific antibody (DSA) positive and ABO incompatible kidney transplantation. AB - Using desensitization protocol, we performed a secondary donor specific antibody (DSA) positive and ABO incompatible kidney transplantation. One-hour biopsy showed no C4d deposition. The protocol biopsy after 2 weeks showed diffuse C4d deposition with peritubulitis. After 12 weeks, however, the protocol biopsy showed disappearance of tubulitis in spite of remaining C4d deposition. The recipient was in stable condition with excellent graft function despite high titer of the DSA. Monitoring of protocol biopsy is critical while antibody titer and the interpretation of the histological findings correlating with clinical markers must be considered. PMID- 26031594 TI - A refractory case of subclinical antibody-mediated rejection due to anti-HLA-DQ antibody in a kidney transplant patient. AB - We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases. PMID- 26031595 TI - Treatment of acute antibody-mediated rejection using bortezomib: a case report. AB - Here we report the successful treatment of acute antibody-mediated rejection (AMR) with bortezomib. Bortezomib rescue treatment was administered after a 42 year-old woman failed to respond to steroid pulse and plasmapheresis with intravenous immunoglobulin (IVIG). The patient underwent a second renal transplantation with a deceased donor kidney. She was treated pre-operatively with rituximab (200 mg/body) and underwent plasmapheresis twice (day-1 and operation day) because ELISA screening revealed that her pre-operative peak panel reactive antibody (PRA) composition was 100% class I and 100% class II and 15 times of cross-match positive history during the waiting period for transplantation. The patients received induction therapy with Simulect (an IL-2 blocking agent). A 1-hour protocol biopsy revealed C4d-positivity and mild peritubular capillary inflammation. This was suggestive of early AMR-associated changes. After transplantation, the patient underwent plasmaphereses (nine times) with low-dose IVIG (2 mg/kg). Despite this treatment regimen, serum creatinine levels increased to 3.4 mg/dL on post-transplant day 15. A second graft biopsy was performed, which showed overt AMR with glomerulitis, peritubular capillary inflammation and no C4d deposition. On post-operative day (POD) 22, treatment with four doses of bortezomib (1.3 mg/m(2) ) was initiated with the patient's consent. On POD 55, renal function had recovered and serum creatinine was 1.5 mg/dL. In summary, bortezomib was administered as a rescue treatment for a patient who developed AMR that was refractory to a combination of plasmaphereses with low-dose IVIG and preemptive administration of rituximab. PMID- 26031596 TI - Recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation. AB - Post-transplant hyperglycaemia of diabetic patients may cause recurrent diabetic kidney disease (DKD) in kidney allografts. We report a patient with slowly progressive DKD with calcineurin inhibitor toxicity (CNI) toxicity after the kidney transplantation. A 28-year-old female with type 1 diabetes mellitus underwent successful kidney transplantation from her mother in April 2003, and the kidney graft survived for more than 10 years. She was treated with combined immunosuppressive therapy consisting of cyclosporine and mycophenolate mofetil. After transplantation, she continued to take insulin injection four times per day, but her glycosylated haemoglobin (HbA1c) was above 10%. Protocol allograft kidney biopsies performed 5 and 10 years after transplantation revealed the recurrence of slowly progressive diabetic kidney disease. In addition, arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity (CNI) was detected with progression. Post-transplant hyperglycaemia causes recurrent diabetic kidney disease (DKD) in kidney allografts, but its progression is usually slow. For long-term management, it is important to prevent the progression of the calcineurin inhibitor arteriolopathy, as well as maintain favourable glycaemic control. PMID- 26031597 TI - Focal segmental glomerular sclerosis recurrence with massive proteinuria and anuria immediately after kidney transplantation. AB - Here, we report a case of focal segmental glomerular sclerosis (FSGS) recurrence immediately (47 minutes) after transplantation. A 1-hour biopsy specimen showed large periodic acid-Schiff-positive granules within the cells of the swollen proximal tubule, while electron microscopy revealed podocyte swelling and partial foot process effacement. These findings were worse on day 2 biopsy. Massive proteinuria and anuria were then observed. Two courses (2 * 2 times) of plasmapheresis and rituximab were administered, and the graft function gradually recovered. A day 22 biopsy specimen showed improvement in findings compared to those observed on day 2. One year after transplantation, no signs of FSGS recurrence are evident, and graft function remains good. PMID- 26031598 TI - A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification. AB - Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies. PMID- 26031599 TI - Phospholipase A2 receptor positive membranous nephropathy long after living donor kidney transplantation between identical twins. AB - Although membranous nephropathy (MN) is a commonly observed cause of post transplant glomerulonephritis, distinguishing de novo from recurrent MN in kidney allograft is often difficult. Phospholipase A2 receptor (PLA2R) staining is useful for diagnosing recurrent MN in allografts similarly to idiopathic MN in native kidney. No specific treatment strategy has been established for MN, especially when accompanied with HCV infection in kidney transplant recipients. This report describes a 66-year-old man who was diagnosed as having PLA2R positive membranous nephropathy accompanied with already-known IgA nephropathy and HCV infection 26 years after kidney transplantation conducted between identical twins. PLA2R was detected along capillary loops, implying that this patient is affected by the same pathogenic mechanism as idiopathic MN, not secondary MN associated with other disorders such as HCV infection. The patient successfully achieved clinical remission after steroid therapy. PMID- 26031600 TI - Insights into the Mechanism of Carbon Monoxide Dehydrogenase at Atomic Resolution. AB - Unexpected similarities: Atomic-resolution structures of CO2- and NCO(-)-bound nickel-containing carbon monoxide dehydrogenases (Ni-CODHs) reveal that the reaction pathway of this enzyme involves an intermediate that is generated by two electron reduction. PMID- 26031601 TI - Genetic studies on the Cayo Santiago rhesus macaques: A review of 40 years of research. AB - Genetic studies not only contribute substantially to our current understanding of the natural variation in behavior and health in many species, they also provide the basis of numerous in vivo models of human traits. Despite the many challenges posed by the high level of biological and social complexity, a long lifespan and difficult access in the field, genetic studies of primates are particularly rewarding because of the close evolutionary relatedness of these species to humans. The free-ranging rhesus macaque (Macaca mulatta) population on Cayo Santiago (CS), Puerto Rico, provides a unique resource in this respect because several of the abovementioned caveats are of either minor importance there, or lacking altogether, thereby allowing long-term genetic research in a primate population under constant surveillance since 1956. This review summarizes more than 40 years of genetic research carried out on CS, from early blood group typing and the genetic characterization of skeletal material via population-wide paternity testing with DNA fingerprints and short tandem repeats (STRs) to the analysis of the highly polymorphic DQB1 locus within the major histocompatibility complex (MHC). The results of the paternity studies also facilitated subsequent studies of male dominance and other factors influencing male reproductive success, of male reproductive skew, paternal kin bias, and mechanisms of paternal kin recognition. More recently, the CS macaques have been the subjects of functional genetic and gene expression analyses and have played an important role in behavioral and quantitative genetic studies. In addition, the CS colony has been used as a natural model for human adult-onset macular degeneration, glaucoma, and circadian rhythm disorder. Our review finishes off with a discussion of potential future directions of research on CS, including the transition from STRs to single nucleotide polymorphism (SNP) typing and whole genome sequencing. PMID- 26031602 TI - A new subgenotype 2.1d isolates of classical swine fever virus in China, 2014. AB - The lapinized attenuated vaccine against classical swine fever (CSF) has been used in China for over half a century and has generally prevented large-scale outbreaks in recent years. However, since late 2014, a large number of new cases of CSF were detected in many immunized pig farms in China. Several of these CSV viruses were isolated and characterized. Phylogenetic and genomic sequence analyses indicate that these new isolates, as well as some reference isolates, form a new subgenotype named 2.1d, and share several consistent molecular characteristics. Since these new isolates emerged in disparate geographic regions within 5 months, this suggests that these isolates may be widespread. Given that current vaccines do not appear to provide effective protection against this new subgenotype, further investigation of these strains is urgently needed. PMID- 26031603 TI - Chromophobe renal cell carcinoma with neuroendocrine and neuroendocrine-like features. Morphologic, immunohistochemical, ultrastructural, and array comparative genomic hybridization analysis of 18 cases and review of the literature. AB - Chromophobe renal cell carcinoma (CRCC) with neuroendocrine differentiation (CRCCND) has only recently been described. Eighteen cases of CRCC with morphologic features suggestive of neuroendocrine differentiation were selected from among 624 CRCCs in our registry. The tissues were fixed in neutral formalin, embedded in paraffin, cut into 4- to 5-MUm-thick sections, and stained with hematoxylin and eosin. As CRCC with neuroendocrine features, tumors with following morphology were suggested: (1) trabecular/palisading/ribbon-like, gyriform, insular, glandular, and solid pattern; (2) uniform polygonal cells formed in small islets; and (3) cribriform pattern in combination with palisading. Selected cases were further analyzed using immunohistochemistry, electron microscopy, array comparative genomic hybridization, and fluorescence in situ hybridization. Cases were classified as CRCCND or CRCC with neuroendocrine like features (CRCCND-L) based on the immunohistochemical expression of neuroendocrine markers: CRCCND, 4 cases, age range 49 to 79 years, size ranged from 2.2 to 22 cm, and CRCCND-L, 14 cases, age range 34 to 74 years, size range 3.8 to 16.5 cm. Follow-up information was available for 11 of 18 patients aged 0.5 to 12 years. Two of 4 CRCCNDs showed aggressive clinical course with metastatic spreading. Chromophobe renal cell carcinomas with neuroendocrine differentiation were focally positive for CD56 (4/4), synaptophysin (4/4), chromogranin A (1/4), and neuron-specific enolase (3/4). All 14 CRCCND-Ls were mostly negative or very weakly focally positive for some of the aforementioned markers. All 18 tumors were positive for cytokeratin 7 and CD117. Ultrastructural analysis showed poorly preserved neuroendocrine granules only in 2 of 4 analyzed CRCCNDs. Losses of chromosomes 1, 2, 6, and 10 were found in all analyzable CRCCNDs, whereas multiple losses (chromosomes 1, 2, 6, 10, 13, 17, and 21) and gains (chromosomes 4, 11, 12, 14, 15, 16, 19, and 20) were found in CRCCND-L. PMID- 26031605 TI - Anatomical organization of descending cortical projections orchestrating the patterns of cortically induced rhythmical jaw muscle activity in guinea pigs. AB - Repetitive electrical microstimulation to the cortical masticatory area (CMA) evokes distinct patterns of rhythmical jaw muscle activities (RJMAs) in animals. This study aimed to investigate the characteristics of the descending projections from the CMA, associated with distinct patterns of RJMAs, to the thalamus, midbrain, pons and medulla in guinea pigs. RJMAs with continuous masseter and digastric bursts (CB-RJMAs) and stimulus-locked digastric sub-bursts (SLB-RJMAs) were induced from the anterior and posterior areas of the rostral region of the lateral agranular cortex, and chewing-like RJMAs from the rostral region of the granular cortex. Anterograde tracer, biotinylated dextran amine, was injected into the three cortical areas. The cortical area inducing CB-RJMAs had strong ipsilateral projections to the motor thalamus, red nucleus, midbrain reticular formation, superior colliculus, parabrachial nucleus, and supratrigeminal region, and contralateral projections mainly to the lateral reticular formation around the trigeminal motor nucleus (Vmo). The cortical area inducing SLB-RJMAs had moderate projections to the motor thalamus and lateral reticular formation around the Vmo, but few projections to the midbrain nuclei. The cortical area inducing chewing-like RJMAs had strong projections to the ipsilateral sensory thalamus and contralateral trigeminal sensory nuclei, and moderate projections to the lateral reticular formation. The three cortical areas consistently had few projections to the ventromedial reticular formation. The present study demonstrates that multiple direct and indirect descending projections from the CMA onto the premotor systems connecting the trigeminal motoneurons represent the neuroanatomical repertoires for generating RJMAs during the distinct phases of natural ingestive behavior. PMID- 26031604 TI - Differentiating zones at periodontal ligament-bone and periodontal ligament cementum entheses. AB - BACKGROUND AND OBJECTIVE: The structural and functional integrity of bone periodontal ligament (PDL)-cementum complex stems from the load-bearing attachment sites (entheses) between soft (PDL) and hard (bone, cementum) tissues. These attachment sites are responsible for the maintenance of a bone-PDL-cementum complex biomechanical function. The objective was to investigate changes in spatiotemporal expression of key biomolecules in developing and functionally active entheses. MATERIAL AND METHODS: Multilabeling technique was performed on hemimandibles of 3 wk and 3 mo-old scleraxis-GFP transgenic mice for CD146, CD31, NG2, osterix and bone sialoprotein. Regions of dominant stretch within the PDL were evaluated by identifying directionality of collagen fibrils, PDL fibroblasts and PDL cell cytoskeleton. RESULTS: CD146+ cells adjacent to CD31+ vasculature were identified at PDL-bone enthesis. NG2+ cells were located at coronal bone-PDL and apical cementum-PDL entheses in the 3-wk-old group, but at 3 mo, NG2 was positive at the entheses of the apical region and alveolar crest. NG2 and osterix were colocalized at the osteoid and cementoid regions of the PDL-bone and PDL cementum entheses. Bone sialoprotein was prominent at the apical region of 3-wk old mice. The directionality of collagen fibers, fibroblasts and their cytoskeleton overlapped, except in the apical region of 3 wk. CONCLUSION: Colocalization of biomolecules at zones of the PDL adjacent to attachment sites may be essential for the formation of precementum and osteoid interfaces at a load-bearing bone-PDL-tooth fibrous joint. Biophysical cues resulting from development and function can regulate recruitment and differentiation of stem cells potentially from a vascular origin toward osteo- and cemento-blastic lineages at the PDL-bone and PDL-cementum entheses. Investigating the coupled effect of biophysical and biochemical stimuli leading to cell differentiation at the functional attachment sites is critical for developing regeneration strategies to enable functional reconstruction of the periodontal complex. PMID- 26031606 TI - Suspension of oysters reduces the populations of Vibrio parahaemolyticus and Vibrio vulnificus. AB - Vibrio parahaemolyticus (Vp) and Vibrio vulnificus (Vv) are associated with the consumption of raw oysters and cause illnesses ranging from simple gastroenteritis to life-threatening septicaemia. These halophilic bacteria are frequently found in marine and estuarine systems, accumulating within the tissues of a number of aquatic organisms and passing on to humans after consumption, through contaminated water, or via open wounds. As benthic organisms capable of filtering 40 gallons of water per hour, sediment is an important source of potentially pathogenic vibrios in oysters destined for raw consumption. This research used off-bottom oyster culture to reduce vibrio concentrations in oysters. Colony hybridization was used to enumerate Vp and Vv in bottom and suspended oysters. Vv and Vp concentrations were generally lower in oysters suspended off-bottom, and suspension decreased vibrio loads in oysters by an average of 13%. Suspension of oysters reduced vibrio concentrations. SIGNIFICANCE AND IMPACT OF THE STUDY: This study found that oyster suspension significantly reduced some populations of potentially pathogenic vibrios. These results indicate that oyster suspension could be a viable approach for preharvest treatment to reduce illness in consumers of raw oysters. PMID- 26031607 TI - Calcium hypochlorite as a dentin deproteinization agent: Microleakage, scanning electron microscopy and elemental analysis. AB - PURPOSE: This study investigated the influence of collagen removal with calcium hypochlorite on the surface morphology of acid-etched dentin and on the microleakage of composite restorations. In addition, the elemental composition (EC) of dentin after removal of the collagen fibrils was analyzed. MATERIALS AND METHODS: Forty third molars received two cavities and were divided into four groups according to dentin treatment: CTRL-no pre-treatment; Na10-10% NaOCl for 30 s; Ca10-10% CaOCl for 30 s, and Ca15-15% CaOCl for 30 s. The cavities were filled using an acetone-based adhesive system and a resin composite; they were then subjected to thermal cycling for 5,000 cycles, immersed in methylene blue for 4 h and sectioned into 1-mm thick slabs. Two examiners evaluated two slices per tooth using a stereomicroscope and assigned the degree of infiltration (scores 0-3). The data were analyzed using the Kruskal-Wallis (alpha = 0.05). Four teeth received surface treatment according to the groups and were submitted to SEM and EDS to carry at the EC. RESULTS: There was no significant difference between the experimental groups (P = 0.533). CaOCl alters the morphology and surface composition of the dentin, resulting in an increase in the amount of calcium in the interface. CONCLUSIONS: When used prior to an acetone-based adhesive system, CaOCl did not produce any differences in microleakage when compared to the CTRL group or to the Na10 group. PMID- 26031608 TI - Noninvasive assessment of myocardial mechanics of the left ventricle in rabbits using velocity vector imaging. AB - BACKGROUND: Our study aimed to investigate the feasibility of velocity vector imaging (VVI) to analyze left ventricular (LV) myocardial mechanics in rabbits at basal state. MATERIAL AND METHODS: The animals used in this study were 30 New Zealand white rabbits. All rabbits underwent routine echocardiography under VVI mode at basal state. The 2-dimensional (2-D) echocardiography images acquired included parasternal left long-axis views and short-axis views at the level of LV mitral valve, papillary muscles, and apex. Images were analyzed by VVI software. RESULTS: At basal state, longitudinal LV velocity decreased from the basal to the apical segment (P<0.05). In the short axis direction, the highest peak myocardial velocity was found between the anterior septum and anterior wall for each segment at the same level; the peak strains and strain rates (SR) were the highest in the anterior and lateral wall compared to other segments (all P<0.05). During systole, LV base rotated in a clockwise direction and LV apex rotated in a counter-clockwise direction, while during diastole, both LV base and apex rotated in the direction opposite to systole. The rotation angle, rotation velocity and unwinding velocity in the apical segment were greater than the basal segment (P<0.05). CONCLUSIONS: VVI is a reliable tool for evaluating LV myocardial mechanics in rabbits at basal state, and the LV long-axis short-axis and torsional motions reflect the normal regular patterns. Our study lays the foundation for future experimental approaches in rabbit models and for other applications related to the study of human myocardial mechanics. PMID- 26031610 TI - Physiotherapist-led neck-specific exercise improves pain, disability and self efficacy in chronic whiplash-associated disorders. PMID- 26031609 TI - IL-4 and IL-13 induce protection from complement and melittin in endothelial cells despite initial loss of cytoplasmic proteins: membrane resealing impairs quantifying cytotoxicity with the lactate dehydrogenase permeability assay. AB - Endothelial cell activation and injury by the terminal pathway of complement is important in various pathobiological processes, including xenograft rejection. Protection against injury by human complement can be induced in porcine endothelial cells (ECs) with IL-4 and IL-13 through metabolic activation. However, despite this resistance, the complement-treated ECs were found to lose membrane permeability control assessed with the small molecule calcein. Therefore, to define the apparent discrepancy of permeability changes vis-a-vis the protection from killing, we now investigated whether IL-4 and IL-13 influence the release of the large cytoplasmic protein lactate dehydrogenase (LDH) in ECs incubated with complement or the pore-forming protein melittin. Primary cultures of ECs were pre-treated with IL-4 or IL-13 and then incubated with human serum as source of antibody and complement or melittin. Cell death was assessed using neutral red. Membrane permeability was quantitated measuring LDH release. We found that IL-4-/IL-13-induced protection of ECs from killing by complement or melittin despite loss of LDH in amounts similar to control ECs. However, the cytokine-treated ECs that were protected from killing rapidly regained effective control of membrane permeability. Moreover, the viability of the protected ECs was maintained for at least 2 days. We conclude that the protection induced by IL 4/IL-13 in ECs against lethal attack by complement or melittin is effective and durable despite severe initial impairment of membrane permeability. The metabolic changes responsible for protection allow the cells to repair the membrane injury caused by complement or melittin. PMID- 26031611 TI - Early physical rehabilitation may improve physical quality of life domains in patients admitted to ICU with sepsis syndromes. PMID- 26031612 TI - Role of patient-reported outcomes and other efficacy endpoints in the drug approval process in Europe (2008-2012). AB - The present study aimed at systematically reviewing the role and extent of patient-reported outcomes (PROs) usage within the package of scientific evidence considered for marketing authorization (MA). All regulatory information published by the European Medicines Agency (EMA) for products authorized between January 2008 and December 2012 and appearing in the European Public Assessment Report (EPAR) database was examined for efficacy endpoints. The endpoints here considered included: PROs, clinician reported outcomes (CROs), and laboratory reported outcomes (LROs). LROs were the most frequently reported endpoints. Out of the 180 products here selected, 99 (55%), 67 (37%), and 30 (17%), respectively, used LROs, CROs and PROs as primary endpoints (PEs). PROs as any endpoints were used in 82 (46%) products. Out of these, PROs were documented as PE in 30 (37%), with 27 (33%) products having used PROs both as primary and non PEs. PRO usage was most frequently identified with nervous system and antineoplastic agents. During the study period, the use of all the three types of endpoints appeared to be static. Both the regulatory bodies and the industry should ensure complete and clear reporting of all endpoints used, including PROs, to improve transparency. PMID- 26031613 TI - Structural effects on the photophysical properties of mono-beta-diketonate and bis-beta-diketonate Eu(III) complexes. AB - Two ligands, mono-beta-diketone (p-methoxylbenzoyl)trifluoroacetone (MBTF) and bis-beta-diketone 1,2-bis(4,4'-bis(4,4,4-trifluoro-1,3-dioxobutyl))phenoxyl ethane (BTPE) with similar chemical structures, have been designed and prepared for the purpose of building the relationship between the structures and luminescence properties of Eu(iii) complexes. Structures of the Eu(iii) complexes [Eu(MBTF)3(DMSO)(H2O)] and [Eu2(BTPE)3(DMSO)4] have been defined by single crystal X-ray crystallography. The mono-beta-diketone complex [Eu(MBTF)3(DMSO)(H2O)] is a mononuclear structure, the central Eu(iii) ion is coordinated by eight oxygen atoms from three ligands and two solvents, in a distorted trigonal-dodecahedral (8-TDH) geometry. Whereas, the bis-beta-diketone complex [Eu2(BTPE)3(DMSO)4] adopts a triple-stranded dinuclear structure in which the two Eu(iii) ions are helically wrapped by three bis-bidentate ligands, and each Eu(iii) ion is eight-coordinated by six oxygen atoms from the ligands and two oxygen atoms from the coordinated DMSO molecules, in a distorted square antiprismatic (8-SAP) geometry. The photophysical properties related to the electronic transition are characterized by the absorbance spectra, the emission spectra, the emission quantum yields, the emission lifetimes, and the radiative (kr) and nonradiative rate constants (knr). The mono-beta-diketone complex [Eu(MBTF)3(DMSO)(H2O)] offers a relatively high emission quantum yield (38%, in solid) compared to that observed in the bis-beta-diketone complex [Eu2(BTPE)3(DMSO)4] (25%, in solid). This enhancement of emission quantum yield in the mono-beta-diketone complex can be attributed to its lower site symmetry around the Eu(iii) ion, lower non-radiative rate constant and higher energy transfer efficiency from the ligand to the metal ion. PMID- 26031614 TI - Improved synthesis and application of [(11) C]benzyl iodide in positron emission tomography radiotracer production. AB - Positron emission tomography has increased the demand for new carbon-11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [(11) C]benzyl iodide ([(11) C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [(11) C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D2 antagonist [(11) C]clebopride as a proof of concept. [(11) C]BnI was synthesized from [(11) C]CO2 via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one-pot procedure, [(11) C]BnI was synthesized in 11 min from [(11) C]CO2 with high yield, purity, and specific activity, 52 +/- 3% (end of the cyclotron bombardment), 95 +/- 3%, and 123 +/- 17 GBq/umol (end of the synthesis), respectively. Changes in the [(11) C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid-phase intermediate purification. [(11) C]Clebopride was synthesized within 28 min from [(11) C]CO2 in an isolated decay-corrected yield of 11 +/- 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 +/- 4 GBq/umol (n = 3) at the end of the synthesis. Conversion of [(11) C]BnI to product was 82 +/- 11%. The reliable synthesis of [(11) C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development. PMID- 26031615 TI - Controlling the morphology of metal-triggered collagen peptide assemblies through ligand alteration. AB - A number of methods have been explored to promote the higher order assembly of collagen peptide triple helices. In one case, NCoH, a complex hierarchical metal promoted assembly was observed to form micron-scaled florettes with a ruffled surface topology at the nanoscale. In an effort to elucidate the role of the ligands in this collagen peptide assemblage, we reduced the number of carboxylates within the N-terminal ligand to produce a new peptide, ICoH. A striking difference in the morphology of the metal-triggered material was observed with ICoH, with stacked arrays of nanofibrils predominating. As the peptide to metal ion ratio was increased, the length of the stacks of fibrils was also observed to increase. These data demonstrate that a significantly less complex assembly process occurs with the removal of a single carboxylate moiety from the metal binding ligand at the termini of the collagen peptide. PMID- 26031616 TI - Detection of a divergent variant of grapevine virus F by next-generation sequencing. AB - The complete genome sequence of a South African isolate of grapevine virus F (GVF) is presented. It was first detected by metagenomic next-generation sequencing of field samples and validated through direct Sanger sequencing. The genome sequence of GVF isolate V5 consists of 7539 nucleotides and contains a poly(A) tail. It has a typical vitivirus genome arrangement that comprises five open reading frames (ORFs), which share only 88.96 % nucleotide sequence identity with the existing complete GVF genome sequence (JX105428). PMID- 26031617 TI - Boceprevir for Chronic Genotype 1 Hepatitis C Virus in the Current Health Care Setting in Greece: A Cost-effectiveness Analysis. AB - PURPOSE: Boceprevir, as an add-on to the standard of care (SOC) for chronic genotype 1 hepatitis C virus (G1 HCV), pegylated interferon + ribavirin for 48 weeks (PEG + RBV), has been reported to have a clinical profile superior to that of SOC alone. The objective of the present study was to compare the cost effectiveness of triple therapy with PEG + RBV + boceprevir to that of SOC in treatment-naive and treatment-experienced patients with G1 HCV in Greece. METHODS: A Markov model that simulated the quality-adjusted life expectancy and corresponding costs of treating G1 HCV infection provided the basis of the analysis. Treatment strategies under consideration were those in the Phase III boceprevir trials: (1) boceprevir response-guided therapy (shortened treatment duration for early responders); (2) fixed-duration (4-week) SOC plus 44 weeks of triple therapy; and (3) 48-week SOC. Efficacy data and the baseline characteristics of the study population were based on data from the SPRINT-2 (Serine Protease Inhibitor Therapy 2) and RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) clinical trials. Health care resource utilization and costs reflect the local clinical setting, with a 3% discount per annum, and were assessed from a third-party payer perspective. FINDINGS: Triple therapy was projected to reduce liver complications (eg, decompensated cirrhosis, hepatocellular carcinoma, need for liver transplantation, and liver-related death) by 44% to 45% and 49% to 53% in treatment-naive and treatment-experienced patients, respectively, over a lifetime horizon, leading to corresponding gains of 0.87 and 1.25 quality-adjusted life years gained per patient. Taking into account the costs of medications, treatment, and outcomes management, the estimated incremental cost-effectiveness ratios of triple therapy versus SOC were ?10,003 and ?10,852 per quality-adjusted life-years gained in treatment-naive and treatment-experienced patients. Extensive sensitivity analyses suggested that the findings were robust over a wide range of inputs. IMPLICATIONS: Based on the findings from the present analysis, the addition of boceprevir to PEG + RBV for the treatment of patients with G1 HCV may be a cost-effective alternative in the health care setting in Greece. PMID- 26031619 TI - Vestibulo-ocular dysfunction in pediatric sports-related concussion. AB - OBJECT: The objective of this study was 2-fold: 1) to examine the prevalence of vestibulo-ocular dysfunction (VOD) among children and adolescents with acute sports-related concussion (SRC) and postconcussion syndrome (PCS) who were referred to a multidisciplinary pediatric concussion program; and 2) to determine if VOD is associated with the development of PCS in this cohort. METHODS: The authors conducted a retrospective review of all patients with acute SRC (presenting 30 days or less postinjury) and PCS (3 or more symptoms for at least 1 month) referred to a multidisciplinary pediatric concussion program between September 2013 and July 2014. Initial assessment included clinical history, physical examination, and Post-Concussion Symptom Scale assessment. Patients were also assessed for VOD, which was defined as more than one subjective vestibular and oculomotor complaint (dizziness, blurred vision, and so on) and more than one objective physical examination finding (abnormal smooth pursuits, saccades, vestibulo-ocular reflex, and so on). This study was approved by the local institutional ethics review board. RESULTS: A total of 101 patients (mean age 14.2 years, SD 2.3 years; 63 male and 38 female patients) participated, including 77 (76.2%) with acute SRC and 24 (23.8%) with PCS. Twenty-two of the 77 patients (28.6%) with acute SRC and 15 of the 24 (62.5%) with PCS met the clinical criteria for VOD. The median duration of symptoms was 40 days (interquartile range [IQR] 28.5-54 days) for patients with acute SRC who had VOD compared with 21 days (IQR 13-32 days) for those without VOD (p = 0.0001). There was a statistically significant increase in the adjusted odds of developing PCS among patients with acute SRC who had VOD compared with those without VOD (adjusted OR 4.10; 95% CI 1.04-16.16). CONCLUSIONS: Evidence of VOD was detected in a significant proportion of children and adolescents with acute SRC and PCS who were referred to a multidisciplinary pediatric concussion program. This clinical feature was a significant risk factor for the subsequent development of PCS in this pediatric acute SRC cohort. PMID- 26031618 TI - Bayesian Estimation of Vancomycin Pharmacokinetics in Obese Children: Matched Case-Control Study. AB - PURPOSE: The study objective was to compare different body size descriptors that best estimate vancomycin Vd and clearance (CL). METHODS: Patients between 3 months and 21 years old who received vancomycin for >=48 hours from 2003 to 2011 were evaluated in this matched case-control study. Cases had body mass index in the >=85th percentile; controls were nonobese individuals who were matched by age and baseline serum creatinine (SCr). Using a 1-compartment model with first-order kinetics, Bayesian post hoc individual Vd and CL were estimated. FINDINGS: Analysis included 87 matched pairs with 389 vancomycin serum concentrations. Median ages were 10.0 (interquartile range [IQR], 4.8-15.2) years for cases (overweight and obese children) and 10.2 (IQR, 4.5-14.8) years for controls (normal-weight children). Median weights were 44.0 (IQR, 23.4-78.1) kg for cases and 31.3 (IQR, 16.8-47.1) kg for controls. Mean (SD) for the baseline SCr values were also similar between the groups: 0.51 (0.22) (IQR, 0.34-0.67) mg/dL and 0.48 (0.20) (IQR, 0.30-0.60) mg/dL for the cases and controls, respectively. Actual weight and allometric weight (ie, weight(0.75)) were used in the final model to estimate Vd and CL, respectively. The mean Vd and CL, based on weight, for cases were lower than controls by 0.012 L/kg and 0.014 L/kg/h, respectively. IMPLICATIONS: In obese children, actual weight and allometric weight are reasonable, convenient estimations of body fat to use for estimating vancomycin Vd and CL, respectively. However, these pharmacokinetic differences between obese children and those with normal weights are small and may not likely to be clinically relevant in dose variation. PMID- 26031620 TI - Neuroimaging findings in pediatric sports-related concussion. AB - OBJECT: The goal in this review was to summarize the results of clinical neuroimaging studies performed in patients with sports-related concussion (SRC) who were referred to a multidisciplinar ypediatric concussion program. METHODS: The authors conducted a retrospective review of medical records and neuroimaging findings for all patients referred to a multidisciplinary pediatric concussion program between September 2013 and July 2014. Inclusion criteria were as follows: 1) age <= 19 years; and 2) physician-diagnosed SRC. All patients underwent evaluation and follow-up by the same neurosurgeon. The 2 outcomes examined in this review were the frequency of neuroimaging studies performed in this population (including CT and MRI) and the findings of those studies. Clinical indications for neuroimaging and the impact of neuroimaging findings on clinical decision making were summarized where available. This investigation was approved by the local institutional ethics review board. RESULTS: A total of 151 patients (mean age 14 years, 59% female) were included this study. Overall, 36 patients (24%) underwent neuroimaging studies, the results of which were normal in 78% of cases. Sixteen percent of patients underwent CT imaging; results were normal in 79% of cases. Abnormal CT findings included the following: arachnoid cyst (1 patient), skull fracture (2 patients), suspected intracranial hemorrhage (1 patient), and suspected hemorrhage into an arachnoid cyst (1 patient). Eleven percent of patients underwent MRI; results were normal in 75% of cases. Abnormal MRI findings included the following: intraparenchymal hemorrhage and sylvian fissure arachnoid cyst (1 patient); nonhemorrhagic contusion (1 patient); demyelinating disease (1 patient); and posterior fossa arachnoid cyst, cerebellar volume loss, and nonspecific white matter changes (1 patient). CONCLUSIONS: Results of clinical neuroimaging studies are normal in the majority of pediatric patients with SRC. However, in selected cases neuroimaging can provide information that impacts decision making about return to play and retirement from the sport. PMID- 26031621 TI - Interpretation of pretransfusion testing in obstetrical patients who have received antepartum Rh immunoglobulin prophylaxis. AB - BACKGROUND AND OBJECTIVES: Determining whether anti-D represents active or passive alloimmunization after RhIg administration is challenging. The objectives were to use antibody reaction strength to differentiate patients who may have become RhD alloimmunized during pregnancy from those manifesting passive anti-D and to investigate which methods work best for this determination. MATERIALS AND METHODS: Data were collected from patients residing in the Edmonton region of Canada, >=18 years old, undergoing antibody screening in late pregnancy, who received 300 MUg (1500 IU) of RhIg in the preceding 120 days. A total of 1106 tests were performed on 1050 blood samples from 963 patients: 640 by PEG, 156 by gel-card and 310 by solid-phase methodology. RESULTS: PEG was the least sensitive to passive anti-D, with significantly fewer positive results at >=8 weeks after RhIg compared to the other methods. Strength of reactivity and time since RhIg injection could be used to identify patients at high risk using PEG as a 4+ reaction at any time, >=3+ at >2 weeks, >=2+ at >6 weeks and >=1+ at >14 weeks. Similarly, the gel-card method thresholds were 4+ at >5 weeks, >=3+ at >10 weeks and >=2+ at >15 weeks. Reaction strength by solid-phase was too variable to establish useful thresholds by this method. Infant RhD status did not significantly affect results. CONCLUSION: Patients can be risk stratified for alloimmunization by anti-D reaction strength and time after RhIg administration. The PEG method was the best of those investigated, but the gel-card method can also be used. PMID- 26031622 TI - Post-translational mechanisms are associated with fertility restoration of cytoplasmic male sterility in sugar beet (Beta vulgaris). AB - Genetic conflict between cytoplasmically inherited elements and nuclear genes arising from their different transmission patterns can be seen in cytoplasmic male sterility (CMS), the mitochondrion-encoded inability to shed functional pollen. CMS is associated with a mitochondrial open reading frame (ORF) that is absent from non-sterility inducing mitochondria (S-orf). Nuclear genes that suppress CMS are called restorer-of-fertility (Rf) genes. Post-transcriptional and translational repression of S-orf mediates the molecular action of Rf that encodes a class of RNA-binding proteins with pentatricopeptide repeat (PPR) motifs. Besides the PPR-type of Rfs, there are also non-PPR Rfs, but the molecular interactions between non-PPR Rf and S-orf have not been described. In this study, we investigated the interaction of bvORF20, a non-PPR Rf from sugar beet (Beta vulgaris), with preSatp6, the S-orf from sugar beet. Anthers expressing bvORF20 contained a protein that interacted with preSATP6 protein. Analysis of anthers and transgenic calli expressing a FLAG-tagged bvORF20 suggested the binding of preSATP6 to bvORF20. To see the effect of bvORF20 on preSATP6, which exists as a 250-kDa protein complex in CMS plants, signal bands of preSATP6 in bvORF20-expressing and non-expressing anthers were compared by immunoblotting combined with Blue Native polyacrylamide gel electrophoresis. The signal intensity of the 250-kDa band decreased significantly, and 200- and 150 kDa bands appeared in bvORF20-expressing anthers. Transgenic callus expressing bvORF20 also generated the 200- and 150-kDa bands. The 200-kDa complex is likely to include both preSATP6 and bvORF20. Post-translational interaction between preSATP6 and bvORF20 appears to alter the higher order structure of preSATP6 that may lead to fertility restoration in sugar beet. PMID- 26031623 TI - Stimuli-Responsive Frustrated Lewis-Pair-Type Reactivity of a Tungsten Iminoazaphosphiridine Complex. AB - Reactions of 3-imino-azaphosphiridine complexes 1 a,b with carbodiimides 2 a,b, isocyanates 3 a,b, and carbon dioxide are described. Whereas exchange of the carbodiimide unit occurs in the first case, an overall ring expansion takes place with phenyl isocyanate (3 a) and carbon dioxide to yield complexes 4 and 5 bearing novel 1,3,5-oxazaphospholane ligands; the isopropyl derivative 3 b did not react under these conditions. DFT calculations provide insight into the pathway of the reaction with carbon dioxide with model complex 1 c, revealing effects of initial non-covalent interactions with the substrate onto the ring bonding, thus triggering an initially masked frustrated Lewis-pair-type behavior. PMID- 26031624 TI - Printed interdigital electrodes on plastic film for tumor cells density monitoring. AB - Printed sensor has been introduced as a rapid and cost-effective platform for biomedical applications, especially for wearable biosensing and point-of-care diagnosis. In this paper, we reported a tumor cell density monitoring device with printed interdigital electrodes on a plastic film. Numerical simulation of electrical impedance spectroscopy shows good agreement with the experimental measurement of DI water and PBS solution. Different concentrations of cancer cells were used to demonstrate the capability of cell culture monitoring. The developed device is highly cost-effective and easy for fabrication, which may have great potentials in low-cost analysis of biological cells. In a word, this paper shows a more rapid and simple cell counting method as compared to tedious microscope cell counting. PMID- 26031625 TI - Efficacy and safety of a cisplatin and paclitaxel induction regimen followed by chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this phase II trial was to evaluate the tolerability, safety, and efficacy of a non-5-fluorouracil (5-FU)-based induction chemotherapy followed by chemoradiotherapy (CRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Sixty patients with stage III to IV HNSCC were treated with induction paclitaxel and cisplatin (TP; paclitaxel 175 mg/m(2) and cisplatin 80 mg/m(2) , 3 cycles) followed by CRT (cisplatin 100 mg/m(2) ; D1, 22, and 43 of radiotherapy). RESULTS: Fifty-six patients (93.3%) completed 3 cycles of induction TP (no treatment-related deaths), 52 (86.7%) completed definitive CRT per protocol (adverse event [AE] grade >=2 in 53.3%). The overall response rate after induction TP was 82.5% for patients with resectable disease and 55.5% for unresectable disease (p = .023), and complete response (CR) rate after CRT was 70.0% for patients with resectable disease and 30.0% for unresectable disease (p = .005). CONCLUSION: Induction TP followed by cisplatin based-CRT was well-tolerated, safe, and had high overall response rate in selected patients with locally advanced HNSCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E970-E980, 2016. PMID- 26031627 TI - Molecular diagnosis of melanoma-have we arrived? PMID- 26031628 TI - Enhanced Chemotherapeutic Behavior of Open-Caged DNA@Doxorubicin Nanostructures for Cancer Cells. AB - In cancer therapy, it is imperative to increase the efficacy and reduce side effects of chemotherapeutic drugs. Nanotechnology offers the unique opportunity to overcome these barriers. In particular, in the last few years, DNA nanostructures have gained attention for their biocompatibility, easy customized synthesis and ability to deliver drugs to cancer cells. Here, an open-caged pyramidal DNA@Doxorubicin (Py-Doxo) nanostructure was constructed with 10 DNA sequences of 26-28 nucleotides for drug delivery to cancer cells. The synthesized DNA nanostructures are sufficiently stable in biological medium. Py-Doxo exhibited significantly enhanced cytotoxicity of the delivered doxorubicin to breast and liver cancer cells up to twofold compared to free doxorubicin. This study demonstrates the importance of the shape and structure of the designed transporter DNA nanostructures for biomedical applications. PMID- 26031629 TI - Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. AB - To determine whether reactive astrocytes stimulated by brain injury can transdifferentiate into functional new neurons, we labeled these cells by injecting a glial fibrillary acidic protein (GFAP) targeted enhanced green fluorescence protein plasmid (pGfa2-eGFP plasmid) into the striatum of adult rats immediately following a transient middle cerebral artery occlusion (MCAO) and performed immunolabeling with specific neuronal markers to trace the neural fates of eGFP-expressing (GFP(+)) reactive astrocytes. The results showed that a portion of striatal GFP(+) astrocytes could transdifferentiate into immature neurons at 1 week after MCAO and mature neurons at 2 weeks as determined by double staining GFP-expressing cells with betaIII-tubulin (GFP(+)-Tuj-1(+)) and microtubule associated protein-2 (GFP(+)-MAP-2(+)), respectively. GFP(+) neurons further expressed choline acetyltransferase, glutamic acid decarboxylase, dopamine receptor D2-like family proteins, and the N-methyl-D-aspartate receptor subunit R2, indicating that astrocyte-derived neurons could develop into cholinergic or GABAergic neurons and express dopamine and glutamate receptors on their membranes. Electron microscopy analysis indicated that GFP(+) neurons could form synapses with other neurons at 13 weeks after MCAO. Electrophysiological recordings revealed that action potentials and active postsynaptic currents could be recorded in the neuron-like GFP(+) cells but not in the astrocyte-like GFP(+) cells, demonstrating that new GFP(+) neurons possessed the capacity to fire action potentials and receive synaptic inputs. These results demonstrated that striatal astrocyte-derived new neurons participate in the rebuilding of functional neural networks, a fundamental basis for brain repair after injury. These results may lead to new therapeutic strategies for enhancing brain repair after ischemic stroke. PMID- 26031630 TI - Carbon monoxide: A new player in the redox regulation of connexin hemichannels. AB - Carbon monoxide (CO) is a gaseous transmitter that is known to be involved in several physiological processes, but surprisingly it is also becoming a promising molecule to treat several pathologies including stroke and cancer. CO can cross the plasma membrane and activate guanylate cyclase, increasing the cGMP concentration and activating some kinases, including PKG. The other mechanism of action involves induction of protein carbonylation. CO is known to directly and indirectly modulate the function of ion channels at the plasma membrane, which in turn have important repercussions in the cellular behavior. One group of these channels is hemichannels, which are formed by proteins known as connexins (Cxs). Hemichannel allows not only the flow of ions through their pore but also the release of molecules such as ATP and glutamate. Therefore, their modulation not only impacts cellular function but also cellular communication, having the capability to affect tissular behavior. Here, we review the most recent results regarding the effect of CO on Cx hemichannels and their possible repercussions on pathologies. PMID- 26031632 TI - Cardiovascular genetics: technological advancements and applicability for dilated cardiomyopathy. AB - Genetics plays an important role in the pathophysiology of cardiovascular diseases, and is increasingly being integrated into clinical practice. Since 2008, both capacity and cost-efficiency of mutation screening of DNA have been increased magnificently due to the technological advancement obtained by next generation sequencing. Hence, the discovery rate of genetic defects in cardiovascular genetics has grown rapidly and the financial threshold for gene diagnostics has been lowered, making large-scale DNA sequencing broadly accessible. In this review, the genetic variants, mutations and inheritance models are briefly introduced, after which an overview is provided of current clinical and technological applications in gene diagnostics and research for cardiovascular disease and in particular, dilated cardiomyopathy. Finally, a reflection on the future perspectives in cardiogenetics is given. PMID- 26031631 TI - Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality. AB - Men diagnosed with nonmetastatic prostate cancer have a long life expectancy, and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may affect disease-specific and overall mortality. A total of 926 men participating in the Physicians' Health Study diagnosed with nonmetastatic prostate cancer completed diet questionnaires for a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer-specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95% CI, 1.00-6.42; Ptrend = 0.02) for prostate cancer specific mortality and 1.67 (95% CI, 1.16-2.42; Ptrend = 0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all cause mortality (HRQuartile 4 vs. Quartile 1: 0.64; 95% CI, 0.44-0.93; Ptrend = 0.02); the relationship with prostate cancer-specific mortality was inverse but not statistically significant. A post-diagnostic Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis. PMID- 26031633 TI - Maastricht experience with the second generation endoscopic laser balloon ablation system for the atrial fibrillation treatment. PMID- 26031634 TI - Haemodynamics in a patient with Fontan physiology undergoing laparoscopic cholecystectomy. AB - Laparoscopic surgery in patients with Fontan circulation is a haemodynamic challenge; venous return may be compromised by insufflation of carbon dioxide into the abdomen (increasing intra-abdominal pressure), the use of reverse Trendelenburg position and positive pressure ventilation. Combined with an increase in pulmonary vascular resistance due to hypercarbia, cardiac output may be reduced. However, for non-haemodynamic reasons, laparoscopic surgery has advantages over open surgery: less postoperative pain, shorter hospital stay, a reduction in postoperative wound infections and a reduction of respiratory complications. In this case report, we present a patient with Fontan circulation who underwent uneventful laparoscopic cholecystectomy. PMID- 26031635 TI - A white raven detected by imaging. AB - The purpose of this case report is to describe a rare case of a patient with a phaeochromocytoma with several cardiovascular complications, which can be attributed to the tumour. Detection of a phaeochromocytoma sometimes needs a 'Sherlock Holmes spirit' or simply time. PMID- 26031636 TI - Atypical aortic coarctation as a cause of a cardiomyopathy. AB - Atypical locations for aortic coarctation have been previously described. However, to our knowledge, no case has been described of a rapidly progressive dilated cardiomyopathy caused by an atypical coarctation, with a rapid normalisation of ventricular function after treatment. PMID- 26031637 TI - Diagnostic dilemmas in a patient with multivascular embolic stroke. AB - We describe a patient admitted to the intensive care unit with aphasia, which was due to an embolic ischaemic cerebral stroke associated with a previously unknown patent foramen ovale. Eventually, this finding during echocardiography led us to the diagnosis of pancreatic cancer. The thrombotic complications of pancreatic cancer, in combination with a large, patent foramen ovale, support the mechanism of a paradoxical embolism through the patent foramen ovale as the cause of cerebral ischaemic stroke. PMID- 26031638 TI - Ameliorating effect of the novel dipeptidyl peptidase-4 inhibitor teneligliptin on psoriasis: A report of two cases. AB - Dipeptidyl peptidase-4 inhibitors are a new class of antidiabetic agents also shown to possess immunomodulatory functions. Although various dipeptidyl peptidase-4 inhibitors have been widely used and assumed to be administrated in many patients with psoriasis accompanied by type 2 diabetic mellitus, only two studies have shown that sitagliptin, a dipeptidyl peptidase-4 inhibitor, improved the cutaneous symptom of psoriasis independently of its antihyperglycemic effect. We report two cases of psoriatic skin lesions that obviously ameliorated after initiation of therapy with teneligliptin, a novel dipeptidyl peptidase-4 inhibitor. This report strengthens the notion that dipeptidyl peptidase-4 inhibitors clinically exert an ameliorating effect on psoriatic lesions. Considering the pharmacokinetic data that indicate the high penetrative ability of teneligliptin into skin tissue, teneligliptin may be considered an effective agent for improving skin lesions of psoriasis. PMID- 26031639 TI - Thousand mile journey. Part II: collaborative steps to advance the management of groin pain in athletes. PMID- 26031640 TI - The next step towards rational treatment for 'The sportsman's groin'. PMID- 26031641 TI - Some athletes are immature...skeletally. PMID- 26031642 TI - I had a dream. PMID- 26031643 TI - Doha agreement meeting on terminology and definitions in groin pain in athletes. AB - BACKGROUND: Heterogeneous taxonomy of groin injuries in athletes adds confusion to this complicated area. AIM: The 'Doha agreement meeting on terminology and definitions in groin pain in athletes' was convened to attempt to resolve this problem. Our aim was to agree on a standard terminology, along with accompanying definitions. METHODS: A one-day agreement meeting was held on 4 November 2014. Twenty-four international experts from 14 different countries participated. Systematic reviews were performed to give an up-to-date synthesis of the current evidence on major topics concerning groin pain in athletes. All members participated in a Delphi questionnaire prior to the meeting. RESULTS: Unanimous agreement was reached on the following terminology. The classification system has three major subheadings of groin pain in athletes: 1. Defined clinical entities for groin pain: Adductor-related, iliopsoas-related, inguinal-related and pubic related groin pain. 2. Hip-related groin pain. 3. Other causes of groin pain in athletes. The definitions are included in this paper. CONCLUSIONS: The Doha agreement meeting on terminology and definitions in groin pain in athletes reached a consensus on a clinically based taxonomy using three major categories. These definitions and terminology are based on history and physical examination to categorise athletes, making it simple and suitable for both clinical practice and research. PMID- 26031645 TI - Men at higher risk of groin injuries in elite team sports: a systematic review. AB - BACKGROUND: Groin injuries are common in sports, particularly multidirectional team sports, but incidence rates across sports other than football (soccer) have been poorly documented. METHODS: A systematic review (initially using PubMed and SportDiscus databases) was performed to record incidence of groin and groin region injuries in sports. Inclusion criteria included presentation of groin injury incidence data for at least 10 team/squad seasons. RESULTS: Data from 31 studies were included. These used varying injury definitions and also considered varying injury categories from general to specific (all groin/hip region injuries, groin injuries, adductor muscle strains, intra-articular hip injuries). When playing the same sport, men had greater injury incidence of groin injury than women (relative risk, RR 2.45, 95% CI 2.06 to 2.92). Sports with high incidences of groin injury included ice hockey and the football codes. There is variation by player position for rate of groin injury in many sports. Hip injuries have become more commonly diagnosed over the past decade in Australian football (p=0.001) and other sports. CONCLUSIONS: There is moderate evidence that men have a higher risk of groin injury than women when playing the same sport. There is some evidence that hip injuries are being increasingly diagnosed in the subset of 'groin injuries' in recent years. It is recommended that injury epidemiology consensus statements aim to include a number of relevant sports to improve injury incidence comparisons among different sports. PMID- 26031644 TI - Minimum reporting standards for clinical research on groin pain in athletes. AB - Groin pain in athletes is a priority area for sports physiotherapy and sports medicine research. Heterogeneous studies with low methodological quality dominate research related to groin pain in athletes. Low-quality studies undermine the external validity of research findings and limit the ability to generalise findings to the target patient population. Minimum reporting standards for research on groin pain in athletes are overdue. We propose a set of minimum reporting standards based on best available evidence to be utilised in future research on groin pain in athletes. Minimum reporting standards are provided in relation to: (1) study methodology, (2) study participants and injury history, (3) clinical examination, (4) clinical assessment and (5) radiology. Adherence to these minimum reporting standards will strengthen the quality and transparency of research conducted on groin pain in athletes. This will allow an easier comparison of outcomes across studies in the future. PMID- 26031646 TI - Which factors differentiate athletes with hip/groin pain from those without? A systematic review with meta-analysis. AB - BACKGROUND: Hip and groin injuries are common in many sports. Understanding the factors differentiating athletes with hip/groin pain from those without these injuries could facilitate management and prevention. OBJECTIVE: Conduct a systematic review and meta-analysis of the literature on factors differentiating athletes with and without hip/groin pain. METHODS: The review was registered as PROSPERO CRD42014007416 and a comprehensive, systematic search was conducted in June 2014. Inclusion criteria were: cross-sectional, cohort or case-control study designs of n>10 that examined outcome measures differentiating athletes with and without hip/groin pain. Two authors independently screened search results, assessed study quality, and performed data extraction. Methodological heterogeneity was determined and data pooled for meta-analysis when appropriate. A best evidence synthesis was performed on the remaining outcome measures. RESULTS: Of 2251 titles identified, 17 articles were included of which 10 were high quality. Sixty two different outcome measures were examined, 8 underwent meta-analysis. Pooled data showed strong evidence that athletes with hip/groin pain demonstrated: pain and lower strength on the adductor squeeze test, reduced range of motion in hip internal rotation and bent knee fall out; however, hip external rotation range was equivalent to controls. Strong evidence was found that lower patient-reported outcome (PRO) scores, altered trunk muscle function, and moderate evidence of bone oedema and secondary cleft sign were associated with hip/groin pain. CONCLUSIONS: PROs, pain and reduced strength on the adductor squeeze test, reduced range of motion in internal rotation and bent knee fall out are the outcome measures that best differentiate athletes with hip/groin pain from those without this pain. PMID- 26031647 TI - Systematic review: laparoscopic treatment of long-standing groin pain in athletes. AB - OBJECTIVES: No single aetiological factor has been proven to cause long-standing groin pain in athletes and no sole operative technique (either open or laparoscopic) has been shown to be the preferred method of repair. The aim of this systematic review was to determine whether there are any differences in the return to full sporting activity following laparoscopic repair of groin pain in athletes. DATA SOURCES: The minimal access approaches include laparoscopic transabdominal pre-peritoneal (TAPP) or endoscopic total extraperitoneal (TEP) techniques. A systematic literature search was performed in PubMed, SCOPUS, UpToDate and the Cochrane Library databases. Series reporting laparoscopic repair (TAPP/TEP) of groin pain in adult (>18 years) athletes were included. The primary outcome was return to full sporting activity and secondary outcomes included percentage success rates and complications of operations. RESULTS: Only 18 studies fulfilled the search criteria with both laparoscopic and sports hernia repairs. The studies were mainly observational with some reporting comparative data, but no large randomised controlled trials were detected. The median return to sporting activity of 4 weeks (28 days) was the same for the TAPP as well as TEP techniques. No real difference in secondary outcome measures was shown. More reported cases to date in the literature used the TAPP technique compared with TEP repair (n=605 vs n=266). CONCLUSIONS: Laparoscopic surgery for elite athlete groin pain is increasingly becoming more common with almost 1000 patients reported since 1997. No particular laparoscopic technique appears to offer any advantage over the other. PMID- 26031648 TI - Pubic apophysitis: a previously undescribed clinical entity of groin pain in athletes. AB - BACKGROUND: Sport-related pubalgia is often a diagnostic challenge in elite athletes. While scientific attention has focused on adults, there is little data on adolescents. Cadaveric and imaging studies identify a secondary ossification centre located along the anteromedial corner of pubis beneath the insertions of symphysial joint capsule and adductor longus tendon. Little is known about this apophysis and its response to chronic stress. AIM: We report pubic apophysitis as a clinically relevant entity in adolescent athletes. METHODS: The clinical and imaging findings in 26 highly trained adolescent football players (15.6 years +/- 1.3) who complained of adductor-related groin pain were reviewed. The imaging features (X-ray 26/26, US 9/26, MRI 11/26, CT 7/26) of the pubic apophyses in this symptomatic group were compared against those of a comparison group of 31 male patients (age range 9-30 years) with no known history of groin pain or pelvic trauma, who underwent pelvic CT scans for unrelated medical reasons. RESULTS: All symptomatic subjects presented with similar history and physical findings. The CT scans of these patients demonstrated open pubic apophyses with stress-related physeal changes (widening, asymmetry and small rounded cyst-like expansions) that were not observed in the comparison group. No comparison subject demonstrated apophyseal maturity before 21 years of age, and immaturity was seen up to the age of 26 years. CONCLUSIONS: This retrospective case series identifies pubic apophyseal stress (or 'apophysitis') as an important differential consideration in the adolescent athlete who presents with groin pain. PMID- 26031649 TI - Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide Rich Peptides. AB - Disulfide-rich peptides containing three or more disulfide bonds are promising therapeutic and diagnostic agents, but their preparation is often limited by the tedious and low-yielding folding process. We found that a single cystine-to diaminodiacid replacement could significantly increase the folding efficiency of disulfide-rich peptides and thus improve their production yields. The practicality of this strategy was demonstrated by the synthesis and folding of derivatives of the MU-conotoxin SIIIA, the preclinical hormone hepcidin, and the trypsin inhibitor EETI-II. NMR and X-ray crystallography studies confirmed that these derivatives of disulfide-rich peptide retained the correct three dimensional conformations. Moreover, the cystine-to-diaminodiacid replacement enabled structural tuning, thereby leading to an EETI-II derivative with higher bioactivity than the native peptide. PMID- 26031650 TI - Prognostic impact of CD109 expression in myxofibrosarcoma. AB - BACKGROUND: CD109, a TGF-beta co-receptor, is reported to be preferentially expressed during the early stages of tumorigenesis in several carcinoma types. Myxofibrosarcoma is one of the most common soft-tissue sarcomas found in elderly patients. This study aimed to elucidate the impact of CD109 expression in myxofibrosarcoma on prognosis and recurrence. METHODS: Immunohistochemical staining for CD109 was performed on archival specimens from 37 patients. The Fisher exact test was used to evaluate association between CD109 expression and other clinicopathological features. Survival analysis was performed using Kaplan Meier curves, and the prognostic significance was evaluated using the log-rank test. Multivariate analysis of factors was performed using Cox regression analysis. RESULTS: CD109 overexpression was significantly associated with surgical stage and distant metastasis (P = 0.00499, and 0.011, respectively). The frequency of CD109 overexpression was approximately 10% and CD109 overexpression was significantly associated with decreased overall survival (P = 0.004). Five year overall survival rates 77% and 0% for CD109-negative and CD109-positive patients, respectively. In multivariate analysis, CD109 overexpression was the only independent risk factor for poor outcome (P = 0.02; hazard ratio, 10.64; 95% confidence interval, 1.47-76.91). CONCLUSIONS: Immunohistochemical CD109 expression in myxofibrosarcoma was associated with poor prognosis. PMID- 26031651 TI - Transplantation tolerance: context matters. AB - Costimulation blockade has been one of the most studied strategies to achieve immune tolerance, particularly in transplantation. Yet, in spite of the robust nature of the tolerance-inducing potential of costimulation blockade, a comprehensive understanding of the molecular and cellular mechanisms underlying tolerance induction is still missing. Nevertheless, progress has been continuously made. In this issue of the European Journal of Immunology, Chai et al. [Eur. J. Immunol. 2015. 45: 2017-2027] show that transplantation tolerance induced with an anti-CD154 monoclonal antibody relies on the coexistence of several tolerogenic mechanisms rather than one simple regulatory mechanism. These observations highlight the importance of concerted actions involving multiple pathways, namely apoptosis, acquisition of regulatory cells, or inhibition of proliferation, all of which contribute to the induction and maintenance of robust immune tolerance. A better understanding of these distinct tolerogenic pathways may lead to the development of better tolerance-inducing therapeutics. PMID- 26031652 TI - Cavotricuspid-Dependent Atrial Flutter in Patients With Prior Atriotomy: 12-Lead ECG Interpretation and Electroanatomical Characteristics. AB - BACKGROUND: The aim of this study was to describe the electrocardiogram (ECG) morphology and electroanatomical characteristics of counterclockwise tricuspid annular atrial flutter (CCWTA-AFL) in the patients with prior atriotomy. METHODS AND RESULTS: This retrospective study included 34 patients with CCWTA-AFL after cardiac surgery and 20 patients with typical CCWTA-AFL without prior surgery. For patients in the postsurgical group, 19 had single-loop CCWTA-AFL and 15 had a double loop CCWTA-AFL. For single loop CCWTA-AFL the F-wave in lead I was very flat in l7 of 19 patients. The F-wave morphology in the inferior leads and V1 were found to be similar to typical AFL in 14 of 19 patients. For double loop CCWTA-AFL, F-waves were positive in lead I in 13 out of 15 patients. A long isoelectric activation was measured between F-waves in most of the patients. The presence of isoelectric segments between F-waves suggested a double loop AFL, which had a sensitivity of 86.7% and a specificity of 100%. Moreover, flat F waves in lead I suggested a single loop AFL, which had a sensitivity of 89.5% and specificity of 86.7%. All patients in the group without prior cardiac surgery had typical ECGs features of CCWTA-AFL. None of the patients showed isoelectric segments between F-waves in the inferior leads. The amplitudes of most of the leads were higher than those for single loop CCWTA-AFL in patients with prior surgery. PMID- 26031653 TI - The Authors' Reply: The association of systemic oxidative stress with insulin resistance: mechanistic insights from studies in Bartter's and Gitelman's syndromes. PMID- 26031654 TI - Cutaneous involvement in systemic anaplastic large cell lymphoma. PMID- 26031655 TI - Influenza surveillance in Europe: comparing intensity levels calculated using the moving epidemic method. AB - OBJECTIVES: Although influenza-like illnesses (ILI) and acute respiratory illnesses (ARI) surveillance are well established in Europe, the comparability of intensity among countries and seasons remains an unresolved challenge. The objective is to compare the intensity of ILI and ARI in some European countries. DESIGN AND SETTING: Weekly ILI and ARI incidence rates and proportion of primary care consultations were modeled in 28 countries for the 1996/1997-2013/2014 seasons using the moving epidemic method (MEM). We calculated the epidemic threshold and three intensity thresholds, which delimit five intensity levels: baseline, low, medium, high, and very high. The intensity of 2013/2014 season is described and compared by country. RESULTS: The lowest ILI epidemic thresholds appeared in Sweden and Estonia (below 10 cases per 100 000) and the highest in Belgium, Denmark, Hungary, Poland, Serbia, and Slovakia (above 100 per 100 000). The 2009/2010 season was the most intense, with 35% of the countries showing high or very high intensity levels. The European epidemic period in season 2013/2014 started in January 2014 in Spain, Poland, and Greece. The intensity was between low and medium and only Greece reached the high intensity level, in weeks 7 to 9/2014. Some countries remained at the baseline level throughout the entire surveillance period. CONCLUSIONS: Epidemic and intensity thresholds varied by country. Influenza-like illnesses and ARI levels normalized by MEM in 2013/2014 showed that the intensity of the season in Europe was between low and medium in most of the countries. Comparing intensity among seasons or countries is essential for understanding patterns in seasonal epidemics. An automated standardized model for comparison should be implemented at national and international levels. PMID- 26031656 TI - Propagation of pathology through brain networks in neurodegenerative diseases: from molecules to clinical phenotypes. AB - The cellular mechanisms underlying the stereotypical progression of pathology in neurodegenerative diseases are incompletely understood, but increasing evidence indicates that misfolded protein aggregates can spread by a self-perpetuating neuron-to-neuron transmission. Novel neuroimaging techniques can help elucidating how these disorders spread across brain networks. Recent knowledge from structural and functional connectivity studies suggests that the relation between neurodegenerative diseases and distinct brain networks is likely to be a strict consequence of diffuse network dynamics. Diffusion tensor magnetic resonance imaging also showed that measurement of white matter tract involvement can be a valid surrogate to assess the in vivo spreading of pathological proteins in these conditions. This review will introduce briefly the main molecular and pathological substrates of the most frequent neurodegenerative diseases and provide a comprehensive overview of neuroimaging findings that support the "network-based neurodegeneration" hypothesis in these disorders. Characterizing network breakdown in neurodegenerative diseases will help anticipate and perhaps prevent the devastating impact of these conditions. PMID- 26031657 TI - Fluorescence Response of Conjugated Polyelectrolyte in an Immiscible Two-Phase System via Nonelectrostatic Interaction with Surfactants. AB - This paper reports a unique fluorescence (FL) response and diverse applications of conjugated polyelectrolyte (CPE) through nonelectrostatic interaction with appropriate (bio)surfactants in an immiscible two-phase system. A sulfonated microporous conjugated polymer (SMCP) with a conformation-variable intramolecular stacked structure was used as the CPE film. Despite the extremely high hydrophilicity, the SMCP film responded significantly to the hydrophobic circumstances, either physicochemically or electronically, in the presence of water-in-oil (w/o)-type nonionic surfactants with appropriate hydrophile lipophile balance (HLB) values. The polymer film became fully wet with hydrophobic solvents due to the addition of small amounts of (bio)surfactant to reveal remarkable FL emission enhancement and chromism. Microcontact and inkjet printing using the SMCP film (or SMCP-adsorbed paper) and the surfactant solution as substrate and ink, respectively, provided high-resolution FL images due to the distinctive surfactant-induced FL change (SIFC) characteristic. Moreover, the additional electrostatic interaction of SMCP film with oppositely charged surfactants further enhanced the FL emission. Our findings will help comprehensive understanding of the nonelectrostatic SIFC mechanism of CPEs and development of novel SIFC-active materials. PMID- 26031658 TI - Synthesis of New Benzocyclotrimer Analogues: New Receptors for Tetramethylammonium Ion Recognition. AB - Using a [2 + 2 + 2] cycloaddition/Mitsunobu reaction sequence, a convenient synthesis to access new benzocyclotrimer analogues has been developed. The new receptors have the geometry and functionality capable of recognizing the tetramethylammonium ion in the gas phase and in solution. PMID- 26031659 TI - Overexpression of PLAP-1 in bone marrow stromal cells inhibits the rat critical size skull defect repair. AB - Periodontal ligament-associated protein-1 (PLAP-1) is an osteogenisis negative regulatory gene that inhibits the differentiation of rat bone marrow stromal cells (rBMSCs) into osteoblasts in vitro. The aim of this study was to verify whether PLAP-1 acted as an inhibitory factor of rBMSCs in rat critical-size skull defect repair in vivo. Six-week old male Wistar rats treated with a drill-hole injury were randomly assigned into five groups PLAP-1-transfected rBMSC group, empty vector-transfected rBMSC group, normal rBMSC group, collagen group and blank control group according to the treatment factors. Skull specimens were obtained at 8 weeks after surgery. X-ray examination, histological observation of hard tissue slices (HE, Masson staining and von Kossa staining), immunohistochemical staining were applied to evaluate the repair effects. X-ray examination showed that repair effect of the PLAP-1-transfected rBMSC group was significantly worse than that of the empty vector-transfected rBMSC group and normal rBMSC group. In HE staining, regenerated bone could only be observed in the partial defect area of the PLAP-1-transfected rBMSC group. However, new bone filled nearly the entire defects in the empty vector-transfected rBMSC group and normal rBMSC group. Mineralization of new bone in the two groups was significantly higher than that of the PLAP-1-transfected rBMSC group, according to Masson and von Kossa staining. Meanwhile, the transfected PLAP-1 gene worked well in vivo. Positive expression of PLAP-1 protein was only distributed in the newly formed bone of the PLAP-1-transfected rBMSC group, no positive staining was observed in the other four groups. Overexpression of PLAP-1 in rBMSCs inhibits new bone formation and mineralization in rat critical-size skull defects in vivo. PMID- 26031660 TI - Determination of astragaloside III in rat plasma by liquid chromatography-tandem mass spectrometry and its application to a rat pharmacokinetic study. AB - Astragaloside III (AST III), a naturally occurring saponin compound isolated from Radix Astragali, has been demonstrated to have anti-gastric ulcer, immunomodulatory and antitumor effects. To evaluate its pharmacokinetics in rats, a rapid, sensitive and specific high-performance liquid chromatography-tandem mass spectrometric (HPLC-MS/MS) method has been developed and validated for the quantification of astragaloside III in rat plasma. Samples were pretreated using a simple protein precipitation with methanol-acetonitrile (50:50, v/v) and the chromatographic separation was performed on a C18 column by a gradient elution using a mobile phase consisting of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. Astragaloside III and the internal standard (buspirone) were detected using a tandem mass spectrometer in positive multiple reaction monitoring mode. Method validation revealed excellent linearity over the range of 5.00-5000 ng/mL together with satisfactory intra- and inter-day precision, accuracy and recovery. Stability testing showed that astragaloside III spiked into rat plasma was stable for 24 h at 20 degrees C temperature, for up to 30 days at -80 degrees C, and during three freeze-thaw cycles. The method was successfully used to investigate the pharmacokinetic profile of AST III after oral (10 mg/kg) and intravenous (1.0 mg/kg) administration in rats. The oral absolute bioavailability of AST III was calculated to be 4.15 +/- 0.67% with an elimination half-life value of 2.13 +/- 0.11 h, suggesting its poor absorption and/or strong metabolism in vivo. PMID- 26031661 TI - FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. AB - C9ORF72 repeat expansion is the most common genetic mutation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Abnormal dipeptide repeat proteins (DPRs) generated from repeat-associated non-AUG (RAN) translation of repeat-containing RNAs are thought to be pathogenic; however, the mechanisms are unknown. Here we report that (GR)80 and (PR)80 are toxic in neuronal and non neuronal cells in Drosophila. In contrast to reported shorter poly(GR) forms, (GR)80 is mostly localized throughout the cytosol without detectable accumulation in the nucleolus, accompanied by suppression of Notch signaling and cell loss in the wing. Some Notch target genes are also downregulated in brains and iPSC derived cortical neurons of C9ORF72 patients. Increased Notch expression largely suppressed (GR)80-induced cell loss in the wing. When co-expressed in Drosophila, HeLa cells, or human neurons, (GA)80 recruited (GR)80 into cytoplasmic inclusions, partially decreasing the toxicity of (GR)80 and restoring Notch signaling in Drosophila. Thus, different DPRs have opposing roles in cell loss and we identify the Notch pathway as one of the receptor signaling pathways that might be compromised in C9ORF72 FTD/ALS. PMID- 26031662 TI - Introduction to Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease. PMID- 26031663 TI - Identification of prostamides, fatty acyl ethanolamines, and their biosynthetic precursors in rabbit cornea. AB - Arachidonoyl ethanolamine (anandamide) and pros-taglandin ethanolamines (prostamides) are biologically active derivatives of arachidonic acid. Although available through different precursor phospholipids, there is considerable overlap between the biosynthetic pathways of arachidonic acid-derived eicosanoids and anandamide-derived prostamides. Prostamides exhibit physiological actions and are involved in ocular hypotension, smooth muscle contraction, and inflammatory pain. Although topical application of bimatoprost, a structural analog of prostaglandin F2alpha ethanolamide (PGF2alpha-EA), is currently a first-line treatment for ocular hypertension, the endogenous production of prostamides and their biochemical precursors in corneal tissue has not yet been reported. In this study, we report the presence of anandamide, palmitoyl-, stearoyl-, alpha linolenoyl docosahexaenoyl-, linoleoyl-, and oleoyl-ethanolamines in rabbit cornea, and following treatment with anandamide, the formation of PGF2alpha-EA, PGE2-EA, PGD2-EA by corneal extracts (all analyzed by LC/ESI-MS/MS). A number of N-acyl phosphatidylethanolamines, precursors of anandamide and other fatty acyl ethanolamines, were also identified in corneal lipid extracts using ESI-MS/MS. These findings suggest that the prostamide and fatty acid ethanolamine pathways are operational in the cornea and may provide valuable insight into corneal physiology and their potential influence on adjacent tissues and the aqueous humor. PMID- 26031665 TI - Dual Role of the 1,2,3-Triazolium Ring as a Hydrogen-Bond Donor and Anion-pi Receptor in Anion-Recognition Processes. AB - Several bis(triazolium)-based receptors have been synthesized as chemosensors for anion recognition. The central naphthalene core features two aryltriazolium side arms. NMR experiments revealed differences between the binding modes of the two triazolium rings: one triazolium ring acts as a hydrogen-bond donor, the other as an anion-pi receptor. Receptors 9(2+)?2BF4(-) (C6H5), 11(2+)?2BF4(-) (4-NO2 C6H4), and 13(2+)?2BF(4-) (ferrocenyl) bind HP2O7(3-) anions in a mixed-binding mode that features a combination of hydrogen-bonding and anion-pi interactions and results in strong binding. On the other hand, receptor 10(2+)?2 BF4(-) (4 CH3O-C6H4) only displays combined Csp2-H/anion-pi interactions between the two arms of the receptors and the bound anion rather than triazolium (CH)(+)???anion hydrogen bonding. All receptors undergo a downfield shift of the triazolium protons, as well as the inner naphthalene protons, in the presence of H2PO4(-) anions. That suggests that only hydrogen-bonding interactions exist between the binding site and the bound anion, and involve a combination of cationic (triazolium) and neutral (naphthalene) C-H donor interactions. Theoretical calculations relate the electronic structure of the substituent on the aromatic group with the interaction energies and provide a minimum-energy conformation for all the complexes that explains their measured properties. PMID- 26031664 TI - Comparative transcriptomic analysis revealed adaptation mechanism of Phrynocephalus erythrurus, the highest altitude Lizard living in the Qinghai Tibet Plateau. AB - BACKGROUND: Organisms living at high altitudes must overcome three major environmental challenges: hypoxia, cold, and intense UV radiation. The molecular mechanisms that enable these challenges to be overcome have mainly been studied in endothermic organisms; relatively little attention has been paid to poikilothermic species. Here, we present deep transcriptome sequencing in two closely related lizards, the high altitude-dwelling Phrynocephalus erythrurus and the lowland-dwelling P. putjatia, to identify candidate genes under positive selection and to explore the convergent evolutionary adaptation of poikilothermic animals to high altitude life. RESULTS: More than 70 million sequence reads were generated for each species via Illumina sequencing. De novo assembly produced 56,845 and 63,140 transcripts for P. erythrurus and P. putjatia, respectively. P. erythrurus had higher Ka/Ks ratios than P. putjatia, implying an accelerated evolutionary rate in the high altitude lizard lineage. 206 gene ontology (GO) categories with accelerated evolutionary rates and 43 candidate positively selected genes were detected along the P. erythrurus lineage. Some of these GO categories have functions associated with responses to hypoxia, energy metabolism and responses to UV damage. We also found that the high-altitude ranid frog R. kukunoris had higher Ka/Ks ratios than the closely related low-altitude frog R. chensinensis, and that the functional categories with accelerated evolutionary rates in R. kukunoris overlapped extensively with those detected along the P. erythrurus lineage. CONCLUSIONS: The mechanisms of high altitude adaptation in P. erythrurus were tentatively inferred. By comparing two pairs of low- and high altitude poikilothermic species, we found that similar functional categories had undergone positive selection in high altitude-dwelling Phrynocephalus and Rana lineages, indicating that similar mechanisms of adaptation to high altitude might have evolved in both genera. Our findings provide important guidance for future functional studies on high altitude adaptation in poikilothermic animals. PMID- 26031666 TI - Consumption of hot beverages and foods and the risk of esophageal cancer: a meta analysis of observational studies. AB - BACKGROUND: Previous studies have mostly focused on the effects of specific constituents of beverages and foods on the risk of esophageal cancer (EC). An increasing number of studies are now emerging examining the health consequences of the high temperature of beverages and foods. We conducted a meta-analysis to summarize the evidence and clarify the association between hot beverages and foods consumption and EC risk. METHODS: We searched the PubMed, Embase, and Web of Science databases for relevant studies, published before May 1, 2014, with the aim to estimate the association between hot beverage and food consumption and EC risk. A random-effect model was used to pool the results from the included studies. Publication bias was assessed by using the Begg test, the Egger test, and funnel plot. RESULTS: Thirty-nine studies satisfied the inclusion criteria, giving a total of 42,475 non-overlapping participants and 13,811 EC cases. Hot beverage and food consumption was significantly associated with EC risk, with an odds ratio (OR) of 1.82 (95% confidence interval [CI], 1.53-2.17). The risk was higher for esophageal squamous cell carcinoma, with a pooled OR of 1.60 (95% CI, 1.29-2.00), and was insignificant for esophageal adenocarcinoma (OR: 0.79; 95% CI: 0.53-1.16). Subgroup analyses suggests that the association between hot beverage and food consumption and EC risk were significant in Asian population (OR: 2.06; 95% CI: 1.62-2.61) and South American population (OR: 1.52; 95% CI: 1.25-1.85), but not significant in European population (OR: 0.95; 95% CI: 0.68 1.34). CONCLUSIONS: Hot beverage and food consumption is associated with a significantly increased risk of EC, especially in Asian and South American populations, indicating the importance in changing people's dietary habits to prevent EC. PMID- 26031668 TI - Role of Leadership in Narrowing the Gap between Science and Practice: Improving Treatment Outcomes at the Systems Level. AB - It's been well documented that health care does not reliably transfer what we know from science into clinical practice. As a result, Americans do not always receive the care suggested by the scientific evidence. Despite the best intentions of a dedicated and skilled healthcare workforce, this can often lead to poor clinical outcomes. As research and technology rapidly advance, this gap between science and practice appears to be widening. There is an increasing public concern about a lack of access to appropriate treatment, pervasiveness of unsafe practices, and wasteful uses of precious health care resources leading to suboptimum treatment outcomes. Leadership has a critical role in creating and sustaining the environment that supports health services for individuals and populations that increase the likelihood of desired health outcomes and are consistent with current professional knowledge. Leadership has some responsibility to improve outcomes by insuring effective use of evidence-based treatment guidelines; measurement-based care; knowledge and skills management; care coordination; and information technologies. This paper addresses leadership issues in these components of a system's ability to improve treatment outcomes. PMID- 26031667 TI - Safety of intra-arterial treatment in acute ischaemic stroke patients on oral anticoagulants. A cohort study and systematic review. AB - BACKGROUND AND PURPOSE: An elevated international normalized ratio (INR) of >1.7 is a contraindication for the use of intravenous thrombolytics in acute ischaemic stroke. Local intra-arterial therapy (IAT) is considered a safe alternative. The safety and outcome of IAT were investigated in patients with acute ischaemic stroke using oral anticoagulants (OACs). METHODS: Data were obtained from a large national Dutch database on IAT in acute stroke patients. Patients were categorized according to the INR: >1.7 and <=1.7. Primary outcome was symptomatic intracerebral hemorrhage (sICH), defined as deterioration in the National Institutes of Health Stroke Scale score of >=4 and ICH on brain imaging. Secondary outcomes were clinical outcome at discharge and 3 months. Occurrence of outcomes was compared with risk ratios and corresponding 95% confidence intervals. Further, a systematic review and meta-analysis on sICH risk in acute stroke patients on OACs treated with IAT was performed. RESULTS: Four hundred and fifty-six patients were included. Eighteen patients had an INR > 1.7 with a median INR of 2.4 (range 1.8-4.1). One patient (6%) in the INR > 1.7 group developed a sICH compared with 53 patients (12%) in the INR <= 1.7 group (risk ratio 0.49, 95% confidence interval 0.07-3.13). Clinical outcomes did not differ between the two groups. Our meta-analysis showed a first week sICH risk of 8.1% (95% confidence interval 3.9%-17.1%) in stroke patients with elevated INR treated with IAT. CONCLUSION: The use of OACs, leading to an INR > 1.7, did not seem to increase the risk of an sICH in patients with an acute stroke treated with IAT. PMID- 26031669 TI - An Integrated Pain Clinic Model. PMID- 26031670 TI - Treatment of rats with Jiangzhi Capsule improves liquid fructose-induced fatty liver: modulation of hepatic expression of SREBP-1c and DGAT-2. AB - BACKGROUND: Jiangzhi Capsule is an Australian listed patented traditional Chinese medicine and has been used for management of lipid abnormalities over the past 10 years. To obtain a better understanding regarding Jiangzhi Capsule, the present study investigated the effects and underlying mechanisms of Jiangzhi Capsule on chronic fructose overconsumption-induced lipid abnormalities. METHODS: Male rats were treated with liquid fructose in their drinking water over 14 weeks. Jiangzhi Capsule was co-administered (once daily, by oral gavage) during the last 7 weeks. Indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by real-time PCR, Western blot and/or immunohistochemistry. RESULTS: Treatment with Jiangzhi Capsule (100 mg/kg) attenuated fructose-induced excessive triglyceride accumulation and Oil Red O-stained area in the liver. This effect was accompanied by amelioration of hyperinsulinemia. There was no significant difference in intakes of fructose and chow, and body weight between fructose control and fructose Jiangzhi Capsule treated groups. Mechanistically, Jiangzhi Capsule downregulated fructose stimulated hepatic overexpression of sterol regulatory element binding protein (SREBP)-1/1c at the mRNA and protein levels. Accordingly, the SREBP-1c downstream genes, acetyl-CoA carboxylase-1 and stearoyl-CoA desaturase-1, were also inhibited. In addition, acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver was also inhibited after Jiangzhi Capsule treatment. In contrast, Jiangzhi Capsule affected neither carbohydrate response element binding protein, peroxisome proliferator-activated receptor (PPAR)-gamma and DGAT-1, nor PPAR-alpha and its target genes. CONCLUSIONS: These findings demonstrate the anti-steatotic action of Jiangzhi Capsule in fructose-fed rats, and modulation of hepatic SREBP-1c and DGAT-2 involved in hepatic de novo synthesis of fatty acids and triglyceride, respectively. Our findings provide an evidence-based and mechanistic understanding of Jiangzhi Capsule supporting its application for the prevention and/or treatment of fatty liver and its associated disorders in clinical practice. PMID- 26031671 TI - Predicting cardiovascular risk in type 2 diabetes: the heterogeneity challenges. AB - Type 2 diabetes mellitus has reached epidemic proportions around the world, and the increase in cardiovascular risk attributable to diabetes estimated to range from 2- to 4-fold poses grave public health concern. Though in some contexts type 2 diabetes has been equated with coronary heart disease equivalent risk, there is considerable evidence that incremental cardiovascular risk does not uniformly affect all people with type 2 diabetes. This heterogeneity in cardiovascular risk is multifactorial and only partially understood but is a key consideration for our understanding of the nexus of diabetes and cardiovascular disease and for the development of optimal and individualized cardiovascular risk reduction strategies. This review provides a brief synopsis of the concept of cardiovascular risk heterogeneity in diabetes, including epidemiologic evidence, discussion of established and potential determinants of heterogeneity, and clinical, research, and regulatory implications. PMID- 26031672 TI - Lipid effects and cardiovascular disease risk associated with glucose-lowering medications. AB - Diabetes is a global epidemic, associated with a high burden of complications and 4.6 million deaths annually worldwide. As a result of decreasing levels of physical activity and increasing rates of obesity, diabetes is shifting from a disease affecting the elderly to one that affects younger patients or even children. Thus, aggressive treatment and optimal control of risk factors is the key to improve outcomes in those patients. Accumulating evidence of the cardiovascular and lipid effects of glucose-lowering medications suggest that treatment efficacy in diabetes can be further improved. This review provides an overview of the lipid effects and cardiovascular disease risk of current anti diabetic medications and highlights opportunities and challenges in clinical practice. PMID- 26031673 TI - LDL, HDL, VLDL, and CVD Prevention: Lessons from Genetics? AB - Over the past years, genetic studies on lipid traits have substantially extended our understanding of the relationship between lipid metabolism and coronary artery disease (CAD). Thereby, novel pathways and interactions in lipid metabolism unraveled by genetic studies have led to promising novel treatment strategies that are currently evaluated for prevention and treatment of CAD, such as low-density lipoprotein cholesterol (LDL-C) lowering by inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). This review article discusses findings from recent genetic studies and their implications for the understanding of the relation between lipid metabolism and CAD as well as the development of novel therapeutic strategies supported by these studies. PMID- 26031675 TI - Is irritable bowel syndrome a dysbiotic bowel syndrome? PMID- 26031674 TI - Limb ischemia: cardiovascular diagnosis and management from head to toe. AB - Peripheral arterial disease (PAD) affects an estimated 27 million people in Europe and North America. Limb ischemia, defined as ischemic rest pain, ischemic ulcerations, or ischemic gangrene, represents the most severe manifestation of PAD and is associated with significant cardiovascular and limb morbidity and mortality. Critical limb ischemia (CLI), defined as limb ischemia symptoms for greater than 2 weeks, is characterized by a cascade of hemodynamically significant macrovascular atherosclerotic obstruction and microvascular changes culminating in decreased muscle perfusion, disrupted muscle energy metabolism, and inflammation. In contrast, acute limb ischemia (ALI) is defined as limb ischemia symptoms characterized by sudden onset of less than 2 weeks duration resulting in hemodynamically compromised limb perfusion. Diagnosis of both ALI and CLI is dependent on history, physical examination, and a combination of anatomic and hemodynamic assessment of the limb. Given that the risk factors for ALI and CLI overlap with risk factors for atherosclerotic coronary and neurovascular disease, the management of limb ischemia is focused on both endovascular or surgical limb salvage and cardiovascular risk factor control. Despite advancements in endovascular and surgical revascularization techniques, limb morbidity remains high; clinical trials of angiogenic and cell-based therapies are ongoing. Cardiovascular risk reduction in patients with limb ischemia also remains suboptimal and future studies will focus on novel antiplatelet agents. PMID- 26031676 TI - Experience with cultivated microbiota transplant: ongoing treatment of Clostridium difficile patients in Sweden. PMID- 26031677 TI - Feces transplantation for recurrent Clostridium difficile infection: US experience and recommendations. PMID- 26031678 TI - Anaerobically cultivated human intestinal microbiota as first-line treatment for Clostridium difficile infection. PMID- 26031679 TI - Immune modulation by non-digestible and non-absorbable beta-1,3/1,6-glucan. PMID- 26031680 TI - What did we learn today? PMID- 26031681 TI - Introducing the thematic cluster. PMID- 26031682 TI - Factors affecting infant gut microbiota and possible consequences for health. PMID- 26031683 TI - We all need friends. PMID- 26031684 TI - Feces transplantation - EU recommendations. PMID- 26031686 TI - Opportunities to assess factors contributing to the development of the intestinal microbiota in infants living in developing countries. AB - Recent evidence suggests that establishment of a healthy gut microbiota shortly after birth is important to achieve optimal growth and development of children. Being born into a resource-poor environment presents challenges to the establishment of a healthy gut microbial flora in the newborn. Among these challenges are births that occur at home, traditional pre-lacteal feeding of newborns leading to failure to initiate lactation, poor sanitation and water quality, early environmental exposure to, and infection with, enteric or other pathogens, suboptimal breast feeding duration and intensity, deficiencies in weaning and childhood diets contributing to micro- and macro-nutrient deficiencies, and the frequent use of antibiotics. These factors should be considered in the design and implementation of preventive and therapeutic interventions aimed at improving the health and development of these children. PMID- 26031685 TI - Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. AB - Clinical observations suggest that gut and dietary factors transiently worsen and, in some cases, appear to improve behavioral symptoms in a subset of persons with autism spectrum disorders (ASDs), but the reason for this is unclear. Emerging evidence suggests ASDs are a family of systemic disorders of altered immunity, metabolism, and gene expression. Pre- or perinatal infection, hospitalization, or early antibiotic exposure, which may alter gut microbiota, have been suggested as potential risk factors for ASD. Can a common environmental agent link these disparate findings? This review outlines basic science and clinical evidence that enteric short-chain fatty acids (SCFAs), present in diet and also produced by opportunistic gut bacteria following fermentation of dietary carbohydrates, may be environmental triggers in ASD. Of note, propionic acid, a major SCFA produced by ASD-associated gastrointestinal bacteria (clostridia, bacteroides, desulfovibrio) and also a common food preservative, can produce reversible behavioral, electrographic, neuroinflammatory, metabolic, and epigenetic changes closely resembling those found in ASD when administered to rodents. Major effects of these SCFAs may be through the alteration of mitochondrial function via the citric acid cycle and carnitine metabolism, or the epigenetic modulation of ASD-associated genes, which may be useful clinical biomarkers. It discusses the hypothesis that ASDs are produced by pre- or post natal alterations in intestinal microbiota in sensitive sub-populations, which may have major implications in ASD cause, diagnosis, prevention, and treatment. PMID- 26031688 TI - Fibrous dysplasia of the temporal bone secondary to ear surgery: a case report. AB - INTRODUCTION: In this report, we describe the clinical course, diagnostic features and management of a patient with fibrous dysplasia of the temporal bone 7 years after middle ear surgery on the same side. CASE PRESENTATION: A 16-year old Caucasian girl presented to our hospital with a growing bone lesion in the roof of the left temporal bone. She had undergone a previous tympanoplasty at 7 years of age because of a cholesteatoma. At the time of that first surgery, no radiological or histological signs indicated a bone disorder. A computed tomographic scan of the temporal bone showed a lesion with rarefaction areas and lytic images inside that affected the roof of the cavity to the tegmen tympani without alterations in the inner ear. A surgical revision of the ear cavity was performed by resecting the lesion and regularizing the cavity. The histopathologic study confirmed fibrous dysplasia. The patient progressed satisfactorily after surgery with no evidence of recurrence. CONCLUSION: To the best of our knowledge, this is the first report of fibrous dysplasia of the temporal bone secondary to ear surgery. PMID- 26031689 TI - A systematic review of the outcomes reported in multimodal pain therapy for chronic pain. AB - BACKGROUND AND OBJECTIVE: There are no recommendations provided for the outcome domains of chronic pain that should be explicitly considered in each clinical trial to describe the efficacy and effectiveness of multimodal pain therapy (MPT). Our aims were to summarize all reported outcome domains in studies assessing the effects of MPT for chronic pain, and to subsequently inform a consensus-based development of a core outcome set of domains in this field. DATABASE AND DATA TREATMENT: Medline, Embase and AMED were searched for studies reporting on chronic pain for at least 3 months that applied MPT and investigated outcome domains. All reported outcome domains were extracted from eligible articles. The patient-reported outcome measurement information system (PROMIS) was applied for conceptual classification. RESULTS: From 3626 potentially relevant titles, 70 studies were included. The median and maximal numbers of outcome domains were 8 and 34, respectively. Although most studies (n = 45/70) assessed a combination of all three core health areas, i.e. physical, mental and social health, there was great variation in the specific domains chosen to address these core health areas. No outcome domain was measured consistently in all studies. After selection of all outcome domains which were reported in at least 10% of all studies included, we identified 14 different outcome domains, mostly operationalized through the domains pain intensity (n = 56/70) and depressive symptoms (n = 42/70). CONCLUSIONS: The current lack of standardization of outcome domains in MPT studies hinders to readily compare interventions from different trials and is a barrier towards evidence-based decision making. Based on these results, the development of a core outcome set of domains for MPT has been initiated. PMID- 26031690 TI - In Reply to Letter to the Editor "Bilateral Total Hip Arthroplasty has Similar Complication Rates to Unilateral Total Hip Arthroplasty". PMID- 26031687 TI - GUT in FOCUS Symposium NOBEL FORUM, Karolinska Institutet, February 2nd 2015. PMID- 26031691 TI - Direct-Indirect Class V Restorations: A Novel Approach for Treating Noncarious Cervical Lesions. AB - Noncarious cervical lesions are highly prevalent and may have different etiologies. Regardless of their origin, be it acid erosion, abrasion, or abfraction, restoring these lesions can pose clinical challenges, including access to the lesion, field control, material placement and handling, marginal finishing, patient discomfort, and chair time. This paper describes a novel technique for minimizing these challenges and optimizing the restoration of noncarious cervical lesions using a technique the author describes as the class V direct-indirect restoration. With this technique, clinicians can create precise extraoral margin finishing and polishing, while maintaining periodontal health and controlling polymerization shrinkage stress. CLINICAL SIGNIFICANCE: The clinical technique described in this article has the potential for being used routinely in treating noncarious cervical lesions, especially in cases without easy access and limited field control. Precise margin finishing and polishing is one of the greatest benefits of the class V direct-indirect approach, as the author has seen it work successfully in his practice over the past five years. PMID- 26031693 TI - Nursing management of aggression in a Singapore emergency department: A qualitative study. AB - In Singapore, anecdotal evidence suggests that nurses are concerned about managing aggressive incidents in the emergency department. In this study, registered nurses' perceptions of managing aggressive patients in an emergency department were explored. Ten registered nurses from the emergency department of an acute public hospital in Singapore were interviewed. Four overarching themes emerged from the thematic analysis: (i) impact of aggressive patients on nurses; (ii) nursing assessment of aggressive behaviors; (iii) nursing management of aggressive behaviors; and (iv) organizational support and responsiveness. Further research is required to better support nurses to deliver optimal care for aggressive patients and achieve positive and effective outcomes. PMID- 26031694 TI - The relationship between challenging behaviours, mood and interest/pleasure in adults with severe and profound intellectual disabilities. AB - BACKGROUND: We investigated whether current mood and interest/pleasure ratings in adults with moderate to profound intellectual disabilities were predictive of challenging behaviour [self-injurious behaviour (SIB), aggressive/destructive behaviour and stereotypic behaviour] and vice versa. METHOD: In this combined cross-sectional and longitudinal study, staff members of a Hungarian residential facility completed translated versions of the Behaviour Problems Inventory-Short Form (BPI-S), the Challenging Behaviour Interview (CBI) and the Mood, Interest and Pleasure Questionnaire-Short Form (MIPQ-S) for 50 participants at two time points, approximately 4 to 5 months apart. RESULTS: Bivariate correlations from data concurrently assessed at Time-1 showed significant linear relationships between the SIB (both frequency and severity scores) and Interest/Pleasure sub scales, and the Aggressive/Destructive Behaviour (severity scores) and the MIPQ-S Mood sub-scales (unadjusted for multiple correlations). All of these effects were found with the BPI-S data, but not with the CBI. Multiple regression analyses revealed that (1) low interest/pleasure assessed at Time-1 predicted high SIB (frequency and severity) at Time-2. (2) Interest/pleasure was not predictive of aggressive or stereotypic behaviour. (3) Mood at Time-1 did not predict any of the three types of behaviour problems at Time-2. (4) In reverse, high SIB (frequency and severity) at Time-1 predicted low interest/pleasure ratings at Time-2. (5) Surprisingly, frequent aggressive/destructive behaviour predicted high interest/pleasure. (6) Stereotypic behaviour scores at Time-1 did not predict interest/pleasure ratings at Time-2. Again, all of these effects were only found with the BPI-S data, but not with the CBI. Internal consistency, test retest reliability and concurrent validity of the Hungarian versions of all three questionnaires had generally satisfactory outcomes. DISCUSSION: The fact that increasingly frequent and severe SIB was predicted by declining measures of interest/pleasure is consistent with previous studies. Contrary to those earlier studies, however, we found that SIB was not predicted by mood and that aggressive/destructive behaviour actually predicted future elevated mood. Implications for future research regarding the directional relationship between affective states such as mood and interest and pleasure, on the one hand, and challenging behaviour, on the other, were discussed. PMID- 26031695 TI - Introducing a New Technique for Limb Prepping in Orthopedic Surgeries: Designing, Construction, and Evaluation of Limb-Lifting Assistive Device. AB - Lifting and holding patients' limbs while preparing the skin for orthopedic surgeries may be a lengthy process causing work-related musculoskeletal disorders (MSDs) for preoperative team members. Studies reported weight limits for lifting and holding limbs; whenever this weight is greater than a specific amount, additional staff or assistive devices are needed because nurses and support staff working in orthopedic operating rooms (ORs) are at high risk of MSDs. The aim of this study was to demonstrate the design, construction, and effectiveness of a limb-lifting assistive device installed in the OR of 5 Azar Hospital affiliated with Golestan University of Medical Sciences and used during the surgical preparation process. PMID- 26031696 TI - Needlestick and Sharps Injuries Among Nurses at a Teaching Hospital in China. AB - Needlestick and sharps injuries (NSIs) are a major occupational injury to health care workers worldwide. This study aimed to report the prevalence and risk factors of NSIs among nurses working at a Chinese teaching hospital. From 463 nurses, 402 completed questionnaires were obtained. A total of 261 (64.9%) nurses reported needlestick or sharps injuries. NSIs were more common among females, young nurses, surgical nurses, and junior nurses. Logistic regression analysis suggests that age and work department were independent risk factors for NSIs. By type of devices, syringe needles accounted for the highest proportion of all NSIs (59%), followed by glass items (22%), and trocar core/catheter wires (4%). NSIs remain an important occupational hazard issue or Chinese nurses. Programs must be developed to prevent injuries caused by needlesticks and sharps. PMID- 26031697 TI - Device therapy: Remote monitoring-the benefits of keeping in touch. PMID- 26031699 TI - Atrial fibrillation: Uninterrupted oral anticoagulation in patients undergoing catheter ablation. PMID- 26031700 TI - Risk factors: Hand grip strength predicts cardiovascular risk. PMID- 26031698 TI - Total artificial hearts: past, present, and future. AB - A practical artificial heart has been sought for >50 years. An increasing number of people succumb to heart disease each year, but the number of hearts available for transplantation remains small. Early total artificial hearts mimicked the pumping action of the native heart. These positive-displacement pumps could provide adequate haemodynamic support and maintain the human circulation for short periods, but large size and limited durability adversely affected recipients' quality of life. Subsequent research into left ventricular assist devices led to the use of continuous-flow blood pumps with rotating impellers. Researchers have attempted to integrate this technology into modern total artificial hearts with moderate clinical success. The importance of pulsatile circulation remains unclear. Future research is, therefore, needed into positive displacement and rotary total artificial hearts. PMID- 26031701 TI - A rapidly growing epidermoid cyst in an intrapancreatic accessory spleen treated by laparoscopic spleen-preserving distal pancreatectomy: Report of a case. AB - Epidermoid cysts arising in an intrapancreatic accessory spleen are exceedingly rare, furthermore the natural course of them is hardly known. We report a case correctly diagnosed with epidermoid cyst in an intrapancreatic accessory spleen, followed by 1 year observation, finally underwent surgical treatment. The patient presented with diarrhea. Contrast-enhanced computed tomography (CT) revealed a pancreatic cyst 20 mm in diameter, surrounded by a solid component showing the same enhancement as the spleen, suggesting the presence of an epidermoid cyst in an intrapancreatic accessory spleen. One year later, back discomfort developed, and a CT scan revealed that the cyst had grown to 38 mm in diameter. To obtain a definitive diagnosis, we performed a laparoscopic spleen-preserving distal pancreatectomy. The histopathological diagnosis was compatible with an epidermoid cyst in an intrapancreatic accessory spleen, which is benign. The postoperative course was uneventful. This case demonstrates that an epidermoid cyst arising in an intrapancreatic accessory spleen can rapidly grow, even if it is benign. Laparoscopic spleen-preserving distal pancreatectomy can be a useful procedure, with the advantages of low invasiveness and organ preservation, for the treatment of benign or low-grade malignant tumors located in the pancreatic body or tail. PMID- 26031702 TI - Heat-shock-protein 90 protects from downregulation of HIF-1alpha in calcineurin induced myocardial hypertrophy. AB - AIM OF THE STUDY: Capillary/myocyte mismatch is a hallmark of maladaptive myocardial hypertrophy, but the exact mechanisms of this phenomenon remain unknown. We therefore aimed to evaluate the role of calcineurin A in the regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a calcineurin overexpressing mouse model of myocardial hypertrophy. METHODS AND RESULTS: Mice overexpressing calcineurin A (CnATg) showed persistent upregulation of HIF-1 alpha protein without evidence of a reduction in capillary density despite progressive myocardial hypertrophy. Likewise, overexpression of calcineurin A in isolated cardiomyocytes induced upregulation of HIF-1 alpha protein. In contrast, NFAT-overexpression had no such effect, implying that NFAT-independent mechanisms were responsible for increased HIF-1 alpha levels. In addition, inhibition of HSP90 via the HSP90-inhibitor 17-AAG or siRNA abolished calcineurin A-induced upregulation of HIF-1 alpha. Consequently, upregulation of HIF-1 alpha target genes like VEGF-A, BNIP-3 or PGK-1 was also inhibited by either 17-AAG or siRNA directed against HSP90. Finally, when CnATg mice were treated with 17-AAG, they demonstrated reduced left ventricular function and capillary density. CONCLUSIONS: We describe here for the first time that overexpression of the phosphatase calcineurin A prevents the development of a capillary/myocyte mismatch despite progressive myocardial hypertrophy. This effect was mediated by HSP-90 induced stabilization of HIF-1 alpha. Further work is needed to understand this unexpected cardioprotective effect of calcineurin A. PMID- 26031703 TI - Measuring the metrics: Correlating t-tubule structure and muscle contraction in the intact heart. PMID- 26031704 TI - Low occurrence of the HLA-C*04:09N allele in a large Hungarian cohort. AB - The presence of null alleles may affect the outcome of stem cell transplantation. HLA-C*04:09N was defined as 'common' with a frequency of 2-5/1000 in Caucasians, and its presence is routinely tested as part of haplotypes HLA-A*02:01/A*23:01 B*44:03-DRB1*07:01-DQB1*02:01. We aimed to investigate HLA-C*04:09N in a representative Hungarian cohort. HLA-typing data of 7345 unrelated persons were analyzed. The presence of HLA-C*04:09N was excluded in 157 chromosomes with either serology typing or with an allele-specific polymerase chain reaction for HLA-C*04:09N. HLA-C*04:09N was identified in a single chromosome with HLA-A*02, B*44, C*04, DRB1*07 resulting in a HLA-C*04:09N allele frequency of 0.0068% (1/14,690). This is approximately a 10- to 40-fold lower frequency compared with the previous data. Our results emphasize the need of precise local population specific HLA-data, allowing appropriate modifications of local HLA-typing protocols. PMID- 26031705 TI - High-throughput multiplex cpDNA resequencing clarifies the genetic diversity and genetic relationships among Brassica napus, Brassica rapa and Brassica oleracea. AB - Brassica napus (rapeseed) is a recent allotetraploid plant and the second most important oilseed crop worldwide. The origin of B. napus and the genetic relationships with its diploid ancestor species remain largely unresolved. Here, chloroplast DNA (cpDNA) from 488 B. napus accessions of global origin, 139 B. rapa accessions and 49 B. oleracea accessions were populationally resequenced using Illumina Solexa sequencing technologies. The intraspecific cpDNA variants and their allelic frequencies were called genomewide and further validated via EcoTILLING analyses of the rpo region. The cpDNA of the current global B. napus population comprises more than 400 variants (SNPs and short InDels) and maintains one predominant haplotype (Bncp1). Whole-genome resequencing of the cpDNA of Bncp1 haplotype eliminated its direct inheritance from any accession of the B. rapa or B. oleracea species. The distribution of the polymorphism information content (PIC) values for each variant demonstrated that B. napus has much lower cpDNA diversity than B. rapa; however, a vast majority of the wild and cultivated B. oleracea specimens appeared to share one same distinct cpDNA haplotype, in contrast to its wild C-genome relatives. This finding suggests that the cpDNA of the three Brassica species is well differentiated. The predominant B. napus cpDNA haplotype may have originated from uninvestigated relatives or from interactions between cpDNA mutations and natural/artificial selection during speciation and evolution. These exhaustive data on variation in cpDNA would provide fundamental data for research on cpDNA and chloroplasts. PMID- 26031706 TI - Comparison of EGFR mutation detection between the tissue and cytology using direct sequencing, pyrosequencing and peptide nucleic acid clamping in lung adenocarcinoma: Korean multicentre study. AB - BACKGROUND: The importance of sensitive methods for the detection of epidermal growth factor receptor (EGFR) mutation is emphasized. The aim of this study is to perform comparative and concordance analyses of direct sequencing, pyrosequencing and peptide nucleic acid (PNA) clamping for detecting EGFR gene mutations using archived tissue and cytology specimens. METHODS: Samples from a total of 112 cases, which were diagnosed with adenocarcinoma of the lung at nine hospitals in Korea were collected. Using the above three methods, the concordance rates of EGFR mutations in exons 18, 19, 20 and 21 were analysed and validated in comparative tissue and cytology specimens. RESULTS: Comparison of EGFR mutation detection between the tissue and cytology had a high concordance rate. The diagnostic performance of pyrosequencing and PNA clamping in tissue was higher than that of direct sequencing as well as cytology. Additionally, among some of the patients who had EGFR wild type by single method, EGFR mutations were detected by other methods. Cytology specimens had a diagnostic performance for the detection of EGFR mutations. CONCLUSIONS: Cytology specimens had a diagnostic performance for the detection of EGFR mutations that was comparable to that of tissues. For detecting EGFR mutations, pyrosequencing or PNA clamping was more sensitive than direct sequencing. In EGFR mutation negative patients who are difficult to obtain tissue, repeating test using pyrosequencing or PNA clamping is recommended to improve the detection rate of EGFR mutation than only one, especially in cytology. PMID- 26031707 TI - Toxic effects of hydrogen sulfide: experience with three simultaneous patients. PMID- 26031708 TI - The Complementary Nature of Patient-Reported Outcomes and Adverse Event Reporting in Cooperative Group Oncology Clinical Trials: A Pooled Analysis (NCCTG N0591). AB - CONTEXT: Clinical trials use clinician-graded adverse events (AEs) and patient reported outcomes (PROs) to describe symptoms. OBJECTIVES: The aim of the study was to examine the agreement between PROs and AEs in the clinical trial setting. METHODS: Patient-level data were pooled from seven North Central Cancer Treatment Group, two Southwest Oncology Group, and three Radiation Therapy Oncology Group lung studies that included both PROs and AE data. Ten-point changes (on a 0-100 scale) in PRO scores were considered clinically significant differences (CSDs). PRO score changes were compared to AE grade (Gr) categories (2+ yes vs. no and 3+ yes vs. no) using Wilcoxon rank-sum or two-sample t-tests between Gr categories. Incidence rates and concordance of CSD in PRO scores and AE Gr categories were compiled. Spearman correlations were computed between PRO scores and AE severity. RESULTS: PROs completed by patients (n = 1013) were the Uniscale, Lung Cancer Symptom Scale (LCSS), Functional Assessment of Cancer Therapy-Lung (FACT-L), Symptom Distress Scale, and/or Functional Living Index-Cancer. Significantly worse PRO score changes were found for the FACT-L in patients with Gr 2+ AEs. Worse scores were seen for the Uniscale for patients with Gr 2+ AEs (P = 0.07) and LCSS for patients with Gr 3+ AEs (P = 0.09). Agreement between incidence of any Gr 2+ (Gr 3+) AE and a CSD in PROs ranged from 27% to 67% (36%-61%). Correlations between PRO scores and AE severity were low: -0.06 Uniscale, -0.03 LCSS, 0.10 FACT-L, -0.11 Symptom Distress Scale, and -0.51 Functional Living Index-Cancer. CONCLUSION: These results support previous work and an a priori hypothesis that AEs and PROs measure differing aspects of the disease experience and are complementary. PMID- 26031710 TI - Symptom Control Trials in Patients With Advanced Cancer: A Qualitative Study. AB - CONTEXT: Symptom control research in patients with advanced cancer is not common. This may be the result of a belief that this research is unethical, not practical, or that patients are not interested. However, the experiences of cancer patients who have actually taken part in symptom control research near the end of life have never been detailed. OBJECTIVES: The objective was to explore the experiences of patients with advanced cancer who had taken part in symptom control trials. METHODS: A prospective two-center study was undertaken using grounded theory methodology. Theoretical sampling was used to recruit patients from one of two double-blind, randomized, placebo-controlled trials studying novel analgesic agents for cancer-related pain. Participants completed one semistructured interview. Recruitment and interviewing continued until data saturation was achieved. RESULTS: Twenty-one participants were recruited. Fifteen (71%) were male, with a mean age of 62 years. Key themes identified included reasons for trial participation, participants' interactions with the trial staff, and participants' responses to the effect the trial had on their pain. In general, participants regarded taking part in a clinical trial as a positive experience, and potentially improving overall well-being. Crucially, this was not related to whether there had been an improvement in symptoms. CONCLUSION: The findings provide grounds for optimism that patients with advanced cancer may benefit from taking part in symptom control trials, supporting the paradigm that participation in symptom control research should be encouraged in this population. PMID- 26031711 TI - Phage T4-induced DNA breaks activate a tRNA repair-defying anticodon nuclease. AB - The natural role of the conserved bacterial anticodon nuclease (ACNase) RloC is not known, but traits that set it apart from the homologous phage T4-excluding ACNase PrrC could provide relevant clues. PrrC is silenced by a genetically linked DNA restriction-modification (RM) protein and turned on by a phage-encoded DNA restriction inhibitor. In contrast, RloC is rarely linked to an RM protein, and its ACNase is regulated by an internal switch responsive to double-stranded DNA breaks. Moreover, PrrC nicks the tRNA substrate, whereas RloC excises the wobble nucleotide. These distinctions suggested that (i) T4 and related phage that degrade their host DNA will activate RloC and (ii) the tRNA species consequently disrupted will not be restored by phage tRNA repair enzymes that counteract PrrC. Consistent with these predictions we show that Acinetobacter baylyi RloC expressed in Escherichia coli is activated by wild-type phage T4 but not by a mutant impaired in host DNA degradation. Moreover, host and T4 tRNA species disrupted by the activated ACNase were not restored by T4's tRNA repair system. Nonetheless, T4's plating efficiency was inefficiently impaired by AbaRloC, presumably due to a decoy function of the phage encoded tRNA target, the absence of which exacerbated the restriction. PMID- 26031709 TI - Phenotypic and Molecular Evidence Suggests That Decrements in Morning and Evening Energy Are Distinct but Related Symptoms. AB - CONTEXT: Little is known about energy levels in oncology patients and their family caregivers. OBJECTIVES: This study sought to identify latent classes of participants, based on self-reported energy levels and evaluate for differences in phenotypic and genotypic characteristics between these classes. METHODS: Energy subscale scores from the Lee Fatigue Scale were used to determine latent class membership. Morning and evening energy scores were obtained just before, during, and for four months after the completion of radiation therapy. Genetic associations were evaluated for 15 proinflammatory and anti-inflammatory cytokine genes. RESULTS: Two latent classes with distinct morning energy trajectories were identified. Participants who were younger, female, not married/partnered, black, and had more comorbidities, and a lower functional status were more likely to be in the low morning energy class. Two polymorphisms (IL2 rs1479923 and NFKB1 rs4648110) were associated with morning energy latent class membership. Two latent classes with distinct evening energy trajectories were identified. Participants who were younger and male and who had more comorbidities, decreased body weight, and a lower functional status were more likely to be in the moderate evening energy class. Five different polymorphisms (IL1R2 rs4141134, IL6 rs4719714, IL17A rs8193036, NFKB2 rs1056890, and TNFA rs1800683) were associated with evening energy latent class membership. CONCLUSION: This study provides preliminary evidence that decrements in morning and evening energy are associated with different phenotypic risk factors and cytokine gene variations. PMID- 26031712 TI - Ridge augmentation using recombinant human fibroblast growth factor-2 with biodegradable gelatin sponges incorporating beta-tricalcium phosphate: a preclinical study in dogs. AB - BACKGROUND AND OBJECTIVE: Fibroblast growth factor-2 (FGF-2) regulates the proliferation and differentiation of osteogenic cells, resulting in the promotion of bone formation. Biodegradable gelatin sponges incorporating beta-tricalcium phosphate (beta-TCP) have been reported as a scaffold, which has the ability to control growth factor release, offering sufficient mechanical strength and efficient migration of mesenchymal cells. In this study, we evaluated the effects of the combined use of recombinant human FGF-2 (rhFGF-2) and gelatin/beta-TCP sponge on ridge augmentation in dogs. MATERIAL AND METHODS: Six male beagle dogs were used in this study. Twelve wk after tooth extraction, bilateral 10 * 5 mm (width * depth) saddle-type defects were created 3 mm apart from the mesial side of the maxillary canine. At the experimental sites, the defects were filled with gelatin/beta-TCP sponge infiltrated with 0.3% rhFGF-2, whereas gelatin/beta-TCP sponge infiltrated with saline was applied to the control sites. Eight wk after surgery, qualitative and quantitative analyses were performed. RESULTS: There were no signs of clinical inflammation at 8 wk after surgery. Histometric measurements revealed that new bone height at the experimental sites (2.98 +/- 0.65 mm) was significantly greater than that at the control sites (1.56 +/- 0.66 mm; p = 0.004). The total tissue height was greater at the experimental sites (6.62 +/- 0.66 mm) than that at the control sites (5.95 +/- 0.74 mm), although there was no statistical significant difference (p = 0.051). Cast model measurements revealed that the residual defect height at the experimental sites (2.31 +/- 0.50 mm) was significantly smaller than that at the control sites (3.51 +/- 0.78 mm; p = 0.012). CONCLUSION: The combined use of rhFGF-2 and gelatin/beta TCP sponge promotes ridge augmentation in canine saddle-type bone defects. PMID- 26031713 TI - Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation. AB - Extracorporeal photopheresis (ECP) is a commonly used treatment for severe graft versus-host-disease (GVHD). We sought to evaluate the effects of ECP over a prolonged period on forced expiratory volume in 1 s (FEV1) in patients with pulmonary GVHD. We identified eight patients who developed new airflow obstruction following allogeneic stem cell transplantation and a substantial decline in FEV1 despite receiving corticosteroids and standard therapy for pulmonary GVHD. Those eight patients were treated with ECP for a period of 1 year, with a primary endpoint of FEV1 change during this treatment period. Over the first 3 months of ECP, there was no further decline in FEV1 in seven of the eight patients. However, over the 1 year period, only two of the eight patients had stability in FEV1. The rate of FEV1 decline was substantially less once ECP was initiated, though the median FEV1 continued to decline over 1 year of therapy. All patients survived through the first year of ECP therapy. There was a significant decrease in the median dose of prednisone per patient throughout the 12 months of ECP treatment. ECP shows promise in slowing rate of decline of FEV1 in pulmonary GVHD, though the effects may not be long lived. J. Clin. Apheresis 31:347-352, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26031714 TI - [Current treatment of sensorineural hearing loss and chronic tinnitus]. PMID- 26031717 TI - Effect of an exercise and weight control curriculum: views of obesity among exercise science students. AB - Awareness of effective weight management strategies is necessary to prepare exercise science students for future work with obesity. Exercise science faculty members developed a course related to exercise as a therapeutic tool and options available for weight loss. The purpose of the present study was to investigate student views of weight management and obesity, which can be a difficult task using traditional methods such as Likert scale surveys. To investigate student views relative to the course content, Q methodology, which is a mixed-method research approach, was used at the beginning and end of the course. Students completed a Q sort, ranking 44 statements related to obesity in accordance to their own points of view. The pretest/posttest design enabled an opportunity to determine if course goals were accomplished and if student perceptions related to obesity were transformed. Factor analysis of precourse sorts revealed that students possessed a naive singular view of weight-related concepts. Analysis of sorts at course completion resulted in a two-factor solution revealing changes in perspective; some students took on a health professional type of view, whereas others demonstrated antifat views. In conclusion, the findings revealed key variables that should be addressed in curricula involving therapeutic obesity interventions. An improved curriculum based on these results should better encourage students to develop a broad comprehension of multifactorial causes and treatment for weight management and obesity. Implementing the use of Q methodology may serve as a valuable asset to measure and evaluate subjectivity of obesity discrimination. Antifat attitudes among exercise science students may influence future clients' potential achievements. PMID- 26031715 TI - Screening for Chlamydia trachomatis in Egyptian women with unexplained infertility, comparing real-time PCR techniques to standard serology tests: case control study. AB - BACKGROUND: To study the prevalence of Chlamydia infection in women with primary and secondary unexplained infertility using ELISA technique for antibody detection and real time, fully automated PCR for antigen detection and to explore its association with circulating antisperm antibodies (ASA). METHODS: A total of 50 women with unexplained infertility enrolled in this case control study and a control group of 44 infertile women with a known cause of infertility. Endocervical specimens were collected for Chlamydia antigen detection using PCR and serum samples for antibodies detection. Circulating anti-sperm antibodies were detected using sperm antibody Latex Agglutination tests. RESULTS: The overall prevalence of Chlamydial infection in unexplained infertility cases as detected by both ELISA and PCR was 40 % (20/50). The prevalence of current Chlamydial genital infection as detected by real-time PCR was only 6.0 % (3/50); two of which were also IgM positive. Prevalence of ASA was 6.0 % (3/50); all were sero-negative for anti-C.trachomatis IgM and were PCR negative. CONCLUSION: The incidence of Chlamydial infection in Egyptian patients with unexplained infertility is relatively high. In the setting of fertility investigations; screening for anti. C.trachomatis antibodies using ELISA, and treatment of positive cases should be considered. The presence of circulating ASA does not correlate with the presence of old or current Chlamydia infection in women with unexplained infertility. PMID- 26031718 TI - Explorations in statistics: the analysis of change. AB - Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This tenth installment of Explorations in Statistics explores the analysis of a potential change in some physiological response. As researchers, we often express absolute change as percent change so we can account for different initial values of the response. But this creates a problem: percent change is really just a ratio, and a ratio is infamous for its ability to mislead. This means we may fail to find a group difference that does exist, or we may find a group difference that does not exist. What kind of an approach to science is that? In contrast, analysis of covariance is versatile: it can accommodate an analysis of the relationship between absolute change and initial value when percent change is useless. PMID- 26031720 TI - Online quizzes promote inconsistent improvements on in-class test performance in introductory anatomy and physiology. AB - Review quizzes can provide students with feedback and assist in the preparation for in-class tests, but students often do not voluntarily use self-testing resources. The purpose of the present study was to evaluate if taking a mandatory online review quiz alters performance on subsequent in-class tests. During two semesters of a single-semester introductory anatomy and physiology course, students were required to complete brief online quizzes after each textbook chapter had been covered during lecture as well as the day before an in-class test. During the next two semesters, students were not required to take the online review quizzes. Overall scores on chapter specific in-class tests were higher (P < 0.05) during the semesters in which students took online review quizzes (82.9 +/- 14.3%) compared with when they did not (78.7 +/- 15.5%), but all in-class tests were not improved. Scores on comprehensive midterm examinations were higher (83.0 +/- 12.9% vs. 78.9 +/- 13.7%, P < 0.05) but not on final examinations (72.4 +/- 13.8% vs. 71.8 +/- 14.0%) between those with online review quizzes and those without, respectively. Overall scores on in-class tests and comprehensive examinations were higher (P < 0.05) during the semesters in which students took online review quizzes (83.4 +/- 16.8%) compared with when they did not (80.3 +/- 17.6%). These data suggest that an online review quiz taken the day before an in-class test increases performance on some in-class tests. However, online review quizzes taken after completion of each chapter do not consistently enhance performance on comprehensive examinations. PMID- 26031721 TI - The development and implementation of a new medical biology major including physiology. AB - In response to the Howard Hughes Medical Institute/Association of American Medical Colleges Scientific Foundations for Future Physicians (SFFP) report and a concern for better preparing undergraduates for future doctoral programs in the health professions, the deans of the College of Arts and Sciences and Division of Basic Biomedical Sciences of Sanford School of Medicine of the University of South Dakota formed an ad hoc Premedical Curriculum Review Committee with representatives from the science departments and medical school. The Committee began by reviewing the university's suggested premedical curriculum and matching it to the proposed competencies from the SFFP to document duplications and deficiencies. The proposed changes in the Medical College Admission Test for 2015 were also evaluated. The Committee proposed a stronger premedical curriculum, with the development of some new courses, including an inquiry-based physiology course with team-based learning, to more fully address SFFP competencies. These analyses convinced the university that a new major would best help students achieve the competencies and prepare them for admission exams. Thus, a new Medical Biology major was proposed to the South Dakota Board of Regents and accepted for its initial offering in 2012. The new major has been broadly advertised to future students and is successful as a recruiting tool for the university. This article details the process of evaluating the curriculum and designing the new major, describes some of the difficulties in its implementation, and reviews outcomes from the new major to date. PMID- 26031719 TI - Exercise, cognitive function, and aging. AB - Increasing the lifespan of a population is often a marker of a country's success. With the percentage of the population over 65 yr of age expanding, managing the health and independence of this population is an ongoing concern. Advancing age is associated with a decrease in cognitive function that ultimately affects quality of life. Understanding potential adverse effects of aging on brain blood flow and cognition may help to determine effective strategies to mitigate these effects on the population. Exercise may be one strategy to prevent or delay cognitive decline. This review describes how aging is associated with cardiovascular disease risks, vascular dysfunction, and increasing Alzheimer's disease pathology. It will also discuss the possible effects of aging on cerebral vascular physiology, cerebral perfusion, and brain atrophy rates. Clinically, these changes will present as reduced cognitive function, neurodegeneration, and the onset of dementia. Regular exercise has been shown to improve cognitive function, and we hypothesize that this occurs through beneficial adaptations in vascular physiology and improved neurovascular coupling. This review highlights the potential interactions and ideas of how the age-associated variables may affect cognition and may be moderated by regular exercise. PMID- 26031722 TI - Effectiveness of inquiry-based learning in an undergraduate exercise physiology course. AB - The present study was conducted to investigate the effects of changing a laboratory physiology course for undergraduate students from a traditional step by-step guided structure to an inquiry-based approach. With this aim in mind, quantitative and qualitative evaluations of learning outcomes (individual subject specific tests and group interviews) were performed for a laboratory course in cardiorespiratory exercise physiology that was conducted in one year with a traditional step-by-step guided manual (traditional course) and the next year completed with an inquiry-based structure (I-based course). The I-based course was a guided inquiry course where students had to design the experimental protocol and conduct their own study on the basis of certain predefined criteria (i.e., they should evaluate respiratory responses to submaximal and maximal exercise and provide indirect and direct measures of aerobic exercise capacity). The results indicated that the overall time spent on the experimental course as well as self-evaluated learning outcomes were similar across groups. However, students in the I-based course used more time in preparation (102 +/- 5 min) than students in the traditional course (42 +/- 3 min, P < 0.05), and 65 +/- 5% students in the I-based course searched for additional literature before experimentation compared with only 2 +/- 1% students in the traditional course. Furthermore, students in the I-based course achieved a higher (P < 0.05) average score on the quantitative test (45 +/- 3%) compared with students in the traditional course (31 +/- 4%). Although students were unfamiliar with cardiorespiratory exercise physiology and the experimental methods before the course, it appears that an inquiry-based approach rather than one that provides students with step-by-step instructions may benefit learning outcomes in a laboratory physiology course. PMID- 26031723 TI - A faculty development program integrating cross-cultural care into a gastrointestinal pathophysiology tutorial benefits students, tutors, and the course. AB - A specific faculty development program for tutors to teach cross-cultural care in a preclinical gastrointestinal pathophysiology course with weekly longitudinal followup sessions was designed in 2007 and conducted in the same manner over a 6 yr period. Anonymous student evaluations of how "frequently" the course and the tutor were actively teaching cross-cultural care were performed. The statements "This tutor actively teaches culturally competent care" and "Issues of culture and ethnicity were addressed" were significantly improved over baseline 2004 data. These increases were sustained over the 6-yr period. A tutor's overall rating as a teacher was moderately correlated with his/her "frequently" actively teaching cross-cultural care (r = 0.385, P < 0. 001). Course evaluation scores were excellent and put the course into the group of preclinical courses with the top ratings. Students in the Race in Curriculum Group asked that the program be expanded to other preclinical courses. In conclusion, from 2007 to 2012, a faculty development program for teaching cross-cultural care consistently increased the discussion of cross-cultural care in the tutorial and course over each year beginning with 2007 compared with the baseline year of 2004. Our data suggest that cross-cultural care can be effectively integrated into pathophysiology tutorials and helps improve students' satisfaction and tutors' ratings. Teaching cross-cultural care in a pathophysiology tutorial did not detract from the course's overall evaluations, which remained in the top group over the 6-yr period. PMID- 26031724 TI - Investigation of blood flow and the effect of vasoactive substances in cutaneous blood vessels of Xenopus laevis. AB - In the present study, a preparation of frog skin was presented, which can be used to demonstrate the basic concepts of blood flow regulation in a very clear and attractive way to high school and university students. In a freshly euthanized Xenopus, a patch of abdominal skin was exposed from the internal side and viewed with a USB microscope while it remained connected to a functioning circulatory system. In this way, it was possible to obtain sharp images of arteries and veins and to visualize blood flow. This allows students to learn about the functional differences between arteries and veins and about the complexity of hemodynamics as well as the particularities of the amphibian pulmocutaneous circulation. Students can then quantitatively estimate the effect of norepinephrine and epinephrine on the diameter of blood vessels by simply superfusing the skin patch with a series of solutions of the two substances. They can also test the effect of alpha-adrenergic receptor blockers, used to treat high blood pressure, on the norepinephrine-induced muscle tonus of blood vessels. PMID- 26031725 TI - Background music in the dissection laboratory: impact on stress associated with the dissection experience. AB - Notable challenges, such as mental distress, boredom, negative moods, and attitudes, have been associated with learning in the cadaver dissection laboratory (CDL). The ability of background music (BM) to enhance the cognitive abilities of students is well documented. The present study was designed to investigate the impact of BM in the CDL and on stress associated with the dissection experience. After 8 wk of normal dissection without BM, various genres of BM were introduced into the cadaver dissection sessions of 260 medical and dental students for 3 wk. Feedback on the impact of BM on students in the CDL and students' attitude were accessed using a questionnaire. Psychological stress assessment was done using Psychological Stress Measure 9. Two batches of 30 students each were made to dissect same areas of the body for 2 h, one batch with BM playing and the other batch without. The same examination was given to both groups at the end. Over 90% of the participants expressed a desire to incorporate BM into the CDL; 87% of the sampled population that expressed love for music also reported BM to be a very useful tool that could be used to enhance learning conditions in the CDL. A strong positive relationship was established between love for music and its perception as a tool for learning in the CDL (P < 0.001). Students that studied under the influence of BM had significantly higher scores (P < 0.001) in the overall examination result. BM reduced the level of stress associated with the dissection experience by ~33%. PMID- 26031726 TI - Improving consistency in large laboratory courses: a design for a standardized practical exam. AB - Laboratory courses serve as important gateways to science, technology, engineering, and mathematics education. One of the challenges in assessing laboratory learning is to conduct meaningful and standardized practical exams, especially for large multisection laboratory courses. Laboratory practical exams in life sciences courses are frequently administered by asking students to move from station to station to answer questions, apply knowledge gained during laboratory experiments, interpret data, and identify various tissues and organs using various microscopic and gross specimens. This approach puts a stringent time limit on all questions regardless of the level of difficulty and also invariably increases the potential risk of cheating. To avoid potential cheating in laboratory courses with multiple sections, the setup for practical exams is often changed in some way between sections. In laboratory courses with multiple instructors or teaching assistants, practical exams may be handled inconsistently among different laboratory sections, due to differences in background knowledge, perceptions of the laboratory goals, or prior teaching experience. In this article, we describe a design for a laboratory practical exam that aims to align the assessment questions with well-defined laboratory learning objectives and improve the consistency among all laboratory sections. PMID- 26031727 TI - Are your students ready for anatomy and physiology? Developing tools to identify students at risk for failure. AB - High failure rates in introductory college science courses, including anatomy and physiology, are common at institutions across the country, and determining the specific factors that contribute to this problem is challenging. To identify students at risk for failure in introductory physiology courses at our open enrollment institution, an online pilot survey was administered to 200 biology students. The survey results revealed several predictive factors related to academic preparation and prompted a comprehensive analysis of college records of >2,000 biology students over a 5-yr period. Using these historical data, a model that was 91% successful in predicting student success in these courses was developed. The results of the present study support the use of surveys and similar models to identify at-risk students and to provide guidance in the development of evidence-based advising programs and pedagogies. This comprehensive approach may be a tangible step in improving student success for students from a wide variety of backgrounds in anatomy and physiology courses. PMID- 26031728 TI - A new approach for laboratory exercise of pathophysiology in China based on student-centered learning. AB - Student-centered learning is generally defined as any instructional method that purportedly engages students in active learning and critical thinking. The student-centered method of teaching moves the focus from teaching to learning, from the teachers' conveying course concepts via lecture to the understanding of concepts by students. The student-centered method has been used extensively in lecture courses in China; however, there is little evidence of its use in laboratory courses. The purpose of the present study was to describe the implementation of a student-centered method in a pathophysiology laboratory course. The use of student-centered learning strategies in an undergraduate laboratory course was well received by both students and teachers. Here, students had to take on responsibility for their own learning and, thus, became more accountable. Moreover, they reported increased active learning, skill development, information collection, and retention. In addition, mean scores for the quiz were significantly higher in the student-centered method compared with the traditional teaching method. The shift from teacher-centered delivery to a student-centered model led to a positive change, in which the learners drove the process and were guided, not directed, by the teacher. PMID- 26031729 TI - Collaborative teaching strategies lead to retention of skills in acid-base physiology: a 2-yr follow-up study. PMID- 26031730 TI - Understanding the impact of arterial stenosis on blood flow through a tissue. PMID- 26031731 TI - The art and practice of gratitude: practicing an overlooked skill to help undergraduate biology students become successful professionals. PMID- 26031732 TI - The gastrointestinal system: a piece of cake. PMID- 26031733 TI - Chest ultrasound integrated teaching of respiratory system physiology to medical students: a first experience. PMID- 26031734 TI - A simple, inexpensive model to demonstrate how contraction of GI longitudinal smooth muscle promotes propulsion. PMID- 26031735 TI - Undergraduate students as promoters of science dissemination: a strategy to increase students' interest in physiology. PMID- 26031736 TI - What is the best definition of the term "hyperventilation"? PMID- 26031737 TI - Efficacy of a Physician-Led Multiparametric Telemonitoring System in Very Old Adults with Heart Failure. AB - OBJECTIVES: To evaluate the effect of an innovative model integrating telemonitoring of vital parameters and telephone support on 6-month survival and hospital admissions of elderly adults with heart failure (HF). DESIGN: Parallel arm, randomized trial. SETTING: Geriatric acute care ward and outpatient clinic at Policlinico Campus Biomedico (Rome, Italy). PARTICIPANTS: Individuals with HF aged 65 and older (mean age 80) randomly assigned to intervention (n = 50) or control (n = 46). Participants had an average ejection fraction of 46%. INTERVENTION: Telemonitoring system (receives and communicates oxygen saturation, heart rate, and blood pressure readings) and office-hours telephonic support provided by a geriatrician. MEASUREMENTS: Combination of all-cause death and hospital admissions. RESULTS: The two groups were similar with the exception of the prevalence of women and of disability (both more common in the control group). Three patients for each group were lost to follow-up (final analyzed sample size: 90). Incidence of the main outcome was 42% in the control group and 21% in the intervention group (relative risk = 0.51, 95% confidence interval (CI) = 0.26-0.98). The results were unchanged after taking into account the setting of enrollment, sex, and disability (hazard ratio = 0.42, 95% CI = 0.19-0.94). CONCLUSION: Telemonitoring of elderly people with HF is feasible and reduces the risk of death and hospitalization. Further studies are needed to confirm these findings and evaluate the cost-efficacy of the service. PMID- 26031738 TI - Characteristics of a cohort of children with Juvenile Idiopathic Arthritis and JIA-associated Uveitis. AB - BACKGROUND: Juvenile idiopathic arthritis-associated uveitis (JIA-U) can lead to poor visual outcomes and impact a child's quality of life (QOL) and function. Our aim is to identify risk markers of JIA-U and examine differences in the QOL of children with JIA and JIA-U. METHODS: Rheumatology and ophthalmology record reviews and questionnaires were completed every 4-6 months on 287 children with JIA. We collected arthritis, uveitis, and QOL data. We examined data through last study visit. RESULTS: There were 52/287 (18%) children with JIA-U who were younger at arthritis diagnosis, had oligoarticular persistent JIA, and ANA positive. Confirmed uveitis predictors were age at JIA diagnosis (OR = 0.86) and oligoarticular subtype (OR = 5.92). They had worse vision specific QOL and function, but similar general QOL. Blindness occurred in 17.5% of children but was more common in African American children compared to non-Hispanic Caucasian children ((5/7 (71%) vs. 2/29 (7%), p <0.001) despite a similar uveitis prevalence (22% vs. 16%). Both races had similar complications, although band keratopathy was more frequent in African Americans (75% vs. 15.6%, p = 0.003). CONCLUSIONS: We confirm young age at JIA diagnosis and the oligoarticular JIA subtype as predictors of uveitis development. Although we were unable to identify predictors of ocular complications or blindness, AA children appeared to have a more severe disease course manifested by increased ocular complications, vision loss and blindness. Potential causes that warrant additional study include underlying disease severity, access to medical care and referral bias. Further investigation of the risk factors for vision-compromising uveitis and its' long term effects should be conducted in a large racially diverse population. PMID- 26031739 TI - [Reversible posterior encephalopathy syndrome and cardiomyopathy after bevacizumab therapy]. AB - INTRODUCTION: Bevacizumab is an antibody directed against VEGF-A. It is approved for the treatment of many cancer diseases. Its side effects are currently not well known by physicians. CASE REPORT: A 70-year-old female with metastatic colonic adenocarcinoma was admitted in the intensive care unit because of a coma, four days after having received a combined monthly chemotherapy containing bevacizumab, oxaliplatine, 5 fluorouracil, and folinic acid for the fourth time. On clinical examination, she presented with lower limbs spasticity and hypertension. Etiologic investigations, including cerebral tomodensitometry, cerebrospinal fluid examination, psychotropic drugs urinary testing, and electroencephalogram, were negative. Consciousness improved without any other treatment than nicardipine and urapidil, but the patient was initially confused. Cerebral magnetic resonance imaging showed changes suggestive of posterior reversible encephalopathy syndrome, but also involving frontal lobes. There were additional biological and echocardiographic changes suggestive of cardiac involvement. The patient recovered completely of both cardiac and neurologic manifestations 10 days later. CONCLUSION: Physicians should be aware of cardiovascular adverse effects of bevacizumab. High blood pressure must be treated to avoid more severe complications. When a posterior reversible encephalopathy syndrome occurs, cardiac involvement should be investigated. PMID- 26031741 TI - Organonickel(IV) chemistry: a new catalyst? AB - With scorpionate ligands finding their way into organonickel chemistry, the state of the art of present-day nickel(IV) chemistry is highlighted. Will rapid C?X coupling reactions emerge as a domain of higher-oxidation-state nickel chemistry? PMID- 26031740 TI - Markers for the identification of tendon-derived stem cells in vitro and tendon stem cells in situ - update and future development. AB - The efficacy of tendon-derived stem cells (TDSCs) for the promotion of tendon and tendon-bone junction repair has been reported in animal studies. Modulation of the tendon stem cell niche in vivo has also been reported to influence tendon structure. There is a need to have specific and reliable markers that can define TDSCs in vitro and tendon stem cells in situ for several reasons: to understand the basic biology of TDSCs and their subpopulations in vitro; to understand the identity, niches and functions of tendon/progenitor stem cells in vivo; to meet the governmental regulatory requirements for quality of TDSCs when translating the exciting preclinical findings into clinical trial/practice; and to develop new treatment strategies for mobilizing endogenous stem/progenitor cells in tendon. TDSCs were reported to express the common mesenchymal stem cell (MSC) markers and some embryonic stem cell (ESC) markers, and there were attempts to use these markers to label tendon stem cells in situ. Are these stem cell markers useful for the identification of TDSCs in vitro and tracking of tendon stem cells in situ? This review aims to discuss the values of the panel of MSC, ESC and tendon-related markers for the identification of TDSCs in vitro. Important factors influencing marker expression by TDSCs are discussed. The usefulness and limitations of the panel of MSC, ESC and tendon-related markers for tracking stem cells in tendon, especially tendon stem cells, in situ are then reviewed. Future research directions are proposed. PMID- 26031742 TI - Early neuroprotective effect with lack of long-term cell replacement effect on experimental stroke after intra-arterial transplantation of adipose-derived mesenchymal stromal cells. AB - BACKGROUND AIMS: Adipose-derived mesenchymal stromal cells (AD-MSCs) have high proliferative capacity and ability to secrete trophic factors. Although intra arterial (IA) transplantation of stem cells induces efficient engraftment to the host brain, it is unclear whether engrafted cells exert their long-term therapeutic effects through a bystander mechanism or a cell replacement mechanism. METHODS: After induction of ischemia in rats by middle cerebral artery occlusion, we transplanted human AD-MSCs into their carotid arteries with the use of a micro-needle, and we then investigated the therapeutic effects during the early and late phases of ischemia by means of in vivo magnetic resonance imaging, functional and histological analyses. RESULTS: During the early phase of cerebral ischemia, IA transplantation of AD-MSCs attenuated inflammation and enhanced endogenous neurogenesis. Transplanted animals showed a marked improvement in functional tests during the early phase of cerebral ischemia that was less prominent but still significant during the late phase of cerebral ischemia. Although the transplanted cells effectively migrated to the infarct area, only a small number of engrafted cells survived at 8 weeks after transplantation and differentiated into neuronal, glial and endothelial cells. CONCLUSIONS: IA transplantation of human AD-MSCs provides an effective therapeutic modality in a rodent model of stroke, of which the main effects are mediated by a bystander mechanism at the early phase of ischemia. PMID- 26031743 TI - Human adipose-derived stromal cells in a clinically applicable injectable alginate hydrogel: Phenotypic and immunomodulatory evaluation. AB - BACKGROUND AIMS: Clinical trials have documented beneficial effects of mesenchymal stromal cells from bone marrow and adipose tissue (ASCs) as treatment in patients with ischemic heart disease. However, retention of transplanted cells is poor. One potential way to increase cell retention is to inject the cells in an in situ cross-linked alginate hydrogel. METHODS: ASCs from abdominal human tissue were embedded in alginate hydrogel and alginate hydrogel modified with Arg Gly-Asp motifs (RGD-alginate) and cultured for 1 week. Cell viability, phenotype, immunogenicity and paracrine activity were determined by confocal microscopy, dendritic cell co-culture, flow cytometry, reverse transcriptase quantitative polymerase chain reaction, Luminex multiplex, and lymphocyte proliferation experiments. RESULTS: ASCs performed equally well in alginate and RGD-alginate. After 1 week of alginate culture, cell viability was >93%. Mesenchymal markers CD90 and CD29 were reduced compared with International Society for Cellular Therapy criteria. Cells sedimented from the alginates during cultivation regained the typical level of these markers, and trilineage differentiation was performed by standard protocols. Hepatocyte growth factor mRNA was increased in ASCs cultivated in alginates compared with monolayer controls. Alginates and alginates containing ASCs did not induce dendritic cell maturation. ASCs in alginate responded like controls to interferon-gamma stimulation (licensing), and alginate culture increased the ability of ASCs to inhibit lymphocyte proliferation. DISCUSSION: ASCs remain viable in alginates; they transiently change phenotype in alginate hydrogel but regain the phenotype of monolayer controls upon release. Cells maintain their paracrine potential while in alginates; the combination of ASCs and alginate is non-immunogenic and, in fact, immunosuppressive. PMID- 26031744 TI - Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice. AB - BACKGROUND AIMS: Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS. METHODS: Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed. RESULTS: A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED CM attenuated the BLM-induced pro-inflammatory response and generated an anti inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow-derived macrophages into M2-like cells, which expressed high levels of Arginase1, CD206 and Ym-1. DISCUSSION: Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell-based ARDS therapies. PMID- 26031745 TI - Comparison between posterior dynamic stabilization and posterior lumbar interbody fusion in the treatment of degenerative disc disease: a prospective cohort study. AB - BACKGROUND: Few studies compared radiographic and clinical outcomes between posterior dynamic stabilization (PDS) and posterior lumbar intervertebral fusion (PLIF) in treating degenerative disc disease (DDD). METHODS: A total of 176 consecutive patients who underwent posterior instrumented spinal surgery for degenerative disc disease between January 2007 and January 2009 were prospectively divided into two groups-PDS and PLIF. All patients included in the analysis were followed up for 3 years. Demographic distribution, perioperative complications, and radiographic and clinical outcomes were compared between the two groups. RESULTS: The amount of intraoperative blood loss and drained volume was significantly greater in the PLIF group compared with the PDS group (881.1 ml versus 737.4 ml, p = 0.004). The length of stay of patients who had PLIF surgery (20.9 days) was significantly longer (p = 0.033) than that of patients who underwent PDS surgery (18.9 days). Patients with PLIF surgery had higher total costs than those with PDS surgery (US$12826.8 versus US$11654.5, p = 0.002). No statistically significant differences existed in back visual analogue scale (VAS), leg VAS, or Oswestry disability index (ODI) scores between the PDS and PLIF groups of patients at each time point. CONCLUSIONS: Compared with PLIF, PDS have advantages on blood loss, length of stay in hospital, total charges, and radiographic outcomes, but no advantages on leg and back VAS or ODI scores. High quality randomized controlled trials are still required in the future. PMID- 26031746 TI - Roles and responsibilities in newborn care in four African sites. AB - OBJECTIVES: To explore roles and responsibilities in newborn care in the intra- and postpartum period in Nigeria, Tanzania and Ethiopia. METHODS: Qualitative data were collected using in-depth interviews with mothers, grandmothers, fathers, health workers and birth attendants and were analysed through content and framework analyses. RESULTS: We found that birth attendants were the main decision-makers and care takers in the intrapartum period. Birth attendants varied across sites and included female relatives (Ethiopia and Nigeria), traditional birth attendants (Tanzania and Nigeria), spiritual birth attendants (Nigeria) and health workers (Tanzania and Nigeria). In the early newborn period, when the mother is deemed to be resting, female family members assumed this role. The mothers themselves only took full responsibility for newborn care after a few days or weeks. The early newborn period was protracted for first-time mothers, who were perceived as needing training on caring for the baby. Clear gender roles were described, with newborn care being considered a woman's domain. Fathers had little physical contact with the newborn, but played an important role in financing newborn care, and were considered the ultimate decision-maker in the family. CONCLUSION: Interventions should move beyond a focus on the mother-child dyad, to include other carers who perform and decide on newborn care practices. Given this power dynamic, interventions that involve men have the potential to result in behaviour change. PMID- 26031748 TI - Metabolic study of androsta-1,4,6-triene-3,17-dione in horses using liquid chromatography/high resolution mass spectrometry. AB - Androsta-1,4,6-triene-3,17-dione (ATD) is an irreversible steroidal aromatase inhibitor and is marketed as a supplement. It has been reported to effectively reduce estrogen biosynthesis and significantly increase the levels of endogenous steroids such as dihydrotestosterone and testosterone in human. ATD abuses have been reported in human sports. Its metabolism in human has been studied, and the in vitro metabolic study of ATD in horses has been reported, however, little is known about its biotransformation and elimination in horses. This paper describes the in vitro and in vivo metabolism studies of ATD in horses, with an objective of identifying the target metabolites with the longest detection time for controlling ATD abuse. In vitro metabolism studies of ATD were performed using homogenized horse liver. ATD was found to be extensively metabolized, and its metabolites could not be easily characterized by gas chromatography/mass spectrometry (GC/MS) due to insufficient sensitivity. Liquid chromatography/high resolution mass spectrometry (LC/HRMS) was therefore employed for the identification of in vitro metabolites. The major biotransformations observed were combinations of reduction of the olefin groups and/or the keto group at either C3 or C17 position. In addition, mono-hydroxylation in the D-ring was observed along with reduction of the olefin groups and/or the keto group at C17 position. Fourteen in vitro metabolites, including two epimers of androsta-1,4,6 trien-17-ol-3-one (M1a, M1b), androsta-4,6-diene-3,17-dione (M2), boldione (M3), androsta-4,6-diene-17beta-ol-3-one (M4), androsta-4,6-diene-3-ol-17-one (M5), boldenone and epi-boldenone (M6a, M6b), four stereoisomers of hydroxylated androsta-1,4,6-trien-17-ol-3-one (M7a to M7d), and two epimers of androsta-1,4 diene-16alpha,17-diol (M8a, M8b), were identified. The identities of all metabolites, except M1a, M5, M7a to M7d, were confirmed by matching with authentic reference standards using LC/HRMS. For the in vivo metabolism studies, two thoroughbred geldings were each administered with 800 mg of ATD by stomach tubing. ATD, and twelve out of the fourteen in vitro metabolites, including M1a, M1b, M2, M4, M5, M6, M7a to M7d, M8a and M8b, were detected in post administration urine. Two additional urinary metabolites, namely stereoisomers of hydroxylated androsta-4,6-dien-17-ol-3-one (M9a, M9b), were tentatively identified by mass spectral interpretation. Elevated level of testosterone was also observed. In post-administration blood samples, only the parent drug, M1b and M2 were identified. This study showed that the detection of ATD administration would be best achieved by either monitoring the metabolites M1b (androsta-1,4,6-trien-17beta-ol-3-one) or M4 (both excreted as sulfate conjugates) in urine, which could be detected for up to a maximum of 77 h post administration. The analyte of choice for plasma is M1b, which could be detected for up to 28 h post administration. PMID- 26031747 TI - Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients. AB - Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron-exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients' sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype-phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights. PMID- 26031749 TI - Comparison of Various Rhinoplasty Techniques and Long-Term Results. PMID- 26031750 TI - Epigenetic dynamics during preimplantation development. AB - Successful mammalian development requires descendants of single-cell zygotes to differentiate into diverse cell types even though they contain the same genetic material. Preimplantation dynamics are first driven by the necessity of reprogramming haploid parental epigenomes to reach a totipotent state. This process requires extensive erasure of epigenetic marks shortly after fertilization. During the few short days after formation of the zygote, epigenetic programs are established and are essential for the first lineage decisions and differentiation. Here we review the current understanding of DNA methylation and histone modification dynamics responsible for these early changes during mammalian preimplantation development. In particular, we highlight insights that have been gained through next-generation sequencing technologies comparing human embryos to other models as well as the recent discoveries of active DNA demethylation mechanisms at play during preimplantation. PMID- 26031751 TI - Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. AB - O-glycosylation of the nuclear pore complex (NPC) by O-linked N-acetylglucosamine (O-GlcNAc) is conserved within metazoans. Many nucleoporins (Nups) comprising the NPC are constitutively O-GlcNAcylated, but the functional role of this modification remains enigmatic. We show that loss of O-GlcNAc, induced by either inhibition of O-GlcNAc transferase (OGT) or deletion of the gene encoding OGT, leads to decreased cellular levels of a number of natively O-GlcNAcylated Nups. Loss of O-GlcNAc enables increased ubiquitination of these Nups and their increased proteasomal degradation. The decreased half-life of these deglycosylated Nups manifests in their gradual loss from the NPC and a downstream malfunction of the nuclear pore selective permeability barrier in both dividing and post-mitotic cells. These findings define a critical role of O-GlcNAc modification of the NPC in maintaining its composition and the function of the selectivity filter. The results implicate NPC glycosylation as a regulator of NPC function and reveal the role of conserved glycosylation of the NPC among metazoans. PMID- 26031752 TI - In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases. AB - How metastases develop is not well understood and no genetic mutations have been reported as specific metastatic drivers. Here we have addressed the idea that epigenetic reprogramming by GLI-regulated pluripotent stemness factors promotes metastases. Using primary human colon cancer cells engrafted in mice, we find that transient expression of OCT4, SOX2, KLF4 +/- cMYC establishes an enhanced pro-metastatic state in the primary tumor that is stable through sequential engraftments and is transmitted through clonogenic cancer stem cells. Metastatic reprogramming alters NANOG methylation and stably boosts NANOG and NANOGP8 expression. Metastases and reprogrammed EMT-like phenotypes require endogenous NANOG, but enhanced NANOG is not sufficient to induce these phenotypes. Finally, reprogrammed tumors enhance GLI2, and we show that GLI2(high) and AXIN2(low), which are markers of the metastatic transition of colon cancers, are prognostic of poor disease outcome in patients. We propose that metastases arise through epigenetic reprogramming of cancer stem cells within primary tumors. PMID- 26031754 TI - Histopathology and immune histochemistry of red tattoo reactions. Interface dermatitis is the lead pathology, with increase in T-lymphocytes and Langerhans cells suggesting an allergic pathomechanism. AB - BACKGROUND: The majority of tattoo reactions are affiliated to red pigmented areas and often suspected to be allergic in nature. A sizeable series of biopsies of such reactions has not previously been performed. The aim of this study was to type and grade epidermal and dermal changes in tattoo reactions to red/red nuances by microscopy and immunochemistry relevant for the assessment of a possible allergic pathomechanism. METHODS: Skin biopsies were taken from red tattoo reactions, graded by conventional microscopy and stained for T and B lymphocytes, Langerhans cells, macrophages and tumour necrosis factor (TNF) alpha. RESULTS: The study included 19 biopsies from 19 patients. The culprit colours were red/pink (n = 15) and purple/bordeaux (n = 4). Interface dermatitis was clearly the lead pathology found in 78% of samples, overlapped with granulomatous (in 32%) and pseudolymphomatous reaction patterns (in 32%). Epidermal hyperkeratosis (in 89%) was common as was leakage of red pigment across the dermo-epidermal junction, with transepidermal elimination (in 28%). The dermal cellular infiltration was dominated by T-lymphocytes (in 100%), Langerhans cells (in 95%) and macrophages (in 100%). TNF-alpha was common. CONCLUSION: The predominant histological pattern of chronic tattoo reactions in red/red nuances is interface dermatitis. T-lymphocytes and Langerhans cells are increased suggesting an allergic pathomechanism. TNF-alpha may contribute to reactions. In many cases, overlapping reactive patterns were identified. PMID- 26031755 TI - Detecting the influence of rare stressors on rare species in Yosemite National Park using a novel stratified permutation test. AB - Statistical models often use observational data to predict phenomena; however, interpreting model terms to understand their influence can be problematic. This issue poses a challenge in species conservation where setting priorities requires estimating influences of potential stressors using observational data. We present a novel approach for inferring influence of a rare stressor on a rare species by blending predictive models with nonparametric permutation tests. We illustrate the approach with two case studies involving rare amphibians in Yosemite National Park, USA. The endangered frog, Rana sierrae, is known to be negatively impacted by non-native fish, while the threatened toad, Anaxyrus canorus, is potentially affected by packstock. Both stressors and amphibians are rare, occurring in ~10% of potential habitat patches. We first predict amphibian occupancy with a statistical model that includes all predictors but the stressor to stratify potential habitat by predicted suitability. A stratified permutation test then evaluates the association between stressor and amphibian, all else equal. Our approach confirms the known negative relationship between fish and R. sierrae, but finds no evidence of a negative relationship between current packstock use and A. canorus breeding. Our statistical approach has potential broad application for deriving understanding (not just prediction) from observational data. PMID- 26031756 TI - Tumor-related gene expression levels in pulmonary pleomorphic carcinoma. AB - BACKGROUND: Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer that belongs to the family of sarcomatoid carcinomas and is associated with poor prognosis. We investigated the expressions of tumor-related genes in resected PPC specimens. METHODS: Specimens resected from patients with PPC from July 2006 through April 2012 were investigated. Tumor segments were collected from the specimens by micro-dissection to extract mRNA, then RT-PCR was performed according to Dannenberg's tumor profile method for semi-quantitation of tumor-related gene mRNA. To compare with other types of lung cancer, data from stage-matched adenocarcinoma (AC) and squamous cell carcinoma (SCC) cases in our database were also examined. RESULTS: The gene expression levels of thymidylate synthase were significantly higher in PPC and SCC as compared to the AC specimens (p < 0.001). The levels of dihydropyrimidine dehydrogenase and thymidine phosphorylase mRNA in PPC showed a similar tendency to those in SCC, in contrast to AC. Furthermore, the expression level of excision repair cross-complementation group 1 mRNA in PPC specimens was similar to that reported in NSCLC, while the level of vascular endothelial growth factor (VEGF) expression was higher as compared to that reported for colorectal cancer. CONCLUSIONS: Although gene expression of tumor cannot be directly correlated to its sensitivity for anti cancer drugs, it is likely that PPC tumors are not sensitive to anti-metabolic drugs. Anti-VEGF therapy may be a candidate for PPC, while cisplatin also remains a viable option. PMID- 26031757 TI - XPD Functions as a Tumor Suppressor and Dysregulates Autophagy in Cultured HepG2 Cells. AB - BACKGROUND: Recent clinical studies have linked polymorphisms in the xeroderma pigmentosum group D (XPD) gene, a key repair gene involved in nucleotide excision repair, to increased risk of hepatocellular carcinoma (HCC). However, the cellular effects of XPD expression in cultured HCC cells remain largely uncharacterized. Therefore, the aim of this study was to characterize the in vitro cellular effects of XPD expression on the HCC cell line HepG2. MATERIAL AND METHODS: HepG2 cells were transfected as follows to create four experimental groups: pEGFP-N2/XPD plasmid (XPD) group, EGFP-N2 plasmid (N2) control group, lipofectamineTM 2000 (lipid) control group, and non-transfected (CON) control group. An MTT cell proliferation assay, Annexin V-APC apoptosis assay, colony formation assay, scratch wound migration assay, Transwell migration assay, and Western blotting of the autophagic proteins LC3 and p62 were conducted. RESULTS: XPD expression significantly inhibited HepG2 cell proliferation (p<0.05), significantly promoted HepG2 cell apoptosis (p<0.05), significantly inhibited HepG2 colony formation (p<0.05), significantly decreased HepG2 cells' migratory ability (p<0.05), and significantly lowered HepG2 cells' invasive capacity (p<0.05). Western blotting showed that XPD expression significantly increased LC3 expression (p<0.05) and significantly reduced p62 expression (p<0.05). CONCLUSIONS: XPD expression serves as a tumor suppressor and dysregulates autophagic protein degradation in HepG2 cells in vitro. Further in vivo pre clinical studies and clinical trials are needed to validate XPD's potential as a tumor-suppressive gene therapy. PMID- 26031758 TI - Evaluation of micropollutant removal and fouling reduction in a hybrid moving bed biofilm reactor-membrane bioreactor system. AB - A hybrid moving bed biofilm reactor-membrane bioreactor (MBBR-MBR) system and a conventional membrane bioreactor (CMBR) were compared in terms of micropollutant removal efficiency and membrane fouling propensity. The results show that the hybrid MBBR-MBR system could effectively remove most of the selected micropollutants. By contrast, the CMBR system showed lower removals of ketoprofen, carbamazepine, primidone, bisphenol A and estriol by 16.2%, 30.1%, 31.9%, 34.5%, and 39.9%, respectively. Mass balance calculations suggest that biological degradation was the primary removal mechanism in the MBBR-MBR system. During operation, the MBBR-MBR system exhibited significantly slower fouling development as compared to the CMBR system, which could be ascribed to the wide disparity in the soluble microbial products (SMP) levels between MBBR-MBR (4.02 6.32 mg/L) and CMBR (21.78 and 33.04 mg/L). It is evident that adding an MBBR process prior to MBR treatment can not only enhance micropollutant elimination but also mitigate membrane fouling. PMID- 26031759 TI - Killer immunoglobulin receptor genes and their HLA-C ligand are associated with Type 1 diabetes in an Eastern Indian population. AB - AIM: Killer immunoglobulin-like receptors (KIRs) and their interaction with HLA class I ligands have been shown to be associated with Type 1 diabetes mellitus. The aim of our study was to investigate the influence of KIR genes and their HLA C ligands for susceptibility to Type 1 diabetes in patients from Eastern India. METHODS: A total of 135 patients with Type 1 diabetes and 98 healthy subjects from Eastern India were typed for KIR genes and HLA-C ligands using PCR-based genotyping. The frequencies of these genes were compared between patients and controls. RESULTS: Comparison of KIR genes between Type 1 diabetes patients and healthy subjects revealed significantly different frequencies of KIRs 2DL2 and 2DS4. The presence of HLA-C1 was negatively associated with disease. The presence of both HLA-C1 and -C2 showed a negative association with Type 1 diabetes, whereas the absence of C1 and presence of C2 was positively associated with disease. Stratification analysis of HLA-C ligands and KIRs showed significant associations between Type 1 diabetes and 2DL2+/C1-, 2DL2-/C1+, 2DL3+/C1+, 2DL3+/C1- and 2DS2+/C1-. CONCLUSIONS: Our results suggest that the interaction of KIRs with HLA-C ligands are significant and certain combinations contribute to susceptibility to and protection against Type 1 diabetes. PMID- 26031760 TI - Olfactory identification deficits and increased mortality in the community. AB - OBJECTIVE: To examine the association between odor identification deficits and future mortality in a multiethnic community cohort of older adults. METHODS: Participants were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Follow-up occurred at 2-year intervals with information on death obtained from informant interviews and the National Death Index. RESULTS: During follow-up (mean = 4.1 years, standard deviation = 2.6), 349 of 1,169 (29.9%) participants died. Participants who died were more likely to be older (p < 0.001), be male (p < 0.001), have lower UPSIT scores (p < 0.001), and have a diagnosis of dementia (p < 0.001). In a Cox model, the association between lower UPSIT score and mortality (hazard ratio [HR] = 1.07 per point interval, 95% confidence interval [CI] = 1.05-1.08, p < 0.001) persisted after controlling for age, gender, education, ethnicity, language, modified Charlson medical comorbidity index, dementia, depression, alcohol abuse, head injury, smoking, body mass index, and vision and hearing impairment (HR = 1.05, 95% CI = 1.03-1.07, p < 0.001). Compared to the fourth quartile with the highest UPSIT scores, HRs for mortality for the first, second, and third quartiles of UPSIT scores were 3.81 (95% CI = 2.71-5.34), 1.75 (95% CI = 1.23-2.50), and 1.58 (95% CI = 1.09-2.30), respectively. Participant mortality rate was 45% in the lowest quartile of UPSIT scores (anosmia) and 18% in the highest quartile of UPSIT scores. INTERPRETATION: Impaired odor identification, particularly in the anosmic range, is associated with increased mortality in older adults even after controlling for dementia and medical comorbidity. PMID- 26031761 TI - Consistent copy number changes and recurrent PRKAR1A mutations distinguish Melanotic Schwannomas from Melanomas: SNP-array and next generation sequencing analysis. AB - Melanotic Schwannomas (MS) are rare tumors that share histological features with melanocytic tumors and schwannomas. However, their genetics are poorly understood. To elucidate the genetic characteristics of MS, we performed genome wide studies in a series of cases. Twelve MS cases were available for the study. Genomic DNAs extracted from formalin-fixed paraffin embedded tumor tissues were subjected to copy number (CN) and allelic imbalance (AI) analysis by Single Nucleotide Polymorphism (SNP)-array and screened for mutations in coding exons of 341 key cancer-associated genes using a hybrid capture-based next-generation sequencing (NGS) assay. Sanger sequencing was used to further verify recurrent mutations detected by NGS study. SNP-array analysis revealed remarkably stereotypic chromosomal abnormalities in MS. Hypodiploidy was common, typically involving monosomies of chromosomes 1, 2, and 17. All 12 samples showed mutations in PRKAR1A gene, including 2 cases with 2 mutations each. The 14 mutations were scattered across PRKAR1A, and most were inactivating mutations. AI on 17q, presenting as loss of heterozygosity with or without CN losses, combined with a PRKAR1A mutation was observed in 9/12 MS cases. The remaining 3 cases included the two samples harboring two mutations in PRKAR1A. MS exhibits a stereotypic pattern of chromosomal losses. In contrast, melanomas are typically characterized by the presence of multiple CN aberrations, without demonstrable differences in the frequency of losses and gains. Inactivation of both alleles of PRKAR1A by "two hits" observed in almost all cases underscores the central role of PRKAR1A in the pathogenesis of this neoplasm. (c) 2015 Wiley Periodicals, Inc. PMID- 26031763 TI - Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection. AB - Herpes simplex virus type-1 (HSV-1) is ubiquitous and is able to establish a lifelong persistent latent infection in neurons of infected individuals. It has been estimated that in approximately 70% of the population over 50 years old, the virus enters the brain and infects neurons, and possibly undergoes recurrent reactivation episodes during lifetime, especially in immunodepressed individuals. We previously showed that the sensors AMP-dependent kinase (AMPK) and Sirtuin 1 (Sirt1), involved in survival pathways and neuroprotection, were affected during the course of HSV-1 infection. To evaluate if natural activators of the AMPK/Sirt1 axis, such as Resveratrol and Quercetin could reduce viral propagation and/or counteract the effects of neuronal infection, we analyzed progeny virion production, neuronal viability and neurodegenerative events during HSV-1 infection. We found that the activators of AMPK/Sirt1 axis, increased the viability of infected neurons, significantly reduced the viral titer in the supernatant and the expression of viral genes. More importantly, pretreatment of neurons with Resveratrol or Quercetin significantly reduced the levels of caspase 3 cleaved- and hyperphosphorylated tau associated with HSV-1 infection. These results suggest that activators of the AMPK/Sirt1 axis could be potentially useful in reducing the risk of HSV-1 productive infection in neurons and the cellular damage associated with reactivation episodes. PMID- 26031762 TI - Does nebulized fentanyl relieve dyspnea during exercise in healthy man? AB - Few therapies exist for the relief of dyspnea in restrictive lung disorders. Accumulating evidence suggests that nebulized opioids selective for the mu receptor subtype may relieve dyspnea by modulating intrapulmonary opioid receptor activity. Our respective primary and secondary objectives were to test the hypothesis that nebulized fentanyl (a mu-opioid receptor agonist) relieves dyspnea during exercise in the presence of abnormal restrictive ventilatory constraints and to identify the physiological mechanisms of this improvement. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of 250 MUg nebulized fentanyl, chest wall strapping (CWS), and their interaction on detailed physiological and perceptual responses to constant work rate cycle exercise (85% of maximum incremental work rate) in 14 healthy, fit young men. By design, CWS decreased vital capacity by ~20% and mimicked the negative consequences of a mild restrictive lung disorder on exercise endurance time and on dyspnea, breathing pattern, dynamic operating lung volumes, and diaphragmatic electromyographic and respiratory muscle function during exercise. Compared with placebo under both unrestricted control and CWS conditions, nebulized fentanyl had no effect on exercise endurance time, integrated physiological response to exercise, sensory intensity, unpleasantness ratings of exertional dyspnea. Our results do not support a role for intrapulmonary opioids in the neuromodulation of exertional dyspnea in health nor do they provide a physiological rationale for the use of nebulized fentanyl in the management of dyspnea due to mild restrictive lung disorders, specifically those arising from abnormalities of the chest wall and not affiliated with airway inflammation. PMID- 26031764 TI - Combined treatment with oral finasteride and topical minoxidil in male androgenetic alopecia: a randomized and comparative study in Chinese patients. AB - Finasteride at 1 mg/day and 5% topical minoxidil are effective in male androgenetic alopecia (MAGA). However, studies describing their effects in Chinese individuals are scarce. 450 Chinese MAGA patients were randomly assigned to receive finasteride (n = 160), minoxidil (n = 130) and combined medication (n = 160) for 12 months. The patients returned to the clinic every 3 months for efficacy evaluation. And efficacy was evaluated in 428 men at treatment end, including 154, 122, and 152 in the finasteride, 5% minoxidil, and combination groups, respectively. All groups showed similar baseline characteristics, including age at enrollment, and duration and severity of alopecia (p > 0.05). At 12 months, 80.5, 59, and 94.1% men treated with finasteride, 5% minoxidil and the combination therapy showed improvement, respectively. Adverse reactions were rare (finasteride, 1.8%; minoxidil, 6.1%), and disappeared right after drug withdrawal. In conclusion, finasteride is superior to 5% minoxidil, while the combined medication showed the best efficacy. PMID- 26031765 TI - The influence of linguistic and cognitive factors on the time course of verb based implicit causality. AB - In three eye-tracking experiments the influence of the Dutch causal connective "want" (because) and the working memory capacity of readers on the usage of verb based implicit causality was examined. Experiments 1 and 2 showed that although a causal connective is not required to activate implicit causality information during reading, effects of implicit causality surfaced more rapidly and were more pronounced when a connective was present in the discourse than when it was absent. In addition, Experiment 3 revealed that-in contrast to previous claims the activation of implicit causality is not a resource-consuming mental operation. Moreover, readers with higher and lower working memory capacities behaved differently in a dual-task situation. Higher span readers were more likely to use implicit causality when they had all their working memory resources at their disposal. Lower span readers showed the opposite pattern as they were more likely to use the implicit causality cue in the case of an additional working memory load. The results emphasize that both linguistic and cognitive factors mediate the impact of implicit causality on text comprehension. The implications of these results are discussed in terms of the ongoing controversies in the literature-that is, the focusing-integration debate and the debates on the source of implicit causality. PMID- 26031767 TI - Three-dimensional co-culture of hepatic progenitor cells and mesenchymal stem cells in vitro and in vivo. AB - INTRODUCTION: Here we co-cultured hepatic progenitor cells (HPCs) and mesenchymal stem cells (MSCs) to investigate whether the co-culture environments could increase hepatocytes form. METHODS: Three-dimensional (3D) co-culture model of HPCs and MSCs was developed and morphological features of cells were continuously observed. Hepatocyte specific markers Pou5f1/Oct4, AFP, CK-18 and Alb were analyzed to confirm the differentiation of HPCs. The mRNA expression of CK-18 and Alb was analyzed by RT-PCR to investigate the influence of co-culture model to the terminal differentiation process of mature hepatocytes. The functional properties of hepatocyte-like cells were detected by continuously monitoring the albumin secretion using Gaussia luciferase assays. Scaffolds with HPCs and MSCs were implanted into nude mouse subcutaneously to set up the in vivo co-culture model. RESULTS: Although two groups formed smooth spheroids and high expressed of CK-18 and Alb, hybrid spheroids had more regular structures and higher cell density. CK-18 and Alb mRNA were at a relatively higher expression level in co culture system during the whole cultivation time (P < 0.05). Albumin secretion rates in the hybrid spheroids had been consistently higher than that in the mono culture spheroids (P < 0.05). In vivo, the hepatocyte-like cells were consistent with the morphological features of mature hepatocytes and more well differentiated hepatocyte-like cells were observed in the co-culture group. CONCLUSIONS: HPCs and MSCs co-culture system is an efficient way to form well differentiated hepatocyte-like cells, hence, may be helpful to the cell therapy of hepatic tissues and alleviate the problem of hepatocytes shortage. PMID- 26031768 TI - Efficacy of the Mirasol pathogen reduction technology system against severe fever with thrombocytopenia syndrome virus (SFTSV). AB - Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tickborne virus in the Bunyaviridae family. This virus has recently been found in China, Japan and Korea. The risk of transfusion-transmitted SFTSV infection (TTI-SFTSV) is a concern because person-to-person transmission resulting from contact with SFTSV contaminated blood has been reported. Therefore, we investigated the efficacy of the Mirasol pathogen reduction technology (PRT) system for inactivating SFTSV in vitro. The Mirasol PRT system achieved a > 4.11 log10 reduction value (LRV) for SFTSV. In conclusion, we showed that the Mirasol PRT system could potentially be used to reduce the risk of TTI-SFTSV. PMID- 26031766 TI - Linking classification and therapeutic management of vasculitides. AB - Vasculitides are classified by the size, type and location of the predominantly involved vessels and by their primary or secondary nature. Their treatment depends on the type of vasculitis, its etiology (when known), and its severity and must be further adjusted by the individual characteristics and comorbidities of patients. In this paper, we review how the classification and definition of vasculitides have evolved over the past years and how it has affected therapeutic changes. As new genetic markers are being discovered and the pathogenesis of vasculitides continues to be elucidated, further modifications in classification and treatment can be expected. PMID- 26031769 TI - Genetic and structural variation in the SH2B1 gene in the Belgian population. AB - OBJECTIVE: Animal studies, genome-wide association and genomic structural variation studies have identified the SH2B1 gene as a candidate gene for obesity. Therefore, we have designed an extensive mutation and copy number variation (CNV) analysis investigating the prevalence of genetic and structural variations in SH2B1 in the Belgian population. DESIGN AND METHODS: In the first part of this study, we performed a mutation screen for variants in the SH2B1 coding region in 581 obese children and adolescents and 433 healthy, lean individuals with high resolution melting curve analysis followed by direct sequencing. In the second part of this study, Multiplex Amplicon Quantification (MAQ) analysis was used to identify CNVs in the distal SH2B1-containing chr.16p11.2 region in 421 obese children and adolescents with no developmental delay or behavioral phenotype. RESULTS: Mutation analysis resulted in the identification of fifteen rare non synonymous heterozygous variants. Several of these were found both in lean and obese subjects, suggesting that these are neutral polymorphisms. However, six private, heterozygous, non-synonymous variations were present in obese children only. Furthermore, we also identified six missense variants solely in lean individuals. CNV analysis could not identify carriers of the distal 16p11.2 deletion in our population. CONCLUSION: Our mutation analysis has demonstrated that variation in the SH2B1 gene is frequent in both lean and obese groups, with distinctive variations being present on either side of the weight spectrum. Although the equal variation frequency does not immediately support disease causality, it cannot be excluded that some variations are weight-increasing or decreasing. Further functional testing of the variants will be necessary to fully understand the impact of these variants on SH2B1. We were not able to detect carriers of the distal 16p11.2 deletion in our study population. As we excluded patients with developmental or behavioral problems, we suggest that in addition to obesity, the distal deletion might predispose for these traits. Further characterization of the phenotype is therefore necessary to clearly identify the phenotype of the distal 16p11.2 microdeletion syndrome. PMID- 26031770 TI - Successful combined liver/kidney transplantation from a donor with Pompe disease. AB - Pompe disease results from inherited deficiency of the enzyme acid alpha glucosidase resulting in lysosomal accumulation of glycogen primarily in skeletal muscle. Reported is the first case in which a donor with late onset Pompe disease (LOPD) was successfully used for deceased donor liver and kidney transplantation. This case demonstrates co-operative transplant surgery and genetic medicine evaluation and risk estimation for donors with inherited metabolic disorders some of which may be suitable for donation of selected organs for transplantation. PMID- 26031772 TI - The Antioxidant Effect of Fermented Papaya Preparation in the Oral Cavity. AB - Oxidative stress has been recognized to play important roles in various diseases, including of the oral cavity. However, nutritional supplementation of antioxidants to ameliorate the consequences of oxidative stress is debatable. One caveat is that oxidative status is often measured under non-physiological conditions. Here, we investigated the antioxidant potential of fermented papaya preparation (FPP), a product of yeast fermentation of Carica papaya Linn, under conditions that prevail in the oral cavity. Employing highly sensitive luminol dependent chemiluminescence assays, we show that its antioxidant capacity was augmented by saliva (up to 20-fold, p < 0.0001, at 10 mg) and its components (mucin, albumin) as well as by red blood cells (RBC) and microorganisms present in the normal and pathological environment of the oral cavity. Polyphenols are major plant antioxidants. Using the Folin-Ciocalteu's assay, a very low amount of phenols was measured in FPP suspended in a salt solution. However, its suspension in saliva, albumin, mucin or RBC produced up to sixfold increase, p < 0.001, compared with the sum of polyphenols assayed separately. The results suggested that these enhancing effects were due to the solubilization of antioxidant polyphenols in FPP by saliva proteins and the binding to RBC and microorganisms, thus increasing their availability and activity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26031773 TI - Liquid-phase step-by-step growth of an iron cyanide coordination framework on LiCoO2 particle surfaces. AB - Surface modification of inorganic objects with metal-organic frameworks (MOFs) - organic-inorganic hybrid framework materials with infinite networks - opens wide windows for potential applications. In order to derive a target property, the key is the ability to fine tune the degree of modification. Solution-based step-by step growth techniques provide excellent control of layer thickness which can be varied with the number of deposition cycles. Such techniques with MOFs have been mainly applied to flat substrates, but not to particle surfaces before. Here, we present the facile surface modification of inorganic particles with a framework compound under operationally simple ambient conditions. A solution-based sequential technique involving the alternate immersion of LiCoO2 (LCO) - a positive electrode material for a lithium ion battery - into FeCl2.4H2O and K3[Fe(CN)6] solutions results in the formation of Prussian blue (PB) nanolayers on the surface of the LCO particles (PBNL@LCO). The PB growth is finely controlled by the number of immersion cycles. An electrochemical cell with PBNL@LCO as a positive electrode material exhibits a discharge capacity close to the specific capacity of LCO. The results open a new direction for creating suitable interfacial conditions between electrode materials and electrolytes in secondary battery materials. PMID- 26031774 TI - Pycnogenol prevents peritoneal adhesions. AB - PURPOSE: This study tested the ability of pycnogenol, an extract from the bark of the French maritime pine (Pinus pinaster), to prevent intra-abdominal adhesions. METHODS: Thirty female Wistar albino rats were separated randomly into three equal groups: Group (1) the control group, which underwent surgery, but was given no drug; Group (2) given 10 mg/kg of pycnogenol dissolved in normal saline intraperitoneally for 10 days after surgery; and Group (3) given 0.1 mL of normal saline for 10 days intraperitoneally after surgery. On post-operative day 10, all of the animals were killed and any adhesions were evaluated macroscopically and histopathologically. RESULTS: The macroscopic adhesion scores (mean +/- SD) for Groups 1, 2, and 3 were 2.5 +/- 0.53, 0.60 +/- 0.70, and 2.0 +/- 0.82, respectively. The macroscopic adhesion score was significantly lower in Group 2 than in Groups 1 and 3 (p < 0.001). All three components of the histopathological evaluation (inflammation, fibrosis, and neovascularization) were significantly lower in Group 2 than in Groups 1 or 3 (p < 0.001, p < 0.001, and p = 0.004, respectively). CONCLUSIONS: Pycnogenol was found to be effective at preventing surgery-related adhesions in an animal model. PMID- 26031776 TI - KRAS discordance between primary and recurrent tumors after radical resection of colorectal cancers. AB - BACKGROUND: Although KRAS shows high concordance between primary and metastatic colorectal cancers, recent studies have reported discordance and intra-tumoral heterogeneity. To evaluate KRAS concordance between primary colorectal cancers and recurrent tumors after radical resection, we performed this study. METHODS: Between January 2007 and August 2013, among patients underwent radical resection for primary colorectal cancers and tissue sampling of recurred tumors including resection or biopsy, 74 patients whose both primary and recurred tumor tissues were available for KRAS analysis were enrolled. The clinical and pathologic data were retrospectively revised and KRAS analyses were performed. RESULTS: The patients with initial M1 stage showed significantly higher KRAS discordance rate (54.5%). The KRAS concordance rate was 79.7% (n = 59). Forty-two patients (56.8%) showed the wild-to-wild type and 17 (22.9%) showed the mutant-to-mutant type. The discordance rate was 20.3% (n = 15). Eight patients (10.8%) showed the wild-to mutant type, and 7 (9.5%) showed the mutant-to-wild type. Among 15 discordance cases, intra-tumoral heterogeneity was found in 26.7% (n = 4). CONCLUSIONS: There is 20.3% KRAS discordance between primary and recurrent tumors, which is higher rate than is generally known. For selection of the effective target agent, KRAS analysis of recurred tumors will be necessary, if it is available. PMID- 26031775 TI - miR-16 promotes the apoptosis of human cancer cells by targeting FEAT. AB - BACKGROUND: Although human cancers have heterogeneous combinations of altered oncogenes, some crucial genes are universally dysregulated in most cancers. One such gene, FEAT (faint expression in normal tissues, aberrant overexpression in tumors), is uniformly overexpressed in a variety of human cancers and plays an important role in tumorigenesis by suppressing apoptosis. However, the precise molecular mechanism through which FEAT is upregulated during tumorigenesis remains largely unknown. METHODS: In this study, we used bioinformatic analyses to search for miRNAs that potentially target FEAT. We examined the expression of FEAT protein level by western blotting and miR-16 level by qRT-PCR assay. Cancer cell lines (A549, MCF-7 and Huh-7) with miR-16 upregulation and FEAT silencing were established and the effects on apoptosis of cancer cells in vitro were assessed. Luciferase reporter assay was also performed to investigate the interaction between miR-16 and FEAT. RESULTS: We identified a specific target site for miR-16 in the 3'-untranslated region (3'-UTR) of FEAT. Consistent with the bioinformatic analyses, we identified an inverse correlation between the miR 16 and FEAT protein levels in lung cancer, breast cancer, and hepatocellular cancer tissues. We then experimentally validated miR-16 as a direct regulator of FEAT using cell transfection and luciferase assays. Finally, we demonstrated that the repression of FEAT by miR-16 promoted the apoptosis of cancer cells. CONCLUSIONS: Our findings provide the first clues regarding the role of miR-16 as a tumor suppressor in cancer cells through the inhibition of FEAT translation. PMID- 26031777 TI - Hormonal 'minipuberty' influences the somatic development of boys but not of girls up to the age of 6 years. AB - OBJECTIVE: Hormonal 'minipuberty' refers to a transient sex-specific surge of LH, FSH, testosterone (T) and estradiol (E2) in the first few months of life. We hypothesized a potential long-term effect of this hormonal surge on somatic parameters in the following years and therefore designed this longitudinal study. DESIGN: A hierarchical multiple regression analysis was used to analyse the potential influence of hormone concentrations during minipuberty on anthropometric measurements conducted in the first 6 years of life. PATIENTS: Thirty-five healthy babies (17 male, 18 female) were the participants. MEASUREMENTS: Testosterone, E2, SHBG, LH and FSH were measured at the ages of four, eight and 20 weeks. Anthropometric measurements were taken eight times in the first 12 months, then every 6 months up to the age of 6 years. RESULTS: A significant negative effect was found in boys between testosterone and LH levels at 8 weeks and body weight up to the age of 6 years and BMI up to 6 years (LH) and 3 years (T), respectively. A further negative effect was found between E2 levels at the age of 20 weeks and body weight as well as body length in the years that followed. A positive effect was observed between E2 at the age of 4 weeks and skinfold thickness up to the age of 6 years in boys. No significant effects were found in girls. CONCLUSIONS: The findings seem to reflect an up to now unknown long-term influence of the physiological early hormonal surge on the subsequent male but not female somatic development. PMID- 26031778 TI - Synthesis, biological evaluation and molecular modeling studies of new 2,3 diheteroaryl thiazolidin-4-ones as NNRTIs. AB - In a focused exploration, thiazolidin-4-ones with different C-2 and N-3 substituent groups were synthesized and evaluated as non-nucleoside reverse transcriptase inhibitors against HIV-1. This has led to new active compounds sporting heteroaryls at both C-2 and N-3 positions prompting to view them in the backdrop of nevirapine. To assign the molecular attributes for the activity, the compounds are investigated by docking them into non-nucleoside inhibitor-binding pocket of HIV-1 reverse transcriptase (RT). The most active compounds of this series (7d and 7f) shared spatial features with nevirapine with added molecular flexibility. Furthermore, in molecular dynamics simulations carried out for up to 10 ns, the compounds 7d and 7f showed consistency in their interactions with non nucleoside inhibitor-binding pocket of HIV-1 RT and suggested Tyr319 and Val106 as potential residues for H-bond interaction with these molecules. These results open new avenues for the exploration of 2,3-diheteroaryl thiazolidin-4-ones for prevention of HIV-1. PMID- 26031779 TI - EGF-Induced Connexin43 Negatively Regulates Cell Proliferation in Human Ovarian Cancer. AB - Connexin43 (Cx43) has been shown to regulate cell proliferation and its downregulation is correlated with poor prognosis and survival in several types of human cancer. Cx43 expression levels are frequently downregulated in human ovarian cancer, suggesting a potential role for Cx43 in regulating the progression of this disease. Epidermal growth factor (EGF) is a well characterized hormone that stimulates ovarian cancer cell proliferation. Although EGF is able to regulate Cx43 expression in other cell types, it is unclear whether EGF can regulate Cx43 expression in ovarian cancer cells. Additionally, it remains unknown whether Cx43 is involved in EGF-stimulated ovarian cancer cell proliferation. In the present study, we demonstrate that treatment with EGF upregulates Cx43 expression in two ovarian cancer cell lines, SKOV3 and OVCAR4. Although treatment with EGF activates both ERK1/2 and Akt signaling pathways, pharmacological inhibition and siRNA-mediated knockdown suggest that only the activation of Akt1 is required for EGF-induced Cx43 upregulation. Functionally, Cx43 knockdown enhanced basal and EGF-induced cell proliferation, whereas the proliferative effects of EGF were reduced by Cx43 overexpression. Co-treatment with the gap junction inhibitor carbenoxolone did not alter the suppressive effects of Cx43 overexpression on EGF-induced cell proliferation, suggesting a gap junction-independent mechanism. This study reveals an important role for Cx43 as a negative regulator of EGF-induced human ovarian cancer cell proliferation. PMID- 26031780 TI - Nutrition and Atherosclerosis. AB - Cardiovascular disease (CVD) is a universal problem in modern society. Atherosclerosis is the leading cause of CVD resulting in high rate of mortality in the population. Nutrition science has focused on the role of essential nutrients in preventing deficiencies, at the present time, the nutritional strategies are crucial to promote health and intervene with these global noncommunicable diseases. In many cases, diet is a major driving force, which is much easier to change and follow than other factors. It is important to establish that the first strategy to treat atherosclerosis is to modify lifestyle habits, focusing on the beneficial properties of specific nutrients. In the last decades, epidemiological, clinical and experimental studies have demonstrated that diet plays a central role in the prevention of atherosclerosis. In this review we will focus on the effect of specific foods, nutrients and bioactive compounds, including epidemiological facts, potential mechanisms of action and dietary recommendations to reduce the risk of atherosclerosis. In particular, we include information about fiber, plant sterols and stanols, niacin, taurine, olive oil, omega 3 fatty acids, antioxidants, minerals, methyl nutrients and soy. In addition, we also show that dysbiosis of the intestinal microbiota associated with a consumption of certain animal food sources can generate some metabolites that are involved in the development of atherosclerosis and its consequences on CVD. According to the epidemiological, clinical and experimental studies we suggest a recommendation for some dietary foods, nutrients and bioactive compounds to support the complementary clinical management of patients with atherosclerosis. PMID- 26031781 TI - In vivo time-lapse imaging of mitochondria in healthy and diseased peripheral myelin sheath. AB - The myelin sheath that covers a large amount of neurons is critical for their homeostasis, and myelinating glia mitochondria have recently been shown to be essential for neuron survival. However morphological and physiological properties of these organelles remain elusive. Here we report a method to analyze mitochondrial dynamics and morphology in myelinating Schwann cells of living mice using viral transduction and time-lapse multiphoton microscopy. We describe the distribution, shape, size and dynamics of mitochondria in live cells. We also report mitochondrial alterations in Opa1(delTTAG) mutant mice cells at presymptomatic stages, suggesting that mitochondrial defects in myelin contribute to OPA1 related neuropathy and represent a biomarker for the disease. PMID- 26031782 TI - A nuclear-encoded chloroplast-targeted S1 RNA-binding domain protein affects chloroplast rRNA processing and is crucial for the normal growth of Arabidopsis thaliana. AB - Despite the fact that a variety of nuclear-encoded RNA-binding proteins (RBPs) are targeted to the chloroplast and play essential roles during post transcriptional RNA metabolism in the chloroplast, the physiological roles of the majority of chloroplast-targeted RBPs remain elusive. Here, we investigated the functional role of a nuclear-encoded S1 domain-containing RBP, designated SDP, in the growth and development of Arabidopsis thaliana. Confocal analysis of the SDP green fluorescent protein revealed that SDP was localized to the chloroplast. The loss-of-function sdp mutant displayed retarded seed germination and pale-green phenotypes, and grew smaller than the wild-type plants. Chlorophyll a content and photosynthetic activity of the sdp mutant were much lower than those of wild-type plants, and the structures of the chloroplast and the prolamellar body were abnormal in the sdp mutant. The processing of rRNAs in the chloroplast was defective in the sdp mutant, and SDP was able to bind chloroplast 23S, 16S, 5S and 4.5S rRNAs. Notably, SDP possesses RNA chaperone activity. Transcript levels of the nuclear genes involved in chlorophyll biosynthesis were altered in the sdp mutant. Collectively, these results suggest that chloroplast-targeted SDP harboring RNA chaperone activity affects rRNA processing, chloroplast biogenesis and photosynthetic activity, which is crucial for normal growth of Arabidopsis. PMID- 26031783 TI - Attenuated Age-Related Increases in Arterial Stiffness in Japanese and American Women. AB - BACKGROUND: The United States and Japan have similar standards of living, healthcare systems, and industrializations but exhibit markedly divergent life expectancies both at birth and at later ages (50 or 65 years old). Arterial stiffness has been widely regarded as a barometer of biological or physiological aging and could provide insight into the inter-country differences. OBJECTIVES: To determine whether the increases in arterial stiffness across the adult age range are greater in U.S. than Japanese adults. DESIGN: Cross-sectional analyses. SETTING: Laboratory-based study. PARTICIPANTS: Healthy, nonsmoking Japanese (n = 400) and U.S. (n = 400) adults without cardiovascular and other chronic diseases. MEASUREMENTS: Indices of arterial stiffness, including carotid-femoral (cfPWV) and brachial-ankle pulse wave velocity (baPWV) were measured, along with a variety of ancillary measures. The recruitment method, measurement technique, and protocol were standardized and identical between U.S. and Japanese facilities. RESULTS: cfPWV and baPWV increased progressively with advancing age in all subgroups (stratified according to sex and country). The rates of age-related increases in arterial stiffness were not different between U.S. and Japanese men, but age-associated increases in cfPWV were significantly greater in U.S. than Japanese women, widening the intercountry differences at older age ranges. CONCLUSION: Japanese women had smaller increases in central arterial stiffness with advancing age than U.S. women. PMID- 26031784 TI - Cervical cancer: squamocolumnar junction ablation--tying up loose ends? PMID- 26031785 TI - Proteomic analysis of cellular soluble proteins from human bronchial smooth muscle cells by combining nondenaturing micro 2DE and quantitative LC-MS/MS. 2. Similarity search between protein maps for the analysis of protein complexes. AB - Human bronchial smooth muscle cell soluble proteins were analyzed by a combined method of nondenaturing micro 2DE, grid gel-cutting, and quantitative LC-MS/MS and a native protein map was prepared for each of the identified 4323 proteins [1]. A method to evaluate the degree of similarity between the protein maps was developed since we expected the proteins comprising a protein complex would be separated together under nondenaturing conditions. The following procedure was employed using Excel macros; (i) maps that have three or more squares with protein quantity data were selected (2328 maps), (ii) within each map, the quantity values of the squares were normalized setting the highest value to be 1.0, (iii) in comparing a map with another map, the smaller normalized quantity in two corresponding squares was taken and summed throughout the map to give an "overlap score," (iv) each map was compared against all the 2328 maps and the largest overlap score, obtained when a map was compared with itself, was set to be 1.0 thus providing 2328 "overlap factors," (v) step (iv) was repeated for all maps providing 2328 * 2328 matrix of overlap factors. From the matrix, protein pairs that showed overlap factors above 0.65 from both protein sides were selected (431 protein pairs). Each protein pair was searched in a database (UniProtKB) on complex formation and 301 protein pairs, which comprise 35 protein complexes, were found to be documented. These results demonstrated that native protein maps and their similarity search would enable simultaneous analysis of multiple protein complexes in cells. PMID- 26031786 TI - The Women Independently Living Alone with a Medical Alert Device (WILMA) trial. AB - Women are more likely to live alone compared with men, and therefore have more difficulty activating emergency medical systems for stroke. The goal of this study was to examine the benefit of wearing medical alert devices to activate emergency medical systems for elderly women living alone. This was a randomized, controlled pilot trial. Women over 60 with at least 1 stroke risk factor were recruited from Southeast Michigan. Subjects received either a medical alert device or control. The primary outcome was change in health-related quality of life (HRQOL) from baseline to 90 days of wearing the device or control. A planned sample size of 320 could not be reached, and the trial was stopped at 265 women randomized prior to data examination. On average, the treatment group was older, reported lower prevalence of high cholesterol, and was less likely to complete follow-up. There was a nonsignificant smaller loss of healthy days in the past month in the intervention group (0.46) compared with the control group (2.23) (p = 0.213). Similarly, the secondary outcomes of changes in anxiety, depression, and changes in perceived isolation did not differ by treatment and control groups. This study did not establish improvement in HRQOL among women who wore the device compared with those that did not, nor the feasibility of a trial to study the efficacy of medical alert devices in elderly women. Newer devices that use cellular technology may be more accepted than the landline-based system used in this study. PMID- 26031787 TI - An exploratory trial exploring the use of a multiple intelligences teaching approach (MITA) for teaching clinical skills to first year undergraduate nursing students. AB - BACKGROUND: The teaching and learning of clinical skills is a key component of nurse education programmes. The clinical competency of pre-registration nursing students has raised questions about the proficiency of teaching strategies for clinical skill acquisition within pre-registration education. OBJECTIVES: This study aimed to test the effectiveness of teaching clinical skills using a multiple intelligences teaching approach (MITA) compared with the conventional teaching approach. DESIGN: A randomised controlled trial was conducted. Participants were randomly allocated to an experimental group (MITA intervention) (n=46) and a control group (conventional teaching) (n=44) to learn clinical skills. SETTING: Setting was in one Irish third-level educational institution. PARTICIPANTS: Participants were all first year nursing students (n=90) in one institution. METHODS: The experimental group was taught using MITA delivered by the researcher while the control group was taught by a team of six experienced lecturers. Participant preference for learning was measured by the Index of Learning Styles (ILS). Participants' multiple intelligence (MI) preferences were measured with a multiple intelligences development assessment scale (MIDAS). All participants were assessed using the same objective structured clinical examination (OSCE) at the end of semester one and semester two. MI assessment preferences were measured by a multiple intelligences assessment preferences questionnaire. The MITA intervention was evaluated using a questionnaire. RESULTS: The strongest preference on ILS for both groups was the sensing style. The highest MI was interpersonal intelligence. Participants in the experimental group had higher scores in all three OSCEs (p<0.05) at Time 1, suggesting that MITA had a positive effect on clinical skill acquisition. Most participants favoured practical examinations, followed by multiple choice questions as methods of assessment. MITA was evaluated positively. CONCLUSION: The study findings support the use of MITA for clinical skills teaching and advance the understanding of how MI teaching approaches may be used in nursing education. PMID- 26031788 TI - Aquarium microbiome response to ninety-percent system water change: Clues to microbiome management. AB - The bacterial community composition and structure of water from an established teleost fish system was examined before, during and after a major water change to explore the impact of such a water-change disturbance on the stability of the aquarium water microbiome. The diversity and evenness of the bacterial community significantly increased following the 90% water replacement. While the change in bacterial community structure was significant, it was slight, and was also weakly correlated with changes in physicochemical parameters. Interestingly there was a significant shift in the correlative network relationships between operational taxonomic units from before to after the water replacement. We suggest this shift in network structure is due to the turnover of many taxa during the course of water replacement. These observations will inform future studies into manipulation of the microbiome by changing system environmental parameter values to optimize resident animal health. PMID- 26031789 TI - Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk. AB - BACKGROUND AND PURPOSE: Low density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). METHODS: A Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke. RESULTS: In the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006). CONCLUSIONS: The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted. PMID- 26031790 TI - Multidrug-resistant Pseudomonas aeruginosa endophthalmitis in a silicone oil filled eye treated with piperacillin/tazobactam: report of a case and review of literature. AB - The incidence of endophthalmitis after pars plana vitrectomy is low. Silicone oil is a tamponading agent which has anti-microbial activity. Post-operative endophthalmitis following vitrectomy with silicone oil tamponade has been rarely reported. We describe the case of a young male who underwent pars plana vitrectomy with silicone oil for retinal detachment with a giant retinal tear. He developed a clinical picture suggestive of endophthalmitis on the first post operative day, and vitreous culture grew multidrug-resistant Pseudomonas aeruginosa. He was treated with intravitreal piperacillin/tazobactam, along with appropriate surgical management. This was followed by resolution of the infection with a remarkable improvement in visual acuity. This is the first case of multidrug-resistant Pseudomonas aeruginosa endophthalmitis following pars plana vitrectomy with silicone oil treated successfully with piperacillin/tazobactam. PMID- 26031791 TI - IOP measurement: importance of methodology. PMID- 26031792 TI - Influence of indoor and outdoor activities on progression of myopia during puberty. AB - The purpose of this study was to investigate whether time spent on indoor and outdoor activities or the other possible risk factors including age, gender, parental history, and initial refraction was associated with progression of myopia, during puberty. Fifty eyes of 50 myopic children aged 9-14 years were enrolled in the study. The parents were interviewed to determine the amounts of time in hours per day spent on reading and writing, using computer, watching TV, and outdoor activities (i.e., sports, games, or being outdoor with no activities) on an average day. The annual myopia progression rate (diopters per year) was calculated for each subject and was used in the statistical analyses. The mean initial age of the subjects was 10.9 +/- 1.5 (ranging from 9 to 14) years. The mean follow-up period was 33.3 +/- 10.3 (ranging from 17 to 55) months. There was a significant increase in the mean myopia value of the subjects after follow-up period (p < 0.001). The mean daily time spent on reading and writing and initial refraction value were independently associated with annual myopic progression rate. On the other hand, age, gender, parental myopia, and the mean daily times spent on computer use, watching TV, and outdoor activities had no correlations with annual myopia progression rate. The present study showed that myopia progression was associated with time spent on reading and writing and initial refraction value, during puberty. However, myopia progression was not associated with parental myopia, age, gender, and daily times spent on using computer, watching TV, and outdoor activities. PMID- 26031793 TI - Changes in diversity of cultured bacteria resistant to erythromycin and tetracycline in swine manure during simulated composting and lagoon storage. AB - This study investigated the impact of composting and lagoon storage on survival and change in diversity of tetracycline-resistant (Tc(r) ) and erythromycin resistant (Em(r) ) bacteria and the resistance genes they carry in swine manure. Treatments were arranged as a 2 * 2 factorial design: composting vs lagoon storage and 0 vs 1% Surround WP Crop Protectant (a clay product) in three replicates. After 48 days of treatments, resistant bacteria were enumerated by selective plating and identified by 16S rRNA gene sequencing. The erm and the tet gene(s) carried by the resistant isolates were screened using class-specific PCR assays. The plate counts of Tc(r) and Em(r) bacteria decreased by 4-7 logs by composting, but only by 1-2 logs by the lagoon treatment. During the treatments, Acinetobacter gave way to Pseudomonas and Providencia as the largest resistant genera. The clay product had little effect on survival or diversity of resistant bacteria. Of six classes of erm and seven classes of tet genes tested, changes in prevalence were also noted. The results indicate that composting can dramatically shift Tc(r) and Em(r) bacterial populations, and composting can be an effective and practical approach to decrease dissemination of antibiotic resistance from swine farms to the environment. SIGNIFICANCE AND IMPACT OF THE STUDY: The presented research provided evidence that composting is much more effective than lagoon storage in dramatically decreasing culturable bacteria resistant to erythromycin and tetracycline in swine manure. Considerable diversity changes of resistant bacteria were also demonstrated during composting or lagoon storage. Overall, Acinetobacter was the major resistant genus in untreated swine manure, but pseudomonads and Providencia became the major resistant genera after the treatments. This is the first study that investigated diversity changes of cultured bacteria resistant to these two antibiotics during composting and lagoon storage of swine manure. New genes encoding resistance to the two antibiotics were also implied in the cultured isolates. PMID- 26031794 TI - The novel HLA-DRB1*12:01:06 allele detected in a Taiwanese unrelated hematopoietic stem cell donor. AB - One nucleotide substitution at residue 267 of HLA-DRB1*12:01:01 results in a new allele, HLA-DRB1*12:01:06. PMID- 26031795 TI - Effect of Different In Vitro Aging Methods on Color Stability of a Dental Resin Based Composite Using CIELAB and CIEDE2000 Color-Difference Formulas. AB - PURPOSE: To evaluate the effect of different in vitro aging methods on color change (CC) of an experimental dental resin-based composite using CIELAB (DeltaEab ) and CIEDE2000 (DeltaE00 ) color-difference formulas. MATERIALS AND METHODS: The CC was evaluated with a spectrophotometer (CM700d, Konica Minolta, Tokyo, Japan) according to the CIE chromatic space. Disk-shaped specimens (Phi = 5 * 1 mm thick) (N = 10) were submitted to different in vitro aging methods: 30 days of water aging (WA); 120 hours of ultraviolet light aging (UVA); or 300 hours of an accelerated artificial aging (AAA) method with cycles of 4 hours of UV-B light exposure and 4 hours of moisture condensation to induce CC. The temperature was standardized at 37 degrees C for all aging methods. CC was evaluated with DeltaEab and DeltaE00 formulas. Differences in individual Lab coordinates were also calculated. Data for the individual color parameters were submitted to one-way analysis of variance and Tukey's test for multiple comparisons (alpha = 0.05). RESULTS: All in vitro aging methods tested induced CC, in the following order: WA: DeltaEab = 0.83 (0.1); DeltaE00 = 1.15 (0.1) < AAA: DeltaEab = 5.64 (0.2); DeltaE00 = 5.01 (0.1) < UVA: DeltaEab = 6.74 (0.2); DeltaE00 = 6.03 (0.4). No changes in L* or a* coordinates were >=1; the methods with UV aging showed a yellowing effect due a large positive change in b*. CONCLUSIONS: All in vitro aging methods tested induced a CC, but to different extents. Changes in color followed similar trends, but with different absolute values when calculated with the CIELAB and the CIEDE2000 formulas. CLINICAL SIGNIFICANCE: Establishing the efficacy of different artificial aging methods and differences between color change using CIELAB and CIEDE2000 formulas are important to standardize color stability evaluations and facilitate the comparison of outcomes from different studies in the literature. PMID- 26031796 TI - Alzheimer's disease associated with sporadic cerebral amyloid angiopathy in an elderly patient. PMID- 26031797 TI - Reactivation of hepatitis B virus during treatment with hydroxyurea in an elderly patient with essential thrombocythemia. PMID- 26031798 TI - Expertise of pharmacists expected in the framework of long-term care insurance. PMID- 26031799 TI - Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice. AB - Since their discovery, innate lymphoid cells (ILCs) have been the subject of intense research. As their name implies, ILCs are innate cells of lymphoid origin, and can be grouped into subsets based on their cytotoxic activity, cytokine profile, and the transcriptional requirements during ILC differentiation. The main ILC groups are "killer" ILCs, comprising NK cells, and "helper-like" ILCs (including ILC1s, ILC2s, and ILC3s). This review examines the origin, differentiation stages, and plasticity of murine and human ILC3s. ILC3s express the retinoic acid receptor (RAR) related orphan receptor RORgammat and the signature cytokines IL-22 and IL-17. Fetal ILC3s or lymphoid tissue inducer cells are required for lymphoid organogenesis, while postnatally developing ILC3s are important for the generation of intestinal cryptopatches and isolated lymphoid follicles as well as for the defence against pathogens and epithelial homeostasis. Here, we discuss the transcription factors and exogenous signals (including cytokines, nutrients and cell-to-cell interaction) that drive ILC3 lineage commitment and acquisition of their distinctive effector program. PMID- 26031803 TI - Bile duct kinking after adult living donor liver transplantation: Case reports and literature review. AB - Regeneration of the partial allograft and the growth of children may cause kinking of the biliary tract after pediatric living donor liver transplantation (LDLT), but bile duct kinking after adult LDLT is rarely reported. We herein presented two patients who suffered from anastomotic strictures caused by severe bile duct kinking after LDLT. The first patient was a 57-year-old woman with hepatitis B virus (HBV)-related liver cirrhosis, who developed biliary stricture 5 months after receiving right-lobe LDLT. Subsequently, endoscopic and percutaneous treatments were attempted, but both failed to solve the problem. The second was a 44-year-old woman also having HBV-related liver cirrhosis. Biliary stricture occurred 14 months after LDLT. Likewise, the guide wire failed to pass through the stricture when endoscopic interventions were conducted. Afterwards, both of the two cases underwent reexploration, showing that compensatory hypertrophy of the allografts resulted in kinking and sharp angulation of the bile ducts, and the anastomotic sites were found to be severely stenotic. Finally, re-anastomosis by Roux-en-Y procedure was successfully performed, and long-term stenosis-free survival was achieved in both of them. Our experience suggests that bile duct kinking after LDLT may play a role in the high incidence of anastomotic strictures in adult LDLT recipients, which may also result in the treatment failure of the non-surgical techniques for anastomotic strictures. Re anastomosis in the form of Roux-en-Y hepaticojejunostomy is an effective surgical option for the treatment of such a condition. PMID- 26031800 TI - TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi. AB - We have identified a phosphate transporter (TcPho91) localized to the bladder of the contractile vacuole complex (CVC) of Trypanosoma cruzi, the etiologic agent of Chagas disease. TcPho91 has 12 transmembrane domains, an N-terminal regulatory SPX (named after SYG1, Pho81 and XPR1) domain and an anion permease domain. Functional expression in Xenopus laevis oocytes followed by two-electrode voltage clamp showed that TcPho91 is a low-affinity transporter with a Km for Pi in the millimolar range, and sodium-dependency. Epimastigotes overexpressing TcPho91 green fluorescent protein have significantly higher levels of pyrophosphate (PPi ) and short-chain polyphosphate (polyP), suggesting accumulation of Pi in these cells. Moreover, when overexpressing parasites were maintained in a medium with low Pi , they grew at higher rates than control parasites. Only one allele of TcPho91 in the CL strain encodes for the complete open reading frame, while the other one is truncated encoding for only the N-terminal domain. Taking advantage of this characteristic, knockdown experiments were performed resulting in cells with reduced growth rate as well as a reduction in PPi and short-chain polyP levels. Our results indicate that TcPho91 is a phosphate sodium symporter involved in Pi homeostasis in T. cruzi. PMID- 26031804 TI - Effectiveness of tailored support for people with Type 2 diabetes after a first acute coronary event: a multicentre randomized controlled trial (the Diacourse ACE study). AB - AIMS: To evaluate the effectiveness of a tailored, supportive intervention strategy in influencing diabetes-related distress, health status, well-being and clinical outcomes in people with Type 2 diabetes shortly after a first acute coronary event. METHODS: People with Type 2 diabetes and a recent first acute coronary event (n = 201) were randomized to the intervention group (three home visits by a diabetes nurse) or the attention control group (one telephone consultation). Outcomes were measured after discharge (baseline) and at 5 months (follow-up) using validated questionnaires for diabetes-related distress (Problem Areas in Diabetes), well-being (WHO Well-Being Index) and health status (Euroqol 5 Dimensions; Euroqol Visual Analogue Scale). ancova was used to analyse change over-time differences between groups. RESULTS: Follow-up data were available for 81 participants in the intervention group (66.0 +/- 9.3 years, 76% male) and 80 in the control group (65.6 +/- 9.4 years, 75% male) participants. Mean diabetes related distress was low after hospital discharge (intervention group: 8.2 +/- 10.1; control group: 9.2 +/- 12.4) and did not change after 5 months (intervention group: 9.2 +/- 12.4; control group: 9.0 +/- 11.2). Baseline well being was less favourable but improved significantly in the intervention group (baseline: 58.5 +/- 28.0; follow-up: 65.5 +/- 23.7; P = 0.005), but not in the control group (baseline: 57.5 +/- 25.2; follow-up: 59.6 +/- 24.4; P = 0.481). Health status also improved in the intervention group (baseline: 69.9 +/- 17.3; follow-up: 76.8 +/- 15.6; P < 0.001) but not in the control group (baseline: 68.6 +/- 15.9; follow-up: 69.9 +/- 16.7; P = 0.470). A significant group effect was found for health status (F = 7.9; P = 0.006). CONCLUSIONS: Although the intervention had no effect on diabetes-related distress, this might be at least partially attributable to very low levels of diabetes-related distress at baseline. Interestingly, health status scores and well-being, which were less favourable at baseline, both improved after the tailored support intervention. PMID- 26031805 TI - The influence of self-esteem and social support on the relationship between stigma and depressive symptomology in parents caring for children with intellectual disabilities. AB - BACKGROUND: This study explored the synergistic relationship between stigma, self esteem and social support, as predictors of depressive symptomology in parents of children with disabilities (e.g. Autism and Down syndrome). METHOD: One hundred and seventy-three parents (115 parents of children with disabilities and 58 control parents) completed measures of perceived stigma, self-esteem, social support and depressive symptoms. RESULTS: Parents of children with disabilities reported more depressive symptomology; additionally, stigma, self-esteem and social support were associated with depressive symptomology. Moreover, the association between stigma and depressive symptomology was mediated by self esteem, i.e. parents who reported higher stigma were lower on self-esteem and more depressed. Further, this path varied as a function of emotional support. CONCLUSION: Results highlight the need for tailored interventions that offer parents effective strategies in dealing with stigma through social support and self-esteem. PMID- 26031806 TI - Reaction of Ni(2+) and SnS as a Way to Form Ni@SnS and Sn2Ni3S2 Nanocrystals: Control of Product Formation and Shape. AB - Reductive diffusion of Ni(2+) into SnS particles was shown to selectively form Sn2Ni3S2, hybrid, or even core-shell Ni@SnS, Ni1.523Sn, and Ni3S2, by tuning the reaction conditions at low temperatures. The mechanism of Ni(2+) reduction and diffusion into SnS was observed in ethylene glycol, which served both as solvent and reducing agent. Tuning of reaction temperature and duration, morphology of the template SnS, and the application of ethylenediamine as supporting chelating agent, influence the formation of the final products. Their formation was controlled by carefully adjusting redox and equilibrium reactions. The products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy analysis (EDX). PMID- 26031807 TI - Age estimation based on pulp chamber volume of first molars from cone-beam computed tomography images. AB - AIM: To establish a method that can be used for human age estimation on the basis of pulp chamber volume of first molars and to identify whether the method is good enough for age estimation in real human cases. MATERIALS AND METHODS: CBCT images of 373 maxillary first molars and 372 mandibular first molars were collected to establish the mathematical model from 190 female and 213 male patients whose age between 12 and 69 years old. The inclusion criteria of the first molars were: no caries, no excessive tooth wear, no dental restorations, no artifacts due to metal restorative materials present in adjacent teeth, and no pulpal calcification. All the CBCT images were acquired with a CBCT unit NewTom VG (Quantitative Radiology, Verona, Italy) and reconstructed with a voxel-size of 0.15mm. The images were subsequently exported as DICOM data sets and imported into an open source 3D image semi-automatic segmenting and voxel-counting software ITK-SNAP 2.4 for the calculation of pulp chamber volumes. A logarithmic regression analysis was conducted with age as dependent variable and pulp chamber volume as independent variables to establish a mathematical model for the human age estimation. To identify the precision and accuracy of the model for human age estimation, another 104 maxillary first molars and 103 mandibular first molars from 55 female and 57 male patients whose age between 12 and 67 years old were collected, too. Mean absolute error and root mean square error between the actual age and estimated age were used to determine the precision and accuracy of the mathematical model. The study was approved by the Institutional Review Board of Peking University School and Hospital of Stomatology. RESULTS: A mathematical model was suggested for: AGE=117.691-26.442*ln (pulp chamber volume). The regression was statistically significant (p=0.000<0.01). The coefficient of determination (R(2)) was 0.564. There is a mean absolute error of 8.122 and root mean square error of 5.603 between the actual age and estimated age for all the tested teeth. CONCLUSION: The pulp chamber volume of first molar is a useful index for the estimation of human age with reasonable precision and accuracy. PMID- 26031808 TI - Offspring of primiparous mothers do not experience greater mortality or poorer growth: Revisiting the conventional wisdom with archival records of Rhesus Macaques. AB - Female mammals often begin to reproduce before achieving somatic maturity and therefore face tradeoffs between allocating energy to reproduction or their own continued development. Constraints on primiparous females are associated with greater reproductive failure, and first-born infants often have slower growth and greater mortality and morbidity than infants born to multiparous females. Effects of early life investment may persist even after weaning when juveniles are no longer dependent on maternal care and mother's milk. We investigated the long term consequences of birth order in a large sample of rhesus macaques, Macaca mulatta, assigned to the outdoor breeding colony at the California National Primate Research Center (n = 2,724). A joint model for growth and mortality over the first three years of life allowed us to explicitly connect growth rates to survival. As expected, males are born heavier and grow faster relative to females. However, contrary to expectations, later-born males face substantially lower survival probability during their first three years, whereas first-born males survive at greater rates similar to both first-born and later-born females. Primiparous mothers are less likely to conceive during the subsequent breeding season, suggesting that their reproductive costs are greater than those of multiparous mothers. We speculate that compensatory tactics, both behavioral and physiological, of first-born offspring and their mothers, as well as the novel ecology of the captive environment, underlie these findings. The results presented here provide new insights into how maternal and infant life history tradeoffs may influence developmental trajectories even after the period of maternal dependence. Am. J. Primatol. 77:963-973, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26031809 TI - HDAC6 mediates HIV-1 tat-induced proinflammatory responses by regulating MAPK-NF kappaB/AP-1 pathways in astrocytes. AB - Human immunodeficiency virus (HIV)-1 transactivator of transcription (Tat) is a viral protein that induces extensive neuroinflammation by up-regulating proinflammatory mediators, including cytokines, chemokines, and adhesion molecules. Histone deacetylase 6 (HDAC6) has been implicated in the transcriptional regulation of inflammatory genes. In this study, we investigated the possible role of HDAC6 in HIV-1 Tat-induced up-regulation of proinflammatory mediators in astrocytes. HIV-1 Tat augmented HDAC6 expression, which was correlated with a reduction in acetylated alpha-tubulin in CRT-MG human astroglioma cells and primary mouse astrocytes. Knockdown and pharmacological inhibition of HDAC6 significantly inhibited HIV-1 Tat-induced expression of CCL2, CXCL8, and CXCL10 chemokines; adhesion molecules; and subsequent adhesion of monocytes to astrocytes. HDAC6 knockdown attenuated HIV-1 Tat-induced activation of mitogen-activated protein kinase species, including ERK, JNK, and p38. Furthermore, HDAC6 knockdown suppressed HIV-1 Tat-induced activation of NF-kappaB and AP-1. Thus, HDAC6 is involved in HIV-1 Tat-induced expression of proinflammatory genes by regulating mitogen-activated protein kinase-NF-kappaB/AP 1 pathways and serves as a molecular target for HIV-1 Tat-mediated neuroinflammation GLIA 2015;63:1953-1965. PMID- 26031810 TI - Circular RNA and Splicing: Skip Happens. PMID- 26031811 TI - Incorporating a primary care practicum in midwifery education. AB - INTRODUCTION: There is a shortage of primary care providers in the United States. As more individuals obtain health insurance coverage with the Patient Protection and Affordable Care Act, the number seeking care will increase dramatically. Both the Institute of Medicine and the American College of Nurse-Midwives state that certified nurse-midwives and certified midwives should function at their full scope of practice, which includes primary care services as delineated by the Core Competencies for Basic Midwifery Practice. Nonetheless, the percentage of midwives who self-identify as primary care providers is decreasing. Dedicated primary care educational experiences may increase student confidence and encourage the incorporation of primary care into midwifery practice after graduation. METHODS: Midwifery students in 2 cohorts completed questionnaires before and after a dedicated primary care practicum to study changes in the perceived level of confidence in primary care provision. The students in cohort A participated in 45 hours of primary care clinical time, whereas the students in cohort B participated in 88 hours of primary care clinical time. Postclinical focus groups provided qualitative data on student perceptions and attitudes about the clinical experience. Student responses were coded by cohort and analyzed using qualitative descriptive analysis. RESULTS: Seventeen midwifery students from 2 cohorts completed questionnaires. Students in both cohorts reported increased perceived confidence in almost all primary care domains. DISCUSSION: Participation in a dedicated primary care clinical rotation increased student perceived confidence in primary care practice. The inclusion of designated primary care clinical education in nurse-midwifery education may contribute to meeting the national need for primary care providers. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26031813 TI - Pattern of soluble CD5 and CD6 lymphocyte receptors in critically ill patients with septic syndromes. AB - PURPOSE: Soluble forms of CD5 and CD6 lymphocyte surface receptors (sCD5 and sCD6) are molecules that seem to prevent experimental sepsis when exogenously administered. The aim of this study was to assess sCD5 and sCD6 levels in patients with septic syndromes. MATERIALS AND METHODS: The study population consisted of 218 patients admitted to the medical intensive care unit (ICU) presenting either septic syndromes or noninfectious systemic inflammatory response syndrome at admission or within the first 48 hours. The sCD5 and sCD6 levels were analyzed by sandwich enzyme-linked immunosorbent assay. RESULTS: Almost 50% of the patients had undetectable levels of sCD5 or sCD6, with no differences in clinical or biological variables with detectable patients. There was a correlation between the delta Sequential Organ Failure Assessment score and both sCD6 and sCD5 levels in all groups. Patients with sCD5 or sCD6 levels greater than 1500 ng/mL presented a higher in-ICU mortality (P < .05). Logistic regression analysis showed that increased sCD6 levels were associated with an increased risk of in-ICU mortality. CONCLUSIONS: Levels of sCD5 and sCD6 in critically ill patients with systemic inflammatory response syndrome present a high variation and an elevated proportion of undetectability. Levels of sCD6 are associated with an increased risk of mortality in these patients. PMID- 26031814 TI - [Repeated tracheal resection for non-neoplastic restenosis]. AB - Treatment of patients with recurrent cicatrical tracheal stenosis after previous circular tracheal resection is one of the most difficult problems in thoracic surgery at present time. In most cases repeated radical surgery as new resection is declined in favour of palliative treatment. It is often associated with lingering or perpetual preserving of T-shape or tracheostomy tube and respiratory tract stenting. Development of thoracic surgery last years permits to perform repeated tracheal resections with restoration of respiratory tract integrity by using of new tracheal anastomosis. For the last 4 years 6 such operations were performed with satisfactory immediate and remote results. Diagnostic algorithm before repeated surgery is similar to those before primary intervention. Special attention should be attended to state of remained parts of respiratory tract, degree and length of stenosis and tracheomalacia which may be result of divergence of edges of the primary anastomosis. Preserving of not less than 1/4 primary length of intact trachea with its satisfactory mobility is main condition for this surgery because it will permit to perform new anastomosis without high tension. Risk of postoperative complications after repeated operations is not higher than those after primary resection. But at present time these operations are in competence of small number of specialists and medical institutions with serious experience in thoracic surgery. PMID- 26031815 TI - [Clinical and ultrasonic predictors of postoperative complications after carotid endarterectomy]. AB - For the period from 2007 to 2012 carotid endarterectomy was performed in 150 patients with cerebrovascular insufficiency I-IV degrees and atherosclerotic lesion of carotid arteries. Dynamic observation was performed by using of duplex scanning of brachiocephalic arteries, transcranial duplex scanning, multislice CT with contrast study of extracranial and intracranial arteries. Different degrees of vascular wall thickening of operated internal carotid artery including neo- and myointimal hyperplasia, restenosis and other complications were observed in 19 (12.6%) patients after carotid endarterectomy on background of cerebrovascular insufficiency progressing. It was revealed that transient ischemic attack or stroke, acute heart failure in early postoperative period, arterial hypertension with crisis course predominantly, diabetes mellitus 2 type, obesity, male sex, elderly age and smoking were clinical markers for complications after carotid endarterectomy. Ultrasonic markers of complications after carotid endarterectomy included terms of development and degree of vascular wall thickening in case of neointimal hyperplasia and restenosis, hyperperfusion syndrome and stroke, significant changes of blood flow velocity and indexes of peripheral vascular resistance. PMID- 26031816 TI - [Optimization of infusion therapy in large abdominal operations]. AB - Volume and consist of infusion therapy determine in many respects postoperative period in patients who underwent large abdominal operations. Purposeful infusion therapy controlled according to monitoring of stroke volume variability is perspective. It was proved that evaluation of this parameter allows to optimize consist and volume of transfused solutions intraoperatively. Use of purposeful infusion therapy was accompanied by decreasing of number of postoperative complications and duration of intensive care unit stay after large abdominal operations. PMID- 26031817 TI - [Mini-invasive technologies in complex treatment of esophagus cancer]. AB - It was evaluated mini-invasive endovideosurgical technologies using in complex treatment of esophagus cancer. The investigation included 28 patients with thoracic esophagus cancer. Age of patients operated in terms from April 2012 to December 2013 was from 42 to 74 years (mean 61.7 +/- 8.7 years). Only surgical treatment was used in 10 patients. Neoadjuvant chemotherapy and radiotherapy were performed in 18 patients. Hybrid mini-invasive esophagectomy (laparoscopic stomach mobilization and right-side thoracotomy) were used in 14 cases. The frequency of postoperative complications was 35.5%. Mini-invasive endovideosurgical esophagectomy was done in 14 patients. The frequency of postoperative complications was 57.1%. There were not deaths. Our experience demonstrates good results of mini-invasive technologies using in treatment of patients with esophagus cancer. Endovideosurgical methods permit to perform adequate volume of surgery in case of oncological diseases. PMID- 26031818 TI - [The program of accelerated rehabilitation after esophagoplasty (fast track surgery) in esophageal cancer surgery]. AB - Esophagectomy with simultaneous plasty in patient with esophageal cancer is still associated with a high incidence of postoperative complications and long-stay patient in the clinic. The purpose of our report is to inform the use of the program of accelerated rehabilitation after esophagectomy in a prospective study of 13 patients during the period from 2010 to 2011 year and the role of the anesthesiologist in its implementation. Methods aimed at the preoperative examination, minimally invasive surgery, thoracic epidural anesthesia/analgesia with local anesthetics as a component of anesthesia and postoperative analgesia, early extubation and mobilization of the patient with the implementation of breathing exercises, early enteral feeding, and the planned short postoperative stay in resuscitation and hospital were used. Postoperative complications were observed in 3 (23/1%) patients: one patient (7/7%) had right-side pneumonia, two patients (15/4%) had right-side pneumothorax requiring emergency re drainage. The average intensive care stay was 2 (1-4) days, postoperative hospital stay--9 (7 12) days. Further monitoring of the patients did not show any long-term complications. The results confirm that it is possible to optimize the healing perioperative process in patients after esophagectomy with simultaneous plasty by using of accelerated rehabilitation program without the risk of increasing the frequency of postoperative complications. it will provide the reduction of length of hospital stay. In view of multifaceted and controversial issue the following researches in this direction are necessary. PMID- 26031819 TI - [Laparoscopic techniques in stage abdominal sanation for common pyoperitonitis]. AB - An experience of treatment of 949 patients with common pyoperitonitis demonstrates that effectiveness of surgical tactics depend on stage of multiorgan dysfunction. Laparoscopy decreases traumatism of additional surgery to diagnostic procedure in 68.1% of cases providing compensation of multiorgan dysfunction. 36.7% of patients with multiorgan dysfunction subindemnification need for stage lavage which is performed successfully by using of laparoscopy. 88.8% of patients in this group recovered. It is necessary to remember that carboxy-peritoneum and its removal during laparoscopic lavage are associated with functional strain of cardiovascular and respiratory system in patients with peritonitis and multiorgan dysfunction decompensation. High risk of irreversible function failure does not allow to implement potential of laparoscopic stage abdominal sanitation. In this situation maximal mortality (91.9%) was observed. PMID- 26031820 TI - [Improvement of treatment results of acute cholecystitis]. AB - The aim of this study was investigation of treatment results of acute cholecystitis according to suggested forms of cholecystitis by international experts in the research (Tokyo-2007). It was analyzed the immediate treatment results of 1399 patients with acute cholecystitis for the last 4 years in the Chelyabinsk Regional Hospital No3. 912 patients had acute cholecystitis I degree (easy cholecystitis), 270 patients--II (moderate) degree and 217 patients--III degree (severe cholecystitis). It was operated 1281 patients. Operating activity was 91.5%. Postoperative mortality in whole patients group was 0.78%. The authors suggested the main principles such as early, differentiated by the volume operative interventions according to graduations of investigation "Tokyo-2007". Controlled trial of treatment results of patients randomized on three degrees of acute cholecystitis observed appropriateness of allocation of these groups. It is necessary for differentiated treatment and improvement of treatment results of patients with acute cholecystitis. PMID- 26031821 TI - [Anesthetic management of robot-assisted radical prostatectomy]. AB - The authors have an experience in performing of 700 radical prostatectomies by using of daVinci-robot. The main factors determining parameters of operation and anesthesia are presented in the article. The authors give recommendations for optimization of anesthetic management. The main features of patient preparation for robot-assisted radical prostatectomy, parameters of anesthesia and postoperative management of patients are presented in the article. PMID- 26031822 TI - [The results of combined ozone therapy using in complex treatment of soft tissues infections in patients with diabetes mellitus type II]. AB - Levels of interleukins-6, 8, 10, TNF-alpha and basic fibroblast growth factor (bFGF) were examined in peripheral blood of 60 patients with diabetes mellitus type II and soft tissues infections. It was revealed the elevated levels of proinflammatory (IL-6, 8), anti-inflammatory (IL-10) cytokines and basic fibroblast growth factor at the time of admission. Application of combined ozone therapy including ozonated autohemotherapy and superficial management of wounds with ozone-oxygen mixture resulted in significant decrease of IL-6, 8, 10 production and high level of bFGF on blood serum. Thus effective local bactericidal impact of ozone in combination with normalization of proinflammatory cytokines levels and preserved high level of bFGF in peripheral blood provide better results of wound healing process in patients with diabetes mellitus type II. PMID- 26031823 TI - [Analysis of remote results of simultaneous hernioalloplasty and abdominoplasty in patients with postoperative ventral hernias and obesity]. AB - It was performed a comparative research of remote results including local status and life quality of simultaneous surgical treatment in 64 patients with postoperative ventral hernias (W1-W4) and obesity (1-3 degrees). It was compared advanced hernioalloplasty with new synthetic materials including Prolene-Monocryl composite mesh and absorbable adhesion barrier INTERCEED (TC7) in combination with abdominoplasty and hernioalloplasty with the same materials. It was concluded that simultaneous hernioalloplasty and abdominoplasty contributed statistically significant (p < 0.01) decreasing of number of recurrent hernias in 2 times, body mass index and body mass on 24% in comparison with single alloplasty. PMID- 26031824 TI - [Appendicitis is an adaptation disease]. PMID- 26031825 TI - [One-stage surgical treatment of severe closed combined liver trauma]. PMID- 26031826 TI - [Epithelioid hemangioma of inferior vena cava]. PMID- 26031827 TI - Two novel tyrosine-containing peptides (Tyr(4)) of the adipokinetic hormone family in beetles of the families Coccinellidae and Silphidae. AB - Novel members of the adipokinetic hormone family of peptides have been identified from the corpora cardiaca (CC) of two species of beetles representing two families, the Silphidae and the Coccinellidae. A crude CC extract (0.3 gland equivalents) of the burying beetle, Nicrophorus vespilloides, was active in mobilizing trehalose in a heterologous assay using the cockroach Periplaneta americana, whereas the CC extract (0.5 gland equivalents) of the ladybird beetle, Harmonia axyridis, exhibited no hypertrehalosemic activity. Primary sequences of one adipokinetic hormone from each species were elucidated by liquid chromatography coupled to electrospray mass spectrometry (LC-MS). The multiple MS(N) electrospray mass data revealed an octapeptide with an unusual tyrosine residue at position 4 for each species: pGlu-Leu-Thr-Tyr-Ser-Thr-Gly-Trp amide for N. vespilloides (code-named Nicve-AKH) and pGlu-Ile-Asn-Tyr-Ser-Thr-Gly-Trp amide for H. axyridis (code-named Harax-AKH). Assignment of the correct sequences was confirmed by synthesis of the peptides and co-elution in reversed-phase high performance liquid chromatography with fluorescence detection or by LC-MS. Moreover, synthetic peptides were shown to be active in the heterologous cockroach assay system, but Harax-AKH only at a dose of 30 pmol, which explains the negative result with the crude CC extract. It appears that the tyrosine residue at position 4 can be used as a diagnostic feature for certain beetle adipokinetic peptides, because this feature has not been found in another order other than Coleoptera. PMID- 26031828 TI - Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free L-arginine in humans. AB - Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis, whereas L-arginine (Arg) and L-homoarginine (hArg) serve as substrates for NO synthesis. ADMA and other methylated arginines are generally believed to exclusively derive from guanidine (N (G))-methylated arginine residues in proteins by protein arginine methyltransferases (PRMTs) that use S adenosylmethionine (SAM) as the methyl donor. L-Lysine is known for decades as a precursor for hArg, but only recent studies indicate that arginine:glycine amidinotransferase (AGAT) is responsible for the synthesis of hArg. AGAT catalyzes the formation of guanidinoacetate (GAA) that is methylated to creatine by guanidinoacetate methyltransferase (GAMT) which also uses SAM. The aim of the present study was to learn more about the mechanisms of ADMA and hArg formation in humans. Especially, we hypothesized that ADMA is produced by N (G)-methylation of free Arg in addition to the known PRMTs-involving mechanism. In knockout mouse models of AGAT- and GAMT-deficiency, we investigated the contribution of these enzymes to hArg synthesis. Arg infusion (0.5 g/kg, 30 min) in children (n = 11) and ingestion of high-fat protein meals by overweight men (n = 10) were used to study acute effects on ADMA and hArg synthesis. Daily Arg ingestion (10 g) or placebo for 3 or 6 months by patients suffering from peripheral arterial occlusive disease (PAOD, n = 20) or coronary artery disease (CAD, n = 30) was used to study chronic effects of Arg on ADMA synthesis. Mass spectrometric methods were used to measure all biochemical parameters in plasma and urine samples. In mice, AGAT but not GAMT was found to contribute to plasma hArg, while ADMA synthesis was independent of AGAT and GAMT. Arg infusion acutely increased plasma Arg, hArg and ADMA concentrations, but decreased the plasma hArg/ADMA ratio. High-fat protein meals acutely increased plasma Arg, hArg, ADMA concentrations, as well as the plasma hArg/ADMA ratio. In the PAOD and CAD studies, plasma Arg concentration increased in the verum compared to the placebo groups. Plasma ADMA concentration increased only in the PAOD patients who received Arg. Our study suggests that in humans a minor fraction of free Arg is rapidly metabolized to ADMA and hArg. In mice, GAMT and N (G)-methyltransferases contribute to ADMA and hArg synthesis from Arg, whereas AGAT is involved in the synthesis of hArg but not of ADMA. The underlying biochemical mechanisms remain still elusive. PMID- 26031829 TI - Reassuring News for Genetically Tested, Appropriately Treated, Low-Risk LQTS Patients. PMID- 26031830 TI - Next-Generation Therapeutics for IBD. AB - Various novel drugs have recently been evaluated in clinical trials showing promising effects in patients with inflammatory bowel disease (IBD). Here, we summarize the recent literature in the area of emerging therapies in the field of IBD, with specific focus on anti-integrin antibodies, such as vedolizumab (anti alpha4beta7) and etrolizumab (anti-rhuMAb beta7), and the Janus kinase (JAK) inhibitor tofacitinib. Moreover, we will discuss efficacy and safety data of golimumab (a new subcutaneous anti-tumor necrosis factor (TNF) antibody), Avaxia (an orally delivered anti-TNF antibody), and Budesonide MMX; all have been developed for the treatment of ulcerative colitis. Other therapeuticals that might find their way to the market the coming years include the anti-mucosal vascular addressin cell adhesion molecule (MAdCAM) PF-00547659, small molecules (including laquinimod and the CCR9 antagonist Vercirnon), as well as an orally active SMAD7 antisense oligonucleotide that showed clinical benefit in Crohn's disease patients. PMID- 26031831 TI - How can we boost colorectal and hepatocellular cancer screening among underserved populations? AB - Colorectal cancer (CRC) and hepatocellular carcinoma (HCC) are common causes of cancer incidence and mortality in the USA, particularly among underserved populations such as racial/ethnic minorities, the under-/uninsured, and individuals with low socioeconomic status. Although screening can reduce cancer related mortality, participation is suboptimal among underserved populations, likely serving as the largest contributor to observed inequities in HCC and CRC outcomes among US populations. In this narrative review, we highlight inequities across populations in the USA with respect to incidence and mortality for CRC and HCC and highlight potential causes, with a focus on screening rates. In addition, drawing from the recent literature, we highlight promising strategies for increasing screening for HCC and CRC and propose future research and policy solutions to optimize screening rates. With focused implementation of screening strategies and novel research, the burden of HCC and CRC can be reduced among underserved populations. PMID- 26031832 TI - A comprehensive review of noninvasive liver fibrosis tests in pediatric nonalcoholic Fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) and its spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis have been increasing in the pediatric population. The presence and severity of fibrosis in patients with NAFLD are important prognostic factors for the risk of disease progression to cirrhosis. The gold standard for staging liver fibrosis is a liver biopsy. However, given the risks of this procedure, especially in the pediatric population, the development of noninvasive markers to diagnose and monitor progression of NAFLD is desirable. This paper will review recently developed noninvasive methods for diagnosing liver fibrosis in children with NAFLD. These include simple fibrosis scores, advanced biochemical markers, and radiologic imaging studies. Simple fibrosis scores use readily available laboratory tests; available one include AST/ALT ratio, AST to platelet ratio index (APRI), fibrosis (FIB)-4 index, NAFLD fibrosis score (NFS), pediatric NAFLD fibrosis index (PNFI), and pediatric NALFD fibrosis score (PNFS). Advanced biochemical markers include biomarkers of hepatocyte cell death such as cytokeratin 18 fragment levels, and markers of extracellular matrix turnover such as the Enhanced Liver Fibrosis (ELF) test and hyaluronic acid. Radiologic imaging studies estimate liver stiffness as a surrogate for liver fibrosis; these include transient elastography (TE), magnetic resonance elastography (MRE), and acoustic radiation force impulse imaging (ARFI). PMID- 26031833 TI - Psychometric properties and feasibility of the Swedish version of the Philadelphia Geriatric Center Morale Scale. AB - PURPOSE: Morale is related to psychological well-being and quality of life in older people. The Philadelphia Geriatric Center Morale Scale (PGCMS) is widely used to assess morale. The purpose of this study was to evaluate the psychometric properties and feasibility of the Swedish version of the 17-item PGCMS among very old people. METHODS: The Umea 85+/GERDA study included Swedish-speaking people aged 85, 90 and 95 years and older, from Sweden and Finland. Participants were interviewed in their own homes using a predefined set of questions. In the main sample, 493 individuals answered all 17 PGCMS items (aged 89.0 +/- 4.3 years). Another 105 answered between 1 and 16 questions (aged 89.6 +/- 4.4 years). A convenience sample was also collected, and 54 individuals answered all 17 PGCMS items twice (aged 84.7 +/- 6.7 years). The same assessor restated the questions within 1 week. RESULTS: Cronbach's alpha was 0.74 among those who answered all 17 questions in the main sample. Confirmatory factor analysis was used to test the construct validity of the most widely used version of the PGCMS, with 17 items and three factors, and showed a generally good fit. Among those answering between 1 and 17 PGCMS questions, 92.6 % (554/598) answered 16 or 17. The convenience sample was used for intra-rater test-retesting, and the intraclass correlation coefficient (ICC) was 0.89. The least significant change between two assessments, with 95 % confidence interval, was 3.53 PGCMS points. CONCLUSION: The Swedish version of the PGCMS seems to have satisfactory psychometric properties and feasibility among very old people. PMID- 26031834 TI - Transflip mutations produce deletions in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is driven by the inactivation of the tumor suppressor genes (TSGs), CDKN2A (P16) and SMAD4 (DPC4), commonly by homozygous deletions (HDs). Using a combination of high density single-nucleotide polymorphism (SNP) microarray and whole genome sequencing (WGS), we fine-mapped novel breakpoints surrounding deletions of CDKN2A and SMAD4 and characterized them by their underlying structural variants (SVs). Only one third of CDKN2A and SMAD4 deletions (6 of 18) were simple interstitial deletions, rather, the majority of deletions were caused by complex rearrangements, specifically, a translocation on one side of the TSG in combination with an inversion on the other side. We designate these as "TransFlip" mutations. Characteristics of TransFlip mutations are: (1) a propensity to target the TSGs CDKN2A and SMAD4 (P < 0.005), (2) not present in the germline of the examined samples, (3) non recurrent breakpoints, (4) relatively small (47 bp to 3.4 kb) inversions, (5) inversions can be either telomeric or centromeric to the TSG, and (6) non reciprocal, and non-recurrent translocations. TransFlip mutations are novel complex genomic rearrangements with unique breakpoint signatures in pancreatic cancer. We hypothesize that they are a common but poorly understood mechanism of TSG inactivation in human cancer. (c) 2015 Wiley Periodicals, Inc. PMID- 26031835 TI - Class I and II histone deacetylase expression in human chronic periodontitis gingival tissue. AB - BACKGROUND AND OBJECTIVE: Histone deacetylase inhibitors (HDACi) are being considered to treat chronic inflammatory diseases at low doses. Currently HDACi that are more specific are being developed to target particular HDACs; therefore, this study aimed to determine levels and distribution of class I and II HDAC in human gingival samples obtained from patients with chronic periodontitis. MATERIAL AND METHODS: Gingival biopsies were obtained from patients with and without (mild inflammation, no bone loss) periodontitis. Total RNA was isolated for real-time quantitative polymerase chain reaction to determine expression of HDACs 1-10. Immunohistochemistry was used to determine protein distribution of HDACs 1, 5, 8 and 9. Factor VIII, CD3 and tartrate resistant acid phosphatase (TRAP) were detected in serial sections to identify blood vessels, lymphocytes, pre-osteoclasts and osteoclasts cells respectively. Tumour necrosis factor alpha (TNF-alpha) expression was also assessed. RESULTS: mRNA for HDAC 1, 5, 8 and 9 were significantly upregulated in chronic periodontitis gingival tissues compared to non-periodontitis samples (p < 0.05). Significantly higher HDAC 1 protein expression was observed in chronic periodontitis samples (p < 0.05), and was associated with CD3, TRAP and TNF-alpha-positive cells. HDAC 1, 5, 8 and 9 were expressed strongly by the factor VIII-positive microvasculature in the chronic periodontitis gingival tissues. CONCLUSIONS: HDAC 1, 5, 8 and 9 expression was higher in gingival tissues from patients with chronic periodontitis compared to non-periodontitis samples. Results suggest that these HDACs could therefore be targeted with specific acting HDACi. PMID- 26031836 TI - Metabolic profiling reveals ethylene mediated metabolic changes and a coordinated adaptive mechanism of 'Jonagold' apple to low oxygen stress. AB - Apples are predominantly stored in controlled atmosphere (CA) storage to delay ripening and prolong their storage life. Profiling the dynamics of metabolic changes during ripening and CA storage is vital for understanding the governing molecular mechanism. In this study, the dynamics of the primary metabolism of 'Jonagold' apples during ripening in regular air (RA) storage and initiation of CA storage was profiled. 1-Methylcyclopropene (1-MCP) was exploited to block ethylene receptors and to get insight into ethylene mediated metabolic changes during ripening of the fruit and in response to hypoxic stress. Metabolic changes were quantified in glycolysis, the tricarboxylic acid (TCA) cycle, the Yang cycle and synthesis of the main amino acids branching from these metabolic pathways. Partial least square discriminant analysis of the metabolic profiles of 1-MCP treated and control apples revealed a metabolic divergence in ethylene, organic acid, sugar and amino acid metabolism. During RA storage at 18 degrees C, most amino acids were higher in 1-MCP treated apples, whereas 1-aminocyclopropane-1 carboxylic acid (ACC) was higher in the control apples. The initial response of the fruit to CA initiation was accompanied by an increase of alanine, succinate and glutamate, but a decline in aspartate. Furthermore, alanine and succinate accumulated to higher levels in control apples than 1-MCP treated apples. The observed metabolic changes in these interlinked metabolites may indicate a coordinated adaptive strategy to maximize energy production. PMID- 26031837 TI - Income gradients in oral health according to child age. AB - This study aimed to confirm whether the well-known income disparities in oral health seen over the life course are indeed absent in 9- to 11-yr-old children, and to explore the role of access to dental care in explaining the age-profile of the income gradient in child oral health. We used data from the 2007 United States National Survey of Children's Health. Income gradients in parental reports of children's decayed teeth or cavities, toothache, broken teeth, bleeding gums, and fair/poor condition of teeth were assessed in stratified analyses according to age of child (1-5, 6-8, 9-11, 12-14, and 15-17 yr), using survey logistic regression to control for family-, parental-, and child-level covariates. Health insurance status and use of preventive dental care were the indicators for children's access to dental care. The adjusted ORs for the effect of family income on having decayed teeth or cavities, toothache, and fair/poor condition of teeth were not significant in 9- to 11-yr-old children. Different age-patterns were found for broken teeth and bleeding gums. The attenuation of the income gradients in having decayed teeth or cavities, toothache, and fair/poor condition of teeth, previously seen in 9- to 11-yr-old children, was also seen in 15- to 17 , 12- to 14-, and 6- to 8-yr-old children, respectively, after controlling for children's access to dental care. This study supports the attenuation of income inequalities in oral health in 9- to 11-yr-old children. Access to dental care could attenuate income gradients in oral health in other age groups. PMID- 26031839 TI - Phaseolin expression in tobacco chloroplast reveals an autoregulatory mechanism in heterologous protein translation. AB - Plastid DNA engineering is a well-established research area of plant biotechnology, and plastid transgenes often give high expression levels. However, it is still almost impossible to predict the accumulation rate of heterologous protein in transplastomic plants, and there are many cases of unsuccessful transgene expression. Chloroplasts regulate their proteome at the post transcriptional level, mainly through translation control. One of the mechanisms to modulate the translation has been described in plant chloroplasts for the chloroplast-encoded subunits of multiprotein complexes, and the autoregulation of the translation initiation of these subunits depends on the availability of their assembly partners [control by epistasy of synthesis (CES)]. In Chlamydomonas reinhardtii, autoregulation of endogenous proteins recruited in the assembly of functional complexes has also been reported. In this study, we revealed a self regulation mechanism triggered by the accumulation of a soluble recombinant protein, phaseolin, in the stroma of chloroplast-transformed tobacco plants. Immunoblotting experiments showed that phaseolin could avoid this self-regulation mechanism when targeted to the thylakoids in transplastomic plants. To inhibit the thylakoid-targeted phaseolin translation as well, this protein was expressed in the presence of a nuclear version of the phaseolin gene with a transit peptide. Pulse-chase and polysome analysis revealed that phaseolin mRNA translation on plastid ribosomes was repressed due to the accumulation in the stroma of the same soluble polypeptide imported from the cytosol. We suggest that translation autoregulation in chloroplast is not limited to heteromeric protein subunits but also involves at least some of the foreign soluble recombinant proteins, leading to the inhibition of plastome-encoded transgene expression in chloroplast. PMID- 26031838 TI - Current Methods for Automated Filtering of Multiple Sequence Alignments Frequently Worsen Single-Gene Phylogenetic Inference. AB - Phylogenetic inference is generally performed on the basis of multiple sequence alignments (MSA). Because errors in an alignment can lead to errors in tree estimation, there is a strong interest in identifying and removing unreliable parts of the alignment. In recent years several automated filtering approaches have been proposed, but despite their popularity, a systematic and comprehensive comparison of different alignment filtering methods on real data has been lacking. Here, we extend and apply recently introduced phylogenetic tests of alignment accuracy on a large number of gene families and contrast the performance of unfiltered versus filtered alignments in the context of single gene phylogeny reconstruction. Based on multiple genome-wide empirical and simulated data sets, we show that the trees obtained from filtered MSAs are on average worse than those obtained from unfiltered MSAs. Furthermore, alignment filtering often leads to an increase in the proportion of well-supported branches that are actually wrong. We confirm that our findings hold for a wide range of parameters and methods. Although our results suggest that light filtering (up to 20% of alignment positions) has little impact on tree accuracy and may save some computation time, contrary to widespread practice, we do not generally recommend the use of current alignment filtering methods for phylogenetic inference. By providing a way to rigorously and systematically measure the impact of filtering on alignments, the methodology set forth here will guide the development of better filtering algorithms. PMID- 26031840 TI - Pregabalin enhances the antinociceptive effect of oxycodone and morphine in thermal models of nociception in the rat without any pharmacokinetic interactions. AB - BACKGROUND: Oxycodone is increasingly being used in combination with pregabalin. Pregabalin use is prevalent in opioid-dependent individuals. A high number of deaths caused by the co-use of gabapentinoids and opioids occur. It is not known whether pregabalin affects concentrations of oxycodone or morphine in the central nervous system. METHODS: Effects of pregabalin on acute oxycodone or morphine induced antinociception, tolerance and sedation were studied using tail-flick, hot plate and rotarod tests in male Sprague-Dawley rats. Concentrations of pregabalin, opioids and their major metabolites in the brain were quantified by mass spectrometry. RESULTS: In the hot plate test, morphine (2.5 mg/kg, s.c.) caused antinociception of 28% maximum possible effect (MPE), whereas pregabalin (50 mg/kg, i.p.) produced 8-10% MPE. Co-administration of pregabalin and morphine resulted in antinociception of 63% MPE. Oxycodone (0.6 mg/kg s.c.) produced antinociception of 18% MPE, which increased to 39% MPE after co-administration with pregabalin. When pregabalin 10 mg/kg was administered before oxycodone (0.6 mg/kg, s.c.) or morphine (2.5 mg/kg), only the effect of oxycodone was potentiated in the tail-flick and the hot plate tests. Brain concentrations of the opioids, their major metabolites and pregabalin were unchanged. Pregabalin co administration (50 mg/kg, i.p., once daily) did not prevent the development of morphine tolerance. CONCLUSIONS: Pregabalin potentiated antinociceptive and sedative effects of oxycodone and morphine in acute nociception. Co administration of pregabalin with the opioids did not affect the brain concentrations of oxycodone or morphine. Pregabalin did not prevent morphine tolerance. PMID- 26031841 TI - Executive dysfunction and balance function post-stroke: A cross-sectional study. AB - OBJECTIVES: This study investigated the: (1) prevalence of executive dysfunction (ED); (2) demographic and clinical differences between participants with ED and without ED and; (3) independent association between executive function (EF) and balance post-stroke. DESIGN: Prospective observational cross-sectional study. SETTING: Four large acute hospitals. PARTICIPANTS: Convenience sample of people with first stroke. MAIN OUTCOME: Balance function. SECONDARY OUTCOMES: EF, stroke severity, depression and global cognition. METHODS: Descriptive statistics were used to report the prevalence of ED post-stroke. Comparisons of demographic and clinical characteristics were made between participants with ED and participants without ED using independent t-tests. Hierarchical multiple linear regression analysis determined the association between EF and balance post-stroke. RESULTS: Participant (n=100) age ranged from 31 to 98 years, time since stroke ranged from 4 to 180 days and the participants reported formal education ranging from 7 to 21 years. Participants with ED had more severe strokes (BADS) [median (IQR) vs. median (IQR), p-value] [(44 (16) vs. (51 (7), p<0.01], poorer global cognition [24 (6) vs. 29 (2), p<0.01] and poorer balance [29 (40) vs. 46.5 (17), p<0.01] in comparison with participants without ED. Age (beta=-0.24, p<0.05), years in education, (beta=-0.21, p<0.05), stroke severity (beta=0.71, p<0.01), time since stroke, (beta=-0.17, p<0.01) and EF (beta=0.19, p<0.05) were independently associated with balance post-stroke. The total variance in balance explained by the model was 72%. CONCLUSIONS: ED is independently associated with balance post stroke. Physiotherapists should consider this when developing rehabilitation strategies to improve balance post-stroke. PMID- 26031842 TI - Tumor vascular targeted liposomal-bortezomib minimizes side effects and increases therapeutic activity in human neuroblastoma. AB - Neuroblastoma is a childhood cancer with poor long-term prognosis in advanced stages. A major aim in neuroblastoma therapy is to develop targeted drug delivery systems to ameliorate drug therapeutic index and efficacy. In this study, a novel bortezomib (BTZ) liposomal formulation was set-up and characterized. Since BTZ is freely permeable across the lipidic bilayer, an amino-lactose (LM) was synthesized as complexing agent to entrap BTZ inside the internal aqueous compartment of stealth liposomes. High encapsulation efficiency was achieved by a loading method based on the formation of boronic esters between the boronic acid moiety of BTZ and the hydroxyl groups of LM. Next, NGR peptides were linked to the liposome surface as a targeting-ligand for the tumor endothelial cell marker, aminopeptidase N. Liposomes were characterized for size, Z-potential, polydispersity index, drug content, and release. Lyophilization in the presence of cryoprotectants (trehalose, sucrose) was also examined in terms of particle size changes and drug leakage. BTZ was successfully loaded into non-targeted (SL[LM-BTZ]) and targeted (NGR-SL[LM-BTZ]) liposomes with an entrapment efficiency of about 68% and 57%, respectively. These nanoparticles were suitable for intravenous administration, presenting an average diameter of 170nm and narrow polydispersity. Therefore, orthotopic NB-bearing mice were treated with 1.0 or 1.5mg/kg of BTZ, either in free form or encapsulated into liposomes. BTZ loaded liposomes showed a significant reduction of drug systemic adverse effects with respect to free drug, even at the highest dose tested. Moreover, mice treated with 1.5mg/kg of NGR-SL[LM-BTZ] lived statistically longer than untreated mice (P=0.0018) and SL[LM-BTZ]-treated mice (P=0.0256). Our results demonstrate that the novel vascular targeted BTZ formulation is endowed with high therapeutic index and low toxicity, providing a new tool for future applications in neuroblastoma clinical studies. PMID- 26031844 TI - Treatment of lipoid proteinosis with ablative Er:YAG laser resurfacing. AB - Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis characterized by deposition of amorphous hyaline material in different parts of the body, especially the skin and mucous membranes. Disfiguring lesions predominantly affect facial appearance. There is no curative therapy and treatment options are limited to symptomatic approaches. Facial disfigurement in this disease may have an huge negative effect on the patients' psychology and quality of life. With this regard, the patients may benefit very much from symptomatic treatments. Four patients with LP were treated with Er:YAG laser to ablate disfiguring lesions on the face. Patients were followed up for 14 months to 2 years. We obtained favorable clinical and aesthetic results in all cases with Er:YAG laser treatment and did not observe any recurrences during the follow up. Depending on our observations Er-YAG laser can be accepted as an effective tool for dermal accumulations and scars of LP with precise ablation capability and favorable esthetic results. PMID- 26031843 TI - Systematic in vitro toxicological screening of gold nanoparticles designed for nanomedicine applications. AB - Gold nanoparticles (AuNP) are increasingly being applied in the biomedical field as therapeutics, contrast agents, and in diagnostic systems, motivating investigations of their toxicity that might arise from accidental exposure. While other work has investigated the toxicological response to gold nanoparticles for industrial purposes, here we have surveyed formulations that have been developed for biomedical use, are in clinical trials or have been FDA-approved. The AuNP library tested contains a range of shapes, including spheres, rods and shells, that possess a range of coatings, such as silica, citrate, lipoprotein, polymaleic acid, polyethylene glycol, DNA and others. Good cytocompatibility for all formulations was observed after 1 h of incubation. However after 24 h exposure, a nanorod and a spherical DNA coated formulation resulted in toxicity. The coating material was the only factor that influenced toxicity. AuNP exposure seemed to have no effect on cell cytoskeleton deformation and cell spreading. Cell uptake, as measured by computed tomography and ICP-OES, as well as TEM images of cells, confirmed strong AuNP uptake for certain formulations, but there was no correlation with toxicity. No glove translocation occurred, therefore, nitrile gloves are an adequate safety precaution for working with the AuNP studied. In conclusion, the majority of AuNP formulations tested have very low adverse effects. PMID- 26031845 TI - Inattentional blindness is influenced by exposure time not motion speed. AB - Inattentional blindness is a striking phenomenon in which a salient object within the visual field goes unnoticed because it is unexpected, and attention is focused elsewhere. Several attributes of the unexpected object, such as size and animacy, have been shown to influence the probability of inattentional blindness. At present it is unclear whether or how the speed of a moving unexpected object influences inattentional blindness. We demonstrated that inattentional blindness rates are considerably lower if the unexpected object moves more slowly, suggesting that it is the mere exposure time of the object rather than a higher saliency potentially induced by higher speed that determines the likelihood of its detection. Alternative explanations could be ruled out: The effect is not based on a pop-out effect arising from different motion speeds in relation to the primary-task stimuli (Experiment 2), nor is it based on a higher saliency of slow moving unexpected objects (Experiment 3). PMID- 26031846 TI - The Mycobacterium tuberculosis protein pair PE9 (Rv1088)-PE10 (Rv1089) forms heterodimers and induces macrophage apoptosis through Toll-like receptor 4. AB - Toll-like receptor (TLR)-mediated interactions of Mycobacterium tuberculosis (M. tb) with macrophages are major determinant in the outcome of innate immune defence and subsequent adaptive immune responses. Here we report a novel interaction of the M. tb protein pair PE9 (Rv1088)-PE10 (Rv1089) with the macrophage TLR4 leading to apoptosis and modulation of cytokine levels. We demonstrate that the two proteins physically interact, and that PE9 is required for the cell wall localization of PE10 in Mycobacterium smegmatis. Interaction of the PE9-PE10 complex with TLR4 in THP-1 macrophages was associated with increased levels of phospho-IRF-3, which correlated with an increase in transcript levels of its target gene interferon-beta. THP-1 macrophages treated with PE9-PE10 complex showed multiple hallmarks of apoptosis and modulation of interleukin (IL) 1b and IL-10 levels. All of these effects were abrogated when cells were treated either with an antibody to PE10 or an anti-TLR4 antibody, indicating that the complex specifically interacts with TLR4 through PE10, establishing this protein pair as a TLR4 ligand. This novel observation of two proline-glutamate (PE) proteins forming functional heterodimers represents a considerable expansion of the PE_PPE repertoire in the context of receptor engagement and the concomitant modulation of host responses by this unique class of proteins. PMID- 26031848 TI - Vagotomy and subsequent risk of Parkinson's disease. AB - OBJECTIVE: Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. We investigated the risk of PD in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect, whereas superselective vagotomy has a minor effect. METHODS: We constructed cohorts of all patients in Denmark who underwent vagotomy during 1977-1995 and a matched general population cohort by linking Danish registries. We used Cox regression to compute hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Risk of PD was decreased in patients who underwent truncal (HR = 0.85; 95% CI = 0.56-1.27; follow-up of >20 years: HR = 0.58; 95% CI: 0.28-1.20) compared to superselective vagotomy. Risk of PD was also decreased after truncal vagotomy when compared to the general population cohort (overall adjusted HR = 0.85; 95% CI: 0.63-1.14; follow-up >20 years, adjusted HR = 0.53; 95% CI: 0.28-0.99). In patients who underwent superselective vagotomy, risk of PD was similar to the general population (HR = 1.09; 95% CI: 0.84-1.43; follow-up of >20 years: HR = 1.16; 95% CI: 0.80-1.70). Statistical precision of risk estimates was limited. Results were consistent after external adjustment for unmeasured confounding by smoking. INTERPRETATION: Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD. PMID- 26031847 TI - The Swiss National Registry for Primary Immunodeficiencies: report on the first 6 years' activity from 2008 to 2014. AB - The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care of patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymized clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of 348 patients are registered in Switzerland, indicating an estimated minimal prevalence of 4.2 patients per 100 000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19 091 registered patients: 'predominantly antibody disorders' are the most common diseases observed (n = 217/348, 62%), followed by 'phagocytic disorders' (n = 31/348, 9%). As expected, 'predominantly antibody disorders' are more prevalent in adults than in children (78 versus 31%). Within this category, 'common variable immunodeficiency disorder' (CVID) is the most prevalent PID (n = 98/217, 45%), followed by 'other hypogammaglobulinaemias' (i.e. a group of non-classified hypogammaglobulinaemias) (n = 54/217, 25%). Among 'phagocytic disorders', 'chronic granulomatous disease' is the most prevalent PID (n = 27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high, with a median of 6 years for CVID and more than 3 years for 'other hypogammaglobulinaemias'. PMID- 26031849 TI - Direct competitive chemiluminescence immunoassays based on gold-coated magnetic particles for detection of chloramphenicol. AB - Direct competitive chemiluminescence immunoassays (CLIA) based on gold-coated magnetic nanospheres (Au-MNPs) were developed for rapid analysis of chloramphenicol (CAP). The Au-MNPs were modified with carboxyl groups and amino groups by 11-mercaptoundecanoic acid (MUA) and cysteamine respectively, and then were respectively conjugated with CAP base and CAP succinate via an activating reaction using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). NSP-DMAE-NHS, a new and effective luminescence reagent, was employed to label anti-CAP antibody (mAb) as a tracer in direct CLIA for CAP detection using a 'homemade' luminescent measurement system that was set up with a photomultiplier tube (PMT) and a photon counting unit linked to a computer. The sensitivities and limits of detection (LODs) of the two methods were obtained and compared according to the inhibition curves. The 50% inhibition concentration (IC50 ) values of the two methods were about 0.044 ng/mL and 0.072 ng/mL respectively and LODs were approximately 0.001 ng/mL and 0.006 ng/mL respectively. To our knowledge, they were much more sensitive than any traditional enzyme-linked immunosorbent assay (ELISA) ever reported. Moreover, the new luminescence reagent NSP-DMAE-NHS is much more sensitive and stable than luminol and its derivatives, contributing to the sensitivity enhancement. PMID- 26031850 TI - Consent for third molar tooth extractions in Australia and New Zealand: a review of current practice. AB - BACKGROUND: Informed consent is the legal requirement to educate a patient about a proposed medical treatment or procedure so that he or she can make informed decisions. The purpose of the study was to examine the current practice for obtaining informed consent for third molar tooth extractions (wisdom teeth) by oral and maxillofacial surgeons in Australia and New Zealand. METHODS: An online survey was sent to 180 consultant oral and maxillofacial surgeons in Australia and New Zealand. Surgeons were asked to answer (yes/no) whether they routinely warned of a specific risk of third molar tooth extraction in their written consent. RESULTS: Seventy-one replies were received (39%). The only risks that surgeons agreed should be routinely included in written consent were a general warning of infection (not alveolar osteitis), inferior alveolar nerve damage (temporary and permanent) and lingual nerve damage (temporary and permanent). CONCLUSIONS: There is significant variability among Australian and New Zealand oral and maxillofacial surgeons regarding risk disclosure for third molar tooth extractions. We aim to improve consistency in consent for third molar extractions by developing an evidence-based consent form. PMID- 26031851 TI - Arthroscopic Evaluation of Impingement and Osteochondral Lesions in Chronic Lateral Ankle Instability. AB - BACKGROUND: Anterolateral impingement associated with intra-articular synovitis, scarring, and fibrosis is a less recognized feature in patients with chronic lateral ankle instability. The aim of our study was to ascertain the incidence of intra-articular synovitis, osteochondral lesions (OCLs), impingement lesions (both intra- and extra-articular), and other associated pathologies in patients undergoing modified Brostrom-Gould ankle ligament reconstruction. METHODS: We performed a retrospective review of all patients who underwent arthroscopically assisted modified Brostrom-Gould ankle ligament reconstruction for symptomatic recurrent ankle instability. Patients who had previous ankle surgery or inflammatory arthropathy were excluded. Ankle arthroscopy was performed prior to reconstruction in all patients. Data were obtained from clinical and radiological records including magnetic resonance imaging scans. Arthroscopic findings were recorded in detail intraoperatively. A total of 100 patients (53 females and 47 males) with an average age of 37 years (range, 15-65 years) were reviewed over a 10-year period. RESULTS: Sixty-three patients (63%) had intra-articular synovitis mostly in the anterior and/or anterolateral compartment, which required arthroscopic debridement. Seventeen patients (17%) were found to have OCLs, and 12 (12%) patients had anterior bony impingement lesions. CONCLUSION: This study found a high incidence of anterior/anterolateral synovitis in patients with chronic lateral ankle instability. However, there was a relatively low incidence of anterior bony impingement lesions or OCLs in our series. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26031852 TI - Beaming for Charcot Foot Reconstruction. AB - Charcot arthropathy commonly affects the midfoot and is often an extremely difficult and challenging surgical problem. Operative treatment with medial column arthrodesis using large intramedullary bolts or screws is an evolving and increasingly popular technique called "beaming." The technique is described here. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 26031853 TI - Role of peroxisome proliferator-activated receptor alpha in the expression of hepatic fatty acid oxidation-related genes in chickens. AB - Liver is the most important target organ for investigation of lipid metabolism in domestic fowls. However, little is known about the regulatory mechanism of fatty acid oxidation in chicken liver. In mammals, proliferator-activated receptor alpha (PPARalpha), a transcription factor, plays an essential role in the regulation of hepatic fatty acid oxidation. The aim of the present study was to investigate the regulatory mechanisms of PPARalpha-induced gene expression involved in hepatic fatty acid oxidation in chickens in vivo and in vitro. WY14643, a PPARalpha agonist, significantly increased the messenger RNA (mRNA) levels of carnitine palmitoyltransferase 1a (CPT1a) and acyl-coenzyme A oxidase (ACO), but not long-, middle- and short-chain acyl-coenzyme A dehydrogenase (LCAD, MCAD and SCAD, respectively), hydroxyacyl-coenzyme A dehydrogenase (HAD), and PPARalpha itself in chicken hepatoma cells. In contrast, WY14643 significantly increased the mRNA levels of CPT1a, ACO, MCAD, SCAD, HAD and PPARalpha in human hepatoma cells. The mRNA levels of CPT1a and ACO in the liver were significantly increased by 6 h of fasting in chickens, whereas the mRNA levels of LCAD, MCAD, SCAD and HAD were unchanged. These results suggest that, unlike in mammals, CPT1a and ACO might play an important role in PPARalpha induced fatty acid oxidation in the liver of chickens. PMID- 26031854 TI - [Ganglion block. Celiac plexus neurolysis]. AB - BACKGROUND: Pain originating from the organs of the upper abdomen, especially in patients suffering from inoperable carcinoma of the pancreas or advanced inflammatory conditions, is difficult to treat in a significant number of patients. STANDARD RADIOLOGICAL PROCEDURES: Computed tomography (CT) guided neurolysis is the most commonly used technique for neurolysis of the celiac plexus. Ethanol is used to destroy the nociceptive fibers passing through the plexus and provides an effective means of diminishing pain arising from the upper abdomen. METHODS: Using either an anterior or posterior approach, a 22 G Chiba needle is advanced to the antecrural space and neurolysis is achieved by injecting a volume of 20-50 ml of ethanol together with a local anesthetic and contrast medium. PERFORMANCE: In up to 80% of patients suffering from tumors of the upper abdomen, CT-guided celiac plexus neurolysis diminishes pain or allows a reduction of analgesic medication; however, in some patients the effect may only be temporary necessitating a second intervention. In inflammatory conditions, celiac neurolysis is often less effective in reducing abdominal pain. PRACTICAL RECOMMENDATIONS: The CT-guided procedure for neurolysis of the celiac plexus is safe and effective in diminishing pain especially in patients suffering from tumors of the upper abdomen. The procedure can be repeated if the effect is only temporary. PMID- 26031856 TI - [Multifocal hypodense space-occupying lesions in both kidneys]. PMID- 26031855 TI - [Osteoidosteoma. From diagnosis to treatment]. AB - An osteoid osteoma is a benign bone-forming tumor which usually presents in childhood and adolescence and is characterized by extensive nocturnal pain. Computed tomography (CT) is used to reveal the typical radiolucent nidus surrounded by a sclerotic reaction and in magnetic resonance imaging (MRI) a nidal enhancement and perifocal edema can confirm the diagnosis. Having shown excellent success rates radiofrequency ablation has become the treatment of choice which allows minimally invasive and precise destruction of nidal tumor tissue. By using thermal protection techniques and multiple ablation positions successful therapy of perineural tumors and niduses with diameters of more than 2 cm are possible. PMID- 26031857 TI - Nurses' perceptions of working with families in the paediatric intensive care unit. AB - BACKGROUND: Research exploring nurses' experiences working with families in paediatric intensive care unit (PICU) is limited. No studies have been undertaken in a mixed adult-paediatric ICU. OBJECTIVES: To explore nurses' perceptions of working with families of critically ill children in a mixed adult-paediatric intensive care unit (ICU). DESIGN: Descriptive qualitative design. METHODOLOGY: Five PICU nurses participated in semi-structured interviews. Data were analysed using thematic analysis. Trustworthiness was enhanced using an audit trail, member checks and peer review of all data. RESULTS: Three main themes and one overarching theme emerged. Role confusion and delineation examined the roles which nurses ascribed to themselves and the families; and demonstrated the conflict which could arise if roles were challenged. Information sharing demonstrated the positive and negative ways in which nurses utilized information with families in their daily practice. The contextual environment of the PICU scrutinized the physical, cultural and institutional factors which impacted on the nurses' ability to work with families in the PICU. Finally, the overarching theme Competing values explores the interplay between the nurses' personal values and those of the PICU and the institution. CONCLUSIONS: Working with families in a mixed adult-paediatric ICU is influenced by multiple personal and institutional factors. The value placed on families and on the time nurses spent with them often competed for priority with nurses' other values and the wider culture of the PICU. The potential for role confusion, the management of information and the physical environment of the PICU further contributed to variability in nurses' working with families. RELEVANCE TO CLINICAL PRACTICE: The results highlighted a need for education for both nurses and medical staff who work with families of critically ill children. Additionally, the need for each PICU to have a written policy on family presence and participation is crucial to guide practice and maintain continuity of care. PMID- 26031858 TI - Extraordinary Changes in the Electronic Structure and Properties of CdS and ZnS by Anionic Substitution: Cosubstitution of P and Cl in Place of S. AB - Unlike cation substitution, anion substitution in inorganic materials such as metal oxides and sulfides would be expected to bring about major changes in the electronic structure and properties. In order to explore this important aspect, we have carried out first-principles DFT calculations to determine the effects of substitution of P and Cl on the properties of CdS and ZnS in hexagonal and cubic structures and show that a sub-band of the trivalent phosphorus with strong bonding with the cation appears in the gap just above the valence band, causing a reduction in the gap and enhancement of dielectric properties. Experimentally, it has been possible to substitute P and Cl in hexagonal CdS and ZnS. The doping reduces the band gap significantly as predicted by theory. A similar decrease in the band gap is observed in N and F co-substituted in cubic ZnS. Such anionic substitution helps to improve hydrogen evolution from CdS semiconductor structures and may give rise to other applications as well. PMID- 26031859 TI - Capsule reading is resources consuming. How can we make the best of it? PMID- 26031860 TI - Obscure gastrointestinal bleeding: Which factors are associated with positive capsule endoscopy findings? AB - BACKGROUND: Capsule endoscopy is a first line examination to evaluate obscure gastrointestinal bleeding. The identification of factors associated with the detection of lesions by capsule endoscopy could improve resource utilization and patient selection. OBJECTIVES: To identify factors associated with positive capsule endoscopy findings in patients with obscure gastrointestinal bleeding. METHODS: Retrospective, single-center study, including 203 patients (214 capsule endoscopy procedures) submitted to capsule endoscopy in the setting of obscure gastrointestinal bleeding. Type of obscure gastrointestinal bleeding, number of units of packed red blood cells transfused, type of positive finding, number of endoscopy studies performed prior to capsule endoscopy, comorbidities, medication and Charlson index were evaluated. Overt bleeding was subdivided into ongoing and previous gastrointestinal bleeding. Only lesions with high hemorrhagic potential (P2) were classified as positive findings. RESULTS: The mean age was 62.2 years and 59.7% of patients were female. Most patients were referred for occult gastrointestinal bleeding (64.5%), while 35.5% were referred for overt gastrointestinal bleeding (63.2% previous-overt gastrointestinal bleeding). The most frequent positive findings included ulcers/ erosions (34%) and angioectasias (32%). In univariate analysis, the identification of positive findings was significantly higher in those with ongoing-overt bleeding (p < 0.001), advanced age (p =0.003), increasing number of pre-capsule endoscopies (p < 0.001), increasing transfusion requirements (p < 0.001), moderate/severe renal disease (p = 0.009) and antiplatelet drugs (p = 0.021) and NSAID intake (p = 0.005). In multivariate analysis, positive findings were significantly higher only in those with ongoing-overt bleeding (odds ratio [OR] 18.68, 95% confidence interval [CI] 3.98-85.6, p < 0.001), higher transfusion requirements (OR 1.23, 95% CI 1.1-1.4, p < 0.001) and NSAID intake (OR 5.9, 95% CI 2.1-17.3, p = 0.001). CONCLUSIONS: Capsule endoscopy should be used early in obscure gastrointestinal bleeding. Ongoing-overt bleeding, higher transfusion requirements and NSAIDs intake were associated with positive findings on capsule endoscopy. PMID- 26031861 TI - Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: An analysis of 500 cases. AB - BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the analmargin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016). PMID- 26031862 TI - Drug consumption and additional risk factors associated with microscopic colitis: Case-control study. AB - BACKGROUND: Microscopic colitis has now emerged as a common cause of chronic diarrhoea, but its aetiology remains unknown. Some studies suggest that commonly prescribed drugs and other additional risk factors may be triggers. AIMS: To evaluate the effects of drug intake and other risk factors on microscopic colitis patients. METHODS: A prospective, case-control study with all consecutive adult patients referred to the Hospital General de Tomelloso (Ciudad Real, Spain) for chronic watery diarrhoea (from 2008 to 2011) was performed. Microscopic colitis was diagnosed following the commonly accepted histopathological criteria. RESULTS: 46 consecutive new cases of microscopic colitis and 317 chronic diarrhoea controls were recruited. Five independent risk factors significantly associated with microscopic colitis were identified: Abdominal pain (OR 3.25; 95%CI, 1.49-7.08), weight loss (OR 2.67; 95%CI, 1.16-6.15), celiac disease (OR 15.3; 95%CI, 3.70-63.5), topiramate intake (OR 13.6; 95%CI, 1.84- 100.8), and older age at diagnosis (OR 1 year increase 1.022; 95%CI, 1.002-1.042). Use of non steroidal anti-inflammatory drugs was associated with microscopic colitis in the subgroup of patients who fulfilled irritable bowel syndrome criteria (38.5% vs. 10.8%; p < 0.017). CONCLUSIONS: Microscopic colitis is associated with autoimmune disease, an increased age at diagnosis, topiramate intake and only in a sub-group of irritable bowel disease patients with non-steroidal anti-inflammatory drugs. PMID- 26031863 TI - Normal values for water-perfused esophageal high-resolution manometry. AB - BACKGROUND: Normal values for water-perfused esophageal high-resolution manometry have still not been established in our environment, despite its generalized use and the recommendation to determine reference values for each Motility Unit based on their equipment. Normal values established with solid-state highresolution manometry are currently being used as reference values for water-perfused high resolution manometry. OBJECTIVES: To obtain normal values for water-perfused esophageal high-resolution manometry, based on the esophageal motility analysis of healthy subjects. METHODS: 16 healthy volunteers without history of digestive complaints or esophageal symptoms were included. 22-channel water-perfused high resolution manometry was performed. RESULTS: Normal values were calculated as 5th 95th percentile ranges for the following parameters; upper esophageal sphincter resting pressure (UESRP) (40-195 mmHg); upper esophageal sphincter residual pressure (UESResP) (30-115 mmHg), contractile front velocity (CFV) (2.4-7.1 cm/s), distal contractile integral (DCI) (285-2820 mmHg.s.cm), distal contraction latency (DL) (6.1-10.9 s), intrabolus pressure (IBP) (7-19 mmHg), integrated relaxation pressure (IRP 4s) (2-20 mmHg), lower esophageal sphincter resting pressure(LESRP) (5-54 mmHg), esophageal shortening (Es) (0.3-1.3 cm) and lower esophageal sphincter lift (LESL) (0,1-1,2 cm). CONCLUSION: Normal values for the most important parameters (such as IRP 4s, DL and CFV), obtained using a 22 channel waterperfused system resemble previously published data from other perfusion devices. However, there exist small but significant variations compared with values established with solid-state highresolution manometry. Thus, when using water-perfused catheters, caution is required when normative values are used that were established with solid-state catheters. PMID- 26031864 TI - Feasibility of endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) and biopsy (FNB) with a new slim linear echoendoscope. AB - BACKGROUND: Endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) and biopsy (FNB) is considered a very accurate and safe tool for sampling extra intestinal tumors. Standard echoendosocopes for FNA/FNB are large with a sharpened tip that can be associated with complications. A new slim linearechoendoscope have been developed trying to overcome this limitation. AIM: Of the present study was to evaluate the feasibility; safety and diagnostic yield of this newly developed slim echoendoscope for performing EUS-guided FNA/FNB. METHODS: A pilot observational study was performed. Consecutive patients submitted for a EUS-FNA/FNB were prospectively included in the study. Patients underwent EUS procedure using the new slim linear PENTAX-echoendoscope. Tissue acquisition was done with standard and histology needles. Feasibility and diagnostic yield were evaluated. A descriptive analysis was performed. RESULTS: 87 patients were included (mean age 66.7 years (range 24-90 years), 45 male. Mean size was of lesions sampled were 33.43 +/- 20.8 mm. Esophagus intubation and access to the second portion of the duodenum (D2) were considered easy in all 87 cases (100%). Nineteen procedures (21.8%) were performed from the esophagus, 42 (48.3%) from the stomach, 22 (25.3%) cases from duodenal bulb, and 4 (4.6%) cases from D2. EUS-FNB was feasible in 85 cases (97.7%), failed in 2 pancreatic lesions accessed from D2. Diagnostic yield was 86.21% (95%CI 77.4- 91.9) in the intention to-treat analysis and 88.24% (95%CI 79.7- 93.5) in per-protocol analysis. There were no complications related to the technique. CONCLUSION: Performing a EUS FNA/FNB with the newly designed slim scope is feasible and safe for cyto histopathology diagnosis of intra-intestinal and extra-intestinal mass lesions. PMID- 26031865 TI - Enteric neuropathy associated to diabetes mellitus. AB - Diabetes mellitus (DM) is a group of diseases highly prevalent nowadays. Its different types produce very similar symptoms with acute and chronic complications. Amongst these, gastrointestinal (GI) dysmotility, associated with the development of neuropathy in the enteric nervous system (ENS) is recognized. The objective is to review the current knowledge on GI dysmotility and enteric neuropathy associated to diabetes mellitus. The different functional and structural alterations within the digestive tract in diabetic patients and animal models are described. Finally, the therapeutic and preventive strategies tested so far in the context of enteric diabetic neuropathy are briefly summarized.In conclusion, amongst the alterations described in DM, the loss of inhibitory intrinsic innervation of the gut is most remarkable. Different therapeutic and/or preventive strategies, including the use of insulin, nerve growth factor or antioxidants, as well as myenteric neuron transplantation, are proposed. PMID- 26031866 TI - Gastroduodenal artery aneurysm presenting as a pancreatic mass. PMID- 26031867 TI - Pseudoaneurysm of the cystic artery: An uncommon cause of upper gastrointestinal bleeding in a case of xanthogranulomatous cholecystitis. PMID- 26031868 TI - Double pylorus. PMID- 26031869 TI - A peripheral approach allowing successful endoscopic submucosal dissection for early colorectal carcinoma near the diverticula. PMID- 26031870 TI - Endoscopic submucosal dissection (ESD) of antral subepithelial lesion suspected of malignancy. AB - Subepithelial gastric tumours comprise a heterogeneous group of lesions. Endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) is a useful approach but cannot always offer a definitive diagnosis to guide future therapeutic decisions. In the case we describe, biopsy samples of an antral subepithelial lesion and cytological analysis obtained with an EUS-FNA suggested the diagnosis of an adenocarcinoma. Endoscopic submucosal dissection (ESD) allowed en bloc resection of the tumour ensuring diagnosis and providing a definitive treatment. PMID- 26031871 TI - An adult case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative disorder with severe hepatic dysfunction and megalosplenia. AB - Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder (EBV+T/NK-LPD) is a continuous spectrum of diseases that share a common feature observed in T cells and NK cells: Excessive lymphoid proliferation. This disease is rare in adults and predominantly affects children with high mortality. Herein, we present a case of EBV+T-LPD that occurred in an adult with clinical manifestations of hepatic dysfunction and megalosplenia. The patient received a splenectomy at a local hospital for the treatment of megalosplenia. Before surgery, she exhibited mild hepatomegaly and normal liver function. However, after the operation, abdominal computed tomography (CT) showed obvious hepatomegaly and severely damaged liver function. After a final diagnosis of EBV+TLPD at our hospital, the patient received combination therapy with antiviral and immunosuppressive agents. At the 4-month follow-up visit, hepatic function was normal and the size of the liver decreased. Because this patient presented with hepatomegaly before the splenectomy and because hepatic dysfunction rapidly progressed after surgery, an early diagnosis of EBV+T-LPD was crucial. Splenectomy may be recommended before liver involvement to reduce negative postoperative effects on the liver. PMID- 26031872 TI - [Biosimilars in inflamatory bowel disease: Management and care]. PMID- 26031873 TI - Advances and pitfalls in the management of small bowel polyps in Peutz-Jeghers syndrome. PMID- 26031874 TI - Comment on conservative management of isolated dissection of the superior mesenteric artery. PMID- 26031875 TI - Gastric fundus splenosis mimicking stromal tumor. PMID- 26031876 TI - Giant Meckel's diverticulum torsioned. An unnusual presentation. PMID- 26031877 TI - Crohn's disease and systemic lupus erythematosus: A rare and challenging association. PMID- 26031878 TI - Hemocholecyst: A rare cause of acute abdomen. PMID- 26031879 TI - Well differentiated neuroendocrine tumor of the appendix and low-grade appendiceal mucinous neoplasm presenting as a collision tumor. PMID- 26031880 TI - Pylephlebitis and liver abscesses secondary to acute advanced appendicitis. PMID- 26031881 TI - Updated Guidelines for Childhood Pneumonia Management: A Promising Role for Lung Ultrasound. PMID- 26031883 TI - Editorial overview: Musculoskeletal: Are there common targets to prevent age related changes in muscle, cartilage and bone? PMID- 26031882 TI - Anti-diabetic and Anti-hyperlipidemic Effects and Safety of Salacia reticulata and Related Species. AB - Extracts of Salacia reticulata Wight (Hypocrataceae) roots, stems, and leaves have been used in Asia for hundreds of years for the folkloric treatment of diabetes and other health problems. Constituents that have been identified as exhibiting anti-diabetic effects include salacinol, kotalanol, ponkorinol, salaprinol, and their corresponding de-0-sulfonated compounds. Mangiferin, kotalagenin 16-acetate and various proanthocyanidin oligomers have also been isolated. Studies indicate that Salacia extracts modulate multiple targets that influence carbohydrate and lipid metabolism including alpha-glucosidase, aldose reductase, pancreatic lipase, peroxisomal proliferator-activated receptor-alpha, glucose transporter-4 mediated glucose uptake, and angiotensin II type 1 receptor. Furthermore, Salacia extracts exhibit free radical scavenging, antioxidant and hepatoprotectant activities. In human studies, Salacia extracts have been shown to decrease plasma glucose and insulin levels, decrease HbA1c, and modulate serum lipid levels with no adverse effects being reported. Similar results have been demonstrated in rat and mouse models as well as in vitro systems. Safety of S. reticulata and other Salacia species as S. oblonga and S. chinensis in rats and mice indicate that extracts are exceedingly safe. No clinical studies have examined the effects of Salacia extracts on human weight loss, although weight loss and decreases in weight gain have been demonstrated in animal models. Because of the large number of pharmacologically active compounds, it is difficult to establish standards for extracts. PMID- 26031884 TI - BOLD fMRI of cerebrovascular reactivity in the middle cerebral artery territory: A 100 volunteers' study. AB - BACKGROUND AND PURPOSE: The assessment of cerebrovascular reactivity (CVR) has shown promising results for its use in medical diagnosis and prognosis, especially in patients suffering from severe intracranial arterial stenosis. However, its quantification remains uncertain because of a large variability inherent in brain anatomy and in methodological settings. To overcome this variability, we provide lateralization index (LI) values for CVR within the middle cerebral artery territory to detect CVR impairment. MATERIALS AND METHODS: We assessed CVR in 100 volunteers (41 females; 47.52 +/- 21.58 years) without cervico-encephalic arterial stenosis using BOLD-fMRI contrast with a block-design hypercapnic challenge. Averaged end-tidal CO2 was used as a physiological regressor for statistical analyses with a general linear model. We measured %BOLD signal-change in segmented gray matter regions of interest in the middle cerebral artery territory (MCA). We calculated a laterality index according to the following formula: LI=(CVRleft-CVRright)/(CVRleft+CVRright). We tested the effects of methodological settings (i.e. hypercapnic gas, gas administration means, MR acquisition and sex) on %BOLD signal change and LI values with analysis of variance. RESULTS: No adverse effects of the hypercapnic challenge were reported. LI values were independent of experimental conditions. Mean LI calculated in MCA territories was 0.016 +/- 0.031, giving the lower and upper limits of 95% (m +/- 2SD) of this population distribution at]-0.05; 0.08[. CONCLUSION: LI can effectively help us to overcome measurement variabilities. Therefore, it can be used to detect abnormal asymmetries in CVR and identify patients at higher risk of ischemic stroke. PMID- 26031885 TI - Somatic symptom disorders without known physical causes: one disease with many names? AB - Patients complaining of pain or fatigue in the absence of known physical diseases constitute a high percentage of those seeking general medical care. Depending upon the type of physician/specialist consulted, those individuals may receive disease labels that range from an implied psychological origin such as somatoform or psychosomatic disease, or to a presumed physical disease such as fibromyalgia. Although all these conditions are regularly associated with fatigue, we have provided a new label suggesting another disease category, "systemic exertion intolerance disease," which replaces the previous "chronic fatigue syndrome." All these conditions have common, overlapping features that usually consist of both fatigue and pain, and, in the absence of definitive objective confirmation, might be best classified under one heading such as somatic symptom disorder. Management of these disorders is challenging, but suggestions for proper identification and treatment are presented. PMID- 26031886 TI - Integration of Genomics in Primary Care. AB - Primary care is changing rapidly. The wide-scale expansion of electronic medical records is redefining the way we approach chronic disease management, and automated decision support is increasingly being leveraged to reduce risk and optimize quality. Many of these interventions are now beginning to integrate genomic data. We explore the convergence of these 2 forces (expansion of clinical informatics and integration of translational genomics), and we highlight several applications where these forces are helping our patients avoid potentially preventable events. Because gene-environment interactions are dynamic, the utility of gene-based decision support varies over time. Primary care providers will serve a key role as our patients navigate these changes. PMID- 26031887 TI - Desmopressin to Prevent Rapid Sodium Correction in Severe Hyponatremia: A Systematic Review. AB - BACKGROUND: Hyponatremia is common among inpatients and is associated with severe adverse outcomes such as osmotic demyelination syndrome. Current guidelines recommend serum sodium concentration correction targets of no more than 8 mEq/L per day in patients at high risk of osmotic demyelination syndrome. Desmopressin is recommended to control high rates of serum sodium concentration correction in severe hyponatremia. However, recommendations are based on limited data. The objective of this study is to review current strategies for DDAVP use in severe hyponatremia. METHODS: Systematic literature search of 4 databases of peer reviewed studies was performed and study quality was appraised. RESULTS: The literature search identified 17 observational studies with 80 patients. We found 3 strategies for desmopressin administration in hyponatremia: 1) proactive, where desmopressin is administered early based on initial serum sodium concentration; 2) reactive, where desmopressin is administered based on changes in serum sodium concentration or urine output; 3) rescue, where desmopressin is administered after serum sodium correction targets are exceeded or when osmotic demyelination appears imminent. A proactive strategy of desmopressin administration with hypertonic saline was associated with lower incidence of exceeding serum sodium concentration correction targets, although this evidence is derived from a small case series. CONCLUSIONS: Three distinct strategies for desmopressin administration are described in the literature. Limitations in study design and sample size prevent definitive conclusions about the optimal strategy for desmopressin administration to correct hyponatremia. There is a pressing need for better quality research to guide clinicians in managing severe hyponatremia. PMID- 26031888 TI - Exercise and Health: Dose and Response, Considering Both Ends of the Curve. AB - Over the past 60 years, an enormous body of data has demonstrated that exercise is good for health. Recently, however, there has been concern that repetitive intense exercise may have deleterious cardiovascular effects. To evaluate this possibility, I have reviewed the health response to exercise, with particular attention to the body's minimum daily requirement and to the maximum amount that is safe and effective. PMID- 26031889 TI - Postmodern Stress Disorder (PMSD): A Possible New Disorder. AB - The murder of cardiovascular surgeon, Michael Davidson, MD, suggests the existence of a new disorder, postmodern stress disorder. This disorder is characterized by repetitive exposure to digital images of violence in a variety of electronic media, including films, television, video games, music videos, and other online sources. This disorder appears to be a variant of posttraumatic stress disorder, and shares with it excessive stimulation of the amygdala and loss of the normal inhibitory inputs from the orbitofrontal cingulate cortical gyrus. In postmodern stress disorder, repetitive digital microtraumas appear to have an effect similar to that of macrotraumas of warfare or civilian assaults. Other elements of the disorder include the development of fixed ideas of bullying or public shaming, access to weapons, and loss of impulse control. This syndrome could explain a number of previously inexplicable murders/suicides. Violence against health care professionals is a profound concern for the medical profession, as are assaults on nonclinicians. The recommendation is made to change forensic procedures to include obtaining historic information concerning the use of digital media during investigations of violent crimes and murders so that the disorder may be further characterized. Gaining an understanding of this disorder will require a multidisciplinary approach to this life-threatening public health problem. Research should also focus on the development and evaluation of possible antidotes to postmodern toxicities. PMID- 26031890 TI - How should teaching on whole person medicine, including spiritual issues, be delivered in the undergraduate medical curriculum in the United Kingdom? AB - BACKGROUND: Although the General Medical Council recommends that United Kingdom medical students are taught 'whole person medicine', spiritual care is variably recognised within the curriculum. Data on teaching delivery and attainment of learning outcomes is lacking. This study ascertained views of Faculty and students about spiritual care and how to teach and assess competence in delivering such care. METHODS: A questionnaire comprising 28 questions exploring attitudes to whole person medicine, spirituality and illness, and training of healthcare staff in providing spiritual care was designed using a five-point Likert scale. Free text comments were studied by thematic analysis. The questionnaire was distributed to 1300 students and 106 Faculty at Queen's University Belfast Medical School. RESULTS: 351 responses (54 staff, 287 students; 25 %) were obtained. >90 % agreed that whole person medicine included physical, psychological and social components; 60 % supported inclusion of a spiritual component within the definition. Most supported availability of spiritual interventions for patients, including access to chaplains (71 %), counsellors (62 %), or members of the patient's faith community (59 %). 90 % felt that personal faith/spirituality was important to some patients and 60 % agreed that this influenced health. However 80 % felt that doctors should never/rarely share their own spiritual beliefs with patients and 67 % felt they should only do so when specifically invited. Most supported including training on provision of spiritual care within the curriculum; 40-50 % felt this should be optional and 40 % mandatory. Small group teaching was the favoured delivery method. 64 % felt that teaching should not be assessed, but among assessment methods, reflective portfolios were most favoured (30 %). Students tended to hold more polarised viewpoints but generally were more favourably disposed towards spiritual care than Faculty. Respecting patients' values and beliefs and the need for guidance in provision of spiritual care were identified in the free-text comments. CONCLUSIONS: Students and Faculty generally recognise a spiritual dimension to health and support provision of spiritual care to appropriate patients. There is lack of consensus whether this should be delivered by doctors or left to others. Spiritual issues impacting patient management should be included in the curriculum; agreement is lacking about how to deliver and assess. PMID- 26031892 TI - Utilization of mixtures of aromatic N-donor ligands of different coordination ability for the solvothermal synthesis of thiostannate containing molecules. AB - Utilization of mixtures of differently coordinating aromatic N-donor ligands leads to the formation of the two new compounds {[Ni(phen)2]2Sn2S6}.4,4' bipy.1/2H2O I and {[Ni(phen)2]2Sn2S6}.2,2'-bipy II that could be prepared under solvothermal conditions (4,4'-bipy = 4,4'-bipyridine, C10H8N2; phen = 1,10 phenanthroline, C12H8N2; 2,2'-bipy = 2,2'-bipyridine, C10H8N2). In the structures of both compounds Ni-S bond formation is observed which is highly unusual when only bidentate N-donor ligands are applied in the reaction mixture. The detailed analysis of the crystal structure indicates that the presence of 4,4'-bipy and 2,2'-bipy molecules are essential for the stabilization of the arrangement of the constituents. The main structural motif {[Ni(phen)2]2Sn2S6} is arranged generating off center parallel stacking of the phen ligands. The empty spaces between the {[Ni(phen)2]2Sn2S6} moieties are occupied by either 2,2'-bipy (I) or 4,4'-bipy (II) molecules which are oriented towards the phen ligands to form intermolecular pi-pi interactions. PMID- 26031891 TI - Efficacy of ESS in chronic rhinosinusitis with and without nasal polyposis: a Danish cohort study. AB - Endoscopic sinus surgery (ESS) for patients with severe chronic rhinosinusitis (CRS) has become a well-established treatment in cases where medical therapy fails. Even though CRS patients are divided into two subgroups, CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP), most studies present only results for the total cohort. This prospective cohort study evaluated the efficacy of ESS on both quality of life and olfactory function measures, in a cohort of Danish CRS patients diagnosed according to the EPOS criteria, with results analysed separately for the CRSwNP and CRSsNP subgroups. All 97 CRS patients who underwent ESS over an 18-month trial period were evaluated preoperative by SNOT-22 score, Sniffin' Sticks score, modified Lund-Kennedy endoscopic score and Lund-Mackay CT score. Patient outcomes were reevaluated at clinical follow-up 1 and 6 months postoperative. ESS efficiently and immediately improved quality of life for both CRSwNP and CRSsNP patients, with over 50 % reduction in SNOT-22 score 1 month after surgery, which sustained 6 months postoperative. Olfactory function measured by Sniffin' Sticks score showed overall improvement in both groups. ESS efficiently improved quality of life in both CRSwNP and CRSsNP patients, and surgery lead to an overall improvement in olfactory function. However, a minor proportion of patients experienced deterioration in olfactory function after ESS. PMID- 26031893 TI - Image-guided video assisted thoracoscopic surgery (iVATS) - phase I-II clinical trial. AB - PURPOSE: To facilitate localization and resection of small lung nodules, we developed a prospective clinical trial (ClinicalTrials.gov number NCT01847209) for a novel surgical approach which combines placement of fiducials using intra operative C-arm computed tomography (CT) guidance with standard thoracoscopic resection technique using image-guided video-assisted thoracoscopic surgery (iVATS). METHODS: Pretrial training was performed in a porcine model using C-arm CT and needle guidance software. Methodology and workflow for iVATS was developed, and a multi-modality team was trained. A prospective phase I-II clinical trial was initiated with the goal of recruiting eligible patients with small peripheral pulmonary nodules. Intra-operative C-arm CT scan was utilized for guidance of percutaneous marking with two T-bars (Kimberly-Clark, Roswell, GA) followed by VATS resection of the tumor. RESULTS: Twenty-five patients were enrolled; 23 underwent iVATS, one withdrew, and one lesion resolved. Size of lesions were: 0.6-1.8 cm, mean = 1.3 +/- 0.38 cm.. All 23 patients underwent complete resection of their lesions. CT imaging of the resected specimens confirmed the removal of the T-bars and the nodule. Average and total procedure radiation dose was in the acceptable low range (median = 1501 MUGy*m(2), range 665-16,326). There were no deaths, and all patients were discharged from the hospital (median length of stay = 4 days, range 2-12). Three patients had postoperative complications: one prolonged air-leak, one pneumonia, and one ileus. CONCLUSIONS: A successful and safe step-wise process has been established for iVATS, combining intra-operative C-arm CT scanning and thoracoscopic surgery in a hybrid operating room. PMID- 26031895 TI - Changing blue fluorescent protein to green fluorescent protein using chemical RNA editing as a novel strategy in genetic restoration. AB - Using the transition from cytosine of BFP (blue fluorescent protein) gene to uridine of GFP (green fluorescent protein) gene at position 199 as a model, we successfully controlled photochemical RNA editing to effect site-directed deamination of cytidine (C) to uridine (U). Oligodeoxynucleotides (ODNs) containing 5'-carboxyvinyl-2'-deoxyuridine ((CV) U) were used for reversible photoligation, and single-stranded 100-nt BFP DNA and in vitro-transcribed full length BFP mRNA were the targets. Photo-cross-linking with the responsive ODNs was performed using UV (366 nm) irradiation, which was followed by heat treatment, and the cross-linked nucleotide was cleaved through photosplitting (UV, 312 nm). The products were analyzed using restriction fragment length polymorphism (RFLP) and fluorescence measurements. Western blotting and fluorescence-analysis results revealed that in vitro-translated proteins were synthesized from mRNAs after site-directed RNA editing. We detected substantial amounts of the target-base-substituted fragment using RFLP and observed highly reproducible spectra of the transition-GFP signal using fluorescence spectroscopy, which indicated protein stability. ODNc restored approximately 10% of the C-to-U transition. Thus, we successfully used non-enzymatic site-directed deamination for genetic restoration in vitro. In the near future, in vivo studies that include cultured cells and model animals will be conducted to treat genetic disorders. PMID- 26031894 TI - The complete methylome of Helicobacter pylori UM032. AB - BACKGROUND: The genome of the human gastric pathogen Helicobacter pylori encodes a large number of DNA methyltransferases (MTases), some of which are shared among many strains, and others of which are unique to a given strain. The MTases have potential roles in the survival of the bacterium. In this study, we sequenced a Malaysian H. pylori clinical strain, designated UM032, by using a combination of PacBio Single Molecule, Real-Time (SMRT) and Illumina MiSeq next generation sequencing platforms, and used the SMRT data to characterize the set of methylated bases (the methylome). RESULTS: The N4-methylcytosine and N6 methyladenine modifications detected at single-base resolution using SMRT technology revealed 17 methylated sequence motifs corresponding to one Type I and 16 Type II restriction-modification (R-M) systems. Previously unassigned methylation motifs were now assigned to their respective MTases-coding genes. Furthermore, one gene that appears to be inactive in the H. pylori UM032 genome during normal growth was characterized by cloning. CONCLUSION: Consistent with previously-studied H. pylori strains, we show that strain UM032 contains a relatively large number of R-M systems, including some MTase activities with novel specificities. Additional studies are underway to further elucidating the biological significance of the R-M systems in the physiology and pathogenesis of H. pylori. PMID- 26031896 TI - Association between vitamin D deficiency and periodontal status in current smokers. AB - OBJECTIVES: The aim of this study was to examine whether vitamin D level is associated with periodontitis using a representative sample of Korean adults. METHODS: A total of 6011 subjects who participated in the fourth Korea National Health and Nutrition Examination Survey (KNHANES) were examined. Vitamin D deficiency was defined as 25-hydroxyvitamin D serum concentrations to be under or equal to 20 ng/ml. We assessed periodontal conditions by Community Periodontal Index (CPI) and defined higher CPI as >=code 3. Multivariate logistic regression analyses were performed adjusting for sociodemographics, oral and general health behaviors, and systemic health status. All analyses considered a complex sampling design, and a subgroup analysis was performed to determine estimates stratified according to the effect modifier. RESULTS: There was no association between vitamin D deficiency and higher CPI after adjusting for the covariates in the total sample. According to the strata of smoking, the significant association was found in only current smokers after adjusting for the covariates including pack years (odds ratio: 1.53, 95% confidence interval: 1.07-2.18). CONCLUSIONS: A significant association between vitamin D deficiency and periodontal status was found in only current smokers. Smoking could modify the effect of vitamin D on periodontitis. PMID- 26031897 TI - Bioregulation. AB - During the 20th century great progress was made in genetics and biochemistry, and these were combined into a molecular biological understanding of functions of macromolecules. Further great discoveries will be made about bioregulations, applicable to scientific problems such as cell development and evolution, and to illnesses including heart disease through defective control of cholesterol production, and to neurological cell-based diseases. The "War Against Cancer" is still far from won. The present generation of scientists can develop clinical applications from recent basic science discoveries. PMID- 26031898 TI - Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review. AB - OBJECTIVE: To evaluate whether rituximab at a low dose of 250 mg/m(2) * 2 may be as effective as at higher dosages, most commonly 375 mg/m(2)*4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection. METHODS: We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search. RESULTS: The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant. CONCLUSION: Rituximab at a low dosage of 250 mg/m(2) * 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC. PMID- 26031899 TI - On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives. AB - Adjuvants are compounds incorporated into vaccines to enhance immunogenicity and the development of these molecules has become an expanding field of research in the last decades. Adding an adjuvant to a vaccine antigen leads to several advantages, including dose sparing and the induction of a more rapid, broader and strong immune response. Several of these molecules have been approved, including aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), virosomes and AS04. Adjuvants have recently been implicated in the new syndrome named "ASIA Autoimmune/inflammatory Syndrome Induced by Adjuvants", which describes an umbrella of clinical conditions including post-vaccination adverse reactions. Recent studies implicate a web of mechanisms in the development of vaccine adjuvant-induced autoimmune diseases, in particular, in those associated with aluminium-based compounds. Fewer and unsystematised data are instead available about other adjuvants, despite recent evidence indicating that vaccines with different adjuvants may also cause specific autoimmune adverse reactions possible towards different pathogenic mechanisms. This topic is of importance as the specific mechanism of action of each single adjuvant may have different effects on the course of different diseases. Herein, we review the current evidence about the mechanism of action of currently employed adjuvants and discuss the mechanisms by which such components may trigger autoimmunity. PMID- 26031900 TI - Hepatic, gastric and intestinal first-pass effects of vitexin-2''-O-rhamnoside in rats by ultra-high-performance liquid chromatography. AB - Previous research in our laboratory found that the absolute bioavailability of vitexin-2''-O-rhamnoside (VR) was quite low at 4.89%. A rapid and sensitive UHPLC method using hesperidin as an internal standard was therefore developed and validated to investigate the reasons for this by determining VR in rat plasma after administering intravenously, intraportally (5 mg/kg), intraduodenally and intragastrically (40 mg/kg) to the rat model of the hepatic, gastric and intestinal first-pass effects. As only a high intestinal first-pass effect of VR was found, that is, there existed a low bioavailability of VR (2.40%), inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A), including verapamil, cyclosporin A and midazolam, and absorption enhancers, including bile salts and borneol, combined with VR, were instilled into duodenum to evaluate the effects on bioavailability of VR. The results demonstrated that area under the concentration-time curve (AUC) values of VR slightly increased after administration of verapamil, cyclosporin A and midazolam, indicating that CYP3A and P-gp do not play an important role in the first-pass effect in the intestine. AUC values of VR significantly increased after administering bile salts or borneol, indicating that the low bioavailability of VR was mainly related to its poor absorption in the intestine. PMID- 26031901 TI - Genome-wide association study of leukotriene modifier response in asthma. AB - Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G * E) GWAS model, we evaluated 12 week change in forced expiratory volume in 1 second (DeltaFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 * 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean DeltaFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 * 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs. PMID- 26031903 TI - A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space. AB - Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space. PMID- 26031902 TI - Chromatin dynamics during cellular differentiation in the female reproductive lineage of flowering plants. AB - Sexual reproduction in flowering plants offers a number of remarkable aspects to developmental biologists. First, the spore mother cells - precursors of the plant reproductive lineage - are specified late in development, as opposed to precocious germline isolation during embryogenesis in most animals. Second, unlike in most animals where meiosis directly produces gametes, plant meiosis entails the differentiation of a multicellular, haploid gametophyte, within which gametic as well as non-gametic accessory cells are formed. These observations raise the question of the factors inducing and modus operandi of cell fate transitions that originate in floral tissues and gametophytes, respectively. Cell fate transitions in the reproductive lineage imply cellular reprogramming operating at the physiological, cytological and transcriptome level, but also at the chromatin level. A number of observations point to large-scale chromatin reorganization events associated with cellular differentiation of the female spore mother cells and of the female gametes. These include a reorganization of the heterochromatin compartment, the genome-wide alteration of the histone modification landscape, and the remodeling of nucleosome composition. The dynamic expression of DNA methyltransferases and actors of small RNA pathways also suggest additional, global epigenetic alterations that remain to be characterized. Are these events a cause or a consequence of cellular differentiation, and how do they contribute to cell fate transition? Does chromatin dynamics induce competence for immediate cellular functions (meiosis, fertilization), or does it also contribute long-term effects in cellular identity and developmental competence of the reproductive lineage? This review attempts to review these fascinating questions. PMID- 26031904 TI - Perceived fatigue is highly prevalent and debilitating in patients with mitochondrial disease. AB - Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. Our aim was to determine the prevalence and assess for comorbidities associated with clinically relevant fatigue in patients with mitochondrial disease. A cross sectional postal survey of patients with mitochondrial disease was undertaken using a validated self-completion, patient-reported outcome measures (response rate: 60%; n = 132). The prevalence and perceived functional impact of experienced fatigue were assessed using the Fatigue Impact Scale. Other putative biological mechanisms were evaluated using the Hospital Anxiety Depression scale and Epworth sleepiness scale. Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale >= 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale >= 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype. Future evaluation of causal factors in mitochondrial disease-associated fatigue is warranted with the potential to guide future treatment modalities. PMID- 26031905 TI - Healthcare Proxy Awareness of Suspected Infections in Nursing Home Residents with Advanced Dementia. AB - OBJECTIVES: To determine healthcare proxy involvement in decision-making regarding infections in individuals with advanced dementia. DESIGN: Prospective cohort study. SETTING: Thirty-five Boston-area nursing homes (NHs). PARTICIPANTS: NH residents with advanced dementia and their proxies (N = 362). MEASUREMENTS: Charts were abstracted monthly (up to 12 months) for documentation of suspected infections and provider-proxy discussions for each episode. Proxies were interviewed within 8 weeks of the infection to determine their awareness and decision-making involvement. Factors associated with proxy awareness and discussion documentation were identified. RESULTS: There were 496 suspected infections; proxies were reached for interview for 395 (80%). Proxy-provider discussions were documented for 207 (52%) episodes, yet proxies were aware of only 156 (39%). Proxies participated in decision-making for 89 (57%) episodes of which they were aware. Proxy awareness was associated with antimicrobial use (adjusted odds ratio (AOR) = 3.43, 95% confidence interval (CI) = 1.94-6.05), hospital transfer (AOR = 3.00, 95% CI = 1.19-7.53), infection within 30 days of death (AOR = 3.32, 95% CI = 1.54-7.18), and fewer days between infection and study interview (AOR = 2.71, 95% CI = 1.63-4.51). Discussion documentation was associated with the resident residing in a dementia special care unit (AOR = 1.71, 95% CI = 1.04-2.80), the resident not on hospice (AOR = 3.25, 95% CI = 1.31 8.02), more provider visits (AOR = 1.71, 95% CI = 1.07-2.75), proxy visits of more than 7 h/wk (AOR = 1.93, 95% CI = 1.02-3.67), and episode within 30 days of death (AOR = 3.99, 95% CI = 1.98-8.02). CONCLUSION: Proxies are unaware of and do not participate in decision-making for most suspected infections that NH residents with advanced dementia experience. Proxy awareness of episodes and documentation of provider-proxy discussions are not congruent. PMID- 26031906 TI - Community-Based Health Education has Positive Influence on the Attitude to Cervical Cancer Screening among Women in Rural Nepal. AB - The main purpose of this study was to assess the knowledge of cervical cancer among women in rural Nepal and explore the feasibility and impact of a community based awareness program on cervical cancer. Community-based educational meetings on cervical cancer and its prevention were conducted among women's groups in rural Nepal. Through a questionnaire, the women's baseline knowledge of risk factors, symptoms, and perceived risk of cervical cancer were identified. The willingness to participate in cervical cancer screening was compared before and after the educational meeting. The meetings were followed by a cervical cancer screening program. Among the 122 participants at the educational meeting, only 6 % had heard of cervical cancer. Their baseline knowledge of risk factors and symptoms was poor. The proportion of women willing to participate in cervical screening increased from 15.6 to 100 % after attending the educational meeting. All the study subjects participated in the screening program. Additionally, the study participants recruited a further 222 of their peers for screening. Poor knowledge of cervical cancer among women in rural Nepal highlights the urgency of public awareness programs for cervical cancer at a national level. A community based awareness program can change women's attitude to cervical screening, and women's groups can play a major role in promoting participation in cervical cancer screening programs. PMID- 26031907 TI - Contactless conductometric determination of methanol and ethanol in samples containing water after their electrophoretic desalination. AB - Determination of the contents of methanol and ethanol in aqueous solutions was performed by measuring the permittivity of solutions using a contactless conductivity detector (C(4) D) normally used for detection in capillary electrophoresis. The detection cell is a section of a fused silica capillary with an internal diameter of 50 MUm with a pair of conductivity electrodes on the external walls. The C(4) D response to samples of methanol/water and ethanol/water mixtures is linear in the concentration interval of approx. 40-100% v/v alcohol content. In the analysis of technical samples of methanol and ethanol, the determination is disturbed by the presence of even trace amounts of salts. This interference can be effectively eliminated by integrated electrophoretic desalination of the sample by the application of a direct current electric voltage with a magnitude of 10 kV to the capillary with the injected sample zone. Under these conditions, the ions migrate out of the sample zone and the detector response is controlled purely by the permittivity of the solvent/water zone. Desalinating is effective for NaCl contents in the range from 0 to 5 mmol/L NaCl. The effectiveness of the desalinating process has been verified on MeOH/water samples and in determination of the ethanol content in distilled beverages normally available in the retail network. PMID- 26031908 TI - Bifidobacterium animalis subsp. lactis in prevention of common infections in healthy children attending day care centers - Randomized, double blind, placebo controlled study. AB - BACKGROUND & AIMS: The aim of our study was to investigate the role of Bifidobacterium animalis subsp. lactis (BB-12((r))) in the prevention of common (gastrointestinal and respiratory) infections in healthy children who attend day care centers. METHODS: We conducted a randomized, double-blind, placebo controlled trial in 210 children who attend day care centers. They were randomly allocated to receive placebo (Placebo group, n = 106) or BB-12((r)) at a dose of 10(9) colony-forming units (CFU) (Intervention group, n = 104) during the 3-month intervention period. RESULTS: Intention to treat analysis was used. There were overall 99 infections in Placebo group and 97 in Intervention group (incidence rate ratio = 1.0014, p = 0.992, Poisson regression model). Overall 65 children (61.3%) in Placebo group and 67 (64.4%) in Intervention group had common infections (p = 0.642). Mean number of infections per child was 0.93 (range 0-3) in Placebo group and 0.93 (range 0-3) in Intervention group (p = 0.898). There was no difference in secondary (duration of symptoms, number of children with gastrointestinal and respiratory tract infections, absence from day care center due to infections, use of antibiotics) and exploratory (type of gastrointestinal and respiratory tract infection) endpoints between groups. CONCLUSION: Results of performed study show that BB-12((r)) has no effect on the prevention of gastrointestinal and respiratory tract infections in healthy children who attend day care centers. PMID- 26031909 TI - Homologues of Genetic Transformation DNA Import Genes Are Required for Rhodobacter capsulatus Gene Transfer Agent Recipient Capability Regulated by the Response Regulator CtrA. AB - Gene transfer agents (GTAs) morphologically resemble small, double-stranded DNA (dsDNA) bacteriophages; however, their only known role is to package and transfer random pieces of the producing cell genome to recipient cells. The best understood GTA is that of Rhodobacter capsulatus, termed RcGTA. We discovered that homologues of three genes involved in natural transformation in other bacteria, comEC, comF, and comM, are essential for RcGTA-mediated gene acquisition. This paper gives genetic and biochemical evidence that RcGTA-borne DNA entry into cells requires the ComEC and ComF putative DNA transport proteins and genetic evidence that putative cytoplasmic ComM protein of unknown function is required for recipient capability. Furthermore, the master regulator of RcGTA production in <1% of a cell population, CtrA, which is also required for gene acquisition in recipient cells, is expressed in the vast majority of the population. Our results indicate that RcGTA-mediated gene transfer combines key aspects of two bacterial horizontal gene transfer mechanisms, where donor DNA is packaged in transducing phage-like particles and recipient cells take up DNA using natural transformation-related machinery. Both of these differentiated subsets of a culture population, donors and recipients, are dependent on the same response regulator, CtrA. IMPORTANCE: Horizontal gene transfer (HGT) is a major driver of bacterial evolution and adaptation to environmental stresses. Traits such as antibiotic resistance or metabolic properties can be transferred between bacteria via HGT; thus, HGT can have a tremendous effect on the fitness of a bacterial population. The three classically described HGT mechanisms are conjugation, transformation, and phage-mediated transduction. More recently, the HGT factor GTA was described, where random pieces of producing cell genome are packaged into phage-like particles that deliver DNA to recipient cells. In this report, we show that transport of DNA borne by the R. capsulatus RcGTA into recipient cells requires key genes previously thought to be specific to natural transformation pathways. These findings indicate that RcGTA combines central aspects of phage-mediated transduction and natural transformation in an efficient, regulated mode of HGT. PMID- 26031910 TI - Genetic and Proteomic Analyses of Pupylation in Streptomyces coelicolor. AB - Pupylation is a posttranslational modification peculiar to actinobacteria wherein proteins are covalently modified with a small protein called the prokaryotic ubiquitin-like protein (Pup). Like ubiquitination in eukaryotes, this phenomenon has been associated with proteasome-mediated protein degradation in mycobacteria. Here, we report studies of pupylation in a streptomycete that is phylogentically related to mycobacteria. We constructed mutants of Streptomyces coelicolor lacking PafA (Pup ligase), the proteasome, and the Pup-proteasome system. We found that these mutants share a high susceptibility to oxidative stress compared to that of the wild-type strain. Remarkably, we found that the pafA null mutant has a sporulation defect not seen in strains lacking the Pup-proteasome system. In proteomics experiments facilitated by an affinity-tagged variant of Pup, we identified 110 pupylated proteins in S. coelicolor strains having and lacking genes encoding the 20S proteasome. Our findings shed new light on this unusual posttranslational modification and its role in Streptomyces physiology. IMPORTANCE: The presence of 20S proteasomes reminiscent of those in eukaryotes and a functional equivalent of ubiquitin, known as the prokaryotic ubiquitin-like protein (Pup), in actinobacteria have motivated reevaluations of protein homeostasis in prokaryotes. Though the Pup-proteasome system has been studied extensively in mycobacteria, it is much less understood in streptomycetes, members of a large genus of actinobacteria known for highly choreographed life cycles in which phases of morphological differentiation, sporulation, and secondary metabolism are often regulated by protein metabolism. Here, we define constituents of the pupylome in Streptomyces coelicolor for the first time and present new evidence that links pupylation and the oxidative stress response in this bacterium. Surprisingly, we found that the Pup ligase has a Pup-independent role in sporulation. PMID- 26031911 TI - Hypoxemia, Sleep Disturbances, and Depression Correlated with Fatigue in Neuromyelitis Optica Spectrum Disorder. AB - AIMS: Among patients with neuromyelitis optica spectrum disorder (NMOSD), fatigue is commonly complained about and is one of the most debilitating symptoms. This study aimed to investigate the incidence of fatigue and explore impacting factors attributed to fatigue in NMOSD. METHODS: Thirty-three patients with NMOSD and twenty matched healthy controls were enrolled. A battery of self-reported questionnaires was conducted to assess quality of sleep, daytime sleepiness, fatigue, depression, and level of activity of daily life. The structure of sleep was assessed by polysomnography with blood oxygen saturation monitored by noninvasive pulse oximeter. Brain and spinal cord lesions were evaluated by MRIs. RESULTS: Fatigue was more severe and more prevalent among the patients with NMOSD compared with controls (fatigue score which ranges from 0 to 11 with higher scores indicating more severe fatigue: 6.4 +/- 0.6 vs. 3.8 +/- 0.4, P = 0.002; incidence, 64% vs. 35%, P = 0.043), and it was negatively associated with daily activity level (r = 0.455, P = 0.008). The patients with fatigue had higher Pittsburgh Sleep Quality Index score, higher Epworth Sleepiness Scale score, lower blood oxygen state, and higher depression score than patients without fatigue; blood oxygen was especially negatively correlated with fatigue (nadir SpO2 , r = -0.558, P = 0.001; mean SpO2 , r = -0.457, P = 0.007); depression was also positively correlated with fatigue (r = 0.599, P < 0.001). CONCLUSION: Patients with NMOSD experienced significant fatigue, which had an obvious impact on their daily activity. Fatigue in these patients was related to hypoxemia, sleep disturbances, and depression. PMID- 26031912 TI - Self-Assembly of Fluorescent Hybrid Core-Shell Nanoparticles and Their Application. AB - In this work, a fluorescent hybrid core-shell nanoparticle was prepared by coating a functional polymer shell onto silver nanoparticles via a facile one-pot method. The biomolecule poly-L-lysine (PLL) was chosen as the polymer shell and assembled onto the silver core via the amine-reactive cross-linker, 3,3' dithiobis(sulfosuccinimidylpropionate). The fluorescent anticancer drug, doxorubicin, was incorporated into the PLL shell through the same linkage. As the cross-linker possesses a thiol-cleavable disulfide bond, disassembly of the PLL shell was observed in the presence of glutathione, leading to controllable doxorubicin release. The silver core there provided an easily modified surface to facilitate the shell coating and ensures the efficient separation of as-prepared nanoparticles from their reaction mixture through centrifugation. Cell assays show that the prepared hybrid fluorescent nanoparticles can internalize into cells possessing excellent biocompatibility prior to the release of doxorubicin, terminating cancer cells efficiently as the doxorubicin is released at the intracellular glutathione level. Such properties are important for designing smart containers for target drug delivery and cellular imaging. PMID- 26031913 TI - Global climate change attitudes and perceptions among south American zoo visitors. AB - There is a substantial gap between the scientific evidence for anthropogenic climate change and the human response to this evidence. Perceptions of and responses to climate change can differ among regions of the world, as well as within countries. Therefore, information about the public's attitudes and perceptions related to climate change is essential to the development of relevant educational resources. In the present study, zoo visitors in four South American countries responded to a questionnaire regarding their attitudes and perceptions toward global climate change. Results indicated that most respondents are already highly concerned about global climate change and are interested in greater engagement in pro-environmental behaviors. Visitors also perceive various obstacles to engagement in climate change mitigation behaviors. We discuss the results of our study in terms of addressing visitors' climate change attitudes and perceptions within the social and emotional context of zoo settings. PMID- 26031914 TI - Phenotypic expression and prevalence of ESBL-producing Enterobacteriaceae in samples collected from patients in various wards of Mulago Hospital, Uganda. AB - BACKGROUND: Resistance to extended-spectrum cephalosporins among Enterobacteriaceae has been reported yet they serve as the last line treatment for severe infections in Uganda and other countries. This resistance often leads to nosocomial infection outbreaks and therapeutic failures from multidrug resistant bacteria. The main objective of this study was to determine the prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in clinical samples of patients in various wards of Mulago Hospital; Uganda's main national referral and teaching hospital. METHODS: This cross-sectional study was conducted between January-April, 2014. Purposive consecutive sampling was used to collect pus swab, urine, blood and CSF samples from patients in the various wards. A total of 245 consecutive, non-repetitive, clinical samples were obtained and tested for phenotypic ESBL production using the Double Disc Synergy Test using cefotaxime, ceftazidime, cefotaxime-clavulanic acid and ceftazidime-clavulanic acid. RESULTS: Results show that 47 % of the 245 samples had Enterobacteriaceae isolates. Of these isolates 62 % were ESBL producers while 38 % were of non-ESBL phenotype. E. coli was the most isolated organism (53.9 %), followed by K. pneumoniae (28.7 %). Majority of Enterobacteriaceae organisms were isolated from urine samples, followed by pus samples and of these 64.9 % and 47.4 % were ESBL-producers respectively. Klebsiella pneumoniae had the highest percentage of ESBL producers (72.7 %). There was a higher percentage of isolates showing resistance to ceftazidime (73 %) compared to cefotaxime (57.5 %). All Enterobacter cloacae isolates showed resistance to ceftazidime. There were no statistically significant association between phenotype (ESBL/non-ESBL) and patients' age or gender or Enterobacteriaceae spp. CONCLUSIONS: This study reveals a high prevalence of ESBL producing organisms in Mulago Hospital and high levels of resistance to third generation cephalosporins. In addition to undertaking appropriate infection control measures, there is urgent need for formulation of an antibiotic policy in Uganda to prevent spread of these organisms. This also calls for continuous monitoring and reporting of the presence of such organisms in order to ensure rational and judicious use of antibiotics by clinicians. PMID- 26031915 TI - Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia. AB - Great progress has recently been achieved in the understanding of the genomic alterations driving chronic lymphocytic leukemia (CLL). Nevertheless, the specific molecular mechanisms governing chromatin remodeling in CLL are unknown. Here we report the genetic and functional characterization of somatic mutations affecting the chromatin remodeler CHD2, one of the most frequently mutated genes in CLL (5.3%) and in monoclonal B lymphocytosis (MBL, 7%), a B-cell expansion that can evolve to CLL. Most of the mutations affecting CHD2, identified by whole exome sequencing of 456 CLL and 43 MBL patients, are either truncating or affect conserved residues in functional domains, thus supporting a putative role for CHD2 as a tumor suppressor gene. CHD2 mutants show altered nuclear distribution, and a chromodomain helicase DNA binding protein 2 (CHD2) mutant affected in its DNA-binding domain exhibits defective association with active chromatin. Clinicobiological analyses show that most CLL patients carrying CHD2 mutations also present mutated immunoglobulin heavy chain variable region genes (IGHVs), being the most frequently mutated gene in this prognostic subgroup. This is the first study providing functional evidence supporting CHD2 as a cancer driver and opens the way to further studies of the role of this chromatin remodeler in CLL. PMID- 26031916 TI - Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy. AB - Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration. PMID- 26031917 TI - Promising therapies in multiple myeloma. PMID- 26031918 TI - Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy. AB - Targeting the stromal cell-derived factor 1alpha (SDF-1alpha)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell-derived factor 1 (SDF-1)alpha-induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1alpha/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and beta-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1alpha/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications. PMID- 26031919 TI - The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice. AB - Inhibition of lysine-specific demethylase 1 (LSD1) has been shown to induce fetal hemoglobin (HbF) levels in cultured human erythroid cells in vitro. Here we report the in vivo effects of LSD1 inactivation by a selective and more potent inhibitor, RN-1, in a sickle cell disease (SCD) mouse model. Compared with untreated animals, RN-1 administration leads to induced HbF synthesis and to increased frequencies of HbF-positive cells and mature erythrocytes, as well as fewer reticulocytes and sickle cells, in the peripheral blood of treated SCD mice. In keeping with these observations, histologic analyses of the liver and spleen of treated SCD mice verified that they do not exhibit the necrotic lesions that are usually associated with SCD. These data indicate that RN-1 can effectively induce HbF levels in red blood cells and reduce disease pathology in SCD mice, and may therefore offer new therapeutic possibilities for treating SCD. PMID- 26031920 TI - Risk of Parkinson's disease following anxiety disorders: a nationwide population based cohort study. AB - BACKGROUND AND PURPOSE: Anxiety is potentially a pre-motor symptom of Parkinson's disease (PD). Our aim was to investigate the association between anxiety and subsequent PD risk in a population-based sample. METHODS: A total of 174 776 participants, who were free of prior PD, dementia and stroke, were enrolled from Taiwan National Health Insurance Research Database between 1 January 2005 and 31 December 2005. The association between anxiety at the beginning of the study and the incidence of PD was examined using a Cox regression model. Information regarding comorbidities, especially depression, and concomitant medication use was adjusted in the proportional hazards models. RESULTS: Over an average follow up of 5.5 years, 2258 incident PD cases were diagnosed. After adjusting for age, sex, comorbidities and concomitant medication use, patients with anxiety were more likely to develop PD than subjects without anxiety [adjusted hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.26-1.51]. Anxiety severity was dose dependently associated with increased likelihood of PD: crude HR 1.27 (95% CI 1.11-1.44) for mild anxiety, 1.35 (95% CI 1.19-1.53) for moderate anxiety and 2.36 (95% CI 2.13-2.62) for severe anxiety (P < 0.0001). Results were similar after adjustment for age, sex, comorbid depression and other PD risk factors, and in the sensitivity analyses excluding participants with comorbid depression or with a PD diagnosis <3 years after anxiety diagnosis, and controlling for Charlson's scores. CONCLUSIONS: The likelihood of developing PD was greater amongst patients with anxiety than patients without anxiety, and the severity of anxiety correlated with risk of PD. PMID- 26031921 TI - Clinical and demographic characteristics predictive of treatment outcomes for certolizumab pegol in moderate to severe Crohn's disease: analyses from the 7 year PRECiSE 3 study. AB - BACKGROUND: Clinical factors were previously identified as predictors of short term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). AIM: To identify factors that influence long-term remission of CD with CZP treatment. METHODS: Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey-Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI <=4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. RESULTS: Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P < 0.05 for all). Predictors for loss of remission (N = 437) included HBI, serum albumin concentration, haematocrit, smoking status and exposure. Predictors of maintenance of remission (N = 437) included haematocrit, IBD surgery, HBI, disease duration, serum albumin concentration and exposure. Significant predictors were confirmed with stepwise multivariate regression models. CONCLUSIONS: These analyses identified several influential parameters for short-and long-term remission of Crohn's disease with certolizumab pegol treatment. The data yield valuable hypotheses regarding factors that influence certolizumab pegol treatment. More investigation is needed. (ClinicalTrials.gov identifier NCT00552058). PMID- 26031922 TI - Brief report: generalization weaknesses in verbally fluent children and adolescents with autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) have difficulty generalizing i.e., relating new stimuli to past experiences. Few experimental studies have addressed this weakness, despite its impact on intervention effects. In a reanalysis of data (de Marchena et al. Cognition 119(1):96-113, 2011), we tested a novel form of generalization-the ability to transfer a strategy used in one context to a similar context-in verbally fluent youth with ASD and matched typically developing controls. Participants with ASD were subtly less likely to learn from experience; their generalizations were less consistent. Generalization in ASD correlated with receptive vocabulary but not age, suggesting a link to language development. A richer understanding of how to promote generalization in ASD will advance both theory and practice. PMID- 26031923 TI - No Evidence of Emotional Dysregulation or Aversion to Mutual Gaze in Preschoolers with Autism Spectrum Disorder: An Eye-Tracking Pupillometry Study. AB - The 'gaze aversion hypothesis', suggests that people with Autism Spectrum Disorder (ASD) avoid mutual gaze because they experience it as hyper-arousing. To test this hypothesis we showed mutual and averted gaze stimuli to 23 mixed ability preschoolers with ASD (M Mullen DQ = 68) and 21 typically-developing preschoolers, aged 2-5 years, using eye-tracking technology to measure visual attention and emotional arousal (i.e., pupil dilation). There were no group differences in attention to the eye region or pupil dilation. Both groups dilated their pupils more to mutual compared to averted gaze. More internalizing symptoms in the children with ASD related to less emotional arousal to mutual gaze. The pattern of results suggests that preschoolers with ASD are not dysregulated in their responses to mutual gaze. PMID- 26031924 TI - Defining treatment response and symptom remission for anxiety disorders in pediatric autism spectrum disorders using the Pediatric Anxiety Rating Scale. AB - This study examined optimal guidelines to assess treatment response and remission for anxiety in youth with autism spectrum disorders (ASD) using the Pediatric Anxiety Rating Scale (PARS). Data was collected for 108 children aged 7-16 years with comorbid anxiety and ASD before and after receiving cognitive behavior therapy. Optimal cut-offs on the PARS were assessed using signal detection analyses using receiver operating characteristic methods. Maximum agreement with response criteria was achieved at 15 % reduction in symptoms on the PARS. Maximum agreement with remission criteria was achieved at 40 % reduction in symptoms, or at a score of 10 or below at post-treatment. Results have implications for standardizing criteria used in research trials and clinical practice. PMID- 26031926 TI - Building a Research Trajectory. PMID- 26031925 TI - Soluble human leukocyte antigen (sHLA)-G levels may predict early onset of schizophrenia in male patients. PMID- 26031927 TI - Preoperative prediction of risk in colorectal surgery. PMID- 26031928 TI - Sucessful use of thalidomide in severe gastrointestinal Behcet's disease. PMID- 26031930 TI - Endoscopic therapy in early adenocarcinomas (Barrett's cancer) of the esophagus. AB - The incidence of early esophageal adenocarcinoma has been increasing significantly in recent decades. Prognosis depends greatly on the choice of treatment. Early cancers can be treated by endoscopic resection, whereas advanced carcinomas have to be sent for surgery. Esophageal resection is associated with high perioperative mortality (1-5%) even in specialized centers. Early diagnosis enables curative endoscopic treatment option. Patients with gastrointestinal symptoms and a familial risk for esophageal cancer should undergo upper gastrointestinal endoscopy. High-definition endoscopes have been developed with technical add-on that helps endoscopists to find fine irregularities in the esophageal mucosa, but interpreting the findings remains challenging. In this review we discussed novel and old diagnostic procedures and their values, as well as our own recommendations and those of the authors discussed for the diagnosis and treatment of early Barrett's carcinoma. Endoscopic resection is the therapy of choice in early esophageal adenocarcinoma. It is mandatory to perform a subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions. PMID- 26031929 TI - Health-care interventions to promote and assist tobacco cessation: a review of efficacy, effectiveness and affordability for use in national guideline development. AB - AIMS: This paper provides a concise review of the efficacy, effectiveness and affordability of health-care interventions to promote and assist tobacco cessation, in order to inform national guideline development and assist countries in planning their provision of tobacco cessation support. METHODS: Cochrane reviews of randomized controlled trials (RCTs) of major health-care tobacco cessation interventions were used to derive efficacy estimates in terms of percentage-point increases relative to comparison conditions in 6-12-month continuous abstinence rates. This was combined with analysis and evidence from 'real world' studies to form a judgement on the probable effectiveness of each intervention in different settings. The affordability of each intervention was assessed for exemplar countries in each World Bank income category (low, lower middle, upper middle, high). Based on World Health Organization (WHO) criteria, an intervention was judged as affordable for a given income category if the estimated extra cost of saving a life-year was less than or equal to the per capita gross domestic product for that category of country. RESULTS: Brief advice from a health-care worker given opportunistically to smokers attending health care services can promote smoking cessation, and is affordable for countries in all World Bank income categories (i.e. globally). Proactive telephone support, automated text messaging programmes and printed self-help materials can assist smokers wanting help with a quit attempt and are affordable globally. Multi session, face-to-face behavioural support can increase quit success for cigarettes and smokeless tobacco and is affordable in middle- and high-income countries. Nicotine replacement therapy, bupropion, nortriptyline, varenicline and cytisine can all aid quitting smoking when given with at least some behavioural support; of these, cytisine and nortriptyline are affordable globally. CONCLUSIONS: Brief advice from a health-care worker, telephone helplines, automated text messaging, printed self-help materials, cytisine and nortriptyline are globally affordable health-care interventions to promote and assist smoking cessation. Evidence on smokeless tobacco cessation suggests that face-to-face behavioural support and varenicline can promote cessation. PMID- 26031931 TI - Effect of obstructive sleep apnoea on diabetic retinopathy and maculopathy: a systematic review and meta-analysis. AB - AIMS: To summarize the association between obstructive sleep apnoea and diabetic retinopathy and diabetic maculopathy, and to examine the effects of oxygen desaturation index, mean and minimum oxygen saturation and time spent with < 90% oxygen saturation on diabetic retinopathy and diabetic maculopathy. METHODS: A systematic search was performed for papers published from inception to January 2014 in MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews using indexed terms and free text. Additional searches were carried out for grey literature. Two authors conducted the study selection and quality assessment. Data extraction was performed by the main author and checked by the other authors. RESULTS: One cohort study and 15 cross-sectional studies were included for narrative synthesis and three for meta-analyses. There was no convincing evidence that obstructive sleep apnoea was associated with diabetic retinopathy, although some evidence suggested that obstructive sleep apnoea was associated with greater severity of diabetic retinopathy and advanced diabetic retinopathy in people with Type 2 diabetes. Only six studies examined the impact of obstructive sleep apnoea on diabetic maculopathy and our narrative review suggests there is an association in Type 2 diabetes. Oxygen desaturation index, mean oxygen saturation or time spent with < 90% oxygen saturation were not associated with diabetic retinopathy, and insufficient evidence was available to draw conclusions on their effects on diabetic maculopathy; however, there was evidence from both narrative synthesis and meta-analysis that minimum oxygen saturation had an impact on diabetic retinopathy (pooled odds ratio 0.91, 95% CI 0.87-0.95; I(2) = 0%). CONCLUSIONS: There is a need for large cohort studies with long-term follow-up data to examine the long-term effects of obstructive sleep apnoea and other sleep variables on advanced retinal disease in diabetes. PMID- 26031932 TI - Effect of Bleaching Treatment on Fatigue Resistance and Flexural Strength of Bovine Dentin. AB - PURPOSE: To determine the effects of bleach on dentin fatigue resistance and flexural strength. MATERIALS AND METHODS: Eighty bovine dentin specimens (2 * 2 * 17 mm) were treated with: placebo or 10% carbamide peroxide bleach. Treatment was applied for 6 hours/day for 2 or 8 weeks. After treatment, 10 specimens per group were subjected to fatigue testing (10(6) cycles) whereas the other 10 were stored in artificial saliva as fatigue controls. The specimens undergoing fatigue were checked daily for visible signs of fracture and excluded from subsequent flexural strength tests if fractured. Fatigue control and surviving fatigued specimens were subjected to flexural strength testing. Chi-square, Kruskal-Wallis, factorial analysis of variance (p < 0.05) and Mann-Whitney (p < 0.002) tests were performed. RESULTS: There were significant differences in fatigue resistance (p = 0.003) and flexural strength rank scores (p < 0.0001) among the groups. None of the specimens in the "8-week bleach" group survived the fatigue testing. Fatigue (p = 0.005) and interaction of time and treatment (p = 0.039) were significant factors in the flexural strength results. Fatigued specimens had lower flexural strength than nonfatigued and "8-week bleach" had lower flexural strength than placebo and "2-week bleach" groups. CONCLUSIONS: Prolonged direct bleaching of bovine dentin reduces its fatigue resistance and flexural strength in vitro. Further research is needed in this area. CLINICAL SIGNIFICANCE: It remains prudent to advise patients to limit their exposure to tooth bleaching materials by avoiding direct application of bleach to exposed dentin and by minimizing the duration of bleach treatment. PMID- 26031933 TI - Size Effect of Graphene Oxide on Modulating Amyloid Peptide Assembly. AB - Protein misfolding and abnormal assembly could lead to aggregates such as oligomer, proto-fibril, mature fibril, and senior amyloid plaques, which are associated with the pathogenesis of many amyloid diseases. These irreversible amyloid aggregates typically form in vivo and researchers have been endeavoring to find new modulators to invert the aggregation propensity in vitro, which could increase understanding in the mechanism of the aggregation of amyloid protein and pave the way to potential clinical treatment. Graphene oxide (GO) was shown to be a good modulator, which could strongly control the amyloidosis of Abeta (33-42). In particular, quartz crystal microbalance (QCM), circular dichroism (CD) spectroscopy, and atomic force microscopy (AFM) measurements revealed the size dependent manner of GO on modulating the assembly of amyloid peptides, which could be a possible way to regulate the self-assembled nanostructure of amyloid peptide in a predictable manner. PMID- 26031934 TI - The importance of assessing the rate of bone turnover and the balance between bone formation and bone resorption during daily teriparatide administration for osteoporosis: a pilot study. AB - This study aimed to examine the importance of simultaneously measuring bone formation and resorption markers during daily teriparatide administration. In 135 women with osteoporosis, bone mineral density (BMD) was measured at 0, 24, and 48 weeks after teriparatide administration. Bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b were measured at 0, 4, 12, 24, 36, and 48 weeks. Subanalyses were performed in groups divided according to the BMD change at 48 weeks (increased and decreased groups), history of fragility fracture (acute and chronic groups), and treatment prior to teriparatide administration (alendronate, raloxifene, and naive groups). The scatter diagram of multiple of median formation (MoMf) and multiple of median resorption (MoMr) showed that the distribution gradually spread to a high turnover by week 24. A significant correlation was observed between the rate of change in BMD at week 48 and the turnover rate [?(MoMf(2) + MoMr(2))] at week 0. Significant differences were observed in the turnover rate between the acute and chronic groups at weeks 0 and 4 and between the groups divided according to prior treatment from week 0 to 24. Because the assessment of either bone formation markers or bone resorption markers may result in erroneous data, it is necessary to assess them together during teriparatide treatment. The turnover rate at treatment initiation is a useful indicator to predict changes in BMD. When evaluating the turnover rate and balance (MoMf/MoMr), one should consider patient characteristics, including history of fragility fracture and prior treatment. PMID- 26031935 TI - IFITM5 mutations and osteogenesis imperfecta. AB - Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed. PMID- 26031936 TI - Oral health behaviors and bone mineral density in South Korea: the 2008-2010 Korean National Health and Nutrition Examination Survey. AB - The purpose of this study was to examine the association between oral health behaviors and bone mineral density (BMD) by using data from the Korean National Health and Nutrition Examination Survey conducted in 2008-2010. We included 6,620 subjects (3,140 men aged more than 50 years and 3,480 postmenopausal women). BMD was measured at three sites-namely, the lumbar spine, total femur, and femur neck. Oral health behaviors were assessed by use of a self-administered questionnaire in the Korean National Health and Nutrition Examination Survey. After adjustment for all covariates, BMD of the lumbar spine and femur neck tended to increase as the frequency of tooth brushing increased in men (p trend = 0.020 and p trend = 0.028, respectively). Women using secondary oral products had increased lumbar spine BMD compared with women who did not use secondary oral products. However, after adjustment for all covariates, no significant relationship was observed between BMD and the use of secondary oral products. As the frequency of tooth brushing and the number of secondary oral products used increased, the prevalence of osteoporosis decreased. The frequency of tooth brushing is associated with increased lumbar spine and femur neck BMD in South Korean men. PMID- 26031937 TI - A case of lateral sinus insufficiency with acute otitis media: Early surgical intervention for prevention of lateral sinus thrombosis. AB - OBJECTIVE: To describe a case of lateral sinus insufficiency, presumably occurring just prior to lateral sinus thrombosis (LST), and to discuss the importance of early surgical intervention and the pathophysiology of full-blown LST. CASE REPORT: A 4-year-old boy developed headaches and vomiting after exhibiting typical symptoms of acute otitis media. Contrast-enhanced CT revealed narrowing of the sigmoid sinus medially by gas and low-density material. We diagnosed the patient with suspected LST and consequently performed mastoidectomy. A large amount of bloody pus was found in the mastoid cavity and below the bony sinus plate. Sigmoid sinus blood flow was completely restored after drainage of the hemorrhagic and purulent material, and the patient recovered fully. CONCLUSION: Because of the anatomical features of the dural venous sinus, hemorrhage per diapedesis may be strongly associated with the development of LST. In the patient with suspected LST, early diagnosis and surgery prior to the development of intravenous thrombus are key for full recovery from this condition. PMID- 26031940 TI - Can Past Stenting and Blood Lipid Levels Affect the Graft Patency After Coronary Artery Bypass Surgery? PMID- 26031938 TI - Swa2, the yeast homolog of mammalian auxilin, is specifically required for the propagation of the prion variant [URE3-1]. AB - Yeast prions require a core set of chaperone proteins including Sis1, Hsp70 and Hsp104 to generate new amyloid templates for stable propagation, yet emerging studies indicate that propagation of some prions requires additional chaperone activities, demonstrating chaperone specificity beyond the common amyloid requirements. To comprehensively assess such prion-specific requirements for the propagation of the [URE3] prion variant [URE3-1], we screened 12 yeast cytosolic J-proteins, and here we report a novel role for the J-protein Swa2/Aux1. Swa2 is the sole yeast homolog of the mammalian protein auxilin, which, like Swa2, functions in vesicle-mediated endocytosis by disassembling the structural lattice formed by the protein clathrin. We found that, in addition to Sis1, [URE3-1] is specifically dependent upon Swa2, but not on any of the 11 other J-proteins. Further, we show that [URE3-1] propagation requires both a functional J-domain and the tetratricopeptide repeat (TPR) domain, but surprisingly does not require Swa2-clathrin binding. Because the J-domain of Swa2 can be replaced with the J domains of other proteins, our data strongly suggest that prion-chaperone specificity arises from the Swa2 TPR domain and supports a model where Swa2 acts through Hsp70, most likely to provide additional access points for Hsp104 to promote prion template generation. PMID- 26031939 TI - Decreased glutathione reductase2 leads to early leaf senescence in Arabidopsis. AB - Glutathione reductase (GR) catalyzes the reduction of glutathione disulfide (GSSG) to reduced glutathione (GSH) and participates in the ascorbate-glutathione cycle, which scavenges H2 O2 . Here, we report that chloroplastic/mitochondrial GR2 is an important regulator of leaf senescence. Seed development of the homozygous gr2 knockout mutant was blocked at the globular stage. Therefore, to investigate the function of GR2 in leaf senescence, we generated transgenic Arabidopsis plants with decreased GR2 using RNAi. The GR2 RNAi plants displayed early onset of age-dependent and dark- and H2 O2 -induced leaf senescence, which was accompanied by the induction of the senescence-related marker genes SAG12 and SAG13. Furthermore, transcriptome analysis revealed that genes related to leaf senescence, oxidative stress, and phytohormone pathways were upregulated directly before senescence in RNAi plants. In addition, H2 O2 accumulated to higher levels in RNAi plants than in wild-type plants and the levels of H2 O2 peaked in RNAi plants directly before the early onset of leaf senescence. RNAi plants showed a greater decrease in GSH/GSSG levels than wild-type plants during leaf development. Our results suggest that GR2 plays an important role in leaf senescence by modulating H2 O2 and glutathione signaling in Arabidopsis. PMID- 26031941 TI - Can significance of aortic sinus vortices be assessed using the assumptions in the model of Aboelkassem et al.? PMID- 26031942 TI - Inhibition of cell adhesion and immune responses in the mouse model of collagen induced arthritis with a peptidomimetic that blocks CD2-CD58 interface interactions. AB - CD2 and CD58 are two important costimulatory molecules involved in generating the signal II required for normal immune signaling. However, this interaction can be targeted to be of benefit in cases of abnormal immune signaling seen in autoimmune diseases. Our objective in this study was to design a peptidomimetic (compound 7) based on a beta-strand structure of the adhesion domain of CD2 protein to inhibit CD2-CD58 protein-protein interaction and its effect on immunomodulation in the collagen-induced arthritis (CIA) model. The ability of compound 7 to bind to CD58 protein was assessed using flow cytometry. The effect of compound 7 on modulating the immune response was evaluated in an autoimmune disease using CIA in mice. The stability of compound 7 was evaluated in mouse serum using mass spectrometry. Antibody (Ab) binding inhibition studies suggested that compound 7 binds to CD58 protein. Compound 7 was successful in modulating immune responses when administered in the CIA mouse model along with reducing anti-collagen Ab levels and decreasing the level of interferon gamma (IFN-gamma) relative to control treatments. Compound 7 was found to be nonimmunogenic and stable in mouse serum up to 48 h. Results suggest that compound 7 can serve as a lead compound for immunomodulation, and could be a therapeutic agent for the autoimmune disease rheumatoid arthritis (RA). PMID- 26031943 TI - Cerebral Hypoperfusion and Hypometabolism Detected by Arterial Spin Labeling MRI and FDG-PET in Early-Onset Alzheimer's Disease. AB - BACKGROUND AND PURPOSE: Early-onset Alzheimer's disease (EOAD) is frequently associated with atypical clinical presentations and its early detection remains a challenging issue. In this study, we used arterial spin labeling (ASL), a noninvasive perfusion MRI sequence, and [(18)F]-FDG-PET to detect the perfusion and metabolic features in patients with EOAD. METHODS: All patients were investigated in the French reference center for young-onset dementia and were assessed by MRI, including a pseudo-continuous ASL (pCASL) sequence, and [(18)F] FDG-PET. Quantitative analyses and intermodality comparison with correlation analysis were made after data processing including correction of partial volume effects, cortical projection, and specific intensity normalization. RESULTS: We prospectively included 37 patients with EOAD with a mean age of 58.3 years. The areas of most severe hypoperfusion detected with ASL were located in the parietal lobes, the precuneus, the right posterior cingulate cortex, and the frontal lobes (P < .05). The areas of lowest glucose metabolism detected by [(18)F]-FDG-PET were identified in the temporoparietal cortex and the precuneus (P < .05). Hypometabolic regions were more extensive than hypoperfused regions on ASL maps whereas ASL highlighted alterations in the frontal lobes without apparent hypometabolism on [(18)F]-FDG-PET maps. CONCLUSIONS: ASL and [(18)F]-FDG-PET detected pathological areas of similar distribution mainly located in the inferior parietal lobules and local zones in the temporal cortex in patients with EOAD. Our preliminary study showed that ASL and [(18)F]-FDG-PET may have a complementary role in combination with structural MRI for the assessment of suspected EOAD. PMID- 26031944 TI - [The effect of prosthesis-patient mismatchon early myocardial remodeling after aortic valve replacement]. AB - The reductionofan effective orifice area is associated with the development of the phenomenon of prosthesis-patient mismatch (PPM). The purpose of this study was to evaluate the impact of PPM on the immediate results of surgical treatment in patients with aortic valve stenosis. The study included 50 patients who underwent aortic valve replacement. All patients were divided into 2 groups: with PPM (27 patients) and without it (23 patients). Immediate postoperative results were not statistically different. Analysis of echocardiographic data showed worse results in patients with PPM. It was marked reduction of LV EDV on 23.43 +/- 8.93 ml in the group without PPM and on 16.5 +/- 1.76 ml in patients with PPM (p<0.05). Also it was noted a greater decrease of pulmonary artery pressure (16.56 +/- 12.94 mm Hg) compared with the group with PPM (8.44 +/- 7.38 mm Hg), p<0.05. The presence of PPM in patients after aortic valve replacement leads to a slower reverse remodeling of the myocardium. PMID- 26031945 TI - [Simultaneous brachiocephalic arteries reconstruction and coronary artery bypass grafting]. AB - It is presented the results of simultaneous surgical treatment of 55 patients with brachiocephalic arteries lesion and ischemic heart disease. All patients underwent reconstructive operations on brachiocephalic arteries and CABG. The features of diagnosis and surgical stage are described. The indications for this method are defined. The authors studied russian and world experience; complications of simultaneous operations are presented. It is suggested ways for improvement of results of simultaneous reconstructions. PMID- 26031946 TI - [Lung-preserving surgical treatment of patients with bronchial carcinoid]. AB - Isolated bronchus resection for central cancer was performed in 25 patients including preoperative bronchoscopic removal of exophytic tumor in 20 (80%) observations in thoracic department of P. Gertsen Moscow Research Cancer Institute. According to morphological study typical carcinoid was diagnosed in 23 (92%) patients, atypical - in 2 (8%) cases. All patients underwent conventional mediastinal lymphadenectomy. Postoperative complications after bronchus resection developed in 6 (33.3%) patients. There were no deaths. Overall 5- and 10-year survival was 100% and 96% respectively. The authors consider that by strict indications combination of endoscopic removal with isolated bronchus resection preserves all pulmonary parenchyma without prejudice for surgical radicalism. PMID- 26031947 TI - [Volumes of lymphadenectomy in gastric cancer surgery]. AB - It is summarized an experience of 1528 resections for gastric cancer supplemented by D1-, D2-, D2,5- and D3-lymphadenectomy in 751, 241, 359 and 177 patients resrectively. Unconventional type D2.5 means D2-lymphodis section with additional lymphadenectomy along hepatoduodenal ligament and superior retropancreatic nodes as well as omental bursa removal with lymphodis section of esophageal opening crura. Analysis of immediate and remote results is presented. It is concluded that D3-lymphadenectomy is minimally preferred over D2.5-type in gastric cancer staging. D3-lymphodis section has the largest number of especially purulent and pancreatogenic postoperative complications. D2.5-lymphadenectomy significantly increases 5-year survival in comparison with D2-lymphodis section (from 51.2 +/- 4.9 to 64.0 +/- 4.1%; p<0.001) and may be chosen for any radical surgery for gastric cancer including early forms. Localized proximal tumors which are in distinctive for metastasis into hepatoduodenal ligament lymph nodes are exception. D3-lymphodis section did not impact on survival in comparison with D2,5-lymphadenectomy. Only patients with antral cancer after distal subtotal gastric resection had 5-year survival increasing on 8 % (from 60.6 +/- 7.5 to 68.5 +/- 6.3%). PMID- 26031948 TI - [Robot-assisted resection of duodenal inferior horizontal part and duodeno jejunal transition]. AB - Robot-assisted resection of duodenal inferior horizontal part and duodeno-jejunal transition was performed in 5 patients with tumors in this area including gastrointestinal stromal tumor in 4 cases and jejunal adenocarcinoma in 1 case. It is suggested there section method with vertical and inferior horizontal parts and pancreatic head dissection right-to-left. There were no intra- and postoperative complications. Robot-assisted resection of duodenal inferior horizontal part and duodeno-jejunal transition may be successfully used for tumors with diameter less than 5-6 cm. PMID- 26031949 TI - [Minimally invasive surgical treatment of gastrointestinal stromal tumor]. AB - It was operated 24 patients with gastrointestinal stromal tumor (GIST). Robot assisted method was applied in 15 observations, laparoscopy - in 9 patients. Laparoscopic operations were preferable for GIST localized in anterior wall or greater curvature of stomach, in small intestine and caecum. Robot-assisted GIST removal was performed in case its location in posterior wall of stomach, on lesser curvature of stomach, in duodenum, what required organ's dissection or had a risk of great vessel injury. PMID- 26031950 TI - [Prevention of reflux-esophagitis after gastrectomy]. AB - It is presented the results of gastrectomy in 431 patients with varying reconstructive-reparative stage. Patients were divided into two comparable groups. The main group consisted of 146 patients who underwent developed technique with food reservoir performing after gastrectomy. Control group included 285 patients after conventional digestive tract reconstruction. It was concluded that 30.4% of patients have entero-esophageal reflux, in 21.7% and 8.7% of patients endoscopic and morphological signs of reflux-esophagitis were observed respectively. Suggested technique creates gas bubble providing obturator mechanism and decreasing the frequency of entero-esophageal reflux to 26.3% and reflux-esophagitis to 5.3%. It proves advantage of suggested method of gastroplasty for prevention of reflux-esophagitis in comparison with traditional digestive tract reconstruction after gastrectomy. PMID- 26031951 TI - [Treatment of paracolostomic hernias using polypropylene mesh]. AB - It was analyzed the results of treatment of 23 patients with large paracolostomic hernias. Twenty patients underwent colostomy suturing and hernial ring Onlay plasty with polypropylene mesh without tension. Onlay-plasty of hernial ring with own tissues and polypropylene mesh and colostomy reconstruction outside of implant were performed in 3 patients. Onlay-alloplasty with polypropylene mesh "PROLENE" is effective method of treatment of postoperative paracolostomic ventral hernias with colostomy closing as well as with its reconstruction outside of implant. PMID- 26031952 TI - [Laparoscopic diagnosis and treatment of early adhesive small bowel obstruction after gynecological surgery]. AB - It is presented the results of diagnostic and curative laparoscopic interventions in 33 patients with acute early adhesive small bowel obstruction. Ileus developed after surgical treatment (laparotomy) of different gynecological diseases. Laparoscopy appeared as the most informative diagnostic method to confirm diagnosis in all patients, to estimate state of abdominal cavity and small pelvis organs what can help to determine method of surgical treatment. Contraindications for laparoscopic surgery were identified in 12 (36.4%) patients and conversion to laparotomy was applied in this group. Postoperative complications were diagnosed in 1 (8.3%) patient. 2 (16.6%) patients died. Early adhesive ileus was resolved laparoscopically in 21 (63.6%) of 33 patients. Recurrent acute early adhesive ileus was detected in 1 (4.7%) patient. PMID- 26031953 TI - [Use of meshendoprostheses with diamond-like carbon coating in abdominal hernias surgery]. AB - It is presented the results of implantation of meshendoprostheses with and without carbon coating for surgical treatment of abdominal hernias in experiment and clinical practice. It was shown that diamond-like carbon coating minimizes primary tissue reaction against foreign material and provides complete implant's biological integration into subcutaneous connective tissue as are active encapsulation with connective tissue. Suggested meshendoprostheses with diamond like carbon coating decrease local inflammatory reaction in operated area and thereby reduce number of exudative complications in early postoperative period. PMID- 26031954 TI - [Algorithm of surgical treatment of patients with consequences of burn injury]. AB - Rehabilitation of patients suffering from consequences of burn injury is actual problem in plastic surgery. There is no unified strategy defining optimal terms and stages of treatment, possibility and advisability of simultaneous interventions on different anatomical areas, combination of surgical and conservative treatment while it is necessary for decrease of rehabilitation terms in victims. On basis of twelve-year experience of 1246 patients with consequences of burn injury the authors developed universal algorithm for optimization of surgical treatment, improvement of results and reduction of treatment time. PMID- 26031955 TI - [New approach to postoperative delirium treatment]. AB - The efficiency of different drugs for sedation was studied in 51 patients after large abdominal operations complicated by postoperative delirium. Diagnosis of postoperative delirium was established according to CAM-ICU criteria. Dexmedetomidine has demonstrated significantly decreased duration of delirium and hospital stay in intensive care unit in comparison with haloperidol. Besides, patients which received dexmedetomidine preserved opportunity for verbal contact. Also these patients interacted better with department's stuff. PMID- 26031956 TI - [Immunological aspects in spleen ruptures surgery due to closed abdominal trauma]. AB - The remote results of immunity investigation in 30 patients after organ preserving surgery and in 30 patients after splenectomy forspleen rupture are presented in the article. Indexes of cellular and humoral immunity were normal and life quality did not differ from that in healthy individuals after organ preserving operations with splenic artery ligation. Splenectomy leads to deterioration of life quality and disorders in cellular immunity including decrease of T-helpers/inductors cells (CD4), immunoregulatory index (CD3/CD4) and general number of T-lymphocytes (CD3) in some cases on background of compensatory increase of normal killers (CD16). It was observed significant decrease of IgG and IgM levels. Values of IgA and cytokines IL-1, IL-2, IL-6 and TNF remained normal. Level of immunosuppression is reduced due to development of splenosis. PMID- 26031957 TI - [New antibiotic in treatment of surgical infection: the first experience]. PMID- 26031958 TI - [Use of greater omentum for arrosive hemorrhage in tracheal surgery]. PMID- 26031959 TI - [Endovascular treatment of proper liver artery aneurysm complicated by intestinal bleeding]. PMID- 26031960 TI - [Thoracoscopic removal of giant leiomyoma of lower thoracic esophagus]. PMID- 26031961 TI - Group belongingness and collective action: Effects of need to belong and rejection sensitivity on willingness to participate in protest activities. AB - Engaging in political protests are becoming increasingly common, and considering the potential, individual, costs and the low probability of affecting the political outcome, it is necessary to understand the motivations behind such actions. The desire to be part of a social group is deeply rooted in human nature, and previous research proposes that the groups one belongs to may influence the decision to engage in protests. We build on this research and suggest that social exclusion, individual fear of exclusion and need to belong interact in explaining who is likely to become engaged. In two studies, one natural experiment and one lab-experiment, we show that social exclusion increase willingness to participate in protests for individuals high in both rejection sensitivity and need to belong. We conclude that contextual factors, such as exclusion or marginalization should be considered in relation to individual level personality factors when explaining who is likely to become engaged in political protests. These results are important since they suggest that some people engage in politics simply due to social reasons and are less ideologically motivated. PMID- 26031962 TI - Cutaneous leishmaniasis in travellers: a focus on epidemiology and treatment in 2015. AB - Imported cutaneous leishmaniasis (CL) is a growing problem with increasing global travel to endemic areas. Returned travellers seeking care encounter significant barriers to treatment, including diagnostic delays and difficult access to anti leishmanial drugs. Treatment recommendations in non-endemic settings are a moving target, reflecting recent developments in Leishmania diagnostics and therapeutics. Accumulating experience with molecular-based species identification has enabled species-directed therapy. Clinicians are reevaluating more toxic traditional regimens in light of newly approved therapeutic agents and emerging data on local cutaneous treatments. Referral centers are implementing treatment decision algorithms designed to maximize efficacy while minimizing adverse events. Although management strategies continue to evolve, treatment of CL in non endemic settings remains controversial. Persistent reliance on expert opinion reflects lack of research focused on travellers and limited randomized controlled trial evidence. We herein review the current epidemiology of cutaneous leishmaniasis in travellers and species-specific evidence for available therapies. PMID- 26031963 TI - Eliminating Infections in the ICU: CLABSI. AB - Central line-associated bloodstream infections (CLABSI) are one of the leading causes of death in the USA and around the world. As a preventable healthcare associated infection, they are associated with significant morbidity and excess costs to the healthcare system. Effective and long-term CLABSI prevention requires a multifaceted approach, involving evidence-based best practices coupled with effective implementation strategies. Currently recommended practices are supported by evidence and are simple, such as appropriate hand hygiene, use of full barrier precautions, avoidance of femoral lines, skin antisepsis, and removal of unnecessary lines. The most successful and sustained improvements in CLABSI rates further utilize an adaptive component to align provider behaviors with consistent and reliable use of evidence-based practices. Great success has been achieved in reducing CLABSI rates in the USA and elsewhere over the past decade, but more is needed. This article aims to review the initiatives undertaken to reduce CLABSI and summarizes the sentinel and recent literature regarding CLABSI and its prevention. PMID- 26031966 TI - A national support service. PMID- 26031967 TI - Registration at the time of graduation. PMID- 26031964 TI - Transplantation in the tropics: lessons on prevention and management of tropical infectious diseases. AB - Tropical infectious diseases (IDs) remain a rare complication in transplant recipients even in tropical settings, but this topic has become increasingly important during the last decade due to multiple factors. Interestingly, non tropical countries report most of the experiences with tropical diseases. The reported experience from non-endemic regions, however, does not always reflect the experience of endemic areas. Most of the guidelines and recommendations in the literature may not be applicable in tropical settings due to logistical difficulties, cost, and lack of proven benefit. In addition, certain post transplant prevention measures, as prophylaxis and reducing exposure risk, are not feasible. Nonetheless, risk assessment and post-transplant management of tropical IDs in tropical areas should not be neglected, and clinicians need to have a higher clinical awareness for tropical ID occurring in this population. Herein, we review the more significant tropical ID in transplant patients, focusing on relevant experience reported by tropical settings. PMID- 26031968 TI - Testing the AMB score - can it distinguish patients who are suitable for ambulatory care? AB - The Royal College of Physicians' Acute care toolkit 10 has recommended the use of the AMB score as an aid to determining patients suitable for ambulatory care. As this score has only been previously validated in one centre, the present study calculated the score of 200 patients referred to the medical take to see if it successfully identified patients who had a length of stay of less than 12 hours. In our test centre, the score was found to have a reduced sensitivity compared with the original centre (88 vs 96%) and a positive predictive value of 39%. Therefore in our hospital this was not a useful scoring system, and other trusts need to be aware that the AMB score may not be as effective as the original study suggested. PMID- 26031965 TI - Empiric antimicrobial therapy in severe sepsis and septic shock: optimizing pathogen clearance. AB - Mortality and morbidity in severe sepsis and septic shock remain high despite significant advances in critical care. Efforts to improve outcome in septic conditions have focused on targeted, quantitative resuscitation strategies utilizing intravenous fluids, vasopressors, inotropes, and blood transfusions to correct disease-associated circulatory dysfunction driven by immune-mediated systemic inflammation. This review explores an alternate paradigm of septic shock in which microbial burden is identified as the key driver of mortality and progression to irreversible shock. We propose that clinical outcomes in severe sepsis and septic shock hinge upon the optimized selection, dosing, and delivery of highly potent antimicrobial therapy. PMID- 26031969 TI - Implementation of NICE clinical guideline 95 on chest pain of recent onset: experience in a district general hospital. AB - The National Institute for Health and Care Excellence (NICE) CG95 clinical guideline on chest pain of recent onset was published in 2010. There is debate over whether the proposed strategy improves patient care and its implications on service costs. Following a six-month pilot, 472 consecutive patient records were audited for pre-test probability of significant coronary artery disease, investigations performed and outcomes. Low- and moderate-risk patients had an unexpectedly low rate of coronary disease and revascularisation. Computerised tomography coronary angiography (CTCA) and stress echocardiography performed similarly, though the latter was more resource intensive. High-/very high-risk patients frequently required revascularisation and greater than 10% of each group had prognostically significant disease, going against the recommendation that very high risk patients do not undergo angiography. There were frequent protocol deviations and training clinic staff in the new approach was challenging. In conclusion, implementing NICE CG95 is feasible but presents challenges. Staff require training to follow the protocol consistently. Functional testing had no benefits over anatomical testing with CTCA, which may allow cost savings in some departments. PMID- 26031970 TI - Diabetes patient at risk score - a novel system for triaging appropriate referrals of inpatients with diabetes to the diabetes team. AB - The acceptability, uptake and effectiveness of a new referral tool - the diabetes patient at risk (DPAR) score - were evaluated and the timeliness of review of referred inpatients by the diabetes team was measured. For this, a snapshot survey of ward healthcare professionals (HCPs) and a review of all DPAR referrals to the diabetes team between 1 September 2013 and 31 January 2014 were undertaken. All referrals in November 2013 were audited for timeliness of review. 77% of HCPs agreed/strongly agreed that the tool improved access to the diabetes team. 76% of referrals were from nurses. 80% of who should have been referred were referred; the remaining had already been reviewed by the diabetes team and therefore did not require referral. Only 11% of referrals were inappropriate. All DPAR referrals were reviewed within the stipulated time period in November 2013. Overall, the DPAR system was well accepted, successfully identified appropriate referrals and facilitated referrals in a timely manner to the diabetes team. PMID- 26031971 TI - Comparison of ESC and NICE guidelines for patients with suspected coronary artery disease: evaluation of the pre-test probability risk scores in clinical practice. AB - The European Society of Cardiology (ESC) and UK National Institute for Health and Care Excellence (NICE) have recently published guidelines for investigating patients with suspected coronary artery disease (CAD). Both provide a risk score (RS) to assess the pre-test probability for CAD to guide clinicians to undertake the most effective investigation. The aim of the study was to establish whether there is a difference between the two RS models. We retrospectively reviewed records of 479 patients who presented to a UK district general hospital with chest pain between August 2011 and April 2013. The RS was calculated using ESC and NICE guidelines and compared. From the 479 patients, 277 (58%) were male and the mean age was 60 years. The mean RS was greater using NICE guidelines compared with ESC (66.3 vs 47.9%, 18.4% difference; p<0.0001). The difference in mean RS was smaller in patients with typical chest pain (13.0%). When we divided the cohort based on NICE criteria into 'high'- and 'low'-risk groups, the difference in the mean RS was 24.3% in the 'high'-risk group (p<0.001) compared with 2.8% in the 'low'-risk group. The UK NICE risk score model overestimates risk compared with the ESC model. PMID- 26031972 TI - Serum potassium levels as an outcome determinant in acute medical admissions. AB - The relationship between serum potassium levels and mortality in acute medical admissions is uncertain. In particular, the relevance of minor abnormalities in potassium level or variations within the normal range remains to be determined. We performed a retrospective cohort study of all emergency medical admissions to St James's Hospital (Dublin, Ireland) between 2002 and 2012. We used a stepwise logistic regression model to predict in-hospital mortality, adjusting risk estimates for major predictor variables. There were 67,585 admissions in 37,828 patients over 11 years. After removing long-stay patients, 60,864 admissions in 35,168 patients were included in the study. Hypokalaemia was present in 14.5% and hyperkalaemia in 4.9%. In-hospital mortality was 3.9, 5.0, and 18.1% in the normokalaemic, hypokalaemic and hyperkalaemic groups respectively. Hypokalaemic patients had a univariate odds ratio (OR) of 1.29 for in-hospital mortality (95% confidence interval (CI) 1.16-1.43; p<0.001). Hyperkalaemic patients had a univariate OR for in-hospital mortality of 5.2 (95% CI 4.7-5.7; p<0.001). The ORs for an in-hospital death for potassium between 4.3 and 4.7 mmol/l, and 4.7 and 5.2 mmol/l, were 1.73 (95% CI 1.51-1.99) and 2.97 (95% CI 2.53-3.50) respectively. Hyperkalaemia and hypokalaemia are associated with increased mortality. PMID- 26031973 TI - Blood alanine aminotransferase levels >1,000 IU/l - causes and outcomes. AB - Standard medical education dictates that the vast majority of cases of an alanine aminotransferase (ALT) level >1,000 IU/l will be due to acute ischaemia, acute drug-induced liver injury (DILI) (usually paracetamol) or acute viral hepatitis. There are very few references in the literature to other potential causes of an ALT >1,000 IU/l nor to the prognosis ascribed to each aetiology. In this study, we have confirmed that the main causes of a dramatic ALT rise are ischaemic liver injury, DILI and viral hepatitis. Common bile duct stones and hepatitis E are two causes for which there needs to be a high index of suspicion as the necessary tests may not be in the clinician's first-line investigation panel. Failing to find a cause and determining that the cause was ischaemic both have poor prognostic implications. PMID- 26031974 TI - MTHFR 677C/T and 1298A/C mutations and non-alcoholic fatty liver disease. AB - Common genetic mutations encountered in folate metabolism may result in increased homocysteine (Hcy) levels. It has been reported that increased serum Hcy levels may affect the intracellular fat metabolism and may cause enhanced fatty infiltration in the liver resulting in non-alcoholic fatty liver disease (NAFLD). In total, 150 patients diagnosed with FLD by ultrasound examination and 136 healthy control patients that do not have any fatty infiltration in the liver were included in the study. Patients were grouped as mild (n = 88), moderate (n = 38) or severe (n = 24) according to the stage of fatty liver in ultrasound. Serum liver function tests, Hcy, folic acid and vitamin B12 levels of the patients were studied. The genetic MTHFR C677T and A1298C polymorphisms of the patients were also evaluated. Although there was no significant difference in vitamin B12 and folic acid levels, in the severe group, Hcy levels were significantly higher than that of control and mild groups (p<0.001). By contrast, there was no significant difference in heterozygote MTHFR 677C/T and 1298A/C mutations, both MTHFR 677C/T and MTHFR 1298A/C mutations were more common in NAFLD groups compared with the control patients (p<0.001). We have determined increased Hcy levels and increased prevalence of homozygote MTHFR 677C/T and MTHFR 1298A/C mutations in patients with NAFLD compared with healthy controls. Larger studies are warranted to clarify the etiological role of the MTHFR mutations and Hcy levels in FLD. PMID- 26031975 TI - Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy. AB - Although recognised as a cause of chronic diarrhoea for over forty years, diagnostic tests and treatments for bile acid malabsorption (BAM) remain controversial. Recent National Institute for Health and Care Excellence (NICE) guidelines highlighted the lack of evidence in the field, and called for further research. This retrospective study explores the BAM subtype and severity, the use and response to bile acid sequestrants (BAS) and the prevalence of abnormal colonic histology. 264 selenium-75-labelled homocholic acid conjugated taurine (SeHCAT)-tested patient records were reviewed and the severity and subtype of BAM, presence of colonic histopathology and response to BAS were recorded. 53% of patients tested had BAM, with type-2 BAM in 45% of patients with presumed irritable bowel syndrome. Colonic histological abnormalities were similar overall between patients with (29%) or without (23%) BAM (p = 0.46) and between BAM subtypes, with no significant presence of inflammatory changes. 63% of patients with BAM had a successful BAS response which showed a trend to decreased response with reduced severity. Colestyramine was unsuccessful in 44% (38/87) and 45% of these (17/38) were related to medication intolerance, despite a positive SeHCAT. 47% (7/15) of colestyramine failures had a successful colesevelam response. No patient reported colesevelam intolerance. Quantifying severity of BAM appears to be useful in predicting BAS response. Colesevelam was better tolerated than colestyramine and showed some efficacy in colestyramine failures. Colestyramine failure should not be used to exclude BAM. Colonic histology is of no relevance. PMID- 26031976 TI - Making healthcare safer by understanding, designing and buying better IT. AB - When nobody or nothing notices an error, it may turn into patient harm. We show that medical devices ignore many errors, and therefore do not adequately support patient safety. In addition to causing preventable patient harm, errors are often reported ignoring potential flaws in medical device design, and front line staff may therefore be inappropriately blamed. We present some suggestions to improve reporting and the procurement of hospital equipment. PMID- 26031977 TI - A review of the health effects of smoking shisha. AB - There is emerging evidence, although at early stages, of various detrimental health effects after smoking shisha. With regard to the cardiovascular system, there is a significant acute rise in cardiovascular markers, such as heart rate and blood pressure. The long-term effects on the cardiovascular system are yet to be established. Shisha smoking has also been significantly associated with lung cancer. Various other forms of cancer have also been documented, but have not reached statistical significance and require further research. Finally, shisha smoking increases the risk of infection and has been associated with outbreaks in the Middle East. Therefore, with the increasing consumption of shisha in Europe, especially in the UK, more research is required to tackle this potential public health threat. PMID- 26031978 TI - Physical activity and health in adolescence. AB - Adolescence represents a critical period of development during which personal lifestyle choices and behaviour patterns establish, including the choice to be physically active. Physical inactivity, sedentary behaviour and low cardiorespiratory fitness are strong risk factors for the development of chronic diseases with resulting morbidity and mortality, as well as economic burden to wider society from health and social care provision, and reduced occupational productivity. Worrying trends in adverse physical activity behaviours necessitate urgent and concerted action. Healthcare professionals caring for adolescents and young adults are ideally placed and suited to deliver powerful messages promoting physical activity and behaviour change. Every encounter represents an opportunity to ask about physical activity, provide advice, or signpost to appropriate pathways or opportunities. Key initial targets include getting everyone to reduce their sedentary behaviour and be more active, with even a little being more beneficial than none at all. PMID- 26031979 TI - Drug therapy in headache. AB - All physicians will encounter patients with headaches. Primary headache disorders are common, and often disabling. This paper reviews the principles of drug therapy in headache in adults, focusing on the three commonest disorders presenting in both primary and secondary care: tension-type headache, migraine and cluster headache. The clinical evidence on the basis of which choices can be made between the currently available drug therapies for acute and preventive treatment of these disorders is presented, and information given on the options available for the emergency parenteral treatment of refractory migraine attacks and cluster headache. PMID- 26031980 TI - Fever of unknown origin. AB - More than 50 years after the first definition of fever of unknown origin (FUO), it still remains a diagnostic challenge. Evaluation starts with the identification of potential diagnostic clues (PDCs), which should guide further investigations. In the absence of PDCs a standardised diagnostic protocol should be followed with PET-CT as the imaging technique of first choice. Even with a standardised protocol, in a large proportion of patients from western countries the cause for FUO cannot be identified. The treatment of FUO is guided by the final diagnosis, but when no cause is found, antipyretic drugs can be prescribed. Corticosteroids should be avoided in the absence of a diagnosis, especially at an early stage. The prognosis of FUO is determined by the underlying cause. The majority of patients with unexplained FUO will eventually show spontaneous remission of fever. We describe the definition, diagnostic workup, causes and treatment of FUO. PMID- 26031981 TI - Infectious causes of fever of unknown origin. AB - The causes of fever of unknown origin (FUO) are changing because advances in clinical practice and diagnostics have facilitated the identification of some infections. A variety of bacterial infections can cause FUO, and these can be divided into those that are easy to identify using culture and those that require serological or molecular tests for identification. A number of viral, parasitic and fungal infections can also cause prolonged fever. This article summarises the clinical features and diagnostic strategy of these infections. PMID- 26031982 TI - The ying and yang of fever in rheumatic disease. AB - Fevers are relatively common in rheumatic disease, largely due to the fact that the inflammatory process is driven by inflammatory mediators that function as endogenous pyrogens. Since the immune system's sensors cannot accurately distinguish between endogenous and exogenous (pathogen-derived) pyrogens a major challenge for physicians and rheumatologists has been to decipher patterns of clinical signs and symptoms to inform clinical decision making. Here we describe some of the common pitfalls and clinical challenges, and highlight the importance of a systematic approach to investigating the rheumatic disease patient presenting with fever. PMID- 26031983 TI - Malignant causes of fever of unknown origin. AB - The presence of fever in malignancy usually indicates infection, though transfusion, thrombosis and drugs are also culprits. However, particularly in some tumour types, fever can also be a paraneoplastic syndrome, caused by the malignancy itself. This can be a difficult diagnosis to establish and presents a therapeutic challenge to the physician when the underlying malignancy is not easily treated. PMID- 26031984 TI - Autoinflammatory syndromes as causes of fever of unknown origin. AB - The systemic autoinflammatory syndromes often present with recurrent fevers. They have proved exceptionally informative about the innate immune system. Although extremely rare, they are important to recognise, as many can now be completely controlled by long-term drug therapies. Diagnosis relies on clinical suspicion followed by genetic testing. PMID- 26031986 TI - Lesson of the month 1: Acute flecainide overdose and the potential utility of lipid emulsion therapy. AB - Lipid-emulsion therapy (Intralipid(r)) has been advocated as a potential treatment for the management of cardio-toxicity arising from lipid-soluble drugs, particularly those acting upon sodium channels. This, on the basis of a number of ex vivo studies and animal models, suggests that partitioning a drug into lipid could alter its pharmacokinetics and result in significant clinical improvements. Its subsequent use in clinical case series has been seen as confirmation of this mechanism of action. While there are undoubtedly instances where lipid emulsion therapy has been associated with a desirable outcome in humans, as described in this case report, clinicians are reminded that they should not attribute causality, on this basis alone. PMID- 26031987 TI - Lesson of the month 2: Chronic erythematous painless plaque on the eyelid co presenting with multiple ulcerated nodules on the extremities. AB - Cutaneous leishmaniasis is a parasitic disease caused by the Leishmania species, transmitted by the bite of an infected sandfly. The typical cutaneous lesion is a painless ulcer with a raised, indurated margin and often covered with an adherent crust. The lesions are mostly located on exposed sites such as the face and the extremities. Eyelid involvement is rare, making up only 2-5% of cases with facial cutaneous leishmaniasis. Herein, we report a 50-year-old male who presented with an erythematous plaque on the upper eyelid and multiple ulcerated nodules located on the extremities. Following microscopic examination of the lesional smear, a diagnosis of cutaneous leishmaniasis was made, and the patient was successfully treated with intramuscular meglumine antimonate therapy. PMID- 26031988 TI - Angel's wing appearance on chest radiograph - progressive massive fibrosis. PMID- 26031990 TI - Response. PMID- 26031989 TI - Brugada phenocopies are the leading differential diagnosis of Brugada syndrome. PMID- 26031991 TI - A new kid on the block: the role of physician associates. PMID- 26031992 TI - Inverse psoriasis. PMID- 26031993 TI - Survey on the attitudes of hospital doctors towards the terms 'acopia' and 'social admission' in clinical practice. AB - Letters not directly related to articles published in Clinical Medicine and presenting unpublished original data should be submitted for publication in this section. Clinical and scientific letters should not exceed 500 words and may include one table and up to five references. PMID- 26031994 TI - Mixed-species associations in cuxius (genus Chiropotes). AB - Polyspecific or mixed-species associations, where two or more species come together to forage and travel as a unit, have been reported in many primate species. These associations appear to offer a number of benefits to the species involved including increased foraging efficiency and decreased risk of predation. While several researchers have suggested that cuxius (genus Chiropotes) form mixed-species associations, previous studies have not identified the circumstances under which cuxius form associations or whether they form associations more often than would be expected by chance. Here we present data on the formation of mixed-species associations by four species of cuxius at eight different sites in Brazil, Suriname, and Guyana. We analyzed data from two of the study sites, (Biological Dynamics of Forest Fragments Project (BDFFP), Brazil and the Upper Essequibo Conservation Concession (UECC), Guyana, to assess whether associations occurred more than would be expected by chance encounters and identify the factors influencing their formation. Cuxius showed a high degree of inter-site variation in the frequency of time spent in association (ranging from 2 to 26% of observation time) and duration of associations (mean duration from 22 min to 2.5 hr). Sapajus apella was the most common association partner at most sites. At BDFFP, cuxius formed associations more frequently but not for longer duration than expected by chance. For much of the year at UECC, associations were not more frequent or longer than chance. However, during the dry season, cuxius formed associations with S. apella significantly more often and for longer duration than predicted by chance. Cuxius at UECC formed associations significantly more often when in smaller subgroups and when foraging for insects, and alarm called significantly less frequently during associations. We suggest cuxius form mixed-species associations at some sites as an adaptive strategy to decrease predation risk and/or increase foraging efficiency. PMID- 26031995 TI - Factors associated with pain and disability reduction following exercise interventions in chronic whiplash. AB - BACKGROUND: Some studies support the prescription of exercise for people with whiplash-associated disorders (WAD); however, the response is highly variable. Further research is necessary to identify factors which predict response. METHODS: This is a secondary analysis of a randomized, multicentre controlled clinical trial of 202 volunteers with chronic WAD (grades 2 and 3). They received either neck-specific exercise with, or without a behavioural approach, or prescription of physical activity for 12 weeks. Treatment response, defined as a clinical important reduction in pain or disability, was registered after 3 and 12 months, and factors associated with treatment response were explored using logistic regression. RESULTS: Participation in the neck-specific exercise group was the only significant factor associated with both neck pain and neck disability reduction both at 3 and 12 months. Patients in this group had up to 5.3 times higher odds of disability reduction and 3.9 times higher odds of pain reduction compared to those in the physical activity group. Different baseline features were identified as predictors of response depending on the time point examined and the outcome measure selected (pain vs. disability). CONCLUSION: Factors associated with treatment response after exercise interventions differ in the short and long term and differ depending on whether neck pain or disability is considered as the primary outcome. Participation in a neck-specific exercise intervention, in contrast to general physical activity, was the only factor that consistently indicated higher odds of treatment success. These results support the prescription of neck-specific exercise for individuals with chronic WAD. PMID- 26031996 TI - Determination of the mutant allele frequency in patients with neurofibromatosis type 2 and somatic mosaicism by means of deep sequencing. AB - Neurofibromatosis Type 2 (NF2) is an autosomal disorder caused by mutations of the NF2 gene. More than half of all NF2 patients have unaffected parents and carry de novo mutations, which may be of prezygotic or postzygotic origin. The latter can result in mosaicism, which is relatively common in NF2 patients. Previous studies indicated that, in 50% of patients with mosaic NF2 mutations, the mutant allele is only detectable by Sanger sequencing of PCR products amplified from tumor tissue but not from blood samples. In order to establish a highly sensitive method that has the power to detect low levels of NF2 mutant alleles from blood samples of mosaic NF2 patients, we performed ultra deep sequencing and calculated the percentage of mutant and wildtype NF2 alleles. The mutant allele frequencies detected ranged from 2.6% to 19.7%. In three patients, however, the NF2 mutation previously identified in tumor tissue was not identified in blood samples by means of deep sequencing, suggesting absence of mutant cells in the blood. Remarkably, we observed a correlation between the age at onset of the disease and the mutant allele frequency. Our study indicates that ultra deep sequencing is an effective and highly sensitive method to determine the mutant allele frequency in patients with mosaic NF2 gene mutations, which enables extended phenotype/correlations in these patients. (c) 2015 Wiley Periodicals, Inc. PMID- 26031997 TI - Mental Health Among Adolescents Exposed to a Tornado: The Influence of Social Support and Its Interactions With Sociodemographic Characteristics and Disaster Exposure. AB - Approximately 25% of youths experience a natural disaster and many experience disaster-related distress, including symptoms of posttraumatic stress disorder (PTSD) and depression. This study contributes to the literature by examining PTSD and depressive symptoms among 2,000 adolescents (50.9% female, 70.5% White) assessed after exposure to tornadoes in 2011. The authors hypothesized that greater tornado exposure, female sex, and younger age would be associated with distress, and that social support would interact with these associations. Analyses showed that PTSD symptoms were associated with lower levels of social support (beta = -.28, p < .001), greater tornado exposure (beta = .14, p < .001), lower household income (beta = -.06, p = .013, female sex (beta = -.10, p < .001), and older age (beta = .07, p = .002), with a 3-way interaction between tornado exposure, sex, and social support (beta = -.06, p = .017). For boys, the influence of tornado exposure on PTSD symptoms increased as social support decreased. Regardless of level of tornado exposure, low social support was related to PTSD symptoms for girls; depressive symptom results were similar. These findings were generally consistent with the literature and provide guidance for intervention development focused on strengthening social support at the individual, family, and community levels. PMID- 26031998 TI - Dental treatment need and dental general anesthetics among preschool-age children with cleft lip and palate in northern Finland. AB - Cleft lip and palate incidence is high in northern Finland. This study aimed to investigate the proportion of children in need of restorative dental treatment among cleft lip and palate patients in northern Finland, as well as their need for dental treatment under general anesthesia. The records of 183 cleft lip and palate patients, treated in Oulu University Hospital from 1997 to 2013, were reviewed. Data on dental caries were analyzed in association with cleft type, considering also the presence of syndromes. The frequency of dental general anesthetic (DGA) use, and of treatments, were also analyzed. Dental treatment need was most frequently observed, in this rather limited study population, in patients with the most severe deformities, namely bilateral cleft lip and palate, of whom 60% had caries. Among the study population, 11.5% (n = 21) had a syndrome. Of those, 57.1% had dental caries at the age of 3 or 6 yr, and only four could be treated without a DGA. Dental treatment under general anesthesia was performed in 14.8% of cleft patients without a syndrome, but in 38.1% of those with a syndrome. General anaesthesia is required for the provision of dental care more often in cleft (17.5%) than in non-cleft (0.2%) patients, and especially for those with a syndrome. PMID- 26031999 TI - Bacterial remodelling of the host epigenome: functional role and evolution of effectors methylating host histones. AB - The modulation of the chromatin organization of eukaryotic cells plays an important role in regulating key cellular processes including host defence mechanisms against pathogens. Thus, to successfully survive in a host cell, a sophisticated bacterial strategy is the subversion of nuclear processes of the eukaryotic cell. Indeed, the number of bacterial proteins that target host chromatin to remodel the host epigenetic machinery is expanding. Some of the identified bacterial effectors that target the chromatin machinery are 'eukaryotic-like' proteins as they mimic eukaryotic histone writers in carrying the same enzymatic activities. The best-studied examples are the SET domain proteins that methylate histones to change the chromatin landscape. In this review, we will discuss SET domain proteins identified in the Legionella, Chlamydia and Bacillus genomes that encode enzymatic activities targeting host histones. Moreover, we discuss their possible origin as having evolved from prokaryotic ancestors or having been acquired from their eukaryotic hosts during their co-evolution. The characterization of such bacterial effectors as modifiers of the host chromatin landscape is an exciting field of research as it elucidates new bacterial strategies to not only manipulate host functions through histone modifications but it may also identify new modifications of the mammalian host cells not known before. PMID- 26032000 TI - The Illicit Use of Prescription Stimulants on College Campuses: A Theory-Guided Systematic Review. AB - The illicit use of prescription stimulants (IUPS) is a substance use behavior that remains prevalent on college campuses. As theory can guide research and practice, we provide a systematic review of the college-based IUPS epidemiological literature guided by one ecological framework, the theory of triadic influence (TTI). We aim to assess prevalence, elucidate the behavior's multietiological nature, and discuss prevention implications. Peer-reviewed studies were located through key phrase searches (prescription stimulant misuse and college, "prescription stimulant misuse" and "college," illicit use of prescription stimulants in college, and nonmedical prescription stimulant use in college students) in electronic databases (PubMed, PubMed Central, and EBSCO Host) for the period 2000 to 2013. Studies meeting inclusion criteria had their references reviewed for additional eligible literature. Statistically significant correlates of IUPS in the 62 retrieved studies were organized using the three streams of influence and four levels of causation specified in the TTI. Results show that the prevalence of IUPS varies across campuses. Additionally, findings suggest the behavior is multifaceted, as correlates were observed within each stream of influence and level of causation specified by the TTI. We conclude that IUPS is prevalent in, but varies across, colleges and is influenced by intrapersonal and broader social and societal factors. We discuss implications for prevention and directions for future research. PMID- 26032001 TI - Work organization on smallholder dairy farms: a process unique to each farm. AB - The way smallholder farms organize and carry out work impacts their ability to secure their livelihoods and meet growing demand for agricultural products. This study investigates the way dairy family farms in Brazil manage their workforce to achieve their objectives of production and income. Fifteen smallholder farms were surveyed using the QuaeWork method to understand the work organization on each farm. A high diversity of workloads was found, but these do not appear to be strictly related to the farms' production systems. The high variability of workloads is linked to the available workforce, technical choices, and the delegation of tasks to an external workforce. Farmers can decrease their workload by adopting milking mechanization, silage, hiring labor, and increasing the duration of the work day. Work organization depends on a farmer's personal choices, rendering the whole issue of workforce management a process unique to each farm. PMID- 26032002 TI - Statistical process control for electron beam monitoring. AB - PURPOSE: To assess the electron beam monitoring statistical process control (SPC) in linear accelerator (linac) daily quality control. We present a long-term record of our measurements and evaluate which SPC-led conditions are feasible for maintaining control. METHODS: We retrieved our linac beam calibration, symmetry, and flatness daily records for all electron beam energies from January 2008 to December 2013, and retrospectively studied how SPC could have been applied and which of its features could be used in the future. A set of adjustment interventions designed to maintain these parameters under control was also simulated. RESULTS: All phase I data was under control. The dose plots were characterized by rising trends followed by steep drops caused by our attempts to re-center the linac beam calibration. Where flatness and symmetry trends were detected they were less-well defined. The process capability ratios ranged from 1.6 to 9.3 at a 2% specification level. Simulated interventions ranged from 2% to 34% of the total number of measurement sessions. We also noted that if prospective SPC had been applied it would have met quality control specifications. CONCLUSIONS: SPC can be used to assess the inherent variability of our electron beam monitoring system. It can also indicate whether a process is capable of maintaining electron parameters under control with respect to established specifications by using a daily checking device, but this is not practical unless a method to establish direct feedback from the device to the linac can be devised. PMID- 26032003 TI - On the parametrization of lateral dose profiles in proton radiation therapy. AB - PURPOSE: The accurate evaluation of the lateral dose profile is an important issue in the field of proton radiation therapy. The beam spread, due to Multiple Coulomb Scattering (MCS), is described by the Moliere's theory. To take into account also the contribution of nuclear interactions, modern Treatment Planning Systems (TPSs) generally approximate the dose profiles by a sum of Gaussian functions. In this paper we have compared different parametrizations for the lateral dose profile of protons in water for therapeutical energies: the goal is to improve the performances of the actual treatment planning. METHODS: We have simulated typical dose profiles at the CNAO (Centro Nazionale di Adroterapia Oncologica) beamline with the FLUKA code and validated them with data taken at CNAO considering different energies and depths. We then performed best fits of the lateral dose profiles for different functions using ROOT and MINUIT. RESULTS: The accuracy of the best fits was analyzed by evaluating the reduced chi(2), the number of free parameters of the functions and the calculation time. The best results were obtained with the triple Gaussian and double Gaussian Lorentz-Cauchy functions which have 6 parameters, but good results were also obtained with the so called Gauss-Rutherford function which has only 4 parameters. CONCLUSIONS: The comparison of the studied functions with accurate and validated Monte Carlo calculations and with experimental data from CNAO lead us to propose an original parametrization, the Gauss-Rutherford function, to describe the lateral dose profiles of proton beams. PMID- 26032004 TI - Microradiosurgical cortical transections generated by synchrotron radiation. AB - PURPOSE: Microplanar X-ray beams (microbeams) originated by synchrotron sources have been delivered to the visual brain cortex regions in rodents to create microscopically narrow lesions. The effects of microbeams mimic those generated by microsurgical subpial transections (also known as multiple subpial transections) but are obtained in a low-invasive way. METHODS: Image-guided atlas based microbeam cortical transections have been generated on seven 1 month-old Wistar rats. An array of 10 parallel beams of 25 microns in thickness and spaced of 200 micron center-to-center was centered on the visual cortex and deposited an incident dose of 600 Gy. RESULTS: The procedure was well tolerated by rats. After recovery, rats showed regular behavior, no sign of gross visual impairment and regular weight gain. After 3 months, rats were sacrificed and brains histologically examined. Cortical transections resembling those obtained through a surgical incision were found over the irradiated region. Remarkable sparing of the cortical columns adjacent to the transections was observed. No sign of radionecrosis was evident at least at this time point. CONCLUSIONS: The visual brain cortex transected by synchrotron-generated microbeams showed an incision like path of neuronal loss while adjacent non irradiated columns remained intact. These preliminary findings, to be further investigated also using other techniques, suggest that microbeam radiosurgery can affect the cortex at a cellular level providing a potential novel and attractive tool to study cortical function. PMID- 26032005 TI - The optimal tomotherapy treatment planning parameters for extremity soft tissue sarcomas. AB - BACKGROUND AND PURPOSE: To determine the optimum combination of treatment parameters between pitch, field width (FW) and modulation factor (MF) for extremity sarcomas in tomotherapy. MATERIALS AND METHODS: Six patients previously treated for extremity sarcomas (3 arms and 3 legs) with tomotherapy were included in this study. 288 treatment plans were recalculated, corresponding to all combinations between 2 FW (2.5 and 5 cm), 4 MF (1.5, 2, 2.5 and 3) and 6 pitches (0.215, 0.287, 0.43 and 3 off-axis pitches). The treatment parameters (MF, FW or pitch) are modified between each plan, and the calculation is relaunched for 400 iterations, without modifying the optimisation constraints of the plan under which the patient has been treated. RESULTS: We suggest eliminating the 0.43 pitch and never combining a 0.215 pitch with an MF <= 2. We also do not recommend using an MF = 1.5 unless treatment time is an absolute priority over plan quality. We did not see any advantage in using Chen off-axis pitches, except for targets far from the axis (>15 cm) treated with a high pitch. A combination of MF = 2/FW = 5 cm/pitch = 0.287 gives plans of acceptable quality, combined with reduced treatment times. These conclusions are true only for extremity sarcomas treated in 2 Gy/fraction. CONCLUSIONS: We have shown that the choice of pitch/MF/FW combination is crucial for the treatment of extremity sarcomas in tomotherapy: some produce good dosimetric quality with a reduced irradiation time, while others may increase the time without improving the quality. PMID- 26032006 TI - Relevance of Bt toxin interaction studies for environmental risk assessment of genetically modified crops. AB - In recent years, different Bacillus thuringiensis (Bt) toxin-encoding genes have been combined or 'stacked' in genetically modified (GM) crops. Synergism between Bt proteins may occur and thereby increase the impact of the stacked GM event on nontarget invertebrates compared to plants expressing a single Bt gene. On the basis of bioassay data available for Bt toxins alone or in combination, we argue that the current knowledge of Bt protein interactions is of limited relevance in environmental risk assessment (ERA). PMID- 26032007 TI - Disruption of human vigilin impairs chromosome condensation and segregation. AB - Appropriate packaging and condensation are critical for eukaryotic chromatin's accommodation and separation during cell division. Human vigilin, a multi-KH domain nucleic acid-binding protein, is associated with alpha satellites of centromeres. DDP1, a vigilin's homolog, is implicated with chromatin condensation and segregation. The expression of vigilin was previously reported to elevate in highly proliferating tissues and increased in a subset of hepatocellular carcinoma patients. Other studies showed that vigilin interacts with CTCF, contributes to regulation of imprinted genes Igf2/H19, and colocalizes with HP1alpha on heterochromatic satellite 2 and beta-satellite repeats. These studies indicate that human vigilin might be involved in chromatin remodeling and regular cell growth. To investigate the potential role of human vigilin in cell cycle, the correlations between vigilin and chromosomal condensation and segregation were studied. Depletion of human vigilin by RNA interference in HepG2 cells resulted in chromosome undercondensation and various chromosomal defects during mitotic phase, including chromosome misalignments, lagging chromosomes, and chromosome bridges. Aberrant polyploid nucleus in telophase was also observed. Unlike the abnormal staining pattern of chromosomes, the shape of spindle was normal. Furthermore, the chromatin showed a greater sensitivity to MNase digestion. Collectively, our findings show that human vigilin apparently participates in chromatin condensation and segregation. PMID- 26032008 TI - Motivating medical students to do research: a mixed methods study using Self Determination Theory. AB - BACKGROUND: It is widely accepted that all medical graduates should understand the uses and methods of rigorous research, with a need to promote research to graduates who will pursue an academic career. This study aimed to explore, identify and explain what motivates and demotivates medical students to do research. METHODS: A convergent parallel mixed methods study was conducted. Cross sectional quantitative survey data (n = 579) and qualitative semi-structured interview findings (n = 23) data were separately collected and analysed. Informed by Self-Determination Theory (SDT), quantitative and qualitative findings were integrated to develop a model for the factors associated with medical students' expressed motivation to do research, and related to clinical and research learning activities at different stages in an undergraduate medical program. RESULTS: Only 7.5% of students had research experience prior to entering the program. Survey results revealed that students who had experienced exposure to the uncertainties of clinical practice through clerkships (Pre-Clinical (48%) vs Clinical Years (64%), p < 0.001), and a sense of achievement through supported compulsory research activities which were conducted as a team (Pre- Community Research (51%) vs Post-Community Research (66%), p < 0.001), were more likely to view future research activities positively. When integrated with qualitative findings using the three SDT domains of autonomy, competence and relatedness, eight major themes were identified: Self & Time, Career, Bureaucracy, Financial, Confidence, Clinical Relevance, Research as a Social Activity, and Personal Relevance. The findings suggest that motivation to do research is associated with increasing internalization of intrinsic motivators; in particular those associated with competence (Confidence) and relatedness (Clinical Relevance, Research as a Social Activity). CONCLUSIONS: SDT is useful for understanding the motivation of individuals and how curriculum can be designed to optimise motivation. Study findings suggest that well supported compulsory research activities that incorporate group learning and elements of choice may promote motivation to do research, and potentially, careers in research, even in a research naive student body. PMID- 26032009 TI - Comparison of erythropoietin resistance in hemodialysis patients using calcitriol, cinacalcet, or paricalcitol. AB - The erythropoiesis-stimulating agent (ESA) hyporesponsiveness index (EHRI) calculated as the weekly dose of EPO divided by weight (kg) divided by hemoglobin level (g/dL) has been considered useful to assess ESA resistance. Recent evidence suggests that active vitamin D, cinacalcet, and paricalcitol use may be related with lower ESA resistance. We conducted this observational cross-sectional study to investigate ESA resistance calculated by the EHRI among patients using calcitriol, cinacalcet, and paricalcitol. Participants underwent a medical history taken, physical examination, measurement of biochemical analysis, calculation of dialysis adequacy, and EHRI. Sixty-five patients did not receive any treatment regarding vitamin D, paricalcitol, and cinacalcet (group 1), 41 were taking only vitamin D (group 2), 50 were taking only paricalcitol (group 3), 19 were taking only cinacalcet (group 4), and 21 were taking paricalcitol + cinacalcet (group 5). The EHRI values for groups 1, 2, 3, 4, and 5 were 11.36 +/- 8.72, 11.58 +/- 5.72, 8.29 +/- 5.54, 9.49 +/- 4.61, and 8.91 +/- 4.44 respectively (P =.034). Post hoc analysis showed that the EHRI differed between group 1 and group 3 (P =.017) and between group 2 and group 3 (P =.006). In linear regression analysis, use of paricalcitol was independently associated with EHRI. In conclusion, paricalcitol use was associated with lower EHRI levels as a measure of ESA resistance. PMID- 26032010 TI - The increased use of computed tomography angiography and magnetic resonance angiography as the sole imaging modalities prior to infrainguinal bypass has had no effect on outcomes. AB - BACKGROUND: Angiography remains the gold standard imaging modality before infrainguinal bypass. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) have emerged as noninvasive alternatives for preoperative imaging. We sought to examine contemporary trends in the utilization of CTA and MRA as isolated imaging modalities before infrainguinal bypass and to compare outcomes following infrainguinal bypass in patients who underwent CTA or MRA versus those who underwent conventional arteriography. METHODS: Patients undergoing infrainguinal bypass within the Vascular Study Group of New England were identified (2003-2012). Patients were stratified by preoperative imaging modality: CTA/MRA alone or conventional angiography. Trends in utilization of these modalities were examined and demographics of these groups were compared. Primary end points included primary patency, secondary patency, and major adverse limb events (MALE) at 1 year as determined by Kaplan-Meier analysis. Multivariable Cox proportional hazards models were constructed to evaluate the effect of imaging modality on primary patency, secondary patency, and MALE after adjusting for confounders. RESULTS: In 3123 infrainguinal bypasses, CTA/MRA alone was used in 462 cases (15%) and angiography was used in 2661 cases (85%). Use of CTA/MRA alone increased over time, with 52 (11%) bypasses performed between 2003 and 2005, 189 (41%) bypasses performed between 2006 and 2009, and 221 (48%) bypasses performed between 2010 and 2012 (P < 0.001). Patients with CTA/MRA alone, compared with patients with angiography, more frequently underwent bypass for claudication (33% vs. 26%, P = 0.001) or acute limb ischemia (13% vs. 5%, P < 0.0001), more frequently had prosthetic conduits (39% vs. 30%, P = 0.001), and less frequently had tibial/pedal targets (32% vs. 40%, P = 0.002). After adjusting for these and other confounders, multivariable analysis demonstrated that the use of CTA/MRA alone was not associated with a significant difference in 1 year primary patency (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.78 1.16), secondary patency (HR 1.30, 95% CI 0.99-1.72), or MALE (HR 1.08, 95% CI 0.89-1.32). CONCLUSIONS: CTA and MRA are being increasingly used as the sole preoperative imaging modality before infrainguinal bypass. This shift in practice patterns appears to have no measurable effect on outcomes at 1 year. PMID- 26032011 TI - The sticky platelet syndrome during carotid endarterectomy. AB - The sticky platelet syndrome is a congenital disorder, characterized by abnormal platelet aggregation in response to epinephrine and/or adenosine phosphate. We present a case of intraoperative carotid artery thrombosis, after patch angioplasty. The successful repair was only feasible on administration of antiplatelet therapy. Presence of sticky platelet syndrome should be considered during vascular operative interventions, and load of antiplatelet agents should be given in patients with unexplained repeated thrombosis of arterial repair, as we described and reported this case. PMID- 26032012 TI - C1q, antibodies and anti-C1q autoantibodies. AB - The complement system has long been known for its role in combating infections. More recently the complement system is becoming increasingly appreciated for its role in processes that range from waste transport, immune tolerance and shaping of the adaptive immune response. Antibodies represent the humoral part of the adaptive immune response and the complement system interacts with antibodies in several ways. Activated complement fragments impact on the production of antibodies, the complement system gets activated by antibodies and complement proteins can be the target of (auto)antibodies. In this review, written to celebrate the contributions of Prof. Dr. M.R. Daha to the field of immunology and especially complement, we will focus on C1q and its various interactions with antibodies. We will specifically focus on the mechanisms by which C1q will interact with monomeric IgG versus polymerized IgG and fluid-phase IgM versus solid-phase IgM. In addition in this review we will discuss in detail how C1q itself is targeted by autoantibodies and how these autoantibodies are currently considered to play a role in human disease. PMID- 26032013 TI - Anti-inflammatory effects of benzenediamine derivate FC-98 on sepsis injury in mice via suppression of JNK, NF-kappaB and IRF3 signaling pathways. AB - FC-98, a synthesized benzenediamine derivate, was reported to regulate Toll-like receptor 9-induced activation of dendritic cells in our previous study. In this study, we evaluated the anti-inflammatory properties of FC-98 both in macrophages and in septic mouse models. By using enzyme-linked immunosorbent assay and real time quantitative PCR, we found that FC-98 (6.25, 25 and 100MUM) dose-dependently attenuated lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein (MCP-1) productions in RAW264.7 and primary mouse peritoneal macrophages. These inhibitory effects were not due to inducing cell cytotoxicity or altering LPS binding or TLR4 expression. Subsequently, western blot, immunofluorescence and luciferase reporter assays were used to investigate the underlying mechanisms of its anti-inflammatory activities. Results showed that FC-98 blocked activation of the c-Jun N-terminal kinase (JNK), nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3) signaling pathways. In vivo, FC-98 (30 or 100mg/kg) was intraperitoneally administrated into LPS-induced or CLP-induced sepsis mice. It was observed to enhance the survival rate, inhibit pro inflammatory mediator production, improve organ injuries and suppress bacterial propagation. In conclusion, FC-98 effectively inhibited macrophage inflammatory responses and ameliorated sepsis in mice through down-regulation of both MyD88 and TRIF-dependent pathways. These results suggest that FC-98 could be a promising therapeutic agent for inflammatory diseases. PMID- 26032014 TI - Conceptualising professionalism in occupational therapy through a Western lens. AB - INTRODUCTION: The term professionalism is embedded within curriculum and occupational therapy documents, yet, explicit discussion of the concept is lacking in the literature. This paper strives for a greater understanding of how professionalism is currently conceptualised within Western occupational therapy literature. METHODS: A broad literature search was conducted and included international peer-reviewed and grey literature from Western cultures including Australia, Canada, New Zealand, the United Kingdom and the United States. To enrich understanding, some documents from medicine were also included. FINDINGS: Professionalism is widely upheld as a core construct of occupational therapy. However, an evidence-based consensus of the specific elements of professionalism guiding occupational therapy practice is lacking. Currently, understanding of professionalism is largely based on multiple, isolated concepts presented in Western professional association documents. RELEVANCE TO CLINICAL PRACTICE: Acknowledging the multifaceted and multicultural nature of professionalism is essential to begin systematically delineating and conceptualising elements of professionalism specific to occupational therapy. LIMITATIONS: This review has been conducted from a solely Western cultural lens. RECOMMENDATIONS FOR FURTHER RESEARCH: Additional work to highlight differences specific to international contexts, cultures, and societal influences is needed to enrich the understanding of professionalism in occupational therapy practice. PMID- 26032015 TI - Blue excitable green emitting Ce(3+) doped CaS phosphor for w-LEDs. AB - CaS:Ce(3+) is an efficient green-emitting (535 nm) phosphor, excitable with blue light (450-470 nm) and was synthesized via a solid-state reaction method by heating under a reducing atmosphere. The luminescent properties, photoluminescent (PL) excitation and emission of the phosphor were analyzed by spectrofluorophotometry. The excitation and emission peaks of the CaS:Ce(3+) phosphor lay in the visible region, which made them relevant for light-emitting diode (LED) application for the generation of white light. Judd-Oflet parameters were calculated and revealed that green light emitted upon blue illumination. The prepared phosphor had strong blue absorption at 470 nm and a broad green emission band range from 490-590 nm with the peak at 537 nm. The characteristics of the CaS:Ce(3+) phosphor make it suitable for use as a wavelength tunable green emitting phosphor for three band white LEDs pumped by a blue LED (470 nm). The Commission International de l'Eclairage co-ordinates were calculated by a spectrophotometric method using the spectral energy distribution (0.304, 0.526) and confirm the green emission. The potential application of this phosphor is as a phosphor-converted white light-emitting diode. PMID- 26032016 TI - Feasibility, acceptability, and characteristics associated with adherence and completion of a culturally relevant internet-enhanced physical activity pilot intervention for overweight and obese young adult African American women enrolled in college. AB - BACKGROUND: African American women are one of the least active demographic groups in the US, with only 36% meeting the national physical activity recommendations in comparison to 46% of White women. Physical activity begins to decline in African American women in adolescence and continues to decline into young adulthood. Yet, few interventions have been developed to promote physical activity in African American women during this critical period of life. The purpose of this article was to evaluate the acceptability and feasibility of a culturally-relevant Internet-enhanced physical activity pilot intervention for overweight/obese African American college females and to examine psychosocial and behavioral characteristics associated with intervention adherence and completion. METHODS: A 6-month single group pre-posttest design was used. Participants (n = 27) accessed a culturally-relevant Social Cognitive Theory-based physical activity promotion website while engaging in a minimum of four moderate-intensity physical activity sessions each week. Acceptability and feasibility of the intervention was assessed by participant retention and a consumer satisfaction survey completed by participants. RESULTS: Fifty-six percent of participants (n = 15) completed the intervention. Study completers were more physically active at baseline (P = 0.05) and had greater social support for exercise from family members (P = 0.04). Sixty percent of study completers (n = 9) reported the website as "enjoyable" or "very enjoyable" to use and 60% (n = 9) reported increased motivation from participation in the physical activity program. Moreover, 87% (n = 13) reported they would recommend the website to a friend. CONCLUSIONS: Results provide some preliminary support for the acceptability and feasibility of an Internet-enhanced physical activity program for overweight/obese African American women, while highlighting important limitations of the approach. Successful promotion of physical activity in college aged African American women as they emerge into adulthood may result in the development of life-long healthy physical activity patterns which may ultimately reduce physical activity-related health disparities in this high risk underserved population. Future studies with larger samples are needed to further explore the use of Internet-based programs to promote physical activity in this population. PMID- 26032018 TI - Imatinib treatment of therapy resistant generalized deep morphea. PMID- 26032017 TI - Characterizing the neurotranscriptomic states in alternative stress coping styles. AB - BACKGROUND: Animals experience stress in many contexts and often successfully cope. Individuals exhibiting the proactive versus reactive stress coping styles display qualitatively different behavioral and neuroendocrine responses to stressors. The predisposition to exhibiting a particular coping style is due to genetic and environmental factors. In this study we explore the neurotranscriptomic and gene network biases that are associated with differences between zebrafish (Danio rerio) lines selected for proactive and reactive coping styles and reared in a common garden environment. RESULTS: Using RNA-sequencing we quantified the basal transcriptomes from the brains of wild-derived zebrafish lines selectively bred to exhibit the proactive or reactive stress coping style. We identified 1953 genes that differed in baseline gene expression levels. Weighted gene coexpression network analyses identified one gene module associated with line differences. Together with our previous pharmacological experiment, we identified a core set of 62 genes associated with line differences. Gene ontology analyses reveal that many of these core genes are implicated in neurometabolism (e.g. organic acid biosynthetic and fatty acid metabolic processes). CONCLUSIONS: Our results show that proactive and reactive stress coping individuals display distinct basal neurotranscriptomic states. Differences in baseline expression of select genes or regulation of specific gene modules are linked to the magnitude of the behavioral response and the display of a coping style, respectively. Our results expand the molecular mechanisms of stress coping from one focused on the neurotransmitter systems to a more complex system that involves an organism's capability to handle neurometabolic loads and allows for comparisons with other animal taxa to uncover potential conserved mechanisms. PMID- 26032019 TI - Studies on Bronchodilator Activity of Salvia officinalis (Sage): Possible Involvement of K+ Channel Activation and Phosphodiesterase Inhibition. AB - The aqueous methanolic extract of the aerial parts of Salvia officinalis (So.Cr) was studied to provide possible underlying mechanism(s) for its medicinal use in asthma using the in vivo bronchodilatory assay and isolated tracheal preparations. S. officinalis (1-10 mg/kg) dose-dependently inhibited carbachol (CCh)-induced bronchospasm in anesthetized rats with three-fold greater potency than the positive control, aminophylline. In tracheal preparations, So.Cr inhibited the low K+ (25 mM)-induced contractions. Pretreatment of the tissues with 4-aminopyridine reversed the inhibitory effect of the plant extract against low K+ , whereas glibenclamide did not show any effect, thus showing the involvement of voltage-sensitive K+ channels. When tested against the CCh-induced pre-contractions for the involvement of any additional mechanism, interestingly, the extract showed a dose-dependent (0.03-0.1 mg/mL) inhibitory effect and shifted the inhibitory concentration response curves of isoprenaline to the left, thus showing phosphodiesterase enzyme inhibitory-like action, similar to that of papaverine. These results indicate that the crude extract of S. officinalis possesses bronchodilatory activity mediated predominantly via activation of voltage-dependent K+ channels and inhibition of phosphodiesterase enzyme; thus, this study provides sound pharmacological basis for its medicinal use in hyperactive airways disorders such as asthma and cough. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26032021 TI - Idiopathic stuttering priapism treated with salbutamol orally: a case report. AB - Recurrent ischaemic priapism also known as stuttering priapism is an uncommon form of ischaemic priapism, and its treatment is not yet clearly defined. If left untreated, it may evolve into classic form of acute ischaemic priapism and lead to erectile dysfunction due to fibrosis of corpora cavernosa. Several drugs have been proposed with variable results and only supported with level three or four of evidence. Hormonal therapy such as cyproterone acetate, oestrogen, bicalutamide or Lh-Rh agonist are often effective but can cause side effects such as hypogonadal state and infertility. Other medical options are 5-alpha-reductase and phosphodiesterase-5 inhibitors, ketoconazole, baclofen, digoxin, gabapentin and beta-2-agonist terbutaline. We report the first case of stuttering priapism treated with beta-2-agonist salbutamol. PMID- 26032020 TI - Abnormal synaptic Ca(2+) homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice. AB - OBJECTIVE: Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the alpha1A subunit of CaV 2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. METHODS: We employed in vivo multiphoton microscopy of the genetically encoded Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. RESULTS: FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. INTERPRETATION: Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs. PMID- 26032022 TI - Hepatokines: unlocking the multi-organ network in metabolic diseases. AB - In the face of urbanisation, surplus energy intake, sedentary habits and obesity, type 2 diabetes has developed into a major health concern worldwide. Commonly overlooked in contemporary obesity research, the liver is emerging as a central regulator of whole body energy homeostasis. Liver-derived proteins known as hepatokines are now considered attractive targets for the development of novel type 2 diabetes treatments. This commentary presents examples of three leading hepatokines: fetuin-A, the first to be described and correlated with increased inflammation and insulin resistance; angiopoietin-like protein (ANGPTL)8/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question; and fibroblast growth factor 21 (FGF21), an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions. Novel discoveries in hepatokine research may lead to promising biomarkers and treatments for metabolic disorders and type 2 diabetes. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). PMID- 26032023 TI - Inverse association between fasting plasma glucose and risk of ventricular arrhythmias. AB - AIMS/HYPOTHESIS: In nondiabetic individuals, low values of fasting plasma glucose (FPG) have been associated with an increased risk of cardiovascular events. Identification of the potential mechanisms behind this association could help to elucidate the relationship between glycaemia and cardiovascular disease. We aimed to determine the association between FPG and ventricular arrhythmias. METHODS: FPG and other cardiometabolic risk factors were measured in a population-based cohort of 2,482 men without a known history of type 2 diabetes mellitus at baseline. Associations between FPG levels and incident cases of ventricular arrhythmias (ventricular tachycardia or fibrillation events ascertained using the National Hospital Discharge Register) were estimated using Cox regression analysis adjusted for potential confounders. RESULTS: During a median follow-up of 23.3 (interquartile range 18.5-25.3) years, 74 (2.9%) incident events were recorded. In a multivariable analysis adjusted for age, systolic BP, smoking status, LDL- and HDL-cholesterol, and C-reactive protein, the HR for ventricular arrhythmia per 1 mmol/l higher baseline FPG was 0.58 (95% CI 0.34, 0.98); this estimate did not materially change after further adjustment for BMI, alcohol consumption, triacylglycerols and history of ischaemic heart disease (0.50 [95% CI 0.28, 0.89]). CONCLUSIONS/INTERPRETATION: In this nondiabetic male population, FPG was inversely associated with incident risk of ventricular arrhythmias. While our results could help clarify the relationship between low glucose levels and cardiovascular risk, further studies are required to confirm these findings in other populations. PMID- 26032024 TI - Growth of GaN Layers on Sapphire by Low-Temperature-Deposited Buffer Layers and Realization of p-type GaN by Magesium Doping and Electron Beam Irradiation (Nobel Lecture). AB - This Review is a personal reflection on the research that led to the development of a method for growing gallium nitride (GaN) on a sapphire substrate. The results paved the way for the development of smart display systems using blue LEDs. The most important work was done in the mid to late 80s. The background to the author's work and the process by which the technology that enables the growth of GaN and the realization of p-type GaN was established are reviewed. PMID- 26032027 TI - Double-malate bridging tri-lanthanoid cluster encapsulated arsenotungstates: syntheses, structures, luminescence and magnetic properties. AB - Five members of a new family of polyoxometalate (POM)-ligated trinuclear lanthanoid (Ln) clusters with the general formula K20Li2[Ln3(MU3 OH)(H2O)8(AsW9O33)(AsW10O35(mal))]2.17H2O [Ln = Dy (1Dy), Tb (2Tb), Gd (3Gd), Eu (4Eu), and Sm (5Sm), mal = malate] have been synthesized, all of which consist of the dimeric {[Ln3(MU3-OH)(H2O)8(AsW9O33)[AsW10O35(mal)]}(11-) polyanion constructed from a {AsW9O33} and a {AsW10O35(mal)} building block linked by a tri Ln cluster [Ln3(MU3-OH)(H2O)8](8+), where the two malate ligands play a key bridging role. The {AsW10O35(mal)} subunit can be viewed as the {AsW9O33} building block anchoring an additional tungsten center [WO2(mal)]. The electrospray ionization mass (ESI-MS) spectra indicate that the dimeric fragments of 1Dy and 2Tb are unstable, which are apt to produce the subunit [KH5Ln3(OH)(H2O)(AsW9O33)2](4-) in solution. The solid-state photoluminescence measurements display the yellowish green emission for 1Dy and 5Sm, green emission for 2Tb and reddish orange emission for 4Eu, which are attributed to the Ln(III) f-f electron transitions. Magnetic property studies indicate that 1Dy displays probable SMM behaviour with slow magnetization relaxation, whereas the weak antiferromagnetic interactions exist in two {Ln3} clusters for 2Tb-5Sm. PMID- 26032026 TI - Catheter-based Renal Denervation as a Treatment for Pulmonary Hypertension: Hope or Hype? PMID- 26032025 TI - Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type. AB - INTRODUCTION: Mesomelic dysplasias are a group of skeletal disorders characterised by shortness of the middle limb segments (mesomelia). They are divided into 11 different categories. Among those without known molecular basis is mesomelic dysplasia Savarirayan type, characterised by severe shortness of the middle segment of the lower limb. OBJECTIVE: To identify the molecular cause of mesomelic dysplasia Savarirayan type. METHODS AND RESULTS: We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3. The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4. All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae. We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated with abnormalities in skeletal development, other mutational mechanisms than loss of function of the deleted genes have to be considered. Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia. CONCLUSIONS: Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae. PMID- 26032028 TI - Accuracy of imputation of single nucleotide polymorphism marker genotypes from low-density panels in Japanese Black cattle. AB - Using target and reference fattened steer populations, the performance of genotype imputation using lower-density marker panels in Japanese Black cattle was evaluated. Population imputation was performed using BEAGLE software. Genotype information for approximately 40,000 single nucleotide polymorphism (SNP) markers by Illumina BovineSNP50 BeadChip was available, and imputation accuracy was assessed based on the average concordance rates of the genotypes, varying equally spaced SNP densities, and the number of individuals in the reference population. Two additional statistics were also calculated as indicators of imputation performance. The concordance rates tended to be lower for SNPs with greater minor allele frequencies, or those located near the ends of the chromosomes. Longer autosomes yielded greater imputation accuracies than shorter ones. When SNPs were selected based on linkage disequilibrium information, relative imputation accuracy was slightly improved. When 3000 and 10,000 equally spaced SNPs were used, the imputation accuracies were greater than 90% and approximately 97%, respectively. These results indicate that combining genotyping using a lower-density SNP chip with genotype imputation based on a population of individuals genotyped using a higher-density SNP chip is a cost effective and valid approach for genomic prediction. PMID- 26032030 TI - [Editorial]. PMID- 26032031 TI - [Regulation of Positive and Negative Emotions as Mediator between Maternal Emotion Socialization and Child Problem Behavior]. AB - The present study investigated five to six year old children's ability to regulate negative and positive emotions in relation to psychosocial problem behavior (N=53). It was explored, whether mothers' supportive and nonsupportive strategies of emotion socialization influence children's problem behavior by shaping their emotion regulation ability. Mothers reported on children's emotion regulation and internalizing and externalizing problem behavior via questionnaire, and were interviewed about their preferences for socialization strategies in response to children's expression of negative affect. Results showed that children with more adaptive expression of adequate positive emotions had less internalizing behavior problems. When children showed more control of inadequate negative emotions, children were less internalizing as well as externalizing in their behavior. Furthermore, results indicated indirect relations of mothers' socialization strategies with children's problem behavior. Control of inadequate negative emotions mediated the link between non-supportive strategies on externalizing problem behavior. Results suggest that emotion regulatory processes should be part of interventions to reduce the development of problematic behavior in young children. Parents should be trained in dealing with children's emotions in a constructive way. PMID- 26032032 TI - [Self-reported Anxiety and Regulation Strategies in Primary School-age Children]. AB - We examined the self-reported anxiety in different situations (social anxiety, cognitive fears, fears of injury) and the use of regulation strategies (problem orientation, problem avoidance and seeking social support) in a sample of N=175 primary school children (mean age 8 years 4 months). At time of recruitment we oversampled for children with internalizing symptoms. In addition, mothers rated the overall anxiety of their children. According to their mothers 14.3% of the children showed anxiety symptoms in an abnormal range which is comparable to prevalence rates of children from population samples. 19.4% of the children described themselves as being anxious in an abnormal range. The correlations between different measures of children's self-reported anxieties were low to moderate. We found no significant correlations between mothers' and children's reports. The higher children's self-reported overall and cognitive anxiety, the more frequently they reported seeking social support in frightening situations. Girls reported more frequently pm cognitive fears than boys. Regarding regulation strategies we found that boys reported more problem orientation than girls whereas girls reported more social support seeking than boys. The results are discussed and practical implications are outlined. PMID- 26032033 TI - [Self-reported Emotion Regulation Strategies in Children and Adolescents with Mental Disorders]. AB - Emotion regulation (ER) is extensively researched in the context of psychopathology. It is quite controversial if deficits in ER are related to psychopathology across disorders or specifically linked to certain forms of psychopathology. Furthermore, it appears unclear if there are differences in ER depending on the specific emotion to be regulated. There are only few studies comparing different forms of psychopathology in terms of ER, specifically in childhood and adolescence. We explored ER in a consecutive clinical sample seeking help in two outpatient university clinics (N=129, age: 7-17 years, 45% female). In a first step, the ER of all children and adolescents seeking professional help for emotional and behavioral problems was compared with the ER characteristics of children and adolescents identified in school samples. In a second step, the clinical sample was divided into different groups of psychopathology, comparing the associations of different types of psychopathology with ER. ER in the clinical sample differed significantly from children and adolescents in school settings. The clinical sample was particularly characterized by a lack of adaptive strategies, and only partially by an increased use of maladaptive strategies. Further analysis revealed no specific deficits in the ER depending on types of psychopathology. The findings suggest a transdiagnostic and emotion-overarching conceptualization of ER in childhood and adolescence. PMID- 26032034 TI - [Emotion Regulation in Adolescents with Nonsuicidal Self-Injury]. AB - Nonsuicidal self-injury (NSSI) is a prevalent and impairing condition that was newly included in DSM-5 in the section III criteria for further research. Difficulties in emotion regulation play an important role in the development and maintenance of NSSI. This study investigated the emotion regulation in female adolescents with NSSI according to DSM-5 (n=55), clinical control adolescents with mental disorders without NSSI (n=30), and nonclinical control adolescents (n=58) using self-report questionnaires and interviews. As expected, results indicated that adolescents with NSSI have significantly more difficulties in emotion regulation compared to healthy controls. In addition, adolescents with NSSI reported also significantly more difficulties in impulse control, lack of emotional clarity, difficulties engaging in goal-directed behavior, and limited access to emotion regulation strategies compared to nonclinical and clinical controls. Adolescents with NSSI felt significantly more often sadness compared to clinical controls (d=0.66) and compared to other emotions. Adolescents with NSSI indicated significantly less often happiness compared to nonclinical controls (d=1.83). Results support that adolescents with NSSI have difficulties in emotion regulation and that these difficulties are even more pronounced than in adolescents with other mental disorders. Clinical implications will be discussed. PMID- 26032038 TI - Removal of normal ovaries in women under age 51 at the time of hysterectomy. AB - OBJECTIVE: Despite recommendation for ovarian conservation in low-risk, premenopausal women, bilateral oophorectomy is often performed. The purpose of this study was to investigate factors associated with removal of normal ovaries at the time of hysterectomy for benign indication in women age <51 years. STUDY DESIGN: Demographics, indication for surgery, adnexal pathology, and surgical approach were analyzed for hysterectomies from a voluntary, statewide surgical quality collaborative. Cases were excluded if the surgical indication was cancer, pelvic mass, or obstetric, or if age was >50 years. Cases were categorized according to pathology of the adnexal specimen as cancer, benign findings, normal ovary, or no ovarian specimen. Variables including demographics, medical comorbidities, and surgical characteristics were analyzed to identify characteristics associated with oophorectomy at the time of hysterectomy. A logistic regression model was then developed to identify factors independently associated with removal of normal ovaries. RESULTS: A total of 6789 subjects were included. Oophorectomy was performed in 44.2% of women (n = 3002). In all, 23.1% (n = 1565) had normal ovaries on pathology. Incidental ovarian cancer was found in 0.2% (n = 12), and benign pathology was found in 21% (n = 1425). Removal of normal ovaries was less likely when the surgical approach was vaginal (18%) as opposed to laparoscopic (23.1%) or abdominal (26.0%). With adjustment, abdominal (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.43-2.09]) and laparoscopic (OR, 1.27; 95% CI, 1.08-1.50) approach showed significantly higher odds of normal ovary removal compared to vaginal hysterectomy. Age 46-50 years was also significantly associated (OR, 1.78; 95% CI, 1.53-2.07). Surgical indications associated with increased oophorectomy with normal resultant pathology were family history of cancer (OR, 3.09; 95% CI, 1.94-4.94), endometrial hyperplasia (OR, 2.36; 95% CI, 1.38-4.01), endometriosis (OR, 2.01; 95% CI, 1.30-3.09), and cervical dysplasia (OR, 1.91; 95% CI, 1.12-3.28). CONCLUSION: Removal of histologically normal ovaries is performed in nearly 1 of every 4 women age <51 years undergoing hysterectomy for benign indications. Factors associated include age closer to menopause, surgical approach, and certain indications for hysterectomy. Reducing the rate of elective oophorectomy in low-risk, premenopausal women may be a target for quality improvement efforts. Future work should continue to evaluate this practice, associated factors, physician counseling, and patient decision-making. PMID- 26032039 TI - Supraumbilical primary trocar insertion for laparoscopic access: the relationship between points of entry and retroperitoneal vital vasculature by imaging. AB - OBJECTIVES: Advances in laparoscopy have demonstrated that supraumbilical primary ports can be desirable in complex cases with large masses. This study evaluated distances to vital retroperitoneal vasculature that were encountered with 45- and 90-degree angle entry from the umbilicus and 2 commonly described supraumbilical entry points at 3 and 5 cm cephalad from the umbilicus. STUDY DESIGN: Retrospective analysis of computed tomography scans of the abdomen and pelvis from 100 randomly selected women who were 18-50 years old with normal anatomy was performed. Three-dimensional models of sagittal sections were generated using IMPAX software. Measurements from the abdominal wall at the umbilicus and 3 and 5 cm cephalad with 45- and 90-degree angles to retroperitoneal structures were performed. RESULTS: With 90-degree angle entry, the abdominal wall thickness (AWT) was thinnest at the umbilicus; however, the thickness at 3 and 5 cm was similar. AWT increased at all sites with 45-degree angle entry, and the same pattern was observed. AWT and intraperitoneal distance positively correlated with body mass index and supraumbilical entry points. With 90-degree angle entry, the aorta was 1.9 cm (95% confidence interval [CI], 1.4-2.4) and 2.5 cm (95% CI, 2.0 2.9) farther away at 3 and 5 cm cephalad compared with umbilical entry. In one third of the cases, regardless of port placement, a vascular structure other than the aorta was the most anterior vessel. With 45-degree angle entry at the umbilicus, no vessels were encountered. With 45-degree angle entry at 3 and 5 cm cephalad, the aorta was the most anterior vessel in 1% and 2% of cases, respectively, and was noted to be 1.0 cm (95% CI, 1.0-1.0) and 2.3 cm (95% CI, 1.2-3.3) farther away than with 90-degree angle entry. A vessel other than the aorta was encountered in 4% and 7% of cases at 3 and 5 cm, respectively. CONCLUSION: According to theoretic modeling, supraumbilical primary port placement can be implemented safely in laparoscopy. With supraumbilical entry, the distance to retroperitoneal vessels was greater than at the umbilicus. Compared with a 90-degree angle, with a 45-degree angle entry, it was uncommon to encounter vasculature, and all measured distances were greater. PMID- 26032040 TI - Reply: To PMID 24560557. PMID- 26032041 TI - Effects of dexamethasone on quality of recovery following vaginal surgery: a randomized trial. AB - OBJECTIVE: Dexamethasone is a corticosteroid with minimal side effects that may improve quality of recovery. We sought to evaluate standard use of this medication prior to vaginal reconstructive surgery. STUDY DESIGN: This was a double-blind, randomized, placebo-controlled trial of women undergoing vaginal reconstructive surgery for pelvic organ prolapse. Patients scheduled for an intraperitoneal vaginal vault suspension, with general anesthesia and an overnight stay, were enrolled. The intervention arm received dexamethasone 60 minutes prior to surgery, and controls received placebo. Postoperative pain medications, antiemetics, and voiding trials were standardized. Our primary outcome was the difference in Quality of Recovery (QoR-40) scores on postoperative day 1. Secondary measures included Postoperative Nausea and Vomiting Intensity scores, and visual analog scales for nausea/vomiting, and pain. Our power calculation demonstrated 31 subjects in each group would be necessary to document difference in QoR-40 scores; to allow for attrition, a goal of 74 subjects was set. RESULTS: Seventy-four women were enrolled and randomized. Two withdrew, 9 were excluded, and 63 were analyzed (36 placebo, 27 dexamethasone). The mean age was 63 years. No significant differences were noted among demographics other than American Society for Anesthesiologists class; there were greater numbers of dexamethasone subjects that were class 3 (5 vs 11; P = .030). Postoperatively, more patients in the placebo group required promethazine as a rescue antiemetic for control of their nausea/vomiting (11 vs 2; P = .029). Placebo subjects also failed their voiding trials more frequently, which remained following a logistic regression controlling for suburethral sling (30 vs 15; P = .037). Regarding the QoR-40 following surgery, the emotional state domain declined less in dexamethasone patients (-14.3, interquartile range [IQR], 16.8 vs -4.6, IQR, 20.1; P = .042), indicating better symptoms. Whereas pain scales were similar, the visual analog scales for nausea/vomiting was lower in dexamethasone subjects (0.7; IQR, 4.1 vs 0.4; IQR, 1.4; P = .042). Postoperative Nausea and Vomiting Intensity scores were not significantly different; nevertheless, twice as many placebo subjects had severe range symptoms (4 vs 2; P = .47). No adverse effects from the dexamethasone were noted. CONCLUSION: Use of dexamethasone prior to vaginal reconstructive surgery was associated with less nausea/vomiting and need for antiemetics as well as greater success with voiding trials. Furthermore, quality of recovery was enhanced, suggesting use of dexamethasone should be considered for these patients. PMID- 26032042 TI - Survey of male perceptions regarding the vulva. AB - OBJECTIVE: The purpose of this study was to characterize male preferences of vulvar appearance, their awareness of labiaplasty, and their knowledge of genital anatomy. STUDY DESIGN: Men 18-80 years old were recruited via emails sent by an Internet provider to participate in a 27-question web-based survey. The questionnaire included images and queried demographics, men's familiarity with vulvar anatomy, preferences regarding labial appearance, and awareness of labiaplasty. Two deployments to >150,000 email addresses were sent. Demographic data were described using frequencies for categoric variables and mean measures of central tendency for continuous variables. Logistic regression models were used to analyze associations between demographics and responses. RESULTS: Two thousand four hundred three men responded to the survey. After excluding incomplete and ineligible surveys, 1847 surveys were analyzed. The median age of respondents was 55 years. The majority was white (87%), married (68%), employed (69%), and had completed high school or beyond (97%). One-third of the respondents lived in the South, with the other regions nearly equally represented. A significant majority, 95%, reported having been sexually active with women, and 86% felt comfortable labeling the vulvar anatomy. With regard to preferences, more respondents considered smaller labia attractive compared to large labia; yet 36% of the men remained neutral. Men also showed a preference for partially or completely groomed genitals compared to natural hair pattern. Whereas 51% of participants believed the appearance of a woman's labia influenced their desire to engage in sexual activity, 60% denied it affected sexual pleasure. Only 42% of men were familiar with labiaplasty, and 75% of all respondents would not encourage a female partner to change her genital appearance. Multivariable analysis revealed younger age to be associated with preferences for small labia and complete genital hair removal, as well as familiarity with labiaplasty. CONCLUSION: In this national survey, men demonstrated familiarity with the female anatomy, but many did not feel it impacted sexual desire or pleasure. Moreover, the majority lacked strong preferences for a specific vulvar appearance and would not encourage a female partner to alter her genital appearance surgically. PMID- 26032043 TI - Reply: To PMID 25025939. PMID- 26032044 TI - Skin incision for cesarean delivery in morbidly obese women. PMID- 26032045 TI - Updates in Psychosomatic Medicine: 2014. AB - BACKGROUND: The amount of literature published annually related to psychosomatic medicine is vast; this poses a challenge for practitioners to keep up-to-date in all but a small area of expertise. OBJECTIVES: To introduce how a group process using volunteer experts can be harnessed to provide clinicians with a manageable selection of important publications in psychosomatic medicine, organized by specialty area, for 2014. METHODS: We used quarterly annotated abstracts selected by experts from the Academy of Psychosomatic Medicine and the European Association of Psychosomatic Medicine in 15 subspecialties to create a list of important articles. RESULTS: In 2014, subspecialty experts selected 88 articles of interest for practitioners of psychosomatic medicine. For this review, 14 articles were chosen. CONCLUSIONS: A group process can be used to whittle down the vast literature in psychosomatic medicine and compile a list of important articles for individual practitioners. Such an approach is consistent with the idea of physicians as lifelong learners and educators. PMID- 26032046 TI - Silicon oxide based materials for controlled release in orthopedic procedures. AB - By virtue of excellent tissue responses in bone tissue, silicon oxide (silica) based materials have been used for bone tissue engineering. Creating nanoscale porosity within silica based materials expands their applications into the realm of controlled release area. This additional benefit of silica based materials widens their application in the orthopedic fields in a major way. This review discusses the various chemical and physical forms of silica based controlled release materials, the release mechanisms, the applications in orthopedic procedures and their overall biocompatibility. PMID- 26032047 TI - Novel 4-heteroaryl-antipyrines as DPP-IV inhibitors. AB - Type 2 diabetes mellitus is a vast growing progressive disease that almost affects one person among every twelve globally. Regardless the availability of wide variety of oral hypoglycemics, only one-third of patients achieves proper glycemic control. With the advantage of the low risk of hypoglycemia, DPP-IV attracted the attention of medicinal chemists as a new target for oral hypoglycemics. In this report, a lead compound 1, with antipyrine scaffold, was obtained, and its binding mode was calculated. Several derivatives with bridged nitrogenous heterocycles have been synthesized via multicomponent reaction under controlled microwave heating conditions. The antidiabetic activity versus DPP-IV protein was evaluated and compared with sitagliptin. Compounds with smaller- or medium-sized nitrogenous bridges were comparable with sitagliptin in terms of DPP IV inhibitory activity, potentially via targeting Glu203 and Glu204. The oral hypoglycemic activities of compounds with submicromolar IC50 values were further evaluated using diabetic mouse model. PMID- 26032050 TI - Profile of children with urinary tract infection and the utility of urine dipstick as a diagnostic tool. AB - BACKGROUND: Urinary tract infection is a common problem in children and its early diagnosis and treatment is important to prevent long-term complications. Urine dipstick can be an important tool in this respect. The aim of this study is to look at the utility of urine dipstick as a diagnostic tool for UTI and will also see the clinical profile of children with UTI and sensitivity pattern of antibiotics among the isolates of urine culture. METHODS: Urine samples of all children below 14 years of age who were suspected of urinary tract infection were sent for routine microscopic examination and dipstick testing. Urine culture and sensitivity were sent for those samples that were tested positive for nitrite, leucocyte esterase activity or both. For every fifth sample, which is dipstick negative, a culture and sensitivity testing was done. RESULTS: Among 110 children enrolled, 32(29%) cases had significant bacteriuria. Out of 32 culture positive cases 18(56%) were female. Fever was the main complaint (62.5%)). Escherichia Coli was isolated in 81.25% of cases. Amikacin was sensitive in 93% and amoxicillinwas resistant in 82%. The sensitivity, specificity, positive predictive value, negative predictive value of nitrite test was 65%, 80%, 58%, 85% respectively; those of leucocyte esterase are 84%, 55%, 43%, 89% respectively; those for significant microscopic pyuria >10/hpf were 65%, 74%, 51%, 84% respectively. CONCLUSIONS: E. Coli is the commonest uropathogen in children with UTI. Amikacin is the most sensitive antibiotic against all the isolates. A positive dipstick both for nitrite and leucocyte esterase is associated with high sensitivity and specificity for urinary tract infection as compared to either of them positive alone. In addition, urine WBC >=10/hpf is associated with high probability of UTI. PMID- 26032048 TI - Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease that causes demyelination of neurons in the central nervous system. Traditional therapies for MS have involved anti-inflammatory and immunosuppressive drugs with significant side effects that often only provide short-term relief. A more desirable outcome of immunotherapy would be to protect against disease before its clinical manifestation or to halt disease after its initiation. One attractive approach to accomplish this goal would be to restore tolerance by targeting immunoregulatory cell networks. Although much of the work in this area has focused on CD4(+) Foxp3(+) regulatory T cells, other studies have investigated natural killer T (NKT) cells, a subset of T cells that recognizes glycolipid antigens in the context of the CD1d glycoprotein. Studies with human MS patients have revealed alterations in the numbers and functions of NKT cells, which have been partially supported by studies with the experimental autoimmune encephalomyelitis model of MS. Additional studies have shown that activation of NKT cells with synthetic lipid antigens can, at least under certain experimental conditions, protect mice against the development of MS-like disease. Although mechanisms of this protection remain to be fully investigated, current evidence suggests that it involves interactions with other immunoregulatory cell types such as regulatory T cells and immunosuppressive myeloid cells. These studies have provided a strong foundation for the rational design of NKT-cell-based immunotherapies for MS that induce tolerance while sparing overall immune function. Nevertheless, additional pre-clinical and clinical studies will be required to bring this goal to fruition. PMID- 26032049 TI - Bioenergetic analysis of human peripheral blood mononuclear cells. AB - Leucocytes respond rapidly to pathogenic and other insults, with responses ranging from cytokine production to migration and phagocytosis. These are bioenergetically expensive, and increased glycolytic flux provides adenosine triphosphate (ATP) rapidly to support these essential functions. However, much of this work is from animal studies. To understand more clearly the relative role of glycolysis and oxidative phosphorylation in human leucocytes, especially their utility in a translational research setting, we undertook a study of human peripheral blood mononuclear cells (MNCs) bioenergetics. Glycolysis was essential during lipopolysaccharide (LPS)-mediated interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha production, as 2-deoxy-D-glucose decreased significantly the output of all three cytokines. After optimizing cell numbers and the concentrations of all activators and inhibitors, oxidative phosphorylation and glycolysis profiles of fresh and cryopreserved/resuscitated MNCs were determined to explore the utility of MNCs for determining the bioenergetics health profile in multiple clinical settings. While the LPS-induced cytokine response did not differ significantly between fresh and resuscitated cells from the same donors, cryopreservation/resuscitation significantly affected mainly some measures of oxidative phosphorylation, but also glycolysis. Bioenergetics analysis of human MNCs provides a quick, effective means to measure the bioenergetics health index of many individuals, but cryopreserved cells are not suitable for such an analysis. The translational utility of this approach was tested by comparing MNCs of pregnant and non-pregnant women to reveal increased bioenergetics health index with pregnancy but significantly reduced basal glycolysis and glycolytic capacity. More detailed analysis of discrete leucocyte populations would be required to understand the relative roles of glycolysis and oxidative phosphorylation during inflammation and other immune responses. PMID- 26032051 TI - An assessment of candidal colonization and species differentiation in head and neck cancer patients receiving radiation. AB - BACKGROUND: Oral colonization with Candida species has been observed in upto 93% of patients receiving radiation for head and neck cancer. With immunosuppression there is a trend of emergence of rare species. The present study aimed to assess species and colonization of candida at different stages of radiation therapy for head and neck cancer. METHODS: Oral rinses of thirty cancer patients receiving a six weeks course of radiation therapy for head and neck cancer were taken at two intervals; first at the start of radiation (0 Grays), and second at completion of radiation (60 Grays). The oral rinse was streaked onto a differential media (CHROMagar(r)) plates and incubated at 37oC for 48 hours. Colony forming units (CFU) were counted and species were differentiated. Fifteen healthy controls were compared. RESULTS: The candida albicans colony count (CFU/ml) at baseline, 0 Grays radiation ranged from 50 to 1820 CFU/ml in cases and from 0 to 300 CFU/ml in controls. C. albicans was seen in all cases (100%) and most of the controls (86.66%). Other species such as C. Krusei, C. parapsilosis, C .tropicalis, and C. glabrata were observed with a frequency of 10%, 6.66%, 3.33%, and 3.33% respectively in the cases. However, no species other than C. albicans was observed in controls. CONCLUSIONS: Immunosupression of radiation therapy patients led to the development of species other than Candida albicans, which is the most prevalent species. Thus it can be inferred that there is emergence of the opportunistic fungal pathogens in patients with immunosupression. PMID- 26032052 TI - Clinical characteristics of children with febrile seizure. AB - BACKGROUND: Febrile seizure is common in children below five years of age. This study was conducted to evaluate the clinical profile of children presenting with febrile seizure in a teaching hospital. METHODS: This was a descriptive retrospective study among children presenting with febrile seizure in a teaching hospital from July 2009 to June 2013. Children between six months to six years were included in the study while patients with prior episodes of afebrile seizures, abnormal neurodevelopment and not meeting the age criteria were excluded. Patient's demographic and clinical data were collected from the in patients records and analyzed. RESULTS: This study included 103 children with febrile seizure. Out of which 67% were male. Simple febrile seizure and complex febrile seizure were observed in 76.7% and 23.3% of patients respectively. Majority of children (71.8%)had generalized tonic clonic seizure followed by tonic seizures. Most of children (72.8%) who developed first episode of seizure were below 24 months of age with the mean age of 20.7 (+/-12.1) months. Overall 33% of patients developed recurrence of febrile seizure and first episode of febrile seizure at age one year or below was associated with the seizure recurrence. Upper respiratory tract infections were the commonest cause of fever in these children. CONCLUSIONS: Febrile seizure was observed predominantly in children below age of two years and simple febrile seizure was the ommonest variety. Recurrence of febrile seizure was common and significantly associated with the first episode of febrile seizure at the age of one year or below. PMID- 26032053 TI - Prevalent Causes of Low Back Pain and its Impact among Nurses Working in Sahid Gangalal National Heart Centre. AB - BACKGROUND: Nursing is considered as caring profession and nurse is a person who provides holistic care to the individual or community. Nurse's jobs vary from simple task to more complex one and are at risk of various occupational health problems. Among those, musculoskeletal problem including low back pain (LBP) is commonest one. Thus this study examines the prevalence and perceived causes of low back pain and its impact among the nurses working in national heart centre. METHODS: A descriptive cross-sectional study design was used. After informed verbal consent, 50 nurses were selected purposively. Semi structured self administered questionnaires with single and multiple response items were distributed to them and were collected next day. Response rate was 100%. Data was analyzed using the Statistical Package for the Social Sciences (SPSS) version 16 for windows. Descriptive statistics i.e., percentage, mean and chi square was used to interpret the data. For multiple responses, percentage was calculated in terms of total responses therefore exceeds 100%. RESULTS: Among 50 nurses, 78% of nurses were suffering from LBP. Study found that LBP was predominant among married nurses (88%) compared to unmarried (69%). Prolonged standing (82%), heavy physical workload and frequent bending & twisting (51% each) were some perceived causes of low back pain. Due to LBP, 44% were not able to perform their job properly, 33% became less productive, 28% had restriction in work and 26% could not provide quality care to the patient. CONCLUSIONS: Three fourth of nurses working at national heart centre were suffering from low back pain which indicates high prevalence. Therefore it is recommended to maintain proper body mechanics and use supportive devices like back belts, knee cap, and chair with back rest during patient care. PMID- 26032054 TI - Total anti-oxidant capacity of saliva in chronic periodontitis patients before and after periodontal treatment. AB - BACKGROUND: Periodontal disease is among the most common inflammatory conditions which is associated with many different factors. One of the contributing factors to the pathogenesis of this condition may compromise the defensive mechanism of antioxidants. The present study evaluates the antioxidant capacity of saliva in periodontal patients before and after periodontal treatment. METHODS: In this cross sectional study, 31 patients systemically healthy non smokers with chronic periodontitis were recruited. The antioxidant capacity of saliva was measured before the initial phase of periodontal therapy and after completion of the treatment. Data were analyzed using SPSS 19 software. Paired T-Test, Independent sample T-test and ANOVA tests were used as appropriated. RESULTS: The mean and standard deviation antioxidant capacity of the saliva after the treatment.(0.962+/- 0.287uM)was significantly higher than before the treatment (0.655 +/- 0.281 uM ,p<0.001). The mean difference of antioxidant capacity of the saliva before and after periodontal treatment was higher among men than among women; however, the difference was not significant (P=0.07). The mean difference of salivary antioxidant capacity was not significantly differed among different ages (P=0.772). CONCLUSIONS: The antioxidant capacity of saliva was higher after periodontal therapy among patients with periodontal disease, however the change was not varied across the ages and gender. Therefore, the alterations in the defensive mechanism of antioxidants could be the key factors contribute to the pathogenesis of periodontal diseases. PMID- 26032055 TI - Prevalence and Associated Factors of Alcoholism among Tuberculosis Patients in Udupi Taluk, Karnataka, India: A Cross Sectional Study. AB - BACKGROUND: Tuberculosis (TB) is a major public health problem in India. Several studies carried out in India have shown alcoholism as a risk factor for tuberculosis mortality, factor for default in TB and reason for non-compliance under the Revised National Tuberculosis Control Program (RNTCP). The aim of this study was to assess the prevalence, pattern and associated factors of alcohol use among tuberculosis patients in Udupi taluk, Karnataka, India. METHODS: A cross sectional study was conducted with the complete enumeration of all the cases undergoing Directly Observed Treatment Short-course (DOTS) treatment in Primary Health Centre and Community Health Centre of Udupi taluk from March to April 2013. Interview was conducted to obtain the socio-demographic and health information and participants were screened using WHO developed Alcohol Use Disorders Identification Test (AUDIT) for alcohol use. RESULTS: Out of 123 participants, 78% were males, 86.2% were Hindu, 79.7% were married and 88.6% were from low socio-economic status. About 20.3% (n=25) participants were alcoholic. Among them, 44% were low risk drinkers, 32% were hazardous drinkers, 4% were harmful drinkers and 20% were alcohol dependent. Age, sex, occupation, tobacco use, perceived health status and discrimination due to tuberculosis positive status were significantly associated with alcohol use. On logistic regression sex, tobacco use, perceived health status and facing discrimination due infection with tuberculosis were found to be factors associated with alcohol use. CONCLUSIONS: This study found a high prevalence of alcoholism among tuberculosis patients which is of concern and has to be addressed. PMID- 26032056 TI - Lived Experiences of the Staff Nurses during First Six months of their Employment in a University Hospital, Kavre. AB - BACKGROUND: Nursing is a profession within the health care sector focused on the care of individuals, families, and communities so they may attain, maintain, or recover optimal health and quality of life. Role transition is the natural phenomena among the professionals; however, the transition of newly graduated nurses into clinical practice is commonly perceived as stressful. METHODS: It is a phenomenological qualitative study. By adopting purposive sampling technique, 6 nurses were recruited in the study. In-depth interview, audio tape and field notes were maintained to collect data. Nursing leaders and nursing superintendent were also involved to get supplement data via interview and focus group discussion. RESULTS: Beginning a new job was really stressful to the new nurses. Feelings of inadequacy, fear of making errors at work, lack of competency and confidence and sudden loss of supervision from the instructors were the common sources of the stress. Four major themes; stressful initial days, leaving the nest, supporting work environment and hierarchical work pattern were emerged. The new graduates require formal orientation program, opportunities for professional development, provision of preceptors during initial days, warm and welcoming attitude among the seniors and supportive environment to help them easing a role transition. CONCLUSIONS: In order to retain and recruit new nurses the findings obtained through triangulated data need to keep in mind by the nursing administrators, educators and managers in a health care setting. And this in turn ultimately results in enhanced patient care in the health care setting. PMID- 26032057 TI - Comparative study of prevalence of pterygium at high altitude and Kathmandu Valley. AB - BACKGROUND: Pterygium is a fleshy fibrovascular growth of conjunctiva encroaching upon the superficial cornea towards the visual axis in the interpalpebral fissure. The study aims to compare the prevalence of pterygium at high altitude and Kathmandu. METHODS: A cross sectional quantitative study organized by Professional Support Service Nepal was conducted at Mustang and Kathmandu Valley in the Tibetan and Thakali population. The sample size at Mustang is 222 and Kathmandu Valley is 186. RESULTS: At Mustang, pterygium was present in 40 males (38.5%) and 48 females (40.7%) while at Kathmandu, pterygium was present in 6 males (8.8%) and 17 females (14.4%). Pterygium was present in 20.7% (n=12) at the altitude of 2710 meters, 28.8% (n=21) at an altitude of 2900 meters, 56.6% (n=30) at 3500 meters and 65.8% (n=25) at 3800 meters. The prevalence of Pterygium was significantly high with the rise in altitude (p value=0.000). Pterygium was present in 12.4% (n=23) at Kathmandu.The prevalence of pterygium at high altitude as compared with Kathmandu was also statistically significant (p value = 0.000).Pterygium was present in <40years in 40% and =/>40years in 39.5% at high altitude. At Kathmandu,pterygium was present in <40years in 8.2% and=/> 40years in 13.9%.At Mustang, among participants with the duration of stay at high altitude up to 20 years, pterygium was present in 36.1% (n=13) and those with >20years, pterygium was present in 40.3%(n=75). CONCLUSIONS: Pterygium has significantly higher prevalence at high altitude as compared to lower altitude. PMID- 26032058 TI - Iodized Salt Use and Salt Iodine Content among Household Salts from Six Districts of Eastern Nepal. AB - BACKGROUND: Universal salt iodization is considered the best strategy for controlling iodine deficiency disorders in Nepal. This study was done to find iodized salt use among Nepalese population and the iodine content of household salts. METHODS: Six districts (Siraha, Saptari, Jhapa, Udayapur, Ilam and Panchthar) were chosen randomly from 16 districts of eastern Nepal for the study. In each district, three schools (private and government) were chosen randomly for sample collection. A total of 1803 salt samples were collected from schools of those districts. For sample collection a clean air tight plastic pouch was provided to each school child and was asked to bring approximately 15 gm of their kitchen salt. The information about type of salt used; 'two child logo' iodized salt or crystal salt was obtained from each child and salt iodine content was estimated using iodometric titration. RESULTS: At the time of study, 85% (n=1533) of Nepalese households were found to use iodized salt whereas 15% (n=270) used crystal salt. The mean iodine content in iodized and crystal salt was 40.8+/ 12.35 ppm and 18.43+/-11.49 ppm respectively. There was significant difference between iodized and crystal salts use and salt iodine content of iodized and crystal salt among different districts (p value <0.001 at confidence level of 95%). Of the total samples, only 169 samples (9.4% of samples) have iodine content<15 ppm. CONCLUSIONS: Most Nepalese households have access to iodized salt most salt samples have sufficient iodine content. PMID- 26032059 TI - Retrospective study on early outcome of acute burn injuries treated at Nepal Cleft and Burn Centre of Public Health Concern Trust-Nepal. AB - BACKGROUND: Nepal Cleft & Burn Center, Kirtipur Hospital, Kathmandu has been providing the acute burn care since 2013 with 10 ICU beds, 32 general beds and two operating rooms. This study analyses the demographics of and early outcome in the acute burn patients. METHODS: This is a descriptive retrospective study of the clinical data of acute burn patients admitted from January 1 to December 31, 2014. RESULTS: There were 78 patients from 3 months to 88 years of age with a median age of 29 years. Forty six (58.9%) were females and 32 (41.1%) were males. Most of the injuries (n=57; 73%) occurred inside the house. Flame burn was the commonest mode of injury (n= 48, 61.6%). Only eleven (14.1%) patients arrived on the same day of the injury. The time elapsed was from 1 to 67 days with a median of 5 days. Only two (2.5%) patients had poured water for more than 20 minutes. Range of total body surface area (TBSA) involved was 1% to 70% with a median of 12%. Range of hospital stay was 1 to 105 days with a median of 17 days. Sixty (76.9%) patients underwent 102 surgical operations. Twenty six (33.3%) patients needed blood transfusion. A total of 15 (19.2%) patients died. None survived a burn injury of more than 40% TBSA. CONCLUSIONS: Treatment of acute burn is very challenging with high mortality rate. A lot of effort is needed to change the present standard of care. Awareness programs on First Aid treatment of burn injuries together with the preventive programs focused on high risk population such as females and children in a large scale needs to be organized as soon as possible. PMID- 26032060 TI - Successfully managed case of celphos poisoning: a case report and review. AB - Aluminium phosphide poisoning is one of the major causes of suicidal deaths in developing countries like Nepal. It is one of the common fumigant available and is within easy access. It is primarily used for crop protection. However, it is one of the misused chemicals to commit suicide. In this case, the patient had hyperglycaemia, atrial fibrillation, severe metabolic acidosis, and shock and yet survived. The key to her survival was aggressive supportive management. Therefore, knowing all the prognostic factors along with aggressive management can be life saving in conditions when no antidotes are available. PMID- 26032061 TI - Accessory hepatic lobe in right lumbar region - an incidental finding. AB - An accessory lobe of liver is a rare congenital anomaly which can be detected incidentally or can even present as acute surgical emergency due to torsion. We report a case of accessory hepatic lobe in right lumbar region in a 21years old female who came for a ultrasound abdomen for lower abdominal pain. We report the importance of ultrasonography and Computed Tomogram (CT) scan for the diagnosis of accessory hepatic lobe. PMID- 26032062 TI - Institutionalising of public health. AB - Though public health situation in Nepal is under-developed, the public health education and workforce has not been prioritised. Nepal should institutionalise public health education by means of accrediting public health courses, registration of public health graduates in a data bank and increasing job opportunities for public health graduates in various institutions at government sector. PMID- 26032063 TI - Pesticides in vegetable and food commodities: environment and public health concern. AB - Haphazard use of pesticides in the field and stored food commodities for the control of insect and pest has been a serious problem from view of environment and public health. The nutritional value of these is suppressed due to addition of toxins. The increased trend of Non communicable disease and communicable diseases may have close relation with the nutritious value and life styles associated with. The impacts on health should be considered as important issues from the view of public health. The article gives emphasis on organic farming & Integrated Pest Management (IPM) to minimize the harm of chemicals. It is deemed essential to think again about the current trend of malnutrition & obesity overweight among the Nepalese people and relationship with pesticides on the foods and vegetables. PMID- 26032064 TI - The hidden burden of Neglected Tropical Diseases: a call for inter-sectoral collaboration in Nepal. PMID- 26032065 TI - Platinum electrode modification: Unique surface carbonization approach to improve performance and sensitivity. AB - Many microfluidic devices, also known as lab-on-a-chip devices, employ electrochemical detection methods using microelectrodes. Miniaturizing electrodes inevitably reduces electrode sensitivity and decreases the S/N, which limits applications within microfluidic devices. However, microelectrode surface modification can increase the surface area and sensitivity. In the present work, we report substantial improvement in platinum electrode performance and sensitivity by coating with carbon from red blood cells. The larger goal of this work was to measure DC electrical resistances of red blood cell suspensions in a microchannel for hematocrit determination. It was observed that as current responses of red blood cell suspensions were measured, the platinum electrode performance (reproducibility and S/N) improved with time. The platinum electrode electrocatalytic activity for red blood cell current measurements improved by 140%. Systematic experimentation revealed that red blood cells adsorb and carbonize the platinum electrode surfaces. The electrode surfaces before and after performance improvements were analyzed by field emission scanning electron microscopy, energy dispersive spectrometry, and Raman spectrometry. The formed carbon layers on the electrode surfaces were found to be proteomic and increased surface area with a porous three-dimensional structure, thus improving performance and stabilizing currents. PMID- 26032066 TI - A combination of solid-phase extraction and dispersive solid-phase extraction effectively reduces the matrix interference in liquid chromatography-ultraviolet detection during pyraclostrobin analysis in perilla leaves. AB - Perilla leaves contain many interfering substances; thus, it is difficult to protect the analytes during identification and integration. Furthermore, increasing the amount of sample to lower the detection limit worsens the situation. To overcome this problem, we established a new method using a combination of solid-phase extraction and dispersive solid-phase extraction to analyze pyraclostrobin in perilla leaves by liquid chromatography with ultraviolet absorbance detection. The target compound was quantitated by external calibration with a good determination coefficient (R(2) = 0.997). The method was validated (in triplicate) with three fortification levels, and 79.06- 89.10% of the target compound was recovered with a relative standard deviation <4. The limits of detection and quantification were 0.0033 and 0.01 mg/kg, respectively. The method was successfully applied to field samples collected from two different areas at Gwangju and Muan. The decline in the resiudue concentrations was best ascribed to a first-order kinetic model with half-lives of 5.7 and 4.6 days. The variation between the patterns was attributed to humidity. PMID- 26032067 TI - [Protective effect of heart-fatty acid binding protein on lipopolysaccharide induced cardiomyocyte damage]. AB - OBJECTIVE: To observe the protective effect of heart-fatty acid binding protein (H-FABP) on lipopolysaccharide (LPS)-induced cardiomyocyte damage. METHODS: The cardiomyocytes were isolated and cultured from 1-3 days old neonatal rats. The specific siRNA or plasmid of H-FABP were transfected into cells to alter H-FABP expression, which was evaluated by Western blot and quantitative-PCR. LPS-induced cardiomyocyte damage and inflammation were estimated by detecting the contents of lactate dehydrogenase(LDH), TNF-alpha, and IL-1beta as well as cell viability. RESULTS: LPS treatment induced inflammation and cell damage indicated by a decrease in cell viability and an increase in LDH, TNF-alpha and IL-1beta in the medium. When H-FABP was downregulated by siRNA transfection, the LPS-induced inflammation and cell damage were augmented. In contrast, when H-FABP was overexpressed by pcDNA3.1-H-FABP transfection, the LPS-induced inflammation and cell damage were suppressed. CONCLUSION: H-FABP protects cardiomyocytes from LPS induced inflammation and cell injury. PMID- 26032068 TI - [Effect of accutase dissociation and passage on the apoptosis of human striatum derived neural stem cells]. AB - OBJECTIVE: To explore the status of apoptosis in human striatum derived neural stem cells (NSCs) aft er accutase dissociation and passage. METHODS: The NSCs were isolated from fetuses obtained through spontaneous abortion at 13- 18 weeks of pregnancy, which formed neurospheres in vitro. At passages of 3-5, the neurospheres were disassociated into single cell by accutase digestion and then passaged. At 1, 24 and 72 h after passage, the apoptosis of NSCs was measured by several methods, including active caspase-3 or TUNEL staining for fixed cells, Annexin V, Hoechst or PI staining for live cells. RESULTS: At all of the 3 time points, the staining of TUNEL and active caspase-3 overlapped perfectly. The apoptosis rate of NSCs increased significantly from 20%-25% at 1 h to 75%-80% at 24 h after passage (P<0.01). At 72 h, the apoptosis rate was significantly decreased as compared to that at 24 h time point because of the self-renewal and proliferation of survived NSCs (P<0.01). CONCLUSION: Many cells in the neurospheres formed by human striatum-derived NSCs underwent apoptosis soon after accutase disassociation. For NSCs cultured in vitro, anti-apoptosis treatments might be a good method to increase the self-renewal and the proliferation of NSCs. PMID- 26032069 TI - [Assessment of the right ventricle function of fetus by spatio-temporal image correlation]. AB - OBJECTIVE: To evaluate the superiority, feasibility and clinical signifi cance of the four-dimensional spatio-temporal image correlation (STIC) in detection of the right ventricle function of fetus. METHODS: Th e STIC dynamic images of 180 normal fetal hearts at 24+0 to 37+6 weeks of gestation were obtained by the three dimensional (3D) probe. Th e post-process evaluation was done off -line with the virtual organ computer-aided analysis (VOCAL) software. The computer recorded the right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), and then calculated the right stroke volume (RSV), the right cardiac output (RCO) and the right ejection fraction (REF). RCO was standardized by biometric measurements obtained at prenatal screening, including head circumference (HC), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW). RESULTS: The overall successful rate in image acquisition was 83.89% and the repeatability was favorable. After the standardization of fetal biometric parameters (HC, AC, FL) and the right ventricle function indexes (RVEDV, RVESV, RSV), RCO was increased with the gestational age while the REF and RCO/EFW fluctuated within a certain range. CONCLUSION: STIC technique can accurately and objectively measure the fetal ventricular volume and it might be a potential strategy in the clinical assessment of the fetal cardiac function. PMID- 26032070 TI - [Novaferon ameliorates dextran sulfate sodium-induced colitis and downregulates expression of TNF-alpha in mice]. AB - OBJECTIVE: To explore the effects of novaferon on dextran sulfate sodium (DSS) induced colitis and expression of TNF-alpha in mice and to evaluate the efficacy of novaferon on ulcerative colitis and the possible mechanisms. METHODS: A total of 70 BALB/C mice [weight (20.0+/-2.0) g, 8-week years old, female, pathogen free] were randomly divided into 7 groups: a normal group, a model group, a mesalazine treatment group, a prednisone treatment group, a low-dose novaferon group, a middle-dose novaferon group and a high-dose novaferon group (10 mice per group). The normal group-mice were given distilled water. The ulcerative colitis model was established by treated the mice with 4% DSS for 7 continuous days. At the 8th day, the mice in the all of drug treatment groups were injected corresponding drugs (i.p.). During the experiment, the general situation, daily weight, stool trait and occult blood were recorded, and the mice were killed on the 14th day. The disease activity index (DAI), colon length, histological scores were assessed. Immunohistochemistry was used to measure the expression of TNF alpha in colonic mucosa. RESULTS: 1) The mice treated with DSS solution showed diarrhea, mucous stool and bloody stool, and the DAI score increased gradually. The mesalazine, predinison and nofaferon could ameliorate the general situation of the mice, reduce the DAI and histological scores, and reverse the decrease in the colon length. 2) Compared with the model group, the DAI scores were significantly decreased in the novaferon groups (at low, middle or high dose), the mesalazine group or the prednisone group (all P<0.01), but there was no difference among the mesalazine group, the prednisone group and the low-dose novaferon group (all P>0.05). The efficacy of novaferon in the middle-dose group and the high-dose group are better than that in the mesalazine group, the prednisone group and the low-dose novaferon group (all P<0.01). The efficacy of novaferon showed a dose-dependent manner. 3) The injury of colonic mucosa was relatively mild in the novaferon groups (at low-dose, middle-dose or high-dose), the mesalazine group and the prednisone group, and there were partial glands and less inflammatory cells. Compared with the model group, there was statistics difference (all P<0.05). The tissue injury was significantly alleviated, and the DAI score was decreased in the high-dose novaferon group compared the middle-dose novaferon group (P<0.05), but there was no significant difference between the low dose novaferon group and the middle-dose novaferon group or between the mesalazine group and the prednisone group (both P>0.05). 4) The TNF-alpha expression was significantly down-regulated in the novaferon groups (at low-dose, middle-dose or high-dose), the mesalazine group and the prednisone group compared with model group (all P<0.01); but there was no significant difference between the mesalazine group and the prednisone group (P>0.05); the decrease of TNF-alpha expression by novaferon displayed a dose-dependent manner. Compared with the mesalazine group or the prednisone group, the TNF-alpha expression in novaferon groups at all dosages was dramatically reduced (all P<0.01). CONCLUSION: Novaferon can improve the DAI scores and colonic tissue injury in ulcerative colitis induced by DSS in mice, and down-regulate the TNF-alpha expression in dose-dependent manner. PMID- 26032071 TI - [Effect of artenisiae scopariae and poriae powder on calpain-2 expression in liver tissue from rats with obstructive jaundice]. AB - OBJECTIVE: To explore the eff ect of artenisiae scopariae and poriae powder (ASPD) on calpain-2 expression in liver tissue from rats with obstructive jaundice. METHODS: The rat model of obstructive jaundice was established. SD rats was divided into the control group, the obstructive jaundice group, the obstructive jaundice model plus ASPD group, the obstructive jaundice model plus saline group. Th e serum levels of TBIL, ALT, AST and other biochemical indexes were detected. The pathological changes of liver tissue were evaluated by HE staining. The calpain-2 mRNA and protein expression in liver was measured by Real time PCR and immunohistochemistry or Western blot, respectively. RESULTS: The calpain-2 mRNA and protein expression levels were significantly up-regulated in live tissues from the rats with obstructive jaundice in a time-dependent manner. The ASPD could inhibit the calpain-2 expression in rats with obstructive jaundice concomitant with the decreased liver damage and the improved liver function, suggesting that calpain-2 was involved in endoplasmic reticulum stress-mediated cellular apoptosis and the occurrence of obstructive jaundice. CONCLUSION: ASPD could be used for patients with obstructive jaundice to promote the recovery of liver function after operation and to reduce the incidence of complications, which provide a theoretical basis for the reasonable application of traditional Chinese medicine in the peroperative period. PMID- 26032072 TI - [A study on the effect of icaritin on rat chondrocytes]. AB - OBJECTIVE: To investigate the eff ect of icaritin on proliferation and apoptosis in rat chondrocytes and to provide new theory for osteochondropathy treatment. METHODS: Icaritin (with a purity of 99%) at different concentrations (0, 4, 8, 16, 32, 64 MUmol/L) was incubated with rat chondrocytes for different time. The cell proliferation and apoptosis was assayed by MTT and fl ow cytometry, respectively. RESULTS: Compared with the control group, the cell proliferation was increased in the groups with icaritin at 4 or 8 MUmol/L (P<0.05), whereas the proliferation was decreased in the groups with icaritin at 16, 32 or 64 MUmol/L groups compared to the control group (P<0.05); the cell apoptosis ratio in the group with icaritin at 4 MUmol/L was obviously lower than that in the control group aft er incubation of icaritin for 24 h and 48 h. Beyond 4 MUmol/L, the higher concentration of icaritin, the higher apoptosis ratio of cell. However, it did not show a time-dependent manner at a same concentration of icaritin. CONCLUSION: The icaritin at low concentration (4 or 8 MUmol/L) can promote rat chondrocyte proliferation and inhibit cell apoptosis, while the effect of icaritin on rat chondrocyte at high concentration was reversed. PMID- 26032073 TI - [Comparison of the clinical efficacy between simple vertebral canal decompression and decompression plus laminoplasty]. AB - OBJECTIVE: To observe the clinical efficacy of the simple expansion of the spinal canal decompression, decompression plus hydroxyapatite/polyamide artificial lamina reconstruction, and decompression plus titanium mesh reconstruction in the treatment of spinal canal stenosi. METHODS: A total of 39 patients with lumbar spinal stenosis (with or without disc herniation, spondylolisthesis less than I degree), who received therapy of surgery from January, 2011 to January, 2012, were retrospectively analyzed. All patients were divided into 3 groups: a laminectomy surgery alone group (group A, n=15), a decompression plus hydroxyapatite/polyamide artificial lamina reconstruction group (group B, n=14), and a laminectomy decompression plus reconstruction with titanium mesh group (group C, n=10). Intraoperative situation, the postoperative excellent rate and JOA score were analyzed. RESULTS: The duration and blood loss in surgery in group A was much less than that in the group B and C (P<0.05), but there was no statistical significance between the group B and C. The postoperative excellent rate in three groups were similar in 3 months (P>0.05). Twelve months after the surgery, the group B and C showed advantage over the group A (P<0.05). JOA scores in 3 and 12 months after the surgery were all greater than that before the surgery (P<0.05). There was no difference in excellent rates in 3 groups in 3 months after the operation (P>0.05); the group B and C showed advantage over the group A in 12 months after the operation (P<0.05). No serious complications were related to the surgery in the 3 groups. Imaging changes were not significant difference. CONCLUSION: The decompression plus hydroxyapatite/polyamide artificial lamina reconstruction and the decompression plus titanium mesh reconstruction show advantages in long-term effect over the simple vertebral canal decompression. PMID- 26032074 TI - Value of triage early warning score for trauma patients in an emergency department. AB - OBJECTIVE: To evaluate the predictive accuracy of the triage early warning score (TEWS) in the prognosis and emergency treatment for trauma patients admitted to the emergency department (ED). METHODS: A total of 456 trauma patients (>12 years old) admitted to ED at an education and research hospital in approximately 4 months were prospectively studied. Th e TEWS was recorded in all patients. Th e primary end-point was during 28 days and the emergency responses (such as cardiopulmonary resuscitation/electrical defibrillation, mechanical ventilation) in the ED. RESULTS: Patients with TEWS less than or equal to 9, from 10 to 13, or greater or equal to 14 had mortality rates of 0.98%, 52.63%, or 80%, respectively. An increase in 1 point within the range of 17-point TEWS would be associated with an odds ratio (OR) of 2.14 for death [95% confidence interval (CI): 1.759 to 2.604]. In predicting mortality rates during 28 days, the cut point was greater than 8, the sensitivity was 87.10% (95% CI: 70.2% to 96.4%), the specificity was 92.47% (95% CI: 89.5% to 94.8%), and the areas under the receiver operating characteristic curves (AUCROC) was 0.929 (95% CI: 0.902 to 0.951). Th e AUCROC of TEWS in predicting the emergency responses for CPR/electrical defibrillation application or mechanical ventilation was 0.969 (95% CI: 0.949 to 0.983) or 0.897 (95% CI: 0.865 to 0.923), respectively. CONCLUSION: TEWS is effective in predicting the prognosis and emergency treatment for trauma patients admitted to ED. PMID- 26032075 TI - [Intervention and therapeutic effect of siRNA-HDAC5 on abnormal histone modification in non-obese diabetic mice]. AB - OBJECTIVE: To evaluate therapeutic eff ect of siRNA-HDAC5 on non-obese diabetic (NOD) mice by using small interference RNA (siRNA) technique to knock down the expression of HDAC5 in spleen CD4+ T cells. METHODS: NOD mice, 12-weeks old, were randomly divided into 3 groups and were given normal saline, siRNA-Control or siRNA-HDAC5 through caudal vein injection. The spleens and other samples were collected at the 18th, 24th or 30th week. The blood glucose was tested by blood glucose meter. The urinary albumin and serum levels of IL-1, IL-6, IL-18, and TNF alpha were detected by ELISA. The mRNA levels of CD11a, CCR5, and CX3CR1 in spleen CD4+ T cells were measured by quantitative Real-time PCR. The HDAC5 protein level in spleen CD4+ T cell was detected by Western blot. RESULTS: Compared with the control group, the siRNA-HDAC5 group showed a significant decrease in blood glucose, urine albumin excretion rate, serum cytokine and the mRNA levels of CD11a, CCR5, and CX3CR1, consist with the decrease in protein level of HDAC5. CONCLUSION: Inhibition of HDAC5 expression in NOD mice could effectively alleviate the onset and development of kidney damage caused by diabetes. PMID- 26032076 TI - [Inhibitory effect of galangin on DNA topoisomerases in lung cancer cells]. AB - OBJECTIVE: To explore the eff ect of galangin on DNA topoisomerases in lung cancer cells A549 and H46 as well on cell growth. METHODS: The inhibitory effect of galangin on the growth of A549 and H46 cells was analyzed by MTT method. The effect of galangin on Topo I activity was detected by the agarose gel electrophoresis method. Furthermore, the interaction between galangin and Topo I was evaluated by fluorescence spectroscopy. Finally, the eff ect of galangin on the Topo I structure was discussed. RESULTS: Galangin could induce the apoptosis of A549 and H46 cells (IC50 was 0.221 mmol/L and 0.173 mmol/L, respectively). Agarose gel electrophoresis showed that galangin exerted significant inhibitory effect on Topo I activity. Fluorescence spectrum analysis showed that galangin was able to quench Topo I fluorescence, and hydrophobic interaction was the main driving force. Circular dichroism analysis showed that galangin induced Topo I conformation change and increased the content of alpha-helix, which prevented the formation of active center and in turn led to the decrease in Topo I activity. Molecular simulation results showed that galangin could bind to the active center of Topo I to form hydrogen bonds with the catalytic site at Arg364 and Asn352. CONCLUSION: Galangin is able to inhibit Topo I activity and to reduce the unwinding rate of single stranded DNNA in tumor cells, which plays an important role in induction of A549 and H46 cell apoptosis. PMID- 26032077 TI - [Single nucleotide polymorphism of miR-149 and susceptibility of rheumatoid arthritis]. AB - OBJECTIVE: To investigate the association between microRNA (miR)-149 polymorphism and susceptibility to rheumatoid arthritis (RA ), as well as the clinical characteristics in patients with RA . METHODS: A total of 200 RA patients and 120 healthy controls were recruited from Department of Rheumatology and Immunology of Nanjing First Hospital. After obtaining the informed consent, we collected 2 mL of anti-coagulated venous blood samples from all studied subjects to isolate the whole blood genomic DNA, and the clinical data were collected as well. Single nucleotide polymorphisms of miR-149 rs22928323 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Correlation between single nucleotide polymorphisms and clinical features were compared. RESULTS: The frequencies of TT, TC and CC for rs22928323 of miR-149 were 25.3%, 51.1% and 23.6% or 18.3%, 20.0% and 61.7% in the patients or the healthy controls, respectively. The onset risk of allele C in RA patients was increased compared with allele T [OR=1.38, 95% CI (1.01-1.75), P=0.023]. There were no significant difference in rheumatoid factor, blood urine nitrogen, antikeratin antibody, and other clinical characteristics among the 3 genotypes in RA patients (P>0.05). CONCLUSION: SNP rs22928323 in miR-149 is correlated with RA in the east of Chinese Han population, whereas there is no correlation between miR-149 polymorphism and clinical characteristics in patients with RA. PMID- 26032078 TI - [Screening of the anti-tumor active fraction from Ipomoea batatas Lam. (cv.simon) leaves]. AB - OBJECTIVE: Three fractions (SM, SM-A, SM-B) were prepared from different polarity parts of Ipomoea batatas Lam. (cv.simon) leaves and the anti-tumor potency as well as the dose-response relations were evaluated. METHODS: The anti-tumor activities of fraction SM, SM-A or SM-B were screened by MTS in human hepatic cancer Hep3B cells, lung cancer A549 cells or gastric carcinoma MGC803 cells, respectively. RESULTS: The three fractions all showed anti-tumor activities in three cancer cells with different sensitivity. Among them, SM-B was the most potent fraction with IC50 values at 15.17 mg/L, 72.64 mg/L or 165.47 mg/L in MGC803 cells, A549 cells or Hep3B cells, respectively (P<0.05). CONCLUSION: Th e extraction of Brazil sweet potato leaves displayed anti-tumor activity and SM-B was the most potent fraction. PMID- 26032079 TI - [Application of "chimney graft" technique for thoracic endovascular aneurysm repair in aortic arch lesions]. AB - OBJECTIVE: To explore the safety and efficacy of "chimney graft" technique during thoracic endovascular aneurysm repair (TEVAR) in aortic arch lesions. METHODS: Th e methods, results and the incidence of complications in 25 patients, who received "chimney stent" therapy for aortic arch disease, were reviewed and analyzed. RESULTS: From August, 2010 to August, 2014, 25 aortic arch lesions were treated by TEVAR with "chimney stent", 18 patients were male and 7 were female. The average age was 38-78(65+/-5.8) years old. Five patients received "chimney stents" for left common carotid artery, while 20 patients received "chimney stent" for left subclavian artery. Three cases showed small amount of Type I leak under immediate postoperative angiography without treatment. The leak was disappeared 1month later. Two patients appeared left upper limb weakness and one of them showed dizzinesss simultaneously. Both of them recovered gradually in follow-up process. Th ere was no limb ischemia or necrosis. Th e locations of aortic and "chimney stent" were stable without any migration and leak complications. CONCLUSION: "Chimney graft" technique is a safe and effective treatment for aortic arch lesions due to lack of proximal anchoring zone. The follow up results in a short-term is satisfied. PMID- 26032080 TI - [Diagnostic value of transbronchial lung biopsy in pulmonary alveolar proteinosis]. AB - OBJECTIVE: To evaluate the diagnostic value and limits of transbronchial lung biopsy (TBLB) in pulmonary alveolar proteinosis (PAP). METHODS: The complete hospital data from Second Xiangya Hospital, Central South University, between June, 2006 and December, 2012, were analyzed retrospectively in 25 patients with PAP (who were diagnosed pathologically by TBLB or not by TBLB) and in 4 patients with other disease (who were misdiagnosed by TBLB). RESULTS: Among the 25 patients with PAP, 14 patients were confirmed by TBLB in the fi rst time [TBLB positive rate in the first time was 56% (14/25)]; 6 patients who were misdiagnosed by TBLB in the fi rst time were confirmed by TBLB in the second time [the positive rate in the second time was 24% (6/25)]. Th e total positive rate was 80% (20/25). Th e total negative rate was 20% (5/25). Five patients with PAP, who showed negative results in TBLB analysis, were confirmed by the typical CT as well as the whole lung lavage. In addition, 4 patients with other diseases were misdiagnosed as PAP by TBLB. CONCLUSION: TBLB is a very good diagnosis method. But the negative results in the first time cannot exclude PAP. TBLB should be repeated if conditions allow. If clinical manifestation and CT results are typical, it can be used for diagnosis of PAP combined with the positive results from bronchoalveolar lavage fluid check. However, for non-typical cases, it needs TBLB pathological diagnosis. PMID- 26032081 TI - [Reconstruction of deep wounds in old patients with cutaneous malignant tumor after artificial dermis combined with negative pressure wound therapy]. AB - OBJECTIVE: To evaluate the effects of artificial dermis combined with negative pressure wound therapy on repairing wound aft er resection of cutaneous malignant tumor in elderly. METHODS: The clinical data of 34 hospitalized patients with cutaneous malignant tumor from July, 2009 to February, 2014 were retrospectively analyzed. The patients received local enlarged excision, artificial dermis covered wounds and 12-16 days of negative pressure wound therapy plus a free skin graft transplant on the surface with an artificial dermis. Recovery and complication aft er operation were assessed. RESULTS: All wounds were restored successfully with good appearance. None severe infection happened. CONCLUSION: Artificial dermis combined with negative pressure wound therapy can repair wound efficiently aft er cutaneous malignant tumor resection was performed for old patients. PMID- 26032082 TI - [Clinical analysis of malignant glaucoma after glaucoma surgery]. AB - OBJECTIVE: To explore the risk factors, the ciliary body anatomy structures, the therapeutic methods and the prognosis for malignant glaucoma through retrospectively collecting the clinical data from primary angle-closure glaucoma (PACG) patients. METHODS: Clinical data in 1183 patients (1456 eyes) with PACG were collected between July, 2010 and May, 2014 from Xiangya Hospital, Central South University. Thirty patients (38 eyes) were diagnosed as malignant glaucoma. According to symptom, these patients were divided into a PACG group (1418 eyes) and a malignant glaucoma group (38 eyes); according to age, they were divided into a 3-40 years old group (171 eyes), a 41-70 years old group (1016 eyes) and a >=71 years old group (269 eyes); according to therapeutic methods, they were divided into a drug therapy group (5 eyes), a lens extraction group (6 eyes) and a vitrectomy surgery group (27 eyes); according to the different method of surgery, they were divided into a vitrectomy group (27 eyes), a nonvitrectomy group (11 eyes). The age, sex, anterior chamber depth (ACD), axial length (AL), lens thickness (LT), visual acuity, intraocular pressure, therapeutic methods and surgery history were recorded. Meanwhile, the ciliary body thickness (CBT), trabecular ciliary process angle (TCA) and lens diameter were measured by ultrsound biomicroscopy (UBM). RESULTS: Male and female ratio was 1:2 in the malignant glaucoma group. The average age [(51.87+/-12.92) years] in the malignant glaucoma group was less than that in the PACG group [(57.87+/-8.78) years](P<0.05). Malignant glaucoma was more likely to occur in the first 3 months after PACG trabeculectomy with a rate of 85.7%. The LT [(4.33+/-0.67) mm], AL[(21.44+/-1.18) mm] and ACD [(2.12+/-0.41) mm] in the malignant glaucoma group were less than those in the PACG group [(4.81+/-0.50), (22.17+/-0.97) and (2.49+/ 0.48) mm, respectively](all P<0.05). The CBT0, CBT1, CBTmax, TCA and lens diameter in the malignant glaucoma group were less than those in the PACG group (all P<0.05). CONCLUSION: Female PACG patients, with short axial length, shallow anterior chamber, thin lens, thin ciliary body, small trabecular ciliary process angle and short lens diameter, are more likely to suffer from malignant glaucoma. Vitrectomy can significantly reduce intraocular pressure. PMID- 26032083 TI - [Item selection for perinatal maternal health literacy scale]. AB - OBJECTIVE: To establish a more reliable and accurate scale of perinatal maternal health literacy during perinatal period by selecting items form existing scale. METHODS: Two rounds of inquiry were performed by 14 experts on mother and children to evaluate the necessary and importance of 56 items by Delphi method, in which 50 items were retained. Th en we proceeded a cross-sectional survey in 350 woman who just gave birth 1-3 days before. 10% of them were selected to retest aft er 1 week. Based on these data, we used 6 different methods to select items and kept those that could pass by at least 3 different methods. The methods used in data analysis were Chi-square test, correlation coefficient method (2 kinds), factor analysis, Cronbach alpha coefficient method and the retest reliability method. RESULTS: The Person correlation coefficient was 0.507 (P=0.004). By using the 6 statistical methods, we deleted 9 items through Chi square test, 25 items through correlation coefficient method 1, 1 item through correlation coefficient method 2, 19 items through Cronbach alpha coefficient method, 8 items through factor analysis and 37 items through retest reliability method. In the end, 33 items were retained for the novel scale of maternal health literacy during perinatal period. CONCLUSION: Simplified novel scale is acquired, which need to do large efforts before extensive use, such as large sample survey, reliability and validity test. PMID- 26032084 TI - [Advance in study on endothelial colony-forming cells]. AB - Endothelial colony-forming cells (ECFCs), different from classical endothelial progenitor cells, are late endothelial progenitor cells with the capability to promote angiogenesis. Recent studies showed that ECFCs have a huge angiogenesis potential in the restoration of ischemic hearts, lungs or brains. They are also able to induce the expression of vascular related factor to promote angiogenesis in repair of limb ischemia or bone injury. Furthermore, ECFCs possess a strong homing effect for tumor, which is closely related to tumor occurrence, development and prognosis. Thus, ECFCs are a novel direction for vascular regeneration study, and may lead to ground-breaking progresses in fields of tissue regeneration and tumor. PMID- 26032085 TI - Identifying candidates with favorable prognosis following liver transplantation for hepatocellular carcinoma: Data mining analysis. AB - BACKGROUND AND OBJECTIVES: The optimal cutoff of each value in configuring selection criteria for pre-transplant assessment of hepatocellular carcinoma (HCC) remains uncertain. METHODS: To build a predictive model for recurrent HCC, we performed data mining analysis on patients who underwent LT for HCC at University Health Network (n = 246). The model was externally validated using a cohort from the Scientific Registry of Transplant Recipients (SRTR) database (n = 9,769). RESULTS: Among 246 patients, 14.6% (n = 36) experienced recurrent HCC within 2.5 years post-LT. The risk prediction model for recurrent HCC identified two subgroups with low-risk (total tumor diameter [TTD] <4 cm and serum alpha fetoprotein [AFP] <73 ng/ml, n = 135) and with high-risk (TTD >4 cm and/or AFP >73 ng/ml, n = 111). The reproducibility of the model was validated through the SRTR database; overall patient survival rate was significantly better in low-risk group than high-risk group (P < 0.0001). Using Cox regression model, this yardstick, not Milan criteria, was revealed to efficiently predict post transplant survival independent of underlying characteristics (P < 0.0001). CONCLUSIONS: Grouping LT candidates with pre-LT HCC by the cutoffs of TTD 4 cm and AFP 73 ng/ml which were unearthed by data mining analysis efficiently classify patients according by the post-transplant prognosis. PMID- 26032086 TI - MicroRNAs Provide Feedback Regulation of Epithelial-Mesenchymal Transition Induced by Growth Factors. AB - As regulators in gene expression, microRNAs take part in most biological processes including cell differentiation, apoptosis, cell cycle, and epithelial to-mesenchymal transition (EMT). In order to evaluate their roles in EMT process, microRNA expression profile changes induced by EGF or TGF-beta treatment on nasopharyngeal carcinoma cell HK-1 were analyzed, and miR-21, miR-148a, miR-505, and miR-1207-5p were found to be upregulated in growth factors-induced EMT process. miR-21 is already known as an oncogenic miRNA to promote metastasis, however, the exact functions of other three miRNAs in EMT are unclear. To our surprise, we found that miR-148a, miR-505, and miR-1207-5p can suppress EMT and metastasis phenotypes in HK-1 cells both in vitro and in vivo, which may relate to their inhibition on EMT and Wnt signaling molecules. MiRNAs confer robustness to biological processes by posttranscriptional repression of key transcriptional programs that are related to previous developmental stages or to alternative cell fates. Our findings indicate that miRNA feedback circuit is tuned to respond to growth factors-induced EMT, and we suggested a new negative feedback loop which may be an important element of the EMT process and confer biological robustness. PMID- 26032087 TI - Complex interactions among residues within pore region determine the K+ dependence of a KAT1-type potassium channel AmKAT1. AB - KAT1-type channels mediate K(+) influx into guard cells that enables stomatal opening. In this study, a KAT1-type channel AmKAT1 was cloned from the xerophyte Ammopiptanthus mongolicus. In contrast to most KAT1-type channels, its activation is strongly dependent on external K(+) concentration, so it can be used as a model to explore the mechanism for the K(+) -dependent gating of KAT1-type channels. Domain swapping between AmKAT1 and KAT1 reveals that the S5-pore-S6 region controls the K(+) dependence of AmKAT1, and residue substitutions show that multiple residues within the S5-Pore linker and Pore are involved in its K(+) -dependent gating. Importantly, complex interactions occur among these residues, and it is these interactions that determine its K(+) dependence. Finally, we analyzed the potential mechanism for the K(+) dependence of AmKAT1, which could originate from the requirement of K(+) occupancy in the selectivity filter to maintain its conductive conformation. These results provide new insights into the molecular basis of the K(+) -dependent gating of KAT1-type channels. PMID- 26032088 TI - DSDecode: A Web-Based Tool for Decoding of Sequencing Chromatograms for Genotyping of Targeted Mutations. PMID- 26032089 TI - Characterization of Panax ginseng UDP-Glycosyltransferases Catalyzing Protopanaxatriol and Biosyntheses of Bioactive Ginsenosides F1 and Rh1 in Metabolically Engineered Yeasts. AB - Ginsenosides, the main pharmacologically active natural compounds in ginseng (Panax ginseng), are mostly the glycosylated products of protopanaxadiol (PPD) and protopanaxatriol (PPT). No uridine diphosphate glycosyltransferase (UGT), which catalyzes PPT to produce PPT-type ginsenosides, has yet been reported. Here, we show that UGTPg1, which has been demonstrated to regio-specifically glycosylate the C20-OH of PPD, also specifically glycosylates the C20-OH of PPT to produce bioactive ginsenoside F1. We report the characterization of four novel UGT genes isolated from P. ginseng, sharing high deduced amino acid identity (>84%) with UGTPg1. We demonstrate that UGTPg100 specifically glycosylates the C6 OH of PPT to produce bioactive ginsenoside Rh1, and UGTPg101 catalyzes PPT to produce F1, followed by the generation of ginsenoside Rg1 from F1. However, UGTPg102 and UGTPg103 were found to have no detectable activity on PPT. Through structural modeling and site-directed mutagenesis, we identified several key amino acids of these UGTs that may play important roles in determining their activities and substrate regio-specificities. Moreover, we constructed yeast recombinants to biosynthesize F1 and Rh1 by introducing the genetically engineered PPT-producing pathway and UGTPg1 or UGTPg100. Our study reveals the possible biosynthetic pathways of PPT-type ginsenosides in Panax plants, and provides a sound manufacturing approach for bioactive PPT-type ginsenosides in yeast via synthetic biology strategies. PMID- 26032090 TI - Behind the Wheel: Predictors of Driving Exposure in Older Drivers. AB - OBJECTIVES: To explore and deepen understanding of factors influencing driving exposure for older drivers. DESIGN: Cross-sectional. SETTING: Baseline data on function and driving exposure from 1 week of driving were evaluated. PARTICIPANTS: A convenience sample of 380 drivers aged 75 and older, residing in northwest Sydney, was recruited. Participants were required to be the primary drivers of their own vehicle. MEASUREMENTS: Driver function was evaluated using the DriveSafe and DriveAware clinic-based assessments to measure visual attention to the driving environment and awareness of driving ability. Demographic information was obtained through interview. An in-vehicle monitoring device with data logger and GPS receiver, was used to measure driving exposure in 362 of 380 participants' vehicles. Driving exposure outcomes were total distance driven, furthest distance traveled from home, and average trip length. Factors influencing these exposure outcomes were analyzed using generalized linear regression. RESULTS: Drivers typically drove 100 km in local and surrounding areas during the week. Function was predictive of all driving exposure outcomes. Drivers with lower levels of function drove fewer kilometers and took shorter trips closer to home. Age, health status, and personal circumstance (e.g., rural residence) also influenced exposure, but sex did not. CONCLUSION: Using objective measures, this study provides evidence that function, age, health status, and personal circumstance influence driving exposure of older drivers. Understanding how older people use driving to preserve their independence is important for exploring safe driving strategies for older people. PMID- 26032091 TI - Decreased expression of dual specificity phosphatase 22 in colorectal cancer and its potential prognostic relevance for stage IV CRC patients. AB - Dual specificity phosphatase 22 (DUSP22) is a novel dual specificity phosphatase that has been demonstrated to be a cancer suppressor gene associated with numerous biological and pathological processes. However, little is known of DUSP22 expression profiling in colorectal cancer and its prognostic value. Our study aims to investigate the role of DUSP22 expression in the prognosis of colorectal cancer. We detected the mRNA expression in 92 paired primary colorectal cancer tissues and the corresponding adjacent normal tissues by using QuantiGenePlex assay. The Friedman test was used to determine the statistical difference of gene expression. Kaplan-Meier survival analysis was performed. Mann Whitney test and Kruskal-Wallis test were used to conduct data analyses to determine the prognostic value. Statistical significance was set at P < 0.05. In 74 of 92 cases, DUSP22 mRNA was reduced in primary colorectal cancer tissues, compared to the adjacent normal tissues. The mRNA levels of DUSP22 were significantly lower in colorectal cancer tissues than in adjacent normal tissues (0.0290 vs. 0.0658; P < 0.001). Low expression of DUSP22 correlated significantly with large tumor size (P = 0.013). No association was observed between DUSP22 mRNA expression and differentiation, histopathological type, tumor invasion, lymph node metastases, metastases, TNM stage, and Duke's phase (all P > 0.05). Kaplan-Meier analysis indicated that DUSP22 expression had no significant relationship with overall survival in all patients (P > 0.05). Interestingly, low expression level of DUSP22 in stage IV patients had a poor survival measures with a marginal P value (P = 0.07). Reduced DUSP22 expression was found in colorectal cancer specimens. Low expression level of DUSP22 in stage IV patients had a poor survival outcome. Further study is required for the investigation of the role of DUSP22 in colorectal cancer. PMID- 26032092 TI - Curcumin inhibits growth of prostate carcinoma via miR-208-mediated CDKN1A activation. AB - Prostate cancer (PC) is a prevalent cancer in aged men. Curcumin is an active ingredient that has been extracted from the rhizome of the plant Curcuma longa. Recently, a potential of Curcumin against PC has been reported in PC, whereas the underlying molecular mechanisms are not completely understood. Here, we studied the effects of low-dose Curcumin on PC cell growth. Curcumin (from 0.2 to 0.8 MUmol/l) dose-dependently inhibited the proliferation of PC cells, without affecting cell apoptosis. Further analyses showed that Curcumin dose-dependently increased a cell cycle suppressor CDKN1A at protein levels, but not mRNA levels, in PC cells, suggesting that Curcumin may regulate the translation of CDKN1A, as well as a possible involvement of miRNA intervention. From all CDKN1A-3'-UTR binding miRNAs, we found that miR-208 was specifically inhibited in PC cells dose dependently by Curcumin. Moreover, miR-208 was found to bind CDKN1A to suppress its expression. In a loss-of-function experiment, PC cells that overexpressed miR 208 failed to decrease cell proliferation in response to Curcumin. Together, these data suggest that Curcumin inhibits growth of PC via miR-208-mediated CDKN1A activation. PMID- 26032093 TI - Expressions of miR-181a and miR-20a in RPMI8226 cell line and their potential as biomarkers for multiple myeloma. AB - Multiple myeloma (MM) is characterized by clonal proliferation of malignant plasma cells in the bone marrow. The anti-tumor activity of bortezomib (a proteosome inhibitor) in MM is challenged by emergence of drug resistance. MicroRNAs (miR) regulate and orchestrate multiple cellular pathways. We investigate the contribution miR-181a and miR-20a expressions' on cell proliferation and apoptosis in RPMI8226 cell line and their influence on bortezomib treatment. RNA isolation, quantitative real-time PCR (qRT-PCR), cell proliferation assay, cell cycle analysis, and cell apoptosis assay were done. Statistical analysis was performed using SPSS 17.0 software (SPSS, Chicago, IL, USA). P values of less than 0.05 were considered statistically significant. RPMI8226 cells seeded in 96-well plates and treated for 24 h with different concentrations of bortezomib showed dose-dependent growth inhibition; expression of both miR-181a and miR-20a were inhibited by bortezomib. We found decrease of miR-181a (60%) and miR-20a (30%) in cells transfected with 20-nM inhibitor. A relative increase of 14-fold in miR-181a and 11-fold in miR-20a was observed in cells transfected with mimics of the same concentration. Transient low expression of miR-181a/20a inhibited proliferation at day 4, and overexpression of miR-181a promoted proliferation. Cells transfected with miR-181a/20a inhibitor within day 4 showed lower survival rate, and low expression of miR-181a on the fourth day after transfection promoted apoptosis. Our findings suggest that miR-181a/20a has a higher expression in MM. miR-181-a expression is proportional to MM tumor burden and could be a biomaker for monitoring treatment. miR-20a shows the potential of a diagnostic biomarker. PMID- 26032094 TI - TKTL1 expression and its downregulation is implicated in cell proliferation inhibition and cell cycle arrest in esophageal squamous cell carcinoma. AB - It is well known that tumor cells mainly depend on the nonoxidative pathway of the pentose phosphate pathway (PPP), and transketolase-like 1 (TKTL1), a kind of crucial metabolism enzyme, participates in the regulation of PPP; notably, overwhelming evidence has demonstrated that TKTL1 plays pivotal roles in the development and progression of multiple tumors. However, there were no reports about the role of TKTL1 in esophageal squamous cell carcinoma (ESCC). Here, we investigated TKTL1 expression and preliminarily elucidated its underlying biological functions in ESCC. We found that TKTL1 exhibited the high expression in ESCC tissues and cells, and the survival rate of patients with negative TKTL1 expression was significantly higher than that of patients with positive TKTL1 staining (P < 0.05). Additionally, significant correlations of TKTL1 expression with histologic grade, clinical stage, and lymph node metastasis were found (P < 0.05). Subsequently, TKTL1 small interfering RNA (siRNA) significantly reduced TKTL1 messenger RNA (mRNA), and protein levels companied with the marked reduce of total transketolase activity but did not affect TKT and TKTL1 mRNA level. More importantly, TKTL1 siRNA obviously induced cell cycle arrest in G0/G1 phase and suppressed cell proliferation in vitro and in vivo coupled with the reduced cyclin D1 and cdk4 levels as well as decrease of Ki-67 proliferation index in EC1 cells. Taken altogether, our results suggest that TKTL1 as a key prognostic factor may be a novel target for therapy of the patients with ESCC. PMID- 26032095 TI - Preoperative lymphocyte-monocyte and platelet-lymphocyte ratios as predictors of overall survival in patients with bladder cancer undergoing radical cystectomy. AB - Although pretreatment neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR) are reportedly associated with clinical outcomes of many cancers, their roles in patients with bladder cancer (BCa) who undergo radical cystectomy (RC) have not been widely investigated. We analyzed relationships between preoperative NLR, LMR, PLR, and overall survival (OS) in 124 BCa patients undergoing RC. OS curves were drawn using the Kaplan Meier method and evaluated using the log-rank test. Relationships between OS and potential confounding variables were determined using Cox's proportional hazard regression model. Decreased LMR was associated with shorter OS (P = 0.012); OS in the low PLR group was significantly longer than that in the high PLR group (P = 0.029), and NLR was not significantly associated with oncological outcomes. However, after adjusting for confounding variables, patients in the high-LMR group indicated >30% decreased mortality than the low-LMR group (hazard ratio 0.674; 95% confidence interval 0.412-0.890; P = 0.003), and PLR was not an independent predictor of OS. Our results show that preoperative LMR is a better prognostic factor in BCa patients undergoing RC, compared with NLR and PLR. PMID- 26032097 TI - Comparison of the genetic variation of captive ring-tailed lemurs with a wild population in Madagascar. AB - Genetic variability among captive and wild ring-tailed lemurs (Lemur catta) was assessed using mitochondrial and nuclear DNA data. A 529 bp segment of mtDNA was sequenced and 9 microsatellite loci were genotyped for 286 ring-tailed lemurs. Samples were obtained from the well-studied L. catta population at the Beza Mahafaly Special Reserve and from captive animals at six institutions worldwide. We found evidence of possible patrilineal contribution but the absence of matrilineal contribution from the Beza area, and haplotypes not found in Beza but present in Ambohimahavelona, Andringitra Massif, and other unknown locations, in the sampled captive population, indicating that the founders of the captive population originated from a wide geographic range. Total genetic variation and relatedness in captive L. catta in the six institutions were similar in extent to that of the wild population in Beza. Based on the diverse origins of the captive population founders our results suggest the erosion of genetic diversity in the captive population. Sampled individuals from the same institution were more closely related to each other than members of a social group in the wild. Individuals housed at different institutions were less closely related than those of different social groups at Beza, indicating lower genetic exchange between captive institutions than between social groups in a locality in the wild. Our findings underscore the usefulness of genotyping in determining the geographic origin of captive population founders, obtaining pedigree information if paternity is uncertain, and in maximizing preservation of extant genetic diversity in captivity. PMID- 26032098 TI - Understanding the molecular basis for differences in responses of fish estrogen receptor subtypes to environmental estrogens. AB - Exposure to endocrine disrupting chemicals (EDCs) can elicit adverse effects on development, sexual differentiation, and reproduction in fish. Teleost species exhibit at least three subtypes of estrogen receptor (ESR), ESR1, ESR2a, and ESR2b; thus, estrogenic signaling pathways are complex. We applied in vitro reporter gene assays for ESRs in five fish species to investigate the ESR subtype specificity for better understanding the signaling pathway of estrogenic EDCs. Responses to bisphenol A, 4-nonylphenol, and o,p'-DDT varied among ESR subtypes, and the response pattern of ESRs was basically common among the different fish species. Using a computational in silico docking model and through assays quantifying transactivation of the LBD (using GAL-LBD fusion proteins and chimera proteins for the ESR2s), we found that the LBD of the different ESR subtypes generally plays a key role in conferring responsiveness of the ESR subtypes to EDCs. These results also indicate that responses of ESR2s to EDCs cannot necessarily be predicted from the LBD sequence alone, and an additional region is required for full transactivation of these receptors. Our data thus provide advancing understanding on receptor functioning for both basic and applied research. PMID- 26032099 TI - Electrochemical Peptide Biosensor Based on in Situ Silver Deposition for Detection of Prostate Specific Antigen. AB - In this work, we have demonstrated a novel electrochemical method based on target induced cleavage of a specific peptide for sensitive analysis of prostate specific antigen (PSA) by using silver enhancement. First, multiwalled carbon nanotubes/poly(amidoamine) dendrimers (MWCNTs-PAMAM) nanohybrids were assembled on the electrode to bind the peptide. Subsequently, dithiobis(succinimidylpropionate) (DSP)@Au@SiO2 was prepared as a tracing tag and covalent bond with the peptides via the inherent interaction between DSP and the amino of peptide. In the presence of PSA, the peptide was specifically recognized and cleaved, resulting in the loss of the tracing tag in electrode surface. Thereafter, silver enhancement was performed on the left DSP@Au@SiO2 nanohybrids. The electrochemical stripping signal of the deposited silver was used to monitor this process. Under optimal conditions, the proposed biosensor achieved a wide line from 0.001 to 30 ng mL(-1) with a detection limit of 0.7 pg mL(-1). This work demonstrated the combination of the direct transduction of peptide cleavage events with the highly sensitive silver enhancement method, providing a promising effective strategy for PSA detection. PMID- 26032100 TI - Density equalizing mapping of the global tuberculosis research architecture. AB - BACKGROUND: Tuberculosis belongs to the lung infectious diseases with the highest impact on global burden of disease. Yet there is no concise scientometric study about tuberculosis research. Therefore, the NewQiS project elected this subject as focus of an in depth analysis to perform density equalizing mapping in combination with scientometrics. METHOD: In this retrospective study all publications related to tuberculosis research listed in the Web of Science database between 1900 and 2012 were identified, analyzed and submitted to density equalizing mapping procedures. RESULTS: In total 58,319 entries on TBC were identified with the USA being the most productive country with 11,788 publications, followed by the United Kingdom (4202), India (3456), France (2541), South Africa (1840), Germany (1747) and China (1427). Concerning the citations rate Denmark leads with 43.7 citations per article, followed by Latvia (39.1), Gambia (38.3), Senegal (34.9), and the Netherlands (31.4). Chart techniques demonstrates a widely ramified international network with a focus the joint work of USA, the UK and South Africa. CONCLUSIONS: This is the first density equalizing and scientometric study that addresses tuberculosis research over a period of 112 years. It illustrates global tuberculosis research architecture and stresses the need for strengthening global research efforts and funding program. PMID- 26032101 TI - Moving on in life after intensive care--partners' experience of group communication. AB - BACKGROUND: Partners have a burdensome time during and after their partners' intensive care period. They may appear to be coping well outwardly but inside feel vulnerable and lost. Evaluated interventions for partners on this aspect are limited. AIM: The aim of this study was to describe the experience of participating in group communication with other partners of former intensive care patients. DESIGN: The study has a descriptive intervention-based design where group communication for partners of former, surviving intensive care unit (ICU) patients was evaluated. METHODS: A strategic selection was made of adult partners to former adult intensive care patients (n = 15), 5 men and 10 women, aged 37-89 years. Two group communication sessions lasting 2 h were held at monthly intervals with three to five partners. The partners later wrote, in a notebook, about their feelings of participating in group communications. To deepen the understanding of the impact of the sessions, six of the partners were interviewed. Content analysis was used to analyse the notebooks and the interviews. FINDINGS: Three categories were identified: (1) Emotional impact, the partners felt togetherness and experienced worries and gratitude, (2) Confirmation, consciousness through insight and reflection and (3) The meeting design, group constellation and recommendation to participate in group communication. CONCLUSION: Partners of an intensive care patient are on a journey, constantly trying to adapt to the new situation and find new strategies to ever-changing circumstances. Group communications contributed to togetherness and confirmation. To share experiences with others is one way for partners to be able to move forward in life. RELEVANCE TO CLINICAL PRACTICE: Group communication with other patients' partners eases the process of going through the burden of being a partner to an intensive care patient. Group communications needs to be further developed and evaluated to obtain consensus and evidence for the best practice. PMID- 26032102 TI - Skeletal muscle proteins: a new approach to delimitate the time since death. AB - PURPOSE: Skeletal muscle tissue is proposed as a forensic model tissue with strong potential, as it is easily accessible and its true-to-life state structure and function is well known. Despite this strong potential, skeletal muscle degradation studies are rare. The aim of this study was to test if a skeletal muscle-based protein analysis is applicable to delimitate the time since death. METHODS: Under standard conditions, two pigs were stored either at 22 degrees C for 5 days or 4 degrees C for 21 days. Their Mm. biceps femori were sampled periodically for analyses of ten skeletal muscle proteins postmortem. RESULTS: All analyzed proteins can serve as markers for a delimitation of the time since death. Desmin, nebulin, titin, and SERCA 1 displayed distinct protein patterns at certain points of time. The other five proteins, alpha-actinin, calsequestrin-1, laminin, troponin T-C, and SERCA 2, showed no degradation patterns within the analyzed postmortem time frame. CONCLUSIONS: Referring to specific skeletal muscle proteins, results showed short-term stabilities for just a minority of analyzed proteins, while the majority of investigated proteins displayed characteristics as long-term markers. Due to specific patterns and the possibility to determine definite constraints of the presence, absence, or pattern alterations of single proteins, the feasibility of porcine skeletal muscle as forensic model tissue is outlined and the potential of skeletal muscle as forensic model tissue is underlined, especially with respect to later postmortem phases, which so far lack feasible methods to delimitate the time since death. PMID- 26032103 TI - Genetics: Mutations underlying azoospermia identified on the X chromosome. PMID- 26032104 TI - Therapy: Metformin takes a new route to clinical efficacy. PMID- 26032106 TI - Dietary prevention of obesity and cardiometabolic disease. PMID- 26032105 TI - Skeletal changes through the lifespan--from growth to senescence. AB - Age-related fragility fractures are an enormous public health problem. Both acquisition of bone mass during growth and bone loss associated with ageing affect fracture risk late in life. The development of high-resolution peripheral quantitative CT (HRpQCT) has enabled in vivo assessment of changes in the microarchitecture of trabecular and cortical bone throughout life. Studies using HRpQCT have demonstrated that the transient increase in distal forearm fractures during adolescent growth is associated with alterations in cortical bone, which include cortical thinning and increased porosity. Children with distal forearm fractures in the setting of mild, but not moderate, trauma also have increased deficits in cortical bone at the distal radius and in bone mass systemically. Moreover, these children transition into young adulthood with reduced peak bone mass. Elderly men, but not elderly women, with a history of childhood forearm fractures have an increased risk of osteoporotic fractures. With ageing, men lose trabecular bone primarily by thinning of trabeculae, whereas the number of trabeculae is reduced in women, which is much more destabilizing from a biomechanical perspective. However, age-related losses of cortical bone and increases in cortical porosity seem to have a much larger role than previously recognized, and increased cortical porosity might characterize patients at increased risk of fragility fractures. PMID- 26032107 TI - Risk factors: Diabetes, fractures and mortality--statin therapy. PMID- 26032108 TI - Bone: Reversal of age-related decline in fracture repair--the benefits of a youthful circulation. PMID- 26032109 TI - Preventing beta-cell apoptosis and T2DM with microRNAs--a role for miR-200? PMID- 26032110 TI - The expanding field of IgG4-mediated neurological autoimmune disorders. AB - At least 13 different disease entities affecting the central nervous system, peripheral nervous system and connective tissue of the skin or kidneys are associated with immunoglobulin G4 (IgG4) immune reactivity. IgG4 has always been considered a benign, non-inflammatory subclass of IgG, in contrast to the well known complement-activating pro-inflammatory IgG1 subclass. A comprehensive review of these IgG4 autoimmune disorders reveals striking similarities in epitope binding and human leukocyte antigen (HLA) associations. Mechanical interference of extracellular ligand-receptor interactions by the associated IgG4 antibodies seems to be the common/converging disease mechanism in these disorders. PMID- 26032111 TI - Breast cancer metastasis burden in sentinel nodes analysed using one-step nucleic acid amplification predicts axillary nodal status. AB - BACKGROUND: In breast cancer patients undergoing sentinel lymph node biopsy (SLNB) analysis using one-step nucleic acid amplification (OSNA), clarity is required as to the risk factors for non-sentinel lymph node (NSLN) involvement upon axillary lymph node dissection (ALND). This study aims to identify these factors, including categorising by extent of sentinel node positivity: solitary positive node (solitary), multiple nodes with some positive (multiple incomplete positive), or multiple nodes all of which are positive (multiple all positive). METHODS: We conducted a cohort study using prospectively collected data on 856 SLNBs analysed using OSNA, from patients with cT1-3 clinically node-negative invasive breast cancer. ALND was performed for 289 positive SLNBs. RESULTS: NSLN metastases were identified in 73 (25.3%) ALNDs. Significant factors for NSLN involvement on multivariate analysis were: SLNB macrometastases (cytokeratin-19 mRNA count >5000 copies/MUl) (adj.OR = 3.01; 95% CI, 1.61-5.66; p = 0.0006), multiple all positive vs. multiple incomplete positive SLNB (adj.OR = 2.92; 95% CI, 1.38-6.19; p = 0.0050), and undergoing mastectomy (adj.OR = 1.89; 95% CI, 1.00-3.55; p = 0.0486). Amongst multiple incomplete positive SLNBs, an 8.8% NSLN risk was identified when only micrometastases were present. CONCLUSION: Extent of sentinel lymph node positivity measured using OSNA predicts NSLN metastasis risk, aiding decisions surrounding axillary treatment. PMID- 26032112 TI - Interleukin-1 blockade in neuro-Behcet's disease: a case-based reflection. PMID- 26032113 TI - Natural disasters and dialysis care in the Asia-Pacific. AB - The impact of natural disasters on the provision of dialysis services has received increased attention in the last decade following Hurricane Katrina devastating New Orleans in 2005. The Asia-Pacific is particularly vulnerable to earthquakes, tsunami, typhoons (also known as cyclones and hurricanes) or storms and flooding. These events can seriously interrupt provision of haemodialysis with adverse effects for patients including missed dialysis, increased hospitalization and post-traumatic stress disorder. Furthermore, haemodialysis patients may need to relocate and experience prolonged periods of displacement from family and social supports. In contrast to haemodialysis, most literature suggests peritoneal dialysis in a disaster situation is more easily managed and supported. It has become apparent that dialysis units and patients should be prepared for a disaster event and that appropriate planning will result in reduced confusion and adverse outcomes should a disaster occur. Numerous resources are now available to guide dialysis units, patients and staff in preparation for a possible disaster. This article will examine the disaster experiences of dialysis units in the Asia-Pacific, the impact on patients and staff, methods employed to manage during the disaster and suggested plans for reducing the impact of future disasters. PMID- 26032114 TI - The effects of proton pump inhibition on patient-reported severity of dyspepsia when receiving dual anti-platelet therapy with clopidogrel and low-dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial. AB - BACKGROUND: Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined. AIM: To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. METHODS: We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. RESULTS: Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 +/- 0.17 vs. 6.40 +/- 0.17, P = 0.001, and 10.61 +/- 0.07 vs. 11.00 +/- 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 +/- 0.35 vs. 7.10 +/- 0.37, P = 0.020 for pain intensity; 10.36 +/ 0.12 vs. 10.93 +/- 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. CONCLUSIONS: In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline. PMID- 26032115 TI - Kinetics of CO2 exchange with carbonic anhydrase immobilized on fiber membranes in artificial lungs. AB - Artificial lung devices comprised of hollow fiber membranes (HFMs) coated with the enzyme carbonic anhydrase (CA), accelerate removal of carbon dioxide (CO2) from blood for the treatment of acute respiratory failure. While previous work demonstrated CA coatings increase HFM CO2 removal by 115 % in phosphate buffered saline (PBS), testing in blood revealed a 36 % increase compared to unmodified HFMs. In this work, we sought to characterize the CO2 mass transport processes within these biocatalytic devices which impede CA coating efficacy and develop approaches towards improving bioactive HFM efficiency. Aminated HFMs were sequentially reacted with glutaraldehyde (GA), chitosan, GA and afterwards incubated with a CA solution, covalently linking CA to the surface. Bioactive CA HFMs were potted in model gas exchange devices (0.0119 m(2)) and tested for esterase activity and CO2 removal under various flow rates with PBS, whole blood, and solutions containing individual blood components (plasma albumin, red blood cells or free carbonic anhydrase). Results demonstrated that increasing the immobilized enzyme activity did not significantly impact CO2 removal rate, as the diffusional resistance from the liquid boundary layer is the primary impediment to CO2 transport by both unmodified and bioactive HFMs under clinically relevant conditions. Furthermore, endogenous CA within red blood cells competes with HFM immobilized CA to increase CO2 removal. Based on our findings, we propose a bicarbonate/CO2 disequilibrium hypothesis to describe performance of CA-modified devices in both buffer and blood. Improvement in CO2 removal rates using CA modified devices in blood may be realized by maximizing bicarbonate/CO2 disequilibrium at the fiber surface via strategies such as blood acidification and active mixing within the device. PMID- 26032116 TI - Influence of synthetic polyethylene glycol hydrogels on new bone formation during mandibular augmentation procedures in Goettingen minipigs. AB - Polyethylene glycol hydrogels (PEG) have been used as slow release carrier for osteoinductive growth factors in order to achieve a retarded delivery. However, there have been concerns about negative effects on bone regeneration. This study aims to test whether PEG hydrogels themselves affect new bone formation (NBF), when used as a carrier during mandibular augmentation procedures. In a randomized split-mouth design, bilateral mandibular bone defects were surgically created in 12 Goettingen minipigs, and subsequently augmented, using PEG hydrogel on one side of the mandible. The contralateral sides, without PEG, served as controls. After 4 and 12 weeks, bone formation was evaluated in six animals each. A comparison of the data, using a three-way analysis of variance (ANOVA), revealed a significant effect of the healing time and the region of the graft on the distribution and enhancement of NBF (P < .0001, respectively). Although a 0.3% (95%-CI [-5.5; 4.8]) lower volume density of newly formed bone could be observed over all PEG hydrogel sections, in contrast to the contralateral controls, the analysis revealed no clinically significant effects of the PEG hydrogel treatment on the total level (P = 0.90), and the distribution of NBF (P = 0.54). In conclusion, PEG hydrogels do not affect NBF when used as a carrier for osteoinductive growth factors during mandibular augmentation procedures. PMID- 26032117 TI - The Struggle for Equity: An Examination of Surgical Services at Two NGO Hospitals in Rural Haiti. AB - BACKGROUND: Health systems must deliver care equitably in order to serve the poor. Both L'Hopital Albert Schweitzer (HAS) and L'Hopital Bon Sauveur (HBS) have longstanding commitments to provide equitable surgical care in rural Haiti. HAS charges fees that demonstrate a preference for the rural population near the hospital, with free care available for the poorest. HBS does not charge fees. The two hospitals are otherwise similar in surgical capacity and rural location. METHODS: We retrospectively reviewed operative case-logs at both hospitals from June 1 to Aug 31, 2012. The records were compared by total number of operations, geographic distribution of patients and number of elective operations. Using geography as a proxy for poverty, we analyzed the equity achieved under the financial systems at both hospitals. RESULTS: Patients from the rural service area received 86% of operations at HAS compared to 38% at HBS (p < 0.001). Only 5% of all operations at HAS were performed on patients from outside the service area for elective conditions compared to 47% at HBS (p < 0.001). Within its rural service area, HAS performed fewer operations on patients from the most destitute areas compared to other locations (40.3 vs. 101.3 operations/100,000 population, p < 0.001). CONCLUSIONS: Using fees as part of an equity strategy will likely disadvantage the poorest patients, while providing care without fees may encourage patients to travel from urban areas that contain other hospitals. Health systems striving to serve the poor should continually evaluate and seek to improve equity, even within systems that provide free care. PMID- 26032118 TI - Transversus abdominis plane (TAP) block after robot-assisted laparoscopic hysterectomy: a randomised clinical trial. AB - BACKGROUND: Transversus abdominis plane (TAP) block is widely used as a part of pain management after various abdominal surgeries. We evaluated the effect of TAP block as an add-on to the routine analgesic regimen in patients undergoing robot assisted laparoscopic hysterectomy. METHODS: In a prospective blinded study, 70 patients scheduled for elective robot-assisted laparoscopic hysterectomy were randomised to receive either TAP block (ropivacaine 0.5%, 20 ml on each side) or sham block (isotonic saline 0.9%, 20 ml on each side). All patients had patient controlled analgesia (PCA) with morphine on top of paracetamol and ibuprofen or diclofenac. For the first 24 post-operative hours, we monitored PCA morphine consumption and pain scores with visual analogue scale (VAS) at rest and while coughing. Post-operative nausea and number of vomits (PONV) were recorded. RESULTS: Sixty-five patients completed the study, 34 receiving TAP block with ropivacaine and 31 receiving sham block with isotonic saline. We found no differences in median (interquartile range) morphine consumption the first 24 h between the TAP block group [17.5 mg (6.9-36.0 mg)] and the placebo group [17.5 mg (2.9-38.0 mg)] (95% confidence interval 10.0-22.6 mg, P = 0.648). No differences were found for VAS scores between the two groups, calculated as area under the curve/1-24 h, neither at rest (P = 0.112) nor while coughing (P = 0.345), or for PONV between groups. CONCLUSIONS: In our study, the TAP block combined with paracetamol and Nonsteroidal anti-inflammatory drugs (NSAID) treatment, had no effect on morphine consumption, VAS pain scores, or frequency of nausea and vomiting after robot-assisted laparoscopic hysterectomy compared with paracetamol and NSAID alone. PMID- 26032119 TI - Dutch Multidisciplinary Guideline for Invasive Treatment of Pain Syndromes of the Lumbosacral Spine. AB - OBJECTIVES: When conservative therapies such as pain medication or exercise therapy fail, invasive treatment may be indicated for patients with lumbosacral spinal pain. The Dutch Society of Anesthesiologists, in collaboration with the Dutch Orthopedic Association and the Dutch Neurosurgical Society, has taken the initiative to develop the guideline "Spinal low back pain," which describes the evidence regarding diagnostics and invasive treatment of the most common spinal low back pain syndromes, that is, facet joint pain, sacroiliac joint pain, coccygodynia, pain originating from the intervertebral disk, and failed back surgery syndrome. METHODS: The aim of the guideline is to determine which invasive treatment intervention is preferred for each included pain syndrome when conservative treatment has failed. Diagnostic studies were evaluated using the EBRO criteria, and studies on therapies were evaluated with the Grading of Recommendations Assessment, Development and Evaluation system. For the evaluation of invasive treatment options, the guideline committee decided that the outcome measures of pain, function, and quality of life were most important. RESULTS: The definition, epidemiology, pathophysiological mechanism, diagnostics, and recommendations for invasive therapy for each of the spinal back pain syndromes are reported. DISCUSSION: The guideline committee concluded that the categorization of low back pain into merely specific or nonspecific gives insufficient insight into the low back pain problem and does not adequately reflect which therapy is effective for the underlying disorder of a pain syndrome. Based on the guideline "Spinal low back pain," facet joint pain, pain of the sacroiliac joint, and disk pain will be part of a planned nationwide cost effectiveness study. PMID- 26032120 TI - Assistants' in nursing perceptions of their social place within mental health care settings. AB - An international nurse shortage, tightening fiscal constraints, and increased service demands have seen health systems increasingly turn to employing assistants in nursing (AIN) as a cost-effective means to meet demand. This paper describes social positioning from the perspective of 11 AIN who were employed to work in specialist mental health settings in a metropolitan health service in Sydney. Data was collected by means of semistructured interviews. Interview questions encouraged AIN to explore their experience with reference to positioning within the service, role perception, role development, staff relationship, and role satisfaction. Thematic analysis was utilized to generate themes and explore meaning within the data. The following themes emerged: role definition and clarity; socialization and adaptation; and enhancing education. Analysis suggests that whilst AIN were integrated into mainstream service, the scope of activities or role remains geographically variable and inconsistent. Encouragingly, as AIN became familiar with their work environments and teams, they considered themselves to be of value and were able to play a meaningful role. A desire for learning and a need for continuing education also emerged as a primary theme. Findings from the data suggest that AIN in the mental health setting remain a novel and, to some extent, poorly utilized resource. PMID- 26032122 TI - Critical Appraisal: Bulk-fill Composites, Part I. AB - The Journal of Esthetic and Restorative Dentistry published a Critical Appraisal of bulk-fill flowable composite resins by Dr. Ricardo Walter in early 2013 (JERD 2013;25(1):72-6). Since then, new bulk-fill composite options have become available and have rapidly achieved great popularity. This two-part Critical Appraisal reviews some of the more recent information on the various bulk-fill options. PMID- 26032121 TI - Design and baseline findings of a large-scale rapid response to an HIV outbreak in people who inject drugs in Athens, Greece: the ARISTOTLE programme. AB - AIMS: To (i) describe an intervention implemented in response to the HIV-1 outbreak among people who inject drugs (PWIDs) in Greece (ARISTOTLE programme), (ii) assess its success in identifying and testing this population and (iii) describe socio-demographic characteristics, risk behaviours and access to treatment/prevention, estimate HIV prevalence and identify risk factors, as assessed at the first participation of PWIDs. DESIGN: A 'seek, test, treat, retain' intervention employing five rounds of respondent-driven sampling. SETTING: Athens, Greece (2012-13). PARTICIPANTS: A total of 3320 individuals who had injected drugs in the past 12 months. INTERVENTION: ARISTOTLE is an intervention that involves reaching out to high-risk, hard-to-reach PWIDs ('seek'), engaging them in HIV testing and providing information and materials to prevent HIV ('test') and initiating and maintaining anti-retroviral and opioid substitution treatment for those testing positive ('treat' and 'retain'). MEASUREMENTS: Blood samples were collected for HIV testing and personal interviews were conducted. FINDINGS: ARISTOTLE recruited 3320 PWIDs during the course of 13.5 months. More than half (54%) participated in multiple rounds, resulting in 7113 visits. HIV prevalence was 15.1%. At their first contact with the programme, 12.5% were on opioid substitution treatment programmes and the median number of free syringes they had received in the preceding month was 0. In the multivariable analysis, apart from injection-related variables, homelessness was a risk factor for HIV infection in male PWIDs [odds ratio (OR) yes versus no = 1.89, 95% confidence interval (CI) = 1.41, 2.52] while, in female PWIDS, the number of sexual partners (OR for > 5 versus one partner in the past year = 4.12, 95% CI = 1.93, 8.77) and history of imprisonment (OR yes versus no = 2.76, 95% CI = 1.43, 5.31) were associated with HIV. CONCLUSIONS: In Athens, Greece, the ARISTOTLE intervention for identifying HIV-positive people among people who inject drugs (PWID) facilitated rapid identification of a hidden population experiencing an outbreak and provided HIV testing, counselling and linkage to care. According to ARISTOTLE data, the 2011 HIV outbreak in Athens resulted in 15% HIV infection among PWID. Risk factors for HIV among PWID included homelessness in men and history of imprisonment and number of sexual partners in women. PMID- 26032123 TI - Enantioselective Arylation of N-Tosylimines by Phenylboronic Acid Catalysed by a Rhodium/Diene Complex: Reaction Mechanism from Density Functional Theory. AB - A DFT study of the reaction mechanism of the rhodium-catalysed enantioselective arylation of (E)-N-propylidene-4-methyl-benzenesulfonamide by phenylboronic acid [Lin et al J. Am. Chem. Soc. 2011, 133, 12394] is reported. The catalyst ([{Rh(OH)(diene)}2]) includes a chiral diene ligand and the reaction is conducted in 1,4-dioxane in the presence of drying agents (4 A molecular sieves). Because phenylboronic acid is in equilibrium with phenylboroxin and water under the reaction conditions, three catalytic cycles are proposed that differ in the way the transmetallation and the release of the product are brought about, depending on the availability of phenylboronic acid, water and boroxin in the reaction medium. Based on computations, a new mechanism for the title reaction is proposed, in which phenylboronic acid plays the double role of "aryl source" and proton donor. This path does not require the presence of adventitious water molecules, in keeping with a reaction conducted in a dry medium. Comparisons with the generally accepted mechanism for arylation of enones proposed by Hayashi and co-workers (J. Am. Chem. Soc. 2002, 124, 5052) show that the latter mechanism is less favourable and is not expected to operate in the case of the N-tosylimine substrate considered herein. Finally, the possibility that phenylboroxin is the aryl source has also been investigated, but is not found to be competitive. PMID- 26032124 TI - Soil bacterial diversity patterns and drivers along an elevational gradient on Shennongjia Mountain, China. AB - Understanding biological diversity elevational pattern and the driver factors are indispensable to develop the ecological theories. Elevational gradient may minimize the impact of environmental factors and is the ideal places to study soil microbial elevational patterns. In this study, we selected four typical vegetation types from 1000 to 2800 m above the sea level on the northern slope of Shennongjia Mountain in central China, and analysed the soil bacterial community composition, elevational patterns and the relationship between soil bacterial diversity and environmental factors by using the 16S rRNA Illumina sequencing and multivariate statistical analysis. The results revealed that the dominant bacterial phyla were Acidobacteria, Actinobacteria, Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria and Verrucomicrobia, which accounted for over 75% of the bacterial sequences obtained from tested samples, and the soil bacterial operational taxonomic unit (OTU) richness was a significant monotonous decreasing (P < 0.01) trend with the elevational increasing. The similarity of soil bacterial population composition decreased significantly (P < 0.01) with elevational distance increased as measured by the Jaccard and Bray-Curtis index. Canonical correspondence analysis and Mantel test analysis indicated that plant diversity and soil pH were significantly correlated (P < 0.01) with the soil bacterial community. Therefore, the soil bacterial diversity on Shennongjia Mountain had a significant and different elevational pattern, and plant diversity and soil pH may be the key factors in shaping the soil bacterial spatial pattern. PMID- 26032125 TI - Self-reported diabetes self-management competence and support from healthcare providers in achieving autonomy are negatively associated with diabetes distress in adults with Type 1 diabetes. AB - AIM: To investigate the associations of self-perceived competence in diabetes management and autonomy support from healthcare providers with diabetes distress in adults with Type 1 diabetes mellitus that is not optimally controlled [HbA(1c) >= 64 mmol/mol (8.0%)]. METHODS: This cross-sectional study comprised blood sampling and three self-report questionnaires, the Problem Areas in Diabetes scale, the Perceived Competence in Diabetes Scale and a measure of autonomy support by healthcare providers, the Health Care Climate Questionnaire. We fitted blockwise linear regression models to assess the associations between Problem Areas in Diabetes score and the variables of interest (autonomy support and perceived diabetes competence), controlling for clinical and sociodemographic variables. RESULTS: Of the study sample [n = 178; mean age 36.7 (+/-10.7) years], 31.5% had long-term complications and 43.2% reported elevated (>=40) Problem Areas in Diabetes scores. A significant negative association was found between autonomy support and Problem Areas in Diabetes score (B = -3.61, P = 0.001), indicating that lower autonomy support was associated with greater diabetes distress. When perceived competence was controlled, it mediated the association of autonomy support with diabetes distress, reducing it to non-significance. There was a significant negative association between perceived competence and Problem Areas in Diabetes score (B = -8.89, P < 0.001), indicating that lower perceived competence was associated with greater perceived distress. CONCLUSIONS: There was an indirect (fully mediated) relationship between autonomy support and diabetes distress; autonomy support was associated with increased perceived competence, which, in turn, was associated with reduced distress. Healthcare providers' communication styles enhancing perceived competence through autonomy support may contribute to effective treatment for people with Type 1 diabetes and suboptimum glycaemic control. PMID- 26032126 TI - MR relaxometry in chronic liver diseases: Comparison of T1 mapping, T2 mapping, and diffusion-weighted imaging for assessing cirrhosis diagnosis and severity. AB - BACKGROUND: MR relaxometry has been extensively studied in the field of cardiac diseases, but its contribution to liver imaging is unclear. We aimed to compare liver and spleen T1 mapping, T2 mapping, and diffusion-weighted MR imaging (DWI) for assessing the diagnosis and severity of cirrhosis. METHODS: We prospectively included 129 patients with normal (n=40) and cirrhotic livers (n=89) from May to September 2014. Non-enhanced liver T1 mapping, splenic T2 mapping, and liver and splenic DWI were measured and compared for assessing cirrhosis severity using Child-Pugh score, MELD score, and presence or not of large esophageal varices (EVs) and liver stiffness measurements using Fibroscan((r)) as reference. RESULTS: Liver T1 mapping was the only variable demonstrating significant differences between normal patients (500+/-79ms), Child-Pugh A patients (574+/ 84ms) and Child-Pugh B/C patients (690+/-147ms; all p-values <0.00001). Liver T1 mapping had a significant correlation with Child-Pugh score (Pearson's correlation coefficient of 0.46), MEDL score (0.30), and liver stiffness measurement (0.52). Areas under the receiver operating characteristic curves of liver T1 mapping for the diagnosis of cirrhosis (O.85; 95% confidence intervals (CI), 0.77-0.91), Child-Pugh B/C cirrhosis (0.87; 95%CI, 0.76-0.93), and large EVs (0.75; 95%CI, 0.63-0.83) were greater than that of spleen T2 mapping, liver and spleen DWI (all p-values<0.01). CONCLUSION: Liver T1 mapping is a promising new diagnostic tool for assessing cirrhosis diagnosis and severity, showing higher diagnostic accuracy than liver and spleen DWI, while T2 mapping is not reliable. PMID- 26032127 TI - Screening for significant chronic liver disease by using three simple ultrasound parameters. AB - OBJECTIVES: Chronic liver diseases remain asymptomatic for many years. Consequently, patients are diagnosed belatedly, when cirrhosis is unmasked by lifethreatening complications. We aimed to identify simple ultrasound parameters for the screening of patients with unknown significant chronic liver disease. METHODS: Three hundred and twenty seven patients with chronic liver disease, liver biopsy, and ultrasound examination were included in the derivation set. 283 consecutive patients referred for ultrasound examination were included in the validation set; those selected according to the ultrasound parameters identified in the derivation set were then referred for specialized consultation including non-invasive fibrosis tests and ultimately liver biopsy if liver fibrosis was suspected. RESULTS: In the derivation set, three ultrasound parameters were independent predictors of severe fibrosis: liver surface irregularity, spleen length (>110mm), and demodulation of hepatic veins. The association of >=2 of the three above parameters provided 49.1% sensitivity and 86.9% specificity. In the validation set, at >=2 of the three parameters were present in 23 (8%) of the patients. Among these patients, 8 had liver fibrosis (F>=1), 5 had significant fibrosis (F>=2) and two cirrhosis. CONCLUSION: The generalized search of three simple ultrasound signs in patients referred for abdominal ultrasound examination may be an easy way to detect those with silent but significant chronic liver disease. PMID- 26032128 TI - Missed pancreatic ductal adenocarcinoma: Assessment of early imaging findings on prediagnostic magnetic resonance imaging. AB - OBJECTIVE: To investigate the early imaging findings and growth rate of pancreatic ductal adenocarcinoma (PDAC), and to assess whether MR imaging detects early PDAC better than CT. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the requirement for informed consent. Twenty-two patients were included, and two radiologists, by consensus, assessed the presence of focal lesions, interruption of the main pancreatic duct (MPD), MPD dilatation, and pancreatitis, volume doubling time (VDT) of PDAC on prediagnostic MR imaging. Two other observers independently reviewed three image sets (CT images, unenhanced MR images, and unenhanced and contrast-enhanced MR images) for the detection of early PDAC. Paired Wilcoxon signed rank test and receiver operating characteristic (ROC) curve analysis were used for statistical analyses. RESULTS: In 20 (90.9%) patients, prediagnostic MR exams showed abnormality, and all of them showed focal lesions on the first abnormal prediagnostic MR exams. Thirteen lesions (65%) showed no MPD interruption and one lesion (5%) was accompanied by pancreatitis. The mean VDT of PDAC was 151.7 days (range, 18.3-417.8 days). Diagnostic performance of unenhanced MR images (Az, 0.971-0.989) and combined unenhanced and contrast-enhanced MR images (Az, 0.956 0.963) was significantly better than that of CT images (Az, 0.565-0.583; p<0.01) for both observers, CONCLUSION: The most common early imaging finding of PDAC on prediagnostic MR exams was a focal lesion with no MPD interruption with a mean volume doubling time of five months. MR imaging was superior to CT for the detection of early PDAC. PMID- 26032129 TI - Application of parametric ultrasound contrast agent perfusion studies for differentiation of hyperplastic adrenal nodules from adenomas-Initial study. AB - OBJECTIVES: To evaluate the possibilities of differentiation of non-malignant adrenal masses with the application of the new technique for the evaluation of enhancement after administration of an ultrasound contrast agent: parametric imaging. PATIENTS AND METHODS: 34 non-malignant adrenal masses in 29 patients were evaluated in a dynamic examination after the administration of ultrasound contrast agent with parametric imaging. Patterns on parametric imaging of arrival time were evaluated. The final diagnosis was based on CT, MRI, biochemical studies, follow up and/or histopathology examination. RESULTS: The study included: 12 adenomas, 10 hyperplastic nodules, 7 myelolipomas, 3 pheochromocytomas, hemangioma with hemorrhage and cyst. The pattern of peripheral laminar inflow of Sonovue on parametric images of arrival time of was 100% sensitive for hyperplastic nodules and 83% specific in regard to adenomas. CONCLUSIONS: Parametric contrast enhanced ultrasound may accurately differentiate hyperplastic adrenal nodules from adenomas and could be complementary to CT or MRI. Incorporation of perfusion studies to CT or MRI could possibly enable one shop complete characterization of adrenal masses. This could deliver additional information in diagnostics of patients with Conn Syndrome and warrants further studies in this cohort of patients. PMID- 26032130 TI - Measurement of single-kidney glomerular filtration function from magnetic resonance perfusion renography. AB - Glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidney, and is considered to be the reference standard in the evaluation of renal function. There are many ways to test the GFR clinically, such as serum creatinine concentration, blood urea nitrogen and SPECT renography, however, they're all not a good standard to evaluate the early damage of renal function. In recent years, the improvement of MRI hardware and software makes it possible to reveal physiological characteristics such as renal blood flow or GFR by dynamic contrast enhancement magnetic resonance perfusion renography (DEC MRPR). MRPR is a method used to monitor the transit of contrast material, typically a gadolinium chelate, through the renal cortex, the medulla, and the collecting system. This review outlines the basics of DCE MRPR included acquisition of dynamic MR perfusion imaging, calculation of the contrast concentration from signal intensity and compartment models, and some challenges of MRPR method faced in prospective clinical application. PMID- 26032131 TI - CT colonography with rectal iodine tagging: Feasibility and comparison with oral tagging in a colorectal cancer screening population. AB - PURPOSE: To evaluate feasibility, diagnostic performance, patient acceptance, and overall examination time of CT colonography (CTC) performed through rectal administration of iodinated contrast material. MATERIALS AND METHODS: Six-hundred asymptomatic subjects (male:female=270:330; mean 63 years) undergoing CTC for colorectal cancer screening on an individual basis were consecutively enrolled in the study. Out of them, 503 patients (group 1) underwent CTC with rectal tagging, of which 55 had a total of 77 colonic lesions. The remaining 97 patients (group 2) were randomly selected to receive CTC with oral tagging of which 15 had a total of 20 colonic lesions. CTC findings were compared with optical colonoscopy, and per-segment image quality was visually assessed using a semi-quantitative score (1=poor, 2=adequate, 3=excellent). In 70/600 patients (11.7%), CTC was performed twice with both types of tagging over a 5-year follow-up cancer screening program. In this subgroup, patient acceptance was rated via phone interview two weeks after CTC using a semi-quantitative scale (1=poor, 2=fair, 3=average, 4=good, 5=excellent). RESULTS: Mean per-polyp sensitivity, specificity, positive and negative predictive values of CTC with rectal vs oral tagging were 96.1% (CI95% 85.4/99.3%) vs 89.4% (CI95% 65.4/98.1%), 95.3% (CI95% 90.7/97.8%) vs 95.8% (CI95% 87.6/98.9%), 86.0% (CI95% 73.6/93.3) vs 85.0% (CI95% 61.1/96.0%), and 98.8% (CI95% 95.3/99.8%) vs 97.2% (CI95% 89.4/99.5%), respectively (p>0.05). Polyp detection rates were not statistically different between groups 1 and 2 (p>0.05). Overall examination time was significantly shorter with rectal than with oral tagging (18.3+/-3.5 vs 215.6+/-10.3 minutes, respectively; p<0.0001). CONCLUSIONS: Rectal iodine tagging can be an effective alternative to oral tagging for CTC with the advantages of greater patient acceptance and lower overall examination time. PMID- 26032132 TI - Early response or nonresponse at week 2 and week 3 predict ultimate response or nonresponse in adolescents with schizophrenia treated with olanzapine: results from a 6-week randomized, placebo-controlled trial. AB - In adults with schizophrenia, early response/non-response (ER/ENR) to antipsychotics at 2 weeks robustly predicts ultimate response/non-response (UR/UNR). However, less data about the predictive value of ER/ENR exist in adolescents with schizophrenia. Post hoc analysis of a 6-week trial in adolescents aged 13-17 with schizophrenia were randomized 2:1 to olanzapine or placebo. ER was defined as >=20 % reduction in Brief Psychiatric Rating Scale children (BPRS-C) total score at week 2 (ER2) or 3 (ER3); UR was defined with increasing stringency as total BPRS-C score reduction >=20, >=30, >=40 or >=50 %; remission was defined cross-sectionally using Andreasen et al. (2005) criteria. By week 2 (n = 69) and 3 (n = 66), olanzapine-treated youth achieved 73.3 and 85.5 % of their overall BPRS-C score reduction at 6 weeks last observation carried forward. ER and ENR patients did not differ significantly regarding baseline demographic, illness and treatment variables. ER 2 (frequency = 68.1 %) and ER 3 (frequency = 65.2 %) significantly predicted UR and remission (p = 0.0044-p < 0.0001), with ER3 having more predictive power. A >= 20 % BPRS-C reduction threshold for ER had best predictive validity (area under the curve = 0.88-0.92). At 6 weeks, patients with ER had significantly greater improvements in BPRS-C, Clinical Global Impressions Improvement and Severity scores, greater cross-sectional remission and less all-cause discontinuation (p = 0.047-p < 0.0001). Adverse event profiles were similar in the ER and ENR groups. Adolescents with schizophrenia experienced the majority of symptomatic improvement early during olanzapine treatment. ER predicted UR and remission, with ER3 having best predictive power. A >= 20 % improvement threshold for defining ER was confirmed as a robust outcome indicator. PMID- 26032134 TI - The cell wall amidase AmiB is essential for Pseudomonas aeruginosa cell division, drug resistance and viability. AB - The physiological function of cell wall amidases has been investigated in several proteobacterial species. In all cases, they have been implicated in the cleavage of cell wall material synthesized by the cytokinetic ring. Although typically non essential, this activity is critical for daughter cell separation and outer membrane invagination during division. In Escherichia coli, proteins with LytM domains also participate in cell separation by stimulating amidase activity. Here, we investigated the function of amidases and LytM proteins in the opportunistic pathogen Pseudomonas aeruginosa. In agreement with studies in other organisms, (Pa) AmiB and three LytM proteins were found to play crucial roles in P. aeruginosa cell separation, envelope integrity and antibiotic resistance. Importantly, the phenotype of amidase-defective P. aeruginosa cells also differed in informative ways from the E. coli paradigm; (Pa) AmiB was found to be essential for viability and the successful completion of cell constriction. Our results thus reveal a key role for amidase activity in cytokinetic ring contraction. Furthermore, we show that the essential function of (Pa) AmiB can be bypassed in mutants activated for a Cpx-like envelope stress response, suggesting that this signaling system may elicit the repair of division machinery defects in addition to general envelope damage. PMID- 26032135 TI - A Time-Trend Economic Analysis of Cancer Drug Trials. AB - BACKGROUND: Scientific advances have led to the discovery of novel treatments with high prices. The cost to publicly fund high-cost drugs may threaten the sustainability of drug budgets in different health care systems. In oncology, there are concerns that health-benefit gains are diminishing over time and that the economic evidence to support funding decisions is too limited. METHODS: To assess the additional costs and benefits gained from oncology drugs over time, we used treatment protocols and efficacy results from U.S. Food and Drug Administration records to calculate cost-effectiveness ratios for drugs approved to treat first- and second-line metastatic or advanced breast, colorectal, and non-small cell lung cancer during the years 1994-2013. We assessed reimbursement recommendations reached by health technology assessment agencies in the U.K., Australia, and Canada. RESULTS: Cost-effectiveness ratios were calculated for 50 drugs approved by the U.S. regulator. The more recent approvals were often based on surrogate efficacy outcomes and had extremely high costs, often triple the costs of drugs approved in previous years. Over time, the effectiveness gains have increased for some cancer indications; however, for other indications (non small cell lung and second-line colorectal cancer), the magnitude of gains in effectiveness decreased. Reimbursement recommendations for drugs with the highest cost-effectiveness ratios were the most inconsistent. CONCLUSION: Evaluation of the clinical benefits that oncology drugs offer as a function of their cost has become highly complex, and for some clinical indications, health benefits are diminishing over time. There is an urgent need for better economic evidence from oncology drug trials and systematic processes to inform funding decisions. IMPLICATIONS FOR PRACTICE: High-cost oncology drugs may threaten the ability of health care systems to provide access to promising new drugs for patients. In order to make better drug-funding decisions and enable equitable access to breakthrough treatments, discussions in the oncology community should include economic evidence. This study summarizes the extra benefits and costs of newly approved drugs from pivotal trials during the postgenomic era of drug discovery. The reader will gain an appreciation of the need for economic evidence to make better drug-reimbursement decisions and the dynamics at play in today's oncology drug market. PMID- 26032136 TI - Geriatric Assessment of Older Adults With Cancer During Unplanned Hospitalizations: An Opportunity in Disguise. AB - BACKGROUND: Geriatric assessment (GA) is an important tool for management of older cancer patients; however, GA research has been performed primarily in the outpatient setting. The primary objective of this study was to determine feasibility of GA during an unplanned hospital stay. Secondary objectives were to describe deficits found with GA, to assess whether clinicians recognized and addressed deficits, and to determine 30-day readmission rates. MATERIALS AND METHODS: The study was designed as an extension of an existing registry, "Carolina Senior: Registry for Older Patients." Inclusion criteria were age 70 and older and biopsy-proven solid tumor, myeloma, or lymphoma. Patients had to complete the GA within 7 days of nonelective admission to University of North Carolina Hospital. RESULTS: A total of 142 patients were approached, and 90 (63%) consented to participation. All sections of GA had at least an 83% completion rate. Overall, 53% of patients reported problems with physical function, 63% had deficits in instrumental activities of daily living, 34% reported falls, 12% reported depression, 31% had >=10% weight loss, and 12% had abnormalities in cognition. Physician documentation of each deficit ranged from 20% to 46%. Rates of referrals to allied health professionals were not significantly different between patients with and without deficits. The 30-day readmission rate was 29%. CONCLUSION: GA was feasible in this population. Hospitalized older cancer patients have high levels of functional and psychosocial deficits; however, clinician recognition and management of deficits were poor. The use of GA instruments to guide referrals to appropriate services is a way to potentially improve outcomes in this vulnerable population. IMPLICATIONS FOR PRACTICE: Geriatric assessment (GA) is an important tool in the management of older cancer patients; however, its primary clinical use has been in the outpatient setting. During an unplanned hospitalization, patients are extremely frail and are most likely to benefit from GA. This study demonstrates that hospitalized older adults with cancer have high levels of functional deficits on GA. These deficits are under-recognized and poorly managed by hospital-based clinicians in a tertiary care setting. Incorporation of GA measures during a hospital stay is a way to improve outcomes in this population. PMID- 26032137 TI - Posterior Reversible Encephalopathy Syndrome in Patients With Cancer. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized by neurologic symptoms with typical lesions on neuroimaging and may be associated with chemotherapy and immunosuppressive agents used in patients with cancer. We described the spectrum of PRES at a major cancer center. METHODS: We reviewed charts of adults with PRES between 2005 and 2011 at Memorial Sloan Kettering Cancer Center for clinical information and outcome. RESULTS: We identified 21 women (68%) and 10 men (median cohort age: 58 years). Solid tumors (n = 22, 71%) were more common than hematologic (n = 8) or primary brain malignancies (n = 1). Prior brain irradiation (16%) and central nervous system metastases (10%) were uncommon. There were 55% who received chemotherapy or targeted therapy within the month preceding PRES, including 6 patients who received bevacizumab; PRES followed allogeneic stem cell transplantation in 5 (16%). Presenting symptoms included confusion (71%), seizure (58%), and headache (48%). Maximum systolic and diastolic blood pressures were similar among patients grouped by cancer type, chemotherapy or bevacizumab use, and atypical imaging. Moreover, 37% of patients with both magnetic resonance imaging (MRI) and computed tomography (CT) had normal CT concurrent with PRES on MRI, and 84% returned to neurologic baseline at a median of 7.5 days (range: 1-167 days) from onset. Successful anticonvulsant taper was achieved in 51%. Chemotherapy rechallenge was attempted in 41% without recurrent PRES. Autopsy revealed nonspecific changes isolated to radiographically affected areas in one of two patients. CONCLUSION: Recent chemotherapy, particularly bevacizumab, is common in cancer patients with PRES. Clinical and radiographic presentations may vary; MRI appears more sensitive than CT. Anticonvulsant taper and chemotherapy rechallenge is often possible. IMPLICATIONS FOR PRACTICE: Posterior reversible encephalopathy syndrome is characterized by neurologic symptoms with typical lesions on neuroimaging and may be associated with chemotherapy and immunosuppressive agents used in patients with cancer. Clinical and radiographic presentations are protean, and magnetic resonance imaging is more sensitive than computed tomography. Recovery is common, and many patients can be successfully rechallenged with the apparently offending chemotherapy agent or regimen. PMID- 26032138 TI - Delays in Breast Cancer Presentation and Diagnosis at Two Rural Cancer Referral Centers in Rwanda. AB - BACKGROUND: Breast cancer incidence is increasing in low- and middle-income countries (LMICs). Mortality/incidence ratios in LMICs are higher than in high income countries, likely at least in part because of delayed diagnoses leading to advanced-stage presentations. In the present study, we investigated the magnitude, impact of, and risk factors for, patient and system delays in breast cancer diagnosis in Rwanda. MATERIALS AND METHODS: We interviewed patients with breast complaints at two rural Rwandan hospitals providing cancer care and reviewed their medical records to determine the diagnosis, diagnosis date, and breast cancer stage. RESULTS: A total of 144 patients were included in our analysis. Median total delay was 15 months, and median patient and system delays were both 5 months. In multivariate analyses, patient and system delays of >=6 months were significantly associated with more advanced-stage disease. Adjusting for other social, demographic, and clinical characteristics, a low level of education and seeing a traditional healer first were significantly associated with a longer patient delay. Having made >=5 health facility visits before the diagnosis was significantly associated with a longer system delay. However, being from the same district as one of the two hospitals was associated with a decreased likelihood of system delay. CONCLUSION: Patients with breast cancer in Rwanda experience long patient and system delays before diagnosis; these delays increase the likelihood of more advanced-stage presentations. Educating communities and healthcare providers about breast cancer and facilitating expedited referrals could potentially reduce delays and hence mortality from breast cancer in Rwanda and similar settings. IMPLICATIONS FOR PRACTICE: Breast cancer rates are increasing in low- and middle-income countries, and case fatality rates are high, in part because of delayed diagnosis and treatment. This study examined the delays experienced by patients with breast cancer at two rural Rwandan cancer facilities. Both patient delays (the interval between symptom development and the patient's first presentation to a healthcare provider) and system delays (the interval between the first presentation and diagnosis) were long. The total delays were the longest reported in published studies. Longer delays were associated with more advanced-stage disease. These findings suggest that an opportunity exists to reduce breast cancer mortality in Rwanda by addressing barriers in the community and healthcare system to promote earlier detection. PMID- 26032146 TI - Prosthodontic Rehabilitation with a Telescopic Prosthesis of a Nonsyndromic Oligodontia Patient. AB - Oligodontia is the congenital absence of six or more permanent teeth, excluding the third molars. Oligodontia of permanent dentition is a rare occurrence. Preservation of the remaining deciduous dentition in such situations is important for both functional and esthetic rehabilitation of the patient. This clinical report describes the rehabilitation of a 16-year-old male with oligodontia of permanent teeth treated by an interdisciplinary team of prosthodontist, pedodontist, and orthodontist. The remaining deciduous dentition was endodontically treated. Occlusal vertical dimension (OVD) of the deciduous dentition was assessed. A full-mouth single piece porcelain-fused-to-metal telescopic prosthesis for the maxillary and mandibular arches was planned with a minimal increase in OVD. The telescopic prosthesis provided excellent retention, stability, esthetics, and stress equalization on the remaining deciduous dentition. Maintenance of oral hygiene procedures was simplified for the adolescent with the telescopic prosthesis. Preservation of remaining deciduous dentition and fabrication of a telescopic prosthesis in this patient provided an effective esthetic and functional rehabilitation. PMID- 26032139 TI - Histology of Testicular Biopsies Obtained for Experimental Fertility Preservation Protocol in Boys with Cancer. AB - PURPOSE: Cryopreservation of testicular tissue with subsequent reimplantation after therapy has the potential to preserve fertility for prepubertal boys with cancer. We present the histology and feasibility of testicular tissue procurement for this novel approach. MATERIALS AND METHODS: We performed a prospective cohort study of boys at significant risk for treatment associated gonadotoxicity who were eligible for an experimental research protocol between 2008 and 2011. Open testicular biopsy was performed while the patients were anesthetized for another treatment related procedure. Half of the specimen was reserved for cryopreservation, while the other half was used for research purposes. Semithin sections of the biopsy specimens were evaluated for histological features and compared to age adjusted reference values. RESULTS: A total of 34 boys underwent biopsy between March 2008 and October 2011. Of the patients 29 had solid tumors and 5 underwent hematopoietic stem cell transplantation for benign disease. A total of 27 patients had adequate tissue for histological analysis. Median patient age was 8.7 years (IQR 2.2 to 11.5). All children had either normal (81.5% of patients) or increased (18.5%) numbers of germ cells per tubule for their age. However, 5 of 26 patients (19%) older than 6 months had no evidence of adult dark spermatogonia and 9 of 16 (56%) older than 6 years had no evidence of primary spermatocytes on biopsy, which would be expected based on age norms. These findings are suggestive of abnormal germ cell maturation. CONCLUSIONS: The preliminary histological findings of abnormal spermatogenesis maturation in the testes of prepubertal boys with cancer warrants further investigation. PMID- 26032147 TI - Divergence in sink contributions to population persistence. AB - Population sinks present unique conservation challenges. The loss of individuals in sinks can compromise persistence; but conversely, sinks can improve viability by improving connectivity and facilitating the recolonization of vacant sources. To assess the contribution of sinks to regional population persistence of declining populations, we simulated source-sink dynamics for 3 very different endangered species: Black-capped Vireos (Vireo atricapilla) at Fort Hood, Texas, Ord's kangaroo rats (Dipodomys ordii) in Alberta, and Northern Spotted Owls (Strix occidentalis caurina) in the northwestern United States. We used empirical data from these case studies to parameterize spatially explicit individual-based models. We then used the models to quantify population abundance and persistence with and without long-term sinks. The contributions of sink habitats varied widely. Sinks were detrimental, particularly when they functioned as strong sinks with few emigrants in declining populations (e.g., Alberta's Ord's kangaroo rat) and benign in robust populations (e.g., Black-capped Vireos) when Brown-headed Cowbird (Molothrus ater) parasitism was controlled. Sinks, including ecological traps, were also crucial in delaying declines when there were few sources (e.g., in Black-capped Vireo populations with no Cowbird control). Sink contributions were also nuanced. For example, sinks that supported large, variable populations were subject to greater extinction risk (e.g., Northern Spotted Owls). In each of our case studies, new context-dependent sinks emerged, underscoring the dynamic nature of sources and sinks and the need for frequent re-assessment. Our results imply that management actions based on assumptions that sink habitats are generally harmful or helpful risk undermining conservation efforts for declining populations. PMID- 26032148 TI - Implicit affectivity and rapid processing of affective body language: An fMRI study. AB - Previous research has revealed affect-congruity effects for the recognition of affects from faces. Little is known about the impact of affect on the perception of body language. The aim of the present study was to investigate the relationship of implicit (versus explicit) affectivity with the recognition of briefly presented affective body expressions. Implicit affectivity, which can be measured using indirect assessment methods, has been found to be more predictive of spontaneous physiological reactions than explicit (self-reported) affect. Thirty-four healthy women had to label the expression of body postures (angry, fearful, happy, or neutral) presented for 66 ms and masked by a neutral body posture in a forced-choice format while undergoing functional magnetic resonance imaging (fMRI). Participants' implicit affectivity was assessed using the Implicit Positive and Negative Affect Test. Measures of explicit state and trait affectivity were also administered. Analysis of the fMRI data was focused on a subcortical network involved in the rapid perception of affective body expressions. Only implicit negative affect (but not explicit affect) was correlated with correct labeling performance for angry body posture. As expected, implicit negative affect was positively associated with activation of the subcortical network in response to fearful and angry expression (compared to neutral expression). Responses of the caudate nucleus to affective body expression were especially associated with its recognition. It appears that processes of rapid recognition of affects from body postures could be facilitated by an individual's implicit negative affect. PMID- 26032149 TI - Interpretation and use of the 5-level EQ-5D response labels varied with survey language among Asians in Singapore. AB - OBJECTIVES: This study aimed to investigate the comparability of the English, Chinese, and Malay versions of the 5-level EQ-5D (EQ-5D-5L) response labels in Singapore. STUDY DESIGN AND SETTING: Visitors to a primary care institution in Singapore (n = 743) were asked to complete two exercises: (1) rating the severity of the EQ-5D-5L response labels presented in English, Chinese, or Malay using a 0 100 numeric rating scale and (2) using the labels to describe various hypothetical health problems. Label ratings and choices between language versions were compared using regression analysis. RESULTS: Perceived severity of the English and Chinese labels was similar. Compared with their English counterparts, the Malay label "slight(ly)" was rated as more severe (adjusted mean difference: 10.5 to 14.5) and "unable"/"extreme(ly)" as less severe (adjusted mean difference: -13.3 to -11.0) (P < 0.001 for all). The Malay labels "no(t)" and "unable"/"extreme(ly)" and the less severe Chinese labels were more frequently used to describe hypothetical health problems than their English counterparts. CONCLUSION: Interpretation and use of the EQ-5D-5L response labels vary among Singaporeans using different language versions of the instrument. Future studies need to investigate ways to reduce the variations and increase the cross-cultural measurement equivalence of the instrument. PMID- 26032150 TI - Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids. AB - OBJECTIVES: Bowel dysfunction has been recognized as a predominant side effect of opioid use. Even though the effects of opioids on the stomach and small and large intestines have been well studied, there are limited data on opioid effects on esophageal function. The aim of this study was to compare esophageal pressure topography (EPT) of patients taking opioids at the time of the EPT (<=24 h) with chronic opioid users who were studied off opioid medications for at least 24 h using the Chicago classification v3.0. METHODS: A retrospective review identified 121 chronic opioid users who completed EPT between March 2010 and August 2012. Demographic and manometric data were compared between the two groups using general linear models or chi(2). RESULTS: Of the 121 chronic opioid users, 66 were studied on opioid medications (<=24 h) and 55 were studied off opioid medications for at least 24 h. Esophagogastric junction (EGJ) outflow obstruction was significantly more prevalent in patients using opioids within 24 h compared with those who did not (27% vs. 7%, P=0.004). Mean 4 s integrated relaxation pressure was also significantly higher in patients studied on opioids (10.71 vs. 6.6 mm Hg, P=0.025). Resting lower esophageal sphincter pressures tended to be higher on opioids (31.61 vs. 26.98 mm Hg, P=0.25). Distal latency was significantly lower in patients studied on opioids (6.15 vs. 6.74 s, P=0.044). CONCLUSIONS: Opioid use within 24 h of EPT is associated with more frequent EGJ outflow obstruction and spastic peristalsis compared with when opioid use is stopped for at least 24 h before the study. PMID- 26032151 TI - Diagnosis of Esophageal Motility Disorders: Esophageal Pressure Topography vs. Conventional Line Tracing. AB - OBJECTIVES: Enhanced characterization of esophageal peristaltic and sphincter function provided by esophageal pressure topography (EPT) offers a potential diagnostic advantage over conventional line tracings (CLT). However, high resolution manometry (HRM) and EPT require increased equipment costs over conventional systems and evidence demonstrating a significant diagnostic advantage of EPT over CLT is limited. Our aim was to investigate whether the inter-rater agreement and/or accuracy of esophageal motility diagnosis differed between EPT and CLT. METHODS: Forty previously completed patient HRM studies were selected for analysis using a customized software program developed to perform blinded independent interpretation in either EPT or CLT (six pressure sensors) format. Six experienced gastroenterologists with a clinical focus in esophageal disease (attendings) and six gastroenterology trainees with minimal manometry experience (fellows) from three academic centers interpreted each of the 40 studies using both EPT and CLT formats. Rater diagnoses were assessed for inter rater agreement and diagnostic accuracy, both for exact diagnosis and for correct identification of a major esophageal motility disorder. RESULTS: The total group agreement was moderate (kappa=0.57; 95% CI: 0.56-0.59) for EPT and fair (kappa=0.32; 0.30-0.33) for CLT. Inter-rater agreement between attendings was good (kappa=0.68; 0.65-0.71) for EPT and moderate (kappa=0.46; 0.43-0.50) for CLT. Inter-rater agreement between fellows was moderate (kappa=0.48; 0.45-0.50) for EPT and poor to fair (kappa=0.20; 0.17-0.24) for CLT. Among all raters, the odds of an incorrect exact esophageal motility diagnosis were 3.3 times higher with CLT assessment than with EPT (OR: 3.3; 95% CI: 2.4-4.5; P<0.0001), and the odds of incorrect identification of a major motility disorder were 3.4 times higher with CLT than with EPT (OR: 3.4; 2.4-5.0; P<0.0001). CONCLUSIONS: Superior inter-rater agreement and diagnostic accuracy of esophageal motility diagnoses were demonstrated with analysis using EPT over CLT among our selected raters. On the basis of these findings, EPT may be the preferred assessment modality of esophageal motility. PMID- 26032152 TI - The diagnostic value of a digital rectal examination compared with high resolution anorectal manometry in patients with chronic constipation and fecal incontinence. AB - OBJECTIVES: Digital rectal examination (DRE) is a simple clinical method to diagnose anorectal disorders. High-resolution antorectal manometry (HRAM) based on a spatiotemporal plot is expected to promote improved diagnostic accuracy. However, there are no reports comparing the effectiveness of DRE and HRAM. The aim of our study was therefore to evaluate the diagnostic value of DRE compared with HRAM. METHODS: A total of 309 consecutive patients with chronic constipation (n=268) or fecal incontinence (n=41) who underwent a standardized DRE, HRAM, and balloon expulsion test were enrolled in this study. The diagnostic yield of DRE compared with HRAM was determined, and agreement between DRE and HRAM data was evaluated. RESULTS: Of the constipated patients, 207 (77.2%) were diagnosed with dyssynergia using HRAM. The sensitivity, specificity, and positive predictive value of DRE in the diagnosis of dyssynergia were 93.2%, 58.7%, and 91.0%, respectively, and moderate agreement was seen between the two modalities (kappa coefficient =0.542, P<0.001). In patients with fecal incontinence, there was moderate agreement in terms of anal squeeze pressure between the two modalities (kappa-coefficient =0.418, P=0.006); however, there was poor agreement for anal resting tone (kappa-coefficient =0.079, P=0.368). CONCLUSIONS: DRE shows high sensitivity and positive predictive value in detecting dyssynergia compared with HRAM, and could therefore be used as a bedside screening test for the diagnosis of this disorder. Further studies are warranted to evaluate the correlation between DRE and HRAM in assessing anal sphincter pressure. PMID- 26032153 TI - Control of acid and duodenogastroesophageal reflux (DGER) in patients with Barrett's esophagus. AB - OBJECTIVES: Symptom eradication in patients with Barrett's esophagus (BE) does not guarantee control of acid or duodenogastroesophageal reflux (DGER). Continued reflux of acid and/or DGER may increase risk of neoplastic progression and may decrease the likelihood of columnar mucosa eradication after ablative therapy. To date, no study has addressed whether both complete acid and DGER control is possible in patients with BE. This prospective study was designed to assess the effect of escalating-dose proton pump inhibitor (PPI) therapy on esophageal acid and DGER. METHODS: Patients with BE (>=3 cm in length) underwent simultaneous ambulatory prolonged pH and DGER monitoring after at least 1 week off PPI therapy followed by testing on therapy after 1 month of twice-daily rabeprazole (20 mg). In those with continued acid and/or DGER, the tests were repeated after 1 month of double-dose (40 mg twice daily) rabeprazole. The primary study outcome was normalization of both acid and DGER. Symptom severity was assessed on and off PPI therapy employing a four-point ordinal scale. RESULTS: A total of 29 patients with BE consented for pH monitoring, of whom 23 also consented for both pH and DGER monitoring off and on therapy (83% male; mean age 58 years; mean body mass index 29; mean Barrett's length 6.0 cm). Median (interquartile range) total % time pH <4 and bilirubin absorbance >0.14 off PPI therapy were 18.4 (11.7-20.0) and 9.7 (5.0-22.2), respectively. In addition, 26/29 (90%) had normalized acid and 18/23 (78%) had normalized DGER on rabeprazole 20 mg. Among those not achieving normalization on 20 mg twice daily, 3/3 (100%) had normalized acid and 4/5 (80%) had normalized DGER on rabeprazole 40 mg twice daily. All subjects had symptoms controlled on rabeprazole 20 mg twice daily. Univariate analysis found no predictor for normalization of physiologic parameters based on demographics. CONCLUSIONS: Symptom control does not guarantee normalization of acid and DGER at standard dose of twice-daily PPI therapy. Normalization of acid and DGER can be achieved in 79% of BE patients on rabeprazole 20 mg p.o. twice daily, and in the majority of the remainder at high-dose twice-daily PPI. In patients undergoing ablative therapy, pH or DGER monitoring may not be needed to ensure normalization of reflux if patients are treated with high-dose PPI therapy. PMID- 26032154 TI - Predictors and Significance of Incomplete Mucosal Recovery in Celiac Disease After 1 Year on a Gluten-Free Diet. AB - OBJECTIVES: In celiac disease, a follow-up biopsy taken 1 year after diagnosis is considered important in monitoring histological recovery. In many cases, recovery is incomplete, and the clinical significance of this is poorly understood. We now investigated associated factors and the significance of imperfect histological recovery in patients in whom the follow-up had been completed. METHODS: Two hundred sixty-three biopsy-proven patients were divided into two groups: histological recovery and incomplete recovery after 1 year on gluten-free diet. Serology, laboratory values, bone mineral density, and different clinical variables were measured at diagnosis and after 1 year. Gastrointestinal symptoms and quality of life were assessed by validated questionnaires. Further, long-term follow-up data on mortality, malignancies, and other severe complications were collected. RESULTS: The incomplete recovery group had more severe mucosal damage (P=0.003), higher antibody values (P=0.017), and more signs of malabsorption (P<0.001) at diagnosis. There was no difference in gender, symptoms or quality of life, family history of celiac disease, or comorbidities. At follow-up, there was still a difference in antibodies (P=0.018) and femoral T-scores (P=0.024). Histologically recovered patients showed better dietary adherence, although it was excellent in both groups (97% vs. 87%, P<0.001). There was no difference in long-term outcomes between groups. CONCLUSIONS: The presence of more severe disease in terms of histology, serology, and signs of malabsorption was associated with histological non-response. In patients with high dietary adherence, incomplete villous recovery after 1 year does not affect the clinical response or long-term prognosis. A personalized approach is required to decide the optimal timing of the follow-up biopsy. PMID- 26032155 TI - The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. AB - OBJECTIVES: Current monoanalyte blood-based biomarkers for the diagnosis and follow-up of neuroendocrine tumors (NETs) do not achieve satisfactory metrics of sensitivity and specificity. We report the sensitivity and selectivity of the PCR based test, the NETest, to detect tumors with reference to other benign and malignant gastrointestinal diseases. METHODS: A total of 179 cases (gastrointestinal tumors: n=81; pancreatic disease: n=98) were prospectively collected and assessed using the NETest or chromogranin A (CgA) to determine metrics for detecting small intestinal and pancreatic NETs. RESULTS: For intestinal carcinoids, the accuracy of the NETest was 93% (all NETs positive and 3 (12%) colorectal tumors were positive). CgA was positive in 80%, but 29% (n=7) of colorectal cancers were CgA positive. For pancreatic disease, the NETest accuracy was 94% (96% NETs positive, 2 (6%) of intraductal papillary mucinous neoplasms (IPMNs) were positive). The accuracy of CgA was 56% (29% of pancreatic NETs were CgA positive). Overall, the NETest was significantly more sensitive than CgA for the detection of small intestinal (area under the curve 0.98 vs. 0.75 P<0.0001) and pancreatic NETs (0.94 vs. 0.52, P<0.0001). NETest scores were elevated (P<0.05) in extensive disease and were more accurate (76-80%) than CgA levels (20-32%). The metrics of the multianalyte NETest met the performance criteria proposed by the National Institutes of Health for biomarkers, whereas CgA measurement did not. CONCLUSIONS: This study demonstrates that a blood-based multianalyte NET gene transcript measurement of well-differentiated small intestinal and pancreatic neuroendocrine tumor disease is sensitive and specific and outperforms the current monoanalyte diagnostic strategy of plasma CgA measurement. PMID- 26032156 TI - Systematic Information to Health-Care Professionals about Vaccination Guidelines Improves Adherence in Patients With Inflammatory Bowel Disease in Anti-TNFalpha Therapy. AB - OBJECTIVES: Implementation of guidelines for prevention of infectious diseases during anti-TNFalpha therapy in patients with inflammatory bowel disease (IBD) is important but difficult. We investigated whether systematic information to health care professionals about these guidelines improves patients' adherence. METHODS: The study comprised three parts: (1) cross-sectional evaluation of baseline vaccination status in all IBD patients in anti-TNFalpha therapy (reference group; n=130); (2) prospective interventional study, where health-care professionals received systematic oral and written information about vaccination guidelines at baseline and at 2-month intervals for 6 months, followed by reassessment of vaccination status (intervention group; n=99); (3) cross-sectional evaluation of representative gastroenterologists' knowledge of guidelines (n=53). Outcomes were assessed by validated questionnaires. RESULTS: Patients' adherence to vaccination guidelines increased significantly after a period of systematic information to health-care professionals. Hence, complete adherence increased from 5 to 26%, partial adherence from 38 to 56%, and complete non-adherence decreased from 57 to 18% (P<0.0001). Adherence to all individual vaccinations except human papilloma virus increased significantly (P<=0.0021). Improvement was independent of disease type and anti-TNFalpha agent. At baseline, only 8% of physicians could identify all elements in the reference guideline. Additional barriers reported by physicians were forgetfulness (32%) and insufficient consultation time (26%). Patient-perceived barriers were costs of vaccinations (35%) and forgetfulness (25%). CONCLUSIONS: Gastroenterologists' limited knowledge of vaccination guidelines during anti-TNFalpha therapy can be overcome by systematic education of health-care professionals. This inexpensive and easily accessible intervention immediately results in markedly improved patient adherence. Remaining obstacles for adherence comprise high vaccination costs and forgetfulness. PMID- 26032157 TI - Malaria-like symptoms associated with a natural Plasmodium reichenowi infection in a chimpanzee. AB - Although Plasmodium infections have never been clearly associated with symptoms in non-human primates, the question of the pathogenicity of Plasmodium parasites in non-human primates still remains unanswered. A young chimpanzee, followed before and after release to a sanctuary, in a semi-free ranging enclosure located in an equatorial forest, showed fever and strong anaemia associated with a high Plasmodium reichenowi infection, shortly after release. The animal recovered from anaemia after several months despite recurrent infection with other Plasmodium species. This may be the first description of malaria-like symptoms in a chimpanzee infected with Plasmodium. PMID- 26032159 TI - Percutaneous closure of patent ductus arteriosus in children using amplatzer duct occluder II: relationship between PDA type and risk of device protrusion into the descending aorta. AB - OBJECTIVES: To compare the efficacy and safety of Amplatzer Duct Occluder II (ADOII) among the various patent ductus arteriosus (PDA) types, and to assess the association between development of aortic obstruction and the PDA type in terms of measurable parameters as the device angulation and distance of upper end protrusion into the aortic lumen. METHODS: Retrospective cohort study involving 50 consecutive subjects who underwent ADO II device closure of PDA. RESULTS: The median age and weight at intervention were 13 months (5.5 months to 18 years) and 11 (6-67) kg respectively. The median smallest ductal diameter by angiography was 3.2 (1.9-5.4) mm. Thirty two patients had type A PDA, 5 had type C, 5 had type D, and 8 had type E. Residual shunt was seen in only 1 patient who had a tubular PDA and resolved within 2 months of the procedure. No device embolization or pulmonary side protrusion were noted. There was a 16% aortic protrusion rate. The median distance of protrusion of the upper end of the device into the aortic lumen was 3.1 (0-9) mm and the median angle formed between the aortic end of the device and the PDA take-off was 10.4 (0-80.6) degrees. These latter parameters of aortic obstruction were significantly higher in the non-conical PDA group as compared to the conical PDA. Nevertheless, there was no significant coarctation due to aortic retention disc protrusion. CONCLUSION: Device closure of PDA using the ADO II is a safe procedure for chosen types of PDA. We demonstrated a novel technique for objective assessment of device protrusion into the descending aorta based on measurable parameters. ADOII device closure of non-conical PDAs warrants closer follow ups. PMID- 26032160 TI - Neural Correlates of Biased Responses: The Negative Method Effect in the Rosenberg Self-Esteem Scale Is Associated with Right Amygdala Volume. AB - Self-esteem is a widely studied construct in psychology that is typically measured by the Rosenberg Self-Esteem Scale (RSES). However, a series of cross sectional and longitudinal studies have suggested that a simple and widely used unidimensional factor model does not provide an adequate explanation of RSES responses due to method effects. To identify the neural correlates of the method effect, we sought to determine whether and how method effects were associated with the RSES and investigate the neural basis of these effects. Two hundred and eighty Chinese college students (130 males; mean age = 22.64 years) completed the RSES and underwent magnetic resonance imaging (MRI). Behaviorally, method effects were linked to both positively and negatively worded items in the RSES. Neurally, the right amygdala volume negatively correlated with the negative method factor, while the hippocampal volume positively correlated with the general self-esteem factor in the RSES. The neural dissociation between the general self-esteem factor and negative method factor suggests that there are different neural mechanisms underlying them. The amygdala is involved in modulating negative affectivity; therefore, the current study sheds light on the nature of method effects that are related to self-report with a mix of positively and negatively worded items. PMID- 26032162 TI - Identification of a novel PARP14-TFE3 gene fusion from 10-year-old FFPE tissue by RNA-seq. AB - Xp11 (TFE3) translocation renal cell carcinoma (RCC) is officially recognized as a distinct subtype of RCC in the 2004 WHO classification. This neoplasm is characterized by several chromosomal translocations between the TFE3-involving Xp11.2 breakpoint and various fusion partners. To date, five partner genes have been identified, that is, PRCC in 1q21, PSF in 1q34, ASPL in 17q25, CLTC in 17q23, and NONO in Xq12; and three additional translocations have been reported with no partner gene being defined: t(X;3)(p11;q23), t(X;10)(p11;q23), and t(X;19)(p11;q13). Here, we report the identification of a novel TFE3 fusion partner, PARP14 in chromosome band3q21. We used RNA-seq on a 10-year-old FFPE (formalin-fixed, paraffin-embedded) tissue sample, which carried t(X;3)(p11;q23) as detected in the original cytogenetic study. The fusion transcript connected the 5'-end of the first two exons of PARP14 to the 3'-end of five exons of TFE3, which was verified by reverse transcription PCR (RT-PCR) and Sanger sequencing. Similar to other TFE3 fusions previously reported, the predicted PARP14-TFE3 product retains the nuclear localization and DNA-binding domains of TFE3. This finding expands the list of TFE3 translocation partner genes and re-emphasizes the essential oncogenic role of TFE3 fusion proteins in this tumor. Our result also clearly demonstrated the feasibility of identifying chromosomal translocation by RNA-seq in clinical FFPE, which are easily accessible and associated with valuable clinical information. (c) 2015 Wiley Periodicals, Inc. PMID- 26032163 TI - A reappraisal of adult thoracic and abdominal surface anatomy via CT scan in Chinese population. AB - Accurate surface anatomy is essential for safe clinical practice. There are numerous inconsistencies in clinically important surface markings among and within contemporary anatomical reference texts. The aim of this study was to investigate key thoracic and abdominal surface anatomy landmarks in living Chinese adults using computed tomography (CT). A total of 100 thoracic and 100 abdominal CT scans were examined. Our results indicated that the following key surface landmarks differed from current commonly-accepted descriptions: the positions of the tracheal bifurcation, azygos vein termination, and pulmonary trunk bifurcation (all below the plane of the sternal angle at vertebral level T5 T6 in most individuals); the superior vena cava formation and junction with the right atrium (most often behind the 1st and 4th intercostal spaces, respectively); and the level at which the inferior vena cava and esophagus traverse the diaphragm (T10 and T11, respectively). The renal arteries were most commonly at L1; the midpoint of the renal hila was most frequently at L2; the 11th rib was posterior to the left kidney in only 29% of scans; and the spleen was most frequently located between the 10th and 12th ribs. A number of significant sex- and age-related differences were noted. The Chinese population was also compared with western populations on the basis of published reports. Reappraisal of surface anatomy using modern imaging tools in vivo will provide both quantitative and qualitative evidence to facilitate the clinical application of these key surface landmarks. PMID- 26032161 TI - In vivo luminescent imaging of NF-kappaB activity and NF-kappaB-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. AB - BACKGROUND: Methods for the detection of the temporal and spatial generation of painful symptoms are needed to improve the diagnosis and treatment of painful neuropathies and to aid preclinical screening of molecular therapeutics. METHODS: In this study, we utilized in vivo luminescent imaging of NF-kappaB activity and serum cytokine measures to investigate relationships between the NF-kappaB regulatory network and the presentation of painful symptoms in a model of neuropathy. RESULTS: The chronic constriction injury model led to temporal increases in NF-kappaB activity that were strongly and non-linearly correlated with the presentation of pain sensitivities (i.e. mechanical allodynia and thermal hyperalgesia). The delivery of NEMO-binding domain peptide reduced pain sensitivities through the inhibition of NF-kappaB activity in a manner consistent with the demonstrated non-linear relationship. Importantly, the combination of non-invasive measures of NF-kappaB activity and NF-kappaB-regulated serum cytokines produced a highly predictive model of both mechanical (R(2) = 0.86) and thermal (R(2) = 0.76) pain centred on the NF-kappaB regulatory network (NF kappaB, IL-6, CXCL1). CONCLUSIONS: Using in vivo luminescent imaging of NF-kappaB activity and serum cytokine measures, this work establishes NF-kappaB and NF kappaB-regulated cytokines as novel multivariate biomarkers of pain-related sensitivity in this model of neuropathy that may be useful for the rapid screening of novel molecular therapeutics. PMID- 26032164 TI - Identification of a novel Picornavirales virus distantly related to posavirus in swine feces. AB - De novo assembly of metagenomic sequencing reads from feces from a clinically normal pig identified two approximately 9 kb contigs which each consisted of a single large open reading frame. While one contig encoded a predicted 2990 amino acid protein with 83 % identity to the recently described posavirus 1, the other contig encoded a predicted 2942 amino acid protein with only 25 % identity limited to the genomic region encoding the RNA-dependent RNA polymerase (RdRp) of posavirus 2. Besides RdRp, search of the conserved domain database identified domains associated with picornavirus capsid proteins but failed to identify picornaviral helicase and proteinase domains. In addition, a domain representing a family of Mycoplasma and Ureaplasma immunoglobulin-blocking virulence proteins was identified near the 5'-terminus. Phylogenetic analysis found a distant relationship between this novel virus, provisionally named posavirus 3, to the unclassified posaviruses and fisavirus which are proposed to represent different genera in a novel family of the Picornavirales. PMID- 26032165 TI - [Squaring the circle is not impossible: a synthetic quality index]. PMID- 26032167 TI - Metabolomic profiling and genomic analysis of wheat aneuploid lines to identify genes controlling biochemical pathways in mature grain. AB - Metabolomics is becoming an increasingly important tool in plant genomics to decipher the function of genes controlling biochemical pathways responsible for trait variation. Although theoretical models can integrate genes and metabolites for trait variation, biological networks require validation using appropriate experimental genetic systems. In this study, we applied an untargeted metabolite analysis to mature grain of wheat homoeologous group 3 ditelosomic lines, selected compounds that showed significant variation between wheat lines Chinese Spring and at least one ditelosomic line, tracked the genes encoding enzymes of their biochemical pathway using the wheat genome survey sequence and determined the genetic components underlying metabolite variation. A total of 412 analytes were resolved in the wheat grain metabolome, and principal component analysis indicated significant differences in metabolite profiles between Chinese Spring and each ditelosomic lines. The grain metabolome identified 55 compounds positively matched against a mass spectral library where the majority showed significant differences between Chinese Spring and at least one ditelosomic line. Trehalose and branched-chain amino acids were selected for detailed investigation, and it was expected that if genes encoding enzymes directly related to their biochemical pathways were located on homoeologous group 3 chromosomes, then corresponding ditelosomic lines would have a significant reduction in metabolites compared with Chinese Spring. Although a proportion showed a reduction, some lines showed significant increases in metabolites, indicating that genes directly and indirectly involved in biosynthetic pathways likely regulate the metabolome. Therefore, this study demonstrated that wheat aneuploid lines are suitable experimental genetic system to validate metabolomics genomics networks. PMID- 26032166 TI - Depletion of p18/LAMTOR1 promotes cell survival via activation of p27(kip1) dependent autophagy under starvation. AB - The MAPK and mTOR signal pathways in endosomes or lysosomes play a crucial role in cell survival and death. They are also closely associated with autophagy, a catabolic process highly regulated under various cellular stress or nutrient deprivation. Recently we have isolated a protein, named p18/LAMTOR1, that specifically regulates the ERK or mTOR pathway in lysosomes. p18/LAMTOR1 also interacts with p27(kip1) . Here we examined how p18/LAMTOR1 plays a role in autophagy under nutrient deprivation. The p18(+/+) MEF cells were more susceptible to cell death under starvation or in the presence of AICAR in comparison with p18(-/-) MEF cells. Cleavage of caspase-3 was increased in p18(+/+) MEF cells under starvation, and phosphorylation at the threonine 198 of p27(kip1) was highly elevated in starved p18(-/-) MEF cells. Furthermore, LC3-II formation and other autophagy-associated proteins were largely increased in p18 deficient cells, and suppression of p27(kip1) expression in p18(-/-) MEF cells mitigated starvation-induced cell death. These data suggest that ablation of p18/LAMTOR1 suppresses starvation-induced cell death by stimulating autophagy through modulation of p27(kip1) activity. PMID- 26032168 TI - Quinine as a potential tracer for medication adherence: A pharmacokinetic and pharmacodynamic assessment of quinine alone and in combination with oxycodone in humans. AB - Effective strategies to monitor pharmacotherapy adherence are necessary, and sensitive biological markers are lacking. This study examined a subtherapeutic dose of quinine as a potential adherence tracer. Primary aims included examination of the plasma and urinary pharmacokinetic profile of once-daily quinine; secondary aims assessed pharmacokinetic/pharmacodynamic interactions with oxycodone (a CYP3A and CYP2D substrate). Healthy, nondependent opioid users (n = 9) were enrolled in this within-subject, double-blind, placebo-controlled inpatient study. Participants received the following oral doses: day 1, oxycodone (30 mg); days 2-4, quinine (80 mg); day 5, quinine and oxycodone (2 hours postquinine). Blood and 24-hour urine samples were collected throughout the study, and pharmacodynamic outcomes were assessed during experimental sessions (days 1, 4, 5). Quinine displayed a plasma Tmax ~2 hours and t1/2 ~10 hours. Oxycodone and noroxycodone parameters (Tmax , Cmax , t1/2 ) were similar with or without quinine present, although drug exposure (AUC) was slightly greater when combined with quinine. No pharmacodynamic interactions were detected, and doses were safely tolerated. During washout, quinine urinary concentrations steadily declined (elimination t1/2 ~16 hours), with a 94% decrease observed 72 hours postdose. Overall, low-dose quinine appears to be a good candidate for a medication additive to monitor adherence for detection of missed medication. PMID- 26032169 TI - Genistein induces apoptosis by stabilizing intracellular p53 protein through an APE1-mediated pathway. AB - Genistein (GEN) has been previously shown to have a proapoptotic effect on cancer cells through a p53-dependent pathway, the mechanism of which remains unclear. One of its intracellular targets, APE1, protects against apoptosis under genotoxic stress and interacts with p53. In this current study, we explored the mechanism of the proapoptotic effect of GEN by examining the APE1-p53 protein protein interaction. We initially showed that the p53 protein level was elevated in GEN-treated human non-small lung cancer A549 cells and cervical cancer HeLa cells. By examining both protein synthesis and degradation, we found that GEN enhances p53 intracellular stability by interfering with the interaction of APE1 and p53, which provided a plausible explanation for how GEN initiates apoptosis. Furthermore, we found that the interaction between APE1 and p53 is important for the degradation of p53 and is dependent on the redox domain of APE1 by utilizing the redox domain mutant APE1 C65A. Our data suggest that the degradation of wild type p53 is blocked when the redox domain of APE1 is masked or interrupted. Based on this evidence, we hereby report a novel mechanism of p53 degradation through an APE1-mediated, redox-dependent pathway. PMID- 26032170 TI - Carbon monoxide modulates cytochrome oxidase activity and oxidative stress in the developing murine brain during isoflurane exposure. AB - Commonly used anesthetics induce widespread neuronal degeneration in the developing mammalian brain via the oxidative-stress-associated mitochondrial apoptosis pathway. Dysregulation of cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, can result in reactive oxygen species (ROS) formation. Isoflurane has previously been shown to activate this enzyme. Carbon monoxide (CO), as a modulator of CcOX, is of interest because infants and children are routinely exposed to CO during low-flow anesthesia. We have recently demonstrated that low concentrations of CO limit and prevent isoflurane-induced neurotoxicity in the forebrains of newborn mice in a dose-dependent manner. However, the effect of CO on CcOX in the context of anesthetic-induced oxidative stress is unknown. Seven-day-old male CD-1 mice underwent 1h exposure to 0 (air), 5, or 100ppm CO in air with or without isoflurane. Exposure to isoflurane or CO independently increased CcOX kinetic activity and increased ROS within forebrain mitochondria. However, exposure to CO combined with isoflurane paradoxically limited CcOX activation and oxidative stress. There were no changes seen in steady-state levels of CcOX I protein, indicating post-translational modification of CcOX as an etiology for changes in enzyme activity. CO exposure led to differential effects on CcOX subunit I tyrosine phosphorylation depending on concentration, while combined exposure to isoflurane with CO markedly increased the enzyme phosphorylation state. Phosphorylation of tyrosine 304 of CcOX subunit I has been shown to result in strong enzyme inhibition, and the relative reduction in CcOX kinetics following exposure to CO combined with isoflurane may have been due, in part, to such phosphorylation. Taken together, the data suggest that CO modulates CcOX in the developing brain during isoflurane exposure, thereby limiting oxidative stress. These CO-mediated effects could have implications for the development of low-flow anesthesia in infants and children to prevent anesthesia-induced oxidative stress. PMID- 26032172 TI - Pyrolytic synthesis and luminescence of porous lanthanide Eu-MOF. AB - A lanthanide metal coordination polymer [Eu2(BDC)3(DMSO)(H2O)] was synthesized by the reaction of europium oxide with benzene-1,3-dicarboxylic acid (H2BDC) in a mixed solution of dimethyl sulfoxide (DMSO) and water under hydrothermal conditions. The crystal structure of Eu2(BDC)3(DMSO)(H2O) was characterized by X ray diffraction (XRD). Thermo-gravimetric analysis of Eu2(BDC)3(DMSO)(H2O) indicated that coordinated DMSO and H2O molecules could be removed to create Eu2(BDC)3(DMSO)(H2O)-py with permanent microporosity, which was also verified by powder XRD (PXRD) and elemental analysis. Both Eu2(BDC)3(DMSO)(H2O) and Eu2(BDC)3(DMSO)(H2O)-py showed mainly Eu-based luminescence and had characteristic emissions in the range 550-700 nm. PMID- 26032171 TI - To remove or not to remove? Removal of the unconditional stimulus electrode does not mediate instructed extinction effects. AB - Following differential fear conditioning, the instruction that the unconditional stimulus will no longer be presented (instructed extinction) reduces differential electrodermal responding to CS+ and CS-, but does not affect differential conditional stimulus valence evaluations. Reductions in differential electrodermal responding have been attributed to the provision of verbal instructions; however, during instructed extinction the unconditional stimulus electrode is often removed as well. This removal could reduce the participants' general arousal levels rendering the detection of differential electrodermal responding difficult. The current study examined this alternative interpretation by comparing the electrodermal responses and conditional stimulus valence evaluations of an instruction/electrode-on group, an instruction/electrode-off group, and a control group who were not instructed. Following instructed extinction, differential electrodermal responding was eliminated in both instruction groups, an effect that was not influenced by the attachment/removal of the electrode. Replicating previous findings, conditional stimulus valence was not affected by instructed extinction. The results suggest that verbal instructions, not unconditional stimulus electrode removal, reduce differential electrodermal responding during instructed extinction manipulations. PMID- 26032173 TI - Characteristics and Survival of 121 Cats Undergoing Excision of Intracranial Meningiomas (1994-2011). AB - OBJECTIVE: To report clinical features and outcomes of cats undergoing excision of intracranial meningiomas. STUDY DESIGN: Retrospective, multicenter case series. SAMPLE POPULATION: One hundred and twenty-one cats. METHODS: Signalment, clinical signs, duration of clinical signs, preoperative drug therapy, diagnostic imaging reports, surgery, histopathology, and outcome were collected from records of cats undergoing excision of intracranial meningiomas. Survival estimates were made using Kaplan-Meier analysis. RESULTS: There were 76/121 neutered males and 83/121 domestic short-hairs. Body weight ranged from 1.5-8.7 kg (median 5.0 kg). Age at diagnosis ranged from 3-18 years (median 12 years). Clinical signs included changes in behavior, ataxia, seizures, visual deficits, circling, and paresis. Duration of neurologic signs ranged from <1-23 months (median 1.25 months). At the time of writing, 13 cats were alive, 54 were dead or euthanatized, and 54 were lost to followup. Seven cats (13% of cats that died; 6% of all cats) died or were euthanatized in the immediate postoperative period (<1 month post-surgery) and 9 cats (17% of all cats that died; 7% of all cats) died from causes related to the meningioma but outside the immediate perioperative period. The median survival time for all cats was 37 months (95% confidence interval 28-54 months). CONCLUSION: Cats undergoing excision of intracranial meningiomas had a low perioperative mortality and a long-term prognosis of more than 3 years. PMID- 26032175 TI - New insight in the treatment of refractory melasma: Laser Q-switched Nd: YAG non ablative fractionated followed by intense pulsed light. AB - The purpose of our study was to verify the results of the association of Q switched Nd: YAG non-ablative fractionated with intense pulsed light, in order to treat patients with refractory melasma. The combination of these two devices seems to be the best treatment to combat hyperpigmentation produced by melasma, with low occurrence of side effects, which may be justified by the selective photothermolysis at subcellular level. PMID- 26032176 TI - Effects of Artemetin on Nitric Oxide Release and Protection against Peroxidative Injuries in Porcine Coronary Artery Endothelial Cells. AB - Artemetin is one of the main components of Achillea millefolium L. and Artemisia absinthium, which have long been used for the treatment of various diseases. To date, however, available information about protective effects of their extracts on the cardiovascular system is scarce. Therefore, we planned to analyze the effects of artemetin on nitric oxide (NO) release and the protection exerted against oxidation in porcine aortic endothelial (PAE) cells. In PAE, we examined the modulation of NO release caused by artemetin and the involvement of muscarinic receptors, beta2-adrenoreceptors, estrogenic receptors (ER), protein kinase A, phospholipase-C, endothelial-NO-synthase (eNOS), Akt, extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen activated protein kinase (p38 MAPK). Moreover, in cells treated with hydrogen peroxide, the effects of artemetin were examined on cell survival, glutathione (GSH) levels, apoptosis, mitochondrial membrane potential and transition pore opening. Artemetin increased eNOS-dependent NO production by the involvement of muscarinic receptors, beta2 adrenoreceptors, ER and all the aforementioned kinases. Furthermore, artemetin improved cell viability in PAE that were subjected to peroxidation by counteracting GSH depletion and apoptosis and through the modulation of mitochondrial function. In conclusion, artemetin protected endothelial function by acting as antioxidant and antiapoptotic agent and through the activation of ERK1/2 and Akt. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26032174 TI - Ureteroscopy and cystoscopy training: comparison between transparent and non transparent simulators. AB - BACKGROUND: Simulators have been widely used to train operational skills in urology, how to improve its effectiveness deserves further investigation. In this paper, we evaluated training using a novel transparent anatomic simulator, an opaque model or no simulator training, with regard to post-training ureteroscopy and cystoscopy proficiency. METHODS: Anatomically correct transparent and non transparent endourological simulators were fabricated. Ten experienced urologists provided a preliminary evaluation of the models as teaching tools. 36 first-year medical students underwent identical theoretical training and a 50-point examination of theoretical knowledge. The students were randomly assigned to receive training with the transparent simulator (Group 1), the non-transparent simulator (Group 2) or detailed verbal instruction only (Group 3). 12 days after the training session, the trainees' skills at ureteral stent insertion and removal were evaluated using the Uro-Scopic Trainer and rated on an Objective Structured Assessment of Technical Skills (OSATS) scale. RESULTS: The new simulators were successfully fabricated in accordance with the design parameters. Of the ten urologists invited to evaluate the devices, 100% rated the devices as anatomically accurate, 90% thought both models were easy to use and 80% thought they were good ureteroscopy and cystoscopy training tools. The scores on the theoretical knowledge test were comparable among the training groups, and all students were able to perform ureteral stent insertion and removal. The mean OSATS scores of groups 1, 2 and 3 were 21.83 +/- 3.64, 18.50 +/- 4.03 and 15.58 +/- 2.23 points, respectively, (p = 0.001). CONCLUSIONS: Simulator training allowed students to achieve higher ureteroscopic and cystoscopic proficiency, and transparent simulators were more effective than non-transparent simulators. PMID- 26032177 TI - C35 Hopanoid Side Chain Biosynthesis: Reduction of Ribosylhopane into Bacteriohopanetetrol by a Cell-Free System Derived from Methylobacterium organophilum. AB - The major bacterial triterpenoids of the hopane series each consist of a C30 triterpene hopane moiety and an additional nonterpene C5 side chain derived from D-ribose and linked through its C-5 carbon atom to the hopane side chain. Bacteriohopanetetrol and aminobacteriohopanetriol are the most common representatives of this natural product series, adenosylhopane and ribosylhopane being putative precursors. Deuterium-labelled ribosylhopane was obtained by hemisynthesis and converted into deuterium-labelled bacteriohopanetetrol in the presence of NADPH, thus giving evidence of this as yet unknown precursor-to product relationship in the bacterial hopanoid metabolic pathway. PMID- 26032179 TI - Congenital insensitivity to pain with anhidrosis. PMID- 26032178 TI - SAMHD1 specifically restricts retroviruses through its RNase activity. AB - BACKGROUND: Human SAMHD1 possesses dual enzymatic functions. It acts as both a dGTP-dependent triphosphohydrolase and as an exoribonuclease. The dNTPase function depletes the cellular dNTP pool, which is required for retroviral reverse transcription in differentiated myeloid cells and resting CD4(+) T cells; thus this activity mainly plays a role in SAMHD1-mediated retroviral restriction. However, a recent study demonstrated that SAMHD1 directly targets HIV-1 genomic RNA via its RNase activity, and that this function (rather than dNTPase activity) is sufficient for HIV-1 restriction. While HIV-1 genomic RNA is a potent target for SAMHD1 during viral infection, the specificity of SAMHD1-mediated RNase activity during infection by other viruses is unclear. RESULTS: The results of the present study showed that SAMHD1 specifically degrades retroviral genomic RNA in monocyte-derived macrophage-like cells and in primary monocyte-derived macrophages. Consistent with this, SAMHD1 selectively restricted retroviral replication, but did not affect the replication of other common non-retro RNA genome viruses, suggesting that the RNase-mediated antiviral function of SAMHD1 is limited to retroviruses. In addition, neither inhibiting reverse transcription by treatment with several reverse transcriptase inhibitors nor infection with reverse transcriptase-defective HIV-1 altered RNA levels after viral challenge, indicating that the retrovirus-specific RNase function is not dependent on processes associated with retroviral reverse transcription. CONCLUSIONS: The results presented herein suggest that the RNase activity of SAMHD1 is sufficient to control the replication of retroviruses, but not that of non-retro RNA viruses. PMID- 26032180 TI - Assessment of the effect of prolonged forced swimming on CD-1 mice sperm morphology with and without antioxidant supplementation. AB - As physical exercise has been shown to negatively affect sperm morphology, this study was undertaken to assess the effect of a 3-min forced swimming protocol during 50 days, with and without administration of antioxidants [N-acetylcysteine (NAC) and trans-resveratrol], on sperm morphology in CD-1 mice. Forty-four 13 week-old CD-1 mice were randomly allocated to four different groups: mice not submitted to exercise, control group (CG), mice submitted to swimming without administration of antioxidants (EX), mice submitted to swimming that received trans-resveratrol supplementation [exercise group (EX)+Resv] and mice submitted to swimming exercise that received NAC supplementation (EX+NAC). The EX showed 30.5% of spermatozoa with normal morphology, showing significant differences with regard to the CG, which showed 58.5%. The groups receiving antioxidant supplements showed significantly higher percentages of spermatozoa with normal morphology in comparison with the EX group (EX+Resv: 64.1%, EX+NAC: 48.2%). The imposed model of forced swimming caused alterations in sperm morphology. The antioxidants employed seem to be suitable antioxidants for avoiding exercise associated sperm morphology anomalies in prolonged forced swimming exercise. Trans-resveratrol has proven to be more efficient for this purpose. PMID- 26032181 TI - A latent class analysis of trauma based on a nationally representative sample of US adolescents. AB - PURPOSE: Traumatic events in adolescence rarely occur in isolation. Multiple traumatic experiences are prevalent, diverse and a well-established risk factor for mental health disorders. The aim of this study was to explore and explain the heterogeneity in trauma profiles in a nationally representative sample of US adolescents. METHOD: Using latent class analysis, data on 10,123 adolescents aged between 13 and 18 from the National Comorbidity Survey Adolescent Supplement were examined. In addition, the relationships between the emergent classes and demographic and clinical variables were explored. RESULTS: A four-class solution was the best fit of adolescent trauma patterns, with classes labelled as low risk, sexual assault risk, non-sexual risk and high risk. When compared to the low risk class, those in the other classes were significantly more likely not to live with either biological parent, display symptoms indicative of mood and anxiety disorders, and to have higher rates of disorder comorbidity. CONCLUSIONS: This provides evidence of four distinct groups of adolescents who have experienced a variety of traumas. Evidence demonstrates the increased risk of adolescents with a history of trauma meeting the diagnostic criteria for not only individual disorders but also comorbidity across disorder categories. PMID- 26032183 TI - Sulfated Carbon Quantum Dots as Efficient Visible-Light Switchable Acid Catalysts for Room-Temperature Ring-Opening Reactions. AB - Acid catalytic processes play a classic and important role in modern organic synthesis. How well the acid can be controlled often plays the key role in the controllable synthesis of the products with high conversion yield and selectivity. The preparation of a novel, photo-switchable solid-acid catalyst based on carbon quantum dots is described. The carbon quantum dots are decorated with small amounts of hydrogensulfate groups and thus exhibit a photogenerated acidity that produces a highly efficient acid catalysis of the ring opening of epoxides with methanol and other primary alcohols. This reversible, light switchable acidity is shown to be due to photoexcitation and charge separation in the carbon quantum dots, which create an electron withdrawing effect from the acidic groups. The catalyst is easily separated by filtration, and we demonstrate multiple cycles of its recovery and reuse. PMID- 26032182 TI - Social networks, mental health problems, and mental health service utilization in OEF/OIF National Guard veterans. AB - PURPOSE: Low social support and small social network size have been associated with a variety of negative mental health outcomes, while their impact on mental health services use is less clear. To date, few studies have examined these associations in National Guard service members, where frequency of mental health problems is high, social support may come from military as well as other sources, and services use may be suboptimal. METHODS: Surveys were administered to 1448 recently returned National Guard members. Multivariable regression models assessed the associations between social support characteristics, probable mental health conditions, and service utilization. RESULTS: In bivariate analyses, large social network size, high social network diversity, high perceived social support, and high military unit support were each associated with lower likelihood of having a probable mental health condition (p < .001). In adjusted analyses, high perceived social support (OR .90, CI .88-.92) and high unit support (OR .96, CI .94-.97) continued to be significantly associated with lower likelihood of mental health conditions. Two social support measures were associated with lower likelihood of receiving mental health services in bivariate analyses, but were not significant in adjusted models. CONCLUSIONS: General social support and military-specific support were robustly associated with reduced mental health symptoms in National Guard members. Policy makers, military leaders, and clinicians should attend to service members' level of support from both the community and their units and continue efforts to bolster these supports. Other strategies, such as focused outreach, may be needed to bring National Guard members with need into mental health care. PMID- 26032184 TI - Retrospective evaluation of the clinical and laboratory data from 300 patients of various hematological malignancies with chromosome 3 abnormalities. AB - This retrospective study was designed to evaluate the clinical and laboratory behaviors of chromosome 3 abnormalities by analyzing the morphological, cytogenetic, and follow-up data from 300 patients of various hematological malignancies with chromosome 3 abnormalities. From the results, trisomy 3, translocation (3q), and del(3) were the abnormal types most frequently observed (>10%) among the chromosome 3 abnormalities. In hematological malignancies, chromosome 3 abnormalities were most frequently seen in the patients with acute myeloid leukemia (AML) (24.7%) and myelodysplastic syndrome (MDS) (16%), followed by those with acute lymphocytic leukemia (ALL) (13.7%) and multiple myeloma (MM) (12.7%). In this series, genomic losses were the most frequent genetic abnormalities in AML, ALL, and hybrid acute leukemia (HAL) patients, whereas structural rearrangements were frequently seen in chronic myeloid leukemia (CML) and MDS patients, and genomic gains in MM, lymphoma and chronic lymphocytic leukemia (CLL) patients. Chromosome 3 abnormalities mainly occurred as a component of a complex abnormality (251/300) rather than a sole one (14/300). Survival analysis demonstrated a statistical difference between the patients with trisomy 3, who had a better prognosis, and patients with del(3), who had a worse prognosis in this series (P < 0.05). Abnormalities in chromosome 3 may imply an unfavorable outcome in CML and ALL. PMID- 26032185 TI - A cross sectional study evaluating screening using maternal anthropometric measurements for outcomes of childbirth in Ugandan mothers at term. AB - BACKGROUND: Birth related newborn and maternal mortality/morbidity remains high in most of sub-Saharan Africa compared to the rest of the world. In this low income region there is a need for valid, low cost, easy to use mass screening tests. This study looked at the screening value of maternal: height, weight and pelvis height, for assessing the outcomes of parturition in Ugandan mothers at term. METHODS: This was a multi site cross-sectional study on mothers with singleton pregnancies in labour at various hospitals in different parts of Uganda. A summary of the details of the pregnancy, maternal height, weight and the delivery record were captured and analysed to generate descriptive and inferential (multilevel logistic regression analysis) and diagnostic (Receiver Operator Curve analysis) statistics. RESULTS: We recruited 1146 mothers from all the study sites during the study period of whom 987 (86.13%) had normal deliveries and healthy babies. Mothers with adverse outcomes included 107 mothers that had caesarean section and 52 mothers who had vaginal deliveries with foetal Apgar score of <=7 at 5 min of whom 11 had fresh still births. Maternal height (Adj OR 0.97, 95% CI 0.94-1.00) and maternal pelvis height (Adj OR 0.73, 95% CI 0.61-0.86) were significantly associated with adverse pregnancy outcomes. The combination of maternal: height (<150 cm), weight (>55.7 kg) and pelvis height (>8.95 cm) had the best diagnostic value with a combined area under the curve of 0.60. CONCLUSIONS: It was observed that an increase in either maternal pelvis height or maternal height was associated with a significant reduction in adverse pregnancy outcomes. The cut off values of all three evaluated maternal anthropometric measurements were of low test accuracy as screening tests even when used together. Further research is needed to develop low cost screening tools for use in low income settings. PMID- 26032186 TI - A study on immunomodulatory mechanism of Polysaccharopeptide mediated by TLR4 signaling pathway. AB - BACKGROUND: Polysaccharopeptide (PSP), isolated from Coriolus versicolor COV-1 strain, is a protein-bound polysaccharide widely used as immunoadjuvant for cancer immunotherapy. Although the immunomodulatory activity of PSP has been well established, the precise molecule mechanisms of its biological activity have yet to be fully elucidated. METHODS: In the present study, we first investigated the immunomodulatory activity of PSP in peritoneal macrophages from C57BL/10J (TLR4(+/+)) and C57BL/10ScCr (TLR4(-/-)) mice carrying a defective toll-like receptor-4 (TLR4) gene and then evaluated PSP for its effect on tumor inhibition rates and the immune organ index in above two different strains of mice. In addition, PSP were also evaluated for its activation of TLR4, TLR4-downstream molecules (TRAF6, NF-kappaB and AP-1) in spleens of tumor-bearing C57BL/10J (TLR4(+/+)) and C57BL/10ScCr (TLR4(-/-)) mice. RESULTS: The results showed that PSP had adjuvant activities in stimulating expressions of cytokines as well as TLR4, TRAF6, phosphorylation of NF-kappaB p65 transcription factors and phosphorylation of c-Jun (a component of the transcription factor AP-1) in peritoneal macrophages from C57BL/10J (TLR4(+/+)) mice but not from C57BL/10ScCr (TLR4(-/-)) mice. In vivo PSP as well as Adriamycin (ADM) decreased the mean weights of tumors compared with normal saline and PSP increased thymus index and spleen index relative to ADM in tumor-bearing C57BL/10J (TLR4(+/+)) mice but not in C57BL/10ScCr (TLR4(-/-)) mice. CONCLUSIONS: We demonstrated that PSP activates peritoneal macrophages in vitro via TLR4 signaling pathway and PSP functions its immunoregulatory effect in vivo also via TLR4 signaling pathway. These data strongly suggest TLR4 signaling pathway is involved in PSP-mediated immunomodulatory activities. PMID- 26032187 TI - Solvent-dependent zinc(II) coordination polymers with mixed ligands: selective sorption and fluorescence sensing. AB - Starting from the same metal salts and mixed organic ligands of 1,3,5-tris(1 imidazolyl)benzene (tib) and 2-bromo-1,4-benzenedicarboxylic acid (H2BDC-Br), two novel zinc(II) coordination polymers [Zn2(tib)2(BDC-Br)]2.2SO4.17H2O (1) and [Zn4(tib)2(BDC-Br)3(H2O)4SO4].7.5H2O.2.5DMF (2) (DMF = N,N-dimethylformamide) were obtained by using different solvent systems of DMF/H2O and DMF/EtOH/H2O, respectively. 1 is an unusual (3,4)-connected 3D net with a Point symbol of {4.8.10(4)}{4.8.10}, while 2 is a complicated 1D chain, which is further connected to form a 3D supramolecular architecture by hydrogen bonding interactions. In particular, 1 and 2 exhibit selective adsorption of CO2 over N2 and show good selectivity for detection of acetone via fluorescence quenching. PMID- 26032188 TI - The effect of Curcuma longa extracted (curcumin) on the quality of cryopreserved boar semen. AB - The aim of this study was to determine the optimal concentration of curcumin needed for cryopreservation of boar semen. Semen samples (n = 9) were collected from nine Duroc boars which having proven fertility were used for routine artificial insemination. Semen samples were collected and divided into six groups (groups A-F) according to various concentrations of curcumin in freezing extender (i.e. 0, 0.125, 0.25, 0.50, 0.75 and 1.0 mmol/L, respectively). The semen was frozen by traditional liquid nitrogen vapor method and stored at -196 degrees C in the liquid nitrogen tank. After storage, frozen semen samples were thawed at 50 degrees C for 12 s and evaluated for progressive motility, viability and acrosome integrity. The present results indicated that the addition of curcumin at 0.25 (group C) or 0.50 mmol/L curcumin (group D) yielded the higher percentage of progressive motility (33.3 and 36.1%, respectively) (P < 0.001). A significantly higher percentage of acrosome integrity was found in groups B (29.7%), C (31.1%) and D (30.2%) than in the other groups (P < 0.01). However, there was no significant difference in percentage of viability among groups. In conclusion, addition to the freezing extender of curcumin during cryopreservation at a concentration of 0.25 or 0.50 mmol/L is the optimal concentration of curcumin for improving the quality (i.e. increased progressive motility and acrosome integrity) of cryopreserved boar semen. PMID- 26032189 TI - Development of emergency response tools for accidental radiological contamination of French coastal areas. AB - The Fukushima nuclear accident resulted in the largest ever accidental release of artificial radionuclides in coastal waters. This accident has shown the importance of marine assessment capabilities for emergency response and the need to develop tools for adequately predicting the evolution and potential impact of radioactive releases to the marine environment. The French Institute for Radiological Protection and Nuclear Safety (IRSN) equips its emergency response centre with operational tools to assist experts and decision makers in the event of accidental atmospheric releases and contamination of the terrestrial environment. The on-going project aims to develop tools for the management of marine contamination events in French coastal areas. This should allow us to evaluate and anticipate post-accident conditions, including potential contamination sites, contamination levels and potential consequences. In order to achieve this goal, two complementary tools are developed: site-specific marine data sheets and a dedicated simulation tool (STERNE, Simulation du Transport et du transfert d'Elements Radioactifs dans l'environNEment marin). Marine data sheets are used to summarize the marine environment characteristics of the various sites considered, and to identify vulnerable areas requiring implementation of population protection measures, such as aquaculture areas, beaches or industrial water intakes, as well as areas of major ecological interest. Local climatological data (dominant sea currents as a function of meteorological or tidal conditions) serving as the basis for an initial environmental sampling strategy is provided whenever possible, along with a list of possible local contacts for operational management purposes. The STERNE simulation tool is designed to predict radionuclide dispersion and contamination in seawater and marine species by incorporating spatio-temporal data. 3D hydrodynamic forecasts are used as input data. Direct discharge points or atmospheric deposition source terms can be taken into account. STERNE calculates Eulerian radionuclide dispersion using advection and diffusion equations established offline from hydrodynamic calculations. A radioecological model based on dynamic transfer equations is implemented to evaluate activity concentrations in aquatic organisms. Essential radioecological parameters (concentration factors and single or multicomponent biological half-lives) have been compiled for main radionuclides and generic marine species (fish, molluscs, crustaceans and algae). Dispersion and transfer calculations are performed simultaneously on a 3D grid. Results can be plotted on maps, with possible tracking of spatio-temporal evolution. Post-processing and visualization can then be performed. PMID- 26032190 TI - Helping behavior induced by empathic concern attenuates anterior cingulate activation in response to others' distress. AB - Helping behavior is motivated by empathic concern for others in distress. Although empathic concern is pervasive in daily life, its neural mechanisms remain unclear. Empathic concern involves the suppression of the emotional response to others' distress, which occurs when individuals distance themselves emotionally from the distressed individual. We hypothesized that helping behavior induced by empathic concern, accompanied by perspective-taking, would attenuate the neural activation representing aversive feelings. We also predicted reward system activation due to the positive feeling resulting from helping behavior. Participant underwent functional magnetic resonance imaging while playing a virtual ball-toss game. In some blocks ("concern condition"), one player ("isolated player") did not receive ball-tosses from other players. In this condition, participants increased ball-tosses to the isolated player (helping behavior). Participants then evaluated the improved enjoyment of the isolated player resulting from their helping behavior. Anterior cingulate activation during the concern condition was attenuated by the evaluation of the effect of helping behavior. The right temporoparietal junction, which is involved in perspective-taking and the dorsal striatum, part of the reward system, were also activated during the concern condition. These results suggest that humans can attenuate affective arousal by anticipating the positive outcome of empathic concern through perspective-taking. PMID- 26032191 TI - Glaucoma drainage devices: risk of exposure and infection. AB - PURPOSE: To identify risk factors for device exposure and intraocular infection following implantation of a glaucoma drainage device. DESIGN: Retrospective case series. METHODS: The medical records of adult patients undergoing glaucoma drainage device implantation at an academic medical center between 2000 and 2010 were reviewed. Main outcome measures included device exposure and intraocular infection. RESULTS: Seven hundred and sixty-three cases were identified. These included 702 primary implants (ie, the first drainage device implanted into an eye) and 61 sequential implants. Among 702 primary implants, there were 41 cases of exposure (5.8%). None of the potential risk factors were statistically significant. Implant location was found to be a marginally significant risk factor. The exposure rates for inferior and superior implants were 12.8% (5 of 39) and 5.4% (36 of 663), respectively (P = .056). The highest rate of exposure for primary implants occurred in the inferior-nasal quadrant (17.2%, 5 of 29). The rate of exposure for sequential devices was 13.1% (8 of 61), with the highest rate also found in the inferior-nasal quadrant (20%, 5 of 25). Of 49 total exposures, 8 were associated with intraocular infection (16.3%). Exposures over inferior implants were more likely to be associated with infection than exposures over superior implants (41.7% vs 8.1%; P = .0151). CONCLUSION: Implant location approached, but did not reach, statistical significance as a risk factor for exposure. Exposures over inferior implants place patients at a higher risk of infection than superior exposures. More studies are needed to identify modifiable risk factors for device exposure. PMID- 26032192 TI - Communicating the promise for ocular gene therapies: challenges and recommendations. AB - PURPOSE: To identify challenges and pose solutions for communications about ocular gene therapy between patients and clinicians as clinical research progresses. DESIGN: Literature review with recommendations. METHODS: Literature review of science communication best practices to inform recommendations for patient-clinician discussions about ocular gene therapy. RESULTS: Clinicians need to employ communications about ocular gene therapy that are both attentive to patient priorities and concerns and responsive to other sources of information, including overly positive news media and the Internet. Coverage often conflates research with therapy-clinical trials are experimental and are not risk free. If proven safe and efficacious, gene therapy may present a treatment but not a cure for patients who have already experienced vision loss. Clinicians can assist patients by providing realistic estimates for lengthy clinical development timelines and positioning current research within models of clinical translation. This enables patients to weigh future therapeutic options when making current disease management decisions. CONCLUSIONS: Ocular gene therapy clinical trials are raising hopes for treating a myriad of hereditary retinopathies, but most such therapies are many years in the future. Clinicians should be prepared to counter overly positive messaging, found in news media and on the Internet, with optimism tempered by evidence to support the ethical translation of gene therapy and other novel biotherapeutics. PMID- 26032193 TI - Graft failure and intraocular pressure control after keratoplasty in iridocorneal endothelial syndrome. AB - PURPOSE: To describe and compare graft survival and intraocular pressure (IOP) control after penetrating keratoplasty (PK) and Descemet stripping automated endothelial keratoplasty (DSAEK) in eyes with iridocorneal endothelial (ICE) syndrome. DESIGN: Retrospective case series. METHODS: Multicenter study conducted at the Singapore National Eye Centre (SNEC) and Price Vision Group. Twenty-nine consecutive eyes with ICE syndrome that underwent keratoplasty between 1991 and 2011 were identified from the SNEC transplant database and Price Vision Group patient database and the following data extracted: demographics, graft failure, IOP indices, and glaucoma treatment pre- and postkeratoplasty. The main outcome measures were graft failure and need for additional IOP-lowering treatment after keratoplasty. RESULTS: The mean follow-up duration was 7.0 +/- 4.9 years in the PK group (n = 17) and 4.0 +/- 2.6 years in the DSAEK group (n = 12). After a mean of 4.1 +/- 3.1 years, 37.9% of grafts (11/29) failed: 7 PK compared to 4 DSAEK (P = .72). The graft failure rate was 50% in eyes with prekeratoplasty glaucoma surgery vs 31.6% in those without (P = .43). Additional glaucoma treatment was required in 37.9% of eyes (11/29): 41.2% of PK eyes and 50% of DSAEK eyes (P = .28) Eyes that had undergone glaucoma surgery before keratoplasty were less likely to require escalation of IOP-lowering therapy postkeratoplasty (9.1% vs 50%, P = .03). CONCLUSIONS: One-third of grafts failed after keratoplasty for ICE syndrome at a mean duration of 4 years and additional IOP-lowering treatment was required in 37.9%. Both PK and DSAEK had similar outcomes with regard to graft failure and IOP control. PMID- 26032194 TI - Strengthening Indonesia's health workforce through partnerships. AB - OBJECTIVES: Indonesia faces critical challenges pertaining to human resources for health (HRH). These relate to HRH policy, planning, mismatch between production and demand, quality, renumeration, and mal-distribution. This paper provides a state of the art review of the existing conditions in Indonesia, innovations to tackle the problems, results of the innovations to date, and a picture of the on going challenges that have yet to be met. STUDY DESIGN/METHODS: Reversing this crisis level shortage of HRH requires an inclusive approach to address the underlying challenges. In 2010 the government initiated multi-stakeholder coordination for HRH, using the Country Coordination and Facilitation approach. The process requires committed engagement and coordination of relevant stakeholders to address priority health needs. This manuscript is a formative evaluation of the program using documentary study and analysis. RESULTS: Consistent with Indonesia's decentralized health system, since 2011 local governments also started establishing provincial multi-stakeholder committees and working groups for HRH development. Through this multi-stakeholder approach with high level government support and leadership, Indonesia was able to carry out HRH planning by engaging 164 stakeholders. Multi-stakeholder coordination has produced positive results in Indonesia by bringing about a number of innovations in HRH development to achieve UHC, fostered partnerships, attracted international attention, and galvanized multi-stakeholder support in improving the HRH situation. This approach also has facilitated mobilizing technical and financial support from domestic and international partners for HRH development. CONCLUSIONS: Applying the multi-stakeholder engagement and coordination process in Indonesia has proved instrumental in advancing the country's work to achieve Universal Health Coverage and the Millennium Development Goals by 2015. Indonesia continues to face an HRH crisis but the collaborative process provides an opportunity to achieve results. Indonesia's experience indicates that irrespective of geographical or economic status, countries can benefit from multi stakeholder coordination and engagement to increase access to health workers, strengthen health systems, as well as achieve and sustain UHC. PMID- 26032195 TI - Hunger measurement complexity: is the Global Hunger Index reliable? PMID- 26032196 TI - Association of usual self-reported dietary intake with ecological momentary measures of affective and physical feeling states in children. AB - BACKGROUND: Little is known about the relationship between dietary intake and affective and physical feeling states in children. PURPOSE: The current study used Ecological Momentary Assessment (EMA) to examine how usual dietary intake is cross-sectionally associated with both average affective and physical feeling state ratings and rating variability in children. METHODS: Children (N = 110, mean age = 11.0 +/- 1.2 years, 52.5% male, 30.1% Hispanic/Latino) completed EMA measures of affective and physical feeling states 3-7 times per day for a full or partial day (weekday evenings and weekend days and evenings) over a 4-day period. Usual intake of pre-selected dietary components was measured prior to the EMA measurement period using the Block Kids Food Screener. Statistical analyses included mixed models and mixed-effects location scale models. RESULTS: Greater usual fiber intake was cross-sectionally associated with higher average positive affect (PA) ratings, lower variability of NA ratings, and higher variability of physical fatigue ratings. Lower usual glycemic load of diet was cross-sectionally associated with lower variability of NA ratings. Lower usual added sugar intake was cross-sectionally associated with higher average physical energy ratings and lower variability of NA ratings. CONCLUSIONS: Although temporal precedence was not established by these findings, they indicate that characteristics of children's usual dietary intake are cross-sectionally associated with both the average and variability of affective and physical feeling states. EMA offers a promising avenue through which to explore the associations between affective states and diet and has the potential to provide insight into nuances of this relationship. PMID- 26032197 TI - Manipulations of attention during eating and their effects on later snack intake. AB - Manipulation of attention during eating has been reported to affect later consumption via changes in meal memory. The aim of the present studies was to examine the robustness of these effects and investigate moderating factors. Across three studies, attention to eating was manipulated via distraction (via a computer game or TV watching) or focusing of attention to eating, and effects on subsequent snack consumption and meal memory were assessed. The participants were predominantly lean, young women students and the designs were between-subjects. Distraction increased later snack intake and this effect was larger when participants were more motivated to engage with the distracter and were offset when the distractor included food-related cues. Attention to eating reduced later snacking and this effect was larger when participants imagined eating from their own perspective than when they imagined eating from a third person perspective. Meal memory was impaired after distraction but focusing on eating did not affect later meal memory, possibly explained by ceiling effects for the memory measure. The pattern of results suggests that attention manipulations during eating have robust effects on later eating and the effect sizes are medium to large. The data are consistent with previous reports and add to the literature by suggesting that type of attention manipulation is important in determining effects on later eating. The results further suggest that attentive eating may be a useful target in interventions to help with appetite control. PMID- 26032198 TI - Bongkrekic acid analogue, lacking one of the carboxylic groups of its parent compound, shows moderate but pH-insensitive inhibitory effects on the mitochondrial ADP/ATP carrier. AB - Bongkrekic acid, isolated from Burkholderia cocovenenans, is known to specifically inhibit the mitochondrial ADP/ATP carrier. However, the manner of its interaction with the carrier remains elusive. In this study, we tested the inhibitory effects of 17 bongkrekic acid analogues, derived from the intermediates obtained during its total synthesis, on the mitochondrial ATP/ATP carrier. Rough screening of these chemicals, performed by measuring their inhibitory effects on the mitochondrial ATP synthesis, revealed that 4 of them, KH-1, KH-7, KH-16, and KH-17, had moderate inhibitory effects. Further characterization of the actions of these 4 analogues on mitochondrial function showed that KH-16 had moderate; KH-1 and KH-17, weak; and KH-7, negligible side effects of both permeabilization of the mitochondrial inner membrane and inhibition of the electron transport, indicating that only KH-7 had a specific inhibitory effect on the mitochondrial ADP/ATP carrier. Although the parental bongkrekic acid showed a strong pH dependency of its action, the inhibitory effect of KH-7 was almost insensitive to the pH of the reaction medium, indicating the importance of the 3 carboxyl groups of bongkrekic acid for its pH dependent action. A direct inhibitory effect of KH-7 on the mitochondrial ADP/ATP carrier was also clearly demonstrated. PMID- 26032200 TI - The role of endoscopy in dyspepsia. PMID- 26032201 TI - A solvation-free-energy functional: a reference-modified density functional formulation. AB - The three-dimensional reference interaction site model (3D-RISM) theory, which is one of the most applicable integral equation theories for molecular liquids, overestimates the absolute values of solvation-free-energy (SFE) for large solute molecules in water. To improve the free-energy density functional for the SFE of solute molecules, we propose a reference-modified density functional theory (RMDFT) that is a general theoretical approach to construct the free-energy density functional systematically. In the RMDFT formulation, hard-sphere (HS) fluids are introduced as the reference system instead of an ideal polyatomic molecular gas, which has been regarded as the appropriate reference system of the interaction-site-model density functional theory for polyatomic molecular fluids. We show that using RMDFT with a reference HS system can significantly improve the absolute values of the SFE for a set of neutral amino acid side-chain analogues as well as for 504 small organic molecules. PMID- 26032199 TI - Interleukin-10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inflammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti inflammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inflammatory cytokine interleukin-10 (IL-10) is beneficial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10(-/-) mice). The IL-10(-/-) mice showed increased mortality, higher expression of pro inflammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10(-/-) mice showed significantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL-10 during S. pneumoniae infection modulates the expression of pro-inflammatory cytokines and the infiltration of neutrophils into the lungs. This feature of IL-10 is important to avoid excessive inflammation of tissues and to improve host survival, even though bacterial dissemination is less efficient in the absence of this cytokine. PMID- 26032202 TI - Levels and function of regulatory T cells in patients with polymorphic light eruption: relation to photohardening. AB - BACKGROUND: We hypothesized that regulatory T cells (Tregs) are involved in the immunological abnormalities seen in patients with polymorphic light eruption (PLE). OBJECTIVES: To investigate the number and suppressive function of peripheral Tregs in patients with PLE compared with healthy controls. METHODS: Blood sampling was done in 30 patients with PLE [seeking or not seeking 311-nm ultraviolet (UV)B photohardening] as well as 19 healthy controls at two time points: TP1, March to June (before phototherapy); and TP2, May to August (after phototherapy). We compared the number of CD4(+) CD25(high) CD127(-) FoxP3(+) Tregs by flow cytometry and their function by assessing FoxP3 mRNA levels and effector T cell/Treg suppression assays. RESULTS: Tregs isolated from healthy controls significantly suppressed the proliferation of effector T cells at TP1 by 68% (P = 0.0156). In contrast, Tregs from patients with PLE entirely lacked the capacity to suppress effector T-cell proliferation at that time point. The medical photohardening seen in 23 patients with PLE resulted in a significant increase in the median percentage of circulating Tregs [both as a proportion of all lymphocytes; 65 6% increase (P = 0.0049), and as a proportion of CD4(+) T cells; 32.5% increase (P = 0.0049)]. This was accompanied by an increase in the expression of FoxP3 mRNA (P = 0.0083) and relative immunosuppressive function of Tregs (P = 0.083) comparing the two time points in representative subsets of patients with healthy controls tested. Seven patients with PLE not receiving 311 nm UVB also exhibited an increase in the number of Tregs but this was not statistically significant. No significant differences in Treg numbers were observed in healthy subjects between the two time points. CONCLUSIONS: An impaired Treg function is likely to play a role in PLE pathogenesis. A UV-induced increase in the number of Tregs (either naturally or therapeutically) may be a compensatory mechanism by which the immune system counteracts the susceptibility to PLE. PMID- 26032203 TI - Acute bone response to whole body vibration in healthy pre-pubertal boys. AB - The skeleton responds to mechanical stimulation. We wished to ascertain the magnitude and speed of the growing skeleton's response to a standardised form of mechanical stimulation, vibration. 36 prepubertal boys stood for 10 minutes in total on one of two vibrating platforms (high (>2 g) or low (<1 g) magnitude vibration) on either 1, 3 or 5 successive days (n=12 for each duration); 15 control subjects stood on an inactive platform. Blood samples were taken at intervals before and after vibration to measure bone formation (P1NP, osteocalcin) and resorption (CTx) markers as well as osteoprotegerin and sclerostin. There were no significant differences between platform and control groups in bone turnover markers immediately after vibration on days 1, 3 and 5. Combining platform groups, at day 8 P1NP increased by 25.1% (CI 12.3 to 38.0; paired t-test p=0.005) and bone resorption increased by 10.9% (CI 3.6 to 18.2; paired t-test p=0.009) compared to baseline. Osteocalcin, osteoprotogerin and sclerostin did not change significantly. The growing skeleton can respond quickly to vibration of either high or low magnitude. Further work is needed to determine the utility of such "stimulation-testing" in clinical practice. PMID- 26032205 TI - The effects of whole body vibration on mobility and balance in children with cerebral palsy: a systematic review with meta-analysis. AB - OBJECTIVE: We performed a meta-analysis to evaluate the effects of whole-body vibration on physiologic and functional measurements in children with cerebral palsy. DESIGN AND METHODS: We searched MEDLINE, Cochrane Controlled Trials Register, EMBASE, Scielo, CINAHL (from the earliest date available to November 2014) for randomized controlled trials, that aimed to investigate the effects of whole-body vibration versus exercise and/or versus control on physiologic and functional measurements in children with cerebral palsy. Two reviewers independently selected the studies. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated. RESULTS: Six studies with 176 patients comparing whole-body vibration to exercise and/or control were included. Whole-body vibration resulted in improvement in: gait speed WMDs (0.13 95% CI: 0.05 to 0.20); gross motor function dimension E WMDs (2.97 95% CI: 0.07 to 5.86) and femur bone density (1.32 95% CI: 0.28 to 2.36). The meta-analysis also showed a nonsignificant difference in muscle strength and gross motor function dimension D for participants in the whole-body vibration compared with control group. No serious adverse events were reported. CONCLUSIONS: Whole-body vibration may improve gait speed and standing function in children with cerebral palsy and could be considered for inclusion in rehabilitation programs. PMID- 26032206 TI - The impact of vitamin D3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial. AB - OBJECTIVES: We tested the hypothesis that daily vitD3 supplementation increases neuromuscular motor skills, jump power, jump energy, muscular force, and muscular strength. METHODS: This was a secondary analysis of a randomized controlled trial of 12-months of oral 7,000 IU/day vitD3 supplementation or placebo among 56 persons living with HIV aged 9-25 years. Neuromuscular motor skills were quantified using the Bruininks-Oseretsky Test of Motor Proficiency. Power was quantified using peak jump power, and energy was quantified using peak jump height. Muscular force was quantified using isometric ankle plantar- and dorsiflexion, isokinetic knee flexion and extension. Muscular strength was quantified using isometric handgrip strength. RESULTS: After 12-months, serum 25 hydroxyvitamin D [25(OH)D] was higher with supplementation versus placebo (beta=12.1 ng/mL; P<0.001). In intention-to-treat analyses, supplementation improved neuromuscular motor skills versus placebo (beta=1.14; P=0.041). We observed no effect of supplementation on jump power, jump energy, muscular force, or muscular strength outcomes versus placebo. CONCLUSIONS: Among HIV-infected children and young adults supplementation with daily high-dose vitD3 increased concentration of serum 25(OH)D and improved neuromuscular motor skills versus placebo. PMID- 26032207 TI - Gastrocnemius medialis muscle architecture and physiological cross sectional area in adult males with Duchenne muscular dystrophy. AB - OBJECTIVES: To describe muscle size and architecture of the gastrocnemius medialis (GM) muscle in eleven adult males with Duchenne Muscular Dystrophy (DMD, age 24.5+/-5.4 years), and a control group of eleven males without DMD (CTRL, age 22.1+/-0.9 years). METHODS: GM anatomical cross sectional area (ACSA), volume (VOL), physiological cross sectional area (PCSA), fascicle length (Lf) and pennation angle (theta) were assessed using B-Mode Ultrasonography. GM ACSA was measured at 25, 50 and 75% of muscle length (Lm), from which VOL was calculated. At 50% of Lm, sagittal plane images were analysed to determine GM Lf and theta. GM PCSA was calculated as: VOL/Lf. The ratio of Lf and Lm was also calculated. RESULTS: GM ACSA at 50% Lm, VOL and PCSA were smaller in DMD males compared to CTRL males by 36, 47 and 43%, respectively (P<0.01). There were no differences in Lf and theta. GM Lm was 29% shorter in DMD compared to CTRL. Lf/Lm was 29% longer in DMD (P<0.01). CONCLUSIONS: Unlike previous data in children with DMD, our results show significant atrophy in adult males with DMD, and no change in Lf or theta. The shorter Lm may have implications for joint flexibility. PMID- 26032204 TI - Reactions of the rat musculoskeletal system to compressive spinal cord injury (SCI) and whole body vibration (WBV) therapy. AB - Traumatic spinal cord injury (SCI) causes a loss of locomotor function with associated compromise of the musculo-skeletal system. Whole body vibration (WBV) is a potential therapy following SCI, but little is known about its effects on the musculo-skeletal system. Here, we examined locomotor recovery and the musculo skeletal system after thoracic (T7-9) compression SCI in adult rats. Daily WBV was started at 1, 7, 14 and 28 days after injury (WBV1-WBV28 respectively) and continued over a 12-week post-injury period. Intact rats, rats with SCI but no WBV (sham-treated) and a group that received passive flexion and extension (PFE) of their hind limbs served as controls. Compared to sham-treated rats, neither WBV nor PFE improved motor function. Only WBV14 and PFE improved body support. In line with earlier studies we failed to detect signs of soleus muscle atrophy (weight, cross sectional diameter, total amount of fibers, mean fiber diameter) or bone loss in the femur (length, weight, bone mineral density). One possible explanation is that, despite of injury extent, the preservation of some axons in the white matter, in combination with quadripedal locomotion, may provide sufficient trophic and neuronal support for the musculoskeletal system. PMID- 26032208 TI - Skeletal muscle and motor deficits in Neurofibromatosis Type 1. AB - Neurofibromatosis Type 1 (NF1) is a genetic neurocutaneous disorder with multisystem manifestations, including a predisposition to tumor formation and bone dysplasias. Studies over the last decade have shown that NF1 can also be associated with significant motor deficits, such as poor coordination, low muscle tone, and easy fatigability. These have traditionally been ascribed to developmental central nervous system and cognitive deficits. However, recent preclinical studies have also illustrated a primary role for the NF1 gene product in muscle growth and metabolism; these findings are consistent with clinical studies demonstrating reduced muscle size and muscle weakness in individuals with NF1. Currently there is no evidence-based intervention for NF1 muscle and motor deficiencies; this review identifies key research areas where improved mechanistic understanding could unlock new therapeutic options. PMID- 26032209 TI - Physical activity in youth with osteogenesis imperfecta type I. AB - INTRODUCTION: Individuals with Osteogenesis Imperfecta (OI) type I often show muscular weakness. However, it is unclear whether muscular weakness is a consequence of physical inactivity or a result of the disease itself. The aim was to assess muscle function in youth with OI type I and evaluate physical activity (PA). METHODS: Fourteen children with OI type I (mean age [SD]: 12.75 [4.62] years) were compared to 14 age- and gender-matched controls (mean age [SD]: 12.75 [4.59] years). Muscle force and power were determined through mechanography. PA and daily energy expenditure were measured with an accelerometer and a questionnaire. RESULTS: Compared to controls, children with OI type I had lower muscle force and power. OI type I children were as active as their healthy counterparts. CONCLUSIONS: Children and adolescents with OI type I and their healthy counterparts did not reached daily recommendations of PA. Given their muscle function deficit, youth with OI type I would benefit to reach these recommendations to prevent precocious effect of aging on muscles. PMID- 26032210 TI - The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men. AB - OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and 2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75 110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men. PMID- 26032211 TI - Analgesic effect of nasal salmon calcitonin during the early post-fracture period of the distal radius fracture. AB - OBJECTIVES: To investigate the analgesic effect of nasal salmon calcitonin on the post-fracture period of distal radius fracture. METHODS: In this prospective randomized double-blind study, forty-one postmenopausal women with a recent distal radius fracture treated conservatively were randomly assigned to receive either 200 IU of intranasal salmon calcitonin or placebo daily for 3 months following fracture. The assessment of the patient's pain was recorded using the Visual Analogue Scale (VAS). RESULTS: The average age of the calcitonin group was 67.11 (SD, +/-8.68) years and 64.91 (SD, +/-7.48) of the placebo group. In the calcitonin group, the mean VAS score improved from 4.05 to 0.53 while in the placebo group from 3.36 to 0.32. A higher decrease of VAS score during the first post-fracture period was observed in the calcitonin group. CONCLUSIONS: In the study, there is a statistically significant calcitonin mediated analgesic effect in the immediate post fracture period (at 10 days) when compared to placebo group. These results are in accordance with literature referring to the analgesic effect of calcitonin in the acute osteoporotic vertebral compression fracture. Thus calcitonin administration could be recommended to a short term course in acute osteoporotic conservatively treated distal radius fractures. PMID- 26032213 TI - Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy. AB - OBJECTIVES: The plantaris tendon is increasingly recognised as an important factor in midportion Achilles tendinopathy. Its innervation pattern is completely unknown. METHODS: Plantaris tendons (n=56) and associated peritendinous tissue from 46 patients with midportion Achilles tendinopathy and where the plantaris tendon was closely related to the Achilles tendon were evaluated. Morphological evaluations and stainings for nerve markers [general (PGP9.5), sensory (CGRP), sympathetic (TH)], glutamate NMDA receptor and Schwann cells (S-100beta) were made. RESULTS: A marked innervation, as evidenced by evaluation for PGP9.5 reactions, occurred in the peritendinous tissue located between the plantaris and Achilles tendons. It contained sensory and to some extent sympathetic and NMDAR1 positive axons. There was also an innervation in the zones of connective tissue within the plantaris tendons. Interestingly, some of the nerve fascicles showed a partial lack of axonal reactions. CONCLUSION: New information on the innervation patterns for the plantaris tendon in situations with midportion Achilles tendinopathy has here been obtained. The peritendinous tissue was found to be markedly innervated and there was also innervation within the plantaris tendon. Furthermore, axonal degeneration is likely to occur. Both features should be further taken into account when considering the relationship between the nervous system and tendinopathy. PMID- 26032212 TI - Least significant changes and monitoring time intervals for high-resolution pQCT derived bone outcomes in postmenopausal women. AB - BACKGROUND: Least Significant Change (LSC) assists in determining whether observed bone change is beyond measurement precision. Monitoring Time Interval (MTI) estimates time required to reliably detect skeletal changes. MTIs have not been defined for bone outcomes provided by high resolution peripheral quantitative computed tomography (HR-pQCT). The purpose of this study was to determine the LSCs and MTIs for HR-pQCT derived bone area, density and micro architecture with postmenopausal women. METHODS: Distal radius and tibia of 33 postmenopausal women (mean age: 77, SD: +/-7 years), from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos), were measured using HR-pQCT at baseline and 1-year later. We determined LSC from precision errors and divided them by the median annual percent changes to define MTIs for bone area, density, and micro-architecture. RESULTS: Distal radius: HR-pQCT LSCs indicated a 1-8% observed change was needed for reliable monitoring of bone area and density while a 3-18% change was needed for micro-architectural measures. The longest MTIs (>3 years) pertained to cortical and trabecular area and density measures, cortical thickness and bone volume fraction; the shortest MTIs (~2 years) pertained to bone micro-architectural measures (trabecular number, thickness, separation and heterogeneity). Distal tibia: LSCs indicated a <1-5% observed change was needed for reliable monitoring of bone area and density, while a 3-19% change was needed for micro-architectural measures. The longest MTIs (>3 years) pertained to trabecular density, bone volume fraction, number, separation and heterogeneity; the shortest MTIs (~1 year) pertained to cortical and trabecular area, cortical density and thickness. CONCLUSION: MTIs suggest that performing HR-pQCT follow-up measures in postmenopausal women every 2 years at the distal radius and every 1 year at the distal tibia to monitor true skeletal changes as indicated by the LSCs. PMID- 26032214 TI - Effect of daily short-duration weight-bearing on disuse-induced deterioration of musculoskeletal system. AB - OBJECTIVES: To investigate deterioration of musculoskeletal system due to prolonged disuse and the potential of daily short-duration weight-bearing as countermeasures. METHODS: Twenty-four adult male Sprague-Dawley rats were divided into Control Group (CG, no intervention), Tail-suspension Group (TG, tail suspension without treatment), and Weight-Bearing Group (WBG, tail-suspension with 20 min/day, 5 days/week body weight loading). After four weeks of treatment, femur and tibia, soleus and extensor digitorum longus were evaluated for bone and muscle quality respectively. Tensile properties of bone-tendon insertion (BTI) were evaluated using patella-patellar tendon complex. RESULTS: Disuse induced deterioration on bone, muscle, and BTI after four weeks. Compared with CG, TG and WBG showed significant decrease in bone mineral density (BMD) of trabecular bone in distal femur (4.3-15.2%), muscle mass (31.3-52.3%), muscle cross-sectional area (29.1-35%), and failure strength of BTI (23.9-29.4%). Tensile test showed that the failure mode was avulsion of bone at the BTI. No significant difference was detected between TG and WBG for all assessments on bone, muscle, and BTI. CONCLUSIONS: Disuse caused deterioration of bone, muscle, and BTI while daily short-duration of weight-bearing did not prevent this deterioration. Mechanical stimulation with higher intensity and longer duration may be necessary to prevent musculoskeletal deterioration resulted from prolonged disuse. PMID- 26032215 TI - Form follows function: a computational simulation exercise on bone shape forming and conservation. AB - The present paper explores whether the shape of long bone shafts can be explained as a mere result of mechano-adapation. A computer simulation study was conducted in order to investigate adaptation processes of bone-like structures under load patterns comparable to those acting on the diaphysis of long bones. The aim of the study was to have a deeper look into the relationship between typical loading patterns and resulting bone shape and structure. The simulations are based on a mechanistic model approach for mechano-transduction and bone transformation. Results of the simulations are that axial torsion around the long axis is important for the evolvement and maintenance of tube-like structures. Of note such structures can form from a variety of starting geometries, provided that axial torsion is present. The selection of the set-point parameter for the regulation of load adapted bone transformation has an impact on the final structure as well. In conclusion, the present study confirms the mechanical environment's potential to generate shaft-like structures and demonstrates the respective boundary conditions. PMID- 26032217 TI - Persistent knee effusion in a young female. PMID- 26032216 TI - Electrically induced muscle cramps induce hypertrophy of calf muscles in healthy adults. AB - OBJECTIVES: Skeletal muscles usually cramp at short lengths, where the tension that can be exerted by muscle fibers is low. Since high tension is an important anabolic stimulus, it is questionable if cramps can induce hypertrophy and strength gains. In the present study we investigated if electrically induced cramps (EIMCs) can elicit these adaptations. METHODS: 15 healthy male adults were randomly assigned to an intervention (IG; n=10) and a control group (CG; n=5). The cramp protocol (CP) applied twice a week to one leg of the IG, consisted of 3x6 EIMCs, of 5 s each. Calf muscles of the opposite leg were stimulated equally, but were hindered from cramping by fixating the ankle at 0 degrees plantar flexion (nCP). RESULTS: After six weeks, the cross sectional area of the triceps surae was similarly increased in both the CP (+9.0+/-3.4%) and the nCP (+6.8+/ 3.7%). By contrast, force of maximal voluntary contractions, measured at 0 degrees and 30 degrees plantar flexion, increased significantly only in nCP (0 degrees : +8.5+/-8.8%; 30 degrees : 11.7+/-13.7%). CONCLUSION: The present data indicate that muscle cramps can induce hypertrophy in calf muscles, though lacking high tension as an important anabolic stimulus. PMID- 26032218 TI - A protocol to reduce police wait times in the emergency department. AB - Healthcare organizations are increasingly tasked with implementing change initiatives that improve the patient experience and target priorities such as Emergency Department (ED) volumes. This article describes the development, implementation, and outcomes of a collaborative protocol between the Niagara Health System and the Niagara Regional Police Service that resulted in a 57% reduction in police wait times in the ED. Six critical success factors contributed to the outcomes that were achieved and are detailed for those organizations interested in engaging in a similar change initiative. PMID- 26032219 TI - ALC status in in-patient mental health settings: Evidence based on the Ontario Mental Health Reporting System. AB - This article examines the characteristics associated with Alternate Level of Care (ALC) status in mental health in-patient units across Ontario. Using assessment information from the Resident Assessment Instrument-Mental Health, the prevalence of ALC episodes, resource utilization associated with ALC, and demographic and diagnostic characteristics of ALC patients are examined. The effective management of ALC patients should be an important priority for all stakeholders involved in mental health services delivery in Canada. PMID- 26032220 TI - A longitudinal examination of rural status and suicide risk. AB - There is limited research on suicide risk in Canadian home care. Older adults have the highest rates of death by suicide worldwide. This article examines characteristics of rural and urban home care recipients with a hospital or emergency department visit for suicide attempts in Ontario, Canada. Factors that increase or decrease risk for emergent care are identified. This research builds on a growing need for health leadership to ensure that home care providers have appropriate training and resources to assess and respond to potential risk of suicide among frail elders. PMID- 26032221 TI - Changes in the proteome of pad2-1, a glutathione depleted Arabidopsis mutant, during Pseudomonas syringae infection. AB - The involvement of glutathione (GSH) in plant defense against pathogen invasion is an established fact. However, the molecular mechanism conferring this tolerance remains to be explored. Here, proteomic analysis of pad2-1, an Arabidopsis thaliana GSH-depleted mutant, in response to Pseudomonas syringae infection has been performed to explore the intricate position of GSH in defense against biotrophic pathogens. The pad2-1 mutant displayed severe susceptibility to P. syringae infection compared to the wild-type (Col-0) thus re-establishing a fundamental role of GSH in defense. Apart from general up-accumulation of energy metabolism-related protein-species in both infected Col-0 and pad2-1, several crucial defense-related protein-species were identified to be differentially accumulated. Leucine-rich repeat-receptor kinase (LRR-RK) and nucleotide-binding site-leucine-rich repeat resistance protein (NBS-LRR), known to play a pioneering role against pathogen attack, were only weakly up-accumulated in pad2-1 after infection. Transcriptional and post-transcriptional regulators like MYB-P1 and glycine-rich repeat RNA-binding protein (GRP) and several other stress-related protein-species like heat shock protein 17 (HSP17) and glutathione-S-transferase (GST) were also identified to be differentially regulated in pad2-1 and Col-0 in response to infection. Together, the present investigation reveals that the optimum GSH-level is essential for the efficient activation of plant defense signaling cascades thus conferring resistance to pathogen invasion. PMID- 26032222 TI - High-throughput quantification of chloroplast RNA editing extent using multiplex RT-PCR mass spectrometry. AB - RNA editing in plants, animals, and humans modifies genomically encoded cytidine or adenosine nucleotides to uridine or inosine, respectively, in mRNAs. We customized the MassARRAY System (Sequenom Inc., San Diego, CA, USA, www.sequenom.com) to assay multiplex PCR-amplified single-stranded cDNAs and easily analyse and display the captured data. By using appropriate oligonucleotide probes, the method can be tailored to any organism and gene where RNA editing occurs. Editing extent of up to 40 different nucleotides in each of either 94 or 382 different samples (3760 or 15 280 editing targets, respectively) can be examined by assaying a single plate and by performing one repetition. We have established this mass spectrometric method as a dependable, cost-effective and time-saving technique to examine the RNA editing efficiency at 37 Arabidopsis thaliana chloroplast editing sites at a high level of multiplexing. The high throughput editing assay, named Multiplex RT-PCR Mass Spectrometry (MRMS), is ideal for large-scale experiments such as identifying population variation, examining tissue-specific changes in editing extent, or screening a mutant or transgenic collection. Moreover, the required amount of starting material is so low that RNA from fewer than 50 cells can be examined without amplification. We demonstrate the use of the method to identify natural variation in editing extent of chloroplast C targets in a collection of Arabidopsis accessions. PMID- 26032223 TI - Validation of the Automatic Thoughts Questionnaire (ATQ) Among Mainland Chinese Students in Hong Kong. AB - OBJECTIVE: The present study validated the combined version of the 8-item Automatic Thought Questionnaire (ATQ) and 10 positive items from the ATQ-revised among Chinese university students. METHOD: A total of 412 Mainland Chinese university students were recruited in Hong Kong by an online survey. RESULTS: A 14-item Chinese ATQ was derived via item analysis. Satisfactory internal consistency reliability and good split-half reliability were obtained. Exploratory and confirmatory factor analysis revealed a 3-correlated-factor solution for the Chinese ATQ: negative thought, positive thought (emotional), and positive thought (cognitive). The negative ATQ subscale score was positively correlated with negative affect, and negatively correlated with positive affect and life satisfaction. The two positive ATQ subscale scores were negatively correlated with negative affect, and positively correlated with positive affect and life satisfaction. CONCLUSION: The 14-item ATQ is a valid and reliable instrument for measuring automatic thoughts in the Chinese context of Hong Kong. PMID- 26032224 TI - Preliminary Data from the Caring for Older Adults and Caregivers at Home (COACH) Program: A Care Coordination Program for Home-Based Dementia Care and Caregiver Support in a Veterans Affairs Medical Center. AB - Caring for Older Adults and Caregivers at Home (COACH) is an innovative care coordination program of the Durham Veteran's Affairs Medical Center in Durham, North Carolina, that provides home-based dementia care and caregiver support for individuals with dementia and their family caregivers, including attention to behavioral symptoms, functional impairment, and home safety, on a consultation basis. The objectives of this study were to describe the COACH program in its first 2 years of operation, assess alignment of program components with quality measures, report characteristics of program participants, and compare rates of placement outside the home with those of a nontreatment comparison group using a retrospective cohort design. Participants were community-dwelling individuals with dementia aged 65 and older who received primary care in the medical center's outpatient clinics and their family caregivers, who were enrolled as dyads (n = 133), and a control group of dyads who were referred to the program and met clinical eligibility criteria but did not enroll (n = 29). Measures included alignment with Dementia Management Quality Measures and time to placement outside the home during 12 months of follow-up after referral to COACH. Results of the evaluation demonstrated that COACH aligns with nine of 10 clinical process measures identified using quality measures and that COACH delivers several other valuable services to enhance care. Mean time to placement outside the home was 29.6 +/- 14.3 weeks for both groups (P = .99). The present study demonstrates the successful implementation of a home-based care coordination intervention for persons with dementia and their family caregivers that is strongly aligned with quality measures. PMID- 26032225 TI - An inhibitory influence of transposed-letter neighbors on eye movements during reading. AB - Previous research has shown that prior exposure to a word's substitution neighbor earlier in the same sentence can disrupt processing of that word, indicating that interword lexical priming occurs naturally during reading, due to the competition between lexical candidates during word identification. Through the present research, we extended these findings by investigating the effects of prior exposure to a word's transposed-letter neighbor (TLN) earlier in a sentence. TLNs are constituted from the same letters, but in different orders. The findings revealed an inhibitory TLN effect, with longer total reading times for target words, and increased regressions to prime and target words, when the target followed a TLN rather than a control word. These findings indicate that prior exposure to a TLN can disrupt word identification during reading. We suggest that this is caused by a failure of word identification, due to the initial misidentification of the target word (potentially as its TLN) triggering postlexical checking. PMID- 26032226 TI - Examining reference frame interaction in spatial memory using a distribution analysis. AB - Previous research showed competition among reference frames in spatial attention and language. The present studies developed a new distribution analysis to examine reference frame interactions in spatial memory. Participants viewed virtual arrays of colored pegs and were instructed to remember them either from their own perspective or from the perspective aligned with the rectangular floor. Then they made judgments of relative directions from their respective encoding orientation. Those taking the floor-axis perspective showed systematic bias in the signed errors toward their egocentric perspective, while those taking their own perspective showed no systematic bias, both for random and symmetrical object arrays. The bias toward the egocentric perspective was observed when learning a real symmetric regular object array with strong environmental cues for the aligned axis. These results indicate automatic processing of the self reference while taking the floor-axis perspective but not vice versa, and suggest that research on spatial memory needs to consider the implications of competition effects in reference frame use. PMID- 26032227 TI - Subarachnoid haemorrhage mimicking transient ST-segment elevation myocardial infarction. AB - Patients often present to the emergency department with loss of consciousness. The differential diagnosis of such condition may be difficult because of limited clinical information. The authors present a case of subarachnoid haemorrhage (SAH) with initial electrocardiographic (ECG) finding mimicking ST-segment elevation myocardial infarction (STEMI), which was confirmed to resolve in a follow-up study. Accurate and timely diagnosis of SAH-related ST-segment elevation was important, as the therapeutic strategy for SAH is completely different from that for STEMI. If the clinicians do not have other tools for diagnosis, the follow-up ECG may help us make a most possible diagnosis. PMID- 26032229 TI - Policy Options to Promote Smokefree Environments for Children and Adolescents. AB - Secondhand smoke (SHS) exposure among children is associated with a wide variety of adverse health risks, including: asthma, otitis media, respiratory infections, impaired lung growth and function, decreased exercise tolerance, cognitive impairments, behavior problems, and sudden infant death syndrome. Unfortunately, over 40% of children aged 3-11 years-15.1 million children-are currently exposed to SHS, with nearly 70% of black children in this age group being exposed. Over the past three decades, great strides have been made in establishing smokefree environments for adults, ultimately reducing their SHS exposure. Regulations have been passed at the organizational, local, and state levels that increasingly ban smoking in the workplace and public places. Children's SHS exposure patterns, however, differ from adults' exposures, with greater time spent in the home and other potentially unregulated venues (school, child care, and car). This means that children have been afforded relatively less protection from SHS by these smokefree regulations. It is imperative, therefore, to seek alternative options for promoting smokefree environments for children throughout the United States. This article explores policy options that promote smokefree environments for children and adolescents: comprehensive smokefree/tobacco-free policies covering indoor/outdoor public places, housing, private vehicles, and child care, as well as Clinical Guidelines regarding patient/family interviews on smoking, SHS, cessation, and voluntary smokefree efforts. The policy section highlights the role of child and adolescent health practitioners in promoting these policies with the hope of fostering engagement of these key stakeholders in the policy process. Note, there are a wide range of important policy and regulatory strategies aimed at reducing tobacco initiation and use among children, adolescents, and young adults; while essential in tobacco prevention and control efforts, a discussion of these strategies is beyond the scope of this article. PMID- 26032230 TI - Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland. AB - Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies. PMID- 26032231 TI - US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. AB - INTRODUCTION: The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs. AIM: Formulate evidence-based guidelines for optimizing immune tolerance induction (ITI) in patients with hemophilia A and inhibitors. METHODS: Results from the International ITI study and other available evidence were used to develop guidelines for ITI. RESULTS: Predictors of ITI success were identified and recommendations made for ITI with regard to candidates, timing, product, regimen, monitoring, defining success, concurrent immunomodulation, duration of treatment, and bleed management before and during ITI. CONCLUSION: Evidence-based recommendations to guide treatment decisions may increase the likelihood of successful inhibitor eradication and the induction of FVIII tolerance in patients with hemophilia A who develop inhibitory antibodies. PMID- 26032232 TI - Predicted Distribution of Visceral Leishmaniasis Vectors (Diptera: Psychodidae; Phlebotominae) in Iran: A Niche Model Study. AB - Visceral leishmaniasis (VL) is an important vector-borne disease in Iran. Till now, Leishmania infantum has been detected from five species of sand flies in the country including Phlebotomus kandelakii, Phlebotomus major s.l., Phlebotomus perfiliewi, Phlebotomus alexandri and Phlebotomus tobbi. Also, Phlebotomus keshishiani was found to be infected with Leishmania parasites. This study aimed at predicting the probable niches and distribution of vectors of visceral leishmaniasis in Iran. Data on spatial distribution studies of sand flies were obtained from Iranian database on sand flies. Sample points were included in data from faunistic studies on sand flies conducted during 1995-2013. MaxEnt software was used to predict the appropriate ecological niches for given species, using climatic and topographical data. Distribution maps were prepared and classified in ArcGIS to find main ecological niches of the vectors and hot spots for VL transmission in Iran. Phlebotomus kandelakii, Ph. major s.l. and Ph. alexandri seem to have played a more important role in VL transmission in Iran, so this study focuses on them. Representations of MaxEnt model for probability of distribution of the studied sand flies showed high contribution of climatological and topographical variables to predict the potential distribution of three vector species. Isothermality was found to be an environmental variable with the highest gain when used in isolation for Ph. kandelakii and Ph. major s.l., while for Ph. alexandri, the most effective variable was precipitation of the coldest quarter. The results of this study present the first prediction on distribution of sand fly vectors of VL in Iran. The predicted distributions were matched with the disease-endemic areas in the country, while it was found that there were some unaffected areas with the potential transmission. More comprehensive studies are recommended on the ecology and vector competence of VL vectors in the country. PMID- 26032233 TI - Optimum methodology for estimating baseline serum creatinine for the acute kidney injury classification. AB - AIM: This study aimed to investigate how varied methods of determining baseline serum creatinine (SCr) would affect acute kidney injury (AKI) diagnosis and prediction of 60 day mortality in critically ill patients following an episode of AKI. METHODS: This is a single-centre retrospective study conducted at a tertiary referral hospital. All adult intensive care unit (ICU) patients between January and December 2011, who had at least one SCr values measured between 7 days and 180 days before hospital admission and during ICU stay, were analyzed. The baseline SCr was calculated using either the most recent (SCrmost recent ) or the minimum (SCrmin ) value of SCr measurement over the specified assessment period before hospital admission. AKI was defined based on KDIGO SCr definition. The primary outcome was 60 day mortality after ICU admission. RESULTS: A total of 4020 patients were included in the analysis. AKI was detected in 1204 (30.0%) using the SCrmin and 945 (23.5%) using the SCrmost recent (P < 0.001). Compared with patients without AKI regardless of baseline SCr methodology, the 60 day mortality risk of patients who developed AKI using the SCrmin and SCrmost recent was significantly increased (odds ratio (OR) = 3.74; 95% confidence interval (CI) 2.98-4.70). Similarly, the risk of 60 day mortality in patients who met AKI criteria using the SCrmin but not the SCrmost recent was significant higher than in patients without AKI (OR = 2.04; 95% CI 1.36-3.00). CONCLUSION: Using the minimum value of preadmission SCr as a baseline kidney function not only can detect more AKI cases, but also provides the better predictive ability for 60 day mortality. PMID- 26032234 TI - A new look for the journal. PMID- 26032235 TI - The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV 3. AB - BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/DeltaG 42% andDeltaG/DeltaG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/DeltaG vs. DeltaG/DeltaG, P = 0.09; HCV 1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype. PMID- 26032236 TI - Analysis of the structural quality of the CASD-NMR 2013 entries. AB - We performed a comprehensive structure validation of both automated and manually generated structures of the 10 targets of the CASD-NMR-2013 effort. We established that automated structure determination protocols are capable of reliably producing structures of comparable accuracy and quality to those generated by a skilled researcher, at least for small, single domain proteins such as the ten targets tested. The most robust results appear to be obtained when NOESY peak lists are used either as the primary input data or to augment chemical shift data without the need to manually filter such lists. A detailed analysis of the long-range NOE restraints generated by the different programs from the same data showed a surprisingly low degree of overlap. Additionally, we found that there was no significant correlation between the extent of the NOE restraint overlap and the accuracy of the structure. This result was surprising given the importance of NOE data in producing good quality structures. We suggest that this could be explained by the information redundancy present in NOEs between atoms contained within a fixed covalent network. PMID- 26032237 TI - Effect of sedation on fore- and hindlimb lameness evaluation using body-mounted inertial sensors. AB - REASONS FOR PERFORMING STUDY: Diagnostic analgesia is an integral part of equine lameness examinations, but is challenging to perform in uncooperative horses. Using sedation to facilitate this might, because of analgesic and ataxia-inducing effects, interfere with lameness evaluation. OBJECTIVES: To evaluate whether sedation with low-dose xylazine would alter lameness amplitude as measured by body-mounted inertial sensors. STUDY DESIGN: Controlled experiment. METHODS: Forty-four horses were randomly split into 2 groups. Lameness was measured using body-mounted inertial sensors before and after injection of xylazine (0.3 mg/kg bwt) or saline. Sedation was measured at 5, 20 and 60 min following treatment, and lameness evaluations were performed before (Time 0) and at 20 and 60 min after treatment. Forelimb lameness was determined by measuring the vector sum of mean head height maximum and minimum differences between all right and left forelimb strides (n>25) collected with the horse trotting in a straight line. Hindlimb lameness amplitude was determined by measuring mean pelvic height maximum and minimum differences between right and left hindlimb strides. Numbers of horses staying the same, improving or worsening were compared between groups at each time interval. RESULTS: There were no significant differences in head or pelvic movement asymmetry between xylazine and saline treatment groups. However, a few horses with forelimb lameness in the xylazine treatment group showed a large decrease in head movement asymmetry (decrease in forelimb lameness) at 60 min following sedation. CONCLUSIONS: Low-dose sedation with xylazine may be used without the concern of potential lameness-masking effects for hindlimb lameness evaluation, but caution should be used in some horses with forelimb lameness of mild severity. The Summary is available in German - see Supporting information. PMID- 26032238 TI - Deliberate self-harm (and attempted suicide). AB - INTRODUCTION: The lifetime prevalence of deliberate self-harm is about 3% to 5% of the population in Europe and the US, and has been increasing. Familial, biological, and psychosocial factors may contribute. Risks are higher in women and young adults, people who are socially isolated or deprived, and people with psychiatric or personality disorders. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of non-pharmacological treatments for deliberate self-harm in adolescents and adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: Twenty-two studies were included. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: cognitive therapy; continuity of care; dialectical behavioural therapy; emergency card; hospital admission; intensive outpatient follow-up plus outreach; nurse-led case management; problem-solving therapy; psychodynamic interpersonal therapy; and telephone contact. PMID- 26032239 TI - Pharmacokinetic drug-drug interaction assessment of peptibody trebananib in combination with chemotherapies. AB - PURPOSE: To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types. METHODS: PK data of trebananib and chemotherapies (paclitaxel, carboplatin, pegylated liposomal doxorubicin, topotecan, capecitabine, lapatinib, 5-FU, irinotecan, or docetaxel) were collected from trials of ovarian cancer, metastatic breast cancer, colorectal carcinoma, and mixed solid tumor. A dedicated PK DDI study of trebananib and paclitaxel in patients with mixed solid tumors was also conducted. The geometric least squares mean (GLSM) ratios and corresponding 90 % confidence intervals (CI) of C max and AUC were estimated for DDI evaluations. RESULTS: In the PK DDI study of trebananib and paclitaxel, the GLSM ratio (90 % CI) was 1.17 (1.10-1.25) for paclitaxel AUC and 1.30 (1.15-1.48) for paclitaxel C max. The GLSM ratio (90 % CI) for the effect of paclitaxel on trebananib PK was 0.92 (0.87-0.97) for trebananib AUC and 0.98 (0.92-1.05) for trebananib C max. In the remaining studies, the GLSM ratios (90 % CI) of C max and AUC generally ranged from 0.8 to 1.25 or exhibited less than twofold PK variabilities across chemotherapeutic agents. No dose-dependent DDIs were evident. CONCLUSIONS: No PK DDI was deemed clinically meaningful between trebananib and the tested chemotherapeutic agents to warrant dose adjustments. PMID- 26032241 TI - Respiratory Sinus Arrhythmia and its Association with Pain in Women with Fibromyalgia Syndrome. AB - OBJECTIVES: To assess the cardiac autonomic control at rest and during the deep breathing test (DBT) and its association with pain in women with fibromyalgia syndrome (FMS). METHODS: The study included 20 women with FMS and 20 healthy women (control group, CG). The pain was quantified by assessing the pressure pain threshold (PPT), VAS of pain, and the pain component of the SF-36 questionnaire. The RR intervals were recorded in the supine position and during the DBT. The heart rate variability (VHR) was measured by methods in the time and frequency domain. RESULTS: The group with FMS had abnormal cardiac autonomic modulation at rest and during DBT, compared to CG (P < 0.05). Positive correlations were found between PPT and the E/I ratio (r = 0.70), DeltaFC (r = 0.66) and power spectrum density (DEP, r = 0.56) indices of DBT, as well as between pain component of the SF-36 and the E/I ratio (r = 0.49), DeltaFC (r = 0.45) and DEP (r = 0.50) indices of DBT. Significant correlations were observed between the FIQ questionnaire and the LF/HF ratio index in the supine position and the E/I ratio (r = -0.63), DeltaFC (r = -0.54), and DEP (r = -0.51) indices of DBT. CONCLUSIONS: The results of VHR indices during the supine position and the DBT women with FMS suggest impairment of neurocardiac integrity associated with pain and the impact of FMS on the quality of life. PMID- 26032240 TI - Dermal expression of laminin-332 and type IV collagen in humans with severe sepsis. AB - BACKGROUND: An intact basement membrane at the dermal-epidermal junction is essential to the viability of the skin. The effect of sepsis on the basement membrane is unknown. METHODS: Skin biopsies were used to study basement membrane structure in severe sepsis (Day 1). Subsequent biopsies were taken on Day 8 and at 3 months in the survivors. Immunohistochemical staining was undertaken using laminin-223 and type IV collagen. Twenty patients with severe sepsis and four control subjects were included in the analysis. RESULTS: Intensive care unit mortality was 4/20, and total 30-day mortality was 5/20. Exactly, 7/17 of patients with severe sepsis exhibited weak or absent laminin-332 expression and 11/15 exhibited weak or absent type IV collagen expression compared with 0/4 of control subjects on Day 1 in intact skin. The proportion of sepsis patients with weak or absent laminin-332 expression was 5/11 on Day 8 and fell to 1/7 at 3 months. The proportion of sepsis patients with weak or absent type IV collagen expression was 10/11 on Day 8 and 4/7 at 3 months. CONCLUSION: These findings suggest that basement membrane formation may be compromised in patients with severe sepsis. PMID- 26032242 TI - Intransitive competition is widespread in plant communities and maintains their species richness. AB - Intransitive competition networks, those in which there is no single best competitor, may ensure species coexistence. However, their frequency and importance in maintaining diversity in real-world ecosystems remain unclear. We used two large data sets from drylands and agricultural grasslands to assess: (1) the generality of intransitive competition, (2) intransitivity-richness relationships and (3) effects of two major drivers of biodiversity loss (aridity and land-use intensification) on intransitivity and species richness. Intransitive competition occurred in > 65% of sites and was associated with higher species richness. Intransitivity increased with aridity, partly buffering its negative effects on diversity, but was decreased by intensive land use, enhancing its negative effects on diversity. These contrasting responses likely arise because intransitivity is promoted by temporal heterogeneity, which is enhanced by aridity but may decline with land-use intensity. We show that intransitivity is widespread in nature and increases diversity, but it can be lost with environmental homogenisation. PMID- 26032244 TI - Covalent Grafting of Coordination Polymers on Surfaces: The Case of Hybrid Valence Tautomeric Interphases. AB - We have developed a novel approach for grafting coordination polymers, structured as nanoparticles bearing surface reactive carboxylic groups, to amino functionalized surfaces through a simple carbodiimide-mediated coupling reaction. As a proof-of-concept to validate our approach, and on the quest for novel hybrid interphases with potential technological applications, we have used valence tautomeric nanoparticles exhibiting spin transition at or around room temperature. SEM and AFM characterization reveal that the nanoparticles were organized chiefly into a single monolayer while X-ray photoelectron spectroscopy (XPS) measurements confirm that the nanoparticles retain a temperature-induced electronic redistribution upon surface anchorage. Our results represent an effective approach towards the challenging manufacture of coordination polymers. PMID- 26032243 TI - Screening for substance misuse in the dental care setting: findings from a nationally representative survey of dentists. AB - AIMS: The dental setting is a potentially valuable venue for screening for substance misuse. Therefore, we assessed dentists' inquiry of substance misuse through their patient medical history forms and their agreement with the compatibility of screening as part of the dentists' professional role. DESIGN: A nationally representative survey of general dentists using a sampling frame obtained from the American Dental Association Survey Center (November 2010 November 2011). SETTING: United States of America. PARTICIPANTS: A total of 1802 general dentists. MEASUREMENTS: A 38-item survey instrument assessing the relationship between dentists' practice, knowledge, behaviors and attitudes with their query about substance misuse and their belief that such screening is part of their professional role. FINDINGS: Dentists who accepted substance misuse screening as part of their professional role were more likely to query about misuse with their patients (85.8%) compared with those who did not accept such screening as part of their role (68.2%) (P < 0.001). Prior experience and knowledge about substance misuse were the strongest predictors of dentists' inquiry about patient substance use/misuse and acceptance of screening as part of their role in their clinical practice (P < 0.05). CONCLUSION: While more than three-quarters of US dentists report that they ask their patients about substance misuse, two-thirds do not agree that such screening is compatible with their professional role. PMID- 26032245 TI - Gloss and Stain Resistance of Ceramic-Polymer CAD/CAM Restorative Blocks. AB - OBJECTIVE: To evaluate the gloss and stain resistance of several new ceramic polymer CAD/CAM blocks MATERIALS AND METHODS: Specimens (4 mm) were sectioned from: Enamic (polymer-infused ceramic), LAVA Ultimate (nano-ceramic reinforced polymer), e.max (lithium disilicate), Paradigm C (porcelain), and Paradigm MZ100 (composite). Specimens were wet polished on a polishing wheel to either 320 grit silicon paper (un-polished, N = 8) or 2000 grit silicon carbide papers followed by a 0.05 MUm alumina slurry (polished, N = 8). Initial gloss and color (L*a*b*) values were measured. Specimens were stored in a staining solution at 37 degrees C in darkness for 12 days (simulating 1 year). After storage, L*a*b* values re measured. Change in color was reported as DeltaE00 based on the CIEDE2000 formula. Gloss and DeltaE00 were analyzed by two-way analysis of variance (ANOVA) (alpha = .05). Separate one-way ANOVA and Tukey post-hoc analyses were performed for both polish conditions and all materials. RESULTS: Two-way ANOVA showed that factors material, polish and their interaction were significant for both gloss and DeltaE00 (p < .01). Post-hoc analysis reveals that polished specimens had significantly less color change than un-polished specimens for Paradigm C and LAVA Ultimate. E.max had significantly higher gloss and less color change than all other materials. CONCLUSION: The composition and polish of CAD/CAM materials affects gloss and stain resistance. CLINICAL SIGNIFICANCE: Ceramic-polymer hybrid materials can achieve the high gloss required for esthetic restorations. These materials should be polished in order to minimize staining. If polished, all of the tested materials exhibited clinically acceptable color changes at 1 year of simulated staining. (J Esthet Restor Dent 28:S40-S45, 2016). PMID- 26032246 TI - Enabling a Learning Health System through a Unified Enterprise Data Warehouse: The Experience of the Northwestern University Clinical and Translational Sciences (NUCATS) Institute. PMID- 26032247 TI - Prescribing practices and clinical predictors of glucose-lowering therapy within the first year in people with newly diagnosed Type 2 diabetes. AB - AIM: To examine prescribing practices and predictors of glucose-lowering therapy within the first year following diagnosis of Type 2 diabetes mellitus in a clinical care setting. METHODS: We followed people enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort from outpatient hospital clinics and general practices throughout Denmark in 2010-2013. We used Poisson regression to compute age- and gender-adjusted risk ratios (RRs). RESULTS: Among 1158 new Type 2 diabetes mellitus patients, 302 (26%) did not receive glucose lowering therapy within the first year, 723 (62%) received monotherapy [685 (95%) with metformin], and 133 (12%) received more than one drug. Predictors of receiving any vs. no therapy and combination vs. monotherapy were: age < 40 years [RR: 1.29 (95% CI: 1.16-1.44) and 3.60 (95% CI: 2.36-5.50)]; high Charlson Comorbidity Index [RRs: 1.20 (95% CI: 1.05-1.38) and 2.08 (95% CI: 1.16-3.72)]; central obesity [RRs: 1.23 (95% CI: 1.04-1.44) and 1.93 (95% CI: 0.76-4.94)]; fasting blood glucose of >= 7.5 mmol/l [RRs: 1.25 (95% CI: 1.10-1.42) and 1.94 (95% CI: 1.02-3.71)]; and HbA1c >= 59 mmol/mol (>= 7.5%) [RR: 1.26 (95% CI: 1.20 1.32) and 2.86 (95% CI: 1.97-4.14)]. Weight gain >= 30 kg since age 20, lack of physical exercise and C-peptide of < 300 pmol/l also predicted therapy. CONCLUSIONS: Comorbidity, young age, central obesity and poor baseline glycaemic control are important predictors of therapy one year after Type 2 diabetes mellitus debut. PMID- 26032248 TI - Development and field evaluation of a method for detecting carbapenem-resistant bacteria in drinking water. AB - In this study, a fluorogenic heterotrophic plate count test for drinking water was modified in order to detect the presence of carbapenem-resistant bacteria. Antimicrobial agents and concentrations were selected based on recoveries of known carbapenem-resistant and carbapenem-susceptible strains inoculated into simulated samples. The modified method was field-tested on 19 drinking water samples from the New Delhi, India distribution system. Samples exhibiting fluorescence indicated bacterial growth in the presence of the supplemented antimicrobial agents, and organisms from these samples were cultured. Twenty-one Gram-negative isolates were identified from nine of the 19 samples and the meropenem minimum inhibitory concentrations were determined. Ultimately, eight carbapenem-resistant organisms were isolated from five sampling sites within the New Delhi water distribution system. PMID- 26032249 TI - Cicer canariense, an endemic legume to the Canary Islands, is nodulated in mainland Spain by fast-growing strains from symbiovar trifolii phylogenetically related to Rhizobium leguminosarum. AB - Cicer canariense is a threatened endemic legume from the Canary Islands where it can be nodulated by mesorhizobial strains from the symbiovar ciceri, which is the common worldwide endosymbiont of Cicer arietinum linked to the genus Mesorhizobium. However, when C. canariense was cultivated in a soil from mainland Spain, where the symbiovar ciceri is present, only fast-growing rhizobial strains were unexpectedly isolated from its nodules. These strains were classified into the genus Rhizobium by analysis of the recA and atpD genes, and they were phylogenetically related to Rhizobium leguminosarum. The analysis of the nodC gene showed that the isolated strains belonged to the symbiovar trifolii that harbored a nodC allele (beta allele) different to that harbored by other strains from this symbiovar. Nodulation experiments carried out with the lacZ-labeled strain RCCHU01, representative of the beta nodC allele, showed that it induced curling of root hairs, infected them through infection threads, and formed typical indeterminate nodules where nitrogen fixation took place. This represents a case of exceptional performance between the symbiovar trifolii and a legume from the tribe Cicereae that opens up new possibilities and provides new insights into the study of rhizobia-legume symbiosis. PMID- 26032250 TI - Discovery and characterization of thermophilic limonene-1,2-epoxide hydrolases from hot spring metagenomic libraries. AB - The epoxide hydrolases (EHs) represent an attractive option for the synthesis of chiral epoxides and 1,2-diols which are valuable building blocks for the synthesis of several pharmaceutical compounds. A metagenomic approach has been used to identify two new members of the atypical EH limonene-1,2-epoxide hydrolase (LEH) family of enzymes. These two LEHs (Tomsk-LEH and CH55-LEH) show EH activities towards different epoxide substrates, differing in most cases from those previously identified for Rhodococcus erythropolis (Re-LEH) in terms of stereoselectivity. Tomsk-LEH and CH55-LEH, both from thermophilic sources, have higher optimal temperatures and apparent melting temperatures than Re-LEH. The new LEH enzymes have been crystallized and their structures solved to high resolution in the native form and in complex with the inhibitor valpromide for Tomsk-LEH and poly(ethylene glycol) for CH55-LEH. The structural analysis has provided insights into the LEH mechanism, substrate specificity and stereoselectivity of these new LEH enzymes, which has been supported by mutagenesis studies. PMID- 26032251 TI - Nonoptimal codon usage influences protein structure in intrinsically disordered regions. AB - Synonymous codons are not used with equal frequencies in most genomes. Codon usage has been proposed to play a role in regulating translation kinetics and co translational protein folding. The relationship between codon usage and protein structures and the in vivo role of codon usage in eukaryotic protein folding is not clear. Here, we show that there is a strong codon usage bias in the filamentous fungus Neurospora. Importantly, we found genome-wide correlations between codon choices and predicted protein secondary structures: Nonoptimal codons are preferentially used in intrinsically disordered regions, and more optimal codons are used in structured domains. The functional importance of such correlations in vivo was confirmed by structure-based codon manipulation of codons in the Neurospora circadian clock gene frequency (frq). The codon optimization of the predicted disordered, but not well-structured regions of FRQ impairs clock function and altered FRQ structures. Furthermore, the correlations between codon usage and protein disorder tendency are conserved in other eukaryotes. Together, these results suggest that codon choices and protein structures co-evolve to ensure proper protein folding in eukaryotic organisms. PMID- 26032252 TI - Potentially inappropriate prescribing in older patients admitted to psychiatric hospital. AB - OBJECTIVES: The objectives of this study are to determine the prevalence of potentially inappropriate prescribing including potentially inappropriate medications (PIMs) and potential prescription omissions (PPOs) and to assess related risk factors in older people with major psychiatric illness. METHODS: This was a cross-sectional study of older patients hospitalized in a psychiatric hospital (n = 164; mean age 74.9 +/- 7.3 years; 62% female). The primary endpoint was the prevalence of participants receiving PIMs and PPOs, which was assessed by using the Beers criteria 2012 and the screening tool of older person's potentially inappropriate prescriptions (STOPP) and screening tool of alert doctors to the right treatment (START) criteria. Univariate and multivariate logistic regression was used to assess significant risk factors for PIMs in this population. RESULTS: A total of 1269 drugs were prescribed to included patients (range: 0-19 drugs/day). PIMs were identified in 47% and 79% of participants, based on the Beers 2012 and STOPP criteria, respectively. Most PIMs (70%) concerned psychotropic drugs. The STOPP criteria identified more PIMs (331) than the Beers criteria 2012 (199). According to the START criteria, 59% of participants had PPOs. The number of prescribed medications was significantly associated with the occurrence of PIMs according to the Beers 2012 [OR 1.2 (95% CI 1.1-1.3)] and STOPP [OR 1.5 (95% CI 1.3-1.8)] criteria. CONCLUSION: Potentially inappropriate prescribing, as identified by the Beers and STOPP/START criteria, is highly prevalent among older patients hospitalized with major psychiatric illness. However, the focus on psychotropic drugs prescription without taking into account the benefit of these drugs to individual patients may limit the application of the Beers and STOPP criteria in psychiatric hospitals. PMID- 26032253 TI - Amino acids of importance for the antioxidant activity of human serum albumin as revealed by recombinant mutants and genetic variants. AB - AIMS: To determine molecular information about the antioxidant properties of human serum albumin, which is an important extracellular antioxidant. To obtain this information, we studied this function of the protein by using H2O2 as the representative reactive oxygen species and two recombinant mutants and ten genetic variants with single-residue mutations. MAIN METHODS: The antioxidant capabilities of the isoforms were registered as their ability to diminish the H2O2-induced conversion of dihydrorhodamine 123 to rhodamine 123, which can emit fluorescence at 536 nm. Structural properties were examined by circular dichroism and SDS-PAGE. KEY FINDINGS: Cysteine residues are important for the antioxidant function, but their effect depends on their position in the protein, with Cys410 > Cys34 ~ Cys169 (when not involved in forming a disulfide bond). Likewise, the substitution of a glutamic acid at position 122 or 541, but not at 240 or 560, improves the antioxidant effect, perhaps by making the methionine residues in their vicinity, Met123 and Met548, respectively, more accessible for the oxidant. A lysine at position 505, but not at 82 or 570, decreases the oxidative effect. Finally, the mutations D269G and K276N had no effect. In certain cases, albumin acts as a sacrificial antioxidant, as in the case of the mutants C34S and, in particular, R410C and E505K. SIGNIFICANCE: The information gained is of protein chemical relevance, but it may also be helpful in understanding the function of proteins that act as antioxidants in biological systems subjected to oxidative stress in conditions such as inflammation and aging. PMID- 26032254 TI - A selective cannabinoid CB2 agonist attenuates damage and improves memory retention following stroke in mice. AB - AIMS: We have recently demonstrated that treatment with a cannabinoid CB2 agonist was protective in a mouse middle cerebral artery occlusion model of cerebral ischemia/reperfusion injury. The present study aimed to determine whether these protective effects of CB2 agonism would extend to a mouse photoinjury model of permanent ischemia and determine associated alterations in cognition and infarct size. MAIN METHODS: Mice received three injections of the CB2 selective agonist O 1966 or vehicle 1h prior to and 2 and 5days following induction of stroke. Infarct size was assessed at 1, 3, or 7days post-injury and learning and memory effects of injury and O-1966 treatment were assessed on days 6 and 7 using a novel object recognition task and an operant acquisition and retention procedure. KEY FINDINGS: O-1966 treated mice had significantly smaller infarct volumes compared with vehicle treated mice. Photoinjury was also associated with a significant memory impairment on day 7 post-injury, and this deficit was reversed with O-1966 treatment. Surprisingly, sham-operated mice receiving O-1966 treatment showed a significant learning deficit in both the recognition and operant tasks compared with vehicle treated sham mice. SIGNIFICANCE: We conclude that CB2 activation is protective against cognitive deficits and tissue damage following permanent ischemia, but may dysregulate glial or neuronal function of learning and memory circuits in the absence of injury and/or inflammation. PMID- 26032255 TI - Metabolome disruption of the rat cerebrum induced by the acute toxic effects of the synthetic cannabinoid MAM-2201. AB - AIM: The aim of this study is to investigate the metabolome disruption in the rat cerebrum induced by the recently abused synthetic cannabinoid MAM-2201. MAIN METHODS: MAM-2201 was intraperitoneally administered to 6-week Wistar rats at 5 or 15mg/kg (n=5), and the cerebrum metabolome alteration was investigated using a gas chromatography/tandem mass spectrometry (GC/MS/MS)-based metabolomics technique. KEY FINDINGS: MAM-2201 induced oligopnea and hypokinesia at the 5mg/kg dose, while more abnormal symptoms like rotational and seizure-like behaviors were observed at the 15mg/kg dose, suggesting that MAM-2201 induced neurofunctional disruptions. GC/MS/MS detected 72 metabolites in the rat cerebrum. The cerebrum levels of 12 of these metabolites, including intermediates of the tricarboxylic acid cycle (malic acid and succinic acid) and glutamic acid (Glu), were significantly changed in MAM-2201 administered groups compared to the control group. SIGNIFICANCE: The synthetic cannabinoid MAM-2201 can disrupt not only glutamatergic neurotransmission but also energy metabolism in the rat cerebrum. Such disruption may contribute to the abnormal symptoms induced by synthetic cannabinoids. PMID- 26032256 TI - ERK5 regulates basic fibroblast growth factor-induced type 1 plasminogen activator inhibitor expression and cell proliferation in lung fibroblasts. AB - AIMS: bFGF is a potent mitogen of cells associated with fibrosis. Although ERK5 has been reported to play roles in the development of fibrosis, its roles in regulating bFGF-induced fibrotic responses are not understood, especially in lung fibroblasts. The authors investigated the role of ERK5 in bFGF induction of cell proliferation and in induction of PAI-1, a critical regulator of the pathological features of fibrosis, in lung fibroblasts. MAIN METHODS: The role played by ERK5 in bFGF-induced PAI-1 expression was elucidated by perturbing the ERK5 signaling pathway using a specific chemical inhibitor and siRNA of ERK5. The effects of ERK5 signal perturbation on PAI-1 expression were measured at multiple levels by Q-PCR, immunoblotting, ELISA, and reporter gene analysis. The role of MEF2 in bFGF-induced activation of PAI-1 promoter activity via ERK5 was measured using a biotin-labeled DNA pull-down assay, and the effects of ERK5 on the mitogenic effects of bFGF were assessed using a MTT assay. KEY FINDINGS: In both primary human lung fibroblast and lung fibroblast cell lines, inhibition of ERK5 blocked bFGF-induced PAI-1 expression at both mRNA and protein levels and inhibited bFGF induced PAI-1 promoter activity induction by bFGF. Upon stimulation with bFGF, MEF2 directly bound to the consensus sequence of the MEF2 binding site in the PAI 1 promoter. In addition, bFGF-induced PAI-1 up-regulation was inhibited by MEF2 siRNA, and bFGF-induced fibroblast proliferation was blocked by inhibiting ERK5. SIGNIFICANCE: This study reveals a novel role for the ERK5-MEF2 cascade, linking bFGF-induced PAI-1 expression and subsequent mitogenic processes in lung fibroblasts. PMID- 26032257 TI - Analysis and evaluation of antibacterial effects of new herbal formulas, AP-001 and AP-002, against Escherichia coli O157:H7. AB - AIMS: Over the last few years, there has been an increasing interest in the use of natural substances for promoting human and animal health. Antibiotic resistance, enhanced by excessive use of antibiotics, has encouraged human and animal health authorities to consider and employ alternative approaches, including herbal and botanical medicine to combat invading microorganisms. Herein, the essential oils of Thymus vulgaris, Allium cepa, Allium sativum, Eucalyptus globulus, Salvia officinalis, Dianthus caryophyllus, Mentha spicata and Mentha piperita, were evaluated for their antibacterial activities against standard Escherichia coli O157:H7 by disk diffusion method. MAIN METHODS: Minimum Inhibitory Concentrations (MICs) and Minimum Bactericidal Concentrations (MBCs) were assessed via microdilution assay. In the next step, two combinations of these essential oils were formulated. Their in-vitro antibacterial effects were evaluated and compared with a commercially available herbal drug containing T. vulgaris essential oil. KEY FINDINGS: According to the results, the two new formulated essential oil combinations had more potent antibacterial effects against E. coli when compared to the commercial herbal drug. SIGNIFICANCE: The presented data indicate the potential antibacterial activity of these newly formulated essential oil remedies to be employed in the poultry industry in the fight against colibacillosis, although this claim has to be examined in experimental and clinical trials. PMID- 26032258 TI - Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease. AB - AIM: Angiogenesis and chronic inflammation are known to be co-dependent in atherosclerosis and cardiovascular diseases. This study was undertaken to investigate whether simvastatin could affect serum levels of angiostatin, a potent endogenous inhibitor of neovascularization, in patients with ischemic heart disease (IHD). MAIN METHODS: Twenty-six patients with clinically confirmed IHD and hypercholesterolemia were assigned 40 mg/day of simvastatin for 8 weeks. Levels of lipid metabolism, C-reactive protein (C-RP) and other biochemical parameters in serum samples were measured using biochemical analyzer. Serum angiostatin levels were determined by Western blot. Association of serum angiostatin levels with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and C-RP levels was evaluated. KEY FINDINGS: Simvastatin therapy improved the main parameters of lipid metabolism, including statistically significant (P < 0.05) reductions in TC (by 46%) and LDL-C (by 42%), and decreased inflammatory marker C-RP (by 32%), as compared with the baseline. Simvastatin treatment resulted in marked reduction of serum angiostatin level (by 80% in comparison with baseline, P < 0.05). Strong positive correlations between serum angiostatin level versus concentrations of TC, LDL-C, and C-RP were demonstrated before onset of the study (r = 0.48311, 0.6252, and 0.653, respectively) and after simvastatin therapy (r = 0.67752, 0.6485, and 0.8244, respectively). SIGNIFICANCE: We describe for the first time novel pleiotropic effect of statin therapy associated with decrease of serum angiostatin levels. Thus, circulating angiostatin represents an independent additional risk marker for cardiovascular events and could be applied as potential supplementary indicator for evaluation of statin therapy efficacy. PMID- 26032259 TI - Testosterone protects cardiac myocytes from superoxide injury via NF-kappaB signalling pathways. AB - AIMS: Cellular and molecular mechanisms underlying the effects of androgenic hormone testosterone on the heart remain unclear. This study examined the impact of testosterone on viability of cardiac myocytes and the role of NF-kappaB signalling pathways. MATERIALS AND METHODS: Rat H9c2 myocytes were cultured in steroid-free media and incubated with hydrogen peroxide (H2O2, 200 MUM, 6h). NF kappaB expression was knocked down by RelA (p65) siRNA interference. Testosterone (5-100 nM, 24-48 h) was provided into the media and androgen receptor (AR) blocked by flutamide (100 nM). Cell apoptotic/necrotic death was determined by morphological examination and flow-cytometric analysis. Gene expression was examined by Western blotting analysis. KEY FINDINGS: Testosterone supplements reduced the superoxide-induced apoptotic/necrotic death, stimulated NF-kappaB (RelA) expression, activated Akt activity, and inhibited Caspase-3 expression in the cardiac myocytes. The hormonal effects were abolished by either AR blocker flutamide or NF-kappaB-knockdown. Testosterone also induced ERK1/2 activation, which was not affected by flutamide or NF-kappaB knockdown, and blocking the ERK activity did not affect the protective effect of the hormone on the cells. SIGNIFICANCE: This study demonstrates that exogenous testosterone supplementation protects cardiac myocytes from superoxide injury via AR mediation and dependent on normally functional canonical NF-kappaB (RelA/p50) signalling pathways. The NF kappaB signalling may be an important key molecular basis for myocardial benefits of hormone (testosterone) therapy. PMID- 26032260 TI - Effect of intracerebral hydroxytyrosol and its nitroderivatives on striatal dopamine metabolism: A study by in vivo microdialysis. AB - AIMS: The natural phenolic oil compound hydroxytyrosol (HTy) is widely studied because of its antioxidant and neuroprotective properties. Nitroderivatives of HTy have been studied in order to evaluate their putative effects on catechol-O methyltransferase (COMT) activity. MAIN METHODS: To study its effect on dopamine metabolism, nitrohydroxytyrosol and its lipophilic derivatives (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether), were administered into the rat corpus striatum through a microdialysis probe. Other catechols (HTy and the known COMT inhibitor Ro 41-0960) were also studied for comparison. KEY FINDINGS: The olive oil phenolic compounds (nitroderivatives and HTy) increased extracellular levels of 3,4-dihydroxyphenylacetic acid during the perfusion with similar maximum values to that of Ro 41-0960 when comparing to basal dialysate levels (approximately 140%). None of the compound series produced a decrease in the homovanillic acid extracellular levels below 75%. Among all novel compounds studied, both lipophilic nitrocatechols (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether) showed a long-acting effect over time once the perfusion through the microdialysis probe ended. SIGNIFICANCE: In accordance with the actual design of novel COMT inhibitors with a long profile, our results suggest a certain influence of the side chain substituent on the COMT activity that could provide new lipophilic COMT inhibitors. PMID- 26032262 TI - A Technique to Evaluate the Space for Retentive Components under a Removable Prosthesis. AB - Space analysis for retentive components is a critical part of a treatment plan for an implant-retained prosthesis. This article describes a technique to evaluate the retentive component space between the mucosa and intaglio surface of a removable prosthesis. This technique uses a silicone mold to represent the relieved space. Two silicone matrices are fabricated over the silicone space replica as a reference for selecting or fabricating retentive components for the implant-retained removable prosthesis. PMID- 26032261 TI - Automated pipeline for rapid production and screening of HIV-specific monoclonal antibodies using pichia pastoris. AB - Monoclonal antibodies (mAbs) that bind and neutralize human pathogens have great therapeutic potential. Advances in automated screening and liquid handling have resulted in the ability to discover antigen-specific antibodies either directly from human blood or from various combinatorial libraries (phage, bacteria, or yeast). There remain, however, bottlenecks in the cloning, expression and evaluation of such lead antibodies identified in primary screens that hinder high throughput screening. As such, "hit-to-lead identification" remains both expensive and time-consuming. By combining the advantages of overlap extension PCR (OE-PCR) and a genetically stable yet easily manipulatable microbial expression host Pichia pastoris, we have developed an automated pipeline for the rapid production and screening of full-length antigen-specific mAbs. Here, we demonstrate the speed, feasibility and cost-effectiveness of our approach by generating several broadly neutralizing antibodies against human immunodeficiency virus (HIV). PMID- 26032263 TI - Making literature reviews more reliable through application of lessons from systematic reviews. AB - Review articles can provide valuable summaries of the ever-increasing volume of primary research in conservation biology. Where findings may influence important resource-allocation decisions in policy or practice, there is a need for a high degree of reliability when reviewing evidence. However, traditional literature reviews are susceptible to a number of biases during the identification, selection, and synthesis of included studies (e.g., publication bias, selection bias, and vote counting). Systematic reviews, pioneered in medicine and translated into conservation in 2006, address these issues through a strict methodology that aims to maximize transparency, objectivity, and repeatability. Systematic reviews will always be the gold standard for reliable synthesis of evidence. However, traditional literature reviews remain popular and will continue to be valuable where systematic reviews are not feasible. Where traditional reviews are used, lessons can be taken from systematic reviews and applied to traditional reviews in order to increase their reliability. Certain key aspects of systematic review methods that can be used in a context-specific manner in traditional reviews include focusing on mitigating bias; increasing transparency, consistency, and objectivity, and critically appraising the evidence and avoiding vote counting. In situations where conducting a full systematic review is not feasible, the proposed approach to reviewing evidence in a more systematic way can substantially improve the reliability of review findings, providing a time- and resource-efficient means of maximizing the value of traditional reviews. These methods are aimed particularly at those conducting literature reviews where systematic review is not feasible, for example, for graduate students, single reviewers, or small organizations. PMID- 26032264 TI - The day-to-day concurrence of bodily complaints and affect in patients with severe somatoform disorder. AB - Based on the concept of somatization, psychological distress can be experienced as symptoms of physical illness. This suggests a close-fitting intra-individual association between bodily complaints and mood in patients with somatoform disorder (SFD). The contemporaneous day-to-day complaints-mood association was investigated in patients with severe chronic SFD using an ecological momentary assessment (EMA) design. Eleven patients, who had recently received specialized tertiary care treatment for severe chronic SFD, kept an online electronic diary for four consecutive weeks. They were prompted at intervals throughout the day to complete questions on their momentary primary symptoms (pain and fatigue), and mood state (negative and positive). For each measure, day-mean aggregated values were computed and analyzed using linear multilevel (mixed model) regression analysis. Fixed factor results showed that symptoms were associated with both negative mood state (beta = 0.47) and positive mood state (beta = -0.59). Random results, however, indicated large inter-individual differences, with correlations varying between 0.17 and 0.99 for negative affect, and between -0.88 and 0.14 for positive affect. A substantial day-to-day contemporaneous association between symptoms and affect across subjects, as well as large inter-individual differences in this association, were demonstrated in patients with severe chronic SFD. EMA-data showing the relationship between both negative and (inverse) positive mood and complaints has potential clinical relevance: providing SFD patients with feedback consisting of their personal day-to-day concurrency graph may promote their understanding of their own complaints in a broader context than the somatic area. PMID- 26032265 TI - Allelic and copy-number variations of FcgammaRs affect granulocyte function and susceptibility for autoimmune blistering diseases. AB - Low-affinity Fcgamma receptors (FcgammaR) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding FcgammaR exhibit frequent variations in sequence and gene copy number that influence their functional properties. FcgammaR variations also affect the susceptibility to systemic autoimmunity, e.g. systemic lupus erythematosus and rheumatoid arthritis. This raises the question whether FcgammaR variations are also associated with organ-specific autoimmunity, particularly autoantibody-mediated diseases, such as subepidermal autoimmune blistering diseases (AIBD). A multitude of evidence suggests a pathogenic role of neutrophil granulocyte interaction with autoantibodies via FcgammaR. In a two-stage study, we analyzed whether the FcgammaR genotype affects neutrophil function and mRNA expression, and consequently, bullous pemphigoid (BP) disease risk. We compared this to findings in pemphigus vulgaris/foliaceus (PV/PF), two Fc-independent AIBDs. Our results indicate that both allele and copy number variation of FcgammaR genes affect FcgammaR mRNA expression and reactive oxygen species (ROS) release by granulocytes. Susceptibility of BP was associated with FcgammaR genotypes that led to a decreased ROS release by neutrophils, indicating an unexpected protective role for these cells. BP and PV/PF differed substantially regarding the FcgammaR genotype association patterns, pointing towards different disease etiologies. PMID- 26032266 TI - Targeted genome editing in primate embryos. AB - Mosaic mutations and off-target effects caused by CRISPR/Cas9 have led to concerns about the efficiency and specificity of this new technique in non-human primates and other large animals. Here we discuss recent findings from primate embryos, with a focus on the technical issues CRISPR/Cas9 faces before producing non-human primate models of human diseases. PMID- 26032267 TI - Cancer immunotherapy: exploiting neoepitopes. AB - The efficacy of cancer vaccines has long been hampered by insufficient definition of tumor-specific antigens. A recent study by Kreiter et al. published in Nature has provided a blueprint for a patient-tailored approach to develop individualized RNA vaccines. PMID- 26032268 TI - A frightening thought: Neuronal activity enhances tumor growth. AB - Stem cells present in the adult brain are regulated by neuronal activity; malignant gliomas, which most likely originate from this population of cells, could also be regulated in this manner. A recent study by Venkatesh et al. published in Cell has identified Neuroligin-3 (NLGN3) as a mitogen promoting high grade glioma growth. PMID- 26032269 TI - The added value of accounting for activity space when examining the association between tobacco retailer availability and smoking among young adults. AB - BACKGROUND: Despite a declining prevalence in many countries, smoking rates remain consistently high among young adults. Targeting contextual influences on smoking, such as the availability of tobacco retailers, is one promising avenue of intervention. Most studies have focused on residential or school neighbourhoods, without accounting for other settings where individuals spend time, that is, their activity space. We investigated the association between tobacco retailer availability in the residential neighbourhood and in the activity space, and smoking status. METHODS: Cross-sectional baseline data from 1994 young adults (aged 18-25) participating in the Interdisciplinary Study of Inequalities in Smoking (Montreal, Canada, 2011-2012) were analysed. Residential and activity locations served to derive two measures of tobacco retailer availability: counts within 500 m buffers and proximity to the nearest retailer. Prevalence ratios for the association between each tobacco retailer measure and smoking status were estimated using log-binomial regression. RESULTS: Participants encountering high numbers of tobacco retailers in their residential neighbourhood, and both medium and high retailer counts in their activity space, were more likely to smoke compared to those exposed to fewer retailers. While residential proximity was not associated with smoking, we found 36% and 42% higher smoking prevalence among participants conducting activities within medium and high proximity to tobacco retailers compared to those conducting activities further from such outlets. CONCLUSIONS: This study adds to the sparse literature on contextual correlates of smoking among young adults, and illustrates the added value of considering individuals' activity space in contextual studies of smoking. PMID- 26032270 TI - Clinical predictors of mortality following rotational atherectomy and stent implantation in high-risk patients: A single center experience. AB - OBJECTIVES: Our aim was to assess the procedural success and determine the clinical predictors of postprocedure mortality, following rotational atherectomy (RA) and stenting in high-risk patients. BACKGROUND: RA is mainly used to facilitate stenting in complex lesions. Outcomes involving RA and stenting have been investigated, yet high-risk patients have not been adequately described. METHODS: Data of 218 consecutive patients who underwent RA were evaluated in a prospective register. Primary endpoints were the angiographic success and long term mortality. Secondary endpoints were procedural success, consumption of the angioplasty equipment, and periprocedural major adverse cardiac events. The impact of the relevant angiographic and clinical characteristics on long-term mortality was analyzed using uni- and multivariate Cox regression analysis. RESULTS: Mean age of the patients was 70 +/- 8.2 years, diabetes was present in 44%, and chronic renal failure in 29%. Prior myocardial infarction and three vessel disease amounted to 42.2% and 32.6%, respectively. Altogether, 52.8% of patients underwent RA after a failed, non-RA intervention attempt, and 30.7% of cases presented as acute coronary syndromes. Angiographic success was 100%, and all patients received stents after RA. Periprocedural major adverse cardiac events occurred in five (2.3%) patients. Postprocedural death was investigated, with a mean follow-up of 36 months. Mortality amounted to 37.2%. Multivariate analysis revealed that left ventricular ejection fraction < 50%, glomerular filtration rate < 60 ml/min, cardiogenic shock, and diabetes were the only independent mortality predictors. CONCLUSIONS: We have found that RA and stenting is feasible and viable in an elderly high-risk population, with exceptional procedural success and acceptable long-term results. PMID- 26032271 TI - Do school resources influence the relationship between adolescent financial background and their school perceptions? AB - BACKGROUND: Socioeconomic status (SES) influences students' school perceptions and affects their performance, engagement, and personal beliefs. This study examined the effects of school population SES and school resources on the association between student SES and student perceptions. METHODS: School liking, classmate social relationships, family affluence, and experience of hunger were assessed in a nationally representative sample of 12,642 students (grades 5-10) in the 2009-2010 Health Behavior in School-Aged Children study. School characteristics included school meal program, Title 1 dollars received per student, school resources, and urban/rural status. Multilevel analysis was used. RESULTS: At the individual level, both school liking and social relationships were negatively associated with student grade level. Boys liked school less and had more positive perceptions of social relationships than girls. Students in rural schools and who experienced hunger liked schools less and had poorer perceptions of social relationships than their respective counterparts. School level percentage of students eligible for free/reduced meals accounted for 33% of the between-school variance in social relationships. CONCLUSIONS: Family and school economic characteristics and grade level influenced students' school perceptions. The associations between student SES, school population SES, and school perceptions suggests that school health professionals should recognize and address student economic issues at school. PMID- 26032272 TI - Association Between School Policies and Built Environment, and Youth's Participation in Various Types of Physical Activities. AB - BACKGROUND: School environmental characteristics may be associated with youth's participation in different types of physical activities (PAs). This study aimed to identify which school policies and built environmental characteristics were associated with participation in organized, nonorganized, individual, and group based activities. METHODS: This cross-sectional analysis included 776 students in grade 5 or 6 from 16 schools. The school environment was assessed through school based questionnaires completed by school representatives. Types of PA and attainment of PA recommendations were obtained using self-administered student questionnaires. Associations between environment and student PA were examined using multilevel logistic regressions. RESULTS: Schools with favorable active commuting environments were positively associated with girls' participation in organized (odds ratio [OR] = 1.34, confidence interval [CI] = 1.04-1.74) and group-based PA (OR = 1.54, CI = 1.19-1.99) and with boys' odds of participating in individual activities (OR = 1.45, CI = 1.04-2.04). There was also a positive relationship between having a school environment favorable to active commuting and boys' odds of meeting PA recommendations (OR = 2.19, CI = 1.43-3.37). School policies supporting PA were positively associated with girls' odds of participating in nonorganized activities (OR = 1.18, CI = 1.00-1.40). CONCLUSIONS: School environments that favor active commuting may encourage participation in different types of PA. School policies promoting PA also may encourage girls to participate in organized activities. PMID- 26032273 TI - Victimization among Peruvian adolescents: insights into mental/emotional health from the Young Lives study. AB - BACKGROUND: Bullying is a global problem among children and adolescents. The purpose of this study was to explore bully victimization in Peru and to identify potential adverse mental health and social outcomes resulting from bully victimization. METHODS: This study analyzed data from an ongoing prospective cohort of children taking part in the Young Lives study. This study assessed bullying consequences on mental and emotional health in the 3 rounds of data collected among Peruvian adolescents at ages 8, 12, and 15. RESULTS: Bullying by peers was negatively related with age. A factor analysis showed that boys were significantly less likely than girls to suffer emotional and relational problems due to victimization. Additionally, bullying in rounds 2 and 3 of the cohort were significantly correlated with adverse emotional and mental health outcomes in round 3. Lastly, emotional status was positively associated with violent incidences in the schools and at home. CONCLUSIONS: This study shows significant problems with emotional and mental stress as early outcomes associated with victimization in Peru. The findings have implications for treating adolescent health issues like peer victimization. Steps should be taken to address bullying and mental/emotional health in Peru in order to combat subsequent mental health problems. PMID- 26032274 TI - Time trends in bullying behavior in Italy. AB - BACKGROUND: Given the severity of outcomes associated with involvement in bullying and the resources spent in an effort to reduce its prevalence, it is important to investigate trends in the bullying's occurrence. The main aim of this study was to identify trends from 2002 to 2010 in prevalence of bullying and victimization among Italian adolescents. METHODS: The survey reported here is part of the larger population-based cross-sectional (2002, 2006, and 2010) "Health Behaviour in School Aged Children" (HBSC) transnational study. The sample was comprised of 13,174 Italian middle and secondary school students (11- to 15 year-olds; 50.3% girls). Data were collected through a self-report questionnaire. Measures included involvement in bullying as either a perpetrator or a victim. Trends were determined using Gamma statistics. RESULTS: Consistent and robust decreases in the prevalence of bullying between 2002 and 2010 were detected in Italy. During this time frame both frequent and occasional bullying and victimization decreased by half. CONCLUSIONS: We measured a strong decrease in involvement in bullying behavior in Italy, in particular after 2006, when the Italian government invested more systematically in the prevention effort on bullying. This is encouraging news for policymakers and practitioners working in the field of bullying prevention. PMID- 26032275 TI - Aggressive and violent behaviors in the school environment among a nationally representative sample of adolescent youth. AB - BACKGROUND: The purpose of this study was to describe the prevalence of aggressive and violent behaviors in the context of the school environment in a nationally representative sample of adolescent youth and to illustrate these patterns during 2001-2011. METHODS: We analyzed data from 84,734 participants via the Youth Risk Behavior Surveillance System (YRBSS). Frequencies were visualized using heatmaps. One-way analyses of variance and corresponding post hoc tests helped to identify if differences in prevalence fluctuated significantly across all years. RESULTS: Rates of youth feeling unsafe in their school environment, bringing weapons to school, and engaging in physical fighting on school property continue to persist. Findings illustrated that Hispanic youth and youth classified as "other" have emerged as particularly high-risk demographic subgroups over the past decade. Peer victimization and sexual victimization continue to affect girls disproportionately. CONCLUSIONS: Though some variation within demographic subgroups exists, rates of aggressive and violent behaviors in the context of the school environment continue to persist. Implications for the coordinated prevention of aggressive and violent behaviors among adolescent youth are discussed and recommendations for school-based prevention efforts are identified. PMID- 26032276 TI - Weight-related behaviors when children are in school versus on summer breaks: does income matter? AB - BACKGROUND: Income disparities in US youth in academic achievement appear to widen during the summer because of discontinued learning among children from lower-income households. Little is known about whether behavioral risk factors for childhood obesity, such as diet and physical activity, also demonstrate a widening difference by income when children are out of school. METHODS: Data from US children in grades 1-12 in the National Health and Nutrition Examination Survey 2003-2008 (N = 6796) were used to estimate screen time, moderate-to vigorous physical activity (MVPA), and consumption of calories, vegetables, and added sugar. Linear regression was used to compare among children of households <=185% and >185% poverty, as well as during the school year versus on school breaks. RESULTS: Children surveyed during summer breaks consumed fewer vegetables (-0.2 cups/day) and more added sugar (+2.1 teaspoons/day), were more active (+4.6 MVPA minutes/day) and watched more television (+18 minutes/day). However, the nonsignificant interaction between school breaks and income indicated that lower income students were not "less healthy" than higher-income students during the summer breaks. CONCLUSION: Obesity-related risk factors were more prevalent during the summer and among lower-income youths, but the income disparity in these behaviors was not exacerbated when schools are not in session. PMID- 26032277 TI - Middle school-aged child enjoyment of food tastings predicted interest in nutrition education on osteoporosis prevention. AB - BACKGROUND: NEEDs for Bones (NFB), based on the Health Belief Model, is a 4 lesson osteoporosis-prevention curriculum for 11- to 14-year-olds. This study examined the relationship between enjoyment of food tastings and interest in NFB. METHODS: NFB was administered by teachers as part of standard practice and evaluated after the fourth lesson using a 21-item survey. Significant clustering of students within classrooms required use of random-intercept multilevel ordinal regression models in SAS proc GLIMMIX, with students nested within classrooms. Analyses considered tasting experience, eating attitudes, sex, grade, and cohort. RESULTS: Students (N = 1619; 50% girls) participated from 85 fourth to eighth grade classrooms (47% sixth grade and 31% seventh grade) in 16 Pennsylvania SNAP Ed eligible schools over 2 academic years. For all foods tasted, students who did not enjoy the food tasting were less interested in the lesson than students who did enjoy the food tasting (all p < .001); refried beans (odds ratio [OR] = 0.30), soy milk (OR = 0.55), cranapple juice (OR = 0.51), sunflower kernels (OR = 0.48), and Swiss cheese (OR = 0.49). The relationship persisted net of covariates. CONCLUSIONS: Enjoyment of food tasting activities can predict interest in nutrition education on osteoporosis prevention, supporting resource allocation and inclusion of food tasting activities in school-age nutrition education. PMID- 26032278 TI - The role of community, family, peer, and school factors in group bullying: implications for school-based intervention. AB - BACKGROUND: Although an ecological perspective suggests the importance of multiple levels of intervention, most bullying research has emphasized individual and school-focused strategies. This study investigated community and family factors that influence school efforts to reduce odds of group bullying behavior and victimization. METHODS: We used multilevel logistic regression to analyze data from the 2009 Youth in Iceland population school survey (N = 7084, response rate: 83.5%, 50.8% girls). RESULTS: Parental support and time spent with parents were protective against group bullying behavior while worsening relationships with teachers and disliking school increased the likelihood of such behavior. Knowing kids in the area increased the likelihood of group bullying while intergenerational closure was a protective factor. Normlessness was consistently positively related to group bullying. We found no indication of higher-level relationships across the bullying models. Parental support was protective against victimization. Disliking school, intergenerational closure, and anomie/normlessness were strongly and negatively related to victimization. We found some indication of multilevel relationships for victimization. CONCLUSIONS: Findings support efforts to increase family and community connection, closure, and support as a part of school-based intervention. These factors become more important as young people participate in or experience greater odds of group bullying behavior and victimization. PMID- 26032279 TI - Evaluation of the Health-Promoting School Supporting Network in Taiwan. AB - BACKGROUND: Taiwan has advocated health-promoting schools (HPS) since 2001 and established the Health-Promoting School Supporting Network (HPSSN) in 2005 to offer administrative support and consultation. Respondents' opinions about HPSSN and the relationship between these perceptions and HPS implementation were examined. METHODS: In 2011, 800 primary and middle schools were selected through stratified random sampling. School staff members (N = 656) in charge of HPS programs reported their impressions of the HPSSN's support. RESULTS: Respondents were most satisfied with consultants and schools' recognition of responsibilities and rules and their interactions with HPSSN administrators. They were least satisfied with the extent of their HPSSN consultant interaction and believed HPSSN provided insufficient resources to establish HPS. Respondents' consultant partnerships and satisfaction with HPSSN administration significantly predicted HPS implementation. Additionally, the predictive values of healthy policies and school-community relationships were greater than the other 6 HPS components. CONCLUSIONS: HPSSN positively influenced HPS implementation; however, consultant/school partnerships and school resource allocations must be improved. PMID- 26032280 TI - Does depression matter in neuropsychological performances in anorexia nervosa? A descriptive review. AB - OBJECTIVE: This review aims to examine the impact of depressive symptoms on the assessment of cognitive flexibility, central coherence, and decision-making in individuals with anorexia nervosa (AN). METHOD: An online search was carried out using PubMed and PsycInfo. Articles were selected for review if they were published in English between 1990 and 2014 and used the Wisconsin Card Sorting Test, the Trail Making Task parts A and B, the Brixton Test, the Rey-Osterrieth Complex Figure Test, and/or the Iowa Gambling Task. RESULTS: Sixty-two studies were included. Thirty (48%) of the studies statistically assessed the association between depression and neurocognition in AN versus healthy controls. Where significant correlations were found, it became clear that the more serious the depression, the greater the neuropsychological impairment. Only six (10%) studies examined whether increased depressive symptoms were able to eliminate the differences between individuals with AN and healthy controls, and one study found that depressive symptoms did eliminate group differences in cognitive flexibility and decision-making. DISCUSSION: Only a subgroup of articles on neuropsychology in AN adjusted for depression. However, given the role of depression that some articles suggest, future studies should pay closer attention to the evaluation of this potential confounder. PMID- 26032281 TI - Involvement of alpha2-adrenoceptors in inhibitory and facilitatory pain modulation processes. AB - BACKGROUND: In healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only produces hyperalgesia at the site of stimulation but also reduces sensitivity to pressure-pain on the ipsilateral side of the forehead. In addition, HFS augments the ipsilateral trigeminal nociceptive blink reflex and intensifies the ipsilateral component of conditioned pain modulation. The aim of this study was to determine whether alpha2-adrenoceptors mediate these ipsilateral nociceptive influences. METHODS: The alpha2-adrenoceptor antagonist yohimbine was administered to 22 participants in a double-blind, placebo controlled crossover study. In each session, thermal and mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, the combined effect of HFS and yohimbine on the nociceptive blink reflex and on conditioned pain modulation was explored. In this paradigm, the conditioning stimulus was cold pain in the ipsilateral or contralateral temple, and the test stimulus was electrically evoked pain in the forearm. RESULTS: Blood pressure and electrodermal activity increased for several hours after yohimbine administration, consistent with blockade of central alpha2-adrenoceptors. Yohimbine not only augmented the nociceptive blink reflex ipsilateral to HFS but also intensified the inhibitory influence of ipsilateral temple cooling on electrically evoked pain at the HFS-treated site in the forearm. Yohimbine had no consistent effect on primary or secondary hyperalgesia in the forearm or on pressure-pain in the ipsilateral forehead. CONCLUSIONS: These findings imply involvement of alpha2-adrenoceptors both in ipsilateral antinociceptive and pronociceptive pain modulation processes. However, a mechanism not involving alpha2-adrenoceptors appears to mediate analgesia in the ipsilateral forehead after HFS. PMID- 26032283 TI - An appraisal of the short lateral rotators of the hip joint. AB - The short lateral rotators (piriformis, obturator internus, superior and inferior gemelli, obturator internus, and quadratus femoris) are functionally important muscles, significantly contributing to hip joint stability. They act as "postural muscles", holding the femoral head in the acetabulum during hip movements, thus are frequently monitored in gait analysis and for muscle rehabilitation post injury. Despite the need to precisely identify and repair these muscles for stability postoperatively, clinical complications have resulted from the inadequate and inconsistent understanding of their morphological and functional anatomy. Furthermore, the short lateral rotators have complex entheses (osteotendinous insertions on bone) and may be subject to overuse injury in sport. This study aims to review the reported morphology of the short lateral rotators in order to ascertain whether discrepancies exist in our understanding of these muscles, and if further investigation is required to aid in gait analysis, clinical management of hip pathologies, and prevention of overuse injuries. Following a literature search strategy, 59 primary references were retrieved from three databases, with additional 26 anatomical textbooks selected for critical evaluation. Numerous inaccuracies and inconsistencies in the anatomical descriptions of the attachments, patterns of innervation and actions exist, and often insufficiently supported by primary findings. There is also a paucity of information regarding the architectural pattern of the muscles, which would be useful in clarifying the function of these dynamic stabilizers of the hip joint. A better anatomical understanding of these muscles will better inform hip reconstruction and lead to improved surgical outcomes by reducing post operative complications. PMID- 26032282 TI - Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. AB - As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. PMID- 26032284 TI - Diagnosis and prediction of the occurrence of acute mountain sickness measuring oxygen saturation--independent of absolute altitude? AB - PURPOSE: Commercialization of trekking tourism enables untrained persons to participate in trekking tours. Because hypoxia is one of the main purported triggers for acute mountain sickness (AMS), pulse oximetry, which measures arterial oxygen saturation (SPO2), is discussed to be a possible and useful tool for the diagnosis of AMS. The purpose of this study was to evaluate possible associations between SPO2 values and the occurrence of AMS. METHODS: In 204 trekkers, SPO2 values (pulse oximetry) were measured and the Lake Louise Self assessment Score (LLS) was administered over the first 7 days of their trekking tours. RESULTS: During treks at altitudes of 2500-5500 m in Nepal, India, Africa, and South America, 100 participants suffered from mild AMS, 3 participants suffered from severe AMS, and 9 participants reported both mild and severe AMS. The lowest mean SPO2 was 85.5 (95 % confidence interval (CI), 83.9-86.1 %) on day 5. SPO2 and LLS exhibited a weak to moderate negative correlation for all days of the study (rho ranging from -0.142 to -0.370). Calculation of time-shifted associations of 24 and 48 h resulted in the disappearance of most associations. Susceptibility to headaches (odds ratio (OR) 2.9-7.2) and a history of AMS (OR 2.2-3.1) were determined to be potential risk factors for the development of AMS. CONCLUSION: Since there is no strong altitude-independent association between AMS and SPO2 during the first week of high-altitude adaptation, the implementation of pulse oximetry during trekking in order to detect and predict AMS remains questionable. PMID- 26032285 TI - [Highly pigmented stain on the back]. PMID- 26032286 TI - [Anisakis infection with atypical presentation]. PMID- 26032287 TI - Diazoxide preconditioning of endothelial progenitor cells improves their ability to repair the infarcted myocardium. AB - Reduced survival and homing of the transplanted cells in the oxidative stressed ischemic environment limits the potential outcome of cell therapies for myocardial ischemia. Diazoxide (DZ), a highly selective mitochondrial ATP sensitive K(+) channel opener, is known to improve the survival and therapeutic ability of mesenchymal stem cells and skeletal myoblasts for the repair of heart failure. The current study explored the effect of DZ preconditioning in improving the ability of endothelial progenitor cells (EPCs) to counteract, in vitro oxidative stress, and to repair the infarcted myocardium. The EPCs were preconditioned by 30 min incubation with 200 MUM DZ followed by exposure to 200 MUM hydrogen peroxide (H2 O2 ) for 2 h. Non-preconditioned EPCs with and without exposure to H2 O2 were used as control. DZ preconditioning of EPCs resulted in significantly reduced cell injury as shown by reduced lactate dehydrogenase release and expression of annexin V-PE in comparison to untreated EPCs. Furthermore, DZ preconditioned EPCs exhibited upregulated expression of prosurvival genes (VEGF, SDF-1alpha, PCNA, and Bcl2 ), improved chemokines release (VEGF, IGF, and SDF-1alpha), viability, Akt phosphorylation and tube formation. In vivo experiments involved transplantation of DZ preconditioned and untreated EPCs in the left ventricle after permanent ligation of left anterior descending coronary artery in rats. The results demonstrated that DZ EPCs transplanted group showed significant reduction in infarct size along with robust cell proliferation, angiogenesis and improvement in cardiac function. The current study demonstrates that DZ preconditioning enhances EPCs survival under oxidative stress in vitro and their ability to treat myocardial infarction. PMID- 26032288 TI - Dried blood spot analysis for therapeutic drug monitoring of pazopanib. AB - Dried blood spot (DBS) sampling is potentially a more patient-friendly and flexible alternative to venous sampling of pazopanib. This study determined the agreement between pazopanib DBS and plasma concentrations to facilitate implementation of pazopanib DBS sampling into clinical practice. Paired DBS and plasma samples were collected in 12 patients. Pazopanib plasma concentrations were calculated from DBS concentrations using the formula: plasma concentration = DBSconcentration /(1 - hematocrit). Passing-Bablok and Bland-Altman analyses were used to determine the agreement between calculated and measured plasma concentrations. We predefined a clinical acceptance limit of 25% for the Bland Altman analysis. Passing-Bablok analysis showed a small constant (intercept estimate, -8.53 [95%CI, -12.22 to -4.41]) and slightly proportional (slope estimate, 1.15 [95%CI, 1.04-1.24]) bias between calculated and measured concentrations. This bias was clinically nonrelevant, as shown by Bland-Altman analysis; the mean ratio of calculated to measured concentrations was 0.94 (95%CI, 0.65-1.23). The clinical acceptance limits were well within these 95% limits of agreement. More specifically, 92.6% of the data points were within the predefined acceptance limits. Pazopanib plasma concentrations can be accurately calculated from DBS concentrations. Although validation of DBS cards prepared by patients themselves is required, these results show that DBS sampling can be used to monitor pazopanib therapy in clinical practice. PMID- 26032290 TI - Hydrogels in ophthalmic applications. AB - More and more people worldwide are affected by severe eye diseases eventually leading to visual impairment or blindness. In most cases, the treatment involves the application of ophthalmic dosage forms such as eye drops, suspensions or ointments. Unfortunately, some of the therapeutic approaches have major shortcomings, especially in the treatment of the posterior segment of the eye, where many vision-threatening diseases originate. Therefore, research focuses on the development of new materials (e.g., for vitreous substitution) and more advanced drug delivery systems. Hydrogels are an extremely versatile class of materials with many potential applications in ophthalmology. They found widespread application as soft contact lenses, foldable intraocular lenses, in situ gelling formulations for ophthalmic drug delivery and ocular adhesives for wound repair; their use as vitreous substitutes and intravitreal drug delivery systems is currently under investigation. In this article, we review the different applications of hydrogels in ophthalmology with special emphasis placed on the used polymers and their suitability as ocular drug delivery systems. PMID- 26032289 TI - E2F4 Program Is Predictive of Progression and Intravesical Immunotherapy Efficacy in Bladder Cancer. AB - Bladder cancer is a common malignant disease, with non-muscle-invasive bladder cancer (NMIBC) representing the majority of tumors. This cancer subtype is typically treated by transurethral resection. In spite of treatment, up to 70% of patients show local recurrences. Intravesical BCG (Bacillus Calmette-Guerin) immunotherapy has been widely used to treat NMIBC, but it fails to suppress recurrence of bladder tumors in up to 40% of patients. Therefore, the development of prognostic markers is needed to predict the progression of bladder cancer and the efficacy of intravesical BCG treatment. This study demonstrates the effectiveness of an E2F4 signature for prognostic prediction of bladder cancer. E2F4 scores for each sample in a bladder cancer expression dataset were calculated by summarizing the relative expression levels of E2F4 target genes identified by ChIP-seq, and then the scores were used to stratify patients into good- and poor-outcome groups. The molecular signature was investigated in a single bladder cancer dataset and then its effectiveness was confirmed in two meta-bladder datasets consisting of specimens from multiple independent studies. These results were consistent in different datasets and demonstrate that the E2F4 score is predictive of clinical outcomes in bladder cancer, with patients whose tumors exhibit an E2F4 score >0 having significantly shorter survival times than those with an E2F4 score <0, in both non-muscle-invasive, and muscle-invasive bladder cancer. Furthermore, although intravesical BCG immunotherapy can significantly improve the clinical outcome of NMIBC patients with positive E2F4 scores (E2F4>0 group), it does not show significant treatment effect for those with negative scores (E2F4<0 group). IMPLICATIONS: The E2F4 signature can be applied to predict the progression/recurrence and the responsiveness of patients to intravesical BCG immunotherapy in bladder cancer. PMID- 26032291 TI - Evaluation of protein drug stability with vitreous humor in a novel ex-vivo intraocular model. AB - The stability of protein therapeutics during the residence time in the vitreous humor (VH) is an important consideration for intra ocular treatment and can possibly impact therapeutic efficacy and/or treatment intervals. Unavailability of the reliable Ex-vivo intravitreal (ExVit) model to estimate protein stability following IVT has driven the research focus to develop such model which can facilitate protein stability estimation before in-vivo experiments. In this manuscript, we have developed and evaluated three ExVit models, namely, ExVit static, semi-dynamic and dynamic. These models were utilized and compared when studying the in-vitro stability of model protein formulations under simulated intraocular conditions using porcine vitreous humor (VH). The ExVit static model exhibited significant precipitation and aggregation of proteins, most likely due to pH change occurred in the VH after isolation. The semi-dynamic model assessed was composed of two compartments i.e., VH- and buffer-compartment which has effectively stabilized the pH of the VH and facilitated the migration of VH degradation products. However, some limitations related to investigation of long term protein stability were also observed with semi-dynamic model. The dynamic model developed, was comprised of three diffusion controlling barriers (two diffusion controlling membranes and a gel-matrix), which allowed modulation of the diffusion rate of macromolecules. The ability of dynamic model to modulate protein retention time in the VH will overcome the challenges faced by the semi dynamic model such as long-term stability evaluation. PMID- 26032292 TI - Advances in the design of fasted state simulating intestinal fluids: FaSSIF-V3. AB - Biorelevant media are commonly used to simulate the physiological composition of human intestinal fluids (HIF) in in vitro solubility and dissolution investigations. In comparison with the surfactant solutions or blank buffers, these media are able to better reflect the physiological solubility and dissolution behavior of poorly soluble active pharmaceutical ingredients (APIs). The aim of this investigation was to review the composition of FaSSIF and FaSSIF V2 according to recently summarized data about the physiological composition of fasted state human intestinal fluid and propose an updated version, FaSSIF-V3. Furthermore the surface tension was considered as a possible surrogate parameter to gauge the physiological correctness of new versions of biorelevant media. Various prototypes of FaSSIF-V3 were prepared with each of the following five bile salts: taurocholate (TC), glycocholate (GC), tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and glycochenodeoxycholate (GCDC) as well as replacing lecithin with its hydrolysis products, lysolecithin and sodium oleate. Two additional media consisting of a mixture of glycocholate (GC) and taurocholate (TG), with or without 0.2mM cholesterol, were also investigated. Solubilities of ten model compounds in various prototypes of FaSSIF-V3 were measured using HPLC-UV and compared to the solubilities in the existing biorelevant media (FaSSIF and FaSSIF-V2), fasted HIF, blank buffer and a 0.5% sodium dodecyl sulfate (SDS) solution. Additionally, the influence on the surface tension properties of various combinations of bile salts, phospholipids and their hydrolysis products and cholesterol in these media was investigated and an attempt was made to calculate the CMC of the various generations of FaSSIF. The results demonstrated that the amount and the type of phospholipids as well as the type of bile salt had a significant influence on the solubility and surface tension in the various FaSSIF-V3 prototypes and existing biorelevant media. In contrast to results with biorelevant media, it was demonstrated that blank buffers generally underestimate and SDS solutions highly overestimate the physiological relevant solubilities of all investigated APIs. The prototype containing FaSSIF-V3-GC/TC_Chol was able to better reflect the solubilities of the most investigated APIs in fasted HIF than the existing media, and it also matched the physiological surface tension reported for the fasted human gut, and was designated FaSSIF-V3. PMID- 26032293 TI - Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-beta-cyclodextrin based nanoparticles. AB - The aim of this study was to evaluate chitosan (CS)-, glycol chitosan (GCS)- and corresponding thiomer-based nanoparticles (NPs) for delivering dopamine (DA) to the brain by nasal route. Thus, the polyanions tripolyphosphate and sulfobutylether-beta-cyclodextrin (SBE-beta-CD), respectively, were used as polycation crosslinking agents and SBE-beta-CD also in order to enhance the DA stability. The most interesting formulation, containing GCS and SBE-beta-CD, was denoted as DA GCS/DA-CD NPs. NMR spectroscopy demonstrated an inclusion complex formation between SBE-beta-CD and DA. X-ray photoelectron spectroscopy analysis revealed the presence of DA on the external surface of NPs. DA GCS/DA-CD NPs showed cytotoxic effect toward Olfactory Ensheathing Cells only at higher dosage. Acute administration of DA GCS/DA-CD NPs into the right nostril of rats did not modify the levels of the neurotransmitter in both right and left striatum. Conversely, repeated intranasal administration of DA GCS/DA-CD NPs into the right nostril significantly increased DA in the ipsilateral striatum. Fluorescent microscopy of olfactory bulb after acute administration of DA fluorescent-labeled GCS/DA-CD NPs into the right nostril showed the presence of NPs only in the right olfactory bulb and no morphological tissue damage occurred. Thus, these GCS based NPs could be potentially used as carriers for nose-to-brain DA delivery for the Parkinson's disease treatment. PMID- 26032294 TI - Single-Incision Laparoscopic Sterilization of the Cheetah (Acinonyx jubatus). AB - OBJECTIVE: To describe laparoscopic ovariectomy and salpingectomy in the cheetah (Acinonyx jubatus) using single-incision laparoscopic surgery (SILS). STUDY DESIGN: Prospective cohort. ANIMALS: Female cheetahs (Acinonyx jubatus) (n = 21). METHODS: Cheetahs were randomly divided to receive either ovariectomy (n = 11) or salpingectomy (n = 10). The use and complications of a SILS port was evaluated in all of cheetahs. Surgery duration and insufflation volumes of carbon dioxide (CO2 ) were recorded and compared across procedures. RESULTS: Laparoscopic ovariectomy and salpingectomy were performed without complications using a SILS port. The poorly-developed mesosalpinx and ovarian bursa facilitated access to the uterine tube for salpingectomy in the cheetah. The median surgery duration for ovariectomy was 24 minutes (interquartile range 3) and for salpingectomy was 19.5 minutes (interquartile range 3) (P = .005). The median volume of CO2 used for ovariectomy was 11.25 L (interquartile range 3.08) and for salpingectomy was 4.90 L (interquartile range 2.52), (P = .001) CONCLUSIONS: Laparoscopic ovariectomy and salpingectomy can be performed in the cheetah using SILS without perioperative complications. Salpingectomy is faster than ovariectomy and requires less total CO2 for insufflation. PMID- 26032295 TI - Spectroscopic and photoluminescence characterization of Dy(3+) in Sr0.5Ca0.5TiO3 phosphor. AB - The spectroscopic and photoluminescence characteristics of trivalent dysprosium (Dy(3+))-doped Sr0.5Ca0.5TiO3 phosphor materials synthesized via solid-state reaction method were studied. The X-ray diffraction profile confirmed the orthorhombic perovskite structure of the prepared samples. Judd-Ofelt analysis was carried out to obtain the intensity parameters and predicted radiative properties of Sr0.5Ca0.5TiO3:2wt%Dy(3+). The photoluminescence spectrum of Dy(3+) doped Sr0.5Ca0.5TiO3 showed three emission peaks at 481, 574 and 638 nm corresponding to (4)F9/2 ->(6)H15/2, (4)F9/2 ->(6)H13/2 and (4)F9/2 ->(6)H11/2 transitions respectively. The variation of luminescence intensity with different excitation wavelengths and Dy(3+) concentrations is discussed. The decay profiles of (4)F9/2 excited levels of Dy(3+) ions show bi-exponential behaviour and also a decrease in average lifetime with increase in Dy(3+) concentration. Yellow to blue luminescence intensity ratio, CIE chromaticity co-ordinates and correlated color temperature were also calculated for different concentrations of Dy(3+) doped Sr0.5Ca0.5TiO3 phosphor at different lambdaex. PMID- 26032296 TI - Excessive pediatric fasciitis necrotisans due to Pseudomonas aeruginosa infection successfully treated with negative pressure wound therapy. AB - The case of a 10-year old female child is described with a history of myeloproliferative disorder having skin, bone and visceral involvement. Bone marrow biopsy revealed histiocytosis X. During chemotherapy necrotizing fasciitis of the lower abdominal wall was diagnosed. Multiple microbiological cultures taken from the wound base revealed Pseudomonas aeruginosa infection. Surgical necrectomy and application of negative pressure wound therapy (NPWT) was started together with intensive care treatment for sepsis. As both wound and general condition of the patient improved, autologous split thickness skin grafting was carried out in two sitting under continuing NPWT application. The applied skin grafts showed excellent take, the perilesional subcutaneous recesses resolved and complete healing was achieved after 28 days of NPWT treatment. Proper dermatological diagnosis and immediate escharectomy complemented with application of NPWT can be life-saving in the treatment of necrotizing fasciitis. PMID- 26032297 TI - When insanity has gone undiscovered by the courts: The practice of the Norwegian Criminal Cases Review Commission in cases of doubts about insanity. AB - BACKGROUND: England, Scotland and Norway have established Criminal Cases Review Commissions to review the convictions of persons who may have been wrongly found guilty of a criminal offence. AIMS: The aim of this study was to explore the Norwegian Criminal Cases Review Commission (NCCRC) practice when legal insanity constitutes grounds for possible reopening of a criminal case. METHODS: We identified all cases between 2004 and 2012 where an application to the NCCRC to reopen a case was on grounds of concerns about insanity. Data were extracted from records. Differences between reopened and disallowed insanity cases and variables that may explain the NCCRC's decision to reopen a case were analysed using multiple logistic regression. RESULTS: Forty cases were allowed, and 34 disallowed. The NCCRC relied fully and unanimously on the conclusions of the expert reports in making these decisions. In 26 of the 40 cases that the Commission reopened, psychosis had gone undetected by the courts. Such undetected cases were most often discovered in the wake of a new criminal case in connection with the defendant. If the length of the sentence were short, it was less likely that insanity had been considered by the court in the index judgement. CONCLUSIONS: The NCCRC may rely excessively on the forensic psychiatric reports. The experts' conclusions may be uncertain, given that they often have to look back several years to establish mental state and its relevance at the time of the crime. As nearly two-thirds of the reopened insanity cases had been given penalties of under 6 months, it may be asked whether such further investigation of fairly low-level crimes is the best use of resources. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26032298 TI - Tuning the pH Response of i-Motif DNA Oligonucleotides. AB - Cytosine-rich single-stranded DNA oligonucleotides are able to adopt an i-motif conformation, a four-stranded structure, near a pH of 6. This unique pH-dependent conformational switch is reversible and hence can be controlled by changing the pH. Here, we show that the pH response range of the human telomeric i-motif can be shifted towards more basic pH values by introducing 5-methylcytidines (5-MeC) and towards more acidic pH values by introducing 5-bromocytidines (5-BrC). No thermal destabilisation was observed in these chemically modified i-motif sequences. The time required to attain the new conformation in response to sudden pH changes was slow for all investigated sequences but was found to be ten times faster in the 5-BrC derivative of the i-motif. PMID- 26032299 TI - Reply: To PMID 25627679. PMID- 26032300 TI - Joint Toxicity of Lead, Chromium, Cobalt and Nickel to Photobacterium phosphoreum at No Observed Effect Concentration. AB - Joint toxicity of Pb2+, Cr3+, Co2+ and Ni2+ toward Photobacterium phosphoreum (Ph. phosphoreum) at the no observed effect concentration (NOEC) was determined through a factorial experiment. A neural network model was designed according to experimental results and employed for toxicity prediction of unary, binary, ternary and quaternary combinations. The mechanism and trends of joint toxicity were interpreted by quantitative structure-activity relationship, Michaelis Menten kinetic model, and concentration addition (CA) theory. Toxicity was directly related to the covalent index (Xm2r), covalent binding reaction presented a first and zero order reaction at low and high concentration, respectively, and CA accurately predicted toxicity. Additionally, the results showed that low concentrations of heavy metals should be considered when conducting environment risk assessment. PMID- 26032301 TI - A survey study on student preferences regarding pathology teaching in Germany: a call for curricular modernization. AB - BACKGROUND: Pathology is a discipline that provides the basis of the understanding of disease in medicine. The past decades have seen a decline in the emphasis laid on pathology teaching in medical schools and outdated pathology curricula have worsened the situation. Student opinions and thoughts are central to the questions of whether and how such curricula should be modernized. METHODS: A survey was conducted among 1018 German medical students regarding their preferences in pathology teaching modalities and their satisfaction with lecture based courses. A qualitative analysis was performed comparing a recently modernized pathology curriculum with a traditional lecture-based curriculum. The differences in modalities of teaching used were investigated. RESULTS: Student satisfaction with the lecture-based curriculum positively correlated with student grades (spearman's correlation coefficient 0.24). Additionally, students with lower grades supported changing the curriculum (spearman's correlation coefficient 0.47). The majority supported virtual microscopy, autopsies, seminars and podcasts as preferred didactic methods. CONCLUSIONS: The data supports the implementation of a pathology curriculum where tutorials, autopsies and supplementary computer-based learning tools play important roles. PMID- 26032302 TI - Pd-Catalyzed Regioselective Activation of gem-Difluorinated Cyclopropanes: A Highly Efficient Approach to 2-Fluorinated Allylic Scaffolds. AB - An unprecedented Pd-catalyzed regioselective activation of gem-difluorinated cyclopropanes induced by C-C bond cleavage is reported. It provides a general and efficient access to a variety of 2-fluoroallylic amines, ethers, esters, and alkylation products in high Z-selectivity, which are important skeletons in many biologically active molecules. In addition, the transformation represents the first general application of gem-difluorinated cyclopropanes as reaction partners in transition-metal-catalyzed cross-coupling reaction. PMID- 26032303 TI - Whole body perinatal postmortem CT angiography. PMID- 26032304 TI - Women living with HIV/AIDS (WLHA), battling stigma, discrimination and denial and the role of support groups as a coping strategy: a review of literature. AB - BACKGROUND AND OBJECTIVES: Women living with HIV/AIDS, in particular, have been positioned as a latent source of infection, and have captivated culpability and blame leading to a highly stigmatised and discriminated life. Despite the situation, women and their particular concerns have largely been ignored in HIV/AIDS research literature. This review aims to examine and analyze the feelings, experiences and perceptions of Women living with HIV/AIDS (WLHA) and will also access the role of support group as a coping strategy on the basis of 7 primary researches conducted in or on different parts of the world. METHODOLOGY: A systematic literature search was carried out on major data bases ASSIA, CINAHL, Science Direct, Web of Knowledge, Wiley Inter Science, AMED, Pub Med/Bio Med Central, MEDLINE and Cochrane Library. The articles included for review purpose were gauged against the pre-defined inclusion/exclusion criteria and quality assessment checklist resulting in a final 7 papers. FINDINGS/RESULTS: The findings were compiled into five thematic areas: (1) Disclosure as a sensitive issue; (2) Stigma and Discrimination associated with HIV/AIDS and the multidimensional effects on women's health and wellbeing; (3) Internalised Stigma; (4) Women living with HIV/AIDS experiences of being rejected, shunned and treated differently by physicians, family and close friends; (5) Support Group as among the best available interventions for stigma and discrimination. CONCLUSION: Support groups should be offered as a fundamental part of HIV/AIDS services and should be advocated as an effective and useful intervention. Further research is needed to examine the effect of support groups for women living with HIV/AIDS. A community based randomised controlled trial with support group as an intervention and a control group could provide further evidence of the value of support groups. PMID- 26032305 TI - Lead(II) nitrate and hexafluorosilicate complexes with neutral diphosphine coordination. AB - Rare examples of phosphine complexes of lead(II) are reported. The reaction of Pb(NO3)2 with Me2P(CH2)2PMe2, o-C6H4(PMe2)2 or Et2P(CH2)2PEt2 (L-L) in H2O/MeCN gave white [Pb(L-L)(NO3)2], irrespective of the ratio of reagents used. The X-ray structures of [Pb{Me2P(CH2)2PMe2}(NO3)2] and [Pb{o-C6H4(PMe2)2}(NO3)2] reveal chelating diphosphines and kappa(2)-NO3(-) groups occupying one hemisphere about the lead centre with single oxygen bridges to two further nitrate groups from neighbouring molecules completing a distorted eight-coordinate geometry. Using Pb(SiF6).2H2O produced [Pb{o-C6H4(PMe2)2}(H2O)(SiF6)].H2O which has a chelating diphosphine, the water molecule and a coordinated SiF6(2-) group (which could be described as either kappa(1)- or asymmetric kappa(3)-coordinated to the lead), with further Pb-F interactions to neighbouring molecules producing a chain polymer structure. The structure of [Pb{o-C6H4(PMe2)2}(DMF)2(SiF6)].DMF was also determined and contains dimers with fluorosilicate bridges. Adventitious oxygen readily form diphosphine dioxide complexes, and the structures of [Pb{Et2(O)P(CH2)2P(O)Et2}2(NO3)2] and [Pb{Me2P(CH2)2PMe2}{Me2(O)P(CH2)2P(O)Me2}][BF4]2.1/2MeNO2 produced in this way were determined. The former contains eight-coordinate lead with kappa(2)-NO3(-) groups and bridging diphosphine dioxides, which results in an infinite polymer. In the latter the diphosphine is chelated but the diphosphine dioxide bridges between Pb(ii) centres, with coordinated BF4(-) groups completing a very distorted ten-coordinate moiety. Attempts to isolate similar complexes with o C6H4(PPh2)2 or o-C6H4(AsMe2)2 were unsuccessful. PMID- 26032306 TI - Effect of time at pasture and herbage intake on profile of volatile organic compounds of dairy cow milk. AB - Volatile organic compounds (VOCs) in milk were investigated as quantitative markers of herbage intake (HI) at pasture. Eight Holstein cows were fed indoors with concentrate and conserved forages (grass silage, corn silage and hay) (NG), then were divided into three treatments according to the duration of access to pasture: 4 h (G4), 8 h (G8), and 20 h (G20) per day. The HIs were 4.3, 8.6, and 13.0 kg dry matter/day for the G4, G8 and G20 treatments, respectively. Milk from cows was sampled and analyzed VOCs by the steam distillation-extraction method and gas chromatography-mass spectrometry (GC-MS). From the intensity of the GC peak area, the levels of 1-phytene (3,7,11,15-tetramethyl-1-hexadecene) and 2 phytene (3,7,11,15-tetramethyl-2-hexadecene) were lowest in NG treatment and markedly increased with grazing time at pasture. With simple regression analysis on the HI to each diterpenoid, a strong correlation was found between the intensity of 1-phytene in the milk and the HI (r = 0.807, P < 0.001). 1-phytene content in milk could be useful as a quantitative marker of the HI of grazing cows. PMID- 26032307 TI - World Health Assembly tackles air pollution. PMID- 26032309 TI - Rheumatology an in-demand career choice. PMID- 26032310 TI - Why the fuss over disclosure of physician billings? PMID- 26032311 TI - Voriconazole-induced periostitis. PMID- 26032312 TI - Noninsured services provided with insured cataract surgery in Canada: ensuring transparent and fair treatment for patients. PMID- 26032313 TI - Don't ask, don't tell: Canadian policies on radon. PMID- 26032315 TI - Arctic sea ice trends, variability and implications for seasonal ice forecasting. AB - September Arctic sea ice extent over the period of satellite observations has a strong downward trend, accompanied by pronounced interannual variability with a detrended 1 year lag autocorrelation of essentially zero. We argue that through a combination of thinning and associated processes related to a warming climate (a stronger albedo feedback, a longer melt season, the lack of especially cold winters) the downward trend itself is steepening. The lack of autocorrelation manifests both the inherent large variability in summer atmospheric circulation patterns and that oceanic heat loss in winter acts as a negative (stabilizing) feedback, albeit insufficient to counter the steepening trend. These findings have implications for seasonal ice forecasting. In particular, while advances in observing sea ice thickness and assimilating thickness into coupled forecast systems have improved forecast skill, there remains an inherent limit to predictability owing to the largely chaotic nature of atmospheric variability. PMID- 26032314 TI - Preoperative testing before low-risk surgical procedures. AB - BACKGROUND: There is concern about increasing utilization of low-value health care services, including preoperative testing for low-risk surgical procedures. We investigated temporal trends, explanatory factors, and institutional and regional variation in the utilization of testing before low-risk procedures. METHODS: For this retrospective cohort study, we accessed linked population-based administrative databases from Ontario, Canada. A cohort of 1 546 223 patients 18 years or older underwent a total of 2 224 070 low-risk procedures, including endoscopy and ophthalmologic surgery, from Apr. 1, 2008, to Mar. 31, 2013, at 137 institutions in 14 health regions. We used hierarchical logistic regression models to assess patient- and institution-level factors associated with electrocardiography (ECG), transthoracic echocardiography, cardiac stress test or chest radiography within 60 days before the procedure. RESULTS: Endoscopy, ophthalmologic surgery and other low-risk procedures accounted for 40.1%, 34.2% and 25.7% of procedures, respectively. ECG and chest radiography were conducted before 31.0% (95% confidence interval [CI] 30.9%-31.1%) and 10.8% (95% CI 10.8% 10.8%) of procedures, respectively, whereas the rates of preoperative echocardiography and stress testing were 2.9% (95% CI 2.9%-2.9%) and 2.1% (95% CI 2.1%-2.1%), respectively. Significant variation was present across institutions, with the frequency of preoperative ECG ranging from 3.4% to 88.8%. Receipt of preoperative ECG and radiography were associated with older age (among patients 66-75 years of age, for ECG, adjusted odds ratio [OR] 18.3, 95% CI 17.6-19.0; for radiography, adjusted OR 2.9, 95% CI 2.8-3.0), preoperative anesthesia consultation (for ECG, adjusted OR 8.7, 95% CI 8.5-8.8; for radiography, adjusted OR 2.2, 95% CI 2.1-2.2) and preoperative medical consultation (for ECG, adjusted OR 6.8, 95% CI 6.7-6.9; for radiography, adjusted OR 3.6, 95% CI 3.5-3.6). The median ORs for receipt of preoperative ECG and radiography were 2.3 and 1.6, respectively. INTERPRETATION: Despite guideline recommendations to limit testing before low-risk surgical procedures, preoperative ECG and chest radiography were performed frequently. Significant variation across institutions remained after adjustment for patient- and institution-level factors. PMID- 26032316 TI - A seamless approach to understanding and predicting Arctic sea ice in Met Office modelling systems. AB - Recent CMIP5 models predict large losses of summer Arctic sea ice, with only mitigation scenarios showing sustainable summer ice. Sea ice is inherently part of the climate system, and heat fluxes affecting sea ice can be small residuals of much larger air-sea fluxes. We discuss analysis of energy budgets in the Met Office climate models which point to the importance of early summer processes (such as clouds and meltponds) in determining both the seasonal cycle and the trend in ice decline. We give examples from Met Office modelling systems to illustrate how the seamless use of models for forecasting on time scales from short range to decadal might help to unlock the drivers of high latitude biases in climate models. PMID- 26032317 TI - Variability of Arctic sea ice thickness and volume from CryoSat-2. AB - We present our estimates of the thickness and volume of the Arctic Ocean ice cover from CryoSat-2 data acquired between October 2010 and May 2014. Average ice thickness and draft differences are within 0.16 m of measurements from other sources (moorings, submarine, electromagnetic sensors, IceBridge). The choice of parameters that affect the conversion of ice freeboard to thickness is discussed. Estimates between 2011 and 2013 suggest moderate decreases in volume followed by a notable increase of more than 2500 km(3) (or 0.34 m of thickness over the basin) in 2014, which could be attributed to not only a cooler summer in 2013 but also to large-scale ice convergence just west of the Canadian Arctic Archipelago due to wind-driven onshore drift. Variability of volume and thickness in the multiyear ice zone underscores the importance of dynamics in maintaining the thickness of the Arctic ice cover. Volume estimates are compared with those from ICESat as well as the trends in ice thickness derived from submarine ice draft between 1980 and 2004. The combined ICESat and CryoSat-2 record yields reduced trends in volume loss compared with the 5 year ICESat record, which was weighted by the record-setting ice extent after the summer of 2007. PMID- 26032318 TI - Factors affecting projected Arctic surface shortwave heating and albedo change in coupled climate models. AB - We use a large ensemble of simulations from the Community Earth System Model to quantify simulated changes in the twentieth and twenty-first century Arctic surface shortwave heating associated with changing incoming solar radiation and changing ice conditions. For increases in shortwave absorption associated with albedo reductions, the relative influence of changing sea ice surface properties and changing sea ice areal coverage is assessed. Changes in the surface sea ice properties are associated with an earlier melt season onset, a longer snow-free season and enhanced surface ponding. Because many of these changes occur during peak solar insolation, they have a considerable influence on Arctic surface shortwave heating that is comparable to the influence of ice area loss in the early twenty-first century. As ice area loss continues through the twenty-first century, it overwhelms the influence of changes in the sea ice surface state, and is responsible for a majority of the net shortwave increases by the mid-twenty first century. A comparison with the Arctic surface albedo and shortwave heating in CMIP5 models indicates a large spread in projected twenty-first century change. This is in part related to different ice loss rates among the models and different representations of the late twentieth century ice albedo and associated sea ice surface state. PMID- 26032319 TI - Arctic sea ice reduction: the evidence, models and impacts. PMID- 26032320 TI - Recent changes in Antarctic Sea Ice. AB - In contrast to the Arctic, total sea ice extent (SIE) across the Southern Ocean has increased since the late 1970s, with the annual mean increasing at a rate of 186*10(3) km(2) per decade (1.5% per decade; p<0.01) for 1979-2013. However, this overall increase masks larger regional variations, most notably an increase (decrease) over the Ross (Amundsen-Bellingshausen) Sea. Sea ice variability results from changes in atmospheric and oceanic conditions, although the former is thought to be more significant, since there is a high correlation between anomalies in the ice concentration and the near-surface wind field. The Southern Ocean SIE trend is dominated by the increase in the Ross Sea sector, where the SIE is significantly correlated with the depth of the Amundsen Sea Low (ASL), which has deepened since 1979. The depth of the ASL is influenced by a number of external factors, including tropical sea surface temperatures, but the low also has a large locally driven intrinsic variability, suggesting that SIE in these areas is especially variable. Many of the current generation of coupled climate models have difficulty in simulating sea ice. However, output from the better performing IPCC CMIP5 models suggests that the recent increase in Antarctic SIE may be within the bounds of intrinsic/internal variability. PMID- 26032321 TI - Sea-ice thermodynamics and brine drainage. AB - Significant changes in the state of the Arctic ice cover are occurring. As the summertime extent of sea ice diminishes, the Arctic is increasingly characterized by first-year rather than multi-year ice. It is during the early stages of ice growth that most brine is injected into the oceans, contributing to the buoyancy flux that mediates the thermo-haline circulation. Current operational sea-ice components of climate models often treat brine rejection between sea ice and the ocean similarly to a thermodynamic segregation process, assigning a fixed salinity to the sea ice, typical of multi-year ice. However, brine rejection is a dynamical, buoyancy-driven process and the salinity of sea ice varies significantly during the first growth season. As a result, current operational models may over predict the early brine fluxes from newly formed sea ice, which may have consequences for coupled simulations of the polar oceans. Improvements both in computational power and our understanding of the processes involved have led to the emergence of a new class of sea-ice models that treat brine rejection dynamically and should enhance predictions of the buoyancy forcing of the oceans. PMID- 26032322 TI - Evidence linking rapid Arctic warming to mid-latitude weather patterns. AB - The effects of rapid Arctic warming and ice loss on weather patterns in the Northern Hemisphere is a topic of active research, lively scientific debate and high societal impact. The emergence of Arctic amplification--the enhanced sensitivity of high-latitude temperature to global warming--in only the last 10 20 years presents a challenge to identifying statistically robust atmospheric responses using observations. Several recent studies have proposed and demonstrated new mechanisms by which the changing Arctic may be affecting weather patterns in mid-latitudes, and these linkages differ fundamentally from tropics/jet-stream interactions through the transfer of wave energy. In this study, new metrics and evidence are presented that suggest disproportionate Arctic warming-and resulting weakening of the poleward temperature gradient-is causing the Northern Hemisphere circulation to assume a more meridional character (i.e. wavier), although not uniformly in space or by season, and that highly amplified jet-stream patterns are occurring more frequently. Further analysis based on self-organizing maps supports this finding. These changes in circulation are expected to lead to persistent weather patterns that are known to cause extreme weather events. As emissions of greenhouse gases continue unabated, therefore, the continued amplification of Arctic warming should favour an increased occurrence of extreme events caused by prolonged weather conditions. PMID- 26032323 TI - Regional variability in sea ice melt in a changing Arctic. AB - In recent years, the Arctic sea ice cover has undergone a precipitous decline in summer extent. The sea ice mass balance integrates heat and provides insight on atmospheric and oceanic forcing. The amount of surface melt and bottom melt that occurs during the summer melt season was measured at 41 sites over the time period 1957 to 2014. There are large regional and temporal variations in both surface and bottom melting. Combined surface and bottom melt ranged from 16 to 294 cm, with a mean of 101 cm. The mean ice equivalent surface melt was 48 cm and the mean bottom melt was 53 cm. On average, surface melting decreases moving northward from the Beaufort Sea towards the North Pole; however interannual differences in atmospheric forcing can overwhelm the influence of latitude. Substantial increases in bottom melting are a major contributor to ice losses in the Beaufort Sea, due to decreases in ice concentration. In the central Arctic, surface and bottom melting demonstrate interannual variability, but show no strong temporal trends from 2000 to 2014. This suggests that under current conditions, summer melting in the central Arctic is not large enough to completely remove the sea ice cover. PMID- 26032324 TI - Deformation of the gluteal soft tissues during sitting. AB - BACKGROUND: Excessive deformation of soft tissues is considered to be one of the major contributing factors to discomfort and injury for individuals who sit for long periods of time. Soft tissue deformation in research has been measured under the assumption that tissues deform uniaxially below the ischium, with very small or negligible deformations taking place in other directions. Therefore, this study describes the deformation of the gluteus maximus muscle and surrounding fat tissues in the buttock region for seated subjects. METHODS: In vivo measurements of the deformation for the gluteal soft tissues were obtained from MRI scans of six seated subjects. Each subject was scanned in weight-bearing and non-weight bearing sitting postures using a Positional MRI scanner (Fonar 0.6 Tesla IndomitableTM). Deformations were measured below the ischium and the proximal femur. Deformation of the gluteus maximus was also measured in the distal direction along the thigh for each subject. FINDINGS: Our data suggest that soft tissues undergo three-dimensional deformation with considerable components below the ischium (mean of 21.4mm) and in the distal direction along the thigh (mean of 20.3mm). Differences in muscle deformation below the ischium were also observed between obese (mean of 27.4mm) and non-obese subjects (mean of 16.5mm). INTERPRETATION: Findings of this study demonstrate that tissue deformations in sitting include complex three-dimensional motions that are not well approximated by two-dimensional models. PMID- 26032325 TI - Correlation between cell-free mRNA expressions and PLGF protein level in severe preeclampsia. AB - BACKGROUND: Preeclampsia is a major cause of morbidity and mortality, both maternal and perinatal. The etiology and pathophysiology of preeclampsia remain unknown. Research shows the implantation of the placenta in preeclampsia occurs due to incomplete angiogenic imbalance as one of the preeclampsia pathogenesis. PlGF is angiogenic protein which is synthesized in placenta by mRNA PlGF. When damage occurs, mRNA will be released from cell and form cell-free mRNA. This study aims to analyze the differences between the PlGF mRNA expression in severe preeclampsia and normal pregnancy as well as to measure the relationship between cell-free mRNA and levels of PlGF with the incidence of severe preeclampsia. METHODS: The method used in this study is an observational analytic study with cross-sectional design. Blood samples were obtained from patients with preeclampsia and normal pregnancies as the controlling factors in accordance with inclusion and exclusion criterias. Examination of the PlGF level was measured by ELISA method and mRNA PIGF expression was measured by RT-PCR. Physical and laboratory examinations of patients were recorded and collected as data. Calculations were done by statistical analysis. RESULTS: Mean of the cell-free mRNA PlGF expression level in severe preeclampsia is 2.2983 ng/mL within the scale of 1.96-2.83 ng/mL and deviation standard of 0.1897. Using Pearson Analysis Test, the result shows that there is a positive correlation between cell-free mRNA expression and PlGF protein level in severe preeclampsia, with r = 0.640 dan p < 0.004. CONCLUSION: There is no difference between expression of cell-free mRNA PlGF in severe preeclampsia serum and normal pregnancy. There is a significant correlation between expression of cell-free mRNA and PlGF protein level in severe preeclampsia. PMID- 26032327 TI - The novel use of a SenseCam and accelerometer to validate training load and training information in a self-recall training diary. AB - Self-recall training diaries are a frequently used tool to quantify training load and training information. While accelerometers are predominantly used to validate training diaries, they are unable to validate contextual training information. Thus this study aimed to examine the novel use of data fusion from a wearable camera device (SenseCam) and accelerometer to validate a self-recall training diary. Thirty participants filled in a training diary for 1 day while simultaneously wearing a SenseCam and accelerometer. The training diary was validated using Bland-Altman plots, Spearman's rank-order correlation, percentage agreement and kappa measure of agreement between the diary and the SenseCam and accelerometer. The results demonstrated overall agreement, and no bias, between the training diary and the accelerometer for training intensity, and the SenseCam for duration of activity and travel time. A positive correlation was found for duration (r = 0.82, P < 0.001) and intensity (r = 0.67, P < 0.001). Hundred per cent agreement was found between the SenseCam and training diary for activity, training surface and footwear (kappa = 1, P < 0.0001), with a lower agreement noted for sports played (97.3%, kappa = 0.91, P < 0.0001). The self-recall training diary was found to be a valid measure of capturing training load and training information using the combined wearable camera device and accelerometer. PMID- 26032326 TI - Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). AB - BACKGROUND: Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors. RESULTS: CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naive CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells. CONCLUSIONS: This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness. PMID- 26032328 TI - [Research in Radiology: our perspective]. PMID- 26032329 TI - Elucidating the mechanism of action of the clinically approved taxanes: a comprehensive comparison of local and allosteric effects. AB - The clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) target the tubulin protein in microtubules. Despite the clinical success of these agents, the mechanism of action of this class of drugs remains elusive, making rational design of taxanes difficult. Molecular dynamics simulations of these three taxanes with the alphabeta-tubulin heterodimer examine the similarities and differences in the effects of the drugs on tubulin, probing both local and allosteric effects. Despite their structural similarity, the drugs adopt different conformations in the binding site on beta-tubulin. The taxanes similarly increase the helical character of alpha- and beta-tubulins. No correlations are found between microtubule assembly and (i) binding affinity or (ii) the role of the M-loop in enhancing lateral contacts. Instead, changes in intra- and interdimer longitudinal contacts are indicative of the mechanism of action of the taxanes. We find beta:H1-S1', and more importantly beta:H9 and beta:H10, play a role translating the effect of local drug binding in beta tubulin to an allosteric effect in alpha-tubulin and propose that the displacement of these secondary structures towards alpha-tubulin may be used as a predictor of the effect of taxanes on the tubulin heterodimers in rational drug design approaches. PMID- 26032330 TI - Treatment with either obestatin or ghrelin attenuates mesenteric ischemia reperfusion-induced oxidative injury of the ileum and the remote organ lung. AB - To evaluate the effects of exogenous ghrelin or obestatin on intestinal injury and accompanying pulmonary injury, intestinal ischemia-reperfusion (I/R) was induced in rats by obstructing the superior mesenteric artery for 60min, whereas laparotomy was performed in the sham group. At the beginning of the 90-min reperfusion period, the rats were injected with obestatin (100MUg/kg), ghrelin (10ng/kg), or saline intravenously (iv). At the end of reperfusion, the blood, ileum, and lung samples were taken for the histological and biochemical assays. In the saline-treated I/R group, the increased serum interleukin (IL)-1beta level, high damage scores, and elevated tissue malondialdehyde level and collagen content in both tissues were significantly reduced by obestatin or ghrelin. Increased ileal myeloperoxidase activity of the saline-treated I/R group was reduced by treatment with obestatin or ghrelin, whereas increased pulmonary myeloperoxidase activity was reduced with administration of obestatin. Increased DNA fragmentation in the ileum of the saline-treated I/R group was reduced by both peptides. Elevated luminol-lucigenin chemiluminescence levels and nuclear factor kappa B (NF-kappaB) messenger RNA (mRNA) expression in the ileum of the saline-treated-I/R group were significantly decreased by obestatin or ghrelin treatment. I/R-induced depletion of the antioxidant glutathione in both ileal and pulmonary tissues was prevented with either obestatin or ghrelin treatment. Administration of either obestatin or ghrelin exerts similar protective effects against I/R-induced ileal and pulmonary injury, thus warranting further investigation for their possible use against ischemic intestinal injury. PMID- 26032331 TI - Diapause hormone in the Helicoverpa/Heliothis complex: A review of gene expression, peptide structure and activity, analog and antagonist development, and the receptor. AB - This review summarizes recent studies focusing on diapause hormone (DH) in the Helicoverpa/Heliothis complex of agricultural pests. Moths in this complex overwinter in pupal diapause, a form of developmental arrest used to circumvent unfavorable seasons. DH was originally reported in the silkmoth Bombyx mori, a species that relies on DH to induce an embryonic diapause. But, in the case of Helicoverpa/Heliothis, levels of dh transcripts and DH peptides are more abundant in nondiapausing pupae than in diapausing individuals, and DH effectively terminates diapause within a specific temperature range. A structure activity relationship study indicated that the active core of DH is the C-terminal hepta peptide, LWFGPRLa. We designed and synthesized a first generation of DH agonists and identified two agonists (PK-2Abf and PK-Etz) that were nearly 50- and 13-fold more potent than the native hormone. These studies revealed two structural characteristics of DH and its agonists that are essential for interaction with the receptor: a trans-Pro configuration to form a type I beta-turn and a hydrophobic moiety involved in ligand binding. Modification of DH at the active core yielded a potent DH antagonist (DH-Jo, acetyl-GLWA[Jo]RLa) as well as an agonist (DH-2Abf-K). Three compounds (Decyl-1963, Dodecyl-1967, Heptyl-1965) were identified as agents capable of penetrating the cuticle of young pupae and thereby preventing the entry into diapause. DH receptor cDNA was cloned and an effective in vitro high throughput screen system was established for future use. This work sets the stage for further development of DH analogs and antagonists that have the potential to disrupt insect diapause as a tool for pest management. PMID- 26032332 TI - Improving oral hygiene skills among children undergoing treatment at the haemato oncology department - an interventional programme. AB - OBJECTIVES: The aim of this interventional programme was to educate children undergoing treatment at the haemato-oncology department in how to improve their oral hygiene skills. METHODS: Children (and their parents) treated at the haemato oncology department for haematological malignancies and disorders were educated and instructed in how to improve their dental oral hygiene skills. Instructions, demonstration and practice of toothbrushing techniques, as well as interproximal cleaning, were carried out in three separate sessions. In each session, toothbrushing skills were evaluated using the Ashkenazi index to assess improvement in oral hygiene skills over time. Four assessments were performed and recorded for each participant: before the initial explanation; immediately following the explanation; and 3 and 6 weeks following the first visit. RESULTS: Overall, 52 children were enrolled in the programme. The first toothbrushing performance skill evaluation revealed a low score of 10.44 out of a total of 40; this was significantly increased, following the instruction session, to 33.02 (P < 0.001). This improvement was maintained at the follow-up visits at 3 weeks (35.09 +/- 6.3) and 6 weeks (36.34 +/- 8.3). Following the instructions, a significant increase was accomplished in both 'reach' and 'stay' components of the score, to 18.44 out of 20 for 'reach' and 17.9 out of 20 for 'stay' at the last visit (P < 0.01). CONCLUSIONS: Individual supervised toothbrushing education, including a methodological toothbrushing technique, appears to be very effective. Educating medically compromised high-risk patients, such as hospitalised children, might be a good way to improve oral health and prevent future disease in this population. PMID- 26032333 TI - Tuning the crystalline and mesophase structure of olefin block copolymer through self-nucleation and annealing treatments. AB - As a type of novel semi-crystalline block copolymers, the final properties of olefin block copolymers (OBCs) greatly depend on the crystalline and phase separated structures. In the present work, we systematically investigated the influence of self-nucleation and annealing on the lamellar and mesophase separated structure of OBCs. According to the crystalline and melting behavior after self-nucleation and annealing treatments, four different regimes can be recognized with the self-seeding temperature Ts varying from 125 to 109 degrees C. In regime A, only self-nucleation occurs, while it coexists with lamellar thickening in regime B. In regime C, there is only lamellar thickening behavior. The lamellar thickening induced inconsecutive lamellar crystals observed revealed that the rearrangement of the hard blocks, which are next to the soft blocks and trapped in the intermediate regime between crystalline and amorphous phases, into neighboring lamellar crystals should be the mechanism for the lamellar thickening of the OBCs. Surprisingly, no lamellar thickening occurs and a new small melting peak appears at lower temperatures in regime D. Considering the block dispersity of OBCs, the emergence of a small melting peak at lower temperatures can be attributed to the crystallization of the ethylene sequence with relatively weaker crystallization abilities, which are not able to crystallize in a standard crystalline state. Based on these findings, we gained some new understandings on lamellar thickening behavior of OBCs and established the self-nucleation and annealing process as a powerful tool for tuning the crystalline and phase separated structures of OBCs. PMID- 26032334 TI - N-terminus of seed caleosins is essential for lipid droplet sorting but not for lipid accumulation. AB - Caleosin, a calcium-binding protein associated with plant lipid droplets, stimulates lipid accumulation when heterologously expressed in Saccharomyces cerevisiae. Accumulated lipids are stored in cytoplasmic lipid droplets that are stabilised by incorporated caleosin. We designed a set of mutants affecting putative crucial sites for caleosin function and association with lipid droplets, i.e. the N-terminus, the EF-hand motif and the proline-knot motif. We investigated the effect of introduced mutations on caleosin capacity to initiate lipid accumulation and on caleosin sorting within cell as well as on its association with lipid droplets. Our results strongly suggest that the N-terminal domain is essential for proper protein sorting and targeting to lipid droplets but not for enhancing lipid accumulation. PMID- 26032335 TI - Knockout of cyclophilin D in Ppif-/- mice increases stability of brain mitochondria against Ca2+ stress. AB - The mitochondrial peptidyl prolyl isomerase cyclophilin D (CypD) activates permeability transition (PT). To study the role of CypD in this process we compared the functions of brain mitochondria isolated from wild type (BMWT) and CypD knockout (Ppif(-/-)) mice (BMKO) with and without CypD inhibitor Cyclosporin A (CsA) under normal and Ca(2+) stress conditions. Our data demonstrate that BMKO are characterized by higher rates of glutamate/malate-dependent oxidative phosphorylation, higher membrane potential and higher resistance to detrimental Ca(2+) effects than BMWT. Under the elevated Ca(2+) and correspondingly decreased membrane potential the dose response in BMKO shifts to higher Ca(2+) concentrations as compared to BMWT. However, significantly high Ca(2+) levels result in complete loss of membrane potential in BMKO, too. CsA diminishes the loss of membrane potential in BMWT but has no protecting effect in BMKO. The results are in line with the assumption that PT is regulated by CypD under the control of matrix Ca(2+). Due to missing of CypD the BMKO can favor PT only at high Ca(2+) concentrations. It is concluded that CypD sensitizes the brain mitochondria to PT, and its inhibition by CsA or CypD absence improves the complex I-related mitochondrial function and increases mitochondria stability against Ca(2+) stress. PMID- 26032336 TI - Structural and kinetic characterization of recombinant 2-hydroxymuconate semialdehyde dehydrogenase from Pseudomonas putida G7. AB - The first enzyme in the oxalocrotonate branch of the naphthalene-degradation lower pathway in Pseudomonas putida G7 is NahI, a 2-hydroxymuconate semialdehyde dehydrogenase which converts 2-hydroxymuconate semialdehyde to 2-hydroxymuconate in the presence of NAD(+). NahI is in family 8 (ALDH8) of the NAD(P)(+)-dependent aldehyde dehydrogenase superfamily. In this work, we report the cloning, expression, purification and preliminary structural and kinetic characterization of the recombinant NahI. The nahI gene was subcloned into a T7 expression vector and the enzyme was overexpressed in Escherichia coli ArcticExpress as a hexa histidine-tagged fusion protein. After purification by affinity and size exclusion chromatography, dynamic light scattering and small-angle X-ray scattering experiments were conducted to analyze the oligomeric state and the overall shape of the enzyme in solution. The protein is a tetramer in solution and has nearly perfect 222 point group symmetry. Protein stability and secondary structure content were evaluated by a circular dichroism spectroscopy assay under different thermal conditions. Furthermore, kinetic assays were conducted and, for the first time, KM (1.3+/-0.3MUM) and kcat (0.9s(-1)) values were determined at presumed NAD(+) saturation. NahI is highly specific for its biological substrate and has no activity with salicylaldehyde, another intermediate in the naphthalene degradation pathway. PMID- 26032337 TI - Endogenous fatty acids in olfactory hairs influence pheromone binding protein structure and function in Lymantria dispar. AB - The gypsy moth utilizes a pheromone, (7R,8S)-2-methyl-7,8-epoxyoctadecane, for mate location. The pheromone is detected by sensory hairs (sensilla) on the antennae of adult males. Sensilla contain the dendrites of olfactory neurons bathed in lymph, which contains pheromone binding proteins (PBPs). We have extracted and identified free fatty acids from lymph of sensory hairs, and we demonstrate that these function as endogenous ligands for gypsy moth PBP1 and PBP2. Homology modeling of both PBPs, and docking of fatty acids reveal multiple binding sites: one internal, the others external. Pheromone binding assays suggest that these fatty acids increase PBP-pheromone binding affinity. We show that fatty acid binding causes an increase in alpha-helix content in the N terminal domain, but not in the C-terminal peptide of both proteins. The C terminal peptide was shown to form a alpha-helix in a hydrophobic, homogeneous environment, but not in the presence of fatty acid micelles. Through partition assays we show that the fatty acids prevent adsorption of the pheromone on hydrophobic surfaces and facilitate pheromone partition into an aqueous phase. We propose that lymph is an emulsion of fatty acids and PBP that influence each other and thereby control the partition equilibria of hydrophobic odorants. PMID- 26032338 TI - Advances in electron microscopy: A qualitative view of instrumentation development for macromolecular imaging and tomography. AB - Macromolecular imaging and tomography of ice embedded samples has developed into a mature imaging technology, in structural biology today widely referred to simply as cryo electron microscopy.(1) While the pioneers of the technique struggled with ill-suited instruments, state-of-the-art cryo microscopes are now readily available and an increasing number of groups are producing excellent high resolution structural data of macromolecular complexes, of cellular organelles, or the morphology of whole cells. Instrumentation developers, however, are offering yet more novel electron optical devices, such as energy filters and monochromators, aberration correctors or physical phase plates. Here we discuss how current instrumentation has already changed cryo EM, and how newly available instrumentation - often developed in other fields of electron microscopy - may further develop the use and applicability of cryo EM to the imaging of single isolated macromolecules of smaller size or molecules embedded in a crowded cellular environment. PMID- 26032339 TI - Multidimensional persistence in biomolecular data. AB - Persistent homology has emerged as a popular technique for the topological simplification of big data, including biomolecular data. Multidimensional persistence bears considerable promise to bridge the gap between geometry and topology. However, its practical and robust construction has been a challenge. We introduce two families of multidimensional persistence, namely pseudomultidimensional persistence and multiscale multidimensional persistence. The former is generated via the repeated applications of persistent homology filtration to high-dimensional data, such as results from molecular dynamics or partial differential equations. The latter is constructed via isotropic and anisotropic scales that create new simiplicial complexes and associated topological spaces. The utility, robustness, and efficiency of the proposed topological methods are demonstrated via protein folding, protein flexibility analysis, the topological denoising of cryoelectron microscopy data, and the scale dependence of nanoparticles. Topological transition between partial folded and unfolded proteins has been observed in multidimensional persistence. The separation between noise topological signatures and molecular topological fingerprints is achieved by the Laplace-Beltrami flow. The multiscale multidimensional persistent homology reveals relative local features in Betti-0 invariants and the relatively global characteristics of Betti-1 and Betti-2 invariants. PMID- 26032341 TI - First molar size and wear within and among modern hunter-gatherers and agricultural populations. AB - Apart from reflecting modern human dental variation, differences in dental size among populations provide a means for studying continuous evolutionary processes and their mechanisms. Dental wear, on the other hand, has been widely used to infer dietary adaptations and variability among or within diverse ancient human populations. Few such studies have focused on modern foragers and farmers, however, and diverse methods have been used. This research aimed to apply a single, standardized, and systematic quantitative procedure to measure dental size and dentin exposure in order to analyze differences among several hunter gatherer and agricultural populations from various environments and geographic origins. In particular, we focused on sexual dimorphism and intergroup differences in the upper and lower first molars. Results indicated no sexual dimorphism in molar size and wear within the studied populations. Despite the great ethnographic variation in subsistence strategies among these populations, our findings suggest that differences in sexual division of labor do not affect dietary wear patterns. PMID- 26032340 TI - Measuring genetic knowledge: a brief survey instrument for adolescents and adults. AB - Basic knowledge of genetics is essential for understanding genetic testing and counseling. The lack of a written, English language, validated, published measure has limited our ability to evaluate genetic knowledge of patients and families. Here, we begin the psychometric analysis of a true/false genetic knowledge measure. The 18-item measure was completed by parents of children with congenital heart defects (CHD) (n = 465) and adolescents and young adults with CHD (age: 15 25, n = 196) with a mean total correct score of 12.6 [standard deviation (SD) = 3.5, range: 0-18]. Utilizing exploratory factor analysis, we determined that one to three correlated factors, or abilities, were captured by our measure. Through confirmatory factor analysis, we determined that the two factor model was the best fit. Although it was necessary to remove two items, the remaining items exhibited adequate psychometric properties in a multidimensional item response theory analysis. Scores for each factor were computed, and a sum-score conversion table was derived. We conclude that this genetic knowledge measure discriminates best at low knowledge levels and is therefore well suited to determine a minimum adequate amount of genetic knowledge. However, further reliability testing and validation in diverse research and clinical settings is needed. PMID- 26032342 TI - Autosomal dominant diffuse nonepidermolytic palmoplantar keratoderma due to a recurrent mutation in aquaporin-5. PMID- 26032344 TI - Atypical Cause of Lateral Hip Pain Due to Proximal Gluteus Medius Muscle Tear: A Report of 2 Cases. PMID- 26032343 TI - Electron-capture dissociation and ion mobility mass spectrometry for characterization of the hemoglobin protein assembly. AB - Native spray has the potential to probe biophysical properties of protein assemblies. Here we report an investigation using both ECD top-down sequencing with an FTICR mass spectrometer and ion mobility (IM) measurements on a Q-TOF to investigate the collisionally induced unfolding of a native-like heterogeneous tetrameric assembly, human hemoglobin (hHb), in the gas phase. To our knowledge, this is the first report combining ECD and ion-mobility data on the same target protein assembly to delineate the effects of collisional activation on both assembly size and the extent and location of fragmentation. Although the collision-induced unfolding of the hemoglobin assembly is clearly seen by both IMMS and ECD, the latter delineates the regions that increasingly unfold as the collision energy is increased. The results are consistent with previous outcomes for homogeneous protein assemblies and reinforce our interpretation that activation opens the structure of the protein assembly from the flexible regions to make available ECD fragmentation, without dissociating the component proteins. PMID- 26032345 TI - Submental Muscle Activity is Delayed and Shortened During Swallowing Following Stroke. AB - OBJECTIVE: To evaluate the activities of the submental muscles using surface electromyography (sEMG) in patients presenting with dysphagia secondary to middle cerebral artery (MCA) infarction, and to compare the results with those in healthy volunteers. DESIGN: Retrospective study design. SETTING: A dysphagia clinic at a tertiary care university hospital. PARTICIPANTS: Twenty-one patients presenting with dysphagia after unilateral MCA infarction were recruited into the study within 2 months of stroke onset. To serve as a control group, 13 healthy volunteers were enrolled. MAIN OUTCOME MEASURES: The primary sEMG parameters were swallowing onset, pretrigger duration, swallowing duration, and swallowing amplitude. Swallowing functional outcome was evaluated using the Videofluoroscopic Dysphagia Scale and the American Speech-Language-Hearing Association National Outcome Measurement System. RESULTS: Patients with MCA infarction demonstrated significantly delayed swallowing onset (P < .001) and shorter swallowing duration (P = .003) compared with the controls. Duration from the start of sEMG activity and actual laryngeal elevation also was delayed in the patient group (P = .042). At a cut-off point of 0.13 seconds for swallowing onset, sensitivity was 85.7% and specificity was 69.2%. For swallowing duration, sensitivity was 84.6% and specificity was 66.7% with 1.05 seconds as the cut-off point. CONCLUSIONS: Patients with MCA infarction showed not only delayed swallowing onset and pretrigger duration, but also shorter duration of sEMG activity compared with those in healthy volunteers. Our results suggest that dysphagia after stroke might be further compromised by delayed laryngeal response especially after the start of suprahyoid muscle activity, which represents impaired laryngeal protection mechanism. PMID- 26032346 TI - Effects of Crossed Brassiere Straps on Pain, Range of Motion, and Electromyographic Activity of Scapular Upward Rotators in Women With Scapular Downward Rotation Syndrome. AB - BACKGROUND: Scapular downward rotation syndrome manifests as an abnormally downward-rotated scapula at rest or with arm motion and typically results in neck and shoulder pain. The brassiere strap has been suggested as a possible contributing factor to scapula downward rotation and pain in the upper trapezius because of increased downward rotational force on the lateral aspect of the scapula. No study, however, has examined the influences of a modified brassiere strap on pain in and the function of the scapular muscles. OBJECTIVE: To examine the effects of crossed brassiere straps on the pressure pain threshold (PPT) of the upper trapezius, neck rotation range of motion (ROM), and electromyographic activity of the scapular upward rotators in females with scapular downward rotation syndrome. DESIGN: Cross-over design. SETTING: Laboratory. PARTICIPANTS: In total, 15 female subjects with scapular downward rotation syndrome were recruited at hospitals and a local university. METHODS: All participants performed neck rotation and humeral elevation under 2 different conditions: parallel and crossed brassiere straps. MAIN OUTCOME MEASUREMENTS: The PPT of the upper trapezius was measured using an analog algometer, whereas neck rotation ROM was quantified with a 3-dimensional ultrasonic motion analysis system. The electromyographic activities of the upper trapezius, serratus anterior, and lower trapezius during humeral elevation were assessed with a surface electromyography system. Outcome measures were assessed under parallel and crossed brassiere strap conditions, and differences in outcomes between the conditions were analyzed using a paired t-test. RESULTS: The PPT and neck rotation ROM were increased when the subject was wearing the brassiere with crossed versus parallel straps (P < .001). Greater electromyographic activities of the serratus anterior, lower trapezius, and lesser upper trapezius muscles during humeral elevation were found under the crossed strap condition than the parallel strap condition (P < .05). CONCLUSIONS: These findings provide useful information for clinicians when designing management programs to decrease pain and improve biomechanical function for females with scapular downward rotation syndrome. PMID- 26032347 TI - A Retrospective Review of Unintended Effects After Single-Event Multi-Level Chemoneurolysis With Botulinum Toxin-A and Phenol in Children With Cerebral Palsy. AB - BACKGROUND: Single-event multi-level chemoneurolysis (SEMLC) is a single-session procedure that treats various limbs of patients with spasticity at multiple levels with chemoneurolytic agents. Phenol is used in combination with botulinum toxin A (BTX-A) to enable spastic muscles to be treated without overdosing with BTX-A. OBJECTIVE: To review unintended effects (UEs) of SEMLC for children with spastic cerebral palsy (CP). DESIGN: Retrospective chart review. SETTING: Pediatric rehabilitation outpatient clinic at an academic medical center. PARTICIPANTS: The study included 98 children with CP who underwent SEMLC on at least one occasion. INTERVENTIONS: SEMLC. MAIN OUTCOME MEASURES: UEs, the goal achievement for each SEMLC session, and the Gross Motor Function Classification System (GMFCS-ER). RESULTS: A total of 98 subjects and 146 SEMLC procedures were reviewed. Patients had a mean age of 7.56 years (standard deviation, 4.28); 57% were male; and 14 had hemiplegia, 22 had diplegia, 8 had triplegia, and 54 had quadriplegia. Most SEMLCs (72%) were performed with a combination of BTX-A and 5% phenol in a session. UEs were reported for 31/146 (21%) of SEMLC sessions, with 16 of 31 UEs being temporary weakness. The overall incidence of UEs of the group that received combined agent treatment was not different from the group that received BTX-A only (P = .267). Transient pain occurred in 7 of 105 patients who were treated with the combined agents BTX-A and phenol. Dysesthesia did not develop in any of the patients. The type of CP, GMFCS level, number of muscles injected, and doses of medications were not correlated with the incidence of UEs. CONCLUSIONS: SEMLC using combined BTX-A and phenol is a safe procedure for children with spastic CP. It could be a treatment option for patients with diffuse spasticity, because combining agents allowed more muscles to be treated without enduring or serious UEs. Patient and family education is essential to prepare them for the occurrence of common UEs, such as temporary weakness and pain. PMID- 26032348 TI - Assessment of Spasticity With Sonoelastography Following Stroke: A Feasibility Study. AB - OBJECTIVE: To investigate the feasibility of sonoelastography to show muscle stiffness in poststroke spasticity, as well as the relationship between sonoelastography findings and muscle architecture features and clinical spasticity scores in the spastic gastrocnemius. DESIGN: Cross-sectional study. SETTING: University rehabilitation center. PARTICIPANTS: A total of 26 stroke patients with gastrocnemius muscle spasticity (>=1 using the Modified Ashworth Scale score). INTERVENTIONS: None. MAIN OUTCOMES: Sonoelastography parameters (elasticity index and elasticity ratio) and muscle architecture features (muscle fascicle length, fascicle pennation angle, muscle thickness and compressibility) were measured from the medial and lateral gastrocnemius muscle on both the affected and unaffected sides. RESULTS: Both the elasticity index and elasticity ratio on the affected side were significantly increased in both the medial and lateral gastrocnemius compared with those on the unaffected side (P < .05). Of the muscle architecture parameters, the compressibility in the medial and lateral gastrocnemius and the fascicle pennation angle in the lateral gastrocnemius were significantly decreased on the affected side (P < .05). There was no significant difference in other parameters between the affected and unaffected side (P > .05). Sonoelastographic findings showed a weak negative correlation with compressibility and a weak positive correlation with the Modified Ashworth Scale score in the spastic medial gastrocnemius. CONCLUSIONS: It was found to be feasible to assess stiffness in spastic gastrocnemius muscles of stroke patients with sonoelastography. Further studies are needed to confirm the potential role of sonoelastography to help guide treatment of spasticity and its sequelae. PMID- 26032349 TI - Comparative study of postoperative morbidity in dental treatment under general anesthesia in pediatric patients with and without an underlying disease. AB - OBJECTIVES: To identify and quantify the variables and their influence on postoperative morbidity in dental treatment under general anesthesia (GA) in pediatric patients with and without an underlying disease. METHODS: A prospective, descriptive, and comparative analysis was conducted of healthy (n = 49) and disabled/medically compromised (n = 81) children treated under GA. Intra /post-surgical, clinical epidemiology, technical, care-related, and pharmacologic data were gathered, as were postoperative complications. RESULTS: The average age of ASA I patients (6.7 +/- 4.4 years) was younger than that of ASA II-III patients (9.0 +/- 4.5 years). Average hospitalization time was 4.27 +/- 6.5 h in ASA I and 7.41 +/- 6.8 h in ASA II-III. Significant differences were found between the two groups in fillings, pulpotomies, oral surgery, and scaling. Postoperative morbidity in ASA I and ASA II-III was similar both in frequency and severity and decreased during the first 72 h. The most common complication in both groups was toothache. CONCLUSION: Postoperative morbidity is high after dental treatment under GA, but it is not higher in disabled/medically compromised patients. PMID- 26032350 TI - Novel vaccine concept based on back-boost effect in viral infection. AB - A novel vaccine concept is discussed based on recent evidence of a "back-boost" effect in Influenza infection. The initial immune response to the infection is imprinted through an immune memory pathway. The immune memory in the back-boost mechanism could be used in reversed order as a "forward-boost" in the proposed vaccine concept. PMID- 26032351 TI - How Should Disability Be Measured in Older Adults? An Analysis from the Boston Rehabilitative Impairment Study of the Elderly. AB - OBJECTIVES: To determine and compare the predictive validity and responsiveness of the Late-Life Function and Disability Instrument (LLFDI) frequency and limitation dimensions in assessing two critical dimensions of disability: frequency of and limitations in performance of major life roles. DESIGN: Secondary analysis of 2-year follow-up data from the Boston Rehabilitative Impairment Study of the Elderly. SETTING: Primary care. PARTICIPANTS: Community dwelling older adults (>=65) (n = 430) at risk of mobility decline. MEASUREMENTS: The LLFDI frequency and limitation dimensions, self-rated health, hospitalizations, and emergency department (ED) visits over 2 years. Responsiveness measures included effect size (ES) estimates and minimal detectable change (MDC) scores. RESULTS: The LLFDI frequency dimension predicted low self-rated health (odds ratio (OR) = 0.51, P < .001), hospitalizations (OR = 0.68, P < .001), and ED visits (OR = 0.73, P = .003) over 2 years, whereas the limitation dimension did not. The absolute ES was 0.63 for the frequency dimension and 0.81 for the limitation dimension. The proportion of subjects with a decline greater than or equal to the MDC was 10.6% for the frequency dimension and 14.2% for the limitation dimension. For participants who improved greater than or equal to the MDC, the proportion was 1.7% for the frequency dimension and 15.3% for the limitation dimension. CONCLUSION: Frequency of participation in major life roles was a better predictor of adverse outcomes than perceived limitations, although limitations appeared to be more responsive to meaningful change. These results can be used to guide the selection of the most appropriate metric for measuring disability in geriatric research. PMID- 26032352 TI - Examining the Implications of Social Anxiety in a Community Sample of Mainland Chinese Children. AB - OBJECTIVE: The purpose of this study was to examine the implications of social anxiety symptoms in a community sample of elementary school children in mainland China. METHOD: Participants were N = 576 children (309 boys, 267 girls; mean age = 11.52 years, standard deviation = 1.21) attending public elementary schools in Shanghai, People's Republic of China. Multisource assessments included child self reports, teacher ratings, and school records. RESULTS: Confirmatory factor analyses replicated the previously established 3-factor solution for the Social Anxiety Scale for Children-Revised. Social anxiety symptoms were associated with indices of internalizing problems, peer difficulties, and poorer school adjustment. CONCLUSION: Results are discussed in terms of the implications of social avoidance as a particularly maladaptive component of social anxiety in the collectivistic society of China. PMID- 26032353 TI - Anti-GAD antibodies, a rare cause of limbic encephalitis: a case report. PMID- 26032355 TI - Reirradiation of nasopharyngeal carcinoma focusing on volumetric modulated arcs with flattening filter-free beams. AB - OBJECTIVE: The goal of this study was to assess the role of flattening filter free (FFF) beams in volumetric modulated arc radiotherapy for patients with recurrent nasopharyngeal carcinoma (rNPC). METHODS: 13 patients with rNPC were replanned for FFF RapidArc((r)) (RA-FFF) and conventional RapidArc (RA) (Varian Medical Systems, Palo Alto, CA). Quantitative evaluation was performed for the planning target volume (PTV) and organs at risk (OARs). Phantom dose verifications, treatment delivery time and monitor units (MUs) were also assessed. RESULTS: Each technique delivered similar doses to the PTV. RA-FFF had a better sparing effect on the brain stem and normal tissue when compared with RA, whereas RA provided lower mean doses to the skin. No significant difference between the two techniques could be established for other OAR parameters. Both techniques showed equally good gamma scores in dosimetric verification. RA-FFF required more MUs than RA, whereas the delivery time for RA-FFF was slightly shorter than for RA. CONCLUSION: Both treatment plans met the planning objectives. Dose measurements also showed good agreement with computed doses. In addition to slightly faster delivery times, RA-FFF produced better sparing of brain stem and normal tissue with uncompromised target coverage compared with RA. ADVANCES IN KNOWLEDGE: FFF beams have recently been assembled for clinical use. Our findings show RA-FFF is useful in the salvage treatment of rNPC owing to better brain stem and normal tissue sparing with uncompromised target coverage compared with RA. This may be beneficial in the case of tumour invasion close to the brain stem. PMID- 26032356 TI - Assessing the Gap in Female Authorship in Radiology: Trends Over the Past Two Decades. AB - PURPOSE: The aim of this study was to retrospectively identify trends in the representation of female authorship in prominent general radiology journals over the past 2 decades. METHODS: A comprehensive search was conducted for all articles published in 1993, 2003, and 2013 in Radiology, the American Journal of Roentgenology (AJR), European Radiology, and Investigative Radiology. The genders of the first and last authors were collected. Chi-square tests were used for statistical analysis, and P values < .05 were considered to indicate statistical significance. RESULTS: A total of 3,786 articles were reviewed. Overall, women constituted 20.0% authorship, 24.7% of first authors, and 15.2% of senior authors. The average overall female first and senior authorship grew from 19.7% to 32.1% and from 13.6% to 19.1%, respectively from 1993 to 2013. Female first authorship grew over the past 2 decades in the journals reviewed, with significant growth in AJR and Radiology (P < .0001). Female first authorship in the individual journals grew from 16.4%-29.1% in 1993, to 29.1%-34.8% in 2013. Female senior authorship also demonstrated growth in the past 2 decades, growing from 4.3%-17.5% in 1993 to 15.5%-23.2% in 2013. There was significant growth in senior female authorship in Radiology (from 12.1% to 19.2%, P = .004) and European Radiology (from 4.3% to 15.5%, P = .0433). Female senior authorship remained significantly lower than first authorship over the past 2 decades (P = .002, P < .001, and P < .0001). CONCLUSIONS: Although women's growth in first authorship in radiology literature is proportional to their growth in the specialty, they continue to remain a minority, especially in senior authorship, and demonstrate similar participation to other medical specialties. PMID- 26032358 TI - Phospholipase and Aspartyl Proteinase Activities of Candida Species Causing Vulvovaginal Candidiasis in Patients with Type 2 Diabetes Mellitus. AB - Few research had investigated the secretion of phospholipase and aspartyl proteinase from Candida spp. causing infection in females with type 2 diabetes mellitus. This research aimed to investigate the prevalence of vulvovaginal candidiasis (VVC) in diabetic versus non-diabetic women and compare the ability of identified Candida isolates to secrete phospholipases and aspartyl proteinases with characterization of their genetic profile. The study included 80 females with type 2 diabetes mellitus and 100 non-diabetic females within the child bearing period. Candida strains were isolated and identified by conventional microbiological methods and by API Candida. The isolates were screened for their extracellular phospholipase and proteinase activities by culturing them on egg yolk and bovine serum albumin media, respectively. Detection of aspartyl proteinase genes (SAP1 to SAP8) and phospholipase genes (PLB1, PLB2) were performed by multiplex polymerase chain reaction. Our results indicated that vaginal candidiasis was significantly higher among the diabetic group versus nondiabetic group (50% versus 20%, respectively) (p = 0.004). C. albicans was the most prevalent species followed by C. glabrata in both groups. No significant association between diabetes mellitus and phospholipase activities was detected (p = 0.262), whereas high significant proteinase activities exhibited by Candida isolated from diabetic females were found (82.5%) (p = 0.000). Non-significant associations between any of the tested proteinase or phospholipase genes and diabetes mellitus were detected (p > 0.05). In conclusion, it is noticed that the incidence of C. glabrata causing VVC is increased. The higher prevalence of vaginal candidiasis among diabetics could be related to the increased aspartyl proteinase production in this group of patients. PMID- 26032357 TI - DNA-Protein Cross-Links: Formation, Structural Identities, and Biological Outcomes. AB - Noncovalent DNA-protein interactions are at the heart of normal cell function. In eukaryotic cells, genomic DNA is wrapped around histone octamers to allow for chromosomal packaging in the nucleus. Binding of regulatory protein factors to DNA directs replication, controls transcription, and mediates cellular responses to DNA damage. Because of their fundamental significance in all cellular processes involving DNA, dynamic DNA-protein interactions are required for cell survival, and their disruption is likely to have serious biological consequences. DNA-protein cross-links (DPCs) form when cellular proteins become covalently trapped on DNA strands upon exposure to various endogenous, environmental and chemotherapeutic agents. DPCs progressively accumulate in the brain and heart tissues as a result of endogenous exposure to reactive oxygen species and lipid peroxidation products, as well as normal cellular metabolism. A range of structurally diverse DPCs are found following treatment with chemotherapeutic drugs, transition metal ions, and metabolically activated carcinogens. Because of their considerable size and their helix-distorting nature, DPCs interfere with the progression of replication and transcription machineries and hence hamper the faithful expression of genetic information, potentially contributing to mutagenesis and carcinogenesis. Mass spectrometry-based studies have identified hundreds of proteins that can become cross-linked to nuclear DNA in the presence of reactive oxygen species, carcinogen metabolites, and antitumor drugs. While many of these proteins including histones, transcription factors, and repair proteins are known DNA binding partners, other gene products with no documented affinity for DNA also participate in DPC formation. Furthermore, multiple sites within DNA can be targeted for cross-linking including the N7 of guanine, the C-5 methyl group of thymine, and the exocyclic amino groups of guanine, cytosine, and adenine. This structural complexity complicates structural and biological studies of DPC lesions. Two general strategies have been developed for creating DNA strands containing structurally defined, site-specific DPCs. Enzymatic methodologies that trap DNA modifying proteins on their DNA substrate are site specific and efficient, but do not allow for systematic studies of DPC lesion structure on their biological outcomes. Synthetic methodologies for DPC formation are based on solid phase synthesis of oligonucleotide strands containing protein reactive unnatural DNA bases. The latter approach allows for a wider range of protein substrates to be conjugated to DNA and affords a greater flexibility for the attachment sites within DNA. In this Account, we outline the chemistry of DPC formation in cells, describe our recent efforts to identify the cross-linked proteins by mass spectrometry, and discuss various methodologies for preparing DNA strands containing structurally defined, site specific DPC lesions. Polymerase bypass experiments conducted with model DPCs indicate that the biological outcomes of these bulky lesions are strongly dependent on the peptide/protein size and the exact cross-linking site within DNA. Future studies are needed to elucidate the mechanisms of DPC repair and their biological outcomes in living cells. PMID- 26032359 TI - A Bacterial Metabolite, Compound K, Induces Programmed Necrosis in MCF-7 Cells via GSK3beta. AB - Ginsenosides, the major active component of ginseng, are traditionally used to treat various diseases, including cancer, inflammation, and obesity. Among these, compound K (CK), an intestinal bacterial metabolite of the ginsenosides Rb1, Rb2, and Rc from Bacteroides JY-6, is reported to inhibit cancer cell growth by inducing cell-cycle arrest or cell death, including apoptosis and necrosis. However, the precise effect of CK on breast cancer cells remains unclear. MCF-7 cells were treated with CK (0-70 micrometer) for 24 or 48 h. Cell proliferation and death were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Changes in downstream signaling molecules involved in cell death, including glycogen synthase kinase 3beta (GSK3beta), GSK3beta, beta-catenin, and cyclin D1, were analyzed by western blot assay. To block GSK3beta signaling, MCF-7 cells were pretreated with GSK3beta inhibitors 1 h prior to CK treatment. Cell death and the expression of beta-catenin and cyclin D1 were then examined. CK dose- and time-dependently inhibited MCF-7 cell proliferation. Interestingly, CK induced programmed necrosis, but not apoptosis, via the GSK3beta signaling pathway in MCF-7 cells. CK inhibited GSK3beta phosphorylation, thereby suppressing the expression of beta catenin and cyclin D1. Our results suggest that CK induces programmed necrosis in MCF-7 breast cancer cells via the GSK3beta signaling pathway. PMID- 26032360 TI - Real-Time Monitoring of Catheter-Related Biofilm Infection in Mice. AB - This study was done to establish a mouse model for catheter-related biofilm infection suitable to bioluminescence imaging (BLI). Biofilm formation of Pseudomonas aeruginosa (P. aeruginosa) Xen5 grown on catheter disks in vitro and in an implanted mouse model was real-time monitored during a 7-day study period using BLI. The numbers of integrated brightness (IB) and viable bacterial count (VBC) in the biofilm disks in vitro were highest at 24 h after inoculation; the IB of biofilm in vivo was increased until 24 h after implantation. A statistical correlation was observed between IB and VBC in vitro by linear regression analysis. The actual VBC value in vivo can be estimated accurately by IB without sacrifice. In addition, we monitored the change in white blood cells (WBCs) during infection. The number of WBCs on day 7 was significantly higher in the infection group than in the control group. This study indicates that BLI is a simple, fast, and sensitive method to measure catheter biofilm infection in mice. PMID- 26032361 TI - Use of Germ-Free Animal Models in Microbiota-Related Research. AB - The large intestine is a home for trillions of microbiota, which confer many benefits on the host, including production of vitamins, absorption of nutrients, pathogen displacement, and development of the immune system. For several decades, germ-free animals have been used to study the interaction between the host and its microbiota. This minireview describes the technical aspects for establishing and maintaining germ-free animals and highlights the advantages and disadvantages for germ-free animals as experimental models. PMID- 26032362 TI - Synergistic Effect of Slightly Acidic Electrolyzed Water and Ultrasound at Mild Heat Temperature in Microbial Reduction and Shelf-Life Extension of Fresh-Cut Bell Pepper. AB - The objectives of this study were to evaluate the effect of combined treatments (slightly acidic electrolyzed water (SAEW), ultrasound (US), or mild heat (60 degrees C)) on the growth of Listeria monocytogenes and Salmonella enterica serovar Typhimurium in fresh-cut bell pepper, and the shelf-life and sensory quality (color and texture) were followed during storage at 4 degrees C and 25 degrees C. An additional 0.65, 1.72, and 2.70 log CFU/g reduction was achieved by heat treatments at 60 degrees C for 1 min for DW, SAEW, and SAEW+US, respectively. Regardless of the type of pathogen, the combined treatment (SAEW+US+60 degrees C) achieved a significantly (p < 0.05) longer lag time in all treatment groups. This combined treatment also prolonged the shelf-life of bell pepper up to 8 days and 30 h for the storage at 4 degrees C and 25 degrees C, respectively. There was also no significant difference in the color and hardness of treated (SAEW+US+60 degrees C) bell pepper from that of control during the storage. This new hurdle approach is thus expected to improve the microbial safety of bell peppers during storage and distribution. PMID- 26032363 TI - Development of a Microbe-Zeolite Carrier for the Effective Elimination of Heavy Metals from Seawater. AB - The purpose of this study was to investigate the potential of zeolite-supported sulfatereducing bacteria (SRB) in enhancing the removal of Cu(2+), Ni(2+), and Cr(6+) in contaminated seawater. Our results show that SRB-immobilized zeolite carriers can enhance the removal of heavy metals. In addition, heavy metals were generally better removed at conditions of 37 degrees C. Cu(2+), Ni(2+), and Cr(6+) were effectively removed by 98.2%, 90.1%, and 99.8% at 100 parts per million concentration of the heavy metals, respectively. These results indicate that SRB-zeolite carriers hold great potential for use in the removal of cationic heavy metal species from marine environment. PMID- 26032364 TI - Comparative Genomics Reveals the Core and Accessory Genomes of Streptomyces Species. AB - The development of rapid and efficient genome sequencing methods has enabled us to study the evolutionary background of bacterial genetic information. Here, we present comparative genomic analysis of 17 Streptomyces species, for which the genome has been completely sequenced, using the pan-genome approach. The analysis revealed that 34,592 ortholog clusters constituted the pan-genome of these Streptomyces species, including 2,018 in the core genome, 11,743 in the dispensable genome, and 20,831 in the unique genome. The core genome was converged to a smaller number of genes than reported previously, with 3,096 gene families. Functional enrichment analysis showed that genes involved in transcription were most abundant in the Streptomyces pan-genome. Finally, we investigated core genes for the sigma factors, mycothiol biosynthesis pathway, and secondary metabolism pathways; our data showed that many genes involved in stress response and morphological differentiation were commonly expressed in Streptomyces species. Elucidation of the core genome offers a basis for understanding the functional evolution of Streptomyces species and provides insights into target selection for the construction of industrial strains. PMID- 26032365 TI - Cohesion Establishment Factors Stimulate Endonuclease Activity of hFen1 Independently and Cooperatively. AB - Human Fen1 protein (hFen1) plays an important role in Okazaki fragment processing by cleaving the flap structure at the junction between single-stranded (ss) DNA and doublestranded (ds) DNA, an intermediate formed during Okazaki fragment processing, resulting in ligatable nicked dsDNA. It was reported that hChlR1, a member of the cohesion establishment factor family, stimulates hFen1 nuclease activity regardless of its ATPase activity. In this study, we found that cohesion establishment factors cooperatively stimulate endonuclease activity of hFen1 in in vivo mimic condition, including replication protein-A-coated DNA and high salt. Our findings are helpful to explain how a DNA replication machinery larger than the cohesion complex goes through the cohesin ring structure on DNA during S phase in the cell cycle. PMID- 26032366 TI - Histone H3 is Digested by Granzyme A During Compromised Cell Death in the Raji Cells. AB - Granzyme A (GzmA) was identified as a cytotoxic T lymphocyte protease protein expressed in the nucleus. A number of nuclear proteins are well known as GzmA substrates, and GzmA is related with caspase-independent apoptosis. Histones H1, H2B, and H3 were identified as GzmA substrates through in vitro experiment with purified nucleosome. Here, we demonstrated that histone H3 was cleaved by GzmA in vivo during staurosporine-induced cell death. Moreover, histone H3 cleavage was blocked by the GzmA inhibitor nafamostat mesylate and by GzmA knockdown using siRNA. Taken together, we verified that histone H3 is a real substrate for GzmA in vivo in the Raji cells treated by staurosporin. PMID- 26032367 TI - Skin Anti-Aging Activities of Bacteriochlorophyll a from Photosynthetic Bacteria, Rhodobacter sphaeroides. AB - In this work, the anti-aging skin effects of bacteriochlorophyll a isolated from Rhodobacter sphaeroides are first reported, with notably low cytotoxicity in the range of 1% to 14% in adding 0.00078 (% (w/w)) of the extracts, compared with the normal growth of both human dermal fibroblast and keratinocyte cells without any treatment as a control. The highest production of procollagen from human fibroblast cells (CCD-986sk) was observed as 221.7 ng/ml with 0.001 (% (w/w)) of bacteriochlorophyll a, whereas 150 and 200 ng/ml of procollagen production resulted from addition of 0.001 (% (w/w)) of the photosynthetic bacteria. The bacteriochlorophylla- induced TNF-alpha production increased to 63.8%, which was lower secretion from HaCaT cells than that from addition of 0.00005 (% (w/w)) of bacteriochlorophyll a. Additionally, bacteriochlorophyll a upregulated the expression of genes related to skin anti-aging (i.e., keratin 10, involucrin, transglutaminase-1, and MMPs), by up to 4-15 times those of the control. However, crude extracts from R. sphaeroides did not enhance the expression level of these genes. Bacteriochlorophyll a showed higher antioxidant activity of 63.8% in DPPH free radical scavenging than those of water, ethanol, and 70% ethanol extracts (14.0%, 57.2%, and 12.6%, respectively). It was also shown that the high antioxidant activity could be attributed to the skin anti-aging effect of bacteriochlorophyll a, although R. sphaeroides itself would not exhibit significant anti-aging activities. PMID- 26032369 TI - Retraction: Topological analysis and functional study of the inner membrane protein YciB in Escherichia coli. PMID- 26032368 TI - A New Shuttle Plasmid That Stably Replicates in Clostridium acetobutylicum. AB - We have developed a new shuttle plasmid, designated as pLK1-MCS that can replicate in both Clostridium acetobutylicum and Escherichia coli, by combining the pUB110 and pUC19 plasmids. Plasmid pLK1-MCS replicated more stably than previously reported plasmids containing either the pIM13 or the pAMbeta1 replicon in the absence of antibiotic selective pressure. The transfer frequency of pLK1 MCS into C. acetobutylicum was similar to the transfer frequency of other shuttle plasmids. We complemented C. acetobutylicum ML1 (that does not produce solvents such as acetone, butanol, and ethanol owing to loss of the megaplasmid pSOL1 harboring the adhE1-ctfAB-adc operon) by introducing pLK1-MCS carrying the adhE1 ctfAB-adc operon into C. acetobutylicum ML1. The transformed cells were able to resume anaerobic solvent production, indicating that the new shuttle plasmid has the potential for practical use in microbial biotechnology. PMID- 26032370 TI - Inhibition of Monoamine Oxidase by Anithiactins from Streptomyces sp. AB - Monoamine oxidase (MAO) is found in most cell types and catalyzes the oxidation of monoamines. Three anithiactins (A-C, modified 2-phenylthiazoles) isolated from Streptomyces sp. were tested for inhibitory activity of two isoforms, MAO-A and MAO-B. Anithiactin A was effective and selective for the inhibition of MAO-A, with an IC50 value of 13.0 uM; however, it was not effective for the inhibition of MAO-B. Anithiactins B and C were weaker inhibitors for MAO-A and MAO-B. Anithiactin A was a reversible and competitive inhibitor for MAO-A with a Ki value of 1.84 uM. The hydrophobic methyl substituent in anithiactin A may play an important role in the inhibition of MAO-A. It is suggested that anithiactin A is a selective reversible inhibitor for MAO-A, with moderate potency, and can be considered a new potential lead compound for further development of novel reversible inhibitors for MAO-A. PMID- 26032371 TI - Evaluating a Quality Improvement Program for Cervical Cancer Screening at an Urban Safety Net Clinic. AB - This article evaluates a quality improvement program for improving guideline consistent cervical cancer screening practices in an urban safety net clinic. Quality improvement initiatives that combine policy with practice are particularly timely in light of the alignment of cervical cancer screening guidelines released in 2012 by the most influential national organizations. A descriptive comparison design was employed using the Healthy People 2020 target of 93% screened according to guidelines. Provider-, patient-, and workflow-based strategies included (1) addition of a clinical decision support system, (2) provider educational outreach, (3) patient reminder letters, and (4) development of a clinic procedure manual. Through the application of an established quality measurement tool, three quality indicators were measured: screened according to evidence-based guidelines, not screened, and screened more frequently than recommended. Data from the sample (N = 1,032) were collected at baseline and 12 months postimplementation. Each quality indicator category was significant at follow-up. Patients screened according to guidelines nearly doubled while the number of underscreened patients was reduced by nearly half. Similarly, there was a threefold decrease in patients screened more frequently than recommended. Clinical administrators, quality improvement specialists, and health care providers in primary care settings can use the strategies implemented in this study as a starting point for continuous quality improvement initiatives for cervical cancer screening. PMID- 26032372 TI - Long-term health consequences of exposure to burn pits in Iraq and Afghanistan. PMID- 26032373 TI - Origins of military medical care as an essential source of morale. PMID- 26032374 TI - Sending soldiers to fight Ebola. PMID- 26032375 TI - Providing care to children in times of war. AB - The Geneva Conventions stipulate that an occupying power must ensure adequate health care delivery to noncombatants. Special emphasis is given to children, who are among the most vulnerable in a conflict zone. Whether short-term pediatric care should be provided by Military Treatment Facilities to local nationals for conditions other than combat-related injury is controversial. A review of 1,197 children without traumatic injury cared for during 10 years in Iraq and Afghanistan was conducted. Mortality rates were less than 1% among patients with surgical conditions and resource utilization was not excessive. In view of international humanitarian law and these outcomes, children with nontraumatic conditions can and should be considered for treatment at Military Treatment Facilities. The ability to correct the condition and availability of resources necessary to do so should be taken into account. PMID- 26032376 TI - Tobacco use policy in military housing. AB - Secondhand smoke and thirdhand smoke (e.g., smoke residues found on walls and floors) are known to pose health hazards. Some landlords and cities have therefore established smoke-free policies for multiunit housing. The military is in effect the largest landlord in the United States, with approximately 630,000 units of housing. We reviewed the service-level tobacco control policies of the Army, the Air Force, and the Navy and Marine Corps (which share a policy) for references to housing, to see if personnel are adequately protected from secondhand and thirdhand smoke. Policies covering most family housing and all housing for single enlisted personnel fail to fully protect residents from secondhand or thirdhand smoke. The current review of tobacco control policy in the military should recommend a consistent policy of tobacco-free living quarters. PMID- 26032377 TI - Hemorrhage control by law enforcement personnel: a survey of knowledge translation from the military combat experience. AB - BACKGROUND: Military data demonstrate that exsanguinating hemorrhage is the leading cause of potentially preventable combat death. The purpose of this study was to evaluate attitudes and approaches of civilian law enforcement personnel in the management of acute hemorrhagic trauma. METHODS: Anonymous survey administered via an online distribution mechanism. RESULTS: 1,317 U.S. law enforcement personnel began the survey. 370 respondents (30.4%) reported their agencies issued tourniquets, whereas 48.8% indicated their agencies had provided specific training in tourniquet application. Pressure dressings were provided to 43.6% of respondents while hemostatic agents were available to 29.8%. Tourniquets were considered the intervention most likely to save a life, but were also deemed most likely to possibly cause harm or injury if used inappropriately. 43 respondents (0.036%) stated they were aware of circumstances within the past year in which an officer in their agency sustained injuries where a tourniquet could have been used, but was not. CONCLUSIONS: Hemorrhage control supplies are being issued to less than half of the responding officers. When used, these interventions were generally thought to be effective. Further study is needed to delineate specific medical interventions, and therefore training and equipment, needed by law enforcement personnel. PMID- 26032378 TI - Relationship Between Toxoplasma gondii and Mood Disturbance in Women Veterans. AB - BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite with zoonotic potential that causes acute and chronic diseases, which has been associated with schizophrenia, depression, bipolar disorder, and suicidal behavior. Military personnel may be at increased risk for exposure to the parasite when deployed to countries with high prevalence rates. METHODS: Women Veterans were recruited to participate in the study at an event to recognize women Veterans and later through e-mails. Blood samples were collected from 70 women Veterans (mean age: 47 years) and analyzed for T. gondii IgG titer. Participants completed a demographic instrument, Center for Epidemiologic Studies Depression scale, Profile of Mood States (POMS), and Post-Traumatic Stress Disorder Checklist-Military. RESULTS: The infectivity rate was lower than the rate in the United States (11.4% [8 out of 70 were seropositive], but 6 of the 8 [75%] had been deployed outside the United States. Pearson correlations and t tests showed significant relationships between T. gondii seropositivity and Center for Epidemiologic Studies Depression score), POMS-depression, POMS confusion, and POMS-anger subscale scores, and total mood disturbance score. CONCLUSIONS: This study is the first to describe biobehavioral relationships between chronic T. gondii infection, depression, and dysphoric moods in a military veteran population. PMID- 26032379 TI - Operation United Assistance: infectious disease threats to deployed military personnel. AB - As part of the international response to control the recent Ebola outbreak in West Africa, the Department of Defense has deployed military personnel to train Liberians to manage the disease and build treatment units and a hospital for health care volunteers. These steps have assisted in providing a robust medical system and augment Ebola diagnostic capability within the affected nations. In order to prepare for the deployment of U.S. military personnel, the infectious disease risks of the regions must be determined. This evaluation allows for the establishment of appropriate force health protection posture for personnel while deployed, as well as management plans for illnesses presenting after redeployment. Our objective was to detail the epidemiology and infectious disease risks for military personnel in West Africa, particularly for Liberia, along with lessons learned from prior deployments. PMID- 26032380 TI - Differential Diagnosis of Candida Species With Real-Time Polymerase Chain Reaction and Melting Temperature Analyses (RTPCR-MTA). AB - Genus Candida covers more than 50 species, half of which can cause infections in humans. Some of the Candida species exhibit drug resistance; therefore, there is an urgent need for rapid and accurate differentiation for rendering appropriate and effective management. Here, we report a new methodology employing real-time polymerase chain reaction (RTPCR) and melting temperature analyses (MTA) procedures. Fungal ribosomal internal transcribed spacer 2 (ITS2) has been confirmed with variable nucleotide sequences, which makes it possible to differentiate one species from another by checking their melting temperature following PCR amplification. The universal primers (panFg) covering entire ITS2 region, from 5.8S to 28S rRNA genes, were designed to differentially identify most Candida species with RTPCR-MTA procedure. Nucleic acids from five genomes of closely related Candida species, which were experimentally spiked into human blood, were extracted and amplified. PCR amplicons were called for melting temperature of Candida albicans (87.49 degrees C), C. glabrata (86.85 degrees C), C. krusei (90.24 degrees C), C. parapsilosis (86.22 degrees C), and C. tropicalis (86.08 degrees C). The melting temperature of each amplicon was consistent and reproducible in three replicate experiments (SD +/- 0.04-0.32). The new RTPCR-MTA methodology showed promise in differential diagnosis of closely related Candida species from environmental and clinical samples. PMID- 26032381 TI - Neurocognitive performance and prior injury among U.S. Department of Defense military personnel. AB - This study examined the neurocognitive performance of U.S. military personnel completing the Automated Neuropsychological Assessment Metrics (version 4) TBI Military (ANAM4 TBI-MIL) battery as part of the Department of Defense Neurocognitive Functional Assessment Program. Descriptive analyses utilizing the ANAM4TBI Military Performance Database were performed. We examined ANAM Composite Score (ACS) differences between five injury subgroups (no injury, brain injury with current symptoms, brain injury without current symptoms, nonbrain injury with current symptoms, and nonbrain injury without current symptoms) using general linear mixed modeling. Almost 11% (70,472/641,285) reported brain injury in the 4 years before assessment. The ACS differed significantly by injury group (p < 0.0001). In comparison to the no injury group, those reporting brain injury with current symptoms (d = -0.44) and nonbrain injury with current symptoms (d = 0.24) demonstrated significantly reduced ACS scores (p < 0.0001) indicative of reduced neurocognitive proficiency. In this population-based study of U.S. military personnel, neurocognitive performance was significantly associated with reported injury within the past 4 years among those experiencing current symptoms. Occupational programs focusing on prospective brain health of injured population groups are warranted. PMID- 26032382 TI - Alcohol-Related Consequences Mediating PTSD Symptoms and Mental Health-Related Quality of Life in OEF/OIF Combat Veterans. AB - Veterans returning from Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) have been found to be at increased risk for post-traumatic stress disorder (PTSD) and alcohol use disorders, leading to negative mental health related quality of life (MHRQoL). The current study examined the unique impact of alcohol consumption levels versus alcohol-related consequences on the relationship between PTSD symptoms and MHRQoL in a sample of OEF/OIF combat veterans (N = 205, median age 29, 95% men). Mediation analyses indicated that the effect of PTSD symptoms on MHRQoL was explained only by alcohol-related consequences and not by alcohol consumption. Findings highlight the importance of including alcohol-related consequences in clinical assessment and intervention programs for OEF/OIF veterans. Additionally, this study enhances knowledge regarding the underlying mechanisms of functional impairment related to PTSD and alcohol use disorders. PMID- 26032383 TI - Evaluating the implementation and sustainability of a program for enhancing veterans' intimate relationships. AB - The Warrior to Soul Mate (W2SM) program is a grassroots initiative on the part of Veterans Affairs chaplain services to provide relationship enhancement skills to veterans and significant others based on the Practical Application of Intimate Relationship Skills model. To examine the implementation and sustainability of the W2SM program, two online surveys were sent to each participating facility's W2SM leader. The first examined how individual W2SM events were conducted (100% response rate, 67 surveys) and the second assessed facility-level issues impacting program sustainability (100% response rate, 23 surveys). Four sites were selected for qualitative interviews based on levels of sustainability. In 2013, W2SM served 1,664 people including 847 veterans, incurring reasonable program costs when compared to other intensive Veterans Affairs services. However, there have been important systematic (e.g., contracting processes) and resource (e.g., time, concern over funding) challenges that are reflected in the wide range of predicted program sustainability. PMID- 26032384 TI - Mindfulness-based stress reduction for veterans exposed to military sexual trauma: rationale and implementation considerations. AB - Military sexual trauma (MST) represents a significant public health concern among military personnel and Veterans and is associated with considerable morbidity and suicide risk. It is estimated that 22% of Veteran women and 1% of Veteran men experienced sexual assault or repeated, threatening sexual harassment during their military service. Exposure to traumatic stress has detrimental effects on emotion regulation, which refers to a set of strategies used to modulate different components of emotion at different points on the trajectory of an emotional response. Mindfulness-based interventions offer approaches to health that focus on mind and body practices that can help regulate the experience and expression of difficult emotions. Mindfulness-based stress reduction (MBSR) is an evidence-based therapy shown to be effective for depression, anxiety, and post traumatic stress disorder. This article discusses the rationale for providing MBSR to Veterans who have been exposed to MST. The article also discusses ways to facilitate implementation of this practice in the U.S. Department of Veterans Affairs health care system. We address potential barriers to care and ways to facilitate implementation at the patient, provider, organization/local, and policy levels. MBSR is likely to be an important component of a comprehensive approach to care for Veterans exposed to MST. PMID- 26032385 TI - Development of a multilevel prevention program for improved relationship functioning in active duty military members. AB - The relationships and families of active duty (AD) service members have been tremendously strained by deployments and high operations' tempo. This study involves the first steps in developing a multilevel approach to preventing relationship problems that integrates universal, selective, and indicated prevention/intervention. Such an approach has tremendous empirical support for parenting problems, but no similar program exists for couple problems. We conducted two studies with U.S. Air Force Security Forces members. Study 1 elicited the target population's topics of highest interest. For almost all topics, 70% to 95% of participants who desired information reported being underserved by current prevention offerings (i.e., not receiving needed information). Using the top topics generated in Study 1, we developed prevention information/action planning sheets on 18 relationship issues. In Study 2, we had AD members who gave feedback on the form and content of the sheets. Overall, AD members believed that the sheets were moderately to very useful and were presented well, had pithy but comprehensive information and conveyed the content well. Results imply that a multilevel approach may be a useful complement to formal services in meeting underserved military members' needs and that further research and development of this dissemination vector for evidence-based information is warranted. PMID- 26032386 TI - Mental health predictors of veterans willingness to consider research participation. AB - This study aimed to determine whether mental health factors predict Veterans' willingness to hear about research participation opportunities. A sample of 954 Veterans completed measures to assess psychological functioning and were asked about interest in clinical research opportunities and willingness to share de identified personal data with researchers. Of these Veterans, 75.8% were willing to listen to research opportunities at their local VA, and 100% agreed to share de-identified information. Poorer mental health correlated with a greater willingness to listen to research opportunities implying that Veterans who are experiencing a greater degree of mental health impairment may be overrepresented in clinical studies. PMID- 26032387 TI - Treatment of chemical warfare agent casualties: retention of knowledge and self perceived competency among military physicians and paramedics. AB - OBJECTIVE: Specialized training of medical teams for chemical warfare agent (CWA) events is important to save lives. We aimed to evaluate the retention of knowledge (ROK) and self-perceived competency (SPC) of military medical personnel in delivering treatment during CWA events. METHODS: A questionnaire and a multiple-choice examination were sent to military physicians and paramedics, evaluating their CWA, ROK, and SPC (study group [SG]). Their assessment was compared to medical personnel immediately post training (reference group [RG]). SG was subdivided into two groups: G1 <= 1 year and G2 > 1 year, past training. RESULTS: Overall, 135 participants responded (35-RG, 65% physicians). Self reported ROK and SPC were significantly higher in RG compared to SG and in G1 compared to G2. Test scores were higher in RG compared to SG, but similar in G1 and G2 groups. SPC was lower compared to ROK in the entire cohort and subgroups. A moderate correlation was found between the self-and test-assessed scores (Pearson correlation coefficient 0.45, p < 0.001). Physicians received significantly (p = 0.01) higher test scores in RG compared with paramedics. CONCLUSIONS: ROK and SPC among military medical personnel for treatment of CWA casualties deteriorate significantly as early as 1 year post training, SPC > ROK. Thus, we recommend CWA refresher training at least every year. PMID- 26032389 TI - Chauncy, the copper thermal manikin. PMID- 26032388 TI - A content analysis of military commander messages about tobacco and other health issues in military installation newspapers: what do military commanders say about tobacco? AB - Military installation newspapers are a primary means used by military commanders to communicate information about topics important to military personnel including leadership, training issues, installation events, safety concerns, and vital health issues. We conducted a content analysis of military commanders' messages about health issues that were published in online military installation newspapers/newsfeeds. We identified a total of 75 publicly accessible installation newspapers/newsfeeds with commanders' messages (n = 39 Air Force, n = 19 Army, n = 7 Navy, n = 1 Marine, and n = 9 Joint Bases). Commander messages published from January 2012 to December 2012 were collected, screened, and coded. Coder inter-rater reliability was 98.9%. Among the 2,479 coded commanders' messages, 132 (5.3%) addressed a health topic as the primary focus. There were no significant differences between service branches in the percentage of health oriented messages (chi(2) = 5.019, p = 0.285). The most commonly addressed health topics were exercise/fitness (23.5%), other mental health concerns (19.7%), alcohol/driving under the influence (13.6%), and suicide (12.1%). Tobacco use was directly addressed as a primary health aim in only two commanders' messages (1.5%). Health topics, and particularly tobacco-related content, are rarely written about by military commanders. The absence of tobacco-related health messages from line leadership contributes to the perception that tobacco control is a low priority. PMID- 26032390 TI - Case study illustrating risks of garrison unit watch for soldiers at risk of suicide. AB - Unit watch over suicidal patients by nonmedical soldiers is often necessary in a deployed environment, but this strategy's risks may outweigh its benefits in a garrison environment. This case study illustrates risks of unit watches that are difficult for medical personnel to effectively mitigate. The suicidal soldier in question was placed on a unit watch in lieu of psychiatric hospitalization, utilizing a plan agreed upon by all parties. However, within 2 days, the plan had degenerated to an unacceptable degree. A commander is always legally responsible for subordinate soldiers' conduct, but from a patient safety perspective, medical professionals must account for the inevitable periods of decreased oversight within a unit. Medical professionals who recommend a unit watch must consider the risks associated with this course of action, including instances such as the error chain detailed in this case. PMID- 26032391 TI - Drug-induced liver injury from initial dose of infliximab. AB - Acute hepatotoxicity secondary to infliximab can occur with or without autoimmunity. A growing body of infliximab drug-induced liver injury cases without autoantibody formation is emerging. Nearly all other reported cases occur after at least three doses. This suggests infliximab may have a direct cytotoxic effect on the liver. We report a case of drug-induced liver injury resulting after an initial dose of infliximab. PMID- 26032392 TI - Traumatic ulnar artery pseudoaneurysm following a grenade blast: report of a case. AB - Vascular injuries comprised a small percentage of total injuries requiring medevac in the Iraq and Afghanistan conflicts; however, their impact cannot be overstated. This case highlights an individual who sustained a grenade blast injury leading to hemorrhage, and forearm compartment syndrome. He was initially treated with irrigation and debridement, forearm fasciotomy, and delayed primary closure. The patient developed persistent ulnar neuropathy and hypothenar atrophy despite a normal initial vascular examination. During reconstructive surgery, he was discovered to have a proximal ulnar artery pseudoaneurysm. Upper extremity pseudoaneurysms are a rare sequelae following vascular injury, but have significant consequences for the patient and are identifiable by imaging. PMID- 26032393 TI - Multimodal analgesia in abdominal sepsis: a case report of liposome bupivacaine in ultrasound-guided rectus sheath blocks after unexpected open hemi-colectomy. AB - OBJECTIVE: Contrasted with open laparotomy, the risk-benefit ratio of epidural anesthesia in laparoscopic surgery frequently disfavors its use. The presence of abdominal sepsis also affects utilization with concerns about the risks of epidural abscess and hypotension. In the unplanned conversion to open laparotomy, postoperative pain control becomes more difficult. We discuss utilization of rectus sheath blocks with liposome bupivacaine as a component of multimodal analgesia in a patient with abdominal sepsis from a perforated appendix. CASE REPORT: A 33-year-old healthy male Soldier presented with a perforated appendix. Treatment consisted of urgent laparoscopic appendectomy that was subsequently converted to an open right hemicolectomy. Bilateral rectus sheath blocks were performed with liposome bupivacaine before awakening to mitigate postoperative pain. The patient reported mild postoperative pain scores, was able to ambulate comfortably on the day of surgery, and had early return of bowel function. CONCLUSIONS: This case describes rectus sheath blocks with liposomal bupivacaine for postoperative pain control and to hasten functional recovery following an unplanned conversion to open hemicolectomy. This application provided many of the benefits of epidural analgesia while avoiding some of its most serious risks, making it a valuable analgesic option for the patient with abdominal sepsis. PMID- 26032394 TI - Gluteal abscess and bacteremia following promethazine injection in a Marine. AB - Intramuscular injection is routinely used and rarely leads to adverse events such as abscess or tissue necrosis. Intramuscular promethazine has been documented to cause these problems. We discuss the case of a previously healthy 19-year-old U.S. Marine, who was diagnosed with methicillin sensitive Staphylococcus aureus bacteremia and abscess formation after receiving intramuscular promethazine for vomiting. After confirmation of abscess formation via magnetic resonance imaging, he underwent percutaneous drainage. He improved and was treated with 6 weeks of cefazolin. This case demonstrates an unusual and severe adverse reaction associated with intramuscular promethazine administration. Additionally, this case highlights the importance of proper antiseptic technique before promethazine administration and calls into question the utility and safety of intramuscular promethazine when oral dissolving antiemetic medications are available. PMID- 26032395 TI - Effect of undercorrection on myopia progression in 12-year-old children. AB - BACKGROUND: To prospectively observe the effects of undercorrection of myopia on myopia progression and axial elongation in a population of 12-year-old Chinese children. METHODS: A total of 2,267 children in the Anyang Childhood Eye Study were examined at baseline, and 1,769 were followed for 1 year. Ocular examinations included cycloplegic autorefraction, axial length, visual acuity, vertometry, and accommodative lag. Questionnaires were completed by children and parents. Undercorrection of myopia was determined at baseline if presenting visual acuity could be improved by at least 2 lines with subjective refraction. RESULTS: Of 253 myopic children with spectacles and available information, 120 (47.4 %) were undercorrected (-4.63D to -0.50D) and 133 (52.6 %) were fully corrected. In a multivariate model adjusting for age, gender, number of myopic parents, time spent on near work and outdoor activities per day, usage and time for wearing spectacles per day, children with undercorrection had significantly more baseline myopia (P < 0.01) and longer axial length (P = 0.03) than children with full correction. However, there were no significant differences in myopia progression (P = 0.46) and axial elongation (P = 0.96) at 1 year between the two groups of children. The regression analysis showed that myopia progression significantly decreased with increasing amount of undercorrection (r (2) = 0.02, P = 0.02) in all children. Accommodative lag significantly decreased with increasing amounts of undercorrection (P < 0.01). CONCLUSIONS: Based on this 1 year study in Chinese children, undercorrection or full correction of myopia by wearing spectacles did not show any differences in myopia progression or axial elongation. PMID- 26032397 TI - Assessments of outcome in haemophilia - what is the added value of QoL tools? AB - INTRODUCTION: Access to treatment and especially to long-term regular replacement treatment with clotting factor concentrates (prophylaxis) have caused dramatic contrasts in the clinical picture between haemophilia populations. An individual patient with severe haemophilia age 20 years can have normal joints or can be severely crippled and unable to work. Assessment of outcome in a standardized way has therefore become essential. AIM: Discuss the relevance and utility of the different outcome assessment tools in patient groups with different access to treatment. METHODS: In the last decade new outcome assessment tools specific for haemophilia have been developed that measure all aspects of health according to the International Classification of Functioning, Disability and Health (ICF) model. These tools are directed at assessing the clinical and radiological status of joints as well as overall functioning, such as participation and psychosocial aspects, evaluating overall health-related quality of life (HRQOL). For deciding which tools to use in clinical practice or research, one needs to consider the specific context with regard to disease burden, healthcare environment and socioeconomic background of the patients being evaluated. CONCLUSION: Prospective systematic assessment of outcome in haemophilia and related bleeding disorders is important. Based upon recent literature a critical appraisal of outcome tools is described. PMID- 26032396 TI - Aggressive multiple sclerosis: proposed definition and treatment algorithm. AB - Multiple sclerosis (MS) is a CNS disorder characterized by inflammation, demyelination and neurodegeneration, and is the most common cause of acquired nontraumatic neurological disability in young adults. The course of the disease varies between individuals: some patients accumulate minimal disability over their lives, whereas others experience a rapidly disabling disease course. This latter subset of patients, whose MS is marked by the rampant progression of disability over a short time period, is often referred to as having 'aggressive' MS. Treatment of patients with aggressive MS is challenging, and optimal strategies have yet to be defined. It is important to identify patients who are at risk of aggressive MS as early as possible and implement an effective treatment strategy. Early intervention might protect patients from irreversible damage and disability, and prevent the development of a secondary progressive course, which thus far lacks effective therapy. PMID- 26032398 TI - Effects of shoe sole geometry on toe clearance and walking stability in older adults. AB - Thirty-five percent of people above age 65 fall each year, and half of their falls are associated with tripping: tripping, an apparently 'mundane' everyday problem, therefore, significantly impacts on older people's health and associated medical costs. To avoid tripping and subsequent falling, sufficient toe clearance during the swing phase is crucial. We previously found that a rocker-shaped shoe sole enhances toe clearance in young adults, thereby decreasing their trip-risk. This study investigates whether such sole design also enhances older adults' toe clearance, without inadvertently affecting their walking stability. Toe clearance and its variability are reported together with measures of walking stability for twelve older adults, walking in shoes with rocker angles of 10 degrees , 15 degrees , and 20 degrees . Surface inclinations (flat, incline, decline) were chosen to reflect a potential real-world environment. Toe clearance increased substantially from the 10 degrees to the 15 degrees rocker angle (p=0.003) without compromising measures of walking stability (p>0.05). A further increase in rocker angle to 20 degrees resulted in less substantial enhancement of toe clearance and came at the cost of a decrease in gait speed on the decline. The novelty of this investigation lies in the exploration of the trade-off between reduction of trip-risk through footwear design and adverse effects on walking stability on real-life relevant surfaces. Our two studies suggest that the current focus on slip-resistance in footwear design may need to be generalised to include other factors that affect trip-risk. PMID- 26032399 TI - Food Safety Hazards and Microbiological Zoonoses in European Meat Imports Detected in Border Inspection in the Period 2008-2013. AB - Microbiological contaminations and other food safety hazards are omnipresent within the European Union (EU) and a considerable risk for consumers, particularly in imported meat and meat products. The number of rejections at external EU borders has been increasing in recent years. Official authorities in each member state are therefore obliged to notify border rejections of food and animal feed due to a direct or indirect risk to human or animal health. This study explored the trends and temporal and spatial distribution of notifications on food safety hazards between January 2008 and December 2013 with a special emphasis on microbiological zoonoses in meat and meat products including poultry at border checks resulting from the rapid alert system for food and feed (RASFF). Results indicated that border rejection notifications are increasing exponentially, frequently due to Salmonella in poultry and shiga-toxin-producing E. coli in meat and meat products. PMID- 26032400 TI - Ezrin contributes to impaired podocyte migration and adhesion caused by advanced glycation end products. AB - AIM: Podocytes are specialized epithelial cells that play a critical role in the glomerular filtration barrier. Podocyte abnormalities are linked to increasing albuminuria and progression to end-stage renal failure as observed in diabetic nephropathy. Advanced glycation end products (AGEs) have been strongly linked to the development of diabetic nephropathy, and we have previously shown that AGEs inhibit ezrin actions in proximal tubule cells. As ezrin plays a key role in controlling podocyte foot process integrity, the present study investigated the contribution of ezrin to AGE-induced podocyte damage. METHODS: Conditionally immortalized human podocytes were cultured with or without AGEs, and changes in morphology, protein expression and cell function were analyzed. RESULTS: Fully differentiated podocytes had long finger-like protrusions forming slit diaphragm structures. Immunofluorescence showed ezrin is mainly localized to the cell membrane with intense fluorescence on cellular protrusions. After AGE-BSA treatment for 6 days, podocytes were rounder with fewer protrusions. Western blotting showed a time-dependent reduction in ezrin levels compared with BSA treated cells. AGE-BSA treatment reduced podocyte adhesion to fibronectin and inhibited migration. Overexpression of ezrin completely reversed AGE-BSA inhibition of podocyte adhesion to fibronectin and partially reversed AGE-induced inhibition of migration. CONCLUSION: These results show a role for ezrin in AGE induced podocyte damage and suggest a new avenue for possible therapeutic intervention in diabetic nephropathy. PMID- 26032401 TI - Whole plantar nerve conduction study with disposable strip electrodes. AB - INTRODUCTION: A new method to evaluate whole plantar nerve conduction with disposable strip electrodes (DSEs) is described. METHODS: Whole plantar compound nerve action potentials (CNAPs) were recorded at the ankle. DSEs were attached to the sole for simultaneous stimulation of medial and lateral plantar nerves. We also conducted medial plantar nerve conduction studies using an established method and compared the findings. RESULTS: Whole plantar CNAPs were recorded bilaterally from 32 healthy volunteers. Mean baseline to peak amplitude for CNAPs was 26.9 +/- 11.8 MUV, and mean maximum conduction velocity was 65.8 +/- 8.3 m/s. The mean amplitude of CNAPs obtained by our method was 58.2% higher than that of CNAPs obtained by the Saeed method (26.9 MUV vs. 17.0 MUV; P < 0.0001). CONCLUSIONS: The higher mean amplitude of whole plantar CNAPs obtained by our method suggests that it enables CNAPs to be obtained easily, even in elderly people. PMID- 26032402 TI - Undetectable anti-TNF drug levels in patients with long-term remission predict successful drug withdrawal. AB - BACKGROUND: Low drug levels are associated with emerging loss of response to anti TNF. However, this may not be the case in patients with long-term remission. AIM: To investigate the outcome of anti-TNF discontinuation in patients with long-term remission and incidental undetectable drug levels. METHODS: A retrospective cohort study examining the duration of relapse-free survival in IBD patients in remission who discontinued infliximab or adalimumab having undetectable drug levels. RESULTS: Forty eight patients who discontinued anti-TNF while in remission and had available drug levels were identified in two centres in France and Israel (infliximab-treated 35, adalimumab-13, Crohn's disease 30, ulcerative colitis 18, mean treatment duration of 22.7 +/- 12.4 months). Endoscopy/MRE before stopping showed absence of active inflammation in 40/42 (95%) of evaluated patients, while inflammatory biomarkers (CRP and/or Calprotectin) were completely normal in only 31/48 (65%) of patients. During 12 months median follow-up, relapse occurred in 16/20 (80%) of patients who stopped anti-TNF while having measurable drug levels compared with 9/28 (32%) of patients who had undetectable drug levels (OR: 8.4, 95% CI: 2.2-32, P = 0.002). Relapse-free survival after anti-TNF cessation was significantly longer in patients with absent drug compared to those with detectable drug (P < 0.001, log rank test). On multivariate analysis, a patient's decision to stop therapy was weakly associated and abnormal inflammatory biomarkers and detectable drug levels were both strongly and independently associated with a higher risk of relapse after drug discontinuation. CONCLUSION: Incidental finding of undetectable anti-TNF drug levels in patients with stable long-term deep remission may identify a subset of patients whose clinical remission is no longer dependent on anti-TNF treatment. PMID- 26032403 TI - Enhanced photocurrent density of hematite thin films on FTO substrates: effect of post-annealing temperature. AB - Fluorine doped tin oxide (FTO) is widely used as a substrate in the synthesis of a photo-reactive semiconductor electrode for solar water splitting. The hematite film on the surface of the FTO substrate annealed at 700 degrees C showed an enhanced photocurrent value with a maximum photocurrent of 0.39 mA cm(-2) at 1.23 V vs. RHE under 1 sun illumination. This is a much enhanced photocurrent value of the hematite films than that of those annealed at temperatures lower than 700 degrees C. This is a promising approach for the enhancement of the photoelectrochemical properties of metal oxide thin films. This work reports on the mechanism of the annealing process of the synthesized hematite film to enhance the photocurrent value. Furthermore, this can be used for the enhanced efficiency of the solar water splitting reaction. PMID- 26032404 TI - Anatomical variations in epididymal-testicular fusion in stallions and their possible clinical significance. AB - REASONS FOR PERFORMING STUDY: Fusion anomalies of the epididymis with the testis may be clinically relevant in horses. However, anatomical variations in epididymal-testicular fusion have not been classified, and their clinical significance is unknown. OBJECTIVES: To describe anatomical variations and clinical significance of epididymal-testicular fusion in stallions. STUDY DESIGN: Anatomical study of testes from castrations, and description of 2 clinical cases with atypical epididymal-testicular fusion. METHODS: A total of 104 testes were obtained from equine castrations. Eight patterns of epididymal-testicular fusion were identified. Two clinical cases with epididymal dislocation were also described. RESULTS: Close attachment of the entire epididymis to the testis was the most common pattern of fusion (40%). Ninety-five per cent of cryptorchid testes and 34% of scrotal testes in the studied sample had elongated proper ligaments of the testes. Dislocation of the epididymal tail was observed in 2 stallions that had atypically long proper ligaments inserted on the dorsal aspect of the testes. CONCLUSIONS: Patterns of epididymal-testicular fusion can vary in stallions. Elongated proper ligaments of the testes occur mostly in cryptorchid testes but are also found in stallions with scrotal testes. Epididymal dislocation may develop in stallions with long proper ligaments that are inserted dorsally on the testes. PMID- 26032406 TI - Symptoms and side effects in chronic non-cancer pain patients: clinical implications and development of new assessment tools. AB - OBJECTIVE: To improve a 41-item screening tool evaluated in our previous study by making it more simple and convenient to patients and at the same time maintain the level of information and the sensitivity. METHODS: In a prospective, two period questionnaire study, patients suffering from chronic pain of non-cancer origin for more than 6 months, were asked to fill in two questionnaires: QSSE-41 or QSSE-33 and SF-36. The first part of the study (QSSE-41) included an age- and sex-matched control group. RESULTS: A total of 67 patients were included in QSSE 41 and 60 patients in QSSE-33. In QSSE-41, the mean number of symptoms reported by the patient group (12.3) was significantly higher than those reported by the controls (6.8) (P < 0.001). Out of the total number of symptoms, 40.3% were reported to be side effects caused by analgesics, and out of those 61.3% were reported as acceptable and 38.7% as unacceptable side effects. In the QSSE-33, the mean number of symptoms reported by the patient group was 13.6. Out of the total number of symptoms, 46.3% were reported to be side effects caused by analgesics, and out of those 56.4% were reported as acceptable and 43.6% as unacceptable side effects. CONCLUSIONS: This new and shorter screening tool QSSE 33 may substitute the original QSSE-41 and in clinical use, contribute substantially to a more comprehensive and detailed understanding of symptoms/side effects and may consequently lead to improved therapies. PMID- 26032405 TI - Genetics of systemic sclerosis. AB - Systemic sclerosis (SSc) is connective tissue disorder in which fibrosis of the skin and internal organs is the main hallmark. Despite the difficulties of studying a complex disease, significant advances have been achieved in the SSc genetics field. In this review, we will describe the firmest genetic susceptibility markers known to date. We will analyze the most recent findings in the HLA region and in non-HLA genes. Furthermore, we will propose functional connections of these loci with the mechanisms involved in SSc pathogenesis. However, only non-HLA genetic regions that have been associated with SSc at the genome-wide significance level or that have been reported to be associated with the disease in at least two different independent studies will be considered. In spite of the increasing number of SSc genetic susceptibility factors identified, further studies with larger sample sizes, deeper phenotype characterization of the patients and innovative analyses will be needed to translate SSc genetics into clinical practice and patient care in the future. PMID- 26032407 TI - Local and Systemic Changes in Pain Sensitivity After 4 Weeks of Calf Muscle Stretching in a Nonpainful Population: A Randomized Trial. AB - BACKGROUND: Stretching is often used in clinical practice for a variety of purposes, including pain therapy. The possible mechanism behind the effect of stretching remains to be clarified. AIM: To investigate whether 4 weeks of unilateral stretching of the calf muscles would affect local and central pain sensitivity. METHOD: This study was a randomized assessor-blinded clinical study. Healthy participants (age 18 to 40) were included and randomized. Participants in the intervention group were instructed to perform 2 stretching exercises targeting the calf muscles; 3 times 30 seconds, 7 days a week for 4 weeks on the dominant leg. Participants in the control group were instructed not to do any stretching for 4 weeks. Pressure pain threshold (PPT) and temporal summation (TS) of pressure pain were measured on the stretched calf, the contra-lateral calf, and contra-lateral lower arm using a computerized cuff algometer. Analyses of variance on the per-protocol population (defined as participants that adhered to the protocol) were used to assess group differences in the changes from baseline. RESULT: Forty healthy volunteers were included, of which 34 participants adhered to the protocol (15 intervention group/19 control group). No statistically significant group differences in the changes from baseline were found regarding PPT and TS measurements for the stretched calf, the contra-lateral calf, and the arm. CONCLUSION: Four weeks of regular stretching of the calf muscles does not affect pressure pain sensitivity, suggesting that pressure pain sensitivity is unaffected by stretching in a healthy population. The mechanisms underlying any benefits of regular stretching remain to be explained. PMID- 26032408 TI - Lack of host specificity leads to independent assortment of dipterocarps and ectomycorrhizal fungi across a soil fertility gradient. AB - Plants interact with a diversity of microorganisms, and there is often concordance in their community structures. Because most community-level studies are observational, it is unclear if such concordance arises because of host specificity, in which microorganisms or plants limit each other's occurrence. Using a reciprocal transplant experiment, we tested the hypothesis that host specificity between trees and ectomycorrhizal fungi determines patterns of tree and fungal soil specialisation. Seedlings of 13 dipterocarp species with contrasting soil specialisations were seeded into plots crossing soil type and canopy openness. Ectomycorrhizal colonists were identified by DNA sequencing. After 2.5 years, we found no evidence of host specificity. Rather, soil environment was the primary determinant of ectomycorrhizal diversity and composition on seedlings. Despite their close symbiosis, our results show that ectomycorrhizal fungi and tree communities in this Bornean rain forest assemble independently of host-specific interactions, raising questions about how mutualism shapes the realised niche. PMID- 26032409 TI - Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein coupled Receptor Kinases. AB - G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 A resolution. GRK5 in complex with the ATP analog 5'-adenylyl beta,gamma-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly conserved feature that is divided into three segments as follows: the C-lobe tether, the active-site tether (AST), and the N-lobe tether (NLT). This domain is fully resolved in GRK5 and reveals novel interactions with the nucleotide and N-lobe. Similar to other AGC kinases, the GRK5 AST is an integral part of the nucleotide binding pocket, a feature not observed in other GRKs. The AST also mediates contact between the kinase N- and C-lobes facilitating closure of the kinase domain. The GRK5 NLT is largely displaced from its previously observed position in other GRKs. Moreover, although the autophosphorylation sites in the NLT are >20 A away from the catalytic cleft, they are capable of rapid cis autophosphorylation suggesting high mobility of this region. In summary, we provide a snapshot of GRK5 in a partially closed state, where structural elements of the kinase domain C-tail are aligned to form novel interactions to the nucleotide and N-lobe not previously observed in other GRKs. PMID- 26032410 TI - Amino Acid Availability Regulates the Effect of Hyperinsulinemia on Skin Protein Metabolism in Pigs. AB - The effects of amino acid supply and insulin infusion on skin protein kinetics (fractional synthesis rate (FSR), fractional breakdown rate (FBR), and net balance (NB)) in pigs were investigated. Four-month-old pigs were divided into four groups as follows: control, insulin (INS), amino acid (AA), and INS + AA groups based on the nutritional and hormonal conditions. l-[ring (13)C6]Phenylalanine was infused. FBR was estimated from the enrichment ratio of arterial phenylalanine to intracellular free phenylalanine. Plasma INS was increased (p < 0.05) in the INS and INS + AA groups. Plasma glucose was maintained by infusion of glucose in the groups receiving INS. The interventions did not change the NB of skin protein. However, the interventions affected the FSR and FBR differently. An infusion of INS significantly increased both FSR and FBR, although AA infusion did not. When an AA infusion was added to the infusion of insulin (INS + AA group), FSR and FBR were both lower when compared with the INS group. Our data demonstrate that in anesthetized pigs INS infusion did not exert an anabolic effect, but rather it increased AA cycling into and out of skin protein. Because co-infusion of AAs with INS ameliorated this effect, it is likely that the increased AA cycling during INS infusion was related to AA supply. Although protein kinetics were affected by both INS and AAs, none of the interventions affected the skin protein deposition. Thus, skin protein content is closely regulated under normal circumstances and is not subject to transient changes in AAs or hormonal concentrations. PMID- 26032411 TI - Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor. AB - G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and thus represent important targets for the development of novel therapeutic drugs. In the course of a GRK2 structure-based drug design campaign, one inhibitor (CCG215022) exhibited nanomolar IC50 values against both GRK2 and GRK5 and good selectivity against other closely related kinases such as GRK1 and PKA. Treatment of murine cardiomyocytes with CCG215022 resulted in significantly increased contractility at 20-fold lower concentrations than paroxetine, an inhibitor with more modest selectivity for GRK2. A 2.4 A crystal structure of the GRK5.CCG215022 complex was determined and revealed that the inhibitor binds in the active site similarly to its parent compound GSK180736A. As designed, its 2-pyridylmethyl amide side chain occupies the hydrophobic subsite of the active site where it forms three additional hydrogen bonds, including one with the catalytic lysine. The overall conformation of the GRK5 kinase domain is similar to that of a previously determined structure of GRK6 in what is proposed to be its active state, but the C-terminal region of the enzyme adopts a distinct conformation. The kinetic properties of site-directed mutants in this region are consistent with the hypothesis that this novel C-terminal structure is representative of the membrane-bound conformation of the enzyme. PMID- 26032412 TI - Structure-Function Analyses of the Interactions between Rab11 and Rab14 Small GTPases with Their Shared Effector Rab Coupling Protein (RCP). AB - Rab GTPases recruit effector proteins, via their GTP-dependent switch regions, to distinct subcellular compartments. Rab11 and Rab25 are closely related small GTPases that bind to common effectors termed the Rab11 family of interacting proteins (FIPs). The FIPs are organized into two subclasses (class I and class II) based on sequence and domain organization, and both subclasses contain a highly conserved Rab-binding domain at their C termini. Yeast two-hybrid and biochemical studies have revealed that the more distantly related Rab14 also interacts with class I FIPs. Here, we perform detailed structural, thermodynamic, and cellular analyses of the interactions between Rab14 and one of the class I FIPs, the Rab-coupling protein (RCP), to clarify the molecular aspects of the interaction. We find that Rab14 indeed binds to RCP, albeit with reduced affinity relative to conventional Rab11-FIP and Rab25-FIP complexes. However, in vivo, Rab11 recruits RCP onto biological membranes. Furthermore, biophysical analyses reveal a noncanonical 1:2 stoichiometry between Rab14-RCP in dilute solutions, in contrast to Rab11/25 complexes. The structure of Rab14-RCP reveals that Rab14 interacts with the canonical Rab-binding domain and also provides insight into the unusual properties of the complex. Finally, we show that both the Rab coupling protein and Rab14 function in neuritogenesis. PMID- 26032413 TI - SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-beta Signaling Pathway Targeting the Type II Receptor. AB - Appropriate cellular signaling is essential to control cell proliferation, differentiation, and cell death. Aberrant signaling can have devastating consequences and lead to disease states, including cancer. The transforming growth factor-beta (TGF-beta) signaling pathway is a prominent signaling pathway that has been tightly regulated in normal cells, whereas its deregulation strongly correlates with the progression of human cancers. The regulation of the TGF-beta signaling pathway involves a variety of physiological regulators. Many of these molecules act to alter the activity of Smad proteins. In contrast, the number of molecules known to affect the TGF-beta signaling pathway at the receptor level is relatively low, and there are no known direct modulators for the TGF-beta type II receptor (TbetaRII). Here we identify SPSB1 (a Spry domain containing Socs box protein) as a novel regulator of the TGF-beta signaling pathway. SPSB1 negatively regulates the TGF-beta signaling pathway through its interaction with both endogenous and overexpressed TbetaRII (and not TbetaRI) via its Spry domain. As such, TbetaRII and SPSB1 co-localize on the cell membrane. SPSB1 maintains TbetaRII at a low level by enhancing the ubiquitination levels and degradation rates of TbetaRII through its Socs box. More importantly, silencing SPSB1 by siRNA results in enhanced TGF-beta signaling and migration and invasion of tumor cells. PMID- 26032414 TI - Novel Biological Substrates of Human Kallikrein 7 Identified through Degradomics. AB - Kallikrein-related peptidases (KLKs) are a group of serine proteases widely expressed in various tissues and involved in a wide range of physiological and pathological processes. Although our understanding of the pathophysiological roles of most KLKs has blossomed in recent years, identification of the direct endogenous substrates of human KLKs remains an unmet objective. In this study we employed a degradomics approach to systemically investigate the endogenous substrates of KLK7 in an effort to understand the molecular pathways underlying KLK7 action in skin. We identified several previously known as well as novel protein substrates. Our most promising candidates were further validated with the use of targeted quantitative proteomics (selected reaction monitoring methods) and in vitro recombinant protein digestion assays. Our study revealed midkine, CYR61, and tenascin-C as endogenous substrates for KLK7. Interestingly, some of these substrates (e.g. midkine) were prone to proteolytic cleavage only by KLK7 (and not by other skin-associated KLKs), whereas others (e.g. CYR61 and tenascin C) could be digested by several KLKs. Furthermore, using melanoma cell line, we show that KLK7-mediated cleavage of midkine results in an overall reduction in the pro-proliferative and pro-migratory effect of midkine. An inverse relation between KLK7 and midkine is also observed in human melanoma tissues. In summary, our degradomics approach revealed three novel endogenous substrates for KLK7, which may shed more light on the pathobiological roles of KLK7 in human skin. Similar substrate screening approaches could be applied for the discovery of biological substrates of other protease. PMID- 26032415 TI - The Cholesterol-dependent Cytolysin Membrane-binding Interface Discriminates Lipid Environments of Cholesterol to Support beta-Barrel Pore Insertion. AB - The majority of cholesterol-dependent cytolysins (CDCs) utilize cholesterol as a membrane receptor, whereas a small number are restricted to the GPI-anchored protein CD59 for initial membrane recognition. Two cholesterol-binding CDCs, perfringolysin O (PFO) and streptolysin O (SLO), were found to exhibit strikingly different binding properties to cholesterol-rich natural and synthetic membranes. The structural basis for this difference was mapped to one of the loops (L3) in the membrane binding interface that help anchor the toxin monomers to the membrane after receptor (cholesterol) binding by the membrane insertion of its amino acid side chains. A single point mutation in this loop conferred the binding properties of SLO to PFO and vice versa. Our studies strongly suggest that changing the side chain structure of this loop alters its equilibrium between membrane-inserted and uninserted states, thereby affecting the overall binding affinity and total bound toxin. Previous studies have shown that the lipid environment of cholesterol has a dramatic effect on binding and activity. Combining this data with the results of our current studies on L3 suggests that the structure of this loop has evolved in the different CDCs to preferentially direct binding to cholesterol in different lipid environments. Finally, the efficiency of beta-barrel pore formation was inversely correlated with the increased binding and affinity of the PFO L3 mutant, suggesting that selection of a compatible lipid environment impacts the efficiency of membrane insertion of the beta-barrel pore. PMID- 26032416 TI - HIV-1 Vpr Protein Enhances Proteasomal Degradation of MCM10 DNA Replication Factor through the Cul4-DDB1[VprBP] E3 Ubiquitin Ligase to Induce G2/M Cell Cycle Arrest. AB - Human immunodeficiency virus type 1 Vpr is an accessory protein that induces G2/M cell cycle arrest. It is well documented that interaction of Vpr with the Cul4 DDB1[VprBP] E3 ubiquitin ligase is essential for the induction of G2/M arrest. In this study, we show that HIV-1 Vpr indirectly binds MCM10, a eukaryotic DNA replication factor, in a Vpr-binding protein (VprBP) (VprBP)-dependent manner. Binding of Vpr to MCM10 enhanced ubiquitination and proteasomal degradation of MCM10. G2/M-defective mutants of Vpr were not able to deplete MCM10, and we show that Vpr-induced depletion of MCM10 is related to the ability of Vpr to induce G2/M arrest. Our study demonstrates that MCM10 is the natural substrate of the Cul4-DDB1[VprBP] E3 ubiquitin ligase whose degradation is regulated by VprBP, but Vpr enhances the proteasomal degradation of MCM10 by interacting with VprBP. PMID- 26032417 TI - Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment. AB - Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, which include basal, luminal, and neuroendocrine cells. Two types of P-SCs have been identified in both human and mouse adult prostates based on prostasphere or organoid cultures, cell lineage tracing, renal capsule implantation, and expression of luminal- and basal-specific proteins. The sphere-forming P-SCs are from the basal cell compartment that express P63, and are therefore designated as basal P-SCs (P-bSCs). Luminal P-SCs (P-lSCs) express luminal cytokeratins and Nkx3.1. Herein, we report that the type 2 FGF receptor (FGFR2) signaling axis is crucial for preserving stemness and preventing differentiation of P-bSCs. FGFR2 signaling mediated by FGFR substrate 2alpha (FRS2alpha) is indispensable for formation and maintenance of prostaspheres derived from P63(+) P-bSCs. Ablation of Fgfr2 in P63(+) cells in vitro causes the disintegration of prostaspheres. Ablation of Fgfr2 in vivo reduces the number of P63-expressing basal cells and enriches luminal cells. This suggests a basal stem cell-to-luminal cell differentiation. In addition, ablation of Fgfr2 in P63(+) cells causes defective postnatal development of the prostate. Therefore, the data indicate that FGFR2 signaling is critical for preserving stemness and preventing differentiation of P-bSCs. PMID- 26032418 TI - Factors Associated with Nitric Oxide-mediated beta2 Integrin Inhibition of Neutrophils. AB - This investigation explored the mechanism for inhibition of beta2 integrin adhesion molecules when neutrophils are exposed to nitric oxide ((*)NO). Roles for specific proteins were elucidated using chemical inhibitors, depletion with small inhibitory RNA, and cells from knock-out mice. Optimal inhibition occurs with exposures to a (*)NO flux of ~ 28 nmol/min for 2 min or more, which sets up an autocatalytic cascade triggered by activating type 2 nitric-oxide synthase (NOS-2) and NADPH oxidase (NOX). Integrin inhibition does not occur with neutrophils exposed to a NOX inhibitor (Nox2ds), a NOS-2 inhibitor (1400 W), or with cells from mice lacking NOS-2 or the gp91(phox) component of NOX. Reactive species cause S-nitrosylation of cytosolic actin that enhances actin polymerization. Protein cross-linking and actin filament formation assays indicate that increased polymerization occurs because of associations involving vasodilator-stimulated phosphoprotein, focal adhesion kinase, and protein disulfide isomerase in proximity to actin filaments. These effects were inhibited in cells exposed to ultraviolet light which photo-reverses S-nitrosylated cysteine residues and by co-incubations with cytochalasin D. The autocatalytic cycle can be arrested by protein kinase G activated with 8-bromo-cyclic GMP and by a high (*)NO flux (~ 112 nmol/min) that inactivates NOX. PMID- 26032419 TI - Prostate Sphere-forming Stem Cells Are Derived from the P63-expressing Basal Compartment. AB - Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, including basal, luminal, and neuroendocrine cells. Multiple methods have been used to identify P-SCs in adult prostates. These include in vivo renal capsule implantation of a single epithelial cell with urogenital mesenchymal cells, in vitro prostasphere and organoid cultures, and lineage tracing with castration-resistant Nkx3.1 expression (CARN), in conjunction with expression of cell type-specific markers. Both organoid culture and CARN tracing show the existence of P-SCs in the luminal compartment. Although prostasphere cells predominantly express basal cell-specific cytokeratin and P63, the lineage of prostasphere-forming cells in the P-SC hierarchy remains to be determined. Using lineage tracing with P63(CreERT2), we show here that the sphere forming P-SCs are P63-expressing cells and reside in the basal compartment. Therefore we designate them as basal P-SCs (P-bSCs). P-bSCs are capable of differentiating into AR(+) and CK18(+) organoid cells, but organoid cells cannot form spheres. We also report that prostaspheres contain quiescent stem cells. Therefore, the results show that P-bSCs represent stem cells that are early in the hierarchy of overall prostate tissue stem cells. Understanding the contribution of the two types of P-SCs to prostate development and prostate cancer stem cells and how to manipulate them may open new avenues for control of prostate cancer progression and relapse. PMID- 26032420 TI - Spleen Tyrosine Kinase (Syk) Mediates IL-1beta Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection. AB - Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1beta is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1beta provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1beta and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1beta secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1beta secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL 1beta secretion. Maturation of pro-IL-1beta during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1beta secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue. PMID- 26032421 TI - Polyamine-independent Expression of Caenorhabditis elegans Antizyme. AB - Degradation of ornithine decarboxylase, the rate-limiting enzyme of polyamine biosynthesis, is promoted by the protein antizyme. Expression of antizyme is positively regulated by rising polyamine concentrations that induce a +1 translational frameshift required for production of the full-length protein. Antizyme itself is negatively regulated by the antizyme inhibitor. In our study, the regulation of Caenorhabditis elegans antizyme was investigated, and the antizyme inhibitor was identified. By applying a novel GFP-based method to monitor antizyme frameshifting in vivo, we show that the induction of translational frameshifting also occurs under stressful conditions. Interestingly, during starvation, the initiation of frameshifting was independent of polyamine concentrations. Because frameshifting was also prevalent in a polyamine auxotroph double mutant, a polyamine-independent regulation of antizyme frameshifting is suggested. Polyamine-independent induction of antizyme expression was found to be negatively regulated by the peptide transporter PEPT 1, as well as the target of rapamycin, but not by the daf-2 insulin signaling pathway. Stress-dependent expression of C. elegans antizyme occurred morely slowly than expression in response to increased polyamine levels, pointing to a more general reaction to unfavorable conditions and a diversion away from proliferation and reproduction toward conservation of energy. Interestingly, antizyme expression was found to drastically increase in aging individuals in a postreproductive manner. Although knockdown of antizyme did not affect the lifespan of C. elegans, knockdown of the antizyme inhibitor led to a significant reduction in lifespan. This is most likely caused by an increase in antizyme mediated degradation of ornithine decarboxylase-1 and a resulting reduction in cellular polyamine levels. PMID- 26032422 TI - Complex Formation between Two Biosynthetic Enzymes Modifies the Allosteric Regulatory Properties of Both: AN EXAMPLE OF MOLECULAR SYMBIOSIS. AB - Allostery, where remote ligand binding alters protein function, is essential for the control of metabolism. Here, we have identified a highly sophisticated allosteric response that allows complex control of the pathway for aromatic amino acid biosynthesis in the pathogen Mycobacterium tuberculosis. This response is mediated by an enzyme complex formed by two pathway enzymes: chorismate mutase (CM) and 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS). Whereas both enzymes are active in isolation, the catalytic activity of both enzymes is enhanced, and in particular that of the much smaller CM is greatly enhanced (by 120-fold), by formation of a hetero-octameric complex between CM and DAH7PS. Moreover, on complex formation M. tuberculosis CM, which has no allosteric response on its own, acquires allosteric behavior to facilitate its own regulatory needs by directly appropriating and partly reconfiguring the allosteric machinery that provides a synergistic allosteric response in DAH7PS. Kinetic and analytical ultracentrifugation experiments demonstrate that allosteric binding of phenylalanine specifically promotes hetero-octameric complex dissociation, with concomitant reduction of CM activity. Together, DAH7PS and CM from M. tuberculosis provide exquisite control of aromatic amino acid biosynthesis, not only controlling flux into the start of the pathway, but also directing the pathway intermediate chorismate into either Phe/Tyr or Trp biosynthesis. PMID- 26032424 TI - Therapeutically Targetable ALK Mutations in Leukemia. AB - Genome sequencing is revealing a vast mutational landscape in leukemia, offering new opportunities for treatment with targeted therapy. Here, we identify two patients with acute myelogenous leukemia and B-cell acute lymphoblastic leukemia whose tumors harbor point mutations in the ALK kinase. The mutations reside in the extracellular domain of ALK and are potently transforming in cytokine independent cellular assays and primary mouse bone marrow colony formation studies. Strikingly, both mutations conferred sensitivity to ALK kinase inhibitors, including the FDA-approved drug crizotinib. On the basis of our results, we propose that tumors harboring ALK mutations may be therapeutically tractable for personalized treatment of certain aggressive leukemias with ALK inhibitors. PMID- 26032426 TI - Correction: HOXB7, a Homeodomain Protein, Is Overexpressed in Breast Cancer and Confers Epithelial-Mesenchymal Transition. PMID- 26032425 TI - Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline. AB - Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. PMID- 26032427 TI - Adolescents from affluent city districts drink more alcohol than others. AB - AIMS: To estimate the level of alcohol consumption and problems among adolescents in city districts in Oslo, Norway with different socio-economic composition; to test whether differences in alcohol consumption are related to district differences in socio-demographic characteristics; and to analyse whether such associations remain significant after controlling for individual-level variables. DESIGN: Cross-sectional survey using multi-level linear regression analyses with individual responses at the lowest level and city-district data at the highest level. SETTING: Oslo, Norway. PARTICIPANTS: A total of 6635 secondary school students, in 62 schools, living in 15 different city districts. MEASUREMENTS: Frequency of alcohol consumption and alcohol intoxication; alcohol problems; and individual characteristics such as immigrant status, religious involvement and parental norms with regard to alcohol. Socio-economic indicators in city districts, such as education, income and unemployment, were combined into a district-level socio-economic index (DLSI). FINDINGS: DLSI scores were related positively to alcohol use (r = 0.31, P < 0.01) and alcohol intoxication (r = 0.25, P < 0.01) but negatively to alcohol problems among alcohol users (r = 0.18, P < 0.01). DLSI scores remained significant for alcohol consumption and alcohol intoxication, after controlling for individual-level variables (P < 0.01), but this was not the case for alcohol problems. CONCLUSION: Adolescents in affluent areas of Oslo, Norway report the highest levels of alcohol consumption and alcohol intoxication of all areas; neighbourhood characteristics such as education, income and unemployment levels seem to play a role in such drinking behaviour. Alcohol users in poorer districts reported more alcohol problems than those in other districts; however, here neighbourhood effects do not seem to play a role. PMID- 26032428 TI - Highly stereoselective [4+2] and [3+2] spiroannulations of 2-(2-oxoindolin-3 ylidene)acetic esters catalyzed by bifunctional thioureas. AB - A new Michael-Michael cascade reaction between 2-(2-oxoindolin-3-ylidene)acetic esters 1 and nitroenoates 2, catalyzed by bifunctional thioureas, is investigated. The combination of the two Michael reactions results in a novel and facile [4+2] or [3+2] spiroannulation process, which is characterized by the following features: 1) two carbon-carbon bonds and four stereocenters, including a quaternary spiro carbon, are formed under mild conditions; 2) an unprecedented and stereochemically defined substitution pattern on the spirocarbocyclic unit is obtained; 3) the double-bond configuration of the donor-acceptor nitroenoate 2 determines the absolute configuration of the spiro center, whereas the remaining stereocenters are formed under control of the catalyst. The effect on the final stereochemical outcome of structural variations of each starting material, catalyst, and experimental conditions is analyzed in detail. In particular, the use of specifically designed chiral nitroenoates enables diverse polyfunctional spirocyclohexane derivatives containing six consecutive stereogenic centers to be constructed. To our knowledge, this is the first asymmetric organocatalytic strategy enabling both five- and six-membered beta-nitro spirocarbocyclic oxindoles. PMID- 26032429 TI - Clinical profile of diabetic ketoacidosis in tertiary hospitals in China: a multicentre, clinic-based study. AB - AIMS: To evaluate the clinical profile of patients with diabetic ketoacidosis in tertiary hospitals in China. METHODS: A retrospective study of patients hospitalized with diabetic ketoacidosis between 2010 and 2012 was carried out in 15 tertiary hospitals around China. Clinical and laboratory data were collected. Patients were classified based on clinical diagnosis and treatment history. Groups were compared for differences in vital statistics and biochemical profiles at presentation. RESULTS: The study comprised 643 patients with diabetic ketoacidosis: 308 patients (47.9%) with Type 1 diabetes, 294 patients (45.7%) with Type 2 diabetes and 41 patients (6.4%) with atypical diabetes. Three hundred and eighty-eight diabetic ketoacidosis episodes (60.3%) were in patients with known diabetes. The most common precipitating factor was infection (40.1%), followed by unknown causes (36.9%) and non-compliance with anti-diabetes treatment (16.8%). At presentation, gastrointestinal symptoms and dehydration were more common in the Type 1 diabetes group. For new-onset diabetes, only 74.4% and 55.9% of patients were evaluated for beta-cell function and autoantibodies for classification. Only 67% of patients with diabetic ketoacidosis received appropriate fluid therapy and 56% patients with severe acidosis received bicarbonate therapy. The length of hospital stay was 10.0 (7.0-14.0) days. The mortality rate was 1.7%, and was much higher in Type 2 diabetes than that in Type 1 diabetes (3.2% vs. 0.4%, P < 0.01). CONCLUSIONS: Type 2 and Type 1 diabetes contribute to a similar proportion of cases presenting with diabetic ketoacidosis in China. Admissions with diabetic ketoacidosis are still associated with significant mortality and prolonged hospitalization. The efficiency of diabetic ketoacidosis management needs to be improved by implementing the updated guidelines. PMID- 26032430 TI - Development of a pan-serotype reverse transcription loop-mediated isothermal amplification assay for the detection of dengue virus. AB - During dengue outbreaks, acute diagnosis at the patient's point of need followed by appropriate supportive therapy reduces morbidity and mortality. To facilitate needed diagnosis, we developed and optimized a reverse transcription loop mediated isothermal amplification (RT-LAMP) assay that detects all 4 serotypes of dengue virus (DENV). We used a quencher to reduce nonspecific amplification. The assay does not require expensive thermocyclers, utilizing a simple water bath to maintain the reaction at 63 degrees C. Results can be visualized using UV fluorescence, handheld readers, or lateral flow immunochromatographic tests. We report a sensitivity of 86.3% (95% confidence interval [CI], 72.7-94.8%) and specificity of 93.0% (95% CI, 83.0-98.1%) using a panel of clinical specimens characterized by DENV quantitative reverse transcription-polymerase chain reaction. This pan-serotype DENV RT-LAMP can be adapted to field-expedient formats where it can provide actionable diagnosis near the patient's point of need. PMID- 26032431 TI - Appropriateness of expectorated sputum cultures in the hospital setting. AB - We assessed whether expectorated sputum samples are ordered according to national guidelines and the impact of culture results on patient management. Overall, guidelines for ordering sputum samples were followed for 23% (18/78) of patients. Results affected treatment in 18% (14/79) of cases. Reducing inappropriate sputum cultures may have significant economic savings in the hospital system. PMID- 26032432 TI - Efficacy and safety of a biosimilar rituximab in biologic naive patients with active rheumatoid arthritis. AB - Biosimilar usage in rheumatology is set to increase over the next few years. This study reports the efficacy and toxicity of a rituximab biosimilar in biologic naive patients with active rheumatoid arthritis who had inadequately responded to methotrexate. In 21 patients, over a follow-up period of 36 months, it demonstrated prolonged benefit in a majority (10 in remission with disease activity score 28 (DAS28) erythrocyte sedimentation rate (ESR) <2.6 and 9 in low disease activity state with DAS28 ESR between 3.2 and 2.6) and was well tolerated. PMID- 26032433 TI - Evaluation of the Canadian Rheumatology Association Choosing Wisely recommendation concerning anti-nuclear antibody (ANA) testing. AB - The objective of this study was to evaluate the Canadian Rheumatology Association Choosing Wisely recommendation concerning anti-nuclear antibody (ANA) testing. Patients with joint pain/stiffness/swelling were assessed to determine if ANA testing was indicated. An a priori threshold was set before ANA testing would be considered. Those who did not have ANA testing ordered were followed for 1 year to determine if any of them went on to have a diagnosis of systemic lupus erythematosus (SLE) or other connective tissue disease. A parallel study was conducted with a similar a priori threshold for the use of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody testing in the diagnosis of rheumatoid arthritis (RA), and again, patients were followed for 1 year. A total of 866 subjects were examined, 509 females (58.8 %) and 357 males (41.2 %). The mean age of the group was 47.5 +/- 16.8 years. The mean duration of symptoms was 12.0 +/- 5.6 weeks. Of the 866 subjects, 68 met an a priori threshold for ordering ANA, RF, and anti-CCP testing. Of these 68, there was a newly diagnosed case of SLE, 4 newly diagnosed cases of RA, and 3 cases of polymyalgia rheumatica. The remaining 798 subjects were followed for approximately 1 year and none developed evidence of SLE, RA, or other connective tissue disease. In the evaluation of non-specific musculoskeletal symptoms, setting an a priori threshold for ordering serology in keeping with the spirit of the Canadian Rheumatology Association Choosing Wisely recommendation for antibody testing results in a very low risk of missing a case of systemic lupus erythematosus or rheumatoid arthritis. PMID- 26032434 TI - Structure of a thermophilic F1-ATPase inhibited by an epsilon-subunit: deeper insight into the epsilon-inhibition mechanism. AB - F1-ATPase (F1) is the catalytic sector in F(o)F1-ATP synthase that is responsible for ATP production in living cells. In catalysis, its three catalytic beta subunits undergo nucleotide occupancy-dependent and concerted open-close conformational changes that are accompanied by rotation of the gamma-subunit. Bacterial and chloroplast F1 are inhibited by their own epsilon-subunit. In the epsilon-inhibited Escherichia coli F1 structure, the epsilon-subunit stabilizes the overall conformation (half-closed, closed, open) of the beta-subunits by inserting its C-terminal helix into the alpha3beta3 cavity. The structure of epsilon-inhibited thermophilic F1 is similar to that of E. coli F1, showing a similar conformation of the epsilon-subunit, but the thermophilic epsilon-subunit stabilizes another unique overall conformation (open, closed, open) of the beta subunits. The epsilon-C-terminal helix 2 and hook are conserved between the two structures in interactions with target residues and in their positions. Rest of the epsilon-C-terminal domains are in quite different conformations and positions, and have different modes of interaction with targets. This region is thought to serve epsilon-inhibition differently. For inhibition, the epsilon subunit contacts the second catches of some of the beta- and alpha-subunits, the N- and C-terminal helices, and some of the Rossmann fold segments. Those contacts, as a whole, lead to positioning of those beta- and alpha- second catches in epsilon-inhibition-specific positions, and prevent rotation of the gamma-subunit. Some of the structural features are observed even in IF1 inhibition in mitochondrial F1. PMID- 26032435 TI - Relationship between metabolic and vascular conditions and cognitive decline among older Mexican Americans. AB - OBJECTIVE: Metabolic and vascular conditions have been independently associated with dementia and cognitive decline among older adults, but research on the combined effects that these conditions have on cognitive decline, especially among older Mexican Americans, is lacking. The purpose of this study was to examine the relationship between metabolic and vascular conditions and cognitive decline among older Mexican Americans. METHODS: The final sample included 2767 participants of the Hispanic Established Populations for the Epidemiologic Study of the Elderly. Linear mixed-effects regression was used to model cognitive decline across six examinations (1993-2007) according to the number (zero, one, two, and three to four) of metabolic and vascular conditions (hypertension, diabetes, stroke, and heart attack). RESULTS: Of the 2767 participants included in the final sample, 777 had zero conditions, 1314 had one condition, 553 had two conditions, and 123 had three to four conditions. Participants with two or three to four conditions had significantly greater cognitive decline compared with participants with zero or one condition. Stroke had the largest effect size on cognitive decline based on the proportion of variance that stroke accounted for in the linear mixed-effects model. CONCLUSION: Mexican American older adults with multiple metabolic and vascular conditions exhibit greater cognitive decline than those with zero or one condition. Public health interventions designed to reduce the prevalence of chronic metabolic and vascular conditions, in particular stroke, may limit the severity of cognitive decline among older Mexican Americans. PMID- 26032437 TI - Outcome in TAVI patients with symptomatic aortic stenosis not fulfilling PARTNER study inclusion criteria. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has rapidly evolved to the standard-of-care for inoperable patients with severe, symptomatic aortic valve stenosis, and to an alternative treatment option for high-risk patients. However, the randomized PARTNER trial excluded patients with conditions frequently encountered in daily clinical practice. METHODS: From 2006 to 2011, 467 high-risk patients, who underwent transfemoral TAVI (Edwards Sapien n = 166; Medtronic CoreValve n = 301) at two German centers were divided into a "PARTNER like" (n = 227) and a "Real-World" cohort (n = 240), based on the original PARTNER trial in- and exclusion criteria. Differences in 30-day and 2-year mortality and morbidity were assessed. RESULTS: Mean age of patients was 80 +/- 8 years with a logistic EuroSCORE of 22 +/- 16%. The most frequent exclusion criteria were previous PCI (15.4%), prior valve surgery (13.7%), chronic renal failure (12.0%), and severe mitral regurgitation (10.8%). Despite significant differences in baseline data, estimated perioperative mortality in terms of STS and logistic EuroScore was identical between both groups. However, patients in the "Real-World" cohort had a non-significant trend towards a higher 30-day mortality (10.0% vs. 6.7%, P = 0.088) and a significantly higher 2-year mortality (23.3% vs. 14.5%, P = 0.016) compared with patients of the "PARTNER-like" cohort. CONCLUSION: Patients meeting PARTNER study exclusion criteria had an acceptable outcome at 30 days and 2 years, however, with significant differences to "PARTNER like" patients. Still, our results indicate that also real-life patients with relevant comorbidities, who would have been excluded from the randomized PARTNER trials, benefit from TAVI with acceptable short- and long-term outcome. PMID- 26032438 TI - Fabricating Complete Dentures with CAD/CAM and RP Technologies. AB - Two techological approaches for fabricating dentures; computer-aided design and computer-aided manufacturing (CAD/CAM) and rapid prototyping (RP), are combined with the conventional techniques of impression and jaw relation recording to determine their feasibility and applicability. Maxillary and mandibular edentulous jaw models were produced using silicone molds. After obtaining a gypsum working model, acrylic bases were crafted, and occlusal rims for each model were fabricated with previously determined standard vertical and centric relationships. The maxillary and mandibular relationships were recorded with guides. The occlusal rims were then scanned with a digital scanner. The alignment of the maxillary and mandibular teeth was verified. The teeth in each arch were fabricated in one piece, or set, either by CAM or RP. Conventional waxing and flasking was then performed for both methods. These techniques obviate a practitioner's need for technicians during design and provide the patient with an opportunity to participate in esthetic design with the dentist. In addition, CAD/CAM and RP reduce chair time; however, the materials and techniques need further improvements. Both CAD/CAM and RP techniques seem promising for reducing chair time and allowing the patient to participate in esthetics design. Furthermore, the one-set aligned artificial tooth design may increase the acrylic's durability. PMID- 26032436 TI - Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats. AB - Depression during pregnancy has been linked to in utero stress and is associated with long-lasting symptoms in offspring, including anxiety, helplessness, attentional deficits, and social withdrawal. Depression is diagnosed in 10-20% of expectant mothers, but the impact of antidepressant treatment on offspring development is not well documented, particularly for females. Here, we used a prenatal stress model of maternal depression to test the hypothesis that in utero antidepressant treatment could mitigate the effects of prenatal stress. We also investigated the effects of prenatal stress and antidepressant treatment on gene expression related to GABAergic and serotonergic neurotransmission in the amygdala, which may underlie behavioral effects of prenatal stress. Nulliparous female rats were implanted with osmotic minipumps delivering clinically-relevant concentrations of escitalopram and mated. Pregnant dams were exposed to 12 days of mixed-modality stressors, and offspring were behaviorally assessed in adolescence (postnatal day 28) and adulthood (beyond day 90) to determine the extent of behavioral change. We found that in utero stress exposure, regardless of escitalopram treatment, increased anxiety-like behavior in adolescent females and profoundly influenced amygdala expression of the chloride transporters KCC2 and NKCC1, which regulate GABAergic function. In contrast, prenatal escitalopram exposure alone elevated amygdala expression of 5-HT1A receptors. In adulthood, anxiety-like behavior returned to baseline and gene expression effects in the amygdala abated, whereas deficits emerged in novel object recognition for rats exposed to stress during gestation. These findings suggest prenatal stress causes age-dependent deficits in anxiety-like behavior and amygdala function in female offspring, regardless of antidepressant exposure. PMID- 26032439 TI - Biocompatibility of low molecular weight polymers for two-phase partitioning bioreactors. AB - Two phase partitioning bioreactors (TPPBs) improve the efficiency of fermentative processes by limiting the exposure of microorganisms to toxic solutes by sequestering them into a non-aqueous phase (NAP). A potential limitation of this technology, when using immiscible organic solvents as the NAP, is the cytoxicity that these materials may exert on the microbes. An improved TPPB configuration is one in which polymeric NAPs are used to replace organic solvents in order to take advantage of their low cost, improved handling qualities, and biocompatibility. A recent study has shown that low molecular weight polymers may confer improved solute uptake relative to high molecular weight polymers (i.e., have higher partition coefficients), but it is unknown whether sufficiently low molecular weight polymers may inhibit cell growth. This study has investigated the biocompatibility of a range of low molecular weight polymers, and compared trends in biocompatibility to the well-established "critical log P" concept. This was achieved by determining the biocompatibility of polypropylene glycol polymers over a molecular weight (MW) range of 425-4,000 to Saccharomyces cerevisiae and Pseudomonas putida, two organisms which have been previously used in TPPB systems. The lower MW polymers were shown to have lower average log P values, and showed more cytotoxicity than polymers of the same structure but with higher molecular weight. Since polymers are generally polydisperse (i.e., polymer samples contain a distribution of MWs), removal of the lower MW fractions via water washing was found to result in improved polymer biocompatibility. These results suggest that the critical log P concept remains useful for describing the toxicity of polymeric substances of different MWs, although it is complicated by the presence of the low MW fractions in the polymers arising from polydispersity. PMID- 26032440 TI - A long-term fatty fish intervention improved executive function in inpatients with antisocial traits and a history of alcohol and drug abuse. AB - The aim of the present study was to investigate the effects of fatty fish consumption on cognitive functioning in a group of inpatients characterized by antisocial behavior. Eighty-three male forensic inpatients participated in this study. Participants were randomly assigned into a Fish or a Control group (e.g., meat, chicken, pork). One decision-making task, the Iowa Gambling Task (IGT), and one planning task, the Tower of Hanoi (ToH), were administered before (pre-test) and at the end of the intervention period (post-test). For the IGT the Fish group showed improved performance from pre- to post- test. Moreover, the Fish group showed significantly better performance than the Control group on the IGT at post test. The Fish group also demonstrated improved performance from pre- to post test on the ToH; however, this was limited to participants with a history of substance abuse. Further, the improvement was only significant for tasks with high working memory load (5-7 move problems), and not for tasks with low working memory load (1-4 move problems). The Control group showed no improvement on any of the tasks regardless of alcohol or drug abuse history. The present study suggests that regular fatty fish consumption may improve executive functions in forensic inpatients with antisocial traits and a history of substance abuse. Thus, the current results may have important implications with regard to health care interventions. PMID- 26032441 TI - Modeling outcomes of approaches to sustained human and snow leopard coexistence. AB - The snow leopard (Uncia uncia) is in danger of extinction. Killing to protect livestock is among the primary causes of its decline. Efforts to mitigate this threat have focused on balancing the need to conserve the snow leopard with the needs of local people in snow leopard habitat, many of whom rely on raising livestock for their livelihoods. Conservation of the snow leopard has the characteristics of a public good, and outside funding is required to support conservation efforts. There are 5 commonly discussed approaches to resolving this issue: (1) direct payments for conservation, (2) investments in protection from predation, (3) damage compensation payments, (4) investments in better livestock husbandry, and (5) leases of pastureland for wild prey. After a review of these 5 conservation strategies, an economic-ecologic model, which includes the interactions between the snow leopard, its wild prey, and livestock, is used to evaluate the 2 most promising conservation strategies. The model reveals that investments in protection from predation and leases of pastureland for wild prey are effective but only in delaying the eventual extinction of the snow leopard. To preserve the snow leopard, these approaches must be applied more aggressively and new ones explored. PMID- 26032442 TI - Validation of the yale-brown obsessive compulsive scale modified for binge eating. AB - OBJECTIVE: Establish the Yale-Brown obsessive compulsive scale modified for binge eating (YBOCS-BE) as a fit for purpose measure of treatment benefit in clinical trials of binge eating disorder (BED). METHODS: YBOCS-BE psychometric properties were evaluated with data from a Phase 2 randomized controlled trial of lisdexamfetamine dimesylate in 260 adults with BED. Assessments included: Cohen's effect size estimates of item-level sensitivity and scale-level external responsiveness; item-to-total correlations; Cronbach's alpha for internal consistency reliability; Spearman correlations against reference measures for construct validity; known-groups analyses for discriminating ability; t tests of within-group differences between baseline and post baseline visits for internal responsiveness; and multiple anchor-based approaches to estimate minimum clinically important change (MCIC). RESULTS: No significant distribution anomalies were seen. Items appear sensitive to treatment group differences. Item to-total correlations were positive. Internal consistency is 0.81. Large correlations (>0.50) were seen between YBOCS-BE score change and the Clinical Global Impression-Improvement (CGI-I; 0.58) and score changes for the following; number of binge days (0.38), Clinical Global Impression-Severity (CGI-S; 0.57), the disinhibition (0.57) and hunger (0.52) subscales of the Three-Factor Eating Questionnaire (TFEQ), and the Barratt Impulsiveness Scale (BIS-11; 0.58). MCIC estimates range from -4 to -17. DISCUSSION: The YBOCS-BE was found to be a reliable and valid measure of an important and unique concept in BED-related clinical studies. Study limitations include using protocol-defined BED severity level and the exclusion of psychiatric comorbidities. PMID- 26032443 TI - Coagulation status in dogs with naturally occurring Angiostrongylus vasorum infection. AB - OBJECTIVES: Angiostrongylus vasorum infection is associated with bleeding tendencies in approximately one-third of clinical cases. The cause of the coagulopathy is poorly understood but may be related to disseminated intravascular coagulation. Thromboelastography is a global evaluation of coagulation and has not been described in a cohort of dogs with this disease. MATERIALS AND METHODS: Thromboelastography in association with other measures of coagulation including prothrombin and activated partial thromboplastin times, antithrombin percentage activity and D-dimer and von Willebrand factor concentrations was evaluated in a group of 30 dogs with A. varosum infection. RESULTS: A total of 18 dogs had signs of bleeding on physical examination. Thromboelastography was consistent with hypocoagulation in 17 of these dogs. There was no association between any of the other measures and hypocoagulation on thromboelastography. Abnormal coagulation times were not significantly associated with bleeding. Only fibrinogen concentration was significantly lower in dogs that were bleeding compared with those that were not (P = 0 . 026). D-dimer concentrations were increased in 22/25 cases in the study; however, other coagulation parameters were more variable. CLINICAL SIGNIFICANCE: Although the changes identified in this study were not consistent, there is activation of coagulation within this population, possibly consistent with an intravascular disseminated coagulopathy. PMID- 26032444 TI - Effects of Dietary Copper and Zinc Supplementation on Growth Performance, Tissue Mineral Retention, Antioxidant Status, and Fur Quality in Growing-Furring Blue Foxes (Alopex lagopus). AB - A 4*2 factorial experiment with four supplemental levels of copper (0, 20, 40, or 60 mg copper per kg dry matter) from copper sulfate and two supplemental levels of zinc (40 or 200 mg zinc per kg dry matter) from zinc sulfate was conducted to investigate the effects of dietary copper and zinc supplementation on growth performance, tissue mineral retention, antioxidant status, and fur quality in growing-furring blue foxes. One hundred and twenty healthy 15-week-old male blue foxes were randomly allocated to eight dietary treatments with 15 replicates per treatment for a 70-day trial from mid-September to pelting in December. The average daily gain and feed conversion ratio were increased with copper supplementation in the first 35 days as well as the overall period (P<0.05). In addition, copper supplementation tended to increase feed intake during the first 35 days (P<0.10). Diets supplemented with 200 mg/kg zinc did not affect body gain (P>0.10) and feed intake (P>0.10) but improved feed conversion (P<0.05) compared with those supplemented 40 mg/kg zinc throughout the experiment. No copper*zinc interaction was observed for growth performance except that a tendency (P=0.09) was found for feed intake in the first 35 days. Supplementation of copper or zinc improved crude fat digestibility (P<0.01) but had no effects on the digestibility of other nutrients. Fecal copper was increased with both copper (P<0.01) and zinc addition (P<0.05). However, fecal zinc was affected only by dietary zinc addition (P<0.01). Mineral contents in serum and kidney were not affected by dietary treatments (P>0.05). However, the level of copper in the liver was increased with copper supplementation (P<0.05) and tended to decrease with zinc supplementation (P=0.08). Dietary zinc addition tended to increase the activity of alkaline phosphatase (P=0.07). The activities of copper-zinc superoxide dismutase and catalase tended to increase by copper (P=0.08) and zinc addition (P=0.05). Moreover, a copper*zinc interaction was observed for catalase in the experiment (P<0.05). Serum malondialdehyde concentration decreased with the increasing of dietary copper and zinc levels (P<0.05). The activity of glutathione peroxidase tended to increase by copper addition (P=0.09). For fur quality, foxes fed diets supplemented with high copper had larger skin length and darker pelts than those fed the basal diet without copper addition (P<0.05). In conclusion, this study demonstrated that dietary copper and zinc supplementation can improve growth by increasing feed intake and improving fat digestibility. Additionally, copper and zinc can enhance the antioxidant capacity of blue foxes. This study also indicates that additional zinc up to 200 mg/kg did not exert significant adverse effects on the copper metabolism of growing-furring blue foxes. PMID- 26032445 TI - Analysis of Mineral Elements, Metabolism, and Inflammation Indexes in the Plasma of Dairy Cows Suffering from Different Degrees of Lameness. AB - In the plasma of dairy cows with 1-5 points of lameness, the mineral elements [calcium (Ca), iron (Fe), copper (Cu), zinc (Zn), iodine (I), selenium (Se), molybdenum (Mo), and chromium (Cr)], the energy metabolic indicators [triglyceride (TG), glucose (Glu), total cholesterol (CHO), nonesterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), lactate (LA), and blood urea nitrogen (BUN)], and inflammatory indexes [bovine haptoglobin (BoHp), histamine (HIS), and immunoglobulin G (IgG)] were measured, respectively. Furthermore, the correlations of the measured indicators with the degrees of lameness were analyzed. The results showed that in the plasma of dairy cows with 2/3-5 points of lameness, for the mineral elements' levels, Ca, Cu, I, Se, and Fe significantly decreased, Cr significantly increased, and Mo showed a decreasing trend; for levels of the energy metabolism indicators, NEFA and BHBA significantly decreased, BUN and LA significantly increased, and Glu, CHO, and TG showed an increasing trend; for inflammation indexes, the concentrations of HIS, BoHp, and IgG all significantly increased; and further analysis indicated that the Mo, Fe, NEFA, BUN, BHBA, IgG, Ca, and Se had a significant correlation with the degrees of lameness. Resulting data revealed the changes of mineral elements, metabolism, and inflammation indexes in the plasma of dairy cows suffering from different degrees of lameness, which will provided basic knowledge for in-depth understanding of lameness in dairy cows. PMID- 26032446 TI - Severe pain during local infiltration for spinal anaesthesia predicts post caesarean pain. AB - BACKGROUND: Quantitative sensory testing (QST) measures response to painful stimuli and has been used to predict post-caesarean pain. Pain reported upon intravenous cannulation was shown to predict epidural analgesic use and pain intensity during labour. We hypothesized that pain intensity reported by women upon local anaesthesia injection (ILA) for spinal anaesthesia may predict acute pain after caesarean delivery (CD). METHODS: In a prospective observational trial, 229 women undergoing elective CD under spinal anaesthesia were enrolled. Using standardized script before ILA, women received ILA (lidocaine 1% 2.5 mL via 25 G needle), and provided an ILA score after the injection [verbal numeric pain scale (VNPS); 0-100]. Demographic data, average, peak pain (at rest, with movement and uterine cramping) and analgesic requests were recorded for the first 24 h. RESULTS: Fourteen percent of women experienced severe pain (VNPS >=70) upon ILA. Good correlation was noted between ILA and pain scores at rest and upon mobilization during the 24 h following surgery (average resting pain r = 0.529, p < 0.001, average pain at mobilization r = 0.483, p < 0.0001). Severe acute postoperative pain (VNPS >=70) was predicted by severe ILA pain with a sensitivity of 91.6% and specificity of 93.3%. CONCLUSION: This is the first study evaluating a clinical measure to predict post-caesarean pain. Our main findings were that 14% of women experience severe pain upon ILA, which was associated with increased pain during the first 24 h. PMID- 26032447 TI - The medial temporal lobes distinguish between within-item and item-context relations during autobiographical memory retrieval. AB - During autobiographical memory retrieval, the medial temporal lobes (MTL) relate together multiple event elements, including object (within-item relations) and context (item-context relations) information, to create a cohesive memory. There is consistent support for a functional specialization within the MTL according to these relational processes, much of which comes from recognition memory experiments. In this study, we compared brain activation patterns associated with retrieving within-item relations (i.e., associating conceptual and sensory perceptual object features) and item-context relations (i.e., spatial relations among objects) with respect to naturalistic autobiographical retrieval. We developed a novel paradigm that cued participants to retrieve information about past autobiographical events, non-episodic within-item relations, and non episodic item-context relations with the perceptuomotor aspects of retrieval equated across these conditions. We used multivariate analysis techniques to extract common and distinct patterns of activity among these conditions within the MTL and across the whole brain, both in terms of spatial and temporal patterns of activity. The anterior MTL (perirhinal cortex and anterior hippocampus) was preferentially recruited for generating within-item relations later in retrieval whereas the posterior MTL (posterior parahippocampal cortex and posterior hippocampus) was preferentially recruited for generating item context relations across the retrieval phase. These findings provide novel evidence for functional specialization within the MTL with respect to naturalistic memory retrieval. PMID- 26032448 TI - Editorial Comment from Dr Long to Usefulness of sonourethrography for penile abscess as a result of xanthogranulomatous granuloma in the corpus cavernosum of an adult: A case report. PMID- 26032449 TI - Spontaneous Generation of Chirality in Simple Diaryl Ethers. AB - We studied the spontaneous formation of chiral crystals of four diaryl ethers, 3 phenoxybenzaldehyde, 1; 1,3-dimethyl-2-phenoxybenzene, 2; di(4-aminophenyl) ether, 3; and di(p-tolyl) ether, 4. Compounds 1, 3, and 4 form conformationally chiral molecules in the solid state, while the chirality of 2 arises from the formation of supramolecular helices. Compound 1 is a liquid at ambient temperature, but 2-4 are crystalline, and solid-state CD-spectroscopy showed that they could be obtained as optically active bulk samples. It should be noted that the optical activity arise upon crystallization, and no optically active precursors were used. Indeed, even commercial samples of 3 and 4 were found to be optically active, giving evidence for the ease at which total spontaneous resolution may occur in certain systems. PMID- 26032450 TI - In situ field application of electrokinetic remediation for an As-, Cu-, and Pb contaminated rice paddy site using parallel electrode configuration. AB - The applicability of an in situ electrokinetic process with a parallel electrode configuration was evaluated to treat an As-, Cu-, and Pb-contaminated paddy rice field in full scale (width, 17 m; length, 12.2 m; depth, 1.6 m). A constant voltage of 100 V was supplied and electrodes were spaced 2 m apart. Most As, Cu, and Pb were bound to Fe oxide and the major clay minerals in the test site were kaolinite and muscovite. The electrokinetic system removed 48.7, 48.9, and 54.5 % of As, Cu, and Pb, respectively, from the soil during 24 weeks. The removal of metals in the first layer (0-0.4 m) was higher than that in the other three layers because it was not influenced by groundwater fluctuation. Fractionation analysis showed that As and Pb bound to amorphous Fe and Al oxides decreased mainly, and energy consumption was 1.2 kWh/m(3). The standard deviation of metal concentration in the soil was much higher compared to the hexagonal electrode configuration because of a smaller electrical active area; however, the electrode configuration removed similar amounts of metals compared to the hexagonal system. From these results, it was concluded that the electrokinetic process could be effective at remediating As-, Cu-, and Pb-contaminated paddy rice field in situ. PMID- 26032451 TI - Characterization of water reservoirs affected by acid mine drainage: geochemical, mineralogical, and biological (diatoms) properties of the water. AB - This work presents a combination of geochemical, mineralogical, and biological data obtained in water reservoirs located in one of the most paradigmatic mining regions, suffering from acid mine drainage (AMD) problems: the Iberian Pyrite Belt (IPB). Four water reservoirs located in the Spanish sector of the IBP, storing water for different purposes, were selected to achieve an environmental classification based on the effects of AMD: two mining dams (Gossan and Aguas Acidas), a reservoir for industrial use (Sancho), and one with water used for human supply (Andevalo). The results indicated that the four reservoirs are subject to the effect of metallic loads from polluted rivers, although with different levels: Aguas Acidas > Gossan > Sancho >= Andevalo. In accordance, epipsammic diatom communities have differences in the respective composition and dominant taxa. The dominant diatoms in each reservoir indicated acid water: Pinnularia acidophila and Pinnularia aljustrelica were found in the most acidic dams (Gossan and Aguas Acidas, with pH <3), Pinnularia subcapitata in Sancho (pH 2.48-5.82), and Eunotia exigua in Andevalo (pH 2.34-6.15). PMID- 26032452 TI - Natural deep eutectic solvent mediated pretreatment of rice straw: bioanalytical characterization of lignin extract and enzymatic hydrolysis of pretreated biomass residue. AB - The present investigation demonstrated pretreatment of lignocellulosic biomass rice straw using natural deep eutectic solvents (NADESs), and separation of high quality lignin and holocellulose in a single step. Qualitative analysis of the NADES extract showed that the extracted lignin was of high purity (>90 %), and quantitative analysis showed that nearly 60 +/- 5 % (w/w) of total lignin was separated from the lignocellulosic biomass. Addition of 5.0 % (v/v) water during pretreatment significantly enhanced the total lignin extraction, and nearly 22 +/ 3 % more lignin was released from the residual biomass into the NADES extract. X ray diffraction studies of the untreated and pretreated rice straw biomass showed that the crystallinity index ratio was marginally decreased from 46.4 to 44.3 %, indicating subtle structural alterations in the crystalline and amorphous regions of the cellulosic fractions. Thermogravimetric analysis of the pretreated biomass residue revealed a slightly higher T dcp (295 degrees C) compared to the T dcp (285 degrees C) of untreated biomass. Among the tested NADES reagents, lactic acid/choline chloride at molar ratio of 5:1 extracted maximum lignin of 68 +/- 4 mg g(-1) from the rice straw biomass, and subsequent enzymatic hydrolysis of the residual holocellulose enriched biomass showed maximum reducing sugars of 333 +/- 11 mg g(-1) with a saccharification efficiency of 36.0 +/- 3.2 % in 24 h at 10 % solids loading. PMID- 26032453 TI - Sequential extraction of inorganic mercury in dumped blast furnace sludge. AB - Blast furnace sludge (BFS) is an industrial waste with elevated mercury (Hg) contents due to the enrichment during the production process of pig iron. To investigate the potential pollution status of dumped BFS, 14 samples with total Hg contents ranging from 3.91 to 20.8 mg kg(-1) from five different locations in Europe were sequentially extracted. Extracts used included demineralized water (fraction 1, F1), 0.1 mol L(-1) CH3COOH + 0.01 mol L(-1) HCl (F2), 1 mol L(-1) KOH (F3), 7.9 mol L(-1) HNO3 (F4), and aqua regia (F5). The total recovery ranged from 72.3 to 114 %, indicating that the procedure was reliable when adapted to this industrial waste. Mercury mainly resided in the fraction of "elemental" Hg (48.5-98.8 %) rather being present as slightly soluble Hg species associated with sludge particles. Minor amounts were found as mercuric sulfide (F5; 0.725-37.3 %) and Hg in crystalline metal ores and silicates (F6; 2.21-15.1 %). The ecotoxically relevant fractions (F1 and F2) were not of significance (F1, 0.61), with a few (=6) showing moderate agreement (kappa>0.41). Reliability scores were only slightly lower when just the more homogeneous group of individuals with high Schizotypal Personality Questionnaire (SPQ) scores were examined. As expected, high SPQ scores were associated with a high level of self-disorders. In sum, the results suggest that self-disorders can be measured reliably in non-clinical samples and are particularly frequent in individuals with pronounced schizotypical traits. PMID- 26032463 TI - A bizarre attack on the freedom of scientific expression. PMID- 26032464 TI - Effective use of photodynamic therapy on the treatment of chronic leg ulcers: a pilot study. PMID- 26032465 TI - A fluorescent chemosensor based on naphthol for detection of Zn(2). AB - A simple naphthol-based fluorescent receptor 1 was prepared and evaluated for its fluorescence response to heavy metal ions. Receptor 1 exhibits an 'off-on-type' mode with high selectivity in the presence of Zn(2+) ion. The selectivity of 1 for Zn(2+) is the consequence of combined effects of chelation-enhanced fluorescence (CHEF), C = N isomerization and pi-pi stacking interaction between the two naphthalene rings. PMID- 26032466 TI - Fibroids (uterine myomatosis, leiomyomas). AB - INTRODUCTION: Between 50% and 77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, mass and pressure effects, infertility, or recurrent pregnancy loss. Risk factors for fibroids include obesity, having no children, and no long term use of the oral contraceptive pill. Fibroids tend to shrink or fibrose after the menopause. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of surgical/interventional radiological treatments in women with fibroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: Five studies were included. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: magnetic resonance-guided focused ultrasound surgery versus no/sham treatment; magnetic resonance-guided focused ultrasound surgery versus other interventions (hysterectomy, myomectomy, hysteroscopic resection, rollerball endometrial ablation, thermal balloon ablation, thermal myolysis with laser); uterine artery embolisation versus no/sham treatment; uterine artery embolisation versus hysterectomy; uterine artery embolisation versus myomectomy; uterine artery embolisation versus other interventions (magnetic resonance-guided focused ultrasound surgery, hysteroscopic resection, rollerball endometrial ablation, thermal balloon ablation, thermal myolysis with laser). PMID- 26032467 TI - Evaluation of the Impact Personality Disorder Project - A psychologically informed consultation, training and mental health collaboration approach to probation offender management. AB - BACKGROUND: The Camden and Islington Impact Personality Disorder Project provided psychologically informed consultation and training to probation staff in a Public Protection Unit and staff in two 'approved premises' (probation hostels) working with high-risk prison sentenced offenders on licence in the community; some direct therapeutic work was also conducted jointly with probation officers. Most of the offenders had behaviours associated with personality disorder, although had not necessarily received a diagnosis of personality disorder. AIMS: To evaluate this service (the intervention) and test the hypothesis that its work would be associated with a reduction in recalls to prison. METHODS: Local and national probation records were used to identify all prison recalls made by 10 consistently available probation officers for 1 year before the intervention and up to 3 years after its introduction; reasons for recall and evidence of new arrests or charges were also extracted. RESULTS: There was a significant decrease in rate of recalls in the first year of the intervention, sustained over the second year and, for the smaller number of officers still available, also over the third year. Non-compliance with supervision as a reason for recall was cut by two-thirds; other reductions were in responses to 'challenging' behaviours. There was no evidence of increase in serious further offending. CONCLUSIONS: Our findings provide preliminary evidence that psychologically informed practice by probation officers supervising offenders at highest risk of serious harm re offending can reduce the rate of recall to prison, a costly alternative to maintaining offenders in the community, without apparently reducing community safety. Further research should clarify the extent to which the intervention helped the officers merely to tolerate challenging behaviours from these offenders and the extent of real change in the behaviours. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26032468 TI - "Click Chemistry" for the Simple Determination of Fatty-Acid Uptake and Degradation: Revising the Role of Fatty-Acid Transporters. AB - Fatty acids (FAs) have numerous functions in all living organisms, ranging from structural roles and energy production to the biosynthesis of secondary metabolites. Because of the high energy content of exogenous FAs, their acquisition is central of metabolism, and several biological systems are known, although their precise roles are not yet entirely clear. We investigated the roles of FadD (CoA ligase) and FadL (FA transporter) in different bacterial strains by using an improved version of click-chemistry-assisted labelling of azido-FAs. The high sensitivity of this method allows a direct and precise assessment of FA metabolism, and is thus far better suited than growth experiments. Our results show that although FA activation is indeed essential for FA degradation, their transport can be independent of transporters like FadL. PMID- 26032471 TI - [Rehabilitation for paraplegics]. AB - Paraplegia permanently impairs the lives of patients and puts them at risk for other medical complications. Rehabilitation is very complex and has to be adjusted to the specific needs of the patient; it requires an interdisciplinary team with special training. Initial treatment of paraplegic patients aims to enable life at home whenever feasible or a nursing institution that can accommodate the patient's needs. For this, it is necessary that the patient is in stable condition, urinary and bowel continence has been established, ability to communicate is restored, and the patient is mobile within his/her means. Occupational rehabilitation should also have been started or at least offered. Another important element in the comprehensive care of paraplegic patients is lifelong follow-up. PMID- 26032472 TI - [Medical intervention and justification]. PMID- 26032473 TI - Highly Efficient Glutathione Peroxidase and Peroxiredoxin Mimetics Protect Mammalian Cells against Oxidative Damage. AB - Novel isoselenazoles with high glutathione peroxidase (GPx) and peroxiredoxin (Prx) activities provide remarkable cytoprotection to human cells, mainly by exhibiting antioxidant activities in the presence of cellular thiols. The cytotoxicity of the isoselenazoles is found to be significantly lower than that of ebselen, which is being clinically evaluated by several groups for the treatment of reperfusion injuries and stroke, hearing loss, and bipolar disorder. The compounds reported in this paper have the potential to be used as therapeutic agents for disorders mediated by reactive oxygen species. PMID- 26032475 TI - Suspecting and Testing for Alpha-1 Antitrypsin Deficiency-An Allergist's and/or Immunologist's Perspective. AB - Alpha-1 antitrypsin deficiency (AATD) is a hereditary, monogenic disorder with no unique clinical features. AATD can be difficult to diagnose as patients commonly present with respiratory symptoms often mistaken for other respiratory syndromes such as asthma or smoking-related chronic obstructive pulmonary disease. In addition, symptoms related to AATD may also affect other organs, including the liver, vasculature, and skin. The severity of AATD varies between individuals, and in severe cases, the irreversible lung damage can develop into emphysema. Early diagnosis is critical to enable the implementation of lifestyle changes and therapeutic options that can slow further deterioration of pulmonary tissue. Once AATD is suspected, a range of tests are available (serum alpha-1 proteinase inhibitor [A1-PI] level measurement, phenotyping, genotyping, gene sequencing) for confirming AATD. Currently, intravenous infusion of A1-PI is the only therapy that directly addresses the underlying cause of AATD, and has demonstrated efficacy in a recent randomized, placebo-controlled trial. This review discusses the etiology, testing, and management of AATD from the allergist's and/or immunologist's perspective. It aims to raise awareness of the condition among physicians who care for people with obstructive lung disorders and are therefore likely to see patients with obstructive lung disease that may, in fact, prove to be AATD. PMID- 26032474 TI - Small-particle Inhaled Corticosteroid as First-line or Step-up Controller Therapy in Childhood Asthma. AB - BACKGROUND: Because randomized controlled trials of established pediatric asthma therapies are expensive and difficult to perform, observational studies may fill gaps in the evidence base. OBJECTIVES: To compare the effectiveness of representative small-particle inhaled corticosteroid (ICS) with that of standard size-particle ICS for children initiating or stepping up ICS therapy for asthma (analysis 1) and to compare the effectiveness of ICS dose step-up using small particle ICS with adding long-acting beta2-agonist (LABA) to the ICS (analysis 2). METHODS: These historical matched cohort analyses drew on electronic medical records of children with asthma aged 5 to 11 years. Variables measured during 2 consecutive years (1 baseline year for confounder definition and 1 outcome year) included risk-domain asthma control (no hospital attendance for asthma, acute oral corticosteroids, or lower respiratory tract infection requiring antibiotics) and rate of severe exacerbations (asthma-related emergency, hospitalization, or oral corticosteroids). RESULTS: In the initiation population (n = 797 in each cohort), children prescribed small-particle ICS versus standard size-particle ICS experienced greater odds of asthma control (adjusted odds ratio, 1.49; 95% CI, 1.10-2.02) and lower severe exacerbation rate (adjusted rate ratio, 0.56; 95% CI, 0.35-0.88). Step-up outcomes (n = 206 in each cohort) were also significantly better for small-particle ICS, with asthma control adjusted odds ratio of 2.22 (95% CI, 1.23-4.03) and exacerbations adjusted rate ratio of 0.49 (95% CI, 0.27 0.89). The number needed to treat with small-particle ICS to achieve 1 additional child with asthma control was 17 (95% CI, 9-107) for the initiation population and 5 (95% CI, 3-78) for the step-up population. Outcomes were not significantly different for stepped-up small-particle ICS dose versus ICS/LABA combination (n = 185 in each cohort). CONCLUSIONS: Initiating or stepping up the ICS dose with small-particle ICS rather than with standard size-particle ICS is more effective and shows similar effectiveness to add-on LABA in childhood asthma. PMID- 26032476 TI - Predictors of Repeat Epinephrine Administration for Emergency Department Patients with Anaphylaxis. AB - BACKGROUND: Risk factors that predict which patients with anaphylaxis might require repeat doses of epinephrine are poorly understood. OBJECTIVE: The objective of this study was to identify risk factors associated with the need for multiple doses of epinephrine during an anaphylactic reaction. METHODS: Patients were included if they met diagnostic criteria for anaphylaxis on presentation to the emergency department (ED) at our academic medical center between April 2008 and February 2014. Data were collected on allergic history, presenting signs and symptoms, anaphylaxis management, and disposition. Univariable and multivariable analyses were performed to estimate associations between possible risk factors and the need for multiple doses. RESULTS: Of 582 ED patients with anaphylaxis, 45 (8%) required multiple doses of epinephrine. By multivariable analysis, factors associated with the need for repeat doses were a history of anaphylaxis (odds ratio [OR], 2.5 [95% CI, 1.3-4.7]; P = .005), the presence of flushing or diaphoresis (OR, 2.4 [95% CI, 1.3-4.5]; P = .007), and the presence of dyspnea (OR, 2.2 [95% CI, 1.0-5.0]; P = .046). Patients who received more than 1 dose were more likely to be admitted to the general medical floor (OR, 2.8 [95% CI, 1.1-7.2]; P = .03) or intensive care unit (OR, 7.6 [95% CI, 3.7-15.6]; P < .001). CONCLUSION: Patients with a history of anaphylaxis, flushing or diaphoresis, or dyspnea may require multiple doses of epinephrine to treat anaphylactic reactions. Patients who require more than 1 dose are more likely to be admitted to the hospital, thus increasing health care resource utilization. PMID- 26032478 TI - Ovarian responses of dairy buffalo cows to timed artificial insemination protocol, using new or used progesterone devices, during the breeding season (autumn-winter). AB - This study evaluated the effect of new or used P4 devices on the ovarian responses of dairy buffalo that were administered an estradiol (E2) plus progesterone (P4)-based timed artificial insemination (TAI) protocol during the breeding season. On the first day of the TAI protocol, 142 cows were randomly assigned to receive one of the following: a new device (New; 1.0 g of P4; n = 48); a device that had previously been used for 9 days (Used1x, n = 47); or a device that had previously been used for 18 days (Used2x, n = 47). Ultrasound was used to evaluate the following: the presence of a corpus luteum (CL); the diameter of the dominant follicle (ODF) during protocol; ovulatory response; and pregnancies per AI (P/AI). Despite similar responses among the treatments, there was a significant positive association of the ODF during TAI protocol with ovulatory responses and number of pregnancies. In conclusion, satisfactory ovarian responses and a satisfactory pregnancy rate were achieved when grazing dairy buffalo were subjected to the TAI protocol in breeding season, independent of whether a new or used P4 device was used. Furthermore, the presence of the larger follicle was associated with a higher ovulation rate and higher P/AI following TAI. PMID- 26032477 TI - Ginkgo biloba extract (Egb761) attenuates zinc-induced tau phosphorylation at Ser262 by regulating GSK3beta activity in rat primary cortical neurons. AB - In the brain, an excessive amount of zinc promotes the deposition of beta-amyloid proteins and the intraneuronal accumulation of neurofibrillary tangles composed of hyperphosphorylated tau proteins. These consequences are key neuropathological traits that reflect Alzheimer's disease. Egb761, a standardized Ginkgo biloba extract, is a powerful antioxidant known to exhibit neuroprotective actions. In this study, we investigated whether Egb761 can counteract the zinc-induced tau phosphorylation in rat primary cortical neurons. To determine the modification of tau phosphorylation by Egb761 treatment, we conducted Western blot analyses, MTT assay, ROS measurements and immunocytochemistry. We found that zinc-induced tau phosphorylation occurred at Ser262 in a time- and dose-dependent manner while other tau sites were not phosphorylated. Tau phosphorylation at Ser262 was increased 30 min after zinc treatment and peaked 3 h after zinc treatment (control: 100 +/- 1.2%, 30 min: 253 +/- 2.24%, 3 h: 373 +/- 1.3%). Interestingly, Egb761 treatment attenuated the zinc-induced tau hyperphosphorylation at Ser262 in a concentration-dependent manner while the antioxidant N-acetylcysteine showed a similar effect. Furthermore, Egb761 prevented the zinc-induced activation of p38 MAPK and GSK3beta, as well as the zinc-induced increase in ROS production and neuronal cell death. Lithium chloride also inhibited the zinc-induced tau phosphorylation but did not affect ROS levels. These results suggest the potential of Egb761 for inhibiting the zinc-induced tau phosphorylation at Ser262 through its anti-oxidative actions involving the regulation of GSK3beta. Therefore, Egb761 may be a candidate for the treatment of tauopathy present in neurological disorders such as Alzheimer's disease. PMID- 26032479 TI - Erratum. The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. PMID- 26032480 TI - "Losing the tombola": a case study describing the use of community consultation in designing the study protocol for a randomised controlled trial of a mental health intervention in two conflict-affected regions. AB - BACKGROUND: Community consultation is increasingly recommended, and in some cases, required by ethical review boards for research that involves higher levels of ethical risk such as international research and research with vulnerable populations. In designing a randomised control trial of a mental health intervention using a wait list control, we consulted the community where the research would be undertaken prior to finalising the study protocol. The study sites were two conflict-affected locations: Grozny in the Chechen Republic and Kitchanga in eastern Democratic Republic of Congo. METHODS: Group discussions with a range of community members were held in both study sites. Facilitators used a prepared set of questions to guide the discussions and to solicit feedback on the value of the research as well as on the study design. Specific questions were asked about enablers and barriers to participation in the research. RESULTS: Six groups were held in Grozny and thirteen in Kitchanga. The majority of individuals and groups consulted supported the research, and understood the purpose. In Grozny, the main concern raised was the length of the waiting period. Barriers to both waiting and returning for follow up were identified. In Kitchanga, there was a strong reaction against the wait list control and against randomisation. The consultations provided information on unanticipated harms to the community, allowing changes to the study design to mitigate these harms and increase acceptability of the study. It also served to inform the community of the study, and through engaging with them early, helped promote legitimacy and joint responsibility. CONCLUSION: Community consultation prior to finalising the study design for a mental health intervention trial in two humanitarian settings proved feasible. Our experience reinforces the importance of community consultation before the study design is finalised and the importance of broad consultation that includes both community leaders and the potential study participants. PMID- 26032481 TI - Probiotics for weight loss: a systematic review and meta-analysis. AB - The intestinal microbiota has been reported to be one of the potential determinants of obesity in recent human and animal studies. Probiotics may affect the gut microbiota to modulate obesity. This systematic review aims to summarize and critically evaluate the evidence from clinical trials that have tested the effectiveness of probiotics or foods containing probiotics as a treatment for weight loss. Literature searches of electronic databases such as PubMed, Cochrane Library, and EMBASE were conducted. Methodological quality was assessed using body weight and body mass index (BMI). Initial searches yielded 368 articles. Of these, only 9 met the selection criteria. Because of insufficient data, only 4 of the studies were randomized controlled trials (RCTs) that compared the therapeutic efficacy of probiotics with placebo. The meta-analysis of these data showed no significant effect of probiotics on body weight and BMI (body weight, n = 196; mean difference, -1.77; 95% confidence interval, -4.84 to 1.29; P = .26; BMI, n = 154; mean difference, 0.77; 95% confidence interval, -0.24 to 1.78; P = .14). However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were too low to draw definitive conclusions. Thus, more rigorously designed RCTs are necessary to examine the effect of probiotics on body weight in greater detail. Collectively, the RCTs examined in this meta-analysis indicated that probiotics have limited efficacy in terms of decreasing body weight and BMI and were not effective for weight loss. PMID- 26032482 TI - Quercetin supplementation does not enhance cerebellar mitochondrial biogenesis and oxidative status in exercised rats. AB - The present study tested the hypothesis that quercetin may inhibit the mitochondrial and antioxidant adaptations induced by exercise in cerebellar tissue. Thirty-five 6-week-old Wistar rats were randomly allocated into the following groups: quercetin, exercised (Q-Ex; n = 9); quercetin, sedentary (Q Sed; n = 9); no quercetin, exercised (NQ-Ex; n = 9); and no quercetin, sedentary (NQ-Sed; n = 8). After 6 weeks of quercetin supplementation and/or exercise training, cerebellums were collected. Protein carbonyl content (PCC), sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), messenger RNA levels, citrate synthase (CS), and mitochondrial DNA were measured. When Q-Sed was compared with NQ-Sed, PCC (P < .005) showed decreased levels, whereas PGC-1alpha, sirtuin 1 (both, P < .01), mitochondrial DNA (P < .001), and CS (P < .01) increased. However, when Q-Ex was compared with Q-Sed, PCC showed increased levels (P < .001), whereas CS decreased (P < .01). Furthermore, the NQ Ex group experienced an increase in PGC-1alpha messenger RNA levels in comparison with NQ-Sed (P > .01). This effect, however, did not appear in Q-Ex (P < .05). Therefore, we must hypothesize that either the dose (25 mg/kg) or the length of the quercetin supplementation period that was used in the present study (or perhaps both) may impair exercise-induced adaptations in cerebellar tissue. PMID- 26032483 TI - Taiwanin A incorporated polyurethane fiber sheets for prevention of postoperative cancer recurrence. AB - In this study, we propose a single solution for prevention of postoperative complications and recurrence of highly metastatic gastrointestinal tract cancers. Here, we demonstrate preparation and characterization of Taiwanin A incorporated polyurethane fiber sheets with excellent mechanical properties and sustained drug release. Sheets with elastic modulus of 8 MPa and ultimate tensile strength of 30 MPa will provide support on surgical staple line preventing leakage at anastomosis. Slight burst release of the drug within 7 days (15%) and further sustained release will inhibit proliferation and migration of remaining cancer cells and maintain locoregional high drug concentration to prevent recurrence of the disease. High elasticity of the material will promote healing process without impeding natural peristalsis movement of gastrointestinal organs. PMID- 26032484 TI - Frontotemporal lobar dementia and amyotrophic lateral sclerosis associated with c9orf72 expansion. AB - An intronic GGGGCC repeat expansion in c9orf72 gene has been identified as the most common genetic cause of frontotemporal lobar dementia (FTLD), amyotrophic lateral sclerosis (ALS) and FTLD-ALS. The discovery of c9orf72 gene has led to important scientific progresses and has considerably changed our clinical practice over the last few years. This paper summarizes the common and less typical phenotypes associated with c9orf72 expansion, the complex pathological pattern characterized by p62/dipeptide repeat aggregates, as well as the pathological mechanisms by which the expansion might produce neurodegeneration implicating loss-of-function, RNA toxicity, RNA-binding protein sequestration and accumulation of dipeptide repeats. We also discuss the recommendations and limits for genetic testing and counseling in clinical practice. PMID- 26032485 TI - [The brain and the muscles of genetics]. PMID- 26032486 TI - Research results from a registry supporting efforts to improve maternal and child health in low and middle income countries. AB - The National Institute of Child Health and Human Development created and continues to support the Global Network for Women's and Children's Health Research, a partnership between research institutions in the US and low-middle income countries. This commentary describes a series of 15 papers emanating from the Global Network's Maternal and Newborn Health Registry. Using data from 2010 to 2013, the series of papers describe nearly 300,000 pregnancies in 7 sites in 6 countries - India (2 sites), Pakistan, Kenya, Zambia, Guatemala and Argentina. These papers cover a wide range of topics including several dealing with efforts made to ensure data quality, and others reporting on specific pregnancy outcomes including maternal mortality, stillbirth and neonatal mortality. Topics ranging from antenatal care, adolescent pregnancy, obstructed labor, factors associated with early initiation of breast feeding and maintenance of exclusive breast feeding and contraceptive usage are presented. In addition, case studies evaluating changes in mortality over time in 3 countries - India, Pakistan and Guatemala - are presented. In order to make progress in improving pregnancy outcomes in low-income countries, data of this quality are needed. PMID- 26032487 TI - Discovery of new 4-alkoxyquinazoline-based derivatives as potent VEGFR2 inhibitors. AB - VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty-one 4-alkoxyquinazoline-based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 nm (for VEGFR2) and 0.25 MUm (for MCF-7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4ASE active site, and the result showed that compound 3h could bind well at the 4ASE active site. PMID- 26032488 TI - Editorial Comment. PMID- 26032489 TI - Editorial Comment. PMID- 26032491 TI - Safety evaluation of Angelica gigas: Genotoxicity and 13-weeks oral subchronic toxicity in rats. AB - As a well-known traditional medicine, Angelica gigas (AG) and its active constituents, including decursin and decursinol, have been shown to possess several health beneficial properties such as anti-bacterial, immunostimulating, anti-tumor, neuroprotective, anti-nociceptive and anti-amnestic activities. However, there is lack of toxicity studies to assess potential toxicological concerns, especially long-term toxicity and genotoxicity, regarding the AG extract. Therefore, the safety of AG extract was assessed in subchronic toxicity and genotoxicity assays in accordance with the test guidelines published by the Organization for Economic Cooperation and Development. In a subchronic toxicity study for 13 weeks (125, 250, 500, 1000 and 2000 mg/kg body weight, delivered by gavage), data revealed no significant adverse effects of the AG extract in food consumption, body weight, mortality, hematology, biochemistry, necropsy, organ weight and histopathology throughout the study in male and female rats. These results suggest that no observed adverse effect level of the AG extract administered orally was determined to be greater than 2000 mg/kg/day, the highest dose tested. In addition, a battery of tests including Ames test, in vitro chromosome aberration assay and in vivo micronucleus assay suggested that the AG extract was not genotoxic. In conclusion, the AG extract appears to be safe as a traditional medicine for oral consumption. PMID- 26032492 TI - Bioaccessibility of micron-sized powder particles of molybdenum metal, iron metal, molybdenum oxides and ferromolybdenum--Importance of surface oxides. AB - The European chemical framework REACH requires that hazards and risks posed by chemicals, including alloys and metals, that are manufactured, imported or used in different products (substances or articles) are identified and proven safe for humans and the environment. Metals and alloys need hence to be investigated on their extent of released metals (bioaccessibility) in biologically relevant environments. Read-across from available studies may be used for similar materials. This study investigates the release of molybdenum and iron from powder particles of molybdenum metal (Mo), a ferromolybdenum alloy (FeMo), an iron metal powder (Fe), MoO2, and MoO3 in different synthetic body fluids of pH ranging from 1.5 to 7.4 and of different composition. Spectroscopic tools and cyclic voltammetry have been employed to characterize surface oxides, microscopy, light scattering and nitrogen absorption for particle characterization, and atomic absorption spectroscopy to quantify released amounts of metals. The release of molybdenum from the Mo powder generally increased with pH and was influenced by the fluid composition. The mixed iron and molybdenum surface oxide of the FeMo powder acted as a barrier both at acidic and weakly alkaline conditions. These findings underline the importance of the surface oxide characteristics for the bioaccessibility of metal alloys. PMID- 26032493 TI - Association and comparison between visual inspection and bitewing radiography for the detection of recurrent dental caries under restorations. AB - PURPOSE: The aim of the present study was to investigate, in posterior teeth, the association between the characteristics of the margins of a restoration visually inspected and the presence, under restorations, of recurrent or residual dental caries detected by radiographic examination. Furthermore, the agreement between visual inspection and radiographs to detect dental caries was assessed. METHODS: Eighty-five permanent molars and premolars with resin restorations on the interproximal and/or occlusal faces, from 18 patients, were submitted for visual inspection and radiographic examination. The visual inspection involved the criteria of the International Caries Detection and Assessment System (ICDAS). Bitewing radiographs were used for the radiographic examination. Logistic regression was used to analyse the association between the characteristics of the margins of a restoration assessed by visual inspection (absence of dental caries, or early, established, inactive and active lesions) and the presence of recurrent caries detected by radiographs. Kappa coefficients were calculated for determining agreement between the two methods. RESULTS: The Kappa coefficient for agreement between visual inspection and radiographic examination was 0.19. Established lesions [odds ratio (OR) = 9.89; 95% confidence interval (95% CI): 2.94-33.25; P < 0.05] and lesion activity (OR = 2.57; 95% CI: 0.91-7.27; P < 0.05) detected by visual inspection, were associated with recurrent or residual dental caries detected by radiographs. Restorations with established and active lesions at the margins had a greater chance of exhibiting recurrent or residual lesions in the radiographic examination. CLINICAL SIGNIFICANCE: The present findings demonstrate that restorations with established and active lesions at the margins when visually inspected often require removal and retreatment. PMID- 26032494 TI - BOWS (bioinformatics open web services) to centralize bioinformatics tools in web services. AB - BACKGROUND: Bioinformaticians face a range of difficulties to get locally installed tools running and producing results; they would greatly benefit from a system that could centralize most of the tools, using an easy interface for input and output. Web services, due to their universal nature and widely known interface, constitute a very good option to achieve this goal. RESULTS: Bioinformatics open web services (BOWS) is a system based on generic web services produced to allow programmatic access to applications running on high-performance computing (HPC) clusters. BOWS intermediates the access to registered tools by providing front-end and back-end web services. Programmers can install applications in HPC clusters in any programming language and use the back-end service to check for new jobs and their parameters, and then to send the results to BOWS. Programs running in simple computers consume the BOWS front-end service to submit new processes and read results. BOWS compiles Java clients, which encapsulate the front-end web service requisitions, and automatically creates a web page that disposes the registered applications and clients. CONCLUSIONS: Bioinformatics open web services registered applications can be accessed from virtually any programming language through web services, or using standard java clients. The back-end can run in HPC clusters, allowing bioinformaticians to remotely run high-processing demand applications directly from their machines. PMID- 26032495 TI - Efficient and dynamic nuclear localization of green fluorescent protein via RNA binding. AB - Classical nuclear localization signal (NLS) sequences have been used for artificial localization of green fluorescent protein (GFP) in the nucleus as a positioning marker or for measurement of the nuclear-cytoplasmic shuttling rate in living cells. However, the detailed mechanism of nuclear retention of GFP-NLS remains unclear. Here, we show that a candidate mechanism for the strong nuclear retention of GFP-NLS is via the RNA-binding ability of the NLS sequence. GFP tagged with a classical NLS derived from Simian virus 40 (GFP-NLS(SV40)) localized not only in the nucleoplasm, but also to the nucleolus, the nuclear subdomain in which ribosome biogenesis takes place. GFP-NLS(SV40) in the nucleolus was mobile, and intriguingly, the diffusion coefficient, which indicates the speed of diffusing molecules, was 1.5-fold slower than in the nucleoplasm. Fluorescence correlation spectroscopy (FCS) analysis showed that GFP NLS(SV40) formed oligomers via RNA binding, the estimated molecular weight of which was larger than the limit for passive nuclear export into the cytoplasm. These findings suggest that the nuclear localization of GFP-NLS(SV40) likely results from oligomerization mediated via RNA binding. The analytical technique used here can be applied for elucidating the details of other nuclear localization mechanisms, including those of several types of nuclear proteins. In addition, GFP-NLS(SV40) can be used as an excellent marker for studying both the nucleoplasm and nucleolus in living cells. PMID- 26032496 TI - Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities. AB - Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activated GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. PMID- 26032497 TI - Five pectinase gene expressions highly responding to heat stress in rice floral organs revealed by RNA-seq analysis. AB - Heat stress hurts rice, and floral organs are mostly sensitive to heat stress. We aimed to unravel molecular responses to heat stress in rice floral organs using Illumina/Solexa sequencing technology for addressing the increasing concern of globle warming. At meiophase of the pollen mother cell (pulvinus flat), the plants were stressed for 3 d at 38 C, and RNA was extracted from the stressed pistil and stamen for RNA-Seq sequencing to build the heat stress transcriptom library. A total of 7178 defferentially expressed genes (DEGs) between the normal and heat stress libraries were significant, 61% up-regulated and 39% down regulated. The 7178 DEGs were significantly classified to 34 gene ontology (GO) categories, and 11 of the GO categories were significantly enriched. The GO:0016787 for hydrolase activity of molecular function was mostly enriched with the least probability, and included 11 DEGs named Hy1 - Hy11. Expression levels of five DEGs, Hy4 - Hy6 and Hy9 - Hy10 for starch and sucrose metablism via pectinase, increased 12 - 14 times in response to the heat stress. Further investigation of the five DEGs for pectin metabolism and association with reported heat responsive genes may help develop a molecular strategy to remedy heat damage in rice. PMID- 26032498 TI - Spondin 1 promotes metastatic progression through Fak and Src dependent pathway in human osteosarcoma. AB - Spondin 1 (SPON1) is cell adhesion protein that involved in attachment of sensory neuron cells and outgrowth of neurites. Its cellular functions and related mechanisms in cancers, however, remain largely unexplored. In this study, we first identified that SPON1 acts a critical factor in the metastatic progression of osteosarcoma through analysis of a GEO dataset. Then we demonstrated that SPON1 was significantly up-regulated in 72 osteosarcoma specimens compared with benign osteochondroma samples and elevated SPON1 was positively correlated with MMP9 expression. Knockdown of SPON1 expression in two metastatic osteosarcoma cell lines, HKOS and KRIB, dramatically suppressed cell migration and invasion. Treatment with recombinant SPON1 protein in two non-metastatic osteosarcoma cell lines, HOS and U2OS, significantly promoted cell migration and invasion in vitro. Meanwhile, suppression of SPON1 in KHOS cells resulted in decreased pulmonary metastasis in vivo. Mechanistically, we determined that the effects of SPON1 on osteosarcoma cell motility were primarily mediated through Fak and Src dependent pathway. Taken together, our study provides evidence of the contributions of SPON1 and the Fak and Src signaling to the progression of osteosarcoma and suggests that this axis may represent a potential therapeutic target for osteosarcoma. PMID- 26032499 TI - Alternaria extract activates autophagy that induces IL-18 release from airway epithelial cells. AB - Alternaria alternata is a major outdoor allergen that causes allergic airway diseases. Alternaria extract (ALT-E) has been shown to induce airway epithelial cells to release IL-18 and thereby initiate Th2-type responses. We investigated the underlying mechanisms involved in IL-18 release from ALT-E-stimulated airway epithelial cells. Normal human bronchial epithelial cells and A549 human lung adenocarcinoma cells were stimulated with ALT-E in the presence of different inhibitors of autophagy or caspases. IL-18 levels in culture supernatants were measured by ELISA. The numbers of autophagosomes, an LC3-I to LC3-II conversion, and p62 degradation were determined by immunofluorescence staining and immunoblotting. 3-methyladenine and bafilomycin, which inhibit the formation of preautophagosomal structures and autolysosomes, respectively, suppressed ALT-E induced IL-18 release by cells, whereas caspase 1 and 8 inhibitors did not. ALT-E stimulation increased autophagosome formation, LC-3 conversion, and p62 degradation in airway epithelial cells. LPS-stimulation induced the LC3 conversion in A549 cells, but did not induce IL-18 release or p62 degradation. Unlike LPS, ALT-E induced airway epithelial cells to release IL-18 via an autophagy dependent, caspase 1 and 8 independent pathway. Although autophagy has been shown to negatively regulate canonical inflammasome activity in TLR stimulated macrophages, our data indicates that this process is an unconventional mechanism of IL-18 secretion by airway epithelial cells. PMID- 26032500 TI - Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential. AB - Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. PMID- 26032501 TI - Proteomic analyses reveal the key roles of BrlA and AbaA in biogenesis of gliotoxin in Aspergillus fumigatus. AB - The opportunistic human pathogenic fungus Aspergillus fumigatus primarily reproduces by forming a large number of asexual spores (conidia). Sequential activation of the central regulators BrlA, AbaA and WetA is necessary for the fungus to undergo asexual development. In this study, to address the presumed roles of these key developmental regulators during proliferation of the fungus, we analyzed and compared the proteomes of vegetative cells of wild type (WT) and individual mutant strains. Approximately 1300 protein spots were detectable from 2-D electrophoresis gels. Among these, 13 proteins exhibiting significantly altered accumulation levels were further identified by ESI-MS/MS. Markedly, we found that the GliM and GliT proteins associated with gliotoxin (GT) biosynthesis and self-protection of the fungus from GT were significantly down-regulated in the DeltaabaA and DeltabrlA mutants. Moreover, mRNA levels of other GT biosynthetic genes including gliM, gliP, gliT, and gliZ were significantly reduced in both mutant strains, and no and low levels of GT were detectable in the DeltabrlA and DeltaabaA mutant strains, respectively. As GliT is required for the protection of the fungus from GT, growth of the DeltabrlA mutant with reduced levels of GliT was severely impaired by exogenous GT. Our studies demonstrate that AbaA and BrlA positively regulate expression of the GT biosynthetic gene cluster in actively growing vegetative cells, and likely bridge morphological and chemical development during the life-cycle of A. fumigatus. PMID- 26032502 TI - Atomic force microscopy imaging reveals the formation of ASIC/ENaC cross-clade ion channels. AB - ASIC and ENaC are co-expressed in various cell types, and there is evidence for a close association between them. Here, we used atomic force microscopy (AFM) to determine whether ASIC1a and ENaC subunits are able to form cross-clade hybrid ion channels. ASIC1a and ENaC could be co-isolated from detergent extracts of tsA 201 cells co-expressing the two subunits. Isolated proteins were incubated with antibodies against ENaC and Fab fragments against ASIC1a. AFM imaging revealed proteins that were decorated by both an antibody and a Fab fragment with an angle of ~120 degrees between them, indicating the formation of ASIC1a/ENaC heterotrimers. PMID- 26032503 TI - Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1. AB - Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF) induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3 kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. PMID- 26032504 TI - Ablation of Dicer leads to widespread perturbation of signaling pathways. AB - Dicer is an essential ribonuclease involved in the biogenesis of miRNAs. Previous studies have reported downregulation of Dicer in multiple cancers including hepatocellular carcinoma. To identify signaling pathways that are altered upon Dicer depletion, we carried out quantitative phosphotyrosine profiling of liver tissue from Dicer knockout mice. We employed antibody-based enrichment of phosphotyrosine containing peptides coupled with SILAC spike-in approach for quantitation. High resolution mass spectrometry-based analysis identified 349 phosphotyrosine peptides corresponding to 306 unique phosphosites of which 75 were hyperphosphorylated and 78 were hypophosphorylated. Several receptor tyrosine kinases including MET, PDGF receptor alpha, Insulin-like growth factor 1 and Insulin receptor as well as non-receptor tyrosine kinases such as Src family kinases were found to be hyperphosphorylated upon depletion of Dicer. In addition, signaling molecules such as IRS-2 and STAT3 were hyperphosphorylated. Activation of these signaling pathways has been implicated previously in various types of cancers. Interestingly, we observed hypophosphorylation of molecules including focal adhesion kinase and paxillin. Our study profiles the perturbed signaling pathways in response to dysregulated miRNAs resulting from depletion of Dicer. Our findings warrant further studies to investigate oncogenic effects of downregulation of Dicer in cancers. PMID- 26032505 TI - Sub-chronic administration of LY294002 sensitizes cervical cancer cells to chemotherapy by enhancing mitochondrial JNK signaling. AB - Chemo-sensitization is used to improve the efficacy of chemotherapeutic agents against cancers, and understanding the precise molecular mechanisms of chemo sensitization could lead to safer and more effective approaches to treat cancer. We have previously demonstrated that mitochondrial c-Jun N-terminal Kinase (JNK) signaling is a critical component of cell death. Mitochondrial JNK signaling is coordinated on the scaffold protein Sab. In this work, we developed a sub-chronic chemo-sensitization model by exposing HeLa cells to low-dose (2 MUM) LY294002. We found that this treatment increased Sab expression on mitochondria, an effect not observed in acute exposures. To examine the role of Sab in chemo-sensitization, we ectopically expressed and silenced Sab in HeLa cells. We found that elevating Sab levels in HeLa cells increased the efficacy of chemotherapeutic agents, paclitaxel and cisplatin, while silencing Sab decreased the sensitivity of cells towards these agents. The effect of Sab-mediated signaling appeared to be dependent upon mitogen dependent protein kinases (MAPKs) as ablation of Sab's MAPK-binding motifs prevented chemo-sensitization. These results suggest that mitochondrial JNK signaling is an adaptable signaling pathway that can be enhanced or restored in cancer cells to improve therapeutic efficacy. PMID- 26032506 TI - Backscattering intensity measurements in optical coherence tomography as a method to identify parathyroid glands. AB - BACKGROUND AND OBJECTIVE: Previous studies have shown that the use of optical coherence tomography (OCT) permits the differentiation between parathyroid tissue, thyroid tissue, lymph nodes and adipose tissue. We investigated the backscattering intensity profiles of OCT images in order to determine whether significant differences between these tissue types exist. METHODS: Mean backscattering intensity profiles were obtained from OCT images of parathyroid glands, thyroid tissue, lymph nodes and adipose tissue. The profiles were analyzed employing Fisher's Linear Discriminant Analysis (LDA). The results were cross validated employing improved parameter estimation techniques. RESULTS: Mean backscattering intensity profiles from 300 OCT images of 34 patients undergoing thyroid or parathyroid surgery were analyzed. The overall rate of correct classifications was 96.15%. The cross validation employing improved parameter estimation techniques yielded results identical to those derived from Fisher's LDA. CONCLUSION: Besides the individual assessment of OCT images by interpreting morphological criteria, backscattering intensity measurements can reliably distinguish between different tissue entities. PMID- 26032507 TI - Midazolam as an anticonvulsant antidote for organophosphate intoxication--A pharmacotherapeutic appraisal. AB - OBJECTIVE: This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication. METHODS: Benzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action. RESULTS: Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic gamma-aminobutyric acid (GABA)A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings. SIGNIFICANCE: In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence. PMID- 26032509 TI - Uniform stable observer for the disturbance estimation in two renewable energy systems. AB - In this study, an observer for the states and disturbance estimation in two renewable energy systems is introduced. The restrictions of the gains in the proposed observer are found to guarantee its stability and the convergence of its error; furthermore, these results are utilized to obtain a good estimation. The introduced technique is applied for the states and disturbance estimation in a wind turbine and an electric vehicle. The wind turbine has a rotatory tower to catch the incoming air to be transformed in electricity and the electric vehicle has generators connected with its wheels to catch the vehicle movement to be transformed in electricity. PMID- 26032510 TI - NADPH Oxidase-Mediated Superoxide Production by Intermediary Bacterial Metabolites of Dibenzofuran: A Potential Cause for Trans-Mitochondrial Membrane Potential (DeltaPsim) Collapse in Human Hepatoma Cells. AB - Dibenzofuran is a direct precursor of extremely toxic compounds such as dioxins. It is widely distributed persistent organic pollutant in environment that potentiate oxidative stress, apoptosis, and necrosis through bioactivation in HepG2 cells. An alkalotolerent Pseudomonas strain ISTDF1 can metabolize dibenzofuran as a sole source of carbon and energy through diverse dioxygenation. However, there is a paucity of information about the potential toxic effects of the intermediary metabolites that are formed during treatment with dibenzofuran. We have assessed and discovered the potential mechanism of toxicity induced by metabolites of dibenzofuran that were formed at 18 and 36 h. Cell viability, CYP1A2 induction, ROS activity, Superoxide production, mitochondrial NADPH oxidase activity, and mitochondrial trans-membrane potential were studied using different assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), confocal laser scanning microscopy, and flow cytometry. Analysis revealed formation of 2-(1-carbonyl methylidine)-2,3-dihydrobenzofuranlidene after 18 h of bacterial treatment due to oxygenation at carbon (C3-C4). This compound induces higher mitochondrial NADPH oxidase-dependent superoxide production that makes it more toxic than the parent compound. It was evident that after 36 h of bacterial treatment, toxicity induced by dibenzofuran and its metabolites was completely removed. This study highlights the fact that despite of efficient biodegradation of toxicants, bioactive toxic intermediates can be formed. Therefore, it is necessary to assess the toxicity of each intermediary for complete mitigation of associated risk. PMID- 26032508 TI - Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia. AB - Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry. PMID- 26032511 TI - Correlation of Cigarette Smoke-Induced Pulmonary Inflammation and Emphysema in C3H and C57Bl/6 Mice. AB - Cigarette smoke (CS)-exposed mice have been used to model airway inflammation and emphesema in humans; however, the impact of exposure duration, sex, and strain differences in susceptibility to progression of airway inflammation and to emphesema are poorly investigated. This study was designed to determine the association between inflammation and emphysema by exposing 2 strains of mice, C3H/HeN (C3H) and C57BL/6 (Bl/6), to filtered air (FA) or CS for 10, 16, or 22 weeks. Both genders and strains of CS-exposed mice developed pulmonary inflammation as characterized by cell counts in the bronchoalveolar lavage fluid (BALF) and the levels of matrix metalloproteinases (MMPs) in the BALF. CS exposure caused persistently higher number of BALF macrophages in C3H compared to BL/6 mice, while more BALF neutrophils and persistently higher MMP-2 and MMP-9 levels were observed in BL/6 mice. The mean linear intercept (Lm) increased progressively by 26%, 33%, and 55% at 10, 16, and 22 weeks, respectively, in CS exposed C3H mice compared to the matched air controls. In BL/6 mice, although CS exposure also increased the Lm compared to FA controls, no further increase in Lm beyond the levels observed at 16 weeks of exposure was observed by 22 weeks. These findings suggest that extent of inflammation is not associated with severity of emphysema and underscores the importance of carefully selecting the mouse strains and endpoints when exploring effective treatments for emphesema. PMID- 26032513 TI - Late-onset caloric restriction alters skeletal muscle metabolism by modulating pyruvate metabolism. AB - Caloric restriction (CR) attenuates age-related muscle loss. However, the underlying mechanism responsible for this attenuation is not fully understood. This study evaluated the role of energy metabolism in the CR-induced attenuation of muscle loss. The aims of this study were twofold: 1) to evaluate the effect of CR on energy metabolism and determine its relationship with muscle mass, and 2) to determine whether the effects of CR are age dependent. Young and middle-aged rats were randomized into either 40% CR or ad libitum (AL) diet groups for 14 wk. Major energy-producing pathways in muscles, i.e., glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), were examined. We found that the effects of CR were age dependent. CR improved muscle metabolism and normalized muscle mass in middle-aged animals but not young animals. CR decreased glycolysis and increased the cellular dependency for OXPHOS vs. glycolysis in muscles of middle aged rats, which was associated with the improvement of normalized muscle mass. The metabolic reprogramming induced by CR was related to modulation of pyruvate metabolism and increased mitochondrial biogenesis. Compared with animals fed AL, middle-aged animals with CR had lower lactate dehydrogenase A content and greater mitochondrial pyruvate carrier content. Markers of mitochondrial biogenesis, including AMPK activation levels and SIRT1 and COX-IV content, also showed increased levels. In conclusion, 14 wk of CR improved muscle metabolism and preserved muscle mass in middle-aged animals but not in young developing animals. CR-attenuated age-related muscle loss is associated with reprogramming of the metabolic pathway from glycolysis to OXPHOS. PMID- 26032512 TI - Developmental Regulation of Drug-Processing Genes in Livers of Germ-Free Mice. AB - Very little is known about the effect of gut microbiota on the ontogeny of drug processing genes (DPGs) in liver. In this study, livers were harvested from conventional (CV) and germ-free (GF) male and female mice from 1 to 90 days of age. RNA-Seq in livers of 90-day-old male mice showed that xenobiotic metabolism was the most downregulated pathway within the mRNA transcriptome in absence of intestinal bacteria. In male livers, the mRNAs of 67 critical DPGs partitioned into 4 developmental patterns (real-time-quantitative polymerase chain reaction): Pattern-1 gradually increased to adult levels in livers of CV mice and were downregulated in livers of GF mice, as exemplified by the major drug-metabolizing enzymes cytochrome 3a (Cyp3a) family, which are prototypical pregnane X receptor (PXR)-target genes. Genes in Pattern-2 include Cyp1a2 (aryl hydrocarbon receptor target gene), Cyp2c family, and Cyp2e1, which were all upregulated mainly at 90 days of age; as well as the peroxisome proliferator-activated receptor alpha (PPARalpha)-target genes Cyp4a family and Aldh3a2, which were upregulated not only in 90-days adult age, but also between neonatal and adolescent ages (from 1 to 30 days of age). Genes in Pattern-3 were enriched predominantly in livers of 15-day-old mice, among which the sterol-efflux transporter dimers Abcg5/Abcg8 were downregulated in GF mice. Genes in Pattern-4 were neonatal-enriched, among which the transporter Octn1 mRNA tended to be lower in GF mice at younger ages but higher in adult GF mice as compared with age-matched CV mice. Protein assays confirmed the downregulation of the PXR-target gene Cyp3a protein (Western-blot and liquid chromatography tandem mass spectroscopy), and decreased Cyp3a enzyme activities in male GF livers. Increased microsomal-Cyp4a proteins and nuclear PPARalpha were also observed in male GF livers. Interestingly, in contrast to male livers, the mRNAs of Cyp2c or Cyp4a were not readily upregulated in female GF livers approaching adult age, suggesting the maturation of female-specific hormones interferes with the interactions between intestinal microbiota and DPG ontogeny. In conclusion, intestinal microbiota markedly impacts the ontogeny of many hepatic DPGs in a gender-specific manner. PMID- 26032514 TI - Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations. AB - Proteasome inhibitors (PI) and immunomodulatory agents (IMIDs) have improved the overall survival (OS) of patients with multiple myeloma (MM), but concerns have been raised about increased incidence of extramedullary disease (EMD) after the combined use of PIs and IMIDs for upfront therapy. We evaluated whether the addition of lenalidomide to bortezomib-based front-line regimens precipitated earlier development of EMD. We reviewed the charts of 117 MM patients (median follow-up from diagnosis 6.1 years; range 0.1-10.2 years) enrolled in eight clinical trials of first-line treatment with bortezomib-based regimens, with or without lenalidomide. We assessed development of EMD as extraosseous (distant from bone) or osseous (originating from bone) plasmacytomas. The primary endpoint was time from diagnosis until development of EMD, based on imaging, biopsy and/or physical examination. Any form of EMD at progression was observed in 40 (34.2%) patients, including 21 (18%) osseous, 8 (7%) extraosseous and 11 (9%) both osseous and extraosseous. Median OS was 0.9 years (range 0.1-4.8 years) after extraosseous EMD development. Sensitivity analyses with follow-up times truncated at 5 years detected no statistically significant difference in rates of any EMD form between the two groups (P > 0.2 for each comparison). Therefore, we observed no evidence that bortezomib-lenalidomide-based front-line therapy precipitates earlier EMD. PMID- 26032515 TI - Residue-level global and local ensemble-ensemble comparisons of protein domains. AB - Many methods of protein structure generation such as NMR-based solution structure determination and template-based modeling do not produce a single model, but an ensemble of models consistent with the available information. Current strategies for comparing ensembles lose information because they use only a single representative structure. Here, we describe the ENSEMBLATOR and its novel strategy to directly compare two ensembles containing the same atoms to identify significant global and local backbone differences between them on per-atom and per-residue levels, respectively. The ENSEMBLATOR has four components: eePREP (ee for ensemble-ensemble), which selects atoms common to all models; eeCORE, which identifies atoms belonging to a cutoff-distance dependent common core; eeGLOBAL, which globally superimposes all models using the defined core atoms and calculates for each atom the two intraensemble variations, the interensemble variation, and the closest approach of members of the two ensembles; and eeLOCAL, which performs a local overlay of each dipeptide and, using a novel measure of local backbone similarity, reports the same four variations as eeGLOBAL. The combination of eeGLOBAL and eeLOCAL analyses identifies the most significant differences between ensembles. We illustrate the ENSEMBLATOR's capabilities by showing how using it to analyze NMR ensembles and to compare NMR ensembles with crystal structures provides novel insights compared to published studies. One of these studies leads us to suggest that a "consistency check" of NMR-derived ensembles may be a useful analysis step for NMR-based structure determinations in general. The ENSEMBLATOR 1.0 is available as a first generation tool to carry out ensemble-ensemble comparisons. PMID- 26032516 TI - Overexpression of tissue-nonspecific alkaline phosphatase increases the expression of neurogenic differentiation markers in the human SH-SY5Y neuroblastoma cell line. AB - Patients suffering from the rare hereditary disease hypophosphatasia (HPP), which is based on mutations in the ALPL gene, tend to develop central nervous system (CNS) related issues like epileptic seizures and neuropsychiatric illnesses such as anxiety and depression, in addition to well-known problems with the mineralization of bones and teeth. Analyses of the molecular role of tissue nonspecific alkaline phosphatase (TNAP) in transgenic SH-SY5Y(TNAPhigh) neuroblastoma cells compared to SH-SY5Y(TNAPlow) cells indicate that the enzyme influences the expression levels of neuronal marker genes like RNA-binding protein, fox-1 homolog 3 (NEUN) and enolase 2, gamma neuronal (NSE) as well as microtubule-binding proteins like microtubule-associated protein 2 (MAP2) and microtubule-associated protein tau (TAU) during neurogenic differentiation. Fluorescence staining of SH-SY5Y(TNAPhigh) cells reveals TNAP localization throughout the whole length of the developed projection network and even synapsin Iota co-localization with strong TNAP signals at some spots at least at the early time points of differentiation. Additional immunocytochemical staining shows higher MAP2 expression in SH-SY5Y(TNAPhigh) cells and further a distinct up regulation of tau and MAP2 in the course of neurogenic differentiation. Interestingly, transgenic SH-SY5Y(TNAPhigh) cells are able to develop longer cellular processes compared to control cells after stimulation with all-trans retinoic acid (RA). Current therapies for HPP prioritize improvement of the bone phenotype. Unraveling the molecular role of TNAP in extraosseous tissues, like in the CNS, will help to improve treatment strategies for HPP patients. Taking this rare disease as a model may also help to dissect TNAP's role in neurodegenerative diseases and even improve future treatment of common pathologies. PMID- 26032517 TI - hMOF (human males absent on the first), an oncogenic protein of human oral tongue squamous cell carcinoma, targeting EZH2 (enhancer of zeste homolog 2). AB - OBJECTIVES: MOF (males absent on the first) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. In mammals, MOF plays critical roles in transcription activation by acetylating histone H4 at K16. Human MOF (hMOF) essentially participates in behaviour of several human cancers. However, its role in human oral tongue squamous cell carcinoma (OTSCC) remains elusive, but we propose that hMOF regulates OTSCC cell population growth. MATERIALS AND METHODS: Real time PCR and western blot analysis were applied, and it was found that hMOF level was up-regulated in human OTSCC. High hMOF expression predicted poor overall and disease-free survival. hMOF knockdown attenuated OTSCC cell growth and transformation. RESULTS: EZH2 (enhancer of zeste homolog 2) was up-regulated in human OTSCC tissues and its level positively correlated with level of hMOF. hMOF knockdown inhibited EZH2 expression by reducing its promoter activity. Moreover, we have demonstrated that EZH2 was critically essential for function of hMOF in human OTSCC. CONCLUSIONS: Human males absent on the first regulated OSTCC growth through EZH2, thus EZH2 may serve as a candidate for anti-OTSCC therapy. PMID- 26032518 TI - Stability of Diagnoses of Cognitive Impairment, Not Dementia in a Veterans Affairs Primary Care Population. AB - OBJECTIVES: To describe the stability of cognitive impairment, not dementia (CIND) in a longitudinal cohort of primary care veterans. To examine the association between baseline brief cognitive screening tests, demographic and clinical characteristics, and cognitive decline. DESIGN: Follow-up cognitive assessment after an average of 2.5 years of a cohort of veterans in primary care whose baseline status was CIND or normal cognition. SETTING: Three Department of Veterans Affairs primary care clinics. PARTICIPANTS: Subjects with CIND at baseline and a sampling of subjects with baseline normal cognition. MEASUREMENTS: Veterans underwent a standard assessment, including neuropsychological tests and informant interview. RESULTS: Of 293 potentially eligible individuals, 186 enrolled in the follow-up study. Of the 131 subjects with a baseline diagnosis of CIND, 16 (12%) progressed to dementia, 88 (67%) continued to have a diagnosis of CIND, and 27 (21%) improved to normal cognition. Of the 55 subjects with a baseline diagnosis of normal cognition, one (2%) progressed to dementia, 17 (31%) progressed to CIND, and 37 (67%) remained cognitively normal. In bivariate analyses, poorer performance on baseline cognitive screening tests was associated with cognitive decline, whereas Framingham Stroke Risk Profile (FSRP) and education were not. Similarly, higher scores on cognitive screening tests were associated with return to normal cognition. In multivariable logistic regression models, lower baseline Mini-Cog and Modified Mini-Mental State scores were associated with cognitive decline, whereas Memory Impairment Screen scores, FSRP, and years of education were not. CONCLUSION: A minority of subjects had worsening of cognitive function sufficient to change diagnostic category. Over an average of 2.5 years, subjects diagnosed with CIND at baseline reverted to normal cognition at a higher rate than progressed to dementia. Cognitive screening tests addressing multiple domains of cognitive impairment were predictive of cognitive decline. PMID- 26032519 TI - Stressors and starting points for health-promoting interventions in medical school from the students' perspective: a qualitative study. AB - INTRODUCTION: Medical education is considered very challenging and connected with high levels of psychosocial stress for students. The aim of this study was to identify stressors and possible starting points for health-promoting interventions from the perspective of the students themselves. METHODS: We conducted two focus groups with medical students from pre-clinical and clinical semesters. We analyzed the data using content analysis following Mayring's approach. RESULTS: The stressors in the pre-clinical stage of medical education were more diverse and perceived as more intense than those in the clinical stage. They comprised contextual factors and individual behaviour. Participants mentioned the weekly examinations as a specific stressor. The existing absence regulations gave the participants the impression that they should not be absent through illness at any point during the course, and this idea further promoted presenteeism. Peer groups and mentoring programmes were perceived as helpful. CONCLUSIONS: Stressors and starting points for health-promoting interventions are closely related to the medical curriculum and its organization. As such, the curriculum itself-in addition to programmes aimed at improving stress management should primarily stand at the centre of activities for enhancing students' health. PMID- 26032520 TI - Hypertension and cochlear hearing loss. AB - This paper presents a review of experimental and clinical research on the contribution of hypertension to cochlear hearing loss. Hypertension is one of the crucial risk factors underlying pathophysiological processes taking place in the cochlea. Several mechanisms explaining these processes have been described, mainly in animal models, such as the disturbance of the inner ear potassium recycling process due to the detrimental action of natriuretic hormone, and the decrease in the cochlear oxygen partial pressure. Current evidence linking hypertension to sensorineural high-frequency cochlear hearing loss in humans may be confounded by other concomitant diseases or risk factors such as age, coronary artery disease, diabetes, obesity, hyperlipidemia, smoking and noise exposure. Therefore, further research in this field is clearly needed. PMID- 26032521 TI - Prevalence and predictors of suicidality among medical students in a public university. AB - BACKGROUND: Undergraduate medical students have been the most distressed group among the student population. Depression and anxiety have been found to be more prevalent in this group of students compared to others. OBJECTIVE: This study was conducted to determine the prevalence and predictors of suicidality among undergraduate medical students in a public university. METHODS: This was an analytical cross-sectional study, conducted in a public university in Selangor, Malaysia. Data were collected using self-administered questionnaires from January to February 2013, and analysed using the Statistical Package for Social Sciences Software (version 21). RESULTS: Out of 625 undergraduate medical students, 537 (85.9%) participated in the study. The prevalence of the suicidality among undergraduate medical students was 7.0%. The significant predictors of suicidality based on multiple logistic regression were the respondent's lifetime suicide attempts (Adjusted Odds Ratio, AOR 10.4, 95% CI 2.7 to 40.9); depression (AOR 5.9, 95% CI 1.5 to 23.0); breaking off a steady love relationship (AOR 5.4, 95% CI 1.3 to 22.4); hopelessness (AOR 4.9, 95% CI 1.1 to 21.6); and something valued being lost or stolen (AOR 4.4, 95% CI 1.2 to 15.9). CONCLUSION: These findings indicate that mental health care services should be strengthened at university level. The results show a need for an intervention programme to reduce suicidality among the undergraduate medical students. PMID- 26032522 TI - A Survey on the Choice of Transportation to come to Emergency Department among Patients with Acute Coronary Syndrome of A Community in Malaysia. AB - BACKGROUND: Good coronary care begins from the patient's home, including early transportation. As such, it is recommended that the patients activate ambulances, rather than to use their own transportations to reach the hospitals. It is not known whether Malaysian patients prefer to use private transportations or ambulances when they develop chest pain. OBJECTIVES: This study is conducted to explore the question of the choice of transportation modes among patients with acute coronary syndrome and the reasons behind their choices. METHODS: This is a structured interview survey on patients diagnosed with acute coronary syndrome (ACS) in emergency department of Hospital Universiti Sains Malaysia from April 2012 to September 2012. RESULTS: Out of the 110 patients surveyed, 105 (95.5%) patients chose to use own transportation when they developed symptoms suggestive of ACS. Only 3 patients (2.7%) came to the emergency department within 1 hour of onset, and all these 3 patients chose to use ambulances as their modes of transportation. None of the patients who chose own transportation came within the first hour of symptoms onset. This is shown to be statistically significant (p<0.001). The level of education as well as past history of ischemic heart disease did not significantly influence the patients' choice of transportation. CONCLUSION: The admonishment by various international resuscitation councils that patients with chest pain should be transported via ambulances may not be as straightforward as it seems. Numerous local and regional socio-cultural and logistic factors may need to be addressed. PMID- 26032523 TI - Prevalence and Associated Factors of Low Back Pain among Clinicians of A Major Referral Hospital. AB - OBJECTIVES: Low back pain (LBP) is one of the most common health problems faced by health care professionals due to their occupational lifestyle. This study aimed to quantify the prevalence of LBP among clinicians, and to identify its associated factors. METHODS: A cross sectional study was carried out in King Khalid University Hospital (KKUH) among 460 clinicians from different specialties. A validated questionnaire of 21 items was used to collect data. Chi square test and odds ratios were used to observe and measure the association between categorical variables. Binary logistic regression by Wald method was used to identify independent factors associated with LBP (yes/no). RESULTS: The prevalence of LBP was found to be 59.4% (244) with 38% of them reported as severe. The distribution of prevalence among consultants, registrars and residents was 110 (45.1%), 91 (37.3%) and 43 (17.6%) respectively. Out of 114 (46.7%) surgeons who suffer from LBP we found, orthopaedic surgeons had 10.2% prevalence of LBP. Male clinician (odds ratio: 1.7; 95% Confidence Interval (CI): 1.1- 2.8), consultant (4.1; 95% CI: 2.1-8.3), registrar (2.2; 95% CI: 1.2-4.2), more than 10 hours/week near bedside (1.8; 95% CI: 1.1-3.0), bending backwards at work (8.3; 95% CI: 5.1-13.4) and pulling objects during work (3.1; 95% CI: 1.7 5.6) were found to be independent statistically significant associated factors of LBP. CONCLUSION: The high prevalence of LBP among clinicians and its associated factors indicates that clinicians should maintain good posture and avoid sudden movements during working hours in hospital to reduce this occupational health problem. PMID- 26032524 TI - Usage of Traditional and Complementary Medicine (T & CM): Prevalence, Practice and Perception among Post Stroke Patients Attending Conventional Stroke Rehabilitation in A Teaching Hospital in Malaysia. AB - INTRODUCTION: The lack of evidence that proves the benefit of traditional and complementary medicines (T & CM) in treating chronic medical conditions does not deter its usage among patients worldwide. Prevalence of usage among post-stroke patients in Malaysia especially is unknown. This study aims to determine the prevalence, practice and perception of T & CM use among stroke survivors attending an outpatient rehabilitation program in a teaching hospital. METHODS: A cross-sectional study was conducted among 104 post stroke patients attending an outpatient rehabilitation program. A structured self-administered questionnaire was used to collect data on sociodemographic and clinical profile of patients, as well as types of therapy used and perception on T & CM usage. Descriptive analysis was done, and bivariate analysis was used to determine associations between categorical data. RESULTS: Mean age of patients was 62 years (SD 12.2), 54% were Chinese and 75% of the patients had ischaemic stroke. Mean age of T & CM users was younger compared to non- T & CM users (61 years vs. 66 years, p=0.04). Two-thirds (66%) of patients admitted to concurrent T & CM usage while attending conventional post stroke rehabilitation. Acupuncture (40.4%), massage (40.4%) and traditional Chinese medicine (11.5%) were the most common T & CM used. Positive perception was recorded in terms of ability of T & CM usage to relieve post stroke symptoms (68%), and it was safe to use because it was made from 'natural sources'. Negative perception recorded: T & CM caused significant adverse effects (57.6%) and was not safe to be used in combination with other conventional medicines (62.5%). CONCLUSIONS: Concurrent T & CM usage among post-stroke patients attending structured outpatient rehabilitation program is widely practised especially acupuncture, massage and traditional Chinese medicines. Overall the perception towards its use is favourable. PMID- 26032525 TI - Immunochemical faecal occult blood test for colorectal cancer screening: a systematic review. AB - A systematic review on the effectiveness and costeffectiveness of Immunochemical faecal occult IFOBT for CRC screening was carried out. A total of 450 relevant titles were identified, 41 abstracts were screened and 18 articles were included in the results. There was fair level of retrievable evidence to suggest that the sensitivity and specificity of IFOBT varies with the cut-off point of haemoglobin, whereas the diagnostic accuracy performance was influenced by high temperature and haemoglobin stability. A screening programme using IFOBT can be effective for prevention of advanced CRC and reduced mortality. There was also evidence to suggest that IFOBT is cost-effective in comparison with no screening, whereby a two-day faecal collection method was found to be costeffective as a means of screening for CRC. Based on the review, quantitative IFOBT method can be used in Malaysia as a screening test for CRC. The use of fully automated IFOBT assay would be highly desirable. PMID- 26032526 TI - Bleeding Jejunal GIST: An uncommon cause of Gastrointestinal Bleeding. AB - Gastrointestinal stromal tumours (GIST) are rare gastrointestinal tumours and are one of the causes of obscure gastrointestinal bleeding. We report a case of massive gastrointestinal bleeding secondary to bleeding jejunal GIST in a 43 years old gentleman. Endoscopic intervention failed to identify the source of bleeding and CT Angiography (CTA) showed a jejunal mass and patient underwent laparotomy and resection of the bleeding jejunal GIST. This article highlights the rare cause of the massive GI bleeding and also emphasise the role of CTA in obscure GI bleeding. PMID- 26032527 TI - Pedunculated subcutaneous lipoma in the popliteal fossa causing eczema. AB - Pedunculated subcutaneous lipoma in the popliteal fossa extending through the superficial fascia causing chronic irritant dermatitis of the adjacent skin with "psoriatic-like" plaque. To the author's knowledge, no similar case has been reported in the literature. PMID- 26032528 TI - Tell tale of tablets in bronchus. AB - Foreign body (FB) aspiration is an emergency of concern at all ages. However, in adults, it can present with atypical symptoms such as shortness of breath, wheezing or rarely cyanosis. Aspiration of oral medications is seen in the elderly population with impairment of protective airway mechanism. Treatment of choice is endoscopic removal of the foreign body. We report such a case of foreign body aspiration (potassium chloride tablet), diagnosed on imaging and subsequently developed bronchostenosis. There are a very few reported cases of oral potassium supplement aspiration and associated complications in the literature. PMID- 26032529 TI - Insufficiency fractures related to low-dose adefovir dipivoxil treatment for chronic hepatitis B. AB - We present a case of a 53-year-old woman who developed multifocal insufficiency fractures associated with adefovir dipivoxil (ADV) induced osteomalacia, including recurring metatarsal insufficiency fractures and a subtrochanteric femoral insufficiency fracture requiring surgical fixation. She had received low dose ADV treatment for 59 months for chronic hepatitis B viral infection at the time of presentation with subtrochanteric fracture. Imaging evidence of multifocal insufficiency fractures and metabolic disease on background of hypophosphatemia is attributed to hypophosphatemic osteomalacia from adefovir induced renal proximal tubular dysfunction. Radiologists and clinicians should be aware of the possibility of insufficiency fractures in patients receiving ADV therapy to avoid delayed diagnosis and progression of high-risk proximal femoral fractures. PMID- 26032530 TI - Simultaneous omental infarction and acute appendicitis in a child. AB - It is crucial to realize that both omental infarction and acute appendicitis can occur simultaneously in the children as both diseases are managed differently. Omental infarction itself is rare in the pediatric group, and its association with acute appendicitis is even rarer. Both diseases usually present with right sided abdominal pain. Ultrasound is the choice of imaging modality in the investigation of abdominal pain in the children. It should not be content if omental infarction is detected, whilst the normal appendix is not seen. We reported a case of simultaneous omental infarction and acute appendicitis in a child who presented with 3 days history of right sided abdominal pain. It was diagnosed preoperatively by ultrasound. Prompt surgical intervention was proceeded and the child made uneventful recovery. PMID- 26032531 TI - A rare cause of pain in the perineum. AB - Isolated internal iliac aneurysms are rare. We report a case of an uncommon presentation of perineal pain and tenesmus in a man caused by the pressure effects of the aneurysm. He had a successful endovascular exclusion and thrombosis of his aneurysm. On follow up of more than 3 years he remains free of all symptoms and no recurrence of the aneurysm. PMID- 26032532 TI - Chronic tibial osteomyelitis in children. A case review at hospital tengku ampuan afzan, kuantan. AB - Osteomyelitis in children has various clinical manifestations causing diagnostic and therapeutic difficulties. Inappropriate treatment of acute osteomyelitis may lead to chronic, serious and complicated condition. Chronic osteomyelitis continues to be a major cause of morbidity and disability in children living in developing countries. We present three cases of tibial osteomyelitis that have different presentations and sequalae. Our intention is to alert our colleagues, particularly primary physicians, regarding the variety of presentation and the important of early diagnosis and treatment to reduce the risk of morbidity following osteomyelitis. PMID- 26032533 TI - Dysphagia lusoria - a rare cause of prolonged Dysphagia. AB - A 64-year-old man presented with prolonged history of intermittent dysphagia with sensation of food sticking at his upper chest. Physical examination was unremarkable, and an upper endoscopy did not reveal the underlying cause. On computed tomography scan of thorax, an aberrant right subclavian artery was seen coursing posterior to the esophagus resulting in external compression, which is a typical radiological feature of Dysphagia Lusoria. The pathophysiology, clinical features, imaging features and updated treatment modalities of this rare disease are discussed. PMID- 26032534 TI - Can intra-articular therapies prior to total knee arthroplasty increase the risk of periprosthetic infection? AB - Intra-articular therapies, such as steroid injection, viscosupplement injection and acupuncture, are common non-surgical options for patients with osteoarthritis of the knee. With any intra-articular injection or acupuncture procedure, there is a potential for inoculation with bacteria leading to possible knee infection. The authors report a patient who incurred an acute infection found after a total knee arthroplasty attributed to prior acupuncture procedure done as part of conservative treatment. PMID- 26032535 TI - Combined laparoscopic and thoracoscopic repair of a large traumatic diaphragmatic hernia: a case report. AB - Traumatic diaphragmatic hernia is a well known complication of blunt trauma to the abdomen and thorax. In the acute setting, laparotomy is mandatory. In this current era, this condition can be managed with minimally invasive surgery. We hereby report a case of delayed large left diaphragmatic hernia that was repaired with a combination of laparoscopic and thoracoscopic approach. PMID- 26032536 TI - Using facebook for medical education: will students respond? AB - There is little information about the willingness of medical students to participate in Facebook for education. I analyzed my interactions with students for the past 14 months to estimate the quantity of student interaction. A Facebook Group was created. Students friend requests were accepted, but "friending" was never solicited. Questions were created around a clinical situation and posted. Forty questions were posted. 5/40 questions were about physics/chemistry. 24 questions focused on basic medical sciences. 11 questions were primarily about clinical medicine. In fourteen months, 533/810 (66%) college students joined the Group. In all, 163/533 students (30%) responded at least once. Half of all responses were comments; the rest were clicks on the "like" button. The average number of responses was 9.5 unique students/question. If participation is voluntary, and targeted students are large in number, one can expect about 66% of students to become members of a site, and about 30% of these to interact. For any given question posted on the site, about 2% of members will respond, regardless of the nature of question: clinically oriented or basic. PMID- 26032537 TI - Emerging therapies in immunoglobulin A nephropathy. AB - Despite advances in our understanding of immunoglobulin A nephropathy (IgAN) over the past decade, there are currently no specific therapies capable of targeting key pathways involved in the pathogenesis of the disease. Recent studies have, however, provided new insights into important molecular pathways that are likely to be amenable to therapeutic manipulation in the future. Specifically, a deeper understanding of the role of mucosal immunity, B-cell activation and mesangial cell activation in IgAN has provided the impetus for a number of exciting phase II/III clinical trials in IgAN. In this review, we examine some of these on-going studies, first examining studies that clarify the role of traditional immunosuppression in IgAN, then focusing on novel therapies in early clinical studies, looking closely at the rationale for these agents in relation to our current understanding of the pathogenesis of IgAN. Finally, we examine emerging pathways and therapeutic agents that have the potential to be developed as novel therapies in the coming years. It is hoped that as we continue to develop a greater understanding of IgAN, emerging therapies will soon become a reality in the day-to-day treatment of patients with IgAN. PMID- 26032538 TI - Guido Tarone (1951-2015). PMID- 26032539 TI - Prevalence, species distribution and antimicrobial resistance patterns of methicillin-resistant staphylococci in Lithuanian pet animals. AB - BACKGROUND: The bacterial genus Staphylococcus consists of many species that causes infections in pet animals. Antimicrobial resistant staphylococci cause infections that are difficult to treat and they are important from the point of one health perspective. The aim of this study was to determine the prevalence of methicillin-resistant Staphylococcus (MRS) species, including methicillin resistant S. aureus (MRSA) in diseased pet animals (Group A) and kennel dogs (Group B) in Lithuania and to characterize the isolates according to their antimicrobial resistance. RESULTS: Twenty-one MRS isolates were obtained from 395 clinical samples (5.3 %; CI 95 % 3.5-8.0) of Group A animals. Sixteen, four and one isolates were from dogs, cats and a pet rabbit, respectively. The mecA gene was present in 20 isolates, whereas one isolate was positive for the mecC gene. Twenty-one MRS isolates (20.0 %; CI 95 % 13.5-28.6) were obtained from the vagina of female dogs (n = 105) (Group B). All isolates carried the mecA gene. Twelve MRS species were isolated of which S. pseudintermedius was the most common (18/42) followed by S. haemolyticus (8/42) and S. lentus (4/42). MRSA was not found. All MRS strains were susceptible to vancomycin, linezolid, daptomycin and quinupristin/dalfopristin. Resistance to tetracycline (16/21), clindamycin (15/21) and erythromycin (14/21) was the most common types of resistance in Group A animals. Three isolates also demonstrated resistance to rifampin. Resistance toward gentamicin (16/21), ciprofloxacin (15/21), macrolides (15/21) and tetracycline (12/21) was the most common in kennel dogs (Group B). The most common genes encoding resistance to antimicrobials (excluding beta-lactams) in isolates from Group A pets were tetK (21/42), aph(3')-IIIa (11/42) and aac(6')-Ie aph(2'')-Ia (9/42). CONCLUSIONS: A wide range of MRS species were found in pet animals in Lithuania. MRSA was not found. PMID- 26032540 TI - Molecular and biochemical characterization of bifunctional pyruvate decarboxylases and pyruvate ferredoxin oxidoreductases from Thermotoga maritima and Thermotoga hypogea. AB - Hyperthermophilic bacteria Thermotoga maritima and Thermotoga hypogea produce ethanol as a metabolic end product, which is resulted from acetaldehyde reduction catalysed by an alcohol dehydrogenase (ADH). However, the enzyme that is involved in the production of acetaldehyde from pyruvate is not well characterized. An oxygen sensitive and coenzyme A-dependent pyruvate decarboxylase (PDC) activity was found to be present in cell free extracts of T. maritima and T. hypogea. Both enzymes were purified and found to have pyruvate ferredoxin oxidoreductase (POR) activity, indicating their bifunctionality. Both PDC and POR activities from each of the purified enzymes were characterized in regards to their optimal assay conditions including pH dependency, oxygen sensitivity, thermal stability, temperature dependency and kinetic parameters. The close relatedness of the PORs that was shown by sequence analysis could be an indication of the presence of such bifunctionality in other hyperthermophilic bacteria. This is the first report of a bifunctional PDC/POR enzyme in hyperthermophilic bacteria. The PDC and the previously reported ADHs are most likely the key enzymes catalysing the production of ethanol from pyruvate in bacterial hyperthermophiles. PMID- 26032541 TI - Prostate cancer: Treatment with ADT impairs cognitive performance. PMID- 26032542 TI - Stones: Now the drugs don't work: tamsulosin is ineffective as medical expulsive therapy. PMID- 26032545 TI - Prostate cancer: Why statins are beneficial. PMID- 26032546 TI - Pharmacology: How abiraterone works. PMID- 26032547 TI - What is the stone-free rate following flexible ureteroscopy for kidney stones? PMID- 26032549 TI - Prostate cancer: Optimizing prostate cancer survivorship care. PMID- 26032550 TI - Prostate cancer: Cabazitaxel-a key therapeutic option in prostate cancer. PMID- 26032554 TI - Kidney cancer: Carbonic anhydrase IX in resected clear cell RCC. PMID- 26032551 TI - Targeting glycogen metabolism in bladder cancer. AB - Metabolism has been a heavily investigated topic in cancer research for the past decade. Although the role of aerobic glycolysis (the Warburg effect) in cancer has been extensively studied, abnormalities in other metabolic pathways are only just being understood in cancer. One such pathway is glycogen metabolism; its involvement in cancer development, particularly in urothelial malignancies, and possible ways of exploiting aberrations in this process for treatment are currently being studied. New research shows that the glycogen debranching enzyme amylo-alpha-1,6-glucosidase, 4-alpha-glucanotransferase (AGL) is a novel tumour suppressor in bladder cancer. Loss of AGL leads to rapid proliferation of bladder cancer cells. Another enzyme involved in glycogen debranching, glycogen phosphorylase, has been shown to be a tumour promoter in cancer, including in prostate cancer. Studies demonstrate that bladder cancer cells in which AGL expression is lost are more metabolically active than cells with intact AGL expression, and these cells are more sensitive to inhibition of both glycolysis and glycine synthesis--two targetable pathways. As a tumour promoter and enzyme, glycogen phosphorylase can be directly targeted, and preclinical inhibitor studies are promising. However, few of these glycogen phosphorylase inhibitors have been tested for cancer treatment in the clinical setting. Several possible limitations to the targeting of AGL and glycogen phosphorylase might also exist. PMID- 26032555 TI - Gramella lutea sp. nov., a Novel Species of the Family Flavobacteriaceae Isolated from Marine Sediment. AB - A strictly aerobic, Gram stain-negative, yellowish-orange-pigmented, non-motile, rod-shaped strain designated YJ019(T) was isolated from marine sediment collected at Hwangwooji, a natural pond in Jeju island, Republic of Korea. Preliminary analysis based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the family Flavobacteriaceae within the phylum Bacteroidetes and that it showed the highest sequence similarity (97.7 %) to Gramella gaetbulicola RA5-111(T). The hybridization values for DNA-DNA relatedness between strain YJ019(T) and the type strains of the five validly described Gramella species were lower than 70 %, which is accepted as the phylogenetic definition of a novel species. The DNA G+C content of strain YJ019(T) was 38.4 mol%. The major menaquinone was MK-6, and iso-C15:0, iso-C17:0 3-OH and summed feature 3 (C16:1 omega7c and/or C16:1 omega6c) were the major (>10 %) cellular fatty acids. A complex polar lipid profile was present consisting of phosphatidylethanolamine, an unidentified aminophospholipid, two unidentified aminolipids and two unidentified lipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel species for which the name Gramella lutea sp. nov. is proposed. The type strain of Gramella lutea sp. nov. is YJ019(T) (=KCTC 42382(T) = NBRC 110751(T)). PMID- 26032553 TI - Developing proteomic biomarkers for bladder cancer: towards clinical application. AB - Clinical use of proteomic biomarkers has the potential to substantially improve the outcomes of patients with bladder cancer. An unmet clinical need evidently exists for noninvasive biomarkers, which might enable improvements in both the diagnosis and prognosis of patients with bladder cancer, as well as improved monitoring of patients for the presence of recurrence. Urine is considered the optimal noninvasive source of proteomic biomarkers in patients with bladder cancer. Currently, a number of single-protein biomarkers have been detected in urine and tissue using a variety of proteomic techniques, each having specific conceptual considerations and technical implications. Promising preclinical data are available for several of these proteins; however, the combination of single urinary proteins into multimarker panels might better encompass the molecular heterogeneity of bladder cancer within this patient population, and prove more effective in clinical use. PMID- 26032556 TI - Silicon-based quantum dots induce inflammation in human lung cells and disrupt extracellular matrix homeostasis. AB - Quantum dots (QDs) are nanocrystalline semiconductor materials that have been tested for biological applications such as cancer therapy, cellular imaging and drug delivery, despite the serious lack of information of their effects on mammalian cells. The present study aimed to evaluate the potential of Si/SiO2 QDs to induce an inflammatory response in MRC-5 human lung fibroblasts. Cells were exposed to different concentrations of Si/SiO2 QDs (25-200 MUg.mL(-1)) for 24, 48, 72 and 96 h. The results obtained showed that uptake of QDs was dependent on biocorona formation and the stability of nanoparticles in various biological media (minimum essential medium without or with 10% fetal bovine serum). The cell membrane damage indicated by the increase in lactate dehydrogenase release after exposure to QDs was dose- and time-dependent. The level of lysosomes increased proportionally with the concentration of QDs, whereas an accumulation of autophagosomes was also observed. Cellular morphology was affected, as shown by the disruption of actin filaments. The enhanced release of nitric oxide and the increase in interleukin-6 and interleukin-8 protein expression suggested that nanoparticles triggered an inflammatory response in MRC-5 cells. QDs decreased the protein expression and enzymatic activity of matrix metalloproteinase (MMP)-2 and MMP-9 and also MMP-1 caseinase activity, whereas the protein levels of MMP-1 and tissue inhibitor of metalloproteinase-1 increased. The present study reveals for the first time that silicon-based QDs are able to generate inflammation in lung cells and cause an imbalance in extracellular matrix turnover through a differential regulation of MMPs and tissue inhibitor of metalloproteinase-1 protein expression. PMID- 26032557 TI - Negative outcomes associated with medication in patients with chronic atrial fibrillation who present at the emergency department. AB - WHAT IS KNOWN AND OBJECTIVE: Medication is the main treatment option for patients with chronic atrial fibrillation. However, medication can have negative effects. We aimed to detect negative outcomes associated with medication that led to patients with chronic atrial fibrillation presenting themselves to hospital emergency departments. We assessed the severity of those outcomes and comment on whether they could have been avoided. METHODS: This descriptive, cross-sectional study included all patients with chronic atrial fibrillation who attended the emergency department of our tertiary hospital. We used the Dader method to identify and evaluate the negative outcomes associated with medication through interviews with patients and scrutiny of the clinical charts. RESULTS AND DISCUSSION: Of the 198 eligible patients who presented at the emergency department, 134 (67.7%) did so because of negative outcomes associated with medication (41% related to necessity, 32.1% to effectiveness and 26.9% to safety); 67.9% of those negative outcomes could have been avoided. In terms of severity, 6.7% were mild, 31.3% moderate, 51.5% severe and 10.4% fatal. The Anatomical Therapeutic Chemical Classification anatomical group most frequently associated with negative outcomes was the cardiovascular system, followed by blood/blood-forming organs. WHAT IS NEW AND CONCLUSION: A high percentage of patients with chronic atrial fibrillation presenting at hospital emergency departments had negative outcomes associated with medication. Some led to deaths. More than half of these were severe, and most could have been avoided. PMID- 26032558 TI - Minimally symptomatic mcardle disease, expanding the genotype-phenotype spectrum. AB - INTRODUCTION: We report the clinical, biochemical, and molecular findings in a Cypriot family with minimally symptomatic McArdle disease. METHODS: Myophosphorylase in muscle was assessed by histochemistry, quantitative spectrophotometry, and western blot analysis. Mutation identification was performed by PCR amplification of all PYGM exons, followed by bidirectional sequencing. Screening for the new mutation was performed by restriction enzyme analysis. RESULTS: We found that a novel c.1151C>T transition in exon 10 of the myophosphorylase gene (PYGM) is associated with minimally symptomatic McArdle disease. Homozygous carriers displayed an ischemic exercise response characterized by a blunted increase in post-exercise blood lactate levels in conjunction with an exaggerated increase in ammonia. Myophosphorylase activity in muscle was 3.75% of normal, whereas the size and abundance of the enzyme were unaffected. CONCLUSIONS: These findings expand the genotype-phenotype spectrum of McArdle disease and suggest that enzymatic activity as low as 4% may be sufficient to ameliorate the phenotype. PMID- 26032559 TI - Disease-modifying Antirheumatic Drugs for the Treatment of Low Back Pain: A Systematic Review of the Literature. AB - Low back pain (LBP) is a common source of pain and disability, which has an enormous adverse impact on affected individuals and the community as a whole. The etiologies of LBP are protean and local inflammation contributes to the majority of these processes. Although an array of potent disease-modifying anti-rheumatic drugs (DMARDs), which are typically anti-inflammatory in character, have become clinically available only corticosteroids are routinely used for the treatment of LBP. To further investigate this potentially underutilized therapy, we reviewed the available literature to determine the role of DMARDs in the treatment of LBP. Our results show that the current DMARD use for LBP is indeed limited in scope and is characterized by isolated use and empiric selection of drugs from a range of available DMARDs. Moreover, the dose, frequency, and route of drug administration are selected arbitrarily and deviated from treatment protocols proposed for the management of other inflammatory conditions. The literature published on this topic is of low quality, and the results of the reviewed trials were inconclusive or demonstrated only short-term efficacy of these medications. Based on the findings of this review, we recommend that the future DMARD use for LBP is initially limited to patients with debilitating disease who are unresponsive to conventional treatments, and the criteria for drug selection and routes of drug administration are clearly defined and may be modeled after treatment protocols for other inflammatory conditions. PMID- 26032560 TI - The p53 family and the hypoxia-inducible factors (HIFs): determinants of cancer progression. AB - HIFs have long been associated with resistance to therapy, metastasis, and poor survival rates in cancer patients. In parallel, although the tumor-suppressor p53 acts as the first barrier against tumor transformation, its inactivation also appears to be crucial for enabling cancer progression at advanced stages. p53 has been proposed to antagonize HIF, and emerging evidence suggests that the p53 siblings p63 and p73 also participate in this interplay. Crosstalk between HIFs and the p53 family acts as a determinant of cancer progression through regulating angiogenesis, the tumor microenvironment, dormancy, metastasis, and recurrence. We discuss the possible mechanisms underlying this regulation and the controversies in this field in an attempt to provide a unified view of current knowledge. PMID- 26032561 TI - Designing a New Class of Bases for Nucleic Acid Quadruplexes and Quadruplex Active Ligands. AB - A new class of quadruplex nucleobases, derived from 3-deazaguanine, has been designed for various applications as smart quadruplex ligands as well as quadruplex-based aptamers, receptors, and sensors. An efficient strategy for modifying the guanine quadruplex core has been developed and tested by using quantum chemistry methods. Several potential guanine derivatives modified at the 3- or 8-position or both are analyzed, and the results compared to reference systems containing natural guanine. Analysis of the formation energies (BLYP D3(BJ)/def2-TZVPP level of theory, in combination with the COSMO model for water) in model systems consisting of two and three stacked tetrads with Na(+) /K(+) ion(s) inside the internal channel indicates that the formation of structures with 3-halo-3-deazaguanine bases leads to a substantial gain in energy, as compared to the corresponding reference guanine complexes. The results cast light on changes in the noncovalent interactions (hydrogen bonding, stacking, and ion coordination) in a quadruplex stem upon modification of the guanine core. In particular, the enhanced stability of the modified quadruplexes was shown to originate mainly from increased pi-pi stacking. Our study suggests the 3-halo-3 deazaguanine skeleton as a potential building unit for quadruplex systems and smart G-quadruplex ligands. PMID- 26032563 TI - Babies get it right. AB - Infants use a region on the right side of their brain to distinguish between human faces and objects. PMID- 26032562 TI - An internal thioester in a pathogen surface protein mediates covalent host binding. AB - To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a 'chemical harpoon'. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions. PMID- 26032564 TI - Rapid categorization of natural face images in the infant right hemisphere. AB - Human performance at categorizing natural visual images surpasses automatic algorithms, but how and when this function arises and develops remain unanswered. We recorded scalp electrical brain activity in 4-6 months infants viewing images of objects in their natural background at a rapid rate of 6 images/second (6 Hz). Widely variable face images appearing every 5 stimuli generate an electrophysiological response over the right hemisphere exactly at 1.2 Hz (6 Hz/5). This face-selective response is absent for phase-scrambled images and therefore not due to low-level information. These findings indicate that right lateralized face-selective processes emerge well before reading acquisition in the infant brain, which can perform figure-ground segregation and generalize face selective responses across changes in size, viewpoint, illumination as well as expression, age and gender. These observations made with a highly sensitive and objective approach open an avenue for clarifying the developmental course of natural image categorization in the human brain. PMID- 26032565 TI - Balloon valvuloplasty for congenital aortic stenosis: Multi-center safety and efficacy outcome assessment. AB - OBJECTIVE: To describe contemporary outcomes of balloon aortic valvuloplasty (BAVP) performed in 22 US centers. BACKGROUND: BAVP constitutes first-line therapy for congenital aortic stenosis (cAS) in many centers. METHODS: We used prospectively-collected data from two active, multi-institutional, pediatric cardiac catheterization registries. Acute procedural success was defined, for purposes of this review, as a residual peak systolic gradient<=35 mm Hg and no more than mild aortic regurgitation (AR) for patients with isolated cAS. For patients with mixed aortic valve disease, a residual peak systolic gradient<=35 mm Hg without worsening of AR was considered successful outcome. RESULTS: In 373 patients with a median age of 8 months (1 day to 40 years of age) peak systolic gradient had a median of 59 [50, 71] mm Hg pre-BAVP and 22 [15, 30] mm Hg post BAVP (P<0.001). Procedural success was achieved in 160 patients (71%). The factors independently associated with procedural success were: first time intervention (OR=2.0 (1.0, 4.0) P=0.04), not-prostaglandin dependent, (OR=3.5 (1.5, 8.1); P=0.003), and isolated cAS (absence of AR) (OR=2.1 (1.1-3.9); P=0.03). Twenty percent of patients experienced adverse events, half of which were of high severity. There was no procedural mortality. Neonatal status was the only factor associated with increased risk of high severity adverse events (OR 3.7; 95% CI 1.5-9.0). CONCLUSION: In the current era, BAVP results in procedural success (gradient reduction with minimal increase in AR) in 71% of patients treated at US centers where BAVP is considered first-line therapy relative to surgery. PMID- 26032566 TI - Baseline grey matter volume of non-transitioned "ultra high risk" for psychosis individuals with and without attenuated psychotic symptoms at long-term follow up. AB - INTRODUCTION: Two thirds of individuals identified as ultra-high risk (UHR) for psychosis do not transition to psychosis over the medium to long-term (non transition; UHR-NT). Nevertheless, many of these individuals have persistent attenuated psychotic symptoms (APS). The current study examined whether there were differences in baseline grey matter volume (i.e. at initial identification as UHR) in UHR-NT individuals whom had APS compared to those without APS (No-APS) at medium to long-term follow-up. METHODS: Participants were help-seeking individuals who were identified as being at UHR for psychosis between 2 and 12years previously (mean=7.5). The sample consisted of 109 participants who underwent a Magnetic Resonance Imaging scan at baseline and who had not been observed to develop a psychotic disorder over the follow-up period (UHR-NT). Using voxel-based morphometry, baseline grey matter volume (GMV) was compared between participants with (N=30) and without (N=79) APS at follow-up. RESULTS: At baseline, the APS and No-APS groups were clinically indistinguishable. At follow up, the APS group had significantly worse symptoms and impaired functioning. Individuals with APS had reduced baseline GMV in frontal, temporal, posterior and cingulate regions compared to those without APS at follow-up. Reduced GMV was associated with more severe positive, negative and depressive symptoms and lower global functioning in the combined UHR-NT cohort. These associations were independent of later APS outcome. DISCUSSION: This study found that differences in regional GMV are discernible at an early stage of UHR and may be specific to individuals who have APS and psychopathology at follow-up. Our findings suggest that lower GMV at baseline may confer neurobiological risk for later APS and/or increased psychopathology while the absence of these structural abnormalities might be protective. PMID- 26032567 TI - Virtual reality job interview training and 6-month employment outcomes for individuals with schizophrenia seeking employment. AB - BACKGROUND: Individuals with schizophrenia have low employment rates and the job interview presents a critical barrier for them to obtain employment. Virtual reality training has demonstrated efficacy at improving interview skills and employment outcomes among multiple clinical populations. However, the effects of this training on individuals with schizophrenia are unknown. This study evaluated the efficacy of virtual reality job interview training (VR-JIT) at improving job interview skills and employment outcomes among individuals with schizophrenia in a small randomized controlled trial (n=21 VR-JIT trainees, n=11 waitlist controls). METHODS: Trainees completed up to 10h of virtual interviews using VR JIT, while controls received services as usual. Primary outcome measures included two pre-test and two post-test video-recorded role-play interviews scored by blinded raters with expertise in human resources and self-reported interviewing self-confidence. Six-month follow-up data on employment outcomes were collected. RESULTS: Trainees reported that the intervention was easy-to-use, helpful, and prepared them for future interviews. Trainees demonstrated increased role-play scores between pre-test and post-test while controls did not (p=0.001). After accounting for neurocognition and months since prior employment, trainees had greater odds of receiving a job offer by 6month follow-up compared to controls (OR: 8.73, p=0.04) and more training was associated with fewer weeks until receiving a job offer (r=-0.63, p<0.001). CONCLUSIONS: Results suggest that VR JIT is acceptable to trainees and may be efficacious for improving job interview skills in individuals with schizophrenia. Moreover, trainees had greater odds of receiving a job offer by 6-month follow-up. Future studies could evaluate the effectiveness of VR-JIT within community-based services. PMID- 26032568 TI - Targeting negative symptoms in schizophrenia: results from a proof-of-concept trial assessing prefrontal anodic tDCS protocol. PMID- 26032569 TI - Colonic transit diagnostic test shows significant gastrointestinal hypomotility in clozapine-treated patients in comparison with subjects treated with other antipsychotics. AB - BACKGROUND: Constipation occurs in 25-60% of the subjects during administration of the antipsychotic drug (AP) clozapine (CLZ). METHODS: We used a colonic transit diagnostic test that quantifies in a single abdominal X-ray the number of silver O-ring markers out of 25 units ingested five days before. The quantity of markers is directly proportional to the degree of gastrointestinal hypomotility, and elimination of over 80% of the markers is considered normal. The test was applied to three groups of AP-treated subjects for at least three consecutive months: CLZ alone (n=45), CLZ+Other APs (n=28), and Other APs (n=64). RESULTS: The number of remaining markers at day 5 (mean+/-S.D.) was significantly higher in the CLZ alone (10.8+/-10.6) and in the CLZ+Other APs (9.7+/-9.7) groups than in the Other AP group (4.5+/-6.7), Kruskal-Wallis test: p=0.004. No significant associations were found between the number of markers, age, AP dose and treatment duration. All subjects who passed <80% of markers - which approximately corresponds to the 60th percentile of marker elimination - showed a scattered marker distribution along the colon, thus suggesting colon inertia. In subjects with hypomotility, 38.5% of the CLZ group, 25% of the CLZ+Other APs group, and 25% of the Other APs group were negative for the Rome III clinical criteria of constipation, thus showing objective, not subjective, hypomotility. CONCLUSIONS: This study objectively confirms significant gastrointestinal hypomotility associated with CLZ administration. PMID- 26032571 TI - Cognitive functioning and cortisol profiles in first episode major depression. AB - Major Depressive Disorder (MDD) is often associated with high levels of stress and disturbances in the Hypothalamic Pituitary Adrenal (HPA) system, yielding high levels of cortisol, in addition to cognitive dysfunction. Previous studies have shown a relationship between cortisol profile and cognitive functioning in recurrent MDD in general. More specifically, the association between hypercortisolism and cognitive functioning, such as memory and Executive Functioning (EF), and also more recently cortisol suppression has been explored. However, no studies have investigated these relationships in patients diagnosed with first episode MDD. The aim of the present study was to examine the relationship between cortisol levels before and after the Dexamethasone suppression test (DST) and cognitive function in first episode MDD patients. Twenty-one patients meeting the DSM-IV criteria for a first episode of MDD diagnosis were included in the study. The control group was matched for age, gender and education level. Cortisol was measured in saliva collected with Salivette sampling devices. Saliva samples were collected 4 times during a 24 hours period over two consecutive days: at awakening, after 45 minutes, after 7 hours and at 11 pm. Dexamethasone (1.0 mg) was given orally on Day 1 at 11 pm. The neuropsychological test battery consisted of standardized tests measuring executive functioning (EF) and memory functioning. Cortisol levels did not differ significantly between patients and controls on Day 1, except for the last sample before Dexamethasone administration, where the control group showed higher levels. Both groups showed suppression after Dexamethasone. On Day 2 there was a significant difference between groups at the third sample, showing a significantly lower level in the control group, suggesting that the controls have a more effective suppression profile than the patients. There were no significant correlations between cortisol levels before or after Dexamethasone and cognitive measures. The results indicate impairment on HPA-axis functioning in first episode MDD patients, with less suppression functioning compared to healthy controls, but no relationship between cortisol profile and cognitive functioning in EF or Memory. PMID- 26032570 TI - Longer rest intervals do not attenuate the superior effects of accumulated exercise on arterial stiffness. AB - PURPOSE: To examine and compare the acute effects of moderate-intensity continuous and accumulated exercise in three bouts with different intervals on arterial stiffness. METHOD: Nineteen healthy young males (mean age = 24.7 years) were randomized to no-exercise control (CON), continuous exercise (CE, 30-min cycling), accumulated exercise with 10-min intervals (AE10, 3 * 10-min cycling, 10-min interval), and accumulated exercise with 60-min intervals (AE60, 3 * 10 min cycling, 60-min interval) trial in balanced self-control crossover design. The intensity in all the exercise trials was set at 50% heart rate reserve. Cardio-ankle vascular index (CAVI), an index of arterial stiffness, was measured at baseline (BL), immediately after (0 min) and 60 min after the completion of the exercise. RESULTS: CAVI remained stable (6.8 +/- 0.1, 6.8 +/- 0.2, 6.9 +/- 0.1 at BL, 0 and 60 min, respectively) in CON trial. Immediately after exercise, CAVI in CE, AE10 and AE60 trials all decreased significantly to similar degree compared to CON trial (P < 0.05 for CE, AE10 and AE60 vs. CON). Though CAVI in CE trial returned to baseline level after 60 min of recovery, CAVI in both AE10 and AE60 trials remained significantly low compared to CON trial (P < 0.01 for AE10 and AE60 vs. CON). CONCLUSION: When the total duration and relative intensity were matched, the effects of accumulated exercise in three bouts were superior to continuous exercise. Elongation of intervals between bouts did not attenuate the superior effects of accumulated exercise on arterial stiffness. TRIAL REGISTRATION: ChiCTR-OTRCC-14005229. PMID- 26032572 TI - (R)-Salsolinol, a product of ethanol metabolism, stereospecifically induces behavioral sensitization and leads to excessive alcohol intake. AB - Ethanol is oxidized in the brain to acetaldehyde, which can condense with dopamine to generate (R/S)-salsolinol [(RS)-SAL]. Racemic salsolinol [(RS)-SAL] is self-infused by rats into the posterior ventral tegmental area (VTA) at significantly lower concentrations than those of acetaldehyde, suggesting that (RS)-SAL is a most active product of ethanol metabolism. Early studies showed that repeated intraperitoneal or intra-VTA administration of (RS)-SAL (10 mg/kg) induced conditioned place preference, led to locomotor sensitization and increased voluntary ethanol consumption. In the present study, we separated the (R)- and (S)-enantiomers from a commercial (RS)-SAL using a high-performance liquid chromatography with electrochemical detection system fitted with a beta cyclodextrin-modified column. We injected (R)-SAL or (S)-SAL (30 pmol/1.0 MUl) into the VTA of naive UChB rats bred as alcohol drinkers to study whether one or both SAL enantiomers are responsible for the motivated behavioral effects, sensitization and increase in voluntary ethanol intake. The present results show that repeated administration of (R)-SAL leads to (1) conditioned place preference; (2) locomotor sensitization; and (3) marked increases in binge-like ethanol intake. Conversely, (S)-SAL did not influence any of these parameters. Overall, data indicate that (R)-SAL stereospecifically induces motivational effects, behavioral sensitization and increases ethanol intake. PMID- 26032573 TI - Association of mean arterial pressure during cardiopulmonary bypass with acute kidney injury. PMID- 26032574 TI - Cultural beliefs about health professionals and perceived empathy influence continuity of cancer screening following a negative encounter. AB - Negative health care encounters have implications for preventive medical services and continuity of health care. This study examined cultural and interpersonal psychological factors involved in health care interactions that may ameliorate the detrimental effects of negative encounters. A mixed-methods approach was implemented to examine the relations among positive cultural beliefs about health professionals, perceived professional empathy, interpersonal emotions, and continuity of cancer screening among 237 Latin American (Latino) and non-Latino White (Anglo) American women who reported a negative health care encounter. Multi group structural equation modeling revealed that for Latino and Anglo women, positive cultural beliefs about health professionals in general were associated with higher perceptions of empathy regarding a professional involved in a negative encounter. In addition, for Latino women, perceptions of higher professional empathy and less negative emotions were associated with better continuity of cancer screening. Interventions designed to improve professionals' empathy skills and diverse patients' perceptions of professionals could improve patient-professional relations. PMID- 26032575 TI - Metastable charge-transfer state of californium(iii) compounds. AB - Among a series of anomalous physical and chemical properties of Cf(iii) compounds revealed by recent investigations, the present work addresses the characteristics of the optical spectra of An(HDPA)3.H2O (An = Am, Cm, and Cf), especially the broadband photoluminescence from Cf(HDPA)3.H2O induced by ligand-to-metal charge transfer (CT). As a result of strong ion-ligand interactions and the relative ease of reducing Cf(iii) to Cf(ii), a CT transition occurs at low energy (<3 eV) via the formation of a metastable Cf(ii) state. It is shown that the systematic trend in CT transitions of the lanthanide series is not paralleled by actinide elements lighter than Cf(iii), and californium represents a turning point in the periodicity of the actinide series. Analyses and modeling of the temperature dependent luminescence dynamics indicate that the metastable Cf(ii) charge transfer state undergoes radiative and non-radiative relaxations. Broadening of the CT transition arises from strong vibronic coupling and hole-charge interactions in the valence band. The non-radiative relaxation of the metastable CT state results from a competition between phonon-relaxation and thermal tunneling that populates the excited states of Cf(iii). PMID- 26032576 TI - Keratoconjunctivitis in a group of Icelandic horses with suspected gamma herpesvirus involvement. AB - REASONS FOR PERFORMING STUDY: The role of equid gamma-herpesviruses on ocular surface diseases has been disputed, because the diagnosis is usually based on clinical symptoms and detection of viral DNA from samples obtained from live animals. OBJECTIVES: To describe the clinical course, results of polymerase chain reaction (PCR) analysis, in situ hybridisation, cell culture and pathohistological findings of select cases in a presumed outbreak of herpesvirus infection in a group of 15 Icelandic horses. STUDY DESIGN: Case series. METHODS: Pooled ocular and nasal swabs and peripheral blood mononuclear cells of horses diagnosed clinically with herpesvirus-associated keratoconjunctivitis were analysed for presence of equine herpesviruses (EHV)-2 and EHV-5 nucleic acid using real-time PCR. Necropsy specimens from one horse, subjected to euthanasia due to deterioration of clinical symptoms were examined histopathologically, and analysed for presence of EHV-2 and EHV-5 nucleic acid using real-time PCR. In situ hybridisation and cell culture of select samples were performed. RESULTS: All horses with symptoms of severe keratoconjunctivitis were positive for presence of either EHV-2 and/or EHV-5 nucleic acid using real-time PCR. Assessment of necropsy specimens of the most severely affected case, revealed presence of EHV-2 and/or EHV-5 nucleic acid in several ocular and extraocular anatomical locations. The remaining horses responded favourably to symptomatic treatment. CONCLUSIONS: This case series illustrates a severe outbreak of keratoconjunctivitis in a group of Icelandic horses, with suspected gamma herpesvirus involvement. For the first time equid gamma-herpesviruses were detected in intraocular anatomical locations. PMID- 26032577 TI - Lesion patterns of single small subcortical infarct and its association with early neurological deterioration. AB - Early neurological deterioration (END), happening in the acute phase of infarct, is not rare in patients with single small subcortical infarction (SSSI). The aim of this study was to investigate the lesion patterns of SSSI and its association with END as well as functional outcome at 90 days after onset. 227 patients with acute SSSI in the perforator territory of MCA were prospectively recruited from Yangzhou No.1 People's Hospital between May 2010 and Jan 2014 and divided into proximal SSSI (pSSSI) and distal SSSI (dSSSI) according to the lesion patterns. END was defined as a change in National Institutes of Health Stroke Scale score >=2 points in the first 72 h after admission. Functional outcome at 90 days after onset was assessed using the modified Rankin Score (mRS) and dichotomized as good (0-2) and poor (>=3). Of them, 93 (40.97%) patients had pSSSI and 134 (59.03%) patients had dSSSI. Univariate analysis found that the risk factors profiles differ significantly between patients with pSSSI and those with dSSSI (P < 0.05). During hospitalization, 60 (26.43%) patients experienced END during the first 72 h after admission, and 46 (22.01%) patients had poor outcome at 90 days after onset. After adjusting for potential confounders, pSSSI pattern (OR 2.242, 95% CI 1.165-4.313, P = 0.016) was an independent predictor of END and that the END (OR 2.637, 95% CI 1.208-5.759, P = 0.015) independently predicted the poor outcome at 90 days after onset. The pSSSI patterns might predict END for patients with SSSI in the MCA perforating territory. PMID- 26032578 TI - A novel CLN2/TPP1 mutation in a patient with late infantile neuronal ceroid lipofuscinosis. PMID- 26032579 TI - The neuroplastic effect of working memory training in healthy volunteers and patients with schizophrenia: Implications for cognitive rehabilitation. AB - We conducted an activation likelihood estimation (ALE) meta-analysis to quantitatively review the existing working memory (WM) training studies that investigated neural activation changes both in healthy individuals and patients with schizophrenia. ALE analysis of studies in healthy individuals indicates a widespread distribution of activation changes with WM training in the frontal and parietal regions, especially the dorsolateral prefrontal cortex, the medial frontal cortex and the precuneus, as well as subcortical regions such as the insula and the striatum. WM training is also accompanied by activation changes in patients with schizophrenia, mainly in the dorsolateral prefrontal cortex, the precuneus and the fusiform gyrus. Our results demonstrate that WM training is accompanied by changes in neural activation patterns in healthy individuals, which may provide the basis for understanding neuroplastic changes in patients with schizophrenia. PMID- 26032580 TI - On the influence of typicality and age of acquisition on semantic processing: Diverging evidence from behavioural and ERP responses. AB - Various behavioural studies show that semantic typicality (TYP) and age of acquisition (AOA) of a specific word influence processing time and accuracy during the performance of lexical-semantic tasks. This study examines the influence of TYP and AOA on semantic processing at behavioural (response times and accuracy data) and electrophysiological levels using an auditory category member-verification task. Reaction time data reveal independent TYP and AOA effects, while in the accuracy data and the event-related potentials predominantly effects of TYP can be found. The present study thus confirms previous findings and extends evidence found in the visual modality to the auditory modality. A modality-independent influence on semantic word processing is manifested. However, with regard to the influence of AOA, the diverging results raise questions on the origin of AOA effects as well as on the interpretation of offline and online data. Hence, results will be discussed against the background of recent theories on N400 correlates in semantic processing. In addition, an argument in favour of a complementary use of research techniques will be made. PMID- 26032581 TI - Implant Impression Techniques for the Edentulous Jaw: A Summary of Three Studies. AB - PURPOSE: Precise implant-supported restorations require accurate impressions. Transfer, pick-up, and splinted pick-up are commonly used techniques. Several in vitro studies have compared these impression techniques; however, all studies used mechanical evaluation methods. The purpose of this study was to compare the discrepancies of these impression techniques digitally in vitro and in vivo. MATERIALS AND METHODS: Four dental implants were inserted in ten polymer mandibular models bilaterally in the regions of the first molars and canines. Three different impressions were made of each model and the models (original and stone casts) were scanned and digitized. Clinically, four implants were inserted in ten edentulous jaws; transfer and splinted pick-up impressions were made. With inspection software, discrepancies between the different impressions were calculated. RESULTS: The mean discrepancies in the in vitro study of the original polymer model to stone casts were 124 +/- 34 MUm for the transfer type, 116 +/- 46 MUm for the pick-up type, and 80 +/- 25 MUm for the splinted pick-up type, resulting in a mean discrepancy between the transfer and splinted pick-up type of 44 MUm (124 - 80 MUm). Clinically, the mean discrepancy between these two impression techniques was 280 MUm. CONCLUSIONS: The differing results between the transfer and splinted pick-up techniques of in vitro and in vivo data showed the need for clinical data; however, splinted pick-up impressions seemed to produce the most precise results. PMID- 26032582 TI - Reinforcing the 'gauntlet' of thymic negative selection via exosomal transfer of self-antigens. PMID- 26032583 TI - Older people experiencing homelessness show marked impairment on tests of frontal lobe function. AB - OBJECTIVE: Reported rates of mild and moderate cognitive impairment in older people experiencing homelessness range from 5-80%. The objective of this study was to determine the prevalence and characteristics of cognitive impairment in older people experiencing homelessness in the inner city of Sydney, Australia. METHOD: Men and women experiencing homelessness aged 45 years and over in the inner city were screened for cognitive impairment. Participants who scored 26 or below on the mini-mental state examination and/or were impaired on any one of the clock-drawing test, the verbal fluency test and the trail-making test, part B were then assessed with a semi-structured interview, including the 21-item Depression Anxiety Stress Scale and the 12-item General Health Questionnaire. RESULTS: Screening of 144 men and 27 women aged between 45 years and 93 years identified cognitive impairment in 78%. Subsequently, high rates of mental and physical illness were identified, and 75% of subjects who were cognitively impaired performed poorly on frontal lobe tests. The trail-making test, part B was the most sensitive measure of frontal function. CONCLUSIONS: This study demonstrated that a large majority of older people experiencing homelessness, in the inner city of a high-income country, showed impairment on tests of frontal lobe function, a finding that could have significant implications for any medical or psychosocial intervention. PMID- 26032584 TI - Escherichia coli O157:H7--Discerning Facts from Fiction: An Integrated Research and Extension Project for Multiple Audiences. AB - The O157:H7 (EcO157) epidemiology of Shiga-toxin-producing Escherichia coli (STEC) in cattle is complex, and myths about pre-harvest control are perpetuated. The objectives of this project were to identify perpetuated misinformation and inform four audiences about evidence-based risks and pre-harvest control of EcO157 by addressing: (i) EcO157 epidemiology and pre-harvest control; (ii) how food safety policy is created; and (iii) how to present accurate information about EcO157. An environmental scan using a daily Internet search helped identify themes for education. A literature review of pre-harvest control measures contributed to the development of educational materials (fact sheets, website, web presentations and conferences). Conference 1 was a webinar with 315 registrants, 10 countries including 41 US states and four Canadian provinces. Most participants felt confident in using their new knowledge, more than half felt confident enough to answer EcO157 questions from the public and many would recommend the recorded version of the webinar to colleagues. Conference 2 was live in the Washington, DC, area with most participants employed by the US government. All agreed that they better understood pre-harvest control, how food safety policy was made, and were confident they could create an effective message about STEC pre-harvest control. Videos were posted and received 348 Internet visitors within 2 months. Conference 3 was a webinar with a live audience and Twitter feeds, targeting people who give nutrition advice. Almost all ranked the programme good to excellent and relevant to their work. About 25% indicated that they would share: 'grass-fed beef is not safer than grain-fed', 25% would share information on effectiveness of cattle vaccines, and 14% would share information on message mapping. Across all conferences, major changes in knowledge included the following: there is no additional risk of EcO157 shedding from grain-fed versus grass-fed cattle, pre-harvest vaccination is efficacious, and production systems (pasture versus confinement) do not affect EcO157 shedding rates. PMID- 26032585 TI - Evaluation of Tetrahydropalmatine Enantiomers on the Activity of Five Cytochrome P450 Isozymes in Rats Using a Liquid Chromatography / Mass Spectrometric Method and a Cocktail Approach. AB - The aim was to evaluate the effects of tetrahydropalmatine (THP) enantiomers on the activity of five cytochrome P450 (CYP450) isozymes in vivo. A liquid chromatography / mass spectrometric (LC-MS) method was developed for simultaneous determination of five specific probe substrates including metoprolol (2D6), caffeine (1A2), dapsone (3A4), chlorzoxazone (2E1), and tolbutamide (2C9) in rat plasma. Analytes were separated with the mobile phase consisting of 0.1% acetic acid aqueous solution and acetonitrile in a gradient elution. The mass spectrometric detection via selected ion monitoring (SIM) was operated in both positive ion mode (for metoprolol m/z 268, caffeine m/z 195, and dapsone m/z 249) and negative ion mode (for chlorzoxazone m/z 168 and tolbutamide m/z 269) in the same run. Linear correlation was obtained (r(2) > 0.99) over the concentration range of 0.050-25.0 ug/mL for caffeine and dapsone, 0.025-10.0 ug/mL for metoprolol, 0.050-50.0 ug/mL for chlorzoxazone, and 0.25-100.0 ug/mL for tolbutamide. Intra- and interday precision were less than 12.09%. The matrix effect ranged from 87.50% to 109.25% and the absolute recoveries were greater than 70%. The method was successfully applied to evaluate the effect of THP enantiomers on the activity of CYP450 isozymes by a cocktail approach. The pharmacokinetic results of five probe drugs indicated that there were stereoselective differences between the two THP enantiomers, i.e., d-THP had the potential to inhibit the activities of CYP2D6 and CYP1A2 isozymes, while l-THP inhibited CYP1A2 isozyme and induced CYP3A4 and CYP2C9 isozymes. PMID- 26032586 TI - Physician Acceptance of a Physician-Pharmacist Collaborative Treatment Model for Hypertension Management in Primary Care. AB - Physician-pharmacist collaborative care (PPCC) is effective in improving blood pressure (BP) control, but primary care provider (PCP) engagement in such models has not been well-studied. The authors analyzed data from PPCC referrals to 108 PCPs, for patients with uncontrolled hypertension, assessing the proportion of referral requests approved, disapproved, and not responded to, and reasons for disapproval. Of 2232 persons with uncontrolled hypertension, PPCC referral requests were sent for 1516 (67.9%): 950 (62.7%) were approved, 406 (26.8%) were disapproved, and 160 (10.6%) received no response. Approval rates differed widely by PCP with a median approval rate of 75% (interquartile range, 41%-100%). The most common reasons for disapproval were: PCP prefers to manage hypertension (19%), and BP controlled per PCP (18%); 8% of cases were considered too complex for PPCC. Provider acceptance of a PPCC hypertension clinic was generally high and sustained but varied widely among PCPs. No single reason for disapproval predominated. PMID- 26032587 TI - Dihydromyricetin improves glucose and lipid metabolism and exerts anti inflammatory effects in nonalcoholic fatty liver disease: A randomized controlled trial. AB - Ampelopsis grossedentata, a medicinal and edible plant, has been widely used in China for hundreds of years, and dihydromyricetin is the main active ingredient responsible for its various biological actions. We investigated the effects of dihydromyricetin on glucose and lipid metabolism, inflammatory mediators and several biomarkers in nonalcoholic fatty liver disease. In a double-blind clinical trial, sixty adult nonalcoholic fatty liver disease patients were randomly assigned to receive either two dihydromyricetin or two placebo capsules (150 mg) twice daily for three months. The serum levels of alanine, aspartate aminotransferase, gamma-glutamyl transpeptidase, glucose, low-density lipoprotein cholesterol and apolipoprotein B, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly decreased in the dihydromyricetin group compared with the placebo group. In the dihydromyricetin group, the serum levels of tumor necrosis factor-alpha, cytokeratin-18 fragment and fibroblast growth factor 21 were decreased, whereas the levels of serum adiponectin were increased at the end of the study. We conclude that dihydromyricetin supplementation improves glucose and lipid metabolism as well as various biochemical parameters in patients with nonalcoholic fatty liver disease, and the therapeutic effects of dihydromyricetin are likely attributable to improved insulin resistance and decreases in the serum levels of tumor necrosis factor alpha, cytokeratin-18, and fibroblast growth factor 21. PMID- 26032588 TI - ORBITOFRONTAL THICKNESS AS A MEASURE FOR TREATMENT RESPONSE PREDICTION IN OBSESSIVE-COMPULSIVE DISORDER. AB - BACKGROUND: Early prediction of treatment response could reduce exposure to ineffective treatments and optimize the use of medical resources. Neuroimaging techniques have been used to identify biomarkers that are predictive of outcomes. The aims of this study were to investigate orbitofrontal cortex (OFC) thickness as a potential morphometric biomarker to discriminate outcomes in obsessive compulsive disorder (OCD) and then to reexamine this biomarker in an independent cohort METHODS: Using a logistic regression model based on the mean baseline thickness of subregions of the OFC, we estimated the probability of treatment response in 29 treatment-naive OCD patients who participated in a clinical trial. That algorithm was then tested in an independent cohort of 12 patients with a confirmed diagnosis of refractory OCD RESULTS: Among the treatment-naive OCD patients, measures of OFC thickness statistically significantly differentiated responders (n = 13) and nonresponders (n = 16), with an overall classification accuracy of ~80%, a sensitivity of 77% (10/13), and a specificity of 81% (13/16). Of the refractory OCD patients in the second independent cohort, 67% were correctly classified as nonresponders. The most discriminative measures in the initial cohort of treatment-naive patients were the thicknesses of the left and right medial OFC (P = .009 and P = .028, respectively) CONCLUSIONS: We found OFC thickness to be a strong predictor of treatment response in treatment-naive OCD patients. Although there are not yet any brain imaging biomarkers with clinical utility, our results highlight the potential of these measures as tools for predicting treatment outcomes in OCD. PMID- 26032589 TI - Functional response of the fungus Hirsutella rhossiliensis to the nematode, Heterodera glycines. AB - Functional response is a key index in determining the population fluctuation in predation. However, the lack of operable research system limits the studies on functional response of fungal predators. Hirsutella rhossiliensis is a dominant parasite of the soybean cyst nematode, Heterodera glycines. In a soil microcosm bioassay, we determined fungal biomass at different days within 21 days after inoculation, and parasitism rate of H. glycines by the fungus was determined. The functional response of H. rhossiliensis to H. glycines was established and found to be Holling's type III, which was influenced by mycelial densities. Meanwhile, we conducted anti-fungal analysis of metabolic fractions extracted from H. rhossiliensis to explain the potential mechanism of the intraspecific competition illustrated by functional response. The result of anti-fungal experiments indicated that the fungal predators had more complicated interaction at population level than expected, which might be regulated by self-inhibition metabolite(s). This study was the first functional response study of fungal predators in microcosm. With the increasing recognition of emerging fungal threats to animal, plant, and ecosystem health, the methodologies and hypotheses proposed in this study might inspire further research in fungal ecology. PMID- 26032590 TI - High quality reference genome of drumstick tree (Moringa oleifera Lam.), a potential perennial crop. AB - The drumstick tree (Moringa oleifera Lam.) is a perennial crop that has gained popularity in certain developing countries for its high-nutrition content and adaptability to arid and semi-arid environments. Here we report a high-quality draft genome sequence of M. oleifera. This assembly represents 91.78% of the estimated genome size and contains 19,465 protein-coding genes. Comparative genomic analysis between M. oleifera and related woody plant genomes helps clarify the general evolution of this species, while the identification of several species-specific gene families and positively selected genes in M. oleifera may help identify genes related to M. oleifera's high protein content, fast-growth, heat and stress tolerance. This reference genome greatly extends the basic research on M. oleifera, and may further promote applying genomics to enhanced breeding and improvement of M. oleifera. PMID- 26032591 TI - The conformational states of talin autoinhibition complex and its activation under forces. AB - Talin is an integrin-binding protein located at focal adhesion site and serves as both an adapter and a force transmitter. Its integrin binding activity is regulated by the intramolecular autoinhibition interaction between its F3 and RS domains. Here, we used atomic force microscopy to measure the strength of talin autoinhibition complex. Our results suggest that the lifetime of talin autoinhibition complex shows weak catch bond behavior and does not change significantly at smaller forces, while it drops rapidly at larger forces (>10 pN). Moreover, besides the complex conformation revealed by crystal structure, our molecular dynamics (MD) simulations indicate the possible existence of another stable conformation. Further analysis indicates that forces may regulate the equilibrium of the two stable binding states and result in the non exponential force dependence of the binding lifetime. Our findings reveal a negative regulation mechanism on talin activation and provide a new point of view on the function of talin in focal adhesion. PMID- 26032592 TI - New-onset diabetes mellitus after pediatric liver transplantation. AB - In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy. PMID- 26032593 TI - Rhodium-Catalyzed [3+2+2] and [2+2+2] Cycloadditions of Two Alkynes with Cyclopropylideneacetamides. AB - It has been established that a cationic rhodium(I)/H8 -binap complex catalyzes the [3+2+2] cycloaddition of 1,6-diynes with cyclopropylideneacetamides to produce cycloheptadiene derivatives through cleavage of cyclopropane rings. In contrast, a cationic rhodium(I)/(S)-binap complex catalyzes the enantioselective [2+2+2] cycloaddition of terminal alkynes, acetylenedicarboxylates, and cyclopropylideneacetamides to produce spiro-cyclohexadiene derivatives which retain the cyclopropane rings. PMID- 26032594 TI - One Crystal, Two Temperatures: Cryocooling Penalties Alter Ligand Binding to Transient Protein Sites. AB - Interrogating fragment libraries by X-ray crystallography is a powerful strategy for discovering allosteric ligands for protein targets. Cryocooling of crystals should theoretically increase the fraction of occupied binding sites and decrease radiation damage. However, it might also perturb protein conformations that can be accessed at room temperature. Using data from crystals measured consecutively at room temperature and at cryogenic temperature, we found that transient binding sites could be abolished at the cryogenic temperatures employed by standard approaches. Changing the temperature at which the crystallographic data was collected could provide a deliberate perturbation to the equilibrium of protein conformations and help to visualize hidden sites with great potential to allosterically modulate protein function. PMID- 26032595 TI - Compact and modular multicolour fluorescence detector for droplet microfluidics. AB - Multicolour fluorescence detection is often necessary in droplet microfluidics, but typical detection systems are complex, bulky, and expensive. We present a compact and modular detection system capable of sub-nanomolar sensitivity utilizing an optical fibre array to encode spectral information recorded by a single photodetector. PMID- 26032596 TI - PubMed-supported clinical term weighting approach for improving inter-patient similarity measure in diagnosis prediction. AB - BACKGROUND: Similarity-based retrieval of Electronic Health Records (EHRs) from large clinical information systems provides physicians the evidence support in making diagnoses or referring examinations for the suspected cases. Clinical Terms in EHRs represent high-level conceptual information and the similarity measure established based on these terms reflects the chance of inter-patient disease co-occurrence. The assumption that clinical terms are equally relevant to a disease is unrealistic, reducing the prediction accuracy. Here we propose a term weighting approach supported by PubMed search engine to address this issue. METHODS: We collected and studied 112 abdominal computed tomography imaging examination reports from four hospitals in Hong Kong. Clinical terms, which are the image findings related to hepatocellular carcinoma (HCC), were extracted from the reports. Through two systematic PubMed search methods, the generic and specific term weightings were established by estimating the conditional probabilities of clinical terms given HCC. Each report was characterized by an ontological feature vector and there were totally 6216 vector pairs. We optimized the modified direction cosine (mDC) with respect to a regularization constant embedded into the feature vector. Equal, generic and specific term weighting approaches were applied to measure the similarity of each pair and their performances for predicting inter-patient co-occurrence of HCC diagnoses were compared by using Receiver Operating Characteristics (ROC) analysis. RESULTS: The Areas under the curves (AUROCs) of similarity scores based on equal, generic and specific term weighting approaches were 0.735, 0.728 and 0.743 respectively (p < 0.01). In comparison with equal term weighting, the performance was significantly improved by specific term weighting (p < 0.01) but not by generic term weighting. The clinical terms "Dysplastic nodule", "nodule of liver" and "equal density (isodense) lesion" were found the top three image findings associated with HCC in PubMed. CONCLUSIONS: Our findings suggest that the optimized similarity measure with specific term weighting to EHRs can improve significantly the accuracy for predicting the inter-patient co-occurrence of diagnosis when compared with equal and generic term weighting approaches. PMID- 26032597 TI - Intimate partner violence among women with eating disorders during the perinatal period. AB - OBJECTIVE: Prevalence of intimate partner violence (IPV) during pregnancy is estimated to be 4%-8%. Women with mental health difficulties are at increased risk for IPV during the perinatal period. Prevalence of IPV is high among women with eating disorders (ED); however, prevalence of IPV during the perinatal period among women with ED is unknown. METHOD: We studied women from a population based cohort, the Avon Longitudinal Study of Parents and Children. Prevalence and odds of physical and emotional IPV during and after the perinatal period was investigated among women with lifetime ED, with (n = 174) or without pregnancy shape and weight concern and/or purging behaviors (n = 189), and women with no ED (n = 8723). RESULTS: Women with lifetime ED showed higher prevalence of IPV during and after the perinatal period (physical = 9.6%-14.3% and emotional = 24.1%-28.1%). Lifetime ED was associated with higher odds of physical IPV during the perinatal period (odds ratio: 2.34, 95% confidence interval: 1.11-4.93, p = .03). Lifetime ED with and without pregnancy shape and weight concerns and/or purging was associated with higher odds of IPV after the perinatal period, and higher odds of reporting emotional IPV at all time points. Associations were moderated by partner's response to pregnancy and maternal experience of childhood sexual abuse. DISCUSSION: Mothers with ED and their children may be vulnerable to negative effects due to maternal ED and IPV combined, both of which have been associated with severe and long-lasting harmful consequences. Partner's response to pregnancy and maternal experience of childhood sexual abuse might contribute to the association between ED and IPV perinatally. PMID- 26032599 TI - Renin-angiotensin system blockade: Its contribution and controversy. AB - Angiotensin II is a key biological peptide in the renin-angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin-angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin-angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin angiotensin system blockade use might in fact increase the incidence of cancer, so renin-angiotensin system blockade use has become somewhat controversial. Although the renin-angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin-angiotensin system up to the present time. PMID- 26032600 TI - Clearance of primary necrotic cells by non-professional phagocytes. AB - BACKGROUND INFORMATION: Homotypic internalisation of tumour cells has frequently been observed in tumour tissue sections. Events of non-professional phagocytosis, however, may also occur in normal tissue if the number of dying cells exceeds the phagocytic capacity of professional phagocytes such as macrophages and dendritic cells. The aim of this study was to investigate the molecular background of non professional phagocytosis of primary necrotic cells by neighbouring tumour cells and normal skin fibroblasts. RESULTS: We demonstrate that homotypic and heterotypic uptake of necrotic cells is a feature common to various cell types. Investigating critical stimuli of necrotic cell clearance we found that non professional phagocytes require cytoskeleton rearrangement, recognition of phosphatidylserine and GTPase activity of dynamin II, which is normally engaged in endocytosis. Additionally, we have observed an accumulation of adhesion molecule E-cadherin, phosphorylated actin-linker protein ezrin, lysosomal associated membrane protein 1 and microtubule-associated protein 1 light chain 3 at the site of engulfment. Loss of membrane integrity and an increase in the intracellular level of heat-shock protein 70 in the necrotic cells have also been observed. CONCLUSIONS: Our results shed light on the mechanism of necrotic cell removal by tumour cells and normal skin fibroblasts in vitro. It is reasonable to assume that this process has a physiological relevance in inflammation and autoimmune disease in normal tissue as well as in tumours regarding immune cell infiltration. We conclude that necrotic cell clearance by non-professional phagocytes contributes to the phagocytic activity by macrophages and that this process may prevent release of proinflammatory damage-associated molecular pattern molecules. PMID- 26032601 TI - Characteristics of Work- and Non-work-Related Farm Injuries. AB - PURPOSE: Farm-related injuries are an important public health problem in agriculture because of their impact on individuals, families, and farm operations. While surveillance programs such as the Census of Fatal Occupational Injuries is available to track fatal agricultural injuries, more work is needed to examine the burden of nonfatal agricultural injuries. METHODS: Data involving agricultural injuries were collected from the Iowa Trauma Registry from January 1, 2005, through December 31, 2011. A total of 2,490 trauma patients were found to have been classified as having a farm-related injury. These nonfatal farm related injuries were compared by work-relatedness, injury severity score, length of hospital stay, and hospital discharge status. Also reported are the age and gender of the trauma patients, as well as the population of the county in which the injury occurred. RESULTS: In our analysis, we found that work- versus nonwork relatedness had little effect on injury severity, but that work-related injuries did result in longer average hospital stays. Injuries occurring in counties of lower population size tended to be slightly more severe and be more likely to have nonroutine discharges. CONCLUSIONS: Farm environments pose hazards which are persistent for those working and living on the farm, regardless of whether or not they are engaged in work-related activities. Public health prevention approaches that consider work and nonwork farm environments may be helpful in designing interventions to reduce injury. PMID- 26032598 TI - Recent advances in 3D time-resolved contrast-enhanced MR angiography. AB - Contrast-enhanced magnetic resonance angiography (CE-MRA) was first introduced for clinical studies approximately 20 years ago. Early work provided 3-4 mm spatial resolution with acquisition times in the 30-second range. Since that time there has been continuing effort to provide improved spatial resolution with reduced acquisition time, allowing high resolution 3D time-resolved studies. The purpose of this work is to describe how this has been accomplished. Specific technical enablers have been: improved gradients allowing reduced repetition times, improved k-space sampling and reconstruction methods, parallel acquisition, particularly in two directions, and improved and higher count receiver coil arrays. These have collectively made high-resolution time-resolved studies readily available for many anatomic regions. Depending on the application, ~1 mm isotropic resolution is now possible with frame times of several seconds. Clinical applications of time-resolved CE-MRA are briefly reviewed. PMID- 26032602 TI - Response of rare, common and abundant bacterioplankton to anthropogenic perturbations in a Mediterranean coastal site. AB - Bacterioplankton communities are made up of a small set of abundant taxa and a large number of low-abundant organisms (i.e. 'rare biosphere'). Despite the critical role played by bacteria in marine ecosystems, it remains unknown how this large diversity of organisms are affected by human-induced perturbations, or what controls the responsiveness of rare compared to abundant bacteria. We studied the response of a Mediterranean bacterioplankton community to two anthropogenic perturbations (i.e. nutrient enrichment and/or acidification) in two mesocosm experiments (in winter and summer). Nutrient enrichment increased the relative abundance of some operational taxonomic units (OTUs), e.g. Polaribacter, Tenacibaculum, Rhodobacteraceae and caused a relative decrease in others (e.g. Croceibacter). Interestingly, a synergistic effect of acidification and nutrient enrichment was observed on specific OTUs (e.g. SAR86). We analyzed the OTUs that became abundant at the end of the experiments and whether they belonged to the rare (<0.1% of relative abundance), the common (0.1-1.0% of relative abundance) or the abundant (>1% relative abundance) fractions. Most of the abundant OTUs at the end of the experiments were abundant, or at least common, in the original community of both experiments, suggesting that ecosystem alterations do not necessarily call for rare members to grow. PMID- 26032605 TI - Advances in affinity ligand-functionalized nanomaterials for biomagnetic separation. AB - The downstream processing of proteins remains the most significant cost in protein production, and is largely attributed to rigorous chromatographic purification protocols, where the stringency of purity for biopharmaceutical products sometimes exceeds 99%. With an ever burgeoning biotechnology market, there is a constant demand for alternative purification methodologies, to ameliorate the dependence on chromatography, while still adhering to regulatory concerns over product purity and safety. In this article, we present an up-to date view of bioseparation, with emphasis on magnetic separation and its potential application in the field. Additionally, we discuss the economic and performance benefits of synthetic ligands, in the form of peptides and miniaturized antibody fragments, compared to full-length antibodies. We propose that adoption of synthetic affinity ligands coupled with magnetic adsorbents, will play an important role in enabling sustainable bioprocessing in the future. PMID- 26032604 TI - Clinical outcome in MPFL reconstruction with and without tuberositas transposition. AB - PURPOSE: There are several surgical options for recurrent patella dislocations. As the reconstruction of the medial patellofemoral ligament (MPFL) has been proven to restore stability, it has become more accepted. Aim of this study was to investigate the clinical outcome after MPFL reconstruction as an isolated procedure or in association with a transposition of the tibial tubercle (in case of patella alta or an excessive TT-TG) in a large prospective cohort study. Additionally, the effect on patellar height was analysed radiographically using the Caton-Deschamps index. METHODS: In a large prospective cohort study of 129 knees in 124 patients (81 females, 48 males, mean age 22.8 +/- 7.7 years), 91 knees received primary MPFL reconstruction (group 1) and 38 were a combination with a transposition of the tibial tubercle (group 2). The clinical follow-up was evaluated using KOOS and Kujala scores preoperatively and 1 year postoperatively. Patient satisfaction, complications and revision surgery were recorded. RESULTS: Overall, Kujala improved significantly from 53.5 (SD 22.7) preoperatively to 74.7 (SD 20.5) postoperatively (p < 0.01). All KOOS subdomains improved significantly (p < 0.01). No significant difference for Kujala score between groups was noticed. Revision rate was (5/129) 3.9 %. Reconstruction was supplemented with a transfer of the tibial tuberosity in (38/129) 29.4 % of the cases and shows a comparable outcome. CONCLUSION: MPFL reconstruction is a viable treatment option for episodic patellar dislocation. A concomitant tuberositas transposition is useful in selected patients. LEVEL OF EVIDENCE: I. PMID- 26032603 TI - Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records. AB - OBJECTIVE: To compare time to diagnosis of the typically slow-growing Type I (low grade serous, low-grade endometrioid, mucinous, clear cell) and the more aggressive Type II (high-grade serous, high-grade endometrioid, undifferentiated, carcinosarcoma) invasive epithelial ovarian cancer (iEOC). DESIGN: Multicentre observational study. SETTING: Ten UK gynaecological oncology centres. POPULATION: Women diagnosed with primary EOC between 2006 and 2008. METHODS: Symptom data were collected before diagnosis using patient questionnaire and primary-care records. We estimated patient interval (first symptom to presentation) using questionnaire data and diagnostic interval (presentation to diagnosis) using primary-care records. We considered the impact of first symptom, referral and stage on intervals for Type I and Type II iEOC. MAIN OUTCOME MEASURES: Patient and diagnostic intervals. RESULTS: In all, 78% of 60 Type I and 21% of 134 Type II iEOC were early-stage. Intervals were comparable and independent of stage [e.g. median patient interval for Type I: early-stage 0.3 months (interquartile range 0.3-3.0) versus late-stage 0.3 months (interquartile range 0.3-4.5), P = 0.8]. Twenty-seven percent of women with Type I and Type II had diagnostic intervals of at least 9 months. First symptom (questionnaire) was also similar, except for the infrequent abnormal bleeding (Type I 15% versus Type II 4%, P = 0.01). More women with Type I disease (57% versus 41%, P = 0.04) had been referred for suspected gynaecological cancer. Median time from referral to diagnosis was 1.4 months for women with iEOC referred via a 2-week cancer referral to any specialty compared with 2.6 months (interquartile range 2.0-3.7) for women who were referred routinely to gynaecology. CONCLUSION: Overall, shorter diagnostic delays were seen when a cancer was suspected, even if the primary tumour site was not recognised to be ovarian. Despite differences in carcinogenesis and stage for Type I and Type II iEOC, time to diagnosis and symptoms were similar. Referral patterns were different, implying subtle symptom differences. If symptom-based interventions are to impact on ovarian cancer survival, it is likely to be through reduced volume rather than stage-shift. Further research on histological subtypes is needed. TWEETABLE ABSTRACT: No difference in time to diagnosis for Type I versus Type II invasive epithelial ovarian cancers. PMID- 26032606 TI - Stem and leaf hydraulic properties are finely coordinated in three tropical rain forest tree species. AB - Coordination of stem and leaf hydraulic traits allows terrestrial plants to maintain safe water status under limited water supply. Tropical rain forests, one of the world's most productive biomes, are vulnerable to drought and potentially threatened by increased aridity due to global climate change. However, the relationship of stem and leaf traits within the plant hydraulic continuum remains understudied, particularly in tropical species. We studied within-plant hydraulic coordination between stems and leaves in three tropical lowland rain forest tree species by analyses of hydraulic vulnerability [hydraulic methods and ultrasonic emission (UE) analysis], pressure-volume relations and in situ pre-dawn and midday water potentials (Psi). We found finely coordinated stem and leaf hydraulic features, with a strategy of sacrificing leaves in favour of stems. Fifty percent of hydraulic conductivity (P50 ) was lost at -2.1 to -3.1 MPa in stems and at -1.7 to -2.2 MPa in leaves. UE analysis corresponded to hydraulic measurements. Safety margins (leaf P50 - stem P50 ) were very narrow at -0.4 to 1.4 MPa. Pressure-volume analysis and in situ Psi indicated safe water status in stems but risk of hydraulic failure in leaves. Our study shows that stem and leaf hydraulics were finely tuned to avoid embolism formation in the xylem. PMID- 26032607 TI - Germany is set to introduce e-health cards by 2018. PMID- 26032608 TI - Monitoring the growth of the neural representations of new animal concepts. AB - Although enormous progress has recently been made in identifying the neural representations of individual object concepts, relatively little is known about the growth of a neural knowledge representation as a novel object concept is being learned. In this fMRI study, the growth of the neural representations of eight individual extinct animal concepts was monitored as participants learned two features of each animal, namely its habitat (i.e., a natural dwelling or scene) and its diet or eating habits. Dwelling/scene information and diet/eating related information have each been shown to activate their own characteristic brain regions. Several converging methods were used here to capture the emergence of the neural representation of a new animal feature within these characteristic, a priori-specified brain regions. These methods include statistically reliable identification (classification) of the eight newly acquired multivoxel patterns, analysis of the neural representational similarity among the newly learned animal concepts, and conventional GLM assessments of the activation in the critical regions. Moreover, the representation of a recently learned feature showed some durability, remaining intact after another feature had been learned. This study provides a foundation for brain research to trace how a new concept makes its way from the words and graphics used to teach it, to a neural representation of that concept in a learner's brain. PMID- 26032609 TI - What drives diffusion of new cancer therapies? PMID- 26032610 TI - New evidence for link between coffee and risk of endometrial cancer. PMID- 26032611 TI - Immune profiling of tumors may better stage early cancers. PMID- 26032612 TI - FDA approves new agent for multiple myeloma. PMID- 26032615 TI - Salicylic acid is required for Mi-1-mediated resistance of tomato to whitefly Bemisia tabaci, but not for basal defense to this insect pest. AB - Plant defense to pests or pathogens involves global changes in gene expression mediated by multiple signaling pathways. A role for the salicylic acid (SA) signaling pathway in Mi-1-mediated resistance of tomato (Solanum lycopersicum) to aphids was previously identified and its implication in the resistance to root knot nematodes is controversial, but the importance of SA in basal and Mi-1 mediated resistance of tomato to whitefly Bemisia tabaci had not been determined. SA levels were measured before and after B. tabaci infestation in susceptible and resistant Mi-1-containing tomatoes, and in plants with the NahG bacterial transgene. Tomato plants of the same genotypes were also screened with B. tabaci (MEAM1 and MED species, before known as B and Q biotypes, respectively). The SA content in all tomato genotypes transiently increased after infestation with B. tabaci albeit at variable levels. Whitefly fecundity or infestation rates on susceptible Moneymaker were not significantly affected by the expression of NahG gene, but the Mi-1-mediated resistance to B. tabaci was lost in VFN NahG plants. Results indicated that whiteflies induce both SA and jasmonic acid accumulation in tomato. However, SA has no role in basal defense of tomato against B. tabaci. In contrast, SA is an important component of the Mi-1-mediated resistance to B. tabaci in tomato. PMID- 26032616 TI - Office-based laryngeal injection of botulinum toxin for paradoxical vocal fold motion in a child. AB - We describe the case of a 13-year-old girl with paradoxical vocal fold motion (PVFM) who failed to improve with repeated medical treatment, speech therapy and psychotherapy, but was successfully treated with botulinum toxin A (BTX-A) injection to the vocal folds. For delivering the BTX-A we used a channeled fiber optic laryngoscope under local anesthesia, in an office setting. The patient remained asymptomatic of PVFM for 5 months, was successfully treated again with the same method, and had no important side effects. PMID- 26032617 TI - (18)F-sodium fluoride PET/CT for the in vivo visualization of Monckeberg's sclerosis in a diabetic patient. AB - Diabetes is a major frequent cause of atherosclerosis vascular disease. Arterial calcification in diabetic patients is responsible for peripheral vascular involvement. Molecular imaging using (18)F-sodium fluoride ((18)F-NaF) positron emission tomography (PET)/computed tomography (CT) has been recently proposed as a marker to study the in vivo mineralization process in the atheroma plaque. A 69 year-old man with a history of type 2 diabetes and no clinical evidence of peripheral arterial disease underwent an (18)F-NaF PET/CT scan. A linear, well defined (18)F-NaF uptake was detected along the femoral arteries. In addition, the CT component of the PET/CT identified an unsuspected "tram-track" calcification in his femoral arteries, suggestive of medial calcification (Monckeberg's sclerosis). In other vascular territories, focal (18)F-NaF uptake was also detected in carotid and aorta atheroma plaques. Molecular imaging with (18)F-NaF PET/CT might provide new functional information about the in vivo vascular calcification process in diabetic patients. PMID- 26032619 TI - Synthesis and Anticonvulsant Activity of Substituted-1,3-diazaspiro[4.5]decan-4 ones. AB - A series of novel spiroimidazolidinone derivatives 6a-d and 8a-x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5- and 83.6-fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test. PMID- 26032618 TI - Spatial profiles of markers of glycolysis, mitochondria, and proton pumps in a rat glioma suggest coordinated programming for proliferation. AB - BACKGROUND: In cancer cells in vitro, the glycolytic pathway and the mitochondrial tricarboxylic acid (TCA) cycle are programmed to produce more precursor molecules, and relatively less ATP, than in differentiated cells. We address the questions of whether and where these changes occur in vivo in glioblastomas grown from C6 cells in rat brain. These gliomas show some spatial organization, notably in the upregulation of membrane proton transporters near the rim. RESULTS: We immunolabeled pairs of proteins (as well as DNA) on sections of rat brains containing gliomas, measured the profiles of fluorescence intensity on strips 200 um wide and at least 3 mm long running perpendicular to the tumor rim, and expressed the intensity in the glioma relative to that outside. On averaged profiles, labeling of a marker of the glycolytic pathway, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), was, as expected, greater in the glioma. Over distances up to 2.5 mm into the glioma, expression of a marker of the TCA cycle, Tom20, a pre-protein receptor on the translocation complex of the mitochondrial outer membrane, was also upregulated. The ratio of upregulation of Tom20 to upregulation of GAPDH was, on average, slightly greater than one. Near the rim (0.4-0.8 mm), GAPDH was expressed less and there was a peak in the mean ratio of 1.16, SEM = 0.001, N = 16 pairs of profiles. An antibody to V-ATPase, which, by pumping protons into vacuoles contributes to cell growth, also indicated upregulation by about 40%. When compared directly with GAPDH, upregulation of V ATPase was only 0.764, SD = 0.016 of GAPDH upregulation. CONCLUSIONS: Although there was considerable variation between individual measured profiles, on average, markers of the glycolytic pathway, of mitochondria, and of cell proliferation showed coherent upregulation in C6 gliomas. There is a zone, close to the rim, where mitochondrial presence is upregulated more than the glycolytic pathway, in agreement with earlier suggestions that lactate is taken up by cells near the rim. PMID- 26032620 TI - 'Women now wear trousers': men's perceptions of family planning in the context of changing gender relations in western Kenya. AB - Gender inequity has been closely linked with unmet need for family planning among women in sub-Saharan Africa but the factors related to male family planning disapproval are not well-understood. This qualitative study explored men's perspectives of gender roles and cultural norms as they pertain to family planning. Twelve small group meetings were held with 106 married men in Nyanza Province, Kenya. Shifting gender relations made the definitions of manhood more tenuous than ever. Men's previous identities as sole breadwinners, which gave them significant control over decision-making, were being undermined by women's increasing labour force participation. While many men viewed family planning positively, fears that family planning would lead to more female sexual agency and promiscuity or that male roles would be further jeopardised were widespread and were major deterrents to male family planning approval. By addressing such fears, gender-sensitive programmes could help more men to accept family planning. Increased family planning education for men is needed to dispel misconceptions regarding family planning side-effects. Focusing on the advantages of family planning, namely financial benefits and reduced conflict among couples, could resonate with men. Community leaders, outreach workers and healthcare providers could help shift men's approval of joint decision-making around family size to other reproductive domains, such as family planning use. PMID- 26032622 TI - Photoisomerization action spectroscopy: flicking the protonated merocyanine spiropyran switch in the gas phase. AB - Laser spectroscopy and ion mobility spectrometry are combined to provide structural and photochemical information on photoisomerizing molecules in the gas phase. The strategy exploits the fact that an ion packet propelled through buffer gas by an electric field separates spatially and temporally into its constituent isomers because of small differences in their collision cross sections. Isomers selected by an electrostatic ion gate are exposed to wavelength tunable radiation, promoting formation of photoisomers that are separated in a second ion mobility stage. The approach is demonstrated for protonated merocyanine and spiropyran isomers formed through electrospray ionization. Four isomers are observed whose relative abundances depend on pretreatment of the electrosprayed solution with either ultraviolet or visible light, and on collisional excitation before the ions are launched into the drift tube. The observations are interpreted in the light of accurate double-hybrid density functional theory calculations for the protonated spiropyran and merocyanine isomers that are used to predict structures, relative energies, isomerization barriers, collision cross sections and electronic absorption spectra. The two most abundant isomers, are merocyanine forms, in which the proton resides on the quinone oxygen atom, with either a trans or cis central bond in the linking polymethine chain. These two mero forms can be interconverted through photoexcitation, with different wavelength dependences for the forward and reverse photoisomerization processes. Protonated spiropyran is formed from protonated merocyanine isomers through collisional activation, but in only minor amounts through their photo-excitation over the 300-700 nm range. PMID- 26032621 TI - No evidence for Fabaceae Gametophytic self-incompatibility being determined by Rosaceae, Solanaceae, and Plantaginaceae S-RNase lineage genes. AB - BACKGROUND: Fabaceae species are important in agronomy and livestock nourishment. They have a long breeding history, and most cultivars have lost self incompatibility (SI), a genetic barrier to self-fertilization. Nevertheless, to improve legume crop breeding, crosses with wild SI relatives of the cultivated varieties are often performed. Therefore, it is fundamental to characterize Fabaceae SI system(s). We address the hypothesis of Fabaceae gametophytic (G)SI being RNase based, by recruiting the same S-RNase lineage gene of Rosaceae, Solanaceae or Plantaginaceae SI species. RESULTS: We first identify SSK1 like genes (described only in species having RNase based GSI), in the Trifolium pratense, Medicago truncatula, Cicer arietinum, Glycine max, and Lupinus angustifolius genomes. Then, we characterize the S-lineage T2-RNase genes in these genomes. In T. pratense, M. truncatula, and C. arietinum we identify S RNase lineage genes that in phylogenetic analyses cluster with Pyrinae S-RNases. In M. truncatula and C. arietinum genomes, where large scaffolds are available, these sequences are surrounded by F-box genes that in phylogenetic analyses also cluster with S-pollen genes. In T. pratense the S-RNase lineage genes show, however, expression in tissues not involved in GSI. Moreover, levels of diversity are lower than those observed for other S-RNase genes. The M. truncatula and C. arietinum S-RNase and S-pollen like genes phylogenetically related to Pyrinae S genes, are also expressed in tissues other than those involved in GSI. To address if other T2-RNases could be determining Fabaceae GSI, here we obtained a style with stigma transcriptome of Cytisus striatus, a species that shows significant difference on the percentage of pollen growth in self and cross-pollinations. Expression and polymorphism analyses of the C. striatus S-RNase like genes revealed that none of these genes, is the S-pistil gene. CONCLUSION: We find no evidence for Fabaceae GSI being determined by Rosaceae, Solanaceae, and Plantaginaceae S-RNase lineage genes. There is no evidence that T2-RNase lineage genes could be determining GSI in C. striatus. Therefore, to characterize the Fabaceae S-pistil gene(s), expression analyses, levels of diversity, and segregation analyses in controlled crosses are needed for those genes showing high expression levels in the tissues where GSI occurs. PMID- 26032623 TI - Synthesis and biological evaluation of benzo[d][1,3]dioxol-5-yl chalcones as antiproliferating agents. AB - A series of chalcone derivatives were designed, synthesized, and evaluated for their cytotoxic potential. These molecules have showed promising cytotoxic activity with IC50 values ranging from 5.24 to 63.12 MUm. Among them, conjugates 16k, 16m and 16t showed significant antiproliferative activity with IC50 values ranging from 5.24 to 10.39 MUm in MDA-MB-231 cell line. These compounds were further investigated for their effect on cell membrane blebbing, chromatin condensation, DNA fragmentation, Hoechst staining, annexin V, and cell cycle arrest (G2/M). The Western blot experiments revealed up regulation of pro apoptotic Bax and downregulation of antiapoptotic Bcl-2. The studies also indicated reduction of mitochondrial membrane potential and increase in the levels of caspase-3 and caspase-7. PMID- 26032624 TI - Factors affecting the uptake of cervical cancer screening among nurses in Singapore. AB - OBJECTIVE: To identify factors other than socioeconomic status that influence participation in cervical cancer screening. METHODS: A prospective, questionnaire based, cross-sectional study was conducted among all female nurses working at Singapore General Hospital, Singapore, between November 1 and December 15, 2013. Characteristics assessed included age, knowledge score (0-10, on the basis of 10 true-or-false statements), perceived risk of cervical cancer, and health facility use. RESULTS: Among 2000 nurses, 1622 (81.1%) responded. The mean knowledge score was 4.70+/-1.76. Among 1593 nurses who reported on self-perception of risk, 97 (6.1%) reported high risk, 675 (42.4%) reported low risk, and 821 (51.5%) reported uncertainty. Of the 815 nurses reporting on their history of screening, 344 (42.2%) were screened regularly, 103 (12.6%) underwent opportunistic screening, and 368 (45.2%) had never undergone screening. The likelihood of screening was increased among women aged 35-4years, those who had recent experience of medical screening, those who had recently had a specialist consultation, or those who had recently had a consultation with a gynecologist (P<0.001 for all). Nurses undergoing regular screening reported positive effects of a doctor's recommendation, husband's encouragement, people talking about screening, and people close to the respondent undergoing screening. CONCLUSION: Advocacy and herd signaling positively influenced the cervical cancer screening rate. PMID- 26032625 TI - Partial shading of lateral branches affects growth, and foliage nitrogen- and water-use efficiencies in the conifer Cunninghamia lanceolata growing in a warm monsoon climate. AB - The degree to which branches are autonomous in their acclimation responses to alteration in light environment is still poorly understood. We investigated the effects of shading of the sapling crown of Cunninghamia lanceolata (Lamb.) Hook on the whole-tree and mid-crown branch growth and current-year foliage structure and physiology. Four treatments providing 0, 50, 75 and 90% shading compared with full daylight (denoted as Treatment(0), Treatment(50%), Treatment(75%) and Treatment(90%), and Shaded(0), Shaded(50%), Shaded(75%) and Shaded(90%) for the shaded branches and Sunlit(0), Sunlit(50%), Sunlit(75%) and Sunlit(90%) for the opposite sunlit branches under natural light conditions, respectively), were applied over two consecutive growing seasons. Shading treatments decreased the growth of basal stem diameter, leaf dry mass per unit leaf area, stomatal conductance, transpiration rate, the ratio of water-soluble to structural leaf nitrogen content, photosynthetic nitrogen-use efficiency and instantaneous and long-term (estimated from carbon isotope composition) water-use efficiency in shaded branches. Differences between shaded and sunlit branches increased with increasing severity and duration of shading. A non-autonomous, partly compensatory behavior of non-shaded branches was observed for most traits, thus reflecting the dependence between the traits of sunlit branches and the severity of shading of the opposite crown half. The results collectively indicated that tree growth and branch and leaf acclimation responses of C. lanceolata are not only affected by the local light environment, but also by relative within-crown light conditions. We argue that such a non-autonomous branch response to changes in light conditions can improve whole-tree resource optimization. These results contribute to better understanding of tree growth and utilization of water and nitrogen under heterogeneous light conditions within tree canopies. PMID- 26032626 TI - A pilot randomised controlled trial to assess the utility of an e-learning package that trains users in adverse drug reaction causality. AB - OBJECTIVES: Causality assessment of adverse drug reactions (ADRs) by healthcare professionals is often informal which can lead to inconsistencies in practice. The Liverpool Causality Assessment Tool (LCAT) offers a systematic approach. An interactive, web-based, e-learning package, the Liverpool ADR Causality Assessment e-learning Package (LACAeP), was designed to improve causality assessment using the LCAT. This study aimed to (1) get feedback on usability and usefulness on the LACAeP, identify areas for improvement and development, and generate data on effect size to inform a larger scale study; and (2) test the usability and usefulness of the LCAT. METHODS: A pilot, single-blind, parallel group, randomised controlled trial hosted by the University of Liverpool was undertaken. Participants were paediatric medical trainees at specialty training level 1+ within the Mersey and North-West England Deaneries. Participants were randomised (1 : 1) access to the LACAeP or no training. The primary efficacy outcome was score by correct classification, predefined by a multidisciplinary panel of experts. Following participation, feedback on both the LCAT and the LACAeP was obtained, via a built in survey, from participants. KEY FINDINGS: Of 57 randomised, 35 completed the study. Feedback was mainly positive although areas for improvement were identified. Seventy-four per cent of participants found the LCAT easy to use and 78% found the LACAeP training useful. Sixty-one per cent would be unlikely to recommend the training. Scores ranged from 4 to 13 out of 20. The LACAeP increased scores by 1.3, but this was not significant. CONCLUSIONS: Improving the LACAeP before testing it in an appropriately powered trial, informed by the differences observed, is required. Rigorous evaluation will enable a quality resource that will be of value in healthcare professional training. PMID- 26032627 TI - Glomerular Diseases Dependent on Complement Activation, Including Atypical Hemolytic Uremic Syndrome, Membranoproliferative Glomerulonephritis, and C3 Glomerulopathy: Core Curriculum 2015. PMID- 26032628 TI - Long-term Stability of Urinary Biomarkers of Acute Kidney Injury in Children. AB - BACKGROUND: Recent meta-analyses support the utility of urinary biomarkers for the diagnosis and prognosis of acute kidney injury. It is critical to establish optimal sample handling conditions for short-term processing and long-term urinary storage prior to widespread clinical deployment and meaningful use in prospective clinical trials. STUDY DESIGN: Prospective study. SETTING & PARTICIPANTS: 80 children (median age, 1.1 [IQR, 0.5-4.2] years) undergoing cardiac surgery with cardiopulmonary bypass at our center. 50% of patients had acute kidney injury (defined as >=50% increase in serum creatinine from baseline). PREDICTORS: We tested the effect on biomarker concentrations of short term urine storage in ambient, refrigerator, and freezer conditions. We also tested the effects of multiple freeze-thaw cycles, as well as prolonged storage for 5 years. OUTCOMES: Urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and interleukin 18 (IL-18). MEASUREMENTS: All biomarkers were measured using commercially available kits. RESULTS: All 3 biomarkers were stable in urine stored at 4 degrees C for 24 hours, but showed significant degradation (5.6%-10.1% from baseline) when stored at 25 degrees C. All 3 biomarkers showed only a small although significant decrease in concentration (0.77%-2.9% from baseline) after 3 freeze-thaw cycles. Similarly, all 3 biomarkers displayed only a small but significant decrease in concentration (0.84%-3.2%) after storage for 5 years. LIMITATIONS: Only the 3 most widely studied biomarkers were tested. Protease inhibitors were not evaluated. CONCLUSIONS: Short-term storage of urine samples for measurement of NGAL, KIM-1, and IL-18 may be performed at 4 degrees C for up to 24 hours, but not at room temperature. These urinary biomarkers are stable at -80 degrees C for up to 5 years of storage. Our results are reassuring for the deployment of these assays as biomarkers in clinical practice, as well as in prospective clinical studies requiring long-term urine storage. PMID- 26032629 TI - Health impacts from living near a major industrial park in Oman. AB - BACKGROUND: Oman is heading towards heavy industrialisation with rapid establishment of new industrial parks. One of these, the Sohar Industrial Zone (SIZ) started to operate in 2006 and includes many industries that potentially affect local air quality and the health status of its surrounding residents. The study aim was to assess the health effects in a population of >= 20 years old, living in the residential area around the SIZ. METHODS: Area-specific health care visits data for acute respiratory diseases (ARD), asthma, conjunctivitis and dermatitis were obtained for the period between January 1, 2006, and December 31, 2010. Exposure was defined as distance from the SIZ to determine high, intermediate, and control exposure zones (<= 5, > 5-10, and >= 20 km from the SIZ respectively). Generalized additive models were used to model age and gender adjusted monthly health events for the selected diseases, adjusted for age and gender-specific population smoking prevalence. The high and intermediate exposure zones were later combined in the models because of their similarity of effects. Exposure effect modification by age, gender and socio-economic status (SES) were examined. RESULTS: Living within the high and intermediate exposure zones was associated with a greater risk ratio for ARD (RR: 2.02; 95 % CI: 1.88-2.17), asthma (RR: 3.61; 95 % CI: 2.96-4.41), conjunctivitis (RR: 2.83; 95 % CI: 2.47 3.24), and dermatitis (RR: 2.11; 95 % CI: 1.86-2.39), compared to the control exposure zone. Greater exposure effects were observed amongst ages >= 50 years and lower SES groups. CONCLUSION: This is the first study carried out in Oman to assess the link between environmental exposure and health. These findings hope to contribute to building up evidence for environmental health and sustainable development policy in the country. PMID- 26032630 TI - Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion. AB - Perfluorooctane sulfonate (PFOS) is a fluorinated organic compound. This chemical is neurotoxic and can alter the pituitary secretion. This is an initial study aimed at knowing the toxic effects of high doses of PFOS on prolactin secretion and the possible mechanisms involved in these alterations. For that, adult male rats were orally treated with 3.0 and 6.0 mg of PFOS/kg body weight (b.w.)/day for 28 days. At the end of the treatment, the serum levels of prolactin and estradiol as well as the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were quantified in the anterior and in the mediobasal hypothalamus. PFOS, at the administered doses, reduced prolactin and estradiol secretion, increased the concentration of dopamine and GABA in the anterior hypothalamus, and decreased the ratios DOPAC/dopamine and HVA/dopamine in this same hypothalamic area. The outcomes reported in this study suggest that (1) high doses of PFOS inhibit prolactin secretion in adult male rats; (2) only the periventricular-hypophysial dopaminergic (PHDA) neurons seem to be involved in this inhibitory effect but not the tuberoinfundibular dopaminergic (TIDA) and the tuberohypophysial dopaminergic (THDA) systems; (3) GABAergic cells from the paraventricular and supraoptic nuclei could be partially responsible for the PFOS action on prolactin secretion; and finally (4) estradiol might take part in the inhibition exerted by elevated concentration of PFOS on prolactin release. PMID- 26032632 TI - Food safety assessment of an antifungal protein from Moringa oleifera seeds in an agricultural biotechnology perspective. AB - Mo-CBP3 is an antifungal protein produced by Moringa oleifera which has been investigated as potential candidate for developing transgenic crops. Before the use of novel proteins, food safety tests must be conducted. This work represents an early food safety assessment of Mo-CBP3, using the two-tiered approach proposed by ILSI. The history of safe use, mode of action and results for amino acid sequence homology using the full-length and short contiguous amino acids sequences indicate low risk associated to this protein. Mo-CBP3 isoforms presented a reasonable number of alignments (>35% identity) with allergens in a window of 80 amino acids. This protein was resistant to pepsin degradation up to 2 h, but it was susceptible to digestion using pancreatin. Many positive attributes were presented for Mo-CBP3. However, this protein showed high sequence homology with allergens and resistance to pepsin digestion that indicates that further hypothesis-based testing on its potential allergenicity must be done. Additionally, animal toxicity evaluations (e.g. acute and repeated dose oral exposure assays) must be performed to meet the mandatory requirements of several regulatory agencies. Finally, the approach adopted here exemplified the importance of performing an early risk assessment of candidate proteins for use in plant transformation programs. PMID- 26032631 TI - Genotoxicity study of silver nanoparticles in bone marrow cells of Sprague-Dawley rats. AB - The antimicrobial properties of silver nanoparticles (Ag-NPs) have resulted in their extensive application in consumer and health care products. Although Ag-NPs have great potential benefits, their side effects are unknown and seem inevitable due to their ability to reach the nucleus and damage genetic material. This study aimed to determine genotoxic potential of Ag-NPs using mitotic index (MI), DNA damage (comet assay), structural chromosome aberrations (SCA), micronuclei (MN) formation as genetic endpoints and induction of reactive oxygen species (ROS) as oxidative stress endpoint in bone marrow of Sprague-Dawley rats. Four groups of five male rats were orally administered Ag-NPs, once a day for five days with doses of 5, 25, 50, 100, mg/Kg. A control group was also made of five rats. Bone marrow samples were collected 24 h after the last treatment following standard protocols. Ag-NPs exposure significantly increased (p < 0.05) the induction of ROS, number of SCA, the frequency of micro-nucleated cells, damaged the DNA and decreased the mitotic index compared to negative control. The results suggest that Ag-NPs may have the potential to induce oxidative stress mediated genotoxicity in rats. Further characterization of their genotoxicity and also their potential health implications should be monitored regularly. PMID- 26032633 TI - Sesame allergy threshold dose distribution. AB - BACKGROUND: Sesame is a relevant food allergen in France. Compared to other allergens there is a lack of food challenge data and more data could help sesame allergy risk management. The aim of this study is to collect more sesame challenge data and investigate the most efficient food challenge method for future studies. METHOD: Records of patients at University Hospital in Nancy (France) with objective symptoms to sesame challenges were collected and combined with previously published data. An estimation of the sesame allergy population threshold was calculated based on individual NOAELs and LOAELs. Clinical dosing schemes at Nancy were investigated to see if the optimal protocol for sesame is currently used. RESULTS: Fourteen patients (10 M/4 F, 22 +/- 14.85 years old) with objective symptoms were added to previously published data making a total of 35 sesame allergic patients. The most sensitive patient reacted to the first dose at challenge of 1.02 mg sesame protein. The ED05 ranges between 1.2 and 4.0 mg of sesame protein (Log-Normal, Log-Logistic, and Weibull models) and the ED10 between 4.2 and 6.2 mg. The optimal food challenge dosing scheme for sesame follows semi-log dose increases from 0.3 to 3000 mg protein. CONCLUSION: This article provides a valuable update to the existing clinical literature regarding sesame NOAELs and LOAELs. Establishment of a population threshold for sesame could help in increasing the credibility of precautionary labelling and decrease the costs associated with unexpected allergic reactions. Also, the use of an optimal dosing scheme would decrease time spent on diagnostic and thereafter on the economic burden of sesame allergy diagnosis. PMID- 26032634 TI - Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism. AB - BACKGROUND: Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice. METHODS: In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. RESULTS: Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFalpha and IL1beta followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin. CONCLUSION: Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice. PMID- 26032635 TI - Fractional CO2 laser assisted delivery of topical anesthetics: A randomized controlled pilot study. AB - BACKGROUND AND OBJECTIVES: Many dermatological procedures are performed under local anesthesia. Topical anesthesia requires prolonged occlusion and is often insufficient. Infiltration anesthesia is associated with discomfort. Pretreatment with an ablative fractional laser (AFXL) may enhance penetration of topical drugs, including lidocaine. Primary aim of this study was to assess whether AFXL pretreatment enhances the efficacy of two regularly used anesthetics: (i) articain hydrochloride 40 mg/ml + epinephrine 10 MUg/ml solution (AHES); (ii) lidocaine 25 mg/g + prilocaine 25 mg/g cream (EMLA cream). Secondary aim was to assess which anesthetic is superior on AFXL pretreated skin. MATERIALS AND METHODS: In 10 healthy subjects, four 1 cm(2) test regions on the back were randomized to [A] AFXL pretreatment (fractional CO2 laser, 5% density, 2.5 mJ/microbeam) + topical application of AHES, [B] AFXL pretreatment + EMLA cream, [C] sham AFXL + AHES, and [D] sham AFXL + EMLA cream. After ten minutes, an AFXL pass (35 mJ/microbeam) was given as pain stimulus at each test region. Pain was scored on a 0-10 visual analogue scale (VAS) after each stimulus. RESULTS: AFXL pretreatment was not considered painful. Median VAS scores for the pain stimulus were [A] 2.35, [B] 3.15, [C] 4.55, and [D] 4.35. VAS scores were significantly lower for region [A] (AFXL + AHES) versus region [B] (AFXL + EMLA; P < 0.01) and versus region [C] (sham AFXL + AHES; P < 0.01). VAS scores were not significantly different for region [B] (AFXL + EMLA) versus region [D] (sham AFXL + EMLA, P = 0.15). CONCLUSION: AFXL pretreatment at very low settings gives significant pain reduction already within ten minutes when AHES is used as topical anesthetic. AHES is clearly superior to EMLA cream on AFXL pretreated skin. Possibly, a liquid solution penetrates more easily into the AFXL channels than a cream. Further research should determine the clinical efficacy of laser assisted topical anesthesia and the exact role of the type of anesthetic, its vehicle and the laser settings. PMID- 26032636 TI - Why 'spiritism'? AB - Some of the early representatives of psychoanalysis had a lifelong interest in certain 'occult' phenomena. Although several theories were born for the purpose of understanding the interest of Sigmund Freud, Carl Gustav Jung or Sandor Ferenczi in spiritualism and related phenomena, interpreters usually ignore the changing cultural meaning and significance of modern occult practices like spiritualism. The aim of the present essay is to outline the cultural and historical aspects of spiritualism and spiritism in Hungary, and thus to shed new light on the involvement of Ferenczi - and other Hungarian psychoanalysts like Geza Roheim, Istvan Hollos, and Mihaly Balint - in spiritualism and spiritism. The connections between spiritualism and the Budapest School of Psychoanalysis will be discussed, highlighting the cultural and scientific significance of Hungarian spiritualism and spiritism in the evolution of psychoanalysis. Taking into account the relative lack of the scientific research in the field of spiritism in Hungary, it can be pointed out that Ferenczi undertook a pioneering role in Hungarian psychical research. PMID- 26032637 TI - Participation in recreation and cognitive activities as a predictor of cognitive performance of adults with/without Down syndrome. AB - OBJECTIVE: The Cognitive Activity Theory suggests an association between participation in cognitive activities during midlife and cognitive functioning in the short term. We examined the impact of participation in cognitively stimulating activities conveyed during leisure activities on crystallized and fluid tests' performance among adults with intellectual disabilities (ID). METHOD: Adults (n = 32; chronological age = 25-55) with non-specific ID and with Down syndrome rated the frequency of their participation in leisure activities. Pursuits included more cognitively involving (reading, participating in academic courses) and less cognitively involving (cooking, dancing) activities. Three judges ranked activities according to their cognitive load on a 1 (few cognitive components) to 5 (many cognitive components) points scale. The findings indicate two new scales: cognitively stimulating activities and recreational stimulating activities. The crystallized battery included phonemic fluency, synonyms, idioms, and verbal metaphors. The fluid battery included the Homophone Meaning Generation Test, Metaphoric Triad Test, Novel Metaphors Test, and Trail Making Test. RESULTS: Hierarchal regression with chronological and mental age, recreational, and cognitively stimulating activities indicated that participation in recreational activities contributed significantly to the explained variance of word fluency. Participation in cognitive activities contributed significantly to the explained variance of most of the crystallized and fluid tests. CONCLUSIONS: The findings support the Cognitive Activity Theory in populations with ID. The findings also support the Compensation Age Theory: not only endogenous factors (age, etiology, IQ level), but also exogenous factors such as life style determining the cognitive functioning of adults with ID. However, frequency and the cognitive load of the activities influenced their cognitive functioning. PMID- 26032639 TI - Nicotinic modulation of auditory evoked potential electroencephalography in a rodent neurodevelopmental model of schizophrenia. AB - Schizophrenia is a chronic disease that has been hypothesized to be linked to neurodevelopmental abnormalities. Schizophrenia patients exhibit impairments in basic sensory processing including sensory gating deficits in P50 and mismatch negativity (MMN). Neuronal nicotinic acetylcholine receptor (nAChR) agonists have been reported to attenuate these deficits. Gestational exposure of rats to methylazoxymethanol acetate (MAM) at embryonic day 17 leads to developmental disruption of the limbic-cortical system. MAM exposed offspring show neuropathological and behavioral changes that have similarities with those seen in schizophrenia. In this study, we aimed to assess whether N40 auditory sensory gating (the rodent form of P50 gating) and MMN deficits as measures of auditory evoked potential (AEP) electroencephalography (EEG) are present in MAM rats and whether nAChR agonists could attend the deficit. E17 male MAM and sham rats were implanted with cortical electrodes at 2 months of age. EEG recordings evaluating N40 gating and MMN paradigms were done comparing effects of vehicle (saline), nicotine and the alpha7 agonist ABT-107. Deficits were seen for MAM rats compared to sham animals in both N40 auditory sensory gating and MMN AEP recordings. There was a strong trend for N40 deficits to be attenuated by both nicotine (0.16mg/kg i.p. base) and ABT-107 (1.0mg/kg i.p. base). MMN deficits were significantly attenuated by ABT-107 but not by nicotine. These data support the MAM model as a useful tool for translating pharmacodynamic effects in clinical medicine studies of novel therapeutic treatments for schizophrenia. PMID- 26032638 TI - Biosynthesis and actions of 5-oxoeicosatetraenoic acid (5-oxo-ETE) on feline granulocytes. AB - The 5-lipoxygenase product 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is the most powerful human eosinophil chemoattractant among lipid mediators and could play a major pathophysiological role in eosinophilic diseases such as asthma. Its actions are mediated by the OXE receptor, orthologs of which are found in many species from humans to fish, but not rodents. The unavailability of rodent models to examine the pathophysiological roles of 5-oxo-ETE and the OXE receptor has substantially hampered progress in this area. As an alternative, we have explored the possibility that the cat could serve as an appropriate animal model to investigate the role of 5-oxo-ETE. We found that feline peripheral blood leukocytes synthesize 5-oxo-ETE and that physiologically relevant levels of 5-oxo ETE are present in bronchoalveolar lavage fluid from cats with experimentally induced asthma. 5-Oxo-ETE (EC50, 0.7nM) is a much more potent activator of actin polymerization in feline eosinophils than various other eicosanoids, including leukotriene (LT) B4 and prostaglandin D2. 5-Oxo-ETE and LTB4 induce feline leukocyte migration to similar extents at low concentrations (1nM), but at higher concentrations the response to 5-oxo-ETE is much greater. Although high concentrations of selective human OXE receptor antagonists blocked 5-oxo-ETE induced actin polymerization in feline granulocytes, their potencies were about 200 times lower than for human granulocytes. We conclude that feline leukocytes synthesize and respond to 5-oxo-ETE, which could potentially play an important role in feline asthma, a common condition in this species. The cat could serve as a useful animal model to investigate the pathophysiological role of 5-oxo-ETE. PMID- 26032640 TI - Interspecies differences in the metabolism of methotrexate: An insight into the active site differences between human and rabbit aldehyde oxidase. AB - Several drug compounds have failed in clinical trials due to extensive biotransformation by aldehyde oxidase (AOX) (EC 1.2.3.1). One of the main reasons is the difficulty in scaling clearance for drugs metabolised by AOX, from preclinical species to human. Using methotrexate as a probe substrate, we evaluated AOX metabolism in liver cytosol from human and commonly used laboratory species namely guinea pig, monkey, rat and rabbit. We found that the metabolism of methotrexate in rabbit liver cytosol was several orders of magnitude higher than any of the other species tested. The results of protein quantitation revealed that the amount of AOX1 in human liver was similar to rabbit liver. To understand if the observed differences in activity were due to structural differences, we modelled rabbit AOX1 using the previously generated human AOX1 homology model. Molecular docking of methotrexate into the active site of the enzyme led to the identification of important residues that could potentially be involved in substrate binding and account for the observed differences. In order to study the impact of these residue changes on enzyme activity, we used site directed mutagenesis to construct mutant AOX1 cDNAs by substituting nucleotides of human AOX1 with relevant ones of rabbit AOX1. AOX1 mutant proteins were expressed in Escherichia coli. Differences in the kinetic properties of these mutants have been presented in this study. PMID- 26032641 TI - Re: Double-Layered Closure of Chronic Oroantral Fistulas Using a Palatal Rotational Flap and Suturing of the Sinus Membrane Perforation: Is It a Successful Technique? PMID- 26032642 TI - Reply: To PMID 25498338. PMID- 26032643 TI - Can Preoperative Psychological Assessment Predict Outcomes After Temporomandibular Joint Arthroscopy? AB - PURPOSE: Psychological assessment has been used successfully to predict patient outcomes after cardiothoracic and bariatric surgery. The purpose of this study was to determine whether preoperative psychological assessment could be used to predict patient outcomes after temporomandibular joint arthroscopy. MATERIALS AND METHODS: Consecutive patients with temporomandibular dysfunction (TMD) who could benefit from arthroscopy were enrolled in a prospective cohort study. All patients completed the Millon Behavior Medicine Diagnostic survey before surgery. The primary predictor variable was the preoperative psychological scores. The primary outcome variable was the difference in pain between the pre- and postoperative periods. The Spearman rank correlation coefficient and the Pearson product-moment correlation were used to determine the association between psychological factors and change in pain. Univariable and multivariable analyses were performed using a mixed-effects linear model and multiple linear regression. A P value of .05 was considered significant. RESULTS: Eighty-six patients were enrolled in the study. Seventy-five patients completed the study and were included in the final analyses. The mean change in visual analog scale (VAS) pain score 1 month after arthroscopy was -15.4 points (95% confidence interval, -6.0 to -24.7; P < .001). Jaw function also improved after surgery (P < .001). No association between change in VAS pain score and each of the 5 preoperative psychological factors was identified with univariable correlation analyses. Multivariable analyses identified that a greater pain decrease was associated with a longer duration of preoperative symptoms (P = .054) and lower chronic anxiety (P = .064). CONCLUSIONS: This study has identified a weak association between chronic anxiety and the magnitude of pain decrease after arthroscopy for TMD. Further studies are needed to clarify the role of chronic anxiety in the outcome after surgical procedures for the treatment of TMD. PMID- 26032644 TI - Association Between Glycosylated Hemoglobin and Cardiovascular Events and Mortality in Older Adults without Diabetes Mellitus in the General Population: The Leiden 85-Plus Study. AB - OBJECTIVES: To examine the association between glycosylated hemoglobin (HbA1c) and incident cardiovascular disease and mortality in 85-year-old individuals without diabetes mellitus from the general population. DESIGN: Population-based prospective follow-up study. SETTING: General population. PARTICIPANTS: Individuals without known diabetes mellitus (N = 445, n = 291 female). MEASUREMENTS: HbA1c levels were categorized into three groups (<5.0% (31 mmol/mol), 5.0-5.7% (31-39 mmol/mol; reference), 5.7-6.5% (39-48 mmol/mol)). RESULTS: At baseline, a history of myocardial infarction (MI) was more prevalent in subjects in the highest HbA1c group (18%) than in the reference group (7%) (P = .001). Prospectively, those with the highest level of HbA1c at baseline had a risk of incident MI during the 5-year follow-up that was 3.6 (95% confidence interval = 1.5-8.3) times as great as that of the reference group. No association was found between HbA1c level and incident stroke, cardiovascular mortality, or all-cause mortality. CONCLUSION: In individuals aged 85 and older without diabetes mellitus, higher HbA1c is associated with greater risk of MI but not with stroke and mortality. PMID- 26032645 TI - EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles. AB - The EsxB protein from Bacillus anthracis belongs to the WXG100 family, a group of proteins secreted by a specialized secretion system. We have determined the crystal structures of recombinant EsxB and discovered that the small protein (~10 kDa), comprised of a helix-loop-helix (HLH) hairpin, is capable of associating into two different helical bundles. The two basic quaternary assemblies of EsxB are an antiparallel (AP) dimer and a rarely observed bisecting U (BU) dimer. This structural duality of EsxB is believed to originate from the heptad repeat sequence diversity of the first helix of its HLH hairpin, which allows for two alternative helix packing. The flexibility of EsxB and the ability to form alternative helical bundles underscore the possibility that this protein can serve as an adaptor in secretion and can form hetero-oligomeric helix bundle(s) with other secreted members of the WXG100 family, such as EsxW. The highly conserved WXG motif is located within the loop of the HLH hairpin and is mostly buried within the helix bundle suggesting that its role is mainly structural. The exact functions of the motif, including a proposed role as a secretion signal, remain unknown. PMID- 26032646 TI - Erythrophagocytosis of myeloblasts in acute myeloid leukaemia exhibiting chromosome 8p abnormality and extramedullary disease. PMID- 26032647 TI - Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation. AB - BACKGROUND: Current approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk. METHODS: Based on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC. RESULTS: The HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist. CONCLUSIONS: This approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor beta activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases. PMID- 26032648 TI - Validation of chronic kidney disease risk categorization system in Chinese patients with kidney disease: A cohort study. AB - AIM: To validate the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines risk stratification system based on the combination of estimated glomerular filtration rate (eGFR) and proteinuria. METHODS: This was a cohort study. A total of 1219 study population were recruited. Estimated GFR and proteinuria measured by using 24 h urine protein excretion rate (PER) were predictors. Adverse outcomes included all-cause mortality (ACM) and end-stage renal disease (ESRD). Follow-up was done by regular visit, telephone interview and electronic medical records. RESULTS: Over a median follow-up of 4.6 years, 153 (12.6%) and 43 (3.5%) patients experienced ESRD and ACM, respectively. On multivariable analysis, the adjusted hazard ratio for ESRD and ACM (compared with patients with eGFR > 60 mL/min per 1.7 m2) was of 29.8 and 3.6 for those with eGFR of 15-29 mL/min per 1.73 m2, respectively. The adjusted hazard ratio for ESRD and ACM (compared with patients with PER < 150 mg/24h) was of 15.9 and 3.9 for those with PER > 500 mg/24h. Higher KDIGO guidelines risk categories (indicating lower eGFR or higher proteinuria) were associated with a graded increase in the risk for the ESRD (P < 0.001) and ACM (P < 0.001). Reclassification of KDIGO guidelines risk categories yielded net reclassification improvements for those with ESRD or ACM event (NRIevents ) of 33.3% or 30.2%. CONCLUSION: Lower eGFR and higher proteinuria are risk factors for ESRD and ACM in Chinese patients. The KDIGO guidelines risk categorization system assigned patients who went on to have the event to more appropriate CKD risk categories. PMID- 26032649 TI - Tenofovir: What We Have Learnt After 7.5 Million Person-Years of Use. AB - Tenofovir was licensed for use in patients with HIV in 2001 and since then has become a firmly established anti-retroviral in both guidelines and routine practice. Data have been presented from many pivotal studies-informing on its efficacy, use, and adverse features-and there are also over 7.5 million patient years of experience to date. We explore the data on this nucleotide reverse transcriptase inhibitor in HIV presented since 2008-focusing on efficacy, side effects, and utility. PMID- 26032651 TI - Colorectal malignant adenoma: do all high-risk lesions need surgery? PMID- 26032650 TI - Performance of biopsy factors in predicting unfavorable disease in patients eligible for active surveillance according to the PRIAS criteria. AB - BACKGROUND: To assess the added value of biopsy factors, like maximum cancer length in a core (MCL), cumulative cancer length (CCL), cumulative length of positive cores (CLPC), percentage of cancer involvement in positive cores (CIPC) and the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria in patients who underwent radical prostatectomy (RP) but eligible for active surveillance (AS). METHODS: From January 2002 to December 2007, 750 consecutive subjects underwent RP. We identified 147 (19.07%) patients who were eligible for AS based on PRIAS criteria: clinical stage T1c or T2, PSA level of ? 10 ng ml(-1), Gleason score ? 6, PSA-D of <0.2 ng ml(-2) and one or two positive biopsy cores. We calculated the diagnostic accuracy of biopsy factors in determining pathological confirmed unfavorable disease. Decision curve analysis (DCA) were performed. RESULTS: Of all subjects, 95 patients (66.43%) had favorable whereas 48 had (33.57%) unfavorable disease. On multivariate analyses, the inclusion of MCL, CCL, CLPC and CIPC significantly increased the accuracy of the base multivariate model in predicting unfavorable disease. The gain in predictive accuracy for MCL in a core, CCL, CLPC and CIPC ranged from 13 to 27%. The DCA shows that adding MCL, CCL, CLPC and CIPC resulted in a greater net benefit when the probability of ranges between 15 and 50%. The models can be applied at the cost of missing not more than 16.83% of unfavorable disease. CONCLUSIONS: Our findings suggested that the addition of these biopsy factors to PRIAS criteria has the potential to significantly increase the ability to detect unfavorable disease. PMID- 26032652 TI - Analysis of dispersal effects in metapopulation models. AB - The interplay between local dynamics and dispersal rates in discrete metapopulation models for homogeneous landscapes is studied. We introduce an approach based on scalar dynamics to study global attraction of equilibria and periodic orbits. This approach applies for any number of patches, dispersal rates, or landscape structure. The existence of chaos in metapopulation models is also discussed. We analyze issues such as sensitive dependence on the initial conditions or short/intermediate/long term behaviours of chaotic orbits. PMID- 26032653 TI - Persistence versus extinction for a class of discrete-time structured population models. AB - We provide sharp conditions distinguishing persistence and extinction for a class of discrete-time dynamical systems on the positive cone of an ordered Banach space generated by a map which is the sum of a positive linear contraction A and a nonlinear perturbation G that is compact and differentiable at zero in the direction of the cone. Such maps arise as year-to-year projections of population age, stage, or size-structure distributions in population biology where typically A has to do with survival and individual development and G captures the effects of reproduction. The threshold distinguishing persistence and extinction is the principal eigenvalue of (II-A)(-1)G'(0) provided by the Krein-Rutman Theorem, and persistence is described in terms of associated eigenfunctionals. Our results significantly extend earlier persistence results of the last two authors which required more restrictive conditions on G. They are illustrated by application of the results to a plant model with a seed bank. PMID- 26032654 TI - Asymptomatic chronic gastritis decreases metformin tolerance in patients with type 2 diabetes. AB - WHAT IS KNOWN AND OBJECTIVE: Digestive disorders represent the most common metformin side effects for type 2 diabetes. The mechanism of these metformin side effects is unclear. The aim of this study was to assess whether asymptomatic chronic gastritis could influence metformin tolerance in patients with type 2 diabetes. METHODS: Demographic, anthropometric, ultrasound and laboratory data were obtained from 144 metformin naive patients with diabetes. The diagnosis of chronic gastritis was based on endoscopic and histopathological examination, and H. pylori infection was assessed based on (13) C urea breath test (UBT). All subjects started metformin at 500 mg/day and increasing progressively to 1500 mg/day over 4 weeks. A score of gastrointestinal side effects (abdominal pain, diarrhoea, nausea, vomiting, bloating and anorexia) was assessed each week, and metformin dose was adjusted as appropriate. RESULTS AND DISCUSSION: Based on endoscopy, 64 patients were categorized as non-gastritis subjects and 80 as chronic gastritis subjects. At baseline, there is no statistical difference in gastrointestinal symptoms between two groups. With metformin, the mean scores for gastrointestinal symptoms in the non-gastritis and gastritis subjects were 1.02 +/- 1.71 vs. 2.18 +/- 2.05 (P = 0.001), 0.20 +/- 0.65 vs. 0.50 +/- 0.89 (P = 0.022), 0 vs. 0.06 +/- 0.24 (P = 0.024) and 1.08 +/- 1.03 vs. 1.71 +/- 1.66 (P = 0.028). The mean final metformin dose used by gastritis subjects was 706.24 +/- 568.90 mg, significantly less than the mean dose used by non-gastritis subjects (1101.56 +/- 578.58 mg, P = 0.001). After adjustment for age and sex, the odds ratio (OR) for a final metformin dose of less than 1500 mg/day was found to be 2.76 (95% CI 1.38-5.53, P = 0.004) for chronic gastritis subjects. The OR for a final metformin dose of less than 1000 mg/day was found to be 3.98 (95% CI 1.91 8.27, P = 0.001) for chronic gastritis subjects. WHAT IS NEW AND CONCLUSIONS: Our data suggest that pre-existing non-symptomatic gastritis was associated with metformin-related gastrointestinal side effects. PMID- 26032655 TI - Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study. AB - OBJECTIVE: To evaluate whether liraglutide or roflumilast significantly affects body weight when compared to metformin in obese women with PCOS. DESIGN/MAIN OUTCOME MEASURE: A 12-week prospective randomized open-label study was conducted with 45 obese women with PCOS diagnosed by the ASRM-ESHRE Rotterdam criteria. They were randomized to metformin (MET) 1000 mg BID or liraglutide (LIRA) 1.2 mg QD s.c. or roflumilast (ROF) 500 mcg QD. The primary outcome was change in measures of obesity. RESULTS: Forty-one patients (aged 30.7 +/- 7.9 years, BMI 38.6 +/- 6.0 kg/m2, mean +/- SD) completed the study. Subjects treated with LIRA lost on average 3.1 +/- 3.5 kg (p = 0.006), on ROF 2.1 +/- 2.0 kg (p = 0.002) vs. 0.2 +/- 1.83 kg in MET group. BMI decreased for 1.1 +/- 1.26 kg/m2 in LIRA (p = 0.006), for 0.8 +/- 0.99 kg/m2 in ROF (p = 0.001) vs. 0.1 +/- 0.67 kg/m2 in MET. LIRA was superior to MET in reducing weight (p = 0.022), BMI (p = 0.020), waist circumference (p = 0.007). LIRA also resulted in decrease in VAT area (p = 0.015) and more favorable dynamics in glucose homeostasis during OGTT. ROF resulted in reduction of waist circumference (p = 0.023). In addition, ROF led to testosterone reduction (p = 0.05) and increase in menstrual frequencies (p = 0.009) when compared to baseline. CONCLUSION: Short-term monotherapy with liraglutide or roflumilast was associated with significant weight loss in obese PCOS. Liraglutide was superior to metformin, whereas roflumilast resulted in greater, yet not statistically significant, mean weight loss when compared to metformin. Reduction of body weight with liraglutide resulted in improvement of body composition. TRIAL REGISTRATION: ClinicalTrials.gov NCT02187250 . PMID- 26032656 TI - Evaluation of heart involvement in calpainopathy (LGMD2A) using cardiovascular magnetic resonance. AB - INTRODUCTION: Cardiac dysfunction occurs in several forms of limb girdle muscular dystrophy (LGMD). The aim of this study was to investigate cardiac involvement in calpainopathy (LGMD2A). METHODS: Cardiovascular evaluation was performed in 10 patients with genetically verified LGMD2A by echocardiography, 3 Tesla - cardiovascular magnetic resonance, 24-h electrocardiography recordings with heart rate variability (HRV) analysis, and 24-h blood pressure recordings. RESULTS: No patient with calpainopathy showed impairment of left or right ventricular function. One patient had a small amount (2% of left ventricle mass) of late gadolinium enhancement. HRV analysis revealed no significant difference compared with external reference data. CONCLUSIONS: The main finding of this study is the lack of cardiac involvement in patients with calpainopathy. Cardiac involvement was not found, even in individuals with advanced age and greater disease severity. Furthermore, we did not observe an overall reduction of cardiac autonomic regulation in calpainopathy. PMID- 26032657 TI - Patient-reported outcome measures versus inertial performance-based outcome measures: A prospective study in patients undergoing primary total knee arthroplasty. AB - BACKGROUND: Outcome assessment of total knee arthroplasty (TKA) by subjective patient reported outcome measures (PROMs) may not fully capture the functional (dis-)abilities of relevance. Objective performance-based outcome measures could provide distinct information. An ambulant inertial measurement unit (IMU) allows kinematic assessment of physical performance and could potentially be used for routine follow-up. AIM: To investigate the responsiveness of IMU measures in patients following TKA and compare outcomes with conventional PROMs. METHODS: Patients with end stage knee OA (n=20, m/f=7/13; age=67.4 standard deviation 7.7 years) were measured preoperatively and one year postoperatively. IMU measures were derived during gait, sit-stand transfers and block step-up transfers. PROMs were assessed by using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Society Score (KSS). Responsiveness was calculated by the effect size, correlations were calculated with Spearman's rho correlation coefficient. RESULTS: One year after TKA, patients performed significantly better at gait, sit-to-stand transfers and block step-up transfers. Measures of time and kinematic IMU measures demonstrated significant improvements postoperatively for each performance-based test. The largest improvement was found in block step-up transfers (effect size=0.56-1.20). WOMAC function score and KSS function score demonstrated moderate correlations (Spearman's rho=0.45 0.74) with some of the physical performance-based measures pre- and postoperatively. CONCLUSION: To characterize the changes in physical function after TKA, PROMs could be supplemented by performance-based measures, assessing function during different activities and allowing kinematic characterization with an ambulant IMU. PMID- 26032658 TI - Stemmed femoral implants show lower failure rates in revision total knee arthroplasty. AB - BACKGROUND: Stemmed femoral implants are not universally used in revision total knee arthroplasty. The aim of this study was to evaluate whether the re-revision rate would be greater for revision total knees performed without stemmed femoral implants compared with revision total knees performed with stemmed femoral implants. METHODS: All revision cases performed at a single institution between 2004 and 2011 were retrospectively reviewed. A total of 130 revision total knee arthroplasty procedures (63 Group 1; 67 Group 2) met the inclusion criteria. RESULTS: Revisions performed without femoral stems failed more often than revisions with femoral stems (44% vs 9%, p<0.001) despite more severe pre operative bone loss in groups that were revised with stems (p<0.05). CONCLUSIONS: We recommend that femoral stems be used routinely in procedures where a femoral implant is revised following a prior total knee arthroplasty. PMID- 26032659 TI - Efficient Hole Extraction from a Hole-Storage-Layer-Stabilized Tantalum Nitride Photoanode for Solar Water Splitting. AB - One of the major hurdles that impedes the practical application of photoelectrochemical (PEC) water splitting is the lack of stable photoanodes with low onset potentials. Here, we report that the Ni(OH)x/MoO3 bilayer, acting as a hole-storage layer (HSL), efficiently harvests and stores holes from Ta3N5, resulting in at least 24 h of sustained water oxidation at the otherwise unstable Ta3N5 electrode and inducing a large cathodic shift of ~600 mV in the onset potential of the Ta3N5 electrode. PMID- 26032660 TI - Carbon monoxide poisoning deaths in the United States, 1999 to 2012. AB - BACKGROUND: Unintentional, non-fire related (UNFR) carbon monoxide (CO) poisoning deaths are preventable. Surveillance of the populations most at-risk for unintentional, non-fire related (UNFR) carbon monoxide (CO) poisoning is crucial for targeting prevention efforts. OBJECTIVE: This study provides estimates on UNFR CO poisoning mortality in the United States and characterizes the at-risk populations. METHODS: We used 1999 to 2012 data to calculate death rates. We used underlying and multiple conditions variables from death records to identify UNFR CO poisoning cases. RESULTS: For this study, we identified 6136 CO poisoning fatalities during 1999 to 2012 resulting in an average of 438 deaths annually. The annual average age-adjusted death rate was 1.48 deaths per million. Fifty four percent of the deaths occurred in a home. Age-adjusted death rates were highest for males (2.21 deaths per million) and non-Hispanic blacks (1.74 deaths per million). The age-specific death rate was highest for those aged >=85 years (6.00 deaths per million). The annual rate of UNFR CO poisoning deaths did not change substantially during the study period, but we observed a decrease in the rate of suicide and unintentional fire related cases. CONCLUSION: CO poisoning was the second most common non-medicinal poisonings death. Developing and enhancing current public health interventions could reduce ongoing exposures to CO from common sources, such as those in the residential setting. PMID- 26032661 TI - Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest. AB - INTRODUCTION: Hypoxic hepatitis (HH) is commonly observed in out-of-hospital cardiac arrest (OHCA) survivors. The objective of this study was to investigate the incidence, clinical courses, and outcomes of as well as predisposing factors for HH in OHCA survivors. METHODS: The study was based on a registry of cardiac arrest cases from 2009 to 2012 at a tertiary university hospital. We assessed patients' serum aminotransferase levels on return of spontaneous circulation (ROSC) and at 6, 12, 24, 48, and 72 hours postarrest. Hypoxic hepatitis was defined as a rapid increase in serum aminotransferase that reached at least 20 times the upper limit of normal. The patients were classified into 2 groups: the HH group and the non-HH group; we then analyzed the outcomes of the HH group. Independent predisposing factors to HH in this cohort were identified. RESULTS: Of a total of 535 OHCA cases, 148 patients were enrolled in this study. Hypoxic hepatitis was identified in 13.5% (n = 20) of them. Serum aminotransferase rapidly increased in the first day after return of spontaneous circulation. Of the patients who developed HH, 5 (25%) survived to hospital discharge, and none of these individuals had good neurologic outcomes (Glasgow-Pittsburgh cerebral performance categories 1 and 2). Using multivariate logistic regression, we found that the no flow time was independent predictors of HH (odds ratio, 1.085 [95% confidence interval, 1.027-1.146]; P = .003). CONCLUSIONS: Hypoxic hepatitis occurred frequently in survivors of OHCA. The no flow time was an independent risk factor for HH, which was significantly related to death and poor neurologic outcomes. PMID- 26032662 TI - Analysis of risk classification for massive transfusion in severe trauma using the gray zone approach. AB - BACKGROUND: The Traumatic Bleeding Severity Score (TBSS) was developed to predict the need for massive transfusion (MT). The aim of this study is evaluation of clinical thresholds for activation of a MT protocol using the gray zone approach based on TBSS. METHODS: This is a single-center retrospective study of trauma patients, admitted from 2010 to 2013. The TBSS on admission was calculated, and the accuracy of predicting MT was analyzed using area under the receiver operating characteristic curve. Risk classification for MT was made using sensitivity/specificity. The gray zone (indeterminate risk) was defined from a sensitivity of 95% to a specificity of 95%, patients were separated into MT and non-MT groups, and their clinical characteristics were compared. RESULTS: A total of 264 patients were enrolled, with an area under the TBSS curve of 0.967 (95% confidence interval, 0.94-0.99). A TBSS of 10 points or less resulted in a sensitivity of 96.5% with 146 patients in this group, and 3.4% (5/146) of them received MT. A TBSS of 17 points or higher had a specificity of 97.8%, which included 72 patients, and 94.4% (68/72) of them received MT. Forty-six patients had a TBSS from 11 to 16 points (gray zone), and 26.1% (12/46) of them received MT. Comparing the MT group (12/46) and non-MT group (34/46), coagulopathy and extravasation on computed tomographic scan were more prevalent in the MT group. CONCLUSION: The TBSS is highly accurate in predicting the need for MT, and a risk classification for needing MT was created based on TBSS. PMID- 26032663 TI - Retrograde non trans-septal balloon mitral valvotomy in mitral stenosis with interrupted inferior vena cava, left superior vena cava, and hugely dilated coronary sinus. AB - A 22-year-old woman with severe mitral stenosis was referred to us for further evaluation and management. She was found to have severe mitral stenosis, severe tricuspid regurgitation with dilated right atrium and right ventricle with persistent left superior vena cava and hugely dilated coronary sinus. Valve was suitable for balloon mitral valvotomy. Cardiac catheterization showed interrupted inferior vena cava with azygos continuation to right atrium and large left superior vena cava draining to coronary sinus which was very much dilated. Right trans-jugular approach was tried for balloon mitral valvotomy, but was unsuccessful due to a very large right atrium and coronary sinus. Retrograde non trans-septal approach was used and balloon valvotomy was done successfully using a 24 mm * 40 mm TYSHAK balloon without any major complication. Reduction in the transmitral pressure gradient on cardiac catheterization data and transthoracic echocardiography confirmed successful procedure. Balloon mitral valvotomy can be done successfully in patients with the above unusual cardiac anatomy with no major procedural complications. PMID- 26032664 TI - Maternal and zygotic transcriptomes in the appendicularian, Oikopleura dioica: novel protein-encoding genes, intra-species sequence variations, and trans spliced RNA leader. AB - RNA sequencing analysis was carried out to characterize egg and larval transcriptomes in the appendicularian, Oikopleura dioica, a planktonic chordate, which is characterized by rapid development and short life cycle of 5 days, using a Japanese population of the organism. De novo transcriptome assembly matched with 16,423 proteins corresponding to 95.4% of the protein-encoding genes deposited in the OikoBase, the genome database of the Norwegian population. Nucleotide and amino acid sequence identities between the Japanese and Norwegian O. dioica were estimated to be around 91.0 and 94.8%, respectively. We discovered 175 novel protein-encoding genes: 144 unigenes were common to both the Japanese and Norwegian populations, whereas 31 unigenes were not found in the OikoBase genome reference. Among the total 12,311 unigenes, approximately 63% were detected in egg-stage RNAs, whereas 99% were detected in larval stage RNAs; 3772 genes were up-regulated, and 1336 genes were down-regulated more than four-fold in the larvae. Gene ontology analyses characterized gene activities in these two developmental stages. We found a messenger RNA (mRNA) 5' trans-spliced leader, which was observed in 40.8% of the total unique transcripts. It showed preferential linkage to adenine at the 5' ends of the downstream exons. Trans splicing was observed more frequently in egg mRNAs compared with larva-specific mRNAs. PMID- 26032665 TI - The mental health of children of migrant workers in Beijing: the protective role of public school attendance. AB - The present study aims to understand the mental health status of an understudied group of migrant children - children of migrant workers in China. A total of 1,466 children from Beijing participated in the study that compared migrant children (n = 1,019) to their local peers (n = 447) in public and private school settings. Results showed that overall, migrant children reported more internalizing and externalizing mental health problems and lower life satisfaction than local peers. However, public school attendance served as a protective factor for migrant children's mental health. The mental health status of migrant children attending public schools, including externalizing problems as well as friend and school satisfaction, was not different from local children. In addition, our data indicates that the protective effect of public school attendance for migrant children may be even more salient among girls than boys, and for younger children than older children. PMID- 26032666 TI - Do we need another discipline in medicine? From epidemiology and evidence-based medicine to cognitive medicine and medical thinking. PMID- 26032667 TI - Investigating Possible Effects of Ethnicity and Age on Gambling as an Escape. AB - Previous research has shown that there are a number of risk factors for disordered and problem gambling, including an individual's ethnicity and age. Endorsing gambling as an escape has also been shown to contribute to and maintain disordered gambling. The present study examined potential interactions between ethnicity and age as they relate to disordered gambling, as well as if ethnicity and age would be predictors of endorsing gambling as an escape. Three hundred fifteen adults from the United States completed measures relating to gambling. Participants were grouped into ethnic categories of Caucasian and non-Caucasian, and age groups of 18-25, 26-35, 36-55, and 56 years old and above. Non-Caucasians reported more gambling problems than Caucasians. A significant interaction was found between ethnicity and age for 36-55 year olds. Overall, participants were more likely to gamble for positive than negative reinforcement. However, only gambling as an escape was a significant predictor of disordered gambling. Implications and limitations are discussed with the thought that these results are informative to practitioners treating disordered gambling. PMID- 26032668 TI - What are VBAC Women Seeking and Sharing? A Content Analysis of Online Discussion Boards. AB - BACKGROUND: In the United States, one-third of pregnancies result in a cesarean delivery. In subsequent pregnancies, mothers must decide whether to pursue a vaginal birth after a cesarean (VBAC) or a repeat cesarean delivery. Pregnant women frequently turn to the Internet for support and information. METHODS: We analyzed 300 posts from a popular online discussion board created for pregnant women who are in the process of deciding to have a VBAC and compared them to 300 posts from a discussion board for pregnant women in general. RESULTS: Women contemplating a VBAC sought more information on health care providers, more information about labor and delivery, and actively sought birth narratives from other women. Over one-third of VBAC posters shared a birth story, whereas this activity was rare on the general discussion board. Activity on the VBAC board suggested more involvement in the online community (longer entries and more feedback). CONCLUSIONS: Many women considering VBAC seek a substantial amount of information and emotional support from online discussion boards. Knowledge of information sought can assist health care providers in more fully meeting the needs of VBAC candidates. PMID- 26032669 TI - Impact of borderline minimum inhibitory concentration on the outcome of invasive infections caused by Enterobacteriaceae treated with beta-lactams: a systematic review and meta-analysis. AB - Minimum inhibitory concentrations (MICs) have been used to denote susceptibility in vitro and to guide clinical practice. Our objective was to investigate whether the clinical outcomes of patients with invasive infections caused by Enterobacteriaceae treated with beta-lactams were worse among those with a borderline susceptible MIC according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints than those with a lower MIC. Studies reporting MICs of beta-lactams used for infection and clinical outcome were identified through a systematic literature search. Isolates were classified as "highly susceptible" (HS, those with MIC <=1 dilution below the susceptibility breakpoint for the antibiotic used) and "borderline susceptible" (BS, isolates with MIC at the susceptibility breakpoint) using EUCAST criteria. Clinical outcomes were clinical cure and 30-day mortality. A meta-analysis was performed. Twenty-four studies were included. Taking all antimicrobials into consideration, the meta-analysis revealed no significant difference in mortality between HS and BS [odds ratio (OR) = 0.58; 95 % confidence interval (CI): 0.28-1.21; p = 0.148). However, HS was associated with higher cure rates than BS (OR = 3.73; 95 % CI: 1.76-7.92; p < 0.001). For specific antibiotics, no differences were found except for piperacillin-tazobactam, where higher clinical cure and lower mortality rates were seen with HS compared with BS isolates (OR = 3.17; 95 % CI: 1.09-9.20; p = 0.034 and OR = 0.12; 95 % CI: 0.02-0.92; p = 0.042; respectively). Our data suggest that HS isolates are associated with higher clinical cure rates than BS isolates according to EUCAST susceptibility breakpoints; this effect was evident only for piperacillin-tazobactam, probably because of limited numbers. PMID- 26032670 TI - Organic matter quantity and source affects microbial community structure and function following volcanic eruption on Kasatochi Island, Alaska. AB - In August 2008, Kasatochi volcano erupted and buried a small island in pyroclastic deposits and fine ash; since then, microbes, plants and birds have begun to re-colonize the initially sterile surface. Five years post-eruption, bacterial 16S rRNA gene and fungal internal transcribed spacer (ITS) copy numbers and extracellular enzyme activity (EEA) potentials were one to two orders of magnitude greater in pyroclastic materials with organic matter (OM) inputs relative to those without, despite minimal accumulation of OM (< 0.2%C). When normalized by OM levels, post-eruptive surfaces with OM inputs had the highest beta-glucosidase, phosphatase, NAGase and cellobiohydrolase activities, and had microbial population sizes approaching those in reference soils. In contrast, the strongest factor determining bacterial community composition was the dominance of plants versus birds as OM input vectors. Although soil pH ranged from 3.9 to 7.0, and %C ranged 100*, differentiation between plant- and bird-associated microbial communities suggested that cell dispersal or nutrient availability are more likely drivers of assembly than pH or OM content. This study exemplifies the complex relationship between microbial cell dispersal, soil geochemistry, and microbial structure and function; and illustrates the potential for soil microbiota to be resilient to disturbance. PMID- 26032671 TI - Wnt-5a prevents Abeta-induced deficits in long-term potentiation and spatial memory in rats. AB - Although the neurotoxicity of amyloid beta (Abeta) protein in Alzheimer's disease (AD) has been reported widely, the exact molecular mechanism underlying the Abeta induced synaptic dysfunction and memory impairment remains largely unclear. Growing evidence indicates that wingless-type (Wnt) signaling plays an important role in neuronal development, synapse formation and synaptic plasticity. In the present study, we investigated the neuroprotective action of Wnt-5a against the synaptic damage and memory deficit induced by Abeta25-35 by using in vivo electrophysiological recording and Morris water maze (MWM) test. We found that intracerebroventricular (i.c.v.) injection of Abeta25-35 alone did not affect the baseline field excitatory postsynaptic potentials (fEPSPs) and the paired-pulse facilitation (PPF) in the hippocampal CA1 region of rats, but significantly suppressed high frequency stimulation (HFS) induced long-term potentiation (LTP); pretreatment with Wnt-5a prevented the Abeta25-35-induced suppression of hippocampal LTP in a dose-dependent manner; soluble Frizzled-related protein (sFRP), a specific Wnt antagonist, effectively attenuated the protective effects of Wnt-5a. In MWM test, Abeta25-35 alone significantly disrupted spatial learning and memory ability of rats, while pretreatment with Wnt-5a effectively prevented the impairments induced by Abeta25-35. These results in the present study demonstrated for the first time the neuroprotective effects of Wnt-5a against Abeta-induced in vivo synaptic plasticity impairment and memory disorder, suggesting that Wnt signaling pathway is one of the important targets of Abeta neurotoxicity and Wnt-5a might be used as one of the putative candidates for the therapeutic intervention of AD. PMID- 26032672 TI - Long non-coding RNA uc.217 regulates neurite outgrowth in dorsal root ganglion neurons following peripheral nerve injury. AB - The intrinsic regeneration capacity of dorsal root ganglion (DRG) neurons can be activated after sciatic nerve injury, and peripheral nerve regeneration is a complex process regulated by multiple molecular responses and signaling pathways. Long non-coding RNAs (lncRNAs) are RNA transcripts > 200 nucleotides in length without protein-coding potential. They regulate gene expression at epigenetic, transcriptional and post-transcriptional levels, and are thus involved in many biological processes and human diseases. However, the role and mechanisms of lncRNAs in regulating the responses of DRG neurons to sciatic nerve injury are not fully investigated. We have previously analysed the expression profiles of lncRNAs and mRNAs in L4-6 DRGs, following rat sciatic nerve transection, by microarray analysis, and constructed a coexpression network of dysregulated lncRNAs and coding genes. In this study, one of these dysregulated lncRNAs, uc.217, was chosen for detailed examination of its expression changes and regulative functions in regenerative DRG neuronal outgrowth. Quantitative real time PCR and in situ hybridisation confirmed that the expression of uc.217 was down-regulated in DRG neurons after sciatic nerve injury. Silencing of uc.217 expression by small interfering RNA could significantly promote neurite outgrowth in cultured DRG neurons. Moreover, bioinformatic analysis and experimental validation were performed to identify several potential targets of uc.217, which were involved in the regulation of DRG neuron outgrowth. Collectively, our results suggested that a new lncRNA, uc.217, played an important regulative role in peripheral nerve regeneration. PMID- 26032673 TI - High prevalence of syringe lending among HIV-positive people who inject drugs in Bangkok, Thailand. AB - BACKGROUND: Syringe sharing continues to be a major driver of the HIV pandemic. In light of efforts to enhance access to sterile syringes and promote secondary prevention among HIV-positive individuals, we sought to identify the prevalence and correlates of used syringe lending among self-reported HIV-positive people who inject drugs (PWID) in Bangkok, Thailand. FINDINGS: We used bivariable statistics to examine factors associated with self-reported syringe lending among self-reported HIV-positive PWID participating in the Mitsampan Community Research Project, a serial cross-sectional study of PWID in Bangkok, between June 2009 and October 2011. In total, 127 individuals were eligible for this analysis, including 25 (19.7%) women. Twenty-one (16.5%) participants reported syringe lending in the prior 6 months. Factors significantly associated with syringe lending included daily methamphetamine injection (odds ratio (OR) = 10.2, 95% CI, 2.1-53.6), daily midazolam injection (OR = 3.1, 95% CI, 1.1-8.7), use of drugs in combination (OR = 4.5, 95% CI, 1.0-41.6), injecting with others on a frequent basis (OR = 4.25, 95% CI, 1.3-18.3), and not receiving antiretroviral therapy (OR = 2.9, 95% CI, 1.1-7.9). CONCLUSIONS: A high prevalence of syringe lending was observed among self-reported HIV-positive PWID in Bangkok, which was associated with high intensity drug use, polysubstance use, and frequently injecting with others. It is particularly concerning that individuals who lent syringes were more likely to be untreated for HIV disease given the known benefits of antiretroviral provision on the prevention of HIV transmission. These findings underscore the need to expand access to sterile syringes and HIV treatment among HIV-positive PWID in Thailand. PMID- 26032674 TI - SCF increases in utero-labeled stem cells migration and improves wound healing. AB - Diabetic skin wounds lack the ability to heal properly and constitute a major and significant complication of diabetes. Nontraumatic lower extremity amputations are the number one complication of diabetic skin wounds. The complexity of their pathophysiology requires an intervention at many levels to enhance healing and wound closure. Stem cells are a promising treatment for diabetic skin wounds as they have the ability to correct abnormal healing. Stem cell factor (SCF), a chemokine expressed in the skin, can induce stem cells migration, however the role of SCF in diabetic skin wound healing is still unknown. We hypothesize that SCF would correct the impairment and promote the healing of diabetic skin wounds. Our results show that SCF improved wound closure in diabetic mice and increased HIF-1alpha and vascular endothelial growth factor (VEGF) expression levels in these wounds. SCF treatment also enhanced the migration of red fluorescent protein (RFP)-labeled skin stem cells via in utero intra-amniotic injection of lenti-RFP at E8. Interestingly these RFP+ cells are present in the epidermis, stain negative for K15, and appear to be distinct from the already known hair follicle stem cells. These results demonstrate that SCF improves diabetic wound healing in part by increasing the recruitment of a unique stem cell population present in the skin. PMID- 26032675 TI - State and Local Perspective on Implementation of the Centers for Disease Control and Prevention Dog Confinement Agreement. AB - The Centers for Disease Control and Prevention (CDC) works in conjunction with state, territorial, local and tribal agencies (STLTAs) to prevent the transmission of infectious agents. Issuance of confinement agreements using CDC Form 75.37 'Notice to Owners and Importers of Dogs' to importers of dogs that are not vaccinated or incompletely vaccinated against rabies is part of the agency's regulatory programme to prevent the entry of dogs infected with rabies. Although this is a regulatory programme that depends heavily on partnerships between CDC and STLTAs, CDC had never formally evaluated the acceptability of the confinement agreement process with these partners. Thus, a short survey of nine STLTAs was conducted to evaluate whether these partners have enough personnel and resources to implement the regulation and their general opinions of the confinement agreement process. The results illustrate that CDC partners are dissatisfied to some extent with the process, and there are multiple issues limiting their success in enforcing the regulation. PMID- 26032676 TI - Nocturnal Blood Pressure Surge Behind Morning Surge in Obstructive Sleep Apnea Syndrome: Another Phenotype of Systemic Hemodynamic Atherothrombotic Syndrome. PMID- 26032684 TI - EMOTION-PROCESSING BIASES AND RESTING EEG ACTIVITY IN DEPRESSED ADOLESCENTS. AB - BACKGROUND: Although theorists have posited that adolescent depression is characterized by emotion-processing biases (greater propensity to identify sad than happy facial expressions), findings have been mixed. Additionally, the neural correlates associated with putative emotion-processing biases remain largely unknown. Our aim was to identify emotion-processing biases in depressed adolescents and examine neural abnormalities related to these biases using high density resting EEG and source localization. METHODS: Healthy (n = 36) and depressed (n = 23) female adolescents, aged 13-18 years, completed a facial recognition task in which they identified happy, sad, fear, and angry expressions across intensities from 10% (low) to 100% (high). Additionally, 128-channel resting (i.e., task-free) EEG was recorded and analyzed using a distributed source localization technique (low-resolution electromagnetic tomography (LORETA)). Given research implicating the dorsolateral prefrontal cortex (DLPFC) in depression and emotion processing, analyses focused on this region. RESULTS: Relative to healthy youth, depressed adolescents were more accurate for sad and less accurate for happy, particularly low-intensity happy faces. No differences emerged for fearful or angry facial expressions. Further, LORETA analyses revealed greater theta and alpha current density (i.e., reduced brain activity) in depressed versus healthy adolescents, particularly in the left DLPFC (BA9/BA46). Theta and alpha current density were positively correlated, and greater current density predicted reduced accuracy for happy faces. CONCLUSION: Depressed female adolescents were characterized by emotion-processing biases in favor of sad emotions and reduced recognition of happiness, especially when cues of happiness were subtle. Blunted recognition of happy was associated with left DLPFC resting hypoactivity. PMID- 26032685 TI - Naringin rescued the TNF-alpha-induced inhibition of osteogenesis of bone marrow derived mesenchymal stem cells by depressing the activation of NF-kB signaling pathway. AB - Naringin exhibits antiinflammatory activity and is shown to induce bone formation. Yet the impact of naringin on inflammation-affected bone marrow derived mesenchymal stem cell (BM-MSC), a promising tool for the regenerative treatment of bone injury, remained to be investigated. We first cultured and characterized the BM-MSCs in vitro and observe the effects of treatments of TNF alpha, naringin, or the combination of both on osteogenic differentiation. TNF alpha administered at the concentration of 20 ng/ml results in significant reductions in MSC's cell survival, alkaline phosphatase activity and expressions of two osteogenic genes, Runx2 and Osx. Simultaneous treatment of both TNF-alpha and naringin is able to rescue such reductions. Further mechanistic studies indicate that TNF-alpha treatment activates the NF-kB signaling pathway, evidenced by elevated p-IkBalpha level as well as the increased nuclear fraction of NF-kB subunit, p65. Finally, treatment with both TNF-alpha and naringin decreases expressions of p-IkBalpha and nuclear p65, and thus represses NF-kB pathway activated by sole TNF-alpha treatment. Our findings provide a molecular basis by which naringin restores the TNF-alpha-induced damage in MSCs and provide novel insights into the application of naringin in the MSC-based treatments for inflammation-induced bone injury. PMID- 26032686 TI - Defective roles of ATP7B missense mutations in cellular copper tolerance and copper excretion. AB - Wilson's disease (WD) is a hereditary disorder of copper metabolism resulting from mutations within ATP7B. Clinical investigations showed that ATP7B missense mutations cause a wide variety of symptoms in WD patients, which implies that those mutations might affect ATP7B function in a number of ways and each would have deleterious consequences on normal copper distribution and lead to WD. Nonetheless, it is still unknown about the influences of those mutations on ATP7B function of increasing copper excretion and enhancing cellular copper tolerance. Here we established the stable expression cell lines of wild-type (WT) ATP7B and its four missense mutants (R778L, R919G, T935M and P992L), tested cellular copper tolerance and copper excretion using those cell lines, and also observed cellular distribution of WT ATP7B proteins and those mutants in transiently transfected cells. We found that extrinsic expressing WT ATP7B reduced CuCl2-induced copper accumulation and enhanced cellular copper tolerance by accelerating copper excretion, which was selectively compromised by R778L and P992L mutations. Further investigation showed that R778L mutation disrupted the subcellular localization and trafficking of ATP7B proteins, whereas P992L mutation only affected the trafficking of ATP7B. This indicates that ATP7B missense mutants have distinct effects on cellular copper tolerance. PMID- 26032688 TI - One-Step Synthesis of Self-Supported Nickel Phosphide Nanosheet Array Cathodes for Efficient Electrocatalytic Hydrogen Generation. AB - Nickel phosphide is an emerging low-cost, earth-abundant catalyst that can efficiently reduce water to generate hydrogen. However, the synthesis of nickel phosphide catalysts usually involves multiple steps and is laborious. Herein, a convenient and straightforward approach to the synthesis of a three-dimensional (3D) self-supported biphasic Ni5 P4 -Ni2 P nanosheet (NS) array cathode is presented, which is obtained by direct phosphorization of commercially available nickel foam using phosphorus vapor. The synthesized 3D Ni5 P4 -Ni2 P-NS array cathode exhibits outstanding electrocatalytic activity and long-term durability toward the hydrogen evolution reaction (HER) in acidic medium. The fabrication procedure reported here is scalable, showing substantial promise for use in water electrolysis. More importantly, the approach can be readily extended to synthesize other self-supported transition metal phosphide HER cathodes. PMID- 26032687 TI - Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition. AB - Although the epidermal growth factor receptor (EGFR) is overexpressed and/or amplified in more than 50 % of all glioblastomas (GBM), therapeutic targeting of the EGFR has not yet been successful. Since histone deacetylases (HDAC) have been described as controlling EGFR expression, we combined the EGFR tyrosine kinase inhibitor erlotinib with different HDAC inhibitors (HDACi) and investigated the benefit of combinatorial therapy for glioblastoma cells. Using representative models of EGFR-amplified, erlotinib-sensitive and -resistant GBM with or without EGFRvIII expression, we determined proliferation, migration, and EGFR-dependent signaling in response to erlotinib and HDACi alone or in combination. HDACi significantly inhibited proliferation of erlotinib-resistant GBM cells, partially restored their sensitivity to erlotinib, and also significantly reduced proliferation of all treatment-naive cell lines tested. In combination with erlotinib, the development of resistance was prevented. The multitargeted EGFR/HDAC-inhibitor CUDC-101 exhibited similar effects. However, inhibition of cell migration was only achieved by targeting EGFR, and HDACi exhibited no additive effect. Mechanistically, we identified an HDACi-dependent decrease of EGFR/EGFRvIII protein expression underlying the anti-proliferative effects of HDACi. In conclusion, HDACi in combination with erlotinib might serve as a treatment option for newly diagnosed, treatment-naive tumors irrespective of their EGFR status, as well as for treatment-refractory, EGFR-overexpressing GBM. PMID- 26032689 TI - Folic-Acid-Targeted Self-Assembling Supramolecular Carrier for Gene Delivery. AB - A targeting gene carrier for cancer-specific delivery was successfully developed through a "multilayer bricks-mortar" strategy. The gene carrier was composed of adamantane-functionalized folic acid (FA-AD), an adamantane-functionalized poly(ethylene glycol) derivative (PEG-AD), and beta-cyclodextrin-grafted low molecular-weight branched polyethylenimine (PEI-CD). Carriers produced by two different self-assembly schemes, involving either precomplexation of the PEI-CD with the FA-AD and PEG-AD before pDNA condensation (Method A) or pDNA condensation with the PEI-CD prior to addition of the FA-AD and PEG-AD to engage host-guest complexation (Method B) were investigated for their ability to compact pDNA into nanoparticles. Cell viability studies show that the material produced by the Method A assembly scheme has lower cytotoxicity than branched PEI 25 kDa (PEI-25KD) and that the transfection efficiency is maintained. These findings suggest that the gene carrier, based on multivalent host-guest interactions, could be an effective, targeted, and low-toxicity carrier for delivering nucleic acid to target cells. PMID- 26032690 TI - A fully integrated microdevice for biobarcode assay based biological agent detection. AB - An integrated microdevice, consisting of a micropump, a passive mixer, a magnetic separation chamber, and a microcapillary electrophoretic channel, was constructed for biobarcode assay based multiplex biological agent detection in a sample-to answer-out manner within 30 min with high sensitivity. PMID- 26032691 TI - Acute exacerbations of chronic obstructive pulmonary disease: diagnosis, management, and prevention in critically ill patients. AB - Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is a substantial source of disability in the United States. Moderate-to severe acute exacerbations of COPD (AECOPD) can progress to respiratory failure, necessitating ventilator assistance in patients in the intensive care unit (ICU). Patients in the ICU with AECOPD requiring ventilator support have higher morbidity and mortality rates as well as costs compared with hospitalized patients not in the ICU. The mainstay of management for patients with AECOPD in the ICU includes ventilator support (noninvasive or invasive), rapid-acting inhaled bronchodilators, systemic corticosteroids, and antibiotics. However, evidence supporting these interventions for the treatment of AECOPD in critically ill patients admitted to the ICU is scant. Corticosteroids have gained widespread acceptance in the management of patients with AECOPD necessitating ventilator assistance, despite their lack of evaluation in clinical trials as well as controversies surrounding optimal dosage regimens and duration of treatment. Recent studies evaluating the safety and efficacy of corticosteroids have found that higher doses are associated with increased adverse effects, which therefore support lower dosing strategies, particularly for patients admitted to the ICU for COPD exacerbations. This review highlights recent findings from the current body of evidence on nonpharmacologic and pharmacologic treatment and prevention of AECOPD in critically ill patients. In addition, the administration of bronchodilators using novel delivery devices in the ventilated patient and the conflicting evidence surrounding antibiotic use in AECOPD in the critically ill is explored. Further clinical trials, however, are warranted to clarify the optimal pharmacotherapy management for AECOPD, particularly in critically ill patients admitted to the ICU. PMID- 26032692 TI - Syntenin and syndecan in the biogenesis of exosomes. AB - Cells communicate with their environment in various ways, including by secreting vesicles. Secreted vesicles are loaded with proteins, lipids and RNAs that compose 'a signature' of the cell of origin and potentially can reprogram recipient cells. Secreted vesicles recently gained in interest for medicine. They represent potential sources of biomarkers that can be collected from body fluids and, by disseminating pathogenic proteins, might also participate in systemic diseases like cancer, atherosclerosis and neurodegeneration. The mechanisms controlling the biogenesis and the uptake of secreted vesicles are poorly understood. Some of these vesicles originate from endosomes and are called 'exosomes'. In this review, we recapitulate recent insight on the role of the syndecan (SDC) heparan sulphate proteoglycans, the small intracellular adaptor syntenin and associated regulators in the biogenesis and loading of exosomes with cargo. SDC-syntenin-associated regulators include the endosomal sorting complex required for transport accessory component ALG-2-interacting protein X, the small GTPase adenosine 5'-diphosphate-ribosylation factor 6, the lipid-modifying enzyme phospholipase D2 and the endoglycosidase heparanase. All these molecules appear to support the budding of SDC-syntenin and associated cargo into the lumen of endosomes. This highlights a major mechanism for the formation of intraluminal vesicles that will be released as exosomes. PMID- 26032693 TI - Implications of paraureteral diverticulum for the management of vesicoureteral reflux. AB - OBJECTIVES: To investigate the clinical importance of paraureteral diverticulum in the management of vesicoureteral reflux by analyzing the relationship between paraureteral diverticulum and recurrent urinary tract infections. METHODS: We retrospectively reviewed 131 children diagnosed with vesicoureteral reflux. We diagnosed vesicoureteral reflux and paraureteral diverticulum by initial voiding cystourethrography and defined "delayed ureteral drainage" as the presence of contrast media in the upper urinary tract on delayed films after voiding. We analyzed the relationships between paraureteral diverticulum, delayed ureteral drainage and recurrent urinary tract infections. RESULTS: The mean age at diagnosis of vesicoureteral reflux was 20.7 months. Of the 202 refluxing ureters, 55 (27.2%) had a paraureteral diverticulum. Of the 55 ureters with paraureteral diverticulum, 51 (92.7%) showed delayed ureteral drainage of refluxing contrast, which was significantly higher than the percentage of delayed ureteral drainage in ureters without paraureteral diverticulum (P < 0.001). On multivariate analysis of the effect of reflux grade or paraureteral diverticulum on delayed ureteral drainage of refluxing contrast, the odds ratio of paraureteral diverticulum was 11.47 (P < 0.001). In addition, the risk of recurrent urinary tract infections increased in ureters with paraureteral diverticulum (P = 0.020). CONCLUSIONS: In patients with vesicoureteral reflux and paraureteral diverticulum, the risk of recurrent febrile urinary tract infections seems to increase. Therefore, more progressive surveillance and treatment protocols should be considered in these patients. PMID- 26032694 TI - In vivo quantitative whole-brain T1 rho MRI of multiple sclerosis. AB - BACKGROUND: To apply quantitative whole-brain T1 -rho (T1rho ) and T2 imaging to the detection and quantification of brain changes resulting from multiple sclerosis (MS). METHODS: Twenty-three MS patients with clinically isolated syndrome (10) and relapsing remitting MS (13) phenotypes, compared with 24 age matched healthy controls were imaged at 3 Tesla. An axial T1rho -weighted three dimensional turbo spin echo sequence with a variable flip angle and fluid suppression was used. Spin-lock times of 0, 20, 40, 60, 80, and 100 ms were used. Corresponding T2 maps were also acquired. RESULTS: Whole brain white matter (WM) T1rho maps were elevated compared with controls (P = 0.002). WM lesion T1rho and T2 values were highly correlated (r = 0.83), but T1rho demonstrated 25% better contrast to noise ratio (P < 0.001). WM lesion T1rho correlated with disease duration. Gray matter T1rho was negatively correlated with the Expanded Disability Status Scale, r = -0.45, P = 0.03. Normal appearing gray matter and cortical gray matter lesions were negatively correlated on T1rho , but not on T2 (rT1rho = -0.63, pT1rho = 0.03; rT2 = -0.17, pT2 = 0.6). CONCLUSION: T1rho MRI demonstrates enhanced lesion contrast compared with T2 , and in some cases may provide complementary information. T1rho may provide a useful measure of demyelinating processes in MS. PMID- 26032696 TI - Do English healthcare settings use 'Choice Architecture' principles in promoting healthy lifestyles for people with psoriasis? An observational study. AB - BACKGROUND: The influence of environmental factors in shaping behaviour is becoming increasingly prominent in public health policy, but whether health promotion strategies use this knowledge is unknown. Health promotion is important in the management of psoriasis, a long-term inflammatory skin condition, and health centre waiting areas are ideal places to promote health information to such patients. We systematically examined patient information materials containing either general, or specific, health messages for patients with psoriasis. METHODS: An observation schedule was used to record the frequency and quality of leaflets and posters addressing lifestyle behaviour change in health centre waiting areas. Content analysis was used to analyse: frequency, characteristics and standard of the materials. RESULTS: Across 24 health centres 262 sources of lifestyle information were recorded (median per site = 10; range = 0-40). These were mainly: generic posters/displays of lifestyle support (n = 113); and generic materials in waiting areas (n = 98). Information quality was poor and poorly displayed, with no high quality psoriasis-specific patient materials evident. CONCLUSIONS: There is little attempt to promote healthy lifestyle as an important aspect of psoriasis management in the clinic environment. Evidence about using environmental cues/techniques to prompt behaviour change in people with psoriasis does not currently inform the design and display of such information in standard health centre settings, which are prime locations for communicating messages about healthy lifestyle. Future research should test the efficacy and impact of theory-informed, high quality health promotion messages on health outcomes for patients with psoriasis. PMID- 26032695 TI - Disparities in Colorectal Cancer Treatment Delay Within Appalachia--The Role of For-Profit Hospitals. AB - BACKGROUND: Appalachian residents have a higher overall cancer burden than the rest of the United States because of the unique features of the region. Treatment delays vary widely within Appalachia, with colorectal cancer patients undergoing median treatment delays of 5 days in Kentucky compared to 9 days for patients in Pennsylvania, Ohio, and North Carolina combined. OBJECTIVE: This study identified the source of this disparity in treatment delay using statistical decomposition techniques. METHODOLOGY: This study used linked 2006 to 2008 cancer registry and Medicare claims data for the Appalachian counties of Kentucky, Pennsylvania, Ohio, and North Carolina to estimate a 2-part model of treatment delay. An Oaxaca Decomposition of the 2-part model revealed the contribution of the individual determinants to the disparity in delay between Kentucky counties and the remaining 3 states. RESULTS: The Oaxaca Decomposition revealed that the higher percentage of patients treated at for-profit facilities in Kentucky proved the key contributor to the observed disparity. In Kentucky, 22.3% patients began their treatment at a for-profit facility compared to 1.4% in the remaining states. Patients initiating treatment at for-profit facilities explained 79% of the observed difference in immediate treatment (<2 days after diagnosis) and 72% of Kentucky's advantage in log days to treatment. CONCLUSIONS: The unique role of for-profit facilities led to reduced treatment delay for colorectal cancer patients in Kentucky. However, it remains unknown whether for-profit hospitals' more rapid treatment converts to better health outcomes for colorectal cancer patients. PMID- 26032697 TI - A novel in situ gas stripping-pervaporation process integrated with acetone butanol-ethanol fermentation for hyper n-butanol production. AB - Butanol is considered as an advanced biofuel, the development of which is restricted by the intensive energy consumption of product recovery. A novel two stage gas stripping-pervaporation process integrated with acetone-butanol-ethanol (ABE) fermentation was developed for butanol recovery, with gas stripping as the first-stage and pervaporation as the second-stage using the carbon nanotubes (CNTs) filled polydimethylsiloxane (PDMS) mixed matrix membrane (MMM). Compared to batch fermentation without butanol recovery, more ABE (27.5 g/L acetone, 75.5 g/L butanol, 7.0 g/L ethanol vs. 7.9 g/L acetone, 16.2 g/L butanol, 1.4 g/L ethanol) were produced in the fed-batch fermentation, with a higher butanol productivity (0.34 g/L . h vs. 0.30 g/L . h) due to reduced butanol inhibition by butanol recovery. The first-stage gas stripping produced a condensate containing 155.6 g/L butanol (199.9 g/L ABE), which after phase separation formed an organic phase containing 610.8 g/L butanol (656.1 g/L ABE) and an aqueous phase containing 85.6 g/L butanol (129.7 g/L ABE). Fed with the aqueous phase of the condensate from first-stage gas stripping, the second-stage pervaporation using the CNTs-PDMS MMM produced a condensate containing 441.7 g/L butanol (593.2 g/L ABE), which after mixing with the organic phase from gas stripping gave a highly concentrated product containing 521.3 g/L butanol (622.9 g/L ABE). The outstanding performance of CNTs-PDMS MMM can be attributed to the hydrophobic CNTs giving an alternative route for mass transport through the inner tubes or along the smooth surface of CNTs. This gas stripping-pervaporation process with less contaminated risk is thus effective in increasing butanol production and reducing energy consumption. PMID- 26032698 TI - Gestational weight gain and the risk of offspring obesity at 10 and 16 years: a prospective cohort study in low-income women. AB - OBJECTIVE: To study the association between gestational weight gain (GWG) and offspring obesity risk at ages chosen to approximate prepuberty (10 years) and postpuberty (16 years). DESIGN: Prospective pregnancy cohort. SETTING: Pittsburgh, PA, USA. SAMPLE: Low-income pregnant women (n = 514) receiving prenatal care at an obstetric residency clinic and their singleton offspring. METHODS: Gestational weight gain was classified based on maternal GWG-for gestational-age Z-score charts and was modelled using flexible spline terms in modified multivariable Poisson regression models. MAIN OUTCOME MEASURES: Obesity at 10 or 16 years, defined as body mass index (BMI) Z-scores >=95th centile of the 2000 CDC references, based on measured height and weight. RESULTS: The prevalence of offspring obesity was 20% at 10 years and 22% at 16 years. In the overall sample, the risk of offspring obesity at 10 and 16 years increased when GWG exceeded a GWG Z-score of 0 SD (equivalent to 30 kg at 40 weeks); but for gains below a Z-score of 0 SD there was no relationship with child obesity risk. The association between GWG and offspring obesity varied by prepregnancy BMI. Among mothers with a pregravid BMI <25 kg/m(2) , the risk of offspring obesity increased when GWG Z-score exceeded 0 SD, yet among overweight women (BMI >=25 kg/m(2) ), there was no association between GWG Z-scores and offspring obesity risk. CONCLUSIONS: Among lean women, higher GWG may have lasting effects on offspring obesity risk. PMID- 26032699 TI - Decreasing transobturator sling groin pain without decreasing efficacy using TVT Abbrevo. AB - INTRODUCTION AND HYPOTHESIS: Groin pain following a transobturator (TO) midurethral sling is not uncommon and can be difficult to manage. We sought to determine if decreasing the mesh burden in the groin would decrease pain. The primary objective was to compare the incidence of post-operative groin pain following placement of full-length TVT-Obturator versus the shorter TVT-Abbrevo. Secondarily, we aimed to compare the efficacy between both devices 6 months after surgery. METHODS: This is a retrospective cohort study of all women who underwent a TO midurethral sling by the division of urogynecology at one institution between 1 January 2007 and 31 October 2013. Charts were reviewed and the incidence of post-operative groin pain in the two groups dichotomized as present or absent and compared using a Chi-squared test. Validated questionnaire scores of the groups were compared using t tests. RESULTS: There were 125 patients who received a TVT-Obturator and 100 patients who received a TVT-Abbrevo. No differences in demographic data were present between the groups. Twelve patients (9.6 %) in the TVT-Obturator group and 1 patient (1 %) in the TVT-Abbrevo group experienced bothersome groin pain (P value = 0.007). The complete pre- and 6 month post-operative ISI, UDI-6 and PFIQ-7 scores were available for 76 (61 %), 47 (38 %), and 45 (36 %) patients following TVT-Obturator and 57 (57 %), 30 (30 %), and 28 (28 %) following TVT-Abbrevo treatment. At 6 months the mean improvement in questionnaire scores for the TVT-Obturator and TVT-Abbrevo groups were as follows: 5.0 and 5.1 for ISI (P value = 0.9), 8.3 and 7.9 for UDI-6 (P value = 0.8), and 4.8 and 6.1 for PFIQ-7 (P value = 0.4). CONCLUSION: Use of TVT Abbrevo reduces post-operative groin pain compared with the full-length TVT Obturator, without any reduction in efficacy. PMID- 26032700 TI - Prevalence and types of drug-resistant variants in Chinese patients with acute hepatitis B. AB - The presence of therapy-associated hepatitis B virus (HBV) variants is the main drawback of antiviral therapy for HBV infection. Moreover, drug-resistant variants are more insensitive to a second agent and more therapy-associated mutations will be present. To apply better nucleos(t)ide analogues (NA) and reduce the occurrence of resistance, the prevalence and types of drug-resistant mutations in acute hepatitis B patients were investigated in this study. One hundred three HBV DNA-positive patients with symptomatic acute hepatitis B that were observed from 2011 to 2013 were enrolled. Direct polymerase chain reaction sequencing was used firstly to screen HBV reverse-transcriptase domain to detect HBV mutants. Five lamivudine-resistant variants were identified. Clonal sequencing was performed for 5 resistance-positive samples and 10 other random samples. Interestingly, all detected samples harbored drug-resistant mutations, although with different percentage. Thirteen harbored lamivudine-related alone (five) or together with other NA related mutations (five with adefovir, one with entecavir, and one with telbivudine), and two of them harbored adefovir-related mutations. Also, mutations associated with four currently used NA were all detected, and the frequency is in accordance with the popularity of NA used in clinical practice. These data suggest that drug-resistant variants are present in patients with acute hepatitis B and NA should be applied more carefully for chronic hepatitis B patients developed from acute hepatitis B. PMID- 26032701 TI - Gastrointestinal stromal tumour in a recipient with kidney transplantation. AB - Immunosuppression is associated with an increased risk of post-transplant malignancies. Gastrointestinal stromal tumours are the most common mesenchymal tumours of the gastrointestinal tract. However, they have seldom been reported recipient with transplantation. In this report, a 46-year-old woman, a recipient with kidney transplantation, who developed a gastric tumour is presented. Removal of this tumour required a partial gastrectomy. Histopathology and immunohistochemistry examinations revealed a high-risk gastric stromal tumour. Adjuvant imatinib mesylate treatment was initiated. There was no evidence of tumour recurrence at 12-month follow-up. PMID- 26032702 TI - Leucocytosis in clozapine-treated patients as predictor of loss of treatment response? AB - Anecdotal evidence tends to suggest clozapine treatment as a cause of leucocytosis in schizophrenic patients, however, no conclusive evidence is available on this topic. We report the clinical cases of two schizophrenic men who were diagnosed with clozapine-related leucocytosis. The clozapine treatment was performed at a dose between 200 and 400 mg/day. When leucocytosis appeared, there was a loss of response to clozapine in both patients. Clozapine-induced leucocytosis in schizophrenic patients could be correlated to occurrence of psychotic symptomatology. PMID- 26032703 TI - Halogravity traction in the preoperative treatment of scoliosis in twins with Marfan syndrome. AB - We report on the influence of the duration of halogravity traction for achieving curve correction in monozygotic twins with Marfan syndrome who underwent posterior spinal fusion. Review of the medical charts and standard radiograph analysis of twin girls treated at our department was performed. Halogravity traction with a four-pin skull construct was applied for 3 weeks in twin A and for 2 weeks in twin B with a maximum of 20% body weight used. Both were on a 24 hours-day halogravity traction regime. Achieved thoracic curve correction after halogravity traction was 31% in twin A and 18% in twin B. Although less curve correction after traction was achieved in twin B, this had no significant implications on final postoperative curve correction. Halogravity traction can be a useful tool in the preoperative treatment of scoliosis in patients with Marfan syndrome if applied for 3 weeks. In order to avoid complications, we propose that lower weights be used with a starting weight of 1.5 kg increased by 1 kg daily until 20% body weight is reached. PMID- 26032704 TI - Cervical dermatomal zona misdiagnosed as ulnar nerve entrapment. AB - Herpes zoster is a secondary reactivation of primary contagious varicella-zoster virus in the dorsal root ganglia. While thoracic zona is common, cervical dermatomal zona is a rare segmental complication of herpes zoster and can be easily misdiagnosed as other diseases. This article describes a patient with initial neuralgia without dermatomal lesions that was treated as ulnar nerve entrapment syndrome until manifestation of herpetiform cutaneous lesions appeared. It is important that clinicians should be aware of the possibility of zoster infection when evaluating the onset of neuralgia in a dermatomal distribution in the upper limb, especially without rash. PMID- 26032705 TI - Dental management of Rothmund-Thomson syndrome with partial anodontia. AB - Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive trait disease. It is characterised by skin, eye and skeletal abnormalities. Abnormalities associated with teeth include abnormal crown and root formations, rudimentary or hypoplastic teeth, microdontia and multiple missing teeth. In the present case, there were multiple decayed primary teeth and multiple congenitally missing permanent teeth. Mandibular left primary first molar (tooth 74) was pulpally involved and obturated with mineral trioxide ggregate. Follow-up after 2 years revealed successful obturation. PMID- 26032706 TI - Tertiary paediatric hospital admissions in children and young people with cerebral palsy. AB - BACKGROUND: Many previous studies that have investigated hospital admissions in children and young people with cerebral palsy lack information on cerebral palsy severity and complexity. Consequently, little is known about factors associated with the frequency and type of hospital admissions in this population. This study used hospital admission data available for all children and young people known to a population-based cerebral palsy register to describe the patterns of use of tertiary paediatric hospital services over a 5-year period. METHODS: This was a retrospective cohort analysis of routinely collected admission data from the two tertiary paediatric hospitals in the Australian state of Victoria. Data on admissions of individuals born between 1993 and 2008 registered on the Victorian Cerebral Palsy Register were analysed (n = 2183). RESULTS: Between 2008 and 2012, 53% of the cohort (n = 1160) had at least one same-day admission, and 46% (n = 996) had one or more multi-day admissions. Those with a moderate to severe motor impairment and those with a co-diagnosis of epilepsy had more admissions, and for multi-day admissions, longer lengths of stay, P < 0.05. Across all severity levels, respiratory and musculoskeletal diseases were the most frequently reported reasons for medical and surgical admissions, respectively. All-cause readmission rates for urgent multi-day stays within 7, 30 and 365 days of an index admission were 10%, 23% and 63%, respectively. CONCLUSIONS: The reasons for hospital admissions reported here reflect the range of comorbidities experienced by children and young people with cerebral palsy. This study highlights priority areas for prevention, early diagnosis and medical management in this group. Improved primary and secondary prevention measures may decrease non-elective hospital admissions and readmissions in this group and reduce paediatric inpatient resource use and healthcare expenditure attributable to cerebral palsy. PMID- 26032707 TI - [Off-label drug use of the misoprostol in gynecology & obstetrics: From a medico economics benefit to a potential legal risk]. AB - The scandal of the Mediator(r) case led the legislature to take measures in order to regulate off-label drugs prescriptions. Indeed the law issued in December 29th, 2011 on strengthening the safety of drugs and all derivative health products came to pave the way for an "over-cautious" practice of medicine in line with the precautionary principle erected as a constitutional principle. The supervision of off-label prescribing has had a direct impact on the exercise of the medical profession and has resurrected the issues related to the freedom of prescription, the obligation to provide information to patients and in general their whole responsibility. It is important to mention that the prescribing act is part of the freedom and the strict prerogative of those skilled in the art: the physician in this case. The off-label prescription is commonly accepted in certain specialties, such as anesthesia and intensive care, oncology or pediatrics where it is even subject of a memorandum of use because of concerns regarding the availability of forms adapted to children. However, the physician must ensure that no appropriate therapeutic alternative is available and inform the patient, fundamental principle of the right to respect for the will of the person. Off-label use of the prostaglandin-E1 analogue misoprostol in obstetrics and gynecology is a good example. In fact, this drug obtained a marketing authorization for the treatment or prevention of peptic ulcers and other stomach disorders, is commonly used off-label when inducing labour or intrauterine device insertion. These are the issues that need to be clarify and carefully assessed in order to help physicians to understand the impact of the law and the state of the jurisprudence on the exercise of their profession. PMID- 26032708 TI - Prenatal diagnosis of critical isolated congenital heart disease: dismantling silos to provide better care. PMID- 26032709 TI - Re: Assessment by three-dimensional power Doppler ultrasound of cerebral blood flow perfusion in fetuses with congenital heart disease. S. Zeng, J. Zhou, Q. Peng, L. Tian, G. Xu, Y. Zhao, T. Wang and Q. Zhou. Ultrasound Obstet Gynecol 2015; 45: 649-656. PMID- 26032710 TI - Re: Maternal hyperoxygenation improves left heart filling in fetuses with atrial septal aneurysm causing impediment to left ventricular inflow. A. Channing, A. Szwast, S. Natarajan, K. Degenhardt, Z. Tian and J. Rychik. Ultrasound Obstet Gynecol 2015; 45: 664-669. PMID- 26032711 TI - Reply: To PMID 25042845. PMID- 26032712 TI - Re: Risk of miscarriage following amniocentesis and chorionic villus sampling. PMID- 26032713 TI - Re: Ultrasound guidance during embryo transfer: a systematic review and meta analysis of randomized controlled trials. PMID- 26032714 TI - Reproducibility of brain-cognition relationships using three cortical surface based protocols: An exhaustive analysis based on cortical thickness. AB - People differ in their cognitive functioning. This variability has been exhaustively examined at the behavioral, neural and genetic level to uncover the mechanisms by which some individuals are more cognitively efficient than others. Studies investigating the neural underpinnings of interindividual differences in cognition aim to establish a reliable nexus between functional/structural properties of a given brain network and higher order cognitive performance. However, these studies have produced inconsistent results, which might be partly attributed to methodological variations. In the current study, 82 healthy young participants underwent MRI scanning and completed a comprehensive cognitive battery including measurements of fluid, crystallized, and spatial intelligence, along with working memory capacity/executive updating, controlled attention, and processing speed. The cognitive scores were obtained by confirmatory factor analyses. T1 -weighted images were processed using three different surface-based morphometry (SBM) pipelines, varying in their degree of user intervention, for obtaining measures of cortical thickness (CT) across the brain surface. Distribution and variability of CT and CT-cognition relationships were systematically compared across pipelines and between two cognitively/demographically matched samples to overcome potential sources of variability affecting the reproducibility of findings. We demonstrated that estimation of CT was not consistent across methods. In addition, among SBM methods, there was considerable variation in the spatial pattern of CT-cognition relationships. Finally, within each SBM method, results did not replicate in matched subsamples. PMID- 26032715 TI - The evolution of sexually antagonistic phenotypes. AB - Sexual conflict occurs whenever there is sexually antagonistic selection on shared traits. When shared traits result from interactions (e.g., mating rate) and have a different genetic basis in each sex (i.e., interlocus conflict), then sex-specific traits that shift the value of these interaction traits toward the sex-specific optimum will be favored. Male traits can be favored that increase the fitness of their male bearers, but decrease the fitness of interacting females. Likewise, female traits that reduce the costs of interacting with harmful males may simultaneously impose costs on males. If the evolution of these antagonistic traits changes the nature of selection acting on the opposite sex, interesting coevolutionary dynamics will result. Here we examine three current issues in the study of sexually antagonistic interactions: the female side of sexual conflict, the ecological context of sexual conflict, and the strength of evidence for sexually antagonistic coevolution. PMID- 26032716 TI - Evolution of new functions de novo and from preexisting genes. AB - How the enormous structural and functional diversity of new genes and proteins was generated (estimated to be 10(10)-10(12) different proteins in all organisms on earth [Choi I-G, Kim S-H. 2006. Evolution of protein structural classes and protein sequence families. Proc Natl Acad Sci 103: 14056-14061] is a central biological question that has a long and rich history. Extensive work during the last 80 years have shown that new genes that play important roles in lineage specific phenotypes and adaptation can originate through a multitude of different mechanisms, including duplication, lateral gene transfer, gene fusion/fission, and de novo origination. In this review, we focus on two main processes as generators of new functions: evolution of new genes by duplication and divergence of pre-existing genes and de novo gene origination in which a whole protein coding gene evolves from a noncoding sequence. PMID- 26032717 TI - Signaling in lymphocyte activation. AB - The fate of T and B lymphocytes, the key cells that direct the adaptive immune response, is regulated by a diverse network of signal transduction pathways. The T- and B-cell antigen receptors are coupled to intracellular tyrosine kinases and adaptor molecules to control the metabolism of inositol phospholipids and calcium release. The production of inositol polyphosphates and lipid second messengers directs the activity of downstream guanine-nucleotide-binding proteins and protein and lipid kinases/phosphatases that control lymphocyte transcriptional and metabolic programs. Lymphocyte activation is modulated by costimulatory molecules and cytokines that elicit intracellular signaling that is integrated with the antigen-receptor-controlled pathways. PMID- 26032718 TI - Interaction between Neurogenesis and Hippocampal Memory System: New Vistas. AB - During the last decade, the questions on the functionality of adult neurogenesis have changed their emphasis from if to how the adult-born neurons participate in a variety of memory processes. The emerging answers are complex because we are overwhelmed by a variety of behavioral tasks that apparently require new neurons to be performed optimally. With few exceptions, the hippocampal memory system seems to use the newly generated neurons for multiple roles. Adult neurogenesis has given the dentate gyrus new capabilities not previously thought possible within the scope of traditional synaptic plasticity. Looking at these new developments from the perspective of past discoveries, the science of adult neurogenesis has emerged from its initial phase of being, first, a surprising oddity and, later, exciting possibility, to the present state of being an integral part of mainstream neuroscience. The answers to many remaining questions regarding adult neurogenesis will come along only with our growing understanding of the functionality of the brain as a whole. This, in turn, will require integration of multiple levels of organization from molecules and cells to circuits and systems, ultimately resulting in comprehension of behavioral outcomes. PMID- 26032721 TI - Cattle rabies vaccination--A longitudinal study of rabies antibody titres in an Israeli dairy herd. AB - In contrast to many regions of the world where rabies is endemic in terrestrial wildlife species, wildlife rabies has been controlled in Israel by oral rabies vaccination programs, but canine rabies is re-emerging in the northern area of the Golan Heights. From 2009 to 2014 there were 208 animal rabies cases in Israel; 96 (46%) were considered introduced primary cases in dogs, triggering 112 secondary cases. One third (37/112) of the secondary cases were in cattle. Rabies vaccination is voluntary for cattle in Israel, except those on public exhibit. Rabies vaccination schedules for cattle vary based on farm practices and perception of risk. In this study 59 cattle from a dairy farm which routinely vaccinates against rabies were assigned into six groups according to age and vaccination histories. Four groups contained adult cows which had received one previous rabies vaccination, one group of adults had received two previous vaccinations, and one group was unvaccinated calves. Serum samples were collected and the cows were vaccinated with a commercial rabies vaccine. Sera were again collected 39 days later and the calf group re-vaccinated and re-sampled 18 days later. Sera were analyzed for the presence of rabies virus neutralizing antibodies using the rapid immunofluorescent antibody test. Cattle with antibody titres >= 0.5 IU/ml were considered to be protected against rabies. Twenty-six of 27 adult cattle (96%) vaccinated once at less than five months old did not have protective titres. Sixty percent (6/10) cattle vaccinated once at around six months of age did have adequate titres. Cattle previously vaccinated twice (n=10; 100%) with an 18 month interval between inoculations, had protective titres and protective antibody titres following booster vaccination (n=51; 100%). The anamnestic response of cattle to a killed rabies vaccine was not affected by the time interval between vaccinations, which ranged from 12 to 36 months. These results suggest that calves from vaccinated cows should not be vaccinated before six months old to avoid maternal antibody interference. Whilst most cattle older than six months old will be protected after a single inoculation, a second inoculation ensures a higher antibody levels for improved protection. Cattle receiving an effective priming dose responded well to a booster up to 36 months later. Such results demonstrate the effectiveness of rabies vaccination in cattle and the added value of a second dose to ensure a prolonged immune response against rabies. PMID- 26032722 TI - Investigating the potential of reported cattle mortality data in Switzerland for syndromic surveillance. AB - Systems for the identification and registration of cattle have gradually been receiving attention for use in syndromic surveillance, a relatively recent approach for the early detection of infectious disease outbreaks. Real or near real-time monitoring of deaths or stillbirths reported to these systems offer an opportunity to detect temporal or spatial clusters of increased mortality that could be caused by an infectious disease epidemic. In Switzerland, such data are recorded in the "Tierverkehrsdatenbank" (TVD). To investigate the potential of the Swiss TVD for syndromic surveillance, 3 years of data (2009-2011) were assessed in terms of data quality, including timeliness of reporting and completeness of geographic data. Two time-series consisting of reported on-farm deaths and stillbirths were retrospectively analysed to define and quantify the temporal patterns that result from non-health related factors. Geographic data were almost always present in the TVD data; often at different spatial scales. On farm deaths were reported to the database by farmers in a timely fashion; stillbirths were less timely. Timeliness and geographic coverage are two important features of disease surveillance systems, highlighting the suitability of the TVD for use in a syndromic surveillance system. Both time series exhibited different temporal patterns that were associated with non-health related factors. To avoid false positive signals, these patterns need to be removed from the data or accounted for in some way before applying aberration detection algorithms in real-time. Evaluating mortality data reported to systems for the identification and registration of cattle is of value for comparing national data systems and as a first step towards a European-wide early detection system for emerging and re emerging cattle diseases. PMID- 26032720 TI - Control of organ growth by patterning and hippo signaling in Drosophila. AB - Control of organ size is of fundamental importance and is controlled by genetic, environmental, and mechanical factors. Studies in many species have pointed to the existence of both organ-extrinsic and -intrinsic size-control mechanisms, which ultimately must coordinate to regulate organ size. Here, we discuss organ size control by organ patterning and the Hippo pathway, which both act in an organ-intrinsic fashion. The influence of morphogens and other patterning molecules couples growth and patterning, whereas emerging evidence suggests that the Hippo pathway controls growth in response to mechanical stimuli and signals emanating from cell-cell interactions. Several points of cross talk have been reported between signaling pathways that control organ patterning and the Hippo pathway, both at the level of membrane receptors and transcriptional regulators. However, despite substantial progress in the past decade, key questions in the growth-control field remain, including precisely how and when organ patterning and the Hippo pathway communicate to control size, and whether these communication mechanisms are organ specific or general. In addition, elucidating mechanisms by which organ-intrinsic cues, such as patterning factors and the Hippo pathway, interface with extrinsic cues, such as hormones to control organ size, remain unresolved. PMID- 26032723 TI - Sheffield NHS trust and council pay L27,000 in damages after failing to agree patient's care budget. PMID- 26032719 TI - Neurogenesis in the adult avian song-control system. AB - New neurons are added throughout the forebrain of adult birds. The song-control system is a model to investigate the addition of new long-projection neurons to a cortical circuit that regulates song, a learned sensorimotor behavior. Neuroblasts destined for the song nucleus HVC arise in the walls of the lateral ventricle, and wander through the pallium to reach HVC. The survival of new HVC neurons is supported by gonadally secreted testosterone and its downstream effectors including neurotrophins, vascularization, and electrical activity of postsynaptic neurons in nucleus RA (robust nucleus of the arcopallium). In seasonal species, the HVC->RA circuit degenerates in nonbreeding birds, and is reconstructed by the incorporation of new projection neurons in breeding birds. There is a functional linkage between the death of mature HVC neurons and the birth of new neurons. Various hypotheses for the function of adult neurogenesis in the song system can be proposed, but this remains an open question. PMID- 26032725 TI - Control of bovine tuberculosis in New Zealand in the face of a wildlife host: a compiled review of 50 years of programme policy, design and research. PMID- 26032724 TI - Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study. AB - We investigated whether the gut microbiota differed in 48 postmenopausal breast cancer case patients, pretreatment, vs 48 control patients. Microbiota profiles in fecal DNA were determined by Illumina sequencing and taxonomy of 16S rRNA genes. Estrogens were quantified in urine. Case-control comparisons employed linear and unconditional logistic regression of microbiota alpha-diversity (PD_whole tree) and UniFrac analysis of beta-diversity, with two-sided statistical tests. Total estrogens correlated with alpha-diversity in control patients (Spearman Rho = 0.37, P = .009) but not case patients (Spearman Rho = 0.04, P = .77). Compared with control patients, case patients had statistically significantly altered microbiota composition (beta-diversity, P = .006) and lower alpha-diversity (P = .004). Adjusted for estrogens and other covariates, odds ratio of cancer was 0.50 (95% confidence interval = 0.30 to 0.85) per alpha diversity tertile. Differences in specific taxa were not statistically significant when adjusted for multiple comparisons. This pilot study shows that postmenopausal women with breast cancer have altered composition and estrogen independent low diversity of their gut microbiota. Whether these affect breast cancer risk and prognosis is unknown. PMID- 26032727 TI - Discovery of benzylidene derivatives as potent Syk inhibitors: synthesis, SAR analysis, and biological evaluation. AB - Four scaffolds of varied benzylidene derivatives were synthesized and evaluated as Syk inhibitors for the treatment of rheumatoid arthritis (RA). Among these 31 compounds, 3-benzylidene pyrrolidine-2,5-dione derivatives (including 12k) universally showed good Syk inhibitory activities in the low micromolar to submicromolar range. In the cellular profiling, compound 12k, the most efficient compound, showed excellent antiproliferative activity against fibroblast-like synoviocytes (FLS)-RA, and demonstrated potencies for suppression of IL-6 and MMP 3 secretion almost equal to R406 (positive control). The oral efficacy of 12k in the murine collagen-induced arthritis model was significant, despite being weaker than R406. Taken together, all preliminary pharmacological results supported 12k as a potential small-molecule inhibitor targeting Syk for the treatment of RA. PMID- 26032728 TI - Characterizing the Free-Energy Landscape of MDM2 Protein-Ligand Interactions by Steered Molecular Dynamics Simulations. AB - Inhibition of p53-MDM2 interaction by small molecules is considered to be a promising approach to re-activate wild-type p53 for tumor suppression. Several inhibitors of the MDM2-p53 interaction were designed and studied by the experimental methods and the molecular dynamics simulation. However, the unbinding mechanism was still unclear. The steered molecular dynamics simulations combined with Brownian dynamics fluctuation-dissipation theorem were employed to obtain the free-energy landscape of unbinding between MDM2 and their four ligands. It was shown that compounds 4 and 8 dissociate faster than compounds 5 and 7. The absolute binding free energies for these four ligands are in close agreement with experimental results. The open movement of helix II and helix IV in the MDM2 protein-binding pocket upon unbinding is also consistent with experimental MDM2-unbound conformation. We further found that different binding mechanisms among different ligands are associated with H-bond with Lys51 and Glu25. These mechanistic results may be useful for improving ligand design. PMID- 26032726 TI - The hypoxic tumor microenvironment and drug resistance against EGFR inhibitors: preclinical study in cetuximab-sensitive head and neck squamous cell carcinoma cell lines. AB - BACKGROUND: Increased expression of the epidermal growth factor receptor (EGFR) is observed in more than 90% of all head and neck squamous cell carcinomas (HNSCC). Therefore, EGFR has emerged as a promising therapeutic target. Nevertheless, drug resistance remains a major challenge and an important potential mechanism of drug resistance involves the hypoxic tumor microenvironment. Therefore, we investigated the cytotoxic effect of the EGFR targeting agents cetuximab and erlotinib under normoxia versus hypoxia. FINDINGS: Three cetuximab-sensitive HNSCC cell lines (SC263, LICR-HN2 and LICR-HN5) were treated with either cetuximab or erlotinib. Cells were incubated under normal or reduced oxygen conditions (<0.1% O2) for 24 or 72 h immediately after drug addition. Cell survival was assessed with the sulforhodamine B assay. Cetuximab and erlotinib established a dose-dependent growth inhibition under both normal and prolonged reduced oxygen conditions in all three HNSCC cell lines. However, a significantly increased sensitivity to cetuximab was observed in SC263 cells exposed to hypoxia for 72 h (p = 0.05), with IC50 values of 2.38 +/- 0.59 nM, 0.64 +/- 0.38 nM, and 0.10 +/- 0.05 nM under normoxia, hypoxia for 24 h and hypoxia for 72 h, respectively. LICR-HN5 cells showed an increased sensitivity towards erlotinib when cells were incubated under hypoxia for 24 h (p = 0.05). CONCLUSIONS: Our results suggest that both EGFR-inhibitors cetuximab and erlotinib maintain their growth inhibitory effect under hypoxia. These results suggest that resistance to anti-EGFR therapy in HNSCC is probably not the result of hypoxic regions within the tumor and other mechanisms are involved. PMID- 26032729 TI - The effects of a tailored intensive care unit delirium prevention protocol: A randomized controlled trial. AB - BACKGROUND: A decreased incidence of delirium following the application of non pharmacologic intervention protocols to several patient populations has been previously reported. However, few studies have been conducted to examine the effects of their application to intensive care unit (ICU) patients. OBJECTIVES: To examine the effects of applying a tailored delirium preventive protocol, developed by the authors, to ICU patients by analyzing its effects on delirium incidence, in-hospital mortality, ICU readmission, and length of ICU stay in a Korean hospital. DESIGN: A single-blind randomized controlled trial. SETTINGS: A 1049-bed general hospital with a 105-bed ICU. PARTICIPANTS: Sixty and 63 ICU patients were randomly assigned to the intervention and control groups, respectively. METHODS: The researchers applied the delirium prevention protocol to the intervention group every day for the first 7 days of ICU hospitalization. Delirium incidence, mortality, and re-admission to the ICU during the same hospitalization period were analyzed by logistic regression analysis; the 7- and 30-day in-hospital mortality by Kaplan-Meier survival and Cox proportional hazard regression analysis; and length of ICU stay was assessed by linear regression analysis. RESULTS: Application of the protocol had no significant effect on delirium incidence, in-hospital mortality, re-admission to the ICU, or length of ICU stay. Whereas the risk of 30-day in-hospital mortality was not significantly lower in the intervention than in the control group (OR: 0.33; 95% CI: 0.10 1.09), we found a significantly decreased 7-day in-hospital mortality in the intervention group after protocol application (HR: 0.09; 95% CI: 0.01-0.72). CONCLUSIONS: Application of a tailored delirium prevention protocol to acute stage patients during the first 7 days of ICU hospitalization appeared to reduce the 7-day in-hospital risk of mortality only for this patient population. PMID- 26032730 TI - The relationship of staffing and work environment with implicit rationing of nursing care in Swiss nursing homes--A cross-sectional study. AB - BACKGROUND: Implicit rationing of nursing care refers to the withdrawal of or failure to carry out necessary nursing care activities due to lack of resources, in the literature also described as missed care, omitted care, or nursing care left undone. Under time constraints, nurses give priority to activities related to vital medical needs and the safety of the patient, leaving out documentation, rehabilitation, or emotional support of patients. In nursing homes, little is known about the occurrence of implicit rationing of nursing care and possible contributing factors. OBJECTIVES: The purpose of this study was (1) to describe levels and patterns of self-reported implicit rationing of nursing care in Swiss nursing homes and (2) to explore the relationship between staffing level, turnover, and work environment factors and implicit rationing of nursing care. DESIGN: Cross-sectional, multi-center sub-study of the Swiss Nursing Home Human Resources Project (SHURP). SETTINGS: Nursing homes from all three language regions of Switzerland. PARTICIPANTS: A random selection of 156 facilities with 402 units and 4307 direct care workers from all educational levels (including 25% registered nurses). METHODS: We utilized data from established scales to measure implicit rationing of nursing care (Basel Extent of Rationing of Nursing Care), perceptions of leadership ability and staffing resources (Practice Environment Scale of the Nursing Work Index), teamwork and safety climate (Safety Attitudes Questionnaire), and work stressors (Health Professions Stress Inventory). Staffing level and turnover at the unit level were measured with self-developed questions. Multilevel linear regression models were used to explore the proposed relationships. RESULTS: Implicit rationing of nursing care does not occur frequently in Swiss nursing homes. Care workers ration support in activities of daily living, such as eating, drinking, elimination and mobilization less often than documentation of care and the social care of nursing homes residents. Statistically significant factors related to implicit rationing of care were the perception of lower staffing resources, teamwork and safety climate, and higher work stressors. Unit staffing and turnover levels were not related to rationing activities. CONCLUSIONS: Improving teamwork and reducing work stressors could possibly lead to less implicit rationing of nursing care. Further research on the relationship of implicit rationing of nursing care and resident and care worker outcomes in nursing homes is requested. PMID- 26032731 TI - Personalised nutrition: the role of new dietary assessment methods. AB - Food records or diaries, dietary recalls and FFQ are methods traditionally used to measure dietary intake; however, advancing technologies and growing awareness in personalised health have heightened interest in the application of new technologies to assess dietary intake. Dietary intake data can be used in epidemiology, dietary interventions and in the delivery of personalised nutrition advice. Compared with traditional dietary assessment methods, new technologies have many advantages, including their ability to automatically process data and provide personalised dietary feedback advice. This review examines the new technologies presently under development for the assessment of dietary intakes, and their utilisation and efficacy for personalising dietary advice. New technology-based methods of dietary assessment can broadly be categorised into three key areas: online (web-based) methods, mobile methods and sensor technologies. Several studies have demonstrated that utilising new technologies to provide tailored advice can result in positive dietary changes and have a significant impact on selected nutrient and food group intakes. However, comparison across studies indicates that the magnitude of change is variable and may be influenced by several factors, including the frequency and type of feedback provided. Future work should establish the most effective combinations of these factors in facilitating dietary changes across different population groups. PMID- 26032732 TI - Interaction of frataxin, an iron binding protein, with IscU of Fe-S clusters biogenesis pathway and its upregulation in AmpB resistant Leishmania donovani. AB - Leishmania donovani is a unicellular protozoon parasite that causes visceral leishmaniasis (VL), which is a fatal disease if left untreated. Certain Fe-S proteins of the TCA cycle and respiratory chain have been found in the Leishmania parasite but the precise mechanisms for their biogenesis and the maturation of Fe S clusters remains unknown. Fe-S clusters are ubiquitous cofactors of proteins that perform critical cellular functions. The clusters are biosynthesized by the mitochondrial Iron-Sulphur Cluster (ISC) machinery with core protein components that include the catalytic cysteine desulphurase IscS, the scaffold proteins IscU and IscA, and frataxin as an iron carrier/donor. However, no information regarding frataxin, its regulation, or its role in drug resistance is available for the Leishmania parasite. In this study, we characterized Ld-frataxin to investigate its role in the ISC machinery of L. donovani. We expressed and purified the recombinant Ld-frataxin protein and observed its interaction with Ld IscU by co-purification and pull-down assay. Furthermore, we observed that the cysteine desulphurase activity of the purified Ld-IscS protein was stimulated in the presence of Ld-frataxin and Ld-IscU, particularly in the presence of iron; neither Ld-frataxin nor Ld-IscU alone had significant effects on Ld-IscS activity. Interestingly, RT-PCR and western blotting showed that Ld-frataxin is upregulated in AmpB-resistant isolates compared to sensitive strains, which may support higher Fe-S protein activity in AmpB-resistant L. donovani. Additionally, Ld-frataxin was localized in the mitochondria, as revealed by digitonin fractionation and indirect immunofluorescence. Thus, our results suggest the role of Ld-frataxin as an iron binding/carrier protein for Fe-S cluster biogenesis that physically interacts with other core components of the ISC machinery within the mitochondria. PMID- 26032734 TI - Minimal, negligible and negligent interventions. AB - Many interventions are not disruptive enough of the patterns that entrench poor health and health inequities. Ways forward may require a break with tradition to embrace system-focussed theory, complex logic modelling, and ways of funding and responding to problems that address the competition of ideas and needs. PMID- 26032733 TI - Intervenable factors associated with suicide risk in transgender persons: a respondent driven sampling study in Ontario, Canada. AB - BACKGROUND: Across Europe, Canada, and the United States, 22-43 % of transgender (trans) people report a history of suicide attempts. We aimed to identify intervenable factors (related to social inclusion, transphobia, or sex/gender transition) associated with reduced risk of past-year suicide ideation or attempt, and to quantify the potential population health impact. METHODS: The Trans PULSE respondent-driven sampling (RDS) survey collected data from trans people age 16+ in Ontario, Canada, including 380 who reported on suicide outcomes. Descriptive statistics and multivariable logistic regression models were weighted using RDS II methods. Counterfactual risk ratios and population attributable risks were estimated using model-standardized risks. RESULTS: Among trans Ontarians, 35.1 % (95 % CI: 27.6, 42.5) seriously considered, and 11.2 % (95 % CI: 6.0, 16.4) attempted, suicide in the past year. Social support, reduced transphobia, and having any personal identification documents changed to an appropriate sex designation were associated with large relative and absolute reductions in suicide risk, as was completing a medical transition through hormones and/or surgeries (when needed). Parental support for gender identity was associated with reduced ideation. Lower self-reported transphobia (10(th) versus 90(th) percentile) was associated with a 66 % reduction in ideation (RR = 0.34, 95 % CI: 0.17, 0.67), and an additional 76 % reduction in attempts among those with ideation (RR = 0.24; 95 % CI: 0.07, 0.82). This corresponds to potential prevention of 160 ideations per 1000 trans persons, and 200 attempts per 1,000 with ideation, based on a hypothetical reduction of transphobia from current levels to the 10(th) percentile. CONCLUSIONS: Large effect sizes were observed for this controlled analysis of intervenable factors, suggesting that interventions to increase social inclusion and access to medical transition, and to reduce transphobia, have the potential to contribute to substantial reductions in the extremely high prevalences of suicide ideation and attempts within trans populations. Such interventions at the population level may require policy change. PMID- 26032735 TI - The countertransference: When painful traumatic traces sustain the countertransference and reveal themselves to the psychoanalyst ... 14 years later! AB - Although she experienced, as did the many psychoanalysts before her, the countertransferential dynamics of disgust towards a patient presenting great deficiency in terms of mentalization capacity, the author strives to understand what urged her to tolerate the patient, to invest in her and lead her to develop a capacity for internalization, after 6 years of analytic work filled with transgressive-transferential acting-out. Fourteen years later, she becomes aware of the way in which the revival of some grief related to traumatic traces in her own lived experience, sustained, without her knowledge, a saviour/countertransference, creating a specific transferential countertransferential spiral which rescued a situation whose advent could have been compromised. This could happen thanks to what she refers to as the unique inter-relation between her and this particular patient. PMID- 26032736 TI - Activity involvement and quality of life of people at different stages of dementia in long term care facilities. AB - OBJECTIVES: Involvement in activities is assumed to positively influence the quality of life of people with dementia, yet activity provision in long-term care remains limited. This study aims to provide more insight into the value of activity involvement for domains of the quality of life of long-term dementia care residents, taking resident characteristics and cognitive status into account. METHOD: Data were derived from 144 long-term care facilities participating in the second measurement (2010/2011) of the living arrangements for dementia study. Amongst 1144 residents, the relationship between time involved in activities (activity pursuit patterns; RAI-MDS) and quality of life (Qualidem) was studied using multilevel linear regression analyses. Analyses were adjusted for residents' age, gender, neuropsychiatric symptoms, ADL dependency and cognition. To check for effect modification of cognition, interactions terms of the variables activity involvement and cognitive status were added to the analyses. RESULTS: Despite resident's cognitive status, their activity involvement was significantly related to better scores on care relationship, positive affect, restless tense behaviour, social relations, and having something to do. A negative relationship existed between the activity involvement and positive self-image. The explained variance in the quality of life between residents caused by the activity involvement was small. CONCLUSION: Activity involvement seems to be a small yet important contributor to higher well-being in long-term care resident at all stages of dementia. Adjusting activities to individual preferences and capabilities might enlarge this relationship. Further research is needed to confirm this hypothesis, using measurement instruments less sensitive to recall bias and differentiating between the active and passive activity involvement. PMID- 26032737 TI - Controversial fluorescence in situ hybridization cytogenetic abnormalities in chronic lymphocytic leukaemia: new insights from a large cohort. AB - The significance of rarer cytogenetic abnormalities in chronic lymphocytic leukaemia (CLL) remains controversial. We performed fluorescence in situ hybridization (FISH) prior to initial therapy on 618 CLL patients seen at our centre between 2005 and 2012. With a median follow-up of 5.6 years, we found that 55 patients harbouring 14q32 rearrangements without t(14;18) had a shorter time to first treatment (TTFT) (median 26 months, P = 0.03) than patients with t(14;18) (median not reached). Patients with mono- or bi-allelic del(13q) as a sole abnormality had a similarly long TTFT (median not reached). Those patients who harboured 3 or more FISH abnormalities without del(17p) had a short TTFT (4.6 months), comparable to patients with del(17p) (8 months); however, the overall survival for patients with 3 or more FISH abnormalities was longer than for patients with del(17p) with 0 or 1 additional abnormalities (median not reached vs. 54 months). FISH cytogenetics remains a useful genetic tool in the clinic, even in the era of next generation sequencing and, as such, our data provide valuable new insights for counselling patients. PMID- 26032738 TI - Pharmaceutical companies and their drugs on social media: a content analysis of drug information on popular social media sites. AB - BACKGROUND: Many concerns have been raised about pharmaceutical companies marketing their drugs directly to consumers on social media. This form of direct to-consumer advertising (DTCA) can be interactive and, because it is largely unmonitored, the benefits of pharmaceutical treatment could easily be overemphasized compared to the risks. Additionally, nonexpert consumers can share their own drug product testimonials on social media and illegal online pharmacies can market their services on popular social media sites. There is great potential for the public to be exposed to misleading or dangerous information about pharmaceutical drugs on social media. OBJECTIVE: Our central aim was to examine how pharmaceutical companies use social media to interact with the general public and market their drugs. We also sought to analyze the nature of information that appears in search results for widely used pharmaceutical drugs in the United States on Facebook, Twitter, and YouTube with a particular emphasis on the presence of illegal pharmacies. METHODS: Content analyses were performed on (1) social media content on the Facebook, Twitter, and YouTube accounts of the top 15 pharmaceutical companies in the world and (2) the content that appears when searching on Facebook, Twitter, and YouTube for the top 20 pharmaceutical drugs purchased in the United States. Notably, for the company-specific analysis, we examined the presence of information similar to various forms of DTCA, the audience reach of company postings, and the quantity and quality of company consumer interaction. For the drug-specific analysis, we documented the presence of illegal pharmacies, personal testimonials, and drug efficacy claims. RESULTS: From the company-specific analysis, we found information similar to help-seeking DTCA in 40.7% (301/740) of pharmaceutical companies' social media posts. Drug product claims were present in only 1.6% (12/740) of posts. Overall, there was a substantial amount of consumers who interacted with pharmaceutical companies through commenting (23.9%, 177/740). For the drug-specific analysis, we found that the majority of search results contained drug product claims (69.4%, 482/695); more claims mentioned only benefits (44.8%, 216/482) relative to only risks (27.2%, 131/482). Additionally, approximately 25% (150/603) of posts on Twitter and YouTube were presented as personal testimonials. A considerable percentage of content on Facebook contained advertisements for illegal online pharmacies (17%, 16/92). CONCLUSIONS: Pharmaceutical companies avoid making drug product claims on their social media accounts but frequently post content that is consistent with FDA definitions for help-seeking DTCA. Thousands of people often view content posted by pharmaceutical companies on social media; users also share company postings making both direct and indirect influence possible. Finally, people are likely to be exposed to drug product claims and information about illegal pharmacies when searching for information about popular pharmaceutical drugs on social media. PMID- 26032739 TI - Optimistic, pessimistic, realistic: Event-related potential evidence for how depressive symptoms influences expectation formation in the Human brain. AB - Recent research suggested a link between the prediction mechanism and depressive symptoms. While healthy people tend to maintain unrealistic optimism in the face of reality challenging their beliefs, depressed people show systematic pessimism. However, it remains unclear at which stage these individual differences in optimism/pessimism arise in the brain. In the current study we designed a simple gambling task with two difficulty levels, the easy game and the hard game. Participants were required to press one of four keys to gain a bonus signalled by a sinusoidal tone. For three of the four keys, the probability of getting a large bonus was 80% in the easy game and 8% in the hard game. In both games, the fourth key, randomly determined in each trial, yielded a large bonus with a probability of 100%. This arrangement allowed us to observe less/more depressed participants' optimistic/pessimistic expectations about hitting the key that guarantees a large bonus. The opposite expectation patterns of less/more depressed participants were reflected on the N1 amplitude. Meanwhile, all participants were well aware of the true probability of obtaining certain bonus in each game as reflected on the P3 amplitude. The results suggest that the subjective system (tracking subjective beliefs) and the objective system (tracking objective evidence) are dissociable in the human brain, with the former feeding information into sensory areas and the latter representing prediction errors on a higher level. Moreover, individual differences arise from variability in the former rather than the latter. PMID- 26032740 TI - The effect of concentration and duration of normobaric oxygen in reducing caspase 3 and -9 expression in a rat-model of focal cerebral ischaemia. AB - The aim of this study was to determine the effect of different concentrations of normobaric oxygen (NBO) on neurological function and the expression of caspase-3 and -9 in a rat model of acute cerebral ischaemia. Sprague-Dawley rats (n=120) were randomly divided into four groups (n=30 per group), including 3 groups given NBO at concentrations of 33%, 45% or 61% and one control group given air (21% oxygen). After 2h of ischaemic occlusion, each group was further subdivided into six subgroups (n=5) during reperfusion according to the duration (3, 6, 12, 24, 48 or 72h) and concentration of NBO (33%, 45% or 61%) or air treatment. The Fluorescence Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to detect caspase-3 and -9 mRNA and protein relative expression respectively. The Neurologic Impairment Score (NIS) was significantly lower in rats given 61% NBO >=3h after reperfusion when compared to the control group (P<0.05, Mann-Whitney U). NBO significantly reduced caspase-3 and -9 mRNA and protein expression when compared to the control group at all NBO concentrations and time points (P<0.05, ANOVA). The expression of caspase-3 and 9 was lower in the group given 61% NBO compared any other group, and this difference was statistically significant when compared to the group given 33% NBO for >=48h and the control group (both P<0.05, ANOVA). These findings indicate that NBO may inhibit the apoptotic pathway by reducing caspase-3 and -9 expression, thereby promoting neurological functional recovery after stroke. PMID- 26032741 TI - A statistical comparison of EEG time- and time-frequency domain representations of error processing. AB - Successful behavior relies on error detection and subsequent remedial adjustment of behavior. Researchers have identified two electrophysiological signatures of error processing: the time-domain error-related negativity (ERN), and the time frequency domain increased power in the delta/theta frequency bands (~2-8 Hz). The relationship between these two signatures is not entirely clear: on the one hand they occur after the same type of event and with similar latency, but on the other hand, the time-domain ERP component contains only phase-locked activity whereas the time-frequency response additionally contains non-phase-locked dynamics. Here we examined the ERN and error-related delta/theta activity in relation to each other, focusing on within-subject analyses that utilize single trial data. Using logistic regression, we constructed three statistical models in which the accuracy of each trial was predicted from the ERN, delta/theta power, or both. We found that both the ERN and delta/theta power worked roughly equally well as predictors of single-trial accuracy (~70% accurate prediction). Furthermore, a model including both measures provided a stronger overall prediction compared to either model alone. Based on these findings two conclusions are drawn: first, the phase-locked part of the EEG signal appears to be roughly as predictive of single-trial response accuracy as the non-phase locked part; second, the single-trial ERP and delta/theta power contain both overlapping and independent information. PMID- 26032743 TI - Bilateral primary motor cortex circuitry is modulated due to theta burst stimulation to left dorsal premotor cortex and bimanual training. AB - Motor preparatory and execution activity is enhanced after a single session of bimanual visuomotor training (BMT). Recently, we have shown that increased primary motor cortex (M1) excitability occurs when BMT involves simultaneous activation of homologous muscles and these effects are enhanced when BMT is preceded by intermittent theta burst stimulation (iTBS) to the left dorsal premotor cortex (lPMd). The neural mechanisms underlying these modulations are unclear, but may include interhemispheric interactions between homologous M1s and connectivity with premotor regions. The purpose of this study was to investigate the possible intracortical and interhemispheric modulations of the extensor carpi radials (ECR) representation in M1 bilaterally due to: (1) BMT, (2) iTBS to lPMd, and (3) iTBS to lPMd followed by BMT. This study tests three related hypotheses: (1) BMT will enhance excitability within and between M1 bilaterally, (2) iTBS to lPMd will primarily enhance left M1 (lM1) excitability, and (3) the combination of these interventions will cause a greater enhancement of bilateral M1 excitability. We used single and paired-pulse transcranial magnetic stimulation (TMS) to quantify M1 circuitry bilaterally. The results demonstrate the neural mechanisms underlying the early markers of rapid functional plasticity associated with BMT and iTBS to lPMd primarily relate to modulations of long-interval inhibitory (i.e. GABAB-mediated) circuitry within and between M1s. This work provides novel insight into the underlying neural mechanisms involved in M1 excitability changes associated with BMT and iTBS to lPMd. Critically, this work may inform rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury. PMID- 26032742 TI - Changes in brain volume in response to estradiol levels, amphetamine sensitization and haloperidol treatment in awake female rats. AB - Estrogen has been shown to further ameliorate symptoms when administered in conjunction with antipsychotics in patients with schizophrenia. We have previously shown that chronic haloperidol (HAL) treatment reduces amphetamine (AMPH)-induced locomotor activity in AMPH-sensitized rats, but only when paired with high levels of the estrogen, 17-beta estradiol. In addition, we reported estradiol-dependent responses to AMPH in AMPH-sensitized rats as measured by functional magnetic resonance imaging. It is thus clear that estradiol and antipsychotics both affect the rat brain, however the mechanism by which this occurs is unknown. The aim of the current study was to assess this interaction by investigating the effects of estradiol, AMPH and HAL on brain volume changes in awake female rats. Repeated exposure to AMPH resulted in an overall reduction in brain volume, regardless of hormonal status (i.e. no, low or high estradiol). Similarly, chronic HAL treatment further reduced brain volume compared to acute treatment. Hormonal status affected hippocampal volume with rats receiving low estradiol replacement showing larger volume; this difference was no longer significant after repeated exposure to AMPH. Finally, we found changes in volume in response to AMPH throughout hippocampal components (i.e. CA1-CA3 and dentate) as well as components of the mesocortical system. In conclusion, brain volume seems to be influenced by hormonal status, as well as exposure to AMPH and haloperidol treatment. These findings implicate areas where estradiol, amphetamine and antipsychotics may be producing volumetric changes in the brain, pointing the way to where future studies should focus. PMID- 26032744 TI - Physical training improves non-spatial memory, locomotor skills and the blood brain barrier in diabetic rats. AB - Type 1 diabetes mellitus (T1DM) progressively affects cognitive domains, increases blood-brain barrier (BBB) permeability and promotes neurovascular impairment in specific brain areas. Physical exercise, on the other hand, has beneficial effects on brain functions, improving learning and memory. This study investigated the effects of treadmill training on cognitive and motor behavior, and on the expression of proteins related to BBB integrity, such as claudin-5 and aquaporin-4 (AQP4) in the hippocampus and striatum in diabetic rats. For this study, 60 Wistar rats were divided into four groups (n=15 per group): non-trained control (NTC), trained control (TC), non-trained diabetic (NTD), trained diabetic (TD). After diabetic induction of 30 days by streptozotocin injection, the exercise groups were submitted to 5 weeks of running training. After that, all groups were assessed in a novel object-recognition task (NOR) and the rotarod test. Additionally, claudin-5 and AQP4 levels were measured using biochemical assays. The results showed that exercise enhanced NOR task performance and rotarod ability in the TC and TD animals. Diabetes produced a decrease in claudin 5 expression in the hippocampus and striatum and reduced AQP4 in the hippocampus. Exercise preserved the claudin-5 content in the striatum of TD rats, but not in the hippocampus. The reduction of AQP4 levels produced by diabetes was not reversed by exercise. We conclude that exercise improves short-term memory retention, enhances motor performance in diabetic rats and affects important structural components of the striatal BBB. The results obtained could enhance the knowledge regarding the neurochemical benefits of exercise in diabetes. PMID- 26032745 TI - Comparison of Wells and Revised Geneva Rule to Assess Pretest Probability of Pulmonary Embolism in High-Risk Hospitalized Elderly Adults. AB - OBJECTIVES: To assess and compare the diagnostic power for pulmonary embolism (PE) of Wells and revised Geneva scores in two independent cohorts (training and validation groups) of elderly adults hospitalized in a non-emergency department. DESIGN: Prospective clinical study, January 2011 to January 2013. SETTING: Unit of Internal Medicine inpatients, University of Catania, Italy. PARTICIPANTS: Elderly adults (mean age 76 +/- 12), presenting with dyspnea or chest pain and with high clinical probability of PE or D-dimer values greater than 500 ng/mL (N = 203), were enrolled and consecutively assigned to a training (n = 101) or a validation (n = 102) group. The clinical probability of PE was assessed using Wells and revised Geneva scores. MEASUREMENTS: Clinical examination, D-dimer test, and multidetector computed angiotomography were performed in all participants. The accuracy of the scores was assessed using receiver operating characteristic analyses. RESULTS: PE was confirmed in 46 participants (23%) (24 training group, 22 validation group). In the training group, the area under the receiver operating characteristic curve was 0.91 (95% confidence interval (CI) = 0.85-0.98) for the Wells score and 0.69 (95% CI = 0.56-0.82) for the revised Geneva score (P < .001). These results were confirmed in the validation group (P < .05). The positive (LR+) and negative likelihood ratios (LR-) (two indices combining sensitivity and specificity) of the Wells score were superior to those of the revised Geneva score in the training (LR+, 7.90 vs 1.34; LR-, 0.23 vs 0.66) and validation (LR+, 13.5 vs 1.46; LR-, 0.47 vs 0.54) groups. CONCLUSION: In high-risk elderly hospitalized adults, the Wells score is more accurate than the revised Geneva score for diagnosing PE. PMID- 26032746 TI - Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases. AB - This short article examines the usefulness of fast simulations of conformational transition paths in elucidating enzymatic mechanisms and guiding drug discovery for protein kinases. It applies the transition path method in the MOIL software package to simulate the paths of conformational transitions between six pairs of structures from the Protein Data Bank. The structures along the transition paths were found to resemble experimental structures that mimic transient structures believed to form during enzymatic catalysis or conformational transitions, or structures that have drug candidates bound. These findings suggest that such simulations could provide quick initial insights into the enzymatic mechanisms or pathways of conformational transitions of proteins kinases, or could provide structures useful for aiding structure-based drug design. PMID- 26032747 TI - Biobanking of Human Retinas: The Next Big Leap for Eye Banks? AB - Retinal degenerative diseases are one of the main clinical causes of incurable and severe visional impairment. Thus, extensive research effort is put into the development of new causal therapeutic options. Promisingly, a number of studies showed regenerative capacity in specific retinal regions (the ciliary epithelium, retinal pigmented epithelium, iris, and Muller glia cells). However, most recent research studies are based on animal models or in vitro cultured cells, probably because of the limited availability of human posterior eye tissues (vitreous, retina, and choroid). To address this, we showed in our previous reports that eye banks with large numbers of globes collected yearly could set up biorepositories/biobanks where these precious tissues are isolated, quality controlled, and finally stored for scientists and clinicians wanting to access human tissues and test their own hypotheses. These precious human posterior eye tissues could be used for further research purposes, epidemiological studies, and target validation of newly developed drugs. In addition, this could be a promising and challenging option to retrieve potential retinal stem and progenitor cells from different parts of the retina and could be a breakthrough in the future delivery of ex vivo prepared customized (histocompatible) retinal tissue on scaffolds for transplantation purposes. In this Perspective, we will consider how the biorepositories could influence the future strategies for retinal stem cell therapies. PMID- 26032748 TI - Autologous Hematopoietic Stem Cell Transplantation-10 Years of Data From a Developing Country. AB - Intensive chemotherapy followed by autologous stem cell transplantation is the treatment of choice for patients with hematological malignancies. The objective of the present study was to evaluate the outcomes of patients with mainly lymphoma and multiple myeloma after autologous stem cell transplant. The pretransplant workup consisted of the complete blood count, an evaluation of the liver, kidney, lung, and infectious profile, chest radiographs, and a dental review. For lymphoma, all patients who achieved at least a 25% reduction in the disease after salvage therapy were included in the study. Mobilization was done with cyclophosphamide, followed by granulocyte colony-stimulating factor, 300 ug twice daily. The conditioning regimens included BEAM (carmustine, etoposide, cytarabine, melphalan) and high-dose melphalan. A total of 206 transplants were performed from April 2004 to December 2014. Of these, 137 were allogeneic transplants and 69 were autologous. Of the patients receiving an autologous transplant, 49 were male and 20 were female. Of the 69 patients, 26 underwent transplantation for Hodgkin's lymphoma, 23 for non-Hodgkin's lymphoma, and 15 for multiple myeloma and 4 and 1 for Ewing's sarcoma and neuroblastoma, respectively. The median age +/- SD was 34 +/- 13.1 years (range, 4-64). A mean of 4.7 * 108 +/ 1.7 mononuclear cells per kilogram were infused. The median time to white blood cell recovery was 18.2 +/- 5.34 days. Transplant-related mortality occurred in 10 patients. After a median follow-up period of 104 months, the overall survival rate was 86%. High-dose chemotherapy, followed by autologous stem cell transplant, is an effective treatment option for patients with hematological malignancies, allowing further consolidation of response. PMID- 26032749 TI - Assessment of the Tumorigenic Potential of Spontaneously Immortalized and hTERT Immortalized Cultured Dental Pulp Stem Cells. AB - Dental pulp stem cells (DPSCs) provide an exciting new avenue to study neurogenetic disorders. DPSCs are neural crest-derived cells with the ability to differentiate into numerous tissues including neurons. The therapeutic potential of stem cell-derived lines exposed to culturing ex vivo before reintroduction into patients could be limited if the cultured cells acquired tumorigenic potential. We tested whether DPSCs that spontaneously immortalized in culture acquired features of transformed cells. We analyzed immortalized DPSCs for anchorage-independent growth, genomic instability, and ability to differentiate into neurons. Finally, we tested both spontaneously immortalized and human telomerase reverse transcriptase (hTERT)-immortalized DPSC lines for the ability to form tumors in immunocompromised animals. Although we observed increased colony-forming potential in soft agar for the spontaneously immortalized and hTERT-immortalized DPSC lines relative to low-passage DPSC, no tumors were detected from any of the DPSC lines tested. We noticed some genomic instability in hTERT-immortalized DPSCs but not in the spontaneously immortalized lines tested. We determined that immortalized DPSC lines generated in our laboratory, whether spontaneously or induced, have not acquired the potential to form tumors in mice. These data suggest cultured DPSC lines that can be differentiated into neurons may be safe for future in vivo therapy for neurobiological diseases. PMID- 26032750 TI - Reponse to 'Estimating the autonomic function from heart rate variability in mechanically ventilated patients after spinal cord injury'. PMID- 26032751 TI - Estimating the autonomic function from heart rate variability in mechanically ventilated patients after spinal cord injury. PMID- 26032752 TI - Perspectives on strategies and challenges in the conversation about stem cells for spinal cord injury. AB - STUDY DESIGN: Qualitative study. OBJECTIVE: To examine how trusted communication between individuals with spinal cord injury (ISCIs) and physicians who care for ISCIs is affected by the discussion of advances in stem cell research and interventions locally and abroad. SETTING: Canada and the United States (US). METHODS: Semi-structured interviews with ISCIs and physicians. A thematic analysis approach was applied to more than 12 h of data to derive prominent themes and describe relationships between them. RESULTS: A convergence of factors involving transparency impact trusted communication between ISCIs and physicians about stem cells and spinal cord injury (SCI). ISCIs expressed that trusted communication is strengthened when physicians exhibit caring, attentive and positive attitudes that are underpinned by domain-specific knowledge and scholarship. Perceived reluctance to communicate or lack of knowledge poses significant challenges. Physicians also emphasised the importance of transparency for trusted communication but expressed that the still limited clinical reality of treatment choices for SCI and the pressures imposed by external resources are significant stressors that complicate the communication landscape. Both groups cited the range and variable quality of information sources, and the difficulty associated with navigating them, as priorities for action that would remediate these tensions. CONCLUSIONS: (1) Epistemic transparency should be privileged over silence. (2) A new generation of innovations in research and clinical trial dissemination about stem cells for SCI is needed to remedy the perceived inadequacies of existing information content and accessibility. PMID- 26032753 TI - Variation in warfarin prescribing and dosing in the UK: a national survey of anticoagulation clinics. AB - WHAT IS KNOWN AND OBJECTIVE: Clinical practice in the initiation, prescribing, dosing and monitoring of warfarin in the UK varies, but this has not been adequately documented. The objective was to undertake a survey on current clinical practice in this area, and how it compares with national guidelines that have been developed by the British Committee for Standards in Haematology. METHODS: A national online survey of anticoagulation clinics was performed using Survey Monkey((r)) . The survey was designed to capture data for prescribing, dosing and monitoring of anticoagulation with warfarin. RESULTS: Of 85 clinics who responded to the survey, most were run by secondary care (68%), facilitated by specialist nurses (58%) and followed standard guidelines for the management of warfarin (87%). The majority of clinics indicated their target international normalized ratio (INR) for patients with atrial fibrillation (AF) (69/73; 94.5%) was between 2.0 and 3.0, but the indicated target INR for mechanical heart valves was more variable. Initiation and loading dosing regimens were a major source of variability with uncertainty surrounding individual patient factors such as age, ethnicity and BMI. WHAT IS NEW AND CONCLUSIONS: Current practice amongst UK anticoagulation clinics largely follows current national guidelines but better guidance on dosing, taking into account factors that determine interindividual variability in daily warfarin dose requirements would improve and standardize oral anticoagulation with warfarin. PMID- 26032754 TI - Polymyalgia rheumatica: strategies for efficient practice and quality assurance. AB - Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease in persons over the age of 50 years. There are many diseases which mimic PMR, for which reason a careful diagnostic approach is required. While it is thought to be exquisitely responsive to glucocorticosteroid therapy, many patients respond incompletely and/or develop serious side effects over the protracted disease course. Improved methods for classification and disease assessment together with standardized treatment approaches and outcome assessments can serve to improve the care of patients with this disease. PMID- 26032755 TI - Student perspectives on post-simulation debriefing. AB - BACKGROUND: Structured debriefing is an essential part of effective learning from simulation. The advocacy-inquiry method (AIM) is a newer debriefing model where the facilitator seeks to understand the student's underlying rationale for their decisions. METHODS: We surveyed two cohorts of 21 final-year medical students who had experienced AIM debriefing during a simulation programme across two semesters. Data were collected on students' prior experience of debriefing, their perceptions of being involved in AIM, and which aspects of the curriculum they felt AIM addressed best. RESULTS: The age ranged from 22 to 31 years; 74 per cent (n = 31) were female. Fifty-seven per cent (n = 24) of the group had prior experience of simulation and 88 per cent of these (n = 21) had experienced dedicated debriefing time, mainly using Pendleton's guidelines. Ninety-one per cent (n = 38) of the students felt that the area covered best using AIM was clinical assessment. Seventy-one per cent of students (n = 30) felt that they were encouraged to 'explore and challenge [their] underlying thoughts, attitudes and beliefs' during the debriefing. Only two students (5%) agreed with the statement that they felt uncomfortable during the debriefing exercise. Students in the second semester were less likely to want the lead clinician to 'just tell me what to do' (p = 0.009). Students perceive AIM as an acceptable method of debriefing DISCUSSION: Our findings demonstrate that students perceive AIM as an acceptable method of debriefing. We suggest that the second cohort's attitudes towards being 'told what to do' are the result of maturing learning styles throughout their final year. The direct questioning involved is acceptable to the majority of students and we encourage the use of AIM debriefing in an undergraduate setting. PMID- 26032756 TI - Pharyngeal-cervical-brachial/Miller-Fisher overlap: A possible central variant. PMID- 26032757 TI - Outcomes of inhaled nitric oxide in preterm neonates - a five-year experience in a tertiary neonatal centre. AB - AIM: To review the outcome of preterm neonates treated with iNO. METHODS: The neonatal electronic database was reviewed between April 1, 2009 and March 31, 2014. RESULTS: In the five-year period, 142 babies were treated with iNO. Forty two preterm neonates <34(+0) weeks were included in this review. During this period, the use of iNO in preterm neonates <26(+0) weeks rose from 1.4% to 4.8% and the mortality was significantly higher in this group (69%). CONCLUSION: There is an increasing trend in using iNO as a rescue treatment in preterm neonates. The outcomes were very poor in the preterm neonates <26(+0) weeks. A cautious approach is warranted in the absence of robust evidence to support the use of iNO, in preterm neonates <26(+0) weeks. PMID- 26032758 TI - A novel approach to the management of a central giant cell granuloma with denosumab: A case report and review of current treatments. AB - PURPOSE: To describe the efficacy of denosumab in the treatment of an aggressive giant cell granuloma of the mandible. METHODS: Denosumab was administered to a patient with a large aggressive giant cell granuloma of the mandible resistant to standard medical therapy. The effectiveness and response was measured on the basis of patient symptoms and radiological parameters. RESULTS: A significant reduction in patient symptoms was reported in association with tumour regression on follow up radiographs. CONCLUSION: This report demonstrates potential use of denosumab in aggressive giant cell granulomas of the jaws that have been resistant to medical therapy. PMID- 26032759 TI - Polyetheretherketone custom-made implants for craniofacial defects: Report of 14 cases and review of the literature. AB - BACKGROUND: Craniofacial defects tend to carry functional and esthetic consequences for the patient. The complex shapes in this region make such reconstructions a challenging procedure and the most suitable material to be used remains controversial. METHODS: We report a series of 14 patients whose craniofacial defects were reconstructed using a computer designed PEEK-PSI (Polyetheretherketone- Patient Specific Implant). We analyzed the complications and outcomes of PEEK custom-made implants and compared our results with those of other case series reported in the current literature. RESULTS: Fourteen patients underwent craniofacial reconstruction using a PEEK-PSI. Three cases involved a one-step primary reconstruction and the rest of cases underwent a delayed reconstruction. Two cases (14.3 %) presented infection and only in one case was the implant definitively removed. Esthetic results were considered to be highly satisfactory. CONCLUSION: With CAD-CAM techniques, it is possible to prefabricate an individual implant. The ideal material for reconstructing maxillofacial defects does not exist, but PEEK has demonstrated good outcomes. When autologous bone is not available or, in selected cases with large or complex defects in the maxillofacial area, PEEK is one of the best options to reconstruct these defects. However, further studies are needed to determine the long-term results. PMID- 26032760 TI - Survival predictor for penetrating cardiac injury; a 10-year consecutive cohort from a scandinavian trauma center. AB - BACKGROUND: Penetrating cardiac injuries in Europe have been poorly studied. We present a 10-year outcome for patients with penetrating heart injuries at Oslo University Hospital. METHODS: Data from 01.01.2001 until 31.12.2010 was collected from the Oslo University Hospital Trauma Registry and from the patients' records. RESULTS: Thirty-one patients were admitted with a penetrating cardiac injury. Fourteen patients survived (45%). Four out of 8 patients (50%) with gunshot wounds survived compared to 10 out of 23 (44%) with stab wounds. Median (quartiles) for the following values were: Injury Severity Score 25 (21-35), Revised Trauma Score 0 (0-6,9), Probability of Survival 0,015 (0,004-0,956), Glasgow Coma Scale 3 (3-13). Thirteen patients had signs of life on admission and survived. Eighteen patients were admitted without signs of life and received emergency department thoracotomy. Eight of these had no signs of life at the scene of injury and did not survive. Out of the remaining 10 patients, one survived. CONCLUSIONS: The outcome of patients with penetrating cardiac injury reaching the emergency department with signs of life was excellent. Hemodynamic instability indicates immediate surgery. Stable patients with penetrating thoracic trauma and possible cardiac injury detected by imaging should be considered for conservative treatment. PMID- 26032761 TI - Synthesis of Cyclic Carbonates Catalysed by Aluminium Heteroscorpionate Complexes. AB - New aluminium scorpionate based complexes have been prepared and used for the synthesis of cyclic carbonates from epoxides and carbon dioxide. Bimetallic aluminium(heteroscorpionate) complexes 9-14 were synthesised in very high yields. The single-crystal X-ray structures of 12 and 13 confirm an asymmetric kappa(2) NO-MU-O arrangement in a dinuclear molecular disposition. These bimetallic aluminium complexes were investigated as catalysts for the synthesis of cyclic carbonates from epoxides and carbon dioxide in the presence of ammonium salts. Under the optimal reaction conditions, complex 9 in combination with tetrabutylammonium bromide acts as a very efficient catalyst system for the conversion of both monosubstituted and internal epoxides into the corresponding cyclic carbonates showing broad substrate scope. Complex 9 and tetrabutylammonium bromide is the second most efficient aluminium-based catalyst system for the reaction of internal epoxides with carbon dioxide. A kinetic study has been carried out and showed that the reactions were first order in complex 9 and tetrabutylammonium bromide concentrations. Based on the kinetic study, a catalytic cycle is proposed. PMID- 26032762 TI - Neonatal outcome after fetal anemia managed by intrauterine transfusion. AB - In-utero transfusion is now well under control and improves the survival of foetuses monitored for fetal anemia with a survival rate of more than 80 %. The aim was to evaluate short-term neonatal outcome after fetal severe anemia managed by intrauterine transfusions. We did a retrospective study of all neonates born after management of severe fetal anemia (n = 93) between January 1999 and January 2013 in our regional center. The two main causes of anemia were maternal red blood cell alloimmunization (N = 81, 87 %) and Parvovirus B19 infection (N = 10, 10.8 %). In the alloimmunization group, phototherapy was implemented in 85.2 % of cases with a maximum level of bilirubin of 114.4 +/- 60.7 (mg/dl). Transfusion and exchange transfusion were, respectively, required in 51.9 % and in 34.6 % of cases. One neonate presented a convulsive episode, and we observed three neonatal deaths. In the parvovirus group, none of the child had anemia at birth and no management was necessary. CONCLUSION: Contemporary management of Rhesus disease is associated with encouraging neonatal outcomes. In case of Parvovirus infection, no specific management is necessary at. But, in all cases of fetal anemia, children should be followed up with particular attention to neurologic development. WHAT IS KNOWN: * In-utero transfusion is now well under control and improves the survival of fetuses monitored for fetal anemia. * Limited studies are available on the effect of IUT on postnatal outcome in infants with a history of fetal anemia. What is New: * Contemporary management of severe Rhesus disease is associated with encouraging neonatal outcomes. * The majority of infants can be managed with phototherapy and a limited number of top-up transfusions and exchange transfusions. In case of Parvovirus infection, the short-term neonatal outcome is excellent. PMID- 26032763 TI - Carbon Monoxide Poisoning from Portable Electrical Generators. AB - BACKGROUND: Portable electrical generators have been responsible for over 800 accidental carbon monoxide (CO) poisoning deaths in the United States from 1999 2012. OBJECTIVES: Because mortality figures are typically the only data reported with regard to the adverse effects of generators, we describe a nonfatal segment of the poisoned population to further emphasize the significance of the problem. METHODS: Unidentifiable information about patients treated in the United States with hyperbaric oxygen for acute CO poisoning was prospectively reported by participating centers. Those patients poisoned by portable generators were selected for analysis. RESULTS: Of 1604 patients reported from August 1, 2008 to July 31, 2011, there were 264 accidentally poisoned by portable generators. Exposures occurred in 151 incidents in 33 states. In 99 incidents, poisoning occurred in a residence. Average patient age was 37 +/- 20 years (range 1 to 90+ years). Of those poisoned, 146 (55%) were non-Hispanic white, 57 (22%) were black, 52 (20%) were Hispanic white, 4 (2%) were Asian, and 4 (2%) were Native American. English was spoken by 96%. The most common symptoms included headache (62%), dizziness (52%), and loss of consciousness (50%). Blood carboxyhemoglobin levels averaged 22.7 +/- 9.0% (range 2.3-48.3%). Thirty-six patients demonstrated evidence of cardiac ischemia. CONCLUSIONS: Acute, severe CO poisoning from portable electric generators is common in the United States, likely affecting an estimated 4000 individuals annually, occurring predominantly in residential settings, and affecting English language-speaking individuals. PMID- 26032764 TI - Impact of Mixed Aortic Valve Stenosis on VARC-2 Outcomes and Postprocedural Aortic Regurgitation in Patients Undergoing Transcatheter Aortic Valve Implantation: Results From the International Multicentric Study PRAGMATIC (Pooled Rotterdam-Milan-Toulouse in Collaboration). AB - OBJECTIVES: We sought to evaluate the impact of mixed aortic stenosis (MAS) on postprocedural aortic regurgitation (PPAR) and clinical outcomes after transcatheter aortic valve implantation (TAVI). BACKGROUND: The impact of MAS of TAVI outcomes is unknown. METHODS AND RESULTS: Data from a multicenter registry were retrospectively analysed. Outcomes were compared between patients with pure aortic stenosis (PAS; associated AR<1+/3+) and MAS (associated AR>=1+/3+). Study objectives were PPAR incidence and short- and long-term mortality. Overall, 1,062 patients were included: 419 (39.4%) with MAS and 643 (60.5%) with PAS. At 30 days, there were no differences in mortality, however, a higher incidence of major bleeding (22.7% vs. 16.8%; P=0.016), PPAR>=1+/3+ (42.6% vs. 26.5%; P<0.001) and lower device success (89.3% vs. 93.3%; P=0.019) was observed in patients with MAS. Of note, MAS was an independent predictor of PPAR>=1+/3+ at multivariable analysis (OR: 2.882; CI: 1.851-4.488; P<0.001). At 2 years of follow-up, no survival differences were present between MAS and PAS groups. Similarly, following stratification for PPAR>=1+/3+, MAS had no protective effect on survival as compared with PAS. CONCLUSIONS: MAS was associated with lower device success and higher PPAR incidence. However, despite these findings, it had no influence on long-term postoperative outcomes. PMID- 26032765 TI - Three new strategies to improve the accuracy of monothermal caloric screening testing. AB - OBJECTIVE: The objective was to find a way to estimate the value of inter-ear difference (IED) through monothermal caloric screening testing (MCST) that can be used at any laboratory, controlling and minimising the resulting error. METHODS: We retrospectively included in this study 2304 patients from our department to whom a videonystagmography with caloric testing was performed between 2003 and 2011. The IED was calculated in 3 different ways: Using the values of the 4 caloric stimulations (bithermal form) and using only the 2 same-temperature values (warm monothermal and cool monothermal forms). We studied 3 strategies to improve the accuracy of MCST: Analysis of variables that could impair the prediction, delimitation of a grey area of insufficient prediction and location of a maximum utility cut-off point. RESULTS: Correcting Jongkees' formula with the value for spontaneous nystagmus makes it possible to include subjects with spontaneous nystagmus or nystagmus inversion. Establishing 2 cut-off points to classify the subjects avoids approximately 38% of bithermal stimulations performed with a sensitivity and specificity of 95%. Maximum utility was obtained diagnosing as healthy those subjects with IED values lesser than or equal to 16% in warm MCST when the pathological IED was set as greater than 20%. CONCLUSION: New statistical tools help clinicians to make decisions that affect their patients based on the results of MCST. PMID- 26032766 TI - Perineuronal net degradation in epilepsy. AB - OBJECTIVE: We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin-positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE. METHODS: The pilocarpine chemoconvulsant rodent epilepsy model was used to characterize the degradation of the aggrecan component of the PN in the hippocampus following SE. Chondroitinase ABC (ChABC) was used to degrade the PN in mice. Onset, number, and duration of pentylenetetrazole (PTZ)-induced seizures were assessed. RESULTS: The loss of the PN in the hippocampus following SE is at least partially related to degradation of the aggrecan PN component by MMP activity. Forty-eight hours after SE, a neoepitope created by MMP cleavage of aggrecan was present and concentrated around parvalbumin-positive interneurons. The increase in aggrecan cleavage products was found at 48 h, 1 week, and 2 months after SE, with different fragments predominating over time. We demonstrate ongoing aggrecan proteolysis and fragment accumulation in the hippocampus of adult control rats, as well as in SE-treated animals. Degradation of the PN alters the seizure response to PTZ. ChABC treatment caused an increase in myoclonic seizures following PTZ administration, a delayed onset of Racine stage 4/5 seizure, and a decreased duration of Racine stage 4/5 seizure. SIGNIFICANCE: Status epilepticus increases MMP proteolysis of aggrecan, pointing to MMP activity as one mechanism of PN degradation post-SE. There is accumulation of aggrecan fragments in adult rat hippocampus of both control and SE-exposed animals. Loss of the PN was associated with increased numbers of myoclonic seizures; it also, delayed and shortened the duration of Racine stage 4/5 seizures, suggesting a complex relationship between the PN and seizure susceptibility. PMID- 26032767 TI - What are the primary influences on treatment decisions? How does this reflect on evidence-based practice? Indications from the discipline of speech and language therapy. AB - RATIONALE, AIMS AND OBJECTIVES: Four pillars of evidence underpin evidence-based behavioural practice: research evidence, practice evidence, patient evidence and contextual evidence. However, it is unknown which of these pillars or other factors are used by clinicians such as speech and language therapists (SLTS) when making treatment choices. The aim of this study was to identify the factors underpinning SLTs' treatment decisions and contextualize findings in terms of evidence-based practice (EBP). METHODS: Ethical approval was obtained for the electronic questionnaire-based study. A questionnaire was designed, piloted and then sent via gatekeepers to SLTs to ascertain agreement with a range of statements potentially underpinning treatment choices. RESULTS: A total of 249 respondents completed the survey. The respondents defined themselves as dynamic and pragmatic practitioners with an appreciation for the four pillars of EBP. Using factor analysis, treatment decisions were found to rely primarily on practice evidence and pragmatic considerations. Qualifications, clinical experience and the patient group an SLT works with further influenced attitudes and treatment decisions. Those with additional qualifications and experience were identified as more autonomous, more scientific in their treatment choices and less influenced by patient preferences. CONCLUSION: Factors influencing decision making did not clearly align with the four pillars of EBP, the principal influences being practice evidence and pragmatic constraints. The findings of this study have implications for understanding why specific treatment choices are made. Attempts to improve practice should focus on a range of evidence sources and take into account clinician's specific needs depending on career stage, post qualification status and patient group factors of their practice. PMID- 26032768 TI - Increased CRP levels may be a trait marker of suicidal attempt. AB - Suicide is a leading cause of death worldwide. Identifying biomarkers will help enhance our understanding of suicidal pathophysiology and improve its prevention. Therefore, we investigated CRP levels in 600 depressed inpatients: 520 patients had a lifetime history of suicide attempts and 80 patients did not have any history of suicide attempts. For all patients, we assessed socio-demographic features, lifetime Axis I DSM-IV diagnoses, depression intensity, suicidal ideation, characteristics of suicidal history, and history of childhood trauma. The day following admission, fasting blood tests yielded samples collected for the measurement of high sensitivity hs-CRP. CRP levels were associated with a history of suicide attempts. The risk of suicide attempts increased with higher levels of CRP in a dose-response way before and after adjustments for age, gender, chronic diseases, addiction and anxiety comorbidities, antidepressants use, smoking status and sexual abuse. Noteworthy, the association between CRP levels and history of suicide attempts remained significant after having excluded patients with chronic diseases. There was no significant difference in CRP levels between patients who attempted suicide more or less than a week before plasma sampling, and no significant difference in CRP levels was evidenced between high vs low suicidal ideation. In conclusion, this is the first study suggesting that CRP may be a trait marker for suicidal vulnerability by associating CRP levels and a lifetime history of suicide attempts in depressed inpatients. Therefore, determining the inflammatory marker profile of individuals exhibiting suicidal behaviors could be relevant for anticipating behaviors and refining new therapeutic opportunities. PMID- 26032769 TI - Platelet-derived extracellular vesicles in plateletpheresis concentrates as a quality control approach. AB - BACKGROUND: Platelet-derived extracellular vesicles (PL-EVs) are present in plateletpheresis concentrates (PCs) and may influence the quality of PCs. The aim of the study was to analyze PC-derived PL-EVs and to correlate them with standard quality control (QC) variables of PCs and with donor-specific laboratory variables. STUDY DESIGN AND METHODS: PL-EVs were analyzed by standard as well as advanced high-sensitivity flow cytometry (FCM) and nanoparticle tracking analysis. A hematology analyzer was applied to the determination of platelet (PLT) count and immature PLT fraction (IPF). Functional capacity of PLTs (CD62P in response to thrombin receptor-activating peptide 6 activation) was measured by FCM. All in vitro measurements were carried out on Day 0 and on Day 5. Altogether, a total of 42 PC samples, 15 irradiated on Day 0, were investigated. RESULTS: Externalization of CD62P, as an indicator of intact PLT function, significantly decreased during in vitro PLT senescence and CD62P expression inversely correlated with increased PL-EV levels. Interestingly, in fresh PCs a significant correlation was found between PL-EVs and different hemapheresis instruments, duration of apheresis, and IPF count in peripheral blood of the donor before apheresis. In senescent PCs, the body mass index of donors inversely correlated with the PL-EV counts. CONCLUSION: Loss of PLT function in PCs was associated with increased PL-EV levels. Shedding of PL-EVs depends on shear stress influenced by different hemapheresis settings and diverse preanalytical conditions of donors. PL-EV analysis may stimulate new quality and apheresis strategies for more vital PLTs for transfusion. PMID- 26032770 TI - Cas9-chromatin binding information enables more accurate CRISPR off-target prediction. AB - The CRISPR system has become a powerful biological tool with a wide range of applications. However, improving targeting specificity and accurately predicting potential off-targets remains a significant goal. Here, we introduce a web-based CR: ISPR/Cas9 O: ff-target P: rediction and I: dentification T: ool (CROP-IT) that performs improved off-target binding and cleavage site predictions. Unlike existing prediction programs that solely use DNA sequence information; CROP-IT integrates whole genome level biological information from existing Cas9 binding and cleavage data sets. Utilizing whole-genome chromatin state information from 125 human cell types further enhances its computational prediction power. Comparative analyses on experimentally validated datasets show that CROP-IT outperforms existing computational algorithms in predicting both Cas9 binding as well as cleavage sites. With a user-friendly web-interface, CROP-IT outputs scored and ranked list of potential off-targets that enables improved guide RNA design and more accurate prediction of Cas9 binding or cleavage sites. PMID- 26032771 TI - Mechanism of heat stress-induced cellular senescence elucidates the exclusive vulnerability of early S-phase cells to mild genotoxic stress. AB - Heat stress is one of the best-studied cellular stress factors; however, little is known about its delayed effects. Here, we demonstrate that heat stress induces p21-dependent cellular senescence-like cell cycle arrest. Notably, only early S phase cells undergo such an arrest in response to heat stress. The encounter of DNA replication forks with topoisomerase I-generated single-stranded DNA breaks resulted in the generation of persistent double-stranded DNA breaks was found to be a primary cause of heat stress-induced cellular senescence in these cells. This investigation of heat stress-induced cellular senescence elucidates the mechanisms underlying the exclusive sensitivity of early S-phase cells to ultra low doses of agents that induce single-stranded DNA breaks. PMID- 26032772 TI - I-COMS: Interprotein-COrrelated Mutations Server. AB - Interprotein contact prediction using multiple sequence alignments (MSAs) is a useful approach to help detect protein-protein interfaces. Different computational methods have been developed in recent years as an approximation to solve this problem. However, as there are discrepancies in the results provided by them, there is still no consensus on which is the best performing methodology. To address this problem, I-COMS (interprotein COrrelated Mutations Server) is presented. I-COMS allows to estimate covariation between residues of different proteins by four different covariation methods. It provides a graphical and interactive output that helps compare results obtained using different methods. I COMS automatically builds the required MSA for the calculation and produces a rich visualization of either intraprotein and/or interprotein covariating positions in a circos representation. Furthermore, comparison between any two methods is available as well as the overlap between any or all four methodologies. In addition, as a complementary source of information, a matrix visualization of the corresponding scores is made available and the density plot distribution of the inter, intra and inter+intra scores are calculated. Finally, all the results can be downloaded (including MSAs, scores and graphics) for comparison and visualization and/or for further analysis. PMID- 26032774 TI - Risk Factors for Severe Secondary Postpartum Hemorrhages: A Historical Cohort Study. AB - BACKGROUND: The predictive factors of secondary postpartum hemorrhage (PPH) are little known. Our principal objective was to determine if immediate PPH is a risk factor for severe secondary PPH. We also sought to identify other factors associated with severe secondary PPH. METHODS: Our historical cohort study included all women who gave birth (>= 22 weeks) in our level III hospital from 2004 through 2013. The hospital discharge database enabled us to identify all women readmitted during the 42-day postpartum period or who underwent a surgical, medical, or interventional radiology procedure during their immediate postpartum hospitalization. We then examined all medical records to identify the cases involving severe secondary PPH. We studied the known risk factors of secondary PPH and assessed other potential ones: maternal age, multiple pregnancy, induction of labor, cesarean birth, preterm birth, and stillbirth. RESULTS: The study included 63 women with a severe secondary PPH and 25,696 women without a secondary PPH. Immediate PPH (aOR 2.7 [95% CI 1.3-5.6]) and maternal age >= 35 years (aOR 2.0 [95% CI 1.1-3.7]) were the only factors associated with severe secondary PPH. DISCUSSION: This cohort study confirms that immediate PPH is a risk factor for severe secondary PPH and reports for the first time an association between secondary PPH and advanced maternal age. It is likely that risk factors for immediate PPH are also risk factors for severe secondary PPH and thus that immediate PPH may be an intermediate factor between its own known risk factors and secondary PPH. PMID- 26032773 TI - Quantification of mesocosm fish and amphibian species diversity via environmental DNA metabarcoding. AB - Freshwater fauna are particularly sensitive to environmental change and disturbance. Management agencies frequently use fish and amphibian biodiversity as indicators of ecosystem health and a way to prioritize and assess management strategies. Traditional aquatic bioassessment that relies on capture of organisms via nets, traps and electrofishing gear typically has low detection probabilities for rare species and can injure individuals of protected species. Our objective was to determine whether environmental DNA (eDNA) sampling and metabarcoding analysis can be used to accurately measure species diversity in aquatic assemblages with differing structures. We manipulated the density and relative abundance of eight fish and one amphibian species in replicated 206-L mesocosms. Environmental DNA was filtered from water samples, and six mitochondrial gene fragments were Illumina-sequenced to measure species diversity in each mesocosm. Metabarcoding detected all nine species in all treatment replicates. Additionally, we found a modest, but positive relationship between species abundance and sequencing read abundance. Our results illustrate the potential for eDNA sampling and metabarcoding approaches to improve quantification of aquatic species diversity in natural environments and point the way towards using eDNA metabarcoding as an index of macrofaunal species abundance. PMID- 26032775 TI - Family Violence and Child Sexual Abuse Among South Asians in the US. AB - Family violence, including child sexual abuse (CSA), is a significant public health problem in the United States. It is particularly difficult to assess family violence and CSA among South Asians because it is often hidden due to cultural and familial stigma. A web-based survey was administered to a convenience sample (n = 368) of South Asian adults in the US. One-fourth (25.2 %) of the sample reported CSA; 13.8 % reported abuse involving exposure; 21.5 % reported abuse involving touching; 4.5 % reported attempted sexual intercourse; and 3.5 % reported forced sexual intercourse. Adjusted odds ratios found that participants who reported any relationship violence were significantly more likely to have experienced CSA (OR 2.28; 95 % CI 1.26-4.13); and suicide attempt was significantly associated with CSA (OR 3.96; 95 % CI 1.27-12.3). The findings presented in this formative study will assist in guiding future studies and interventions for South Asians in the United States. PMID- 26032776 TI - Assessment of acute oxaliplatin-induced cold allodynia: a pilot study. AB - BACKGROUND: Following oxaliplatin treatment, acute neurotoxicity symptoms are suggested to be correlated with both the development and degree of chronic neuropathy. AIMS: The aim of this clinical commentary was to examine different methods to assess acute cold allodynia and dysesthesia in patients treated with adjuvant oxaliplatin. METHODS: Nine patients over the age of 18 years scheduled for standard adjuvant treatment with capecitabine and oxaliplatin were included. Patients were asked to come for two visits: a baseline visit before and a follow up visit within 5 days after treatment. Patients were examined with questionnaires, thermal tests, and the thermal grill. RESULTS: All patients reported neurotoxicity, and they all had abnormal cold sensitivity. The only significant changes observed were increased ratings of pain, unpleasantness, and pricking sensations to holding a ~8 degrees C metal cylinder for 10 s and an increased intensity of unpleasantness and pricking sensation to the 20-s contact with the 10 degrees C plates of the thermal grill on the palmar hand. CONCLUSIONS: he results showed that the palm of the hand is the most sensitive part of the body when detecting oxaliplatin-induced cold allodynia, and the use of a cold metal cylinder seems as a promising sensitive method. PMID- 26032777 TI - The core root microbiome of sugarcanes cultivated under varying nitrogen fertilizer application. AB - Diazotrophic bacteria potentially supply substantial amounts of biologically fixed nitrogen to crops, but their occurrence may be suppressed by high nitrogen fertilizer application. Here, we explored the impact of high nitrogen fertilizer rates on the presence of diazotrophs in field-grown sugarcane with industry standard or reduced nitrogen fertilizer application. Despite large differences in soil microbial communities between test sites, a core sugarcane root microbiome was identified. The sugarcane root-enriched core taxa overlap with those of Arabidopsis thaliana raising the possibility that certain bacterial families have had long association with plants. Reduced nitrogen fertilizer application had remarkably little effect on the core root microbiome and did not increase the relative abundance of root-associated diazotrophs or nif gene counts. Correspondingly, low nitrogen fertilizer crops had lower biomass and nitrogen content, reflecting a lack of major input of biologically fixed nitrogen, indicating that manipulating nitrogen fertilizer rates does not improve sugarcane yields by enriching diazotrophic populations under the test conditions. Standard nitrogen fertilizer crops had improved biomass and nitrogen content, and corresponding soils had higher abundances of nitrification and denitrification genes. These findings highlight that achieving a balance in maximizing crop yields and minimizing nutrient pollution associated with nitrogen fertilizer application requires understanding of how microbial communities respond to fertilizer use. PMID- 26032778 TI - Contemporary management of phosphorus retention in chronic kidney disease: a review. AB - Hyperphosphatemia is the most common metabolic complications of end-stage kidney disease (ESKD). Large observational studies have identified hyperphosphatemia as an independent risk factor for cardiovascular disease and mortality in dialysis patients and subsequent studies found that subtle increases in serum phosphate levels even within the normal range are also associated with increased risk for death in predialysis and non-kidney disease population. On the basis of these results, current national practice guidelines advocate more aggressive treatment of hyperphosphatemia to lower serum phosphate targets than in the past . Treatment of hyperphosphatemia requires to strict management through dietary restriction, oral phosphate binders, and dialysis. Calcium-based phosphate binders have low cost and widespread use but cause vascular calcification and hypercalcemia. Non-calcium-based phosphate binders are effective but expensive. Bixalomer is a new Ca-free, metal-free, potent phosphate binder, non hydrochloride, and non-absorptive polymer, which improves metabolic acidosis. FGF 23 appears as a promising target for novel therapeutic approaches to improve clinical outcomes of CKD patients. This review focuses on novel therapeutic approaches dealing with hyperphosphatemia in chronic kidney disease. PMID- 26032779 TI - Improvement of NADPH-dependent P450-mediated biotransformation of 7alpha,15alpha diOH-DHEA from DHEA by a dual cosubstrate-coupled system. AB - Hydroxylation of DHEA to 7alpha,15alpha-diOH-DHEA was catalyzed by NADPH dependent cytochrome P450 monooxygenase from Colletotrichum lini. By adding coenzyme precursor nicotinic acid, the NADPH/NADP ratio was significantly increased, and the 7alpha,15alpha-diOH-DHEA molar conversion was enhanced from 37.37% to 50.85%. To improve the availability of intracellular NADPH, a dual cosubstrate-coupled system consisting of nicotinic acid and glucose was investigated in C. lini. Using 20mM nicotinic acid and 15g/L glucose as cosubstrate for NADPH regeneration, the 7alpha,15alpha-diOH-DHEA molar conversion was dramatically increased by 74.58%. The conversion course was simultaneously shortened by 30h. Moreover, a fed-batch transformation model was established to diminish DHEA toxicity to C. lini and further increase DHEA concentration. The maximum concentration of DHEA was elevated to 15g/L using a three-batch transformation in a coenzyme regeneration system, and 7alpha,15alpha-diOH-DHEA production of 11.21g/L could be achieved after 60h of biotransformation. These results demonstrated that this strategy was promising for steroids hydroxylation. PMID- 26032780 TI - "It's very complicated": a qualitative study of medicines management in intermediate care facilities in Northern Ireland. AB - BACKGROUND: Intermediate care (IC) describes a range of services targeted at older people, aimed at preventing unnecessary hospitalisation, promoting faster recovery from illness and maximising independence. Older people are at increased risk of medication-related adverse events, but little is known about the provision of medicines management services in IC facilities. This study aimed to describe the current provision of medicines management services in IC facilities in Northern Ireland (NI) and to explore healthcare workers' (HCWs) and patients' views of, and attitudes towards these services and the IC concept. METHODS: Semi structured interviews were conducted, recorded, transcribed verbatim and analysed using a constant comparative approach with HCWs and patients from IC facilities in NI. RESULTS: Interviews were conducted with 25 HCWs and 18 patients from 12 IC facilities in NI. Three themes were identified: 'concept and reality', 'setting and supply' and 'responsibility and review'. A mismatch between the concept of IC and the reality was evident. The IC facility setting dictated prescribing responsibilities and the supply of medicines, presenting challenges for HCWs. A lack of a standardised approach to responsibility for the provision of medicines management services including clinical review was identified. Whilst pharmacists were not considered part of the multidisciplinary team, most HCWs recognised a need for their input. Medicines management was not a concern for the majority of IC patients. CONCLUSIONS: Medicines management services are not integral to IC and medicine-related challenges are frequently encountered. Integration of pharmacists into the multidisciplinary team could potentially improve medicines management in IC. PMID- 26032782 TI - Validity of Medical Student Questionnaire Data in Prediction of Rural Practice Choice and Its Association With Service Orientation. AB - PURPOSE: The validity of medical student projection of, and predictors for, rural practice and the association of a measure of service orientation, projected practice accessibility to the indigent, were investigated. METHODS: West Virginia (WV) medical student online pre- and postrural rotation questionnaire data were collected during the time period 2001-2009. Of the 1,517 respondent students, submissions by 1,271 met the time interval criterion for inclusion in analyses. Subsequent WV licensing data were available for 461 in 2013. These 2 databases were used to assess for validity of projection of rural practice, for predictors of rural practice, and for student projected accessibility of the future practice to indigent patients. FINDINGS: There were statistically significant associations between both pre- and postrotation projections of rural practice and subsequent rural practice. The most significant independent predictors of rural practice were student rural background, reported primary care intent, prediction of rural practice and projection of greater accessibility of the future practice to indigent patients. For scoring of practice access, there were trends for higher scoring by rural students and rural practitioners, with greater pre-post increases for those with urban hometowns. CONCLUSIONS: This study demonstrates the utility of medical student questionnaires for projections of numbers of future rural physicians. It suggests that students with a rural background, rural practice intent, or greater service orientation are more likely to enter rural practice. It also suggests that students, particularly those with urban hometowns, are influenced by rural rotation experiences in forecasting greater practice accessibility and in entering rural practice. PMID- 26032781 TI - Association between human papillomavirus and Epstein - Barr virus DNA and gene promoter methylation of RB1 and CDH1 in the cervical lesions: a transversal study. AB - BACKGROUND: Human papillomavirus (HPV) inactivates the retinoblastoma 1 (RB1) gene by promoter methylation and reduces cellular E-cadherin expression by overexpression of DNA methyltransferase 1 (DNMT1). The Epstein-Barr virus (EBV) is an oncogenic virus that may be related to cervical carcinogenesis. In gastric cancer, it has been demonstrated that E-cadherin gene (CDH1) hypermethylation is associated with DNMT1 overexpression by EBV infection. Our aim was to analyze the gene promoter methylation frequency of RB1 and CDH1 and verify the association between that methylation frequency and HPV and EBV infection in cervical lesions. METHODS: Sixty-five samples were obtained from cervical specimens: 15 normal cervices, 17 low-grade squamous intraepithelial lesions (LSIL), 15 high-grade squamous intraepithelial lesions (HSIL), and 18 cervical cancers. HPV and EBV DNA testing was performed by PCR, and the methylation status was verified by MSP. RESULTS: HPV frequency was associated with cervical cancer cases (p = 0.005) but not EBV frequency (p = 0.732). Viral co-infection showed a statistically significant correlation with cancer (p = 0.027). No viral infection was detected in 33.3% (5/15) of controls. RB1 methylated status was associated with cancer (p = 0.009) and HPV infection (p = 0.042). CDH1 methylation was not associated with cancer (p = 0.181). Controls and LSIL samples did not show simultaneous methylation, while both genes were methylated in 27.8% (5/18) of cancer samples. In the presence of EBV, CDH1 methylation was present in 27.8% (5/18) of cancer samples. Only cancer cases presented RB1 promoter methylation in the presence of HPV and EBV (33.3%). CONCLUSIONS: The methylation status of both genes increased with disease progression. With EBV, RB1 methylation was a tumor-associated event because only the cancer group presented methylated RB1 with HPV infection. HPV infection was shown to be significantly correlated with cancer conditions. The global methylation frequency was higher when HPV was present, showing its epigenetic role in cervical carcinogenesis. Nevertheless, EBV seems to be a cofactor and needs to be further investigated. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1159157579149317 . PMID- 26032783 TI - Human and animal health on three continents--a biography of the early life of Karl Friedrich Meyer (1884-1974). AB - Karl Friedrich Meyer (KF) was born and educated as a veterinarian in Europe; he researched infectious diseases in Europe, South Africa and the United States. He is one of the true forefathers of the 'one health-one medicine' concept. The broad scope of his research covered botulism, leptospirosis, brucellosis, plague, ornithosis, Western equine encephalitis, mussel poisoning and clostridia. This manuscript adds some more details of his early biography. PMID- 26032784 TI - Evaluation of a polysaccharide conjugate vaccine to reduce colonization by Campylobacter jejuni in broiler chickens. AB - BACKGROUND: Campylobacter jejuni is a leading bacterial cause of food-borne illness in humans. Symptoms range from mild gastroenteritis to dysentery. Contaminated chicken meat is the most common cause of infection. Broiler chickens become colonized with high numbers of C. jejuni in the intestinal tract, but do not become clinically ill. Vaccination of broiler chicks to control colonization by C. jejuni is challenging because immune function is limited in the first 2 weeks post-hatch and immune suppressive maternal antibodies are common. In addition, there is little time for induction of immunity, since broilers reach slaughter weight by 5-6 weeks of age. In the current study the immunogenicity of a C. jejuni capsular polysaccharide-diphtheria toxoid conjugated vaccine (CPSconj), administered subcutaneously with various adjuvants was assessed and the efficacy of vaccination for reducing cecal colonization after experimental challenge was evaluated by determining colony-forming units (CFU) of C. jejuni in cecal contents. RESULTS: The CPSconj vaccine was immunogenic when administered as three doses at 3, 4 and 5 weeks of age to specific pathogen free chicks lacking maternal antibodies (seroconversion rates up to 75%). Commercial broiler chicks (having maternal antibodies) receiving two doses of CPSconj vaccine at 7 and 21 days of age did not seroconvert before oral challenge at 29 days, but 33% seroconverted post challenge; none of the placebo-injected, challenged birds seroconverted. Vaccinated birds had significantly lower numbers of C. jejuni in cecal contents than control birds at necropsy (38 days of age). CFU of C. jejuni did not differ significantly among groups of birds receiving CPSconj vaccine with different adjuvants. In two trials, the mean reduction in CFU associated with vaccination was 0.64 log10 units. CONCLUSIONS: The CPSconj vaccine was immunogenic in chicks lacking maternal antibodies, vaccinated beginning at 3 weeks of age. In commercial broiler birds (possessing maternal antibodies) vaccinated at 7 and 21 days of age, 33% of birds seroconverted by 9 days after challenge, and there was a modest, but significant, reduction in cecal counts of C. jejuni. Further studies are needed to optimize adjuvant, route of delivery and scheduling of administration of this vaccine. PMID- 26032785 TI - Emergent approaches to the meta-analysis of multiple heterogeneous complex interventions. AB - BACKGROUND: Multiple interventions meta-analysis has been recommended in the methodological literature as a tool for evidence synthesis when a heterogeneous set of interventions is included in the same review-and, more recently, when a heterogeneous set of complex interventions is included. However, there is little guidance on the use of this method with complex interventions. This article suggests two approaches to model complexity and heterogeneity through this method. DISCUSSION: 'Clinically meaningful units' groups interventions by modality or similar theory of change, whereas 'components and dismantling' separates out interventions into combinations of components and either groups interventions by the combination of components they demonstrate or extracts effects for each identified component and, possibly, interactions between components. Future work in systematic review methodology should aim to understand how to develop taxonomies of components or theories of change that are internally relevant to the studies in these multiple interventions meta-analyses. SUMMARY: Despite little meaningful prior guidance to its use in this context, multiple interventions meta-analysis has the potential to be a useful tool for synthesising heterogeneous sets of complex interventions. Researchers should choose an approach in accordance with their specific aims in their systematic review. PMID- 26032786 TI - Allocation of food allergy responsibilities and its correlates for children and adolescents. AB - This study examined the degree to which children and adolescents with food allergy accept responsibility for their own care, and the extent to which greater self-management is associated with past history of a life-threatening allergic reaction or anxiety. For children (n = 190), caregiver and patient report of self management was consistent, but agreement was poor for adolescent dyads (n = 59). History of a life-threatening allergic reaction was associated with greater self management for children only, while among adolescents, it was associated with greater anxiety. Given that shifting to self-management may be challenging, discussion and preparation about this process is warranted. PMID- 26032787 TI - Distraction, not hunger, is associated with lower mood and lower perceived work performance on fast compared to non-fast days during intermittent fasting. AB - Using a repeated measures design, 16 females recorded hunger, distraction, mood and perceived work performance on two consecutive fast days, on two earlier and on two subsequent consecutive non-fast days, during intermittent fasting. Using regression analyses, low positive mood was associated with higher distraction (beta = -0.38, p < 0.01), and lower perceived work performance was associated with higher distraction (beta = -0.50, p < 0.01) and lower positive mood (beta = 0.59, p = 0.01). No associations were found with hunger (largest beta = -0.11, p = 0.15). Associations between mood, perceived work performance and distraction but not hunger mirror those found in traditional dieting and suggest no benefit for attention from intermittent fasting-type regimes. PMID- 26032788 TI - Gut-directed guided affective imagery as an adjunct to dietary modification in irritable bowel syndrome. AB - This work aimed to study the effect of guided affective imagery on the irritable bowel syndrome. A total of 15 irritable bowel syndrome patients received guided affective imagery and 19 patients served as controls. Symptom severity and irritable bowel syndrome quality of life were measured at baseline and 8 weeks. Symptom severity decreased following guided affective imagery compared to controls (-1.5 +/- 1.9 vs 0.1 +/- 1.6, p = 0.04). Irritable bowel syndrome quality of life increased following guided affective imagery compared to controls (12.1 +/- 12.5 vs -0.7 +/- 16.2, p < 0.01). Guided affective imagery predicted reduced symptom severity (odds ratio = 5.71, p = 0.02) and increased irritable bowel syndrome quality of life (odds ratio = 17.88, p = 0.01). Guided affective imagery combined with dietary modification may be beneficial in the management of irritable bowel syndrome, however larger studies are required. PMID- 26032790 TI - Normal-weight and overweight female adolescents with and without extreme weight control behaviours: Emotional distress and body image concerns. AB - The objective of this study was to analyse emotional distress and concerns related to body image in 712 normal-weight and overweight adolescent girls. A total of 12.3 per cent of the normal-weight girls and 25 per cent of the overweight girls showed extreme weight-control behaviours. In normal-weight adolescents, their engagement in extreme weight-control behaviours was associated with high levels of somatic symptoms, a drive for thinness and control over eating. In overweight girls, high levels of drive for thinness and anxiety were associated with extreme weight-control behaviours. Finally, the implications for preventive and therapeutic programmes are discussed. PMID- 26032789 TI - Food cravings mediate the relationship between chronic stress and body mass index. AB - This study examined the relationships between chronic stress, food cravings, and body mass index. A community-based sample of adults (N = 619) completed a comprehensive assessment battery and heights and weights were measured. Chronic stress had a significant direct effect on food cravings, and food cravings had a significant direct effect on body mass index. The total effect of chronic stress on body mass index was significant. Food cravings partially mediated the relationship between chronic stress and body mass index. These findings are consistent with research that chronic stress may potentiate motivation for rewarding substances and behaviors and indicate that high food cravings may contribute to stress-related weight gain. PMID- 26032791 TI - Understanding self-reported staging of dietary behavior in low-income women. AB - This study examined self-reported staging for the goal of eating a low-fat diet and several specific dietary consumption behaviors to understand better readiness for dieting. Self-assessed motivation, food frequency measures, and psychosocial variables were obtained from 2057 low-income women enrolled in the Maryland Food for Life Program. Results indicated that staging of specific dietary consumption behaviors was significantly related to staging for the global goal of eating a low-fat diet. Women evaluate their motivation about eating low-fat diets based on perceived efforts and specific activities related to dietary consumption with important implications for dietary behavior change measurement and interventions. PMID- 26032792 TI - Body image and college women's quality of life: The importance of being self compassionate. AB - This study explored self-compassion as a mediator between body dissatisfaction, social comparison based on body image and quality of life in 662 female college students. Path analysis revealed that while controlling for body mass index, self compassion mediated the impact of body dissatisfaction and unfavourable social comparisons on psychological quality of life. The path model accounted for 33 per cent of psychological quality of life variance. Findings highlight the importance of self-compassion as a mechanism that may operate on the association between negative body image evaluations and young women's quality of life. PMID- 26032793 TI - The impact of a school-based gardening intervention on intentions and behaviour related to fruit and vegetable consumption in children. AB - A total of 77 children (34 boys, 43 girls, mean age +/- standard deviation = 9 +/ 1 years) participated in this study; 46 children (intervention) undertook a 12 week school gardening programme and 31 children acted as controls. Measures of the Theory of Planned Behaviour and fruit and vegetable consumption were taken pre- and post-intervention. Repeated measures analysis of variance and hierarchical regression analysis indicated that the intervention group increased daily consumption of fruits and vegetables and increased intentions, attitudes, norms, and perceived behavioural control related to fruit and vegetable consumption. Attitudes, norms and perceived behavioural control significantly predicted changes in fruit and vegetable consumption. PMID- 26032794 TI - Weight perception in overweight adolescents: Associations with body change intentions, diet and physical activity. AB - This study examined the association of weight perception and weight satisfaction with body change intentions and weight-related behaviours in 928 overweight adolescents (aged 11-18 years, 44% female). Accurate perception of weight was associated with trying to lose weight and inaccurate perception was associated with trying to gain muscle. Weight dissatisfaction was associated with trying to lose weight and gain muscle. Accurate weight perception and weight dissatisfaction were not associated with healthy weight-related behaviours. Awareness of overweight and body dissatisfaction may be detrimental to the adoption of healthy weight-control behaviours. Interventions with overweight adolescents should encourage body satisfaction, rather than promoting awareness of overweight. PMID- 26032795 TI - Trans fatty acid intake and emotion regulation. AB - We examined whether there is a relationship between trans fatty acid intakes and emotion regulation, mediated by positive or negative affect. Archival data on 1699 men and 3293 women were used to measure trans fatty acid intake at baseline, positive, and negative affects and emotion regulation at follow-up. Higher trans fatty acid intake related to subsequent difficulties with emotional awareness (p = 0.045), clarity (p = 0.012), and regulation strategies (p = 0.009). Affect mediated these relationships. Lower trans fatty acid intake associated with increased positive and decreased negative affects which, in turn, associated with improved emotion regulation. Trans fatty acid intakes may be associated with subsequent ability to regulate emotions. PMID- 26032796 TI - Sleep and food intake: A multisystem review of mechanisms in children and adults. AB - The foods we eat have substantial impact on our health, and excessive food intake is associated with numerous long-term health conditions. It is therefore essential to understand the factors influencing this crucial health behavior. Research has identified sleep problems as one such factor; however, little research has examined how sleep problems impact food intake. Using a multisystemic perspective, this article proposes a variety of ways in which sleep problems likely increase food intake and illustrates the need for research to empirically examine these underlying mechanisms. Such research would have important treatment implications for health conditions often treated with dietary interventions. PMID- 26032797 TI - Promoting health behaviour in Portuguese children via Short Message Service: The efficacy of a text-messaging programme. AB - A Short Message Service programme was adapted to monitor three health behaviours and provide supportive feedback. The study aimed to evaluate the effectiveness of the programme to increase fruit/vegetable consumption and physical activity and to decrease screen time. A total of 139 Portuguese children, aged 8-10 years, grouped by classroom, were randomly assigned to an intervention (8 weeks of monitoring/feedback) or a control condition. Participants had their key behaviours assessed at baseline, post-intervention and follow-up. A three-level hierarchical linear model was developed. Results showed that the monitoring and feedback programme significantly increased fruit and vegetable consumption over time. PMID- 26032798 TI - Understanding same-sex male and female partners' restrained eating in the context of their relationships. AB - This study examined weight status and dietary restraint among same-sex couples using Actor-Partner Interdependence Models. Body mass indices and restrained eating behaviors (i.e., cognitive dietary restraint, uncontrolled eating, and emotional eating) were assessed for members of 144 same-sex couples (72 lesbian and 72 gay couples; mean age = 33.74 years, standard deviation = 11.27 years). Results indicated that both men and women who were relatively heavy and who had relatively thin partners were at particular risk of engaging in restrained eating. These findings extend our understanding of partner comparison processes within the context of same-sex relationships in determining men and women's eating behaviors. PMID- 26032799 TI - Like mother, like daughter? An examination of the emotive responses to food. AB - The modelling of sub-clinical eating disorders and emotive responses to food between mothers and their early adolescent daughters was investigated. Twenty dyads viewed images of food and rated their levels of happiness, fear and disgust. Results suggest similarities between mothers' and daughters' emotive responses, but the exact nature of this relationship differed across food type and response type. Disordered eating was only related to responses to the low calorie foods. Furthermore, mother's eating disorders symptoms were related to concerns about shape and weight in the daughters (all ps < .05). These results suggest a transmission of emotive responses to food within the dyad which may inform family-based intervention efforts in the prevention of eating disorders in young women. PMID- 26032800 TI - Association of biological, psychological and lifestyle risk factors for eating disturbances in adolescents. AB - We aimed to assess the association of several risk factors for eating disturbances in adolescents. Participants were 448 girls and boys aged 12-15 years. Being female, higher body mass index, internalisation of standard of appearance, perfectionism, body dissatisfaction, number of lifetime addictive behaviours and lower self-esteem were associated with higher eating disturbance scores, whereas frequency of sedentary behaviours and physical activity were not (R(2) ? 41%). Findings suggest the need to guide prevention efforts towards the broad spectrum of individual potentially modifiable factors. A non-specific comprehensive perspective may be adequate to prevent problems related to weight, body image and drug use. PMID- 26032801 TI - Multidimensional analysis of food-allergic children and adolescents' self concept: A comparison with a healthy matched sample. AB - The study investigated self-concept in food-allergic youths and matched healthy controls. Global and domain-specific self-concepts were assessed in 154 participants (9-19 years) using the Multidimensional Self-Concept Scale. Statistical analysis assessed differences between the two samples and effects of asthma, dermatitis, age, and gender among patients. Significant differences were found for Total Scale score and for Competence and Physical scores. Patients showed clinically problematic self-concepts in Global, Competence, and Family domains. Age was found to be associated with the Total score. Health professionals should consider food-allergic patients' personality development. Further studies could examine disease-specific consequences and interventions. PMID- 26032802 TI - Gender differences found in a qualitative study of a disordered eating prevention programme: What do boys have to say? AB - Qualitative studies examining gender differences of eating disorder prevention programmes are scarce. We aimed to evaluate gender differences in adolescents who participated in a larger study on effectiveness of a disordered eating prevention programme. Perceptions of eating, female and male aesthetic models, media influences, prevention programmes and emerging topics from 12 school-going boys who received a media-literacy programme (n = 4), media-literacy plus nutrition awareness programme (n = 4) or neither (n = 4) were explored using Interpretative Phenomenological Analysis and compared with previous results in girls. Findings suggest that the prevention programme is effective for both genders. Gender differences and consumer-culture influences may be considered in future interventions. PMID- 26032803 TI - Exploring the motives and mental health correlates of intentional food restriction prior to alcohol use in university students. AB - This study explored the prevalence of and motivations behind 'drunkorexia' - restricting food intake prior to drinking alcohol. For both male and female university students (N = 3409), intentionally changing eating behaviour prior to drinking alcohol was common practice (46%). Analyses performed on a targeted sample of women (n = 226) revealed that food restriction prior to alcohol use was associated with greater symptomology than eating more food. Those who restrict eating prior to drinking to avoid weight gain scored higher on measures of disordered eating, whereas those who restrict to get intoxicated faster scored higher on measures of alcohol abuse. PMID- 26032804 TI - The relation of anxiety, depression, and stress to binge eating behavior. AB - This study aimed to extend the literature by examining several psychological factors (i.e. depression, anxiety, and stress) in relation to binge eating. Data were collected via online surveys from a community sample of men and women of diverse backgrounds. The main study hypotheses were supported, indicating a unique relation between anxiety and binge eating, and between stress and binge eating, independent of the impact of depression. Gender differences are discussed. The results of this study suggest a need for a more detailed examination of negative affect in binge eating. Furthermore, the role of anxiety may be important for future research. PMID- 26032805 TI - Nutrient-centrism and perceived risk of chronic disease. AB - This experiment explored consequences of two common lay theories about the diet disease link: nutrient-centrism, the belief that nutrients (e.g. potassium) are crucial to staving off disease, and whole-food centrism, the belief that whole foods (e.g. bananas), containing these nutrients in their natural context, are most beneficial. Depicting an individual's diet in terms of nutrients rather than whole foods containing these nutrients reduced the perceived likelihood that the individual would experience leading diet-related diseases (e.g. heart disease, diabetes). Although nutrition experts increasingly emphasize the health benefits of natural whole foods, people nevertheless appear to privilege nutrients when estimating disease risks. PMID- 26032806 TI - The meaning of colours in nutrition labelling in the context of expert and consumer criteria of evaluating food product healthfulness. AB - Qualitative and quantitative studies were conducted to explore the effect of front-of-pack nutrition labels on the perceived healthfulness of food products. Consumers were found to hold beliefs about colours and their fit to product categories that influence the assessment process. Consumers associate certain colours with product healthfulness. Yellow, blue, green and red were found to be evocative of health. Heather, pink and celadon suggested an artificial thus unhealthful product. The impact of labels on healthfulness assessment was observed only in the unhealthful category. The findings show the complexity of psychological processes in the perception of food healthfulness. PMID- 26032807 TI - Type D personality and dietary intake: The mediating effects of coping style. AB - This study aimed to investigate the relationship between Type D and dietary intake and to determine whether this relationship is mediated by coping. In a cross-sectional study, 187 healthy participants completed a self-report questionnaire measuring Type D personality, dietary intake and coping. Results showed that Type D was associated with maladaptive coping and significantly less healthy food intake, including more consumption of fat and sugar, and significantly less consumption of fruit and vegetables. Regression analyses showed that this relationship was partially mediated by coping. The results suggest that Type D personality may represent a risk factor for unhealthy eating. PMID- 26032809 TI - TURN Score Predicts 90-day Outcome in Acute Ischemic Stroke Patients After IV Thrombolysis. AB - BACKGROUND AND PURPOSE: We developed the TURN score for predicting symptomatic intracerebral hemorrhage (sICH) after IV thrombolysis. Our purpose was to evaluate its ability to predict 90-day outcome. METHODS: We retrospectively analyzed data from 303 patients who received IV rt-PA during the NINDS rt-PA trial. Severe outcome was defined as 90-day modified Rankin scale (mRS) scores >=5, 90-day Barthel index (BI) scores <60 and 90-day Glasgow Outcome Scale (GOS) scores >2. Excellent outcome was defined as 90-day mRS scores <=1, 90-day BI scores >=95 and 90-day GOS scores = 1. Agreement between TURN and 90-day outcome was assessed by univariate logistic regression reporting odds ratios (OR) and by areas under the receiver operating characteristic curves (AUROC). TURN was also compared with 6 other scores for predicting sICH or severe outcome. RESULTS: TURN predicted 90-day mRS >=5 with OR 5.73, 95% confidence interval (3.60, 9.10), P < 0.001 and AUROC 0.83, 95% confidence interval (0.77, 0.89). TURN also predicted 90-day mRS <=1 with OR 5.24, 95% confidence interval (3.43, 7.99), P < 0.001 and AUROC 0.80, 95% confidence interval (0.74, 0.85). TURN predicted 90-day mRS >=5 with OR significantly higher than DRAGON (2.30, P = 0.01), ASTRAL (1.18, P < 0.001), HAT (2.89, P = 0.05) and SEDAN (2.16, P = 0.01), and with AUROC significantly higher than SPAN-100 (0.64, P < 0.001) and SEDAN (0.71, P = 0.01). Likewise, TURN predicted 90-day mRS <=1 with OR significantly higher than Stroke TPI (2.89, P = 0.05), DRAGON (2.29, P = 0.01), ASTRAL (1.15, P < 0.001), HAT (2.71, P = 0.04) and SEDAN (2.15, P = 0.01), and with AUROC significantly higher than SPAN-100 (0.58, P < 0.001) and SEDAN (0.70, P = 0.01). Similar results were obtained using 90-day BI and 90-day GOS scores. CONCLUSIONS: TURN predicted 90 day outcome with comparable or better accuracy compared to several existing clinical scores. PMID- 26032808 TI - Complications Associated with Decompressive Craniectomy: A Systematic Review. AB - Decompressive craniectomy (DC) has been used for many years in the management of patients with elevated intracranial pressure and cerebral edema. Ongoing clinical trials are investigating the clinical and cost effectiveness of DC in trauma and stroke. While DC has demonstrable efficacy in saving life, it is accompanied by a myriad of non-trivial complications that have been inadequately highlighted in prospective clinical trials. Missing from our current understanding is a comprehensive analysis of all potential complications associated with DC. Here, we review the available literature, we tabulate all reported complications, and we calculate their frequency for specific indications. Of over 1500 records initially identified, a final total of 142 eligible records were included in our comprehensive analysis. We identified numerous complications related to DC that have not been systematically reviewed. Complications were of three major types: (1) Hemorrhagic (2) Infectious/Inflammatory, and (3) Disturbances of the CSF compartment. Complications associated with cranioplasty fell under similar major types, with additional complications relating to the bone flap. Overall, one of every ten patients undergoing DC may suffer a complication necessitating additional medical and/or neurosurgical intervention. While DC has received increased attention as a potential therapeutic option in a variety of situations, like any surgical procedure, DC is not without risk. Neurologists and neurosurgeons must be aware of all the potential complications of DC in order to properly advise their patients. PMID- 26032811 TI - India's critical care doctors are highly stressed, survey finds. PMID- 26032810 TI - Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. AB - BACKGROUND: Although the prevalence of obesity is higher among women than men, they are somewhat protected from the associated cardiometabolic consequences. The increase in cardiovascular disease risk seen after the menopause suggests a role for estrogens. There is also growing evidence for the importance of estrogen on body fat and metabolism in males. We hypothesized that that estrogen administration would ameliorate the adverse effects of obesity on metabolic parameters in males. METHODS: Male and female C57Bl/6 mice were fed control or obesogenic (DIO) diets from 5 weeks of age until adulthood. Glucose tolerance testing was performed at 13 weeks of age. Mice were killed at 15 weeks of age and liver and adipose tissue were collected for analysis of gene expression. A second cohort of male mice underwent the same experimental design with the addition of estradiol pellet implantation or sham surgery at 6 weeks. RESULTS: DIO males had greater mesenteric adipose deposition and more severe increases in plasma glucose, insulin and lipids than females. Treatment of males with estradiol from 6 weeks of age prevented DIO-induced increases in adipose tissue mass and alterations in glucose-insulin homeostasis. We also identified sex differences in the transcript levels and activity of hepatic and adipose glucocorticoid metabolizing enzymes. Estrogen treatment feminized the pattern of DIO-induced changes in glucocorticoid metabolism, rendering males similar to females. CONCLUSIONS: Thus, DIO induces sex-specific changes in glucose-insulin homeostasis, which are ameliorated in males treated with estrogen, highlighting the importance of sex steroids in metabolism. Given that altered peripheral glucocorticoid metabolism has been observed in rodent and human obesity, our results also suggest that sexually dimorphic expression and activity of glucocorticoid metabolizing enzymes may have a role in the differential metabolic responses to obesity in males and females. PMID- 26032812 TI - T Helper 2 Cytokine Signaling in Bone Marrow-Derived Fibroblasts: A Target for Renal Fibrosis. PMID- 26032814 TI - Myrtucommulone-A Induces both Extrinsic and Intrinsic Apoptotic Pathways in Cancer Cells. AB - Myrtucommulone-A is the active compound derived from Myrtus communis. The molecular targets of myrtucommulone-A is widely unknown, which impedes its potential therapeutic use. In this study, we demonstrated the cytotoxicity of MC A and its potential to induce apoptosis in cancer cells. Myrtucommulone-A was also found to be antiproliferative and strongly inhibited cancer cell migration. Eighty four apoptotic pathway genes were used to assess the effect of myrtucommulone-A on cancer cells. Myrtucommulone-A mediated an increase in apoptotic genes including Fas, FasL, Gadd45a, Tnf, Tnfsf12, Trp53, and caspase 4. The increase in myrtucommulone-A dose (25 MUM versus 6.25 MUM) also upregulated the expression of genes, which are involved mainly in apoptosis, regulation of apoptosis, role of mitochondria in apoptotic signaling, cytokine activity, and tumor necrosis factor signaling. Our data indicate that myrtucommulone-A could be utilized as a potential therapeutic compound with its molecular targets in apoptotic pathways. PMID- 26032813 TI - JAK3/STAT6 Stimulates Bone Marrow-Derived Fibroblast Activation in Renal Fibrosis. AB - Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. Bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblast precursors in the kidney are not fully understood. In this study, we investigated the role of the Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT6) signaling pathway in the activation of bone marrow-derived fibroblasts. In cultured mouse monocytes, IL-4 or IL-13 activated STAT6 and induced expression of alpha-smooth muscle actin and extracellular matrix proteins (fibronectin and collagen I), which was abolished by a JAK3 inhibitor (CP690,550) in a dose dependent manner or blocked in the absence of STAT6. In vivo, STAT6 was activated in interstitial cells of the obstructed kidney, an effect that was abolished by CP690,550. Mice treated with CP690,550 accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys compared with vehicle-treated mice. Treatment with CP690,550 also significantly reduced myofibroblast transformation, matrix protein expression, fibrosis development, and apoptosis in obstructed kidneys. Furthermore, STAT6-deficient mice accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys, produced less extracellular matrix protein, and developed much less fibrosis. Finally, wild-type mice engrafted with STAT6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts in the obstructed kidneys and showed less severe renal fibrosis compared with wild type mice engrafted with STAT6(+/+) bone marrow cells. Our results demonstrate that JAK3/STAT6 has an important role in bone marrow-derived fibroblast activation, extracellular matrix production, and interstitial fibrosis development. PMID- 26032815 TI - Estimation and evaluation of management options to control and/or reduce the risk of not complying with commercial sterility. AB - In a previous study, a modular process risk model, from the raw material reception to the final product storage, was built to estimate the risk of a UHT aseptic line of not complying with commercial sterility (Pujol et al., 2015). This present study was focused on demonstrating how the model (updated version with uncertainty and variability separated and 2(nd) order Monte Carlo procedure run) could be used to assess quantitatively the influence of management options. This assessment was done in three steps: pinpoint which process step had the highest influence on the risk, identify which management option(s) could be the most effective to control and/or reduce the risk, and finally evaluate quantitatively the influence of changing process setting(s) on the risk. For Bacillus cereus, it was identified that during post-process storage in an aseptic tank, there was potentially an air re-contamination due to filter efficiency loss (efficiency loss due to successive in-place sterilizations after cleaning operations), followed by B. cereus growth. Two options were then evaluated: i) reducing by one fifth of the number of filter sterilizations before renewing the filters, ii) designing new UHT-aseptic lines without an aseptic tank, i.e. without a storage period after the thermal process and before filling. Considering the uncertainty in the model, it was not possible to confirm whether these options had a significant influence on the risk associated with B. cereus. On the other hand, for Geobacillus stearothermophilus, combinations of heat treatment time and temperature enabling the control or reduction in risk by a factor of ca. 100 were determined; for ease of operational implementation, they were presented graphically in the form of iso-risk curves. For instance, it was established that a heat treatment of 138 degrees C for 31s (instead of 138 degrees C for 25s) enabled a reduction in risk to 18*10(-8) (95% CI=[10; 34]*10( 8)), instead of 578*10(-8) (95% CI=[429; 754]*10(-8)) initially. In conclusion, a modular risk model, as the one exemplified here with a UHT-aseptic line, is a valuable tool in process design and operation, bringing definitive quantitative elements into the decision making process. PMID- 26032816 TI - Multi-wavelength single-molecule fluorescence analysis of transcription mechanisms. AB - Multi-wavelength single molecule fluorescence microscopy is a valuable tool for clarifying transcription mechanisms, which involve multiple components and intermediates. Here we describe methods for the analysis and interpretation of such single molecule data. The methods described include those for image alignment, drift correction, spot discrimination, as well as robust methods for analyzing single-molecule binding and dissociation kinetics that account for non specific binding and photobleaching. Finally, we give an example of the use of the resulting data to extract the kinetic mechanism of promoter binding by a bacterial RNA polymerase holoenzyme. PMID- 26032817 TI - Defining bacterial regulons using ChIP-seq. AB - Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is a powerful method that identifies protein-DNA binding sites in vivo. Recent studies have illustrated the value of ChIP-seq in studying transcription factor binding in various bacterial species under a variety of growth conditions. These results show that in addition to identifying binding sites, correlation of ChIP seq data with expression data can reveal important information about bacterial regulons and regulatory networks. In this chapter, we provide an overview of the current state of knowledge about ChIP-seq methodology in bacteria, from sample preparation to raw data analysis. We also describe visualization and various bioinformatic analyses of processed ChIP-seq data. PMID- 26032818 TI - Pertussis vaccination in adult trauma patients: Are we missing an opportunity? AB - INTRODUCTION: Trauma centers commonly administer tetanus prophylaxis to patients sustaining open wounds. In the United States, there are different vaccinations available for adult administration: tetanus/diphtheria toxoid (Td) or tetanus/reduced diphtheria and acellular pertussis (Tdap). The importance of the Tdap preparation lies in its vaccination against pertussis while providing tetanus immunity. Vaccination against pertussis is paramount for disease prevention. In recent decades, there has been a steady rise in pertussis cases. This epidemic increase caused the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) to recommend the routine use of Tdap when tetanus prophylaxis is indicated. OBJECTIVES: The aim of this study was to gather data on which formulation of tetanus vaccination is currently being given to adult trauma patients. We hoped to increase awareness of the expanded recommendations for vaccination against pertussis when tetanus prophylaxis is indicated, thus providing patients with protection against pertussis. METHODS: An institutional review board exempt, web-based, nationwide survey was sent to adult trauma center coordinators that could be located via an Internet search. Questions included trauma center level designation, number of trauma evaluations per year, zip code, hospital description (university, university affiliated, or community), and which vaccination is given for adults <65 years and those >=65. At the conclusion of the survey, hyperlinks to the CDC ACIP recommendations were provided as an educational tool. RESULTS: A total of 718 emails were successfully sent and 439 (61%) completed surveys were returned. Level 4/5 centers had the highest compliance rates for those patients between ages 18 and 64 (93%), followed by level 2/3 (87%), and then level 1 centers (57%). Among all centers, the use of Tdap was lower in the >=65 year group. Level 2 trauma centers were the most compliant with this age group (61%) followed by level 4/5 (57%) and level 1 (43%) centers. CONCLUSION: With the increase in pertussis cases, vaccination remains crucial to prevention. The CDC recommendations for Tdap have existed for adults <65 years since 2005 and those >=65 years since 2012. However, many adult trauma centers do not adhere to the current CDC ACIP guidelines for tetanus/pertussis vaccination. In particular, level 1 trauma centers and those classified as university hospitals have the lowest rate of compliance with these recommendations. Through this survey, trauma centers were educated on current recommendations. Increased vaccination of trauma patients with Tdap should improve protection against this virulent pathogen. PMID- 26032819 TI - Improving breast cancer survivors' knowledge using a patient-centered intervention. AB - BACKGROUND: Low-income, minority women with breast cancer experience a range of barriers to receiving survivorship information. Our objective was to test a novel, patient-centered intervention aimed at improving communication about survivorship care. METHODS: We developed a wallet card to provide oncologic and follow-up care survivorship information to breast cancer patients. We used a prospective, pre-post design to assess the intervention at a safety net hospital. The intervention was given by a patient navigator or community health worker. RESULTS: Patient knowledge (n = 130) of personal cancer history improved from baseline pretest to 1 week after the intervention for stage (66-93%; P < .05), treatment (79-92%; P < .05), and symptoms of recurrence (48-89%; P < .05), which was retained at 3 months. The intervention reduced the number of patients who were unsure when their mammogram was due (15-5% at 1 week and 6% at 3 months; P < .05). Nearly 90% reported they would be likely to share their survivorship card with their providers. CONCLUSION: A patient-centered survivorship card improved short-term recall of key survivorship care knowledge and seems to be effective at reducing communication barriers for this population. Further studies are warranted to assess long-term retention and the impact on receipt of appropriate survivorship follow-up care. PMID- 26032820 TI - Practicality of using galvanic skin response to measure intraoperative physiologic autonomic activation in operating room team members. AB - BACKGROUND: Physiologic and psychological stress are commonly experienced by operating room (OR) personnel, yet there is little research about the stress levels in OR teams and their impact on performance. Previously published procedures to measure physiologic activation are invasive and impractical for the OR. The purpose of this study was to determine the practicality of a new watch sized device to measure galvanic skin response (GSR) in OR team members during high-fidelity surgical simulations. METHODS: Interprofessional OR teams wore sensors on the wrist (all) and ankle (surgeons and scrub nurses/technicians) during the orientation, case, and debriefing phases for 17 simulations of a surgical airway case. Data were compared across all simulation phases, collectively and for each professional group. RESULTS: Forty anesthesiology residents, 35 surgery residents, 27 OR nurses, 12 surgical technicians, and 7 CRNAs participated. Collectively, mean wrist GSR levels significantly increased from orientation phase to the case (0.40-0.62 MUS; P < .001) and remained elevated even after the simulation was over (0.40-0.67 MUS; P < .001). Surgery residents were the only group that demonstrated continued increases in wrist GSR levels throughout the entire simulation (change in GSR = 0.21 to 0.32 to 0.11 MUS; P < .01). Large intraindividual differences (<= 200 times) were found in both wrist and ankle GSR. There was no correlation between wrist and ankle data. CONCLUSION: Continuous GSR monitoring of all professionals during OR simulations is feasible, but would be difficult to implement in an actual OR environment. Large variation in individual levels of physiologic activation suggests complementary qualitative research is needed to better understand how people respond to stressful OR situations. PMID- 26032821 TI - Occult metastases in node-negative breast cancer: A Surveillance, Epidemiology, and End Results-based analysis. AB - INTRODUCTION: The role of immunohistochemistry (IHC) for detecting occult lymph node disease in patients initially found to be node-negative by routine pathology is controversial. In this study, we evaluated trends associated with overall survival in node-negative breast cancer patients staged by IHC. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients with invasive breast adenocarcinoma and negative lymph nodes on routine pathology between 2004 and 2011 who underwent IHC to evaluate for occult nodal disease. Overall survival stratified by N-stage was compared with Kaplan-Meier analysis. Multivariate analysis was performed using a Cox proportional hazards model. RESULTS: Overall, 93,070 patients were identified, including 4,657 patients with isolated tumor cells (<0.2 mm diameter or <200 cells) and 6,720 patients with micrometastases (0.2-2 mm diameter). Kaplan-Meier curves demonstrated a difference in overall survival across all groups (P < .0001). On multivariate analysis, micrometastases remained an independent predictor for survival compared with IHC-negative patients (hazard ratio 1.40, 95% confidence interval 1.28 1.53), whereas isolated tumor cells were not a significant predictor (hazard ratio 1.05, 95% confidence interval 0.92-1.20). CONCLUSION: Patients with occult micrometastases in axillary lymph nodes found via IHC demonstrated a significant overall survival difference, but isolated tumor cells have no prognostic significance. PMID- 26032822 TI - Opportunity lost: Adjuvant chemotherapy in patients with stage III colon cancer remains underused. AB - INTRODUCTION: There is strong evidence supporting the efficacy of adjuvant chemotherapy for patients with pathologic, stage III colon cancer. This study examines differences in adherence to evidence-based adjuvant chemotherapy guidelines for pathologic, stage III colon cancer cases across hospital and patient subgroups. METHODS: Patients with stage III colon cancer were identified from the 2003 to 2011 National Cancer Data Base (NCDB). A logistic regression model was used to estimate the odds of receipt of adjuvant chemotherapy across varying hospital and patient characteristics. A multivariable Cox proportional hazards model was used to estimate the association between receipt of adjuvant chemotherapy and 5-year survival. Risk adjusted observed/expected (O/E) outcome ratios were calculated for each hospital to compare hospital-specific quality of care during the study period. RESULTS: A total of 124,008 patients met the inclusion criteria. Adjuvant chemotherapy was not administered to 34%. The rates of adjuvant chemotherapy have shown little improvement over time (63% in 2003 vs 66% in 2011). The Cox model indicates that patients receiving adjuvant chemotherapy had better survival (hazard ratio = 0.48, 95% confidence interval 0.47-0.49). Analysis of risk adjusted O/E ratios indicated no consistent pattern as to which hospitals were performing optimally or subopitmally over time. CONCLUSION: There has been no meaningful improvement in receipt of chemotherapy in patients with stage III colon cancer. The fact that chemotherapy is not being considered or offered to more than 20% of patients with node-positive colon cancer suggests that there are substantial process failures across many institutions and regions in the United States. PMID- 26032823 TI - Splenic preservation during open and minimally-invasive distal pancreatectomy. PMID- 26032824 TI - Blood transfusion and adverse surgical outcomes: The good and the bad. AB - INTRODUCTION: Every experienced surgeon has a patient whose life was saved by a blood transfusion (the "good"). In contrast, an overwhelming amount of evidence suggests that perioperative blood transfusion can be associated with adverse surgical outcomes (the "bad"). We wondered what patient characteristics, if any, can explain this clinical dichotomy with certain patients benefiting from transfusion, whereas others are harmed by this intervention. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Project database containing patient information entered between 2010 and 2012 to identify differences in mortality and morbidity among patients receiving blood transfusion within 72 hours of their operative procedure compared with those who did not receive any blood. We calculated the relative risk of developing a serious complication or of operative mortality in propensity-stratified patients with equivalent predicted risk of developing a serious complication or operative mortality. RESULTS: There were 470,407 patients in the study group. Of these, 32,953 patients (7.0%) received at least a single blood transfusion within 72 hours of operation. The percent of transfused patients who died or developed serious morbidity was 11.3% and 55.4% compared with 1.3% and 6.1% in nontransfused patients (both P < .001). Operative mortality, rates of failure to rescue, and serious postoperative complications are increased in patients who receive a postoperative transfusion, both in unadjusted comparisons and in propensity-matched comparisons. Dividing patients into regression-stratified deciles with equal numbers of deaths in each group found that patients at the greatest risk for development of death or serious complications had nonsignificant risk of harm from blood transfusion, whereas patients in the least risk deciles had between an 8- and 12-fold increased risk of major adverse events associated with transfusion. CONCLUSION: We found that high-risk patients do not have a significant risk from blood transfusion, but low-risk patients have between an 8- and 10-fold excess risk of adverse outcomes when they receive a blood transfusion. We speculate that careful preoperative assessment of transfusion risk and intervention based on this assessment could minimize operative morbidity and mortality, especially because the patients at least risk are more likely to undergo elective operations and provide time for therapeutic interventions to improve transfusion risk profiles. PMID- 26032825 TI - Anxiolytic medication is an independent risk factor for 30-day morbidity or mortality after surgery. AB - BACKGROUND: This study examined the effects of the use of anxiolytic medications (AXM) and antidepressant medications (ADMs) on outcomes after noncardiac surgery. STUDY DESIGN: A single-center review of prospectively obtained, perioperative and 30-day outcome data, including AXM and ADM use at admission, as part of the National Surgery Quality Improvement Program. RESULTS: Of the 1846 patients undergoing surgery, 380 (20.6%) were taking an ADM, 288 (15.6%) AXM, 124 (6.7%) were taking both, and 545 (29.5%) were taking either at the time of admission. Both ADM and AXM patients more often were female than nonusers, had a greater American Society of Anesthesiologists class and suffered more from hypertension, COPD, and dyspnea (all P < .005). AXM patients also were more often smokers. ADM patients had a greater mortality and a greater risk of an infective complication, but these effects did not remain after adjustment for procedure and comorbid risks. Patients taking AXM had greater duration of stay, as well as an increased incidence of return to the operating room, infections, wound occurrences, and cardiovascular or cerebrovascular events (all P < .005). After adjustment, AXM was associated with greater combined major morbidity or mortality (odds ratio 1.72, 95% confidence interval 1.08-2.73, P = .023). CONCLUSION: AXM was used by 16% of patients in our institution undergoing a noncardiac operation and was an independent risk factor for poorer short-term outcome after surgery. ADM was found to be used by 21% of patients but was not an independent risk factor for poor outcome. PMID- 26032826 TI - Surgical never events and contributing human factors. AB - INTRODUCTION: We report the first prospective analysis of human factors elements contributing to invasive procedural never events by using a validated Human Factors Analysis and Classification System (HFACS). METHODS: From August 2009 to August 2014, operative and invasive procedural "Never Events" (retained foreign object, wrong site/side procedure, wrong implant, wrong procedure) underwent systematic causation analysis promptly after the event. Contributing human factors were categorized using the 4 levels of error causation described by Reason and 161 HFACS subcategories (nano-codes). RESULTS: During the study, approximately 1.5 million procedures were performed, during which 69 never events were identified. A total of 628 contributing human factors nano-codes were identified. Action-based errors (n = 260) and preconditions to actions (n = 296) accounted for the majority of the nano-codes across all 4 types of events, with individual cognitive factors contributing one half of the nano-codes. The most common action nano-codes were confirmation bias (n = 36) and failed to understand (n = 36). The most common precondition nano-codes were channeled attention on a single issue (n = 33) and inadequate communication (n = 30). CONCLUSION: Targeting quality and interventions in system improvement addressing cognitive factors and team resource management as well as perceptual biases may decrease errors and further improve patient safety. These results delineate targets to further decrease never events from our health care system. PMID- 26032827 TI - Rate of lower-extremity ultrasonography in trauma patients is associated with rate of deep venous thrombosis but not pulmonary embolism. AB - BACKGROUND: Disparate lower-extremity ultrasonography (LUS) screening practices among trauma institutions reflecta lack of consensus regarding screening indications and whether screening improves outcomes. We hypothesized that LUS screening for deep-vein thrombosis (DVT) is not associated with a reduced incidence of pulmonary embolism (PE). METHODS: The 2012 ACS National Trauma Data Bank Research Data Set was queried to identify 442,108 patients treated at institutions reporting at least one LUS and at least one DVT. Institutions performing LUS on more than 2% of admitted patients were designated high screening facilities and remaining institutions were designated low-screening facilities. Patient characteristics and risk factors were used to develop a logistic regression model to assess the independent associations between LUS and DVT and between LUS and PE. RESULTS: Overall, DVT and PE were reported in 0.94% and 0.37% of the study population, respectively. DVT and PE were reported more commonly in designated high-screening than low-screening facilities (DVT: 1.12% vs 0.72%, P < .0001; PE: 0.40% vs 0.33%, P = .0004). Multivariable logistic regression demonstrated that LUS was associated independently with DVT (odds ratio 1.43, confidence interval 1.34-1.53) but not PE (odds ratio 1.01, confidence interval 0.92-1.12) (c-statistic 0.86 and 0.85, respectively). Sensitivity analyses performed at various rates for designating HS facilities did not alter the significance of these relationships. CONCLUSION: LUS in trauma patients is not associated with a change in the incidence of PE. Aggressive LUS DVT screening protocols appear to detect many clinically insignificant DVTs for which subsequent therapeutic intervention may be unnecessary, and the use of these protocols should be questioned. PMID- 26032828 TI - Improvement in patient-reported physical and mental health after parathyroidectomy for primary hyperparathyroidism. AB - BACKGROUND: The majority of patients with primary hyperparathyroidism (PHPT) are diagnosed without the classic signs of renal or osseous complications. Vague and subjective symptoms have been attributed to PHPT but have been difficult to measure during the medical encounter. The Patient-Reported Outcomes Measurement Information System (PROMIS) of the National Institutes of Health contains validated measures of physical and mental health that can be administered by the use of computer-adaptive testing (CAT). The objective of this study was to evaluate the feasibility of PROMIS assessment in the clinical setting to measure changes in patient-reported health before and after parathyroidectomy. We hypothesized that patients undergoing parathyroidectomy for PHPT would report greater improvement in mental and physical health compared with control patients. METHODS: Adult PHPT patients scheduled for parathyroidectomy and control patients requiring diagnostic thyroid operation were enrolled prospectively during a 6 month period. Patients were administered clinically relevant PROMIS health domains via CAT at a preoperative visit and 3 weeks after operation. A change in score of 5 or greater for each PROMIS instrument was defined as clinically important. Statistical significance of pre/post-surgery changes in scores was determined using paired t tests. RESULTS: A total of 35 patients with PHPT and 9 control patients completed the study. The mean number of PROMIS items answered during an assessment was 67 (range 51-121, SD 15.4). Median completion time was 8.2 minutes (range 3.4-38.4, SD 4.7). Clinically important improvement after parathyroidectomy in the PHPT group was greater than in the control group in 5 PROMIS domains. The score improvement experienced by PHPT patients was 8.8 in Fatigue, 6.7 in Sleep-Related Impairment, 5.0 in Anxiety, 7.0 in Applied Cognition, and 6.2 in Depression (all P < .05). CONCLUSION: PROMIS is an efficient clinical assessment platform for measuring patient-reported outcomes in PHPT via CAT. Several domains of physical and mental health in patients with PHPT show statistically and clinically important improvement after parathyroidectomy. PMID- 26032829 TI - Preoperative platelet to lymphocyte ratio predicts outcome of patients with pancreatic ductal adenocarcinoma after pancreatic resection. AB - BACKGROUND: Inflammation plays a crucial role in tumor growth, metastasis, and survival. The preoperative platelet-to-lymphocyte ratio (PLR) has been reported as a significant prognostic indicators in several digestive malignancies. Our objective was to evaluate whether preoperative PLR is a prognostic index in resected pancreatic ductal adenocarcinoma. METHODS: Data from 131 patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma were available from a prospectively maintained database. The patients were divided into groups according to a preoperative PLR of <150 or >=150. Survival data were analyzed. RESULTS: In univariate and multivariate analyses, a preoperative PLR of >=150 was a significant and independent risk factor for cancer recurrence and poor survival, respectively (disease-free survival [DFS]; P= .0014, P = .047; OS, P <= .01each). Similarly, lymph node metastasis, and moderate or poor differentiation were independent risk factors for cancer recurrence, whereas tumor diameter, positive surgical margin, and moderate or poor differentiation were independent risk factors for poor patient survival (P <= .05 each). CONCLUSION: The preoperative PLR in patients with pancreatic ductal adenocarcinoma was an independent predictor in DFS and overall survival after elective resection. Measurement of the PLR may help decision making in the postoperative management of patients with pancreatic ductal adenocarcinoma. PMID- 26032830 TI - Transplantation of human stem cell-derived hepatocytes in an animal model of acute liver failure. AB - INTRODUCTION: Hepatocyte cell transplantation can be life-saving in patients with acute liver failure (ALF); however, primary human hepatocyte transplantation is limited by the scarcity of donor hepatocytes. We investigated the effect of stem cell-derived, hepatocyte-like cells in an animal xenotransplant model of ALF. METHODS: Intraperitoneal d-galactosamine was used to develop a lethal model of ALF in the rat. Human induced pluripotent stem cells (iPSC), human mesenchymal stem cells, and human iPSC combined with human endothelial cells (iPSC + EC) were differentiated into hepatocyte-like cells and transplanted into the spleens of athymic nude rats with ALF. RESULTS: A reproducible lethal model of ALF was achieved with nearly 90% death within 3 days. Compared with negative controls, rats transplanted with stem cell-derived, hepatocyte-like cells were associated with increased survival. Human albumin was detected in the rat serum 3 days after transplantation in more than one-half the animals transplanted with hepatocyte like cells. Only animals transplanted with iPSC + EC-derived hepatocytes had serum human albumin at 14 days posttransplant. Transplanted hepatocyte-like cells homed to the injured rat liver, whereas the ECs were only detected in the spleen. CONCLUSION: Transplantation of stem cell-derived, hepatocyte-like cells improved survival with evidence of in vivo human albumin production. Combining ECs may prolong cell function after transplantation. PMID- 26032831 TI - The relationship between duration of stay and readmissions in patients undergoing bariatric surgery. AB - BACKGROUND: Hospital readmissions are a quality indicator in bariatric surgery. In recent years, duration of stay after bariatric surgery has trended down greatly. We hypothesized that a shorter postoperative hospitalization does not increase the likelihood of readmission. METHODS: The University HealthSystem Consortium (UHC) is an alliance of academic medical centers and affiliated hospitals. The UHC's clinical database contains information on inpatient stay and returns (readmissions) up to 30 days after discharge. A multicenter analysis of outcomes was performed by the use of data from the January 2009 to December 2013 for patients 18 years and older. Patients were identified by bariatric procedure International Classification of Diseases, Ninth Revision, codes and restricted by diagnosis codes for morbid obesity. RESULTS: A total of 95,294 patients met inclusion criteria. The mean patient age was 45.4 (+/-0.11) years, and 73,941 (77.6%) subjects were female. There were 5,423 (5.7%) readmissions within the study period. Patients with hospitalizations of 3 days and more than 3 days were twice and four times as likely to be readmitted than those with hospitalizations of one day, respectively (P < .001). CONCLUSION: Patients with longer postoperative hospitalizations were more likely to be readmitted after bariatric surgery. Early discharge does not appear to be associated with increased readmission rates. PMID- 26032832 TI - Evaluation of the Fukuoka Consensus Guidelines for intraductal papillary mucinous neoplasms of the pancreas: Results from a systematic review of 1,382 surgically resected patients. AB - BACKGROUND: International consensus guidelines to guide management of intraductal papillary mucinous neoplasms (IPMN) were revised in Fukuoka and published in 2012. However, despite widespread acceptance of the Fukuoka Consensus Guidelines (FCG), the utility of these guidelines have not been well-validated. This systematic review was performed to evaluate the clinical utility of the FCG. DESIGN: A computerized search of the PubMed and Scopus databases was performed to identify all studies evaluating the utility of the FCG in surgically resected IPMN. IPMN were stratified according to the FCG as high risk (HR), worrisome risk (WR), and low risk (LR). HR and WR IPMN were termed FCG+ve and LR IPMN were termed FCG-ve. RESULTS: Seven studies analyzing 1,382 patients were included. There were 402 malignant neoplasms (29%), including 242 invasive IPMNs. There were 1,000 IPMN classified as FCG+ve. The FCG+ve group had a positive predictive value (PPV) ranging from 27 to 62% and the FCG-ve group had negative predictive value ranging from 82 to 100%. Pooled analysis demonstrated that there was 362 of 1,000 (36%) malignant FCG+ve IPMN and 342 of 382 (90%) benign FCG-ve IPMN. PPV of the HR group and the WR groups alone were 104 of 158 (66%) and 75 of 261 (29%), respectively. Forty of 382 (11%), including 22 (6%) invasive FCG-ve IPMN, were malignant. Twenty-six malignant including 18 invasive FCG-ve IPMN were reported from a single study. When the results from this study were excluded, there were only 14 of 241 malignant neoplasms (6%), including 4 of 241 (2%) invasive FCG-ve IPMN in the remaining 6 studies. CONCLUSION: The FCG+ve criteria had a similarly low PPV compared with the 2006 consensus criteria. Stratification of IPMN into HR and WR groups resulted in a higher PPV in the HR group. Some malignant and even invasive IPMN may be missed by the FCG criteria. PMID- 26032835 TI - Flow field induced particle accumulation inside droplets in rectangular channels. AB - Particle concentration is a basic operation needed to perform washing steps or to improve subsequent analysis in many (bio)-chemical assays. In this article we present field free, hydrodynamic accumulation of particles and cells in droplets flowing within rectangular micro-channels. Depending on droplet velocity, particles either accumulate at the rear of the droplet or are dispersed over the entire droplet cross-section. We show that the observed particle accumulation behavior can be understood by a coupling of particle sedimentation to the internal flow field of the droplet. The changing accumulation patterns are explained by a qualitative change of the internal flow field. The topological change of the internal flow field, however, is explained by the evolution of the droplet shape with increasing droplet velocity altering the friction with the channel walls. In addition, we demonstrate that accumulated particles can be concentrated, removing excess dispersed phase by splitting the droplet at a simple channel junction. PMID- 26032834 TI - USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance. AB - BACKGROUND: Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. METHODS: We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. RESULTS: USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. CONCLUSION: USP1 mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. PMID- 26032833 TI - CGRP as a neuropeptide in migraine: lessons from mice. AB - Migraine is a neurological disorder that is far more than just a bad headache. A hallmark of migraine is altered sensory perception. A likely contributor to this altered perception is the neuropeptide calcitonin gene-related peptide (CGRP). Over the past decade, CGRP has become firmly established as a key player in migraine. Although the mechanisms and sites of action by which CGRP might trigger migraine remain speculative, recent advances with mouse models provide some hints. This brief review focuses on how CGRP might act as both a central and peripheral neuromodulator to contribute to the migraine-like symptom of light aversive behaviour in mice. PMID- 26032836 TI - Comments on 'Joint modeling of survival and longitudinal non-survival data: current methods and issues. Report of the DIA Bayesian Joint Modeling Working Group'. PMID- 26032837 TI - Discussion on 'Joint modeling of survival and longitudinal non-survival data' by Gould et al. PMID- 26032838 TI - Commentary on 'Joint modeling of survival and longitudinal non-survival data: current methods and issues'. PMID- 26032839 TI - Responses to discussants of 'Joint modeling of survival and longitudinal non survival data: current methods and issues. report of the DIA Bayesian joint modeling working group'. PMID- 26032840 TI - A new method for measuring osteoclast formation by electrical impedance. AB - Osteoclasts are important target cells for osteoporosis treatment. Recently, a real-time cell analysis (RTCA) system was developed to observe cell morphology and adhesion; however, the use of RTCA to study osteoclastogenesis has not been reported. Here, we investigated whether osteoclast formation could be monitored in real-time using RTCA. The cell index determined via electrical impedance using RTCA, and the number of osteoclasts exhibited a significant positive correlation. RTCA was useful for determining the effect of (-)-epigallocatechin-3-gallate on the inhibition of bone resorption. We established a new method of measuring osteoclast formation in real-time using RTCA. PMID- 26032841 TI - Erratum to: The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. PMID- 26032842 TI - Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels. AB - RATIONALE: In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. OBJECTIVES: The aim of this study was to find out whether elevated serum levels (>=5 mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. METHODS: Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5 mg/l) and pathological (>5 mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. RESULTS: Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0 % (clozapine), 11.9 % (quetiapine), and 24.2 % (active moiety of risperidone), respectively. CONCLUSIONS: In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations. PMID- 26032843 TI - Sustained Blood Pressure Control Following Discontinuation of a Pharmacist Intervention for Veterans. AB - Clinical pharmacists are utilized in Veterans Health Administration (VHA) facilities to assist with management of patients with chronic conditions including hypertension. The goal of this study was to examine blood pressure (BP) control after discontinuation of an intensive pharmacist-managed intervention. The study was conducted at a single Midwest VHA medical center and two affiliated community-based outpatient clinics. Patients with uncontrolled BP received an intensive pharmacist intervention for the first 6 months. Patients were then stratified based on whether their BP was controlled or not and were randomized to either continue the intervention for another 24 months (30 month total time period) or the intervention was discontinued following one-time receipt of educational materials. Mean systolic and diastolic BPs were reduced (P<.001) in diabetic patients (8.0+/-14.4 mm Hg and 4.0+/-9.1 mm Hg, respectively) and in nondiabetic patients (14.0+/-16.4 mm Hg and 5.0+/-10.0 mm Hg, respectively) following the 6-month intervention, with 54% of the total sample achieving BP control. BP control and the reduction in mean BP was maintained to a similar degree in both study groups at 12, 18, 24, and 30 months. There were no significant differences in BP at any of the follow-up periods in patients who did and did not receive the continued pharmacist intervention. This study found that BP control was maintained for at least 24 months following discontinuation of an intensive pharmacist intervention. These findings were seen in both the group that had a continued pharmacist intervention and in the group that had a one-time educational session when the intervention was discontinued. This study suggests that once BP control is achieved following a pharmacist intervention, patients can be referred back to their primary care provider for continued follow-up. PMID- 26032844 TI - Catalytic Ketone Hydrodeoxygenation Mediated by Highly Electrophilic Phosphonium Cations. AB - Ketones are efficiently deoxygenated in the presence of silane using highly electrophilic phosphonium cation (EPC) salts as catalysts, thus affording the corresponding alkane and siloxane. The influence of distinct substitution patterns on the catalytic effectiveness of several EPCs was evaluated. The deoxygenation mechanism was probed by DFT methods. PMID- 26032845 TI - Sexual conflict maintains variation at an insecticide resistance locus. AB - BACKGROUND: The maintenance of genetic variation through sexually antagonistic selection is controversial, partly because specific sexually-antagonistic alleles have not been identified. The Drosophila DDT resistance allele (DDT-R) is an exception. This allele increases female fitness, but simultaneously decreases male fitness, and it has been suggested that this sexual antagonism could explain why polymorphism was maintained at the locus prior to DDT use. We tested this possibility using a genetic model and then used evolving fly populations to test model predictions. RESULTS: Theory predicted that sexual antagonism is able to maintain genetic variation at this locus, hence explaining why DDT-R did not fix prior to DDT use despite increasing female fitness, and experimentally evolving fly populations verified theoretical predictions. CONCLUSIONS: This demonstrates that sexually antagonistic selection can maintain genetic variation and explains the DDT-R frequencies observed in nature. PMID- 26032847 TI - Betulinic Acid and its Derivatives as Potential Antitumor Agents. AB - Betulinic acid (BA) is a lupane-type pentacyclic triterpene, distributed ubiquitously throughout the plant kingdom. BA and its derivatives demonstrate multiple bioactivities, particularly an antitumor effect. This review critically describes the recent research on isolation, synthesis, and derivatization of BA and its natural analogs betulin and 23-hydroxybetulinic acid. The subsequent part of the review focuses on the current knowledge of antitumor properties, combination treatments, and pharmacological mechanisms of these compounds. A 3D QSAR analysis of 62 BA derivatives against human ovarian cancer A2780 is also included to provide information concerning the structure-cytotoxicity relationships of these compounds. PMID- 26032846 TI - Coacervate delivery of HB-EGF accelerates healing of type 2 diabetic wounds. AB - Chronic wounds such as diabetic ulcers pose a significant challenge as a number of underlying deficiencies prevent natural healing. In pursuit of a regenerative wound therapy, we developed a heparin-based coacervate delivery system that provides controlled release of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) within the wound bed. In this study, we used a polygenic type 2 diabetic mouse model to evaluate the capacity of HB-EGF coacervate to overcome the deficiencies of diabetic wound healing. In full-thickness excisional wounds on NONcNZO10 diabetic mice, HB-EGF coacervate enhanced the proliferation and migration of epidermal keratinocytes, leading to accelerated epithelialization. Furthermore, increased collagen deposition within the wound bed led to faster wound contraction and greater wound vascularization. Additionally, in vitro assays demonstrated that HB-EGF released from the coacervate successfully increased migration of diabetic human keratinocytes. The multifunctional role of HB-EGF in the healing process and its enhanced efficacy when delivered by the coacervate make it a promising therapy for diabetic wounds. PMID- 26032848 TI - High level of Sema3C is associated with glioma malignancy. AB - BACKGROUND: Malignant gliomas are characterized by the tendency of cancerous glial cells to infiltrate into normal brain tissue, thereby complicating targeted treatment of this type of cancer. Recent studies suggested involvement of Sema3C (semaphorin 3C) protein in tumorigenesis and metastasis in a number of cancers. The role of Sema3C in gliomagenesis is currently unclear. In this study, we investigated how expression levels of Sema3C in post-operative glioma tumors are associated with the malignancy grade and the survival of the patient. FINDINGS: Western blot analysis was used for detection of Sema3C protein levels in 84 different grade glioma samples: 12 grade I astrocytomas, 30 grade II astrocytomas, 17 grade III astrocytomas, and 25 grade IV astrocytomas (glioblastomas). Sema3C mRNA levels in gliomas were analysed by real-time PCR. Several statistical methods have been used to investigate associations between Sema3C protein and mRNA levels and clinical variables and survival outcome. The results demonstrated that protein levels of Sema3C were markedly increased in glioblastomas compared to grade I-III astrocytoma tissues and were significantly associated with the shorter overall survival of patients. High accumulation of Sema3C positively associated with the age of patients and pathological grade, but did not correlate with patient's gender. Sema3C mRNA levels showed no association with either grade of glioma or patient survival. CONCLUSIONS: The data presented in this work suggest that the increased levels of Sema3C protein may be associated with the progression of glioma tumor and has a potential as a prognostic marker for outcome of glioma patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1564066714158642. PMID- 26032849 TI - Comparison of Serum Uric Acid, Bilirubin, and C-Reactive Protein as Prognostic Biomarkers of In-Hospital MACE Between Women and Men With ST-Segment Elevation Myocardial Infarction. AB - Levels of C-reactive protein (CRP), uric acid (UA), and total bilirubin (TB) are associated with coronary artery disease and major adverse cardiac events (MACEs) in patients with ST-segment elevation myocardial infarction (STEMI). We retrospectively included 1167 patients with STEMI who underwent percutaneous coronary intervention and routine blood sampling. The study cohort consisted of 803 patients (73.1% male, mean age 62.5 +/- 13.4 years). In men, the levels of CRP, TB, and UA were significantly higher in the MACE than in the non-MACE group (P < .05). The receiver-operating characteristic (ROC) analysis shows that CRP (area under the curve [AUC]: 0.59; 95% confidence interval [CI]: 0.53-0.66; P = .014) and TB (AUC: 0.58; 95% CI: 0.51-0.65; P = .019) are significantly associated with MACE but not UA (AUC: 0.61; 95% CI: 0.42-0.76; P = .083). Logistic regression revealed CRP (odds ratio [OR] 1.01; 95% CI: 1.00-1.01; P = .006) and TB (OR 2.03; 95% CI: 1.12-3.40; P = .007) as an independent predictor for MACE. In women, none of the biomarkers was associated with MACE by ROC analysis or logistic regression analysis. This study demonstrated that high CRP and TB serum levels have a prognostic association with in-hospital MACE in male patients with STEMI. PMID- 26032850 TI - Menopause Status and Percutaneous Coronary Intervention. PMID- 26032851 TI - Women With Early Menopause Have Higher Rates of Target Lesion Revascularization After Percutaneous Coronary Intervention. AB - Early menopause has been found to be associated with higher risk of cardiovascular disease. Our objective was to investigate the impact of early menopause on clinical outcomes for women undergoing percutaneous coronary intervention (PCI). We observed female patients with coronary artery disease (CAD) undergoing PCI and found that women with early menopause (<=46 years old) were more likely to have CAD risk factors and more severe coronary lesions. During the 18-month follow-up, early menopause was associated with similar risk of death and myocardial infarction but higher risk of target lesion revascularization (TLR; 7.8% vs 5.3%, P = .003) and major adverse cardiovascular events (MACEs; 11.3% vs 9.0%, P = .007). After adjustment, early menopause was an independent risk factor for 18-month MACEs (hazard ratio [HR], 1.54; 95% confidence interval [CI] 1.18-2.00) and TLR (HR 1.61; 95% CI 1.21-2.13). In conclusion, for women undergoing PCI, early menopause is associated with higher risk of MACE, which is mainly driven by risk of TLR. PMID- 26032852 TI - Effectiveness of a PLISSIT model intervention in patients with type 2 diabetes mellitus in primary care: design of a cluster-randomised controlled trial. AB - BACKGROUND: Sexual dysfunction is prevalent in patients with type 2 diabetes mellitus, but remains one of the most frequently neglected complications in diabetes care. Both patients and care providers appear to have difficulty with discussing sexual problems in diabetes care. A sexual counselling model for care providers, such as the PLISSIT model, might be a useful tool to improve the discussion of sexual issues in patients with type 2 diabetes mellitus. PLISSIT stands for Permission, Limited Information, Specific Suggestions, and Intensive Therapy. Even though the use of the PLISSIT model has often been recommended in diabetes care, no evidence with regards to its effectiveness in patients with type 2 diabetes mellitus exists. This study describes the design of a cluster randomised controlled trial evaluating the effectiveness of a PLISSIT-model intervention in men and women with type 2 diabetes mellitus in primary care. METHODS/DESIGN: Patients with type 2 diabetes mellitus, aged 40-75 years, who indicate to be dissatisfied about their sexual functioning and that they would like to talk about their sexual problem(s) with their general practitioner are recruited. All participants receive an information leaflet from the practice nurse. In the intervention group, each participant will also receive sexual counselling based on the PLISSIT model from their general practitioner. In the control group, usual care will be provided to those participants requesting an appointment with their general practitioner when the information leaflet was not deemed sufficient. Primary outcomes include sexual functioning, satisfaction about sexual function, and quality of life. Secondary outcomes are depressive symptoms, sexual distress, emotional well-being, and treatment satisfaction. Outcomes will be measured by means of self-report questionnaires at baseline, and after 3 and 12 months post-baseline. Treatment satisfaction will be assessed in telephone interviews. DISCUSSION: This paper describes the design of a cluster randomised controlled trial that will investigate the effectiveness of a PLISSIT model intervention in patients with type 2 diabetes mellitus in primary care. Our study will add important and currently missing insight into the effectiveness of PLISSIT on important patient-reported outcomes of men and women with type 2 diabetes mellitus. TRIAL REGISTRATION: Dutch Trial Registry NTR4807 . PMID- 26032853 TI - Non-animal collagens as new options for cosmetic formulation. AB - OBJECTIVE: To examine the potential of non-animal collagens as a new option for cosmetic applications. METHODS: Non-animal collagens from three species, Streptococcus pyogenes, Solibacter usitatus and Methylobacterium sp 4-46, have been expressed as recombinant proteins in Escherichia coli using a cold-shock, pCold, expression system. The proteins were purified using either metal affinity chromatography or a simple process based on precipitation and proteolytic digestion of impurities, which is suitable for large-scale production. Samples were examined using a range of analytical procedures. RESULTS: Analyses by gel electrophoresis and mass spectrometry were used to examine the purity and integrity of the products. Circular dichroism spectroscopy showed stabilities around 38 degrees C, and calculated pI values were from 5.4 to 8.6. UV-visible light spectroscopy showed the clarity of collagen solutions. The collagens were soluble at low ionic strength between pH 5 and pH 8, but were less soluble under more acidic conditions. At lower pH, the insoluble material was well dispersed and did not form the fibrous associations and aggregates found with animal collagens. The materials were shown to be non-cytotoxic to cells in culture. CONCLUSIONS: These novel, non-animal collagens may be potential alternatives to animal collagens for inclusion in cosmetic formulations. PMID- 26032854 TI - Sharp penetrating wounds: spectrum of imaging findings and legal aspects in the emergency setting. AB - The main cause of severe civilian trauma is not the same all over the world; while in Europe the majority of cases are due to blunt traumatic injury, in the United States, penetrating gunshot wounds are the most common. Penetrating wounds can be classified into two different entities: gunshot wounds, or more technically ballistic traumas, and sharp penetrating traumas, also identifiable with non-ballistic traumas. Sharp penetrating injuries are mainly caused by sharp pointed objects such as spears, nails, daggers, knives, and arrows. The type of injuries caused by sharp pointed objects depends on the nature and shape of the weapon, the amount of energy in the weapon or implement when it strikes the body, whether it is inflicted upon a moving or a still body, and the nature of the tissue injured. In the assessment of hemodynamically stable patients with sharp penetrating wounds, the main imaging procedure is Multidetector Computed Tomography (MDCT), especially used in complicated cases of penetrating injuries with an important impact on the final therapeutic choice. The diagnostic approach has been changed by MDCT due to its technical improvements, in particular, faster data acquiring and upgraded image reconstructions. PMID- 26032855 TI - Multiple Ligands Targeting Cholinesterases and beta-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore. AB - Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50 = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent. PMID- 26032856 TI - Inhibition of stress mediated cell death by human lactate dehydrogenase B in yeast. AB - We report the identification of human L- lactate dehydrogenase B (LDHB) as a novel Bax suppressor. Yeast heterologously expressing LDHB is also resistant to the lethal effects of copper indicating that it is a general suppressor of stress mediated cell death. To identify potential LDHB targets, LDHB was expressed in yeast mutants defective in apoptosis, necrosis and autophagy. The absence of functional PCD regulators including MCA1, YBH3, cyclophilin (CPR3) and VMA3, as well as the absence of the pro-survival autophagic pathway (ATG1,7) did not interfere with the LDHB mediated protection against copper indicating that LDHB functions independently of known PCD regulators or by simply blocking or stimulating a common PCD promoting or inhibitory pathway. Measurements of lactate levels revealed that short-term copper stress (1.6 mM, 4 h), does not increase intracellular levels of lactate, instead a three-fold increase in extracellular lactate was observed. Thus, yeast cells resemble mammalian cells where different stresses are known to lead to increased lactate production leading to lactic acidosis. In agreement with this, we found that the addition of exogenous lactic acid to growth media was sufficient to induce cell death that could be inhibited by the expression of LDHB. Taken together our results suggest that lactate dehydrogenase is a general suppressor of PCD in yeast. PMID- 26032857 TI - simMSG: an experimental design tool for high-throughput genotyping of hybrids. AB - Hybridization between closely related species, whether naturally occurring or laboratory generated, is a useful tool for mapping the genetic basis of the phenotypic traits that distinguish species. The development of next-generation sequencing techniques has greatly improved our ability to assign ancestry to hybrid genomes. One such next-generation sequencing technique, multiplexed shotgun genotyping (or MSG), can be a powerful tool for genotyping hybrids. However, it is difficult a priori to predict the accuracy of MSG in natural hybrids because accuracy depends on ancestry tract length and number of ancestry informative markers. Here, we present a simulator, 'simMSG', that will allow researchers to design MSG experiments and show that in many cases MSG can accurately assign ancestry to hundreds of thousands of sites in the genomes of natural hybrids. The simMSG tool can be used to design experiments for diverse applications including QTL mapping, genotyping introgressed lines or admixture mapping. PMID- 26032858 TI - Unravelling nocebo effect: the mediating effect of anxiety between anticipation and pain at wound dressing change. AB - AIMS AND OBJECTIVES: The purpose of this study was to examine the mediating effect of anxiety in the relationship between anticipation and pain in people with chronic wounds. BACKGROUND: Pain is common in people with chronic wounds. Anticipation or negative expectation of discomfort has been shown to have an augmenting effect on pain; also known as nocebo hyperalgesia. DESIGN: This was a cross-sectional study with repeated measures. METHODS: Prior to dressing change, anticipatory pain level was evaluated by a 11-point numerical rating scale and anxiety by the Six-items State-Trait Anxiety Inventory (STAI-6). During wound dressing changes, pain was measured before dressing removal, at dressing removal, at cleansing and dressing application using the numerical scale. RESULTS: Analysis was completed based on the data from a convenience sample of 96 patients. Participants reported more pain at cleansing and dressing removal than baseline. High levels of anticipation, anxiety and pain at dressing change for wounds were related to heavy exudate and wound that were covered with necrotic tissue. Finally, the relationship between anticipation and pain perception was mediated by anxiety. CONCLUSION: Anticipation of pain triggers anxiety that can lead to increased pain. RELEVANCE TO CLINICAL PRACTICE: There is a need to incorporate evaluation of anxiety and personal expectations as part of comprehensive pain assessment. Clinicians should be aware of the impact of emotions and anticipation on overall pain experience. PMID- 26032859 TI - Antimalarial Effect of 3-Methoxy-1,2-Dioxetanes on the Erythrocytic Cycle of Plasmodium falciparum. AB - The antimalarial activity of peroxides most likely originates from their interaction with iron(II) species located inside the malaria parasite, which forms destructive radical species through a Fenton-like mechanism. This article reports the first evaluation of the in vitro antimalarial activity of three peroxides of the class 1,2-dioxetanes against Plasmodium falciparum; the results reveal that the studied 3-methoxy-1,2-dioxetanes display significant antimalarial activity, at a similar level as artemisinin and also that their reactivity toward iron(II) correlate linearly with their antimalarial activity. PMID- 26032860 TI - Bovine tuberculosis in New Zealand; reviewing the past and looking forward. PMID- 26032861 TI - Surgical decision-making in acute appendicitis. AB - BACKGROUND: Acute appendicitis is one of the most common acute abdominal conditions. Among other parameters, the decision to perform surgical exploration in suspected appendicitis involves diagnostic accuracy, patient age and co morbidity, patient's own wishes, the surgeon's core medical values, expected natural course of non-operative treatment and priority considerations regarding the use of limited resources. Do objective clinical findings, such as radiology and laboratory results, have greater impact on decision-making than "soft" clinical variables? In this study we investigate the parameters that surgeons consider significant in decision-making in cases of suspected appendicitis; specifically we describe the process leading to surgical intervention in real settings. The purpose of the study was to explore the process behind the decision to undertake surgery on a patient with suspected appendicitis as a model for decision-making in surgery. METHODS: All appendectomy procedures (n = 201) at the Department of Surgery at Karolinska University Hospital performed in 2009 were retrospectively evaluated. Every two consecutive patients seeking for abdominal pain after each case undergoing surgery were included as controls. Signs and symptoms documented in the medical records were registered according to a standardized protocol. The outcome of this retrospective review formed the basis of a prospective registration of patients undergoing appendectomy. During a three month period in 2011, the surgeons who made the decision to perform acute appendectomy on 117 consecutive appendectomized patients at the Karolinska University Hospital, Huddinge, and Sodersjukhuset, were asked to answer a questionnaire about symptoms, signs and diagnostic measures considered in their treatment decision. They were also asked which three symptoms, signs and diagnostic measures had the greatest impact on their decision to perform appendectomy. RESULTS: In the retrospective review, tenderness in the right fossa had the greatest impact (OR 76) on treatment decision. In the prospective registration, the most frequent symptom present at treatment decision was pain in the right fossa (94 %). Tenderness in the right fossa (69 %) was also most important for the decision to perform surgery. Apart from local status, image diagnostics and blood sample results had the greatest impact. CONCLUSION: Local tenderness in the right fossa, lab results and the results of radiological investigations had the greatest impact on treatment decision. PMID- 26032862 TI - Control of the blood-brain barrier function in cancer cell metastasis. AB - Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain-metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood-brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis. PMID- 26032863 TI - Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases. AB - OBJECTIVES: To identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment. PATIENTS AND METHODS: A retrospective review of patients with mRCC in an outpatient clinic was carried out for the period January 2006 to November 2011. Patient characteristics, including demographics, laboratory data and outcomes, were analysed. Baseline characteristics were compared using chi-squared and t-tests and overall survival (OS) and cancer-specific survival (CSS) rates were estimated using Kaplan-Meier methods. Predictors of OS were analysed using Cox regression. RESULTS: A total of 228 patients were reviewed, of whom 44 (19.3%) had PM and 184 (81.7%) had metastases to sites other than the pancreas. The distribution of baseline characteristics was equal in both groups, with the exception of a higher incidence of previous nephrectomy, diabetes and number of metastatic sites in the PM group. Four patients had isolated PM, but the majority of patients (68%) with PM had at least three different organ sites of metastases, as compared with 29% in patients without PM (P < 0.01). The distribution of organ sites of metastases was similar, excluding the pancreas, in those with and those without PM (P > 0.05). The median OS was 39 months (95% confidence interval [CI] 24-57, hazard ratio 0.66, 95% CI 0.42-0.94; P = 0.02) for patients with PM, compared with 26 months (95% CI 21-31) for patients without PM (P < 0.01). CSS was 42 months (95% CI 30-57) in the PM group and 27 months (95% CI 22-33) in the control group (P = 0.05). CONCLUSIONS: Despite a higher number of affected organ sites in the PM cohort, mRCC behaviour in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumour features associated with PM may represent a less aggressive tumour phenotype. PMID- 26032864 TI - Prediction of peri-operative adverse respiratory events in children: the role of exhaled nitric oxide. AB - Increased levels of exhaled nitric oxide (eNO) may be a more objective predictor in identifying children at higher risk of peri-operative adverse respiratory events than the presence of risk factors such as recent cold or wheeze. Children with either none or >= 2 risk factors had eNO measured before surgery and any peri-operative adverse respiratory events were recorded. We found that an elevated eNO level was only predictive of adverse respiratory events in children with >= 2 risk factors (OR 2.96 (95% CI 1.48-5.93), p = 0.002). The presence of risk factors had a better predictive capability than a raised eNO level (OR 3.83 (95% CI 1.85-7.95), p < 0.001). The combination of both predictors did not improve the predictive capability for adverse respiratory events (OR 1.93 (95% CI 1.44-2.59), p < 0.001). We conclude that measuring eNO levels does not lead to improved prediction of adverse respiratory events and that, in routine clinical practice, an accurate history of risk factors remains the most appropriate tool for successfully identifying children at risk of peri-operative adverse respiratory events. PMID- 26032865 TI - Are rigid management protocols stifling innovation in cancer treatment? PMID- 26032866 TI - The prognostic value of plasma soluble CD40 ligand levels in patients with nasopharyngeal carcinoma. AB - BACKGROUND: Serum soluble CD40 ligand (sCD40L) concentrations are increased in patients with nasopharyngeal carcinoma (NPC). This study further evaluated the relationship between plasma sCD40L concentrations and long-term survival of NPC. METHODS: Plasma sCD40L concentrations of 312 patients and 312 healthy controls were determined using an ELISA. The associations of plasma sCD40L concentrations with 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival were investigated by univariate and multivariate analyses. RESULTS: Plasma sCD40L concentrations were substantially higher in patients than in healthy subjects and also correlated highly with tumor classification, lymph node classification and tumor node metastasis stage. sCD40L emerged as an independent predictor for 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival using univariate and multivariate Cox regression analysis. CONCLUSIONS: High plasma sCD40L concentration is correlated with stage progression of NPC as well as associated with poor survival of NPC. It is suggested that sCD40L should have the potential to be a prognostic biomarker for NPC. PMID- 26032867 TI - Can we improve the delivery of bedside teaching? PMID- 26032868 TI - Effort analysis of gender differences in cardiovascular response: Further evidence involving a traditionally feminine incentive. AB - Participants were presented a moderately- or impossibly difficult cumulative mental addition task with instructions that they could win a traditionally feminine- or masculine incentive if they achieved a 90% success rate. When the incentive was feminine, systolic blood pressure responses during the task period were stronger under moderately difficult conditions among women, but low irrespective of difficulty among men - creating a gender difference only when difficulty was moderate. By contrast, when the incentive was masculine, systolic , mean arterial- and, to a lesser degree, diastolic blood pressure responses during the task period were stronger under moderately difficult conditions irrespective of gender. The former finding confirmed expectations and adds substantively to the body of evidence favoring a recent effort analysis of gender influence on CV response to performance challenge. The latter findings conflict with what was first expected, but can be understood in terms of post hoc reasoning extended in light of participants' ratings of the masculine incentive. PMID- 26032869 TI - Psychophysiological responses to eye contact in adolescents with social anxiety disorder. AB - We investigated whether eye contact is aversive and negatively arousing for adolescents with social anxiety disorder (SAD). Participants were 17 adolescents with clinically diagnosed SAD and 17 age- and sex-matched controls. While participants viewed the stimuli, a real person with either direct gaze (eye contact), averted gaze, or closed eyes, we measured autonomic arousal (skin conductance responses) and electroencephalographic indices of approach-avoidance motivation. Additionally, preferred viewing times, self-assessed arousal, valence, and situational self-awareness were measured. We found indications of enhanced autonomic and self-evaluated arousal, attenuated relative left-sided frontal cortical activity (associated with approach-motivation), and more negatively valenced self-evaluated feelings in adolescents with SAD compared to controls when viewing a face making eye contact. The behavioral measures and self assessments were consistent with the physiological results. The results provide multifaceted evidence that eye contact with another person is an aversive and highly arousing situation for adolescents with SAD. PMID- 26032870 TI - Dermoscopic Findings in Trichoblastoma. AB - Trichoblastoma is a benign cutaneous neoplasm that is clinically and histologically similar to basal cell carcinoma. We report the dermoscopic features seen in 2 cases of facial trichoblastoma. One case presented with very short, delicate, scarcely branching telangiectases against a pearly white background. In the second case, the veins were also short and scarcely branching, but they were arranged in a crown pattern, with white striae and milia-like cysts. Although dermoscopic evidence of fine, scarcely branching telangiectases is not specific to a diagnosis of trichoblastoma, these features may be useful for differentiating this neoplasm from nodular basal cell carcinoma. PMID- 26032871 TI - The role of phototherapy in cutaneous chronic graft-vs-host disease: a retrospective study and review of the literature. AB - INTRODUCTION AND OBJECTIVES: Cutaneous chronic graft-vs-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. Phototherapy is a therapeutic option for patients with skin involvement and for those who require high doses of corticosteroids. We analyze the cases treated in our department and review the literature. MATERIAL AND METHODS: All patients with GVHD treated with phototherapy in the dermatology department of Hospital Universitario y Politecnico la Fe in Valencia, Spain between March 2011 and October 2014 were identified. Data were gathered retrospectively. RESULTS: There were 16 patients: 10 treated with psoralen-UV-A and 6 with narrowband-UV-B. Complete response was achieved in 9 patients and partial response in 7; 2 patients with partial responses relapsed after treatment. Ten patients were able to decrease their dose of corticosteroids during treatment, and a further 3 decreased the number of other immunosuppressant drugs. No serious adverse effects occurred. CONCLUSIONS: Phototherapy is a good therapeutic option for patients with chronic GVHD with extensive cutaneous involvement, as well as for those who fail to respond to topical treatment or who have become steroid-dependent. The main benefits are that, as the treatment targets the skin, it reduces corticosteroid requirements and has a good safety profile. Treatment must be individualized and, in our experience, both the initial dose and the maximum dose per session can be lower than for other diseases. PMID- 26032872 TI - Pink Papules Arranged Linearly. PMID- 26032873 TI - Use of the Burow triangle or wedge-shaped resection during the repair of infraorbital defects. PMID- 26032874 TI - Editorial Comment from Dr Sakakibara to Measurement of oxyhemoglobin concentration changes in interstitial cystitis female patients: A near-infrared spectroscopy study. PMID- 26032875 TI - Work engagement in nursing: an integrative review of the literature. AB - AIM: To critically review empirical research about work engagement in nursing and to synthesise the findings to better understand this construct. BACKGROUND: Empirical research shows that engagement is positively related to work performance, workers' health and client loyalty in different professions. It is, therefore, necessary to increase our understanding about engagement in nursing. EVALUATION: An integrative literature search was conducted to identify articles and studies on work engagement in nursing that were published between January 1990 and December 2013 in the following databases: PsycINFO, MEDLINE and CINAHL. KEY ISSUES: The factors that influence engagement were divided into four areas of analysis: organisational antecedents; individual antecedents; and factors related to managers' leadership and outcomes of engagement. CONCLUSION: There is clear evidence that the quality of care by nurses improves through engagement. However, this depends on contextual factors such as structural empowerment and social support and on dispositional factors such as efficacy and optimism. It is also evident that nurse managers are key to promoting engagement. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers and leaders may promote improvements in leadership behaviours and a context of optimism and self-efficacy as a way of increasing work engagement. PMID- 26032876 TI - Evaluation of prescribing and patient use of target-specific oral anticoagulants in the outpatient setting. AB - WHAT IS KNOWN AND OBJECTIVE: Pharmacist-managed anticoagulation programmes have been shown to improve appropriate use of warfarin, but few programmes have included the new target-specific oral anticoagulants (TSOACs) in their protocols. A greater understanding of TSOAC prescribing, monitoring and administration is needed to identify common errors in the current outpatient practice. The objective of this study is to assess the rate of errors related to prescribing, baseline monitoring and patient administration of TSOACs. METHODS: A retrospective chart review was conducted to identify patients on TSOAC therapy in each of four outpatient practice sites. Data were abstracted to include TSOAC indication, dosage and frequency prescribed, pertinent past medical history, and laboratory monitoring obtained at the time of TSOAC initiation. In addition, patients were contacted by telephone to assess TSOAC adherence, storage, administration and incidence of adverse events. RESULTS AND DISCUSSION: A total of 395 patients were included in the evaluation. Prescribers did not obtain baseline laboratory values within 1 week before or after the time of TSOAC initiation for a majority of study patients. At the time of TSOAC initiation, two patients had abnormally elevated alanine aminotransferase, six had elevated total bilirubin, and 43 had low haemoglobin. A majority (61%) of study patients were prescribed an appropriate TSOAC dose based upon their indication and renal function; however, dosing accuracy could not be determined for all patients as baseline serum creatinine was not obtained by prescribers for 148 patients (37%) at the time of prescribing. TSOACs were dosed inappropriately according to baseline serum creatinine in six patients, and two patients receiving treatment for venous thromboembolism were maintained on a high dose of rivaroxaban for an inappropriate duration. A total of 157 (40%) patients were available by phone and agreed to answer questions regarding their current TSOAC use. Twenty-four patients (23%) reported taking rivaroxaban inappropriately without food, and six patients (14%) endorsed inappropriate storage of dabigatran. Ten patients (6%) reported missing at least one TSOAC dose per week, and 25 (16%) described minor bleeding with their TSOAC. WHAT IS NEW AND CONCLUSION: Inappropriate prescribing, monitoring and administration of TSOACs occurred frequently in patients not formally enrolled in an anticoagulation monitoring programme. These results indicate a need for more thorough patient education at the time of TSOAC initiation, as well as improved prescriber education regarding recommended TSOAC dosing and monitoring. PMID- 26032877 TI - Genetic Characterization of Porcine Circovirus Type 2 (PCV2) in Pigs of Bhutan. AB - Porcine circovirus (PCV) is a small non-enveloped virus with a single-stranded circular DNA with two antigenically and genetically different species, PCV1 and PCV2. Among these two, PCV2 is responsible for multifactorial disease syndromes, the most important disease known as PCV2-systemic disease (PCV2-SD), previously known as post-weaning multisystemic wasting syndrome (PMWS). The epidemiological situation is dynamically changing and new strains including recombinant PCV2 have emerged in Asia. In Bhutan, pigs are important livestock and play a very important role in providing meat and income for rural farmers. Although high rate of pigs seropositive against PCV2 was described in Bhutan, there was no virological evidence for PCV2 infections. This study was conducted to confirm the presence of PCV2 through detection of PCV2 DNA and molecular characterization of PCV2 strains in tissue and blood samples collected from Bhutanese pigs. Porcine circovirus type 2 genome was detected in 16 of 34 tissue samples pigs from the government farm. In 9 pigs, very high level of viral replication indicated that PCV2-SD was detected. Phylogenetic analysis performed with a set of GenBank sequences revealed that the Bhutanese PCV2 strains belonged to the PCV2b genotype and grouped with cluster 1C. PMID- 26032878 TI - Suction/Inspiration against resistance or standardized Mueller maneuver : a new breathing technique to improve contrast density within the pulmonary artery: a pilot CT study. AB - OBJECTIVE: Our aim was to prospectively investigate whether the recently introduced suction/inspiration against resistance breathing method leads to higher computed tomography (CT) contrast density in the pulmonary artery compared to standard breathing. MATERIAL AND METHODS: The present study was approved by the Medical Ethics committee and all subjects gave written informed consent. Fifteen patients, each without suspicious lung emboli, were randomly assigned to four different groups with different breathing maneuvers (suction against resistance, Valsalva, inspiration, expiration) during routine CT. Contrast enhancement in the central and peripheral sections of the pulmonary artery were measured and compared with one another. RESULTS: Peripheral enhancement during suction yielded increased mean densities of 138.14 Hounsfield units (HU) (p = 0.001), compared to Valsalva and a mean density of 67.97 HU superior to inspiration (p = 0.075). Finally, suction in comparison to expiration resulted in a mean increase of 30.51 HU (p = 0.42). Central parts of pulmonary arteries presented significantly increased enhancement values (95.74 HU) for suction versus the Valsalva technique (p = 0.020), while all other mean densities were in favour of suction (versus inspiration: p = 0.201; versus expiration: p = 0.790) without reaching significance. CONCLUSION: Suction/Inspiration against resistance is a promising technique to improve contrast density within pulmonary vessels, especially in the peripheral parts, in comparison to other breathing maneuvers. KEY POINTS: * Suction/Inspiration against resistance is promising to improve contrast density within the pulmonary artery. * Patients potentially suffering pulmonary embolism are able to follow suction/inspiration against resistance. * Contrast density after suction is superior in comparison to other breathing maneuvers. PMID- 26032879 TI - Comparison of magnetic resonance elastography and diffusion-weighted imaging for differentiating benign and malignant liver lesions. AB - OBJECTIVES: Comparison of magnetic resonance elastography (MRE) and diffusion weighted imaging (DWI) for differentiating malignant and benign focal liver lesions (FLLs). METHODS: Seventy-nine subjects with 124 FLLs (44 benign and 80 malignant) underwent both MRE and DWI. MRE was performed with a modified gradient echo sequence and DWI with a free breathing technique (b = 0.500). Apparent diffusion coefficient (ADC) maps and stiffness maps were generated. FLL mean stiffness and ADC values were obtained by placing regions of interest over the FLLs on stiffness and ADC maps. The accuracy of MRE and DWI for differentiation of benign and malignant FLL was compared using receiver operating curve (ROC) analysis. RESULTS: There was a significant negative correlation between stiffness and ADC (r = -0.54, p < 0.0001) of FLLs. Malignant FLLs had significantly higher mean stiffness (7.9kPa vs. 3.1kPa, p < 0.001) and lower mean ADC (129 vs. 200 * 10(-3)mm(2)/s, p < 0.001) than benign FLLs. The sensitivity/specificity/positive predictive value/negative predictive value for differentiating malignant from benign FLLs with MRE (cut-off, >4.54kPa) and DWI (cut-off, <151 * 10(-3)mm(2)/s) were 96.3/95.5/97.5/93.3% (p < 0.001) and 85/81.8/88.3/75% (p < 0.001), respectively. ROC analysis showed significantly higher accuracy for MRE than DWI (0.986 vs. 0.82, p = 0.0016). CONCLUSION: MRE is significantly more accurate than DWI for differentiating benign and malignant FLLs. KEY POINTS: * MRE is superior to DWI for differentiating benign and malignant focal liver lesions. * Benign lesions with large fibrous components may have higher stiffness with MRE. * Cholangiocarcinomas tend to have higher stiffness than hepatocellular carcinomas. * Hepatocellular adenomas tend to have lower stiffness than focal nodular hyperplasia. * MRE is superior to conventional MRI in differentiating benign and malignant liver lesions. PMID- 26032880 TI - Angiomyolipoma (AML) without visible fat: Ultrasound, CT and MR imaging features with pathological correlation. AB - OBJECTIVE: To compare imaging findings with histopathology in AML without visible fat (AMLwvf). MATERIAL AND METHODS: With IRB approval, we identified 18 AMLwvf that underwent CT between 2002-2014. A radiologist measured NECT-attenuation, corticomedullary (CM) and nephrographic (NG) enhancement, echogenicity relative to renal cortex (RC) (N = 5), T2W (T2AML/T2RC) signal-intensity (SI), and chemical-shift SI ([SIIN-PHASE - SIOPPOSED-PHASE]/SIIN-PHASE) indices (N = 6). A pathologist re-evaluated 15/18 AMLwvf for 1) < or > 25% adipocytes/high-power field (HPF), 2) "many or few" blood vessels. Comparisons were performed using chi square and independent t-tests. RESULTS: 73.3%(11/15) of AMLwvf had <25% adipocytes/HPF and 86.7%(13/15) had "many" blood vessels. NECT-attenuation was 41.8(+/-6.9) HU. 61.1 %(11/18) of AMLwvf were hyper-attenuating and 38.9%(7/18) iso-attenuating; attenuation was associated with %-adipocytes/HPF, (p = 0.01). CM/NG enhancement were 63.3(+/-20.8)/51.7(+/-15.5) HU. 72.2%(13/18) of AMLwvf had wash-out enhancement, with no association with amount of blood vessels at pathology, (p = 0.68). No difference in echogenicity was noted by histology (p > 0.05). All AMLwvf were T2-hypointense (SI ratio = 0.61 [+/-0.1]). 2/6 AMLwvf showed SI drop on chemical-shift MRI; both were iso-attenuating and were associated with >25% adipocytes/HPF (p = 0.04). CONCLUSIONS: AMLwvf are typically T2-hypointense and hyper-attenuating with wash-out enhancement due to abundant smooth muscle and vessels respectively. Iso-attenuating AMLwvf with microscopic fat on MRI contain more adipocytes/HPF. KEY POINTS: * Five percent of AML do not demonstrate detectable fat on imaging * These AML are hyperattenuating and T2 hypointense due to abundant smooth muscle * These AML show washout enhancement without association to vessel count at histopathology * Iso-attenuating AML with microscopic fat on MRI show >25% adipocytes/HPF * The term "AML without visible fat" is proposed to reduce ambiguity. PMID- 26032881 TI - Alternative strategies in newborns and infants with major co-morbidities to improve congenital heart surgery outcomes at an emerging programme. AB - INTRODUCTION: Debilitating patient-related non-cardiac co-morbidity cumulatively increases risk for congenital heart surgery. At our emerging programme, flexible surgical strategies were used in high-risk neonates and infants generally considered in-operable, in an attempt to make them surgical candidates and achieve excellent outcomes. MATERIALS AND METHODS: Between April, 2010 and November, 2013, all referred neonates (142) and infants (300) (average scores: RACHS 2.8 and STAT 3.0) underwent 442 primary cardiac operations: patients with bi-ventricular lesions underwent standard (n=294) or alternative (n=19) repair/staging strategies, such as pulmonary artery banding(s), ductal stenting, right outflow patching, etc. Patients with uni-ventricular hearts followed standard (n=96) or alternative hybrid (n=34) staging. The impact of major pre operative risk factors (37%), standard or alternative surgical strategy, prematurity (50%), gestational age, low birth weight, genetic syndromes (23%), and major non-cardiac co-morbidity requiring same admission surgery (27%) was analysed on the need for extracorporeal membrane oxygenation, mortality, length of intubation, as well as ICU and hospital length of stays. RESULTS: The need for extracorporeal membrane oxygenation (8%) and hospital survival (94%) varied significantly between surgical strategy groups (p=0.0083 and 0.028, respectively). In high-risk patients, alternative bi- and uni-ventricular strategies minimised mortality, but were associated with prolonged intubation and ICU stay. Major pre-operative risk factors and lower weight at surgery significantly correlated with prolonged intubation, hospital length of stay, and mortality. DISCUSSION: In our emerging programme, flexible surgical strategies were offered to 53/442 high-risk neonates and infants with complex CHDs and significant non-cardiac co-morbidity, in order to buffer risk and achieve patient survival, although at the cost of increased resource utilisation. PMID- 26032882 TI - Using adrenaline during neonatal resuscitation may have an impact on serum cardiac troponin-T levels. AB - AIM: It has been suggested that serum cardiac troponin-T (cTnT) can predict the severity of neonatal hypoxic-ischaemic encephalopathy. We evaluated whether cTnT was better correlated with adrenaline during cardiopulmonary resuscitation (CPR) than with the severity of the insult itself, based on the Apgar scores. METHODS: Serum cTnT was analysed in 47 asphyxiated newborn infants treated with hypothermia. Blood samples and resuscitation data were collected from medical records, and multiple linear regressions were used to evaluate the effect of the treatment and the Apgar scores on cTnT levels. RESULTS: The infants were divided into three groups: the no CPR group (n = 29) just received stimulation and ventilation, the CPR minus adrenaline group (n = 9) received cardiac compression and ventilation and the CPR plus adrenaline group (n = 9) received complete CPR, including adrenaline. In the univariate analysis, the five and ten-minute Apgar scores were significantly lower in the CPR plus adrenaline group and the cTnT was significantly higher. Multiple regression analysis showed significantly higher cTnT values in the CPR plus adrenaline group, but no significant relationship between cTnT and the Apgar scores. CONCLUSION: Although cTnT correlated with the severity of the insult in neonatal hypoxic-ischaemic encephalopathy, the levels may have been affected by adrenaline administered during CPR. PMID- 26032884 TI - Long-range dependencies make the difference-Comment on "A stochastic model for EEG microstate sequence analysis". PMID- 26032883 TI - Characterising seizures in anti-NMDA-receptor encephalitis with dynamic causal modelling. AB - We characterised the pathophysiology of seizure onset in terms of slow fluctuations in synaptic efficacy using EEG in patients with anti-N-methyl-d aspartate receptor (NMDA-R) encephalitis. EEG recordings were obtained from two female patients with anti-NMDA-R encephalitis with recurrent partial seizures (ages 19 and 31). Focal electrographic seizure activity was localised using an empirical Bayes beamformer. The spectral density of reconstructed source activity was then characterised with dynamic causal modelling (DCM). Eight models were compared for each patient, to evaluate the relative contribution of changes in intrinsic (excitatory and inhibitory) connectivity and endogenous afferent input. Bayesian model comparison established a role for changes in both excitatory and inhibitory connectivity during seizure activity (in addition to changes in the exogenous input). Seizures in both patients were associated with a sequence of changes in inhibitory and excitatory connectivity; a transient increase in inhibitory connectivity followed by a transient increase in excitatory connectivity and a final peak of excitatory-inhibitory balance at seizure offset. These systematic fluctuations in excitatory and inhibitory gain may be characteristic of (anti NMDA-R encephalitis) seizures. We present these results as a case study and replication to motivate analyses of larger patient cohorts, to see whether our findings generalise and further characterise the mechanisms of seizure activity in anti-NMDA-R encephalitis. PMID- 26032885 TI - Oscillatory activity reflects differential use of spatial reference frames by sighted and blind individuals in tactile attention. AB - Touch can be localized either on the skin in anatomical coordinates, or, after integration with posture, in external space. Sighted individuals are thought to encode touch in both coordinate systems concurrently, whereas congenitally blind individuals exhibit a strong bias for using anatomical coordinates. We investigated the neural correlates of this differential dominance in the use of anatomical and external reference frames by assessing oscillatory brain activity during a tactile spatial attention task. The EEG was recorded while sighted and congenitally blind adults received tactile stimulation to uncrossed and crossed hands while detecting rare tactile targets at one cued hand only. In the sighted group, oscillatory alpha-band activity (8-12Hz) in the cue-target interval was reduced contralaterally and enhanced ipsilaterally with uncrossed hands. Hand crossing attenuated the degree of posterior parietal alpha-band lateralization, indicating that attention deployment was affected by external spatial coordinates. Beamforming suggested that this posture effect originated in the posterior parietal cortex. In contrast, cue-related lateralization of central alpha-band as well as of beta-band activity (16-24Hz) were unaffected by hand crossing, suggesting that these oscillations exclusively encode anatomical coordinates. In the blind group, central alpha-band activity was lateralized, but did not change across postures. The pattern of beta-band activity was indistinguishable between groups. Because the neural mechanisms for posterior alpha-band generation seem to be linked to developmental vision, we speculate that the lack of this neural mechanism in blind individuals is related to their preferred use of anatomical over external spatial codes in sensory processing. PMID- 26032887 TI - The Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) data repository. AB - Arterial spin labeling (ASL) MRI provides an accurate and reliable measure of cerebral blood flow (CBF). A rapidly growing number of CBF measures are being collected both in clinical and research settings around the world, resulting in a large volume of data across a wide spectrum of study populations and health conditions. Here, we describe a central CBF data repository with integrated processing workflows, referred to as the Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN). The CBFBIRN provides an integrated framework for the analysis and comparison of CBF measures across studies and sites. In this work, we introduce the main capabilities of the CBFBIRN (data storage, processing, and sharing), describe what types of data are available, explain how users can contribute to the data repository and access existing data from it, and discuss our long-term plans for the CBFBIRN. PMID- 26032888 TI - The Northwestern University Neuroimaging Data Archive (NUNDA). AB - The Northwestern University Neuroimaging Data Archive (NUNDA), an XNAT-powered data archiving system, aims to facilitate secure data storage; centralized data management; automated, standardized data processing; and simple, intuitive data sharing. NUNDA is a federated data archive, wherein individual project owners regulate access to their data. NUNDA supports multiple methods of data import, enabling data collection in a central repository. Data in NUNDA are available by project to any authorized user, allowing coordinated data management and review across sites. With NUNDA pipelines, users capitalize on existing procedures or standardize custom routines for consistent, automated data processing. NUNDA can be integrated with other research databases to simplify data exploration and discovery. And data on NUNDA can be confidently shared for secure collaboration. PMID- 26032886 TI - Cardiorespiratory fitness modifies the relationship between myocardial function and cerebral blood flow in older adults. AB - A growing body of evidence indicates that cardiorespiratory fitness attenuates some age-related cerebral declines. However, little is known about the role that myocardial function plays in this relationship. Brain regions with high resting metabolic rates, such as the default mode network (DMN), may be especially vulnerable to age-related declines in myocardial functions affecting cerebral blood flow (CBF). This study explored the relationship between a measure of myocardial mechanics, global longitudinal strain (GLS), and CBF to the DMN. In addition, we explored how cardiorespiratory affects this relationship. Participants were 30 older adults between the ages of 59 and 69 (mean age=63.73years, SD=2.8). Results indicated that superior cardiorespiratory fitness and myocardial mechanics were positively associated with DMN CBF. Moreover, results of a mediation analysis revealed that the relationship between GLS and DMN CBF was accounted for by individual differences in fitness. Findings suggest that benefits of healthy heart function to brain function are modified by fitness. PMID- 26032889 TI - Visual processing at goal and effector locations is dynamically enhanced during motor preparation. AB - Previous theoretical and experimental works has shown that preparing to act causes enhanced perceptual processing at movement-relevant locations. Up until now, this has focused almost exclusively on the goal of an action, neglecting the role of the effector. We addressed this by measuring changes in visual processing across time during motor preparation at both goal and effector locations. We compared event related potentials (ERPs) elicited by task-irrelevant visual probe stimuli at both goal and effector locations during motor preparation. Participants were instructed to place their hands on two starting positions (effector locations) and an auditory tone instructed them to immediately move to one of two target buttons (goal locations). Probe stimuli were presented in the interval between the offset of the cue and the execution of the movement at either a goal or an effector location. Probes were presented randomly at either 100ms, 200ms or 300ms after the auditory cue. Analysis of the visual N1 ERP showed enhanced visual processing at moving vs. not-moving goal locations across all three SOAs. At effector locations, enhanced processing for the moving vs. not moving effector was only observed during the middle (200ms) SOA. These results demonstrate, for the first time, simultaneous perceptual enhancement of goal and effector locations during motor preparation. We interpret these results as reflecting a temporally and spatially specific dynamic attentional map of the environment that adapts to maximise efficiency of movement by selectively weighting processing of multiple functional components of action in parallel. PMID- 26032891 TI - The GIRK2 subunit is involved in IS-like seizures induced by GABA(B) receptor agonists. AB - OBJECTIVE: Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of gamma-aminobutyric acid (GABA) B receptor (GABA(B)R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABA(B)R-mediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response duration) phenotype induced in the Ts mice by GABA(B)R agonists. METHODS: GIRK2(-/-), (+/ ), and (+/+) mice were treated with gamma-butyrolactone (GBL), a pro-drug of the GABA(B)R agonist gamma-hydroxybutyric acid, and the specific GABA(B)R agonist baclofen (BAC) under continuous EEG monitoring. These drugs induce epileptiform bursts, extensor spasms, and an electrodecremental response (EDR) in Ts mice at low doses, and in wild-type mice at high doses. A dose-response curve was ascertained with two treatment groups: GBL (100, 200, and 400 mg/kg) and BAC (4, 8, 12, and 16 mg/kg). We determined the baseline, the presence and duration of electrodecremental epochs (EDEs), and quantified acute epileptic extensor spasms. RESULTS: Analysis of EEG and behavior of GIRK2(-/-), (+/-), and (+/+) mice after treatment with GABA(B)R agonists and antagonists, indicate that GIRK2(-/-) mice are highly resistant to GABA(B)R agonist-induced EEG and behavioral changes. SIGNIFICANCE: These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms. PMID- 26032890 TI - Group differences in MEG-ICA derived resting state networks: Application to major depressive disorder. AB - Functional magnetic resonance imaging (fMRI) studies have revealed the existence of robust, interconnected brain networks exhibiting correlated low frequency fluctuations during rest, which can be derived by examining inherent spatio temporal patterns in functional scans independent of any a priori model. In order to explore the electrophysiological underpinnings of these networks, analogous techniques have recently been applied to magnetoencephalography (MEG) data, revealing similar networks that exhibit correlated low frequency fluctuations in the power envelope of beta band (14-30Hz) power. However, studies to date using this technique have concentrated on healthy subjects, and no method has yet been presented for group comparisons. We extended the ICA resting state MEG method to enable group comparisons, and demonstrate the technique in a sample of subjects with major depressive disorder (MDD). We found that the intrinsic resting state networks evident in fMRI appeared to be disrupted in individuals with MDD compared to healthy participants, particularly in the subgenual cingulate, although the electrophysiological correlates of this are unknown. Networks extracted from a combined group of healthy and MDD participants were examined for differences between groups. Individuals with MDD showed reduced correlations between the subgenual anterior cingulate (sgACC) and hippocampus in a network with primary nodes in the precentral and middle frontal gyri. Individuals with MDD also showed increased correlations between insulo-temporal nodes and amygdala compared to healthy controls. To further support our methods and findings, we present test/re-test reliability on independent recordings acquired within the same session. Our results demonstrate that group analyses are possible with the resting state MEG-independent component analysis (ICA) technique, highlighting a new pathway for analysis and discovery. This study also provides the first evidence of altered sgACC connectivity with a motor network. This finding, reliable across multiple sessions, suggests that the sgACC may partially mediate the psychomotor symptoms of MDD via synchronized changes in beta-band power, and expands the idea of the sgACC as a hub region mediating cognitive and emotional symptomatic domains in MDD. Findings of increased connectivity between the amygdala and cortical nodes further support the role of amygdalar networks in mediated depressive symptomatology. CLINICAL TRIALS IDENTIFIER: NCT00024635 (ZIA MH002927-04). PMID- 26032892 TI - Imaging and Tailoring the Chirality of Domain Walls in Magnetic Films. AB - Electric-current-induced magnetization switching is a keystone concept in the development of spintronics devices. In the last few years this field has experienced a significant boost with the discovery of ultrafast domain wall motions and very low threshold currents in structures designed to stabilize chiral spin textures. Imaging domain-wall spin textures in situ, while fabricating magnetic multilayer structures, is a powerful way to investigate the forces stabilizing this type of chirality, and informs strategies to engineer structures with controlled spin textures. Here, recent results applying spin polarized low-energy electron microscopy to image chiral domain walls in magnetic multilayer films are summarized. Providing a way to measure the strength of the asymmetric exchange interaction that causes the chirality, this approach can be used to tailor the texture and handedness of magnetic domain walls by interface engineering. These results advance understanding of the underlying physics and offer new insights toward the design of spintronic devices. PMID- 26032893 TI - Evaluation of a novel helium ionization detector within the context of (low-)flow modulation comprehensive two-dimensional gas chromatography. AB - The present research is focused on the use and evaluation of a novel helium ionization detector, defined as barrier discharge ionization detector (BID), within the context of (low-)flow modulation comprehensive two-dimensional gas chromatography (FM GC*GC). The performance of the BID device was compared to that of a flame ionization detector (FID), under similar FM GC*GC conditions. Following development and optimization of the FM GC*GC method, the BID was subjected to fine tuning in relation to acquisition frequency and discharge flow. Moreover, the BID performance was measured and compared to that of the FID, in terms of extra-column band broadening, sensitivity and dynamic range. The comparative study was carried out by using standard compounds belonging to different chemical classes, along with a sample of diesel fuel. Advantages and disadvantages of the BID system, also within the context of FM GC*GC, are critically discussed. In general, the BID system was characterized by a more limited dynamic range and increased sensitivity, compared to the FID. Additionally, BID and FID contribution to band broadening was found to be similar under the operational conditions applied. Particular attention was devoted to the behaviour of the FM GC*GC-BID system toward saturated and aromatic hydrocarbons, for a possible future use in the field of mineral-oil food contamination research. PMID- 26032894 TI - India is declared free of maternal and neonatal tetanus. PMID- 26032895 TI - MP2RAGE for deep gray matter measurement of the brain: A comparative study with MPRAGE. AB - BACKGROUND: To compare magnetization-prepared two rapid acquisition gradient echoes (MP2RAGE) imaging with conventional MPRAGE imaging for deep gray matter (GM) segmentation, reproducibility, contrast ratio (CR) and contrast-to-noise ratio (CNR), and to evaluate reproducibility of T1 maps derived from MP2RAGE. METHODS: MP2RAGE and MPRAGE imaging were conducted twice for each of 20 volunteers on a 3 Tesla MRI scanner. Images were normalized and segmented using SPM12 with the DARTEL algorithm. Reproducibility of segmentation was evaluated using coefficients of variation (COVs) of deep GM probability maps between first and second scans, which was compared between MP2RAGE and MPRAGE. Differences in deep GM probability were compared voxel-wise. CR and CNR analyses were conducted using regions of interest. COVs of T1 maps were also evaluated. RESULTS: Comparison of GM probability maps demonstrated that putamen, caudate nucleus and thalamus were segmented significantly larger in MP2RAGE than in MPRAGE, and MP2RAGE was inferior only at some areas of globus pallidus and lateral thalamus (P < 0.05; false discovery rate, FDR). CRs of deep GM structures were significantly better in MP2RAGE (P < 0.0001). COVs of deep GM probability maps were significantly higher at large areas of the deep GM in MPRAGE (P < 0.05, FDR). COVs ranged from 0.50 to 3.31% in MP2RAGE and from 0.62 to 4.12% in MPRAGE. COVs of the T1 map were around 2%. CONCLUSION: MP2RAGE yields greater reproducibility and better tissue contrast than MPRAGE in deep GM. T1 maps derived from MP2RAGE were highly reliable. MP2RAGE is useful for measurement and analysis of deep GM. PMID- 26032896 TI - Proton Order-Disorder Phenomena in a Hydrogen-Bonded Rhodium-eta(5)-Semiquinone Complex: A Possible Dielectric Response Mechanism. AB - A newly synthesized one-dimensional (1D) hydrogen-bonded (H-bonded) rhodium(II) eta(5)-semiquinone complex, [Cp*Rh(eta(5)-p-HSQ-Me4)]PF6 ([1]PF6; Cp* = 1,2,3,4,5 pentamethylcyclopentadienyl; HSQ = semiquinone) exhibits a paraelectric antiferroelectric second-order phase transition at 237.1 K. Neutron and X-ray crystal structure analyses reveal that the H-bonded proton is disordered over two sites in the room-temperature (RT) phase. The phase transition would arise from this proton disorder together with rotation or libration of the Cp* ring and PF6( ) ion. The relative permittivity epsilonb' along the H-bonded chains reaches relatively high values (ca., 130) in the RT phase. The temperature dependence of (13)C CP/MAS NMR spectra demonstrates that the proton is dynamically disordered in the RT phase and that the proton exchange has already occurred in the low temperature (LT) phase. Rate constants for the proton exchange are estimated to be 10(-4)-10(-6) s in the temperature range of 240-270 K. DFT calculations predict that the protonation/deprotonation of [1](+) leads to interesting hapticity changes of the semiquinone ligand accompanied by reduction/oxidation by the pi-bonded rhodium fragment, producing the stable eta(6)-hydroquinone complex, [Cp*Rh(3+)(eta(6)-p-H2Q-Me4)](2+) ([2](2+)), and eta(4)-benzoquinone complex, [Cp*Rh(+)(eta(4)-p-BQ-Me4)] ([3]), respectively. Possible mechanisms leading to the dielectric response are discussed on the basis of the migration of the protonic solitons comprising of [2](2+) and [3], which would be generated in the H-bonded chain. PMID- 26032897 TI - Improved photosynthetic performance during severe drought in Nicotiana tabacum overexpressing a nonenergy conserving respiratory electron sink. AB - Chloroplasts have means to manage excess reducing power but these mechanisms may become restricted by rates of ATP turnover. Alternative oxidase (AOX) is a mitochondrial terminal oxidase that uncouples the consumption of reducing power from ATP synthesis. Physiological and biochemical analyses were used to compare respiration and photosynthesis of Nicotiana tabacum wild-type (WT) plants with that of transgenic lines overexpressing AOX, under both well-watered and drought stress conditions. With increasing drought severity, AOX overexpression acted to increase respiration in the light (RL ) relative to WT. CO2 and light response curves indicated that overexpression also improved photosynthetic performance relative to WT, as drought severity increased. This was not due to an effect of AOX amount on leaf water status or the development of the diffusive limitations that occur due to drought. Rather, AOX overexpression dampened photosystem stoichiometry adjustments and losses of key photosynthetic components that occurred in WT. The results indicate that AOX amount influences RL , particularly during severe drought, when cytochrome pathway respiration may become increasingly restricted. This impacts the chloroplast redox state, influencing how the photosynthetic apparatus responds to increasing drought severity. In particular, the development of biochemical limitations to photosynthesis are dampened in plants with increased nonenergy conserving RL . PMID- 26032898 TI - Diffusion tensor imaging reveals no white matter impairments among adults with autism spectrum disorder. AB - Abnormalities within white matter (WM) have been identified in autism spectrum disorder (ASD). Although there is some support for greater neurobiological deficits among females with ASD, there is little research investigating sex differences in WM in ASD. We used diffusion tensor imaging (DTI) to investigate WM aberration in 25 adults with high-functioning ASD and 24 age-, sex- and IQ matched controls. Tract-based spatial statistics (TBSS) was used to explore differences in WM in major tract bundles. The effects of biological sex were also investigated. TBSS revealed no differences in fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), or axial diffusivity (AD) between groups. There were no effects of biological sex. We consider whether methodological differences between past studies have contributed to the highly heterogeneous findings in the literature. Finally, we suggest that, among a high functioning sample of adults with ASD, differences in WM microstructure may not be related to clinical impairment. PMID- 26032899 TI - Informing management on the future structure of hospital care: an extrapolation of trends in demand and costs in lung diseases. AB - OBJECTIVE: The planning of health care management benefits from understanding future trends in demand and costs. In the case of lung diseases in the national German hospital market, we therefore analyze the current structure of care, and forecast future trends in key process indicators. METHODS: We use standardized, patient-level, activity-based costing from a national cost calculation data set of respiratory cases, representing 11.9-14.1 % of all cases in the major diagnostic category "respiratory system" from 2006 to 2012. To forecast hospital admissions, length of stay (LOS), and costs, the best adjusted models out of possible autoregressive integrated moving average models and exponential smoothing models are used. RESULTS: The number of cases is predicted to increase substantially, from 1.1 million in 2006 to 1.5 million in 2018 (+2.7 % each year). LOS is expected to decrease from 7.9 to 6.1 days, and overall costs to increase from 2.7 to 4.5 billion euros (+4.3 % each year). Except for lung cancer (-2.3 % each year), costs for all respiratory disease areas increase: surgical interventions +9.2 % each year, COPD +3.9 %, bronchitis and asthma +1.7 %, infections +2.0 %, respiratory failure +2.6 %, and other diagnoses +8.5 % each year. The share of costs of surgical interventions in all costs of respiratory cases increases from 17.8 % in 2006 to 30.8 % in 2018. CONCLUSIONS: Overall costs are expected to increase particularly because of an increasing share of expensive surgical interventions and rare diseases, and because of higher intensive care, operating room, and diagnostics and therapy costs. PMID- 26032900 TI - Investigation of mid-infrared emission characteristics and energy transfer dynamics in Er(3+) doped oxyfluoride tellurite glass. AB - Er(3+) doped oxyfluoride tellurite glasses have been prepared. Three Judd-Ofelt parameters Omegat (t=2, 4, 6) and radiative properties are calculated for prepared glasses. Emission characteristics are analyzed and it is found that prepared glasses possess larger calculated predicted spontaneous transition probability (39.97 s(-1)), emission cross section sigmaem (10.18 * 10(-21)cm(2)) and sigmaem * Deltalambdaeff (945.32 * 10(-28)cm(3)), corresponding to the 2.7 MUm emission of Er(3+): (4)I11/2-> (4)I13/2 transition. The results suggest that the prepared glasses might be appropriate optical material for mid-infrared laser application. Moreover, rate equation analysis which is rarely used in bulk glass has been carried out to explain the relationship between emission intensity and Er(3+) concentration. The calculation results show that with the increment of Er(3+) concentration, the energy transfer up-conversion rate of (4)I13/2 state increases while the rate of (4)I11/2 state reduces, resulting in the change of 2.7 MUm emission. PMID- 26032901 TI - Intersensory selective attention and temporal orienting operate in parallel and are instantiated in spatially distinct sensory and motor cortices. AB - Knowledge about the sensory modality in which a forthcoming event might occur permits anticipatory intersensory attention. Information as to when exactly an event occurs enables temporal orienting. Intersensory and temporal attention mechanisms are often deployed simultaneously, but as yet it is unknown whether these processes operate interactively or in parallel. In this human electroencephalography study, we manipulated intersensory attention and temporal orienting in the same paradigm. A continuous stream of bisensory visuo-tactile inputs was presented, and a preceding auditory cue indicated to which modality participants should attend (visual or tactile). Temporal orienting was manipulated blockwise by presenting stimuli either at regular or irregular intervals. Using linear beamforming, we examined neural oscillations at virtual channels in sensory and motor cortices. Both attentional processes simultaneously modulated the power of anticipatory delta- and beta-band oscillations, as well as delta-band phase coherence. Modulations in sensory cortices reflected intersensory attention, indicative of modality-specific gating mechanisms. Modulations in motor and partly in somatosensory cortex reflected temporal orienting, indicative of a supramodal preparatory mechanism. We found no evidence for interactions between intersensory attention and temporal orienting, suggesting that these two mechanisms act in parallel and largely independent of each other in sensory and motor cortices. PMID- 26032902 TI - Social Marketing Risk-Framing Approaches for Dental Sealants in Rural American Indian Children. AB - OBJECTIVE: To compare three variants of a culturally relevant and theoretically based message to determine the most influential risk-framing approach for improving intention to place dental sealants for preschool children. DESIGN AND SAMPLE: A convenience sample of adult, American Indian participants (n = 89) attending a community health fair were assigned to view a gain-framed, loss framed, or mix-framed dental sealant message. MEASURES: We compared participants' scores on a 46-item survey to determine the relative effect of the frame assignment on seven indices of behavior change. RESULTS: The mean difference in participants' stage-of-change scores (x = 1.17, n = 89, SD = 1.90) demonstrated a significant improvement for all groups after watching the dental sealant message t88 = 5.81, p < .0001, 95% CI [0.77-1.57]. Self-efficacy was the only construct for which we detected a statistically significant difference as a function of frame assignment. Overall, the mix-framed message resulted in the highest scores. The gain-framed message was the least influential on four constructs. This finding is in contrast to findings that gain-framed oral health messages are most influential (Gallagher & Updegraff, 2012; O'Keefe & Jensen, 2007). CONCLUSIONS: Community advisory board members determined to use the mix-framed approach in an oral health social marketing campaign with a rural, American Indian audience. PMID- 26032903 TI - The impact of economic recession on health-care and the contribution by nurses to promote individuals' dignity. AB - The health sector is facing many challenges, and there is a need to maintain the delivery of high-quality health-care. Issues related to equity and access to health-care have emerged in a context of an economic recession in which the sustainability of the health system depends on everyone, including the actions and decisions of professionals. Therefore, nurses and their skills may be the answer to ethical, professional and community health management, but this recession could lead to major problems in the education of nurses in daily health care practice. Due to the limited availability of resources, nurses are increasingly taking leadership positions, continuing to develop their critical abilities and thinking skills, and considering sciences such as deontology and ethics. The main goals of this study were to reflect on the economic recession and its impact on health-care and to demonstrate the contribution of nursing to the sustainability of health-care and in the promotion of individuals' dignity. The authors conclude that health-care depends on economic redistribution and, in this context, needs to be equitable and fair. Nurses have the responsibility to develop their profession according to the underlying sciences and can therefore strategically help the healthcare system. PMID- 26032904 TI - Is medial elbow pain correlated with cubital tunnel syndrome? An electrodiagnostic study. AB - INTRODUCTION: Medial elbow pain is often considered to be a symptom associated with ulnar neuropathy at the elbow (UNE). We examined the relationship between medial elbow pain and a positive electrodiagnostic (EDx) test result for UNE. METHODS: We performed a retrospective review of 884 patients referred for EDx evaluation of UNE. Regression models were used to determine the odds ratios between clinical findings and a positive EDx result for UNE. RESULTS: Patients reported medial elbow pain in 44.3% of cases. Clinical factors that correlated with a positive EDx study result for UNE included male gender, small and ring finger numbness, ulnar intrinsic weakness, and age. Medial elbow pain was negatively correlated with a positive EDx result. CONCLUSIONS: This study demonstrates a negative correlation between medial elbow pain and a positive EDx result for UNE. Medial elbow pain should not be considered a clear diagnostic symptom of UNE. PMID- 26032905 TI - Interaction between common variants of FTO and MC4R is associated with risk of PCOS. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common and complex endocrine metabolic disease. One of the well-documented characteristics of PCOS is obesity or overweightness. It is possible to be genetically predisposed to becoming obese or overweight, and several potentially causative single nucleotide polymorphisms (SNPs), such as rs9939609 (A/T) in the fat mass, and obesity-associated gene (FTO) and rs17782313 (T/C) in the melanocortin-4 receptor gene (MC4R), have been investigated. Further investigation of association between obesity-associated SNPs and PCOS susceptibility will contribute to a better understanding of the disease. METHODS: In the present study, we enrolled 733 patients with PCOS and 892 control subjects. The common variants FTO rs9939609 and MC4R rs17782313 were genotyped and their relationship with obesity-related traits was evaluated. RESULTS: Rs9939609 and rs17782313 are associated with PCOS and obesity-related traits and profiles. The association found between PCOS and FTO rs9939609 (p=0.0302) was attenuated after adjustment for BMI (p=0.187). MC4R rs17782313 did not confer an increased risk for PCOS (p=0.368) even after adjustments (p=0.715). Interestingly, the interaction of FTO and MC4R polymorphisms was more significantly associated with PCOS (p=0.031, adjusted for age and BMI). The FTO variant rs9939609 is associated with Chinese women with PCOS; however, this association is affected by BMI. CONCLUSIONS: The combined pathogenic effect of FTO and MC4R polymorphisms indicates a direct role of the interaction between FTO and MC4R polymorphisms in the development of PCOS. PMID- 26032906 TI - A two-way clustering framework to identify disparities in multimorbidity patterns of mental and physical health conditions among Australians. AB - Multimorbidity is present in more than one quarter of the population in Australia, and its prevalence increases with age. Greater multimorbidity burden among individuals is always associated with poor health-related outcomes, including quality of life, health service utilization and mortality, among others. It is thus significant to identify the heterogeneity in multimorbidity patterns in the community and determine the impact of multimorbidity on individual health outcomes. In this paper, I propose a two-way clustering framework to identify clusters of most significant non-random comorbid health conditions and disparities in multimorbidity patterns among individuals. This framework can establish a clustering-based approach to determine the association between multimorbidity patterns and health-related outcomes and to calculate a multimorbidity score for each individual. The proposed method is illustrated using simulated data and a national survey data set of mental health and wellbeing in Australia. PMID- 26032907 TI - End-of-life preferences of the general public: Results from a Japanese national survey. AB - PURPOSE: To determine under different End-of-Life (EoL) scenarios the preferences of the general public for EoL care setting and Life-sustaining-Treatments (LST), and to develop a new framework to assess these preferences. METHOD: Using a 2 stage, geographical cluster sampling method, we conducted a postal survey across Japan of 2000 adults, aged 20+. Four EoL scenarios were used: cancer, cardiac failure, dementia and persistent vegetative state (PVS). RESULTS: We received 969 valid responses (response rate 48.5%). Preference for EoL care setting varied by illness with those wishing to spend EoL at home only 39% for cancer, 22% for cardiac failure, and 10-11% for dementia and PVS. Preference for LST differed by scenario and treatment type. In cancer, cardiac failure and dementia, about half to two thirds expressed a preference for antibiotics and fluid drip infusion but few for nasogastric (NG) tube feeding, percutaneous endoscopic gastrostomy (PEG), ventilation or cardiopulmonary resuscitation (CPR). Although our models accounted for only 3-9% of the variance, preferences to receive LST were associated with preference to spend EoL in hospital for cancer and cardiac failure but not dementia. CONCLUSIONS: Few people preferred to die at home, while a preference for hospital was largely determined by factors other than preference for LST. PMID- 26032908 TI - Do patients want doctors to talk about spirituality? A systematic literature review. AB - OBJECTIVE: The aim of this systematic literature review was to ascertain the patient perspective regarding the role of the doctor in the discussion of spirituality. METHODS: We conducted a systematic search in ten databases from inception to January 2015. Eligible papers reported on original research including patient reports of discussion of spirituality in a medical consultation. Papers were separated into qualitative and quantitative for the purposes of analysis and quality appraisal with QualSyst. Papers were merged for the final synthesis. RESULTS: 54 studies comprising 12,327 patients were included. In the majority of studies over half the sample thought it was appropriate for the doctor to enquire about spiritual needs in at least some circumstances (range 2.1-100%, median 70.5%), but patient preferences were not straightforward. CONCLUSION: While a majority of patients express interest in discussion of religion and spirituality in medical consultations, there is a mismatch in perception between patients and doctors regarding what constitutes this discussion and therefore whether it has taken place. PRACTICE IMPLICATIONS: This review demonstrated that many patients have a strong interest in discussing spirituality in the medical consultation. Doctors should endeavor to identify which patients would welcome such conversations. PMID- 26032909 TI - Nitrogen and fluorine dual-doped mesoporous graphene: a high-performance metal free ORR electrocatalyst with a super-low HO2(-) yield. AB - In this study, we successfully, for the first time, prepared nitrogen and fluorine dual-doped mesoporous graphene (NF-MG) via the thermal treatment of graphene oxide/polyaniline composites (GO/PANI) and NH4F. Benefiting from the synergistic effect of N and F co-doping into the G framework, the oxygen reduction reaction performance of the optimal catalyst (NF-MG3) is comparable with the-state-of-the-art Pt/C catalyst in an alkaline medium, which makes it an ideal candidate as an efficient metal-free ORR electrocatalyst in fuel cells. PMID- 26032910 TI - Competition, coinfection and strain replacement in models of Bordetella pertussis. AB - Pertussis, or whooping cough, is an important respiratory infection causing considerable infant mortality worldwide. Recently, incidence has risen in countries with strong vaccine programmes and there are concerns about antigenic shift resulting in vaccine evasion. Interactions between pertussis and non vaccine-preventable strains will play an important role in the evolution and population dynamics of pertussis. In particular, if we are to understand the role strain replacement plays in vaccinated settings, it will be essential to understand how strains or variants of pertussis interact. Here we explore under what conditions we would expect strain replacement to be of concern in pertussis. We develop a dynamic transmission model that allows for coinfection between Bordetella pertussis (the main causative agent of pertussis) and a strain or variant unaffected by the vaccine. We incorporate both neutrality (in the sense of ecological/population genetic neutrality) and immunity into the model, leaving the specificity of the immune response flexible. We find that strain replacement may be considerable when immunity is non-specific. This is in contrast to previous findings where neutrality was not considered. We conclude that the extent to which models reflect ecological neutrality can have a large impact on conclusions regarding strain replacement. This will likely have onward consequences for estimates of vaccine efficacy and cost-effectiveness. PMID- 26032911 TI - Serum soluble CD40 ligand levels after acute intracerebral hemorrhage. AB - BACKGROUND: Soluble CD40 ligand (sCD40L) is associated with inflammation. This study aimed to assess the prognostic value of sCD40L for clinical outcomes of acute intracerebral hemorrhage (ICH) patients. MATERIALS AND METHODS: The serum sCD40L levels of 110 patients and 110 age- and gender-matched healthy controls were measured using sandwich immunoassays. The relationships between serum sCD40L levels and 1-week mortality, 6-month mortality, 6-month overall survival, 6-month unfavorable outcome (modified Rankin Scale score >2), and ICH severity including hematoma volume and National Institutes of Health Stroke Scale (NIHSS) score were assessed using multivariate analysis. RESULTS: Compared with healthy controls, ICH patients had higher serum sCD40L levels. Serum sCD40L levels were correlated positively with hematoma volumes and NIHSS scores using a multivariate linear regression. Multivariate analysis results indicated that sCD40L was identified an independent predictor of 1-week mortality, 6-month mortality, 6-month unfavorable outcome and 6-month overall survival. sCD40L also showed high predictive performances for 1-week mortality, 6-month mortality and 6-month unfavorable outcome based on receiver operating characteristic curve. CONCLUSIONS: Elevated serum sCD40L levels are independently associated with ICH severity and clinical outcomes. And sCD40L has potential to be a good prognostic biomarker of ICH. PMID- 26032912 TI - Re: Chung et al.'s Letter to the Editor in response to: Early detection of abnormal left ventricular relaxation in acute myocardial ischemia with a quadratic model. Med Eng Phys 2014;36(September (9)):1101-5 by Morimont et al. PMID- 26032913 TI - A systematic study on dysregulated microRNAs in cervical cancer development. AB - MicroRNAs (miRNAs) are short regulatory RNAs that modulate the transcriptome and proteome at the post-transcriptional level. To obtain a better understanding on the role of miRNAs in the progression of cervical cancer, meta-analysis and gene set enrichment analysis were used to analyze published cervical cancer miRNA studies. From 85 published reports, which include 3,922 cases and 2,099 noncancerous control tissue samples, 63 differentially expressed miRNAs (DEmiRNAs) were identified in different stages of cervical cancer development (CIN 1-3 and CC). It was found that some of the dysregulated miRNAs were associated with specific stages of cervical cancer development. To illustrate the impact of miRNAs on the pathogenesis of cervical cancer, a miRNA-mRNA interaction network on selected pathways was built by integrating viral oncoproteins, dysregulated miRNAs and their predicted/validated targets. The results indicated that the deregulated miRNAs at the different stages of cervical cancer were functionally involved in several key cancer related pathways, such as cell cycle, p53 and Wnt signaling pathways. These dysregulated miRNAs could play an important role in cervical cancer development. Some of the stage-specific miRNAs can also be used as biomarkers for cancer classification and monitoring the progression of cancer development. PMID- 26032914 TI - Dynamic expression patterns of Pax6 during spermatogenesis in the mouse. AB - Spermatogenesis is a series of complex processes to generate mature sperm, and various molecules play crucial roles in regulating these processes. Previous studies imply a possibility that a transcriptional factor Pax6, a key player of brain and sensory organ development, could be involved in spermatogenesis, but neither expression nor function of Pax6 in the adult testis has been examined yet. In the present study, we described for the first time Pax6 expression dynamics in the adult mouse testis. Using cell-type-specific markers, the expression of Pax6 was detected in 67.0% of promyelocytic leukemia zinc finger (Plzf)-positive type A spermatogonia. The expression of Pax6 was also observed in p63-positive spermatocytes and round spermatids. We did not detect any expression of Pax6 in Sox9-positive Sertoli cells or in elongated spermatids and mature sperm. High-resolution analyses revealed that Pax6 formed a single dot-like structure during mid-phase of the pachytene spermatocyte. This dot-like structure co-localized with gammaH2A.X demarcating XY body, a domain in which X and Y chromosomes are silenced and compartmentalized. These results may suggest a novel role of Pax6 in spermatogenesis. PMID- 26032915 TI - A prion reduction filter does not completely remove endogenous prion infectivity from sheep blood. AB - BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a transmissible spongiform encephalopathy affecting humans, acquired initially through infection with bovine spongiform encephalopathy (BSE). A small number of vCJD cases have been acquired through the transfusion of blood from asymptomatic donors who subsequently developed vCJD. Filter devices that selectively bind the infectious agent associated with prion disease have been developed for removal of infection from blood. This study independently assessed one such filter, the P-CAPT filter, for efficacy in removing infectivity associated with the BSE agent in sheep blood. The sheep BSE model has previously been used to evaluate the distribution of infectivity in clinically relevant blood components. This is the first study to assess the ability of the P-CAPT filter to remove endogenous infectivity associated with blood components prepared from a large animal model. STUDY DESIGN AND METHODS: Paired units of leukoreduced red blood cells (LR-RBCs) were prepared from donors at the clinical stage of infection and confirmed as having BSE. One cohort of recipients was transfused with LR-RBCs alone, whereas a parallel cohort received LR and P-CAPT-filtered RBCs (LR-RBCs-P-CAPT). RESULTS: Of 14 recipients, two have been confirmed as having BSE. These sheep had received LR-RBCs and LR RBCs-P-CAPT from the same donor. CONCLUSIONS: The results indicate that, after leukoreduction and P-CAPT filtration, there can still be sufficient residual infectivity in sheep RBCs to transmit infection when transfused into a susceptible recipient. PMID- 26032916 TI - Patterns and predictors of medication discrepancies in primary care. AB - RATIONALE, AIMS AND OBJECTIVES: Identifying medication discrepancies across transitions of care is a common patient safety problem. Research examining relations between medication discrepancies and adherence, however, is limited. The objective of this investigation is to explore the relations between adherence and patient-provider medication discrepancies, and to test the hypothesis that non-adherence would be associated with medication discrepancies. METHODS: Three hundred twenty-eight outpatients completed a current medication list and measures of health literacy, adherence, perceived physical functioning and subjective well being. Patient lists were compared with active medications in the electronic medical record. Multivariate analyses identified demographic, clinical and patient-reported variables associated with discrepancies involving prescribed daily medications. RESULTS: Despite high rates of self-reported adherence, patients reported taking fewer medications than the number of active medications in their medical record (3.79 vs. 4.83, P < 0.001). We identified one or more discrepancies in most records (294/328 or 89.6%). Identified discrepancies were completely reconciled in only 21.1% of patients with discrepancies. Discrepancies were associated with lower health literacy, poorer physical health status and subjective well-being, and poorer adherence to the regimen patients believed they had been prescribed. Multivariate analysis indicated that the number of medical record-reported medications and subjective well-being independently predicted the presence of discrepancies. CONCLUSIONS: Findings suggest a complex relation between treatment adherence and medication discrepancies in which patient well being and regimen complexity work in tandem to create discordance between patient and provider medication plans. Simplifying regimens when possible and attending to patient life satisfaction may improve adherence to a regimen constructed jointly between patient and provider. PMID- 26032917 TI - Response of bacterial colonization in Nematostella vectensis to development, environment and biogeography. AB - The establishment of host-bacterial colonization during development is a fundamental process influencing the fitness of many organisms, but the factors controlling community membership and influencing the establishment of the microbial ecosystem during development are poorly understood. The starlet sea anemone Nematostella vectensis serves as a cnidarian model organism due to the availability of laboratory cultures and its high tolerance for broad ranges of salinity and temperature. Here, we show that the anemone's epithelia are colonized by diverse bacterial communities and that the composition of its microbiota is tightly coupled to host development. Environmental variations led to robust adjustments in the microbial composition while still maintaining the ontogenetic core signature. In addition, analysis of bacterial communities of Nematostella polyps from five different populations revealed a strong correlation between host biogeography and bacterial diversity despite years of laboratory culturing. These observed variations in fine-scale community composition following environmental change and for individuals from different geographic origins could represent the microbiome's contribution to host acclimation and potentially adaptation, respectively, and thereby contribute to the maintenance of homeostasis due to environmental changes. PMID- 26032918 TI - An isolated myeloid blast crisis presenting as optic nerve sarcoma in a patient with chronic myeloid leukaemia treated with imatinib. PMID- 26032919 TI - Predictive and prognostic biomarkers for neoadjuvant chemoradiotherapy in locally advanced rectal cancer. AB - Locally advanced rectal cancer is regularly treated with trimodality therapy consisting of neoadjuvant chemoradiation, surgery and adjuvant chemotherapy. There is a need for biomarkers to assess treatment response, and aid in stratification of patient risk to adapt and personalise components of the therapy. Currently, pathological stage and tumour regression grade are used to assess response. Experimental markers include proteins involved in cell proliferation, apoptosis, angiogenesis, the epithelial to mesenchymal transition and microsatellite instability. As yet, no single marker is sufficiently robust to have clinical utility. Microarrays that screen a tumour for multiple promising candidate markers, gene expression and microRNA profiling will likely have higher yield and it is expected that a combination or panel of markers would prove most useful. Moving forward, utilising serial samples of circulating tumour cells or circulating nucleic acids can potentially allow us to demonstrate tumour heterogeneity, document mutational changes and subsequently measure treatment response. PMID- 26032920 TI - Design of New Ligands for the Palladium-Catalyzed Arylation of alpha-Branched Secondary Amines. AB - In Pd-catalyzed C-N cross-coupling reactions, alpha-branched secondary amines are difficult coupling partners and the desired products are often produced in low yields. In order to provide a robust method for accessing N-aryl alpha-branched tertiary amines, new catalysts have been designed to suppress undesired side reactions often encountered when these amine nucleophiles are used. These advances enabled the arylation of a wide array of sterically encumbered amines, highlighting the importance of rational ligand design in facilitating challenging Pd-catalyzed cross-coupling reactions. PMID- 26032922 TI - Initial immunological changes as predictors for house dust mite immunotherapy response. AB - BACKGROUND: Although specific immunotherapy is the only aetiological treatment for allergic disorders, the underlying mechanisms are not fully understood. Specific immunotherapy induces changes in lymphocyte Th subsets from Th2 to Th1/Treg. Whether differences in immunological patterns underlie patient response to immunotherapy has not yet been established. OBJECTIVES: We studied the immunological changes occurring during a 1-year period of Dermatophagoides pteronyssinus (DP) immunotherapy and their relation with clinical outcome. METHODS: We included 34 patients with DP allergy who received subcutaneous specific immunotherapy (SCIT) for 1 year. Following treatment, patients were classified as responders or non-responders. Fourteen allergic subjects who did not receive SCIT were included as controls. Peripheral blood was obtained at 0, 1, 3, 6 and 12 months and cultured with nDer p 1. Phenotypic changes, cytokine production and basophil response were analysed by flow cytometry; transcription factors were measured by mRNA quantification. Serum immunoglobulin levels were also measured. RESULTS: After 1 year of SCIT, 82% of cases showed improved symptoms (responders). Although increases in sIgG4 were observed, BAT reactivity was not modified in these patients. Increases in T-BET/FOXP3 as well as nDer p 1 specific Th1/Treg frequencies were also observed, along with a decrease in Th2, Th9 and Th17. These changes corresponded to changes in cytokine levels. CONCLUSION: Patients who respond well to DP-SCIT show immunological differences compared to non-responders. In responders, basal differences include a lower frequency of Th1 and higher frequencies of Th2, Th9 and Th17 cells. After 1 year of treatment, an increased production of sIgG4 was observed in responders, along with a change in Th2 response towards Th1/Treg. PMID- 26032923 TI - Defect detection around rebars in concrete using focused ultrasound and reverse time migration. AB - Experimental and numerical investigations have been performed to assess the feasibility of damage detection around rebars in concrete using focused ultrasound and a Reverse Time Migration (RTM) based subsurface imaging algorithm. Since concrete is heterogeneous, an unfocused ultrasonic field will be randomly scattered by the aggregates, thereby masking information about damage(s). A focused ultrasonic field, on the other hand, increases the possibility of detection of an anomaly due to enhanced amplitude of the incident field in the focal region. Further, the RTM based reconstruction using scattered focused field data is capable of creating clear images of the inspected region of interest. Since scattering of a focused field by a damaged rebar differs qualitatively from that of an undamaged rebar, distinct images of damaged and undamaged situations are obtained in the RTM generated images. This is demonstrated with both numerical and experimental investigations. The total scattered field, acquired on the surface of the concrete medium, is used as input for the RTM algorithm to generate the subsurface image that helps to identify the damage. The proposed technique, therefore, has some advantage since knowledge about the undamaged scenario for the concrete medium is not necessary to assess its integrity. PMID- 26032921 TI - LGI Proteins and Epilepsy in Human and Animals. AB - Leucine-rich glioma-inactivated (LGI) protein was first thought to have a suppressor effect in the formation of some cancers. Developments in physiology and medicine made it possible to characterize the function of the LGI protein family and its crucial role in different conditions more precisely. These proteins play an important role in synaptic transmission, and dysfunction may cause hyperexcitability. Genetic mutation of LGI1 was confirmed to be the cause of autosomal dominant lateral temporal lobe epilepsy in humans. The LGI2 mutation was identified in benign familial juvenile epilepsy in Lagotto Romagnolo (LR) dogs. Cats with familial spontaneous temporal lobe epilepsy have been reported, and the etiology might be associated with LGI protein family dysfunction. In addition, an autoimmune reaction against LGI1 was detected in humans and cats with limbic encephalitis. These advances prompted a review of LGI protein function and its role in different seizure disorders. PMID- 26032924 TI - MRI characterization of temporal lobe epilepsy using rapidly measurable spatial indices with hemisphere asymmetries and gender features. AB - INTRODUCTION: The paucity of morphometric markers for hemispheric asymmetries and gender variations in hippocampi and amygdalae in temporal lobe epilepsy (TLE) calls for better characterization of TLE by finding more useful prognostic MRI parameter(s). METHODS: T1-weighted MRI (3 T) morphometry using multiple parameters of hippocampus-parahippocampus (angular and linear measures, volumetry) and amygdalae (volumetry) including their hemispheric asymmetry indices (AI) were evaluated in both genders. The cutoff values of parameters were statistically estimated from measurements of healthy subjects to characterize TLE (57 patients, 55% male) alterations. RESULTS: TLE had differential categories with hippocampal atrophy, parahippocampal angle (PHA) acuteness, and several other parametric changes. Bilateral TLE categories were much more prevalent compared to unilateral TLE categories. Female patients were considerably more disposed to bilateral TLE categories than male patients. Male patients displayed diverse categories of unilateral abnormalities. Few patients (both genders) had combined bilateral appearances of hippocampal atrophy, amygdala atrophy, PHA acuteness, and increase in hippocampal angle (HA) where medial distance ratio (MDR) varied among genders. TLE had gender-specific and hemispheric dominant alterations in AI of parameters. Maximum magnitude of parametric changes in TLE includes (a) AI increase in HA of both genders, (b) HA increase (bilateral) in female patients, and (c) increase in ratio of amygdale/hippocampal volume (unilateral, right hemispheric), and AI decrease in MDR, in male patients. CONCLUSION: Multiparametric MRI studies of hippocampus and amygdalae, including their hemispheric asymmetry, underscore better characterization of TLE. Rapidly measurable single-slice parameters (HA, PHA, MDR) can readily delineate TLE in a time-constrained clinical setting, which contrasts with customary three dimensional hippocampal volumetry that requires many slice computation. PMID- 26032926 TI - Two-dimensional silicon monolayers generated on c-BN(111) substrate. AB - Silicene, a buckled two-dimensional honeycomb structure of silicon, has been experimentally synthesized on very few substrates. Furthermore, synthesizing silicene with a Dirac point is another hot research area. However, only silicene grown on Ag(111) has been reported to have a Dirac point, which has lowered the expectations of researchers. Here, three Si monolayer structures, a Si chain-type structure, a two-dimensional hexagonal close packed compound structure, and a two dimensional hexagonal close packed structure, are generated on a c-BN(111) substrate using a particle-swarm optimization algorithm implemented in CALYPSO code. Band structure calculations show that all three structures exhibit a metallic nature. In particular, due to the absolutely flat conformation of the latter two structures, a linear dispersion exists near the Fermi energy level, indicating that charge carriers can transport like massless Dirac fermions. Our results open an alternative way of searching for other two-dimensional silicon monolayers with Dirac points. PMID- 26032925 TI - CT perfusion during delayed cerebral ischemia after subarachnoid hemorrhage: distinction between reversible ischemia and ischemia progressing to infarction. AB - INTRODUCTION: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) can be reversible or progress to cerebral infarction. In patients with a deterioration clinically diagnosed as DCI, we investigated whether CT perfusion (CTP) can distinguish between reversible ischemia and ischemia progressing to cerebral infarction. METHODS: From a prospectively collected series of aSAH patients, we included those with DCI, CTP on the day of clinical deterioration, and follow-up imaging. In qualitative CTP analyses (visual assessment), we calculated positive and negative predictive value (PPV and NPV) with 95% confidence intervals (95%CI) of a perfusion deficit for infarction on follow-up imaging. In quantitative analyses, we compared perfusion values of the least perfused brain tissue between patients with and without infarction by using receiver-operator characteristic curves and calculated a threshold value with PPV and NPV for the perfusion parameter with the highest area under the curve. RESULTS: In qualitative analyses of 33 included patients, 15 of 17 patients (88%) with and 6 of 16 patients (38%) without infarction on follow-up imaging had a perfusion deficit during clinical deterioration (p = 0.002). Presence of a perfusion deficit had a PPV of 71% (95%CI: 48-89%) and NPV of 83% (95%CI: 52-98%) for infarction on follow-up. Quantitative analyses showed that an absolute minimal cerebral blood flow (CBF) threshold of 17.7 mL/100 g/min had a PPV of 63% (95%CI: 41-81%) and a NPV of 78% (95%CI: 40-97%) for infarction. CONCLUSIONS: CTP may differ between patients with DCI who develop infarction and those who do not. For this purpose, qualitative evaluation may perform marginally better than quantitative evaluation. PMID- 26032927 TI - Will Team-Based Care Really be Implemented? PMID- 26032928 TI - Fluoroscopically guided large balloon dilatation for treating congenital esophageal stenosis in children. AB - PURPOSE: We aimed to evaluate the safety and clinical effectiveness of fluoroscopically guided large balloon dilatation for treating congenital esophageal stenosis in children. METHODS: Our study included seven children (mean age 4.0 years) who underwent a total of ten balloon dilatation sessions. The initial balloon diameters were 10-15 mm. The technical success, clinical success (improved food intake and reduced dysphagia within 1 month following the first balloon dilatation), dysphagia recurrence, and complications were retrospectively evaluated. RESULTS: Technical and clinical success rates were 100 %. During the mean 38-month follow-up period after the first balloon dilatation, 3 (43 %) patients underwent only one additional balloon dilatation 4-5 months after the first balloon dilatation for dysphagia recurrence. Two of them showed improvement without further recurrence, while the remaining one underwent partial esophagectomy. Well-contained transmural esophageal rupture (type 2) occurred in two (29 %, 2/7) patients and during two (20 %, 2/10) balloon dilatation sessions. All ruptures were successfully treated conservatively. CONCLUSIONS: Our study showed that fluoroscopically guided large balloon dilatation seems to be a simple and effective primary treatment technique for congenital esophageal stenosis in children. Esophageal ruptures were not uncommon although they were not fatal. PMID- 26032929 TI - Irreversible electroporation for nonthermal tumor ablation in patients with hepatocellular carcinoma: initial clinical experience in Japan. AB - PURPOSE: This clinical study was conducted to evaluate the safety and short-term outcomes of irreversible electroporation (IRE) for the treatment of patients with hepatocellular carcinoma (HCC) in Japan. MATERIALS AND METHODS: The study was designed in a prospective setting. Five patients (3 men and 2 women; mean age, 66.6 +/- 5.8 years) with 6 HCCs were enrolled and treated using percutaneous ultrasound (US)-guided IRE. Safety was assessed based on adverse events and laboratory values. Local control was assessed using contrast-enhanced US with a perflubutane microbubble contrast agent, contrast-enhanced multiphase CT, and gadoxetic acid-enhanced MRI (EOB-MRI) at designated points. RESULTS: The tumors ranged in diameter from 11 to 28 mm (mean diameter, 17.5 +/- 6.3 mm). Five of the 6 tumors (83 %) were successfully treated, with no local recurrence to date (mean follow-up 244 +/- 55 days). In 1 lesion located in liver segment 1, residual tumor was diagnosed at 7 days after intervention by follow-up EOB-MRI. No serious complications related to the IRE procedure were observed. CONCLUSION: The results of this study suggest that image-guided percutaneous IRE can achieve satisfactory local disease control, particularly for small HCCs, and is well tolerated by patients. PMID- 26032930 TI - Myopathy in older people receiving statin therapy: a systematic review and meta analysis. AB - OBJECTIVE: The aim of the present study was to determine the risk of myopathy in older people receiving statin therapy. METHODS: Eligible studies were identified searching Ovid Medline, EMBASE, Scopus, CINAHL, Cochrane and PSYCHINFO databases (1987 to July 2014). The selection criteria comprised randomized controlled studies that compared the effects of statin monotherapy and placebo on muscle adverse events in the older adult (65+ years). Data were extracted and assessed for validity by the authors. Odds ratios and 95% confidence intervals (CIs) were used to calculate binary outcomes. Evidence from included studies were pooled in a meta-analysis using Revman 5.3. RESULTS: The trials assessed in the systematic review showed little or no evidence of a difference in risks between treatment and placebo groups, with myalgia [odds ratio (OR) 1.03, 95% CI 0.90, 1.17; I(2) = 0%; P = 0.66] and combined muscle adverse events (OR 1.03, 95% CI 0.91, 1.18; I(2) = 0%; P = 0.61) (myopathy). No evidence was found for an increased risk of rhabdomyolysis (OR 2.93, 95% CI 0.30, 28.18; I(2) = 0%; P = 0.35) in the seven trials that reported this. No trials reported mortality due to a muscle-related event. Discontinuations due to an adverse effect were reduced in the treatment group compared with placebo (OR 0.74, 95% CI 0.50, 1.09; I(2) = 0%; P = 0.13). CONCLUSION: The results obtained from the present review suggest that statins are relatively safe, even in older people. There was no evidence to suggest an increased risk of myopathy in older adults receiving statin therapy. There is slightly increased seen with rhabdomyolysis when compared with the general population, although the event is relatively rare. Statins should be prescribed to elderly people who need it, and not withheld, as its myopathy safety profile is tolerable. PMID- 26032931 TI - Non-clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys. AB - Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post-mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen-specific antibody titers were determined by enzyme-linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME + AS15 and dHER2 + AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME + AS15 and all injections of dHER2 + AS15. No treatment-related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment-free period. Transient but significant differences in biochemistry parameters were observed post-injection: lower albumin/globulin ratios (p501 + AS15), and higher bilirubin, urea and creatinine (dHER2 + AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME + AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501 + AS15. These results suggest a favorable safety profile of the AS15-containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines. PMID- 26032932 TI - Estimated Human and Economic Burden of Four Major Adult Vaccine-Preventable Diseases in the United States, 2013. AB - Low uptake of routinely recommended adult immunizations is a public health concern. Using data from the peer-reviewed literature, government disease surveillance programs, and the US Census, we developed a customizable model to estimate human and economic burden caused by four major adult vaccine-preventable diseases (VPD) in 2013 in the United States, and for each US state individually. To estimate the number of cases for each adult VPD for a given population, we multiplied age-specific incidence rates obtained from the literature by age specific 2013 Census population data. We then multiplied the estimated number of cases for a given population by age-specific, estimated medical and indirect (non medical) costs per case. Adult VPDs examined were: (1) influenza, (2) pneumococcal disease (both invasive disease and pneumonia), (3) herpes zoster (shingles), and (4) pertussis (whooping cough). Sensitivity analyses simulated the impact of various epidemiological scenarios on the total estimated economic burden. Estimated US annual cost for the four adult VPDs was $26.5 billion (B) among adults aged 50 years and older, $15.3B (58 %) of which was attributable to those 65 and older. Among adults 50 and older, influenza, pneumococcal disease, herpes zoster, and pertussis made up $16.0B (60 %), $5.1B (19 %), $5.0B (19 %), and $0.4B (2 %) of the cost, respectively. Among those 65 and older, they made up $8.3B (54 %), $3.8B (25 %), $3.0B (20 %), and 0.2B (1 %) of the cost, respectively. Most (80-85 %) pneumococcal costs stemmed from nonbacteremic pneumococcal pneumonia (NPP). Cost attributable to adult VPD in the United States is substantial. Broadening adult immunization efforts beyond influenza only may help reduce the economic burden of adult VPD, and a pneumococcal vaccination effort, primarily focused on reducing NPP, may constitute a logical starting place. Sensitivity analyses revealed that a pandemic influenza season or change in size of the US elderly population could increase these costs dramatically. PMID- 26032933 TI - The development of online doctor reviews in China: an analysis of the largest online doctor review website in China. AB - BACKGROUND: Since the time of Web 2.0, more and more consumers have used online doctor reviews to rate their doctors or to look for a doctor. This phenomenon has received health care researchers' attention worldwide, and many studies have been conducted on online doctor reviews in the United States and Europe. But no study has yet been done in China. Also, in China, without a mature primary care physician recommendation system, more and more Chinese consumers seek online doctor reviews to look for a good doctor for their health care concerns. OBJECTIVE: This study sought to examine the online doctor review practice in China, including addressing the following questions: (1) How many doctors and specialty areas are available for online review? (2) How many online reviews are there on those doctors? (3) What specialty area doctors are more likely to be reviewed or receive more reviews? (4) Are those reviews positive or negative? METHODS: This study explores an empirical dataset from Good Doctor website, haodf.com-the earliest and largest online doctor review and online health care community website in China-from 2006 to 2014, to examine the stated research questions by using descriptive statistics, binary logistic regression, and multivariate linear regression. RESULTS: The dataset from the Good Doctor website contained 314,624 doctors across China and among them, 112,873 doctors received 731,543 quantitative reviews and 772,979 qualitative reviews as of April 11, 2014. On average, 37% of the doctors had been reviewed on the Good Doctor website. Gynecology-obstetrics-pediatrics doctors were most likely to be reviewed, with an odds ratio (OR) of 1.497 (95% CI 1.461-1.535), and internal medicine doctors were less likely to be reviewed, with an OR of 0.94 (95% CI 0.921-0.960), relative to the combined small specialty areas. Both traditional Chinese medicine doctors and surgeons were more likely to be reviewed than the combined small specialty areas, with an OR of 1.483 (95% CI 1.442-1.525) and an OR of 1.366 (95% CI 1.337-1.395), respectively. Quantitatively, traditional Chinese medicine doctors (P<.001) and gynecology-obstetrics-pediatrics doctors (P<.001) received more reviews than the combined small specialty areas. But internal medicine doctors received fewer reviews than the combined small specialty areas (P<.001). Also, the majority of quantitative reviews were positive-about 88% were positive for the doctors' treatment effect measure and 91% were positive for the bedside manner measure. This was the case for the four major specialty areas, which had the most number of doctors-internal medicine, gynecology-obstetrics-pediatrics, surgery, and traditional Chinese medicine. CONCLUSIONS: Like consumers in the United States and Europe, Chinese consumers have started to use online doctor reviews. Similar to previous research on other countries' online doctor reviews, the online reviews in China covered almost every medical specialty, and most of the reviews were positive even though all of the reviewing procedures and the final available information were anonymous. The average number of reviews per rated doctor received in this dataset was 6, which was higher than that for doctors in the United States or Germany, probably because this dataset covered a longer time period than did the US or German dataset. But this number is still very small compared to any doctor's real patient population, and it cannot represent the reality of that population. Also, since all the data used for analysis were from one single website, the data might be biased and might not be a representative national sample of China. PMID- 26032934 TI - The effect of physically applied alpha hydroxyl acids on the skin pore and comedone. AB - OBJECTIVE: Alpha hydroxy acids (AHA) have been recognized as commonly used therapy for acne. Our studies examined whether an additional effect of physical treatment using chemical peeling combined with negative pressure and compared with AHA treatment only occurs in acne-prone subjects. METHODS: The chemical peeling agent used 4% of an AHA solution (mixture of 1000 mL of carbonated water, 20 mL of glycolic acid and 20 mL of lactic acid). All subjects' faces were randomly divided into test and control groups. The test group was treated with chemical peeling combined with a physical effect, and the control group applied chemical peeling alone. For the 23 healthy females (average age: 30.17 +/- 5.06 year), we measured sebum output level by light transmission, pore area and number by optical image analyser, and comedone counting before treatment and at 1, 2 and 4 weeks after a single treatment. RESULTS: Compared to the before treatment, whiteheads and blackheads were significantly decreased at 1, 2 and 4 weeks in the test group (P < 0.05), but for the control group, whiteheads and blackheads showed a tendency to decrease at 1, 2 and 4 weeks. Also at 1 week, whiteheads and blackheads of the test group significantly decreased compared to the control group (P < 0.05). Pore area and number significantly decreased at 1 week (P < 0.05), and the sebum output level was significantly decreased at 4 weeks (P < 0.05) only in the test group, which did not show any significant group difference for individual parameters. CONCLUSION: 4% AHA solution combined with a physical effect had rapidly improving effects on whiteheads and blackheads synergistically. Combined physical therapy may have more impact on pore size and seborrhoea. PMID- 26032935 TI - Shared Decision-Making: Evaluating the Evidence for Access to MR-Conditional Devices to Allow Patients and Providers to Make Informed and Collaborative Choices in the 21st Century. PMID- 26032936 TI - The ongoing debate of the utility of magnetic resonance imaging conditional neuromodulation devices. PMID- 26032937 TI - The utility of the clock drawing test in detection of delirium in elderly hospitalised patients. AB - OBJECTIVES: Delirium is common neuropsychiatric condition among elderly inpatients. The clock drawing test (CDT) has been used widely as bedside screening tool in assessing cognitive impairment in elderly people. Previous studies which evaluate its usefulness in delirium reported conflicting results. The objective of this study was to evaluate the utility of CDT to detect delirium in elderly medical patients. METHOD: Prospective, observational, longitudinal study. All acute medical admissions 70 years of age and above were approached within 72 hours of admission for recruitment. Patients eligible for inclusion were assessed four times, twice weekly during admission. Assessment included Confusion Assessment Method (CAM), Delirium Rating Scale (DRS-98R), Montreal Cognitive Assessment (MoCA), Acute Physiology and Chronic Health Evaluation II (APACHE) II, and CDT. Data was analysed using a linear mixed effect model. RESULTS: Three hundred and twenty-three assessments with the CDT were performed on 200 subjects (50% male, mean age 81.13; standard deviation: 6.45). The overall rate of delirium (CAM+) during hospitalisation was 23%. There was a significant negative correlation between the CDT and DRS-R98 scores (Pearson correlation r = 0.618, p < 0.001), CDT and CAM (Spearman's rho = -0.402, p < 0.001) and CDT and total MoCA score (Pearson's r = 0.767, p < 0.001). However, when the data were analysed longitudinally controlling for all the factors, we found that cognitive function and age were significant factors associated with CDT scores (p < .0001): neither the presence nor the severity of delirium had an additional significant effect on the CDT. CONCLUSION: CDT score reflects cognitive impairment, independently of the presence or severity of delirium. The CDT is not a suitable test for delirium in hospitalised elderly patients. PMID- 26032939 TI - Posterior predictive checks of coalescent models: P2C2M, an R package. AB - Bayesian inference operates under the assumption that the empirical data are a good statistical fit to the analytical model, but this assumption can be challenging to evaluate. Here, we introduce a novel r package that utilizes posterior predictive simulation to evaluate the fit of the multispecies coalescent model used to estimate species trees. We conduct a simulation study to evaluate the consistency of different summary statistics in comparing posterior and posterior predictive distributions, the use of simulation replication in reducing error rates and the utility of parallel process invocation towards improving computation times. We also test P2C2M on two empirical data sets in which hybridization and gene flow are suspected of contributing to shared polymorphism, which is in violation with the coalescent model: Tamias chipmunks and Myotis bats. Our results indicate that (i) probability-based summary statistics display the lowest error rates, (ii) the implementation of simulation replication decreases the rate of type II errors, and (iii) our r package displays improved statistical power compared to previous implementations of this approach. When probabilistic summary statistics are used, P2C2M corroborates the assumption that genealogies collected from Tamias and Myotis are not a good fit to the multispecies coalescent model. Taken as a whole, our findings argue that an assessment of the fit of the multispecies coalescent model should accompany any phylogenetic analysis that estimates a species tree. PMID- 26032938 TI - Variability in utilization of drug eluting stents in United States: Insights from nationwide inpatient sample. AB - OBJECTIVES: We studied the trends and predictors of drug eluting stent (DES) utilization from 2006 to 2011 to further expound the inter-hospital variability in their utilization. BACKGROUND: We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) between 2006 and 2011 using ICD-9-CM procedure code, 36.06 (bare metal stent) or 36.07 (drug eluting stents) for Percutaneous Coronary Intervention (PCI). Annual hospital volume was calculated using unique identification numbers and divided into quartiles for analysis. METHODS AND RESULTS: We built a hierarchical two level model adjusted for multiple confounding factors, with hospital ID incorporated as random effects in the model. About 665,804 procedures (weighted n = 3,277,884) were analyzed. Safety concerns arising in 2006 reduced utilization DES from 90% of all PCIs performed in 2006 to a nadir of 69% in 2008 followed by increase (76% of all stents in 2009) and plateau (75% in 2011). Significant between-hospital variation was noted in DES utilization irrespective of patient or hospital characteristics. Independent patient level predictors of DES were (OR, 95% CI, P-value) age (0.99, 0.98-0.99, <0.001), female(1.12, 1.09-1.15, <0.001), acute myocardial infarction(0.75, 0.71-0.79, <0.001), shock (0.53, 0.49-0.58, <0.001), Charlson Co morbidity index (0.81,0.77-0.86, <0.001), private insurance/HMO (1.27, 1.20-1.34, <0.001), and elective admission (1.16, 1.05-1.29, <0.001). Highest quartile hospital (1.64, 1.25-2.16, <0.001) volume was associated with higher DES placement. CONCLUSION: There is significant between-hospital variation in DES utilization and a higher annual hospital volume is associated with higher utilization rate of DES. (c) 2015 Wiley Periodicals, Inc. PMID- 26032940 TI - 'Let's talk about sex' - A Knowledge, Attitudes and Practice study among Paediatric Nurses about Teen Sexual Health in Hong Kong. AB - AIMS AND OBJECTIVES: To explore the knowledge, attitudes and practices of paediatric nurses in Hong Kong towards adolescent sexual health issues. BACKGROUND: In Hong Kong, teens are becoming more sexually permissive. As a result, early sexual activity, Sexually transmitted diseases (STD) and unplanned pregnancies among adolescents are increasing. Paediatric nurses are potentially excellent sexual health educators; however, studies in other countries have reported that nurses have inadequate knowledge and skills about sexual health. Little is known about the knowledge, attitudes and practices of nurses in Hong Kong related to teen sexual health. DESIGN: This is a cross-sectional survey study. The survey was developed after an extensive literature review and partially adapted from previously validated questionnaires on nursing needs, knowledge, attitude and practice. METHODS: An anonymous self-administered questionnaire in Chinese was distributed to 500 nurses in Hong Kong attending a local paediatric conference. Participants (n = 394) were recruited using convenience sampling methods. Survey data were analysed using descriptive statistics, correlation tests and logistic regression analyses. RESULTS: The majority of nurses had a high awareness of the importance of sexual healthcare, but rarely felt knowledgeable or comfortable discussing sexual health issues with adolescents. Higher comfort level was associated with higher frequency of practice with an average adjusted odds ratios of 2.64. Inadequate or lack of training (39.4%) was the most significant barrier in providing adolescent sexual health screening and counselling. CONCLUSION: Nurses' clinical practices towards adolescent's sexual health issues were influenced by their perceived comfort level followed by their self-ranked knowledge and training experience. Further specific training on communication, counselling and general sexual health should be provided to nurses in Hong Kong. RELEVANCE TO CLINICAL PRACTICE: Nurses' comfort level was the most important factor influencing their clinical practice with teens. Further specific training should be provided to nurses in Hong Kong to improve adolescent sexual health. PMID- 26032941 TI - Implementing supported self-management for asthma: a systematic review and suggested hierarchy of evidence of implementation studies. AB - BACKGROUND: Asthma self-management remains poorly implemented in clinical practice despite overwhelming evidence of improved healthcare outcomes, reflected in guideline recommendations over three decades. To inform delivery in routine care, we synthesised evidence from implementation studies of self-management support interventions. METHODS: We systematically searched eight electronic databases (1980 to 2012) and research registers, and performed snowball and manual searches for studies evaluating implementation of asthma self-management in routine practice. We included, and adapted systematic review methodology to reflect, a broad range of implementation study designs. We extracted data on study characteristics, process measures (for example, action plan ownership), asthma control (for example, patient reported control questionnaires, days off school/work, symptom-free days) and use of health services (for example, admissions, emergency department attendances, unscheduled consultations). We assessed quality using the validated Downs and Black checklist, and conducted a narrative synthesis informed by Kennedy's whole systems theoretical approach (considering patient, practitioner and organisational components and the interaction between these). RESULTS: We included 18 studies (6 randomised trials, 2 quasi-experimental studies, 8 with historical controls and 3 with retrospective comparators) from primary, secondary, community and managed care settings serving a total estimated asthma population of 800,000 people in six countries. In these studies, targeting professionals (n = 2) improved process, but had no clinically significant effect on clinical outcomes. Targeting patients (n = 6) improved some process measures, but had an inconsistent impact on clinical outcomes. Targeting the organisation (n = 3) improved process measures, but had little/no effect on clinical outcomes. Interventions that explicitly addressed patient, professional and organisational factors (n = 7) showed the most consistent improvement in both process and clinical outcomes. Authors highlighted the importance of health system commitment, skills training for professionals, patient education programmes supported by regular reviews, and on-going evaluation of implementation effectiveness. CONCLUSIONS: Our methodology offers an exemplar of reviews synthesising the heterogeneous implementation literature. Effective interventions combined active engagement of patients, with training and motivation of professionals embedded within an organisation in which self management is valued. Healthcare managers should consider how they can promote a culture of actively supporting self-management as a normal, expected, monitored and remunerated aspect of the provision of care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (registration number: CRD42012002898 ) Accessed 24 May 2015. PMID- 26032942 TI - Maternal Alcohol Consumption before and during Pregnancy and the Risks of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Epidemiologic studies have reported conflicting results regarding maternal alcohol consumption before and during pregnancy, and the risk of congenital heart defects (CHDs). However, a systematic review and meta-analysis of the association between maternal alcohol consumption and CHDs in offspring has not been conducted. DESIGN: We searched MEDLINE and EMBASE for articles catalogued between their inception and February 16, 2015; we identified relevant published studies that assessed the association between maternal alcohol consumption and CHD risk. Two authors independently assessed the eligibility of the retrieved articles and extracted data from them. Study-specific relative risk estimates were pooled by random-effects or fixed-effects models. RESULTS: From the 1527 references, a total of 19 case-control studies and four cohort studies were enrolled in this meta-analysis. The summary of 23 studies related to CHDs indicated an overall pooled relative risk of 1.13 (95% confidence interval: 0.96, 1.29) among mothers drinking before or during pregnancy. Statistically significant heterogeneity was detected (Q = 196.61, P < .001, I(2) = 88.8%) with no publication bias (Egger's test: P = .157). We conducted stratified and meta regression analyses to identify the origin of the heterogeneity among studies. CONCLUSION: In summary, this meta-analysis provided no positive association between maternal alcohol consumption and risk of CHDs. PMID- 26032943 TI - Fungi predatory activity on embryonated Toxocara canis eggs inoculated in domestic chickens (Gallus gallus domesticus) and destruction of second stage larvae. AB - The objective of this study was to evaluate the infectivity of Toxocara canis eggs after interacting with isolated nematophagous fungi of the species Duddingtonia flagrans (AC001) and Pochonia chlamydosporia (VC4), and test the predatory activity of the isolated AC001 on T. canis second stage larvae after 7 days of interaction. In assay A, 5000 embryonated T. canis eggs previously in contact with the AC001 and VC4 isolated for 10 days were inoculated into domestic chickens (Gallus gallus domesticus), and then these animals were necropsied to collect material (digested liver, intestine, muscles and lungs) at 3-, 7-, 14-, and 21-day intervals after inoculation. In assay A, the results demonstrated that the prior interaction of the eggs with isolated AC001 and VC4 decreases the amount of larvae found in the collected organs. Difference (p < 0.01) was observed in the medium larvae counts recovered from liver, lung, intestine, and muscle of animals in the treated groups when compared to the animals in the control group. At the end of assay A, a percentage reduction of 87.1 % (AC001) and 84.5 % (VC4) respectively was recorded. In the result of assay B, the isolated AC001 showed differences (p < 0.01) compared to the control group, with a reduction of 53.4 % in the recovery of L2. Through these results, it is justified to mention that prior interaction of embryonated T. canis eggs with the tested fungal isolates were efficient in reducing the development and migration of this parasite, in addition to the first report of proven predatory activity on L2. PMID- 26032944 TI - Identification criteria of the rare multi-flagellate Lophomonas blattarum: comparison of different staining techniques. AB - Bronchopulmonary lophomoniasis (BPL) is an emerging disease of potential importance. BPL is presented by non-specific clinical picture and is usually accompanied by immunosuppression. Culture of Lophomonas blattarum is difficult and its molecular diagnosis has not yet been developed. Therefore, microscopic examination of respiratory samples, e.g., bronchoalveolar lavage (BAL) or sputum, is the mainstay of BPL diagnosis. Creola bodies and ciliocytophthoria are two forms of bronchial cells which occur in chest diseases with non-specific clinical picture like that of BPL. Both forms could be misrecognized as multi-flagellates because of their motile cilia in the wet mounts and due to shape variability of L. blattarum in stained smears. The aim of the study is to compare different staining techniques for visualizing L. blattarum to improve the recognition and diagnosis of BPL, to distinguish respiratory epithelial cells from L. blattarum and to decide which stain is recommended in suspected cases of BPL. BAL samples from patients which contain L. blattarum, creola bodies, and ciliocytophthoria were collected then wet mounts were examined. The BAL samples were also stained by Papanicolaou (PAP), Giemsa, hematoxylin and eosin (H & E), trichrome, Gram, and Diff-Quik (DQ) stains. The different staining techniques were compared regarding the stain quality. In wet mounts, the ciliary movement was coordinate and synchronous while the flagellar movement was wavy and leaded to active swimming of L. blattarum. In stained slides, bronchial cells were characterized by the presence of basal nucleus and the terminal bar from which the cilia arise. Trichrome was the best stain in demonstration of cellular details of L. blattarum. H & E, PAP, and Giemsa stains showed good quality of stains. Gram and DQ stains showed only pale hues of L. blattarum. We recommended adding Wheatley's trichrome staining to the differential diagnosis workup of cases of non-specific chest infections, especially when BPL is suspected, to avoid overdiagnosis or underdiagnosis of it. PMID- 26032945 TI - The secret life of extracellular vesicles in metal homeostasis and neurodegeneration. AB - Biologically active metals such as copper, zinc and iron are fundamental for sustaining life in different organisms with the regulation of cellular metal homeostasis tightly controlled through proteins that coordinate metal uptake, efflux and detoxification. Many of the proteins involved in either uptake or efflux of metals are localised and function on the plasma membrane, traffic between intracellular compartments depending upon the cellular metal environment and can undergo recycling via the endosomal pathway. The biogenesis of exosomes also occurs within the endosomal system, with several major neurodegenerative disease proteins shown to be released in association with these vesicles, including the amyloid-beta (Abeta) peptide in Alzheimer's disease and the infectious prion protein involved in Prion diseases. Abeta peptide and the prion protein also bind biologically active metals and are postulated to play important roles in metal homeostasis. In this review, we will discuss the role of extracellular vesicles in Alzheimer's and Prion diseases and explore their potential contribution to metal homeostasis. PMID- 26032946 TI - The ISoP CommSIG for Improving Medicinal Product Risk Communication: A New Special Interest Group of the International Society of Pharmacovigilance. PMID- 26032947 TI - Alginate and DNA Gels Are Suitable Delivery Systems for Diabetic Wound Healing. AB - Diabetic foot ulcers (DFU) represent a severe health problem and an unmet clinical challenge. In this study, we tested the efficacy of novel biomaterials in improving wound healing in mouse models of diabetes mellitus (DM). The biomaterials are composed of alginate- and deoxyribonucleic acid (DNA)-based gels that allow incorporation of effector cells, such as outgrowth endothelial cells (OEC), and provide sustained release of bioactive factors, such as neuropeptides and growth factors, which have been previously validated in experimental models of DM wound healing or hind limb ischemia. We tested these biomaterials in mice and demonstrate that they are biocompatible and can be injected into the wound margins without major adverse effects. In addition, we show that the combination of OEC and the neuropeptide Substance P has a better healing outcome than the delivery of OEC alone, while subtherapeutic doses of vascular endothelial growth factor (VEGF) are required for the transplanted cells to exert their beneficial effects in wound healing. In summary, alginate and DNA scaffolds could serve as potential delivery systems for the next-generation DFU therapies. PMID- 26032948 TI - Higher Levels of Serum Triglycerides were Associated with Postoperative Deep Vein Thrombosis After Total Hip Arthroplasty in Patients with Nontraumatic Osteonecrosis of the Femoral Head. AB - This retrospective study aimed to evaluate the association of serum lipids and deep vein thrombosis (DVT) risk following total hip arthroplasty (THA) in patients with nontraumatic osteonecrosis of the femoral head (ONFH). A total of 224 nontraumatic ONFH patients were enrolled. Serum levels of triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were detected preoperatively. All the patients underwent unilateral lower extremity venography on postoperative days 3 to 5 for DVT screening. In females, patients who were venogram positive for DVT had a higher serum TG level than those who were venogram negative for DVT (P = .029) and a higher TG level was associated with an increased DVT risk (P = .042). Serum TG levels considerably affect DVT risk after THA in female nontraumatic ONFH patients. PMID- 26032950 TI - Calculating the probability of random sampling for continuous variables in submitted or published randomised controlled trials. AB - In a previous paper, one of the authors (JBC) used a chi-squared method to analyse the means (SD) of baseline variables, such as height or weight, from randomised controlled trials by Fujii et al., concluding that the probabilities that the reported distributions arose by chance were infinitesimally small. Subsequent testing of that chi-squared method, using simulation, suggested that the method was incorrect. This paper corrects the chi-squared method and tests its performance and the performance of Monte Carlo simulations and ANOVA to analyse the probability of random sampling. The corrected chi-squared method and ANOVA method became inaccurate when applied to means that were reported imprecisely. Monte Carlo simulations confirmed that baseline data from 158 randomised controlled trials by Fujii et al. were different to those from 329 trials published by other authors and that the distribution of Fujii et al.'s data were different to the expected distribution, both p < 10(-16) . The number of Fujii randomised controlled trials with unlikely distributions was less with Monte Carlo simulation than with the 2012 chi-squared method: 102 vs 117 trials with p < 0.05; 60 vs 86 for p < 0.01; 30 vs 56 for p < 0.001; and 12 vs 24 for p < 0.00001, respectively. The Monte Carlo analysis nevertheless confirmed the original conclusion that the distribution of the data presented by Fujii et al. was extremely unlikely to have arisen from observed data. The Monte Carlo analysis may be an appropriate screening tool to check for non-random (i.e. unreliable) data in randomised controlled trials submitted to journals. PMID- 26032949 TI - Reasons for disagreement regarding illnesses between older patients with multimorbidity and their GPs - a qualitative study. AB - BACKGROUND: Chronic conditions are the most common themes in doctor-patient communication, especially for older patients with multimorbidity and their GPs. Former quantitative studies identified a variety of socio-demographic and health related factors which were associated with the (dis-)agreement between medical records and patient self-reported diseases. The aim of this qualitative study was to identify reasons for disagreement regarding illnesses between patients and their GPs. METHODS: We conducted three focus groups with GPs (n = 15) and three focus groups with multimorbid patients aged 65 to 85 (n = 21). The participants were recruited from the MultiCare Cohort Study. Focus groups were audiotaped and transcribed verbatim. The transcripts of the focus groups were analysed using the qualitative content analysis according to Mayring. Categories were determined deductively and inductively. RESULTS: The analysis revealed seven themes concerning reasons for disagreement regarding illnesses between patients and their GPs: problems with communication and cooperation between health care professionals, disease management by the GP and the patient, the documentation behaviour of the GP, communication challenges between GP and patient, differences in the understanding of a disease between GP and patient, the prioritization and rating of diseases by GP and patient and obliviousness, repression and avoidance by the patient. CONCLUSIONS: For older patients with multimorbidity, our study demonstrated that there is a need to enhance the cooperation between GPs, specialists and outpatient care, a demand to improve doctor-patient communication and a need for interventions to increase patients' knowledge of diseases. PMID- 26032951 TI - Activity-Based Protein Profiling of Rhomboid Proteases in Liposomes. AB - Although activity-based protein profiling (ABPP) has been used to study a variety of enzyme classes, its application to intramembrane proteases is still in its infancy. Intramembrane proteolysis is an important biochemical mechanism for activating proteins residing within the membrane in a dormant state. Rhomboid proteases (intramembrane serine proteases) are embedded in the lipid bilayers of membranes and occur in all phylogenetic domains. The study of purified rhomboid proteases has mainly been performed in detergent micelle environments. Here we report on the reconstitution of rhomboids in liposomes. Using ABPP, we have been able to detect active rhomboids in large and giant unilamellar vesicles. We have found that the inhibitor profiles of rhomboids in micelles and liposomes are similar, thus validating previous inhibitor screenings. Moreover, fluorescence microscopy experiments on the liposomes constitute the first steps towards activity-based imaging of rhomboid proteases in membrane environments. PMID- 26032952 TI - A dose-finding, cross-over study to evaluate the effect of a Nestorone(r)/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women. AB - OBJECTIVE: This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90 95% of cycles. METHODS: This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4.5 mg NES/1.5 mg E2). Participants applied gel daily to a fixed area on the abdomen for 21 consecutive days. They were interviewed regarding their experiences using the gel. RESULTS: Eighteen participants were randomized; 16 completed the study. Median NES C(max) values for low, medium and high dose groups at day 21 were 318.6 pmol/L, 783.0 pmol/L and 1063.8 pmol/L, respectively. Median maximum follicular diameter was higher with the lowest dose with 16.2 mm versus 10.0 and 10.4 mm with the medium and high doses, respectively. Among adherent participants, ovulation was inhibited in all dose groups, except for one participant in the medium dose (6.7%) that had luteal activity and an ultrasound image suggestive of a luteinized unruptured follicle. There were few reports of unscheduled bleeding, with more episodes reported for the lower dose. Adverse events were mild, and no skin irritation was reported from gel application. CONCLUSION: While all three doses blocked ovulation effectively and were evaluated as safe and acceptable, the medium dose was considered the lowest effective dose based on a more adequate suppression of follicular development. Further development of this novel contraceptive delivering NES and E2 is warranted and has potential for improved safety compared to ethinyl-estradiol based methods. PMID- 26032953 TI - Novel fluorescence in situ hybridization-based definition of bacille Calmette Guerin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies. AB - OBJECTIVES: To present a molecular definition of bacille Calmette-Guerin (BCG) failure that incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident, which can be used to enhance trial designs for patients with non-muscle-invasive bladder cancer. PATIENTS AND METHODS: We used data from 143 patients who were followed prospectively for 2 years during intravesical BCG therapy, during which time FISH assays were collected and correlated to clinical outcomes. RESULTS: Of the 95 patients with no evidence of tumour at 3-month cystoscopy, 23 developed tumour recurrence and 17 developed disease progression by 2 years. Patients with a positive FISH test at both 6 weeks and 3 months were more likely to develop tumour recurrence (17/37 patients [46%] and 16/28 patients [57%], respectively) than patients with a negative FISH test (6/58 patients [10%] and 3/39 patients [8%], respectively; both P < 0.001). Using hazard ratios for recurrence with positive 6-week and 3-month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3-month cystoscopy and positive FISH result could be considered to have 'molecular BCG failure' and could be enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy. CONCLUSIONS: Patients with positive early FISH and negative 3-month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression. This definition is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm. PMID- 26032954 TI - The PAUL Suit((c)) : an experience of ageing. AB - BACKGROUND: An ageing population worldwide makes it increasingly important that health students understand issues that elderly people face and can provide empathic care to them. CONTEXT: This teaching department in an isolated rural setting developed an interprofessional learning session to assist health students to understand issues of functional loss and social isolation that can affect elderly people. INNOVATION: The Premature Ageing Unisex Leisure (PAUL) Suit((c)) was developed as part of a 1-day learning session for undergraduate health students - including students of medicine, nursing and allied health - attending clinical placement in far-west New South Wales. The suit was developed locally and can be adjusted to simulate a wide range of functional losses in the wearer. Students undertake a range of daily tasks in the community while wearing the suit in the company of a student 'carer'. Over the past 4 years, approximately 140 students have participated in the simulation. Post-simulation evaluations report that students gain a greater understanding of some functional issues associated with ageing, and of the social isolation that can be associated with these. The experiential nature of the activity leads to some powerful insights. This activity is an innovative, experiential tool to deepen students understanding of issues related to ageing IMPLICATIONS: This activity is an innovative, experiential tool to deepen students understanding of issues relating to ageing. The interprofessional nature of the activity is an important factor in the success of the day, and produces a wide range of shared insights. The activity also enhances the partnerships between the university, the health service and the local community. Our experience supports the value of simulation in providing a deep learning opportunity in the area of ageing and disability. PMID- 26032955 TI - Quantification of Trapezius Muscle Innervation During Neck Dissections: Cervical Plexus Versus the Spinal Accessory Nerve. AB - OBJECTIVES: Despite increasing use of selective, nerve-sparing surgical techniques during neck dissections, the reported rate of postoperative paralysis of the trapezius muscle is still high. The aim of the study is to measure and compare motor inflow to the trapezius muscle, in order to better understand the peripheral neuroanatomy. METHODS: Intraoperative nerve monitoring (electroneurography) in patients undergoing routine neck dissection (n=18). The innervation of the 3 functional parts of the trapezius muscle was mapped and quantified through compound muscle action potentials. RESULTS: In 18/18 (100%) of the patients, the spinal accessory nerve (SAN) innervated all parts of the trapezius muscle. In 7/18 (39%) of the patients, an active motor branch from the cervical plexus was detected, equally distributed to all functional parts of the trapezius muscle, at levels comparable to the SAN. CONCLUSIONS: Compared to the SAN, branches from cervical plexus provide a significant amount of neural input to all parts of the trapezius muscle. Intraoperative nerve monitoring can be used in routine neck dissections to detect these branches, which may be important following surgical injury to the SAN. PMID- 26032956 TI - Enigmas of IDH mutations in hematology/oncology. AB - The discovery of oncogenic mutations in isocitrate dehydrogenase (IDH) enzymes has highlighted the delicate interplay of metabolism, cellular signaling, and transcriptional regulation that was off-focus for some time in the genomic era. Although IDH inhibitors are being evaluated for clinical efficacy, an in-depth understanding of disease pathogenesis linked to IDH mutations is required to develop rational combination treatments and to be evaluated in the clinic. To gain such an understanding, several questions need to be addressed: Why do IDH mutations occur selectively in subsets of a disease entity although they are found to be present in a very heterogeneous set of unrelated tumors? Why are 2 hydroxyglutarate-producing tumors specifically selected for the R-enantiomer and not for the S-enantiomer? Are the changes in 2-hydroxyglutarate-induced DNA methylation primary or secondary alterations in tumorigenesis? What are the roles of hypoxia-inducible factor (HIF) and its prolyl 4-hydroxylases in IDH-mutant tumors? Here, we address these questions and discuss the consequences for basic and clinical research related to IDH-mutant tumors. PMID- 26032957 TI - Chronic electroacupuncture of the ST36 point improves baroreflex function and haemodynamic parameters in heart failure rats. AB - Electroacupuncture (EA) has been used to treat many diseases, including heart failure (HF). This study aimed to evaluate the effects of chronic stimulation in the ST36 acupuncture point on haemodynamic parameters and baroreflex function in rats with HF. Cardiovascular parameters assessed were heart rate (HR), blood pressure (BP), and the reflex cardiovascular response of HR triggered by stimulation of baroreceptors in animals with HF subsequent to acute myocardial infarction (AMI). Male Wistar rats were divided into three groups: Sham Control - animals without HF and without EA; HF Control group - animals with HF and without EA; and HF EA group - animals with HF that received the EA protocol. Six weeks after surgical induction of AMI, the EA protocol (8 weeks, 5 times a week) was performed. The protocol was applied with EA at the ST36 point, frequency of 2 Hz, pulse of 0.3 ms and intensity of 1-3 mA for 30 min. Haemodynamic parameters and baroreceptor function were assessed. There was no difference between groups in the variables HR, systolic blood pressure (SBP) and diastolic blood pressure (DBP), which were evaluated with awake animals (p>0.05). There was an increase in the mean arterial pressure (MAP) in the HF EA group compared to the HF Control group (p<0.05). The maximum gain of the baroreflex heart rate response (Gain) was higher in the HF EA group than the HF Control and Sham Control groups. Chronic EA in the ST36 point increased the MAP and baroreflex sensitivity in rats with HF. PMID- 26032958 TI - Activation of the Mitochondrial Fragmentation Protein DRP1 Correlates with BRAF(V600E) Melanoma. PMID- 26032959 TI - Formation of Hexagonally Packed Hollow Hoops and Morphology Transition in RAFT Ethanol Dispersion Polymerization. AB - Similar to the traditional self-assembly strategy, polymerization induced self assembly and reorganization (PISR) can produce a myriad of polymeric morphologies through morphology transitions. Besides the chain length ratio (R) of the hydrophobic to the hydrophilic blocks, the chain mobility in the intermediate nano-objects, which is a requisite for morphology transition, is a determining factor in the formation of the final morphology. Although various morphologies have been fabricated, hexagonally packed hollow hoops (HHHs) with highly ordered internal structure have not, to the best of our knowledge, been prepared by PISR. In this article, the fabrication of HHHs through morphology transition from large compound vesicles to HHHs is reported. HHHs with highly regular internal structure may have significance in theoretical research and practical applications of nanomaterials. PMID- 26032960 TI - Conflict management style of Jordanian nurse managers and its relationship to staff nurses' intent to stay. AB - AIM: To explore the relationship between conflict management styles used by nurse managers and intent to stay of staff nurses. BACKGROUND: Nursing shortages require managers to focus on the retention of staff nurses. Understanding the relationship between conflict management styles of nurse managers and intent to stay of staff nurses is one strategy to retain nurses in the workforce. METHODS: A cross-sectional descriptive quantitative study was carried out in Jordan. The Rahim organization conflict inventory II (ROCI II) was completed by 42 nurse managers and the intent to stay scale was completed by 320 staff nurses from four hospitals in Jordan. The anova analysis was carried out. RESULTS: An integrative style was the first choice for nurse managers and the last choice was a dominating style. The overall level of intent to stay for nurses was moderate. Nurses tend to keep their current job for 2-3 years. There was a negative relationship between the dominating style as a conflict management style and the intent to stay for nurses. CONCLUSION: The findings of the present study support the claim that leadership practices affect the staff nurses' intent to stay and the quality of care. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers can improve the intent to stay for staff nurses if they use the appropriate conflict management styles. PMID- 26032961 TI - Editorial Comment from Dr Furuta to Measurement of oxyhemoglobin concentration changes in interstitial cystitis female patients: A near-infrared spectroscopy study. PMID- 26032963 TI - Generation of Redox Imbalance Mediates the Cytotoxic Effect of Malabaricone-A in a Multidrug Resistant Cell Line. AB - Multidrug resistance (MDR) refers to cross-resistance to a range of structurally and functionally unrelated compounds, and is accompanied by an elevated expression of ATP driven cell-membrane transporters. The cytotoxicity of Malabaricone-A (MAL-A), a diarylnonanoid derived from Myristica malabarica was demonstrated in leukemic cell lines, but its effectiveness in drug-resistant cancer cell lines has not been evaluated. Accordingly, this study tested its cytotoxic potential in a T-lymphoblastic leukemic cell line, CCRF CEM and its MDR counterpart, CEM/ADR5000. The effectiveness of MAL-A was 1.8 fold higher in CEM/ADR5000 than CCRF CEM cell line, the IC50 being value 5.40 +/- 1.41 vs. 9.72 +/- 1.08 ug/ml, respectively, suggesting that MAL-A demonstrated 'collateral sensitivity'. This cytotoxicity of MAL-A was attributed to an enhanced generation of oxidative stress, as the IC50 value increased following the addition of an anti-oxidant, N-acetyl cysteine (NAC). Furthermore, MAL-A depleted glutathione and inhibited glutathione peroxidase activity, which too contributed towards generation of a redox imbalance. This culminated in an apoptosis mediated cell death as evident by mitochondrial membrane depolarization, enhanced caspase-3 activity, increased externalization of phosphatidylserine and an increase in the sub G0/G1 population. Collectively, compounds with pro-oxidant activity have promising therapeutic potential in drug resistant phenotypes, worthy of future pharmacological consideration. PMID- 26032964 TI - Revision of the Synthesis and Pharmacological Activity of a Reported Translation Inhibitor. AB - 4EGI-1 is the prototype of a novel class of anticancer agents targeting translation. Patented drug-like analogue 1 was synthesized and examined for inhibition of translation and cytotoxicity in cancer cells. Unexpectedly, 1 was found inactive in both assays. PMID- 26032962 TI - Impact of preoperative 5alpha-reductase inhibitors on perioperative blood loss in patients with benign prostatic hyperplasia: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The ability of 5alpha-reductase inhibitors (5ARIs) to decrease blood loss during transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) remains controversial. We aimed to conduct a meta-analysis of all randomized controlled trials (RCTs) to establish the role of 5ARI use prior to TURP. METHODS: We searched studies from the electronic databases PubMed, Embase, Scopus, and Cochrane Library from inception to March 25, 2014. Meta analysis was performed using the statistical software Review Manager version 5.1. RESULTS: Seventeen RCTs including 1489 patients were examined. We observed that preoperative treatment with finasteride can decrease total blood loss, blood loss per gram of resected prostate tissue, hemoglobin level alteration, microvessel density (MVD), and vascular endothelial growth factor level. Neither finasteride nor dutasteride reduced operative time, prostate volume, or the weight of gland resected. In contrast, pretreatment with dutasteride before TURP did not decrease the total blood loss or MVD. CONCLUSIONS: Pretreatment with finasteride does seem to reduce perioperative blood loss related to TURP for BPH patients. However, the effect of preoperative dutasteride was inconclusive. Further studies are required to strengthen future recommendations regarding the use of 5ARI as a standard pre TURP treatment and its optimal regimen. PMID- 26032965 TI - Major Accidents (Gray Swans) Likelihood Modeling Using Accident Precursors and Approximate Reasoning. AB - Compared to the remarkable progress in risk analysis of normal accidents, the risk analysis of major accidents has not been so well-established, partly due to the complexity of such accidents and partly due to low probabilities involved. The issue of low probabilities normally arises from the scarcity of major accidents' relevant data since such accidents are few and far between. In this work, knowing that major accidents are frequently preceded by accident precursors, a novel precursor-based methodology has been developed for likelihood modeling of major accidents in critical infrastructures based on a unique combination of accident precursor data, information theory, and approximate reasoning. For this purpose, we have introduced an innovative application of information analysis to identify the most informative near accident of a major accident. The observed data of the near accident were then used to establish predictive scenarios to foresee the occurrence of the major accident. We verified the methodology using offshore blowouts in the Gulf of Mexico, and then demonstrated its application to dam breaches in the United Sates. PMID- 26032966 TI - The value of the preoperative 1-h pad test with pessary insertion for predicting the need for a mid-urethral sling following pelvic prolapse surgery: a cohort study. AB - PURPOSE: Part of the patients with pelvic organ prolapse but without symptoms of stress urinary incontinence (SUI) may demonstrate SUI after prolapse surgery (occult SUI), and no optimal preoperative screening method is currently available for it. The aim of this study was to estimate the value of the preoperative 1-h pad test with pessary insertion for predicting the need for a mid-urethral sling (MUS) following prolapse surgery. METHODS: Two hundred and six patients were enrolled for advanced prolapse without complaining of urinary incontinence (UI) in this prospective cohort study. Exclusion criteria included prior or concomitant anti-incontinence surgery. Preoperatively, a stress test, the 1-h pad test and uroflowmetry were performed with prolapse reduction. Primary outcome was postoperative de novo UI. Median follow-up was 31 months (range 12-48 months). RESULTS: Of the 206 patients, 45 (21.8 %) had evidence of occult SUI preoperatively, 62 (30.1 %) exhibited de novo UI postoperatively, and only 13 (6.3 %) opted MUSs. Patients with occult SUI experienced higher de novo UI rate (53.3 vs. 23.6 %; P = 0.000). The OSUI and concomitant hysterectomy were identified as independent risk factors related to de novo UI (P = 0.000, P = 0.044). We performed receiver operating characteristic (ROC) curve analysis to evaluate the value of preoperative 1-h pad test. The area under ROC curve was 0.816 +/- 0.085 (95 % CI 0.649-0.983); the cutoff value was 1.9 g (sensitivity 80.0 %, specificity 83.9 %). CONCLUSIONS: The preoperative 1-h pad test with prolapse reduction is feasible for screening occult SUI, and more than 1.9 g may be a practical indicator of a postoperative subsequent MUS. PMID- 26032967 TI - Identification of Suitable Areas for West Nile Virus Circulation in Tunisia. AB - West Nile virus (WNV) is a mosquito-transmitted Flavivirus belonging to the Japanese encephalitis antigenic complex of the Flaviviridae family. It is transmitted primarily by the bite of infected mosquitoes, particularly Culex spp. and Aedes/Ochlerotatus spp., which acquire the virus by feeding on viraemic birds. Humans, horses and other mammals are regarded as incidental or dead-end hosts. In the last decades, an increasing number of cases of WNV infection in horses and humans have been notified in the Mediterranean basin. In Tunisia, human cases of WNV-related meningoencephalitis were detected in 1997, 2003, 2007, 2010, 2011 and 2012. Based on the analysis of climatic and environmental conditions found in the locations where human cases have been reported in 2012, the aim of this study was to identify similar areas in Tunisia potentially at risk of disease occurrence. Data related to 85 neuroinvasive West Nile fever (WNF) human cases were georeferenced and a set of environmental and climatic variables (wetlands and humid areas, normalized difference vegetation index (NDVI), temperatures and elevation, migratory bird settlements) were used in the analysis. Areas, ecologically similar to those where human cases were detected, were identified using the Mahalanobis distance statistic. A leave-one-out cross validation was performed to validate the sensitivity of the model, and 78 of 85 points were correctly classified. PMID- 26032968 TI - Risk for prolonged QT interval and associated outcomes in children with early restrictive eating patterns. AB - Aim This study aimed to describe the frequency of QTc prolongation in children with restrictive eating disorders early in the course of disease admitted for inpatient therapy, to determine the frequency of associated ventricular arrhythmia, and to evaluate the relationship between QTc interval and concomitant electrolyte abnormalities and rate of weight loss. METHODS: This was a retrospective cohort study of patients aged 11-25 years with early restrictive eating disorders. RESULTS: In all, 82 patients met the inclusion criteria (84% female). In total, 9.8% had prolonged QTc interval during hospitalisation. Patients with prolonged QTc had significantly higher resting heart rates (p=0.006), but there was no association with hypokalaemia (p=0.31), hypomagnesaemia (p=0.43), hypophosphataemia (p=1), or rate of weight loss (p=1). CONCLUSION: Mild QTc prolongation in patients with restrictive eating disorders is not related to electrolyte abnormalities or rate of weight loss in this population, suggesting that investigation about other potential risk factors of prolonged QTc interval may be warranted. PMID- 26032969 TI - Stability of amoxicillin and amoxicillin/clavulanic acid reconstituted in isotonic saline. PMID- 26032970 TI - Polymorphisms in the FK506 binding protein 5 gene are associated with attention deficit hyperactivity disorder and diurnal cortisol levels. AB - AIM: Previous studies have shown an association between childhood attention deficit hyperactivity disorder (ADHD) and a down-regulated hypothalamus-pituitary adrenal axis (HPA axis) with low diurnal cortisol levels. Given the role of the FK506 binding protein 5 (FKBP5) as an important regulator of the negative feedback system of the HPA axis, we set out to investigate possible associations between single nucleotide polymorphisms (SNPs) in FKBP5 in relation to ADHD and diurnal cortisol levels. METHODS: Children with ADHD (n = 81) and healthy comparisons (n = 88) collected saliva four times during a regular school day for radioimmunoassay analysis of cortisol and for genotyping of five SNPs in FKBP5 (rs9296158, rs1360780, rs9470080, rs7748266 and rs9394309). RESULTS: We found associations between SNP genotypes and ADHD as well as between genotypes and diurnal cortisol levels. One of these SNPs, rs9470080, was significantly associated with both ADHD and lower cortisol levels. CONCLUSION: This study contributes to previous findings on a down-regulated HPA axis in children with ADHD by demonstrating an association between ADHD, lower cortisol levels and SNPs of the FKBP5-gene. The relevance of these findings for the development and shaping of ADHD symptoms needs to be approached in larger samples, preferably also taking stress reactivity into consideration. PMID- 26032971 TI - Evolution of the beta-amylase gene in the temperate grasses: Non-purifying selection, recombination, semiparalogy, homeology and phylogenetic signal. AB - Low-copy nuclear genes (LCNGs) have complex genetic architectures and evolutionary dynamics. However, unlike multicopy nuclear genes, LCNGs are rarely subject to gene conversion or concerted evolution, and they have higher mutation rates than organellar or nuclear ribosomal DNA markers, so they have great potential for improving the robustness of phylogenetic reconstructions at all taxonomic levels. In this study, our first objective is to evaluate the evolutionary dynamics of the LCNG beta-amylase by testing for potential pseudogenization, paralogy, homeology, recombination, and phylogenetic incongruence within a broad representation of the main Pooideae lineages. Our second objective is to determine whether beta-amylase shows sufficient phylogenetic signal to reconstruct the evolutionary history of the Pooid grasses. A multigenic (ITS, matK, ndhF, trnTL, and trnLF) tree of the study group provided a framework for assessing the beta-amylase phylogeny. Eight accessions showed complete absence of selection, suggesting putative pseudogenic copies or other relaxed selection pressures; resolution of Vulpia alopecuros 2x clones indicated its potential (semi) paralogy; and homeologous copies of allopolyploid species Festuca simensis, F. fenas, and F. arundinacea tracked their Mediterranean origin. Two recombination events were found within early-diverged Pooideae lineages, and five within the PACCMAD clade. The unexpected phylogenetic relationships of 37 grass species (26% of the sampled species) highlight the frequent occurrence of non-treelike evolutionary events, so this LCNG should be used with caution as a phylogenetic marker. However, once the pitfalls are identified and removed, the phylogenetic reconstruction of the grasses based on the beta-amylase exon+intron positions is optimal at all taxonomic levels. PMID- 26032972 TI - Antiepileptic drugs alter the expression of placental carriers: An in vitro study in a human placental cell line. AB - OBJECTIVE: Antiepileptic drugs (AEDs) affect the expression of carriers for drugs and nutrients at several blood-tissue barriers, but their impact on placental carriers is largely unknown. Our aim was to study the effects of AEDs in human placental cells on the expression of carriers for hormones, nutrients, and drugs: folate placental uptake carriers (reduced folate carrier, RFC; folate receptor alpha, FRalpha) and efflux transporters (breast cancer resistance protein, BCRP and multidrug resistance protein 2) and thyroid hormone uptake transporters (l type amino acid transporter-LAT1 and organic anion transporting polypeptides OATPs). METHODS: The human trophoblast BeWo cells were incubated with phenytoin (PHT), valproic acid (VPA), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), or their vehicles at concentrations that mostly represent their therapeutic range. RT-PCR and western blot analysis were utilized to study the effects of AEDs on carriers' mRNA and protein expression, respectively. The activity of BCRP was evaluated by accumulation studies. RESULTS: Compared with controls, VPA-treated cells displayed half the levels of RFC mRNA and protein (p < 0.05) and up to 2.7-fold increases in BCRP mRNA and protein expression (p < 0.05), together with enhanced BCRP activity. PHT increased the expression of BCRP and LAT1 by 2.9-fold and 2.5-fold, respectively (p < 0.01). LTG modulated the levels of FRalpha transcript and protein, whereas LEV altered those of RFC, LAT1, and OATPs 1A2 and 4A1. CBZ affected carrier expression at the mRNA but not the protein level. All the AEDs altered to a modest extent the transcription of nuclear receptors known to regulate transporter expression. SIGNIFICANCE: These findings suggest a possible effect of AEDs on placental transport mechanisms for folate and thyroid hormones as well as those involved in the elimination of potential toxins from the fetus. Identification of AED effects on the placental barrier could be a first step toward a more rational pharmacotherapy and supplemental therapy in pregnant women with epilepsy. PMID- 26032973 TI - Gallium Nitride Nanowires and Heterostructures: Toward Color-Tunable and White Light Sources. AB - Gallium-nitride-based light-emitting diodes have enabled the commercialization of efficient solid-state lighting devices. Nonplanar nanomaterial architectures, such as nanowires and nanowire-based heterostructures, have the potential to significantly improve the performance of light-emitting devices through defect reduction, strain relaxation, and increased junction area. In addition, relaxation of internal strain caused by indium incorporation will facilitate pushing the emission wavelength into the red. This could eliminate inefficient phosphor conversion and enable color-tunable emission or white-light emission by combining blue, green, and red sources. Utilizing the waveguiding modes of the individual nanowires will further enhance light emission, and the properties of photonic structures formed by nanowire arrays can be implemented to improve light extraction. Recent advances in synthetic methods leading to better control over GaN and InGaN nanowire synthesis are described along with new concept devices leading to efficient white-light emission. PMID- 26032974 TI - Dual processes of false recognition in kindergarten children and elementary school pupils. AB - We investigated the contribution of monitoring processes to the emergence of false memories in children. Two age groups were compared, assuming lower monitoring ability at preschool age compared with older children. We also manipulated whether elementary school pupils responded in the memory test with or without time pressure. Furthermore, the frequency of list presentation was manipulated within participants. We found that presenting lists thrice compared with only once increased the number of false memories in kindergarten children and in elementary school pupils responding under time pressure but reduced false memories in elementary school pupils responding without time pressure. These findings indicate that kindergarten children still lack the ability to monitor the source of the activation of critical items of Deese-Roediger-McDermott lists. PMID- 26032975 TI - Warm temperature acclimation impacts metabolism of paralytic shellfish toxins from Alexandrium minutum in commercial oysters. AB - Species of Alexandrium produce potent neurotoxins termed paralytic shellfish toxins and are expanding their ranges worldwide, concurrent with increases in sea surface temperature. The metabolism of molluscs is temperature dependent, and increases in ocean temperature may influence both the abundance and distribution of Alexandrium and the dynamics of toxin uptake and depuration in shellfish. Here, we conducted a large-scale study of the effect of temperature on the uptake and depuration of paralytic shellfish toxins in three commercial oysters (Saccostrea glomerata and diploid and triploid Crassostrea gigas, n = 252 per species/ploidy level). Oysters were acclimated to two constant temperatures, reflecting current and predicted climate scenarios (22 and 27 degrees C), and fed a diet including the paralytic shellfish toxin-producing species Alexandrium minutum. While the oysters fed on A. minutum in similar quantities, concentrations of the toxin analogue GTX1,4 were significantly lower in warm acclimated S. glomerata and diploid C. gigas after 12 days. Following exposure to A. minutum, toxicity of triploid C. gigas was not affected by temperature. Generally, detoxification rates were reduced in warm-acclimated oysters. The routine metabolism of the oysters was not affected by the toxins, but a significant effect was found at a cellular level in diploid C. gigas. The increasing incidences of Alexandrium blooms worldwide are a challenge for shellfish food safety regulation. Our findings indicate that rising ocean temperatures may reduce paralytic shellfish toxin accumulation in two of the three oyster types; however, they may persist for longer periods in oyster tissue. PMID- 26032977 TI - Graphene Quantum Dots Assembled with Metalloporphyrins for "Turn on" Sensing of Hydrogen Peroxide and Glucose. AB - Noncovalent and multifunctional hybrids have been generated via pi-pi stacking and electrostatic interactions by combining the nanometer-scale graphene structure of graphene quantum dots (GQDs) with Fe(III) 5,10,15,20-tetrakis(1 methyl-4-pyridyl)porphine (FeTMPyP). The inner filter effect (IFE) of FeTMPyP on the GQDs results in substantial PL quenching of the GQDs. The quenched PL of GQDs by the FeTMPyP can be switched back "on" in response to the reaction between FeTMPyP and H2 O2 , which causes rupture of the cyclic tetrapyrrolic nucleus with consequential loss of iron from FeTMPyP, and then proceeds further to produce colorless dipyrroles and monopyrroles. This "turn on" system can be applied for simple and convenient H2 O2 sensing and can be further extended to the detection of glucose in combination with the specific catalytic effect of glucose oxidase (GOx) through the oxidation of glucose and formation of H2 O2 . Because of the inherent synthetic control available for the design of metalloporphyrins, the GQDs-based optical sensing approach described here has the potential to be highly versatile for other target analytes. PMID- 26032976 TI - Influence of temporal regularization and radial undersampling factor on compressed sensing reconstruction in dynamic contrast enhanced MRI of the breast. AB - BACKGROUND: To evaluate the influence of temporal sparsity regularization and radial undersampling on compressed sensing reconstruction of dynamic contrast enhanced (DCE) MRI, using the iterative Golden-angle RAdial Sparse Parallel (iGRASP) MRI technique in the setting of breast cancer evaluation. METHODS: DCE MRI examinations of the breast (n = 7) were conducted using iGRASP at 3 Tesla. Images were reconstructed with five different radial undersampling schemes corresponding to temporal resolutions between 2 and 13.4 s/frame and with four different weights for temporal sparsity regularization (lambda = 0.1, 0.5, 2, and 6 times of noise level). Image similarity to time-averaged reference images was assessed by two breast radiologists and using quantitative metrics. Temporal similarity was measured in terms of wash-in slope and contrast kinetic model parameters. RESULTS: iGRASP images reconstructed with lambda = 2 and 5.1 s/frame had significantly (P < 0.05) higher similarity to time-averaged reference images than the images with other reconstruction parameters (mutual information (MI) >5%), in agreement with the assessment of two breast radiologists. Higher undersampling (temporal resolution < 5.1 s/frame) required stronger temporal sparsity regularization (lambda >= 2) to remove streaking aliasing artifacts (MI > 23% between lambda = 2 and 0.5). The difference between the kinetic-model transfer rates of benign and malignant groups decreased as temporal resolution decreased (82% between 2 and 13.4 s/frame). CONCLUSION: This study demonstrates objective spatial and temporal similarity measures can be used to assess the influence of sparsity constraint and undersampling in compressed sensing DCE-MRI and also shows that the iGRASP method provides the flexibility of optimizing these reconstruction parameters in the postprocessing stage using the same acquired data. PMID- 26032978 TI - Effect of enzymatic hydrolysis on surface activity and surface rheology of type I collagen. AB - We describe the adsorption behaviour and rheological properties of a calf skin type I collagen, and of its hydrolysates obtained using a Clostridium histolyticum collagenase (CHC) under moderate conditions (pH 7, 37 degrees C). The effect of CHC concentration (2*10(-9)-2*10(-6)M) and incubation time (35 85min) was studied and optimised to achieve the highest decrease of surface tension and the highest dilational surface viscoelasticity of the adsorbed layers. SDS-PAGE electrophoresis and reverse-phase high performance liquid chromatography (RP-HPLC) were used to characterise the hydrolysis products. The results show that even simple modifications (heat treatment, pH change, partial hydrolysis) of collagen enhances its surface properties, especially in terms of surface dilational elasticity modulus. The use of low enzyme concentration (CHC to-collagen molar ratio of 4*10(-3)) and short incubation time (<45min) results in moderately hydrolysed products with the highest ability to lower surface tension (gamma=53.9mNm(-1)) forming highly elastic adsorbed layers (surface dilational elasticity, E'=74.5mNm(-1)). PMID- 26032979 TI - Adaptive radiation versus 'radiation' and 'explosive diversification': why conceptual distinctions are fundamental to understanding evolution. AB - Adaptive radiation is the rise of a diversity of ecological roles and role specific adaptations within a lineage. Recently, some researchers have begun to use 'adaptive radiation' or 'radiation' as synonymous with 'explosive species diversification'. This essay aims to clarify distinctions between these concepts, and the related ideas of geographic speciation, sexual selection, key innovations, key landscapes and ecological keys. Several examples are given to demonstrate that adaptive radiation and explosive diversification are not the same phenomenon, and that focusing on explosive diversification and the analysis of phylogenetic topology ignores much of the rich biology associated with adaptive radiation, and risks generating confusion about the nature of the evolutionary forces driving species diversification. Some 'radiations' involve bursts of geographic speciation or sexual selection, rather than adaptive diversification; some adaptive radiations have little or no effect on speciation, or even a negative effect. Many classic examples of 'adaptive radiation' appear to involve effects driven partly by geographic speciation, species' dispersal abilities, and the nature of extrinsic dispersal barriers; partly by sexual selection; and partly by adaptive radiation in the classical sense, including the origin of traits and invasion of adaptive zones that result in decreased diversification rates but add to overall diversity. PMID- 26032980 TI - Feature-Motivated Simplified Adaptive PCNN-Based Medical Image Fusion Algorithm in NSST Domain. AB - Multimodality medical image fusion plays a vital role in diagnosis, treatment planning, and follow-up studies of various diseases. It provides a composite image containing critical information of source images required for better localization and definition of different organs and lesions. In the state-of-the art image fusion methods based on nonsubsampled shearlet transform (NSST) and pulse-coupled neural network (PCNN), authors have used normalized coefficient value to motivate the PCNN-processing both low-frequency (LF) and high-frequency (HF) sub-bands. This makes the fused image blurred and decreases its contrast. The main objective of this work is to design an image fusion method that gives the fused image with better contrast, more detail information, and suitable for clinical use. We propose a novel image fusion method utilizing feature-motivated adaptive PCNN in NSST domain for fusion of anatomical images. The basic PCNN model is simplified, and adaptive-linking strength is used. Different features are used to motivate the PCNN-processing LF and HF sub-bands. The proposed method is extended for fusion of functional image with an anatomical image in improved nonlinear intensity hue and saturation (INIHS) color model. Extensive fusion experiments have been performed on CT-MRI and SPECT-MRI datasets. Visual and quantitative analysis of experimental results proved that the proposed method provides satisfactory fusion outcome compared to other image fusion methods. PMID- 26032982 TI - Decreased activity with increased background network efficiency in amnestic MCI during a visuospatial working memory task. AB - Recent studies have demonstrated the working memory impairment in patients with amnestic mild cognitive impairment (aMCI). However, the neurophysiological basis of the working memory deficit in aMCI is poorly understood. The aim of this study was to explore the abnormal activity during encoding and recognition procedures, as well as the reorganization of the background network maintaining the working memory state in aMCI. Using event-related fMRI during a visuospatial working memory task with three recognition difficulty levels, the task-related activations and network efficiency of the background network in 17 aMCI patients and 19 matched controls were investigated. Compared with cognitively healthy controls, patients with aMCI showed significantly decreased activity in the frontal and visual cortices during the encoding phase, while during the recognition phase, decreased activity was detected in the frontal, parietal, and visual regions. In addition, increased local efficiency was also observed in the background network of patients with aMCI. The results suggest patients with aMCI showed impaired encoding and recognition functions during the visuospatial working memory task, and may pay more effort to maintain the cognitive state. This study extends our understanding of the impaired working memory function in aMCI and provides a new perspective to investigate the compensatory mechanism in aMCI. PMID- 26032981 TI - Distinct roles of DNMT1-dependent and DNMT1-independent methylation patterns in the genome of mouse embryonic stem cells. AB - BACKGROUND: DNA methylation patterns are initiated by de novo DNA methyltransferases DNMT3a/3b adding methyl groups to CG dinucleotides in the hypomethylated genome of early embryos. These patterns are faithfully maintained by DNMT1 during DNA replication to ensure epigenetic inheritance across generations. However, this two-step model is based on limited data. RESULTS: We generated base-resolution DNA methylomes for a series of DNMT knockout embryonic stem cells, with deep coverage at highly repetitive elements. We show that DNMT1 and DNMT3a/3b activities work complementarily and simultaneously to establish symmetric CG methylation and CHH (H = A, T or C) methylation. DNMT3a/3b can add methyl groups to daughter strands after each cycle of DNA replication. We also observe an unexpected division of labor between DNMT1 and DNMT3a/3b in suppressing retrotransposon long terminal repeats and long interspersed elements, respectively. Our data suggest that mammalian cells use a specific CG density threshold to predetermine methylation levels in wild-type cells and the magnitude of methylation reduction in DNMT knockout cells. Only genes with low CG density can be induced or, surprisingly, suppressed in the hypomethylated genome. Lastly, we do not find any association between gene body methylation and transcriptional activity. CONCLUSIONS: We show the concerted actions of DNMT enzymes in the establishment and maintenance of methylation patterns. The finding of distinct roles of DNMT1-dependent and -independent methylation patterns in genome stability and regulation of transcription provides new insights for understanding germ cell development, neuronal diversity, and transgenerational epigenetic inheritance and will help to develop next-generation DNMT inhibitors. PMID- 26032983 TI - Toward smart implant synthesis: bonding bioceramics of different resorbability to match bone growth rates. AB - Craniofacial reconstructive surgery requires a bioactive bone implant capable to provide a gradual resorbability and to adjust to the kinetics of new bone formation during healing. Biomaterials made of calcium phosphate or bioactive glasses are currently available, mainly as bone defect fillers, but it is still required a versatile processing technique to fabricate composition-gradient bioceramics for application as controlled resorption implants. Here it is reported the application of rapid prototyping based on laser cladding to produce three-dimensional bioceramic implants comprising of a calcium phosphate inner core, with moderate in vitro degradation at physiological pH, surrounded by a bioactive glass outer layer of higher degradability. Each component of the implant is validated in terms of chemical and physical properties, and absence of toxicity. Pre-osteoblastic cell adhesion and proliferation assays reveal the adherence and growth of new bone cells on the material. This technique affords implants with gradual-resorbability for restoration of low-load-bearing bone. PMID- 26032984 TI - Using CBPR to Assess Client Needs at a Social Service Agency. AB - Community-based participatory research (CBPR) has become an important research approach for universities to partner with social service agencies by uniting them in project design, planning, implementation, and evaluation. OBJECTIVES: This study involved FOCUS, an urban social service agency, and Rutgers College of Nursing (RUCON) collaboratively conducting a needs assessment to compare the health needs of its clients and their employees' perception of their clients health needs, utilizing CBPR. DESIGN: Qualitative data was collected using the focus group method, field notes, photographs, and observation. The employees of FOCUS facilitated focus groups, participant recruitment, and transcribed and translated data. RESULTS: Three themes emerged: Health Education, Cost of Health Care, and Barriers to Health Care. CONCLUSION: This study contributes to the growing body of knowledge of integrating the CBPR approach when conducting a community needs assessment with a social service agency. The CBPR approach closely reflects the identified health needs of its clients resulting in interventions that will meet their specific health needs. PMID- 26032985 TI - Campaigners challenge patent applications for hepatitis C drug in five countries. PMID- 26032986 TI - Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity: reply. PMID- 26032987 TI - A neural mechanism of phase-locked responses to sinusoidally amplitude-modulated signals in the inferior colliculus. AB - The central nucleus of the inferior colliculus (ICc) is an auditory region that receives convergent inputs from a large number of lower auditory nuclei. ICc neurons phase-lock to low frequencies of sinusoidally amplitude-modulated (SAM) signals but have a different mechanism in the phase-locking from that in neurons of lower nuclei. In the mustached bat, the phase-locking ability in lower nuclei is created by the coincidence of phase-locked excitatory and inhibitory inputs that have slightly different latencies. In contrast, the phase-locking property of ICc neurons is little influenced by the blocking of inhibitory synapses. Moreover, ICc neurons exhibit different characteristics in the spike patterns and synchronicity, classified here by three types of ICc neurons, or sustained, onset, and non-onset phase-locking neurons. However it remains unclear how ICc neurons create the phase-locking ability and the different characteristics. To address this issue, we developed a model of ICc neuronal population. Using this model, we show that the phase-locking ability of ICc neurons to low SAM frequencies is created by an intrinsic membrane property of ICc neuron, limited by inhibitory ion channels. We also show that response characteristics of the three types of neurons arise from the difference in an inhibitory effect sensitive to SAM frequencies. Our model reproduces well the experimental results observed in the mustached bat. These findings provide necessary conditions of how ICc neurons can give rise to the phase-locking ability and characteristic responses to low SAM frequencies. PMID- 26032988 TI - The practice of nursing research: getting ready for 'ethics' and the matter of character. AB - Few would argue with the idea that nursing research should be conducted ethically yet obtaining ethical approval is considered by many to have become unnecessarily burdensome. This brief article investigates the idea that there might be a relationship between the level of perceived burdensomeness of the research ethics application process on the one hand and the character of the nurse-researcher on the other. Given that nurses are required to be other-regarding, a nurse who undertakes research primarily for self-regarding reasons would seem to be acting in ways inconsistent with the aims of nursing as set out in nursing codes. It is suggested that the self-regarding nurse-researcher may find the ethics application process more burdensome than the other-regarding nurse-researcher who, it is further suggested, is engaged with nursing research as a practice in the technical sense in which that term has been developed by the philosopher Alasdair MacIntyre. PMID- 26032989 TI - Micro push-out bond strength of resin cement in roots exhibiting the butterfly effect. AB - The aim of this study was to determine the bond strength of resin cement in root sections with or without butterfly effect. Fifteen single-rooted human maxillary central incisors were decoronated and prepared up to size 40. After post space preparation, the resin cement was placed into the post space and the fiber posts were luted. 1 mm thickness slices were obtained and the presence of the butterfly effect was recorded. A push-out test was then used to measure the bond strength between the resin cement and root dentin. Data were analyzed using independent samples of t and chi(2) tests (p = 0.05). The sections exhibiting butterfly effect showed higher push-out bond strength values than those of without butterfly effect (p < 0.05). Butterfly effect can influence the push-out bond strength. Thus, this phenomena should be taken into account, when push-out bond strength test is performed. Root sections exhibiting butterfly effect resulted in higher push-out bond strength values to root sections without butterfly effect. PMID- 26032990 TI - Genetic relatedness and recombination analysis of Allorhizobium vitis strains associated with grapevine crown gall outbreaks in Europe. AB - AIMS: To analyse genetic diversity and epidemiological relationships among 54 strains of Allorhizobium vitis isolated in Europe during an 8-year period and to assess the relative contribution of mutation and recombination in shaping their diversity. METHODS AND RESULTS: By using random amplified polymorphic DNA (RAPD) PCR, strains studied were distributed into 12 genetic groups. Sequence analysis of dnaK, gyrB and recA housekeeping genes was employed to characterize a representative subcollection of 28 strains. A total of 15 different haplotypes were found. Nucleotide sequence analysis suggested the presence of recombination events in A. vitis, particularly affecting dnaK locus. Although prevalence of mutation over recombination was found, impact of recombination was about two times greater than mutation in the evolution of the housekeeping genes analysed. CONCLUSIONS: The RAPD analysis indicated high degree of genetic diversity among the strains. However, the most abundant RAPD group was composed of 35 strains, which could lead to the conclusion that they share a common origin and were distributed by the movement of infected grapevine planting material as a most common way of crossing long distances. Furthermore, it seems that recombination is acting as an important driving force in the evolution of A. vitis. As no substantial evidence of recombination was detected within recA gene fragment, this phylogenetic marker could be reliable to characterize phylogenetic relationships among A. vitis strains. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrated clear epidemiological relationship between majority of strains studied, suggesting a need for more stringent phytosanitary measures in international trade. Moreover, this is the first study to report recombination in A. vitis. PMID- 26032991 TI - Changes in estrone and estradiol levels during follicle development: a retrospective large-scale study. AB - BACKGROUND: The improved reagent for measuring estradiol (E2), the ST AIA-PACK iE2 reagent, has a higher specificity for the measurement of E2 levels than the original ST AIA-PACK E2 reagent, because of its lower cross-reactivity with estrone (E1). As we had E2 data obtained with either of the reagents, we analyzed changes in E1 and E2 levels during follicle development. METHODS: The study included 14371 serum hormone measurements from 4412 patients who underwent oocyte retrieval or frozen/thawed embryo transfer in natural cycle in vitro fertilization in Shinbashi YUME clinic, Tokyo, between June 2011 and May 2014. The age of the patients ranged from 24 to 48 year (mean and standard deviation, 39.8 +/- 4.0 year). Patients were categorized into three age groups (<38 year, 38 40 year, and >40 year) and into 10 groups of largest follicle diameter from 11 to 20 mm, with 1-mm intervals. Serum E2 levels were measured in the follicular phase with either the ST AIA-PACK E2 reagent or the ST AIA-PACK iE2 reagent, and the data were compared. Also, for 26 randomly selected samples, E2 was measured using both reagents, together with E1 and E3, and the E1/E2 ratios were compared. RESULTS: E2 concentrations measured with the ST AIA-PACK iE2 reagent were significantly lower than those measured with the ST AIA-PACK E2 reagent in the largest follicle diameter category of 11-17 mm in the <38 year group, in the largest follicle diameter category of 11-18 mm in the 38-40 year group, and in the largest follicle diameter category of 11-15 mm in the >40 year group. The serum E1/E2 ratio in the 26 samples was 3.4 +/- 1.1 and 0.7 +/- 0.1 in the early follicular phase and in the ovulatory phase, respectively. CONCLUSIONS: The difference between the E2 concentrations measured with the ST AIA-PACK E2 reagent and the ST AIA-PACK iE2 reagent tended to decrease as the follicle diameter increased, particularly in the older patients, which suggests E1 secretion is more abundant in the early follicular phase and in younger patients than in the ovulatory phase and in older patients. PMID- 26032992 TI - Discriminating features of gait performance in progressive supranuclear palsy. AB - INTRODUCTION: Progressive supranuclear palsy (PSP) is the most common form of atypical Parkinsonism; however it is underdiagnosed and often misdiagnosed as Parkinson's disease (PD). METHODS: We investigated gait initiation (GI) and gait performance in a total of 36 participants (12 PSP, 12 PD and 12 healthy age- and gender-matched controls) to gain further insight into specific motor deficits that characterize dynamic postural control and gait in PSP. Anticipatory postural adjustments (APAs), quantified by center of pressure (COP) displacement and speed prior to an initial heel off, and the maximum distance (COPCOM) between COP and center of mass (COM) during all three GI phases were calculated to evaluate dynamic postural control. Steady-state gait performance was also evaluated and compared across the groups. RESULTS: APAs in PSP were significantly altered such that the posterior COP shift is profoundly diminished when compared to PD (p < 0.05). Moreover, proper velocity control during GI in PSP was affected, particularly in the mediolateral direction, when compared to PD (p < 0.05). The diminished COPCOM distance is further indicative of more severe dynamic postural instability in PSP than in PD (p < 0.05). Significant differences in spatiotemporal parameters, inter-step variability, and asymmetry during gait in PSP, in comparison with PD were also identified (all p's < 0.05). CONCLUSION: The present study reveals that the compensatory GI strategy in PSP is distinct from PD and paradoxically induces lateral instability. Further, gait performance in PSP is slower and more variable which could be the consequence of lateral instability and fear of falling. PMID- 26032993 TI - A non-parametric approach to estimate the total deviation index for non-normal data. AB - Concordance indices are used to assess the degree of agreement between different methods that measure the same characteristic. In this context, the total deviation index (TDI) is an unscaled concordance measure that quantifies to which extent the readings from the same subject obtained by different methods may differ with a certain probability. Common approaches to estimate the TDI assume data are normally distributed and linearity between response and effects (subjects, methods and random error). Here, we introduce a new non-parametric methodology for estimation and inference of the TDI that can deal with any kind of quantitative data. The present study introduces this non-parametric approach and compares it with the already established methods in two real case examples that represent situations of non-normal data (more specifically, skewed data and count data). The performance of the already established methodologies and our approach in these contexts is assessed by means of a simulation study. PMID- 26032994 TI - Age dependency of ischaemic stroke subtypes and vascular risk factors in western Norway: the Bergen Norwegian Stroke Cooperation Study. AB - OBJECTIVES: Age dependency of acute ischaemic stroke aetiology and vascular risk factors have not been adequately evaluated in stroke patients in Norway. Aims of this study were to evaluate how stroke subtypes and vascular risk factors vary with age in a western Norway stroke population. MATERIALS AND METHODS: Patients aged 15-100 years consecutively admitted to our neurovascular centre with acute ischaemic stroke between 2006 and 2012 were included. The study population was categorized as young (15-49 years), middle-aged (50-74 years) or elderly (>= 75 years). Stroke aetiology was defined by TOAST criteria. Risk factors and history of cardiovascular disease were recorded. RESULTS: In total, 2484 patients with acute cerebral infarction were included: 1418 were males (57.3%). Mean age was 70.8 years (SD +/- 14.9), 228 patients were young, 1126 middle-aged, and 1130 were elderly. The proportion of large-artery atherosclerosis and of small-vessel occlusion was highest among middle-aged patients. The proportion of cardioembolism was high at all ages, especially among the elderly. The proportion of stroke of other determined cause was highest among young patients. Some risk factors (diabetes mellitus, active smoking, angina pectoris, prior stroke and peripheral artery disease) decreased among the elderly. The proportions of several potential causes increased with age. CONCLUSION: The proportion of stroke subtypes and vascular risk factors are age dependent. Age 50-74 years constitutes the period in life where cardiovascular risk factors become manifest and stroke subtypes change. PMID- 26032995 TI - [Hydatidosis: epidemiological, clinical, diagnostic and therapeutic aspects]. AB - Hydatidosis or cystic echinococcosis (CE) is a parasitic zoonosis caused by Echinococcus granulosus. Its life cycle involves dogs, sheep and sometimes other animals. CE has a worldwide distribution, with greater prevalence in temperate zones. In Spain, Castile and Leon, La Rioja, Navarre, Aragon, and the Mediterranean coast are the areas where it is most commonly diagnosed, although there have also been published cases in other regions, such as Cantabria. Clinical signs and symptoms of EC may be related to the mass effect of the cyst, its superinfection or anaphylactic reactions secondary to its rupture. Because of its slow growth, diagnosis is usually made in adulthood by combining clinical symptoms with imaging and serological tests. There is no universal consensus on the management of CE. Treatment is based mainly on three pillars: medical treatment (mainly albendazole), surgery, and percutaneous drainage. The choice of the most appropriate approach is based on the patient's symptoms and the characteristics of the cysts. PMID- 26032996 TI - [The late media emergency of smallpox vaccine, news coverage of Spanish press (1999-2004)]. AB - INTRODUCTION: Discussions on the need for smallpox virus preservation in 1999 focused attention on an eradicated disease 20 years ago. Smallpox was replaced as a potential candidate to be used as a bioterrorist weapon because of the international alarm scenario produced after the 11/9 events in USA. The reactivation of a vaccine which remained forgotten was the direct consequence. The initial target groups were the security forces of America. Spain was also among the countries that were interested in acquiring the smallpox vaccine. The aim of this study is to analyze the considerable media coverage of smallpox obtained in our country. METHODS: Systematic review of published news in the four largest national daily newspapers (ABC, El Mundo, El Pais and La Vanguardia) for the period 1999-2004 of the Dow Jones Factiva document database. "Smallpox" were used as a key word. From the obtained data, a qualitative and quantitative analysis was done. RESULTS: 416 reviews were analyzed; the newspaper El Mundo was the most interested in these news (158 citations, 37.98%). Most of the news were published in 2003 (152, 36.5%) The year with more news about smallpox (2003) coincides with the purchase of vaccines in Spain. The type of messages in the news was highly changeable over this six-year period. Those related to "politics and diplomacy", "epidemiological risk", "bioterrorism" and "vaccine" were predominant. CONCLUSIONS: The alarm raised around the smallpox vaccination was a media phenomenon due to political strategy issues rather than a real public health problem. PMID- 26032997 TI - A practice-based observational study on the use of micafungin in Surgical Critical Care Units. AB - INTRODUCTION: Echinocandins are first-line therapy in critically ill patients with invasive Candida infection (ICI). This study describes our experience with micafungin at Surgical Critical Care Units (SCCUs). METHODS: A multicenter, observational, retrospective study was performed (12 SCCUs) by reviewing all adult patients receiving 100 mg/24h micafungin for >=72h during ad-mission (April 2011-July 2013). Patients were divided by ICI category (possible, probable + proven), 24h-SOFA (<7, >=7) and outcome. RESULTS: 72 patients were included (29 possible, 13 probable, 30 proven ICI). Forty patients (55.6%) presented SOFA >=7. Up to 78.0% patients were admitted after urgent surgery (64.3% with SOFA <7 vs. 90.3% with SOFA >=7, p=0.016), and 84.7% presented septic shock. In 66.7% the site of infection was intraabdominal. Forty-nine isolates were recovered (51.0% C. albicans). Treatment was empirical (59.7%), microbiologically directed (19.4%), rescue therapy (15.3%), or anticipated therapy and prophylaxis (2.8% each). Empirical treatment was more frequent (p<0.001) in possible versus probable + proven ICI (86.2% vs. 41.9%). Treatment (median) was longer (p=0.002) in probable + proven versus possible ICI (13.0 vs. 8.0 days). Favorable response was 86.1%, without differences by group. Age, blood Candida isolation, rescue therapy, final MELD value and %MELD variation were significantly higher in patients with non-favorable response. In the multivariate analysis (R2=0.246, p<0.001) non-favorable response was associated with positive %MELD variations (OR=15.445, 95%CI= 2.529-94.308, p=0.003) and blood Candida isolation (OR=11.409, 95%CI=1.843-70.634, p=0.009). CONCLUSION: High favorable response was obtained, with blood Candida isolation associated with non-favorable response, in this series with high percentage of patients with intraabdominal ICI, septic shock and microbiological criteria for ICI. PMID- 26032998 TI - [Role of double strand DNA break repair for quinolone sensitivity in Escherichia coli: therapeutic implications]. AB - INTRODUCTION: Quinolones are one of the types of antibiotics with higher resistance rates in the last years. At molecular level, quinolones block type II topoisomerases producing double strand breaks (DSBs). These DSBs could play a double role, as inductors of the quinolone bactericidal effects but also as mediators of the resistance and tolerance mechanisms. MATERIAL AND METHODS: In this work we have studied the molecular pathways responsible for DSBs repair in the quinolone susceptibility: the stalled replication fork reversal (recombination-dependent) (RFR), the SOS response induction, the translesional DNA synthesis (TLS) and the nucleotide excision repair mechanisms (NER). For this reason, at the European University in Madrid, we analysed the minimal inhibitory concentration (MIC) to three different quinolones in Escherichia coli mutant strains coming from different type culture collections. RESULTS: recA, recBC, priA and lexA mutants showed a significant reduction on the MIC values for all quinolones tested. No significant changes were observed on mutant strains for TLS and NER. DISCUSSION: These data indicate that in the presence of quinolones, RFR mechanisms and the SOS response could be involved in the quinolone susceptibility. PMID- 26032999 TI - Profiles and clinical management of hepatitis C patients in Spain: disHCovery study. AB - INTRODUCTION: To assess the clinical profile and management of patients with hepatitis C (HCV) infection in an observational study in Spanish hospitals. METHODS: The study included an initial cross-sectional phase (study phase I), in which investigators at 48 hospitals from 14 Spanish regions collected data from approximately 20 consecutive patients each (a total of 1,000 patients) to assess the general features of HCV-infected patients of any genotype. During the second phase (study phase II), data from 878 patients that were infected exclusively with genotype 1 HCV were assessed retrospectively. Eight pre-defined clinical profiles were established, in order to assess clinical and previous treatments characteristics. RESULTS: Among the HCV-infected individuals that were analysed during the first part, HCV genotype 1 was found to be predominant (with a prevalence of 76.6%), prevailing the subtype 1b (69.8%), with other significant groups infected by genotype 3 (12.3%) and 4 (7.4%). In the second part of the study, 44% of the HCV genotype 1-infected patients were at a F3/F4 fibrosis stage. 15.9% had never been treated, and previously unsuccessfully treated patients that were no longer receiving anti-HCV treatment accounted for 50.8% of cases. Individuals with a sustained virologic response (SVR) to previous dual therapies (based on Interferon and Ribavirin) were only 14.5% and patients under treatment during the study accounted for the remaining 18.8%. A total of 713 patients (81.2%) in the second phase were not receiving any type of therapy over the period analysed, mainly due to the anticipation of new anti-HCV drugs (41.8%), SVR achievement (17.8%) and unresponsiveness to therapies available at the time of the study (9.5%). CONCLUSIONS: HCV genotype 1, predominately 1b, is the most prevalent type in Spain. Advanced fibrosis or cirrhosis is frequent in this group, mainly patients not yet cured. PMID- 26033000 TI - Nebulized medication is not associated with nosocomial infections. A pilot study. AB - INTRODUCTION: Nebulized devices are commonly used in the treatment of respiratory infection, and other respiratory diseases. It has been reported nosocomial infections in cystic fibrosis patients as a result of the use of contaminated devices. However, little is known about nosocomial infections secondary to aerosolized therapy in COPD patients admitted for acute exacerbation. METHODS: Thirty consecutive patients (13 males) were included. All of them received aerosolized medication. Each patient used their own facemask and nebulizer cup, which were stored in the room after its use. Samples from nebulizer cups were obtained on days 0, 4 and 7. In addition, sputum samples were obtained on day 0 (prior to any nebulization) and on day 7, and cultivated in enriched media. RESULTS: Only nine nebulizer cups had positive microbiological cultures. Coagulase negative staphylococci (CoNS) were isolated in all cases. Sputum samples could be obtained in 27 patients. None grew CoNS after 7 days of aerosolized therapy. Gram-negative non-fermenting bacilli were isolated in three patients without concomitant grown in nebulizer cups. CONCLUSIONS: We did not find any nosocomial infection related to aerosolize medications in COPD patients admitted for acute exacerbation. PMID- 26033001 TI - [New methodological advances: algorithm proposal for management of Clostridium difficile infection]. AB - INTRODUCTION: Clostridium difficile infection (CDI) is considered the most common cause of health care-associated diarrhea and also is an etiologic agent of community diarrhea. The aim of this study was to assess the potential benefit of a test that detects glutamate dehydrogenase (GDH) antigen and C. difficile toxin A/B, simultaneously, followed by detection of C. difficile toxin B (tcdB) gene by PCR as confirmatory assay on discrepant samples, and to propose an algorithm more efficient. MATERIAL AND METHODS: From June 2012 to January 2013 at Hospital Infantil Universitario Nino Jesus, Madrid, the stool samples were studied for the simultaneous detection of GDH and toxin A/B, and also for detection of toxin A/B alone. When results between GDH and toxin A/B were discordant, a single sample for patient was selected for detection of C. difficile toxin B (tcdB) gene. RESULTS: A total of 116 samples (52 patients) were tested. Four were positive and 75 negative for toxigenic C. difficile (Toxin A/B, alone or combined with GDH). C. difficile was detected in the remaining 37 samples but not toxin A/B, regardless of the method used, except one. Twenty of the 37 specimens were further tested for C. difficile toxin B (tcdB) gene and 7 were positive. DISCUSSION: The simultaneous detection of GDH and toxin A/B combined with PCR recovered undiagnosed cases of CDI. In accordance with our data, we propose a two step algorithm: detection of GDH and PCR (in samples GDH positive). This algorithm could provide a superior cost-benefit ratio in our population. PMID- 26033002 TI - [Isolated iliac aneurysm and positive FTA-Abs test]. PMID- 26033003 TI - [Peritonitis due to Salmonella serovar Albany in a patient on continuous ambulatory peritoneal dialysis]. PMID- 26033004 TI - [Comment on "The need to implement biomarker strategies to optimize the start and duration of antibiotic treatment"]. PMID- 26033005 TI - [Pharmaceutical intervention in duration of antimicrobial treatment at hospital ambit--Author's response]. PMID- 26033006 TI - [Comment on "Evolution of the serotype coverage for the current anti-pneumococcal vaccines"]. PMID- 26033007 TI - Sheath-shunt technique for avoiding lower limb ischemia during complex endovascular aneurysm repair. AB - Complex aortic aneurysms are now being repaired by endovascular techniques, albeit with a potentially increased risk of lower limb ischemia-reperfusion injury. We report a simple technique to maintain perfusion to the lower limb during endovascular repair, using one additional introducer sheath placed antegrade, distal to the stent graft introduction site, and connected to the side arm of the working sheath in the contralateral artery. This allows continuous perfusion of the limb distal to the main stent graft introduction site. In our initial experience with 12 cases, with confirmed occlusion of the native arterial system by the stent graft introducer sheath, arterial occlusion time was 165 +/- 84 minutes. Use of the sheath-shunt technique resulted in pulsatile flow in all cases, with an average flow of 42.2 +/- 13.2 mL/min, and actual ischemia time was reduced to 14 +/- 11 minutes. There were no complications related to the use of this technique. Given the limited risk of this technique coupled with a potential benefit, we propose its consideration in patients undergoing complex endovascular repair. PMID- 26033008 TI - The Society for Vascular Surgery's objective performance goals for lower extremity revascularization are not generalizable to many open surgical bypass patients encountered in contemporary surgical practice. AB - OBJECTIVE: In 2009, the Society for Vascular Surgery (SVS) established objective performance goals (OPG) for lower extremity bypass (LEB) in patients with critical limb ischemia (CLI) based on pooled data from previously performed prospective studies in an effort to provide a benchmark and historical control for future trials. However, patients with a prosthetic conduit and end-stage renal disease were excluded from this cohort. In contemporary practice, many patients do not meet the criteria for SVS OPG inclusion, making generalization of the SVS OPG difficult. The goal of this study was to establish safety and efficacy measures for patients who were excluded from the original SVS OPG analysis. METHODS: All patients who underwent LEB for CLI in the Vascular Study Group of New England (VSGNE) from 2003 to 2013 were identified. Patients were stratified into OPG-eligible and non-OPG-eligible cohorts. Outcomes included 30 day major adverse limb events, 30-day major adverse cardiovascular events, 1-year survival, and 1-year freedom from amputation. The SVS OPG methodology was used to create new performance goals for the non-OPG-eligible patients. RESULTS: We identified 3609 patients: 2360 OPG (65%) vs 1249 non-OPG (35%), and overall results were stratified as a function of OPG status. The 30-day major adverse limb event rate was 5.0% (5.5% non-OPG vs 4.4% OPG; P = .34), and the 30-day major adverse cardiovascular event rate was 7.3% (9.2% non-OPG vs 6.2% OPG; P = .001). At 1 year, survival was 84% (75.9% non-OPG vs 88.3% OPG; P < .001), and freedom from amputation was 86.9% (80.9% non-OPG vs 90.1% OPG; P < .001). CONCLUSIONS: The SVS OPG were attainable in New England for the population of patients who would have met SVS OPG study cohort inclusion criteria. However, 35% of the patients who underwent LEB for CLI in the last 10 years fell outside of these criteria by having end-stage renal disease or requiring a prosthetic conduit. We therefore suggest new benchmarks for these high-risk populations. PMID- 26033009 TI - Discussion. PMID- 26033010 TI - A patient with multiple paradoxical emboli. AB - We present a case report of simultaneous pulmonary emboli and paradoxical embolism to the cerebellum causing a stroke and severe ischemia to the left leg. This patient had risk factors for thromboembolic events that included autoimmune disease, cancer, and recent pelvic surgery. The presence of a perforate foramen ovale was suspected on his initial presentation and confirmed with echocardiography. For acute leg ischemia, this patient underwent emergent left common femoral embolectomy. The potential benefit of immediate anticoagulation had to be weighed against the risk of hemorrhagic transformation of his cerebellar stroke with possible compression of the fourth ventricle. In the end, full anticoagulation was delayed with interval placement of a retrievable inferior vena cava filter. This case illustrates the challenges faced in treating a patient with multiple paradoxical emboli. PMID- 26033011 TI - Poststent ballooning is associated with increased periprocedural stroke and death rate in carotid artery stenting. AB - BACKGROUND: Whereas carotid endarterectomy (CEA) remains the "gold standard" treatment, given its low complication rate, carotid artery stenting (CAS) has emerged as a valid alternative in patients with prohibitive surgical risks. However, the application of CAS has been scrutinized, given its increased perioperative risk in comparison to CEA. Operators follow general guidelines in intraoperative techniques in CAS. However, few of those are evidence based. We believe that a specific outcome-driven examination of the effect of pre- and poststent deployment ballooning is warranted. The objective of this study was to analyze the effect of prestent ballooning (pre-SB) and poststent ballooning (post SB) on hemodynamic depression (HD) and perioperative stroke or death. METHODS: We performed a retrospective analysis of all patients who had CAS between 2005 and 2014 in the Vascular Quality Initiative database. Logistic regression analyses of the effect of different pre-SB and post-SB combinations on HD and the 30-day stroke and death rate were performed. We excluded patients who had no protection device, those with isolated common carotid artery lesions, and those who had no ballooning at all. The models controlled for patient age, gender, comorbidities, smoking status, symptomatic status, history of previous ipsilateral CEA, preoperative medications, and ipsilateral degree of stenosis. RESULTS: A total of 3772 patients who underwent CAS were included for analysis. Average age of patients was 69.8 +/- 9.6 years, with 63% being male. The overall perioperative stroke and death rate was 3.0%. Compared with pre-SB only technique, the combined pre-SB and post-SB technique had a 2.1-fold increase in HD (odds ratio, 2.13; 95% confidence interval, 1.51-3.01; P < .001) and 2.4-fold increase in perioperative stroke and death rate (odds ratio, 2.37; 95% confidence interval, 1.01-5.62; P < .050). CONCLUSIONS: Compared with pre-SB alone, the use of post-SB increases the chances of perioperative HD and stroke and death rate in patients undergoing CAS. Post-SB should be used only in those cases with severe residual stenosis. PMID- 26033012 TI - Hyperbaric oxygen for patients with above-knee amputations, persistent ischemia, and nonreconstructable vascular disease. AB - We describe four patients with above-knee amputations whose stump wounds failed to heal. After numerous revascularization attempts, these patients were diagnosed with nonreconstructable pelvic and groin vascular disease and were facing hip disarticulation. With the addition of hyperbaric oxygen treatment to vigilant wound care and negative pressure therapy, these patients healed their amputation stumps and were fit with prostheses. At their most recent follow-up, all patients were ambulating and using their prostheses. PMID- 26033013 TI - Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis. AB - Extracellular Ca(2+) influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca(2+) entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague-Dawley rats. Our data demonstrated that ethanol (0-400mM) dose-dependently increased hepatocyte injury and 100mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca(2+) overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. PMID- 26033014 TI - Cancer incidence and metolachlor use in the Agricultural Health Study: An update. AB - Metolachlor, a widely used herbicide, is classified as a Group C carcinogen by the U.S. Environmental Protection Agency based on increased liver neoplasms in female rats. Epidemiologic studies of the health effects of metolachlor have been limited. The Agricultural Health Study (AHS) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993-1997. We evaluated cancer incidence through 2010/2011 (NC/IA) for 49,616 applicators, 53% of whom reported ever using metolachlor. We used Poisson regression to evaluate relations between two metrics of metolachlor use (lifetime days, intensity-weighted lifetime days) and cancer incidence. We saw no association between metolachlor use and incidence of all cancers combined (n = 5,701 with a 5-year lag) or most site-specific cancers. For liver cancer, in analyses restricted to exposed workers, elevations observed at higher categories of use were not statistically significant. However, trends for both lifetime and intensity-weighted lifetime days of metolachor use were positive and statistically significant with an unexposed reference group. A similar pattern was observed for follicular cell lymphoma, but no other lymphoma subtypes. An earlier suggestion of increased lung cancer risk at high levels of metolachlor use in this cohort was not confirmed in this update. This suggestion of an association between metolachlor and liver cancer among pesticide applicators is a novel finding and echoes observation of increased liver neoplasms in some animal studies. However, our findings for both liver cancer and follicular cell lymphoma warrant follow-up to better differentiate effects of metolachlor use from other factors. PMID- 26033015 TI - When Siberia came to the Netherlands: the response of continental black-tailed godwits to a rare spring weather event. AB - 1. Extreme weather events have the potential to alter both short- and long-term population dynamics as well as community- and ecosystem-level function. Such events are rare and stochastic, making it difficult to fully document how organisms respond to them and predict the repercussions of similar events in the future. 2. To improve our understanding of the mechanisms by which short-term events can incur long-term consequences, we documented the behavioural responses and fitness consequences for a long-distance migratory bird, the continental black-tailed godwit Limosa limosa limosa, resulting from a spring snowstorm and three-week period of record low temperatures. 3. The event caused measurable responses at three spatial scales - continental, regional and local - including migratory delays (+19 days), reverse migrations (>90 km), elevated metabolic costs (+8.8% maintenance metabolic rate) and increased foraging rates (+37%). 4. There were few long-term fitness consequences, however, and subsequent breeding seasons instead witnessed high levels of reproductive success and little evidence of carry-over effects. 5. This suggests that populations with continued access to food, behavioural flexibility and time to dissipate the costs of the event can likely withstand the consequences of an extreme weather event. For populations constrained in one of these respects, though, extreme events may entail extreme ecological consequences. PMID- 26033016 TI - Phylogenetic Analysis of Severe Fever with Thrombocytopenia Syndrome Virus in South Korea and Migratory Bird Routes Between China, South Korea, and Japan. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease. The SFTS virus (SFTSV) has been detected in the Haemaphysalis longicornis, which acts as a transmission host between animals and humans. SFTSV was first confirmed in China in 2009 and has also been circulating in Japan and South Korea. However, it is not known if a genetic connection exists between the viruses in these regions and, if so, how SFTSV is transmitted across China, South Korea, and Japan. We therefore hypothesize that the SFTSV in South Korea share common phylogenetic origins with samples from China and Japan. Further, we postulate that migratory birds, well-known carriers of the tick H. longicornis, are a potential source of SFTSV transmission across countries. Our phylogenetic analysis results show that the SFTSV isolates in South Korea were similar to isolates from Japan and China. We connect this with previous work showing that SFTSV-infected H. longicornis were found in China, South Korea, and Japan. In addition, H. longicornis were found on migratory birds. The migratory bird routes and the distribution of H. longicornis are concurrent with the occurrence of SFTSV. Therefore, we suggest that migratory birds play an important role in dispersing H. longicornis-borne SFTSV. PMID- 26033017 TI - Prevalence and Risk Factors for Blastocystis Infection Among Children and Caregivers in a Child Care Center, Bangkok, Thailand. AB - In September 2009, a cross-sectional study was conducted to evaluate parasitic infections in a child care center in Khlong Toei, Bangkok, Thailand. Of 503 children and staff members, 258 (51.3%) stool samples and questionnaires were obtained. The most common parasitic infection was Blastocystis sp. (13.6%). Blastocystis sp. subtype 3 was predominantly found (80.0%), followed by subtypes 2 (12.0%) and 1 (8.0%). The prevalence of Blastocystis infection varied among different age groups. The prevalence of Blastocystis infection in non-HIV infected children aged < 10 and 10-19 years were 14.5% and 10.3%, respectively, which were not significantly different. All 31 HIV-infected children were not infected with Blastocystis sp. The most likely reason could be the result of properly using prevention measures for this specific group. PMID- 26033018 TI - The Influence of Episode Severity on Caregiver Recall, Care-seeking, and Treatment of Diarrhea Among Children 2-59 Months of Age in Bihar, Gujarat, and Uttar Pradesh, India. AB - Increased diarrheal episode severity has been linked to better 2-week recall and improved care-seeking and treatment among caregivers of children under five. Using cross-sectional data from three Indian states, we sought to assess the relationship between episode severity and the recall, care-seeking, and treatment of childhood diarrhea. Recall error was higher for episodes with onset 8-14 days (31.2%) versus 1-7 days (4.8%) before the survey, and logistic regression analysis showed a trend toward increased severity of less recent compared with more recent episodes. This finding indicates that data collection with 2-week recall underestimates diarrhea prevalence while overestimating the proportion of severe episodes. There was a strong correlation between care-seeking and dehydration, fever, vomiting, and increased stool frequency and duration. Treatment with oral rehydration salts was associated with dehydration, vomiting, and higher stool frequency, and trends were established between therapeutic zinc supplementation and increased duration and stool frequency. However, state and care-seeking sector were stronger determinants of treatment than episode severity, illustrating the need to address disparities in treatment quality across regions and delivery channels. Our findings are of importance to researchers and diarrhea management program evaluators aiming to produce accurate estimates of diarrheal outcomes and program impact in low- and middle-income countries. PMID- 26033019 TI - Multinational Disease Surveillance Programs: Promoting Global Information Exchange for Infectious Diseases. AB - Cross-border surveillance for emerging diseases such as Ebola and other infectious diseases requires effective international collaboration. We surveyed representatives from 12 multinational disease surveillance programs between January 2013 and April 2014. Our survey identified programmatic similarities despite variation in health priorities, geography, and socioeconomic context, providing a contemporary perspective on infectious disease surveillance networks. PMID- 26033020 TI - Medical and Indirect Costs Associated with a Rocky Mountain Spotted Fever Epidemic in Arizona, 2002-2011. AB - Rocky Mountain spotted fever (RMSF) is an emerging public health issue on some American Indian reservations in Arizona. RMSF causes an acute febrile illness that, if untreated, can cause severe illness, permanent sequelae requiring lifelong medical support, and death. We describe costs associated with medical care, loss of productivity, and death among cases of RMSF on two American Indian reservations (estimated population 20,000) between 2002 and 2011. Acute medical costs totaled more than $1.3 million. This study further estimated $181,100 in acute productivity lost due to illness, and $11.6 million in lifetime productivity lost from premature death. Aggregate costs of RMSF cases in Arizona 2002-2011 amounted to $13.2 million. We believe this to be a significant underestimate of the cost of the epidemic, but it underlines the severity of the disease and need for a more comprehensive study. PMID- 26033021 TI - An Unusual Cause of a Breast Mass in a Patient from China. AB - Sparganosis is a parasitic infection caused by Spirometra spp. and often presents as a subcutaneous swelling, most commonly noticed in the abdominal wall or extremities. Amphibians such as frogs ingest infected copepods (crustaceans that have ingested coracidia, i.e., Spirometra spp. embryos) and serve as a secondary intermediate host. Complete surgical excision is recommended for definitive diagnosis and treatment. Granulomatous inflammation is the most common histologic finding. Although dissemination can occur, most cases are localized. Serum enzyme linked immunosorbent assay (ELISA) has been suggested as a potential surveillance tool. Medical therapy with antiparasitic agents, such as praziquantel, is not typically recommended but may be effective at high doses. Preventing recurrence thus depends on adequate surgical removal of the parasite. We report a case of a breast mass caused by sparganosis infection in a Chinese female whose likely exposure was due to frog consumption. The diagnosis was confirmed on surgical excision and no systemic antiparasitic therapy was required. PMID- 26033022 TI - Jamestown Canyon Virus Disease in the United States-2000-2013. AB - Jamestown Canyon virus (JCV) is a mosquito-borne orthobunyavirus in the California serogroup that can cause an acute febrile illness, meningitis, or meningoencephalitis. We describe epidemiologic and clinical features for JCV disease cases occurring in the United States during 2000-2013. A case of JCV disease was defined as an acute illness in a person with laboratory evidence of a recent JCV infection. During 2000-2013, we identified 31 cases of JCV disease in residents of 13 states. The median age was 48 years (range, 10-69) and 21 (68%) were male. Eleven (35%) case patients had meningoencephalitis, 6 (19%) meningitis, 7 (23%) fever without neurologic involvement, and 7 (23%) had an unknown clinical syndrome. Fifteen (48%) were hospitalized and there were no deaths. Health-care providers and public health officials should consider JCV disease in the differential diagnoses of viral meningitis and encephalitis, obtain appropriate specimens for testing, and report cases to public health authorities. PMID- 26033023 TI - A Case of Diabetic Ketoacidosis Following Chikungunya Virus Infection. AB - Chikungunya is a mosquito-borne viral disease that has recently become endemic in the Caribbean, including the island of Puerto Rico. We present the case of a 50 year-old Puerto Rican man who traveled to St. Louis for business and was diagnosed with acute chikungunya virus infection with atypical features causing diabetic ketoacidosis. This case highlights the need to keep tropical infectious diseases on the differential diagnosis in appropriate individuals and the ways in which tropical infectious diseases can masquerade as part of common presentations. PMID- 26033024 TI - Molecular Detection of Leptospira in Two Returned Travelers: Higher Bacterial Load in Cerebrospinal Fluid Versus Serum or Plasma. AB - Leptospirosis is a potentially severe illness in returned travelers. Patients often present with fever, headache, and neck pain, which may lead to a workup for meningitis including the acquisition of cerebrospinal fluid (CSF). Although Leptospira DNA has been detected in CSF by polymerase chain reaction (PCR), little data exist regarding the utility of testing CSF in addition to serum or plasma obtained on presentation. In this report, we present two cases of leptospirosis in returned travelers presenting with fever and headache. Our first patient had neutrophilic meningitis, and Leptospira was detectable only in CSF obtained on admission. The second patient had a normal CSF profile, but Leptospira was detected in CSF at a bacterial load 5- to 10-fold higher than that in plasma. CSF is an important specimen for the diagnosis of Leptospira by molecular methods and may yield an actionable diagnosis in the absence of leptospiremia. PMID- 26033025 TI - When Potentially Lifesaving Drugs are Both Experimental and in Very Short Supply: A Clinician's Story from the Front Lines of the Battle Against Ebola. PMID- 26033026 TI - Production of Toxocara cati TES-120 Recombinant Antigen and Comparison with its T. canis Homolog for Serodiagnosis of Toxocariasis. AB - Toxocariasis is a cosmopolitan zoonotic disease caused by the infective larvae of Toxocara canis and T. cati. Diagnosis in humans is usually based on clinical symptoms and serology. Immunoglobulin G (IgG)-enzyme-linked immunosorbent assay kits using T. canis excretory-secretory (TES) larval antigens are commonly used for serodiagnosis. Differences in the antigens of the two Toxocara species may influence the diagnostic sensitivity of the test. In this study, T. cati recombinant TES-120 (rTES-120) was cloned, expressed, and compared with its T. canis homolog in an IgG4-western blot. The diagnostic sensitivity and specificity of T. cati rTES-120 were 70% (33/47) and 100% (39/39), respectively. T. canis rTES-120 showed 57.4% sensitivity and 94.4% specificity. When the results of assays using rTES-120 of both species were considered, the diagnostic sensitivity was 76%. This study shows that using antigens from both Toxocara species may improve the serodiagnosis of toxocariasis. PMID- 26033027 TI - The Impact of Six Annual Rounds of Mass Drug Administration on Wuchereria bancrofti Infections in Humans and in Mosquitoes in Mali. AB - Wuchereria bancrofti prevalence and transmission were assessed in six endemic villages in Sikasso, Mali prior to and yearly during mass drug administration (MDA) with albendazole and ivermectin from 2002 to 2007. Microfilaremia was determined by calibrated thick smear of night blood in adult volunteers and circulating filarial antigen was measured using immunochromatographic card test in children < 5 years of age. Mosquitoes were collected by human landing catch from July to December. None of the 686 subjects tested were microfilaremic 12 months after the sixth MDA round. More importantly, circulating antigen was not detected in any of the 120 children tested, as compared with 53% (103/194) before the institution of MDA. The number of infective bites/human/year decreased from 4.8 in 2002 to 0.04 in 2007, and only one mosquito containing a single infective larva was observed 12 months after the final MDA round. Whether this dramatic reduction in transmission will be sustained following cessation of MDA remains to be seen. PMID- 26033028 TI - Dengue Fever Among Renal Transplant Recipients: A Series of 10 Cases in a Tropical Country. AB - This is a case series of 10 consecutive renal allograft recipients, followed at a tertiary hospital in northeast Brazil, with a confirmed diagnosis of dengue. Five of the patients needed hospitalization. Half of them were males and age ranged from 19 to 60 years with a median of 38.2 years. They had been transplanted for a mean of 5 days to 166 months. Four patients developed dengue hemorrhagic fever (DHF). All patients had myalgia and headache. All of them, except one, had fever. Positive dengue serology (IgM) was found in all patients. No patient died. Dengue is an important infectious disease that can affect renal transplant recipients, mainly in endemic areas. Its presentation seems to be similar to that seen in immunocompetent patients. PMID- 26033029 TI - Evaluation of efficacy of prion reduction filters using blood from an endogenously infected 263K scrapie hamster model. AB - BACKGROUND: The P-Capt prion reduction filter (MacoPharma) removes prion infectivity in model systems. This independent evaluation assesses prion removal from endogenously infected animal blood, using CE-marked P-Capt filters, and replicates the proposed use of the filter within the UK Blood Services. STUDY DESIGN AND METHODS: Two units of blood, generated from 263K scrapie-infected hamsters, were processed using leukoreduction filters (LXT-quadruple, MacoPharma). Approximately 100 mL of the removed plasma was added back to the red blood cells (RBCs) and the blood was filtered through a P-Capt filter. Samples of unfiltered whole blood, the prion filter input (RBCs plus plasma and SAGM [RBCPS]), and prion-filtered leukoreduced blood (PFB) were injected intracranially into hamsters. Clinical symptoms were monitored for 500 +/- 1 day, and brains were assessed for spongiosis and prion protein deposit. RESULTS: In Filtration Run 1, none of the 50 challenged animals were diagnosed with scrapie after inoculation with the RBCPS fraction, while two of 190 hamsters injected with PFB were infected. In Filtration Run 2, one of 49 animals injected with RBCPS and two of 193 hamsters injected with PFB were infected. Run 1 reduced the infectious dose (ID) by 1.467 log (>1.187 log and <0.280 log for leukoreduction and prion filtration, respectively). Run 2 reduced prion infectivity by 1.424 log (1.127 and 0.297 log, respectively). Residual infectivity was estimated at 0.212 +/- 0.149 IDs/mL (Run 1) and 0.208 +/- 0.147 IDs/mL (Run 2). CONCLUSION: Leukoreduction removed the majority of infectivity from 263K scrapie hamster blood. The P-Capt filter removed a proportion of the remaining infectivity, but residual infectivity was observed in two independent processes. PMID- 26033030 TI - Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization. AB - Iron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron(III) binding of paired combinations of the licensed iron chelators desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) suggest conditions under which chelators can combine as 'shuttle' and 'sink' molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine-based detection system for intracellular iron removal from the human hepatocyte cell line (HuH-7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a half-maximum effect can be reduced by 3.8-fold when only 1 MUmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron-chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second 'sink' chelator. PMID- 26033032 TI - Regulation of orexigenic AgRP neurons: A third way? AB - Arcuate AgRP neurons are critical for food intake. Two pathways leading to AgRP neuron activation and food intake include regulation by peripheral hormones leptin and ghrelin, and neuronal regulation via glutamatergic inputs. In a recent article in Cell Reports, Yang et al. demonstrate 'a third way,' regulation by resident astrocytes. PMID- 26033031 TI - Upregulated PFTK1 promotes tumor cell proliferation, migration, and invasion in breast cancer. AB - PFTK1 was a cell division cycle 2-related serine/threonine protein kinase, which was up-regulated in breast cancer tissues and breast cancer lines. And up regulated PFTK1 was highly associated with grade, axillary lymph node status, and Ki-67. Moreover, Kaplan-Meier curve showed that up-regulated PFTK1 was related to the poor breast carcinoma patients' overall survival. Here, we first discovered and confirmed that cyclin B was a new interacting protein of PFTK1, and the complex might increase the amount of DVL2, which triggers Wnt/beta-catenin signaling pathway. Furthermore, knockdown of PFTK1 attenuated cell proliferation, anchorage-independent cell growth, and cell migration and invasion by inhibiting the transcriptional activation of beta-catenin for cyclin D1, MMP9, and HEF1, whereas exogenous expression of PFTK1 might promote MDA-MB-231 cells proliferation, migration, and invasion via promoting PFTK1-DVL2-beta-catenin axis. Our findings supported the notion that up-regulated PFTK1 might promote breast cancer progression and metastasis by activating Wnt signaling pathway through the PFTK1-DVL2-beta-catenin axis. PMID- 26033033 TI - C-Cell Neoplasia in Asymptomatic Carriers of RET Mutation in Extracellular Cysteine-Rich and Intracellular Tyrosine Kinase Domain. AB - Germline mutations in RET proto-oncogene associated with multiple endocrine neoplasia type 2 (MEN2) may affect codons for the extracellular cysteine-rich (ECR) or the intracellular tyrosine kinase (ITK) domain of the transmembrane receptor tyrosine kinase protein. We compared C-cell pathology in asymptomatic carriers of RET mutation affecting the 2 domains. Twenty-two asymptomatic carriers (median age, 9.5 years), 10 with mutations in the ECR (codons 634, 611, 618, and 620) and 12 with mutations in the ITK domain (codons 804, 790, 891, and 918), underwent total thyroidectomy. C-cell hyperplasia was identified in 16 (73%), was multifocal and/or bilateral in 11, and was associated with medullary thyroid carcinoma (MTC) in 10 thyroids. When comparing the ECR and ITK groups in 21 carriers from MEN2A/familial MTC families, C-cell hyperplasia was more frequent in the former (90% versus 55%), as was multifocality (70% versus 27%) and MTC (60% versus 27%), despite the significantly younger median age in the former group (5 versus 23 years, P = .04). One asymptomatic carrier had de novo codon 918 mutation (MEN2B) and showed bilateral microcarcinoma with lymph node metastasis at presentation and progressive disease on follow-up. In conclusion, asymptomatic carriers of high-risk RET mutations affecting the ECR were significantly younger and frequently showed C-cell neoplasia, multifocality, and MTC when compared with mutations affecting the ITK domain in the MEN2A/familial MTC families. The presence of C-cell disease, its severity, and aggressiveness correlated with the mutated codon and with increasing age. PMID- 26033035 TI - Regioselective Nucleophilic Functionalization of Antiaromatic Nickel(II) Norcorroles. AB - Treatment of antiaromatic nickel(II) norcorrole with potassium cyanide provided nickel(II) 3-cyanonorcorrole with perfect regioselectivity without the help of a catalyst. The reaction of the nickel(II) norcorrole with phenol or thiophenol in the presence of a base also yielded substitution products. The antiaromatic 16pi conjugation system in the norcorrole core was preserved in the functionalized products. Introduction of phenylthio groups significantly decreased the HOMO-LUMO gap and enhanced the near IR absorption property. PMID- 26033034 TI - Hybrid Calcium Phosphate-Polymeric Micelles Incorporating Gadolinium Chelates for Imaging-Guided Gadolinium Neutron Capture Tumor Therapy. AB - Gadolinium (Gd) chelates-loaded nanocarriers have high potential for achieving magnetic resonance imaging (MRI)-guided Gd neutron capture therapy (GdNCT) of tumors. Herein, we developed calcium phosphate micelles hybridized with PEG polyanion block copolymers, and incorporated with the clinical MRI contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA/CaP). The Gd-DTPA/CaP were nontoxic to cancer cells at the concentration of 100 MUM based on Gd-DTPA, while over 50% of the cancer cells were killed by thermal neutron irradiation at this concentration. Moreover, the Gd-DTPA/CaP showed a dramatically increased accumulation of Gd-DTPA in tumors, leading to the selective contrast enhancement of tumor tissues for precise tumor location by MRI. The enhanced tumor-to-blood distribution ratio of Gd-DTPA/CaP resulted in the effective suppression of tumor growth without loss of body weight, indicating the potential of Gd-DTPA/CaP for safe cancer treatment. PMID- 26033036 TI - How Does a Patient's Primary Renal Disease Impact Chronic Dialysis Management?: Diseases With a High Risk of Extrarenal Complications. PMID- 26033037 TI - B-cell non-Hodgkin lymphoma and pseudo-Gaucher cells in a lymph node fine needle aspiration. PMID- 26033039 TI - The role of magnetic-electric coupling in exciton-coupled ECD spectra: the case of bis-phenanthrenes. AB - Apparent exceptions to the exciton chirality method may arise for chromophores undergoing transitions which are both electric- and magnetic-dipole allowed, for example bis-phenanthrenes. We present a computational approach to calculate exciton-coupled CD spectra based on a quantum-mechanical description of the excitonic parameters, which also includes the solvent effects. PMID- 26033038 TI - Cyst Gastrostomy and Necrosectomy for the Management of Sterile Walled-Off Pancreatic Necrosis: a Comparison of Minimally Invasive Surgical and Endoscopic Outcomes at a High-Volume Pancreatic Center. AB - INTRODUCTION: Walled-off pancreatic necrosis (WON) is a sequela of acute necrotizing pancreatitis in 15-40% of cases. We sought to compare the outcomes of minimally invasive surgical and endoscopic cyst gastrostomy (CG) and necrosectomy for the management for sterile WON at a tertiary care high-volume pancreas center. METHOD: This is a retrospective review of patients who underwent minimally invasive surgical or endoscopic CG and necrosectomy for clinically sterile WON between 2008 and 2013. Peri-procedural outcomes including costs were analyzed and compared. RESULTS: Twenty patients underwent minimally invasive surgical (robotic = 14, laparoscopic = 6) CG and necrosectomy, and 20 patients underwent endoscopic treatment. The surgical cohort had a larger median cyst size and higher CCI score. For the surgical cohort, median OR time was 167.5 min, estimated blood loss was 30 ml, and 65% underwent concomitant cholecystectomy. There was no mortality in either group and no difference in complication rates (20%). The failure rate was similar (15 versus 10%, P = 0.66). Although surgery was associated with a lower re-intervention rate (0 versus 1, P = 0.008), the endotherapy group was associated with shorter total LOS (inclusive of re interventions) (7 versus 3 days, P = 0.032). The cost of the index procedure was significantly higher for the surgery group (P = 0.014); however, when considering all readmissions and re-interventions until resolution of the WON, the total cost was similar for both groups. CONCLUSION: Minimally invasive surgical and endoscopic CG and necrosectomy are comparable treatments for sterile WON in terms of outcomes and overall cost. The surgical approach may be considered advantageous when a concomitant cholecystectomy is required. PMID- 26033040 TI - Reply to "Association of Serum Uric Acid Concentration With Metabolic Risk Factors in Patients With Type 2 Diabetes". PMID- 26033041 TI - High frequency of SLC22A12 variants causing renal hypouricemia 1 in the Czech and Slovak Roma population; simple and rapid detection method by allele-specific polymerase chain reaction. AB - Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245_1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245_1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245_1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245_1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations. PMID- 26033042 TI - Colon perforation related to percutaneous nephrolithotomy: from diagnosis to treatment. AB - We present our experience with the largest series of colon perforation (CP) as complication of percutaneous nephrolithotomy (PNL). From January 1998 to August 2014, 22 cases that presented with PNL-related CP from seven referral centers were retrospectively reviewed. The patients with CP were evaluated in terms of probable risk factors. Peri-operative and postoperative findings, timing of diagnosis, and treatment modalities of the CP were reviewed. Of the 22 patients, previous ipsilateral renal surgery (n:2) and retrorenal colon (n:5) were the risk factors for CP. The CP was directly visualized via nephroscopy during the surgery in 3 (13.6%) and with nephrostography at the end of the procedure in 4 patients (18.2%). In two patients, perforation was realized via the passage of contrast into the colon with nephrostography on the postoperative second day. Postoperative passage of feces through the nephrostomy tube was seen in six patients. The clinical signs in 13 cases directed CP diagnosis. The confirmation of the CP was achieved with a CT scan in all the patients. The patients with extraperitoneal perforation were primarily managed conservatively. Open surgical treatment was performed in cases with intraperitoneal perforation (n:5) and those with extraperitoneal perforation resistant to conservative treatment (n:5). Meticulous evaluation of the risk factors preoperatively is the initial step in the prevention of CP. Timely diagnosis plays essential role in the management of this PNL complication. Although extraperitoneal CP may be managed conservatively, surgery is required for intraperitoneal CPs. PMID- 26033043 TI - Volatile organic compounds generated by cultures of bacteria and viruses associated with respiratory infections. AB - Respiratory infections (RI) can be viral or bacterial in origin. In either case, the invasion of the pathogen results in production and release of various volatile organic compounds (VOCs). The present study examines the VOCs released from cultures of five viruses (influenza A, influenza B, adenovirus, respiratory syncitial virus and parainfluenza 1 virus), three bacteria (Moraxella catarrhalis, Haemophilus influenzae and Legionella pneumophila) and Mycoplasma pneumoniae isolated colonies. Our results demonstrate the involvement of inflammation-induced VOCs. Two significant VOCs were identified as associated with infectious bacterial activity, heptane and methylcyclohexane. These two VOCs have been linked in previous studies to oxidative stress effects. In order to distinguish between bacterial and viral positive cultures, we performed principal component analysis including peak identity (retention time) and VOC concentration (i.e. area under the peak) revealing 1-hexanol and 1-heptadecene to be good predictors. PMID- 26033045 TI - Does Playing Sports Video Games Predict Increased Involvement in Real-Life Sports Over Several Years Among Older Adolescents and Emerging Adults? AB - Given the extreme popularity of video games among older adolescents and emerging adults, the investigation of positive outcomes of video game play during these developmental periods is crucial. An important direction for research in this area is the investigation of a link between sports video game play and involvement in real-life sports among youth. Yet, this association has not been examined in the long-term among older adolescents and emerging adults, and thus represents an exciting new area for discovery. The primary goal of the current study, therefore, was to examine the long-term association between sports video game play and involvement in real-life sports clubs among older adolescents and emerging adults. In addition, we examined whether self-esteem was an underlying mechanism of this longitudinal association. We surveyed older adolescents and emerging adults (N = 1132; 70.6 % female; M age = 19.06 years, range of 17-25 years at the first assessment) annually over 3 years about their video game play, self-esteem, and involvement in real-life sports. We found a long-term predictive effect of sports video game play on increased involvement in real-life sports over the 3 years. Furthermore, we demonstrated that self-esteem was an underlying mechanism of this long-term association. Our findings make an important contribution to an emerging body of literature on the positive outcomes of video game play, as they suggest that sports video game play may be an effective tool to promote real-life sports participation and physical activity among older adolescents and emerging adults. PMID- 26033044 TI - The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients. AB - AIM: Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase beta-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib. METHODS: The influence of rs11623866 (c. 609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel +/- lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis. RESULTS: The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group. CONCLUSIONS: Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response. PMID- 26033046 TI - Performance of an artefact reduction algorithm in the diagnosis of in vitro vertical root fracture in four different root filling conditions on CBCT images. AB - AIM: To evaluate the influence of an artefact reduction algorithm (ARA) and several root filling materials on the detection of root fractures on cone-beam computed tomography (CBCT) images. METHODOLOGY: Forty-four teeth were divided into control and fractured groups and scanned on a Picasso Trio CBCT device under four conditions: unrestored, filled with gutta-percha cones, cast-gold or fibreglass posts; either with or without applying the ARA. Three calibrated examiners assessed the images. ROC analysis, anova and pairwise Tukey LSD test were performed. RESULTS: No significant difference between the groups with and without the ARA was observed. There was no significant interaction between the algorithm and root condition. On the other hand, there was a significant difference in the mean values of sensitivity (Sn) and accuracy (Ac) amongst the different root filling groups (P <= 0.001). CONCLUSIONS: The application of the ARA did not influence the diagnosis of root fractures, and its effects did not depend on root conditions. In relation to the filling materials, gold posts reduced the overall CBCT diagnostic ability, regardless of the use of the ARA. PMID- 26033048 TI - Proximal femoral fractures: the quest to improve outcomes. PMID- 26033047 TI - A Platform to Build Mobile Health Apps: The Personal Health Intervention Toolkit (PHIT). AB - Personal Health Intervention Toolkit (PHIT) is an advanced cross-platform software framework targeted at personal self-help research on mobile devices. Following the subjective and objective measurement, assessment, and plan methodology for health assessment and intervention recommendations, the PHIT platform lets researchers quickly build mobile health research Android and iOS apps. They can (1) create complex data-collection instruments using a simple extensible markup language (XML) schema; (2) use Bluetooth wireless sensors; (3) create targeted self-help interventions based on collected data via XML-coded logic; (4) facilitate cross-study reuse from the library of existing instruments and interventions such as stress, anxiety, sleep quality, and substance abuse; and (5) monitor longitudinal intervention studies via daily upload to a Web-based dashboard portal. For physiological data, Bluetooth sensors collect real-time data with on-device processing. For example, using the BinarHeartSensor, the PHIT platform processes the heart rate data into heart rate variability measures, and plots these data as time-series waveforms. Subjective data instruments are user data-entry screens, comprising a series of forms with validation and processing logic. The PHIT instrument library consists of over 70 reusable instruments for various domains including cognitive, environmental, psychiatric, psychosocial, and substance abuse. Many are standardized instruments, such as the Alcohol Use Disorder Identification Test, Patient Health Questionnaire-8, and Post-Traumatic Stress Disorder Checklist. Autonomous instruments such as battery and global positioning system location support continuous background data collection. All data are acquired using a schedule appropriate to the app's deployment. The PHIT intelligent virtual advisor (iVA) is an expert system logic layer, which analyzes the data in real time on the device. This data analysis results in a tailored app of interventions and other data-collection instruments. For example, if a user anxiety score exceeds a threshold, the iVA might add a meditation intervention to the task list in order to teach the user how to relax, and schedule a reassessment using the anxiety instrument 2 weeks later to re-evaluate. If the anxiety score exceeds a higher threshold, then an advisory to seek professional help would be displayed. Using the easy-to-use PHIT scripting language, the researcher can program new instruments, the iVA, and interventions to their domain-specific needs. The iVA, instruments, and interventions are defined via XML files, which facilities rapid app development and deployment. The PHIT Web based dashboard portal provides the researcher access to all the uploaded data. After a secure login, the data can be filtered by criteria such as study, protocol, domain, and user. Data can also be exported into a comma-delimited file for further processing. The PHIT framework has proven to be an extensible, reconfigurable technology that facilitates mobile data collection and health intervention research. Additional plans include instrument development in other domains, additional health sensors, and a text messaging notification system. PMID- 26033049 TI - Dealing with the predicted increase in demand for revision total knee arthroplasty: challenges, risks and opportunities. AB - Worldwide rates of primary and revision total knee arthroplasty (TKA) are rising due to increased longevity of the population and the burden of osteoarthritis. Revision TKA is a technically demanding procedure generating outcomes which are reported to be inferior to those of primary knee arthroplasty, and with a higher risk of complication. Overall, the rate of revision after primary arthroplasty is low, but the number of patients currently living with a TKA suggests a large potential revision healthcare burden. Many patients are now outliving their prosthesis, and consideration must be given to how we are to provide the necessary capacity to meet the rising demand for revision surgery and how to maximise patient outcomes. The purpose of this review was to examine the epidemiology of, and risk factors for, revision knee arthroplasty, and to discuss factors that may enhance patient outcomes. PMID- 26033050 TI - A review of long-term outcomes for late presenting developmental hip dysplasia. AB - Successful management of late presenting hip dislocation in childhood is judged by the outcome not just at skeletal maturity but well beyond into adulthood and late middle age. This review considers different methods of treatment and looks critically at the handful of studies reporting long-term follow-up after successful reduction. PMID- 26033051 TI - No effect of the infiltration of local anaesthetic for total hip arthroplasty using an anterior approach: a randomised placebo controlled trial. AB - Only limited data are available regarding the infiltration of local anaesthetic for total hip arthroplasty (THA), and no studies were performed for THA using the anterior approach. In this prospective, randomised placebo-controlled study we investigated the effect of both standard and reverse infiltration of local anaesthetic in combination with the anterior approach for THA. The primary endpoint was the mean numeric rating score for pain four hours post-operatively. In addition, we recorded the length of hospital stay, the operating time, the destination of the patient at discharge, the use of pain medication, the occurrence of side effects and pain scores at various times post-operatively. Between November 2012 and January 2014, 75 patients were included in the study. They were randomised into three groups: standard infiltration of local anaesthetic, reversed infiltration of local anaesthetic, and placebo. There was no difference in mean numeric rating score for pain four hours post-operatively (p = 0.87). There were significantly more side effects at one and eight hours post-operatively in the placebo group (p = 0.02; p = 0.03), but this did not influence the mobilisation of the patients. There were no differences in all other outcomes between the groups. We found no clinically relevant effect when the infiltration of local anaesthetic with ropivacaine and epinephrine was used in a multimodal pain protocol for THA using the anterior approach. PMID- 26033052 TI - Increased incidence of femoral fractures in small femurs and women undergoing uncemented total hip arthroplasty - why? AB - The aim of this study was to investigate the relationship between the geometry of the proximal femur and the incidence of intra-operative fracture during uncemented total hip arthroplasty (THA). We studied the pre-operative CT scans of 100 patients undergoing THA with an uncemented femoral component. We measured the anteroposterior and mediolateral dimensions at the level of division of the femoral neck to calculate the aspect ratio of the femur. Wide variations in the shape of the femur were observed, from round, to very narrow elliptic. The femurs of women were narrower than those of men (p < 0.0001) and small femurs were also narrower than large ones. Patients with an intra-operative fracture of the calcar had smaller and narrower femurs than those without a fracture (p < 0.05) and the implanted Corail stems were smaller in those with a fracture (mean size 9 vs 12, p < 0.0001). The variability of the shape of the femoral neck at the level of division contributes to the understanding of the causation of intra-operative fractures in uncemented THA. PMID- 26033053 TI - Hydroxyapatite ceramic-coated femoral components in young patients followed up for 17 to 25 years: an update of a previous report. AB - This study reports the results of 38 total hip arthroplasties (THAs) in 33 patients aged < 50 years, using the JRI Furlong hydroxyapatite ceramic (HAC) coated femoral component. This represents an update of previous reports of the same cohort at ten and 16 years, which were reported in 2004 and 2009, respectively. We describe the survival, radiological and functional outcomes at a mean follow-up of 21 years (17 to 25). Of the surviving 34 THAs, one underwent femoral revision for peri-prosthetic fracture after 21 years, and one patient (one hip) was lost to follow-up. Using aseptic loosening as the end-point, 12 hips (31.5%) needed acetabular revision but none needed femoral revision, demonstrating 100% survival (95% confidence interval 89 to 100). In young patients with high demands, the Furlong HAC-coated femoral component gives excellent long-term results. PMID- 26033054 TI - Triple taper stem design shows promising fixation and bone remodelling characteristics: radiostereometric analysis in a randomised controlled trial. AB - Cemented femoral stems with force closed fixation designs have shown good clinical results despite high early subsidence. A new triple-tapered stem in this category (C-stem AMT) was introduced in 2005. This study compares this new stem with an established stem of similar design (Exeter) in terms of migration (as measured using radiostereometric analysis), peri-prosthetic bone remodelling (measured using dual energy x-ray densitometry, DXA), Oxford Hip Score, and plain radiographs. A total of 70 patients (70 hips) with a mean age of 66 years (53 to 78) were followed for two years. Owing to missing data of miscellaneous reasons, the final analysis represents data from 51 (RSA) and 65 (DXA) patients. Both stems showed a typical pattern of migration: Subsidence and retroversion that primarily occurred during the first three months. C-stem AMT subsided less during the first three months (p = 0.01), before stabilising at a subsidence rate similar to the Exeter stem from years one to two. The rate of migration into retroversion was slightly higher for C-stem AMT during the second year (p = 0.03). Whilst there were slight differences in movement patterns between the stems, the C-stem AMT exhibits good early clinical outcomes and displays a pattern of migration and bone remodelling that predicts good clinical performance. PMID- 26033055 TI - Lifetime cost effectiveness of different brands of prosthesis used for total hip arthroplasty: a study using the NJR dataset. AB - There is little evidence on the cost effectiveness of different brands of hip prostheses. We compared lifetime cost effectiveness of frequently used brands within types of prosthesis including cemented (Exeter V40 Contemporary, Exeter V40 Duration and Exeter V40 Elite Plus Ogee), cementless (Corail Pinnacle, Accolade Trident, and Taperloc Exceed) and hybrid (Exeter V40 Trilogy, Exeter V40 Trident, and CPT Trilogy). We used data from three linked English national databases to estimate the lifetime risk of revision, quality-adjusted life years (QALYs) and cost. For women with osteoarthritis aged 70 years, the Exeter V40 Elite Plus Ogee had the lowest risk of revision (5.9% revision risk, 9.0 QALYs) and the CPT Trilogy had the highest QALYs (10.9% revision risk, 9.3 QALYs). Compared with the Corail Pinnacle (9.3% revision risk, 9.22 QALYs), the most commonly used brand, and assuming a willingness-to-pay of L20,000 per QALY gain, the CPT Trilogy is most cost effective, with an incremental net monetary benefit of L876. Differences in cost effectiveness between the hybrid CPT Trilogy and Exeter V40 Trident and the cementless Corail Pinnacle and Taperloc Exceed were small, and a cautious interpretation is required, given the limitations of the available information. However, it is unlikely that cemented brands are among the most cost effective. Similar patterns of results were observed for men and other ages. The gain in quality of life after total hip arthroplasty, rather than the risk of revision, was the main driver of cost effectiveness. Cite this article: Bone Joint J 2015;97-B:762-70. PMID- 26033056 TI - The outcome of femoral component revision arthroplasty with impaction allograft bone grafting and a cemented polished Exeter stem: A prospective cohort study of 208 revision arthroplasties with a mean follow-up of ten years. AB - We report the clinical and radiographic outcomes of 208 consecutive femoral revision arthroplasties performed in 202 patients (119 women, 83 men) between March 1991 and December 2007 using the X-change Femoral Revision System, fresh frozen morcellised allograft and a cemented polished Exeter stem. All patients were followed prospectively. The mean age of the patients at revision was 65 years (30 to 86). At final review in December 2013 a total of 130 patients with 135 reconstructions (64.9%) were alive and had a non re-revised femoral component after a mean follow-up of 10.6 years (4.7 to 20.9). One patient was lost to follow-up at six years, and their data were included up to this point. Re operation for any reason was performed in 33 hips (15.9%), in 13 of which the femoral component was re-revised (6.3%). The mean pre-operative Harris hip score was 52 (19 to 95) (n = 73) and improved to 80 (22 to 100) (n = 161) by the last follow-up. Kaplan-Meier survival with femoral re-revision for any reason as the endpoint was 94.9% (95% confidence intervals (CI) 90.2 to 97.4) at ten years; with femoral re-revision for aseptic loosening as the endpoint it was 99.4% (95% CI 95.7 to 99.9); with femoral re-operation for any reason as the endpoint it was 84.5% (95% CI 78.3 to 89.1); and with subsidence >= 5 mm it was 87.3% (95% CI 80.5 to 91.8). Femoral revision with the use of impaction allograft bone grafting and a cemented polished stem results in a satisfying survival rate at a mean of ten years' follow-up. PMID- 26033057 TI - The accuracy of positioning of a custom-made implant within a large acetabular defect at revision arthroplasty of the hip. AB - We evaluated the accuracy with which a custom-made acetabular component could be positioned at revision arthroplasty of the hip in patients with a Paprosky type 3 acetabular defect. A total of 16 patients with a Paprosky type 3 defect underwent revision surgery using a custom-made trabecular titanium implant. There were four men and 12 women with a median age of 67 years (48 to 79). The planned inclination (INCL), anteversion (AV), rotation and centre of rotation (COR) of the implant were compared with the post-operative position using CT scans. A total of seven implants were malpositioned in one or more parameters: one with respect to INCL, three with respect to AV, four with respect to rotation and five with respect to the COR. To the best of our knowledge, this is the first study in which CT data acquired for the pre-operative planning of a custom-made revision acetabular implant have been compared with CT data on the post-operative position. The results are encouraging. PMID- 26033058 TI - A randomised trial of all-polyethylene and metal-backed tibial components in unicompartmental arthroplasty of the knee. AB - This randomised trial evaluated the outcome of a single design of unicompartmental arthroplasty of the knee (UKA) with either a cemented all polyethylene or a metal-backed modular tibial component. A total of 63 knees in 45 patients (17 male, 28 female) were included, 27 in the all-polyethylene group and 36 in the metal-backed group. The mean age was 57.9 years (39.6 to 76.9). At a mean follow-up of 6.4 years (5 to 9.9), 11 all-polyethylene components (41%) were revised (at a mean of 5.8 years; 1.4 to 8.0) post-operatively and two metal backed components were revised (at one and five years). One revision in both groups was for unexplained pain, one in the metal-backed group was for progression of osteoarthritis. The others in the all-polyethylene group were for aseptic loosening. The survivorship at seven years calculated by the Kaplan-Meier method for the all-polyethylene group was 56.5% (95% CI 31.9 to 75.2, number at risk 7) and for the metal-backed group was 93.8% (95% CI 77.3 to 98.4, number at risk 16) This difference was statistically significant (p < 0.001). At the most recent follow-up, significantly better mean Western Ontario and McMaster Universities Arthritis Index Scores were found in the all-polyethylene group (13.4 vs 23.0, p = 0.03) but there was no difference in the mean Knee injury and Osteoarthritis Outcome scores (68.8; 41.4 to 99.0 vs 62.6; 24.0 to 100.0), p = 0.36). There were no significant differences for range of movement (p = 0.36) or satisfaction (p = 0.23). This randomised study demonstrates that all-polyethylene components in this design of fixed bearing UKA had unsatisfactory results with significantly higher rates of failure before ten years compared with the metal back components. PMID- 26033059 TI - Patient-reported outcomes after total and unicompartmental knee arthroplasty: a study of 14,076 matched patients from the National Joint Registry for England and Wales. AB - Whether to use total or unicompartmental knee replacement (TKA/UKA) for end-stage knee osteoarthritis remains controversial. Although UKA results in a faster recovery, lower rates of morbidity and mortality and fewer complications, the long-term revision rate is substantially higher than that for TKA. The effect of each intervention on patient-reported outcome remains unclear. The aim of this study was to determine whether six-month patient-reported outcome measures (PROMs) are better in patients after TKA or UKA, using data from a large national joint registry (NJR). We carried out a propensity score-matched cohort study which compared six-month PROMs after TKA and UKA in patients enrolled in the NJR for England and Wales, and the English national PROM collection programme. A total of 3519 UKA patients were matched to 10 557 TKAs. The mean six-month PROMs favoured UKA: the Oxford Knee Score was 37.7 (95% confidence interval (CI) 37.4 to 38.0) for UKA and 36.1 (95% CI 35.9 to 36.3) for TKA; the mean EuroQol EQ-5D index was 0.772 (95% CI 0.764 to 0.780) for UKA and 0.751 (95% CI 0.747 to 0.756) for TKA. UKA patients were more likely to achieve excellent results (odds ratio (OR) 1.59, 95% CI 1.47 to 1.72, p < 0.001) and to be highly satisfied (OR 1.27, 95% CI 1.17 to 1.39, p < 0.001), and were less likely to report complications than those who had undergone TKA. UKA gives better early patient-reported outcomes than TKA; these differences are most marked for the very best outcomes. Complications and readmission are more likely after TKA. Although the data presented reflect the short-term outcome, they suggest that the high revision rate for UKA may not be because of poorer clinical outcomes. These factors should inform decision-making in patients eligible for either procedure. PMID- 26033060 TI - A new form of surgical treatment for patients with avascular necrosis of the talus and secondary osteoarthritis of the ankle. AB - A new method of vascularised tibial grafting has been developed for the treatment of avascular necrosis (AVN) of the talus and secondary osteoarthritis (OA) of the ankle. We used 40 cadavers to identify the vascular anatomy of the distal tibia in order to establish how to elevate a vascularised tibial graft safely. Between 2008 and 2012, eight patients (three male, five female, mean age 50 years; 26 to 68) with isolated AVN of the talus and 12 patients (four male, eight female, mean age 58 years; 23 to 76) with secondary OA underwent vascularised bone grafting from the distal tibia either to revascularise the talus or for arthrodesis. The radiological and clinical outcomes were evaluated at a mean follow-up of 31 months (24 to 62). The peri-malleolar arterial arch was confirmed in the cadaveric study. A vascularised bone graft could be elevated safely using the peri-malleolar pedicle. The clinical outcomes for the group with AVN of the talus assessed with the mean Mazur ankle grading scores, improved significantly from 39 points (21 to 48) pre-operatively to 81 points (73 to 90) at the final follow-up (p = 0.01). In all eight revascularisations, bone healing was obtained without progression to talar collapse, and union was established in 11 of 12 vascularised arthrodeses at a mean follow-up of 34 months (24 to 58). MRI showed revascularisation of the talus in all patients. We conclude that a vascularised tibial graft can be used both for revascularisation of the talus and for the arthrodesis of the ankle in patients with OA secondary to AVN of the talus. PMID- 26033061 TI - The medial column Synthes Midfoot Fusion Bolt is associated with unacceptable rates of failure in corrective fusion for Charcot deformity: Results from a consecutive case series. AB - Charcot neuro-osteoarthropathy (CN) of the midfoot presents a major reconstructive challenge for the foot and ankle surgeon. The Synthes 6 mm Midfoot Fusion Bolt is both designed and recommended for patients who have a deformity of the medial column of the foot due to CN. We present the results from the first nine patients (ten feet) on which we attempted to perform fusion of the medial column using this bolt. Six feet had concurrent hindfoot fusion using a retrograde nail. Satisfactory correction of deformity of the medial column was achieved in all patients. The mean correction of calcaneal pitch was from 6 degrees (-15 degrees to +18 degrees ) pre-operatively to 16 degrees (7 degrees to 23 degrees ) post-operatively; the mean Meary angle from 26 degrees (3 degrees to 46 degrees ) to 1 degrees (1 degrees to 2 degrees ); and the mean talometatarsal angle on dorsoplantar radiographs from 27 degrees (1 degrees to 48 degrees ) to 1 degrees (1 degrees to 3 degrees ). However, in all but two feet, at least one joint failed to fuse. The bolt migrated in six feet, all of which showed progressive radiographic osteolysis, which was considered to indicate loosening. Four of these feet have undergone a revision procedure, with good radiological evidence of fusion. The medial column bolt provided satisfactory correction of the deformity but failed to provide adequate fixation for fusion in CN deformities in the foot. In its present form, we cannot recommend the routine use of this bolt. PMID- 26033062 TI - Management of infected nonunion of the long bones by a multidisciplinary team. AB - Infected nonunion of a long bone continues to present difficulties in management. In addition to treating the infection, it is necessary to establish bony stability, encourage fracture union and reconstruct the soft-tissue envelope. We present a series of 67 infected nonunions of a long bone in 66 patients treated in a multidisciplinary unit. The operative treatment of patients suitable for limb salvage was performed as a single procedure. Antibiotic regimes were determined by the results of microbiological culture. At a mean follow-up of 52 months (22 to 97), 59 patients (88%) had an infection-free united fracture in a functioning limb. Seven others required amputation (three as primary treatment, three after late failure of limb salvage and one for recalcitrant pain after union). The initial operation achieved union in 54 (84%) of the salvaged limbs at a mean of nine months (three to 26), with recurrence of infection in 9%. Further surgery in those limbs that remained ununited increased the union rate to 62 (97%) of the 64 limbs treated by limb salvage at final follow-up. The use of internal fixation was associated with a higher risk of recurrent infection than external fixation. PMID- 26033063 TI - Is it time to revisit the AO classification of fractures of the distal radius? Inter- and intra-observer reliability of the AO classification. AB - We conducted an observational radiographic study to determine the inter- and intra-observer reliability of the AO classification of fractures of the distal radius. Plain posteroanterior and lateral radiographs of 456 patients with an acute fracture of the distal radius were classified by a consultant orthopaedic hand specialist and two specialist trainees, and the k coefficient for the inter- and intra-observer reliability of the type, group and subgroup classification was calculated. Only the type of fracture (A, B or C) was found to provide substantial intra-observer reliability (k type 0.65). The inclusion of 'group' and 'subgroup' into the classification reduced the inter-observer reliability to fair (kgroup 0.29, ksubgroup = 0.28) and the intra-observer reliability to moderate (kgroup 0.53, ksubgroup 0.49). Disagreement was found to arise between specific subgroups, which may be amenable to clarification. PMID- 26033064 TI - Up-regulation of acid-sensing ion channels in the capsule of the joint in frozen shoulder. AB - The purpose of this study was to evaluate the expression of acid-sensing ion channels (ASICs) in the capsule and synovial fluid of patients with frozen shoulder. Capsular tissue and synovial fluid were obtained from 18 patients with idiopathic frozen shoulder (FS group) and 18 patients with instability of the shoulder (control group). The expressions of ASIC1, ASIC2, and ASIC3 in the capsule were determined using the reverse transcriptase-polymerase chain reaction, immunoblot analysis, and immunohistochemistry (IHC). The concentrations in synovial fluid were evaluated using an enzyme-linked immunosorbent assay. The mRNA expression of ASIC1, ASIC2 and ASIC3 in the capsule were significantly increased in the FS group compared with the control group. The protein levels of these three ASICs were also increased. The increased expressions were confirmed by IHC. Of the ASICs, ASIC3 showed the greatest increase in both mRNA and levels of expression compared with the control group. The levels of ASIC1 and ASIC3 in synovial fluid were significantly increased in the FS group. This study suggests that ASICs may play a role as mediators of inflammatory pain and be involved in the pathogenesis of frozen shoulder. PMID- 26033065 TI - Is cross-screw fixation superior to plate for radial neck fractures? AB - This study compares the outcomes of two methods of fixation of displaced fractures of the radial neck. The 58 patients with a mean age of 38.5 years (18 to 56), were treated in a non randomised study with screws (n = 29) or a plate and screws (n = 29) according to the surgeon's preference. The patients were reviewed at one year. Radiographs and functional evaluations were carried out up to one year post-operatively, using the Broberg and Morrey functional evaluation score, range of movement, and assessment of complications. The mean functional scores did not differ significantly between groups (90 (55 to 100) vs 84; 50 to 100, p = 0.09), but the mean range of forearm rotation in screw group was significantly better than in the plate group (152 degrees ; 110 degrees to 170 degrees vs 134 degrees ; 80 degrees to 170 degrees , p = 0.001). Although not statistically significant, the screw group had a lower incidence of heterotopic ossification than the plate group (n = 1) than the plated group (n = 3) and the pathology was graded as less severe. PMID- 26033066 TI - Porous titanium granules are better than autograft bone as a bone void filler in lateral tibial plateau fractures: A randomised trial. AB - A total of 20 patients with a depressed fracture of the lateral tibial plateau (Schatzker II or III) who would undergo open reduction and internal fixation were randomised to have the metaphyseal void in the bone filled with either porous titanium granules or autograft bone. Radiographs were undertaken within one week, after six weeks, three months, six months, and after 12 months. The primary outcome measure was recurrent depression of the joint surface: a secondary outcome was the duration of surgery. The risk of recurrent depression of the joint surface was lower (p < 0.001) and the operating time less (p < 0.002) when titanium granules were used. The indication is that it is therefore beneficial to use porous titanium granules than autograft bone to fill the void created by reducing a depressed fracture of the lateral tibial plateau. There is no donor site morbidity, the operating time is shorter and the risk of recurrent depression of the articular surface is less. PMID- 26033067 TI - The management and outcome of open fractures of the femur sustained on the battlefield over a ten-year period. AB - This is a retrospective study of survivors of recent conflicts with an open fracture of the femur. We analysed the records of 48 patients (48 fractures) and assessed the outcome. The median follow up for 47 patients (98%) was 37 months (interquartile range 19 to 53); 31 (66%) achieved union; 16 (34%) had a revision procedure, two of which were transfemoral amputation (4%). The New Injury Severity Score, the method of fixation, infection and the requirement for soft tissue cover were not associated with a poor outcome. The degree of bone loss was strongly associated with a poor outcome (p = 0.00204). A total of four patients developed an infection; two with S. aureus, one with E. coli and one with A. baumannii. This study shows that, compared with historical experience, outcomes after open fractures of the femur sustained on the battlefield are good, with no mortality and low rates of infection and late amputation. The degree of bone loss is closely associated with a poor outcome. PMID- 26033068 TI - The value of the high-sensitivity modified Glasgow prognostic score in predicting the survival of patients with a soft-tissue sarcoma. AB - The aim of this study was to determine whether the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) could predict the disease-specific survival and oncological outcome in adult patients with non-metastatic soft-tissue sarcoma before treatment. A total of 139 patients treated between 2001 and 2012 were retrospectively reviewed. The Hs-mGPS varied between 0 and 2. Patients with a score of 2 had a poorer disease-specific survival than patients with a score of 0 (p < 0.001). The estimated five-year rate of disease-specific survival for those with a score of 2 was 0%, compared with 85.4% (95% CI 77.3 to 93.5) for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (75.3%, 95% CI 55.8 to 94.8; p < 0.001). Patients with a score of 2 also had a poorer event-free rate than those with a score of 0 (p < 0.001). Those with a score of 2 also had a poorer event-free survival than did those with a score of 1 (p = 0.03). A multivariate analysis showed that the Hs-mGPS remained an independent predictor of survival and recurrence. The Hs-mGPS could be a useful prognostic marker in patients with a soft-tissue sarcoma. PMID- 26033069 TI - The vascularised fibular graft for limb salvage after bone tumour surgery: a multicentre study. AB - Vascularised fibular grafts (VFGs ) are a valuable surgical technique in limb salvage after resection of a tumour. The primary objective of this multicentre study was to assess the risk factors for failure and complications for using a VFG after resection of a tumour. The study involved 74 consecutive patients (45 men and 29 women with mean age of 23 years (1 to 64) from four tertiary centres for orthopaedic oncology who underwent reconstruction using a VFG after resection of a tumour between 1996 and 2011. There were 52 primary and 22 secondary reconstructions. The mean follow-up was 77 months (10 to 195). In all, 69 patients (93%) had successful limb salvage; all of these united and 65 (88%) showed hypertrophy of the graft. The mean time to union differed between those involving the upper (28 weeks; 12 to 96) and lower limbs (44 weeks; 12 to 250). Fracture occurred in 11 (15%), and nonunion in 14 (19%) patients. In 35 patients (47%) at least one complication arose, with a greater proportion in lower limb reconstructions, non-bridging osteosynthesis, and in children. These complications resulted in revision surgery in 26 patients (35%). VFG is a successful and durable technique for reconstruction of a defect in bone after resection of a tumour, but is accompanied by a significant risk of complications, that often require revision surgery. Union was not markedly influenced by the need for chemo- or radiotherapy, but should not be expected during chemotherapy. Therefore, restricted weight-bearing within this period is advocated. PMID- 26033070 TI - Rebound growth after hemiepiphysiodesis: An animal-based experimental study of incidence and chronology. AB - Rebound growth after hemiepiphysiodesis may be a normal event, but little is known about its causes, incidence or factors related to its intensity. The aim of this study was to evaluate rebound growth under controlled experimental conditions. A total of 22 six-week-old rabbits underwent a medial proximal tibial hemiepiphysiodesis using a two-hole plate and screws. Temporal growth plate arrest was maintained for three weeks, and animals were killed at intervals ranging between three days and three weeks after removal of the device. The radiological angulation of the proximal tibia was studied at weekly intervals during and after hemiepiphysiodesis. A histological study of the retrieved proximal physis of the tibia was performed. The mean angulation achieved at three weeks was 34.7 degrees (standard deviation (sd) 3.4), and this remained unchanged for the study period of up to two weeks. By three weeks after removal of the implant the mean angulation had dropped to 28.2 degrees (sd 1.8) (p < 0.001). Histologically, widening of the medial side was noted during the first two weeks. By three weeks this widening had substantially disappeared and the normal columnar structure was virtually re-established. In our rabbit model, rebound was an event of variable incidence and intensity and, when present, did not appear immediately after restoration of growth, but took some time to appear. PMID- 26033071 TI - Combining Botulinum Toxin (A) Injection With Peripheral Nerve Stimulation in a Patient for Intractable Ophthalmic Postherpetic Neuralgia. AB - BACKGROUND: Postherpetic neuralgia (PHN) is a particularly challenging neuropathic pain condition, especially when it involves the trigeminal nerve. Peripheral nerve stimulation (PNS) can provide 50-70% improvement in pain to many who fail medical management. However, this pain relief can be incomplete, and residual pain may persist for many years. Here we report a case that was successfully managed by a novel technique of combining supraorbital nerve stimulation with botulinum toxin type A (BTA) for intractable ophthalmic PHN. CASE: A 73-year-old man presented with burning, stabbing, constant, severe pain in the ophthalmic branch of left trigeminal nerve dermatome, which had been present for a year. A permanent PNS provided 50% pain relief, but there was residual pain in the left orbital area that has remained, which was refractory to pharmaceutical treatment. Because of the restricted location of the residual pain, this patient was an appropriate candidate for BTA injection. RESULTS: Following the BTA injection, the patient had a significant improvement in pain relief and this continued for six months without any oral medication. CONCLUSIONS: In a patient with trigeminal PHN, local injection of BTA effectively reduced pain remaining after treatment with PNS. PMID- 26033072 TI - Positive affect predicts everyday problem-solving ability in older adults. AB - OBJECTIVES: Increased symptom endorsement on the short form of the Centre for Epidemiologic Studies Depression (CES-D) Scale has been previously associated with lower everyday problem-solving (EPS) ability in older adults. However, given the multifactorial and complex nature of depressive symptoms, it remains unclear whether certain symptoms/aspects of depression account for this relationship. We examined established factor scores on the full version of the CES-D to assess their utility as predictors of EPS in an older adult cohort. METHODS: Community dwelling older adults (n = 103; age: 51-91) were administered the CES-D along with a measure of EPS ability assessing both social and practical EPS. Regression analyses were used to determine the relationships between variables. RESULTS: Analyses revealed that increased CES-D scores predicted worse EPS ability in older adults (beta = -.17, p < .05) beyond the effects of age, gender, and education. Regression analyses examining each CES-D factor score revealed that decreased positive affect (loss of hope/enjoyment in life; beta = -.21, p < .01) remained the only significant predictor of decreased overall EPS scores beyond demographic variables, while depressed affect, interpersonal, and somatic factors were not significant predictors. Positive affect predicted both practical, as well as social EPS scores. CONCLUSIONS: Current results extend previous findings by showing that the relationship between increased depressive symptoms and decreased EPS ability in older age may be primarily driven by anhedonia as opposed to other depressive symptoms. PMID- 26033073 TI - Long-term outcomes with first- vs. second-generation drug-eluting stents in saphenous vein graft lesions. AB - BACKGROUND: As compared with bare metal stents, first-generation drug-eluting stents (DES) improved post-procedural outcomes in aortocoronary saphenous vein graft (SVG) lesions, but there is limited information on outcomes after use of second-generation DES in SVGs. METHODS: We compared the outcomes of patients who received first- (n = 81) with those who received second-generation (n = 166) DES in SVG lesions at our institution between 2006 and 2013. Major adverse cardiac events (MACE) were defined as the composite of all-cause death, myocardial infarction, and target vessel revascularization. RESULTS: Mean age was 66.0 +/- 8.1 years and 97.6% of the patients were men. Mean SVG age was 11.1 +/- 0.4 years. First-generation DES were sirolimus-eluting (n = 17) and paclitaxel eluting (n = 64) stents. Second-generation DES were everolimus-eluting (n = 115) and zotarolimus-eluting (n = 51) stents. Median follow-up was 41 months. At 2 years post-procedure, patients with first- and second-generation DES had similar rates of death (20.91% vs. 20.27%, P = 0.916), target lesion revascularization (16.39% vs. 20.00%, P = 0.572), target vessel revascularization (20.97% vs. 23.16%, P = 0.747), myocardial infarction (26.15% vs. 23.00%, P = 0.644), and MACE (43.5% vs. 40.87%, P = 0.707), respectively. CONCLUSIONS: Outcomes with first- and second-generation DES in SVGs are similar. Novel stent designs are needed to further improve the clinical outcomes in this challenging patient and lesion subgroup. (c) 2015 Wiley Periodicals, Inc. PMID- 26033074 TI - Health value & perceived control over health: behavioural constructs to support Type 2 diabetes self-management in clinical practice. AB - AIMS AND OBJECTIVES: To explore health value and perceived control over health in relation to self-management behaviours in adults with Type 2 diabetes mellitus. BACKGROUND: Helping people to modify health related behaviour in diabetes is complex due to a multitude of factors. Exploring the meaning of the constructs of Modified Social Learning Theory could be beneficial to identifying people at risk of poor diabetes self-management. DESIGN: An exploratory qualitative study. METHODS: Thirteen adults with insulin-treated Type 2 diabetes mellitus were purposively sampled. Data were collected through semi-structured interviews. An in-depth thematic analysis was carried out. RESULTS: Health became a value priority on diagnosis of Type 2 diabetes mellitus. Participants described holding both terminal (relating to desired end states) and instrumental (a means to an end) health values pre-diagnosis but these became instrumental post-diagnosis to meet new lifestyle needs and maintain their quality of life. Descriptions of 'conflicts' in locus of control beliefs when managing Type 2 diabetes mellitus demonstrated influences on levels of self-efficacy and health value. Common themes that impacted on diabetes self-management included co-morbidities, medication management, blood glucose monitoring and reasoning for Type 2 diabetes mellitus. CONCLUSIONS: Locus of control beliefs, levels of self-efficacy and health value were influenced by complications associated with Type 2 diabetes mellitus. The findings on Modified Social Learning Theory and instrumental health value as a moderator to health behaviour resulted in the development of a proposed framework with potential practical utility. RELEVANCE TO CLINICAL PRACTICE: This research demonstrates the relevance of exploring the constructs of Modified Social Learning Theory (MSLT) in relation to diabetes self-management behaviours in Type 2 diabetes mellitus. The proposed Type 2 diabetes mellitus Self-management Behaviour Support framework incorporates Modified Social Learning Theory and instrumental health value as the theoretical basis for development and could provide clinical nurses and doctors with a tool that will allow for in depth assessment and planning of Type 2 diabetes mellitus patients' self management behaviours. PMID- 26033075 TI - The barriers and facilitators to the implementation of clinical guidance in elective orthopaedic surgery: a qualitative study protocol. AB - BACKGROUND: Clinical guidelines in orthopaedic surgery aim to improve the efficiency, quality and outcomes of patient care by ensuring that treatment recommendations are based on the best available evidence. The simple provision of guidelines, however, does not ensure fidelity or guarantee their uptake and use in surgical practice. Research exploring the factors that affect surgeons' use of evidence and guidelines has focused on understanding what evidence exists for current clinical decisions. This narrowed scope emphasises the technical, educational and accessibility issues but overlooks wider factors that help explain how and why guidelines are not implemented and used in surgery. It is also important to understand how we can encourage the implementation processes in practice. By taking a social science perspective to examine orthopaedic surgery, we move beyond the narrow focus and explore how and why clinical guidelines struggle to achieve full uptake. We aim to explore guideline uptake to discover the factors that contribute to, or complicate, appropriate implementation in this field. We need to go beyond traditional views and experimental methods to examine the barriers and facilitators of implementation in real-life NHS surgical practice. These could be multifactorial, linked to individual, organisational or contextual influences, which act on the guideline implementation process. METHODS/DESIGN: We will use ethnographic methods to conduct case studies in three English NHS hospitals. Within each case, we will conduct observations, interviews and analysis of key documents to understand experiences, complex processes and decisions made and the role of clinical guidance and other sources of evidence within orthopaedic surgery. The data will be transcribed and analysed thematically. Comparisons will be made within cases and across cases. DISCUSSION: Guidelines are a fundamental part of clinical practice, and various factors must be considered when preparing for their successful implementation into organisations. Understanding the views and experiences of a range of surgical, clerical and managerial staff across multiple orthopaedic departments will capture the complexity and variety of factors that can influence surgical decisions. The findings of our study will identify the specific features of orthopaedic practice to help guide the development of strategies to facilitate guideline uptake in everyday surgical work. PMID- 26033076 TI - Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study. AB - BACKGROUND: Previous investigations have presumed a potential therapeutic effect of statin therapy in patients with acute respiratory distress syndrome (ARDS). Statins are expected to attenuate inflammation in the lungs of patients with ARDS due to their anti-inflammatory effects. Clinical investigations of the role of statin therapy have revealed contradictory results. This study aimed to investigate whether pretreatment and continuous therapy with statins in patients with sepsis-associated ARDS are associated with 28-day survival according to disease severity (mild, moderate, or severe). METHODS: Patients with sepsis associated ARDS from the surgical intensive care were enrolled in this prospective observational investigation. ARDS was classified into three groups (mild, moderate, and severe); 28-day mortality was recorded as the primary outcome variable and organ failure was recorded as secondary outcome variable. Sequential Organ Failure Assessment scores and the requirements for organ support were evaluated throughout the observational period to assess organ failure. RESULTS: 404 patients with sepsis-associated ARDS were enrolled in this investigation. The distribution of the ARDS subgroups was 13 %, 59 %, and 28 % for mild, moderate, and severe disease, respectively. Statin therapy improved 28 day survival exclusively in the patients with severe ARDS compared with patients without statin therapy (88.5 % and 62.5 %, respectively; P = 0.0193). To exclude the effects of several confounders, we performed multivariate Cox regression analysis, which showed that statin therapy remained a significant covariate for mortality (hazard ratio, 5.46; 95 % CI, 1.38-21.70; P = 0.0156). Moreover, after carrying a propensity score-matching in the severe ARDS cohort, Kaplan-Meier survival analysis confirmed the improved 28-day survival among patients with statin therapy (P = 0.0205). Patients with severe ARDS who received statin therapy had significantly more vasopressor-free days compared with those without statin therapy (13 +/- 7 and 9 +/- 7, respectively; P = 0.0034), and they also required less extracorporeal membrane oxygenation (ECMO) therapy and had more ECMO-free days (18 +/- 9 and 15 +/- 9, respectively; P = 0.0873). CONCLUSIONS: This investigation suggests a beneficial effect of continuous statin therapy in patients with severe sepsis-associated ARDS and a history of prior statin therapy. Further study is warranted to elucidate this potential effect. PMID- 26033077 TI - Pharmacological Approaches to Delaying Disability Progression in Patients with Multiple Sclerosis. AB - In individuals with multiple sclerosis, physical and cognitive disability progression are clinical and pathophysiological hallmarks of the disease. Despite shortcomings, particularly in capturing cognitive deficits, the Expanded Disability Status Scale is the assessment of disability progression most widely used in clinical trials. Here, we review treatment effects on disability that have been reported in large clinical trials of disease-modifying treatment, both among patients with relapsing-remitting disease and among those with progressive disease. However, direct comparisons are confounded to some degree by the lack of consistency in assessment of disability progression across trials. Confirmed disability progression (CDP) is a more robust measure when performed over a 6 month than a 3-month interval, and reduction in the risk of 6-month CDP in phase III trials provides good evidence for the beneficial effects on disability of several high-efficacy treatments for relapsing-remitting disease. It is also becoming increasingly clear that therapies effective in relapsing-remitting disease have little impact on the course of progressive disease. Given that the pathophysiological mechanisms, which lead to the long-term accrual of physical and cognitive deficits, are evident at the earliest stages of disease, it remains a matter of debate whether the most effective therapies are administered early enough to afford patients the best long-term outcomes. PMID- 26033078 TI - Timing of Gastrostomy Tube Feeding in Three-stage Palliation of Single-ventricle Physiology. AB - OBJECTIVE: Gastrostomy tube (G-tube) placement during three-stage surgical palliation of single-ventricle cardiac physiology has been shown to improve weight gain in this population of infants who often suffer from inadequate feeding. The optimal timing of this intervention is unclear and requires further investigation. DESIGN: A retrospective review of all patients who underwent G tube placement at any stage of surgical palliation of single-ventricle physiology from January 2005 to December 2012 was performed at a single congenital cardiac surgery center. Analysis of weight gain and survival was undertaken by comparing patients who received the G-tube either less than or greater than 90 days after the first surgical stage. RESULTS: Fifty-four patients were identified that met the criteria, 26 (48%) of which received the G-tube within 90 days of stage 1, while 28 (52%) patients received the tube at greater than 90 days. Percentage of weight gain at time of discharge from stage 1 was significantly higher for group B (A: median 9.9%, interquartile range [IQR] 4.9-29.8; B: median 29.0%, IQR 16.0 44.3; P = .05). However, total hospital length of stay was decreased for the patients who received G-tubes earlier (A: median 60 days, IQR 35-100; B: median 83, IQR 48-184) as was intensive care unit length of stay (A: median 27 days, IQR 13-69; B: median 48, IQR 16-119) by nearly half, although not statistically significant (P = .47). Survival to time of discharge from stage 1 surgery was not significantly different between earlier tube placements vs. later (92% vs. 100%, respectively; P = .14). Multivariable analysis found inclusion of fundoplication to predict weight gain (P = .006) at time of first discharge. CONCLUSION: Earlier placement of G-tube may increase the rate of recovery from stage 1 of multistage palliative cardiac surgery for single-ventricle physiology. Fundoplication may improve perioperative weight gain when indicated. PMID- 26033079 TI - Calcaneus secundarius--a relevant differential diagnosis in ankle pain: a case report and review of the literature. AB - INTRODUCTION: Accessory ossicles of the foot are a common finding. Although mostly asymptomatic, they can gain clinical relevance by trauma or stress on the complex biomechanical system of the foot. There are few reports on the entity of symptomatic calcaneus secundarius. Furthermore, the current literature does not address the need for awareness of calcaneus secundarius as a differential diagnosis in cases of persistent posttraumatic ankle pain. CASE PRESENTATION: We present the case of a 51-year-old Indo-European man with a medical history of persistent load-dependent ankle pain over 3 decades. At presentation after an acute ankle sprain, we diagnosed a traumatized calcaneus secundarius. Surgical excision led to a complete recovery. More than 1 year postoperative he is still asymptomatic. CONCLUSIONS: With the presented case and review of the literature we demonstrate the clinical relevance of calcaneus secundarius. Depending on size and alignment, calcaneus secundarius can alter the biomechanics in the subtalar region generating pain at the ankle. If a patient has persistent sinus tarsi syndrome, a painful limited subtalar range of motion or repetitive ankle sprains, then calcaneus secundarius should be considered in differential diagnosis. Likewise when a fracture of the anterior process of the calcaneus or a calcaneonavicular coalition is suspected, calcaneus secundarius should be considered a possible diagnosis by all clinicians confronted with foot and ankle pain. PMID- 26033080 TI - Effects of two exercise protocols on postural balance of elderly women: a randomized controlled trial. AB - BACKGROUND: The aging process reduces both sensory capabilities and the capabilities of the motor systems responsible for postural control, resulting in a high number of falls among the elderly. Some therapeutic interventions can directly interrupt this process, including physical exercise. This study compares and examines the effects of two exercise protocols on the balance of elderly women. METHODS: Elderly women who participated in a local church project (n = 63) were randomly divided into three groups: the proprioceptive neuromuscular facilitation group (PNFG), Pilates group (PG), and control group (CG). Of the 63 women, 58 completed the program. A training program involving 50-min sessions was performed in the PNFG and PG three times a week for 4 weeks. The elderly women in the CG received no intervention and continued with their daily activities. Stabilometric parameters, the Berg Balance Scale score, functional reach test, and timed up and go test (TUG test) were assessed before and 1 month after participation. RESULTS: In the comparison among groups, the women in the PNFG showed a significant reduction in most of the stabilometric parameters evaluated and better Berg Balance Scale score, functional reach test result, and TUG test result than did women in the CG (p < 0.05). Women in the PG showed significantly better performance on the functional reach test and TUG test than did women in the CG (p < 0.05). CONCLUSIONS: Women in the PNFG showed significantly better static and dynamic balance than did women in the CG. Women in the PG also showed better dynamic balance than did women in the CG. However, no significant differences were observed in any of the balance variables assessed between the PNFG and PG. TRIAL REGISTRATION: clinicaltrials.gov, number NCT02278731. PMID- 26033081 TI - Genetic modifiers and oligogenic inheritance. AB - Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance and expressivity of causal alleles has been modest, in part because of the methodological challenges in identifying genetic modifiers. Nonetheless, the progressive discovery of modifier alleles has improved both our interpretative ability and our analytical tools to dissect such phenomena. In this review, we analyze the genetic properties and behaviors of modifiers as derived from studies in patient populations and model organisms and we highlight conceptual and technological tools used to overcome some of the challenges inherent in modifier mapping and cloning. Finally, we discuss how the identification of these modifiers has facilitated the elucidation of biological pathways and holds the potential to improve the clinical predictive value of primary causal mutations and to develop novel drug targets. PMID- 26033083 TI - Management of chronic hepatitis B in patients from special populations. AB - Here we review the management of chronic hepatitis B (CHB) in four special categories of patients: CHB in pregnancy, in patients on immunosuppressive treatments, in patients undergoing liver transplantation, and in patients coinfected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV). PMID- 26033082 TI - The chimpanzee model for hepatitis B virus infection. AB - Even before the discovery of hepatitis B virus (HBV), it was known that chimpanzees (Pan troglodytes) are susceptible to human hepatitis viruses. The chimpanzee is the only primate animal model for HBV infections. Much like HBV infected human patients, chimpanzees can develop acute and chronic HBV infections and consequent hepatitis. Chimpanzees also develop a cellular immune response similar to that observed in humans. For these reasons, the chimpanzee has proven to be an invaluable model for investigations on HBV-driven disease pathogenesis and also the testing of novel antiviral therapies and prophylactic approaches. PMID- 26033085 TI - The JNK Signaling Pathway Is a Novel Molecular Target for S-Propargyl- L Cysteine, a Naturally-Occurring Garlic Derivatives: Link to Its Anticancer Activity in Pancreatic Cancer In Vitro and In Vivo. AB - Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease worldwide. Although significant improvement has been made in understanding its pathophysiology, only small portion of patients with PDA are likely to benefit from curative surgery and current chemotherapy. Thus, there is an urgent need for developing novel effective therapeutic approaches to the treatment of PDA. Today, garlic products have become an important source of effective compounds for the treatment of cancer. We have recently identified a novel garlic active component, S-propargyl-L-cysteine (SPRC), an analogue of S-Allyl Cysteine (SAC). Although its anticancer activity has been shown against several cancers, the mechanism of action is not fully understood. The present study was first designed to determine the anticancer activity of SPRC in PDA and the underlying mechanisms of action in vitro and in vivo. Our results demonstrated that SPRC reduced cell viability and colony formation, inhibited cell proliferation, induced G2/M phase cell cycle arrest and apoptosis in human PDA cells with various p53 statuses (HPAC, p53 wt; Panc-1, p53 mt). Furthermore, SPRC inhibited tumor growth in Panc-1 xenograft models. We also demonstrated that SPRC achieved its anticancer effects by regulation of the JNK protein levels through increasing its phosphorylation and decreasing its polyubiquitination-mediated degradation. In conclusion, SPRC has significant anti-PDA activity and the effects do not depend on p53 status, presumably through activating the JNK signaling pathway, providing a basis for the development of this compound as a novel target anticancer therapeutic agent for PDA. PMID- 26033084 TI - Seizures and epilepsy: an overview for neuroscientists. AB - Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions. PMID- 26033086 TI - Aerosol Delivery in the Treatment of Lung Cancer. AB - Intratumoral delivery of drugs, enabling increased local concentrations in the tumor microenvironment, might be superior to systemic administration in promoting antitumor activity and minimizing the systemic side effects of some drugs. Unfortunately, not all human cancers are amenable to drug injection into the tumor site. Lung cancers are candidate tumors for taking advantage of local delivery, being accessible via the endobronchial space by aerosol administration. Inhalation of aerosolized drugs is a promising option in the management of lung diseases and currently represents the standard treatment for asthma and chronic obstructive pulmonary disease. Besides a high local concentration, the advantages of aerosol administration of medications to the lung include reduced distribution to the systemic circulation and pain- and needle-free delivery. Several therapeutic agents have been explored for inhalation in lung malignancies, including chemotherapeutic agents, cytokines, Toll-like receptor agonists, monoclonal antibodies, genes and antisense oligonucleotides, demonstrating the feasibility of aerosol delivery, the potential antitumor effects and the reduced side effects compared with systemic treatment. In this review we summarize preclinical and clinical data regarding aerosol delivery of these drugs in the treatment of lung cancer. PMID- 26033087 TI - Identification of Drug Targets in Helicobacter pylori by in silico Analysis: Possible Therapeutic Implications for Gastric cancer. AB - Helicobacter pylori colonize stomach, inducing gastritis, ulcers and gastric cancer. Drugs are used to relieve pain, but not H. pylori infections. Hence, there is a need for discovery of drug targets and drugs for H. pylori. An objective of this current study is to identify drug targets for H. pylori. RAST was used to compare genomes of 23 H. pylori strains with Homo sapiens sapiens, other Helicobacter species (H. acinonychis, H. hepaticus, H. mustalae) and among them, to identify 13471 unique genes. Bacterial genes which are non-homologous to humans and essential for pathogen are identified using BLASTp. Later, 29 potential drug targets were identified by subjecting these genes to property analysis. Eleven of the 29 drug targets are already experimentally validated, lending credence to our approach. These methods have enabled rapid identification of drug targets with possible therapeutic implications for gastric cancer. PMID- 26033088 TI - Molecular and Clinical Aspects of the Target Therapy with the Calcimimetic Cinacalcet in the Treatment of Parathyroid Tumors. AB - Parathyroid tumors are almost invariably associated with parathormone (PTH) hypersecretion resulting in primary (PHPT) or secondary (SHPT) hyperparathyroidism. PHPT is the third most common endocrine disorder with a prevalence of 1-2% in post-menopausal women; SHPT is a major complication of chronic kidney failure, the prevalence of which is increasing. The calciumsensing receptor (CASR) is the key molecule regulating PTH synthesis and release from the parathyroid cells in response to changes in extracellular calcium concentrations. A potent calcimimetic, cinacalcet, has been developed in the last ten years and made available for medical treatment of both PHPT and SHPT. Cinacalcet has been demonstrated to be effective in inhibiting PTH secretion, though the drug fails to normalize PTH release, both in PHPT and SHPT patients with different degrees of disease severity, including patients with parathyroid carcinomas and with MEN1 related parathyroid tumors. Here we reviewed the molecular aspects of CASR target therapy and the effect of the CASR gene single nucleotide polymorphisms. Clinical data concerning the efficacy and safety of cinacalcet in controlling hyperparathyroidism are reported, focusing on the treatment of the different types of parathyroid tumors. Finally, limits of this target therapy are analyzed, pointing out the lack of efficacy in improving kidney and bone morbidities in PHPT and cardiovascular diseases in SHPT. Though cinacalcet is a target therapeutic option for parathyroid tumors, further approaches are warranted to fully control these metabolic disorders and the underlying tumors. PMID- 26033089 TI - Concentration and retention of Toxoplasma gondii oocysts by marine snails demonstrate a novel mechanism for transmission of terrestrial zoonotic pathogens in coastal ecosystems. AB - The parasite Toxoplasma gondii is an environmentally persistent pathogen that can cause fatal disease in humans, terrestrial warm-blooded animals and aquatic mammals. Although an association between T. gondii exposure and prey specialization on marine snails was identified in threatened California sea otters, the ability of kelp-dwelling snails to transmit terrestrially derived pathogens has not been previously investigated. The objective of this study was to measure concentration and retention of T. gondii by marine snails in laboratory aquaria, and to test for natural T. gondii contamination in field collected snails. Following exposure to T. gondii-containing seawater, oocysts were detected by microscopy in snail faeces and tissues for 10 and 3 days respectively. Nested polymerase chain reaction was also applied as a method for confirming putative T. gondii oocysts detected in snail faeces and tissues by microscopy. Toxoplasma gondii was not detected in field-collected snails. Results suggest that turban snails are competent transport hosts for T. gondii. By concentrating oocysts in faecal pellets, snails may facilitate entry of T. gondii into the nearshore marine food web. This novel mechanism also represents a general pathway by which marine transmission of terrestrially derived microorganisms can be mediated via pathogen concentration and retention by benthic invertebrates. PMID- 26033090 TI - Engineering selection stringency on expression vector for the production of recombinant human alpha1-antitrypsin using Chinese Hamster ovary cells. AB - BACKGROUND: Expression vector engineering technology is one of the most convenient and timely method for cell line development to meet the rising demand of novel production cell line with high productivity. Destabilization of dihydrofolate reductase (dhfr) selection marker by addition of AU-rich elements and murine ornithine decarboxylase PEST region was previously shown to improve the specific productivities of recombinant human interferon gamma in CHO-DG44 cells. In this study, we evaluated novel combinations of engineered motifs for further selection marker attenuation to improve recombinant human alpha-1 antitrypsin (rhA1AT) production. Motifs tested include tandem PEST elements to promote protein degradation, internal ribosome entry site (IRES) mutations to impede translation initiation, and codon-deoptimized dhfr selection marker to reduce translation efficiency. RESULTS: After a 2-step methotrexate (MTX) amplification to 50 nM that took less than 3 months, the expression vector with IRES point mutation and dhfr-PEST gave a maximum titer of 1.05 g/l with the top producer cell pool. Further MTX amplification to 300 nM MTX gave a maximum titer of 1.15 g/l. Relative transcript copy numbers and dhfr protein expression in the cell pools were also analysed to demonstrate that the transcription of rhA1AT and dhfr genes were correlated due to the IRES linkage, and that the strategies of further attenuating dhfr protein expression with the use of a mutated IRES and tandem PEST, but not codon deoptimization, were effective in reducing dhfr protein levels in suspension serum free culture. CONCLUSIONS: Novel combinations of engineered motifs for further selection marker attenuation were studied to result in the highest reported recombinant protein titer to our knowledge in shake flask batch culture of stable mammalian cell pools at 1.15 g/l, highlighting applicability of expression vector optimization in generating high producing stable cells essential for recombinant protein therapeutics production. Our results also suggest that codon usage of the selection marker should be considered for applications that may involve gene amplification and serum free suspension culture, since the overall codon usage and thus the general expression and regulation of host cell proteins may be affected in the surviving cells. PMID- 26033091 TI - Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. AB - In developing liver, cholangiocytes derive from the hepatoblasts and organize to form the bile ducts. Earlier work has shown that the SRY-related High Mobility Group box transcription factor 9 (SOX9) is transiently required for bile duct development, raising the question of the potential involvement of other SOX family members in biliary morphogenesis. Here we identify SOX4 as a new regulator of cholangiocyte development. Liver-specific inactivation of SOX4, combined or not with inactivation of SOX9, affects cholangiocyte differentiation, apico-basal polarity and bile duct formation. Both factors cooperate to control the expression of mediators of the Transforming Growth Factor-beta, Notch, and Hippo Yap signaling pathways, which are required for normal development of the bile ducts. In addition, SOX4 and SOX9 control formation of primary cilia, which are known signaling regulators. The two factors also stimulate secretion of laminin alpha5, an extracellular matrix component promoting bile duct maturation. We conclude that SOX4 is a new regulator of liver development and that it exerts a pleiotropic control on bile duct development in cooperation with SOX9. PMID- 26033092 TI - Resistant: hypertension, patient, or physician? PMID- 26033093 TI - Guideline of guidelines: urinary incontinence. AB - The objective of the article is to review key guidelines on the management of urinary incontinence (UI) to guide clinical management in a practical way. Guidelines produced by the European Association of Urology (updated in 2014), the Canadian Urological Association (updated in 2012), the International Consultation on Incontinence (updated in 2012), and the National Collaborating Centre for Women's and Children's Health (updated in 2013) were examined and their recommendations compared. In addition, specialised guidelines produced by the collaboration between the American Urological Association and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction on overactive bladder and the use of urodynamics were reviewed. The Appraisal of Guidelines for Research and Evaluation II (AGREE) instrument was used to evaluate the quality of these guidelines. There is general agreement between the groups on the recommended initial evaluation and the use of conservative therapies for first line treatment, with a limited role for imaging or invasive testing in the uncomplicated patient. These groups have greater variability in their recommendations for invasive procedures; however, generally the mid-urethral sling is recommended for uncomplicated stress UI, with different recommendations on the approach, as well as the comparability to other treatments, such as the autologous fascial sling. This 'Guideline of Guidelines' provides a summary of the salient similarities and differences between prominent groups on the management of UI. PMID- 26033095 TI - Orbital free DFT versus single density equation: a perspective through quantum domain behavior of a classically chaotic system. AB - The orbital free density functional theory and the single density equation approach are formally equivalent. An orbital free density based quantum dynamical strategy is used to study the quantum-classical correspondence in both weakly and strongly coupled van der Pol and Duffing oscillators in the presence of an external electric field in one dimension. The resulting quantum hydrodynamic equations of motion are solved through an implicit Euler type real space method involving a moving weighted least square technique. The Lagrangian framework used here allows the numerical grid points to follow the wave packet trajectory. The associated classical equations of motion are solved using a sixth order Runge Kutta method and the Ehrenfest dynamics is followed through the solution of the time dependent Schrodinger equation using a time dependent Fourier Grid Hamiltonian technique. Various diagnostics reveal a close parallelism between classical regular as well as chaotic dynamics and that obtained from the Bohmian mechanics. PMID- 26033097 TI - Measles: eliminated but not eradicated. PMID- 26033094 TI - Evaluating processes of care and outcomes of children in hospital (EPOCH): study protocol for a randomized controlled trial. AB - BACKGROUND: The prevention of near and actual cardiopulmonary arrest in hospitalized children is a patient safety imperative. Prevention is contingent upon the timely identification, referral and treatment of children who are deteriorating clinically. We designed and validated a documentation-based system of care to permit identification and referral as well as facilitate provision of timely treatment. We called it the Bedside Paediatric Early Warning System (BedsidePEWS). Here we describe the rationale for the design, intervention and outcomes of the study entitled Evaluating Processes and Outcomes of Children in Hospital (EPOCH). METHODS/DESIGN: EPOCH is a cluster-randomized trial of the BedsidePEWS. The unit of randomization is the participating hospital. Eligible hospitals have a Pediatric Intensive Care Unit (PICU), are anticipated to have organizational stability throughout the study, are not using a severity of illness score in hospital wards and are willing to be randomized. Patients are >37 weeks gestational age and <18 years and are hospitalized in inpatient ward areas during all or part of their hospital admission. Randomization is to either BedsidePEWS or control (no severity of illness score) in a 1:1 ratio within two strata (<200, >= 200 hospital beds). All-cause hospital mortality is the selected primary outcome. It is objective, independent of do-not-resuscitate status and can be reliably measured. The secondary outcomes include (1) clinical outcomes: clinical deterioration, severity of illness at and during ICU admission, and potentially preventable cardiac arrest; (2) processes of care outcomes: immediate calls for assistance, hospital and ICU readmission, and perceptions of healthcare professionals; and (3) resource utilization: ICU days and use of ICU therapies. DISCUSSION: Following funding by the Canadian Institutes of Health Research and local ethical approvals, site enrollment started in 2010 and was closed in February 2014. Patient enrollment is anticipated to be complete in July 2015. The results of EPOCH will strengthen the scientific basis for local, regional, provincial and national decision-making and for the recommendations of national and international bodies. If negative, the costs of hospital-wide implementation can be avoided. If positive, EPOCH will have provided a scientific justification for the major system-level changes required for implementation. TRIAL REGISTRATION: NCT01260831 ClinicalTrials.gov date: 14 December 2010. PMID- 26033098 TI - Pain, agitation, and delirium guidelines: nurses' involvement in development and implementation. AB - The 2013 American College of Critical Care Medicine/Society of Critical Care Medicine clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit serves as a living example of nurses' involvement in the development and implementation of professional guidelines. Nurses who served on this guideline-writing panel describe their experiences. Specific examples from the pain, agitation, and delirium guidelines for care are used to explore the roles of the nurse leader, nurse informaticist, staff nurse, and nurse researcher in relationship to guideline implementation. PMID- 26033099 TI - Effective pain management and improvements in patients' outcomes and satisfaction. AB - Adequate pain management is a compelling and universal requirement in health care. Despite considerable advancements, the adverse physiological and psychological implications of unmanaged pain remain substantially unresolved. Ineffective pain management can lead to a marked decrease in desirable clinical and psychological outcomes and patients' overall quality of life. Effective management of acute pain results in improved patient outcomes and increased patient satisfaction. Although research and advanced treatments in improved practice protocols have documented progressive improvements in management of acute and postoperative pain, little awareness of the effectiveness of best practices persists. Improved interventions can enhance patients' attitudes to and perceptions of pain. What a patient believes and understands about pain is critical in influencing the patient's reaction to the pain therapy provided. Use of interdisciplinary pain teams can lead to improvements in patients' pain management, pain education, outcomes, and satisfaction. PMID- 26033100 TI - Posttraumatic stress syndrome associated with stays in the intensive care unit: importance of nurses' involvement. AB - More patients in the intensive care unit are surviving their critical illnesses because of advances in medical care. This change in survival has led to an increased awareness of the emotional consequences of being critically ill. Posttraumatic stress disorder has been identified in approximately 9% to 27% of critically ill patients compared with 7% of the general US population. Risk factors such as treatment with mechanical ventilation, sedation, delusional memories, and agitation are associated with development of posttraumatic stress disorder in patients in the intensive care unit. Individuals with posttraumatic stress disorder are more likely to experience negative physical and psychiatric health outcomes and a lower quality of life than are patients without the disorder. Early identification and treatment of patients experiencing these signs and symptoms may reduce these physical and psychological comorbid conditions. Through careful monitoring of medications, early mobilization, sleep promotion, and pain management, nurses may be able to reduce signs and symptoms of posttraumatic stress disorder. PMID- 26033101 TI - Vulnerability of older patients in critical care. AB - One of the patient characteristics in the AACN Synergy Model is vulnerability. Vulnerability is defined in the model as the susceptibility to actual or potential stressors that may adversely affect patients' outcomes. The risk of vulnerability increases in older patients in critical care units. PMID- 26033102 TI - Progressive mobility as a team effort in transitional care. AB - With changing health care, progressive care nurses are working in diverse practice settings to meet patient care needs. Progressive care is practiced along the continuum from the intensive care unit to home. The benefits of early progressive mobility are examined with a focus on the interdisciplinary collaboration for care in a transitional care program of a skilled nursing facility. The program's goals are improved functional status, self-care management, and home discharge with reduced risk for hospital readmission. The core culture of the program is interdisciplinary collaboration and team partnership for care of patients and their families. PMID- 26033103 TI - Summer learning. PMID- 26033104 TI - Time frames for sepsis screening criteria. PMID- 26033105 TI - Education and simulation training of pediatric intensive care unit nurses to care for open heart surgery patients. PMID- 26033107 TI - I am a critical care nurse. AB - Kevin Xuereb, RN, is a staff nurse in the burn intensive care unit at New York Presbyterian-Weill Cornell Hospital in New York. PMID- 26033108 TI - Hiring appropriate providers for different populations: acute care nurse practitioners. AB - Acute care nurse practitioners, prepared as providers for a variety of populations of patients, continue to make substantial contributions to health care. Evidence indicates shorter stays, higher satisfaction among patients, increased work efficiency, and higher quality outcomes when acute care nurse practitioners are part of unit- or service-based provider teams. The Consensus Model for APRN Regulation: Licensure, Accreditation, Certification, and Education outlines detailed guidelines for matching nurse practitioners' education with certification and practice by using a population-focused algorithm. Despite national support for the model, nurse practitioners and employers continue to struggle with finding the right fit. Nurse practitioners often use their interest and previous nursing experience to apply for an available position, and hospitals may not understand preparation or regulations related to matching the appropriate provider to the work environment. Evidence and regulatory guidelines indicate appropriate providers for population-focused positions. This article presents history and recommendations for hiring acute care nurse practitioners as providers for different populations of patients. PMID- 26033109 TI - Surgeon is struck off for behaviour "fundamentally incompatible" with being a doctor. PMID- 26033110 TI - Possible role of cortactin phosphorylation by protein kinase Calpha in actin bundle formation at growth cone. AB - BACKGROUND INFORMATION: Cortactin contributes to growth cone morphogenesis by forming with dynamin, ring-shaped complexes that mechanically bundle and stabilise F-actin. However, the regulatory mechanism of cortactin action is poorly understood. RESULTS: Immunofluorescence microscopy revealed that protein kinase C (PKC) alpha colocalises with cortactin at growth cone filopodia in SH SY5Y neuroblastoma cells. PKC activation by phorbol 12-myristate 13-acetate causes cortactin phosphorylation, filopodial retraction and F-actin-bundle loss. Moreover, PKCalpha directly phosphorylates cortactin in vitro at S135/T145/S172, mitigating both cortactin's actin-binding and actin-crosslinking activity, whereas cellular expression of a phosphorylation-mimetic cortactin mutant hinders filopodial formation with a significant decrease of actin bundles. CONCLUSIONS: Our results indicate that PKC-mediated cortactin phosphorylation might be implicated in the maintenance of growth cone. PMID- 26033111 TI - Probability screening in manuscripts submitted to biomedical journals--an effective tool or a statistical quagmire? PMID- 26033112 TI - Predictive factors for oocyte retrieval failure in controlled ovarian hyperstimulation protocols: a retrospective observational cohort study. AB - BACKGROUND: Oocyte retrieval failure following an ovarian hyperstimulation protocol is uncommon in assisted reproductive technology (ART) programs. We analyzed the predictive factors for oocyte retrieval failure following controlled ovarian hyperstimulation (COH) with gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist protocols in ART programs. METHODS: This study was a retrospective cohort observational study. In total, 744 cycles from 361 patients who underwent controlled ovarian hyperstimulation with GnRH agonist long protocol or antagonist protocol were analyzed. Treatment cycles with oocyte retrieval failure and with one or more oocytes retrieved were compared to determine predictive factors for oocyte retrieval failure using univariate and multilevel multivariate logistic regression analyses. RESULTS: Oocyte retrieval failure occurred in 38 cycles (5.1%). The oocyte retrieval failure rate of the GnRH antagonist protocol (8.1%) was significantly higher than that of the GnRH agonist long protocol (3.7%). On multilevel multivariate logistic analysis, cycles with GnRH antagonist protocol (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.05 8.96), estradiol level on the day of human chorionic gonadotropin (hCG) injection (OR 0.997, 95% CI 0.996-0.998), and luteinizing hormone (LH) level on the day of hCG injection (OR 1.19, 95% CI 1.06-1.33) were independent predictive factors for oocyte retrieval failure. The efficacy of estradiol and LH levels on the day of hCG injection for predicting oocyte retrieval failure was evaluated using receiver operating characteristic curves. In all cycles, the areas under the curve (AUCs) for estradiol and LH were 0.84 and 0.63, respectively, for all cycles; 0.84 and 0.52, respectively, for cycles with GnRH agonist long protocol; and 0.81 and 0.82, respectively, for cycles with GnRH antagonist protocol. CONCLUSIONS: Our results suggest that in cycles with GnRH antagonist protocol, the levels of estradiol and LH on the day of hCG injection might be predictive factors for oocyte retrieval failure. This relationship may provide useful information to both patients and physicians for developing better COH protocols in ART programs. PMID- 26033113 TI - Concurrent Validity of New Subscale Scores for the Booklet Category Test. AB - The Booklet Category Test (BCT) is a neuropsychological test of cognitive dysfunction that provides only one overall error score indicative of global impairment. It does not, however, delineate specific domains that might be impaired. The aim of this study is to concurrently validate 13 new BCT subscales using legacy instruments in patients with nonpenetrating traumatic brain injury (TBI). Eighty-nine patients with mild, moderate, and severe TBI completed a battery of neuropsychology tests. Partial correlations controlling for age were performed and there were significant correlations between the a priori selected scores from legacy measures of major cognitive domains and both BCT total errors and subscale scores. Additional analysis showed that several subscales were able to differentiate between performance levels on the legacy measures. Overall, our results showed that the subscales measured cognitive skills beyond global impairment, supporting the use of the BCT subscales in a population with TBI. PMID- 26033114 TI - Assessing Intimate Relationships of Chinese Couples in Taiwan Using the Marital Satisfaction Inventory-Revised. AB - The current study examined the psychometric characteristics of the Chinese translation of the Marital Satisfaction Inventory-Revised (MSI-R) in a community sample of 117 couples from Taiwan. The Chinese MSI-R demonstrated moderate to strong internal consistency. Confirmatory factor analysis revealed similar scale factor structures in the Taiwanese and U.S. standardization samples. Mean profile comparisons between the current Taiwanese sample and the original MSI-R standardization sample revealed statistically significant but small differences on several subscales. Overall, the psychometric characteristics of the Chinese MSI-R lend support to its use with couples from diverse cultural backgrounds whose sole or preferred language is Chinese. It may also be appropriate to use the MSI-R in clinical settings for prevention or intervention efforts directed at Chinese-speaking couples. The implications of these findings for clinical and research purposes are discussed. PMID- 26033115 TI - Case-based discussions: UK surgical trainee perceptions. AB - BACKGROUND: An increasing emphasis on accountability led to the development of the Intercollegiate Surgical Curriculum Project (ISCP) in the UK. A major feature of ISCP was a focus on competence with the institution of formative assessments to aid learning and provide portfolio evidence. Case-based discussions (CBDs) are one of the main formative assessments used at all stages of training. The aim of this study was to review the use of CBDs by surgical trainees to determine if and when they are useful, and whether they are perceived as being used correctly. METHODS: Semi-structured interviews were carried out with both higher and core surgical trainees. Inductive reasoning principles were used to analyse and interpret the responses to open questions. Common themes were determined and thematic analysis was carried out. RESULTS: Forty-two surgical trainees (21 core and 21 higher trainees) were interviewed. Core trainees felt that CBDs were more likely to be used correctly, and both groups thought that they were a positive feature of training. Few stated that they were used to shape training needs. Positive themes identified included the provision of feedback, identifying learning portfolio evidence and encouraging reflection. Negative themes included a 'tick-box' mentality and that the value was diminished by a lack of engagement with the process from trainers. Case-based discussions are one of the main formative assessments used at all stages of training CONCLUSION: Trainees regarded CBDs as a positive feature allowing the discussion of complicated cases, and encouraging higher thinking and reflection; however, concerns were raised regarding their implementation, which has led to a diminishing of their value. PMID- 26033116 TI - Replacing corn with pearl millet (raw and sprouted) with and without enzyme in chickens' diet. AB - An experiment was conducted to compare a commercial corn-soya bean meal diet with a pearl millet (raw and sprouted) diet containing less soya bean meal, alone or in combination with exogenous enzyme, on growth performance and ileal villus development of chicks. Two-hundred-and-forty-one-day-old male broilers (10/pen) were randomly allocated to one of the following dietary treatments: (i) a standard corn-soya bean meal control diet (CTL); (ii) a raw pearl millet-soya bean meal diet (PM); (iii) a sprouted pearl millet-soya bean meal diet (SPM); (iv) CTL + exogenous enzymes (CE); (v) PM + exogenous enzymes (PE); and (vi) SPM + exogenous enzymes (SPE) with four replicate pens/treatment. Body weight of birds at day 21 did not differ between those fed the CTL, and SPM and PE diets. In comparison with feeding broilers the CTL diet, feeding the PE and SPM diets caused significant decrease in feed intake, but with equivalent growth and feed efficiency. However, at day 21, feed conversion ratio did not differ between birds fed the CTL diet and those fed the PM, PE and SPM diets. At day 21, broilers fed the PM and PE diets had longer villi (p < 0.05) than those fed the CTL diet. At day 21, villi width was reduced (p < 0.05) by raw pearl millet supplementation than CTL diet. It is concluded that, in comparison with corn, broiler diets formulated with sprouted pearl millet or pearl millet with enzyme require less soya bean meal and can be used to improve growth performance traits and villus development. PMID- 26033117 TI - Cleavage of bovine adenovirus type 3 non-structural 100K protein by protease is required for nuclear localization in infected cells but is not essential for virus replication. AB - The L6 region of bovine adenovirus type 3 (BAdV-3) encodes a non-structural protein named 100K. Rabbit antiserum raised against BAdV-3 100K recognized a protein of 130 kDa at 12-24 h and proteins of 130, 100, 95 and 15 kDa at 36-48 h after BAdV-3 infection. The 100K species localized to the nucleus and the cytoplasm of BAdV-3-infected cells. In contrast, 100K localized predominantly to the cytoplasm of the transfected cells. However, BAdV-3 infection of cells transfected with 100K-enhanced yellow fluorescent protein-expressing plasmid detected fluorescent protein in the nucleus of the cells, suggesting that other viral proteins may be required for the nuclear localization of 100K. Interaction of BAdV-3 100K with BAdV-3 33K protein did not alter the cytoplasmic localization of 100K. However, co-expression of BAdV-3 100K and BAdV-3 protease localized 100K to the nucleolus of the transfected cells. Subsequent analysis suggested that BAdV-3 protease cleaves 100K at two identified potential protease cleavage sites (aa 740-745 and 781-786) in transfected or BAdV-3-infected cells. The cleaved C terminus (107 aa) was localized to the nucleolus of the transfected cells. Further analysis suggested that the cleaved C terminus contains a bipartite nuclear localization signal and utilizes import receptor importin-alpha3 of the classical importin-alpha/beta transport pathway for nuclear transport. Successful isolation of recombinant BAdV-3 expressing mutant 100K (substitution of alanine for glycine in the potential protease cleavage site) suggested that cytoplasmic cleavage of BAdV-3 100K by adenoviral protease is not essential for virus replication. PMID- 26033118 TI - Assessment of neutralizing and non-neutralizing antibody responses against Porcine circovirus 2 in vaccinated and non-vaccinated farmed pigs. AB - Vaccination is the most efficacious procedure to curtail Porcine circovirus 2 (PCV2)-associated diseases (PCVAD). Experimental studies indicate that PCV2 vaccine-induced virus-neutralizing antibodies play a major role in protection from PCVAD. However, the immune response to PCV2 vaccination of pigs on farms is less clear. Analysing groups of age-matched vaccinated and non-vaccinated farmed pigs, we found significantly increased levels of virus-neutralizing antibodies only in vaccinated pigs belonging to the age group with the highest risk for developing PCVAD. Serum levels of PCV2 genomes were not different between corresponding age groups. Levels of antibodies directed against a linear peptide from the PCV2 capsid protein correlated with those of virus-neutralizing antibodies and reached the highest levels in older, non-vaccinated animals, pointing towards an intense interaction between PCV2-infected cells and the immune system. In conclusion, current PCV2 vaccines are in need of improvement to induce stronger and more rapid immunity to prevent PCV2 infection. PMID- 26033119 TI - Club cells, their secretory protein, and COPD. PMID- 26033120 TI - Ventilator-associated pneumonia: the role of emerging therapies and diagnostics. PMID- 26033121 TI - Running short on time: lung transplant evaluation for telomere-related pulmonary fibrosis. PMID- 26033122 TI - POINT: Do physicians have a responsibility to provide recommendations regarding goals of care to surrogates of dying patients in the ICU? Yes. PMID- 26033123 TI - COUNTERPOINT: Do physicians have a responsibility to provide recommendations regarding goals of care to surrogates of dying patients in the ICU? No. PMID- 26033124 TI - Rebuttal from Dr Hutchison. PMID- 26033125 TI - Rebuttal from Dr Veatch. PMID- 26033127 TI - BLUE-protocol and FALLS-protocol: two applications of lung ultrasound in the critically ill. AB - This review article describes two protocols adapted from lung ultrasound: the bedside lung ultrasound in emergency (BLUE)-protocol for the immediate diagnosis of acute respiratory failure and the fluid administration limited by lung sonography (FALLS)-protocol for the management of acute circulatory failure. These applications require the mastery of 10 signs indicating normal lung surface (bat sign, lung sliding, A-lines), pleural effusions (quad and sinusoid sign), lung consolidations (fractal and tissue-like sign), interstitial syndrome (lung rockets), and pneumothorax (stratosphere sign and the lung point). These signs have been assessed in adults, with diagnostic accuracies ranging from 90% to 100%, allowing consideration of ultrasound as a reasonable bedside gold standard. In the BLUE-protocol, profiles have been designed for the main diseases (pneumonia, congestive heart failure, COPD, asthma, pulmonary embolism, pneumothorax), with an accuracy > 90%. In the FALLS-protocol, the change from A lines to lung rockets appears at a threshold of 18 mm Hg of pulmonary artery occlusion pressure, providing a direct biomarker of clinical volemia. The FALLS protocol sequentially rules out obstructive, then cardiogenic, then hypovolemic shock for expediting the diagnosis of distributive (usually septic) shock. These applications can be done using simple grayscale machines and one microconvex probe suitable for the whole body. Lung ultrasound is a multifaceted tool also useful for decreasing radiation doses (of interest in neonates where the lung signatures are similar to those in adults), from ARDS to trauma management, and from ICUs to points of care. If done in suitable centers, training is the least of the limitations for making use of this kind of visual medicine. PMID- 26033128 TI - Mechanical ventilation for severe asthma. AB - Acute exacerbations of asthma can lead to respiratory failure requiring ventilatory assistance. Noninvasive ventilation may prevent the need for endotracheal intubation in selected patients. For patients who are intubated and undergo mechanical ventilation, a strategy that prioritizes avoidance of ventilator-related complications over correction of hypercapnia was first proposed 30 years ago and has become the preferred approach. Excessive pulmonary hyperinflation is a major cause of hypotension and barotrauma. An appreciation of the key determinants of hyperinflation is essential to rational ventilator management. Standard therapy for patients with asthma undergoing mechanical ventilation consists of inhaled bronchodilators, corticosteroids, and drugs used to facilitate controlled hypoventilation. Nonconventional interventions such as heliox, general anesthesia, bronchoscopy, and extracorporeal life support have also been advocated for patients with fulminant asthma but are rarely necessary. Immediate mortality for patients who are mechanically ventilated for acute severe asthma is very low and is often associated with out-of-hospital cardiorespiratory arrest before intubation. However, patients who have been intubated for severe asthma are at increased risk for death from subsequent exacerbations and must be managed accordingly in the outpatient setting. PMID- 26033126 TI - Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. AB - BACKGROUND: ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans. METHODS: We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts. RESULTS: In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS. CONCLUSIONS: Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively. PMID- 26033129 TI - Surgical management of OSA in adults. AB - OSA is a common, often chronic, condition requiring long-term therapy. Given the prevalence of OSA, as well as its significant health-related sequelae, a range of medical and surgical treatments have been developed and used with varying success depending on individual anatomy and patient compliance. Although CPAP is the primary treatment, many patients cannot tolerate this treatment and require alternative therapies. In this clinical scenario, surgery is often warranted and useful. Surgical management is aimed at addressing obstruction in the nasal, retropalatal, and retroglossal/hypopharyngeal regions, and many patients have multiple levels of obstruction. This review presents a comprehensive overview of research findings on a wide spectrum of surgical approaches currently used by sleep clinicians when other therapeutic modalities fail to achieve positive outcomes. PMID- 26033130 TI - Emergency Medical Treatment and Labor Act: what every physician should know about the federal antidumping law. AB - Since 1986, the Emergency Medical Treatment and Labor Act (EMTALA) has imposed an obligation on hospitals and physicians to evaluate and stabilize patients who present to a hospital ED seeking care. Available sanctions for noncompliance include fines, damages awarded in civil litigation, and exclusion from Medicare. EMTALA uses several terms that are familiar to physicians (eg, "emergency medical condition," "stabilize," and "transfer"), but the statutory definitions do not map neatly onto the way in which these terms are used and understood in clinical settings. Thus, there is potential for a mismatch between a physician's on-the spot professional judgment and what the statute demands. We review what every physician should know about EMTALA and answer six common questions about the law. PMID- 26033131 TI - The role of noninvasive ventilation in the management and mitigation of exacerbations and hospital admissions/readmissions for the patient with moderate to severe COPD (multimedia activity). AB - As seen in this CME online activity (available at http://journal.cme.chestnet.org/home-niv-copd), COPD is a common and debilitating disease and is currently the third leading cause of death in the United States. The role of noninvasive ventilation (NIV) in the management of severe, hypercapnic COPD has been controversial. However, it was concluded that current data would support the following recommendations. Patients with COPD with a waking Paco2 > 50 to 52 mm Hg, an overnight Paco2 > 55 mm Hg, or both who are symptomatic and compliant with other therapies should be eligible for NIV. In addition, multiple previous hospital admissions for COPD exacerbation, requiring noninvasive/invasive mechanical ventilation, strongly suggest a need for chronic NIV. Patients with COPD with a BMI > 30 kg/m2 respond particularly well to this therapy. When the decision is made to start NIV, this treatment is probably best initiated during a short hospitalization, although this can be accomplished in the clinic, home, or sleep laboratory if well-trained clinicians are available. Newer modes of NIV such as volume-assured pressure support, particularly with autotitrating expiratory positive airway pressure (EPAP), may create the opportunity for home NIV initiation easier for less experienced physicians. Regardless of the mode selected, inspiratory pressures must be in the 20 to 25 cm H2O range to meaningfully increase tidal volume, reduce work of breathing, and, importantly, reduce waking arterial Paco2. EPAP is currently set at 4 to 5 cm H2O, although future technologies may allow this to be individualized to maximally reduce auto-positive end expiratory pressure. The NIV device should have a backup rate although it is controversial as to whether this should be set at a high (18-20 breaths/min) vs a low (8-10 breaths/min) rate. The proper use of NIV in appropriately chosen patients with COPD can improve quality of life and increase survival. Ongoing studies are assessing if the frequency of future hospitalizations can be reduced with NIV. Thus, NIV should be strongly considered in any patients with COPD meeting the criteria described here. PMID- 26033132 TI - Technique for repair of fractures and separations involving the cartilaginous portions of the anterior chest wall. AB - Internal fixation of the ribs has been shown in numerous studies to decrease complications following traumatic rib fractures. Anterior injuries to the chest wall causing cartilaginous fractures, although rare, can cause significant disability and can lead to a variety of complications and, therefore, pose a unique clinical problem. Here, we report the surgical technique used for four patients with internal fixation of injuries to the cartilaginous portions of the chest wall treated at our center. All patients had excellent clinical outcomes and reported improvement in symptoms, with no associated complications. Patients who have injuries to the anterior portions of the chest wall should be considered for internal fixation of the chest wall when the injuries are severe and can lead to clinical disability. PMID- 26033133 TI - Pregnant patient with progressive hypoxemic respiratory failure. PMID- 26033134 TI - A man with pleural effusion and ascites. AB - A male lifelong nonsmoker aged 58 years with no prior asbestos exposure complained of gradual worsening breathlessness over 3 months. This was associated with abdominal and leg swelling and a 2-kg weight loss. He had no fever, night sweats, hemoptysis, joint pain, rash, abdominal pain, chest pain, or orthopnea. The patient had no recent travel or contact with pulmonary TB. He had stage I left-side testicular seminoma treated with left-sided radical orchidectomy 10 years previous and recently received a diagnosis of Child's B alcoholic liver cirrhosis. His hepatitis B and C screen result was normal. PMID- 26033135 TI - A 43-year-old man with antisynthetase syndrome presenting with acute worsening of dyspnea. AB - A 43-year-old man with antisynthetase syndrome was seen in our pulmonary clinic for worsening dyspnea. He was recently diagnosed with antisynthetase syndrome because he had nonspecific interstitial pneumonitis on a surgical lung biopsy and polymyositis associated with anti-Jo-1 and anti-SSA-52 autoantibodies. Along with his worsening dyspnea, he also had a dry cough, lower extremity edema, and abdominal distension. He had gained 11 kg over 1 month. He had been taking prednisone 40 mg daily 2 months prior, which had been recently weaned to 20 mg daily. He had also been on mycophenolate mofetil but had recently discontinued it on his own. PMID- 26033136 TI - A 52-year-old man with palpitations and a solitary pulmonary nodule. AB - A 52-year-old white man presented to a pulmonary clinic for evaluation of a 2.3 * 1.7 cm lung nodule. The patient had originally presented to his cardiologist for palpitations. The palpitations were described as a "fluttering" sensation, occurring daily, more often at rest, but not associated with syncope. At the time, he denied dyspnea, paroxysmal nocturnal dyspnea, or orthopnea. The patient had a coronary artery calcium scoring test done, which revealed a lobulated, well circumscribed, smoothly marginated lower lobe nodule, and he was sent to a pulmonary clinic for further evaluation. The patient denied shortness of breath, chest pain, cough, wheezing, or hemoptysis. He denied fatigue, night sweats, or weight loss. He had a 1 pack-year smoking history and stopped cigarettes 30 years ago but still smoked two to three cigars monthly. His family history was only significant for early coronary artery disease. He was an avid marathon runner who worked as an athletic equipment manager for a prominent sports team in Arizona. PMID- 26033137 TI - 29-year-old man presenting with progressive dyspnea, oculocutaneous albinism, and epistaxis. AB - A 29-year-old man with a history of oculocutaneous albinism presented to the ED complaining of progressive dyspnea on exertion. One month prior to admission, the patient had begun to experience worsening dyspnea provoked by routine household activities. Additionally, he had developed a nonproductive cough, exacerbated by cold weather. He denied associated chest pain, hemoptysis, fever, chills, or night sweats. He denied any new exposures or sick contacts in the recent past. A review of systems was significant for a history of epistaxis and frequent bruising. Born in Honduras, he had immigrated to the United States approximately 10 years prior to his presentation to our facility. Furthermore, there was no family history of albinism, bleeding disorders, or pulmonary disease. PMID- 26033138 TI - Long-latency sensory-evoked responses and prognosis in cardiac arrest survivors. PMID- 26033139 TI - Response. PMID- 26033140 TI - Impaired quality of life in chronic hypersensitivity pneumonitis. PMID- 26033141 TI - Bicarbonate or base excess in early obesity hypoventilation syndrome: a methodologic viewpoint. PMID- 26033142 TI - Comments on predictors of clinical use of pleurodesis and/or indwelling pleural catheter therapy for malignant pleural effusion. PMID- 26033143 TI - Response. PMID- 26033144 TI - A curious case of pill aspiration. PMID- 26033145 TI - Response. PMID- 26033146 TI - Pulmonary ultrasonography: staying within the lines prevents us finding something better on the other side. PMID- 26033147 TI - Response. PMID- 26033148 TI - When right is redundant. PMID- 26033149 TI - A Polymeric Bowl for Multi-Agent Delivery. AB - This paper describes a simple system for multi-agent delivery. The system consists of a biodegradable polymer particle with a hollow interior, together with a hole on its surface that can be completely or partially sealed via thermal annealing. A hydrophobic dye, Nile-red, entrapped within the shell of hollow particles presents a sustained release behavior while methylene blue, a hydrophilic model agent, encapsulated in the hollow interior shows a fast release manner. The release profiles of the probes can be further independently controlled by encapsulating methylene blue-loaded polymer nanoparticles, instead of free dye, in the hollow particle with a small hole on its surface. PMID- 26033151 TI - [Not Available]. PMID- 26033150 TI - [Not Available]. PMID- 26033152 TI - Re: R. Houston Thompson, Tom Atwell, Grant Schmit, et al. Comparison of partial nephrectomy and percutaneous ablation for cT1 renal masses. Eur Urol 2015;67:252 9. PMID- 26033153 TI - Prebiopsy Multiparametric Magnetic Resonance Imaging for Prostate Cancer Diagnosis in Biopsy-naive Men with Suspected Prostate Cancer Based on Elevated Prostate-specific Antigen Values: Results from a Randomized Prospective Blinded Controlled Trial. AB - BACKGROUND: Multiparametric magnetic resonance imaging (MP-MRI) may improve the detection of clinically significant prostate cancer (PCa). OBJECTIVE: To compare MP-MRI transrectal ultrasound (TRUS)-fusion targeted biopsy with routine TRUS guided random biopsy for overall and clinically significant PCa detection among patients with suspected PCa based on prostate-specific antigen (PSA) values. DESIGN, SETTING, AND PARTICIPANTS: This institutional review board-approved, single-center, prospective, randomized controlled trial (April 2011 to December 2014) included 130 biopsy-naive patients referred for prostate biopsy based on PSA values (PSA <20 ng/ml or free-to-total PSA ratio <=0.15 and PSA <10 ng/ml). Patients were randomized 1:1 to the MP-MRI or control group. Patients in the MP MRI group underwent prebiopsy MP-MRI followed by 10- to 12-core TRUS-guided random biopsy and cognitive MRI/TRUS fusion targeted biopsy. The control group underwent TRUS-guided random biopsy alone. INTERVENTION: MP-MRI 3-T phased-array surface coil. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the number of patients with biopsy-proven PCa in the MP-MRI and control groups. Secondary outcome measures included the number of positive prostate biopsies and the proportion of clinically significant PCa in the MP-MRI and control groups. Between-group analyses were performed. RESULTS AND LIMITATIONS: Overall, 53 and 60 patients were evaluable in the MP-MRI and control groups, respectively. The overall PCa detection rate and the clinically significant cancer detection rate were similar between the MP-MRI and control groups, respectively (64% [34 of 53] vs 57% [34 of 60]; 7.5% difference [95% confidence interval (CI), -10 to 25], p=0.5, and 55% [29 of 53] vs 45% [27 of 60]; 9.7% difference [95% CI, -8.5 to 27], p=0.8). The PCa detection rate was higher than assumed during the planning of this single-center trial. CONCLUSIONS: MP-MRI/TRUS fusion targeted biopsy did not improve PCa detection rate compared with TRUS guided biopsy alone in patients with suspected PCa based on PSA values. PATIENT SUMMARY: In this randomized clinical trial, additional prostate magnetic resonance imaging (MRI) before prostate biopsy appeared to offer similar diagnostic accuracy compared with routine transrectal ultrasound-guided random biopsy in the diagnosis of prostate cancer. Similar numbers of cancers were detected with and without MRI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01357512. PMID- 26033154 TI - Effects of fire and CO2 on biogeography and primary production in glacial and modern climates. AB - Dynamic global vegetation models (DGVMs) can disentangle causes and effects in the control of vegetation and fire. We used a DGVM to analyse climate, CO2 and fire influences on biome distribution and net primary production (NPP) in last glacial maximum (LGM) and pre-industrial (PI) times. The Land surface Processes and eXchanges (LPX) DGVM was run in a factorial design with fire 'off' or 'on', CO2 at LGM (185 ppm) or PI (280 ppm) concentrations, and LGM (modelled) or recent climates. Results were analysed by Stein-Alpert decomposition to separate primary effects from synergies. Fire removal causes forests to expand and global NPP to increase slightly. Low CO2 greatly reduces forest area (dramatically in a PI climate; realistically under an LGM climate) and global NPP. NPP under an LGM climate was reduced by a quarter as a result of low CO2 . The reduction in global NPP was smaller at low temperatures, but greater in the presence of fire. Global NPP is controlled by climate and CO2 directly through photosynthesis, but also through biome distribution, which is strongly influenced by fire. Future vegetation simulations will need to consider the coupled responses of vegetation and fire to CO2 and climate. PMID- 26033155 TI - Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta-analysis. AB - OBJECTIVE: To determine whether caesarean delivery in the first pregnancy is a risk factor for unexplained antepartum stillbirth in a second pregnancy. DESIGN: A population-based retrospective cohort study and meta-analysis. SETTING: All maternity units in Scotland. PARTICIPANTS: A cohort of 128 585 second births, 1999-2008. METHODS: Time-to-event analysis and random-effects meta-analysis. MAIN OUTCOME MEASURE: Risk of unexplained antepartum stillbirth in a second pregnancy. RESULTS: There were 88 stillbirths among 23 688 women with a previous caesarean delivery (2.34 per 10 000 women per week) and 288 stillbirths in 104 897 women who had previously delivered vaginally (1.67 per 10 000 women per week, P = 0.002). When analysed by cause, women with a previous caesarean delivery had an increased risk of unexplained stillbirth (hazard ratio, HR 1.47; 95% confidence interval, 95% CI 1.12-1.94; P = 0.006) and, as previously observed, the excess risk was apparent from 34 weeks of gestation onwards. The risk did not differ in relation to the indication of the caesarean delivery, and was independent of maternal characteristics and previous obstetric complications. We identified three other comparable studies (two in North America and one in Europe), and meta analysis of these studies showed a statistically significant association between previous caesarean delivery and the risk of antepartum stillbirth in the second pregnancy (pooled HR 1.40; 95% CI 1.10-1.77; P = 0.006). CONCLUSIONS: Women who have had a previous caesarean delivery are at increased risk of unexplained stillbirth in the second pregnancy. TWEETABLE ABSTRACT: Caesarean first delivery is associated with an increased risk of unexplained stillbirth in the next pregnancy. PMID- 26033156 TI - Working in a 'third space': a closer look at the hybridity, identity and agency of nurse practitioners. AB - Nurse practitioners (NPs), as advanced practice nurses, have evolved over the years to become recognized as an important and growing trend in Canada and worldwide. In spite of sound evidence as to the effectiveness of NPs in primary care and other care settings, role implementation and integration continue to pose significant challenges. This article utilizes postcolonial theory, as articulated by Homi Bhabha, to examine and challenge traditional ideologies and structures that have shaped the development, implementation and integration of the NP role to this day. Specifically, we utilize Bhabha's concepts of third space, hybridity, identity and agency in order to further conceptualize the nurse practitioner role, to examine how the role challenges some of the inherent assumptions within the healthcare system and to explore how development of each to these concepts may prove useful in integration of nurse practitioners within the healthcare system. Our analysis casts light on the importance of a broader, power structure analysis and illustrates how colonial assumptions operating within our current healthcare system entrench, expand and re-invent, as well as mask the structures and practices that serve to impede nurse practitioner full integration and contributions. Suggestions are made for future analysis and research. PMID- 26033157 TI - Brain natriuretic peptide levels variation after left atrial appendage occlusion. AB - OBJECTIVE: To explore the variations of brain natriuretic peptide (BNP) secretion after left atrial appendage occlusion. BACKGROUND: Left atrial appendage occlusion has been increasingly performed in the last few years, however little is known about the physiological consequences of left atrial appendage occlusion. Left atrial appendage regulates partially intravascular volume via release of brain natriuretic peptide. Brain natriuretic peptide levels have been related to increased risk of stroke in atrial fibrillation patients. METHODS: Venous blood samples were obtained in consecutive patients undergoing left atrial appendage occlusion before, 24 hr after device implantation and at the first visit after discharge (45-60 days) for BNP measurement. RESULTS: Left atrial appendage occlusion was performed in 34 patients with non-valvular atrial fibrillation and contraindication to long-term oral anticoagulation or at high-risk of bleeding. There were no differences in BNP levels between baseline and 24 hr after device implantation. However left atrial appendage closure resulted in a significant decrease in BNP levels at the first follow-up visit (45-60 days) compared to baseline measurements (759.90 pg ml(-1) vs. 636.90 pg ml(-1) , P = 0.013). CONCLUSIONS: Left atrial appendage occlusion modifies BNP levels. These levels decrease after left atrial appendage occlusion. The clinical consequences of these findings need to be evaluated in further studies. (c) 2015 Wiley Periodicals, Inc. PMID- 26033158 TI - Cochlear implant music: A first-person perspective. PMID- 26033159 TI - Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis. AB - DICER1 plays a critical role in microRNA (miRNA) biogenesis. Recurrent somatic 'hotspot' mutations at the four metal-binding sites within the RNase IIIb domain of DICER1 were identified in ovarian sex cord-stromal tumours and have since been described in other paediatric tumours. In this study, we screened the RNase IIIb domain of DICER1 in 290 endometrial tumours and identified six cases with hotspot mutations, including two cases affected by an atypical G1809R mutation directly adjacent to a metal-binding site. Using Illumina and Sanger targeted resequencing, we observed and validated biallelic DICER1 mutations in several cases with hotspot mutations. Through in vitro DICER1 cleavage assays, small RNA deep sequencing and real-time PCR, we demonstrated that mutations adding a positively charged side chain to residue 1809 have similar detrimental effects on 5p miRNA production to mutations at the metal-binding sites. As expected, 5p miRNAs were globally reduced in tumours and cell lines with hotspot mutations. Pathway analysis of gene expression profiles indicated that genes de-repressed due to loss of 5p miRNAs are strongly associated with pathways regulating the cell cycle. Using a Dicer1-null mouse cell line model, we found that expression of DICER1 hotspot mutants promoted cell proliferation, whereas wild-type (WT) DICER1 inhibited cell proliferation. Furthermore, targets of let-7 family miRNAs are enriched among the up-regulated genes, suggesting that loss of let-7 may be impacting downstream pathways. Our results reveal that DICER1 hotspot mutations are implicated in common malignancies and may constitute a unique oncogenic pathway. PMID- 26033160 TI - A Rapid and High-Throughput Assay for the Estimation of Conversions of Ene Reductase-Catalysed Reactions. AB - A fast and sensitive colorimetric assay (FRED, fast and reliable ene-reductases detection) that allows the estimation of levels of conversion of ene-reductase (ER)-catalysed reactions has been developed. The activated olefin is reduced by ER at the expense of NAD(P)H cofactor, whose regeneration is carried out in situ by the glucose/glucose dehydrogenase system. Subsequently, the consumption of the co-substrate glucose is determined colorimetrically by a multienzymatic system. The FRED assay offers a wide range of possible applications, from enzyme fingerprinting and kinetic analysis, to primary screening of enzyme libraries and optimisation of ERs' performances under different reaction conditions. PMID- 26033161 TI - What are the minimum requirements for ketogenic diet services in resource-limited regions? Recommendations from the International League Against Epilepsy Task Force for Dietary Therapy. AB - Despite the increasing use of dietary therapies for children and adults with refractory epilepsy, the availability of these treatments in developing countries with limited resources remains suboptimal. One possible contributory factor may be the costs. There is often reported a significant perceived need for a large ketogenic diet team, supplements, laboratory studies, and follow-up visits to provide this treatment. The 2009 Epilepsia Consensus Statement described ideal requirements for a ketogenic diet center, but in some situations this is not feasible. As a result, the International League Against Epilepsy (ILAE) Task Force on Dietary Therapy was asked to convene and provide practical, cost effective recommendations for new ketogenic diet centers in resource-limited regions of the world. PMID- 26033162 TI - Predicting risk of symptomatic intracerebral hemorrhage and mortality after treatment with recombinant tissue-plasminogen activator using SEDAN score. AB - BACKGROUND AND PURPOSE: The most feared complication after treatment with recombinant tissue-plasminogen activator (rt-PA) is the occurrence of symptomatic intracerebral hemorrhage (sICH). The aims of the study were to predict the risk of sICH (ECASS II definition) after a therapy with rt-PA and to examine whether associations exist between SEDAN score and the early mortality in patients with acute ischemic stroke in a monocenter study. METHODS: During a 6-year period (2008-2013), 542 consecutive stroke patients (mean age, 73 +/- 3 years; 51.1% women; median NIHSS score, 11) treated with IV thrombolysis were included in a monocenter study. SICH was diagnosed in according to the with ECASS II definition. RESULTS: The absolute risk for sICH revealed 9.2% (95% CI, 6.5-11.4) of patients treated with IV thrombolysis and was 0%, 4.6% (95% CI, 1.3-7.9), 6.6% (95% CI, 3.3-10.5), 13.5% (95% CI, 6.7-19.2), 23.6% (95% CI, 12.7-34.5), and 26.7% (95% CI, 12.7-34.5) for 0, 1, 2, 3, 4, and >=5 SEDAN points. Logistic regression revealed that sICH was associated with increasing SEDAN scores (OR, 1.93 per SEDAN point; 95% CI, 1.51-2.46; P < 0.001). The predictive performance was assessed with area under a receiver operating characteristic curve (0.73; 95% CI, 0.65-0.80; P < 0.001). During hospitalization (median, 9 days), 53 patients (9.8%; 95% CI, 7.4-12.45) died. In-hospital mortality was higher in patients with than those without sICH (30 vs 7.7%; P < 0.001), and it was increased with increasing SEDAN score (OR, 1.45 per point; 95% CI, 1.12-1.89; P = 0.005). CONCLUSIONS: Higher SEDAN score was associated with an increased risk of sICH and early mortality in this monocenter study. PMID- 26033163 TI - Osteoarthritic changes in vervet monkey knees correlate with meniscus degradation and increased matrix metalloproteinase and cytokine secretion. AB - OBJECTIVE: Meniscus injury increases osteoarthritis risk but its pathobiology in osteoarthritis is unclear. We hypothesized that older adult vervet monkeys would exhibit knee osteoarthritic changes and the degenerative menisci from these animals would secrete matrix metalloproteinases (MMPs) and pro-inflammatory cytokines that contribute to the development of osteoarthritis. DESIGN: In a cross sectional analysis of healthy young adult (9-12 years) and old (19-26 years) adult female vervet monkeys, knees were evaluated in vivo with computed tomography (CT) imaging, and joint tissues were morphologically graded at necropsy. Meniscus explants were subsequently cultured to evaluate meniscal MMP and cytokine secretion. RESULTS: CT images revealed significant bony osteoarthritic changes in 80% of older monkeys which included increases in osteophyte number and meniscal calcification. Meniscus and cartilage degradation scores were greater in the older monkeys and were positively correlated (r > 0.7). Menisci from older animals exhibiting osteoarthritic changes secreted significantly more MMP-1, MMP-3, and MMP-8 than healthy menisci from younger monkeys. Older menisci without significant osteoarthritic changes secreted more IL-7 than healthy young menisci while older osteoarthritic menisci secreted more IL-7 and granulocyte-macrophage colony-stimulating factor than healthy older menisci. CONCLUSIONS: Aged vervets develop naturally occurring knee osteoarthritis that includes involvement of the meniscus. Degenerative menisci secreted markedly increased amounts of matrix-degrading enzymes and inflammatory cytokines. These factors would be expected to act on the meniscus tissue and local joint tissues and may ultimately promote osteoarthritis development. These finding also suggest vervet monkeys are a useful animal model for studying the progression of osteoarthritis. PMID- 26033164 TI - Metabolic stress-induced joint inflammation and osteoarthritis. AB - Osteoarthritis (OA) is a heterogeneous disorder with several risk factors. Among them, obesity has a major impact on both loading and non-loading joints. Mechanical overload and activity of systemic inflammatory mediators derived from adipose tissue (adipokines, free fatty acids (FFA), reactive oxygen species (ROS)) provide clues to the increased incidence and prevalence of OA in obesity. Recently, research found greater OA prevalence and incidence in obese patients with cardiometabolic disturbances than "healthy" obese patients, which led to the description of a new OA phenotype - metabolic syndrome (MetS)-associated OA. Indeed, individual metabolic factors (diabetes, dyslipidemia, and hypertension) may increase the risk of obesity-induced OA. This review discusses hypotheses based on pathways specific to a metabolic factor in MetS-associated OA, such as the role of advanced glycation end products (AGEs) and glucose toxicity. A better understanding of these phenotypes based on risk factors will be critical for designing trials of this specific subset of OA. PMID- 26033165 TI - The effects of oxygen level and glucose concentration on the metabolism of porcine TMJ disc cells. AB - OBJECTIVE: To determine the combined effect of oxygen level and glucose concentration on cell viability, ATP production, and matrix synthesis of temporomandibular joint (TMJ) disc cells. DESIGN: TMJ disc cells were isolated from pigs aged 6-8 months and cultured in a monolayer. Cell cultures were preconditioned for 48 h with 0, 1.5, 5, or 25 mM glucose DMEM under 1%, 5%, 10%, or 21% O2 level, respectively. The cell viability was measured using the WST-1 assay. ATP production was determined using the Luciferin-Luciferase assay. Collagen and proteoglycan synthesis were determined by measuring the incorporation of [2, 3-(3)H] proline and [(35)S] sulfate into the cells, respectively. RESULTS: TMJ disc cell viability significantly decreased (P < 0.0001) without glucose. With glucose present, decreased oxygen levels significantly increased viability (P < 0.0001), while a decrease in glucose concentration significantly decreased viability (P < 0.0001). With glucose present, decreasing oxygen levels significantly reduced ATP production (P < 0.0001) and matrix synthesis (P < 0.0001). A decreased glucose concentration significantly decreased collagen synthesis (P < 0.0001). The interaction between glucose and oxygen was significant in regards to cell viability (P < 0.0001), ATP production (P = 0.00015), and collagen (P = 0.0002) and proteoglycan synthesis (P < 0.0001). CONCLUSIONS: Although both glucose and oxygen are important, glucose is the limiting nutrient for TMJ disc cell survival. At low oxygen levels, the production of ATP, collagen, and proteoglycan are severely inhibited. These results suggest that steeper nutrient gradients may exist in the TMJ disc and it may be vulnerable to pathological events that impede nutrient supply. PMID- 26033166 TI - A clinically realistic large animal model of intra-articular fracture that progresses to post-traumatic osteoarthritis. AB - OBJECTIVE: Translation of promising treatments for post-traumatic osteoarthritis (PTOA) to patients with intra-articular fracture (IAF) has been limited by the lack of a realistic large animal model. To address this issue we developed a large animal model of IAF in the distal tibia of Yucatan minipigs and documented the natural progression of this injury. DESIGN: Twenty-two fractures were treated using open reduction and internal fixation with either an anatomic reduction or an intentional 2-mm step-off. Pre-operatively, and 3 days, 1, 2, 4, 8, and 12 weeks post-operatively, animals were sedated for synovial fluid draws and radiographs. Limb loading was monitored at the same time points using a Tekscan Walkway. Animals were sacrificed at 12 weeks and the limbs were harvested for histological evaluation. RESULTS: All animals achieved bony union by 12 weeks, facilitating nearly complete recovery of the initial 60% decrease in limb loading. TNFalpha, IL1beta, IL6, and IL8 concentrations in the fractured limbs were elevated (P < 0.05) at specific times during the 2 weeks after fracture. Histological cartilage degeneration was more severe in the step-off group (0.0001 < P < 0.27 compared to normal) than in the anatomic reconstruction group (0.27 < P < 0.99 compared to normal). CONCLUSIONS: This model replicated key features of a human IAF, including surgical stabilization, inflammatory responses, and progression to osteoarthritic cartilage degeneration, thereby providing a potentially useful model for translating promising treatment options to clinical practice. PMID- 26033167 TI - Microbial dynamics during conversion from supragingival to subgingival biofilms in an in vitro model. AB - The development of dental caries and periodontal diseases result from distinct shifts in the microbiota of the tooth-associated biofilm. This in vitro study aimed to investigate changes in biofilm composition and structure, during the shift from a 'supragingival' aerobic profile to a 'subgingival' anaerobic profile. Biofilms consisting of Actinomyces oris, Candida albicans, Fusobacterium nucleatum, Streptococcus oralis, Streptococcus mutans and Veillonella dispar were aerobically grown in saliva-containing medium on hydroxyapatite disks. After 64 h, Campylobacter rectus, Prevotella intermedia and Streptococcus anginosus were further added along with human serum, while culture conditions were shifted to microaerophilic. After 96 h, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola were finally added and the biofilm was grown anaerobically for another 64 h. At the end of each phase, biofilms were harvested for species specific quantification and localization. Apart from C. albicans, all other species gradually increased during aerobic and microaerophilic conditions, but remained steady during anaerobic conditions. Biofilm thickness was doubled during the microaerophilic phase, but remained steady throughout the anaerobic phase. Extracellular polysaccharide presence was gradually reduced throughout the growth period. Biofilm viability was reduced during the microaerophilic conversion, but was recovered during the anaerobic phase. This in vitro study has characterized the dynamic structural shifts occurring in an oral biofilm model during the switch from aerobic to anaerobic conditions, potentially modeling the conversion of supragingival to subgingival biofilms. Within the limitations of this experimental model, the findings may provide novel insights into the ecology of oral biofilms. PMID- 26033169 TI - A case series of 15 women inadvertently exposed to magnetic resonance imaging in the first trimester of pregnancy. AB - Information on the safety of first-trimester exposure to diagnostic magnetic resonance imaging (MRI) remains scarce. We are reporting a case series of 15 consecutive pregnant women who underwent an MRI scan with a 1.5-Tesla scanner of either the head (n = 5), cervical spine (n = 4), lumbar spine (n = 4), pelvis (n = 1) or knee (n = 1) in their first trimester of pregnancy (mean gestational age at exposure: 3.8 weeks). Patients were prospectively followed up until the completion of their pregnancy. Two cases received gadolinium as a contrast agent. There were 15 babies born alive. Of them, one baby was born with the left kidney not visualised by ultrasound examination, and another one with an overlapping toe in the right foot. None of these abnormalities were considered by the authors related to the MRI exposure. In conclusion, our study provides support to published preliminary evidence regarding the safety of MRI in the first-trimester pregnant women. PMID- 26033168 TI - Test-retest reliability of freesurfer measurements within and between sites: Effects of visual approval process. AB - In the last decade, many studies have used automated processes to analyze magnetic resonance imaging (MRI) data such as cortical thickness, which is one indicator of neuronal health. Due to the convenience of image processing software (e.g., FreeSurfer), standard practice is to rely on automated results without performing visual inspection of intermediate processing. In this work, structural MRIs of 40 healthy controls who were scanned twice were used to determine the test-retest reliability of FreeSurfer-derived cortical measures in four groups of subjects-those 25 that passed visual inspection (approved), those 15 that failed visual inspection (disapproved), a combined group, and a subset of 10 subjects (Travel) whose test and retest scans occurred at different sites. Test-retest correlation (TRC), intraclass correlation coefficient (ICC), and percent difference (PD) were used to measure the reliability in the Destrieux and Desikan Killiany (DK) atlases. In the approved subjects, reliability of cortical thickness/surface area/volume (DK atlas only) were: TRC (0.82/0.88/0.88), ICC (0.81/0.87/0.88), PD (0.86/1.19/1.39), which represent a significant improvement over these measures when disapproved subjects are included. Travel subjects' results show that cortical thickness reliability is more sensitive to site differences than the cortical surface area and volume. To determine the effect of visual inspection on sample size required for studies of MRI-derived cortical thickness, the number of subjects required to show group differences was calculated. Significant differences observed across imaging sites, between visually approved/disapproved subjects, and across regions with different sizes suggest that these measures should be used with caution. PMID- 26033170 TI - Acute pulmonary embolism following gynaecological surgery. PMID- 26033172 TI - Puerperal ischaemic stroke caused by moyamoya disease: A case report. PMID- 26033171 TI - Infiltrating mucinous appendicular carcinoma during pregnancy. A case report and review of the literature. PMID- 26033173 TI - Osteomyelitis of the pubic symphysis - A case report. PMID- 26033174 TI - A Modular Synthesis of Modified Phosphoanhydrides. AB - Phosphoanhydrides (P-anhydrides) are ubiquitously occurring modifications in nature. Nucleotides and their conjugates, for example, are among the most important building blocks and signaling molecules in cell biology. To study and manipulate their biological functions, a diverse range of analogues have been developed. Phosphate-modified analogues have been successfully applied to study proteins that depend on these abundant cellular building blocks, but very often both the preparation and purification of these molecules are challenging. This study discloses a general access to P-anhydrides, including different nucleotide probes, that greatly facilitates their preparation and isolation. The convenient and scalable synthesis of, for example, (18) O labeled nucleoside triphosphates holds promise for future applications in phosphoproteomics. PMID- 26033175 TI - Synergistic effects of fire and elephants on arboreal animals in an African savanna. AB - Disturbance is a crucial determinant of animal abundance, distribution and community structure in many ecosystems, but the ways in which multiple disturbance types interact remain poorly understood. The effects of multiple disturbance interactions can be additive, subadditive or super-additive (synergistic). Synergistic effects in particular can accelerate ecological change; thus, characterizing such synergies, the conditions under which they arise, and how long they persist has been identified as a major goal of ecology. We factorially manipulated two principal sources of disturbance in African savannas, fire and elephants, and measured their independent and interactive effects on the numerically dominant vertebrate (the arboreal gekkonid lizard Lygodactylus keniensis) and invertebrate (a guild of symbiotic Acacia ants) animal species in a semi-arid Kenyan savanna. Elephant exclusion alone (minus fire) had negligible effects on gecko density. Fire alone (minus elephants) had negligible effects on gecko density after 4 months, but increased gecko density twofold after 16 months, likely because the decay of fire-damaged woody biomass created refuges and nest sites for geckos. In the presence of elephants, fire increased gecko density nearly threefold within 4 months of the experimental burn; this occurred because fire increased the incidence of elephant damage to trees, which in turn improved microhabitat quality for geckos. However, this synergistic positive effect of fire and elephants attenuated over the ensuing year, such that only the main effect of fire was evident after 16 months. Fire also altered the structure of symbiotic plant-ant assemblages occupying the dominant tree species (Acacia drepanolobium); this influenced gecko habitat selection but did not explain the synergistic effect of fire and elephants. However, fire-driven shifts in plant-ant occupancy may have indirectly mediated this effect by increasing trees' susceptibility to elephant damage. Our findings confirm the importance of fire * elephant interactions in structuring arboreal wildlife populations. Where habitat modification by megaherbivores facilitates co occurring species, fire may amplify these effects in the short term by increasing the frequency or intensity of herbivory, leading to synergy. In the longer term, tree mortality due to both top kill by fire and toppling by large herbivores may reduce overall microhabitat availability, eliminating the synergy. PMID- 26033176 TI - Understanding Small-Molecule Interactions in Metal-Organic Frameworks: Coupling Experiment with Theory. AB - Metal-organic frameworks (MOFs) have gained much attention as next-generation porous media for various applications, especially gas separation/storage, and catalysis. New MOFs are regularly reported; however, to develop better materials in a timely manner for specific applications, the interactions between guest molecules and the internal surface of the framework must first be understood. A combined experimental and theoretical approach is presented, which proves essential for the elucidation of small-molecule interactions in a model MOF system known as M2 (dobdc) (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate; M = Mg, Mn, Fe, Co, Ni, Cu, or Zn), a material whose adsorption properties can be readily tuned via chemical substitution. It is additionally shown that the study of extensive families like this one can provide a platform to test the efficacy and accuracy of developing computational methodologies in slightly varying chemical environments, a task that is necessary for their evolution into viable, robust tools for screening large numbers of materials. PMID- 26033177 TI - Chemotoxicity recurrence in older patients: Risk factors and effectiveness of preventive strategies-a prospective study. AB - BACKGROUND: The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) and adjustment rules after severe toxicity are derived by consensus, but to the authors' knowledge little is known regarding the determinants of toxicity recurrence, especially in the elderly. METHODS: The authors prospectively accrued 200 patients (aged >=65 years) before chemotherapy. For those with CTCAE grade 3 to 4 nonhematologic or CTCAE grade 4 hematologic toxicities (severe toxicity), the duration and functional impact, treatment modifications, and severe toxicity recurrence were recorded. The regimen's toxicity was adjusted with the MAX2 index, the average of the most frequent grade 4 hematologic toxicities and the most frequent grade 3 to 4 nonhematologic toxicities reported in publications of a regimen. RESULTS: The median patient age was 73 years (range, 65-90 years). Among 163 patients who were evaluable for toxicity after >=1 treatment cycle (receiving on average 4.73 cycles), 82 had severe toxicity, 10 were discontinued for toxicity, 6 were discontinued for other reasons, and 5 patients had died. Sixty-one patients received further chemotherapy: 41 without dose modification (16 with secondary prevention measures) and 20 with dose modifications. Without modification, 19 patients (46%) experienced toxicity recurrence (0 deaths). With modification, 7 patients (35%) experienced a toxicity recurrence (1 death). On univariate analysis, treatment intent, hospitalization, duration-adjusted activities of daily living (ADL), quality of life impact, and fatigue were associated with dose modification. ADL remained associated on multivariate analysis (P = .02). On univariate analysis for toxicity recurrence, Eastern Cooperative Oncology Group performance status and MAX2 score demonstrated an association, with only the latter found to remain statistically significant on multivariate analysis (P = .04). CONCLUSIONS: If a severe toxicity does not have a long duration of impact on ADL, oncologists are less inclined to modify treatment. With proper supportive measures, this leads to recurrence risks similar to those shown in patients with modified treatment, with low risks of toxic deaths overall. PMID- 26033178 TI - Cellular, particle and environmental parameters influencing attachment in surface waters: a review. AB - Effective modelling of the fate and transport of water-borne pathogens is needed to support federally required pollution-reduction plans, for water quality improvement planning, and to protect public health. Lack of understanding of microbial-particle interactions in water bodies has sometimes led to the assumption that bacteria move in surface waters not associated with suspended mineral and organic particles, despite a growing body of evidence suggesting otherwise. Limited information exists regarding the factors driving interactions between micro-organisms and particles in surface waters. This review discusses cellular, particle and environmental factors potentially influencing interactions and in-stream transport. Bacterial attachment in the aquatic environment can be influenced by properties of the cell such as genetic predisposition and physiological state, surface structures such as flagella and fimbriae, the hydrophobicity and electrostatic charge of the cell surface, and the presence of outer-membrane proteins and extracellular polymeric substances. The mechanisms and degree of attachment are also affected by characteristics of mineral and organic particles including the size, surface area, charge and hydrophobicity. Environmental conditions such as the solution chemistry and temperature are also known to play an important role. Just as the size and surface of chemical particles can be highly variable, bacterial attachment mechanisms are also diverse. PMID- 26033179 TI - Surgical Outcomes After Debulking Surgery for Intraabdominal Ovarian Growing Teratoma Syndrome: Analysis of 38 Cases. AB - BACKGROUND: The goal, methods, and results of surgery for growing teratoma syndrome (GTS) in men after testicular cancer have been well described. The main surgical challenge relates to the need for vascular or thoracic procedures. But little is known about GTS in women, particularly regarding the optimal management of intraabdominal disease. This study aimed to evaluate the surgical management and outcomes (recurrences and fertility) for a large series of ovarian GTS. METHODS: This study retrospectively analyzed patients treated for an ovarian immature teratoma (IT) who subsequently experienced abdominal GTS requiring surgery. RESULTS: Between 1983 and 2014, 196 cases of IT were referred to the authors' institution or treated there, and 38 patients (19 %) subsequently experienced a GTS, including 10 cases of gliomatosis peritonei (containing exclusively pure mature glial tissue). The median age at diagnosis was 26 years (range 8-41 years), and the mean delay between IT and GTS diagnosis was 7 months (range 3-84 months). Surgical resection included peritonectomy (n = 22), diaphragmatic peritoneal resection (n = 14), bowel resection (n = 8), and splenectomy (n = 5). Conservative surgery was possible for 20 patients. Complete cytoreductive surgery was achieved for 25 patients. The mean follow-up period was 73 months (range 3-263 months). At least one recurrence developed for 10 patients (in the form of mature disease in all, and 8 of these patients had an initial complete resection. Five patients had a pregnancy. One patient died of complications from the disease (pulmonary embolism in a patient with bowel obstruction). CONCLUSIONS: The overall prognosis of abdominal GTS is good. The surgical procedures for GTS are similar to those used in debulking surgery for epithelial cancer. Whenever technically possible, a conservative surgery should be performed because spontaneous fertility is possible. Recurrent GTS is frequent even after complete surgery. PMID- 26033181 TI - 2015 Presidential Address--Society of Surgical Oncology: The Next 75 Years. PMID- 26033180 TI - Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. AB - BACKGROUND: Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. METHODS: Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. RESULTS: Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4-28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow up 13.0 [8.5-17.9] months), local recurrence occurred in 17 (15 %) patients. CONCLUSION: For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure. PMID- 26033182 TI - Alpha-synuclein negatively regulates Notch1 intracellular domain protein stability through promoting interaction with Fbw7. AB - Notch signaling pathway is well known that it is involved in regulating cell fate, proliferation and homeostasis. In this study, we show a novel function of alpha-synuclein (SNCA) to promote degradation of Notch1 intracellular domain (Notch1-IC) through Fbw7, ubiquitin E3 ligase. We identified that SNCA inhibits Notch1 transcription activity and diminishes the interaction between Notch1-IC and RBP-Jk. We also found decrease of Notch1-IC protein stability by exogenous and endogenous SNCA through proteasomal pathway, not through lysosomal pathway. And, we found that SNCA promotes interaction between Notch1-IC and Fbw7. Furthermore, SNCA directly interacts with Fbw7. SNCA increases ubiquitination of Notch-IC by Fbw7 through interaction with Fbw7. Together, these results suggest that SNCA is a novel regulator of Notch1-IC transcriptional activity with acting as an enhancer of the interaction of Notch1-IC and Fbw7 with increasing degradation of Notch1-IC. PMID- 26033183 TI - Activation of hypothalamic oxytocin neurons following tactile stimuli in rats. AB - Gentle touching or stroking has anxiolytic actions and contributes to the establishment of an intimate relationship between individuals. Oxytocin administration also has anxiolytic actions and facilitates social behaviors. In this study, we examined effects of stroking stimuli on activation of oxytocin neurons and emission of 50-kHz ultrasonic vocalizations, an index of positive emotion, in rats. The number of oxytocin neurons expressing Fos protein was increased in the hypothalamus, especially in the dorsal zone of the medial parvicellular part of the paraventricular nucleus. The number of 50-kHz ultrasonic vocalizations was also increased. These findings suggest that pleasant sensory stimuli activate hypothalamic oxytocin neurons. PMID- 26033184 TI - Multiple actions of a D3 dopamine receptor agonist, PD128907, on GABAergic inhibitory transmission between medium spiny neurons in mouse nucleus accumbens shell. AB - The nucleus accumbens (NAc) plays a crucial role in pathophysiological responses, such as reward-related behaviors, addiction, depression and schizophrenia, through activation of dopaminergic system in the midbrain area. Principal cells in the NAc are medium spiny neurons (MSNs), which constitute the majority (90 95%) of NAc neuron populations in rodents. MSNs are mutually connected to form networks of lateral inhibition. Our previous study showed that activation of D2 like receptors presynaptically inhibited GABAergic transmission between MSN-MSN connections in the NAc. D2-like receptors in MSNs have been reported to consist of D2 and D3 receptors, but their functional roles remain to be elucidated. This study, therefore, aimed at examining the effects of D3 receptor activation on MSN MSN connections using PD128907, a preferential D3 dopamine receptor agonist, and whole cell recordings from MSNs in acute slices including the NAc. In more than half of cells tested, PD128907 reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner. However, the agonist caused multiple actions, namely, decrease, increase and no significant changes, in the amplitude as well as the frequency of sIPSCs in individual cells. Our data, together with the results from previous studies, show that dopamine could suppress GABAergic transmission, i.e., lateral inhibition between some of MSNs, via activation of both D2 and D3 receptors. PMID- 26033185 TI - Effect of tactile stimulation on primary motor cortex excitability during action observation combined with motor imagery. AB - We aimed to investigate the effects of the tactile stimulation to an observer's fingertips at the moment that they saw an object being pinched by another person on the excitability of observer's primary motor cortex (M1) using transcranial magnetic stimulation (TMS). In addition, the above effects were also examined during action observation combined with the motor imagery. Motor evoked potentials (MEP) were evoked from the subjects' right first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles. Electrical stimulation (ES) inducing tactile sensation was delivered to the subjects' first and second fingertips at the moment of pinching action performed by another person. Although neither the ES nor action observation alone had significant effects on the MEP amplitude of the FDI or ADM, the FDI MEP amplitude which acts as the prime mover during pinching was reduced when ES and action observation were combined; however, no such changes were seen in the ADM. Conversely, that reduced FDI MEP amplitude was increased during the motor imagery. These results indicated that the M1 excitability during the action observation of pinching action combined with motor imagery could be enhanced by the tactile stimulation delivered to the observer's fingertips at the moment corresponding to the pinching being observed. PMID- 26033186 TI - Gender and brain regions specific differences in brain derived neurotrophic factor protein levels of depressed individuals who died through suicide. AB - Considerable evidence supports the view that depressive illness and suicidal behaviour stem from perturbations of neuroplasticity. Presently, we assessed whether depressed individuals who died by suicide displayed brain region-specific changes in brain derived neurotrophic factor (BDNF) and whether such effects varied by gender. Using postmortem samples from non-psychiatric controls and depressed individuals who died by suicide, BDNF protein levels were assessed within the hippocampus and frontopolar prefrontal cortex using Western blot. As expected, BDNF levels were reduced within the frontopolar prefrontal cortex among female depressed suicides; however, males showed no such effect. Contrastingly, within the hippocampus, depressed male but not female suicides displayed significant reductions of BDNF protein levels. Although the mechanisms driving the gender and brain region specific BDNF changes are unclear, our data do support the notion that complex alterations of neuroplasticity may be fundamentally involved in the illness. PMID- 26033187 TI - Urokinase-type plasminogen activator resulting from endometrial carcinogenesis enhances tumor invasion and correlates with poor outcome of endometrial carcinoma patients. AB - The purpose of this study was to identify the dysregulated genes involved in the tumorigenesis and progression of endometrial endometrioid adenocarcinoma (EEC), and their possible mechanisms. Endometrial specimens including normal endometrial tissues, atypical endometrial hyperplasia, and EEC were analyzed. The expression profiles were compared using GeneChip Array. The gene expression levels were determined by real-time RT-PCR in the training and testing sets to correlate the clinico-pathological parameters of EEC. Immunoblotting, in vitro cell migration and invasion assays were performed in human endometrial cancer cell lines and their transfectants. In microarray analysis, seven dysregulated genes were identified. Only the levels of urokinase-type plasminogen activator (uPA) were higher in EEC with deep myometrial invasion, positive lympho-vascular space invasion, lymph node metastasis, and advanced stages. After multivariate analysis, uPA was the only independent poor prognostic factor for disease-free survival in the EEC patients (hazard ratio: 4.65, p = 0.03). uPA may enhance the migratory and invasive capabilities of endometrial tumor cells by the phosphorylation of ERK1/2, Akt and p38 molecules. uPA is a dysregulated gene involved in the tumorigenesis, bio-pathological features and outcomes of EEC. uPA may be a potential molecule and target for the detection and treatment of EEC. PMID- 26033188 TI - The success of assisted colonization and assisted gene flow depends on phenology. AB - Global warming will jeopardize the persistence and genetic diversity of many species. Assisted colonization, or the movement of species beyond their current range boundary, is a conservation strategy proposed for species with limited dispersal abilities or adaptive potential. However, species that rely on photoperiodic and thermal cues for development may experience conflicting signals if transported across latitudes. Relocating multiple, distinct populations may remedy this quandary by expanding genetic variation and promoting evolutionary responses in the receiving habitat--a strategy known as assisted gene flow. To better inform these policies, we planted seeds from latitudinally distinct populations of the annual legume, Chamaecrista fasciculata, in a potential future colonization site north of its current range boundary. Plants were exposed to ambient or elevated temperatures via infrared heating. We monitored several life history traits and estimated patterns of natural selection to determine the adaptive value of plastic responses. To assess the feasibility of assisted gene flow between phenologically distinct populations, we counted flowers each day and estimated the degree of temporal isolation between populations. Increased temperatures advanced each successive phenological trait more than the last, resulting in a compressed life cycle for all but the southern-most population. Warming altered patterns of selection on flowering onset and vegetative biomass. Population performance was dependent on latitude of origin, with the northern most population performing best under ambient conditions and the southern-most performing most poorly, even under elevated temperatures. Among-population differences in flowering phenology limited the potential for genetic exchange among the northern- and southern-most populations. All plastic responses to warming were neutral or adaptive; however, photoperiodic constraints will likely necessitate evolutionary responses for long-term persistence, especially when involving populations from disparate latitudes. With strategic planning, our results suggest that assisted colonization and assisted gene flow may be feasible options for preservation. PMID- 26033189 TI - Resource availability hypothesis: Perceived financial and caloric status affect individuals' height preferences for potential partners. AB - Height is an important concern in human mate choices. Prior research indicates that people who live in areas with abundant resources differ from those who live in areas with scarce resources regarding height preferences. Based on a health maximizing principle, we propose a resource availability account for such differences. Compared with women's height preferences, men's height preferences are hypothesized to be more dependent on either financial or caloric resource availability. Specifically, taller females would be more preferred by males who are poor in resources than those who are rich in resources. Results from three studies supported these hypotheses. In Study 1, men from remote areas of China who had lower family income preferred taller women more than those from eastern China who had higher family income. In Study 2, men who were financially dissatisfied preferred taller women more than those who were financially satisfied. In Study 3, men with low caloric status preferred taller women more than men with high caloric status. In addition, women's height preferences in Studies 1, 2 and 3 were less determined by resource availability. These findings suggest that height preferences are changeable, depending on financial or caloric status. PMID- 26033190 TI - Estimation of infection prevalence and sensitivity in a stratified two-stage sampling design employing highly specific diagnostic tests when there is no gold standard. AB - In this work, we describe a two-stage sampling design to estimate the infection prevalence in a population. In the first stage, an imperfect diagnostic test was performed on a random sample of the population. In the second stage, a different imperfect test was performed in a stratified random sample of the first sample. To estimate infection prevalence, we assumed conditional independence between the diagnostic tests and develop method of moments estimators based on expectations of the proportions of people with positive and negative results on both tests that are functions of the tests' sensitivity, specificity, and the infection prevalence. A closed-form solution of the estimating equations was obtained assuming a specificity of 100% for both tests. We applied our method to estimate the infection prevalence of visceral leishmaniasis according to two quantitative polymerase chain reaction tests performed on blood samples taken from 4756 patients in northern Ethiopia. The sensitivities of the tests were also estimated, as well as the standard errors of all estimates, using a parametric bootstrap. We also examined the impact of departures from our assumptions of 100% specificity and conditional independence on the estimated prevalence. PMID- 26033191 TI - Early Impairment of Cardiac Function and Asynchronization of Systemic Amyloidosis with Preserved Ejection Fraction Using Two-Dimensional Speckle Tracking Echocardiography. AB - AIMS: To observe the ventricular global and regional function of the patients with systemic amyloidosis using two-dimensional speckle tracking echocardiography. METHODS: The study enrolled 31 consecutive biopsy-proved patients with systemic amyloidosis who underwent echocardiographic examination and EF >= 55% and 37 age- and gender-matched healthy controls. We compared systolic strain and strain rate, diastolic strain rate, time to peak strain, peak delay time in longitudinal, radial, circumferential directions in 16 left ventricular segments. The global peak systolic longitudinal and radial strain of left ventricle, peak systolic longitudinal strain and strain rate, diastolic strain rate of right ventricular free wall were also compared. RESULTS: (1) Global peak systolic longitudinal strain (GPSLS), peak systolic longitudinal strain (PSLS) and strain rate (PSLSR), peak early diastolic longitudinal strain rate (PELSR) in 16 segments were decreased in case (P < 0.05). (2) Peak systolic radial strain and strain rate of inferoseptum and inferolateral at the level of papillary muscle were lower (P < 0.05), and peak early diastolic radial strain rate (PERSR) was reduced (P < 0.05). (3) Peak early diastolic circumferential strain rate was lower (P < 0.05). (4) Time to peak systolic longitudinal, radial, circumferential strain was longer, and peak delay time at the same level retarded (P < 0.05). (5) Into right ventricular wall, PSLS and PSLSR at mid-segment, and PSLSR, PELSR, peak atrial systolic longitudinal strain rate (PALSR) at basal were reduced (P < 0.05). (6) Inverse correlation between interventricular septum (IVS) thickness and GPSLS and GPSRS was found (P < 0.05). CONCLUSION: Systolic and diastolic dysfunction existed in systemic amyloidosis with preserved EF. Mechanical contraction disorder may be one reason for systolic dysfunction. GPLSR and GPRSR were negatively related to IVS thickness. PMID- 26033192 TI - [Is self-confidence a factor for successful breastfeeding?]. AB - CONTEXT: Maternal self-confidence and self-efficacy in breastfeeding are recognized as factors positively associated with the initiation and duration of breastfeeding. OBJECTIVE: To evaluate the importance of this association using the Breast Feeding Self-Efficacy Scale (BSES). METHOD: This prospective study was conducted in 2012 in the Jeanne-de-Flandre maternity department in the Lille University Hospital (France). During their time in the maternity department, breastfeeding mothers who participated in the study completed the BSES, a brief self-assessment of their feelings of self-efficacy relating to breastfeeding. They then received follow-up telephone interviews at 1 and 3 months postpartum. RESULTS: One hundred and forty-nine mothers were included in the study. Breastfeeding rates were 86.5% at 1 month and 60% at 3 months. The BSES score of mothers who continued to breastfeed at 1 and 3 months was significantly higher than the score of mothers who had already weaned their children, with an AUROC of 0.72 at 3 months. This confirmed the reliability of the BSES for predicting adherence to breastfeeding. The BSES score of mothers who had previously breastfed was significantly higher than for those breastfeeding for the first time. The threshold score for the BSES was determined as 116/165. CONCLUSION: It is important that mothers who lack confidence in their ability to breastfeed be identified early, whether on the maternity ward or even before this point. The value of BSES-based breastfeeding support intervention needs to be evaluated through randomized trials. PMID- 26033193 TI - Non-invasive ventilation is useful in paediatric intensive care units if children are appropriately selected and carefully monitored. AB - Non-invasive ventilation (NIV) is commonly used in paediatric intensive care units (PICUs) for respiratory failure. This review aims to improve paediatricians' understanding of NIV, by specifying technical or practical considerations, giving advice about selecting patients and presenting pertinent published data about NIV in different circumstances. CONCLUSION: NIV is useful in PICUs if children are appropriately selected and carefully monitored. Technological advances and future clinical research will improve its use and success rate in PICU. PMID- 26033194 TI - Ternary chalcogenide micro-pseudocapacitors for on-chip energy storage. AB - We report the successful fabrication of a micro-pseudocapacitor based on ternary nickel cobalt sulfide for the first time, with performance substantially exceeding that of previously reported micro-pseudocapacitors based on binary sulfides. The CoNi2S4 micro-pseudocapacitor exhibits a maximum energy density of 18.7 mW h cm(-3) at a power density of 1163 mW cm(-3), and opens up an avenue for exploring a new family of ternary oxide/sulfide based micro-pseudocapacitors. PMID- 26033195 TI - A great divide. PMID- 26033196 TI - DNA double-strand breaks induce the expression of flavin-containing monooxygenase and reduce root meristem size in Arabidopsis thaliana. AB - Plants use various mechanisms to cope with environmental stresses, which often threaten genome integrity. In Arabidopsis, DNA double-strand breaks (DSBs) reduce root meristem size in a SOG1-dependent manner. SOG1 is a key transcription factor controlling the response to DNA damage. However, the underlying mechanism remains largely unknown. In this study, we found that treatment with the DSB inducer zeocin increased the accumulation of H2O2 in root tips. Chromatin immunoprecipitation analysis showed that SOG1 directly binds to the promoter of FMO1, which encodes a flavin-containing monooxygenase and is associated with the production of reactive oxygen species (ROS), H2O2 in particular. Indeed, zeocin induced the expression of FMO1 in a SOG1-dependent manner, and neither the sog1 nor the fmo1 knockout mutant exhibited higher H2O2 accumulation in root tips. Consequently, both sog1 and fmo1 could tolerate exposure to zeocin, in terms of root growth and the maintenance of the meristem size. However, transgenic plants over-expressing FMO1 also accumulated H2O2 in response to zeocin exposure, suggesting that other ROS-synthesis genes are also involved in the regulation of ROS production. We conclude that SOG1-mediated regulation of ROS homeostasis plays a key role in the reduction of root meristem size under DNA stress conditions. PMID- 26033197 TI - Interactions between water temperature and contaminant toxicity to freshwater fish. AB - Warming of freshwaters as a result of climate change is expected to have complex interactions with the toxicity of contaminants to aquatic organisms. The present study evaluated the effects of temperature on the acute toxicity of endosulfan, chlorpyrifos, and phenol to 3 warm water species of fish-silver perch, rainbowfish, and western carp gudgeon-and 1 cold water species, rainbow trout. Endosulfan was more toxic to silver perch at 30 degrees C and 35 degrees C than at 15 degrees C, 20 degrees C and 25 degrees C during short exposures of 24 h, but at 96 h, temperature had no effect on toxicity. Toxicity to rainbow trout increased with increasing temperature, whereas warm water species exhibited maximum toxicity at around 30 degrees C, decreasing again toward 35 degrees C. Chlorpyrifos became more toxic to all species with increasing temperature. Phenol toxicity to all species decreased at low to intermediate temperatures; but as temperatures increased further toward the upper thermal limit, phenol became more toxic. Increasing toxicity in the upper thermal range of cold water species may contribute to upstream range contraction in rivers with high toxicant loads. In contrast, warm water species may not exhibit a range shift within rivers as a result of interactions between temperature and toxicity. Catchment management to offset global warming at local scales may present opportunities to mitigate increased toxicity of contaminants to fish. PMID- 26033198 TI - Critical biogeochemical functions in the subsurface are associated with bacteria from new phyla and little studied lineages. AB - Nitrogen, sulfur and carbon fluxes in the terrestrial subsurface are determined by the intersecting activities of microbial community members, yet the organisms responsible are largely unknown. Metagenomic methods can identify organisms and functions, but genome recovery is often precluded by data complexity. To address this limitation, we developed subsampling assembly methods to re-construct high quality draft genomes from complex samples. We applied these methods to evaluate the interlinked roles of the most abundant organisms in biogeochemical cycling in the aquifer sediment. Community proteomics confirmed these activities. The eight most abundant organisms belong to novel lineages, and two represent phyla with no previously sequenced genome. Four organisms are predicted to fix carbon via the Calvin-Benson-Bassham, Wood-Ljungdahl or 3-hydroxyproprionate/4-hydroxybutarate pathways. The profiled organisms are involved in the network of denitrification, dissimilatory nitrate reduction to ammonia, ammonia oxidation and sulfate reduction/oxidation, and require substrates supplied by other community members. An ammonium-oxidizing Thaumarchaeote is the most abundant community member, despite low ammonium concentrations in the groundwater. This organism likely benefits from two other relatively abundant organisms capable of producing ammonium from nitrate, which is abundant in the groundwater. Overall, dominant members of the microbial community are interconnected through exchange of geochemical resources. PMID- 26033199 TI - Protein-protein interactions within the ensemble, eukaryotic V-ATPase, and its concerted interactions with cellular machineries. AB - The V1VO-ATPase (V-ATPase) is the important proton-pump in eukaryotic cells, responsible for pH-homeostasis, pH-sensing and amino acid sensing, and therefore essential for cell growths and metabolism. ATP-cleavage in the catalytic A3B3 hexamer of V1 has to be communicated via several so-called central and peripheral stalk units to the proton-pumping VO-part, which is membrane-embedded. A unique feature of V1VO-ATPase regulation is its reversible disassembly of the V1 and VO domain. Actin provides a network to hold the V1 in proximity to the VO, enabling effective V1VO-assembly to occur. Besides binding to actin, the 14-subunit V ATPase interacts with multi-subunit machineries to form cellular sensors, which regulate the pH in cellular compartments or amino acid signaling in lysosomes. Here we describe a variety of subunit-subunit interactions within the V-ATPase enzyme during catalysis and its protein-protein assembling with key cellular machineries, essential for cellular function. PMID- 26033200 TI - The master switchers in the aging of cardiovascular system, reverse senescence by microRNA signatures; as highly conserved molecules. AB - The incidence of CVD increases with aging, because of long-term exposure to risk factors/stressors. Aging is a complex biological process resulting in progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The main hallmarks of aging are cellular senescence, stem cell exhaustion, and altered intracellular communication. The major hallmarks of senescence are mitochondrial dysfunction, genomic instability, telomere attrition and epigenetic alterations, all of which contributing to cellular aging. Such events are controls by a family of small, non-coding RNAs (miRNAs) that interact with component of cellular senescence pathway; mitochondrial biogenesis/removal, DNA damage response machinery and IGF-1 signaling pathway. Here, we review recent in vivo/in vitro reports that miRNAs are key modulators of heart senescence, and act as master switchers to influence reprogramming pathway. We discuss evidence that abrupt deregulation of some mit-miRNAs governing senescence programs underlies age-associated CVD. In particular, due to the highly conserved nature and well-recognized target sites, miRNAs have been defined as master switchers in controlling heart progenitor cell biology. Modulation of mit-miRNA expression holds the great promise in switching off/on cellular senescence/reprogramming to rejuvenate stem cells to aid regenerative process. PMID- 26033201 TI - Association of Serum Uric Acid Concentration With Metabolic Risk Factors in Patients With Type 2 Diabetes. PMID- 26033202 TI - Exposure to systemic antibacterial medications during pregnancy and risk of childhood cancer. AB - BACKGROUND: Up to one-third of women receive prescriptions for systemic antibacterial medications during pregnancy. This paper looks at the association between maternal use of systemic antibacterial medications during pregnancy and childhood cancer risk in the offspring using the prospective data on medication. METHODS: A population-based follow-up study was carried out using Danish and Swedish register data. Exposure was maternal redemption of a prescription for a systemic antibacterial in the 3 months prior to pregnancy and during pregnancy (exposure window) documented in the national prescription registers, and offspring were followed up from birth to a cancer diagnosis, death, emigration, day before 15th birthday or end of follow-up, whichever came first. Timing, dosage, specific medication types and types of childhood cancer were also considered. RESULTS: Mothers of 35.1% (n = 506,194) of the children filled at least one prescription for systemic antibacterials during the exposure window. Exposed children had a hazard ratio of 1.08 (95% confidence interval: 0.97, 1.20) compared with unexposed children. Statistically significant results were found for some specific medications (for example, 'other antibacterials'/Anatomical Therapeutic Chemical code J01X) and combinations of cancer types and specific medications (leukaemia and other antibacterials, and hepatic cancers and tetracyclines). CONCLUSIONS: The results of this study indicate that most antibacterial drugs used during pregnancy were not related to childhood cancer risk in the offspring. However, some may be associated with the development of some specific types of childhood cancers. Our findings need to be replicated in an independent data source. PMID- 26033203 TI - Theory of mind difficulties in patients with alcohol dependence: beyond the prefrontal cortex dysfunction hypothesis. AB - BACKGROUND: Previous studies have shown that alcohol-dependent (AD) individuals have difficulties inferring other people's emotion, understanding humor, and detecting a faux pas. This study aimed at further understanding the nature of such "Theory of Mind" (ToM) difficulties. METHODS: A total of 34 recently detoxified AD and 34 paired controls were compared based on 2 nonverbal and video based false belief tasks. These tasks were designed to identify 3 different types of deficits: (i) a deficit in dealing with the general task demands, (ii) a selective deficit in self-perspective inhibition, and (iii) a deficit in tracking the other person's mental state. (i) and (ii) are compatible with the hypothesis of a prefrontal cortex dysfunction being at the origin of AD individuals' social difficulties, while (iii) would suggest the possible contribution of a dysfunction of the temporo-parietal junction in explaining the social difficulties. RESULTS: Group analyses highlighted that AD individuals performed worse on the 2 false belief tasks than controls. Individual analyses showed, however, that just under half of the AD individuals were impaired compared to controls. Moreover, most of the AD individuals who were impaired showed a deficit in tracking the other person's belief. This deficit was linked to disease-related factors such as illness duration, average alcohol consumption, and craving but not to general reasoning abilities, depression, anxiety, or demographic variables. CONCLUSIONS: Just under half of the AD individuals tested showed a ToM deficit, and in most cases, the deficit concerned the tracking of other people's mental states. Such a type of deficit has previously been associated with lesions to the temporo-parietal brain areas, indicating that a prefrontal cortex dysfunction may not be the sole origin of the social cognition deficits observed in alcohol dependence. PMID- 26033205 TI - Effects of Spinal Cord Stimulation on Pain Thresholds and Sensory Perceptions in Chronic Pain Patients. AB - OBJECTIVE: Spinal cord stimulation (SCS) has been in clinical use for nearly four decades. In earliest observations, researchers found a significant increase in pain threshold during SCS therapy without changes associated with touch, position, and vibration sensation. Subsequent studies yielded diverse results regarding how SCS impacts pain and other sensory thresholds. This pilot study uses quantitative sensory testing (QST) to objectively quantify the impact of SCS on warm sensation, heat pain threshold, and heat pain tolerance. MATERIALS AND METHODS: Nineteen subjects with an indwelling SCS device for chronic pain were subjected to QST with heat stimuli. QST was performed on an area of pain covered with SCS-induced paresthesia and an area without pain and without paresthesia, while the SCS was turned off and on. The temperature at which the patient detected warm sensation, heat pain, and maximal tolerable heat pain was used to define the thresholds. RESULTS: We found that all three parameters, the detection of warm sensation, heat pain threshold, and heat pain tolerance, were increased during the period when SCS was on compared with when it was off. This increase was observed in both painful and non-painful sites. CONCLUSION: The observed pain relief during SCS therapy seems to be related to its impact on increased sensory threshold as detected in this study. The increased sensory threshold on areas without pain and without the presence of SCS coverage may indicate a central (spinal and/or supra-spinal) influence from SCS. PMID- 26033204 TI - Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation. AB - Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and alpha-smooth muscle actin (alpha-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and alpha-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation. PMID- 26033206 TI - Paradoxical effects of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activator gingerol on NG115-401L neuronal cells: failure to augment ER Ca(2+) uptake and protect against ER stress-induced cell death. AB - Perturbation of endoplasmic reticulum (ER) Ca(2+) homeostasis and ER stress are thought to underlie a spectrum of defects encompassing major societal diseases such as diabetes and neurodegeneration. In this report we used the NG115-401L neuronal cell line to test the hypothesis that neuroprotection against ER stress may be conferred by pharmacological stimulation of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pumps. We report that the SERCA activator gingerol stimulates SR microsomal Ca(2+)-ATPase activity and restores enzymatic function in the presence of potent SERCA blockers. Yet, enzyme protection in isolated membranes does not extend to protection from ER stress in intact NG115 401L cells. Surprisingly, gingerol not only failed to protect cells from SERCA blocker-induced ER stress and cell death, the compound itself potently induced cell death. Also, we report that gingerol failed to augment ER Ca(2+) uptake, a result contradictory to what has been observed in muscle. Unexpectedly, gingerol discharged ER Ca(2+) stores and coupled robustly to Ca(2+) influx pathways. These observations suggest that gingerol is not acting as a traditional SERCA blocker as thapsigargin mediated ER Ca(2+) store depletion fails to stimulate Ca(2+) influx in the NG115-401L cell phenotype. Moreover, cell death induced by gingerol, in contrast to the classic SERCA inhibitors, is not accompanied by increases in reactive oxygen species production or enzymatic caspase activity. These results argue for a finer regulatory control on SERCA function with gingerol's actions revealing potentially novel routes of coupling altered pump regulation to the assembly of functional Ca(2+) influx units and activation of cell death pathways. PMID- 26033207 TI - In vivo potency of different ligands on voltage-gated sodium channels. AB - The Ranvier nodes of thick myelinated nerve fibers contain almost exclusively voltage-gated sodium channels (Navs), while the unmyelinated fibers have several receptors (e.g., cannabinoid, transient receptor potential vanilloid receptor 1), too. Therefore, a nerve which contains only motor fibers can be an appropriate in vivo model for selective influence of Navs. The goals were to evaluate the potency of local anesthetic drugs on such a nerve in vivo; furthermore, to investigate the effects of ligands with different structures (arachidonic acid, anandamide, capsaicin and nisoxetine) that were proved to inhibit Navs in vitro with antinociceptive properties. The marginal mandibular branch of the facial nerve was explored in anesthetized Wistar rats; after its stimulation, the electrical activity of the vibrissae muscles was registered following the perineural injection of different drugs. Lidocaine, bupivacaine and ropivacaine evoked dose-dependent decrease in electromyographic activity, i.e., lidocaine had lower potency than bupivacaine or ropivacaine. QX-314 did not cause any effect by itself, but its co-application with lidocaine produced a prolonged inhibition. Nisoxetine had a very low potency. While anandamide and capsaicin in high doses caused about 50% decrease in the amplitude of action potential, arachidonic acid did not influence the responses. We proved that the classical local anesthetics have high potency on motor nerves, suggesting that this method might be a reliable model for selective targeting of Navs in vivo circumstances. It is proposed that the effects of these endogenous lipids and capsaicin on sensory fibers are not primarily mediated by Navs. PMID- 26033208 TI - Could less be more?-A systematic review and meta-analysis of sublobar resections versus lobectomy for non-small cell lung cancer according to patient selection. AB - OBJECTIVES: There is renewed interest in performing segmentectomies and wedge resections for selected patients with early-stage non-small cell lung cancer. However, comparative data on sublobar resections versus lobectomies include 'intentionally selected' patients who could tolerate either procedure, or 'compromised' patients who could only undergo sublobar resections due to significant comorbidities or insufficient cardiopulmonary reserve. To address this important point, the present meta-analysis aimed to compare the survival outcomes of sublobar resections and segmentectomies versus lobectomies based on patient selection and surgical intent. METHODS: A systematic review was performed using 6 online databases to identify all comparative studies that presented survival data on sublobar resections versus lobectomy procedures. These studies were then categorized according to the patient selection process for those who underwent sublobar resections. Patients were considered 'intentionally selected' if they could have tolerated either procedure, 'compromised' if they underwent a sublobar resection due to ineligibility for a lobectomy, or 'non-specified'. RESULTS: Fifty-four studies, including a single randomized controlled trial, involving 38,959 patients were found to meet the predefined selection criteria. For sublobar resections, comparative data demonstrated no significant difference in overall survival in the 'intentionally selected' group, but a significantly worse outcome for sublobar resections in the 'compromised group'. Similarly, for the comparison of segmentectomies versus lobectomies, available data demonstrated no significant difference in overall survival in the 'intentionally selected' group, but a significantly worse outcome for segmentectomy in the 'compromised group'. CONCLUSIONS: The present meta-analysis was the first to emphasize the patient selection process to compare 'intentionally selected' and 'compromised' patients who underwent sublobar resections versus lobectomies. Our results suggested that segmentectomies may be a feasible alternative for selected patients who could tolerate either procedure. These patients generally had tumours that were <2cm, located peripherally with favourable histopathology, and with ground-glass opacity on imaging. PMID- 26033210 TI - Molecular basis for odorant receptor tuning: a short C-terminal sequence is necessary and sufficient for selectivity of mosquito Or8. AB - A birth-and-death evolutionary model for odorant receptor gene repertoires presumes the creation of repertoires with the capacity for high-level diversity and rapid ligand specificity change. This changes the recognised odour space, directly affecting fitness-related behaviours and ultimately affecting adaptation to new environments and resources. The proximate molecular mechanisms underlying the tuning of odorant receptor repertoires, and thus peripheral olfaction, are unclear. In the present study, we report a concrete example of this model of odorant receptor evolution leading to rapid changes in receptor tuning that leave the peripheral neuronal circuitry intact. We identified a conserved odorant receptor gene in mosquitoes, Or8, which in Culex quinquefasciatus underwent a duplication and inversion event. The paralogues differ in only minor structural changes manifesting at the C-terminus. We assessed the specificity of the paralogous odorant receptors and receptor neurones. We found that the functional tuning of the receptor was indeed reflected in minor differences in amino acid structure. Specifically, we found that enantiomeric specificity of these mosquito Or8 paralogues relies on eight C-terminal amino acids encoded in the final exon of the gene; thus, the birth of a paralogous odorant receptor can change the tuning of the peripheral olfactory system. PMID- 26033209 TI - Using facebook to recruit young adult veterans: online mental health research. AB - BACKGROUND: Veteran research has primarily been conducted with clinical samples and those already involved in health care systems, but much is to be learned about veterans in the community. Facebook is a novel yet largely unexplored avenue for recruiting veteran participants for epidemiological and clinical studies. OBJECTIVE: In this study, we utilized Facebook to recruit a sample of young adult veterans for the first phase of an online alcohol intervention study. We describe the successful Facebook recruitment process, including data collection from over 1000 veteran participants in approximately 3 weeks, procedures to verify participation eligibility, and comparison of our sample with nationally available norms. METHODS: Participants were young adult veterans aged 18-34 recruited through Facebook as part of a large study to document normative drinking behavior among a large community sample of veterans. Facebook ads were targeted toward young veterans to collect information on demographics and military characteristics, health behaviors, mental health, and health care utilization. RESULTS: We obtained a sample of 1023 verified veteran participants over a period of 24 days for the advertising price of approximately US $7.05 per verified veteran participant. Our recruitment strategy yielded a sample similar to the US population of young adult veterans in most demographic areas except for race/ethnicity and previous branch of service, which when we weighted the sample on race/ethnicity and branch a sample better matched with the population data was obtained. The Facebook sample recruited veterans who were engaged in a variety of risky health behaviors such as binge drinking and marijuana use. One fourth of veterans had never since discharge been to an appointment for physical health care and about half had attended an appointment for service compensation review. Only half had attended any appointment for a mental health concern at any clinic or hospital. Despite more than half screening positive for current probable mental health disorders such as post-traumatic stress disorder, depression, anxiety, only about 1 in 3 received mental health care in the past year and only 1 in 50 received such care within the past month. CONCLUSIONS: This work expands on the work of other studies that have examined clinical samples of veterans only and suggests Facebook can be an adequate method of obtaining samples of veterans in need of care. TRIAL REGISTRATION: Clinicaltrials.gov NCT02187887; http://clinicaltrials.gov/ct2/show/NCT02187887 (Archived by WebCite at http://www.webcitation.org/6YiUKRsXY). PMID- 26033211 TI - Importance of Internal Porosity for Glucan Adsorption in Mesoporous Carbon Materials. AB - To better understand the adsorption of long-chain poly(1 -> 4)-beta-D-glucans on carbon surfaces as well as interactions responsible for this adsorption, we use a comparative study involving mesoporous carbon-silica composite materials that have been etched to varying degrees and all-atom molecular dynamics simulations. The materials synthesized as part of this etching study consist of an as synthesized composite material (MCN-MSN), MCN-MSN-0.5 (composite materials consisting of 50% carbon by mass), MCN-MSN-0.3 (composite materials consisting of 70% carbon by mass), and MCN, in which silica etching was conducted using an aqueous ethanolic solution of either NaOH or HF. Data for the adsorption of long chain glucans to these materials from concentrated aqueous HCl (37 wt %) solution demonstrate a direct relationship between the amount of beta-glu adsorption and the magnitude of exposed carbon mesopore surface area, which systematically increases and is also accompanied by an increase in the mesopore size during silica etching. This demonstrates beta-glu adsorption as occurring on internal carbon mesopores rather than exclusively on the external carbon surface. These experimental data on adsorption were corroborated by molecular dynamics (MD) simulations of beta-glu adsorption to a graphene bilayer separated by a distance of 3.2 nm, chosen to correspond to the carbon mesopore diameter of the experimental system. Simulation results using a variety of beta-glu solvent systems demonstrate the rapid adsorption of a beta-glu strand on the graphitic carbon surface via axial coupling and are consistent with experimentally observed trends in fast adsorption kinetics. Solvent-mediated effects such as small-scale hydrophobicity and preferential interactions with ions are shown to play important roles in modulating glucan adsorption to carbon surfaces, whereas experimental data on hydrophobically modified silica demonstrate that hydrophobicity in and of itself is insufficient to cause beta-glu adsorption from concentrated aqueous HCl solution. PMID- 26033212 TI - Capsule Commentary on Williams et al., Factors Underlying Quality Problems with Alcohol Screening Prompted by a Clinical Reminder in Primary Care: A Multisite Qualitative Study. PMID- 26033213 TI - Capsule Commentary on Lee et al., Patient use of Email, Facebook, and Physicians' Websites to Communicate with Physicians: A National Online Survey of Retail Pharmacy Users. PMID- 26033214 TI - Measuring Burnout in Primary Care Staff. PMID- 26033215 TI - Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. AB - Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades the essential amino acid l-tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1-deficient((-/-)) mice were crossed with Apc(Min/+) mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1-methyltryptophan (1-mT) also resulted in no significant differences in tumor size and number in Apc(Min/+) mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro inflammatory cytokines and a significant decrease in the number of Foxp3-positive regulatory T cells in the colon tumors of Ido1((-/-)) mice. Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment. PMID- 26033216 TI - The PM10 fraction of road dust in the UK and India: Characterization, source profiles and oxidative potential. AB - Most studies of road dust composition have sampled a very wide range of particle sizes, but from the perspective of respiratory exposure to resuspended dusts, it is the PM10 fraction which is of most importance. The PM10 fraction of road dust samples was collected at two sites in Birmingham, UK (major highway and road tunnel) and one site in New Delhi, India. Dust loadings were found to be much higher for New Delhi compared to Birmingham, while concentrations of several species were much higher in the case of Birmingham. Detailed chemical source profiles were prepared for both cities and previously generated empirical factors for source attribution to brake wear, tyre wear, and crustal dust were successfully applied to the UK sites. However, 100% of the mass for the Indian site could not be accounted for using these factors. This study highlights the need for generation of local empirical estimation factors for non-exhaust vehicle emissions. A limited number of bulk road dust and brake pad samples were also characterized. Oxidative potential (OP) was also determined for a limited number of PM10 and bulk road dust samples, and Cu was found to be a factor significantly associated with OP in PM10 and bulk road dust. PMID- 26033217 TI - Support of Nerve Conduction by Respiring Myelin Sheath: Role of Connexons. AB - Recently, we have demonstrated that myelin conducts an extramitochondrial oxidative phosphorylation, hypothesizing a novel supportive role for myelin in favor of the axon. We have also hypothesized that the ATP produced in myelin could be transferred thought gap junctions. In this work, by biochemical, immunohistochemical, and electrophysiological techniques, the existence of a connection among myelin to the axon was evaluated, to understand how ATP could be transferred from sheath to the axoplasm. Data confirm a functional expression of oxidative phosphorylation in isolated myelin. Moreover, WB and immunohistochemistry on optic nerve slices show that connexins 32 and 43 are present in myelin and colocalize with myelin basic protein. Interestingly, addition of carbenoxolone or oleamide, two gap junction blockers, causes a decrease in oxidative metabolism in purified myelin, but not in mitochondria. Similar effects were observed on conduction speed in hippocampal Schaffer collateral, in the presence of oleamide. Confocal analysis of optic nerve slices showed that lucifer yellow (that only passes through aqueous pores) signal was found in both the sheath layers and the axoplasma. In the presence of oleamide, but not with oleic acid, signal significantly decreased in the sheath and was lost inside the axon. This suggests the existence of a link among myelin and axons. These results, while supporting the idea that ATP aerobically synthesized in myelin sheath could be transferred to the axoplasm through gap junctions, shed new light on the function of the sheath. PMID- 26033218 TI - Overexpression of hsp27 Rescued Neuronal Cell Death and Reduction in Life- and Health-Span in Drosophila melanogaster Against Prolonged Exposure to Dichlorvos. AB - Long-term exposure to dichlorvos (O,O-dimethyl-2,2-dichlorovinyl phosphate (DDVP), an organophosphate pesticide) is reported to exert neurotoxicity, i.e., generation of reactive oxygen species (ROS), oxidative damage, and neuronal cell death along with life- and health-span reduction in nontarget organisms including humans. However, studies on genetic modulation towards neuroprotection against prolonged DDVP exposure are elusive. Hsp27 (a small heat shock protein) is involved in various cellular processes and thus has attained emphasis as a therapeutic target. We aimed to examine the protective effect of hsp27 overexpression against prolonged DDVP exposure using an in vivo model Drosophila melanogaster. Flies were exposed to 15.0 ng/ml DDVP for a prolonged period to examine neuronal cell death, locomotor performance, and lifespan. After prolonged exposure, cell death, ROS level, glutathione depletion, nicotinamide adenine dinucleotide phosphate level (NADPH), glucose-6-phosphate dehydrogenase (G6PD), and thioredoxin reductase (TrxR) activities were examined in fly brain tissues at different days of age (days 10, 20, and 30). Flies with ubiquitous overexpression of hsp27 showed better resistance (improved lifespan and locomotor performance) in comparison to that targeted to motor neurons and nervous system. These flies also exhibited lesser intracellular ROS level and glutathione depletion by restoring G6PD activity, NADPH level, and TrxR activity in their brains thereby resisted neuronal cell death. Conversely, hsp27 knockdown flies exhibited reversal of the above endpoints. The study evidenced the neuroprotective efficacy of hsp27 overexpression against prolonged DDVP exposure and favored Hsp27 as a therapeutic target towards achieving better organismal (including human) health against long-term chemical exposure. PMID- 26033219 TI - Effects of Ghrelin on the Proteolytic Pathways of Alzheimer's Disease Neuronal Cells. AB - Ghrelin is an orexigenic hormone with a role in the onset and progression of neurodegenerative disorders. It has been recently associated to Alzheimer's disease (AD) for its neuroprotective and anti-apoptotic activity. In the present study, we dissected the effect of ghrelin treatment on the two major intracellular proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy, in cellular models of AD (namely SH-SY5Y neuroblastoma cells stably transfected with either the wild-type AbetaPP gene or the 717 valine-to-glycine AbetaPP-mutated gene). Ghrelin showed a growth-promoting effect on neuronal cells inducing also time-dependent modifications of the growth hormone secretagogue receptor type 1 (GHS-R1) expression. Interestingly, we demonstrated for the first time that ghrelin was able to activate the proteasome in neural cells playing also a role in the interplay between the UPS and autophagy. Our data provide a novel mechanism by which circulating hormones control neural homeostasis through the regulation of proteolytic pathways implicated in AD. PMID- 26033220 TI - Variability of inter-observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): independent analysis from a phase II trial. AB - OBJECTIVE: To evaluate how many patients could have undergone partial nephrectomy (PN) rather than radical nephrectomy (RN) before and after neoadjuvant axitinib therapy, as assessed by five independent urological oncologists, and to study the variability of inter-observer agreement. PATIENTS AND METHODS: Pre- and post systemic treatment computed tomography scans from 22 patients with clear cell renal cell carcinoma in a phase II neoadjuvant axitinib trial were reviewed by five independent urological oncologists. R.E.N.A.L. nephrometry score and kappa statistics were calculated. RESULTS: The median R.E.N.A.L. nephrometry score changed from 11 before treatment to 10 after treatment (P = 0.002). Five tumours with moderate complexity before axitinib treatment remained moderate complexity after treatment. Of 17 tumours with high complexity before axitinib treatment, three became moderate complexity after treatment. The overall kappa statistic was 0.611. Moderate-complexity kappa was 0.611 vs a high-complexity kappa of 0.428. Before axitinib treatment the kappa was 0.550 vs 0.609 after treatment. After treatment with axitinib, all five reviewers agreed that only five patients required RN (instead of eight before treatment) and that 10 patients could now undergo PN (instead of three before treatment). The odds of PN feasibility were 22.8-times higher after treatment with axitinib. CONCLUSIONS: There is considerable variability in inter-observer agreement on the feasibility of PN in patients treated with neoadjuvant targeted therapy. Although more patients were candidates for PN after neoadjuvant axitinib therapy, it remains difficult to identify these patients a priori. PMID- 26033221 TI - Zucker diabetic fatty rats, a model for type 2 diabetes, develop an inner ear dysfunction that can be attenuated by losartan treatment. AB - Hearing loss secondary to diabetes remains under debate. In our study, we used Zucker Diabetic Fatty (ZDF) rats as an animal model of type 2 diabetes to investigate whether (1) hearing ability impairment and structural alterations of the inner ear occur in diabetes and (2) an angiotensin II receptor blocker (losartan) can protect rats from diabetic damage. Homozygous mutants were treated with a placebo or losartan and heterozygous animals served as non-diabetic controls. All animals underwent immunohistochemical and electronmicroscopical analysis. Functional testing of hearing ability was performed by click-evoked auditory brainstem responses. The present study showed significant sensorineural hearing impairment in placebo-treated diabetic rats (hearing threshold, 45.0 +/- 2.1 dB SPL) compared to both non-diabetic controls (34.7 +/- 4 dB SPL) and losartan-treated diabetic rats (36.1 +/- 7.4 dB SPL). Concurrently, the functional decline in the placebo-treated rats was associated with significant morphological abnormalities, particularly in the intermediate cells of the stria vascularis and with strial dysfunction. These degenerative changes were indicated by the down-regulation of several pumps, ionic and cellular channels, which are involved in the cycling of K(+) and the maintenance of the endocochlear potential essential for the hearing process. Thus, the inner ear can be regarded as a target organ during hyperglycemic disorders and a metabolically induced "diabetic otopathy" may be added to angiopathy, nephropathy and neuropathy as a specific complication of diabetes mellitus. Blockade of the angiotensin II receptor can prevent this "diabetic otopathy" despite hyperglycemic serum levels. PMID- 26033222 TI - Rasburicase-induced methaemoglobinaemia and G6PD deficiency in an unusual suspect. PMID- 26033223 TI - Conformational dynamics of a short antigenic peptide in its free and antibody bound forms gives insight into the role of beta-turns in peptide immunogenicity. AB - Earlier immunological experiments with a synthetic 36-residue peptide (75-110) from Influenza hemagglutinin have been shown to elicit anti-peptide antibodies (Ab) which could cross-react with the parent protein. In this article, we have studied the conformational features of a short antigenic (Ag) peptide ((98)YPYDVPDYASLRS(110)) from Influenza hemagglutinin in its free and antibody (Ab) bound forms with molecular dynamics simulations using GROMACS package and OPLS-AA/L all-atom force field at two different temperatures (293 K and 310 K). Multiple simulations for the free Ag peptide show sampling of ordered conformations and suggest different conformational preferences of the peptide at the two temperatures. The free Ag samples a conformation crucial for Ab binding (beta-turn formed by "DYAS" sequence) with greater preference at 310 K while, it samples a native-like conformation with relatively greater propensity at 293 K. The sequence "DYAS" samples beta-turn conformation with greater propensity at 310 K as part of the hemagglutinin protein also. The bound Ag too samples the beta turn involving "DYAS" sequence and in addition it also samples a beta-turn formed by the sequence "YPYD" at its N-terminus, which seems to be induced upon binding to the Ab. Further, the bound Ag displays conformational flexibility at both 293 K and 310 K, particularly at terminal residues. The implications of these results for peptide immunogenicity and Ag-Ab recognition are discussed. PMID- 26033224 TI - Positive predictive value of non-invasive prenatal screening for fetal chromosome disorders using cell-free DNA in maternal serum: independent clinical experience of a tertiary referral center. AB - BACKGROUND: Non-invasive prenatal screening (NIPS) for fetal chromosome abnormalities using cell-free deoxyribonucleic acid (cfDNA) in maternal serum has significantly influenced prenatal diagnosis of fetal aneuploidies since becoming clinically available in the fall of 2011. High sensitivity and specificity have been reported in multiple publications, nearly all of which have been sponsored by the commercial performing laboratories. Once results are returned, positive and negative predictive values (PPVs, NPVs) are the performance metrics most relevant to clinical management. The purpose of this report is to present independent data on the PPVs of NIPS in actual clinical practice. METHODS: Charts were retrospectively reviewed for patients who had NIPS and were seen March 2012 to December 2013 in a tertiary academic referral center. NIPS results were compared to diagnostic genetic test results, fetal ultrasound results, and clinical phenotype/outcomes. The PPV was calculated using standard epidemiological methods. Correlation between screen results and both maternal age at delivery and gestational age at time of screening was assessed using Wilcoxon's rank sum test. RESULTS: Of 632 patients undergoing NIPS, 92 % of tests were performed in one of the four major commercial laboratories offering testing. However, all four laboratories are represented in both the normal and abnormal results groups. There were 55 abnormal NIPS results. Forty-one of 55 abnormal NIPS results were concordant with abnormal fetal outcomes, 12 were discordant, and 2 were undetermined. The PPV for all conditions included in the screen was 77.4 % (95 % CI, 63.4 - 87.3). Of 578 patients with normal NIPS results, normal pregnancy outcome was confirmed for 156 (27 %) patients. This incomplete follow up of normal NIPS results does not affect PPV calculations, but it did preclude calculations of sensitivity, specificity, and NPV. Maternal age at delivery was significantly lower for patients with abnormal discordant results, compared to patients with abnormal concordant results (P = 0.034). Gestational age at time of screening was not associated with concordance of screen results (P = 0.722). CONCLUSIONS: The experience of using NIPS in clinical practice confirms that abnormal results cannot be considered diagnostic. Pre-test counseling should emphasize this. Diagnostic genetic testing should always be offered following abnormal NIPS results. PMID- 26033225 TI - Charcot neuroarthropathy after simultaneous pancreas-kidney transplantation: risk factors, prevalence, and outcome. AB - We retrospectively analyzed outcome and risk factors of developing Charcot foot (CF) in 100 patients with type 1 diabetes mellitus who underwent a simultaneous pancreas-kidney (SPK) transplantation. Patients who developed CF after SPK transplantation had significantly higher mortality (56% vs. 18%) and more frequently graft failure (44% vs. 13%). Recipients with CF also experienced acute rejections more frequently (78% vs. 41%). They furthermore had higher pre transplant values of HbA1c , received cyclosporine and azathioprine more often, and had significantly higher cumulative corticosteroid use. Patients transplanted in an earlier era (1992-1998) received cyclosporine and azathioprine more often and had a significantly higher cumulative corticosteroid use with the higher prevalence of CF. Conversely, patients with diabetes transplanted more recently (1999-2012) received lower doses of corticosteroids as part of their tacrolimus based immunosuppressive therapy, resulting in fewer CF attacks. In conclusion, development of CF after SPK is associated with poor patient and graft outcome. Poor pre-transplant diabetic control and the use of high-dose corticosteroids are risk factors for the development of CF. We recommend reduction in or even total avoidance of corticosteroids after SPK transplantation. Given the importance of the diagnosis of CF on outcome, a systematic examination of SPK patients' feet is recommended. PMID- 26033226 TI - Isolation and Total Synthesis of Kirkamide, an Aminocyclitol from an Obligate Leaf Nodule Symbiont. AB - The new C7N aminocyclitol kirkamide (1) was isolated from leaf nodules of the plant Psychotria kirkii by using a genome-driven (1)H NMR-guided fractionation approach. The structure and absolute configuration were elucidated by HRMS, NMR, and single-crystal X-ray crystallography. An enantioselective total synthesis was developed, which delivered kirkamide (1) on a gram scale in 11 steps and features a Ferrier carbocyclization and a Pd-mediated hydroxymethylation. We propose that kirkamide is synthesized by Candidatus Burkholderia kirkii, the obligate leaf symbiont of Psychotria kirkii. Kirkamide (1) was shown to be toxic to aquatic arthropods and insects, thus suggesting that bacterial secondary metabolites play a protective role in the Psychotria/Burkholderia leaf nodule symbiosis. PMID- 26033227 TI - Multiple-locus variable-number tandem-repeat analysis (MLVA) genotyping of human Brucella isolates in Malaysia. AB - BACKGROUND: Brucellosis is one of the most common zoonotic diseases worldwide. It can cause acute febrile illness in human and is a major health problem. Studies in human brucellosis in Malaysia is limited and so far no genotyping studies has been done on Brucella isolates. The aim of the study was to determine the genetic diversity among Brucella species isolated from human brucellosis, obtained over a 6-year period (2009-2014). METHODS: In this study, the genotypic characteristics of 43 human Brucella melitensis isolates were analysed using multiple-locus variable-number tandem-repeat analysis (MLVA) which consisted of eight minisatellite loci (panel 1) and eight microsatellite loci; panels 2A (3 microsatellite loci) and panel 2B (5 microsatellite loci). Two human Brucella suis isolates were also investigated using the MLVA assay. RESULTS: Using panel 1 (MLVA8), two genotypes namely genotype 43 and 44 were obtained from the 43 B. melitensis isolates. Using the combination of panels 1 and 2A loci (MLVA11), two genotypes were obtained while using the complete panels 1, 2A and 2B, nine genotypes were obtained. The polymorphisms in using the complete panels (MLVA16) were observed in three loci from panel 2B, which showed a diversity index higher than 0.17. All B. melitensis isolates were closely related to the East Mediterranean group. For B. suis isolates, only genotype 6 and genotype 33 were obtained using panel 1 and MLVA11 respectively. CONCLUSION: In conclusion, the results of the present study showed a low genetic diversity among B. melitensis and B. suis isolates from human patients. Based on the MLVA16 assay, B. melitensis belonging to the East Mediterranean group is responsible for the vast majority of Brucella infections in our Malaysian patients. To our knowledge, this is the first genotyping study of human Brucella isolates in Malaysia. PMID- 26033228 TI - Mammary-type myofibroblastoma of the right thigh: a case report and review of the literature. AB - INTRODUCTION: Mammary-type myofibroblastoma of the soft tissue is a very rare, benign, mesenchymal neoplasm with myofibroblastic differentiation. To date, 20 cases of extra-mammary myofibroblastoma have been described in literature. To the best of our knowledge, this is the largest extra-mammary myofibroblastoma described in the literature, and the first case reported in this location. CASE PRESENTATION: A 50-year-old Pakistani man presented with a long history of a painless, huge lump on his right thigh. His clinical examination showed normal looking skin and there was no inguinal lymphadenopathy. The mass was excised with a clinical impression of soft tissue sarcoma. Gross examination showed a huge, well-circumscribed soft tissue mass measuring 34 cm in its largest dimension and weighing approximately 13 kg. It was partially covered by fat tissue. Histologically, the lesion was composed of a haphazard arrangement of bland spindle-shaped cell fascicles in a thick collagenous and myxoid background. The neoplastic cells showed diffuse and patchy positivity for CD34 and desmin, respectively. No recurrence was seen following surgical excision over a follow-up period of five months. CONCLUSIONS: Mammary-type myofibroblastoma of the soft tissue is a benign soft tissue neoplasm, and no malignant behavior and/or recurrence after surgical resection has been described, regarding its size and location. As an extremely rare tumor, the correct diagnosis and prompt management is important, and requires careful clinical and pathological workup to rule out the possibility of a malignant neoplasm. PMID- 26033229 TI - Anxiety and Depression in Adolescents With Epilepsy. AB - The present study examined anxiety and depression in adolescents with epilepsy and the association of these disorders with seizure-related and sociodemographic variables. The Hospital Anxiety and Depression Scale was administered to 140 children with epilepsy and 50 children with asthma aged 10 to 18 years attending mainstream schools. Adolescents with epilepsy had significantly higher scores on the depression subscale than those with asthma (5.2 +/- 3.3 vs 4.2 +/- 3.2, P = .032). Anxiety subscale scores and the frequency of anxiety and depression in both the epilepsy and asthma groups were not statistically significant. In the epilepsy group, 32.8% had anxiety and 22.1% had depression. Factors associated with anxiety were older age at the time of the study and polytherapy (2 or more antiepileptic drugs). Adolescents who had been seizure-free for 12 months or more at time of the study were less likely to experience anxiety. Factors associated with depression were medical comorbidities, female gender, frequent seizures, and younger age of seizure onset. A common risk factor for both anxiety and depression was the duration of epilepsy. Anxiety and depression were also highly associated with each other. Affective disorders are common in epilepsy and screening for psychiatric symptoms is required. PMID- 26033231 TI - Repulsive Apoptosis During Exposure of Mesencephalic Neural Stem Cells to Silver Nanoparticles in a Neurosphere Assay In Vitro. AB - Neurodevelopmental toxicity of silver nanoparticles (AgNPs) remains largely unknown. In this study, we applied a neurosphere assay for neurodevelopmental effects of AgNPs. The neural stem cells were isolated from rat mesencephalon. They were cultured as a sphere. In an assay with coated plates, cells appeared by anchoraging on the dish and then started to migrate along the radial axis from the neurosphere. AgNPs inhibited cell migration in a dose-dependent manner. There was a linear correlation between the inhibition of migration and the logarithm of the particle concentration (1.25-10 MUg/ml); the half-maximal inhibitory concentration was 0.41 MUg/ml for 16-h exposure. Preceding migrated cells were retarded and/or collapsed by exposure to AgNPs: lower doses of AgNPs (0.31-1.2 MUg/ml) caused a 42% retardation for 48 h, while higher doses of AgNPs (2.5-10 MUg/ml) collasped migrating cells. Furthermore, collapsed cells were TUNEL positive and showed a defect in the mitochondrial membrane potential. Thus, we showed the neurodevelopmental toxicity of AgNPs using an in vitro neurosphere assay system. PMID- 26033230 TI - Consensus recommendations on the use of daylight photodynamic therapy with methyl aminolevulinate cream for actinic keratoses in Australia. AB - Australia has the highest prevalence of actinic keratoses (AK) worldwide. Because of the risk of transformation of AK to invasive squamous cell carcinomas, consensus guidelines recommend that AK are removed using appropriate therapies to prevent progression to invasive disease. Daylight photodynamic therapy (PDT) is emerging as an efficacious treatment for AK, particularly for patients who require treatment of large areas of chronic actinic damage that can be exposed easily to daylight. Daylight PDT with methyl aminolevulinate (MAL) cream is a simple treatment for AK, almost painless, well tolerated and convenient, requiring minimal time in the clinic. Randomised controlled studies from northern Europe and Australia support the use of daylight PDT as an effective therapy for grade I and II AK on the face and scalp. There is sufficient daylight to conduct daylight PDT in Australia at any time of the year and during most weather conditions. Hence, daylight PDT with MAL can be included as an effective and well tolerated new treatment option for the treatment of AK in Australia. These consensus recommendations provide guidelines for Australian clinicians on the use of daylight PDT in the treatment of diagnosed AK. PMID- 26033232 TI - State of the Art Detection System for Curcumin Analog. AB - In spite of the need for sensing bisdemethoxycurcumin analog (BDMCA), there is no detection system available so far. For the first time, we have demonstrated a sensing system for detecting BDMCA. Initially, chitosan thin films of three different molecular weights (low, average, high) were tested for the conductivity. The high molecular weight chitosan film was found to produce higher conductance and hence, used as the substrate. Addition of BDMCA to this substrate induced a significant conductance change (as revealed by impedance analyzer), making the detection system qualitative. Addition of increasing concentrations of BDMCA produced significantly concomitant increase in the conductivity (observed as decrease in current density as revealed by cyclic voltammetry) making the sensor quantitative. Our results show that this chitosan based electrochemical sensing system can be used for the rapid quantitative detection of BDMCA. As there is no BDMCA sensor available so far, this type of detection is very essential to monitor the pharmacokinetic behavior, the therapeutic dosage, bioavailability and related toxicity of BDMCA in different formulations and samples. PMID- 26033233 TI - Targeted Cancer Therapy: The Next Generation of Cancer Treatment. AB - Cancer is one of the leading causes of death in the United States along with heart disease. The hallmark of cancer treatment has been conventional chemotherapy. Chemotherapeutic drugs are designed to target not only rapidly dividing cells, such as cancer cells, but also certain normal cells, such as intestinal epithelium. Over the past several years, a new generation of cancer treatment has come to the forefront, i.e, targeted cancer therapies. Like conventional chemotherapy, targeted cancer therapies use pharmacological agents that inhibit growth, increase cell death and restrict the spread of cancer. As the name suggests, targeted therapies interfere with specific proteins involved in tumorigenesis. Rather than using broad base cancer treatments, focusing on specific molecular changes which are unique to a particular cancer, targeted cancer therapies may be more therapeutically beneficial for many cancer types, including lung, colorectal, breast, lymphoma and leukemia. Moreover, recent advances have made it possible to analyze and tailor treatments to an individual patient's tumor. There are three main types of targeted cancer therapies; 1) monoclonal antibodies, 2) small molecule inhibitors and 3) immunotoxins. This review will discuss these three classes of targeted therapies in detail, as well as the biology behind targeted cancer therapies. PMID- 26033234 TI - In Vitro Protective Potentials of Annona muricata Leaf Extracts Against Sodium Arsenite-induced Toxicity. AB - Sodium arsenite (NaAsO2) is a metalloid which is present widely in the environment and its chronic exposure can contribute to the induction of oxidative stress, resulting in disturbances in various metabolic functions including liver cell death. Hence, there is a need to develop drugs from natural sources, which can reduce arsenic toxicity. While there have been reports regarding the antioxidant and protective potentials of Annona muricataleaf extracts, our study is the first ofits kind to extend these findings by specifically evaluating its ability to render protection against sodium arsenite (NaAsO2) induced toxicity (10 MUM) in WRL-68 (human hepatic cells) and human erythrocytes by employing XTT and haemolysis inhibition assays respectively. The methanolic extract exhibited higher activity than the aqueous extract in both assays. The results showed a dose-dependent decrease in arsenic toxicity in both WRL-68 cells and erythrocytes, suggesting the protective nature of Annona muricatato mitigate arsenic toxicity. Hence the bioactive extracts can further be scrutinized for the identification and characterization of their principal contributors. PMID- 26033235 TI - Mental practice in surgical training. PMID- 26033236 TI - Active immunization with Tocilizumab mimotopes induces specific immune responses. AB - BACKGROUND: Tocilizumab is a humanized monoclonal antibody showing high-affinity binding to both soluble interleukin-6 receptor (sIL-6R) and membrane bound IL-6R (mIL-6R), thereby preventing pro-inflammatory effects of IL-6. However, therapeutic antibodies still have practical limitations. To overcome these limitations, we generated Tocilizumab specific epitope mimics by using the phage display technology and tested whether the peptide mimics could induce similar humoral responses in mice immunized with the peptides. RESULTS: Seven phage mimics were obtained by using phage display peptide library. Four phage mimics (YHTTDKLFYMMR, YSAYEFEYILSS, KTMSAEEFDNWL and LTSHTYRSQADT) were shown to mimic Tocilizumab epitope using immunoassays. The mimotopes were conjugated to immunogenic carrier proteins and used to intraperitoneally immunize BALB/c mice. Sera from the mimotopes immunized mice not only showed specific binding to recombinant IL-6R, but can also IL-6R expressed in Hela, U-937, Jurkat cell lines and in fibroblast-like synoviocytes from patients with RA (FLS-RA). Furthermore, sera from mice immunized with mimotopes-KLH conjugate could reduce the level of phosphorylated- signal transducers and activator of transcription (STAT3), STAT3, phosphorylated- extracellular signal-regulated kinase (Erk) 1/2 and Erk1/2 in HeLa and Jurkat cells. Antibody-dependent cellular cytotoxicity (ADCC) assay showed that antibodies induced by mimotopes-KLH conjugate could elicit specific lysis in Hela and U-937 cells. CONCLUSIONS: From phage display library, we successfully isolated four Tocilizumab mimotopes which induced specific humoral and cellular reponses in vitro and in vivo. PMID- 26033237 TI - Children's understanding of embarrassment: integrating mental time travel and mental state information. AB - The current study investigated 4- to 8-year-olds' (N = 81) understanding of embarrassment and their ability to integrate temporal and mental state information to predict and explain emotions. Participants heard stories describing characters commit trivial social transgressions, and then the next day, characters found themselves in the same situation that led to the previous transgression. For some story endings, participants were asked to predict and explain how the character felt, and for others, participants were told the character started to feel embarrassed and they were asked to explain why. Participants' responses were coded and analysed using nonparametric statistical tests. Kruskal-Wallis analyses revealed significant developments occur between 6 and 8 years in children's understanding of embarrassment and their ability to explain individual's emotion as caused by anticipating the reoccurrence of a previous embarrassing event. Younger children demonstrated a basic knowledge of embarrassment but failed to demonstrate more advanced understanding of the emotion. Findings from the current study indicate children reach a more mature understanding of embarrassment and the implications of committing social transgressions between 7 and 8 years. Finally, the current study contributes to the literature on children's ability to infer mental states and temporally connect experiences. PMID- 26033238 TI - Association of percentile ranking with citation impact and productivity in a large cohort of de novo NIMH-funded R01 grants. AB - Previous reports from National Institutes of Health and National Science Foundation have suggested that peer review scores of funded grants bear no association with grant citation impact and productivity. This lack of association, if true, may be particularly concerning during times of increasing competition for increasingly limited funds. We analyzed the citation impact and productivity for 1755 de novo investigator-initiated R01 grants funded for at least 2 years by National Institute of Mental Health between 2000 and 2009. Consistent with previous reports, we found no association between grant percentile ranking and subsequent productivity and citation impact, even after accounting for subject categories, years of publication, duration and amounts of funding, as well as a number of investigator-specific measures. Prior investigator funding and academic productivity were moderately strong predictors of grant citation impact. PMID- 26033239 TI - Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. AB - There is mounting evidence to suggest aberrant astrocytic function in depression and suicide. Independent studies have reported astrocytic abnormalities in certain brain regions, but it remains unclear whether this is a brain-wide phenomenon. The present study examined this question by measuring glial fibrillary acidic protein (GFAP) expression in postmortem brain samples from suicide completers and matched non-psychiatric controls. Suicide completers were selected based on their recent characterization as low GFAP expressors in the prefrontal cortex, (Brodmann areas 8/9 and 10). Real-time PCR and immunoblotting were used to measure GFAP gene expression and protein levels in BA4 (primary motor cortex), BA17 (primary visual cortex), cerebellar cortex, mediodorsal thalamus and caudate nucleus. We found downregulation of GFAP mRNA and protein in the mediodorsal thalamus and caudate nucleus of depressed suicides compared with controls, whereas GFAP expression in other brain regions was similar between groups. Furthermore, a regional comparison including all samples revealed that GFAP expression in both subcortical regions was, on average, between 11- and 15 fold greater than in cerebellum and neocortex. Examining astrocyte morphology by immunohistochemistry showed that astrocytes in both thalamus and caudate displayed larger cell bodies and extended more ramified processes across larger domains than the previously described cortical astrocytes. This study reveals that astrocytic abnormalities are not brain wide and suggests that they are restricted to cortical and subcortical networks known to be affected in mood disorders. Additionally, our results show a greater diversity in human astrocytic phenotypes than previously thought. PMID- 26033240 TI - Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms. AB - Adults with psychotic disorders have dysconnectivity in critical brain networks, including the default mode (DM) and the cingulo-opercular (CO) networks. However, it is unknown whether such deficits are present in youth with less severe symptoms. We conducted a multivariate connectome-wide association study examining dysconnectivity with resting state functional magnetic resonance imaging in a population-based cohort of 188 youths aged 8-22 years with psychosis-spectrum (PS) symptoms and 204 typically developing (TD) comparators. We found evidence for multi-focal dysconnectivity in PS youths, implicating the bilateral anterior cingulate, frontal pole, medial temporal lobe, opercular cortex and right orbitofrontal cortex. Follow-up seed-based and network-level analyses demonstrated that these results were driven by hyper-connectivity among DM regions and diminished connectivity among CO regions, as well as diminished coupling between frontal and DM regions. Collectively, these results provide novel evidence for functional dysconnectivity in PS youths, which show marked correspondence to abnormalities reported in adults with established psychotic disorders. PMID- 26033241 TI - GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper. AB - Endoplasmic reticulum (ER) release and cell-surface export of many G protein coupled receptors (GPCRs) are tightly regulated. For gamma-aminobutyric acid (GABA)B receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell-surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gatekeepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function. PMID- 26033242 TI - Association of Alzheimer's related genotypes with cognitive decline in multiple domains: results from the Three-City Dijon study. AB - Several genetic polymorphisms have been associated with Late Onset Alzheimer's Disease (LOAD), but there has been limited evidence on whether these polymorphisms predict intermediary stage outcomes such as cognitive changes in prospective community-based studies. Our aim was to evaluate whether polymorphisms previously established as predictors of LOAD also predict worse cognitive function and accelerated decline across multiple cognitive domains. We analyzed data from the 3C-Dijon study, in which 4931 respondents aged 65+ were examined up to 5 times over 10 years with a neuropsychological assessment. We evaluated the associations of polymorphisms in APOE, CR1, BIN1, CLU, PICALM, ABCA7, MS4A6A, CD33, MS4A4E and CD2AP with level and change in 5 neuropsychological tests, assuming a dominant effect model. To optimize measurement, we used a mixed regression model with a latent process for each cognitive domain: global cognition (Mini Mental State Examination); verbal fluency (Isaac's Set Test); visual memory (Benton Visual Retention Test); information processing (Trail Making Test B) and literacy (National Adult Reading Test). APOE was associated with accelerated decline in global cognition and verbal fluency. Only two non-APOE genetic polymorphisms were associated with cognitive decline: CR1 was associated with rate of change in verbal fluency and BIN1 was associated with rate of change in global cognition. In a large prospective population-based study of dementia-free individuals, only a few cognitive domains were associated with established LOAD risk alleles. The most consistent associations were for global cognition and verbal fluency. PMID- 26033244 TI - Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C reactive protein, interleukin-6 and tumour necrosis factor-alpha. AB - Childhood trauma confers higher risk of adulthood physical and mental illness; however, the biological mechanism mediating this association remains largely unknown. Recent research has suggested dysregulation of the immune system as a possible biological mediator. The present paper conducted a meta-analysis to establish whether early-life adversity contributes to potentially pathogenic pro inflammatory phenotypes in adult individuals. A systematic search of Pubmed, PsycINFO, EMBASE, Scopus and Medline identified 25 articles for the meta analysis, including 18 studies encompassing a sample of 16 870 individuals for C reactive protein (CRP), 15 studies including 3751 individuals for interleukin-6 (IL-6) and 10 studies including 881 individuals for tumour necrosis factor-alpha (TNF-alpha). Random-effects meta-analysis showed that individuals exposed to childhood trauma had significantly elevated baseline peripheral levels of CRP (Fisher's z=0.10, 95% confidence interval (CI)=0.05-0.14), IL-6 (z=0.08, 95% CI=0.03-0.14) and TNF-alpha (z=0.23, 95% CI=0.14-0.32). Subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these impact differentially the single inflammatory markers. Moreover, meta regression revealed greater effect sizes in clinical samples for the association between childhood trauma and CRP but not for IL-6 or TNF-alpha. Age, body mass index (BMI) and gender had no moderating effects. The analysis demonstrates that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma. PMID- 26033245 TI - Hepatic NAD salvage pathway is enhanced in mice on a high-fat diet. AB - Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme for NAD salvage and the abundance of Nampt has been shown to be altered in non alcoholic fatty liver disease. It is, however, unknown how hepatic Nampt is regulated in response to accumulation of lipids in the liver of mice fed a high fat diet (HFD). HFD mice gained more weight, stored more hepatic lipids and had an impaired glucose tolerance compared with control mice. NAD levels as well as Nampt mRNA expression, protein abundance and activity were significantly increased in HFD mice. Enhanced NAD levels were associated with deacetylation of p53 and Nfkappab indicating increased activation of Sirt1. Despite impaired glucose tolerance and increased hepatic lipid levels in HFD mice, NAD metabolism was significantly enhanced. Thus, improved NAD metabolism may be a compensatory mechanism to protect against negative impact of hepatic lipid accumulation. PMID- 26033243 TI - Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. AB - The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d= 0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness. PMID- 26033247 TI - Xenograft models for adrenocortical carcinoma. AB - Adrenocortical carcinomas (ACCs) are rare, heterogeneous and very malignant endocrine tumors with a poor prognosis. An important prerequisite to optimize existing therapeutic regimens and to develop novel therapeutic strategies are preclinical disease models. In recent years molecular and genetic profiling of surgical tumor specimen led to the identification of novel interesting markers. However, precise involvement of these markers in tumorigenesis and their functional relevance in therapeutic outcome is still under investigation. Xenograft models are important tools for such functional studies as they bear the potential to mimic the complexity of solid tumors including tumor cells, stroma and blood vessels. Thus, for the successful and safe development of novel therapeutic strategies xenograft models remain to be indispensable experimental tools. Here we provide an overview on currently existing xenograft models for ACC, their tissue origins, establishment, implications as well as limitations. PMID- 26033246 TI - Phosphorylation of Ser-279/282 and Tyr-265 positions on Cx43 as possible mediators of VEGF-165 inhibition of pregnancy-adapted Ca2+ burst function in ovine uterine artery endothelial cells. AB - Normal pregnancy requires increased uterine endothelial cell driven vasodilation that is related to increases in sustained Ca2+ signaling via increased connexin 43 (Cx43) gap junction function. Preeclampsia, a hypertensive disorder of pregnancy associated with endothelial dysfunction, is also linked with down regulation of Ca2+ driven vasodilator production and increased levels of vascular endothelial growth factor (VEGF). Cx43 function can be acutely down-regulated by phosphorylation of multiple inhibitory residues and VEGF is known to promote phosphorylation of Cx43. Herein, we show that VEGF-165 promotes Cx43 phosphorylation at Ser-279/282 and Tyr-265 residues and blocks pregnancy-adapted Ca2+ signaling in ovine uterine artery endothelial cells (UAEC). Pharmacological Src and ERK kinase pathway inhibitors (PP2 and U0126) reverse these phosphorylations and rescue Ca2+ signaling. We also report a nutraceutical Src inhibitor, t10,c12 conjugated linoleic acid (10,12 CLA), rescues Ca2+ signaling in UAEC and therefore may have therapeutic potential for preeclampsia. PMID- 26033248 TI - Ubiquitin specific protease 2 acts as a key modulator for the regulation of cell cycle by adiponectin and leptin in cancer cells. AB - Adiponectin and leptin, both produced from adipose tissue, cause cell cycle arrest and progression, respectively in cancer cells. Ubiquitin specific protease 2 (USP-2), a deubiquitinating enzyme, is known to impair proteasome-induced degradation of cyclin D1, a critical cell cycle regulator. Herein, we investigated the effects of these adipokines on USP-2 expression and its potential role in the modulation of cell cycle. Treatment with globular adiponectin (gAcrp) decreased, whereas leptin increased USP-2 expression both in human hepatoma and breast cancer cells. In addition, overexpression or gene silencing of USP-2 affected cyclin D1 expression and cell cycle progression/arrest by adipokines. Adiponectin and leptin also modulated in vitro proteasomal activity, which was partially dependent on USP-2 expression. Taken together, our results reveal that modulation of USP-2 expression plays a crucial role in cell cycle regulation by adipokines. Thus, USP-2 would be a promising therapeutic target for the modulation of cancer cell growth by adipokines. PMID- 26033250 TI - Advances in the management of fungal infections. PMID- 26033251 TI - Antifungal drug resistance among Candida species: mechanisms and clinical impact. AB - The epidemiology of Candida infections has changed in recent years. Although Candida albicans is still the main cause of invasive candidiasis in most clinical settings, a substantial proportion of patients is now infected with non-albicans Candida species. The various Candida species vary in their susceptibility to the most commonly used antifungal agents, and the intrinsic resistance to antifungal therapy seen in some species, along with the development of acquired resistance during treatment in others, is becoming a major problem in the management of Candida infection. A better understanding of the mechanisms and clinical impact of antifungal drug resistance is essential for the efficient treatment of patients with Candida infection and for improving treatment outcomes. Herein, we report resistance to the azoles and echinocandins among Candida species. PMID- 26033252 TI - Antifungal stewardship in daily practice and health economic implications. AB - During recent years, inappropriate antifungal use has contributed to the global increase in antifungal resistance and has played a role in the shift in the aetiology of invasive fungal infections. Moreover, overuse of antifungals may also lead to higher toxicity associated with unnecessary medication exposure and to increased healthcare costs. Antifungal stewardship (AFS) programmes consist of multidisciplinary interventions, led by specialists in infectious disease, microbiology and pharmacy that cooperate and communicate with the major prescribing departments in order to optimise antifungal therapies evaluating the indication, dose, streamlining and duration. Herein, we review the available evidence for the use of AFS and their impact on health economics. We also describe our AFS program, the successive steps we followed and the main difficulties we found. PMID- 26033253 TI - Public Perception of Climate Change: The Importance of Knowledge and Cultural Worldviews. AB - The importance of knowledge for lay people's climate change concerns has been questioned in recent years, as it had been suggested that cultural values are stronger predictors of concern about climate change than knowledge. Studies that simultaneously measured knowledge related to climate change and cultural values have, however, been missing. We conducted a mail survey in the German-speaking part of Switzerland (N = 1,065). Results suggested that cultural worldviews and climate-related knowledge were significantly related with people's concern about climate change. Also, cultural worldviews and climate-relevant knowledge appeared important for people's willingness to change behaviors and to accept climate change policies. In addition, different types of knowledge were found to have different impacts on people's concern about climate change, their willingness to change behaviors, and their acceptance of policies about climate change. Specifically, causal knowledge significantly increased concern about climate change and willingness to support climate-friendly policies. We therefore concluded that risk communication should focus on causal knowledge, provided this knowledge does not threaten cultural values. PMID- 26033249 TI - Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome. AB - Considering the current trends in life expectancy, women in the modern era are challenged with facing menopausal symptoms as well as heightened disease risk associated with increasing adiposity and metabolic dysfunction for up to three decades of life. Treatment strategies to combat metabolic dysfunction and associated pathologies have been hampered by our lack of understanding regarding the biological underpinnings of these clinical conditions and our incomplete understanding of the effects of estrogens and the tissue-specific functions and molecular actions of its receptors. In this review we provide evidence supporting a critical and protective role for the estrogen receptor alpha specific form in the maintenance of metabolic homeostasis and insulin sensitivity. Studies identifying the ER-regulated pathways required for disease prevention will lay the important foundation for the rational design of targeted therapeutics to improve women's health while limiting complications that have plagued traditional hormone replacement interventions. PMID- 26033254 TI - Comparison of Four Sections for Analyzing Running Mechanics Alterations During Repeated Treadmill Sprints. AB - We compared different approaches to analyze running mechanics alterations during repeated treadmill sprints. Thirteen active male athletes performed five 5-second sprints with 25 seconds of recovery on an instrumented treadmill. This approach allowed continuous measurement of running kinetics/kinematics and calculation of vertical and leg stiffness variables that were subsequently averaged over 3 distinct sections of the 5-second sprint (steps 2-5, 7-10, and 12-15) and for all steps (steps 2-15). Independently from the analyzed section, propulsive power and step frequency decreased with fatigue, while contact time and step length increased (P < .05). Except for step frequency, all mechanical variables varied (P < .05) across sprint sections. The only parameters that highly depend on running velocity (propulsive power and vertical stiffness) showed a significant interaction (P < .05) between the analyzed sections, with smaller magnitude of fatigue-induced change observed for steps 2-5. Considering all steps or only a few steps during early, middle, or late phases of 5-second sprints provides similar mechanical outcomes during repeated treadmill sprinting, although acceleration induces noticeable differences between the sections studied. Furthermore, quantifying mechanical alterations from the early acceleration phase may not be readily detectable, and is not recommended. PMID- 26033255 TI - Thermoresponsive AuNPs Stabilized by Pillararene-Containing Polymers. AB - Pillararene-containing thermoresponsive polymers are synthesized via reversible addition-fragmentation chain transfer polymerization using pillararene derivatives as the effective chain transfer agents for the first time. These polymers can self-assemble into micelles and form vesicles after guest molecules are added. Furthermore, such functional polymers can be further applied to prepare hybrid gold nanoparticles, which integrate the thermoresponsivity of polymers and molecular recognition of pillararenes. PMID- 26033256 TI - Australian doctors face two years in jail for reporting asylum seekers' health. PMID- 26033258 TI - Mitotic chromosome length scales in response to both cell and nuclear size. AB - Multicellular development requires that cells reduce in size as a result of consecutive cell divisions without increase in embryo volume. To maintain cellular integrity, organelle size adapts to cell size throughout development. During mitosis, the longest chromosome arm must be shorter than half of the mitotic spindle for proper chromosome segregation. Using high-resolution time lapse microscopy of living Caenorhabditis elegans embryos, we have quantified the relation between cell size and chromosome length. In control embryos, chromosome length scaled to cell size. Artificial reduction of cell size resulted in a shortening of chromosome length, following a trend predicted by measurements from control embryos. Disturbing the RAN (Ras-related nuclear protein)-GTP gradient decoupled nuclear size from cell size and resulted in chromosome scaling to nuclear size rather than cell size; smaller nuclei contained shorter chromosomes independent of cell size. In sum, quantitative analysis relating cell, nuclear, and chromosome size predicts two levels of chromosome length regulation: one through cell size and a second in response to nuclear size. PMID- 26033257 TI - Alternative splicing converts STIM2 from an activator to an inhibitor of store operated calcium channels. AB - Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca(2+) dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2beta, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2beta does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2beta mutants and Orai1-STIM2beta chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals. PMID- 26033259 TI - The relationship between waiting times and 'adherence' to the Scottish Intercollegiate Guidelines Network 98 guideline in autism spectrum disorder diagnostic services in Scotland. AB - The aim of this study was to explore the extent to which the Scottish Intercollegiate Guidelines Network 98 guidelines on the assessment and diagnosis of autism spectrum disorder were adhered to in child autism spectrum disorder diagnostic services in Scotland and whether there was a significant relationship between routine practice which more closely reflected these recommendations (increased adherence) and increased waiting times. Retrospective, cross-sectional case note analysis was applied to data from 80 case notes. Adherence ranged from a possible 0 (no adherence) to 19 (full adherence). Overall, 17/22 of the recommendations were adhered to in over 50 of the 80 cases and in 70 or more cases for 11/22 of the recommendations, with a mean adherence score of 16 (standard deviation = 1.9). No significant correlation was found between adherence and total wait time for untransformed (r = 0.15, p = 0.32) or transformed data (r = 0.12, p = 0.20). The results indicated that the assessment and diagnostic practices were consistent with the relevant Scottish Intercollegiate Guidelines Network 98 guideline recommendations. Increased adherence to the 19 included recommendations was not significantly related to increased total waiting times, indicating that the Scottish Intercollegiate Guidelines Network 98 recommendations have generally been integrated into practice, without a resultant increase in patient waits. PMID- 26033260 TI - Agreement between preoperative transvaginal ultrasound and intraoperative macroscopic examination for assessing myometrial infiltration in low-risk endometrioid carcinoma. AB - OBJECTIVE: To compare diagnostic performance of preoperative transvaginal ultrasound (TVS) and intraoperative macroscopic examination for determining myometrial infiltration in women with low-risk endometrial cancer, and to estimate the agreement between the two methods. METHODS: This was a single-center observational study comprising women with preoperative diagnosis of well- or moderately differentiated endometrioid carcinoma of the endometrium. All women underwent preoperative TVS by a single examiner. According to the examiner's subjective impression, myometrial infiltration was stated as >= 50% or < 50%. Surgical staging was performed in all cases. Intraoperative macroscopic examination of the removed uterus was performed by pathologists who were unaware of the ultrasound findings, and myometrial infiltration was stated as >= 50% or < 50%. Definitive histological diagnosis of myometrial infiltration was made by frozen section analysis and was used as the gold standard. Sensitivity and specificity with 95% CIs were calculated for TVS and intraoperative macroscopic inspection and compared using McNemar's test. Agreement between TVS and intraoperative macroscopic inspection was estimated using Cohen's kappa index (kappa) and percentage of agreement. RESULTS: Of 209 eligible women, 152 were ultimately included. Mean (+/- SD) age was 60.9 +/- 10.2 years, with a range of 32-91 years. Definitive histological diagnosis revealed that myometrial infiltration was < 50% in 114 women and >= 50% in 38 women. Sensitivity and specificity of TVS for detecting deep myometrial infiltration were 81.6% and 89.5%, respectively, whereas the respective values for intraoperative macroscopic examination were 78.9% and 90.4% (McNemar's test, P > 0.05 when comparing TVS and intraoperative macroscopic examination). Agreement between methods was moderate with kappa = 0.54 (95% CI, 0.39-0.69) and percentage of agreement of 82%. CONCLUSIONS: Although the agreement between preoperative TVS and intraoperative macroscopic examination for detecting deep myometrial infiltration was only moderate, both methods had similar accuracy when compared with frozen section histology. Preoperative TVS might reasonably be proposed as a method for assessing myometrial infiltration as an alternative to intraoperative macroscopic examination, especially when performed by an experienced examiner and image quality is not poor. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26033261 TI - Simultaneous determination of five triterpene acids in rat plasma by liquid chromatography-mass spectrometry and its application in pharmacokinetic study after oral administration of Folium Eriobotryae effective fraction. AB - Folium Eriobotryae effective fraction (FEA), the extract of Folium Eriobotryae, had been used as anti-hyperglycemia and anti-hyperlipemia medicine in China. A previous study indicated that euscaphic acid, maslinic acid, corosolic acid, oleanolic acid and ursolic acid, the five structurally similar triterpene acids (containing two groups of structural isomers), are the major components of FEA. In the present study, we developed a specific and reliable LC-MS method for simultaneous determination of the five triterpene acids in rat plasma, and further investigated their pharmacokinetic properties after oral administration of FEA. Following a simple sample preparation, chromatographic separation was achieved on a C18 column with a mobile phase composed of methanol-0.1% ammonium acetate (80:20, v/v). Quantification was achieved by monitoring the selected ions at m/z 487.6 for euscaphic acid, m/z 471.5 for maslinic acid and corosolic acid, m/z 455.5 for oleanolic acid and ursolic acid and m/z 469.5 for internal standard. The method was validated to be specific, accurate and precise over the concentration ranges of 10-3000 ng/mL with limits of detections of 5 ng/mL for the five triterpene acids. Finally, the method was successfully applied to the pharmacokinetic study of the five structurally similar triterpene acids in rats after oral administration of FEA. PMID- 26033262 TI - Frequency of human platelet antigens (HPA)-1, -2, -5 and -15 in Brazilian blood donors and establishment of a panel of HPA-typed donors. AB - OBJECTIVES: The aim of this study is to keep a record of regular human platelet antigens (HPA)-typed blood donors and to compare their allele frequencies with those reported in other populations. BACKGROUND: HPA are polymorphisms expressed on platelet membrane glycoproteins. They can generate an immune response leading to platelet alloimmunisation that may show clinical manifestations, such as neonatal alloimmune thrombocytopenia, post-transfusion purpura and platelet refractoriness. Platelet alloimmunisation is not uncommon, therefore, for an optimum management, it is advantageous to establish a panel of typed platelets to help matched platelets selection in HPA-alloimmunised patients transfusion. METHODS: The polymerase chain reaction (PCR)-allele-specific primers and PCR restriction fragment length polymorphism methods were used to determine the genotypes of HPA-1, -2, -5 and -15 systems of 337 blood donors. RESULTS: The three genotypes (AA, AB and BB) were found in all HPA systems analysed, and the most frequent genotypes were AA for HPA-1, -2 and -5 systems (mean: 0.732) and AB for HPA-15 system (mean: 0.523). Allele frequencies were 0.148, 0.155, 0.140 and 0.430 for HPA-1b, -2b, -5b and -15b, respectively, and they were similar to those found in Caucasian populations, especially for HPA-1. However, the B allele was more frequent in all HPA systems when compared with Amazon Indians, and the frequency of the B allele in our study was higher in HPA-1 and -15 systems and lower in HPA-2 and -5 systems in comparison with sub-Saharan African populations. CONCLUSIONS: A record of HPA-typed donors would enable rapid identification and selection of donors when HPA-compatible platelets are required for transfusion. PMID- 26033263 TI - Do experienced physiotherapists and final year physiotherapy trainees apply similar force during posterior-to-anterior lumbar mobilization techniques? AB - This study aims to quantify the force applied during posterior-to-anterior lumbar vertebrae mobilizations of different grades (I to IV) and compare that force between experienced physiotherapists and final year physiotherapy students. Four experienced physiotherapists and four final year physiotherapy students participated in this study along with five healthy asymptomatic individuals. A manual therapy table positioned over three force plates allowed for measurements of the force oscillation frequency and intensity applied during grade I, II, III and IV posterior-to-anterior (PA) mobilizations at two lumbar vertebral levels (L2 and L4). Mixed model ANOVAs were used to compare the force applied between the experienced physiotherapists and students, and between the various grades. The results showed that the mean oscillation frequency was similar between the groups for all grades. Grade I and grade IV PA mobilizations showed similar mean oscillation frequency as did grade II and III PA mobilizations. The minimum and maximum force applied was higher for the physiotherapists than for the students for all mobilization grades (p values < 0.05). Similar mean maximum force values were recorded for PA mobilizations between grade I and II and between grade III and grade IV. Grade III and IV PA mobilizations yielded higher mean maximum force values than those recorded during grade I and grade II PA mobilizations. The method used in this study allowed for quantification of the force applied during lumbar PA mobilizations. Experienced physiotherapists apply greater force than physiotherapy students across all grades, despite similar oscillation frequency. PMID- 26033264 TI - Trace-Metal Enrichment and Pollution in Coastal Sediments in the Northern Tyrrhenian Sea, Italy. AB - This study evaluated the distribution pattern and pollution of chromium, arsenic (As), manganese (Mn), nickel, lead, and copper in surface sediments along the northern Latium coast of the Tyrrhenian Sea in Italy. The enrichment factor, geoaccumulation index, and potential toxicity response index were used to evaluate the degree of contamination. These results show As and Mn contamination. The high enrichment and contamination levels of As and Mn are located in two hot spots. These elevations are due to naturally high levels of As and Mn in the Mignone River and the Marangone Stream as well as the intense human activity in the area including the largest energy production site in Europe (Torrevaldaliga Nord coal-fired power plant) and of one of the most important ports for cruise traffic in the Mediterranean Sea. PMID- 26033265 TI - Adjuvant intensity-modulated radiotherapy (IMRT) with concurrent paclitaxel and cisplatin in cervical cancer patients with high risk factors: A phase II trial. AB - OBJECTIVE: To evaluate the safety and efficacy of adjuvant intensity-modulated radiotherapy (IMRT) with concurrent paclitaxel and cisplatin (TP) in early stage cervical cancer patients with high risk factors after radical hysterectomy. METHODS: Patients who underwent radical hysterectomy for FIGO stage IB-IIA cervical cancer and had high risk factors for recurrence were recruited. One cycle of TP was delivered before and after concurrent chemoradiotherapy, respectively. Concurrent chemoradiotherapy began 21 days after the start of the initial cycle of the chemotherapy with two cycles of TP delivered on day 1 and day 29 of radiotherapy. Primary endpoints were overall survival (OS) and relapse free survival (RFS), with toxicities, local-regional control (LC) and distant failure (DF) rate as secondary endpoints. RESULTS: Between 2008 and 2012, 67 patients were evaluable. The 2 and 4-year RFS rates were 98.2% and 92.9%. Corresponding OS rates were 100%, and 98.0%, respectively. The 4-year LC and DF rates were 98.0% and 5.2%, respectively. Grade 3-4 acute leucopenia, neutropenia and thrombocytopenia occurred in 25.4%, 11.9% and 1.5% of patients, respectively. There were 89.6% and 59.7% patients experienced acute vomiting and diarrhea, but only 6.0% and 6.0% patients were grade 3, respectively. No case of chronic toxicity exceeded grade 2. CONCLUSION: Adjuvant concurrent IMRT with paclitaxel plus cisplatin are safe and effective in early stage cervical cancer patients with high risk factors for recurrence following radical hysterectomy. PMID- 26033266 TI - Red blood cell storage duration is not associated with clinical outcomes for acute chest syndrome in children with sickle cell disease. AB - BACKGROUND: Providers commonly transfuse sickle cell disease (SCD) patients with fresh red blood cells (RBCs) as treatment for acute chest syndrome (ACS). The objective of this study was to determine if there is an association between the storage duration of RBCs and length of hospitalization and oxygen requirement after transfusion in pediatric SCD patients with ACS. STUDY DESIGN AND METHODS: This is a retrospective cohort study of pediatric SCD patients with ACS treated with a simple RBC transfusion over 8.5 years at a single institution. Multivariate generalized estimation equation analysis was used to identify associations between storage duration of RBCs and outcome measures. RESULTS: A total of 234 ACS episodes in 131 subjects were included. The median storage duration of the oldest unit of transfused RBCs was 17 days (interquartile range, 11-26). The majority of ACS episodes, 77.4%, were treated with 1 unit of transfused RBCs; 20.9% received 2 units; and 1.7% received 3 or more units of RBCs. There was no association between the storage duration of the oldest unit of transfused RBCs and either duration of hospitalization or supplemental oxygen requirement after transfusion in multivariate analyses. CONCLUSION: This retrospective study is one of the first to investigate the role of the storage lesion in children with SCD and does not support the preferential transfusion of fresh RBCs for ACS. Ultimately, a randomized controlled trial is necessary to determine whether the storage age of RBCs affects outcomes for patients with SCD and ACS. PMID- 26033267 TI - Comparisons of two types of teleostean pseudobranchs, silver moony (Monodactylus argenteus) and tilapia (Oreochromis mossambicus), with salinity-dependent morphology and ion transporter expression. AB - There are essentially four different morphological types of pseudobranchs in teleosts, including lamellae-free, lamellae semi-free, covered, and embedded types. In the euryhaline silver moony (Monodactylus argenteus), the pseudobranch belongs to the lamellae semi-free type, which is characterized by one row of filaments on the opercular membrane and fusion on the buccal edge. The pseudobranchial epithelium of the moony contains two types of Na(+), K(+)-ATPase (NKA)-rich cells: chloride cells (CCs) and pseudobranch-type cells (PSCs). Our results revealed increased expression of NKA, the Na(+), K(+), 2Cl(-) cotransporter (NKCC), and the cystic fibrosis transmembrane conductance regulator (CFTR) for Cl(-) secretion and CCs profiles in the pseudobranchs of seawater (SW) acclimated silver moonies, which indicates the potential role of pseudobranchs containing CCs in hypo-osmoregulation. In contrast, the pseudobranch of the Mozambique tilapia (Oreochromis mossambicus) belongs to the embedded type, which is covered by the connective tissues and only contains PSCs but not CCs. No sign of NKCC and CFTR-immunoreactivity (IR) was found in the pseudobranchs of SW and freshwater (FW) tilapia. However, higher NKA protein expression and larger sizes of NKA-IR PSCs were found in the pseudobranchs of FW-acclimated tilapia. Moreover, in the FW-acclimated moony, NKA-IR PSCs also exhibited higher numbers and larger sizes than in the SW individuals. Taken together, similar responses in low-salinity environments in different types of pseudobranchs indicated that the salinity-dependent morphologies of PSCs might be involved in critical functions for FW teleosts. PMID- 26033269 TI - Multiband multislab 3D time-of-flight magnetic resonance angiography for reduced acquisition time and improved sensitivity. AB - PURPOSE: To explore the use of multiband (MB) imaging in multislab (MS) 3D time of-flight-magnetic resonance angiography (TOF-MRA) and to improve acquisition time efficiency (TA), inflow contrast and sensitivity in vessel detection. THEORY AND METHODS: TOF-MRA is commonly used for imaging intracranial vessels. A MB-MS 3D-TOF-MRA sequence was implemented to excite and acquire multiple slabs simultaneously. Controlled aliasing in parallel imaging results in higher acceleration was used in addition to improve the quality of image reconstruction. Compared to a standard protocol which acquired three slabs in total the MB-MS protocol reduced the thickness by 3 while simultaneously acquiring data from 3 slabs. The total TA was also reduced by a factor 3. RESULTS: This technique maintains contrast-to-noise ratio while reducing TA, compared to standard single band/MOTSA acquisitions, leading to an increase in CNR/TA of 1.65 compared to the standard protocol. Furthermore, the strong inflow contrast and increased magnetization transfer contrast caused by the MB excitation pulses improves the sharpness of the vessel borders which is reflected by a 5% higher full width at half maximum of the vessel size and a 17% higher slope of the vessel borders compared to the standard single-band acquisition. CONCLUSION: MB-MS 3D-TOF-MRA can appreciably accelerate image acquisition and combines the high spatial resolution of 3D imaging with the additional inflow contrast advantage of thinner slab acquisitions without introducing excessive noise arising from the MB reconstruction. PMID- 26033268 TI - The Use of Cholinesterase Inhibitors Across All Stages of Alzheimer's Disease. AB - Current pharmacological therapy for Alzheimer's disease (AD) includes the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine and the N-methyl D-aspartate receptor antagonist memantine. Based on the results of randomized controlled trials and several meta-analyses, ChEIs appear to show modest but statistically significant improvements on several measures, including cognition and global functioning. Given their modest effects, there is a lack of consensus among clinicians regarding issues related to initiation, optimal duration, and discontinuation of ChEI therapy across the spectrum of AD. There is evidence from long-term observational controlled studies that early initiation and persistent exposure to AD therapy lead to delays in nursing home admission and significantly slower rates of cognitive and functional impairment. In the moderate to severe stages of AD, therapeutic trials of higher dose ChEIs and the addition of memantine are recommended for patients who are no longer responding to lower doses. While side effects are generally mild and gastrointestinal in nature, these events can lead to significant morbidity in more susceptible patients with advanced disease. Patients should thus be regularly monitored for any potential serious side effects of ChEI therapy, which also may include syncope and bradycardia. At the terminal stages of AD, such as when patients become hospice eligible, attempts to cautiously discontinue all medications not necessary for quality of life, including AD drugs, should be made. PMID- 26033270 TI - Ectomycorrhizal fungi mediate indirect effects of a bark beetle outbreak on secondary chemistry and establishment of pine seedlings. AB - Dendroctonus ponderosae has killed millions of Pinus contorta in western North America with subsequent effects on stand conditions, including changes in light intensity, needle deposition, and the composition of fungal community mutualists, namely ectomycorrhizal fungi. It is unknown whether these changes in stand conditions will have cascading consequences for the next generation of pine seedlings. To test for transgenerational cascades on pine seedlings, we tested the effects of fungal inoculum origin (beetle-killed or undisturbed stands), light intensity and litter (origin and presence) on seedling secondary chemistry and growth in a glasshouse. We also tracked survival of seedlings over two growing seasons in the same stands from which fungi and litter were collected. Fungal communities differed by inoculum origin. Seedlings grown with fungi collected from beetle-killed stands had lower monoterpene concentrations and fewer monoterpene compounds present compared with seedlings grown with fungi collected from undisturbed stands. Litter affected neither monoterpenes nor seedling growth. Seedling survival in the field was lower in beetle-killed than in undisturbed stands. We demonstrate that stand mortality caused by prior beetle attacks of mature pines have cascading effects on seedling secondary chemistry, growth and survival, probably mediated through effects on below-ground mutualisms. PMID- 26033271 TI - Impact of functional training on cardiac autonomic modulation, cardiopulmonary parameters and quality of life in healthy women. AB - Functional training (FT) promotes benefits in various physical abilities; however, its effect on autonomic modulation, cardiorespiratory parameters and quality of life in the healthy adult population is unknown, and thus, the aim of this study was to evaluate the influence of FT on these variables in healthy young women. The study consisted of 29 women, distributed into two groups: the FT Group (FTG; n = 13; 23 +/- 2.51 years; 21.90 +/- 2.82 kg m(-) 2) and the Control Group (CG; n = 16; 20.56 +/- 1.03 years; 22.12 +/- 3.86 kg m(-) 2). The FTG performed periodized FT for 12 weeks, three times a week. The following were evaluated: autonomic modulation (heart rate variability), cardiorespiratory parameters and quality of life (SF-36 Questionnaire). The Student's t-test for unpaired data or the Mann-Whitney test was used to compare the differences obtained between the final moment and the initial moment of the studied groups (P<0.05). The FTG demonstrated significant improvements in quality of life and autonomic modulation (P<0.05), but not in the cardiorespiratory parameters. Functional training was able to produce improvements in autonomic modulation and quality of life. PMID- 26033272 TI - Transcatheter closure of postmyocardial infarction, iatrogenic, and postoperative ventricular septal defects: The Mayo Clinic experience. AB - OBJECTIVES: To determine event-free survival after transcatheter closure of ventricular septal defect (VSD), and to identify predictors of adverse events (AE) in post myocardial infarction VSD (post-MI VSD) subgroup. BACKGROUND: There are limited data on mid-term follow-up after transcatheter VSD closure. METHODS: Retrospective review of 27 cases of transcatheter VSD closure (post-MI = 18 and non-ischemic = 9) performed from 1999 to 2013. We defined AE as death, device embolization, hemolysis requiring blood transfusion, heart block and reintervention. RESULTS: In the post-MI VSD subgroup, mean age and follow-up was 69 +/- 11 and 7.3 +/- 7 years, respectively. AE occurred in 8 (44%) patients (death-3, device embolization-1, hemolysis-1, surgical VSD closure-2, reintervention-1). Event-free survival was 56% at 1 month and 5 years, and all AE occurred in the periprocedural period. Cardiogenic shock (HR: 3.21, CI: 1.82 5.41, P = 0.002), and VSD closure in acute phase (HR: 2.14, CI: 1.12-4.31, P = 0.004) were independent predictors of AE. In the non-ischemic VSD subgroup, mean age and follow-up was 49 +/- 15 and 8.7 +/- 8 years, respectively. AE occurred in 3 (33%) patients (late death-1, surgical VSD closure-2). For the entire cohort, freedom from death was 89% and 85% at 1 month and 5 years, and event-free survival was 70% and 61% at 1 month and 5 years. CONCLUSIONS: Transcatheter closure of post-MI VSD carries a moderate risk of periprocedural complications but low event rates afterwards. By comparison, device closure of non-ischemic VSD has lower periprocedural morbidity but some patients continued to experience AE during follow-up. PMID- 26033273 TI - Evaluating the role of anxiety sensitivity in barriers to cessation and reasons for quitting among smokers with asthma. AB - The aim of the present study was to examine the unique predictive ability of anxiety sensitivity (AS) in terms of perceived barriers to cessation and smoking cessation motives among daily smokers with asthma (n = 125, 54% male, Mage = 37.7 years, SD = 12.1). As hypothesized, after controlling for the effects of race, asthma control, negative affect, and smoking rate, AS significantly predicted greater barriers to cessation, and reasons for quitting related to health concerns and self-control. Contrary to hypotheses, AS did not significantly predict external reasons for quitting. These findings suggest that smokers with asthma who are fearful of physiological arousal may be a particularly 'at-risk' population for smoking cessation difficulties due, in part, to greater perceived barriers to cessation. Interventions focused on enhancing intrinsic motivation for quitting and reducing AS may be most effective for this population. PMID- 26033274 TI - The ubiquitous ATP molecule: could it be the elusive thermal mediator igniting skin perfusion and sweating in the heat-stressed human? PMID- 26033275 TI - Short and sweet: cardiovascular and metabolic improvements in just one hour per week. PMID- 26033276 TI - Rational Design of a Ratiometric Fluorescent Probe Based on Arene-Metal-Ion Contact for Endogenous Hydrogen Sulfide Detection in Living Cells. AB - We report the design and development of a fluorescent Cd(II) ion complex that is capable of the ratiometric detection of H2 S in living cells. This probe exploits the metal-ion-induced emission red shift resulting from direct contact between the aromatic ring of a fluorophore and a metal ion (i.e., arene-metal-ion or "AM" contact). The Cd(II) complex displays a large emission blue shift upon interaction with H2 S as the Cd(II) -free ligand is released by the formation of cadmium sulfide. Screening of potential ligands and fluorophores led to the discovery of a pyronine-type probe, 6?Cd(II) , that generated a sensitive and rapid ratio value change upon interaction with H2 S, without interference from the glutathione that is abundant in the cell. The membrane-impermeable 6?Cd(II) was successfully translocated into live cells by using an oligo-arginine peptide and pyrenebutylate as carriers. As such, 6?Cd(II) was successfully applied to the ratiometric detection of both exogenous and endogenous H2 S produced by the enzymes in living cells, thus demonstrating the utility of 6?Cd(II) in biological fluorescence analysis. PMID- 26033277 TI - Corrigendum: Extreme expansion of the olfactory receptor gene repertoire in African elephants and evolutionary dynamics of orthologous gene groups in 13 placental mammals. PMID- 26033278 TI - Nocturnal periodic limb movements decrease antioxidant capacity in post-stroke women. AB - OBJECTIVES: Considerable evidence suggests that periodic limb movements during sleep (PLMS) are associated with cardiovascular risk and poor stroke outcome. However, the pathogenesis for this association in stroke patients remains largely unknown. MATERIALS AND METHODS: This cross-sectional study enrolled 112 consecutive patients who were admitted to rehabilitation ward due to ischemic stroke. Polysomnography and laboratory tests for oxidative stress and inflammatory biomarkers including C-reactive protein, interleukin 6, total antioxidant capacity (TAC), and urinary 8-hydroxy-2-deoxyguanosine were conducted. RESULTS: Patients were stratified into three categories according to their PLMS index. Patients in the PLMS index >=15 group were significantly older (P = 0.011), presented a significantly higher National Institute of Health Stroke Scale at stroke onset (P = 0.032), and lower Barthel index (P = 0.035) than patients in the PLMS index <5 group. The level of TAC differed significantly (P = 0.018) among the three groups. Multivariate linear regression analyses show that the PLMS index was negatively and independently correlated with TAC (P = 0.024) in women. Besides, multivariate logistic regression analyses also reveal that patients with a PLMS index >=15 compared with the referent PLMS index <5 had a 7.58-fold increased relative hazard for stroke recurrence (odds ratio 7.58, [1.31 43.88], P = 0.024). CONCLUSIONS: This study suggests that PLMS was independently associated with decreased antioxidant capacity in women with ischemic stroke. PMID- 26033279 TI - Tbo-Filgrastim versus Filgrastim during Mobilization and Neutrophil Engraftment for Autologous Stem Cell Transplantation. AB - There are limited data available supporting the use of the recombinant granulocyte colony-stimulating factor (G-CSF), tbo-filgrastim, rather than traditionally used filgrastim to mobilize peripheral blood stem cells (PBSC) or to accelerate engraftment after autologous stem cell transplantation (ASCT). We sought to compare the efficacy and cost of tbo-filgrastim to filgrastim in these settings. Patients diagnosed with lymphoma or plasma cell disorders undergoing G CSF mobilization, with or without plerixafor, were included in this retrospective analysis. The primary outcome was total collected CD34(+) cells/kg. Secondary mobilization endpoints included peripheral CD34(+) cells/MUL on days 4 and 5 of mobilization, adjunctive use of plerixafor, CD34(+) cells/kg collected on day 5, number of collection days and volumes processed, number of collections reaching 5 million CD34(+) cells/kg, and percent reaching target collection goal in 1 day. Secondary engraftment endpoints included time to neutrophil and platelet engraftment, number of blood product transfusions required before engraftment, events of febrile neutropenia, and length of stay. A total of 185 patients were included in the final analysis. Patients receiving filgrastim (n = 86) collected a median of 5.56 * 10(6) CD34(+) cells/kg, compared with a median of 5.85 * 10(6) CD34(+) cells/kg in the tbo-filgrastim group (n = 99; P = .58). There were no statistically significant differences in all secondary endpoints with the exception of apheresis volumes processed (tbo-filgrastim, 17.0 liters versus filgrastim, 19.7 liters; P < .01) and mean platelet transfusions (tbo-filgrastim, 1.7 units versus filgrastim, 1.4 units; P = .04). In conclusion, tbo-filgrastim demonstrated similar CD34(+) yield compared with filgrastim in mobilization and post-transplantation settings, with no clinically meaningful differences in secondary efficacy and safety endpoints. Furthermore, tbo-filgrastim utilization was associated with cost savings of approximately $1406 per patient utilizing average wholesale price. PMID- 26033280 TI - Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia. AB - Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia. PMID- 26033281 TI - Cost-Effectiveness of Autologous Hematopoietic Stem Cell Transplantation for Elderly Patients with Multiple Myeloma using the Surveillance, Epidemiology, and End Results-Medicare Database. AB - In the past decade, the number of autologous hematopoietic stem cell transplants (Auto HSCT) for older patients with multiple myeloma (MM) has increased dramatically, as has the cost of transplantation. The cost-effectiveness of this modality in patients over age 65 is unclear. Using the Surveillance, Epidemiology, and End Results-Medicare database to create a propensity-score matched sample of patients over age 65 between 2000 and 2007, we compared the survival and cost for those who received Auto HSCT to those who did not undergo transplantation but survived at least 6 months after diagnosis, and we calculated an incremental cost-effectiveness ratio (ICER). Two hundred seventy patients underwent transplantation. Median overall survival from diagnosis in those who underwent transplantation was significantly longer than in patients who did not (58 months versus 37 months, P < .001). For patients living longer than 2 years, the median monthly cost during the first year was significantly different, but the middle and last year of life costs were similar. The median cost of the first 100 days after transplantation was $60,000 (range, $37,000 to $85,000). The resultant ICER was $72,852 per life-year gained. Survival after transplantation was comparable to that in those who underwent transplantation patients under 65 years and significantly longer than older patients who did not undergo transplantation. With an ICER less than $100,000/life-year gained, Auto HSCT is cost-effective when compared with nontransplantation care in the era of novel agents and should be considered, where clinically indicated, for patients over the age of 65. PMID- 26033282 TI - Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study. AB - Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted. (clinicaltrials.gov: NCT01385124). PMID- 26033284 TI - Nursing Students' and Tutors' Satisfaction With a New Clinical Competency System Based on the Nursing Interventions Classification. AB - PURPOSE: To assess students' satisfaction with their clinical tutors, their clinical practices, and tutors' satisfaction with the new approach of clinical placements and tutorship. METHODS: A cross-sectional study was used, with a study population of second and third year nursing students and clinical tutors. RESULTS: Global satisfaction was 7.47 (SD 1.61) (range from 1 to 9). Regarding students' satisfaction, 75.67% of the items were equal to or greater than 4 (range from 1 to 5). The overall mean score was 4.05 (DE 1.08). CONCLUSIONS AND IMPLICATIONS FOR NURSING PRACTICE: A competency-structured practicum, assessed through the Nursing Interventions Classification and supported on information and communications technologies, is a reliable and valid method that encourages students and tutors to an active participation, and implies a high degree of satisfaction in both tutors and students. PMID- 26033283 TI - Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life. AB - Ocular involvement can be quite symptomatic in patients with chronic graft-versus host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P < .001), compared with patients without ocular GVHD. In conclusion, this large, multicenter, prospective study shows that ocular GVHD affects 57% of patients within 2 years of chronic GVHD diagnosis. Women, patients on higher doses of prednisone at study entry, and those with a history of acute GVHD were at higher risk for ocular GVHD. Strong evidence suggests that ocular GVHD is associated with worse overall health-related QOL. PMID- 26033285 TI - Primary testicular diffuse large B-cell lymphoma: morphological and immunophenotypical study with characterization of the T-cell component of the tumor microenvironment. PMID- 26033286 TI - Health-related quality-of-life results from PALETTE: A randomized, double-blind, phase 3 trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or after prior chemotherapy-a European Organization for research and treatment of cancer soft tissue and bone sarcoma group global network study (EORTC 62072). AB - BACKGROUND: Health-related quality of life (HRQoL) was an exploratory endpoint in the PALETTE trial, a global, double-blind, randomized, phase 3 trial of pazopanib 800 mg versus placebo as second-line or later treatment for patients with advanced soft tissue sarcoma (N = 369). In that trial, progression-free survival was significantly improved in the pazopanib arm (median, 4.6 vs 1.6 months; hazard ratio, 0.31; P < .001), and toxicity of pazopanib consisted mainly of fatigue, diarrhea, nausea, weight loss, and hypertension. METHODS: HRQoL was assessed using the 30-item core European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline and at weeks 4, 8, and 12 in patients who received treatment on protocol. The primary HRQoL endpoint was the EORTC QLQ-C30 global health status scale. RESULTS: Compliance with HRQoL assessments was good, ranging from 94% at baseline to 81% at week 12. Differences in scores on the EORTC QLQ-C30 global health status subscale between the 2 treatment arms were not statistically significant and did not exceed the predetermined, minimal clinically important difference of 10 points (P = .291; maximum difference, 3.8 points). Among the other subscales, the pazopanib arm reported significantly worse symptom scores for diarrhea (P < .001) loss of appetite (P < .001), nausea/vomiting (P < .001), and fatigue (P = .012). In general, HRQoL scores tended to decline over time in both arms. CONCLUSIONS: HRQoL did not improve with the receipt of pazopanib. However, the observed improvement in progression-free survival without impairment of HRQoL was considered a meaningful result. The toxicity profile of pazopanib was reflected in the patients' self-reported symptoms but did not translate into significantly worse overall global health status during treatment. PMID- 26033287 TI - Octahedral Chiral-at-Metal Iridium Catalysts: Versatile Chiral Lewis Acids for Asymmetric Conjugate Additions. AB - Octahedral iridium(III) complexes containing two bidentate cyclometalating 5-tert butyl-2-phenylbenzoxazole (IrO) or 5-tert-butyl-2-phenylbenzothiazole (IrS) ligands in addition to two labile acetonitrile ligands are demonstrated to constitute a highly versatile class of asymmetric Lewis acid catalysts. These complexes feature the metal center as the exclusive source of chirality and serve as effective asymmetric catalysts (0.5-5.0 mol % catalyst loading) for a variety of reactions with alpha,beta-unsaturated carbonyl compounds, namely Friedel Crafts alkylations (94-99% ee), Michael additions with CH-acidic compounds (81 97% ee), and a variety of cycloadditions (92-99% ee with high d.r.). Mechanistic investigations and crystal structures of an iridium-coordinated substrates and iridium-coordinated products are consistent with a mechanistic picture in which the alpha,beta-unsaturated carbonyl compounds are activated by two-point binding (bidentate coordination) to the chiral Lewis acid. PMID- 26033289 TI - Inactivation of Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes in apple juice at different pH levels by gaseous ozone treatment. AB - AIMS: We investigated the effect of ozone treatment of apple juice at different pH levels for inactivation of Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes. METHODS AND RESULTS: Apple juice (pH 3.0, 4.0 and 5.0) inoculated with the three pathogens were treated with gaseous ozone (3.0 l min(-1) flow rate and 2.0-3.0 g m(-3) ) for up to 4 min. Ozone treatment (4 min) of pH 3.0 apple juice resulted in >5.36 log CFU ml(-1) reduction of E. coli O157:H7. Ozone treatment of pH 4.0 and 5.0 apple juice for 4 min reduced this pathogen by 5.12 log CFU ml(-1) and 1.86 log CFU ml(-1) respectively. The combination of low pH and ozone showed a great antimicrobial effect in apple juice. Salm. Typhimurium and L. monocytogenes showed a reduction trend similar to E. coli O157:H7. There were no significant changes of colour values when apple juice was treated with ozone, except for b values. Among all ozone treated samples, the browning index was lower than that of nontreated samples and there were no significant differences in total phenolic contents. CONCLUSIONS: In conclusion, ozone treatment of low pH apple juice was significantly effective in inactivation of foodborne pathogens while maintaining acceptable apple juice quality. SIGNIFICANCE AND IMPACT OF THE STUDY: The antimicrobial effect of ozone treatment on foodborne pathogens in apple juice can be reinforced by lowering the pH of apple juice. PMID- 26033288 TI - 3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures. AB - A 3D printable and highly stretchable tough hydrogel is developed by combining poly(ethylene glycol) and sodium alginate, which synergize to form a hydrogel tougher than natural cartilage. Encapsulated cells maintain high viability over a 7 d culture period and are highly deformed together with the hydrogel. By adding biocompatible nanoclay, the tough hydrogel is 3D printed in various shapes without requiring support material. PMID- 26033290 TI - Krokodile Injectors in Ukraine: Fueling the HIV Epidemic? AB - This study was designed to assess the characteristics of krokodile injectors, a recent phenomenon in Ukraine, and HIV-related risk factors among people who inject drugs (PWID). In three Ukraine cities, Odessa, Donetsk and Nikolayev, 550 PWID were recruited between December 2012 and October 2013 using modified targeted sampling methods. The sample averaged 31 years of age and they had been injecting for over 12 years. Overall, 39 % tested positive for HIV, including 45 % of krokodile injectors. In the past 30 days, 25 % reported injecting krokodile. Those who injected krokodile injected more frequently (p < 0.001) and they injected more often with others (p = 0.005). Despite knowing their HIV status to be positive, krokodile users did not reduce their injection frequency, indeed, they injected as much as 85 % (p = 0.016) more frequently than those who did not know their HIV status or thought they were negative. This behavior was not seen in non-krokodile using PWID. Although only a small sample of knowledgeable HIV positive krokodile users was available (N = 12), this suggests that krokodile users may disregard their HIV status more so than nonkrokodile users. In spite of widespread knowledge of its harmful physical consequences, a growing number of PWID are turning to injecting krokodile in Ukraine. Given the recency of krokodile use the country, the associated higher frequency of injecting, a propensity to inject more often with others, and what could be a unique level of disregard of HIV among krokodile users, HIV incidence could increase in future years. PMID- 26033292 TI - Contribution of water chemistry and fish condition to otolith chemistry: comparisons across salinity environments. AB - This study quantified the per cent contribution of water chemistry to otolith chemistry using enriched stable isotopes of strontium ((86) Sr) and barium ((137) Ba). Euryhaline barramundi Lates calcarifer, were reared in marine (salinity 40), estuarine (salinity 20) and freshwater (salinity 0) under different temperature treatments. To calculate the contribution of water to Sr and Ba in otoliths, enriched isotopes in the tank water and otoliths were quantified and fitted to isotope mixing models. Fulton's K and RNA:DNA were also measured to explore the influence of fish condition on sources of element uptake. Water was the predominant source of otolith Sr (between 65 and 99%) and Ba (between 64 and 89%) in all treatments, but contributions varied with temperature (for Ba), or interactively with temperature and salinity (for Sr). Fish condition indices were affected independently by the experimental rearing conditions, as RNA:DNA differed significantly among salinity treatments and Fulton's K was significantly different between temperature treatments. Regression analyses did not detect relations between fish condition and per cent contribution values. General linear models indicated that contributions from water chemistry to otolith chemistry were primarily influenced by temperature and secondly by fish condition, with a relatively minor influence of salinity. These results further the understanding of factors that affect otolith element uptake, highlighting the necessity to consider the influence of environment and fish condition when interpreting otolith element data to reconstruct the environmental histories of fish. PMID- 26033291 TI - Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor. AB - Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2(-/-) macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced beta-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field. PMID- 26033293 TI - Trophic ecology and food consumption of fishes in a hypersaline tropical lagoon. AB - This study evaluated the trophic ecology (diet composition, trophic strategy, similarities and overlap between species, feeding period and food consumption) of six benthivorous fish species in Araruama Lagoon, the largest hypersaline tropical lagoon on the east coast of South America, with an area of 210 km(2) and an average salinity of 52. The burrfish Chilomycterus spinosus fed on Anomalocardia flexuosa shell deposits, ingesting associated fauna. The caitipa mojarra Diapterus rhombeus differed from all other species, having not only the highest proportions of algae and Nematoda, but also feeding on polychaete tentacles. The two mojarras Eucinostomus spp. showed similar trophic strategies, feeding mostly on Polychaeta. The corocoro grunt Orthopristis ruber also fed mainly on Polychaeta, but differed from Eucinostomus spp. in secondary items. The whitemouth croacker Micropogonias furnieri fed mainly on small Crustacea at night, showing a high number of secondary prey items with low frequencies and high prey-specific abundance. The daily food consumption (g food g(-1) fish mass) for Eucinostomus argenteus was 0.012 and was 0.031 and 0.027 for M. furnieri in two different sampling events. The diet similarities between Araruama Lagoon and other brackish and marine environments indicate that hypersalinity is not a predominant factor shaping the trophic ecology of fishes in this lagoon. The stability of hypersaline conditions, without a pronounced gradient, may explain the presence of several euryhaline fishes and invertebrates well adapted to this condition, resulting in a complex food web. PMID- 26033294 TI - Local scale, coastal currents influence recruitment to freshwater populations in the European eel Anguilla anguilla: a case study from the Isle of Man. AB - This study examines juvenile Anguilla anguilla (<30 cm) abundance in five study catchments on the Isle of Man. Preliminary results suggest that juvenile abundance is negatively correlated with increasing coastal current speed at river mouth entry (P < 0.05). These findings indicate that at least under some circumstances, tidally driven coastal currents may influence recruitment to freshwater habitats; therefore, it is presumed that high coastal current speed at the entry to river mouths may reduce the likelihood of freshwater entry. PMID- 26033295 TI - Effects of perceived social support and family demands on college students' mental well-being: A cross-cultural investigation. AB - The effects of perceived social support and family demands on college students' mental well-being (perceived stress and depression) were assessed in 2 samples of Jordanian and Turkish college students. Statistically significant negative correlations were found between perceived support and mental well-being. Multiple regression analyses showed that perceived family support was a better predictor of mental well-being for Jordanian students, while perceived support from friends was a better predictor of mental well-being for Turkish students. Perceived family demands were stronger predictors of mental well-being for participants from both ethnic groups. Jordanian and Turkish participants who perceived their families to be too demanding were more likely to report higher depression and stress levels. None of the interactions between social support or family demands and either of the 2 demographic variables were statistically significant. These findings provide a more nuanced view of the relationship between social support and mental health among college students, and point to the relevance of some cultural and situational factors. They also draw further attention to the detrimental effects of unrealistic family demands and pressures on the mental health of college youths. PMID- 26033296 TI - There are no whole truths in meta-analyses: all their truths are half-truths. PMID- 26033297 TI - The Value of Quality Improvement Process in the Detection and Correction of Common Errors in Echocardiographic Hemodynamic Parameters in a Busy Echocardiography Laboratory. AB - BACKGROUND: Accurate assessment of cardiac structures, ventricular function, and hemodynamics is essential for any echocardiographic laboratory. Quality improvement (QI) processes described by the American Society of Echocardiography (ASE) and the Intersocietal Commission (IAC) should be instrumental in reaching this goal. METHODS: All patients undergoing transthoracic echocardiogram (TTE) followed by cardiac catheterization within 24 hours at Christiana Care Health System in 2011 and 2012 were identified, with 126 and 133 cases, respectively. Hemodynamic parameters of diastolic function and pulmonary artery systolic pressure (PASP) on TTE correlated poorly with catheterization in 2011. An educational process was developed and implemented at quarterly QI meetings based on ASE and IAC recommendations to target frequently encountered errors and provide methods for improved performance. The hemodynamic parameters were then reexamined in 2012 postintervention. RESULTS: Following the QI process, there was significant improvement in the correlation between invasive and echocardiographic hemodynamic measurements in both systolic and diastolic function, and PASP. This reflected in significant better correlations between echo and cath LVEF [R = 0.88, ICC = 0.87 vs. R = 0.85, ICC = 0.85; P < 0.001], average E/E' and of left ventricle end-diastolic pressure (LVEDP) [R = 0.62 vs. R = 0.09, P = 0.006] and a better correlation for PASP [R = 0.77, ICC = 0.77 vs. R = 0.30, ICC = 0.31; P = 0.05] in 2012 compared to 2011. CONCLUSION: The QI process, as recommended by ASE and IAC, can allow for identification as well as rectification of quality issues in a large regional academic medical center hospital. PMID- 26033298 TI - An approach to fuzzy soft sets in decision making based on grey relational analysis and Dempster-Shafer theory of evidence: An application in medical diagnosis. AB - OBJECTIVE: The existing methods of fuzzy soft sets in decision making are mainly based on different kinds of level soft sets, and it is very difficult for decision makers to select a suitable level soft set in most instances. The goal of this paper is to present an approach to fuzzy soft sets in decision making to avoid selecting a suitable level soft set and to apply this approach to solve medical diagnosis problems. METHODS: This approach combines grey relational analysis with the Dempster-Shafer theory of evidence. It first utilizes grey relational analysis to calculate the grey mean relational degree, by which we calculate the uncertain degree of various parameters. Then, on the basis of the uncertain degree, the suitable basic probability assignment function of each independent alternative with each parameter can be obtained. Next, we apply Dempster-Shafer rule of evidence fusion to aggregate these alternatives into a collective alternative, by which these alternatives are ranked and the best alternative is obtained. Finally, we compare this approach with the mean potentiality approach. RESULTS: The results demonstrate the effectiveness and feasibility of this approach vis-a-vis the mean potentiality approach, Feng's method, Analytical Hierarchy Process and Naive Bayes' classification method because the measure of performance of this approach is the same as that of the mean potentiality approach, and the belief measure of the whole uncertainty falls from the initial mean 0.3821 to 0.0069 in an application of medical diagnosis. CONCLUSION: An approach to fuzzy soft sets in decision making by combining grey relational analysis with Dempster-Shafer theory of evidence is introduced. The advantages of this approach are discussed. A practical application to medical diagnosis problems is given. PMID- 26033299 TI - Fluorescent Sulfur-Tagged Europium(III) Coordination Polymers for Monitoring Reactive Oxygen Species. AB - Oxidative stress caused by reactive oxygen species (ROS) is harmful to biological systems and implicated in various diseases. A variety of selective fluorescent probes have been developed for detecting ROS to uncover their biological functions. Generally, the preparation of the fluorescent probes usually undergoes multiple synthetic steps, and the successful fluorescent sensing usually relies on trial-and-error tests. Herein we present a simple way to prepare fluorescent ROS probes that can be used both in biological and environmental systems. The fluorescent europium(III) coordination polymers (CPs) are prepared by simply mixing the precursors [2,2'-thiodiacetic acid and Eu(NO3)3.6H2O] in ethanol. Interestingly, with the increase of reaction temperature, the product undergoes a morphological transformation from microcrystal to nanoparticle while the structure and fluorescent properties retain. The fluorescence of the sulfur tagged europium(III) CPs can be selectively quenched by ROS, and thus, sensitive and selective monitoring of ROS in aerosols by the microcrystals and in live cells by the nanoparticles has been achieved. The results reveal that the sulfur tagged europium(III) CPs provide a novel sensor for imaging ROS in biological and environmental systems. PMID- 26033300 TI - Talking about sensitive topics during the advance care planning discussion: A peek into the black box. AB - OBJECTIVE: Advance care planning (ACP) discussions are emphasized as a valuable way of improving communication about end-of-life care. Yet we have very little knowledge of what goes on during actual ACP discussions. The aim of our study was to explore how the sensitive topics of end-of-life decisions are addressed in concrete ACP discussions, with special focus on doctor-patient interactions. METHOD: Following a discourse-analysis approach, the study uses the concept of doctor and patient "voices" to analyze 10 directly observed and audiotaped ACP discussions among patients, relatives, and a physician, carried out in connection with a pilot study conducted in Denmark. RESULTS: Previous studies of directly observed patient-physician discussions about end-of-life care show largely ineffective communication, where end-of-life issues are toned down by healthcare professionals, who also tend to dominate the discussions. In contrast, the observed ACP discussions in our study were successful in terms of addressing such sensitive issues as resuscitation and life-prolonging treatment. Our analysis shows that patients and relatives were encouraged to take the stage, to reflect, and to make informed choices. Patients actively explored different topics and asked questions about their current situation, but some also challenged the concept of ACP, especially the thought of being able to take control of end-of life issues in advance. SIGNIFICANCE OF RESULTS: Our analysis indicates that during discussions about sensitive end-of-life issues the healthcare professional will be able to pose and explore sensitive ACP questions in a straightforward manner, if the voices that express empathy and seek to empower the patient in different ways are emphasized. PMID- 26033301 TI - Role of lattice defects in catalytic activities of graphene clusters for fuel cells. AB - Defects are common but important in graphene, which could significantly tailor the electronic structures and physical and chemical properties. In this study, the density functional theory (DFT) method was applied to study the electronic structure and catalytic properties of graphene clusters containing various point and line defects. The electron transfer processes in oxygen reduction reaction (ORR) on perfect and defective graphene clusters in fuel cells was simulated, and the free energy and reaction energy barrier of the elementary reactions were calculated to determine the reaction pathways. It was found that the graphene cluster with the point defect having pentagon rings at the zigzag edge, or line defects (grain boundaries) consisting of pentagon-pentagon-octagon or pentagon heptagon chains also at the edges, shows the electrocatalytic capability for ORR. Four-electron and two-electron transfer processes could occur simultaneously on graphene clusters with certain types of defects. The energy barriers of the reactions are comparable to that of platinum(111). The catalytic active sites were determined on the defective graphene. PMID- 26033302 TI - Functional role of the C-terminal tail of the archaeal ribosomal stalk in recruitment of two elongation factors to the sarcin/ricin loop of 23S rRNA. AB - Two types of elongation factors alternate in their binding to the factor-binding center of the ribosome. Both binding events are accompanied by GTP hydrolysis and drive the translation elongation cycle. The multicopy ribosomal protein family, termed the stalk, contributes actively to the elongation process. Recent evidence indicates that the mobile C-terminal tail of archaeal stalk aP1 directly interacts with both the elongation factors aEF1A and aEF2. To investigate the functional significance of these interactions in recruitment of elongation factors to the factor-binding center of the ribosome, we substituted the archaeal stalk complex aL10*aP1 for the bL10*bL12 stalk complex in the Escherichia coli 50S subunit. The resultant hybrid ribosome accessed archaeal aEF1A and aEF2 in a manner dependent on the C-terminal tail containing the hydrophobic residues Leu103, Leu106 and Phe107. Bases G2659 and A2660 in the sarcin/ricin loop (SRL) of 23S rRNA were protected against DMS modification by both factors as was A1067 by aEF2. Mutagenesis indicated that this protection was dependent on the intact C terminal tail of aP1. The results suggest a crucial role for the interactions between the stalk C-terminal tail and elongation factors in their recruitment to the SRL of 23S rRNA within the ribosome. PMID- 26033303 TI - Legacy of road salt: Apparent positive larval effects counteracted by negative postmetamorphic effects in wood frogs. AB - Road salt runoff has potentially large effects on wetland communities, but is typically investigated in short-term laboratory trials. The authors investigated effects of road salt contamination on wood frogs (Rana sylvatica) by combining a field survey with 2 separate experiments. The field survey tested whether wood frog larval traits were associated with road salt contamination in natural wetlands. As conductivity increased, wood frog larvae were less abundant, but those found were larger. In the first experiment of the present study, the authors raised larvae in outdoor artificial ponds under 4 salt concentrations and measured larval vital rates, algal biomass, and zooplankton abundance. Salt significantly increased larval growth, algal biomass, and decreased zooplankton abundance. In the second experiment, the authors raised larvae to metamorphosis in the presence and absence of salt contamination and followed resulting juvenile frogs in terrestrial pens at high and low densities. Exposure to road salt as larvae caused juvenile frogs to have greater mortality in low-density terrestrial environments, possibly because of altered energy allocation, changes in behavior, or reduced immune defenses. The present study suggests that low concentrations of road salt can have positive effects on larval growth yet negative effects on juvenile survival. These results emphasize the importance of testing for effects of contaminants acting through food webs and across multiple life stages as well as the potential for population-level consequences in natural environments. PMID- 26033304 TI - Insecticide resistance in pollen beetles over 7 years - a landscape approach. AB - BACKGROUND: In spite of considerable interest in the impact of pesticides on pest populations, few attempts have been made to link resistance patterns of insect pests to land-use features across spatial and temporal scales. We hypothesise that pollen beetle pesticide resistance increases in areas with a high proportion of oilseed rape and with an even mixture of winter and spring oilseed rape owing to high pesticide selection pressure in such areas. RESULTS: Here, we investigated 7 years of lambda-cyhalothrin (Karate((r)) ) resistance in field collected pollen beetle adults from a total of 180 sampling points across ten regions in Sweden. We found a positive effect on pollen beetle pesticide resistance of proportion of oilseed rape and even spring-winter oilseed rape mixture. However, this was true only for the regional spatial scale. Significant land-use effects in the long-term models, with oilseed rape data averaged over a longer (4 years) period of time, suggested an effect of regional landscape history on current pest resistance. CONCLUSION: For successful control of pollen beetle pesticide resistance, we suggest a long-term regional strategy for oilseed rape management. This land-use approach provides a framework for further investigations that integrate resistance management into landscape research. PMID- 26033305 TI - Inner Mongolian steppe arbuscular mycorrhizal fungal communities respond more strongly to water availability than to nitrogen fertilization. AB - Plant community productivity and species composition are primarily constrained by water followed by nitrogen (N) availability in the degraded semi-arid grasslands of Inner Mongolia. However, there is a lack of knowledge on how long-term N addition and water availability interact to influence the community structure of arbuscular mycorrhizal (AM) fungi, and whether AM fungi contribute to the recovery of degraded grasslands. Soils and roots of the dominant plant species Stipa grandis and Agropyron cristatum were sampled under two water levels and N) rates after 8 years. The abundance and diversity of AM fungi remained relatively resilient after the long-term addition of water and N. Variation in the AM fungal communities in soils and roots were affected primarily by watering. AM fungal abundance and operational taxonomic unit (OTU) richness were significantly correlated with average aboveground net primary productivity and biomass of plant functional groups. Hyphal length density was significantly correlated with plant richness, the average biomass of S. grandis and perennial forbs. Both water and plant biomass had a considerable influence on the AM fungal assemblages. The tight linkages between AM fungi with aboveground plant productivity highlight the importance of plant-microbe interactions in the productivity and sustainability of these semi-arid grassland ecosystems. PMID- 26033306 TI - Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas. AB - OBJECTIVE: We aimed to clarify whether dual inhibition of PI3K/MAPK and MAPK pathways synergistically suppresses cell growth in endometrial cancer cells. METHODS: We exposed a panel of 12 endometrial cancer cell lines to a PI3K/mTOR inhibitor (voxtalisib, SAR245409) and/or a MEK inhibitor (pimasertib). The effect of each drug singly or in combination was evaluated by MTT assay, flow cytometry, and immunoblotting. Combination indexes (CIs) were calculated using the Chou Talalay method to evaluate the synergy. RESULTS: The IC50 values for SAR245409 and pimasertib varied from 0.5 MUM to 7 MUM and from 0.1 MUM to >20 MUM, respectively. A combination of both compounds (1 MUM SAR245409 and 30 nM pimasertib) caused a synergistic antitumor effect in 6 out of 12 endometrial cell lines (CI, 0.07-0.46). The synergistic effect was exclusively observed in 6 pimasertib-sensitive cell lines (IC50 of pimasertib, <=5 MUM). We found that 30 nM pimasertib, a concentration much lower than the IC50 for each cell line, was sufficient to cause a synergistic effect with SAR245409. Flow cytometric analysis showed that this combination significantly increased the population of G1 cells. However, a combination of rapamycin (an mTOR inhibitor) and pimasertib did not induce a synergistic effect in endometrial cancer cells, except for HEC-1B cells. CONCLUSIONS: The combination of a PI3K/mTOR inhibitor and a MEK inhibitor induced a synergistic antitumor effect in certain endometrial cancer cells. This study underscores the importance of using optimized doses of antitumor agents, singly or in combination, in treating endometrial cancer. PMID- 26033307 TI - Intraoperative radiation therapy (IORT) for gynecologic malignancies. AB - Every year almost 95,000 women are diagnosed with a gynecologic malignancy and over 28,000 women will succumb to their disease. For patients with an isolated locoregional recurrence after primary therapy, surgical resection may sometimes provide a chance of cure. To optimize the chance of local control intraoperative radiation therapy (IORT) has been used. The combination of salvage surgery and IORT has resulted in reasonable control in the IORT field. The addition of external beam radiation to limited volumes seems to result in improved disease control over surgery and IORT alone. Side effects are closely related to radical surgery, although neuropathy is seen more frequently after IORT; especially if doses of >20Gy are prescribed. Margin status remains critical, even with IORT. PMID- 26033308 TI - Obstructive Sleep Apnea Using Watch-PAT 200 Is Independently Associated With an Increase in Morning Blood Pressure Surge in Never-Treated Hypertensive Patients. AB - This study aimed to examine the association between obstructive sleep apnea (OSA) and morning blood pressure surge in never-treated patients with essential hypertension. This prospective study included a total of 58 patients (mean age, 51.7 years; 55.2% men) with never-treated essential hypertension. The patients were divided into non-OSA (n=23, 49.3+/-12.7 years) and OSA (n=35, 53.2+/-9.8 years) groups. The OSA group was defined as having an apnea-hypopnea index level >5 as measured by the Watch-PAT 200. The authors collected 24-hour ambulatory BP, plasma aldosterone concentration, and plasma renin activity data from all of the patients. The measured sleep-trough morning systolic blood pressure (SBP) increases were higher in the OSA group than in the non-OSA group (28.7+/-11.8 mm Hg vs 19.6+/-12.8 mm Hg, P=.008). The sleep-trough morning SBP increase was inversely correlated with the lowest oxygen saturation (r=-0.272, P=.039). OSA known to be associated with increased daytime and nocturnal sympathetic activity was associated with significantly higher sleep-trough morning SBP levels in this study. PMID- 26033309 TI - Postdetoxification Factors Predicting Alcohol-Related Emergency Room Visits 12 to 24 Months After Discharge: Results from a Prospective Study of Patients with Alcohol Dependence. AB - BACKGROUND: Relapse is common in patients with alcohol dependence, even after detoxification. The aims of this prospective study were to investigate changes affecting patients during the first 6 months after discharge from hospitalization for detoxification and to determine the influence of these changes on the likelihood of alcohol-related emergency room (ER) visits in the following 18 month period. METHODS: The study included 88 patients hospitalized for participation in a detoxification program in the addiction department of a university hospital in Rennes, France. Alcohol consumption, psychiatric symptoms, and life events were investigated by addiction specialists during hospitalization and 6 months afterward. For each patient, the number of alcohol-related ER visits in the last 6 months was prospectively recorded at the hospital 12, 18, and 24 months after hospitalization. The rate ratios of ER visits as a function of sociodemographic variables and changes observed 6 months after discharge were estimated using Poisson regression with autoregressive errors. RESULTS: Nearly half of the patients (47.7%) had ER visits in the 12- to 24-month period following discharge. The likelihood of ER visits was higher for patients living with friends/parents and for those with aggravated psychiatric symptoms, negative changes in their family life, and who had a medical follow-up in the 6 months after discharge. In contrast, the likelihood of ER visits was lower for patients living with children and those with improved psychiatric morbidity. Alcohol consumption and psychiatric symptoms at baseline had no significant effect. CONCLUSIONS: Monitoring changes in psychiatric symptoms and family life early after a detoxification program may help identify patients who are vulnerable to relapse in the subsequent 18-month period. Systematic screening for these changes as early as possible, in combination with appropriate treatment and the establishment of a social support system, could be fundamental in avoiding further relapses and ER visits. PMID- 26033311 TI - A 10-minute prototype assay for tissue degradation monitoring in clinical specimens. AB - We recently identified alpha II spectrin as a Tissue Degradation Indicator (TDI) and demonstrated that intrinsic spectrin-breakdown levels reliably reveal tissue degradation status in biospecimens. With the present study, we introduce an in vitro biological assay to mimic the endogenous spectrin-breakdown process and serve as degradation monitor (DM). By initiating the DM at the time of specimen collection and by attaching the DM to respective specimens, specimen degradation can be assessed by DM readout without specimen consumption. Using a protease inhibitory assay and protease-targeted immunoassays, we identified calpain as the protease responsible for degradation-induced spectrin breakdown. To recapitulate spectrin degradation in vitro, we developed several enzymatic assays in test tubes by incubating recombinant spectrins and synthetic Fluorescence Resonance Energy Transfer (FRET)-based spectrin peptides with purified human and porcine calpains. The in vitro assays reliably performed in different environments for a limited time due to loss of calpain activity. To maintain longer calpain activity, we introduced cultured cells as calpain providers into the in vitro assays. Under a variety of degradative conditions, including 4 degrees C, 13 degrees C, 23 degrees C, 29 degrees C, 37 degrees C, freezing, and freeze-thaw steps, we compared the use of this prototype DM to the intrinsic spectrin cleavage assay (ISCA) in specimen degradation assessment using animal models. A strong correlation (r=0.9895) was detected between the DM-revealed degradation and the ISCA-revealed degradation. Notably, the DM-based degradation assessment takes only 10min and does not jeopardize the tissue itself, whereas the ISCA based degradation assessment needs to sacrifice tissues and takes several hours to accomplish. Our data suggests the application of an in vitro degradation monitor for fast, real time, and non-invasive assessment of specimen degradation. This observation could lead to a transformative product dedicated to biospecimen quality control. This study also addresses critical, yet unmet needs for developing a universal standard for specimen degradation measurement. PMID- 26033310 TI - Possible cause for altered spatial cognition of prepubescent rats exposed to chronic radiofrequency electromagnetic radiation. AB - The effects of chronic and repeated radiofrequency electromagnetic radiation (RFEMR) exposure on spatial cognition and hippocampal architecture were investigated in prepubescent rats. Four weeks old male Wistar rats were exposed to RF-EMR (900 MHz; SAR-1.15 W/kg with peak power density of 146.60 MUW/cm(2)) for 1 h/day, for 28 days. Followed by this, spatial cognition was evaluated by Morris water maze test. To evaluate the hippocampal morphology; H&E staining, cresyl violet staining, and Golgi-Cox staining were performed on hippocampal sections. CA3 pyramidal neuron morphology and surviving neuron count (in CA3 region) were studied using H&E and cresyl violet stained sections. Dendritic arborization pattern of CA3 pyramidal neuron was investigated by concentric circle method. Progressive learning abilities were found to be decreased in RF EMR exposed rats. Memory retention test performed 24 h after the last training revealed minor spatial memory deficit in RF-EMR exposed group. However, RF-EMR exposed rats exhibited poor spatial memory retention when tested 48 h after the final trial. Hirano bodies and Granulovacuolar bodies were absent in the CA3 pyramidal neurons of different groups studied. Nevertheless, RF-EMR exposure affected the viable cell count in dorsal hippocampal CA3 region. RF-EMR exposure influenced dendritic arborization pattern of both apical and basal dendritic trees in RF-EMR exposed rats. Structural changes found in the hippocampus of RF EMR exposed rats could be one of the possible reasons for altered cognition. PMID- 26033312 TI - Comparison of caudal bupivacaine alone with bupivacaine plus two doses of dexmedetomidine for postoperative analgesia in pediatric patients undergoing infra-umbilical surgery: a randomized controlled double-blinded study. AB - BACKGROUND: Data are still insufficient about the effects of different concentrations of caudal dexmedetomidine when used to prolong postoperative analgesia in children. The aim of this study was to assess the analgesic efficacy and side effects of two doses of caudal dexmedetomidine (1 and 2 MUg.kg(-1)) co administered with bupivacaine in terms of postoperative pain scores and requirement of postoperative analgesia over 24 h in children undergoing infra umbilical surgery. METHODS: Ninety-one children, aged 1-6 years, undergoing infra umbilical surgery were included and randomly allocated into three groups of caudal block. Group B received 0.25% bupivacaine 2 mg.kg(-1) (0.8 ml.kg(-1)). Groups BD1 and BD2 received dexmedetomidine 1 and 2 MUg.kg(-1), respectively along with bupivacaine 2 mg.kg(-1) in a total volume of 0.8 ml.kg(-1). Anesthesia was induced and maintained with sevoflurane in 100% oxygen. Hemodynamic and other routine intraoperative monitoring was carried out in addition to endtidal sevoflurane concentration. Time to spontaneous eye opening and postoperative pain and sedation scores were recorded in addition to time to first analgesia, paracetamol analgesic requirements, and any side effects during the first 24 postoperative hours. RESULTS: Time to first analgesia requirement was significantly longer in BD1 and BD2 groups compared to B group with mean values (95% CI) of 809 min (652-965), 880 (733-1026), and 396 (343-448), respectively, P < 0.001. Postoperative paracetamol analgesic requirements over 24 h were higher in group B compared to BD1 and BD2 groups (Mean (95% CI): 3.2 (2.9-3.5) doses, 1.9 (1.5-2.3), and 1.6 (1.3-1.9), respectively), P < 0.001. The dexmedetomidine groups had significantly higher postoperative sedation scores compared to plain bupivacaine group that were dose dependent and for longer time in BD2 group. Two patients in BD2 group developed bradycardia and hypotension, and one developed urine retention compared to none in other groups. CONCLUSION: A 1 MUg.kg(-1) dose of caudal dexmedetomidine achieved comparable prolongation of postoperative analgesia to 2 MUg.kg(-1) dose, with shorter duration of postoperative sedation and lower incidence of other side effects. PMID- 26033313 TI - DC type 2 polarization depends on both the allergic status of the individual and protease activity of Per a 10. AB - Cockroach proteases are important risk factors for asthma development in predisposed individuals. In the present study, effect of allergic status of patients on DCs polarization in response to protease allergen Per a 10 was investigated. Cockroach-allergic, other-allergic patients and healthy individuals were selected following the guidelines of ATS/ARIA. Monocyte-derived dendritic cells (DCs) were generated from the selected individuals and stimulated with Per a 10. Flow cytometric analysis showed a significantly high expression of CD80 and CD86 on DCs from cockroach-allergic patients after Per a 10 stimulation as compared to healthy individuals or other-allergic patients (P<0.05). Per a 10 induced comparable level of CD83 expression on DCs from all the 3 groups, showing it was irrespective of the allergic status. CD40 expression was significantly low (P<0.05) on the DCs from cockroach-allergic patients as compared to healthy individuals or other-allergic patients. Further, proteolytically active Per a 10 induced lower CD40 expression on DCs than the heat-inactivated Per a 10 (P<0.05) indicating role of protease activity in the generation of an immune response. The sCD40 level in active Per a 10 stimulated DC cultures was significantly higher than in heat-inactivated Per a 10 (P<0.05). There was two-fold decrease (P<0.05) in IL-12 production by active Per a 10-stimulated DCs than heat-inactivated Per a 10-stimulated DCs. Per a 10-stimulated DCs from cockroach-allergic patients secreted high levels of IL-5, IL-6, TNF-alpha than that from healthy individuals or other-allergic patients (P<0.05). Furthermore, Per a 10-stimulated DCs from cockroach-allergic patients induced increased secretions of IL-4, IL-5, IL-6, TNF alpha and low IL-12 by T cells as compared to those from other groups (P<0.05). Thus, in presence of Per a 10 allergen, polarization of DCs shifts toward type 2 in cockroach-allergic patients but not in the healthy individuals or other allergic patients. In conclusion, both allergic status of the individual and protease activity of Per a 10 are important parameters that participate in DCs polarization. PMID- 26033314 TI - Effect of immobilisation materials on viability and fermentation activity of dairy starter culture in whey-based substrate. AB - BACKGROUND: The main objectives of the paper were to study influence of immobilisation of dairy starter culture 'Lactoferm ABY 6' on fermentation and probiotic potential of fermented whey-based substrate. RESULTS: Fermentation with free cells takes 1.5 h less than fermentation with encapsulated cells, but samples with encapsulated cells have better characteristics after 28 days of storage. Chitosan coating provides additional protection of cells in bile salt solution (95.86% of viable cells compared to the initial number) and simulated gastric juice (37.8% for pH 2.5) compared to the alginate beads (94.54% in bile salt solution and 36.18% in simulated gastric juice for pH 2.5). Free cells had a drastic reduction in the number of viable cells (83.0% in bile salt solution and no viable cells in simulated gastric juice for pH 2.5). CONCLUSION: Samples with alginate beads and chitosan-coated alginate beads have significantly (P < 0.05) higher viable cell count than samples with free cells, during 4 h monitoring survival at pH 2.5, pH 3.0 and 0.3% bovine bile solution. These beads can be used to improve survival of probiotic cells in fermented whey-based beverage during storage and consummation, which improves the quality of the product. PMID- 26033315 TI - Connecting genotypes, phenotypes and fitness: harnessing the power of CRISPR/Cas9 genome editing. AB - One of the fundamental goals in evolution and ecology is to identify the genetic basis of adaptive phenotypes. Unfortunately, progress towards this goal has been hampered by a lack of genetic tools available for nonmodel organisms. The exciting new development of the CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 (CRISPR-associated nuclease 9) genome-editing system now promises to transform the field of molecular ecology by providing a versatile toolkit for manipulating the genome of a wide variety of organisms. Here, we review the numerous applications of this groundbreaking technology and provide a practical guide to the creation of genetic knockouts, transgenics and other related forms of gene manipulation in nonmodel organisms. We also specifically discuss the potential uses of the CRISPR/Cas9 system in ecological and evolutionary studies, which will further advance the field towards the long standing goal of connecting genotypes, phenotypes and fitness. PMID- 26033316 TI - Rituximab as a treatment for severe atopic eczema: failure to improve in three consecutive patients. AB - Biological therapies may provide the breakthrough in treating moderate to severe atopic eczema (AE) that is unresponsive to standard therapy. Rituximab has been shown to benefit some patients in published case series, and so we treated three consecutive patients with severe AE with rituximab. Despite achieving low/absent peripheral blood CD19 + B-cell numbers following rituximab administration, this was not associated with clinical benefit as there was no major change in pre- and post-treatment Eczema Area and Severity Index (34, 64.4 and 42.2 compared with 33.2, 66 and 56.4, respectively). We would therefore recommend that that there is a compelling need for a formal, double-blind, placebo-controlled study to demonstrate efficacy of rituximab as a treatment of moderate to severe AE. PMID- 26033317 TI - Size of Submicrometer Particles Measured by FCS: Correction of the Confocal Volume. AB - When fluorescence correlation spectroscopy (FCS) in combination with a confocal microscope is used to determine the hydrodynamic radius a of particles comparable to or larger than the linear size sigma of the confocal volume of the microscope, a correction must be used that depends on the a(2)/sigma(2) ratio and the distribution of the dye within the particle. Here we present the experimental validation of the theoretically predicted approximate correction necessary for appropriate measurements of the size of uniformly fluorescently labeled spheres of radius comparable to the size of the confocal volume. We also test the approximate correction formula for different ranges of the a/sigma ratio and propose a simple procedure to obtain the correct nanoparticle size from such a measurement. PMID- 26033318 TI - Neuroprotective effects of electroacupuncture on hypoxic-ischemic encephalopathy in newborn rats are associated with increased expression of GDNF-RET and protein kinase B. AB - OBJECTIVE: To explore the neuroprotective effects of electroacupuncture (EA) on hypoxic-ischemic encephalopathy (HIE) and to further investigate the role of glial cell line-derived neurotrophic factor (GDNF) family receptor member RET (rearranged during transfection) and its key downstream phosphatidylinositol 3 kinase (PI-3K)/protein kinase B (Akt) pathway in the process. METHODS: A total of 220 seven-day-old SD rats (of either sex, from 22 broods) were randomly divided into two groups, one (30 rats) for sham-surgery group and the other (190 rats) for HIE model group. The HIE model was established using the left common carotid artery ligation method in combination with hypoxic treatment. The successfully established rats were randomly divided into five groups, including control model group, EA group, sham-EA group, antagonist group and antagonist plus electroacupuncture group, with 35 rats in each group. Baihui (GV 20), Dazhui (GV 14), Quchi (LI 11) and Yongquan (KI 1) acupoints were chosen for acupuncture. EA was performed at Baihui and Quchi for 10 min once a day for continuous 1, 3, 7 and 21 days, respectively. The rats were then killed after the operation and injured cerebral cortex was taken for the measurement of neurologic damage by hematoxylin-eosin (HE) staining and the degenerative changes of cortical ultrastructure by transmission electron microscopy. RET mRNA level and Akt protein level were detected by real-time reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively. RESULTS: EA could ameliorate neurologic damage of the first somatic sensory area (S1Tr) and alleviate the degenerative changes of ultrastructure of cortical neurons in rats subjected to HIE. And the longer acupuncture treatment lasted, the better its therapeutic effect would be. This was accompanied by gradually increased expression of GDNF family receptor RET at the mRNA level and its downstream signaling Akt at the protein level in the ischemic cortex. CONCLUSION: EA has neuroprotective effects on HIE and could be a potential therapeutic strategy for HIE in the neonate. Activation of RET/Akt signaling pathway might be involved in this process. PMID- 26033319 TI - Condylar asymmetry in patients with juvenile idiopathic arthritis: Could it be a sign of a possible temporomandibular joints involvement? AB - OBJECTIVES: The aim of the study was to evaluate the condylar and ramal asymmetry of the mandible in patients with juvenile idiopathic arthritis (JIA) using orthopantomographies (OPTs). METHODS: A total of 30 JIA patients with confirmed diagnosis of JIA and a routine OPT, seeking for orthodontic therapy, free of specific symptoms of temporomandibular joint involvement, and 30 normal matched subjects with OPT were comprised in the study. The method of Habets et al. was used to compare the condyles and rami in OPT. The significance of between-group differences were assessed using Mann-Whitney test. RESULTS: The results showed a high significant difference in the range of asymmetry of the condyle, being the patient group highly asymmetrical (P < 0.0001). No differences were found in the range of asymmetry of the ramus between groups (P = 0.47). The intra-group comparison between males and females showed a difference in the patient group (P = 0.04), being the females more asymmetric. CONCLUSIONS: Knowing that the temporomandibular joint (TMJ) is highly susceptible to inflammatory alterations during growth, even in absence of symptomatology, and being the OPT a cost benefit favorable imaging tool widespread in the dental field, the latter could be used as a first screening examination in JIA patients to calculate the condylar asymmetry index. The use of this screening tool will help the physicians in addressing the patients that should undergo a more detailed TMJ imaging to early detect TMJ abnormalities and to early set up a targeted therapy of the related cranial growth alterations. PMID- 26033321 TI - Robot-assisted intracorporeal pyramid neobladder. AB - OBJECTIVE: To describe a robot-assisted intracorporeal pyramid neobladder reconstruction technique and report operative and perioperative metrics, postoperative upper tract imaging, neobladder functional outcomes, and oncological outcomes. PATIENTS AND METHODS: In all, 20 patients (19 male and one female) with a mean (sd; range) age of 57.2 (12.4; 31.0-78.2) years underwent robot-assisted radical cystectomy (RARC). Most cases were <=pT1 (17 patients) and the remaining three patients had muscle-invasive bladder cancer (MIBC) at RARC histopathology. Although half of the patients (10) actually had MIBC at transurethral resection histopathology. All patients underwent RARC, bilateral pelvic lymphadenectomy, and intracorporeal neobladder formation using a pyramid detubularised folding pouch configuration. RESULTS: The median estimated blood loss was 250 mL and operating time was 5.5 h. The mean (sd) number of lymph nodes removed was 16.5 (7.8) and median hospital stay was 10 days. Early postoperative complications included urinary tract infection (UTI) (four patients), ileus (four), diarrhoea and vomiting (three), postoperative collection (two), and blocked stent (one). Late postoperative complications included UTI (seven patients), neobladder stone (two), voiding Hem-o-Loc (two), neobladder leak (two), diarrhoea and vomiting (one), uretero-ileal stricture (one), vitamin B12 deficiency (one), and port-site hernia (one). There was no evidence of hydronephrosis in 18 patients with a median follow-up of 21.5 months. At 24 months, recurrence-free survival was 86% and overall survival was 100%. In all, 19 patients and 13 patients reported 6-month day time and night time continence, respectively. CONCLUSIONS: The pyramid neobladder is technically feasible using a robotic platform and provides satisfactory functional outcomes at median of 21.5 months. PMID- 26033320 TI - Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype. AB - Gastric cancer (GC), one of the most common human cancers, can be classified into gastric or intestinal phenotype according to mucin expression. TP53 mutation, allelic deletion of the APC gene and nuclear staining of beta-catenin are frequently detected in the intestinal phenotype of GC, whereas CDH1 gene mutation, microsatellite instability and DNA hypermethylation of MLH1 are common events in the gastric phenotype of GC. Our Serial Analysis of Gene Expression (SAGE) and Escherichia coli ampicillin secretion trap (CAST) analyses revealed that CDH17, REG4, OLFM4, HOXA10, DSC2, TSPAN8 and TM9SF3 are upregulated in GC and that CLDN18 is downregulated in GC. Expression of CDH17, REG4, HOXA10 and DSC2 and downregulation of CLDN18 are observed in the intestinal phenotype of GC. In contrast, OLFM4 is expressed in the gastric phenotype of GC. Expression of TSPAN8, TM9SF3 and HER2 are not associated with either gastric or intestinal phenotypes. Ectopic CDX2 expression plays a key function in the GC intestinal phenotype. MUC2, CDH17, REG4, DSC2 and ABCB1 are direct targets of CDX2. Importantly, these genes encode transmembrane/secretory proteins, indicating that the microenvironment as well as cancer cells are also different between gastric and intestinal phenotypes of GC. PMID- 26033322 TI - Variability in growth tracking is associated with body mass index at 17 years of age. AB - AIM: Variability in individual growth tracking and its association with body mass index (BMI) in later life remains insufficiently explored. Our aim was to investigate growth tracking variabilities from birth up to the end of growth at 17 years of age and their relationship to BMI. METHODS: Data were obtained from the personal health records of 1492 healthy children - 762 boys and 730 girls - who were born full term in 1990 in the city and surrounding villages of Vilnius in Lithuania. The analysis of growth tracking was performed using two methods: tracing the main percentiles and the changes in standard deviation scores for height and BMI. RESULTS: Most of the boys and girls changed one growth track for height and BMI. However, girls from birth to two years of age and 11-17 years of age were the most likely to change two growth tracks for the growth indices. Children who were underweight at 17 years of age changed significantly more BMI tracks during the first two years of life (2.19 +/- 1.21) than overweight and obese 17-year-olds (1.75 +/- 1.14). CONCLUSION: This study of 1492 healthy children at 17 years of age showed that great individual variability in the growth tracking of body mass index in early life was associated with being underweight at 17 years of age. PMID- 26033323 TI - Detection of equine herpesvirus-4 and physiological stress patterns in young Thoroughbreds consigned to a South African auction sale. AB - BACKGROUND: The prevalence of equine herpesvirus types-1 and -4 (EHV-1 and -4) in South African Thoroughbreds at auction sales is currently undefined. Commingling of young Thoroughbreds from various populations together with physiological stress related to their transport and confinement at a sales complex, may be associated with shedding and transmission of EHV-1 and -4. This prospective cohort study sampled 90 young Thoroughbreds consigned from eight farms, originating from three provinces representative of the South African Thoroughbred breeding demographic to a sales complex. Nasal swabs for quantitative real-time polymerase chain reaction (qPCR) assay to detect EHV-1 and -4 nucleic acid and blood samples for enzyme-linked immunosorbent assay for EHV-1 and -4 antibodies were collected from all horses on arrival and departure. Additional nasal swabs for qPCR were obtained serially from those displaying pyrexia and, or nasal discharge. Daily faecal samples were used for determination of faecal glucocorticoid metabolite (FGM) concentrations as a measurement of physiological stress and these values were modelled to determine the factors best explaining FGM variability. RESULTS: EHV-4 nucleic acid was detected in 14.4 % and EHV-1 from none of the animals in the study population. Most (93.3 %) and very few (1.1 %) of this population showed antibodies indicating prior exposure to EHV-4 and EHV-1 respectively. Pyrexia and nasal discharge were poor predictors for detecting EHV-4 nucleic acid. The horses' FGM concentrations increased following arrival before decreasing for most of the remaining study period including the auction process. Model averaging showed that variation in FGM concentrations was best explained by days post-arrival and transport duration. CONCLUSIONS: In this study population, sales consignment was associated with limited detection of EHV 4 nucleic acid in nasal secretions, with most showing prior exposure to EHV-4 and very few to EHV-1. The physiological stress response shown by most reflected the combination of stressors associated with transport and arrival and these are key areas for future investigation into management practices to enhance health and welfare of young Thoroughbreds during sales consignment. PMID- 26033324 TI - Molecular dynamics study on folding and allostery in RfaH. AB - Upon being released from the N-terminal domain (NTD), the C-terminal domain (CTD) switches from alpha-helix conformation to beta-barrel conformation, which converts RfaH from a transcription factor into an activator of translation. The alpha->beta conformational change may be viewed as allosteric transition. We use molecular dynamics simulations of coarse-grained off-lattice model to study the thermal folding of NTD, CTD, RfaH and the allosteric transition in CTD. The melting temperatures from the specific heat profiles indicate that the beta barrel conformation is much more stable than the alpha-helix conformation. Two helices in alpha-helix conformation have similar thermodynamic stabilities and the melting temperatures for beta sheets show slight dispersion. Under the interaction with NTD, CTD is greatly stabilized and the cooperativity for thermal folding is also significantly improved. The alpha->beta allosteric transition can be approximately described by a two-state model and three parallel pathways are identified. The transition state ensemble, quantified by a Tanford beta-like parameter, resembles the alpha-helix and beta-barrel conformations almost to the same extent. PMID- 26033325 TI - Tocilizumab and steroid boli for treatment-resistant anterior necrotizing scleritis. PMID- 26033326 TI - Efficacy of inhibition of IL-1 in patients with rheumatoid arthritis and type 2 diabetes mellitus: two case reports and review of the literature. AB - INTRODUCTION: Rheumatoid arthritis is an autoimmune arthritis in which two inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, play a critical role in the induction and progression of the disease. Several reports and data from registries have discussed the association between chronic inflammatory diseases and disorders in intermediary metabolism, pointing out that prevalence of peripheral insulin resistance and type 2 diabetes mellitus is increased among patients with rheumatoid arthritis. In addition, several studies have shown that type 2 diabetes mellitus may be considered an interleukin-1beta inflammatory-mediated process, and both preclinical and clinical observations have reported the usefulness of interleukin-1 antagonism therapy in this disease. CASE PRESENTATION: We describe the case of a 58-year-old Caucasian woman and a 74 year-old Caucasian man with rheumatoid arthritis associated with type 2 diabetes mellitus. In these patients, the inhibition of interleukin-1beta not only induced remission for rheumatoid arthritis, but successfully controlled their metabolic status. CONCLUSIONS: We report the positive effects of the inhibition of interleukin-1 in two patients with rheumatoid arthritis associated with type 2 diabetes mellitus, with both reaching the therapeutic targets of their diseases by using a single biological agent and tapering or discontinuing their antidiabetic therapies. These findings suggest that targeting interleukin-1 might be considered a good therapeutic option for the treatment of rheumatoid arthritis associated with type 2 diabetes mellitus. PMID- 26033327 TI - Parameter identification of Droop model: an experimental case study. AB - Mathematical modeling and the development of predictive dynamic models are of paramount importance for the optimization, state estimation, and control of bioprocesses. This study is dedicated to the identification of a simple model of microalgae growth under substrate limitation, i.e., Droop model, and describes the design and instrumentation of a lab-scale flat-plate photobioreactor, the associated on-line and off-line instrumentation, the collection of experimental data, and the parameter identification procedure. In particular, a dedicated methodology for parameter identification is discussed, including the determination of an initial parameter set using an analytical procedure, the selection of a cost function, the evaluation of confidence intervals as well as direct and cross-validation tests. PMID- 26033329 TI - Novel Atypical Antipsychotics: Metabolism and Therapeutic Drug Monitoring (TDM). AB - Medicinal chemistry is continually developing and testing new drugs and drug candidates to satisfactorily address the needs of patients suffering from schizophrenia. In the last few years, some significant additions have been made to the list of widely available atypical antipsychotics. In particular, iloperidone, asenapine and lurasidone have been approved by the USA's Food and Drug Administration in 2009-10. In this paper, the most notable metabolic characteristics of these new drugs are addressed, with particular attention to their potential for pharmacokinetic interactions, and to the respective advantages and disadvantages in this regard. Moreover, current perspectives on the therapeutic drug monitoring (TDM) of the considered drugs are discussed. Since TDM is most valuable when it allows the personalisation and optimisation of therapeutic practices, it is even more interesting in the case of novel drugs, such as those discussed here, whose real impact in terms of side and toxic effects on very large populations is still unknown. Some analytical notes, related to TDM application, are included for each drug. PMID- 26033328 TI - Production of oleanane-type sapogenin in transgenic rice via expression of beta amyrin synthase gene from Panax japonicus C. A. Mey. AB - BACKGROUND: Panax japonicus C. A. Mey. is a rare traditional Chinese herbal medicine that uses ginsenosides as its main active ingredient. Rice does not produce ginsenosides because it lacks a key rate-limiting enzyme (beta-amyrin synthase, betaAS); however, it produces a secondary metabolite, 2,3 oxidosqualene, which is a precursor for ginsenoside biosynthesis. RESULTS: In the present study, the P. japonicus betaAS gene was transformed into the rice cultivar 'Taijing 9' using an Agrobacterium-mediated approach, resulting in 68 rice transgenic plants of the T0 generation. Transfer-DNA (T-DNA) insertion sites in homozygous lines of the T2 generation were determined by using high-efficiency thermal asymmetric interlaced PCR (hiTAIL-PCR) and were found to vary among the tested lines. Approximately 1-2 copies of the betaAS gene were detected in transgenic rice plants. Real-time PCR and Western blotting analyses showed that the transformed betaAS gene could be overexpressed and beta-amyrin synthase could be expressed in rice. HPLC analysis showed that the concentration of oleanane type sapogenin oleanolic acid in transgenic rice was 8.3-11.5 mg/100 g dw. CONCLUSIONS: The current study is the first report on the transformation of P. japonicus betaAS gene into rice. We have successfully produced a new rice germplasm, "ginseng rice", which produces oleanane-type sapogenin. PMID- 26033331 TI - India's urban middle class has high prevalence of cardiometabolic risk factors, finds study. PMID- 26033330 TI - Additive gamma frailty models with applications to competing risks in related individuals. AB - Epidemiological studies of related individuals are often complicated by the fact that follow-up on the event type of interest is incomplete due to the occurrence of other events. We suggest a class of frailty models with cause-specific hazards for correlated competing events in related individuals. The frailties are based on sums of gamma distributed variables and offer closed form expressions for the observed intensities. An inference procedure with a recursive baseline estimator is proposed, and its large sample properties are established. The estimator readily handles cluster left-truncation as occurring in the Nordic twin registers. The performance in finite samples is investigated by simulations and an example on prostate cancer in twins is provided for illustration. PMID- 26033332 TI - The Effect of Combination of Video Feedback and Audience Feedback on Social Anxiety: Preliminary Findings. AB - Although video feedback (VF) is shown to improve appraisals of social performance in socially anxious individuals, its impact on state anxiety during a social situation is mixed. The current study investigated the effect of combined video feedback and audience feedback (AF) on self-perceptions of performance and bodily sensations as well as state anxiety pertaining to a speech task. Forty-one socially anxious students were randomly allocated to combined video feedback with audience feedback (VF + AF), video feedback only (VF), audience feedback only (AF), or a control condition. Following a 3-min speech, participants in the VF + AF, VF, and AF conditions watched the videotape of their speech with cognitive preparation in the presence of three confederates who served as audience, and/or received feedback from the confederates, while the control group watched their videotaped speech without cognitive preparation. Both VF + AF and AF conditions improved distorted appraisal of performance and bodily sensations as well as state anxiety. The clinical implications of these findings are discussed. PMID- 26033333 TI - Image Analysis or Stereology: Which to Choose for Quantifying Fibrosis? PMID- 26033334 TI - Development and validation of an LC-MS/MS method for the determination of bullatine A in rat plasma: application to a pharmacokinetic study. AB - Bullatine A is a diterpenoid alkaloid of Xue-Shang-Yi-Zhi-Hao (Aconitum brachypodum), which is widely used in traditional Chinese medicine for the treatment of rheumatism and pain. The plasma levels of bullatine A were measured by a rapid and sensitive LC-MS/MS method. Samples were prepared using acetonitrile precipitation and the separation of bullatine A was achieved on a Capcell Pak MG-C18 column by isocratic elution using acetonitrile (phase A) and 0.1% formic acid (phase B, pH 4.0; A:B, 30:70, v/v) as the mobile phase at a flow rate of 0.5 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometer by multiple-reaction monitoring of the transitions at m/z 344.2 -> 105.2 for bullatine A and m/z 256.2 -> 167.1 for the internal standard. The linearity was found to be within the concentration range of 1.32-440 ng/mL with a lower limit of quantification of 1.32 ng/mL. Only 1.3 min was needed for an each analytical run. This method was successfully applied in the determination of the active component bullatine A in rat plasma after intramuscular administration of A. brachypodum injection. PMID- 26033335 TI - Anti-D alloimmunisation in pregnant women with DEL phenotype in China. AB - OBJECTIVES: To analyse anti-D alloimmunisation in pregnant women with D-elute (DEL) phenotype in China, for developing a predictive model to evaluate whether a person with the DEL phenotype can receive RhD-positive blood. BACKGROUND: Alloanti-D acquired by pregnancy or transfusion is one of the major causes of both haemolytic disease among newborns and haemolytic transfusion reactions. To date, there is little data available about the antigenic properties and immunogenicity of extremely weak D variants known as DEL. METHODS: RHD genotyping and D epitope mapping were performed using gene sequencing and comprehensive immunohaematological methods, respectively. DEL pregnant women carrying an RhD positive fetus were tested for the presence of alloanti-D. RESULTS: A total of 130 of 142 (91.5%) pregnant women with a DEL phenotype were confirmed to carry the RHD (K409K) allele. Among 12 DEL women who appeared to have RHD-CE-D hybrid alleles, there were 1 RHD-CE (4-7)-D, 7 RHD-CE(4-9)-D, and 4 RHD-CE (2-5)-D alleles. Alloanti-D antibodies were detected in 6 of 142 DEL women, and all the six women had the partial DEL phenotype. CONCLUSION: The data indicate that partial DEL women appear at risk of alloimmunization to the D antigen. RhD immune globulin prophylaxis is necessary for partial DEL women. Partial DEL patients should receive only RhD-negative RBCs, whereas DEL patients with complete expression of antigen can safely receive RhD-positive RBCs. PMID- 26033336 TI - Description and clinical application of the Pulfrich effect. AB - BACKGROUND: In 1922, German physicist Carl Pulfrich described an illusory binocular perceptual disturbance in which an object moving across an observer's field of vision is perceived as traveling along a curved trajectory. OBJECTIVE: To review the discovery of the Pulfrich effect, and subsequent clinical applications. METHODS: We translated Pulfrich's description and searched for subsequent publications using electronic databases and review of reference lists in identified publications. RESULTS: In 1901, Pulfrich developed an optical device to accurately compare stereoscopic photographs, but brightness difference between plates caused distance misperceptions that interfered with precise measurements. Pulfrich proposed that this Stereo-Effekt resulted from interocular differences in perceptual latency. He induced the effect by placing a smoked glass in front of one eye. The resulting perceptual disparity creates an apparently curved trajectory of an object moving sideways across the field of vision. Pulfrich also recognized that visual pathway disorders can produce a pathologic Stereo-Effekt. In 1925, Grimsdale demonstrated this in a man with unilateral retrobulbar optic neuritis and suggested treatment with a neutral density filter (NDF) over the good eye. Not until the 1970s, however, was the Pulfrich effect evaluated as a diagnostic test for retrobulbar optic neuritis and the therapeutic efficacy of an NDF confirmed. CONCLUSION: Although the clinical importance of the Pulfrich effect was suggested by Pulfrich and quickly confirmed, it took decades before its diagnostic utility and the efficacy of an NDF were assessed. Recognition remains clinically important to minimize safety risks and mislabeling, and because resulting misperceptions can be easily treated. PMID- 26033337 TI - Calcified pseudoneoplasm of the neuraxis. PMID- 26033338 TI - Transient ocular tilt reaction and Tullio phenomenon: A rare association. PMID- 26033339 TI - Imaging prodromal Parkinson disease: The Parkinson Associated Risk Syndrome Study. PMID- 26033340 TI - Healthy diet and lifestyle and risk of stroke in a prospective cohort of women. PMID- 26033341 TI - Clinical Reasoning: A 45-year-old man with acute onset of multifocal weakness and paresthesias. PMID- 26033342 TI - Emerging Subspecialties in Neurology: Telestroke and teleneurology. PMID- 26033344 TI - Preparation of Furo[3,2-c]coumarins from 3-Cinnamoyl-4-hydroxy-2H-chromen-2-ones and Acyl Chlorides: A Bu3P-Mediated C-Acylation/Cyclization Sequence. AB - A Bu3P-mediated cyclization reaction of 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones though electrophilic addition of acyl chlorides towards the synthesis of highly functionalized furo[3,2-c]coumarins bearing a phosphorus ylide moiety is described. These unprecedented cyclization reaction proceeds under mild reaction conditions within short reaction times (1 min to 1 h), and can be further applied in the synthesis of alkenyl-substituted furo[3,2-c]coumarins by the treatment with carbonyl electrophiles under basic conditions. PMID- 26033343 TI - Teaching NeuroImages: Corpus callosum splenium hyperintensity in fragile X associated tremor ataxia syndrome. PMID- 26033345 TI - Coupling Infusion and Gyration for the Nanoscale Assembly of Functional Polymer Nanofibers Integrated with Genetically Engineered Proteins. AB - Nanofibers featuring functional nanoassemblies show great promise as enabling constituents for a diverse range of applications in areas such as tissue engineering, sensing, optoelectronics, and nanophotonics due to their controlled organization and architecture. An infusion gyration method is reported that enables the production of nanofibers with inherent biological functions by simply adjusting the flow rate of a polymer solution. Sufficient polymer chain entanglement is obtained at Berry number > 1.6 to make bead-free fibers integrated with gold nanoparticles and proteins, in the diameter range of 117-216 nm. Integration of gold nanoparticles into the nanofiber assembly is followed using a gold-binding peptide tag genetically conjugated to red fluorescence protein (DsRed). Fluorescence microscopy analysis corroborated with Fourier transform infrared spectroscopy (FTIR) data confirms the integration of the engineered red fluorescence protein with the nanofibers. The gold nanoparticle decorated nanofibers having red fluorescence protein as an integral part keep their biological functionality including copper-induced fluorescence quenching of the DsRed protein due to its selective Cu(+2) binding. Thus, coupling the infusion gyration method in this way offers a simple nanoscale assembly approach to integrate a diverse repertoire of protein functionalities into nanofibers to generate biohybrid materials for imaging, sensing, and biomaterial applications. PMID- 26033346 TI - Reliability of Two Methods for Identifying the Postural Phase of Gait Initiation in Healthy and Poststroke Subjects. AB - This study aims to compare 2 methods of assessing the postural phase of gait initiation, in regard to intrasession reliability, in healthy and poststroke subjects. As a secondary aim, this study aims to analyze anticipatory postural adjustments during gait initiation based on the center of pressure (CoP) displacements in poststroke participants. The CoP signal was acquired during gait initiation in 15 poststroke subjects and 23 healthy controls. Postural phase was identified through a baseline-based method and a maximal displacement-based method. In both healthy and poststroke participants, higher intraclass correlation coefficient and lower coefficient of variation values were obtained with the baseline-based method when compared with the maximal displacement-based method. Poststroke participants presented decreased CoP displacement backward and toward the first swing limb compared with controls when the baseline-based method was used. With the maximal displacement based method, there were differences between groups only regarding backward CoP displacement. Postural phase duration in medial-lateral direction was also increased in poststroke participants when using the maximal displacement based method. The findings obtained indicate that the baseline-based method is more reliable detecting the onset of gait initiation in both groups, while the maximal displacement-based method presents greater sensitivity for poststroke participants. PMID- 26033347 TI - Transfemoral Device Occlusion and Minimally Invasive Surgical Repair for Doubly Committed Subarterial Ventricular Septal Defects. AB - Transfemoral device occlusion and minimally invasive surgical repair are performed for doubly committed subarterial ventricular septal defect (dcVSD) to reduce the invasiveness of the conventional surgical repair through a median sternotomy. However, few studies have compared them in terms of effectiveness and cost. Inpatients with isolated dcVSD who had undergone transfemoral device occlusion or minimally invasive surgical repair from January 2011 to June 2014 were reviewed for a comparative investigation between the two procedures. Procedure success was achieved in 36 transfemoral (75 %) and in 36 surgical (100 %) procedures (p = 0.001). Transfemoral patients were older, with a VSD size similar to that of surgical patients (14.5 +/- 11.7 vs 4.4 +/- 2.9 years, p < 0.001; 4.5 +/- 1.5 vs 4.4 +/- 1.3 mm, p = 0.577, respectively). No significant difference was observed in complication rates between the two treatment groups (p = 1). No large residual shunt was observed. Small residual shunt was noted in two transfemoral patients and four surgical patients (p = 0.674). All these small residual shunts closed spontaneously during follow-up. The surgical repair costs 26 % less than the device occlusion (Yuan 22063.2 +/- 343.9 vs Yuan 29970.1 +/- 1335.2, p < 0.001), where most of the cost was attributed to the occluder in the amount of Yuan 19,500. Compared with device occlusion, minimally invasive surgical repair can provide superior efficacy and comparable complication rates. In addition, it is 26 % cheaper than device occlusion. In low-income countries where healthcare resources are limited, medical resources must be judiciously allocated to the treatment that allows for effective treatment of the largest number of patients. PMID- 26033348 TI - Stop-Smoking Medication Use, Subsidization Policies, and Cessation in Canada. AB - INTRODUCTION: In 2000, Quebec began reimbursing stop-smoking medications (SSMs) through their provincial public drug insurance plan. Several other Canadian provinces have since begun offering SSM subsidies. Clinical trials indicate that SSMs can increase quit success; however, little evidence exists on patterns of use in "real-world" settings and impact on population quit rates. This study examines Canadian trends in SSM use and quit success over time, comparing provinces with differing subsidization policies. METHODS: Secondary analyses were conducted in 2014 using nationally representative Canadian Tobacco Use Monitoring Survey data, 2004-2012, for current and former smokers who made a quit attempt in the past 2 years (N=26,094). Regression models tested for differences in SSM use and quit success in provinces with differing SSM coverage (i.e., none, partial, or comprehensive). RESULTS: Smokers were more likely to use nicotine replacement therapy (NRT) in jurisdictions with comprehensive SSM coverage versus jurisdictions with partial (OR=1.39, 95% CI=1.22, 1.59) or no coverage (OR=1.43, 95% CI=1.21, 1.68). Prescription medication use was more likely in provinces with partial (versus no) coverage (OR=1.27, 95% CI=1.01, 1.59). Overall, smokers who attempted to quit were more likely to remain abstinent in jurisdictions with comprehensive versus partial (OR=1.20, 95% CI=1.12, 1.28) or no coverage (OR=1.23, 95% CI=1.00, 1.50). An interaction between coverage and cigarettes per day was observed, suggesting potentially greater impact of comprehensive coverage among heavier smokers. CONCLUSIONS: Comprehensive subsidization policies are associated with modest increases in NRT use and quit success, but do not appear to impact prescription SSM use. PMID- 26033349 TI - A Novel Diabetes Prevention Intervention Using a Mobile App: A Randomized Controlled Trial With Overweight Adults at Risk. AB - INTRODUCTION: Mobile phone technology may be a cost-effective and convenient way to deliver proven weight-loss interventions and thereby prevent or delay onset of type 2 diabetes. The purpose of this study was to examine the feasibility and efficacy of a diabetes prevention intervention combined with a mobile app and pedometer in English-speaking overweight adults at risk for type 2 diabetes. DESIGN: RCT. PARTICIPANTS: Participants included 61 overweight adults with a mean age (SD) of 55.2 (9.0) years. Seventy-seven percent were women, 48% were racial/ethnic minorities, and baseline BMI was 33.3 (6.0). INTERVENTION: The curriculum was adapted from the Diabetes Prevention Program, with the frequency of in-person sessions reduced from 16 to six sessions and group exercise sessions replaced by a home-based exercise program. A study-developed mobile phone app and pedometer augmented the intervention and provided self-monitoring tools. MAIN OUTCOME MEASURE: Weight loss. RESULTS: Data were collected in 2012 and 2013 and were analyzed in 2014. In intention-to-treat analyses, the intervention group (n=30) lost an average of 6.2 (5.9) kg (-6.8% [5.7%]) between baseline and 5 month follow-up compared to the control group's (n=31) gain of 0.3 (3.0) kg (0.3% [5.7%]) (p<0.001). The intervention group's steps per day increased by 2,551 (4,712) compared to the control group's decrease of 734 (3,308) steps per day (p<0.001). In comparison, the intervention group had greater reductions in hip circumference (p<0.001); blood pressure (p<0.05); and intake of saturated fat (p=0.007) and sugar-sweetened beverages (p=0.02). The intervention had no significant effect on fasting lipid or glucose levels. CONCLUSIONS: The significant weight loss resulting from this modified combined mobile app and pedometer intervention for overweight adults warrants further investigation in a larger trial. PMID- 26033350 TI - Up to 7 Years of Sustained Weight Loss for Weight-Loss Program Completers. AB - INTRODUCTION: Two issues remain elusive in weight management programs: significant, long-term weight-loss maintenance and widely accessible programs that produce significant weight loss for reasonable costs. The purpose of this study is to determine the long-term weight loss of participants who consecutively renew their annual membership in Take Off Pounds Sensibly (TOPS), a national, nonprofit, low-cost, peer-led weight-loss program. METHODS: This completers' analysis was a retrospective cohort study of overweight and obese men and women who joined TOPS in 2005-2011 and consecutively renewed their annual membership at least once. Data were analyzed from June to October 2013. TOPS participants' weights are sent to the national database when they join and at the time of their annual renewal; thus, follow-up weight is only available for those who renew their membership. Among 207,469 individuals who joined during the study period, 74,629 (35.9%) had at least one consecutive annual renewal and were included in the study. RESULTS: Cumulative mean (95% CI) weight change as a percentage of initial weight ranged from -6.0% (-6.0%, -5.9%) for 74,629 participants who renewed at 1 year to -8.3% (-8.7%, -7.8%) for 2,289 participants with 7 years of consecutive annual renewal. CONCLUSIONS: In the subset of individuals who choose to renew their program membership, TOPS can effectively promote maintenance of clinically significant weight loss for an extended period of time. RCTs are needed to further evaluate this low-cost, widely available program, which could be a viable option to treat overweight and obesity. PMID- 26033352 TI - Risk-Based Sampling: I Don't Want to Weight in Vain. AB - Recently, there has been considerable interest in developing risk-based sampling for food safety and animal and plant health for efficient allocation of inspection and surveillance resources. The problem of risk-based sampling allocation presents a challenge similar to financial portfolio analysis. Markowitz (1952) laid the foundation for modern portfolio theory based on mean variance optimization. However, a persistent challenge in implementing portfolio optimization is the problem of estimation error, leading to false "optimal" portfolios and unstable asset weights. In some cases, portfolio diversification based on simple heuristics (e.g., equal allocation) has better out-of-sample performance than complex portfolio optimization methods due to estimation uncertainty. Even for portfolios with a modest number of assets, the estimation window required for true optimization may imply an implausibly long stationary period. The implications for risk-based sampling are illustrated by a simple simulation model of lot inspection for a small, heterogeneous group of producers. PMID- 26033351 TI - 'Porosome' discovered nearly 20 years ago provides molecular insights into the kiss-and-run mechanism of cell secretion. AB - Secretion is a fundamental cellular process in living organisms, from yeast to cells in humans. Since the 1950s, it was believed that secretory vesicles completely merged with the cell plasma membrane during secretion. While this may occur, the observation of partially empty vesicles in cells following secretion suggests the presence of an additional mechanism that allows partial discharge of intra-vesicular contents during secretion. This proposed mechanism requires the involvement of a plasma membrane structure called 'porosome', which serves to prevent the collapse of secretory vesicles, and to transiently fuse with the plasma membrane (Kiss-and-run), expel a portion of its contents and disengage. Porosomes are cup-shaped supramolecular lipoprotein structures at the cell plasma membrane ranging in size from 15 nm in neurons and astrocytes to 100-180 nm in endocrine and exocrine cells. Neuronal porosomes are composed of nearly 40 proteins. In comparison, the 120 nm nuclear pore complex is composed of >500 protein molecules. Elucidation of the porosome structure, its chemical composition and functional reconstitution into artificial lipid membrane, and the molecular assembly of membrane-associated t-SNARE and v-SNARE proteins in a ring or rosette complex resulting in the establishment of membrane continuity to form a fusion pore at the porosome base, has been demonstrated. Additionally, the molecular mechanism of secretory vesicle swelling, and its requirement for intra vesicular content release during cell secretion has also been elucidated. Collectively, these observations provide a molecular understanding of cell secretion, resulting in a paradigm shift in our understanding of the secretory process. PMID- 26033353 TI - The matrikine PGP as a potential biomarker in COPD. AB - The lack of a well-characterized biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD) has increased interest toward finding one, because this would provide potential insight into disease pathogenesis and progression. Since persistent neutrophilia is an important hallmark in COPD Pro Gly-Pro (PGP), an extracellular matrix-derived neutrophil chemoattractant, has been suggested to be a potential biomarker in COPD. The purpose of this review is to critically examine both biological and clinical data related to the role of PGP in COPD, with particular focus on its role as a clinical biomarker and potential therapeutic target in disease. The data provided in this review will offer insight into the potential use of PGP as end point for future clinical studies in COPD lung disease. Following PGP levels during disease might serve as a guide for the progression of lung disorders. PMID- 26033354 TI - Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4. AB - Microfibrillar-associated protein 4 (MFAP4) is localized to elastic fibers in blood vessels and the interalveolar septa of the lungs and is further present in bronchoalveolar lavage. Mfap4 has been previously suggested to be involved in elastogenesis in the lung. We tested this prediction and aimed to characterize the pulmonary function changes and emphysematous changes that occur in Mfap4 deficient (Mfap4(-/-)) mice. Significant changes included increases in total lung capacity and compliance, which were evident in Mfap4(-/-) mice at 6 and 8 mo but not at 3 mo of age. Using in vivo breath-hold gated microcomputed tomography (micro-CT) in 8-mo-old Mfap4(-/-) mice, we found that the mean density of the lung parenchyma was decreased, and the low-attenuation area (LAA) was significantly increased by 14% compared with Mfap4(+/+) mice. Transmission electron microscopy (TEM) did not reveal differences in the organization of elastic fibers, and there was no difference in elastin content, but a borderline significant increase in elastin mRNA expression in 3-mo-old mice. Stereological analysis showed that alveolar surface density in relation to the lung parenchyma and total alveolar surface area inside of the lung were both significantly decreased in Mfap4(-/-) mice by 25 and 15%, respectively. The data did not support an essential role of MFAP4 in pulmonary elastic fiber organization or content but indicated increased turnover in young Mfap4(-/-) mice. However, Mfap4(-/-) mice developed a spontaneous loss of lung function, which was evident at 6 mo of age, and moderate air space enlargement, with emphysema-like changes. PMID- 26033355 TI - Influenza induces IL-8 and GM-CSF secretion by human alveolar epithelial cells through HGF/c-Met and TGF-alpha/EGFR signaling. AB - The most severe complication of influenza is viral pneumonia, which can lead to the acute respiratory distress syndrome. Alveolar epithelial cells (AECs) are the first cells that influenza virus encounters upon entering the alveolus. Infected epithelial cells produce cytokines that attract and activate neutrophils and macrophages, which in turn induce damage to the epithelial-endothelial barrier. Hepatocyte growth factor (HGF)/c-Met and transforming growth factor-alpha (TGF alpha)/epidermal growth factor receptor (EGFR) are well known to regulate repair of damaged alveolar epithelium by stimulating cell migration and proliferation. Recently, TGF-alpha/EGFR signaling has also been shown to regulate innate immune responses in bronchial epithelial cells. However, little is known about whether HGF/c-Met signaling alters the innate immune responses and whether the innate immune responses in AECs are regulated by HGF/c-Met and TGF-alpha/EGFR. We hypothesized that HGF/c-Met and TGF-alpha/EGFR would regulate innate immune responses to influenza A virus infection in human AECs. We found that recombinant human HGF (rhHGF) and rhTGF-alpha stimulated primary human AECs to secrete IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF) strongly and IL-6 and monocyte chemotactic protein 1 moderately. Influenza infection stimulated the secretion of IL-8 and GM-CSF by AECs plated on rat-tail collagen through EGFR activation likely by TGF-alpha released from AECs and through c-Met activated by HGF secreted from lung fibroblasts. HGF secretion by fibroblasts was stimulated by AEC production of prostaglandin E2 during influenza infection. We conclude that HGF/c-Met and TGF-alpha/EGFR signaling enhances the innate immune responses by human AECs during influenza infections. PMID- 26033356 TI - Positive Aspects of Family Caregiving for Dementia: Differential Item Functioning by Race. AB - OBJECTIVES: Due to increasing interest in the positive experiences associated with family caregiving, potential demographic group differences were examined on the Positive Aspects of Caregiving (PAC) scale at both the item and scale levels. METHOD: Family caregivers (N = 642) completed the PAC as part of their participation in the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) clinical trial. Multiple indicators, multiple causes models were used to examine potential differential item functioning (DIF) across demographic subgroups. RESULTS: Overall PAC scale scores indicated that both Hispanics and African Americans experienced more PAC than Whites. Two items with statistically significant (p < .004) and practically meaningful (odds ratio > 2.0) DIF were found for African American caregivers. After controlling for the underlying unidimensional construct, African Americans reported that caregiving gave them "a more positive attitude toward life" and enabled them to "appreciate life more" than either Whites or Hispanics. No instances of meaningful DIF were found between Hispanics and Whites, women and men, or spouses and nonspouses. DISCUSSION: PAC scores differ significantly by race. In addition, 2 items with meaningful race DIF identify content areas that are particularly relevant to the cultural experiences of African American caregivers. PMID- 26033358 TI - Student giving health advice to family and friends. AB - BACKGROUND: This study explored graduate-entry medical students' experiences of health-advice requests from their family and friends. METHODS: This was a descriptive thematic analysis study involving a convenience sample of medical students from the University of Warwick 4-year MB ChB graduate-entry medicine programme. Each participating student attended a one-to-one semi-structured interview. Audio recordings of the interviews were transcribed verbatim and analysed thematically. Data saturation of the main themes was achieved following 14 interviews. FINDINGS: Of the 14 students, eight (57%) were males and six (43%) were females. Students were asked to advise on a range of human and veterinary health issues. They were prepared to offer advice on health issues that they felt competent to manage: for example, first-aid scenarios that a 'reasonable layperson' or a first-aider would be able to help with. The nature of health advice given by students became increasingly complex as they progressed through their degree programme; however, they generally refrained from giving advice on complex health issues and chose to refer the individual to seek help from competent professionals instead. DISCUSSION: Previous research highlighted inappropriate advice could delay individuals seeking help from competent professionals, resulting in adverse clinical outcomes; however, we recommend that students should not be discouraged to act as good Samaritans. Instead, educators could help them to explore the professionalism and ethical issues raised by these requests, and the practical ways of handling these requests sensitively through discussion of case scenarios with acceptable and inappropriate behaviours. This study explored graduate-entry medical students' experiences of health-advice requests from their family and friends. PMID- 26033357 TI - UCEPR: Ultrafast localized CEST-spectroscopy with PRESS in phantoms and in vivo. AB - PURPOSE: Chemical exchange saturation transfer (CEST) is a contrast mechanism enhancing low-concentration molecules through saturation transfer from their exchangeable protons to bulk water. Often many scans are acquired to form a Z spectrum, making the CEST method time-consuming. Here, an ultrafast localized CEST-spectroscopy with PRESS (UCEPR) is proposed to obtain the entire Z-spectrum of a voxel using only two scans, significantly accelerating CEST. THEORY AND METHODS: The approach combines ultrafast nonlocalized CEST spectroscopy with localization using PRESS. A field gradient is applied concurrently with the saturation pulse producing simultaneous saturation of all Z-spectrum frequencies that are also spatially encoded. A readout gradient during data acquisition resolves the spatial dependence of the CEST responses into frequency. UCEPR was tested on a 3T scanner both in phantoms and in vivo. RESULTS: In phantoms, a fast Z-spectroscopy acquisition of multiple pH-variant iopamidol samples was achieved with four- to seven-fold acceleration as compared to the conventional CEST methods. In vivo, amide proton transfer (APT) in white matter of healthy human brain was measured rapidly in 48 s and with high frequency resolution (<= 0.2 ppm). CONCLUSION: Compared with conventional CEST methods, UCEPR has the advantage of rapidly acquiring high-resolution Z-spectra. Potential in vivo applications include ultrafast localized Z-spectroscopy, quantitative, or dynamic CEST studies. PMID- 26033359 TI - Is hepato-imino diacetic acid scan a better imaging modality than abdominal ultrasound for diagnosing acute cholecystitis? AB - BACKGROUND: The role of hepato-imino diacetic acid scan (HIDA) in the diagnosis of acute cholecystitis remains controversial when compared with the more commonly used abdominal ultrasound (AUS). METHODS: The diagnostic imaging workup of 1,217 patients who presented to the emergency department at a single hospital with acute abdominal pain and suspicion of acute cholecystitis was reviewed to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AUS and HIDA. RESULTS: In patients undergoing both imaging modalities, HIDA had significantly higher sensitivity (90.7% vs 64.0%, P < .001) and specificity (71.4% vs 58.4%, P = .005) than AUS for the diagnosis of acute cholecystitis. Additionally, PPV and NPV of HIDA (56.2% and 95.0%, respectively) were higher than PPV and NPV of AUS (38.4% and 80.0%, respectively) when both imaging modalities were used for the same patient. CONCLUSION: In adults with acute abdominal pain, HIDA significantly increases the accuracy of the correct diagnosis. PMID- 26033360 TI - Wrong surgery: why does not the Universal Protocol solve the problem? PMID- 26033361 TI - Percutaneous drainage for giant pyogenic liver abscess--is it safe and sufficient? AB - BACKGROUND: Large size is a predictor of failure of percutaneous drainage (PD) for pyogenic liver abscess (PLA). This article serves to establish the safety and sufficiency of PD in giant PLA (GPLA). METHODS: A retrospective review of all GPLA patients treated at a tertiary care academic hospital from 2001 to 2011 was performed. A GPLA is defined as an abscess greater than or equal to 10 cm size based on imaging. RESULTS: Forty patients (24 men, 60%) were treated for GPLA. All but 1 patient (98%) was managed with PD and the mean duration of drainage was 9 days (range 1 to 23 days). One patient underwent operative drainage. Three patients (7.7%) needed secondary procedures after the initial PD. One patient (2.6%) failed PD and subsequently underwent operative drainage. Among the patients who underwent PD, the overall morbidity was 25%; the median length of hospital stay was 13 days (range 5 to 31 days) and 1 (2.6%) mortality. CONCLUSIONS: Large size itself is not a contraindication for PD. PD is safe and sufficient even in GPLA patients. PMID- 26033362 TI - Omega-3 supplementation during pregnancy to prevent recurrent intrauterine growth restriction: systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy of omega-3 supplementation during pregnancy in preventing intrauterine growth restriction (IUGR) in women with apparently uncomplicated singleton pregnancy and previous IUGR pregnancy. METHODS: For this systematic review, the research protocol was designed a priori. Searches were performed in electronic databases for studies published from inception of each database to December 2014. A combination of search terms was used including 'fish oil', 'long chain polyunsaturated fatty acids', 'intrauterine growth restriction', 'small for gestational age' and 'omega-3'. We included all randomized controlled trials (RCTs) of women with an uncomplicated singleton pregnancy and a prior IUGR pregnancy who were randomized to receive prophylactic treatment with omega-3 supplementation or either placebo or no treatment (control). Trials that included women with multiple gestations and those with only biochemical outcomes available were excluded. Pooled estimates were based on relative risk (RR) with 95% CI. Primary outcome was incidence of IUGR as defined in the RCTs. RESULTS: Three RCTs including 575 women with uncomplicated singleton pregnancy with prior IUGR were analyzed. Women who received omega-3 supplementation during pregnancy had the same incidence of IUGR, defined as estimated fetal weight < 5(th) or < 3(rd) centiles, as had controls (22.8% vs 20.2%, respectively; RR, 1.13 (95% CI, 0.83-1.54)). Compared to controls, women who received omega-3 supplementation delivered later (mean difference, 1.4 (95% CI, 1.28-1.63) weeks), had a longer latency (mean difference, 2 (95% CI, 1.73 2.08) weeks), had a similar incidence of perinatal death (2.1% vs 3.3%, respectively; RR, 0.60 (95% CI, 0.15-2.42)) and similar birth weight (mean difference, 50 g (95% CI, -26 to 246 g)). CONCLUSIONS: Omega-3 supplementation during pregnancy does not prevent recurrence of IUGR in women with uncomplicated singleton pregnancy and a previous IUGR pregnancy. PMID- 26033363 TI - Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1 TLR4 signaling in rat tubulo-epithelial cells. AB - BACKGROUND AND PURPOSE: Angiotensin II is a vaso-constrictive peptide that regulates blood pressure homeostasis. Even though the inflammatory effects of AngII in renal pathophysiology have been studied, there still exists a paucity of data with regard to the mechanism of action of AngII-mediated kidney injury. The objective of this study was to elucidate the mechanistic role of HMGB1-TLR4 signaling in AngII-induced inflammation in the kidney. EXPERIMENTAL APPROACH: Rat tubular epithelial cells (NRK52E) were treated with AngII over a preset time course. In another set of experiments, HMGB1 was neutralized and TLR4 was knocked down using small interfering RNA targeting TLR4. Cell extracts were subjected to RT-PCR, immunoblotting, flow cytometry, and ELISA. KEY RESULTS: AngII-induced inflammation in NRK52E cells increased gene and protein expression of TLR4, HMGB1 and key proinflammatory cytokines (TNFalpha and IL1beta). Pretreatment with Losartan (an AT1 receptor blocker) attenuated the AngII-induced expression of TLR4 and inflammatory cytokines. TLR4 silencing was used to elucidate the specific role played by TLR4 in AngII-induced inflammation. TLR4siRNA treatment in these cells significantly decreased the AngII-induced inflammatory effect. Consistent observations were made when the Ang II treated cells were pretreated with anti-HMGB1. Downstream activation of NFkappaB and rate of generation of ROS was also decreased on gene silencing of TLR4 and exposure to anti-HMGB1. CONCLUSIONS AND IMPLICATIONS: These results indicate a key role for HMGB1-TLR4 signaling in AngII-mediated inflammation in the renal epithelial cells. Our data also reveal that AngII-induced effects could be alleviated by HMGB1-TLR4 inhibition, suggesting this pathway as a potential therapeutic target for hypertensive renal dysfunctions. PMID- 26033364 TI - MicroRNA-101 overexpression by IL-6 and TNF-alpha inhibits cholesterol efflux by suppressing ATP-binding cassette transporter A1 expression. AB - BACKGROUND: MicroRNAs play key roles in regulating cholesterol homeostasis. Here, we investigated the role of microRNA-101 (miR-101) in regulating ATP-binding cassette transporter A1 (ABCA1) expression and cholesterol efflux under non inflammatory and inflammatory conditions in human THP-1-derived macrophages and HepG2 hepatoblastoma cells. METHODS: The cell lines were transfected with one of four lentiviral vectors: miR-101, miR-101 control, anti-miR-101, or anti-miR-101 control. A luciferase reporter assay was used to examine miR-101 binding to the 3' untranslated region (UTR) of ABCA1. Western blotting was conducted to assess ABCA1 protein expression. Cells were loaded with BODIPY-cholesterol and stained with oil red O to assess cholesterol efflux. RESULTS: The luciferase activity assay revealed that wild-type miR-101 binding at site 2 significantly repressed ABCA1 3' UTR activity, suggesting that miR-101 directly targets the ABCA1 mRNA at site 2. In both cell lines, Western blotting revealed that miR-101 expression negatively regulates ABCA1 protein expression and significantly suppresses cholesterol efflux to ApoA1 under both low-density lipoprotein (LDL) and non-LDL conditions, which was confirmed by pronounced lipid inclusions visible by oil red O staining. In HepG2 cells, both IL-6 and TNF-alpha treatments produced significant miR-101 overexpression; however, in THP-1-derived macrophages, only IL-6 treatment produced significant miR-101 overexpression. Anti-mir-101 transfection under both IL-6 and TNF-alpha treatment conditions led to ABCA1 upregulation, indicating that miR-101 expression represses ABCA1 expression under inflammatory conditions. CONCLUSIONS: miR-101 promotes intracellular cholesterol retention under inflammatory conditions through suppressing ABCA1 expression and suggests that the miR-101-ABCA1 axis may play an intermediary role in the development of NAFLD and vascular atherosclerosis. PMID- 26033366 TI - Influence of pseudo-resistance on the effect of renal denervation on 24-hour ambulatory blood pressure levels. AB - BACKGROUND: Renal denervation (RDN) is a promising treatment option in addition to medical antihypertensive treatment in patients suffering from resistant hypertension. Despite the growing interest in RDN, the negative result of the Symplicity HTN-3 trial led to a debate on the efficacy of RDN. METHODS: We systematically investigated the effects of RDN, evaluated by 24-hr ambulatory blood pressure measurements (ABPM), in a consecutive series of patients with resistant hypertension, which was defined by a mean office systolic blood pressure (SBP) >160 mm Hg (>150 mm Hg in patients with diabetes). Patients with a mean 24-hr SBP of less than 130 mm Hg at baseline were classified as pseudo resistant, while all other patients were classified as true-resistant. After six months, we analyzed the response rates in true-resistant and in pseudo-resistant patients, respectively, by the means of 24-hr ABPM. Thereby, patients with a reduction of more than 5 mm Hg in 24-hr SBP were classified as responders. RESULTS: RDN was performed in 106 patients. By 24-hr ABPM, 20 patients (18.9%) were classified as pseudo-resistant patients. In this cohort, we only found two responders (response rate 10%) six months after RDN. By contrast, in true resistant patients, the response rate was almost 60% and the mean BP reduction was -18.6/-9 mm Hg in 24-hr ABPM. CONCLUSIONS: We found a significant BP reduction in almost 60% of patients with true-resistant hypertension, but only in 10% in patients with pseudo-resistant hypertension. According to our results, patient selection seems to be crucial for acceptable response rates after RDN. PMID- 26033367 TI - Romiplostim in the management of the thrombocytopenic surgical patient. AB - BACKGROUND: Thrombopoietin receptor agonists increase platelet (PLT) counts and are approved for the treatment of chronic immune thrombocytopenia (ITP). These agents may also be useful for the management of thrombocytopenia in patients requiring surgical procedures. STUDY DESIGN AND METHODS: We conducted a retrospective review of patients with thrombocytopenia (baseline PLT count, <150 * 10(9) /L) who received romiplostim before planned operative procedures. We characterized patient demographics, dosing and duration of romiplostim use, success in achieving PLT counts high enough for surgery, and clinical outcomes. RESULTS: Eighteen patients underwent a total of 22 operative procedures, including three Jehovah's Witnesses who underwent five procedures. Etiologies of thrombocytopenia included mild ITP (not on romiplostim at baseline), liver disease, hematologic malignancy, and drug-related thrombocytopenia. Median PLT count at romiplostim initiation was 47 * 10(9) /L (range, 11 * 10(9) -120 * 10(9) /L). All patients experienced a PLT count increase over a median of 4 weeks; median PLT count at surgery was 144 * 10(9) /L (range, 28 * 10(9) -370 * 10(9) /L). PLT counts increase to more than 150 * 10(9) /L in four of five Jehovah's Witness patients by the time of surgery. There were no surgical delays or cancellations due to thrombocytopenia. Four bleeding events occurred; none were fatal and none occurred at a PLT count of fewer than 80 * 10(9) /L. No definitive thromboembolic events occurred. CONCLUSION: Romiplostim successfully increased preoperative PLT counts allowing operative interventions, was well tolerated, did not lead to any significant thromboembolic events, and avoided the need for transfusion. Romiplostim may be of clinical utility in the preoperative management of thrombocytopenic patients, especially those unable to receive or unresponsive to PLT transfusion. PMID- 26033368 TI - The Cardiovascular Effects of Obesity on Ventricular Function and Mass in Patients after Tetralogy of Fallot Repair. AB - OBJECTIVES: To determine the cardiovascular effects of obesity on patients with tetralogy of Fallot (TOF) repair. STUDY DESIGN: Ventricular performance measures were compared between obese (body mass index [BMI] >=95%), overweight (85% <=BMI <95%), and normal weight subjects (BMI <85%) in a retrospective review of patients with TOF who underwent cardiac magnetic resonance from 2005-2010. Significance was P < .05. RESULTS: Of 260 consecutive patients with TOF, 32 were obese (12.3%), 48 were overweight (18.5%), and 180 were normal weight (69.2%). Biventricular mass was increased in obese compared with normal weight patients with right ventricular mass more affected than left ventricular mass. Obese patients demonstrated decreased biventricular end-diastolic volume (EDV) and stroke volume (SV) when indexed to body surface area (BSA) with an increased heart rate when compared with normal weight patients; cardiac index, ejection fraction, and pulmonary regurgitation fraction were similar. When indexed to ideal BSA, biventricular EDV and SV were similar. EDV and SV for overweight patients were nearly identical to normal weight patients with ventricular mass in between the other 2 groups. CONCLUSIONS: Approximately 12% of patients after TOF repair referred for cardiac magnetic resonance in a tertiary referral center are obese with increased biventricular mass. Obese patients and normal weight patients have similar cardiac indices, however, when indexed to actual BSA, obese patients demonstrate decreased EDV and SV with increased heart rate and similar cardiac indices. When indexed to ideal BSA, no differences in biventricular volumes were noted. PMID- 26033369 TI - Actinoallomurus bryophytorum sp. nov., an endophytic actinomycete isolated from moss (Bryophyta). AB - A novel endophytic actinomycete, strain NEAU-TX1-15(T), was isolated from moss, collected from Wuchang, Heilongjiang province, north China. A polyphasic taxonomic study was carried out to establish the status of strain NEAU-TX1-15(T). Morphological and chemotaxonomic properties of strain NEAU-TX1-15(T) are consistent with the description of the genus Actinoallomurus. Strain NEAU-TX1 15(T) was observed to form short spiral or looped spore chains on aerial hyphae. The cell wall peptidoglycan was found to contain lysine and meso-diaminopimelic acid. The major menaquinones were identified as MK-9(H6) and MK-9(H8). The only phospholipid identified was phosphatidylglycerol. The major fatty acid was identified as iso-C16:0. Analysis of the 16S rRNA gene sequence supports the assignment of the novel strain to the genus Actinoallomurus, as it exhibits 99.2 % gene sequence similarity to that of Actinoallomurus yoronensis NBRC 103686(T). However, the low level of DNA-DNA relatedness allowed the strain to be differentiated from its close relative. Moreover, strain NEAU-TX1-15(T) could also be differentiated from A. yoronensis NBRC 103686(T) and other Actinoallomurus species showing high 16S rRNA gene sequence similarity (>98.0 %) by cultural and physiological characteristics. Therefore, the combination of phenotypic and chemotaxonomic data, and the DNA-DNA hybridization value, indicated that strain NEAU-TX1-15(T) represents a novel species of the genus Actinoallomurus for which the name Actinoallomurus bryophytorum sp. nov. is proposed. The type strain is NEAU-TX1-15(T) (=CGMCC 4.7200(T) = JCM 30340(T)). PMID- 26033370 TI - Opsoclonus-myoclonus syndrome associated with a nasopharyngeal tumor in an adult: a case report. AB - INTRODUCTION: Opsoclonus-myoclonus syndrome is a rare autoimmune syndrome usually seen in children and very rarely in adults. It typically presents with a triad of opsoclonus, myoclonus and ataxia, and is most often associated with a tumor or after an infection or vaccination. Around half of all adult cases are paraneoplastic in origin, and isolated case reports include associations with lung, breast and ovarian cancers. To the best of our knowledge, this is the first ever reported case of paraneoplastic opsoclonus-myoclonus syndrome occurring in association with a nasopharyngeal carcinoma. CASE PRESENTATION: A 50-year-old British Caucasian woman presented with left-sided otalgia and subjective hearing loss. Over the coming weeks she developed subacute confusion and dizziness, leading to recurrent falls. Her clinical examination revealed opsoclonus, myoclonus and signs of cerebellar dysfunction. Subsequent magnetic resonance imaging revealed a left-sided nasopharyngeal carcinoma, which was confirmed on biopsy. A tapering dose of steroids and a five-day course of intravenous immunoglobulins, followed by a combination of chemo-radiotherapy for the nasopharyngeal carcinoma, led to a significant clinical improvement. At six months follow-up she had no signs of focal neurological deficit, apart from the inability to tandem walk. We believe that the typical clinical features, presence of a tumor and response to treatment support a paraneoplastic aetiology. CONCLUSIONS: We show that a nasopharyngeal carcinoma can be associated with adult onset opsoclonus-myoclonus syndrome. Both neurologists and otorhinolaryngologists must be aware of such a presentation. Prognosis of the syndrome depends on early and adequate management of the tumor, therefore prompt identification of the syndrome and the underlying tumor is essential. PMID- 26033371 TI - Hybrid SPECT/CT for the assessment of a painful hip after uncemented total hip arthroplasty. AB - BACKGROUND: The diagnosis of hip pain after total hip replacement (THR) represents a highly challenging question that is of increasing concern to orthopedic surgeons. This retrospective study assesses bone scintigraphy with Hybrid SPECT/CT for the diagnosis of painful THR in a selected cohort of patients. METHODS: Bone SPECT/CT datasets of 23 patients (mean age 68.9 years) with a painful hip after THR were evaluated. Selection of the patients required an inconclusive radiograph, normal serum levels of inflammatory parameters (CRP and ESR) or a negative aspiration of the hip joint prior to the examination. The standard of reference was established by an interdisciplinary adjudication-panel using all imaging data and clinical follow-up data (>12 month). Pathological and physiological uptake patterns were defined and applied. RESULTS: The cause of pain in this study group could be determined in 18 out of 23 cases. Reasons were aseptic loosening (n = 5), spine-related (n = 5), heterotopic ossification (n = 5), neuronal (n = 1), septic loosening (n = 1) and periprosthetic stress fracture (n = 1). In (n = 5) cases the cause of hip pain could not be identified. SPECT/CT imaging correctly identified the cause of pain in (n = 13) cases, in which the integrated CT-information led to the correct diagnosis in (n = 4) cases, mainly through superior anatomic correlation. Loosening was correctly assessed in all cases with a definite diagnosis. CONCLUSIONS: SPECT/CT of THA reliably detects or rules out loosening and provides valuable information about heterotopic ossifications. Furthermore differential diagnoses may be detected with a whole body scan and mechanical or osseous failure is covered by CT-imaging. SPECT/CT holds great potential for imaging-based assessment of painful prostheses. PMID- 26033372 TI - Variable phosphorus uptake rates and allocation across microbial groups in the oligotrophic Gulf of Mexico. AB - Microbial uptake of dissolved phosphorus (P) is an important lever in controlling both microbial production and the fate and cycling of marine P. We investigated the relative role of heterotrophic bacteria and phytoplankton in P cycling by measuring the P uptake rates of individual microbial groups (heterotrophic bacteria and the phytoplankton groups Synechococcus, Prochlorococcus and picoeukaryotic phytoplankton) in the P-depleted Gulf of Mexico. Phosphorus uptake rates were measured using incubations with radiolabelled phosphate and adenosine triphosphate coupled with cell sorting flow cytometry. We found that heterotrophic bacteria were the dominant consumers of P on both a biomass basis and a population basis. Biovolume normalized heterotrophic bacteria P uptake rate per cell (amol P MUm(-3) h(-1)) was roughly an order of magnitude greater than phytoplankton uptake rates, and heterotrophic bacteria were responsible for generally greater than 50% of total picoplankton P uptake. We hypothesized that this variation in uptake rates reflects variation in cellular P allocation strategies, and found that, indeed, the fraction of cellular P uptake utilized for phospholipid production was significantly higher in heterotrophic bacteria compared with cyanobacterial phytoplankton. These findings indicate that heterotrophic bacteria have a uniquely P-oriented physiology and play a dominant role in cycling dissolved P. PMID- 26033373 TI - Caring for Residents of Eldercare Facilities: A Concept Analysis. AB - PURPOSE: To report the results of an evolutionary concept analysis of caring in facilities that provide care for elders. SOURCES: Cumulative indices for CINAHL, ERIC, Academic Search Complete, PsychINFO, Medline, and CEPTS. RESULTS: Caring is an interactive process characterized by seeing, helping, and communicating, which are analogous to two wheels with one axle. Caring is preceded by individuality and followed by well-being. CONCLUSION: The findings explicate the core components of caring in facilities that provide care for elders. IMPLICATIONS: The metaphor of an axle and wheel can guide caregivers in delivering effective care as the demand for improved well-being of residents of eldercare facilities increases. PMID- 26033374 TI - Longitudinal average attributable fraction as a method for studying time-varying conditions and treatments on recurrent self-rated health: the case of medications in older adults with multiple chronic conditions. AB - PURPOSE: The objective is to modify the longitudinal extension of the average attributable fraction (LE-AAF) for recurrent outcomes with time-varying exposures and control for covariates. METHODS: We included Medicare Current Beneficiary Survey participants with two or more chronic conditions enrolled from 2005 to 2009 with follow-up through 2011. Nine time-varying medications indicated for nine time-varying common chronic conditions and 14 of 18 forward-selected participant characteristics were used as control variables in the generalized estimating equations step of the LE-AAF to estimate associations with the recurrent universal health outcome self-rated health (SRH). Modifications of the LE-AAF were made to accommodate these indicated medication-condition interactions and covariates. Variability was empirically estimated by bias-corrected and accelerated bootstrapping. RESULTS: In the adjusted LE-AAF, thiazide, warfarin, and clopidogrel had significant contributions of 1.2%, 0.4%, 0.2%, respectively, to low (poor or fair) SRH; whereas there were no significant contributions of the other medications to SRH. Hyperlipidemia significantly contributed 4.6% to high SRH. All the other conditions except atrial fibrillation contributed significantly to low SRH. CONCLUSIONS: Our modifications to the LE-AAF method apply to a recurrent binary outcome with time-varying factors accounting for covariates. PMID- 26033375 TI - Clustering of retrospectively reported and prospectively observed time-to pregnancy. AB - PURPOSE: Given reportedly high clustering but limited validity of retrospectively reported time-to-pregnancy (TTP), we assessed within-woman clustering for retrospectively reported TTPs alone and including gold-standard prospectively observed TTPs among women with 2 or more retrospectively reported and 1 or more prospectively observed TTPs. We further investigated whether past trying times inform future trying time among women with 1 or more retrospectively reported and 1 or more prospectively observed TTPs. METHODS: Five hundred one couples attempting pregnancy were prospectively observed until human chorionic gonadotropin pregnancy or 12 months of trying. Women reported TTP for past planned pregnancies. Clustering as measured by the frailty variance was estimated using discrete Cox frailty models, adjusted for age, body mass index, smoking at each attempt. Utility of past attempts to inform future attempts was assessed with discrete Cox models and relative risk regression, adjusted for enrollment age, body mass index, smoking. RESULTS: Seventy-five women with 2 or more prior pregnancies contributed 180 retrospective and 91 prospective TTPs for frailty modeling. Retrospectively reported TTP clustering was high (frailty variance = 0.89) but substantially lower when including prospectively observed TTPs (frailty variance = 0.42). Among 202 women with 1 or more prior pregnancies, past trying times did not inform future trying time. CONCLUSIONS: TTP recall rather than TTP may account for clustering. Past trying times may not inform future trying times. PMID- 26033376 TI - Rasmussen encephalitis with dual pathology in a patient without seizures: case report and literature review. AB - PURPOSE: Rasmussen encephalitis without seizures is rare. We report a case of Rasmussen encephalitis and cortical dysplasia without epilepsy as well as describe the imaging, pathology, and clinical course and review the literature to investigate whether this may represent a rare subset of Rasmussen encephalitis. CASE REPORT: We report the case of a 12-year-old girl with a history of cognitive decline and right arm weakness. Magnetic resonance imaging demonstrated diffuse left hemispheric cortical and subcortical atrophy suggestive of Rasmussen encephalitis. The patient had no clinical history of seizures, and electroencephalography did not demonstrate epileptiform abnormalities. Craniotomy for open brain biopsy was performed, and histopathologic evaluation identified Rasmussen encephalitis with cortical dysplasia (dual pathology). CONCLUSIONS: To the best of our knowledge, this is the third case of Rasmussen encephalitis diagnosed by both imaging and histopathology that had no clinical or electroencephalographic evidence of seizures and is the only case of Rasmussen encephalitis with cortical dysplasia without epilepsy. PMID- 26033377 TI - Skull base connections between the middle meningeal and internal carotid arteries. AB - BACKGROUND: External to internal carotid artery anastomoses are normally found in man. However, such connections at the skull base between the cavernous internal carotid artery and middle meningeal artery are rarely discussed in the literature and when present, are difficult, if not impossible, to see with imaging studies unless pathologically enlarged. Therefore, the aim of the present anatomic study was to investigate such connections via cadaveric dissection. MATERIALS AND METHODS: In 12 latex-injected adult cadaveric heads (24 sides), microdissection was performed to investigate for connections at the skull base between the cavernous part of the internal carotid and middle meningeal arteries. Additionally, neck dissections were performed to observe for atherosclerosis of the internal carotid artery. Statistical analyses were performed for differences between sides and gender. RESULTS: On 14 sides (58.3%) (nine left and five right sides), arterial anastomoses were identified between the middle meningeal and internal carotid arteries. All connections were small with a mean length of 8 mm and a mean diameter of 0.9 mm. These connections were found between the lateral aspect of the cavernous internal carotid artery and the medial side of the main trunk of the middle meningeal artery on 64.3% of sides, the anterior branch of the middle meningeal artery on 7% of sides, and the posterior branch of the middle meningeal artery on 28.6% of sides. The size of the middle meningeal and internal carotid arteries was within normal limits in all specimens. Although not statistically significant, connections tended to be more frequently found on the left sides. CONCLUSIONS: The majority of cadaveric sides in our study were found to have anastomoses at the skull base between the cavernous segment of the internal carotid and middle meningeal arteries. These very small connections would most likely not be visualized on imaging studies. These connections most likely function in times of carotid artery ischemia that is chronic in nature (e.g., Moya Moya disease) and may, in the past, have been misidentified as a human rete mirabile. PMID- 26033378 TI - Spontaneous thoracic epidural hematoma: a case report and literature review. AB - Spinal epidural hematoma is a rare neurosurgical emergency in respect of motor and sensory loss. Identifiable reasons for spontaneous hemorrhage are vascular malformations and hemophilias. We presented a case of spontaneous epidural hematoma in an 18-year-old female patient who had motor and sensory deficits that had been present for 1 day. On MRI, there was spinal epidural hematoma posterior to the T2-T3 spinal cord. The hematoma was evacuated with T2 hemilaminectomy and T3 laminectomy. Patient recovered immediately after the surgery. Literature review depicted 112 pediatric cases (including the presented one) of spinal epidural hematoma. The female/male ratio is 1.1:2. Average age at presentation is 7.09 years. Clinical presentations include loss of strength, sensory disturbance, bowel and bladder disturbances, neck pain, back pain, leg pain, abdominal pain, meningismus, respiratory difficulty, irritability, gait instability, and torticollis. Most common spinal level was cervicothoracic spine. Time interval from symptom onset to clinical diagnosis varied from immediate to 18 months. Spinal epidural hematoma happened spontaneously in 71.8 % of the cases, and hemophilia was the leading disorder (58 %) in the cases with a definable disorder. Partial or complete recovery is possible after surgical interventions and factor supplementations. PMID- 26033379 TI - Long-term outcomes in treatment of deformational plagiocephaly and brachycephaly using helmet therapy and repositioning: a longitudinal cohort study. AB - OBJECTIVES: Deformational plagiocephaly and/or brachycephaly (DPB) is a misshapen head presenting at birth or shortly thereafter, caused by extrinsic forces on an infant's malleable cranium. There are two treatment methods available for DPB: helmeting and repositioning. Little is known about the long-term outcomes of these two treatment options. The purpose of this study was to examine children who received helmeting or repositioning therapy for DPB as infants and compare the long-term head shape outcomes of the two groups. METHODS: A longitudinal cohort study design was used to evaluate change in head shape of the two groups. One hundred children (50 helmeted, 50 repositioned) were initially evaluated at 6 months or younger for DPB. Anthropometric skull measurements taken as infants before treatment were compared with measurements taken for this study. Inclusion criteria included initial clinic visit at age 6 months or younger, evaluation by the same practitioner, and current age 2-10 years. Cephalic index and cranial vault asymmetry were calculated based on caliper measurements. RESULTS: Data from 100 children were evaluated for this study. Significant differences between the treatment groups in the mean change in cephalic index (p = 0.003) and cranial vault asymmetry (p < 0.001) were found; the children that used helmet therapy demonstrated greater improvement. CONCLUSIONS: This is one of the larger published long-term outcome studies comparing children that used helmets and repositioning to treat their DPB as infants. The data suggest that infants will have more improvement in head shape with a helmet than with repositioning. PMID- 26033380 TI - Optic nerve sheath diameter as a criterion for endoscopic third ventriculostomy failure in children. PMID- 26033381 TI - Vertical laryngeal position and oral pressure variations during resonance tube phonation in water and in air. A pilot study. AB - Resonance tube phonation in water (RTPW) is commonly used in voice therapy, particularly in Finland and Sweden. The method is believed to induce a lowering of the vertical laryngeal position (VLP) in phonation as well as variations of the oral pressure, possibly inducing a massage effect. This pilot study presents an attempt to measure VLP and oral pressure in two subjects during RTPW and during phonation with the free tube end in air. VLP is recorded by means of a dual-channel electroglottograph. RTPW was found to lower VLP in the subjects, while it increased during phonation with the tube end in air. RTPW caused an oral pressure modulation with a bubble frequency of 14-22 Hz, depending mainly on the depth of the tube end under the water surface. The results indicate that RTPW lowers the VLP instantly and creates oral pressure variations. PMID- 26033382 TI - Common use of dietary supplements for bipolar disorder: a naturalistic, self reported study. AB - BACKGROUND: Dietary supplements are taken by about half of Americans. Knowledge of dietary supplement use is important because they may interact with prescription drugs or other supplements, cause adverse reactions including psychiatric symptoms, or contain inherently toxic ingredients or contaminants. This study explores the use of dietary supplements by patients with bipolar disorder in the US. METHODS: Data were obtained from an ongoing, naturalistic study of patients with bipolar disorder who received pharmacological treatment as usual. The patients self-reported their daily mood, sleep, and medications taken, including all drugs prescribed for bipolar disorder or that the patient felt impacted their mood. These included other prescribed drugs, over-the-counter drugs and dietary supplements. Drugs that received premarketing approval from the FDA were not included as dietary supplements. Patient demographics and daily medication use were characterized. RESULTS: Data were available from 348 patients in the US who returned a mean 249.5 days of data. In addition to prescribed psychiatric drugs, 101 of the 348 patients (29 %) used a dietary supplement for at least 7 days and 69 (20 %) used a supplement long term (for at least 50 % of days). Of the 101 supplement users, 72 (71.3 %) took one supplement daily. The 101 patients tried over 40 different supplements, and the long-term users took 19 different supplements. The most commonly taken supplements for both groups were fish oil, B vitamins, melatonin, and multivitamins. Patients using supplements were more likely to be white (p < 0.001), older (p = 0.009), and ill for more years (p = 0.025). CONCLUSIONS: Many patients with bipolar disorder use dietary supplements in addition to prescribed drugs. Physicians should obtain detailed information about all dietary supplements taken by patients with bipolar disorder. PMID- 26033383 TI - Antiviral Activity of Synthetic Aminopyrrolic Carbohydrate Binding Agents: Targeting the Glycans of Viral gp120 to Inhibit HIV Entry. AB - The binding abilities of a set of structurally related aminopyrrolic synthetic receptors for mannosides, endowed with antimycotic activity against yeast and yeast-like pathogens bearing mannoproteins on their cell surface, have been investigated towards the highly mannosylated gp120 and gp41 glycoproteins of the HIV envelope. A pronounced binding interaction with both glycoproteins was observed by SPR for most of the investigated compounds. Comparison of their binding properties towards the glycoproteins with their binding affinities toward mannosides revealed a direct correlation, supporting their role as carbohydrate binding agents (CBAs). Cytostatic activity studies revealed antiproliferative activity dependent on the nature and the structure of compounds. Antiviral activity studies against a broad panel of DNA and RNA viruses showed inhibitory effect against HIV infection of the T-lymphocyte CEM cell line for two compounds, suggesting antiviral activity similar to other CBAs, such as the nonpeptidic pradimicin antibiotics. PMID- 26033384 TI - Amperometric detection in the presence of carbon nanotubes dispersed in background electrolyte: Evaluating its suitability for capillary electrokinetic chromatography separations of polyphenolic compounds. AB - This work reports on the positive effects observed upon both the separation and analytical signals in electrophoretic separations of selected phenolic compounds when using aqueous BGE containing carbon nanotubes (CNTs) in connection to electrochemical detection (ECD). The influence of the presence of surfactant coated CNTs in the BGE upon the amperometric response of probe compounds was evaluated under hydrodynamic regime in capillary flow injection experiments as well as electrophoretic separations. Among the surfactants employed to disperse CNTs within BGE, SDS shows the best results in terms of dispersion stability and degree of dispersion of the CNTs. ECD allows working with BGEs containing CNTs concentrations of, at least, 24.0 mg/L without increasing of baseline noise, on the opposite to that reported when using UV-visible detection, and the presence of CNTs in the BGE improves the electrochemical response of some of the tested compounds. These benefits were reflected in higher sensibility in the electrochemical signal and additional improved resolution in the electrophoretic separation of (+/-)-catechin and sinapic acid when using these BGE containing CNTs. PMID- 26033385 TI - An analysis of the medical specialty training system in Spain. AB - In this paper, we analyse the medical specialty training system in Spain (the so called "residency system"). In order to do so, we a) summarize its historical evolution; b) describe the five major architectural pillars on which the system is currently based; c) analyse the special contract of the specialist-in training; d) discuss the three major challenges for the medical specialist training future: the evolution and expansion of the residency system to other health professions, the issue of grouping specialties with a common core trunk and the continuity of the learning process; and e) draw four conclusions that may be relevant for those who are in the process of developing or revising their own medical specialization systems. PMID- 26033386 TI - Effect of Systemic Inflammation on the Function of Insulin and Glucose Metabolism in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology characterized by chronic inflammation of the synovial membranes and articular structures of the joints. The concomitant comorbidities are important in the management and treatment of patients with RA, because they decrease their life quality and expectancy - with cardiovascular diseases being the most common comorbidities and primary cause of death in RA. Traditional cardiovascular risk factors, such as diabetes mellitus (DM) and insulin resistance (IR) are prevalent in these patients. The prevalence of DM in RA patients has not been well established and the association between these diseases is controversial. On the other hand, several epidemiological studies support the association between RA and IR, with the latter being linked to systemic inflammatory markers, including C reactive protein and erythrocyte sedimentation rate. Patients with RA who underwent glucocorticoid therapy were also determined to have a defective insulin sensitivity and pancreatic beta-cell dysfunction. It has been proposed that systemic inflammation due to RA may result in insulin resistance - moreover, studies have examined the effect of inflammatory cytokines such as TNF-alpha, IL 6 and IL-1 on insulin sensitivity and glucose metabolism. Likewise, the association between RA and IR, and its role on the different characteristics of the disease, such as duration, activity, and treatment with glucocorticoids has not been well defined. A gap in the current understanding regarding the role that the systemic inflammation and the different RA characteristics have on the insulin function and glucose metabolism of RA patients suggest that more studies are required to elucidate these mechanisms. PMID- 26033387 TI - Skeletal muscle contractility and fatigability in adults with cystic fibrosis. AB - BACKGROUND: Recent discovery of cystic fibrosis transmembrane conductance regulator expression in human skeletal muscle suggests that CF patients may have intrinsic skeletal muscle abnormalities potentially leading to functional impairments. The aim of the present study was to determine whether CF patients with mild to moderate lung disease have altered skeletal muscle contractility and greater muscle fatigability compared to healthy controls. METHODS: Thirty adults (15 CF and 15 controls) performed a quadriceps neuromuscular evaluation using single and paired femoral nerve magnetic stimulations. Electromyographic and mechanical parameters during voluntary and magnetically-evoked contractions were recorded at rest, during and after a fatiguing isometric task. Quadriceps cross sectional area was determined by magnetic resonance imaging. RESULTS: Some indexes of muscle contractility tended to be reduced at rest in CF compared to controls (e.g., mechanical response to doublets stimulation at 100 Hz: 74+/-30 Nm vs. 97+/-28 Nm, P=0.06) but all tendencies disappeared when expressed relative to quadriceps cross-sectional area (P>0.5 for all parameters). CF and controls had similar alterations in muscle contractility with fatigue, similar endurance and post exercise recovery. CONCLUSIONS: We found similar skeletal muscle endurance and fatigability in CF adults and controls and only trends for reduced muscle strength in CF which disappeared when normalized to muscle cross-sectional area. These results indicate small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) muscle alterations in CF with mild to moderate lung disease. PMID- 26033388 TI - A critical examination of the ergogenic/therapeutic effects of supplementation to increase nitric oxide bioavailability. PMID- 26033390 TI - Will India's national health policy deliver universal health coverage? PMID- 26033389 TI - Acetylation of lysine 9 on histone H3 is associated with increased pro inflammatory cytokine release in a cigarette smoke-induced rat model through HDAC1 depression. AB - OBJECTIVE AND DESIGN: Cigarette smoke (CS)-induced inflammation is critical in chronic obstructive pulmonary disease (COPD). However, the role of acetylation at histone 3 lysine 9 (H3K9) in COPD inflammation remains unclear. The present study assessed the effect of acetylation of H3K9 on transcription both in rat lungs and in macrophages. METHODS: Sprague-Dawley rats were exposed to CS for either 6 or 12 weeks and rat lungs were collected. Rat macrophages were subjected to 20 % cigarette smoke extract (CSE) for 48 h. RESULTS: CS increased MCP-1 and IL-8 expressions at both mRNA and protein levels in rat lungs after 6 and 12 weeks; increased TNF-alpha and MMP9 expressions at both levels were noted only after 12 weeks. CSE increased these genes expression in macrophages after 48 h exposure. Increased abundance of acetylated H3K9 protein in rat lungs and in macrophages were associated with decreased expression of histone deacetylase-1(HDAC1). Chromatin immunoprecipitation demonstrated increased level of acetylated H3K9 on promoter regions of these genes both in vivo and in vitro. Knockdown of HDAC1 increased these genes mRNA expression. CONCLUSIONS: CS increased H3K9 acetylation and subsequently altered the expression of pro-inflammatory mediators and protease genes through HDAC1 depression in CS-induced rat lungs and in macrophages. PMID- 26033391 TI - Patient-reported outcomes enhance understanding of the impact of pazopanib in soft tissue sarcoma. PMID- 26033392 TI - Identification of universal selectivity-determining positions in cytochrome P450 monooxygenases by systematic sequence-based literature mining. AB - Cytochrome P450 monooxygenases (CYPs) are a large, highly diverse protein family with a common fold. The sequences, structures, and functions of CYPs have been extensively studied resulting in more than 53,000 scientific articles. A sequence based literature mining algorithm was designed to systematically analyze this wealth of information on SNPs, designed mutations, structural interactions, or functional roles of individual residues. Structurally corresponding positions in different CYPs were compared and universal selectivity-determining positions were identified. Based on the Cytochrome P450 Engineering Database (www.CYPED.BioCatNet.de) and a standard numbering scheme for all CYPs, 4000 residues in 168 CYPs mentioned in 2400 articles could be assigned to 440 structurally corresponding standard positions of the CYP fold, covering 96% of all standard positions. Seventeen individual standard positions were mentioned in the context of more than 32 different CYPs. The majority of these most frequently mentioned positions are located on the six substrate recognition sites and are involved in control of selectivity, such as the well-studied position 87 in CYP102A1 (P450(BM-3)) which was mentioned in the articles on 63 different CYPs. The recurrent citation of the 17 frequently mentioned positions for different CYPs suggests their universal functional relevance. PMID- 26033393 TI - Extra-media thickness and epicardial fat: Comparison of a novel carotid artery ultrasound index and a well-established cardiac magnetic resonance fat quantification method. AB - BACKGROUND AND AIM: Epicardial and pericardial fat are well-established surrogate markers of cardiovascular diseases and complications. Extra-media thickness (EMT) is a novel ultrasound index corresponding to arterial adventitia and adipose tissue. We aimed to evaluate the association between carotid EMT and epicardial fat (EF) and pericardial fat (PF) and their relation to cardiovascular risk and metabolic syndrome (MS). METHODS AND RESULTS: One hundred consecutive patients (age: 51.7 +/- 15.4 years; males 70%) scheduled for cardiac magnetic resonance (CMR) were prospectively included in the study. Anthropometric parameters, CMR indices of EF and PF, both common carotid arteries EMT, and ultrasound indices of visceral and subcutaneous fat were measured in patients. In our study group, 53% of patients represented a very high cardiovascular risk, overweight or obesity was found in 68%, high body fat in 45%, and MS in 59% of individuals. Mean EMT (662 +/- 129 MUm) was significantly associated with EF area (r = 0.46; p < 0.001) and PF area (r = 0.3; p < 0.001). Among all fat indices, only EMT (MS+ 736 +/- 140 MUm vs. MS-658 +/- 97 MUm; p = 0.002) and EF area (MS+ 870 +/- 451 mm(2) vs. MS 668 +/- 333 mm(2); p = 0.02) were significantly increased in patients with MS compared with individuals without MS. Multivariable regression analysis also showed that mean EMT is independently associated with number of cardiovascular risk factors (b = 0.005; p < 0.001). Moreover, very high cardiovascular risk subjects showed significantly increased EMT/BMI (p < 0.001) and EF area/BMI (p = 0.03) ratios. However, there was no significant association between EMT/BMI and EF area/BMI values (p = ns). CONCLUSIONS: Our study showed the first findings on the relations between a novel ultrasound index EMT and EF assessed in a reference method of CMR. Carotid EMT may be a new surrogate marker, including both periarterial fat as a major component and arterial adventitia, which may provide additional data on cardiometabolic risk beyond that derived form a well established EF alone. PMID- 26033395 TI - Prevalence by sex of preclinical carotid atherosclerosis in newly diagnosed type 2 diabetes. AB - BACKGROUND AND AIMS: There is clinical trial evidence that only early, intensive risk factor control can reduce cardiovascular disease (CVD) morbidity and mortality in type 2 diabetes (T2DM). However, there is little information regarding preclinical atherosclerosis at diabetes diagnosis. We assessed carotid atherosclerosis in new-onset T2DM and control individuals without prior CVD. METHODS AND RESULTS: In a cross-sectional case-control study, we determined intima-media thickness (IMT) and plaque (IMT >=1.5 mm) by ultrasound at all carotid sites in new-onset T2DM patients and controls. We assessed 106 T2DM patients, median age 62 years, 46% women, 19% smokers, 54% with hypertension, and 41% with dyslipidemia and 99 non-diabetic subjects matched by age, sex, and cardiovascular risk factors. Compared to controls, T2DM patients had higher common carotid artery (CCA)-IMT (median 0.725 vs. 0.801 mm, p = 0.01), bulb-IMT (0.976 vs. 1.028 mm, p = 0.12), and internal carotid artery (ICA)-IMT (0.727 vs. 0.802 mm, p = 0.04). The prevalence of total plaque (60% vs. 72%, p = 0.06), ICA plaque (20% vs. 42%, p < 0.01), and harboring >=3 plaques (16% vs. 35% p < 0.01) was also higher in T2DM. Plaque score (sum of maximum plaque heights) was also higher (p < 0.01) in T2DM. Diabetic women showed more advanced carotid atherosclerosis than diabetic men when they were compared with their respective non-diabetic counterparts. CONCLUSIONS: There is a high prevalence of preclinical atherosclerosis (carotid plaque presence and burden) in new-onset T2DM subjects, especially in women. Early, still reversible, preclinical atherosclerosis may explain in part why early intervention is effective to prevent CVD in this patient population. PMID- 26033394 TI - Visceral adiposity and left ventricular remodeling: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND AND AIMS: Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AND RESULTS: We performed a post-hoc analysis on 1151 participants from MESA with cardiac magnetic resonance quantification of LV mass and LV mass-to volume ratio (LVMV, an index of concentricity) and computed tomographic-derived SQ and VF area. Multivariable regression models to estimate association between height-indexed SQ and VF area (per cm(2)/m) with height-indexed LV mass (per height(2.7)) and LVMV were constructed, adjusted for clinical, biochemical, and demographic covariates. We found that both VF and SQ area were associated with height-indexed LV mass (rho = 0.36 and 0.12, P < 0.0001, respectively), while only VF area was associated with LVMV (rho = 0.28, P < 0.0001). Individuals with above-median VF had lower LV ejection fraction, greater indexed LV volumes and mass, and higher LVMV (all P < 0.001). In multivariable models adjusted for weight, VF (but not SQ) area was associated with LV concentricity and LV mass index, across both sexes. CONCLUSION: Visceral adiposity is independently associated with LV concentricity, a precursor to heart failure. Further study into the role of VF in LV remodeling as a potential therapeutic target is warranted. PMID- 26033396 TI - Visceral obesity, but not metabolic syndrome, is associated with the presence of post-thrombotic syndrome. AB - INTRODUCTION: The relationship between metabolic syndrome (MetS), and the development of post-thrombotic syndrome (PTS) is currently unknown. MATERIALS AND METHODS: We enrolled 120 patients with a previous episode of deep venous thrombosis (DVT) diagnosed more than 2years apart from the enrollment. Presence of MetS was identified according to NCEP ATP III criteria and Villalta Score (VS) was used to establish the presence of PTS (VS>=5). RESULTS: We identified 49 (40.8%) subjects with clinical diagnosed of PTS. Patients with or without PTS showed comparable age and temporal distance from DVT event. We observed higher BMI (p=0.005) and waist circumference (p=0.006) among subjects with VS>=5 as compared to patients without PTS. No differences between the two groups were found in terms of lipid profile, blood pressure, diabetes, hs-CRP level and ongoing medications. The prevalence of MetS was equally distributed among patients with or without PTS (20% vs 26% respectively, p=0.64). Among the individual components of MetS only the prevalence of visceral adiposity was significantly increased in subjects affected by PTS (OR 2.81, p=0.008). Moreover, a significant linear correlation was found between VS and waist circumference in the entire cohort (r=0,354, p<0.0001). CONCLUSION: There is no evidence of association between MetS and PTS. However, the degree of visceral adiposity is strongly correlated with the presence and severity of post-thrombotic disease. PMID- 26033398 TI - Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: results from Assessing Platelet Activity in Coronary Heart Disease (APACHE). AB - INTRODUCTION: There is a large inter-individual variation in response to clopidogrel treatment and previous studies have indicated higher risk of thrombotic events in patients with high residual platelet reactivity (HRPR), but the optimal time-point for testing is not established. The aim of this study was to investigate the optimal time-point for aggregometry testing and the risk of major adverse cardiac events associated with HRPR. METHOD AND RESULTS: We included 125 patients with ACS (73 with STEMI, and 71 received abciximab). The prevalence of HRPR varied substantially over time. The rate of HRPR in patients treated and not treated with abciximab were 43% vs 67% (p=0.01) before, 2% vs 23% (p=0.001) 6-8h after, 8% vs 9% (p=0.749) 3days after, and 23% vs 12% (p=0.138) 7 9 days after loading dose of clopidogrel. We found HRPR in 18% of the patients but only four ischemic events during 6months follow-up, with no significant difference between HRPR patients compared to the rest of the population. There were 3 TIMI major bleedings, all of which occurred in the low residual platelet reactivity (LRPR) group. CONCLUSION: There is a large variation in platelet reactivity over time, also depending on adjunctive therapy, which has a large impact on optimal time-point for assessment. We found HRPR in almost 1 in 5 patients, but very few MACE, and not significantly higher in HRPR patients. In a contemporary ACS population, with low risk for stent thrombosis, the predictive value of HRPR for ischemic events will probably be low. PMID- 26033399 TI - Management of disseminated intravascular coagulation: a survey of the International Society on Thrombosis and Haemostasis. AB - INTRODUCTION: It is not clear if and how international guidelines on the management of disseminated intravascular coagulation (DIC) are translated in routine clinical practice. MATERIALS AND METHODS: A survey was conducted among different specialists who treat DIC. The survey examined six hypothetical case scenarios including the diagnosis of DIC, the treatment of non-overt and overt DIC with or without thrombosis, and the management of DIC patients at risk of bleeding or actively bleeding. RESULTS: There were 191 respondents and 73 returned complete questionnaires. Most of respondents were specialists in hematology (48%) or intensive care (30%). In suspected overt or non-overt DIC, only one third use formal diagnostic scores while two thirds rely on a broad panel of coagulation tests independently of any score. In non-overt DIC, 68% provide no treatment, but monitor laboratory tests. Monitoring was considered by 48% of respondents in overt DIC without thrombosis or bleeding. When a thrombotic or bleeding complication ensues, 29% consider intervening only if the event is major. In DIC patients judged at risk of bleeding, 67% use prophylactic transfusions, mostly fresh-frozen plasma (73%) and platelets (65%). Active bleeding is often managed with fresh-frozen plasma (83%) and platelet transfusions (68%) as first line and recombinant activated factor VII (31%) as second line treatment. CONCLUSIONS: This survey shows a largely heterogeneous approach of clinicians to the diagnosis and management of DIC. There is limited use of diagnostic scores despite guidelines' recommendations. The prevalent attitude seems monitoring DIC and limiting treatment to the underlying disease, unless thrombosis or bleeding develop, but modalities varied considerably. PMID- 26033397 TI - Women's values and preferences for thromboprophylaxis during pregnancy: a comparison of direct-choice and decision analysis using patient specific utilities. AB - BACKGROUND: Women with a history of venous thromboembolism (VTE) have an increased recurrence risk during pregnancy. Low molecular weight heparin (LMWH) reduces this risk, but is costly, burdensome, and may increase risk of bleeding. The decision to start thromboprophylaxis during pregnancy is sensitive to women's values and preferences. Our objective was to compare women's choices using a holistic approach in which they were presented all of the relevant information (direct-choice) versus a personalized decision analysis in which a mathematical model incorporated their preferences and VTE risk to make a treatment recommendation. METHODS: Multicenter, international study. Structured interviews were on women with a history of VTE who were pregnant, planning, or considering pregnancy. Women indicated their willingness to receive thromboprophylaxis based on scenarios using personalized estimates of VTE recurrence and bleeding risks. We also obtained women's values for health outcomes using a visual analog scale. We performed individualized decision analyses for each participant and compared model recommendations to decisions made when presented with the direct-choice exercise. RESULTS: Of the 123 women in the study, the decision model recommended LMWH for 51 women and recommended against LMWH for 72 women. 12% (6/51) of women for whom the decision model recommended thromboprophylaxis chose not to take LMWH; 72% (52/72) of women for whom the decision model recommended against thromboprophylaxis chose LMWH. CONCLUSIONS: We observed a high degree of discordance between decisions in the direct-choice exercise and decision model recommendations. Although which approach best captures individuals' true values remains uncertain, personalized decision support tools presenting results based on personalized risks and values may improve decision making. PMID- 26033400 TI - Assessment of health-related quality of life in end-stage chronic obstructive pulmonary disease and non-small-cell lung cancer patients in Serbia. AB - OBJECTIVE: Under conditions in which palliative care has not yet become part of clinical practice, the differences in palliative care needs between patients with cancer and other life-limiting diseases can yield knowledge that will be very valuable for future planning. The aim of our investigation was to compare health related quality of life (HRQoL) for patients with end-stage chronic obstructive pulmonary disease (COPD) and those with non-small-cell lung cancer (NSCLC) in Belgrade, Serbia. We also evaluated the influence of demographic, socioeconomic, and clinical factors on HRQoL for both patient groups. METHOD: This cross sectional study included 100 NSCLC patients (stages IIIb and IV) and 100 patients with stage IV COPD. Measures included the SF-36 questionnaire, the EORTC QLQ-C30, the St. George's Respiratory Questionnaire, and the Beck Depression Inventory (BDI). Associations of demographic, socioeconomic, and clinical factors with QoL were examined using linear regression analyses. RESULTS: The COPD group scored significantly lower compared to NSCLC patients in all SF-36 domains except for bodily pain. Additionally, a significantly higher level of depressive symptoms was observed in COPD patients. A worse physical QoL for COPD patients was independently associated with a longer duration of unemployment, a lack of wage earning, lower Karnofsky Performance Status (KPS) scores, and higher levels of depression. A worse mental QoL for COPD patients was related to a longer duration of disease, poorer KPS scores, and higher BDI scores. The independent variables significantly associated with worse physical and mental QoL of NSCLC patients were lower KPS and higher BDI scores. SIGNIFICANCE OF RESULTS: A worse QoL, a significantly higher level of depressive symptoms, and adverse socioeconomic status in the COPD group imposes the need for development of more intensive psychosocial and community support for COPD patients during implementation of palliative care. PMID- 26033401 TI - MET in gastric cancer--discarding a 10% cutoff rule. AB - AIMS: We aimed to develop a putative predictive biomarker score for future hepatocyte growth factor receptor (MET)-targeted therapy of gastric cancer (GC). METHODS AND RESULTS: MET expression and MET amplification were analysed by immunohistochemistry (IHC) and chromogenic in-situ hybridization (CISH) in 470 GC patients. Immunostaining was documented with the HistoScore. The percentage area of MET-amplified tumour cell clones was assessed by virtual microscopy. The expression of MET was heterogeneous in primary and metastatic GC. Immunostaining intensity (MET-IHC 2+/3+) correlated with MET amplification and a positive MET status was defined by a combination of MET-IHC 2+ or 3+ with MET amplification, or MET-IHC 3+ without MET amplification. The prognostic significance of the MET status was independent from the percentage area of positive tumour cells (e.g. <10 versus >=10%). MET-positive GCs were microsatellite stable and of KRAS/PIK3CA wild-type. MET-positive GCs had a very poor prognosis, with a median survival of 5.4 months and a hazard ratio of 2.126. CONCLUSIONS: A combination of immunohistochemistry and CISH is suitable to assess MET status. If MET status is used as a predictive biomarker, prospective studies should pay specific attention to adequate tissue sampling, should ignore cutoff values for tumour areas, may consider the KRAS and PIK3CA genotype as negative predictive markers and should carry out the analysis expeditiously. PMID- 26033402 TI - Isolation and genetic characterization of viable Toxoplasma gondii from tissues and feces of cats from the central region of China. AB - Cats are important in the epidemiology of toxoplasmosis because they are the only definitive hosts that excrete environmentally resistant Toxoplasma gondii oocysts. Little is known of feline toxoplasmosis in China and most of the literature is in Chinese. Here we summarized all published reports on feline toxoplasmosis in English and report first identification of oocyst excretion by naturally infected cats in China. Unfrozen tissues of 42 cats and feces of 360 cats from China were bioassayed in mice for isolation of T. gondii. Antibodies to T. gondii were found in 21 of 42 (50%) of cats by the modified agglutination test (cut-off 1:25). Viable T. gondii was isolated from tissues of eight of 21 seropositive but not from 21 seronegative (<1:25) cats. Viable T. gondii was isolated from feces of one cat. DNA derived from cell cultured tachyzoites of all nine T. gondii isolates was characterized by PCR-RFLP at 10 loci (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico). Four genotypes were found; the genotypes of tissue isolates were ToxoDB #9 in six, ToxoDB #2 in one, and ToxoDB #17 in one. The fecal isolate was ToxoDB #1.To our knowledge, the present study is the first isolation of T. gondii from cat feces from China. PMID- 26033403 TI - Long-term Care Insurance and Carers' Labor Supply - A Structural Model. AB - In Germany, individuals in need of long-term care receive support through benefits of the long-term care insurance. A central goal of the insurance is to support informal care provided by family members. Care recipients can choose between benefits in kind (formal home care services) and benefits in cash. From a budgetary perspective, family care is often considered a cost-saving alternative to formal home care and to stationary nursing care. However, the opportunity costs resulting from reduced labor supply of the carer are often overlooked. We focus on the labor supply decision of family carers and the incentives set by the long-term care insurance. We estimate a structural model of labor supply and the choice of benefits of family carers. We find that benefits in kind have small positive effects on labor supply. Labor supply elasticities of cash benefits are larger and negative. If both types of benefits increase, negative labor supply effects are offset to a large extent. However, the average effect is significantly negative. PMID- 26033404 TI - Removal of rotavirus and adenovirus from artificial ground water using hydrochar derived from sewage sludge. AB - AIMS: To determine the pathogenic virus removal performance of an adsorbent produced from hydrothermal carbonization of sewage sludge. METHODS AND RESULTS: The removal of human pathogenic rotavirus and adenovirus was investigated with columns of 10 cm saturated sand with and without amendments of 1.5% (w/w) hydrochar. Virus concentrations were determined with reverse transcription (RT) quantitative polymerase chain reaction (qPCR). The experiments with sand showed 1 log removal, while the columns with 1.5% (w/w) hydrochar amendment showed 2 to >3 log removal for both viruses. Deionized (DI) water flushing into the virus retaining columns revealed that the secondary energy minimum played a larger role in the attachment of rotavirus onto hydrochar surfaces than adenovirus. Improved virus removal may be attributed to the introduction of hydrophobic and/or meso macro surface structures of the hydrochar providing favourable attachment sites for viruses. CONCLUSIONS: Hydrochar amended sand beds showed improved virus removal efficiencies exceeding 99.6% corresponding to 2.4 log removal. The addition of humic acid in the influent did not hinder the adsorptive removal of viruses. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests that hydrochar derived from sewage sludge can be used as an adsorbent for virus removal in water treatment. PMID- 26033405 TI - Pulse Pressure and Cognitive Decline in Stroke Patients With White Matter Changes. AB - The authors hypothesized that both high and low pulse pressure (PP) may predict cognitive decline in stroke/transient ischemic attack (TIA) patients with white matter changes (WMCs). The authors prospectively followed up 406 ischemic stroke/TIA patients with confluent WMCs over 18 months. PP was measured at 3 to 6 months after stroke/TIA and categorized into four groups by quartile. Cognition was assessed 3 to 6 months and 15 to 18 months after stroke/TIA using the Clinical Dementia Rating and Mini-Mental State Examination (MMSE). Logistic regression showed that patients in the first quartile of PP had a 5.9-fold higher risk for developing cognitive decline than patients in the third quartile (odds ratio, 5.9; 95% confidence interval, 1.7-20.6), while patients in the fourth quartile had a 3.5-fold higher risk for cognitive decline than those in the third quartile (odds ratio, 3.5; 95% confidence interval, 1.0-12.4). This U-shaped relationship was also evident between PP and cognitive decline in MMSE, underlining the role of arterial stiffness and hypoperfusion in cognitive decline related to small vessel disease. PMID- 26033406 TI - Microbial reporter gene assay as a diagnostic and early warning tool for the detection and characterization of toxic pollution in surface waters. AB - Surface water samples constantly receive a vast mixture of micropollutants mainly originating from wastewater treatment plants (WWTPs). High-throughput live cell arrays provide a promising method for the characterization of the effects of chemicals and the associated molecular mechanisms. In the present study, this test system was evaluated for the first time for the characterization of a set of typical surface water extracts receiving effluent from WWTPs. The extracts containing complex mixtures of micropollutants were analyzed for the expression of 90 stress responsive genes in the Escherichia coli reporter gene assay. The most affected pathways and the genes most sensitive to surface water samples suggested prominent stress-responsive pathways for wastewater-impacted surface water, such as oxidative stress, DNA damage, and drug resistance. Samples strongly affecting particular pathways were identified by statistical analysis of gene expression. Transcription data were correlated with contamination data from chemical screening and percentages of wastewater in the samples. Samples with particular effects and outstanding chemical composition were analyzed. For these samples, hypotheses on the alteration of the transcription of genes involved in drug resistance and DNA repair attributable to the presence of pharmaceuticals were drawn. PMID- 26033407 TI - Influence of exercise training and eating behavior on arterial stiffness in young healthy students. AB - AIM: Increased arterial stiffness is an important risk factor for the development of cardiovascular disease. The aim of the present study was to compare arterial function and other anthropometric parameters in trained vs sedentary, healthy young students. Furthermore, the study explores the relationship between arterial stiffness and eating behavior in these students. METHODS: Two groups of healthy university students were recruited for this study. The first group consisted of 10 men and 8 women (mean age: 23.27 +/- 3.2 years) with an athletic predisposition. Furthermore, over the course of 6 months this group participated in 60-min training sessions designed as interval training circuits with a frequency of three to five times a week. For comparison, a group of age-matched sedentary students (5 men and 13 women; 24.27 +/- 2.6 years) were recruited from the same institution. Weight, height, body mass index (BMI), as well as neck and abdominal circumferences (ABs) were recorded. Arterial tension, heart rate, arterial stiffness measurements were simultaneously determined. Lastly, all students completed a 51-item "Eating Behavior Patterns Questionnaire". RESULTS: Age, weight, BMI, AB, and blood pressure were not significantly different between the two groups (p > 0.05). The moderately aerobic trained students showed a significantly lower heart rate, neck circumference, and arterial stiffness as compared with their untrained, sedentary counterparts. Additionally, pulse wave velocity (PWV) measurements were correlated to a lower weight, heart rate, blood pressure, AB, and neck circumference (p < 0.05) found in trained subjects at the end of the 6-month training period. Furthermore, the nutritional habit analysis showed that in the sedentary group, snacking, emotional eating, and cultural/lifestyle behaviors are positively correlated with PWV (p < 0.05). CONCLUSION: Healthy subjects with higher PWV may benefit from consistent aerobic exercise training to improve arterial stiffness. Our eating behavior study shows that healthy eating may improve vascular function and therefore can reduce the risk of cardiovascular diseases. PMID- 26033408 TI - Knowledge and Attitudes of Patients and Their Relatives Toward Electroconvulsive Therapy in China. AB - PURPOSE: To examine the knowledge and attitudes of patients and their relatives as well as patients' subjective experience with electroconvulsive therapy (ECT) in China. DESIGN AND METHODS: Up to 420 responders including patients receiving ECT (n = 210) and their relatives (n = 210) were assessed with self-reported questionnaires. FINDINGS: Patients and their relatives did not receive adequate information before ECT, particularly about the mode of its delivery, risks, and adverse effects. The most common adverse effect of ECT reported by patients was memory impairment. Both patients and their relatives had positive attitudes toward ECT and appeared satisfied with its therapeutic effects. PRACTICE IMPLICATIONS: Mental health professionals need to address the inadequate information on ECT provided to patients and their relatives prior to the treatment. PMID- 26033409 TI - Physico-chemical properties and fatty acid composition of pomegranate, cherry and pumpkin seed oils. AB - BACKGROUND: Nut and seed oils are often considered waste products but in recent years they have been receiving growing interest due to their high concentration of hydrophilic and lipophilic bioactive components, which have important pharmacological properties on human health. The aim of this work was to compare the physico-chemical and biochemical properties of pomegranate (Punicagranatum), sweet cherry (Prunusavium) and pumpkin (Cucurbita maxima) seed oils obtained by solvent extraction. RESULTS: High amount of linoleic acid was found in the cherry and pumpkin seed oils, while pomegranate seed oil showed relevant content of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) along to eicosapentaenoic acid (EPA) and nervonic acid. Pumpkin seed oil had high concentration of carotenoids, while pomegranate oil was the best absorber in the UV-A and UV-B ranges. CONCLUSION: Pomegranate, cherry and pumpkin seed oils can be an excellent source of bioactive molecules and antioxidant compounds such as polyphenols, carotenoids and unsaturated fatty acids. These seed oils can be included both as preservatives and functional ingredients in the food, pharmaceutical and cosmetic fields and can contribute to disease prevention and health promotion. Moreover, high absorbance of UV light indicates a potential use of these oils as filters from radiations in the food, pharmaceutical, and cosmetic fields. PMID- 26033411 TI - Postoperative hypoalbuminemia following surgery related to craniosynostosis. AB - BACKGROUND: An episode of postoperative phenytoin toxicity in a patient undergoing surgery related to craniosynostosis highlighted the presence of hypoalbuminemia. We believe that hypoalbuminemia contributed to the altered pharmacokinetics of phenytoin in this case. OBJECTIVES: To establish the incidence of postoperative hypoalbuminemia in patients undergoing surgery related to craniosynostosis and to investigate the likely etiology. METHODS: Data on 114 patients undergoing surgery for craniosynostosis over a 2-year period at Oxford Children's Hospital, between May 2011 and May 2013, were retrospectively reviewed. Twenty-two patients were excluded due to incomplete data. This cohort represents the entire population for whom transfusion data had been formally collected at our institution. Preoperative and day 1 postoperative serum albumin levels were collected from the hospital laboratory database. Data regarding blood loss and intra-operative fluid management were reviewed from the anesthetic database. Linear regression analysis was used to establish the relationship between percentage drop in serum albumin with: (i) milliliters per kilogram (ml.kg(-1)) volume of albumin-poor fluids used intra-operatively and (ii) percentage estimated red cell mass loss. RESULTS: All patients experienced a statistically significant drop in serum albumin. The mean difference in albumin was 17.1 g.l(-1), 95% CI (16.1-18.0) (P < 0.001). Expressed as a percentage, the mean reduction was 37.9% (range 16-61%), SD 9.7. The decrease in albumin was associated with an increase in estimated red cell mass loss (P < 0.001) and an increased ml.kg(-1) volume of albumin-poor fluids given (P < 0.001). CONCLUSION: Hemodilution due to large volume blood loss and transfusion with albumin-poor fluids is strongly associated with postoperative hypoalbuminemia in patients undergoing surgery related to craniosynostosis. Practitioners should be aware of this risk and the implications of postoperative hypoalbuminemia in this population. PMID- 26033412 TI - 17th annual conference of the international society for bipolar disorders, june 3 6, 2015, toronto, Canada. PMID- 26033413 TI - Reducing Staphylococcus aureus growth on Ti alloy nanostructured surfaces through the addition of Sn. AB - beta-type Ti alloys containing Nb are exciting materials for numerous orthopedic and dental applications due to their exceptional mechanical properties. To improve their cytocompatibility properties (such as increasing bone growth and decreasing infection), the surfaces of such materials can be optimized by adding elements and/or nanotexturing through anodization. Because of the increasing prevalence of orthopedic implant infections, the objective of this in vitro study was to add Sn and create unique nanoscale surface features on beta-type Ti alloys. Nanotubes and nanofeatures on Ti-35Nb and Ti-35Nb-4Sn alloys were created by anodization in a HF-based electrolyte and then heat treated in a furnace to promote amorphous structures and phases such as anatase, a mixture of anatase rutile, and rutile. Samples were characterized by SEM, which indicated different morphologies dependent on the oxide content and method of modification. XPS experiments identified the oxide content which resulted in a phase transformation in the oxide layer formed onto Ti-35Nb and Ti-35Nb-4Sn alloys. Most importantly, regardless of the resulting nanostructures (nanotubes or nanofeatures) and crystalline phase, this study showed for the first time that adding Sn to beta type Ti alloys strongly decreased the adhesion of Staphylococcus aureus (S. aureus; a bacteria which commonly infects orthopedic implants leading to their failure). Thus, this study demonstrated that beta-type Ti alloys with Nb and Sn have great promise to improve numerous orthopedic applications where infection may be a concern. PMID- 26033414 TI - Detrimental effects of electron beam irradiation on the cowpea bruchid Callosobruchus maculatus. AB - BACKGROUND: Electron beam (eBeam) irradiation technology is an environmentally friendly, chemical-free alternative for disinfesting insect pests of stored grains. The underlying hypothesis is that specific doses of eBeam will have defined detrimental effects on the different life stages. We evaluated the effects of eBeam exposure in a range of doses (0.03-0.12 kGy) on the development of the cowpea bruchid (Callosobruchus maculatus) at various stages of its life cycle. RESULTS: Differential radiosensitivity was detected during egg development. Early and intermediate stages of eggs never hatched after exposure to a dose of 0.03 kGy, whereas a substantial portion of black-headed (i.e. late) eggs survived irradiation even at 0.12 kGy. However, further development of the hatched larvae was inhibited. Although midgut protein digestion remained intact, irradiated larvae (0.06 kGy or higher) failed to develop into normal living adults; rather, they died as pupae or abnormally eclosed adults, suggesting a detrimental effect of eBeam on metamorphosis. Emerged irradiated pupae had shorter longevity and were unable to produce any eggs at 0.06 kGy or higher. At this dose range, eggs laid by irradiated adults were not viable. eBeam treatment shortened adult longevity in a dose-dependent manner. Reciprocal crosses indicated that females were more sensitive to eBeam exposure than their male counterparts. Dissection of the female reproductive system revealed that eBeam treatment prevented formation of oocytes. CONCLUSION: eBeam irradiation has very defined effects on cowpea bruchid development and reproduction. A dose of 0.06 kGy could successfully impede cowpea burchid population expansion. This information can be exploited for post-harvest insect control of stored grains. PMID- 26033415 TI - Not the time or the place: the missing spatio-temporal link in publicly available genetic data. AB - Genetic data are being generated at unprecedented rates. Policies of many journals, institutions and funding bodies aim to ensure that these data are publicly archived so that published results are reproducible. Additionally, publicly archived data can be 'repurposed' to address new questions in the future. In 2011, along with other leading journals in ecology and evolution, Molecular Ecology implemented mandatory public data archiving (the Joint Data Archiving Policy). To evaluate the effect of this policy, we assessed the genetic, spatial and temporal data archived for 419 data sets from 289 articles in Molecular Ecology from 2009 to 2013. We then determined whether archived data could be used to reproduce analyses as presented in the manuscript. We found that the journal's mandatory archiving policy has had a substantial positive impact, increasing genetic data archiving from 49 (pre-2011) to 98% (2011-present). However, 31% of publicly archived genetic data sets could not be recreated based on information supplied in either the manuscript or public archives, with incomplete data or inconsistent codes linking genetic data and metadata as the primary reasons. While the majority of articles did provide some geographic information, 40% did not provide this information as geographic coordinates. Furthermore, a large proportion of articles did not contain any information regarding date of sampling (40%). Although the inclusion of spatio-temporal data does require an increase in effort, we argue that the enduring value of publicly accessible genetic data to the molecular ecology field is greatly compromised when such metadata are not archived alongside genetic data. PMID- 26033416 TI - Clinical characteristics and quality-of-life in patients surviving a decade of prostate cancer with bone metastases. AB - OBJECTIVE: To describe characteristics and quality-of-life (QoL), and to define factors associated with long-term survival in a subgroup of patients with prostate cancer with M1b disease. PATIENTS AND METHODS: The study was based on 915 patients from a prospective randomised multicentre trial (No. 5) by the Scandinavian Prostate Cancer Group, comparing parenteral oestrogen with total androgen blockade. Long-term survival was defined as patients having an overall survival of >=10 years, and logistic regression models were constructed to identity clinical predictors of survival. QoL during follow-up was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire - C30 version 1 (EORTC-C30) ratings. RESULTS: In all, 40 (4.4%) of the 915 men survived for >10 years. Factors significantly associated with increased likelihood of surviving for >10 years in the univariate analyses were: absence of cancer-related pain; Eastern Cooperative Oncology Group (ECOG) performance status of <2; negligible analgesic consumption; T-category of 1-2; prostate-specific antigen (PSA) level of <231 MUg/L; and a Soloway score of 1. In the multivariate analyses, ECOG performance status of <2, PSA level of <231 MUg/L, and Soloway score of 1, were all independent predictors of long-term survival. All subscales of the EORTC-C30 were higher in this group than for patients with short survival, but slowly declined over the decade. CONCLUSION: A subgroup of patients with prostate cancer with M1b disease and certain characteristics showed a positive long-term response to androgen-deprivation therapy with an acceptable QoL over a decade or more. Independent predictors of long-term survival were identified as ECOG performance status of <2, limited extent of bone metastases (Soloway score of 1), and a PSA level of <231 MUg/L at the time of enrolment. PMID- 26033417 TI - Effectiveness of Rinse Water during In-Place Cleaning of Stainless Steel Pipe Lines. AB - The 1st step of any Clean-In-Place (CIP) operation is a prerinse with water. The purpose of this step is to remove the bulk of food material remaining in the processing lines after production period has ended. It is known that this prerinse step can be a very water intensive process. The objective of this investigation was to measure the influence of CIP parameters (flow characteristics, water temperature, and contact time) on the effectiveness of prerinse water in removing dairy-based deposits from stainless steel pipe surfaces and to compare the rinse effectiveness of unused to reused rinse water. A pilot-scale CIP system was operated to rinse 304 stainless steel pipe sections of 3 different pipe diameters. The velocity of the rinse water was varied from 0.72 to 2.26 m/s. The rinse water temperatures were 22 degrees C, 45 degrees C, and 67 degrees C. The contact times between rinse water and deposited film were 20 and 60 s. Rinse effectiveness was expressed as the ratio of the amount of protein residue removed from the pipe surface during rinsing, as compared to the magnitude of the initial protein deposit. The rinse effectiveness varied from 73.1% to 94.9% for the range of the CIP parameters investigated. High velocities of rinse water provided a higher level of rinse effectiveness. Increasing the rinse water temperature from 23 degrees C to 45 degrees C improved rinse effectiveness significantly (P < 0.05). This impact was not significant when the water temperature was increased from 45 degrees C to 67 degrees C and at higher rinse water velocities. Similarly, longer contact time provided less improvement in rinse effectiveness at higher temperatures and velocities as compared to lower temperatures and velocities. There were no significant differences in rinse effectiveness when comparing reused and unused water (normal tap water) within the range of velocities evaluated. PRACTICAL APPLICATION: The rinse steps are important components of the CIP operation and have direct impact on the amounts of water and energy used for the entire processing operation. The efficiency of rinse water can be improved significantly by the selection of appropriate combinations of operating parameters. For example, higher velocities of rinse water (2.26 m/s) provide significant improvements on rinse effectiveness when compared to current commercial practice (1.52 m/s). The careful selection of rinse water temperature and velocity can result in overall reductions in water and energy used for cleaning operations. The reuse of water for a 2nd or 3rd pass provides additional opportunities for reducing water requirements without influencing effectiveness. PMID- 26033418 TI - A functional approach for research on cognitive control: Analysing cognitive control tasks and their effects in terms of operant conditioning. AB - Cognitive control is an important mental ability that is examined using a multitude of cognitive control tasks and effects. The present paper presents the first steps in the elaboration of a functional approach, which aims to uncover the communalities and differences between different cognitive control tasks and their effects. Based on the idea that responses in cognitive control tasks qualify as operant behaviour, we propose to reinterpret cognitive control tasks in terms of operant contingencies and cognitive control effects as instances of moderated stimulus control. We illustrate how our approach can be used to uncover communalities between topographically different cognitive control tasks and can lead to novel questions about the processes underlying cognitive control. PMID- 26033419 TI - Preparation of Nickel-Aluminum-Containing Layered Double Hydroxide Films by Secondary (Seeded) Growth Method and Their Electrochemical Properties. AB - Thin films of nickel-aluminum-containing layered double hydroxide (NiAl-LDH) have been prepared on nickel foil and nickel foam substrates by secondary (seeded) growth of NiAl-LDH seed layer. The preparation procedure consists of deposition of LDH seeds from a colloidal suspension on the substrate by dip coating, followed by hydrothermal treatment of the nanocrystals to form the LDH film. The secondary grown film is found to provide a higher crystallinity and more uniform composition of metal cations in the film layer than the in situ grown film on seed-free substrate under identical hydrothermal conditions. A systematic investigation of the film evolution process reveals that the crystallite growth rate is relatively fast for the secondary grown film because of the presence of LDH nanocrystal seeds. Electrochemical performance of the resulting NiAl-LDH films as positive electrode material was further assessed as an example of their practical applications. The secondary grown film electrode delivers improved recharge-discharge capacity and cycling stability compared with that of the in situ grown film, which can be explained by the existence of a unique microstructure of the former. Our findings show an example for the effective fabrication of LDH film with controllable microstructure and enhanced application performance through a secondary (seeded) growth procedure. PMID- 26033420 TI - Getting the basics right resolves most cases of uncontrolled and problematic asthma. AB - AIM: The prevalence of true therapy-resistant asthma among children whose asthma remains uncontrolled, despite daily controller therapy, is unknown. The aim of this study was to investigate the underlying causes in children with uncontrolled asthma. METHODS: This was a retrospective chart review of 142 children aged from five to 17 years over a five-year period. The patients had uncontrolled asthma and were referred by general practitioners to a hospital-based paediatric asthma clinic. RESULTS: An underlying cause for uncontrolled asthma was found in 138 children (97.2%). The causes were poor adherence (n = 53, 37.3%), ongoing exposure to environmental triggers (n = 40, 28.2%), comorbidities (n = 28, 19.7%), incorrect inhaler technique (n = 11, 7.7%) and incorrect diagnosis (n = 6, 4.2%). After properly addressing these basics in asthma management, the asthma was well controlled in all 138 patients and lung function was normal. Only four children (2.8%) fulfilled the criteria for true therapy-resistant asthma. CONCLUSION: A remedial cause in the basics of asthma management could be found in 97% of children with uncontrolled asthma referred to a hospital-based asthma clinic. True therapy-resistant asthma was found to be very rare in children. PMID- 26033421 TI - Reply. PMID- 26033422 TI - Discovery of a Novel Polymer for Human Pluripotent Stem Cell Expansion and Multilineage Differentiation. AB - A scalable and cost-effective synthetic polymer substrate that supports robust expansion and subsequent multilineage differentiation of human pluripotent stem cells (hPSCs) with defined commercial media is presented. This substrate can be applied to common cultureware and used off-the-shelf after long-term storage. Expansion and differentiation of hPSCs are performed entirely on the polymeric surface, enabling the clinical potential of hPSC-derived cells to be realized. PMID- 26033423 TI - Validation and scopolamine-reversal of latent learning in the water maze utilizing a revised direct platform placement procedure. AB - The Morris water maze is routinely used to explore neurobiological mechanisms of working memory. Humans can often acquire working memory relevant to performing a task by mere sensory observation, without having to actually perform the task followed by reinforcement. This can be modeled in the water maze through direct placement of a rat on the escape platform so that it can observe the location, and then assessing the subject's performance in swimming back to the platform. However, direct placement procedures have hardly been studied for two decades, reflecting a controversy about whether direct placement resulted in sufficiently rapid and direct swims back to the platform. In the present study, utilizing revised training methods, a more comprehensive measure of trajectory directness, a more rigorous sham-trained control procedure and an optimal placement-test interval, rats swam almost directly back to the platform in under 4s, significantly more quickly and directly than sham-trained subjects. Muscarinic cholinergic mechanisms, which are inactivated by scopolamine, are essential to memory for standard learning paradigms in the water maze. This experiment determined whether this would also be true for latent learning. ANOVA revealed significant negative effects of scopolamine on both speed and accuracy of trajectory, as well as significant positive effects of direct placement training vs. sham-training. In a probe trial, placement-trained animals without scopolamine spent significantly more time and path length in the target quadrant than trained rats with scopolamine and sham-trained rats without scopolamine. Scopolamine impairments are likely due to effects on memory, since the same dose had little effect on performance with a visible platform. The revised direct placement model offers a means of further comparing the neural mechanisms of latent learning with those of standard instrumental learning. PMID- 26033424 TI - Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice. AB - We recently observed that the addition of caffeine (a nonselective adenosine receptor antagonist) to a 20% ethanol solution significantly altered the intoxication profile of male C57BL/6J (B6) mice induced by voluntary binge-like consumption in the 'Drinking-in-the-Dark' (DID) paradigm. In the current study, the roles of A1 and A2A adenosine receptor subtypes, specifically, in binge-like ethanol consumption and associated locomotor effects were explored. Adult male B6 mice (PND 60-70) were allowed to consume 20% ethanol (v/v) or 2% sucrose (w/v) for 6days via DID. On day 7, mice received a systemic administration (i.p.) of the A1 antagonist DPCPX (1, 3, 6mg/kg), the A2A antagonist MSX-3 (1, 2, 4mg/kg), or vehicle immediately prior to fluid access in DID. Antagonism of the A1 receptor via DPCPX was found to dose-dependently decrease binge-like ethanol intake and associated blood ethanol concentrations (p's<0.05), although no effect was observed on sucrose intake. Antagonism of A2A had no effect on ethanol or sucrose consumption, however, MSX-3 elicited robust locomotor stimulation in mice consuming either solution (p's<0.05). Together, these findings suggest unique roles for the A1 and A2A adenosine receptor subtypes in binge-like ethanol intake and its associated locomotor effects. PMID- 26033425 TI - Empirical Bayes scan statistics for detecting clusters of disease risk variants in genetic studies. AB - Recent developments of high-throughput genomic technologies offer an unprecedented detailed view of the genetic variation in various human populations, and promise to lead to significant progress in understanding the genetic basis of complex diseases. Despite this tremendous advance in data generation, it remains very challenging to analyze and interpret these data due to their sparse and high-dimensional nature. Here, we propose novel applications and new developments of empirical Bayes scan statistics to identify genomic regions significantly enriched with disease risk variants. We show that the proposed empirical Bayes methodology can be substantially more powerful than existing scan statistics methods especially so in the presence of many non disease risk variants, and in situations when there is a mixture of risk and protective variants. Furthermore, the empirical Bayes approach has greater flexibility to accommodate covariates such as functional prediction scores and additional biomarkers. As proof-of-concept we apply the proposed methods to a whole-exome sequencing study for autism spectrum disorders and identify several promising candidate genes. PMID- 26033426 TI - Clinical outcome of cisplatin-based chemotherapy is associated with the polymorphisms of GSTP1 and XRCC1 in advanced non-small cell lung cancer patients. AB - INTRODUCTION: This study is to evaluate the association of polymorphisms of glutathione S-transferase P1 (GSTP1), copper-transporting P-type adenosine triphosphatase A (ATP7A) and X-ray repair cross-complementing group 1 (XRCC1) with the efficacy and toxicity of cisplatin-based treatment in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: The outcomes of 97 advanced non-small cell lung cancer patients treated with cisplatin-based chemotherapy were estimated. GSTP1, ATP7A, and XRCC1 genetic polymorphisms were determined via polymerase chain reaction of restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Association of the polymorphisms with the efficacy and toxicity of cisplatin was analyzed, respectively. RESULTS: Significant associations were observed between GSTP1 A313G and response rate (RR) (p = 0.027), disease control rate (DCR) (p = 0.019), and progression-free survival (PFS) (p = 0.044), respectively. Patients with AG and GG of GSTP1 have notably lower risk of anemia (p = 0.046). XRCC1 A1196G was associated with the incidence of lymphopenia (p = 0.024) and diarrhea (p = 0.020). ATP7A C2299G was not related with RR, DCR, PFS, and the risk of toxicity. CONCLUSIONS: Advanced NSCLC patients with AA genotype of GSTP1 would obtain better curative effect followed with more risk of anemia when treated by cisplatin-based chemotherapy. ATP7A C2299G does not impact the efficacy and toxicity of cisplatin-based chemotherapy. XRCC1 1196A allele could predict the incidence of lymphopenia and diarrhea. PMID- 26033427 TI - Survivin siRNA increases sensitivity of primary cultures of ovarian cancer cells to paclitaxel. AB - PURPOSE: This aim of this study was to use ovarian cancer cells shed in ascitic fluid to establish primary cultures and subsequently use it to detect drug resistance to paclitaxel. Survivin siRNA was used to down regulate survivin expression and effect on paclitaxel resistance was also evaluated. METHODOLOGY: Ascitic fluid along with corresponding primary tumor tissue was collected from twenty untreated epithelial ovarian cancer patients. Ten primary cultures were established from ascites obtained from untreated ovarian cancer patients in MCDB 105 and M199 medium (ratio 1:1). Knockdown of survivin was done using siRNA and sensitivity to paclitaxel was evaluated by MTT assay. RESULTS: Grape-like clusters of ovarian cancer cells present in ascites attached and gave a characteristic cobble stone appearance. Treatment with survivin siRNA resulted in a fivefold decrease in survivin expression in primary cultures. Survivin siRNA treatment significantly increased the sensitivity of the primary ovarian cancer cell cultures to paclitaxel. CONCLUSION: Ascitic cancer cells reflect the molecular profile of tumor and can be used to diagnose resistance to chemotherapy. This study also establishes that high survivin expression is also responsible for resistance to paclitaxel. PMID- 26033428 TI - A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma. AB - PURPOSE: The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. PATIENTS AND METHODS: Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m(2) days 1-7 and 15-21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. RESULTS: Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44%) had gross total resection. O(6) methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9% (95% CI 9.3-40.0%). The median PFS and overall survival (OS) were 4.2 months (95% CI 3.6-5.4 months) and 7.3 months (95% CI 5.8 8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19%; 95% CI 7.2-36.4) were long-term survivors, with a median PFS and OS (50% events) of 9.5 months (95% CI 7.9-23.6) and 15.4 (95% CI 8.9-NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. CONCLUSIONS: This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy. PMID- 26033429 TI - Tobramycin Variants with Enhanced Ribosome-Targeting Activity. AB - With the increased evolution of aminoglycoside (AG)-resistant bacterial strains, the need to develop AGs with 1) enhanced antimicrobial activity, 2) the ability to evade resistance mechanisms, and 3) the capability of targeting the ribosome with higher efficiency is more and more pressing. The chemical derivatization of the naturally occurring tobramycin (TOB) by attachment of 37 different thioether groups at the 6''-position led to the identification of generally poorer substrates of TOB-targeting AG-modifying enzymes (AMEs). Thirteen of these displayed better antibacterial activity than the parent TOB while retaining ribosome-targeting specificity. Analysis of these compounds in vitro shed light on the mechanism by which they act and revealed three with clearly enhanced ribosome-targeting activity. PMID- 26033431 TI - Biomimetic Mussel Adhesive Inspired Anchor to Design ZnO@Poly(3-Hexylthiophene) Hybrid Core@Corona Nanoparticles. AB - The functionalization of zinc oxide (ZnO) nanoparticles by poly(3-hexylthiophene) (P3HT) brush is completed by the combination of a mussel inspired biomimetic anchoring group and Huisgen cyclo-addition "click chemistry." Herein, the direct coupling of an azide modified catechol derivative with an alkyne end functionalized P3HT is described. This macromolecular binding agent is used to access core@corona ZnO@P3HT with a stable and homogeneous conjugated organic corona. Preliminary photoluminescence measurement proves an efficient electron transfer from the donor P3HT to the acceptor ZnO nanoparticles upon grafting, thus demonstrating the potential of such a combination in organic electronics. PMID- 26033430 TI - Examining the Impact of Separate Components of a Multicomponent Intervention Designed to Reduce At-Risk Drinking Among Older Adults: The Project SHARE Study. AB - BACKGROUND: Health promotion interventions often include multiple components and several patient contacts. The objective of this study was to examine how participation within a multicomponent intervention (Project SHARE) is associated with changes in at-risk drinking among older adults. METHODS: We analyzed observational data from a cluster-randomized trial of 31 primary care physicians and their patients aged >=60 years, at a community-based practice with 7 clinics. Recruitment occurred between 2005 and 2007. At-risk drinkers in a particular physician's practice were randomly assigned as a group to usual care (n = 640 patients) versus intervention (n = 546 patients). The intervention included personalized reports, educational materials, drinking diaries, in-person physician advice, and telephone counseling by health educators (HEs). The primary outcome was at-risk drinking at follow-up, defined by scores on the Comorbidity Alcohol Risk Evaluation Tool (CARET). Predictors included whether a physician patient alcohol risk discussion occurred, HE call occurred, drinking agreement with the HE was made, and patients self-reported keeping a drinking diary as suggested by the HE. RESULTS: At 6 months, there was no association of at-risk drinking with having had a physician-patient discussion. Compared to having had no HE call, the odds of at-risk drinking at 6 months were lower if an agreement was made or patients reported keeping a diary (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37 to 0.90), or if an agreement was made and patients reported keeping a diary (OR 0.52, CI 0.28 to 0.97). At 12 months, a physician patient discussion (OR 0.61, CI 0.38 to 0.98) or an agreement and reported use of a diary (OR 0.45, CI 0.25) were associated with lower odds of at-risk drinking. CONCLUSIONS: Within the Project SHARE intervention, discussing alcohol risk with a physician, making a drinking agreement, and/or self-reporting the use of a drinking diary were associated with lower odds of at-risk drinking at follow-up. Future studies targeting at-risk drinking among older adults should consider incorporating both intervention components. PMID- 26033432 TI - Elevated temperature is more effective than elevated [CO2 ] in exposing genotypic variation in Telopea speciosissima growth plasticity: implications for woody plant populations under climate change. AB - Intraspecific variation in phenotypic plasticity is a critical determinant of plant species capacity to cope with climate change. A long-standing hypothesis states that greater levels of environmental variability will select for genotypes with greater phenotypic plasticity. However, few studies have examined how genotypes of woody species originating from contrasting environments respond to multiple climate change factors. Here, we investigated the main and interactive effects of elevated [CO2 ] (CE ) and elevated temperature (TE ) on growth and physiology of Coastal (warmer, less variable temperature environment) and Upland (cooler, more variable temperature environment) genotypes of an Australian woody species Telopea speciosissima. Both genotypes were positively responsive to CE (35% and 29% increase in whole-plant dry mass and leaf area, respectively), but only the Coastal genotype exhibited positive growth responses to TE . We found that the Coastal genotype exhibited greater growth response to TE (47% and 85% increase in whole-plant dry mass and leaf area, respectively) when compared with the Upland genotype (no change in dry mass or leaf area). No intraspecific variation in physiological plasticity was detected under CE or TE , and the interactive effects of CE and TE on intraspecific variation in phenotypic plasticity were also largely absent. Overall, TE was a more effective climate factor than CE in exposing genotypic variation in our woody species. Our results contradict the paradigm that genotypes from more variable climates will exhibit greater phenotypic plasticity in future climate regimes. PMID- 26033433 TI - A Bayesian estimate of the concordance correlation coefficient with skewed data. AB - Concordance correlation coefficient (CCC) is one of the most popular scaled indices used to evaluate agreement. Most commonly, it is used under the assumption that data is normally distributed. This assumption, however, does not apply to skewed data sets. While methods for the estimation of the CCC of skewed data sets have been introduced and studied, the Bayesian approach and its comparison with the previous methods has been lacking. In this study, we propose a Bayesian method for the estimation of the CCC of skewed data sets and compare it with the best method previously investigated. The proposed method has certain advantages. It tends to outperform the best method studied before when the variation of the data is mainly from the random subject effect instead of error. Furthermore, it allows for greater flexibility in application by enabling incorporation of missing data, confounding covariates, and replications, which was not considered previously. The superiority of this new approach is demonstrated using simulation as well as real-life biomarker data sets used in an electroencephalography clinical study. The implementation of the Bayesian method is accessible through the Comprehensive R Archive Network. PMID- 26033435 TI - Gender Influence on Long-Term Weight Loss and Comorbidities After Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass: a Prospective Study With a 5 Year Follow-up. AB - BACKGROUND: Gender might be important in predicting outcomes after bariatric surgery. The aim of the study was to investigate the influence of gender on long term weight loss and comorbidity improvement after laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: A cohort of 304 consecutive patients underwent surgery in 2006-2009: 162 (98 women, 64 men) underwent LSG and 142 (112 women, 30 men) underwent LRYGB. The mean follow-up time was 75.8 +/- 8.4 months (range, 60-96 months). RESULTS: Overall mean (95% CI) reduction in BMI was 23.5 (24.3-22.7) kg/m(2) after 5 years, with no statistical difference between LSG and LRYGB groups (P = 0.94). The overall means +/- standard deviations of %EBMIL after 5 years were 78.8 +/- 23.5 and 81.6 +/- 21.4 in the LSG and LRYGB groups, respectively. Only for LSG group %EBMIL after 24-36 and 60 months differed significantly between male and female patients (P = 0.003 versus P = 0.06 in LRYGB), and 89 versus 90% of patients showed improvements in comorbidities in the LSG and LRYGB groups, respectively. Only two patients (women) were lost to follow-up: 1/162 (0.6%) for LSG at the 4th year and 1/142 (0.7%) for LRYGB to the 5th year. CONCLUSIONS: LSG was more effective in obese male than in female patients in terms of %EBMIL, with no difference in comorbidities. LRYGB elicited similar results in both genders in terms of %EBMIL and comorbidities. PMID- 26033434 TI - Anticancer potential of the histone deacetylase inhibitor-like effects of flavones, a subclass of polyphenolic compounds: a review. AB - Cancer is characterized by the uncontrolled division of cells, followed by their invasion to other tissues. These kinds of cellular abnormalities arise as a result of the accumulation of genetic mutations or epigenetic alterations. Targeting genetic mutations by drugs is a conventional treatment approach. Nowadays, the development and use of epigenetic drugs are burgeoning, owing to the advancements in epigenetic research. The therapeutic intervention of cancer development by histone deacetylase inhibitors (HDACIs) holds promise for helping to control the disease, but their nonspecific functions impose certain side effects. Therefore, the search for more HDACIs becomes essential. Plentiful literature on the versatility of dietary components including flavones, a class of the flavonoid group, has already established these compounds to be better anticancer agents. The present review focuses on the significance of flavones with regard to their HDACI-mimicking effects as suggested by the recent evidences. The review also proposes an in-depth screening of flavones in future studies, in the hope that flavones may provide a better alternative to synthetic HDACIs. PMID- 26033437 TI - Recreational fishing eye injuries and eye protection. PMID- 26033436 TI - Risk of lung cancer and consumption of vegetables and fruit in Japanese: A pooled analysis of cohort studies in Japan. AB - International reviews have concluded that consumption of fruit and vegetables might decrease the risk of lung cancer. However, the relevant epidemiological evidence still remains insufficient in Japan. Therefore, we performed a pooled analysis of data from four population-based cohort studies in Japan with >200 000 participants and >1700 lung cancer cases. We computed study-specific hazard ratios by quintiles of vegetable and fruit consumption as assessed by food frequency questionnaires. Summary hazard ratios were estimated by pooling the study-specific hazard ratios with a fixed-effect model. In men, we found inverse associations between fruit consumption and the age-adjusted and area-adjusted risk of mortality or incidence of lung cancer. However, the associations were largely attenuated after adjustment for smoking and energy intake. The significant decrease in risk among men remained only for a moderate level of fruit consumption; the lowest summary hazard ratios were found in the third quintile of intake (mortality: 0.71, 95% confidence interval 0.60-0.84; incidence: 0.83, 95% confidence interval 0.70-0.98). This decrease in risk was mainly detected in ever smokers. Conversely, vegetable intake was positively correlated with the risk of incidence of lung cancer after adjustment for smoking and energy intake in men (trend P, 0.024); the summary hazard ratio for the highest quintile was 1.26 (95% confidence interval 1.05-1.50). However, a similar association was not detected for mortality from lung cancer. In conclusion, a moderate level of fruit consumption is associated with a decreased risk of lung cancer in men among the Japanese population. PMID- 26033439 TI - Erratum to: Ultrasound-guided joint injections for MR arthrography in pediatric patients: how we do it. PMID- 26033438 TI - Phase I/II study of weekly PM00104 (Zalypsis(r)) in patients with relapsed/refractory multiple myeloma. PMID- 26033440 TI - Three-dimensional digital microfluidic manipulation of droplets in oil medium. AB - We here develop a three-dimensional DMF (3D DMF) platform with patterned electrodes submerged in an oil medium to provide fundamental solutions to the technical limitations of 2D DMF platforms and water-air systems. 3D droplet manipulation on patterned electrodes is demonstrated by programmably controlling electrical signals. We also demonstrate the formation of precipitates on the 3D DMF platform through the reaction of different chemical samples. A droplet containing precipitates, hanging on the top electrode, can be manipulated without adhesion of precipitates to the solid surface. This method could be a good alternative strategy to alleviate the existing problems of 2D DMF systems such as cross-contamination and solute adsorption. In addition, we ascertain the feasibility of temperature-controlled chemical reaction on the 3D DMF platform by introducing a simple heating process. To demonstrate applicability of the 3D DMF system to 3D biological process, we examine the 3D manipulation of droplets containing mouse fibroblasts in the 3D DMF platform. Finally, we show detachment of droplets wrapped by a flexible thin film by adopting the electro-elasto capillarity (EEC). The employment of the EEC may offer a strong potential in the development of 3D DMF platforms for drug encapsulation and actuation of microelectromechanical devices. PMID- 26033441 TI - Stereoselective Organocatalytic Synthesis of Oxindoles with Adjacent Tetrasubstituted Stereocenters. AB - Oxindoles with adjacent tetrasubstituted stereocenters were obtained in high yields and stereoselectivities by organocatalyzed conjugate addition reactions of monothiomalonates (MTMs) to isatin-derived N-Cbz ketimines. The method requires only a low catalyst loading (2 mol %) and proceeds under mild reaction conditions. Both enantiomers are accessible in good yields and excellent stereoselectivities by using either Takemoto's catalyst or a cinchona alkaloid derivative. The synthetic methodology allowed establishment of a straightforward route to derivatives of the gastrin/cholecystokinin-B receptor antagonist AG 041R. PMID- 26033442 TI - Anemia and Oxygen Delivery. AB - Clinical assessment of tissue oxygenation is challenging. Anemia reflects a decreased oxygen carrying capacity of the blood and its significance in the perioperative setting relates largely to the associated risk of insufficient oxygen delivery and cellular hypoxia. Until meaningful clinical measures of tissue oxygenation are available in veterinary practice, clinicians must rely on evaluation of a patient's hemodynamic and ventilatory performance, along with biochemical and hemogasometric measurements. Blood transfusion is used commonly for treatment of perioperative anemia, and may improve tissue oxygenation by normalizing the rheologic properties of blood and enhancing perfusion, independent of increases in oxygen carrying capacity. PMID- 26033443 TI - Assessment of Fluid Balance and the Approach to Fluid Therapy in the Perioperative Patient. AB - Perioperative patients can be highly dynamic and have various metabolic, physiologic, and organ system derangements that necessitate smart monitoring strategies and careful fluid therapy. The interplay between changing patient status, therapeutic interventions, and patient response makes effective monitoring crucial to successful treatment. Monitoring the perioperative patient and an approach to fluid therapy are discussed in this text. PMID- 26033445 TI - Theory and computation of hot carriers generated by surface plasmon polaritons in noble metals. AB - Hot carriers (HC) generated by surface plasmon polaritons (SPPs) in noble metals are promising for application in optoelectronics, plasmonics and renewable energy. However, existing models fail to explain key quantitative details of SPP to-HC conversion experiments. Here we develop a quantum mechanical framework and apply first-principles calculations to study the energy distribution and scattering processes of HCs generated by SPPs in Au and Ag. We find that the relative positions of the s and d bands of noble metals regulate the energy distribution and mean free path of the HCs, and that the electron-phonon interaction controls HC energy loss and transport. Our results prescribe optimal conditions for HC generation and extraction, and invalidate previously employed free-electron-like models. Our work combines density functional theory, GW and electron-phonon calculations to provide microscopic insight into HC generation and ultrafast dynamics in noble metals. PMID- 26033446 TI - Ultrafast charge carrier relaxation and charge transfer processes in CdS/CdTe thin films. AB - Ultrafast transient absorption pump-probe spectroscopy (TAPPS) has been employed to investigate charge carrier relaxation in cadmium sulfide/cadmium telluride (CdS/CdTe) nanoparticle (NP)-based thin films and electron transfer (ET) processes between CdTe and CdS. Effects of post-growth annealing treatments to ET processes have been investigated by carrying out TAPPS experiments on three CdS/CdTe samples: as deposited, heat treated, and CdCl2 treated. Clear evidence of ET process in the treated thin films has been observed by comparing transient absorption (TA) spectra of CdS/CdTe thin films to those of CdS and CdTe. Quantitative comparison between ultrafast kinetics at different probe wavelengths unravels the ET processes and enables determination of its rate constants. Implication of the photoinduced dynamics to photovoltaic devices is discussed. PMID- 26033447 TI - The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty: a meta-analysis of 2720 cases. AB - AIMS: To evaluate the safety and efficacy of tranexamic acid (TXA) in total knee arthroplasty (TKA) and total hip arthroplasty (THA). The specific endpoints assessed in this meta-analysis include the total blood loss, the incidence rate of deep vein thrombosis (DVT) and pulmonary embolisms (PE), the number of patients requiring at least 1 U of red blood cell following surgery. BACKGROUND: The prevalence of THA and TKA is increasing and both are usually accompanied by considerable blood loss. TXA has been reported to reduce total blood loss in many orthopaedic surgeries. TXA administration continues to be a controversial topic in the literature about joint arthroplasty, and many studies have reported substantial doubt with respect to its benefits and safety. METHODS/MATERIALS: We conducted a meta-analysis that combined all data from available randomised controlled trials, regardless the methods of TXA administration, which included administrated intravenously, intra-articularly, topically or orally. Finally, available data from the 39 included trials were pooled for analysis. Then, mean differences with 95% confidence intervals (CIs) was calculated for continuous outcomes and relative risks with 95% CIs for dichotomous outcomes. RESULTS: This meta-analysis suggests that the administration of TXA significantly reduced blood loss and the need for allogeneic blood transfusion, without apparent increased risk of DVT or PE thromboembolic complications. CONCLUSION: To our knowledge, this meta-analysis is more powerful and persuasive than any other published before. It suggests that the use of TXA reduced the risk of blood loss and the need for allogeneic blood transfusion significantly, without apparent increased risk of DVT or PE complications. PMID- 26033448 TI - Thiostrepton interacts covalently with Rpt subunits of the 19S proteasome and proteasome substrates. AB - Here, we report a novel mechanism of proteasome inhibition mediated by Thiostrepton (Thsp), which interacts covalently with Rpt subunits of the 19S proteasome and proteasome substrates. We identified Thsp in a cell-based high throughput screen using a fluorescent reporter sensitive to degradation by the ubiquitin-proteasome pathway. Thiostrepton behaves as a proteasome inhibitor in several paradigms, including cell-based reporters, detection of global ubiquitination status, and proteasome-mediated labile protein degradation. In vitro, Thsp does not block the chymotrypsin activity of the 26S proteasome. In a cell-based IkappaBalpha degradation assay, Thsp is a slow inhibitor and 4 hrs of treatment achieves the same effects as MG-132 at 30 min. We show that Thsp forms covalent adducts with proteins in human cells and demonstrate their nature by mass spectrometry. Furthermore, the ability of Thsp to interact covalently with the cysteine residues is essential for its proteasome inhibitory function. We further show that a Thsp modified peptide cannot be degraded by proteasomes in vitro. Importantly, we demonstrate that Thsp binds covalently to Rpt subunits of the 19S regulatory particle and forms bridges with a proteasome substrate. Taken together, our results uncover an important role of Thsp in 19S proteasome inhibition. PMID- 26033449 TI - Determination and validation of hupehenine in rat plasma by UPLC-MS/MS and its application to pharmacokinetic study. AB - In this work, a sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for determination of hupehenine in rat plasma was developed and validated. After addition of imperialine as an internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 * 100 mm, 1.7 um) with 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring mode was used for quantification using target fragment ions m/z 416.3 -> 98.0 for hupehenine, and m/z 430.3 -> 138.2 for IS. Calibration plots were linear throughout the range 2-2000 ng/mL for hupehenine in rat plasma. Mean recoveries of hupehenine in rat plasma ranged from 92.5 to 97.3%. Relative standard deviations of intra-day and inter-day precision were both <6%. The accuracy of the method was between 92.7 and 107.4%. The method was successfully applied to a pharmacokinetic study of hupehenine after either oral or intravenous administration. For the first time, the bioavailability of hupehenine was reported as 13.4%. PMID- 26033450 TI - Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. AB - Deltex-3-like (DTX3L), an E3 ligase, is a member of the Deltex (DTX) family and is also called B-lymphoma and BAL-associated protein (BBAP). Previously, we established RFP/RET-transgenic mice, in which systemic hyperpigmented skin, benign melanocytic tumor(s) and melanoma(s) develop stepwise. Here we showed that levels of Dtx3l/DTX3L in spontaneous melanoma in RFP/RET-transgenic mice and human melanoma cell lines were significantly higher than those in benign melanocytic cells and primarily cultured normal human epithelial melanocytes, respectively. Immunohistochemical analysis of human tissues showed that more than 80% of the melanomas highly expressed DTX3L. Activity of FAK/PI3K/AKT signaling, but not that of MEK/ERK signaling, was decreased in Dtx3l/DTX3L-depleted murine and human melanoma cells. In summary, we demonstrated not only increased DTX3L level in melanoma cells but also DTX3L-mediated regulation of invasion and metastasis in melanoma through FAK/PI3K/AKT but not MEK/ERK signaling. Our analysis in human BRAFV600E inhibitor-resistant melanoma cells showed about 80% decreased invasion in the DTX3L-depleted cells compared to that in the DTX3L intact cells. Thus, DTX3L is clinically a potential therapeutic target as well as a potential biomarker for melanoma. PMID- 26033451 TI - Targeting tumors with a killer-reporter adenovirus for curative fluorescence guided surgery of soft-tissue sarcoma. AB - Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP 401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future. PMID- 26033452 TI - Effects of RAL signal transduction in KRAS- and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer. AB - Our understanding of oncogenic signaling pathways has strongly fostered current concepts for targeted therapies in metastatic colorectal cancer. The RALA pathway is novel candidate due to its independent role in controlling expression of genes downstream of RAS.We compared RALA GTPase activities in three colorectal cancer cell lines by GTPase pull-down assay and analyzed the transcriptional and phenotypic effects of transient RALA silencing. Knocking-down RALA expression strongly diminished the active GTP-bound form of the protein. Proliferation of KRAS mutated cell lines was significantly reduced, while BRAF mutated cells were mostly unaffected. By microarray analysis we identified common genes showing altered expression upon RALA silencing in all cell lines. None of these genes were affected when the RAF/MAPK or PI3K pathways were blocked.To investigate the potential clinical relevance of the RALA pathway and its associated transcriptome, we performed a meta-analysis interrogating progression-free survival of colorectal cancer patients of five independent data sets using Cox regression. In each dataset, the RALA-responsive signature correlated with worse outcome.In summary, we uncovered the impact of the RAL signal transduction on genetic program and growth control in KRAS- and BRAF-mutated colorectal cells and demonstrated prognostic potential of the pathway-responsive gene signature in cancer patients. PMID- 26033453 TI - Aberrant plasma levels of circulating miR-16, miR-107, miR-130a and miR-146a are associated with lymph node metastasis and receptor status of breast cancer patients. AB - Within the multicenter SUCCESS trial, we investigated the association of plasma microRNAs with different subtypes of invasive breast cancer.Six miRs (miR-16, miR 27a, miR-107, miR-130a, miR-132 and miR-146a) were selected from microarray profiling and further validated in plasma of 111 breast cancer patients before and after chemotherapy and 46 healthy women by quantitative real-time PCR.Plasma levels of miR-16 (p = 0.0001), miR-27a (p = 0.039) and miR-132 (p = 0.020) were higher in breast cancer patients before chemotherapy than healthy women. With the exception of miR-16, the increased levels of miR-27a (p = 0.035) and miR-132 (p = 0.025) decreased after chemotherapy to those observed in healthy women. Levels of miR-16 (p = 0.019), miR-107 (p = 0.036), miR-130a (p = 0.027) and miR-146a (p = 0.047) were different between lymph node -positive and -negative patients, while the levels of miR-130a (p = 0.001) and miR-146a (p = 0.025) also differed between HER2-positive and -negative status. Estrogen-receptor negative tumors displayed higher concentrations of circulating miR-107 than their counterparts (p = 0.035). However, overexpression of miR-107 in MCF-7 cells did not downregulate estrogen receptor protein. Altered expression levels of miR-107 influenced the migration and invasion behavior of MCF-7 and MDA-MB-231 cells.Our data indicate differential concentrations of plasma miR-16, miR-107, miR-130a and miR-146a in different breast cancer subtypes, suggesting a potential role of these miRs in breast cancer biology and tumor progression. PMID- 26033454 TI - Insulin/IGF1-PI3K-dependent nucleolar localization of a glycolytic enzyme- phosphoglycerate mutase 2, is necessary for proper structure of nucleolus and RNA synthesis. AB - Phosphoglycerate mutase (PGAM), a conserved, glycolytic enzyme has been found in nucleoli of cancer cells. Here, we present evidence that accumulation of PGAM in the nucleolus is a universal phenomenon concerning not only neoplastically transformed but also non-malignant cells. Nucleolar localization of the enzyme is dependent on the presence of the PGAM2 (muscle) subunit and is regulated by insulin/IGF-1-PI3K signaling pathway as well as drugs influencing ribosomal biogenesis. We document that PGAM interacts with several 40S and 60S ribosomal proteins and that silencing of PGAM2 expression results in disturbance of nucleolar structure, inhibition of RNA synthesis and decrease of the mitotic index of squamous cell carcinoma cells. We conclude that presence of PGAM in the nucleolus is a prerequisite for synthesis and initial assembly of new pre ribosome subunits. PMID- 26033455 TI - A multicentre observational study for early diagnosis of Gaucher disease in patients with Splenomegaly and/or Thrombocytopenia. AB - Gaucher disease (GD) is the most common lysosomal disorder resulting from deficient activity of the beta-glucosidase enzyme that causes accumulation of glucosylceramide in the macrophage-monocyte system. Notably, because of non specific symptoms and a lack of awareness, patients with GD experience long diagnostic delays. The aim of this study was to apply a diagnostic algorithm to identify GD type 1 among adults subjects referred to Italian haematology outpatient units because of splenomegaly and/or thrombocytopenia and, eventually, to estimate the prevalence of GD in this selected population. One hundred and ninety-six subjects (61 females, 135 males; mean age 47.8 +/- 18.2 years) have been enrolled in the study and tested for beta-glucosidase enzyme activity on dried blood spot (DBS). Seven of 196 patients have been diagnosed with GD, (5 females and 2 males) with mean age 31.8 +/- 8.2 years, with a prevalence of 3.6% (with a prevalence of 3.6% (I95% CI 1.4-7.2; 1/28 patients) in this population. These results show that the use of an appropriate diagnostic algorithm and a simple diagnostic method, such as DBS, are important tools to facilitate the diagnosis of a rare disease even for not disease-expert physicians. PMID- 26033456 TI - Second-order motion-compensated spin echo diffusion tensor imaging of the human heart. AB - PURPOSE: Myocardial microstructure has been challenging to probe in vivo. Spin echo-based diffusion-weighted sequences allow for single-shot acquisitions but are highly sensitive to cardiac motion. In this study, the use of second-order motion-compensated diffusion encoding was compared with first-order motion compensated diffusion-weighted imaging during systolic contraction of the heart. METHODS: First- and second-order motion-compensated diffusion encoding gradients were incorporated into a triggered single-shot spin echo sequence. The effect of contractile motion on the apparent diffusion coefficients and tensor orientations was investigated in vivo from basal to apical level of the heart. RESULTS: Second order motion compensation was found to increase the range of systolic trigger delays from 30%-55% to 15%-77% peak systole at the apex and from 25%-50% to 15% 79% peak systole at the base. Diffusion tensor analysis yielded more physiological transmural distributions when using second-order motion-compensated diffusion tensor imaging. CONCLUSION: Higher-order motion-compensated diffusion encoding decreases the sensitivity to cardiac motion, thereby enabling cardiac DTI over a wider range of time points during systolic contraction of the heart. PMID- 26033457 TI - Male burying beetles extend, not reduce, parental care duration when reproductive competition is high. AB - Male parents spend less time caring than females in many species with biparental care. The traditional explanation for this pattern is that males have lower confidence of parentage, so they desert earlier in favour of pursuing other mating opportunities. However, one recent alternative hypothesis is that prolonged male parental care might also evolve if staying to care actively improves paternity. If this is the case, an increase in reproductive competition should be associated with increased paternal care. To test this prediction, we manipulated the level of reproductive competition experienced by burying beetles, Nicrophorus vespilloides (Herbst, 1783). We found that caregiving males stayed for longer and mated more frequently with their partner when reproductive competition was greater. Reproductive productivity did not increase when males extended care. Our findings provide support for the increased paternity hypothesis. Extended duration of parental care may be a male tactic both protecting investment (in the current brood) and maximizing paternity (in subsequent brood(s) via female stored sperm) even if this fails to maximize current reproductive productivity and creates conflict of interest with their mate via costs associated with increased mating frequency. PMID- 26033458 TI - Implementing hospital-based baby boomer hepatitis C virus screening and linkage to care: Strategies, results, and costs. AB - BACKGROUND/OBJECTIVE: The US Preventive Services Task Force recommends 1-time hepatitis C virus (HCV) screening of all baby boomers (born 1945-1965). However, little is known about optimal ways to implement HCV screening, counseling, and linkage to care. We developed strategies following approaches used for HIV to implement baby boomer HCV screening in a hospital setting and report results as well as costs. DESIGN/PATIENTS: Prospective cohort of 6140 baby boomers admitted to a safety-net hospital in South Texas from December 1, 2012 to January 31, 2014 and followed to December 10, 2014. PROCEDURES/MEASUREMENTS: The HCV screening program included clinician/staff education, electronic medical record algorithm for eligibility and order entry, opt-out consent, anti-HCV antibody test with reflex HCV RNA, personalized inpatient counseling, and outpatient case management. Outcomes were anti-HCV antibody-positive and HCV RNA-positive results. RESULTS: Of 3168 eligible patients, 240 (7.6%) were anti-HCV positive, which was more likely (P < 0.05) for younger age, men, and uninsured. Of 214 (89.2%) patients tested for HCV RNA, 134 (4.2% of all screened) were positive (chronic HCV). Among patients with chronic HCV, 129 (96.3%) were counseled, 108 (80.6%) received follow-up primary care, and 52 (38.8%) received hepatology care. Five patients initiated anti-HCV therapy. Total costs for start-up and implementation for 14 months were $286,482. CONCLUSIONS: This inpatient HCV screening program diagnosed chronic HCV infection in 4.2% of tested patients and linked >80% to follow-up care. Yet access to therapy is challenging for largely uninsured populations, and most programmatic costs of the program are not currently covered. PMID- 26033459 TI - Does Intra-articular Platelet-Rich Plasma Injection Provide Clinically Superior Outcomes Compared With Other Therapies in the Treatment of Knee Osteoarthritis? A Systematic Review of Overlapping Meta-analyses. AB - PURPOSE: The aims of this study were (1) to perform a systematic review of meta analyses evaluating platelet-rich plasma (PRP) injection in the treatment of knee joint cartilage degenerative pathology, (2) to provide a framework for analysis and interpretation of the best available evidence to provide recommendations for use (or lack thereof) of PRP in the setting of knee osteoarthritis (OA), and (3) to identify literature gaps where continued investigation would be suggested. METHODS: Literature searches were performed for meta-analyses examining use of PRP versus corticosteroids, hyaluronic acid, oral nonsteroidal anti-inflammatory drugs, or placebo. Clinical data were extracted, and meta-analysis quality was assessed. The Jadad algorithm was applied to determine meta-analyses that provided the highest level of evidence. RESULTS: Three meta-analyses met the eligibility criteria and ranged in quality from Level II to Level IV evidence. All studies compared outcomes of treatment with intra-articular platelet-rich plasma (IA-PRP) versus control (intra-articular hyaluronic acid or intra articular placebo). Use of PRP led to significant improvements in patient outcomes at 6 months after injection, and these improvements were seen starting at 2 months and were maintained for up to 12 months. It is unclear if the use of multiple PRP injections, the double-spinning technique, or activating agents leads to better outcomes. Patients with less radiographic evidence of arthritis benefit more from PRP treatment. The use of multiple PRP injections may increase the risk of self-limited local adverse reactions. After application of the Jadad algorithm, 3 concordant high-quality meta-analyses were selected and all showed that IA-PRP provided clinically relevant improvements in pain and function compared with the control treatment. CONCLUSIONS: IA-PRP is a viable treatment for knee OA and has the potential to lead to symptomatic relief for up to 12 months. There appears to be an increased risk of local adverse reactions after multiple PRP injections. IA-PRP offers better symptomatic relief to patients with early knee degenerative changes, and its use should be considered in patients with knee OA. LEVEL OF EVIDENCE: Level IV, systematic review of Level II through IV studies. PMID- 26033460 TI - Anatomic Single-Graft Anterior Cruciate Ligament Reconstruction Restores Rotational Stability: A Robotic Study in Cadaveric Knees. AB - PURPOSE: First, we aimed to investigate the ability of a single bone-patellar tendon-bone graft placed in the anatomic center of the femoral and tibial attachment sites to restore normal tibiofemoral compartment translations and tibial rotation. Second, we aimed to investigate what combination of anterior load and internal rotation torque applied during a pivot-shift test produces maximal anterior tibiofemoral subluxations. METHODS: We used a 6-df robotic simulator to test 10 fresh-frozen cadaveric specimens under anterior cruciate ligament (ACL)-intact, ACL-sectioned, and ACL-reconstructed conditions measuring anterior translations of the medial, central, and lateral tibiofemoral compartments and degrees of tibial rotation. Specimens were loaded under Lachman, anterior limit, and internal rotation conditions, as well as 3 different pivot shift conditions. RESULTS: On ACL sectioning, compartment translations in the Lachman and 3 pivot-shift tests increased significantly and were restored to ACL intact values after single-graft ACL reconstruction. In the pivot-shift tests, the single graft restored lateral and medial compartment translations (e.g., group 3, within 1.3 +/- 0.6 mm and 0.8 +/- 0.6 mm, respectively, of the ACL intact state and internal rotation within 0.7 degrees +/- 1.2 degrees ). Anterior subluxation of the medial compartment during pivot-shift loading was reduced when internal rotation torque was increased from 1 to 5 Nm (P < .0001). CONCLUSIONS: A single-graft ACL reconstruction performed at the central femoral and tibial ACL attachment sites restored anterior-posterior translation and tibial rotation motion limits. In addition, rotational knee stability as defined by tibiofemoral compartment translations was restored under all simulated pivot shift testing conditions. CLINICAL RELEVANCE: This study provides in vitro evidence to support the clinical use of single-graft ACL reconstructions in restoring tibiofemoral compartment translations. It also shows the advantage of describing ACL insufficiency in terms of medial and lateral compartment subluxations as compared with the common approach of describing changes in central tibial translations and rotations. PMID- 26033461 TI - Revision Hip Arthroscopy Indications and Outcomes: A Systematic Review. AB - PURPOSE: To identify the indications and outcomes in patients undergoing revision hip arthroscopy. METHODS: The electronic databases Embase, Medline, HealthStar, and PubMed were searched from 1946 to July 19, 2014. Two blinded reviewers searched, screened, and evaluated the data quality of the studies using the Methodological Index for Non-Randomized Studies scale. Data were abstracted in duplicate. Agreement and descriptive statistics are presented. RESULTS: Six studies were included (3 prospective case series and 3 retrospective chart reviews), with a total of 448 hips examined. The most common indications for revision hip arthroscopy included residual femoroacetabular impingement (FAI), labral tears, and chondral lesions. The mean interval between revision arthroscopy and the index procedure was 25.6 months. Overall, the modified Harris Hip Score improved by a mean of 33.6% (19.3 points) from the baseline score at 1 year follow-up. In 14.6% of patients, further surgical procedures were required, including re-revision hip arthroscopy (8.0%), total hip replacement (5.6%), and hip resurfacing (1.0%). Female patients more commonly underwent revision hip arthroscopy (59.7%). CONCLUSIONS: The current evidence examined in this review supports revision hip arthroscopy as a successful intervention to improve functional outcomes (modified Harris Hip Score) and relieve pain in patients with residual symptoms after primary FAI surgery, although the outcomes are inferior when compared with a matched cohort of patients undergoing primary hip arthroscopy for FAI. The main indication for revision is a candidate who has symptoms due to residual cam- or pincer-type deformity that was either unaddressed or under-resected during the index operation. However, it is important to consider that the studies included in this review are of low-quality evidence. Surgeons should consider incorporating a minimum 2-year follow-up for individuals after index hip-preservation surgery because revisions tended to occur within this time frame. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 26033462 TI - Outcomes of Open Versus Endoscopic Repair of Abductor Muscle Tears of the Hip: A Systematic Review. AB - PURPOSE: To compare the outcome of open versus endoscopic gluteal tendon repair. METHODS: An extensive review of PubMed was conducted by 2 independent reviewers for articles containing at least 1 of the following search terms: gluteus medius, gluteus medius tear, gluteus medius tendinopathy, gluteus medius repair, hip abductors, hip abductor tears, hip abductor repair, hip rotator cuff, hip rotator cuff repair, trochanteric bursa, trochanteric bursitis, trochanteric bursectomy, peritrochanteric procedures, peritrochanteric repair, and peritrochanteric arthroscopy. This yielded 313 articles. Of these articles, 7 satisfied the following inclusion criteria: description of an open or endoscopic gluteal repair with outcomes consisting of patient-reported outcome scores, patient satisfaction, strength scores, pain scores, and complications. RESULTS: Three studies on open gluteal repairs and 4 on endoscopic gluteal repairs met the inclusion criteria. In total, there were 127 patients who underwent open procedures and 40 patients who underwent endoscopic procedures. Of the 40 patients who underwent endoscopic procedures, 15 had concomitant intra-articular procedures documented, as compared with 0 in the open group. The modified Harris Hip Score was common to 1 study on open repairs and 3 studies on endoscopic repairs. The scores were similar for follow-up periods of 1 and 2 years. Visual analog pain scale scores were reported in 1 study on open gluteal repairs and 1 study on endoscopic repairs and were similar between the 2 studies. Improvement in abductor strength was also similarly reported in selected studies between the 2 groups. The only difference between the 2 groups was the reported incidence of complications, which was higher in the open group. CONCLUSIONS: Open and endoscopic gluteal repairs have similar patient-reported outcome scores, pain scores, and improvement in abduction strength. Open techniques have a higher reported complication rate. Randomized studies of sufficient numbers of patients are required to ultimately determine if one technique produces superior patient outcomes over the other. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 26033463 TI - The Effect of Traction Force and Hip Abduction Angle on Pudendal Nerve Compression in Hip Arthroscopy: A Cadaveric Model. AB - PURPOSE: To investigate the site of pudendal nerve compression and the relation between traction force and abduction angle regarding pressure levels at setup for hip arthroscopy. METHODS: A total of 17 hips from 9 fresh-frozen cadavers (6 male and 3 female cadavers) were used. The pudendal nerves were dissected, and 3 FlexiForce force sensors (Tekscan, Boston, MA) were implanted on the pudendal nerve where the inferior rectal nerve, perineal nerve, and dorsal nerve of the clitoris/penis emerge. A custom-made traction table in a supine position was used with a padded perineal post of 9 cm. Recordings were made at 0, 10, 20, 30, and 40 kg of traction at varying hip abduction angles of 0 degrees , 15 degrees , 30 degrees , and 45 degrees . RESULTS: The tuber ischiadicum (perineal nerve) and genital region (dorsal nerve of penis/clitoris) had statistically higher pressure values when compared with the pudendal canal (inferior rectal nerve) (P < .05). There was a significant increase in forces acting on the pudendal nerve with increasing application of 0 to 40 kg of traction in steps of 10 kg, with the exception of the pudendal canal sensor and reading of the perineal nerve sensor at 45 degrees of hip abduction (P < .004 with Bonferroni correction for significant values). On the contrary, hip abduction angle had no statistically significant effect on pudendal nerve compression. (All specific P values with Bonferroni correction were greater than .003.) CONCLUSIONS: To avoid nerve palsy completely, the etiopathogenesis of compressive neuropathy should be identified. The location for compression and relation between different traction positions and forces are clarified in this study. This information can be used for further research and prevention. CLINICAL RELEVANCE: This study adds objective data on the etiopathogenesis of pudendal nerve compression, which potentially contributes to prevention of pudendal nerve palsy as a common complication of hip arthroscopy. PMID- 26033464 TI - Message from the president of the Japanese Society for Apheresis. PMID- 26033467 TI - Leishmania infantum trypanothione reductase is a promiscuous enzyme carrying an NADPH:O2 oxidoreductase activity shared by glutathione reductase. AB - BACKGROUND: Leishmania infantum is a protozoan of the trypanosomatid family causing visceral leishmaniasis. Leishmania parasites are transmitted by the bite of phlebotomine sand flies to the human host and are phagocyted by macrophages. The parasites synthesize N1-N8-bis(glutationyl)-spermidine (trypanothione, TS2), which furnishes electrons to the tryparedoxin-tryparedoxin peroxidase couple to reduce the reactive oxygen species produced by macrophages. Trypanothione is kept reduced by trypanothione reductase (TR), a FAD-containing enzyme essential for parasite survival. METHODS: The enzymatic activity has been studied by stopped flow, absorption spectroscopy, and amperometric measurements. RESULTS: The study reported here demonstrates that the steady-state parameters change as a function of the order of substrates addition to the TR-containing solution. In particular, when the reaction is carried out by adding NADPH to a solution containing the enzyme and trypanothione, the KM for NADPH decreases six times compared to the value obtained by adding TS2 as last reagent to start the reaction (1.9 vs. 12MUM). More importantly, we demonstrate that TR is able to catalyze the oxidation of NADPH also in the absence of trypanothione. Thus, TR catalyzes the reduction of O2 to water through the sequential formation of C(4a) (hydro)peroxyflavin and sulfenic acid intermediates. This NADPH:O2 oxidoreductase activity is shared by Saccharomyces cerevisiae glutathione reductase (GR). CONCLUSIONS: TR and GR, in the absence of their physiological substrates, may catalyze the electron transfer reaction from NADPH to molecular oxygen to yield water. GENERAL SIGNIFICANCE: TR and GR are promiscuous enzymes. PMID- 26033468 TI - Assessing electronic health record systems in emergency departments: Using a decision analytic Bayesian model. AB - In the last decade, health providers have implemented information systems to improve accuracy in medical diagnosis and decision-making. This article evaluates the impact of an electronic health record on emergency department physicians' diagnosis and admission decisions. A decision analytic approach using a decision tree was constructed to model the admission decision process to assess the added value of medical information retrieved from the electronic health record. Using a Bayesian statistical model, this method was evaluated on two coronary artery disease scenarios. The results show that the cases of coronary artery disease were better diagnosed when the electronic health record was consulted and led to more informed admission decisions. Furthermore, the value of medical information required for a specific admission decision in emergency departments could be quantified. The findings support the notion that physicians and patient healthcare can benefit from implementing electronic health record systems in emergency departments. PMID- 26033469 TI - Detection of fetal copy number variants by non-invasive prenatal testing for common aneuploidies. AB - OBJECTIVE: To evaluate the clinical performance of non-invasive prenatal testing (NIPT) in detecting fetal copy number variants (CNVs). METHODS: NIPT of cell-free fetal DNA was performed retrospectively, using stored maternal plasma, at an average gestational age of 21.1 weeks in 117 pregnant women who had previously undergone invasive prenatal testing for chromosome microarray analysis (CMA). Among the fetal samples tested by CMA, 18 had positive results (CNVs > 1 megabase (Mb)) and 99 had negative results (CNVs < 1 Mb or without CNVs detected). The results of NIPT and CMA were then compared. RESULTS: In the 11 CMA-positive samples with CNVs > 5 Mb, the detection rate of CNVs was 90.9%; the one case missed by NIPT had a fetal fraction of 4.7%. For the other seven CMA-positive samples with CNVs < 5 Mb, the detection rate was 14.3%; only one case with a 2.82 Mb duplication was detected, with a fetal fraction of 26.7%. For 35.7% (5/14) of CNVs detected by both NIPT and CMA, the differences in fragment length were within +/- 1 Mb. In this study, the overall sensitivity and specificity of NIPT for detecting CNVs > 1 Mb were 61.1% and 95.0%, respectively, with a false positive rate of 5.0%. CONCLUSIONS: Our results demonstrate that NIPT for common aneuploidies can detect fetal CNVs > 5 Mb with high sensitivity, provided that fetal fraction is high enough, without increasing sequencing depth. The detection power of NIPT is determined mostly by fetal fraction and CNV size. A positive NIPT screening result for CNVs must be interpreted with caution and validated by additional diagnostic study. PMID- 26033470 TI - Outcomes and prognostic factors in modern era management of major salivary gland cancer. AB - OBJECTIVES: There is a dearth of prospective evidence regarding cancer of the major salivary glands. Outcomes and management of major salivary gland are based largely on retrospective series spanning many decades and changes in surgical, radiation, imaging and systemic therapy strategies and technique. We sought to report contemporary patterns of relapse and prognostic factors for major salivary gland cancer. MATERIALS AND METHODS: 112 patients with major salivary gland cancers underwent resection with or without adjuvant therapy between January 1997 and September 2010. Outcomes were documented with follow-up until December 2014. Survival was calculated by the Kaplan-Meier method. Log-rank test and Cox proportional hazards regression were performed with locoregional control (LRC), distant control (DC) and overall survival (OS) as the primary outcome variables. RESULTS: Median follow-up was 55.1 months. Rates of LRC for stage I/II and III/IV at five years were 95.7% and 61.9% respectively. Rates of DC at five years for stage I/II and III/IV were 93% and 56.9% respectively. Multivariate analysis identified larger tumor size, clinical nerve involvement and in parotid cancers, advanced T stage, no adjuvant radiation, and older age at diagnosis to be associated with increased risk of locoregional recurrence (all p<0.05). Distant metastasis was associated with sublingual site, degree of clinical nerve involvement, high grade, tumor size and in parotid tumors additionally deep lobe involvement on multivariate analysis (all p<0.05). CONCLUSION: Several prognostic factors were identified that may help guide decisions regarding adjuvant therapy. DM remains a significant concern in the management of this disease. PMID- 26033471 TI - Soft tissue metastasis in p16-positive oropharynx carcinoma: Prevalence and association with distant metastasis. AB - BACKGROUND: Ungraded extracapsular spread (ECS) has been found non-prognostic in p16-positive, surgically-treated oropharynx squamous cell carcinoma (OPSCC). However, soft tissue metastasis (STM), the highest ECS grade, is reported prognostic. Our study's objective is to explore STM relative to distant metastasis (DM), the most frequent recurrence site in surgically-treated p16 positive OPSCC. METHODS: Primary p16-positive OPSCC patients undergoing transoral surgery (TOS) and neck dissections were identified from a prospectively-assembled database. DM and regional recurrence (RR) rates, and DM-free survival (DMFS) were compared in pN+patients without STM (group I) and with STM (group II). RESULTS: Of 222 patients, 202 had pN+disease: 147 (73%) in group I and 55 (27%) in group II. The DM rate was 6.7% (n=15/222) overall. The DM rates were 4% (n=6/147) vs. 16.4% (n=9/55), RR rates were 2% (n=3) vs. 5% (n=3), and 5-year DMFS rates were 94.8% vs. 82.4%, in groups I and II respectively. STM was significantly associated with poorer DMFS (HR=4.6, 95% CI: 1.65, 13.03, p=0.004), an observation driven by its effect in the T3-T4 and not the T1-T2 subset. Amongst patients receiving adjuvant therapy, STM's association with poorer DMFS was lost in multivariable analysis; high T-classification, however, remained significant (HR=5.16, 95% CI: 1.43, 18.52, p=0.012). Five-year DMFS for STM patients was 82.2% in chemoradiation (37% T3-T4) vs. 85.6% in radiation (35% T3-T4) group. CONCLUSIONS: STM was significantly associated with DM and DMFS, but only in the T3-T4, not T1-T2 subset; no significant association was seen with RR. In patients receiving adjuvant therapy, only high T-classification was associated with DMFS, not STM. Chemoradiation used as adjuvant therapy was not associated with better DMFS in STM patients for any T-classification. PMID- 26033472 TI - Belgian multicenter experience with intestinal transplantation. AB - Intestinal transplantation (ITx) has evolved from an experimental procedure toward a clinical reality but remains a challenging procedure. The aim of this survey was to analyze the multicenter Belgian ITx experience. From 1999 to 2014, 24 ITx in 23 patients were performed in Belgium, divided over five centers. Median recipient age was 38 years (8 months-57 years); male/female ratio was 13/10; six were children; and 17 adults. Intestinal failure was related to intestinal ischemia (n = 5), volvulus (n = 5), splanchnic thrombosis (n = 4), Crohn (n = 2), pseudo-obstruction (n = 2), microvillus inclusion (n = 2), Churg Strauss (n = 1), necrotizing enterocolitis (n = 1), intestinal atresia (n = 1), and chronic rejection (n = 1). Graft type was isolated ITx (n = 9), combined liver-ITx (n = 11) and multivisceralTx (n = 4). One was a living donor-related transplantation and five patients received simultaneously a kidney graft. Early acute rejection occurred in 8; late acute rejection in 4; and chronic rejection in 2. Two patients developed a post-transplant lymphoproliferative disease. Nine patients have died. Among 14 survivors at last follow-up, 11 have been transplanted for more than 1 year. None of the latter has developed renal failure, and all were nutritionally independent with a Karnofsky score > 90%. One /five-year patient and graft survivals were 71.1%, 62.8%, 58.7% and 53.1%, respectively. Based on this experience, ITx has come of age in Belgium as a lifesaving and potentially quality of life restoring therapy. PMID- 26033473 TI - Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE). AB - Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression, and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1h every day. Allowing only 1h every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioral changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease. PMID- 26033474 TI - Angiopoietin-like 4: A double-edged sword in atherosclerosis and ischemic stroke? AB - Ischemic stroke is one of the leading causes of death in the world, and thus is a major public health concern. Atherosclerosis, also known as atherogenesis, is a crucial risk factor for cerebral ischemia, yet how it develops remains largely unknown. It has been found, however, that angiopoietin-like protein 4 (ANGPTL4), a protein expressed in vascular endothelial cells, plays a role in the pathophysiology of atherosclerosis and may therefore be involved in ischemic stroke. ANGPTL4 activity is associated with endothelial cell integrity, inflammation, oxidative stress, and lipid metabolism. ANGPTL4 also serves as a potent inhibitor of the lipoprotein lipase, and may inhibit atherogenesis via regulating inflammatory signaling and lipid metabolism. In addition, ANGPTL4 plays a role in the regulation of oxidative stress. However, there currently exists a controversy on the role of ANGPTL4 in endothelial cells. Some studies indicate that ANGPTL4 can protect the integrity of endothelial cells, while others have shown that it can be destructive to the endothelium, thereby leading to the initiation of atherosclerosis. Thus, the effects of ANGPTL4 on development of atherosclerosis and thereby ischemic stroke, are undefined. Further research is needed to better understand ANGPTL4-mediated signaling pathways in endothelial function and to determine its potentials as therapeutic target for atherosclerosis and ischemic stroke. PMID- 26033475 TI - Discrepancies between direct catheter and echocardiography-based values in aortic stenosis. AB - OBJECTIVES: The goal of this article is to examine the correlation of catheter (cath) based and echocardiographic assessment of aortic stenosis (AS) in a community-based academic hospital setting, particularly in the degree that decision to refer for surgery is altered. BACKGROUND: Current guidelines discourage AS evaluation by invasive pressure measurement if echocardiography (echo) is adequate, but several studies show sizable differences between echo and cardiac catheterization lab (CCL) measurements. We examine this correlation using high quality CCL techniques. METHODS: Sequential patients with suspected AS by echo (n = 40) aged 61-94 underwent catheterization with pressure gradients via left ventricular pressure wire and ascending aorta catheter. The echos leading to the catheterization were independently reviewed by an expert panel to assess the quality of community-based readings. RESULTS: CCL changed assessment of severity of aortic valve area (AVA) by more than 0.3 cm(2) in 25% and 0.5 cm(2) in 8%. Values changed to over or under the surgical threshold of AVA < 1 cm(2) in 30% of the patients. Pearson correlation of 0.35 between measurements of AVA by echo and CCL is lower than earlier studies, which often reported correlation values of 0.90 or greater. Echo expert reviews provided minimal improvement in discrepancies (Pearson correlation of 0.46), suggesting quality of initial interpretation was not the issue. CONCLUSIONS: Cath-echo correlation of AS severity is lower in contemporaneous practice than previously assumed. This can alter the decision for aortic valve replacement. Sole reliance on echo-derived assessment of AS may at times be problematic. PMID- 26033476 TI - EphB4 Expressing Stromal Cells Exhibit an Enhanced Capacity for Hematopoietic Stem Cell Maintenance. AB - The tyrosine kinase receptor, EphB4, mediates cross-talk between stromal and hematopoietic populations during bone remodeling, fracture repair and arthritis, through its interactions with the ligand, ephrin-B2. This study demonstrated that transgenic EphB4 mice (EphB4 Tg), over-expressing EphB4 under the control of collagen type-1 promoter, exhibited higher frequencies of osteogenic cells and hematopoietic stem/progenitor cells (HSC), correlating with a higher frequency of long-term culture-initiating cells (LTC-IC), compared with wild type (WT) mice. EphB4 Tg stromal feeder layers displayed a greater capacity to support LTC-IC in vitro, where blocking EphB4/ephrin-B2 interactions decreased LTC-IC output. Similarly, short hairpin RNA-mediated EphB4 knockdown in human bone marrow stromal cells reduced their ability to support high ephrin-B2 expressing CD34(+) HSC in LTC-IC cultures. Notably, irradiated EphB4 Tg mouse recipients displayed enhanced bone marrow reconstitution capacity and enhanced homing efficiency of transplanted donor hematopoietic stem/progenitor cells relative to WT controls. Studies examining the expression of hematopoietic supportive factors produced by stromal cells indicated that CXCL12, Angiopoietin-1, IL-6, FLT-3 ligand, and osteopontin expression were more highly expressed in EphB4 Tg stromal cells compared with WT controls. These findings indicate that EphB4 facilitates stromal mediated support of hematopoiesis, and constitute a novel component of the HSC niche. PMID- 26033477 TI - Indirect activation elicits strong correlations between light and electrical responses in ON but not OFF retinal ganglion cells. AB - KEY POINTS: To improve the quality of vision elicited by retinal prosthetics, elicited neural activity should resemble physiological signalling patterns; here, we hypothesized that electric stimulation that activates the synaptic circuitry of the retina would lead to closer matches than that which activates ganglion cells directly. We evaluated this hypothesis by comparing light and electrical responses in different types of ganglion cells. In contrast to the similarity in their light responses, electrical responses in ON and OFF cells of the same type were quite distinct. Further, electrical and light responses in the same cell were much better correlated in ON vs. OFF ganglion cells. Stimuli that activated photoreceptors yielded better correlations than those which activated bipolar cells. Our results suggest that the closer match to physiology in the ON signal transmitted to the brain may help to explain preferential reports of 'bright' phosphenes during earlier clinical trials. ABSTRACT: To improve the efficacy of microelectronic retinal prosthetics it will be necessary to better understand the response of retinal neurons to electric stimulation. While stimulation that directly activates ganglion cells generally has the lowest threshold, the similarity in responsiveness across cells makes it extremely difficult for such an approach to re-create cell-type specific patterns of neural activity that arise normally in the healthy retina. In contrast, stimulation that activates neurons presynaptic to ganglion cells utilizes at least some of the existing retinal circuitry and therefore is thought to produce neural activity that better matches physiological signalling. Surprisingly, the actual benefit(s) of this approach remain unsubstantiated. Here, we recorded from ganglion cells in the rabbit retinal explant in response to electrical stimuli that activated the network. Targeted cells were first classified into known types via light responses so that the consistency of electrical responses within individual types could be evaluated. Both transient and sustained ON ganglion cells exhibited highly consistent electrical response patterns which were distinct from one another. Further, properties of the response (interspike interval, latency, peak firing rate, and spike count) in a given cell were well correlated to the corresponding properties of the light response for that same cell. Electric responses in OFF ganglion cells formed two groups, distinct from ON groups, and the correlation levels between electric and light responses were much weaker. The closer match in ON pathway responses may help to explain some preferential reporting of bright stimuli during psychophysical testing. PMID- 26033478 TI - Fear responses to safety cues in anxious adolescents: Preliminary evidence for atypical age-associated trajectories of functional neural circuits. AB - Adolescent anxiety is common and impairing and often persists into adulthood. There is growing evidence that adult anxiety is characterized by abnormal fear responses to threat and safety cues, along with perturbations in fear-related neural circuits. Although some of this work has been extended to adolescents, with promising results, it is not yet clear whether changes in these circuits across developmental age varies between anxious and non-anxious adolescents. Here we used fMRI to examine how age modulates neural responses as adolescents are exposed to threat and safety cues. Participants were 15 anxious and 11 non anxious adolescents (age 12-17) who completed a fear conditioning paradigm. The paradigm incorporated a threat cue comprising a neutral face which was paired with a fearful, screaming face, a safety cue comprising a different neutral face, and a control stimulus. Across the whole sample, neural activation to the threat cue (relative to the control cue) correlated positively with age in a number of regions, including the dorsal anterior cingulate and bilateral dorsolateral prefrontal cortex (PFC). However, neural activation to the safety cue (relative to the control cue) was modulated differently by age in the two groups: a more positive association between activation and age was observed in the control group compared to the anxious group in various regions including medial and dorsolateral PFC, anterior insula, and amygdala. These findings suggest that maturation of the neural substrates of fear responses to safety cues may be perturbed in anxious adolescents, potentially contributing to the emergence and maintenance of anxiety disorders in adulthood. PMID- 26033479 TI - Alantolactone induces G1 phase arrest and apoptosis of multiple myeloma cells and overcomes bortezomib resistance. AB - Several sesquiterpene lactones have been extracted and demonstrated to exert various pharmacological functions in a variety of cancers. Here, we investigated anti-tumor effect of alantolactone, an allergenic sesquiterpene lactone, on human multiple myeloma (MM) and showed alantolactone inhibited growth of MM cells, both in the presence or absence of bone marrow (BM)-derived stromal cells (HS-5), and subsequent G1 phase arrest, and apoptosis as demonstrated by increased Annexin V/7-AAD binding, caspase-3 or caspase-9 activation and down-modulation of activation of extracellular signal-regulated kinases 1/2. In addition, alantolactone reduced the secretion of MM survival and growth-related cytokines, vascular endothelial growth factor, from MM cells or HS-5 cells, and inhibited cytokine-induced osteoclastogenesis. Notably, alantolactone also inhibited cell proliferation in bortezomib-resistant MM cells. Taken together, alantolactone exerted anti-tumor effect on MM by suppressing cell proliferation, triggering apoptosis, partly damaging the BM microenvironment and overcoming proteasome inhibitor resistance, suggesting alantolactone may be a novel therapeutic approach for the treatment of human MM. PMID- 26033480 TI - Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells. AB - Inflammation plays a pivotal role in modulating the radiation responsiveness of tumors. We determined that an inflammation response prior to irradiation contributes to radiotherapy resistance in non-small cell lung cancer (NSCLC) cells. In the clonogenic survival assay, activation of the inflammation response by lipopolysaccharide (LPS) decreased the degree of radiosensitivity in NCI-H460 cells (relatively radiosensitive cells), but had no effect in A549 cells (relatively radioresistant cells). LPS-induced radioresistance of NCI-H460 cells was also confirmed with a xenograft mouse model. The radioresistant effect observed in NCI-H460 cells was correlated with inhibition of apoptotic cell death due to reduced Caspase 3/7 activity. Moreover, we found that the levels of reactive oxygen species (ROS) were synergistically elevated in NCI-H460 cells by treatment with LPS and radiation. Increased ROS generation negatively affected the activity of protein phosphatase 1 (PP1). Decreased PP1 activity did not lead to Bad dephosphorylation, consequently resulting in the inhibition of irradiation induced mitochondrial membrane potential loss and apoptosis. We confirmed that pre-treatment with a PP1 activator and LPS sensitized NCI-H460 cells to radiation. Taken together, our findings provided evidence that PP1 activity is critical for radiosensitization in NSCLC cells and PP1 activators can serve as promising radiosensitizers to improve therapeutic efficacy. PMID- 26033481 TI - Solving the ecological puzzle of mycorrhizal associations using data from annotated collections and environmental samples - an example of saddle fungi. AB - The relation between ecological and genetic divergence of Helvella species (saddle fungi) has been perplexing. While a few species have been clearly demonstrated to be ectomycorrhizal fungi, ecological roles of many other species have been controversial, alternately considered as either saprotrophic or mycorrhizal. We applied SATe to build an inclusive deoxyribonucleic acid sequence alignment for the internal transcribed spacers (ITS) of annotated Helvella species and related environmental sequences. Phylogenetic informativeness of ITS and its regions were assessed using PhyDesign. Mycorrhizal lineages present a diversity of ecology, host type and geographic distribution. In two Helvella clades, no Helvella ITS sequences were recovered from root tips. Inclusion of environmental sequences in the ITS phylogeny from these sequences has the potential to link these data and reveal Helvella ecology. This study can serve as a model for revealing the diversity of relationships between unculturable fungi and their potential plant hosts. How non-mycorrhizal life styles within Helvella evolved will require expanded metagenomic investigation of soil and other environmental samples along with study of Helvella genomes. PMID- 26033482 TI - Transanal total mesocolic excision (taTME) as part of ileoanal pouch formation in ulcerative colitis--first report of a case. PMID- 26033483 TI - Comparison between conventional and endoscopic injection in aluminum potassium tannic acid sclerosing therapy. PMID- 26033484 TI - Facile Synthesis of Functionalized Carbene Metal Complexes from Coordinated Isonitriles. AB - The scope and limitations of the isonitrile-based NHC template synthesis were investigated with a series of precursors containing a nucleophilic amine in combination with tethered electrophiles. In the case of alkynes and phosphonic esters as electrophiles no ring closure was observed and new functionalized NAC gold complexes were obtained. By the use of unsaturated esters and phosphonic esters as Michael acceptors in the amine precursors, ester-modified gold and palladium NHC complexes were accessible in high efficiency. PMID- 26033485 TI - Information about foregone rewards impedes dynamic decision-making in older adults. AB - "Making an informed decision" implies that more information leads to better decisions, yet it may be the case that additional information biases decisions in a systematic and sometimes detrimental manner. In the present study, we examined the effect of additional information on older adults' decision-making using a task for which available rewards were dependent on the participant's recent pattern of choices. The optimal strategy was to forego the immediately rewarding option in favor of the option that yielded larger delayed reward. We found that providing information about true foregone rewards - the reward that would have been received had the participant chosen the other option - significantly reduced older adults' decision-making performance. However, false foregone rewards - foregone rewards manufactured to make the long-term option appear more immediately rewarding - led older adults to perform at a level equal to younger adults. We conclude that providing information about foregone rewards biases older adults toward immediate rewards at a greater rate than younger adults, leading to poorer older adult performance when immediate rewards and long-term rewards conflict, but intact performance when immediate rewards and long-term rewards appear to align. PMID- 26033486 TI - Complexation and Catenation in Aqueous Media Using a Self-Assembled Pd(II) Metallacyclic Receptor. AB - A M2L2 rectangular-shaped metallacycle, obtained by metal-directed self-assembly of a 2-(pyridin-4-ylmethyl)-2,7-diazapyrenium salt and [(en)Pd(NO3)2 (en=ethylenediamine), has been investigated as a molecular receptor for a wide range of aromatic substrates in water. Complexation and catenation of the receptor with selected mono- and polycyclic aromatic substrates produced 1:1 inclusion complexes and [2]catenanes in a highly efficient fashion, as determined by NMR and UV/Vis spectroscopic techniques, as well as single-crystal X-ray crystallography. Furthermore, the thermodynamic and kinetic features of the complexation processes have been analyzed for selected model guests. PMID- 26033488 TI - beta-Actin as a loading control: Less than 2 MUg of total protein should be loaded. AB - For the purpose of data normalization in Western blot analysis, journal editors and reviewers usually require authors to reprobe the Western blot membrane with a beta-actin-specific antibody after detecting the target protein. In most cases, however, beta-actin is overloaded, which results in a failure to detect differences in protein loading. In this study, we attempted to optimize the amount of protein loaded for beta-actin detection to permit suitable Western blot analysis data normalization. Our data suggest that less than 2 MUg of total protein should be loaded when beta-actin is used as a loading control. We also suggest avoiding reprobing the membrane with a beta-actin-specific antibody. PMID- 26033487 TI - Increased robustness of early embryogenesis through collective decision-making by key transcription factors. AB - BACKGROUND: Understanding the mechanisms by which hundreds of diverse cell types develop from a single mammalian zygote has been a central challenge of developmental biology. Conrad H. Waddington, in his metaphoric "epigenetic landscape" visualized the early embryogenesis as a hierarchy of lineage bifurcations. In each bifurcation, a single progenitor cell type produces two different cell lineages. The tristable dynamical systems are used to model the lineage bifurcations. It is also shown that a genetic circuit consisting of two auto-activating transcription factors (TFs) with cross inhibitions can form a tristable dynamical system. RESULTS: We used gene expression profiles of pre implantation mouse embryos at the single cell resolution to visualize the Waddington landscape of the early embryogenesis. For each lineage bifurcation we identified two clusters of TFs - rather than two single TFs as previously proposed - that had opposite expression patterns between the pair of bifurcated cell types. The regulatory circuitry among each pair of TF clusters resembled a genetic circuit of a pair of single TFs; it consisted of positive feedbacks among the TFs of the same cluster, and negative interactions among the members of the opposite clusters. Our analyses indicated that the tristable dynamical system of the two-cluster regulatory circuitry is more robust than the genetic circuit of two single TFs. CONCLUSIONS: We propose that a modular hierarchy of regulatory circuits, each consisting of two mutually inhibiting and auto-activating TF clusters, can form hierarchical lineage bifurcations with improved safeguarding of critical early embryogenesis against biological perturbations. Furthermore, our computationally fast framework for modeling and visualizing the epigenetic landscape can be used to obtain insights from experimental data of development at the single cell resolution. PMID- 26033489 TI - Low dose photodynamic-therapy induce immune escape of tumor cells in a HIF-1alpha dependent manner through PI3K/Akt pathway. AB - As a regulatory approved antitumor therapy, photodynamic therapy (PDT) shows poor effect in clinical application. The current study aimed at investigating the mechanism through which low-dose PDT affects the immune escape ability of Lewis lung carcinoma (LLC) cells. Our data show that low-dose PDT could increase HIF 1alpha expression through the activation of the PI3K/Akt pathway. Our results also show that low-dose PDT treatment can increase tumor growth rate in C57BL/6 mice, reducing the survival of tumor-bearing mice. Furthermore, low-dose PDT could increase regulatory T cells (Tregs) number, decrease the cytotoxic T lymphocytes (CTLs) number, and induce CTLs apoptosis in co-culture system in vitro. The immunosuppression caused by low dose PDT could be partially abolished by knocking down the hypoxia-inducible factor 1alpha (HIF-1alpha) and blocking the phosphatidylinositol 3-kinase (PI3K). Our results suggest that low dose PDT may enhance immune escape of LLC cells in a HIF-1alpha dependent manner through PI3K/Akt pathway. The present study thus offers a new insight on elucidating the mechanism whereby low dose PDT induces tumor progression and therapy-resistance, providing a novel approach for cancer immunotherapy. PMID- 26033490 TI - Transcriptional regulation of SLURP2, a psoriasis-associated gene, is under control of IL-22 in the skin: A special reference to the nested gene LYNX1. AB - A novel nicotinic acetylcholine (ACh) receptor (nAChR)-mediated transduction pathway, regulating keratinocyte function, has been elucidated in studies of secreted mammalian Ly6/urokinase plasminogen activator receptor-related protein (SLURP)-1 and -2. SLURPs are members of Ly6/neurotoxin superfamily (Ly6SF) of proteins containing the unique three-finger domain in their three-dimensional structure. Some endogenously expressed Ly6SF proteins (such as LYNX1, SLURP-1, and SLURP-2) modulate the function of nAChR, either as allosteric and/or orthosteric modulators, or as antagonists. Although the expression and functions of SLURP-1 and SLURP-2 in keratinocytes are well documented, the expression and the modes of action of LYNX1 in keratinocytes are unknown. Additionally, a particular hybrid transcript, LYNX1-SLURP2, which contains both LYNX1 and SLURP-2 sequences, with unknown function, has been reported. Furthermore, although SLURP2 is a gene strongly induced in psoriatic skin lesions, the mechanisms controlling SLURP2 expression are largely unknown. To better understand the function of nAChRs in keratinocytes, we investigated the expression profiles of LYNX1, LYNX1 SLURP-2, and SLURP-2 in keratinocytes under various inflammatory conditions. We found that keratinocytes express LYNX1 and SLURP2, but not LYNX1-SLURP2, at mRNA and protein levels. IL-22 treatment increased SLURP2 expression in keratinocytes, but this effect was completely abolished by IFN-gamma. Furthermore, the IL-22 induced up-regulation of SLURP2 was completely suppressed by the inhibitor or siRNA for STAT3, a major transcriptional factor downstream of IL-22. These findings provide new insights into the nAChR-mediated regulatory mechanism of SLURP-2 expression in keratinocytes. PMID- 26033491 TI - The activation of M2 muscarinic receptor inhibits cell growth and survival in human glioblastoma cancer stem cells. AB - The involvement of muscarinic receptors in cancer has been reported. Recently we have demonstrated that the activation of M2 muscarinic receptors, through arecaidine propargyl ester, arrests cell proliferation and induces apoptosis in primary and established glioblastoma cell lines. Considering the inability of conventional drugs to completely counteract the growth of glioblastoma cancer stem cells (GSCs), we have investigated the effect produced by arecaidine on GSC growth and survival. The expression of M2 receptors has been analyzed in GSC cell lines derived from human biopsies. Based on the M2 receptor expression levels, we have selected two gliolastoma cell lines (GB7 and GB8). In both cell lines the treatment with arecaidine decreased GCS cell growth. GB7 cells exhibited a time- and dose-dependent decrease of cell proliferation. Moreover arecaidine caused a reduced cell survival in particular in GB8 cell line. These effects appear to be mediated by M2 receptor activation as suggested by pharmacological experiments performed in the presence of M1 and M3 preferring antagonists (pirenzepine and 4 DAMP respectively) and M2/M4 antagonist methoctramine. M2 receptor silencing by siRNA has further confirmed that the inhibition of cell growth arecaidine-induced was mediated by the M2 receptor activation. These results suggest that the M2 receptors may represent a new interesting therapeutic tool to counteract glioblastoma cancer stem cell growth and survival. PMID- 26033492 TI - Identification of cholinergic chemosensory cells in mouse tracheal and laryngeal glandular ducts. AB - Specialized epithelial cells in the respiratory tract such as solitary chemosensory cells and brush cells sense the luminal content and initiate protective reflexes in response to the detection of potentially harmful substances. The majority of these cells are cholinergic and utilize the canonical taste signal transduction cascade to detect "bitter" substances such as bacterial quorum sensing molecules. Utilizing two different mouse strains reporting expression of choline acetyltransferase (ChAT), the synthesizing enzyme of acetylcholine (ACh), we detected cholinergic cells in the submucosal glands of the murine larynx and trachea. These cells were localized in the ciliated glandular ducts and were neither found in the collecting ducts nor in alveolar or tubular segments of the glands. ChAT expression in tracheal gland ducts was confirmed by in situ hybridization. The cholinergic duct cells expressed the brush cell marker proteins, villin and cytokeratin-18, and were immunoreactive for components of the taste signal transduction cascade (Galpha-gustducin, transient receptor potential melastatin-like subtype 5 channel = TRPM5, phospholipase C(beta2)), but not for carbonic anhydrase IV. Furthermore, these cells expressed the bitter taste receptor Tas2r131, as demonstrated utilizing an appropriate reporter mouse strain. Our study identified a previously unrecognized presumptive chemosensory cell type in the duct of the airway submucosal glands that likely utilizes ACh for paracrine signaling. We propose that these cells participate in infection-sensing mechanisms and initiate responses assisting bacterial clearance from the lower airways. PMID- 26033493 TI - Evaluation of the effect of MPL and delivery route on immunogenicity and protectivity of different formulations of FimH and MrpH from uropathogenic Escherichia coli and Proteus mirabilis in a UTI mouse model. AB - Urinary tract infections (UTIs) caused by Escherichia coli and Proteus mirabilis are an important cause of morbidity and with the high rate of relapse and spread of multi-drug resistant pathogens, pose a significant public health challenge worldwide. Lack of an efficacious commercial vaccine targeting both uropathogens makes development of a combined vaccine highly desirable. In this study the immunogenicity and protective efficacy of different formulations of FimH of UPEC, MrpH of P. mirabilis and their fusion protein (MrpH.FimH) subcutaneously administered with and without Monophosphoryl lipid A (MPL) adjuvant were evaluated. Our data showed that the subcutaneously administered proteins induced both serum and mucosal IgG, which MPL significantly improved developing a mixed Th1 and Th2 immune response. However, the preparations induced a higher systemic and mucosal IgG and IL-2 levels by this route compared to the intranasal. Immunization of mice with MrpH.FimH fusion with MPL or a mixture of FimH, MrpH and MPL conferred the highest protection of the bladder and kidneys when challenged with UPEC and P. mirabilis in a UTI mouse model. Therefore considering these results MrpH.FimH fusion with MPL administered subcutaneously or intranasally could be a promising vaccine candidate for elimination of UTIs caused by UPEC and P. mirabilis. PMID- 26033494 TI - Ozone promotes regeneration by regulating the inflammatory response in zebrafish. AB - Ozone is thought to advance wound healing by inhibiting inflammation, but the mechanism of this phenomenon has not been determined. Although the zebrafish is often used in regeneration experiments, there has been no report of zebrafish treated with ozonated water. We successfully established a zebrafish model of ozonated water treatment and demonstrate that ozonated water stimulates the regeneration of the zebrafish caudal fin, its mechanism, and time dependence. The growth rate of the caudal fin and the number of neutrophils migrating to the caudal fin wound after resection were higher in the experimental (ozonated) group than in the control group, preliminarily confirming that ozone-promoted regeneration is related to the stimulation of an early inflammatory response by ozone. Ozone modulated the expression of tumor necrosis factor-alpha (TNF-alpha) in two ways by regulating interleukin 10 (IL-10) expression. Therefore, ozone promotes tissue regeneration by regulating the inflammatory pathways. This effect of ozone in an experimental zebrafish model is demonstrated for the first time, confirming its promotion of wound healing and the mechanism of its effect in tissue regeneration. These results will open up new directions for ozone and regeneration research. PMID- 26033495 TI - Assessing the three-dimensional collagen network in soft tissues using contrast agents and high resolution micro-CT: Application to porcine iliac veins. AB - The assessment of the three-dimensional architecture of collagen fibers inside vessel walls constitutes one of the bases for building structural models for the description of the mechanical behavior of these tissues. Multiphoton microscopy allows for such observations, but is limited to volumes of around a thousand of microns. In the present work, we propose to observe the collagenous network of vascular tissues using micro-CT. To get a contrast, three staining solutions (phosphotungstic acid, phosphomolybdic acid and iodine potassium iodide) were tested. Two of these stains were showed to lead to similar results and to a satisfactory contrast within the tissue. A detailed observation of a small porcine iliac vein sample allowed assessing the collagen fibers orientations within the medial and adventitial layers of the vein. The vasa vasorum network, which is present inside the adventitia of the vein, was also observed. Finally, the demonstrated micro-CT staining technique for the three-dimensional observation of thin soft tissues samples, like vein walls, contributes to the assessment of their structure at different scales while keeping a global overview of the tissue. PMID- 26033497 TI - Expression analysis of HSP70 in the testis of Octopus tankahkeei under thermal stress. AB - The gene encoding heat shock protein 70 (HSP70) was identified in Octopus tankahkeei by homologous cloning and rapid amplification of cDNA ends (RACE). The full-length cDNA (2471 bp) consists of a 5'-untranslated region (UTR) (89 bp), a 3'-UTR (426 bp), and an open reading frame (1956 bp) that encodes 651 amino acid residues with a predicted molecular mass of 71.8 kDa and an isoelectric point of 5.34. Based on the amino acid sequence analysis and multiple sequence alignment, this cDNA is a member of cytoplasmic hsp70 subfamily of the hsp70 family and was designated as ot-hsp70. Tissue expression analysis showed that HSP70 expression is highest in the testes when all examined organs were compared. Immunohistochemistry analysis, together with hematoxylin-eosin staining, revealed that the HSP70 protein was expressed in all spermatogenic cells, but not in fibroblasts. In addition, O. tankahkeei were heat challenged by exposure to 32 degrees C seawater for 2 h, then returned to 13 degrees C for various recovery time (0-24 h). Relative expression of ot-hsp70 mRNA in the testes was measured at different time points post-challenge by quantitative real-time PCR. A clear time dependent mRNA expression of ot-hsp70 after thermal stress indicates that the HSP70 gene is inducible. Ultrastructural changes of the heat-stressed testis were observed by transmission electron microscopy. We suggest that HSP70 plays an important role in spermatogenesis and testis protection against thermal stress in O. tankahkeei. PMID- 26033498 TI - Structural genomics for drug design against the pathogen Coxiella burnetii. AB - Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high-throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure-based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25-fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. PMID- 26033499 TI - Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. AB - BACKGROUND: The objective of this study was to determine the efficacy and safety of locoregional therapy (LRT) combined with arsenic trioxide (As2 O3 ) treatment in primary hepatocellular carcinoma (HCC) patients. METHODS: One hundred twenty five primary HCC patients were recruited for a randomized controlled study. Patients were randomly divided into group A (n = 61) and group B (n = 64). All patients received transarterial chemoembolization. Group A patients were given As2 O3 at 10 mg/d for 4 courses (21 days per course) with a 2-week interval between courses. Survival times, therapeutic responses, extrahepatic metastases, and adverse events were recorded. RESULTS: A better therapeutic response was found in group A patients, as shown by higher objective response rate (ORR) and clinical benefit rate (CBR) values in group A versus group B (ORR, 81.96% [95% confidence interval (CI), 72.32%-91.62%] vs 59.37% [95% CI, 47.34%-71.41%], chi(2) = 7.650, P < .05; CBR, 95.08% [95% CI, 89.66%-100.00%] vs 81.25% [95% CI, 71.69%-90.81%], chi(2) = 5.659, P < .05). There were fewer patients with extrahepatic metastases in group A versus group B (group A, 6 cases or 9.84% [95% CI, 2.36%-17.31%]; group B, 12 cases or 18.75% [95% CI, 9.19%-28.31%]). The survival rate for group A patients was significantly higher than that for group B patients (P < .05). No significant differences were found between the 2 groups in terms of hematology or digestive system, liver, or kidney dysfunction except for facial and limb edema. CONCLUSIONS: LRT combined with As2 O3 treatment prevents extrahepatic metastasis and prolongs the survival time for primary HCC patients. PMID- 26033500 TI - Reflecting on 'Health technology appraisal and the courts: accountability for reasonableness and the judicial model of procedural justice'. PMID- 26033501 TI - DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study. AB - AIMS: FOXL2 mutation has been consistently identified in adult granulosa cell tumours (A-GCTs). DICER1 mutations have been described predominantly in Sertoli Leydig cell tumours (SLCTs). The prognostic implication of these mutations remains uncertain, as moderately sized studies have yielded variable outcomes. Our aim was to determine the implications of DICER1 and FOXL2 mutations in 156 ovarian sex cord-stromal tumours (SCSTs). METHODS AND RESULTS: FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. DICER1 mutations in the RNase IIIb domain were found in six of 19 SLCTs, two of eight J GCTs, and one of 12 undifferentiated SCSTs (Und-SCSTs). Comparison of DICER1 mutated SLCTs with DICER1-non-mutated SLCTs showed that patient age at diagnosis was lower and oestrogen receptor expression was more frequent in DICER1-mutated tumours. With a median follow-up of 22 months, two of five DICER1-mutated SLCTs relapsed, in contrast to none of eight DICER1-non-mutated tumours. CONCLUSIONS: Our results suggest that, in contrast to FOXL2 mutations in A-GCT, DICER1 mutations in SLCT might be more useful for prognosis than for diagnosis. However, study of a larger cohort of patients is necessary to establish this. Identification of genetic alterations in SCST offers promising therapeutic options. PMID- 26033502 TI - Cancer of Unknown Primary origin in the genomic era: Elucidating the dark box of cancer. AB - Cancer of Unknown Primary (CUP) comprises a heterogeneous disease group with diagnosis of metastatic malignancy in the absence of an identifiable primary site after diagnostic work up. CUP may either resemble a specific primary tumor site sharing common clinicopathological characteristics and prognosis, or present as a distinct disease entity with undifferentiated pathological features, usually bearing dismal prognosis. Diagnosis and management have traditionally been based on clinicopathological characteristics and therapeutic strategies have been mainly empirical. In the last decade, the advent of massive gene sequencing and the advances in genomic technologies have shed light on the genomic landscape of CUP. Several gene panel tests are currently commercially available and are used in an effort to correlate the genomic characteristics of a specific CUP tumor to those of a known primary tumor, guiding thus therapeutic management. Nevertheless, these efforts are hampered by the rarity of CUP and the inability to validate the results of such tests due to the paucity of randomized clinical trials. In the current work, we provide an overview of CUP with emphasis on the impact of the genome sequencing technologies on diagnosis and management of these tumors. We also discuss potential implications of genomics for the future treatment of CUP and address the challenges of the implementation of these therapeutic strategies in routine clinical practice. PMID- 26033496 TI - Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. AB - Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2. PMID- 26033504 TI - Attrition Bias in Panel Data: A Sheep in Wolf's Clothing? A Case Study Based on the Mabel Survey. AB - This paper investigates the nature and consequences of sample attrition in a unique longitudinal survey of medical doctors. We describe the patterns of non response and examine if attrition affects the econometric analysis of medical labour market outcomes using the estimation of physician earnings equations as a case study. We compare the econometric gestimates obtained from a number of different modelling strategies, which are as follows: balanced versus unbalanced samples; an attrition model for panel data based on the classic sample selection model; and a recently developed copula-based selection model. Descriptive evidence shows that doctors who work longer hours, have lower years of experience, are overseas trained and have changed their work location are more likely to drop out. Our analysis suggests that the impact of attrition on inference about the earnings of general practitioners is small. For specialists, there appears to be some evidence for an economically significant bias. Finally, we discuss how the top-up samples in the Medicine in Australia: Balancing Employment and Life survey can be used to address the problem of panel attrition. PMID- 26033503 TI - Inpatient versus outpatient onsets of acute myocardial infarction. AB - BACKGROUND: There are few studies on patients suffering acute myocardial infarction (AMI) when already in hospital for other reasons; therefore, this study aimed to compare patients with in-hospital-onset AMI admitted for either medical or surgical reasons versus patients with outpatient-onset AMI. METHODS: Patients enrolled in the AMIS Plus registry from 2002 to 2014 were analyzed. The main endpoint was in-hospital mortality. RESULTS: Among 35,394 AMI patients, 356 (1%) had inpatient-onset AMI following hospital admission due to other pathologies (surgical 175, non-surgical 181). These patients were older (74 vs. 66 years; P<0.001), more often female (35% vs. 27%; P<0.001), had less frequently ST-elevation myocardial infarction (35.5% vs. 55.5%; P<0.001), but higher risk profiles: hypertension (83% vs. 62%; P<0.001), diabetes (28% vs. 20%; P=0.001), known coronary artery disease (54% vs. 35%; P<0.001), and more comorbidities (Charlson Comorbidity Index above 1 in 51% vs. 22%; P<0.001) than those with outpatient-onset AMI. Percutaneous coronary intervention was less frequently applied (OR 0.45; 95% CI 0.36-0.57), and they were less likely to be treated with aspirin (OR 0.43; 95% CI 0.37-0.59), P2Y12 blockers (OR 0.42; 0.34-0.52) or statins (OR 0.51; 95% CI 0.41-0.63). Crude mortality was higher (14.3% vs. 5.5%; P<0.001) and inpatient-onset AMI was an independent predictor of in-hospital mortality (OR 2.35; 95% CI 1.63-3.39; P<0.001). CONCLUSIONS: Patients with in hospital-onset AMI were at greater risk of death than those with outpatient-onset AMI. More work is needed to improve the identification of hospitalized patients at risk of AMI in order to provide the appropriate management. PMID- 26033505 TI - Libyan Thymus capitatus essential oil: antioxidant, antimicrobial, cytotoxic and colon pathogen adhesion-inhibition properties. AB - AIMS: In the present work, the Libyan wild-growing Thymus capitatus essential oil (EO) was evaluated for its biological properties. METHODS AND RESULTS: Carvacrol (68.19%) and thymol (12.29%) were found to be the main compounds of the oil. Antioxidant properties, determined by 2,2-diphenylpicrylhydrazyl (DPPH) assay, revealed that IC50 values were 119, 403 and 105 MUg ml(-1) for oil, thymol and carvacrol respectively. Microdilution method showed strong antibacterial and especially antifungal potential. Tetrazolium (MTT) colorimetric assay indicated moderate cytotoxicity towards human cell lines MRC-5, HCT 116 and HT-29 (IC50 = 30-150 MUg ml(-1)). In adhesion-inhibition assay oil and main compounds reduced adhesion of Escherichia coli and Listeria monocytogenes on colon cells HT-29 (51 and 39% of inhibition against L. monocytogenes and E. coli respectively). CONCLUSIONS: Essential oil of Th. capitatus showed moderate cytotoxic activity, together with excellent antimicrobial effect, in particular against fungi, and significant potential to reduce pathogen colonization in colon. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report that EO of Th. capitatus could protect against colonization of pathogens to colon epithelium. Thymus capitatus from Libya should be recognized as possible new source of natural antioxidants, antimicrobials as well as possible source of new chemotherapeutics. PMID- 26033506 TI - Antibiotic Prescription Practices of Pediatricians and Pediatric Residents in Hospital Care in Greece. AB - INTRODUCTION: The administration of antibiotics for the treatment of pediatric illnesses is common, reaching one third of pediatric patients. This paper aims to identify the antibiotic prescription practices of pediatricians and to explore the associations between prescribing practices and a series of socio-demographic and professional determinants in Greece. MATERIAL AND METHOD: A cross-sectional study was conducted in public hospitals providing secondary and tertiary pediatric care from January to July 2012. A self-administered questionnaire was developed and tested in a pilot study, focusing on respondents' characteristics, their practices and attitudes related to prescribing antibiotics in common childhood diseases, diagnostic uncertainty, and parental demand. Multivariate regression analysis was performed. RESULTS: In total, 275 physicians responded to the questionnaire (61% response rate). The majority of the physicians prescribed antibiotics empirically in possible group A streptococcus infections (56.9%) and implemented the "watchful waiting" approach in acute otitis media (65.5%); further, they did not feel diagnostic uncertainty (74%) and were not affected by parental demand (81%). Finally, when prescribing, they did not take into consideration the drug cost (64.4%). Gender, physicians' experience, and the type of hospital (specialized or general hospital) were identified as prognostic factors of prescribing practices. CONCLUSION: Our findings could provide decision makers with insights into how to manage physicians' prescription practices in order to reduce the high rates of antibiotic consumption that Greece is facing nowadays. PMID- 26033507 TI - Real-Time Ultrawide Field Image Evaluation of Retinopathy in a Diabetes Telemedicine Program. AB - OBJECTIVE: To evaluate the ability of trained nonphysician retinal imagers to perform diabetic retinopathy (DR) evaluation at the time of ultrawide field retinal (UWF) imaging in a teleophthalmology program. RESEARCH DESIGN AND METHODS: Clinic patients with diabetes received Joslin Vision Network protocol retinal imaging as part of their standard medical care. Retinal imagers evaluated UWF images for referable DR at the time of image capture. Training of the imagers included 4 h of standardized didactic lectures and 12 h of guided image review. Real-time evaluations were compared with standard masked gradings performed at a centralized reading center. RESULTS: A total of 3,978 eyes of 1,989 consecutive patients were imaged and evaluated. By reading center evaluation, 3,769 eyes (94.7%) were gradable for DR, 1,376 (36.5%) had DR, and 580 (15.3%) had referable DR. Compared with the reading center, real-time image evaluation had a sensitivity and specificity for identifying more than minimal DR of 0.95 (95% CI 0.94-0.97) and 0.84 (0.82-0.85), respectively, and 0.99 (0.97-1.00) and 0.76 (0.75-0.78), respectively, for detecting referable DR. Only three patients with referable DR were not identified by imager evaluation. CONCLUSIONS: Point-of-care evaluation of UWF images by nonphysician imagers following standardized acquisition and evaluation protocols within an established teleophthalmology program had good sensitivity and specificity for detection of DR and for identification of referable retinal disease. With immediate image evaluation, <0.1% of patients with referable DR would be missed, reading center image grading burden would be reduced by 60%, and patient feedback would be expedited. PMID- 26033508 TI - Seeing Is Believing: Using Skype to Improve Diabetes Outcomes in Youth. AB - OBJECTIVE: The objective of this study was to compare the relative effectiveness of two modes of delivering Behavioral Family Systems Therapy for Diabetes (BFST D) to improve adherence and glycemic control among adolescents with type 1 diabetes with suboptimal glycemic control (HbA(1c) >=9.0% [>=74.9 mmol/mol]): face to face in clinic (Clinic) and Internet videoconferencing (Skype) conditions. RESEARCH DESIGN AND METHODS: Adolescents aged 12 to 18 years and at least one adult caregiver were randomized to receive BFST-D via the Clinic or Skype condition. Participants completed up to 10 therapy sessions within a 12 week period. Changes in youth- and parent-reported adherence and glycemic control were compared before and after the intervention and at follow-up assessment. RESULTS: Using an intent-to-treat analytic approach, no significant between-group differences were identified between the before, after, and follow-up assessments. Groups were collapsed to examine the overall effects of BFST-D on adherence and glycemic control. Results identified that statistically significant improvements in adherence and glycemic control occurred from before to after the intervention; improvements were maintained at 3-month follow-up. CONCLUSIONS: Delivery of BFST D via Internet-based videoconferencing is viable for addressing nonadherence and suboptimal glycemic control in adolescents with type 1 diabetes, potentially reducing important barriers to care for youth and families. PMID- 26033509 TI - Cerebral White Matter Lesions as a Clinically Relevant Intermediate Target of Cerebrovascular Prevention. PMID- 26033510 TI - Latent cognitive effects from low-level polychlorinated biphenyl exposure in juvenile European starlings (Sturnus vulgaris). AB - Ecotoxicology research on polychlorinated biphenyl (PCB) mixtures has focused principally on short-term effects on reproduction, growth, and other physiological endpoints. Latent cognitive effects from early life exposure to low level PCBs were examined in an avian model, the European starling (Sturnus vulgaris). Thirty-six birds, divided equally among 4 treatment groups (control = 0 ug, low = 0.35 ug, intermediate = 0.70 ug, and high = 1.05 ug Aroclor 1254/g body weight), were dosed 1 d through 18 d posthatch, then tested 8 mo to 9 mo later in captivity in an analog to an open radial arm maze. Birds were subject to 4 sequential experiments: habituation, learning, cue selection, and memory. One half of the birds did not habituate to the test cage; however, this was not linked to a treatment group. Although 11 of the remaining 18 birds successfully learned, only 1 was from the high-dosed group. Control and low-dosed birds were among the only treatment groups to improve trial times throughout the learning experiment. High-dosed birds were slower and more error-prone than controls. Cue selection (spatial or color cues) and memory retention were not affected by prior PCB exposure. The results indicate that a reduction in spatial learning ability persists among birds exposed to Aroclor 1254 during development. This may have implications for migration ability, resource acquisition, and other behaviors relevant for fitness. PMID- 26033511 TI - pH Impedance vs. traditional pH monitoring in clinical practice: an outcome study. AB - BACKGROUND: The addition of impedance to 24-h pH monitoring has allowed detection of weakly acidic reflux, but the extent to which pH-impedance (pH-MII) monitoring improves outcomes is unknown. METHODS: This was a prospective observational study. Patients referred for pH or pH-MII monitoring completed a standardized questionnaire on improvement in the dominant symptom, their satisfaction, and treatment at 3 and 12 months after the test during a telephone interview. RESULTS: A total of 184 patients (mean age, 52 years, range, 19-82 years; 35 % with typical symptoms; and 89 % tested off therapy) completed pH (n = 92) or pH MII monitoring (n = 92) over a period of 15 months. The two arms were similar in terms of demographic, clinical, and endoscopic variables. Ten patients in the pH MII arm showed evidence of weakly acidic reflux disease. There was no difference in the percentage of patients in the pH and pH-MII monitoring arms who experienced improvement in their dominant symptom after 3 (58 vs. 63 %; p = 0.621) or 12 months (66 vs. 70 %; p = 0.234), and the same was true for patient satisfaction. There were also no between-group difference in the use of proton pump inhibitors (PPIs) after 3 (63 vs. 68.5 %; p = 0.437) or 12 months (47 vs. 60.5 %; p = 0.051). PPIs were prescribed more frequently after a positive test (p < 0.001) although they were used by 45.6 % of the negative patients. Only one patient underwent fundoplication. CONCLUSIONS: Two-thirds of patients undergoing pH-MII monitoring experience a positive outcome, similarly to what occurs after traditional pH monitoring. Physicians often pay little attention to the test results, especially if they are negative. PMID- 26033512 TI - Experiences of Patients in Acute and Closed Psychiatric Wards: A Systematic Review. AB - PURPOSE: To obtain insight into the patients' experiences during treatment in an acute, closed psychiatric ward. DESIGN AND METHODS: A systematic literature search was conducted in the databases Medline, Embase, CINAHL, and Cochrane. FINDINGS: Ten articles were selected. Four main themes emerged from the literature: (a) the inappropriate use of the ward rules, (b) nurses' lack of time for interacting with patients, (c) the feeling of humiliation, and (d) the involvement of significant others. PRACTICE IMPLICATIONS: Nurses can use the findings of this systematic review to improve quality of care in acute psychiatric units. PMID- 26033513 TI - Impact of electron beam irradiation on quality of sea buckthorn (Hippophae rhamnoides L.) oil. AB - BACKGROUND: Sea buckthorn oil is a valuable product that can be incorporated into daily foodstuffs, cosmetics or pharmaceuticals. The effect of accelerated electron irradiation up to 8 kGy on quality characteristics of sea buckthorn oil was investigated in this study. RESULTS: Irradiation had no significant influence on phenolic content. Conversely, carotenoid content, antioxidant activity, and oxidative status suffered alterations as the irradiation dose increased. Although no colour changes were visible for oil irradiated up to 3 kGy, the total colour difference indicated clearly changes that involved a two-step pattern associated with slow degradation of oil colour up to 3 kGy, followed by a fast degradation up to 8 kGy. Some changes of the oil spectral features related to the frequency and intensity of some bands have been found after irradiation, indicating an alteration of the structural integrity induced by irradiation. CONCLUSION: The present investigation may be a useful starting point for irradiation processing of food or non-food matrices containing sea buckthorn oil. Thus, sea buckthorn oil safety can be ensured with minimal undesirable changes in its quality by applying irradiation doses up to 3 kGy, which allow control of the microbial contamination depending on microorganism type and initial microbial load. PMID- 26033514 TI - Upregulation of CD200 is associated with regulatory T cell expansion and disease progression in multiple myeloma. AB - Immune dysfunction is an important feature of multiple myeloma (MM) leading to infections, enhancement of tumour growth and resistance to chemotherapy. The overexpression of CD200, expansion of T regulatory (Treg) cell and increased levels of immune modulatory cytokines like IL10, IL6 and transforming growth factor beta (TGFbeta) were suggested to have a role in this context. The aim of this study was to assess CD200 expression, Treg percentage by flow cytometry and immune modulatory cytokines (IL10, IL6, TGFbeta) by enzyme-linked immunosorbent assay in MM patients at diagnosis. This study included 50 MM patients at diagnosis and 20 healthy controls. The positive CD200 expression was detected in 72% of MM patients. Among the CD200 positive group, 4/13 patients (30.8%) were classified as stage I, 18/23 (78.3%) were in stage II and 14/14 (100%) were in stage III; according to International scoring system. Treg percentage was significantly higher in stage III, followed by stage II then stage I (p < 0.01). Serum IL6, IL10 and TGFbeta were significantly higher in MM patients as compared with controls (p < 0.01, p < 0.01, p < 0.05, respectively). The increased expression of CD200 and Treg percentages was associated with increased severity biomarkers (serum LDH and beta2 microglobulin). The degree of CD200 expression was significantly positively correlated to Treg percentage (r = 0.565, p < 0.01). Analysis of the CD200 negative patients had a better progression free survival (p = 0.032) and overall survival (p = 0.04) as compared with those positive for CD200 expression. These findings illustrate a clear correlation between myeloma cell CD200 expression level and the frequency of immunosuppressive Treg cells. In conclusion, increased expression of CD200, expansion of suppressive Treg cells and elevation of cytokines might have a role in MM progression in this cohort of patients. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26033515 TI - How do we utilize a transfusion safety officer? AB - The hospital transfusion safety officer (TSO) serves an important role in improving transfusion safety outside of the laboratory through education, active surveillance of the transfusion process (patient identification, blood administration, appropriate ordering practices, transfusion reactions, incidents, and near misses), patient blood management (blood utilization review, minimization of perioperative blood loss, documentation review), quality improvement (transfusion guidelines development, transfusion committee or peer review participation, massive transfusion protocols), and research. We provide a description of how we utilize our hospital-based TSO to improve transfusion safety and ensure compliance with regulatory requirements and maintenance of certification at our institution. PMID- 26033516 TI - Blood flow conditioning reduces kidney injury in high risk cardiac surgery patients. PMID- 26033517 TI - Chronic cigarette smoke exposure induces microbial and inflammatory shifts and mucin changes in the murine gut. AB - Inflammatory bowel diseases (IBD) are complex multifactorial diseases characterized by an inappropriate host response to an altered commensal microbiome and dysfunctional mucus barrier. Cigarette smoking is the best known environmental risk factor in IBD. Here, we studied the influence of chronic smoke exposure on the gut microbiome, mucus layer composition and immune factors in conventional mice. We compared smoke-exposed with air-exposed mice (n = 12) after a smoke exposure of 24 weeks. Both Illumina sequencing (n = 6) and denaturing gradient gel electrophoresis (n = 12) showed that bacterial activity and community structure were significantly altered in the colon due to smoke exposure. Interestingly, an increase of Lachnospiraceae sp. activity in the colon was observed. Also, the mRNA expression of Muc2 and Muc3 increased in the ileum, whereas Muc4 increased in the distal colon of smoke-exposed mice (n = 6). Furthermore, we observed increased Cxcl2 and decreased Ifn-gamma in the ileum, and increased Il-6 and decreased Tgf-beta in the proximal colon. Tight junction gene expression remained unchanged. We infer that the modulating role of chronic smoke exposure as a latently present risk factor in the gut may be driven by the altered epithelial mucus profiles and changes in microbiome composition and immune factors. PMID- 26033518 TI - Are preformed endotracheal tubes appropriately designed for pediatric patients? AB - BACKGROUND: The aim of the study was to examine different brands of preformed oral and nasal endotracheal tubes (ETT) and to assess whether the bend placement gave acceptable guidance for ETT depth positioning in children. METHODS: The distance from the vertex of the bend to the tip (bend-to-tip distance) of seven brands of preformed oral and nasal ETTs were measured. Front teeth-to-carina (FTC) and nares-to-carina (NC) distance data from orally (0-19 years) and nasally (0-8 years) intubated children were used to assess the risk of endobronchial intubation if a preformed ETT had been placed with its bend at the front teeth or nares. RESULTS: While the bend-to-tip distance of a cuffed oral preformed ETT only differed by 0-1 cm from a same size ETT from another brand, uncuffed oral ETTs differed by 0-4 cm. The bend-to-tip distance of cuffed and uncuffed ETTs of the same brand and size differed by 0-3 cm. Had preformed cuffed oral ETTs been placed with their bends at the front teeth in children of the FTC reference group, endobronchial intubation would have occurred in 0-27% of the patients, depending on the size and brand of the used ETT. In contrast to oral ETTs, the bend-to-tip distance of cuffed nasal ETTs differed more (0-5.5 cm) between brands, and uncuffed nasal ETTs less (0-3 cm). Also, the bend-to-tip distance of a cuffed nasal ETT was consistently greater (2-9 cm) than that of a same brand and size nasal uncuffed ETT. Had a preformed cuffed nasal ETT been placed with its bend at the nares in the NC reference group, 50-100% of the patients would have been endobronchially intubated. CONCLUSION: The bend-to-tip distance of preformed ETTs varies between brands, especially for nasal tubes. Some preformed tubes are not well suited for routine use in children. There is a high risk for accidental endobronchial intubation if a cuffed preformed ETT is positioned with its bend at the front teeth or nares in a young child. ETT tube tip position needs to be carefully controlled when a preformed ETT is used in a child. PMID- 26033519 TI - The genetic structure of Nautilus pompilius populations surrounding Australia and the Philippines. AB - Understanding the distribution of genetic diversity in exploited species is fundamental to successful conservation. Genetic structure and the degree of gene flow among populations must be assessed to design appropriate strategies to prevent the loss of distinct populations. The cephalopod Nautilus pompilius is fished unsustainably in the Philippines for the ornamental shell trade and has limited legislative protection, despite the species' recent dramatic decline in the region. Here, we use 14 microsatellite markers to evaluate the population structure of N. pompilius around Australia and the Philippines. Despite their relative geographical proximity, Great Barrier Reef individuals are genetically isolated from Osprey Reef and Shark Reef in the Coral Sea (FST = 0.312, 0.229, respectively). Conversely, despite the larger geographical distances between the Philippines and west Australian reefs, samples display a small degree of genetic structure (FST = 0.015). Demographic scenarios modelled using approximate Bayesian computation analysis indicate that this limited divergence is not due to contemporary gene flow between the Philippines and west Australia. Instead, present-day genetic similarity can be explained by very limited genetic drift that has occurred due to large average effective population sizes that persisted at both locations following their separation. The lack of connectivity among populations suggests that immigrants from west Australia would not facilitate natural recolonization if Philippine populations were fished to extinction. These data help to rectify the paucity of information on the species' biology currently inhibiting their conservation classification. Understanding population structure can allow us to facilitate sustainable harvesting, thereby preserving the diversity of genetically distinct stocks. PMID- 26033520 TI - Comorbid alcohol dependence disorder may be related to aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) in bipolar II disorder, but only to ALDH2 in bipolar I disorder, in Han Chinese. AB - OBJECTIVES: A high prevalence rate of bipolar disorder (BP) comorbid with alcohol dependence (AD) (BP+AD) in Western patients with BP has been reported, but whether this is true for Han Chinese with BP is uncertain. We explored the prevalence of BP+AD in a Han Chinese population with BP, and investigated the effect of alcohol-metabolizing genotypes on bipolar I disorder (BP-I) + AD and bipolar II disorder (BP-II) + AD. METHODS: Healthy controls (HCs) (n = 672) and 18- to 65-year-old patients with BP (BP-I: n = 530; BP-II: n = 788) were recruited. Patients with any other major or minor mental illnesses, neurological disorders, or organic mental disorders were excluded. A polymerase chain reaction and restriction fragment length polymorphism analysis was used to determine genotypes for alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), two alcohol-metabolizing enzymes. RESULTS: AD comorbidity rates were 11.7% with BP-I and 17.1% with BP-II. Significantly fewer patients with BP not comorbid with AD (BP-AD) carried the AHD1B*1 allele than did the HCs. Logistic regression analysis showed a main effect of ALDH2*1/*1 only in the BP-I-AD group. In BP+AD patients, logistic regression analysis showed main effects of ALDH2*1/*1 and ADH1B*1/*1 only in the BP-II+AD group. CONCLUSIONS: Having BP-II+AD may be related to ALDH2 and ADH1B, but having BP-I+AD may be related only to ALDH2. We conclude that ALDH2 and ADH1B have different effects in Han Chinese patients with BP-I+AD and BP-II+AD. PMID- 26033521 TI - The Elimination of Listeria Monocytogenes Attached to Stainless Steel or Aluminum Using Multiple Hurdles. AB - Ready-to-eat luncheon meats sliced in retail delis have been found to pose the greatest risk of foodborne illness from Listeria monocytogenes among all ready-to eat foods. Slicers used in delis have many removable parts that are connected with seals and gaskets, with spaces, cracks and crevices that are difficult to clean adequately and may provide a niche for L. monocytogenes survival. Standard cleaning and sanitizing practices used by deli employees may not eliminate Listeria in these niches. Moist heat is known to be more effective against L. monocytogenes than dry heat at the same temperature and time. The study reported here investigated the effects of moist heat combined with quaternary ammonium compounds (5 or 10 ppm), chlorine (10 or 25 ppm) or peracetic acid (10 or 25 ppm) on inactivating L. monocytogenes attached to stainless steel or aluminum coupons cut from commercial deli meat slicer components. All sanitizers when used alone resulted in a 2- to 3-log reduction of L. monocytogenes on stainless steel or aluminum surfaces, while moist heat alone resulted in a 3- to 4-log reduction. When combined with heat the quaternary ammonium was used at 5 ppm, peracetic acid at 10 ppm and chlorine at 10 ppm. When the 2 lethal treatments were combined there was a 5- to7-log reduction as compared to initial inoculation. PRACTICAL APPLICATION: The results of this study will provide a better understanding and potential methods for the sanitization of industrial deli meat slicers. In turn, the knowledge gained from this study can reduce the risk of contamination and outbreaks of L. monocytogenes and other food-borne pathogens for consumers. PMID- 26033522 TI - Banana fruit NAC transcription factor MaNAC5 cooperates with MaWRKYs to enhance the expression of pathogenesis-related genes against Colletotrichum musae. AB - Plants respond to pathogen attack by the modulation of a large set of genes, which are regulated by different types of transcription factor (TF). NAC (NAM/ATAF/CUC) and WRKY are plant-specific families of TFs, and have received much attention as transcriptional regulators in plant pathogen defence. However, the cooperation between NAC and WRKY TFs in the disease response remains largely unknown. Our previous study has revealed that two banana fruit WRKY TFs, MaWRKY1 and MaWRKY2, are involved in salicylic acid (SA)- and methyl jasmonate (MeJA) induced resistance against Colletotrichum musae via binding to promoters of pathogenesis-related (PR) genes. Here, we found that MaNAC1, MaNAC2 and MaNAC5 were up-regulated after C. musae infection, and were also significantly enhanced by SA and MeJA treatment. Protein-protein interaction analysis showed that MaNAC5 physically interacted with MaWRKY1 and MaWRKY2. More importantly, dual-luciferase reporter (DLR) assay revealed that MaNAC5, MaWRKY1 and MaWRKY2 were transcriptional activators, and individually or cooperatively activated the transcriptional activities of MaPR1-1, MaPR2, MaPR10c and MaCHIL1 genes. Collectively, our results indicate that MaNAC5 cooperates with MaWRKY1 and MaWRKY2 to regulate the expression of a specific set of PR genes in the disease response, and to contribute at least partially to SA- and MeJA-induced pathogen resistance. PMID- 26033524 TI - Hepatocellular carcinoma: To resect or to transplant? PMID- 26033523 TI - Acidosis is a key regulator of osteoblast ecto-nucleotidase pyrophosphatase/phosphodiesterase 1 (NPP1) expression and activity. AB - Previous work has shown that acidosis prevents bone nodule formation by osteoblasts in vitro by inhibiting mineralisation of the collagenous matrix. The ratio of phosphate (Pi ) to pyrophosphate (PPi ) in the bone microenvironment is a fundamental regulator of bone mineralisation. Both Pi and PPi , a potent inhibitor of mineralisation, are generated from extracellular nucleotides by the actions of ecto-nucleotidases. This study investigated the expression and activity of ecto-nucleotidases by osteoblasts under normal and acid conditions. We found that osteoblasts express mRNA for a number of ecto-nucleotidases including NTPdase 1-6 (ecto-nucleoside triphosphate diphosphohydrolase) and NPP1 3 (ecto-nucleotide pyrophosphatase/phosphodiesterase). The rank order of mRNA expression in differentiating rat osteoblasts (day 7) was Enpp1 > NTPdase 4 > NTPdase 6 > NTPdase 5 > alkaline phosphatase > ecto-5-nucleotidase > Enpp3 > NTPdase 1 > NTPdase 3 > Enpp2 > NTPdase 2. Acidosis (pH 6.9) upregulated NPP1 mRNA (2.8-fold) and protein expression at all stages of osteoblast differentiation compared to physiological pH (pH 7.4); expression of other ecto nucleotidases was unaffected. Furthermore, total NPP activity was increased up to 53% in osteoblasts cultured in acid conditions (P < 0.001). Release of ATP, one of the key substrates for NPP1, from osteoblasts, was unaffected by acidosis. Further studies showed that mineralised bone formation by osteoblasts cultured from NPP1 knockout mice was increased compared with wildtypes (2.5-fold, P < 0.001) and was partially resistant to the inhibitory effect of acidosis. These results indicate that increased NPP1 expression and activity might contribute to the decreased mineralisation observed when osteoblasts are exposed to acid conditions. PMID- 26033525 TI - Spectroscope and molecular model identify the behavior of doxorubicin-SPION binding to bovine hemoglobin. AB - To provide reference for the bio-safety evaluation of doxorubicin-loaded SPION, the interaction of bovine hemoglobin (BHb) with the drug delivery was investigated by multi-spectroscopic techniques and molecular modeling calculation. Multi-spectroscopic results indicated that DOX-SPION unfolded the conformation of BHb, decreased the content of alpha-helix from 38.89% to 35.08%, which verified the changes of protein's secondary structure quantificationally. Stern-Volmer analysis and molecular model showed there were two static interaction modes corresponding to the two reaction steps: DOX first immobilized on the particle adhered to the external region of BHb, leading to the increasing exposure of chromophore group, rendering particles to bond to the original hemoglobin central cavity (Site 2) in sequence. They finally generated a stable bioconjugate via hydrogen bonds. This work indicated that the drug delivery has deleterious effects on the frame conformation of BHb, affecting its physiological function. PMID- 26033526 TI - Highly Efficient Orange and Red Phosphorescent Organic Light-Emitting Diodes with Low Roll-Off of Efficiency using a Novel Thermally Activated Delayed Fluorescence Material as Host. AB - MTXSFCz with thermally activated delayed fluorescence is synthesized. Orange and red phosphorescent organic light-emitting diodes (PHOLEDs) with low efficiency roll-off exhibit external quantum efficiencies (EQE) up to 11.8% and 15.6%. The efficient upconversion from triplet to singlet of the host reduces the triplet density and thus affords a low efficiency roll-off of PHOLEDs. PMID- 26033527 TI - Diversified Structural Basis of a Conserved Molecular Mechanism for pH-Dependent Dimerization in Spider Silk N-Terminal Domains. AB - Conversion of spider silk proteins from soluble dope to insoluble fibers involves pH-dependent dimerization of the N-terminal domain (NT). This conversion is tightly regulated to prevent premature precipitation and enable rapid silk formation at the end of the duct. Three glutamic acid residues that mediate this process in the NT from Euprosthenops australis major ampullate spidroin 1 are well conserved among spidroins. However, NTs of minor ampullate spidroins from several species, including Araneus ventricosus ((Av)MiSp NT), lack one of the glutamic acids. Here we investigate the pH-dependent structural changes of (Av)MiSp NT, revealing that it uses the same mechanism but involves a non conserved glutamic acid residue instead. Homology modeling of the structures of other MiSp NTs suggests that these harbor different compensatory residues. This indicates that, despite sequence variations, the molecular mechanism underlying pH-dependent dimerization of NT is conserved among different silk types. PMID- 26033528 TI - Evaluation of a revised version of computer-assisted diagnosis system, BONENAVI version 2.1.7, for bone scintigraphy in cancer patients. AB - OBJECTIVE: BONENAVI is a computer-assisted diagnosis system that analyzes bone scintigraphy automatically. We experienced more than a few segmentation errors with the previous BONENAVI version (2.0.5). We have since obtained a revised version (2.1.7) and evaluate it. METHODS: Bone scans of patients were analyzed by BONENAVI version 2.0.5 and a revised version 2.1.7 with regard to segmentation errors, sensitivity, and specificity. Patients with skeletal metastases from prostate cancer, lung cancer, breast cancer, and other cancers were included in the study as true-positive cases. Patients with no skeletal metastasis (regardless of hot spots), and patients with abnormal bone scans but no skeletal metastasis were included as negative cases. Bone-scan patients were subjected to artificial neural network (ANN) evaluation. Values equal to or above 0.5 were regarded as positive, and those below 0.5 as negative. The patients whose clinical status did not correspond to their ANN scores were assessed for any similarities. RESULTS: The frequency of segmentation errors was statistically significantly reduced when using BONENAVI version 2.1.7. The differences in sensitivity and specificity for the results of version 2.0.5 versus version 2.1.7 were not different, giving a high Cohen's kappa coefficient. In the patients who showed an increased ANN value with version 2.1.7, a few false-positive thoracic lesions were identified. Patients whose ANN value was significantly high with version 2.0.5 showed no tendencies. CONCLUSION: Revised BONENAVI version 2.1.7 for bone scintigraphy was superior with regard to segmentation errors. However, its sensitivity and specificity were similar to those of version 2.0.5. The false positive identification of thoracic lesions in revised version 2.1.7 might be subject to remedy. PMID- 26033529 TI - Northward displacement of optimal climate conditions for ecotypes of Eriophorum vaginatum L. across a latitudinal gradient in Alaska. AB - Plants are often genetically specialized as ecotypes attuned to local environmental conditions. When conditions change, the optimal environment may be physically displaced from the local population, unless dispersal or in situ evolution keep pace, resulting in a phenomenon called adaptational lag. Using a 30-year-old reciprocal transplant study across a 475 km latitudinal gradient, we tested the adaptational lag hypothesis by measuring both short-term (tiller population growth rates) and long-term (17-year survival) fitness components of Eriophorum vaginatum ecotypes in Alaska, where climate change may have already displaced the optimum. Analyzing the transplant study as a climate transfer experiment, we showed that the climate optimum for plant performance was displaced ca. 140 km north of home sites, although plants were not generally declining in size at home sites. Adaptational lag is expected to be widespread globally for long-lived, ecotypically specialized plants, with disruptive consequences for communities and ecosystems. PMID- 26033530 TI - Connecting the latent multinomial. AB - Link et al. (2010, Biometrics 66, 178-185) define a general framework for analyzing capture-recapture data with potential misidentifications. In this framework, the observed vector of counts, y, is considered as a linear function of a vector of latent counts, x, such that y=Ax, with x assumed to follow a multinomial distribution conditional on the model parameters, theta. Bayesian methods are then applied by sampling from the joint posterior distribution of both x and theta. In particular, Link et al. (2010) propose a Metropolis-Hastings algorithm to sample from the full conditional distribution of x, where new proposals are generated by sequentially adding elements from a basis of the null space (kernel) of A. We consider this algorithm and show that using elements from a simple basis for the kernel of A may not produce an irreducible Markov chain. Instead, we require a Markov basis, as defined by Diaconis and Sturmfels (1998, The Annals of Statistics 26, 363-397). We illustrate the importance of Markov bases with three capture-recapture examples. We prove that a specific lattice basis is a Markov basis for a class of models including the original model considered by Link et al. (2010) and confirm that the specific basis used in their example with two sampling occasions is a Markov basis. The constructive nature of our proof provides an immediate method to obtain a Markov basis for any model in this class. PMID- 26033531 TI - Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. AB - Genotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0.16, and leucopenia was more common in carriers of the T allele (odds ratio, 7.20; 95% confidence interval, 2.49-20.80; P = 2.7 * 10(-4) ). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40.7, 29.3 and 8.8 mg/m(2) for patients with CC, CT and TT genotypes, respectively (P < 0.001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted. PMID- 26033533 TI - Is Extracorporeal Membrane Oxygenation More Effective Than Standard Measures in Critically Ill Adults? PMID- 26033532 TI - Emergency Department Management of Atrial Fibrillation and Flutter and Patient Quality of Life at One Month Postvisit. AB - STUDY OBJECTIVE: We identify characteristics of patients with atrial fibrillation or flutter associated with favorable assessments of emergency department (ED) effectiveness and 30-day quality of life. METHODS: As part of a prospective observational study of ED management and short-term outcomes of patients with nonvalvular atrial fibrillation or flutter, we adapted a disease-specific quality of-life instrument. By telephone, we administered the Atrial Fibrillation Effect on Quality-of-life survey to patients 30 days after an ED visit in which they were treated for newly diagnosed or recent-onset atrial fibrillation or flutter and discharged home. We also asked respondents to rate the effectiveness of ED treatment. Using data prospectively collected in the ED and extracted from electronic health records, we recorded rhythm management (cardioversion attempts and type) and patient and ED treatment characteristics. Using multivariable regression, we examined the association between these characteristics and patient reported effectiveness of ED treatment ("very effective" or not) and any atrial fibrillation or flutter quality-of-life effect. RESULTS: Six hundred fifty-two eligible ED patients (response rate 89%) treated between May 2011 and November 2012 completed follow-up. Of these patients, 454 (69.6%) reported that their ED treatment was "very effective" and 113 (17.3%) reported no quality-of-life influence. In multivariable analyses, there was an association between ED electrocardioversion and perceived ED effectiveness (P<.05) but none between treatment strategy and 30-day atrial fibrillation or flutter quality-of-life score. Respondents who were younger, women, and had worse pre-ED self-reported health (P<.05) were more likely to report a quality-of-life effect. CONCLUSION: In this observational study, ED rhythm management strategy was associated with greater perceived effectiveness of the ED visit but not with a difference in 30 day quality-of-life score. PMID- 26033534 TI - Prenatal diagnosis of the VACTERL association using routine ultrasound examination. AB - BACKGROUND: The prognosis and early neonatal management of the VACTERL association depend mainly on the severity of malformations ascertained prenatally. METHODS: Here we reviewed the spectrum of clinical features observed in cases of VACTERL association ascertained prenatally through ultrasound examination but examined at birth and compared them with cases ascertained postnatally. RESULTS: From 1995 to 2011, a total of 19 cases of VACTERL association were observed in our center; 10 were ascertained prenatally and confirmed after birth whereas 9 were ascertained only after birth. The types and frequencies of malformations observed prenatally were as follows: renal malformations (45%), tracheoesophageal fistula (44%), cardiac malformations (20%), vertebral (13%), and limb (11%) defects. Anal atresia was never detected using routine prenatal ultrasound examination. CONCLUSION: Further studies of fetuses with the VACTERL association are necessary to better delineate the malformations spectrum observed prenatally to improve the early recognition of the VACTERL association. PMID- 26033535 TI - Coagulation and infective endocarditis: sooner or later. PMID- 26033536 TI - Injury-Related Mortality Over 12 Years in a Cohort of Patients with Alcohol Use Disorders: Higher Mortality Among Young People and Women. AB - BACKGROUND: The goal of this study was to estimate excess death due to external causes among 18- to 64-year-olds with alcohol use disorder (AUD) who were treated at public outpatient treatment centers, and the time elapsed from treatment initiation to death. METHODS: We conducted a retrospective longitudinal study among 7,012 outpatients aged 18 to 64 years who began treatment for AUD between 1997 and 2007. Deaths due to external causes (intentional and unintentional injuries) were monitored until the end of 2008. Person-years (PY) of follow-up and crude mortality rates (CMRs) were calculated for all study variables, for each sex, and for 2 age groups (18 to 34 and 35 to 64 years). Standardized mortality ratios (SMRs) were estimated by age group and sex. Survival was analyzed using the Kaplan-Meier method and Cox regression. RESULTS: We recorded 114 deaths due to external causes. The CMR was 2.7 per 1,000 PY (95% confidence interval [CI]: 2.2 to 3.2), with significant gender differences only among younger individuals (CMR for males = 3.9 per 1,000 PY [95% CI: 2.2 to 5.5] and CMR for females = 2.8 per 1,000 PY [95% CI: 0.1 to 5.6]). Unintentional injury was the most common cause of death (n = 65), of which acute poisoning (n = 25; 38.5%) and traffic accidents (n = 15; 23.1%) were the most prevalent. Suicide accounted for 91.8% (n = 49) of deaths from intentional injuries. The excess of mortality between the AUD group and the general population (SMR) was 9.5 higher than in the general population (95% CI: 7.9 to 11.4), with significant differences between genders (SMR = 6.1 [95% CI: 4.9 to 7.5] in males and SMR = 20.4 [95% CI: 13.9 to 29.9] in females). Approximately 35% of deaths among individuals aged <35 years and 60% among women occurred within a year of initiating treatment. CONCLUSIONS: This study highlights the importance of excess of mortality among people with AUD and patients' vulnerability during the initial years of treatment. Preventing premature deaths due to external causes among women and younger patients with AUD is a priority. PMID- 26033537 TI - Tuning organic carbon dioxide absorbents for carbonation and decarbonation. AB - The reaction of carbon dioxide with a mixture of a superbase and alcohol affords a superbase alkylcarbonate salt via a process that can be reversed at elevated temperatures. To utilize the unique chemistry of superbases for carbon capture technology, it is essential to facilitate carbonation and decarbonation at desired temperatures in an easily controllable manner. Here, we demonstrate that the thermal stabilities of the alkylcarbonate salts of superbases in organic solutions can be tuned by adjusting the compositions of hydroxylic solvent and polar aprotic solvent mixtures, thereby enabling the best possible performances to be obtained from the various carbon dioxide capture agents based on these materials. The findings provides valuable insights into the design and optimization of organic carbon dioxide absorbents. PMID- 26033538 TI - MscCG from Corynebacterium glutamicum: functional significance of the C-terminal domain. AB - Corynebacterium glutamicum is used in microbial biotechnology for the production of amino acids, e.g., glutamate and lysine. Excretion of glutamate into the surrounding medium under production conditions is mediated by MscCG, an MscS-type mechanosensitive channel. In difference to most other MscS-type channel proteins, MscCG carries, in addition to the N-terminal pore domain, a long C-terminal domain that amounts to about half of the size of the protein and harbors an additional transmembrane segment. Here we study the impact of the C-terminal domain on both functions of MscCG as mechanosensitive channel and as glutamate exporter. Sequential truncations of the C-terminal domain were applied, as well as deletion of particular subdomains, replacement of these segments by other amino acid sequences, and sequence randomization. Several parameters of cell physiology and bioenergetics of the obtained mutants related to both glutamate excretion and response to osmotic stress were quantified. All three subdomains of the C-terminal domain, i.e., the periplasmic loop, the fourth transmembrane segment, and the cytoplasmic loop, proved to be of core significance for MscCG function, in particular for glutamate excretion. PMID- 26033539 TI - Curvature-dependent protein-lipid bilayer interaction and cell mechanosensitivity. AB - Cells respond to applied external forces through different mechanosensitive processes, with many of them based on the interaction between membrane-embedded proteins and their lipid environments. This interaction can depend on membrane curvature at the location of such proteins. Here we elucidate the general characteristics of a macroscopically defined protein-lipid bilayer interaction based on a mismatch between the shape of the protein surface and the surrounding membrane curvature. It is shown how the parameters of this interaction are related to the experimentally determined distribution of membrane-embedded proteins between highly curved tubular and flat membrane regions of a giant phospholipid vesicle. The results obtained for such distribution of potassium channel KvAP are presented as an example. Possible participation of the curvature dependent protein-lipid bilayer interaction in mechanosensitive processes is indicated. PMID- 26033540 TI - Steered molecular dynamics approach for promising drugs for influenza A virus targeting M2 channel proteins. AB - We have used steered molecular dynamics simulation to investigate the molecular interactions between four M2 inhibitors (amantadine, rimantadine, and two other amantadine derivatives) and the M2 protein channels of influenza A virus H5N1, including the wild type (WT) and three previously identified drug-resistant variants (G34A, S31N, and V27A). The binding free energies between these four inhibitors and the M2 channel of the WT and the three mutants were also determined by use of the molecular mechanics-Poisson-Boltzmann surface area method. Our study provides important insight into binding affinity, including detailed energy components and interactions at the molecular level of four potential inhibitors with the M2 channel of drug-resistant strains; this may assist further experimental study and strategies for rational design of new inhibitors. PMID- 26033542 TI - Characterization of Heterogeneity in Childhood Immunization Coverage in Central Florida Using Immunization Registry Data. AB - Despite high vaccine coverage in the United States in general, and in the State of Florida specifically, some children miss scheduled vaccines due to health system failures or vaccine refusal by their parents. Recent experiences with outbreaks in the United States suggest that geographic clustering of un(der)vaccinated populations represent a threat to the elimination status of some vaccine-preventable diseases. Immunization registries continue to expand and play an important role in efforts to track vaccine coverage and use. Using nearly 700,000 de-identified immunization records from the Florida Department of Health immunization information system (Florida SHOTSTM) for children born during 2003 2014, we explored heterogeneity and potential clustering of un(der)vaccinated children in six counties in central Florida-Brevard, Lake, Orange, Oseola, Polk, and Seminole-that represent a high-risk area for importation due to family tourist attractions in the area. By zip code, we mapped the population density, the percent of children with religious exemptions, the percent of children on track or overdue for each vaccine series without and with exemptions, and the numbers of children with no recorded dose of each vaccine. Overall, we found some heterogeneity in coverage among the counties and zip codes, but relatively consistent and high coverage. We found that some children with an exemption in the system received the vaccines we analyzed, but exemption represents a clear risk factor for un(der)immunization. We identified many challenges associated with using immunization registry data for spatial analysis and potential opportunities to improve registries to better support future analyses. PMID- 26033541 TI - Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling. AB - Embryonic stem cells (ESCs) possess pluripotency, which is the capacity of cells to differentiate into all lineages of the mature organism. Increasing evidence suggests that the pluripotent state of ESCs is regulated by a combination of extrinsic and intrinsic factors. The underlying mechanisms, however, are not completely understood. Here, we show that March5, an E3 ubiquitin ligase, is involved in maintaining mouse-ESC (mESC) pluripotency. Knockdown of March5 in mESCs led to differentiation from naive pluripotency. Mechanistically, as a transcriptional target of Klf4, March5 catalyses K63-linked polyubiquitination of Prkar1a, a negative regulatory subunit of PKA, to activate PKA, thereby inhibiting the Raf/MEK/ERK pathway. Moreover, March5 is able to replace a MEK/ERK inhibitor to maintain mESC pluripotency under serum-free culture conditions. In addition, March5 can partially replace the use of Klf4 for somatic cell reprogramming. Collectively, our study uncovers a role for the Klf4-March5-PKA ERK pathway in maintaining the stemness properties of mESCs. PMID- 26033543 TI - Treatment outcomes of sinonasal malignant melanoma: a Korean multicenter study. AB - BACKGROUND: The aim of this work was to evaluate factors that influence local recurrence and survival after surgical resection of sinonasal malignant melanoma, using a large population-based multicenter study in Korea. METHODS: Retrospective analysis was performed for 155 newly diagnosed sinonasal malignant melanoma patients gathered from 15 university hospitals throughout Korea. Demographic data, tumor characteristics, surgical approach, adjuvant treatment, recurrence, and outcomes were analyzed. RESULTS: Three-year and 5-year overall survival rates were 48.8% and 40.1%, respectively. Local recurrence rate was 46.6%, with a mean recurrence time of 15.5 months. On multivariate analysis, patients who underwent surgery that included an endoscopic approach showed decreased local recurrence rate (p = 0.042) and increased survival rate (hazard ratio [HR], 1.702; 95% confidence interval [CI], 1.007 to 2.875; p = 0.047) compared to those who underwent an external approach. Patients with postoperative radiotherapy showed a decreased local recurrence rate (p = 0.001), but without impact on survival rate. Male gender, tumor beyond the nasal cavity, and presence of distant metastasis were associated with poor survival. CONCLUSION: An endoscopic-including surgical approach was associated with improved local control and survival in sinonasal malignant melanoma patients. Postoperative radiotherapy helped increase the local control rate. PMID- 26033544 TI - Incidence, risk factors, and reasons for hospitalization among glioblastoma patients receiving chemoradiation. AB - Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score >= 70. Twenty-six percent of patients underwent gross total resection, 77 % received >= 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P < .001). Nearly half of the hospitalizations were due to generalized weakness (17 % of hospitalizations), seizures (16 %), or venous thromboembolism (13 %). On multivariate analysis, age (odds ratio [OR], 1.03; 95 % CI, 1.002-1.060; P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P < .001) were associated with risk of hospitalization. Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival. PMID- 26033545 TI - Radio-chemotherapy improves survival in IDH-mutant, 1p/19q non-codeleted secondary high-grade astrocytoma patients. AB - Isocitrate dehydrogenase (IDH) mutations are beginning to drive decisions on therapy for glioma patients. Here we sought to determine the impact of adjuvant treatment in patients with IDH-mutant, 1p/19q non-codeleted secondary high-grade astrocytoma (sHGA) WHO grades III/IV. Clinical data of 109 sHGA patients grades III/IV, in addition to IDH mutation-, 1p/19q-codeletion- and MGMT-promoter methylation status-were retrospectively analyzed. Survival analysis in relation to adjuvant treatment modalities and molecular profiling were performed. Out of 109 patients, 88 patients (80.7 %) harbored IDH mutations, 30 patients had a 1p/19q-codeletion (27.5 %) and 69 patients (63.3 %) exhibited a methylated MGMT promoter status. At a median follow-up of 9.8 years, 62 patients (57 %) died. The postsurgical treatment included: radio-chemotherapy (RT-CT; 54.5 %), RT alone (19.3 %), and CT alone (22.7 %). The median overall survival (OS) in the entire group was 3.4 years (1.9-6.7 years). Patients who received RT-CT had a significantly longer OS compared with those who underwent RT alone (6.5 vs. 1.2 years, HR 0.35, CI 0.32-0.51, p = 0.011). In the IDH-mutant 1p/19q non-codeleted sHGA subgroup the RT-CT cohort had a significantly longer OS in comparison to the RT cohort (6.4 vs. 1.2 years, HR 2.7, CI 1.1-6.5, p = 0.022). In the stepwise multivariable Cox model for OS of all 88 IDH-mutant sHGA patients, survival was strongly associated with only one factor, namely, adjuvant RT-CT at diagnosis of a sHGA. This retrospective long-term study demonstrates that RT and CT (mostly PCV) significantly improves progression-free and overall survival in IDH-mutant secondary high-grade astrocytoma patients, regardless of 1p/19q-codeletion status. PMID- 26033546 TI - Corpus callosum involvement and postoperative outcomes of patients with gliomas. AB - Corpus callosum involvement is associated with poorer survival in high grade glioma (HGG), but the prognostic value in low grade glioma (LGG) is unclear. To determine the prognostic impact of corpus callosum involvement on progression free survival (PFS) and overall survival (OS) in HGG and LGG, the records of 233 glioma patients treated from 2008 to 2011 were retrospectively reviewed. Preoperative magnetic resonance (MR) images were used to identify corpus callosum involvement. Age, sex, preoperative Karnofsky performance scale, postoperative Eastern Cooperative Oncology Group (ECOG) score and extent of resection (EOR) were evaluated with respect to PFS and OS. The incidence of corpus callosum involvement was similar among HGG (14 %) and LGG (14.5 %). Univariate analysis revealed that PFS and OS were significantly shorter in both WHO grade II and grade IV glioma with corpus callosum involvement (both, p < 0.05). Multivariate analysis showed that grade II glioma with corpus callosum involvement have shorter PFS (p = 0.03), while EOR, instead of corpus callosum involvement (p = 0.16), was an independent factor associated with PFS in grade IV glioma (p < 0.05). Corpus callosum involvement was no longer significantly associated with OS after adjusting age, gender, EOR, preoperative and postoperative performance status (p = 0.16, 0.17 and 0.56 in grade II, III and IV gliomas, respectively). Corpus callosum involvement happened in both LGG and HGG, and is associated with lower EOR and higher postoperative ECOG score both in LGG and HGG. Corpus callosum involvement tends to be an independent prognostic factor for PFS in LGG, but not for OS in LGG or in HGG. PMID- 26033547 TI - Serum levels of GFAP and EGFR in primary and recurrent high-grade gliomas: correlation to tumor volume, molecular markers, and progression-free survival. AB - Our aim was to study the association of two potential serum biomarkers glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) with prognostic markers such as IDH1 mutation, tumor burden, and survival in patients with high-grade gliomas (HGG). Additionally, our objective was to evaluate the potential of serum EGFR as a surrogate marker for EGFR status in the tumor. Pre operative serum samples were prospectively collected from patients with primary (n = 17) or recurrent (n = 10) HGG. Serum GFAP and EGFR levels were determined by ELISA and studied for correlation with molecular markers including EGFR amplification, tumor volume in contrast-enhanced T1-weighted MRI, and progression free survival (PFS). Pre-operative serum GFAP level of >=0.014 ng/ml was 86 % sensitive and 85 % specific for the diagnosis of glioblastoma. High GFAP was related to the lack of IDH1 mutation (P = 0.016), high Ki67 proliferation index (P < 0.001), and poor PFS (HR 5.9, CI 1.2-29.9, P = 0.032). Serum GFAP correlated with enhancing tumor volume in primary (r = 0.64 P = 0.005), but also in recurrent HGGs (r = 0.76 P = 0.011). In contrast, serum EGFR levels did not differ between HGG patients and 13 healthy controls, and were not related to EGFR status in the tumor. We conclude that high serum GFAP associates with IDH1 mutation-negative HGG, and poor PFS. Correlation with tumor burden in recurrent HGG implicates the potential of serum GFAP for detection of tumor recurrence. Our results suggest that circulating EGFR is not derived from glioma cells and cannot be used as a marker for EGFR status in the tumor. PMID- 26033548 TI - Ex vivo confocal microscopy imaging to identify tumor tissue on freshly removed brain sample. AB - Confocal microscopy is a technique able to realize "optic sections" of a tissue with increasing applications. We wondered if we could apply an ex vivo confocal microscope designed for dermatological purpose in a routine use for the most frequent brain tumors. The aim of this work was to identify tumor tissue and its histopathological hallmarks, and to assess grading criteria used in neuropathological practice without tissue loss on freshly removed brain tissue. Seven infiltrating gliomas, nine meningiomas and three metastases of carcinomas were included. We compared imaging results obtained with the confocal microscope to frozen sections, smears and tissue sections of formalin-fixed tissue. Our results show that ex vivo confocal microscopy imaging can be applied to brain tumors in order to quickly identify tumor tissue without tissue loss. It can differentiate tumors and can assess most of grading criteria. Confocal microscopy could represent a new tool to identify tumor tissue on freshly removed sample and could help in selecting areas for biobanking of tumor tissue. PMID- 26033549 TI - Stable isotope dilution HILIC-MS/MS method for accurate quantification of glutamic acid, glutamine, pyroglutamic acid, GABA and theanine in mouse brain tissues. AB - In this study, we developed the stable isotope dilution hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC-MS/MS) technique for the accurate, reasonable and simultaneous quantification of glutamic acid (Glu), glutamine (Gln), pyroglutamic acid (pGlu), gamma-aminobutyric acid (GABA) and theanine in mouse brain tissues. The quantification of these analytes was accomplished using stable isotope internal standards and the HILIC separating mode to fully correct the intramolecular cyclization during the electrospray ionization. It was shown that linear calibrations were available with high coefficients of correlation (r(2) > 0.999, range from 10 pmol/mL to 50 mol/mL). For application of the theanine intake, the determination of Glu, Gln, pGlu, GABA and theanine in the hippocampus and central cortex tissues was performed based on our developed method. In the region of the hippocampus, the concentration levels of Glu and pGlu were significantly reduced during reality-based theanine intake. Conversely, the concentration level of GABA increased. This result showed that transited theanine has an effect on the metabolic balance of Glu analogs in the hippocampus. PMID- 26033550 TI - Seasonal polyphenism in wing coloration affects species recognition in rubyspot damselflies (Hetaerina spp.). AB - Understanding how phenotypic plasticity evolves and in turn affects the course of evolution is a major challenge in modern biology. By definition, biological species are reproductively isolated, but many animals fail to distinguish between conspecifics and closely related heterospecifics. In some cases, phenotypic plasticity may interfere with species recognition. Here, we document a seasonal polyphenism in the degree of dark wing pigmentation in smoky rubyspot damselflies (Hetaerina titia) - a shift so pronounced that it led early researchers to classify different forms of H. titia as separate species. We further show how the seasonal colour shift impacts species recognition with the sympatric congener Hetaerina occisa. Interspecific aggression (territorial fights) and reproductive interference (mating attempts) are much more frequent early in the year, when H. titia more closely resembles H. occisa, compared to later in the year when the dark phase of H. titia predominates. Using wing colour manipulations of tethered damselflies, we show that the seasonal changes in interspecific interactions are caused not only by the seasonal colour shift but also by shifts in discriminatory behaviour in both species. We also experimentally tested and rejected the hypothesis that learning underlies the behavioural shifts in H. occisa. An alternative hypothesis, which remains to be tested, is that the seasonal polyphenism in H. titia wing coloration has resulted in the evolution of a corresponding seasonal polyphenism in species recognition in H. occisa. This study illustrates one of the many possible ways that plasticity in species recognition cues may influence the evolution of interspecific interactions. PMID- 26033551 TI - PinX1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis by suppressing MMP-2 via NF kappaB-dependent transcription. AB - PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) is a novel cloned gene which has been identified as a major haploinsufficient tumor suppressor essential for maintaining telomerase activity, the length of telomerase and chromosome stability. This study explored the clinical significance and biological function of PinX1 in human clear cell renal cell carcinoma (ccRCC). The clinical relevance of PinX1 in ccRCC was evaluated using tissue microarray and immunohistochemical staining in two independent human ccRCC cohorts. Our data demonstrated that PinX1 expression was dramatically decreased in ccRCC tissues compared with normal renal tissues and paired adjacent non-tumor tissues. Low PinX1 expression was significantly correlated with depth of invasion, lymph node metastasis and advanced TNM stage in patients, as well as with worse overall and disease specific survival. Cox regression analysis revealed that PinX1 expression was an independent prognostic factor for ccRCC patients. Moreover, PinX1 inhibited the migration and invasion of ccRCC by suppressing MMP-2 expression and activity via NF-kappaB-dependent transcription in vitro. In vivo studies confirmed that PinX1 negatively regulated ccRCC metastasis and the expression of MMP-2 and NF-kappaB p65. These findings indicate that PinX1 suppresses ccRCC metastasis and may serve as a ccRCC candidate clinical prognostic marker and a potential therapeutic target. PMID- 26033552 TI - NLRP3 gene polymorphisms in Iranian patients with recurrent aphthous stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common disorder with an unclear etiopathogenesis. Involvement of the immune system in the development of this condition is strongly suggested. As the variations in the inflammasome related NLRP3 gene have been suggested to affect immune system activity, this case-control study was performed to determine whether these genetic variants are associated with RAS. METHODS: We studied a group of 69 Iranian patients with RAS in comparison with 56 healthy controls. We determined four single nucleotide polymorphisms (SNPs) of NLRP3 and performed association analyses of NLRP3. Genotyping was conducted using the TaqMan method. RESULTS: The NLRP3 rs3806265 T allele was significantly more frequent in the patients with RAS than in the healthy controls (P = 0.003). While a significant negative association was found between the C allele at the same position with RAS (P = 0.003), the TT genotype was significantly more frequent at position rs3806265 in NLRP3 in patient group than in the controls (P = 0.002). However, the frequency of CT genotype at the same position was significantly higher in healthy controls than in the case category (P = 0.002). CONCLUSIONS: Considering the high frequency of the presence of NLRP3 rs3806265 TT genotype in patients with RAS, it seems that this gene polymorphism could affect individual susceptibility to RAS. PMID- 26033554 TI - Surface plasmon enhanced up-conversion from NaYF4:Yb/Er/Gd nano-rods. AB - The surface plasmons that are enabled by grating coupling in two-dimensional gold nano-particle arrays (AuNPAs) affected the spectral characteristics of the up conversion (UC) emission from Yb(3+)-Er(3+)-Gd(3+) co-doped sodium yttrium fluoride (NaYF4:Yb/Er/Gd) nano-rods. The red emission of NaYF4:Yb/Er/Gd nano-rods at 660 nm (excited with a 980 nm diode laser) was significantly enhanced by the interaction with the AuNPAs. The geometric characteristics of the gold nanoparticles influenced the position of the surface plasmon resonance, and their near field strengths. The intensity of the red emission normalized versus the green emission reached 1.4, measured against a reference film in the absence of the metallic nanostructures. The lifetime for the green and red emission decreased steadily as the periodicity decreased (relative to the reference), reaching about 6% reduction for the 350 nm AuNPA. A qualitative agreement was obtained between the experimental results and finite difference time domain (FDTD) calculations. PMID- 26033555 TI - [Diagnosis of maternofetal infections]. AB - Prevention is an essential aspect of management of infections that can be transmitted from mother to fetus during pregnancy: The prescription and interpretation of serologic markers differ according to clinical context: screening, counts, clinical signs, or ultrasound signs. Testing for rubella IgG antibodies is recommended at the beginning of pregnancy, in the absence of written results proving either immunity or previous vaccination with two doses. Monthly serologic monitoring (IgG and IgM) is recommended for woman lacking immunity to toxoplasmosis. Diagnosis of a primary infection requires the concomitant detection of IgG and IgM. Nonetheless, the presence of specific IgM is not necessarily a marker of recent infection. IgG avidity must be measured to confirm or rule out a recent primary infection when IgM is positive. The observation of stable antibody titers is often inaccurately considered to be reassuring. In fact, depending on the individuals tested and especially the technique used, antibodies may reach a plateau several days or several weeks after the onset of the infection. Clinical diagnosis of rubella is not reliable, and its rarity today means that physicians are unlikely to recognize it or consider it as a possible differential diagnosis. Nonetheless, residual circulation of the rubella virus continues in France. A chickenpox rash is diagnosed clinically. For atypical eruptions, the virus can be sought directly in the vesicular fluid. Serology is not helpful in this case. PMID- 26033553 TI - Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semisolid magnetization transfer reference (EMR) signals: II. Comparison of three EMR models and application to human brain glioma at 3 Tesla. AB - PURPOSE: To evaluate the use of three extrapolated semisolid magnetization transfer reference (EMR) methods to quantify amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) signals in human glioma. METHODS: Eleven patients with high-grade glioma were scanned at 3 Tesla. aEMR(2) (asymmetric magnetization-transfer or MT model to fit two-sided, wide-offset data), sEMR(2) (symmetric MT model to fit two-sided, wide-offset data), and sEMR(1) (symmetric MT model to fit one-sided, wide-offset data) were assessed. ZEMR and experimental data at 3.5 ppm and -3.5 ppm were subtracted to calculate the APT and NOE signals (APT(#) and NOE(#)), respectively. RESULTS: The aEMR(2) and sEMR(1) models provided quite similar APT(#) signals, while the sEMR(2) provided somewhat lower APT(#) signals. The aEMR(2) had an erroneous NOE(#) quantification. Calculated APT(#) signal intensities of glioma (~4%), much larger than the values reported previously, were significantly higher than those of edema and normal tissue. Compared with normal tissue, gadolinium-enhancing tumor cores were consistently hyperintense on the APT(#) maps and slightly hypointense on the NOE(#) maps. CONCLUSION: The sEMR(1) model is the best choice for accurately quantifying APT and NOE signals. The APT-weighted hyperintensity in the tumor was dominated by the APT effect, and the MT asymmetry at 3.5 ppm is a reliable and valid metric for APT imaging of gliomas at 3T. PMID- 26033556 TI - [Influenza and pregnancy]. AB - Influenza is a respiratory disease caused by influenza viruses. The virus is responsible for pandemics by emergence of new viral strains, then for seasonal flu by antigenic drift. Seasonal flu is more frequent and severe in pregnant women, with increased risk of pneumonia and increased risk of hospitalization (but no increased death reported). Pandemic flu is more severe in pregnant women, with increased risk of pneumonia and increased mortality. Influenza vaccination is recommended for all women who are or will be pregnant (in any trimester) during influenza season. After closed contact with a flu case or in case of symptoms compatible with flu, early oseltamivir-based treatment (prophylactic in the first situation, curative in the latter one) is recommended, at any term of pregnancy. The occurrence of flu symptoms in a pregnant woman requires medical evaluation to confirm the diagnosis or identify any alternative infection requiring appropriate therapy like listeriosis, chorioamniotitis, pyelonephritis or viral primo-infection. PMID- 26033557 TI - [Acute herpesviridae hepatitis during pregnancy: A review]. AB - Viral hepatitis are well defined during pregnancy, including hepatitis A, B, C, D or E. In contrast, viral hepatitis called non-alphabetic, like viruses Herpesviridae family hepatitis [cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV) or herpes simplex virus (HSV)] are rarely described. The aim of this article is to make a focus on the care of these viral herpesviridae hepatitis during pregnancy. Herpes hepatitis is more common during pregnancy, with a neonatal risk at peripartum period. VZV infection can cause disease to the fetus, with possible vertical transmission, and induce congenital or neonatal varicella. While EBV infection during pregnancy seems benign, the CMV is a high risk of birth defects. The management of these patients therefore depends on the gestational age, but especially the type of virus involved. The diagnosis is therefore essential to adapt treatment and obstetrical care. PMID- 26033558 TI - [Syphilis and pregnancy]. AB - Syphilis is a sexually transmitted disease responsible for a congenital severe infection. Congenital syphilis is complicated by fetal loss/neonatal death (50%), prematurity (25%) and major long term sequelae in other surviving children (20%). Every woman delivering a stillborn after 20WG should be tested for syphilis. Early screening is the cornerstone of prevention, and should be repeated in women at higher risk of contamination. Maternal management relies on early benzathine penicillin administration. Neonatal management relies on early diagnosis and prompt adequate penicillin therapy. PMID- 26033559 TI - [Pregnancy and viral hepatitis B and C]. AB - The screening for HBsAg is a medical obligation in France during pregnancy. A serovaccination with antiHBs immunoglobulins (100 IU) and a 1st dose of vaccine (10 MUg) has to be realized during the first 12 hours of life when the mother is HBsAg+. The serovaccination failures are related to high maternal viral load (HBV DNA>7 log IU/mL). In this case, a treatment with analogue (tenofovir) associated with serovaccination could be performed during the last trimester of pregnancy. The risk of mother-to-child transmission of virus C is around 3 to 5% in case of HCV-RNA positive without co-infection with HIV. The mode of delivery is unchanged in case of maternal HBV or HCV. Breast-feeding is not contra-indicated in case of maternal HBV or HCV infection. PMID- 26033560 TI - [The pregnant traveller]. AB - Pregnancy is a physiological situation that requires specific and careful preparation before travel. Malaria, dengue fever and viral hepatitis E are more severe in pregnancy and at higher risk of adverse obstetrical outcome. Medical and obstetrical contra-indications to travel should be listed during pre-travel evaluation. Vaccine indications are the same as in the general population, and must be discussed after a rigorous benefit-risk analysis. Pregnant women should avoid or delay travel in areas of high malarial chloroquino-resistance. PMID- 26033561 TI - Update on Takayasu's arteritis. AB - Takayasu arteritis (TAK) is a rare, chronic large-vessel vasculitis (LVV) that predominantly affects aorta, its major branches and the pulmonary arteries. Recent advances in the genetics, clinical course, prognosis, disease assessment with biomakers/imaging/new scoring systems and new treatment options in TAK are discussed in this review. New imaging modalities such as MRAngiography (MRA) and 18-FDG-PET seem to have replaced conventional angiography for the initial diagnosis in recent years. MRA and 18-FDG-PET are also promising for the assessment of disease activity. New tools for disease assessment such as Indian Takayasu Arteritis Score (ITAS2010) and colour-Doppler ultrasonography score (CDUS) aim to quantify disease activity better, however different imaging modalities, used in routine follow-up, are not sufficiently incorporated in these scoring systems. Prognosis is possibly getting better with lower mortality in recent years, however there are still widely different vascular intervention rates in clinical series. Leflunomide, TNF-alpha antagonists and tocilizumab are new options in patients resistant to conventional therapies. PMID- 26033562 TI - Recent pathogenetic advances in ANCA-associated vasculitis. AB - Since the discovery of anti-neutrophil cytoplasmic autoantibodies (ANCA), great strides have been made in elucidating the etiology and pathogenesis of disease. In this article, we review recent published key breakthroughs in understanding the pathogenesis of ANCA vasculitis, including some that may lead to novel therapeutics. These breakthroughs have occurred in multiple areas of investigation. A European genome-wide association study (GWAS) revealed the importance of the genetic contribution of proteinase 3 (PR3) and its endogenous inhibitor, alpha (1)-antitrypsin as well as HLA risk. Epigenetic modification of autoantigen genes appears to contribute to perpetuation of disease and possibly relapse risk. Autoantigen excision, a novel method to detect autoantibody epitopes using mass spectrometry, not only revealed pathogenic epitopes in myeloperoxidase (MPO)-ANCA vasculitis and identified unique MPO-ANCA responsible for the majority of ANCA-negative small vessel vasculitis, but has vast applicability to other autoantibody-mediated diseases. An explosion of biomarker studies has revealed circulating cytokines and alternative complement pathway products that may predict active disease. Interestingly, alternative complement pathway blockade in the murine model of disease is protective and a clinical trial in humans using an oral alternative complement pathway inhibitor is underway. Increasing clarity of the role of B and T cells in disease pathogenesis is ongoing. B cell depleting agents have shown great utility in remission induction and maintenance, and monitoring specific B cell subsets during the disease course may have predictive power for remission maintenance. Despite these substantial advances, more research is needed including, but not limited to, validation of existing discoveries. As additional novel discoveries emerge, so will novel therapies, and it is with great hope that these collective insights will ultimately lead to prevention and cure. PMID- 26033563 TI - Improving the reliability of verbal communication between primary care physicians and pediatric hospitalists at hospital discharge. AB - INTRODUCTION: Timely and reliable verbal communication between hospitalists and primary care physicians (PCPs) is critical for prevention of medical adverse events but difficult in practice. Our aim was to increase the proportion of completed verbal handoffs from on-call residents or attendings to PCPs within 24 hours of patient discharge from a hospital medicine service to >=90% within 18 months. METHODS: A multidisciplinary team collaborated to redesign the process by which PCPs were contacted following patient discharge. Interventions focused on the key drivers of obtaining stakeholder buy-in, standardization of the communication process, including assigning primary responsibility for discharge communication to a single resident on each team and batching calls during times of maximum resident availability, reliable automated process initiation through leveraging the electronic health record (EHR), and transparency of data. A run chart assessed the impact of interventions over time. RESULTS: The percentage of calls initiated within 24 hours of discharge improved from 52% to 97%, and the percentage of calls completed improved to 93%. Results were sustained for 18 months. Standardization of the communication process through hospital telephone operators, use of the discharge order to ensure initiation of discharge communication, and batching of phone calls were associated with improvements in our measures. CONCLUSION: Reliable verbal discharge communication can be achieved through the use of a standardized discharge communication process coupled with the EHR. PMID- 26033564 TI - Rare but Life-Threatening Complication: Delayed Common Iliac Vein Perforation by Hemodialysis Catheter. PMID- 26033566 TI - On the difficulty to communicate with fMRI-based protocols used to identify covert awareness. AB - Assessment of awareness in patients with disorders of consciousness such as patients in a vegetative state (unresponsive wakefulness syndrome, UWS) and patients in a minimally conscious state (MCS) remains difficult, with a high rate of misdiagnosis (around 40%). While patients with UWS have no awareness, patients with MCS have partial preservation of conscious awareness. To improve the assessment of awareness in these patients, recent functional neuroimaging protocols have been developed. However, does the complexity of realizing and interpreting these functional magnetic resonance imaging (fMRI) investigation protocols, which are currently carried out by only a few specialist teams, permit generalizable use in clinical routine? In this study, 32 healthy volunteers, by definition perfectly conscious and able to efficiently communicate, performed the protocol proposed by Monti et al. in 2010. Four methods (comprising the method proposed by Monti et al., a mean squared error-based method, a correlation-based method, and a support vector machine-based method) were tested for correctly and accurately interpreting the communication task. Firstly, the different instructions for the localizer and the communication tasks had no effect on activations. Secondly, 25% of participants (8/32) did not provide the expected patterns of activations during fMRI tasks (four for each imagery task). However, this did not necessarily prevent the classification methods from correctly guessing the answers during the communication task. Conversely, these classification methods may fail to detect the correct answers even though participants activated the expected brain areas. None of the four methods produced 100% correct detection during the communication phases. The correlation based method obtained the best results with an error rate of 4.2%. The results of this study demonstrate that fMRI-based communication paradigms may not be robust enough to reliably detect awareness in all aware patients. There is still a need to develop new statistical and analytical methods before considering their generalization in clinical routine. PMID- 26033567 TI - [Hydrogen sulfide: A promising therapy in neuroprotection following cardiac arrest?]. AB - Each year, in France, the number of cardiac arrests is evaluated between 30,000 to 50,000. When a patient survives, he undergoes a post-resuscitation syndrome which can aggravate the injuries and for which nowadays, no medication is available. In some kinds of cardiac arrest, a hypothermia protocol can be applied with a need for monitoring because of the appearance of side effects. In this context, hydrogen sulfide, which is a gasotransmitter with numerous physiological and pharmacological properties, may be interesting. Indeed, its use could protect against oxidative, inflammatory and apoptotic troubles induced by the post resuscitation syndrome. The implied biochemical mechanisms are adenosine triphosphate potassium channels activation and cytochrome c oxidase inhibition. This molecule can also induce a suspended animation state characterized by a metabolism decrease, which could give a delay for physicians to start a therapeutic monitoring. Thus, in spite of a modest and sometimes contradictory literature, this compound could become the first neuroprotective molecule in cardiac arrest. PMID- 26033565 TI - Dysregulated TNFalpha promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity. AB - BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is increased in patients with headache, neuropathic pain, periodontal and temporomandibular disease. This study and others have utilized TNF receptor 1/2 (TNFR1/2) knockout (KO) animals to investigate the effect of TNFalpha dysregulation in generation and maintenance of chronic neuropathic pain. The present study determined the impact of TNFalpha dysregulation in a trigeminal inflammatory compression (TIC) nerve injury model comparing wild-type (WT) and TNFR1/2 KO mice. METHODS: Chromic gut suture was inserted adjacent to the infraorbital nerve to induce the TIC model mechanical hypersensitivity. Cytokine proteome profiles demonstrated serology, and morphology explored microglial activation in trigeminal nucleus 10weeks post. RESULTS: TIC injury induced ipsilateral whisker pad mechanical allodynia persisting throughout the 10-week study in both TNFR1/2 KO and WT mice. Delayed mechanical allodynia developed on the contralateral whisker pad in TNFR1/2 KO mice but not in WT mice. Proteomic profiling 10weeks after chronic TIC injury revealed TNFalpha, interleukin-1alpha (IL-1alpha), interleukin-5 (IL-5), interleukin-23 (IL-23), macrophage inflammatory protein-1beta (MIP-1beta), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased more than 2-fold in TNFR1/2 KO mice compared to WT mice with TIC. Bilateral microglial activation in spinal trigeminal nucleus was detected only in TNFR1/2 KO mice. p38 mitogen-activated protein kinase (MAPK) inhibitor and microglial inhibitor minocycline reduced hypersensitivity. CONCLUSIONS: The results suggest the dysregulated serum cytokine proteome profile and bilateral spinal trigeminal nucleus microglial activation are contributory to the bilateral mechanical hypersensitization in this chronic trigeminal neuropathic pain model in the mice with TNFalpha dysregulation. Data support involvement of both neurogenic and humoral influences in chronic neuropathic pain. PMID- 26033568 TI - Transvaginal/transrectal ultrasound for preoperative identification of high-risk cases in well- or moderately differentiated endometrioid carcinoma. AB - OBJECTIVE: To evaluate the role of transvaginal/transrectal ultrasound for preoperative identification of high-risk cases among women with well differentiated (G1) or moderately differentiated (G2) endometrioid carcinoma of the endometrium. METHODS: This was a single-center prospective observational cohort study comprising a consecutive series of women with a preoperative diagnosis of G1/G2 endometrioid carcinoma of the endometrium. All women underwent transvaginal or transrectal ultrasound examination by a single examiner. According to the examiner's subjective impression, patients were considered high risk if myometrial infiltration was >= 50% and/or involvement of the cervix and/or adnexa was suspected. FIGO surgical staging was performed in all cases. According to definitive histological data regarding myometrial infiltration, cervical involvement and adnexal involvement, women were classified as low risk (no myometrial infiltration, no cervical involvement and no adnexal involvement) or high risk (myometrial infiltration >= 50% and/or cervical involvement and/or adnexal involvement). Sensitivity, specificity and positive (LR+) and negative (LR-) likelihood ratios, with 95% CIs, of transvaginal/transrectal ultrasound for detecting stage >= IB were calculated. Agreement between risk determined by transvaginal/transrectal ultrasound and postoperative definitive histology was calculated. RESULTS: Of 209 eligible women, 169 were included in the study. Mean (+/- SD) age of the study cohort was 60.7 +/- 10.3 years, with a range of 32-91 years. Sensitivity, specificity, LR+ and LR- of transvaginal/transrectal ultrasound identifying high-risk cases according to myometrial infiltration, cervical involvement and adnexal involvement were 78.0% (95% CI, 63.7-88.0%), 89.1% (95% CI, 81.7-93.8%), 7.14 (95% CI, 4.19-12.18) and 0.25 (95% CI, 0.15 0.42), respectively. CONCLUSIONS: Preoperative transvaginal/transrectal ultrasound may play a significant role in identifying high-risk cases among those with G1/G2 endometrioid carcinoma of the endometrium according to preoperative biopsy, and could be a useful test in this clinical setting. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26033569 TI - A comparison of mental state examination documentation by junior clinicians in electronic health records before and after the introduction of a semi-structured assessment template (OPCRIT+). AB - OBJECTIVES: The mental state examination (MSE) provides crucial information for healthcare professionals in the assessment and treatment of psychiatric patients as well as potentially providing valuable data for mental health researchers accessing electronic health records (EHRs). We wished to establish if improvements could be achieved in the documenting of MSEs by junior doctors within a large United Kingdom mental health trust following the introduction of an EHR based semi-structured MSE assessment template (OPCRIT+). METHODS: First, three consultant psychiatrists using a modified version of the Physician Documentation Quality Instrument-9 (PDQI-9) blindly rated fifty MSEs written using OPCRIT+ and fifty normal MSEs written with no template. Second, we conducted an audit to compare the frequency with which individual components of the MSE were documented in the normal MSEs compared with the OPCRIT+MSEs. RESULTS: PDQI-9 ratings indicated that the OPCRIT+MSEs were more 'Thorough', 'Organized', 'Useful' and 'Comprehensible' as well as being of an overall higher quality than the normal MSEs. The audit identified that the normal MSEs contained fewer mentions of the individual components of 'Thought content', 'Anxiety' and 'Cognition & Insight'. CONCLUSIONS: These results indicate that a semi-structured assessment template significantly improves the quality of MSE recording by junior doctors within EHRs. Future work should focus on whether such improvements translate into better patient outcomes and have the ability to improve the quality of information available on EHRs to researchers. PMID- 26033570 TI - Quantitative proteomic analysis of mitochondria from human ovarian cancer cells and their paclitaxel-resistant sublines. AB - Paclitaxel resistance is a major obstacle for the treatment of ovarian cancer. The chemoresistance mechanisms are partly related to the mitochondria. Identification of the relevant proteins in mitochondria will help in clarifying the possible mechanisms and in selecting effective chemotherapy for patients with paclitaxel resistance. In the present study, mitochondria from two paclitaxel sensitive human ovarian cancer cell lines (SKOV3 and A2780) and their corresponding resistant cell lines (SKOV3-TR and A2780-TR) were isolated. Guanidine-modified acetyl-stable isotope labeling and liquid chromatography hybrid linear ion trap Fourier-transform ion cyclotron resonance mass spectrometry (LC-FTICR MS) were performed to find the expressed differential proteins. Comparative proteomic analysis revealed eight differentially expressed proteins in the ovarian cancer cells and their paclitaxel-resistant sublines. Among them, mimitin and 14-3-3 zeta/delta were selected for further research. The effects of mimitin and 14-3-3 zeta/delta were explored using specific siRNA interference in ovarian cancer cell lines and immunohistochemistry in human tissue specimens. The downregulation of mimitin and 14-3-3 zeta/delta using specific siRNA in paclitaxel-resistant ovarian cancer cells led to an increase in the resistance index to paclitaxel. Multivariate analyses demonstrated that lower expression levels of the mimitin and 14-3-3 zeta/delta proteins were positively associated with shorter progression-free survival (PFS) and overall survival (OS) in patients with primary ovarian cancer (mimitin: PFS: P = 0.041, OS: P = 0.003; 14-3-3 zeta/delta: PFS: P = 0.031, OS: P = 0.011). Mimitin and 14-3-3 protein zeta/delta are potential markers of paclitaxel resistance and prognostic factors in ovarian cancer. PMID- 26033572 TI - Capillary electrophoretic study of green fluorescent hollow carbon nanoparticles. AB - CE coupled with laser-induced fluorescence and UV absorption detections has been applied to study the complexity of as-synthesized green fluorescent hollow carbon nanoparticles (HC-NP) samples. The effects of pH, type, and concentration of the run buffer and SDS on the separation of HC-NP are studied in detail. It is observed that phosphate run buffer is more effective in separating the HC-NP and the optimal run buffer is found to be 30 mM phosphate and 10 mM SDS at pH 9.0. The CE separation of this HC-NP is based on the difference in size and electrophoretic mobility of HC-NP. Some selected HC-NP fractions are collected and further characterized by UV-visible absorption and photoluminescence (PL) spectroscopy, MS, and transmission electron microscopy. The fractionated HC-NP show profound differences in absorption, emission characteristics, and PL quantum yield that would have been otherwise misled by studying the complex mixture alone. It is anticipated that our CE methodology will open a new initiative on extensive studies of individual HC-NP species in the biomedical, catalysis, electronic, and optical device, energy storage, material, and sensing field. PMID- 26033571 TI - Further evidence that paroxysmal nocturnal haemoglobinuria is a disorder of defective cell membrane lipid rafts. AB - The glycolipid glycosylphosphatidylinositol anchor (GPI-A) plays an important role in lipid raft formation, which is required for proper expression on the cell surface of two inhibitors of the complement cascade, CD55 and CD59. The absence of these markers from the surface of blood cells, including erythrocytes, makes the cells susceptible to complement lysis, as seen in patients suffering from paroxysmal nocturnal haemoglobinuria (PNH). However, the explanation for why PNH affected hematopoietic stem/progenitor cells (HSPCs) expand over time in BM is still unclear. Here, we propose an explanation for this phenomenon and provide evidence that a defect in lipid raft formation in HSPCs leads to defective CXCR4- and VLA-4-mediated retention of these cells in BM. In support of this possibility, BM-isolated CD34(+) cells from PNH patients show a defect in the incorporation of CXCR4 and VLA-4 into membrane lipid rafts, respond weakly to SDF 1 stimulation, and show defective adhesion to fibronectin. Similar data were obtained with the GPI-A(-) Jurkat cell line. Moreover, we also report that chimeric mice transplanted with CD55(-/-) CD59(-/-) BM cells but with proper GPI A expression do not expand over time in transplanted hosts. On the basis of these findings, we propose that a defect in lipid raft formation in PNH-mutated HSPCs makes these cells more mobile, so that they expand and out-compete normal HSPCs from their BM niches over time. PMID- 26033573 TI - An Alternative Anionic Polyelectrolyte for Aqueous PEDOT Dispersions: Toward Printable Transparent Electrodes. AB - Organic conducting polymers are promising electrode materials for printable organic electronics. One of the most studied conducting polymers is PEDOT: PSS, which is sufficiently conductive and transparent, but which shows some drawbacks, such as hygroscopicity and acidity. A new approach to stabilize PEDOT in aqueous dispersions involves the replacement of PSS with a basic polyanion based on a polystyrene backbone with (trifluoromethylsulfonyl)imide (TSFI) side groups. The PEDOT: PSTFSIK dispersions were obtained by oxidative polymerization of EDOT in an aqueous PSTFSIK solution and were characterized with regard to their composition, morphology, doping, rheological behavior, and optoelectronic performance. The PEDOT: PSTFSIK dispersions showed excellent printability and good optoelectronic performance (238 Ohm sq(-1) at 91% transmittance, sigma>260 S cm(-1)) and were successfully integrated as flexible electrodes in OLED and OPV devices. PMID- 26033574 TI - [Treatment preferences of elderly patients with mental disorders]. AB - BACKGROUND: Successful treatment in psychosomatic medicine requires intrinsic motivation of the patient and the belief that the chosen therapeutic option can help. Depression, somatization disorder and generalized anxiety disorder (GAD) are frequent mental disorders in the elderly population. Finding a suitable and successful treatment for elderly people with mental disorders is often difficult. Undertreatment and the utilization of inappropriate healthcare services are frequent. OBJECTIVE: Treatment preferences of elderly patients with mental disorders were ascertained in order to evaluate the motivation for psychotherapy or other therapeutic measures. MATERIAL AND METHODS: The data were derived from the 8-year follow-up of the epidemiological study on chances of prevention, early recognition and optimized therapy of chronic diseases in the elderly population (ESTHER), a population-based cohort study in Saarland, Germany. A total of 3124 patients aged 55-84 years were included in this analysis. The treatment preferences were documented using a questionnaire with 12 different answer categories. The occurrence of depression, somatization disorder and GAD was collated using the patient health questionnaire (PHQ-D). RESULTS: Physiotherapy and inpatient rehabilitation were the most frequently named treatment preferences in all three subgroups of patients with mental disorders. Psychotherapy was the preferred treatment for 18.3 % of depressive patients, for 15.0 % of somatization patients and for 15.7 % of GAD patients. CONCLUSION: Mentally ill elderly patients in Germany preferred physical treatment techniques, such as physiotherapy and inpatient rehabilitation over psychotherapy. Discussion is needed over the reasons for these findings and the clinical implications. PMID- 26033575 TI - [Organization and perception of low threshold services for older migrants in communities. Chances for social participation in the context of voluntary engagement]. AB - BACKGROUND: There is still a problematic situation in Germany for older migrants, who can be characterized by poverty, lack of knowledge of the healthcare system, generation conflicts and social exclusion. AIM: The objective of this article is the analysis of the chances for social participation of older migrants from two perspectives. MATERIAL AND METHODS: This qualitative study is based on an interdisciplinary research project sponsored by the German Federal Ministry of Education and Research entitled "Cultures of social participation in local communities" (KUSTIS) from the promotion program "Social innovations for quality of life in old age " (SILQUA) and presents selected results from two subprojects. The investigation explored the possibilities for social participation by older migrants in two suburbs of Bremen in Germany, Gropelingen and Vahr, which have higher than average migrant Turkish and Russian populations. The results of the 3 year study are presented. The first subproject looked at how 40 migrants aged 60 years and over perceived the support from migrant low threshold services and focused on their wishes and needs using a qualitative content analysis. The second subproject investigated the voluntary engagement for older migrants in an intercultural context through considering the views of volunteers who worked with older migrants (28 interviews and 4 focus groups). RESULTS AND CONCLUSION: Both subprojects complement each other to provide an integrated view of low threshold services for older migrants. The analysis shows the significance of migrant organizations for social participation, the heterogeneity of life circumstances, the motivation of engagement and the need for social acknowledgement. PMID- 26033576 TI - Antagonists of Metabotropic Glutamate Receptors Prevent the Development of Audiogenic Seizures. AB - Pretreatment with mGluR1 antagonist AIDA (1 mg/kg) nearly completely prevented the onset of tonic-clonic seizures and increased generation of NO in the cerebral cortex of rats with genetically determined audiogenic reaction to acoustic stimulation. Administration of mGluR5 antagonist MPEP (10 mg/kg) before audiogenic exposure was followed by a significant decrease in the degree of seizure and partially prevented increased generation of NO due to acoustic stimulation. These data indicate that mGlu receptors and NO play an important role in the pathogenetic mechanisms of audiogenic seizures. PMID- 26033577 TI - Postischemic Responsiveness of Pial Vessels to Hypercapnia. AB - Reactions of pial vessels to hypercapnia were studied in Wistar rats one week after global cerebral ischemia. In ischemic rats, the responsiveness of pial vessels to hypercapnia was diminished, which promoted a decrease in cerebral perfusion reserve. Changes in vascular responsiveness in the arterial and venous subdivisions of the vascular bed were observed and probably resulted from ischemia-provoked down-regulation of the vascular tone. PMID- 26033578 TI - Different Myocardial Sensitivity in Newborn and Mature Rats to Selective Stimulation of M3 Cholinoreceptors. AB - The effects of selective activation of subtype 3 muscarinic (M3) receptors on electrical activity of isolated preparations of the atrial and ventricular myocardium of the newborn and 4-month-old rats were examined. Application of muscarinic receptor agonist pilocarpine (10(-5) M) in preparations with M2 cholinoreceptors blocked by selective antagonist methoctramine (10(-7) M) decreased the duration of action potentials in the atrial and ventricular myocardium. Selective blocker of M3 cholinoreceptors 4-DAMP (10(-8) M) prevented this effect. While stimulation of ventricular M3 cholinoreceptors with pilocarpine was significantly stronger in newborn pups than in mature rats, similar stimulation of atrial receptors revealed no significant difference in both groups. PMID- 26033579 TI - Electrical Rhythms Revealed by Harmonic Analysis of a High-Resolution Cardiogram. AB - The front-end low-noise electronic amplifiers and high-throughput computing systems made it possible to record ECG with a high resolution in the low frequency range including the respiration and Mayer frequencies and to analyze ECG with digital filtering technique and harmonic analysis. These tools yielded ECG spectra of narcotized rats, which contained the characteristic pulsatile triplets and pentaplets with splitting constant equal to respiration rate, as well as the peaks at respiration and Mayer frequencies. The harmonic analysis of ECG determined the frequency parameters employed to tune the software bandpass filters, which revealed the respiratory (R) and Mayer (M) waves in the time domain with the amplitudes of 20-30 MUV amounting to 5% ECG amplitude. The depolarizing myorelaxant succinylcholine chloride capable to trigger various types of arrhythmias, transiently increased R-wave, inhibited M-wave, and provoked a negative U-wave within a heartbeat ECG cycle synchronously with inspiration. It is hypothesized that M-, R-, and U-waves in ECG reflect cardiotropic activity of autonomic nervous system. The respective spectral peaks in ECG can be employed to assess intensity of sympathetic and parasympathetic cardiotropic influences, their balance, and the risk of arrhythmias. PMID- 26033580 TI - Mitral and Aortic Valvulitis in Primary Chronic Septic Endocarditis. AB - Results of long-term prospective follow-up of patients with early stages of mitral and aortic valvulitis and primary chronic septic endocarditic are presented. Clinical diagnostics of the diseases is described and the key role is assigned to pathognomic (absolute) clinical symptoms. The tendency to progressive fibrosis of endocardial structures with subsequent gradual development of valve dysfunction and stenosis (especially for the mitral valve) is revealed. It is shown that early treatment increases the effective valve area and promotes reversion of mitral stenosis. The possibility of early diagnostics of primary chronic septic endocarditis in combination with adequate etiopathogenetic therapy provide the basis for prevention of acquired valvular disease. PMID- 26033581 TI - Correction of Hormonal and Metabolic Disorders in Male Rats with Developing Experimental Diabetes. AB - Synthetic radioinert androgen methyltrienolone administered daily for 2 weeks to male rats with severe diabetes led to a sharp increase in blood testosterone and was accompanied by reduction in glucose level due to an increase in tissue sensitivity to insulin. Normalization of plasma testosterone concentration contributed to saturation of active androgen receptors in the myocardium with testosterone; the number of free receptors decreased by 1.8 times. Testosterone that diminishes the catabolic effects of glucocorticoids improved the state of the myocardium, which was confirmed by activation of DNA and RNA synthesis. PMID- 26033582 TI - Role of Endogenous Factors in Response of Erythrocyte Membrane in Patients with Cardiovascular Diseases under Conditions of Ischemic Exposure. AB - We studied specific features of erythrocyte membrane response to short-term occlusion of the brachial artery in patients with cardiovascular pathology. Under ischemic conditions, processes of sorption were primarily intensified in patients with effort angina and processes of hemoglobin binding with erythrocyte membrane predominated in patients with essential hypertension. These changes in the cell membrane were related to modulation of aggregation properties of erythrocytes (in patients with angina) and plasminogen activity (in patients with essential hypertension). They can also be associated with changes in glucose levels (effort angina) and uric acid (essential hypertension) whose effects can be significantly modified by other endogenous factors. PMID- 26033583 TI - Characteristics of Diffusion in the Corticospinal Tract of Patients with Early Stage of Schizophrenia: Diffusion Tensor Magnetic Resonance Imaging. AB - Specific features of diffusion in the cerebral corticospinal tract of patients with early stages of schizophrenia were studied using methods of diffusion tensor magnetic-resonance imaging and magnetic resonance spectroscopy. A decrease in the coefficient of fractional anisotropy in the posterior limb of the internal capsule and an increase in diffusion coefficient in the radiate crown and motor cortex were observed. The results reflect different mechanisms of changes in water diffusion in various areas of the corticospinal tract: changes in nerve fiber microstructure in the internal capsule of the left hemisphere and a decrease in their density in the motor cortex and radiate crown. PMID- 26033584 TI - Lympho- and Hemodynamics in Dogs with Acute Experimental Pancreatitis. AB - Dogs with experimental pancreatitis showed increased lymph fl ow, impaired rheological properties of the lymph and blood plasma, and increased plasma and blood levels of glucose, ALT, and AST. PMID- 26033585 TI - Amino Acid Correction of Regulatory Volume Decrease Evoked by Hypotonic Stress in Mouse Oocytes In Vitro. AB - Regulatory volume decrease in response to hypotonic stress is typical of the oocytes and early mouse embryos. Changes in the kinetics of osmotic reaction can be used as a marker of the modulating effect of the incubation medium on transmembrane transport in embryonic cells. Quantitative laser scanning microtomography (QLSM) was used to measure oocyte volume. In this paper, it is shown that addition of 5 MUM glycine, taurine, or GABA, as well as ATP to Dulbecco's medium abolished the regulatory volume decrease in mature mouse oocytes. PMID- 26033586 TI - Antioxidant Defense System after Single and Chronic Administration of Obestatin and Its Fragment (1-4) to Normal and Overweight Male Rats. AB - We studied the effects of anorectic peptide obestatin and its fragment (1-4) on the antioxidant defense system in animals with normal and experimentally induced increased body weight. In rats with normal body weight, no changes in activity of the antioxidant defense system 1 week after single administration of the substances. After chronic administration of obestatin and fragment (1-4) for 1 week, total antioxidant capacity of the plasma decreased; obestatin also lowered the content of TBA-reactive products. In the overweight rats, SOD-like activity in the plasma increased 1 week after chronic administration of obestatin. Hence, obestatin and its fragment (1-4) induced changes in the antioxidant defense system only after chronic administration. PMID- 26033587 TI - Antithrombotic Activity of a New Hypoglycemic Compound Limiglidole in Mouse Model of Cell Thrombosis. AB - Antithrombotic activity of hypoglycemic compound limiglidole that exhibits antiplatelet activity 2-fold exceeded activity of antiplatelet agent acetylsalicylic acid in the mouse model of systemic collagen-epinephrine thrombosis. Limiglidole signifi cantly reduced the relative and mean area of blood clots in the sections of mouse lungs. PMID- 26033588 TI - Cytoprotective Effect of Afobazole and Its Main Metabolite M-11. AB - Cell damage depending on activity of quinone reductase 2 (MT3 receptor) was simulated in experiments on bone marrow cell suspension and assessed by menadione induced DNA breaks measured by comet assay. We analyzed the protective effect of afobazole interacting with MT1, MT3, sigma1 receptors, and monoamine oxidase A and its main metabolite M11 that specifi cally binds to MT3 receptors. Both compounds reduced the level of menadione-induced DNA damage (afobazole was effective in lower concentrations in comparison with M-11). Conclusion was made on the contribution of MT3 receptors to the protective effect of afobazole, but the observed concentration differences indicate possible contribution of other targets of anxiolytic drug to the protective mechanisms. PMID- 26033589 TI - Effects of Phenibut and Citrocard on Non-Competitive and Competitive Behavior during Provoked Aggression in Animals. AB - Anti-aggressive effects of phenibut (25 mg/kg) and its structural analogue citrocard (50 mg/kg) were revealed in rats under condition of provoked intraspecific aggression. These substances significantly decreased manifestations of aggression in animals: they increased the latency of attacks and reduced their number. Anti-aggressive effects of citrocard were more pronounced than effects of phenibut under conditions of non-competitive aggression induced by fear of inescapable painful exposure or under conditions of competitive aggression reflecting the ability of animals to reveal adaptive social communicative skills in aversive situation. PMID- 26033590 TI - Intraperitoneal Administration of Muramyl Dipeptide beta-Heptylglycoside to Pregnant and Non-Pregnant Female Mice Modulates Production of Th1/Th2/Th17/Tr1 Cytokines by Splenocytes Ex Vivo. AB - Muramyl dipeptide beta-heptylglycoside (C7MDP) was administered to non-pregnant CBA female mice and pregnant mice after non-abortion-prone mating (CBA*BALB/c) and mating associated with a high rate of spontaneous abortion (CBA*DBA/2). In non-pregnant females, C7MDP increased the production of IL-2, IL-4, IL-5, IL-6, IL-17, IFNgamma, TNFalpha, and GM-CSF at constant production of IL-1alpha and IL 10. C7MDP increased the production of IL-10 and IL-17 and suppressed the production of IFNgamma on day 8 of gestation in non-abortion-prone mouse couples and stimulated the synthesis of IL-4 and IFNgamma, reduced IL-5 production, and slightly increased IL-1alpha secretion after abortion-prone mating. On day 14 of gestation, C7MDP elevated the yield of IL-2, IL-4, IFNgamma, TNFalpha, and GM-CSF in CBA*BALB/c and CBA*DBA/2 couples and IL-17 in the fi rst variant of mating. PMID- 26033591 TI - Involvement of PI3K, MAPK ERK1/2 and p38 in Functional Stimulation of Mesenchymal Progenitor Cells by Alkaloid Songorine. AB - We studied the role of intracellular signaling molecules PI3K, MARK ERK1/2, and r38 in stimulation of realization of the growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Inhibitors of PI3K, ERK1/2 and r38 canceled the increase in proliferative activity of progenitor cells, the blockers of ERK1/2 and r38 reduced the intensity of progenitor cell differentiation. PMID- 26033592 TI - Chrono- and Immunocorrection of Inflammatory Disorders of Internal Reproductive Organs in Women of Reproductive Age. AB - We compared the effectiveness of immunomodulators used in the treatment of patients with chronic salpingitis and oophoritis with or without changes in succinate dehydrogenase (SDH) activity in blood lymphocytes at incubation with the drug. Diurnal variations in individual reaction of SDH in blood lymphocytes to thymalin or ridostin were revealed. In the groups of women receiving ridostin or thymalin during the reaction of lymphocyte SDH to it, improvement of clinical laboratory and immunological parameters was observed in the majority of the patients and no effect was found in a lesser group of patients than in the groups treated with drugs during the absence of lymphocyte SDH reaction thereto. The timing of the presence of SDH reaction to drugs in the immunocompetent cells makes it possible to set the optimal daily regime of their application and to select a drug that would be most effective in each particular case. PMID- 26033593 TI - Changed Serum Cytokine Profile in Mice in Response to Streptococcus A Culture. AB - Comparative analysis of serum cytokine profiles of CBA mice was carried out 1, 5, 24, and 48 h after intraperitoneal injection of killed culture of different streptococcus A types. The production of cytokines in response to different streptococcus types varied. The highest level was recorded in response to types 1M and 3T+M, more often detected in invasive streptococcal infection. The highest levels of IL-2 were recorded in response to 1M (47-fold increase in comparison with the control) and 3T+M streptococcus types (more than 10-fold increase). Injections of these types also led to an increase of IFN-gamma level (15.6 and 11.3 times, respectively). The level of TNF-alpha increased less (3.6 times in response to 3T+M and 2.6 times in response to 1M type). The levels of IL-5, IL 10, and IL-12 increased 2-3-fold. Injections of 1T and 5M types led to just a 2 fold increase of cytokine levels. These data indicated induction of the immune response trend by mainly Th1 or mixed Th1/Th2 pattern in response to group A streptococcus antigens. PMID- 26033594 TI - Role of Biological Characteristics of Staphylococcus epidermidis in Intraerythrocytic Invasion and in Modulation of Erythrocyte Catalase and Superoxide Dismutase Activities in Experimental Generalized Infection. AB - Studies on mouse model of generalized Staphylococcus epidermidis infection have demonstrated that erythrocytes more often contained microorganisms with pronounced antihemoglobin activity and less frequently with hemolytic activity. Infection with S. epidermidis strains characterized by pronounced hemolytic or antihemoglobin activities was associated with inhibition of erythrocyte catalase and superoxide dismutase activities in all cases, except infection with strains with high antihemoglobin activity, when superoxide dismutase activity increased. PMID- 26033595 TI - Synchronization of the Estrous Cycle against the Background of Increased Excitability in Rats Selected for Catatonic Type of Reaction. AB - Selection for the elevation of catatonic type of reaction in female GC rats ("genetic" and "catatonia") was followed by an increase in the number of intense running episodes in response to acoustic stimulation. The observed changes are typical of increased general excitability in these animals. The phenomenon of estrous cycle synchronization was confirmed by variations in the concentrations of estradiol and progesterone in groups of Wistar and GC rats differing by the degree of synchronization. Some differences were found in the concentration of main sex hormones in the blood from female GC and Wistar rats. PMID- 26033596 TI - Simulation of Chemoperfusion Treatment for Abdominal Carcinomatosis. AB - Experimental perfusion system and technology for normothermic and hyperthermic intraperitoneal chemoperfusion are developed for the treatment of abdominal carcinomatosis in rats with transplanted ovarian cancer. MTD of cisplatin in normothermic intraperitoneal chemoperfusion and hyperthermic perfusion are 40 and 20 mg/kg, i.e. by 10- and 5-fold higher than the dose of this cytostatic for routine intraperitoneal injection. Normothermic intraperitoneal chemoperfusion with cisplatin increases median survival time by 200% (p=0.039) in comparison with intraperitoneal injection. PMID- 26033597 TI - Study of Hamadryas Baboons (Papio Hamadryas) Ability to Solve Object Manipulation Tasks. AB - Cognitive ability to solve object manipulation tasks was evaluated by "string pulling" and "transparent tube" tests. The string pulling task was solved by 7 of 11 animals. The task of object extraction from the tube was too difficult, not a single animal solved it. The authors conclude that Hamadryas baboons demonstrated rather poor ability to solve object manipulation tasks. PMID- 26033598 TI - Morphological Analysis of Neurovascular Changes in the Brain in Unilateral Occlusion of the Common Carotid Artery. AB - Morphological analysis of changes in the brain structures of rats with unilateral occlusion of the common carotid artery showed vascular disorders and neuronal involvement in the anteroparietal cortex and hippocampal CA1 filed on the ipsilateral side. PMID- 26033599 TI - Experimental Modeling of Proliferative Vitreoretinopathy. An Experimental Morphological Study. AB - A model of proliferative vitreoretinopathy induced by simultaneous intravitreal injection of recombinant IL-1beta and platelet concentrate is created and its main morphological manifestations are studied on Chinchilla rabbits. The model reflects pathogenesis of proliferative vitreoretinopathy: epiretinal membrane with the formation of retinal plication, traction detachment of the retina; moderate inflammatory reaction in the uveal tract, in the optic nerve infundibulum, in the vitreous body; intact structural elements of the retina, dissociation of the retinal pigmented epithelium cells with their subsequent migration. The model is adequate to the clinical picture of proliferative vitreoretinopathy in humans, which recommends it for experimental studies of the efficiency of drug therapy and prevention of this disease. PMID- 26033600 TI - Effect of Conditioned Medium and Bone Marrow Stem Cell Lysate on the Course of Acetaminophen-Induced Liver Failure. AB - A composition containing culture medium conditioned by mesenchymal stem cells and mesenchymal stem cell lysate improves biochemical parameters, reduces inflammation, and stimulates regenerative processes in the liver. PMID- 26033601 TI - Peptide Regulation of Cells Renewal Processes in Kidney Tissue Cultures from Young and Old Animals. AB - Polypeptide complex isolated from calf kidneys stimulates the processes of cell renewal in organotypic kidney tissue cultures from young and old rats. The polypeptide complex enhances expression of proliferation marker Ki-67 and reduces expression of proapoptotic peptide p53 in kidney explants obtained from young and old animals. Short peptides T-31 (AED) and T-35 (EDL) also stimulate proliferation and reduce apoptosis of the kidney cells, but to a lesser degree than the polypeptide complex. The results provide the basis for further investigation of the polypeptide complex as a preparation for the therapy of kidney diseases, including age-related pathologies. PMID- 26033602 TI - Acceleration of Angiogenesis after Paravasal Injection of Mesenchymal Stem Cells at the Site of Modeled Venous Thrombosis. AB - The results of transplantation of autologous bone marrow multipotent mesenchymal stem cells carrying GFP gene and labeled with cell nucleus-specific dye DAPI near the thrombosed vein in rat hind limb were studied by methods of luminescent microscopy. It was demonstrated that autologous multipotent mesenchymal stem cells participate in the formation of granulations at the site of surgery. The blood fl ow in the thrombosed great vein was always restored through thrombolysis. We observed no signs of incorporation of the transplanted cells into the wall of the great vessel, clot recanalization, or formation of collaterals. Small branches of the great vein in the affected region were also thrombosed. The blood fl ow in these branches was always restored with participation of the transplanted cells or through clot recanalization or through obliteration of the thrombosed vessels and formation of new vessels. The transplanted cells and structures formed by them were gradually replaced by the recipient cells. PMID- 26033603 TI - Peculiarities of Gene Transfer into Mesenchymal Stem Cells. AB - Murine mesenchymal stem cells in long-term bone marrow culture were genetically labeled using lentiviral vector carrying enhanced green fluorescent protein (eGFP) reporter gene under SFFV promoter or without it. We studied the developmental fate of labeled mesenchymal stem cells in stromal cell layers of long-term bone marrow culture and in ectopic hemopoietic foci formed by these stromal layers under the renal capsule of syngeneic mice. The frequency of labeled polypotent stromal precursors (fibroblast CFU) was analyzed in adherent cell layers of long-term culture and ectopic foci formed from them. The proportion of labeled fibroblast CFU in ectopic foci increased by 10 times in case of implantation of adherent cell layers infected with lentivirus containing eGFP reporter gene without promoter. eGFP expression leads to rejection of labeled stromal cells. Labeling with eGFP-carrying vector without promoter makes possible long-term tracking of mesenchymal stromal cells. PMID- 26033604 TI - Stimulation of Proliferation and Differentiation of Rat Resident Myocardial Cells with Apoptotic Bodies of Cardiomyocytes. AB - Using the cell model of regenerative cardiomyogenesis (formation of contracting cardiomyocyte colonies from resident stem cells), we found that the addition of cardiomyocyte-derived apoptotic bodies to the culture of neonatal myocardial cells stimulated proliferation and differentiation of cardiomyocyte precursors and the frequency of their contraction was 1.5-fold higher than in the control. Systemic administration of cardiomyocyte-derived apoptotic bodies to Wistar rats with chronic postinfarction heart failure during the early period of myocardial remodeling considerably improved the contractile function of the heart. PMID- 26033605 TI - Effect of In Vitro Cold Exposure on Phagocytic Activity of Human Peripheral Blood Neutrophils. AB - Experiments on peripheral blood leukocytes from healthy donors using the biochemiluminescent method demonstrated the possibility of in vitro modulating phagocytic activity of neutrophils by cold exposure. Cold exposure at 2 degrees C for 30 min increased phagocytic activity of cells, while slow cooling to -2 degrees C reduced it. PMID- 26033606 TI - Effect of Monocyte-Like THP-1 Cells on the Formation of Vascular Tubes by EA.Hy926s Endothelial Cells in the Presence of Cytokines. AB - The interaction of endothelial cells with cells of the microenvironment, including monocytes/ macrophages, and extracellular matrix during angiogenesis is controlled by cytokines. The stimulating effect bFGF, IL-8, and VEGF on the formation of capillary-like structures by endothelial cells was demonstrated in both monoculture and in co-culture with THP-1 cells; in the latter case, the effects of bFGF and VEGF were more pronounced. IL-8 reduced branching of vascular tubes in co-culture in comparison with monoculture of endothelial cells. Placental growth factor PlGF had no effect of tube formation by endothelial cells in monoculture, but in co-culture with THP-1 cells this cytokine in high concentrations exhibited proangiogenic activity. TGFb inhibited the formation of vascular tubes by endothelial cells and its antiangiogenic potential was more pronounced in co-culture with THP-1 cells. PMID- 26033607 TI - Long-Term Changes in Proliferative Capacity of Thymocytes and Splenocytes in Mouse Progeny after Stimulation of Maternal Lymphocyte Proliferation at Early Terms of Pregnancy. AB - We studied the possibility of prenatal programming of proliferative potential of thymocytes and splenocytes in the offspring of C57Bl/6 mice via concanavalin A mitogen stimulation of lymphocyte proliferation in maternal organism at the early terms of pregnancy before the formation of immune system organs in the embryo. The offspring demonstrated elevated proliferative activity of thymocytes and splenocytes, enhanced lymphocyte proliferation, and increased production of IL-2 in in vitro response to concanavalin A during the prepubertal period and puberty. Mitogen stimulation of the maternal immune system in early pregnancy results in long-term enhancement of the proliferative potential of thymus and splenic cells in the offspring. PMID- 26033608 TI - Immune Homeostasis of Human Gastric Mucosa in Helicobacter pylori Infection. AB - We present the results of electron microscopic, microbiological, immunohistochemical, and molecular genetic studies of gastric biopsy specimens taken for diagnostic purposes according by clinical indications during examination of patients with gastrointestinal pathology. Immune homeostasis of the gastric mucosa against the background of infection with various pathogen strains of Helicobacter pylori was studied in patients of different age groups with peptic ulcer, gastritis, metaplasia, and cancer. Some peculiarities of Helicobacter pylori contamination in the gastric mucosa were demonstrated. Immune homeostasis of the gastric mucosa in different pathologies was analyzed depending on the Helicobacter pylori genotype. PMID- 26033609 TI - Dipeptides Increase Functional Activity of Human Skin Fibroblasts. AB - We analyzed the effect of dipeptide Glu-Trp and isovaleroyl-Glu-Trp in concentrations of 0.2, 2 and 20 MUg/ml and Actovegin preparation on functional activity of human skin fibroblasts. Dipeptides, especially Glu-Trp, produce a stimulating effect on human skin fibroblasts and their effect is equivalent to that of Actovegin. Dipeptides stimulate cell renewal processes by activating synthesis of Ki-67 and reducing expression of caspase-9 and enhance antioxidant function of the cells by stimulating the expression of Hsp-90 and inducible NO synthase. These findings suggest that dipeptides are promising candidates for preparations stimulating reparative processes. PMID- 26033610 TI - Optimization of the Method of Buccal Epithelial Cell Isolation and Culturing on Collagen Substrate for Ophthalmologic Application. AB - We performed morphofunctional analysis of cultured rabbit buccal epithelial cells in the primary culture, during passaging, and upon interaction with collagen substrates. Three different morphological types were identified. It was demonstrated that precursors of rabbit buccal epithelium were characterized by high proliferative activity, retain their biological properties throughout long term culturing, and adhere to various collagen substrates. PMID- 26033611 TI - Functionally Active Gap Junctions between Connexin 43-Positive Mesenchymal Stem Cells and Glioma Cells. AB - The formation of functional gap junctions between mesenchymal stem cells and cells of low-grade rat glioma C6 cells was studied in in vitro experiments. Immunocytochemical analysis with antibodies to connexin 43 extracellular loop 2 showed that mesenchymal stem cells as well as C6 glioma cells express the main astroglial gap junction protein connexin 43. Analysis of migration activity showed that mesenchymal stem cells actively migrate towards C6 glioma cells. During co-culturing, mesenchymal stem cells and glioma C6 form functionally active gap junctions mediating the transport of cytoplasmic dye from glioma cells to mesenchymal stem cells in the opposite direction. Fluorometry showed that the intensity of transport of low-molecular substances through heterologous gap junctions between mesenchymal stem cells and glioma cells is similar to that through homologous gap junctions between glioma cells. This phenomenon can be used for the development of new methods of cell therapy of high-grade gliomas. PMID- 26033612 TI - Postoperative complications in elderly patients with gastric cancer. AB - BACKGROUND: Elderly patients undergoing gastrectomy are expected to be at high risk of postoperative complications. This retrospective multicenter cohort study assessed complications and long-term outcomes after gastrectomy for gastric cancer (GC). METHODS: A total of 993 patients with GC who had undergone gastrectomy were included, comprising 186 elderly patients (age >= 80 y, E group) and 807 nonelderly patients (age <= 79 y, NE group). Preoperative comorbidities, operative results, postoperative complications, and clinical outcomes were compared between the groups. RESULTS: Clavien-Dindo grade >=1 postoperative complications, pneumonia (P = 0.02), delirium (P < 0.001), and urinary tract infection (P < 0.001) were more common in the E group. Postoperative pneumonia was associated with mortality in this group (P < 0.001). Three patients (1.6%) died after surgery, each of whom had pneumonia. Severe postoperative complication was independently prognostic of overall (hazard ratio, 4.69; 95% confidence interval, 2.40-9.14; P < 0.001) and disease-specific (hazard ratio, 6.41; 95% confidence interval 2.92-14.1; P < 0.001) survival in the E group. CONCLUSIONS: In elderly patients with GC, clinical outcomes are strongly associated with severe postoperative complications. Preventing such complications may improve survival. PMID- 26033613 TI - The Effect of Child Sexual Abuse on Men: Toward a Male Sensitive Measure. AB - Child sexual abuse (CSA) is a trauma that affects males in substantial numbers, sometimes in ways that are gender-specific (e.g., compromised masculine identity, confusion regarding sexuality). Much of the identification of the male-specific outcomes has been derived from practitioner experience and small qualitative studies. The current study explores gender-specific outcomes and describes the development of a scale to measure the effects of CSA on men. First, qualitative interviews with 20 men who were sexually abused in childhood were thematically analyzed. The emergent themes of sexuality, self-concept, psychological and emotional well-being, and social functioning were used to construct a 30-item instrument which was later completed by 147 men with histories of CSA. The dimensionality of the 30 items was then assessed for suitability as scales using confirmatory factor analysis (CFA). The final instrument, the Male Sexual Abuse Effects Scale (MSAES), combines three subscales: Negative Identity, Guilt and Self-Blame, and Psychological and Emotional Well-Being. Items concerning masculine identity were shown to be valid in the scale. MSAES scores were compared with the General Health Questionnaire-28 (GHQ-28) and found to be significantly correlated. GHQ-28 clinical thresholds were applied to differentiate clinical from nonclinical cases; an independent-samples t test showed that the clinical cases from the GHQ-28 had high scores on the MSAES. The new scale has the potential to help clinicians and researchers identify men who have been severely affected by CSA and who should be of clinical concern. PMID- 26033614 TI - Competence of Trauma Social Workers: The Relationship Between Field of Practice and Secondary Traumatization, Personal and Environmental Variables. AB - In recent years, there has been growing interest in examining role competence and the factors that can contribute to a sense of role competence among social workers. In the present study, we used the occupational competence model (OCM) as a basis for examining the contribution of the personal dimension (mastery, self esteem, and secondary traumatization),environmental dimension (support systems), and occupational dimension (exposure to the field of family violence) to the social worker's subjective sense of role competence. Participants in the study were 214 social workers employed at centers for prevention of family violence, at shelters for victims of violence against women, and at social service bureaus. The findings indicate that in the occupational dimension, the contribution of exposure to work in the field of family violence contributed significantly to two components of the participants' subjective sense of role competence: general sense of role competence and task knowledge/problem solving. In the personal dimension, the contribution of secondary traumatization and mastery to a sense of role competence was significant. In the environmental dimension (i.e., support systems), the specific contribution of managerial support to the participants' sense of role competence was significant. In light of these findings, practical recommendations for developing a sense of role competence among social workers are provided. PMID- 26033615 TI - The Roles of Dominance, Jealousy, and Violent Socialization in Chinese Dating Abuse. AB - Attitude toward women and relationship violence in Chinese societies has been shaped by a history of Confucian patriarchy. Studies suggest that this patriarchal orientation continues to influence modern-day dating behaviors and rates of relationship violence. This study examined through the lens of the intergenerational transmission of violence theory the effects of dominance and jealousy on the likelihood of physical assault and how violent socialization moderates these effects. A maximum likelihood path analysis with robust standard errors was conducted for a total of 915 individuals from Beijing, Shanghai, and Taiwan who participated in the International Dating Violence Study from 2001 to 2006. Results revealed that dominance and violent socialization were significantly associated with assault victimization and perpetration. Violent socialization also significantly amplified the associations between dominance and both minor and severe assault victimization. Jealousy, however, was only associated with severe assault perpetration. Clinical implications and further research directions are discussed. PMID- 26033616 TI - Effects of Poly-Victimization on Adolescent Social Support, Self-Concept, and Psychological Distress. AB - Past research has demonstrated the particularly damaging effects of exposure to multiple forms of victimization, or "poly-victimization," on youth mental health. The primary objective of the present study is to begin to identify the mechanisms that help explain its powerful impact. Analyses are based on two waves of longitudinal data from the National Survey of Children's Exposure to Violence (NatSCEV), conducted in 2008 and 2010, that comprised a telephone sample of 1,186 youth ages 10 to 17. Using structural equation modeling, we examine direct and indirect effects on distress symptoms of increased, decreased, and stable high poly-victimization between Waves 1 and 2 compared to no or low victimization in both waves. Specifically, we consider the extent to which reductions in core psychosocial resources, including family support, peer support, self-esteem, and mastery, mediate the relationship between these poly-victimization conditions and distress. Relative to stable low victimization, both increased poly-victimization and stable high poly-victimization were associated with declines in all four resources. However, only self-esteem and mastery significantly mediated the association between poly-victimization and distress, with mastery showing the strongest effect. Although significant indirect effects were evident, poly victimization still had a strong direct effect on distress with resource factors controlled. Findings support the hypothesis that the potent effect of poly victimization on youth mental health is, in part, due to its damaging influence on core psychosocial resources. PMID- 26033617 TI - Oasis desert farming selects environment-specific date palm root endophytic communities and cultivable bacteria that promote resistance to drought. AB - Oases are desert-farming agro-ecosystems, where date palm (Phoenix dactylifera L.) plays a keystone role in offsetting the effects of drought and maintaining a suitable microclimate for agriculture. At present, abundance, diversity and plant growth promotion (PGP) of date palm root-associated bacteria remain unknown. Considering the environmental pressure determined by the water scarcity in the desert environments, we hypothesized that bacteria associated with date palm roots improve plant resistance to drought. Here, the ecology of date palm root endophytes from oases in the Tunisian Sahara was studied with emphasis on their capacity to promote growth under drought. Endophytic communities segregated along a north-south gradient in correlation with geo-climatic parameters. Screening of 120 endophytes indicated that date palm roots select for bacteria with multiple PGP traits. Bacteria rapidly cross-colonized the root tissues of different species of plants, including the original Tunisian date palm cultivar, Saudi Arabian cultivars and Arabidopsis. Selected endophytes significantly increased the biomass of date palms exposed to repeated drought stress periods during a 9 month greenhouse experiment. Overall, results indicate that date palm roots shape endophytic communities that are capable to promote plant growth under drought conditions, thereby contributing an essential ecological service to the entire oasis ecosystem. PMID- 26033618 TI - A New Strategy for Fluorogenic Esterase Probes Displaying Low Levels of Non specific Hydrolysis. AB - A new design for fluorescence probes of esterase activity that features a carboxylate-side pro-fluorophore is demonstrated with boron dipyrromethene (BODIPY)-based probes 1 a and 1 b. Because the design relies on the enzyme catalyzed hydrolysis of an ester group that is not electronically activated, these probes exhibit a stability to background hydrolysis that is far superior to classical alcohol-side profluorophore-based probes, large signal-to-noise ratios, reduced sensitivity to pH variations, and high enzymatic reactivity. The utility of probe 1 a was established with a real-time fluorescence imaging experiment of endogenous esterase activity that does not require washing of the extracellular medium. PMID- 26033619 TI - Experts plan to recommend immediate antiretroviral therapy for people with HIV. PMID- 26033620 TI - A Novel Loading Method for Doxycycline Liposomes for Intracellular Drug Delivery: Characterization of In Vitro and In Vivo Release Kinetics and Efficacy in a J774A.1 Cell Line Model of Mycobacterium smegmatis Infection. AB - Doxycycline (doxy) is used in treating intracellular and extracellular infections. Liposomal (LE) antibiotics allow low-frequency dosing and extended efficacy compared with standard (STD) formulations. We developed a novel sulfuric acid-loading method for doxycycline liposomes (LE-doxy). We hypothesized that a single s.c. injection of LE-doxy would be detectable in serum for at least 2 weeks at concentrations equal to or better than STD-doxy and would be bactericidal in an in vitro Mycobacterium smegmatis infection of J774A.1 macrophage cells. Liposomes were encapsulated by sulfuric acid gradient loading, and release kinetics were performed in vitro and in vivo. LE-doxy made using 8.25 mg/ml doxycycline loaded for 24 hours achieved 97.77% capture in 1,2-dipalmitoyl sn-glycero-3-phosphocholine (DPPC) and 43.87% in sphingomyelin (sphing). Rats were injected s.c. with 50 mg/kg LE-doxy or 5 mg/kg STD-doxy, and serial blood samples were collected. Pharmacokinetics were analyzed using high-performance liquid chromatography. Liver and injection site skin samples were collected at euthanasia (4 weeks postinjection). Minimal histologic tissue reactions occurred after injection of STD (nonliposomal), DPPC, or sphing-doxy. DPPC-doxy had slightly faster in vitro leakage than sphing liposomes, although both were detectable at 264 hours. The mean residence time for DPPC was the highest (111.78 hours), followed by sphing (56.00 hours) and STD (6.86 hours). DPPC and sphing doxy were detectable at 0.2 MUg/ml in serum at 336 hours postadministration. LE doxy was not toxic to J774A.1 cells in vitro and produced inhibition of viable Mycobacterium smegmatis at 24 and 48 hours. LE-doxy will require further testing in in vivo infection models. PMID- 26033621 TI - Early Changes in Cytochrome P450s and Their Associated Arachidonic Acid Metabolites Play a Crucial Role in the Initiation of Cardiac Hypertrophy Induced by Isoproterenol. AB - Cytochrome P450 enzymes (P450s), along with their cardioprotective metabolites the epoxyeicosatrienoic acids (EETs) and cardiotoxic metabolite 20 hydroxyeicosatetraeonic acid (20-HETE), were found to be altered in cardiac hypertrophy; however, it is unclear whether these changes are causal or epiphenomenon. Therefore, we hypothesized that P450s and their metabolites play a crucial role in the initiation of cardiac hypertrophy. To test our hypothesis, rats and RL-14 cells were treated with the hypertrophic agonist isoproterenol for different time periods. Thereafter, in vivo heart function and wall thickness were assessed using echocardiography. Moreover, the role of P450 epoxygenases, omega-hydroxylases, and soluble epoxide hydrolase (sEH) were determined at mRNA, protein, and activity levels using real-time polymerase chain reaction, Western blot, and liquid chromatography-mass spectrometry, respectively. Our results show that in vivo and in vitro hypertrophy was initiated after 72 hours and 6 hours of isoproterenol treatment, respectively. Studies performed at the prehypertrophy phase showed a significant decrease in P450 epoxygenases along with a significant induction of sEH activity. Consequently, lower EET and higher dihydroxyeicosatrienoic acid levels were observed during this phase. However, significant increases in P450 omega-hydroxylase along with its associated metabolite, 20-HETE, were detected only in vivo. Interestingly, increasing EET levels by P450 epoxygenase induction, sEH inhibition, or exogenous administration of EET prevented the initiation of cardiac hypertrophy through a nuclear factor kappaB-mediated mechanism. Taken together, these findings reveal a crucial role of P450 epoxygenases and EETs in the development of cardiac hypertrophy, which could uncover novel targets for prevention of heart failure at early stages. PMID- 26033624 TI - Erratum. PMID- 26033623 TI - Rebuttal: Comparison of multislice computed tomography findings between bicuspid and tricuspid aortic valves before and after transcatheter aortic valve implantation. PMID- 26033622 TI - Mitochondrial function at extreme high altitude. AB - At high altitude, barometric pressure falls and with it inspired P(O2), potentially compromising O2 delivery to the tissues. With sufficient acclimatisation, the erythropoietic response increases red cell mass such that arterial O2 content (C(aO2)) is restored; however arterial P(O2)(P(aO2)) remains low, and the diffusion of O2 from capillary to mitochondrion is impaired. Mitochondrial respiration and aerobic capacity are thus limited, whilst reactive oxygen species (ROS) production increases. Restoration of P(aO2) with supplementary O2 does not fully restore aerobic capacity in acclimatised individuals, possibly indicating a peripheral impairment. With prolonged exposure to extreme high altitude (>5500 m), muscle mitochondrial volume density falls, with a particular loss of the subsarcolemmal population. It is not clear whether this represents acclimatisation or deterioration, but it does appear to be regulated, with levels of the mitochondrial biogenesis factor PGC-1alpha falling, and shows similarities to adapted Tibetan highlanders. Qualitative changes in mitochondrial function also occur, and do so at more moderate high altitudes with shorter periods of exposure. Electron transport chain complexes are downregulated, possibly mitigating the increase in ROS production. Fatty acid oxidation capacity is decreased and there may be improvements in biochemical coupling at the mitochondrial inner membrane that enhance O2 efficiency. Creatine kinase expression falls, possibly impairing high-energy phosphate transfer from the mitochondria to myofibrils. In climbers returning from the summit of Everest, cardiac energetic reserve (phosphocreatine/ATP) falls, but skeletal muscle energetics are well preserved, possibly supporting the notion that mitochondrial remodelling is a core feature of acclimatisation to extreme high altitude. PMID- 26033625 TI - New training pathways to dual certification in nuclear medicine and radiology. PMID- 26033626 TI - ABNM Maintenance of Certification: Getting It Right. PMID- 26033628 TI - Deadlines for Appropriate Use Criteria loom; resolutions remain unclear. PMID- 26033631 TI - Sequential S(N)Ar Reaction/Suzuki-Miyaura Coupling/C-H Direct Arylations Approach for the Rapid Synthesis of Tetraaryl-Substituted Pyrazoles. AB - A rapid synthesis of 1,3,4,5-tetraaryl-substituted pyrazoles has been achieved through a sequence of SN Ar reaction/Suzuki-Miyaura coupling/Pd-catalyzed direct arylations that used 3-iodo-1H-pyrazole as a scaffold. Pyrazoles with four different aryl groups were synthesized in a straightforward manner with no extra synthetic steps, such as protection/deprotection or the introduction of activating/directing groups, using readily available substrates and reagents. The developed synthetic approach enabled the structurally diverse synthesis of multiaryl-substituted pyrazoles without using a glovebox technique. PMID- 26033632 TI - Stool Testing for Colorectal Cancer Screening. AB - Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality and is widely recommended. However, despite the demonstrated benefits of screening and ongoing efforts to improve screening rates, a large percentage of the population remains unscreened. Noninvasive stool based tests offer great opportunity to enhance screening uptake. The evidence supporting the use of both fecal immunochemical testing (FIT) and stool DNA (sDNA) has been growing rapidly and both tests are now commercially available for use. Other stool biomarkers (eg, RNA and protein based) are also actively under study both for use independently and as adjuncts to the currently available tests. This mini review provides current, state of the art knowledge about noninvasive stool based screening. It includes a more detailed examination of those tests currently in use (ie, FIT and sDNA) but also provides an overview of stool testing options under development (ie, protein and RNA). PMID- 26033634 TI - Spatial sequence memory and spatial error monitoring in the Groton Maze Learning Task (GMLT): A validation study of GMLT sub-measures in healthy children. AB - The stepping-stone variant of the hidden pathway maze learning (HPML) task paradigm has been extensively used to investigate cognitive functions in neuropsychology and neuropharmacology. Previous studies have used total error across trials, as well as rule-break errors and learning errors, to define spatial memory and/or executive function in healthy and impaired adults and children. However, the construct validity of performance measures on HPML tasks has not been established in healthy children. To assess the construct validity of measures of exploratory and rule-break errors on the Groton Maze Learning Task (GMLT) measures of spatial sequence memory (Corsi Blocks Task) and spatial error monitoring (Continuous Paired Associate Learning; CPAL) were used. The results indicate that Corsi span predicted GMLT spatial sequence memory and CPAL accuracy predicted GMLT spatial error monitoring. The construct validity of the GMLT as a measure of spatial memory and executive function are discussed with regard to prior research using HPML tasks in neuropsychological contexts. PMID- 26033633 TI - Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer. AB - BACKGROUND: Previous publications have demonstrated conflicting results regarding body mass index (BMI) and prostate cancer (CaP) outcomes after definitive radiotherapy (RT) before the dose escalation era. The goal of the current study was to determine whether increasing BMI was associated with outcomes in men with localized CaP who were treated with dose-escalated RT. METHODS: The authors identified patients with localized (T1b-T4N0M0) CaP who were treated with definitive intensity-modulated RT and image-guided RT from 2001 through 2010. BMI was analyzed as a continuous variable. Adjusting for confounders, multivariable competing risk and Cox proportional hazards regression models were used to assess the association between BMI and the risk of biochemical failure (BF), distant metastases (DM), cause-specific mortality (CSM), and overall mortality. RESULTS: Of the 1442 patients identified, approximately 20% had a BMI <25 kg/m(2) , 48% had a BMI of 25 to 29.9 kg/m(2) , 23% had a BMI of 30 to 34.9 kg/m(2) , 6% had a BMI of 35 to 39.9 kg/m(2) , and 4% had a BMI of >=40 kg/m(2) . The median follow up was 47.6 months (range, 1-145 months), with a median age of 68 years (range, 36-89 years). The median dose was 78 grays (range, 76-80 grays) and 30% of patients received androgen deprivation therapy. Increasing BMI was found to be inversely associated with age (P<.001) and pretreatment prostate-specific antigen level (P = .018). On multivariable analysis, increasing BMI was associated with an increased risk of BF (hazard ratio [HR], 1.03; 95% confidence interval [95% CI], 1.00-1.07 [P = .042]), DM (HR, 1.07; 95% CI, 1.02-1.11 [P = .004]), CSM (HR, 1.15; 95% CI, 1.07-1.23 [P<.001]), and overall mortality (HR, 1.05; 95% CI, 1.02 1.08 [P = .004]). CONCLUSIONS: For patients with CaP receiving dose-escalated intensity-modulated RT with daily image-guidance, increasing BMI appears to be associated with an increased risk of BF, DM, CSM, and overall mortality. PMID- 26033636 TI - Optimizing respiratory function assessments to elucidate the impact of obesity on respiratory health. AB - There is an increasing prevalence of obesity worldwide and its impact on respiratory health is of significant concern. Obesity affects the respiratory system by several mechanisms, including by direct mechanical changes due to fat deposition in the chest wall, abdomen and upper airway, as well as via systemic inflammation. The increased mechanical load in obese individuals leads to reduced chest wall and lung compliance and increased work of breathing. While there is generally minimal effect on spirometric values, as body mass index increases, the expiratory reserve volume, and hence functional residual capacity, reduces, often approaching residual volume in more severe obesity. The majority of evidence however suggests that obese individuals free from lung disease have relatively normal gas exchange. The link between asthma and obesity, while initially unclear, is now recognized as being a distinct asthma phenotype. While studies investigating objective markers of asthma have shown that there is no association between obesity and airway hyper-responsiveness, a recent working group identified obesity as a major risk factor for the development of asthma in all demographic groups. Although the temptation may be to attribute obesity as the cause of dyspnoea in symptomatic obese patients, accurate respiratory assessment of these individuals is necessary. Lung function tests can confirm that any altered physiology are the known respiratory consequences of obesity. However, given that obesity causes minimal changes in lung function, significant abnormalities warrant further investigation. An important consideration is the knowledge that many of the respiratory physiology consequences of obesity are reversible by weight loss. PMID- 26033635 TI - Experience-dependent plasticity of dendritic spines of layer 2/3 pyramidal neurons in the mouse cortex. AB - Previous studies have shown that sensory and motor experiences play an important role in the remodeling of dendritic spines of layer 5 (L5) pyramidal neurons in the cortex. In this study, we examined the effects of sensory deprivation and motor learning on dendritic spine remodeling of layer 2/3 (L2/3) pyramidal neurons in the barrel and motor cortices. Similar to L5 pyramidal neurons, spines on apical dendrites of L2/3 pyramidal neurons are plastic during development and largely stable in adulthood. Sensory deprivation via whisker trimming reduces the elimination rate of existing spines without significant effect on the rate of spine formation in the developing barrel cortex. Furthermore, we show that motor training increases the formation and elimination of dendritic spines in the primary motor cortex. Unlike L5 pyramidal neurons, however, there is no significant difference in the rate of spine formation between sibling dendritic branches of L2/3 pyramidal neurons. Our studies indicate that sensory and motor learning experiences have important impact on dendritic spine remodeling in L2/3 pyramidal neurons. They also suggest that the rules governing experience dependent spine remodeling are largely similar, but not identical, between L2/3 and L5 pyramidal neurons. PMID- 26033637 TI - ABO desensitization affects cellular immunity and infection control after renal transplantation. AB - The impact of ABO desensitization on overall immunity, infectious control, and alloreactivity remains unknown. We compared 35 ABO-incompatible kidney transplant recipients (KTRs) to a control of 62 ABO compatible KTRs. Samples were collected before, at +1, +2, +3, +6, and +12 months post-transplantation. CMV-, BKV specific, and alloreactive T cells were measured using an interferon-gamma ELISPOT assay. The extent of immunosuppression was quantified by enumeration of lymphocyte subpopulations and cytokines. No differences were observed for 5-year allograft survival and function between both groups (P > 0.05). However, ABO incompatible KTRs were more likely to develop CMV infection, BKV-associated nephropathy, and severe sepsis (P = 0.001). Interestingly, ABO-incompatible KTRs with poor HLA-match showed the highest rates of infections and inferior allograft function (P < 0.05). CD3+, CD4+ T-cell counts, interferon-gamma and IL-10 levels were lower in ABO-incompatible KTRs early post-transplantation (P < 0.05). Likewise, ABO-incompatible KTRs showed impaired BKV- and CMV-specific T-cell immunity (P < 0.05). ABO-incompatible KTRs showed lower frequencies of alloreactive T cells (P < 0.05). Our data suggest T-cell depletion due to ABO desensitization, which may contribute to the increased risk of T-cell-dependent infections. Elimination of B cells serving as antigen-presenting cells, thereby causing impaired T-cell activation, plays a significant role in both impaired infection control and reduced alloreactive T-cell activation. PMID- 26033638 TI - Expression of the cellular prion protein affects posttransfusion recovery and survival of red blood cells in mice. AB - BACKGROUND: Cellular prion protein (PrP(C) ) is expressed on various cell types including red blood cells (RBCs). The PrP(C) plays a key role in the pathogenesis of prion diseases, but its physiologic function remains unclear. PrP(C) is expressed on CD34+ hematopoietic stem cells and its expression is regulated during blood cell differentiation including the erythroid line. STUDY DESIGN AND METHODS: We investigated the role of PrP(C) in RBC survival in circulation by transfusing a mix of biotin-labeled RBCs from wild-type (WT) and PrP knockout (KO) mice to groups of recipient mice (WT and KO). The proportion of biotinylated RBCs in peripheral blood was estimated by flow cytometry. RESULTS: KO RBCs displayed a markedly higher first-day posttransfusion recovery but had a decreased survival in circulation when compared to WT RBCs. Similar results were obtained in all groups of transfused mice, irrespective of RBCs biotinylation level. In addition, we confirmed this finding in an analogous study using Tga20 mice overexpressing PrP(C) and KO mice of a different genetic background. CONCLUSION: Our results demonstrate that PrP(C) expression affects RBC recovery and survival in circulation. PMID- 26033639 TI - Association between concurrent genital bleeding and cervical cancer: a cross sectional study. AB - INTRODUCTION: Genital bleeding may be a common symptom among women with cervical cancer. MATERIAL AND METHODS: Cross-sectional study evaluating whether the prevalence of cervical smear results is different in women with and without clinical information about concurrent genital bleeding. RESULTS: The sample consisted of 2 324 836 smears; of these, 0.4% had clinical information on genital bleeding. When stratified by age group, women with genital bleeding had a higher chance of a cytological result of a high-grade squamous intraepithelial lesion [30-49 years odds ratio (OR) 2.38; 95% confidence interval (CI) 1.60-3.53 and >=50 years OR 6.30; 95%CI 3.72-10.67), of squamous cell carcinoma (SCC) (30-49 years OR 24.70; 95%CI 11.96-51.03 and >=50 years OR 48.91; 95%CI 31.28-76.47) and of atypical glandular cells (30-49 years OR 5.72; 95%CI 3.30-9.93 and >=50 years OR 11.56; 95%CI 5.96-22.45); there was also a higher chance of adenocarcinoma for women >=50 years (OR 53.13; 95%CI 28.08-100.51). The sensitivity of genital bleeding for women aged 18-29 years was 0.4% for high-grade squamous intraepithelial lesion (HSIL); for women 30-49 years old the rate was 0.9% for HSIL, 8.6% for SCC and 2.1% for atypical glandular cells of undetermined significance (AGUS), while for women aged from 50 years or more the rates were 2.0% for HSIL, 13.7% for SCC, 3.6% for AGUS and 14.7% for adenocarcinoma. CONCLUSION: Women >=30 years old with genital bleeding should be referred for colposcopy to rule out the possibility of cervical cancer. PMID- 26033640 TI - Evaluation and comparison of the relationship between NOEC and EC10 or EC20 values in chronic Daphnia toxicity testing. AB - Hypothesis-based no-effect-concentration (NOEC) and regression-based x% effect concentration (ECx) values are common statistical approaches used to summarize ecotoxicological effects. Controversy over the NOEC model has prompted a movement toward discontinuation of the NOEC in favor of ECx, but the best x% effect surrogate for NOEC has not yet been determined. Historically, 10% and 20% effect concentrations (EC10 and EC20) have been treated as NOEC analogs. Given these measurements' importance to ecotoxicology, further understanding of the relationships between NOEC and EC10 or EC20 is crucial. In the present study, a metadataset of daphnid chronic toxicity tests was compiled to analyze the strength and significance of NOEC:EC10 and NOEC:EC20 relationships. The impact of endpoint (e.g., mortality, reproduction) and test condition parameters (e.g., pH, temperature) on NOEC:EC10 and NOEC:EC20 was evaluated. Mortality endpoints were most sensitive 51% of the time, with growth and reproductive endpoints constituting the remainder, underscoring the value of using multiple endpoints to evaluate toxic effects rather than relying on reproduction as the a priori most sensitive endpoint. When test condition parameters were less restricted (e.g., pH, hardness), the NOEC:EC20 association was more robust, suggesting that variability introduced by test implementation increased variability in ECx calculation. The analysis revealed that, overall, EC10 was a more suitable analog than EC20 for NOEC. Recommendations include refinement and reporting of the test parameters pH and hardness to minimize variability in ECx calculation. PMID- 26033641 TI - A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with <=2% and >2% blood eosinophils. AB - BACKGROUND: A six month study of the p38 MAPK inhibitor, losmapimod, suggested a trend in reducing COPD exacerbations with the 15 mg twice daily dose. OBJECTIVE AND METHODS: Using data from this study which evaluated the efficacy of twice daily losmapimod, 2.5 mg, 7.5 mg, and 15 mg, versus placebo in patients with moderate-to-severe COPD, we analysed the effect of losmapimod in reducing the rate of moderate/severe exacerbations in patient subgroups with <=2% and >2% blood eosinophils at baseline. Lung function, fibrinogen and hsCRP were also evaluated. RESULTS: In the <=2% eosinophil subgroup, there was an exposure related reduction in the rate of moderate/severe exacerbations with losmapimod relative to placebo (losmapimod 15 mg: 55% reduction; losmapimod 7.5 mg: 29%; losmapimod 2.5 mg: 10%); with the 15 mg dose reaching statistical significance (15 mg/placebo mean rate ratio [95% CI]: 0.45 [0.22; 0.90]). There was also an improvement in lung function with 15 mg losmapimod over Weeks 1-12. No improvement in the rate of moderate/severe exacerbations or post-bronchodilator FEV1 was observed for subjects treated with Losmapimod compared to placebo in the patient subgroup with blood eosinophils >2% at baseline. Transient reductions in fibrinogen and hsCRP were observed with losmapimod 7.5 mg and 15 mg in both eosinophil subgroups. CONCLUSIONS: These findings indicate eosinophil-related heterogeneity within COPD and suggest that losmapimod could be a potential therapy to reduce exacerbations in COPD patients with eosinophil levels <=2%. This needs to be explored further in a prospectively designed study with pre specified criteria for blood eosinophil subgroups in COPD patients. PMID- 26033642 TI - Lung function in pulmonary hypertension. AB - Breathlessness is a common symptom in pulmonary hypertension (PH) and an important cause of morbidity. Though this has been attributed to the well described pulmonary vascular abnormalities and subsequent cardiac remodelling, changes in the airways of these patients have also been reported and may contribute to symptoms. Our understanding of these airway abnormalities is poor with conflicting findings in many studies. The present review evaluates these studies for the major PH groups. In addition we describe the role of cardiopulmonary exercise testing in the assessment of pulmonary arterial hypertension (PAH) by evaluating cardiopulmonary interaction during exercise. As yet, the reasons for the abnormalities in lung function are unclear, but potential causes and the possible role of inflammation are discussed. Future research is required to provide a better understanding of this to help improve the management of these patients. PMID- 26033643 TI - FVC deterioration, airway obstruction determination, and life span in Ataxia telangiectasia. AB - RATIONALE: Forced vital capacity (FVC) values decrease with progress of the disease in Ataxia telangiectasia (AT). OBJECTIVE: To study the effect of this process on airway obstruction determination and life span in AT. METHODS: Clinical data and yearly best spirometry maneuvers were collected retrospectively from 37 AT patients (196 spirometry tests) during 5.4 +/- 1.8yrs (initial age 4 21 y). Twelve patients were walking (7 of them had recurrent respiratory system infections); 25 subjects were confined to wheelchair, of them 8 patients were towards end-stage lung disease. Spirometry indices included Forced Vital Capacity (FVC), mid-expiratory-flow (FEF25-75), and tidal volume (VT). We calculated FEF25 75/FVC and VT/FVC ratios. RESULTS: FVC declined from 67 +/- 8 while walking to 19 +/- 6 %predicted values. FEF25-75 values that were elevated (116 +/- 23 %predicted) while walking, decreased to 69 +/- 27 %predicted at end-stage where 7 patients responded to bronchodilators. VT/FVC ratio was 0.25 +/- 0.06 while walking, increased to 0.35 once on wheelchairs, and further increased to 0.57 +/- 0.19 at end-stage disease. FEF25-75/FVC ratio was 2.54 +/- 0.70 above normal (~1.0) increasing to 4.16 +/- 0.75 at end stage. A sharp elevation was seen in FEF25-75/FVC ratio when FEV1 was still ~45 %predicted and 2-years prior to death. CONCLUSIONS: Having a low baseline-FVC (60% predicted) artificially raises FEF25 75 values, so FEF25-75 of "mild obstruction" values may indicate severe airway obstruction in AT subjects. VT/FVC and FEF25-75/FVC ratios may therefore assist in revealing higher than normal breathing effort. The results further suggest adding VT/FVC and FEF25-75/FVC ratios to pulmonary function assessments in patients with AT. PMID- 26033644 TI - An approach to confirmatory testing of subpopulations in clinical trials. AB - In oncology studies with immunotherapies, populations of "super-responders" (patients in whom the treatment works particularly well) are often suspected to be related to biomarkers. In this paper, we explore various ways of confirmatory statistical hypothesis testing for joint inference on the subpopulation of putative "super-responders" and the full study population. A model-based testing framework is proposed, which allows to define, up-front, the strength of evidence required from both full and subpopulations in terms of clinical efficacy. This framework is based on a two-way analysis of variance (ANOVA) model with an interaction in combination with multiple comparison procedures. The ease of implementation of this model-based approach is emphasized and details are provided for the practitioner who would like to adopt this approach. The discussion is exemplified by a hypothetical trial that uses an immune-marker in oncology to define the subpopulation and tumor growth as the primary endpoint. PMID- 26033645 TI - Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells. AB - Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling. PMID- 26033646 TI - Comparative proteomic analysis of Taurine, Indicine, and crossbred (Bos taurus * Bos indicus) bull spermatozoa for identification of proteins related to sperm malfunctions and subfertility in crossbred bulls. AB - Subfertility is one of the most common problems observed among Taurine * Indicine crossbred bulls in tropical countries; however, the etiology remain unknown in most of the cases. In present study, we compared the proteomic profile of spermatozoa from crossbred bulls (Bos taurus * Bos indicus) against their purebred parent lines (Holstein Friesian [Taurine] and Tharparkar [Indicine]) to find out alteration in expressions of proteins, if any. The proteomic profiles of freshly ejaculated spermatozoa from these breeds were compared by two-dimensional difference gel electrophoresis, and differentially expressed proteins were identified through mass spectrometry. It was observed that compared to Holstein Friesian, nine proteins were underexpressed and eight proteins were overexpressed (P < 0.05) in the spermatozoa of crossbred bulls. Similarly, four proteins were overexpressed and four proteins were underexpressed (P < 0.05) in the spermatozoa of crossbred bulls compared to Tharparkar bulls. In concurrent three breed comparison, 14 proteins were found to be differentially expressed (P < 0.05) between these breeds. From the findings of the study, it is apparent that the expression levels of several functionally significant proteins are either upregulated or downregulated in spermatozoa of crossbred bulls, which might be related to high incidence of subfertility in these bulls. PMID- 26033647 TI - [The effect of ligustrazin in intestinal ischemia reperfusion injury generated on rats]. AB - BACKGROUND: Intestinal ischemia is a serious and common clinical status. It develops as result of superior mesenteric artery (SMA) obstruction caused by many etiologic factors. Sepsis and multiple organ failure could develop following intestinal ischemia. The present study aimed to investigate the effects of ligustrazin, which has a vasodilator impact on intestinal ischemia. METHODS: Forty male Wistar rats were divided into three groups randomly. Sham operation was performed on Group S (n=7); mesenteric ischemia and then 60 minutes reperfusion of the intestine process was performed on Group MI (n=7); mesenteric ischemia and then 60 minutes reperfusion of the intestine process was performed and 80 mg/kg ligustrazin was administrated intraperitoneally on Group MI+L (n=7). Intestinal tissue samples were taken for tissue MDA, SDO and nitric oxide (NO) levels, and ileum and jejunum samples were taken for histopathologic examination. RESULTS: Tissue MDA levels and tissue NO levels of Group MI-L was determined to have significantly decreased. Tissue SOD levels were found similar to Group S. Chiu classification score of the jejunum and ileum was determined to have decreased in Group MI-L compared to Group MI. DISCUSSION: As a result of this study, Ligustrazin was found to adjust lipid peroxidation in biochemical parameters during mesenteric I-R and decrease the severity of damage of I-R on the histopathological scores of the jejunum and ileum. PMID- 26033648 TI - Comparison of early surgical alternatives in the management of open abdomen: a randomized controlled study. AB - BACKGROUND: Abdominal compartment syndrome (ACS) is a clinical syndrome characterized by progressive intraabdominal organ dysfunction resulting from an acute increase in intra-abdominal pressure (IAP). In the absence of prompt treatment, ACS can lead to lethal organ failure. Treatment of ACS is achieved by immediate decompression of the abdominal cavity. As to how and when decompression laparotomy should be performed depends on the clinical condition of the patients. There is limited data regarding outcomes of abdominal closure techiques. The present study aimed to investigate two different temporary closure methods, the vacuum assisted closure (VAC) and Bogota bag techniques, in 40 patients who underwent decompressive laparotomy as part of the management of ACS. METHODS: The study included 40 patients who developed ACS during follow-up or following trauma and abdominal surgery. As part of the treatment for ACS, these patients underwent decompressive laparotomy at the Cukurova University Medical Faculty, General Surgery Department and followed up in the Intensive Care Unit of the same hospital. VAC and Bogota bag procedures were performed as temporary closure methods for the treatment of ACS. Patients were randomly assigned to each of the two groups according to the temporary closure method performed. Clinical, laboratory, mortality and morbidity results of the patients in both groups were compared. RESULTS: Demographic features of the patients (age, sex, body mass index, co-morbidities) were similar between the two groups. The most common reason of ACS was gastrointestinal perforation in 12 (30%) patients. Decrease in incision width was significantly faster in the VAC group than in the Bogota group. Primary closure of fascia was considered appropriate in 16.9 days in the VAC group and 20.5 days in the Bogota bag group. The decrease in abdominal pressure was similar between the two groups on days 1, 4 and 7 but appeared to be significantly lower on day 14 in the VAC group. 12 patients (30%) died during the study. Among the deceased patients, 5 (12%) were in the VAC group, whereas, 7 (17.5%) belonged to the Bogota bag group. CONCLUSION: Based on these results, it is suggested that VAC has advantages when compared to the Bogota bag as a temporary closure method in the management of abdominal compartment syndrome. PMID- 26033649 TI - Assessment of the relation of violence and burnout among physicians working in the emergency departments in Turkey. AB - BACKGROUND: Violence and burnout are frequently seen among medical doctors; however, the relation is not clear. This study aimed to assess the violence and its possible effects on burnout in physicians working in emergency units. METHODS: This cross-sectional study targeted all physicians working in the emergency units of Pamukkale University Hospital, County and City Hospitals, 112 Emergency Services, and Private Hospitals in Denizli. Data were obtained by means of a self-administered questionnaire that consisted of questions on the demographics of the participants, Turkish version of the Maslach Burnout Inventory, and of the perpetrators of violence. What was also documented on the questionnaire was whether participants had been subjected to or had witnessed any verbal or physical violence during the previous one month of emergency physicians' certification program. RESULTS: A total of one hundred and seventy four physicians were included into the study (85% of the targeted group). Many of the participants were between 24 and 59 years of age, with a mean age of 36.8+/ 5.8 years. Married male doctors working in the City Hospital made up the majority. There were significant associations between emotional exhaustion and total violence (p=0.012) and verbal violence (p=0.016); depersonalization and total violence (p=0.021) and verbal violence (p=0.012). CONCLUSION: The results presented here indicated that there was a strong relation between burnout and violence experienced by physicians working in emergency units. Violence in the emergency department has a substantial effect on the physicians' well-being. PMID- 26033650 TI - The analysis of scoring systems predicting mortality in geriatric emergency abdominal surgery. AB - BACKGROUND: Accurate measurement of surgical outcomes, proper evaluation of hospitals and surgeons regardless of case can be performed by mortality prediction models. The aim of this study was to analyze factors affecting mortality, present our clinical experience and patient profile and evaluate different scoring systems in use of these patients. METHODS: A retrospective review of one hundred and twelve geriatric patients who underwent major abdominal emergency surgery between 2004 and 2008 was performed. APACHE II, ODIN, SAPS II expanded, P-POSSUM, Manheim peritonitis and Charlson comorbidity index, Goldman and ASA scores were calculated using patient data. Sensitivity, positive predictive value and Odd's ratio were calculated to predict the mortality for these scoring systems. RESULTS: The overall mortality rate for our patients was found 33.9%. The factors affecting mortality in this study were found to be the duration of initial complaint, requirement of intensive care unit, requirement of mechanical ventilation and its duration, the presence of coexisting disease and peritonitis. CONCLUSION: According to our study, in this particular group of patients, APACHE II scoring system is more valid and accurate in estimating the mortality risk when compared to other scoring systems. PMID- 26033651 TI - Repairing post burn scar contractures with a rare form of Z-plasty. AB - BACKGROUND: Although many precautions have been introduced into early burn management, post burn contractures are still significant problems in burn patients. In this study, a form of Z-plasty in combination with relaxing incision was used for the correction of contractures. METHODS: Preoperatively, a Z advancement rotation flap combined with a relaxing incision was drawn on the contracture line. Relaxing incision created a skin defect like a rhomboid. Afterwards, both limbs of the Z flap were incised. After preparation of the flaps, advancement and rotation were made in order to cover the rhomboid defect. Besides subcutaneous tissue, skin edges were closely approximated with sutures. RESULTS: This study included sixteen patients treated successfully with this flap. It was used without encountering any major complications such as infection, hematoma, flap loss, suture dehiscence or flap necrosis. All rotated and advanced flaps healed uneventfully. In all but one patient, effective contracture release was achieved by means of using one or two Z-plasty. In one patient suffering severe left upper extremity contracture, a little residual contracture remained due to inadequate release. CONCLUSION: When dealing with this type of Z-plasty for mild contractures, it offers a new option for the correction of post burn contractures, which is safe, simple and effective. PMID- 26033652 TI - The frequency of type 2 second-degree and third-degree atrioventricular block induced by blunt chest trauma in the emergency department: A multicenter study. AB - BACKGROUND: Conduction disturbances including type 2 second-degree atrioventricular block (Mobitz II) and third-degree atrioventricular block following blunt chest trauma are probably rare. Moreover, the pathophysiological mechanisms responsible for this rare dysrhythmia following trauma are not well understood yet. In this study, it was aimed to identify the frequency of this dysrhythmia associated with trauma. METHODS: Two hundred and fifty-three consecutive Mobitz II block and third-degree atrioventricular block patients admitted to the Emergency Department of Internal Medicine between January 2012 and March 2013 were evaluated. Only four patients with Mobitz II block and third degree atrioventricular block associated with trauma were enrolled into the present study. The level of atrioventricular block was defined according to electrocardiographic characteristics. RESULTS: Only four (mean age: 40.2+/-19.7 years, two male) of 253 patients were associated with trauma. All patients had normal coronary arteries in coronary angiography or multislice computed tomography. Permanent pacemaker was performed in two patients with third-degree atrioventricular block. None of the patients had coronary artery disease or hypertension. CONCLUSION: Rare clinical cases in the literature confirm that blunt chest trauma can cause conduction defects, which are usually transient. However, patients with blunt chest trauma must need an electrocardiographic evaluation for atrioventricular block upon admission and in the follow-up period. PMID- 26033653 TI - Fixation of distal femoral fractures: Restoration of the knee motion. AB - BACKGROUND: Most of healed lower femoral fractures resulted in various degree of loss of the knee motion. Flexion deficit is a serious problem for the Eastern persons that are where squatting and sitting on the ground are necessary for daily activities. The aims of this study were to compare outcomes of using condylar buttress plate and dynamic condylar screw (DCS) in treatment of distal femoral fractures. Secondly, we present our clinical experience for optimizing the technical application of the studied implants. METHODS: Two groups (plate and DCS) of 57 patients were treated for 59 lower femoral fractures with condylar buttress plate or DCS and followed prospectively for 24 months. RESULTS: Plate group reported adequate reduction in 67% and varus angulation in 13.3% of the fractures. DCS group reported adequate reduction in 72.4% and posterior angulations in 17% of the fractures. Other reasons for inadequacy of reduction were reported in both groups. Full knee motion range was achieved in 50% of plate group and in 55% of DCS group. 75% and 90% satisfactory functional outcomes were reported in the plate and DCS groups respectively. CONCLUSION: Both implants nearly achieved equal results concerning restoration of knee motion range. The condylar buttress plate and DCS are liable for technical optimization. PMID- 26033654 TI - Evaluation of the medical malpractice cases concluded in the General Assembly of Council of Forensic Medicine. AB - BACKGROUND: Malpractice is an occasion that occurs due to defective treatment in the course of providing health services. Neither all of the errors within the medical practices are medical malpractices, nor all of the medical malpractices result in harm and judicial process. Injuries occurring at the time of treatment process may result from a complication or medical malpractice. This study aims to evaluate the reports of the controversial cases brought to trial with the claim of medical malpractice, compiled by The Council of Forensic Medicine. METHODS: Our study includes all of the cases brought to the Ministry of Justice, Council of Forensic Medicine General Assembly with the claim of medical malpractice within a period of 11 years between 2000 and 2011 (n=330). RESULTS: In our study, we saw that 33.3% of the 330 cases were detected as "medical malpractice" by the General assembly. Within this 33.3% segment cases, 14.2% of them resulted from treatment errors such as wrong or incomplete treatment and surgery, use of wrong medication, running late for a true diagnosis after necessary examination, inappropriate medical processes as well as applied treatment having causality with an emergent injury to the patient. 9.7% of them emerged from diagnosis errors like failure to diagnose, wrong diagnosis, lack of consultation request, lack of transfer to a top centre, lack of intervention resulting from not recognizing the postoperative complication on time. 8.8% of them occurred because of careless intervention such as lack of necessary care and attention, lack of post operation follow-ups, lack of essential informing, absenteeism when called for a patient, intervention under suboptimal conditions. Whereas 0.3% of them developed from errors due to inexperience, 0.3% of them were detected to have occurred because of the administrative mistakes following malfunction of healthcare system. CONCLUSION: It is very important to analyze the errors properly in order to get the medical malpractice under control. Going through the errors, on which process of health service they occur and their owners; keeping the record of all examinations and treatments in the course of health service regularly and properly will be a cornerstone for both occupational and forensic medicine practices to be standardized. PMID- 26033655 TI - [The impact of obesity on the outcomes of the patients operated on due to Schatzker type I and type II tibial plateau fractures]. AB - BACKGROUND: This study aimed to conduct a clinical and radiological analysis of treatment results in Schatzker type I and type II tibial plateau fractures and investigate the effect of Body Mass Index on these results. METHODS: A total of 64 patients (44 male [68.8%], 20 female [31.3%]; mean age 21-80; range 45.05+/ 13.47 years) undergoing surgery for Schatzker type I and type II tibial plateau fractures were included into the study. Clinical and radiological results were evaluated according to Rasmussen scores. During evaluation, BMI of the patients was reported. The effects of obesity on these clinical and radiological results were further evaluated. RESULTS: In Schatzker type II cases, there was an indirect 48.4% statistically significant relation (p<0.01) between Rasmussen Clinical scores and age. DISCUSSION: In Type II fractures, the results of obese patients were found to be worse when compared to patients with normal weight. While obesity is not a problem which can be overcome in a short time interval, close follow-up and careful rehabilitation are essential to achieve good results in this group of patients. PMID- 26033656 TI - [The importance of electrocardiography in the clinical course of electric injuries]. AB - BACKGROUND: The aim of the present study was to investigate the demographic and clinical characteristics of electrical injuries, type of electrical current and the importance of electrocardiography in clinical course. METHODS: Fifty-three patients (50 males [94.3%], 3 females [5.7%]; mean age 34.5+/-9.6; range 19 to 61 years) with electrical injuries treated in the burn center between 2011 and 2012 were retrospectively analyzed. The patients were evaluated for demographic and clinical characteristics, electrocardiographic findings and clinical outcomes. RESULTS: The electrocardiography findings of the patients were as follows: twenty seven normal, twelve sinus tachycardia, three atrial fibrillation, seven right bundle brunch block, and four ventricular extra-systole. There was no mortality among patients with electrocardiographic findings of normal, right bundle brunch block, and ventricular extra-systole. Four patients with sinus tachycardia and one patient with atrial fibrillation died. Electrocardiographic findings of the patients wounded by high-voltage electricity were: two normal, two sinus tachycardia, and one atrial fibrillation. DISCUSSION: Mortality was higher in patients with sinus tachycardia and atrial fibrillation in the electrocardiography at the time of admission. These ECG findings were more often in patients wounded by high-voltage electricity. Therefore, electrocardiographic findings and type of the electrical current may provide prognostic value in the clinical course of patients. PMID- 26033657 TI - Unilateral spontaneous adrenal hemorrhage in a young patient. AB - The objective of this study was to report an unusual case of unilateral adrenal hematoma in; a 19-year-old young man who did not have a history of any specific systemic disease. The patient was admitted to hospital with chest pain that lasted for one day. Preoperative contrast-enhanced computerized tomography evaluated an adrenal mass (sized, 10.5 x 12.7 cm) adjacent to the anterior of the left kidney, and findings were indicative of adrenal hematoma. The final pathological diagnosis was adrenal adenoma. PMID- 26033658 TI - The repair of complex penile defect with composite anterolateral thigh and vascularized fascia lata flap. AB - One-stage reconstruction of complex penile defects with functional and cosmetic results is a challenging procedure. The selection of proper technique and materials for reconstruction depends on the type of the deficient tissue components, the size of the wound surface, and the donor site. This article presented a case of a partial penile and urethral defect due to an infection in the previous surgical site. The patient was treated with a perforator based pedicled composite anterolateral thigh flap combined with vascularized fascia lata. The urethral defect was reconstructed with the vascularized fascia lata. The remaining part of the flap was used for the resurfacing of the right cavernous body and penile skin defect. There was no fistula and the urinary caliber was accepted as good. The pedicled composite anterolateral thigh flap contains various tissue components suitable for a functional and cosmetic reconstruction of complex penile defects using the one-stage technique. PMID- 26033659 TI - [Penetrating cardiac injury in blunt trauma: a case report]. AB - Cardiac injuries may rarely be observed due to blunt thoracic traumas. Cardiac injury often creates a life-threatening condition requiring urgent surgical intervention, and follow-up of these patients should be carefully carried out in the perioperative period. These injuries depend on various factors including clinical presentation, type of injury, the time that passes until the patient reaches the hospital, bleeding, cardiac tamponade, or additional injuries. This article aimed to report a case who suffered penetrating cardiac injury in blunt thoracic trauma. Evaluated in the emergency department due to a motor vehicle accident, the 61-year-old male patient's chest x-ray revealed pulmonary contusion, rib fractures and cardiac tamponade. The patient was operated emergently. Right atrial injury was observed in the operation. The cardiac injury was repaired with primary suture technique. Cardiac injury in patients with blunt thoracic trauma is likely to be observed. In these patients, careful physical examination, early diagnosis, and treatment are very important. PMID- 26033660 TI - [Neodymium magnet injury causing nasal fracture: a case report]. AB - In parallel with technological developments, small size but strong magnets are commonly used in modern devices. In terms of foreign body injuries, magnet injuries are quite rare. However, due to their unique characteristics, there are some difficulties in their management. The magnetic field generated by the magnet affects the surgical instruments and make treatment difficult. In this case report, a nasal injury due to neodymium magnet and our alternative approach for its management was reported. PMID- 26033661 TI - Molecular Weight Effects on the Glass Transition and Confinement Behavior of Polymer Thin Films. AB - Nanoscale polymer thin films exhibit strong confinement effects on Tg arising from free surfaces. However, the coupled influence of molecular weight (MW) and surface effects on Tg is not well understood for low MW film systems below the entanglement length. Utilizing atomistically informed coarse-grained molecular dynamics simulations for poly(methyl methacrylate) (PMMA), it is demonstrated that the decrease in free-standing film Tg with respect to bulk is more significant for low MW compared to high MW systems. Investigation of the local interfacial properties reveals that the increase in the local free volume near the free surface is greater for low MW, explaining the MW dependence of Tg confinement behaviors. These findings corroborate recent experiments on low MW films, and highlight the relationship between nanoconfinement phenomena and local free volume effects arising from free surfaces. PMID- 26033662 TI - Aqueous extract of tomato seeds attenuates rotenone-induced oxidative stress and neurotoxicity in Drosophila melanogaster. AB - BACKGROUND: Tomato seeds, a major by-product from the food processing industry, constitute a rich source of bioactives and a large population consumes tomato (either in raw or cooked form). In the present study, initially we assessed the antioxidant activity of aqueous extract of tomato seeds (TSE) in selected chemical systems and further explored the neuroprotective effects of TSE utilising the rotenone (ROT) model of neurotoxicity in Drosophila. RESULTS: Adult male flies (Oregon K) were fed TSE-enriched medium (0.1-0.2%) with or without ROT (500 umol L(-1)) for 7 days. The propensity of TSE to protect flies against ROT induced lethality, locomotor phenotype, oxidative stress and neurotoxicity was investigated. TSE offered marked protection against ROT-induced mortality, while survivors exhibited improved locomotor phenotype. TSE significantly attenuated ROT-induced oxidative stress, mitochondrial dysfunctions, protein carbonyls content, restored the cholinergic function and dopamine levels. CONCLUSION: We hypothesise that the efficacy of tomato seed extract to attenuate ROT-mediated neurotoxicity may be largely related to the combined antioxidant activity of bioactives resulting in abrogation of oxidative stress and mitochondrial dysfunction. More importantly, our approach provides an experimental paradigm to rapidly assess the potential neuroprotective effects of common dietary components employing Drosophila, since it corroborates previous evidence in a mouse model. PMID- 26033663 TI - Seeing what you want. AB - There has been recent interest in the hypothesis that we can directly perceive some of each other's mental features. One popular strategy for defending that hypothesis is to claim that some mental features are embodied in a way that makes them available to perception. Here I argue that this view would imply a particular limit on the kinds of mental feature that would be perceptible (Section 2). I sketch reasons for thinking that the view is not yet well motivated (Section 3). And I present an alternative, epistemological strategy (Section 4). The epistemological strategy is to discern which features of our environment are perceptible by reflection on our capacity to identify them. If the epistemological strategy is accepted it becomes plausible that we sometimes directly perceive some of each other's mental features. But it becomes implausible to suppose that our perceptual access is limited in the way the embodied view would imply. I end by sketching reasons to think that we sometimes directly perceive each other's desires (Section 5). PMID- 26033664 TI - Continuing debates on direct social perception: Some notes on Gallagher's analysis of "the new hybrids". AB - This commentary argues that Gallagher's account of direct social perception has remained underdeveloped in several respects. Gallagher has not provided convincing evidence to support his claim that mindreading is rare in social situations. He and other direct perception theorists have not offered a substantive critique of standard theories of mindreading because they have attacked a much stronger claim about the putative unobservability of mental states than most theories of mindreading imply. To provide a genuine alternative to standard theories of mindreading, the direct perception theorist needs to provide more detailed answers to the following questions: What are the criteria for distinguishing perceptual processes from non-perceptual processes? How exactly does direct social perception function on the subpersonal level? What is the content of direct social perception? How does direct perception theory relate to more recent developments in the mindreading literature? PMID- 26033666 TI - Evidence for internuclear signaling in drosophila embryogenesis. AB - BACKGROUND: Syncytial nuclei in Drosophila embryos undergo their first 13 divisions nearly synchronously. In the last several cell cycles, these division events travel across the anterior-posterior axis of the syncytial blastoderm in a wave. The phenomenon is well documented but the underlying mechanisms are not yet understood. RESULTS: We study timing and positional data obtained from in vivo imaging of Drosophila embryos. We determine the statistical properties of the distribution of division times within and across generations with the null hypothesis that timing of division events is an independent random variable for each nucleus. We also compare timing data with a model of Drosophila cell cycle regulation that does not include internuclear signaling, and to a universal model of phase-dependent signaling to determine the probable form of internuclear signaling in the syncytial embryo. CONCLUSIONS: The statistical variance of division times is lower than one would expect from uncoordinated activity. In fact, the variance decreases between the 10th and 11th divisions, which demonstrates a contribution of internuclear signaling to the observed synchrony and division waves. Our comparison with a coupled oscillator model leads us to conclude that internuclear signaling must be of Response/Signaling type with a positive impulse. PMID- 26033665 TI - Transforming ecosystems: When, where, and how to restore contaminated sites. AB - Chemical contamination has impaired ecosystems, reducing biodiversity and the provisioning of functions and services. This has spurred a movement to restore contaminated ecosystems and develop and implement national and international regulations that require it. Nevertheless, ecological restoration remains a young and rapidly growing discipline and its intersection with toxicology is even more nascent and underdeveloped. Consequently, we provide guidance to scientists and practitioners on when, where, and how to restore contaminated ecosystems. Although restoration has many benefits, it also can be expensive, and in many cases systems can recover without human intervention. Hence, the first question we address is: "When should we restore contaminated ecosystems?" Second, we provide suggestions on what to restore-biodiversity, functions, services, all 3, or something else--and where to restore given expected changes to habitats driven by global climate change. Finally, we provide guidance on how to restore contaminated ecosystems. To do this, we analyze critical aspects of the literature dealing with the ecology of restoring contaminated ecosystems. Additionally, we review approaches for translating the science of restoration to on-the-ground actions, which includes discussions of market incentives and the finances of restoration, stakeholder outreach and governance models for ecosystem restoration, and working with contractors to implement restoration plans. By explicitly considering the mechanisms and strategies that maximize the success of the restoration of contaminated sites, we hope that our synthesis serves to increase and improve collaborations between restoration ecologists and ecotoxicologists and set a roadmap for the restoration of contaminated ecosystems. PMID- 26033667 TI - Positive peritoneal fluid fungal cultures in postoperative peritonitis after bariatric surgery. AB - Postoperative peritonitis (POP) is a common surgical complication after bariatric surgery (BS). We assessed the importance of positive fungal cultures in these cases of POP admitted to the intensive care unit. Clinical features and outcome were compared in 25 (41%) Candida-positive patients (6 (22%) fluconazole resistant Candida glabrata) and 36 patients without Candida infection. Candida infections were more commonly isolated in late-onset peritonitis and were often associated with multidrug-resistant bacteria. Risk factors for intensive care unit mortality (19.6%) were diabetes and superobesity. Candida infections, including fluconazole-resistant strains, are common in POP after BS. These data encourage the empirical use of a broad-spectrum antifungal agent. PMID- 26033668 TI - Impact of routine bedside infectious disease consultation on clinical management and outcome of Staphylococcus aureus bacteraemia in adults. AB - Staphylococcus aureus bacteraemia (SAB) is a common, serious infection that is associated with high rates of morbidity and mortality. Evidence suggests that infectious disease consultation (IDC) improves clinical management in patients with SAB. We examined whether the introduction of a routine bedside IDC service for adults with SAB improved clinical management and outcomes compared to telephone consultation. We conducted an observational cohort study of 571 adults with SAB at a teaching hospital in the United Kingdom between July 2006 and December 2012. A telephone consultation was provided on the day of positive blood culture in all cases, but an additional bedside IDC was provided after November 2009 (routine IDC group). Compared to patients in the pre-IDC group, those in the routine IDC group were more likely to have a removable focus of infection identified, echocardiography performed and follow-up blood cultures performed. They also received longer courses of antimicrobial therapy, were more likely to receive combination antimicrobial therapy and were more likely to have SAB recorded in the hospital discharge summary. There was a trend towards lower mortality at 30 days in the routine IDC group compared to the pre-IDC group (12% vs. 22%, p 0.07). Our findings suggest that routine bedside IDC should become the standard of care for adults with SAB. PMID- 26033670 TI - Burden, seasonal pattern and symptomatology of acute respiratory illnesses with different viral aetiologies in children presenting at outpatient clinics in Hong Kong. AB - Respiratory viruses cause acute respiratory diseases with a broad and overlapping spectrum of symptoms. We examined the clinical symptoms and explored the patterns of various respiratory viral infections in children in Hong Kong. Among 2090 specimens collected from outpatient care (2007-2010), 1343 (64.3%) were positive for any virus by the xTAG assay, and 81 (3.9%) were positive for co-infection. The most frequently detected viruses among children aged 6-15 years were enterovirus/rhinovirus and influenza virus A, whereas most non-influenza viruses were more frequently detected in younger children. Higher body temperature was more common for illnesses associated with influenza viruses than for those associated with non-influenza viruses, but other symptoms were largely similar across all infections. The seasonality pattern varied among different viruses, with influenza virus A being the predominant virus detected in winter, and enterovirus/rhinovirus being more commonly detected than influenza virus A in the other three seasons, except for 2009. PMID- 26033669 TI - Carriage of extended-spectrum beta-lactamases in pig farmers is associated with occurrence in pigs. AB - Livestock may serve as a reservoir for extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). The objectives of this study were to determine the prevalence of carriage with ESBL-PE in pig farmers, family members and employees, and its association with carriage in pigs. Rectal swabs were taken from 2388 pigs (398 pooled samples) on 40 pig farms and faecal samples were obtained from 142 humans living or working on 34 of these farms. Presence of ESBL-PE was determined by selective plating (agar). ESBL genes were analysed by PCR or microarray analysis, and gene sequencing. Genotypes and plasmids were determined by multilocus sequence typing and PCR-based replicon typing for selected isolates. ESBL genes were detected in Escherichia coli from eight humans (6%) (blaCTX-M-1, n = 6; blaTEM-52, n = 1 and blaCTX-M-14, n = 1) on six farms. In 157 pig isolates (107 pooled samples) on 18 farms (45%) ESBL genes were detected (blaCTX-M-1, n = 12; blaTEM-52, n = 6; and blaCTX-M-14, n = 3). Human and pig isolates within the same farm harboured similar ESBL gene types and had identical sequence and plasmid types on two farms (e.g. E. coli ST-453, blaCTX-M-1, IncI1), suggesting clonal transmission. For the remaining farms, sequence types, but not plasmid types, differed. Human ESBL carriage was associated with average number of hours working on the farm per week (OR = 1.04, 95% CI 1.02-1.06) and presence of ESBLs in pigs (OR = 12.5, 95% CI 1.4-111.7). Daily exposure to pigs carrying ESBL-PE is associated with ESBL carriage in humans. PMID- 26033671 TI - Twelve years of dengue surveillance in Belgian travellers and significant increases in the number of cases in 2010 and 2013. AB - During 12 years of surveillance in Belgium, dengue virus (DENV) infection was diagnosed in 676 of 7771 (8.7%) returning travellers by the use of ELISA, RT-PCR, and/or antigen detection. Men and women were equally infected. The mean age of the patients was 36.78 years (range, 3-77 years). Most of the infections occurred after a stay in Asia (55.9%), followed by the Americas (31.8%), Africa (7.2%), Oceania (1.0%), and Europe (0.4%). The number of patients coming from Africa increased as of 2009, to reach a proportion of 17% in 2011. The most prevalent serotype was DENV-1, followed by DENV-2, DENV-3, and DENV-4. Two remarkable increases in dengue incidence were noticed in 2010 and 2013. PMID- 26033672 TI - Bacillus anthracis meningitis during an outbreak of injectional anthrax, Scotland, UK. PMID- 26033673 TI - To Our Friend and Colleague Koji Nakanishi: "Happy 90th Birthday". PMID- 26033674 TI - Reducing the frequency of wearing high-heeled shoes and increasing ankle strength can prevent ankle injury in women. PMID- 26033675 TI - A clinician's guide to drug-drug interactions with direct-acting antiviral agents for the treatment of hepatitis C viral infection. AB - The US Food and Drug Administration has recently approved a number of new direct acting antiviral agents for the treatment of chronic hepatitis C virus that have significantly increased the likelihood of a virological cure. These agents are highly effective but present a substantial risk for a host of clinically relevant drug-drug interactions. These interactions must be considered both when starting and stopping any medication, including over-the-counter medications and herbal supplements. These drug-drug interactions can increase the risk of toxicity or decrease the likelihood of treatment response. Knowledge of these interactions is paramount in optimizing the success of antiviral therapy. CONCLUSION: In this review we summarize the available data regarding drug-drug interactions for direct-acting antiviral agents, the interactions being the most clinically relevant that are currently known; this review is intended to serve as a clinician's guide to understanding and managing these complex interactions. (Hepatology 2016;63:634-643). PMID- 26033676 TI - Combining metagenomics with metaproteomics and stable isotope probing reveals metabolic pathways used by a naturally occurring marine methylotroph. AB - A variety of culture-independent techniques have been developed that can be used in conjunction with culture-dependent physiological and metabolic studies of key microbial organisms in order to better understand how the activity of natural populations influences and regulates all major biogeochemical cycles. In this study, we combined deoxyribonucleic acid-stable isotope probing (DNA-SIP) with metagenomics and metaproteomics to characterize an uncultivated marine methylotroph that actively incorporated carbon from (13) C-labeled methanol into biomass. By metagenomic sequencing of the heavy DNA, we retrieved virtually the whole genome of this bacterium and determined its metabolic potential. Through protein-stable isotope probing, the RuMP cycle was established as the main carbon assimilation pathway, and the classical methanol dehydrogenase-encoding gene mxaF, as well as three out of four identified xoxF homologues were found to be expressed. This proof-of-concept study is the first in which the culture independent techniques of DNA-SIP and protein-SIP have been used to characterize the metabolism of a naturally occurring Methylophaga-like bacterium in the marine environment (i.e. Methylophaga thiooxydans L4) and thus provides a powerful approach to access the genome and proteome of uncultivated microbes involved in key processes in the environment. PMID- 26033678 TI - Nares-to-carina distance in children: does a 'modified Morgan formula' give useful guidance during nasal intubation? AB - BACKGROUND: Knowledge of the normal nares-to-carina (NC) distance might prevent accidental bronchial intubation and be helpful when designing preformed endotracheal tubes (ETT). OBJECTIVE: The aim was to measure NC distance and to examine whether a height/length-based 'modified Morgan formula' would give useful guidance for nasotracheal ETT depth positioning. METHODS: Two groups were studied. A younger group consisted of nasally intubated postoperative patients. In these, NC distance was obtained as the sum of ETT length and the distance from the ETT tip to the carina, as measured from an anteroposterior chest X-ray. An older group consisted of children who had undergone computerized tomography (CT) examination including head, neck, and chest. In these, NC was measured directly from the CT image. The modified Morgan formula was derived from the NC vs height/length relationship. RESULTS: Nares-to-carina distance was best predicted by a linear equation based on patient height. The equation in the younger group (1 day-8 years, n = 57) was: NC (cm) = 0.14 * height + 5.8, R(2) = 0.90, and in the older group (2.1-20 years, n = 45): NC (cm) = 0.15 * height + 3.4, R(2) = 0.93. The equation for the groups combined (n = 102) was: NC (cm) = 0.14 * height + 6.2, R(2) = 0.97. Based on the latter equation, a modified Morgan formula was identified as: ETT position at nares in cm = 0.12 * height + 5. If the ETT had been placed as calculated by this formula, the ETT tip would have been at 85 + 5% (mean +/- sd) of NC distance, and the ETT tip-to-carina distance would have been 3.1 +/- 1.1 cm (range 0-6.6). Bronchial intubation would not have occurred in any child, but a comparison to tracheal length measurements indicates that ETT tip position could be too proximal in some children. CONCLUSION: The study confirms previous reports: NC distance can be well predicted from height/length. A modified Morgan formula might decrease the risk for accidental endobronchial intubation in infants and children, but ETT position need to be confirmed by auscultation or other verification. PMID- 26033679 TI - Fluorescence Dynamics of Monocyclodextrin- and Bis(thiol-cyclodextrin)-Coumarin C153 Complexes. AB - The solvation and confinement of coumarin C153 within supramolecular host/guest complexes based on beta-cyclodextrin (beta-CD) and 6-deoxy-6-thio-beta cyclodextrin (beta-CD-SH) in water are studied by fluorescence spectroscopy. For beta-CD/C153, the 1:1 complex is proposed, and for beta-CD-SH/C153 both the 1:1 and 2:1 complexes are believed to be formed. The 2:1 beta-CD-SH/C153 complex has an association constant of 4.2*10(5) M(-1) and a C153 population of 82 %, which are interestingly high values, indicating that the proposed beta-CD-SH dimers structure are connected by covalent disulfide bonds; this is supported by mass spectrometry. Solvation related to fast hydrogen-bond rearrangement as a part of fluorescence relaxation is determined by the ultrafast components of time resolved spectroscopy to be 3 and 7 ps for the 1:1 beta-CD/C153 and 2:1 beta-CD SH/C153 complexes, respectively. PMID- 26033680 TI - Subcellular localization of the sigma-1 receptor in retinal neurons - an electron microscopy study. AB - The Sigma-1 receptor (S1R) is known to play a protective role in the central nervous system including the retina. A major barrier for understanding the underlying mechanism is an ambiguity of S1R subcellular localizations. We thus conducted the first electron microscopy (EM) study of S1R subcellular distribution in the mouse retina. Immuno-EM imaging showed previously under appreciated S1R presence in photoreceptor cells. Unlike in other cell types in previous reports, in photoreceptor cells S1R was found in the nuclear envelope but not localized in the endoplasmic reticulum (ER), raising a possibility of S1R mediated modulatory mechanisms different than conventionally thought. While in bipolar cells S1R was detected only in the nuclear envelope, in ganglion cells S1R was identified predominantly in the nuclear envelope and found in the ER as well. A predominant localization of S1R in the nuclear envelope in all three retinal neurons implicates a potential role of S1R in modulating nuclear activities. Moreover, its absence in the plasma membrane and presence in the subsurface ER cisternae that are juxtaposed to the plasma membrane in ganglion cells may lend mechanistic insights generally important for frequently reported S1R modulations of ion channels in neurons. PMID- 26033681 TI - Parecoxib Protects Mouse Cortical Neurons Against OGD/R Induced Neurotoxicity by Up-Regulating Bcl-2. AB - Ischemic stroke remains a significant problem that is the major cause of death and disability worldwide. Parecoxib is clinically used for short-term management of postoperative pain. Administration of parecoxib in rats has been reported to protect against the cerebral ischemia/reperfusion. However, the neuroprotective mechanism of parecoxib is still largely unknown. In this study, we found parecoxib could protect against neurotoxicity induced by 4 h oxygen-glucose deprivation (OGD) plus reoxgenation for 20 h, a widely used in vitro model of ischemia/reperfusion. In addition, we characterized the molecular mechanism of parecoxib's neuroprotection. We found parecoxib was able to activate CREB, and subsequently maintained the expression of Bcl-2, which is an important mitochondria-associated protein. Inhibition of endogenous Bcl-2 expression by transfection of Bcl-2-shRNA significantly attenuated the neuroprotective effects of parecoxib treatment. Furthermore, ATP production assay and mitochondrial membrane potential (DeltaPsim) assay suggested that parecoxib exerted neuroprotective effect against OGD/R by maintaining the function of mitochondria. These data suggested that parecoxib treatment is a potential therapeutic approach for protecting against ischemia/reperfusion injury. PMID- 26033682 TI - Anti-oxidation and Antiapoptotic Effects of Chondroitin Sulfate on 6 Hydroxydopamine-Induced Injury Through the Up-Regulation of Nrf2 and Inhibition of Mitochondria-Mediated Pathway. AB - The purpose of the study was to investigate the protective effect and molecular mechanism of chondroitin sulfate (CS) against 6-hydroxydopamine (6-OHDA) induced toxicity in the human neuroblastoma cell line SH-SY5Y. The results showed that CS could protect SH-SY5Y cells against 6-OHDA-induced injury. The subsequent mechanism study showed that the anti-oxidation of CS may partly be mediated through inhibiting the intracellular reactive oxygen species overproduction, recovering the reduction of nuclear NF-E2-related factor-2 (Nrf2) expression and the reduction of antioxidants activity induced by 6-OHDA. Furthermore, CS pretreatment significantly attenuated 6-OHDA-induced cell apoptosis and nuclear condensation. 6-OHDA-induced dysfunctions, including the decrease of mitochondrial membrane potential (DeltaPsim), increase of intracellular free Ca(2+), imbalance of Bcl-2/Bax ratio, release of Cyt-c from the mitochondria and activation of caspase-3 and caspase-9 were attenuated by CS pretreatment, which demonstrated that CS suppressed 6-OHDA-induced apoptosis in SH-SY5Y cells possibly through mitochondria protection. These results suggest that CS exhibits anti-oxidation through the up-regulation of Nrf2 along with endogenous antioxidant, and reduces apoptosis via inhibiting the mitochondrial pathway to protect SH-SY5Y cells damaged by 6-OHDA. PMID- 26033684 TI - Role of Balloon-Sheathed Intraductal Ultrasonography for Patients with Extensive Pneumobilia. AB - Intraductal ultrasonography (IDUS) is one of the most useful diagnostic tools for various extrahepatic biliary diseases. However, conventional IDUS has some limitations in providing accurate cross-sectional imaging of the bile duct in patients with extensive pneumobilia. Using a balloon-sheathed catheter, the US system (balloon-sheathed IDUS) can overcome these limitations. Sixteen patients underwent balloon-sheathed IDUS during endoscopic retrograde cholangiography. The balloon-sheathed IDUS was inserted via a transpapillary route when visualization of the bile duct with conventional IDUS was distorted by extensive pneumobilia. The patient group had a mean age of 65.5 years, and 56.3% (9/16) were male. The balloon-sheathed IDUS permitted successful visualization of the bile duct in all patients, regardless of the extent of pneumobilia. Using this system, remnant common bile duct stones were detected in five patients (31.3%), and cholangiocarcinoma was detected in one patient (6.3%). The balloon-sheath IDUS aided in stone sweeping. No significant complications, including bleeding, perforation, or pancreatitis, occurred in any of the patients. The balloon sheathed catheter US system was useful and safe for biliary IDUS in patients with extensive pneumobilia. PMID- 26033683 TI - p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1. AB - p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1, and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity. PMID- 26033685 TI - IgG4-Associated Cholangitis Can Mimic Hilar Cholangiocarcinoma. AB - IgG4-associated cholangitis can mimic hilar cholangiocarcinoma. Previously reported patients with IgG4-associated cholangitis mimicking cholangiocarcinoma had elevated serum IgG4 levels and long-segment biliary strictures. However, in the absence of other diagnostic criteria for malignancy, IgG4-associated cholangitis should remain a consideration among patients with normal serum IgG4 and a hilar mass suspicious for cholangiocarcinoma. The presence of a hilar mass and a malignant-appearing biliary stricture in two patients with normal serum IgG4 prompted further evaluation and subsequent concomitant liver and bile duct resection and reconstruction. The diagnosis of IgG4-associated cholangitis was established during the pathologic evaluation of the resected specimens. IgG4 associated cholangitis is a known imitator of hilar cholangiocarcinoma and should be considered in the differential diagnosis even among serologically IgG4 negative patients with a hilar mass prior to operative resection. PMID- 26033686 TI - Adnexal involvement in bullous pemphigoid. PMID- 26033687 TI - Inhibition of Cycloartenol Synthase (CAS) Function in Tobacco BY-2 Cells. AB - Tobacco BY-2 cell suspensions are our preferred model for studying isoprenoid biosynthesis pathways, due to their easy genetic transformation and the efficient absorption of metabolic precursors, intermediates, and/or inhibitors. Using this model system, we have analyzed the effects of chemical and genetic blockage of cycloartenol synthase (CAS, EC 5.4.99.8), an oxidosqualene cyclase that catalyzes the first committed step in the sterol pathway of plants. BY-2 cells were treated with RO 48-8071, a potent inhibitor of oxidosqualene cyclization. Short-term treatments (24 h) resulted in accumulation of oxidosqualene with no changes in the final sterol products. Interestingly, long-term treatments (6 days) induced down-regulation in gene expression not only of CAS but also of the SMT2 gene coding sterol methyltransferase 2 (EC 2.1.1.41). This explains some of the increase in 24-methyl sterols at the expense of the 24-ethyl sterols stigmasterol and sitosterol. In our alternative strategy, CAS gene expression was partially blocked by using an inducible artificial microRNA. The limited effectiveness of this approach might be explained by some dependence of the machinery for RNAi formation on an operating MVA/sterol pathway. For comparison we checked the effect of RO 48-8071 on a green cell suspension of Arabidopsis and on seedlings, containing a small spectrum of triterpenes besides phytosterols. Triterpenes remained essentially unaffected, but phytosterol accumulation was clearly diminished. PMID- 26033688 TI - Maternal occupational pesticide exposure and risk of congenital heart defects in the National Birth Defects Prevention Study. AB - BACKGROUND: Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsistent. METHODS: We examined maternal occupational exposure to fungicides, insecticides, and herbicides for 3328 infants with CHDs and 2988 unaffected control infants of employed mothers using data for 1997 through 2002 births from the National Birth Defects Prevention Study, a population-based multisite case-control study. Potential pesticide exposure from 1 month before conception through the first trimester of pregnancy was assigned by an expert-guided task-exposure matrix and job history details self-reported by mothers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS: Maternal occupational exposure to pesticides was not associated with CHDs overall. In examining specific CHD subtypes compared with controls, some novel associations were observed with higher estimated pesticide exposure: insecticides only and secundum atrial septal defect (OR = 1.8; 95% CI, 1.3-2.7, 40 exposed cases); both insecticides and herbicides and hypoplastic left heart syndrome (OR = 5.1; 95% CI, 1.7-15.3, 4 exposed cases), as well as pulmonary valve stenosis (OR = 3.6; 95% CI, 1.3-10.1, 5 exposed cases); and insecticides, herbicides, and fungicides and tetralogy of Fallot (TOF) (OR = 2.2; 95% CI, 1.2-4.0, 13 exposed cases). CONCLUSION: Broad pesticide exposure categories were not associated with CHDs overall, but examining specific CHD subtypes revealed some increased odds ratios. These results highlight the importance of examining specific CHDs separately. Because of multiple comparisons, additional work is needed to verify these associations. PMID- 26033690 TI - Light-Fueled Microscopic Walkers. AB - The first microscopic artificial walker equipped with liquid-crystalline elastomer muscle is reported. The walker is fabricated by direct laser writing, is smaller than any known living terrestrial creatures, and is capable of several autonomous locomotions on different surfaces. PMID- 26033689 TI - PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer. AB - Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell-cell adhesion in prostate cancer aggressiveness by examining the functional implications of both E cadherin and Desmoglein 2 (DSG2). E-cadherin expression was first examined using immunofluorescence in 50 normal prostate tissues and in a cohort of 414 prostate cancer patients. Correlation and survival analyses were performed to assess its clinical significance. In primary prostate cancer patients, reduced expression of both E-cadherin and DSG2 is significantly associated with an earlier biochemical recurrence. Transgenic DU145 E-cadherin knockdown and constitutively active AKT overexpression lines were generated. Functional implications of such genetic alterations were analyzed in vitro and in vivo, the latter by using tumorigenesis as well as extravasation and metastatic tumor formation assays. We observed that loss of E-cadherin leads to impaired primary and metastatic tumor formation in vivo, suggesting a tumor promoter role for E-cadherin in addition to its known role as a tumor suppressor. Activation of AKT leads to a significant reduction in E-cadherin expression and nuclear localization of Snail, suggesting a role for the PI3K/AKT signaling pathway in the transient repression of E-cadherin. This reduced expression may be regulated by separate mechanisms as neither the loss of E-cadherin nor activation of AKT significantly affected DSG2 expression. In conclusion, these findings illustrate the critical role of cell-cell adhesion in the progression to aggressive prostate cancer, through regulation by the PI3K pathway. PMID- 26033691 TI - Characterization of a non-classical MHC class II gene in the vulnerable Chinese egret (Egretta eulophotes). AB - Genes of the major histocompatibility complex (MHC) are valuable makers of adaptive genetic variation in evolutionary ecology research, yet the non classical MHC genes remain largely unstudied in wild vertebrates. In this study, we have characterized the non-classical MHC class II gene, Egeu-DAB4, in the vulnerable Chinese egret (Ciconiiformes, Ardeidae, Egretta eulophotes). Gene expression analyses showed that Egeu-DAB4 gene had a restricted tissue expression pattern, being expressed in seven examined tissues including the liver, heart, kidney, esophagus, stomach, gallbladder, and intestine, but not in muscle. With respect to polymorphism, only one allele of exon 2 was obtained from Egeu-DAB4 using asymmetric PCR, indicating that Egeu-DAB4 is genetically monomorphic in exon 2. Comparative analyses showed that Egeu-DAB4 had an unusual sequence, with amino acid differences suggesting that its function may differ from those of classical MHC genes. Egeu-DAB4 gene was only found in 30.56-36.56 % of examined Chinese egret individuals. Phylogenetic analysis showed a closer relationship between Egeu-DAB4 and the DAB2 genes in nine other ardeid species. These new findings provide a foundation for further studies to clarify the immunogenetics of non-classical MHC class II gene in the vulnerable Chinese egret and other ciconiiform birds. PMID- 26033693 TI - Modeling and forecasting Acinetobacter baumannii resistance to set appropriate use of cefoperazone-sulbactam: Results from trend analysis of antimicrobial consumption and development of resistance in a tertiary care hospital. AB - BACKGROUND: Antibiotic resistance in Acinetobacter baumannii (AB) is increasingly recognized as a major threat to global health. The extensive use of antimicrobial chemotherapy in clinical environments is considered a factor associated with the enhanced occurrence of antimicrobial resistance. METHODS: The autoregressive integrated moving average model was used to forecast the trend of drug resistance of AB in the coming years, combined with assessment of relationships between antibiotic consumption and AB resistance to set appropriate antibiotic use. RESULTS: A total of 4,377 AB isolates were collected and were associated with a resistance rate of >80% of major antibiotics. A significant increase in resistance in AB to cefoperazone-sulbactam (C-S) (r(2) = 0.98, P = .001) was observed. C-S consumption was correlated with the development of resistance in AB (r = 0.99, P = .02). From 2009-2012, the percentage of AB resistance to C-S was <35%; however, it increased sharply (67.3%) because the annual consumption of C-S was >20 defined daily dose (DDD)/1,000 patient days in 2013.Increased consumption of C-S may contribute to the emergence of multidrug-resistant AB and the increasing prevalence of hospital-acquired infection. CONCLUSION: A recommendation of limiting the use of C-S to <20 DDD/1,000 patient days annually was proposed for inhibiting the sharp increment of the AB resistance rate in our hospital. PMID- 26033692 TI - Association of KIR3DL1/S1 and HLA-Bw4 with CD4 T cell counts in HIV-infected Mexican mestizos. AB - Certain genotypic combinations of killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA) have been associated with favourable outcomes after exposure to human immunodeficiency virus in Caucasoid and African populations. Human immunodeficiency virus (HIV) infection is characterized by a rapid exhaustion of CD4 cells, which results in impaired cellular immunity. During this early phase of infection, it is thought that the natural killer (NK) cells represent the main effector arm of the host immune response to HIV. This study investigates whether KIR and HLA factors are associated to CD4 T cell numbers after HIV infection in Mexican mestizos as assessed at the time of initial medical evaluation and subsequent clinical follow-up. KIR and HLA-B gene carrier frequency differences were compared between groups of patients stratified by CD4 T cell numbers as assessed during their first medical evaluation (a point in time at which all patients were anti-retroviral therapy naive). In addition, the influence that these genetic factors have on averaged historical CD4 cell counts in patients subjected to follow-up (mostly therapy-experienced) was also evaluated. Our results suggest a protective role for the HLA-Bw4 and KIR3D + Bw4 combination in both therapy-naive and therapy-experienced patients. This report furthers our understanding on the way that immune genes modulate HIV disease progression in less-studied human populations such as the Mexican mestizos with a special focus on CD4 T cell number and behaviour. PMID- 26033694 TI - HIV-1 variability and viral load technique could lead to false positive HIV-1 detection and to erroneous viral quantification in infected specimens. AB - OBJECTIVES: Viral load (VL) testing is used for early HIV diagnosis in infants (EID) and for detecting early therapeutic failure events, but can be affected by HIV genetic variability. Dried blood samples (DBS) increase VL access and EID in remote settings and when low blood volume is available. METHODS: This study compares VL values using Siemens VERSANT HIV-1 RNA 1.0 kPCR assay (kPCR) and Roche CAP/CTM Quantitative test v2.0 (CAP/CTM v2.0) in 176 DBS carrying different HIV-1 variants collected from 69 Equatoguinean mothers and their infants with known HIV-1 status (71 infected, 105 uninfected). RESULTS: CAP/CTM v2.0 provided false positive VLs in 11 (10.5%) cases. VL differences above 0.5 log10 were observed in 42/49 (87.5%) DBS, and were above 1 log10 in 18 cases. CAP/CTM v2.0 quantified all the 41 specimens with previously inferred HIV-1 variant by phylogenetic analysis (68.3% recombinants) whereas kPCR only identified 90.2% of them, and was unable to detect 14.3% of 21 CRF02_AG viruses. CAP/CTM v2.0 showed higher sensitivity than kPCR (95.8% vs. 70.1%), quantifying a higher rate of viruses in infected DBS from subjects under antiretroviral exposure at sampling time compared to kPCR (94.7% vs. 96.2%, p-value<0.001). kPCR showed maximum specificity (100%) whereas for CAP/CTM v2.0 was 89.5%. CONCLUSIONS: VL assays should increase their sensitivity and specificity to avoid overestimated HIV-1 quantifications, which could be interpreted as virological failure events, or false negative diagnostic results due to genetic variability. We recommend using the same VL technique for each patient during antiretroviral therapy monitoring. PMID- 26033695 TI - Tuberculosis-related knowledge is associated with patient outcomes in shantytown residents; results from a cohort study, Peru. AB - OBJECTIVES: Tuberculosis is frequent among poor and marginalized people whose limited tuberculosis-related knowledge may impair healthcare access. We characterised tuberculosis-related knowledge and associations with delayed treatment and treatment outcome. METHODS: Tuberculosis patients (n = 943), people being tested for suspected tuberculosis (n = 2020), and randomly selected healthy controls (n = 476) in 16 periurban shantytowns were interviewed characterizing: socio-demographic factors; tuberculosis risk-factors; and patients' treatment delay. Principle component analysis was used to generate a tuberculosis-related knowledge score. Patients were followed-up for median 7.7 years. Factors associated with tuberculosis treatment delay, treatment outcome and tuberculosis recurrence were assessed using linear, logistic and Cox regression. RESULTS: Tuberculosis-related knowledge was poor, especially in older people who had not completed schooling and had never been diagnosed with tuberculosis. Tuberculosis treatment delay was median 60 days and was more delayed for patients who were poorer, older, had more severe tuberculosis and in only unadjusted analysis with incomplete schooling and low tuberculosis-related knowledge (all p <= 0.03). Lower than median tuberculosis-related knowledge was associated with tuberculosis recurrence (unadjusted hazard ratio = 2.1, p = 0.008), and this association was independent of co-morbidities, disease severity and demographic factors (multiple regression adjusted hazard ratio = 2.6, p = 0.008). CONCLUSIONS: Low tuberculosis related knowledge independently predicted tuberculosis recurrence. Thus health education may improve tuberculosis prognosis. PMID- 26033697 TI - Citrus psorosis virus 24K protein interacts with citrus miRNA precursors, affects their processing and subsequent miRNA accumulation and target expression. AB - Sweet orange (Citrus sinensis), one of the most important fruit crops worldwide, may suffer from disease symptoms induced by virus infections, thus resulting in dramatic economic losses. Here, we show that the infection of sweet orange plants with two isolates of Citrus psorosis virus (CPsV) expressing different symptomatology alters the accumulation of a set of endogenous microRNAs (miRNAs). Within these miRNAs, miR156, miR167 and miR171 were the most down-regulated, with almost a three-fold reduction in infected samples. This down-regulation led to a concomitant up-regulation of some of their targets, such as Squamosa promoter binding protein-like 9 and 13, as well as Scarecrow-like 6. The processing of miRNA precursors, pre-miR156 and pre-miR171, in sweet orange seems to be affected by the virus. For instance, virus infection increases the level of unprocessed precursors, which is accompanied by a concomitant decrease in mature species accumulation. miR156a primary transcript accumulation remained unaltered, thus strongly suggesting a processing deregulation for this transcript. The co immunoprecipitation of viral 24K protein with pre-miR156a or pre-miR171a suggests that the alteration in the processing of these precursors might be caused by a direct or indirect interaction with this particular viral protein. This result is also consistent with the nuclear localization of both miRNA precursors and the CPsV 24K protein. This study contributes to the understanding of the manner in which a virus can alter host regulatory mechanisms, particularly miRNA biogenesis and target expression. PMID- 26033698 TI - Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference. AB - This article summarizes discussions at the March 2014 conference organized by the University of Florida (UF) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), entitled "Orlando Inhalation Conference: Approaches in International Regulation." The special focus of the conference was on global scientific and regulatory issues associated with the testing and demonstration of equivalence for the registration of orally inhaled drug products (OIDPs) in the United States, Europe, Brazil, China, and India. The scope included all types of OIDPs throughout their lifecycle, e.g., innovator/brand name products, generics, modifications due to lifecycle management, device changes, etc. Details were presented for the U.S. "weight of evidence approach" for registration of generic products (which includes demonstration of in vitro and in vivo equivalence, as well as quantitative and qualitative sameness, and device similarity). The European "stepwise" approach was elucidated, and the thinking of regulatory agencies in the major emerging markets was clarified. The conference also highlighted a number of areas that would benefit from further research and discussion, especially around patient/device interface and human factor studies, statistical methods and criteria for demonstrating equivalence, the relative roles of in vivo and in vitro tests, and appropriate designs and metrics for in vivo studies of inhaled drugs. PMID- 26033696 TI - Candida tropicalis bloodstream infection: Incidence, risk factors and outcome in a population-based surveillance. AB - OBJECTIVE: To assess the current clinical features and determinants of outcome of Candida tropicalis bloodstream infection (BSI). METHODS: A population-based surveillance on Candida BSI was conducted from May 2010 to April 2011 in 29 Spanish hospitals. Antifungal susceptibility testing (EUCAST methodology) was centrally performed. The characteristics and outcome of C. tropicalis BSI episodes were compared with those due to other species. RESULTS: Fifty-nine out of 752 episodes (7.8%) were due to C. tropicalis (annual incidence: 0.62 cases per 100,000 population). Resistance to fluconazole and voriconazole was found in 23.2% and 26.8% of isolates. Breakthrough BSI occurred in 10.5% of episodes. Risk factors for C. tropicalis BSI were age (odds ratio [OR]: 1.01; P-value = 0.05), underlying leukaemia (OR: 4.77; P-value = 0.001) and chronic lung disease (OR: 2.62; P-value = 0.002). There were no differences in clinical failure (persistent BSI for >=72 h after initiation of therapy and/or 30-day all-cause mortality) between C. tropicalis (39.6%) and non-C. tropicalis groups (45.6%). The appropriateness of antifungal therapy or the fluconazole MIC values had no significant impact on outcome, whereas early central venous catheter removal exerted a protective effect. CONCLUSIONS: C. tropicalis BSI was associated with advanced age, haematological malignancy and respiratory comorbidity. We found no correlation between the unexpectedly high resistance rate to azoles observed and outcome. PMID- 26033699 TI - [Renal cysts - A novel complication of crizotinib treatment for lung cancer]. AB - We report the case of a woman with an ALK positive lung adenocarcinoma, who developed bilateral complex renal cysts 17 months after the introduction of treatment with crizotinib. Clinical investigation led to the conclusion that the cysts were due to anticancer drug. Regression of the renal cysts was observed one month after cessation of the crizotinib. This case illustrates that specific and little known toxicities can occur with these novel molecules which have entered use for the management of lung cancer. PMID- 26033700 TI - The Akt inhibitor, triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFbeta-induced pulmonary fibrosis. AB - BACKGROUND AND PURPOSE: Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt-mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear. EXPERIMENTAL APPROACH: We investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and TGFbeta-induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice. KEY RESULTS: Akt1(-) (/) (-) mice were protected from chronic hypoxia-induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFbeta-induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia- and TGFbeta-induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1(-) (/) (-) mice lungs expressed less TSP1. Moreover, TSP1(-) (/) (-) mice were resistant to adMyrAkt1-induced pulmonary fibrosis. CONCLUSIONS AND IMPLICATIONS: Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease. PMID- 26033701 TI - Multivariate analysis of PRISMA optimized TLC image for predicting antioxidant activity and identification of contributing compounds from Pereskia bleo. AB - Multivariate analysis of thin-layer chromatography (TLC) images was modeled to predict antioxidant activity of Pereskia bleo leaves and to identify the contributing compounds of the activity. TLC was developed in optimized mobile phase using the 'PRISMA' optimization method and the image was then converted to wavelet signals and imported for multivariate analysis. An orthogonal partial least square (OPLS) model was developed consisting of a wavelet-converted TLC image and 2,2-diphynyl-picrylhydrazyl free radical scavenging activity of 24 different preparations of P. bleo as the x- and y-variables, respectively. The quality of the constructed OPLS model (1 + 1 + 0) with one predictive and one orthogonal component was evaluated by internal and external validity tests. The validated model was then used to identify the contributing spot from the TLC plate that was then analyzed by GC-MS after trimethylsilyl derivatization. Glycerol and amine compounds were mainly found to contribute to the antioxidant activity of the sample. An alternative method to predict the antioxidant activity of a new sample of P. bleo leaves has been developed. PMID- 26033702 TI - Prefrontal cortex and hippocampus in behavioural flexibility and posttraumatic functional recovery: reversal learning and set-shifting in rats. AB - Within one experiment and one T-maze, we examined the consequences of (i) bilateral lesions of the anteromedial prefrontal cortex (PFC), (ii) bilateral transections of the fimbria-fornix (FF), or (iii) combined lesions of both PFC and FF (COMB) on rats' ability to perform reversal or set-shifting. Postoperatively, the animals were trained to perform a spatial discrimination go right task. This was followed by (1) a spatial reversal go-left task (reversal learning), or (2) a visual pattern discrimination task (set-shift). Neither single (PFC or FF) lesion nor combined (COMB) lesions affected the animals' ability to acquire the original spatial discrimination task. Regarding the reversal learning, the performance of the PFC and the FF groups was not significantly different from that of the sham operated control animals (Sham). In contrast, animals with combined lesion of both structures were impaired on both error rate and acquisition speed relative to all other groups. Regarding the set shifting, all lesioned groups were impaired relative to the Sham group both regarding the error rate and the acquisition speed. There was, however, no difference in the degree of impairment between the lesioned groups. We conclude that both the PFC and the hippocampus contributed to the mediation of the reversal learning and set-shifting. During functional recovery of reversal learning, these two structures exhibited a mutual dependency, whilst the functional recovery of set-shifting was mediated by a substrate outside these two structures. PMID- 26033703 TI - Assessment of Tissue Level of Histone Deactylase-2 (HDAC-2) in Patients With Mycosis Fungoides. AB - BACKGROUND: Histone deactylases (HDAC) have a role in the pathogenesis of mycosis fungoides (MF) through their actions on different apoptosis pathways. OBJECTIVE: To assess the possible role played by HDAC-2 in MF by estimating the tissue expression of HDAC2 mRNA in different stages of MF. METHODS: This study included 28 MF patients and 30 controls. The HDAC-2 levels were detected by real-time polymerase chain reaction (PCR). Correlations of HDAC-2 levels with clinical presentation and different stages of MF were analyzed. RESULTS: Mean HDAC-2 level was significantly higher in patients (P < .001) than in controls. HDAC-2 highest mean value was significantly detected in patients with stage IIb, and the lowest mean value was detected in patients with stage Ia (P < .001). CONCLUSION: Up regulation of tissue HDAC-2 in MF patients might develop a new approach in the understanding of the pathogenesis of MF. Histone deactylases are important targets for molecular cancer therapeutics. PMID- 26033704 TI - Smoking ban cuts admissions for child respiratory infections. PMID- 26033705 TI - Does anemia-polycythemia complicating twin-twin transfusion syndrome affect outcome after fetoscopic laser surgery? AB - OBJECTIVE: Twin anemia-polycythemia sequence (TAPS) can occur as a unique disease or as a complication of twin-twin transfusion syndrome (TTTS). Middle cerebral artery (MCA) Doppler studies are not currently part of the routine evaluation of monochorionic twins since they are not used in the Quintero staging system. As such, the true incidence of TAPS is unknown. We aimed to compare the characteristics and outcomes of twin pregnancies with TTTS complicated by spontaneous anemia-polycythemia vs those with TTTS alone. METHODS: This was a secondary analysis of data collected prospectively from a cohort of 156 consecutive patients undergoing fetoscopic laser surgery for TTTS, between October 2011 and August 2014. TAPS was defined as discordance in the preoperative MCA peak systolic velocity (PSV), with one twin fetus having MCA-PSV <= 1.0 multiples of the median (MoM) and the other having MCA-PSV >= 1.5 MoM. Maternal demographics as well as preoperative, operative and postoperative variables were analyzed. RESULTS: Included in the final analysis were 133 patients with complete records: 11 cases with TTTS with anemia-polycythemia and 122 cases with TTTS alone. There was no difference in maternal body mass index, gestational age (GA) at procedure, rate of preterm prelabor rupture of membranes or GA at delivery between the two groups. Patients with TTTS and anemia-polycythemia were more likely to be older (P = 0.03) and parous (P = 0.04) and had a significantly lower number of placental anastomoses (P = 0.01). The dual live-birth rate was similar for both groups (P = 0.76). CONCLUSION: Cases of TTTS with anemia-polycythemia were more likely to be found in parous and older women and were characterized by fewer vascular anastomoses. TTTS with anemia-polycythemia was not associated with worse perinatal outcome after laser therapy. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26033706 TI - Nonconvulsive status epilepticus following implantation of subdural grid electrodes in a brain tumor patient. PMID- 26033707 TI - Circulating DNA of HOTAIR in serum is a novel biomarker for breast cancer. AB - Long non-coding HOX transcript antisense intergenic RNA (HOTAIR) plays an important role in breast cancer. The purpose of this study was to determine whether circulating HOTAIR can be used for breast cancer diagnosis. HOTAIR in serum was measured by PCR-based direct detection. Reverse transcriptase and DNase I treatment were used to distinguish the DNA and RNA forms of HOTAIR. To determine whether circulating HOTAIR is a biomarker for breast cancer, the DNA of HOTAIR from breast cancer patients and healthy controls was measured at both the discovery stage (48 individuals) and an independent validation stage (156 individuals). The diagnostic accuracy was assessed by the receiver operating characteristic curve (ROC) and the area under the curve (AUC). We showed that the major form of HOTAIR-derived fragment in serum is DNA rather than RNA in our study, the same as for MALAT-1, another well-described lincRNA. A higher circulating DNA level of HOTAIR was found in patients at the discovery stage (P = 0.0008). ROC analysis revealed that the circulating HOTAIR DNA distinguished breast cancer patients from healthy individuals (AUC = 0.799). This finding was confirmed at the validation stage. Though circulating MALAT-1 DNA was altered in the discovery stage, it showed no significant difference in the validation stage. In the entire set of 204 samples, the circulating HOTAIR DNA showed a 2.15-fold change in patients compared with healthy controls (P < 0.0001, AUC = 0.786). The optimal cutoff value for diagnosis was 0.30 with sensitivity of 80.0 % and specificity of 68.3 %. Moreover, a correlation between the DNA level of circulating HOTAIR and the progress of breast cancer was established. We have demonstrated that the circulating DNA of HOTAIR is a potential biomarker for breast cancer. PMID- 26033708 TI - Quality of life (QoL) in metastatic breast cancer patients with maintenance paclitaxel plus gemcitabine (PG) chemotherapy: results from phase III, multicenter, randomized trial of maintenance chemotherapy versus observation (KCSG-BR07-02). AB - The therapeutic goals are palliative for metastatic breast cancer (MBC) and include prolongation of survival with good quality of life (QoL) and symptom control. The purpose of this study was to examine QoL among women with MBC treated on KCSG-BR07-02 with maintenance of paclitaxel plus gemcitabine (PG) chemotherapy after achieving disease control to initial six cycles of PG chemotherapy or observation. Patients were randomized to either maintenance chemotherapy or observation until progression. QoL was assessed using EORTC QLQ C30 and BR-23. QoL at each cycle was compared between the two treatment arms using the 2-sample t test. Generalized estimating equation method was used to examine the overall difference between the two treatments in QoL. All reported p values are 2 sided. There were no statistically significant differences between two arms in most of the component of the EORTC QLQ-C30 and BR-23 (p > 0.05). There was no significant difference between two treatments (p = 0.6094 for QLQ C30, p = 0.5516 for BR23) at baseline, and there did not exist significant change over the cycle (p = 0.0914 for QLQ-C30, p = 0.7981 for BR23). There was no significant interaction effect between treatment and cycle (p = 0.5543 for QLQ C30. p = 0.5817 for BR23). Maintenance PG chemotherapy in patients with MBC achieving disease control with an initial six cycles of PG chemotherapy resulted in better PFS and OS compared to observation without impeding QoL. PMID- 26033709 TI - Engineering Homochiral Metal-Organic Frameworks by Spatially Separating 1D Chiral Metal-Peptide Ladders: Tuning the Pore Size for Enantioselective Adsorption. AB - The reaction of the chiral dipeptide glycyl-L(S)-glutamate with Co(II) ions produces chiral ladders that can be used as rigid 1D building units. Spatial separation of these building units with linkers of different lengths allows the engineering of homochiral porous MOFs with enhanced pore sizes, pore volumes, and surface areas. This strategy enables the synthesis of a family of isoreticular MOFs, in which the pore size dictates the enantioselective adsorption of chiral molecules (in terms of their size and enantiomeric excess). PMID- 26033710 TI - Dental trauma in Brazilian children and adolescents with cerebral palsy. AB - BACKGROUND: Assessing the frequency and factors associated with dental trauma in pediatric populations with cerebral palsy is important for the planning and implementation of prevention and health promotion programs. The aim of this study was to determine the prevalence and factors associated with dental trauma in children and adolescents with cerebral palsy. MATERIAL AND METHODS: Cross sectional study with a non-probabilistic sample of 80 patients aged 2-18 years was treated in a rehabilitation institution in northeastern Brazil. Caregivers completed a socioeconomic questionnaire, while oral exams were performed by a calibrated investigator (K = 0.75-1.00), with record of the Dental Trauma Index, DMFT and dmft, and Dental Aesthetics and malocclusion indices. Bivariate and multivariate Poisson regression analyses (alpha = 0.05) were performed with the Statistical Package for Social Sciences, version 17. RESULTS: The prevalence of dental trauma was 36.3%, enamel fracture was the most common trauma (89.1%), and the upper central incisors were the most affected dental elements (63.0%). Patients with dental trauma were male, aged 7-18 years, with family income more than one minimum wage, caregiver's education over 4 years, increased overjet, lip hypotonia, quadriplegia, epilepsy, oral breathing, and severe communication skills. The presence of dental trauma was not associated with socioeconomic characteristics (gender, age, family income, and caregiver's educational level), oral health perception, and systemic and oral conditions (dental caries, malocclusion, and lip hypotonia) were evaluated (P > 0.05). CONCLUSION: The prevalence of dental trauma was high, but not associated with clinical variables and evaluated socioeconomic indicators. PMID- 26033712 TI - NeuroGASTRO 2015, June 4-6, 2015, Istanbul, Turkey. PMID- 26033711 TI - Heart rate turbulence and deceleration capacity for risk prediction of serious arrhythmic events in Marfan syndrome. AB - OBJECTIVE: Marfan syndrome (MFS) is associated with a substantial risk for ventricular arrhythmia and sudden cardiac death (SCD). We used heart rate turbulence (HRT) and deceleration capacity (DC), to evaluate the risk stratification for these patients. METHODS: We enrolled 102 patients [45 male (44.1 %), age 40.5 +/- 14.6 years] with MFS. Blood samples were obtained to determine N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Transthoracic echocardiography studies were conducted to evaluate heart function parameters and a 24-h holter ECG was performed. An analysis of two HRT parameters, turbulence onset (TO) and turbulence slope (TS), and DC was performed. Therefore, optimal cut-off values were calculated. Primary endpoint was the combination of SCD, ventricular arrhythmia and arrhythmogenic syncope. Secondary endpoint was total mortality. RESULTS: During a follow-up of 1145 +/- 491 days, 12 (11.7 %) patients reached the primary and 8 (7.8 %) patients the secondary endpoint. Patients reaching the primary were significantly older, had a higher burden of premature ventricular complexes and NT-proBNP levels and lower values of LVEF, DC and HRT TS. Multivariate analysis identified NT-proBNP (HR 1.25, 95 % CI 1.01-1.56, p = .04) and the abnormal HRT (abnormal TS and/or TO (HR 7.04, 95 % CI 1.07-46.27, p = .04) as independent risk predictor of arrhythmogenic events. CONCLUSION: Patients with Marfan syndrome are at risk for severe ventricular arrhythmias and SCD. Abnormal HRT parameters and NT-proBNP values are independent risk factors for arrhythmogenic events and SCD. The assessment of these tools may help predicting SCD patients with MFS. PMID- 26033713 TI - Mesotubular-Structured Hybrid Membrane Nanocontainer for Periodical Monitoring, Separation, and Recovery of Cobalt Ions from Water. AB - Exposure to toxins can cause deleterious effects even at very low concentrations. We have developed an optical sensor, filter, and extractor (i.e., containerlike) in a nanoscale membrane (NSM) for the ultratrace sensing, separation, and recovery of Co(2+) ions from water. The design of the NSM is successfully controlled by dense decoration of a hydrophobic oil-hydrophilic receptor onto mesoscale tubular-structured silica nanochannels made of a hybrid anodic alumina membrane. The particular structure of the nanocontainer is ideal to control the multiple functions of the membrane, such as the optical detection/recognition, rejection/permeation, and recovery of Co(2+) species in a single step. A typical sensor, filter, and extractor assessment experiment was performed by using a benchtop contact time technique and a flow-through cell detector to allow for precise control of the optical detection and exclusive rejection of target ions and the permeation of nontarget metal ions in water. This nanocontainer membrane has great potential to meet the increasing needs of purification and separation of Co(2+) ions. PMID- 26033714 TI - CD48-deficient T-lymphocytes from DMBA-treated rats have de novo mutations in the endogenous Pig-a gene. AB - A major question concerning the scientific and regulatory acceptance of the rodent red blood cell-based Pig-a gene mutation assay is the extent to which mutants identified by their phenotype in the assay are caused by mutations in the Pig-a gene. In this study, we identified T-lymphocytes deficient for the glycosylphosphatidylinositol-anchored surface marker, CD48, in control and 7,12 dimethylbenz[a]anthracene (DMBA)-treated rats using a flow cytometric assay and determined the spectra of mutations in the endogenous Pig-a gene in these cells. CD48-deficient T-cells were seeded by sorting at one cell per well into 96-well plates, expanded into clones, and exons of their genomic Pig-a were sequenced. The majority (78%) of CD48-deficient T-cell clones from DMBA-treated rats had mutations in the Pig-a gene. The spectrum of DMBA-induced Pig-a mutations was dominated by mutations at A:T, with the mutated A being on the nontranscribed strand and A -> T transversion being the most frequent change. The spectrum of Pig-a mutations in DMBA-treated rats was different from the spectrum of Pig-a mutations in N-ethyl-N-nitrosourea (ENU)-treated rats, but similar to the spectrum of DMBA mutations for another endogenous X-linked gene, Hprt. Only 15% of CD48-deficient mutants from control animals contained Pig-a mutations; T-cell biology may be responsible for a relatively large fraction of false Pig-a mutant lymphocytes in control animals. Among the verified mutants from control rats, the most common were frameshifts and deletions. The differences in the spectra of spontaneous, DMBA-, and ENU-induced Pig-a mutations suggest that the flow cytometric Pig-a assay detects de novo mutation in the endogenous Pig-a gene. PMID- 26033715 TI - When should we test patients with familial ataxias for SCA31? A misdiagnosed condition outside Japan? PMID- 26033716 TI - Cause, effect and consequence? Painful small fiber sensory polyneuropathy and impaired glycemia. PMID- 26033717 TI - Callosal damage and cognitive deficits in chronic carbon monoxide intoxication: A diffusion tensor imaging study. AB - PURPOSE: To evaluate the correlation between microstructural damage in the corpus callosum (CC) and the cognitive performance of patients with or without delayed encephalopathy (DE) after carbon monoxide (CO) intoxication in the chronic stage. METHODS: Diffusion tensor imaging (DTI) was performed more than 6 months after CO intoxication for 10 patients with DE and 10 patients without DE recruited from out-patient clinics, as well as for 15 normal controls (NCs). Using a probabilistic tractography method to parcel the CC based on fiber projections to cortical connectivity patterns, the DTI indices were calculated in the CC subregions and further correlated with cognitive performance. RESULTS: The DE group exhibited significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) values in the prefrontal, premotor, primary motor, primary sensory, parietal, and occipital CC subregions than did the NCs. The DE group also exhibited significantly lower FA values in the prefrontal and premotor subregions than did the non-DE group. Lower FA and higher RD values in the CC subregions were associated with poorer scores on the symbol search test. CONCLUSIONS: CO intoxication may cause lower FA and higher RD in the CC subregions, with subsequent cognitive impairment. This finding suggests that selective CC damage after CO intoxication is more profound in patients with DE. PMID- 26033718 TI - Structural determinants of interaction, trafficking and function in the ClC 2/MLC1 subunit GlialCAM involved in leukodystrophy. AB - KEY POINTS: The extracellular domain of GlialCAM is necessary for its targeting to cell junctions, as well as for interactions with itself and MLC1 and ClC-2. The C-terminus of GlialCAM is not necessary for interaction but is required for targeting to cell junctions. The first three residues of the transmembrane segment of GlialCAM are required for GlialCAM-mediated ClC-2 activation. ABSTRACT: Mutations in the genes encoding the astrocytic protein MLC1, the cell adhesion molecule GlialCAM or the Cl(-) channel ClC-2 underlie human leukodystrophies. GlialCAM binds to itself, to MLC1 and to ClC-2, and directs these proteins to cell-cell contacts. In addition, GlialCAM dramatically activates ClC-2 mediated currents. In the present study, we used mutagenesis studies combined with functional and biochemical analyses to determine which parts of GlialCAM are required to perform these cellular functions. We found that the extracellular domain of GlialCAM is necessary for cell junction targeting and for mediating interactions with itself or with MLC1 and ClC-2. The C-terminus is also necessary for proper targeting to cell-cell junctions but is not required for the biochemical interaction. Finally, we identified the first three amino acids of the transmembrane segment of GlialCAM as being essential for the activation of ClC-2 currents but not for targeting or biochemical interaction. Our results provide new mechanistic insights concerning the regulation of the cell biology and function of MLC1 and ClC-2 by GlialCAM. PMID- 26033720 TI - Risk Factors for Resistance to beta-Lactam/beta-Lactamase Inhibitors and Ertapenem in Bacteroides Bacteremia. AB - The objective of this study was to determine risk factors for the development of resistance to beta-lactams/beta-lactamase inhibitors (betaL/betaLIs) and ertapenem among Bacteroides species bacteremia. We conducted a retrospective case control study of 101 adult patients with Bacteroides species bacteremia at a 1,051-bed tertiary care medical center. The duration of exposure to betaL/betaLIs (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.08 to 2.31) was the only independent risk factor for resistance. PMID- 26033719 TI - Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para aminosalicylic acid susceptibility and resistance. AB - para-Aminosalicylic acid (PAS) entered clinical use in 1946 as the second exclusive drug for the treatment of tuberculosis (TB). While PAS was initially a first-line TB drug, the introduction of more potent antitubercular agents relegated PAS to the second-line tier of agents used for the treatment of drug resistant Mycobacterium tuberculosis infections. Despite the long history of PAS usage, an understanding of the molecular and biochemical mechanisms governing the susceptibility and resistance of M. tuberculosis to this drug has lagged behind that of most other TB drugs. Herein, we discuss previous studies that demonstrate PAS-mediated disruption of iron acquisition, as well as recent genetic, biochemical, and metabolomic studies that have revealed that PAS is a prodrug that ultimately corrupts one-carbon metabolism through inhibition of the formation of reduced folate species. We also discuss findings from laboratory and clinical isolates that link alterations in folate metabolism to PAS resistance. These advancements in our understanding of the basis of the susceptibility and resistance of M. tuberculosis to PAS will enable the development of novel strategies to revitalize this and other antimicrobial agents for use in the global effort to eradicate TB. PMID- 26033721 TI - Characterization of pKP-M1144, a Novel ColE1-Like Plasmid Encoding IMP-8, GES-5, and BEL-1 beta-Lactamases, from a Klebsiella pneumoniae Sequence Type 252 Isolate. AB - IMP-8 metallo-beta-lactamase was identified in Klebsiella pneumoniae sequence type 252 (ST252), isolated in a Portuguese hospital in 2009. blaIMP-8 was the first gene cassette of a novel class 3 integron, In1144, also carrying the blaGES 5, blaBEL-1, and aacA4 cassettes. In1144 was located on a ColE1-like plasmid, pKP M1144 (12,029 bp), with a replication region of limited nucleotide similarity to those of other RNA-priming plasmids, such as pJHCMW1. In1144 and pKP-M1144 represent an interesting case of evolution of resistance determinants in Gram negative bacteria. PMID- 26033722 TI - Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents. AB - In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6"-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64 fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID- 26033723 TI - Activity of Meropenem Combined with RPX7009, a Novel beta-Lactamase Inhibitor, against Gram-Negative Clinical Isolates in New York City. AB - Multidrug-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are endemic to hospitals in New York City and other regions. RPX7009 is a novel beta-lactamase inhibitor with activity against serine carbapenemases. We tested the activity of meropenem plus RPX7009 against 4,500 recent Gram-negative clinical isolates from 11 New York City hospitals. The meropenem-RPX7009 combination was found to have excellent in vitro activity against Escherichia coli, K. pneumoniae, and Enterobacter spp., including multidrug-resistant (MDR) KPC-producing strains. Overall, 131/133 (98.5%) KPC producing Enterobacteriaceae strains were inhibited by meropenem (<=1 MUg/ml) plus RPX7009 (8 MUg/ml). In a limited number of strains, the combination appeared to have reduced activity against KPC-producing K. pneumoniae isolates with diminished ompK35 and ompK36 expression. The addition of RPX7009 did not affect the activity of meropenem against Acinetobacter baumannii and Pseudomonas aeruginosa. The meropenem-RPX7009 combination shows promise as a novel agent against KPC-producing Enterobacteriaceae and deserves further study. Other approaches will be needed to address multidrug-resistant A. baumannii and P. aeruginosa, which typically possess different mechanisms of carbapenem resistance. PMID- 26033724 TI - Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G0/G1 Arrest followed by Necrotic Cell Death in Leishmania donovani. AB - The aim of the present study was to synthesize silver (Ag) and titanium dioxide (TiO2) nanoparticles (NPs) using green synthesis from aqueous leaf extract of Euphorbia prostrata as antileishmanial agents and to explore the underlying molecular mechanism of induced cell death. In vitro antileishmanial activity of synthesized NPs was tested against promastigotes of Leishmania donovani by alamarBlue and propidium iodide uptake assays. Antileishmanial activity of synthesized NPs on intracellular amastigotes was assessed by Giemsa staining. The leishmanicidal effect of synthesized Ag NPs was further confirmed by DNA fragmentation assay and by cell cycle progression and transmission electron microscopy (TEM) of the treated parasites. TEM analysis of the synthesized Ag NPs showed a spherical shape with an average size of 12.82 +/- 2.50 nm, and in comparison to synthesized TiO2 NPs, synthesized Ag NPs were found to be most active against Leishmania parasites after 24 h exposure, with 50% inhibitory concentrations (IC50) of 14.94 MUg/ml and 3.89 MUg/ml in promastigotes and intracellular amastigotes, respectively. A significant increase in G0/G1 phase of the cell cycle with a subsequent decrease in S (synthesis) and G2/M phases compared to controls was observed. The growth-inhibitory effect of synthesized Ag NPs was attributed to increased length of S phase. A decreased reactive oxygen species level was also observed, which could be responsible for the caspase independent shift from apoptosis (G0/G1 arrest) to massive necrosis. High molecular-weight DNA fragmentation as a positive consequence of necrotic cell death was also visualized. We also report that the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by synthesized Ag NPs. The green-synthesized Ag NPs may provide promising leads for the development of cost-effective and safer alternative treatment against visceral leishmaniasis. PMID- 26033725 TI - Lack of Artemisinin Resistance in Plasmodium falciparum in Uganda Based on Parasitological and Molecular Assays. AB - We evaluated markers of artemisinin resistance in Plasmodium falciparum isolated in Kampala in 2014. By standard in vitro assays, all isolates were highly sensitive to dihydroartemisinin (DHA). By the ring-stage survival assay, after a 6-h DHA pulse, parasitemia was undetectable in 40 of 43 cultures at 72 h. Two of 53 isolates had nonsynonymous K13-propeller gene polymorphisms but did not have the mutations associated with resistance in Asia. Thus, we did not see evidence for artemisinin resistance in Uganda. PMID- 26033726 TI - Molecular Analysis of the embCAB Locus and embR Gene Involved in Ethambutol Resistance in Clinical Isolates of Mycobacterium tuberculosis in France. AB - Modification of codon 306 in embB is regarded as the main mechanism leading to ethambutol (ETB) resistance in clinical isolates of Mycobacterium tuberculosis. However, numerous mutations elsewhere in the embCAB locus and in embR, a putative transcriptional activator of this locus, have been reported to be involved in ETB resistance. Here, we investigated the diversity of nucleotide variations observed in embCAB and embR in M. tuberculosis complex isolates from France. These regions were sequenced in 71 ETB-resistant (ETB-R) and 60 ETB-susceptible (ETB-S) clinical isolates of known phylogenetic lineages. The 131 isolates had 12 mutations corresponding to phylogenetic markers. Among the 60 ETB-S isolates, only 3 (5%) had nonsynonymous mutations that were not phylogenetic markers. Among the 71 ETB-R isolates, 98% had mutations in embCAB that likely contribute to ETB resistance: 70% had mutations located in embB codon 306, 406, or 497; 13% had mutations located outside these three positions between codons 296 and 426; and 15% had mutations corresponding to mutations in the embC-embA intergenic region. We found a strong association between resistance to ETB and the presence of mutations in embB and the embC-embA intergenic region (P < 0.001). In contrast, the mutations detected in embC and embA were not involved in ETB resistance, and no mutation was detected in embR. These results strongly suggest that the sensitivity of diagnostic assays for detecting ETB resistance based on testing of embB codon 306 can be increased by testing of the embB region between codons 296 and 497 and by including the embC-embA intergenic region between positions -8 and -21. PMID- 26033727 TI - Ultrashort Antimicrobial Peptides with Antiendotoxin Properties. AB - Release of lipopolysaccharide (LPS) (endotoxin) from bacteria into the bloodstream may cause serious unwanted stimulation of the host immune system. Some but not all antimicrobial peptides can neutralize LPS-stimulated proinflammatory responses. Salt resistance and serum stability of short antimicrobial peptides can be boosted by adding beta-naphthylalanine to their termini. Herein, significant antiendotoxin effects were observed in vitro and in vivo with the beta-naphthylalanine end-tagged variants of the short antimicrobial peptides S1 and KWWK. PMID- 26033728 TI - Upregulation of Cysteine Synthase and Cystathionine beta-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress. AB - Cysteine metabolism is considered essential for the crucial maintenance of a reducing environment in trypanosomatids due to its importance as a precursor of trypanothione biosynthesis. Expression, activity, functional rescue, and overexpression of cysteine synthase (CS) and cystathionine beta-synthase (CbetaS) were evaluated in Leishmania braziliensis promastigotes and intracellular amastigotes under in vitro stress conditions induced by hydrogen peroxide (H2O2), S-nitroso-N-acetylpenicillamine, or antimonial compounds. Our results demonstrate a stage-specific increase in the levels of protein expression and activity of L. braziliensis CS (LbrCS) and L. braziliensis CbetaS (LbrCbetaS), resulting in an increment of total thiol levels in response to both oxidative and nitrosative stress. The rescue of the CS activity in Trypanosoma rangeli, a trypanosome that does not perform cysteine biosynthesis de novo, resulted in increased rates of survival of epimastigotes expressing the LbrCS under stress conditions compared to those of wild-type parasites. We also found that the ability of L. braziliensis promastigotes and amastigotes overexpressing LbrCS and LbrCbetaS to resist oxidative stress was significantly enhanced compared to that of nontransfected cells, resulting in a phenotype far more resistant to treatment with the pentavalent form of Sb in vitro. In conclusion, the upregulation of protein expression and increment of the levels of LbrCS and LbrCbetaS activity alter parasite resistance to antimonials and may influence the efficacy of antimony treatment of New World leishmaniasis. PMID- 26033729 TI - Combination Therapy against Polymicrobial Infection, Including by NDM-1-Producing Enterobacteriaceae Resistant to Colistin. PMID- 26033730 TI - Biofilm Formation Caused by Clinical Acinetobacter baumannii Isolates Is Associated with Overexpression of the AdeFGH Efflux Pump. AB - Chronic wound infections are associated with biofilm formation, which in turn has been correlated with drug resistance. However, the mechanism by which bacteria form biofilms in clinical environments is not clearly understood. This study was designed to investigate the biofilm formation potency of Acinetobacter baumannii and the potential association of biofilm formation with genes encoding efflux pumps, quorum-sensing regulators, and outer membrane proteins. A total of 48 clinically isolated A. baumannii strains, identified by enterobacterial repetitive intergenic consensus (ERIC)-PCR as types A-II, A-III, and A-IV, were analyzed. Three representative strains, which were designated A. baumannii ABR2, ABR11, and ABS17, were used to evaluate antimicrobial susceptibility, biofilm inducibility, and gene transcription (abaI, adeB, adeG, adeJ, carO, and ompA). A significant increase in the MICs of different classes of antibiotics was observed in the biofilm cells. The formation of a biofilm was significantly induced in all the representative strains exposed to levofloxacin. The levels of gene transcription varied between bacterial genotypes, antibiotics, and antibiotic concentrations. The upregulation of adeG correlated with biofilm induction. The consistent upregulation of adeG and abaI was detected in A-III-type A. baumannii in response to levofloxacin and meropenem (1/8 to 1/2* the MIC), conditions which resulted in the greatest extent of biofilm induction. This study demonstrates a potential role of the AdeFGH efflux pump in the synthesis and transport of autoinducer molecules during biofilm formation, suggesting a link between low dose antimicrobial therapy and a high risk of biofilm infections caused by A. baumannii. This study provides useful information for the development of antibiofilm strategies. PMID- 26033731 TI - Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner. AB - Tuberculosis is a severe disease affecting millions worldwide. Unfortunately, treatment strategies are hampered both by the prohibitively long treatment regimen and the rise of drug-resistant strains. Significant effort has been expended in the search for new treatments, but few options have successfully emerged, and new treatment modalities are desperately needed. Recently, there has been growing interest in the synergistic antibacterial effects of copper ions (Cu(II/I)) in combination with certain small molecular compounds, and we have previously reported development of a drug screening strategy to harness the intrinsic bactericidal properties of Cu(II/I). Here, we describe the copper dependent antimycobacterial properties of disulfiram, an FDA-approved and well tolerated sobriety aid. Disulfiram was inhibitory to mycobacteria only in the presence of Cu(II/I) and exerted its bactericidal activity well below the active concentration of Cu(II/I) or disulfiram alone. No other physiologically relevant bivalent transition metals (e.g., Fe(II), Ni(II), Mn(II), and Co(II)) exhibited this effect. We demonstrate that the movement of the disulfiram-copper complex across the cell envelope is porin independent and can inhibit intracellular protein functions. Additionally, the complex is able to synergistically induce intracellular copper stress responses significantly more than Cu(II/I) alone. Our data suggest that by complexing with disulfiram, Cu(II/I) is likely allowed unfettered access to vulnerable intracellular components, bypassing the normally sufficient copper homeostatic machinery. Overall, the synergistic antibacterial activity of Cu(II/I) and disulfiram reveals the susceptibility of the copper homeostasis system of Mycobacterium tuberculosis to chemical attacks and establishes compounds that act in concert with copper as a new class of bacterial inhibitors. PMID- 26033732 TI - Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus. AB - The rapidly growing nontuberculous mycobacterial species Mycobacterium abscessus has recently emerged as an important pathogen in patients with cystic fibrosis (CF). Treatment options are limited because of the organism's innate resistance to standard antituberculous antibiotics, as well as other currently available antibiotics. New antibiotic approaches to the treatment of M. abscessus are urgently needed. The goal of the present study was to assess the growth inhibitory activity of different Ga compounds against an American Type Culture Collection (ATCC) strain and clinical isolates of M. abscessus obtained from CF and other patients. In our results, using Ga(NO3)3 and all of the other Ga compounds tested inhibited the growth of ATCC 19977 and clinical isolates of M. abscessus. Inhibition was mediated by disrupting iron uptake, as the addition of exogenous iron (Fe) restored basal growth. There were modest differences in inhibition among the isolates for the same Ga chelates, and for most Ga chelates there was only a slight difference in potency from Ga(NO3)3. In contrast, Ga protoporphyrin completely and significantly inhibited the ATCC strain and clinical isolates of M. abscessus at much lower concentrations than Ga(NO3)3. In in vitro broth culture, Ga-protoporphyrin was more potent than Ga(NO3)3. When M. abscessus growth inside the human macrophage THP-1 cell line was assessed, Ga protoporphyrin was >20 times more active than Ga(NO3)3. The present work suggests that Ga exhibits potent growth-inhibitory capacity against the ATCC strain, as well as against antibiotic-resistant clinical isolates of M. abscessus, including the highly antibiotic-resistant strain MC2638. Ga-based therapy offers the potential for further development as a novel therapy against M. abscessus. PMID- 26033733 TI - Increased Vancomycin Susceptibility in Mycobacteria: a New Approach To Identify Synergistic Activity against Multidrug-Resistant Mycobacteria. AB - Mycobacterium tuberculosis is wrapped in complex waxes, impermeable to most antibiotics. Comparing Mycobacterium bovis BCG and M. tuberculosis mutants that lack phthiocerol dimycocerosates (PDIM) and/or phenolic glycolipids with wild type strains, we observed that glycopeptides strongly inhibited PDIM-deprived mycobacteria. Vancomycin together with a drug targeting lipid synthesis inhibited multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates. Our study puts glycopeptides in the pipeline of potential antituberculosis (TB) agents and might provide a new antimycobacterial drug-screening strategy. PMID- 26033734 TI - Altered Competitive Fitness, Antimicrobial Susceptibility, and Cellular Morphology in a Triclosan-Induced Small-Colony Variant of Staphylococcus aureus. AB - Staphylococcus aureus can produce small-colony variants (SCVs) that express various phenotypes. While their significance is unclear, SCV propagation may be influenced by relative fitness, antimicrobial susceptibility, and the underlying mechanism. We have investigated triclosan-induced generation of SCVs in six S. aureus strains, including methicillin-resistant S. aureus (MRSA). Parent strains (P0) were repeatedly passaged on concentration gradients of triclosan using a solid-state exposure system to generate P10. P10 was subsequently passaged without triclosan to generate X10. Susceptibility to triclosan and 7 antibiotics was assessed at all stages. For S. aureus ATCC 6538, SCVs were further characterized by determining microbicide susceptibility and competitive fitness. Cellular morphology was examined using electron microscopy, and protein expression was evaluated through proteomics. Triclosan susceptibility in all SCVs (which could be generated from 4/6 strains) was markedly decreased, while antibiotic susceptibility was significantly increased in the majority of cases. An SCV of S. aureus ATCC 6538 exhibited significantly increased susceptibility to all tested microbicides. Cross-wall formation was impaired in this bacterium, while expression of FabI, a target of triclosan, and IsaA, a lytic transglycosylase involved in cell division, was increased. The P10 SCV was 49% less fit than P0. In summary, triclosan exposure of S. aureus produced SCVs in 4/6 test bacteria, with decreased triclosan susceptibility but with generally increased antibiotic susceptibility. An SCV derived from S. aureus ATCC 6538 showed reduced competitive fitness, potentially due to impaired cell division. In this SCV, increased FabI expression could account for reduced triclosan susceptibility, while IsaA may be upregulated in response to cell division defects. PMID- 26033736 TI - Iridium-Catalyzed Dynamic Kinetic Isomerization: Expedient Synthesis of Carbohydrates from Achmatowicz Rearrangement Products. AB - A highly stereoselective dynamic kinetic isomerization of Achmatowicz rearrangement products was discovered. This new internal redox isomerization provided ready access to key intermediates for the enantio- and diastereoselective synthesis of a series of naturally occurring sugars. The nature of the de novo synthesis also enables the preparation of both enantiomers. PMID- 26033735 TI - TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus. AB - The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo, TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard of-care drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development. PMID- 26033737 TI - Label-free bead-based metallothionein electrochemical immunosensor. AB - A novel microfluidic label-free bead-based metallothionein immunosensors was designed. To the surface of superparamagnetic agarose beads coated with protein A, polyclonal chicken IgY specifically recognizing metallothionein (MT) were immobilized via rabbit IgG. The Brdicka reaction was used for metallothionein detection in a microfluidic printed 3D chip. The assembled chip consisted of a single copper wire coated with a thin layer of amalgam as working electrode. Optimization of MT detection using designed microfluidic chip was performed in stationary system as well as in the flow arrangement at various flow rates (0 1800 MUL/min). In stationary arrangement it is possible to detect MT concentrations up to 30 ng/mL level, flow arrangement allows reliable detection of even lower concentration (12.5 ng/mL). The assembled miniature flow chip was subsequently tested for the detection of MT elevated levels (at approx. level 100 MUg/mL) in samples of patients with cancer. The stability of constructed device for metallothionein detection in flow arrangement was found to be several days without any maintenance needed. PMID- 26033738 TI - Letter regarding: Bronchoscopic guidance of endovascular stenting limits airway compression. PMID- 26033739 TI - The worldwide distribution of genetically and phylogenetically diverse Bacillus cereus isolates harbouring Bacillus anthracis-like plasmids. AB - Bacillus cereus is a close relative of B. anthracis, the causative agent of anthrax whose pathogenic determinants are located on pXO1 and pXO2 plasmids. Bacillus anthracis-like plasmids have been also noted among B. cereus, however, genetic features of B. cereus harbouring these elements remain largely undescribed, especially from the global perspective. Herein, we present the genetic polymorphism, population structure and phylogeny of B. cereus with pXO1 /pXO2-like plasmids originating from Argentina, Kazakhstan, Kenya and Poland. The plasmids were found in about 17% of the isolates, but their frequencies and expression of replicons differed within and between populations. In the multi locus sequence typing, the bacteria exhibited high genetic polymorphism reflected by 116 sequencing types, including 84 singletons and 10 clonal complexes, which mainly consisted of isolates of the same origin. The phylogenetic analysis of pXO1-/pXO2-like positive B. cereus isolates revealed six independent clades; in certain clades individual populations predominated. Generally, B. cereus with pXO1-/pXO2-like plasmids did not indicate the genetic relationship with B. anthracis, and cannot be classified into an evolutionary independent anthrax line within the B. cereus group. Our report is of a crucial importance for discovering the genetic specificity and evolution of B. cereus bacilli. PMID- 26033740 TI - [Oral health and hygiene status in galician schoolchildren]. AB - OBJECTIVE: The aim of this study is to determine the oral health and hygiene status in 12 year-old Galician schoolchildren. METHOD: A cross-sectional study was conducted on a sample of 1267 schoolchildren. The fieldwork was carried out in the 2010-2011 academic year. Information regarding socio-demographic status, dietary habits, and oral hygiene practices was obtained through a structured self report questionnaire given to the children at school. Dental examination to evaluate plaque and caries was carried out according to World Health Organization criteria. The prevalence and mean with 95% confidence intervals were calculated and logistic regression models were ajusted. RESULTS: Out of a total of 1045 pupils who participated in the study, 35% showed incorrect removal of dental plaque, and the prevalence of caries was 39.3%. Those who belonged to a lower socioeconomic group showed a higher prevalence of caries. Those who brushed their teeth daily had better oral hygiene. CONCLUSIONS: Educational programmes need to be designed and implemented in order to improve dental health and hygiene. PMID- 26033741 TI - [Is familial screening useful in selective immunoglobulin A deficiency?]. AB - INTRODUCTION: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown. OBJECTIVES: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening. PATIENTS AND METHODS: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR. RESULTS: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones. CONCLUSIONS: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients. PMID- 26033742 TI - [Gastrointestinal involvement in Langerhans cell histiocytosis]. PMID- 26033743 TI - Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P <= 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. PMID- 26033744 TI - Effects of dietary inulin on bacterial growth, short-chain fatty acid production and hepatic lipid metabolism in gnotobiotic mice. AB - In literature, contradictory effects of dietary fibers and their fermentation products, short-chain fatty acids (SCFA), are described: On one hand, they increase satiety, but on the other hand, they provide additional energy and promote obesity development. We aimed to answer this paradox by investigating the effects of fermentable and non-fermentable fibers on obesity induced by high-fat diet in gnotobiotic C3H/HeOuJ mice colonized with a simplified human microbiota. Mice were fed a high-fat diet supplemented either with 10% cellulose (non fermentable) or inulin (fermentable) for 6 weeks. Feeding the inulin diet resulted in an increased diet digestibility and reduced feces energy, compared to the cellulose diet with no differences in food intake, suggesting an increased intestinal energy extraction from inulin. However, we observed no increase in body fat/weight. The additional energy provided by the inulin diet led to an increased bacterial proliferation in this group. Supplementation of inulin resulted further in significantly elevated concentrations of total SCFA in cecum and portal vein plasma, with a reduced cecal acetate:propionate ratio. Hepatic expression of genes involved in lipogenesis (Fasn, Gpam) and fatty acid elongation/desaturation (Scd1, Elovl3, Elovl6, Elovl5, Fads1 and Fads2) were decreased in inulin-fed animals. Accordingly, plasma and liver phospholipid composition were changed between the different feeding groups. Concentrations of omega-3 and odd-chain fatty acids were increased in inulin-fed mice, whereas omega-6 fatty acids were reduced. Taken together, these data indicate that, during this short-term feeding, inulin has mainly positive effects on the lipid metabolism, which could cause beneficial effects during obesity development in long-term studies. PMID- 26033745 TI - Osteopontin Promotes Hepatic Progenitor Cell Expansion and Tumorigenicity via Activation of beta-Catenin in Mice. AB - Upregulation of osteopontin (OPN) has been found in hepatic progenitor cells (HPCs) in several liver diseases with portal biliary proliferation. Here, we investigated the role of HPC-derived autocrine OPN in regulating HPC expansion, migration, and hepatocarcinogenesis in mice. Five-week-old, weighing between 18 and 20 g of either wild type (WT) or OPN gene knockout (OPN-KO) male mice were treated with modified choline-deficient, ethionine-supplemented diet (modified choline-deficient [MCDE]) for 2 weeks to induce HPC production, or 6-12 months to induce tumorigenesis. Epithelial cell adhesion molecule EpCAM(+) CD45(-) cells isolated from mouse liver and liver epithelial progenitor cells were used for in vitro study. OPN was blocked by specific antibody or RNAi-mediated silence to investigate the role of OPN. To evaluate correlation between OPN expression and beta-catenin activity, expressions of OPN and beta-catenin were assessed in human liver cancer specimens. We found autocrine OPN promotes HPC expansion and migration by decreasing membranous E-cadherin and increasing free cytoplasmic beta-catenin via binding to alphav integrin and activating Src activity. Depletion of OPN significantly attenuated MCDE-induced hepatocarcinogenesis. Clinical evidence revealed a strong correlation of high OPN expression with cytoplasmic/nuclear expression of beta-catenin in 43 cases of human combined hepatocellular carcinoma and cholangiocarcinoma and mixed intrahepatic cholangiocarcinoma and 80 cases of hepatocellular carcinoma. Our results indicate that autocrine OPN plays a crucial role in HPC expansion, migration, and subsequent oncogenic transformation of HPCs, which may provide a new insight into hepatocarcinogenesis. PMID- 26033746 TI - Assessment of trace element impacts on agricultural use of water from the Dan River following the Eden coal ash release. AB - Catastrophic events require rapid, scientifically sound decision making to mitigate impacts on human welfare and the environment. The objective of this study was to analyze potential impacts of coal ash-derived trace elements on agriculture following a 35,000-tonne release of coal ash into the Dan River at the Duke Energy Steam Station in Eden, North Carolina. We performed scenario calculations to assess the potential for excessive trace element loading to soils via irrigation and flooding with Dan River water, uptake of trace elements by crops, and livestock consumption of trace elements via drinking water. Concentrations of 13 trace elements measured in Dan River water samples within 4 km of the release site declined sharply after the release and were equivalent within 5 d to measurements taken upriver. Mass-balance calculations based on estimates of soil trace-element concentrations and the nominal river water concentrations indicated that irrigation or flooding with 25 cm of Dan River water would increase soil concentrations of all trace elements by less than 0.5%. Calculations of potential increases of trace elements in corn grain and silage, fescue, and tobacco leaves suggested that As, Cr, Se, Sr, and V were elements of most concern. Concentrations of trace elements measured in river water following the ash release never exceeded adopted standards for livestock drinking water. Based on our analyses, we present guidelines for safe usage of Dan River water to diminish negative impacts of trace elements on soils and crop production. In general, the approach we describe here may serve as a basis for rapid assessment of environmental and agricultural risks associated with any similar types of releases that arise in the future. PMID- 26033747 TI - Prognostic significance of acquired copy-neutral loss of heterozygosity in acute myeloid leukemia. AB - BACKGROUND: Chromosomal abnormalities are important in the diagnosis and prognosis of patients with acute myeloid leukemia (AML). Genomic microarray techniques detect recurrent copy-neutral loss of heterozygosity (cnLOH) in addition to copy number aberrations. However, the clinical utility has not been fully established. Therefore, in the current study, the authors examined the prognostic impact of acquired cnLOH in patients with AML, including complete remission (CR) rate, duration of CR, and overall survival (OS). METHODS: A total of 112 consecutive patients with AML who were undergoing chromosome genomic array testing (CGAT) at the Seattle Cancer Care Alliance were included in the current study. DNA from the bone marrow or blood was analyzed with a microarray platform with both single-nucleotide polymorphism (SNP) probes and non-SNP probes to identify acquired cnLOH. Results were correlated with cytogenetic, molecular, immunophenotypic, and other clinicopathological findings. RESULTS: Patients with cnLOH demonstrated a shorter duration of CR (hazard ratio, 1.87; P =.04) and worse OS (HR, 1.82; P = .03). Multivariate analyses confirmed the independent predictive value of cnLOH for early disease recurrence (P =.02). These results largely reflected those in patients with intermediate and unfavorable cytogenetics. Most strikingly, 13q cnLOH was found to demonstrate a 6.64-fold higher rate of disease recurrence (P =.006) and 3.45-fold worse OS (P = .02) and was enriched with the FLT3-ITD (Fms-related tyrosine kinase 3-internal tandem duplication) mutation. CONCLUSIONS: CnLOH has important prognostic significance in patients with AML. CGAT can replace imbalance fluorescence in situ hybridization and the authors recommend the routine use of CGAT to detect cnLOH, particularly among patients with intermediate-risk cytogenetics. PMID- 26033748 TI - Superparamagnetic iron oxide nanoparticles as a means to track mesenchymal stem cells in a large animal model of tendon injury. AB - The goal of this study was to establish an SPIO-based cell-tracking method in an ovine model of tendonitis and to determine if this method may be useful for further study of cellular therapies in tendonitis in vivo. Functional assays were performed on labeled and unlabeled cells to ensure that no significant changes were induced by intracellular SPIOs. Following biosafety validation, tendon lesions were mechanically (n = 4) or chemically (n = 4) induced in four sheep and scanned ex vivo at 7 and 14 days to determine the presence and distribution of intralesional cells. Ovine MSCs labeled with 50 ug SPIOs/mL remained viable, proliferate, and undergo tri-lineage differentiation (p < 0.05). Labeled ovine MSCs remained detectable in vitro in concentrated cell numbers as low as 10 000 and in volumetric distributions as low as 100 000 cells/mL. Cells remained detectable by MRI at 7 days, as confirmed by correlative histology for dually labeled SPIO+/GFP+ cells. Histological evidence at 14 days suggested that SPIO particles remained embedded in tissue, providing MRI signal, although cells were no longer present. SPIO labeling has proven to be an effective method for cell tracking for a large animal model of tendon injury for up to 7 days post injection. The data obtained in this study justify further investigation into the effects of MSC survival and migration on overall tendon healing and tissue regeneration. PMID- 26033749 TI - Severity of personality disorders and domains of general personality dysfunction related to attachment. AB - This is the first study to link attachment to both severity of total DSM-IV personality disorder (PD) traits and domains of general personality dysfunction, using a sample of 72 inpatients from New York City. We assessed a measure of global PD severity and the core domains of personality functioning using the severity indices of personality problems (SIPP-118). Attachment was measured with the experience in close relationships-revised (ECR-R) and the relationship style questionnaire (RSQ). Global PD severity correlated most strongly with attachment anxiety (r = 0.65). Regression of the SIPP-118 domains on attachment produced models that accounted for a substantial proportion of variance in those scales (R(2) ranging from 28.2 to 54.2%). SIPP-118 relational capacities were the strongest predictor of ECR-R avoidance (beta = -0.88) and anxiety (beta = -0.58), as well as RSQ secure (beta = 0.53) and fearful (beta = -0.65). In conclusion, insecure attachment strongly related to the severity of global PD traits and specifically to relational capacities, which are a higher-order domain of general personality dysfunction. These findings provide further evidence that interpersonal problems are at the core of PDs and that attachment could constitute an important mediator of the social dysfunction in persons with personality pathology. PMID- 26033750 TI - Photoinduced Acrylate Polymerization: Unexpected Reduction in Chain Branching. AB - The branching stemming from midchain radical formation in n-butyl acrylate polymerization is investigated via melt-state (13) C NMR measurements. The dependence of the degree of branching (DB) on the monomer conversion of the system is examined for photoinduced polymerizations, revealing a steady increase in branching with conversion. For polymerization at moderate light intensities, an increase in branching from 0.03% to 0.37% is observed for polymerizations at 60 degrees C, which is fivefold below the level of branching observed in thermally initiated polymerizations under otherwise identical reaction conditions. The reason for this overall reduction in branching remains momentarily unclear; yet, a strong dependence of branching on light intensity is observed. While polymerization under a 1 W LED lamp results at almost full monomer conversion in branching degrees of 0.22%, polymerization under a 400 W lamp yields 1.81% of chain branches. PMID- 26033751 TI - Possible Involvement of Avoidant Attachment Style in the Relations Between Adult IBS and Reported Separation Anxiety in Childhood. AB - Irritable bowel syndrome (IBS) in adults as well as separation anxiety disorder (SAD) and recurrent abdominal pain (RAP) in childhood are associated with anxiety and somatization. Our aim was to examine possible associations between IBS in adulthood and SAD in childhood. Patients with IBS and healthy subjects completed a demographic questionnaire, the Separation Anxiety Symptom Inventory (SASI), the Somatization Subscale of Symptom Checklist-90-R (SCL-90-R), the Attachment Style Questionnaire, and a retrospective self-report questionnaire regarding RAP. Compared with controls, patients with IBS were characterized by an avoidant attachment style and scored higher on the SCL-90-R scale regarding the tendency to somatization (25.35 +/- 7.47 versus16.50 +/- 4.40, p < 0.001). More patients with IBS (25% versus 7.5%) reported RAP in childhood, but contrary to prediction, also had significantly lower SASI scores. Adults with IBS were characterized by somatization, insecure attachment style and recalled higher rates of RAP and surprisingly less symptoms of SAD in childhood. Based on these results, an etiological model for IBS is suggested, in which an avoidant attachment style and a tendency to somatization play an important role in the development of IBS. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26033752 TI - Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: an important role for CXCL1. AB - Obesity and alcohol consumption often coexist and work synergistically to promote steatohepatitis; however, the underlying mechanisms remain obscure. Here, we demonstrate that feeding mice a high-fat diet (HFD) for as little as 3 days markedly exacerbated acute ethanol binge-induced liver neutrophil infiltration and injury. Feeding mice with an HFD for 3 months plus a single binge of ethanol induced much more severe steatohepatitis. Moreover, 3-day or 3-month HFD-plus ethanol binge (3d-HFD+ethanol or 3m-HFD+ethanol) treatment markedly up-regulated the hepatic expression of several chemokines, including chemokine (C-X-C motif) ligand 1 (Cxcl1), which showed the highest fold (approximately 20-fold and 35 fold, respectively) induction. Serum CXCL1 protein levels were also markedly elevated after the HFD+ethanol treatment. Blockade of CXCL1 with a CXCL1 neutralizing antibody or genetic deletion of the Cxcl1 gene reduced the HFD+ethanol-induced hepatic neutrophil infiltration and injury, whereas overexpression of Cxcl1 exacerbated steatohepatitis in HFD-fed mice. Furthermore, expression of Cxcl1 messenger RNA was up-regulated in hepatocytes, hepatic stellate cells, and endothelial cells isolated from HFD+ethanol-fed mice compared to mice that were only given the HFD, with the highest fold induction observed in hepatocytes. In vitro stimulation of hepatocytes with palmitic acid up-regulated the expression of Cxcl1 messenger RNA, and this up-regulation was attenuated after treatment with an inhibitor of extracellular signal-regulated kinase 1/2, c Jun N-terminal kinase, or nuclear factor kappaB. In addition, hepatic or serum levels of free fatty acids were higher in HFD+ethanol-fed mice than in the control groups. CONCLUSION: An HFD combined with acute ethanol consumption synergistically induces acute liver inflammation and injury through the elevation of hepatic or serum free fatty acids and subsequent up-regulation of hepatic CXCL1 expression and promotion of hepatic neutrophil infiltration. PMID- 26033753 TI - Management of severe and rigid idiopathic scoliosis. AB - Frequently, severe idiopathic scoliosis patients are first seen in a spine centre after years of deformity evolution, presenting with large curves, severe rib hump, shoulder and trunk imbalance and cardiorespiratory complications related to neglected scoliosis. Severe rigid idiopathic scoliosis has <25% of correction on bending films and major curve over 90 degrees . Adequate mobilization of this type of deformity is necessary to achieve maximal correction, often requiring more extensive surgical intervention, with care taken to avoid clinical and neurological complications. Halo traction, internal temporary distraction, releases, osteotomies and apical vertebral resection are often used in combination to achieve optimal results. Indications must be tailored by surgeons considering resources, deformity characteristics and patient's profile. Vertebral resection procedures may have potential neurological and clinical risks and should be one of the last treatment options performed by experienced surgical team. Neuromonitoring is essential during these procedures. PMID- 26033756 TI - Epidemiology of GIST in the Era of Histology Codes--Letter. PMID- 26033755 TI - How are spousal depressed mood, distress, and quality of life associated with risk of depressed mood in cancer survivors? Longitudinal findings from a national sample. AB - BACKGROUND: Spouses of cancer survivors experience both positive and negative effects from caregiving. However, it is less clear what role spousal well-being may have on cancer survivors. This study aimed to determine the impact of spousal psychosocial factors on survivor depressed mood and whether this association differed by gender. METHODS: We examined longitudinal data on cancer survivors and their spouses (n = 910 dyads) from the 2004-2012 Medical Expenditures Panel Survey and a matched sample of cancer-free dyads. Subjects reported depressed mood, psychologic distress, and mental and physical health-related quality of life (HRQoL) at two time points (T1/T2). Dyadic multilevel models evaluated the impact of psychosocial factors at T1 on depressed mood at T2, controlling for sociodemographics, cancer type, survivor treatment status, and depressed mood at T1. RESULTS: Cancer survivors whose spouses reported depressed mood at T1 were 4.27 times more likely to report depressed mood at T2 [95% confidence interval (CI), 2.01-9.07]; this was stronger for female survivors (OR, 9.49; 95% CI, 2.42 37.20). Better spousal mental and physical HRQoL at T1 were associated with a 30% decrease in survivor depressed mood risk at T2. Most spillover effects were not observed in comparison dyads. CONCLUSION: Depressed mood and poor HRQoL in spouses may increase the risk of depressed mood in cancer survivors. The risk may be especially strong for female survivors. IMPACT: Identifying and improving spousal mental health and HRQoL problems may reduce the risk of depressed mood in cancer survivors. Future research should examine whether incorporating spousal care into psychooncology and survivorship programs improves survivor outcomes. PMID- 26033757 TI - Gene-occupation interactions in lung cancer risk--letter. PMID- 26033758 TI - Primary chondroblastic osteosarcoma of the breast. AB - Pure sarcomas of the breast are uncommon, accounting for less than 1% of primary breast malignant tumors. Mammary osteogenic sarcomas are very rare and less than 100 cases have been reported in literature. They mainly affect older and middle aged women and are highly aggressive. We report an additional case in a 56-year old woman. Histological and immunohistological characteristics were similar to those described in other localizations. Differential diagnosis involves phyllodes sarcoma, breast metaplastic carcinoma with chondroid and osteoid differentiation, osteosarcoma of the ribs, and metastatic osteosarcoma. The prognosis is poor. PMID- 26033760 TI - [The second kidney transplantation in Spain]. AB - The first two living donor kidney transplants in our country (isotransplant and homotransplant respectively) were reported in 1961. We reviewed the clinical history of the renal homotransplant performed between father and son, more than half a century ago, by Carlos Younger de la Pena and Ramiro Rivera at "La Paloma' Clinic in Madrid. We comment on the organizational, legal, immunobiological and technical difficulties in those times when the successful future of transplantation was barely in sight. From the XXI Century we can see the long path of renal transplantation during the XX century. Despite all the initial troubles and failures our present must recognize, and so does it, the work and dedication of the pioneers. PMID- 26033759 TI - Error-Prone Repair of DNA Double-Strand Breaks. AB - Preserving the integrity of the DNA double helix is crucial for the maintenance of genomic stability. Therefore, DNA double-strand breaks represent a serious threat to cells. In this review, we describe the two major strategies used to repair double strand breaks: non-homologous end joining and homologous recombination, emphasizing the mutagenic aspects of each. We focus on emerging evidence that homologous recombination, long thought to be an error-free repair process, can in fact be highly mutagenic, particularly in contexts requiring large amounts of DNA synthesis. Recent investigations have begun to illuminate the molecular mechanisms by which error-prone double-strand break repair can create major genomic changes, such as translocations and complex chromosome rearrangements. We highlight these studies and discuss proposed models that may explain some of the more extreme genetic changes observed in human cancers and congenital disorders. PMID- 26033762 TI - [Substitution urethroplasty. Long term follow up results in a group of 50 patients]. AB - OBJECTIVES: To assess the results of substitution urethroplasty after a long follow-up in a group of 50 patients. METHODS: We conducted a retrospective study of patients with diagnosis of urethral stricture treated by augmentation techniques in the period 1999-2009. We included patients with penile and bulbar urethral stricture and, penile skin or oral mucosa as substitute tissue type. Urethral strictures of the meatus or fossa navicularis and posterior urethra, and other endoscopic or surgical procedures were excluded from the study. RESULTS: Fifty patients were included. Penile skin was used in 26 cases and buccal mucosa in 24. The average follow-up was 108 months. Recurrence rate was 25% in the cases in which oral mucosa was used as substitute tissue and 30.7% in the penile skin group. Of the 14 cases with recurrence of the stricture, 13 (92%) did so in the first five years of follow-up. Only one case was a recurrent stricture after six years of surgery. CONCLUSIONS: The recurrence of the stricture after augmentation urethroplasty occurs, in the majority of cases, in the first five years. After this period of time recurrence is very rare. Oral mucosa showed better results as substitute tissue in the urethral stricture surgery. PMID- 26033761 TI - [100 cases of three-piece Inflatable Penile Prosthesis with new scrotal pump: Evaluation of 3 specialised centres]. AB - OBJECTIVES: The aim is to assess our experience with new Coloplast TitanTM Inflatable Penile Prosthesis (IPP) with One-Touch Release (OTR) pump. Our 3 main focuses of attention will be prosthesis performance and patient and partner satisfaction in our first 100 cases in 3 specialised centres by 2 principal surgeons. METHODS: Retrospective review was used to assess the Coloplast TitanTM OTR implant procedures/cases in our departments (from October 2009 to December 2012). The changes in Erection Function (EF), Intercourse Satisfaction (IS), overall satisfaction of the patient and partner were assessed by use of the following questionnaires: EF and IS domains of the International Index of Erectile Function (IIEF) and modified EDITS. RESULTS: Mean patient age (N = 100) was 54.2 years old (range: 20-77) with a mean length of follow-up of 21 months (range: 6-44). Mean length of prosthesis implanted was 18.6 cm (14-23.5). Only 3% of patients showed complications requiring surgical exploration. Good prosthesis performance was assessed in 99 patients (99%). Differences in the IIEF-EF and IIEF-IS domain before and after surgery were +16.8 and +6.4 respectively. Patient and partner overall satisfaction were 90% and 84% respectively in modified EDITS. The average number of postoperative teaching sessions needed to teach the patient how to operate the device was 1.28 (1-4). CONCLUSIONS: The Coloplast TitanTM OTR IPP was easy to implant, inflate, and deflate with high levels of EF improvement, patient and partner satisfaction. A small number of postoperative teaching sessions were required for the patient to properly operate the device. PMID- 26033763 TI - [Risk assessment in children with lithogenic kidney stones]. AB - OBJECTIVE: The aim of this study was to describe the lithogenic risk profile of pediatric patients with lithiasis. METHODS: We retrospectively analyzed the metabolic studies in 24-hour urine samples in 47 pediatric patients with lithiasis. Biochemical determinations were made in blood and 24-hour urine. Oxalate calcium, brushite, struvite and uric acid salt saturations were calculated. 49 healthy children were used as a control group. RESULTS: No significant differences were found in biochemical blood parameters between children with stones and the group without stones. Calciuria, uricosuria and phosphaturia, oxalate calcium, brushite and uric acid saturations were higher in lithiasic children. In the multivariate analysis, using a logistic regression model, we only found hypercalciuria as lithogenic risk factor. (OR = 1.96 p <0.002). CONCLUSIONS: Urinary metabolic abnormalities and elevated salt saturations in urine are a frequent finding in children with urolithiasis, but in our study we only found hypercalciuria as an independent risk factor for the formation of lithiasis. PMID- 26033764 TI - Which treatment method should be used in pregnant patients with ureteral calculi? Two center comparative study. AB - OBJECTIVES: We aimed to compare ureterolithotripsy and inserting only ureteral-j stent in terms of efficiency, safety and patient comfort in treatment of ureteral calculi in pregnant patients. METHODS: Seventy patients who developed hydronephrosis due to ureteral calculi during pregnancy, and on whom endoscopic intervention was performed were included in the study. In a center, the stones were broken up by ureteroscopy, and then ureteral stents (JJ) were placed if needed. In the other center, nothing was performed on the stones, and only ureteral stents (JJ) was placed. For the statistical analysis, Pearson's chi squared test and the Mann-Whitney U tests were used and the significance level was determined as p < 0.05. RESULTS: The average age of the patients was 26.2 years (18-39) and the average gestational week was 23.4 weeks (8-36). While no significant difference was found between the two groups in terms of the frequency of complications (p=0.381) and post-operative pyelonephritis (p=0.2), the need for additional intervention in the group on whom ureteroscopy was performed was found to be less (9.7% vs. 31%; p=0.032). Moderate or severe LUTS or flank pain during the period between the procedure and the birth was found to be significantly less in the group in which ureterolithotripsy was performed (14% vs. 55%; p=0.036). CONCLUSIONS: Ureterolithotripsy is a safe and more comfortable procedure than only ureteral double-j insertion on pregnant patients with ureterolithiasis. PMID- 26033765 TI - [Greenlight-XPS laser vaporization, the new standard of treatment in men with myasthenia gravis and benign prostatic obstruction]? AB - Patients with Benign Prostatic Obstruction (BPO) and Myasthenia Gravis (MG) treated with Transurethral Resection of the prostate (TURP) show a high incidence of urinary incontinence due to unnoticed damage to muscle fibres of the external sphincter. Photoselective laser vaporization could be an alternative treatment based on the hypothesis that using Laser as energy source in the treatment of BPH prevents sphincter damage because the energy is not transmitted outside the fiber tip. METHODS: We report the case of a man diagnosed of MG and symptomatic BPO treated satisfactorily with photoselective laser vaporization (GreenLight-XPS). RESULTS: Patient did not experienced postoperative secondary incontinence. CONCLUSIONS: Laser photoselective vaporization (GreenLight-XPS) could be the standard treatment for men with MG and BPO, whose prostate volume is less than 60 cc who are candidates for surgical treatment. Despite the extremely low incidence of these cases, further investigations are needed to confirm this affirmation. PMID- 26033766 TI - [Voiding syndrome of gynaecological origin: the importance of good physical examination]. AB - OBJECTIVES: Urologists daily evaluate many women with voiding disturbances, but proper physical examination has only rarely been previously performed. CASE DESCRIPTION: Case 1: 16-year-old woman presenting augmented daytime urinary frequency and nocturia without enuresis, with drop-by-drop micturition. Case 2: 80-year-old woman with urgency. She referred normal voiding with insensitive urinary loss the hour after. PHYSICAL EXAMINATION: adhesion of the labia minora. TREATMENT: Surgical section of the adhered area in the midline was performed with satisfactory aesthetic and clinical results. CONCLUSIONS: The adhesion of the labia minora is an acquired disease, more frequent in girls under 2 years. Several predisposing factors have been proposed: oestrogen deprivation, inadequate personal care, local irritants, infections or previous trauma. Differential diagnosis is required among three congenital pathologies: vaginal agenesis, imperforated hymen and ambiguous genitalia. Cases in postpubertal or postmenopausal women, or refractory to medical treatment are considered for surgery. PMID- 26033767 TI - Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy. AB - Boron neutron capture therapy (BNCT) is a promising cancer therapy modality that utilizes the nuclear capture reaction of epithermal neutrons by boron-10 resulting in a localized nuclear fission reaction and subsequent cell death. Since cellular destruction is limited to approximately the diameter of a single cell, primarily only cells in the neutron field with significant boron accumulation will be damaged. However, the emergence of BNCT as a prominent therapy has in large part been hindered by a paucity of tumor selective boron containing agents. While L-boronophenylalanine and sodium borocaptate are the most commonly investigated clinical agents, new agents are desperately needed due to their suboptimal tumor selectivity. This review will highlight the various strategies to improve tumor boron delivery including: nucleoside and carbohydrate analogs, unnatural amino acids, porphyrins, antibody-dendrimer conjugates, cationic polymers, cell-membrane penetrating peptides, liposomes and nanoparticles. PMID- 26033768 TI - Modeling and Prediction of Solvent Effect on Human Skin Permeability using Support Vector Regression and Random Forest. AB - PURPOSE: The solvent effect on skin permeability is important for assessing the effectiveness and toxicological risk of new dermatological formulations in pharmaceuticals and cosmetics development. The solvent effect occurs by diverse mechanisms, which could be elucidated by efficient and reliable prediction models. However, such prediction models have been hampered by the small variety of permeants and mixture components archived in databases and by low predictive performance. Here, we propose a solution to both problems. METHODS: We first compiled a novel large database of 412 samples from 261 structurally diverse permeants and 31 solvents reported in the literature. The data were carefully screened to ensure their collection under consistent experimental conditions. To construct a high-performance predictive model, we then applied support vector regression (SVR) and random forest (RF) with greedy stepwise descriptor selection to our database. The models were internally and externally validated. RESULTS: The SVR achieved higher performance statistics than RF. The (externally validated) determination coefficient, root mean square error, and mean absolute error of SVR were 0.899, 0.351, and 0.268, respectively. Moreover, because all descriptors are fully computational, our method can predict as-yet unsynthesized compounds. CONCLUSION: Our high-performance prediction model offers an attractive alternative to permeability experiments for pharmaceutical and cosmetic candidate screening and optimizing skin-permeable topical formulations. PMID- 26033769 TI - Differing relationship between hypercholesterolemia and a bicuspid aortic valve according to the presence of aortic valve stenosis or aortic valve regurgitation. AB - OBJECTIVES: To assess the difference in hyperlipidemia between patients with bicuspid aortic valve (BAV) and those with a normal aortic valve (NAV), and to compare aortic valve stenosis (AS), with aortic valve regurgitation (AR). METHODS: Among 32 patients with BAV and 142 patients with NAV who underwent aortic valve replacement, 81 patients had AR and 91 patients had AS. The preoperative clinical characteristics were compared between the BAV and NAV patients. Patients with replacement of the ascending aorta were included, and those who underwent combined valvular surgery, coronary artery bypass grafting, or statin treatment were excluded. RESULTS: The proportions of females patients (p = 0.42), patients with diabetes (p = 0.26) and patients on dialysis (p = 0.69) were similar in the two groups. Mean age was significantly lower, the mean diameter of the ascending aorta was significantly larger, and the rate of surgical intervention for the ascending aorta was significantly higher in the BAV group than in the NAV group (all p < 0.0001). The mean levels of low-density lipoprotein cholesterol (LDL) (p < 0.0001) and total cholesterol (TC) (p = 0.0003) were significantly higher in the BAV group than in the NAV group, in the analysis of only patients with AS, whereas these levels did not differ significantly between the groups, when only patients with AR were considered. CONCLUSION: BAV with AS is associated with hypercholesterolemia. However, BAV with AR was not associated with hypercholesterolemia. PMID- 26033770 TI - Multicenter investigation of lifestyle-related diseases and visceral disorders in thalidomide embryopathy at around 50 years of age. AB - BACKGROUND: In utero exposure to thalidomide causes a wide range of birth defects, including phocomelia, hearing loss and visceral disorders, known as thalidomide embryopathy (TE). Fifty years after the first report of TE, we conducted the first cross-sectional multicenter study to investigate the development of lifestyle-related diseases and identify risk factors for visceral disorders in subjects with TE. METHODS: Seventy-six cases with TE (31 men, 45 women) underwent medical examinations between 2011 and 2014 to determine the types of TE-related anomalies (limbs, auditory organs, or visceral organs) and lifestyle-related diseases present. Logistic multiple regression analyses, adjusted for gender and age, were conducted between TE and lifestyle-related diseases and to evaluate association between block vertebra and gallbladder aplasia. RESULTS: Fatty liver (FL), nonalcoholic FL disease and dyslipidemia were detected in 52.6%, 35.0%, and 23.7% of subjects, respectively, with higher incidences among men. Dyslipidemia was detected in 40.0% of subjects with FL and was significantly associated with FL (odds ratio = 8.86; p = 0.008). Block vertebrae were detected in 44.4% of subjects with gallbladder aplasia, and this association was significant (odds ratio = 9.96; p = 0.006). CONCLUSION: Subjects with TE have also a risk for lifestyle-related disease as well as the general Japanese population. In addition, cervical spine radiography and magnetic resonance imaging are recommended to assess block vertebrae in subjects with TE with gallbladder aplasia who develop shoulder pain. PMID- 26033771 TI - New echocardiographic predictors of clinical outcome in patients presenting with heart failure and a preserved left ventricular ejection fraction: a subanalysis of the Ka (Karolinska) Ren (Rennes) Study. AB - OBJECTIVES: To identify electrocardiographic and echocardiographic predictors of mortality and hospitalizations for heart failure (HF) in the KaRen study. BACKGROUND: KaRen is a prospective, observational study of the long-term outcomes of patients presenting with heart failure and a preserved ejection fraction (HFpEF). METHOD: We identified 538 patients who presented with acute cardiac decompensation, a >100 pg/mL serum b-type natriuretic peptide (BNP) or >300 pg/mL N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and a left ventricular ejection fraction (LVEF) >45%. After 4-8 weeks of standard treatment, 413 patients (mean age = 76 +/- 9 years, 55.9% women) returned for analyses of their clinical status, laboratory screen, and detailed electrocardiographic and Doppler echocardiographic recordings. They were followed for a mean of 28 months thereafter. The primary study endpoint was time to death from all causes or first hospitalization for heart failure. RESULTS: Mean LVEF was 62.4 +/- 6.9% and median NT-proBNP 1410 pmol/L. PR interval >200 ms was present in 11.2% of patients and 14.9% had a >120 ms QRS duration, with left bundle branch block in only 6.3%. Over a mean follow-up of 28 months, 177 patients (42.9%) reached a primary study endpoint, including 61 deaths and 116 hospitalizations for heart failure. After adjustment for age, gender, New York Heart Association class, atrial fibrillation history, creatinine, sodium, BNP, ejection fraction, and right ventricular fractional shortening, only E/e' remained as a predictor, with a hazard ratio = 1.49 and P = 0.0012. CONCLUSION: The incidence of hospitalizations for HF and deaths in KaRen was high and E/e' predicted adverse clinical outcomes. These observations should help in the risk stratification and therapy of HFpEF. PMID- 26033772 TI - Quantitative analysis of commensal Escherichia coli populations reveals host specific enterotypes at the intra-species level. AB - The primary habitat of the Escherichia coli species is the gut of warm-blooded vertebrates. The E. coli species is structured into four main phylogenetic groups A, B1, B2, and D. We estimated the relative proportions of these phylogroups in the feces of 137 wild and domesticated animals with various diets living in the Ile de France (Paris) region by real-time PCR. We distinguished three main clusters characterized by a particular abundance of two or more phylogroups within the E. coli animal commensal populations, which we called "enterocolitypes" by analogy with the enterotypes defined in the human gut microbiota at the genus level. These enterocolitypes were characterized by a dominant (>50%) B2, B1, or A phylogroup and were associated with different host species, diets, and habitats: wild and herbivorous species (wild rabbits and deer), domesticated herbivorous species (domesticated rabbits, horses, sheep, and cows), and omnivorous species (boar, pigs, and chickens), respectively. By analyzing retrospectively the data obtained using the same approach from 98 healthy humans living in Ile de France (Smati et al. 2013, Appl. Environ. Microbiol. 79, 5005-5012), we identified a specific human enterocolitype characterized by the dominant and/or exclusive (>90%) presence of phylogroup B2. We then compared B2 strains isolated from animals and humans, and revealed that human and animal strains differ regarding O-type and B2 subgroup. Moreover, two genes, sfa/foc and clbQ, were associated with the exclusive character of strains, observed only in humans. In conclusion, a complex network of interactions exists at several levels (genus and intra-species) within the intestinal microbiota. PMID- 26033773 TI - Functional characterization of the UDP-xylose biosynthesis pathway in Rhodothermus marinus. AB - UDP-glucuronic acid dehydrogenase (UGD) and UDP-xylose synthase (UXS) are the two enzymes responsible for the biosynthesis of UDP-xylose from UDP-glucose. Several UGDs from bacterial sources, which oxidize UDP-glucose to glucuronic acid, have been found and functionally characterized whereas only few reports on bacterial UXS isoforms exist. Rhodothermus marinus, a halothermophilic bacterium commonly found in hot springs, proved to be a valuable source of carbohydrate active enzymes of biotechnological interest, such as xylanases, mannanases, and epimerases. However, no enzymes of R. marinus involved in the biosynthesis or modification of nucleotide sugars have been reported yet. Herein, we describe the cloning and characterization of two putative UGD (RmUGD1 and RmUGD2) and one UXS (RmUXS) isoform from this organism. All three enzymes could be expressed in recombinant form and purified to near homogeneity. UPLC- and NMR-based activity tests showed that RmUGD1 and RmUXS are indeed active enzymes, whereas no enzymatic activity could be detected by RmUGD2. Both RmUGD1 and RmUXS showed a temperature optimum of 60 degrees C, with almost no loss of activity after 1 h exposure at 70 degrees C. No metal ions were required for enzymatic activities. Zn(2+) ions strongly inhibited both enzymes. RmUGD1 showed higher salt tolerance and had a higher pH optimum than RmUXS. Furthermore, RmUGD1 was inhibited by UDP xylose at higher concentrations. By coupling recombinant RmUXS and RmUGD1, UDP xylose could be successfully synthesized directly from UDP-glucose. The high activity of the herein described enzymes make RmUGD1 and RmUXS the first thermo tolerant biocatalysts for the synthesis of UDP-glucuronic acid and UDP-xylose. PMID- 26033774 TI - Highly Ordered 1D Fullerene Crystals for Concurrent Control of Macroscopic Cellular Orientation and Differentiation toward Large-Scale Tissue Engineering. AB - A highly aligned 1D fullerene whisker (FW) scaffold in a centimeter area is fabricated by interfacial alignment. The resulting aligned FW scaffold enables concurrent control over cellular orientation and differentiation to muscle cells. This aligned FW scaffold is made by a facile method, and hence the substrate is a promising alternative to other cell scaffolds for tissue engineering. PMID- 26033775 TI - Reply. PMID- 26033776 TI - Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to risk of different breast cancer subgroups: a Malmo Diet and Cancer Study. AB - PURPOSE: Thyroid hormone level has been positively associated with breast cancer risk and with breast cancer cell proliferation and growth. Although breast cancer is a heterogeneous disease, this is the first study assessing pre-diagnostic levels of free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and thyroid peroxidase antibodies (TPO-Ab) in relation to breast cancer subgroups and aggressiveness. METHODS: The Malmo Diet and Cancer Study collected blood samples from 17,035 women between 1991 and 1996. Free T3, free T4, TSH, and TPO-Ab were analyzed in 676 incident breast cancer cases and 680 controls. Breast tumors were classified according to tumor size, axillary lymph node involvement, histological grade, histological type, hormone receptor status (ER, PgR), as well as Ki67, cyclin D1, and p27. Odds ratios of different breast cancer subgroups were calculated using a logistic regression analysis adjusted for potential confounders. RESULTS: High fT4 was associated with a statistically significant higher risk of overall breast cancer, small, grade I, ER-positive, PgR-positive, and cyclin D1 low tumors. The associations for ER and PgR were verified in a heterogeneity analysis. Low TPO-Ab was associated with a higher risk of overall breast cancer, ductal, large, ER-positive, PgR-positive, cyclin D1 low, and p27 high tumors. The heterogeneity analysis verified the association for tumor size. Free T3 was not associated with overall breast cancer risk, but in the heterogeneity analysis, high fT3 was associated with tumor size and expression of p27. There were no strong associations between TSH and overall breast cancer risk or any tumor subgroup. CONCLUSION: High pre-diagnostic fT4 levels and low pre-diagnostic TPO-Ab levels were associated with an increased risk of breast cancer. This increase was mainly limited to a higher incidence rate of less aggressive breast cancer subgroups. PMID- 26033777 TI - Trends in the incidence of cervical cancer and severe precancerous lesions in Denmark, 1997-2012. AB - PURPOSE: The incidence of cervical cancer, including squamous cell carcinoma (SCC), has been decreasing in several developed countries since the onset of organized screening programs; in some countries, however, the incidence of adenocarcinoma has increased among young women. We investigated the Danish incidence trends during 1997-2011 when cervical screening coverage was high. Incidences of cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) were also assessed, with the latest part of the study period coinciding with introduction of free-of-charge human papillomavirus (HPV) vaccination. METHODS: Using nationwide registries, we estimated age specific and age-standardized incidence rates and estimated annual percentage change (EAPC). RESULTS: The incidence of SCC decreased significantly, especially in women aged >=45 years [EAPC: -3.1 % (95 % CI -4.3 to -2.5)], whereas the incidence of adenocarcinoma increased significantly, from 2.4 to 3.1/100,000 primarily due to increases in women aged <=44 years [EAPC: 4.3 % (95 % CI 1.8 6.7)]. The incidences of CIN3 and AIS increased significantly from 94.7 to 156.5/100,000 and 3.3 to 11.3/100,000, respectively, but, importantly, they decreased significantly during 2009-2012 in women aged <=20 years. CONCLUSIONS: The Danish screening program has successfully reduced the incidence of cervical cancer, especially of SCC in older women; however, the program has not significantly reduced the incidence in young women or the incidence of adenocarcinoma, which is increasing. Decreases in the incidences of CIN3 and AIS in age groups with high HPV vaccine coverage may herald a future decrease in cervical cancer incidence in young Danish women. PMID- 26033778 TI - Direct Vasodilators and Sympatholytic Agents. AB - Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of alpha-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications. PMID- 26033779 TI - Keggin-Type Polyoxometalate-Based Metal-Organic Networks for Photocatalytic Dye Degradation. AB - The reaction of Keggin-type polyoxometalate (POM) units, transition-metal (TM) ions, and a rigid bis(imidazole) ligand (1,4-bis(1-imidazolyl)benzene (bimb)) in a hydrothermal environment led to the isolation of four new POM-based metal organic networks, [H2 L][CuL][SiW12 O40 ]?2 H2 O (1), [H2 L]2 [Co(H2 O)3 L][SiW11 CoO39 ]?6 H2 O (2), KH[CuL]2 [SiW11 CoO39 (H2 O)]?2 H2 O (3), and [CuL]4 [GeW12 O40 ]?H2 O (4; L=bimb). All four compounds were characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction. Compounds 1 and 3 are new 3D networks with 1D channels. Compounds 2 and 4 contain 2D networks, which further stack into 3D supramolecular networks. The contributions of pH value, the negative charge of the POM, and the TM coordination modes to the construction of 3D networks were elucidated by comparing the synthetic conditions and structures of compounds 1-4. The photocatalytic properties of compounds 1-4 were investigated using methylene blue (MB) degradation under UV light. All compounds showed good catalytic activity and structural stability. The possible catalytic mechanism was discussed on the basis of active-species trapping experiments. The different photocatalytic activities of compounds 1-4 were explained by comparison of the band gaps of different POM species and different packing modes of POM units in these hybrid compounds. PMID- 26033780 TI - Funding cuts threaten US academic medical research, say deans. PMID- 26033781 TI - Visible-Light Photoredox-Catalyzed Semipinacol-Type Rearrangement: Trifluoromethylation/Ring Expansion by a Radical-Polar Mechanism. AB - A visible-light-mediated photoredox-catalyzed semipinacol-type rearrangement proceeding via 1,2 alkyl migration was developed. In this transformation, trifluoromethylation of the C=C bond of alpha-(1-hydroxycycloalkyl)-substituted styrene derivatives is followed by ring expansion of the 1-hydroxycycloalkyl group to deliver novel cycloalkanones with all-carbon quaternary centers. The reaction proceeds via a radical-polar mechanism, with trifluoromethylation (radical) and ring expansion (ionic) occurring in the same transformation. PMID- 26033782 TI - Etiology and pathogenesis of robin sequence in a large Dutch cohort. AB - Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re discussed and a final conclusion was drawn. We included 191 RS patients. After re evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated. PMID- 26033783 TI - Cyclooxygenase 2 inhibition in patients with non-small cell lung cancer: Is this still a valid target for therapy? PMID- 26033784 TI - Experiences in Close Relationships - Psychometric properties among patients with personality disorders. AB - Patients with personality disorders represent maladaptive attachment strategies, influencing the quality of their interpersonal relationships. Within these patient populations, it is important to have a measure, easily applied, to assess such strategies. A widely used instrument is Experiences in Close Relationships (ECR), assessing two constructs called avoidance and anxiety. Lately, two short forms of ECR have been proposed, called ECR-S and ECR-N12. The aim of this study is to investigate the psychometric properties of the Norwegian @version of ECR and its two short forms in a sample of patients with mainly personality disorders. An internal consistency and confirmatory factor analysis of ECR, ECR-S and ECR-N12 from 495 patients was conducted, as well as an exploratory factor analysis of ECR. The internal consistency of ECR was found questionable. Confirmatory factor analysis revealed a poor model fit based on ECR and ECR-S. The ECR-N12 revealed a mediocre fit, indicating a potential for improvement. Exploratory factor analysis indicated two different aspects of avoidance and three aspects of anxiety. This five-factor solution was called ECR-FF. Inferences from scores based on ECR should be derived with care. A revision of ECR and ECR N12 is warranted, and further studies are needed to investigate the validity of ECR-FF. PMID- 26033785 TI - Reconstruction of Block Copolymer Micelles to Long-Range Ordered Dense Nanopatterns Via Light-Tunable Hydrogen-Bonding Association. AB - Controlling the orientation and long-range order of nanostructures is a key issue in the self-assembly of block copolymer micelles. Herein, a versatile strategy is presented to transform one-component oxime-based block copolymer micelles into long-range ordered dense nanopatterns. Photoisomerization provides a straightforward and versatile approach to convert the hydrogen-bonding association from inward dimerization (E-type oxime motifs, slightly desolvated in ethyl acetate) into outward interchain association (Z-type ones, highly desolvated in ethyl acetate). This increases the glass transition temperature in bulk and converts swollen micelles into compact spherical micelles in solution. The reconstruction of these micelles on various substrates demonstrates that the phase transformation enables reconstruction of spherical micelles into mesoscopic sheets, nanorods, nanoworms, nanowires, networks, and eventually into long-range ordered and densely packed textile-like and lamellar nanopatterns on a macroscopic scale by adjusting E/Z-oxime ratio and solvent-evaporation rate. PMID- 26033786 TI - ED Triage Decision-Making With Mental Health Presentations: A "Think Aloud" Study. AB - INTRODUCTION: Triage is the process whereby persons presenting to the emergency department are quickly assessed by a nurse and their need for care and service is prioritized. Research examining the care of persons presenting to emergency departments with psychiatric and mental health problems has shown that triage has often been cited as the most problematic aspect of the encounter. Three questions guided this investigation: Where do the decisions that triage nurses make fall on the intuitive versus analytic dimensions of decision making for mental health presentations in the emergency department, and does this differ according to comfort or familiarity with the type of mental health/illness presentation? How do "decision aids" (i.e., structured triage scales) help in the decision-making process? To what extent do other factors, such as attitudes, influence triage nurses' decision making? METHODS: Eleven triage nurses participating in this study were asked to talk out loud about the reasoning process they would engage in while triaging patients in 5 scenarios based on mental health presentations to the emergency department. RESULTS: Themes emerging from the data were tweaking the results (including the use of intuition and early judgments) to arrive at the desired triage score; consideration of the current ED environment; managing uncertainty and risk (including the consideration of physical reasons for presentation); and confidence in communicating with patients in distress and managing their own emotive reactions to the scenario. DISCUSSION: Findings support the preference for using the intuitive mode of decision making with only tacit reliance on the decision aid. PMID- 26033787 TI - A 4-year-old girl with malaise, squint and restricted neck movement. PMID- 26033788 TI - Using mobile devices for teaching and learning in clinical medicine. PMID- 26033789 TI - Effect of diosmetin on airway remodeling in a murine model of chronic asthma. AB - Bronchial asthma, one of the most common allergic diseases, is characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. The anti-oxidant flavone aglycone diosmetin ameliorates the inflammation in pancreatitis, but little is known about its impact on asthma. In this study, the effects of diosmetin on chronic asthma were investigated with an emphasis on the modulation of airway remodeling in BALB/c mice challenged with ovalbumin (OVA). It was found that diosmetin significantly relieved inflammatory cell infiltration, goblet cell hyperplasia, and collagen deposition in the lungs of asthmatic mice and notably reduced AHR in these animals. The OVA-induced increases in total cell and eosinophil counts in bronchoalveolar lavage fluid were reversed, and the level of OVA-specific immunoglobulin E in serum was attenuated by diosmetin administration, implying an anti-Th2 activity of diosmetin. Furthermore, diosmetin remarkably suppressed the expression of smooth muscle actin alpha chain, indicating a potent anti-proliferative effect of diosmetin on airway smooth muscle cells (ASMCs). Matrix metallopeptidase-9, transforming growth factor-beta1, and vascular endothelial growth factor levels were also alleviated by diosmetin, suggesting that the remission of airway remodeling might be attributed to the decline of these proteins. Taken together, our findings provided a novel profile of diosmetin with anti-remodeling therapeutic benefits, highlighting a new potential of diosmetin in remitting the ASMC proliferation in chronic asthma. PMID- 26033790 TI - The Impact of Addressing Adherence in Pharmacist-Managed Pharmacotherapy Clinics. AB - PURPOSE: The primary objective of this study was to determine the change in the adherence questionnaire score from the initial pharmacist intervention to 60 to 90 days follow-up. The secondary objective of this study was to investigate the impact of the type of pharmacist intervention on questionnaire scores. METHODS: Administration of an adherence questionnaire to guide interventions has become the standard of care for patients during appointments with clinical pharmacy specialists at 3 primary care clinics. Subjects who received a questionnaire between November 4, 2013, and January 15, 2014, were included. These subjects received a second questionnaire 60 to 90 days after the first questionnaire to identify changes resulting from the pharmacist's interventions. A scoring system was utilized to quantify patients' responses to both the preintervention and postintervention questionnaires. The type of intervention completed was determined at each pharmacist's clinical discretion. RESULTS: Adherence scores increased significantly 60 to 90 days after administration of the questionnaire with a pharmacist's intervention. Medication reminders, simplifying medication regimens, discount program referrals, disease-state information, medication information, and therapeutic interchanges, all increased adherence scores. CONCLUSION: A standardized tool to assess and address adherence was effectively utilized by 9 pharmacists at 3 clinics. The use of a standardized tool to guide adherence interventions is an effective way to increase adherence to medication therapy. PMID- 26033791 TI - Antimicrobial Stewardship in the Emergency Department: Challenges, Opportunities, and a Call to Action for Pharmacists. AB - Antimicrobial resistance is a national public health concern. Misuse of antimicrobials for conditions such as upper respiratory infection, urinary tract infections, and cellulitis has led to increased resistance to antimicrobials commonly utilized to treat those infections, such as sulfamethoxazole/trimethoprim and flouroquinolones. The emergency department (ED) is a site where these infections are commonly encountered both in ambulatory patients and in patients requiring admission to a hospital. The ED is uniquely positioned to affect the antimicrobial use and resistance patterns in both ambulatory settings and inpatient settings. However, implementing antimicrobial stewardship programs in the ED is fraught with challenges including diagnostic uncertainty, distractions secondary to patient or clinician turnover, and concerns with patient satisfaction to name just a few. However, this review article highlights successful interventions that have stemmed inappropriate antimicrobial use in the ED setting and warrant further study. This article also proposes other, yet to be validated proposals. Finally, this article serves as a call to action for pharmacists working in antimicrobial stewardship programs and in emergency medicine settings. There needs to be further research on the implementation of these and other interventions to reduce inappropriate antimicrobial use to prevent patient harm and curb the development of antimicrobial resistance. PMID- 26033792 TI - Rational Use of Second-Generation Antipsychotics for the Treatment of ICU Delirium. AB - Delirium, described as an acute neuropsychiatric syndrome, occurs commonly in critically ill patients and leads to many negative outcomes including increased mortality and long-term cognitive deficits. Despite the lack of clinical data supporting the use of antipsychotics for the management of intensive care unit (ICU) delirium, pharmacological interventions are often needed to control acutely agitated patients. Given that the most current guidelines do not advocate the use of haloperidol for either the prevention or treatment of ICU delirium due to a lack of evidence, second-generation antipsychotics (SGAs) have been commonly used as alternatives to haloperidol for ICU patients with delirium. Nonetheless, the evidence supporting the use of SGAs to treat ICU delirium remains limited. This review is designed to assess the available clinical evidence and highlights the different neuropharmacological and safety properties of SGAs in order to guide the rational use of SGAs for the treatment of ICU delirium. PMID- 26033793 TI - The Impact of Health Literacy Level on Inhaler Technique in Patients With Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Inhaled medications are recommended as first-line treatment for chronic obstructive pulmonary disease (COPD) and can reduce exacerbations and hospitalizations. Low health literacy is associated with poor inhaler technique. OBJECTIVE: This study examined whether handouts written specifically for patients with low health literacy are more effective in showing patients how to use their medications when compared to standard education materials. METHODS: A prospective, experimental study was performed at a community-based hospital. Patients included in the study were admitted to the hospital with a diagnosis of COPD, taking at least 1 inhaled medication and identified as having low health literacy based on a Rapid Estimate of Adult Literacy in Medicine-Short Form. Low health literacy handouts were compared against the standard hospital educational materials for inhalers. Correct technique during each demonstration was evaluated using a standardized checklist. RESULTS: Mean baseline scores for inhaler technique were 12.2 +/- 2.2 steps correct for the control group and 13.4 +/- 1.3 for the low health-literacy group of the 18 maximum points ( P = nonsignificant). The mean change in inhaler technique score for the control group was 1.0 +/- 1.8, while the mean change in inhaler technique score for the low health-literacy group was 2.1 +/- 2.7 ( P = .03). PMID- 26033794 TI - Physicians' Preferences for Communication of Pharmacist-Provided Medication Therapy Management in Community Pharmacy. AB - OBJECTIVES: (1) To identify physicians' preferences in regard to pharmacist provided medication therapy management (MTM) communication in the community pharmacy setting; (2) to identify physicians' perceived barriers to communicating with a pharmacist regarding MTM; and (3) to determine whether Missouri physicians feel MTM is beneficial for their patients. METHODS: A cross-sectional prospective survey study of 2021 family and general practice physicians registered with MO HealthNet, Missouri's Medicaid program. RESULTS: The majority (52.8%) of physicians preferred MTM data to be communicated via fax. Most physicians who provided care to patients in long-term care (LTC) facilities (81.0%) preferred to be contacted at their practice location as opposed to the LTC facility. The greatest barriers to communication were lack of time and inefficient communication practices. Improved/enhanced communication was the most common suggestion for improvement in the MTM process. Approximately 67% of respondents reported MTM as beneficial or somewhat beneficial for their patients. CONCLUSIONS: Survey respondents saw value in the MTM services offered by pharmacists. However, pharmacists should use the identified preferences and barriers to improve their currently utilized communication practices in hopes of increasing acceptance of recommendations. Ultimately, this may assist MTM providers in working collaboratively with patients' physicians. PMID- 26033795 TI - Contraceptive Methods. AB - The prevention of pregnancy remains an important part of the practice of medicine. Contraception can occur at a number of points in the basic reproductive biological process and through a number of contraceptive product options. Pharmacists are health care providers appropriately positioned to assist patients in suitable contraceptive product selection based on their personal situations and lifestyles. This article provides an overview of available products for prevention of pregnancy and associated risks and benefits. Contraceptive products are categorized by their hormonal content and method of action. Hormonal options include oral contraceptive pills, contraceptive patch, implants, injection, intravaginal, and intrauterine devices. Barrier products prevent pregnancy by creating a physical obstacle to the successful fertilization of an egg by sperm. All products and methods are associated with benefits and potential complications that must be considered as patients, and health care providers select the most satisfactory option. PMID- 26033796 TI - Success With Extended-Infusion Meropenem After Recurrence of Baclofen Pump Related Achromobacter Xylosoxidans Meningitis in an Adolescent. AB - A 13-year-old female experienced a recurrence of baclofen pump-related central nervous system (CNS) infection caused by Achromobacter, despite absence of retained foreign material. Due to the failure of meropenem (120 mg/kg/d in divided doses every 8 hours and infused over 30 minutes) in the initial infection, the dose was infused over 4 hours during the recurrence. Meropenem is an antibiotic for which efficacy is time dependent, and 4-hour versus 30-minute infusions have been shown to prolong the time the concentration of the antibiotic exceeds the minimum inhibitory concentration (MIC) of the organism at the site of infection (T>MIC). Meropenem serum concentrations were obtained and indicated that T>MIC was at least 75% of the dosing interval. Our patient improved with no noted recurrences or adverse effects on the extended-infusion meropenem regimen. Utilization of extended-infusion beta-lactam dosing whenever possible in the treatment of serious infections caused by gram-negative organisms should be considered, as this dosing appears to be safe and improves the probability of achieving pharmacokinetic/pharmacodynamic goals. PMID- 26033797 TI - Computational Study of Proton Transfer in Tautomers of 3- and 5-Hydroxypyrazole Assisted by Water. AB - The tautomerism of 3- and 5-hydroxypyrazole is studied at the B3LYP, CCSD and G3B3 computational levels, including the gas phase, PCM-water effects, and proton transfer assisted by water molecules. To understand the propensity of tautomerization, hydrogen-bond acidity and basicity of neutral species is approached by means of correlations between donor/acceptor ability and H-bond interaction energies. Tautomerism processes are highly dependent on the solvent environment, and a significant reduction of the transition barriers upon solvation is seen. In addition, the inclusion of a single water molecule to assist proton transfer decreases the barriers between tautomers. Although the second water molecule further reduces those barriers, its effect is less appreciable than the first one. Neutral species present more stable minima than anionic and cationic species, but relatively similar transition barriers to anionic tautomers. PMID- 26033799 TI - Reply to J.N. Primrose et al and C.-H. Kohne. PMID- 26033798 TI - Safety and Efficacy of Simeprevir/Sofosbuvir in Hepatitis C-Infected Patients With Compensated and Decompensated Cirrhosis. AB - Risks and benefits of simeprevir plus sofosbuvir (SIM+SOF) in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virological responses (SVR) of SIM+SOF with and without ribavirin (RBV) in patients with Child-Pugh (CP)-B/C versus CP-A cirrhosis and compared to matched untreated controls. This study was of a multicenter cohort of adults with hepatitis C virus genotype 1 and cirrhosis treated with SIM+SOF with/without RBV for 12 weeks. Controls were matched on treatment center, age, CP class, and Model for End-Stage Liver Disease (MELD) score. Of 160 patients treated with SIM+SOF with/without RBV, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (interquartile range, 8-11). Sustained virological response at week 12 (SVR12) was achieved by 73% of CP-B/C versus 91% of CP-A (P < 0.01). CP-B/C versus CP-A had more early treatment discontinuations (11% vs. 1%), adverse events (AEs) requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%), and hepatic decompensating events (20% vs. 3%; all P < 0.01). There were 2 deaths: 1 CP-B/C (liver related) and 1 CP-A (not liver related). In multivariate analysis, CP-B/C independently predicted lack of SVR12 (odds ratio, 0.27; 95% confidence interval: 0.08-0.92). In comparing SIM+SOF-treated patients versus matched untreated controls, AEs requiring hospitalization (9% vs. 13%; P = 0.55), infections (8% vs. 6%; P = 0.47), and events of decompensation (9% vs. 10%; P = 0.78) occurred at similar frequency. CONCLUSIONS: SIM+SOF with/without RBV has lower efficacy and higher rates of AEs in patients with CP-B/C cirrhosis, compared to CP-A. Frequency of adverse safety outcomes were similar to matched untreated controls, suggesting that safety events reflect the natural history of cirrhosis and are not related to treatment. PMID- 26033800 TI - Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer. AB - PURPOSE: To identify predictors of discontinuation of adjuvant hormone therapy in patients with breast cancer. PATIENTS AND METHODS: We conducted a record-linkage study based on data from Stockholm-Gotland Breast Cancer Register, Swedish Prescribed Drug Register, and self-reported questionnaire. Women diagnosed with breast cancer between 2005 and 2008 in Stockholm, Sweden, were prospectively followed for 5 years until 2013, starting from their first prescription of tamoxifen or aromatase inhibitors (N = 3,395). RESULTS: Family history of ovarian cancer (hazard ratio [HR], 1.55; 95% CI, 1.19 to 2.02); younger (< 40 years; HR, 1.39; 95% CI, 1.08 to 1.78) and older (>= 65 years; HR, 1.15; 95% CI, 1.03 to 1.28) age; higher Charlson comorbidity index (>= 2 v 0; HR, 1.35; 95% CI, 1.03 to 1.76); and use of analgesics (HR, 1.33; 95% CI, 1.16 to 1.52), hypnotics/sedatives (HR, 1.24; 95% CI, 1.07 to 1.43), GI drugs (HR, 1.25; 95% CI, 1.08 to 1.43), and hormone replacement therapy (HR, 1.27; 95% CI, 1.08 to 1.49) were identified as baseline predictors for hormonal treatment discontinuation. Use of analgesics (HR, 1.22; 95% CI, 1.08 to 1.37), hypnotics/sedatives (HR, 1.21; 95% CI, 1.07 to 1.37), antidepressants (HR, 1.22; 95% CI, 1.06 to 1.40), or GI drugs (HR, 1.27; 95% CI, 1.13 to 1.43), and switching therapy between tamoxifen and aromatase inhibitors (HR, 1.50; 95% CI, 1.23 to 1.83) during the first year of hormonal treatment were associated with increased risk of discontinuation during the next 4 years. CONCLUSION: Predictors identified in our study can be used in developing targeted intervention to prevent adjuvant hormone therapy discontinuation and subsequently to improve breast cancer outcomes. PMID- 26033802 TI - Early Gains Versus Late Pains: Management Options in Stage I Testicular Cancer. PMID- 26033803 TI - Primum Non Nocere: Of Course! But How? PMID- 26033804 TI - Surveillance for Stage I Nonseminoma Testicular Cancer: Outcomes and Long-Term Follow-Up in a Population-Based Cohort. PMID- 26033805 TI - Management of Clinical Stage I Testicular Cancer: How Should We Define Success? PMID- 26033806 TI - Reply to G. Daugaard et al, K. Lu, and L.C. Pagliaro et al. PMID- 26033807 TI - Recommendations Regarding Computed Tomography Imaging in Follow-Up for Stage I Nonseminoma Testicular Cancer Remain a Challenge. PMID- 26033808 TI - Primum Non Nocere: What Hurts in Clinical Stage I Testicular Cancer? PMID- 26033801 TI - Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. AB - PURPOSE: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-alpha-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. PATIENTS AND METHODS: At diagnosis, patients age <= 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included >= two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-alpha-2b (0.5 to 1.0 MUg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). RESULTS: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-alpha-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-alpha-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-alpha-2b and for stopping prematurely, respectively. Median IFN-alpha-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-alpha-2b and provided toxicity information reported grade >= 3 toxicity during IFN-alpha-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-alpha-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. CONCLUSION: At the preplanned analysis time, MAP plus IFN-alpha-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-alpha-2b or stopped prematurely. Long-term follow-up for events and survival continues. PMID- 26033809 TI - Surgery After Relapse in Stage I Nonseminomatous Testicular Cancer. PMID- 26033810 TI - Risk and Cause of Death in Patients Diagnosed With Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based Study. AB - PURPOSE: Myeloproliferative neoplasms (MPNs) are associated with a shortened life expectancy. We assessed causes of death in patients with MPN and matched controls using both relative risks and absolute probabilities in the presence of competing risks. PATIENTS AND METHODS: From Swedish registries, we identified 9,285 patients with MPN and 35,769 matched controls. A flexible parametric model was used to estimate cause-specific hazard ratios (HRs) of death and cumulative incidence functions, each with 95% CIs. RESULTS: In patients with MPN, the HRs of death from hematologic malignancies and infections were 92.8 (95% CI, 70.0 to 123.1) and 2.7 (95% CI, 2.4 to 3.1), respectively. In patients age 70 to 79 years at diagnosis (the largest patient group), the HRs of death from cardiovascular and cerebrovascular disease were 1.5 (95% CI, 1.4 to 1.7) and 1.5 (95% CI, 1.3 to 1.8), respectively; all were statistically significantly elevated compared with those of controls. In the same age group, no difference was observed in the 10 year probability of death resulting from cardiovascular disease in patients with MPN versus controls (16.8% v 15.2%) or cerebrovascular disease (5.6% v 5.2%). In patients age 50 to 59 years at diagnosis, the 10-year probability of death resulting from cardiovascular and cerebrovascular disease was elevated, 4.2% versus 2.1% and 1.9% versus 0.4%, respectively. Survival in patients with MPN increased over time, mainly because of decreased probabilities of dying as a result of hematologic malignancies, infections, and, in young patients, cardiovascular disease. CONCLUSION: Patients with MPN had an overall higher mortality rate than that of matched controls, primarily because of hematologic malignancy, infections, and vascular events in younger patients. Evidently, there is still a need for effective disease-modifying agents to improve patient outcomes. PMID- 26033811 TI - Reply to L.C. Pagliaro et al. PMID- 26033812 TI - Is Progression-Free Survival the Right End Point in Trials of Patients With Clearly Resectable, Borderline Resectable, and Unresectable Liver-Limited Colorectal Cancer? PMID- 26033813 TI - Accurate Prediction and Validation of Response to Endocrine Therapy in Breast Cancer. AB - PURPOSE: Aromatase inhibitors (AIs) have an established role in the treatment of breast cancer. Response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Accurate biomarkers are urgently needed to predict response in these settings and to determine which individuals will benefit from adjuvant AI therapy. PATIENTS AND METHODS: Pretreatment and on-treatment (after 2 weeks and 3 months) biopsies were obtained from 89 postmenopausal women who had estrogen receptor-alpha positive breast cancer and were receiving neoadjuvant letrozole for transcript profiling. Dynamic clinical response was assessed with use of three-dimensional ultrasound measurements. RESULTS: The molecular response to letrozole was characterized and a four-gene classifier of clinical response was established (accuracy of 96%) on the basis of the level of two genes before treatment (one gene [IL6ST] was associated with immune signaling, and the other [NGFRAP1] was associated with apoptosis) and the level of two proliferation genes (ASPM, MCM4) after 2 weeks of therapy. The four-gene signature was found to be 91% accurate in a blinded, completely independent validation data set of patients treated with anastrozole. Matched 2-week on-treatment biopsies were associated with improved predictive power as compared with pretreatment biopsies alone. This signature also significantly predicted recurrence-free survival (P = .029) and breast cancer -specific survival (P = .009). We demonstrate that the test can also be performed with use of quantitative polymerase chain reaction or immunohistochemistry. CONCLUSION: A four-gene predictive model of clinical response to AIs by 2 weeks has been generated and validated. Deregulated immune and apoptotic responses before treatment and cell proliferation that is not reduced 2 weeks after initiation of treatment are functional characteristics of breast tumors that do not respond to AIs. PMID- 26033814 TI - Reply to J. Beyer, T. Tandstad et al, S. Gillessen et al, J. Oldenburg et al, and L.C. Pagliaro et al. PMID- 26033815 TI - Reply to M. Bouattour et al. PMID- 26033816 TI - Reply to C. Rusner et al, L.C. Pagliaro et al, and K. Lu. PMID- 26033817 TI - Reply to L.C. Pagliaro et al. PMID- 26033818 TI - On Nonharming: The Debate Continues in Stage I Testicular Cancer. PMID- 26033819 TI - Mental Health Services for Parents Who Lost a Child to Cancer: If We Build Them, Will They Come? AB - PURPOSE: To examine bereavement mental health service use, barriers to use, and factors associated with use in parents bereaved by cancer. PATIENTS AND METHODS: A multicenter, cross-sectional study of 120 parents bereaved by cancer between 6 months and 6 years after their loss was performed. Parents completed self-report assessments of mental health service use and barriers, prolonged grief, depression, anxiety, attachment styles, and sense of meaning by phone, in person, or on their own. RESULTS: Forty-one percent of bereaved parents were currently using mental health services (talk therapy, psychotropic medication, and/or a support group), most commonly within the first 2 years after their loss. Talk therapy was the most frequently used service, although 36% of parents who discontinued therapy did so because it was not helpful. Forty percent of parents who wanted bereavement support reported they were not receiving services. The most common barriers to service use were that it was too painful to speak about the loss (64%) and too difficult to find help (60%). Factors associated with current mental health service use included more recent loss, prior mental health service use, subclinical/increased depression, insecure attachment styles, and a decreased sense of meaning. Minority parents were more likely to have unmet needs than nonminority parents. CONCLUSION: Parents appear to need, want, and often access bereavement mental health services, which could be offered in oncology settings. However, barriers to service use must be addressed, particularly for those with more debilitating grief symptoms and for minorities. High treatment dropout rates suggest the importance of improving retention, training providers, and developing effective grief interventions. PMID- 26033820 TI - Negative Trials for Foreseeable Safety Reasons in Advanced Hepatocellular Carcinoma: How Long Are We Going to Take Lightly Pharmacokinetics of Tyrosine Kinase Inhibitors? PMID- 26033821 TI - Cetuximab Is Contraindicated in the Perioperative Treatment of Colorectal Liver Metastases. PMID- 26033822 TI - Novel alginate-based nanocarriers as a strategy to include high concentrations of hydrophobic compounds in hydrogels for topical application. AB - The cutaneous penetration of hydrophobic active molecules is of foremost concern in the dermatology and cosmetic formulation fields. The poor solubility in water of those molecules limits their use in hydrophilic forms such as gels, which are favored by patients with chronic skin disease. The aim of this work is to design a novel nanocarrier of hydrophobic active molecules and to determine its potential as an ingredient of a topical form. The nanocarrier consists of an oily core surrounded by a protective shell of alginate, a natural polysaccharide isolated from brown algae. These calcium alginate-based nanocarriers (CaANCs) were prepared at room temperature and without the use of organic solvent by an accelerated nanoemulsification-polymer crosslinking method. The size (hydrodynamic diameter ~200 nm) and surface charge (zeta potential ~ - 30 mV) of the CaANCs are both compatible with their application on skin. CaANCs loaded with a fluorescent label were stable in model hydrophilic galenic forms under different storage conditions. Curcumin was encapsulated in CaANCs with an efficiency of ~95%, fully retaining its antioxidant activity. The application of the curcumin-loaded CaANCs on excised human skin led to a significant accumulation of the active molecules in the upper layers of the skin, asserting the potential of these nanocarriers in active pharmaceutical and cosmetic ingredients topical delivery. PMID- 26033823 TI - Does Modified Footwear Improve Gait After Ankle Arthrodesis? AB - Rocker bottom shoes are commonly recommended for patients who have undergone ankle arthrodesis. Limited data are available to support this recommendation. In the present case-control study, 2 groups of participants were identified for the investigation: a study group (SG) of 9 patients who had previously undergone ankle arthrodesis and a normal group (NG) of 9 healthy volunteers. Gait data were collected using a video recorder while the participants walked barefoot and wearing rocker bottom shoes. These data were analyzed using computer-based gait analysis software. The total motion was calculated and averaged for each group for walking barefoot and wearing rocker bottom shoes. All participants completed the Short Musculoskeletal Function Assessment and the American Orthopaedic Foot and Ankle Society questionnaires. The total motion of the SG wearing rocker bottom shoes increased 4.8 degrees (range 3.4 degrees to 6.9 degrees ) on mean average, an improvement compared with walking barefoot (p < .05). In the NG, the shoe wear had no effect on the total motion (p = .59). Although the total motion in the SG approached the mean average of the total motion of the NG, it remained significantly less than that of the NG (p < .05). Additionally, the SG scored worse than the NG on both outcomes questionnaires (p < .05). Rocker bottom shoes had no effect on gait velocity. In conclusion, rocker bottom shoes significantly improve the total motion of ankle arthrodesis patients toward normal. PMID- 26033824 TI - Evaluating Component Migration: Comparing Two Generations of the INBONE((r)) Total Ankle Replacement. AB - Although total ankle replacement (TAR) designs have radically evolved, the compressive forces at the ankle can cause aseptic loosening, talar subsidence, and implant failure. The purpose of the present report was to compare the implant migration associated with the INBONE((r)) I, a TAR system with a stemmed talar component, and the newer generation INBONE((r)) II, a TAR system without a stemmed talar component (Wright Medical Technology, Inc., Arlington, TN). Because core decompression could weaken the integrity of the talus, we hypothesized that the stemmed component would result in greater implant migration. A total of 35 consecutive patients (age 58.2 +/- 12.1 years; 23 men) were included. Of these 35 patients, 20 (57.1%) had been treated with the INBONE((r)) I and 15 (42.9%) with the INBONE((r)) II. To assess implant migration, using anteroposterior radiographs, the distance from the apex of the tibial component to the most distal aspect of the talar stem or to the mid-saddle of the nonstemmed component was measured. The measurements were recorded from the immediate postoperative radiographs and the 12-month postoperative radiographs. Implant migration was quantified as the difference between the 12-month and the immediate postoperative measurements. Despite our hypothesis, no significant difference was found in implant migration between the INBONE((r)) I (0.7 +/- 1.2 mm) and INBONE((r)) II (0.6 +/- 1.3 mm, p = .981). However, previously published data have suggested that implant migration can continue for >=2 years after surgery. Therefore, additional investigations with larger sample sizes and longer follow-up periods are needed to draw definitive conclusions. PMID- 26033825 TI - Patterning of Fibroblast and Matrix Anisotropy within 3D Confinement is Driven by the Cytoskeleton. AB - Effects of 3D confinement on cellular growth and matrix assembly are important in tissue engineering, developmental biology, and regenerative medicine. Polydimethylsiloxane wells with varying anisotropy are microfabicated using soft lithography. Microcontact printing of bovine serum albumin is used to block cell adhesion to surfaces between wells. The orientations of fibroblast stress fibers, microtubules, and fibronectin fibrils are examined 1 day after cell seeding using laser scanning confocal microscopy, and anisotropy is quantified using a custom autocorrelation analysis. Actin, microtubules, and fibronectin exhibit higher anisotropy coefficients for cells grown in rectangular wells with aspect ratios of 1:4 and 1:8, as compared to those in wells with lower aspect ratios or in square wells. The effects of disabling individual cytoskeletal components on fibroblast responses to anisotropy are then tested by applying actin or microtubule polymerization inhibitors, Rho kinase inhibitor, or by siRNA-mediated knockdown of AXL or cofilin-1. Latrunculin A decreases cytoskeletal and matrix anisotropy, nocodazole ablates both, and Y27632 mutes cellular polarity while decreasing matrix anisotropy. AXL siRNA knockdown has little effect, as does siRNA knockdown of cofilin-1. These data identify several specific cytoskeletal strategies as targets for the manipulation of anisotropy in 3D tissue constructs. PMID- 26033826 TI - Anterior Cortical Development During Adolescence in Bipolar Disorder. AB - BACKGROUND: Increasing evidence supports a neurodevelopmental model for bipolar disorder (BD), with adolescence as a critical period in its development. Developmental abnormalities of anterior paralimbic and heteromodal frontal cortices, key structures in emotional regulation processes and central in BD, are implicated. However, few longitudinal studies have been conducted, limiting understanding of trajectory alterations in BD. In this study, we performed longitudinal neuroimaging of adolescents with and without BD and assessed volume changes over time, including changes in tissue overall and within gray and white matter. Larger decreases over time in anterior cortical volumes in the adolescents with BD were hypothesized. Gray matter decreases and white matter increases are typically observed during adolescence in anterior cortices. It was hypothesized that volume decreases over time in BD would reflect alterations in those processes, showing larger gray matter contraction and decreased white matter expansion. METHODS: Two high-resolution magnetic resonance imaging scans were obtained approximately 2 years apart for 35 adolescents with bipolar I disorder (BDI) and 37 healthy adolescents. Differences over time between groups were investigated for volume overall and specifically for gray and white matter. RESULTS: Relative to healthy adolescents, adolescents with BDI showed greater volume contraction over time in a region including insula and orbitofrontal, rostral, and dorsolateral prefrontal cortices (p < .05, corrected), including greater gray matter contraction and decreased white matter expansion over time, in the BD compared with the healthy group. CONCLUSIONS: The findings support neurodevelopmental abnormalities during adolescence in BDI in anterior cortices, including altered developmental trajectories of anterior gray and white matter. PMID- 26033828 TI - Treatment with omalizumab in a 16-year-old Caucasian girl with refractory solar urticaria. PMID- 26033827 TI - Genetic variation affects congenital heart defect susceptibility in offspring exposed to maternal tobacco use. AB - BACKGROUND: Congenital heart defects (CHDs) are among the most prevalent and serious birth defects, occurring in 8 to 10 of every 1000 live births in the United States. Epidemiologic studies have reported an association between CHDs and maternal smoking, but it remains unknown how genes impact the susceptibility of offspring to CHDs in the presence of maternal tobacco use. METHODS: Using data from 403 case- and 219 control-parental triads enrolled in the National Birth Defects Prevention Study between 1998 and 2008, we investigated the association between CHDs and maternal and infant genetic variants involved in the tobacco metabolism and DNA repair pathways among mothers who smoked prenatally. RESULTS: The maternal genotypes of single nucleotide polymorphisms in the excision repair cross-complementation group 1 (ERCC1), poly (ADP-ribose) polymerase 2 (PARP2), and ERCC5 genes were identified to be significantly associated with the occurrence of CHDs in the presence of maternal tobacco use. Our analysis also revealed a moderate association between the infant genotypes of polymorphisms in the O-sialoglycoprotein endopeptidase (OSGEP) gene and increased risk of CHDs among mothers who smoked. CONCLUSION: Our study provides evidence that maternal and infant polymorphisms within the ERCC1, PARP2, ERCC5, and OSGEP genes are associated with CHD risk in the presence of maternal tobacco use. These results may provide insight into the susceptibility of having a pregnancy affected by CHDs among women who smoke. PMID- 26033829 TI - Postmortem cytology: Alive and well in the practice of autopsy and forensic pathology. PMID- 26033831 TI - Evaluation of (4-Arylpiperidin-1-yl)cyclopentanecarboxamides As High-Affinity and Long-Residence-Time Antagonists for the CCR2 Receptor. AB - Animal models suggest that the chemokine ligand 2/CC-chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure-kinetics relationships (SKRs). Herein we report new findings on the structure-affinity relationships (SARs) and SKRs of the reference compound MK-0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4-arylpiperidine group suggest that lipophilic hydrogen-bond-accepting substituents at the 3-position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3-Br: Ki =2.8 nM, residence time (t(res))=243 min; 3-iPr: Ki =3.6 nM, t(res) =266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3-position, can also prolong t(res); this was most prominently observed in MK-0483 (Ki =1.2 nM, t(res) =724 min) and a close analogue (Ki =7.8 nM) with a short residence time. PMID- 26033832 TI - Investigation on the Surface-Confined Self-Assembly Stabilized by Hydrogen Bonds of Urea and Amide Groups: Quantitative Analysis of Concentration Dependence of Surface Coverage. AB - Formation of a hydrogen-bond network via an amide group is a key driving force for the nucleation-elongation-type self-assembly that is often seen in biomolecules and artificial supramolecular assemblies. In this work, rod-coil like aromatic compounds bearing an amide (1 a-3 a) or urea group (1 u-3 u) were synthesized, and their self-assemblies on a 2-D surface were investigated by scanning tunneling microscopy (STM). According to the quantitative analysis of the concentration dependence of the surface coverage, it was revealed that the strength of the hydrogen bond (i.e., amide or urea) and the number of non hydrogen atoms in a molecular component (i.e., size of core and length of alkyl side chain) play a primary role in determining the stabilization energy during nucleation and elongation processes of molecular ordering on the HOPG surface. PMID- 26033830 TI - Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer. AB - BACKGROUND: Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM). METHODS: Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2 related pathways and evaluate EGFR tyrosine kinase inhibitor resistance. RESULTS: A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms. CONCLUSIONS: The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib. PMID- 26033833 TI - Fetal akinesia deformation sequence due to a congenital disorder of glycosylation. AB - Congenital disorders of Glycosylation (CDG) are increasingly emerging as a major underlying etiology for patients with complex neurogenetic malformations and dysmorphic features. We describe a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to CDG-DPAGT1. Pregnancy was complicated by reduced fetal movements. At birth, the patient was evaluated for intrauterine growth restriction, bilateral cataracts, and multiple joint contractures. She had markedly reduced spontaneous movements, hypotonia, weak cry, and poor suck. She had ventilator-dependent central respiratory depression. Brain MRI showed delayed myelination and an incomplete cerebellar vermis. Transferrin isoelectric focusing was suggestive of a type I congenital disorder of glycosylation. Sequencing revealed a homozygous missense mutation in dolichyl-phosphate N acetylglucosaminephosphotransferase (DPAGT1), exon 3, p.Leu118Val, consistent with DPAGT1-CDG. There have been seventeen previously reported cases of DPAGT1 CDG, including two similar cases with multiple contractures. This case highlights the importance of considering congenital disorders of glycosylation in the differential diagnosis for arthrogryposis. PMID- 26033834 TI - Digital gene expression profiling of a series of cytologically indeterminate thyroid nodules. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) has been widely accepted as the most crucial step in the preoperative assessment of thyroid nodules. Testing for the expression of specific genes should improve the accuracy of FNAC diagnosis, especially when it is performed in samples with indeterminate cytology. METHODS: In total, 69 consecutive FNACs that had both cytologic and histologic diagnoses were collected, and expression levels of 34 genes were determined in RNA extracted from FNAC cells by using a custom digital mRNA counting assay. A supervised k-nearest neighbor (K-nn) learning approach was used to build a 2-class prediction model based on a subset of 27 benign and 26 malignant FNAC samples. Then, the K-nn models were used to classify the 16 indeterminate FNAC samples. RESULTS: Malignant and benign thyroid nodules had different gene expression profiles. The K-nn approach was able to correctly classify 10 FNAC samples as benign, whereas only 1 sample was grouped in the malignant class. Two malignant FNAC samples were incorrectly classified as benign, and 3 of 16 samples were unclassified. CONCLUSIONS: Although the current data will require further confirmation in a larger number of cases, the preliminary results indicate that testing for specific gene expression appears to be useful for distinguishing between benign and malignant lesions. The results from this study indicate that, in indeterminate FNAC samples, testing for cancer specific gene expression signatures, together with mutational analyses, could improve diagnostic accuracy for patients with thyroid nodules. PMID- 26033835 TI - Periconceptional changes in weight and risk of delivering offspring with conotruncal heart defects. AB - BACKGROUND: Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-control study of 296 conotruncal cases and 695 nonmalformed controls we explored whether weight loss during early pregnancy was associated with an increased risk of d-transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF) conotruncal defects. METHODS: During telephone interviews women were asked whether they were dieting to lose weight or using weight loss remedies during 2 months before or 2 months after conception, and how much weight they gained or lost in the first 2 months of pregnancy or during the year before pregnancy. RESULTS: Odds ratios for dieting to lose weight and use of weight loss remedies for dTGA and TOF were not substantially elevated and all had confidence intervals that included 1.0. Mothers who had a loss of >5 lbs in the first 2 months of pregnancy as well as mothers who lost and gained >5 lbs in the first 2 months of pregnancy also did not show a significant increased risk of delivering case infants when compared with women with no weight change in the year before pregnancy. CONCLUSION: Given current recommendations about limited weight gain for obese pregnant women, these data indicate that dieting may not substantially increase a fetus' risk of having a conotruncal defect. PMID- 26033836 TI - Presence of brain pathology in deceased subjects with and without chronic obstructive pulmonary disease. AB - Patients with chronic obstructive pulmonary disease (COPD) have extrapulmonary co morbidities, such as cardiovascular disease, musculoskeletal wasting and neuropsychological conditions. To date, it remains unknown whether and to what extent COPD is associated with a higher prevalence of brain pathology. Therefore, the aim of this retrospective study was to compare the prevalence of neuropathological brain changes between deceased donors with and without COPD. Brain autopsy reports of age-matched donors with (n = 89) and without COPD (n = 89) from the Netherlands Brain Bank were assessed for demographics, cause of death, co-morbidities and brain pathology. The prevalence of degenerative brain changes was comparable for donors with and without COPD (50.6% vs. 61.8%, p > 0.05). Neoplastic brain changes were reported in a minority of the donors (5.6% vs. 10.1%, p > 0.05). After correction for cerebrovascular accident or cardiac cause of death and Charlson co-morbidity index score, the prevalence of vascular brain changes was higher among control versus COPD donors (27.0% vs. 11.2%, adjusted p = 0.013, odds ratio = 2.98). Brain autopsy reports of donors with and without COPD did not reveal differences in the presence of degenerative or neoplastic brain changes. Vascular brain changes were described more often in controls. Prospective studies including spirometry and structural and functional brain imaging should corroborate our findings. PMID- 26033837 TI - A longitudinal assessment of sleep variables during exacerbations of chronic obstructive pulmonary disease. AB - Although sleep disturbance is common in chronic obstructive pulmonary disease (COPD), relatively little is known on the effect of the exacerbation on sleep quality. Accordingly, we longitudinally assessed sleep variables during exacerbations and clinical stability. This is a sub-study of a larger observational analysis. Inclusion criteria were clinically stable COPD and two or more clinical exacerbations in the preceding 12 months. Patients were followed for approximately 6 months and during this time the following were recorded daily: (1) COPD exacerbations, which were determined in two ways, clinically and symptom defined using the exacerbations of chronic pulmonary disease tool (EXACT); (2) daytime sleepiness, which was measured using the Stanford Sleepiness Scale; (3) subjective awakenings, which was measured from a sleep diary; and (4) sleep duration, efficiency, and objective awakenings, which was measured from actigraphy. These variables for exacerbation and non-exacerbation days were compared. Seventeen patients (9 male, age 63 +/- 12 years, forced expiratory volume in 1 second 52 +/- 20%) entered data over 135 +/- 18 days. During this time, 15 patients had 27 symptom-defined exacerbations and 8 had 9 clinically reported exacerbations. Symptom-defined exacerbation days were 26% of the total study days. More daytime sleepiness, decreased total sleep time (TST), and decreased sleep efficiency (SE) were present during exacerbations compared with clinical stability (p < 0.001). These disturbances tended to be greater during clinically reported exacerbations than during unreported events (p < 0.05). Increased daytime sleepiness, less TST, and poorer SE are present during COPD exacerbations. PMID- 26033838 TI - Intracellularly Degradable, Self-Assembled Amphiphilic Block Copolycurcumin Nanoparticles for Efficient In Vivo Cancer Chemotherapy. AB - Intracellularly degradable, self-assembled amphiphilic biotin-poly(ethylene glycol)-b-poly(curcumin-dithiodipropionic acid) nanoparticles are developed. They display excellent in vivo anticancer efficacy, benefitted from their high tumor targeted accumulation and stimuli-triggered intracellular drug release. They can be loaded with other anticancer drugs (e.g., doxorubicin) to exploit the synergy of combinational dual-drug therapy to further enhance in vivo anticancer efficacy. PMID- 26033839 TI - Three-Component Supramolecular System with Multistimuli-Responsive Properties in Water. AB - Hyperbranched polyethylenimine terminated with isobutyramide groups (HPEI-IBAm), 4-(phenylazo)benzoic acid (PABA), and alpha-cyclodextrin (alpha-CD) were assembled together at pH~7 to form the three-component supramolecular complexes that were verified by (1) H and 2D ROESY (1) H NMR spectroscopy. UV/Vis spectrometric titration experiments showed that the content of alpha-CD in the three-component complexes was less than the feed amount and it was difficult for all the PABA units in the complexes to further form complexes with alpha-CD. The obtained three-component supramolecular complexes exhibited thermoresponsive properties in water. Increasing the alpha-CD concentration led to a sharp increase in the cloud point temperature (Tcp ) at the beginning, but after the [alpha-CD]/[PABA] ratio was in the region of 1.3-1.6, the Tcp increased gradually When the concentration of alpha-CD was low, a higher concentration of PABA led to a lower Tcp , however, the opposite was observed when the concentration of alpha CD was high. For the three-component complex, increasing the alpha-CD concentration at pH~7 or at pH~9 led to different Tcp temperatures. In the low alpha-CD concentration range, adjusting the pH from ~7-~9 resulted in an increase in the Tcp , similar but not so pronounced as that of the two-component system of HPEI-IBAm/[PABA]. When the concentration of alpha-CD was high, adjusting the pH from ~7-~9 decreased the Tcp ; this observation is different to that of the two component system of HPEI-IBAm/[PABA]. Reversible trans-to-cis photoisomerization of azobenzene units in the complexes occurred, following irradiation with UV or visible light. Trans-to-cis isomerization of azobenzene units decreased the Tcp . However, this result differed to that of the two-component system of HPEI IBAm/PABA. PMID- 26033840 TI - Target Fishing by Cross-Docking to Explain Polypharmacological Effects. AB - Drugs may have polypharmacological phenomena, that is, in addition to the desired target, they may also bind to many undesired or unknown physiological targets. As a result, they often exert side effects. In some cases, off-target interactions may lead to drug repositioning or to explaining a drug's mode of action. Herein we present an in silico approach for target fishing by cross-docking as a method to identify new drug-protein interactions. As an example and proof of concept, this method predicted the peroxisome proliferator-activated receptor (PPAR)-gamma as a target of ethacrynic acid, which may explain the hyperglycemic effect brought on by this molecule. The antagonistic effect of ethacrynic acid on PPAR gamma was validated in a transient transactivation assay using human HEK293 cells. The cross-docking approach also predicted the potential mechanisms of many other drug side effects and discloses new drug repositioning opportunities. These putative interactions are described herein, and can be readily used to discover therapeutically relevant drug effects. PMID- 26033841 TI - De Novo 17q24.2-q24.3 microdeletion presenting with generalized hypertrichosis terminalis, gingival fibromatous hyperplasia, and distinctive facial features. AB - Generalized hypertrichosis is a feature of several genetic disorders, and the nosology of these entities is still provisional. Recent studies have implicated chromosome 17q24.2-q24.3 microdeletion and the reciprocal microduplication in a very rare form of congenital generalized hypertrichosis terminalis (CGHT) with or without gingival hyperplasia. Here, we report on a 5-year-old Egyptian girl born to consanguineous parents. The girl presented with CGHT and gingival hyperplasia for whom we performed detailed clinical, pathological, and molecular studies. The girl had coarse facies characterized by bilateral epicanthic folds, thick and abundant eyelashes, a broad nose, full cheeks, and lips that constituted the distinctive facial features for this syndrome. Biopsy of the gingiva showed epithelial marked acanthosis and hyperkeratosis with hyperplastic thick collagen bundles and dense fibrosis in the underlying tissues. Array analysis indicated a 17q24.2-q24.3 chromosomal microdeletion. We validated this microdeletion by real time quantitative PCR and confirmed a perfect co-segregation of the disease phenotype within the family. In summary, this study indicates that 17q24.2-q24.3 microdeletion caused CGHT with gingival hyperplasia and distinctive facies, which should be differentiated from the autosomal recessive type that lacks the distinctive facies. PMID- 26033842 TI - Actual drawing of histological images improves knowledge retention. AB - Medical students have to process a large amount of information during the first years of their study, which has to be retained over long periods of nonuse. Therefore, it would be beneficial when knowledge is gained in a way that promotes long-term retention. Paper-and-pencil drawings for the uptake of form-function relationships of basic tissues has been a teaching tool for a long time, but now seems to be redundant with virtual microscopy on computer-screens and printers everywhere. Several studies claimed that, apart from learning from pictures, actual drawing of images significantly improved knowledge retention. However, these studies applied only immediate post-tests. We investigated the effects of actual drawing of histological images, using randomized cross-over design and different retention periods. The first part of the study concerned esophageal and tracheal epithelium, with 384 medical and biomedical sciences students randomly assigned to either the drawing or the nondrawing group. For the second part of the study, concerning heart muscle cells, students from the previous drawing group were now assigned to the nondrawing group and vice versa. One, four, and six weeks after the experimental intervention, the students were given a free recall test and a questionnaire or drawing exercise, to determine the amount of knowledge retention. The data from this study showed that knowledge retention was significantly improved in the drawing groups compared with the nondrawing groups, even after four or six weeks. This suggests that actual drawing of histological images can be used as a tool to improve long-term knowledge retention. PMID- 26033843 TI - Maternal factors in the origin of isolated oesophageal atresia: A population based case-control study. AB - BACKGROUND: In most patients affected by isolated oesophageal atresia (IOA) the etiology is largely unknown. Thus, the aim of this study was to analyze potential risk factors in mothers. METHODS: The study samples included 221 cases with IOA, 356 matched and 38,151 population controls without any defect in the population based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980 to 1996. Only those exposures were evaluated that were medically recorded in prenatal maternity logbooks during the critical period of IOA. RESULTS: The findings of this case-control study suggested that the mothers of cases with IOA had a higher proportion of first delivery and lower socioeconomic status. Acute respiratory diseases (odds ratio [OR] 95% confidence interval [CI], 3.8, 1.8-8.1) and essential hypertension treated with nifedipine (OR 95% CI, 3.8, 1.7-8.7) in the mothers of cases associated with a higher risk for IOA in their children. CONCLUSION: First delivery, lower socioeconomic status, acute respiratory diseases and essential hypertension treated with nifedipine in the mothers may associate with a higher risk for IOA in their children. PMID- 26033844 TI - Waikato Teledermatology: a pilot project for improving access in New Zealand. AB - INTRODUCTION: Teledermatology can improve access to specialist dermatological advice. We describe a retrospective review of the first 12 months of Waikato Teledermatology (WT), a low-cost, secure, website-based, store-and-forward teledermatology network using the Collegium Telemedicus platform. METHODS: We determined specialist response time, referral metrics, patient diagnosis and progress reports from the network's database. The programme's value was evaluated by post-pilot online surveys of referrers and specialist dermatologists. RESULTS: WT was used by 31 referring doctors for 309 consultations with four dermatologists between July 2013 and June 2014. Mean and median specialist response time was 2.07 hours (range: 0.13-5.64 hours). The researchers categorized the referrals as tumours (56.8%) and rashes (43.2%), including inflammatory dermatoses (51.9%), infection (18.1%), uncertain (16.5%), miscellaneous (7.5%), and of environmental origin (6%). Thirty tumours were biopsied, including nine melanomas and three basal cell carcinomas. A total of 158 progress reports and 35 survey responses were received. Reported advantages included decreased delay, improved accuracy of diagnosis and treatment compared to that made without specialist input, decreased unnecessary procedures such as biopsies of undiagnosed conditions, and increased appropriate referrals for face to-face assessment, thus leading to cost savings for the patient and the health care system. The major disadvantages were the time burden for clinicians to complete consultations, the lack of integration with the patients' usual electronic medical record and absence of funding. DISCUSSION: WT proved an effective and acceptable approach to improving patient access to dermatologic services. PMID- 26033845 TI - Telemedicine in US Army soldiers with type 1 diabetes. AB - A retrospective study of a telemedicine clinic for active duty US Army soldiers with type 1 diabetes was conducted. Fifty-one consecutive patients (mean age 33.9 years) were enrolled into the clinic. All soldiers with known or newly diagnosed type 1 diabetes received three weekly office visits for intensive diabetes education. After this, all communication occurred via a messaging system consisting of texting, web-based download, and/or email to a diabetes management team. For urgent matters, 24/7 direct paging or telephone access was provided. Routine adjustments in insulin dosing were accomplished via email. Soldiers were followed for a mean of 17.1 months. Baseline, three-month, and end of study glycated hemoglobin (A1C) values were 9.8, 7.3, and 6.9, respectively. There were no significant differences in end of study A1C levels between patients with known vs. newly diagnosed type 1 diabetes, nor were there any differences between those patients who received insulin via pump therapy vs. multiple daily injections. Telemedicine was safe and effective in lowering A1C levels in US Army soldiers with type 1 diabetes. PMID- 26033846 TI - The quest for affinity chromatography ligands: are the molecular libraries the right source? AB - Affinity chromatography separations of proteins call for highly specific ligands. Antibodies are the most obvious approach; however, except for specific situations, technical and economic reasons are arguments against this choice especially for preparative purposes. With this in mind, the rationale is to select the most appropriate ligands from collections of pre-established molecules. To reach the objective of having a large structural coverage, combinatorial libraries have been proposed. These are classified according to their nature and origin. This review presents and discusses the most common affinity ligand libraries along with the most appropriate screening methods for the identification of the right affinity chromatography selective structure according to the type of library; a side-by-side comparison is also presented. PMID- 26033847 TI - Graphene Oxides Show Angiogenic Properties. AB - Angiogenesis, a process resulting in the formation of new capillaries from the pre-existing vasculature plays vital role for the development of therapeutic approaches for cancer, atherosclerosis, wound healing, and cardiovascular diseases. In this report, the synthesis, characterization, and angiogenic properties of graphene oxide (GO) and reduced graphene oxide (rGO) have been demonstrated, observed through several in vitro and in vivo angiogenesis assays. The results here demonstrate that the intracellular formation of reactive oxygen species and reactive nitrogen species as well as activation of phospho-eNOS and phospho-Akt might be the plausible mechanisms for GO and rGO induced angiogenesis. The results altogether suggest the possibilities for the development of alternative angiogenic therapeutic approach for the treatment of cardiovascular related diseases where angiogenesis plays a significant role. PMID- 26033848 TI - Synthesis of 2D/2D Structured Mesoporous Co3O4 Nanosheet/N-Doped Reduced Graphene Oxide Composites as a Highly Stable Negative Electrode for Lithium Battery Applications. AB - Mesoporous Co3O4 nanosheets (Co3 O4 -NS) and nitrogen-doped reduced graphene oxide (N-rGO) are synthesized by a facile hydrothermal approach, and the N rGO/Co3O4 -NS composite is formulated through an infiltration procedure. Eventually, the obtained composites are subjected to various characterization techniques, such as XRD, Raman spectroscopy, surface area analysis, X-ray photoelectron spectroscopy (XPS), and TEM. The lithium-storage properties of N rGO/Co3O4 -NS composites are evaluated in a half-cell assembly to ascertain their suitability as a negative electrode for lithium-ion battery applications. The 2D/2D nanostructured mesoporous N-rGO/Co3O4 -NS composite delivered a reversible capacity of about 1305 and 1501 mAh g(-1) at a current density of 80 mA g(-1) for the 1st and 50th cycles, respectively. Furthermore, excellent cyclability, rate capability, and capacity retention characteristics are noted for the N-rGO/Co3O4 NS composite. This improved performance is mainly related to the existence of mesoporosity and a sheet-like 2D hierarchical morphology, which translates into extra space for lithium storage and a reduced electron pathway. Also, the presence of N-rGO and carbon shells in Co3O4 -NS should not be excluded from such exceptional performance, which serves as a reliable conductive channel for electrons and act as synergistically to accommodate volume expansion upon redox reactions. Ex-situ TEM, impedance spectroscopy, and XPS, are also conducted to corroborate the significance of the 2D morphology towards sustained lithium storage. PMID- 26033849 TI - Synthesis, Chiral Separation, Absolute Configuration Assignment, and Biological Activity of Enantiomers of Retro-1 as Potent Inhibitors of Shiga Toxin. AB - The Shiga toxin (Stx) family is composed of related protein toxins produced by the bacteria Shigella dysenteriae and certain pathogenic strains of E. coli. No effective therapies for Stx intoxication have been developed yet. However, inhibitors that act on the intracellular trafficking of these toxins may provide new options for the development of therapeutic strategies. This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of Retro-1, a compound active against Stx and other such protein toxins. Retro-1 works by inhibiting retrograde transport of these toxins inside cells. In vitro experiments proved that the configuration of the stereocenter at position 5 is not crucial for the activity of this compound. X-ray diffraction data revealed (S)-Retro-1 to be slightly more active than (R)-Retro-1. PMID- 26033850 TI - Disclosure of psychiatric manifestations of 22q11.2 deletion syndrome in medical genetics: A 12-year retrospective chart review. AB - Individuals with 22q11.2 deletion syndrome (22qDS) have increased risk for psychiatric disorders. However, while medical geneticists self-report discussing psychiatric features of 22qDS with families (though often only when the child is older), most parents of children with 22qDS report receiving information about the psychiatric manifestations of 22qDS from non-medical sources. In an attempt to reconcile these previous findings, we sought to objectively determine the frequency with which medical geneticists discuss the potential psychiatric manifestations of 22qDS: (i) in letters to referring physicians and (ii) with families, and to explore plans for follow-up. We abstracted data from charts of patients with 22qDS who were referred to a single medical genetics center between January 1, 2000 and December 31, 2012. Psychiatric disorders were discussed in consult letters to referring physicians for n = 57 (46%) of the 125 patients who met inclusion criteria-making them less frequently discussed than all other features of 22qDS. Despite exhaustive review of charts, the content of discussions with families was typically unclear. Follow-up in medical genetics was suggested for 50 people but only 18 (36%) of these patients returned. Disclosure of psychiatric features of 22qDS to families is necessary so that psychiatric disorders can be identified in time for early intervention to be implemented to achieve better prognosis for those affected. These empiric data offer some explanation as to why psychiatric services are underused by individuals with 22qDS. PMID- 26033851 TI - Medical student preferences for self-directed study resources in gross anatomy. AB - Gross anatomy instruction in medical curricula involve a range of resources and activities including dissection, prosected specimens, anatomical models, radiological images, surface anatomy, textbooks, atlases, and computer-assisted learning (CAL). These resources and activities are underpinned by the expectation that students will actively engage in self-directed study (SDS) to enhance their knowledge and understanding of anatomy. To gain insight into preclinical versus clinical medical students' preferences for SDS resources for learning gross anatomy, and whether these vary on demographic characteristics and attitudes toward anatomy, students were surveyed at two Australian medical schools, one undergraduate-entry and the other graduate-entry. Lecture/tutorial/practical notes were ranked first by 33% of 156 respondents (mean rank +/- SD, 2.48 +/- 1.38), textbooks by 26% (2.62 +/- 1.35), atlases 20% (2.80 +/- 1.44), videos 10% (4.34 +/- 1.68), software 5% (4.78 +/- 1.50), and websites 4% (4.24 +/- 1.34). Among CAL resources, Wikipedia was ranked highest. The most important factor in selecting CAL resources was cost (ranked first by 46%), followed by self assessment, ease of use, alignment with curriculum, and excellent graphics (each 6-9%). Compared with preclinical students, clinical students ranked software and Acland's Video Atlas of Human Anatomy higher and felt radiological images were more important in selecting CAL resources. Along with other studies reporting on the quality, features, and impact on learning of CAL resources, the diversity of students' preferences and opinions on usefulness and ease of use reported here can help guide faculty in selecting and recommending a range of CAL and other resources to their students to support their self-directed study. PMID- 26033852 TI - The National Birth Defects Prevention Study: A review of the methods. AB - BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States. METHODS: Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living). RESULTS: There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014. CONCLUSION: The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers. PMID- 26033853 TI - Single-step multiresidue determination of ten multiclass veterinary drugs in pork, milk, and eggs using liquid chromatography with tandem mass spectrometry. AB - A multiclass, multiresidue determination method is reported for the detection of ten veterinary drugs, including scopolamine, metoclopramide, acriflavine, berberine, tripelennamine, diphenhydramine, acrinol, triamcinolone, loperamide, and roxithromycin in pork, milk, and eggs. The method involves a simple extraction using 0.1% formic acid in acetonitrile, followed by defatting with n hexane, centrifugation, and filtration prior to liquid chromatography with tandem mass spectrometric analysis. As ion suppression and enhancement effects are reported, matrix-matched calibrations are used for quantification, with determination coefficients >=0.9765. For the majority of the tested analytes, the intra- and interday accuracy (expressed as recovery %) range from 70.6 to 94.6% and from 70.1 to 93.3%, respectively, and the precision (expressed as relative standard deviation) ranges from 0.5 to 19.8% and from 2.8 to 18.4% in all matrices. The limits of quantification range between 0.5 and 10 ng/g. The validated tandem mass spectrometry method is successfully applied to market samples; the target analytes are not detected in any of the tested samples. In terms of accuracy, no extract cleanup is deemed necessary. The developed method is feasible for the simultaneous detection of the tested analytes in pork, milk, and eggs. PMID- 26033854 TI - Calcite Single Crystals as Hosts for Atomic-Scale Entrapment and Slow Release of Drugs. AB - Doxorubicin (DOX)/CaCO3 single crystals act as pH responsive drug carrier. A biomimetic approach demonstrates that calcite single crystals are able, during their growth in the presence of doxorubicin, to entrap drug molecules inside their lattice along specific crystallographic directions. Alterations in lattice dimensions and microstructural parameters are determined by means of high resolution synchrotron powder diffraction measurements. Confocal microscopy confirms that doxorubicin is uniformly embedded in the crystal and is not simply adsorbed on the crystal surface. A slow release of DOX was obtained preferentially in the proximity of the crystals, targeting cancer cells. PMID- 26033856 TI - Binding Mode of Acetylated Histones to Bromodomains: Variations on a Common Motif. AB - Bromodomains, epigenetic readers that recognize acetylated lysine residues in histone tails, are potential drug targets in cancer and inflammation. Herein we review the crystal structures of human bromodomains in complex with histone tails and analyze the main interaction motifs. The histone backbone is extended and occupies, in one of the two possible orientations, the bromodomain surface groove lined by the ZA and BC loops. The acetyl-lysine side chain is buried in the cavity between the four helices of the bromodomain, and its oxygen atom accepts hydrogen bonds from a structural water molecule and a conserved asparagine residue in the BC loop. In stark contrast to this common binding motif, a large variety of ancillary interactions emerge from our analysis. In 10 of 26 structures, a basic side chain (up to five residues up- or downstream in sequence with respect to the acetyl-lysine) interacts with the carbonyl groups of the C terminal turn of helix alphaB. Furthermore, the complexes reveal many heterogeneous backbone hydrogen bonds (direct or water-bridged). These interactions contribute unselectively to the binding of acetylated histone tails to bromodomains, which provides further evidence that specific recognition is modulated by combinations of multiple histone modifications and multiple modules of the proteins involved in transcription. PMID- 26033857 TI - Image-based systems biology. PMID- 26033855 TI - Mass spectrometric phosphoproteome analysis of HIV-infected brain reveals novel phosphorylation sites and differential phosphorylation patterns. AB - PURPOSE: To map the phosphoproteome and identify changes in the phosphorylation patterns in the HIV-infected and uninfected brain. EXPERIMENTAL DESIGN: Parietal cortex from individuals with and without HIV infection were lysed and trypsinized. The peptides were labeled with iTRAQ reagents, combined, phospho enriched by titanium dioxide chromatography, and analyzed by LC-MS/MS with high resolution. RESULTS: Our phosphoproteomic workflow resulted in the identification of 112 phosphorylated proteins and 17 novel phosphorylation sites in all the samples that were analyzed. The phosphopeptide sequences were searched for kinase substrate motifs, which revealed potential kinases involved in important signaling pathways. The site-specific phosphopeptide quantification showed that peptides from neurofilament medium polypeptide, myelin basic protein, and 2'-3' cyclic nucleotide-3' phosphodiesterase have relatively higher phosphorylation levels during HIV infection. CONCLUSIONS AND CLINICAL RELEVANCE: This study has enriched the global phosphoproteome knowledge of the human brain by detecting novel phosphorylation sites on neuronal proteins and identifying differentially phosphorylated brain proteins during HIV infection. Kinases that lead to unusual phosphorylations could be therapeutic targets for the treatment of HIV-associated neurocognitive disorders. PMID- 26033862 TI - Implementation of integral feedback control in biological systems. AB - Integral control design ensures that a key variable in a system is tightly maintained within acceptable levels. This approach has been widely used in engineering systems to ensure offset free operation in the presence of perturbations. Several biological systems employ such an integral control design to regulate cellular processes. An integral control design motif requires a negative feedback and an integrating process in the network loop. This review describes several biological systems, ranging from bacteria to higher organisms in which the presence of integral control principle has been hypothesized. The review highlights that in addition to the negative feedback, occurrence of zero order kinetics in the process is a key element to realize the integral control strategy. Although the integral control motif is common to these systems, the mechanisms involved in achieving it are highly specific and can be incorporated at the level of signaling, metabolism, or at the phenotypic levels. PMID- 26033864 TI - Effect of acupuncture on postoperative adhesive intestinal obstruction. PMID- 26033865 TI - Brain responses to acupuncture stimulation in the prosthetic hand of an amputee patient. AB - This report describes the brain responses to acupuncture in an upper limb amputee patient. A 62-year-old male had previously undergone a lower left arm amputation following an electrical accident. Using functional MRI, we investigated brain responses to acupuncture stimulation in the aforementioned amputee under three conditions: (a) intact hand, (b) prosthetic hand (used by the patient), and (c) fake fabric hand. The patient described greater de qi sensation when he received acupuncture stimulation in his prosthetic hand compared to a fake hand, with both stimulations performed in a similar manner. We found enhanced brain activation in the insula and sensorimotor cortex in response to acupuncture stimulation in the amputee's prosthetic hand, while there was only minimal activation in the visual cortex in response to acupuncture stimulation in a fake hand. The enhanced brain responses to acupuncture stimulation of the patient's prosthetic hand might be derived from cortical reorganisation, as he has been using his prosthetic hand for over 40 years. Our findings suggest the possible use of acupuncture stimulation in a prosthetic hand as an enhanced sensory feedback mechanism, which may represent a new treatment approach for phantom limb pain. PMID- 26033863 TI - Developments in our understanding of the genetic basis of birth defects. AB - Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects. PMID- 26033866 TI - Soft tissue swelling and cold abscess after embedded acupuncture. PMID- 26033867 TI - Preparation and characterization of macroporous monoliths imprinted with erythromycin. AB - The synthesis of macroporous molecularly imprinted monoliths was performed using the monomers system 2-hydroxyethyl methacrylate-ethylene glycol dimethacrylate and erythromycin as a template. The copolymerization was carried out in situ inside 50 mm * 4.6 mm i.d. stainless-steel tubing. The morphology of the monoliths was examined with scanning electron microscopy. The porous characteristics were determined both from the data of hydrodynamic permeability of monoliths and by means of mercury intrusion porosimetry. The retention parameters of target substance (erythromycin), values of calculated imprinting factors and apparent dynamic dissociation constants were obtained for monoliths prepared with the application of different amount of template (4, 8 and 12 mol%). The separations of the mixtures azithromycin/erythromycin and ciprofloxacin/erythromycin were demonstrated. Additionally, the possibility of erythromycin quantification in human blood plasma was shown. PMID- 26033868 TI - A portal into biology education: an annotated list of commonly encountered terms. PMID- 26033869 TI - A high-enrollment course-based undergraduate research experience improves student conceptions of scientific thinking and ability to interpret data. AB - We present an innovative course-based undergraduate research experience curriculum focused on the characterization of single point mutations in p53, a tumor suppressor gene that is mutated in more than 50% of human cancers. This course is required of all introductory biology students, so all biology majors engage in a research project as part of their training. Using a set of open-ended written prompts, we found that the course shifts student conceptions of what it means to think like a scientist from novice to more expert-like. Students at the end of the course identified experimental repetition, data analysis, and collaboration as important elements of thinking like a scientist. Course exams revealed that students showed gains in their ability to analyze and interpret data. These data indicate that this course-embedded research experience has a positive impact on the development of students' conceptions and practice of scientific thinking. PMID- 26033870 TI - Breaking the cycle: future faculty begin teaching with learner-centered strategies after professional development. AB - The availability of reliable evidence for teaching practices after professional development is limited across science, technology, engineering, and mathematics disciplines, making the identification of professional development "best practices" and effective models for change difficult. We aimed to determine the extent to which postdoctoral fellows (i.e., future biology faculty) believed in and implemented evidence-based pedagogies after completion of a 2-yr professional development program, Faculty Institutes for Reforming Science Teaching (FIRST IV). Postdocs (PDs) attended a 2-yr training program during which they completed self-report assessments of their beliefs about teaching and gains in pedagogical knowledge and experience, and they provided copies of class assessments and video recordings of their teaching. The PDs reported greater use of learner-centered compared with teacher-centered strategies. These data were consistent with the results of expert reviews of teaching videos. The majority of PDs (86%) received video ratings that documented active engagement of students and implementation of learner-centered classrooms. Despite practice of higher-level cognition in class sessions, the items used by the PDs on their assessments of learning focused on lower-level cognitive skills. We attributed the high success of the FIRST IV program to our focus on inexperienced teachers, an iterative process of teaching practice and reflection, and development of and teaching a full course. PMID- 26033871 TI - PORTAAL: A Classroom Observation Tool Assessing Evidence-Based Teaching Practices for Active Learning in Large Science, Technology, Engineering, and Mathematics Classes. AB - There is extensive evidence that active learning works better than a completely passive lecture. Despite this evidence, adoption of these evidence-based teaching practices remains low. In this paper, we offer one tool to help faculty members implement active learning. This tool identifies 21 readily implemented elements that have been shown to increase student outcomes related to achievement, logic development, or other relevant learning goals with college-age students. Thus, this tool both clarifies the research-supported elements of best practices for instructor implementation of active learning in the classroom setting and measures instructors' alignment with these practices. We describe how we reviewed the discipline-based education research literature to identify best practices in active learning for adult learners in the classroom and used these results to develop an observation tool (Practical Observation Rubric To Assess Active Learning, or PORTAAL) that documents the extent to which instructors incorporate these practices into their classrooms. We then use PORTAAL to explore the classroom practices of 25 introductory biology instructors who employ some form of active learning. Overall, PORTAAL documents how well aligned classrooms are with research-supported best practices for active learning and provides specific feedback and guidance to instructors to allow them to identify what they do well and what could be improved. PMID- 26033872 TI - Building national capacity for research mentor training: an evidence-based approach to training the trainers. AB - Research mentor training (RMT), based on the published Entering Mentoring curricula series, has been shown to improve the knowledge and skills of research mentors across career stages, as self-reported by both the mentors engaged in training and their mentees. To promote widespread dissemination and empower others to implement this evidence-based training at their home institutions, we developed an extensive, interactive, multifaceted train-the-trainer workshop. The specific goals of these workshops are to 1) increase facilitator knowledge of an RMT curriculum, 2) increase facilitator confidence in implementing the curriculum, 3) provide a safe environment to practice facilitation of curricular activities, and 4) review implementation strategies and evaluation tools. Data indicate that our approach results in high satisfaction and significant confidence gains among attendees. Of the 195 diverse attendees trained in our workshops since Fall 2010, 44% report implementation at 39 different institutions, collectively training more than 500 mentors. Further, mentors who participated in the RMT sessions led by our trained facilitators report high facilitator effectiveness in guiding discussion. Implications and challenges to building the national capacity needed for improved research mentoring relationships are discussed. PMID- 26033873 TI - Body temperature measurements in pigs during general anaesthesia. AB - The aim was to compare rectal, pharyngeal and oesophageal temperature measurements in anaesthetized pigs. Data were compared using the Bland-Altman method, and correlation coefficients and error measures were calculated. Sixty six sets of data were collected from 16 pigs weighing 16.2 +/- 4.2 kg. The bias (and 95% limit of agreement) for rectal and pharyngeal compared with oesophageal temperature were 0.69 (-1.18 to 2.57) C and 0.22 (-0.84 to 1.28) C, respectively. The correlation coefficients for rectal and pharyngeal compared with oesophageal temperature were 0.47 and 0.87, respectively. The absolute error for rectal and pharyngeal compared with oesophageal temperature was 0.7 +/- 0.9C and 0.2 +/- 0.5C, respectively. Pharyngeal temperature measurement may be more suitable than rectal temperature measurement for estimation of oesophageal temperature during general anaesthesia of pigs. PMID- 26033874 TI - Cell Sheet-Based Tissue Engineering for Organizing Anisotropic Tissue Constructs Produced Using Microfabricated Thermoresponsive Substrates. AB - In some native tissues, appropriate microstructures, including orientation of the cell/extracellular matrix, provide specific mechanical and biological functions. For example, skeletal muscle is made of oriented myofibers that is responsible for the mechanical function. Native artery and myocardial tissues are organized three-dimensionally by stacking sheet-like tissues of aligned cells. Therefore, to construct any kind of complex tissue, the microstructures of cells such as myotubes, smooth muscle cells, and cardiomyocytes also need to be organized three dimensionally just as in the native tissues of the body. Cell sheet-based tissue engineering allows the production of scaffold-free engineered tissues through a layer-by-layer construction technique. Recently, using microfabricated thermoresponsive substrates, aligned cells are being harvested as single continuous cell sheets. The cell sheets act as anisotropic tissue units to build three-dimensional tissue constructs with the appropriate anisotropy. This cell sheet-based technology is straightforward and has the potential to engineer a wide variety of complex tissues. In addition, due to the scaffold-free cell-dense environment, the physical and biological cell-cell interactions of these cell sheet constructs exhibit unique cell behaviors. These advantages will provide important clues to enable the production of well-organized tissues that closely mimic the structure and function of native tissues, required for the future of tissue engineering. PMID- 26033876 TI - MA-NOTMP: A Triazacyclononane Trimethylphosphinate Based Bifunctional Chelator for Gallium Radiolabelling of Biomolecules. AB - In the past few years, gallium-68 has demonstrated significant potential as a radioisotope for positron emission tomography (PET), and the optimization of chelators for gallium coordination is a major goal in the development of radiopharmaceuticals. Methylaminotriazacyclononane trimethylphosphinate (MA NOTMP), a new C-functionalized triazacyclononane derivative with phosphinate pendant arms, presents excellent coordination properties for (68) Ga (low ligand concentration, labelling at low pH even at room temperature). A "ready-to-be grafted" bifunctional chelating agent (p-NCS-Bz-MA-NOTMP) was prepared to allow (68) Ga labelling of sensitive biological vectors. Conjugation to a bombesin(7 14) derivative was performed, and preliminary in vitro experiments demonstrated the potential of MA-NOTMP in the development of radiopharmaceuticals. This new chelator is therefore of major interest for labelling sensitive biomolecules, and further in vivo experiments will soon be performed. PMID- 26033875 TI - Proteomics, biomarkers, and HIV-1: A current perspective. AB - Despite more than three decades of extensive research, HIV-1 infection although well controlled with cART, remains incurable. Multifactorial complexity of the viral life-cycle poses great challenges in understanding molecular mechanisms underlying this infection and the development of biomarkers, which we hope will lead us to its eradication. For a more in-depth understanding of how the virus interacts with host target cells, T cells and macrophages, proteomic profiling techniques that offer strategies to investigate the proteome in its entirety were employed. Here, we review proteomic studies related to HIV-1 infection and discuss perspectives and limitations of proteomic and systems biology approaches in future studies. PMID- 26033877 TI - Applying the intention-to-treat principle in practice: Guidance on handling randomisation errors. AB - BACKGROUND: The intention-to-treat principle states that all randomised participants should be analysed in their randomised group. The implications of this principle are widely discussed in relation to the analysis, but have received limited attention in the context of handling errors that occur during the randomisation process. The aims of this article are to (1) demonstrate the potential pitfalls of attempting to correct randomisation errors and (2) provide guidance on handling common randomisation errors when they are discovered that maintains the goals of the intention-to-treat principle. METHODS: The potential pitfalls of attempting to correct randomisation errors are demonstrated and guidance on handling common errors is provided, using examples from our own experiences. RESULTS: We illustrate the problems that can occur when attempts are made to correct randomisation errors and argue that documenting, rather than correcting these errors, is most consistent with the intention-to-treat principle. When a participant is randomised using incorrect baseline information, we recommend accepting the randomisation but recording the correct baseline data. If ineligible participants are inadvertently randomised, we advocate keeping them in the trial and collecting all relevant data but seeking clinical input to determine their appropriate course of management, unless they can be excluded in an objective and unbiased manner. When multiple randomisations are performed in error for the same participant, we suggest retaining the initial randomisation and either disregarding the second randomisation if only one set of data will be obtained for the participant, or retaining the second randomisation otherwise. When participants are issued the incorrect treatment at the time of randomisation, we propose documenting the treatment received and seeking clinical input regarding the ongoing treatment of the participant. CONCLUSION: Randomisation errors are almost inevitable and should be reported in trial publications. The intention-to-treat principle is useful for guiding responses to randomisation errors when they are discovered. PMID- 26033878 TI - Development and piloting of a decision aid for women considering participation in the Sentinel Node Biopsy versus Axillary Clearance 2 breast cancer trial. AB - BACKGROUND/AIMS: This study aimed to (1) develop a decision aid for women considering participation in the Sentinel Node Biopsy versus Axillary Clearance 2 (SNAC-2) breast cancer surgical trial and (2) obtain evidence on its acceptability, feasibility, and potential efficacy in routine trial clinical practice via a two-stage pilot. METHODS: The decision aid was developed according to International Patient Decision Aid Standards. Study 1: an initial pilot involved 25 members of the consumer advocacy group, Breast Cancer Network Australia. Study 2: the main pilot involved 20 women eligible to participate in the SNAC-2 trial in New Zealand. In both pilots, a questionnaire assessed: information and involvement preferences, decisional conflict, SNAC-2 trial related understanding and attitudes, psychological distress, and general decision aid feedback. A follow-up telephone interview elicited more detailed feedback on the decision aid design and content. RESULTS: In both pilots, participants indicated good subjective and objective understanding of SNAC-2 trial and reported low decisional conflict and anxiety. The decision aid was found helpful when deciding about trial participation and provided additional, useful information to the standard trial information sheet. CONCLUSION: The development and two-stage piloting process for this decision aid resulted in a resource that women found very acceptable and helpful in assisting decision-making about SNAC-2 trial participation. The process and findings provide a guide for developing other trial decision aids. PMID- 26033879 TI - Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing. AB - BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups. METHODS: The FA genes were analyzed using a next generation sequencing approach in two unrelated families. RESULTS: The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of function mutation with a severe phenotype characterized by multiple malformations. CONCLUSION: The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling. PMID- 26033880 TI - Microsphere-Incorporated Hybrid Thermogel for Neuronal Differentiation of Tonsil Derived Mesenchymal Stem Cells. AB - Neuronal differentiation of tonsil-derived mesenchymal stem cells (TMSCs) is investigated in a 3D hybrid system. The hybrid system is prepared by increasing the temperature of poly(ethylene glycol)-poly(l-alanine) aqueous solution to 37 degrees C through the heat-induced sol-to-gel transition, in which TMSCs and growth factor releasing microspheres are suspended. The in situ formed gel exhibits a modulus of 800 Pa at 37 degrees C, similar to that of brain tissue, and it is robust enough to hold the microspheres and cells during the 3D culture of TMSCs. The neuronal growth factors are released over 12-18 d, and the TMSCs in a spherical shape initially undergo multipolar elongation during the 3D culture. Significantly higher expressions of the neuronal biomarkers such as nuclear receptor related protein (Nurr-1), neuron specific enolase, microtubule associated protein-2, neurofilament-M, and glial fibrillary acidic protein are observed in both mRNA level and protein level in the hybrid systems than in the control experiments. This study proves the significance of a controlled drug delivery concept in tissue engineering or regenerative medicine, and a 3D hybrid system with controlled release of growth factors from microspheres in a thermogel can be a very promising tool. PMID- 26033881 TI - Development of an image pre-processor for operational hyperspectral laryngeal cancer detection. AB - Hyperspectral imaging (HSI) is a technology with high potential in the field of non-invasive detection of cancer. However, in complex imaging situations like HSI of the larynx with a rigid endoscope, various image interferences can disable a proper classification of cancerous tissue. We identified three main problems: i) misregistration of single images in a HS cube due to patient heartbeat ii) image noise and iii) specular reflections (SR). Consequently, an image pre-processor is developed in the current paper to overcome these image interferences. It encompasses i) image registration ii) noise removal by minimum noise fraction (MNF) transformation and iii) a novel SR detection method. The results reveal that the pre-processor improves classification performance, while the newly developed SR detection method outperforms global thresholding technique hitherto used by 46%. The novel pre-processor will be used for future studies towards the development of an operational scheme for HS-based larynx cancer detection. RGB image of the larynx derived from the hyperspectral cube and corresponding specular reflections (a) manually segmented and (b) detected by a novel specular reflection detection method. PMID- 26033882 TI - Design and validation of conditional ligands for HLA-B*08:01, HLA-B*15:01, HLA B*35:01, and HLA-B*44:05. AB - We designed conditional ligands restricted to HLA-B*08:01, -B*35:01, and -B*44:05 and proved the use of a conditional ligand previously designed for HLA-B*15:02 together with HLA-B*15:01. Furthermore, we compared the detection capabilities of specific HLA-B*15:01-restricted T cells using the HLA-B*15:01 and HLA-B*15:02 major histocompatibility complex (MHC) multimers and found remarkable differences in the staining patterns detected by flow cytometry. These new conditional ligands greatly add to the application of MHC-based technologies in the analyses of T-cell recognition as they represent frequently expressed HLA-B molecules. This expansion of conditional ligands is important to allow T-cell detection over a wide range of HLA restrictions, and provide comprehensive understanding of the T-cell recognition in a given context. PMID- 26033890 TI - Maternal occupational exposure to polycyclic aromatic hydrocarbons and craniosynostosis among offspring in the National Birth Defects Prevention Study. AB - BACKGROUND: Evidence in animal models and humans suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) may lead to birth defects. To our knowledge, this relationship has not been evaluated for craniosynostosis, a birth defect characterized by the premature closure of sutures in the skull. We conducted a case-control study to examine associations between maternal occupational exposure to PAHs and craniosynostosis. METHODS: We used data from craniosynostosis cases and control infants in the National Birth Defects Prevention Study (NBDPS) with estimated delivery dates from 1997 to 2002. Industrial hygienists reviewed occupational data from the computer-assisted telephone interview and assigned a yes/no rating of probable occupational PAH exposure for each job from 1 month before conception through delivery. We used logistic regression to assess the association between occupational exposure to PAHs and craniosynostosis. RESULTS: The prevalence of exposure was 5.3% in case mothers (16/300) and 3.7% in control mothers (107/2,886). We observed a positive association between exposure to PAHs during the 1 month before conception through the third month of pregnancy and craniosynostosis (odds ratio [OR] = 1.75; 95% confidence interval [CI], 1.01-3.05) after adjusting for maternal age and maternal education. The number of cases for each craniosynostosis subtype limited subtype analyses to sagittal craniosynostosis; the odds ratio remained similar (OR = 1.76, 95% CI, 0.82-3.75), but was not significant. CONCLUSION: Our findings support a moderate association between maternal occupational exposure to PAHs and craniosynostosis. Additional work is needed to better characterize susceptibility and the role PAHs may play on specific craniosynostosis subtypes. PMID- 26033891 TI - Physical profiling and IR spectroscopy: simple and effective methods to discriminate between genuine and counterfeit samples of Viagra(r) and Cialis(r). AB - Counterfeit medicines are a global threat to public health. High amounts enter the European market, enforcing the need for simple techniques to help customs detect these pharmaceuticals. This study focused on physical profiling and IR spectroscopy to obtain a prime discrimination between genuine and illegal Viagra(r) and Cialis(r) medicines. Five post-tableting characteristics were explored: colour, mass, long length, short length, and thickness. Hypothesis testing showed that most illegal samples (between 60 and 100%) significantly differ from the genuine medicines, in particular for mass and long length. Classification and Regression Trees (CART) analysis resulted in a good discrimination between genuine and illegal medicines (98.93% correct classification rate for Viagra(r), 99.42% for Cialis(r)). Moreover, CART confirmed the observation that mass and long length are the key physical characteristics which determine the observed discrimination. IR analysis was performed on tablets without blister and on tablets in intact blister. These data were analyzed using Soft Independent Modelling of Class Analogy (SIMCA) and Partial Least Squares - Discriminant Analysis (PLS-DA). Supervised techniques needed to be applied since Principal Component Analysis (PCA) was not able to generate the desired discrimination. Our study shows that a perfect discrimination between genuine and illegal medicines can be made by both SIMCA and PLS-DA without removing the tablets from the blister. This approach has the advantage of keeping the blister intact. Our study demonstrates that these user friendly techniques are reliable methods to aid customs to obtain a prime distinction between genuine and illegal samples on the spot. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26033892 TI - Neural Mechanisms of Temporal Resolution of Attention. AB - The dynamic nature of the world requires that our visual representations are continuously updated. These representations are more precise if there is a narrow time window over which information is averaged. We assess the neural processes of visual updating by testing patients with lesions including inferior parietal cortex, control patients and healthy adults on a continuous visual monitoring task. In Experiment 1, observers kept track of the changing spatial period of a luminance grating and identified the final spatial period after the stimulus disappeared. Healthy older adults and neurological controls were able to perform better than simulated guesses, but only 3 of 11 patients with damage including parietal cortex were able to reach performance that differed from simulated guesses. The effects were unrelated to lesion size. Poor performance on this task is consistent with an inability to selectively attend to the final moment at which the stimulus was seen. To investigate the temporal limits of attention, we varied the rate of stimulus change in Experiment 2. Performance remained poor for some patients even with slow 2.5 Hz change rates. The performance of 4 patients with parietal damage displayed poor temporal precision, namely recovery of performance with slower rates of change. PMID- 26033893 TI - Bringing light into the dark site of infection. PMID- 26033894 TI - 3 D Hierarchical Porous Carbon for Supercapacitors Prepared from Lignin through a Facile Template-Free Method. AB - Lignin-derived hierarchical porous carbon (LHPC) was prepared through a facile template-free method. Solidification of the lignin-KOH solution resulted in KOH crystalizing within lignin. The crystalized KOH particles in solid lignin acted both as template and activating agent in the heat-treatment process. The obtained LHPC, exhibiting a 3D network, consisted of macroporous cores, mesoporous channels, and micropores. The LHPC comprised 12.27 at % oxygen-containing groups, which resulted in pseudocapacitance. The LHPC displayed a capacitance of 165.0 F g(-1) in 1 M H2 SO4 at 0.05 A g(-1) , and the capacitance was still 123.5 F g(-1) even at 10 A g(-1) . The LHPC also displayed excellent cycling stability with capacitance retention of 97.3 % after 5000 galvanostatic charge-discharge cycles. On account of the facile preparation of LHPC, this paper offers a facile alternative method for the preparation of hierarchical porous carbon for electrochemical energy storage devices. PMID- 26033895 TI - Hyperbole as Harmful as Cocaine. PMID- 26033896 TI - Isolation and characterization of a newly identified impurity in methamphetamine synthesized via reductive amination of 1-phenyl-2-propanone (P2P) made from phenylacetic acid/lead (II) acetate. AB - A trace processing impurity found in certain methamphetamine exhibits was isolated and identified as trans-N-methyl-4-methyl-5-phenyl-4-penten-2-amine hydrochloride (1). It was determined that this impurity was produced via reductive amination of trans-4-methyl-5-phenyl-4-penten-2-one (4), which was one of a cluster of related ketones generated during the synthesis of 1-phenyl-2 propanone (P2P) from phenylacetic acid and lead (II) acetate. This two-step sequence resulted in methamphetamine containing elevated levels of 1. In contrast, methamphetamine produced from P2P made by other methods produced insignificant (ultra-trace or undetectable) amounts of 1. These results confirm that 1 is a synthetic marker compound for the phenylacetic acid and lead (II) acetate method. Analytical data for 1 and 4, and a postulated mechanism for the production of 4, are presented. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26033897 TI - Cardiac 123I-MIBG Imaging for Clinical Decision Making: 22-Year Experience in Japan. AB - Cardiac neuroimaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) has been officially used in clinical practice in Japan since 1992. The nuclear cardiology guidelines of the Japanese Circulation Society, revised in 2010, recommended cardiac (123)I-MIBG imaging for the management of heart failure (HF) patients, particularly for the assessment of HF severity and prognosis of HF patients. Consensus in North American and European countries regarding incorporation into clinical practice, however, has not been established yet. This article summarizes 22 y of clinical applications in Japan of (123)I-MIBG imaging in the field of cardiology; these applications are reflected in cardiology guidelines, including recent methodologic advances. A standardized cardiac (123)I-MIBG parameter, the heart-to-mediastinum ratio (HMR), is the basis for clinical decision making and enables common use of parameters beyond differences in institutions and studies. Several clinical studies unanimously demonstrated its potent independent roles in prognosis evaluation and risk stratification irrespective of HF etiologies. An HMR of less than 1.6-1.8 and an accelerated washout rate are recognized as high risk indicators of pump failure death, sudden cardiac death, and fatal arrhythmias and have independent and incremental prognostic values together with known clinical variables, such as left ventricular ejection fraction and brain natriuretic peptide. Another possible use of this imaging technique is the selection of therapeutic strategy, such as pharmacologic treatment and nonpharmacologic treatment with an implantable cardioverter-defibrillator or cardiac resynchronization device; however, this possibility remains to be investigated. Recent multiple-cohort database analyses definitively demonstrated that patients who were at low risk for lethal events and who were defined by an HMR of greater than 2.0 on (123)I-MIBG studies had a good long-term prognosis. Future investigations of cardiac (123)I-MIBG imaging will contribute to better risk stratification of low-risk and high-risk populations, to the establishment of cost-effective use of this imaging technique for the management of HF patients, and to worldwide acceptance of this imaging technique in clinical cardiology practice. PMID- 26033898 TI - Have imagers aptly or inadvertently overlooked the neuronal myocardial compartment? PMID- 26033899 TI - Neuronal dysfunction and medical therapy in heart failure: can an imaging biomarker help to "personalize" therapy? AB - (123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging is a tool for evaluating one of the fundamental pathophysiologic abnormalities seen in heart failure (HF), that of an upregulated sympathetic nervous system and its effect on the myocardium. Although this imaging technique offers information about prognosis for patients treated with contemporary guideline-based HF therapies and improves risk stratification, there are neither rigorous nor sufficient outcome data to suggest that this imaging tool can guide therapeutic decision making or better target subsets of patients with HF for particular therapies. PMID- 26033900 TI - 123I-MIBG SPECT for Evaluation of Patients with Heart Failure. AB - Heart failure (HF) is characterized by activation of the sympathetic cardiac nerves. The condition of cardiac sympathetic nerves can be evaluated by (123)I metaiodobenzylguanidine ((123)I-MIBG) imaging. Most cardiac (123)I-MIBG studies have relied on measurements from anterior planar images of the chest. However, it has become progressively more common to include SPECT imaging in clinical and research protocols. This review examines recent trends in (123)I-MIBG SPECT imaging and evidence that provides the basis for the increased use of the procedure in the clinical management of patients with HF. (123)I-MIBG SPECT has been shown to be complementary to planar imaging in patients with HF in studies of coronary artery disease after an acute myocardial infarction. Moreover, (123)I MIBG SPECT has been used in numerous studies to document regional denervation for arrhythmic event risk assessment. For better quantification of the size and severity of innervation abnormalities in (123)I-MIBG SPECT, programs and protocols specifically for (123)I have been developed. Also, the introduction of new solid-state cameras has created the potential for more rapid SPECT acquisitions or a reduction in radiopharmaceutical activity. Although PET imaging has superior quantitative capabilities, (123)I-MIBG SPECT is, for the foreseeable future, the only widely available nuclear imaging method for assessing regional myocardial sympathetic innervation. PMID- 26033901 TI - The role of echocardiography in heart failure. AB - Data from echocardiography provide a cornerstone in the management of heart failure. All imaging techniques can provide an ejection fraction, but the versatility of echocardiography makes it unique in the provision of volumes, diastolic function, right ventricular function, hemodynamics, and valvular regurgitation. The early detection of heart failure has been facilitated by the assessment of global longitudinal strain, which is also useful in later heart failure for the assessment of left ventricular synchrony. The use of echocardiography has been associated with favorable outcomes, probably on the basis of facilitation of appropriate therapy. This review examines the evidence provided by echocardiography and its application in specific settings. Although the guidelines emphasize that no single test satisfies all imaging requirements in heart failure, and other modalities can provide additional information about specific questions (especially tissue characterization), echocardiography is indispensable in the management of heart failure. PMID- 26033903 TI - Introduction to cardiac neuronal imaging: a clinical perspective. AB - Procedures for noninvasive and minimally invasive imaging of cardiac neurons and neuronal function using radiolabeled compounds were developed in the second half of the 20th century. The foundation for these procedures was several centuries of research that identified the structural components of the autonomic nervous system and explored the means by which neurotransmitters such as acetylcholine and norepinephrine contributed to neuronal control of target organ effector cells. This article provides a brief clinical overview of modern approaches to the assessment of cardiac neurons as an introduction to the in-depth articles on the current status of cardiac neuronal imaging presented in this supplement. PMID- 26033902 TI - Role of Cardiac MR Imaging in Cardiomyopathies. AB - Cardiac MR imaging has made major inroads in the new millennium in the diagnosis and assessment of prognosis for patients with cardiomyopathies. Imaging of left and right ventricular structure and function and tissue characterization with late gadolinium enhancement (LGE) as well as T1 and T2 mapping enable accurate diagnosis of the underlying etiology. In the setting of coronary artery disease, either transmurality of LGE or contractile reserve in response to dobutamine can assess the likelihood of recovery of function after revascularization. The presence of scar reduces the likelihood of a response to medical therapy and to cardiac resynchronization therapy in heart failure. The presence and extent of LGE relate to overall cardiovascular outcome in cardiomyopathies. A major role for cardiac MR imaging in cardiomyopathies is to identify myocardial scar for diagnostic and prognostic purposes. PMID- 26033904 TI - Cardiac CT Angiography in Congestive Heart Failure. AB - Cardiac CT angiography has become an important tool for the diagnosis and treatment of congestive heart failure. Differentiation of ischemic from nonischemic cardiomyopathy; evaluation of myocardial perfusion; characterization of hypertrophic cardiomyopathy, left ventricular noncompaction, and arrhythmogenic right ventricular dysplasia; and delineation of congenital heart defects and valvular abnormalities are the primary diagnostic applications. Therapeutic use includes visualization of the coronary venous anatomy for optimal implementation of cardiac resynchronization therapy and evaluation of left ventricular assist devices and transplant vasculopathy. PMID- 26033905 TI - Global and Regional Myocardial Innervation Before and After Ablation of Drug Refractory Ventricular Tachycardia Assessed with 123I-MIBG. AB - Cardiac innervation is a critical component of ventricular arrhythmogenesis that can be noninvasively assessed with (123)I-MIBG. However, the effect of ventricular tachycardia (VT) ablation on global and regional left ventricular sympathetic innervation and clinical outcomes has not been previously assessed. METHODS: In this prospective, single-center feasibility study, 13 patients with cardiomyopathy (n = 9 ischemic, n = 4 nonischemic) who were scheduled to undergo ablation of drug-refractory VT underwent 15-min and 4-h (123)I-MIBG scans before and 6 mo after the ablation procedure. Planar and arrhythmia-specific 757-segment analysis of short-axis SPECT images was performed in all datasets. RESULTS: Global innervation assessed with heart-to-mediastinal ratio and washout rates was preserved in all patients at baseline (1.8 [continuous variables are expressed as median and quartile: Q1-Q3, 1.7-2.4] and 54% [Q1-Q3, 47%-67%]) and did not change significantly at the 6-mo follow-up (1.9 [Q1-Q3, 1.6-2.2], P = 0.9; and 56% [Q1 Q3, 41%-62%], P = 0.6). However, segmental analysis demonstrated that ischemic patients had larger areas of abnormal innervation at baseline (52.1% vs. 19.6%, P = 0.011) and at the 6-mo follow-up (56.7% vs. 27.5%, P = 0.011) than the nonischemic patients. Innervation defects affected 40% of the inferior segments in all ischemic cardiomyopathy patients, whereas they affected only 10% of inferior segments in 75% of nonischemic patients. When segmental data were further analyzed in denervated (DZ), transition (TZ), and normal (NZ) zones, there were changes in these designated innervation categories from baseline to the 6-mo follow-up for ischemic (19% DZ, 59% TZ, 22% NZ) and nonischemic (6% DZ, 45% TZ, 15% NZ) patients. In ischemic patients, relative changes were significantly greater in the TZ segments than in the DZ, which demonstrated the second highest proportional changes (P = 0.028). Receiver operating characteristic curves defined best cutoffs of DZ, TZ, and NZ as less than 30.5%, 30.6%-47.1%, and more than 47.1%, respectively. CONCLUSION: Patients with ischemic cardiomyopathy have larger areas of abnormal innervation than those with nonischemic cardiomyopathy. Although VT ablation did not change global innervation, a novel arrhythmia-specific segmental analysis demonstrated significant dynamic changes in innervation categories and allowed quantitative definitions of DZ, TZ, and NZ. These findings provide novel insights into the mechanics of sympathetic innervation in patients undergoing VT ablation and may have diagnostic and therapeutic implications. PMID- 26033906 TI - An electrophysiologist perspective on risk stratification in heart failure: can better understanding of the condition of the cardiac sympathetic nervous system help? AB - Heart failure is often complicated by arrhythmias that can adversely affect the quality of life and increase the risk for sudden cardiac death. Current risk stratification strategies for sudden cardiac death in the heart failure patient are not ideal, with much potential for further refinement. Overactivation of the sympathetic nervous system has been shown to be associated with worsening heart failure as well as arrhythmic events. Recent advances in our understanding of the autonomic nervous system and new methods for quantification of the pathologic activation of the sympathetic nerves have triggered increasing interest in this field. This viewpoint focuses on the need for and challenges of risk stratification of sudden death in the heart failure patient and discusses the potential value of measuring sympathetic nervous system activity to better stratify risk and to select patients with heart failure for implantable cardioverter defibrillator therapy. PMID- 26033907 TI - Chemistry and biology of radiotracers that target changes in sympathetic and parasympathetic nervous systems in heart disease. AB - Following the discovery of the sympathetic and parasympathetic nervous system, numerous adrenoceptor drugs were radiolabeled and potent radioligands were prepared in order to image the beta-adrenergic and the muscarinic systems. But the greatest effort has been in preparing noradrenaline analogs, such as norepinephrine, (11)C-metahydroxyephedrine, and (123)I-metaiodobenzylguanidine that measure cardiac sympathetic nerve varicosities. Given the technical and clinical challenges in designing and validating targeted adrenoceptor-binding radiotracers, namely the heavily weighted flow dependence and relatively low target-to-background ratio, both requiring complicated mathematic analysis, and the inability of targeted adrenoceptor radioligands to have an impact on clinical care of heart disease, the emphasis has been on radioligands monitoring the norepinephrine pathway. The chemistry and biology of such radiotracers, and the clinical and prognostic impact of these innervation imaging studies in patients with heart disease, are examined. PMID- 26033915 TI - Continuous removal of endocrine disruptors by versatile peroxidase using a two stage system. AB - The oxidant Mn(3+) -malonate, generated by the ligninolytic enzyme versatile peroxidase in a two-stage system, was used for the continuous removal of endocrine disrupting compounds (EDCs) from synthetic and real wastewaters. One plasticizer (bisphenol-A), one bactericide (triclosan) and three estrogenic compounds (estrone, 17beta-estradiol, and 17alpha-ethinylestradiol) were removed from wastewater at degradation rates in the range of 28-58 ug/L.min, with low enzyme inactivation. First, the optimization of three main parameters affecting the generation of Mn(3+) -malonate (hydraulic retention time as well as Na malonate and H2 O2 feeding rates) was conducted following a response surface methodology (RSM). Under optimal conditions, the degradation of the EDCs was proven at high (1.3-8.8 mg/L) and environmental (1.2-6.1 ug/L) concentrations. Finally, when the two-stage system was compared with a conventional enzymatic membrane reactor (EMR) using the same enzyme, a 14-fold increase of the removal efficiency was observed. At the same time, operational problems found during EDCs removal in the EMR system (e.g., clogging of the membrane and enzyme inactivation) were avoided by physically separating the stages of complex formation and pollutant oxidation, allowing the system to be operated for a longer period (~8 h). This study demonstrates the feasibility of the two-stage enzymatic system for removing EDCs both at high and environmental concentrations. PMID- 26033914 TI - Quantitative proteomics reveals differential regulation of protein expression in recipient myocardium after trilineage cardiovascular cell transplantation. AB - Intramyocardial transplantation of cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs) derived from human induced pluripotent stem cells (hiPSCs) has beneficial effects on the post-infarction heart. However, the mechanisms underlying the functional improvements remain undefined. We employed large-scale label-free quantitative proteomics to identify proteins that were differentially regulated following cellular transplantation in a swine model of myocardial infarction (MI). We identified 22 proteins that were significantly up regulated after trilineage cell transplantation compared to both MI and Sham groups. Among them, 12 proteins, including adenylyl cyclase-associated protein 1 and tropomodulin-1, are associated with positive regulation of muscular contraction whereas 11 proteins, such as desmoplakin and zyxin, are involved in embryonic and muscular development and regeneration. Moreover, we identified 21 proteins up-regulated and another 21 down-regulated in MI, but reversed after trilineage cell transplantation. Proteins up-regulated after MI but reversed by transplantation are related to fibrosis and apoptosis. Conversely, proteins down regulated in MI but restored after cell therapy are regulators of protein nitrosylation. Our results show that the functionally beneficial effects of trilineage cell therapy are accompanied by differential regulation of protein expression in the recipient myocardium, which may contribute to the improved cardiac function. PMID- 26033916 TI - Performance and sensitivity evaluation of 3D spot detection methods in confocal microscopy. AB - Reliable 3D detection of diffraction-limited spots in fluorescence microscopy images is an important task in subcellular observation. Generally, fluorescence microscopy images are heavily degraded by noise and non-specifically stained background, making reliable detection a challenging task. In this work, we have studied the performance and parameter sensitivity of eight recent methods for 3D spot detection. The study is based on both 3D synthetic image data and 3D real confocal microscopy images. The synthetic images were generated using a simulator modeling the complete imaging setup, including the optical path as well as the image acquisition process. We studied the detection performance and parameter sensitivity under different noise levels and under the influence of uneven background signal. To evaluate the parameter sensitivity, we propose a novel measure based on the gradient magnitude of the F1 score. We measured the success rate of the individual methods for different types of the image data and found that the type of image degradation is an important factor. Using the F1 score and the newly proposed sensitivity measure, we found that the parameter sensitivity is not necessarily proportional to the success rate of a method. This also provided an explanation why the best performing method for synthetic data was outperformed by other methods when applied to the real microscopy images. On the basis of the results obtained, we conclude with the recommendation of the HDome method for data with relatively low variations in quality, or the Sorokin method for image sets in which the quality varies more. We also provide alternative recommendations for high-quality images, and for situations in which detailed parameter tuning might be deemed expensive. PMID- 26033917 TI - Hydrogen Storage Materials for Mobile and Stationary Applications: Current State of the Art. AB - One of the limitations to the widespread use of hydrogen as an energy carrier is its storage in a safe and compact form. Herein, recent developments in effective high-capacity hydrogen storage materials are reviewed, with a special emphasis on light compounds, including those based on organic porous structures, boron, nitrogen, and aluminum. These elements and their related compounds hold the promise of high, reversible, and practical hydrogen storage capacity for mobile applications, including vehicles and portable power equipment, but also for the large scale and distributed storage of energy for stationary applications. Current understanding of the fundamental principles that govern the interaction of hydrogen with these light compounds is summarized, as well as basic strategies to meet practical targets of hydrogen uptake and release. The limitation of these strategies and current understanding is also discussed and new directions proposed. PMID- 26033919 TI - Reproductive and Developmental Toxicity of Orally Administered Botanical Composition, UP446-Part II: Effects on Prenatal and Postnatal Development, Including Maternal Function in Sprague-Dawley Rats. AB - Almost all herbal remedies could be therapeutic at one dose and toxic at another. These facts become more troubling and a double threat when uncharacterized medicinal herbs are blended together and used by expectant mothers as a supplement to conventional pregnancy management with an inherent belief of considering herbal remedies as harmless. Here we describe the potential adverse effects of UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, on the maternal and their first filial generation (F1) developmental and functional toxicity following exposure at doses of 250, 500, and 1000 mg/kg/day. Maternal gestation, viability index, sex ratio, body weight, and food consumption were evaluated. F1 growth and development, sexual function including mating index, fertility, implantation, and embryo mortality were also assessed. Test substance impacts on the maternal (F0) or F1 reproductive parameters were very minimal. There were no statistically significant differences in implantation, parturition, viability, and neonates' sex ratios. There were no significant changes in maturation, behavioral, or functional developments between groups. No treatment-related prenatal or postnatal in-life or necropsy abnormalities were observed. Therefore, the no observed adverse effect level in the prenatal and postnatal developments, including maternal function study was considered to be greater than 1000 mg/kg. PMID- 26033920 TI - Direct observation of tropomyosin binding to actin filaments. AB - Tropomyosin is an elongated alpha-helical coiled coil that binds to seven consecutive actin subunits along the long-pitch helix of actin filaments. Once bound, tropomyosin polymerizes end-to-end and both stabilizes F-actin and regulates access of various actin-binding proteins including myosin in muscle and nonmuscle cells. Single tropomyosin molecules bind weakly to F-actin with millimolar Kd , whereas the end-to-end linked tropomyosin associates with about a 1000-fold greater affinity. Despite years of study, the assembly mechanism of tropomyosin onto actin filaments remains unclear. In this study, we used total internal reflection fluorescence microscopy to directly monitor the cooperative binding of fluorescently labeled tropomyosin molecules to phalloidin-stabilized actin filaments. We find that tropomyosin molecules assemble from multiple growth sites after random low-affinity binding of single molecules to actin. As the length of the tropomyosin chain increases, the probability of detachment decreases, which leads to further chain growth. Tropomyosin chain extension is linearly dependent on the concentration of tropomyosin, occurring at approximately 100 monomers/(MUM*s). The random tropomyosin binding to F-actin leads to discontinuous end-to-end association where gaps in the chain continuity smaller than the required seven sequential actin monomers are available. Direct observation of tropomyosin detachment revealed the number of gaps in actin-bound tropomyosin, the time course of gap annealing, and the eventual filament saturation process. PMID- 26033921 TI - The Development of a Continuous Intravascular Glucose Monitoring Sensor. AB - BACKGROUND: Glycemic control in hospital intensive care units (ICU) has been the subject of numerous research publications and debate over the past 2 decades. There have been multiple studies showing the benefit of ICU glucose control in reducing both morbidity and mortality. GlySure Ltd has developed a glucose monitor based on a diboronic acid receptor that can continuously measure plasma glucose concentrations directly in a patient's vascular system. The goal of this study was to validate the performance of the GlySure CIGM system in different patient populations. METHODS: The GlySure Continuous Intravascular Glucose Monitoring (CIGM) System was evaluated in both the Cardiac ICU (33 patients) and MICU setting (14 patients). The sensor was placed through a custom CVC and measured the patients' blood glucose concentration every 15 seconds. Comparison blood samples were taken at 2 hourly then 4 hourly intervals and measured on a YSI 2300 STAT Plus or an i-STAT. RESULTS: Consensus error grid analysis of the data shows that the majority of the data (88.2% Cardiac, and 95.0% MICU) fell within zone A, which is considered to be clinically accurate and all data points fell within zones A and B. The MARD of the Cardiac trial was 9.90% and the MICU trial had a MARD of 7.95%. Data analysis showed no significant differences between data generated from Cardiac and MICU patients or by time or glucose concentration. CONCLUSIONS: The GlySure CIGM System has met the design challenges of measuring intravascular glucose concentrations in critically ill patients with acceptable safety and performance criteria and without disrupting current clinical practice. The accuracy of the data is not affected by the patients' condition. PMID- 26033923 TI - HPLC-Q-TOF-MS/MS Analysis of the Constituents in the Rat Biological Fluids After Oral Administration of Qing Ru Xiao granules. AB - A high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry method was established to detect as many constituents in rat biological fluids as possible after oral administration of Qing Ru Xiao granules (QRX). An Agilent Poroshell 120 EC-C18 column was adopted to separate the sample constituents, and mass spectra were acquired in positive and negative ion modes. First, the fingerprints of QRX were established, resulting in 28 components being detected within 30 min. Among these compounds, 11 were tentatively identified by comparing the retention times and mass spectral data with those of reference standards and the reference literature; the other 17 components were tentatively assigned solely based on the mass spectrometry data. Furthermore, metabolites in rat plasma and urine after oral administration of QRX were also analyzed. A total of 15 compounds were identified, including 13 prototypes and 2 metabolites through metabolic pathways of oxidation. This is the first systematic study on the metabolic profiling of QRX. PMID- 26033922 TI - Multicenter Observational Study of the First-Generation Intravenous Blood Glucose Monitoring System in Hospitalized Patients. AB - BACKGROUND: Current methods of blood glucose (BG) monitoring and insulin delivery are labor intensive and commonly fail to achieve the desired level of BG control. There is great clinical need in the hospital for a user-friendly bedside device that can automatically monitor the concentration of BG safely, accurately, frequently, and reliably. METHODS: A 100-patient observation study was conducted at 6 US hospitals to evaluate the first generation of the Intravenous Blood Glucose (IVBG) System (Edwards Lifesciences LLC & Dexcom Inc). Device safety, accuracy, and reliability were assessed. A research nurse sampled blood from a vascular catheter every 4 hours for <= 72 hours and BG concentration was measured using the YSI 2300 STAT Plus Analyzer (YSI Life Sciences). The IVBG measurements were compared to YSI measurements to calculate point accuracy. RESULTS: The IVBG systems logged more than 5500 hours of operation in 100 critical care patients without causing infection or inflammation of a vein. A total of 44135 IVBG measurements were performed in 100 patients with 30231 measurements from the subset of 75 patients used for accuracy analysis. In all, 996 IVBG measurements were time-matched with reference YSI measurements. These pairs had a mean absolute difference (MAD) of 11.61 mg/dl, a mean absolute relative difference (MARD) of 8.23%, 93% met 15/20% accuracy defined by International Organization for Standardization 15197:2003 standard, and 93.2% were in zone A of the Clarke error grid. The IVBG sensors were exposed to more than 200 different medications with no observable effect on accuracy. CONCLUSIONS: The IVBG system is an automated and user-friendly glucose monitoring system that provides accurate and frequent BG measurements with great potential to improve the safety and efficacy of insulin therapy and BG control in the hospital, potentially leading to improved clinical outcomes. PMID- 26033924 TI - Ebola in Antiquity? AB - This article addresses whether Ebola may have been present in an urban setting in Athens in 430 bce and explores the historical importance of the ancient outbreak. New knowledge from today's West African epidemic allows a more accurate assessment of whether Ebola may have caused the Athenian outbreak than was once possible. The Athenian disease, whose etiology remains unknown, developed abruptly with fevers, abdominal pain, vomiting, diarrhea, dehydration, and hemorrhage. It originated in sub-Saharan Africa and was especially contagious to doctors and caregivers. No remedies were effective. But the few survivors who were reexposed to diseased patients were not attacked a second time, suggesting protective immunity. What lessons can we learn from the ancient outbreak that bears a clinical and epidemiologic resemblance to Ebola? The historian Thucydides, an eyewitness and disease sufferer, described how the unsuspecting city panicked as it struggled to handle the rapidly spreading, devastating disease. Moreover, he stressed a theme that has relevance today-namely, that fear and panic intensified the disruption of society and damage to the individual that was directly caused by the disease. Moreover, fear amplified the spread of disease. The destructive nature of fear has remained a signature feature of pestilences that have subsequently caught ill-prepared societies off-guard Bubonic plague in medieval times, AIDS in the 1980s, and Ebola today. The ancient Athenian epidemic is relevant for today's West African Ebola outbreak because it shows how fear and panic can endanger the individual, our society, and our efforts to handle the disease. PMID- 26033925 TI - Dexamethasone-Conjugated Polyamidoamine Dendrimer for Delivery of the Heme Oxygenase-1 Gene into the Ischemic Brain. AB - Heme oxygenase-1 (HO-1) has anti-apoptotic and anti-inflammatory effects. In this study, the HO-1 gene was delivered into the brain using dexamethasone-conjugated polyamidoamine generation 2 (PAMAM G2-Dexa) for the treatment of ischemic stroke. PAMAM G2-Dexa formed stable complexes with plasmid DNA (pDNA). The pDNA delivery efficiency of PAMAM G2-Dexa was higher than that of polyethylenimine (PEI25k, 25 kDa), dexamethasone-conjugated PEI (PEI-Dexa), and PAMAM G2 in Neuro2A cells. Therapeutic effect of PAMAM G2-Dexa/pHO-1 complexes was evaluated in a stroke animal model. PAMAM G2-Dexa delivered pHO-1 more efficiently into the ischemic brain than PEI25k and PEI-Dexa with higher therapeutic effect. Therefore, PAMAM G2-Dexa/pHO-1 complexes may be useful for ischemic stroke gene therapy. PMID- 26033926 TI - Random mutagenesis and selection of organic solvent-stable haloperoxidase from Streptomyces aureofaciens. AB - Haloperoxidases are useful oxygenases involved in halogenation of a range of water-insoluble organic compounds and can be used without additional high-cost cofactors. In particular, organic solvent-stable haloperoxidases are desirable for enzymatic halogenations in the presence of organic solvents. In this study, we adopted a directed evolution approach by error-prone polymerase chain reaction to improve the organic solvent-stability of the homodimeric BPO-A1 haloperoxidase from Streptomyces aureofaciens. Among 1,000 mutant BPO-A1 haloperoxidases, an organic solvent-stable mutant OST48 with P123L and P241A mutations and a high active mutant OST959 with H53Y and G162R mutations were selected. The residual activity of mutant OST48 after incubation in 40% (v/v) 1-propanol for 1 h was 1.8 fold higher than that of wild-type BPO-A1. In addition, the OST48 mutant showed higher stability in methanol, ethanol, dimethyl sulfoxide, and N,N dimethylformamide than wild-type BPO-A1 haloperoxidase. Moreover, after incubation at 80 degrees C for 1 h, the residual activity of mutant OST959 was 4.6-fold higher than that of wild-type BPO-A1. Based on the evaluation of single amino acid-substituted mutant models, stabilization of the hydrophobic core derived from P123L mutation and increased numbers of hydrogen bonds derived from G162R mutation led to higher organic solvent-stability and thermostability, respectively. PMID- 26033927 TI - Recycled Poly(vinyl alcohol) Sponge for Carbon Encapsulation of Size-Tunable Tin Dioxide Nanocrystalline Composites. AB - The recycling of industrial materials could reduce their environmental impact and waste haulage fees and result in sustainable manufacturing. In this work, commercial poly(vinyl alcohol) (PVA) sponges are recycled into a macroporous carbon matrix to encapsulate size-tunable SnO2 nanocrystals as anode materials for lithium-ion batteries (LIBs) through a scalable, flash-combustion method. The hydroxyl groups present copiously in the recycled PVA sponges guarantee a uniform chemical coupling with a tin(IV) citrate complex through intermolecular hydrogen bonds. Then, a scalable, ultrafast combustion process (30 s) carbonizes the PVA sponge into a 3D carbon matrix. This PVA-sponge-derived carbon could not only buffer the volume fluctuations upon the Li-Sn alloying and dealloying processes but also afford a mixed conductive network, that is, a continuous carbon framework for electrical transport and macropores for facile electrolyte percolation. The best-performing electrode based on this composite delivers a rate performance up to 9.72 C (4 A g(-1) ) and long-term cyclability (500 cycles) for Li(+) ion storage. Moreover, cyclic voltammograms demonstrate the coexistence of alloying and dealloying processes and non-diffusion-controlled pseudocapacitive behavior, which collectively contribute to the high-rate Li(+) ion storage. PMID- 26033928 TI - Quantitation of yeast cell-cell fusion using multicolor flow cytometry. AB - Mating of haploid Saccharomyces cerevisiae cells of opposite sex provides a powerful model system to study the cell-cell fusion. However, a rapid and standardized method is much needed for quantitative assessment of fusion efficiency. The gold standard method relies on counting mating pairs in fluorescence microscopy images. This current method is limited by expectancy bias and it is time consuming, restricting the number of both cell-cell fusion events and strains that can be analyzed at once. Automatic approaches present a solution to these limitations. Here, we describe a novel flow cytometric approach that is able to quickly both identify mating pairs within a mixture of gametes and quantify cell fusion efficiency. This method is based on staining the cell wall of yeast populations with different Concanavalin A-fluorophore conjugates. The mating subpopulation is identified as the two-colored events set and fused and unfused mating pairs are subsequently discriminated by green fluorescent protein bimolecular complementation. A series of experiments was conducted to validate a simple and reliable protocol. Mating efficiency in each sample was determined by flow cytometry and compared with the one obtained with the current gold standard technique. The results show that mating pair counts using both methods produce indistinguishable outcomes and that the flow cytometry-based method provides quantitative relevant information in a short time, making possible to quickly analyze many different cell populations. In conclusion, our data show multicolor flow cytometry-based fusion quantitation to be a fast, robust, and reliable method to quantify the cell-cell fusion in yeast. PMID- 26033930 TI - Reply to: Radiation dose reduction thanks to split-bolus multi-1 detector computer tomography (MDCT) in children with non-thoracic neuroblastoma. PMID- 26033931 TI - Differences in risk factors for recurrent versus incident preterm delivery. AB - Risk factors for preterm delivery have been described, but whether risk factors differ in the context of prior preterm delivery history is less understood. We assessed whether known risk factors were different in women with versus without prior preterm delivery using medical records of the first and second singleton deliveries in 25,820 Utah women (2002-2010). Longitudinal transition models with modified Poisson regression calculated adjusted relative risks and 95% confidence intervals, with multiplicative interactions between each preterm risk factor and prior preterm delivery status to explore whether risk factors varied between incident and recurrent preterm delivery at <37 weeks. Fewer second pregnancy factors were associated with recurrent preterm delivery, including alcohol, thyroid disease, and depression. Smoking was associated with increased risk for incident (relative risk (RR) = 1.95, 95% confidence interval (CI): 1.53, 2.49) but not recurrent (RR = 1.09, 95% CI: 0.71, 1.19) preterm delivery, whereas alcohol was associated with an increased risk for recurrent (RR = 2.38, 95% CI: 1.53, 3.71) but not incident (RR = 0.98, 95% CI: 0.67, 1.43; Pinteraction = 0.02 and <0.01) preterm delivery, respectively. Prior term delivery did not necessarily confer protection from known second pregnancy preterm delivery risk factors. In the setting of a prior preterm delivery, many risk factors did not persist. Prior preterm delivery history is important when assessing subsequent preterm delivery risk factors. PMID- 26033932 TI - "Clustering by interviewer": a source of variance that is unaccounted for in single-stage health surveys. AB - Although the impact of interviewers on survey measurement has been studied for more than 85 years, such impacts are rarely considered in the analysis of health surveys. This issue is particularly important with single-stage surveys such as that used in the Behavioral Risk Factor Surveillance System (BRFSS), where there are no sampling clusters in which interviewer effects could be captured. The BRFSS involves an ongoing telephone survey of the health behaviors of US adults and was established in 1984 by the Centers for Disease Control and Prevention. Public-use BRFSS data files are widely used by epidemiologists and public health researchers to describe the health behaviors of adults in the United States. Since its onset, the BRFSS has provided identification codes for telephone interviewers completing BRFSS interviews in its public-use data files; however, a review of BRFSS publications shows no evidence that these codes have been used in estimating standard errors. In this paper we analyze data from the 2012 BRFSS, illustrate both design-based and model-based approaches to incorporating interviewer effects in variance estimation, and find evidence of substantial interviewer effects for 5 key estimates across states. These results suggest that BRFSS analysts should consider accounting for interviewer effects, and we provide example code enabling analysts to do so. We conclude with suggestions regarding possible directions for future research. PMID- 26033933 TI - Substantial Differentiation of Human Neural Stem Cells Into Motor Neurons on a Biomimetic Polyurea. AB - To find the first restorative treatment for spinal cord injury (SCI), researchers have focused on stem cell therapies. However, one obstacle is the lack of an implantable cell scaffold that can support efficient motor neuron (MN) differentiation and proliferation. We aimed to overcome this through the use of an RGD functionalized novel biomimetic polyurea, optimized to encourage efficient differentiation of MNs. Images taken after 14-days showed increased differentiation (~40%) of hNSCs into MNs as well as increased cell count on the biomimetic polymer compared to PDL-Laminin coating, indicating that the RGD polyurea provides a favorable microenvironment for hNSC survival, having promising implications for future SCI therapies. PMID- 26033934 TI - Poly-gamma-glutamic acid produced from Bacillus licheniformis CGMCC 2876 as a potential substitute for polyacrylamide in the sugarcane industry. AB - As an environmentally friendly and industrially useful biopolymer, poly-gamma glutamic acid (gamma-PGA) from Bacillus licheniformis CGMCC 2876 was characterized by the high-resolution mass spectrometry and (1)H NMR. A flocculating activity of 11,474.47 U mL(-1) obtained with gamma-PGA, and the effects of carbon sources, ions, and chemical properties (D-/L-composition and molecular weight) on the production and flocculating activity of gamma-PGA were discussed. Being a bioflocculant in the sugar refinery process, the color and turbidity of the sugarcane juice was IU 1,877.36 and IU 341.41 with 0.8 ppm of gamma-PGA, respectively, which was as good as the most widely used chemically synthesized flocculant in the sugarcane industry--polyacrylamide with 1 ppm. The gamma-PGA produced from B. licheniformis CGMCC 2876 could be a promising alternate of chemically synthesized flocculants in the sugarcane industry. PMID- 26033935 TI - Effects of heat stimulation and l-ascorbic acid 2-phosphate supplementation on myogenic differentiation of artificial skeletal muscle tissue constructs. AB - Although skeletal muscle tissue engineering has been extensively studied, the physical forces produced by tissue-engineered skeletal muscles remain to be improved for potential clinical utility. In this study, we examined the effects of mild heat stimulation and supplementation of a l-ascorbic acid derivative, l ascorbic acid 2-phosphate (AscP), on myoblast differentiation and physical force generation of tissue-engineered skeletal muscles. Compared with control cultures at 37 degrees C, mouse C2C12 myoblast cells cultured at 39 degrees C enhanced myotube diameter (skeletal muscle hypertrophy), whereas mild heat stimulation did not promote myotube formation (differentiation rate). Conversely, AscP supplementation resulted in an increased differentiation rate but did not induce skeletal muscle hypertrophy. Following combined treatment with mild heat stimulation and AscP supplementation, both skeletal muscle hypertrophy and differentiation rate were enhanced. Moreover, the active tension produced by the tissue-engineered skeletal muscles was improved following combined treatment. These findings indicate that tissue culture using mild heat stimulation and AscP supplementation is a promising approach to enhance the function of tissue engineered skeletal muscles. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26033936 TI - Glycosaminoglycans affect heparanase location in CHO cell lines. AB - Glycosaminoglycans (GAG) play a ubiquitous role in tissues and cells. In eukaryotic cells, heparan sulfate (HS) is initially degraded by an endo-beta glucuronidase called heparanase-1 (HPSE). HS oligosaccharides generated by the action of HPSE intensify the activity of signaling molecules, activating inflammatory response, tumor metastasis, and angiogenesis. The aim of the present study was to understand if sulfated GAG could modulate HPSE, since the mechanisms that regulate HPSE have not been completely defined. CHO-K1 cells were treated with 4-methylumbelliferone (4-MU) and sodium chlorate, to promote total inhibition of GAG synthesis, and reduce the sulfation pattern, respectively. The GAG profile of the wild CHO-K1 cells and CHO-745, deficient in xylosyltransferase, was determined after [(35)S]-sulfate labeling. HPSE expression was determined via real-time quantitative polymerase chain reaction. Total ablation of GAG with 4-MU in CHO-K1 inhibited HPSE expression, while the lack of sulfation had no effect. Interestingly, 4-MU had no effect in CHO-745 cells for these assays. In addition, a different enzyme location was observed in CHO-K1 wild-type cells, which presents HPSE mainly in the extracellular matrix, in comparison with the CHO-745 mutant cells, which is found in the cytoplasm. In view of our results, we can conclude that GAG are essential modulators of HPSE expression and location. Therefore, GAG profile could impact cell behavior mediated by the regulation of HPSE. PMID- 26033937 TI - Globally profiling sialylation status of macrophages upon statin treatment. AB - Sialic acids (SAs) are widely expressed on immune cells and their levels and linkages named as sialylation status vary upon cellular environment changes related to both physiological and pathological processes. In this study, we performed a global profiling of the sialylation status of macrophages and their release of SAs in the cell culture medium by using flow cytometry, confocal microscopy and liquid chromatography tandem mass spectrometry (LC-MS/MS). Both flow cytometry and confocal microscopy results showed that cell surface alpha-2,3 linked SAs were predominant in the normal culture condition and changed slightly upon treatment with atorvastatin for 24 h, whereas alpha-2,6-linked SAs were negligible in the normal culture condition but significantly increased after treatment. Meanwhile, the amount of total cellular SAs increased about three times (from 369 +/- 29 to 1080 +/- 50 ng/mL) upon treatment as determined by the LC-MS/MS method. On the other hand, there was no significant change for secreted free SAs and conjugated SAs in the medium. These results indicated that the cell surface alpha-2,6 sialylation status of macrophages changes distinctly upon atorvastatin stimulation, which may reflect on the biological functions of the cells. PMID- 26033938 TI - Antibody recognition of carbohydrate epitopes?. AB - Carbohydrate antigens are valuable as components of vaccines for bacterial infectious agents and human immunodeficiency virus (HIV), and for generating immunotherapeutics against cancer. The crystal structures of anti-carbohydrate antibodies in complex with antigen reveal the key features of antigen recognition and provide information that can guide the design of vaccines, particularly synthetic ones. This review summarizes structural features of anti-carbohydrate antibodies to over 20 antigens, based on six categories of glyco-antigen: (i) the glycan shield of HIV glycoproteins; (ii) tumor epitopes; (iii) glycolipids and blood group A antigen; (iv) internal epitopes of bacterial lipopolysaccharides; (v) terminal epitopes on polysaccharides and oligosaccharides, including a group of antibodies to Kdo-containing Chlamydia epitopes; and (vi) linear homopolysaccharides. PMID- 26033940 TI - Correction. PMID- 26033929 TI - Emerging roles of sumoylation in the regulation of actin, microtubules, intermediate filaments, and septins. AB - Sumoylation is a powerful regulatory system that controls many of the critical processes in the cell, including DNA repair, transcriptional regulation, nuclear transport, and DNA replication. Recently, new functions for SUMO have begun to emerge. SUMO is covalently attached to components of each of the four major cytoskeletal networks, including microtubule-associated proteins, septins, and intermediate filaments, in addition to nuclear actin and actin-regulatory proteins. However, knowledge of the mechanisms by which this signal transduction system controls the cytoskeleton is still in its infancy. One story that is beginning to unfold is that SUMO may regulate the microtubule motor protein dynein by modification of its adaptor Lis1. In other instances, cytoskeletal elements can both bind to SUMO non-covalently and also be conjugated by it. The molecular mechanisms for many of these new functions are not yet clear, but are under active investigation. One emerging model links the function of MAP sumoylation to protein degradation through SUMO-targeted ubiquitin ligases, also known as STUbL enzymes. Other possible functions for cytoskeletal sumoylation are also discussed. PMID- 26033939 TI - Electrogram analysis and pacing are complimentary for recognition of abnormal conduction and far-field potentials during substrate mapping of infarct-related ventricular tachycardia. AB - BACKGROUND: Mapping to identify scar-related ventricular tachycardia re-entry circuits during sinus rhythm focuses on sites with abnormal electrograms or pace mapping findings of QRS morphology and long stimulus to QRS intervals. We hypothesized that (1) these methods do not necessarily identify the same sites and (2) some electrograms are far-field potentials that can be recognized by pacing. METHODS AND RESULTS: From 12 patients with coronary disease and recurrent ventricular tachycardia undergoing catheter ablation, we retrospectively analyzed electrograms and pacing at 546 separate low bipolar voltage (<1.5 mV) sites. Electrograms were characterized as showing evidence of slow conduction if late potentials (56%) or fractionated potentials (76%) were present. Neither was present at (13%) sites. Pacing from the ablation catheter captured 70% of all electrograms. Higher bipolar voltage and fractionation were independent predictors for pace capture. There was a linear correlation between the stimulus to QRS duration during pacing and the lateness of a capturing electrogram (P<0.001), but electrogram and pacing markers of slow conduction were discordant at 40% of sites. Sites with far-field potentials, defined as those that remained visible and not captured by pacing stimuli, were identified at 48% of all pacing sites, especially in areas of low bipolar voltage and late potentials. Initial radiofrequency energy application rendered 74% of targeted sites electrically unexcitable. CONCLUSIONS: Far-field potentials are common in scar areas. Combining analysis of electrogram characteristics and assessment of pace capture may refine identification of substrate targets for radiofrequency ablation. PMID- 26033942 TI - Minimising post-operative risk using a Post-Anaesthetic Care Tool (PACT): protocol for a prospective observational study and cost-effectiveness analysis. AB - INTRODUCTION: While the risk of adverse events following surgery has been identified, the impact of nursing care on early detection of these events is not well established. A systematic review of the evidence and an expert consensus study in post-anaesthetic care identified essential criteria for nursing assessment of patient readiness for discharge from the post-anaesthetic care unit (PACU). These criteria were included in a new nursing assessment tool, the Post Anaesthetic Care Tool (PACT), and incorporated into the post-anaesthetic documentation at a large health service. The aim of this study is to test the clinical reliability of the PACT and evaluate whether the use of PACT will (1) enhance the recognition and response to patients at risk of deterioration in PACU; (2) improve documentation for handover from PACU nurse to ward nurse; (3) result in improved patient outcomes and (4) reduce healthcare costs. METHODS AND ANALYSIS: A prospective, non-randomised, pre-implementation and post implementation design comparing: (1) patients (n=750) who have surgery prior to the implementation of the PACT and (2) patients (n=750) who have surgery after PACT. The study will examine the use of the tool through the observation of patient care and nursing handover. Patient outcomes and cost-effectiveness will be determined from health service data and medical record audit. Descriptive statistics will be used to describe the sample and compare the two patient groups (pre-intervention and post-intervention). Differences in patient outcomes between the two groups will be compared using the Cochran-Mantel-Haenszel test and regression analyses and reported as ORs with the corresponding 95% CIs. CONCLUSIONS: This study will test the clinical reliability and cost-effectiveness of the PACT. It is hypothesised that the PACT will enable nurses to recognise and respond to patients at risk of deterioration, improve handover to ward nurses, improve patient outcomes, and reduce healthcare costs. PMID- 26033941 TI - Individualised cognitive functional therapy compared with a combined exercise and pain education class for patients with non-specific chronic low back pain: study protocol for a multicentre randomised controlled trial. AB - INTRODUCTION: Non-specific chronic low back pain (NSCLBP) is a very common and costly musculoskeletal disorder associated with a complex interplay of biopsychosocial factors. Cognitive functional therapy (CFT) represents a novel, patient-centred intervention which directly challenges pain-related behaviours in a cognitively integrated, functionally specific and graduated manner. CFT aims to target all biopsychosocial factors that are deemed to be barriers to recovery for an individual patient with NSCLBP. A recent randomised controlled trial (RCT) demonstrated the superiority of individualised CFT for NSCLBP compared to manual therapy combined with exercise. However, several previous RCTs have suggested that class-based interventions are as effective as individualised interventions. Therefore, it is important to examine whether an individualised intervention, such as CFT, demonstrates clinical effectiveness compared to a relatively cheaper exercise and education class. The current study will compare the clinical effectiveness of individualised CFT with a combined exercise and pain education class in people with NSCLBP. METHODS AND ANALYSIS: This study is a multicentre RCT. 214 participants, aged 18-75 years, with NSCLBP for at least 6 months will be randomised to one of two interventions across three sites. The experimental group will receive individualised CFT and the length of the intervention will be varied in a pragmatic manner based on the clinical progression of participants. The control group will attend six classes which will be provided over a period of 6-8 weeks. Participants will be assessed preintervention, postintervention and after 6 and 12 months. The primary outcomes will be functional disability and pain intensity. Non-specific predictors, moderators and mediators of outcome will also be analysed. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Mayo General Hospital Research Ethics Committee (MGH-14-UL). Outcomes will be disseminated through publication according to the SPIRIT statement and will be presented at scientific conferences. TRIAL REGISTRATION NUMBER: (ClinicalTrials.gov NCT02145728). PMID- 26033943 TI - Disclosure of researcher allegiance in meta-analyses and randomised controlled trials of psychotherapy: a systematic appraisal. AB - OBJECTIVE: Psychotherapy research may suffer from factors such as a researcher's own therapy allegiance. The aim of this study was to evaluate if researcher allegiance (RA) was reported in meta-analyses and randomised controlled trials (RCTs) of psychotherapeutic treatments. DESIGN: Systematic approach using meta analyses of different types of psychotherapies. DATA SOURCES: Medline, PsycINFO and Cochrane Database of Systematic Reviews. METHODS: We evaluated meta-analyses of RCTs regarding various types of psychotherapies. Meta-analyses were eligible if they included at least one RCT with RA and they were published in journals in Medline, PsycINFO and Cochrane Database of Systematic Reviews with an impact factor larger than 5. RESULTS: We identified 146 eligible meta-analyses that synthesised data from a total of 1198 unique RCTs. Only 25 of the meta-analyses (17.2%) reported allegiance and only 6 (4.1%) used a proper method to control its effect. Of the 1198 eligible primary RCTs, 793 (66.3%) were allegiant. Authors in 25 of these 793 RCTs (3.2%) reported their allegiance while only one study (0.2%) controlled for its effect. CONCLUSIONS: The vast majority among a group of published meta-analyses and RCTs of psychotherapeutic treatments seldom reported and evaluated the allegiance effect. The results of the present study highlight a major lack of this information in meta-analyses and their included studies, though meta-analyses perform slightly better than RCTs. Stringent guidelines should be adopted by journals in order to improve reporting and attenuate possible effects of RA in future research. PMID- 26033944 TI - A cross-sectional study on upright heart rate and BP changing characteristics: basic data for establishing diagnosis of postural orthostatic tachycardia syndrome and orthostatic hypertension. AB - OBJECTIVE: We aimed to determine upright heart rate and blood pressure (BP) changes to suggest diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) and orthostatic hypertension (OHT) in Chinese children. METHODS: In this cross-sectional study, 1449 children and adolescents aged 6-18 years were randomly recruited from two cities in China, Kaifeng in Henan province and Anguo in Hebei province. They were divided into two groups: 844 children aged 6-12 years (group I) and 605 adolescents aged 13-18 years (group II). Heart rate and BP were recorded during an active standing test. RESULTS: 95th percentile (P(95)) of delta heart rate from supine to upright was 38 bpm, with a maximum upright heart rate of 130 and 124 bpm in group I and group II, respectively. P(95) of delta systolic blood pressure (SBP) increase was 18 mm Hg and P(95) of upright SBP was 132 mm Hg in group I and 138 mm Hg in group II. P(95) of delta diastolic blood pressure (DBP) increase was 24 mm Hg in group I and 21 mm Hg in group II, and P(95) of upright DBP was 89 mm Hg in group I and 91 mm Hg in group II. CONCLUSIONS: POTS is suggested when delta heart rate is >= 38 bpm (for easy memory, >= 40 bpm) from supine to upright, or maximum heart rate >= 130 bpm (children aged 6-12 years) and >= 125 pm (adolescents aged 13-18 years), associated with orthostatic symptoms. OHT is suggested when delta SBP (increase) is >= 20 mm Hg, and/or delta DBP (increase) >= 25 mm Hg (in children aged 6-12 years) or >= 20 mm Hg (in adolescents aged 13-18 years) from supine to upright; or upright BP >= 130/90 mm Hg (in children aged 6-12 years) or >= 140/90 mm Hg (in adolescents aged 13-18 years). PMID- 26033945 TI - Association between childhood obesity and use of regular medications in the UK: longitudinal cohort study of children aged 5-11 years. AB - OBJECTIVES: Increasing rates of childhood obesity have been suggested as a possible cause for the increasing prevalence of chronic conditions among adults and children. Few studies have examined whether obese children are more likely to use medications than normal weight children. We investigate this association in the UK. DESIGN: A panel study with repeated observations at ages 5, 7 and 11. SETTING: A general population sample drawn from the Millennium Cohort Study, a UK based birth cohort. PARTICIPANTS: A sample of 9667 children. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcomes were crude and adjusted probabilities of taking any regular medications and the number of medications among overweight and obese children compared with normal weight children. Our secondary outcome was the distribution of medication use by therapeutic classification across body mass index (BMI) groups. RESULTS: Obese children were more likely to use any medication (marginal effect (ME)=0.02, 95% CI 0.01 to 0.03) and to use more medications (ME=0.08, 95% CI 0.04 to 0.12) than normal weight children. Obese children used more medications for respiratory conditions than those of other BMI groups. CONCLUSIONS: Obese children are more likely to use regular medications and have comorbid conditions, even at young ages. This suggests that the cost of prescriptions should be considered when evaluating the economic burden of childhood obesity and that preventative strategies to reduce childhood obesity could be cost-effective in the short as well as in the long term. While more research is needed, both clinicians and policymakers should be aware of these findings when planning prevention and treatment strategies. PMID- 26033946 TI - Women's perception of risks of adverse fetal pregnancy outcomes: a large-scale multinational survey. AB - OBJECTIVE: To determine pregnant women and new mothers' perception of risks in pregnancy. DESIGN, SETTINGS AND PARTICIPANTS: This was a large-scale multinational survey including 9113 pregnant women and new mothers from 18 countries in Europe, North America and Australia. MAIN OUTCOMES: Risk perception scores (0-10) for harmful effects to the fetus were derived for: (1) medicines (over-the-counter medicine and prescribed medicine), (2) food substances (eggs and blue veined cheese), (3) herbal substances (ginger and cranberries) (4) alcohol and tobacco, and (5) thalidomide. RESULTS: Overall, 80% (6453/8131) of women perceived the risk of giving birth to a child with a birth defect to be <= 5 of 100 births. The women rated cranberries and ginger least harmful (mean risk perception scores 1.1 and 1.5 of 10, respectively) and antidepressants, alcohol, smoking and thalidomide as most harmful (7.6, 8.6, 9.2 and 9.4 out of 10, respectively). The perception varied with age, level of education, pregnancy status, profession and geographical region. Noticeably, 70% had not heard about thalidomide, but of those who had (2692/9113), the risk perception scores were 0.4-0.5 points lower in women below 25 years compared to women aged 26-30 years. CONCLUSIONS: In general, women perceived the risks of giving birth to a child with birth defects low, but there were substantial disparities between women's perceived risks and the actual risks when it comes to over-the-counter agents against nausea and prescribed medication. The study revealed that few women knew of thalidomide, suggesting that the general awareness among women of the teratogenic effects of thalidomide is declining, but it has left a general scepticism about safety of medication in pregnancy. This may have some severe consequences if women are left without medical treatments in pregnancy. PMID- 26033947 TI - Risk of bladder cancer in patients with diabetes: a retrospective cohort study. AB - OBJECTIVE: The objective of this study was to examine the association between diabetes, and both urinary bladder cancer (UBC) risk and mortality. METHODS: We conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) linked to the Office of National Statistics (ONS). Patients diagnosed with diabetes mellitus type 1 or 2, or using antidiabetic drugs (ADDs), were compared to matched non-diabetic controls. Cox proportional hazards models were used to estimate the risk and mortality of UBC. We adjusted for age, sex, smoking status and body mass index. RESULTS: The cohort included 329,168 patients using ADD, and 307,315 controls with 1295 and 1071 patients, respectively, diagnosed as having UBC during follow-up. The adjusted HRs of UBC were 0.77 (95% CI 0.57 to 1.05) and 1.04 (95% CI 0.96 to 1.14) for type 1 and 2 diabetes, respectively. These results were similar if we restricted our analysis to an inception cohort. We noticed a small increased risk during the first year after diagnosis (HR=1.26 (95% CI 1.05 to 1.52)), which could be explained by detection bias. There was no influence of the severity of diabetes as measured by the glycated haemoglobin. Mortality of UBC was not increased for patients with either type 1 (HR=0.95 (95% CI 0.39 to 2.34)) or type 2 diabetes (HR=1.16 (95% CI 0.91 to 1.46)). CONCLUSIONS: Neither the risk of UBC nor the mortality from UBC was increased in patients with type 1 and patients with type 2 diabetes in the CPRD data. PMID- 26033948 TI - Which clinical scenarios do surgeons record as complications? A benchmarking study of seven hospitals. AB - OBJECTIVES: To investigate agreement and potential differences in the application and interpretation of the definition among surgical departments of various hospitals. DESIGN: 24 cases were formulated including general, trauma, gastrointestinal and vascular surgery, and based on points of discussion about the definition and ambiguities regarding complication registration as encountered in daily practice. The cases were presented to the surgical staff and residents in seven Dutch hospitals, using the national registration system of complications and an electronic response system. RESULTS: In total, 134 participants responded. Interpretation differences were particularly found regarding: (1) complications considered as logical consequences of a surgical procedure; (2) complications occurring after radiological interventions; (3) severity criteria such as when to consider a complication as a '(probably) permanent damage or function loss'; (4) registering a cancelled operation as a complication and (5) patients with serial complications during hospital stay. CONCLUSIONS: The definition of surgical complications as currently applied in the Netherlands does not ensure a uniform complication registration. Improvement of this registration system is mandatory before benchmarking of these findings in the public domain is appropriate. Modifications of the current definition of a surgical complication, and improved consensus about specific clinical situations and training of surgeons might improve the quality of benchmarking. PMID- 26033949 TI - A prospective study of adverse drug reactions to antiepileptic drugs in children. AB - OBJECTIVES: To prospectively determine the nature and rate of adverse drug reactions (ADRs) in children on antiepileptic drugs (AEDs) and to prospectively evaluate the effect of AEDs on behaviour. SETTING: A single centre prospective observational study. PARTICIPANTS: Children (<18 years old) receiving one or more AEDs for epilepsy, at each clinically determined follow-up visit. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was adverse reactions of AEDs. Behavioural and cognitive functions were secondary outcomes. RESULTS: 180 children were recruited. Sodium valproate and carbamazepine were the most frequently used AEDs. A total of 114 ADRs were recorded in 56 of these children (31%). 135 children (75%) were on monotherapy. 27 of the 45 children (60%) on polytherapy had ADRs; while 29 (21%) of those on monotherapy had ADRs. The risk of ADRs was significantly lower in patients receiving monotherapy than polytherapy (RR: 0.61, 95% CI 0.47 to 0.79, p<0.0001). Behavioural problems and somnolence were the most common ADRs. 23 children had to discontinue their AED due to an ADR. CONCLUSIONS: Behavioural problems and somnolence were the most common ADRs. Polytherapy significantly increases the likelihood of ADRs in children. TRAIL REGISTRATION NUMBER: EudraCT (2007-000565-37). PMID- 26033950 TI - Evidence for changes in beta- and gamma-actin proportions during inner ear hair cell life. AB - Cytoplasmic actin isoforms beta (beta-) and gamma (gamma-) perform crucial physiological roles in inner ear hair cells (HC). The stereocilium, which is structured by parallel actin filaments composed of both isoforms, is the responsive organelle to mechanical stimuli such as sound, gravity and head movements. Modifications in isoform proportions affect the function of the stereocilia as previously shown in genetic studies of mutant mice. Here, immunogold labeling TEM studies in mice showed that both beta- and gamma-actin isoforms colocalize throughout stereocilia actin filaments, adherens junctions and cuticular plates as early as embryonic stage 16.5. Gold-particle quantification indicated that there was 40% more gamma- actin than beta-actin at E16.5. In contrast, beta- and gamma-actin were equally concentrated in adult stereocilia of cochlear and vestibular HC. Interestingly, all actin-based structures presented almost five-fold more beta-actin than gamma-actin in 22 month- old mice, suggesting that gamma-actin is probably under-expressed during the aging process. These data provide evidence of dynamic modifications of the actin isoforms in stereocilia, cuticular plates and cell junctions during the whole HC life. PMID- 26033951 TI - Search for novel circulating cancer chemopreventive biomarkers of dietary rice bran intervention in Apc(Min) mice model of colorectal carcinogenesis, using proteomic and metabolic profiling strategies. AB - SCOPE: There is strong epidemiological evidence indicating that consumption by humans of whole-grain foods including rice bran may be associated with a low incidence of cancer, especially in the colorectum. Molecular processes associated with cancer development may be retarded by fiber consumption. Consequently, intervention with dietary fiber might be suitable as a cancer chemoprevention strategy in high-risk populations. Here, we searched for putative molecular mechanism-based efficacy biomarkers of rice fiber consumption in the plasma of mice characterized by a genetic propensity to develop gastrointestinal adenomas. The hypothesis was tested that metabolic and proteomic changes in blood reflect the chemopreventive activity of rice bran. METHODS AND RESULTS: Apc(Min) mice received diet supplemented with rice bran at 5, 15, and 30%. Blood and tissue samples were taken. Plasma was subjected to MS-based proteomic and metabolic profiling analyses as well as assessment of hematocrit values. Gastrointestinal tracts were removed and adenomas were counted and their size was measured so that total tumor burden could be calculated. The hypothesis was tested that metabolic and proteomic changes in blood reflect chemopreventive activity. CONCLUSION: Rice bran consumption reduced adenoma burden and number in a dose-related fashion when compared to controls. Metabolic profiling data demonstrated strong clustering of the groups indicating that metabolic pathways are perturbed. Proteomic analysis identified adiponectin as a molecule that was significantly altered, which may play a role in tumor suppression. PMID- 26033952 TI - Identifying low-level sequence variants via next generation sequencing to aid stable CHO cell line screening. AB - Developing stable Chinese hamster ovary (CHO) cell lines for biotherapeutics is an irreversible process and therefore, key quality attributes, such as sequence variants, must be closely monitored during cell line development (CLD) to avoid delay in the developmental timeline, and more importantly, to assure product safety and efficacy. Sequence variants, defined as unintended amino acid substitution in recombinant protein primary structure, result from alteration at either the DNA or the protein level. Here, for the first time, we report the application of transcriptome sequencing (RNAseq) in an IgG1 monoclonal antibody (mAb) CLD campaign to detect, identify, and eliminate cell lines containing low level point mutations in recombinant coding sequence. Among the top eleven mAb producers chosen from transfectant, clone or subclone stages, three of the cell lines contained either missense or nonsense point mutations at a low level of less than 2%. Subsequent LC/MS/MS characterization detected ~3% sequence variants with an amino acid change from Ser to Leu at residue 117 in the heavy chain of transfectants 11 and 27. This substitution is consistent with the RNAseq finding of a C/T mutation located at 407 base pair (TCA->TTA) in the heavy chain coding sequence. Here we demonstrate that RNAseq is a rapid and highly sensitive method to identify low-level genetic mutation de novo corresponding to the amino acid substitution that elicits sequence variant(s). Its implementation in CLD constitutes an early and effective step in identifying desired CHO expression cell lines.